Cryptophycin-39 Unit A Precursor Synthesis by a Tandem Shi Epoxidation and Lactonization Reaction of trans-Styryl Acetic Acid

Abstract

Unit A of cryptophycins is a δ-hydroxy acid with two or four stereogenic centers. The first synthesis of the unit A building block of cryptophycin-39 is based on a catalytic asymmetric Shi epoxidation of trans-styryl acetic acid followed by an in situ lactonization. The scope of this reaction has been investigated with respect to various β,γ-unsaturated carboxylic acids as substrates for the asymmetric synthesis of 4-hydroxy-5-phenyl-tetrahydrofuran-2-ones under Shi conditions.

asymmetric synthesis - bioorganic chemistry - epoxidations - lactones - natural products

References and Notes

1a Schwartz RE. Hirsch CF. Sesin DF. Flor JE. Chartrain M. Fromtling RE. Harris GH. Salvatore MJ. Liesch JM. Yudin K. J. Ind. Microbiol.  1990,  5:  113 

1b Trimurtulu G. Ohtani I. Patterson GML. Moore RE. Corbett TH. Valeriote FA. Demchik L. J. Am. Chem. Soc.  1994,  116:  4729 

1c Golakoti T. Ogino J. Heltzel CE. Husebo TL. Jensen CM. Larsen LK. Patterson GML. Moore RE. Mooberry SL. Corbett TH. Valeriote FA. J. Am. Chem. Soc.  1995,  117:  12030 

1d Kobayashi M. Kurosu M. Ohyabu N. Wang W. Fujii S. Kitagawa I. Chem. Pharm. Bull.  1994,  42:  2196 

1e Kobayashi M. Aoki S. Ohyabu N. Kurosu M. Wang W. Kitagawa I. Tetrahedron Lett.  1994,  35:  7969 

For reviews, see:

1f Eißler S. Stončius A. Nahrwold M. Sewald N. Synthesis  2006,  3747 

1g Eggen M. Georg GI. Med. Res. Rev.  2002,  22:  85 

1h Tius MA. Tetrahedron  2002,  58:  4343 

2a Al-awar RS. Corbett TH. Ray JE. Polin L. Kennedy JH. Wagner MM. Williams DC. Mol. Cancer Ther.  2004,  9:  1061 

2b Smith CD. Zhang X. Mooberry SL. Patterson GM. Moore RE. Cancer Res.  1994,  54:  3779 

3 Chaganty S. Golakoti T. Heltzel C. Moore RE. Yoshida WY. J. Nat. Prod.  2004,  67:  1403 

4a Gardinier KM. Leahy JW. J. Org. Chem.  1997,  62:  7098 

4b Liang J. Moher ED. Moore RE. Hoard DW. J. Org. Chem.  2000,  65:  3143 

4c Pousset C. Haddad M. Larchevêque M. Tetrahedron  2001,  57:  7163 

4d Li L.-H. Tius MA. Org. Lett.  2002,  4:  1637 

4e Mast CA. Eißler S. Stončius A. Stammler H.-G. Neumann B. Sewald N. Chem. Eur. J.  2005,  11:  4667 

5 Eißler S. Nahrwold M. Neumann B. Stammler H.-G. Sewald N. Org. Lett.  2007,  9:  817 

6 Kino R. Daikai K. Kawanami T. Furuno H. Inanaga J. Org. Biomol. Chem.  2004,  2:  1822 

7 van Horn JD. Burrows CJ. Tetrahedron Lett.  1999,  40:  2069 

8a Wang ZX. Tu Y. Frohn M. Zhang JR. Shi Y.
J. Am. Chem. Soc.  1997,  119:  11224 

