Stereoselective synthetic methodologies : mechanistic studies toward natural products
by Richard Ronald Copp
A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in
Chemistry
Montana State University
© Copyright by Richard Ronald Copp (1987)
Abstract:
A mechanistic approach toward stereochemical control in bicyclic ketal synthesis is presented. An
investigation of the stereochemical consequences of the tandem solvomercuration-demercuration
sequence, as applied to 2-alkenyl-3,4-dihydro pyrans, is explored. It is found that methanol addition to
the enol ether moiety is highly stereoselective whereas methoxymercuration is non-selective. The
absence of π-facial differentiation in the 2-alkenyl moiety is revealed through isotopic labeling.
Circumvention of by-product contamination in the synthesis of 2-carboxylate esters of 3,4-dihydro
pyrans is achieved. The scope and limitations of chiral enolate alkylation of C-2 of such systems is
probed through enolate trapping. It is found that nonselective enolization precludes efficient
asymmetric induction. A systematic and critical investigation of factors influencing nucleophilic
addition to 2-acetyl pyran derivatives provides a highly efficient chelation - controlled hydride
reduction method. "STEREOSELECTIVE SYNTHETIC METHODOLOGIES: MECHANISTIC
STUDIES TOWARD
NATURAL PRODUCTS"
by
R ichard Ronald Copp
A th e s is subm itted in partial fulfillm ent
o f th e requirem ents fo r th e d eg ree
of
D octor o f P hilosophy
in
C hem istry
MONTANA. STATE UNIVERSITY
Bozeman, Montana
November 1987
I
ini
U
APPROVAL
o f a th e sis subm itted b y
Richard Ronald Copp
T his th e sis has been read b y each member o f th e th e sis committee
and has b een found to be sa tisfa c to ry reg a rd in g co n te n t, EngUsh u sa g e ,
form at, c ita tio n s, bibhographic s ty le , and c o n siste n c y , and is rea d y fo r
subm ission to th e C ollege o f Graduate S tu d ies.
Kino. I?, ISVT7
Date
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, :^ i
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C
I U-nacj x-wcV
c/ , ijuv'
\C hairperson, Graduate Committee
A pproved for th e Major Department
" / ' * / JV
v v ' //.
Head, Major Departm ent
Date
A pproved for the C ollege o f Graduate S tu d ies
//-/6 -S7 7
Date
Graduate Dean
COPYRIGHT
by
R ichard Ronald Copp
1987
aA11
R ights R eserv ed
iii
STATEMENT OF PERMISSION TO USE
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a
doctoral d eg ree at Montana State U n iv e r sity , I a g ree th a t th e L ibrary
sh all make it available to borrow ers u n d er ru les of th e L ibrary.
I fu rth e r
a g ree th at co p y in g o f th is th e sis is allowable o n ly fo r sch o la rly p u r p o se s ,
c o n sisten t w ith
"fair use" as p re sc r ib e d in th e U . S . C opyright Law.
R eq u ests for e x te n s iv e
co p y in g or rep rod u ction o f th is th e s is should be
r e fer re d to U n iv e r sity Microfilms In ternation al, 300 N orth Zeeb Road, Ann
A rbor, M ichigan 48106, to
whom I h ave gran ted "the e x c lu siv e r ig h t to
rep rod u ce and d istr ib u te copies o f
th e d isserta tio n in and from microfilm
and th e r ig h t to rep rod u ce and d istrib u te
S ign ature
Date
n~/Ti-sy-
b y a b stra ct in a n y form at."
I th ink and th in k for m onths and y e a r s . N in ety -n in e tim es, th e conclusion
is fa ls e . The h u n d red th time I am r ig h t .
—
A lbert E instein
EpptUL -A-L muovz.
(B u t it does m o v e.)
—
A ttrib u ted to Galileo Galilei a fte r his
recantation in 1632.
Fools are not b o rn , th e y are ed u ca ted .
Elbert Hubbard
V
VITA
R ichard Ronald C opp, J r . , th e fir s t son of R ichard and Sharlene
C opp, was born O ctober I , 1959 in A urora, Illin ois. In December of 1981
he rec e iv ed a B achelor o f S cience d eg ree in chem istry from Illinois State
U n iv e r sity and in Janu ary o f 1982 he enrolled in grad u ate school at
Montana State U n iv e r sity .
Upon r ec e iv in g his D octor o f P hilosophy
d e g r e e , u n d er th e d irectorsh ip of P ro fesso r Bradford M undy, he r eceiv ed
an NIH p ostd octoral fellow ship at. th e National C ancer I n stitu te , as an
Intramural R esearch T raining A w ardee.
vi
ACKNOWLEDGEMENTS
It is a p r iv ile g e to acknow ledge th e people who in flu en ced and
con trib u ted to my educational and p erso n a l grow th.
e x te n d e d
to
Tim Schram for
his
gen erou s
Sin cere thanks are
a ssista n c e
w ith my NMR
train in g; to Joe Sears for h is help w ith mass sp ectra l a n a ly sis and fo r
in tro d u cin g me to th e a r t, d iscip lin e and p h ilo so p h y o f Tae Kwon Do; to
my co-w ork ers D ave Joh n son , Dave T h e is te , Dave Barnekow and Rob
H endrickson for the times th e y s e t a sid e th eir work fo r mine; to Lee
Slater for th e tim es I coerced him to p u t down th e p h y sic s homework to
sy n th e siz e b icy clic k eta ls; to P ro fesso r T ed Ichniow ski fo r b e lie v in g in
me; to P ro fesso r Brad M undy for h is enthusiasm and fo r le ttin g me do
th in g s my w ay; to my p a ren ts fo r th eir love and su p p o rt and to my lo v in g
w ife Della for en d u rin g late n ig h t b ou ts w ith word p r o c e s s in g and fo r
sm iling th o se tim es w hen I couldn 't.
vii
TABLE OF CONTENTS
LIST OF TABLES...............
Page
.
............................................................................................ .......
LIST OF FIGURES...............................................................
ABSTRACT .
...................■
......................................................................................................................... X V l
CHAPTER
1.
INTRODUCTION AND BACKGROUND....................................................
±
2.
RESULTS AND DISCUSSION............................................................
29
3.
ASYMMETRIC SYNTHESIS............................................................
51
4.
STEREOSELECTIVE NUCLEOPHILICADDITIONS....................
72
5.
SUMMARY..................................................................................
g8
6.
100
EXPERIMENTAL............... .................. ... .....................................
Preparation of 2-Acetyl-6-Methyl-3,4Dihydro-2H-Pyran [28]............................................................... ....
Preparation of 2-lsopropenyl-6-Methyl-3, 4-Dihydro-2HPyran [ 2 1 ] ...................................... .. ........................................ io i
Solvomercuration/Demercuration of 2-Acetyl-6-Methyl3/4—
Dihydro—
2H—
Pyran [28]...........................................................102
Borohydride Reductions of"l6-Methyl-6-Methoxy-5-(Acetoxy)mercu rial-2-Acety l- te trahydropyran with
NaBH4 and LiBH4 .......................................................................... ....
Preparation of 4-Deuterio-5-Deuterio-7-Methyi
Dioxabicyclot3 .2 .1Joctane [ 68a and68b ]................................... 104
Preparation of 2-Formyl-3, 4-Dihydro-2H-Pyran [58] . . . . 105
Preparation of 2 -(I-Hydroxyethyl)- 3 ,4-Dihydro2H-Pyran [26]........................... ...................................................105
Preparation of 2-Acetyl-3, 4-Dihydro-2H-Pyran [24] .
* 105
Preparation of [ 6 ] from Ketone [ 2 4 ] ............... 7“ . . . . ! . ’ 106
Preparation of 2 -(2-lsopropenyl)-3 ,4-Dihydro2H-Pyran [25]......................................................................
107
Solvomercuration-Demercuration of [25]...................! . ' ! ! ! 108
Synthesis of 2(Carboxymethyl)- 3 ,4-Dihydro-2H- ...................... .
109
Pyran [ 7 0 ] ..................
Preparation of 7,7—
Dimethyl—6 , 8—
Dioxabicyclo
[3.2.1] octane [ 6 ] From [70]. . ...........................................109
E sterificatio n of 3,4—
Dihydro—
2H—
Pyran—
2—
Carboxylic
Acid, Sodium Salt [Tl] with M ethanol.................................... HO
A lternative Preparation of 7,7—
Dimethyl—
6 , 8—
Dioxabicyclo
[3.2.1] Octane [ 6 ] .....................................................
Ill
Preparation of 3 ,4-Dihydro-2H-Pyran Carboxylic*
Acid Chloride [ 7 4 ] ................................................................... .....
viii
TABLE OF CONTENTS (Continued)
Page
Improved Synthesis of 3 ,4-Dihydro-2H-Pyran-Carboxylic
Acid Chloride [ 7 4 ] ......................................... ... ..........................113
Synthesis of 3 ,4-Dihydro-2H-Pyran-2-Carboxylic
Menthol Ester [ 8 2 ] ............................................................................
A lternative Preparation of 3 ,4-Dihydro-2H-Pyran-2Carboxylic-( -)-Menthol Ester [82]............................................. 114
Preparation of 2-Methyl-3, 4-Dihydro-2H-Pyran-2Carboxyli c - (-)Menthol Ester [ 8 3 ] ............................................. 115
A lternative Methylation of [82] with Methyl-pT o luenesulfinate................................................................... ...
ng
A lternative Methylation of [82] Employing HMPA
Co-Solvent..........................................................................................
Attempted E sterificatio n s of [74] with (I r , 2r , 3S )-(-)[N-Benzenesulphonyl-N-(3 ,5-Dimethylphenyl)Amino]-2Bornanol [ 8 4 ] .............................................................................. .....
Preparation of (S)-(+)-2-Pyrrolidinemethanol
(S-Prolinol) [ 88 ] ........................................................... ...
118
Preparation of (S)-(+)-2-Methoxymethylpyrrolidine [91] . . . 119
Preparation of 3 ,4-Dihydro-2H-Pyran-2-Carboxylic-(S)(+)-2-Hydroxymethyl-Pyrrolidine Amide [92] .......................... Hg
Methylation of Amide [ 9 2 ] .......................
120
Preparation of 3,4-Dihydro-2H-Pyran-2-Carboxylic-[(S). (+)-2-(Methoxymethyl)pyrrolidine]Amide [94] . . . . . . . 121
Methylation of Amide [ 9 4 ] .................................................................. 122
Preparation of (-)-Menthyl A crylate.[96] . . . ....................... 122
Attempted Diels-Alder Heterocycloadditions with (-)Menthyl Acrylate . ...................................................................... 123
Procedure for Menthol-Derived Ester Enolate Trapping with
Chlorotrimethylsilane ............................................................... 123
Reduction of Methylvinyl Ketone Dimer with Various
. Reducing Reagents ................................................
124
Procedure for the Determination of Bicyclic Ketal Loss
Due to Rotoryevaporation................................................
125
Reduction of [28] with triispbutylaluminum hydride
(TIBA) (Cyclization Reflpx)
125
Reduction of [28] with Lithium tri-tert-Butoxyaluminohydride (LTBA).( Cyclization a t 20°C) ..................................... 125
Reduction of Methylvinyl Ketone Dimer [28] with MgBr2
and Various Metal Hydride and Grignard Reagents ............... 126
Reduction of [28] -MgBr2 with LTBA................................................ 126
Reduction of [28] -MgBr2 with PhMgBr...................... ...................... 127
Preparation of 3-Hydroxy-2, 7-Octanedione [113]
127
General Procedure for the Reduction of 3-Hydroxy-2,7octanedione [113] with Various Reducing Reagents ............... 128
Preparation of anti-2-Ace.tyl-6-Methoxy-6-Methyl
Tetrahydropyran [28a] .................................................................. 128
Reduction of anti-2-Acetyl-7-Methoxy-7-Methyl-Tetrahydropyran [28a] with.Various ReducingReagents....................... 129
REFERENCES CITED
........................................... 130
ix
LIST OF TABLES
Table
1.
Page
Observed S tereo selectiv ities in Reductions of [28]
and 28 -MgBrg..............................................................................
85
2.
Observed S tereo selectiv ities in Hydride Reductions
of 113..................................... ' . . .................................................89
3.
Observed NOE-Induced Enhancement of Ha of [28].......................... 94
4.
Observed S tereo selectiv ities in Hydride Reductions
of [28a]............................................................... ... . ................... 94
/
\
X
LIST OF FIGURES
Figure
Page
1.
Kims' Synthesis of a Civet Cat Component..................................
3
2.
Fragmentations of Bicyclic Ketals with
Acetyl Iodide ..........................................................................
4
3.
Mundy Synthesis of 12 . . . . .......................................
5
4.
Mundy Synthesis of Solenopsin A .....................................
5
5.
Isobe Bicyclic Ketal Fragmentation. . ....................... . . . .
6
6.
Concurrent Pheromone Syntheses....................................................
7
7.
Model Tandem Oxymercuration-Demercuration
P rocedure.............................
8
8.
Separate Conversions of [24] to [ 6 ] ............................................... 10
9.
Preparations of 21...............................................................................10
10.
Facial S electivity Offered By a Concave Site .......................
11
11.
Proposed Assymmetric Synthesis of the Hop Oil
Constituent 6..................
12
12.
Proposed Asymmetric Synthesis of Frontalin, 3. ....................... 13
13.
Evans' Use of S-Prolinol in Enolate
A lkylations...................................................
14
14.
Helmchen Camphor-Derived Chiral Auxiliary. . . .
...............
15
15.
Corey Application of 8-Pheny!menthol..........................................16
16.
Stereoselective Generation of Ester
E n o la te s......................
16
' 17. Solvent-Dependent D iastereoselectivity ...................................... 17
18.
Chiral Enolate Alkylation a t a Ring C arbon...............................18
19. Alkylation of 2-Carboxyl-Dihydro-2H-Pyrans ..........................
18
xi
LIST OF FIGURES (continued)
Figure
Page
20.
Control of Enolate Stereochem istry............................................. 19
21.
Diels-Alder Reaction with MVK and Methyl
A c ry la te ......................................................................
20
22.
Diels-Alder Reactions Employing (-)-Menthol
D e r iv a tiv e s ...................................................................................... 21
23.
Diels-Alder Reaction with (S)-(+)-3,3Dimethyl-2-Butanol Auxiliary ....................................................
22
24.
Facial D ifferentiation in A crylates............................................. 22
25.
Facial Biasing with 8-Pheny!menthol Auxiliary. . . . . . .
23
26.
Fixed Stereochemistry of Ring Closure in
Bicyclic Ketal Formation . ..............................
24
27.
Stereoselective Grignard Addition to 28...................................... 25
28.
Reaction of Grignard Reagents with 58..........................................26
29.
Hydride Reductions of 2 8 ................................................................ 27
30.
Original Tandem OxymercurationDemercuration-Bicyclic Ketal Preparation.................................... 29
31.
Required cis-S ubstitution Between the
Hydroxyl and Isopropenyl Functions Prior
to Ring Formation.........................
30
32.
Solvomercuration of Ketone [28]. . ..............................................31
33.
Demercuration/Cyclization of ketals
61a and 61b.................................
32
Proposed Non-stereoselective oxymercuration
of Diene [21]......................................................................
32
35.
Ring Opening of 63a..................
33
36.
Proposed Mechanism for Diol Formation..........................................33
34.
' 37.
Proposed Stereochemical Control in Mercurinium
Ion Cyclization..................
34
38. Demercuration with Sodium Borodeuteride.......................................35
xii
LIST OF FIGURES (continued)
Figure
• Page
39.
NMR Spectra for 23, 68a and 6 8 b ..................................... .
36
40.
Relative Non-Stereoselectivity in the Tandem
Solvomercuration-Preparationof Brevicomin ............................
37
41.
Proposed Source of Non-Stereoselection Due
to Rotational Freedom...................................... ............................ 38
42.
Preparation of Ketone [ 2 4 ] ............................................................ 39
43.
Diels-Alder Preparation ofEster [69].
44.
Proposed Outcome of a Diels-Alder Reaction
. . ................................ 41
Employing Acrolein and Methylacrylate..........................................41
45.
A lternative preparation of Ester [70]..........................................42
46. Alternative Preparation of the Hop Oil
Constituent [6 ].......................................................
43
47.
43
Acid-Catalyzed E sterificatio n of T l.........................................
48. Approximation of Dihedral Angles Ha-Hj3 and
Ha-Hc and predicted
Values.........................................................44
49.
50.
Proposed Solvolytic Pathway for Methoxy
Displacement.........................
Proposed Synthetic Utility of Acid
Chloride 74...........................................................
51.
46
47
Proposed Lactonization of Carboxylic
Acid [59]. ..................................... . ..........................
48
52.
Reaction of Tl with Thionyl Chloride .......................................... 49
53.
Preparation of 74 with Oxalyl Chloride ...................................... 50
54.
Synthetic Strategies for Bicyclic Ketal
Synthesis.........................
55. Whitesell Syntheses of .( + )- and
(-)-F ro n talin ..................................................................
52
52
56.
Eliel Syntheses of (+ )- and (-)-F rontalin. . ............................ 53
57.
Oehlschlager Syntheses of (+)- and (-)-endo-
Brevicomin . . . . . . . . . . . . . . . . . . . . . . . .
54
xiii
LIST OF FIGURES (continued)
Figure
page
58.
Matteson Synthesis of (+)-exo-Brevicomin . . . . . . . . .
55
59.
Fraser-Reid Synthesis , of Brevicomin......................
55
60.
Redlich Syntheses of endo-Brevicomin .................
56
61.
Ester Formation with (-)-Menthol ....................
57
62.
Methylation of Menthol-Derived Ester .................
58
63.
Proposed Selectivity Enhancement by
Increasing Steric Demand of Electrophile .............
59
64.
Pyran Ring Conformational Flopping .........................................
60
65.
Proposed n-Stacking, with Camphor-D erivative...........................61
66 .
Proposed Preparation of 8 6 ............................................................ 62
67.
Preparation of S-Prolinol and (S)-(+)-meth-
oxymethylpyr r o lid in e ....................................................................... 64
68 .
Preparation of 92................................... 65
69. Acid-Catalyzed Hydrolysis of S-Prolinol
Derived Amides..................................... 65
70. A lternative Preparation of 92.........................................................66
71. Alkylation of 9 2 .........
72.
Preparation of 94................................... 67
73. Alkylation of 94 . . ......................
74.
67
68
Preparation of Menthyl Acrylate........................ 69
75. Attempted Preparation of 96 by Lewis Acid Catalysis. . . .
69
76. Attempted Cycloaddition Catalyzed by Eu(tfc) ..........
70
77. Apparent Mon-Stereoselective Enolization of 82 . .................
71
'78.
79.
Reaction of Acrolein Dimer with GrignardReagents......... 72
Reaction of Methylvinyl Ketone Dimer with
Grignard Reagents
73
xiv
LIST OF FIGURES (continued)
Figure
Page
80.
Magnesium Complexation with Acrolein D im er.......................... 73
81.
Reduction of 2-Acetyl and 2-Propionyl-6-MethylDihydro-2H-Pyran with Various Reducing Reagents............... ...
74
Cyclic and Dipolar Transition States in
a-Ketol Reductions .............................................
75
82.
83.
Hydride Reduction via Dipolar Mechanism...................................... 76
84.
Plausible Models for the Reduction of 2 8 ...................
85.
Computer-Drawing of 2-Acetyl-6-Methyl3 ,4-Dihydro-2H-Pyran (28)................................................................ 79
86.
Titanium IV Chloride Complexes with P-Alkoxy
Aldehydes.................................................................................
77
80
87.
MgBr2 Complexes with 28....................................................................81
88.
NMR Spectra for 28 -MgBr?........................................................ 82
89.
Conformational Flipping of Pyran [28].......................... . . .
90.
Acid Catalyzed Ring Opening of 28................................................. 86
91.
Required Regioselection in HydrideReductions of 113 . . .
87
92.
Ketal Preparation from Dione [113]
.....................................
87
93.
Cyclic and Dipolar Transition States for
Hydride Reduction of Dione [113] .............................................
88
Conversion of Isomeric Ester Acetals to 7,7^
Dimethy1-6,8-Dioxabicyclo[3.2.1]octane ..................................
91
Preparation of Bicyclic Ketals From Monocyclic
Ketals Derived From Methylvinyl Ketone Dimer .......................
91
96.
^H NMR Resonances for 1 1 9 a .............................
92
97.
Bicyclic Ketal Preparation from 119a . . . ............................... 93
98.
Steric Hinderance Offered by Pyran Ring.................................
95
99.
Cyclic and Dipolar Transition State Rationale
for Stereoselective Bicyclic Ketal Formation .......................
96
94.
95.
83
XV
LIST OF FIGURES (continued)
Figure
100.
Page
Computer drawing of 5-Methyl-5-Methoxy-2-AcetylTetrahydropyran............... ...........................................................97
xvi
ABSTRACT
A m echanistic approach toward stereochem ical control in b icy clic
k etal s y n th e s is is p r e se n te d .
An in v estig a tio n o f th e stereochem ical
co n seq u en ces o f th e tandem solvom ercuration-dem ercuration se q u e n c e , as
applied to 2 -a lk e n y l-3 , 4-d ih yd ro p y r a n s , is ex p lo red . It is found th at
methanol addition to th e enol e th e r m oiety is h ig h ly ste r e o se le c tiv e
w hereas m ethoxym ercuration is n o n -s e le c tiv e .
The a b sen ce o f 71-fa cia l
d ifferen tiation in th e 2-a lk en y l m oiety is rev ea led th ro u g h isotop ic
IabeU ng. C ircum vention o f b y -p r o d u c t contam ination in th e sy n th e s is of
2-carb oxylate e s te r s o f 3 ,4 -d ih y d r o p y ra n s is a ch iev ed . The scope and
Umitations o f chiral enolate alkylation o f C-2 o f su c h sy stem s is probed
th rou gh enolate tra p p in g .
It is fou n d th at n o n se le ctiv e enoUzation
p reclu d es e ffic ie n t asym m etric in d u ctio n .
A system atic and critical
in v e stig a tio n o f fa cto rs in flu en cin g nucleophiU c addition to 2-a c e ty l p y ra n
d eriv a tiv es p ro v id es a h ig h ly e ffic ie n t chelation - controlled h yd rid e
red u ction m ethod.
I
CHAPTER I
INTRODUCTION AND BACKGROUND
B icyelic k etals o f th e 6 , 8 -d ioxab icyclo [ 3 . 2 . 1 ] octa n e1 s e r ie s , I , h ave
b een
th e fo cu s
of atten tion for num erous natural p ro d u cts resea rch
e ffo r ts in rec e n t y e a r s .
