Indian Journal of Chemistry Vol. 48B, December 2009, pp. 1749-1756 Weinreb amide based building blocks for convenient access to various synthetic targets B Sivaraman, B N Manjunath, A Senthilmurugan, K Harikrishna & Aidhen Indrapal Singh* Department of Chemistry, Indian Institute of Technology, Madras, Chennai 600 036, India E-mail: [email protected] Received and accepted 16 August 2009 N-Methoxy-N-methylamide, popularly known as the Weinreb amide (WA), has served as an excellent acylating agent for organolithium and/or organomagnesium reagents and a robust equivalent for an aldehyde group. The stability of the WA functionality, its ease of preparation, the scalability of its reactions and its predictable reactivity are the key features responsible for its prominent use in several synthetic endeavors by the chemists world-wide. The development of WA-based building blocks and synthetic equivalents for interesting synthons has been a long drawn pursuit initiated in nineties and through this mini-review accomplishments in this direction, with particular emphasis on the building blocks, developed recently in the last three years are summarized. Keywords: Weinreb amide, building blocks, synthetic equivalent, FTY 720, olefination, sulfone, α-diketones, 4-aryl- tetrahydroisoquinoline N-Methoxy-N-methylamide 1, popularly addressed as in late nineties has come a long way3a. In this mini- the Weinreb amide, has served as an excellent review, our accomplishments in this direction, with acylating agent for organolithium or organomagnesium particular emphasis on the building blocks, developed reagents and as a robust equivalent for an aldehyde recently in last three years have been summarized3. group1. These two aspects have been exploited Although the initial developments of these synthetic exhaustively in various synthetic endeavors2. equivalents were driven by specific objectivity, their Successful acylation by a variety of organolithium and use is left to one’s imagination and for any synthetic organomagnesium reagents or reductions by lithium endeavors. The interest in deoxy-sugars and acyl aluminum hydride or diisobutylaluminum hydride to anion chemistry lead to the idea of synthesizing two aldehyde is due to the putative and stable tetrahedral WA-based building blocks 4 and 5 (Figure 2). The intermediate 2 or 3 formed upon addition of the first former was aimed with the purpose of two-carbon equivalent of the organometallic species or reducing homologation of acyclic sugar derivatives and the agent (Figure 1). This stability precludes the collapse later for the synthesis of 1,4 diketones through the to a ketone or aldehyde under the reaction conditions acyl anion chemistry. The synthetic equivalent 4, and thus prevents the formation and subsequent N-methoxy-N-methyl-2-phenylsulfonyl-acetamide, possibility of addition to the ketone or aldehyde. The developed for two carbon homologation of alkyl halides, stability of the WA functionality, its ease of can be easily prepared from the reaction of sodium salt preparation, the scalability of its reactions and its of phenylsulfinic acid with α-chloro-N-methoxy-N- predictable reactivity are the four main reasons for the methylacetamide4. Reagent 4 undergoes a clean increasing confidence that synthetic organic chemists alkylation at the active methylene group with various have with regard to the use of the WA in various alkyl halides, especially from the carbohydrate domain 3 synthetic endeavors . under the mild reaction conditions of K2CO3 in DMF (Figure 3). Subsequent reductive desulphonylation with Concept of WA-based building block from our sodium amalgam leads to a two carbon homologated group during late nineties product 6. Reduction of the WA functionality in 6 to Synthesis of new building blocks based upon aldehyde renders the building block 4 equivalent to an Weinreb amide functionality a pursuit initiated by us acetaldehyde carbanion (synthon A) 4. 