Diastereoselective synthesis of chiral β-amino-α-hydroxy-H-phosphinates through hydrophosphinylation of α-amino aldehydes

Article abstract of DOI:10.1016/S0040-4039(01)00911-X

A stereodivergent synthesis of β-amino-α-hydroxy-H-phosphinates was achieved by ALB-catalyzed hydrophosphinylation of N,N-dibenzyl-α-amino aldehydes tuning the chirality of the catalyst.

Full text of DOI:10.1016/S0040-4039(01)00911-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5033–5036
Diastereoselective synthesis of chiral
b-amino-a-hydroxy-H-phosphinates through hydrophosphinylation
of a-amino aldehydes
Takehiro Yamagishi, Kenji Suemune, Tsutomu Yokomatsu* and Shiroshi Shibuya
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 20 April 2001; revised 21 May 2001; accepted 25 May 2001
Abstract—A stereodivergent synthesis of b-amino-a-hydroxy-H-phosphinates was achieved by ALB-catalyzed hydrophosphinyla-
tion of N,N-dibenzyl-a-amino aldehydes tuning the chirality of the catalyst. © 2001 Elsevier Science Ltd. All rights reserved.
The b-amino-a-hydroxyphosphinic acids 1 serve as the
key intermediates for the synthesis of potent inhibitors
of human renin and HIV protease (Fig. 1).1,2 Stereo-
genic carbonꢀphosphorus bond formation processes are
of great interest in stereoselective synthetic sequences of
the b-amino alcohol moiety by the reaction of a-amino
aldehydes with phosphinic nucleophiles, since the stereo-
chemistry of b-amino alcohol is known to be an
important factor to show highly potent protease
inhibitory activity. The initial synthetic route to this
class of compounds, which followed the classical proto-
col through the reaction of N-Boc-a-amino aldehyde
with phosphinic nucleophiles in situ generated from
alkyl-H-phosphinate (HPO(OMe)(Et)) with conven-
tional reagents in combination of TMSCl and an
amine, resulted in a formation of the desired b-amino-
a-hydroxyphosphinic acid derivatives but without
diastereoselectivity.1
Aiming at a highly diastereoselective approach to b-
amino-a-hydroxy-H-phosphinic acids (1: X=H), we
envisaged the use of alkyl phosphinate (H2PO2R) with
a chiral AlLibis(binaphtoxide) (ALB)3 catalyst would
give rise to a formation of b-amino-a-hydroxy-H-phos-
phinic acids with either anti- or syn-stereoselectivity.
Recently, we found that the enantioselective synthesis
of a-hydroxy-H-phosphinates as well as a,a%-dihydroxy-
phosphinates could be achieved by the reaction of
Figure 1.
Scheme 1.
Keywords: diastereoselection; phosphinic acids; derivatives.
* Corresponding author. Tel./fax: +81-426-76-3239; e-mail: yokomatu@ps.toyaku.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00911-X

