New approaches to natural products
by Jong-Gab Jun
A thesis submitted in partial fulfillment of the. requirements for the degree of Doctor of Philosophy in
Chemistry
Montana State University
© Copyright by Jong-Gab Jun (1985)
Abstract:
New approaches to natural products of theoretical and synthetic interest are presented. A methodology
for the cleavage of the 6,8-dioxabicyclo[3.2.1]octane skeletal system is explored by using acetyl iodide,
magnesium bromide, aluminum iodide, aluminum hydride and triethylsilane. It is found that the
fragmentation products reflect the configuration of the ketal isomer; endo-keta Is give cis-alkenes and
exo-keta Is give trans-alkenes. The fragmentation of the ketals gives products (dependent on condition.
The utility of this fragmentation methodology is demonstrated in the formal synthesis of si renin. Also,
a methodology involving vicinal dianions of 1,2-diesters is explored as a rapid entry into a highly
functionalized bicyclic diester. The utility of dienolate methodology in organic synthesis is seen in the
applications to the synthesis of valerane and synthetic approaches to maleimycin and hirsutene. N E W APPROACHES T O
N A T UR AL PRODUCTS
by
Jong-Gab Jun
A thesis submitted in partial fulfillment
of the requirements for the degree
of
Doctor of Philosophy
In
Chemi stry
M O N T A N A STATE U NI VE RS IT Y
Bozeman, Montana
August
1985
©1986
JONG-GAB JUN
All Rights Reserved
J>37g
^
p -4^
ii
APPROVAL
of a thesis
submitted by
Jong-Gab Jun
This thesis has been read by each m e m b e r of the thesis
c o m m i t t e e and has been found to be satisfactory regarding
c o n t e n t , English usage, format, citations, bibliographic style,
and consistency, and is ready for submission to the College of
Graduate Studies.
Approved
for the Major Department
Head, Major Department
Approved for the College of Graduate Studies
Date
Graduate Dean
i ii
STATEMENT O F P ER MI SS IO N T O USE
.In presenting this
requirements
thesis
for a doctoral
in partial
degree at M ontana State University,
I agree that the Library shall m a k e
under
thesis
rules of the Library.
fulfillment of the
it available to borrowers
I further agree that copying
is a ll o wa b le only for scholarly purposes, consistent w i th
"fair, use" as prescribed
in the U.S. Copyright
Law.
for extensive copying or reproduction of this thesis
referred to U niversity M i c r o f i l m s
Road, A nn Arbor,
exclusive right
dissertation
M i c hi g an 48106,
Signature
International,
Requests
should be
300 North Zeeb
to w h o m I have granted "the
to reproduce and distribute copies of the
in and
f ro m m i c r o f i l m and the right to reproduce
and distribute by abstract
Date
this
in any
format."
iv
To m y parents
"Delight yourself
in the Lord and he will give you the desires
o f your hear t ."
Psalms 37:4
V
. VITA
Jong-Gab Jun, the first son of In-kee Jun and Jun-Ok Kim,
w as born in Taegu, Korea on M a y 4, 1953.
After receiving a
Bachelor of Science degree in c h e m is tr y in August, 1979 from
Sogang University, he joined the Korea Institute of Science and
Technology w h e r e he w or k ed as a researcher until August, 1982,
when he came to Mont an a State University to pursue his studies.
vi
ACKNOWLEEX^MENTS
I would
like to take this opportunity to thank Jesus w h o
gave m e a n e w life and a joy of
life.
I extend m y appreciation to m y parents and to Pastor
Kang,
for their e nc ou ragement and for believing
in me.
In-Kyu
To my
fellow researchers, Dan Bruss, Rich Copp, T i m S c h r a m and Joe
Sears,
through
I extend m y gratitude
this project.
Cardellina
for their valuable help and advice
I w ould also like to thank Dr.
John H.
II for the invaluable help of structural
id e n t ification.
I w ou l d especially like to thank Dr. Bradford P. Mundy,
only for all his helpful advice and guidance,
patience w i t h m y
Finally,
but also
not
for his
indecisiveness.
I thank m y wife,
for being together.
You-Kyung and m y son,
Se-Young,
vii
TABLE O F CONTENTS
Page
I N TR O DU CT ION ....................................................
I
Natural Products Derived from Ketals,
Background W or k from Our L a b o r a t o r i e s .................
Natural Products C ontaining 5 -M em be red Rings
Vi a Prope I l a n e s.... ........................
Non-propel l a n e s........... .................
CO OO
RESULTS A N D D I S C U S S I O N . ......... ............ .................
11
Ketal C h e m i s t r y ......... '.................................
F r a g m e n t a t i o n ..........................................
Need for M e c h a n i s m ................................
Further P r o b l e m s ...................................
Other Methods of Fragrmntat io n ..................
Other Unique Chemistry of Bicyclic Ketals......
Attenpt at M ak in g "Coupled" K e t a l ..................
Functionalized Bicycl ic Keta I S y s t e m s ..............
Attempt at Synthesis of S i r e n i n .....................
Dianion C h e m i s t r y .........................................
A N e w Approach to V a l e r a n e ...........................
Possible Use in Maleimycin S y n t h e s i s ..........
Synthesis for Possible Hirsutene Intermediate ....
Sunrmary...........................
11
11
11
14
19
25
30
33
35
39
39
49
54
59
EXPERIMENTAL. ...............
NOTES A N D R E F E R E N C E S .................. ....... ........... ..
I
60
120
Viii
LIST O F TABLES
Table
I.
Table 2 .
r
Reference of
c o n s t a n t for
and coupling
P y r i d i n e ........................
29
Assign me nt of Chemical Shift for axial and
equatorial proton of k e t a l .......................
34
ix
L I S T OF FIGURES
Figure
I.
Figure 2.
The 6 ,8- D i o x a b icyclo [ 3 . 2. I]octane
Skeletal S y s t e m ...................................
j
Natural Products Having Ketal
Structures or Derived
from K e t a l s ..............
2
Figure 3.
Synthesis of B r e v i c o m i n ............
if
Figure 4.
Synthesis of the Mou se P h e r o m o n e ................
if
Figure 5.
Synthesis of 7 , 7 -Dime thy I-6 ,8 -dioxabicyclo
[3.2.1 ] o ct a ne ......................
5
,Figure 6 .
Synthesis of Racemic (cis- 6 -methyltet rah yd ro p yr an - 2- y I )acetic a c i d .....................
5
Figure 7.
Synthesis of the Tussock Moth Pherorrone........
6
Figure 8 .
Synthesis' of Solenopsin A ........................
7
Figure 9.
M o d h e p h e n e ...................................
g
Figure
10.
Total Synthesis of M o d h e p h e n e ...................
9
Figure
11.
Rearrangement of the N-Acyl lactam..............
10
Figure
12 . Synthesis of 2-Subst ituted O x a z o l i n e s ..........
10
Figure
13.
Mycobactic A c i d ...................................
10
Figure
14.
Fragmentation of Cis and Trans 6 - o c t e n - 2 - o n e ..
12
Figure
15.
Proposed M e c h a n i s m for K e t a I Cleavage
w it h Ac I.......................................
13
Cleavage of e x o /e n d o - 7 - D e u t e r iomethyI 5 . 7 -dimethy I- 6 ,8 - d ioxabi cy cl o[ 3. 2 . 1]]o c t a n e . ..
14 .
Figure
Figure
Figure
16.
17.
18.
Cleav ag e of e n d o - 7 - isop ro py 1-5,7-dime thy I 6.8- d i ox a bi c y c lo [ 3 . 2 . 1 ]o c t a n e .................
15
C le avage of 5 ,7 , 7- T r !methyl- 6 ,8-dioxabicyclo
[ 3 . 2 . 1 ] o ct a ne .............
16
.X
Figure
19.
H Transfer in 6 -Acetoxy-7 Ttre thy I -7-octene2 - o n e ...................... '.......................
I/
Atte mpt ed Further Reaction of 6 , 7-Diacetoxy7 -methy I - 2- oc t an on e..............................
18
Other Fragmentations of Deuteriomethyl
Ketal C l e a v a g e ................................... .
]g
Figure 22.
Cleav ag e with M a g n e s i u m b r o m i d e ................
19
Figure 23.
M a g n e s i u m bromide Reaction with
T e t r a h y d r o f u r a n ....................
20
Figure 24.
Cleavage with Triethylsi lane...................
22
Figure 25.
The Selective Ring Opening by T r i et hysil a n e ...
23
Figure 20.
Figure 21.
Figure 26.
Isomer of I ,2 - D i me th yI - (c i s )-6m e th y I tet rahydropyran-2-y I !propane.............
24
Configurations of Isdner of I ,2-Dimethyl (c i s - 6 - m e t h y It etrah yd ro py ra n- 2- yl !prop an e.....
24
Cleavage of 7 -Isopropyl- 5, 7- di me th yI-6,8dioxabicyclo[3.2. I ]octane with A I H 3 ............
25
Cleavage of 7 - Isopropyl-5,7 - d i m e t h y I- 6 ,8 d ioxab icycl o[ 3.2. I ]octane with Al 13 ............
26
NaBH^ Reduction of 2 , 3 -Dime thy I - I- ( 5, 6d im e thy Ipyr id ine- 2-y I )bu t a n o n e .................
30
Possibilities of Coupled Bicyclic ketal
F r a g m e n t a t i o n ....................
31
Preparation of 5 - (n-Bro mo pe nt yI )-7-methy 1-6,8d i o xa bi cycIo [ 3 .2.1]o c t a n e .......................
32
Figure 33.
A ttempted Coupling R e a c t i o n ...........
32
Figure 34.
Formation of 7-Methyl-4-propanal'-6 ,8
d ioxab icycl 0 [3.2. I ]o c t a n e .... ..................
33
Figure 27.
Figure 28.
Figure 29.
Figure 30.
Figure 31.
Figure 32.
Figure 35.
Figure 36.
Isomers of 7 - M e t h y I- 4 - p r op an aI- 6,8
dioxabicyclo[3.2. I ]o c t a n e ..................
35.
Attempted cyclization of 2 - (2-Hydroxymethyl )-
6 - (n-decy I )- 3,4-d ih yd ro-2H-pyr a n ...............
36
-
xi
Figure 37.
Brohni nation of K e t a l ................ ........ . ...
36
Figure 38.
Grieco's
37
Figure 39.
Retro Forrra I Synthesis
Figure 40.
Esterification of 6 , 10-Dimethyl-5,9nonadienoic a c i d ........ .................. .
38
Figure 4 I.
A bs olute Stereochemistry of
40
Figure 42.
Conformations of
Figure 43.
Rao 's Synthesis of V a l e r a n e .......................
41
Figure 44.
Comparison of Conformation of V a l e r a n e ..........
42
Figure 45.
Baldwin's Synthesis of V a l e r a n e . ..................
43
Figure 46.
Dianion of 4 , 5 - D i m et h yI cy cIohexene
dicarboxylate. . . .'................................
44
Dianion M e d iated. S y n t h e s is of c i s - 9 , IO-Bis
(carboxymethy I )-A2 -decal in ......................
45
Retro Synthesis of c i s - 9 , 10 -D im et hyldecal in- 2- e n e ........ .............................
45
Figure 47.
Figure 48.
Synthesis of S i r e n i n ..................
for S ir e n i n .............
I - V a l eran on e.....
38
I - V a l e r a n o n e.................
12 -T hia[4 . 4 . 3 ] p r o p e I I- 3 - e n e .....
40
47
Figure 49.
Synthesis of
Figure 50.
Synthesis of c i s - 9 , I O- Di methyldecalin-2-one...
47
Figure 51.
A ttempted W it t ig Reaction of c i s - 9 , 10Dimethy ldecal in- 2- o n e ............................
48
Figure 52.
Synthesis of V a l e r a n e ......... '.................
Figure 53.
Conformational Assignment
Figure 54.
Structure of M a l e i m y c i n ......................
Figure 55.
N - S u b s t i t u t e d - A^ -cyclopentene-1,2d icarboxy Iic i mides..............................
49
for Valerane.. ......
50
50
51
Figure 56.
Weinrab's Synthesis of M a Ieimyci n. . . ............
51
Figure 57.
Syn the si s of N - B e n z y l s u c c i n i m i d e .................
52
Figure 58.
Attempted Synthesis of Cyclopentanones........
53
x ii
Figure 59.
Synthesis of c i s - 3 - (N-Benzy I )-2,4 - d i o x a b ieye Io
[ 3 . 3 . 0 ] h e p t a n e ............................... ........................................
53
A ttempted Synthesis of 3 - (N-Benzyl)-2,4d ioxobi eye Io[ 3 . 3. 0 ]hep t- A* '^-ene,......... . . . .
34
3 - ( N - B e nz y l)-2,4 -d i o x o t rieye Io [3 .3.3.0]
decane and 3 - ( N-BenzyI )-2,4-dioxotricyclo
[3.3. 2 .0 ] jnonane ....... .......... ...............
54
Structure of H i r s u t e n e , Coriolin and
H ir sutic a c i d .....................................
55
Figure 63.
Retro Synthesis of Hi r s u t e n e .......
56
Figure 64.
D a n h e i s e r 's Cyciopentene Annulat i o n ............
56
Figure 65.
Synthesis of 2 *7 , 7 - T r imethyI-cis- 1 ,5d ic ar boe th ox y -b ic yc lo [3 .3 .0 ] oc ta n- 2- ol ........
57
Figure 66 . Tautomers of 2 -Carboethoxy-4,4-dimethy!cyclo­
h e x a n o n e ......... ............................... .
58
Figure 60.
Figure 61.
Figure 62.
xi i i
ABST RA CT
N e w approaches to natural products of theoretical and
synthetic interest are presented.
A m e th od ol og y for the
cleavage of the 6 ,8 -dioxa bicyclo[3.2.1 ]octane skeletal sy st em is
explored by using acetyl iodide, m a g n e s i u m b r o m i d e , a l u m i n u m
iodide, a l u m i n u m hydride and t r.iethy Is i lane.
It is found that
the f ragmentation products reflect the configuration of the
ketal isomer; e n d o -ketaIs give c i s-alkenes and e x o - k e t a Is give
t rans- a lkenes. The fragmentation of the ketals gives products
dependent on c o n d it ion.
The utility of this fragmentation
m e t h o d o l o g y is d em on str at ed in the formal synthesis of si renin.
Also, a m e t h o d o l o g y involving vicinal dianions of 1,2-diesters
is explored as a rapid entry into a highly f u n c t i o n a l ized
bicyclic diester. , The utility of dienolate m e t h o d o l o g y in
organic synthesis is seen in the applications to the synthesis
of valerahe and synthetic approaches to m a leimycin and
hi'rsutene.
I
CHAPTER I
INTRODUCTION
Qjr
research h a s , as
synthesis methodologies,
choose certain natural
its focus,
rather
found
than synthesis
itself.
products as test molecules
developing n e w methodology..
can be
the development of ne w
We
for the
Evidence for our past
involvement
in the research activity of our group.
Natural Products Derived from Ketals.
Background Work from Our
Laboratories.
The
6,8-dioxabicyclo[3.2.1 ]octane
skeletal
c o m m o n structural component of sugars,
variety of c om p ou n ds
and m etab ol it es
system,
(I),
a
is found in a wide
(Figure
I).
3
2
I
6
7
I
Figure
I.
The 6 ,8- D i o x a b ieye Io [ 3.2.1 ]octane
Skeletal
System
Our group has been c o m m i t t e d to developing n e w approaches
to natural products having this skeletal
i t ( F i g u r e 2).
feature or derived
from
2
'CK
'(CH 2)10CH 3
C H 3( C H 2 ) ^ )
^ M C H 2) ^ C H 3
6
Figure 2.
Natural Products Having Ketal
f ro m Ke t a Is .
The p h er omo ne
Dendroctonus
for the w estern pine bark beetle,
b r e v i c o m i s , has been
2» a n ^ nam ed b r e v i c o m i n H
Lipkowitz
Structures or Derived
(Figure 3).
isolated,
assigned structure
This has been synthesized by
The isolation and identification of 3 as
a phe ro mon e of the m o u s e Mus m u s c u l u s , has recently been
reported^.
by
synthesized 2 and verified
its conversion to e x o -brevi comi n j? (Figure 4).
c om po un d
oil
Born ma nn^
isolated
has been
A similar
identified as a constituent of Japanese hop
from H u m u I s I u pu Ius^
The glandular
its structure
(Figure 5).
secretion of the civet cat
(Viver ra civetta)
is k n ow n as civet and is one of the few a ni ma l-derived perfume
3
materials.
A recent e x am ination of the constituents of civet**
resulted in the isolation of a m inor component
(2 m g from I kg)
w h o s e constitution w as d et erm in ed by spectra I^ and synthetic
m e a n s ^ to be
5_ ( F i g u r e 6 ).
The Douglas
fir tussock m o t h
(O r g y ia pseudot su ga ta ) is a
pernicious defoliator of the fir trees of the N or th western
United States.
identified as
tests
the
The active p heromone constituent has been
(Z)- 6-heneicosen-ll-one^, (j>), h o w e v e r , in
field
(E)-isomer has been found to have equivalent
Q
bioactivity .
Q
In a separate bioassay
, others have
found that a
60:40 (E)/(Z) m i x t u r e of 6> was considerably m o r e active as a
phe ro mo ne than pure material
isolated from female
tussock moths.
This pheromone has been synthesized by our group ( Fi gu re 7)*
The fire ant,
Solenopsis s a e v i s s i m a , derives its name
the painful effects of the v e n o m delivered in its bite.
practical
interest
is the k no wn hemolytic,
antibiotic activity of the venom* *.
from
Of m o r e
insecticidal and
There have been determined
to be a number of tra n s- 2 - m e t h y l - 6-alkyl or alkyny piperidines
serving as constituents of the vendm;
these) was
synthesized
in our group
Solenopsin A,
(Figure
(7), (one of
8 )*
Natural Products Containing 5 - M e m b e r ed Rings
Via Propel lanes
The natural propel lane, m o d h e p h e n e 30.» was
isolated from
the r a y Iess goldenrod and has been the target of several
innovative
syntheses* ^
(Figure
9).
4
Figure 3.
Synthesis
of Brevicomi n
Figure 4.
Synthesis of the Mouse Pheromone
5
Figure
5.
Synthesis
octane
of
7,7-Di m e t h y I - 6 ,8- d i o x a b i c y c l o [3.2.1]
Q) R = H
b) R = COCH 3
PDC
----- ►
Figure 6.
OOH
Synthesis of R a ce mic
2 -y I) acetic acid
(cis- 6 - M e t h y Itetra-hydropyran-
6
Dt-BuLi
2^ 1O1V
CH 3ICH 2I9'
r
(CH2)1CH 3
( cis:trance = 22:78 )
Figure
7.
Synthesis of the Tussock M o th Pheromone
The recent past has w i tn essed a flourish of interest
eye lopentano id c h e m i s t r y ^ .
attributable to the
Much of this
interest
isolation of biologically
in
is
important
eye Iopen tanoid and poIycondensed eye Iopentanoid natural
products.
The e y e ! o p e n tanoids
the synthetic chemist,
highly substituted
represent a complex challenge to
as most of these novel
in addition
compounds are
to possessing the five m em b e r e d
ring skeleton.
M odh ep he n e was chosen as a target molecule and synthesized
in our group *
Critical
to the success of this synthesis was a
d ia ni on -me di at ed eye Io p e n tannuI at ion procedure,
a heteroatom-
ass i sted stereoselective hydrogenation and a d i m e t h y lation of a
carbonyl
(Figure 10).
7
D C cH 11NH,
C 9H19Br
2) Eti^Br
v^ - ( C H 2)9CH 3
'(CH 2)9CH 3
NaBH 4 fMoO 3
NH CH -HCl
— ■^
^(CH2)9CH 3
OH
29
28
DHg
2+
'(CH 2)^qCH 3
2) NaBH 4
7
Figure 8.
NH2 - ( C H 2)9C H:
Synthesis of Solenopsin A
8
Figure
9.
M od he phe ne
N o n - p r o p e I lanes
By analogy to the N - a c y I lactam rearrangement used in our
laboratory
for the synthesis of 2 - su b s t ituted p y r r o l ines and
piperidines^
(Figure
11), K i m ^
envisioned a n e w procedure
preparing 2 - s ub stituted o x a z o Iines.
the N - a c y I- 2 - o x a z o Iidones
12).
This
rearrangement of
in the presence of c a l c i u m oxide has
been shown to provide a n e w entry
(Figure
Thermal
for
initial
success
that a similar approach might
into 2-substituted oxazolines
suggested the possibility
find eventual
synthesis of the natural product,
application
in a
mycobact ic acid 4^3 (Figure
13)1 7 .
Our group has
shown
the utility of n e w protocols
successful c om pl et i on of a number
remains
to be done?
a formal
fragmentation,
synthesis of si renin,
m e t ho d ol o gy
of specific targets.
What
What questions need to be a n s w e r e d ?
next portions of this thesis will
bicyclic ketal
in the
discuss:
In the
a) The m e c h a n i s m of
b) Application of this protocol
c ) Extension of the dianion
for preparing ring systems,
d) A n e w synthesis of
to
9
valerane,
e) Approaches
P re liminary
studies
to the antibiotic,
toward the synthesis of h i rsutene.
MeOOCDIDA
MeOOC-D
MeOOCx^,
2)1,3-di- MeOOCbranopropane
CH3
DLDA
2) 4-brcmo-2-butanone
H3
Me2Zn
DMeLi
2) H+
H3
MeO
38
CH3
H 3C - U ^ - C H 3
CH3
30
Figure 10.
m a i e i m y c i n and
Total Synthesis of Modhephene
TiCl4
f)
Figure
J I.
R ea rr angement of the N-Acyl lactam
Figure
12.
Synthesis of 2 -S ub stituted Oxazolines
Figure
13.
M y c o b a c t ic Acid
11
CHAPTER 2
RESULTS AND DISOUSSICN
Ketal Chemistry
Fragmentation
Need for M e c h a n i s m
A series of bicyclic ketai
fragmentations using acetyl
iodide d e m o n s t r a t e d 1a quite interesting relationship
the trans alkene was
the major
in which
p r o d u c t , just as the exo
orientation prevailed in the k etai.
A useful mecha ni st ic
interpretation w as generated from the observation that there
appeared to be a general
trend that e n d o - k e ta Is gave c i s -alkenes
and e x o - k e t a Is gave t ra n s-alkenes.
that G ri gn ar d additions or hydride
It has been an observation
reductions used
synthes is. Q f -.the bicyclic ketai s always
predo mi nan ce of exo products.
repeated experiment,
result
in the
in the
In the simplest, and m os t often
the e x o - to e n d o - ratio of _l_5 is 60:40.
