The first asymmetric total syntheses of 3((1R,2R)- and 3((1S,2R)-2-(12- methyltridecyl)cyclopropyl)propanoic acid

Article abstract of DOI:10.1016/j.tetlet.2012.09.133

The first efficient total syntheses of 3((1R,2R)- and 3((1S,2R)-2-(12- methyltridecyl)cyclopropyl)propanoic acid have been achieved following a chelation controlled modified Simmon-Smith cyclopropanation, Wittig reaction, Horner-Wadsworth-Emmons olefination, and p-toluenesulfonyl hydrazide catalyzed hydrogenation as key reactions in good overall yield.

Full text of DOI:10.1016/j.tetlet.2012.09.133

Tetrahedron Letters 53 (2012) 6718–6720
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Tetrahedron Letters
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The first asymmetric total syntheses of 3((1R,2R)- and
3((1S,2R)-2-(12-methyltridecyl)cyclopropyl)propanoic acid
⇑
Debendra K. Mohapatra , Nagesh Guguloth, J. S. Yadav
Natural Products Chemistry Division, CSIR-Indian Insititute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first efficient total syntheses of 3((1R,2R)- and 3((1S,2R)-2-(12-methyltridecyl)cyclopropyl)propanoic
acid have been achieved following a chelation controlled modified Simmon–Smith cyclopropanation,
Wittig reaction, Horner–Wadsworth–Emmons olefination, and p-toluenesulfonyl hydrazide catalyzed
hydrogenation as key reactions in good overall yield.
Received 6 September 2012
Revised 29 September 2012
Accepted 30 September 2012
Available online 13 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropane fatty acid
Asymmetric synthesis
Simmon–Smith cyclopropanation
Wittig reaction
Horner–Wadsworth–Emmons olefination
The cyclopropyl ring can be found in a range of naturally
occurring biologically active compounds including those present
in bacterial fatty acids.1 The cyclopropane fatty acids, 3-(2-(12-
methyltridecyl)-4,5-trans-cyclopropyl)propanoic acid, 3-(2-(13-
O
O
HO
HO
H
H
H
1a
1b
methyltetradecyl)-4,5-trans-cyclopropyl)propanoic
acid,
and
3-(2-(12-methyltetradecyl)-4,5-trans-cyclopropyl)propanoic acid,
were recently isolated and characterized for the first time in nature
in the phospholipids of the hermit-crab sponge Pseudospongosor-
ites suberitoides which was collected from the Mona island, Puerto
Rico in 2007.2 These marine fatty acids are quite interesting since
they incorporate an unusual trans 4,5-cyclopropane in addition to
isomethyl branching (1a–1d) (Fig. 1). Pyrrolidine derivatization
combined with spectral analysis was the key in identifying position
of the cyclopropyl, methyl group, and trans-stereochemistry of the
cyclopropyl group. Recently, Carballeira et al. reported the total
synthesis of ( )-3-(2-(12-methyltridecyl)-4,5-trans-cyclopropyl)
propanoic acid and its corresponding cis analog.3 As per our knowl-
edge, there is no information concerning the asymmetric total syn-
thesis of these fatty acids. Because of our interest to synthesize
cyclopropyl bearing biologically active natural products,4 herein,
we disclose the first asymmetric synthesis of 3((1R,2R)- and
3((1S,2R)-2-(12-methyltridecyl)cyclopropyl)propanoic acid (1a)
and (1b), respectively.
H
O
O
HO
HO
H
H
H
H
1c
1d
Figure 1. Structures of cyclopropyl fatty acids 1a, 1b, 1c, and 1d.
hydrogenation which in turn would come from the acetonide
protected diol 3. The diol could be prepared from the aldehyde 4
and TPP salt of long chain compound 5. The salt 5 could be
obtained from the long chain iodo compound 7 where as the alde-
hyde 4 could be synthesized from (R)-2,3-O-isopropylidine glycer-
aldehyde (6) via chelation controlled modified Simmon–Smith
cyclopropanation reaction (Scheme 1).
The synthesis of 1a was commenced from (R)-2,3-O-isopropyl-
idine glyceraldehyde5 (6) which was converted into cyclopropyl
alcohol 4 following a well known protocol via Wittig reaction to
From retrosynthetic perspective, we envisioned that the trans
cyclopropane fatty acid 1a could be derived from the cyclopropane
derivative diene ester 2 via p-toluenesulfonyl hydrazide catalyzed
⇑
Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160512.
E-mail address: mohapatra@iict.res.in (D.K. Mohapatra).
obtain (E)-a,b-unsaturated ester, DIBAL-H reduction, TBDPS ether
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.133