T he fundam ental im portance o f th is
h etero cy clic
system origin ated in carb ohydrate ch em istry and has sin ce
th rou gh its recogn ition as a common stru ctu ra l com ponent in
from in s e c t s , p lan ts and m icrobes.
expand ed
m etabolites
Of p articular in te r e s t,
sy n th e tic m ethodology v iew p o in t, is th e rich a rra y of fu nctional
su b stitu tio n p a ttern s about th e b icy clic sk eleta l fram ew ork.
The
from a
group
regio
and stereochem ical fe a tu re s of ketal su b stitu tio n have p ro v id ed num erous
sy n th e tic c h a lle n g e s .
A number o f p e r n ic io u s, and as y e t u n co n tro lled , bark b e e tle s produce
a n d /o r resp on d to s e x attractan ts w hich ex h ib it v a r y in g su b stitu tio n about
th e 6 , 8 -d io x a b ic y c lo [ 3 . 2 . 1 Joctane r in g sy stem .
isolated
from
th e
female
W estern
pin e
B revicom in, [ 2 ] , has b een
bark
b e e tle ,
D endroctonus
b rev ico m is. 2 The a g g regation pherom one, [ 3 ] , of fem ales o f th e sou th ern
pin e bark b e e tle , D endroctonis fr o n ta lis , has b een named fr o n ta lin . 3
The tr i-s u b stitu te d b icy clic k eta l, m u ltistria tin , [ 4 ] , 4 is th e pheromone fo r
th e European elm bark b eetle S colytu s m u ltistria tis.
E xten sive d estru ctio n o f fo r e st land caused b y th e s e in se c ts has
provid ed th e major im petus for r ese a rc h tow ards e ffic ie n t preparations
of
Al
2
th eir ph erom on es.
com pounds,
in
su c c e s sfu l m ethods
It is fo reseea b le th at large scale p reparations o f th ese
th eir
natural
stereochem ical
fo rm s,
may
r esu lt
in
o f control of th e in s e c ts b y tra p p in g .
Of sig n ifica n t concern in the ca ttle in d u str y is th e h ig h ly s u b s ti­
tu ted k e ta l, [ 5 ] , w hich cau ses a condition known as "paspalum sta g g ers"
when cattle in g e s t Paspalum dilatatum in fec te d w ith C laviceps p a s p a li.5
3
3
4
S tru ctu rally related system s in clu d e 6, a c o n stitu en t o f Japanese
h op , "S h in sh u -w a se " ,6 7, a prod u ct of fa tty acid metabolism in y e a s t ,7 and
'
'
8, th e a g g r e ssio n pherom one of th e mouse Mus m u scu lu s. 8
'I
|
C9H19
x O ^l
0 ------
CH3
x O^
D------ \
('H3
H3C x O^
ID---:---
(CH2)5CO2CH3
7
6
CH3
8
The d iv e r sity in su b stitu tio n and stereo ch em istry o f th e se k e ta ls, as
well
as
th eir
considerab le
biological
in te r e st
in
and
economical
organic
s y n th e s is .
im portance,
has
As a r e s u lt,
sp ark ed
num erous
m ethodologies h ave b een developed w hich p rovid e a c c e ss to many o f th e
d esired su b stitu tio n p a tte r n s.
As a con seq u en ce o f co n tin u in g in te r e sts
in the ch em istry o f b icy clic k e ta ls, r ec e n t en d eavors have u n v eiled u se fu l
fragm entation
m ethodologies
w hich
co n v ert
read ily a c ce ssib le
b icy clic
k etals into oth er in te r e stin g sy n th e tic interm ediates.
Mundy has dem onstrated th e u tility o f clea v in g th e 0 - 8 - C -I bond in
th e preparation of p yran rin g s (F ig u re I ) .
T his p articu lar chemical
m odification resu lted in th e s y n th e s is o f a component of th e glandular
secretio n of th e C ivet c a t, [ 1 0 ] . 9
F igure I .
Kims' S y n th e sis o f a C ivet Cat Component.
4
Our group has
show n th at b icy elic k etals are rea d ily fragm ented
w ith a c ety l iod id e10, r e su ltin g in th e cleavage o f both C -I b rid g in g
oxygen b o n d s.
T his gen eral fragm entation seq u en ce afford s 8 ,e -u n sa tu r a te d en on es
in w hich th e stereo ch em istry o f th e C-7 su b stitu e n t ( endo v s . ex o ) is
r eflec te d in th e geom etry o f th e n ew ly formed olefin m oiety (F igure 2 ).
AcI
CU;
CH3
ex o : e n d o (6 0 : 4 0 )
65 : 3 5 (tra n s: c is)
AcI
2u n 3
CH2CH3
7 1 : 2 9 (tra n s: c is)
exo: e n d o (6 0 : 4 0 )
AcI
CH2CH2Ph
ex o : en d o (6 0 : 4 0 )
Figure 2.
X ^ rTCH2CH2Ph
70 : 3 0 (tr a n s : c is )
Fragm entations of B icy clic Ketals w ith A cety l Iodide.
5
The
s y n th e tic u tility of th e a c ety l iodide-m ediated fragm entation
p roced u re was dem onstrated in the s y n th e s e s of th e s e x a ttractan t of the
D ouglas - fir tu sso ck moth [12] (F ig u re 3) and Solenopsin A , [1 5 ] , a
major c o n stitu en t o f th e venom o f th e fir e a n t,
S olenop sis savissim a
(F igu re 4)
CH3(CH2)9
(CH2)4CH3
(CH2)4CH3
1I
Figure 3. M undy S y n th e sis of [1 2] .
( C H 2 )QCH3
(CH2)9CH3
13
14
CH3
F igure 4.
N ^ ""(CH2) 1OCH;
H
M undy S y n th e sis o f Solenopsin A.
6
In an elegan t s y n th e s is of ( - ) -A llo-yohim b ane, 2 Isobe u tilized a
common
elim ination
p roced u re
to
fragm ent
the
b icy clic
ketal
[16],
r esu ltin g in a h ig h yield o f alcohol [18] (F igu re 5 ).
16
F igure 5.
17
18
Isobe B icyclic Ketal Fragm entation.
The chem istry d isc u sse d th u s fa r , alb eit on ly a c u r so r y exam ination,
clea rly in d icates th e value o f stereo co n tro l in b icy clic k eta l p rep aration s.
C ontinuing w ith p rev io u s in v e stig a tio n s in our
g ro u p , we chose to "fine
tune" e x is tin g m ethodologies, as well as embark
p r o c e d u r e s,
w hich
u tilize
2-c a r b o n y l-su b s titu te d
in e x p e n siv e
on n o v e l, u n d evelop ed
and
d ih y d r o -2 H -p y ra n s.
rea d ily
With
available
em phasis
on
ch em o selectiv ity , r e g io s e le c tiv ity , en a n tio se le ctiv ity and s te r e o se le c tiv ity ,
th e gen eral fo cu s o f th is work will b e d irected
su b stitu e n ts
at
th e
2-p o sitio n
of
con seq u en t functionalization of th e
a d d r e sse d .
b icy clic
d ih y d ro -2 H -p y ra n s.
cy clic enol
In add ition ,
e th e r m oiety will be
T hrough p reviou s in v e stig a tio n s em ploying oxym ercuration-
dem ercuration
dem onstrated
tow ard m odifications of
m ethodology,
d eveloped
by
B ro w n ,13.
Mundy
has
the u tility o f m ercuric sa lts fo r prom oting cyclization s in
k etal p rep aration s. To exp lore th e r e g io s e le c tiv ity of a tan dem
7
oxym ercu ration-d em ercu ration s e q u e n c e , M undy14 reco g n ized th e p o ssib le
sy n th e s is o f brevicom in, [ 2 ] , and 20, th e a g g r e g a tin g pherom one o f th e
Norway
sp ru ce
b e e tle ,
T rypodendron
lineatum ,
from
the
common
to
th e
tandem
interm ediate, [19] (F igu re 6 ).
Figure 6.
The
model
C oncurrent Pheromone S y n th e se s.
reaction
w hich
gave
cred ib ility
oxym ercuration - dem ercuration ketal preparation was th e conversion of
[21] to [23] (F igu re 7 ).
8
Figure 7.
Model Tandem O xym ercuration-D em ereuration
P ro ced u re.
O btaining 23 as th e major p ro d u ct, w ith no d etecta b le formation o f
22, raised two im portant q u estio n s.
formation
of th e
five-m em bered
F irst of a ll, was th e
r in g a con seq u en ce
p referen ce or carbonium ion stab ility?
r eg io se lec tiv e
o f bond
S econ d ly, was there,
p referen ce for th e isop rop en yl m oiety p rior to r in g clo su re;
geminal
m ethyl
g ro u p ,
endo
or
exo,
co n cern in g
both
q u estio n s
contained
an gle
rotational
i . e . w hich
m ercury
prior
to
demer curation ?
J In sig h t
was
obtained
w hen
I 9 was
su b jected to th e oxym ercuration-dem ercuration s e q u e n c e .
B revicom in, [ 2 ] , was ob tain ed , w ith no d etectable p r e se n c e o f [201.
B ecause th e su b stitu tio n p attern o f th e olefin sid e chain p reclu d es s u b ­
stan tial carbonium ion d ifferen tia l, it was reasoned th at
en th a lp y and
e n tr o p y e ffe c ts w ere th e combined d r iv in g fo rce behind five-m em bered
r in g form ation .15
9
The q u estion reg a r d in g rotational p referen ce of th e rea ctin g olefin
sid e chain was an sw ered , in p a r t, b y th e o b servation th a t brevicom in was
obtained as a 45:55 m ixture o f th e e x o :e n d o e th y l iso m ers. T his ind icated
a lack of su b sta n tia l
facial d ifferen tiation of th e double
in th e case of compound 19, prior to r in g c lo su r e .
b on d, at le a st
H ow ever, it was not
known w hether th e lack of facial s e le c tiv ity
origin ated in unim peded
fr e e rotation of th e u n reacted olefin m oiety or
unim peded rotation of th e
mercurinium io n , or b o th .
A dditional
stu d ie s
relev a n t
to
th e se
q u estio n s
seem ed
g r ea tly
w arran ted .
Our group had also applied th e tandem oxym ercu ration - dem ercuration
seq u en ce to th e s y n th e s is of th e hop oil c o n stitu en t, [6 ]
B ecause
th e original s y n th e s is b y th e Japanese w o rk ers17 su ffe r e d sig n ifica n tly
from contam ination of b y -p r o d u c ts , th e goal was to overcom e th e lo ss of
s e le c tiv ity in th e preparation of th e p y ra n sta r tin g m aterials . . The
sy n th e tic s tr a te g y em ployed u tilized th e interm ediate k e to n e , 24, w hich
could b e d ir e ctly co n v erted to 6 b y w ay of addition of m ethyllithium , or
b y a Wittig rea ctio n , follow ed b y th e sol vomer curation p ro ced u re.
(F igu re 8 ).
10
Figure 8.
Separate C onversions o f [24] to [6 ] .
A lth ough compound [24] p ro v ed to be a v e rsa tile sta r tin g material
for n ovel p reparations of [ 6 ] , it was not obtainable in p u re form.
Figure
9 illu stra tes th e contam inants w hich could not be sep a ra ted from
24.
CO]
27
Minor
24
Major
11
The acq u isition o f 24 in pu re form , as well as th e developm ent of
additional
n ovel
prep aration s
of
6,
appeared
to
be
n e c e ssa r y
and
ch a llen g in g .
B ecau se th e bulk of th ese r ese a rc h e ffo r ts cen te r around racemic
sta r tin g m aterials, th e p rod u ct b icy clic k eta ls are obtained as
We recogn ized
th at th e
en an tio selectiv e
manipulation
racem ates.
o f 2-s u b stitu te d
d ih yd ro- 2H -pyrans could r e su lt in th e s y n th e s is of enantiom erically p u re
b icyclic k e ta ls.
Such e ffo r ts would r e su lt in the p rep aration s of op tically
pu re natural p r o d u c ts, as well as chiral
sy n th o n s fo r fu r th e r asymmetric
sy n th e s is en d ea v o rs.
The u se of chiral au xiliaries in asym m etric sy n th e s is h as become well
recogn ized as an e ffic ie n t and gen eral method fo r p r e p a r in g
optically
activ e com pounds.
not o n ly
S everal au xiliaries are now available w hich
are e ffe c tiv e at d ir e ctin g th e stereochem ical outcome o f bon d-form ation,
b u t, also are r e c y c la b le .18
d irect
th e
The d eg ree to w hich a chiral
stereo ch em istry
d ia s te r e o s e le c tiv ity . 19
illu stra ted in Figure 10.
of
a
reaction
has
A gen eral explanation of th is
au xiliary can
b een
phenom enon is
The facial differen tiation o f th e rea ctiv e
is due to th e spacial arrangem ent of th at cen ter w ithin a concave
X= Reactive Center
- R z ,
Figure 10.
term ed
Facial S e le ctiv ity O ffered B y a C oncave S ite.
cen ter
s i t e . 20
12
Given
the
scop e
and
e ffic ie n c y
of
m ethodologies
p r e v io u sly
develop ed in our g ro u p , we reco g n ized th e poten tial s y n th e tic u tility o f
h a v in g a su itab le chiral d ir e ctin g group attach ed to a carb onyl group at
the 2-p o sitio n o f a d ih yd ro-2H -p y ra n sy n th o n .
With th e a b ility to control
th e absolute stereo ch em istry of th e num ber 2 carbon o f th e pyran
r in g ,
we en v isa g ed read y a c c e ss to a number o f op tically a c tiv e b icy clic k e ta ls .
Making u se o f well know n chiral enolate ch em istry, asym m etric
into th e hop oil c o n stitu e n t, [6] (F ig u re 11), and fro n ta lin ,
[3] (F igu re
12) , w ere p rop osed .
R= Chiral Auxiliary
6
Figure 11.
en tries
P roposed Asym m etric S y n th e sis o f th e Hop Oil
C onstitu en t [6 ].
F igure 12.
Proposed Asym m etric S y n th e sis o f F ron talin , [3 ] .
14
Reactions
widespread
chiral
enolates
with
in the current liter a tu r e .21
efficien cy of
as the
of
various
electrophiles
are
Evans22 has demonstrated the
enolate alkylations employing derivatives of S-prolinol [29]
chiral auxiliaries (Figure 13).
1.
2LDA
I-
H3O+
2.
RX
2.
OH-
29
Carboxylic Acid
Electrophile
DpJD2
n-C^Hg-I
94: 6
82%
97: 3
85%
97: 3
■ CH3
CO2H
54%
CH3
96: 4
PhCH2Br
i
CH3
69%
88 : 12
CH3
Figure 13.
81%
Evans' Use of S-Prolinol in Enolate Alkylations
15
Helmchen and co -w o rk ers23 h ave rep orted on th e v e r s a tility o f
cam phor-derived chiral au xiliaries (30 and 31)
(F igu re 14).
fo r enolate alkylations
C orey24 has show n th a t 8-p hehylm enthol en olates [32]
u n d ergo "Michael Addition" w ith h ig h d ia ste r e o se le c tiv ity (F igu re 15).
R
Figure 14.
Helmchen C am phor-D erived Chiral A u x ilia ry .
16
Figure 15.
The
Corey Application of 8-Phenylmenthol
stereochem ical
outcome
attributed to enolate geom etry.
of
enolate
alkylations
has
been
In 1975 Ireland25 reported on the
stereoselective generation of e ster enolates as a function of solven t.
It
was found that in 100% THF the Z-enolate, [3 5 ], is favored w hereas,
in
23% hexamethyl-phosphoramide
(HMPA) in THF, the
E -enolate,
predominates (figu re 16).
XO
36
Figure 16.
Stereoselective Generation of Ester Enolates.
[36],
17
The character of the solvent proved essential in controlling the
diastereoselectivity
derived
of
enolate
a u x ilia ry .2G Figure
17
alkylation
illu strates
with
the
Helmchens
complete
bornanolreversal
in
d ia stereo selectiv ity , with the same auxiliary, b y changing the solvent from
100% THF to THF-HMPT (4 :1 ).
° <
> h
Solvent
d's
Configuration
CH3
PhCH2Br
THF
94: 6
S
CH3
PhCH2Br
THF/HMPAC4: I)
70: 3 0
R
CH2Ph
U
I
C
<-
THF
90: 10
R
CH2Ph
H-C4H9I
THF/HMPAC4: I)
85: 15
S
Figure 17.
cn
X
R2-X
Educt R1
Solvent-D ependent D iastereoselectivity
18
In
view
of
th e
many
im p ressive
exam ples
of
chiral
enolate
alkylations available in th e litera tu re we became in trig u ed b y th e p a u city
of applications in v o lv in g alkylations at r in g carbons
(F ig u re
18) o f
unsym m etrical h e te r o c y c le s .
R*
40
X= 0. N, S
F igure 18.
Chiral Enolate A lkylation at a R ing Carbon.
P reviou s work in our group has rev ea led th e ea se w ith w hich 2c a r b o x y l-su b stitu te d dihydro - 2H -p y ra n s may be alk ylated (F igu re 1 9 ).
Figure 19.
A lkylation of 2 -C a rb o x y l-D ih y d ro -2 H -P y ra n s.
19
The k e y q u estion w hich arose w as; could a su itab le chiral e s te r or
amide
m oiety
d erived
afford
enolate?
sig n ifica n t
diastereofacial
C onsidering th e
d ifferen tia tio n
geom etry of su c h
in
an en olate,
the
we
recogn ized th e p oten tial for control b y w ay o f chelation betw een th e
metal cou n ter ion and th e r in g o x y g e n
(F igu re
2 0 ).
Should eith er
tran sition s ta te , c y c lic , [4 3 ], or dipolar, [4 4 ], be sig n ific a n tly
p erh ap s asym m etric alkylation would p ro ceed e ffic ie n tly .
e ffe c ts of so lv en t p olarity and a u x ilia ry ty p e seem ed
M— 0
A stu d y into th e
h ig h ly w arranted.
R*
43
44
Cyclic
Dipolar
F igure 20.
fa v o r e d ,
Control o f Enolate Stereoch em istry
An a ltern ative approach to a c h ie v in g ch ira lity at C -2 was en v isa g ed
in an
asym m etric D iels-A ld er cycload d ition .
Figure
2 1 Z7
illu stra tes
the
reaction schem e w hich prom pted u s to co n sid er cycload ditions w ith chiral
a u x ilia r ie s.
20
O
O
45
Figure 21.
28
D iels-A ld er R eaction w ith MVK and M ethyl .
A c r y la te .
It was th ou gh t th at replacem ent o f th e m ethoxy group o f m ethyl
acrylate w ith a su itab le chiral d irectin g group m ight r e s u lt in . sig n ifica n t
diastereofacial d ifferen tiation o f th e d ien o p h ile.
Optimal conditions might
th en b e fou nd to e ffe c t th e asym m etric D iels-A ld er
Numerous
exam ples
of
chiral
D iels-A ld er
rea ctio n .
reaction s
of
acrylate
d e r iv a tiv e s h ave appeared in the lite r a tu r e . 28 Early stu d ie s b y
Farmer29
an d
m oderate
S a u e r 30
sh ow ed
th a t
( - ) -m e n th o l
p r o v id e d
d ia ste r e o se le c tiv ity in D iels-A ld er reaction s w ith cyclop en tad ien e
22) .
(F igu re
C orey31 fou nd th at th e d iastereotop ic face d ifferen tia tio n ex erted b y
8-phenylm enthol was sig n ifica n tly h ig h er (F igu re 2 2 ).
O ppolzer32 has
show n th at selectio n d ep en d s on th e n ature of the Lewis acid (F igu re 2 2 ).
Reference
Entry
R
$: MXn
MXn
YieIds(X)
endo(%)
de(%)
29
I
H
I: I. 0
SnCI4
76
89
41
U
O
2
' H
1 :0 .4 3
BF3 - E t 2O
74-81
95
74
32
3
H
I: I. 5
TiCI4
65
92
62
31
4
Rh .
I: I. 5
SnCI4
-
-
32
5
Rh
1 :1 .5
SnCI4
95
32
6
Rh
I: I. 5
TiCl4
32
7
Rh
I: 0. 7
. AICI3
F igure 22.
•
(99)
84
89
83
89
. 90
89
91
65
D ie ls-A ld e r .R eactions Employing ( - ) -M enthol D eriv a tiv es.
22
A comparatively efficient auxiliary,
( S )-(+ )-3 ,3 -d im ethyl-2-butanol
[4 8 ], has been employed b y Sauer33 and the reaction yield has since been
improved b y Greene34 (Figure 23).
48
. 49
Entry
Reference
YieId(X)
endo(%)
de(%)
I
44
. > 95
88
33
2
75
97
80-85
34
Figure 23.
D iels-A lder Reaction with (S )-(+ )-3 ,3 -D im eth y l2-Butanol A uxiliary
The difference in Tt-facial sele c tiv ity offered b y the ( - ) -menthol and
( S )-(+ )-3 ,3 -d im ethyl-2-butanol derived acrylates is particularly noteworthy
The geometrical difference between the two faces of the
an acrylate is illustrated in Figure 2 4 .35
M.
Figure 24.
re
Facial Differentiation in. A crylates.
double bond of
23
T opological b ia sin g o f th e rt-faces o f ary la tes is in h eren t in the
str u c tu r e o f the seco n d a ry alcohol chiral a u x ilia ry . As d ep icted in Figure
23, th e si^ sh ield in g o ffered b y th e t-b u ty l m oeity a ffo rd s r e -se le c tiy e
diene ad d ition .
Figure 25 illu str a te s r e -sh ie ld in g o f th e 8-phenylm enthol a u x ilia ry
w hich rationalizes th e h ig h s i-s e le c tiv e diene addition.
Figure 25.
A w ide
d evelop ed 36
r esp e c tiv e
acry la tes
Facial B ia sin g w ith 8-Phenylm enthol A u x ilia ry
v a r ie ty
w hich
of
camphor- d eriv ed
str a te g ic a lly ,
and
Tt-faces of a c r y la te s.
to pyran
s y n th e s is
atten tion in th e liter a tu r e .
auxiliaries
qu ite
H ow ever,
has
n o t,
as
have
s e le c tiv e ly ,
sin ce b een
sh ield
the
the application o f chiral
y e t,
r e c e iv e d , sig n ifica n t
We w ere th u s prom pted to embark on a s tu d y
in v o lv in g th e D iels-A ld er h eterocycloadd ition of m eth ylvin yl ketone to
various a c r y la te s.
Control of th e stereo ch em istry about C-2 in d ih y d ro -2 H -p y ra n s, b y
w ay o f asym m etric in d u ctio n , in v a ria b ly tra n sla tes into control of th e
stereo ch em istry about C-5 in th e p ro d u ct b icy clic k e ta ls .
As show n in
F igure 26, th e 6-s u b stitu e n t o f p y ra n [5 1 ], bound to a p ro -ch ira l c e n te r ,
alw ays adop ts equatorial su b stitu tio n , w ith r esp e c t to th e p y ra n r in g , in
the c y clized p rod u ct ketal [5 2 ].
