Synthesis of the apoptosis inducing agent apoptolidin. Assembly of the C(16)-C(28) fragment.

Article abstract of DOI:10.1021/ol005769v

[reaction--see text] A stereoselective synthesis of the C(16)-C(28) fragment of the apoptosis inducing agent apoptolidin is described. Key steps include two propionate aldol reactions and a stereoselective Mukaiyama aldol addition of enolsilane 19 to beta

Full text of DOI:10.1021/ol005769v

ORGANIC
LETTERS
2000
Vol. 2, No. 10
1439-1442
Synthesis of the Apoptosis Inducing
Agent Apoptolidin. Assembly of the
C(16)−C(28) Fragment
Gary A. Sulikowski,* Wai-Man Lee, Bohan Jin, and Bin Wu
Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012,
College Station, Texas 77842-3012
sulikowski@mail.chem.tamu.edu
Received March 7, 2000
ABSTRACT
A stereoselective synthesis of the C(16)−C(28) fragment of the apoptosis inducing agent apoptolidin is described. Key steps include two
propionate aldol reactions and a stereoselective Mukaiyama aldol addition of enolsilane 19 to â-methoxy aldehyde 4.
In an effort to identify natural products with selective
cytotoxicity against tumor cells, Hayakawa and co-workers
established several immortalized cell lines in order to screen
soil samples for specific apoptosis inducing agents.1 Utilizing
this screening method, the Hayakawa group reported in 1997
the identification of apoptolidin produced by an actinomycete
identified as Nocardiopsis sp.2 Significantly, apoptolidin was
found to induce cell death in E1A transformed cells but not
in normal cells. The two-dimensional structure of apoptolidin
was reported in 1997 and the stereochemical assignment
followed in 1998 based on extensive NMR analysis and
degradation studies. The structure of apoptolidin consists of
an aglycon (1) and two sugar units located at C(9) and C(27).
The unique pattern of cytotoxicity and molecular architecture
of apoptolidin stimulated our interest in this natural product
as a synthetic target.3 In this Letter we describe the
stereocontrolled assembly of the C(16)-C(28) fragment (2)
of apoptolidin.
Apoptolidinone (1) consists of a 20-membered macrolac-
tone incorporating a unique triene unit and 12 stereogenic
centers, primarily located within the C(16)-C(28) fragment
(Scheme 1). For the purpose of retrosynthetic analysis, the
C(16)-C(28) substructure (2) is represented as the open-
chain tautomer 3. Disconnection at the C(19)-C(20) carbon-
carbon bond of 3 leads to aldehyde 4 and ketone 5. In the
synthetic direction, a Mukaiyama aldol addition of an
enolsilane derivative of 5 to â-alkoxy aldehyde 4 would
proceed with the desired stereoselectivity due to the pro-
pensity of enolsilane additions to â-alkoxy aldehydes to occur
with high anti 1,3-asymmetric induction.4 Turning our
attention to ketone 5, we required two consecutive syn
propionate aldol reactions with opposite absolute stereo-
(1) (a) Hayakawa, Y.; Sohda, K. Y.; Furihata, K.; Kuzuyama, T.; ShinYa,
K.; Seto, H. J. Antibiot. 1996, 49, 974-979. (b) Hayakawa, Y.; Sohda, K.;
Shinya, K.; Hidaka, T.; Seto, H. J. Antibiot. 1995, 48, 954-961.
(2) (a) Hayakawa, Y.; Kim, J. W.; Adachi, H.; Shin-ya, K.; Fujita, K.-
i.; Seto, H. J. Am. Chem. Soc. 1998, 120, 3524-3525. (b) Kim, J. W.;
Adachi, H.; ShinYa, K.; Hayakawa, Y.; Seto, H. J. Antibiot. 1997, 50, 628-
630.
(3) For recent synthetic studies, see: (a) Schuppan, J.; Ziemer, B.; Koert,
U. Tetrahedron Lett. 2000, 41, 621-624. (b) Nicolaou, K. C.; Li, Y.;
Weyershausen, B.; Weit, H.-x. J. Chem. Soc., Chem. Commun. 2000, 307-
308.
10.1021/ol005769v CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/13/2000

