Formal Synthesis of Cytostatin by a Convergent Approach

Abstract

A formal synthesis of cytostatin, an antitumor agent, has been achieved according to a convergent approach involving the coupling of a functionalized organolithium (C1-C8 subunit) with an aldehyde (C9-C13 subunit).

cytostatin - natural products - formal synthesis - dia­stereoselectivity - metathesis

References and Notes

1a Amemiya M. Ueno M. Osono M. Masuda T. Kinoshita N. Nishida C. Hamada M. Ishisuka M. Takeuchi T. J. Antibiot.  1994,  47:  536 

1b Amemiya M. Someno T. Sawa R. Naganawa H. Ishizuka M. Takeuchi T. J. Antibiot.  1994,  47:  541 

2a Yamazaki K. Amemiya M. Ishizuka M. Takeuchi T. J. Antibiot.  1995,  48:  1138 

2b Kawada M. Amemiya M. Ishizuka M. Takeuchi T. Jpn. J. Cancer Res.  1999,  90:  219 

2c Masuda T. Watanabe S. Amemiya M. Ishizuka M. Takeuchi T. J. Antibiot.  1995,  48:  528 

2d Kawada M. Kawatsu M. Masuda T. Ohba S. Amemiya M. Kohama T. Ishizuka M. Takeuchi T. Int. Immunopharm.  2003,  3:  179 

3 Kawada M. Amemiya M. Ishizuka M. Takeuchi T. Biochim. Biophys. Acta: Mol. Cell Res.  1999,  1452:  209 

4 Bialy L. Waldmann H. Angew. Chem. Int. Ed.  2005,  44:  3814 ; and references therein

5a Bialy L. Waldmann H. Angew. Chem. Int. Ed.  2002,  41:  1748 

5b Bialy L. Waldmann H. Chem. Eur. J.  2004,  10:  2759 

6 Marshall JA. Ellis K. Tetrahedron Lett.  2004,  45:  1351 

7 Lawhorn BG. Boga SB. Wolkenberg SE. Colby DA. Gauss C.-M. Swingle MR. Amable L. Honkanen RE. Boger DL. J. Am. Chem. Soc.  2006,  128:  16720 

8 For a review, see: Mengel A. Reiser O. Chem. Rev.  1999,  99:  1191 

This compound was prepared in two steps from butane-1,4-diol by silylation (TBDPSCl, Et₃N, CH₂Cl₂, r.t.) followed by oxidation (PDC, DMF, r.t.), see:

9a Barrett AGM. Flygare JA. J. Org. Chem.  1991,  56:  638 

9b Zhou S. Chen H. Liao W. Chen S.-H. Li G. Ando R. Kuwajima I. Tetrahedron Lett.  2005,  46:  6341 

10a Aiguade J. Hao J. Forsyth CJ. Tetrahedron Lett.  2001,  42:  817 

10b Lafontaine JA. Provencal DP. Gardelli C. Leahy JW. J. Org. Chem.  2003,  68:  4215 

11a Roush WR. Ando K. Powers DB. Palkowitz AD. Halterman RL. J. Am. Chem. Soc.  1990,  112:  6339 

11b Roush WR. Parkowitz AD. Ando K. J. Am. Chem. Soc.  1990,  112:  6348 

12a Roush WR. In Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  p.1-54  

12b Yamamoto Y. Asao N. Chem. Rev.  1993,  93:  2207 

13 Scholl M. Ding S. Lee CW. Grubbs RH. Org. Lett.  1999,  1:  953 

14

The ¹H NMR data of lactone 8, and in particular the coupling constants J _H3-H4, J _H4-H5 and J _H5-H6 as well as the chemical shifts of the methyl groups (H19 and H20) compare favorably well with those reported for structurally related syn,anti-diastereomeric lactones (Figure [1] ). [5] ^{,7 1}H NMR (400 MHz, CD₃OD): δ = 7.69-7.99 (m, 4 H), 7.43-7.37 (m, 6 H), 7.13 (dd, J = 9.6, 6.5 Hz, 1 H, H3), 5.92 (dd, J = 9.6, 0.7 Hz, 1 H, H2), 4.11 (dd, J = 10.5, 3.1 Hz, 1 H, H5), 3.86-3.74 (m, 2 H, 2 H8), 2.55 (m, 1 H, H4), 2.18 (m, 1 H, H7), 2.05 (m, 1 H, H6), 1.37 (m, 1 H, H7), 1.03 (s, 9 H), 0.98 (d, J = 7.1 Hz, 3 H, 3H19), 0.84 (d, J = 6.8 Hz, 3 H, 3 H20).

