31P NMR (121 MHz, CDCl3) 35.5 Hz. limited to alkyl halides activated by neighboring electron-withdrawing groups8,23,24 and are ineffective on unactivated alkyl halides unless forcing conditions are used (i.e., hexamethyl disilazane (HMDS), 110 C). Recently, Liu et al. have shown that HMDS conditions result in racemization of amino acid stereocenters,25 and often even these harsh conditions result in rather low yields.8,26C29 Boyd and Regan reported that this reaction proceeds in good yield at room temperature regardless of the nature of the electrophile,30 but you will find no other examples of this in the literature. The lack of suitable methodology for the introduction of carbonCphosphorus bonds into highly functionalized molecules has led us to investigate new protocols for the formation of these bonds. Results and Discussion Initially, this research focused on the use of Schollkopfs bis-lactim ether 331 in the synthesis of phosphinate pseudopeptide 2 (Plan 2). This approach provides a stereoselective route to the N-terminal amino acid of the pseudopeptide and entails phosphinic acid synthon 4, made up of both the N- and C-terminal PCC bonds of 2. The PX-866 (Sonolisib) phosphinic acid would, in turn, be synthesized via reaction of the nucleophilic PIII reagent, (TMSO)2PH, bis-(trimethylsilyl)-phosphonite (BTSP), and a homoallylic electrophile 5, made up of the carbon backbone of the C-terminal glutaric acid moiety of 2. Reaction of the producing lipase was used,48 but the microorganism was subsequently identified as Amano P (Amano Pharmaceutical Co.).49 We have found that Lipase AK Amano from your same supplier works equally well for this reaction. The producing alcohol 22 was converted to xanthate 23 in 97% yield. Pyrolysis of 23 furnished ethyl 3-(isomer, e.g., 37) could be problematic, and therefore the 2,3-isomer (e.g., 36) was desired. The most common and highly stereoselective method for the stereoselective formation of diols from olefins is the Sharpless asymmetric dihydroxylation.54 Unfortunately, the Sharpless process does not provide good asymmetric induction with disubstituted alcohol 16 with trityl chloride in pyridine provided the trityl ether in 94% yield. Oxidation of 38 was first attempted using the classic Upjohn process56 of catalytic OsO4 and NaIO4, which provided a 90% yield of 1 1.25:1 mixture of the and diols 39 and 40, respectively (Plan 12). The use of the trityl protecting group allowed for easy separation of the two isomers. An alternative oxidant, KMnO4, gave much better selectivity (2,3-(39:40), 6:1) than OsO4 but the reaction yield was much lower, 64% vs 90%, resulting in formation of about the same amount of the desired 2,3-product 39 via either route. On the basis of these results, the OsO4 process is favored because of a more facile workup and less difficult purification of the product than with the KMnO4-based oxidation. The 2 2,3-and 2,3-diols were converted to the acetonides by treatment with 2,2-dimethoxypropane, acetone, and catalytic acid in 96% yield for the 2 2,3-isomer 41, and 95% for the 2 2,3-isomer 42 (Plan 12). Open in a separate window Plan 12 The stereochemistry of the PX-866 (Sonolisib) two oxidation products 39 and 40 was assigned on the basis of their NOESY NMR spectra (Physique 1). The stereochemical assignment is usually supported by the NOE cross-peak observed between the protons on C1 and C3 of 40. There was no NOE observed for the equivalent protons of 39. The 2 2,3-and 2,3-stereochemistry assigned using the NOESY PX-866 (Sonolisib) spectrum of 39 and 40 was further supported by the coupling constant for the C2 and C3 protons on 41 and 42. For compound 41 the (47) and 2,3-(48) isomers of the bromomethyl acetonides, derived from the 3isomer 47, with correct stereochemistry for elaboration to 2, was then used with longer reaction times in an attempt to force the reaction to completion. Unfortunately, even after 1 month only 24% conversion was observed by 31P NMR. As expected, the reaction was PX-866 (Sonolisib) even slower around the isomer 48 with less than 5% Gpc4 conversion after several weeks. The low yields of the desired complex phosphinic acids (e.g., 49 and 50) obtained in the reactions of all isomers of 3-(bromomethyl)-cyclopentane 1,2-acetonides, together with the double bond migration observed with the corresponding cyclopentene (Plan 10), indicated that (bromomethyl)-cyclopentene derivatives would not be effective glutarate surrogates as proposed in our retrosynthetic analysis for the stereoselective synthesis of the C-terminal CCP bond (Plan 3 and Plan 4). Therefore, an alternate route to the desired compounds was explored. Open in a separate window Plan 14 Two possible compounds that could be appended to 15 to furnish the desired product 2 are an acyclic bromomethyl derivative of dimethyl glutarate such as 51 or a methylene.