A flexible and modular stereoselective synthesis of (9R,10S)- dihydrosterculic acid

Article abstract of DOI:10.1016/j.tetasy.2013.01.003

(9R,10S)-Dihydrosterculic acid has been prepared from (S_S,S _S)-1,1-bis(p-tolylsulfinyl)methane in a sequence involving an asymmetric Corey-Chaykovsky cyclopropanation and two sulfoxide/lithium exchange reactions. In most steps, the reaction conditions had to be optimized for the unbranched alkyl substituents, which were prone to Evans-Mislow rearrangements and subsequent degradation.

Full text of DOI:10.1016/j.tetasy.2013.01.003

Tetrahedron: Asymmetry 24 (2013) 165–168
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A flexible and modular stereoselective synthesis
of (9R,10S)-dihydrosterculic acid
⇑
John W. Palko, Peter H. Buist, Jeffrey M. Manthorpe
Carleton University, Department of Chemistry, 1125 Colonel By Drive, 203 Steacie Building, Ottawa, Canada ON K1S 5B6
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 October 2012
Accepted 4 January 2013
(9R,10S)-Dihydrosterculic acid has been prepared from (SS,SS)-1,1-bis(p-tolylsulfinyl)methane in
a
sequence involving an asymmetric Corey–Chaykovsky cyclopropanation and two sulfoxide/lithium
exchange reactions. In most steps, the reaction conditions had to be optimized for the unbranched alkyl
substituents, which were prone to Evans–Mislow rearrangements and subsequent degradation.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
approach to the synthesis of 1 that allows us to prepare enantio-
pure material suitable for mechanistic studies and for the synthesis
Cyclopropane fatty acids, such as dihydrosterculic acid 1 are a
structurally unique class of fatty acids found in a variety of natural
sources.1 The presence of the cyclopropyl ring confers oxidative
stability to lipidic ensembles relative to their olefinic counterparts
while maintaining favorable biophysical characteristics.2 Interest-
ingly, in some plant species, cis-cyclopropyl fatty acids are con-
of structural analogues of 1.
2. Results and discussion
Our plan (Scheme 1) for the synthesis of 1 features the regio-
specific alkylation/protonation of the chiral cyclopropane interme-
diate 3. The latter is potentially available via diastereoselective
methylenation of 4,8 a condensation product derived from the
readily available (SS,SS)-1,1-bis(p-tolylsulfinyl)methane 59 and
dec-9-enal 6.
verted to the corresponding cyclopropenyl compounds by
a
unique syn-dehydrogenation (desaturation) reaction. Cyclopro-
pene fatty acids are potent inhibitors of mammalian stearoyl CoA
D
9 desaturase (SCD)—a therapeutic target for the treatment of dis-
orders related to metabolic syndrome.3 The proposed mechanism
for the cis-cyclopropane to cyclopropene bioconversion involves
stepwise hydrogen removal in a manner similar to that established
for the desaturase-mediated dehydrogenation of cis-olefinic fatty
acids to give acetylenic products.4 It is currently not known with
regard to which enantiomer of 1 is oxidized to the cyclopropenyl
product, sterculic acid. The situation is complicated by the fact that
1 can occur in either enantiomeric form depending on its natural
source.5
After preparing bis(sulfoxide) 5 according to the literature,10 we
turned our attention to the addition/elimination sequence
(Scheme 2). Traditional Knoevenagel conditions perform poorly
with 5;11 and as a result a two-step addition/elimination sequence
has been reported.8,9 However, we found that even under these
mild conditions, aldehydes lacking
a-branching are prone to deg-
radation via a putative alkene migration/Evans–Mislow rearrange-
ment/O–S bond cleavage sequence (Scheme 3). After extensive
experimentation, the best yields of the coupled product were
obtained by reacting the lithium anion of 5 with excess aldehyde
at ꢁ78 °C for 30 min. This afforded two diastereomers of 712 (com-
bined yield of 64%) but minimized the formation of alkene 4 and
concomitant degradation.
The literature procedure for the dehydration of alcohols such as
7 involves the reaction with 2–3 equiv of a water-soluble carbodi-
imide and catalytic amounts of CuCl2 in MeCN at 70 °C for 3–5 h.
However, we found that this reaction was better conducted with
just 1.2 equiv of carbodiimide at room temperature for 8 h. More-
over, the desired product 4 proved unstable to silica gel chroma-
tography. However, we found that after diluting the reaction
mixture with CH2Cl2, filtering through Celite and a short pad of sil-
ica gel, the few remaining impurities did not significantly impact
the subsequent reactions.13
In order to resolve these stereochemical issues, a convenient
approach to the stereoselective synthesis of enantiomeric cyclo-
propyl fatty acids is required as an essential first step. Previous
synthetic efforts in this area include Baird’s synthesis of lactobacil-
lic acid,6 an 11,12-regioisomer of 1, which, with an overall yield of
ꢀ3%, gave us concerns over material throughput. Corey’s approach
to (9R,10S)-dihydrosterculic acid 1 obtained the desired product in
87% ee but did not offer the opportunity to remove the unwanted
enantiomer without recourse to preparative chiral chromatogra-
phy, since all of the intermediates were liquids or non-crystalline
solids.7 Herein we report an efficient and diastereoselective
⇑
Corresponding author. Tel.: +1 613 520 2600x1711; fax: +1 613 520 3749.
E-mail address: jeffrey_manthorpe@carleton.ca (J.M. Manthorpe).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.01.003

