Total synthesis of (-)-mycalolide A [11]

Full text of DOI:10.1021/ja994003r

J. Am. Chem. Soc. 2000, 122, 1235-1236
1235
Total Synthesis of (-)-Mycalolide A
Ping Liu and James S. Panek*
Department of Chemistry
Metcalf Center for Science and Engineering
Boston UniVersity, 590 Commonwealth AVenue
Boston, Massachusetts 02215
ReceiVed NoVember 15, 1999
In 1989 Fusetani and co-workers reported the isolation and
planar structure of (-)-mycalolide A (1), a new secondary
metabolite produced by a sponge of the genus mycale sp.1 This
macrolide belongs to a unique class of tris-oxazole containing
natural products including ulapulides,2 halichondramides,3 and
kabiramides,4 which display a range of potent biological activities.
Foremost among these is mycalolide A, which exhibits potent
antifungal activity against a wide array of pathogenic fungi and
cytotoxicity toward B-16 melanoma cells with IC50 values of 0.5-
1.0 ng/mL.1 Mycalolide A also specifically inhibits the actomyosin
Mg2+-ATPase,5 and serves as a novel actin depolymerizing agent
which may find eventual applications in the pharmacological area
for probing actin-mediated cell functions.6 Recently we have
established the relative and absolute stereochemistry of the
mycalolides through a combination of chemical degradation,
extensive H and 13C NMR analysis, and structural correlation
1
Figure 1. Retrosynthetic analysis of mycalolide A (1).
experiments.7 The unique structural features of these tris-oxazole
containing macrolides have provided the motivation for the
development of synthetic strategies toward these natural products.8
In this communication, we report the first total synthesis of (-)-
mycalolide A (1), which also confirms the relative and absolute
stereochemical assignment of this natural product.9
subunits 4 and 5, which served as our initial targets. It was
envisioned that the stereogenic center of 4 could be accessed by
a hydrolytic kinetic resolution (HKR) of terminal epoxide 6,11
and the anti stereochemical relationship at the C8 and C9 in 5
would be established utilizing our chiral silane methodology.12
Synthesis of subunit 4 (Scheme 1), was initiated by HKR of
the racemic epoxide 6.13 Thus, (()-6 was subjected to the
resolution conditions as described by Jacobsen and co-workers,11
providing (R)-6 of 99% ee in 94% yield.14 Nucleophilic epoxide
ring opening using higher order cuprate 9,15 followed by stan-
nane-iodine exchange and protection of the hydroxyl as its
TBDPS ether, furnished 4 in four steps (64% overall).
Construction of subunit 5 and introduction of the C8-C9
stereocenters (Scheme 2) required an anti selective crotylation
with the tris-oxazole aldehyde 8.8f In the presence of the bidentate
Lewis acid TiCl4, the condensation between (S)-7 and 8 provided
homoallylic alcohol 12 in 65% yield with high diastereoselectivity
(anti/syn > 30:1). This condensation proceeded presumably
through a synclinal transition state, where TiCl4 simultaneously
coordinates to the aldehyde carbonyl and the oxazole nitrogen to
form a five-membered chelate, forcing a turnover of the transition
state-controlled π-facial discrimination to deliver high anti
selectivity.16 Methylation of alcohol 12 (Ag2O/MeI), dihydroxy-
lation of olefin 13 (OsO4/TMANO), and cleavage of the resulting
diol (Pb(OAc)4) completed the preparation of 5.
In planning our synthesis of mycalolide A, convergency was
of course an essential component. Our second consideration was
to extend the utility of chiral silane reagents in the area of acyclic
stereocontrol, and to integrate the use of asymmetric catalysis
with stoichiometric processes in assembling complex molecules.
Retrosynthetic analysis of 1 led to fragments 2 and 3 through
cleavage of the macrolide linkage and the C19-C20 olefin bond
(Figure 1). In the synthetic direction, union of 2 and 3 via a
Schlosser-Wittig reaction10 would be followed by macrocycliza-
tion. Further disconnection of 2 at the C6-C7 σ bond produced
(1) Fusetani, N.; Yasumuro, K.; Matsunaga, S.; Hashimoto, K. Tetrahedron
Lett. 1989, 30, 2809-2812.
(2) Roesener, J. A.; Scheuer, P. J. J. Am. Chem. Soc. 1986, 108, 846-
847.
(3) (a) Matsunaga, S.; Fusetani, N.; Hashimoto, K.; Koseki, K.; Noma,
M.; Noguchi, H.; Sankawa, U. J. Org. Chem. 1989, 54, 1360-1363. (b)
Kernan, M. R.; Molinski, T. F.; Faulkner, D. J. J. Org. Chem. 1988, 53, 5014-
5020.
