Stereoselective synthesis of the C18-C28 fragment of apoptolidin

Article abstract of DOI:10.1016/S0040-4039(99)02134-6

An efficient, stereocontrolled synthesis of the C 18-C28 segment of apoptolidin has been achieved. Key steps are a stannous triflate-mediated aldol reaction, the acylation of a Weinreb amide with an E-alkenyl lithium reagent and the dihydroxylation of a C19-C20 double bond. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02134-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 621–624
Stereoselective synthesis of the C18–C28 fragment of apoptolidin
Julia Schuppan, Burkhard Ziemer and Ulrich Koert ∗
Institut für Chemie, Humboldt Universität zu Berlin, Hessische Straße 1-2, D-10115 Berlin, Germany
Received 22 October 1999; accepted 11 November 1999
Abstract
An efficient, stereocontrolled synthesis of the C18–C28 segment of apoptolidin has been achieved. Key steps are
a stannous triflate-mediated aldol reaction, the acylation of a Weinreb amide with an E-alkenyl lithium reagent and
the dihydroxylation of a C19–C20 double bond. © 2000 Elsevier Science Ltd. All rights reserved.
Specific apoptosis inducers for tumor cells may be useful for treating certain types of cancer.
Apoptolidin, a natural product isolated from Nocardiopsis sp., induces apoptotic cell death in rat glia
cells transformed with the E1A oncogene (IC50 11 ng/ml).1 The relative and absolute configuration
of apoptolidin was established by combined spectroscopic methods.2 Apoptolidin is a 20-membered
macrolide with a side chain at C19 containing a THP-actetal unit. A D-oleandrose-L-olivomycose
disaccharide is located at C27, while a novel sugar, 6-deoxy-4-O-methyl-L-glucose is attached at C9.
As part of a project directed towards the total synthesis of apoptolidin we report here on the
stereoselective synthesis of the C18–C28 fragment 1.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02134-6
tetl 16062

622
Scheme 1.
Starting point for the synthesis of 1 was the β-ketoester 2. A Ru-BINAP catalyzed hydrogenation3
of 2 gave the β-hydroxyester 3 (97% ee determined by HPLC) (Scheme 1). The latter was TBDMS-
protected and subsequently reduced to the aldehyde 4. A stereocontrolled stannous triflate-mediated
aldol reaction4 of the aldehyde 4 with the β-keto imide dipropionyl building block 55 provided the
aldol product 6 in 97% yield with a 96:4 ratio of diastereomers. The stereochemical assignment of the
two new stereocenters was later confirmed by X-ray structure analysis (vide infra). An anti-selective
reduction6 of the 1,3-hydroxyketone functionality in 6 with Me4NBH(OAc)3 gave the 1,3-diol 7 in 74%
yield (stereoselectivity >95:5). A hydroxyl directed Weinreb transamidation provided the corresponding
Weinreb amide4,7 in 81% yield, which was double TMS-protected to yield the silylether 8. As a truncated

623
model for the apoptolidin skeleton a three-carbon organolithium reagent was generated from E-1-bromo-
propene and allowed to react with the Weinreb amide 8 to give the propenyl ketone 9 in 87% yield.
The final synthetic sequence focused on the introduction of the vicinal diol at C19/20 and the ring
closure to the pyranoide ketal. When the α,β-unsaturated ketone 9 was subjected to an asymmetric
Sharpless dihydroxylation8 with AD-mix α, a 3:1 mixture of the two diastereomeric diols was isolated
in 98% yield (Scheme 2). Compound 10 was formed as the major isomer. Treatment of 10 with
PPTS in MeOH/CH2Cl2 cleaved the TMS ethers and induced the ketal formation leading to the target
compound 1.9 The separation of the two dihydroxylation stereoisomers was possible by chromatography
at this stage. The diol 1 was converted into the acetonide 12. An X-ray crystal structure analysis of
12 unambiguously proved the stereochemical assignment of the dihydroxylation reaction as well as the
outcome of the previous steps.10 In order to investigate the effect of substrate control versus ligand
control in the dihydroxylation step the reaction of 9 with AD-mix β was carried out. Again, compound
10 was isolated as the main diastereomer. This indicates that in this case substrate control beats ligand
control. Conducting the dihydroxylation with the cyclized precursor 11 did not increase the selectivity.
In summary, a highly efficient, stereocontrolled route to the C18–C29 fragment of apoptolidin was
developed including full stereochemical proof.
Scheme 2.

624
Acknowledgements
This work was supported by the Fonds der Chemischen Industrie and the Schering AG. We gratefully
acknowledge stimulating discussions with Prof. Dr. U. Eder.
References
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A.; Kim, A. S.; Metternich, R.; Novack, V. J. J. Am. Chem. Soc. 1998, 120, 5921-5942.
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7. Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 4171-4174; Levin, J. L.; Turos, E.; Weinreb, S. M. Synth.
Commun. 1982, 12, 989-993.
8. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; I. Ojima, Ed.; VCH, Weinheim: New York, 1993; pp.
227-272.
9. Spectroscopic data for 1: [α]D=+40; c 0.06, CHCl3; IR (film): 3443, 2929, 1460, 1252, 1112, 836, 777 cm−1; 1H NMR (300
MHz, CDCl3): 0.04 (2 s, 6H, Si-CH3), 0.84–0.88 (m, 12H, CH3-24, Si-C(CH3)3), 1.06 (d, J=6.6 Hz, 3H, CH3-22), 1.25
(d, J=6.6 Hz, 3H, H-18), 1.50 (ddd, J=14.4/7.4/3.9 Hz, 1H, H-26), 1.73 (ddd, J=14.4/8.2/4.2 Hz, 1H, H-26), 1.79–1.86 (m,
1H, H-24), 2.08 (dq, J=10.9/6.6 Hz, 1H, H-22), 3.26 (s, 3H, CH3O-21), 3.25- 3.32 (m, 2H, H-28), 3.31 (s, 3H, CH3O-28),
3.41–3.44 (m, 1H, H-20), 3.76 (dd, J=10.9/4.7 Hz, 1H, H-23), 3.85–3.92 (m, 2H, H-25, H-27), 4.05 (dq, J=6.4/2.4 Hz, 1H,
H-19); 13C NMR (75 MHz, CDCl3): −4.7, −3.9 (Si-CH3), 5.0 (22-CH3), 11.4 (24-CH3), 18.2 (Cq, Si-C(CH3)3), 21.0 (C-
18), 25.9 (CH3, Si-C(CH3)3), 35.9 (C-22), 38.5 (C-26), 38.6 (C-24), 48.7 (21-OCH3), 58.9 (28-OCH3), 66.6 (C-19), 69.4,
69.6 (C-25, C-27), 72.6 (C-23), 75.3 (C-20), 77.2 (C-28), 102.6 (C-21); HRMS (EI) calcd: 361.2410 (M+−C3H7O2); found:
361.2413.
10. Crystal data for 12: Monoclinic, P21, a=8.416(2) Å, b=15.727(5) Å, c=11.472(3) Å, β=108.89(3)°, V=1436.8(7) Å3, Z=2.
4867 independent reflections were collected in the range of 2.28°<2θ<25.00°, being used for the structural refinement by
full-matrix least-squares on F2 using the SHELXL 98 package to a final R=0.0816, wR2=0.1758 and abs. struc. param.
−0.4(5). The data has been deposited at the Cambridge Crystallographic Data Centre (CCDC 136117), 12 Union Road,
Cambridge CB2 1EZ, UK.