Total synthesis of (+)-crocacin A

Article abstract of DOI:10.1016/S0040-4039(03)01171-7

Total synthesis of the potent antifungal and cytotoxic agent (+)-crocacin A is described. The crucial (Z)-5,6-enoic amide moiety in this molecule was built by stereoselective partial reduction of a skipped diyne precursor. The diene, thus obtained, was transformed into a silyl epoxide that was regioselectively opened with an azide ion to furnish an α-azido-β-hydroxyalkylsilane intermediate. Peterson elimination of this β-hydroxysilane component in the final step resulted in the formation of the (Z)-8,9-enamide moiety of the molecule leading to a successful completion of its total synthesis.

Full text of DOI:10.1016/S0040-4039(03)01171-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4989–4992
Total synthesis of (+)-crocacin A
Tushar K. Chakraborty* and Pasunoori Laxman
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 31 March 2003; revised 1 May 2003; accepted 9 May 2003
Abstract—Total synthesis of the potent antifungal and cytotoxic agent (+)-crocacin A is described. The crucial (Z)-5,6-enoic
amide moiety in this molecule was built by stereoselective partial reduction of a skipped diyne precursor. The diene, thus obtained,
was transformed into a silyl epoxide that was regioselectively opened with an azide ion to furnish an a-azido-b-hydroxyalkylsilane
intermediate. Peterson elimination of this b-hydroxysilane component in the final step resulted in the formation of the
(Z)-8,9-enamide moiety of the molecule leading to a successful completion of its total synthesis. © 2003 Elsevier Science Ltd. All
rights reserved.
Crocacins A–D (1–4) were isolated from the myxobac-
terial strains of Chondromyces crocatus (crocacins A–C)
and Chondromyces pediculatus (crocacin D).1,2 The wide
ranging biological activities of crocacins1–3 have
attracted the attention of synthetic chemists.4 While the
synthesis of crocacins C 3 and D 4 have already been
achieved by us and others,4 the much awaited total
synthesis of the other members of the family, namely
crocacins A 1 and B 2, remained elusive due to the
presence of a synthetically challenging 6-aminohexa-
dienoic acid with a skipped (Z,Z)-‘1,4-diene’ moiety in
these molecules. The ‘right half’ of this diene is com-
posed of a conjugated (Z)-enoic amide unit, while the
‘left half’ carries an equally challenging (Z)-enamide
fragment. In this paper, we describe a novel strategy for
the stereoselective construction of this crucial diene
segment based on the following key reactions: (a) a P-2
Ni-assisted stereoselective partial reduction5 of an
appropriate skipped diyne precursor6 to build the corre-
The synthesis was started from propargyl alcohol 5
sponding (Z,Z)-diene intermediate that eventually led
(Scheme 1) which was transformed into a silylated-
to the synthesis of the desired (Z)-5,6-enoic amide
acetylenic product 6 in two steps in 84% overall yield,
(a) reaction of the dianion of 5, prepared by using the
Grignard reagent EtMgBr, with trimethylsilyl chloride
(TMSCl) to give a disilylated intermediate, and (b)
selective deprotection of the O-silyl group under acid-
catalyzed conditions to furnish 6. The primary hydroxyl
group of 6 was protected as the tosylate to give 7 in
93% yield. Next, the propargylic tosylate 7 was coupled
with the 1-alkyne unit 5 in a copper-mediated reaction6
that provided the requisite skipped diyne 8 in 76%
yield. Stereoselective partial reduction of the diyne 8
using P-2 Ni5,6 led to the formation of the skipped
diene 9 as the major product in 53% yield. As the
reduction of the silyl-acetylenic moiety was slower in
moiety; (b) selective epoxidation of the (Z)-vinylsilane
in the ‘left’ terminal of the aforesaid diene intermediate
using mCPBA; (c) regioselective opening of the silyl-
substituted epoxide with an azide ion, based on work
carried out by us and others earlier;7 and (d) subjection
of the resulting b-hydroxysilane to a Peterson elimina-
tion reaction8 in the final stage to furnish selectively the
crucial (Z)-8,9-enamide moiety,9 culminating in the
total syntheses of (+)-crocacin A 1.
Keywords: antifungal; cytotoxin; aldol reaction; Peterson olefination;
enamide; crocacin.
* Corresponding author. Fax: +91-40-27160387, 27160757; e-mail:
chakraborty@iict.ap.nic.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01171-7