(4) Matsunaga, S.; Fusetani, N.; Hashimoto, K. J. Am. Chem. Soc. 1986,
108, 847-849.
(5) Hori, M.; Saito, S.; Shin, Y.; Ozaki, H.; Fusetani, N.; Karaki, H. FEBS
Lett. 1993, 322, 151-154.
(6) Saito, S.; Watabe, S.; Ozaki, H.; Fusetani, N.; Karaki, H. J. Biol. Chem.
1994, 269, 29710-29714.
The assembly of 2 was accomplished by a Kishi-Nozaki
coupling17 between 4 and 5 (Scheme 3). Treatment of 4 and 5
with NiCl2-CrCl2 in THF/DMF at RT afforded allylic alcohol
14 in 80% yield, as a 1:1 mixture of the stereoisomers. This
material was subjected to Dess-Martin18 oxidation to provide
enone 15 quantitatively. Selective deprotection of the primary
(7) Matsunaga, S.; Liu, P.; Celatka, C. A.; Panek, J. S.; Fusetani, N. J.
Am. Chem. Soc. 1999, 121, 5605-5606.
(8) For earlier synthetic studies on related tris-oxazoles, see: (a) Kiefel,
M. J.; Maddock, J.; Pattenden, G. Tetrahedron Lett. 1992, 33, 3227-3230.
(b) Pattenden, G. J. Heterocycl. Chem. 1992, 29, 607-618. (c) Yoo, S.-K.
Tetrahedron Lett. 1992, 33, 2159-2162. (d) Panek, J. S.; Beresis, R. T.;
Celatka, C. A. J. Org. Chem. 1996, 61, 6494-6495. (e) Panek, J. S.; Beresis,
R. T. J. Org. Chem. 1996, 61, 6496-6497. (f) Liu, P.; Celatka, C. A.; Panek,
J. S. Tetrahedron Lett. 1997, 38, 5445-5448. (g) Celatka, C. A.; Liu, P.;
Panek, J. S. Tetrahedron Lett. 1997, 38, 5449-5452. (h) Chattopadhyay, S.
K.; Pattenden, G. Synlett 1997, 1342-1344. (i) Chattopadhyay, S. K.;
Pattenden, G. Synlett 1997, 1345-1348. (j) Liu, P.; Panek, J. S. Tetrahedron
Lett. 1998, 39, 6143-6146. (k) Liu, P.; Panek, J. S. Tetrahedron Lett. 1998,
39, 6147-6150. (l) Kempson, J.; Pattenden, G. Synlett 1999, 533-536.
(9) A total synthesis of one diastereomer of ulapulide A has been reported
(Chattopadhyay, S. K.; Pattenden, G. Tetrahedron Lett. 1998, 39, 6095-6098),
see ref 7.
(11) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 277, 936-938.
(12) (a) For a review see: Masse, C. E.; Panek, J. S. Chem. ReV. 1995,
95, 1293-1316. (b) For a literature precedent of anti-crotylation, see ref 8j.
(13) Racemic 6 was prepared by epoxidation of tert-butyl vinyl acetate
with m-CPBA, which was in turn prepared according to the procedure in:
Ozeki, T.; Kusaka, M. Bull. Chem. Soc. Jpn. 1966, 39, 1995-1998.
(14) The kinetic resolution yield is expressed as a percentage of the
theoretical maximum yield of 50%; the ee was determined by HPLC analysis
of the phenylthio derivatives of 6 with a Chiracel OD column.
(15) Behling, J. R.; Ng, J. S.; Babiak, K. A.; Campbell, A. L.; Elsworth,
E.; Lipshutz, B. H. Tetrahedron Lett. 1989, 30, 27-30.
