A Concise Approach for the
Synthesis of Core Fragment C7-C15 of (+)-Migrastatin
Using Desymmetrization Strategy

J. S. Yadav; P. Naga Lakshmi

doi:10.1055/s-0029-1219785

LETTER

A Concise Approach for the Synthesis of Core Fragment C7-C15 of (+)-Migrastatin Using Desymmetrization Strategy

J. S. Yadav*, P. Naga Lakshmi
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500607, India
Fax: +91(40)27160387; e-Mail: yadavpub@iict.res.in;

Abstract

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Abstract

The core fragment C7-C15 the (+)-migrastatin was constructed in a stereoconvergent manner utilizing desymmetrization approach. The strategy involved the generation of Z-configuration of trisubstituted double bond at C11-C12, epimerization at C10, ring opening of the pyran lactol with C2 Wittig ylide, and regioselective Sharpless dihydroxylation.

Key words

(+)-migrastatin - desymmetrization - epimerization - Sharpless asymmetric dihydroxylation

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References

References and Notes

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Analytical Data for Compound 6 [α]_D ^²5 -54.7 (c 3.0, CHCl₃). IR: ν_max = 2928, 1742, 1455, 1073 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 7.35-7.20 (m, 5 H), 5.38 (d, J = 2.7 Hz, 1 H), 4.70-4.40 (ABq, 2 H), 3.65 (d, J = 4.0 Hz, 1 H), 3.60-3.52 (m, 1 H), 2.75 (q, J = 7.0 Hz, 2 H), 2.30-2.10 (m, 1 H), 2.10-1.96 (m, 1 H), 1.42 (d, J = 6.5 Hz, 3 H), 1.15 (d, J = 6.8 Hz, 3 H), 0.96 (d, J = 6.8 Hz, 3 H). MS: m/z = 290 [M⁺]. Anal. Calcd (%) for C₁₇H₂₂O₄: C, 70.32; H, 7.64. Found: C, 70.01; H, 7.32.

Analytical Data for Compound 8 [α]_D ^²5 +77.6 (c 1.5, CHCl₃). IR (neat): ν_max = 2827, 1739, 1456, 1082 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.36-7.22 (m, 5 H), 4.54 (s, 2 H), 4.52 (s, 1 H), 4.00-3.95 (m, 1 H), 3.86 (t, J = 3.5 Hz, 1 H), 3.72 (s, 3 H), 3.28 (s, 3 H), 2.75-2.64 (m, 1 H), 2.25-2.10 (m, 2 H), 1.14-1.05 (m, 6 H), 1.02 (d, J = 6.6 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 176.0, 138.8, 128.2, 127.2, 127.1, 104.2, 74.9, 71.7, 69.4, 54.7, 51.5, 41.7, 36.4, 32.5, 13.1, 13.0, 7.5. MS: m/z = 307 [M⁺ + 1 - 30]. Anal. Calcd (%) for C₁₉H₂₈O₅: C, 67.83; H, 8.39. Found: C, 67.13; H, 8.26.

Analytical Data for Compound 5
[α]_D ^²5 +35.4 (c 2.0, CHCl₃). IR (KBr): ν_max = 3489, 2924, 2855, 1724, 1460, 1377, 1130, 1073, 1029 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 4.50 (s, 1 H), 4.05 (t, J = 5.3 Hz, 1 H), 3.69-3.55 (m, 3 H), 3.35 (s, 3 H), 3.15-2.98 (br, 1 H), 2.07-1.90 (m, 3 H), 1.67-1.55 (br, 1 H), 1.04 (d, J = 6.8 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.81 (d, J = 6.8 Hz, 3 H), ^¹³C NMR (50 MHz, CDCl₃): δ = 104.2, 75.7, 68.2, 67.6, 54.7, 38.6, 35.9, 35.7, 12.5, 12.5, 7.4. ESI-MS: m/z = 241.1 [M + Na]⁺. HRMS: m/z calcd for C₁₁H₂₂O₄Na [M + Na]⁺: 241.1410; found: 241.1415.

