An Enantioselective Total Synthesis of (-)-Stemoamide

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.

stemoamide - ring closing metathesis - conjugate addition - pyroglutamic acid

References

1a Pilli RA. Ferreira de Olivera MC. Nat. Prod. Rep.  2000,  17:  117 

1b Lin W.-H. Ye Y. Xu R.-S. J. Nat. Prod.  1992,  55:  571 

2a Qin GW. Xu RS. Med. Res. Rev.  1998,  18:  375 

2b Ye Y. Qin G.-W. Xu R.-S. Phytochemistry  1994,  37:  1201 

2c Ye Y. Qin G.-W. Xu R.-S. Phytochemistry  1994,  37:  1205 

2d Ye Y. Qin G.-W. Xu R.-S. J. Nat. Prod.  1994,  57:  655 

2e Brem B. Seger C. Pacher P. Hofer O. Vajrodaya S. Greger H. J. Agric. Food Chem.  2002,  50:  6383 

3a Tuberostemonine: Wipf P. Rector SR. Takahashi H. J. Am. Chem. Soc.  2002,  124:  14848 

3b For stenine see the following: Morimoto Y. Iwahashi M. Nishida K. Hayashi Y. Shirahama H. Angew. Chem., Int. Ed. Engl.  1996,  35:  904 

3c Morimoto Y. Iwahashi M. Kinoshita T. Nishida K. Chem.-Eur. J.  2001,  7:  4107 

3d Wipf P. Kim Y. Goldstein DM. J. Am. Chem. Soc.  1995,  117:  11106 

3e Golden JE. Aube J. Angew. Chem. Int. Ed.  2002,  41:  4316 

3f Chen CY. Hart DJ. J. Org. Chem.  1993,  58:  3840 

3g Ginn JD. Padwa A. Org. Lett.  2002,  4:  1515 

For other stemona alkaloids see the following:

3h Williams DR. Fromhold MG. Earley JD. Org. Lett.  2001,  3:  2721 

3i Kende AS. Martin Hernando JI. Milbank JBJ. Tetrahedron  2002,  58:  61 

3j Martin SF. Barr KJ. Smith DW. Bur SK. J. Am. Chem. Soc.  1999,  121:  6990 

Enantioselective synthesis:

4a Gurjar MK. Reddy DS. Tetrahedron Lett.  2002,  43:  295 

4b Jacobi PA. Lee K. J. Am. Chem. Soc.  2000,  122:  4295 

4c Kinoshita A. Mori M. Heterocycles  1997,  46:  287 

4d Kinoshita A. Mori M. J. Org. Chem.  1996,  61:  8356 

4e Williams DR. Reddy JP. Amato GS. Tetrahedron Lett.  1994,  35:  6417 

For racemic synthesis see the following:

4f Jacobi PA. Lee K. J. Am. Chem. Soc.  1997,  119:  3409 

4g Kohno Y. Narasaka K. Bull. Chem. Soc. Jpn.  1996,  69:  2063 

5

Ester 10 is commercially available.

6 Acevedo CM. Kogut EF. Lipton MA. Tetrahedron  2001,  57:  6353 . The alcohol is also commercially available

7a

Ref. 6.

7b Frieman BA. Bock CW. Bhat KL. Heterocycles  2001,  55:  2099 

8 For an example of alkylation of protected pyroglutamyl alcohol see: Sato Y. Saito N. Mori M. Tetrahedron  1998,  54:  1153 ; also see refs. 4b, 4d

For stereoselective olefination of prolinal derivatives see:

9a Langois N. Radom M.-O. Tetrahedron Lett.  1998,  39:  857 

9b Mulzer J. Shanyoor M. Tetrahedron Lett.  1993,  34:  6545 

9c Moriwake T. Hamano S. Miki D. Saito S. Torii S. Chem. Lett.  1986,  815 

9d Clark JS. Hodgson PB. Goldsmith MD. Blake AJ. Cooke PA. Street LJ. J. Chem. Soc., Perkin Trans. 1  2001,  3325 

9e Lee E. Li KS. Lim J. Tetrahedron Lett.  1996,  37:  1445 

For conjugate addition to γ-amino alkenoates with varied levels of syn selectivity see:

10a Moriwake T. Hamano S. Saito S. Heterocycles  1988,  27:  1135 

10b Le Coz S. Mann A. Thareau F. Taddei M. Heterocycles  1993,  36:  2073 

10c Reetz MT. Röhrig D. Angew. Chem., Int. Ed. Engl.  1989,  28:  1706 

10d Jako I. Uiber P. Mann A. Taddei M. Wermuth CG. Tetrahedron Lett.  1990,  31:  1011 

10e Jako I. Uiber P. Mann A. Wermuth CG. Boulanger T. Norberg B. Evrard G. Durant F. J. Org. Chem.  1991,  56:  5729 

10f Hanessian S. Sumi K. Synthesis  1991,  1083 

10g Hanessian S. Demont E. van Otterlo WAL. Tetrahedron Lett.  2000,  41:  4999 

10i Hanessian S. Wang W. Gai Y. Tetrahedron Lett.  1996,  37:  7477 

10j Paz MM. Sardina FJ. J. Org. Chem.  1993,  58:  6990 

For examples of highly diastereoselective conjugate additions of copper reagents to γ-substituted alkenoates and discussions on stereoselectivity in these reactions see:

11a Yamamoto Y. Chounan Y. Nishii S. Ibuka T. Kitahara H. J. Am. Chem. Soc.  1992,  114:  7652 

11b Roush WR. Lesur BM. Tetrahedron Lett.  1983,  24:  2231 

11c Roush WR. Michaelides MR. Tai DF. Lesur BM. Chong WKM. Harris DJ. J. Am. Chem. Soc.  1989,  111:  2984 

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).

14a For recent reviews on ring-closing metathesis see: Trnka TM. Grubbs RH. Acc. Chem. Res.  2001,  34:  18 

14b Also see: Fürstner A. Angew. Chem. Int. Ed.  2000,  39:  3012 

For the formation of 7-membered azacycles using RCM see the following:

14c Turling CA. Holmes AB. Markwell RE. Pearson ND. J. Chem. Soc., Perkin Trans. 1  1999,  1695 

14d Barrett AGM. Ahmed M. Baker SP. Baugh SPD. Braddock DC. Procopiou PA. White AJP. Williams DJ. J. Org. Chem.  2000,  65:  3716 

14e Martin SF. Chen H.-J. Courtney AK. Liao Y. Pätzel M. Ramser MN. Wagman AS. Tetrahedron  1996,  52:  7251 

14f Colombo L. Di Giacomo M. Vinci V. Colombo M. Manzoni L. Scolastico C. Tetrahedron  2003,  59:  4501 

14g Vo-Thanh G. Boucard V. Sauriat-Dorizon H. Guibe F. Synlett  2001,  37 

14h Lim SH. Ma S. Beak P. J. Org. Chem.  2001,  66:  9056 

14i Beal LM. Liu B. Chu W. Moeller KD. Tetrahedron  2000,  56:  10113 

14j Hoffmann T. Lanig H. Waibel R. Gmeiner P. Angew. Chem. Int. Ed.  2001,  40:  3361 

14k Grossmith CE. Senia F. Wagner J. Synlett  1999,  1660 

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.