Total synthesis of (+)-crocacin C.

Article abstract of DOI:10.1016/S0040-4039(00)02002-5

The first asymmetric synthesis of (+)-crocacin C (3) is described which served to confirm the absolute configuration of this compound. The key step in the sequence was the stereoselective assembly of the (E,E)-diene amide side chain by a Stille cross-coup

Full text of DOI:10.1016/S0040-4039(00)02002-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 497–499
Total synthesis of (+)-crocacin C
Tushar K. Chakraborty* and Sarva Jayaprakash
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 12 September 2000; revised 18 October 2000; accepted 8 November 2000
Abstract—The first synthesis of (+)-crocacin C (3) in optically pure form is achieved following a convergent strategy. The
synthesis also establishes the absolute stereochemistries of this novel class of potent antifungal and highly cytotoxic compounds.
The naturally occurring crocacin C has (6S,7S,8R,9S) configuration, which is also the same for other congeners of the family,
crocacins A, B and D. © 2001 Elsevier Science Ltd. All rights reserved.
Crocacins A–D (1–4), novel antifungals and highly
cytotoxic metabolites were isolated from the myxobacte-
rial strains of chondromyces crocatus and chondromyces
pediculatus.1,2 The biological activity of the major com-
ponent, crocacin A, consists of an effective growth
inhibition of fungi and yeasts, caused by inhibition of
the electron flow within the cytochrome bc1 segment
(complex III) of the respiratory chain.3 Crocacin D
shows a distinctly higher biological activity against
Saccharomyces cerevisiae and higher toxicity in L929
mouse fibroblast cell culture compared to other cro-
cacins.
or -hexadienoic acid (in crocacins A and B) and large
number of double bonds with their respective geometric
constraints make their total synthesis a challenging task.
Although the relative configurations of these molecules
were deduced using 2D-NMR experiments and molecu-
lar modelling studies,1 their absolute stereochemistries
are yet to be determined. We envisaged that the total
synthesis of these molecules would not only provide an
access to larger quantities of them necessary for further
biological studies, but also help to establish their abso-
lute stereochemistries. In this paper, we describe the first
total synthesis of (+)-crocacin C in optically pure form
following an efficient, convergent approach. Our synthe-
sis affirms the relative stereochemistry of the molecule
deduced earlier1 and establishes the absolute configura-
tion of the natural product as (6S,7S,8R,9S).
The structures of crocacin molecules with polyketide-
derived four consecutive stereocentres, unusual dipep-
tides of glycine and a 6-aminohexenoic (in crocacin D)
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02002-5

