Sequential asymmetric hydrogenation of symmetric bis-cinnamic acid derivatives: Synthesis of the C2-symmetric core units of HIV protease inhibitors

Full text of DOI:10.1021/jo961012z

8360
J . Org. Chem. 1996, 61, 8360-8361
Sequ en tia l Asym m etr ic Hyd r ogen a tion of
Sym m etr ic Bis-Cin n a m ic Acid Der iva tives:
Syn th eses of th e C2-Sym m etr ic Cor e Un its
of HIV P r otea se In h ibitor s
Takayuki Doi, Kazunori Hirabayashi,
Masaya Kokubo, Toshikazu Komagata,
Keiji Yamamoto,* and Takashi Takahashi*
Department of Chemical Engineering, Tokyo Institute of
Technology, 2-12-1 Ookayama, Meguro, Tokyo 152, J apan
F igu r e 1.
Received August 5, 1996
Sch em e 1
Asymmetric hydrogenation has been regarded as a
synthetically useful and yet simple manipulation. Rhod-
ium(I) and ruthenium(II) complexes with certain chiral
bidentate phosphines are well known catalysts used to
perform asymmetric hydrogenations with high enantio-
meric bias.1 Herein, we wish to report an approach to
generate the chiral C2-symmetric molecules 1a and 2a
by sequential asymmetric hydrogenation of prochiral bis-
cinnamic acid derivatives 3 and 4, respectively, in one
operation (eqs 1 and 2). The products 1a and 2a are the
step would convert a portion of the minor enantiomer,
formed by the initial hydrogenation step, into a meso
compound. Therefore, the enantiomeric purity of the
dually hydrogenated product would be enhanced to 88%
ee (A2:B2 ) 16:1) at the expense of the formation of the
meso byproducts.
The bis-cinnamic acids 3 and 4 were prepared as shown
in Scheme 1. Lithiation of (Z)-2-bromocinnamaldehyde
diethyl acetal (5)6 (BuLi, hexane), followed by the addi-
tion of DMF, provided enal 6 in 92% yield. Reduction
(NaBH4, MeOH) of 6 and bromination (MsCl, NEt3, LiBr,
THF) of the resulting allylic alcohol gave the allylic
bromide 7 in 75% overall yield. Dialkylation by addition
of KN(TMS)2 (1.1 equiv for 7) to a mixture of 7 and
acetonitrile (0.58 equiv for 7) in ether at 0 °C gave the
adduct 8 in 86% yield.7 The nitrile 8 was converted to
the oxo bis-enal 9 in 71% yield by R-peroxidation-
reduction8 and hydrolysis (LiNEt2, THF; O2; P(OEt)3;
aqueous HCl; aqueous NaHCO3). Oxidation (NaClO2,
NaH2PO4, t-BuOH-H2O, 2-methyl-2-butene)9 of the oxo
bis-enal 9 afforded the desired oxo diacid 3 in 78% yield,
which was purified by recrystallization from 2-propanol.
The acid 4 was prepared starting from 5 and 6 as follows.
Addition of lithiated 5, shown above, to the enal 6
followed by hydrolysis (CuSO4, MeOH-H2O, 40 °C)10
gave the bis-enal 10 in 53% yield. The oxidation9 of 10
to diacid 4 (81%) was performed in the same manner as
the preparation of 3 from 9.
C2-symmetric core unit of the of HIV protease inhibitors2
such as L-700,4172a and A-74704,2b,c respectively (Figure
1). They are not as effective as nonsymmetric inhibitors
at the present time. Recently, however, the C2-symmetric
cyclic urea DM-323 has been reported as an effective
inhibitor.2d,e Therefore, a method for preparing the C2-
symmetric core units in a chiral fashion would be useful
in exploring new inhibitors. We expected that if each
step of the sequential asymmetric hydrogenation of the
symmetric dienes 3 and 4 occurred independently, the
overall reaction could be performed with good overall
asymmetric induction.3-5 Thus, even though the asym-
metric induction for each hydrogenation is moderate, for
example, 60% ee (A:B ) 4:1), the second hydrogenation
(1) Noyori, R. Asymmetric Catalysis In Organic Synthesis; J ohn
Wiley & Sons, Inc.: New York, 1994. Koenig, K. E. In Asymmetric
Synthesis; Morrison, J . D., Ed.; Academic Press, Inc.: New York, 1985;
p 71.
(2) (a) Bone, R.; Vacca, J . P.; Anderson, P. S.; Holloway, M. K. J .
Am. Chem. Soc. 1991, 113, 9382. (b) Erickson, J .; Neidhart, D. J .;
VanDrie, J .; Kempf, D. J .; Wang, X. C.; Norbeck, D. W.; Plattner, J .
