Enantioselective synthesis of phosphinyl peptidomimetics via an asymmetric Michael reaction of phosphonic acids with acrylate derivatives

Article abstract of DOI:10.1016/S0022-328X(01)01388-2

Asymmetric Michael reaction of phosphinic or aminophosphinic acids with acrylate derivatives afforded phosphinyl dipeptidomimetics in excellent yields (>90 percent). Chiral induction of substituents at the α-position of acrylate derivatives of Evans oxazolidinone type auxiliaries was obtained in moderate to excellent diastereomeric and enantiomeric excesses (50-98 percent). Pure diastereomers and enantiomers of phosphinyl dipeptidomimetics 16-19 were also successfully separated by HPLC.

Full text of DOI:10.1016/S0022-328X(01)01388-2

Journal of Organometallic Chemistry 646 (2002) 212–222
www.elsevier.com/locate/jorganchem
Enantioselective synthesis of phosphinyl peptidomimetics via an
asymmetric Michael reaction of phosphinic acids with acrylate
derivatives
Xuewei Liu, X. Eric Hu, Xinrong Tian, Adam Mazur, Frank H. Ebetino *
Procter and Gamble Pharmaceuticals, Health Care Research Center, P.O. Box 8006, Mason, OH 45040-8006, USA
Received 26 July 2001; accepted 9 October 2001
Abstract
Asymmetric Michael reaction of phosphinic or aminophosphinic acids with acrylate derivatives afforded phosphinyl dipepti-
domimetics in excellent yields (\90%). Chiral induction of substituents at the a-position of acrylate derivatives of Evans
oxazolidinone type auxiliaries was obtained in moderate to excellent diastereomeric and enantiomeric excesses (50–98%). Pure
diastereomers and enantiomers of phosphinyl dipeptidomimetics 16–19 were also successfully separated by HPLC. © 2002
Elsevier Science B.V. All rights reserved.
Keywords: Phosphinic acid; Acrylate; Asymmetric Michael reaction; Chiral auxiliary; Phosphinyl peptidomimetics
provide the peptidomimetic chemist additional
metabolically stable isosteres/scaffolds to scan confor-
1. Introduction
mational requirements within receptor ligand pharma-
Peptidomimetic drug design has been a very impor-
cophores. Phosphinic acid isosteres of dipeptide
tant research area in medicinal chemistry because of the
building blocks are therefore likely to find growing
importance of many natural peptides as hormones,
utility in medicinal chemistry.
neurotransmitters, growth factors, cytokines, enzyme
inhibitors, neuromodulators, and modulators of ion
channels and many other biological functions. Work
continues in the field to develop diverse non-peptidic
Inspection of the literature revealed that the classical
approach to prepare phosphinic C[P(O)OHCH2] pep-
tides relies on the synthesis of phosphinyl pseudodipep-
tidic units, which are typically obtained by Michael
scaffolds and amide isosteres to increase metabolic
addition of phosphinic acids with acrylate analogues
stability, to restrict the conformational properties of
[6,7]. In the presence of hexamethyldisilizane (HMDS)
short peptides, and to provide three-dimensional mim-
ics of peptide motifs such as b-turns and a-helices [1,2].
Several studies have demonstrated that the use of phos-
[7], TMSCl [8], BSA [9] or NaOMe [10], Michael addi-
tion of racemic 1-aminophosphinic acids with 2-substi-
tuted acrylates gives mixtures of four stereoisomers, due
phinic acid peptide isosteres can be a very effective
to the presence of two asymmetric carbons as shown in
approach for the development of highly potent and
Fig. 1. Also, complete separation by HPLC proved
selective inhibitors of various Zn metalloproteases [3,4].
difficult due to similar retention times, and two pairs of
These unnatural peptide analogs contain the metaboli-
diastereomers were usually obtained [9].
cally stable phosphinic moiety C[P(O)OHCH2], which
mimics the transition state tetrahedral geometry of a
Often, optically pure diastereomers are needed both
for the determination of absolute configuration and for
scissile peptide bond during enzymatic hydrolysis [5].
studying the relationships between stereochemistry and
Unnatural C[P(O)OHCH2] peptide analogs also
bioactivity. Therefore, the availability and ease of mak-
ing four individual isomers of the phosphinic acid
bearing pseudodipeptidic unit have become crucial to
future developments in this research area. In this paper,
* Corresponding author. Tel.: +1-513-6223630; fax: +1-513-
6221195.
E-mail address: ebetino.fh@pg.com (F.H. Ebetino).
