L-Selectride-Mediated Highly Diastereoselective Asymmetric Reductive Aldol Reaction: Access to an Important Subunit for Bioactive Molecules

Abstract

L-Selectride reduction of a chiral or achiral enone followed by reaction of the resulting enolate with optically active α-alkoxy aldehydes proceeded with excellent diastereoselectivity. The resulting α,α-dimethyl-β-hydroxy ketones are inherent to a variety of biologically active natural products.Asymmetric aldol reactions leading to the stereocontrolled generation of β-hydroxy carbonyl derivatives are among the most important reactions in organic synthesis. 1 Consequently, a number of effective methodologies have been developed over the years. In a series of elegant studies, Stork and co-workers have shown that lithium-ammonia reduction of enones leads to stoichiometric generation of enolates. 2 Since then, reductive aldol reactions in which conjugate reduction followed by aldol reaction of the resulting enolates led to the development of a wide variety of methodologies for the synthesis of β-hydroxy carbonyl derivatives. 3 In recent years, impressive progress has been made in both catalytic 4 and enantioselective 5 reductive aldol processes. In the context of our enantioselective synthesis of (+)-peloruside A, we recently carried out a L-selectride mediated reductive aldol coupling of enone 1 and aldehyde 2 to provide aldol product 3 and its diastereomer as a 4:1 mixture in 92% yield at −78 °C for 1 h. 6,7 The major aldolate 3 was subsequently converted to peloruside A. The overall process is quite practical and offers significant improvement over the direct aldol reaction of related ketone enolate and aldehyde reported recently. 8 Of particular importance, these α,α-dimethyl β-hydroxy carbonyl derivatives are structural features of numerous bioactive natural products like epothilones, 9 mycalamide A 10 and peloruside A. 6 Encouraged by the reasonable diastereoselectivity of the L-selectride mediated reductive aldol process, we have now examined the stereochemical outcome with a variety of chiral and achiral enones and aldehydes bearing an α-β-alkoxy stereocenter. Herein, we report the results of our investigations. Excellent levels of diastereoselectivity are attainable when the enolate from L-selectride reduction is reacted with aldehydes containing an α-chiral center.Our preliminary investigations focused on reactions with model 5 and optically active isopropylidene glyceraldehyde 4. As shown in Scheme 1, enone 5 was prepared in a two stepakghosh@purdue.edu . Supporting Information Available: Experimental procedures and 1 H-and 13 C-NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2010 September 22. (1) reaction of isopropenyl magnesium bromide in diethyl ether followed by Dess-Martin oxidation 11 of the resulting diastereomeric alcohols to enone 5 in 63% yield in 2-steps. Enone 5 was treated with 1·1 equiv of L-selectride at −78 °C for 10 min to form the corresponding lithium enolate. To the resulting enolate, 2 equiv of isopropylidene-Dglyceraldehyde...

Capturing the Essence of Organic Synthesis: From Bioactive Natural Products to Designed Molecules in Today’s Medicine

“…Reaction with chiral isopropylidenebutyraldehyde however, provided a 1:1 mixture of diastereomers. The corresponding reaction with isovaleraldehyde provided a 1:1 mixture of diastereomers 210 , suggesting that the α-chirality of the isopropylidene- d -glyceraldehyde is responsible for the diastereoselectivity as proposed in the stereochemical model 208 116. Indeed, reaction with an achiral enone 211 and isopropylidene- d -glyceraldehyde provided single isomer 212 .…”

“…Recently, we have developed a highly diastereoselective asymmetric reductive aldol reaction 116. As shown in Figure 44, aldol reaction of the enolate generated by addition of l -selectride to enone 207 and isopropylidene- d -glyceraldehyde in ether at −78 °C provided only one single diastereomer 209 , in 70% yield.…”

Synthesis of Bioactive Natural Products by Asymmetric syn- and anti-Aldol Reactions

“…Our exploration of this reductive aldol strategy showed that several representative aldol adducts can be prepared in good yield and high diastereoselectivity when the reactant aldehyde contains an α-chiral center. 4 The synthesis of peloruside A was carried out by removal of the p -methoxybenzyl protecting group and oxidation of the primary alcohol to the corresponding acid, followed by Yamaguchi lactonization to provide macrolactone 69 . This was then converted into (+)-peluroside A.…”

“…3 We will also describe a recent asymmetric reductive aldol process developed in our laboratory in the context of the synthesis of peloruside A, a potent anticancer agent with clinical potential. 4,5 Furthermore, we report an asymmetric aldol-based synthesis of a stereochemically defined bis-tetrahydrofuran (bis-THF) scaffold present in ginkolide natural products. 6 This scaffold has been successfully incorporated in the design and development of Darunavir, a HIV-1 protease inhibitor for the treatment of multi-drug-resistant HIV-1 variants that has recently been approved by the US Food and Drug Administration (FDA).…”

The Mimic of Type II Aldolases Chemistry: Asymmetric Synthesis of β‐Hydroxy Ketones by Direct Aldol Reaction

“…In fact, b-hydroxy ketones can serve as versatile building block for the asymmetric synthesis of carbohydrates, amino acids and many other biomolecules (4)(5)(6). They also provide privileged structural functionalities that exist in many important natural products (7)(8)(9)(10)(11)(12). For example, the b-hydroxy ketones functionalities exist in macrolide classes of antibiotics such as telithromycin and cethromycin which are targeted primarily against Gram-positive bacterial strains including Streptococcus pneumoniae and S. pyogenes, fastidious Gram-negative strains including Haemophilus influenzae and Moraxella catarrhalis, atypicals Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophilia (13).…”