Preparation of phosphinodipeptide analogs as building blocks for pseudopeptides synthesis

Article abstract of DOI:10.1016/S0022-328X(01)01238-4

A simple and effective preparation of phosphinodipeptides, in good overall yields, has been developed. This one pot procedure, allowing the variation of the substituents in α and/or β position to the phosphorus atom and also in α position to the nitrogen atom, consists in the addition of alkyl hypophosphites to imines, followed by Michael-addition on acrylates. To show the value of phosphinodipeptides analogs 1 as synthetic intermediates, selective deprotections of the three functional groups are described.

Full text of DOI:10.1016/S0022-328X(01)01238-4

Journal of Organometallic Chemistry 643–644 (2002) 381–391
www.elsevier.com/locate/jorganchem
Preparation of phosphinodipeptide analogs as building blocks for
pseudopeptides synthesis
Henri-Jean Cristau a,*, Agne`s Coulombeau a, Arielle Genevois-Borella b,
Fre´de´ric Sanchez a, Jean-Luc Pirat a,*
a Laboratoire de Chimie Organique, UMR 5076 du C.N.R.S, Ecole Nationale Supe´rieure de Chimie de Montpellier, 8 Rue de l’Ecole Normale,
34296 Montpellier Cedex 5, France
b A6entis, Centre de Recherche de Vitry-Alfort6ille, 13, Quai Jules Guesde, BP 14, 94403 Vitry-Sur-Seine, France
Received 18 July 2001; accepted 5 September 2001
Dedicated to Franc¸ois Mathey on the occasion of his 60th birthday
Abstract
A simple and effective preparation of phosphinodipeptides, in good overall yields, has been developed. This one pot procedure,
allowing the variation of the substituents in a and/or b position to the phosphorus atom and also in a position to the nitrogen
atom, consists in the addition of alkyl hypophosphites to imines, followed by Michael-addition on acrylates. To show the value
of phosphinodipeptides analogs 1 as synthetic intermediates, selective deprotections of the three functional groups are described.
© 2002 Elsevier Science B.V. All rights reserved.
Keywords: Alkyl hypophosphite; Aminoalkylphosphinic acids; Kabachnik–Fields reaction; Michael addition; Phosphinopeptides
1. Introduction
We recently published the first results concerning a
one-pot synthesis of phosphino-dipeptides [1]. Going
into more details this paper describes the synthetic
method applied to various N-diphenylmethylimines and
acrylates to obtain a large number of phosphinodipep-
tides as building blocks for combinatorial or parallel
peptides synthesis in search of new enzyme inhibitors
[2].
The construction of such compounds requires the
synthesis of the phosphinodipeptide analogs of type 1
as building blocks.
Compounds 1 are generally prepared in a multistep
synthesis from the corresponding adequately protected
1-aminoalkylphosphonous acids by Michael additions
using a basic activation [3], by Michael additions or
Arbuzov reactions using silyl derivatives Ref.
[3b,3c,3d,4], by nucleophilic substitution under basic
conditions [3g,5].
The 1-aminoalkylphosphonous acids themselves can
be synthesized in several ways: by Kabachnik–Fields
type reactions involving addition of hypophosphorous
acid or its derivatives to a CꢀN double bond [6–8], by
the oxime procedure [9], by a Michaelis–Arbuzov reac-
tion with the bis-(trimethylsilyl) phosphonite [6,10], by
alkylation of a suitably protected 1-aminomethylphos-
phinic acid according to the procedure of Scho¨llkopf
[11], by a Mitsunobu reaction on 1-hydroxyalkylphos-
phinates [12], by amination of chloromethylphosphinic
acid [13], or by a Michael reaction of ethyl di-
ethoxymethylphosphonite
domethylenemalonate [14].
with
ethyl
acetami-
In order to develop a convenient preparation of
phosphinodipeptides of type 1, to avoid the synthesis
usually performed stepwise with purification of the
various intermediates, we have developed a general
one-pot synthetic method affording the possibility of
* Corresponding authors. Fax: +33-467-144319.
E-mail address: cristau@cit.enscm.fr (H.-J. Cristau).
0022-328X/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(01)01238-4

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Scheme 1. General way of synthesis for compounds 1.
variation of R1 and R2 groups. Each step of this
reaction was improved separately until the yield was
more than 90%: then, all the steps were carried out
without purification, for parallel synthesis purpose.
We chose to use an in situ generated alkyl hypophos-
phite 2. The addition of alkyl hypophosphite 2 to
various imines afforded the corresponding alkyl phos-
phinates 3. The Michael addition, to several acrylates,
was performed using basic activation, and afforded the
phosphinodipeptides analogs 1.
orthoformates, at various temperature, did not permit
to get a yield more than 90%, in the presence of the
diethoxymethylated compound 4a (7–15%) as by-
product (Table 1).
All the experiments, to hydrolyze selectively 4a,
failed. Also, a reaction without solvent did not permit
to get more than 58% of compound 2a together with
42% of compound 4a. The mixture THF–toluene was
the best solvent for the reaction, and a supplementary
amount of ethyl orthoformate added during the reac-
tion, allowed to get the best yield (89%) of compound
2a with only 7% of compound 4a (entry 2, Table 1).
To get a good yield in the preparation of alkyl
phosphinates 3, without by-product, in the next step,
we decided to purify ethyl hypophosphite 2a by distilla-
tion, but the yield was not better than 24%. Further,
the pure ethyl hypophosphite 2a has to be used immedi-
ately or stocked in dry ethanol at −75 °C, but, even at
−75 °C the purity decreased to 94% after 1 week.
To check the feasibility and selectivity of the next
step (Step 2) of the synthetic (Scheme 1), pure ethyl
hypophosphite 2a (purity\99%) was directly used for
the preparation of the ethyl phosphinate 3a in the
presence of N-diphenylmethylimine. The yield, in
THF–toluene–ethanol (1/1/8) is then higher than 96%.
2. Results and discussion
2.1. Synthesis of alkyl hypophosphites 2 (Step 1)
(Scheme 2)
Alkyl hypophosphites, rather unstable [15] but more
reactive than the hypophosphorous acid usually used
[6a,6b,16], were preferred to the bis-(trimethysilyl)
phosphonite which is highly pyrophoric [17] (Step 1,
Scheme 1).
Such protected hypophosphorous acid derivatives as
starting compounds avoid also a supplementary protec-
tion step of the phosphinic function, which is necessary
if a subsequent Michael addition to an acrylate is done
under basic conditions.
After an exhaustive study of the esterification reac-
tion of hypophosphorous acid by alkyl orthoformates
[18,19], we chose, first, to use the ethyl hypophosphite
2a, instead of methyl hypophosphite 2b frequently
demethylated by nucleophiles.
All the reactions carried out, for the synthesis of
ethyl hypophosphite 2a, with different amounts of ethyl
Scheme 2. Preparation of alkyl hypophosphite 2 (Step 1).
Table 1
Preparation of ethyl hypophosphite 2a

H.-J. Cristau et al. / Journal of Organometallic Chemistry 643–644 (2002) 381–391
383
Table 2
Preparation of methyl phosphinate 3 from methyl hypophosphite 2b and several imines or triazine
ing to the Baylis method [6b] afforded the methyl
phosphinates 3 (Scheme 3) in good yield (79–89%)
(Table 2).
As expected, a mixture of two diastereoisomers, in
near equal amounts, is obtained when R1=Ph or Me.
To improve the yields, the reaction conditions (tem-
perature, solvent, ratio of reagents and rate of addition)
were carefully considered.
Scheme 3. Preparation of methyl phosphinates 3 (Step 2).
