AN ABSTRACT OF THE THESIS OF
Annapoorna Akella
for the degree of
Chemistry presented on August 23, 1991
Master of Science
in
.
Title: The Synthesis of Macrolactones From w-Hydroxy Acyl Xanthates
Redacted for Privacy
Abstract approved:
James D. White
The synthesis of macrolactones from 0-ethyl S-(w-hydroxy acyl)
xanthates is described. The w-hydroxy acids 63, 69, 75, 84, 91, and 96 were
converted to the corresponding silyloxy acids 64, 70, 76, 85, 92, and 97
using tert-butyldimethylsilyl chloride or tert-butyldimethylsilyl triflate.
The
silyloxy acids were converted to the corresponding acid chlorides by treatment
with oxalyl chloride. Treatment of the acid chlorides with potassium 0-ethyl
xanthate provided the 0-ethyl S-(w-tert-butyldimethylsilyloxy) xanthates 65,
71, 77, 86, 93 and 98 which were deprotected with hydrofluoric acid to afford
0-ethyl S-(w-hydroxyacyl) xanthates 66, 72, 78, 87, 94 and 99 respectively.
The 0-ethyl S-(co-hydroxyacyl) xanthates were thermolyzed in the presence of
2,6-di-tert-butyl-4-methylpyridine in octane under refluxing conditions to yield
the lactones 67, 73, 79, 88, 90, 100 accompanied by the dilides 68, 74, 80,
89 and 95.
THE SYNTHESIS OF MACROLACTONES FROM
w-HYDROXYACYL XANTHATES
by
Annapoorna Akella
A THESIS
submitted to
Oregon State University
in partial fulfillment of
the requirements for the
degree of
Master of Science
Completed August 23, 1991
Commencement June 1992
APPROVED
Redacted for Privacy
Professor of Chemistry in charge of major
Redacted for Privacy
Chairman of Department of Chemistry
Redacted for Privacy
Dean of Gradu
School
Date thesis is presented
August 23, 1991
Typed by Stephanie Jorgensen for
Annapoorna Akella
TABLE OF CONTENTS
CHAPTER
II
PAGE
INTRODUCTION
1
PREPARATION AND PYROLYSIS OF co-HYDROXY-
16
ACYL XANTHATES
III
EXPERIMENTAL SECTION
34
IV
BIBLIOGRAPHY
55
LIST OF TABLES
TABLE
PAGE
Preparation of co-tert-Butyldimethylsilyloxy
Acids from w-Hydroxy Acids
II
Preparation of 0-Ethyl S-(w-tert-Butyldimethylsilyloxyacyl) Xanthates from co-tert-Butyldimethylsilyloxy Acids
III
23
25
Preparation of 0-Ethyl S-(co-Hydroxyacyl) Xanthates
from 0-Ethyl S(o)-tert-Butyldimethylsilyloxyacyl)
IV
V
Xanthates
26
Lactonization of Acyl Xanthates
29
Macrolactonization of HO(CH2)nCOOH
29
THE SYNTHESIS OF MACROLACTONES FROM
w- HYDROXY ACYL XANTHATES
I.
INTRODUCTION
The class of macrocyclic lactones, known generally as macrolides, is
one of the largest in natural product chemistry. It includes a wide variety of
structures and has grown enormously during the last two decades, a trend that
is certain to continue with recent developments in fermentation, isolation, and
structural elucidation. Naturally occuring macrocyclic lactones are usually 12-
16 membered, with numerous substituents asymmetrically placed on the ring,
and are often further elaborated with one to three glycoside units.
A macrolide is defined as a molecule containing a large ring (..12
atoms) lactone. Certain naturally occurring macrolides such as erythromycin,
are of considerable pharmacological importance.1
In principle, though not
often in practice, a macrolide can be prepared from the corresponding hydroxy
acid by internal esterification, i.e 1 from 2. Macrocyclic structures with more
than one ester linkage are also classified as macrolides. Thus dilides, trilides,
and tetrolides are compounds with two, three, and four ester linkages within
the molecule.
0
0
O
1
OH
2
Examples of 14-membered macrolides are the antibiotic substances
erythromycin A and B (3 and 4).
The 16-membered class of macrolide
2
antibiotics include leucomycin A3 (5), and the carbomycins. The polyene
macrolide antibiotics are characterized by even larger rings and distinct
hydrophilic (polyhydroxy) and hydrophobic (polyene) zones.2 These
compounds exhibit strong antifungal activity.
membered
Amphotericin B (6), a 38-
macrolide and chainin (7) containing a 28-membered ring are
members of this class.3-4 Cytochalasin B (8) and its congeners were recently
discovered to exhibit biological activities that include antibiotic, antitumor, and
cytostatic action.5 These compounds induce ejection of the cell nucleus,
production of polynuclear cells, and platelet aggregation.
Examples of dilides are pyrenophorin (9) and vermiculine (10) recently
synthesised by several groups. 6-7
Boromycin (11) and a close relative
aplasmomycin are D-valinyl esters of a boric acid complex with a 28membered macrodilide.8 Both have been recently synthesized.9 A number of
32-membered tetrolides with antibiotic and ionophoric properties are known,
an example of which is nonactin (12).10 Several syntheses of nonactin have
been reported."
Alkaloid macrolides are also known.
Senecio species have 12-
membered, Lythraceae have 14-membered, and the carpaine groups have
26-membered macrolide structures.12-14 Large ring lactams such as the ansa
macrolides, streptovaricins, rapamycins, and maytansenoids are included in
the macrolide class.15-16 The ansamycins are a family of macrocyclic lactams
characterized by a polyketide derived aliphatic (ansa) chain linked to non-
adjacent positions on an aromatic nucleus.
In the rifamycin (13) and
streptovaricin series of antibiotics the ansa chain is connected to a
naphthoquinone while in the maytansenoids the ansa chain is connected to a
3
Kishi and coworkers have reported a synthesis of
benzenoid nucleus.
rifamycin S, a useful drug for treatment of tuberculosis.17
NMe2
3
Ri = OH
4
Ri= H
OH
OH
OH OH
..
.-.'
OH
OH OH 0
./ / .../ ,/
..-'.
OH
."...*COOH
OH
NH2
OH
Alb
0
0/y
0/y
1%
193
9
3
7,.
70 IC?7 4*/y. Als
77
9././
3*cii2CoC6,3
5
12
HO
R
OH
CH3O
0.,-/\
OH
CH3C00--_>
1
...,/-\.,,,
NH
1
R2
13
The intense interest in the chemistry of macrolide antibiotics
and other biologically active macrolactones has led to the discovery and
development
of numerous macrolactonization methodologies.
Several
reviews on macrolide synthesis have been published.18
In
principle, macrocyclic systems can always be generated by
cyclization of open chain precursors but this is usually entropically disfavored.
6
As a result, polymerization due to intermolecular rather than intramolecular
reaction can supervene. Alternative methods for macrocycle synthesis include
cleavage of internal bonds in polycyclic systems and ring expansion of smaller
cycles. The following section describes several methods commonly employed
for macrolide synthesis. Generally, these methods involve activation of one or
both functionalities in the hydroxy acid precursor.
The Corey-Nicolaou method
Corey and Nicolaou discovered an efficient procedure for the synthesis
of macrocyclic lactones (Scheme I) in which simultaneous activation of
carboxyl and hydroxyl groups is achieved by utilizing a carboxylic acid
derivative which promotes proton transfer from the hydroxyl function to
carboxylic oxygen.19 The whydroxy acids 14 (n = 5-14) were converted to
their 2-pyridinethiol esters 16 using 2,2'-dipyridine disulfide 15 a nd
triphenylphosphine, which were then subjected to lactonization conditions
(refluxing xylene).
The lactones 19 (n = 5-14) were obtained in good to
excellent yields with varying amounts of dilides.
The
key feature of this
"double activation" method is removal of the hydroxyl proton by the basic
nitrogen of the pyridine nucleus present in the thioester. This protocol has
been applied to the total syntheses of erythronolide A (3) and B (4),
vermiculine (10), brefeldin, aplasmomycin, and monensin.20 -24 In subsequent
studies Gerlach and Thalmann developed a modification of the CoreyNicolaou method (Scheme I) in which silver ion (silver perchlorate or silver
tetrafluoroborate) was used to activate the 2-pyridinethiol esters by
complexation with the sulfur atom to give 21.25
7
Scheme I
/.%
PPh3
HO(CH2)nCO2F1
S
S
N
14
0(CF12)n
15
OH
16
N
N
S
H
H,
"0 0 (CF12)n
O
18
17
1
(CH2)n
N/S
H
19
20
/%
0
N
%\ S )L
I
Ag
21
X
R
I
Ag
x
(CH2)n
O
8
The Masamune method
Masamune developed an efficient method for lactonization of co-hydroxy
acids 14 (Scheme II) in which they were first converted to the corresponding
acid chloride 22 or mixed phosphorous anhydride 23 (acyl phosphate).
These carboxylic acid derivatives were then transformed to their S-tert-butyl
thiolesters 24 using thallous 2-methylpropene-2-thioate. The tert-butylthiol
esters, on treatment with the activating agent mercuric trifluoroacetate, led to
the formation of lactones 19. This methodology has been successfully applied
in the total synthesis of methymycin26.
Scheme It
COCl2
(CH2)n
SCI
OH
22
HO(CH2)nCO2H
14
P0(0E02C1
Et3N,THF
OP0(0E02
TISCMe3
OH
23
(CH 2)n
1
Hg(OCOCF3)2
SCM e 3
&mu., 2+
(CH2)n
SCMe3
OH
H
19
25
24
9
The Mukaiyama method
The macrolactonization method due to Mukaiyama and co-workers
proceeds via activation of the w- hydroxy acid 14 to the corresponding acyloxy
pyridinium salt 27 using 1- methyl -2- chloropyridinium iodide (26) in the
presence of triethylamine as a base (Scheme 111).27 The activated pyridyl
esters 27 undergo lactonization under mild conditions (refluxing acetonitrile).
Medium to large ring lactones can be prepared in good yields by this method.
Scheme III
Et3N
HO(CH2)nCO2H +
14
N
C-IA 3
CI
I
27
26
0
1
CH3
28
19
The Yamaguchi method
A mild lactonization method has been described by Yamaguchi utilizing
mixed carboxylic 2,4,6-trichlorobenzoic anhydrides (Scheme 1V).28 The whydroxy acids 14 (n = 7-14) were taken to the corresponding anhydrides 30
10
with 2,4,6-trichlorobenzoyl chloride (29) and triethylamine.
The resulting
anhydrides 30 were converted to 19 (n = 7-14) in the presence of 4-
The synthesis of 2,4,6- tridemethyl -3 -deoxy
(dimethylamino)pyridine.
methynolide from its seco acid is one of many examples illustrating the
Yamaguchi protocol.
