Lipase-Catalyzed Kinetic Resolution of 4-(N-Boc-amino)-1-alken-3-ols

Abstract

A wide range of 4-(N-Boc-amino)-1-alken-3-ols were efficiently resolved by lipase-catalyzed kinetic resolution. This procedure has been successfully applied to the highly enantioselective synthesis of the taxol side chain.

4-(N-Boc-amino)-1-alken-3-ols - kinetic resolution - lipase - the taxol side chain

References

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<A NAME="RU19203ST-10">10</A>

Prepared as shown below (Scheme [4] ).

Scheme 4 Reagents and conditions: (a) LDA, -78 °C, acrolein; (b) 1 M NaOH-MeOH, H⁺; (c) DPPA-Et₃N-toluene; (d) Boc₂O-Et₃N-DMAP-toluene, r.t., 6 h; (e) Separation by medium-pressure column chromatography (SiO₂); (f) Cs₂CO₃-MeOH, r.t., 12 h.

<A NAME="RU19203ST-11">11</A>

The enantiomeric purities of (3R,4R)-1-OAc, (3S,4S)-1, (3R,4S)-2-OAc, and (3S,4R)-2 were analyzed by HPLC (Chiralcel OD-H or Chiralcel OJ-H, hexane-2-propanol) after being converted to suitably protected compounds as described below (Figure [1] ).

Figure 1 1a: R′ = CONHPh, OD-H, 50:1, 230 nm; 1b: R′ = CONHPh, OD-H, 30:1, 230 nm; 1c: R′ = CONHPh, OD-H, 20:1, 254 nm; 1d: R′ = Bz, OD-H, 50:1, 254 nm; 1e: R′ = H, OJ-H, 50:1, 230 nm; 2a: R′ = Bz, OD-H, 50:1, 254 nm; 2b: R′ = Bz, OD-H, 50:1, 254 nm; 2c: R′ = H, OD-H, 20:1, 230 nm; 2d: R′ = H, OD-H, 20:1, 230 nm; 2e: R′ = Bz, OD-H, 30:1, 254 nm.

<A NAME="RU19203ST-12">12</A>

A typical procedure is as follows: A mixture of 2d (11.4 mmol), 2-propenyl acetate (34.3 mmol), and CAL-B (1.14 g, 0.1 g per mmol of 2d) in toluene (34 mL, 3 mL per mmol of 2d) was stirred at 50 °C for 48 h. The lipase was removed by filtration and the filtrate was concentrated to give crude solids. Purification by column chromatography (SiO₂) afforded (3R,4S)-2d-OAc (5.58 mmol, 49%) and (3S,4R)-2d (5.59 mmol, 49%).

<A NAME="RU19203ST-13A">13a</A> Chen C.-S. Fujimoto Y. Girdaukas G. Sih CJ. J. Am. Chem. Soc.  1982,  104:  7294 

<A NAME="RU19203ST-13B">13b</A> Chen C.-S. Wu S.-H. Girdaukas G. Sih CJ. J. Am. Chem. Soc.  1987,  109:  2812 

<A NAME="RU19203ST-14A">14a</A> (3R,4R)-3-OAc was methanolyzed (K₂CO₃/MeOH, r.t., 40 min) to the corresponding alcohol (3R, 4R)-3, which was analyzed by HPLC (Chiralcel OD-H, hexane-2-propanol = 4:1, 254 nm). (3R,4S)-4-OAc and (3S,4R)-4 were converted to the corresponding phenyl carbamates (PhNCO/Py, r.t., 6 h), which were analyzed by HPLC (Chiralcel OD-H, hexane-2-propanol = 5:1, 254 nm). Ohno reported that the modification of a protecting group at amino moiety changes the enantioselectivity of esterase-catalyzed hydrolysis of esters: Ohno M. Kobayashi S. Iimori T. Wang Y.-F. Izawa T. J. Am. Chem. Soc.  1981,  103:  2405 

<A NAME="RU19203ST-14B">14b</A>

In our case, the reverse of the enantioselectivity was not observed.

<A NAME="RU19203ST-15A">15a</A>

Prepared as follows: A mixture of 2-phenyl-3-hydroxy-4-pentenoic acids (anti/syn = 10:1), readily available by the Mulzer’s protocol, [15b] was subjected to Curtius reaction to give a trans cyclic carbamate as the sole product.

<A NAME="RU19203ST-15B">15b</A> Mulzer J. Segner J. Brüntrup G. Tetrahedron Lett.  1977,  4651 

<A NAME="RU19203ST-15C">15c</A>

The corresponding cis cyclic carbamate was not produced probably due to the intensive retro-aldol reaction of the intermediary β-hydroxy acyl azide. Syn (±)-5 was provided in good yield after N-protection followed by ring opening (Scheme [5] ).

Scheme 5 Reagents and conditions: (a) LDA (2.1 equiv), 0 °C, 1 h, concentrated to dryness; (b) acrolein-THF, 0 °C-r.t., 48 h; (c) DPPA-Et₃N-toluene; (d) Boc₂O-Et₃N-DMAP, THF, 54% in 3 steps; (e) Cs₂CO₃-MeOH, r.t., 12 h, 75%.

<A NAME="RU19203ST-16">16</A>

Methanolysis (K₂CO₃-MeOH, r.t., 40 min) provided the corresponding alcohol, which was analyzed by HPLC (Chiralcel OD-H, hexane-2-propanol = 20:1, 230 nm).

<A NAME="RU19203ST-17">17</A> Wang Z.-M. Kolb HC. Sharpless KB. J. Org. Chem.  1994,  59:  5104