For instance, in the case of compounds 3bb, the
normal addition of methyl hypophosphite 2b to 1.1
equivalent of the corresponding imine in refluxing
methanol affords only 51% of the mixture of
diastereoisomers 3bb. But by a dropwise addition of 1.6
equivalent of the imine (in order to lower and counter-
balance the thermal degradation of the imine) the yield
is increased up to 81%.
Further, the purity of the resulting compounds 3 can
be increased up to 85–95%: under nitrogen, the crude
reaction solution is concentrated in vacuum; to the oil
obtained, dry ether is added at 0 °C and two side-prod-
ucts (hypophosphonous acid and dimethyl phosphonate
4b formed likely by disproportionation of methyl hy-
pophosphite 2b and potentially troublesome for Step 3
of the synthesis) can be filtered out.
Scheme 4. Synthesis of a-substituted acrylates 7 [22].
This result demonstrates the value of the foreseen
synthetic strategy, concerning Step 2.
But, the poor yield in ethyl hypophosphite 2a ob-
tained after distillation, or the poor purity without
distillation, does not permit to proceed with the synthe-
sis using ethyl hypophosphite as starting material. For
our purpose, at each step, the yields have to be around
90%, and all the steps have to be carried out without
intermediate purification.
For all these reasons, we decided to use methyl
hypophosphite 2b, formed in very good yield and purity
(95–99%) (Step 1, Schemes 1 and 2) [18].
In the remaining solution, the main by-product is
then the bis-adduct 5 of the imine on the methyl
hypophosphite 2b, which cannot react further with
acrylates in the next step. The three isomers of the
2.2. Synthesis of methyl phosphinate 3 (Step 2)
(Scheme 3)
Table 3
Preparation of a-substituted acrylates [22,23]
The intermediate 1-aminoalkylphosphonous acids 3
were prepared using the in situ generated methyl hy-
pophosphite 2b. Addition of methyl hypophosphite 2b
to several imines (or triazine) [derived from diphenyl-
methylamine and formaldehyde [6b] (75% yield), or
acetaldehyde [20] (100% yield) or benzaldehyde [21]
(91% yield)] in refluxing anhydrous methanol, accord-
R2
Malonate 6 yield (%) a
Acrylate 7 yield (%) b
n-Bu
n-Pent
CH2Ph
87
98
99
45
55
51
a Determined by 1H-NMR.
b Isolated yield, after distillation.

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Table 4
Preparation of phosphinodipeptide analogs 1
Compound
R1
R2
Base
Nb equivalent base
Product
Yield (%)
3ba
3bc
3ba
3bb
3bb
3bb
3bb
H
Ph
H
Me
Me
Me
Me
Me
Me
Me
Me
n-Bu
n-Pent
CH2Ph
MeONa
MeONa
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
1.1
1.1
0.1
0.1
0.1
0.1
0.1
1ba1
1bc1
1ba1
1bb1
1bb2
1bb3
1bb4
51
93
71
86
78
86
87
To lower the demethylation process, we have used
t-BuOK, an overcrowded base, in catalytic amount (0.1
equivalent) as activating agent. The yield in 1ba1 in-
creases then up to 71% and the adducts 1bb from
differently substituted acrylates are obtained in 78–87%
yields.
Scheme 5. Preparation of phosphinodipeptides analogs 1 (Step 3).
bis-adduct 5bb (overall yield 8.5%) were isolated, sepa-
rated and fully characterized.
2.4. Selecti6e and total deprotection of
phosphinodipeptide analog 1
In order to show the value of phosphinodipeptide
analog 1 as building blocks, examples of selective de-
protection of the various protective groups were per-
formed, in usual ways, on compounds 1bc and 6e, to
obtain either totally deprotected 6c, free amino 6d, free
phosphinic 6e, free amino and phosphinic 6f or free
phosphinic and carboxylic analogs 6g, in quantitative
yields (Table 5).
The separation of two pairs of diastereoisomers was
achieved on compounds 1bc by chromatography on
silica gel. Two compounds were isolated as a white
solid (1bc% and 1bc¦). These compounds were com-
pletely deprotected by using an excess of 47% bromhy-
dric acid at 100 °C, affording compounds 6c in a
quantitative yield as a mixture of two diastereoisomers.
Products 3ba, 3bb and 3bc were directly used, with-
out additional purification, in the Step 3 of the
synthesis.
2.3. Synthesis of phosphinodipeptide analogs 1 (Step 3)
(Scheme 5)
The last step of the synthesis consists in a Michael
addition of the phosphinates 3 to various a-substituted
acrylates 7, which are prepared according to the
method proposed by Steller [22] (Scheme 4, Tables 3
and 4).
The last step (Step 3) of the synthesis was first
performed according to the method developed by Par-
sons et al. [3a], using sodium methanolate as basic
activating agent.
3. Conclusions
With the phenyl-substituted phosphinate 3bc (R1=
Ph) the yield in the adduct 1bc1 corresponding to the
methyl methacrylate (R2=Me) is high (92%), using 1.1
equivalent of sodium methanolate as base.
But in the case of unsubstituted phosphinate 3ba
(R1=Me) the same conditions give only 51% yield,
because a side reaction takes place corresponding to the
demethylation of the methyl phosphinate and resulting
in the formation of the sodium phosphinate 8 as by-
product.
A general three step synthesis has been developed for
the one-pot preparation of phosphinodipeptides 1 by
careful adjusting of each step: (i) preparation of methyl
hypophosphite 2b in high yield and purity (preferred to
ethyl ester), by esterification of hypophosphorous acid
with methyl orthoformate; (ii) dropwise addition of an
excess of imines (or triazin) to a refluxing methanolic
solution of compound 2b for the preparation of com-
pound 3, which can also be partially purified by simple
falling out of by-products; (iii) basic catalysis by t-

H.-J. Cristau et al. / Journal of Organometallic Chemistry 643–644 (2002) 381–391
385
Table 5
Selective and total deprotection of phosphinodipeptides analogs 1
BuOK in order to reduce side reactions, for the addi-
tion of compound 3 on various a-substituted methyl
acrylates.
Merck 15–40 mm, flash chromatography on Merck
40–63 mm or liquid chromatography at normal pres-
sure on Merck 70–200 mm.
This method allows the one-pot preparation of phos-
phinodipeptides as a mixture of diastereoisomers, in
60–80% overall yields, and allows moreover the varia-
tion of the substituents on the carbon in a and/or b
positions to the phosphorus.
All reactions were performed under dry nitrogen in a
flask, magnetic stirrer and a pressure equalizing addi-
tion funnel.
4.2. Synthesis of alkyl hypophosphites 2
Last, in order to show the value of phosphinodipep-
tides analogs 1 as synthetic building blocks for combi-
natorial or parallel synthesis, selective or complete
deprotections of the various protective groups were
performed in almost quantitative yields.
4.2.1. Synthesis of ethyl hypophosphite 2a
To a solution of anhydrous hypophosphorous acid
(0.66 g, 10 mmol) in dry THF (2.4 ml) and toluene (2.4
ml) stirred at 5 °C under N2 was added triethyl ortho-
formate (6.65 ml, 40 mmol). After 1 h at 5 °C, the
mixture was allowed to warm to room temperature
(r.t.) and stirred for 2 h to afford 83% of 2a together
with 6% of anhydrous hypophosphorous acid and 6%
ethyl (diethoxymethyl) hydrogenophosphinate 4a.
4. Experimental
4.1. General
Solvents and substrates were purified by conventional
methods immediately before use. The NMR spectra
were obtained on Bruker AC-200, AC-250 instruments
(1H-NMR at 200.13 and 250.13 MHz, 13C-NMR at
50.32 MHz and 31P-NMR at 81.0 MHz. IR spectra
were recorded using a Perkin–Elmer 377 spectrometer.
