Catalytic asymmetric synthesis of mycocerosic acid

Article abstract of DOI:10.1039/b612593j

The first catalytic asymmetric total synthesis of mycocerosic acid was achieved via the application of iterative enantioselective 1,4-addition reactions and allows for the efficient construction of 1,3-polymethyl arrays with full stereocontrol; further exemplified by the synthesis of tetramethyl-decanoic acid, a component of the preen-gland wax of the graylag goose, Anser anser. The Royal Society of Chemistry.

Full text of DOI:10.1039/b612593j

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Catalytic asymmetric synthesis of mycocerosic acid{
Bjorn ter Horst, Ben L. Feringa* and Adriaan J. Minnaard*
Received (in Cambridge, UK) 1st September 2006, Accepted 6th October 2006
First published as an Advance Article on the web 6th November 2006
DOI: 10.1039/b612593j
Mycocerosic acid, one of the many methyl-branched fatty acids
The first catalytic asymmetric total synthesis of mycocerosic
acid was achieved via the application of iterative enantio-
selective 1,4-addition reactions and allows for the efficient
construction of 1,3-polymethyl arrays with full stereocontrol;
further exemplified by the synthesis of tetramethyl-decanoic
acid, a component of the preen-gland wax of the graylag goose,
Anser anser.
from M. tuberculosis, was first elaborated by Marks and Polgar3 in
the fifties. In 1963 Polgar and Smith4 elucidated the absolute
stereochemistry by degradation studies, which was confirmed
subsequently by the synthesis of mycocerosic acid starting from
chiral pool compounds or via a route involving kinetic resolu-
tion.5,6 These studies confirmed that the natural product was
laevorotatory and possessed an all-R configuration. Rainwater
and Kolattukudy7 studied the biosynthesis of mycocerosic acid
and found that the enzyme responsible was specific for
methylmalonyl-CoA and would not incorporate malonyl-CoA
into fatty acids.
Mycobacterium tuberculosis, the perpetrator of tuberculosis, is still
one of the predominant infectious agents. Irresponsible use of
available antibiotics has resulted in the emergence of resistant
strains. The bacterium has an unusually thick cell wall, which
consists partly of long-chain lipids,1 providing a very hydrophobic
barrier to antibiotics and other molecules. These lipids are
potential drug targets because they induce an immune response
and play an important role in the build up and strength of the cell
wall.2 One of these lipids1 is PDIM A (Fig. 1), a wax which
contains two tetramethyl substituted saturated acids (mycocerosic
acid). For physiological and, especially, immunological studies,
access to pure cell wall lipidic compounds is of paramount
importance. However, in addition to regulatory restrictions,
culturing of M. tuberculosis is difficult and purification of
components from the lipid fraction is complicated. An effective
synthetic route to these lipids is therefore highly desirable but has
not been reported until now.
The 1,3,5,… n-polymethyl alkyl chains (where n = 7, 9, 11,…)
(‘‘deoxypropionate oligomers’’)8 occur widely in many natural
products including fatty acids and lipids,1 marine natural products9
and antibiotics.10 Most of the synthetic procedures reported for
1,3-polymethyl arrays are based on laborious iterative chiral
auxiliary strategies (i.e., enolate alkylations, conjugate additions,
and allylic alkylations).11–13 Very recently, an attractive iterative
catalytic asymmetric procedure for 1,3-dimethyl arrays was
reported by Negishi and co-workers.10,14
Earlier work of our group demonstrated that iterative catalytic
asymmetric conjugate additions of organometallic reagents lead to
excellent stereochemical control in the synthesis of 1,3-methyl
arrays.15 Using a related approach, we reported recently an
efficient strategy for the stereocontrolled synthesis of 1,5,9,n-poly-
methyl alkyl chains (‘‘saturated polyisoprenoids’’), applied in
the synthesis of beta-D-mannosyl phosphomycoketides from
M. tuberculosis.16
We anticipated that the Cu/Josiphos catalyzed iterative
conjugate addition of MeMgBr to unsaturated thioesters17 would
be an excellent strategy for the total synthesis of enantiopure 1
(Scheme 1). The starting material should have a functionality at
the terminus of the unsaturated thioester that is robust under the
iterative reaction conditions (conjugate addition, Pd catalysed
reduction, and Wittig reaction). For this reason we selected 2, an
unsaturated thioester with a protected hydroxyl group, prepared
from glycol in 3 steps. Substrate 2 gave excellent enantioselectivity
(98% ee) and complete regioselectivity in the copper catalysed 1,4-
addition with MeMgBr and 1 mol% of CuBr/5 (Scheme 1). Upon
deprotection, the known lactone 4 was formed, which allowed
confirmation of the absolute stereochemistry.18 The pseudosym-
Fig. 1 PDIM A and mycocerosic acid.
metric bifunctional building block
3 was reduced to the
corresponding aldehyde followed by a Wittig reaction17 to give
thioester 6. The syn-selectivity of the second conjugate addition,
leading to dimethyl thioester 7a, could be established by 1H-NMR
spectroscopy in comparison with anti dimethyl thioester 7b,
prepared using ent-5 (Scheme 1). The ratio syn : anti was higher
than 96 : 4; for details see electronic supplementary information.{
Department of Organic and Molecular Inorganic Chemistry, Stratingh
Institute, University of Groningen, Nijenborgh 4, 9747 AG, Groningen,
The Netherlands. E-mail: B.L.Feringa@rug.nl; A.J.Minnaard@rug.nl
{ Electronic supplementary information (ESI) available: Detailed experi-
mental procedures, 1H and 13C NMR spectroscopic and analytical data of
all compounds in Schemes 1, 2 and 3. See DOI: 10.1039/b612593j
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Chem. Commun., 2007, 489–491 | 489