Analytical Data for Compound 9
[α]_D ^²5 +3.0 (c 1, CHCl₃). IR (KBr): ν_max = 2926, 2856, 1464, 1360, 1177, 1079, 1019, 954 cm^-¹.^¹H NMR (300 MHz, CDCl₃): δ = 7.61 (d, J = 7.7 Hz, 4 H), 7.43-7.28 (m, 6 H), 5.1 (t, J = 5.6 Hz, 1 H), 4.40 (s, 1 H), 3.83-3.60 (m, 3 H), 3.09 (s, 3 H), 2.98 (s, 3 H), 2.24-2.12 (m, 2 H), 1.89-1.73 (m, 1 H), 1.15-1.02 (m, 12 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.91 (d, J = 7.5 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 136.0, 135.8, 134.1, 133.9, 129.7, 129.7, 127.7, 103.7, 80.4, 69.8, 65.5, 60.5, 54.9, 38.8, 37.9, 36.9, 35.0, 27.2, 19.5, 14.4, 13.4, 13.0, 8.15. ESI-MS: m/z = 557.2 [M + Na]⁺. HRMS: m/z calcd for C₂₈H₄₂O₆NaSi [M + Na]⁺: 557.2366; found: 557.2369.

Analytical Data for Compound 4 [α]_D ^²5 +100.9 (c 0.8, CHCl₃). IR (KBr): ν_max = 2960, 2926, 2856, 2827, 1465, 1384, 1108, 1086, 1030, 954 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.66 (d, J = 7.5 Hz, 4 H), 7.43-7.31 (m, 6 H), 5.31 (d, J = 5.2 Hz, 1 H), 4.38 (s, 1 H), 3.93 (s, 1 H), 3.66-3.48 (qd, J = 4.5, 9.8 Hz, 2 H), 3.37 (s, 3 H), 2.21-1.92 (m, 2 H), 1.46 (s, 3 H), 1.21 (d, J = 6.7 Hz, 3 H).1.08 (s, 12 H), 0.85 (d, J = 7.5 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 135.5, 129.4, 129.4, 127.5, 123.7, 101.8, 73.1, 64.6, 54.9, 36.9, 34.0, 26.8, 19.1, 18.6, 14.9. ESI-MS: m/z = 461.2 [M + Na]⁺. HRMS: m/z calcd for C₂₇H₃₈O₃NaSi [M + Na]⁺: 461.2494; found: 461.2487.

Analytical Data for Compound 10 [α]_D ^²5 -14.3 (c 0.5, CHCl₃). IR (KBr): ν_max = 2927, 2856, 1739, 1465, 1427, 1364, 1109 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.69-7.58 (m, 4 H), 7.44-7.31 (m, 6 H), 5.33 (d, J = 5.2 Hz, 1 H), 4.76 (s, 1 H), 3.66-3.55 (m, 1 H), 3.54-3.41 (m, 1 H), 3.05-2.85 (m, 1 H), 2.21-2.01 (m, 1 H), 1.62 (s, 3 H), 1.17 (d, J = 7.3 Hz, 6 H), 1.04 (s, 9 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 176.0, 135.5, 134.7, 129.4, 129.4, 127.7, 127.5, 123.1, 94.9, 77.4, 76.5, 73.6, 64.8, 37.0, 34.8, 26.9, 26.5, 19.2, 18.4, 15.1. ESI-MS: m/z = 445.2 [M + Na]⁺. HRMS: m/z calcd for C₂₆H₃₄O₃NaSi [M + Na]⁺: 445.2174; found: 445.2173.

Analytical Data for Compound 11
[α]_D ^²5 -10.6 (c 1.0, CHCl₃). IR (KBr): ν_max = 3000, 2851, 1750, 1432, 1380, 1210 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.69-7.57 (m, 4 H), 7.44-7.31 (m, 6 H), 5.33 (d, J = 5.2 Hz, 1 H), 4.60 (s, 1 H), 3.61-3.45 (m, 2 H), 2.86-2.76 (m, 1 H), 2.19-1.91 (m, 1 H), 1.62 (s, 3 H), 1.10-0.90 (m, 15 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 176.0, 135.5, 134.7, 129.4, 129.4, 127.7, 127.5, 123.1, 94.9, 77.4, 76.5, 73.6, 64.8, 37.0, 34.8, 26.9, 26.5, 19.2, 18.4, 15.1. ESI-MS: m/z = 445.2 [M + Na]⁺. HRMS: m/z calcd for C₂₆H₃₄O₃NaSi [M + Na]⁺: 445.2174; found: 445.2173.