Cleavage of this ketai with Na I,/AcCl gave a 65:35. ratio of trans
to c i s a Ikenes
(Figure
14).
Althou gh there are several possible ways
results,
w e suggest that a m e c h a n i s m similar to that used by
Goldsmith^
for ether cleavage m a y
This m e c h a n i s m rationalizes
gives
to interpret these
find application (Figure 15).
the observations
t rans-R, and e n d o -R gives c i s-R.
Also,
that e x o -R
the same results
would be Observed if the first acetyl group coordinated with
0- 8 .
60:40(exo:endo)
Figure
65:35(trans:cis)
Frag men ta tio n of Cis and Trans 6 -Oc ten-2-one
14.
To test this m e c ha n is ti c hypothesis,
substrate that w o ul d not
we chose a reaction
be influenced by the differences
bulk of the exo and endo substituents.
The addition
in
of
d e ut e ri omethyI G ri gn ard to the dimer of methyl
vinyl ketone,
(£),
derivatives,
(^8 ).
gave the isomeric d e ut erio bicyclic ketal
The
ratio of the exo and endo deuterio m e t h y I substitution
(2:1) was e asily derived f rom the proton N M R spectrum.
of
this
ketal
(which should experience no steric biases) gave an
alkene m i x t u r e of 49 as shown
in Figure
16.
The cis-methyl
proton (1.66 ppm) at C - 7 is always m o r e downfield
trans-methyl
proton
than the
(1.56 ppm).
As a last test of this m e c h a n i s t i c interpretation,
able
Cleavage
we were
to prepare pure e n d o - 7 - isopropyI- 5, 7- d i m e t h y 1-6,8-
d i oxabicyclo[3.2.1]octane,
(52),
in
65% yield by
the addition
of i so pr o py !m a g n e s i u m chloride to 8.
Fragmentation gave only
the Z-isomer of 7,8~d im e t hyI - 6 -nonen- 2 -one,
only
13% yield.
product
Figure 15.
W e also obtained
(Figure
(53);
h o w e v e r , in
7% of the double bond m ig r a t e d
17).
Proposed Mechanism for Ketal Cleavage with Ac I
I4
<bo/
6 1.26
,CD3
^ h o
L^
' CH6X0-48
6 1.36
3
xCDendo"48
(exorendo = 2:1)
6 1.66
CH-
/ T l
\,
trans-49
(trans:cis = 2:1)
I6.
Figure
Cleavage of e x o /endo-7-Deuteri omet h y I -5,7dimethy I- 6 ,8-di oxab ieye Io[ 3. 2.1 J octane
F r o m these definitive e xperiments on the m e c h a n i s m of the
ketal
fragmentation w e can conclude that the fragmentation
products
reflect the ketal
and e x o - k e t a Is give
isomer; e n d o - k e t a Is give cis-alkenes
tran s- a Ikenes.
Further Problems
Other
(Figure
products appeared
in the cleavage reaction of 52
17), w h i c h gave 64% of very
labile and easily decomposed
product
5_5.
What are they?
support
the proposed m e c h a n i s m ?
as a starting material
the reaction,
the crude material was
56
because of the
to distill
run through a column
15 m m of Florisi I,
p e t r o l e u m ether:ethyl
observed that a tt em pt i ng
to
lack of stereoisomer problems.
of 25 m m x I 50 m m silica gel topped with
using as an eluant,
clues
W e chose the bicyclic ketal
to solve these problems,
simpli ci ty of preparation and
After
Do they give additional
acetate
(7:3).
It was
the crude product directly
resulted in extensive deco mp osition and formation of polymeric
material.
Figure
18 shows
m e t h y I -6-octene-2-one,
octene-2-one,
58,
the products
17.
7-
5 7 , (16% yield) and 6-acetoxy-7-me thy I- 7-
(37% yield) as a major product with 6 ,7-
d iace toxy - 7-me thy 1-2-octanone,
Figure
from the reaction:
_59,
(16% yield).
Cleavage of e n d o - 7 - IsopropyI-5,7 - d i m e t h v I- 6 .8 d i o x a b i e y e l o f i m I ]o c t a n e
Figure
18.
The
^
carbons m o r e
carbonyl
Cleavage of 5,7,7-Trime thy I- 6 ,8- d i o x a b Ieye Io
[ 3 . 2 . I Joctane
C N M R s pe ct r um of 38 shows
than starting material.
of an ester at
170.2 ppm.
11 carbon resonances;
The data also shows
two
the
The 1H N M R s p e c t r u m shows
m ethyl proton of acetate at 2.04 p p m and m e thine proton of C- 6
at 5.14 p p m as a triplet which
is highly deshielded due to the
ester group and adjacent olefin.
C - 7 at
1.70 p p m
is observed.
w he n 4.87 and 4.93 p p m are
Also,
a methyl
This broad singlet
irradiated.
A m a ss
proton peak of
is sharpened
156 amu
is
obtained w hich
is a mu 42 less than the expected molecular
weight.
Mas s -s p ec t ra I reaction triggered by intramolecular H
transfer
involves an
initial
h e t e r o a t o m such as Figure
radical
19.
The unpaired electron
to form a n e w bond to an adjacent
H atom,
site on a saturated
is donated
(in appropriate conformations)
w it h c on comitant cleavage of another bond to that
hydrogen.
Figure
19.
H Transfer
in 6 - A c e t o x y - 7 - m e t h y I-7-octene-2-one
The 13 C N M R s pe ct r um of _59 shows
the starting material
(170.5 and
170.0 ppm).
acetate methyl
(58 and
peaks
and
The
four m o r e carbons
than
indicates two ester car bony I carbons
1H N M R spectrum also
(2.08 and
1.94 ppm).
These
shows
two
two products
53) have a similar structural relationship, and since w e
did not get any
53_ from some reactions, we suspected _59 to be an
intermediate precursor of _58.
To test
this hypothesis,
separated and stirred for two days under the reaction
conditions,
but w e did not get any
58. (Figure 20).
59 was
J8
Figure
20.
Figure 21.
A t t e m pt e d Further Reaction of 6 ,7 -D ia cetoxy- 7m e t h y I - 2 -octanone
Other Fragme nt at ions of Deuteriomethyl
Cleavage
keta I
Also,
the
same
w h e n w e carried out the same reaction on
products
except
F r o m these results,
d euterated
side products,
procedures
(Figure 21 ).
w e can conclude that the fragmentation
reaction, although a unique w a y
has
we got
and before
to m a k e
it has
6 ,e-unsaturated ketones,
true synthetic potential,
for controlling the reaction will
have
to be
found.
Other Meth od s of F ragmentation
An
interesting result was
found during the cleavage
reaction of ketal ^56 w it h acetic anhydride and m a g n e s i u m bromide
(prepared by m i x i n g an equimolar amount of I ,2-dibromoethane and
m a g n e s i u m in anhydrous ether).
This
a ratio of 2:8 with no trace of 57.
gave a very low yield,
suggest
that
fragmentation
Figure 22.
reaction gave
Even though
the differences
involved
(Figure
in the two
22).
Cleavage w i t h M a g n e s i u m bromide
W he n w e used tetrahydrofuran as a solvent
bromide,
this reaction
in product composition
there are different m e c h a n i s m s
processes
58 and 59 in
4-bromobutyl
acetate (6 0 ) was
to m a k e m a g n e s i u m
the major product along
20
w it h
the starting material,
(56).
W e tried a blank
test and
found that tetrahydrofuran reacts w i th m a g n e s i u m b ro mide and
acetic anhydride
Figure 23.
to give
60 in
93% yield (Figure 23).
M a g n e s i u m b r om i de Reaction with Tetrahydrofuran
G r a y 19 reported that
reductive cleavage of the carbon-
oxygen bond of acetals and ketals can be acc om pl is he d by ionic
hydrogenation, e m p l o yi n g triethyl si lane as the reducing agent
and boron
t r i fluoride etherate as
the acid.
We applied this
s ys t em to our bicyclic ketals, _1_5> 5jS and 52, and
yield of C^-Og bond cleavage
to
form alcohol
found high
(Figure 24).
The methyl ketal _1_5 gave only the c i s isomers as a 40:60
mixture
of
85% yield.
procedure
threo alcohol,
(6 1 a ),
and erythro alcohol,
(6 1 b ), in
The formation of cis stereochemistry by this
is readily rationalized by considering an intermediate
borane c om p le x and S^2 hydride displacement
15 showed
in Figure
252 0 .
The previous w o r k by our g r o u p 21 also showed that a l u m i n u m
hydride produced exclusively c i s - o r iented stereoisomers,
and
(6 1 b ),
hydride.
(61a)
in a ratio of 60:40 by regioselective attack of the
A I H 3 w a s prepared by m i x i n g an equimolar amount of
21
lithium a l u m i n u m hydride and a l u m i n u m chloride in anhydrous
ether
solution.
Brown's w o r k on the hydro.geno! ys i s of acetals
and ketals by m ix tu res of lithium a l u m i n u m hydride and a l u m i n u m
chloride in e t h e r 22 has
indicated that,
hydrolysis of d i oxabicyclooctanes,
the hydrogenolysis
reaction
as in the case for th<e
the rate controlling step of
is the cleavage of the C 5-O 6 bond,
w e a ke n ed by the association of its oxygen a t o m w i t h the Lewis
The association of O 6 w i th a l u m i n u m results
acid.
in the
hydride attacking C 5 f ro m the opposite side of the complex
rather
than
Another
the hindered
side.
interesting result c a m e
from the cleavage of 56
w i t h E t 5SiH, w h i c h gave the expected cis alcohol
dehydrated product
mixture,
gave
64 and
6_2 w it h unident ified 63 as a 21 :45:34
respectively.
Also,
the e n d o - b ieye Iic k e t a l , (52),
the expected cis alcohol,
(66a ), and dehydrated products,
65a and 6 5 b , as a 74:12:14 ratio,
respectively.
In contrast
to
the results of the cleavage reactions of 15 , 56 and 52^ with
E t 5SiH, a m o r e substituted and higher chained c om p o u n d at Cy
gave m o r e dehydrated product
than alcohol.
Again,
this
m e c h a n i s m requires that boron trifluoride associates with O 6 and
we ak en
the C 5-O 6 bond w hi c h is attacked by hydride from the
opposite side of the complex
to give cis alcohol.
Followed by
losing H 2O and hydride attacking the c a r b o n ium ion by S^l w hich
gave 65a and 65b (Figure 26).
indicates
the isopropyl
gives
isomer.
the
The model
of this comp ou nd
group could not get
free rotation, which
22
Figure 24.
C le avage w it h Triethylsi Iane
The configurational
the following:
a ss ignments of 65a and 65b are based on
(I) The c i s isomers,
65a and 6 5 b , should exist
at r o o m t em perature as two rapidly equilibrating chair
conformations,
the two protons at Cj and C 5 giving rise to an
23
axial -equator ia I time averaged signal
spectrum.
isomers
Accordingly,
the two axial m et h i n e protons of the cis
resonate at higher
c orresponding
protons
in the proton INMR
of
field
the
(3.10-3.35 ppm)
trans
isomers
(2) To d et er m in e the configuration of
w hich
of 7 Hz w e r e obtained
and
1.77 p p m gave a doublet
for 65a and 9.5 Hz
17 O 0 angles b e tw ee n Cj proton and H^,
doublet of doublet
Hg and
(4.01- 4.12 p p m) 23.
is coupled with H^.
Irradiation of the methyl
Coupling constants
for 6 5 b , indicating 20°
respectively.
protons at 0.84 p p m of 65a gave a
for H^, w hi ch coupled with
the Cj
indicates H a and Hg coupling constant of
corresponds
to 180° angle b e tween
irradiation of 65b methyl
the
the branched propane,
irradiation of the m e t h y le n e protons at
of the Cj proton,
than
proton and
10 Hz and
the two protons.
Also,
protons at 0.70 p p m gave a doublet
H a , w h i c h showed a 4 Hz coupling constant between H a and Hg,
c or re sponding
to 45° betw een
these
two protons
(Figure 27).
Hf
15
Figure 25.
61
The Selective Ring O pe ning by TriethylsiIane
for
24
Figure 26.
Isomer of 1,2-Dimeth yl -( c i s - 6 - m e t h y Itetrahydrop yr a n- 2 - y I ) propane
3H - j H a
Figure 27.
65a
7 Hz
65b
9.5 Hz
(20°)
(170°)
3Ftt3H 0
10 Hz
4 Hz
(180°)
(45°)
Configurations of Isomer of 1,2-Dimethyl-(cis- 6 m e t h y l t e t r a h y d r o p y r a n - 2 -yl) propane
Wh en w e used a l u m i n u m hydride for the endo-isopropyI
bicyclic ketal , (_52), w e obtained an 83% yield of cis alcohol
25
(66a),
and
earlier,
trans alcohol
(66b),
in a
13:87 ratio.
As m e n t io ne d
a l u m i n u m h ydride usually gave c_i_s alcohol and no trans
alcohol but trans alcohol was
the maj or
product
in this case
(Fi g u r e 2 8 ).
Figure
28.
The
Cleavage of 7-Isopropyl-5,7-dimethyl-6,8dioxabicyclo[3.2.1 ]octane with A l H 3
1H N M R s p e c tr um of 66a shows
w h i l e 66b shows
the C 5 proton at 3.43 p p m
the C 5 proton at 4.20 ppm.
This
indicates
that
66a has an axial proton and 66b has an equatorial proton at C 5.
In contrasting the results of the cleavage
reaction of
the
bicyclic ketals with A l H 3 , E t 3SiH and M g B r 2 , we can conclude
that fragmentation of the ketals give products dependent on
condition.
Other Unique C he m is t ry
of Bicyclic Ketals
W h i l e trying to find n ew reducing agents
ketals,
we
very novel
to cleave bicyclic
found that a l u m i n u m iodide and acetonitrile gave a
fragmentation.
The A l l 3 was prepared by refluxing
one equivalent of dry a l u m i n u m foil and
1.6 equivalent of iodine
26
in ca.
IM acetonitrile solution.
e n d o -isopropyl
bicyclic ketal,
cy cI ohexenone-3-y I ) propane,
dim e t h y lpyridine-2-yl)
W e used this s y s t e m with
the
(52), and found 1,2-d i m e t y I -(2-
(67),
butanone,
and
2,3-dimethyl-l-(5,6-
(£ 8 ), as a 31:69
ratio.
These
could be separated by flash chromatography using pet ro le um
ether:ethy I acetate
in a 7:3 ratio.
the starting material, w e obtained
whi ch was analyzed by GLC,
When w e
reacted 2.0 g of
1.7 g of a crude mixture
11' x I /4" of 10% O V - 17 column,
showed 67 and 68 as a 31:69 ratio w i th a few other
y ie l d) of 67 a n d 0.1 5 g (7.3% yield) of 68 an d
d ec om po se d product by
c h ro m at ogr aph y
29.
flash chromatography
indicates
6_7 (Rf = 0.37)
Figure
very minor
H o w e v e r , w e were only able to isolate 0.1 g (6%
impurities.
than
and
(Figure 29).
65$ (Rf =0.25) is a m o re
in the same
solvent
1.16 g of
polar
TLC
compound
system.
Cleavage of 7-Isopropyl-5,7-dimethyl-6,8d i ox a b i c y c l o [ 3 . 2 . I]octane with Al Ij
Structural assign me nt of 6 7 :
only 3 methyl
p e a k s , whic h
(I) The
N M R s p e ct ru m shows
indicates one methyl group is
c h a n g e d , and shows one alkene proton at 3.84 ppm.
A homo
27
decoupling exper im ent gave the environment of the substituted
1,2-dimethyl propane;
singlet
for
irradiation of the 2.36 p p m signal
1.04 p p m methyl
peak and
irradiation of
1.65 p p m
gave
two
and,
the 2.36 p p m m e thine proton also was coupled with
singlets at 0.88 and 0.83 p p m as a isopropyl methyl
m e t h i n e proton.
(2)
cm" * and a G a t e d - ^
carbon at
Finally,
HRMS
indicates
6A
Structural
assign me nt of 68_:
that there are 5 methyl
at
2.63 and
0.92 and 0.85 ppm.
at
two singlets which
Al I of these data m a t ch well with the suggested
structure,
singlets
1669
199.9 p p m and three doublets,
three triplets and three quartets.
j i H i s O.
1.65 p p m
IR indicates a conjugated car bony I at
INMR s p e ct ru m indicates
include one carbonyl
C
gave a
7.71 and
(I) The 1H INMR spectrum shows
p e a k s , two of
2.54 p p m and
them are highly deshielded
three doublets appear
T w o highly deshielded protons
at
1.09,
are observed
7.04 p p m w hich coupled each other and have a
coupling constant of 8 Hz.
Irradiation of the 3.04 p p m signal
(H^) gave a singlet
1.09 p p m methyl
for the
of the 2.01 p p m s ignal
peak and
irradiation
(H) g a v e t w o s i n g l e t s at 0.92 and 0.85
p p m as a isopropyl methyl.
The 3.04 methine proton was
be coupled w it h the 2.01 p p m m e t h i n e
61.09
60.92 and
^ __________ I 0.85
Ha H
63.04
proton.
62.01
found to
28
The above partial
structure should relate
w i t h d r a w i n g group w h i c h deshields H a .
very simple three pieces,
well.
The
but
The 1H N M R spec tr um shows
these do not m a t c h each other
13C s p e c tr um indicates
that
there are
w h i c h have 4 highly d e sh ielded singlets,
quartets w it h no triplets.
(2) The
conjugated carbonyl at 1681 c m
absorbance at
the ketal
structures
4 doublets and 5
IR spectrum shows a
274 n m (C4140) and 239 n m (e6640)
for 2-carbonyl
The H R M S was consistent with
All of these data
the
in ethanol;
that can be put
formula C 13H 19NO.
to react with
N o w w e have several
together as
very
conjugated
indicate that acetonitrile had
to give product 68 .
13 carbons
^ and the UV s pe c t r u m gives an
distinguishable characteristics
p y r i d i n e 2 ''.
to electron
partial
follows:
two methyls
+
+
H
The two protons are coupled
constant of 8 Hz w h ic h
7.04
p p m for C 3 proton
W e can thus put
indicates
(Table
together
following possibilities,
H
and
two protons
to each other w i th a coupling
that
7.71 p p m for C* proton and
I).
these pieces to construct
A and B.
the two
29
Table
I.
Reference of
Pyridine
*H,
and coupling constant
for
^2,3 = **'0- 5. 7
67.46(138.7)
H
33 ,U = 6 . 8 - 9 . I
3 J-j
67.06(125.6)
^2,4 - 0-2.5
3 ^ 5 = 0 . 5 - 1 .8
58.50(149.5)
]
2,6
-
J 2j5 = 0-2.3
To find the correct
alcohol
crystals
structure w e reduced the carbonyl
by using s o d i u m borohydride.
(m.p.
159- 162°C),
6^9, w h o s e
to an
This gave nice white
*H N M R s p e c t r u m
indicates
the c a r b i no I proton at 4.67 p p m as a doublet of d o u b l e t , one
doublet w i t h
w it h adjacent
right
product
tertiary alcohol
(3=9 Hz).
(Figure
30).
(3=3 Hz) and the other
These clearly
doublet
indicate that A is the
30
Figure
N a B H z, Reduction of 2,3-Dime thy I- I - (5,6 -d ime thy I pyr idine- 2 - y l )butanone
30.
The m echanisms of these reactions are not yet known.
Atterrpt at Making "Coupled" KetaI
The bicycJic ketai
ketone as a functional
fragmentation with Ac I and M g B r 2 gave a
group.
Figure 31 shows a lot of variety
of diketones w hi c h can be converted
thiophenes
diketone,
to furans,
from 1,4-diketone and to pyrans,
and also,
a Ido I condensation of
pyrroles,
pyridines
from 1,5-
1,4 -diketone might
give prostaglandins.
As
shown above,
there are a number
if w e can m a k e the coupled bicyclic ketals,
of useful
applications
dimer J_9 w as used as a starting material,
possible.
and was reacted with
m e thy lmagnesi u m b r om i de to give a 50:50 ratio of
erythro alcohol
72."
w er e added to m a k e
equivalent
product.
of
We
Acrolein
threo and
T w o equivalents of tertiary butyl I i thium
the dianion,
I,2-dibromoethane.
followed by addition of 0.5
This
reaction did not give the
imagined a steric effect might hinder
the reaction
31
so w e changed
to 1,5-di bromopentane.
and endo m i x t u r e of ketal
reaction gave an exo
73 as a 66:34 ratio in
wit ho ut any coupled p r od u ct .
ket al
This
51% yield
The same reaction with
20 gave
( F i gu r e 32).
;o
t
^
c h
2
71
(n = 2 )
furan derivatives
71
(n = 2 )
thiophene derivatives
71
(n = 2 )
pyrrole derivatives
71
(n = 2 )
prostaglandin derivatives
N Hn
Figure
71
(n = 3)
71
(n = 3)
31.
pyridine derivatives
%
pyran derivatives
Possibilities of Coupled Bicyclic ketal
F r a g m e n t a t ion
Direct coupling did not occur w i t h our conditions; but
the
reaction gave an alkyl b r om ide w hich w e thought m ight be
substituted w it h another anion of bicyclic ketal
product.
Using £2 w it h
two equivalents of tertiary b u t y l lithiurn
and then 7\3 w as added to this dianion
did not give
to give coupled
the expected product
reactant, but also this
(Figure
33).
32
Figure
32.
Figure 33.
Preparation of 5 - (n- Br om op en ty I )-7-methy 1- 6 ,8 d i o xa b ic yc Io [3.2.1 ] ]oc tane and 5-(n-Bromopentyl)7 - pe nt yl -6, 8- dio xabicyclo[3 . 2 . 1]octane
A ttempted Coupling Reaction.
At this w r it i ng w e have not been successful
coupling of two ketals;
lines.
however,
in this
w o r k continues along these
33
Functionalized Bicyclic ketal Systems
It is another
bicyclic ketals.
alcohol
interesting area
to functionalize simple
W e used m er c u r i c acetate
to cyclize the
72, whic h gave m e r cu ri c c omplex at Q f of bicyclic ketal.
Addition of acrolein under
exo-three,, endo-threo,
21:53:9:17 ratio
in a
radical
conditions
and endo-erythro
gave e x o- er yt hr o,
isomers,
(75), as a
U2% yield (Figure 34).
OH
72
F i g u r e 34.