Reductive cleavage of 7 using Na(CN)BH3 in trifluoroacetic
acid afforded 8 as a ca. 1:5 mixture of C(17) and C(19)
p-methoxyphenyl ethers which were readily separated by
flash chromatography.10 The major isomer was methylated,
the p-methoxyphenyl group was removed, and the resulting
alcohol was oxidized to complete the synthesis of aldehyde
4.
Scheme 1
The synthesis of aldehyde 12, which can be viewed as a
pseudo enantiomer of aldehyde 4, started from methyl ester
9, readily derived from L-ascorbic acid in six easily scalable
steps (Scheme 3).11 Reduction of 9 using LiAlH4 in THF
Scheme 3
chemical control. In this case Crimmins’ aldol methodology
presented an attractive solution since this would require the
preparation of a single acyloxazolidinethione in order to
access both syn aldol isomers.5
Our first objective was the preparation of aldehyde 4
starting from known tris-trimethylsilyl ether 6, readily derived
from L-malic acid (Scheme 2).6,7 Anisylidene formation under
Scheme 2
followed by acetonide removal employing palladium(II)
catalysis and per-silylation provided ent-6.12 Next, conversion
to the 1,3-anisylidene followed by methylation of the
remaining primary alcohol gave 10. We found that reductive
cleavage of 10 with DIBAL in dichloromethane resulted in
selective protection of the C(25) alcohol as its p-methoxy-
(6) Kocienski, P. J.; Yeates, C.; Street, S. D. A.; Campbell, S. F. J. Chem.
Soc., Perkin Trans. 1 1987, 2183-2187.
Noyori conditions followed by benzylation of the resulting
(7) Sprung, M. M.; Nelson, L. S. J. Org. Chem. 1955, 20, 1750-1756.
(8) (a) Breuilles, P.; Oddon, G.; Uguen, D. Tetrahedron Lett. 1997, 38,
6607-6610. (b) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett.
1980, 21, 1357-1358.
primary alcohol gave 1,3-anisylidene 7 as the only isomer.8,9
(4) (a) Evans, D. A.; Yang, M. G.; Dart, M. J.; L.; Duffy, J. L.; Kim, A.
S. J. Am. Chem. Soc. 1995, 117, 9598-9599. (b) Evans, D. A.; Dart, M.
J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322-4343.
(c) Reetz, M. T.; Jung, A. J. Am. Chem. Soc. 1983, 105, 4833-4845.
(5) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883-7884. (b) Crimmins, M. T.; Chaudhary, K. Org. Lett.
2000, 2, 775-777. (c) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.;
Huang, T.-Y. J. Am. Chem. Soc. 1993, 115, 2613-2621. (d) Nerz-Stormes,
M.; Thorton, E. R. J. Org. Chem. 1992, 56, 2489-2498.
(9) All new compounds gave characterization data that are fully consistent
with the assigned structures.
(10) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1984,
2371-2374.
(11) (a) Wei, C. C.; Debernardo, S.; Tengi, J. P.; Borgese, J.; Weigele,
M. J. Org. Chem. 1985, 50, 3462-3467. (b) Tanaka, A.; Yamashita, K.
Synthesis 1987, 570-573.
(12) Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki, H. Tetrahedron
Lett. 1985, 26, 705-708.
1440
Org. Lett., Vol. 2, No. 10, 2000

benzyl ether. A related contrasteric regioselective reduction
of an anisylidene has been reported and attributed to a
chelated intermediate.13 In the current example, we attribute
this regioselectivity to a chelating effect imposed by the
neighboring C(28) methyl ether.14 Finally, benzylation of the
C(27) alcohol, removal of the p-methoxybenzyl group, and
Swern oxidation provided aldehyde 12. Aldol reaction
between 12 and acyloxazolidinethione 13 using 1 equiv of
TiCl4 with (-)-sparteine furnished syn aldol 14 in 96% yield
(>95:5 diastereoselectivity). The assigned syn aldol stereo-
chemistry of the major isomer was consistent with the
observed coupling constant between H(24) and H(25) which
was 3.9 Hz.15 Turning our attention to establishing the
C(25)-C(27) relative stereochemistry, 14 was converted to
acetonide 15 by the reaction sequence shown in Scheme 3
and the relative stereochemistry assigned on the basis of the
Rychnovsky acetonide method.16 Accordingly, the assigned
C(25)-C(27) anti relative stereochemistry was consistent
with the observed chemical shifts for the acetonide methyl
groups and central carbon (cf. 15).
employed 2.1 equiv of TiCl4 in combination with 2.1 equiv
of (-)-sparteine to afford syn aldol adduct 17 in 93% yield
and excellent diastereoselectivity.17 The relative stereochem-
istry assignment of 17 was based on 13C NMR analysis of
the appropriate acetonide derivative.18 Exchange of the
oxazolidinethione auxiliary with N,O-dimethylhydroxylamine
gave the corresponding Weinreb amide which following silyl
protection (TESCl, imidazole) of the remaining hydroxyl
group produced 18.19 Addition of (methoxymethoxy)methyl-
lithium, generated by the in situ transmetalation of (methyl-
oxymethyoxy)methyltributylstannane, to 18 afforded the
corresponding ketone.20 During the course of investigations
into double diastereoselective Mukaiyama aldol addition
reactions, Evans observed that (Z)-enolsilanes favor 1,3-anti-
dimethyl relationships across the emerging keto group as well
as high levels of anti 1,3-asymmetric induction in Lewis acid
promoted enolsilane additions to â-alkoxy aldehydes.4 With
these reports in mind, we prepared (Z)-enolsilane 19 using
Masamune’s base21 and were delighted to observe a single
aldol adduct upon Lewis acid promoted coupling of 4 and
19. Simultaneously, with the formation of a newly formed
carbon-carbon bond, we observed loss of the C(23) silyl
protecting group. The aldol adduct (3) was assigned syn
relative stereochemistry on the basis of an observed 3.3 Hz
coupling constant between H(19) and H(20). Unambiguous
assignment of the C(19)/C(20) and C(22)/C(23) relative
stereochemistry was achieved using the [13C]acetonide
analysis method.
In preparation for a second aldol reaction, silyl protection
(TBSOTf, 2,6-lutidine) of 14 followed by NaBH4 reduction
and Swern oxidation gave aldehyde 16 in 69-80% overall
yield (Scheme 4). Optimal conditions for effecting aldol
reaction between 13 and 16, in the desired non-Evans sense,
Scheme 4
Reduction of ketone 3 with NaBH4 provided triols 20a
and 20b; assignment of the relative configuration of C(19)-
C(23) followed formation and 13C NMR analysis of the
C(19)-C(21) and C(21)-C(23) acetonides. Treatment of 20a
with dimethoxypropane and PPTS afforded the C(19)-C(21)
acetonide, assigned the anti configuration on the basis of
13C NMR acetonide analysis (Scheme 5). The corresponding
Scheme 5
C(21)-C(23) acetonide 22 was derived from 20a following
acetylation of the C(19) hydroxyl group and assigned syn
relative stereochemistry. Taken together, acetonides 21 and
22 confirm the assignment of the C(19)/C(20) and C(22)/
C(23) relative stereochemistry as anti.
(13) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001-7031.
Org. Lett., Vol. 2, No. 10, 2000
1441