This compound has an acid sensitive enone moiety
which was shown to decompose to a furan derivative and propionaldehyde in
the presence of a catalytic amount of hydrochloric acid.
The seco acid
cyclized under Yamaguchi conditions to give a 46% yield of the lactone
without formation of the furan derivative.
Scheme IV
CI
CI
HO(CH2)nCO2H
Et3N,THF
(CH2)
14
CI
Cl
30
29
NMe2
Et 2N HC1,
tottiene, reflux
N
O
H
NI
(CH2)n
Y
CI
NMe2
31
19
0
11
The Mitsunobu method:
Mitsunobu and co-workers have developed a general method for the
synthesis of macrolactones which employs as a cyclization agent triphenylphosphine in combination with diethyl azodicarboxylate (Scheme V).29 In this
procedure w-hydroxy acid 14 is first taken to the alkoxyphosphonium
carboxylate 32, which is converted to the macrolactone 19 in the presence of
diethyl azodicarboxylate. An important difference between this method and
others is that it is the hydroxyl function which is activated in the presence of the
carboxyl group. As a result of the SN2 displacement which forms the lactone,
inversion at the hydroxyl-bearing center is observed in this process. Long
chain hydroxy acids are converted to the corresponding lactones in moderate
to good yields by the Mitsunobu reaction.
Scheme V
HO(CH2)nCO2H
14
PPh3
EtO2CN=NCO2Et
0
32
Ph3P =0
33
19
12
The Keck-Steglich method:
Steglich reported that treatment of a carboxylic acid with an alcohol in
the presence of 4-(dimethylamino)pyridine and dicyclohexylcarbodiimide gave
esters in good yields.30
Keck has modified this method to prepare
macrolactones (Scheme VI).31 It was found that 4-(dimethylamino)pyridine
hydrochloric acid salt and dicyclohexylcarbodiimide in combination with a
co-
hydroxy acid 14 afforded a macrolactone 19 in good yield. In the absence of
a proton donor the urea derivative 34 was the major product. Apparently a
proton source is beneficial for this reaction, and the hydrochloride of DMAP is
effective for this purpose.
Scheme VI
DCC, DMAP HCI
DMAP, EtOH
HO(CH2)nCO2H
14
19
DCC, DMAP
No DMAP HCI
major
O
CO(CH2)n0H
H
(CH2)n
NN
0
19
34
minor
major
13
Other methods
Still and Rowe have reported a surprisingly efficient macrolactonization
method using acid catalysis.32 Lactones were produced from co-hydroxy acids
in the presence of benzenesulfonic acid in good yields.
Several other
methods for the lactonization of long chain hydroxy acids based on the
principle of carbonyl activation have been reported (Scheme VII).
These
include the use of mixed trifluoroacetic anhydrides 35, acyl imidazolides 36,
mixed sulfonic anhydrides 37, and methyl esters 38.
Scheme VII
0
11
35, X = OCOCF3
36, X = N
\_1\1I
37, X= OS02
CH3
38, X= OMe
The Merck group pioneered the trifluoroacetic anhydride
method of carbonyl activation and successfully applied it to the total synthesis
of zearalenone.33
Raphael and co-workers utilized the acyl imidazolide
moiety as an activating group for lactonization during their synthesis of
pyrenophorin (9).34 The acid was converted to its imidazolide derivative using
14
carbonyldiimidazole and, in the presence of a strong base (1,5-diazabicyclo[3.4.0]non-5-ene or sodium tert-amylate), this gave the lactone in 60% yield.
White demonstrated this method for the formation of a 14-membered lactone
42 in 40% yield.35
White and co-workers also employed mixed sulfonic
anhydrides for formation of
macrocyclic lactones (Scheme VIII).35 As an
example, the hydroxy acid 39 was lactonized via its mixed sulfonic anhydride
41, prepared with p-toluenesulfonyl chloride and triethylamine, to give 42 in
52% yield.
Lactonization of w-hydroxy methyl esters has been utilized by a Syntex
group.36 The hydroxy ester was treated with sodium tert-amylate at elevated
temperature to give zearalenone in 8% yield.
This last method imposes
obvious limitations where sensitive functional groups are present due to the
strongly basic conditions.
Scheme VIII
COR
OH
42
39, X = OH
40, X = N
41, X = OS02
CH3
15
In fact, although there are numerous procedures available for the
synthesis of large ring lactones from acyclic hydroxy acids, many of these are
incompatible with sensitive functional groups. Macrolactonization technology
which would complement other methods and, in particular, which would be
sufficiently mild that fragile functionality could be tolerated remains a valid goal
of synthesis. The discussion that follows describes a new protocol for effecting
the construction of macrolactones from w-hydroxy acids which offers features
not found in existing procedures and which has potentially far-reaching
implications for this area of synthesis methodology.
16
IL PREPARATION AND PYROLYSIS OF w- HYDROXYACYL
XANTHATES
The objective of this work was to explore a new method for the
synthesis of macrocyclic lactones in which an acyl xanthate 43 w as
decomposed, either photochemically or thermally, in the presence of an
internal hydroxyl group. It was surmised that the acyl radical 44 resulting from
homolytic fission of the acyl xanthate would be trapped by the nucleophilic
hydroxyl group, leading ultimately to a lactone 46 and xanthic acid 47
(Scheme IX).
Scheme IX
0
S
CLI SA0Et
OH
43
0
?j.
S
OH +
44
SA0Et
45
S
+
46
HSA0Et
47
No comparable method for lactone synthesis has been disclosed in the
literature and, in fact, acyl xanthates represent a little known class of organic
17
compounds. This is to be contrasted with alkyl xanthates which are frequently
employed for reductive removal of oxygen substituents.37
Barton and coworkers were the first to develop an efficient method for
the synthesis of S-acyl xanthates and showed that xanthate derivatives of alkyl
and aryl carboxylic acids are converted into an acyl radical 49 and a xanthate
radical 45 on photolysis in inert media (Scheme X).38 The ultraviolet
absorption characteristic of acyl xanthates at about 400 nm disappears during
the photochemical reaction. The acyl radical 49 can lose carbon monoxide
(50) to generate an alkyl radical 51 which recombines with xanthate radical
45 to furnish a S-alkyl xanthate 52.
Scheme X
0
S
0
by
S
)
R.
RASA0Et
48
+
49
CO
50
+
SA0Et
45
*F1
51
S
RSA0Et
52
In contrast to the photochemical pathway, thermolysis of 0-ethyl Sphenylacetyl xanthate (53) was found to give ethyl phenylacetate (54) and
carbon disulfide (55). It was proposed that the reaction proceeds through a
four-centered transition state as shown in Scheme XI. Photochemical and
18
thermal decomposition of 0- alkylS- phthalylglycyl xanthates gave results
similar to those observed by Barton.39 Thus pyrolytic and photolytic reactions
of acyl xanthates lead to different products.
Scheme XI
0
Phj(
A
S
S
OEt
Et0
53
S
0
PhjLOEt
±
CS2
55
54
Zard has studied the photochemical behavior
of
S-
alkoxycarbonyl xanthates 56. In this work (Scheme XII) the alkoxycarbonyl
radical was captured by an olefin in an intramolecular reaction.49 The exo
methylene radical subsequently combined with the xanthate radical to
generate a terminal xanthate 58 which underwent elimination in the presence
of copper powder to yield an exo methylene lactone 59. The rate of
decarboxylation of the alkoxycarbonyl radical was measured as a function of
the ring size formed.
In the case of n =3, formation of a seven-membered
lactone was slower than decarboxylation, thus yielding S-cyclopentylmethyl0-ethyl xanthate 57 as the major product. In the case of n =1, ring closure of
the acyl radical is faster than decarboxylation and leads to the formation of 58.
19
SchemeXII
n=3, hu
E000SCSOEt
heptane, A
87%
56
57
n=1, by
84%
.....-SCSOEt
Cu / A
Cr0
58
45%
59
The objective of our studies was to explore the thermal
reactivity of an acyl xanthate in the presence of a hydroxyl function as an
intramolecular nucleophile.
It was initially assumed that, during the
thermolysis of the hydroxy xanthate 43, a competition would occur for the acyl
radical between the hydroxyl group at the terminus of the chain and the ethoxy
group from the xanthate moiety. The products could thus, by analogy with the
chemistry shown in Scheme XII, be an ester or a lactone.
In order to examine the thermal reactivity of co-hydroxyacyl xanthates, a
method for their preparation from the corresponding hydroxy acid 60 was
needed. It was assumed that the hydroxy acid would first require protection
and that this would be effected with tert-butyldimethylsilyl chloride to yield the
ether 61. Preparation of the acyl xanthate 62 from the silyloxy acid 61 was
envisioned via the intermediacy of the acid chloride. Thus, treatment of the
20
acid chloride with potassium 0-ethyl xanthate would give the silyloxy xanthate
62 and, finally, removal of the silyl ether function would furnish the substrate
43 for study of its thermal decomposition to lactone 46 and/or other
products.38
Scheme XIII
0
0
S
SAOEt
OH
OTBDMS
OH
60
61
46
OTBDMS
62
43
Since our ultimate goal was the discovery and development
of a macrolactonization method by means of cyclizing long chain hydroxy acyl
xanthates, we selected easily available w-hydroxy acids with carbon number
10.
10-Hydroxydecanoic (63), 12-hydroxydodecanoic (69), 12-hydroxystearic
(75), and 16-hydroxyhexadecanoic (96) acids are commercially available but,
since we were interested in examining a homologous series for lactonization,
missing members of the sequence were acquired by synthesis.
Thus 13-
21
hydroxytridecanoic acid (84), which is not available commercially, was
obtained by homologating 12-(tert-butyldimethylsilyloxy)dodecanoic acid (70).
To this end, carboxylic acid 70 was reduced to the alcohol 81 using borane-
tetrahydrofuran complex and the latter was converted to tosylate 82 by
employing p-toluenesulfonyl chloride in pyridine. The tosylate group of 82
was displaced with sodium cyanide in DMSO to obtain the nitrile 83,
hydrolysis of which was accomplished by refluxing an ethylene glycol solution
of 83 in the presence of 0.3N potassium hydroxide for four days.
This
procedure led to a 92% yield of 84 in which deprotection of the hydroxyl group
had accompanied nitrile hydrolysis (Scheme XIV).
