Catalytic asymmetric synthesis of α-hydroxy phosphonates using the Al-Li-BINOL complex

Full text of DOI:10.1021/jo960180o

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J . Org. Chem. 1996, 61, 2926-2927
extension of this research, we investigated the catalytic
asymmetric hydrophosphonylation of aldehydes promoted
by a heterobimetallic asymmetric catalyst. When we
started this research, Shibuya and Spilling had indepen-
dently reported8 catalytic asymmetric hydrophosphony-
lations of aldehydes using the La-Li-BINOL complex
(LLB). For example, using benzaldehyde (1) as a starting
substrate, Shibuya reported the formation of 2 (98%, 20%
ee, 20 mol % LLB), and Spilling announced the formation
of 3 (58%, 28% ee, 10 mol % LLB). To improve on their
results, we first attempted a catalytic asymmetric hy-
drophosphonylation of 1 using either LPB or the La-
Na-BINOL complex (LSB). However, the enantiomeric
excess of 3 was only 2% ee (LPB) and 32% ee (LSB). After
several attempts, treatment of 1 with 1.1 equiv of
dimethyl phosphite in THF containing 10 mol % ALB,6
another heterobimetallic asymmetric catalyst, at -40 °C
for 25 h gave 3 with 65% ee in 68% yield.9 With this
more satisfactory result, solvent effects were next exam-
ined in detail. We eventually found that exposure of 1
to dimethyl phosphite (1 equiv) in toluene containing 10
mol % ALB at -40 °C for 51 h afforded 3 with 85% ee in
90% yield.10,11 The use of a slight excess of 1 (1.2 equiv)
gave rise to 3 with 90% ee in 95% yield (9 mol % of ALB).
To the best of our knowledge, this is the highest enan-
tiomeric excess in a catalytic asymmetric hydrophosphon-
ylation of 1. Using the procedure described above,
several para-substituted aromatic aldehydes were further
subjected to catalytic asymmetric hydrophosphonylation.
As shown in Table 1, p-chlorobenzaldehyde (4), p-tolu-
aldehyde (6), p-anisaldehyde (8), and p-nitrobenzalde-
hyde (10) were transformed into the corresponding
R-hydroxy phosphonates in an enantioselective manner
(5; 83% ee, 80% yield, 7; 86% ee, 82% yield, 9; 78% ee,
88% yield, 11; 71% ee, 85% yield). It is noteworthy that
a single recrystallization of 3 (85% ee) from ethyl acetate
provided optically pure 3 (60% yield).
Ca ta lytic Asym m etr ic Syn th esis of
r-Hyd r oxy P h osp h on a tes Usin g th e
Al-Li-BINOL Com p lex
Takayoshi Arai, Masahiro Bougauchi,
Hiroaki Sasai, and Masakatsu Shibasaki*
Faculty of Pharmaceutical Sciences, University of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113, J apan
Received J anuary 30, 1996
It is well known that R-hydroxy phosphonates and
phosphonic acids inhibit enzymes such as renin, EPSP
synthase, and HIV protease.1 Moreover, other biologi-
cally significant R-substituted phosphonates and phos-
phonic acids are readily obtainable starting with R-hy-
droxy phosphonates.2 Bioactive γ-amino phosphonic
acids as well as γ-substituted vinyl phosphonates and
phosphonic acids can also be obtained from allylic R-hy-
droxy phosphonates through a 1,3-interchange of func-
tionality.3 It is not surprising that the absolute config-
uration of these phosphoryl compounds influences their
biological properties.4 However, the synthesis of optically
active phosphoryl compounds has only recently begun to
receive attention.5 In this paper, we report the catalytic
asymmetric synthesis of R-hydroxy phosphonates using
the Al-Li-BINOL complex (ALB),6 a heterobimetallic
multifunctional asymmetric catalyst we developed.
We recently reported the first example of an efficient
catalytic asymmetric hydrophosphonylation of imines
promoted by the La-K-BINOL complex (LPB).7 As an
(1) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron Lett.
1990, 31, 5587-5590. Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.
Tetrahedron Lett. 1990, 31, 5591-5594. Sikorski, J . A.; Miller, M. J .;
Braccolino, D. S.; Cleary, D. G.; Corey, S. D.; Font, J . L.; Gruys, K. J .;
Han C. Y.; Lin, K. C.; Pansegrau, P. D.; Ream, J . E.; Schnur, D.; Shah,
A.; Walker, M. C. Phosphorus, Sulfur Silicon Relat. Elem. 1993, 76,
375-378. Paterson, M. L.; Corey, S. D.; Sikorski, J . A.; Walker, M. C.
