comparable yield. Propionitrile (mp -93 °C) was chosen
instead of acetonitrile to enable experimentation at lower
temperature without resorting to the use of mixed solvents.5b
In trials at -78 °C, little formation of 10/11 was observed.
The ring stereochemistry was evident from the chemical
shifts of H11 and H12 (10: δ 4.32, 4.70; 11: 4.71, 5.13).11
The H13 and H14 signals at δ 5.7-5.9 were well isolated
at 600 MHz and showed J ) 15.6 Hz, characteristic of the
E configuration.
Scheme 1. Preparation of Boc Orthoformate 9
Exposure of the separated carbonates 10 and 11 to
methanolic NaOMe afforded 12-epi-2 and 2 (86-90%),
1
whose H and 13C NMR spectra agreed with those of the
11R product pair synthesized by Falck.1 The H11 resonances
occurred at δ 3.53 and 3.71, respectively, consonant with
the assigned syn and anti C11-C12 relationships.12 Saponi-
fication1 of 2 yielded acid 1, which by negative-ion
ESI/MS/MS showed a diagnostic m/z 197 ion arising from
C11/C12 cleavage; in the spectrum of the acid corresponding
to 5, there appeared instead an m/z 223 ion attributable to
C13/C14 cleavage.13
The genesis of 1,3-dioxolan-2-yl cations by ionization of
ortho esters, as depicted in Scheme 2 for the reaction 9fA,
is well documented.4 Subsequent nucleophilic capture with
ring opening typically leads to vicinally functionalized
products such as bromohydrin esters. An orthoformate linked
to a phenolic group gave the bromo formate when treated
with AcBr but cyclized to the chromane under catalysis by
PPTS, demonstrating the influence of the counterion on inter-
vs intramolecular reactivity.4c Here, the latter mode prevails
by isomerization of A to B, which is formulated as an
Epoxidation of 3 on a 3.5-g scale7 afforded the anti (erythro)
epoxy alcohol 4 (49%) plus its syn (threo) diastereomer
(21%). Hydrolysis of 4 provided triol 5 and its more polar
epimer 6 (∼1:1). Treatment of the separated triols with
excess HC(OMe)3 and catalytic PPTS in dichloromethane
gave orthoformates 7 and 8, plus bisorthoformates from
which the 11-OH group could be released by titration of the
reaction mixtures with methanol.8 In this way, 7 and 8 were
obtained reproducibly in 77-78% yield from 5 and 6. The
C11 configurations were assigned at this stage by O-meth-
ylmandelic ester analysis.9 The 11R epimer 7 was converted
to t-butyl carbonate 9 in 94% yield by treatment with Boc2O,
i-Pr2NEt, and DMAP in 2:1 hexane-diethyl ether.10
Reaction of 9 (275 mg) with TMSOTf in EtCN at -20
°C gave trans cyclic carbonate 10 and its cis epimer 11
(4.5:1) in 62% yield (Scheme 2). The useful desformyl
congeners were also obtained in 6% yield. The Boc derivative
of 8 likewise delivered a 5.7:1 trans/cis product mixture in
(3) For a discussion of ScN′ reactions, see: Stork, G.; Poirier, J. M. J.
Am. Chem. Soc. 1983, 105, 1073.
(4) (a) Liang, J.; Moher, E. D.; Moore, R. E.; Hoard, D. W. J. Org.
Chem. 2000, 65, 3143. (b) Li, L.-H.; Tius, M. A. Org. Lett. 2002, 4, 1637.
(c) Li, L.; Chan, T. H. Org. Lett. 2001, 3, 739. (d) Bozell, J. J.; Miller, D.;
Hames, B. R.; Loveless, C. J. Org. Chem. 2001, 66, 3084.
(5) (a) Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.;
Jernstedt, K. K. J. Org. Chem. 1982, 47, 4013. (b) Johnson, W. S.; Chan,
M. F. J. Org. Chem. 1985, 50, 2598. (c) Duan, J. J.-W.; Smith, A. B., III.
J. Org. Chem. 1993, 58, 3703.
(6) Marshall, J. A.; Yanik, M. M. J. Org. Chem. 1999, 64, 3798.
(7) For procedures applicable to the synthesis of 3 on a multigram scale,
see: (a) Iacazio, G.; Langrand, G.; Baratti, J.; Buono, G.; Triantaphylide`s,
C. J. Org. Chem. 1990, 55, 1690. (b) Martini, D.; Iacazio, G.; Ferrand, D.;
Buono, G.; Triantaphylide`s, C. Biocatalysis 1994, 11, 47.
Scheme 2. Ionization of 9 Leading to Cyclic Carbonates and
Methanolysis Affording Transposed Triols
(8) (a) The ratio of exo/endo methoxy epimers, initially 1:4, changes to
3:1 during this methanol treatment, paralleling the behavior of nucleosidic
orthoformates: Bhat, G. A.; Townsend, L. B. J. Chem. Soc., Perkin Trans.
1 1981, 2387. (b) Maillard, M. C.; Nikodijevic, O.; LaNoue, K. F.; Berkich,
D.; Ji, X.-d.; Bartus, R.; Jacobson, K. A. J. Pharm. Sci. 1994, 83, 46. (c)
For a comparison of hydrolysis rates of acyclic vs six-membered cyclic
ortho esters, see: Deslongchamps, P.; Dory, Y. L.; Li, S. Tetrahedron 2000,
56, 3533.
(9) (a) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S.
L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370. (b) Latypov, Sh. K.; Seco,
J. M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 1996, 61, 8569.
(10) (a) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368. The use
of N-methylimidazole proved unsatisfactory in the present case. (b) Hansen,
M. M.; Riggs, J. R. Tetrahedron Lett. 1998, 39, 2705.
(11) (a) Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. J.
Org. Chem. 1982, 47, 4626. (b) Adams, J.; Fitzsimmons, B. J.; Girard, Y.;
Leblanc, Y.; Evans, J. F.; Rokach, J. J. Am. Chem. Soc. 1985, 107, 464.
(12) Lombardo, M.; Girotti, R.; Morganti, S.; Trombini, C. Org. Lett.
2001, 3, 2981.
(13) (a) Wheelan, P.; Zirrolli, J. A.; Murphy, R. C. J. Am. Soc. Mass
Spectrom. 1996, 7, 129. (b) Wheelan, P.; Zirrolli, J. A.; Murphy, R. C. J.
Am. Soc. Mass Spectrom. 1996, 7, 140. (c) Bylund, J.; Ericsson, J.; Oliw,
E. H. Anal. Biochem. 1998, 265, 55.
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