Analytical Data for Compound 3 [α]_D ^²5 +44.3 (c 0.6, CHCl₃). IR (KBr): ν_max = 3420, 2960, 2929, 2858, 1716, 1464, 1428, 1385, 1109, 1035, 703 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.61 (d, J = 6.0 Hz, 4 H), 7.38-7.27 (m, 6 H), 6.87-6.77 (dd, J = 6.0, 15.1 Hz, 1 H), 5.72 (d, J = 15.1 Hz, 1 H), 5.03 (d, J = 9.8 Hz, 1 H), 4.36 (d, J = 9.0 Hz, 1 H), 4.14-4.04 (q, J = 6.7 Hz, 2 H), 3.80-3.60 (dq, J = 3.7, 7.5, 10.5 Hz, 2 H), 3.40-3.28 (m, 2 H), 1.92-1.76 (m, 1 H), 1.65 (s, 3 H), 1.19 (t, J = 6.7 Hz, 3 H), 1.02-0.99 (m, 12 H), 0.60 (d, J = 6.8 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 167.0, 152.6, 136.6, 135.8, 135.8, 135.7, 135.7, 135.6, 133.0, 133.0, 130.1, 130.0, 128.0, 127.9, 127.9, 127.8, 119.7, 74.0, 68.9, 60.3, 37.9, 34.3, 27.0, 27.0, 26.9, 20.0, 19.3, 17.9, 14.4, 13.3. ESI-MS: m/z = 517 [M + Na]⁺. HRMS: m/z calcd for C₃₀H₄₂O₄NaSi [M + Na]⁺: 517.2750; found: 517.2757.

Analytical Data for Compound 13 [α]_D ^²5 +19.7 (c 0.4, CHCl₃). IR (KBr): ν_max = 2959, 2877, 1722, 1650, 1463, 1426, 1385, 1262, 1108, 1065, 1014, 703 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.63-7.53 (m, 4 H), 7.37-7.22 (m, 6 H), 6.87-6.74 (dd, J = 6.6, 15.9 Hz, 1 H), 5.72 (d, J = 15.9 Hz, 1 H), 4.96 (d, J = 9.2 Hz, 1 H), 4.28 (d, J = 9.2 Hz, 1 H), 4.18-4.05 (q, J = 6.6 Hz, 2 H), 3.78-3.52 (dq, J = 3.6, 5.3, 10.2 Hz, 2 H), 3.40-3.28 (m, 1 H), 1.77-1.61 (m, 1 H), 1.57 (s, 3 H), 1.27-1.15 (m, 6 H), 1.05-0.95 (m, 12 H), 0.75 (t, J = 7.9 Hz, 9 H), 0.44-0.30 (q, J = 6.6 Hz, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 167.0, 152.4, 137.4, 135.9, 135.9, 134.2, 134.1, 129.7, 128.6, 127.7, 119.6, 71.2, 66.0, 60.4, 40.4, 34.7, 27.2, 20.7, 19.5, 14.4, 13.9, 7.06, 5.05. ESI-MS: m/z = 631.3 [M + Na]⁺. HRMS: m/z calcd for C₃₆H₅₆O₄NaSi₂ [M + Na]⁺: 631.3614; found: 631.3619.