24
Figure 26.
Fixed S tereoch em istry o f R ing C losure in
B icyclic Ketal Formation.
H ow ever, c o n sid erin g th e im portance of C-7 su b stitu tio n in b icy clic
k e ta ls, a n y seq u en ce n o n -ste r e o se le c tiv e fo r C-7 would cu t in half th e
e ffic a c y of asym m etric control at C -2 in th e p recu rso r 51.
A s tu d y into th e ste r e o se le c tiv e manipulation o f th e carbonyl of 2a c y l-d ih y d r o -2 H -p y r a n s was com pulsory.
dem onstrated
th e
poten tial
fo r
Previous work b y our grou p 37
stereo co n tro l
nu cleoph iles to m ethyl v in y l keton e dim er, [2 8 ].
stu d ied w ere alk yl G rignard r e a g e n ts .
in
th e
addition
of
The variou s nu cleoph iles
The s e le c tiv ity in th e addition of
ethylm agnesium halide could not be determ ined b y GLC as th e isom ers
w ere in sep arab le (F igu re 2 7 ).
R
exo
end o
53
CD3*
60
40
54
Et
55
i-Pr
89
11
56
t-Bu
84
16
57
Ph
75
25
^R eference 39.
F igure 27.
S tereo selectiv e G rignard A ddition to 28.
T he s te r e o se le c tiv ity o f G rignard addition to 28, w ith th e
r ela tiv ely
b u lk y n u cle o p h ile s, w as confirm ed b y an x -r a y cry sta llo g ra p h y s tu d y 38 on
th e e x o -p h e n y l isom er [ 57a] .
To a s s e s s th e ste r e o se le c tiv ity o f G rignard
addition o f a r ela tiv ely "small" n u cleo p h ile, Jun39 fou nd
deuteriom ethyl G rignard r esu lted in an e x o : endo
th at addition of
deuteriom ethyl ratio of
60:40.
The in h eren t sou rce o f stereo d ifferen tia tio n was p rop osed to be
chelation betw een th e incom ing G rignard rea g en t and b o th o x y g e n s o f 2 8 .
Early work b y C ologne40 in w hich acrolein dim er, [5 8 ], was trea ted w ith
a v a r ie ty o f G rignard r e a g e n ts,
show ed th e same tren d toward e x o ­
su b stitu tio n o f th e nucleophile (F ig u re 2 8 ).
26
R
OMgX
Figure 28.
R eaction o f G rignard R eagen ts w ith 58.
Our group
had also found limited s e le c tiv ity in th e red u ction o f
w ith variou s metal h yd rid e
r e a g e n ts.
The d eg ree and
direction
28
of
s e le c tiv ity varied w id ely (F igu re 29) w hich p reclu d ed th e formation of a n y
formal con clu sion s reg a r d in g th e reaction mechanism.
27
exo: endo
Figure 29.
0 . 9 6 to 4 . 0
Hydride Reductions of 28.
To extend our knowledge of stereo selectiv e nucleophilic addition to
28, we embarked on a program to stu d y alkyl-nucleophiles other than
Grignard reagents and the possible e ffects of adding a Lewis acid to
enhance chelation control.
We also decided to pursue several other metal
hydride red ucing reagents and reaction conditions in order to gain
a
fundamental un derstanding of stereocontrol in hydride reductions of 28.
No mechanistic
carbonyl
reported.
stu d ies
manipulations
of
(spectroscopic
or otherw ise)
dihydro- 2H -p yran s
have
been
concerning
previously
T hus, we chose to stu d y the phenomenon of chelation control
b y way of proton NMR spectroscop y.
The in teractivity of m ethylvinyl
ketone dimer with an appropriate Lewis acid, at various tem peratures,
seemed to be a phenomenon worthy of stu d y .
. . 'i
28
In trigu ed
by
com prehensive
upcom ing
th e se
s tu d ie s ,
te x t.
o b se r v a tio n s,
th e
The
r e su lts
we
q u estio n s
stereo ch em istry of so lv en t addition to th e
does fr e e
on
th ree
o f w hich are p r e se n ted in
we
solvom ercuration- dem ercuration p roced u re
to what d eg ree
embarked
a d d ressed
in
th e
the
w ere could we control th e
cy clic enol e th e r moiety
rotation o f th e
alkene
and
sid e chain a ffect
stereofacial differentiation?
With r e s p e c t to asym m etric in d u ctio n , we ask ed could a suitab le and
e ffic ie n t method for th e attachm ent o f chiral a u xiliaries be
developed?
If s o ,
as well as
could we control th e stereo ch em istry of enolization
p rovid e a str o n g bias for diastereoface selection?
F ocu sin g on ste r e o se le c tiv e nucleophilic addition to 2 -a c y l p y r a n s ,
we qu estion ed
th e role o f Lewis acid com plexation and search ed fo r
sp ectro sco p ic ev id en ce of su ch w ith m eth ylvinyl keton e dim er.
It th en
became n e c e s s a r y to in v e stig a te th e e ffe c ts of so lv en t and rea g en t ty p e
on th e interm ediacy of chelated v s . dipolar mechanism s.
29
CHAPTER 2
RESULTS AND DISCUSSION
The one-pot multistep tandem oxym ercuration-dem ercuration bicyclic
ketal preparation sequence provides a rather in terestin g en try into the
6 ,8 - dioxabicylo [3 .2 .1 ] octane
system .
The
complexity
and
plausible
chronology of the series of functional group transformations involved
have recen tly been the focus of active in terest in our research gro u p .
A
number of provocative questions may be asked when one view s a logical
delineation of the original p rocess carried out b y Mundy
Figure 30.
(Figure 30).
Original Tandem Oxymercuration-DemercurationB icyclic Ketal Preparation.
30
The
q u estion s
we
chose
to
a d d ress
w ere:
(I)
what
are
the
stereochem ical im plications o f mercurinium ion formation at each o f th e
double b o n d s , a n d ,
(2) what role does carbonium ion sta b ility p la y in
in flu en cin g th e stereo ch em istry o f r in g closure?
To approach the in tricacies in v o lv ed in the oxym ercuration s te p s ,
fir s t had to look ahead at th e stereochem ical requirem ents of pyran
su b stitu tio n
p rior
to
cyclizatio n .
As
shown in
F igure
31,
we
r in g
a syn -
relationship betw een th e h y d ro x y l and iso p ro p en y l grou p s is req u ired for
r in g c lo su r e .
Figure 31.
R equired cis - S u b stitu tion B etw een th e H ydroxyl and
Isop rop en yl Functions Prior to R ing Formation.
T hus we became in ter e sted in determ ining the stereochem ical outcome
of solvom ercuration of th e enol e th er m oiety.
The model we chose to
in v e stig a te was m ethyl v in y l ketone dim er, [2 8 ].
It seem ed lik ely that
28
would, ex h ib it th e same comformational b ia sin g , with r e s p e c t to the pyran
r in g , as diene [2 1 ].
In ad d ition , th e a b sen ce of the 2-iso p ro p en y l group
in keton e [28] would preclu d e unfavorable olefin
w hich might complicate th e reaction m ixture.
com petition fo r m ercury
31
It should also b e noted th at ow ing to th e rela tiv e in sta b ility of
•i
h em ik etals, 41 we ch ose to su b stitu te methanol fo r w ater, and analyze
the
p rod u ct k e ta l.
I
Treatm ent o f k eton e [28] w ith one eq u ivalen t of m ercuric acetate
and th ree eq u iv a len ts of m ethanol, in THF, followed b y evaporation of
so lv e n t, r esu lted in a sem i-solid .
carbon
reso n a n ces
by
conformational isom ers
13C
in
th e
In tegration of th e carb onyl and
NMR
rev ea led
approxim ate
presum ed th at th e isom ers obtained w ere
th e
ratio
ketal
p r e se n c e
of
two
56:44.
It
was
(F igu re
3 2 ),
of
6ha and 61b
assu m ing th at th e a c ety l group occu pied p seu d o equatorial p o sitio n in g in
[2 8 ].
OCH3
61a
CH3
61b.
F igure 32.
Solvom ercuration of k eton e [2 8 ].
The isom ers 61a and 61b w ere
q u a n tita tiv ely co n v erted to th e
b icy clic k etals 62a and 62b, upon treatm ent w ith sodium b o ro h y d rid e,
followed b y acid catalyzed cyclization (F ig u re 3 3 ).
32
1.
61a
+
61b
---------=2.
62a
F igure 33.
NaBH4
H+
62b
D em ercuration/C yclization of k eta ls 61a and 6 1 b .
The ratio of 62a to 62b was determ ined, b y capillary GLC, to be
approxim ately 60:40.
With str o n g ev id en ce in d ica tin g n o n -ste r e o se le c tiv e solvom ercuration
of th e enol e th er m oiety, we rationalized th at from a rea so n a b ly
conformation w ith th e ( 2-iso p ro p en y l) group equatorial, one
apriori e x p e ct o th er than about a 1:1 m ixture of axial and
assum ed
would n o t,
equatorial
h y d ro x y l su b stitu tio n (F igu re 3 4 ).
F igure 34.
P roposed N o n -ste r eo se lec tiv e oxym ercuration of
D iene [2 1 ].
33
H aving n ea rly equal amounts of cis_ and tran s O H -su b stitu tio n , w ith
r e sp e c t to th e iso p ro p en y l g ro u p , one would e x p e c t th a t on ly the c is isom er would b e capable of c y clizin g .
The tra n s isom er, 63a, might th en
b e su sce p tib le to r in g op en in g as show n in Figure 35.
/^ o
/
6 3a
Figure 35.
R ing O pening of 63a.
R eflectin g on p rev io u s work from our g ro u p , Schw artz had found
th at
diene
th at
ap p lyin g th e tandem solvom ercuration/ dem ercuration p roced ure to
[21] a ffo rd ed , as th e major p r o d u ct, diol [6 5 ].
It was presum ed
diol [65] was formed b y r in g o p en in g followed b y borohyd rid e
red u ction
(F igu re 3 6 ).
65
F igure 36.
P roposed Mechanism fo r Diol Formation.
34
T his fin d in g o ffer s rationale fo r th e moderate y ie ld s often obtained
fo r
th e
ta r g e t
b ic y c lic
k e ta ls .
We
th en
stereochem ical requirem ents of r in g closu re
decided
to
p u rsu e
th e
fo r th e cis isom er [6 3 b ].
F ocu sin g on th e rotational p r e fe re n c es o f th e iso p ro p en y l g ro u p , it w as
recogn ized
th at
n -fa cia l
d ifferen tiation
of
th e
double
bond
could
tran slate into d iastereofacial se le c tiv ity in mercurinium ion form ation/
r in g c lo su r e .
Such an e v e n t would r e su lt in p referen tia l p o sitio n in g of
m ercury in eith er th e exo or the endo 0 7
th e p rod u ct
m ethyl group (F igu re 37) in
b icy clic k e ta l.
CH2- H g —
CH3
endo
CH3
CH2- H g —
exo
F igure 37.
P roposed Stereochem ical Control in Mercurinium
Ion C yclization .
B ecau se dem ercuration w ith b oroh yd rid e r e su lts in geminal dim ethyl
su b stitu tio n of C -7 , th e id e n tity of th e m ethylene con tain in g m ercu ry ,
35
p rior to dem ercu ration, was m asked.
T herefore th e tandem solvom ercura-
tion p roced u re was rep eated w ith d ien e, [2 1 ], follow ed b y dem ercuration
w ith sodium borod eu terid e (F igu re 3 8 ).
The id e n tity of th e m ethylene
carbons b ea rin g m ercu ry p rior to r in g closu re could th en b e determ ined
b y proton NMR in teg ra tio n
of th e
geminal m ethyl sig n a ls
contain ing
deuterium .
D
— Hg,
H3C
0 -------H 3 CDH2
0 -------H 3 CH2-H g -
CH3
CH3
68a
67a
NaBD^
— Hg
D
0 -------H 3CH3
0 -------H 3CH3
CH2-H g 67b
Figure 38.
CDH2
68b
D em ercuration w ith Sodium B orod eu terid e.
36
It has been esta b lish e d that in th e 1H NMR spectrum of ketal [23]
th e exo m ethyl group reso n a tes at about 1.26 ppm and th e endo group
reso n a tes at about 1.36 ppm, rela tiv e to TMS.
As illu stra ted in F igure
39, "lH NMR in tegration of th e 0 7 m ethyl region of 68a and 68b revealed
a ratio of approxim ately 55:45 ( e n d o :ex o ) deuterium su b stitu tio n .
1 . 0 (ppm)
Figure 39.
1H NMR Spectra for 23, 68a and 68b.
37
T his ratio s u g g e s ts th at solvom ercuration of th e iso p ro p en y l group is
la r g ely n o n -s te r e o se le c tiv e .
T h ese
data correlate well w ith M undy1s
p rev io u s o b servation th at solvom ercuration / dem ercuration of diene [19]
resu lted in a 55:45 ratio o f th e endo and exo brevicom ins (F igu re 4 0 ).
+
H t1C
F igure 40.
1.
Hg(OAc)2
2.
NaBH4
HnC
R elative No n -S te r e o se le c tiv ity in th e Tandem
Solvom ercuration-Preparation of B revicom in.
The ch a ra cteristic lack o f n -fa cia l differen tiation o f 'the olefin
chain of
and 19 may b e a ttrib u ted to unim peded ro ta tio n .
illu stra tes th e lo ss of s e le c tiv ity , in th e addition of m ercu ry,
r e su lt if all th ree rotam ers of
Figure
sid e
41
w hich would
con trib u te to the reaction outcom e.
F igure 41.
P roposed Source of No n -S tereo selectio n Due to
R otational Freedom.
39
As a con seq u en ce of obtainin g sig n ifica n t in sig h t into th e scop e and
lim itations of th e tandem solvom ercuration p r o c e d u r e , we w ere
to p u rsu e some related o b je c tiv e s .
We so u g h t to fu r th e r
m odifications of th e enol e th er m oiety and 2 carb onyl
d ih yd ro- 2H-p y ra n s in order to exp an d our arsen al o f
e n tr y into b icy clic k e ta ls .
m otivated
exp lore variou s
su b stitu e n ts of
m ethodologies fo r
R eflectin g on th e
p rev io u s application of th e
solvom ercuration p roced u re to a s y n th e s is o f
6 (F ig u re 8 ) , we chose to
fo cu s on th e d ifficu lties en cou n tered in
obtainin g k eton e [24] in p u re
form (F igu re 4 2 ).
F igure 42.
The
Preparation of Ketone [2 4 ].
isolation
and
su b seq u en t
oxidation
of alcohol
[26]
p roved
troublesom e as th e p rod u ct m ixture was contam inated w ith 10-25% of th e
k eta ls 27a and 27 b .
To fu rth e r a s s e s s th e lim itations o f chem ically
m odifying alcohols lik e 26, an im proved p roced u re fo r th e sy n th e s is of
k eton e [24] was n e e d e d .
B ecau se contact b y n eu tral or acidic pro tic
media prom otes cyclization of [2 6 ], care was taken to e n su re th at th e
isolation and oxidation s te p s ( 5 8 -2 6 -2 4 ) rem ained b a s ic .
40
The s u c c e s s fu l con version of 58 to 24 was a ch iev ed th rou gh th e
follow ing
proced ure:
treatm ent
of
acrolein
dim er, [58]
w ith
excess
m ethyllithium (or m ethylmagnesium brom ide) followed b y qu en ch in g w ith
excess
10% potassium
q u a n tita tiv ely
p rod u ct
was
p u rification .
chloride
h yd ro x id e
and
extraction
afford ed alcohol [2 6 ],
im m ediately
taken
on
w ith
d ieth y l
as a colorless o il.
to
th e
oxidation
The crude
ste p
A lcohol, [2 6 ], was d isso lv ed in fr e sh ly d istilled
(P 2O5 )
and
added
slow ly
to
a stirred
e th e r
solu tion
pyridinium dichrom ate (3 -4 e q u iv a len ts) in fr e s h ly d istilled
w ithout
m ethylene
of
excess
m ethylene
chloride con tain in g sodium acetate and molecular s ie v e s 42 at 0°C .
A fter s tir r in g 8-12 h o u r s , th e r e s u ltin g dark su sp e n sio n was su ction
filter e d and th e filtra te was p a ssed th ro u g h a sh o rt pad o f silica g e l,
affo rd in g p u re keton e [24] in approxim ately 40% iso la ted y ie ld (2 s t e p s ) .
A lth ough
circum vented
th e
overall
y ield
was
m oderate,
th is
procedure
th e problem of contam ination b y in sep arab le b y -p r o d u c ts .
N otew orthy is th e fa c t th at rep eated attem pts to scale up th is procedure
s ix to se v e n grams r e su lts in sig n ifica n t amounts of un oxid ed alcohol [2 6 ].
H aving keton e [24] p u re , the seq u e n c es p r e v io u sly carried out
(F igu re 8) w ere r ep ea ted , r e su ltin g in im proved y ie ld s o f th e hop oil
c o n stitu e n t, [6 ]; i . e . 6 was obtained fr e e o f the u n d esired b y -p r o d u c ts
( 27a)
and (2 7 b ).
We th en decided to explore th e scop e and lim itations o f m odifying
2-c a r b o x y l
d e riv a tiv es
of
d ih y d ro -2 H -p y ra n s
by
m aking u se
of th e
commercially available (A ld rich ) 3 ,4 -d ih y d r o -2 H -p y r a n -2 -c a r b o x y lic acid ,
sodium s a lt, [T l].
We recogn ized th at Tl might s e r v e as a v ersa tile interm ediate in th e
41
preparation of e s te r s w hich have p r e v io u sly b een d ifficu lt to is o la te .
For
exam ple, th e s y n th e s is o f e s te r 69 (a p recu rso r to fro n ta lin ) b y w ay o f a
D iels-A ld er heterocycload d ition (F igu re 43)
th e inseparable b y -p r o d u c t m eth ylvin yl
resu lted in th e formation of
k eton e dim er, [2 8 ].
OCH-.
0
69
F igure 43.
D iels-A ld er Preparation of E ster [6 9 ].
It was th o u g h t th at a /D ie ls - A lder reaction em ploying acrolein and
m ethylacrylate would p roceed in a similar fa sh io n , r e su ltin g in both e ste r
[70] and dimer [58] (F igu re 4 4 ).
F igure 44.
P roposed Outcome of a D iels-A ld er R eaction
Employing A crolein and M ethylacrylate.
42
B ased
on
cycloaddition
p u rsu ed .
th is
was
p rem ise,
not
th e
attem pted
preparation
and
an
of
70
a ltern a tiv e
by
D iels-A ld er
proced ure
was
The p y ra n salt [71] was r eflu x e d in tetrah yd rofu ran (THF) w ith
two eq u iv a len ts o f HMPA.
A queous ex tra ctio n w ith w ater and d ieth y l
e th e r , followed b y silica g e l chrom atography (8 :2 h e x a n e :e th y la ceta te)
afford ed p u re e s te r [70] in approxim ately 62% iso la ted y ie ld .
F igure 45.
A ltern ative preparation of E ster [7 0 ].
R epeated attem pts to e ffe c t th e
co n v ersio n
of Tl to 70 in th e
ab sen ce of HMPA met w ith fa ilu r e, as no reaction was o b s e r v e d .
The s u c c e s sfu l preparation of 70 r e p r e se n ts a su ita b le circum vention
of th e formation of in sep arab le b y -p r o d u c ts obtained b y
cycload dition.
With 70 in h an d, we ch ose to p u rsu e an
sy n th e s is o f th e hop oil co n stitu en t [ 6 ] .
T h u s, e s te r [70]
w ith 2 .5 eq u iv a len ts of m ethyllithium in THF at -78°C .
ca refu lly
qu en ch ed
a cid -ca ta ly zed
D iels-A ld er
w ith
cyclization
two
w ith
qu an titative y ie ld (F ig u re 4 6 ).
eq u iv a len ts
15%
HCl,
of
altern ative
was trea ted
T he reaction was
w a ter,
a ffo rd in g
followed
6
in
by
n ea rly
F igure 46.
We
A ltern ative Preparation of th e Hop Oil
C on stitu en t [6 ] .
th en
a cid -ca ta ly zed
decid ed
e ste r ific a tio n s.
to
exp lore
th e
r e a c tiv ity
of
Tl
in
Treatm ent of Tl w ith 3-5 eq u iv a len ts of
H2SO4 , u s in g methanol as th e so lv e n t, y ield ed e ste r [TO] and th e isom eric
acetals
[ T2a] and [ T2b] (F igu re 4T) in a tem p era tu re-d ep en d en t r a tio .
y^oN a
O
71
Tem perature
35°C
R eflux
Figure 4T..
Ratio of R eaction P rodu cts
5T
58a
58b
O
I
9
I
I
5
A cid -C atalyzed E sterification of T l.
44
The
stereo ch em istry
of
th e
acetals
72a
and
72b ' was
e a sily
elu cid ated w ith 1H NMR sp e c tr o sc o p y , b y u s in g th e K arplus equation43..
A n alysis of D reid ing models rev ea led th e rela tiv e environm ents of th e
acetal
p roton s
m eth ylen e.
w ith
r e sp e c t
to
th e
p roton s
of
th e
adjacent
r in g
M easurement of th e dihedral a n g les (F ig u re 48) betw een th e
acetal proton and th e r esp e c tiv e axial and equatorial p roton s of th e
adjacent m ethylene allows for an approxim ation of th e e x p e cted vicin al
nH -1H coupling p a tte rn s fo r each of th e isom ers 72a and 72b.
CO2CH3
-IS O - O . OHz)
CO2CH3
F igure 48.
A pproxim ation of D ihedral A n gles Ha - Hto and
Ha - Hc and p red icted 3J v a lu e s .
45
B ased
upon
th e
dihedral
an gle
d ep en d en ce
fo r
vicin al
proton
cou p lin g C onstants(3J ) , th e equatorial m ethoxy isom er [72a] way e x p e cted
to exh ib it SJ(Ha -Hb ) of about 9Hz (0 = 175°) and 3J (HaHc ) o f about 1 .5
Hz (6 = 60°) r e s u ltin g in a doublet o f d ou blets p a tte rn .
p a ttern w as a broadened doublet w ith 3J= 8 .4 6 Hz.
isom er [72b] was ex p e cted to ex h ib it 3J= 1 .5 Hz
The
o b serv ed
The axial
m ethoxy
fo r Ha -Hb and
(6 = 60°) w hich w ould r e su lt in a broadened sin g le t sig n a l.
Ha -H c
Such
was
th e o b serv ed p a tte r n .
The p r eferen tia l formation of th e
m ethoxy isom er
was attrib u ted
to th e
more ste r ic a lly hin d ered axial
”Anomeric E ffe c t." 44
A well
accep ted explanation fo r th is phenom enon s u g g e s ts th a t th e ste re o electron ic
e ffe c ts
o f overlap betw een
th e
n o n -b o n d in g -o rb ita l of th e
p yran r in g o x y g e n w ith the an tibond ing orbital of th e m ethoxy o x y g e n
atom, overrid e th e s te r ic in flu en ces of th e m ethoxy su b stitu e n t.
