An Enantioselective Total Synthesis of (-)-Stemoamide

Mukund P. Sibi; Thangaiah Subramanian

doi:10.1055/s-2004-822927

LETTER

An Enantioselective Total Synthesis of (-)-Stemoamide

Mukund P. Sibi*, Thangaiah Subramanian
Department of Chemistry, North Dakota State University, Fargo, ND 58105, USA
Fax: +1(701)2311057; e-Mail: Mukund.Sibi@ndsu.nodak.edu;

Abstract

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Abstract

An enantioselective synthesis of (-)-stemoamide has been achieved in 14 steps starting from pyroglutamyl alcohol in ca. 7% overall yield. The key steps in the strategy are a conjugate addition of a vinyl copper reagent and a ring closing metathesis (RCM) reaction to form the seven-membered ring.

Key words

stemoamide - ring closing metathesis - conjugate addition - pyroglutamic acid

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References

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Procedure for Conjugate Addition: Lithium bromide (2.59 g, 30.1 mmol, 6 equiv) and CuBr·DMS (3.059 g, 15.0 mmol) were placed in a dry round bottomed flask. THF (35 mL) was added to the solids and the reaction mixture was cooled to -78 °C. Vinyl magnesium bromide (30 mL, 0.977 molar solution in THF, 6 equiv) was added dropwise. After stirring for 30 min at the same temperature, ester 8 (1.1072 g, 5 mmol) in THF (10 mL) was added dropwise and the resultant solution was stirred at the same temperature for 10 min and at -40 °C for 50 min. The reaction was quenched with NH₄Cl solution and extracted with Et₂O repeatedly. The combined extracts were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography using EtOAc and hexane (EtOAc-hexane, 1:1) to give the ester 7 (1.02 g, 81%). ¹H NMR (500 MHz, CDCl₃): δ = 1.69-1.76 (m, 1 H), 1.95-2.04 (m, 1 H), 2.25-2.39 (m, 4 H), 2.29 (d, J = 7.0 Hz, 2 H), 2.93 (m, 1 H), 3.05-3.11 (m, 1 H), 3.66 (s, 3 H), 3.75-3.84 (m, 2 H), 5.04 (d, J = 10.0 Hz, 1 H), 5.08 (d, J = 17.5 Hz, 1 H), 5.18 (dd, J = 13.5, 3 Hz, 2 H), 5.73 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 19.5, 30.4, 31.7, 32.4, 39.9, 41.3, 52.1, 60.0, 117.3, 117.9, 135.3, 136.7, 172.7, 175.6. IR (neat): 1733, 1674 cm^-1. [α]_D ²⁵ +17.3 (c = 1.0, MeOH). HRMS: m/z calcd for C₁₄H₂₁NO₃Na⁺: 274.1413; found: 274.1410. The stereochemistry at C-9 was unambiguously established at a later stage (compounds 15 and 17).

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Preparation of the Tricyclic Lactam 6: The iodolactone 17 (0.748 g, 2.2 mmol) was dissolved in degassed toluene (75 mL) in a two-neck round-bottomed flask fitted with a reflux condenser and a rubber septum. Tributyltin hydride (0.722 mL, 2.68 mmol) was added and the reaction heated to 80 °C. A solution of AIBN (60 mg) in toluene (5 mL) was added to the reaction mixture four times with the interval of 1 h. The resultant solution was refluxed for 10 h. The solvent was removed and the residue was chromatographed over silica gel to give 6 as a highly viscous liquid that solidified upon cooling (0.321 g, 70%); mp 42-43 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.51-1.60 (m, 2 H), 1.70 (q, J = 10.5 Hz, 1 H), 1.83-1.85 (m, 1 H), 2.02-2.08 (m, 1 H), 2.36-2.41 (m, 4 H), 2.47-2.53 (m, 1 H), 2.60-2.70 (m, 1 H), 2.76-2.87 (m, 1 H), 4.0 (dt, J = 6.0, 10.5 Hz, 1 H), 4.11-4.14 (m, 1 H), 4.27 (dt, J = 3.0, 10.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 22.9, 25.7, 30.8, 31.2, 34.8, 40.4, 45.1, 56.3, 80.0, 174.3, 174.9. [α]_D ²⁵ -91.9 (c = 1.0, CHCl₃). HRMS: m/z calcd for C₁₁H₁₅NO₃Na: 232.0944; found: 232.0940.

Also see ref. 4c for a similar reduction and establishment of stereocenter at C-9 and C-10.

Lactone 6 could also be methylated to provide C-9, C-10 diepi stemoamide (data not shown).

Mp: 185-186 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.31 (d, J = 6.9 Hz, 3 H), 1.50-1.58 (m, 2 H), 1.72 (quint, J = 10.7 Hz, 1 H), 1.85-1.90 (m, 1 H), 2.0-2.10 (m, 1 H), 2.38-2.45 (m, 4 H), 2.60 (dq, J = 6.9, 12.5 Hz, 1 H), 2.65 (dd, J = 12.3, 14.1 Hz, 1 H), 3.99 (dt, J = 10.8, 6.3 Hz, 1 H), 4.16 (m, 1 H), 4.20 (dt, J = 3.1, 10.3 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.1, 22.5, 25.6, 30.5, 34.8, 37.3, 40.2, 52.7, 55.8, 77.6, 174.0, 177.3. IR (neat): 1768, 1681 cm^-1. [α]_D ²⁵ -191.6 (c = 0.5, MeOH). {Lit. [α]_D ²⁵ -183.5 (c = 1.36, MeOH); [4b] [α]_D ³⁰ -219.3 (c = 0.5, MeOH); [4d] [α]_D -181.6
(c = 0.89, MeOH)}. [4e] HRMS: m/z calcd for C₁₂H₁₇NO₃Na⁺: 246.1100: found: 246.1099.