Total synthesis of (+)-crocacin A

Article abstract of DOI:10.1071/CH03026

The first asymmetric total synthesis of the electron-transport inhibitor crocacin A (1) is described. The key step involved acylation of the anion derived from dienecarbamate (6) with the acid chloride (5) to afford the enamide (14). Desilylation, oxidati

Full text of DOI:10.1071/CH03026

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CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2003, 56, 783–785
Total Synthesis of (+)-Crocacin A∗
John T. FeutrillA and Mark A. RizzacasaA,B
A School of Chemistry, University of Melbourne, Victoria 3010, Australia.
B Author to whom correspondence should be addressed (e-mail: masr@unimelb.edu.au).
The first asymmetric total synthesis of the electron-transport inhibitor crocacin A (1) is described. The key step
involved acylation of the anion derived from dienecarbamate (6) with the acid chloride (5) to afford the enamide (14).
Desilylation, oxidation, andN-deprotectiongaveacid(17), whichwascoupledwithglycinemethylestertoafford(1).
Manuscript received: 24 January 2003.
Final version: 26 April 2003.
8
Crocacin A (1) is a member of a novel group of electron
6
5
transport inhibitors isolated from myxobacteria belonging to
the Chondromyces genus.[1,2] This unusual linear dipeptide
contains a reactive N-acyl enamine or enamide functionality
which is present in several other myxobacteria metabolites[3]
as well as some salicylate-type natural products isolated
from marine sponges.[4] The crocacins A–D (1)–(4) (see
Diagram 1) moderately inhibit the growth of a few Gram-
positive bacteria and are potent inhibitors of animal cell
cultures and several yeast and fungi. The most active is
crocacin D (4) which inhibits the growth of the yeast
Saccharomyces cerevisiae (MIC of 1.4 ng mL−1) and shows
strong toxicity towards L929 mouse fibroblast cell culture
(IC50 of 0.06 mg L−1).[2]
Me Me
11
O
1
NH
OR
O
N
18
H
21
15
OMe OMe
Me
O
Crocacin A; R = Me (1)
Crocacin B; R = H (2)
Me Me
NH2
OMe OMe
Me
NH
O
Crocacin C (3)
Me Me
OMe
O
N
H
OMe OMe
Me
O
O
Some time ago, we reported the first total synthesis of
the primary amide crocacin C (3),[5] which served to confirm
the absolute configuration of the polypropionate fragment
in these compounds. Subsequently, several other groups
reported syntheses of crocacin C (3) which were in agreement
with our stereochemical assignment.[6–8] We also recently
completed the total synthesis of crocacin D (4),[9] the most
active dipeptide in this series, which was closely followed by
a second independent total synthesis.[10] In this preliminary
communication we report the first asymmetric total synthesis
of crocacin A (1).
Crocacin D (4)
Diagram 1.
8
Acylation
Acylation
5
ꢀ
Me Me
ꢀ
12
1
NH
OMe
O
N
H
11
OMe OMe
Me
O
O
Crocacin A (1)
Me Me
H2N
CO2Me
9
A retrosynthetic analysis for crocacin A (1) is shown in
Scheme 1 and is based on the methodology utilized for the
synthesis of crocacin D (4).[9] The N3 C4 peptide bond
could be constructed by simple peptide coupling while we
envisaged that the challenging skipped (Z,Z)-enamide func-
tionality would be formed by acylation[11–15] of the anion
derived from (Z,Z)-dienecarbamate (6) with the known opti-
cally pure acid chloride (5).[9] Dienecarbamate (6) could
be formed by addition of trimethylsilylethanol to the vinyl
isocyanate (7), obtained by Curtius rearrangement of the
corresponding (Z,Z)-N-acylazide, which in turn could be
+
Cl
+
HN
ꢀ
O
OTBS
OMe OMe
(5)
Me
O
O
SiMe3
Isocyanate
addition
(6)
ꢀ
HO
OTBS
N
C
O
(7)
OTBS
(8)
+
Curtius
HO
SiMe3
rearrangement
Scheme 1.
∗ Dedicated to Sir John Cornforth and the Cornforth Foundation for Chemistry.
© CSIRO 2003
10.1071/CH03026
0004-9425/03/080783

