But
Pri
N
Pri
OH
MeO
O
OMe
OMe
MeO
MeO
OMe
OMe
OMe
i
ii–iv
OMe
(
S)-9
MeO
MeO
O
MeO
OMe
MeO
OMe
N
Pri
OH
Pri
But
aS,S)-10
(
S)-11
(
17 : 1 d.r.
v
Pri
Pri
HO
HO
Me
HO
H
O
MeO
MeO
Me
OMe
vi, vii
OMe
OH
OMe
OH
Me
O
H
OH
MeO
MeO
Pri
Me
OMe
(
S)-13
(S)-12
Pri
3
, 84%; vi, BBr ; vii, DMSO,
0
Scheme 2 Reagents and conditions: i, Cu , DMF, reflux, 80%; ii, TFA; iii, Ac
2
O; iv, LiAlH
4
, 72% over 3 steps; v, Pd/C, H
2
2
(COCI) , 81% over 2 steps
(
J. W. W.). The authors also thank Dr K. Drauz of Degussa AG
5 A. E. A. Joseph, S. A. Martin and P. Knox, Br. J. Cancer, 1986, 54,
11.
5
for generous samples of (S)-tert-leucine.
6
T. S. Lin, R. Schinazi, B. P. Griffith, E. M. August, B. H. F. Eriksson,
D. K. Zheng and W. H. Prusoff, Antimicrob. Agents Chemother., 1989,
Footnotes and References
3
3, 2149.
*
†
E-mail: aimeyers@lamar.colostate.edu
Selected data for (S)-8: light yellow oil [a]
7 P. H. Dorsett and E. E. Kerstine, J. Pharm. Sci., 1975, 64, 1073;
R. J. Radloff, L. M. Deck, R. E. Royer and P. L. Vanderjagt, Pharmacol.
Res. Commun., 1986, 18, 1063.
8 L. V. Goryunova and S. A. Vichkanova, Farmakol. Toksikol., 1969, 32,
615.
1
D
3
261 (c 1.2, CHCl ); H NMR
(
(
(
300 MHz, CDCl
3
) d 0.96 (s, 9 H), 1.47 (d, 6 H, J 7.3), 3.40 (s, 3 H), 3.89
s, 3 H), 3.99 (s, 3 H), 4.02–4.14 {m, 5 H [therein 4.07 (s, 3 H)]}, 4.23–4.34
1
3
m, 2 H), 4.98 (s, 2 H), 7.49 (s, 1 H), 8.16 (s, 1 H); C NMR (75 MHz,
) d 31.8, 32.5, 34.9, 32.0, 43.0, 57.6, 62.1, 78.4, 75.2, 85.2, 103.9,
05.0, 119.2, 124.0, 126.3, 128.4, 133.6, 143.3, 148.6, 149.8, 158.1;
CDCl
1
3
9 C. Yu, M. Sten, M. Nordenskjold, B. Lambert, S. A. Matlin and
R. H. Zhou, Mutat. Res., 1986, 164, 71.
max(thin film)/cm2 2952, 1655, 1450, 1263, 1183, 1042; HRMS: calc. for
1
10 (a) J. D. Edwards and J. L. Cashaw, J. Am. Chem. Soc., 1957, 79, 2283;
(b) M. C. Venati, J. Org. Chem., 1981, 46, 3124; (c) D. A. Shirley and
W. L. Dean, J. Am. Chem. Soc., 1957, 79, 1205; (d) P. C. Meltzer,
P. H. Bickford and G. H. Lambert, J. Org. Chem., 1985, 50, 3121; (e)
V. I. Oguyonov, O. S. Petrov, E. P. Tiholov and N. M. Mollov, Helv.
Chim. Acta, 1989, 72, 353.
n
C
‡
25
H
35NO
Selected data for (aS,S)-10: light yellow oil: [a]
) d 0.55 (s, 18 H), 1.48 (d, 12 H, J 7.4), 3.29 (s, 6
H), 3.85 (s, 6 H), 3.98–4.04 {m, 16 H [therein 3.98 (s, 6 H), 4.03 (s, 6 H)]},
5
: 429.2515. Found: 429.2520.
1
D
3
228 (c 1.9, CHCl ); H
NMR (300 MHz, CDCl
3
1
3
4
.30–4.37 (m, 4 H), 5.16 (s, 4 H), 7.50 (s, 2 H); C NMR (75 MHz, CDCl
3
)
d 21.0, 22.1, 24.9, 27.5, 47.3, 49.3, 52.4, 59.1, 67.1, 70.6, 81.4, 109.6, 119.2,
11 T. D. Nelson and A. I. Meyers, Tetrahedron Lett., 1993, 34, 3061.
12 T. D. Nelson and A. I. Meyers, J. Org. Chem., 1994, 59, 2577; A. I.
Meyers and M. J. McKennon, Tetrahedron Lett., 1995, 36, 5869.
13 A brief report on the asymmetric Ullmann coupling leading to the (+)-
apogossypol hexamethyl ether, a degradation product of 13, has
appeared: A. I. Meyers and J. J. Willemsen, Tetrahedron Lett., 1996, 37,
791.
14 S. A. Matlin, R. H. Zhou, G. Bialy, R. P. Bialy, R. H. Naqvi and
M. C. Lindberg, Contraception, 1985, 31, 141.
15 S. A. Matlin, A. G. Belengue, R. Tyson and R. G. Brooks, J. High
Resolut. Chromatogr., 1987, 10, 86.
