Synlett 2004(7): 1211-1214  
DOI: 10.1055/s-2004-822927
LETTER
© Georg Thieme Verlag Stuttgart · New York

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: [email protected];
Further Information

Publication History

Received 22 February 2004
Publication Date:
10 May 2004 (online)

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.

    References

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  • 7a

    Ref. 6.

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5

Ester 10 is commercially available.

12

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).

13

Interestingly, conjugate addition to the corresponding Z-ester gave a 2:1 mixture of diastereomers with 7 as the major product (data not shown).

15

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.

16

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

17

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

18

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.