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T. K. Chakraborty, P. Laxman / Tetrahedron Letters 44 (2003) 4989–4992
Scheme 1. Stereoselective synthesis of 1.
epoxidation at the other terminal. Thus, protection of
the allylic hydroxyl with a bulky protecting group
forced the mCPBA to react preferentially at the other
end giving the required silyl epoxide as the major
product. The trityl group emerged as the best choice for
protecting the hydroxyl function of 9 to facilitate this
preferential epoxidation of the silyl-substituted olefin.
Reaction of 9 with TrCl in the presence of Et3N as base
and a catalytic amount of DMAP in CH2Cl2 furnished
the trityl ether 10 in 82% yield. Compound 10 was
epoxidized with mCPBA to give 11 as the major
product in 55% yield after separating the minor side-
comparison to that of the propargylic alcohol end,
complete reduction of the latter to a single bond, to
some extent, could not be avoided. However, this minor
side-product was easily separated chromatographically.
With the skipped diene 9 in hand, attempts were made
to selectively epoxidize the vinyl silane moiety of the
molecule. However, reaction of 9 with mCPBA resulted
in epoxidation of the allyl alcohol with almost no trace
of the required silyl epoxide. After many trials and
errors, it was found that increasing steric hindrance at
one end of the molecule could enhance the extent of