Scheme XIV
BH3. THF
THF, reflux
TBDMSO(CH2)11CH2OH
TBDMSO(CH2)11CO2H
87%
70
81
TsCI, pyridine
CH2Cl2,24h
55%
TBDMSO(CH2)11CH2CN
TBDMSO(CH2)11 CH2OTs
80%
83
92%
NaCN, DMSO
40 C, 2h
82
0.3N KOH,
ethylene glycol,
reflux,4d
HO(CH2)12CO2H
84
22
15-Hydroxypentadecanoic acid (91), which was also needed as a
member of the series of acyl xanthates, was obtained by hydrolyzing
commercially available cyclopentadecanolide 90.41
Hydrolysis of lactone 90
with potassium tert-butoxide in the presence of water gave 91 in quantitative
yield.
The w-hydroxycarboxylic acids were protected as their silyloxy acids
using tert-butyldimethylsilyl chloride in dimethylformamide and imidazole or
with tert-butyldimethylsilyl triflate in dichloromethane and lutidine. The silyloxy
esters were selectively cleaved using potassium carbonate (methanol,
tetrahydrofuran) to give the silyloxy acids.42
Scheme XV
t-BuMe2SiC1, imidazole and DMF
or
(CH2)nCO2H
R
OH
63,
69,
75,
84,
91,
96,
t- BuMe2SiOTf, lutidine and CH2Cl2
K2CO3, Me0H, THE
n=8
n=10
n=10
n=11
n=13
n=14
R
(CH2)nCO2H
OTBDMS
64,
70,
76,
85,
92,
97,
n=8
n=10
n=10
n=11
n=13
n =14
The sequence for converting the hydroxy acids (63, 69, 75, 84, 91 and
96) to the corresponding silyloxy acids (64, 70, 76, 85, 92 and 97) is
depicted in Scheme XV. Yields and conditions are given in Table I.
23
Table I: Preparation of w-tert-Butyldimethylsilyloxy Acids
from w-Hydroxy Acids
Hydroxy
Acid
co-tert-ButyldimethylR
Conditions
silyloxy Acid
H
B
H
A
n-C6I-113
B
H
B
91
H
A
96
H
A
64
70
76
85
92
97
63
69
75
84
Yield,
98
71
88
77
80
93
A = tert-Butyldimethylsilyl chloride, imidazole, dimethylformamide;
B = tert-Butyldimethylsilyl triflate, lutidine, dichloromethane
The w-silyloxy acids were converted to the corresponding acid chlorides
by treatment of a benzene solution with oxalyl chloride under reflux. The
reaction was monitored by IR spectroscopy, observing a new carbonyl
absorption at 1800cm-1. The solvent was removed and the crude acid
chlorides were used without purification for preparation of acyl xanthates. The
acid chlorides were dissolved in acetone and were reacted with an acetone
solution of commercially available potassium 0-ethyl xanthate at -35°C to give
the acyl xanthates in high yield (Scheme XVI).43
24
Scheme XVI
R
(CH2)nCO2H
OTBDMS
64,
70,
76,
85,
92,
97,
(COCI)2, C6H6, reflux
R
KSCSOEt, -35°C
(CH2)nCOSCSOEt
OTBDMS
n=8
n=10
n=10
65,
71,
77,
86,
93,
98,
n=11
n=13
n=14
n=8
n.10
n=10
n=11
n=13
n=14
The xanthates could not be chromatographed on silica gel, alumina, or
Sephadex; attempts to do so led to decomposition of these compounds.
However, the xanthates could be obtained
in
pure form without
chromatography by using a modification of the original work-up procedure.
This modification involved removal of the solvent acetone, followed
trituration with ether and subsequent filtration.
by
The ethereal layer was
extracted sequentially with sodium bicarbonate, water, and finally sodium
chloride to yield pure acyl xanthate. This procedure was used to convert w-
silyloxy acids 64, 70, 76, 85, 92 and 97
to the corresponding silyloxy
xanthates 65, 71, 77, 86, 93 and 98. The yields obtained for the formation
of the silyloxy xanthates are shown in Table II.
25
Table II: Preparation of 0-Ethyl S-(w-tert-Butyldimethylsilyloxy
Acyl) Xanthates from w-tert-Butyldimethylsilyloxy Acids
w-tert-Butyldimethyl-
0-Ethyl S-(w-tert-Butyldimethyl-
silyloxy Acid
R
silyloxyacyl) Xanthate
Yield, %
64
70
76
85
92
97
H
65
H
71
n-C6H13
77
86
93
98
96
90
96
H
H
H
90
83
79
The final step in the preparation of the w-hydroxyacyl xanthates was
deprotection of the hydroxyl function (Scheme XVII).
Scheme XVII
Rr (CH2)nCOSCSOEt
OTBDMS
65,
71,
77,
86,
93,
98,
n=8
n=10
n=10
n=11
n=13
n=14
HF, CH3CN
(CH2),COSCSOEt
R
OH
66,
72,
78,
87,
94,
99,
n=8
n=10
n=10
n=11
n=13
n=13
Attempts to deblock the hydroxyl function of silyloxyacyl xanthates using
tetra-n-butyl ammonium fluoride led to decomposition. However, removal of
the silyloxy group from these compounds with 48% aqueous HF in acetonitrile
26
was found to be facile and gave the hydroxyacyl xanthates (66, 72, 78, 87,
94 and 99) in good yields as shown in Table III. The hydroxyacyl xanthates
were used for lactonization studies without further purification.
Table III: Preparation of 0-Ethyl S-(w-Hydroxyacyl) Xanthates
from 0-Ethyl S(w-tert-Butyldimethylsilyloxyacyl) Xanthates
0-Ethyl S(w-tert-Butyldimethyl
0-Ethyl S-(w-Hydroxy-
silyloxyacyl) Xanthate
R
acyl) Xanthate
Yield, `)/0
65
H
66
82
71
H
72
96
77
86
93
98
n -C6H13
78
87
94
99
86
H
H
H
96
90
96
Initially the w-hydroxyacyl xanthates were heated in refluxing toluene
and the ratio of monomeric and dimeric lactones was measured by 1 H NMR
spectroscopy. It was found that 0-ethyl S-10-hydroxydecanoyl xanthate (66)
resulted in the exclusive formation of the dilide 68 by this method. On the
other hand, 0-ethyl S-16-hydroxyhexadecanoyl xanthate gave both the
lactone 100 (64%) and the dilide (15%). On the basis of these results
a
careful examination of the thermal reaction of w-hydroxyacyl xanthates was
carried out with the goal of optimizing the formation of macrocyclic lactones
while avoiding dilides and other byproducts.
The search for optimal lactonization conditions was conducted with 0-
ethyl S-12-hydroxydodecanoyl xanthate (72). A study employing solvents of
varying polarity (dioxane, tetrahydrofuran, toluene, xylene, hexane, octane,
27
nonane) suggested that octane was the most suitable for our purpose. After
determination of the preferred solvent, the time required for completion of
reaction was investigated. It was found that pyrolysis of 72 was complete after
a period of 19 h. Performing the reaction for either a shorter or longer time
resulted in recovery of the starting material or the formation of unidentified
products.
Having optimized the solvent and reaction time, the influence of
additives on the decomposition of 72 was tested. Since the byproduct from
the thermal decomposition of 72 would be the xanthic acid 47, which could
perhaps have a deleterious effect on the reaction, it was reasoned that the
addition of a non-nucleophilic base could facilitate lactone formation by
removing this byproduct. Indeed, incorporation of one equivalent of the base
2,6-di-tert-butyl-4-methylpyridine (101) in the reaction medium led to
a
decrease of dilide and a corresponding increase in the amount of monomeric
lactone. 44 Under optimized conditions that included 101, decomposition of
72 gave cyclododecanolide (73) in 54% yield and the dilide 74 in 28% yield.
The co-hydroxyacyl xanthates 66, 78, 87, 94 and 99 were subjected to
thermal decomposition (Scheme XVIII) utilizing these conditions and the
results are summarized in Table IV.
The fact that entropy of activation is responsible for the barrier to closing
medium sized rings is reflected in the more difficult cyclization of 66, 72 and
78. Thus, for complete conversion of 0-ethyl S-10-hydroxydecanoyl xanthate
(66) to lactones a reaction time of 29 h was required. Cyciodecanolide (67)
and the dilide 68 were obtained in 18% and 42% yields respectively from 66.
The hydroxyacyl xanthate 78, when heated under optimized conditions,
required a period of 48 h to undergo complete reaction.
In this case,
28
monomeric and dimeric lactones 79 and 80 were obtained in 34% and 17%
yields respectively.
Scheme XVIII
(CH2)nCOSCSOEt
R
2,6-di-tertButyl-4-methyl
pyridine
Jo-
octane, reflux
OH
0
(CH2)n
+
HC-0
---/Ck.,,R
(CHOn
i
R--k
Fi
66,
72,
78,
87,
94,
99,
n=8
n=10
n.10
n=11
n=13
n=14
67,
73,
79,
88,
90,
100,
n =8
n.10
n.10
n =11
n =13
n =14
00
68,
74,
80,
89,
95,
(CH2)n
n=8
n=10
n=10
n =11
n=13
The gradual release of transannular strain and gain in entropy with
increasing ring size is seen in the cyclizations of 87, 94 and 99. Complete
lactonization of 87 required only 19 h, with formation of cyclotridecanolide
(88) and the dilide 89 in 63% and 21% yields respectively. Similarly, the
thermolysis of hydroxyacyl xanthate 94 proceeded to completion under these
conditions to give lactone 90 and dilide 95 in 75% and 18% yield
respectively. The final substrate 0-ethyl S-16-hydroxyhexadecanoyl xanthate
(99) was decomposed in refluxing octane in the presence of 101 over 19 h to
yield cyclohexadecanolide (100) as the sole product in 81% yield.
29
Table IV: Lactonization of Acyl Xanthates
0-Ethyl S-(w-Hydroxy
Yield, %
Acyl) Xanthate
R
Lactone
dilide
66
72
78
87
94
99
H
16
42
H
54
28
n-C61113
17
H
34
63
75
H
81
H
21
18
A comparison of lactone formation via acyl xanthates with other
lactonization methods (Table V) shows that the xanthate method results in a
greater overall yield of lactone and dilide but that the proportion of lactone is
slightly lower than that reported under Corey-Nicolaou conditions.
Acyl
xanthate pyrolyses were performed under similar dilution conditions (1.05mM)
to those currently employed with other lactonization procedures.
Table V: Macrolactonization of HO(CH2)nCOOH
dIdldld
Yield, `)/0 of Lactone (I) and Dilide (d)
Corey
Keck
Mitsunobu
Mukaiyama
n
I
11
66
7
32
32
12
68
16
77
11
69
14
14
80
5
95
0
84
3
63
12
Xanthate
I
54
63
75
d
28
21
18
30
With the original aim of developing a macrolactonization method
accomplished we performed experiments to probe the nature of the reaction.