Having defined the full stereochemical assignment of 3,
we removed the C(25) TBS protecting group (TBAF, -10
°C) to give pyran 2 as a ca. 5:1 mixture of C(21) anomers
(Scheme 6). The major anomer is assumed to possess the
natural apoptolidin configuration.
Acknowledgment. Support by the National Institutes of
Health and the Welch Foundation (A-1230) is gratefully
acknowledged. High-resolution mass spectra were obtained
at Texas A&M University Mass Spectrometry Service Center
by Drs. Lloyd Sumner and Barbara P. Wolf on a VG
Analytical 70S high-resolution, double-focusing, sectored
(EB) mass spectrometer. Funds to purchase the VG magnetic
instrument were provided by a grant from the National
Science Foundation (CHE-8705697).
Scheme 6
Supporting Information Available: Spectroscopic and
analytical data for compounds 2-4, 6-8, 10-12, 14-19,
and 21-22 and proof of stereochemistry of 17. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL005769V
(15) Heathcock, C. H.; Pirrung, M. C.; Sohn, J. E. J. Org. Chem. 1979,
44, 4294-4299.
(16) (a) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9-17. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R.
Tetrahedron Lett. 1990, 31, 7099-7100.
(17) In Crimmins’ original report (ref 5), Hunig’s base provided superior
selectivity in the non-Evans aldol reaction manifold; in the case of 16 we
found that Hunig’s base led to diminished chemical yield. In contrast (-)-
sparteine provided both high stereoselectivity and chemical yield.
(18) See Supporting Information.
(19) (a) Basha, A.; Lipton, M.; Weibreb, S. M. Tetrahedron Lett. 1977,
4171-4174. As in the case of oxazolidinones, the order of transamination
and beta hydroxy protection is important, see: (b) Evans, D. A.; Gage, J.
R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453.
(20) Johnson, C. R.; Medich, J. R. J. Org. Chem. 1988, 53, 4131-4133.
(21) Masamune, S.; Ellingboe, J. W.; Choy, W. J. Am. Chem. Soc. 1982,
104, 5526-5528.
In summary, we have completed a stereocontrolled syn-
thesis of the C(16)-C(28) fragment of apoptolidin as well
as full stereochemical assignment based on the Rychnovsky
acetonide method. Progress on the total synthesis of apop-
tolidin will be reported in due course.
(14) For a discussion of aluminum as a chelating Lewis acid, see: (a)
Ooi, T.; Kagoshima, N.; Maruoka, K. J. Am. Chem. Soc. 1997, 119, 5754-
5744. (b) Ooi, T.; Uraguchi, D.; N.; K.; Maruoka, K. J. Am. Chem. Soc.
1998, 120, 5327-5328.
1442
Org. Lett., Vol. 2, No. 10, 2000