MS were obtained using a JEOL JMS DX-300 (FAB+).
Elemental analyses were performed by the ‘Service de
Microanalyse du CNRS au De´partement Analyse Ele´-
mentaire, a` Vernaison’. The crude products were
purified by HPLC preparative chromatography on
4.2.1.1. Hypophosphorous acid. 31P-NMR (THF–tolu-
ene): l 5.20 (t, JPꢁH=543.8).
1
4.2.1.2. Ethyl (diethoxymethyl) hydrogenophosphinate
1
4a. 31P-NMR (THF–toluene): l 27.02 (ddt, JPꢁH
=
2
551.7, JPꢁH=3JPꢁH=8.5).
4.2.1.3. Ethyl hypophosphite 2a. 31P-NMR (THF–tolu-
1
3
ene): l 13.16 (tt, JPꢁH=562.4, JPꢁH=9.9). Eb: 31 °C,
2 mmHg.

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4.2.2. Synthesis of methyl hypophosphite 2b
4.3.2. Ethyl (1-diphenylmethylamino)-1phenyl-methyl
hydrogenophosphinate (3a)
To a solution of anhydrous hypophosphorous acid
(0.66 g, 10 mmol) in a mixture of dry THF (2.4 ml) and
toluene (2.4 ml) stirred at 5 °C under N2 is added
trimethyl orthoformate (4.4 ml, 40 mmol). After 1 h at
5 °C, the mixture was allowed to warm to r.t. and
stirred for 2 h to afford 98% of 2b (together with 2% of
dimethyl hydrogenophosphinate 4b).
31P-NMR (EtOH): l 34.05 (ddt, 1JPH=564.5, 2JPH
=
3
1
2
16.7, JPH=8.4), 37.63 (ddt, JPH=562.2, JPH=17.0,
3JPH=8.5), H-NMR (CDCl3): l 1.16 and 1.29 (2t, 3H,
1
3JHH=7.1, OCH2CH3), 2.71 (s, 1H, NH), 3.83–4.22
(m, 3H, CH2 and NCHP), 4.82 and 4.83 (2s, 1H,
CHPh2), 7.01 and 7.14 (2d, 1H, 1JPH=557.0 and
1JPH=559.5, PH), 7.25–7.44 (m, 15H, CHar), 13C-
4.2.2.1. Methyl hypophosphite 2b. 31P-NMR (THF–tol-
NMR: (CDCl3): l 16.25 and 16.37 (2d, JPC=5.6 and
3
1
3
1
uene): l 16.8 (tq, JPꢁH=565.6, JPꢁH=12.7).
3JPC=5.8, CH3), 59.59 and 59.76 (2d, JPC=104.2 and
1JPC=106.1, HNCHP), 62.45 and 63.09 (2d, JPC=7.4
2
2
3
and JPC=7.5, CH2), 63.60 and 63.79 (2d, JPC=15.3
and 16.5, Ph2CH), 127.04–129.07 (m, CHar), 133.99
and 134.13 (2d, JPC=1.8 and JPC=3, Car), 141.76,
141.90, 143.45 et 143.48 (4s, Car).
4.2.2.2. Dimethyl hydrogenophosphinate 4b. 31P-NMR
1
3
(THF–toluene): l 10.70 (dhept, JPꢁH=696.2, JPꢁH
=
2
2
11.8).
The N-diphenylmethylimines are prepared according
to the literature: R1=H [6], R1=CH3 [19], R1=Ph
[19].
4.3.2.1. Synthesis of methyl 1-diphenylmethylamino-
methyl phosphinate (3ba). To the reaction mixture of
methyl hypophosphite 2b (9.78 mmol) is then added dry
MeOH (20 ml) and 2.24 g (3.75 mmol) of 1,3,5-tris-
(diphenylmethyl) hexahydro-triazine. After 7 h reflux,
the solution stays under nitrogen at r.t. The excess in
triazine is filtered out and compound 3ba is obtained in
79% yield in the filtrate which will be used for the next
synthetic step. 31P-NMR (THF–toluene–MeOH, 1/1/
4.2.2.3. Tris(diphenylmethyl) hexahydro 1,3,5-triazine.
Melting point (m.p.): 241.5–245 °C (toluene) (lit.
1
252 °C) [6b], H-NMR (CDCl3): l 3.34 (s, 6H, CH2),
4.72 (s, 3H, CH), 6.99–7.33 (m, 30H, CHar), 13C-NMR:
(CDCl3): l 70.02 (CH), 71.89 (CH2), 126.66, 127.58,
128.29, 142.39 (Car), IR (CHCl3): 3064, 3029, 3009,
2813, 1599, 1492, 1452, 1187, 1175.
1
2
8): l 40.74, H-NMR (CDCl3): l 2.98 (d, 2H, JPH
=
3
11.2, CH2), 3.81 (d, JPH= 8.8, 3H, CH3), 4.86 (s, 1H,
4.2.2.4. N-(Diphenylmethyl) ethanimine (colorless oil).
1H-NMR (CDCl3): l 2.10 (d, 3H, 3JHH=4.8, CH3),
5.40 (s, 1H, CHPh2), 7.23–7.39 (m, 10H, CHar), 7.92
ppm (q, 1H, 3JHH=4.8, CHꢀN), 13C-NMR: (CDCl3): l
22.50 (CH3), 78.71 (CHPh2), 127.07, 127.74, 128.56,
143.86, 161.36.
1
CH), 7.07–7.40 (m, 10H, CHar), 7.08 (d, 1H, JPH
=
=
546.3, PH), 13C-NMR: (CDCl3): l 45.44 (d, JPC
1
106.8, CH2), 52.97 (d, 2JPC=7.3, CH3), 68.24 (d,
3JPC=16.2, CH), 127.28–129.26 (m, Car), 142.47 (Car),
142.66 (Car).
4.3.2.2. Synthesis of methyl 1-diphenylmethylaminoethyl
phosphinate (3bb). To a solution of crude methyl hy-
pophosphite 2b (9.78 mmol) in dry MeOH (13 ml),
under reflux, is added drop-wise in 30 min, a 2 N
solution in MeOH of N-(diphenylmethyl) methanimine
(15.6 mmol) until the disappearing of methyl hypophos-
phite, observed by 31P-NMR. Two isomers of com-
pounds 3bb are observed in 81% overall yield [l 31P:
44.30 ppm (39.5%), 45.30 ppm (41.5%)] in the presence
of hypophosphorus acid [l 31P: 2.50 ppm (3.9%)] and
dimethylhydrogenophosphinate [l 31P: 11.9 ppm
(2.4%)].
4.2.2.5. N-(Diphenylmethyl) phenylmethanimine. m.p.:
99–101 °C (EtOH) (lit. 98–100 °C) [21], 1H-NMR
(CDCl3): l 5.62 (s, CHPh2), 7.19–7.44 and 7.83–7.88
(m, CHar), 8.44 (s, CHꢀN), 13C-NMR: (CDCl3): l
78.03 (CHPh2); 127.11, 127.81, 128.57, 128.59, 128.65,
130.88, 136.45, 144.04 (Car), 160.91 (CꢀN), IR (CHCl3):
3090, 3065, 3029, 3009, 2846, 1951, 1889, 1810, 1644,
1599, 1580, 1492, 1452, 1025.