Analytical Data for Compound 14 [α]_D ^²5 -6.0 (c 0.3, CHCl₃). IR (KBr): ν_max = 3440, 2959, 2877, 1722, 1650, 1463, 1426, 1385, 1262, 1108, 1065, 1014, 703 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.73-7.56 (m, 4 H), 7.48-7.28 (m, 6 H), 5.08 (d, J = 10.2 Hz, 1 H), 4.32 (d, J = 9.3 Hz, 1 H), 4.23-4.20 (m, 2 H), 3.88-3.75 (m, 1 H), 3.69-3.47 (m, 2 H), 3.01-2.84 (m, 2 H), 1.89-1.71 (m, 2 H), 1.70-1.59 (m, 3 H), 1.43-1.21 (m, 3 H), 1.08 (s, 9 H), 0.99 (d, J = 6.6 Hz, 3 H), 0.93-0.74 (m, 12 H), 0.57-0.37 (q, J = 6.6 Hz, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 173.9, 140.6, 135.9, 134.2, 129.6, 128.9, 127.7, 80.0, 71.7, 71.3, 70.5, 66.3, 62.1, 61.3, 59.0, 40.8, 34.9, 32.1, 31.1, 31.1, 29.9, 29.5, 27.2, 22.9, 29.5, 27.2, 22.9, 19.5, 18.5, 17.8, 17.4, 14.4, 14.3, 7.1, 5.5, 5.1, 0.20. ESI-MS: m/z = 665.0 [M + Na]⁺. HRMS: m/z calcd for C₃₆H₅₈O₆NaSi₂ [M + Na]⁺: 665.3669; found: 665.3672.

Analytical Data for Compound 15 [α]_D ^²5 -3.0 (c 0.4, CHCl₃). IR (KBr): ν_max = 3513, 2960, 2874, 1721, 1650,1462, 1426, 1386, 1260, 1109, 1064, 1014 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.70-7.62 (m, 4 H), 7.44-7.32 (m, 6 H), 5.14 (d, J = 10.0 Hz, 1 H), 4.39 (d, J = 9.2 Hz, 1 H), 4.32-4.22 (m, 2 H), 3.87-3.81 (dd, J = 3.3, 9.4 Hz, 1 H), 3.68-3.61 (dd, J = 6.4, 9.4 Hz, 3 H), 3.39-3.32 (m, 1 H), 3.35 (s, 3 H), 3.12-2.97 (m, 1 H), 2.86 (d, J = 9.2 Hz, 1 H), 1.87-1.73 (m, 1 H), 1.65 (s, 3 H), 1.31 (t, J = 7.1 Hz, 3 H), 1.08 (s, 9 H), 1.00 (d, J = 6.9 Hz, 3 H), 0.89-0.79 (m, 12 H), 0.59-0.45 (q, J = 6.6 Hz, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 173.8, 137.3, 135.6, 134.1, 127.4, 134.1, 129.4, 127.4, 85.4, 77.4, 77.1, 77.1, 76.9, 76.5, 71.2, 70.6, 66.0, 61.4, 59.2, 40.5, 33.2, 29.6, 26.9, 19.3, 18.2, 16.7, 14.2, 14.0, 6.9, 4.7. ESI-MS: m/z = 679.0 [M + Na]⁺. HRMS: m/z calcd for C₃₇H₆₀O₆NaSi₂ [M + Na]⁺: 679.3826; found: 679.3837.

Analytical Data for Compound 2 [α]_D ^²5 -3.0 (c 0.4, CHCl₃). IR (KBr) ν_max = 2959, 2877, 1722, 1650, 1463, 1426, 1385, 1262, 1108, 1065, 1014, 703 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.70-7.63 (m, 4 H), 7.45-7.31 (m, 6 H), 5.13 (d, J = 10.1 Hz, 1 H), 4.33 (d, J = 3.2 Hz, 1 H), 4.28-4.15 (m, 3 H), 3.95-3.89 (dd, J = 3.3, 9.4 Hz, 1 H), 3.53-3.40 (m, 2 H), 3.31 (s, 3 H), 2.95-2.82 (m, 1 H),1.89-1.78 (m, 1 H), 1.65 (s, 3 H), 1.32-1.24 (m, 3 H), 1.09 (s, 9 H), 0.97-0.78 (m, 24 H), 0.56-0.45 (m, 6 H), 0.12 (s, 3 H), 0.06 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 136.9, 135.6, 134.1, 127.4, 127.4, 129.3, 86.6, 73.0, 71.9, 66.4, 60.7, 59.5, 40.9, 33.2, 31.9, 31.4, 29.6, 26.9, 25.8, 22.6, 19.3, 18.3, 17.2, 14.2, 6.9, 4.6, -4.4, -5.0. ESI-MS: m/z = 793.6 [M + Na]⁺. HRMS: m/z calcd for C₄₃H₇₄O₆NaSi₃ [M + Na]⁺: 793.6826; found: 793.6837.