J .; Rittenhouse, J . W.; Turon, M.; Wideburg, N.; Kohlbrenner, W. E.;
Simmer, R.; Helfrich, R.; Paul, D. A.; Knigge, M. Science 1990, 249,
527. (c) Kempf, D. J . Eur. Pat. Appl. EP402,646. (d) Lam, P. Y. S.;
J adhav, P. K.; Eyermann, C. J .; Hodge, C. N.; Ru, Y.; Bacheler, L. T.;
Meek, J . L.; Otto, M. J .; Rayner, M. M.; Wong, Y. N.; Chang, C.-H.;
Weber, P. C.; J ackson, D. A.; Sharpe, T. R.; Erickson-Viitanen, S.
Science 1994, 263, 380. (e) J adhav, P. K.; Man, H.-W. Tetrahedron Lett.
1996, 37, 1153.
(3) (a) Hoye, T. R.; Suhadolnik, J . C. J . Am. Chem. Soc. 1985, 107,
5312. (b) Hoye, T. R.; Suhadolnik, J . C. Tetrahedron 1986, 42, 2855.
(c) Muramatsu, H.; Kawano, H.; Ishii, Y.; Saburi, M.; Uchida, Y. J .
Chem. Soc., Chem. Commun. 1989, 769. (d) Aggarwal, V. K.; Evans,
G.; Moya, E.; Dowden, J . J . Org. Chem. 1992, 57, 6390.
(4) For two-directional chain synthesis, see: Schreiber, S. L. Chem.
Scr. 1987, 27, 563.
(5) For sequential asymmetric hydrogenation, see: Kitamura, M.;
Ohkuma, T.; Inoue, S.; Sayo, N. Kumobayashi, H.; Akutagawa, S.;
Ohta, T.; Takaya, H.; Noyori, R. J . Am. Chem. Soc. 1988, 110, 629.
Baba, S. E.; Sartor, K.; Poulin, J .-C.; Kagan, H. B. Bull. Soc. Chim.
Fr. 1994, 131, 525. See also ref. 3c.
(6) Allen, C. F. H.; Edens, C. O., J r. Organic Syntheses; Wiley: New
York, 1955; Collect. Vol. III, p 731.
(7) Cope, A. C.; Holmes, H. L.; House, H. O. Org. React. 1957, 9,
107.
(8) Selikson, S. J .; Watt, D. S. J . Org. Chem. 1975, 40, 267.
(9) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
Kraus, G. A.; Taschner, M. J . J . Org. Chem. 1980, 45, 1175. Bal, B. S.;
Childers, W. E., J r.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
(10) Hydrolysis with
a 1 M hydrogen chloride gave a complex
mixture. The conditions were reported previously, see: Stork, G.;
Takahashi, T.; Kawamoto, I.; Suzuki, T. J . Am. Chem. Soc. 1978, 100,
8272.
S0022-3263(96)01012-2 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 24, 1996 8361
Ta ble 1. Sequ en tia l Asym m etr ic Hyd r ogen a tion of 3 a n d 4
entry
compd
T/°C
H2/atm
time/h
yieldc,d/%
ratio/% (% ee)
1
2
3
4
5
3a
35
35
35
35
25
30
50
50
70
50
24
24
80
24
48
93
91
84
81
92
(R,R)-1b
71 (93):
73 (93):
70 (90):
70 (90):
69 (90):
meso-11
29
27
30
30
31
e
6
7
8
9
10
4b
50
50
50
30
30
50
70
90
55
90
70
70
90
160
240
>95
>95
>95
>95
>95
(R,R)-2b
62 (70):
80 (88):
80 (94):
80 (72):
65 (91):
meso-12
35:
15:
19:
19:
34:
meso-13
3
5
1
1
1
a
b
3 mol % Ru(OAc)2[(S)-BINAP], 2 equiv of NEt3. 10 mol % Ru(OAc)2[(S)-BINAP], 2 equiv of NEt3. c Combined yield of 1b and 11.
Combined yield of 2b, 12, and 13. e The selectivity was determined after reoxidation.
d
Sch em e 2
acid moiety shown above, may have a significant influ-
ence on the enantiomeric excess of the desired product
2. Hydrogenation of diacid 4 using Ru(OAc)2[(S)-BINAP]
as a catalyst and esterification of the reaction mixture
gave a mixture of (R,R)-2b,16 meso-12, and meso-13
(Table 1, entries 6-10).14 Although we had to use 10 mol
% of the catalyst to substrate 4, due presumably to the
steric hindrance around the alkene moieties of 4, the
reaction was completed after 70 h at 50 °C. The enan-
tiomeric excess as well as diastereoselectivity of 2b were
found to be highly dependent on the hydrogen pressure
(entries 6-8).1 Thus, the best chiral induction for (R,R)-
2b (80% selectivity, 94% ee in entry 8) is slightly better
than that observed for 1b. Therefore, the catalyst control
for the bis-cinnamic acid moiety was observed to override
the directed control by the hydroxyl group in this
particular case. Moreover, the minor enantiomers of the
diastereomeric products in the initial step of the sequen-
tial hydrogenation would be preferentially converted to
the meso diastereomers 12 and 13 in the second step,
respectively, owing to the stereochemical preferences in
the double asymmetric processes. When the reaction was
conducted at 30 °C, however, inferior diastereoselectivi-
ties were obtained (entries 9 and 10).
