Total synthesis of (+)-crocacin C

Article abstract of DOI:10.1021/ol016845c

equation presented The total synthesis of (+)-crocacin C is described. The convergent asymmetric synthesis relies on the use of a regio- and diastereoselective epoxidation of an allylic alcohol with m-CPBA followed by epoxide opening with Me₂Cu

Full text of DOI:10.1021/ol016845c

ORGANIC
LETTERS
†
2001
Vol. 3, No. 24
3951-3954
Total Synthesis of (+)-Crocacin C
Luiz C. Dias* and Luciana G. de Oliveira
Instituto de Qu´ımica, UniVersidade Estadual de Campinas, UNICAMP, C.P. 6154,
13083-970 Campinas, SP, Brazil
ldias@iqm.unicamp.br
Received October 2, 2001
ABSTRACT
The total synthesis of (+)-crocacin C is described. The convergent asymmetric synthesis relies on the use of a regio- and diastereoselective
epoxidation of an allylic alcohol with m-CPBA followed by epoxide opening with Me2CuCNLi2 and a Stille cross-coupling between E-vinyl
stannane 5 and E-vinyl iodide 6 to establish the (E,E)-dienamide moiety.
The crocacins A-D (1-4) are a group of compounds that
are regularly found in the extracts of Chondromyces crocatus
and Chondromyces pediulatus and represent a second novel
group of modified peptides from C. crocatus (Scheme 1).1,2
positive bacteria and are potent inhibitors of animal cell
cultures and several yeasts and fungi. Crocacin D shows
higher biological activity against Saccharomyces cereVisiae
as well as higher toxicity in L929 mouse fibroblast cell
culture when compared to crocacins A-C. The relative
configurations of crocacins A-D were proposed by Jansen
and co-workers by means of molecular modeling studies and
NOE experiments.2 The relative and absolute configurations
for crocacin C have been recently confirmed by its first total
synthesis as being 6S,7S,8R,9S.3
Scheme 1
To provide material for more extensive biological evalu-
ation, along with access to novel analogues, we have
undertaken the total synthesis of the polyketide crocacin C.3
Not surprisingly, our first disconnection, summarized in
Scheme 2, involved cleavage of the dienamide portion (C3-
C4 bond) to give E-vinyl stannane 5 (C1-C3 fragment) and
E-vinyl iodide 6 (C4-C11 fragment) bearing four stereogenic
centers.4 Of the available options, we speculate that the C6
and C7 stereocenters could be constructed by epoxide
opening with Me2CuCNLi2. Epoxy alcohol 8 may be further
dissected in a straightforward manner to give allylic alcohol
9. The desired C8 and C9 stereocenters in 9 might be
established through a boron enolate mediated aldol reaction.
The C1-C3 fragment 5 is viewed as arising from an R,â-
acetylenic ester 7 by a stereoselective conjugate organostan-
Crocacin C (3) is a structure fragment of 1, 2, and 4. The
crocacins moderately inhibit the growth of a few Gram-
† This paper is dedicated to the Brazilian Chemical Society (SBQ).
* FAX: +55-19-3788-3023.
(1) Kunze, B.; Jansen, R.; Hofle, G.; Reichenbach, H. J. Antibiot. 1994,
47, 881.
(2) (a) Jansen, R.; Washausen, P.; Kunze, B.; Reichennach, H.; Hofle,
G. Eur. J. Org. Chem. 1999, 1085. (b) Kunze, B.; Jansen, R.; Sasse, F.;
Hofle, G.; Reichenbach, H. J. Antibiot. 1998, 51, 1075.
(3) As this work was in progress, the first two asymmetric total syntheses
of crocacin C were described: (a) Feutrill, J. T.; Lilly, M. J.; Rizzacasa,
M. A. Org. Lett. 2000, 2, 3365. (b) Chakraborty, T. K.; Jayaprakash, S.
Tetrahedron Lett. 2001, 42, 497.
(4) The numbering of 3 follows that suggested in ref 2a.
10.1021/ol016845c CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/02/2001

