Synthesis of Optically Active δ-Dodecalactone via Chiral Resolution Using CPF

Abstract

(R)-6-Heptyltetrahydropyran-2-one and its S-enantiomer were synthesized via chiral resolution of (±)-1-undecen-4-ol by (R)-3a-allyl-3,3a,4,5-tetrahydro-2H-cyclopenta[b]furan (CPF). The R-enantiomer has sophisticated strong, fruity flavor, while the ­flavor of the S-enantiomer is soft and sweet, similar to apricot.

Key words

chiral resolution - acetals - flavor - alkenyl ethers

References and Notes

• 1a Riu-Aumatell M. Peztamames EL. Buxaderas S. J. Agric. Food Chem.  2005,  53:  7837 
• 1b Ito N. Wada S. Yamamoto Y. Takagaki H. Nakamura H. Biosci. Biotechnol. Biochem.  2005,  69:  2416 
• 2 Fukuhara K. Li X.-X. Okamura M. Nakahara K. Hayata Y. J. Jpn. Soc. Hort. Sci.  2005,  74:  300 ; and the references cited therein
• 3 Endo M, Nakano Y, and Yamada T. inventors; JP Patent  2005002010. 
• 4a Nemoto H. Tetrahedron Lett.  1994,  35:  7785 
• 4b Nemoto H. Tsutsumi H. Yuzawa S. Peng X. Zhong W. Xie J. Miyoshi N. Suzuki I. Shibuya M. Tetrahedron Lett.  2004,  45:  1667 
• 4c Zhong W. Xie J. Peng X. Kawamura T. Nemoto H. Tetrahedron Lett.  2005,  46:  7451 
• 4d Nemoto H. Yamada T. Kagaku (Kyoto)  2005,  60:  20 
• 4e Nemoto H. Peng X. Zhong W. Xie J. Kawamura T. Nishida M. Synlett  2005,  3103 
• 4f Nemoto H. inventors; PCT Int. Appl., WO  2005080300. 
• 4g Sakamoto K. Nemoto H. Yuki Gosei Kagaku Kyokaishi  2007,  626 
• 5 Blanco L. Guibé-jampel E. Rousseau G. Tetrahedron Lett.  1988,  28:  1915 
• 8 A technology employing a flow-system simulated moving bed (SMB) column has been applied for the industrial-scale reaction. For an example of recent papers about SMB, see: Paredes G. Mazzotti M. J. Chromatogr. A  2007,  1142:  56 
• 11 Costa AL. Piazza MG. Tagliavini E. Trombini C. Umani-Ronchi A. J. Am. Chem. Soc.  1993,  115:  7001 
• 12 Reetz MT. Pure Appl. Chem.  1988,  60:  1607 
• 16 Endo M, Nakano Y, and Yamada T. inventors; PCT Int. Appl., WO  2004106320. 

6

The synthetic route shown in Scheme [1] was also applicable to all the lactones 1 (n = 3-6).

7

The ΔR _f value between the isopropyl esters 5a and 5b was as large as those between the corresponding methyl or ethyl esters. Thus, the high efficiency of chiral resolution of 3 is not due to the isopropyl ester moiety. Incidentally, the chemical yield of 3 from lactone 2 (85%) was much higher than the chemical yields of the corresponding methyl or ethyl esters (<8%), probably because reversible reaction from 3 to 2 is much slower than those from the corre-sponding methyl or ethyl esters to 2. This is the reason for the choice of the isopropyl ester.

9

TLC equipment was obtained from Merck (1.05715.0009, Silica gel 60F₂₅₄).

10

Although preparations of ca. 30 kg of (R)- and (S)-2 were also carried out in similar manner, it was not a simple batch procedure. Thus, the procedure for a ca. 1-kg scale is described. After isolation and purification, optical rotations of the two enantiomers were measured under new conditions. (R)-2: [α]_D ⁴⁰ +46.9° (c = 1.00, heptane); (S)-2: [α]_D ⁴⁰ -46.4° (c = 1.00, heptane).

13

8a: a colorless oil; [α]_D ²⁰ -36.0° (c = 2.765, CHCl₃). FTIR: 3074, 2927, 1639, 1434 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 5.76-5.91 (m, 2 H), 5.00-5.07 (m, 4 H), 3.75-3.84 (m, 3 H), 2.16-2.28 (m, 3 H), 2.04-2.09 (m, 2 H), 1.93 (ddd, J = 5.2, 6.8, 12.0 Hz, 1 H), 1.68 (dt, J = 7.6, 12.0 Hz, 1 H), 1.48-1.62 (m, 8 H), 1.24-1.31 (m, 9 H), 0.88 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 136.9 (CH), 135.7 (CH), 117.6 (CH₂), 116.5 (C), 73.2 (CH), 65.9 (CH₂), 54.6 (C), 40.6 (CH₂), 39.8 (CH₂), 38.4 (CH₂), 36.5 (CH₂), 35.6 (CH₂), 35.3 (CH₂), 31.9 (CH₂), 29.9 (CH₂), 29.4 (CH₂), 25.1 (CH₂), 22.8 (CH₂), 21.6 (CH₂), 14.2 (CH₃). EI-MS: m/z = 321 [M + 1]⁺. HRMS (EI): m/z calcd for C₂₁H₃₆O₂: 320.2715; found: 320.2714.
8b: a colorless oil; [α]_D ²⁰ -6.7° (c = 4.17, CHCl₃). FTIR: 3074, 2932, 1639, 1434 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 5.78-5.90 (m, 2 H), 4.98-5.06 (m, 4 H), 3.71-3.80 (m, 3 H), 2.32 (t, J = 6.0 Hz, 2 H), 2.25 (dd, J = 6.4, 13.6 Hz, 1 H), 2.03-2.10 (m, 2 H), 1.92 (dt, J = 6.0, 12.4 Hz, 1 H), 1.66 (dt, J = 7.6, 12.0 Hz, 1 H), 1.38-1.63 (m, 8 H), 1.24-1.31 (m, 9 H), 0.88 (t, J = 6.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 136.9 (CH), 135.6 (CH), 117.8 (CH₂), 116.5 (C), 73.4 (CH), 65.7 (CH₂), 54.6 (C), 40.6 (CH₂), 40.5 (CH₂), 38.4 (CH₂), 36.7 (CH₂), 35.1 (CH₂), 34.8 (CH₂), 31.9 (CH₂), 29.8 (CH₂), 29.4 (CH₂), 25.6 (CH₂), 22.7 (CH₂), 21.6 (CH₂), 14.2 (Me). EI-MS: m/z = 321 [M + 1]⁺. HRMS (EI): m/z calcd for C₂₁H₃₆O₂: 320.2715; found: 320.2691.