N otew orthy is th e ap p aren tly equal a b ility of each isom er, 73a and
7 3 b , to cyclize (F igu re 4 9 ).
in itia te d ,
sam ples
com pletion)
a n a ly sis.
and
1 .5
w ere
A fter th e a cid -ca ta ly zed cyclization step was
taken
h ou rs
at
5
m inutes
(approxim ately
2% of
(approxim ately 60% of com pletion) for GC
In tegration of rela tiv e peak areas ind icated n ea rly equal ratios
o f 73a to 73b fo r each sam ple.
T h ese data s u g g e s t th e
interm ediacy of a
so lv o ly tic (S ktx) pathw ay as opposed to (S n 2) displacem ent.
controlled k in etic experim ent seem ed u n n e c e ssa r y
A h ig h ly
and was not p u r s u e d .
Figure 49.
P roposed Solvolytic Pathw ay fo r M ethoxy
D isplacem en t.
H aving dem onstrated
th e
u tility
of th e p y ra n
sa lt
[71]
in th e
preparation of m ethoxy e s t e r s , we ch ose to in v e stig a te th e preparation
acid h a lid e s,
w ith an em phasis on m aintaining th e
a c id -s e n s itiv e
enol
e th er
m oiety
(F ig u re
50).
of
in te g r ity of th e
We fe lt
th at
an acid
chloride su ch as 74 m ight be rea d ily co n v erted into a v a r ie ty of u se fu l
interm ediates b ea rin g a lk y l, alk oxyl or amine fu n c tio n a litie s, in clu d in g
chiral a u x ilia ries.
47
Na
•
71
°
"
Y
o
74
RoNH
R2CuLi
ROH
"
R = Chiral Auxiliary
or highly S u b s t it u t e d Alkyl
F igure 50.
P roposed S yn th etic U tility of A cid Chloride 74.
A lthough h isto rica lly it has b een
chlorides
ad van tages
from
to
carb oxylic
em ploying
carb oxylic acid [7 8 ] .
acids
th e
45
more common to p repare acid
we
carb oxylate
recogn ized
salt
[71]
two
rath er
p articular
than
th e
F ir s t, it was th o u g h t th at attem pts to isolate 78
m ight r e su lt in sig n ifica n t formation of th e lactone [79] b y w ay o f acid
catalyzed lactonization (F igu re 51).
48
F igure 51.
P roposed L actonization of C arboxylic A cid [7 8 ].
S econ d , we reco g n ized th e s e n s itiv ity of th e enol e th er m oiety to
HCl, w hich is a ch a ra cteristic b y -p r o d u c t of acid chloride preparations
from carb oxylic acid s (F ig u re 5 0 ).
T h u s, th e con version of Tl to 74
would r e su lt in th e formation of sodium chloride as. b y -p r o d u c t, w hich
would be in e r t tow ard th e
su b str a te .
Pyran [71] was su sp en d ed in dichlorom ethane, w ith rapid stir r in g ,
and trea ted w ith e x c e s s th ion yl chloride (SOCl2) .
h ou rs,
follow ed
by
filtration
of
sa lts
and
R eflu x in g fo r 2-6
distillation
at
dim inished
p r e ss u r e , afford ed a m ixture of 74 and th e HCl addition p rod u ct [8 0 ], in
v a r y in g ratios (F ig u re 52) and in 20-30% y ie ld .
49
F igure 52.
The
R eaction o f Tl w ith T hionyl C hloride.
formation
of
80
was
p roposed
to
have
r esu lted
from
contam ination of w ater in th e pyran sa lt [ T l ] . T hionyl chloride was ruled
out
as
th e
sou rce
of
H+
as
it
had
been
fr e s h ly
d istilled
from
tr ip h en y lp h o sp h in e . 46 The reaction was rep eated sev e r a l tim es, with and
w ithout th e addition o f p yrid in e as an HCl tra p , a ffo rd in g the same
r e s u lt s .
A lthough
red istillation
of
th e
prod u ct
m ixture
(50-60°C
a s p .)
afford ed p u re T4, th e y ie ld s w ere c o n siste n tly low (10-30% iso la te d ).
w ere th en com pelled to p u rsu e an a ltern a tiv e proced ure in v o lv in g
ch lorid e.
The con version of carb oxylate sa lts to acid chlorides
We
oxalyl
w ith
oxalyl chloride and catalytic dimethylformamide (DMF) has b een p r e v io u sly
docum ented. 46
50
The carb oxylate sa lt [52] was .then treated with oxa ly l chloride at
0°C u n d er a r g o n , in the a b sen ce o f so lv en t (F igu re 5 3 ).
A catalytic
amount o f DMF was ad d ed , followed b y r e flu x in g fo r 2-6 h o u r s . The u su al
w orkup was em ployed, affo rd in g p u re 74 in 54% y ie ld .
R epeated attem pts
to d r y th e p yran sa lt b y prolonged warming u n d er vacuum , prior to
treatm ent w ith oxalyl ch lorid e, failed to improve the y ie ld .
A lthough th e
yield of acid chloride [74] was moderate (54%), the o x a ly l c h lo r id e /DMF
proced ure was an improvement ov er th e previou s 30% y ie ld w ith SOCl2 .
0
0
71
Figure 53.
0
0
74
P rep aration . of 74 w ith Oxalyl C hloride.
51
CHAPTER 3
ASYMMETRIC SYNTHESIS
Our
in v e stig a tio n s
of
chemical
m odifications
of
2-carb on yl
su b stitu e n ts o f dih ydro - 2H - p yra n s p ro v id ed u s w ith a w ealth of b a ck ­
ground
in form ation
fu n c tio n a litie s.
con cern in g
With a c c e ss
to
th e
th e
attachm ent
v e rsa tile
acid
of
rem ovable
chloride
[74]
we
d irected our atten tion tow ard the preparation of p y ra n s b ea rin g chiral
control g r o u p s .
It was recogn ized th at h a v in g a su ita b le chiral a u x ilia ry
co v a len tly bound to th e 2-ca rb o n y l su b stitu e n t might p ro v id e a means b y
w hich asym m etry could b e in d u ced in a carbon - carbon bond
reaction in v o lv in g th e p yran r in g .
C ontrolling th e a b solu te
form ing
co n fig u ra ­
tion o f C-2 su b stitu tio n o f d ih y d ro -2 H -p y ra n s might bode well
fo r th e
preparation of enantiom erically pu re b icy clic k e ta ls .
A num ber o f h ig h ly en a n tio selectiv e sy n th e s e s o f in s e c t pherom ones
have r e c e n tly b een p u b lish ed
in term ed iates.
w hich do not u tilize d ih yd ro-2H -p yran
The sy n th e tic str a te g ie s em ployed in each o f th e rep orted
asym m etric p rep aration s in v o lv e T ype "a" m ethodologies48
C hirality in
str a te g ie s:
th e
p r e cu rso r
k eto -d io ls
r e su lts
from
( I ) asym m etric ind uction em ploying chiral
chiral b u ild in g b lock s d eriv ed from c a rb o h y d r a te s.
two
(F igu re 5 4 ).
co n tra stin g
r ea g en ts and (2 )
52
R
O
F igure 54.
S y n th etic S tra teg ies fo r B icyclic Ketal S y n th e s is .
W hitesell49
has em ployed 8 -phenylm enthol in two n o v el con v ersio n s
o f glycolate e s te r s to (+ )- and ( - ) - frontalin (F ig u re 5 5 ).
Elielso has
dem onstrated th e sy n th e tic u tility o f a chiral 1 ,3 -o x a th ia n e p recu rso r
th e preparation o f each enantiom er o f frontalin (F igu re 5 6 ).
(R)-(+)-Frontalin
F igure 55. W hitesell S y n th e ses o f (+ )- and ( - ) - F rontalin.
in
'i
53
7— S »
/
HO
RO
2 steps
3 steps
,
(-)-Frontalin
89%. 96%ee
Figure 56. . Eliel S y n th e ses of (+ )- and ( - ) - F ron talin .
54
The well know n ” S h arp less E poxidation1'51
p roced u re was em ployed
b y O ehlschlager52 in th e sy n th e s e s of both (+ )- and ( - ) -en d o-b revicom in
(F igu re 5 7 ).
A un iqu e chiral boronic e s te r m ediated s y n th e s is of (+ )-
exo-brevicom in was r e c e n tly rep orted b y M atteson53
(F ig u re 5 8 ).
r~\
A
r
V <^ ^ C H 3
Ox
OH
C
D
(-)-endo-Brevicom in
(+)-endo-Brevicomin
F igure 57.
O ehlschlager S y n th e ses of (+ )- and ( - ) - en d o -B rev ico m in .
55
(+)-exo-Brevicom in
Figure 58.
M atteson S y n th e sis o f (+ )- exo-B revicom in .
In 1982 F ra ser-R eid 54
rep o rted a novel preparation o f ( + )-exo
brevicom in from a chiral b u ild in g u n it d eriv ed from rib ose (F ig u re 5 9 ).
I
CH2CH3
F igure 59.
F raser-R eid S y n th e sis o f Brevicom in.
56
R edlichs5 has r e c e n tly rep orted two a ltern a tiv e s y n th e s e s of both
enantiom ers of e n d o -b r e vicomin sta r tin g from D -rib o se ( F igure 6 0 ).
F igure 60.
R edlich S y n th e ses of en d o -B rev ico m in .
57
The ty p e "a" asym m etric s y n th e s e s o f in se c t ph erom on es, a lb eit,
h ig h ly e n a n tio se le ctiv e, r ep re sen t m ultistep s e q u e n c e s , many of w hich
req u ire ted iou s chrom atographic sep aration s of d ia stereo m ers.
C onsidering
th e low co st and rea d y availab ility o f d ih y d ro -2 H -p y ra n
e n v isa g ed h ig h ly e ffic ie n t en tries into chiral b icy clic
p r e c u r so r s, we
\
k eta ls via ty p e "b"
s tr a te g y , w hich p la u sib ly would req u ire on ly one diastereom er separation
s te p .
C onscious of th e p a u city of p u b lish ed exam ples of ch ira lity tr a n sfe r
to r in g carbons via enolate alkylation (F ig u re 1 9 ), we b eg a n
our stu d ies
w ith a model system em ploying ( - ) -m enthol as th e recy cla b le
d ir e ctin g g ro u p .
chiral
A lth ough menthol had not p r e v io u sly b een rep orted as a
h ig h ly e ffic ie n t chiral au xiliary its low c o st and ro b u st
resista n c e to
chemical degradation o ffered sig n ifica n t appeal.
Treatm ent of acid chloride [74] w ith (-)-m e n th o l [81] (F igure 61)
and p yrid in e afford ed th e d esired diastereom eric e s te r s [82] in a ratio of
approxim ately 1:1 ( 13C NMR) .
Figure 61.
E ster Formation w ith ( - ) -M enthol.
58
E ster [82] was e a sily p u rified via silica gel chrom atography
(8 :2 h exan e: e th y l a c eta te) affo rd in g th e d esired p rod u ct in good y ie ld .
An altern ative p ro ced u re, w hich afford ed iden tical r e s u lts ,
th e
addition
of
74 to
a
cold
(m enthol + n-B u L i) in THE.
(O0C)
solution of lithium
in v o lv ed
m entholate
We th en so u g h t to m ethylate 82 in
attem pt to p repare a p roposed p recu rso r to frontalin (F ig u re 1 2 ).
82 was ex p o sed to 1 .1 eq u ivalen ts of lithium diisopropylam ide
-78°C , follow ed b y e x c e s s m eth yliod id e, a ffo rd in g 83 in
an
T h u s,
(LDA) at
qu an titative y ie ld
(F igu re 6 2 ).
Figure 62.
M ethylation of M enthol-D erived E ster
A n alysis of 83 b y in tegratab le 13C NMR sp e ctro sco p y rev ea led a
diastereom eric
ratio
of
approxim ately
55:45.
R epeated
attem pts
to
in crea se ste r e o se le c tiv ity b y v a r y in g th e tem perature failed to im prove
th e ratio b eyon d 57:43.
We
th en
electro p h ile.
d irected
our
atten tion
to
th e
ste r ic
size
It was th o u g h t th at in c r ea sin g th e siz e of th e
of
th e
lea v in g
g ro u p , L (F igu re 63) m ight r e su lt in enhanced ste r ic in teraction at th e
more encum bered face o f th e chiral en olate.
59
H
Figure 63.
P roposed S e le c tiv ity Enhancement b y In crea sin g S teric
Demand o f E lectrop h ile.
The alkylation p roced u re was th en rep eated em ploying m ethyl p to lu en e- su lfin ate as th e a lk yla tin g r e a g e n t.
The reaction proceed ed in
q u an titative y ie ld (GLC) h ow ev er, th e ste r e o se le c tiv ity enhancem ent was
m odest as 83 was obtained as a 63:37 m ixture o f diastereom ers ( 13C NMR) .
. We th en d ecid ed to stu d y th e e ffe c ts of so lv en t ch aracter on the
stereo ch em istry o f th e d erived en o la te.
R eflectin g on th e p rev io u s
stu d ies b y Ireland 25 (F igu re 16) and Helmchen 26 (F ig u re 17) we elected
to em ploy HMPA as th e c o -so lv e n t in an attem pt to a lter th e enolate
geom etry.
In d eed , we did not rule out th e p o ssib ility th at in THF, b oth
enolate geom etries m ight e x is t , th u s , d efea tin g th e in d u ctiv e capability of
th e chiral a u x ilia ry .
T he alkylation p roced u re was rep ea ted u sin g THF, contain ing 23%
HMPA, and m ethyl p -to lu e n e su lfin a te as th e a lk y la tin g r e a g e n t.
Much to
our disappointm ent, th e o b serv ed d ia ste r eo se lec tiv tty was a m odest 57:43.
60
C areful exam ination o f D reid ing models ind icated that w ith eith er
enolate (E or Z) d eriv ed from 82, th e Tt-facial sh ield in g o ffered b y th e
isop rop yl m oiety o f m enthol,
is
somewhat o ffse t b y p u ck er in g of th e
pyran r in g (F igu re 6 4 ).
F igure 64.
Pyran R ing Conformational Flopping.
We rationalized th at w ith a chiral au x ilia ry b ea rin g a
sig n ifica n tly
larger n -fa cia l sh ie ld in g m oiety the encum brance due to p y ra n rin g fo ld in g
might be favorably, o ffs e t.
We e n v isa g ed em ploying a
(H elm chen) au x ilia ry b ea rin g aryl
Tt-facial sh ield in g
cam phor-derived
grou p s.
Figure 65
illu stra tes th e d esired n -sta c k in g we so u g h t to ach ieve betw een the chiral
au x ilia ry and th e ex te n d e d
n - system o f th e
p y ra n .
61
SOoPh
Figure 65.
P roposed
n - Stack ing w ith C am phor-D erivative.
We th en fo cu sed our atten tion on th e preparation of e ste r [86] from
74 (F ig u re 6 6 ).
62
85.
R= Li
Figure 66.
P roposed Preparation o f 86.
The bornanol d eriv a tiv e [8 4 ], in dichlorom ethane, was trea ted w ith
th ree eq u iv a len ts o f triethylam ine and one eq u ivalen t o f 74 at 20°C fo r
tw elve h o u rs.
u n reacted
84
Rapid ex tra ctio n w ith d ieth y l e th er and w ater afford ed
along
w ith
trace
am ounts
of
sev e r a l
in d istin g u ish a b le
polym eric b y -p r o d u c ts ( 13C NMR and GC/M S).
The reaction was th en r ep ea ted , at r e flu x , follow ed b y evaporation
o f so lv en t u n d er red u ced p r e s s u r e . A n a ly sis o f th e cru de p rod u ct b y th in
la y er chrom atography (TLC) w ith 20:1 p e n ta n e : e th y l a ceta te rev ea led two
p rod u cts (R f = 0.45 and 0 .2 9 ) in tra ce am ounts, and u n rea cted 84
(R r
= 0 .1 6 ) as th e major com ponent.
At th is poin t we recogn ized the
p oten tial in sta b ility o f th e d esired e s te r and omitted aqu eou s
L ikew ise,
GLC a n a ly sis was a v o id ed , fo r fea r th at th e hot
injection p ort may cau se decom position o f 86.
ex tra ctio n .
(>240°C)
63
T h e re fo r e , th e cru d e prod u ct w as ra p id ly taken up in anh ydrous
deuteriochloroform and q u ick ly an alyzed b y 13C NMR and D irect Insertion
Probe
(DIP)
mass sp ectrom etry .
H ow ever,
our d elicate e ffo r ts w ent
unrew arded as no ev id en ce fo r th e ta r g e t e ste r [86] was d e te c ted .
R epeated attem pts
to p repare
86 from its co rresp o n d in g lithium
alkoxide [85] also fa iled , as did an attem pt em ploying calcium h y d rid e56
in place o f p y r id in e , as th e HCl s c a v e n g e r .
We th en rationalized th at
ste r ic in tera ctio n s betw een 74 and th e a u x ilia ry [84] h ig h ly
p rop er orien tation o f th e r ea c tin g c e n te r s .
h y p o th e sis
was
obtained
th ro u g h
p r e v en t
Information in su p p o rt o f th is
p eru sa l
of
th e
lite r a tu r e .
For
esterifica tio n reaction s o f 84, we fou n d no rep orted exam ples em ploying
2 ,2 -d isu b s titu te d acid h a lid e s, nor did we en cou n ter d isc u ssio n s of su c h .
B ecause 74 r e p r e se n ts a 2 ,2 -d isu b s titu te d acid h a lid e, we abandoned
attem pts to prep are 86 and elected to p u rsu e an a ltern a tiv e p ro ced u re,
em ploying S-p r o lin o l-d eriv ed am ides. As p r e v io u sly c it e d ,22 alkylations of
en olates
d eriv ed
from
S -p rolinol
(F ig u re
13)
p ro ceed
w ith
d ia ste r e o se le c tiv ity , y e t th e au x ilia ry is fa r le ss fu n ction alized than
h ig h
its
cam ph or-derived cou n terp a rts.
S-p rolin ol [88] and ( s ) - ( + ) - 2-m eth oxym ethylp yrrolid ine [91]
w ere p rep ared b y th e method of E nders57
and co-w ork ers (F igure 6 7 ).
64
F igure 67.
Preparation o f S-P rolinol and (S )-(+ )-2 - m e t h o x y m eth ylp yrro lid in e.
We th en fo cu sed our atten tion on th e preparation o f 92 (F igu re 6 8 ).
Treatm ent o f s-p ro lin o l w ith p yrid in e and 74, followed b y extraction
dilute HCl (to rem ove p y rid in e) afford ed cru de produ ct w hich
fo r o n ly h alf o f th e material balan ce.
w ith
accou nted .
65
ON - .
OH
H
88
Cl
0
OH
74
92
F igure 68.
Preparation o f 92.
Pure 92 was obtained b y silica g el chrom atography (CH2Cl2) in low
yield (c a . 20%).
E vans58
U n sa tisfied w ith th is p r o c ed u r e , we rev iew ed a rep ort b y
w hich rev ea led th e ease w ith w hich amides d eriv ed from
s-p ro lin o l are h y d ro ly zed in th e p r e se n c e o f aqueous acid (F igu re 6 9 ).
0
i+
R
0
H2
,N
)
R-CO2H
F igure 69. A cid -C atalyzed H yd rolysis o f S-ProUnol D erived
A m id es.
66
It was th en rationalized th at th e acidic conditions o f th e
ste p r esu lted in partial h y d ro ly sis o f th e d esired prod u ct
extraction
[92] w hich would
accou nt for th e lo w .y ie ld obtained.
An a ltern a tiv e preparation o f 92 was found in th e treatm ent o f 70
w ith
s-p r o lin o l,
in
th e
a b sen ce
o f so lv en t
(F ig u re
7 0 ).
Removal o f
methanol b y ev a p o ra tio n , u n d er dim inished p r e s s u r e , a ffo rd ed 92, as a
pale orange o il, in q u an titative y ie ld .
F igure 70.
A ltern ative Preparation o f 92.
A n alysis b y 13C NMR and capillary GC/MS rev ea led e sse n tia lly
p u re 92 as a 1:1 mixture, o f d ia stereo m ers.
The cru de p ro d u ct was th en
taken to th e n e x t ste p w ithout fu rth e r p u rification .
To te s t th e d ia ste r e o se le c tiv ity o f enolate a lk y la tio n , 92 was trea ted
w ith two eq u ivalen ts o f LDA, follow ed b y 1 .3 eq u iv a len ts o f m ethyliodide
(F igu re 7 1 ).
A n alysis o f th e cru d e p ro d u ct b y in teg ra ta b le
ind icated th e p r e se n c e o f polym eric m aterial.
13C NMR
A n a ly sis b y
capillary
GC/MS revealed sev e r a l b y -p r o d u c ts and two b aselin e sep a ra ted
p eak s,
c o n sisten t fo r 93(M"*"), in a ratio o f approxim ately 68:32.
B ased upon the
poor
of
d ia ste r e o se le c tiv ity
o b se r v e d ,
and
b y -p r o d u c ts , th is method was a b an d on ed .
p resen ce
inseparable
67
2LDA
F igure 71.
A lkylation o f 92.
We th en p rep ared th e analog 94 (F ig u re 72) u s in g , a p roced ure
similar to th at fo r 92.
A lkylation o f 94 was sm oothly e ffe c te d u s in g
and m eth yliod id e, (F ig u re 73) a ffo rd in g 93 in qu an titative y ie ld .
F igure 72.
Preparation o f 94.
LDA
68
F igure 73.
Once a g a in ,
55:45
A lkylation o f 94.
th e
r esu ltin g
(GC/MS and 13C NMR) .
diastereom er
ratio
was approxim ately
In view o f th e alm ost total lack o f
d ia ste r e o se le c tiv ity w ith [88] and [91] as th e chiral a u x ilia r ie s,
stu d ies
em ploying additional analogu es of S -p rolin ol seem ed u n w arran ted .
We concluded th at enolate
n -fa c ia l sh ield in g o ffer ed b y the chiral
au xiliaries s tu d ie d , is o ffse t b y unfavorable fo ld in g o f th e p yran r in g
toward th e n -fa c e op p osite th e chiral d ir e ctin g grou p .
We th en tu rn ed our atten tion tow ard D iels-A ld er h eterocycload d ition s
as a method fo r p rep a rin g chiral d ih y d r o -2 H -p y ra n s.
We b eg a n w ith th e
model chiral dienophile [96] in an attem pt to e ffe c t a D iels-A ld er
reaction w ith a heteroatom -containin g d ien e.