4.3. Synthesis of phosphinates 3
4.3.1. Synthesis of ethyl (1-diphenylmethylamino)-1-
phenyl-methyl hydrogenophosphinate (3a)
31P-NMR (THF–toluene–MeOH, 1/1/8): l 44.30
1
3
and 45.30, H-NMR (CDCl3): l 1.35 (dd, 3H, JPH
=
To a solution of pure ethyl hypophosphite 2a (1.14 g,
12 mmol, one equivalent), obtained after distillation, in
dry EtOH (10 ml) is added a solution of 3.29 g (12
mmol, one equivalent) of N-(diphenylmethyl) phenyl
methanimine in dry EtOH. After 4 h reflux, 31P-NMR
shows two diastereoisomers (in a ratio 48/52) corre-
sponding to a 96% overall yields in 3a.
17.7, 3JHH=7.1, CHCH3), 2.86–3.05 (m, 1H, CHCH3),
3.80 and 3.83 (2d, JPH=11.2, OCH3), 5.16 and 5.18
3
1
(2s, 1H, Ph2CH), 6.97 (d, H, JPH=538.1, PH), 7.25–
7.44 (m, 10H, CHar), 13C-NMR(CDCl3): l 12.80 (d,
2JPC=2.1, CHCH3), 48.64 and 48.75 (2d, JPC=108.0,
1
1JPC=109.6, CH3CH), 52.59 and 52.92 (2d, JPC=7.7,
2
2JPC=7.9, OCH3), 64.23 and 64.32 (2d, 3JPC=11.3,

H.-J. Cristau et al. / Journal of Organometallic Chemistry 643–644 (2002) 381–391
387
3JPC=11.9, Ph2CH), 127.12–128.75 (m, CHar), 142.47,
142.61, 143.15 and 143.21 (4s, CHar).
Methyl a-butyl acrylate (yield 45%)
1
Eb: 70 °C 20 mmHg, H-NMR (CDCl3): l 0.91 (t,
3
3H, JHH=7.0, CH3), 1.28–1.49 (m, 4H, CH2), 2.30 (t,
4.3.2.3. Synthesis of methyl 1-diphenylmethylamino-1-
phenyl-methyl phosphinate (3bc). A solution of crude
methyl hypophosphite 2b (9.67 mmol) in dry MeOH
(20 ml) and 2.62 g (9.67 mmol) of N-(diphenylmethyl)
phenylmetanimine is heated for 1 h at reflux. After
cooling under nitrogen at r.t., two isomers are obtained
in 89% overall yield, observed by 31P-NMR, [l 31P:
37.30 ppm (43%), 40.30 ppm (46%)], in the presence of
8.5% of 5bb: three compounds, 5bb1 (4.3%), 5bb2 (2.5%)
and 5bb3 (1.7%). 3bc: 31P-NMR (THF–toluene–
MeOH, 1/1/8): l 37.30 and 40.30.
Compounds 5bb are obtained, as a mixture of three
compounds because of the chirality of the central phos-
phorus atom. After the neutralization of the crude
solution, with HCl 1 N, until pH 7, concentration, and
extraction with ethyl acetate, chromatography on silica
gel (hexane–AcOEt 90/10 to 40/60) each diastereisomer
is isolated pure. 5bb1: Rf=0.33, 5bb2: Rf=0.30, and
5bb3: Rf=0.14 (hexane–AcOEt 50/50).
2H, 3JHH=7.1, CꢀCCH2), 3.75 (s, 3H, OCH3), 5.52
and 6.13 (2m, 2H, ꢀCH2), 13C-NMR (CDCl3): l 13.48
(CH3), 22.04 (CH2), 30.38 (CH2), 31.39 (CH2), 51.18
(OCH3), 123.85 (ꢀCH2), 140.65 (Cꢀ), 167.22 (CꢀO).
Methyl a-pentyl acrylate (yield 55%)
1
Eb: 95 °C 20 mmHg, H-NMR (CDCl3): l 0.90 (t,
3
3H, JHH=6.6, CH3), 1.18–1.54 (m, 6H, CH2), 2.30 (t,
2H, 3JHH=7.4, CꢀCCH2); 3.76 (s, 3H, OCH3), 5.53
and 6.13 (2m, 2H, ꢀCH2), 13C-NMR (CDCl3): l 13.61
(CH3), 22.21 (CH2), 27.90 (CH2), 31.20 (CH2), 31.65
(CH2), 51.15 (OCH3), 123.82 (ꢀCH2), 140.68 (Cꢀ),
167.16 (CꢀO).
Methyl a-benzyl acrylate (yield 51%)
Eb: 130–132 °C 20 mmHg, 1H-NMR (CDCl3): l
3.68 (m, 2H, CH2), 3.74 (s, 3H, OCH3), 5.46 and 6.24
(2m, 2H, ꢀCH2), 7.19–7.35 (m, 5H, CHar), 13C-NMR
(CDCl3): l 38.30 (CH2), 51.86 (OCH3), 126.20 (CH2),
128.55 (Car), 129.07 (Car), 138.90 (Cipso), 140.00 (Cꢀ),
166.70 (CꢀO).
Methyl bis-(1-diphenylmethylamino-1-phenyl-methyl)
phosphinates (5bb).
4.4. Synthesis of phosphinodipeptides analogs 1
5bb1 (DL isomers)
1
m.p.: 137–138 °C, 31P-NMR (CDCl3): l 46.02, H-
4.4.1. General procedure
3
NMR (CDCl3): l 3.17 (d, 6H, JPH=9.9, OCH3), 4.11
The solution containing methyl phosphinate 3 (10
mmol), is concentrated under vacuum. At 0 °C dry
ether (15 ml) is added to the yellow oil under agitation
for 45 min. The white solid is filtrated under nitrogen.
The solid corresponds to hypophosphorous acid and
dimethyl phosphinate. At −5 °C, the solution is, once
again, concentrated under vacuum, and 20 ml of dry
THF are added. To the solution containing 3, was
added, dropwise, at 0 °C, first a solution of 1.1 equiva-
lents of a-alkyl acrylate in dry THF, then, 0.1 equiva-
lent of a solution of sublimed t-BuOK in dry THF. The
reaction mixture was then stirred for 2 h at 0 °C and at
r.t. overnight. The reaction was quenched with 1 N HCl
and extracted with EtOAc. The organic phase was dried
over MgSO4 and evaporated under vacuum. The crude
product, by chromatography on silica gel (15–40 mm)
with hexane–EtOAc (90/10) as the starting eluent, gives
compounds 1 as a viscous oil.
and 4.17 (2d, 2H, 2JPH=14.0 and 2JPH=18.4,
PCHPh), 4.63 and 4.91 (s, 2H, Ph2CH), 7.14–7.40 (m,
30H, CHar), 13C-NMR (CDCl3): l 52.29 (d, JPC=7.5,
2
1
1
OCH3), 57.57 (d, JPC=95.9, PCHN), 59.97 (d, JPC
=
3
96.2, PCHN), 63.54 (d, JPC=14.6, Ph2CH), 63.98 (d,
3JPC=12.3, Ph2CH), 126.98–129.03 (m, CHar), 134.71
2
(d, JPC=3.5 Hz, Car), 135.46 (s, Car), 141.75, 141.98,
143.36 and 143.69 (4s, Car).
5bb2 (meso)
1
m.p.: 136–138 °C, 31P-NMR (CDCl3): l 47.19, H-
3
NMR (CDCl3): l 3.03 (d, 6H, JPH=9.9, OCH3), 4.09
(d, 2H, 2JPH=12.7, PCHPh), 4.69 (s, 2H, Ph2CH),
7.14–7.40 (m, 30H, CHar), 13C-NMR (CDCl3): l 52.38
2
1
(d, JPC=7.6, OCH3), 57.67 (d, JPC=98.3, PCHN),
63.49 (d, 3JPC=14.9, Ph2CH), 127.12–129.06 (m,
2
CHar), 135.53 (d, JPC=4.5 Hz, Car), 142.08 (s, 2Car),
143.6 (s, 2Car).