Attempts to determine the mechanism of this reaction led us to examine the
synthesis and pyrolysis of 0-trifluoroethyl S-(12-hydroxydodecanoyl) xanthate
(102). The strongly electron-withdrawing property of the trifluoroethyl function
of xanthate 102 would be expected to facilitate nucleophilic addition of the
hydroxyl group to the carbonyl moiety, relative to xanthate 72, and hence 102
should undergo more rapid lactone formation in a straightforward, basecatalyzed process.
Scheme XIX
0
S
OH
(CH2)11
PO(OEt)2C1, THE
OH
69
SAOCH2CF3
A.-
KSCSOCH2CF3, acetone (CH2)11
OH
102
Acyl xanthate 102 was prepared in a one-pot procedure from the
hydroxy acid 69. Thus, treatment of 69 with diethyl phosphochloridate,
followed by the addition of potassium 0-trifluoroethyl xanthate, furnished 102
in 33% overall yield. In contrast to 72, 102 was stable to chromatography on
silica gel, a factor that may prove useful in future work. Pyrolysis of 102 in
octane in the presence of 101 for 16 hours furnished only recovered starting
material.
In
contrast, when 102 was heated in the presence of
azobisisobutyronitrile and tri-n-butyltin hydride it cleanly furnished the lactone
31
and dilide in a 1:2 ratio by NMR analysis. This result strongly suggests that a
radical mechanism operates in macrolactone formation from 102. The
intermediacy of an acyl radical 44, as we had originally envisioned (Scheme
IX), would account for our observations. The absence of lactonized material
from the thermolysis of 102 in the presence of 101 implies that a nucleophilic
pathway, which would involve the addition of the hydroxyl group to the
carbonyl carbon of the acyl xanthate, was not operating.
Our observations with acyl xanthate 102 further suggest that
thermolysis of the 0-ethyl xanthates 43 also proceeds via a radical
mechanism (Scheme XX).
On this basis it is speculated that homolytic
cleavage of 43 gives an acyl radical 44 and a xanthate radical 45. Although
attempts to trap the acyl radical with 2,6-di-tert-butyl-4-methylphenol were
unsuccessful, it is likely that 44 and 45 are solvent caged, making them hard
to detect by an external radical trap. 45 It is assumed that the hydroxyl group
attacks the acyl radical 44 in an intramolecular fashion to give the more stable
zwitterionic radical 103 and that this is followed by proton transfer from the
hydroxyl group to the carbonyl oxygen giving the lactol radical 104. The
resonance stabilized xanthate radical 45 then abstracts the hydrogen atom
from 104 to give lactone 46 and xanthic acid 47. The latter subsequently
decomposes to carbon disulfide and ethanol. The role of 2,6-di-tert-butyl-4methylpyridine (101) in this mechanism is uncertain but is probably assisting
the proton transfer from 103 to form 104.
In any event, the results of our
mechanistic experiments suggest that a novel pathway involving acyl radicals
is responsible for the conversion of 43 to lactones and dilides.
32
Scheme XX
0
6
A
43
S
H + .SAOEt
44
1
a
OH
S
+
S
SA0Et
104
103
Y
0
S
+
HSAOEt
47
CS2
+
46
EtOH
+
S)LOEt
33
In conclusion, our results show that the synthesis of macrocyclic
lactones from w-hydroxyacyl xanthate precursors has the potential to become
a widely used method in organic chemistry. The promising indications from
this study provide a solid basis for further exploration of the scope of the
reaction and for a more detailed investigation of its mechanism.
34
III. EXPERIMENTAL SECTION
General
Hydroxy acids were obtained from Aldrich Chemical Company. Other
starting materials and reagents were obtained from commercial sources and
were used without further purification except as described below.
Solvents
used for reactions were reagent grade and were distilled before use. Ether
and tetrahydrofuran were distilled from sodium and benzophenone under an
argon atmosphere. Octane, pyridine, chloroform, and dichloromethane were
distilled from calcium hydride under argon. Ethyl acetate, ether, hexane and
other solvents used for routine flash chromatography were glass distilled.
A rotary evaporator was used to remove solvents from reaction
materials at water aspirator pressure which was typically between 12 and 20
torr. Residual solvent was removed by vacuum pump at pressures less than
0.5 torr. Glassware and other reaction apparatus were either oven dried at
160°C or flame dried under a stream of argon.
Neutral silica gel (E. Merck, 230-400 mesh ASTM) was used for flash
chromatography.
All analytical thin layer chromatography (TLC) was
conducted on either 1.75 x 7 or 2.5 x 7 cm precoated E. Merck TLC plates (0.2
mm layer thickness of silica gel 60 F-254).
Infrared (IR) spectra were measured with a Nicolet 5DXB FT-IR
spectrometer.
Proton nuclear magnetic resonance (NMR) spectra were
obtained with either a Bruker AM 400 or AC 300 spectrometer. Carbon (13C)
NMR spectra were obtained at either 100.1 or 75.4 MHz on the AM 400 or AC
300 spectrometer.
Elemental analyses were performed by Desert Analytics
35
Tucson, AZ. All chemical shifts are reported in parts per million (ppm) upfield
from CDCI3 (99.8%) using the 6-scale. 1H NMR data are tabulated in the order
of chemical shift, multiplicity (s= singlet, d= doublet, t= triplet, q= quartet, m=
multiplet, and b= broad), coupling constant (J) in Hertz and number of protons.
Mass spectra (MS) were obtained using either a Varian MAT CH
Finnigan 4500 spectrometer at an ionization potential of 70 eV.
7 or a
High
resolution mass spectra were recorded using a Kratos MS-50 TC
spectrometer.
10-(tert-Butyldimethylsilyloxy)decanoic Acid (64).
To a stirred solution of 10-hydroxydecanoic acid (63, 0.200 g, 1.06
mmol) in 20 mL of dimethylformamide was added tert-butyldimethylsilyl
chloride (0.325 g,
2.12 mmol) and imidazole (0.217 g, 3.18 mmol). The
reaction mixture was stirred at 45°C for 24 h. To this solution was added water
(10 mL), and the aqueous mixture was extracted thrice with ether (30 mL). The
combined extracts were dried over magnesium sulfate and the solvent was
evaporated under vacuum to yield the silyloxy ester. To a solution of the
silyloxy ester in THF:MeOH (1:1,
20 mL) was added potassium carbonate
(0.161 g, 1.16 mmol), and the mixture was stirred at 25 °C for 1 h. The mixture
was concentrated to approximately 10 mL and diluted with 5 mL of brine. The
resulting aqueous mixture was cooled to 0°C, adjusted to pH 4-5 with aqueous
potassium bisulfate (1 M) and extracted thrice with ether (30 mL). The
combined extracts were dried over magnesium sulfate and evaporated.
Purification by flash chromatography (silica gel,
50% EtOAc in hexane)
yielded 0.316 g (98%) of 64 as an oil: IR (NaCI, neat) 3300, 2930, 1711 cm-
1; 1H NMR (300MHz, CDCI3) 6 3.57
(t,
J=6.0Hz, 2H), 2.31
(t, J=7.4Hz,
2H), 1.45-1.60 (m, 4H), 1.25 (m, 10H), 0.85 (s, 9H), 0.05 (s, 6H); 130
36
NMR (75 MHz, CDCI3) 5 180.1, 63.3, 34.0, 32.8, 29.3, 29.3, 29.0, 25.9,
25.7, 24.6, 18.2; MS m/z: (rel. intensity)
303 (6.0), 245 (20), 75 (100);
HRMS calcd. for C12H2503Si (M+ - C4H9) 245.15729. Found: 245.15728.
Anal. Calcd. for C16H3403Si: C, 63.52; H, 11.32. Found: C, 63.40; H,
11.05.
0-Ethyl S-[10-(tert-Butyldimethylsilyloxy)decanoyl] Xanthate (65).
To a stirred a solution of 64 (0.181 g, 0.59 mmol) in 30 mL of benzene
was added oxalyl chloride (0.106 mL, 1.19 mmol), and the reaction mixture
was heated at reflux for 2 h. The solvent was removed under vacuum to yield
the acid chloride. Potassium 0-ethyl xanthate (0.096 g, 0.59 mmol) in 5 mL of
acetone was added to the acid chloride in 20 mL of acetone at -35°C over 0.5
h with stirring. After 1 h at this temperature the reaction mixture was allowed to
warm to room temperature. The solvent was removed in vacuo, water (10 mL)
was added to the residue, and the aqueous layer was extracted with
methylene dichloride (30 mL).
The extract was washed successively with
saturated sodium bicarbonate, water, and aqueous sodium chloride and dried
over magnesium sulfate. Removal of the solvent under vacuum yielded 0.234
g (96%) of 65 as a yellow oil: IR (NaCI, neat) 2929, 2856, 1737, 1255,
1040, 836 cm-1; 1H NMR (300 MHz, CDCI3) 5 4.66 (q, J=7.0Hz, 2H), 3.55
(t, J=6.0Hz, 2H), 2.55 (t, J=7.0Hz, 2H), 1.64 (m, 2H), 1.45 (m, 5H), 1.35
(bs, 10H), 0.85 (s, 9H), 0.05 (s, 6H); 130 NMR (75 MHz, CDCI3) 5 204.0,
192.1, 70.8, 63.2, 44.1, 32.7, 29.2, 29.0, 28.7, 28.3, 25.9, 24.8, 18.3,
13.4; MS m/z (rel. intensity) 285 (100), 269 (15), 171 (10), 77 (60); HRMS
calcd. for C16H3302Si (M+ C3H50S2): 285.22470. Found: 285.22490.
37
0-Ethyl S-(10-Hydroxydecanoyl) Xanthate (66).
To a suspension of 65 (0.234 g, 0.57 mmol) in 10 mL of acetonitrile
was added 48%HF solution (8 drops) and the reaction mixture was stirred for
0.25 h.
The reaction mixture was quenched with saturated ammonium
chloride (5 mL).
The organic layer was washed twice with sodium
bicarbonate, then water, and dried over magnesium sulfate. The solvent was
removed under vacuum to yield 0.138 g (82%) of 66 as a yellow oil: IR (NaCI,
neat)
3614, 3163, 2928,
1734,
1257,
1038 cm-1; .1H NMR (300 MHz,
CDCI3) 6 4.65 (q, J=7.0Hz, 2H), 3.59 (t, J=7.0Hz, 2H), 2.55
2H), 1.63 (m, 4H), 1.45
(t,
(t, J=7.0Hz,
J=7.4Hz, 3H), 1.25 (bs, 10H); 130 NMR (75
MHz, CDCI3) 6 204.1, 192.1, 70.8, 62.9, 44.0, 32.6, 29.2, 29.0, 28.7, 25.0,
24.9, 24.7, 13.4; MS m/z (rel. intensity) 171 (3.17), 122 (6.35),
121 (2.71),
84 (100); HRMS calcd. for C10H1302 (M+ C3H50S2): 171.13850. Found:
171.13849. HRMS calcd. for C3H50S2: 120.97817. Found: 120.97817.
10-Decanolide (67).
