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During the past year we have developed a new asymmetric tandem Wittig rearrangement/Mannich reaction as described in our original proposal. Asymmetric induction was achieved using a simple chiral auxiliary (2-phenylcyclohexanol), which is commercially available. As illustrated in Table 1, transformations of a number of amino alcohols 3 are generated in good yield with good to excellent stereoselectivity when N-benzyl or N-aryl imines are employed as electrophiles. Reduction of the products with LiAlH₄ affords enantiomerically enriched aminodiols with up to 96% ee.

^a Conditions: 1.0 equiv 1 or 2, 1.5–2 equiv R¹C(H)NR², 3.2 equiv Bu₂BOTf, 4 equiv Et₃N (R = Bn) or iPrNEt₂ (R = allyl), CH₂Cl₂, 0°C → rt → 0°C. ^b Isolated yield (average of two or more experiments).

Use of N-Boc imines affords trisubstituted isoxazolidin-2-ones 4–5 derived from syn-aminoalcohols in moderate yield with excellent stereocontrol (eq 1). In contrast, use of 2-(phenylsulfonyl)amines as electrophiles affords anti-aminoalcohol products 6–7 with high dr (eq 2). In all cases highly enantiomerically enriched aminodiols are obtained (up to 96% ee) after reduction of the products with LiAlH₄. The carbamate functionality is not affected during the reduction; selective reduction of the ester is observed.

The relative stereochemistry of the amino-alcohol product is set during the subsequent Mannich reaction, and is dependent on the nature of the electrophile. In reactions involving N-benzyl or N-Boc imine electrophiles the Mannich reactions occur via boat-like transition state 9 to afford the syn-amino alcohol products 3 and the oxazolidin-2-ones 4–5 (Scheme 1). In contrast, reactions of N-Boc-2-(phenylsulfonyl)amines likely involve intermediate N-Boc iminium ions. The Mannich reactions of the iminium-ions occur via open transition states 10 in which R² is positioned away from the two bulky boron groups. This gives rise to the observed anti-amino alcohol products 6–7.

We have also made two significant advances in the area of tandem Wittig Rearrangement/Aldol Reactions. We have successfully generated vicinal quaternary stereocenters with high stereocontrol through the reaction between O-benzyl-2-phenylcyclohexyl glycolate ester 1 and p-methoxyacetophenone to afford boronate ester 11 in 76% yield as a single stereoisomer (eq 3). Subsequent cleavage of the boronate ester gave 12 in 82% yield (assayed as 88 % ee after subsequent auxiliary cleavage). We have also employed the tandem Wittig rearrangement/Aldol reaction sequence to generate 13, which undergoes an intramolecular Diels-Alder reaction to afford highly substituted, enantiomerically enriched carbocycle 14. Further studies in both of these areas are planned for the coming year, and we also intend to pursue applications of these transformations to the synthesis of important natural products and other targets of interest.