498
T. K. Chakraborty, S. Jayaprakash / Tetrahedron Letters 42 (2001) 497–499
Retrosynthetically, crocacin C can be dissected into two
halves, an aldehyde component 5 and the diethylphos-
phonate 6,4 which could be coupled using Horner–
Wadsworth–Emmons olefination method. The salient
feature of our synthesis is a Ti(IV)-mediated diastereo-
selective aldol reaction5 using a 2-oxazolidinethione-
based chiral auxiliary,6 which was expected to fix the C8
and C9 stereocentres. The remaining two centres, C6
and C7, were planned to be constructed employing
Sharpless asymmetric epoxidation followed by lithium
dimethylcuprate opening of the epoxide ring.
column chromatography to obtain 86% yield of 14. The
bulky substituent at the ‘3-position’ of the ‘2,3-epoxy-
alcohol’ moiety in 13 and also electronic factors helped
to open the epoxide ring more favourably at the less
crowded ‘2-position’ giving an excellent yield of the
1,3-diol. Next, the same three steps, mentioned above
for the conversion of 11 to 12, were repeated on
intermediate 14 to methylate its secondary alcohol fur-
nishing the desired product 1511 in 60% overall yield.
Oxidation of 15 using SO3–pyridine gave the aldehyde
5 in 96% yield.7
Scheme 1 outlines in detail the stereoselective synthesis
of the aldehyde 5. Asymmetric aldol addition of the
titanium enolate derived from the acyloxazolidinethione
86 to cinnamaldehyde 7 gave the ‘non-Evans’ syn aldol
product 95 as the only isolable diastereomer in 89%
yield.7 The relative and absolute stereochemistry of the
product were assigned on the basis of earlier reported
work.5 Controlled reduction of 9 with 1 equivalent of
DIBAL-H gave an intermediate aldehyde,8,9 which was
reacted with the stabilised ylide to obtain a,b-unsatu-
rated ester 10 in 70% yield from 9. The ester function of
10 was subsequently reduced to furnish the diol 11.7
Routine functional group manipulations were carried
out next to methylate the secondary hydroxyl in three
steps in 64% overall yield: selective protection of pri-
mary alcohol as a silyl ether, methylation of secondary
hydroxyl group and finally deprotection of the primary
alcohol. The resulting allylic alcohol 12 was subjected
to Sharpless asymmetric epoxidation using (−)-DIPT to
furnish the expected epoxy alcohol 13 as the only
diastereomer in 93% isolated yield. Regioselective open-
ing of the epoxy alcohol 13 using Me2CuLi gave the
required 1,3-diol 14 as the major product.10 The minor
1,2-diol could be removed easily by standard silica gel
The stage was now set to carry out the coupling of
aldehyde 5 and the diethylphosphonate 6, which was
prepared following the procedure reported earlier.4
Treatment of 5 (Scheme 2) with the anion generated
from 6 using LDA in presence of 1,3-dimethyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidinone (DMPU) at −78°C for
8 h gave the desired E-olefin 16 in 60% yield (based on
20% recovered starting aldehyde). Although the olefina-
tion was slow at −78°C, the reaction temperature could
not be raised due to the formation of considerable
amounts of eliminated product at higher temperatures.
The basic framework of crocacin C in 16 was finally
converted to the natural product 311 in two steps in
66% yield: saponification followed by conversion of the
acid to the amide by a mixed anhydride method.
Our synthetic crocacin C showed rotation [h]2D0 +53.8 (c
0.2, MeOH); lit. value: [h]2D2 +52.2 (c 0.3, MeOH).1 It
was identical in all respects with the naturally occurring
crocacin C having all spectroscopic data11 matching
with those reported for the natural product.1 Thus, the
naturally occurring crocacin C has the (6S,7S,8R,9S)
configuration of the synthetic product reported here.
Since crocacin C is the biogenetic precursor of crocacin
Scheme 1. Stereoselective synthesis of aldehyde 5.

T. K. Chakraborty, S. Jayaprakash / Tetrahedron Letters 42 (2001) 497–499
499
Scheme 2. Coupling of aldehyde 5 and the diethylphosphonate 6 to furnish crocacin C (3).
10. Chakraborty, T. K.; Joshi, S. P. Tetrahedron Lett. 1990,
31, 2043–2046, and references cited therein.
A, B and D, these compounds should also have the
same absolute configuration. Efforts are now on to
achieve the total synthesis of other members of the
family.
11. Selected physical data for 15. Rf=0.4 (silica, 30% EtOAc
in petroleum ether); [h]2D0 −6.5 (c 1, CHCl3); IR (neat):
1
wmax 3450, 2975, 2940, 2875, 2825, 1450, 1100 cm−1; H
NMR (500 MHz, CDCl3, atom numberings of 3): l
7.36–7.17 (m, 5H, aromatic), 6.54 (d, J=16 Hz, 1H,
C11-H), 6.14 (dd, J=16, 7.2 Hz, 1H, C10-H), 4.04 (dd,
J=7.2, 2 Hz, 1H, C9-H), 3.79 (dd, J=11.2, 3.4 Hz, 1H,
C5-H), 3.53 (s, 3H, OCH3), 3.49 (dd, J=11.2, 4.3 Hz,
1H, C5-H%), 3.3 (s, 3H, OCH3), 3.25 (dd, J=9.5, 2.6 Hz,
1H, C7-H), 2.6 (br s, 1H, OH), 1.85 (m, 2H, C6-H and
C8-H), 1.19 (d, J=6.9 Hz, 3H, CH3), 0.89 (d, J=7.2
Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3): l 136.72,
132.09, 129.29, 128.51, 127.51, 126.33, 88.24, 81.16, 64.4,
61.41, 56.28, 42.22, 35.98, 16.1, 10.34; MS (LSIMS): m/z
(%): 301 (20) [M++Na], 246 (10) [M+−CH3OH], 215 (20)
[M++H−2CH3OH].
Acknowledgements
Authors wish to thank Drs. A. C. Kunwar and M.
Vairamani for NMR and mass spectroscopic assistance,
respectively, and CSIR, New Delhi for research fellow-
ship (S.J.) and Young Scientist Award Research Grant
(T.K.C.).
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