A stirred solution of 66 (0.085 g, 0.29 mmol) and 2,6-di-tert-butyl-4methylpyridine (0.059 g, 0.29 mmol) in 180 mL of octane was heated at reflux
for 29 h. Removal of the solvent under vacuum yielded the crude product
which was purified with a Chromatotron plate (2 mm silica plate) eluting with
2% ether-hexane to yield 0.009 g (16%) of 67 as an oil, and 0.022 g (42%) of
68 as a white solid: IR (NaCI, neat) 2848, 2845, 1733, 1258 cm-1; 1H NMR
(300 MHz, CDCI3) 6 4.17 (t, J=4.1Hz, 2H), 2.34 (t, J=2.3Hz, 2H), 1.75 (m,
4H), 1.2-1.6 (m, 10H); 130 NMR (75 MHz, CDCI3) 6 174.2, 64.7, 35.2, 26.1,
25.3, 25.2, 24.6, 24.0, 22.3, 21.2.
38
Dilide 68.
IR (NaCI,
CHCI3)
2920,
2851,
1729 cm-1; 1H NMR (300 MHz,
CDCI3) 6 4.09 (t, J=6.0Hz, 2H), 2.25 (t, J=7.0Hz, 2H), 1.60 (m, 4H), 1.27
(bs, 10H); 13C NMR (75 MHz, CDCI3) 6 173.9, 64.0, 34.8, 29.4, 29.0, 28.6,
26.0, 25.3.
12-(tert-Butyldimethylsilyloxy)dodecanoic Acid (70).
To a stirred solution of 12-hydroxydodecanoic acid (69, 1.000 g, 4.62
mmol) in 20 mL of dimethylformamide was added tert-butyldimethylsilyl
chloride (1.532 g, 10.17 mmol) and imidazole (0.9430 g, 13.86 mmol). The
reaction mixture was stirred at 45°C for 24 h. To this solution was added water
(10 mL), and the aqueous mixture was extracted thrice with ether (30 mL). The
combined extracts were dried over magnesium sulfate and the solvent was
evaporated under vacuum to yield the silyloxy ester. To a solution of the
silyloxy ester in THF:MeOH (1:1, 20 mL) was added potassium carbonate
(0.495 g, 3.5 mmol). The mixture was stirred at 25°C for 1 h. The mixture was
concentrated to approximately 10 mL and diluted with 5 mL of brine, cooled to
00C, adjusted to pH 4-5 with aqueous potassium bisulfate (1 M), and extracted
thrice with ether (30 mL). The combined extracts were dried over magnesium
sulfate and evaporated. Purification by flash chromatography (silica gel, 50%
EtOAc in hexane) yielded 1.304 g (85%) of 70 as an oil: IR (NaCI, neat)
3300, 2950,
2829, 1711, 836 cm-1
J=6.6Hz, 2H), 2.30
(t,
;
1H NMR (300 MHz, CDCI3) 6 3.59 (t,
J=7.5Hz, 2H), 1.45-1.60 (m, 4H), 1.35 (m, 20H),
0.85 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCI3) 6 180.1, 63.2, 34.0,
32.7, 29.5, 29.4, 29.3, 29.1, 29.0, 25.9, 25.7, 24.6, 18.3; MS m/z: (rel.
intensity) 273 (11.77), 255 (100), 75 (71.56); HRMS calcd. for C14H2903Si
(M+
C4H9): 273.18858. Found: 273.18860. HRMS calcd. for C14H2702Si
39
(M+ C4H11O) 255.17802. Found: 255.17800. Anal. Cald. for C18H3503Si:
C, 65.40; H, 11.58. Found: C, 65.40; H, 11.40.
0-Ethyl S[12 -(tert-Butyldimethylsilyloxy)dodecanoyl]
Xanthate
(71).
To a stirred a solution of 70 (0.200 g, 0.60 mmol) in 30 mL of benzene
was added oxalyl chloride (0.107 mL, 1.21 mmol), and the reaction mixture
was heated at reflux for 2 h. The solvent was removed under vacuum to yield
the acid chloride. Potassium 0-ethyl xanthate (0.097g, 0.60mmol) in 5 mL of
acetone was added to the acid chloride in 20 mL of acetone at -35°C during
0.5 h with stirring and after 1 h at this temperature, the mixture was allowed to
warm to room temperature. The solvent was removed in vacuo, water (10 mL)
was added to the residue, and the aqueous layer was extracted with
methylene dichloride (30 mL).
The extract was washed successively with
saturated sodium bicarbonate, water, and aqueous sodium chloride, and was
dried over magnesium sulfate. Removal of the solvent under vacuum yielded
0.365 g (97%) of 71 as a yellow oil: IR (NaCI, neat) 2924, 2917, 1740,
1240, 836 cm-1; 1H NMR (300 MHz, CDCI3) 8 4.65 (q, J=7.0Hz, 2H), 3.60
(t,
J=6.0Hz, 2H), 2.60 (t, J=7.4Hz, 2H), 1.65 (m, 2H), 1.45 (m, 5H), 1.30
(bs, 14H), 0.90 (s, 9H), 0.05 (s, 6H); 130 NMR (75 MHz, CD013) 8 204.1,
192.1, 70.7, 63.2, 44.1, 32.8, 29.5, 29.4, 29.3, 29.1, 28.7, 25.9, 25.7,
24.8, 18.3, 13.4; MS m/z (rel. intensity) 317 (5.1), 313 (50), 255 (60), 122 (60).
HRMS calcd.
for C18H3702Si (M+
313.25630 HRMS Calcd.
Found: 377.16400.
C3H50S2) : 313.25627.
for C17H3303S2Si (M+
C4H9):
Found:
377.16403.
40
0-Ethyl S-(12-Hydroxydecanoyl) Xanthate (72).
To a suspension of 71 (0.135g, 0.31 mmol) in 10 mL of acetonitrile was
added 48%HF solution (4 drops) and the reaction mixture was stirred for 0.25
h. The reaction mixture was quenched with saturated ammonium chloride (5
mL).
The organic layer was washed twice with sodium bicarbonate, then
water, and dried over magnesium sulfate. The solvent was removed under
vacuum to yield 0.089g (90%) of 72 as a yellow oil: IR (NaCI, neat) 3600,
2926,
2854,
1735,
1258 cm-1; 1H NMR (300 MHz, CDCI3) 6 4.65 (q,
J=7.0Hz, 2H), 3.59 (t, J=7.0Hz, 2H), 2.55 (t, J=7.0Hz, 2H), 1.63 (m, 4H),
1.45 (t, J=7.4Hz, 3H), 1.25 (bs, 14H); 13C NMR (75 MHz, CDCI3) 6 204.1,
192.1, 70.8, 63.0, 44.1, 32.5, 29.4, 29.3, 28.7, 28.5, 28.5, 25.8, 24.9,
13.4; MS m/z (rel. intensity) 199 (60), 122 (70), 121 (30). HRMS calcd. for
C12H2302 (M+ C3H50S2): 199.16979 Found: 199.16980. HRMS calcd.
for C3H50S2: 120.97819. Found: 120.97819.
12-Dodecanolide (73).
A stirred solution of 72 (0.105 g, 0.32 mmol) and 2,6-di-tert-butyl-4methylpyridine (0.067 g, 0.32 mmol) in 180 mL of octane was heated at reflux
for 19 h. The solvent was removed under vacuum and and the crude product
was
purified by flash chromatography (silica gel,
10% Et20 in hexane)
yielding 0.035 g (54%) of 73 as an oil, and 0.018 g (28%) of 74 as a white
solid: IR (NaCI, neat) 2931, 2859, 1733, 1247 cm-1; 1H NMR (300 MHz,
CDCI3) 6 4.15 (t, J=5.1Hz, 2H), 2.33 (t, J =3.2Hz, 2H), 1.65 (m, 4H), 1.35
(bs, 14H); 13C NMR (75 MHz, CDCI3) 6 174.2, 64.5, 34.6, 27.3, 26.5, 26.3,
25.3, 24.8, 24.4, 24.1.
41
Dilide 74.
IR (NaCI,
CHCI3) 2917, 2847, 1727 cm-1; 1H NMR (300 MHz,
CDCI3) S 4.10 (t, J=5.9Hz, 2H), 2.30 (t, J=7.1Hz, 2H), 1.65 (m, 4H), 1.35
(bs, 14H); 13C NMR (75 MHz, CDCI3) 8 173.1, 64.5, 34.6, 27.3, 26.5, 26.3,
25.3, 24.8, 24.4, 24.1.
12-(tert-Butyldimethylsilyloxy)octadecanoic Acid
(76).
To a stirred solution of 12-hydroxystearic acid (75, 0.100 g, 0.33 mmol)
in 20 mL of methylene dichloride was added tert-butyldimethylsilyl triflate
(0.193 g, 0.73 mmol) and lutidine (0.106 g, 0.99 mmol). The reaction mixture
was stirred at 00C for 1
h.
The solvent was removed and the residue was
treated with water (5 mL), and this aqueous mixture was extracted thrice with
ether (30 mL). The combined extracts were dried over magnesium sulfate and
the solvent was evaporated under vacuum. To a solution of the silyloxy ester
in THF: Me0H (1:1, 20 mL) was added potassium carbonate (0.080 g, 0.36
mmol), and the mixture was stirred at 25°C for
1
h.
The mixture was
concentrated to approximately 10 mL and diluted with 5 mL of brine. The
resulting aqueous mixture was cooled to 00C, adjusted to pH 4-5 with
aqueous potassium bisulfate (1 M), and extracted thrice with ether (30 mL).
The combined extracts were dried over magnesium sulfate and evaporated.
Purification by flash chromatography (silica gel,
50% EtOAc in hexane)
yielded 0.121g (88%) of 76 as an oil: IR (NaCI, neat) 3300, 2930, 1711,
1255 cm-1; 1H NMR (300 MHz, CDCI3) 8 3.58 (m, J=5.0Hz,
J=7.6Hz, 2H), 1.60 (m, 2H), 1.15-1.45 (bs, 26H), 0.85
(s,
1
H), 2.31
(t,
9H), 0.05 (s,
6H); 13C NMR (75 MHz, CDCI3) 8 179.1, 72.4, 37.1, 33.8, 31 .8, 29.8, 29.5,
29.4, 29.2, 29.0, 29.3, 24.6, 22.6, 14.1; MS m/z (rel. intensity): 358 (3.37),
340 (100), 129 (32.9), 75 (50.2); HRMS calcd. for C201-14203Si (M4- C4H9):
42
358.29030. Found: 358.29030. Anal. Calcd. for C24H5103Si: C, 69.50; H,
12.15. Found: C, 69.60; H, 12.39.
0-Ethyl S-[12-(tert-Butyldimethylsilyloxy)octadecanoyl]
Xanthate
(77).