15a

Acetal 9 was obtained as one major diastereomer (dr > 90:10) having a 1,4-trans-disubstitution pattern based on the coupling constant between H3 and H4 (³ J _H3-H4 = 6.0 Hz), see ref. 15b. However, the diastereomeric ratio varied with the reaction time due to thermodynamic equilibration of 9. Partial equilibration of the compounds bearing an acetalic C1 stereocenter was also noticed during purification on silica gel. This had no consequence since the C1 stereocenter was removed later in the synthesis.

15b Valverde S. Bernabe M. Garcia-Ochoa S. Gomez AM. J. Org. Chem.  1990,  55:  2294 

16 Garegg PJ. Samuelsson B. J. Chem. Soc., Perkin Trans. 1  1980,  2866 

17 Cossy J. Schmitt A. Cinquin C. Buisson D. Belotti D. Bioorg. Med. Chem. Lett.  1997,  7:  1699 

18a Seebach D. Wasmuth D. Helv. Chim. Acta  1980,  63:  197 

18b Frater G. Müller U. Günther W. Tetrahedron  1984,  40:  1269 

19 In model studies, the addition of n-BuLi to aldehyde 17 (Et₂O, -78 °C to -30 °C) and subsequent desilylation (n-Bu₄NF, THF) provided a 70:30 diastereomeric mixture of the secondary alcohols 23 and 24 (68%, Scheme 5). To ascertain that the major diastereomer 23 arose from a Felkin-Anh control, the directed reduction of the β-hydroxy-ketone 25 [Me₄NBH(OAc)₃, MeCN-AcOH, -40 °C to 0 °C] followed by desilylation (n-Bu₄NF, THF) was carried out and led to a 85:15 mixture of the anti-1,3-diol 23 and the syn-1,3-diol 24, see: Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 

20

Compound 20 and its epimer at C9 could be separated by flash chromatography on silica gel. However, the separation of the C9 epimers turned out to be easier for the alkynyl iodide 22.

21

Bis(9H-fluoren-9-ylmethyl)-{(1S,2S,3R)-3-hydroxy-5-iodo-2-methyl-1-[(3S)-3-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)butyl]pent-4-ynyl} phosphate (22): mp 112 °C; [α]_D +46.5 (c 0.4, CHCl₃). IR: 3353, 2360, 1714, 1449, 1380, 1250, 1106, 1070, 987, 739 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.75-7.67 (m, 4 H), 7.54-7.41 (m, 4 H), 7.41-7.20 (m, 8 H), 6.95 (dd, J = 9.5, 6.5 Hz, 1 H), 5.93 (d, J = 9.5 Hz, 1 H), 4.69-4.61 (m, 1 H), 4.36-4.07 (m, 7 H), 3.86 (dd, J = 10.3, 2.4 Hz, 1 H), 2.40 (m, 1 H), 1.83-1.58 (m, 4 H), 1.51-1.41 (m, 1 H), 1.15-1.05 (m, 1 H), 0.98 (d, J = 7.0 Hz, 3 H), 0.89 (d, J = 6.9 Hz, 3 H), 0.78 (d, J = 6.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 164.4 (s), 151.6 (d), 143.1 (s, 2 C), 142.9 (s), 142.8 (s), 141.3 (s, 4 C), 127.9 (d), 127.8 (d), 127.7 (d, 2 C), 127.2 (d, 2 C), 127.1 (d, 2 C), 125.0 (d, 4 C), 120.0 (d) and 119.9 (d, 5 C), 94.8 (s), 83.5 (d), 78.4 [d, ² J(¹³C-³¹P) = 5.8 Hz], 69.4 [t, ² J(¹³C-³¹P) = 4.0 Hz], 69.3 [t, ² J(¹³C-³¹P) = 4.3 Hz], 65.1 (d), 47.9 [d, ³ J(¹³C-³¹P) = 8.4 Hz], 47.8 [d, ³ J(¹³C-³¹P) = 8.7 Hz], 43.9 [d, ³ J(¹³C-³¹P) = 3.6 Hz], 33.8 (d), 30.6 [t, ³ J(¹³C-³¹P) = 4.1 Hz], 30.3 (d), 28.4 (t), 14.7 (q), 10.7 (q), 9.1 (q), 1.1 (s).