A cryloyl chloride was treated w ith e x c e s s p yrid in e and ( - ) -m enthol
affo rd in g [95] in 43% y ie ld (F igu re 7 4 ).
69
F igure 74.
Preparation of M enthyl A cry la te.
M enthyl acrylate was th en trea ted w ith a v a r ie ty o f Lewis acids
(A lC l3 , TiCl4 , SnCl4 , EtAlCl2) in dichlorom ethane, in th e p r e se n c e of
m eth ylvinyl k eton e (F ig u re 7 5 ).
F igure 75.
A ttem pted Preparation o f 96 b y Lewis A cid
C a ta ly sis.
Much to our disappointm ent, all attem pts to p repare [96] b y w ay of
Lewis acid ca ta ly sis failed to p rovid e a n y p ro d u ct.
V arious reaction
conditions w ere stu d ie d , h ow ever, each attem pt afford ed o n ly u n reacted
m enthyl a cry la te.
70
A s a fin al e ffo r t, we attem pted to e ffe c t a D iels-A ld er reaction
betw een m ethyl m ethacrylate and m eth ylvinyl ketone via ca ta ly sis w ith
E u (tfc )3 , (F ig u re 7 6 ), a chiral Lewis acid p r e v io u sly em ployed b y
D a n is h e fs k y .50
E u (tfc )3 , h ow ev er, fa iled to p rovid e a n y p ro d u ct.
F igure 76.
D isappointed
A ttem pted C ycloaddition C atalyzed b y E u'(tfc)3 .
w ith
th e
outcome
o f th is
s tu d y
we w ere str o n g ly
compelled to reevalu ate t h e .enolate alkylation w o rk . A lth ough both e s te r
and am id e-d erived chiral en olates w ere in v e s tig a te d , we had no
in su p p ort o f ste r e o se le c tiv e enolate form ation.
To fu r th e r
ev id en ce
probe (an d
p erh ap s s e ttle ) th is m atter we elected to rep eat th e enolization p roced ure
w hich o ffered th e h ig h e st d eg ree o f d ia stereo selectio n
(a lb eit 6 3 :3 7 ), and
trap th e enolate as a trim eth ylsilyl e th e r .
T hus [82] was deprotonated w ith LDA at -78°C and trea ted w ith
ch lorotrim eth ylsilan e.
Upon rotoryevap oration of th e so lv e n t, th e cru de
prod u ct m ixture was p a sse d th ro u g h a sh o rt column o f silica gel w ith
h e x a n e -e th y l acetate (1 0 :1 ) .
The r e su ltin g p rod u ct was q u ick ly tak en up in deuterochloroform and
an alyzed b y 13C NMR, rev ea lin g app roxim ately 15% u n rea cted [82] and a
complex s e t o f sig n a ls
in th e o lefin ic region
(145-100p p m ).
GC/MS
a n alysis rev ea led th ree major p ro d u cts (4 :1 :1 ) c o n sisten t w ith [82] and
two isom eric s ily l k eten e acetals d eriv ed from [82] (F ig u re 7 7 ).
O
OSi(CH3)3
T.
LDA ■
2. -TMSCI
OSKCHO
3 '3
Figure 77.
T he
data
A pparent N o n -S tereo selectiv e Enolization o f 82.
s tr o n g ly s u g g e s t th a t enolate formation is
n o n -ster e o
sele c tiv e w hich would accou nt fo r th e low d ia stereo selectio n o b serv ed in
th e alkylation p r o c e d u r e s .
It sh ou ld be noted th at th e app arent d iscrep a n cy ( 13C v s . GC/MS)
r eg a rd in g th e p rod u ct ratios is a ttrib u ted to partial h y d ro ly sis o f th e
se n sitiv e sily l e th e r s in in su ffic ie n tly dried so lv en t p rior to mass
sp ectra l a n a ly s is .
We tem porarily abandoned th e se e ffo r ts and tu rn ed our atten tion
tow ard ch elation -con trolled nucleophilic addition to 2-a c e ty l p y r a n s.
72
CHAPTER 4
STEREOSELECTIVE NUCLEOPHILIC ADDITIONS
R ecogn izin g
th e
need
fo r
d iastereofacial
d ifferen tia tio n
of th e
carb onyl of [2 8 ], we b eg a n our stu d ies b y a n a ly zin g p rev io u s work b y
Colonge e t . a l . 10 in w hich acrolein dim er, [5 8 ], was trea ted w ith.a number of
G rignard r e a g e n ts,
alcohols
(F igu re
affo rd in g v a r y in g m ixtures of ery th ro v s .
7 8 ).
th re e
S u b seq u en t treatm ent w ith acid afford ed
th e
b ic y c lic acetals [ 98a] and [ 98b] r e s p e c tiv e ly .
O
58
97a
97b
erythro
three
I
I
98a
98b
Figure 78. R eaction of A crolein Dimer w ith G rignard R eagen ts
In an in v e stig a tio n ex p lo rin g a p oten tial s te r e o se le c tiv e sy n th e s is
of
brevicom in14, Mundy o b serv ed a similar tren d in th e a d d itio n .o f G rignard
r ea g e n ts to [28] (F igu re 7 9 ).
73
To rationalize th e o b serv ed s te r e o se le c tiv ity , Colonge p o stu la ted a
mechanism b y w hich magnesium com plexation w ith b oth o x y g e n atoms of
[58]
fa cilita tes
facial
b ia sin g
of
th e
carb on yl,
r e su ltin g
in
th e
s te r e o se le c tiv e d e liv e r y o f th e n u cleo p h ile. F igure 80 illu str a te s C olonge's
prop osed interm ediate [1 0 0 ].
28
Figure 79.
Me
Me
99a
99b
Major
Minor
R eaction of M ethylvinyl Ketone Dimer w ith
G rignard R e a g e n ts.
H
Mg—HR
OEt
F igure 80.
Magnesium Complexation w ith A crolein Dimer.
74
In an attem pt to a p p ly th e chelation th eo ry to h y d rid e r e d u c tio n s,
M undy trea ted th e p yran interm ediates [28] and [101] w ith a v a r ie ty of
metal h yd rid e r ed u cin g a g e n ts .
The d eg ree of s te r e o se le c tiv ity varied
g r e a tly w ith rea g en t ty p e (F ig u re 8 1 ).
0
0
28
62a
62b
Reagent
exo
endo
L-Selectride
80
20
LiBH4
60
40
NaBH4 '
57
43
KBH4
49
51
LiAIH4
51
49
101
102a
1 02 b
LiBH4
65
35
NaBH4
55
45
KBH4
65
35
LiAIH4
51
49
Figure 81.
R eduction o f 2-A c e ty l and 2 -P rop ion yl-6 -M ethylD ihyd ro-2H -P yran w ith V arious R educing R ea g en ts.
75
In view o f th e se
r e s u lt s , we decid ed
to r e a s s e s s th e origin of
d ia ste r e o se le c tiv ity w ith r e sp e c t to th e various r ea g e n ts capacities fo r
chelation w ith su b s tr a te .
A review of th e litera tu re rev ea led work b y
K atzenellenbogen and B ow lus60 in w hich th e y stu d ied th e red u ction s of a
number of a-ke.tols w ith various aluminum h y d rid e
r e a g e n ts .
T h ey
concluded th at r ea g e n ts monomeric in so lu tio n , nam ely tr iiso b u ty laluminum, 61 p rovid ed th e g r e a te st d eg ree o f s e le c tiv ity , presum ably via a
cy clic tran sition s ta te .
K atzen ellen b ogen , as w ell as o th e r s , 62 ascrib e
variation s in d ia ste r e o se le c tiv ity to r ea g e n t agglom eration; in crea sed ste r ic
bu lk
a sso cia ted w ith th e a g g r eg a ted metal h y d rid e - carbonyl complex
r e su lts in
com petition betw een cy clic and dipolar tra n sitio n sta tes
(F igu re 8 2 ).
M+
“0
HO
O
RsA
OH
^CH3
r L
104
Cyclic
erythro
103
HO
•
■
OH
R5 - V h T ch
Rl H
Dipolar '
1 05
t h re e
F igure 82. C yclic and Dipolar T ran sition States in a-K etol
R ed u ctio n s.
76
In lig h t of th e se o b se r v a tio n s, we e lected to em ploy tr iiso b u ty l
aluminum (T IBA ) and diisobutylalum inum h y d rid e (D IB A H ), a rep o rted ly
b u lk ier tr im e r .63 K atzenellenbogen em ployed a th ree fold molar e x c e s s
TIBA and DIBAH in
th e a -k eto l r ed u c tio n s,
r e a c tiv ity o f th e a -h y d r o x y l fu n ctio n a lity .
of
presum ably due to th e
In th e a b sen ce of h y d ro x y l
in teraction s w ith aluminum, we trea ted m ethyl v in y l k eton e dim er, [2 8 ],
w ith 1 .1 eq u ivalen ts o f TIBA (in to lu en e) and 1 .2 eq u iv a len ts of DIBAH
(in CH2Cl2) at -78°C r e s p e c tiv e ly .
The reaction tem p erature, in each
c a se ,
1 .5
was maintained at -7 8 ° C fo r
h ou rs,
a fter w hich time th e
solu tion s w ere allowed to slow ly warm to 2 0 °C o v e rn ig h t.
cyclization afford ed th e d esired k e ta ls , in good
c o n siste n tly h ig h er th an th o se obtained b y th e
Table
I.
It
sh ou ld
t r i- secbutylborohydride® 4
ste r e o se le c tiv ity
80:20.
be
noted
th at
A cid catalyzed
y ie ld , in e x o :endo ratios
agglom erating r ea g en ts
red u ction
w ith
lithium
(L -S electrid e) also p roceed ed w ith
sig n ifica n t
p ro v id in g th e d esired k eta ls in an e x o :endo ratio of
C onsidering facial b ia sin g due to p y ra n r in g p u ck er in g , th ese data
appear c o n sisten t w ith a
dipolar mechanism
(F igu re 8 3 ).
H-
62a.
F igure 83.
H ydride R eduction v ia Dipolar Mechanism.
77
H aving obtained
agglom eration
vs.
e x te n s iv e
in sig h t in to
d ia ste r e o se le c tiv ity
th e
w ith
nature of rea g en t
th e
2 -a c y l-s u b stitu te d
d ih yd ro-2H -p yran sy ste m , we fe lt th at our data w ere in accord w ith th e
con clu sion s drawn b y th e K atzenellenbogen g ro u p .
H ow ever, th e ab sen ce
of h y d ro x y l fu n ctio n a lity in [28] p reclu d ed th e interm ediacy of alkoxide
formation (F igu re 82) p rior to d e liv e r y of h y d rid e.
We w ere th en compelled to reev a lu a te th e role of electron ic in te r
action s in th e red u ctio n s of [2 8 ].
(F igu re
Two models w ere d ev elo p ed ,
84) fo c u sin g on the rotational p referen ce of th e a cety l m oiety.
H
107
108
Cyclic
Dipolar
F igure 84. P lausible Models fo r th e R eduction o f 28
78
The chelation model [ 107] , analogous to C olonge's prop osed in te r ­
m ediate,
illu str a te s
encum bered
th e
"top" face
p referen tia l
d e liv e r y of h y d rid e
o f the ca rb o n y l.
to the le ss
S u b seq u en t acid catalyzed
cyclization would r e su lt in th e formation of th e en d o -s u b stitu te d ketal
62b .
On th e o th er h an d , red uction via th e dipolar model [ 108] , followed
b y cyclization would r e su lt in th e formation of th e e x o -isom er, 62a.
A n alysis o f D reid ing models o f 2 -a c e ty l-6 -m eth y l-d ih y d ro -2 H -p y r a n , [2 8 ] ,
revealed th e "bottom" facial encum brance o f th e ca rb o n y l, in each model,
due to
To
p u ck er in g of th e pyran r in g . '
a s s is t
our
evaluation
of
th is
matter
we
e lec te d
to
obtain
inform ation r eg a r d in g th e rotational p r eferen ce of th e 2-a c e ty l group of
28. We rationalized th at d ip ole-d ip ole in teraction in v o lv in g th e
carbonyl
and th e r in g o x y g e n would be d ep en d en t upon th e e x te n t to w hich
th e
lone pair electro n s of th e r in g o x y g e n are delocalized .
We th en em ployed th e sem iem pirical molecular orbital program MNDO
(M odified N eglect o f Diatomic O verlap) d eveloped b y D ew a r.65
The data
indicate th at th e p r e fe rr ed ground sta te rotational isom er is that w hich
d irects th e carb onyl dipole fa r th est from the rin g o x y g e n , (F igure 85).
T his s u g g e ste d th at th e interm ediacy o f th e cy clic tra n sitio n sta te [ 107]
is d ep en d en t upon th e ch elatin g a b ility of th e red u cin g r ea g en t.
79
Figure 85.
C om puter-D raw ing of 2 -A c e ty l-6 -M e th y l-3 ,4 -D ih y d ro 2H -P yran.
80
A lthough experim ental r e su lts (F ig u re 81) fa v o r th e dipolar Model,
an ab solu te conclusion as su c h seem ed g r e a tly u n w arranted.
Chelation
con trol, a well docum ented phenom enon, 66 has h isto rica lly been p u r e ly
sp e c u la tiv e , ow ing to a p a u city o f d irect sp ectro sco p ic ev id en ce p ro b in g
th e
s tr u c tu r e s
of p u ta tiv e
concern to our e ffo r ts
interm ediates
in
so lu tio n .
Of additional
was th e realization th at s u c c e s sfu l chelation -
controlled p r o c e sse s trad ition ally h ave b een confined to a cy clic sy ste m s.
A recen t rep ort b y Keck and C astellino22 offered th e fir s t
s p e c t r o s c o p ic
d iastereo selectio n
ev id e n c e
in
su p p o rtin g
nucleophilic
th e
addition
stru ctu ra l
to
J3-alkoxy
available
sou rce
of
a ld e h y d es.
A lthough th eir s tu d y concerned acyclic stereochem ical control (F igu re 86)
application of th e tech n iq u e to pyran [28] show ed considerab le
F igure 86.
Titanium IV Chloride Complexes w ith B -A lkoxy
A ld e h y d e s.
prom ise.
81
R eflectin g
on
our
r e su lts
w ith
C olonge's p o stu la ted interm ediate
G rignard
add ition s
(F ig u re 8 0 ),
r elev a n t Lewis acid fo r com plexation w ith [2 8 ].
to
[28]
and
we ch ose MgBr2 as a
Two p la u sib le com plexes
w ere en v ision ed (F igu re 85) in w hich th e carbonyl of [28] might chelate
w ith MgBr2 .
Br
Ml I I
OEt2
Br — Mg
Br
Mg— Br
OEt2
I 10
109
F igure 87.
MgBr2 Complexes w ith 2 8 .
M ethylvinyl Ketone dim er, [2 8 ], was trea ted w ith M gBr2 -E t2O at 0°C
in
CDCl3
and
a
sample
of
the
r e su ltin g
in trod u ced into th e NMR sp ectro m eter.
solution
was
immediately
Variable tem perature 1H NMR
sp e ctra w ere record ed at +10°, -1 0 ° , -30° and -50°C r e s p e c tiv e ly (F ig u re
88).
82
Br
OEt
A ___ K
4 .0
F igure 88.
3.0
1H NMR Spectra fo r 2 8 -MgBr2
2 . 0 (ppm)
83
The data clea rly in d icate th e formation of a com plex as evid en ced
b y th e sig n ifica n t ch an ge in chemical s h ift of e v e r y sig n a l r e p re sen tin g
s u b s tr a te .
N otew orthy are th e sig n a ls a t ca . 3 .6 ppm and 0 .8 ppm w hich
are due to e th e r and may r ep re sen t a v e ra g in g betw een fr e e and com plexed
s p e c ie s . 68
The sig n ifica n t dow nfield s h iftin g o f th e en tire spectrum fo r th e
com plex,
w ith r e sp e c t to uncom plexed 28, a rg u es in fa v o r th e cy clic
interm ediate c h e la te , [ 109] .
Of p articular sig n ifica n ce is th e change
th e cou p lin g p a tte rn s of th e r in g p roton s (th e broad m ultiplet
in
betw een
th e two m ethyl sig n a ls) th rou gh ou t th e tem peratures s tu d ie d .
It appears
th at w ith coolin g, conform ational flip p in g o f th e p y ra n r in g
(F igu re 89)
is in h ib ite d .
It should b e noted th a t a control stu d y w ith
2 8 , condu cted over th e same tem perature r a n g e , rev ea led
ch an ges in chemical s h ifts or coupling p a tte r n s.
F igure 89.
Conformational F lippin g o f Pyran [2 8 ].
uncom plexed
e sse n tia lly no
84
It seem s reasonab le to assum e th a t analogous to uncom plexed 28, th e
formation of th e
dipolar com plex,
[ 110] ,
would r e su lt in un inh ibited
conform ational flip p in g and a tem p eratu re-in d ep en d en t 1H NMR sp ectru m .
A D reid ing model o f 28 ind icated a p r eferen ce fo r p seu d o -eq u a to ria l
p o sitio n in g o f th e 2-a c e ty l su b stitu e n t.
th e cy clic com plex,
A rg u in g once again in fa v o r of
[ 108] , a Lewis acid com plexed or teth ered betw een
th e two o x y g e n s would in h ib it th e r in g o x y g e n from p a s s in g th ro u g h th e
plane of th e r in g v ia a conformational flo p , r e su ltin g in a sem i-rigid
com plex e x h ib itin g a tem perature - d ep en d en t 1H spectru m .
With
sp ectra l
ev id en ce
str o n g ly
su p p o rtin g
a
sem i-rigid
cy clic
com plex, we e lected to tr e a t th e interm ediate chelate w ith a v a r iety of
G rignard and metal h yd rid e red u cin g r e a g e n ts.
M ethylvinyl keton e dimer
was ex p o sed to MgBr2 -E t2O at -78°C fo r tw en ty to th ir ty m inutes, in
variou s so lv en t s y s te m s , prior to ex p o su re to n u cleop h iles and su b seq u en t
acid
catalyzed
cyclization .
s tu d y ,
com paring
nu cleoph ilic addition to 28 in th e p r e se n c e and a b sen ce o f
MgBr2 , are
summarized in Table I .
em ploying DIBAH.
The
r e s u lts
of th is
One anomaly was o b se rv e d in th e
red u ction s
The n ea rly complete r e v e r sa l in s te r e o -s e le c tiv ity is an
enigma for w hich we o ffer no rationale.
Table I .
O bserved S tereoselectivities in Reductions of 28 and 28-MgBr2 .
I. Reduction
28
Reagent
Solvent
I.Reduction
>
2, Cyclization
62a : 62b
78
Solvent
THF
49
51
THF
NaBHj
4
THF
57
43
—
LiBH,
4
THF
60
40
LiAlHj
4
THF
51
49
68
32
DIBAH
CH2C12
X.
2.Cyclization
KBH,
4
MrtRr
Toluene/THF(3:1)
61
39
—
61
39
—
——
CH^Cl,
37
63
—
TIBA
Toluene
83
17
Toluene
79.6
20.4
L-Selectride
Toluene
80
20
Toluene
7»
21
LTBA
Toluene/THF(4:3)
57
43
THF
3
i-PrMgCl
Toluene
89
11
Toluene
94 .
6
PhMgBr
Toluene
75
25
Toluene
93
7
97
I
86
D ia ste re o se le ctiv ity enhancem ent, due to com plexation w ith MgBr2 ,
was g en era lly m odest.
Two notable ex cep tio n s w ere o b s e r v e d .
phenylm agnesium bromide th e e x o : endo ratio of
93 :7 .
75:25 was im proved to
E ven more dramatic was th e enhancem ent o b se rv e d w ith lithium
tr i-ter t-b u to x y a lu m in o h y d r id e .
was
With
ch anged to 3 :9 7 .
in tr ig u in g .
In th is ca se th e e x o :endo ratio of 57:43
The extrem e r e v e r sa l in s e le c tiv ity was in d eed
C onsidering th e tren d
tow ard e x o -su b stitu tio n
w ith the
variou s red u cin g r ea g e n ts stu d ie d , we concluded th at agglom eration of all
th e red u cin g r ea g e n ts ( o th er than LTBAH) r e su lts in com petition betw een
th e cy clic and dipolar m echanism s.
R eflectin g
on
K atzenellenbogen1s
a -k eto l
red u ctio n s
we
w ere
compelled to make u s e of th e r in g -o p en in g p ro d u ct, 113, w hich r e su lts
from treatm ent of 28 w ith aqueous acid (F ig u re 9 0 ).
F igure 90.
A cid C atalyzed R ing O pening of 28.
S u cc e ssfu l application of 113 to th e preparation o f the b icy clic
ketb ls [ 62a] and [ 62b ] relied on th e r e g io se lec tiv e red u ction of th e 2carbonyl carbon (F igu re 9 1 ).
In th e e v e n t of p r eferen tia l red uction of
th e 7-c a r b o n y l, th e r e su ltin g a lk o x id e, [ 114] , would p reclu d e b icy clic k eta l
form ation.
87
The diketone [ 113] was trea ted w ith a number of r ed u cin g r e a g e n ts,
in
th e
ab sen ce
and
p r e se n c e
cyclization (F igu re 9 2 ).
of MgBr2 ,
followed b y acid catalyzed
In each red u ctio n , th e fo rtu ito u s detection of
k eta ls [ 62a] and [ 62b ] was prom ising as no b y -p r o d u c ts r esu ltin g from
red u ction of th e num ber 7 carbonyl w ere o b se r v e d .
T he red u ction s w ere
g en era lly h ig h in y ie ld w ith u n reacted sta r tin g dione [ 113] r esu ltin g in
some c a se s .
0
Undesired
Desired
115
Figure 91.
I 13
R equired R egioselection in H ydride R eductions
of 113.
I 16
2 7
Figure 92.
Ketal Preparation from Dione [ 113].
.
88
In
th e
ab sen ce
r eg io se lec tio n ,
of
b y -p r o d u c ts
r esu ltin g
from
u n d esired
nam ely 2 ,7 -d io l or 2 ,3 ,7 - t r io l, th e reaction app ears to
p roceed predom inantly v ia th e cy clic model o rig in a lly p rop osed b y Cram .63
Two
sig n ifica n t
w arrant d isc u ssio n .
fa cto rs
su p p o rtin g
th is
mechanism
If th e initial ste p of th e reaction in v o lv es
form ation, it seem s lik e ly th at th e cy clic tran sition sta te
ch elation , activate th e carb onyl at th e 2-p o sitio n ,
su sce p tib le to h y d rid e a tta ck , w ith r e s p e c t to th e
at p o sitio n -7 .
(F igu re
C o n v ersely , interm ediacy of th e
would r e s u lt in b oth carb onyls u n a ctiv a ted and
93)
alkoxide
w ould, th ro u g h
ren d erin g it more
uncom plexed carbonyl
dipolar tran sition sta te
eq u a lly su scep tib le to
attack b y h y d rid e.