adduct 11 in 85% isolated yield and greater than 95%
diastereomeric purity (Scheme 3).6 Transamidation of aldol
11 followed by treatment of the intermediate Weinreb amide
with TBSOTf and 2,6-lutidine or with TESCl and imidazole
in DMF yielded only R,â,γ,δ-unsaturated Weinreb amide
12 in good yields.7 On the basis of this result aldol adduct
11 was converted to primary alcohol 13 after protection of
the OH-function as its TBS ether followed by removal of
the oxazolidinone auxiliary with LiBH4 in MeOH (70% yield,
two steps).6
Scheme 2
Primary alcohol 13 was submitted to oxidation under the
standard Swern conditions,8 and the unpurified aldehyde was
directly subjected to a Horner-Emmons homologation9 with
the requisite stabilized reagent to give an intermediate R,â-
unsaturated ester that was treated with 2 equiv of diisobut-
ylaluminum hydride at 0 °C, producing allylic alcohol 14 in
82% isolated yield for the three-step sequence. It was with
some gratification that epoxidation of allylic alcohol 14 with
m-CPBA proceeded with high regio- and diastereoselectivity
from the opposite side of the C9 tert-butyldimethylsilyl group
to give the anti-epoxy alcohol 15 in high purity (dr 92:8,
94% yield).4,10 It is noteworthy that the diastereoselectivity
associated with this epoxidation was exceptional and com-
pared in both yield and selectivity to related transformations
described earlier by Isobe and later on by Miyashita.10
Epoxide opening proceeded smoothly with high regioselec-
tivity after treatment of epoxy alcohol 15 with Me2CuCNLi2
to give diol 16 in good yield and selectivity, which possesses
the anti-anti-syn stereochemistry concerning the four con-
tiguous stereocenters (Scheme 4).11,13
nyl cuprate addition method, providing control for the E
geometry of the double bond.
Synthesis of fragment C4-C11 began with the known (-)-
acyloxazolidinone, (R)-10, which was most conveniently
prepared by acylation of the corresponding (+)-(R)-oxazo-
lidinone, as described by Evans et al. (Scheme 3).5
Scheme 4
Scheme 3
A sequence of TBS removal and selective protection of
the primary alcohol functionality (TBDPSCl, imidazole,
DMAP, -5 °C) gave 17 in 86% yield (two steps).13
(6) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) Evans, D. A.; Taber, T. R. Tetrahedron Lett. 1980, 21, 4675.
(c) Evans, D. A.; Ng, H. P.; Clark, J. S.; Rieger, D. L. Tetrahedron 1992,
48, 2127.
(7) Levin, J. I.; Turos, E.; Weinreb, S. Synth. Commun. 1982, 12, 989.
(8) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(9) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
(10) (a) Isobe, M.; Kitamura, M.; Mio, S.; Goto, T. Tetrahedron Lett.
1982, 23, 221. (b) Maruyama, K.; Ueda, M.; Sasaki, S.; Iwata, Y.;
Miyazawa, M.; Miyashita, M. Tetrahedron Lett. 1998, 39, 4517.
Asymmetric aldol addition of the boron enolate derived
from oxazolidinone (-)-10 with cinnamaldehyde gave aldol
(5) Evans, D. A.; Gage, J. R. Org. Synth. 1989, 68, 83.
3952
Org. Lett., Vol. 3, No. 24, 2001

