Stereoselective First Total
Synthesis of a Ten-Membered Macrolide from l-Malic
Acid and (2R)-2,3-O-Cyclohexylideneglyceraldehyde

Palakodety Radha Krishna; A. Sreeshailam

doi:10.1055/s-0028-1083531

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Synlett 2008(18): 2795-2798
DOI: 10.1055/s-0028-1083531

LETTER

Stereoselective First Total Synthesis of a Ten-Membered Macrolide from l-Malic Acid and (2R)-2,3-O-Cyclohexylideneglyceraldehyde

Palakodety Radha Krishna*, A. Sreeshailam
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500607, India
Fax: +91(40)27160387; e-Mail: prkgenius@iict.res.in;

Further Information

Publication History

Received 3 July 2008
Publication Date:
15 October 2008 (online)

Abstract
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Abstract

A convergent stereoselective first total synthesis of a novel ten-membered macrolide from l-malic acid and (2R)-2,3-O-cyclohexylideneglyceraldehyde is reported.

Key words

ten-membered macrolide - (2R)-2,3-O-cyclohexylideneglyceraldehyde - l-malic acid - 1,2-syn allylation - Yamaguchi macrolactonization

References and Notes

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12

Spectral Data of Selected Compounds
Compound 9: colorless syrup; [α]_D ^²5 -37.3 (c 2.0, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 7.35-7.17 (m, 5 H), 7.13 (d, J = 8.4 Hz, 2 H), 6.79 (d, J = 8.4 Hz, 2 H), 4.61 (d, J = 9.7 Hz, 2 H), 4.55-4.39 (m, 2 H), 4.31 (d, J = 7.1 Hz, 2 H), 4.04 (t, J = 7.7 Hz, 1 H), 3.86-3.77 (m, 1 H), 3.77 (s, 3 H), 3.67-3.58 (m, 1 H), 3.58-3.41 (m, 2 H), 3.35 (s, 3 H), 3.29-3.02 (m, 1 H), 2.00-1.75 (m, 2 H), 1.75-1.55 (m, 10 H), 1.40-1.30 (m, 2 H). ^¹³C NMR (75 MHz,CDCl₃): δ = 159.0, 137.9, 130.4, 129.2, 128.3, 127.9, 127.7, 113.6, 110.8, 86.3, 82.3, 79.6, 75.3, 72.7, 72.4, 69.5, 66.1, 65.1, 61.0, 57.9, 55.1, 37.0, 35.7, 35.3, 29.6, 24.9. FTIR (neat): 3400, 3090, 2910, 2250, 1110 cm^-¹. ESI-MS: m/z = 539 [M + H]⁺, 556 [M + NH₄]⁺. Anal. Calcd for C₃₂H₄₂O₇: C, 71.35; H, 7.86. Found: C, 71.41; H, 7.79.
Seco acid 2: colorless liquid; [α]_D ^²5 -3.8 (c 3.0, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 7.28 (m, 5 H), 4.72-4.49 (m, 4 H), 4.15-4.05 (m, 1 H), 3.82-3.69 (m, 1 H), 3.69-3.60 (m, 1 H), 3.43-3.25 (m, 7 H), 2.66 (dd, J = 15.8, 4.1 Hz, 1 H), 2.51 (dd, J = 15.8, 7.9 Hz, 1 H), 1.87-1.71 (m, 1 H), 1.66-1.38 (m, 5 H), 1.16 (d, J = 6.0 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 175.7, 138.5, 128.2, 127.9, 127.5, 96.1, 78.2, 74.9, 72.4, 67.7, 58.9, 57.7, 55.5, 34.4, 33.6, 30.0, 24.1, 19.7. FTIR (neat): 3500, 3150, 2930, 1690, 1120 cm^-¹. ESI-MS: m/z = 385 [M + H]⁺, 407 [M + Na]⁺. Anal. Calcd for C₂₀H₃₂O₇: C, 62.48; H, 8.39. Found: C, 62.61; H, 8.31.