8b Wang ZX. Tu Y. Frohn M. Shi Y. J. Org. Chem.  1997,  62:  2328 

8c Shi Y. Acc. Chem. Res.  2004,  37:  488 

8d Wong OA. Shi Y. Chem. Rev.  2008,  108:  3958 

9 Hoard DW. Moher ED. Martinelli MJ. Norman BH. Org. Lett.  2002,  4:  1813 

10 Ager DJ. Anderson K. Oblinger E. Shi Y. VanderRoest J. Org. Process Res. Dev.  2007,  11:  44 

11

Synthesis of (4 R ,5 S )-4-hydroxy-5-phenyl-tetrahydro-furan-2-one (5) trans-Styryl acetic acid (4, 21.8 mmol, 3.54 g) was dissolved in MeCN (210 mL). Aqueous KOH soln (1 M, 21.8 mmol, 21.8 mL), acetate buffer (150 mL, prepared by adding 5.00 mL AcOH to 13.82 g K₂CO₃ in 1000 mL H₂O and pH adjusted to 9.3 by the dropwise addition of concd aq NaOH soln) and n-Bu₄NHSO₄ (0.954 mmol, 324 mg) were added. The solution was cooled to 0 ˚C and Shi catalyst (3, 7.16 mmol, 1.85 g) was added. Freshly prepared Oxone (29.90 mmol, 18.36 g) in aq Na₂EDTA solution (0.4 mM, 0.0432 mmol, 108 mL) and aq K₂CO₃ soln (108 mL, prepared by dissolving 32.00 g K₂CO₃ in 200 mL H₂O) were separately added within 120 min at 0 ˚C. The cooling bath was removed, and the mixture was stirred for 180 min. Aqueous HCl (6 M, 0.36 mol, 60 mL) was carefully added. The solution was extracted with Et₂O (1 × 600 mL and 2 × 500 mL). The combined organic layers were washed with sat. aq NaHCO₃ solution (200 mL) and brine (30 mL). After drying over Na₂SO₄ the solvent was removed in vacuo (40 ˚C) and the crude material was purified by flash chromatography (hexane-EtOAc 3:2) giving a crystalline solid (10.78 mmol, 1.920 g, 82% ee), which was recrystallized from EtOAc (3.5 mL) at 2 ˚C overnight yielding (4R,5S)-4-hydroxy-5-phenyl-tetrahydrofuran-2-one (5, 9.58 mmol, 1.708 g, 44%, 90% ee) as a colorless solid; [α]_D ^²4 2.57 (c 1.38, CHCl₃). HPLC [Chiralpak AD, 2-PrOH-hexane (1:9), 1 mL/min]: t _R = 16.6 min (5), 12.2 min (ent-5). Anal. Calcd (%) for C₁₀H₁₀O₃: C, 67.41; H, 5.66. Found: C, 67.39; H, 5.67. Further analytical data are in accordance with ref. 7.

12

General Procedure for the Synthesis of Substituted trans -Styryl Acetic Acids (Table 1, Entries 2 and 3)
KOt-Bu (13 mmol, 1.469 g) in THF (14 mL) was added to a solution of the substituted benzaldehyde (9 mmol) and
(2-carboxyethyl)triphenylphosphonium bromide (6 mmol, 2.494 g) in THF (12 mL) at 0 ˚C over 15 min. After stirring for additional 15 min at 0 ˚C and overnight at r.t., H₂O (10 mL) and Et₂O (50 mL) were added. The phases were acidified with 6 M aq HCl soln to pH 1 and separated. The aqueous phase was extracted with Et₂O (50 mL). The combined organic phases were extracted with sat. aq NaHCO₃ soln (2 × 60 mL). The sat. aq NaHCO₃ phases were washed with EtOAc (3 × 90 mL), acidified with concd aq HCl to pH 1 and extracted with Et₂O (2 × 75 mL). The organic extracts were washed with H₂O (20 mL) and brine (10 mL). After drying over Na₂SO₄ the solvent was removed in vacuo (40 ˚C) yielding the corresponding substituted trans-styryl acetic acid in 70-74% yield.