166
J. W. Palko et al. / Tetrahedron: Asymmetry 24 (2013) 165–168
O
cleaved preferentially. We can corroborate this result, as we were
H
H
successful in performing the sulfoxide–lithium exchange on 3
and subsequent alkylation with 1-iodooctane proceeded to afford
916,17 in 60% yield (Scheme 4).
18
OH
1
(10S) (9R)
1
The second sulfoxide cleavage required the use of the more
reactive t-BuLi; nevertheless the exchange and protonation with
MeOH proceeded cleanly to give 2 in high yield. It is worth noting
that the use of 3 equiv of t-BuLi afforded higher yields than the re-
ported protocol using 2 equiv.8
H
H
2
Completion of our synthesis required an oxidation state adjust-
ment via oxidative cleavage of the terminal alkene of 2. However,
this proved to be more challenging than anticipated. Typically this
is carried out using KMnO418 but in our hands, some overoxidation
leading to a chain shortened product was observed. We also ex-
plored a dihydroxylation/Lemieux–Johnson cleavage strategy but
the intermediate diol proved to have very poor solubility under
the reaction conditions. An alternative procedure to directly give
the carboxylic acid via the alkene- K2OsO4/oxone in DMF/t-BuOH19
proceeded in poor yield. We ultimately found success with the
Marshall ozonolysis protocol.20 Since 2 was only moderately solu-
ble under the reaction conditions, concentration proved to be crit-
ical and we obtained the desired methyl ester 10 in an optimized
92% yield.
O
S
O
S
p-tol
p-tol
p-tol
3
O
S
O
S
p-tol
Hydrolysis of this lipophilic material to the corresponding acid
using traditional methods can lead to poor yields;6,21,22 accord-
ingly, we opted to use Gassman’s hydrolysis conditions,23 typically
used to cleave tertiary amides, and obtained (9S,10R)-dihydrost-
erculic acid 1 in 89% yield.24
4
O
S
O
S
O
In order to confirm the stereochemistry of the product, we
H
p-tol
p-tol
turned to Tocanne’s CrO3 oxidation protocol,25 whereby the car-
5
6
bons
a to the cyclopropane of methyl ester 10 are converted into
the corresponding ketone (Scheme 5). The regioisomeric ketones
11 and 12 are readily separable by chromatography and afford
much higher optical rotations than the parent quasisymmetrical
unoxidized cyclopropane fatty acid 1 or its ester 10.2 We found
that the rotations of methyl (Z)-8-(2-octanoylcyclopropyl)octano-
ate26 and methyl (Z)-8-(2-octylcyclopropyl)-8-oxooctanoate27 cor-
responded to the naturally occurring 9R,10S stereochemistry of
dihydrosterculic acid.28
Scheme 1. Retrosynthesis of (9R,10S)-dihydrosterculic acid.
Corey–Chaykovsky cyclopropanation14 of alkylidene bis(sulfox-
ide) 4 provided 3 in a good diastereomeric ratio (86:14 dr). The
major diastereomer could then be cleanly separated from the min-
or diastereomer via column chromatography, thus affording us
stereochemically pure material (no minor diastereomer was
observed by 1H NMR), in a two-step isolated yield of 54% for the
major diastereomer 3.15
3. Conclusion
At this stage we had to remove the two sulfoxide groups of the
cyclopropane intermediate 3 and install the second alkyl chain.
Marek et al.8 were able to achieve this via lithium-sulfoxide ex-
change; it should be noted that the more hindered sulfoxide is
In conclusion, we have developed and optimized a convenient,
rapid, and modular synthesis of naturally occurring (9R,10S)-
dihydrosterculic acid 1, which proceeds in 14% yield over 7 steps
O
S
O
S
O
S
O
S
O
S
O
S
O
S
O
S
a
+
p-tol
+
p-tol
p-tol
p-tol
p-tol
p-tol
p-tol
p-tol
R
OH
R
OH
R
5
4
7
7
(S,S,S)-
(R,S,S)-
b
O
S
O
S
O
S
O
S
c
p-tol
p-tol
p-tol
p-tol
R = (CH2)7CH=CH2
R
3
4
Scheme 2. Formation of cyclopropane 3. Reagents and conditions: (a) n-BuLi (1.0 equiv), THF (0.24 M), ꢁ78 °C; dec-9-enal (4.5 equiv), 30 min, 64%; (b) N-cyclohexyl-N0-(2-
morpholinoethyl)carbodiimide metho-p-toluenesulfonate (1.47 equiv), CuCl2 (0.1 equiv), MeCN (0.055 M), rt, 12 h; (c) Me3S(O)I (5.14 equiv), NaH (5.14 equiv), DMSO (0.1 M),
rt, 12 h, 86:14 dr, 54% over 2 steps for 3.

