Highly Efficient, Convergent, and Enantioselective Synthesis of Phthioceranic Acid

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1 Highly Efficient, Convergent, and Enantioselective Synthesis of Phthioceranic Acid Shiqing Xu, Akimichi Oda, Thomas Bobinski, Haijun Li, Yohei Matsueda, and Ei-ichi Negishi Angew. Chem. Int. Ed. 2015, 54, I. Introduction Synthetic challenge There are no heterofunctional groups to assist asymmetric C-C or C-H bond formation. Synthetic strategy comparison Linear-iterative vs convergent Linear-iterative method Deoxypropionate subunits are common structural motifs in a lot of bioactive natural products. Installation of temporary functional or chiral directing groups; one deoxypropionate unit after another; 3-6 steps for one iteration cycle to set one chiral methyl group. Long synthetic steps, low efficiency, use of stoichiometric amount of chiral auxiliaries. Liu lab Peng Zhao 1

2 (1) Glenn C. Micalizio et al.: Literature Summary: Convergent Synthesis of Deoxypropionates [ClTi(OiPr) 3 ]-mediated alkyneallylic alcohol cross-coupling Hydroxyl-directed asymmetric hydrogenation of homoallylic alcohol Micalizio, G. C. et al. Angew. Chem. Int. Ed. 2012, 51, ; J. Am. Chem. Soc. 2007, 129, ; Science of Synthesis, 2012, 33-97; Evans, D. A. et al. Tetrahedron Lett. 1985, 26, ; Brown, J. M. Angew. Chem. Int. Ed. 1987, 26,

3 Literature Summary: Convergent Synthesis of Deoxypropionates (2) Christoph Schneider et al.: Pd-catalyzed Suzuki coupling Ir-catalyzed asymmetric hydrogenation Suzuki coupling: 9-MeO-9-BBN variant No added base Mostly for sp sp 2 and sp 3 sp 2 coupling Schneider, C. et al. Angew. Chem. Int. Ed. 2013, 52, ; Chem. Eur. J. 2014, 20, ; Furstner, A. et al. Chem. Commun., 2012, 48,

4 (3) Varinder K. Aggarwal et al.: Literature Summary: Convergent Synthesis of Deoxypropionates Traceless lithiation borylation protodeboronation Aggarwal, V. K. et al. Nat. Chem. 2014, 6, ; Acc. Chem. Res. 2014, 47, ; Renaud, P. et al. J. Am. Chem. Soc. 2011, 133, ; J. Am. Chem. Soc. 2005, 127,

5 Limitation of current convergent routes Key steps to link fragments together are not suitable for stereoselective construction of the deoxypropionate unit. Extra transformations for certain chiral methyl group, such as asymmetric hydrogenation, are needed where the stereoselectivity is substrate-dependent. Goal of this paper Novel convergent strategy to form deoxypropionate directly in a stereoselective manner. II. Retrosynthetic Analysis ZACA High-yielding, efficient, selective and catalytic asymmetric C-C bond formation C-C bond formation from terminal alkene without requiring any other functional groups Tolerate to various functional groups Tandem ZACA/Pd- or Cu-catalyzed cross coupling Widely applicable and potentially economical Negishi, E. et al. J. Am. Chem. Soc. 1995, 117, ; J. Am. Chem. Soc. 2003, 127, ; Angew. Chem. Int. Ed. 2011, 50, ; Proc. Jpn. Acad., Ser. B 2015, 91,

6 III. Synthesis Optimization on ZACA reaction Table 1: Water effect on the ZACA reaction of 1-octadecene Entry [(+)- (NMI) 2 ZrCl 2 ] a H 2 O Yield (%) b ee (%) c 1 3 mol% none 0 NA 2 1 mol% 100 mol% mol% 50mol% mol% 5 mol% mol% 2 mol% Bimetallic mechanism: Me 2 AlCl-ZrCp 2 MeCl induced carbometallation Catalytic amount of ZrCp 2 Cl 2, but stoichiometric amount of Me 3 Al Mechanistic role of water is unclear here, while there are several examples exist. 6 1 mol% 2 mol% 82 d 77 [a] Freshly prepared. [b] Isolated yield. [c] Determined by 1 HNMR of Mosher ester analysis of the alcohol 6. [d] Yield obtained after 24 hr. Wipf, P. et al. Angew. Chem. Int. Ed. 1993, 32,

