Regio- and Diastereochemical Aspects of the Additions of Li or Zn Derivatives of Methoxypropene to Oxazolidines Derived from Phenylglycinol

Αbstract

Diastereoselective additions of methoxypropene-derived lithium and zinc reagents to oxazolidines are investigated. The ­lithium allylic carbanion reacts with oxazolidines to afford mainly the β-amino alcohols with an enol ether function (γ-adduct) and the zinc derivative leads to amino alcohols with an allyl ether function (α-adduct).

oxazolidine - methoxypropene - organolithium and ­organozinc reagents - β-amino alcohols

References and Notes

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<A NAME="RD09406ST-11">11</A>

Typical Procedure for the Synthesis of Compounds 4. s-BuLi (1.3 M in hexane-cyclohexane, 5.2 mL, 6.8 mmol) was added at -78 °C to a solution of allyl methyl ether (0.60 mL, 6.4 mmol) in THF (10 mL). After stirring for 30 min at -78 °C a solution of oxazolidine (2 mmol) in THF (10 mL) was added dropwise. After the reaction was complete, the mixture was quenched at -78 °C by addition of sat. aq NH₄Cl (15 mL). The aqueous layer was extracted with Et₂O (3 × 15 mL) and the organic layers were combined, dried over MgSO₄ and evaporated. The residue was then purified by chromatography on silica gel.

<A NAME="RD09406ST-12">12</A>

Data for Compound 4d (R = Ph): [2 S ,2 (1 S )]-2-(4-Methoxy-1-phenylbut-3-enylamino)-2-phenylethanol.
Solid, yield 67%; mp 63 °C; [α]_D ²⁰ +37 (c 1.1, CHCl₃). ¹H NMR: δ = 7.33-7.20 (m, 10 H), 5.92 (dt, J = 6.3, 1.3 Hz, 1 H), 4.24 (dd, J = 7.3, 6.3 Hz, 1 H), 3.92 (dd, J = 7.1, 4.6 Hz, 1 H), 3.77 (dd, J = 10.6, 4.6 Hz, 1 H), 3.70 (t, J = 6.4 Hz, 1 H), 3.56 (s, 3 H), 3.53 (dd, J = 10.6, 7.3 Hz, 1 H), 2.9 (br d, 1 H), 2.62-2.45 (m, 2 H), 1.78 (ls, 1 H). ¹³C NMR: 147.7, 144.0, 141.4, 128.5, 128.2, 127.4, 127.1, 127.0, 126.9, 102.5, 65.7, 61.3, 59.6, 59.5, 31.0. IR (CHCl₃): 3374, 3031, 2856, 1660, 1109 cm^-1. Anal. Calcd for C₁₉H₂₃NO₂: C, 76.73; H, 7.80; N, 4.71. Found: C, 76.60; H, 7.83; N, 4.69.

<A NAME="RD09406ST-13">13</A>

Atomic coordinates, bond lengths and angles, and thermal parameters have been deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 293382.

<A NAME="RD09406ST-14">14</A>

This stereochemical outcome is well established for the attack of organometallic reagents onto phenylglycinol-derived oxazolidines, see, ref. 4b and 6a.

<A NAME="RD09406ST-15">15</A>

Typical Procedure for the Synthesis of Compounds 5.
s-BuLi (1.3 M in hexane-cyclohexane, 5.2 mL, 6.8 mmol) was added at -78 °C to a solution of allyl methyl ether (0.60 mL, 6.4 mmol) in THF (10 mL). After stirring for 30 min at -78 °C, a solution of zinc bromide (1 M in THF, 7.2 mL, 7.2 mmol) was added. The mixture was stirred at -78 °C for 40 min and then a solution of oxazolidine (2 mmol) in THF (10 mL) was added dropwise. After completion, the mixture was quenched (at -78 °C for 5a and 5d and at r.t. for 5b and 5c) by addition of sat. aq NH₄Cl (20 mL). The aqueous layer was extracted with Et₂O (3 × 20 mL) and the organic layers were combined, dried over MgSO₄ and evaporated. The residue was purified by chromatography on silica gel.

<A NAME="RD09406ST-16">16</A>

Atomic coordinates, bond lengths and angles, and thermal parameters have been deposited at the Cambridge Crystallographic Data Centre with the deposition numbers CCDC 602015 for 5b, CCDC 612649 for 5d and CCDC 612650 for 5c.

<A NAME="RD09406ST-17">17</A>

Data for Compound 5d (R = Ph): [2 S ,2 (2 S ,1 S )]-2-(2-Methoxy-1-phenylbut-3-enylamino)-2-phenylethanol. Solid, yield 69%; mp 58 °C; [α]_D ²⁰ +38 (c 1.1, CHCl₃). ¹H NMR: δ = 7.32-7.22 (m, 10 H), 5.62-5.54 (m, 1 H), 5.28-5.20 (m, 2 H), 3.89-3.79 (m, 4 H), 3.61-3.56 (m, 1 H), 3.30 (s, 3 H). ¹³C NMR: 141.6, 140.4, 135.5, 128.4, 128.3, 128.0, 127.2, 119.1, 86.1, 65.2, 63.8, 61.1, 56.8. IR (CHCl₃): 3390, 2925, 1764, 1602, 1453, 1094, 699 cm^-1. Anal. Calcd for C₁₉H₂₃NO₂: C, 76.73; H, 7.80; N, 4.71. Found: C, 76.54; H, 7.79; N, 4.54.

<A NAME="RD09406ST-18">18</A> We proved that neither racemization nor epimerization occurred during the formation of the hydrochloride salts. After a basic treatment (NaOH, 1 M), we recovered free unchanged starting amino alcohol.

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<A NAME="RD09406ST-20A">20a</A> Organolithiums in Enantioselective Synthesis   Hodgson DM. Springer; Heidelberg: 2003. 

<A NAME="RD09406ST-20B">20b</A> The Chemistry of Organolithium Compounds   Rappoport Z. Marek I. Wiley; New York: 2004.