Anionic Ring-Contraction Reaction of Cyclic Acetal System: Stereoselective Approach to Multi-Functionalized Oxetanes

Masaki Suzuki; Katsuhiko Tomooka

doi:10.1055/s-2004-817772

LETTER

Anionic Ring-Contraction Reaction of Cyclic Acetal System: Stereoselective Approach to Multi-Functionalized Oxetanes

Masaki Suzuki, Katsuhiko Tomooka*
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan
Fax: +81(3)57343931; e-Mail: ktomooka@apc.titech.ac.jp;

Abstract

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Abstract

The reaction of pantolactone derived bicyclic acetal 1 with alkyl lithiums provides 2,2,4-trisubstituted 3-hydroxy oxetane 2 with high diastereoselectivity.

Key words

acetals - carbanions - stereoselective synthesis - oxetanes - rearrangements

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References

Reviews:

<A NAME="RU27303ST-1A">1a</A> Porco JA. Schreiber SL. In Comprehensive Organic Synthesis Vol. 5: Trost BM. Fleming I. Pergamon; Oxford: 1991. p.151-192

<A NAME="RU27303ST-1B">1b</A> Abe M. Nojima M. J. Synth. Org. Chem., Jpn. 2001, 59: 855

For example:

<A NAME="RU27303ST-2A">2a</A> Thromboxane A₂: Bhalgwat SS. Still WC. J. Am. Chem. Soc. 1985, 107: 6372

<A NAME="RU27303ST-2B">2b</A> Oxetin: Kawata Y. Ikekawa N. Murata M. Omura S. Chem. Pharm. Bull. 1986, 34: 3102

<A NAME="RU27303ST-2C">2c</A> Oxetanocin: Nishiyama S. Yamamura S. J. Synth. Org. Chem., Jpn. 1991, 49: 670

<A NAME="RU27303ST-2D">2d</A> Merrilactone A: Birman VB. Danishefsky SJ. J. Am. Chem. Soc. 2002, 124: 2080

<A NAME="RU27303ST-3A">3a</A> Tomooka K. Yamamoto H. Nakai T. J. Am. Chem. Soc. 1996, 118: 3317

<A NAME="RU27303ST-3B">3b</A> Tomooka K. Yamamoto H. Nakai T. Angew. Chem. Int. Ed. 2000, 39: 4500

All new compounds were fully characterized by IR, ¹H and ¹³C NMR analyses. Data for selected compounds are as follows. Compound α-1a: ¹H NMR (300 MHz, CDCl₃): δ = 7.55-7.52 (m, 2 H), 7.40-7.38 (m, 3 H), 5.98 (d, J = 3.9 Hz, 1 H), 5.85 (s, 1 H), 4.13 (d, J = 3.9 Hz, 1 H), 3.84 (d, J = 8.1 Hz, 1 H), 3.54 (d, J = 8.1 Hz, 1 H), 1.14 (s, 3 H), 1.07 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 137.0, 129.6, 128.4, 126.7, 106.2, 104.7, 88.0, 77.2, 43.0, 24.0, 17.9. Compound β-1a: ¹H NMR (300 MHz, CDCl₃): δ = 7.48-7.44 (m, 2 H), 7.40-7.37 (m, 3 H), 6.09 (s, 1 H), 6.03 (d, J = 3.6 Hz, 1 H), 4.23 (d, J = 3.6 Hz, 1 H), 3.78 (d, J = 8.6 Hz, 1 H), 3.69 (d, J = 8.6 Hz, 1 H), 1.20 (s, 3 H), 1.07 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 137.5, 129.5, 128.4, 126.4, 106.0, 105.7, 88.1, 80.1, 43.0, 25.0, 18.9. IR (neat): 2963, 2873, 1460, 1393, 1222, 1074, 1027, 1008 cm^-1. Anal. Calcd for C₁₃H₁₆O₃: C, 70.89; H, 7.32. Found: C, 71.16; H, 7.26. [α]_D ²⁸ +29.4 (c 3.67, CHCl₃). Compound 2a: ¹H NMR (300 MHz, CDCl₃): δ = 7.61 (d, J = 7.8 Hz, 1 H), 7.41-7.36 (m, 1 H), 7.26-7.25 (m, 3 H), 5.10 (br s, 1 H), 4.92 (d, J = 7.4 Hz, 1 H), 4.44 (d, J = 7.4 Hz, 1 H), 3.63 (d, J = 10.4 Hz, 1 H), 3.00 (d, J = 10.4 Hz, 1 H), 1.60 (br s, 1 H), 0.96 (s, 12 H), 0.84 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 139.2, 128.8, 127.6, 127.2, 126.5, 125.9, 95.9, 88.7, 70.0, 66.7, 39.4, 37.4, 24.7, 24.4, 19.8. IR (reflection): 3235, 2925, 1473, 1391, 1364, 1169, 963, 709, 598 cm^-1. Compound 2e: ¹H NMR (300 MHz, CDCl₃): δ = 4.26 (d, J = 7.0 Hz, 1 H), 4.16 (dd, J = 11.3, 7.0 Hz, 1 H), 3.55 (d, J = 11.1 Hz, 1 H), 3.40 (dd, J = 11.1, 5.3 Hz, 1 H), 2.60 (d, J = 11.3 Hz, 1 H), 2.09 (br s, 1 H), 1.63 (s, 3 H), 0.99 (s, 3 H), 0.97 (s, 9 H), 0.93 (s, 3 H), 0.19 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 103.0, 95.1, 94.1, 82.8, 72.1, 70.0, 37.3, 26.5, 26.2, 20.0, 19.4, 16.6, -4.39, -4.44. IR (neat): 3418, 2956, 2928, 2857, 1472, 1363, 1251, 1123, 835, 777 cm^-1. Compound 6: ¹H NMR (300 MHz, CDCl₃): δ = 7.43-7.29 (m, 5 H), 5.89 (br s, 1 H), 5.45 (dd, J = 2.7, 2.4 Hz, 1 H), 4.56 (br s, 2 H), 4.04 (d, J = 10.5 Hz, 1 H), 3.43 (d, J = 10.5 Hz, 1 H), 1.74 (br s, 1 H), 1.10 (s, 3 H), 1.01 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 141.0, 128.6, 128.3, 128.1, 125.5, 125.3, 91.4, 90.8, 74.4, 66.6, 39.6, 23.5, 20.2. IR (neat): 3332, 2958, 2929, 1454, 1134, 1047, 972, 698 cm^-1.

