Total synthesis of (+)-crocacin D

Article abstract of DOI:10.1021/ol017092x

(formula presented) The first asymmetric synthesis of (+)-crocacin D (4) is described. The key steps in the sequence are the stereoselective assembly of the stereotetrad via a substrate-controlled aldol reaction and anti-selective reduction, formation of

Full text of DOI:10.1021/ol017092x

ORGANIC
LETTERS
2002
Vol. 4, No. 4
525-527
Total Synthesis of (+)-Crocacin D
John T. Feutrill, Michael J. Lilly, and Mark A. Rizzacasa*
School of Chemistry, The UniVersity of Melbourne, Victoria 3010, Australia
masr@unimelb.edu.au
Received November 21, 2001
ABSTRACT
The first asymmetric synthesis of (+)-crocacin D (4) is described. The key steps in the sequence are the stereoselective assembly of the
stereotetrad via a substrate-controlled aldol reaction and anti-selective reduction, formation of the (E,E)-diene by a Stille cross-coupling between
the stannane 8 and vinyl iodide 9, and the acylation of (Z)-enecarbamate 6 with the acid chloride derived from polyketide fragment 16 which
introduced the (Z)-enamide functionality.
The crocacins A (1), B (2), C (3), and D (4) are a group of
electron transport inhibitors recently isolated from myxo-
bacteria belonging to the Chondromyces genus.1,2 These
unusual linear dipeptides contain a reactive N-acyl enamine
or enamide functionality which is present in a number of
other myxobacteria metabolites3 as well as natural products
isolated from marine sponges.4 Compounds 1-4 moderately
inhibit the growth of a few Gram-positive bacteria and are
potent inhibitors of animal cell cultures and several yeasts
and fungi. The most active is crocacin D (4) which showed
an MIC of 1.4 ng mL-1 against the fungus Saccharomyces
cereVisiae and strong toxicity (IC50 of 0.06 mg L-1) toward
L929 mouse fibroblast cell culture.2
total synthesis of the most active compound in this series,
(+)-crocacin D (4).
We reported the first total synthesis of the parent polyketide
crocacin C (3)5 which served to confirm the absolute
configuration of this compound. This first synthesis has been
followed by two others which are in agreement with our
original assignment.6 We now report the first stereoselective
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497. Chakraborty, T. K.; Jayaprakash, S. Laxman, P. Tetrahedron 2001,
57, 9461. (b) Dias, L. C.; de Oliveira, L. G. Org. Lett. 2001, 3, 3951.
The (Z)-enamide present in crocacin D (4) represents a
synthetic challenge, and we were mindful of the sensitivity
of this functional group. In fact, it has been proposed that
an amount of crocacin C (3) may arise from hydrolysis of
the enamide in the other crocacins during isolation.2 This
functionality is also probably responsible for the biological
activity of this series of compounds since the primary amide
3 is essentially inactive.2 Furthermore, it has been shown
that compounds which contain an enamide functionality are
rendered inactive on chemical modification of this group,
10.1021/ol017092x CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/22/2002