0022-328X/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(01)01388-2

X. Liu et al. / Journal of Organometallic Chemistry 646 (2002) 212–222
213
methanol gave racemic (1-(N-Ac-amino)-2-phenyl-
ethyl)phosphonous acid (3). Functionalized mono-
arylphosphinic acids are valuable intermediates for the
preparation of medicinal compounds and synthetic in-
termediates. (2-Naphthalenyl)phosphonous acid (5) was
obtained by slight modification of Montchamp’s
method [13]. We have obtained (2-naphthalenyl)-
phosphonous acid in 78% yield by stirring the reaction
mixture at 96 °C in DMF for 24 h. (2-Phenylethyl)-
phosphonous acid (6) was prepared by the reaction of
red phosphorus with styrene in basic aqueous solution
[14].
The preparation of 2-substituted acrylate derivatives
was carried out as summarized in Scheme 2. The diacid
7 was converted to a-benzylacrylate acid (8) by a
Mannich reaction accompanied by in situ decarboxyla-
tion [15,16]. Acrylic acid 8 was methylated to its ester 9
with trimethylsilyl diazomethane [17]. (S)-4-Benzyl-3-
(2-benzyl-prop-2-enoyl)-1,3-oxazolidin-2-one (10a) and
(S)-4-diphenylmethyl-3-(2-benzyl-prop-2-enoyl)-1,3-
oxazolidin-2-one (10b) were prepared by coupling the
pivaloyl anhydride of acid 8 with the lithium salt of
Evans type auxiliaries (57% for R=benzyl and 55% for
R=diphenylmethyl). A slightly higher yield was ob-
tained than that originally reported 49% for a similar
reaction [18–20], probably due to our higher dilution
conditions and/or alternate preparative HPLC condi-
tions described in the Section 4.
Fig. 1. General structure of phosphinyl peptidomimetic analogs.
we describe the first phosphinic acid-involved asymmet-
ric Michael addition reaction with excellent chiral in-
duction at the a-position (P%1) of acrylate derivatives of
Evans oxazolidinone type auxiliaries. We also report
the isolation of optically pure diastereomers or enan-
tiomers prepared via a Michael addition reaction by
utilizing these auxiliaries.
2. Results and discussion
In this study, phosphinic acids, (1-(N-Ac-amino)-2-
phenylethyl)phosphonous acid (3), (2-naphthalenyl)-
phosphonous acid (5), (2-phenylethyl)phosphonous
acid (6), hypophosphorous acid were chosen for the
nucleophilic Michael addition reaction. Hypophospho-
rous acid (100%) was prepared from the commercially
available 50% aqueous solution according to the
method of Fitch [11]. As shown in Scheme 1, 1-amino-
2-phenylethylphosphonous acid (2) was prepared in
racemic form as previously described [12]. Simple acety-
lation of 2 with acetic anhydride and triethylamine in
In order to study the opportunity for chiral induc-
tion, it was first necessary to find mild conditions for a
potential asymmetric Michael addition reaction. As
summarized in Table 1, several conditions were exam-
Scheme 1.

214
X. Liu et al. / Journal of Organometallic Chemistry 646 (2002) 212–222
Scheme 2.
Table 1
Optimization of Michael addition reaction
Entry
Phosphinic acid
Conditions
Product
Yield (%)
1
2
3
4
5
6
4
4
4
3
3
3
NaOMe, r.t., overnight
NaH, −40 °C, 3 h
LDA, −78 °C, 3 h
TMSCl, iPrNEt2, 0 °C-r.t., 24 h
HMDS, 100–110 °C, 3 h
HMDS, \115 °C, 6 h
11a
11a
11a
11b
11b
13b
82
22
15
94
96
67
ined in the addition of 3 or its methyl ester 4–9. A
number of bases were utilized for this purpose such as
LDA, NaH, and NaOMe, to catalyze the Michael
reaction at low temperature. This allows low tempera-
ture protonation, which is typically required in asym-
metric synthesis. However, some yields were very low
(15% for LDA; 22% for NaH). Sodium methoxide led
to higher yields (82%), but protection of the phos-
phinylhydroxy group was required and poor
diastereoselectivity was observed in preliminary experi-
ments. HMDS has been widely used at elevated temper-
ature (110 °C) to catalyze these reactions and gave an
excellent yield (greater than 90%). But not surprisingly,
110 °C was also an unacceptable temperature for asym-
metric induction. Under these conditions the unwanted
acrylate double bond rearranged product 12 was ob-
served. Also, to confirm the desired Michael regiochem-
istry achieved from 3 and 9 to yield 11, we prepared
acrylate 12 from 9 to allow the synthesis of 13b.