To a stirred a solution of 76 (0.115 g, 0.27 mmol) in 30 mL of benzene
was added oxalyl chloride (0.049 mL, 0.55 mmol), and the reaction mixture
was heated at reflux for 2 h. The solvent was removed under vacuum to yield
the acid chloride. Potassium 0-ethyl xanthate (0.046 g, 0.60 mmol) in 5 mL of
acetone was added to the acid chloride in 20 mL of acetone at -35°C during
0.5 h with stirring.
After 1 h at this temperature the reaction mixture was
allowed to warm to room temperature. The solvent was removed in vacuo,
water (10 mL) was added to the residue, and the aqueous layer was extracted
with methylene dichloride (3C) mL). The extract was washed with saturated
sodium bicarbonate, water, and aqueous sodium chloride, and was dried over
magnesium sulfate. Removal of the solvent under vacuum yielded 0.365 g
(97%) of 77 as a yellow oil: IR (NaCI, neat) 2953, 2951, 2928, 2855, 1738,
1254, 1043, 835 cm-1; 1H NMR (300 MHz, CDCI3) 8 4.64 (q, J=7.0Hz, 2H),
3.57 (t, J=5.4Hz, 1H), 2.60 (t, J=7.4Hz, 2H), 1.62 (m, 4H), 1.48-1.15 (m,
31H), 0.84 (bt, 12H), 0.05 (s, 6H); 130 NMR (75 MHz, CD013) 8 204.0,
192.1, 72.3, 70.8, 44.1, 37.1, 31.8, 29.8, 29.5, 29.5, 29.4, 29.3, 29.1,
28.7, 25.9, 25.2, 24.8, 22.6, 18.1, 14.0, 13.4; MS m/z (rel.intensity): 461
(11.59), 397 (15.99), 122 (15.19), 121 (8.80), 75 (100); HRMS calcd. for
C23H4503S2Si (M+ C4H9): 461.25792. Found: 461.25790. HRMS calcd.
for C24H4902Si (M+ 03H60S2): 397.35016. Found: 397.35020.
43
0-Ethyl S-(12-Hydroxyoctadecanoyl) Xanthate (78).
To a suspension of 77 (0.150 g, 0.28 mmol) in 10 mL of acetonitrile
was added 48%HF solution (4 drops) and the reaction mixture was stirred for
0.25 h.
The reaction mixture was quenched with saturated ammonium
chloride (5 mL). The organic layer was washed twice with sodium bicarbonate
and water, and was dried over magnesium sulfate. The solvent was removed
under vacuum to yield 0.117 g (86%) of 78 as a yellow oil: IR (NaCI, neat)
3600, 2924, 2851, 1728, 1267 cm-1; 1H NMR (300 MHz, CDCI3) 6 4.64 (q,
J=7.0Hz, 2H), 3.54 (m, 1H), 2.56 (t, J=7.0Hz, 2H), 1.62 (m, 4H), 1.481.15 (m, 31H), 0.84 (bt, 3H); 13C NMR (75 MHz, CDCI3) 6 204.1, 192.2,
72.0, 70.8, 44.1, 37.4, 31.8, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1, 28.7, 25.6,
24.8, 22.6, 14.0, 13.5.
12-Octadecanolide (79).
A stirred solution of 78 (0.060 g, 0.14 mmol) and 2,6-di-tert-butyl-4methylpyridine (0.067g, 0.32 mmol) in 180 mL of octane was heated at reflux
for 48 h. The solvent was removed under vacuum and purified by flash
chromatography (silica gel, 10% Et20 in hexane) yielding 0.014 g (34%) of
79 as an oil, and 0.007 g (17%) of 80 as a white solid 79: IR (NaCI, neat)
2929, 2859, 1731 cm-1; 1H NMR (300 MHz, CDCI3) 6 4.91 (m, 1H), 2.1-2.4
(m, 2H), 1.7-1.25 (m, 33H), 0.85 (bt, J=6.2Hz, 3H); 13C NMR (75 MHz,
CDCI3) 6 179.4, 74.4, 35.0, 34.8, 33.3, 29.1, 26.7, 26.4, 26.3, 25.9, 25.3,
24.9, 24.7, 24.5, 24.4, 22.5, 14.0.
Dilide 80.
IR (NaCI,
CHCI3):
1729,
2916, 2923 cm-1; 1H NMR (300 MHz,
CDCI3) 6 4.88 (m, 1 H), 2.20-2.30 (m, 2H), 1.40-1.70 (m, 6H), 1.25 (bs,
44
27H), 0.85 (bt, J=6.2Hz, 3H); 13C NMR (75 MHz, CDCI3) 6 173.6, 73.9,
34.9, 34.4, 34.1, 31.7, 29.7, 29.5, 29.3, 29.1, 25.5, 25.3, 25.1, 22.5, 14.0.
12-( tent-Butyldimethylsilyloxy)dodecanol (81).
To a suspension of 70 (0.400 g,
1.21 mmol) in 20 mL of
tetrahydrofuran was added E3H3THF (1 M, 3.63 mL, 3.63 mmol) and the
reaction mixture was heated at reflux for 2 h.
The excess borane was
quenched with water, and the aqueous layer was extracted twice with ether
(20 mL) and dried over magnesium sulfate. The solvent was removed under
vacuum and the product was purified by flash chromatography (silica gel,
50% EtOAc in hexane) to yield 0.309 g (80%) of 81: IR (neat, NaCI): 3600,
3300, 2928, 2855, 1467, 1254, 1100 cm-1; 1H NMR (300 MHz, CDCI3) 6
3.61-3.54 (m, 4H), 1.56-1.45 (m, 4H), 1.25 (bs, 16H), 0.85 (s, 9H), 0.02 (s,
6H); 130 NMR (75 MHz, CDCI3) 6 63.3, 63.0, 32.8, 32.7, 29.5, 29.4, 25.9,
25.7, 25.7, 18.3.
12-(tert-Butyldimethylsilyloxy)dodecyl p-Toluenesulfonate (82).
To a stirred solution of 81 (0.320 g, 0.67 mmol) in 2 mL of methylene
dichloride at 0°C was added pyridine (0.110 mL,
1.35 mmol) and tosyl
chloride (0.168 g, 0.88 mmol). After 20 h the reaction mixture was diluted with
ethyl acetate and the organic layer was washed several times with ice cold
water, sodium bicarbonate and aqueous sodium chloride and was dried over
magnesium sulfate.
Purification by flash chromatography (silica gel, 15%
EtOAc in hexane) yielded 0.263 g (55%) of 82 as an oil: IR (NaCI, neat):
2928, 2855, 1466, 1344, 1253, 1182, 1088, 837 cm-1; 1H NMR (300 MHz,
CDCI3) 6 7.76 (d, J=6.6Hz, 2H), 7.31 (d, J=8Hz, 2H), 3.99 (t, J=6.4Hz, 2H),
3.58 (t, J=6.5Hz, 2H), 2.42 (s, 3H), 1.60-1.47 (m, 4H), 1.24-1.18 (bs, 16H),
0.85 (s, 9H), 0.02 (s, 6H); 130 NMR (75 MHz, CDCI3) 5 144.5,
133.1,
45
129.7,
127.8, 70.6, 63.3, 32.8, 29.5, 29.5, 29.4, 29.4, 29.3, 28.9, 28.7,
25.9, 25.7, 25.3, 21.6, 18.3.
12-( test-Butyldimethylsilyloxy)dodecanonitrile (83).
To a stirred solution of 82 (0.516 g,
1.09 mmol) in 3 mL of
dimethylsulfoxide was added sodium cyanide (0.080 g,
1.64 mmoL). The
reaction mixture was stirred for 0.5 h at 40°C and was quenched with
saturated ammonium chloride. The aqueous layer was extracted twice with
methylene dichloride (30 mL) and the organic layer was washed with water,
sodium chloride and dried over magnesium sulfate.
Purification by flash
chromatography (silica gel, 50% EtOAc in hexane) yielded 0.285 g (80%) of
83 as an oil: IR (NaCI, neat): 2856, 2247, 1462, 1304, 1145, 1070, 1055,
664, 615, 600 cm-1; 1H NMR (300 MHz, CDCI3) 8 3.58
2.29 (t, J=7.1Hz, 2H), 1.60-1.41
(t,
J=6.7Hz, 2H),
(m, 4H), 1.25 (m, 4H), 0.85 (bs, 16H);
13C NMR (75 MHz, CDCI3) 8 119.8, 63.2, 32.8, 29.5, 29.4, 29.3, 29.2,
28.7, 28.6, 25.9, 25.7, 25.3, 18.3, 17.0.
13-Hydroxytridecanoic Acid (84).
To a stirred solution of 83 (0.380 g, 1.16 mmol) in 20 mL of ethylene
glycol was added 6 mL of 0.3 N potassium hydroxide and the mixture was
heated at reflux for 5 days. The reaction mixture was treated with 0.1 M
H2SO4 until pH 2 was reached, and extracted thrice with ether (45 mL), and
dried over magnesium sulfate.
Removal of solvent under vacuum and
purification by flash chromatography (silica gel,
75% EtOAc in hexane)
yielded 0.248 g (92%) of 84 as a white solid: IR (KBr) 3600-3300 (broad),
2916, 2849, 1698 cm-1; 1H NMR (300 MHz, CDCI3) 6 3.74 (t, J=7.0Hz, 2H),
2.27 (t, J=6.9Hz, 2H), 1.60 (m, 4H), 1.25-1.35 (bs, 18H); 130 NMR (75
46
MHz, CDCI3) 8 178.8, 63.0, 33.8, 32.7, 29.4, 29.4, 29.3, 29.1, 28.9, 25.6,
24.6.
13-(tert-Butyldimethylsilyloxy)tridecanoic Acid (85).
To a stirred solution of 84 (0.248 g, 1.07 mmol) in 20 mL of methylene
dichloride was added tert-butyldimethylsily1 triflate (0.193 g, 0.73 mmol) and
lutidine (0.346 g, 3.23 mmol). The reaction mixture was stirred at 0°C for 1
h.
The solvent was removed, the residue was treated with water (5 mL), and this
aqueous mixture was extracted thrice with ether (30 mL).
