PAPER 1946 Lithium Aldol Reactions of a-Chloroaldehydes Provide Versatile Building Blocks for Natural Product Synthesis Shira D. Halperin, Baldip Kang, Robert Britton* Department of Chemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada Fax +1(778)7824889; E-mail: rbritton@sfu.ca Received 14 March 2011 SYNTHESIS 2011, No. 12, pp 1946–1953xx.xx.2011 Advanced online publication: 06.05.2011 DOI: 10.1055/s-0030-1260032; Art ID: C28311SS © Georg Thieme Verlag Stuttgart · New York Abstract: The lithium aldol reaction of a-chloroaldehydes provides 1,2-anti-configured b-ketochlorohydrins. The scope of this reaction is demonstrated as well as its application to the synthesis of the C4– C15 segment of haterumalide NA. Key words: a-chloroaldehydes, aldol reaction, stereoselective syn- thesis, heterocycles, natural products The rapidly evolving field of organocatalysis continues to provide new building blocks for the asymmetric synthesis of natural products. 1 In particular, the construction of het- erocyclic ring systems has been enabled through various strategies, including Michael addition/cyclization 2,3 or hetero-Diels–Alder reactions. 4 As part of our continuing studies on the stereoselective synthesis of biologically ac- tive natural products, 5 we have demonstrated that lithium aldol reactions of a-chloroaldehydes (e.g., 2, Scheme 1) provide b-ketochlorohydrins (e.g., 3), and that these aldol adducts are readily transformed into various heterocycles (Scheme 2). For example, treatment of b-ketochlorohy- drins with a primary amine followed by a reducing agent leads to 3-hydroxypyrrolidines [e.g., (+)-preussin (5)]. 5c Alternatively, stereoselective reduction of the carbonyl function followed by treatment with AgOTf/Ag 2 O 5a or simply heating in water 5b leads to 3-hydroxytetrahydro- furans (e.g., 7). Importantly, employing the organocata- lytic methods developed by MacMillan 6 and Jørgensen, 7 a range of optically enriched a-chloroaldehydes 8 are now readily available and their use renders enantioselectivity to these processes. Based on the demonstrated utility of b- ketochlorohydrins as building blocks for natural product and heterocycle synthesis, 5 and paucity of examples de- scribing their preparation, 9,10 we sought to further explore and summarize the scope of lithium aldol reactions of a- chloroaldehydes. The results of this study along with the application of these methods to a concise synthesis of the C4 to C15 portion of the cytotoxic marine macrolides haterumalide NA (8) 11 and biselide A (9), 12 are described herein. While several isolated examples of reactions involving a- chloroaldehydes and enolates have been reported, 9 the in- termediate metal aldolates are often directly reduced to alkenes 9c or converted into epoxides. 9a As a notable excep- tion, Stille reported the isolation of a b-ketochlorohydrin from the palladium-catalyzed coupling of tributylaceto- nyltin with a-chlorobutyraldehyde, 9b and Barluenga dem- onstrated that the lithium enolate of ethyl acetate coupled smoothly with a-chloroisovaleraldehyde. 9d Although in both cases the sense and degree of diastereoselectivity was not discussed, theoretical studies 13 predict the prefer- ential formation of the 1,2-anti chlorohydrin in such reac- tions. Interestingly, Somfai has recently reported that the stereochemical outcome of Mukaiyama aldol reactions in- volving a-choroaldehydes is largely dependent on the size of the silyl enol ether, and that sterically hindered enol si- lanes afford 1,2-syn chlorohydrins preferentially. 10 Our interest in the reactions of a-chloroaldehydes 14 originally led us to explore the lithium aldol reaction of 4-phenyl-3- Scheme 1 Preparation of b-ketochlorohydrins from a-chloroalde- hydes O 1. LDA, THF, –78 °C O H Cl 3 O OH Cl 2 (84% ee) 1 3 (93% yield, >20:1 dr) 4 gram scale 3 2. Scheme 2 Previously demonstrated methods for heterocycle syn- thesis via b-ketochlorohydrins, and the cytotoxic marine macrolides haterumalide NA and biselide A O OH Cl 8 1. MeNH 2 , THF r.t., 6 h 2. NaCNBH 3 N OH Me 8 4 (ee >99.5%) (78%) (+)-preussin (5) O OH Cl 3 8 1. Me 4 NBH(OAc) 3 AcOH, MeCN –40 °C (83%) 2. H 2 O, 120 °C 5 min (87%) or 2. AgOTf, Ag 2 O THF, 0 °C to r.t. 12 h (91%) O OH 8 3 6 (84% ee) 7 O O R O OH OAc OH O Cl 1 4 8 11 15 20 haterumalide NA (8): R = H biselide A (9): R = OAc H H