After further analysis to optimize conditions, we were
pleased to discover that reaction of (1-(N-Ac-amino)-2-
phenylethyl)phosphonous acid (3) with TMSCl at low
temperature led to a mild and versatile Michael addi-
tion to 9 that proceeded with excellent yields. More-
over, there was no need for prior protection of the
phosphinylhydroxy moiety function. TMSCl was there-
fore used for the following studies of the asymmetric
Michael addition reaction. As shown in Table 2, these
conditions did in fact allow asymmetric induction via
the Michael addition reaction in very high yield. Thus,

X. Liu et al. / Journal of Organometallic Chemistry 646 (2002) 212–222
215
the phosphinic acid 3 was treated with TMSCl in the
presence of N,N-diisopropylethylamine at room tem-
perature for 3 h. Michael addition to 10a was then
accomplished at room temperature over 24 h followed
by an ethanol quench at −10 °C to yield phosphinyl
dipeptidomimetic (16a) (96%). We were also pleased to
note that a 3:1 ratio of two diastereomers was pro-
duced. We now believe the chiral carbon at the P1% side
chain position of the phosphinyl dipeptide structure 16a
was formed preferentially in the R configuration and we
have assigned it and related analogs as such. This
stereochemical proposal is supported by the evidence
presented at the end of this manuscript.
This asymmetric Michael addition reaction was thus
further studied using four phosphinic acid nucleophiles
3, 5, 6 and hypophosphorous acid, and two auxiliary
derivatives 10a and 10b. As shown in Table 2, most
importantly, even higher asymmetric induction was
achieved via usage of the diphenylmethyl auxiliary on
comparison of products 16a, 17a, 18a, 19a to 16b, 17b,
18b, 19b, respectively, presumably because of the in-
creased steric bulk directing the protonation. Note that
although these results reflect products 16a and 16b
utilizing a racemic mixture of 3, the same ratio of
asymmetric induction was obtained upon utilizing the
Cbz protected form of 3 in the pure R configuration.
Also, similar asymmetric induction was observed with-
out a P1 stereocenter in phosphinic acids 5 and 6.
Because of the complexity of this stereochemical
analysis, we also sought crystallographic confirmation
of our isomeric assignments. To readily prepare suffi-
cient quantities of each isomer for this purpose, the
HMDS procedure was used to prepare intermediates
16a(S, S), 16a(R, S), 17a(S, S), 17a(R, S), 18a(S, S),
and 18a(R, S). Each was separated by HPLC as opti-
cally pure diastereomers or epimers in the case of 16a.
Again, the lack of asymmetric induction was observed
in all cases. To determine the relative configuration of
each pair of isomers and to prepare intermediates for
future elongation of phosphinyl pseudodipeptides to
polypeptide analogs 20, 21, and 22 were synthesized by
hydrolysis of the resulting purified 16a, 17a, and 18a
with lithium hydroxide as shown in Table 3.
The isolation of purified stereoisomers allowed us to
generate crystallographic evidence for the absolute
configuration proposed in Tables 2 and 3. X-ray crystal
analysis of compound 17a(R, S), which is the major
product in the asymmetric Michael reaction with the
TMSCl method, supports this stereochemical predic-
tion. This data shows that in the case of the formation
of 17a(R, S) the benzyl group on the oxazolidinone
also creates enough steric bulk on one face of the
double bond to favor the protonation at the opposite
face of the double bond. X-ray crystal analysis and
related results will be reported later. Since the diphenyl-
methyl oxazolidinone enhances formation of 17b(R, S),
we propose that the R isomer is the preferred major
isomer formed in all cases of asymmetric induction
reported here.