13a

Synthesis of (3 R ,4 R ,5 S )-4-Hydroxy-3-methyl-5-phenyl-tetrahydrofuran-2-one (6) Diisopropylamine (11.56 mmol, 1.6 mL) in THF (28 mL) was cooled to -78 ˚C, then n-BuLi (1.6 M in hexane, 11.49 mmol, 7.2 mL) was added dropwise over 15 min. The solution was stirred for 15 min at -78 ˚C and for 30 min at r.t. The LDA solution was cooled to -78 ˚C again and DMPU (34.87 mmol, 4.2 mL) was added. After 45 min lactone (5, 4.60 mmol, 819 mg) in THF (19.2 mL) was added during 90 min. After stirring for 45 min and addition of THF (16 mL), MeI (46.6 mmol, 2.9 mL) in THF (8.6 mL) was added during 150 min. The solution was stirred overnight at -78 ˚C. Acetic acid (0.6 mL) in THF (1.0 mL) was added, and the suspension was warmed to r.t. Then, 5% aq Na₂SO₃ soln (8.8 mL) was added, and after 5 min the solvent was removed in vacuo (40 ˚C), until a pink suspension remained, which was partitioned between Et₂O (40 mL) and H₂O (20 mL). The aqueous layer was extracted with Et₂O (4 × 60 mL), and the combined organic phases were washed with 5% aq KHSO₄ soln (30 mL) and brine (15 mL). After drying over Na₂SO₄ the solvent was removed in vacuo (40 ˚C), and the residue was purified by flash chromatography (hexane-EtOAc, 7:3). The product (3.80 mmol, 731 mg, 90% ee, 85% de) was recrystallized in EtOAc (1 mL) at -22 ˚C overnight. A colorless solid (6, 3.00 mmol, 576 mg, 65%, >99% ee, 92% de) was obtained; [α]_D ^²4 6.21 (c 1.18, CHCl₃); mp 90 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 7.30-7.50 (m, 5 H), 5.06 (d, J = 7.5 Hz, 1 H), 3.98 (m, 1 H), 2.77 (dq, J = 9.4, 6.9 Hz, 1 H), 2.61 (d, J = 5.0 Hz, 1 H), 1.36 (d, J = 6.9 Hz, 3 H). ^¹³C NMR (126 MHz, CDCl₃): δ = 176.0, 136.6, 128.9, 128.8, 125.7, 84.2, 81.4, 43.6, 12.3. IR (neat): 3409, 3069, 3035, 2974, 2935, 2886, 1732, 1499, 1458, 1363, 1312, 1254, 1184, 1135, 1092, 971, 921, 854, 834, 765, 715, 695, 653 cm^-¹. MS (EI): m/z = 192.1 [M⁺], 174.1 [M⁺ - H₂O], 107.0 [Ph - CHOH⁺]. HRMS (EI): m/z calcd for C₁₁H₁₂O₃ ⁺ [M⁺]: 192.07864; found: 192.07934. HPLC [Chiralpak AD, 2-PrOH-hexane (1:9), 1 mL/min]: t _R = 13.4 min (6), 9.2 min (ent-6). Anal. Calcd (%) for C₁₁H₁₂O₃: C, 68.74; H, 6.29. Found: C, 68.67; H, 6.24.

13b Chen SY. Joullie MM.
J. Org. Chem.  1984,  49:  2168 

13c

CCDC 703492 contains the crystallographic data of 6. They can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

