Aldol reactions of racemic enolizable dioxolan-protected a-substituted-b-ketoaldehydes with representative achiral ketones catalyzed by proline or 5-(2-pyrrolidine-2-yl)-1H-tetrazole in wet DMSO proceed with dynamic kinetic resolution (or via DYKAT with an a-substituted-b-alkoxyaldehyde) to give adducts with high dr and ee.The first examples of proline-catalyzed enantioselective direct intermolecular aldol reactions were reported in a landmark paper by List, Lerner, and Barbas in 2000. 1 In the ensuing decade, this reaction has been extensively studied by numerous research groups, and remarkable progress has been achieved. 2 Despite the impressive stereoselectivity that has been obtained in many examples and with diverse organocatalysts, a continuing limitation to synthetic applications of this process has been the rather narrow substrate scope; that is, few competent ketone donors and mainly simple achiral or aromatic aldehyde acceptors. Our interest in this process stemmed from its possible application to our thiopyran-based synthetic route to polypropionates via stereoselective sequential two-directional aldol reactions of 1 and 2a (Scheme 1). 3 Scheme 1 Proline-catalyzed reaction of 1 with (±)-2a via DKR 8aIn a preliminary study, we established that proline-catalyzed aldol reactions of 1 with simple achiral aldehydes in DMF or DMSO (with controlled amounts of water) are highly diastereo-and enantioselective. 4 This was significant because 3-pentanone is a poor substrate in prolinecatalyzed aldol reactions. 2 Among the scattered examples of proline-catalyzed aldol reactions of chiral aldehydes, 5 generally moderate levels of enantiotopic group selectivity 6 (or double stereodifferentiation) 7 were observed. Nonetheless, we reasoned that because of its near exclusive Felkin diastereoface selectivity, racemic aldehyde (±)-2a would be a good candidate to undergo proline-catalyzed direct aldol with 1 with high enantiotopic group selectivity (i.e., kinetic resolution 6 ). 8 Under optimized conditions, (-)-5a was obtained essentially as a single stereoisomer in a process that proceeded via dynamic kinetic resolution (DKR, 9 Scheme 1). 8 In this paper, we report the extension of this concept to other ketones and aldehydes and simple procedures for the preparation of 5a on >30 gram scale.We next investigated the efficacy of the more soluble catalyst 6. 10 Aldol reactions of 1 with (±)-2a, benzaldehyde (2c), and isobutyraldehyde (2d) catalyzed by 6 (0.2 equiv) were conducted under the conditions previously optimized using 4 (0.5 equiv) revealing that 6 was the superior catalyst for the reactions with (±)-2a and 2c, (Table 1; cf. entries 1, 2, 4, 5, and 7, 8). The individual reactions were optimized by examining the effects of various reaction parameters including the amount of added water, 4 stoichiometry, catalyst loading, and reaction time. A solvent screen revealed that DMF was superior for 2c and DMSO for 2d and (±)-2c. 11 The addition of controlled amounts of water improved all reactions and the adducts 5a, 5c...

The design of novel nucleoside analogues bearing a C2′ all-carbon quaternary center is described. The construction of this all-carbon stereogenic center involves the use of photoredox catalysis to initiate an intramolecular attack of a silyltethered vinyl functionality on a tertiary radical. Density functional theory calculations were performed to explore the origin of the high syn diastereoselectivity obtained through the preferred 5-exo-trig cyclization mode. The intramolecular vinyl addition also enables the preparation of the complementary configuration of the C2′ all-carbon stereocenter when performed after lactonization.

The stereoselectivity of aldol reactions of chiral reactants can be factorized into to three stereocontrol elements: the diastereoface selectivities of the ketone enol(ate) and aldehyde and the relative topicity of the coupling. Application of the multiplicativity rule to these elements leads to the prediction that kinetic resolution (KR) should be possible if all three stereocontrol elements are strongly biased. As a corollary, the enantioselectivity of the kinetic resolution should be switchable by a change in the sense of selectivity of any of the stereocontrol elements. This hypothesis was tested using aldehyde and ketone reactants with high diastereoface selectivities and developing reaction conditions that strongly favor either syn or anti relative topicity. The aldehyde 2 undergoes aldol reactions with near-exclusive Felkin diastereoface selectivity, and hydroxy-protected derivatives of ketone 1 (R = MOM, Et(3)Si, or Ac) undergo aldol reactions with high diastereoface selectivity to give 3,5-trans adducts. High levels of anti and syn relative topicity were obtained with dicyclohexylboron enolates and Ti(O(i)Pr)(4)Li "ate" enolates, respectively. Using these enolates, aldol reactions of (+/-)-2 with (+/-)-1 gave two of the eight possible diastereomeric adducts (3 from a diastereoselective like combination of reactant enantiomers and 4 from a diastereoselective unlike combination) predominantly (>95% of the adducts) in ratios of 0.05-20:1; boron enolates favored the like reaction (3:4, 15-20:1) and Ti "ate" enolates favored the unlike reaction (3:4, 1:10-20). Under these conditions, the ratio of like and unlike products is a measure of the mutual kinetic enantioselection (MKE) and reflects the ratio of the rate constants for the competing like and unlike reactions. For each of the four diastereomers of 1, the reactions with the highest MKEs in favor of the like (3) or unlike products (4) were repeated using highly enantioenriched ketone. These reactions occurred with the expected KR (s = 10-20) allowing selective access to enantioenriched diastereomers of 3 or 4 from (+/-)-2. These adducts are useful for polypropionate synthesis, and this design strategy for KR should be applicable to related processes.

The design of a novel nucleoside scaffold that exhibits an all-carbon quaternary center is reported. This allows for both α- and β-anomers of a given 2'-deoxy-2',2'-difluoro nucleoside analog (NA) to have potential biological activity. Using an intramolecular atom-transfer reaction, an all-carbon quaternary center was obtained without the use of heavy metals and/or harsh conditions. The chemistry developed is efficient, easily scalable and leads to novel libraries of molecules.