J. W. Palko et al. / Tetrahedron: Asymmetry 24 (2013) 165–168
167
O
S
O
S
O
S
O
S
O
S
O
S
O
S
O
S
-
–OH
H
RCH2CHO
p-tol
p-tol
p-tol
p-tol
p-tol
p-tol
p-tol
p-tol
O
OH
8
R
R
R
–OH
O
S
O
O
S
O
O
S
O
S
O
S
[2,3]
S
S
rearrangement
H+
p-tol
p-tol
p-tol
p-tol
p-tol
p-tol
p-tol
p-tol
O
S
R
R
R
R
8
O
O
S
O
S
S
p-tol
+
p-tol
p-tol
HO
S
p-tol
R
Scheme 3. Proposed degradative side-reaction in the addition of 5/8 to unbranched aldehydes.
O
S
O
S
O
S
a
p-tol
p-tol
p-tol
3
9
b
H
H
H
H
c
RO2C
10
1
2
R = Me
R = H
d
Scheme 4. Completion of the synthesis of 1. Reagents and conditions: (a) n-BuLi (3.0 equiv), THF, ꢁ78 to ꢁ40 °C, 1 h; n-C8H17I (10 equiv), 0 °C, 3 h, 60%; (b) t-BuLi (3 equiv),
PhMe (0.5 M), ꢁ78 °C, 10 min; MeOH (66 equiv), ꢁ78 to 0 °C, 1 h, 81%; (c) O3, NaOH (30 equiv), 10:3 CH2Cl2/MeOH (0.02 M), ꢁ78 °C, 92%; (d) t-BuOK (15 equiv), H2O
(20 equiv), THF (0.07 M), rt, 18 h, 89%.
H
MeO2C
H
10
CrO3
AcOH/H2O/CCl4
rt, 3 d
O
H
H
H
H
+
MeO2C
MeO2C
11
12
O
13%
12%
22
[α]D
=
13.9 (c 0.467, Et2O)
= 14.8 (c 0.9, Et2O)}
[α]D22 = +19.6 (c 0.533, Et2O)
{lit.:17 [α]D21 = +20.7 (c 1, Et2O)}
{lit.:17 [α]D
21
Scheme 5. Proof of cyclopropane stereochemistry.