M
Cyclic
F igure 93.
Dipolar
C yclic and Dipolar T ran sition S tates fo r H ydride
R eduction of Dione 113.
A lthough th e red u ction s of dione [113] afford ed th e d esired k eta ls
[ 62a] and [6 2 b ], th e d eg ree o f ste r e o se le c tiv ity was again moderate
(T able 2 ).
Table 2.
113
113 MgBr2
a)
b)
c)
O bserved Stereoselectivities in Hydride Reductions of 113.
Reagent
Solvent
TIBA
Toluene
-78°
I. 5h
55
45
66
DIBAH
Toluene
-78°
2h
54
46
42
LTBA
THF
-78°
2h
17
83
41
NaBH(OAc)3
THF
20°
IOh
40
60
SI3
NaBH(OAc) 3
THF/HOAc(5:1)
20°
IOh
40
60
32b
NaBH(OAc) 3
CH3CN
-40°
Ih
43
57
48
TIBA
Toluene
-78°
1.5h
79
21
60
TIBA
THF
-78°
2h
30
70
84C
DIBAH
THF
-78°
2h
44
56
53
TBA
THF
-78°
2h
33.5
66.5
60
Temperature (0C)
Time
Represents 75% of product mixture which contained 25% unreacted
Represents isolated yield.
Solvent evaporation carried out at O0C.
62a : 62b
(
113 )
%Yield (Crude)
90
T u rn in g once again to th e lite r a tu r e , we fou nd work b y Evans and
co-w ork ers 70 in w hich th e y em ployed ammonium tria ceto x y -b o ro h y d rid e in
th e
red u ction s
d ia ste r eo se lec tiv e
of
13-h y d r o x y
y ie ld s .
k eto n es
The au th ors
a ffo rd in g
1 ,3 -d io ls
s u g g e s t th at th e
in
h ig h
6 -h y d r o x y l
fu n ction d ir e cts th e r ed u cin g rea g en t to th e s y n -fa c e o f th e carb on yl,
r esu ltin g in th e form ation o f a tra n s 1 ,3 -d io l.
In an e ffo r t to a p p ly th is tech n iq u e to our
a -h y d r o x y l sy ste m ,
dione [ 113] was trea ted w ith sodium tria ceto x y b o ro h y d rid e in various molar
ratios and so lv en t sy ste m s.
U n fo rtu n a tely , th e rea g en t fa iled to p rovid e
sig n ifica n t s te r e o se le c tiv ity (T able 2 ).
H aving exp lored th e ste r e o se le c tiv ity o f nu cleoph ilic additions to
th e 2 -a c y l- dih ydro - 2H-p y ra n s and 3 -h y d r o x y -2 , 6 -o cta n ed io n e, we e lected
to te s t one additional
sy stem .
From a p rev io u s s tu d y
in v o lv in g th e
sy n th e s is o f 7 , 7 -d im e th y l-6 , 8 -d io x o b ic y c lo [3 . 2 . 1 ]o c ta n e , [ 6 ] , we realized
th at th e acetals [ 72a] and [ 72b] could be clean ly co n v erted to produ ct via
th e addition o f m ethyllithium follow ed b y su b seq u en t acid
cyclization .
catalyzed
C onversion o f the acetals to the b icy clic sy stem su g g e ste d
th at an analogous k etal system would work as well (F ig u re 9 4 ).
91
CH3
CH3
6
72a
Figure 94.
C onversion of Isom eric E ster A cetals to 7 ,7 D im eth yl-6 ,8 -D ioxab icyclo [ 3 .2 .1 ] o c ta n e . ’
We th en en vision ed
th e preparation o f k eta ls [ 119a] and [119b] b y
r ea c tin g m eth ylvin yl k eton e dimer w ith methanol (F ig u re 95) and te s tin g
th eir p oten tial s te r e o se le c tiv e con version to b icy clic k e ta ls.
F igure 95.
Preparation of B icyclic K etals from M onocyclic
K etals D erived from M ethylvinyl Ketone Dimer.
I
92
Treatm ent o f 28 w ith e x c e s s methanol in th e p r e se n c e o f Dowex 50WX8 cation ex ch a n g e r esin followed b y
afford ed o n ly one isom er.
d istillation o f th e cru d e p r o d u c t,
T his was presum ed to be th e anomeric prod u ct
[119a].
Rationale fo r th is str u c tu r e was b ased on th e reason ab ly-assu m ed
equatorial p o sitio n in g o f th e 2-a c e ty l and 6-m eth yl s u b s titu e n ts , and ,
to the anom eric e ffe c t,
due
p referen tia l axial p o sitio n in g of, th e 6 -alk oxyl
s u b s titu e n t.
Sp ectroscop ic ev id en ce in su p p o rt of the a ssig n e d str u c tu r e fo r
119a was obtained via 1H NMR a n a ly sis.
NOE experim en ts (T able 3)
revealed a sig n ifica n t enhancem ent in th e sig n a l fo r Ha (4.0p pm ) upon
irradiation o f th e m ethoxyl sign a l (3 .2 0 p p m ), in d ica tin g a r ela tiv ely close
th ro u g h -sp a c e
relation sh ip
betw een
th e
two
grou p s
(F ig u re
9 6 ).
Irradiation o f th e k etal m ethyl sig n a l had no app arent a ffe c t on the
sig n a l for Ha .
I . 3 3 ppm H3 C
Figure 96.
Table 3.
1H NMR R esonances fo r 119a.
O bserved NOE Induced Enhancement of Ha Irradiated
Signal (ppm)
%Enhancement o f Ha .
3.20
5 .2
1.33
O
93
We th en stu d ied th e ste r e o se le c tiv ity o f h y d rid e red u ction o f 119a
w ith variou s metal h yd rid e r e a g e n ts .
p rev io u s reaction
Ketal [ 119a] was su b jected to th e
conditions in th e p r e se n c e and a b sen ce of MgBr2 ,
follow ed b y acid catalyzed cyclization to th e co rresp o n d in g b icy clic k eta ls
(F igu re
9 7 ).
T able 4 show s th e e x o :endo ratios o b se rv e d via GLC
in tegration of peak a r e a s .
119a
H3C
CH3
F igure 97.
B icy clic Ketal Preparation from 119a.
The data ind icate a tren d tow ard en d o-m ethyl su b stitu tio n in th e
p rod u ct k eta ls [ 62a] and [ 62b] .
w ith DIBAH.
One u n exp lain ed anomaly was o b se rv e d •
Of p articu lar in te r e st was th e rep eated "higher"
w ith LTBA as was o b se rv e d in th e red u ctio n s of 28 and 113.
s e le c tiv ity
Table 4.
28a
Reaqent
TIBA
O bserved Stereoselectivities in Hydride Reductions of 28a.
Solvent
Toluene
DIBAH
LTBA
28a 'MqBr
62a : 62b
Bxieid (Crude)
4h
34.7
65.3
26
CH2C12
-78°
2h
32.7
67.3
60
Toluene
-78°
4h
61.4
38.6
80
-78°
2h
10
90
21
-78°
2h
11.4
88.6
44
0°
3h
-78°
3h
28.3
71.7
66
-78°
3h
50
50
42
THF
THF
NaBH(OAc) 3
CH3N/HOAc (6:1)
TIBA
THF
LTBA
Time
-78°
TIBA
DIBAH
Temperature(°C)
THF
No Rxn
95
To rationalize
th e
o b serv ed
ste r e o se le c tio n ,
we fo cu sed
on two
im portant fa c to r s ; carb onyl facial b ia sin g o ffered b y th e conformational
fe a tu re s o f the p y ra n r in g , and th e rotational p r eferen ce of th e 2-a c e ty l
grou p .
A n alysis
of
D reid in g
hindrance of th e carb onyl
models
of
119a
ind icate
sig n ifica n t
ste r ic
n -fa c e op p osite Ha in both cy clic [120] and
dipolar [121] models (F igu re 9 8 ).
f
Favored
"""0
/
-H
CH3
y
-V-oY x
-H
0
CH3
120
121
Cyclic
Dipolar
F igure 98.
Favored
S teric H indrance O ffered b y Pyran R in g.
A nalogous to red u ction s of 28, carb onyl red u ction s of 119a appear to
follow a related p a ttern o f ste r e o se le c tiv e b icy clic k eta l form ation.
For
each s u b s tr a te , attack b y h yd rid e to th e le s s encum bered n -fa c e of
th e
carbonyl via th e cy clic tran sition s ta te , [122] will r e su lt in
th e en d o-m eth yl isom er [6 2 b ].
C o n v ersely , the
cyclization to
interm ediacy o f th e d i­
polar model [123] fa v o rs formation of th e ex o -m eth y l isom er [ 62a]
(F igu re 9 9 ).
96
123
62a
Dipolar
Figure 99.
On
th e
C yclic and Dipolar T ran sition State Rationale
fo r S tereo selectiv e B icy clic Ketal Formation.
b a sis
of
ste r ic
a rg u m en ts,
one
would
p red ict
h ig h
s te r e o s e le c tiv ity , should h yd rid e red u ction p roceed so le ly b y w ay of one
o f th e two p o ssib le models (F igu re 9 9 ).
th en
be
rationalized
by
com petition
The o b serv ed variation s m ight
betw een
th e
cy clic
and
dipolar
tran sition s t a t e s .
To fu rth e r probe th is m atter, we so u g h t to q u a n tita tiv ely a s s e s s
rotational p r eferen ce of th e 2-a c e ty l group o f 119a.
th e sem iem perical m olecular orbital program MNDO.
We again
th e
em ployed
97
As we had a n ticip a ted , the p referred g ro u n d -sta te rotational isomer
p roved to be that w hich d irects th e carbonyl dipole fa r th est from the
p yran o x y g e n atom (F igu re 100).
In
lig h t
com petition
of
th e se
betw een
stu d ies
cy clic
and
it
seem s
dipolar
reasonable
models
to
e x is ts
assum e
and
is
that
qu ite
d ep en d en t upon reaction conditions and rea g en t agglom eration.
Figure 100.
Computer Drawing of 5-M eth y l-5 -M eth o x y -2 -A cety lT etra h y d ro p y ra n .
I
98
CHAPTER 5
SUMMARY
T his work has p rovid ed a w ealth o f inform ation reg a r d in g the scop e
and
lim itations
of
ste r e o se le c tiv e ly
m odifying
2-c a r b o n y l-su b stitu te d
dihydro p yran d e r iv a tiv e s . T hrough iso to p ic lab elin g s t u d ie s , th e tandem
solvom ercuration- dem ercuration
protocol
has
been
show n
to
be
non -
s te r e o se le c tiv e w ith r e sp e c t to C-7 su b stitu tio n in th e p rod u ct b icy clic
k e ta ls .
S everal p rev io u s d ifficu lties w ith b y -p r o d u c t contam ination
preparation of 2-a c y l and 2-carb oalk oxy p y ra n s
The
su c c e s sfu l
s y n th e s is
of
in th e
have b een circum ven ted.
3 , 4 -d ih y d r o -2 H -p y r a n -2 -ca r b o x y lic
chloride p ro v id es a v e rsa tile interm ediate suitab le
acid
fo r a w ide v a r iety
of
chemical .m od ification s.
The lim itations o f asym m etric alkylation of chiral lithium enolates
d erived
from
em ploying
2 -c a r b o x y l-3 , 4 -d ih y d ro -2 H -p y ra n s
e ste r
and
amide
fu n ction alized
has
chiral
b een
esta b lish ed
a u x ilia ries.
N on-
ste r e o se le c tiv e en olization , stu d ied b y enolate tra p p in g , was shown to be
th e major factor w hich d efeats asym m etric ind uction .
S ign ifican t p r o g r e ss was made tow ard gain in g a fundam ental u n d er­
sta n d in g o f th e m echanistic in trica cies o f chelation - controlled
addition to 2 -a c y l-d ih y d r o pyran d e r iv a tiv e s.
MNDO
em ployed to show th at in th e ab sen ce o f Lewis a c id s,
nucleophilic
calculations w ere
2-a c e ty l-s u b stitu te d
99
p y ra n s
s tr o n g ly
fa v o r
dipolar
red u ction
m echanism s.
A variable
tem perature 1H NMR s tu d y was u se d to o b serv e th e formation of
ch elate
betw een
m eth ylvin yl
e th e r a te .
k eton e
dimer
and
magnesium
a 1:1
bromide
.
T his experim ent o ffered valuable in sig h t con cern in g th e electron
don ating a b ility of th e r in g o x y g e n a s w ell as th e tem perature depend en t
r ig id ity of th e com plex.
Magnesium bromide com plexation was applied to G rignard and metal
h yd rid e red u ction s o f m eth ylvinyl k eton e dim er, r e s u ltin g , in some c a s e s ,
in 80-94% d ia ste r e o se le c tio n .
The chelation th e o r y was also applied to an unsym m etrical h y d r o x y d ik eton e,
r e d u c tio n s.
r e su ltin g
in
e sse n tia lly
100%
reg io selectio n
in
h y d rid e
100
-•
CHAPTER SIX
EXPERIMENTAL
Carbon
record ed on
and
variab le-tem p eratu re
proton
NMR
sp ectra
w ere
a B ru k er 250 MHz spectrom eter eq u ip p ed w ith a liquid
n itrogen VT u n it and an A sp ect 2000 data p r o c e ssin g sy ste m .
Spectra
w ere obtained u s in g
deuterochloroform a s so lv en t and chemical sh ifts
are rep orted in ppm
w ith r eferen ce to TMS.
Mass sp e ctra l a n alyses
w ere condu cted on a VG
MMI6 sp ectrom eter in terfa ced w ith a Varian
3700 gas chrom atograph
equip ped w ith a 30m D B -I cap illary colum n.
A ccurate
mass
sp ectrom eter.
h exan e
w ere
m easurem ents
w ere
made
A nh ydrous THE, b e n z e n e ,
obtained
by
distillation
on
from calcium h y d rid e.
from
oth erw ise
n o ted ,
atm osphere of a r g o n .
all
rea ctio n s
7070
mass
benzoph en one k e t y l.
and HMPA w ere
Dichlorom ethane was
P 2Os and th ion ylch lorid e was d istilled
U n less
VG
to lu en e, d ie th y l e th er and
TMSCl, diisopropylam ine, trieth ylam in e, p y r id in e ,
d istilled
a
d istilled from
from trip h en y l p h o sp h in e.
w ere
con d u cted
in
an
101
Preparation o f 2 -A cety l-6 -M eth y l-3 ,4 -D ih y d ro -2 H -P y ra n [281.
M ethylvinyl k eton e ( 105mL, 8 8 .2g) was heated to 175°C in an
a u to cla v e ,
for two h o u r s . Evaporation o f un reacted sta r tin g m aterial,
followed b y distillation of th e crude p rod u ct (6 5 -7 0 °C , a sp ) afforded
5 0 .Gg (5Y.4%) o f p u re p rod u ct (G L C ).
IH NMR:
I 3C NMR:
4.53
t
IH
4.2Y
dd
IH
2.25
s
3H
1.9Y
m
4H
1.Y9
s
3H
2 0 9 .6 (p p m ), 1 4 9 .6 , 9 2 .6 , 8001, 2 5 .9 , 2 3 .3 ,
1 9 .9 , 18.9
SOGO(Cnrx) , 2960, 1Y24, 16Y5, 1440, 1390,
1365, 1280, 1240, 11Y0, 1108, 10Y5, 920
IR:
MS:
HO(M+) , 9Y, 69, 55, 43, 41
Preparation of 2-Iso p ro p en y l-6 -M e th y l-3 , 4-D ih yd ro-2H -P yran [2 1 ].
To 9 . Sg o f m ethyltriphenylphosphonium bromide (2Y.4mmol) in
120mL o f anh yd rou s THF at O0C was added 1 1 .OmL o f a 2 . SM solution
(h ex a n e) o f
n -b u tyllith iu m .
A fter 30 m inutes, m eth ylvin yl ketone
dimer (3 .6 1 g ,
2 5 .Ymmol) was added at 20°C .
fo r 12 h o u rs,
a fter w hich time th e p recip ita te was filte r e d (su ctio n )
and w ashed w ith
red u ced p r e ssu r e
5OmL o f Et2O.
The reaction was stirred
The filtra te was con cen trated un der
(a sp ) and th e cru d e produ ct d istilled (35-45°C ,
0 .3 to r r ) a ffo rd in g 1 .6 6 g
(46.6%) o f a colorless liq u id .
GC/MS show ed one p ro d u ct.
A n alysis b y
102
[21] (co n t'd )
IH NMR:
4.83(p pm )
S
IH
4.72
S
IH
4.31
brS
IH
4.06
dd
IH
1.96
m
2H
1.71
S
3H
1.69
S
3H
1.67
m
2H
13C NMR: 1 5 0 .6 (p p m ), 1 4 4 .9 , 1 1 .3 , 9 5 .0 , 7 8 .4 , 2 6 .3 , 2 0 .4 ,
2 0 .0 , 18.6
IR:
3 0 7 0 (c m -i), 2920, 1680, 1440, 1390, 1245,
1170, 1075, 1055, 900
MS:
ISS(M+) , 134, 119, 95, 91, 79, 77, 68, 67, 53,
43, 41
Solvom ercuration/D em ercuration o f 2-A c e ty l-6-M eth y l-3 ,4 D ihyd ro-2H -P yran [2 8 ].
To 1 .1 4 g m ercuric acetate (3.58m mol) in 20mL THF at O0C was
added
0.3mL m ethanol, followed b y a solution of 0 .5 0 g dim er, [2 8 ], in
2 .OmL THF.
an
S tirrin g was contin ued fo r 30 m inutes, a fte r w hich time
additional ISmL of methanol was add ed to a s s is t th e dissolu tion of
m ercuric a c eta te.
A fter 30 m inutes th e so lv en ts w ere rem oved b y
rotoryevap oration a ffo rd in g a p a le-y ello w sem isolid.
A n alysis
p rese n c e o f
o f th e
crude p rod u ct b y
13C NMR ind icated the
two isom eric k e to n es, ( c a . l : l ) along w ith approxim ately
10-15% sta r tin g
m aterial, [2 8 ].
103
The
rem ove
cru de
sem isolid
u n reacted
d ecan ted .
was
m ethyl v in y l
w ashed
w ith
k eton e
1:1
dim er,
Et2O : H exan e, to
and
th e
so lv en ts
D ry in g o f th e cru de p rod u ct b y rotoryevap oration afforded
approxim ately 615mg
cru d e prod u ct w hich was taken d ir e c tly to the
n e x t s te p .
B orohydride R eductions o f 6-M eth y l-6 M eth o x y -5 -(A c eto x y m ercurial) - 2 - A c e ty l-tetra h y d ro p y ra n w ith NaBH4 and LiBHa.
To 307mg o f th e cru d e organom ercurial in IOmL o f THFZH2O (9 :1 )
was
added
darkened
40.5m g NaBH4 w ith s tir r in g .
im m ediately and was s tir r e d an additional 30 m in u tes,
followed b y
carefu l q u en ch in g w ith 5 . OmL 15% HCl.
added and th e
m ixture was allowed to
combined p h a se s w ere
sep a ra ted .
The reaction m ixture
stan d o v e r n ig h t.
The
p a sse d th ro u g h a pad of Hyflo Su per Cel and
The aqueous
la y er was ex tra cted w ith Et2O and th e
combined organ ics w ere w ashed w ith
over Na2SO4 .
Et2O (ISmL) was
bicarb on ate, b rin e and dried
A n alysis b y GC/MS show ed two p ro d u cts id en tified as
62a and 62b (6 0 :4 0 ).
The red u ction p roced u re was rep eated w ith LiBH4 a fford in g
iden tical
r e s u lt s .
[6 2a]iH NMR:
MS:
4.16(p p m )
q
IH
4.03
bs
1 .9 6 -1 .4 3
m
6H
1.42
S
3H
1 .1
d (J = 6 .1 5 )
3H
x .
IH
142(M +), 114, 100, 98, 72, 71, 67, 55, 43, 41
104
[6 2 b ]iH NMR:
MS:
4 .2 5 -4 .1 5
m
2H
2 .1 0 -1 .5 5
m
6H
1.46
S
3H
1.35
d (J= 6.15)
3H
142(M +), 114, 100, 98, 83, 72, 71, 55, 49, 43,
41
Preparation of 4-D eu terio -5 -D eu terio -7 -M eth y l
D ioxabicyclo [ 3 . 2 . 11 octane F68a and 6 8 b ].
M ercuric acetate (914m g, 2.87mmol) was stir re d in 2 . OmL w ater,
followed b y 4 . OmL TH F.
diene
To th e r e su ltin g yellow solu tion was added
[21] (180m g, l.SOmmol) in I . OmL THF, at 23°C .
was stir re d
T he reaction
at 23°C for 30 m in utes, a fter w hich time a solution
con tain in g 55mg
NaBD4 in I . OmL 5% NaOH was a d d ed .
A fter 30
m inutes, th e u su al w orkup was carried out (filtra tio n / e x tr a ctio n ) and
cru de p rod u ct (123m g) was
taken up in 5 . OmL h exan e and stirred
o v ern ig h t w ith 0 .5 g 4A molecular
a c id .
s ie v e s and 20mg p - to lu en esu lfon ic
The m ixture was th en filte r e d , con d en sed and chrom atographed
over SiO2 (10:1 h e x a n e :CH2Cl2) a ffo rd in g
liq u id .
96.3 mg o f a colorless
A n alysis b y GC/MS show ed one p rod u ct.
1H NMR:
1.3
3.85(p pm )
d(J=3.3H z)
IH
2 . 0 - 1.5
m
5H
1.41
S
3H
1.35
m
2.2H ( en d o -CDHg)
1.25
bs
2.8H Ce x o -CDH2)
C NMR: 1 0 7 .3 (p p m ), 8 1 .1 , 8 0 .9 , 3 4 .2 , 2 9 .2 , 2 5 .9 , 2 4 .3 ,
105
13C NMR: 1 0 7 .3 (p p m ), 8 1 .1 , 8 0 .9 , 3 4 .2 , 2 9 .2 , 2 5 .9 , 2 4 .3 ,
2 0 .9 , 17.2
MS:
ISS(M+) , 157, 142, 115, 98, 97, 87, 69, 58,
49, 43
Preparation o f 2 -F orm vl-3 ,4 -D ih y d ro -2 H -P y ra n [5 8 ].
A crolein ( IlOmL, 9 2 .3g) was h eated to 160°C in an autoclave for
two
h o u rs.
liquid
D istillation (50-5 5 oC, a sp ) afforded 41g o f a colorless
(44.4% ).
Sp ectral data fo r th is compound p ro v ed iden tical w ith
literatu re v a lu e s.
Preparation of 2 - (I -H y d r o x y e th y l)- 3 , 4-D ih yd ro-2H -P yran (2 6 ).