The diastereomer ratio was determined by ¹H NMR analysis.

The relative stereochemistry of α-1a and 2e was determined by NOE experiment as shown below (Figure [2] ).

<A NAME="RU27303ST-7A">7a</A> Trost BM. Edstrom ED. Angew. Chem., Int. Ed. Engl. 1990, 29: 520

<A NAME="RU27303ST-7B">7b</A> Tomooka K. Nakamura Y. Nakai T. Synlett 1995, 321

Crystallographic data of 4a and 2b have been deposited with the Cambridge Crystallographic Data Center as supplementary publication no. CCDC 225890 and 225891, respectively. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK [fax: +44 (1223)336033; e-mail:
deposit @ccdc.cam.ac.uk].

The relative stereochemistry of 2c was determined by NOE experiment of its acetal derivative as shown below (Scheme [9] ).

The substrate 2d consisted of a 1:1 mixture of two epimers at the chirality center of s-Bu.

General Procedure for the Ring-Contraction Reaction: To a THF (9 mL) solution of 1a (72.4 mg, 0.33 mmol, 62% dr) was added n-BuLi (1.04 mL, 1.27 M in hexane, 1.32 mmol) dropwise at -78 °C. After the addition, the solution was stirred for 15 min at -78 °C, and the temperature was allowed to rise to 0 °C over a period of 1 h. The resulting mixture was stirred at 0 °C for 1 h, and then sat. NH₄Cl aq was added. The mixture was extracted with Et₂O. The combined organic phase was dried over Na₂SO₄, filtered and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane/Et₂O = 1:1) to give the oxetane 2c (67.8 mg, 74%, >95% dr). In the case of the reaction with MeLi, >10 equiv of MeLi was required to drive the reaction to completion.

Acetal 1b was prepared from (-)-pantolactone in three steps as shown below (Scheme [10] ).

We cannot rule out the possibility that the reaction proceeds via not a free carbene but a related carbenoid intermediate.

The alkyl lithium-promoted carbene or a related carbenoid formation in acetal system, followed by its insertion to alkyl lithium has been reported, see:

<A NAME="RU27303ST-14A">14a</A> Shiner CS. Tsunoda T. Goodman BA. Ingham S. Lee S. Vorndam PE. J. Am. Chem. Soc. 1989, 111: 1381

<A NAME="RU27303ST-14B">14b</A> Boche G. Bosold F. Lohrenz JCW. Opel A. Zulauf P. Chem. Ber. 1993, 126: 1873

The exact origin of the observed stereoselectivity is not clear at present, while it might be considered as the result of i) stereoselective formation of benzylic or propargylic chiral carbanion by the diastereoselective carbene insertion to alkyl lithium (B→C) and/or the efficient epimerization
(at C or D), followed by ii) diastereoselective addition reaction via the chelation intermediate (D).

The lactol 5 was prepared from pantolactone(racemic) in two steps: benzylation of the hydroxy group with benzyl bromide, half-reduction with DIBAL.

<A NAME="RU27303ST-17">17</A> The structure of 6 was determined by ¹H NMR analysis and IR analysis of its derivatives as shown below (Scheme 11).It is known that the oxetane-3-one displays a carbonyl absorption in the IR spectrum at about 1820 cm^-1, see: Thijis L. Cillissen PJM. Zwannenburg B. Tetrahedron 1992, 48: 9985