In order to rationalize the diastereoselectivity ob-
served, we propose this Michael reaction proceeds via a
stepwise process outlined in Scheme 3. The phospho-
rus(III) intermediate 14 is formed initially after addition
of TMSCl to the cooled phosphinic acid 3 in the
presence of diisopropylethylamine. Upon addition of an
acrylate species, the trivalent phosphorus nucleophile
(14) attacks the b-carbon of 10, forming the TMS enol
ether 15 as an intermediate. After 24 h, absolute etha-
nol was added to quench the reaction, resulting in
asymmetric protonation of the TMS enol ether 15 to
Table 2
Asymmetric Michael addition reactions using different phosphinic acids and auxiliaries
Entry
Phosphinic acid
Acrylate, R2
Product
Yield (%)
(R, S)/(S, S)
1
2
3
4
5
6
7
8
3
3
5
5
6
6
PhCH2
Ph2CH
PhCH2
Ph2CH
PhCH2
Ph2CH
PhCH2
Ph2CH
16a
16b
17a
17b
18a
18b
19a
19b
94
90
78
73
91
90
84
78
3/1
86/1
5/1
55/1
12/1
54/1
9/1
H3PO2
H3PO2
25/1

216
X. Liu et al. / Journal of Organometallic Chemistry 646 (2002) 212–222
Table 3
Diastereomers and enantiomers of phosphinyl dipeptides
Entry
1
Phosphinic acid
Yield (%)
96
S/R
1/1
[h]2D0, MeOH
3
16a(S, S): +16.4° a
16a(R, S): −14.6° a
20S: +13.2° a
20R: −13.4° a
2
3
5
6
80
92
1.2/1
1/1
17a(S, S): +51.2°
17a(R, S): −51.8°
21S: +18.1°
21R: −18.0°
18a(S, S): +75.6°
18a(R, S): −54.5°
22S: +7.2°
22R: −7.4°
a An epimeric mixture at the P1 stereocenter exists.
Scheme 3.
Table 4
AM1 energies of intermediates 15 and products 16a and 17b
Product
Intermediate 15
Energy (kcal mol−1
)
Product isomer (P1’)
Energy (kcal mol−1
)
16b (P1 R epimer)
16b (P1 S epimer)
17b
Z
E
Z
E
Z
E
−278.1
−275.4
−278.7
−280.5
−217.4
−219.2
S
R
S
R
S
R
−180.0
−171.8
−182.3
−177.8
−125.0
−115.8
form a chiral center at the a-position of the amide
group in structure 16. The effect of temperature on R/S
ratio was also studied. In the case of 10a, a 3:1 ratio
was obtained upon addition of cold absolute ethanol at
−10 °C. However, quenching the reaction mixture at
−40 and −78 °C, respectively led to no better
stereoselectivity, but the chemical yields were lower.
In order to examine factors contributing to the high
selectivity in the formation of the R isomers (16–18),
we have calculated semiempirical AM1 energies [21] of
the Z and E isomers of the potential enol ethers 15 as
well as the energies of the R, S isomers of 16b (R and
S epimers at P1) and 17b (Table 4) where the factors
inducing asymmetry are clearly enhanced by the

X. Liu et al. / Journal of Organometallic Chemistry 646 (2002) 212–222
217
diphenylmethyl oxazolidinone. High stereoselection fa-
voring the R isomer is likely to result from protonation
of the less hindered side in the trans olefin as depicted
in 15 and consequently, we propose that the E olefin
(with respect to the phosphinate and oxazolidinone) is
the intermediate in this Michael addition. In case of the
Z olefin, the protonation would have to occur from the
more hindered face to produce the R isomer. Interest-
ingly, if the Z olefin was formed in this reaction, its
protonation would lead to the S isomer, since forma-
tion of the latter product would be driven by both
thermodynamic and kinetic factors. As shown in Table
4, the ground state energies of the E and Z isomers are
similar and do not indicate a substantial preference for
the formation of the trans olefin. Therefore, we hypoth-
esize that the preferred formation of 16 (R and S
epimers) and 17b results from the E isomer of the
intermediate 15, which is likely to be produced from a
cyclic intermediate such as a phosphorane or some
other silyl transfer intermediate leading to the amide
and phosphinic acid oxygen atoms residing on the same
face. Formation of 5-member cyclic phosphorane rings
and their opening to enol ethers were documented by
Evans et al. [22] in the conjugate additions of trivalent
phosphorus esters to a,b-unsaturated aldehydes and
ketones.
linear gradient of water containing 0.1% H3PO4 (from
80 to 0%) and MeCN (from 20 to 100%) over 25 min,
with UV detection at 214 nm. Preparative HPLC sepa-
rations were performed on a Polaris C18-A 10 m
column (50 mm×25 cm) operated at room tempera-
ture (r.t.) and eluted at 60 ml min−1 flow rate, using a
linear gradient of water containing 0.1% TFA (from 95
to 0%) and MeCN (from 5 to 100%) over 60 min, with
1
UV detection at 214 nm. H-, 13C- and 31P-NMR were
obtained using Varian 300 and referenced to CD3OD,
CDCl3, or D2O. The yields reported in this paper are
isolated yields.