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T. Yamagishi et al. / Tetrahedron Letters 42 (2001) 5033–5036
aldehydes with alkyl phosphinate activated by ALB.4 In
this paper, we wish to report our experimental results
on chiral ALB-catalyzed hydrophosphinylation of N,N-
dibenzyl-a-amino aldehydes5 with ethyl phosphinate,6
generated from anhydrous phosphinic acid and triethyl
orthoformate in situ, with a high level of diastereofacial
selectivity. The stereochemical outcome of the reaction
can be controlled in either anti- or syn-selective manner
by tuning the chirality of ALB.
To obtain b-amino-a-hydroxy-H-phosphinates in a
highly diastereoselective manner, we next examined the
hydrophosphinylation of N,N-dibenzyl-a-amino alde-
hydes 5a,b in the presence of a catalytic amount of
ALB (Table 1). The excellent ability of the dibenzyl
protective group of 5a,b for the diastereoselective alkyl-
ation through non-chelation control has been demon-
strated.5 Moreover, the dibenzyl protective group might
give rise to steric hindrance around the H-phosphinate
functionality of the adducts and would suppress the
formation of the dimeric side-products corresponding
to 4a,b.
First, we attempted the ALB-catalyzed hydrophos-
phinylation of N-CBz-
L
L
-phenylalaninal 2a7 and N-Boc-
-phenylalaninal 2b8 with ethyl phosphinate (Scheme
As we expected, treatment of ethyl phosphinate with
1). When 2a was treated with ethyl phosphinate in THF
in the presence of (S)-ALB (20 mol%), generated from
(S)-binaphthol, at −40°C for 12 h, adducts 3a and 4a
were produced in 23 and 11% yield, respectively. On
N,N-dibenzyl-
L
-phenylalaninal 5a and N,N-dibenzyl-L-
leucinal 5b in the presence of ALB (20 mol%) for 12 h
afforded the corresponding hydrophosphinylation
products in moderate yields without formation of
detectable side products (entries 1–4).11 An intriguing
result was revealed upon analyzing the diastereoselec-
tivities of the products. In the reaction of 5a with
(S)-ALB, high anti-selectivity (syn-6a:anti-6a=6:94)
was observed (entry 1).12 On the other hand,
hydrophosphinylation of 5a in the presence of (R)-ALB
proceeded with inversed stereoselection to give syn-6a
in a ratio of 87:13 (entry 2). Also, when the reaction of
5b was carried out with (S)- or (R)-ALB, either anti-6b
or syn-6b could be obtained in high stereoselectivity
(entries 3 and 4).13 In the above-mentioned cases,
diastereofacial selectivity was found to be controlled
predominantly by the chirality of the asymmetric cata-
lyst rather than that of the a-amino aldehydes. As
observed in Table 1, the diastereoselectivity of the
hydrophosphinylation with (S)-ALB is generally higher
than that with (R)-ALB.14
1
analyzing the H (400 MHz) and 31P (162 MHz) spec-
trum of the products, there is no evidence that the
reaction proceeded in a diastereoselective manner.9 The
diastereoselectivity was not improved when the reaction
was conducted with (R)-ALB under the same condi-
tion. Also, the reaction of 2b catalyzed by (S)-ALB
afforded 3b and 4b without stereoselectivity. The for-
mation of 4a,b takes place by the activation of the
H-phosphinate group of 3a,b with ALB, followed by
the addition to the a-amino aldehydes.10
Table 1. Hydrophosphinylation of 5a,b with ethyl phos-
phinate in the presence of ALB
The products anti-6a,b and syn-6a,b were obtained as a
1:1 mixture of diastereoisomers arising from the chiral-
ity of the phosphinate group. The diastereomerically
pure anti-6a-A (mp: 149–150°C) was isolated from the
mixture (anti-6a-A and anti-6a-B) upon recrystalliza-
tion from ethyl acetate. The relative stereochemistry of
anti-6a-A was confirmed unambiguously by X-ray crys-
tallographic analysis (Fig. 2).15,16 In the X-ray crystal
structure, the proton Ha of the phosphinate group
appeared to be sterically shielded by the neighboring
hydroxy and ethyloxy groups as well as the phenyl
group. It is noteworthy that Ha located close to the
Entrya
Substrate
ALB
syn:anti
Yield (%)b
1
2
3
4
5a
5a
5b
5b
(S)-ALB
(R)-ALB
(S)-ALB
(R)-ALB
6:94
87:13
2:98
56
66
71
54
94:6
a All reactions were carried out for 12 h.
b Combined yields of syn- and anti-isomers.
Figure 2.

