an early stage in the synthesis. This approach provides a non-
carbohydrate-derived synthesis of analogues of griseusin A
(1).
similar to that observed in analogous aldol products.10,13
Furthermore the 3′,5′-syn stereochemistry of aldol adduct (10)
was confirmed by 13C NMR analysis14 of the acetonide
derivative (15) which was formed after removal of the chiral
auxiliary (Figure 1). The stereochemistry of the minor aldol
products (11 and 12) was established in a similar manner.
The functionality on the C3 side chain of the key naph-
thalene (5) was derived from aldehyde (6). In turn the re-
quired (2R,3R,5R)-aldehyde (6) was prepared via anti aldol
condensation of acyloxazolidinone (8) [derived from ox-
azolidinone (7)8] with (3R)-aldehyde (9) (Scheme 1). Alde-
Scheme 1
Figure 1.
Reductive removal of the chiral auxiliary from the triethyl-
silyl ether (13) of major aldol adduct (10) afforded alcohol
(14) which underwent oxidation to aldehyde (6) using TPAP/
NMO without epimerization.
Union of aldehyde (6) to a naphthalene fragment with the
oxygenation pattern required for assembly of naphthol (5),
initially focused on the use of the organometallic reagents
derived from 3-bromo-1,4,5-trimethoxynaphthalene. This
approach resulted in substantial quantities of 1,4,5-trimeth-
oxynaphthalene being recovered from the reaction together
with elimination of the â-triethylsilyloxy group from the
aldehyde. The three oxygenated substituents on the naph-
thalene ring resulted in a marked increase in the basic
character of the naphthyl anion15 such that protonation by
the aldehyde was occurring.
In light of the difficulties experienced with the above
approach, we next decided to effect C-arylation of aldehyde
(6) using a titanium naphtholate generated from naphthol
(16). This strategy was based on work by Bigi et al.16 and
Casiraghi et al.,17 who have effected regiospecific ortho-
arylation of R-alkoxy and R-amino carbonyl compounds.
hyde (9) was readily available from commercial (3R)-ethyl
3-hydroxybutanoate by protection of the hydroxyl group as
a tert-butyldimethylsilyl ether, lithium borohydride reduction
of the ester to an alcohol,9 followed by oxidation (TPAP,
NMO) to the aldehyde (9).10
(12) Compound 10 was obtained as a colorless oil. Rf: 0.56 (7:3 light
petroleum-ethyl acetate). Found: C, 66.0; H, 7.4; N, 2.6%. C29H41NO6Si
requires C, 66.0; H, 7.8; N, 2.65%. [R]D: -56.11 (c 1.788, CHCl3). υmax
(film), cm-1: 3589-3280 (m, OH), 1784 (s, OCdON), 1703 (s, NCd
OC), 1389 (m, C-N), and 1105 (m, C-O). δH (200 MHz, CDCl3): 0.08
(6H, s, SiMe2), 0.86 (9H, s, But), 1.18 (3H, d, J6′,5′ 6.2 Hz, H6′), 1.67 (1H,
ddd, Jgem 14.3, J4′A,3′ 9.7, and J4′A,5′ 9.7 Hz, H4′A), 1.94 (1H, ddd, Jgem
14.3, J4′B,3′ 3.8 or 1.6, and J4′B,5′ 1.6 or 3.8 Hz, H4′B), 2.60 (1H, dd, Jgem
13.6 and J 9.9 Hz, CHCHAPh), 3.15 (1H, dd, Jgem 13.6 and J 3.3 Hz,
CHCHBPh), 3.54 (1H, d, J 2.2 Hz, OH), 3.94-4.01 (1H, m, H3′), 4.01-
4.17 (3H, m, H5, H5′), 4.53-4.69 (1H, m, H4), 4.61 (2H, s, OCH2Ph),
5.31 (1H, d, J2′,3′ 7.7 Hz, H2′), and 7.17-7.41 (10H, m, Ph). δC (50 MHz,
CDCl3): -5.0, -4.2 (CH3, SiMe2), 17.6 (quat., CMe3), 24.2 (CH3, C6′),
25.6 (CH3, CMe3), 37.7 (CH2, CHCH2Ph), 42.2 (CH2, C4′), 55.2 (CH, C4),
66.2 (CH2, C5), 69.6 (CH, C5′), 72.6 (CH, C3′), 72.8 (CH2, OCH2Ph), 78.8
(CH, C2′), 127.0, 127.8, 128.1, 128.2, 128.6, 129.2 [CH, 2 × Ph, 135.1
(quat., CHCH2Ph), 137.1 (quat., OCH2Ph), 153.3 (quat., C2), and 172.1
(quat., C1′). m/z (LSIMS, NBA matrix): 528 (MH+, 18%).
Precedent for the desired anti aldol coupling between
oxazolidinone (8) and aldehyde (9) was based on work by
Evans et al.11 using tin(II) enolates of oxazolidinones in the
presence of TMEDA. Thus, the stannous enolate of oxazo-
lidinone (8) [generated using Et3N and Sn(OTf)2] was reacted
with aldehyde (9) in the presence of TMEDA to afford an
80% yield of the aldol products (10, 11, and 12) in a 12:3:1
ratio. The aldol products (10, 11, and 12) were separated by
flash chromatography and the 2′,3′-anti stereochemistry of
the major product (10)12 was supported by the magnitude of
the 2′,3′-vicinal coupling constant (J2′,3′ 7.7 Hz) which was
(13) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem Soc. 1992,
114, 9434.
(14) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099.
(15) Jung, M. E.; Hagenah, J. A. J. Org. Chem. 1987, 52, 1889.
(16) (a) Bigi, F; Casnati, G.; Sartori, G.; Araldi, G. Gazz. Chim. Ital.
1990, 120, 413. (b) Bigi, F.; Casnati, G.; Sartori, G.; Araldi, G.; Bocelli,
G. Tetrahedron Lett. 1989, 30, 1121. (c) Bigi, F.; Casnati, G.; Sartori, G.;
Dalprato, C.; Bortolini, R. Tetrahedron Asymmetry 1990, 1, 861.
(8) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757.
(9) Mori, K.; Maemoto, S. Liebigs Ann. Chem. 1987, 863.
(10) Ohta, K.; Miyagawa, O.; Tsutsui, H.; Mitsunobu, O. Bull. Chem.
Soc. Jpn. 1993, 66, 523.
(11) Evans, D. A.; Gage, J. R.; Leighton, J. L.; Kim, A. S. J. Org. Chem.
1992, 57, 1961.
1460
Org. Lett., Vol. 1, No. 9, 1999