4.2. Preparation of phosphinic acids
4.2.1. (1-(N-Ac-amino)-2-phenylethyl)phosphonous acid
(3)
(1-Diphenylmethylamino-2-phenylethyl)phosphonous
acid (HCl salt form) (1). To a refluxing solution of
diphenylmethylamine hydrochloride (43.9 g, 0.2 mol)
and 50% aq. H3PO2 (21 ml, 0.2 mol) in H2O (100 ml)
was added a solution of 90% phenylacetaldehyde (38
ml, 0.3 mol) in H2O (45 ml) with vigorous stirring.
White precipitation appeared when the aldehyde was
added, and refluxing was continued for 2 h. The mix-
ture was cooled with an ice bath and gave a granule of
solid. It was ground with C3H6O in a mortar, washed
with cold C3H6O and dried under vacuum to give pure
product 1 (66.6 g, 86%) as white powder. MS (ESI):
m/z 352.4 [M+1].
3. Conclusion
In summary, the enantioselective Michael addition of
phosphinic or aminophosphinic acids to acrylate
derivatives of a chiral auxiliary offers an efficient entry
into a variety of phosphinic dipeptidomimetics. Aided
by Evans oxazolidinone type auxiliaries, the chirality at
the a-position of acrylate derivatives was stereoselec-
tively controlled during the process of hydrolysis and
protonation of the resulting TMS enol ether.
Diastereomeric and enantiomeric excesses of 50–98%
have been achieved through this process. Pure isomers
can be isolated after separation by HPLC and used as
building blocks in the synthesis of peptidomimetics.
4.2.1.1. (1-Amino-2-phenylethyl)phosphonous acid (2). A
solution of (1-diphenylmethylamino-2-phenylethyl)-
phosphonous acid (1) (HCl salt form, 14.09 g, 36.4
mmol) in 48% aq. HBr (100 ml) of was heated at
100 °C for 2 h until two distinct phases separated. The
mixture was allowed to cool to r.t., the volatile materi-
als were evaporated under reduced pressure, and the
oily residue was partitioned between water and ether.
The aq. layer was washed several times with ether to
remove diphenylmethyl bromide, and water was evapo-
rated again under reduced pressure. The oily residue of
the aminophosphonous acid hydrobromide was dis-
solved in EtOH (250 ml) and propylene oxide was
added dropwise to neutralize the hydrobromide until
precipitation started. The mixture was allowed to stand
at r.t. overnight to complete the precipitation. The solid
was collected by filtration, washed with cold EtOH and
ether, and dried under vacuum to afford aminophos-
phonous acid 2 (6.3 g, 94%). MS (ESI): m/z 186.3
4. Experimental
4.1. General
All reactions were carried out under Ar atmosphere.
Glassware was assembled hot from the drying oven.
Solvents and reagents were used as purchased from
Aldrich Chemical Co., unless otherwise stated. Reac-
tions were monitored by TLC, MS, or LC–MS. Ana-
lytical HPLC was used to determine the purity of
products operated on Polaris C18-A 3 m column (4.6
mm×25 cm) eluted at 1 ml min−1 flow rate, using a
1
[M+1]; m.p. 210–211 °C; H-NMR (CD3OD): l 7.35
1
(m, 5H, Ph), 7.09 (d, J=531 Hz, 1H, HꢀP), 3.21–3.39
(m, 1H, CH), 2.81–2.92 (m, 2H, CH2Ph). 13C-NMR
1
(CD3OD): 136.0, 129.2, 129.0, 127.3, 52.6 (d, J=90
1
Hz); 31P-NMR (121.27 MHz, CD3OD): 17.15 (d, J=
531 Hz).

218
X. Liu et al. / Journal of Organometallic Chemistry 646 (2002) 212–222
4.2.1.2.
(1-(N-Ac-amino)-2-phenylethyl)phosphonous
a yellow solid. It was dissolved in saturated NaHCO3
aq. solution, washed with CH2Cl2 three times. The aq.