5bb3 (meso)
m.p.: 165–169 °C, 31P-NMR (THF–toluene):
l
4.4.2. Methyl (1-diphenylmethylaminomethyl)
(2-methoxycarbonyl-propyl) phosphinate 1ba1 (yield
51%)
48.30, 1H-NMR (CDCl3): l 3.99 (d, 6H, 3JPH=9.8,
2
OCH3), 4.08 (d, 2H, JPH=15.1, PCHPh), 4.68 (s, 2H,
Ph2CH), 7.16–7.37 (m, 30H, CHar), 13C-NMR
(CDCl3): l 54.02 (d, 2JPC=7.6, OCH3), 58.06 (d,
1JPC=99.2, PCHN), 63.54 (d, 3JPC=14.1, Ph2CH),
126.99–128.98 (m, CHar), 134.64 (s, C), 141.41 (s,
2Car), 143.76 (s, 2Car).
31P-NMR (AcOEt): l 51.56 (s) (28%) and 52.05 (s)
1
3
(23%), H-NMR (CDCl3): l 1.34 (d, 6H, JHH=7.1,
CH3), 1.90 and 2.38 (m, 2H, ABMX system, CH2C),
1.97 and 2.43 (m, 2H, ABMX system, CH2C), 2.47 (s,
1H, NH), 2.84–3.00 (m, 3H, CHCO and CH2N), 3.68
and 3.69 (2s, 3H, CO2CH3), 3.70 and 3.73 (2d, 3H,
Acrylates 7 (colorless oils) were prepared using the
method proposed by Steller and by Deslongchamps
[22,23]:
3
3JPH=10.4 and JPH=10.4 Hz, POCH3), 4.81 (s, 1H,
CHPh2), 7.22–7.41 (m, 10H, CHar), 13C-NMR

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H.-J. Cristau et al. / Journal of Organometallic Chemistry 643–644 (2002) 381–391
3
3
(CDCl3): l 19.53 and 19.56 (2d, JPC=9.1 and JPC
=
ABMX system, OPCH2), 2.17 and 2.56 (m, 2H, ABMX
system, OPCH2), 2.74 (s, NH), 2.80–3.06 (m, 1H,
9.1, CH3), 30.32 and 30.41 (2d, 1JPC=92 and 1JPC=92,
CH2C), 34.05 and 34.16 (2d, JPC=3.6 and JPC=2.4,
CHCO), 45.53 and 46.07 (2d, JPC=104.1 and JPC
102.9 Hz, CH2N), 51.80 and 52.01 (2d, JPC=7.3 and
2JPC=6.7, POCH3), 52.49 (s, COCH3), 69.10 and 69.16
(2d, 3JPC=16.3 and 3JPC=16.9, CHPh2), 127.64,
127.68, 127.77, 127.81, 129.03, 129.06, 143.15, 143.22,
2
2
CHCH3), 3.13 and 3.14 (2d, 3H, 3JPH=10.1 and 3JPH
=
1
1
2
=
10.1, OCH3), 3.68 (d, 1H, JPH=15.3, HNCHPh), 3.69
and 3.70 (2s, 3H, OCH3), 3.71 (d, 1H, 2JPH=14.9,
HNCHPh), 4.64 and 4.65 (2s, 1H, Ph2CH), 7.19–7.40
(m, 15H, CHar), 13C-NMR (CDCl3): l: 18.97 and 19.19
(2d, 3JPC=8.4 and 3JPC=9.1, CHCH3), 30.16 and
2
3
3
1
1
143.32, 176.28 and 176.31 ppm (2d, JPC=10.3 JPC
=
30.30 (2d, JPC=92.2 and JPC=92.4, OPCH2), 33.83
9.7 Hz, CꢀO), MS FAB+(NBA): [M+H]+: 376.
and 34.02 (2d, JPC=4.4 and JPC=3.8, OCCH), 51.86
2
2
(d, 2JPC=7.6, OCH3), 51.98 (s, OCH3), 52.01 (d,
1
4.4.3. Methyl (1-diphenylmethylaminoethyl) (2-meth-
oxycarbonyl-propyl) phosphinate (1bb1) (yield 86%)
2JPC=7.3, OCH3), 59.76 and 60.17 (2d, JPC=103.0
and 1JPC=103.0, HNCHP), 63.64 and 63.68 (2d,
3JPC=16.0 and 3JPC=16.0, CHPh2), 127.04, 127.25,
127.56, 127.95, 128.24, 128.51, 128.70, 128.73, 128.77,
31P-NMR (Acetone) l: 54.71 (s), 54.82 (s), 54.95 (s),
55.15 (s), 1H-NMR (CDCl3): l 1.25–1.37 (m, 6H, 2
CH3), 1.76–2.53 (m, 3H, CH2 and NH), 2.69–3.04 (m,
2H, CHCO and CHP), 3.63 (d, 3H, 3JPH=10.1,
POCH3), 3.65 (s, 3H, COCH3), 3,66 (d, 3H, 3JPH=10.1,
POCH3), 3.67 and 3.69 (2s, 6H, COCH3), 3.72 and 3.74
128.81,
128.94
(Car),
135.20
[d,
2JPC=3.8,
(HN)CH(P)Car], 141.97, 142.01, 143.51, 175.83 and
176.03 (2d, 3JPC=10.4 and 3JPC=9.2, CꢀO), MS
+
FAB+(NBA): [M+H]