784
J. T. Feutrill and M. A. Rizzacasa
Cs2CO3, NaI, CuI
HO
OTBS
RO
HO
OTBS
(9) R = H
(10) R = Ms
MsCl, Et3N
80%
(8)
1) Dess-Martin reagent
2,6-lutidine, 0ºC
P2-Ni, H2, EDA
2) NaClO2, NaH2PO4
75% for 2 steps
(11)
HO
OTBS
HO
91% for 2 steps
O
R
OTBS
(12) R = OH
NaH, (PhO)2P(O)N3, 0ºC
44% 2:1 Z:E
(13) R = N3
SiMe3
Toluene, 110ºC
N
HN
O
(7)
OTBS
OTBS
Toluene, 110ºC
C
O
65%
O
TMS
(6)
Scheme 2.
NaHMDS, −78˚C
then (5) in THF
secured by partial reduction of 1,4-alkadiyne (8) followed by
oxidation and acylazide formation.
(6)
Me Me
37%
N
Teoc
OR
Me
O
The synthesis of the required diencarbamate (6) is outlined
in Scheme 2. The known alcohol (9)[16] was converted to
the mesylate (10) which underwent smooth copper-mediated
coupling[17] with propargyl alcohol under slightly modified
conditions[18] to afford the sensitive 1,4-alkadiyne (8). Partial
reduction of crude (8) to (Z,Z)-1,4-diene (11) was achieved
using freshly prepared ‘P-2 Ni’(borohydride-reduced nickel)
catalyst[19,20] under a hydrogen atmosphere in the pres-
ence of ethylenediamine (EDA).[21] This catalyst was far
superior to Lindar’s catalyst which gave erratic results. It
should be noted that the 1,4-diene (11) was far more stable
than its 1,4-alkadiyne precursor (8). Buffered Dess–Martin
periodinane-mediated[22] oxidation of alcohol (11) to the
aldehyde followed by further oxidation[23] to the acid (12)
and subsequent conversion to the azide using Kitahara’s
procedure[24] (NaH, (PhO)2P(O)N3)[25] minimized double-
bond isomerization and provided (Z,Z)-N-acylazide (13)
along with the corresponding (E,Z)-isomer which were eas-
ily separable by flash chromatography. Heating a solution of
(13) in toluene afforded isocyanate (7) which, without isola-
tion, was treated with trimethylsilyl ethanol in boiling toluene
to afford the required carbamate (6) in good yield.
The final sequence to crocacinA (1) is shown in Scheme 3
and begins with the formation of the anion of (6) using
NaHMDS (sodium hexamethyldisilazide) as a base at low
temperature. Addition of the anion solution to a solution of
freshly prepared acid chloride (5)[9] in tetrahydrofuran (THF)
followed by stirring at −78◦C and quenching the reaction
at this temperature afforded enamide (14) protected as the
Teoc (2-trimethylsilylethylcarbamate) derivative. This reac-
tion was sensitive to temperature as well as scale and the acid
obtained by concomitant hydrolysis of acid chloride (5) could
also be isolated and recycled. This resulted in a 37% yield of
OMeOMe
HF.pyridine
pyridine
87%
(14) R = TBS
(15) R = H
1) Dess-Martin reagent
2,6-lutidine, 0˚C
2) NaClO2, NaH2PO4
Me Me
N
R
O
OH
82% for 2 steps
Me
O
OMeOMe
TBAF, 0˚C
(16) R = Teoc
(17) R = H
NaHCO3,
(PhO)2P(O)N3
Me Me
NH
O
OMe
N
H
ClH3N
CO2Me
Me
O
O
OMeOMe
23% for 2 steps
Crocacin A (1)
Scheme 3.
intermediate enamide (14) (52% based on recovered acid).
TheTBS(t-butyldimethylsilyl)etherwasselectivelyremoved
in the presence of the Teoc group using HF–pyridine com-
plex buffered with pyridine[26] to yield alcohol (15) which
was smoothly oxidized to the aldehyde using Dess–Martin
reagent[22] in the presence of 2,6-lutidine. This hindered
base effectively suppressed isomerization of the conjugated
alkene. Further oxidation to the acid afforded (16), which
was treated with TBAF (tetra n-butylammonium fluoride)
to remove the Teoc group. The crude acid (17) was then
coupled[27] with glycine methyl ester to give pure crocacin A
(1) in low yield after chromatographic purification (2.0 mg,
23% for 2 steps). This coupling reaction also afforded an iso-
meric diene as a by-product. It is noteworthy that the skipped
diene system was stable until this late stage and insights
into the mechanism of this unexpected isomerization will
be reported in due course. The synthetic crocacin A (1) was
identical in all respects to the natural material including the
sign and absolute value of the specific rotation.†
19
22
† Data for synthetic (1): [α]D + 126.8 (c 0.077 in MeOH), lit.[2] [α]D + 109.6 (c 1.0 in MeOH). νmax (film)/cm−1 3254, 2973, 2930, 1747, 1658,
1612, 1526, 1442, 1366, 1266, 1202, 1090, 974, 751, 695. λmax (log ε) (MeOH)/nm 206, 211(sh), 216(sh), 255(4.52), 264(sh), 283, 292, 300(sh).
δH (400 MHz, [D6]acetone) 10.05 (1 H, br d, J10.4, H10), 7.98 (1 H, m, H3), 7.46 (2 H, d, J 7.2, H23), 7.30 (2 H, dd, J 11.2 and 8, H24), 7.22