Abstracts of Papers, 203rd American Chemical Society National
Meeting, San Francisco, 1992, ORGN 469. Stowasser, B.; Budt, K-H.;
J ian-Qi, L.; Peyman, A.; Ruppert, D. Tetrahedron Lett. 1992, 33, 6625-
6628. Moore, M. L.; Dreyer, G. B. Prespect. Drug Discovery Des. 1993,
1, 85-108.
(2) Hammerschmidt, F.; Vo¨llenkle, H. Liebigs Ann. Chem. 1989,
577-583. Yokomatsu, T.; Shibuya, S. Tetrahedron: Asymm. 1992, 3,
377-378. Baraldi, P. G.; Guarneri, M.; Moroder, F.; Pollini, G. P.;
Simoni, D. Synthesis 1982, 653-654. Maier, L. Phosphorus, Sulfur
Silicon Relat. Elem. 1993, 76, 379-382.
(3) O¨ hler, E.; Kotzinger, S. Synthesis 1993, 497-502 and references
cited therein. For a review see: Kafarski, P; Lejczak, B. Phosphorus,
Sulfur Silicon Relat. Elem. 1991, 63, 193-215.
Having developed an effective catalytic asymmetric
hydrophosphonylation of aromatic aldehydes, we then
turned our attention to hydrophosphonylation of R,â-
unsaturated aldehydes. First, the reaction of cinnamal-
dehyde (12) was examined. Only one example of a
catalytic asymmetric hydrophosphonylation of 12 has
been previously reported, and LLB has given the corre-
sponding R-hydroxy phosphonate 13 with 41% ee in 73%
yield.8 On the other hand, treatment of 12 with 1 equiv
of dimethyl phosphite in toluene containing 10 mol %
(4) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Wakisaka, K.; Haga,
S.; Sugi, H.; Tanigawa, K.; Suzuki, Y.; Fukawa, K.; Irino, O.; Saita,
O.; Yamabe, S.; Heterocycles 1981, 16, 1205-1242. Atherton, F. R.;
Hall, M. J .; Hassall, C. H.; Lambert, R. W.; Lloyd, W. J .; Ringrose, P.
S. Antimicrob. Agents Chemother. 1979, 15, 696-705. Allen, J . G.;
Atherton, F. R.; Hall, M. J .; Hassall, C. H.; Holmes, S. W.; Lambert,
R. W.; Nisbet, L. J .; Ringrose, P. S. Antimicrob. Agents Chemother.
1979, 15, 684-695.
(5) Gordon, N. J .; Evans, S. A., J r. Phosphorus, Sulfur Silicon Relat.
Elem. 1993, 75, 47-50. Li, Y. F.; Hammerschmidt, F. Tetrahedron:
Asymm. 1993, 4, 109-120. Wynberg, H.; Smaardijk, A. A. Tetrahedron
Lett. 1983, 24, 5899-5900. Sum, V.; Davies, A. J .; Kee, T. P. J . Chem.
Soc., Chem. Commun. 1992, 1771-1773. J acques, J .; Leclercq, M.;
Brienne, M. J . Tetrahedron 1981, 37, 1727-1733. Heisler, A.; Rabiller,
C.; Douillard, R.; Goalou, N.; Ha¨gele, G.; Levayer, F. Tetrahedron:
Asymm. 1993, 4, 959-960. Hoffmann, M. J . Prakt. Chem. 1990, 251-
255. Gordon, N. J .; Evans, S. A., J r. J . Org. Chem. 1993, 58, 5293-
5294. Gajda, T. Tetrahedron: Asymm. 1994, 5, 1965-1972. Spilling,
C. D.; Blazis, V. J .; Koeller, K. J . J . Org. Chem., 1995, 60, 931-940.
Shibuya, S.; Yokomatsu, T.; Yamagishi, T. Synlett 1995, 1035-1036.
(6) Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki,
M. Angew. Chem., Int. Ed. Engl. 1996, 35, 104-106. The structure of
ALB, which consists of Al, Li, and two BINOL units, has been
unequivocally determined by X-ray analysis.
(8) Rath, N. P.; Spilling, C. D. Tetrahedron Lett. 1994, 35, 227-
230. Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron: Asymm.
1993, 4, 1783-1784.
(9) The optical purities of all of the products were determined by
chiral HPLC (DAICEL CHIRALPAK AS or AD), and the absolute
configurations of all of the products were determined by the Mosher
method.
(10) General procedure for catalytic asymmetric hydrophosphony-
lation. Synthesis of 3. ALB was first prepared from LiAlH4 and 2 molar
equiv of (R)-BINOL in THF. See ref 6. After a THF solution of (R)-
ALB (0.1 M, 0.4 mL, 0.04 mmol) was concentrated, the resulting (R)-
ALB powder was redissolved in toluene (0.4 mL). To this toluene
solution was added dimethyl phosphite (37 µL, 0.40 mmol) at room
temperature, and the mixture was further stirred for 30 min at the
same temperature. Benzaldehyde (41 µL, 0.4 mmol) was then added
to the above mixture at -40 °C. After being stirred for 51 h at the
same temperature, the reaction mixture was treated with 1 N HCl
(1.0 mL) and extracted with EtOAc (10 mL × 3). The combined organic
extracts were washed with brine, dried (Na2SO4), and concentrated to
give a residue. Purification by flash chromatography (SiO2, 20%
acetone/hexane) gave the R-hydroxy phosphonate 3 (78 mg, 90%) with
85% ee as a colorless solid (mp ) 86-87 °C).