The combined
extracts were dried over magnesium sulfate and the solvent was evaporated
under vacuum. To a solution of the silyloxy ester in THF:MeOH (1 :1, 20 mL)
was added potassium carbonate (0.163 g, 1.17 mmol) and the mixture was
stirred at 25°C for 1 h. The mixture was concentrated to approximately 10 mL
and diluted with 5 mL of brine. The resulting aqueous solution was cooled to
0°C adjusted to pH 4-5 with aqueous potassium bisulfate (1 M), and extracted
thrice with ether (30 mL). The combined extracts were dried over magnesium
sulfate and evaporated. Purification by flash chromatography (silica gel, 50%
EtOAc in hexane) yielded 0.286 g (77%) of 85 as an oil: IR (NaCI, neat) 3400,
3000, 2928, 1711, 1466, 1253, 1099, 836 cm-1 ; 1H NMR (300 MHz,
CDCI3) 8 3.58 (m, J=6.0Hz, 1 H), 2.33 (t, J=7.4Hz, 2H), 1.49 -1.69 (m, 4H),
1.20-1.40 (bs, 18H), 0.85 (s, 9H), 0.02 (s, 6H); 13C NMR (75 MHz, CDCI3)
6 180.2, 63.3, 34.1, 32.8, 29.5, 29.4, 29.2, 29.0, 25.9, 25.7, 24.6, 18.3;
MS m/z (rel. intensity): 287 (20.20), 269 (99.25), 213 (0.55), 75 (100); HRMS
calcd. for Ci5H3103Si (M+ C4H9): 287.20424. Found: 287.20860. HRMS
calcd. for C13H2502 (M+ C6H15SiO): 213.18545. Found: 213.18420.
47
0-Ethyl S-[13-(tert-Butyldimethylsilyloxy)tridecanoyl]
Xanthate
(86).
To a stirred a solution of 85 (0.102 g, 0.30 mmol) in 30 mL of benzene
was added oxalyl chloride (0..058 mL, 0.66 mmol) and the reaction mixture
was heated at reflux for 2 h. The solvent was removed under vacuum to yield
the acid chloride. Potassium 0-ethyl xanthate (0.046 g, 0.30 mmol) in 5 mL of
acetone was added to the acid chloride in 20 mL of acetone at -35°C during
0.5 h with stirring.
After 1 h at this temperature the reaction mixture was
allowed to warm to room temperature. The solvent was removed in vacuo,
water (10 mL) was added to the residue, and the aqueous layer was extracted
with methylene dichloride (30 mL). The extract was washed successively with
saturated sodium bicarbonate, water and aqueous sodium chloride, and was
dried over magnesium sulfate. Removal of the solvent under vacuum yielded
0.113 g (83%) of 86 as a yellow oil: IR (NaCI, neat) 2928, 2855, 1738,
1254, 1254, 1100, 1042, 836 cm-1; 1H NMR (300 MHz, CDCI3) 8
1465,
4.64 (q, J=7.0Hz, 2H), 3.57 (t, J=7.0Hz, 2H), 2.57 (t, J=7.0Hz, 2H), 1.62
(m, 4H), 1.50 (t, J=7.0Hz, 3H), 1.30 (bs, 18H), 0.90 (s, 9H), 0.05 (s, 6H);
13C NMR (75 MHz, CDCI3) 8 204.0, 192.1, 70.8, 63.2, 44.1, 32.8, 29.5,
29.5, 29.5, 29.3, 29.1, 28.7, 25.9, 25.7, 24.8, 18.3, 13.4;
MS m/z (rel.
intensity): 391(1.24), 327 (5.02), 122 (34.44), 121(12.79), 69 (100); HRMS
calcd. for C19H3902Si (M+
C3H5OS):
327.27192.
Found:
327.27190
HRMS calcd. for C181-13503S2Si (M+ C4H9): 391.17968. Found: 391.17970.
0-Ethyl S-(13-Hydroxytridecanoyl) Xanthate (87).
To a suspension of 86 (0.079 g, 0.23 mmol) in 10 mL of acetonitrile
was added 48°/01-IF solution (4 drops) and the reaction mixture was stirred for
0.25 h.
The reaction mixture was quenched with saturated ammonium
48
chloride (5 mL).
The organic layer was washed twice with sodium
bicarbonate, then water, and dried over magnesium sulfate. The solvent was
removed under vacuum to yield 0.060 g (90%) of 87 as a yellow oil: IR (NaCI,
neat) 3410, 2925, 2853, 1736, 1463, 1258, 1040 cm-1; 1H NMR (300 MHz,
CDCI3) 8 4.64 (q, J=7.0Hz, 2H), 3.57
(t,
J=7.0Hz, 2H), 2.57
(t, J=7.0Hz,
2H), 1.62 (m, 4H), 1.50 (t, J=7.0Hz, 3H), 1.25 (bs, 18H); 13C NMR (75
MHz, CDCI3) 6 204, 192.2, 70.8, 63.0, 44.1, 32.7, 29.4, 29.3, 29.2, 29.1,
28.7, 25.6, 24.8, 13.4; MS m/z (rel. intensity): 213 (21.52), 200 (0.80), 122
(2.55), 121(10.47), 69 (100). HRMS calcd. for C13H2502 (M+ C3H50S2):
213.18545. Found: 213.18550.
13-Tridecanolide (88).
A stirred solution of 87 (0.060 g, 0.17 mmol) and 2,6-di-tert-butyl-4methylpyridine (0.036 g, 0.17 mmol) in 180 mL of octane was heated at reflux
for 48h. The solvent was removed under vacuum and purified by flash
chromatography (silica gel,
10% Et20 in hexane) yielding 0.024 g (63%) of
88 as an oil, and 0.021 g (21 %) of 89 as a white solid 88: IR (NaCI, neat)
2931, 2859, 1734, 1459, 1242 cm-1; 1H NMR (300 MHz, CDCI3) 8 4.14
J=7.0Hz, 2H), 2.36
(t,
(t,
J=4.0Hz, 2H), 1.60-1.70 (m, 4H), 1.20-1.45 (m,
16H); 13C NMR (75 MHz, CDCI3) 8 173.9, 63.2, 34.3, 30.1, 27.5, 26.1,
25.9, 25.7, 25.5, 24.5, 23.9, 23.6, 22.6.
Dilide 89.
IR (NaCI, CHCI3): 2917, 2857, 1728, 1463, 1257cm-1; 1H NMR (300
MHz, CDCI3) 8 4.10 (t, J=6.9Hz, 1H), 2.30 (t, J=7.0Hz, 2H), 1.55 -1.65 (m,
4H), 1.25 (bs, 16H); 130 NMR (75 MHz, CDCI3) 6 174.0, 64.2, 34.5, 29.4,
29.3, 29.3, 29.1, 28.8, 28.5, :26.0, 25.1.
49
15-Hydroxypentadecanoic Acid (91).
To a stirred solution of potassium tert-butoxide (3.40 g, 33.2 mmol) in
50 mL of dry ether cooled to 0°C, was added H2O (0.14 mL, 8.31 mmol) via a
syringe.
The slurry was stirred for 5 min and to this was added the
cyclopentadecanolide (90, 1.000 g, 4.10 mmol) was added. The ice-bath
was removed, and the reaction mixture was stirred at room temperature for 3 h.
and then quenched by adding ice water until two clear layers formed. The
aqueous layer was separated and acidified with concentrated hydrochloric
acid. The acidified solution vvas extracted three times with 50 mL portions of
ether. The ether extracts were combined, dried over magnesium sulfate, and
filtered, and the solvent was evaporated under vacuum to yield 1.074 g
(100%) of pure 91 as a white solid: IR (KBr): 3544, 3300, 2918, 1654,
1097, 819 cm-1; 1H NMR (CD3OD, 300 MHz) S 3.25 (t, J=7.0Hz, 2H), 2.00
(t,
J=6.5Hz, 2H), 1.20-1.40 (m, 4H), 1.05 (bs, 20H); 130 NMR (75 MHz,
CD3OD) 8 177.9, 62.9, 34.9, 33.5, 30.6, 30.4, 30.2, 30.1, 26.8, 25.9.
15-(tert-Butyldimethylsilyloxy)pentadecanoic Acid (92).
To a stirred solution of 91 (0.500 g, 1.90 mmol) in 20 mL of methylene
dichloride was added tert-butyldimethylsilyl triflate (1.023 g, 3.80 mmol) and
lutidine (0.622 g, 5.80 mmol). The reaction mixture was stirred at 00C for 1
h.
The solvent was removed, the residue was treated with water (5 mL) and the
aqueous mixture was extracted thrice with ether (40 mL).
The combined
extracts were dried over magnesium sulfate and the solvent was evaporated
under vacuum. The residual oil (silyloxy ester) was taken up in THF: Me0H
(1:1, 20 mL) and potassium carbonate (0.273 g, 1.98 mmol) was added. The
mixture was stirred at 25°C for 1 h, concentrated to approximately 10 mL, and
diluted with 5 mL of brine. The resulting aqueous mixture was cooled to 0 °C,
50
adjusted to pH 4-5 with aqueous potassium bisulfate (1 M), and extracted
thrice with ether (40 mL). The combined extracts were dried over magnesium
sulfate and evaporated. Purification by flash chromatography (silica gel, 50%
EtOAc in hexane) yielded 0.565 g (80%) of 92 as an oil: IR (KBr): 3200,
2926, 1711, 1101, 836 cm-1; 1H NMR (300 MHz, CDCI3) 6 3.59 (t, J=6.6Hz,
2H), 2.33 (t, J=7.5Hz, 2H), 1.45-1.65 (m, 4H), 1.35 (bs, 20H), 0.85 (s,
9H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCI3) 6 180.1, 63.3, 34.1, 32.8,
29.6, 29.4, 29.2, 29.0, 25.9, 25.7, 24.6, 18.3; MS m/z (rel. intensity): 315
(24),
297 (100),
315.23554.
75 (100). HRMS calcd. for C17H3303Si (M+
Found:
315.23550. HRMS calcd.
for
C4H9):
C17H3102Si (M+
C4H1 10): 297.2250. Found: 297.2250. Anal. Calcd. for C17H3503S1: C,
67.68; H, 11.90. Found: C, 67.69; H, 12.10.
0-Ethyl S -[15 -( tert - Butyldimethylsilyloxy )pentadecanoyl] Xanthate
(93).
To a stirred solution of 92 (0.112 g, 0.30 mmol) in 30 mL of benzene
was added oxalyl chloride (0.058 mL, 0.66 mmol) and the reaction mixture
was heated at reflux for 2 h. The solvent was removed under vacuum to yield
the acid chloride. Potassium 0-ethyl xanthate (0.048 g, 0.30 mmol) in 5 mL of
acetone was added to the acid chloride in 20 mL of acetone at -35°C over 0.5
h with stirring. After 1 h at this temperature the reaction mixture was allowed to
warm to room temperature. The solvent was removed in vacuo, water (10 mL)
was added to the residue, and the aqueous layer was extracted with
methylene dichloride (30 mL).