e.g., saturation of the enamide double bond.7 It has therefore
been postulated that the mode of action involves protonation
of the enamide group followed by nucleophilic attack of the
resultant N-acyliminium ion to form an enzyme conjugate.7,8
Paterson aldol reaction between the tin enolate derived from
ketone 10 and cinnamaldehyde (11).5 In this route, we
encountered problems with deprotection of the PMB ether
in the presence of an allylic methoxy group which neces-
sitated excessive protective group manipulation so we chose
to utilize the TIPS-protected chiral ketone 1214 instead
(Scheme 2).
We elected to investigate a synthetic approach to crocacin
D (4) which involves acylation9 of the anion derived from
(Z)-enecarbamate 6 with an appropriate acyl-activated
polyketide fragment 5 as shown in Scheme 1. This would
Scheme 2
Scheme 1
A tin-mediated aldol reaction12,14 between the enolate
derived from ketone 12 and aldehyde 11 gave a high yield
of the syn-syn adduct 13 (77% + 11% mixture of diastereo-
isomers), and subsequent stereoselective directed reduction13
provided pure anti-diol 14 after flash chromatography.
Methylation then afforded the dimethyl ether and desilylation
gave known alcohol 15.5,6 This new sequence to the common
key intermediate 15 is highly efficient (4 steps from aldehyde
11, 48% overall yield) and represents a significant improve-
ment when compared to our original route (8 steps from 11,
39% overall)5 and those of the other reported syntheses of
crocacin C (3) (both 12 steps from 11, 16%6a and 31%6b
overall). Conversion of alcohol 15 into stannane 8 followed
our published proceedure5,15 and Stille coupling16 between
8 and the known iodide 917 mediated by Pd2(dba)3 in the
presence of Ph3As18 gave the diene ester 16 in excellent yield.
The synthesis of the (Z)-enecarbamate 6 began with
aldehyde 1719 (Scheme 3). A modified WHE reaction using
provide a protected (2-trimethylsilylethyl carbamate or Teoc)
enamide10 which would be more stable to subsequent
chemical manipulation and then easily be unveiled in a final
deprotection step. The enecarbamate 6 could be prepared
from the corresponding (Z)-vinylisocyanate 7 by addition of
trimethylsilylethanol9b,10 while the isocyanate 7 is secured
via Curtius rearrangement of the corresponding (Z)-N-acyl
azide. The required precursor to polyketide 5 could be
constructed by a Stille coupling11 between the known
stannane 8 and vinyl iodide 9 based on our successful
approach to crocacin C (3).5 The C18-C19 bond is
constructed using the highly selective substrate-controlled
asymmetric syn-aldol reaction developed by Paterson,12 and
the desired C16-C19 anti-anti-syn stereotetrad is finally
secured by a directed anti-reduction13 of the aldol adduct.
Our earlier report of the synthesis of stannane 8 utilized a
(7) Wu, Y.; Seguil, O. R.; De Brabander, J. K. Org. Lett. 2000, 2, 4241.
(8) Gentle, C. A.; Bugg, T. D. H. J. Chem. Soc., Perkin Trans. 1 1999,
1279.
(9) (a) Shimasaki, H.; Kagechika, H.; Fukasawa, H.; Kawachi, E.; Shudo,
K. Chem. Pharm. Bull. 1995, 43, 100. (b) Roush, W. R.; Pfeifer, L. A. J.
Org. Chem. 1998, 63, 2062.
(10) Smith, A. B., III; Zheng, J. Synlett 2001, 1019.
(11) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. Farina,
V.; Krishnamurthy V. Scott W. J. In Organic Reactions; J. Wiley and
Sons: Paquette, L. A., Ed.; New York, 1997; p 1.
(13) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
(14) (a) Paterson, I.; Tillyer, R. D. Tetrahedron Lett. 1992, 33, 4233.
(b) Paterson, I.; Chen, D. Y.-K.; Acen˜a, J. L.; Franklin, A. S. Org. Lett.
2000, 2, 1513.
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G. N. J. Chem. Soc., Perkin Trans. 1 1999, 2911.
(16) Dominguez, B.; Iglesias, B.; de Lera, A. R. Tetrahedron 1999, 55,
15071.
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A. J. Am. Chem. Soc. 1994, 116, 11287.
526
Org. Lett., Vol. 4, No. 4, 2002