T. K. Chakraborty, P. Laxman / Tetrahedron Letters 44 (2003) 4989–4992
4991
products which included the di-epoxide and also a
small amount of the other epoxide by chromatography.
References
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As expected, treatment of 11 with NaN3 in the presence
of NH4Cl led to a very facile opening of the epoxide
ring with complete regioselectivity at the silyl-substi-
tuted center to provide the a-azido-b-hydroxyalkyl-
silane intermediate 12 in 78% yield.7a,b Attempted elon-
gation of the allyl alcohol terminal at this stage by trityl
deprotection, oxidation of the primary hydroxyl group
to the acid via an aldehyde and coupling with H-Gly-
OMe, resulted in an intramolecular 1,3-dipolar cycload-
dition reaction between the azido group and the
‘activated ene’ at the aldehyde stage to give an
unwanted triazoline compound. It was, therefore,
decided first to functionalize the azido terminal of 12 to
attach the C11–C27 residue, leaving the extension of
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rain, J.-L.; Santelli, M. Synthesis 1998, 1015–1018. (c)
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Accordingly, the azido group of 12 was selectively
7d
reduced to the amine 13 using LiAlH4 and after
aqueous work-up, the product was coupled directly
with the known acid 14 that was earlier prepared by us
during the synthesis of crocacin C.4c,e Treatment of 14
with
N-hydroxysuccinimide
using
1-ethyl-3-(3-
hydrochloride
(dimethylamino)propyl)carbodiimide
(EDCI) and a catalytic amount of DMAP furnished an
active ester 15, which was reacted with the amine 13 in
CH2Cl2 for 12 h. After the usual aqueous work-up,
chromatographic purification gave the expected amide
16 in 62% yield (from 12). Protection of the secondary
hydroxyl as the tert-butyldimethylsilyl (TBS) ether fur-
nished compound 17 in 97% yield. This was followed
by deprotection of the trityl-protected primary
hydroxyl to give the (Z)-allylic alcohol 18 in 70% yield.
7. (a) Chakraborty, T. K.; Reddy, G. V. Tetrahedron Lett.
1991, 32, 679–682; (b) Chakraborty, T. K.; Reddy, G. V.
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8. (a) Ager, D. J. Org. React. 1990, 38, 1–223; (b) Ager, D.
J. Synthesis 1984, 384–398; (c) Hudrlick, P. F.; Peterson,
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Hudrlick, P. F.; Peterson, D. J. Am. Chem. Soc. 1975, 97,
1464–1468.
9. For earlier work on the synthesis of enamides, see: (a)
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2001, 3, 3955–3957; (b) Bhattacharjee, A.; Seguil, O. R.;
De Brabander, J. K. Tetrahedron Lett. 2001, 42, 1217–
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Tetrahedron Lett. 2000, 41, 3735–3738; (d) Shen, R.;
Porco, J. A., Jr. Org. Lett. 2000, 2, 1333–1336; (e) Snider,
B. B.; Song, F. Org. Lett. 2000, 2, 407–408; (f)
Kuramochi, K.; Watanabe, H.; Kitahara, T. Synlett
2000, 397–399; (g) Brettle, R.; Mosedal, A. J. J. Chem.
Soc., Perkin Trans. 1 1988, 2185–2195; (h) Hudrlik, P. F.;
Hudrlik, A. M.; Rona, R. J.; Misra, R. N.; Withers, G.
P. J. Am. Chem. Soc. 1977, 99, 1993–1996.
A two-step oxidation process transformed 18 into the
acid 19 in 74% yield. The acid 19 was reacted success-
fully with glycine methyl ester using 1-hydroxybenzotri-
azole (HOBt) and EDCI as coupling reagents to furnish
the expected product 20 in 65% yield. Finally, deprotec-
tion of the TBS group of 20 using tetra-n-butylammo-
nium fluoride (TBAF) in THF led to the formation of
an oxy anion intermediate that underwent a smooth in
situ Peterson elimination process, in 86% yield, to
install the final and most important cis enamide moiety
in the framework with complete stereoselectivity result-
ing in the successful completion of the first total synthe-
sis of our target molecule, crocacin A 1. Our synthetic
crocacin A 1 showed rotation [h]2D0=+106.3 (c 0.08,
MeOH); lit. value: [h]2D2=+109.6 (c 1, MeOH).2 It was
identical in all respects with naturally occurring cro-
cacin A having all spectroscopic data10 matching those
reported for the natural product.2 Further work is in
progress.11
10. Selected physical data for 1. Rf=0.4 (silica, 50% EtOAc
in petroleum ether); [h]2D0=+106.3 (c 0.08, MeOH); IR
(neat): wmax 3255, 2933, 2831, 1757, 1655, 1521, 1451,
1263, 1121, 980 cm−1 1H NMR (acetone-d6, 500 MHz,
;
TMS as reference): l 10.03 (d, J=10.75 Hz, 1H, N10-H),
7.95 (t, J=5.5 Hz, 1H, N3-H), 7.45 (d, J=8.0 Hz, 2H,
aromatic ortho-protons), 7.30 (dd, J=8.0, 7.4 Hz, 2H,
aromatic meta-protons), 7.22 (t, J=7.4 Hz, 1H, aromatic
para-proton), 6.82 (ddt, J=10.75, 8.6, 1.5 Hz, 1H, C9-
H), 6.58 (d, J=16.1 Hz, 1H, C21-H), 6.24 (dd, J=16.1,
6.8 Hz, 1H, C20-H), 6.18 (d, J=16.1 Hz, 1H, C14-H),
6.13 (dd, J=16.1, 8.3 Hz, 1H, C15-H), 6.05 (dt, J=11.2,
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 44 (2003) 4989–4992
8.3 Hz, 1H, C6-H), 5.95 (d, J=11.2 Hz, 1H, C5-H), 5.82
(br d, J=1.0 Hz, 1H, C12-H), 4.77 (q, J=8.6 Hz, 1H,
C8-H), 4.07 (m, 3H, C2-H2, C19-H), 3.68 (s, 3H, C1-
OCH3), 3.52 (s, 3H, C17-OCH3), 3.32 (m, 2H, C7-H2),
3.29 (s, 3H, C19-OCH3), 3.19 (dd, J=9.5, 2.3 Hz, 1H,
C17-H), 2.62 (m, 1H, C16-H), 2.26 (d, J=1.0 Hz, 3H,
C13-CH3), 1.57 (m, 1H, C18-H), 1.18 (d, J=7.1 Hz, 3H,
C16-CH3), 0.84 (d, J=6.8 Hz, 3H, C18-CH3); MS
(LSIMS): m/z: 507 [M++H−CH3OH], 539 [M++H].
an apparently trivial step, by saponification using LiOH
in THF–MeOH–H2O system gave an unexpected cyclized
product. The product, which is yet to be characterized
fully, was possibly formed by an intramolecular nucle-
ophilic attack on the 8,9-enamide moiety by the carboxyl-
ate anion as the signals of the 8,9-olefin protons were
1
missing in its H NMR spectrum along with a large shift
in the 10-NH chemical shift. This necessitated devising an
alternate strategy to synthesize crocacin B 2, which will
be reported in due course.
11. Attempted synthesis of crocacin B 2 from crocacin A 1,