The extract was washed successively with
saturated sodium bicarbonate, water and aqueous sodium chloride and was
dried over magnesium sulfate. Removal of the solvent under vacuum yielded
0.118 g (83%) of 93 as a yellow oil: IR (NaCI, neat) 2926, 2855, 1738,
51
1465, 1255, 1102, 1041, 837 cm-1
;
111 NMR (300 MHz, CDCI3) 8 4.64 (q,
J=7.0Hz, 2H), 3.59 (t, J=7.0Hz, 2H), 2.58 (t, J=7.4Hz, 2H), 1.65 (m, 2H),
1.50 (m, 5H), 1.30 (bs, 20H), 0.90 (s, 9H), 0.05 (s, 6H); 130 NMR (75
MHz, CDCI3) 8 204.1, 192.1, 70.7, 63.2, 44.1, 32.8, 30.0, 29.5, 29.4, 29.3,
29.1, 28.7, 25.9, 25.7, 24.8, 18.3, 13.4; MS m/z (rel. intensity): 355 (10.70),
122 (100),
121 (11.82). HRMS calcd. for 021 H 4302Si (M+
C3H 50 S2)
355.30322. Found: 355.30320.
0-Ethyl S-(15-Hydroxypentadecanoyl) Xanthate (94).
To a suspension of 93 (0.118 g, 0.24 mmol) in 10 mL of acetonitrile
was added 48%HF solution (6 drops) and the reaction mixture was stirred for
0.25 h.
The reaction mixture was quenched with saturated ammonium
chloride (5mL). The organic layer was washed twice with sodium bicarbonate,
then water, and dried over magnesium sulfate. The solvent was removed
under vacuum to yield 0.080 g (90%) of 94 as a yellow oil: IR (NaCI, neat)
3357, 2925, 1736, 1463, 1366, 1258, 1110, 1040, 954 cm-1; 1H NMR
(300MHz, CDCI3) 8 4.65 (q, J=7.0Hz, 2H), 3.62 (t, J=7.0Hz, 2H), 2.59
J=7.4Hz, 2H), 1.50-1.70 (m, 4H), 1.46
(t,
(t,
J=7.1Hz, 3H), 1.23 (bs, 20H);
130 NMR (75 MHz, CDCI3) 8 204, 192.2, 70.8, 62.9, 44.1, 32.7, 29.5, 29.3,
29.2, 29.1, 28.7, 25.6, 24.8, 13.4; MS m/z (rel. intensity): 241 (2.96), 239
(5.79), 122 (50.93), 121 (4.79), 71 (100). HRMS calcd. for 015H2902 (M+
C3H50S2): 241.21640. Found: 241.21640.
15-Pentadecanolide (90).
A stirred solution of 94 (0.080 g, 0.22 mmol) and 2,6-di-tert-butyl-4methylpyridine (0.045 g, 0.22 mmol) in 180 mL of octane was heated at reflux
for 19 h. The solvent was removed under vacuum and purified by flash
chromatography (silica gel,
10% Et20 in hexane) yielding 0.040 g (75%) of
52
90 as an oil and 0.010 g (18%) of 95 as a white solid 90: IR (NaCI, neat):
2928, 1736, cm-1; 1H NMR (300 MHz, CDCI3) 8 4.12 (t, J=5.6Hz, 2H), 2.32
(t,
J=7.0Hz, 2H), 1.60-1.70 (m, 4H), 1.20-1.45 (m, 20H); 13C NMR (75
MHz, CDCI3) 6 174.0, 63.9, 34.3, 28.3, 27.7, 27.0, 26.8, 26.6, 26.2, 25.9,
25.8, 25.7, 25.0, 24.9.
Dilide 95.
IR (NaCI, CHCI3): 2917, 2857, 1730, 1463, 1257 cm-1; 1H NMR (300
MHz, CDCI3) 8 4.10 (t, J=6.9Hz, 1H), 2.29 (t, J=7.0Hz, 2H), 1.60-1.70 (m,
4H), 1.25 (bs, 20H); 13C NMR (75 MHz, CDCI3) 8 174.0, 64.2, 34.5, 29.4,
29.3, 29.3, 29.1, 28.9, 28.6, 28.8, 28.5, 26.0, 25.1, 24.5.
16-(tert-Butyldimethylsilyloxy)hexadecanoic Acid (97).
To a stirred solution of 16-hydroxyhexadecanoic acid 96 (0.300 g, 1.01
mmol) in 20 mL of dimethylformamide was added tert-butyldimethylsilyl
chloride (0.365 g,
2.42 mmol) and imidazole (0.224 g, 3.30 mmol). The
reaction mixture was stirred at 45°C for 24 h. To this solution was added water
(10 mL), and the aqueous mixture was extracted thrice with ether (30 mL). The
combined extracts were dried over magnesium sulfate and the solvent was
evaporated under vacuum.
THF:MeOH (1:1,
To a solution of the residual silyloxy ester in
20 mL) was added potassium carbonate (0.360 g, 2.60
mmol) and the mixture was stirred at 25°C for
1
h, concentrated to
approximately 10 mL, and diluted with 5 mL of brine. The resulting aqueous
mixture was cooled to 0°C, adjusted to pH 4-5 with aqueous potassium
bisulfate (1 M), and extracted thrice with ether (30 mL). The combined extracts
were dried over magnesium sulfate and evaporated.
Purification by flash
chromatography (silica gel, 50% EtOAc in hexanes) yielded 0.316 g (94%) of
97: IR (NaCI, neat) 3300, 2923, 1707 cm-1, 1H NMR (300 MHz, CDCI3) 6
53
3.56 (t, J=6.0Hz, 2H), 2.30 (t, J=7.4Hz, 2H), 1.50-1.60 (m, 4H), 1.22 (m,
24H), 0.85 (s, 9H), 0.02 (s, 6H); 13C NMR (75 MHz, CDCI3) 6 179.9, 63.3,
34.0, 32.8, 29.6, 29.4, 29.2, 29.0, 25.9, 25.7, 24.6, 18.3; MS m/z (rel
.intensity): 329 (12.03), 311 (65.58), 25.5 (0.41), 75 (100); HRMS calcd. for
C18H3703S1
C4H9): 329.25090. Found: 329.25090. Anal. Calcd. for
C22H46O3Si: C, 68.33; H, 11.99. Found: C, 68.53; H, 11.88.
0-Ethyl S-[16-(tert-Butyldimethylsilyloxy)hexadecanoyl] Xanthate
(98).
To a stirred a solution of 97 (0.200 g, 0.51 mmol) in 30 mL of benzene
was added oxalyl chloride (0.091 mL, 1.03 mmol) and the reaction mixture
was heated at reflux for 2 h. The solvent was removed under vacuum to yield
the acid chloride. Potassium 0-ethyl xanthate (0.083 g, 0.51 mmol) in 5 mL of
acetone was added to the acid chloride in 20 mL of acetone at -35°C during
0.5 h with stirring.
After 1 h at this temperature the reaction mixture was
allowed to warm to room temperature. The solvent was removed in vacuo,
water (10 mL) was added to the residue, and the aqueous layer was extracted
with methylene dichloride (30 mL). The extract was washed with saturated
sodium bicarbonate, water and aqueous sodium chloride and was dried over
magnesium sulfate.
Removal of the solvent under vacuum yielded 0.200 g
(80%) of 98 as a yellow oil: IR (NaCI, CDCI3) 2923, 2853, 1736, 1465,
1255, cm-1; 1H NMR (300 MHz, CDCI3) 8 4.65 (q, J=7.0Hz, 2H), 3.59
(t,
J=6.5Hz, 2H), 2.56 (t, J=7.41-1z, 2H), 1.65 (m, 2H), 1.45 (m, 5H), 1.30 (bs,
24H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCI3) 6 204.0, 192.1,
70.8, 63.2, 47.0, 44.1, 32.8, 29.6, 29.3, 29.1, 29.0, 28.7, 28.3, 25.9, 25.7,
25.0, 24.8, 18.3, 13.4; MS m/z (rel. intensity): 399 (8.57), 369 (23.71), 357
54
(100), 121 (20.56), 75 (69.11); HRMS calcd. for C22H45O2Si (M+ C4H9):
369.31887. Found: 369.31 890.
0-Ethyl S-(16-Hydroxyhexadecanoyl) Xanthate (99).
To a suspension of 98 (0.100 g, 0.20 mmol) in 10 mL of acetonitrile
was added 48 %HF solution (4 drops) and the reaction mixture was stirred for
0.25 h. The mixture was quenched with saturated ammonium chloride (5 mL).
The organic layer was washed twice with sodium bicarbonate and water, and
dried over magnesium sulfate. The solvent was removed under vacuum to
yield 0.055 g (76%) of 99 as a yellow solid: IR (NaCI, neat) 3600, 2921,
1733,
1463,
1256,
1038 cm-1; 1H NMR (300 MHz, 00013) 6 4.65
(q,
J=7.0Hz, 2H), 3.62 (t, J=6.7Hz, 2H), 2.58 (t, J=7.4Hz, 2H), 1.55-1.70 (m,
4H), 1.46 (t, 3H), 1.25 (bs, 31H); 130 NMR (75 MHz, CDC13) 6 204.1,
192.2, 70.8, 63.0, 44.1, 32.7, 29.5, 29.4, 29.3, 29.3, 29.1, 28.7, 25.6,
24.8, 13.4;
MS m/z (rel.intensity): 255 (6.08), 122 (5.27), 121 (4.19), 98
(100); HRMS calcd. for C15H2902
C3H50S2): 255.23239. Found:
255.23230.
16-Hexadecanolide (100).
A stirred solution of 99 (0.060 g, 0.17 mmol) and 2,6-di-tert-buty1-4methylpyridine (0.035 g, 0.17 mmol) in 180 mL of octane was heated at reflux
for 19 h. The solvent was removed under vacuum and the residue was purified
by flash chromatography (silica gel,
10% Et20 in hexane) yielding 0.032 g
(80%) of 100 as an oil. No trace of the dilide was observed in this reaction: IR
(NaCI,
neat)
1736, cm-1; 1H NMR (300 MHz,
2928,
J=5.6Hz, 2H), 2.29
(t,
00013) 6 4.09 (t,
J=7.0Hz, 2H), 1.59 (m, 4H), 1.29-1.40 (bs, 24H);
130 NMR (75 MHz, 00013) 6 174.1, 64.3, 34.7, 28.7, 28.1, 27.9, 27.8, 27.7,
27.6, 27.0, 26.8, 26.7, 25.6, 25.0.
55
IV.
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