11092 J. Am. Chem. Soc., Vol. 122, No. 45, 2000
Panek and Liu
Recently, an assortment of useful chiral synthons has been
made available as a result of advances in the area of asymmetric
catalysis.26 We were interested in the possibility of incorporating
the catalytic asymmetric strategies into our synthesis, and
envisioned that the stereogenic center in the C1-C6 subunit
could be established using Jacobsen’s HKR of terminal ep-
oxides.19 Bearing in mind the protecting group strategy, tert-
butyl 3,4-epoxybutanoate (6) was chosen as the starting point
of the new synthetic sequence (Scheme 2). Thus, the synthesis
of 4 was initiated by a HKR of the readily available racemic
epoxide 6,27 providing (R)-6 with 99% ee in 94% yield.28
Nucleophilic opening of the resolved epoxide using higher order
cuprate 1629 provided homoallylic alcohol 17 in 76% yield.
Protection of the free hydroxyl as its TBDPS ether followed
by stannane-iodine exchange completed the sequence to subunit
4 (four steps, 61% overall yield).
The advantage of this approach to 4 is that there are no
undesired stereochemical products. The C1 oxidation state is
set, since the product, after conversion of the tert-butyl ester to
the carboxylic acid, would be ready for macrolide formation.
Synthesis of the C7-C19 Subunit. The synthesis of this
subunit centers on the installation of the C8/C9 anti relationship
through a stereoselective crotylation reaction of silane (S)-7 and
trisoxazole aldehyde 8. Previous studies from our laboratory
concerning the reaction of the (E)-crotylsilanes with unfunc-
tionalized, achiral aldehydes have demonstrated universal syn
selectivity in the formation of homoallylic alcohols30 and
ethers.31 The stereochemical outcome of these crotylation
reactions can be explained by an anti-SE mechanism32 in which
the absolute stereochemistry of the newly formed methyl-bearing
center is controlled by the chirality of the silane reagent. In the
cases of double stereodifferentiating condensation reactions
between (E)-crotylsilane reagents and chiral, heterosubstituted
aldehydes, anti bond constructions could be achieved.22 Once
again, the chirality of the methyl-bearing center was determined
by the orientation of the C-SiR3 bond, while the configuration
of the hydroxy-bearing center can be rationalized through Felkin
induction33 or through Cram chelation.34
Figure 4. Retrosynthetic analysis of the C20-C35 fragment 3.
Scheme 1
constructed by substrate-controlled 1,3-anti induction. Inspection
of the C30-C35 subunit revealed an anti-anti stereochemical
triad which, we anticipated, could be installed through a double
stereodifferentiating anti crotylation reaction, a valuable exten-
sion of syn crotylation bond construction recently developed
in our laboratories.22 In the following discussion, the successful
implementation of our synthetic plan is detailed.
Results and Discussion
Synthesis of the C1-C6 Subunit. Our initial approach to
the C1-C6 subunit utilized commercially available (R)-1,2,4-
butanetriol as the source of C3 chirality (Scheme 1). Selective
Accordingly, the use of a bidentate Lewis acid (such as TiCl4)
and the condensation between trisoxazole aldehyde 813h and
silane (S)-7,35 in analogy with the reaction of monooxazole
aldehyde and the (S)-silane reagent,36 would provide a homoal-
t
protection of the 1,3-diol was cleanly achieved with Bu2Si-
(OTf)2/2,6-lutidine in CH2Cl2/DMF (1:1 v/v) and afforded the
primary alcohol 12 in 86% yield. This material was subjected
to a Swern oxidation (oxalyl chloride, DMSO, Et3N, -78 °C
to room temperature)23 to provide aldehyde 13. This aldehyde
was homologated to the five-carbon aldehyde 14 through a two-
step process: one-carbon homologation with (methoxymethyl)-
triphenylphosphonium ylide and hydrolysis of the resulting enol
ether with Hg(OAc)2.24 The C1-C6 subunit was completed
using Takai’s CrCl2-mediated olefination protocol,25 furnishing
(E)-vinyl iodide 15 (E:Z ) 6:1) in 74% yield.
Although the described approach to 15 was acceptable in
terms of overall yield, there were two drawbacks. First, the Takai
olefination provided modest selectivity (E:Z ) 6:1), and in our
hands the E/Z olefin isomers could not be separated by SiO2
chromatography. Second, the requirement of a carboxylate at
C1 necessitated a late-stage oxidation.
(26) (a) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds. ComprehensiVe
Asymmetric Catalysis; Springer: New York, 1999; Vols. 1-3. (b) Ager,
D. J., Ed. Handbook of Chiral Chemicals; Marcel Dekker: New York, 1999.
(c) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH Publishers: New
York, 1993. (d) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
John Wiley & Sons: New York, 1989.
(27) Racemic 6 was prepared by epoxidation of tert-butyl vinylacetate
with m-CPBA, which was in turn prepared according to the procedure
described in Ozeki, T.; Kusaka, M. Bull. Chem. Soc. Jpn. 1966, 39, 1995-
1998.
(28) 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.
(29) Behling, J. R.; Ng, J. S.; Babiak, K. A.; Campbell, A. L.; Elsworth,
E.; Lipshutz, B. H. Tetrahedron Lett. 1989, 30, 27-30.
(30) Panek, J. S.; Cirillo, P. F. J. Org. Chem. 1993, 58, 294-296.
(31) Panek, J. S.; Beresis, R. T.; Xu, F.; Yang, M. J. Org. Chem. 1991,
56, 7341-7344.
(32) Hayashi, T.; Konishi, M.; Ito, H.; Kumada, M. J. Am. Chem. Soc.
1982, 104, 4962-4963.
(33) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9,
2199-2204. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61-
70.
(22) (a) Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996,
118, 12475-12476. (b) Jain, N. F.; Cirillo, P. F.; Pelletier, R.; Panek, J. S.
Tetrahedron Lett. 1995, 36, 8727-8730. (c) Panek, J. S.; Beresis, R. T. J.
Org. Chem. 1993, 58, 809-811.
(23) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
(24) Maercker, A. Org. React. 1965, 14, 270-490.
(25) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408-7410.
(34) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748-
2755. (b) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462-468.
(35) For preparation of (S)-7, see: Panek, J. S.; Yang, M. G.; Solomon,
J. J. Org. Chem. 1993, 58, 1003-1010.
(36) Panek, J. S.; Liu, P. Tetrahedron Lett. 1998, 39, 6147-6150.