epoxidation. Fortunately, however, we succeeded in the
purification of 16 by a PCC oxidation method we developed.7
The successive Lewis acid-mediated rearrangement of 16
affords the allylic alcohol 17, whose stereochemistry has been
determined by 1D and 2D NMR.8 Thus, we have succeeded
in the diastereoselective construction of the hydroxy-bearing
carbon center. The low yield of the allylic alcohol comes
from the formation of a reductive rearrangement product.8
The successive ozonization-cleavage of the CdC bond of
17 gives the open chain keto-aldehyde, which actually exists
in the semiacetal 18 in two isomers (1/1). Protection of the
hydroxy group of 18 with DMP followed by reduction of
ketone carbonyl with NaBH4 in situ gives a mixture of 19
as four isomers (5/5/1/1). We have not made any attempt to
carry out the stereocontrolled reduction of the carbonyl for
the reasons mentioned above. The major reduction product
would be of the â-hydroxy configuration on the basis of
either the transition-state analysis or the final configuration
examination of 2D NMR spectroscopy of the acetonides of
20.9 Finally, the transacetalization of 19 with 1,3-thiopro-
panol, followed by the protection of two hydroxy groups
with TBSCl and then dehydroxylation of the tertiary hydroxy,
gives the compound 21 with the terminal double bond for
the later functionization, which is deacetalized to yield the
intermediate 7 as a mixture of two isomers (5/1).
Scheme 4
22.5c Oxidation of the hydroxy group of 22 with PDC and
then removal of the sulfone with 6% sodium amalgam gives
the compound 23 as a mixture of two isomers (5/1)
corresponding to the open-chain polyhydroxy intermediate
5.10 The successive full deprotection of the carbonyl and the
hydroxy groups with hydrofluoric acid lead to both the
deprotection and the auto-spirocyclization to form the final
spiroketals as an oily mixture of only two C1′′-epimers (5/
1).11 The isolated samples of 4a and 4b (10 mg and 2 mg)
have been obtained by HPLC for structure determination by
1D and 2D NMR and mass spectroscopy.12 Thus, we have
succeeded in the stereocontrolled synthesis of the key mother
spiroketals of the HIV-1 protease inhibitive didemnaketals.
Further total synthetic studies and bioactive investigations
are ongoing.
The coupling of 6 and 7 is carried out as showed in
Scheme 4. Deprotonation of the sulfone 6 with n-BuLi and
then quenching with aldehyde 7 yield the R-hydroxy sulfone
Acknowledgment. This work was supported by NSFC
(No. 29972019 and 29925205), FUKTME of China, the
Yang Teachers’ Fund of the Ministry of Education, and the
Fund of the Ministry of Education (No. 99209).
(4) The literature reported the rearrangement of simple epoxide; here,
we also had success with R-hydroxy epoxide, and the low yield possibly
came from the influence of hydroxy the hydroxy substituent; see: (a)
Gignere, R. J.; Hoffmann, M. R. Tetrahedron Lett. 1981, 22, 5039-5042.
(b) Reggl, L.; Friedman, S.; Wender, I. J. Org. Chem. 1958, 23, 1136.
(5) (a) Ward, D. E.; Rhee, C. K. Synth. Commun. 1988, 18, 1927-1933.
(b) Corey, E. J.; Pyne, S. G.; Su, W. Tetrahedron Lett. 1983, 24, 4883. (c)
Morimoto, Y.; Mikami, A.; Kuwabe, S.; Shirahama, H. Tetrahedron:
Asymmertry 1996, 7, 3371-3390.
(6) (a) Neidigk, D. D.; Morrison, H. J. Chem. Soc., Chem. Commun.
1978, 601-602. (b) Neichinasi, E. H. J. Org. Chem. 1970, 35, 2010-2012.
(7) We have found that the mixture of 10 and its syn-epoxide isomer,
when treated with 1.2 equiv of PCC (pyridine chlorochromate) in dry CH2-
Cl2 for ∼2 h at room temperature, yields the complex products and the
unchanged 10, which is readily isolable.
OL007016E
(10) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeren, T. R.
Tetrahedron Lett. 1976, 17, 3477.
(11) Collington, E. W.; Finch, H.; Smith, I. J. Tetrahedron Lett. 1985,
26, 681-684.
(12) 4a/b. Spectral data of 4a: 1H NMR δ 5.01 (s, 1H), 4.96 (s, 1H),
4.17 (d, 1H, J ) 5.2 Hz), 3.91 (ddd, 1H, J ) 11.5, 5.4, 2.7 Hz), 3.86 (d,
1H, J ) 6.0 Hz), 3.56 (ddd, 1H, J ) 11.7, 6.0, 2.2 Hz), 2.59-0.88 (m,
10H), 2.31 (s, 3H), 1.75 (s, 3H), 1.15 (d, 3H, J ) 7.3 Hz), 0.87 (d, 3H, J
) 6.6 Hz); 13C NMR δ 209.1, 143.9, 113.4, 98.7, 79.3, 78.3, 71.1, 67.3,
44.0, 40.1, 35.3, 31.5, 27.9, 24.8, 24.4, 22.0, 20.9, 18.2. Spectral data of
4b: 1H NMR δ 5.05 (s, 1H), 4.94 (s, 1H), 4.14 (brs, 1H), 4.09 (d, 1H, J
)3.9 Hz), 3.88 (ddd, 1H, J )11.6, 5.7, 2.8 Hz), 3.60 (ddd, 1H, J ) 12.0,
4.0, 2.4 Hz), 2.31-0.88 (m, 10H), 2.32 (s, 3H), 1.73 (s, 3H), 1.18 (d, 3H,
J ) 7.3 Hz), 0.88 (d, 3H, J ) 6.5 Hz); 13C NMR δ 209.5, 143.3, 112.1,
98.8, 79.2, 76.8, 71.3, 67.6, 44.0, 40.1, 31.9, 29.7, 28.2, 24.7, 24.6, 22.1,
20.6, 19.3.
(8) Tu, Y. Q.; Sun, L. D.; Wang, P. Z. J. Org. Chem. 1999, 64, 629-
633.
(9) The NOESY spectra for the major isomer of the acetonides of 20
show the strong correlations between H-5 and H-6 and between both H-5
and H-6 and the same acetonide methyl.
Org. Lett., Vol. 3, No. 6, 2001
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