(10) (a) Schlosser, M.; Schaub, B. J. Am. Chem. Soc. 1982, 104, 5821-
5823. (b) For a review on the Wittig reaction, see: Maryanoff, B. E.; Reitz,
A. B. Chem. ReV. 1989, 89, 863-927.
10.1021/ja994003r CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/16/2000

1236 J. Am. Chem. Soc., Vol. 122, No. 6, 2000
Communications to the Editor
Scheme 1
Scheme 5
Scheme 2
Scheme 3
fragments using a phosphorus-based olefination was not at first
regarded as a difficult one, given the precedence set by Arm-
strong19 and Evans,20 who successfully constructed an (E)-
olefinated mono-oxazole in their calyculin syntheses. We had also
established precedence in model studies of the construction of
the tris-oxazole (E)-olefin by a similar protocol.8g However, the
olefination between 2 and 3 proved to be challenging. Conven-
tional bases such as LDA, KHMDS, and KOtBu with different
solvent systems failed to deliver a useful yield of the desired
product. Further experiments with hindered amine bases were
carried out to circumvent this problem. Gratifyingly, when
aldehyde 3 and the in situ generated Wittig salt derived from 2
were treated with DBU at 0 °C, the desired product 19 was formed
as a single olefin isomer in 86% yield. After removal of the TBS
group (PPTS/EtOH, 65%), the resulting seco acid was subjected
to Yamaguchi conditions,21 providing macrocycle 20 in 66% yield.
Completion of the synthesis of mycalolide A would now require
the installation of the terminal N-methyl formamide and removal
of the TBDPS hydroxyl protecting group at C3. The former was
accomplished by hydrolysis of the acetal (PPTS/wet acetone,
reflux), followed by vinyl formamide formation (PPTS/
HCONHMe),8a while the deprotection step proceeded smoothly
with TBAF/AcOH.22 The synthetic 1 and natural 1 are identical
Scheme 4
TBDPS ether with nBu4NF followed by conversion of the resulting
alcohol to the benzylic bromide (CBr4/PPh3) and hydrolysis of
the tert-butyl ester with TFA, completed the synthesis of fragment
2.
At this stage, 3 was prepared for coupling, which necessitated
a four-step sequence (Scheme 4) beginning with intermediate 16.7
Removal of the pivalate group (DIBAL-H) also effected the
reduction of the ketone to yield a 3:2 mixture of the epimeric
alcohols, which without separation, was subjected to a Dess-
Martin oxidation18 to provide keto aldehyde 17 in 95% yield (two
steps). Completion of fragment 3 was achieved by deprotection
of the PMB group using DDQ and installation of an acetyl group
at C-32 hydroxyl, which is required in the natural product.
With sufficient quantities of fragments 2 and 3 available,
execution of the Schlosser-Wittig10 coupling would construct the
C19-C20 trans olefin and set the stage for macrocyclization
(Scheme 5). The task of achieving a union between these
1
in all aspects including H NMR, 13C NMR, IR, [R]D, and TLC
Rf values in three different solvent systems.
The first total synthesis of (-)-mycalolide A has been achieved
employing a highly convergent and stereocontrolled strategy. The
synthesis serves to confirm the relative and absolute stereochem-
istry,7 as well as illustrate the application of two complementary
chemical processes in the field of asymmetric synthesis, HKR,
and chiral silane based methodology for the synthesis of complex
molecules.
(16) The anti stereochemical assignment was based upon measurement of
the 3JHa, Hb value (10.8 Hz) in the acetonide derived from 12, see Supporting
Information for details.
(17) (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644-5646. (b) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima,
K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048-6050.
(18) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(19) (a) Zhao, Z.; Scarlato, G. R.; Amstrong, R. W. Tetrahedron Lett. 1991,
32, 1609-1612. (b) Ogawa, A. K.; DeMattei, J. A.; Scarlato, G. R.; Tellew,
J. E.; Chong, L. S.; Armstrong, R. W. J. Org. Chem. 1996, 61, 6153-6161.
(20) Evans, D. A.; Gage, J. R.; Leighton J. L. J. Am. Chem. Soc. 1992,
114, 9434-9453.
Acknowledgment. The authors are grateful to Dr. R. T. Beresis
(Merck & Co., Inc.), Prof. E. N. Jacobsen, Dr. S. E. Schaus (Harvard
University), and Ms. C. A. Celatka for helpful discussions. We are
indebted to Professors S. Matsunaga and N. Fusetani of the University
of Tokyo for providing a reference sample of natural (-)-mycalolide A.
Financial support was obtained from the NIH/NCI (R01CA56304).
Supporting Information Available: Experimental procedures, physi-
1
cal and spectral data for all new compounds; photocopies of H NMR
(21) Inanaga, J.; Hirata, F.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989-1993.
and 13C NMR spectra of synthetic 1, comparison of 1H NMR spectra
between synthetic 1 and natural 1 (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(22) (a) All other reagents surveyed including HF‚pyridine, TBAF, HF,
and LiBF4 led to decomposition of the starting material. (b) For a recent
example of using TBAF/AcOH to remove TBS, see: Smith, A. B., III; Ott,
G. R. J. Am. Chem. Soc. 1998, 120, 3935-3948.
JA994003R