A crolein dim er, [5 8 ], (3 .4 4 g , 30.7mmol) was stir re d in SOmL of
anh ydrous THF at -50°C un d er a b lan k et of a rg o n .
M ethylmagnesium
bromide (15.4m L of 3 . OM solution in THF, 1 .5 e q ) was added over 10
m inutes and th e reaction allowed to slow ly warm to O0C over one
hou r.
The reaction was ca refu lly qu en ch ed w ith IOmL o f 5% KOH
and e x tr a cte d
w ith Et2O (4 x 20mL).
w ashed w ith b r in e ,
dried o v er K2CO3 and co n d en sed , a ffo rd in g a
colorless liquid ( 3 .2 0 g ) .
alcoh ols, [2 6 ], in a
The combined organ ics w ere
A nalysis b y GC/MS show ed o n ly th e isom eric
th r e o :ery th ro ratio of 55:45.
q u ick ly tak en to th e n e x t
T he prod u ct was
step w ithout p u rification .
Preparation of 2 -A c ety l-3 ,4 -D ih y d r o -2 H -P y ra n [2 4 ].
To 75mL o f fr e s h ly d istilled dichlorom ethane (P 2O5 ) was added
4 .0 5 g
(I0.7m m ol) of PDC, 4 . Og NaOAC and 4 . Og 4A m olecular s ie v e s .
The m ixture
was cooled to 0°C and trea ted w ith a solution o f 1 .8 1 g
106
of crude alcohol,
[26], in
5mL dichloromethane.
After vigorous
s tirrin g for 5.5 hours (20°C) the thick suspension was gravity filte re d ,
the solid washed with 30mL
condensed.
dichloromethane,
and the f iltr a t e
The crude, product was passed through a 5" x I" pad of
s ilic a gel with hexane:ethyl acetate
(7:3).
Removal of solvent by
rotaryevaporat i on (5°C bath) afforded 700mg of a colorless liquid.
Analysis by GC/MS showed one product determined as
ketone,[24].
I t should be noted th at th is procedure was repeated several times
affording 24 in an isolated yield of 40% from acrolein dimer.
IH NMR:
I 3C NMR:
4.75(ppm)
bs
IH
4.25
d
IH
2.25
S
3H
2.1-1.75
m
5H
208.7(ppm), 142. 5, 101.2, 79.5, 25.7, 23.7, 18.4
MS:
126(M+) , 98 , 97, 83, 55, 43, 41
IR:
3050(cm"1), 2950 , 1720, 1650, 1425, 1360, 1235,
1072, 930, 905
HRMS:
Calculated for C7H10cH' 126•0681
Observed, 126.0681
Preparation of [ 6 ] from Ketone [24],
The ketone [24] (700mg, 5.56mmol), in IOmL dry THF a t
treated with methy!magnesium bromide
THF)
and allowed to s t i r overnight.
0.5mL H2O
O0C, was
(3.8mL of a 3 .IM solution in
The reaction was quenched with
and IOmL 15% HCl and extracted with Et^O (4x25mL).
The organics were dried (MgSO^), filte re d , and treated for
with one drop of concentrated H2SO4 .
bicarbonate, dried,
6 hours
The solution was washed with
condensed, and the crude product passed through a
107
pad of Si02 with
Hexane-ethyl a c e ta te .(7:3) affording 330mg of a
colorless liq u id .
GC/MS
analysis
revealed 6
contaminated with
approximately 30% of three uncharacterized by-products.
IH NMR:
13CNMR:
5.52(ppm)
bs
lH
3.85
bs
IH
2.1-1.5
m
6H
1.45
s
3H
1.28
s
3H
101.8(ppm)(d), 80.2(s), 79.3(d), 3 0 .1 (t), 28.9(g),
2 4 .9 (t), 20.5(g), 15.5(t)
MS:
142(M+) , 124, 109, 96, 84, 81, 71, 68 , 57, 55,
53, 43, 41
HRMS: . Calculated for CgHj^Cb, 142.0993798
Observed, 142.0992279
Preparation of 2-(2-1sopropenyl)-3 ,4-Dihydro-2H-Pyran [25].
To a solution of methyltirphenylphosphonium bromide (15.lg,
1.3eq)
in 125mL dry Et2O and THF (4:1),
n-Butyllithium
(2 .SM solution
was added 17.OmL of
in Et2O).
After 30 minutes the
resulting red solution was treated for 1.5 hours with 4 .Ig (32.Smmol)
of ketone
[24] in
7 .OmL
Et2O was added. After
THF, a fte r which time an additional IOmL
14 hours
Et2O and suction filte re d .
the mixture was treated with wet
The solid was washed with 30mL Et2Q and
combined f iltr a t e condensed by rotoryevaporation.
crude product (40-500C, asp)
GLC
analysis
afforded 1.09g of a colorless liquid.
indicated
targ et
approximately. 7% of unreacted [24].
with pentane-ethyl
(GLC).
D istilla tio n of the
[25]
contaminated with
Chromatography over s ilic a gel
acetate (9:1) afforded 850mg (21%) of pure [25]
108
1H NMR:
6.42(ppm)
d
IH
5.01
S
IH
4.90
S
IH
4.70
bs
IH
4.20
d
IH
2.2-1.65
m
1.77
S
3H
13C NMR:
144.7(ppm), 143.8 , 111.4, 100.2, 78.2, 26.8,
19.9, 18.2
MS:
124(M+) , 109, 95, 93, 81, 68, 67, 55, 53, 41
IR:
3080(cm-1 ), 2920, 1650, 1430, 1240, 1070, 1041,
902
HRMS:
Calculated for C8H12O, 124.0888
Observed, 124.0891
Solvomercuration-Demercuration of [25].
To a solution of Hg(QAc)2 (1.7g, 2 .leg) in
H2O
IOmL THF and 3 .OmL
was added a solution of 314.5mg, [25] (2 .54mmol) in I . OmL THF.
After 45 minutes, the reaction was treated, for 30 minutes, with a
solution
containing IOSmg NaBH^ ( I . leg) in 4 .OmL of 5% NaOH. The
mixture was passed through a pad of Hyflo Super Cell, extracted with
Et2O (4xl5mL),
the organics dried over Na2SO4 and condensed.
crude product was s tirre d for 12 hours
20mg tosic
acid.
The
in ISmL benzene containing
Extraction with bicarbonate, followed by drying
(Na2SO4) and r 0 toryevaporation afforded 95mg of a colorless liguid.
GLC and 13C NMR
analysis
indicated targ et
[6] contaminated with
approximately 10% of an uncharacterized by-product.
109
S y n th e sis o f 2 - (C arb oxy m eth y l)- 3 , 4-D ih yd ro-2H -P yran [701.
The s a lt, [71] , (4 .2 g , 27 .9 mmol) was su sp e n d e d in 20mL d r y
THF and 1 .5 mL o f fr e s h ly d istilled HMPA (CaH2) and an argon
atm osphere was e sta b lis h e d . Iodomethane ( 2 . 6mL, 1 .5 e q ) was injected
and th e reaction
m ixture reflu x ed fo r 14 h o u rs.
cooled to 20° C and
pou red
5 OmL o f h exan e : Et2O (1 :1 )
acid
T he m ixture was
into a sep a ra to ry fu n n el containing
and 5mL H2O.
(2 x IOmL 15%HC1), b rin e and
E xtraction w ith dilute
b icarb on ate, follow ed b y
d r y in g o f th e organic p h a se (N a2SO4 ) and ro ta ry ev a p o ra tio n , afforded
a p ale-yellow liq u id .
D istillation (5 5 -6 1 °C , a s p .) o f th e cru d e prod u ct a ffo rd ed 2 .4 6 g
(62%) of a colorless liq u id .
A n alylsis b y GC/MS show ed one product
determ ined as ta r g e t e s t e r , [7 0 ].
1H NMR:
13CNMR:
MS:
6.42(p p m )
d
IH
4.77
bS
IH
4 .5 0
dd
IH
3.80
S
3H
2 .2 4 -1 .8 0
m
4H
1 7 1 .3(ppm) ( s ) , 1 4 2 .6 (d ), 1 0 0 .9 (d ), 7 3 .0 (d ),
5 2 .2 ( q ) , 2 4 .7 ( t ) , 1 8 .4 (t)
142(M -), 124, 114, 113, HO, 83, 82, 74,
68, 55, 53, 43, 41
Preparation o f 7 , 7-D im eth y l-6 , 8 -D io x a b icy clo [ 3 . 2 . 1 ] Octane
[6] From [7 0 ].
To 1 .0 7 g (7.53m mol) o f e s t e r , [7 0 ], in 2OmL d r y THF at. -78°C
HO
u n d er a b lan k et o f a rg o n , was added m ethyllithium ( 1 3 .SmL of a 1.4M
solution in Et2O, 2 .5 e q ) in one p o r tio n .
The reaction was allowed to
warm to 20°C o v er one hour and s tir r in g continued fo r an additional
1 .5
h ou rs.
Et2O(3 x
The reaction was qu en ch ed w ith H2O and ex tra cted w ith
20mL).
H2SO4 for fiv e
The combined o rgan ics w ere trea ted w ith 3 drops
hou rs and ex tra cted w ith dilute b ica rb o n a te, dried
over Na2SO4 and
c o n d e n se d .
d istilled affo rd in g 170
A n alysis
by
GC/MS
The cru de brown liquid (620mg) was
mg o f a co lo rless liquid (3 5 -4 5 °C , O .Storr).
show ed
ta r g e t ,
[6 ] ,
contam inated
with
approxim ately 3% of k e to n e , [2 4 ].
E sterification o f 3 ,4 -D ih y d ro -2 H -P y ra n -2 -C a rb o x y lic A cid,
Sodium Salt [71] w ith M ethanol.
To 6 . 28g ( 4 1 .Smmol) of Tl was added 5 mL H2O and 5mL o f 15% HCl.
E xtraction w ith Et2O (5 x 2OmL) follow ed b y evaporation o f so lv en t
afford ed 5 .2 5 g o f colorless liq u id .
Methanol (55mL) and one drop of
H2SO4 w ere added and th e reaction r eflu x e d for 14 h o u r s .
was
Methanol
rem oved b y ro ta ry evaporation and th e crude p rod u ct distilled
(5 5 -7 0 °C ,
O.Storr) affo rd in g 3 .3 2 g of a m ixture o f 70, 72a and 72b in
a ratio of
2 .1 5 :1 :4 .8 (G L C ).
s y n - 2 - ( C arbom ethoxy) - 6 -M eth oxy-T etrah yd rop yran [ 72a]
IH NMR.:
4.39(p pm )
dd
IH
4.10
dd
IH
3.78
S
3H
3.51
S
Sn
2 .0 4 -1 .4 0
m
6H
Ill
13C NMR:
MS:
1 7 0 .8 , 1 0 2 .7 , 7 3 .9 , 7 2 .5 , 5 5 .8 , 3 0 .1 , 2 7 .5 ,
21.2
173(M+), 153, 147, 142, 115, 114, 83, 82, 71,
58, 55, 53, 43, 41
a n t i - 2 - ( Carbomethoxy)-6-M ethoxy-Tetrahydorpyran [ 72b]
H NMR:
-ljCNMR:
MS:
4 .8 5 (ppm)
bs
IH
4.39
dd
IH
3.76
S
3H
3.40
S
3H
2 .0 1 -1 .5 0
m
6H
1 7 1 .9 (ppm), 9 8 .3 , 6 7 .8 , 5 4 .6 , 5 1 .7 , 2 8 .7 , 2 7 .9 ,
17.3
174(M+ ) , 173, 159, 147, 142, 115, 114, 83, 82,
71, 58, 55, 53, 43, 41
The procedure was repeated u sin g 5 . Og
s te p was c a r r ie d out a t 35°C.
o f Tl
and the e s t e r i f i c a i t o n
D i s t i l l a t i o n afford ed 3 .5 5 g o f k e ta ls 72a
and 72b (1 :5 ) w ith no apparent d e te c tio n o f 70.
A lte r n a tiv e Preparation o f 7 ,7 -D im e th y l-6 ,8 D io x a b ic y c lo [3 .2 .1 ]O cta n e [ 6 ] .
To a s o lu tio n c o n ta in in g 2 .1 5 g o f a m ixture o f 72b, 72a and 70
(4 1 :9 :1 ) in
(Et^O)
IOOmL THF a t O0C,
o f m eth yllith iu m (4eq).
warm to 20°C
H2 O was
over a p eriod o f
added.
The
product
was
3SmL o f
a 1.4M s o lu tio n
The r ea c tio n was allow ed to slo w ly
2 .5 hours
a ft e r which
m ixture was e x tr a c te d w ith Et20
and th e combined o rg a n ics
crude
was added
d ried
reflu x ed
12
over Na2 SO^
hours
tim e IOmL o f
(4 x 30 mL)
and condensed.
The
in 5OmL benzene co n ta in in g
112
5 Omg
t o s ic
a c id .
The
p rod u ct
was
again
ex tra cted
( dichlorom eth ane/d ilu te bicarbonate) a ffo rd in g 960mg o f a pale brown
liq u id .
P urification o v e r silica g e l w ith pen tan e : e th y la eeta te (7 :3 )
afford ed
600 mg o f a colorless liq u id .
approxim ately
90%
ta r g e t
[6]
A nalysis b y GC/MS revealed
and
app roxim ately
10%
of
un ch aracterized b y -p r o d u c ts .
Preparation of 3 ,4 -D ih y d ro -2 H -P y ra n C arboxylic A cid Chloride
[741.
To 1.52 g o f sa lt [T l] in 3 . OmL d.ry dichlorom ethane at 0°C un der
a
blan ket o f a r g o n , was added 2.6mL o f fr e s h ly d istilled th ionyl
ch lorid e,
(P (O P h )3) .
and d istilled
The reaction w as warmed to 50°C fo r 15 hours
(7 0 -9 0 °C ,a sp ) p r o v id in g 350mg o f a co lo rless liq uid.
A n alysis b y 13C
NMR revealed two p ro d u cts (1 :1 ) presum ed to be
ta r g e t [74] and HCl
ad d u ct [8 0 ].
Upon sc a le -u p o f th e rea ctio n , it was found th at red istillation of
th e p rod u ct m ixture th ro u g h a 13cm v ig r e a u x column (5 0 -5 5 °C , 0 .3 to r r )
afford ed p u re 74.
The id e n tity of th e HCl adduct is sp ecu la tiv e and b a se d upon 13C
NMR
com parison to p u re 74 and th e p r e se n c e of th ree u p field trip let
reson an ces (-C H 2- ) .
A ttem pts to d r y th e sodium s a lt, [7 1 ], b y warming u n d er vacuum ,
prior
to treatm ent w ith th ion yl ch lo rid e, failed to a lter th e reaction
outcom e.
3 , 4-D ih yd ro -2 H -P y ra n -2 -C a rb o x y lic acid chloride [74]
13CNMR:
1 7 2 .6 ( s ) , 1 4 1 .8 (d ), 1 0 1 .3 (d ), 7 9 .3 ( d ) , 2 3 .7 ( t ) ,
1 7 .1 (t)
113
6 - C hloro- T etrah yd rop yran - 2 - C arboxylic A cid C hloride [8 0 ].
13C NMR: 1 7 1 .9 ( S ) , 9 2 .7 ( d ) , 7 6 .6 ( d ) , 3 2 .7 ( t ) , 2 7 .2 ( t ) ,
Improved S y n th e sis of 3 ,4 -D ih v d ro -2 H -P y ra n -C a rb o x y lic Acid
Chloride [ 7 4 ] .
To th e sodium s a lt, [T l], was add ed I . OmL o f fr e s h ly distilled
oxalyl
chloride
at
0°C
(e x o th er m ic !) .
Upon
com plete addition,
exoth erm icity su b sid e d and th e reaction was r eflu x e d 1 .5 h o u r s.
a
Evaporation o f u n reacted oxalyl ch lo rid e, followed b y th e addition of
I . OmL d r y tolu en e (b en zop henone + sodium ) and rep ea ted evaporation,
afford ed a p ale-b row n th ick su sp e n sio n .
D istillation (5 2 -6 0 °C , a sp )
p rovid ed 840mg (53.6%) o f pu re acid ch lo rid e, [74] ( 13C NMR) .
S y n th e sis o f 3 ,4 -D ih y d ro -2 H -P y ra n -2 -C a rb o x y lic M enthol E ster
[8 2 ].
To 371mg (2.53m mol) of acid ch lo rid e, [7 4 ], in 15mL anhydrous
tolu en e at 0°C was added 396mg (I e q ) ( - ) -m enthol follow ed b y 1.5mL
dry
p y r id in e . T he reaction was s tir r e d o v ern ig h t at 20°C un der a
blan ket of
argon.
E xtraction w ith
silica
H2OZEt2O,
follow ed b y chrom atography over
g el w ith h e x a n e -e th y l acetate (9 :1 ) afford ed 317mg (47%) of
p u re (GLC)
diastereom eric
m enthol e s t e r , [8 2 ].
T he p roced u re was rep eated many tim es, a ffo rd in g [82] in y ie ld s as
h ig h as 70%.
114
Diastereomeric [82]:
1H NMR:
6.42(ppm)
d
IH
4.75
m
2H
4.45
m
IH
2.20-1.35
m
I lH
1.26-0.70
m
I lH
170.6(ppm), 170. , 142.86, 142.83, 100.8,
100.7, 75.1, 75. , 73.2, 73.1, 46.9, 34.1, 31.3,
26.1, 24.9, 24.8 23.2, 23.1, 22.0, 20.8, 20.7,
18.5, 18.3, 16.1
13C NMR:
HRMS:
Calculated for Ci6H2603 ' 266.1882
Observed 266.1848
A lternative Preparation of 3,4-Dihydrp-2H-Pyran-2-Carboxylic-(-)Menthol Ester [82].
n-Butyllithium (1.7mL of a 2 .SM solution in hexanes)
dropwise
to
a O0C solution of
(-)-menthol (670mg) in 8mL of an
anhydrous mixture Toluene:Hexane.
chloride
(in 0.5 ml
overnight (0-20°C).
The
followed by 5 mL Et20.
was added
After
30 minutes,
the acid
Toluene) was added and the reaction stirre d
reaction was quenched with
The layers
4 mL H2O
were separated, the organic
phase dried over Na2SO^ and condensed under
reduced pressure.
The crude product was purified over SiG^ with Pentane to yield
840
mg (79%)
of a pale yellow o il.
GC/MS and 33C NMR indicated
an approximately 99% pure mixture of diastereomeric e ste rs.
115
Preparation of 2 -M eth y l-3 ,4 -D ih v d ro -2 H -P y ra n -2 -C a rb o x y ]ic ( - ) Menthol E ster [ 8 3 ] .
LDA was gen erated b y ad d in g 1.4mL of a 2.5M solu tion of n -B u li
( l . l e q ) to 2OmL o f anh yd rou s THF con tain in g 0.48mL d iisop rop yl amine
at
70°C u n d er a r g o n .
mmol),
A fter 20 m in u tes, e s te r , [8 2 ], (830 mg, 3.12
in 2 .0 mL THF, was added drop w ise at -7 8 °C .
was s tir r e d
The reaction
one hou r from -78 to -IOqC then cooled to -60°C and
treated w ith CH3I (0 .2 5 mL, 1 .3 eq ) in one
portion .
th e ice h ath was rem oved and stir r in g continued
u su al w orkup
(ex tra ctio n )
A fter one hour
fo r 2 .5 h o u r s .
followed b y d ry in g o v er
evaporation afford ed 760 mg (87%) o f cru d e yellow o il.
the diastereom eric carb onyls b y 13C
Identical r e su lts
The
Na2SO4 and
Integration of
NMR ind icated a 55:45 m ixture.
w ere obtained w hen th e reaction was
rep eated
m aintaining th e alkylation tem perature at -78° C fo r 3 h r s .
13C NMR: 1 7 2 .8(p p m ), 1 7 2 .7 , l ^ . 6, 1 4 2 .5 , 9 9 .8 , 9 9 .7 , 7 6 .9 ,
7 4 .7 , 4 6 .6 , 4 0 .2 , %A.0, 3 1 .1 , 3 0 .1 , 2 5 .8 , 2 5 .6 ,
2 4 .8 , 2 4 .6 , 2 2 .9 , 22:8^ 2 1 .8 , 2 0 .5 , 1 7 .5 , 1 5 .7 , 15.5
MS:
HRMS:
280(M +), 218, 180, 141, 139, 123, 97, 95, 83, 81,
69, 57, 55, 43, 41
C alculated for Cn7H23O3 , 280.2039
O bserved 280.2042
A ltern ative M ethylation of [82] w ith M efhyl-p ^ T olu en esulfinate.
LDA
was
gen erated
by
com bining
0.25mL
diisopropylam ine
( 1 . 78mmol) w ith 0.75mL o f a 2 . SM solu tion (E t2O) of n-b u tyllith iu m in
20mL of
anh ydrous THF at 0°C fo r 20 m inutes.
E ster, [8 2 ], (390m g, 1.47mmol) in 2mL THF, was added drop w ise
at 0°C .
A fter 1.75 hou rs th e solution was cooled to -7 0 °C , followed
116
b y treatm ent w ith 330mg (1.77m mol) o f m e th y l-p -to lu e n e su lfin a te .
reaction
b y slow
tem perature was maintained at -70°C for 1 .5 h o u r s, followed
warming to 20°C .
p roced u re (E t2O)
p ro d u ct.
The
A fter 12 h o u rs, th e u su a l extraction
was carried o u t, a ffo rd in g 360mg (87.5%) o f crude
A n alysis b y
a 61:39 m ixture o f
13C
NMR in d icated q u an titative con version to
diastereom eric, [8 3 ].
A ltern ative M ethylation o f [82] Employing HMPA C o-S o lv en t.
n-B u tyllith iu m (1 .0 5 ml, 1 .2 eq ) was added to diisopropylam ine
(0 .3 7
ml,
1 .2 eq )
in 25 ml an h yd rou s THE at -70°C u n d er an
atm osphere o f A rgon .
A fter 20 m in u tes, HMPA (0.5m L) and e s te r ,
[8 2 ], in 5 ml THE, was
-40°C over I h r .
added and s tir r in g contin ued from -70 to
T he reaction
was cooled to -78°C and CH3I (0 .2
ml, 1 .5 eq ) was ad d ed . S tirrin g was
3 h rs.
continued from -70 to 20°C over
Et2O and dilu te HCl w ere add ed and th e p h a se s tra n sfered to
a sep aratory fu n n e l.
The la y ers w ere
p h ase ex tr a cte d 4 X 25 ml Et2O.
sep arated and th e aqueous
T he combined
organ ic la y ers w ere
w ashed w ith d ilu te bicarbonate follow ed b y b r in e ,
and co n cen tra ted .
dried o v e r Na2SO4
P urification o v er Si2 w ith 1:1 H ex a n e:eth y la ceta te
afford ed 440 mg o f 83 as a pale yellow o il.
