Formation of Stable Spiro[4.4] Ortho Ester Aminals during the Synthesis of the C26−C32 Oxazole Fragment of Calyculin C

Abstract

Ortho ester aminals (compounds with two nitrogen atoms and an oxygen atom bonded to a sp3 carbon) are occasionally encountered as side products or intermediates in heterocycle syntheses,1 in nucleotide chemistry,2 and in flavonoid chemistry.3 Open-chain ortho ester aminals are prone to disproportionation and further hydrolysis by water or alcohols, but the corresponding polycyclic ortho ester aminals are often stable enough to be isolated. In contrast to the ortho esters, which are rapidly gaining importance in organic synthesis,4 the corresponding aminals have only scarcely been used, possibly due to their instability. The reasons for the hydrolytic stability of the polycyclic ortho ester aminals relative to their open-chain counterparts have not been discussed in detail in the literature, although stereoelectronic effects are likely to play a central role.5 The exo-anomeric effect has been invoked as an explanation for the stability of three simpler derivatives, a monocyclic ortho ester aminal and two spirocyclic analogues.6 Herein, we report the facile formation of stable spirocyclic [4.4] ortho ester aminals and characterization of one isomer (4b) with X-ray crystallography. These compounds cannot benefit from anomeric stabilization (vide infra), and an alternative explanation for their stability as well as the lability of the open-chain derivatives is therefore required and presented. The final step of the synthesis of the C26-C32 oxazole fragment (2a) of calyculin C (1)7 (Scheme 1) requires the oxidation of the oxazolines 3a/3b to the corresponding oxazoles 2a/2b (Scheme 2).8 Along with the desired oxazoles, another set of diastereomeric compounds were formed in up to 52% yield (Table 1). To our surprise, these compounds proved to be the isomeric spirocyclic ortho ester aminals (diastereomeric due to the presence of an additional chiral spiro atom) (4a, pure diastereomer; 4b: 4b′, 2:1 ratio).9 Recrystallization afforded the pure diastereomer 4b from the mixture 4b/4b′. Both oxidation methods employed10 depend on the generation of the ester enolate and subsequent oxidative removal of the oxazoline ring hydrogen.11 The formation of ortho ester aminals 4a/4b in both cases indicates that * To whom correspondence should be addressed. Phone: +358 8 553 1630. Fax: +358 8 553 1629. E-mail: Ari.Koskinen@oulu.fi. (1) For examples, see: (a) Feinauer, R. Angew. Chem. 1966, 78, 938. (b) Doleschall, G.; Lempert, K. Tetrahedron 1968, 24, 5529-5545. (c) Fryer, R. I.; Earley, J. V.; Blount, J. F. J. Org. Chem. 1977, 42, 22122219. (d) Gotthardt, H.; Schenk, K.-H. Angew. Chem. 1985, 97, 604606. (e) Knolker, H.-J.; Boese, R.; Doring, D.; El-Ahl, A.-A.; Hitzemann, R.; Jones, P. G. Chem. Ber. 1992, 125, 1939-1951. (e) Kappe, C. O.; Peters, K.; Peters, E.-M. J. Org. Chem. 1997, 62, 3109-3118. (f) Couture, P.; Warkentin, J. Can. J. Chem. 1997, 75, 1264-1280, 12811294. (2) For an example, see: Anzai, K.; Uzawa, J. J. Org. Chem. 1984, 49, 5076-5080. (3) Lee, Y. T.; Fisher, J. F. J. Org. Chem. 1993, 58, 3712-3721. (4) For a review of ortho esters, see: DeWolfe, R. H. Synthesis 1974, 153-172. For recent use of ortho esters in synthesis, see: Charette, A. B.; Chua, P. Tetrahedron Lett. 1997, 38, 8499-8502 and references therein. (5) Poje, N.; Palkovic, A.; Poje, M. J. Heterocycl. Chem. 1997, 34, 477-483. (6) (a) Bertolasi, V.; Ferretti, V.; Gilli, G.; Marchetti, P.; D’Angeli, F. J. Chem. Soc., Perkin Trans. 2 1990, 2135-2140. (7) Isolation and characterization: Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Koseki, K. J. Org. Chem. 1988, 53, 39303932. For references to recent total or partial syntheses of calyculins, see ref 8. (8) Pihko, P. M.; Koskinen, A. M. P. J. Org. Chem. 1998, 63, 9298. (9) The isomer ratios were determined by 1H NMR. At 365 K, 4a gave only a single set of signals in 1H and 13C NMR. We are grateful to an anynomous reviewer for drawing our attention to this point. (10) (a) Method A: Barrish, J. C.; Singh, J.; Spergel, S. H.; Han, W.; Kissick, T. P.; Kronenthal, D. R.; Mueller, R. H. J. Org. Chem. 1993, 58, 4494-4496. (b) Method B: see ref 8. Scheme 1