(11) The use of diethyl phosphite and dibutyl phosphite gave the
corresponding phosphonates with 73% ee, 39% yield and 67% ee, 42%
yield, respectively.
(7) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J . Org. Chem. 1995,
60, 6656-6657.
S0022-3263(96)00180-6 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 9, 1996 2927
Ta ble 1. Ca ta lytic Asym m etr ic Hyd r op h osp h on yla tion
of Ald eh yd es Ca ta lyzed by ALB
Sch em e 1. Hyd r ogen a tion of Allylic r-Hyd r oxy
P h osp h on a te
Sch em e 2. P ossible Mech a n ism for th e Ca ta lytic
Asym m etr ic Hyd r op h osp h on yla tion of Ald eh yd es
entry
aldehyde
product
time (h)
yield (%)
ee (%)
1
2
1
1
1
4
6
2
3
3
5
7
90
51
90
38
92
115
66
83
83
94
39
39
90
95
80
82
88
85
85
93
72
53
73
85
90
83
86
78
71
82
89
68
55
3a
4
5
6
7
8
9
10
11
8
9
10
12
14
16
18
11
13
15
17
19
believe that ALB is a multifunctional asymmetric cata-
lyst which effectively controls asymmetric hydrophos-
phonylations.12 The lithium naphthoxide moiety func-
tions as a Lowry-Brønsted base and the center aluminum
functions as a Lewis acid. In fact, the reaction proceeded
very slowly to give 3 with 30% ee in 37% yield (-40 °C,
132 h) when the asymmetric catalyst 2113 was used (10
mol %).
In conclusion, we have developed a general method for
the catalytic asymmetric synthesis of R-hydroxy phos-
phonates using ALB as an asymmetric catalyst. Enan-
tiomeric excesses as well as chemical yields of R-hydroxy
phosphonates still need to be improved. However, we
believe that the results described here may lead to
further progress in this area.
a
Benzaldehyde (1.2 equiv) and ALB (9 mol %) were used.
ALB at -40 °C for 83 h furnished the R-hydroxy phos-
phonate 13 with 82% ee in 85% yield. The use of THF
as a solvent gave less satisfactory results: i.e., 13 with
64% ee in 55% yield. The R,â-unsaturated aldehyde 14
was also converted to the R-hydroxy phosphonate 15 with
89% ee in 93% yield. Moreover, reactions of other R,â-
unsaturated aldehydes such as 16 and 18 were also
examined, affording 17 with 68% ee (72%) and 19 with
55% ee (53%), respectively.
In striking contrast to these results, saturated alde-
hydes such as hexanal and cyclohexanecarboxaldehyde
were converted to the corresponding R-hydroxy phospho-
nates in excellent chemical yields, albeit with low enan-
tiomeric excesses ranging from 3 to 24%. This implies
that the development of other types of heterobimetallic
asymmetric catalysts is needed for a catalytic asymmetric
hydrophosphonylation using saturated aldehydes. How-
ever, such R-hydroxy phosphonates were readily obtained
from allylic R-hydroxy phosphonates with relatively high
enantiomeric excesses by simple hydrogenation. For
example, 17 with 68% ee underwent hydrogenation (10%
Pd/C, MeOH, 1 atm H2 pressure, room temperature, 3
h) to give 20 in 98% yield (Scheme 1). The enantiomeric
excess of 20 was confirmed to be 68%, showing that no
racemization occurred during hydrogenation.
Ack n ow led gm en t. This study was financially sup-
ported by a Grant in Aid for Scientific Research from
the Ministry of Education, Science, Culture, and Sports,
J apan.
Su p p or tin g In for m a tion Ava ila ble: Further details of
the characterization of the compounds described (24 pages).
J O960180O
(12) For the discussion of the multifunctional activities of hetero-
bimetallic asymmetric catalysts, see: Sasai, H.; Arai, T.; Satow, Y.;
Houk, K. N.; Shibasaki, M. J . Am. Chem. Soc. 1995, 117, 6194-6198.
(13) The asymmetric catalyst 21 was prepared from ALB by treat-
ment with trimethylsilyl chloride (1.2 equiv) in THF at -78 °C. This
catalyst was then used in toluene as described in ref 10.
A possible mechanism for catalytic asymmetric hydro-
phosphonylation of aldehydes is shown in Scheme 2. We