452, IR (KBr): 3260, 3080,
3
3
(2d, JPH=10.1 and JPH=11.2, POCH3), 5.04, 5.05,
5.06 and 5.07 (4s, CHPh2), 7.20–7.35 (m, 10H, CHar),
3060, 3020, 2940, 2880, 2840, 1720, 1600, 1560, 1495,
1450, 1200, 1160, 1100, 1030, Elemental microanalysis
(C26H30NO4P): Found: C, 68.99; H, 6.68; N, 3.21; P,
6.53. Calc.: C, 69.17; H, 6.70; N, 3.10; P, 6.86%.
13C-NMR (CDCl3): l 12.95 and 13.17 (2d, JPC=3.5
2
and 2JPC=5.5, CCH3), 18.71, 19.20 and 19.22 ppm (3d,
3JPC=7.0, 3JPC=9.0 and 3JPC=9.2, CH3), 28.16,
28.33, 28.63 and 28.81 (4d, 1JPC=88.1, 1JPC=88.3,
1JPC=88.3 and 1JPC=88.7, CH2), 33.74, 33.86 and
4.4.4.2. Fraction 2: 1bc¦.
1
31P-NMR (AcOEt): l 49.50 (s), 50.09 (s), 1H-NMR
(CDCl3): l 1.20 and 1.23 (2d, 3H, 3JHH=7.9 and
3JHH=7.4, CHCH3), 1.60 and 2.22 (m, 2H, ABMX
system, OPCH2), 1.72 and 2.16 (m, 2H, ABMX system,
OPCH2), 2.68–2.86 (m, 1H, CHCH3), 3.09 (s, NH),
2
2
2
33.91 (3d, JPC=3.0, JPC=3.2 and JPC=4.0, CH),
1
1
48.63, 49.18 and 49.39 (3d, JPC=109.2, JPC=107.4
and 1JPC=108.8, CH), 51.48, 51.67 and 51.93 (3d,
2JPC=6.9, 2JPC=7.0 and 2JPC=6.8, OCH3), 51.93,
51.94, 51.95 and 51.96 (4s, CH3), 64.08 and 64.11 (2d,
3JPC=13.8 and 3JPC=13.1, CH), 127.06–128.59 (m,
CHar), 142.35, 142.54, 142.56, 143.55, 143.58, 143.80
and 143.83 (7s, Car), 175.90, 175.93, 176.02 and 176.08
(4d, JPC=9.0, JPC=11.5, JPC=8.4 and JPC=8.7,
CO), MS FAB+: [M+H] +(GT): 390, IR (CHCl3):
3318, 3086, 3067, 3028, 2975, 2946, 2849, 1741, 1601,
1495, 1466, 1219, 1166, 1117, 1045. Elemental micro-
analysis (C21H28NO4P): Found: C, 63.28; H, 7.21; N,
3.60; P, 8.37. Calc.: C, 64.77; H, 7.25; N, 3.60; P, 7.95%
3
3.67 (s, 6H, OCH3), 3.80 and 3.87 (2d, 3H, JPH=10.1
and 3JPH=10.2, OCH3), 3.82 and 3.92 (2d, 1H,
HNCHPh), 4.66 and 4.69 (2s, 1H, Ph2CH), 7.24–7.47
(m, 15H, CHar), 13C-NMR (CDCl3): l 18.69 and 19.14
(2d, 3JPC=7.3 and 3JPC=9.3, CHCH3), 29.54 and
3
3
3
3
1
1
29.68 (2d, JPC=92.7 and JPC=92.9, OPCH2), 33.50
2
2
and 33.58 (2d, JPC=4.3 and JPC=3.6, OCCH), 51.95
(s, OCH3), 52.63 and 53.04 (2d, JPC=7.0 and JPC
2
2
=
7.1, OCH3), 60.20 and 60.58 (2d, 1JPC=99.8 and
1JPC=99.6, HNCHP), 63.79 (3JPC=14.4, CHPh2),
127.07, 127.26, 127.48, 127.90, 128.20, 128.23, 128.54,
128.70, 128.92, 128.93, 128.94, 128.95 (Car), 135.23 (d,
2JPC=3.4, (HN)CH(P)Cipso), 141.80, 141.84, 143.70,
175.73 and 175.93 (2d, 3JPC=11.5 and 3JPC=8.9,
CꢀO), MS FAB+(NBA): [M+H]+: 452, IR: (KBr):
33.23, 3062, 3028, 2980, 2946, 2849, 1737, 1601, 1495,
1451, 1234, 1180, 1100, 1040, Elemental microanalysis
(C26H30NO4P): Found: C, 68.68; H, 6.71; N, 3.22; P,
6.30. Calc.: C, 69.17; H, 6.70; N, 3.10; P, 6.86%.
Sodium 1-diphenylmethylaminomethyl hydrogenophos-
phinate (8).
4.4.4. Methyl (1-diphenylmethylamino-1-phenyl-methyl)
(2-methoxycarbonyl-propyl) phosphinate (1bc1)
(yield 93%)
31P-NMR (Toluene–THF–MeOH): l: 51.92 (s)
(26%), 52.11 (s) (24%), 52.51 (s) (22%), 52.93 (s) (21%),
The crude product, by chromatography on silica gel
(15–40 mm) with hexane–EtOAc (90/10) as the starting
eluent to hexane–EtOAc (60/40), gives two pairs of
diastereoisomers 1bc%1 as a white solid and 1bc1¦ as a
yellow oil.
1
2
31P-NMR (H2O): l 23.49 (dt, JPH=515.4 and JPH
=
4.4.4.1. Fraction 1: 1bc%.
12.3), 1H-NMR: (D2O): l 2.65 (d, 2H, 2JPH=12.4,
HNCH2PO), 4.95 (s, 1H, CHPh2), 7.03 (d, 1JPH=514.7,
PH), 7.27–7.51 ppm (10H, CHar), 13C-NMR (D2O),
1
M.p.: 92–96 °C, 31P-NMR (AcOEt): l 49.01 (s), 49.07
(s), 1H-NMR (CDCl3): l 1.30 and 1.35 (2d, 3H, 3JHH
=
7.0 and 3JHH=7.1, CHCH3), 1.94 and 2.32 (m, 2H,
50.98 (d, JPC=98.1, HNCH2), 70.57 (d, JPC=14.3,
1
3

H.-J. Cristau et al. / Journal of Organometallic Chemistry 643–644 (2002) 381–391
389
Ph2CH), 130.19 (s, CH), 130.31 (s, CH), 131.62 (s,
CH), 144.74 (s, C), IR (KBr): 3610, 3410, 3280, 2810,
2310, 1620, 1600, 1390, 1360, 1200, 1170, 1110, 1100,
820, 710, MS FAB+(NBA): [M+H]+: 284.
7.38 (m, CHar), 13C-NMR (CDCl3): l 12.63, 12.96 and
13.24 ppm (3s,CHCH3), 26.33, 26.56, 26.76 and 26.82
1
(4d, 1JPC=87.5, 1JPC=87.2, 1JPC=88.2 and JPC
=
=
3
87.4, PCH2CH), 39.42, 39.88 and 40.02 (3d, JPC
10.0, 3JPC=11.2 and 3JPC=11.9, PhCH2), 41.21, 41.33,
2
2
2
4.4.5. Methyl 1-diphenylmethylaminoethyl
41.37 and 41.61 (4d, JPC=3.4, JPC=3.1, JPC=3.2
and JPC=4.1, CH2CHCH2), 48.72, 49.32, 49.41 and
2
2-methoxycarbonyl-hexyl phosphinate (1bb2)
31P-NMR (AcOEt): l 53.94 (s), 54.01 (s), 54.16 (s),
54.37 (s), 1H-NMR (CDCl3): l 0.84–0.92 (m, 3H,
49.50 (4d, JPC=109.1, JPC=107.0, JPC=107.5 and
1JPC=110.6, HNCHP), 51.58, 51.68, 51.84 and 51.96
(4d, 2JPC=6.9, 2JPC=7.0, 2JPC=7.0, 2JPC=7.0,
POCH3), 51.82, 51.84, 51.88 and 51.90 (4s, CO2CH3),
1
1
1
CH2CH3),
1.21–1.35
(m,
7H,
HNCHCH3,
CH2CH2CH2CH3), 1.55–2.39 (m, 5H, CHCH2CH2,
OPCH2CH, NH), 2.57–2.95 (m, 2H, OPCHCH3,
3
3
63.96, 64.09, 64.12 and 64.17 (4d, JPC=14.4, JPC
=
3
OCCH), 3.62 (d, 3H, JPH=10.1, POCH3), 3.63 and
13.9, 3JPC=12.9 and 3JPC=12.9, Ph2CH), 126.77–
129.18 (m, CHar), 138.03 and 138.11 (2s, Car), 142.34,
142.40, 142.52, 143.59, 143.63, 143.85 and 143.89 (7s,
3
3.64 (2s, 3H, COCH3), 3.64 (d, JPH=10.1, POCH3),
3.65 and 3.68 (2s, 3H, COOCH3), 3.71 and 3.72 (2d,
3H, 3JPH=10.1, POCH3), 5.04, 5.05, 5.06 and 5.09 ppm
(4s, 1H, Ph2CH), 7.19–7.40 (m, CHar), 13C-NMR
(CDCl3): l 12.95 and 13.30 (2s, HNCHCH3), 13.91 and
3
Car), 174.73, 174.74, 174.98 and 175.20 (4d, JPC=6.0,
3JPC=7.0, 3JPC=43.9 and 3JPC=5.0, OꢀC), IR (CCl4):
3323, 3086, 3062, 3028, 2950, 2849, 1742, 1601, 1500,
1451, 1219, 1170, 1137, 1040, MS FAB+(NBA): [M+
H]+: 466, Elemental microanalysis (C27H32NO4P):
Found: C, 69.60; H, 7.02; N, 3.17; P, 6.30. Calc.: C,
69.66; H, 6.93; N, 3.01; P, 6.65%.