Compound 12b: colorless syrup; [α]_D ^²5 -63.3 (c 0.35, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 6.25 (dd, J = 11.3, 5.8 Hz, 1 H), 5.84 (dd, J = 11.3, 1.8 Hz, 1 H), 4.66-4.52 (m, 1 H), 4.13-3.95 (m, 1 H), 3.77 (t, J = 6.9 Hz, 1 H), 3.25 (s,
3 H), 2.34-1.53 (m, 6 H), 1.36 (d, J = 6.2 Hz, 3 H). ESI-MS: m/z = 225 [M + Na]⁺. Anal. Calcd for C₁₁H₁₈O₄: C, 61.66; H, 8.47. Found: C, 61.53; H, 8.59.
Compound 13a: colorless syrup; [α]_D ^²5 +8.33 (c 0.45, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 7.29 (m, 5 H), 4.81 (d, J = 11.7 Hz, 2 H), 4.67-4.53 (m, 2 H), 4.45 (d, J = 11.7, 1 H), 3.89-3.72 (m, 1 H), 3.46 (m, 1 H), 3.31 (s, 3 H), 3.09 (d, J = 13.5 Hz, 1 H), 2.93 (dd, J = 14.2, 6.6 Hz, 1 H), 2.34-1.69 (m, 2 H), 1.63-1.42 (m, 4 H), 1.18 (d, J = 6.2 Hz, 3 H). ESI-MS: m/z = 345 [M + Na]⁺. Anal. Calcd for C₁₈H₂₆O₇: C, 67.06; H, 8.13. Found: C, 67.21; H, 8.02
Compound 14: colorless syrup; [α]_D ^²5 +10.7 (c 0.55, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 7.46-7.29 (m, 5 H), 5.18-4.98 (m, 1 H), 4.82 (d, J = 11.3 Hz, 1 H), 4.59 (d, J = 11.3 Hz, 1 H), 4.11 (ddd, J = 11.7, 8.4, 3.6 Hz, 1 H), 3.56 (s, 3 H), 3.46-3.34 (m, 1 H), 2.95-2.59 (m, 3 H), 2.53-2.12 (m, 4 H), 2.05-1.90 (m, 1 H) 1.32 (d, J = 6.6 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 208.2, 169.2, 132.9. 129.5, 128.3, 127.6, 81.9, 79.6, 72.1, 71.3, 58.9, 43.9, 40.2, 39.6, 33.2, 19.7. FTIR (neat): 3452, 1733, 1726 cm^-¹. HRMS: m/z calcd for C₁₈H₂₄O₅NaCl [M + Na]⁺: 343.1521; found: 343.1512.
Compound 1: colorless syrup; [α]_D ^²5 +58.0 (c 0.12, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 5.04 (m, 1 H), 4.11 (ddd, J = 11.6, 8.7, 2.9 Hz, 1 H), 3.43 (s, 3 H), 3.35 (ddd, J = 10.2, 8.2, 2.4 Hz, 1 H), 3.09 (br s, 1 H, OH), 2.93 (dd, J = 17.4, 7.7 Hz, 1 H), 2.86 (dd, J = 17.4, 3.4 Hz, 1 H), 2.63 (dd, J = 17.4, 2.9 Hz, 1 H), 2.45 (dd, J = 17.4, 2.4 Hz, 1 H), 2.41 (ddd, J = 13.6, 7.2. 3.8 Hz, 1 H), 2.32 (ddd, J = 14.0, 10.6, 3.4 Hz, 1 H), 2.11 (m, 1 H), 2.02 (m, 1 H), 1.26 (d, J = 6.3 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 208.6, 169.2, 81.9, 71.6, 68.3, 57.3, 41.7, 40.4, 39.7, 33.1, 19.6. FTIR (neat): 3458, 1735, 1726 cm^-¹. HRMS: m/z calcd for C₁₁H₁₈O₅NaCl [M + Na]⁺: 253.1051; found: 253.1048.
Compound 15: colorless syrup; [α]_D ^²5 -105.3 (c 0.15, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 4.57 (m, 1 H), 4.11-4.06 (m, 1 H), 3.47 (m, 1 H), 3.38 (s, 3 H), 3.18 (d, J = 14.1 Hz, 1 H), 2.79-2.55 (m, 3 H), 2.14 (s, 3 H), 2.04 (dd, J = 9.1, 2.0 Hz, 1 H), 1.96-1.78 (m, 3 H). FTIR (neat): 3442, 1734, 1728 cm^-¹. ESI-MS: m/z = 231 [M + H]⁺. Anal. Calcd for C₁₁H₁₈O₅: C, 57.38; H, 7.88. Found: C, 57.51; H, 7.76.