T. Yamagishi et al. / Tetrahedron Letters 42 (2001) 5033–5036
5035
Scheme 2.
phenyl group, showing the distance of Ha–C6 and
Ha–C7 to be 2.89 and 2.88 A, respectively. The steric
surroundings of the P–H moiety in anti-6a would be
important for circumventing the interaction with ALB,
thus preventing its nucleophilic reactivity to aldehydes.
4. Yamagishi, T.; Yokomatsu, T.; Suemune, K.; Shibuya, S.
Tetrahedron 1999, 55, 12125.
5. Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531.
6. Fitch, S. J. J. Am. Chem. Soc. 1964, 86, 61.
7. Ito, A.; Takahashi, R.; Baba, Y. Chem. Pharm. Bull.
1975, 23, 3081.
,
The stereochemistry of anti-6a,b was also confirmed
after converting to b-amino-a-acetoxyphosphonate 7a,b
through sequential acetylation, oxidation, deesterifica-
tion and methyl esterification (Scheme 2). The 1H
NMR spectra of 7a,b were identical with those of the
authentic specimens derived from the known b-amino-
a-hydroxyphosphonate 8a,b17 through acetylation,
deesterification followed by methyl esterification. The
optical purity of 7a derived from anti-6a was deter-
mined to be 99% ee by HPLC analysis on a chiral phase
(DAICEL CHIRALPAK OD column, hexane:EtOH=
20:1). Therefore, it was proved that no racemization of
N,N-dibenzyl-a-amino aldehydes took place during the
hydrophosphinylation.
8. Fehrentz, J.-A.; Castro, B. Synthesis 1983, 676.
9. 1H and 31P NMR spectroscopic analysis has been success-
fully applied to determine the diastereomeric excess of
chiral phosphonate derivatives, see: (a) Yokomatsu, T.;
Yamagishi, T.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1
1997, 1527; (b) Hammerschmidt, F.; Li, Y.-F. Tetra-
hedron 1994, 50, 10253; (c) Kozlowski, J. K.; Rath, N. P.;
Spilling, C. D. Tetrahedron 1995, 51, 6385.
10. Previously, we have found the ALB-catalyzed reaction of
methyl phosphinate with 2.2 equivalents of benzaldehyde
resulted in exclusive formation of the corresponding
dimeric product. See Ref. 4.
11. The moderate yields of products might be due to partial
hydrolysis of the ethyl phopshinate functionality during
the work up.
In conclusion, we have developed a diastereoselective
12. A pair of doublets due to the diastereomeric phosphinate
protons of syn-6a was observed at l 7.15 (d, J=561.7
Hz) and 7.03 (d, J=560.3 Hz), whereas the correspond-
ing signals of anti-6a resonated at l 6.68 (d with small
splits, J=549.5 Hz) and 6.53 (d with small splits, J=
synthesis
of
b-amino-a-hydroxy-H-phosphinates
through hydrophosphinylation of N,N-dibenzyl-a-
amino aldehydes catalyzed by ALB. Both syn and
anti-b-amino-a-hydroxy-H-phosphinate could be pre-
pared selectively by tuning the chirality of ALB. Fur-
ther application of the present hydrophosphinylation
methodology to the synthesis of biologically active
compounds is under investigation.
1
558.0 Hz) in their H NMR (400 MHz, CD3OD) spectra.
The syn/anti ratio was determined by relative ratio of
integral area for these signals.
13. The ratio was determined by 31P NMR (162 MHz,
CD3OD) analysis of the crude products. The
diastereomeric phosphorus atoms of syn-6b resonated at
l 43.64 and 41.92; the corresponding signals of anti-6b
appeared at l 40.32 and 39.00.
Acknowledgements
14. We also examined reactions of 5a with ethyl phosphinate
using 1.5 equivalents of an achiral base such as BuLi,
NaH, La(O-i-Pr)3 and Et3N. It was found that only Et3N
could promote the reaction to afford a mixture of syn-6a
and anti-6a in 43% yield with a low level of diastereo-
selectivity (23:77). Thus, the high chemical yields and
diastereoselectivities, observed when the binaphthol-
modified heterobimetallic complex was employed, may be
accounted for by the simultaneous activation of both
aldehydes and ethyl phosphinate with ALB.3
15. X-Ray crystal data of anti-6a-A were collected by a
Mac-Science MXC18 diffractometer. The structure was
solved by a direct method using SIR-92 (Altomare,
1994)18 and refined with a full matrix least-squares
method. Molecular formula=C25H30NO3P, Mr=423.50,
The authors wish to thank Mr. Haruhiko Fukaya (the
analytical center of this university) for the X-ray crys-
tallographic analysis.
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T. Yamagishi et al. / Tetrahedron Letters 42 (2001) 5033–5036
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