13.92 (2s, CH2CH3), 22.44, 22.46 and 22.52 (3s,
1
CH2CH3), 27.14, 27.49, 27.59 and 27.77 (4d, JPC
=
87.8, 1JPC=87.3, 1JPC=87.7 and 1JPC=88.3,
PCH2CH), 29.04, 29.06, 29.07 and 29.14 (4s, CH2CH3),
3
3
33.47, 34.00, 34.09 and 34.11 (4d, JPC=9.3, JPC
=
3
3
11.0, JPC=11.2 and JPC=11.4, CHCH2CH2), 39.06,
4.5. Selecti6e and total deprotection of
phosphinodipeptide analog 1
39.20, 39.22 and 39.34 (4d, 2JPC=3.6, 2JPC=4.5,
2JPC=3.2 and JPC=3.4, CH2CHCH2), 48.41, 49.31,
2
1
1
1
49.35 and 49.60 (4d, JPC=109.0, JPC=107.4, JPC
=
4.5.1. Total deprotection of phosphinodipeptides analogs
1
1
106.3 and JPC=109.1, HNCHCH3), 51.54 and 51.64
2
2
(2d, JPC=6.9 and JPC=6.9, POCH3), 51.72, 51.75,
51.76 and 51.78 (4s, CO2CH3), 51.78 and 51.92 (2d,
The pair of diastereoisomers 1bc%+1bc¦ (0.6 g, 1.33
mmol) was heated together with an excess of 47% HBr
(2 ml) at 100 °C for 1–2 h until two distinct phases
have separated. The mixture was evaporated to dryness
under reduced pressure and the residue taken up in
water. The aqueous solution was washed several times
with ether to remove diphenylmethyl bromide and then
evaporated to dryness. Deprotected compounds were
obtained as their hydrobromide salts 6c in a quantita-
tive yield.
2JPC=6.9 and 2JPC=6.9 Hz, POCH3), 64.08, 64.09,
3
64.10 and 64.16 (4d, 3JPC=14.2, 3JPC=14.2, JPC
=
14.2 and 3JPC=12.7, Ph2CH), 127.10–128.62 (m,
CHar), 142.41, 142.56, 142.62, 143.59, 143.65, 143.86
and 143.89 (7s, Car), 175.47, 175.54, 175.74 and 175.85
(4d, 3JPC=5.8, 3JPC=7.9, 3JPC=5.2 and 3JPC=5.6,
CO2), IR (CCl4): 3328, 3086, 3067, 3028, 2955, 2931,
2859, 1737, 1601, 1495, 1451, 1219, 1156, 1040, MS
FAB+(NBA) [M+H]+: 432, Elemental microanalysis
(C24H34NO4P): Found: C, 66.91; H, 8.01; N, 3.37; P,
2.00. Calc.: C, 66.80; H, 7.94; N, 3.25; P, 2.18%.
4.5.1.1. 1-Amino-1-phenyl-methyl 2-carboxyl-propyl
phosphinic acid hydrobromide salt (6c).
M.p.: 172–175 °C, 31P-NMR (D2O+NaOH): l 40.14
(s), 40.41 (s), 1H-NMR (D2O+NaOH): l 1.24 (d,
3JHH=7.0, CHCH3), 1.50 and 1.94 (m, 1H, ABMX
system, PCH2), 1.54 and 2.14 (m, 1H, ABMX sys-
tem,PCH2), 2.47–2.73 (m, CHCH3), 3.98 and 4.02 (2d,
4.4.6. Methyl 1-diphenylmethylaminoethyl
2-methoxycarbonyl-heptyl phosphinate (1bb3)
31P-NMR (THF): l 53.35 (s), 53.43 (s), 53.57(s),
53.82 (s). No purification.
2
2
1H, JPH=11.2 and JPH=11.5, PhCH), 7.37–7.52 (m,
CHar), 13C-NMR (D2O+NaOH): 22.11 and 22.48 (2d,
3JPC=3.8 and 3JPC=6.2, CHCH3), 34.06 and 34.31
(2d, 1JPC=89.2 and 1JPC=88.9, PCH2), 39.85 and
40.12 (2d, 2JPC=3.7 and 2JPC=3.2, OꢀCCH), 58.82
and 59.39 (2d, 1JPC=90.4 and 1JPC=90.5, HNCH),
130.00 and 130.04 (2d, 5JPC=2.0 and 5JPC=2.1, CHar),
130.50 and 130.63 (2d, 3JPC=4.5 and 3JPC=4.5, CHar),
131.24 and 131.31 (2d, 4JPC=2.1 and 4JPC=2.2, CHar),
4.4.7. Methyl 1-diphenylmethylaminoethyl
2-benzyl-2-methoxycarbonyl-ethyl phosphinate (1bb4)
31P-NMR (AcOEt): l 53.82 (s), 53.92 (s), 53.98 (s),
54.26 (s), 1H-NMR (CDCl3): l 1.20–1.33 (m, 3H,
CHCH3), 1.88–2.40 (m, 3H, PCH2, NH), 2.65–2.86
(m, 4H, OCCH, CH2CH, PhCH2), 3.57, 3.59, 3.60 and
3.64 (4s, 3H, OCH3), 3.62, 3.65, 3.69 and 3.73 (4d, 3H,
3JPH=10.1, 3JPH=10.1, 3JPH=10.0 and 3JPH=10.1,
POCH3), 5.01, 5.06 and 5.08 (3s, 1H, Ph2CH), 7.15–
2
2
141.54 and 141.95 (2d, JPC=3.1 and JPC=2.2, Car),

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H.-J. Cristau et al. / Journal of Organometallic Chemistry 643–644 (2002) 381–391
3
3
188.63 and 188.67 (2d, JPC=11.1 and JPC=13.4 Hz,
OꢀC).
101.7 and 1JPC=102.3, PCH2CH), 33.98 and 34.18 (2d,
2
2JPC=3.4 and JPC=3.6, CHCH3), 52.43 (s, CO2CH3),
1
3
61.99 (d, JPC=87.3, HNCHPh), 65.84 (d, JPC=6.8,
Ph2CH), 128.92–130.74 (m, CHar), 131.47 and 131.69
(2s, Car), 136.27 and 136.58 (2s, Car), 176.31 and 176.66
(2d, 3JPC=11.8 and 3JPC=10.0, CO2), MS FAB+
(NBA): [M+H]+ 438.
4.5.2. Hydrogenolysis of compound 1bc
To a solution of 1bc (0.4 g, 0.89 mmol) in dry MeOH
(3 ml), was added Pd–C (191 mg, 0.18 mmol). After
consumption of the required volume of hydrogen, the
mixture was filtered on celite, and the filtrate concen-
trated. The crude product, by chromatography on silica
gel with EtOAc as eluent, gives compounds 6d (a
mixture of two diastereoisomers, 241 mg) as a viscous
oil in 95% yield.
4.5.4. Hydrogenolysis of compound 6e
To a solution of 6e (0.4 g, 0.91 mmol) in dry MeOH
(3 ml), was added Pd–C (146 mg, 0.44 mmol). After
consumption of the required volume of hydrogen, the
mixture was filtered on celite, and the filtrate concen-
trated. The crude product, washed with ether to remove
diphenylmethane gives compounds 6f (a mixture of two
diastereoisomers, 246.8 mg) as a white solid in quanti-
tative yield.
