Synthetic Studies on a Cyclic Hexadepsipeptide GE3: Stereoselective Construction of the Acyl Side Chain Segment

Abstract

Stereoselective synthesis of the acyl side chain segment 2 of GE3 (1), a potent inhibitor of cell progression of the cell cycle from the G1 to S phase, has been achieved by using Sharpless’ asymmetric dihydroxylation and Evans’ and Paterson’s stereoselective aldol methodologies.

Key words

GE3 - hexadepsipeptide - asymmetric dihydroxylation - asymmetric aldol reaction - antitumor activity

References

• 1a Sakai Y. Yoshida T. Tsujita T. Ochiai K. Agatsuma T. Saitoh Y. Tanaka F. Akiyama T. Akinaga S. Mizukami T. J. Antibiot.  1997,  50:  659 
• 1b Agatsuma T. Sakai Y. Mizukami T. Saitoh Y. J. Antibiot.  1997,  50:  704 
• 1c Yoshida T. Sakai Y. Mizukami T. Nippon Kagaku Kaishi  1997,  71:  516 
• 2 Hayakawa Y. Nakagawa M. Toda Y. Seto H. Agric. Biol. Chem.  1990,  54:  1007 
• 3 Maehr H. Liu C. Palleroni NJ. Smallheer J. Todaro L. Williams TH. Blount JF. J. Antibiot.  1986,  39:  17 
• 4 Smitka TA. Deeter JB. Hunt AH. Mertz FP. Ellis RM. Boeck LD. Yao RC. J. Antibiot.  1988,  41:  726 
• 5 Nakagawa M. Hayakawa Y. Adachi K. Seto H. Agric. Biol. Chem.  1990,  54:  791 
• 6 Hensens OD. Borris RP. Koupal LR. Caldwell CG. Currie SA. Haidri AA. Homnick CF. Honeycutt SS. Lindermayer SM. Schwartz CD. Weissberger BA. Woodruff HB. Zink DL. Zitano L. Fieldhouse JM. Rollins T. Springer MS. Springer JP. J. Antibiot.  1991,  44:  249 
• 7 Nishiyama Y. Sugawara K. Tomita K. Yamamoto H. Kamei H. Oki T. J. Antibiot.  1993,  46:  921 
• 8 Ueno M. Amemiya M. Someno T. Matsuda T. Iinuma H. Nakagawa H. Hamada M. Ishizuka M. Takeuchi T. J. Antibiot.  1993,  46:  1658 
• 9 Gräfe U. Ritzau SM. Ihn W. Dornberger K. Stengel C. Freck WF. Gutsche W. Härtl A. Paulus EF. J. Antibiot.  1995,  48:  119 
• 10a Umezawa K. Nakazawa K. Uemura T. Ikeda Y. Kondo S. Naganawa H. Kinoshita N. Hashizume H. Hamada M. Takeuchi T. Ohba S. Tetrahedron Lett.  1998,  39:  1389 
• 10b Umezawa K. Nakazawa K. Ikeda Y. Naganawa H. Kondo S. J. Org. Chem.  1999,  64:  3034 
• See for the previous synthetic studies on the acyl side chain of A83586C similar to the structure of GE3:
• 12a Hale KJ. Bhatia GS. Peak SA. Manaviazar S. Tetrahedron Lett.  1993,  34:  5343 
• 12b Hale KJ. Cai J. Manaviazar S. Peak SA. Tetrahedron Lett.  1995,  36:  6965 
• 12c Hale KJ. Cai J. Tetrahedron Lett.  1996,  37:  4233 
• 13a Sharpless KB. Amberg W. Bennani YL. Crispino GA. Hartung J. Jeong K.-S. Kwong H.-L. Morikawa K. Wang Z.-M. Xu D. Zhang X.-L. J. Org. Chem.  1992,  57:  2768 
• 13b Kolb HC. Van Nieuwenhze MS. Sharpless KB. Chem. Rev.  1994,  94:  2483 
• 14a Evans DA. Bartoli J. Shih TL. J. Am. Chem. Soc.  1981,  103:  2127 
• 14b Gage JR. Evans DA. Org. Synth.  1989,  68:  77 
• 14c Gage JR. Evans DA. Org. Synth.  1989,  68:  83 
• 15 Paterson I. Wallace DJ. Velazquez SM. Tetrahedron Lett.  1994,  35:  9083 
• 17 Evans DA. Rieger DL. Bilodeau MT. Urpi F. J. Am. Chem. Soc.  1991,  113:  1047 
• 18 Fukuyama T. Lin S.-C. Li L. J. Am. Chem. Soc.  1990,  112:  7050 
• 19 Hamada Y. Shibata M. Sugiura T. Kato S. Shioiri T. J. Org. Chem.  1987,  52:  1252 
• 20 House HO. Crumrine DS. Teranishi AY. Olmstead HD. J. Am. Chem. Soc.  1973,  95:  3310 
• 21a Atkins GM. Burgess EM. J. Am. Chem. Soc.  1968,  90:  4744 
• 21b Burgess EM. Penton HR. Taylor EA. J. Am. Chem. Soc.  1970,  92:  5224 
• 21c Burgess EM. Penton HR. Taylor EA. J. Org. Chem.  1973,  38:  26 
• 22a Mahoney WS. Bretensky DM. Stryker JM. J. Am. Chem. Soc.  1988,  110:  291 
• 22b Mahoney WS. Stryker JM. J. Am. Chem. Soc.  1989,  111:  8818 
• 22c Bretensky DM. Stryker JM. Tetrahedron Lett.  1989,  30:  5677 

11

The structure of GE3, including the absolute configuration, was deduced to be as shown in Scheme [1] by Sakai and coworkers.

16

The minor enantiomer of 4 was removed after the coupling with enantiomerically pure C5-C14 fragment 5.

23

Compound 2: [α]_D ²³ +20.5 (c 0.19, CHCl₃); IR(neat): 3474, 2956, 2857, 1722, 1462, 1254 cm^-1; ¹H NMR (500 MHz, C₆D₆): δ = 0.70 (d, J = 6.7 Hz, 3 H, C6-CH ₃ ), 1.01 (d, J = 6.8 Hz, 3 H, C10-CH ₃ ), 1.30-1.45 (m, 1 H, C6-H), 1.50-1.60 (m, 13 H, C2-CH ₃ , C5-H, C8-CH ₃ , C12-CH ₃ , C14-H), 1.65-1.80 (m, 2 H, C5-H, C4-H), 2.04 (dd, J = 12.8, 10.3 Hz, C4-H), 2.64 (m, 1 H, C10-H), 3.25 (brs, 1 H, OH), 3.71 (d, J = 6.7 Hz, 1 H, C11-H), 4.01 (d, J = 10.4 Hz, 1 H, C7-H), 4.45 (s, 1 H, OH), 5.01 (d, J = 12.2 Hz, 1 H, ArCH ₂ ), 5.09 (d, J = 12.2 Hz, 1 H, ArCH ₂), 5.30 (d, J = 9.4 Hz, 1 H, C9-H), 5.37 (m, 1 H, C13-H), 7.10-7.20 (m, 5 H, Ar-H); ¹³C NMR (125 MHz, C₆D₆): δ = 11.8, 12.1, 13.0, 16.5, 17.8, 20.0, 27.4, 27.7, 32.3, 36.3, 67.5, 79.4, 81.2, 83.4, 99.7, 120.5, 128.4, 128.6, 128.8, 132.2, 133.1, 135.7, 137.8, 176.0.