layer was acidified to pHB1 with 2 N HCl and ex-
tracted with CH2Cl2. The organic layers were com-
bined, dried over anhydrous Na2SO4 and evaporated
under reduced pressure to give 5 as a light yellow solid
acid (3). To an ice-water chilled solution of aminophos-
phonous acid 2 (200 mg, 1.09 mmol) and Et3N (0.91
ml, 6.5 mmol) in MeOH (8 ml) was added Ac2O (0.31
ml, 3.29 mmol) dropwise. The mixture was stirred for 1
h at r.t. The excess of Et3N, Ac2O and solvent were
removed under high vacuum to give 3 as a colorless oil
1
(1.198 g, 78%). MS (ESI): m/z 193.1 [M+1]; H-NMR
1
3
(247.0 mg, 100%). MS (ESI): m/z 228.2 [M+1]; H-
NMR (CD3OD): l 7.18 (m, 5H, Ph), 6.94 (d, J=523
(CD3OD): l 8.39 (d, J=16 Hz, 1H), 8.04–8.08 (m,
1
3
3
2H), 7.98 (d, J=8 Hz, 1H), 7.80–7.84 (d, J=8 Hz,
1H), 7.69 (d, 1J=563 Hz, 1H, HꢀP), 7.62–7.70 (m,
2H); 13C-NMR (CD3OD): 135.0, 133.3 (d, J=12 Hz),
Hz, 1H, HꢀP), 3.34 (m, 1H, CH), 2.69–2.81 (m, 2H,
CH2Ph), 2.01 (s, 3H, CH3); 13C-NMR l (CD3OD): l
175.4, 139.0, 138.8, 129.0, 128.1, 126.1, 52.2 (d, 1J=100
2
133.2, 128.7, 127.5 (d, J=19 Hz), 127.1, 126.0, 125.9
Hz), 32.8, 21.4; 31P-NMR (CD3OD): 27.40 (d, J=507
(d, 1J=339 Hz) 124.8 (d, 2J=15 Hz); 31P-NMR
1
1
Hz).
(CD3OD): 21.91 (m+m, J=563 Hz).
4.2.1.3. Methyl ester of (1-(N-Ac-amino)-2-phenyl-
ethyl)phosphonous acid (4). To a stirred solution of 3
(300.0 mg, 1.32 mmol) in MeOH (2 ml) and C6H6 (7
ml) was added trimethylsilyldiazomethane (2 M solu-
tion in hexanes, 0.73 ml, 1.45 mmol) at r.t. The mixture
was stirred for 2 h at r.t. and concentrated to give the
corresponding methyl ester 4 (318.0 mg, 1.32 mmol,
4.2.3. (2-Phenylethyl)phosphonous acid (6)
A mixture of red phosphorus (6.2 g, 0.2 mol), KOH
(20 g), water (10 ml), and Me2SO (100 ml) was heated
to 53–55 °C. Styrene (4.3 ml) was added dropwise to
the above solution. The reaction mixture was stirred at
60–65 °C for 3 h, cooled, diluted with water, and
extracted with CH2Cl2. The aq. phase was acidified to
pHB1 and extracted with CH2Cl2. The organic layers
were combined, dried over anhydrous Na2SO4 and
evaporated under reduced pressure to give colorless oil
6 (3.62 g, 11%). MS (ESI): m/z 171.2 [M+1]; 1H-NMR
1
100%). H-NMR (CD3OD): l 7.32 (m, 5H, Ph), 7.01
1
3
(d, J=557 Hz, 1H, HꢀP), 3.85 (d, 3H, CH3, J=12
Hz), 3.35 (m, 1H, CH), 2.86–2.94 (m, 2H, CH2Ph),
2.02 (s, 3H, CH3); 31P-NMR (CD3OD): 30.69 (d, J=
1
1
557 Hz).
(CD3Cl): l 7.06 (m, 5H, Ph), 6.92 (d, J=535 Hz, 1H,
HꢀP), 2.70 (m, 2H) 1.82 (m, 2H); 13C-NMR (CD3Cl):
1
4.2.2. (2-Naphthalenyl)phosphonous acid (5) [13,23]
140.6, 140.4, 128.5, 128.0, 126.3, 31.5 (d, J=91 Hz),
1
27.0; 31P-NMR (CD3Cl): 29.46 (m+m, J=535 Hz).
4.2.2.1. Anilinium hypophosphite. Aniline (9.8 g, 105.0
mmol) was added dropwise to an aq. solution of H3PO2
(50 wt.%, 13.9 g, 10.9 ml) at 0 °C. The light brown
solution rapidly turned into a thick slurry. It was
transferred into a Buchner funnel, washed with chilled
C3H6O and ether to give light yellow needle crystals.