168
J. W. Palko et al. / Tetrahedron: Asymmetry 24 (2013) 165–168
Kwasnieski, O.; Najera, F.; Delouvrie, B.; Marek, I.; Derat, E.; Goddard, J.-P.;
Malacria, M.; Fensterbank, L. Chem. Asian J. 2011, 6, 1825.
10. (a) Reggelin, M.; Weinberger, H.; Spohr, V. Adv. Synth. Catal. 2004, 346, 1295;
(b) Klunder, J. M.; Sharpless, K. B. J. Org. Chem. 1987, 52, 2598.
11. Guerrero-de la Rosa, V.; Ordoñez, M.; Alcudia, F.; Llera, J. M. Tetrahedron Lett.
1985, 36, 4889.
from (SS,SS)-1,1-bis(p-tolylsulfinyl)methane. This route is also ame-
nable to the preparation of any mid-chain cyclopropyl fatty acid in
enantiopure form and is particularly well-suited to the introduc-
tion of isotopic labels at any desired position either as mass labels
or as mechanistic probes. In addition, the door has been opened to
the construction of artificial lipid membrane assemblies bearing
mid-chain chirality.
We are currently preparing analogues of 1 to aid in the elucida-
tion of the mechanism of enzymatic cyclopropane desaturation
and structure–toxicity relationships and our results will be re-
ported in due course.
12. Experimental data for 7: Rf 0.25 (20% EtOAc in hexane, UV, KMnO4).
½
a 2D5
ꢂ
¼ þ136:7 (c 0.48, CHCl3). 1H NMR (CDCl3, 400 MHz): d 7.64 (d, J = 8 Hz,
2H), 7.42 (d, J = 8 Hz, 2H), 7.24 (d, J = 8 Hz, 2H), 7.05 (d, J = 8 Hz), 5.80 (ddt,
J = 17.4, 10.4, 6.6 Hz, 1H), 5.00 (ddd, J = 17.2, 3.86, 1.6 Hz, 1H), 4.94 (ddd,
J = 10.0, 2.0, 1.2 Hz, 1H), 4.51 (m, 1H), 3.94 (d, J = 2.0 Hz, 1H), 3.35 (d, J = 0.8 Hz,
1H), 2.49 (s, 3H), 2.38 (s, 3H), 2.02 (q, J = 7.6 Hz), 1.86 (m, 1H), 1.70 (s, 1H),
1.41–1.09 (m, 10H). 13C NMR (CDCl3, 100 MHz): d 142.2, 141.7, 139.9, 139.0,
138.5, 130.3, 130.3, 129.5, 124.6, 123.8, 114.2, 91.9, 67.0, 34.9, 33.7, 29.2, 28.9,
28.9, 28.8, 25.2, 21.5, 21.3. IR (NaCl plate, cmꢁ1): 3376, 3054, 2926, 2855, 1912,
1640, 1595, 1493, 1453, 1400, 1179, 1083, 1050, 909, 811, 732. HRMS (ESI): m/
z Calcd for C25H35O3S2: 447.2028 (M+H+). Found: 447.2017.
Acknowledgments
13. Best results were obtained by storing 4 at 4 °C and using it within a few days.
14. (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353; (b) Li, A.-H.;
Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341.
P.H.B. and J.M.M. thank NSERC (Discovery and RTI programs).
J.M.M. also thanks Canada Foundation for Innovation (Leaders
Opportunity Fund), Ontario Research Fund, and Carleton University
for financial support. J.W.P. thanks Carleton University for financial
support. The authors thank Prof. Jeff Smith and Karl Wasslen for
performing high resolution mass spectrometry analysis.
15. Experimental data for 3: Rf 0.41 (20% EtOAc in PhMe, UV, KMnO4).
½
a 2D5
ꢂ
¼ ꢁ113:3 (c 0.233, CHCl3). 1H NMR (CDCl3, 400 MHz): d 7.58 (d, J = 8 Hz,
2H), 7.37 (d, J = 8 Hz, 2H), 7.23 (d, J = 8 Hz, 2H), 7.07 (d, J = 8 Hz, 2H), 5.81 (m,
J = 17.2, 10.4, 6.4 Hz, 1H), 5.02 (dd, J = 17.2, 1.6 Hz, 1H), 4.96 (dd, J = 10.4,
0.8 Hz, 1H), 2.49 (s, 3H), 2.41 (s, 3H), 2.05 (q, J = 6.8 Hz, 2H), 1.80-1.62 (m, 6H),
1.40–1.25 (m, 9H). 13C NMR (CDCl3, 100 MHz): d 143.1, 142.2, 139.1, 138.9,
138.4, 130.0, 129.8, 126.5, 125.2, 114.2, 62.9, 33.8, 29.6, 29.3, 29.0, 29.0, 28.9,
27.4, 25.0, 21.6, 21.4, 13.2. IR (NaCl plate, cmꢁ1): 3057, 2925, 2854, 1727, 1639,
1596, 1492, 1449, 1399, 1303, 1178, 1084, 1049, 908, 809, 726. HRMS (ESI): m/
z Calcd for C26H34NaO2S2: 465.1892 (M+Na+). Found: 465.1895.
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¼ þ54:2 (c 0.273,
ꢂ
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