J. Am. Chem. Soc. 1999, 121, 9229-9230
9229
Total Synthesis of Oleandolide
Tao Hu, Norito Takenaka, and James S. Panek*
Department of Chemistry
Boston UniVersity, 590 Commonwealth AVenue
Boston, Massachusetts 02215
ReceiVed July 8, 1999
Over the last three decades, the macrolide antibiotics such as
oleandomycin and erythromycins have had extensive and effective
applications in bacterial chemotherapy. Oleandomycin (1) is
representative of the 14-membered macrolide antibiotics which
is produced by the actinomycete Streptomyces antibioticus,
originally reported by Sobin et al. in 1955.1 The complete structure
of oleandomycin was established in 1960 by Celmer, Woodward,
and co-workers.2 Its absolute configuration was assigned by NMR
techniques in 1965,3 and later confirmed by X-ray analysis.4
Oleandomycin inhibits bacterial RNA-dependent protein synthesis
by binding to the 50-S ribosomal subunit and blocking either
transpeptidation and/or translocation reactions.5 The stereochem-
ical complexity and extensive functionalization of the macrolide
backbones render these molecules synthetically challenging
targets. Three syntheses of oleandolide have been reported, the
later two employed an aldol-based approach to introduce the
polypropionate subunits.6 Herein, we report a highly convergent
total synthesis of oleandolide (2) based on the use of chiral
crotylsilane methodology developed in our laboratories.
Figure 1.
Scheme 1
Our synthesis plan relied upon the use of a diastereoselective
epoxidation of lactone 23 to introduce the C8-epoxide and a Pd-
(0)-catalyzed sp3-sp2 cross-coupling reaction between the left-
and right-hand subunits. These advanced intermediates were
thought to be accessible by the use of Lewis acid promoted
asymmetric crotylations for the introduction of the stereogenic
centers (Figure 1). After conversion of oleandolide into its seco
acid 3, it was further divided into two halves, the left- and right-
hand subunits (C1-C7) and (C8-C13) 4 and 5, respectively.
Further analysis of the individual subunits produced silane
reagents 6-87 of which (S)-7 and (S)-8 were used in two highly
selective double stereodifferentiating anti-crotylations.8 This plan
allowed for the introduction of the (9S)-stereocenter early in the
synthesis, which was critical for an efficient macrocyclization and
the stereoselective introduction of the C8 epoxide.
The synthesis of the left-hand subunit 4 utilizes two asymmetric
crotylations for the introduction of the C3-C4 and C5-C6
stereogenic centers. Its construction began with an asymmetric
crotylation between R-methyl aldehyde 9 and silane (R)-67a
generating homoallylic alcohol 10 (Scheme 1). This syn-selective
crotylation was thought to proceed through an open transition
state where the observed stereochemistry is consistent with an
anti-SE′ mode of addition.8 The homoallylic alcohol 10 was
converted to the silyl protected aldehyde 11 with a three-step
sequence in 87% overall yield. This material was used in a double
stereodifferentiating anti-crotylation reaction with silane (S)-7.7a
The TiCl4 promoted reaction produced the anti homoallylic
alcohol 12 (dr >30:1 5,6-anti/5,6-syn) with Felkin induction. The
silicon protecting group on the aldehyde prevents chelation with
the bidentate Lewis acid while reinforcing Felkin induction, while
the stereochemistry of the emerging methyl group at C6 is
controlled by the absolute chirality of the silane reagent. This
intermediate was converted to acetonide 13 in a three-step
sequence: [i] deprotection of the 1,3-diol (HF‚Py), [ii] selective
protection of the primary hydroxyl as its silyl ether, and [iii]
protection of the C3-C4 diol as its acetonide. The left-hand
subunit was completed by ozonolysis (O3/DMS) of the (E)-double
bond followed by reduction of the crude aldehyde (NaBH4) to
give a primary hydroxyl that was converted directly to the iodide
4 in 91% overall yield.9
The synthesis of the right-hand subunit 5 began with the syn-
selective crotylation of aldehyde 14 with silane (R)-6. This BF3‚
OEt2 promoted reaction gave diol 15 with high selectivity and
installed the C9 stereocenter (Scheme 2).10 This diol was
converted to the R-methyl aldehyde by protection as its bis-TBS-
ether and oxidative cleavage of the double bond (O3/Me2S) to
afford 16. This aldehyde was used in the second double
stereodifferentiating crotylation reaction with chiral â-methylsilane
(S)-87b in CH2Cl2 at -50 °C. The TiCl4-promoted reaction
produced anti homoallylic alcohol 17 (88% yield; dr >30:1, anti/
syn) with Felkin induction.8 This intermediate was converted to
the anti-1,3-diol 18 by oxidation of the trisubstituted double bond
(1) Sobin, B. A.; English, R. A.; Celmer, W. D Antibiot. Annu. 1955, 2,
827-830.
(2) Hochstein, F. A.; Els, H.; Celmer, W. D.; Shapiro, B. L.; Woodward,
R. B. J. Am. Chem. Soc. 1960, 82, 3225-3227.
(3) Celmer, W. D. J. Am. Chem. Soc. 1965, 87, 1797-1799.
(4) Ogura, H.; Furuhata, K.; Harada, Y.; Iitaka, Y. J. Am. Chem. Soc. 1978,
100, 6733-6737.
(5) Wilhem, J. M.; Oleicknick, N. L.; Corcoran, J. W. Antimicrob. Agents
Chemother. 1967, 236-250.
(6) (a) Tatsuta, K.; Kobaysashy W.; Gunji, H.; Masuda, H. Tetrahedron
Lett. 1988, 29, 3975-3978. (b) Paterson, I.; Norcross, R. D.; Ward, R. A.;
Romea, P.; Lister, M. A. J. Am. Chem. Soc. 1994, 116, 12287-12314. (c)
Evans, D. A.; Kim, A. N.; Metternich, R.; Novack, V. J. J. Am. Chem. Soc.
1998, 120, 5921-5942.
(7) (a) Beresis, R. T.; Solomon, J. S.; Yang, M. G.; Jain, N. F.; Panek, J.
S. Org. Synth. 1997, 75, 78-88. (b) Jain, N. F.; Cirillo, P. F.; Schaus, J. V.;
Panek, J. S. Tetrahedron Lett. 1995, 36, 8723-8726.
(8) Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118,
12475-12476.
(9) Corey, E. J.; Pyne, S. G.; Su, W. G. Tetrahedron Lett. 1983, 24, 4883-
4886.
(10) Although the C9-stereocenter would be eventually lost through
oxidation to the ketone, the (9S)-isomer has been shown to be crucial in the
success of the macrocyclization reaction, see ref 6b for further discussion.
10.1021/ja992370x CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/18/1999