The filtrate was concentrated under reduced pressure,
and a second crop of the product was obtained. They
were combined, washed with ether and dried under
high vacuum to provide anilinium hypophosphite (15.8
g, 99.2 mmol, 95%): m.p. 113.5–114.0 °C; 1H-NMR
4.3. Preparation of acrylate analogues
4.3.1. 2-Benzyl acrylic acid (8)
To a stirred solution of benzylmalonic acid (7) (10.0
g, 51.5 mmol) and 37% formalin (21.8 ml, 268.7 mmol)
was added Et2NH (5.3 ml, 51.5 mmol) at r.t. The
solution was stirred at r.t. for 3 h and then was refluxed
for additional 2 h. The reaction mixture was cooled to
r.t., diluted with CHCl3, and extracted with saturated
aq. NaHCO3. The basic aq. layer was acidified with 2 N
HCl to pHB1 and was extracted with CHCl3. The
organic layers were combined, dried over anhydrous
Na2SO4 and evaporated under reduced pressure to give
8 as a white solid (8.193 g, 98%). MS (ESI): m/z 161.3
(D2O) 8.10–8.45 (br s, 3H), 7.12 (d, 2JHP=520 Hz,
2
2H), 7.0–7.4 (m, 5H); 31P-NMR (D2O) 3.7 (t, JPH
=
520 Hz).
1
4.2.2.2. (2-Naphthalenyl)phosphonous acid (5). T solu-
tion of 2-bromonaphthalene (1.656 g, 8.0 mmol), anilin-
ium hypophosphite (1.592 g, 10 mmol), Et3N (3.4 ml,
24 mmol), and tetrakis(triphenylphosphine) (184 mg,
0.16 mmol) in DMF was heated at 90–96 °C for 24 h.
The reaction mixture was concentrated under reduced
pressure, diluted in water, washed with CH2Cl2. The aq.
layer was acidified to pHB1 with 1 N KHSO4 (satu-
rated with NaCl) and extracted with EtOAc. The or-
ganic layers were combined, dried over anhydrous
Na2SO4 and evaporated under reduced pressure to give
[M−1]; H-NMR (CD3Cl): l 7.20–7.37 (m, 5H, Ph),
6.42 (br s, 1H, HCꢁ), 5.62 (br s, 1H, HCꢁ), 3.67 (br s,
2H, CH2); 13C-NMR (CD3Cl): 172.5 (CꢁO), 139.8 (ꢁC),
138.7, 129.3, 129.0, 128.7, 126.7 (H2Cꢁ), 37.8.
4.3.2. Methyl 2-benzyl acrylate (9)
To a stirred solution of 2-benzyl acrylic acid (8) (1.0
g, 6.17 mmol) in MeOH (12 ml) and C6H6 (42 ml) was
added trimethylsilyldiazomethane (2 N solution in hex-
anes, 4.0 ml, 8.02 mmol) at r.t. The mixtures was stirred
for 30 min at r.t. and concentrated to give the corre-

X. Liu et al. / Journal of Organometallic Chemistry 646 (2002) 212–222
219
sponding methyl ester 9 (1.086 g, 6.17 mmol, 100%).
MS (ESI): m/z 177.3 [M+1]; 1H-NMR (CD3Cl): l
7.23–7.34 (m, 5H, Ph), 6.27 (s, 1H, HCꢁ), 5.50 (s, 1H,
HCꢁ), 3.78 (s, 3H), 3.67 (br s, 2H, CH2).
and then cooled down to 0 °C. Methyl 2-benzyl acry-
late (9) (61.8 mg, 0.3 mmol) in MeOH (1 ml) was then
added slowly. The mixture was stirred at r.t. overnight,
and then it was partitioned between water and CH2Cl2.
The organic layer was separated, dried over anhydrous
Na2SO4 and evaporated under reduced pressure to give
11a as a white solid (92.5 mg, 22.2 mmol, 82%).
4.3.3. (S)-4-Benzyl-3-(2-benzyl-prop-2-enoyl)-1,3-
oxazolidin-2-one (10a)
In an 100 ml round-bottom flask, pivaloyl chloride
(1.5 ml, 12.3 mmol) was added to a solution of 2-benzyl
acrylic acid (8) (2.0 g, 12.3 mmol) and N-methylmor-
pholine (1.4 ml, 12.3 mmol) in anhydrous THF (20 ml)
at −78 °C under Ar. In another 100 ml round-bottom
flask, n-BuLi, (1.6 M in hexanes, 6.4 ml, 10.2 mmol)
was added to a solution of (S)-4-benzyl-2-oxazolidi-
none (1.8 g, 10.2 mmol) in anhydrous THF (20 mL) at
−78 °C under Ar. Both of them were stirred for 1 h at
−78 °C. The suspension of acryloyl mixed anhydride
in the former flask was transferred via a cannula at
−78 °C to the latter flask. The resulting mixture was
stirred first at −78 °C for 2 h and then at r.t. for 2 h.
The mixture was diluted in saturated NH4Cl and ex-
tracted with CH2Cl2. The combined organic layers were
washed with brine, dried over Na2SO4 and evaporated
under reduced pressure to give a white solid. It was
further purified on preparative HPLC to provide 10a
(1.87 g, 5.81 mmol, 57%) as white crystals. MS (ESI):
4.4.2. NaH
The reaction was performed as in Section 4.4.1 utiliz-
ing NaH as coupling reagent. Yield 22%.
