Progress towards the Total Synthesis of Scytonemin A: Asymmetric Synthesis of (2S,3R,4R)-4-hydroxy-3-methylproline

Abstract

During the total synthesis of the novel cyclopeptide scytonemin A, the fragment containing two (2S,3R,4R)-4-hydroxy-3-methylproline units was successfully prepared. Two approaches leading to (2S,3R,4R)-4-hydroxy-3-methylproline have been explored. They involve the following key transformations: asymmetric crotylation, Sharpless epoxidation-subsequent epoxide opening, intramolecular amidomercuration-oxidation.

scytonemin A - cyclopeptide - substituted proline - amino acids - asymmetric synthesis

References and Notes

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Procedure for the Synthesis of 4 via Epoxide Opening
Epoxide 5 (0.65 g, 1.6 mmol) was dissolved in MeOH (10 mL). After a catalytic amount of Pd/C (10%) was added, the reaction was exposed to an atmosphere of H₂ at ambient temperature. The reaction was monitored by TLC. After all starting material was consumed (ca. 2 h), the reaction mixture was stirred for an additional 1 h and then filtered through a pad of Celite. The filter cake was washed with MeOH (10 mL). The combined filtrate and washings were concentrated in vacuo to leave the corresponding amine as an oil, which was dissolved in THF-H₂O (20 mL, 1:1) at 0 ˚C and treated with NaHCO₃ (0.25 g, 3.0 mmol) and CbzCl (0.29 mL, 2.0 mmol). The reaction mixture was stirred at r.t. for 3 h and then concentrated in vacuo. The residue was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with EtOAc-hexane (2:3) to give desired product 4 (0.49 g, 75%); [a]_D ^²5 -6.6 (c 0.70, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 7.40-7.29 (m, 5 H), 5.17 (s, 2 H), 4.17 (d, J = 3.3 Hz, 1 H), 4.11 (d, J = 9.0 Hz, 1 H), 3.73 (dd, J = 4.2, 7.1 Hz, 1 H), 3.61-3.58 (m, 4 H), 3.34 (dd, J = 4.1, 11.6 Hz, 1 H), 3.09-3.07 (m, 1 H), 2.18 (dd, J = 6.9, 11.5 Hz, 1 H), 1.12 (d, J = 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.07 (s, 3 H), 0.04 (s, 3 H). ^¹³C NMR (125 MHz, CDCl3): δ = 157.7, 136.3, 128.5 (128.5), 128.2, 128.0 (127.9), 73.4, 72.2, 67.6, 65.7, 62.9, 54.5, 41.4, 25.8 (25.7), 18.0, 13.0, -4.9, -5.0 ppm. ESI-HRMS: m/z calcd for C₂₁H₃₆NO₅Si⁺ [M + H]⁺: 410.2351; found: 410.2375.

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Procedure for the Synthesis of 11 via Amidomercuration-Oxidation
To a stirred solution of compound 8 (0.88 g, 2.40 mmol) in MeCN (20 mL), Hg(OAc)₂ (2.26 g, 7.20 mmol) was added. The reaction mixture was refluxed for 2 h and then cooled to r.t. EtOAc (10 mL) and brine (10 mL) were added, and the mixture was stirred at r.t. for a further 1.5 h and filtered to remove the precipitated inorganic byproduct. The filtrate was separated and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated in vacuo to give 7 as a colorless foam. In a second reaction vessel, oxygen (O₂) was bubbled into a well-stirred solution of NaBH₄ (0.09 g, 2.4 mmol) in DMF (25 mL) at r.t. One hour later, the above intermediate in DMF (25 mL) was slowly added over 2 h, while maintaining the flow of oxygen. Upon completion of addition, the reaction mixture was stirred for additional 2 h and then filtered through a pad of Celite, eluting thoroughly with EtOAc (200 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (EtOAc-hexane, 3:1) to afford the diastereoisomers 11α (0.23 g, 26%) and 11β (0.22 g, 24%).
Analytical Data for 11α
[α]_D ^²5 +28.6 (c 0.54, CHCl₃). ^¹H NMR (500 MHz, CDCl₃); δ = 7.37-7.27 (m, 5 H), 5.22-5.09 (m, 2 H), 4.24-4.02 (m, 2 H), 3.94-3.79 (m, 2 H), 3.72-3.66 (m, 1 H), 3.60-3.55 (m, 1 H), 3.52-3.42 (m, 1 H), 2.46-2.33 (m, 1 H), 1.07 (1.05) (d, J = 7.4 Hz, 3 H), 0.92 (0.91) (s, 9 H), 0.14 (0.09) (s, 6 H) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 156.1 (154.9), 136.7, 128.5, 128.0, 127.9, 73.4 (72.8), 67.1, 62.8 (61.9), 61.5 (59.8), 56.1 (55.4), 41.4 (40.7), 25.7, 18.0, 9.9 (9.7), -4.8,
-5.1 ppm. ESI-HRMS: m/z calcd for C₂₀H₃₄NO₄Si⁺ [M + H]⁺: 380.2252; found: 380.2268.
Analytical Data for 11β [α]_D ^²5 -2.0 (c 0.16, CHCl₃). ^¹H NMR (500 MHz, CDCl₃):
δ = 7.38-7.33 (m, 5 H), 5.35-5.10 (m, 2 H), 4.85 (br, 1 H) 4.05 (br, 1 H), 3.82-3.80 (m, 1 H), 3.70-3.66 (m, 1 H), 3.62-3.58 (m, 2 H), 3.38 (dd, J = 3.0, 13.4 Hz, 1 H), 1.84-1.77 (m, 1 H), 1.06 (d, J = 6.7 Hz, 3 H), 0.87 (s, 9 H), 0.06 (s, 3 H), 0.04 (s, 3 H) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 157.4, 136.4, 128.5, 128.0, 127.8, 72.3, 67.3, 65.9, 65.6, 55.6, 41.4, 25.7, 18.0, 11.9, -4.8, -5.0 ppm. ESI-HRMS: m/z calcd for C₂₀H₃₄NO₄Si⁺ [M + H]⁺: 380.2252; found: 380.2264.

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