In tegration b y 13C NMR
in d icated a 56:44 m ixture o f d ia stereo m ers.
A ttem pted E sterification s of [74] w ith (I R , 2R, 3 S ) - ( - ) - [ N B en zen esu lp h o n y l-N -(3 ,5 -D im eth y lp h en v l)A m in o ]-2 -B o rn a n o l [8 4 ].
To 400mg (0.97m mol)
of chiral a u x ilia ry ,
[8 4 ], in IOmL d ry
chloroform u n d er a b lan k et o f argon was added 190mg (1.3m mol) of
acid
ch lo rid e,
[74]
follow ed
by
O.lmL
of
fr e s h ly
distilled
117
triethylam ine.
The reaction was stirred for 12 hours at 20°C at which time
analysis by TLC showed only starting material.
The reaction was then
brought to reflux for an additional 12 hours.
The solvent was
removed by rotoryevaporation and the crude product analyzed by TLC
with pentaneethylacetate
0.29) appeared,
(20:1).
Two very faint spots (Rf=0.45 and
upon development with acid (CrO3ZH2SO^) spraying,
along with one very dark spot (Rf=0.16) representing unreacted [84].
The crude product was taken up in CDClg and analyzed by ^C
NMR
and DIP-GC/MS,
revealing unreacted [84] and uncharacterized
decomposition products polymeric in nature. No evidence for a newlyformed ester was detected in the ^C
NMR spectrum.
Several altern ativ e procedures for the preparation of e ste r, [86],
were examined, with minimal success, and are presented as follows:
To 509mg (1.23mmol) of chiral auxiliary, [86], in
at
IBmL dry THF
O0C under an atmosphere of argon, was added 0.5mL of a 2 .SM
solution
(Et2O) of n-butyllithium.
After one hour,
the resulting
alkoxide was treated with a solution of I 9Omg (I . 30mmol) of [74] in
8 .OmL of freshly d is tille d hexane and 5 .OmL dry THF.
was refluxed
for
one
The reaction
hour and forty minutes and the solvents
removed by rotaryevaporation,
product was extracted with
providing a brown o il.
The crude
dichloromethane and d ilu te bicarbonate
followed by drying over Na2SO^
and rotaryevaporation
affording 78Omg of a pale-brown o il.
of solvent,
Analysis by 13C NMR failed to
show any evidence for a newly formed ester.
The original procedure, employing triethylamine, was repeated as
118
were two sim ilar procedures employing pyridine and calcium hydride
respectively as HCl scavengers.
None of these methods proved useful
as
[86] was not detected (-^C NMR and
evidence for
targ et ester
GC/MS).
I t should be noted th at unreacted
chiral
auxilary,
in each
procedure, could be recovered by chromatography over s ilic a gel with
hexane-ethyl acetate (10 to 15:1).
R ecrystallization from ethanol-water
(95-5) generally afforded 70-80% recovery of pure [84] which could be
reused in following reactions.
Preparation of (S)-(+)-2-Pyrrolidinemethanol(S-Prolinol)[88].
Following the procedure of Enders ®2, s-proline (12.0g, 0.10
4 mole)
in
was slowly added (in 15 parts I) to a suspension of 6 .Ig LAH
250mL
dry THF.
prevent excessive
The flask was chilled with an ice bath to
reflux.
The addition of
s-proline (exothermic)
required 30 minutes and was followed by refluxing for 1.5 hours.
The
reaction was quenched by slow addition of 30 mL of 15% NaOH. The
liquid was decanted and sa lts
washed with Et^O (2 x BOmL).
Rotoryevaporation followed by d is tilla tio n
of
the crude
product
(71-75°C , 0 .S to rr) afforded 7.9g (75%) of a colorless liquid.
by GC/MS and 13C NMR revealed one product.
^3C NMR:
MS:
64.2(ppm), 59.6, 45.8, 27.1, 25.2
IOl(M+), 100, 70, 68, 55, 54, 43, 41
Analysis
119
Preparation of (S)-(+)-2-Methoxymethylpyrrolidine [91].
Continuing with the procedure of Enders^2,
prolinol (4.0g,
freshly d is tille d s-
39.Bmrnol) was treated with 2.9mL (1.2eq) of methyl
formate a t O0C under a blanket of argon.
The reaction was stirre d
I
for
one hour and condensed by
was
taken up in 4 .OmL dry THFand added
1.14g
(47.Smmol) NaH,
rotaryevaporation.
3.2mL iodomethane
The crude product
to a -SO0C suspension of
(1.3eq) and 2SmL dry THF.
The reaction was warmed to 20°C over 40 minutes then refluxed
for
20 minutes and cooled to
20°C.
Dilute HCl (O.SmL of 15%
aqueous solution) was added, followed by 3SmL of 17% KOH. After
12 hours the
solution was extracted with Et20 (5 x 2SmL) and the
product d is tille d
GC/MS indicated
affording 2.1 g of a colorless liq u id .
90%
target
by-product presumed on the basis
[91]
contaminated with
of mass spectral data
Analysis by
10% of an
(M+=129) to
be (S)-(+)-N-methy1-2-methoxymethyI-p y rro lid in e.
MS: IlS(M+) ,8 4 , 82, 71, 70, 68 , 56, 55, 45, 43, 41
Preparation of 3,4-Dihydro-2H-Pyran-2-Carboxylic-(S)-(+)-2Hydroxymethyl-Pyrrolidine Amide [92].
A -78°C solution containing
s-prolinol (540mg,
5.0 mmol) and
pyridine (1.2 g) in 2SmL of dry THF, was treated with 730 mg of acid
chloride, [74], in 4 .OmL THF.
dissolve the s a lts .
The mixture was warmed to 300C to
After 30 minutes, hexane (ISmL) was added and the
reaction stirre d for 14 hours. The mixture was extracted with Et2O
and
10% HCl,
dried (NaSO4) and condensed affording 590 mg of a
colorless o il which exhibited the odor of pyridine.
Chromatography
120
over SiO2 with
colorless o il.
CH2Cl2 Et2O (1:1) provided 210 mg (ca.20%) of a
Analysis
by GC/MS showed only the diastereomeric
amides, [92].
HEMS: Calculated for Ci 1H17NO3 , 211.1202850 (Scan 617)
Observed, 211.1210937 (Scan 649)
A lternative Preparation of [92] .
s-prolinol (264mg,
2.61mmol) and ester [70] (370mg, leg.) were
combined and warmed to
50°C for 3 hours under an atmosphere of
argon.
Removal of methanol by rotoryevaporation afforded 545 mg
(99%) of a
pale-orange o il.
Analysis by GC/MS and 1^C NMR
revealed only the diastereomeric amides, [92].
It
should be noted th at attempts
to purify crude [92] by
Kugelrhor d is tilla tio n affords product as a pale-yellow o il in
approximately 50% y ield .
Crude product was found to be suitable for
alkylation step s.
Methylation of Amide [92].
LDA (2.9mmol) was prepared from 0.41 mL diisopropylamine and
1.2mL
of
2.5M n-butyllithixim
(in
Et2O) in 20mL dry THF. The
solution was cooled to -78°C and treated with amide
[92] (250mg,
I . ISmmol) in I . OmL THF. After one hour, iodomethane (O.lmL, 1.3eq)
was added and the
temperature maintained a t -78°C for
The reaction was
pale-yellow o il.
extracted
Analysis by
polymer formation
as well as
(Et2OyH2O) affording
1.5 hours.
180mg of a
GC/MS and 13C NMR revealed much
several
minor uncharacterized
121
by-products.
The reaction mixture proved inseparable by preparative
GLC and s ilic a gel
13C NMR analysis.
not possible,
chromatography thus precluding accurate 1H and
Although a complete
we do offer
compounds eluting
the
structure
the mass spectral
capillary GC a t
elucidation was
data for the two
17.28 and 17.68 minutes
respectively (peak ratio s approximately 68:32).
Peak 1037 (Area 559359):
225( + ), 223, 197, 194, 157, .140, 128,
126, 97, 70, 57, 43, 42
Peak 1061 (Area 261796):
225(+), 197, 194, 157, 154, 141, 112,
97, 84, 70, 69, 57, 55, 43, 42
HRMS: Calculated for CioHigNOo, 225.136436
Observed, 225.1346130 (Scan 817)
225.1368103 (Scan 838)
Preparation of 3.4-Dihvdro-2H-Pyran-2-Carboxylic-[(S)-(-f)-2(Methoxymethyl)pyrrolidine] Amide [94].
Pyran e ste r, [70], (525mg,
mixture of
3 .7mmol) was treated with a 500mg
(S)-(+)-2-methoxymethylpyrrolidine (90%) and (S)-(+)-N-
methyl-2-methoxymethylpyrrolidine (10%). After warming to
12
SO0C for
hours the crude product was chromatographed over s ilic a gel with
hexane- ethyl acetate (15:1 followed by 10:1) affording 160mg of the
diastereomeric mixture [94] (GLC).
1HNMR:
6 .4 (ppm)
d
IH
4.8-4.2
m
3H
3.7-3.35
m
4H
3.32
2 . 2- 1. 7
'
s
3H
m
8H
122
MS:
(Scan 724) 225(M+), 197, 181, 180, 157, 152,
124, 97, 83, 70, 55, 45, 41
(Scan 735) 225(M+), 197, 180, 157, 152, 142,
124, 112, 98, 83, 70, 55, 45, 41
IR:
3020(cm-1 ), 2850, 1660, 1452, 1405, 1260,
1103, 1055, 920, 720
Calculated for CigHigNOs, 225.1364936
Observed, 225.1368561 (Scan 505)
HRMS:
225,1372681 (Scan 527)
Methylation of Amide [94].
To 0.15 mL d iisopropylamine (I . 07mmol)
added
in
4 .OmL dry THF was
0.42mL of a 2 . SM solution of n-butyllithium in Et^O a t O0C.
After 20 minutes amide [94]
dropwise a t -78°C. After
added and the reaction
usual extraction
in
1.5 mL THF,
was added
1.5 hours, iodomethane (0.07mL, 1.3eq) was
stirre d a t -780C for 2 hours, followed by the
procedure.
a pale-yellow o il.
(195mg),
Evaporation of solvent afforded 180mg of
GC/MS analysis revealed only the diastereomeric
amides, [95] in a ra tio
MS:
of approximately 39:61.
(Scan 838) 239(M+), 211, 194, 171, 142, 126,
97, 82, 70, 69, 55, 44, 42
(Scan 850) 239(M+), 194, 171, 138, 126, 97, 82,
70, 69, 57, 46, 44, 42
IR:
3025(cm-1 ), 2875, 1640, 1440, 1260, 1045, 860,
725
Preparation of (-)-Menthyl Acrylate [96].
A mixture of acryloyl
(2.1g, 13.4mmol)
was warmed to
chloride (1.34g,
14,7mmol), (-)-menthol
and 2 .OmL pyridine, in 50.OmL dry dichloromethane,
SO0C for
10 hours,
followed by extraction with
123
dichloromethane
and 10% HCl.
The organic phase was dried over
NagSO^ and condensed affording 1.66g of a brown liquid.
Purification
over silic a gel with hexane-ethyl acetate (7:3) provided 1.22g of a
colorless liquid.
13CNMR:
165.6(ppm)(s), 130.l ( t ) , 128.9(d), 74.1(d),
46.9(d), 40.7(t), 34.M t), 31.2(d), 26.2(d), 23.4(t),
21.9(q), 20.6(q), 16.3(q)
Attempted Diels-Alder Heterocycloadditions with (-)-Menthyl
Acrylate.
Four Lewis acid-catalyzed Diels-Alder reactions were attempted
using (-)-menthyI acrylate and methylvinyl ketone. The catalysts used
were AlClg SnCl4 , TiC^, and EtAlClg in 1.0 to 1.4:1 molar ratios with
acrylate.
In each case, no reaction was detected. A representative
procedure is as follows:
To 3I Omg (I . 4mmol) of
d istille d dichloromethane
(-)-menthyl acrylate
in 6 . OmL freshly
(PgOg) at O0C, was added I . OmL of a 25%
solution of ethylaluminum dichloride, under a blanket of nitrogen.
Methylvinyl
ketone (0.2mL,
2eq) was added dropwise over 10-12
minutes and the reaction stirred for 12-14 hours. Analysis by GC/MS
showed only starting material.
Procedure for Menthol-Derived Ester Enolate Trapping with
Chlorotrimethylsilane.
LDA (I . 55mmol) was generated by combining d iisopropylamine
(0.22mL) and n-butyllithium (0.70mL of a 2 .SM solution in EtgO) in 15
mL dry THF at O0C for 15 minutes.
I . OmL THF,
was
Ester (82) (317mg, I . 19mmol), in
added slowly at
-78°C.
After one hour.
124
chlorotrimethyI silane (0.22 mL,
1.73mmol) was added and the reaction
temperature maintained a t -78°C for
condensed by rotory evaporation
chromatographed over
one hour.
(35°C)
and
The solution was
the
s ilic a gel with hexane-ethyl
Removal of solvent afforded 435mg of a colorless
13c NMR indicated approximately 15% unreacted
crude product
acetate ( 10 : 1 ).
liq u id .
[82]
Analysis by
along with
several newly generated o lefin ic signals. Capillary GC/MS revealed a .
complex mixture containing [82] and two peaks (M+=338) as the major
products in a ra tio of approximately (4:1:1).
MS:
Retention
Time
(Minutes)
21:53 :
338(M+) , 201, 200, 184, 129, HO, 83, 82, 75,
73, 69, 55, 43, 41
22:32 :
338(M+), 323, 201, 200, 184, 129, 115, HO,
97, 83, 82, 75, 73, 69, 57, 55, 43, 41
Reduction of Methylvinyl Ketone Dimer with. Various Reducing
Reagents.
The resu lts
of
the borohydride and lithium aluminum hydride
reductions of [28] were taken from the doctoral th esis of Schwartz.
The procedures employing diisobutylaluminum hydride (DIBAH),
triisobutylaluminum hydride (TIBA) and L-Selectride were identical. A
representative procedure using TIBA is described.
I t should be noted th at throughout th is study, isolated yields of
62a and 62b were generally moderate owing to two c r itic a l factors;
loss
due to p a rtia l water so lu b ility during extraction, and loss due to
125
high
volatility d u rin g rotoryev a p o ra tio n .
optimize
No attem pts w ere made to
y ie ld s as em phasis was placed on s te r e o s e le c tiv ity .
P rocedure fo r th e Determ ination o f B icyclic Ketal L oss Due to
R otoryevap oration .
T his p roced u re r e p r e se n ts a gen eral rep rod uction o f th e common
so lv en t removal tech n iq u e u sed th rou gh ou t th is s tu d y . A 440mg sample
contain ing
60% [62a] and 40% [62b] was d isso lv ed in 7 5 .0 mL of Et2 .
The so lv en t
w ith th e bath
was th en rem oved b y rotoryevap oration fo r 1 2 .0 minutes
tem perature maintained at 33-34°C .
r esu ltin g sample
The w eigh t of th e
was 280mg, r ev e a lin g a lo ss of 160mg (36.4% ).
R eduction of [28] with triisobutlyalum inum h y d rid e (T IBA )
( C yclization R e flu x ).
M ethylvinyl k eto n e, [2 8 ], (400m g, 2.86mmol) was tr e a te d , for 1.5
hou rs
at -7 8 °C , w ith TIBA (1.05m L o f a 3 . OM solu tion in tolu en e,
l.le q )
a fter
h o u rs.
w hich time th e reaction was warmed to 20°C for 14
Treatm ent w ith
IOmL of 15% HCl at 65°C fo r 4 h o u rs,
follow ed b y extraction w ith Et2O ,
s o lv e n t,
d r y in g (NaSO4 ) and evaporation of
afford ed 160mg of a p a le-
capillary GLC in tegration of peak areas
yellow liq u id .
A nalysis b y
show ed o n ly 62a and 62b in a
ratio o f approxim ately 83:17.
R eduction of [28] w ith Lithium tri-tert-B u to x y a lu m in o h y d rid e
(LTBA) ( C yclization at 20°C ).
To m eth ylvinyl k eton e dim er, [2 8 ],+ (300m g, 2.14m m ol), in 20mL
d ry
tolu en e at -78°C u n d er a blan ket of arg o n , was added LTBA
(945m g,
3 . 72mmol).
The r e su ltin g su sp en sio n was trea ted w ith 15mL
126
THF, to
e ffe c t d issolu tion o f LTBA . A fter 2 h o u r s , th e reaction was
warmed to
20°C for 30 m inutes and trea ted w ith I . OmL H2O followed
b y 5 . OmL 15%
HCl and ex tra ctio n w ith Et2O (3 x I OmL). Upon
sta n d in g fo r 24 hou rs (20°C ) th e d r y in g a g en t (N a2SO4 ) was filtered
and th e so lv en t evaporated a ffo rd in g 210mg o f cru de co lo rless liquid.
C apillary GC/MS an a ly sis
show ed o n ly [62a] and [62b] in a ratio of
57:43.
R eduction of M ethylvinvl Ketone Dimer [28] w ith MgBr2
V arious Metal H ydride and G rignard R ea g en ts.
The
in v o lv in g
p roced u res
th e
for th e red u ction o f 28-MgBr2 are sim ilar,
addition o f one eq u iv a len t o f MgBr2 -E t2O to 28,
follow ed b y cooling
to -78°C and treatm ent w ith e x c e s s metal hyd rid e
or G rignard r e a g e n t.
A cid -ca ta ly zed cyclization was e ffe c te d b y
r e flu x in g for 30 m inutes or
h ou rs.
and
b y allow ing to stan d at 20°C fo r sev era l
Example p roced u res fo r
R eduction o f [ 28] -MgBr2
LTBA and PhMgBr are show n b elo w .
w ith LTBA.
To [28] (300m g, 2.14mmol) in 25mL d r y THF at 0°C u n d er argon ,
was
added 553mg MgBr2 Et2O (l.O e q ) followed b y rapid cooling to
-78°C .
A fter 20 m in utes, th e m ixture was treated w ith LTBA (1 .3 6 g ,
5 . 3mmol) and
th e tem perature h eld at -78°C fo r 2 h o u rs.
reaction was th en
stan d for 14 h o u r s .
The
trea ted w ith 5 . OmL o f 15% HCl and allowed to
The
organ ics dried (N a2SO4 ) and
prod u ct was ex tra cted w ith Et2O th e
ev a p o ra ted , a ffo rd in g 79mg o f crude
p ro d u ct. GC/MS a n a ly sis revea led [62a] and [62b] (3 :9 7 ) contam inated
w ith approxim ately 10% u n ch aracterized b y -p r o d u c ts .
127
R eaction o f 28-MgBrg w ith PhMgBr.
A m ixture o f [28] (500m g, 3.57mmol) and MgBr2 Et2O (920m g,
I e q .) in
20mL d r y tolu en e at -78°C u n d er a r g o n , was trea ted w ith 0 .5
eq u ivalen ts
PhMgBr (0.6m L o f a 3 . OM solution in Et2O ).
A fter 30 m inutes a secon d aliquot o f PhMgBr was add ed and the
tem perature was slow ly b rou gh t to O0C o v er a period o f 40 m inutes.
The u su al ex tra ctio n /cy cliza tio n seq u en ce Was carried o u t, followed b y
p u rification of th e cru de produ ct b y silica g el chrom atography w ith
h e x a n e -e th y l acetate
(7 :3 )
a ffo rd in g 510mg of a p a le-y ello w oil.
A n alysis b y GC/MS show ed o n ly 57a and 57b (9 3 :7 ).
Preparation o f 3 - H yd roxy- 2 ,7 -O ctanedione [1 1 3 ].
A solution contain ing IOmL a ceto n e, IOmL H2O IOmL THE and 6
drops
o f con cen trated H2SO4 was trea ted fo r 10 m inutes w ith dimer,
[2 8 ],
( 2 .0 g , 14.3m m ol).
The solution was e x tra cted w ith Et2O (5 x
25mL) and th e combined organics w ash ed w ith b icarb on ate, dried over
Na2CO3 and con d en sed
affo rd in g 1 .7 4 g o f crude co lo rless liquid.
A n alysis b y 13C NMR show ed
one p ro d u ct, id en tified a s [1 1 3 ].
It should b e noted th at d istillation and p rep arative GLC analysis
r e s u lts in partial con version to dim er, [2 8 ].
128
13C NMR:
MS:
IH
4 . 2(ppm)
m
3.55
d
IH
2.48
t
2H
2.21
S
3H
2.12
S
3H
1 .9 2 -1 .5 0
m
4H
2 0 9 .9 (p p m ), 2 0 8 .6 ( s ) , 7 6 .4 ( d ) , 4 2 . 6 ( t ) , 3 2 .3 ( t ) ,
2 9 .7 ( q ) , 2 5 .OCq),- 1 8 .7 (t)
ISS(M+) , 140, 115, 113, 97, 85, 71, 59, 57, 55,
45, 43, 41
HRMS:
Calculated fo r CflH14O3 , 158.0942944
O b se rv e d , 158.0944672
General P rocedure for th e R eduction of 3-H y d r o x y -2, 7octanedione 11131 w ith V arious R educing R e a g e n ts,,
All red u ction s o f 113 u tilized th e same proced ure in v o lv in g the
addition of e x c e s s r ed u cin g rea g en t to a cold solution o f 113 or
H S-M gB r2 followed
Reaction
by
acid
catalyzed
(10-15% HCL)
cyclization .
conditions and y ield s are summarized in T able 11.
Preparation of a n ti- 2-A c e ty l- 6-Methoxy-OMethyl-Tetrahydropyran
[2 8 a ].
Treatm ent of m eth ylvinyl keton e dimer ( 2 . S g, 17.9mmol) w ith
20mL o f methanol and 100 mg of Dowex 50W-X8 for 14 h o u r s , followed
b y filtration
and distillation afford ed 2 .3 6 g (76.7%) o f a colorless
liquid ( b .p . 57°C , 0 .4 to r r ).
id en tified as
[ 28a] .
A n alysis b y 13C NMR show ed one product
129
IH NMR:
rl3C NMR:
4.0 (p p m )
dd
IH
3 .2 0
s
3H
2.19
s
3H
1 . 9 -1 .2
m
6H
1.33
s
3H
2 0 9 .1 (ppm ) ( s ) , 1 0 1 .9 ( s ) , 7 5 . 8 ( d ) , 4 7 . 7 ( q ) ,
3 4 . 8 ( t ) , 26. 4( t ), 25.5 ( q ) , 2 3. 5( q ), 18.4(t)
R eduction o f a n ti-2 -A cety l-7 -M eth o x v -7 -M eth v l-T etra h y d ro p y ra n
r28a] w ith V arious R educing R ea g en ts.
The p roced u res for h yd rid e red u ctio n s o f 28a and 28a MgBr2 are
iden tical to th e p roced u res u se d fo r m eth ylvinyl k eton e dimer [28].
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131
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