F o r m a t i o n o f 7 - M e t h y l - 4 - p r o p a n a 1 - 6 , 8 - d i o x a b i e y e Io
L3 . 2 . I Joct ane
The configurational
on the following:
easily
analysis
of
and
1H N M R
groups at Cy are
spectra which gives
1.30-1.34 p p m of endo methyl
the product
four isomers
of isomers of 7_5 are based
(I) exo and endo methyl
identified by their
of the exo methyl
shows
assignments
75 using a 11' x 1/4",
1.18 pp m
group.
GLC
10% O V - 17 column
(A-D) and 1H N M R of A and B s h o w them to exo
isomers w h i l e C and D are shown to endo isomers.
(2 )
Chemical
or equatorial
deshielded
shift of the proton at Q, will
of the proton because equatorial
than axial
proton
(Table
2).
tell
about axial
proton is m o r e
Table 2.
Assignment of Chemical Shift for axial and equatorial
proton of ketal
exo
exo-CHj
endo-CH^
H axial
H equatorial
endo
Irradiation of the
1.50 p p m signals
5.25 p p m for C.
exo,
D
axial
- endo,
(exo-threo),
axial
C
equatorial
- endo,
(endo-erythro)
(Figure
alcohol,
(77^), prepared from 76.
expected product,
B -
(endo-threo),
and
35).
long chain
This
proton at Cz,.
(exo-erythro),
equatorial
W e tried the same reaction w i t h
sharpening
This i n d i c a t e s that A a n d
proton and B and D have axial
T h u s , A can be assigned - exo,
gave
Also,
1.63 p p m signals of A and C gave
of 5.30 p p m for A a n d
C have equatorial
1.18 pp m
1.30-1.34 ppm
1.50 pp m
1.63 ppm
for B and D
s h a r p e n i n g at 5.32 p p m for B a n d 5.2 7 p p m for D.
irradiation of the
;
:
:
:
substituted
reaction did not give the
possibly because of the steric hindrance
(Figure 36).
Another
simple reaction
found in our group.
for halogenation at
Clf of ketal was
To a solution of ketal _56 in carbon
tetrachloride at r o om temperature was added b ro mi ne and the
reaction was
stirred
b ro m o ketal,
(TjO.
(48), (Figure 37).
for
7 hours.
This gave an 88% yield of
The same result was obtained
from ketal,
exo-erythro
exo-threo
endo-threo
endo-erythro
Figure 35.
Isomers of 7 -Me thy I- 4 - p r o p a n a I- 6 ,8- d ioxabieye Io
[ 3 . 2 . 1 Joctane
Attempt at Synthesis of Si renin
Sirenin
(86 ), is a s pe r m attractant
gametes of the water m o l d Al l om yc es 2 ^.
synthesized by G r i e c o 26 (Figure 38).
produced by the female
This has been
36
O H C x /x
S 5^ O H CioHA 0
76
Figure
QoH2^ O d
77
A t t e m p t e d c y c i ization of 2-(2-Hydroxyme thyI)-6 -(ndecyl )-3,4-dihydro-2H-p y ran
36.
\
'0'
CH3
x CD
< IX K
-CH
'CD,
78a
Figure 37.
Bromination of Ketal
We were
formal
in the synthesis of 8J_ (R=OH) as a
synthesis of si renin.
available
also,
interested
from methyl
ketone,
This
intermediate m ight be
(88 ), by halof or m reaction and
88 is the fragmentation from k e t a l , (87^), (Figure 39).
To m a k e ketal,
(87), M V K dimer,
(8 ), was added
to a
solution of 5 - br om o- 2-m et hy1 -2-pentene and m a g n e s i u m in dry
ether
and cyclized by adding
5% aqueous HCl
solution.
The exo
37
R = H
R = [-Pr
(a)
a l l y l magnesi um br omi de.
(c ) Jones oxidation.
(f)
ozonolysis .
(g)
p h o sphonopropionate.
(j)
isopropyl iodide.
Figure 38.
( b ) d i s iamy I b o r a n e , NaOH-HoCb •
(d)
SOCl 2 •
(e) diazome thane, Cu bronze
dimethyl sulfide.
(h) methyl 2-diethyl
(i)
sodium hydride, methyl formate.
(k)
N a B H 4-NaOH, 3N H C l .
(I)
L iAlH4 -
Grieco's Synthesis of Si renin
38
and endo isomers of 87_ w er e obtained as a 84:16 ratio in a
yield.
The majo r exo isomer
is the right starting material
m a k i n g the trans isomer of 8j$ by
gave
the expected
This was
fragmentation.
fragmentation product,
17%
for
Ac I cleavage
88, in a 20% yield.
treated w i t h iodoform reagent to give a positive yellow
precipitate.
Due to
low yield of the
not obtain a prepara t ive Iy useful
iodoform oxidation, w e did
amount of 8J_, thus,
the
product was converted to 89^ and characterized only by H RM S
( F ig u re 4 0).
0
H
HO
81
&
87
Figure 39.
Retro Formal
88
Synthesis
for Sirenin
HO'"81
Figure 40.
89
Esterification of 6 ,10-Dimethyl-5,9-nonadienoic acid
39
Dianion Chemistry
Dianion c h em is try has been shown
to.be a useful and
powerful m e t h o d for ring annulation.
The pioneering work of
W ii k en i ng
for our interest
program.
in our group paved the w a y
in this
Our group is commi tted to the concept of developing
n e w approaches
to natural products using dianion protocols.
Based on the previous work,
knowledge of the value and
w e wi sh ed
to extend our
limitation of the procedure.
A New Approach to Valerane
The valerane skeleton
interesting sesquiterpene
by the reduction
of
form.
The parent c om p o u n d
I-va l er an on e, (9()).
97
Valeriana o ff ic i na l is ^',
sesquiterpene ketones
by several
is a unique and structurally
groups of
.
Valeranone,
groups
investigators,
its structure and absolute
in a c i s - fused deca Iin, ring
Cj^ and Cj 5 m ethyl groups are a-oriented whereas
isopropyl
group
is g - o r iented.
The correctness
structure w as substantiated by two different
I-
valeranones^O.
decal in, valeranone could exist
or
the
in Figure
in at
least
two
system.
The
the C 7
of the proposed
syntheses of d - and
Jn v i e w of the flexible nature of
all-chair c on fo rm at i on s
from
After a great deal of experimentation
it possesses an unusual carbon skeleton having
angular methyl
isolated
is one of the few known n o n isoprenoid
ster eo ch emi st ry w e r e finally established as shown
41^9.
is obtained
two
the cis
interchangeable
such as the "steroid" cis conformation
"nonsteroid" cis c on fo rmation
(Figure 42).
Hartshorn^
UO
32
and H i k i n o j proved
conformation
Figure
that valeranone exists
from a study of
its optical
in the steroid cis
rotatory dispersion.
UI
V
Nonsteroid Cis
Figure 42.
C onformations of
The natural
from
I - V a leranone
I -va lerane, (9_0, was prepared
I -va leranone (9£) by R a o ^ .
The
of the synthetic 9 1a (Figure 43) w e re
those
of
the a uthentic
natural
for comparison
infrared and N M R spectra
found to be
I -valerane,
(91),
identical with
(Figure
44).
OH
OTHP
OTHP
(97.4:2.6)
OTHP
(a)
dihydropyran, H + .
(b)
(C 6H 5 )3P = C H C H 3 .
(c)
B 7H 6 , H 7O 7
(d) C r O 3 .
(e)
C 7H 5O N a , EtOH.
(f) H + .
(g)
dihydropyran
H+(h)
( Q H 5 )3P = C H 2 .
(i ) H 2 , Pd/c.
(j) H + .
(k) C r O 3 .
(I)
H S C H 2C H 2SH, H + .
(m) Raney Ni.
Figure 43.
Ra o's Synthesis of Valerane
42
Synthetic Steroid-cis(d,I)-Valerane
Natural Steroid-cis(I)-Valerane
(Fran Natural (I)-Valerane)
Synthetic Nonsteroid-cis(d,I)-7-Isovalerane
Figure 44.
Comparison of C onformation of V a lerane
The ratio of 9 1a and 9 1b was
to be identical w i t h natural
same
91.
40:60 and only 91a was
found
Baldwin-^,
the
also,
found
ratio of 9 1a and 9 1b by using a p h o t o a n n e l a t ion technique
with a-formyl
ketones
(Figure 45).
43
Va lerane,
with
the decal in structure and cis
seemed to be w el l- s ui te d to the stereochemical
provided by our dianion
ring annulation method.
decided to m a k e this c om po u nd
ring
juncture,
advantage
Thus, we
to test the value of dianion
chemi stry.
9 I q + 91b
91a + 91b
(a)
hv.
(e )
(h )
( j )
H2 ,
Li,
L i ,
(c ) H 2 , Pd/c.
(d)
( C z - H 5 ) 1P C ( C H o )7
TSNHNH2 , E t O H .
(g)
C H 3L i , E t 2O .
N H 3 , t-BuOH.
(i)
ClPO(OEt)2 , T H F , TMEDA.
EtNH2 .
(b )
Pt.
Figure 45.
H+ .
(f)
Baldwin's Synthesis of Valerane
It was
postulated that a vicinal
ester dianion generated
f ro m 9^ m ig ht be a legitimate intermediate if a d i substituted
butane could be
found to act as an electrophile
ring annuI a tion reaction
Figure 46.
in the dianion
(Figure 46).
Dianion of 4 , 5-Dime th y Icyclohexene d i carboxy late
Additional credence to this approach was gleaned
anticipated stability of the dianion generated
from the vicinal
dies t e r, as conjugation of the enolates wou ld serve
the developing charge.
was
the expected
O ne
final
bonus
from the
to stabilize
this reaction offered
formation of only cis-vicinal
diester.
The
dienolate being p re su ma b ly planar to permit conjugation,
implied
that once the first alkylation has occurred the second
displacement w o u l d proceed from the same face, since formation
of the trans
ring
twist betw ee n
juncture w o u l d require the butano group
the two ester residues.
e xa mi n ed by p e rf o rm i ng
When
1.5 equivalents of
cooled,
bicyclic
bright
This hypothesis was
the experiment outlined
in Figure 47.
I,4-dibromobutane w e r e added to the
red THF solution of the dienolate of
diester,
to
(9_3), was
obtained
in 75% yield.
92,
the
45
+ Br(CH2)^Br
^ \ : 0 2 M
e
CO2Me
92
(a)
93
2.5 L D A , T H F , -78° C.
Figure 47.
Dianion M ed ia ted Synthesis of c i s - 9 , IO-Bis
( c ar bo xym et hyI )- /\-dec al in
As expected,
the cis-diester
had been
To transfer
to m a k e
exhaustive characterization revealed that only
formed.
the dies ter to the dimethyl group,
thiapropeI lane,
(9j6),
we proposed
(Figure 48).
CO2Me
=O
CO2Me
93
Figure 48.
Retro Synthesis of c i s - 9 , IO-Dime thy IdecaIin-2-ene
CXir attention was
of sulfide,
(96^).
sequence shown
initially directed toward the synthesis
This was a cc om p l i s h e d by the reaction
in Figure 49.
The diester,
(93) w as
reduced with
46
lithium a l u m i n u m hydride and treatment of the resulting diol
w i th m e t h a n e s uIfonyI chloride
(2J*)’ in. high yield.
in pyridine gave the dimesylate,
Heating ^5
in dry hexamethy lphosphoramide
(HMPA) w i t h anhydrous s o d i u m sulfide
led to sulfide,
(96),
in
93% yield. ■ P aq ue t te 3zf reported that the use of dry H M P A is
essential
to the success of this t wofold S N2 displacement-
c y c l ization.
attack at
In its absence,
the neopentyl
or no 96 is produced.
capacity of HMPA,
the nucleophile
the capability of sulfide
centers
Clearly,
whic h greatly
ion to
is greatly dimini sh ed and Iit tH
the high cation-solvating
reduces the effective size of
relative to its bulk
in other
(especially
protic) media, causes a m ar ke d acceleration of the desired
chemical
change.
Desulfurization of
a cc om p li sh e d by R a n e y- ni ckeI
d i m e t h y l d e c a l in,
in ethanol
solution,
(96),
gave the
(97), in 73% yield and, also, 18% yield of
saturated decal in,
(9 7 a ).
hydr obor at ion to give
at this point,
the sulfide,
This m i x t u r e was
isomeric alcohol,
the unreacted 97a was
subjected to
(98^),
in 9 5% yield and,
separated by silica gel
c ol u mn c h r om a to gr a ph y w i t h p e t r o l e u m ether as a s o l v e n t ; 98 was
isolated w i t h e t h y !acetate as a solvent.
This alcohol,
(98),
was oxidized w i t h p y r i d i n i u m dic h ro ma te to ketone 99 in 93%
yield
(Fi gure 50).
Direct W i t t i g reaction was a t t e mp te d to put the isopropyl
group at the Cg position, but
the expect ed product
this
(Figure 51).
reaction gave 99a instead of
47
Figure 49.
Figure 50.
Synthesis of
i2-Thia [4.4.3]prope Ii- 3 -ene
Synthesis of cis-9,10-Dimethyldecalin-2-one
48
(a)
isopropy 11r i ph eny lp hosphonium bromi d e , n-but yl li th iu m
Figure 51.
We
A t t e m p t e d W it t ig Reaction of cis-9,10Dime thy l d ec a l in-2-one
s imply used
isopropyl Grignard to put the isopropyl
group at C 2 and treatment of the product
oxychloride gave
IOla and
IPO with phosphorous
IOlb as a 45:55 ratio
This m i xt u re was hydrogenated w i th
in a 73% yield.
10% p a l l ad iu m on carbon
hexane and gave 91a and 9_l_b as a 45:55 ratio
in
in 80% yield
(Figure 52).
As m e n t i o n e d earlier,
Rao and Baldwin synthesized 91a and
9 1b as a 40:60 ratio and the reported spectral data
w it h ours.
but
follows:
Irradiation of the 0.83 p p m
in 9jla gave a 0.65% positive NOE effect at
irradiation of 0.84 and 0.79 p p m
positive NOE effect, w h ic h
indicates
in 91b did not
1.51 ppm,
give any
91a is in steroid cis
c on f or m at i on and 9 1b is in nonsteroid cis conf or ma ti on
53).
identical
Also, w e proved the c on fo rmation of 91a and 91b by a
NOE experiment as
resonance
is
(Figure
100
Figure 52.
101a
101b
I
Synthesis of Valerane
Possible Use in Maleimycin Synthesis
M al eimycin,
a n e w bicyclic m a l e i m i d e antibiotic, was
isolated from the culture filtrate of St rep tomyce s showdoensis
and assigned
Also,
structure
102 by Suhado I n i k ^
(Figure
54).
K a s u g a i 36 reported that N - s u b s t i tu t e d - Ai-cyclo­
pen t en e- 1,2-d icar boxy I ic imides
her b i c ida I activities
(Figure
103 have
fungicidal
and
55).
W e i n r a b 37 had previously synthesized m a l e i m y c i n by a longer
route than w e anticipated
the
five-five
(Figure 56).
Our
interest
in making
fused ring s ys te m of this molecule using dianion
annulation suggested a simpler a p p r o a c h .
50
60.83
91a
61.51
60.79
60.84
Figure 53.
Conformational
Assignment
Figure 54.
Structure of Maleimycin
for Valerane
5I
R=ha Io , lower alkyl, lower alkoxy, cyano, aralkyloxy,
h a l o a r a I k yI oxy , aralkylthio, ha Ioaralky Ithio, phenyl naphthyl
Figure 55.
N - Subs 1 1 tu ted-/^*-eye Iopen tene-I , 2-d icar boxy I ic
imi des
X = Br
X = OCOCF3
(a)
S O C l2 .
(b ) B r 2 .
(c)
C H 3O H .
(d)
NaH, D M F .
(e)
acetic anhydride, a m m o n i u m hydroxide.
(f)
t r if Iuoroacetic anhydride.
(g)
N - b r o m o s u c c inimi d e .
(h)
silver
trifluoroacetate.
(i)
pH=4
Figure 56.
Weinrab's Synthesis of Maleimycin
52
W e chose
s uc cinimide as a starting material.
This was N-
substituted w it h the benzyl group because imide proton will
hinder
formation of the needed dianion.
Succinimide,
(104),
benzyl chloride and p o t a s s i u m carbonate were refluxed and gave
N-benzy I succinimide,
(105),
(Figure
57).
104
Figure 57.
Synthesis of N-Benzylsuccinimide
W he n 2.5 equivalents of lithium d i isopropyl a m i d e were
m i x e d w ith
formed;
10 5 , a reddish black color of the dienolate was
but,
propionate.
this dianion did not react with 3 - b r o m o e t h y IYamamoto^
b r o m o e thy!propionate
reported difficulty in e m p l oy in g 3-
in condensations with the dianion of
d i isopropyl succinate and he suspected that the proton exchange
process
was
W e used
fast
(Figure
58).
I,3 - d ibromopropane
for
this dianion reaction and
m a d e c i s - 3 - (N-Benzy I)-2,4-d ioxob ieye Io [ 3.3.0 ]-hep t ane , ( 10 7 ),
60% yield (Figure 59).
In order
Wi I ke ning's ^
reacted w i t h
to
introduce
the
m e t h o d was used.
1,2-double bond
in 107,
The dienolate of
107 was
1.1 equivalents of iodine in the established
in
53
method,
double
but this reaction did not
bond
(Figure
result
in formation of
the
60).
/CO2I-Pr
XXD2FPr
106
Figure 58.
10 5
A ttempted Synthesis of Cyclopentanones
+ BrICH2IgBr
Figure 59.
Synthesis of cis-3-( N - Benzyl )-2,4-diox ob icy d o
[3.3.0]heptane
In an attempt
of
N-CH
to test whether w e w e r e forming the dienolate
10 7 , w e prepared
made
5-5-5
(108) and
each
(Figure 61).
the propel lane of this compound.
5-5-4 (109) propel lanes
W e have
in 25% yield of
54
Figure 61.
3 - (N-Benzy I )-2,4-dio x o t rieye Io [ 3.3.3.O ]decane and
3 -( N- Ben zyl)-2,4-dioxotricyclo[3.3.2.0]nonane
W e also tried pyrolysis and photo reaction of
not
10 9 , but did
f or m the needed double bond.
Even
though w e did not get the target maleimycin,
d em on st rat ed
(1 1 0 ), 5-5-5,
that
the dianion
reaction could
5-5-4 ring annul a tion
this w o rk
introduce 5-5, 5-4
in a convenient way.
Synthesis for Possible Hirsutene Intermediate
Hirsutene,
coriolin,
(1 11), which
is the biogenetic precursor of
( 112), and hirsutic acid,
(113),
is a tricyclic
sesquiterpene hydrocarbon isolated from Coriolus consers.
structure
is shown
Figure 62.
in Figure 62^°.
Structure of H i r s u t e n e , CorioIin and Hirsutic acid
In addition to the synthetic
skeletal
Its
interest elicited by the
features of these terpenoids,
remark ab le physiological
there exists an array of
properties associated w i t h the
c o r i o l in-type s e s q u i t e r p e n e s ^ 1.
The antibiotic and antitumor
activities of c o r i o l in and hirsutic acid dictate an efficient
synthetic approach to these c o m p o u n d s , particularly
their
uncertain
supply
from natural
interesting syntheses have appeared
s ources .^2
to date,
preparation of c o r iol in^3 , hirsutic acid
in view of
Several
describing
the
and h irsutene 40’
.
O j r purpose, again, was to construct ring systems by using
dianion chemistry.
syntheses
F r o m the structure
111, we can derive retro
for surveying the possible route of dianion chemistry
(Figure 63).
Ci s fused 5-5 configuration of
of dianion annulation
120 might
from the vicinal
diester
ring annulation w i th c i s stereochemistry
be a good choice
I 18.
Another
from J_2_[ to J_22^ might
be achieved by D a n h e iser's ^2 annulation m e t h o d whi ch
is
56
presented
in Figure 64.
,/^y-^CC^Et
=O
=O
Figure 63.
Retro Synthesis of Hirsutene
Figure 64.
Danheiser's Cyclopentene Annulat ion
57
W e decided to m a k e
120 as a possible
intermediate of
hirsutene.
As
shown
in Figure 65,
I 14 was prepared from a Ido I
condensation of isobutyraldehyde and methyl
sulfuric acid as a c a t a l y s t ^ .
w hi t e solid
diethyl
I 15 in a 96% yield.
vinyl
Hydrogenation^^ of
enoI ester
shift at
I 14 gave
Carboethoxylation-^ of
carbonate and s od i um hydride produced
The N M R chemical
ketone with
12.22 p p m
I 16a as a m o r e preferable
115 with
I 16 in 68% yield.
indicates the presence of
form than keto ester
116
(Figure 66 ).
Figure
65.
Synthesis of 2,7,7-Trimethyl-cis-l,5-dicarboethoxybicyclo[3.3.0]octan-2-ol
58
&
612.22
(Th T)
Ax/C-OEt
0
C-OEt
A
116
Figure 6 6 .
116a
Tautomers o f
hexanone
Favorskii
2 - C a r b o e t h o x y - 4 ,4-dime t h y ! c y c l o ­
rearrangement of _ H 6 gave
pentane diester,
(118),
4-chlorobutan-2-one,
in a
(_M9),
67% yield.
(prepared
m ethyl vinyl ketone) w er e added
the
vicinal
diester,
was obtained
in
A
(60),
21% yield.
the vicinal c yc l o ­
When
1.5 equivalents
from hydrochlorination of
to the dianion generated
from
the desired bicyclic a l c o h o l , (120),
F r o m this convenient
synthesis of
120, w e envision the possibility of the preparation of
hi rsutene,
(1 11), as
shown
of
in retro
synthesis
(Figure 63).
I
59
Sunmary
The w o r k reported
contributions
in this thesis has m a d e several
to the existing p r o g r a m of synthetic methodology.
The m e c h a n i s m of bicyclic ketal
ously determined.
Other
fragmentation has been u n a m b i g u ­
side products of the fragmentation
reaction provide n e w entries
derivatives.
into pyridine and eye Iohexenone
Details of the stereochemistry of ketal opening
have been determined.
have been developed.
applied to a formal
Additional
N e w m e th od s
The ketal
for ketal
functional iz a t ion
fragmentation protocol
was
synthesis of si renin.
studies directed towards deter mi ni ng the range
of a pplicability of dianion annulation have resulted
stereoselective synthesis of valerane,
to, maleimycin,
important
in:
a) a
b) preliminary approaches
and c) a synthesis of a precursor
to hirsutene.
60
CHAPTER 3
■ E XPERIMENTAL
Reported boiling points and m el t i n g points
are uncorrected.
