The first enantioselective catalytic direct cross-aldol reaction that employs nonequivalent aldehydes has been accomplished using proline as the reaction catalyst. Structural variation in both the aldol donor (R1 = Me, n-Bu, Bn, 91 to >99%) and aldol acceptor (R2 = I-Pr, I-Bu, c-C6H11, Et, Ph, 97-99% ee) are possible while maintaining high reaction efficiency (75-88% yield). Significantly, this new aldol variant allows facile enantioselective access to a broad range of beta-hydroxy aldehydes which are valuable intermediates in polyketide syntheses.

General Information. Commercial reagents were purified prior to use following the guidelines of Perrin and Armarego.1 Non-aqueous reagents were transferred under nitrogen via syringe or cannula. Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporator. Chromatographic purification of products was accomplished using forcedflow chromatography on ICN 60 32-64 mesh silica gel 63 according to the method of Still. were obtained from the UC Irvine Mass Spectral facility. Gas liquid chromatography (GLC) was performed on Hewlett-Packard 6850 and 6890 Series gas chromatographs equipped with a splitmode capillary injection system and flame ionization detectors using a Bodman Chiraldex β-DM

General Information. Commercial reagents were purified prior to use following the guidelines of Perrin and Armarego.1 All solvents were purified according to the method of

The growing study of glycobiology [1] has led to an increased focus upon carbohydrate architecture [2] as an important platform for reaction design and methodological advancement. [3] Application of the aldol reaction [4] to the synthesis of carbohydrates is well-documented; [5] however, the attendant need for protection-group manipulations and oxidation-state adjustments has thus far precluded a broadly utilizable protocol. Intriguingly, a highly expedient two-step carbohydrate synthesis can be envisioned based on an iterative aldol sequence using simple a-oxyaldehydes [Eq. (1)]. While attractive in theory, the practical execution of this carbohydrate strategy would require the invention of two new aldol technologies: a) an enantioselective aldol union of a-oxyaldehyde substrates (Aldol step 1) and b) a diastereoselective aldol coupling between tri-oxy substituted butanals and an a-oxyaldehyde enolate (Aldol step 2). Herein we report the successful development of the first enantioselective organocatalytic coupling of an a-oxyaldehyde (Aldol step 1). This new aldol reaction provides an operationally simple protocol for the stereocontrolled production of polyol architectures and sets the stage for a twostep enantioselective carbohydrate synthesis. [6] The development of a direct, enantioselective catalytic aldol reaction between a-oxyaldehyde substrates (Aldol step 1) is dependent upon three key issues of chemical selectivity. [7] In addition to the traditional requirements of absolute and relative stereocontrol comes the chemoselective constraint that the a-oxyaldehyde reagent A must readily participate as both a nucleophilic and electrophilic coupling partner while the a-oxyaldehyde product B must be inert to in situ enolization or carbonyl addition [Eq. (1)]. Recently, we disclosed an organocatalytic strategy for the highly regioselective, diastereoselective, and enantioselective aldol cross-coupling of a-alkyl-bearing aldehydes [Eq. (2)]. [8] An important feature of this transformation is that the enantioenriched aldehyde products C do not participate in further aldol reactions (by either enamine formation or carbonyl addition). With this in mind, we hoped that such remarkable catalyst-controlled stereo-and chemoselectivity might be extended to the union of a-oxygenated aldehydes [Eq. (3)], thereby allowing the first step in a two-step carbohydrate synthesis to occur [Eq. 1].Our enantioselective organocatalytic a-oxyaldehyde coupling was first examined using l-Proline (10 mol %) and a

Central to the design of a new organocatalyst system for aldehyde–aldehyde aldol reactions is the necessity of iminium geometry control during the enamine addition step (see scheme). Significant structural variation in both the aldol donor and aldol acceptor are possible while maintaining high reaction efficiency and enantioselectivity. TFA=trifluoroacetic acid.