4.5.2.1. Methyl 1-amino-1-phenyl-methyl 2-
methoxycarbonyl-propyl phosphinate (6d).
31P-NMR (CDCl3): l 52.29 (s), 52.38 (s), 1H-NMR
3
(CDCl3): l 1.23 (d, 3H, JHH=7,1 Hz, CHCH3), 1.92
(s, 2H, NH2), 1.68–2.00 and 2.21–2.44 (2m, 2H, 2
ABMX systems, PCH2), 2.72–2.92 (m, CHCH3), 3.39
and 3.40 (2d, 3H, 3JPH=10.1 and 3JPH=10.1, POCH3),
4.5.4.1. 1-Amino-1-phenyl-methyl 2-methoxycarbonyl-
propyl phosphic acid (6d).
2
3.66 (s, CO2CH3), 4.12 and 4.15 (2d, JPH=13.0 and
M.p.: 125–133 °C, 31P-NMR (D2O): l 31.24 (s), 31.32
(s), 1H-NMR (D2O): l 1.19 (d, 3H, 3JHH=7.0,
CHCH3), 1.50–1.69 and 1.92–2.11 (2m, 2H, 2 ABMX
systems, PCH2), 2.56–2.78 (m, CHCH3), 3.69 and 3.70
2JPH=12.3, PhCH), 7.26–7.43 (m, CHar), 13C-NMR
3
3
(CDCl3): l 18.95 and 19.13 (2d, JPC=7.4 and JPC
=
8.1, CHCH3), 28.75 and 29.19 (2d, 1JPC=89.9 and
1JPC=89.9, PCH2), 33.71 and 33.85 (2d, JPC=4.4 and
(2s, 3H, CO2CH3), 4.41(d, 2H, JPH=10.3, HNCH),
2
2
2JPC=3.6, CHCH3), 51.86 (d, 2JPC=7.4, POCH3),
7.41–7.57 (m, 5H, CHar), 13C-NMR (D2O): l 21.19 and
21.27 (2d, 3JPC=8.9 and 3JPC=9.3, CHCH3), 34.17
and 34.24 (2d, 1JPC=97.1 and 1JPC=97.5, PCH2),
36.82 and 36.91 (2d, 2JPC=4.1 and 2JPC=4.5,
CHCH3), 55.32 (s, CO2CH3), 58.13 (d, 1JPC=86.3,
2
51.94 (s, CO2CH3), 51.97 (d, JPC=7.0, POCH3), 56.34
and 56.37 (2d, 1JPC=98.7 and 1JPC=98.7, PhCH),
127.65 and 127.69 (2d, 3JPC=5.1 and 3JPC=5.1, CHar),
127.88 and 127.89 (2d, 5JPC=2.9 and 5JPC=3.0, CHar),
128.56 and 129.56 (2d, 4JPC=2.3 and 4JPC=2.3, CHar),
4
4
HNCH), 130.48 and 130.57 (2d, JPC=4.8 and JPC
=
2
2
137.90 and 138.14 (2d, JPC=4.2 and JPC=4.2, Car),
4.5, CHar), 131.75 and 131.78 (2d, 5JPC=1.9 and
3
3
3
175.86 and 175.95 (2d, JPC=9.7 and JPC=8.3, OꢀC),
IR (CCl4): 3405, 3052, 3000, 2951, 2883, 2849, 1737,
1263, 1214, 1045, MS FAB+ (NBA): [M+H]+ 286.
5JPC=1.9, CHar), 131.96 (d, JPC=1.5, CHar), 135.05
2
2
and 135.12 (2d, JPC=3.7 and JPC=3.7, Car), 181.84
3
3
and 181.85 (2d, JPC=9.3 and JPC=8.2, CO2), MS
FAB+ (NBA): [M+H]+ 272.
4.5.3. Diphenylmethylamino-1-phenyl-methyl
2-methoxycarbonyl-propyl phosphinic acid (6e)
A solution containing 0.2 g of 1bc (0.443 mmol) with
64.3 ml (0.487 mmol) trimethylsilylbromine in 2.2 ml of
dry CH2Cl2 was stirred at r.t. for 3 h. After concentra-
tion of the solution the mixture is dissolved in EtOAc
and an excess of MeOH is added. After another con-
centration of the solution, 194 mg of compounds 6e are
obtained in quantitative yield as a mixture of two
isomers.
4.5.5. 1-Diphenylmethylamino-1-phenyl-methyl
2-carboxyl-propyl phosphinic acid (6g)
The pair of diastereoisomers 1bc%+1bc¦ (0.2 g, 0.44
mmol) in 2 ml of MeOH, is added to 1 ml of NaOH 1
N and stirring 4 h at r.t. The mixture was evaporated to
dryness under reduced pressure and the residue aci-
dified by HCl solution 1 N. The aqueous solution was
washed several times with ether and then evaporated to
dryness. Deprotected compounds 6g were obtained as a
white solid as a mixture of two diastereoisomers (186
mg) in a quantitative yield.
M.p.: 81.2–85.5 °C, 31P-NMR (CDCl3): l 39.31 (s),
1
39.70 (s), H-NMR (CDCl3): l 1.00 and 1.13 (2d, 3H,
3
3JHH=7.1 and JHH=7.1, CHCH3), 1.14 and 1.75 (m,
M.p.: 119.0–132.2 °C, 31P-NMR (D2O): l 34.30 (s),
1
1H, ABMX system, PCH2CH), 1.41 and 1.86 (m, 1H,
ABMX system, PCH2CH), 2.41–2.56 (m, 1H,
CHCH3), 3.54 and 3.56 (2s, 3H, CO2CH3), 4.10 and
34.67 (s), H-NMR (D2O+NaOH): l 1.14 and 1.16
(2d, 3H, 3JHH=6.9 and 3JHH=6.9, CHCH3), 1.48–
1.76 and 1.91–2.22 ppm (2m, 2H, 2 ABMX systems,
PCH2), 2.38–2.64 (m, 1H, CHCH3), 3.58 and 3.59 (2d,
2
2
4.16 (2d, 1H, JPH=11.6 and JPH=11.3, HNCHPh),
5.21 and 5.30 (2s, Ph2CH), 7.28–7.57 (m, 15H, CHar),
2
2
1H, JPH=15.0 and JPH=15.5, HNCHPh), 4.45 and
3
13C-NMR (CDCl3): l 19.27 and 19.29 (2d, JPC=6.4
4.46 (2s, 1H, Ph2CH), 6.85–7.35 (m, 15H, CHar), 13C-
3
1
3
and JPC=9.2, CHCH3), 31.42 and 31.88 (2d, JPC
=
NMR (D2O+NaOH): l 22.19 and 22.28 (2d, JPC
=

H.-J. Cristau et al. / Journal of Organometallic Chemistry 643–644 (2002) 381–391
391
7.3 and 3JPC=8.2, CHCH3), 34.92 and 35.08 (2d,
1JPC=91.8 and 1JPC=91.7, PCH2), 39.82 and 40.09
(2d, 2JPC=3.2 and 2JPC=3.1, CHCH3), 64.55 and
64.67 (2d, 1JPC=97.5 and 1JPC=97.7, HNCHPh),
66.34 and 66.34 (2d, 3JPC=13.5 and 3JPC=13.5,
Ph2CH), 129.22–131.46 (m, CHar), 140.29 and 141.29
(2d, JPC=3.3 and JPC=3.3, Car), 144.73 and 146.50
(2s, CHar), 188.71 (d, 3JPC=12.7, CO2), MS FAB+
(NBA): [M+H]+ 424.
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2
2
Acknowledgements
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Agne`s Coulombeau is grateful to Aventis Pharma
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