The Curtius rearrangement of 2a (DPPA/NEt3/DMAP,
THF, reflux; Ba(OH)2, dioxane/H2O ) 1/2, reflux) gave
the diamine 14 in 50% yield with complete retention of
configuration (Scheme 2).17 The diamine was purified as
a hydrochloric acid salt 15, whose purity was analyzed
by HPLC and 1H NMR of the corresponding diBOC
acetate 16.18
In conclusion, we have demonstrated that sequential
asymmetric hydrogenation of the symmetric dienes 3 and
4 is an attractive method for generating the chiral C2-
symmetric molecules corresponding to the core units of
the inhibitors of HIV protease.
The hydrogenation of diacid 311 using a Ru(OAc)2[(S)-
BINAP] complex proceeded at 35 °C in 24 h, and the
stereoselectivity and enantiomeric excess of products
were determined by those dimethyl esters (Table 1,
entries 1-5).12-14 Both the stereoselectivity and the
enantiomeric excess for 1b are quite insensitive to
changes in hydrogen pressure (entries 1, 2, and 4).
Furthermore, there was no change in selectivity when
the reaction was carried out at 25 °C for 48 h (entry 5).
Reduction of the keto group was also observed when the
reaction mixture was kept at 35 °C for 80 h (entry 3).15
We presume that each step of the sequential asymmetric
hydrogenation occurs quite independently with an asym-
metric induction to the extent of 64-68% ee. Conse-
quently, (R,R)-1b16 and meso-11 are obtained in a ratio
of 70:30, while the optical purity of 1b is markedly
enhanced, 90-93% ee, as compared with that expected
from a single hydrogenation.
In the case of hydrogenation of 4, the diastereoselection
directed by a hydroxyl group (substrate control), in
addition to the chiral catalyst control for the bis-cinnamic
(11) The chiral induction by the rhodium-catalyzed asymmetric
hydrogenation of 3, as an analog of â-arylitaconic acid, failed due to
the steric hindrance of the alkene moiety of 3; see: Christopfel, W. C.;
Vineyard, B. D. J . Am. Chem. Soc. 1979, 101, 4406. Morimoto, T.;
Chiba, M.; Achiwa, K. Tetrahedron Lett. 1989, 30, 735.
(12) For asymmetric hydrogenation by Ru(OAc)2(BINAP), [BINAP
) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl], see: Ohta, T.; Takaya,
H.; Noyori, R. Inorg. Chem. 1988, 27, 566. Takaya, H.; Ohta, T.;
Mashima, K.; Noyori, R. Pure Appl. Chem. 1990, 62, 1135. For
asymmetric hydrogenation by Ru2Cl4(BINAP)2NEt3, see: Ikariya, T.;
Ishii, Y.; Kawano, H.; Arai, T.; Saburi, M.; Yoshikawa, S.; Akutagawa,
S. J . Chem. Soc., Chem. Commun. 1985, 922.
(13) It has been reported that the asymmetric hydrogenation of (E)-
R-methylcinnamic acid by a Ru(OAc)2[(S)-H8-BINAP] complex proceeds
with good enantioselectivity (82% ee), while Ru(OAc)2BINAP complex
affords only 35% ee; see: Zhang, X.; Uemura, T.; Matsumura, K.; Sayo,
N.; Kumobayashi, H.; Takaya, H. Synlett 1994, 501.
(14) The diastereoselectivities were analyzed by HPLC. The enan-
tioselectivities of 1b and 2b were determined by 1H NMR in CDCl3
using a chiral shift reagent Eu(hfc)3 and Eu(dppm)3, respectively.
(15) When the reaction was carried out at 60 °C, complete lacton-
ization was observed in the product where the keto group was also
hydrogenated.
Ack n ow led gm en t. We are grateful to Dr. Masahiko
Terakado for performing preliminary experiments of the
present study. We thank a support from the Ministry
of Education, Science, Sports, and Culture, J apan
(Grant-in-aid No. 06750883).
Su p p or tin g In for m a tion Ava ila ble: NMR spectra and
characterization data (30 pages).
J O961012Z
(17) DPPA (diphenyl phosphorazidate). For the modified Curtius
reaction, see: Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974,
30, 2151. Wittenberger, S. J .; Baker, W. R.; Donner, B. G. Tetrahedron
1993, 49, 1547.
(16) The absolute configuration was determined by conversion into
(2R)-2-benzyl-1,3-propanediol 1-acetate, see: Atsuumi, S.; Nakano, M.;
Koike, Y.; Tanaka, S.; Ohkubo, M.; Yonezawa, T.; Funabashi, H.;
Hashimoto, J .; Morishima, H. Tetrahedron Lett. 1990, 31, 1601.
(18) None of the diastereomers due to epimerization was observed
by HPLC and 270 MHz 1H NMR analyses of its diBOC acetate 16.