Total synthesis of (+)-crocacin D

Article abstract of DOI:10.1016/S0040-4039(02)00289-7

The first total synthesis of the potent antifungal and cytotoxic agent (+)-crocacin D in optically pure form following a convergent strategy is described here. The regioselective ring opening of a silyl-substituted epoxide with an azide ion, based on a me

Full text of DOI:10.1016/S0040-4039(02)00289-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2645–2648
Total synthesis of (+)-crocacin D
Tushar K. Chakraborty* and Pasunoori Laxman
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 10 January 2002; revised 28 January 2002; accepted 6 February 2002
Abstract—The first total synthesis of the potent antifungal and cytotoxic agent (+)-crocacin D in optically pure form following
a convergent strategy is described here. The regioselective ring opening of a silyl-substituted epoxide with an azide ion, based on
a method developed by us earlier, and subsequent subjection of the resulting a-azido-b-hydroxyalkylsilane intermediate to a
Peterson elimination reaction at an appropriate stage during the synthesis constituted the key steps for the stereoselective
construction of the crucial cis enamide moiety of the molecule. © 2002 Published by Elsevier Science Ltd.
Crocacins A–D (1–4), isolated from the myxobacterial
strains of Chondromyces crocatus (crocacins A–C) and
C. pediculatus (crocacin D),1,2 possess wide ranging
biological activities. The major component crocacin A
(1) inhibits the growth of Gram-positive bacteria mod-
erately, but exhibits very effective growth inhibition of
fungi and yeasts, caused by the inhibition of electron
flow within the cytochrome bc1 segment (complex III)
of the respiratory chain.3 Crocacin D (4) shows a
distinctly higher biological activity against Saccha-
romyces cerevisiae and higher toxicity in L929 mouse
fibroblast cell culture compared to other crocacins.
The crocacins represent a second novel group of
modified peptides from C. crocatus. However, unlike
the chondramides isolated earlier,4 crocacins are linear
dipeptides. The main structural features of crocacin
molecules are polyketide derived four consecutive stereo-
centers, unusual dipeptides of glycine and a 6-amino-
hexenoic (in crocacin D) or hexadienoic acid (in cro-
cacins A and B) and a large number of double bonds
with their respective geometric constraints. While the
relative configurations of these molecules were deduced
using 2D NMR experiments and molecular modeling
studies,2 their absolute configurations were established
by the total synthesis of crocacin C.5
Me Me
One of the major problems encountered in the much-
awaited total synthesis of the other members of the
family is the presence of a unique cis enamide moiety in
these molecules, construction of which remained a chal-
lenging task. In this paper, we describe a novel strategy
for the stereoselective synthesis of this crucial structural
moiety6 based on two key reactions, (a) the regioselec-
tive opening of a silyl-substituted epoxide with an azide
ion, based on work carried out by us and others earlier7
and (b) subjection of the resulting a-azido-b-hydroxy-
alkylsilane intermediate to a Peterson elimination
reaction8 at an appropriate stage, leading to a success-
ful first total synthesis of (+)-crocacin D (4).
NH
OR
O
N
H
Me
OMe OMe
O
O
1: crocacin A (R = Me)
2: crocacin B (R = H)
Me Me
NH2
Me
OMe OMe
O
3: crocacin C
7
Me Me
14
10NH
OMe
3
N
H
1
19
O
21
Me
OMe OMe
O
O
The synthesis started with the monosilyl-protected pen-
tane-1,5-diol 5 (Scheme 1), which was transformed into
the silylated-acetylenic product 6 in three steps in 68%
overall yield: (a) the Swern oxidation of the free
hydroxyl group to an aldehyde; (b) olefination of the
aldehyde using Ph3P and CBr4 to give a dibromoolefin;
and finally (c) treatment of the Li–acetylide, generated
4: crocacin D
Keywords: antifungals; cytotoxins; aldol reactions; Peterson olefina-
tion; enamide.
* Corresponding author. Fax: +91-40-7160387, 7160757; e-mail:
chakraborty@iict.ap.nic.in
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00289-7

2646
T. K. Chakraborty, P. Laxman / Tetrahedron Letters 43 (2002) 2645–2648
Scheme 1. Stereoselective synthesis of 13.
1
by adding n-BuLi to the dibromoolefin intermediate,
with trimethylsilyl chloride (TMSCl). Deprotection of
the TBS group of 6 using a catalytic amount of cam-
phorsulfonic acid (CSA) was followed by hydrogena-
tion of the acetylenic moiety using Lindlar’s catalyst to
give the cis vinylsilane 7 in 62% yield. Epoxidation of 7
using mCPBA furnished the cis epoxysilane 8. As
expected, treatment of 8 with NaN3 in the presence of
NH4Cl led to a very facile opening of the epoxide ring
with complete regioselectivity at the silyl-substituted
center to provide the a-azido-b-hydroxyalkylsilane
intermediate 9 in 88% yield.7a,b The azido group of 9
was selectively reduced to the requisite amine 10 using
the H NMR spectrum of 13 which did not show any
trace of the trans isomer. To complete the synthesis of
our target molecule, the primary hydroxyl group of 13
was next subjected to a two-step oxidation protocol to
prepare the corresponding acid. Unfortunately, the
product isolated was not the expected acid. That an
aldehyde was formed in the first step during the oxida-
tion was confirmed. However, the product after the
second step did not have the C8ꢀC9 double bond as
1
indicated by its H NMR spectrum. Although its struc-
ture is yet to be established fully, preliminary investiga-
tions of the spectroscopic data suggest that it is an
intramolecularly cyclized lactone.
7d
LiAlH4 and after aqueous work-up, the product was
Having failed to proceed any further with the enamide
compound 13, it was decided to carry out the Peterson
elimination reaction in the last step of our synthesis
after incorporating the glycine unit as shown in Scheme
2. Thus, the diol 12 was subjected to a routine two-step
reaction sequence involving di-TBS protection followed
by a selective primary deprotection, to prepare the
secondary-hydroxyl protected intermediate 14 in 55%
yield. A two-step oxidation process, identical to that
described in Scheme 1, transformed 14 into the acid 15
in 74% yield. Attempted coupling of 15, following the
conditions outlined in Scheme 1 for 10“11, did not
provide the expected product in good yield and the
major product showed the disappearance of the N10-
amide proton. However, treatment of 15 with isobutyl
chloroformate in the presence of N-methylmorpholine
used directly to couple with the known acid 11 that was
earlier prepared by us during the synthesis of crocacin
C.5a,c To a solution of 11 in CH2Cl2, 1-hydroxybenzo-
triazole (HOBt) and 1-ethyl-3-(3-(dimethylamino)-
propyl)carbodiimide hydrochloride (EDCI) were added
sequentially at 0°C and the reaction mixture was stirred
at that temperature for 15 min, followed by the addi-
tion of a solution of 10 in CH2Cl2. The reaction was
complete in 5 h. After the usual aqueous work-up,
chromatographic purification gave the amide 12 in 57%
yield (from 9). The stage was now set to carry out the
Peterson reaction on compound 12. Treatment of 12
with NaH in THF at 0°C led to the formation of the
enamide 13 in quantitative yield (>96%). The formation
of the cis olefin as the sole product was confirmed by