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Scheme 3 Conditions: (a) LiAlH4 (10 equiv.), THF, overnight; (b)
TBAF (2 equiv.), THF, 5 h; (c) RuCl3?(H2O)x (1 mol%), NaIO4 (4.2
equiv.) in a mixture of CCl4, CH3CN and H2O, 3 h.
the graylag goose Anser anser (Scheme 3). An asymmetric
total synthesis of 15 was recently reported by Negishi and
co-workers.21
Scheme 1 Conditions: (a) MeMgBr (1.2 equiv.), 5?CuBr (1 mol%),
t-BuOMe, 275 uC, overnight; (b) TBAF (2 equiv.), THF, 5 h; (c) 10%
Pd/C (5 mol%), Et3SiH (3 equiv.), CH2Cl2, rt, 20 min; (d) Ph3PCHCOSEt,
CH2Cl2, reflux 24 h; (e) MeMgBr (1.2 equiv.), ent-5.CuBr (1 mol%),
t-BuOMe, 275 uC, overnight.
Treatment of tosylate 10 with an excess of LiAlH4 gave silyl-
protected alcohol 13 in high yield. Deprotection and oxidation as
described for mycocerosic acid gave 2,4,6,8-tetramethyl-decanoic
acid (15) in 15 steps starting from 2 with an overall yield of 13%.
Optical rotation (227.8, c = 0.69, CHCl3) and spectroscopic
data are in agreement with literature values (225.1, c = 0.2,
CHCl3).21
The reaction protocol shown in Scheme 1 was applied four
times in an iterative procedure to arrive at the tetramethyl
substituted compound 8 in ten steps with excellent selectivity19,20
and an overall yield of 21% from 2 (Scheme 2). Twofold reduction
of thioester 8 with DIBALH resulted in alcohol 9, which was
converted subsequently into 10 after treatment with TsCl. The
introduction of the long alkyl chain was achieved by treatment of
10 with C18H37MgBr and 20 mol% of CuBr?SMe2 to give 11,
which was deprotected with TBAF to yield the tetramethyl
substituted alcohol 12. Oxidation of 12 gave mycocerosic acid (1)
in 15 steps with an overall yield of 12% (86% average yield per
step). Optical rotation (26.4, c = 0.94, CHCl3) and spectroscopic
data are in agreement with the literature value4 for the isolated
product (25.62, c = 8.9, CHCl3).
In summary, a highly efficient strategy for the preparation of
deoxypropionates has been developed. It gives access to all
possible stereoisomers since both syn and anti 1,3-polymethyl
arrays are accessible. The methodology is illustrated by the
preparation of two naturally occurring fatty acids, mycocerosic
acid (1) and 2,4,6,8-tetramethyldecanoic acid (15). The overall
yield of these syntheses (12% and 13%, respectively) is such that
these and related compounds can be prepared readily for biological
studies. Further applications using this strategy are in development
currently in our laboratory.
We thank T. D. Tiemersma-Wegman (GC) and A. Kiewiet
(MS) for technical support. Financial support from the
Netherlands Organization for Scientific Research (NWO/CW)
and a generous gift of Josiphos ligand from Solvias, Basel, are
gratefully acknowledged.
To demonstrate the versatility of this iterative synthetic
approach further we decided to synthesize the related tetra-
methyl-substituted fatty acid 15, found in the preen-gland wax of
Scheme 2 Conditions: (a) MeMgBr (1.2 equiv.), 5.CuBr (1 mol%), t-BuOMe, 275 uC, overnight; (b) 10% Pd/C (5 mol%), Et3SiH (3 equiv.), CH2Cl2, rt,
20 min, work up; Ph3PCHCOSEt, CH2Cl2, reflux 24 h; (c) steps a, b were repeated two times followed by step a; (d) DIBALH (2 equiv.), CH2Cl2, 220 uC,
3–4 h, two times; (e) TsCl (2 equiv.), pyridine (2 equiv.), CH2Cl2, overnight; (f) C18H37MgBr (3 equiv.) and CuBr?SMe2 (20 mol%), THF, overnight; (g)
TBAF (2 equiv.), THF, 5 h; (h) RuCl3?(H2O)x (1 mol%), NaIO4 (4.2 equiv.) in a mixture of CCl4, CH3CN and H2O, 3 h.
490 | Chem. Commun., 2007, 489–491
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19 Second addition d.r.; (3S,5R) : (3R,5R) : (3S,5S) : (3R,5S) = 97 : 2 : 1 : 0,
third addition d.r.; (3S,5R,7R) : (3R,5R,7R) : (3S,5S,7R) : (3S,5R,7S) =
95 : 2 : 2 : 1, fourth addition d.r.; (3S,5S,7R,9R) : (3R,5S,7R,9R) :
(3S,5R,7R,9R) : (3S,5S,7S,9R) : (3S,5S,7R,9S) = 94 : 1 : 2 : 2 : 1.
Diastereoisomers less than 0.04% were neglected. Ratios were calculated
from syn/anti ratios (1H-NMR spectroscopy). The final product did not
contain any minor diastereoisomers most probably as a result of the
chromatography steps. See electronic supporting information (ESI){ for
details.
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This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 489–491 | 491