To confirm the relative stereochemistry of the aldol bond
construction and epoxidation steps the 1,3-diols 16 and 17
were transformed to their corresponding isopropylidene
acetals 19 and 20 in good yields (Scheme 5).12,13 The large
21 as the major isomer (E:Z 87:13, 70% yield) after
purification by column chromatography. Ester-amide ex-
change was accomplished by treatment of vinylstannane 21
with Me3Al and NH4Cl in toluene at 50 °C, giving E-
vinylstannane 5 as a crystalline solid after purification by
column chromatography (72% yield, mp 39.5 °C). The
illustrated NOESY interactions between vinylic hydrogen and
the hydrogens of the tributyltin group confirmed the E-
geometry for vinylstannane 5.
Scheme 5
The two-step sequence from 7 to 5 proceeded in an overall
yield of 50.4% and was amenable to a multigram scale-up.
With synthesis of the requisite C1-C3 and C4-C11 frag-
ments in hand, their coupling was undertaken. This was done
by using Stille coupling conditions (Scheme 7).18
Scheme 7
coupling constants between Ha-Hc (11.7 Hz) and Hc-Hd
(11.5 Hz), together with the small observed value between
Hb-Hc (4.4 Hz), unambiguously established the proposed
relative stereochemistry for C6-C7 bond in 19.13 The
stereochemistry of the secondary alcohols at C7 and C9 was
determined on the basis of the 13C NMR analysis of the
corresponding 1,3-diol acetonide 20. 13C NMR resonances
at 23.6, 25.8, and 100.5 are characteristic of an anti
acetonide.12
With compound 17 in hand, only four synthetic operations
remained to arrive at an intermediate suitable for coupling
with E-vinyl stannane 5 (Scheme 4). Methylation with KH
and MeI followed by removal of the TBDPS protecting group
at C5 gave primary alcohol 18 (96% yield, two steps). Dess-
Martin oxidation gave the intermediate aldehyde.14 All that
remained was to carry out the necessary Takai olefination
reaction. Treatment of the unpurified aldehyde with CrCl2
and CHI3 produced E-vinyl iodide 6 (E:Z > 95:05), corre-
sponding to the C4-C11 segment of crocacins in 67%
overall yield for the two-step sequence.15 The 14-step
sequence starting from (-)-10 proceeded in 23% overall
yield and is amenable to a multigram scale-up.
Treatment of a solution of E-vinylstannane 5 and E-vinyl
iodide 6 in NMP with a catalytic amount of Pd2(dba)3 in the
presence of AsPh3 at 60 °C afforded (+)-crocacin C in 69%
yield after purification by silica gel column chromatography
(petroleum ether/EtOAc, 2:1 then 1:3) followed by prepara-
tive RP-HPLC.19,20
The spectroscopic and physical data [1H and 13C NMR,
IR, [R]D, Rf] were identical in all respects with the published
data.2a,20
The total synthesis of crocacin C has been completed.
Notable features of this approach include convergence, a
regio- and diastereoselective epoxidation of an allylic alcohol,
and a Stille cross-coupling between a vinyl stannane and a
vinyl iodide. The synthesis required 15 steps (longest linear
sequence) and produced the desired product in 16% overall
yield. As a result, the route to crocacin C presented here is,
Our approach for preparation of fragment C1-C3 was
initiated with R,â-acetylenic ester 7 following the strategy
developed by Piers et al. (Scheme 6).16,17 Conjugate orga-
(12) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099. (c) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc.
Chem. Res. 1998, 31, 9.
(13) Diols 16 and 17 showed spectral data and physical properties
identical in all respects with published data. See ref 3.
(14) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(b) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (c) Ireland, R.
E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
Scheme 6
(15) (a) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408. (b) Paterson, I.; Lombart, H.; Allerton, C. M. N. Org. Lett. 1999, 1,
19.
(16) Piers, E.; Morton, H. E. J. Org. Chem. 1980, 45, 4263.
(17) Brabander, J. D.; Vandewalle, M. Synthesis 1994, 855.
(18) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Duncton, A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1235.
(c) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813.
(19) (a) Farina, V. Pure Appl. Chem. 1996, 68, 73. (b) Farina, V.;
Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(20) New compounds and the additional isolatable intermediates gave
satisfactory 1H and 13C NMR, IR, HRMS, and analytical data. Yields refer
to chromatographically and spectroscopically homogeneous materials.
nostannyl cuprate addition to ethyl 2-butynoate 7 (-100 to
-78 °C) led to the E-tributylstannyl R,â-unsaturated ester
(11) Johnson, M. R.; Kishi, Y. Tetrahedron Lett. 1979, 20, 4347.
Org. Lett., Vol. 3, No. 24, 2001
3953

in principle, readily applicable for the preparation of cro-
cacins A, B, and D. Further optimization of the synthesis,
as well as application to the preparation of novel structural
analogues of crocacin C is underway, and the results will
be described in a full account of this work.
Carol H. Collins for helpful suggestions about English
grammar and style and Prof. Pedro Lozano for a sample of
AsPh3.
Supporting Information Available: Experimental details
for key transformations, spectral data for key intermediates,
and spectroscopic data for synthetic and natural crocacin C
(3). This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. We are grateful to FAPESP (Funda-
c¸a˜o de Amparo a Pesquisa do Estado de Sa˜o Paulo) and
CNPq (Conselho Nacional de Desenvolvimento Cient´ıfico
e Tecnolo´gico) for financial support. We thank also Prof.
OL016845C
3954
Org. Lett., Vol. 3, No. 24, 2001