Al I N M R spectra w e r e recorded on a Bruker 250 M H z FT-NMR,
the chemical
TMS.
shifts reported in parts per m i ll io n
CDCl^ was
used as a solvent and an
with
relative
internal
to
standard.
Mass spectra w e r e obtained using a VG M M l 6 m a s s spectrometer and
accurate m as s data w e r e obtained using a VG 7070 high resolution
m a s s spectrometer.
B e ck m an
Infrared spectra were
recorded using a
IR - 5 spectrometer w ith absorption frequencies being
reported in reciprocal
centimeters.
G L C analysis w e r e p e rf ormed using a Varian Aerograph series
2700 gas c hr o ma t og r ap h equipped w i th
co Iu m n .
11' x I/4",
10% O V - 17
■61
Preparation of 2 - Ac ety l- 6- m et hy l-3,4-dihydro-2H-pyran
A solution of
b u t e n e - 2 - o n e ),
100 m L
(1.20 mole) of methyl
ketone
(3-
0.5 g of h y d r o q u inone and 50 m L of benzene was
placed
in a steel pressure b o m b and heated at
hours'.
After cooling,
evaporator
and
Collection
f ro m 74°
colorless
vinyl
(8 )
the solvent was
175° C for three
removed via a rotatory
the product was distilled (water aspirator).
liquid
- 77° C gave
56.5 g (0.40 mole)
of a clear,
(67% yield).
The spectral
data were
identical
to previous w o rk5 j.
Preparation of e x o / e n d o - 5 , 7 -D im et hy l- 6 ,8-dioxabicyclo[ 3. 2. 1Joetane
(15)
Acc ord ing to the m e th ods of Lipkowi t z ^ ,
(0.045 g r a m s , 0.0048 mole) was
2-propanol and stirred at
dimer
(8^) (0.50 grams,
placed
s o d i u m borohydride
in a flask w i th
r oom temperature.
10 m L of
Methyl vinyl ketone
0.0036 mole) was added drop wi se and the
reaction stirred for two hours.
the addition of 10 m L w a t e r .
Hydrolysis was accomplished by
The reaction was extracted three
times w i t h m e t h y l e n e chloride and the organics w e r e separated
and dried over anhydrous m a g n e s i u m sulfate.
chloride was
removed by rotatory evaporator.
using a 12' x 1/4",
ratio of 60:40
10% O V - 2 10 c ol u m n
The m e t h yl en e
The G L C analysis
indicated an exo/endo
(97% yield).
The spectral
data was
identical
to previous w o r k - ^ .
62
Preparation of 2 - F o rm yl -3,4-dihydro-2H-pyran
A mixture
(19)
of 84 g (1.5 mole) acrolein (2-pro pe na I), 50 m L
of benzene and 0.25 g of h y d r o q u inone was heated
steel pressure b o mb at
in a stainless
175° C for 3 hours, after w hich time
the solution w as cooled and the benzene and unreacted acrolein
were
removed.
Distillation and collection of the fraction at
40° C ( w a t e r a s p i r a t o r ) g a v e 31.5 g (0.28 m o l e ) of a clear,
colorless
liquid
(37.5% yield).
1H N M R :
9.71
(1H,
2.03
(4H, m ) .
s); 6.51
(1H, d); 4.81
( 1H, m ) ; 4.3
Preparation of 2 - ( I- h yd r o x y h e xy I )-3,4 - d ihydro-2H-pyran
(1H, m) ;
(20)
The n - p e n t y I m a g n e s i u m b ro mide was slowly added to a
solution of
17 g (0.15 mole) of J_9 stirred in 75 m L of dry ether
at O 0 C under nitrogen.
temperature,
After
15 hours
stirring at r o om
the reaction was quenched by adding water and
|f
extracted w i t h ether, was he'cl w i t h brine,
dried over anhydrous
m a g n e s i u m sulfate and reduced in volume.
g (0.1 2' m o I e ) of a c l e a r
l i qu i d (79% yield).
The spectral data were
identical
to previous wo rk
Preparation of c i s/trans-6-Octen-2-one
The
keta I, (_L5), (0.50 g;
the general
analysis
There was obtained 22
(47)
0.0035 mole) was
cleavage procedure by using acetyl
indicated 0.13 g (0.0010 mole)
trans and cis alkenes,
respectively
.
subjected
to
chloride and G L C
of a 65:35 m ix t u r e
(30% yield).
of
63
The spectral
1H N M R of
data were
trans-47:
identical
to previous w o r k 5 ^ .
5.38 (2H, m);
2.4 (2H,
t ); 2.1 (3H, s);
1.98 (2H, q ) ; 1.63 (5H, m ) .
1H N M R
of c I s - 4 7 : 5.45 ( 1H, m); 5.35 ( 1H, m); 2.42
2.15
(3H,
s ); 2.05
(2H,
t) ;
(2H, q ) ; 1.6 (5H, m ) .
Pr ep aration of e xo /e ndo -7 - De ut er io m e t h y l-5>7-dimethyl-6,8d io xa b ic y cl o [3 . 2 . I ] octane
lodomethane-d-j
(48)
(2.5 g , 0.017 mole) was
g (0.017 mole) of m a g n e s i u m in 25 m L
After
2 hours
cooled
slowly added
dry ether •under
stirring at r oom temperature,
the reaction w as quenched with 25 m L of
HCl solution.
( 8 ), in 5
The reaction m i x t u r e was
a l lo w ed to w a r m to r o o m temperature and was stirred
after w h i c h
nitrogen.
the reaction was
to 0° C a n d 1.82 g (0.01 3 m o l e ) of M V K d i m e r
m L dry ether w as added via a syringe.
to 0.42
for
16 hr.,
5% aqueous
The reaction m i x t u r e was extracted w i t h
three 30
m L portions of ether w h ic h w e re combined, washed w i th saturated
brine,
dried over anyhdrous m a g n e s i u m sulfate and reduced
volume
via
mole)
HRMS:
rotatory evaporator.
of a slight
jH N V R :
MS:
the
yellow
liquid
(1H, br s ); 2.0-1.45
(2H,
s ); 1.26
Cal cd
117,
98,
1.48 g (0.0093
(71.6% yield).
3.87
159 (M+ ),
This gave
in
(6H, m ) ; 1.40 (3H,
sj;
1.36
(1H, s).
89,
for C 9H 13O 2D 3 :
71, 43
(base).
159.1338.
Observed:
159.1339.
64
Preparations
of c i s /1r a n s -7-Deu ter i’ome thy I- 6-oc tene- 2-one (49);
6- A ce to xy- 8 ,8 -did eu terio-7-nnethyI-7-octene-2-one (jQa ) ;
>
6- A ce to xy-7-deu t er iome thy I- 7 - oc tene-2-one (5 0 b ) ;
7 - D e u t e r i o m e t h y I - 6,7-dia ce to x y - 2-octanone
(A)
Acetyl chloride,
(0.2 mL,
(51 )
2 e q . ), w a s a d d e d to a
m i x t u r e of 0.4 g (2 eq.) of s o d i u m i od i d e a n d 0.2 g (0.0013
mole) of 48 in 20 m L of acetonitrile at O 0 C under, nitrogen.
The resulting solution w as stirred at r o o m t emperature for 24
hours after w hi c h time the reaction w as quenched by adding
of
15 m L
5% aqueous s o d i u m bisulfite and stirring for 30 m in ut es at
r o o m temperature.
The reaction m i x t u r e was then extracted with
three 30 m L portions of ether w h i ch w e r e combined, washed with
10% aqueous s o d i u m thiosulfate,
and saturated brine,
reduced in volume.
5% aqueous
so di um bicarbonate
dried over anhydrous m a g n e s i u m sulfate and
The crude material was
then run through a
co Iumn of 25 m m x I 50 m m silica gel topped w i t h 15 m m o f
f Iori si I, using p e t r o l e u m ethe r :ethyI acetate
a solvent
system.
(yield:
49;
(B)
bicyclic
The
in a 7:3 ratio as
Reduced volume gave 0.14 g of crude mixture
15.9%,
50; 37.3%,
ketal,
5J_; 15.8%).
(4_8) (0.2 g,
0.0013 mole) was
subjected
to the general cleavage procedure by using m a g n e s i u m b romide and
G L C analysis
indicated 0.02 g of a 2:8 m i xt ur e of 50:5J_ and m o s t
of the s tar ting materia I b a c k .
65
1H N M R of 49:
5.06
( 1H, b r t,
H z ) ; 2.11
(3H,
3 =7.5 Hz); 2.39 (2H, t, 3 =7.5
s);
1.97
1.56 ( 1H, s ); I .6-1.5
1H N M R of 50:
5.14 ( 1H,
(0.8H br
t,
s ); 2.43 (2H,
1H N M R of 5L:
s);
s ); 1.94
(3H,
br s);
4.87
3 =7 Hz); 2.12 (3H,
t,
1.70 (0.8H,
s);
s ) ; 1.40 (1.5H,
MS of 49:
143 (M+ ) , 85
MS of 50:
159 (M+ - CH 2G O ) , 141, 98,
_5l:
s ) ;'
br
s);
1.7-1.5
m).
(1.5H,
MS of
4.9 3 (0.8H,
5.15 ( 1H, m); 2.43 (2H, m);
(3H,
1.66 (2H,
(2H, m ) .
J = 5.5 Hz);
s); 2.04 (3H,
(4H,
(2H, m);
(base),
2.12 (3H, s); 2.08
I.7-1.5
(4H, m ) ; 1.43
s).
69, 43.
43 (base).
159 (M+^ C H 2G O - H 2O) , 141 , 1 1 5, 97, 62,
43
(base).
G en er al Cl ea v ag e of the 6 , 8-Di o x a b i eye I o [ 3 . 2 . I ] oc ta ne System
by Using A c e t y l
Iodide
T w o equivalents of acetyl
chloride
in 10 m L of clean,
acetonitrile w e r e slowly added dropwide,
dry
via an additional
f u n n e l , to a solution of 2 equivalents of s od i u m iodide and
0.5 g of the b i c y c l i c k et al , s t i r r i n g at O 0 C in 20 m L o f
acetonitrile.
The resulting solution was
stirred at room
temperature for 24 hours, after w hi c h time the reaction was
quenched by adding
15 m L of aqueous so di um bisulfite and
stirring for 30 m i nu t es at r o o m temperature.
m i x t u r e w as
The reaction
then extracted with several 5Q m L portions of ether
w h i c h w e r e combined, w a s h e d w i th aqueous sodium thiosulfate,
66
aqueous
s o d i u m bicarbonate, brine and water,
dried over
anhydrous m a g n e s i u m sulfate and reduced in volume.
m at er ia l w as
gel
then run through a co lu mn of 25 m m x 150 m m silica
topped w i t h
acetate
The crude
15 m m of florisil using p e t r o l e u m etherzethyl
in a 7:3 ratio as a solvent
system.
Volume was again
reduced and G L C integrative analysis was used to determine the
a mo u nt of desired product present.
General Cl eavage of the 6 ,8- D i o x a b ieye Io [ 3 .2 . I]octane System by
Using M a g n e s i u m bromide
55
One equivalent of 1,2 - d i b r o m o e thane was added,
via syringe,
to I equivalent of m a g n e s i u m in 30 m L of dry ether under
nitrogen at O 0 C.
After
3 hours stirring at r o om t e m p e r a t u r e ,
ether w as remo ve d via the rotatory evaporator and replaced by 30
m L dry acetonitrile.
Then 2 equivalents of acetic anhydride and
0.5 g of the bicyclic ketal w e r e a d d e d , successively,
stirred
suspension under nitrogen at O 0 C.
solution w as stirred at r o o m temperature for
to this
The resulting
12 hours, after
wh ic h time the reaction was quenched by adding 20 m L of
saturated aqueous
s o d i u m bicarbonate.
then extracted w i th several
The reaction m i x t u r e was
50 m L portions of ether which were
combined, w a s h e d w i t h brine, dried over anhydrous m a g n e s i u m
sulfate and reduced
in volume.
The crude material wa s
then
separated by flash c hr om at o gr ap hy using p e t r o l e u m etherzethyl
acetate
in a 7:3 ratio as a solvent
system.
67
General Cleava ge of the 6 ,8- D i o x a b icyclo [ 3 . 2 . I ]octane System by
Usingl Alunninum Iodide-^
In a dry 25 m L t wo -neck round bottomed flask,
of dry a l u m i n u m foil and
a ce tonitrile solution was
color disappeared.
to this
1.6 equivalents of iodine
in ca. IM
refluxed for 3 hours until
Then 0.5 g of the bicyclic ketal
refluxing reaction m i x t u r e and refluxed
After cooling down to r o om temperature,
poured
I equivalent
the iodine
was added
12 hours.
for
the reaction m ix t u r e was
into 20 m L of w ater and extracted w i t h several
30 m L
portions of ether w h i c h w e r e combined, w as h e d with 5% aqueous
s o di u m hydroxide,
10% aqueous s o d i u m thiosulfate and brine,
dried over anhydrous magnes.ium sulfate and reduced
in volume.
The crude m at er ial w a s then separated by flash chromatography
using p e t r o l e u m e t h e r : e t h y I acetate
in a 7:3 ratio as
a solvent
system.
General
Cl eavage of the 6 ,8-Di o x a b ieye Io [ 3 . 2 . I]octane System by
Using I r i e t h y l s i lane
Ten equivalents of t r iethylsilane and
10 equivalents of
b o r o n t r i fluoride etherate w e r e added sequentially
in 10 m L dry m e t h yl en e chloride at O 0 C
of the b i c y c l ic ketal
under nitrogen.
to the 0.5 g
After
24 hours stirring at r o o m temperature,
the reaction was quenched by adding 20 m L of saturated aqueous
s od i um bicarbonate.
The reaction m i x t u r e was
then extracted
w i t h several 30 m L portions of m e t h y l e n e chloride w h i c h w e re
combined, w a sh e d w i t h brine, dried over anhydrous m a g n e s i u m
68
sulfate and reduced
in volume.
General C le av age of the 6 ,8 -Di o x a b ieye Io [ 3 , 2 . I]octane System
by Using A l u m i n u m H y d r i d e
To a gray suspension of 2 equivalents of a l u m i n u m chloride
in 20 m L of anhydrous ethyl
ether was added drop wi se 0.5
equivalent of l i th i um a l u m i n u m hydride in 20 m L of anhydrous
ethyl ether
was
in an ice bath under nitrogen.
repeated several
the gray slurry w as
the bicyclic ketal
times until all the hydride was added and
stirred for an h o u r .
After
this,
0.2 g of
in 10 m L ether was added at a rate sufficient
for gentle refluxing.
Excess hydride was
Swirling with ether
The m i x t u r e was
refluxed
for 3 hours.
destroyed by the dropwise addition of ca. I
m L of water and 2N sulfuric acid wa s added carefully until
more
reaction occurred in an
separated and the aqueous
times.
brine,
ice bath.
The ether
no
layer was
layer w as extracted w i th ether
three
The c o m b in ed ether solution w as was he d w i t h w a t e r ,
dried over anhydrous m a g n e s i u m sulfate and reduced
in
volume.
Preparation of 7 - I so propyl-5,7-dimethyi-6,8-dioxabicyclo[3.2.1]
octane
(52)
To 1.0 g (0.0071 m o l e ) of 8^ in 40 m L of a n h y d r o u s
tetrahydrofuran under
nitrogen was
added
4.7 m L
(1.3 eq.) of
2 M
isopropyl m a g n e s i u m chloride via a syringe over a period of 10
minutes.
for
The reaction m i x t u r e wa s stirred at r o o m temperature
16 hours,
after w hi c h the reaction was quenched w i t h 25 m L
69
of
5% aqueous HCJ solution and extracted with ether.
The
organic
layer was dried over anhydrous m a g n e s i u m sulfate and
reduced
in volume.
collection of
a colorless
1H N M R :
13C N M R :
MS:
HRMS:
IR:
the
Distillation
fraction at
liquid
84° C gave 0.86 g (0.0047 mole) of
(65% yield).
4.06 ( 1H, br
s ); 2.03- 1.45 ( 7H, m);
(3H,
(3H, d,
s ); 0.94
I 07.0 (s),
25.7
(q),
12. 2
( q) .
184 (M+ ),
141,
Calcd
2941,
(water aspirator) and
1385,
3=7 Hz); 0.80 (3H, d, 3=7 Hz).
85.9 (s ), 78.2 (d),
24. 2
(t),
124,
96, 81,
for C ljH 20O 2 :
1242,
1176,
1.39 (3H, s ); 1.18
19. 1
(q),
71,
(d),
34.1
(t),
17. 3
( t),
15. 9
(q),
55, 43 (base).
184.1463.
1040,
35.1
Observed:
917.
(17.3)
(1 <
1.39(2!
(35.I K J 0.94,0.80
(15.9,12.2)
184.1466.
70
of 7 , 8-Dimethyl-6-honen-2-one
Preparations
7-nonen-2-one
(A)
(53) ; 7,S-Dimethy I-
(54) and u ni de nt if ie d product
(55)
T h e bi c y c l i c ke t a I (0.50 g, 0.0027 m o l e ) ,
(22), w a s
subjected to the general cleavage procedure by using acetyl
iodide to give 0.4 g of reaction product.
5' x 1/4",
20% S E - 30 column,
indicated a
G L C analysis,
using a
16:13:7:64 m i x t u r e
of
5 2 , 5 3 , 5 4 , 5 5 , respectively.
(B)
Thebicyclicketal
(0.50 g, 0.0027 m o l e ) ,
(52) w a s
subjected to the general cleavage procedure by using m a g n e s i u m
b r o m i d e and G L C analysis
starting material,
1H N M R of 53:
1H N M R of
54:
indicated 2% of 22, and m o s t of
(52) was
recovered.
5.07
(lH,t,
(IH,
m); 2.11
(3H, s);
(2H,
m); 1.53
(3H, s ); 0.95
2.41 (2H,
t,
3=5 Hz); 2.39 (2H,
t , 3 = 7 Hz);
1.97
2.11
1.61 ( 6H,
3 = 7 Hz);
t, 3=7 Hz); 2.20
(2H, m);
I .65-1.50 .
(6H, d, 3 = 7 Hz)..
(3H,
s); 2.00 (2H,
s ); 1.59 (3H,
s);
1.55
.(2H, m ) ; 1.32 (2H, m).
1H N M R of
55:
5.17 ( IH, br
s ); 4.98 (1H, s); 4.91
2.65
(IH, m ) ; 2.44 (2H, m);
Hz);
2.12 (3H,
3 = 6.5 Hz);
s);
2.04 (3H,
(1H, s);
2.22 (2H,
t, 3 = 7
s); 1.06 (3H,
1.03 (3H, d, 3=6.5 Hz);
0.90
HO,
55, 43.
d,
(3H,
3 = 7 H z ).
M S of
HRMS:
53:
168 (M+ ) , 150,
Calcd for C n H 2 O-*
95 ( b a s e ) , 80, 67,
168.1514.
Observed:
168.1493.
d,
71
M S of 54:
168 ( M + ), 1 50,
1 35, 1 21 , H O ,
Ca lcd 'for C 1 JH 20O:
HRMS:
M S of 52:
168.1514.
184 ( M + - C H 2CO), 166, 151,
95, 83, 67, 55 (base),
Observed:
123,
168.1512.
108, 9 3 , 81, 67, 55,
43 (base).
HRMS:
TLC:
C al cd
for C jlH 20O 2 :
184.1464.
P e t r o l e u m ether:ethy I acetate
developing
solvent
Observed:
184.1464.
in a 7:3 ratio as a
on silica gel T L C (H2S O zt/Cr 2O y 2 "
visualization).
R f of
(23)
: 0.51
R f of
(24)
: 0.51
Rf
(22)
: 0.40
of
(UV active)
1H
1.61
Preparation of 5 ,7 ,7 - T r imethyI- 6 ,8 - d io x a b ieye Io [ 3 . 2 . I joctane
(26)
A s o l u t i o n c o n t a i n i n g 5.0 g (0.036 m o l e ) of 2 i n 70 m L of
tetrahydrofuran was
stirred under
nitrogen w h i le
15 m L
(1.3 eq.)
of 3.1 M methyl m a g n e s i u m b r om id e was added via a syringe over a
period of 10 minutes.
t em perature
for
The reaction m ix t u r e was
stirred at room
16 hours, after w hich the reaction was quenched
72
with 30 m L of 5% aqueous HCJ
The organic
reduced
layer was dried over anhydrous m a g n e s i u m sulfate and
in volume.
collection of
clear,
the
color less
( 3H,
13C N M R :
fraction at
liquid
s );
(3H,
55° C gave 3.9 g (0.025 mole) of a
81. 1
(q),
24. 2
(d),
( t),
Cal cd for C 9H 16O 2 :
2857,
912,
1370,
1263,
(6H, m ) ; 1 . 4 0
( 3H,
s);
1. 36
s).
156 (M+ ) , 141 , 1 14, 98,
HRMS:
(water aspirator) and
(70% yield).
1. 26
1 07 . 2 (s),
25.8
IR:
Distillation
3.87 ( 1H, br s); 2 . 0 - 1 . 4 5
H NVR:
MS:
solution and extracted with ether.
8 0 . 8 (s),
20.9
81,
(q),
17. 2
29. 2 ( q ) ,
(t).
68 , 43 (base).
156.1151.
1214,
34. 2 ( t ) ,
I 185,
Observed:
1159,
I 129,
156.1149.
1098,
1032,
962,
868 , 849, 829.
1H (
' -133O
3.87(81.1)
1.26(20.9)
(24.2V
(34.2)
\
V
I
/ / vsY Y
/ -5
^ 1'3G(25.8)
U (80.8)
(17.2) / 1.40(29.2)
(107.2)
P r e p a r a t i o n s of 7-Methy I- 6 - o c t e n e - 2 - o n e
m e t h y l - 7-octene-2-one
(58);
(57_); 6 -A ce to xy - 7-
6 ,7-Di acetoxy-7-me thy I-2-octanone
(59)
(A)
T he k e ta l
to the general
(0.50 g, 0.0032 m ol e ) , (56), w a s s u b j e c t e d
cleavage procedure by using acetyl
0.37 g of r e a c t i o n p ro du c t.
20% S E-30 c ol u mn
iodide to give
G L C a n a l y s i s , u s i n g a 5' x 1/4",
indicated a 23:54:23 m ix t u r e of
57,
58,
59
73
respectively.
(B)
T h e k e t a I (2.6 g, 0.0 17 m o l e ) ,
(^56), w a s s u b j e c t e d to
the general cleavage procedure by using m a g n e s i u m b r om id e to
give 0.4 g of. reaction product.