Total Synthesis of (+)-Crocacin A
785
Conclusion
[5] J. T. Feutrill, M. J. Lilly, M. A. Rizzacasa, Org. Lett. 2000,
2, 3365.
The first total synthesis of crocacin A (1) has been achieved
utilizing the acylation of the enecarbamate (6) with acid chlo-
ride (5) as the key step to introduce the sensitive enamide
group. The carbamate (6) was synthesized by a route starting
with known alcohol (9). Studies towards optimization of this
route for the production of crocacin A (1) and B (2) as well
as analogues are currently underway.
[6] T. K. Chakraborty, S. Jayaprakash, Tetrahedron Lett. 2001,
41, 497.
[7] T. K. Chakraborty, S. Jayaprakash, P. Laxman, Tetrahedron
2001, 57, 9461.
[8] L. C. Dias, L. G. de Oliveira, Org. Lett. 2001, 3, 3951.
[9] J. T. Feutrill, M. J. Lilly, M. A. Rizzacasa, Org. Lett. 2002,
4, 525.
[10] T. K. Chakraborty, P. Laxman, Tetrahedron Lett. 2002, 43, 2645.
[11] R. Brettle, A. J. Mosedale, J. Chem. Soc., Perkin Trans. 1988,
2185.
[12] W. R. Roush, L. A. Pfeifer, J. Org. Chem. 1998, 63, 2062.
[13] W. R. Roush, L. A. Pfeifer, T. G. Marron, J. Org. Chem. 1998,
63, 2064.
[14] A. B. Smith III, J. Y. Zheng, Synlett 2001, 1019.
[15] A. B. Smith III, J. Y. Zheng, Tetrahedron 2002, 58, 6455.
[16] S. D. Najdi, M. M. Olmstead, N. E. Schore, J. Organomet.
Chem. 1992, 431, 335.
[17] M. A. Lapitskaya, L. L. Vasiljeva, K. K. Pivnitsky, Synthesis
1993, 65.
[18] A. Spinella, T. Caruso, M. Martino, C. Sessa, Synlett 2001,
1971.
Acknowledgments
We thank the Melbourne Research Grants Scheme for fund-
ing and Dr Rolf Jansen (Gesellschaft für Biotechnologische
Forschung) for kindly providing an authentic sample of
crocacin A (1) as well as copies of the NMR spectra.
Accessory Material
A comparison of the 1H and 13C NMR spectra for syn-
thetic and natural crocacin A (1) is available from Australian
Journal of Chemistry, untilAugust 2008, or from the authors.
[19] H. C. Brown, C. A. Brown, J. Org. Chem. 1963, 85, 1005.
[20] C. A. Brown, V. K. Ahuja, J. Org. Chem. 1973, 38, 2226.
[21] C. A. Brown, V. K. Ahuja, J. Chem. Soc., Chem. Commun.
1973, 553.
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(1 H, dd J 7.2 and 6.8, H25), 6.82 (1 H, dd, J 10.4 and 8.8, H9), 6.58 (1 H, d, J 16, H21), 6.24 (1 H, dd, J 16 and 7.2, H20), 6.19 (1 H, d, J 15.6, H14), 6.14
(1 H, dd J 16 and 8, H15), 6.05 (1 H, dt, J 11.2 and 8.8, H6), 5.95 (1 H, d, J 11.2, H5), 5.81 (1 H, br s, H12), 4.77 (1 H, dt, J 8.4 and 8.4, H8), 4.09–4.07
(3 H, m, H2 and H19), 3.68 (3 H, s, 10-CH3), 3.52 (3 H, s, 17-OCH3), 3.32 (2 H, dd, J 8.8 and 8.4, H7), 3.29 (3 H, s, 19-OCH3), 3.18 (1 H, dd, J 9.6 and 2,
H17), 2.61 (1 H, m, H16), 2.27 (3 H, s, 13-CH3), 1.56 (1 H, m, H18), 1.18 (3 H, d, J 6.8, 16-CH3), 0.86 (3 H, d, J 7.2, 18-CH3). δC (100 MHz, [D6]acetone)
170.6, 168.9, 164.4, 149.8, 143.4, 137.8, 137.7, 135.2, 132.5, 130.3, 129.3, 128.2, 127.2, 125.8, 121.7, 120.9, 104.3, 87.0, 81.7, 61.4, 56.4, 52.3, 43.4, 41.6,
40.8, 26.2, 19.2, 13.6, 10.1. HRMS (ESI) found: 561.2947. Calc. for C31H42N2NaO+6 [M + Na+]: 561.2941.