16 Three reviews on oxazolines and their synthetic utility have appeared
(a) A. I. Meyers and E. D. Mihelich, Angew. Chem., Int. Ed. Engl., 1976,
15, 270; (b) M. Reuman and A. I. Meyers, Tetrahedron Reports, 1985,
837; (c) T. G. Gant and A. I. Meyers, Tetrahedron Reports, 1994,
2297.
17 M. Shimano and A. I. Meyers, J. Am. Chem. Soc., 1994, 116, 10 815.
18 W. S. Johnson and G. H. Daub, Org. React., Wiley, New York, 1950,
vol. 1.
19 M. L. McKennon, A. I. Meyers, K. Drauz and M. Schwarm, J. Org.
Chem., 1993, 58, 3568.
20 R. C. Fuson and E. A. Cleveland, Org. Synth., 1955, Coll. Vol. III,
339.
1
20.8, 123.1, 132.4, 145.2, 147.9, 146.0, 150.5, 151.9, 160.1; nmax (thin
21
film)/cm
2957, 1644, 1594, 1463, 1341, 1242, 1030; calc. for
C
§
50
H
68
N
2
O
10: C, 70.07; H, 7.99. Found: C, 70.25; H, 7.89%.
1
Selected data for (S)-12: colorless oil: [a]
D
193 (c 1.4, CHCl
3
); H NMR
(300 MHz, CDCl
3
) d 1.51 (d, 12 H, J 7.3), 2.16 (s, 6 H), 3.13 (s, 6 H), 3.65
(
s, 6 H), 4.08 {m, 14 H [therein 4.02 (s, 6 H), 4.11 (s, 6 H)]}, 5.35 (s, 4 H),
1
3
7
6
1
1
¶
.39 (s, 2 H); C NMR (75 MHz, CDCl
3
) d 24.2, 25.9, 29.1, 57.8, 62.0,
2.6, 68.4, 82.8, 103.3, 112.3, 117.2, 118.6, 120.5, 124.3, 125.9, 130.0,
34.1, 136.9; nmax(thin film)/cm2 2957, 1654, 1602, 1459, 1290, 1246,
1
50 8
034; calc. for C38H O : C, 71.90; H, 7.94. Found: C, 71.95; H, 7.91%.
Selected data for (S)-gossypol (S)-13: yellow powder: mp 186.1–186.9 °C
2
1
(
(
(
lit., 184 °C); [a]
D 3 3
371 (c 1.1, CHCl ); H NMR (300 MHz, CDCl ) d 1.54
d, 12 H, J 7.0), 2.14 (s, 6 H), 3.88 (septet, 2 H, J 6.9), 5.85 (s, 2 H), 6.39
1
3
s, 2 H), 7.77 (s, 2 H), 11.11 (s, 2 H), 15.11 (s, 2 H); C NMR (75 MHz,
) d 20.5, 20.5, 28.1, 111.9, 114.9, 116.5, 118.2, 129.8, 134.0, 134.4,
CDCl
3
1
1
1
5
∑
43.4, 150.8, 156.0, 199.5; nmax(KBr)/cm2 3377 (br), 1615, 1601, 1440,
335, 1168 cm2 ; HRMS (LSIMS): calc. for C30
1
30 8
H O : 518.1941. Found:
18.1949.
Racemic gossypol came from (i) a synthesis as above using achiral
oxazolines, and (ii) purchased from Sigma. HPLC of the phenylalanine
Schiff base from the Sigma material showed a 60:40 ratio of isomers, an
indication that it originated from natural sources. The synthetic racemic
material gave a 49:51 ± 1 ratio of diastereoisomers from (S)-phenylalanine.
21 L. Huang, S. Yi-Kang, G. Snatzke, D. K. Zheng and J. Zhou, Collect.
Czech. Chem. Commun., 1988, 53, 2664.
22 J. W. Jarozewski, T. Strom-Hausen and L. L. Hansen, Chirality, 1992,
®
HPLC conditions: C18 reverse phase, 5 mm Hypersil -ODS, gradient
MeCN–KH PO
2 4
(0.01 m aq.) 91:9 to 82:18; monitored at 254 nm.
4
, 216; D. K. Zheng, Y. K. Si, J. K. Meng, L. Huang, J. Chem. Soc.,
1
2
J. Longmore, Indian J. Chem., 1886, 5, 200.
R. Adams, R. C. Morris, D. J. Butterbaugh and E. C. Kirkpatrick, J. Am.
Chem. Soc., 1938, 60, 2191 and earlier papers.
Chem. Commun., 1985, 168; D. S. Sampath and P. Balarem, J. Chem.
Soc., Chem. Commun., 1986, 649.
23 B. Brzezinski, J. Olejnk, S. Paszyc and T. F. Aripov, J. Mol. Struct.,
1990, 220, 261; B. Brycki, B. Brzezinski, B. Marciniak and S. Paszyc,
Spectrosc. Lett., 1991, 24, 509.
3
4
National Coordinating Group on Male Fertility Agents, China’s Med.,
1
978, 6, 417.
S. Z. Qian and Z. G. Wang, Annu. Rev. Pharmacol. Toxicol., 1984, 24,
29.
3
Received in Corvallis, OR, USA, 5th May 1997; 7/03043F
1574
Chem. Commun., 1997