G L C analysis
indicated a 2:8
m i x t u r e of _58 and 59 and m o s t of the starting materal. back.
1H N M R of 57.:
3=7.5 Hz); 2.39 (2H, t, 3 =7.5
5.06 ( 1H, br t,
1H N M R of 58:
Hz);
2.11
(3H,
1.56
(3H,
s ); 1.6-1.5
5.14 (1H,
(IH,
br
t,
s ); 1.97 (2H, m);
(3H,
s );
13C N M R o f
57:
2.43 (2H, m);
s ); 1.94 (3H,
1.40
(q),
(3H,
(s),
27.3
s);
132.5
(t),
208.3 (s),
(q),
MS of 57:
HRMS:
59:
br s);
s); 2.08
1.43 (3H,
25.6
(q),
18.0
23.9
(t),
142.8 (s),
31.9 (t),
17.6
(q).
I 12.8 (t),
29.8
(q),
21.1
(q).
170.5 (s),
170.0 (s), 82.4
(s),
76.2
(d),
42.7
(t),
29.8
(q),
28.1
(t), 22.2 (q),
22.1
(t),
22.0
(q),
20.8
(q),
19.7
for C 9HjgO:
156 (M+ - C H 2OO),
1.7-1.5
123.7 (d), 43.1 (t), 29.8
(s),
140 (M+ ) , 122, 82 (base),
Calcd
MS of 58:
(t),
208.4 (s),
2.12 (3H,
I.7-1.5 (4H, m);
I 70.2 (s),
19.4
s ); 1.70 (3H,
s ).
76.8 ( d ), 43.0 (t),
13C N M R o f
3 =7 Hz); 2.12 (3H, s);
t,
(3H,
209.5
13C N M R of 58.:
(2H, m).
s ); 2.43 (2H,
5.15 ( 1H, m);
s);
3=5.5 Hz); 4.93 (1H, br s); 4.87
2.04
1H N M R of 59:
1.66 (3H,
140.1201.
(q).
69, 43.
Observed:
140.1232.
138, 95, 81, 71, 58, 43 (base).
(4H,
HRMS :
Calcd
:
I56.1 I 50.
Observed:
157 (M+ -2 CH 2G O - O H ) , 141 , 1 1 5, 97,
MS of 59:
HRMS:
for C g H |
Ca led
for C g H j 2O 2 :
1 57.1229.
IR o f 57:
1700,
IR o f 58:
1695 ( b r ), 1351 , 1225,
IR O f 59:
1690 (br),
1650 (s h ),
1420,
71,
156.1151.
59, 4 3 (base).
Observed:
157.1201.
1360,
1012.
1220, 1130,
1351,
1H ( 13C )
1.6-1.5(23.9)
2.43(43.0)
1.97(27.3)
5.06(123.7)
2.39(43.1)
(209.5)
(208.3)
1.66(17.6)
(132.5)
(31.9)
5.14(76.8)
(112.8)
2.12(29.8) U 0
1.70(18.0)
1.56(25.6)
(170.2)
2.43(42.7)
2.04(21.1)
(28.1)
5.15(76.2)
(208.4)
2.12(29.8)
(82.4)
(170.0)
1.94(22.0)
2.08(22.2)
Preparation of n-Bromobutyl
1.2-Di b r o m o e thane
acetate
(0.10 g,
0.013 g (I eq.) of m a g n e s i u m
nitrogen.
After
all
in
0.0054 mole) was
15 m L
r oo m temperature
to
dissolved
(ca. 2 Mrs.),
in ice bath and then
for 24 hrs.
(0.00 5 m o I e ) o f l i q u i d (93% yield).
added
tetrahydrofuran under
the m a g n e s i u m was
0.1 m L of acetic anhydride was added
stirring at
(60)
Usual w o r k - u p gave
I g
75
1HNVIR:
4.08
(2H,
(3H,
s ); I .93 (2H, m ) ; 1.79 (2H, m).
13C N M R :
171.0 (s),
20.9
MS:
1 36,
HRMS:
IR:
1H
t, 0 = 6.3 Hz);
63.4 (t),
1 1 5,
33.0 (t),
108,
Calcd for C 6H ljO 2Br:
1715,
(2H,
t, 3 =6.5 Hz);
29.3 ( t ),
27.3
2.04
(t),
(q).
1 34 (M+-60),
2915,
3.42
106, 87,
193.9942.
73,
55, 43 (b as e) .
Observed:
1 93.9949.
740.
C
1.93(29.3)
4.08(63.4)
1.79(27.3)
3.42(33.0)
2.04(20.9)
(171.0)
Preparation of
(6 1 a ) and
I- (cis- 6 -Metby 11e t r a h y d r o p y r a n - 2 - y I )ethanoI
(6 1 b )
The exo /endo m i x t u r e
subjected
silane
(0.3 g,
0.002 mole),
to the general cleavage procedure by using triethyl-
to give 0.25 g (0.0017 mole)
analysis,
using a I I' x 1/4",
40:60 m i x t u r e of
1H N M R of
(_1_5) were
( 6 La) :
of
reaction
10% O V - 1 7 column,
6 1 a , 6 1 b , respectively
3.54 (1H, m);
2.89 ( IH,
m);
indicated a
3.05 ( 1H, m);
1.82 (2H, m);
1.16 (3H, d , 3 = 6.3 Hz);
3=6.4 H z ).
GLC
(85% yield).
3.44 ( 1H, m);
b r s);
product.
1.65-1.41
1.1 I (3H,
d,
(4H,
76
jH N M R of (6JM:
3.80 ( 1H, m); 3.45 (IR, m); 3.2 7 (IR, m);
2.15 (IR, b r s ); 1.83 (2H, m); 1.65-1.28 (4H,
m);
1.14 (3H, d,
3=6.6
MS of
(61a):
HRMS :
MS of ( 6 1 b ) :
HRMS :
for CgHj jO:
99,
81
(b as e) , 7 1, 55,
99.0810.
129 (M + - I 5) , 99 (base),
Ca led
1.11
(3H,
d,
R z ).
129 (M+- I 5),
Ca led
3=6.3 Hz);
for CgHj jO:
99.0810.
43.
Observed:
81,
71,
55,
99.0808.
43.
Observed:
99.0807.
1H
61b
2.89
Preparations
of c i s - 2 - Isopropy I- 6-methy Itetrahydropyran (62);
u n *d e n t ified
(6 3 ), and
I-Me thyl-l-(cis- 6 -me thyltetrahydropyran-
2-y I )ethano I (64)
T h e b ! c y c l i c k e t a l (0. 10 g, 0.0064 mole),
subjected
silane
to the general
cleavage procedure by using
to give 70 m g of reaction product.
11' x 1/4',
10% O V - 17 column,
6 2 , 6 3 , 6 4 , respectively.
(56), w a s
triethyl-
G L C analysis,
using a
indicated a 45:34:21 m ix t u r e of
77
Ih N M R
of (62):
3.37 ( 1H,
m);
2.93 ( 1H, m); 1.60 ( 1H, m);
1.82- 1.05 (6H, m);
(3H, d, 3 = 6 Hz);
1H N M R
of (63):
4.41
( 1H,
m);
( IH, m ) ; 2.47
1.14 (3H, d, 3 = 6 Hz), 0.91
0.84 (3H, d, 3 = 6 Hz).
3.89 ( 1H, m);
3.75 ( 1H, m);
(2H, t, 3 = 6.9 Hz); 2.2-1.35
(I OH, m ); 1.23 (3H, d, 3 = 6.3 Hz);
3=6.2 Hz),
2.58
1.07 (6H, d, 3=7 Hz);
1.17 (3H,
1.00 (6H,
d,
d,
3 = 7 Hz).
1H N M R of (64):
3.44 ( 1H, m);
3.1 I (1H, dd, 3 = 2,
( IH, b r s ); 1.86- 1.05 (6H, m);
1.14 (3H,
d , 3 = 6 Hz);
M S of (62):
142 (M+ ), 99 (base),
HRMS:
for C^Hj jO:
99.0810.
140 (M+ ),
97,
MS of
Calcd
(63):
125,
81,
71,
1.15 (3H,
1.1 I (3H,
73,
55,
43.
Observed:
99.0808.
55 (b as e) , 43.
140.1201.
MS of (64):
158 (M+ ),
125, 99, 81
(base),
HRMS:
for C 9HjgC^:
158.1307.
Observed:
Calcd
C alcd
143,
Observed:
1H
1 .14
2.93
H
s);
s ).
for C 9Hj^O:
HRMS:
11 Hz); 2.74
ft
140.1202.
71,
59, 43.
158.1328
i
78
I ,2-Dime thy I - (cis- 6-methyltetrahydropyran-2-
Preparations of
y I )p r o p a n e
1,2-Di m e thyI-l-(cis- 6 -
(6 5 a ) and (65b);
m e t h y l t e t r a h y d r o p y r a n - 2-yl)propanol
(66a)
T h e b i c y c l i c k e t a I, (0.50 g , 0.0027 mo le ), (5J2), w as
subjected to the general
t r i e t h y s i lane to give
using a 1 1 1 x 1/4",
(65a):
0.47 of
reaction product.
10% O V - 17 column,
m i x t u r e of 6 5 a , 65b,
1H N M R o f
cleavage procedure by using
3.35 ( 1H, m);
of (65b): ' 3.35 (1H,
3.43 (1H,
MS of
HRMS:
Calcd
(65b):
Calcd
2.0 0 ( 1H, m);
0.87
3 = 2, 11 Hz);
for C 1 ^ 220 :
99
(7H, m);
1.12 (3H, d,
s); 0.90 (3H, d,
3 =7
43.
Observed;
(base),
170.1671.
d,
1.88
d, 3 = 7 Hz).
99.0810.
170 (M+ ) , H O ,
0.75 (3H,
(1H, d d ,
99 (base, M +-71 ), 81 , 71, 66 , 55,
for C 6H 11O:
d,
d, 3 = 7 Hz).
0.96 (3H,
(3H,
1.14 (3H,
d, 3=7 Hz);
3.3 0
1 .87- 1.28
(3H,
3 = 6.8 Hz).
d,
(1H, m);
0.86 (3H,
m);
3=6.3 Hz);
HRMS:
0.76 (3H,
0.70 (3H,
(IH, m ) ;
MS o f ('65a):
1.12 (3H, d,
(6H, m ) ; 1.40 ( 1H, m);
3=6.3 Hz);
Hz);
1.22 ( 1H, m);
m ) ; 3.10
1.84- 1.45
of (66a) :
( 1H, m) ; 1.77 (2H, m);
0.88 (3H, d, 3 = 6.8 Hz)"; 0.84
d , 3 = 6.9 Hz);
3 = 7 Hz);
3.11
(5H, m);
3 = 6.3 Hz);
1H N M R
indicated a 12:14:74
66a , respectively.
1.70- 1.35
1H N V R
G L C analysis,
81,
99.0809.
71 , 55,
Observed:
43.
170.1669.
79
MS of
( 66a):
186 ( M + ), 171,
55,
HRMS:
143,
125, 99, 87 (base),
81, 69,
43.
C a l c d f o r C jlH 22O 2 :
186.1619.
Observed:
186.1617.
1M
Preparation of l,2-Dimethyl-l-(cis/trans-6-methyltetrahydropyran-2-yI )propanol (66a) and (66b)
T he b ( c y c l i c keta l
(0.20 g, 0.001 I mo le ),
(_52), w a s
subjected to the general cleavage procedure by using a l u m i n u m
hydride
a
to give 0.17 g of reaction
I I' x 1/4",
10% OV- 17 column,
product.
G L C analysis,
using
indicated a 13:87 m i x t u r e of
66a , 66b , respectively (83% yield).1
*
3
1H N M R of ( 66b):
4.20 ( 1H, m); 3.58 ( 1H, dd,
1.89 ( IH, m,
(3H,
3 = 7 Hz); 1.80- 1.30 (7H, m); 1.23
d , 3 = 6.8 Hz);
3 = 7.9 Hz);
3 =2.8, 11 Hz);
0.92 (3H,
0.84 (3H,
d,
s); 0.90 (3H, d,
3 = 6.9 Hz).
80
M S of ( 66 b):
171 ( M + -I 5), 143,
125, 99, 87 (base),
81, 69, 55,
43.
HRMS:
Cal cd
for C ljH 2 ^ :
186.1620.
Observed:
186.1620.
66b
1H
✓
1.23
I
4.
Preparations
of
1, 2 -D im et hyl-(2-cyclohexanon e-3-yI)propane
and 2,3-Dim e t h y l - l - ( 5 , 6 - di methylpyridine-2-yl)butanone
(67)
(68 )
General cleavage procedure by using a l u m i n u m iodide was
introduced
and this gave
using a
2.0 g (0.011 mole) of the bicyclic ketal,
to
1.73 g of the
I 11 x 1/4",
liquid.
10% O V - 17 col umn
G L C analysis
shows
of
(52),
the product
31:69 ratio of 67^ and
68 , r e s p e c t i v e l y , but 0.1 g (0.0006 m o Ie ) o f 6_7 a n d 0.15 g
(0.00073 mole) of 6J8 w e r e separated w i th
using p e t r o l e u m e t h e r : e t h y I acetate
flash c hr om atography
in a 7:3 ratio as
a solvent
system.
Rf
:0.48
>
1.16 g of decomposed
Rf
: 0.37
>
0.1 g of 67
Rf
:0 . 25
>
0.15 g of 68
1H N M R of 67:
5.84 ( 1H, br s); 2.36 (1H, m);
Hz);
2.02- 1.88 (4H, m);
d , 3 = 7 Hz);
3 = 7 Hz).
product.
2.24 (2H,
1.65 ( 1H, m);
0.88 (3H, d, 3 = 7 Hz);
0.83
t, 3 = 6
1.04 (3H,
(3H, d,
81
1H N M R of 68:
7.7 1 ( 1H, d, J = 8 Hz); 7.04 (IN, d, J = 8 Hz); 3.04
( 1H, m);
2.63 (3H,
13C N M R of 67:
M S of 67:
31.1
(d),
27.4
19.5
(q),
15.8
(q).
HRMS:
121.2
(s),
119.9 ( d ), 50.0 (d),
23.9
(q),
IR of 68 :
(s),
22.9 (t),
159.9
21.4
I 24
157.2 (s),
(q),
18.4
(base),
37.7
21.6 (q),
135.7 (d),
30.2
(q),
(d),
24.4
12.5 (q).
109, 96, 81, 67,
41.
205 (M+ ), 190,
166.1358.
163,
Ca led for Cj ^Hj gNO:
IR of 67:
(t),
(s),
Ca led for CjjHigO:
MS of 68 :
(1H,
125.8 (d), 48.8 (d),
207.3
166 ( M + ), 151, 148,
55,
HRMS:
170.7 (s),
(t),
(q),
s); 2.01
d , 3 = 7 Hz).
1 99.9 (s),
13C NVIR of 68 :
2.54 (3H,
3 =7 Hz); 0.92 (3H, d 3 = 7 Hz);
m ) ; 1.09 (3H, d,
0.85 (3H,
s);
2941,
1669
(C=O),
2941,
1681 (C=O),
1136,
1021,
U V of 68 :
966,
Observed:
134 (base),
106, 79,
205.1466.
Observed:
1456,
1245,
1376,
1587, 1447, 1370,
919,
;274 (4140),
896,
833,
890,
1250,
732.
239 (6640).
1 H ( 13C )
(22.9)
67
2.24(37.7)
1.04(21.6)
(199.9
(170.7)
5.84(125.8)
2.36(48.8)
1.65(31.1)
0.88,0.83(19.5,15.8)
166.1359.
63,
53, 41.
205.1472.
731 .
I 222, I I 90,
82
68
(121.2) 7.71(135.7)
2.54(23.9) O V
7.04(119.9)
^
1.09(21.4)
*N'r
0.92,0.85
(18.4,12.5)
(159.9) ;
(207.3)/
3.04(50.0)
2.01(30.2)
Preparation of 2,3 Dime thy I- I-(5, 6 - d ime thy Ipyridine- 2y I )butano I (69)
To a s o l u t i o n of 0.014 g (0.5 eq.) of s o d i u m b o r o h y d r i d e
10 m L of
isopropanol w a s added
k e t o n e , (68^), and stirred
(10 mL) was added
the
isopropanol,
for
0.015 g (0.00073 mole) of
I hour at
the
room temperature.
Water
to hydrolyze the reaction after evaporation of
the reaction m i x t u r e was extracted with e t h e r ,
dried over m a g n e s i u m sulfate and reduced in volume
0.015 g of slight y e l l o w solid.
( G/ C- mas s indicates
to yield
After w as hi ng w i th pentane
0.0096 g (0.000046 mole) of w h i te
yield).
in
solid was
89:11
obtained
ratio of
isomer).
7.08 ( 1H, d,
3 = 8 Hz);
(64%
M.P. = I 59- 1 62° C
1H NM*:
7.60 (1H, d, 3 = 8 Hz);
d d , 3=3,
9 Hz);
2.54 (3H,
m ) ; 1.78 ( 1H, m);
3 = 7 Hz); 0.89 (3H,
MS:
HRMS:
207 (M+ ) , 174,
s); 2.49 (3H,
1.67 ( 1H, d, 3 = 3 Hz);
t, 3 = 7 Hz);
0.51
Ca led for Cj 3H 2 jNOi
207.1623.
( 1H,
s); 2.29
(1H,
0.95 (3H,
(3H,
136 ( b a se ) , 108, 92, 77, 65,
4.67
t , 3 = 7 Hz).
51 ,
Observed:
t,
4 1.
207.1622.
83
7.60
1H
2.49
1.78
2.54
0.95,0.89
1.67
2.29
Preparation of t hr e o/ e ry th r o- 2- ( I-Hydroxyethy I)-3,4 - d ihydro-2Hp y ran (72 )
Acrolein dimer
(J_9) (0.50 g,
0.0045 mole) was
m L of tetrahydrofuran and stirred at 0° C under
Methyllithium
syringe and
(5.2 m L of
1.3 M
the reaction was
solution) was
stirred
placed
in 30
nitrogen.
then added via a
for seven hours.
The
reaction was hydrolyzed by the addition of 25 m L of water and
w a s stirred an additional half an h o u r .
extracted
The m i x t u r e was
then
three times w i t h ether and the organics w e re combined
and dried over anhydrous m a g n e s i u m sulfate.
0.40 g (0.0031 m o l e ) of erythro alcohol
Evaporation gave
(69% yield).
If 1.5 equivalents of met hy lmagnes iu m bromide are used
instead of m ethyl lithium,
and erythro
1H N M R of
one can get a 50:50 m i x t u r e of threo
isomer-^*
t h r e o - 72:
6.37 ( 1H, br d, 3 = 6 Hz); 4.68 ( 1H, br s);
3.72 ( IH, m ) ; 3.55 ( 1H, m);
3 = 4.7 Hz);
3=6.5
H z ).
2.38
2.15-1.50 (4H, m);
( 1H,
d,
1.19 (3H, d,
IN M R of e r y t h r o - 7 2 :
6.37 (IH, b r d , 3 = 6 Hz); 4.68 ( 1H, b r s);
3.92 ( IH, m);
m);
3.70 ( 1H, m);
1.89 ( 1H, d, 3=4.7 Hz);
2.15-1.50 (4H,
1.19
(3H,
d,
3 = 6.5 Hz).
MS of t h r e o-72:
HRMS:
Calcd
for C 7H 12C^:
MS of e r y t h r o -72:
HRMS:
Calcd
IR:
3305,
128 (M+ ) , 110, 95,
2843,
128.0837.
128 (M+ ) , H O ,
for C 7H 12O 2 :
1644,
83 (base), 71 , 55,
95, 83 (base),
128.0837.
1253,
1088,
Observed:
43.
128.0840.
71 , 55, 43.
Observed:
128.0832.
751.
1B
threo-V^
erythro-72
Preparation of e x o / e n d o - 5 - ( n - B r o m o p e n t y I )-7-meth y I - 6 ,8d i o x a b i c y c l o - [ 3 . 2 . I ]octane
(73)
The m i x t u r e of 0.5 g (0.0039 m o l e ) of the a l c o h o l ,
4.4
m L (2 e q . ) t e r t i a r y b ut y ! l i t h i u m and 0.27 m L
I,5 - d ibromopentane w e r e
66:34.
G L C analysis
(0.5 eq.) of
subjected to the same procedure of (74),
and w h i c h gave 0.65 g (0.0024 mole) of a y el l o w
yield).
(72),
shows
the exo/endo
liquid
isomeric
(51%
ratio to be
85
1H N W R of e x o -73;
4.19 ( 1H, q, 3=6.4 Hz);
3.39 (2H,
t , 3 = 6.8 Hz);
1.16 (3H,
d , 3 = 5.9 Hz).
1H NlVR of e n d o -73:
4.14
(2H,
br
s);
278, 2 76 ( M + ), 234, 232,
69,
HRMS:
Calcd
55,
1.31
( 1H,
br
s);
1.9-1.39 ( 14H, m);
3.39 (2H,
1.9-1.39 ( 14H, m);
M S of ex_o-7J3:
4.02
t, 3 = 6.8 Hz);
(3H,
d,
3 = 5.9 Hz).
1 79, 1 77, 1 00 (base),
4 1.
for C 12H 21O 2Br:
276.0725.
Observed:
276.0717.
M S of e n d o -73:
278, 276 ( M + ), 250, 248, 234, 232,
177,
HRMS:
Calcd
155,
135,
100,
for C 12H 21O 2Br:
82,
1 97, 1 79,
69 (base),
276.0725.
55, 41.
Observed:
276.0724.
1H
exo-73
endo-73
*4.14
Br(CH2)5H j ^ X 6 Br(CH2)5- ^ p H
'H4.19
\
4.14
1.31
Attempted Coupling Reaction of exo/endo-5-(n-Bromopentyl)-7methyl-6,8-dioxabicyclo[3.2.1 joctane, (7_3), w i t h
Hydroxyethy I )-3,4 - d ihydro-2H-pyran
2- ( I -
(72).
Tertiary bu t hy I I ith iu m (0.44 mL,
2 eq.) was
added
to a
s o l u t i o n of 0.05 g (0.00039 m o Ie ) of the a l c o h o l , (7_2) in 10 m L
of tetrahydrofuran at -78° C under nitrogen.
After
10 minutes,
the reaction m i x t u r e w as w a r m e d up to 0° C for I hour and room
t em perature
resulting
for 30 minutes,
solution w as
added
then again cooled down
to 0.11 g (I eq.) of
to O 0 C.