14 Harcken C. Brückner R. Synlett  2001,  718 

15 Lee E. Jeong EJ. Kang EJ. Sung LT. Hong SK. J. Am. Chem. Soc.  2001,  123:  10131 

16 Tripathy NK. Georg GI. Tetrahedron Lett.  2004,  45:  5309 

17

Synthesis of (5 S ,6 S , E )- tert -Butyl-6-[(4 R ,5 S )-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-yl]-5-hydroxyhept-2-enoate (10)
Homoallyl alcohol 9 (0.615 mmol, 170 mg) in CH₂Cl₂ (0.85 mL) was added to a solution of Grubbs II catalyst (0.026 mmol, 22.1 mg) and tert-butylacrylate (0.513 mmol, 74.4 µL) in CH₂Cl₂ (3.4 mL). The solution was refluxed in the dark overnight. The solvent was removed in vacuo (30 ˚C), and the residue was purified by flash chromatography (hexane-EtOAc, 8:2) yielding 10 (0.369 mmol, 138.8 mg, 72%) as a colorless oil; [α]_D ^²4 -7.50 (c 1.10, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 7.28-7.40 (m, 5 H), 6.77 (m, 1 H), 5.80 (d, J = 15.7 Hz, 1 H), 5.38 (d, J = 7.5 Hz, 1 H), 4.70 (dd, J = 3.8, 7.5 Hz, 1 H), 3.50 (m, 1 H), 2.37 (m, 1 H), 2.22 (m, 1 H), 1.58-1.72 (m, 4 H), 1.41-1.56 (m, 12 H), 0.71 (d, J = 6.9 Hz, 3 H). ^¹³C NMR (126 MHz, CDCl₃): δ = 165.5, 144.0, 138.0, 128.2, 127.5, 126.6 125.7, 108.2, 80.3, 79.4, 78.1, 73.5, 38.3, 37.4, 28.2, 26.3 24.7, 11.2. IR (neat): 3453, 2979, 2934, 2360, 1709, 1651, 1494, 1454, 1379, 1367, 1326, 1253, 1210, 1086, 1044, 1029, 1006, 980, 917, 879, 850, 730, 700, 647, 512, 466 cm^-¹. ESI-MS: m/z = 399.2 [M + Na⁺]. ESI-HRMS: m/z calcd for C₂₂H₃₂O₅Na⁺ [M + Na⁺]: 399.21420; found: 399.21373.

18a

Synthesis of (1 S ,2 R ,3 S ,4 S )-3-Methyl-1-phenylhept-6-ene-1,2,4-triol (11) A 5% aq HCl soln (4 mL) was added to a solution of homoallyl alcohol 9 (0.615 mmol, 170.0 mg) in MeOH (6 mL). After refluxing the solution for 90 min MeOH was removed in vacuo (40 ˚C), and the aqueous phase was extracted with Et₂O (5 × 30 mL), dried over MgSO₄, and purified by flash chromatography (hexane-EtOAc, 7:3). A colorless crystalline solid (11, 0.405 mmol, 95.7 mg, 66%) was obtained; [α]_D ^²4 43.59 (c 1.22, CHCl₃); mp 77 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 7.26-7.49 (m, 5 H), 5.80 (m, 1 H), 5.13-5.20 (m, 2 H), 4.70 (δ, J = 7.5 Hz, 1 H), 4.15 (d, J = 7.5 Hz, 1 H), 3.70 (m, 1 H), 2.60 (d, J = 2.5 Hz, 1 H), 2.27-2.44 (m, 3 H), 2.21 (s, 1 H), 1.98 (m, 1 H), 1.16 (d, J = 6.9 Hz, 3 H). ^¹³C NMR (126 MHz, CDCl₃): δ = 141.8, 134.8, 128.6, 128.1, 126.8, 118.4, 75.1 75.0, 74.1, 40.0, 37.2, 11.2. IR (neat): 3545, 3345, 3063, 3030, 2970, 2923, 2360, 2341, 1639, 1493, 1455, 1431, 1404, 1382, 1340, 1269, 1212, 1135, 1071, 1023, 1000, 989, 974, 917, 870, 842, 786, 697, 639, 604, 544, 475, 419 cm^-¹. ESI-MS: m/z = 259.2 [M + Na⁺]. ESI-HRMS: m/z calcd for C₁₄H₂₀O₃Na⁺ [M + Na⁺] 259.13047; found: 259.13030. Anal. Calcd (%) for C₁₄H₂₀O₃: C, 71.16; H, 8.53. Found: C, 71.00; H, 8.60.

18b

CCDC 703493 contains the crystallographic data of 11. They can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.