An expeditious synthesis of the C(38)-C(54) halichondrin B subunit

Full text of DOI:10.1021/jo981181e

6770
J . Org. Chem. 1998, 63, 6770-6771
An Exp ed itiou s Syn th esis of th e C(38)-C(54)
Ha lich on d r in B Su bu n it
Steven D. Burke,* Brian C. Austad,† and Amy C. Hart
Department of Chemistry, University of WisconsinsMadison,
1101 University Avenue, Madison, Wisconsin 53706-1396
Received J une 23, 1998
Halichondrin B (Figure 1) is the most potent of a class of
polyether macrolides isolated in low yield (1.8 × 10-8 to 4.0
× 10-5 %) from a variety of sponge genera.1 With a tubulin-
based mechanism of action as an antimitotic agent, hali-
chondrin B displays an in vitro IC50 value of 0.3 nM against
L1210 leukemia and remarkable in vivo activities against
various chemoresistant human solid tumor xenografts.2
Despite its extremely limited supply from natural sources,
halichondrin B has been recommended by the National
Cancer Institute for stage A preclinical development.2c,d
Synthetic efforts have been described by several groups,3 and
one total synthesis of halichondrin B has been reported.3d
Our earlier synthetic work toward halichondrin B focused
on the C(1)-C(15) and C(20)-C(36) segments of the natural
product.3g-i In this paper, we report the synthesis of the
C(38)-C(54) subunit 1 (Scheme 3) in its natural configura-
tion. Efficient construction of the K, L, M, and N rings,
including 10 asymmetric centers, was accomplished by
exploiting the local C2-symmetry about the C(44)-spiroketal
carbon.
F igu r e 1.
Sch em e 1
Sch em e 2
The known (S)-epoxide 2, available from (S)-malic acid4a-c
or by hydrolytic kinetic resolution of racemic 2,4d,e was
opened with the ethylenediamine complex of lithium acetyl-
ide (Scheme 1).5 Isomerization of the crude terminal alkyne
with KOt-Bu afforded the thermodynamically favored in-
ternal alkyne 3 as the sole product. Reduction of 3 with LAH
in THF resulted in the E-allylic alcohol 4 as a single
geometrical isomer.6 Allylic alcohol 4 was subjected to
J ohnson ortho ester Claisen rearrangement conditions7 to
provide the ethyl ester 5.
Claisen self-condensation of 5 (Scheme 2) was effected by
slow addition of LHMDS (2.5 equiv) and TMEDA (5.0 equiv)
to the ester in THF over 4.5 h at 0 °C, affording the â-keto
ester in good yield. Decarboalkoxylation under Krapcho
conditions8 cleanly provided the C2-symmetric ketone 6 as
* To whom correspondence should be sent. Phone: (608) 262-4941. Fax:
(608) 265-4534. E-mail: burke@chem.wisc.edu.
† Current address: Eisai Research Institute, 4 Corporate Drive, Andover,
MA 01810-2441.
(1) (a) Hirata, Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701. (b) Pettit,
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Schmidt, J . M.; Cerny, R. L.; Hooper, J . N. A.; Rutzler, K. C. J . Med. Chem.
1991, 34, 3339. (c) Pettit, G. R.; Tan, R.; Gao, F.; Williams, M. D.; Doubek,
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a viscous oil (96%). Asymmetric dihydroxylation9 with
Sharpless’s AD-mix-R at 0 °C afforded the C2-symmetric
tetraol, as virtually a single diastereomer, thus setting the
C(40), C(41), C(47), and C(48) stereocenters in one step. Acid-
catalyzed spiroketalization10 of the tetraol with camphor-
sulfonic acid in PhH/MeOH (1:1) yielded the thermodynamic
ratio (1.1:1.0) of the C2-symmetric 1,7-dioxaspiro[5.5]undecane
S0022-3263(98)01181-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/05/1998

Communications
J . Org. Chem., Vol. 63, No. 20, 1998 6771
Sch em e 3
7, and the isomeric, undesired 1,6-dioxaspiro[4.5]decane 8
as a separable mixture of isomers. Operationally, the
mixture of ketals 7 and 8 was debenzylated via hydrogenoly-
sis and then equilibrated with catalytic trifluoroacetic acid
in refluxing methanol to the more favorable thermodynamic
mixture of desired 9, plus 10 and 11 (5:2:1). After separa-
tion, ketals 10 and 11 were recycled to 9 by reexposure to
the equilibrating conditions.
The facial selectivity for the AQN-mediated Sharpless
asymmetric dihydroxylation9,18 of the terminal alkene in 14
proved unsatisfactory for establishing the C(53)-C(54) diol.
Alternatively, homoallylic alcohol 14 was converted to the
corresponding BOC carbonate with excess (BOC)2O and
DMAP. Treatment of the BOC carbonate with iodine
monobromide at -80 °C afforded the iodo carbonate 15 in
excellent yield (96%) and diastereoselectivity (>18:1).19 The
conversion of 15 to triol 16 was best accomplished with 0.5
M aqueous LiOH in DME. After 15 h, the reaction contents
were neutralized and concentrated. The resulting solids
were treated with CSA in refluxing benzene, which ac-
complished the reclosure of the lactone ring and provided
triol 16 in excellent yields from 15. With the global
protecting group scheme for the synthesis of halichondrin
B in mind, the primary alcohol in 16 was selectively
protected as a TBDPS ether, and the two secondary alcohols
were then protected with TIPSOTf and DMAP to afford the
desired C(38)-C(54) segment 1, suitable for subunit cou-
pling.
Selective oxidation of the primary alcohol groups in tetrol
9 (Scheme 3) with tetrapropylammonium perruthenate (VII)
(TPAP)11 afforded the C2-symmetric bislactone 12 as a white
crystalline solid, and confirmation of relative and absolute
stereochemistry was secured by X-ray crystal structure
determination. Monofunctionalization at one end of the C2-
symmetric bislactone was required to desymmetrize 12 and
introduce the C(51)-C(54) side chain.12 To avoid an unfa-
vorable statistical mixture of recovered starting material and
mono- and difunctionalized products, partial conversion of
12 to 13 was executed by lactone olefination13 to the vinyl
ether with 0.7 equivalents of the Tebbe reagent, followed
by hydroboration/oxidation14 with 9-BBN/aq NaBO3. Oxida-
tion of primary alcohol 13 with the Dess-Martin periodi-
nane15 provided the corresponding aldehyde, which was
taken crude into a chelation-controlled allylation.16 TiCl4
promoted reaction with allyltributylstannane17 at -78 °C
provided the homoallylic alcohol 14 as a single diastereomer,
The synthesis of lactone 1 was accomplished in 18 steps
from the known epoxide 2 in an overall 8% yield (based on
recovered starting materials). Work toward the total syn-
thesis of halichondrin B is ongoing and will be described as
developments merit.
1
within the detection limits of H NMR.
Ack n ow led gm en t. Support of this research from the
NIH (Grant CA 74394), Pfizer, and Merck is gratefully
acknowledged, as is support of the departmental NMR
facilities by grants from the NIH (ISIO RRO 8389-01) and
the NSF (CHE-9208463).
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J O981181E
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