°C provided the desired aldol adduct in 85% yield as a 10:1
ratio of inseparable diastereomers as described by Phillips.11
An ensuing transamidation of 6 to the Weinreb amide under
standard condition of the MeN(H)OMe·HCl salt and imida-
zole furnished chiral amide 9 in 91% yield.12 With amide 9
in hand, a directed Simmons-Smith cyclopropanation under
the Charette protocol afforded cyclopropyl carbinol 10 in
91% over two steps from 6 as a 20:1 ratio of diastereomers.13
A subsequent Mitsunobu inversion of the free hydroxyl
moiety of 10, parallel to the efforts of Smith, afforded the
correct C9 acetate 11 in 74% yield as a 12:1 mixture of
diastereomers. Careful treatment of 11 with excess allyl
magnesium bromide concomitantly alkylated the Weinreb
amide moiety and deprotected the secondary alcohol to afford
the necessary ꢀ-hydroxy-ꢀ,γ-unsaturated 12 in 61% over the
two transformations within the same reaction flask. With the
necessary substrate for directed reduction in hand, our focus
turned toward the construction of the necessary dioxolane
aldehyde 5.
Scheme 4. Synthesis of the ꢀ-C-Glycoside 19
Hence, treatment of ketone 12 under the method of Prasad
(Et2BOMe and NaBH4) afforded the required 1,3-syn-diol
as a 10:1 mixture of inseparable diastereomers.14 The crude
diol was then dissolved in CH2Cl2 and treated under standard
ketalization conditions with DMP and PPTS to afford the
acetonide-protected alkene. An ensuing buffered ozonolysis
of the olefinic moiety afforded dioxolane aldehyde 5 in 61%
yield over three steps from 12 and set the stage for a reagent-
controlled Evans aldol reaction.15 Thus, stereoselective (Z)-
enolate formation of the propionyl oxazolidinone 13 was
accomplished under the standard Evans conditions (n-
Bu2BOTf, Et3N); quenching with aldehyde 5 readily afforded
aldol adduct 14 in 86% yield (12:1 dr by 1H NMR) as shown
in Scheme 4. Ensuing protection of the resulting secondary
alcohol 14 was attempted under a variety of conditions.
Treatment of 14 under standard protection conditions with
silyl chlorides and imidazole led to no conversion, even with
heating. The use of silyl triflates and 2,6-lutidine, unfortu-
nately, did not allow for silicon ether formation. However,
the protection of 14 was successful with MOMCl; it afforded
acetal 15 in 91% yield after extensive optimization. Conver-
sion of the oxazolidinone aldol adduct 15 into the desired
lactone 4 was initiated by initially transforming 15 to the
benzyl ester followed by hydrolysis of the acetonide and
subsequent lactonization.16 Along this line, the lithium
alkoxide of benzyl alcohol led to the formation of the
corresponding ester which was used immediately without
purification. Subsequent lactonization was accomplished
under standard hydrolysis conditions by treating the crude
product with aqueous trifluoroacetic acid (TFA) in THF. The
hydroxy lactone 4 was obtained in 66% yield from 15.
With the synthesis of 4 complete, focus shifted toward
the construction of the ꢀ-C-glycoside subunit. Hence, alky-
lation of lactone 4 with allylmagnesium bromide afforded
the intermediate hemiketal 16 which readily underwent
tandem stereoselective oxocarbenium cation formation/
reduction with TFA and Et3SiH to afford the ꢀ-C-glycoside
(as determined by NOE) 19 in 65% yield over the three step
sequence from 4 (in >20:1 dr). Presumably, reductions of
oxocarbenium cations occur via axial addition of Et3SiH to
afford the ꢀ-C-glycoside.17 Of the two possible reactive
conformers, and based on the isolated ꢀ-C-glycoside, the
proposed conformer 18 places all of the substituents at C2,
C3, and C5 in the pseudoequatorial positions. A majority of
our stereoselective endocyclic oxocarbenium reductions have
placed the C3 hydroxyl moiety in the axial position and the
C5 substituent in the pseudo equatorial geometry. Typically,
these oxocarbenium formation/reduction reactions are com-
(11) Guz, N. R.; Phillips, A. J. Org. Lett. 2002, 4, 2253.
(12) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (b)
Rychnovsky, S. D.; Sinz, C. J. Tetrahedron. 2002, 58, 6561. (c) Sibi, M. P.
Org. Prep. Proced. Int. 1993, 25, 15. (d) Mentzel, M.; Hoffman, H. M. R.
J. Prakt. Chem. 1997, 339, 517.
(13) (a) Charette, A.; Label, H. J. Org. Chem. 1995, 60, 2966. (b)
Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1.
(14) Chen, K-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155.
(15) (a) Evans, D. A.; Glorius, F.; Burch, J. D. Org. Lett. 2005, 7, 3331.
(b) Evans, D. A.; Trenkle, W. C.; Zhang, J.; Burch, J. D. Org. Lett. 2005,
7, 3335.
(16) (a) Damon, R. E.; Coppola, G. M. Tetrahedron Lett. 1990, 31, 2849.
(b) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28,
6141. (c) Prashad, M.; Har, D.; Kim, H.-Y.; Repic, D. Tetrahedron Lett.
1998, 39, 7067.
(17) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2000, 122, 168.
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