T. K. Chakraborty, P. Laxman / Tetrahedron Letters 43 (2002) 2645–2648
2647
Scheme 2. Final steps in the synthesis of (+)-crocacin D (4).
References
(NMM) led to a mixed anhydride which reacted suc-
cessfully with glycine methyl ester to furnish 16 in 77%
yield. Finally, deprotection of the TBS group of 16
using tetra-n-butylammonium fluoride (TBAF) in THF
led to the formation of an oxy anion intermediate that
underwent a smooth in situ Peterson elimination pro-
cess, in 78% yield, to install the final and most impor-
tant cis enamide moiety in the framework with
complete stereoselectivity resulting in the successful
completion of the first total synthesis of crocacin D (4).
Our synthetic crocacin D (4) showed rotation [h]D20
+100.3 (c 0.13, MeOH); lit. value: [h]2D2 +109.6 (c 0.56,
MeOH)2 and was identical in all respects with the
naturally occurring crocacin D having all spectroscopic
data9 matching with those reported for the natural
product.2
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In conclusion, a mild method for the synthesis of a cis
enamide starting from an epoxysilane following two
simple steps, silyl-directed epoxide opening with an
azide ion and a Peterson elimination, has been devel-
oped leading to the first total synthesis of (+)-crocacin
D. Although a similar approach using epoxysilanes as
substrates for the synthesis of simple enamides has very
recently been reported,6a its efficacy in the synthesis of
a complex natural product containing this very chal-
lenging structural moiety is realized here for the first
time. This will help us to achieve the total synthesis of
the other members of the family. Further work is
currently in progress.
Acknowledgements
The authors wish to thank Drs. A. C. Kunwar and M.
Vairamani for NMR and mass spectroscopic assistance,
respectively, and CSIR, New Delhi for a research fel-
lowship (P.L.).
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T. K. Chakraborty, P. Laxman / Tetrahedron Letters 43 (2002) 2645–2648
9. Selected physical data for 4. Rf=0.4 (silica, 60% EtOAc in
petroleum ether); [h]2D0 +100.3 (c 0.13, MeOH); IR (neat):
(dd, J=15.7, 8.1 Hz, 1H, C15-H), 5.9 (d, J=1.0 Hz, 1H,
C12-H), 4.66 (dt, J=9, 7.4 Hz, 1H, C8-H), 4.07 (ddd,
J=7.24, 2.4, 1.0 Hz, 1H, C19-H), 3.96 (d, J=5.8 Hz, 2H,
C2-H2), 3.67 (s, 3H, C1-OCH3), 3.51 (s, 3H, C17-OCH3),
3.29 (s, 3H, C19-OCH3), 3.18 (dd, J=9.5, 2.3 Hz, 1H,
C17-H), 2.62 (m, 1H, C16-H), 2.26 (m, 2H, C5-H2), 2.26
(d, J=0.7 Hz, 3H, C13-CH3), 2.12 (m, 2H, C7-H2), 1.67 (m,
2H, C6-H2), 1.57 (m, 1H, C18-H), 1.17 (d, J=7.1 Hz, 3H,
C16-CH3), 0.84 (d, J=6.8 Hz, 3H, C18-CH3); MS (LSIMS):
m/z (%): 509 (23) [M++H−CH3OH], 563 (12) [M++Na].
wmax 3309, 2917, 1742, 1647, 1360, 1176, 1082 cm−1 1H
;
NMR (acetone-d6, 500 MHz, TMS as reference): l 9.10 (d,
J=10 Hz, 1H, N10-H), 7.55 (br m, 1H, N3-H), 7.45 (d,
J=8.0 Hz, 2H, aromatic ortho-protons), 7.31 (dd, J=8.0,
7.4 Hz, 2H, aromatic meta-protons), 7.22 (t, J=7.4 Hz, 1H,
aromatic para-proton), 6.77 (ddt, J=10, 9, 1.5 Hz, 1H,
C9-H), 6.58 (d, J=16.1 Hz, 1H, C21-H), 6.24 (dd, J=16.1,
7.24 Hz, 1H, C20-H), 6.12 (d, J=15.7 Hz, 1H, C14-H), 6.10