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Synlett 2009(6): 941-944  
DOI: 10.1055/s-0028-1088215
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Enantiodivergent Synthesis of Tetra-ortho-Substituted Biphenyls by Enzymatic Desymmetrization

Kumi Okuyama, Koji Shingubara, Shin-ichiro Tsujiyama, Keisuke Suzuki, Takashi Matsumoto*
Department of Chemistry, Tokyo Institute of Technology, 2-12-1, Ookayama, Meguro-ku, Tokyo 152-8551, Japan
Fax: +81(3)57343531; e-Mail: tmatumo@chem.titech.ac.jp;
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Publication History

Received 15 December 2008
Publication Date:
16 March 2009 (online)

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Abstract

Axially chiral, tetra-ortho-substituted biphenyl derivatives were efficiently synthesized through desymmetrization of σ-symmetric precursors by enzyme-catalyzed hydrolysis. Both of the enantiomers were accessible in highly enantioselective manner and in high yield by suitable choice of enzyme.

Key words

biphenyl - asymmetric synthesis - desymmetrization - enzyme catalysis - hydrolysis

    References and Notes

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6

PFL [Pseudomonas fluorescence lipase (Amano, lipase AK)], PLE [pig liver esterase (Sigma)], PCL [Pseudomonas cepacia lipase (Amano, lipase PS)], CRL [Candida rugosa lipase (Amano, lipase AY)], ANL [Aspergillus niger lipase (Amano, lipase A)], PPL [porcine pancreas lipase (Sigma, Type II)], CAL [Candida antarctica lipase (Roche Diagnostics, Chirazyme l-2)], ROL [Rhizopus oryzae
lipase (Amano, lipase F-AP15)] were tested.

7

Enantiomeric purities of biphenyls 6a-c were determined by chiral HPLC analyses [CHIRALPAK® IA (Daicel), Ø 0.46 × 25 cm, hexane-2-PrOH (9:1), 1.0 mL/min, 20 ˚C, 254 nm] t R = 9.2 min for (-)-6a, 14.5 min for (+)-6a; 12.8 min for (-)-6b, 14.8 min for (+)-6b; 9.7 min for (-)-6c, 12.7 min for (+)-6c.

8

The absolute stereostructures of 6a and 6b were determined by X-ray crystallography after derivatization [(-)-campha­nic chloride, DMAP, pyridine] to 16a and 16b, respectively (Figure  [²] ).

The absolute configuration of (+)-6c was determined by chemical correlation with (+)-6a as shown in Scheme  [5] .

Figure 2

Scheme 5 Reagents and conditions: (a) MOMCl, DIPEA, CH2Cl2, 0 to 25 ˚C; (b) 1 M NaOH aq, MeOH, 0 ˚C; (c) (MeO)2SO2, NaH, DMF, 25 ˚C; (d) 10 mol% NiCl2(dppp), DIBAL, Et2O, -20 to 25 ˚C; (e) IBX, DMSO, 25 ˚C; (f) MMPP, MeOH, 0 to 25 ˚C; (g) 1 M NaOH aq, MeOH, 25 ˚C; (h) (MeO)2SO2, NaH, DMF, 25 ˚C; MMPP: mag­nesium monoperoxyphthalate hexahydrate.

9

Though less effective, (R)-6b and (R)-6c were also obtained with CAL or PCL, and (S)-6b was also obtained with PLE. It is interesting to note that the enzymes of microorganism origin (ROL, CAL, PCL) showed R preference and the enzymes of mammalian origin (PPL, PLE) showed S preference, whether necessarily or not.

10

In contrast, the racemization easily occurred under the basic conditions, as revealed by attempted methylation of the phenol in 6a: Treatment of 6a with MeI (3.0 equiv) and K2CO3 (1.5 equiv) in acetone at 50 ˚C afforded the desired methyl ether in 95% yield but with substantial decrease in ee (91%). Formation of the corresponding diacetate 1a and diol 7a, albeit in trace amount, suggested involvement of the intermoleculer acyl migration. Nonetheless, other protections, including methoxymethylation and tert-butyldimethylsilylation, proceeded without affecting enantiomeric integrity.

13

Quinone 15 proved to racemize gradually after isolation [95% ee after three weeks in a refrigerator (4 ˚C)].