Scheme 3
Scheme 4
the phosphonate 18 (Ar ) o-MeC6H4) described by Ando20
gave the (Z)-R,â-unsaturated ester which on hydrolysis
provided the (Z)-acid 19. In the past, the production of (Z)-
enamides by nucleophilic addition to a vinyl isocyanate has
proved problematic due to isomerization of the double
bond.21 Kitahara recognized that this occurred in the step
involved with the synthesis of the N-acyl azide and found
that the use of diphenylphosphoryl azide (DPPA) in the
presence of NaH at 0 °C reduced isomerization and allowed
for the production of (Z)-vinyl isocyanates.22 To our delight,
treatment of acid 19 with DPPA and NaH gave acyl azide
20 and the corresponding (E)-isomer in a favorable ratio of
5.7:1, respectively, which were easily separated by flash
chromatography. Heating azide 20 in toluene at 110 °C
afforded the (Z)-vinyl isocyanate 7 which could be isolated
but was in practice simply treated with trimethylsilylethanol
in situ9b,10 to afford the enecarbamate 6 in excellent yield.
The final steps to crocacin D (4) are shown in Scheme 4.
Hydrolysis of ester 16 gave the derived acid which was
converted into its sodium salt and treated with oxalyl
chloride. A solution of the anion obtained from deprotonation
of 6 with NaHMDS in THF was then added to the resultant
crude acid chloride and this sequence afforded, after chro-
matographic purification, the desired enamide 21. The
coupling constant measured between H8 and H9 was in
accord with the Z stereochemistry (J8,9 ) 8.1 Hz) while the
chemical shift for H8 (5.49 ppm) indicated the electron
density at this center was reduced in comparison to crocacin
D itself (H8: δ 4.67 ppm)2 imparting the desired increased
stability to the enamide system. Selective deprotection of
the primary alcohol in the presence of the Teoc group was
achieved using HF.pyridine buffered with pyridine23 to
provide alcohol 22. Two-step oxidation (Dess-Martin pe-
riodinane24 and then NaClO2/NaH2PO425) cleanly afforded
the required acid which was coupled26 with glycine methyl
ester to give dipeptide 23 in good yield. Exposure of 23 to
TBAF in THF at 0 °C provided (+)-crocacin D (4) {[R]D
+102.7 (c 0.22, MeOH); lit.2 [R]D +109.6 (c 0.56, MeOH)}
which was easily purified by flash chromatography using
NEt3-deactivated silica gel. The synthetic material was
identical to the natural product by all the usual criteria (1H
and 13C NMR, UV, IR, MS and TLC).
In conclusion, the first asymmetric synthesis of (+)-
crocacin D (4) was achieved in 15 linear steps (4.4% overall
yield) from cinnamaldehyde (11). Key steps in this route
are the concurrent introduction of three of the four asym-
metric centers using a substrate-controlled aldol reaction as
well as a Stille coupling to afford the (E,E)-diene system.
Acylation of an enecarbamate anion with an acid chloride
installed the (Z)-enamide moiety. The synthesis of the other
crocacins as well as analogues using this methodology is
currently underway in our laboratory.
Acknowledgment. We are indebted to Dr. Rolf Jansen
(Gesellschaft fu¨r Biotechnologische Forschung) for copies
1
of the H and 13C NMR spectra of crocacin D as well as a
generous amount of authentic sample. We also gratefully
acknowledge funding from the Australian Research Council.
Supporting Information Available: Characterization
data for key intermediates as well as NMR spectra of
synthetic and natural crocacin D (4). This material is
available free of charge via the Internet at http://pubs.acs.org.
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J. Org. Chem. 2001, 66, 2382.
OL017092X
(18) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(19) Prepared in two steps from 1,5-pentanediol: (1) NaH, TBSCl, 0
°C, THF; (2) Dess-Martin periodinane, CH2Cl2, rt.
(23) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992,
114, 9434. For the selective deprotection of a primary TBS ether in the
presence of Tmse esters using the same conditions, see ref 17b.
(24) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
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Tetrahedron Lett. 2000, 41, 3735.
(22) Kuramochi, K.; Watanabe, H.; Kitahara, T. Synlett 2000, 397.
Org. Lett., Vol. 4, No. 4, 2002
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