The
the bicyclic
86
{73), in 5 m L tetrahydrofuran at O 0 C, then stirred for I
ketal,
hour at 0° C and 2 hours at r o o m temperature.
G L C analysis
showed only starting materials.
Preparation of e x o / e n d o - ( n - B r o m o p e n t y I )- 7 - p e n t y I- 6 ,8d i o xa b ic yc l o[ 3 .2 . I]octane
(74)
To a s o l u t i o n of 0.50 g (0.0027 m o l e ) of the a l c o h o l ,
(20),
stirring in 10 m L of tetrahydrofuran at -78° C under ah argon
a t mo s ph e re was
butyl lithium.
slowly added 3 m L
(2 eq.) of 1.8 m ol a r
The resulting solution w as
bath and stirred at O 0 C for
tertiary
transferred to an
ice
I h o u r , after w h i ch time the ice
bath w as removed and the solution stirred at r oo m temperature
for 30 minuses.
After again cooling to O 0 C,
solution was added to 0.37 m L
pentane
(0.0027 mole) of
the resulting
1,5-dibromo-
in 10 m L tetrahydrofuran via a syringe at O 0 C and the
solution m i x t u r e w as
at r o om temperature.
stirred for
I hour at 0° C and
then 2 hours
The reaction wa s quenched w i t h
10 m L of
saturated aqueous a m m o n i u m chloride solution, extracted with 30
m L ether
three times and w ashed w i t h
3% aqueous HCl , brine,
dried over anhydrous m a g n e s i u m sulfate and reduced
in volume
g a v e 0.3 g (0.0009 m o Ie ) of a y e l l o w li qu id (33% yield).
analysis of the product using a 25' x 1/4",
shows
the exo/endo
1H N M R of exo-74:
GLC
10% O V - 17 column
isomeric ratio to be 26:74.
4.17 (1H, br
J = 7 Hz);
s); 3.96 (1H, m);
1.9- 1.2 (22H, m);
3.39
(2H,
t,■
0.88 (3H, br t).
87
1H N M R of e n d o -74:
4.08 (1H, br s); 3.96 (1H, m); 3.39 (2H, t,
3 = 7 Hz);
M S of e xo- 74:
127,
I 14,
for C 16H 2^ B r :
Calcd
0.87 (3H, br
334, 3 32 ( M + ), 263, 261, 234, 232,
(base),
HRMS:
1.9-1.2 (22H, m);
179,
177,
t ).
156
1 00, 69.
332.1350.
Observed:
332.1355.
M S of e n d o -74:
334, 332 ( M + ), 277, 275, 253, 234, 232, 21 1,
179,
HRMS:
Calcd
177, 1,56 (base),
for C 16H 29O 2Br:
135,
332.1350.
113, 69.
Observed:
332.1372.
Preparations of e x o / en d o- 7 -M e th yI-4-pro p a n a I - 6 ,8 d i o x ab i cy cl o [3 . 2 . I ]octane
(75)
To a s o l u t i o n of 0.1 g (0.00078 m o l e ) of the a l c o h o l ,
(72),
stirring in 20 m L of tetrahydrofuran at r o om te mperature was
added
0.3 g
(1.2 eq.) of m e r cu r i c acetate.
stirring at r o o m temperature,
via a rotatory evaporator,
After
overnight
the solution was reduced
then 20 m L of m e t h y l e n e chloride and
0.44 g (10 eq.) of a c r o l e i n w e r e a d d e d s u c c e s s i v e l y .
eq.) of
s o d i u m borohydride was dissolved
then added
After
stirring
for 2 h o u r s , the reaction m i x t u r e was quenched
w i t h d ro pw ise addition of 20.m L of saturated aqueous
bicarbonate
0.09 g (3
in 2.5 m L water and
to the reaction m i x t u r e very slowly.
at r o o m te mp erature
in volume
sodium
solution, and extracted w i t h chloroform, was he d w i t h
brine,
dried over anhydrous m a g n e s i u m sulfate and reduced in
volume
gave
0.060 g (0.00033 mole)
of a slight y e l l o w
liquid
88
(42% yield).
G L C analysis of the product using a 11' x 1/4",
10% O V - 17 c ol um n shows
e nd o-erythro
isomeric
the exo-erythro,
ratio
to be
NiVR o f exo-ery t h r o-75 :
exo-threo,
21:53:9:17.
9.7 3 ( 1H,
b r s ); 5.30 ( 1H, b r s;
( 1H, q, 3 = 6 Hz);
4.11
s ); 2.42 (2H,
9.7 5 (1H,
br
(1H, br
d,
1.90- 1.25;
3 = 6.1 Hz).
s); 5.32 ( 1H, br s); 4.19
( IH, q, 3 = 6.4 Hz);
2.48 (2H,
4.02
t, 3 = 7 Hz);
,(6H , m ) ; 1.18 (3H,
*H NiVR of e x o - t h r e o - 7 5 :
endo-threo,
3.99 ( 1H, br
t, 3=7 Hz);
s);
1.95 (2H, m);
1.78 (2H, m ) ; 1.50 ( 1H, m) ; 1.34 (2H,
br
IH N M R
o fe n d o - t h r e o - 7 5 :
t);
1.18 (3H,
d,
3 = 6.6 Hz).
9.74 ( IH, br s); 5.25 ( 1H, br s);
4.1 I (2H,
Hz);
br d ); 2.42 (2H,
1.90-1.39 (6H, m);
t , 3 =7
1.30 (3H,
d,
3=6 H z ).
^H N M R
of e n d o - e r y t h r o - 7 5 :
9.77 (1H,
br
s);
5.27 ( 1H, br
4.10 (2H, br d); 2.48 (2H,
Hz);
2.15-1.40 (6H, m);
s);
t, 3 = 7
1.34 (3H,
d , 3 = 6.2 H z ).
MS
of e x o - e r y t h r o - 7 5 :
184 (M+ )> 138,
79,
MS
of e x o - t h r e o -75:
112,
7 1 , 67, 5 5 (base),
184 (M+ ),
83,
128,
79,
141,
71, 67,
138,
128,
94
(70%),
83,
43 (60%).
120,
55 (base),
94
(83%),
43 (40%).
89
M S of endo-th r e o- 75:
j 84 ( M + ),
78,
M S of e n d o - e r y t h r o :
67,
71, 67,
Ca lcd for C 10H 16O 3 :
120,
110,
55 (base),
184 ( M + ), 140,
79,
HRMS:
71,
140,
120,
184.1099.
(58%),
94
(76%),
exo-erythro
9.73
1.63
e x o - threo
1.18
/CH3
1H
4.19
9.75
endo-threo
9.74
1.63
endo-erythro
5.25
4.10
2.48
9.77
3
H 0
5.27
83,
43 (63%).
Observed:
3.99
83,
(86%).
43
112,
55 (base),
94
184.1095.
90
Preparation of 2 - ( 2- H yd r ox y me thy I )-3,fr-dihydro-2H-pyran
Acrolein dimer
(Jj)) (I g,
0.009 mole) was placed
of i s o p r o p a n o l a n d c o o l e d to O 0 C.
(76)
in 20 m L
0.17 g (0.5 eq.) of s o d i u m
borohydride w as adde d slowly w i th stirring and the resulting
solution w a s stirred for I hour at r o om temperature.
10 m L of
1wat er was then added and the resulting solution was extracted
w i t h ether,
dried over m a g n e s i u m sulfate and
The alcohol was
next
reduced
not purified, but used directly
in volume.
for the
step.
Preparation of 2 - ( 2 -Hydroxyme thy I )- 6 - (n-decyI )-3,4 - d ihydro-2Hpyran
(77)
To the crude alcohol,
w as added d ro pwise
10 m L
at -78° C under nitrogen.
(76J,
in 20 m L dry tetrahydrofuran
(2 eq.) of
1.8 M
tertiary butyl lithium
The m i x t u r e was
stirred
I hour at O 0
C, 30 m i n u t e s at O 0 C and then 3.8 m L (0.018 m o l e ) of n - d e c y I
iodide w a s added at O 0 C and stirred
I hour at O 0 C, for 2
for
hours at r o o m t em perature 20 m L of water was
reaction m i x t u r e and extracted w i t h ether.
evaporation of solvent
liquid
(44% yield
1H N M R :
4.48 (1H, br s); 3.85 ( 1H, m);
254 ( M + ), 1 87,
41 .
obtained
After drying and
1.0 g (0.0039 mole)
of
f ro m 19).
0.85 (3H,
MS:
there wa s
slowly added to the
1.86- 1.23 (25H, m);
t , 3 = 6 Hz).
169 (base),
141,
128,
I 13, I 00, 85, 70, 55,
91
Preparation of 4 - B r o m o - j ,7,7-1rime thy I- 6 ,8-dioxabieye lo­
ll3. 2. I ]octane
( 7_8) , and 4-Bromo-7-deuter iomethy I- 5, 7-d ime t hy I -
6 ,8- d i o x a b icyclo [ 3 .2.1]octane (78a)
To a solution of 0.20 g (0.0013 mole)
ketal,
(_56), stirring
temperature,
was
of
the bicyciic
in 20 m L of carbon tetrachloride at room
added 0.066 m L
(I eq.) of b ro mi ne via syringe.
The solution w a s stirred for 7 hours,
after w h i ch
time 20 m L of
water w er e added and the resulting solution wa s extracted with
three 20 m L portions of m e t h yl en e chloride w h i c h w e r e combined,
w as h ed w i t h
10% aqueous s o d i u m bicarbonate and brine, dried over
anhydrous m a g n e s i u m sulfate and reduced
g (0.00115 mole)
prepared
of slight- y e l l o w
in volume
to give 0.270
(88% yield).
liquid
78a was
f ro m 4_8.
1H N M R of 78:
4.01
( 1H,
dd);
3.95 ( 1H, br d);
2 .4 - 2 . 1 5 (2H,
i
m); 2.0-1.64 (2H, m ) ; 1.59 (3h , s ); 1.41 (3H,
s );
N V R of 7 8 a :
13C N M R of
1.30
(3H,
Same as 78_ except
7_8:
107.3,
24.6,
MS of 78a:
239, 237 ( M + ), 1 97,
Calcd
89,
54.2,
(1.30 1H,
30.1 , 28.7,
93,
83,
77, 67,
s).
27.4,
1 95, 1 79, 1 77,
55 (base),
1 49,
237.0444.
41.
1 3 1, I 15,
71, 43 (base).
for C 9H] 2B T O 2D 3 :
237.0446.
(2H, s),
20.9.
154 (M+ - H B r ), 111,
97,
1.41
82.2, 80.6,
MS of 78:
HRMS:
s ).
Observed:
92
2.0-1.64
2.4-2.15
Preparation of e x o / e n d o - 5 , 7-Dime thy I - 7-(4-methy I- 3 - p e n t e n e )- 6 , 8-
(87 )
d i o x a b i c y c l o [ 3 . 2 . I ]octane
5 - b r o m o - 2 -m e th y 1-2-pentene
(2.0 g,
0.012 mole) was
added to 0.30 g (0.012 mole) of m a g n e s i u m in 30 m L
at r o o m te mperature under nitrogen.
stirred at O 0 C for 2 hours until
of dry ether
The reaction m i x t u r e was
a dark gray solution
at w h i c h p o i n t 1.4 g (0.010 m o Ie ) o f M V K d i m e r ,
in v ol um e
yield).
G L C analysis
shows
The extracts were
dried over anhydrous m a g n e s i u m sulfate and
reduced
17 c o l u m n
to give
of
1.6 g (0.0070 mole) of
the product
using a
the e x o rendo isomeric ratio
1H N V R of exo-87:
5.09 ( 1H, br
3 = 3.4 Hz);
1.59 (3H,
1H NVIR of e n d o -87:
10 hours at
20 m L of 5% aqueous HCl was added and the
reaction m i x t u r e was extracted w i th e t h e r .
w a s h e d w i t h brine,
formed,
(8), in I 0 m L
dry ether w as slowly added via syringe and stirred
r o o m temperature.
slowly
5.11
( 1H,
(72%
I I' x 1/4",
10% OV-
is 84:16.
t , 3 = 7 Hz); 3.92 ( 1H, br d,
2.15-1.45 (I OH, m);
s );
br
1.40 (3H,
s ) ; 1.26
s);
(3H,
s);
s).
1.66 (3H,
1.33 (3H,
t ); 3.88 (br d);
(I OH, m ) ; 1.67 (3H,
(3H,
liquid
s);
s ).
2.15-1.45
1.60 (3H,
s);
1.41
93
13C NMR of mixture:
M S of e ^ o - 87:
131.3 (s), 124.4 (d),
(d ),
41.3
(t),
34.2
(t),
25.7 (t),
25.6
(q),
24.2
(t),
23.1
(q),
17.9
17.5
(t),
17.3
(q).
M S of e n d o -87:
Calcd
67,
224.1 776.
Observed:
2907,
224.1764.
1 21,
107, 98, 93,
55, 43 (base).
for C u H u O 2 :
IR (mixture):
142, 121 , 1 13 , 98, 93, 82, 69,
224 ( M + ), 1 82, 1 64 , 1 4 1 , 1 35,
81,
HRMS:
(q),
43 (base).
Calcd for C u H 2ZfO 2 :
HRMS:
1H
79.9
224 ( M + ), 164,
55,
107.1 (s), 82.9 (s),
224.1776.
1379,
1241,
Observed:
1198,
1176,
1105,
224.1766.
1041.
( 13C )
(17.5)
exo-87
(34.2
(24.2)
(107.1)
1.40(25.6)
3.92(79.9)
^
5.09(124.4)
(131.3)
1.59(17.9)
(82.9)
>
1.33(23.1)
1.66(17.3)
(25.7)
(41.3)
endo-87
1.41
5.11
Preparation of c i s /1 r a ns-7 , I I-Dimet by Id od eca- 6 ,I0 - d iene-2-one
(8 8 )
A
(87),
solution
of 0.17 g (0.00076 mole) of
in 10 m L a cetonitrile was
the bicyclic
subjected to the general
ketal,
94
cleavage procedure by. using acetyl
(0.00015 mole) of
capillary c ol um n
difficult
MS:
iodide
reaction product.
(SE-30),
to give
0.032 g
G L C analysis,
indicated the p ro d u c t , but
to separate of pure
by using
it was
8j$ (20% yield).
2 08 ( M + ), I 93, 175, 1 50, 1 35,
123,
1 1 9, 1 07, 95, 79, 67,
43 (base).
Calcd for C u H 2ZfO:
HRMS:
208.1827.
Observed:
Preparation of 6 ,1 0-Dime thy I - 5,9 - n o n a d ienoic acid
Methyl
208.1822.
(81) and
6 ,10-dime t,hy I- 5,9-nonad ienoat e (89)
The crude m i x t u r e
water w i t h
(0.11 g) of 8J? was dissolved
I m L of dioxane to produce a homogeneous
Addit io n of I m L of 10% N a O H and
in 2 m L of
solution.
the K I - I 2 reagant dropwise was
followed by shaking until a definite dark color of iodine
persisted.
The m i x t u r e w a s heated
minutes.
Excess
iodine was
in water bath (60° C)
removed by the addition of few drops
of N a O H solution then dilute w i t h w ater
minutes.
to have
and a llowed
The y e l l o w precipitate (CHI 3 ) was
119-121° as a M.P.
extracted w i t h ether.
for 2
to stand
15
filtered and shown
The filtrate was acidified and
Evaporation of the solvent gave a crude
acid w h i c h w a s not purified; but w as refluxed in 10 m L methanol
with
10 drops of sulfuric acid for
I hour.
The metha no l was
evaporated and 20 m L of water and 20 m L of ether was added for
extraction.
gave
15 m g
After drying over MgSCfy, evaporation of solvent
of crude product.
95
MS of 89:
224 ( M + ), 2 09 (base),
55,4
HRMS:
123, 95, 69,
1.
for C h H 2^ O 2 :
Calc d
168, 135,
224.1776.
Observed:
224.1805.
Preparation of 4 ; 5-Dime thy Icyc Iohexene dicarboxylate
A
solution
(92)
15 g (0.099 mole) of c i s - 1,2,3,6-tetra-
of
hydrophthalic a nhydride was m i x e d w i t h I O O m L of m e t h a n o l , and
0.1 m L of concentrate sulfuric acid at
3 hours at reflux,
r oo m temperature.
After
the reaction m i x t u r e was cooled to room
temp er at ure and m et hanol w as evaporated via a rotatory
evaporator.
100 m L of ether was added to the reaction mixture
f
.
■
and w a s h e d w it h 50 m L of 5% aqueous s od i u m bicarbonate solution
followed by saturated brine.
The organic
layer was
dried over
anhydrous m a g n e s i u m sulfate and reduced in volume followed by
distillation
(0.4 m m Hg).
(0.0828 mo le)
1H NMR:
HRMS:
IR:
173.6
198 (M+ ),
(s),
167,
color less
s); 3.66 (6H,
(2H, d d , 3=6,
13C N V R :
MS:
of a clear,
5.65 (2H,
.
Collection
liquid
16.4 g
(84% yield).
s); 3.02 (2H,
t,
3 = 5 Hz);
2.53
16 Hz); 2.33 (2H, dd, 3 = 6 , 16 Hz).
124.8
138,
(d),
107,
Calcd for C 10H 1^ O 4 :
2941,
from 850 -88° C gave
1736 ( C = O ), 1445,
51.6 (q), 39.4
79 (base),
198.0891.
1212,
1036.
(d),
25.4
(t).
59.
Observed:
198.0887.
96
3
3 3.66(51.6)
Preparation of c i s - 9 , IO - B i s (Carboxymethy I)-A ^' decaIin
A solution of
n-buthyllithium,
I 50 m L of dry
mole) of the diester,
bright
At
time
for
I 5 minutes;
(92^), was
red solution w as
this
tet rahydro furan, 7 5 m L of 2.7 M
and 26.1 m L of d i isopropylamine was
under nitrogen at -7 8° C
tetrahydrofuran w as added
then
stirred
13.5 g (0.0682
injected via a syringe and the
stirred
22 g (1.5 eq.) of
(93)
10 minutes.
for an additional
1,4-dibromobutane
in 30 m L dry
to the reaction mixture.
This
resulted
in a lightening of the color of the reaction to a pale
yellow.
After
stirring
for 3 hours at
reaction was quenched by pouring
room temperature,
the
it into excess dilute H C l .
phases w e r e separated and the aqueous phase was extracted
times w i t h 50 m L portions of m e t h y l e n e chloride.
organics w e re dried,
Collection
from
c l e a r , colorless
evaporated and distilled
I 15° - 120° C gave
liquid
three
The combined
(0.4 m m
Hg).
12.9 g (0.0512 mole) of a
(75% yield).
The
97
IH NVTR:
5.57
13C N M R :
(2H,
176.2 (s),
31.3
MS:
252
HRMS:
IR:
s); 3.63
(t),
( M + ), 220,
Calcd
2874,
( 6H,
123.0 (d),
s) ; 2.5-1. 3 ( 12H, m) .
51.3 (q),
45.6 (s),
32.9 (t),
2 1 .8 (t).
192,
1 33 (base),
for C 14H 20O 4 :
91, 79.
252.1360.
1715 (C=O), 1429, 1299,
Observed:
1149, 1079,
252.1356.
1020, 760, 680,
649.
5.57(123.0)
Cf' IxO-CH3
(176.2)
3.63(51.3)
Preparation of c i s - 9 , 10 - B i s ( hydroxymeth y I )-A ^ - d e c a Iin (94)
A s o l u t i o n of 12.9 g (0.0512 m o l e ) of the dies ter, (92),
20 m L of dry tetrahydrofuran was
stirred m i x t u r e
slowly added
(exothermic)
of 4 g (0.1 mole) of L i A l H zt and
tetrahydrofuran.
After
in
to a
100 m L of dry
10 hours stirring at r o o m temperature,
the reaction m i x t u r e was hydrolyzed by slowly adding 60 m L of
ether and 20 m L of water.
and
the ether
saturated
solid
The
inorganic salts w e r e
layer w as w a s h e d w i t h 5% aqueous HCl
brine.
(98% yield).
Evaporation gave
filtered off
followed by
9.79 g (0.0499 mole)
of w hite
98
M.P.
(without
recrystallization)
: 143-145° C
(Ref.
147-149°
C)3 4 .
1H 1N1VR:
5.56 (2H,
Hz);
s ); 3.68 (2H, d, 3 = 10 Hz); 3.56
3.12 (2H, br s);
2.04 (4H, br
s);
(2H, d, 3=10
1.73-1.35
(8H,
m) .
13C b W R
(pyridine + C D C l 3 ) ;
123.8
30.7
178 (M+- H 2O),
MS:
HRMS:
IR:
160,
147,
Ca led for C i 2HigO:
3226 (-CH),
2899,
(d),
(t),
105, 91
65.9 (t),
29.6
(base),
178.1356.
1471 , 1087,
(t),
38.1
20.3
(t).
79, 67, 41.
Observed:
1 058,
(t),
1020,
178.1 355.
1000,
980,
658.
1H ( 13C )
(38.1),
5.56(123.8)
(20.3)
(29.6)
2.04(30.7)
Preparation of c i s - 9 , IO-B is ( m et ha ne su lf o ny lox ym et hy I ) - -decal in
(95)
To an
ice-cold
stirred
m e thanesulfonyl chloride
solution of
12.5 m L
in 20 m L of pyridine was added dropwise
a s o l u t i o n of 9.5 g (0.048 m o l e ) of the diol,
pyridine at 0-5° C.
cold
ice bath,
(0.162 mole) of
After an additional
the reaction was
poured
(9jO,
2 hours
into
in 4 0 m L of
stirring
ice-5% HCI
and extracted w i t h three 50 m L portions of chloroform,
w it h 5% aqueous s o d i u m bicarbonate,
in the
solution
washed
saturated brine and dried
99
over anhydrous m a g n e s i u m sulfate.
(0.0474 mole)
M.P.
of w h i t e
solid
(from methanol):
1H NM?:
5.59 (2H,
s); 4.29
13C N M R :
123.3
28.5
MS:
HRMS:
IR:
(d),
72.8
(t),
20.2
(t).
178 (M+ - Ms 2O),
160,
147,
Calcd for C j2H jgO:
1468,
124.5-125. j)3^
(2H, br d, 3 = 1 7 Hz);
2.02 (2H,
1.58- 1.52 ( 8H, m).
(t),
2890,
(Ref.
(2H, d, 3 = 10 Hz); 4.13 (2H, d, 3 = 10
s); 2.21
b r d, 3=17 Hz);
16.7 g
(98% yield).
