The enantioselective synthesis of bistramide A has been achieved with a longest linear sequence of 18 steps. The synthetic strategy involves the use of a distereoselective glycolate alkylation, an aldol addition of a chlorotitanium enolate of N-acylthiazolidinthione, and a Sharpless asymmetric epoxidation to synthesize the three key fragments.

The hydroboration of allenes is a potentially useful but relatively undeveloped method for synthesis of allylic boranes. [1][2][3][4][5][6][7] The hydroboration of monosubstituted allenes with di (isopinocampheyl)borane [(Ipc) 2 BH] generally gives (E)-allylic boranes 4 with excellent selectivity. 3,4,8 It is inferred, based on work of Wang who studied the hydroborations of 1-alkyl-1-trimethylsilylallenes with 9-BBN and dicyclohexylborane, 5,6 that the hydroboration of allenes 1 with (Ipc) 2 BH proceeds via thermodynamically controlled isomerization 4,9 of the kinetically formed (Z)-allylic borane 2 by way of the methallylborane isomer 3 (Figure 1). 10,11,12 Thus, allene hydroboration has not proven generally useful 8 for synthesis of the (Z)-allylic boranes 2 owing to the facile 1,3-isomerization of 2 that leads to 4 (Figure 1). 4,9,13,14 In connection with an ongoing research problem, we needed to develop a stereocontrolled synthesis of (Z)-allylic borane 2 [R = B(OR') 2 ] and explored the hydroboration of allene 1 [R = B(OR') 2 ] with (Ipc) 2 BH. Because attempts to suppress the 1,3-allylic isomerization of 2 [R = B(OR') 2 ] by performing the hydroboration of 1 with (Ipc) 2 BH even at -78 °C in the presence of transition metal catalysts 15 were unsuccessful, 16 we sought to identify a chiral dialkylborane that would hydroborate allenes 1 with high (Z)-stereoselectivity but without competitive 1,3-isomerization of the initially formed (Z)-allylic borane 2. Based on the unusual thermal isomeric stability of (E)-and (Z)-crotyl-10-TMS-9-borabicyclo[3.3.2]decane reagents, 17,18 we targeted the use of and report herein that 10-TMS-9-borabicyclo[3.3.2]decane 7 19,20 is highly effective as a reagent for kinetically controlled allene hydroboration leading to (Z)-allylic boranes 2. 10 Importantly, of the Soderquist borane 7 has enabled us to synthesize several (Z)-allylboranes that are inaccessible by alternative synthetic methods. 1 Non-racemic borane 7 [10-TMS-9-BBD-H] is easily prepared from pseudoephedrine complex 5 by using Soderquist's procedure (Scheme 1). 19,20 Both enantiomers of 5 are commercially available but also are easily prepared in two steps from B-OMe-9-BBN. 17 We found, however, that generation of 7 from ate complex 6 is best performed in the presence of the allene, owing to the instability of 7. 21 Conditions for the kinetically controlled allene hydroboration were optimized by using 8 as the substrate; stereoselectivity was assessed by subjecting the derived allylboranes to an allylboration-oxidation sequence 3 with benzaldehyde (Table 1). A 1:1 mixture of syn-1,2-diol 11a and the 1,2-anti diastereomer 12a was obtained when the hydroboration of 8 was performed at 20 °C for 2 h (entry 1). Decreasing the hydroboration temperature from 20 °C to 0 °C led to a significant improvement in the reaction diastereoselectivity (87 : 13 favoring 11a, entry 2). The optimal balance between product yield and diastereoselectivity was obtained by performing the allene hydroboration at -10 °C for 5 h (75% yield, 11a:...

An efficient synthesis of LY2886721 (1) in five steps and 46% overall yield from the chiral nitrone cycloadduct 2 is presented. Minimizing formation of a des-fluoro impurity during hydrogenolysis to cleave the isoxazolidine ring and remove the benzyl chiral auxiliary was a key challenge. Installation of the aminothiazine moiety required careful stoichiometry control of the reagents BzNCS and CDI, including in situ conversion monitoring, to minimize byproduct formation. A remarkably regioselective peptide coupling afforded 1 without competing acylation at the aminothiazine nitrogen or bis-acylation. Consideration of the combined chemistry and crystallization process identified an optimal solvent system for the peptide coupling and a reactive crystallization that afforded 1 in high purity and with physical property control. A slurry milling operation near the end of the crystallization, followed by "pH cycles" to digest fines formed during milling, significantly reduced the crystal aspect ratio and provided desirable API bulk density and powder flow properties.

[reactiojn: see text] The enantioselective synthesis of (+)-rogioloxepane A has been achieved in 21 steps from 1,5-hexadien-3-ol. The key steps in the synthesis are an asymmetric glycolate alkylation leading to the diene 2 and a subsequent ring-closing metathesis to construct the oxepene core.

The development of a synthesis of an ORL-1 receptor antagonist is described. The key process improvements in the synthetic sequence include a multikilogram bromination process and the development of a convergent coupling strategy. The process improvements resulted in the production of the active pharmaceutical ingredient (API) on a multikilogram scale.