1750 INDIAN J. CHEM., SEC B, DECEMBER 2009 O Li O O M This approach of homologating halides through the OMe OMe OMe use of reagent 4, becomes very important because two R N R N R N H R Me Me 1 Me carbon homologation of aldehydes with α-stereo- centers do have a fear of epimerization especially 231 with Wittig based reagents under basic conditions. The two carbon homologation of threo-configured iodide 7 enabled efficient synthesis of 4,5-O-isoprop- O O ylidine protected L-rhodinose5 an important trideoxy R H R R1 sugar and that of erythro-configured iodides 8 and 9 Figure 1 have enabled synthesis of another trideoxy sugar, D-amicetose6. With the use of arabino-configured iodide 10 as the alkylating halide for the 4, it Me O furnished the synthesis of 2,3-dideoxy-4,5: 6,7-di-O- N OMe PhO2S OMe Br N isoprop-ylidene-D-arabino-heptose 11, which corres- 4 O 5 Me ponded to C3-C9 fragment of a natural product (+)- aspicillin4. The convenient availability of 4 on multi- gram scale through simple reactions and its successful H O use in two carbon homologation, afforded itself a place in Aldrich catalogue7. Although synthetic O equivalent 4 could chain extend open-chain primary A B halides conveniently, it failed to do the same during an attempt to execute C-C bond formation at the Figure 2 anomeric carbon in the pyranosyl iodide 12. This was O O 1. Alkylation, RX PhO S OMe R OMe 2 N N 2. Desulphonation 6 Me 4 Me 69%-82% O OTBS O I I I O OBn O RX = 7 8 9 O O O I O 10 OH OH O O O O O O OH OH O L-rhodinose D-amicetose [ Acyclic forms of 2,3,6-Trideoxyhexoses 11 L-rhodinose and D-amicetose] OBn OBn O B BnO O SO Ph BnO 2 BnO + 4 BnO X BnO I BnO CON(OMe)Me 12 B: K2CO 3/NaH Figure 3 SIVARAMAN et al.: WEINREB AMIDE BASED BUILDING BLOCKS 1751 probably due to the poor stability of iodide 12 under N-disubstituted)amino ketones 15 (ref. 9, Scheme I). the reaction conditions (Figure 3). Successful alkylation of the carbanion 16 derived from The genesis of synthetic equivalent 5, N-methoxy-N- α-aminonitriles 13, an acyl anion equivalent with 5 is methyl-3-bromopropionamide, derived from 3- the key step. Successful addition of the variety of bromopropanoic acid was a result of our interest in the Grignard reagents onto the alkylated intermediate 17 use of α-aminonitriles 13 as acyl anion equivalents. and unmasking the carbonyl group in the product 18 Synthetic equivalent 5, equivalent to synthon B has under acidic hydrolytic conditions paved the way for been applied to the synthesis of two different targets, the synthesis of 1,4-diketones 14. Nucleophilic an unsymmetrical 1,4 -diketones 14 (ref. 8) and β-(N, displacement of bromine in 5 with various secondary amines and subsequent Grignard addition on to β- O O RMgX amino WA 19 furnished the β-amino ketones 15. N O N O OMe Our failure to accomplish the C-C bond formation R N R 1 R = alkyl, R1 at the anomeric center using 4, inspired us to explore CN Me CN aryl or a strategy similar to the one developed by Kametani et 70%-78% 17 18 hetero aryl CuSO4, aq. MeOH al.10 wherein the phenylthioglycoside 20 had been 16 reflux, 3 h O reacted cleanly with diazo derivative of dimethyl 5 R malonate 21 in the presence of rhodium(II) acetate. R1 R =R =Bn, This lead to the proposal of synthetic equivalent 22 R2 2 3 14 O R2=R3=alkyl, towards the possible accomplishment of the C-C bond HN 68%-79% R2=R3=-(CH2)3- formation under the mild and neutral condition using R3 R =R =-(CH) -O-(CH ) - 2 3 2 2 2 2 rhodium(II) acetate as a catalyst. The synthetic R2 Me RMgX R2 equivalent 22, a crystalline orange colour solid (m.p. -40 oC-0 oC N N N R 82-84ºC) could be readily prepared in 72% yield by R OMe 1.5 h 3 R3 reacting the sulfone WA 4 with tosyl azide in the 19 O R=alkyl, 15 O 11 75%-91% aryl or 65%-83% presence of DBU as a base . When synthetic hetero aryl equivalent 22 was reacted with thioglycoside 20, CN CN using rhodium (II) acetate as a catalyst at RT in O N NaH/ DMF O N dichloromethane, it was found that thioglycoside 20 R R1 1 R =arylor remained unreacted and was completely recovered, R1 =arylor 1 heteroaryl heteroaryl while the diazo compound 22 was completely 13 16 consumed (Scheme II). The intermediate of rhodium Scheme I carbenoid 23 formed under the reaction conditions, N2 OMe TsN3,DBU,DCM 0 oC, 4 h, 72% N 4 PhO2S Me 22 O OAc OAc O 22;Rh(OAc)4.6H2O O SPh AcO SPh X AcO SO 2Ph AcO AcO OAc DCM, 1 h OAc CON(OMe)Me r.t. 20 2 O O MeO OMe O Rh(OAc) N Me N2 OMe PhO2S 21 N PhO S Me O OAc 2 24 O O SPh AcO COOMe 23 AcO OAc COOMe Scheme II 1752 INDIAN J. CHEM., SEC B, DECEMBER 2009 underwent a facile intramolecular C-H insertion at the buiding block 4, or with the reaction of diazo C-H bond of –OMe group to furnish 24. The product compound 22 derived thereof with phenylthioglycol- obtained was evident from 1H NMR data. It showed side 20, prompted further search towards alternatives the presence of three doublet of doublets at δ 4.30, in achieving this objective. Since appending of WA- 4.60 and 4.90 for three protons. Also 13C NMR, along containing fragment at the anomeric position would with DEPT studies showed the presence of methylene enable further derivatization, this objective was carbon at δ 66.4 and methine carbon at δ 67.5 (ref.