121-123°C
3.0 I (6H,
Hz);
Evaporation gave
37.8
123,
(s),
105,
37.2
91
178.1356.
(q),
(base),
1H ( 13C )
(37.8)
943,
850,
763,
(t),
67,
41
178.1355.
I 180
670.
)—SOz-O H 3
xN
5.59(123.3)
79,
Observed:
1340 ( as ymmetric S O 2 stretching)
(symmetric SOg stretching),
30.6
(20.2)
"(28.5)
2.21,2.02(30.6)
'-SO2-CH3
4.29,4.13(72.8)
3.01(37.2)
Preparation of
I2 - T h ia [ 4 .4 .3 ]prope I I-3-ene
The di me sy la t e
12 g (0.15 mole)
(15.4 g;
0.0438 mole),
(96)
(9_5), wa s
m i x ed with
of s o d i u m sulfide (sodium sulfide'9 hydrate was
treated w i t h benzene azeotrope to remove water) and
dry h e x a m e t h y Iphosphor amide,
and heated
I 50 m l of
to 120° C for 24 hours.
The b r ow n is h - c o l o r e d contents w e re cooled to r oo m temperature
and treated with
ether
150 m L of w a t e r , extracted with ether.
layer was w as h ed w it h water,
m a g n e s i u m sulfate and reduced
mole)
M.P.
of w h i t e
solid
5.51
(2H,
(2H, d ,
in volume
to give
dried over
7.9 g (0.041
(93% yield).
(from methanol):
1H N M ? :
saturated brine,
The
84-86°
(Ref.
s ); 2.8 1 (2H,
85-87°)^
br s ); 2.68 (2H, br
s); 2.11
3=7 Hz); 1.97 (2H, d, 3=7 Hz); 1.59-1.33 (8H,
m).
13C N M R :
I 23.5 (d),
44.3 (s),
4 1.2 (t),
32.5 (t),
31.0 (t),
21.6 (t).
MS:
194
HRMS:
IR:
(M+ ), 147,
Calcd
2890,
133,
1 1 9,
for C 12H 18S:
1453,
909,
105,
91
194.1129.
734,
(base),
79, 67,
Observed:
41.
194.1161.
661.
2.81,2.68(41.2)
5.51(123.5)
2.11,1.97(3z.o;
Preparation of c i s - 9 , I0-Dime thy IdecaIin-2-ene
The
propel lane
(2.95 g;
0.0152 mole),
(9j>), was
in 80 m L of ethanol and stirred at reflux with
nickel
for
12 hours.
R a n e y - n icke I was
After cooling
filtered and the
(97)
dissolved
20 g of Raney-
to r o om temperature,
the
filtrate was evaporated.
Saturated brine (50 mL) was added and the reaction was
101
extracted w it h ether,
reduced
dried over anhydrous m a g n e s i u m sulfate and
1.8 g (0.011 mole) of liquid w e r e obtained
in volume.
(7 3% yield) and 0.45 g (0.0027 mole;
dimethyl deca I in,
18% yield)
of
ci s-9,10-
(9 7 a ), w as obtained which are separated after
h y d r o b o r a t i on .
1H
NNR of 97:
5.53
13C N M R of 97:
(2H,
s);
124.5 (d),
1.98-1.28
3 5.1
(s),
( 12H, m ) ; 0.85
34.4 ( t ), 34.1
( 6H,
s).
(t ), 23.9
(t) , 21.7 (q).
MS O F 97:
HRMS:
164 (M+ ) , 149 (base),
Calcd
IR of 97:
1H (
for Cj 2^20 *
2907,
1449,
135,
164.1564.
1374,
909,
C )
1 09, 93,
81,
Observed:
67,
55,
41.
164.1562.
735.
(35.1)
(23.9)
5.53(124.5)
(34.4) t
(34.1)
0.85(21.7)
Preparation of c is - 9, I0-Dime thy I - 2-hydr oxydeca I in ( 98.)
A solution
of
the decal in m i x t u r e (I g of 97j
0.0061 mole,
0.25 g of 9 7 a ) in 40 m L of dry tetrahydrofuran at O 0 C was
connected
to the borane generator
(0.3 g of s od i u m borohydride
in 10 m L of d i g ly m e was slowly added to 2 m L of borontr i f Iuor ide
etherate
in 10 m L of digl yme at r o om t e m p e r a t u r e ) w i th slight
I02
flow of nitrogen.
an hour
After
I h o u r , the reaction m i x t u r e was heated
to 70-80° C, then stirred
temperature,
mixture,
for 2 hours at r o om
3 m L of water was carefully added to the reaction
then oxidized at 30-50° C by adding 5 m L of 3N N a O H ,
followed by 5 m L of 30% hydrogen peroxide.
stirring,
After
the reaction m i x t u r e was extracted w i th ether and
w a s h e d w it h 5% aqueous HCl and saturated brine,
anhydrous m a g n e s i u m sulfate and
point,
w it h
unreacted
97a
(0.25 g) was
p e t r o l e u m ether
liquid,
I hour
(98),
w as
dried over
reduced in volume.
At this
separated by silica
as a solvent,
then
isolated w i th ethyl
gel column
1.05 g (0.00577 mole) of
acetate as a solvent
(95%
yield).
1H N M R :
3.85 ( 1H, br
(3H,
13C N M R :
0.87 (3H, s); 0.85
s ).
67.9 and 66.9 for
carbon.
MS:
s); 2.0-1.0 ( I 5H, m);
182 ( M + ), 164,
Several
the
isomers of the hydroxy I-bearing
peaks were
149 (base),
1 35,
found at 37-31 and 25-21.
1 2 1, 1 09, 95, 82, 67, 55,
42.
HRMS:
IR:
Calcd
for C 12H 22O:
3289 ( - C H ) , 2915,
1449,
182.1671.
I 370,
1242,
Observed:
1040.
182.1670.
Preparation of c i s - 9 , IO - D i m e thyIdecaIin-2-one (99)
The
w i th
hydroxydeca I in (0.79 g;
0.0043 mole),
(98.),
2.5 g (1.5 eq.) of p y r i d i n i u m d ichromate
m e t h y le n e chloride
nitrogen.
was
stirred
in 60 m L of
for 24 hours at r o om temperature under
50 m L of ether was added with 3 g of m a g n e s i u m
sulfate and filtered to m a g n e s i u m s u l fate-f lorisiI- ma gn es iu m
sulfate c olumn several
disappeared.
yellow
From
this
2.35
(3H,
13C N M R :
(2H,
1 99.8,
40.6,
21.3
180 (M+ ), 165,
IR:
Calcd
2899,
br
the dark b r o wn color
0.73 g (0.0041 mole)
of slight
(93% yield).
s); 1.7-1.2 ( I 2H, m);
1.02 (3H, s ); 0.89
s ).
21.7,
HRMS:
reaction,
liquid was obtained
1H N M R :
MS:
times until
38.0,
35.2,
34.8,
33.7,
23.4,
22.9,
(two carbons are hindered).
137,
123,
for C 12H 2cP:
1 709 ( C = O ) , 1447,
1 09 (base),
180.1514.
95,
82,
67,
Observed:
55, 42.
180.1514.
705.
0.89
(199.
1.02
Preparation of c i s - 9 , 10-Dime thy I-2-hydroxy-2 - isopropyldecaI in
( 100 )
To a s o l u t i o n of 0.5 g (0.003 m o l e ) of k e t o n e ,
m L of dry
tetrahydrofuran w as
added
2.1 m L
(9^),
(1.5 eq.) of
i s o p r o p y ! m a g n es iu m chloride at O 0 C under nitrogen.
in 20
2 M
After
2
hours reflux,
m L of water
the reaction m ix t u r e was
and extracted w ith ether,
m a g n e s i u m sulfate and reduced
mole)
of
liquid
0.86
NMR:
MS:
206
HRMS:
IR:
3390
dried over anhydrous
in volume
1.01
(3H,
(3H, d , 3=10 Hz);
74.6 and 74.2
(M+-H 2°)>
Calcd
10
to give
0.5 5 g (0.0025
(88% yield).
2.0- 1.3 ( I 6H, m);
1H N M R :
hydrolyzed by adding
for
the
181 (base),
for C 15H 2gO:
( - C H ) , 2933,
s); 0.88 (3H, d, 3=6 Hz);
0.77
(3H,
s).
isomeric h y d r o x y c a rb o n .
163,
123,
224.2140.
107, 69,
55,
Observed:
44.
224.2136.
1449.
1H ( 13C )
(74.6
0.88,0
Preparations of c i s - 9 ,IO-Dimethy I- 2 - isopropyldecaIin-I-ene
( 1 0 1a ), c is - 9, 10 - Di me t hy l - 2 - i s o p r o p y l d e c a l in-2-ene
To a
(100),
solution
of 0.49 g (0.0022 mole) of h y d r o x y d e c a Iin,
in 10 m L of pyridine was added
oxychloride.
1.0 m L of phosphorous
The reaction m i x t u r e was heated to 90° C and
m a i n t a i n e d at this temperature for 15 minutes,
cool
to r o o m temperature.
hours,
( 1 0 1b )
After a total
the solution w a s poured
slowly and extracted w i t h
then allowed
to
reaction time of 2
into 40 g of
ice-water
very
three 30 m L portions of ether.
The
c om bi ne d ether extracts w e r e w a s h e d with 50 ml of 5% aqueous
105
HCl , 50 m L of 5% s o d i u m bicarbonate,
50 m L of saturated brine
and dried over anhydrous m a g n e s i u m sulfate and reduced
to give 0.33 g (0.0016 mole) of
analysis
This was
to be a 73% yield of a 45:55 m ix ture of
1H N M R of
1 0 1 a:
4.95 ( 1H,
(6H,
1H N M R of
101b:
d,
d,
I^C NMR of mixture:
M S of 1 0 1 a :
Calcd
M S of 1 0 1 b :
t , 3 = 2 Hz);
140.4,
I 63,
s);
101a and
0.80 (3H,
1.9-1.2 ( I 4H, m);
0.83 (6H,
121.3,
shown by G L C
115.5
101b.
1.9- 1.2 ( I 4H, m);
0.83 (3H,
3 = 7 Hz);
2 06 ( M + ), 191,
67,
t , 3 = 1.5 Hz);
3 = 7 Hz);
5.23 ( 1H,
(6H,
HRMS:
liquid.
in volume
0.96
s).
0.96
s).
for sp^ carbon.
I 50, I 35,
1 07 (base), 95, 81,
55, 42.
for C 15h 26 :
206.2035.
206 ( M + ), 191 , 163,
HO
Observed:
(base),
206.2035.
95, 81 , 67, 55,
42.
HRMS:
Calcd
IR of mixture:
for C j 5h 26 :
2907,
206.2034.
Observed:
1449.
1H ( 13C )
0.80
0.83
101b
(115.5)
(140.4)
(121.3)i
206.2053.
106
Preparation of 2 a - I sopropyI-cis-93,
vaierane)
IOg-d imethy IdecaIin
(9 1 a ) , and 2 ft-Isopropy I-cis-93,
(dl-7-Isovalerane)
IOg-dime t h y ldecalin
(9 1 b )
To a solution of 0.30 g (0.0015 mole)
of olefin mixture,
(1 0 1 a ), ( 1 0 1 b ), in 20 m L of h e x a n e w a s a d d e d 0.1 g of
p a l l a d i u m on carbon.
at 60 psi.
The m i x t u r e was hydrogenated
The catalyst was
solvent was
evaporated
9J_a:
to yield
s ); 0.82
0.242 g (0.00116 m ole) of a
m);
165,
69,
0.84 (3H,
s); 0.83 (6H, d,
s).
149,
I 37, I 23, I 09, 95, '83
55, 41.
208.2191.
208 ( M + ), 193 (base),
83,
■.H R M S :
69,
Calcd for C 15H 2 J:
MS of 91b:
(80% yield).
s).
0.79 (3H,
208 ( M + ), I 93,
(base),
HRMS:
(3H,
1 .95 - 1.04 ( 16H,
3 = 6 Hz);
M S of 92a:
for 12 hours
1.86- 1.03 ( 16H, m) ; 0.84 (6H, d, 3 = 10 Hz); 0.83
(3H,
1H N M R of .9Tb:
10%
removed by filtration and the
45:55 m i x t u r e of 9 1 a , and 9 1 b , respectively
1H N M V o f
(racemic
165,
Observed:
151,
137,
208.2180.
123,
109, 95,
55, 4 1.
C alcd for C 15H 2 J:
208.2191.
Observed:
208.2180.
I 07
Attempted Wittig Reaction of
(99)
n - B u t h y l l i t h i u m (0.1 mL;
0.385 g (0.00 I mole) of
10.2 M) was added
to a solution of
i sopropy1 1riphenyI ph os ph on iu m bromide
25 m L of dry ether at O 0 C under nitrogen.
The orange-red
colored reaction m i x t u r e was
stirred
(0.0008 mole)
in 5 m L of ether was
of keton,
(4j7),
to the reaction mixture.
After
for
15 m in ut es
2 hours reflux,
and 0.144 g
slowly added
the solid was
filtered and filtrate was extracted w i th p e t r o l e u m ether,
w it h saturated brine,
in volume.
G L C and G C - M S analysis
220 ( M + - H 2O), 205,
69,
HRMS:
55, 41,
Calcd
indicate 60% yield of 2-
I 95,
181 (base),
220.2189.
Preparation of N -B en zylsuccinimide
chloride
mole),
(52 mL,
and then
(99a).
I 63, I 23, I 07, 95, 81,
28.
for C 16H 2 8 :
S uc cinimide
was he d
dried over m a g n e s i u m sulfate and reduced
b ut y l- c is - 9, 1 0- d im et hyI -2 -hydroxyd e c a Iin
MS:
in
Observed:
220.2187.
( 105)
(30 g, 0.30 mole) was m i x ed with benzyl
0.45 mole) and p o t a s s i u m carbonate
the m i x t u r e was
heated to reflux
(2 1 g,
0.15
for 2 hours.
70 m L of 5% aqueous HCJ was added
to the reaction m i xt ur e and
extracted w i t h chloroform, w as h e d with saturated brine and
reduced
in v ol um e
to give 32 g (0.17 mole) of w h i t e
solid
(57%
yield).
M.P.: 101-1030 c
1HNIVR:
7.39-7.25
j^ C N V R :
177.0
(d),
MS:
(5H, m) ; 4.64
(s),
42.4
135.8
( t),
(s),
28.1
Calcd
for C
1H (13C )
jiH jjN O 2 :
(177.0)
129.0
s); 2.69
(d),
(4H,
128.7
s).
(d),
128.0
( t ).
189 (M+ , base) , 161 , 1 59,
HRMS:
(2H,
132,
1 1 9,
189.0789.
(135.8),
104,
91,
77, 65,
Observed:
51 .
189.0787.
t
N - C H 2^ Q
(128.0)
2.69(28.1)
(128.7)
4.64(42.4)
Preparation of c i s - 3 -(N - B en zyl)-2,4-dioxobicyclo[3.3.0]]heptane
(1 0 7 )
A
solution
(K15),
of
5.0 g (0.026 mole) of N-benzy Is ucc in imi d e ,
in 40 m L of dry tet rahydrof uran was added
solution of
2.5 equivalents
of
of di isopropylamine w a s added
lithiumdiisopropylamide
to 6.5 m L of
in 200 m L of dry tetrahydrofuran at
-78° C.
C and
The reaction m i x t u r e was
then
4 mL
(1.5 eq.) of
to a stirred
(8.5 m L
10.2 M n-butyl lithium
-10° C under nitrogen) at
stirred
for
10 m i n u t e s at
-78°
I ,3-dibromopropane was added and
stirred overnight at r o o m temperature.
100 m L of 5% aqueous HCl
solution was added to the reaction m i x t u r e and extracted with
three 60 m L portions of e t h e r , w as h e d with 5% s od i u m
bicarbonate,
saturated brine and reduced
separation of
in volume.
After
I,3 - d ibromopropane via a silica gel col um n using
ether as a solvent,
3.64 g (0.0159 mole) of liquid was obtained
(60% yield).
1HNlVR:
7.31-7.26
Hz);
13C N M R :
I 80.0
IR:
(s),
45.1
229 (M+ , base),
HRMS:
I 36.0 (s),
(d),
201,
42.3
s); 3.13 (2H,
1695 (C=O),
1389,
I 28.6 (d),
(t),
172,
Calcd for C 14H 15N O 2 :
2915,
4.6 (2H,
br d, 3 = 8.9
2.15-1.60 (4H, m) ; 1.19 (2H, m).
(d),
MS:
(5H, m);
158,
30.4
145,
229.1103.
1340,
I 28.5 (d),
(t),
132,
24.7
104,
Observed:
I 27.8
(t).
91,
67,
51.
229.1101.
1176, 697.
Preparation of 3 - (N-Benzy I )-2,4 - d io x o t ricycIo[ 3 . 3 . 3 . 0 Jdecane
(108)
To a stirred solution of 2.5 equivalents of
d ii so pr op y la m id e
lithium
in 30 m L of dry tetrahydrofuran was added 0.33
g (0.00 H
mole) of J07 in 5 mL of dry tet rahydro furan at -78° C
u n de r n i t r o g e n .
After
10 m i n u t e s , 0.22 m L (1.5 eq. ) of 1,3-
di b r om o pro pa ne was added to the reaction m ix tu re and stirred
overnight at
r o om temperature.
(0.00035 mole)
NM?:
of
7.27
liquid
(5H,
br
W or k- up as usual
gave 0.093 g
(24% yield).
s ); 4.60 ( 2H,
s ); 2.06 ( 4 H , m ) ; I.70 (4H
m) ; I.50 (4H, m ) .
: NVR:
181. 7 (s),
( d ),
63.4
136.3
(s) , 128 .6 (d ),
(s ), 42.4
(t),
36.4
(t),
269 ( M + , base), 241, 229, 213, 200,
109 , 91,
HRMS:
IR:
Calcd
79,
I 28.2
(d ),
27.4
I 27.7
(t).
185 , 172 , 145, 132,
66.
for C 17H i 9N O 2 :
2941 , 1709 (C=O) , 1399,
(13c )
269.1413.
1 353,
I 147, 969,
P
\(181.7)
1.50(27.4)
2.06,1.70(36.4)
Observed:
701.
(136.3)
(128.6)
N-CH 2-0
4.60(42.4)
(127-7)
N-- '(128.2)
269.1403.
Preparation of 3 - (N-Benzy I )-2,4-di ox ot rieye Io [ 3 . 3. 2 . 0]nonane
(1 0 9 )
To a stirred solution of 2.5 equivalents of
lithium
d ii so pr opylamide in I00 m L of dry tet rahydrofuran was added
1.5 g (0.0066 mole)
of
- 78 ° C u n d e r n i t r o g e n .
107
in 20 m L of dry tet rahydrofuran at
A f t e r 10 m i n u t e s ,
0.9 m L (1.5 e q . ) of
I,3-dibromoethane w as added to the reaction m i x t u r e and stirred
overnight at
r o o m temperature.
(0.0017 mole)
1H f M R :
MS:
of
W or k - u p as usual
yielded 0.42 g
the product* (25% yield).
7.6-7.25
(5H, m ) ; 4.63
2 55 ( M + , base), 227,
(2H,
I 99, 171,
s);
I 50,
2.32- 1 .53 (I OH, m).
I 36, 1 23,
I 08, 91, 79,
65.
HRMS:
Ca led for CjgHjyNC^:
255.1259.
Observed:
255.1254.
Preparation of c i s - 3 - ( N- Be n zy I)-2,4 -d i o x o b icyclo [ 3 . 2 . 0 Jhexane
(no)
To a stirred solution of 2.5 equivalents of
lithium
d i i s op r o p y l a m ide in 200 m L dry tetrahydrofuran was
added 2.5 g
(0.013 m o l e ) of benzy Isucc in imi de,
of dry
(10 5),
in 30 ml
tetrahydrofuran at -78° C under nitrogen.
After
10 minutes,
1.71 m L
added
to the reaction
(1.5 eq.) of
1,2-dibromoethane was
m i x t u r e and stirred overnight at r o o m temperature.
usual
work-up,
(46% yield).
there w as
obtained
After
the
1.3 g (0.0060 mole) of product
I I2
1H NMR:
7.38-7.25 (5H, m);
(2H, d d , 3=4,
MS:
2 15 ( M + , base),
77,
65,
4.68 (2H,
7 Hz);
2.75 (2H,
144, 1 32,
A solution of
mL
118,
1 04, 91, 83
215.0946.
Observed:
27.2 m L
(0.30 mole) of
(0.20 mole) of methyl
vinyl
215.0945
(114)
isobutyraldehyde and
ketone was m i x e d at room
t em perature w it h 0.2 m L of concentrated sulfuric acid.
solution w as w a r m e d cautiously
that
water
1.44
54.
Preparation of 4 ,4-Dime thy I- 2 - c y c Iohexenone
16.2
s);
(2H, dd, 3=4, 7 Hz).
1 87, 1 72, 1 59,
Calcd for C j 3H 13N O 2 :
HRMS:
1.01
s);
The
to 45-50° C and m a i n t ai ne d at
temperature by m e a n s of occasional cooling with a coldbath.
t em perature
reaction
(Caution:
is a l lo wed
A violent
reaction m a y
to exceed 65° C).
subsided w it h in about
I hour.
3 hours).
14.9
g (0.12 mole) of clear
1H NMR:
Distillation
(1.6 m m
if the
The e xo thermic
The solution was
refluxed through a D ean-Stark trap until water
(ca.
result
Hg) of
removal ceased
the m i x t u r e gave
liquid at 35-41° C (60% yield)
6.63 (1H, d, 3 = 10 Hz); 5.80 (1H, d, 3 = 10 Hz);
(2H,
t,
3 = 7 Hz);
then
1.83 (2H,
t, 3 = 7 Hz);
2.42
1.13 (6H,
s).
13C N V R :
MS:
124
HRMS:
IR:
199.3
( s),
I 59.6 (d),
32.6
(s),
27.5
(M+ ),
109,
96 (base),
Calcd
2933,
(d),
35.9 (d),
34.2
(d),
(q).
for C g H 12O:
1681
126.6
82,
81,
77, 67,
124.0888.
53,
Observed:
( a,3 -unsaturated C = O ) , 1464,
41.
124.0887.
1383,
1239,
1 125,
805.