D. K. Mohapatra et al. / Tetrahedron Letters 53 (2012) 6718–6720
6719
O
O
O
H
O
ref. 4,6
a
HO
EtO
O
OH
O
O
O
H
H
CHO
1a
2
H
6
4
H
O
H
O
H
O
b
H
H
O
H
H
3
8
O
H
H
OH
HO
H
H
c
H
8
3
H
9
O
d
O
H
H
O
OH
8
Ph3P I
H
10
5
4
O
H
e
EtO
EtO
I
8
H
O
2
O
CHO
O
7
6
f
8
H
H
Scheme 1. Retrosynthetic analysis of 1a.
11
O
g
formation followed by chelation–controlled Simmon–Smith cyclo-
propanation6 and cleavage of the silyl protective group. The result-
ing primary alcohol 4 was oxidized to the corresponding aldehyde
8 with Dess–Martin periodinane7 in CH2Cl2 in 90% yield. The car-
bon–carbon bond formation at C7–C8 was achieved by performing
the Wittig reaction8 of 11-methyldodecyl)triphenylphosphonium
iodide9 with the resulting aldehyde 8 in the presence of NaHMDS
at À78 °C to supply 3 as a single Z-isomer in 89% yield which on
treatment with PPTS in MeOH at room temperature afforded the
diol 9 in 91% yield. Oxidative cleavage of the resulting diol 9 fol-
lowed by two carbon homologation via Horner–Wadsworth–Em-
mons10 olefination with ethyl diethyl phosphonoacetate and
HO
H
H
1a
Scheme 2. Reagents and conditions: (a) DMP, CH2Cl2, NaHCO3, rt, 2 h, 90%; (b) (11-
methyldodecyl) triphenylphosphonium iodide, NaHMDS, THF, 1 h, À78 to 0 °C, 89%;
(c) PPTS, MeOH, 0 °C to rt, 3 h, 91%; (d) NaIO4 impregnated over silica gel, CH2Cl2,
0 °C to rt, 10 min, 94%; (e) triethylphosphonoacetate, NaH, THF, 30 min, 0 °C to rt,
90%; (f) p-TsNHNH2, NaOAc, THF:H2O (1:1), reflux, 12 h, 92%; (g) KOH, EtOH:H2O
(3:1), 0 °C to rt, 2 h, 91%.
O
O
ref. 6
sodium hydride gave the a,b-unsaturated ester 2 in 85% yield over
O
O
OTBDPS
CHO
two steps. Initially, hydrogenation of both the double bonds with
Pd/C, Pd/OH, and Raney Ni in different solvents like MeOH, EtOH,
and toluene ended up with an intractable mixture of products. Fi-
nally, when compound 2 was treated with p-toluenesulfonyl
hydrazide11 and sodium acetate in THF/H2O (1:1) mixture, reaction
went smoothly providing saturated cyclopropyl ester 11 in 92%
yield. Saponification of ester group present in 11 with KOH in
EtOH:H2O (3:1) provided the desired target molecule 1a in 91%
yield (Scheme 2).
H
H
6
12
O
O
5
H
H
13
O
Similarly, total synthesis of 3((1S,2R)-2-(12-methyltride-
cyl)cyclopropyl)propanoic acid (1b) was achieved in good overall
yield starting from the cis-olefination of the aldehyde 6 to obtain
EtO
HO
5
H
H
14
(Z)-a,b-unsaturated ester followed by DIBAL-H reduction, TBDPS
O
protection and cyclopropanation afforded known cyclopropyl
TBDPS ether 12 (Scheme 3). Silyl group deprotection, oxidation
followed by Wittig reaction furnished olefin compound 13. Double
bond reduction under p-toluenesulfonyl hydrazide catalyzed
hydrogenation conditions, acetonide deprotection, oxidative
cleavage of diol, Horner–Wadsworth–Emmons olefination with
ethyl diethyl phosphonoacetate, reduction of double bond under
p-toluenesulfonyl hydrazide catalyzed hydrogenation conditions
followed by saponification gave 3((1S,2R)-2-(12-methyltride-
cyl)cyclopropyl)propanoic acid (1b).
H
H
1b
Scheme 3. Total synthesis of 1b.
(12-methyltridecyl)cyclopropyl)propanoic acid (1b) was achieved
in nine steps with 43% overall yield starting from a known inter-
mediate 12. The key steps are a highly diastereoselective Sim-
mon–Smith cyclopropanation reaction and a p-toluenesulfonyl
hydrazide catalyzed hydrogenation reaction. Following the same
protocol, other related natural products are in the process of syn-
thesis and will be reported in due course.
In conclusion, the first asymmetric total synthesis of 3((1R,2R)-
2-(12-methyltridecyl)cyclopropyl)propanoic acid (1a) was accom-
plished in seven steps with 51.6% overall yield starting from a
known cyclopropyl alcohol intermediate 4. Similarly, 3((1S,2R)-2-

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D. K. Mohapatra et al. / Tetrahedron Letters 53 (2012) 6718–6720
Varadarajan, S.; Mohapatra, D. K.; Datta, A. Tetrahedron Lett. 1998, 39, 1075–
Acknowledgments
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N.G. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, India, for the financial assistance in the form
of fellowship. D.K.M. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, India, for a research grant (INSA Young
Scientist Award Scheme).
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yield.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.
133.
b
a
OH
HO
Br
4
6
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15
16
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