the presence of 4 Å molecular sieves produced acylaminal
9 in 79% yield.
The trimethyl ether of glucal (10) served as the starting
material for our extension of this work to a system that is
more relevant to the synthesis of the mycalamides (Scheme
1). Epoxidation of 10 with dimethyl dioxirane10 followed
Oxidative cyclization of 15 proceeded with excellent
efficiency to provide a 94% yield of 16 and 17 as a 10:1
1
mixture (Figure 5). In contrast to our expectations, H-1H
Scheme 1a
Figure 5. Oxidative entry into the amido trioxadecalin ring system.
NMR coupling constants revealed that 16 adapts a confor-
mation that places the majority of the substituents on the
tetrahydropyran ring in axial orientations. This result, as well
as the stereochemistry of the newly formed acylaminal center,
was confirmed by a NOESY experiment. The tetrahydro-
pyran ring in 17 showed the expected conformation as
a Reagents and conditions: (a) i. dimethyldioxirane, CH2Cl2,
0 °C; ii. trivinylalane, THF, -60 °C to rt, 62%. (b) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 °C to rt, 77%. (c) i. O3, CH2Cl2, -78 °C, then
Ph3P; ii. 13, Ti(O-iPr)4, CH2Cl2, 71%. (d) BnMgCl, CH2Cl2,
-78 °C, then MeOH, HCl. (e) Boc2O, Et3N, CH2Cl2, reflux, 68%
for 2 steps. (f) Bu4NF, THF, 76%. (g) butenyl chloromethyl ether,
i-Pr2NEt, CH2Cl2, reflux, 97%. (h) BH3‚THF, THF, 0 °C, then
NaOOH, 93%. (i) PhI(OAc)2, I2, hν, DCE, 64%.
1
determined by NOESY and H-1H coupling constants.
The unexpected stereochemical outcome16 of the cycliza-
tion reaction warrants further discussion. Our previous
observation that the intermediate oxonium ion in these
transformations is unstable relative to the acyliminium ion
implies a late transition state for the cyclization that reflects
the conformational biases of the product (Figure 6). The
preferential formation of 16, therefore, indicates that 19 is
more stable than 18. The source of this energetic difference
can be attributed to the conformational energetics of the cis-
trioxadecalin ring system. Fuchs and co-workers calculated17
that conformation 20 (Figure 7) of the parent ring system
(the conformation reported for the mycalamides) is 4.3 kcal/
mol higher in energy than conformation 21 (observed in 16).
This preference was ascribed to the presence of strongly
disfavored gauche-CCOC interactions in 20 in contrast to
the anti-relationships found in 21. The energetic penalty
conferred by the axial substituents in 19 is partially offset
by the equatorial orientation of the sterically demanding
branched carbon that bears the carbamate group. This balance
by opening with trivinylalane,11 in accord with Rainier’s
studies,12 proceeded to form 11 as a single diastereomer.
Sulfinyl imine 12 was accessed from 11 through hydroxyl
group protection, oxidative olefin cleavage, and condensation
with Ellman’s sulfinamide 13.13 The instability of the
aldehyde intermediate in this sequence dictated that it be
carried into the condensation step without purification.
Addition of benzylmagnesium chloride to 12 followed by
auxiliary cleavage and carbamate formation provided
homobenzylic carbamate 14. Although this addition pro-
ceeded with complete diastereoselectivity, the stereochem-
istry of the resulting inconsequential stereocenter was not
determined. The hemiacetal surrogate was installed through
a sequence of silyl deprotection, conversion of the resulting
hydroxyl group to a butenoxymethyl ether,14 hydroboration/
oxidation of the terminal olefin, and oxidative etherification
under Suarez’ conditions.15
1
is supported by our observation of ∼4 Hz H-1H coupling
constants around the tetrahydropyran ring of 15, indicative
of a nearly 1:1 mixture of conformers.18 Although the
stabilities of the intermediate oxonium ions need not reflect
(10) (a) Murray, R. W.; Jeyaraman, T. J. Org. Chem. 1985, 50, 2847.
(b) Adam, W.; Bialas, J.; Hadjcarapoglou, L. Chem. Ber. 1991, 124, 2377.
(c) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6661.
(11) Saulnier, M. G.; Kadow, J. F.; Tun, M. M.; Langley, D. R.; Vyas,
D. M. J. Am. Chem. Soc. 1989, 111, 8320.
(12) (a) Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, H. W. B.;
Rainier, J. D. Tetrahedron 2002, 58, 1997. (b) Rainier, J. D.; Cox, J. M.
Org. Lett. 2000, 2, 2707.
(13) (a) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. A.; Ellman, J. A. J.
Am. Chem. Soc. 1998, 120, 8011. (b) Liu, G.; Cogan, D. A.; Ellman, J. A.
J. Am. Chem. Soc. 1997, 119, 9913. (c) Tang, T. P.; Volkman, S. K.; Ellman,
J. E. J. Org. Chem. 2001, 66, 3707.
(14) Bedford, C. D.; Harris, R. N., III.; Howd, R. A.; Goff, D. A.; Koolpe,
G. A.; Petesch, M.; Koplovitz, I.; Sultan, W. E.; Musallam, H. A. J. Med.
Chem. 1989, 32, 504.
(15) de Armas, P.; Concepcio´n, J. I.; Francisco, C. G.; Herna´ndez, R.;
Salazar, J. A.; Sua´rez, E. J. Chem. Soc., Perkin Trans. 1 1989, 405.
(16) For other reports of the inverted conformer in mycalamide studies,
see: (a) Roush, W. R.; Marron, T. G. Tetrahedron Lett. 1993, 34, 5421.
(b) Hoffman, R. W.; Schlapbach, A. Tetrahedron Lett. 1993, 34, 7903.
(17) Golender, L.; Senderowitz, H.; Fuchs, B. THEOCHEM 1996, 370,
221.
(18) For example, see: Roush, W. R.; Sebesta, D. P.; Bennett, C. E.
Tetrahedron 1997, 53, 8825.
Org. Lett., Vol. 5, No. 9, 2003
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