1H ( 13C )
2.42(35.9)
(199.3)
5.80(126.6)
1.83(34.2)
6.63(159.6)
(32.6)
1.13(27.5)
Preparation of 4 , 4 - D i m e t h y I c y clohexanone
Six grams
(0.05 mole) of
(1 14), w e r e dissolved
4,4-dimethyl-2-cyclohexenone,
in 40 m L of glacial acetic acid and 0.2 g
of 10% p a l l a d i u m on carbon was added.
overnight under
( 1 15 )
The m ix t u r e was
60 a t mo s ph e re of hydrogen.
The m i x t u r e was
filtered twice through f Iori si I, and then poured
of 200 m L of water and
I 50 m L of ether.
shaken
into a m ixture
The acetic acid was
neutralized by s lo w addition of solid sodium bicarbonate.
aqueous
ether
layer was
separated and w a s h e d twice w i t h ether.
layers w e r e c om bi n ed and dried.
(0.048 mole) of p ri sm -li ke needles,
to
39-41°
(96% yield).
The
C on centration gave 6.0 g
M.P.
37-39°.
removed a small amount of residual oil and raised
point
The
Sublimation
the m elting
1H NMR:
2.31
(4H,
t , 3 = 7 Hz);
1.63 (4H,
t , 3 = 7 Hz);
37.7
29.7 (s),
1.06 (6H,
s ).
13C N W :
MS:
212.0
126 (M+ ),
HRMS :
IR:
Calcd
2933,
(s),
111,
38.9 (d),
83,
for CgH;
1715
71
:
(base),
(d),
55,
126.1045.
27.3
(q).
43.
Observed:
126.1049.
(C=O).
0
1H
11 (212.0)
(13C )
2.31(38.9)
1.63(37.7)
(29.7)// \
1.06(27.3)
Preparation of 2 -Carb o e tb o x y -4,4 - d imethyI - I-eye Io h e x e n o I (1 16 a)
Into a 250 m L
three-necked
flask was
mole) of 50% s o di u m hydride-oil
nitrogen,
suspension.
placed
5.1 g (0.11
W h i le under
the solid w a s w as he d 3 times with dry toluene and 3
times w i t h anhydrous tetrahydrofuran (solvent r em oved by
syringe).
in dry
A solution of diethyl
tetrahydrofuran
stirred m i x t u r e was
(12.1 mL,
to reflux.
A solution of 4,4-
(5 g, 0.04 mole),
(115),
in
tetrahydrofuran w as slowly added over 45 minutes
was
required
hours and
foaming).
the flask w a s cooled
acetic acid
added,
to remove
0.1 mole)
(25 mL) was added dropwise and the
heated
dimethyl eye lohexanone
carbonate
10 m L
(fast stirring
Heating was continued for 8
in an
ice bath.
A solution of
(40 mL) and saturated brine (50 mL) wa s
followed by ether
of
slowly
(125 mL) and solid s od i u m bicarbonate.
The layers w e r e separated,
with ether
(2 x 50 mL).
w i t h brine,
gave
and
the aqueous phase was extracted
The com b i n e d organic layers were washed
dried and evaporated.
Distillation
5.3 g (0.027 mole) of clear,
color less
(0.63 nmn Hg)
liquid at
74-80° C
(68% yield).
1H N M ? :
12.22
Hz);
t,
13c NM?:
IR:
2.00 (2H, br
I 72.7
(2H, q, 3 = 7 Hz); 2.26 (2H, t, 3 = 7
s);
1.42 (2H,
0.93 (6H,
(s),
I 71.0
t, 3=7 Hz);
(s),
96.3
(s),
28.8
(s),
27.7
198 ( M + ), I 83,
170,
152,
1 42 (base),
(q),
60.0 (t),
26.4
(t ),
I 37,
35.9\(t),
14.1
(q).
1 24 , I 13,
109,
81 , 68, 55, 4 1.
Calcd for C 11H 18O 3 :
2915
1.28 (3H,
s).
(t),
96,
HRMS:
s); 4.18
3 = 7 Hz);
34.3
MS:
( 1H,
(br) , 1653,
1616,
198.1256.
1282,
1 235,
Observed:
1205,
1070,
198.1251.
820.
2- u n 3
1.28(14.1)
Preparation of 6-Bro m o - 2-carboeth o x y -4,4-d imethyI eye Iohexanone
(117)
To a s o l u t i o n of 4.2 g (0.021 m o l e ) of the k e t o ester,
(I 16), in 15 m L of me t h y l e n e chloride was added d r opwise 3.4 g
I
I 16
(0.021 mole) of bro m i n e at 0° C and stirred
temperature.
The Q-B r o m o product w a s
by bubbling a stream of moi s t u r e
hour.
8 hours at
room ■
isomer ized to the y-bromo
through
the solution for
I
5%
Excess hydrogen bromide w a s removed by rinsing w ith
aqueous
sodium bicarbonate and water.
The organic
solvent was
dried over anhydrous m a g n e s i u m sulfate and reduced
The resulting y e l l o w oil
(6.1 g) was
in volume.
used directly
for
the next
step.
Preparation of
1,2 D i c a r b o e t h o x y - 4,4- d i m e t h y lcyclopentane
To a solution of 4 g (0.1 mole) of
sodium hydroxide
(118)
in 25
m L of ethanol and 25 m L of water was added dropwise 6.1 g of
crude b r o moketo ester,
at O 0 C, then reflux
(117), at O 0 C and
for I hour.
stirred
for
1.5 hours
The yel l o w slurry which
resulted was diluted w ith w a t e r , the ethanol
evaporated at
reduced pressure and then the resulting solution was acidified
by adding H C l , extracted w i t h e t h e r , was h e d w i t h
brine,
dried over m a g n e s i u m sulfate and reduced
Distillation
(0.67 m m
Hg) gave 3.4 g
colorless
liquid at 84-90° C
1H N M R :
4.12 (4H, q, 3=7 Hz);
(2H, m ) ; 1.23 (6H,
13C N M R :
174.4
28.6
MS:
(s),
60.1
3.25 (2H, m);
46.3
(d),
(q),
13.8
(q).
242 ( M + ), 227,
197,
196, 1 68, 1 53,
81 , 67,
55,
4 1.
of
the clear,
from 1 1 6 a ).
t, 3 = 7 Hz);
(t),
in volume.
(0.014 mole)
(67% yield
saturated
1.85 (2H, m);
1.02 (6H,
44.1
139,
1.66
s ).
(t), .38.9
(s),
123, 95 (base),
HRMS:
IR:
Calcd
2933,
for C 13H 2204 :
1724
(C=O),
1176,
242.1517.
stirred at O 0 C w h i l e
flask.
evidenced above
litmus paper at
the reaction
distilled product
removal
residue was
the exit port of
(ca. 2 hours).
the
The
reaction was
the m e t h y l e n e chloride solution to a
funnel and rinsing repeated Iy with
bicarbonate solution.
After
little or no HCl
The reaction was deemed complete w hen HCl was
worked up by transferring
separatory
10.2 g of gaseous HCl
into the flask at a rate such that
was detected by wet
reaction
( 119)
chloride solution of 20 g (0.28 mole) of methyl
vinyl ketone was
w ere bubbled
242.1512.
1035.
Preparation of 4 - C h Iorobutan-2-one
A m e t hylene
Observed:
saturated sodium
If this rinse procedure was
omitted,
the
became highly colored and rapidly polymerized.
of the m e t h y l e n e chloride
distilled
(40-41° C at
(0.224 m o l e ) of colorless
liquid
in vacuo,
the reddish
18 m m Hg) to provide
(80% yield).
23.7 g
I 18
1 NMR:
13C N f W :
MS:
IR:
(2H,
(3H,
s ).
204.8
108
HRMS:
3.71
t , 3=6.5 Hz);
(s),
(M+ + 2),
Calcd
45.5
(t),
1368,
0
71, 63, 43
106.0185.
1163,
t, 3=6.5 Hz);
38.0 (t), 30.0
106 (M+ ), 91,
for Q fH 7O C l :
1718 (C=O),
2.90 (2H,
727,
2.18
(q).
(base).
Observed:
106.0189.
649.
(204.8)
2.18 (30.0)
2.90(38.
Q j rX
3.71(45.5)
Preparation of 2,7,7-Trimethyl-(cis)-l,5-dicarboethoxybicyclo[3.3.0]octan-2-ol
(120)
A solution of 2.5 equivalents of
in 50 m L of dry tet rahydrof uran w a s
lithium d i i s opropyIamide
stirred w h i l e cooled to -78°
C a n d 0.70 g (0.0029 m o Ie ) of the dies ter, ( 1 1 8 ), w a s a d d e d
slowly via syringe under
nitrogen.
After
stirring 30 minutes,
0.46 g (1.5 eq.) of I I 9 w a s a d d e d at -78° C.
then stirred for 24 hours at
cautiously adding
ether,
room temperature and quenched by
10% aqueous HCl
solution, extracted with
was h e d w ith saturated brine and then dried over m a g n e s i u m
sulfate.
This gave 0.89 g of an orange syrup w h i c h was
through a silica gel column
acetate)
yield).
The r e a c t i o n w a s
to provide
(5 c m x 45 cm,
0.19 g (0.0061 mole) of
passed
9:1 hexane:ethyl
the product
(21%
1H NM R :
4.09
J= 7 Hz); 4.07 (2H, q, J =7 Hz); 2.9- 1.4
(2H, q,
(9H, m ) ; 1.51 (3H,
t, J = 7 Hz);
13C N M R :
MS:
I 78.9
IR:
1.09 (3H,
173.8
1.24 (3H,
s);
(s),
t , J = 7 Hz);
1.04 (3H,
83.1
(s),
1.21
73.0 (s),
63.6 (s),
(t),
60.6 (t),
50.5 (t),
49.7 (t),
40.5
36.9
(s),
36.8
(t),
32.7
31.2
23.7 (q),
14.0
(q),
13.9
(q).
(q),
312 ( M + ), 266, 241, 221 , I 95 (base),
Calcd
65,
(q),
I 67, 1 49,
(t),
1 21 , I 07,
43.
for C j 7H 2 gO 5 :
3 3 3 3 (-OH), 2924,
1 21 2, 1186,
(3H,
s).
61.4
93, 79,
HRMS:
(s),
s);
312.1936.
17 1 2 (C=O),
Observed:
I 684 (C=O),
I 368,
312.1938.
I 277,
1026, 91 1, 730.
iH ( 13C )
4.09(61.4)
(178.9)
I fN
1.24(14.0) CH3-CH2- 0 ^(y.l
(50.5)-*
I
(83.1)
1.09,1.04(31.2,23.7) {
(49.7)
QzZ^O-CH2—CH3 1.21(13.9)
(173.8)
4.07(60.6)
NOTES A N D REFERENCES
1 2 1
I.
R.M. Si Iver stein, R.G. B r o u n lee, T.E. Bel l a s , D.L. W o o d ,
and L .E .. Broun , S c i e n c e , ( 1968), 159, 889.
2.
K.B. Li p k o w i tz , S. S c a rp o n e , B.P. M u n d y , and W.G. B o r n m a n n ,
3. Org. C h e m . , ( 1979), 44, 486.
3.
D.P. W e i s I w e r , F.3. S c h w e n d e , M. Carmack,
3. O r g . Chem,., ( 1984), 4^, 882.
4.
B.P. M u n d y and W.G. B o r n m a n n , 3. Or g. Chem.,
5264.
5.
Y. Naya and M. K o t a k e , Tet rahedron L e t t . , ( 1967),
6.
B. Maurer, A. Grieder,
(1979), 62, 44, 1096.
7.
D. S e e b a c h and M. P o h m a k o t r , Hel v. Chim. A c t a , ( 1 979), 6 2 ,
843; Y. K i m and B.P. M u n d y , 3. Org. C h e m . , ( 1 982), 47,
3556.
8.
L.M. S m i t h , R.G. S m i t h , T.M,. L o ehr , G.D. D a v e s , 3 r ., G.E.
D a t e r m a n , and R.H. W o h l e b , 3. O r g . C h e m . , (1978), A3, 2361.
9.
G. S t o r k and S.R. D o w d , 3. Am.
2178.
10.
B.P. M u ndy
in p r e s s .
11.
G.A. A d r o u n y , V.3. D e r b e s , and R.C. 3ung, S c i e n c e , (1959),
1 3 0 , 44 9; M.S. B l u m , 3.R. W a l k e r , P.S. C a l l a h a n , and A.F.
Nov a k , S c i e n c e , (1958), 1 2 8 , 306.
12.
3. W r o b e l , K. T a k a h a s h i , V. H o n k a n , G. L a n n o y e , 3.M. C o o k ,
and S.H. Ber tz, CL. Org. C h e m . , ( 1983), 4_8, 139; P.A. W e n d e r
and G.B. D r e y e r , 3_L A fin- C h e m . S o c . , ( 1 982), 1 0 4 , 5805;
M.
Karpf and A.S. D r e i ding, Tetrahedron Lett., (1980), 4569;
H. Schostorez and L.A. P a q u e t t e , 3^_ Am. C h e m . S o c . ,
(1 981 ), 1 0 3 , 722; W. O p p o l z e r a n d F. M a r a z z a , He I v. Chim.
A c t a . , ( 1 981 ), 64, 1 575; W. O p p o l z e r and K. Bat tig,
i b i d , (1981), 64, 2489.
13.
L.A. P a q u e t t e , T e t r a h e d r o n , (1981), T7 > 25; L.A. Pa q u e t t e ,
Topics in Current Chemi s t r y , (1979), 1% 4 1- 165.
14.
D. W i l k e n i n g , B.P. M u n d y , and K.B. L i p k o w i tz,
3. Org. Chem. , ( 1985), in p r e s s .
I 5.
B.P. M u n d y , K.B. L i p k o w i tz, M. Lee, and B.R. L arsen,
3. Org. C h e m . , (1974), 39, 1963.
and M.
and W.
Bjo r k l und,
and
M. N o v o t n y ,
( 1 984), 49,
2459.
Thonrmen, H e l v. Chim. Acta,
Chem.
Soc., ( 1 963), 85,
Tetrahedron Lett., (1985),
I22
16.
B.P. M u n d y a n d Y. Kim, 3. H e t e r o c y c l i c
1221.
Chem., (1982),
----------- -
1 9,
—
17.
P.3. M a u r e r a n d M.3. M i l l e r , 3. Org. Chem.,
235.
---------------
(1981), 46,
—
18.
D.3. G o l d s m i t h , E. K e n n e d y a n d R.G. C a m p b e l l , 3. Org.
Chem., ( 1 975), 40, 3571.
—
19.
D. Rolf, 3.A. B e n n e k and G.R. Gray, 3. C a r b o h y d r a t e Chem.,
( 1 983), 2(4), 373; D. R o l f and G.R. Gray, 3. Am. Chem.
S o c . , ( 1 982), 1 04, 3539.
20.
Y . K i m and B.P. M u n d y , 3. Org. C h e m . , (1982),
21.
Y. Kim., Ph.D. Thesis, M o n t a n a S t a t e U n i v e r s i t y ,
132.
22.
U.E. D i n e r a n d R.K. B r o w n , Can. 3. C h e m . , ( 1 967), 45, 2547;
B.E. L e g g e t ter and R.K. B r o w n , ibid., (I 964) 42, 9T0;
( I 965) 43, I 030.
23.
B. M a u r e r , A. G r i e d e r , and W. T h o m m e n , He I v. Chim. Acta,
( 1 979), 62, 44.
24.
DMS-UV Atlas (Butterwort h s , London,
pyridine-2-carbaldehyde
47,
3556.
( 1 982), p.
1971)
> Heptane
A max
_
231
238
268
(10,000)
(7,800)
(3,750)
25.
L. Mach I is, Plant Physiol., (1958), 11 , 181 ; L. Machl is,
W.H. Nutting, MTW. "WiTTTafns, and H. Rapopor t,
Bi ochemi s t r y , (1966), .5> 2147; L. IWachl is, W.H. Nutting,
a n d H. R a p o p o r t , 3. A m. Chem. S o c . , ( 1 968), 90, 1674;
W.H. N u t t i n g , H. R a p o p o r t , and L. M a c h I i s , fEl d., (1968),
90, 6434.
26.
P.A. Grieco,
3. Mi. Chem.
Soc.,
(1969),
91,
5660.
I23
27.
3. Kr ip in s k y , Collect. Czech. Chem. Corrmun.,
2638.
:
------
28.
P. Narasimha Rao,
29.
3. Kripi nsky, M. R o m a n u k , V. H e r o u t, and F. So rm, Co I Iec t .
Czech. C h em. C o m m u n . , (I 96 3), 28, 3122; E. Hohne,
ib id., ( 1963) 2Ji, 3128; W. K l y n e , S.C. B h a t t a c h a r y y a, S.K.
PaknTkar, C.S. Narayanan, K.S. Kulkarn i, 3. Krepi n s k y ,
M. Romanu k, V. Her o u t , and F. Sorm, Tetrahedron Lett.,
(1964) 1 443; K.S. Ku lkarni , S.K. P a k n i k a r , a n d S.C.
B h a t t a c h a r y y a , T e t r a h e d r o n , (1964) 2j), 1289;
H. Hikino,
Y. H i k i n o , Y. T a k e s h i t a , K. M e g u r o , a n d T. T a k e m o t o ,
C h e m . P h a r m. B u l l . , ( 1963) JJ_, 1207; H. H i k i n o , Y.
Hikino, Y. "Takeshi t a , K. Megur o, and T. Takemoto, ibid.,
(1 965) _1_3, 1 408.
30.
3.A. M a r shall, W. I. Fanta, a n d G.L. Bundy, Tet r a h e d r on
L e t t . , (1965), 4807; E. W e n k e r t a n d D.A. Ber g e s , 3". %m.
C h em. S o c . , ( 1967), 8J9, 2507.
31.
M.P. H a r t s h o r n , D.N. Kirk, a n d W. Klyne, T e t r a h e d r o n Lett.,
32.
H. Hikino, Y. T a k e s h i t a , Y. Hikino,
Pharm. Bull., (1965), 13, 626.
33.
S.W. Baldwin,
3969.
34.
L e o A. P a q u e t t e ,
35.
E.F. E l s t n e r , D.M. C a r n e s , R.3. S u h a d o l n i k, G.P. K r e i s h m a n ,
M.P. S c h w e i z e r , and R.K. Robbins, Biochemistry, ( 1973), 12,
4992.
36.
H. K a s u g a i , 3 a p a n Kokai , 75, 1 21, 433 (Cl, A O IN, C07D), 23
Sep 1975; Chem. Abstr., 8 4 , P26862S.
37.
P.
3 8.
K. Fuk u t a , A. M i s u m i , A. M o r i , N. Ik e d a , H. Y a m a m o t o ,
T e t r a h e d r o n L e t t . , (1 984), 2_5, 669; A. M i s u m i , K. Fukuta,
H. Y a m a m o t o , i b i d . , 671.
3 9.
D. W i l k e n i n g , and B.P. M u n d y , Synth. C o m m u n ., ( 1 984),
1 4 ( 3 ) , 227.
40.
3. Org. C h e m . , ( 1971 ),
(1962),
27,
—
36U_7±, 2426.
(1965) , gg
-
and
R.E. Cawley,
Tetrahedron Lett.,
3. Am. C h em. Soc.,
Singh, and M. Weinreb,
and Y. Takemoto, C h e m .
—
( 1975),
( 1 971 ), 93, 4508.
Tet r a hedron, ( 1976),
32, 2379.
S. N o z o e , 3. F u r u k a w a , U. S a n k a w a , and S. Shi b a t a ,
. Tetrahedron Lett. (1976), 195.
124
41.
R.D. Lit t l e ,
101, 7129.
a n d G.W. M u l l e r ,
42.
P.T. L a n s b u r y , N.Y. W a n g , a n d J.E. R h o d e s , T e t r a h e d r o n
L e t t . , (1979), 1982.
43.
5. D a n i s h e f s k y , R. Z a m b o n i , M. K a h n , and S. 3. E t h e r e d g e,
J . Am. Chem. Soc., (1980), 102, 2097.
44.
B.M. Tr o s t , C.D. S h u e y , F. D i N i m o , Jr., a n d S.S. M c E J vain,
J . An. Chem. S o c ., (1979), 101, 1284.
45.
T. H u d l i c k y , T.M. K u t c h a n , S.R. W i l s o n , and D.T. Mao,
J. Am. Chem. S o c . , ( 1 980), 1 0 2 , 6351; R.L. Funk, and G.L.
H o l t o n , 3. Org. C h e m . , ( 1 984), 4_9, 5021; P.A. W e n d e r , and
J. J. H o w b e r t , T e t r a h e d r o n L e t t . , ( 1982), 2_3, 3 9 8 3; K.
Ta t s u t a , K. Ak im o t o , a n d M. K i n o s h i t a , J. Am. Chem. Soc.,
(1979), 101 , 61 1 8; R.D. Lit t l e , and G.W. M u l l e r , J^ AnL
C h em. Soc., ( 1981 ), 103, 2744.
46.
A.W. R a l s t o n , C.W. Hoerr , a n d L.T. C r e w s ,
(1944), 9, 319.
47.
Prof. R.L. Danheiser
1985.
48.
M.E. Flaugh, T.A. Cr o w e I I and D.S. Far low, J. Org.
(.1980), 45, 5399.
49.
F.G. B o r d w e l l and K.M. W e l lman, J. Org. C h e m . , (1 963), 28,
1350.
50.
L e o A. P a q u e t t e , E. F a r k a s a n d R. Ga l e m m o , JL. Org.
(1981) , 46, 5434.
51.
W.G. Bornmann, M.S.
(1977), p. 41.
52.
K.B. L i p k o w i tz,
(1975).
53.
T.R. Schwartz, Ph.D.
(198 2 ) , p. 106..
Thesis,
M ontana
State University,
54.
M.G. Bj orklund,
(1984), p. 41.
Thesis,
Montana
State University,
55.
D.J. Goldsmith, E. K e n n e d y , and R.G. Canrpbel I, J . Org.
Chem. , ( 1975), 40, 3571 .
(MIT),
Thesis,
Ph.D.
M.S.
J. Am. Chem. Soc.,
------------ ------
( 1 979),
J. Org.
Chem.,
Personal conversation,
Mon t a n a
Thesis,
May
Chem.,
Chem.,
State University,
Montana
State University,
125
56.
M. Vinekananda and 3. Ramesh B a b u , Tetrahedron
(1984), 22, 3497.
:
57.
T. Cohen,
Tetrahedron L e t t . , ( 1983),
2b_, 4163.
Lett.,
MONTANA STATE UNIVERSITY LIBRARIES
GD
111I I I I I! I l III! Ilil l l
1762
1001 0 9 4 9 3
D 378
J951
cop. 2
date
Jun, Jonsr-Gab
New approaches to
natural products
IS S U E D TO
cop.2