14

( S )-9: [α]_D ²⁰ -10.8° (c = 1.56, CHCl₃). FTIR: 3076, 2928, 2857, 1640, 1460 cm^{- 1}. ¹H NMR (400 MHz, CDCl₃): δ = 5.77-5.87 (m, 1 H), 5.00-5.05 (m, 2 H), 3.65-3.71 (m, 1 H), 2.18-2.23 (m, 2 H), 1.29-1.41 (m, 15 H), 0.89 (s, 9 H), 0.05 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 135.5 (CH), 116.5 (CH₂), 72.1 (CH), 42.0 (CH₂), 36.9 (CH₂), 31.9 (CH₂), 29.8 (CH₂), 29.4 (CH₂), 26.0 (CH₂), 25.4 (CH₂), 22.7 (CH₂), 18.3 (C), 14.2 (Me), -4.2 (Me), -4.4 (Me). EI-MS: m/z = 285 [M + 1]⁺. HRMS (EI): m/z calcd for C₁₇H₃₆OSi: 284.2535; found: 284.2543.
( R )-9: [α]_D ²⁰ +10.1° (c = 1.64, CHCl₃). FTIR: 3076, 2930, 1642, 1462 cm^{- 1}. ¹H NMR (400 MHz, CDCl₃): δ = 5.77-5.87 (m, 1 H), 5.00-5.05 (m, 2 H), 3.65-3.71 (m, 1 H), 2.18-2.23 (m, 2 H), 1.29-1.41 (m, 15 H), 0.89 (s, 9 H), 0.05 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 135.5 (CH), 116.5 (CH₂), 72.1 (CH), 42.0 (CH₂), 36.9 (CH₂), 31.9 (CH₂), 29.8 (CH₂), 29.4 (CH₂), 26.0 (CH₂), 25.4 (CH₂), 22.7 (CH₂), 18.3 (C), 14.2 (Me), -4.2 (Me), -4.4 (Me). EI-MS: m/z = 283 [M - 1]⁺. HRMS (EI): m/z calcd for C₁₇H₃₆OSi: 284.2535; found: 284.2529.

15

( S )-10: colorless oil; [α]_D ²⁰ +2.4° (c = 1.56, CHCl₃). FTIR: 3054, 2928, 2856, 2719, 1727, 1470 cm^{- 1}. ¹H NMR (400 MHz, CDCl₃): δ = 9.82 (s, 1 H), 4.15-4.20 (m, 1 H), 2.51-2.52 (m, 2 H), 1.51-1.53 (m, 2 H), 1.20-1.37 (m, 10 H), 0.88 (s, 12 H), 0.08 (s, 3 H), 0.06 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 202.3 (CH), 68.3 (CH), 50.9 (CH₂), 37.9 (CH₂), 31.8 (CH₂), 29.6 (CH₂), 29.3 (CH₂), 25.8 (3 × Me), 25.2 (CH₂), 22.7 (CH₂), 18.1 (C), 14.2 (Me), -4.3 (Me), -4.6 (Me). EI-MS: m/z = 286 [M]⁺. HRMS (EI): m/z calcd for C₁₆H₃₄O₂Si: 286.2328; found: 286.2321.
( R )-10: [α]_D ²⁰ -2.2° (c = 2.42, CHCl₃). FTIR: 3054, 2930, 2720, 1728, 1585, 1470 cm^{- 1}. ¹H NMR (400 MHz, CDCl₃): δ = 9.82 (s, 1 H), 4.15-4.20 (m, 1 H), 2.51-2.52 (m, 2 H), 1.51-1.53 (m, 2 H), 1.20-1.37 (m, 10 H), 0.88 (s, 12 H), 0.08 (s, 3 H), 0.06 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 202.3 (CH), 68.3 (CH), 50.9 (CH₂), 37.9 (CH₂), 31.8 (CH₂), 29.6 (CH₂), 29.3 (CH₂), 25.8 (3 × Me), 25.2 (CH₂), 22.7 (CH₂), 18.1 (C), 14.2 (Me), -4.3 (Me), -4.6 (Me). EI-MS: m/z = 287 [M + 1]⁺. HRMS (EI): m/z calcd for C₁₆H₃₄O₂Si: 286.2328; found: 286.2325.

17

It is well known that compounds bearing a hydroxyl group at an asymmetric allylic or benzylic position can be separated more efficiently than saturated aliphatic alcohols when using most of the other chiral resolving agents. CPF has a similar tendency as described above. However, our investigations have shown that the separation efficiency of CPF is much greater than that of other agents. Chiral resolution of both 3 and 7 was successful and efficient, and we know no other reason for this high efficiency.