7 Stereoselectivity Four-centered syn Me-Zr addition Zr-alkene interaction on the Re face of the alkene Competing side reactions in ZACA Cyclic carbometalation: In hexanes cyclic carbometalation would proceed, while polar solvents, such as CH 2 Cl 2, CH 3 CHCl 2, and (CH 2 Cl) 2, suppress it. H-transfer hydrometalation: Bulky ligand, such as NMI, would suppress it. Ziegler Natta-type alkene polymerization: Use one equiv. or less alkene. 7

8 Synthesis of building block 2a and 3a Tandem ZACA-Negishi coupling Vinylation procedure A: 3 critical factors: Zn(OTf) 2 as additive; Pd(DPEphos)Cl 2 and DIBAL-H in a 1:2 molar ratio; DMF as a solvent. Vinylation procedure B: Alkyl-I --- Alkyl-Li --- Alkyl---ZnX 2 8

9 Synthesis of building block 4 9

10 Optimization on fragments linkage by stereo-selective sp 3 -sp 3 cross-coupling Table 2: Optimization of stereospecific Cu-catalyzed cross-coupling of 4 Entry Catalyst Ligand X Yield (%) a 1 CuI TMEDA Br 40 2 CuI TMEDA Cl 38 3 CuI PMDETA Br 69 4 CuI HMTETA Br 67 5 CuI 2,2 -bipyridyl Br 71 6 CuI 2,2 :6,2 -terpyridine Br 46 7 CuI 1,10-phenanthroline Br 52 8 CuCl 2,2 -bipyridyl Br 62 9 CuI b 2,2 -bipyridyl b Br 75 [a] Isolated yields. [b] CuI (20 mol%) and 2,2 -bipyridyl (40 mol%) were used. TMEDA=N,N,N,N -tetramethylethylenediamine, PMDETA=N,N,N,N,N -pentamethyldiethylenetriamine, HMTETA=1,1,4,7,10,10-hexamethyltriethylenetetramine. Cu-catalyzed cross-coupling reaction of nonactivated alkyl halides/pseudohalides with secondary alkyl Grignard reagents S N 2 mechanism with inversion of configuration Lithium cation may help to stabilize the cuprate complexes Amine additive may suppress undesirable side reactions such as olefin formation via loss of hydrogen halide. Liu, L. et al. J. Am. Chem. Soc. 2012, 134, ; Angew. Chem. Int. Ed. 2011, 50, ; Chem. Commun. 2012, ; Chem. Eur. J. 2014, ; Jarvo, E. R. et al. Tetrahedron 2013, 69,

11 Highly convergent synthesis of phthioceranic acid (1) Catalytic amounts of RuCl 3 plus excess secondary oxidant NaIO 4 RuO 4 shows high selectivity towards cleavage products, not epoxidized or dihydroxylated intermediates. Electron-rich olefins are converted into carboxylic acids. The formation of carboxylic acids requires at least 4 eq. of NaIO 4. CH 3 CN is crucial: it can coordinate with insoluble lower valent ruthenium carboxylate complexes and return it to the catalytic cycle. Summary Longest linear sequence: 8 steps Key steps: ZACA-Pd-catalyzed vinylation, and two sequential Cu-catalyzed stereospecific sp 3 -sp 3 cross-coupling Sharpless, K. B. et al. J. Org. Chem. 1981, 46, ; Gebbink, R. J. M. K. et al. Catal. Sci. Technol., 2014, 4,