4.4.3. LDA
The reaction was performed as in Section 4.4.1 utiliz-
ing LDA as coupling reagent. Yield 15%.
4.4.4. TMSCl
To an ice-cold solution of (1-(N-Ac-amino)-2-
phenylethyl)phosphonous acid (3) (123 mg, 0.54 mmol)
in anhydrous CH2Cl2 (4 ml) were added N,N-diiso-
propylethylamine (0.42 ml, 2.43 mmol) and chloro-
trimethylsilane (0.31 ml, 2.43 mmol) under an Ar
atmosphere. The mixture was stirred for 3 h at r.t. The
mixture was then cooled to 0 °C, and methyl 2-benzyl
acrylate (9) (105.6 mg, 0.60 mmol) was added dropwise.
The solution was stirred at r.t. for 24 h. The mixture
was again cooled to 0 °C and absolute EtOH (0.44 ml)
was added to quench the reaction. After 30 min, the
solvent was removed and the residue was subjected to
separation on preparative HPLC. The final product 11b
(227.3 mg, 0.51 mmol, 94%) was obtained as white
solid.
1
m/z 322.3 [M+1]; H-NMR (CD3Cl): l 7.15–7.38 (m,
10H, 2Ph), 5.61 (s, 1H, HCꢁ), 5.41 (br s, 1H, HCꢁ),
4.62 (m, 1H, NCH); 4.14 (m, 2H, OCH2); 3.81 (s, 2H,
ꢁCCH2Ph); 2.56–3.24 (dd+dd, 2J=180 Hz, 3J=13
Hz, 2H, PhCH2); 13C-NMR (CD3Cl): 170.5 (CꢁO),
153.2, 143.8, 137.6, 135.1, 129.6, 129.2, 128.8, 127.6,
127.0, 122.0, 66.8, 55.5, 39.3, 37.7.
4.3.4. (S)-4-Diphenylmethyl-3-(2-benzyl-prop-2-enoyl)-
1,3-oxazolidin-2-one (10b)
4.4.5. HMDS
A
mixture of (1-(N-Ac-amino)-2-phenylethyl)-
Compound 10b was synthesized by the same method
as used for 10a on 10.2 mmol scale. Compound 10b
(2.24 g, 5.63 mmol, 55%) was obtained as white crys-
tals. MS (ESI): m/z 398.3 [M+1]; 1H-NMR (CD3Cl): l
7.18–7.38 (m, 15H, 3Ph), 5.33 (s, 1H, HCꢁ), 5.20 (br s,
phosphonous acid (3) (246.0 mg, 1.08 mmol) and
1,1,1,3,3,3-hexamethyldisilazane (0.92 ml, 5.40 mmol)
was heated at 110 °C for 1 h under Ar, then methyl
2-benzyl acrylate (9) (211.2 mg, 1.2 mmol) was added
dropwise. The resulting mixture was stirred at 105–
110 °C for additional 3 h and cooled to 70 °C. Ethanol
(2 ml) was added and the mixture was cooled to r.t.
slowly. The solvent was removed under vacuum, the
residue was dissolved in MeOH (5 ml) and purified on
preparative HPLC. The final product 11b (419.6 mg,
1.04 mmol, 96%) was obtained as a white solid. MS
2
1H, HCꢁ), 5.40 (m, 1H, NCHP); 4.56 (dd, J=111 Hz,
3J=6 Hz 2H, OCH2); 3.66 (d, 3J=16 Hz, 1H, CHPh2);
3.51 (s, 2H, PhCH2); 13C-NMR (CD3Cl): 170.3 (CꢁO),
153.0, 143.1, 139.7, 138.5, 137.6, 129.8, 129.5, 129.3,
129.0, 128.7, 128.1, 127.5, 127.3, 126.9, 121.6, 65.7,
56.6, 52.1, 39.0.
1
(ESI): m/z 404.2 [M+1]; H-NMR (CD3OD): l 7.16–
4.4. Study of optimal reagents and conditions for
Michael addition reaction
7.30 (m, 10H, 10Ph), 4.52 (m, 1H, PCHN), 3.60 (ss, 3H,
OCH3), 3.15–3.26 (m, 1H, CHCO), 2.73–3.15 (m, 4H,
2PhCH2), 1.80–2.30 (m, 2H, PCH2CCO), 1.79 (ss, 3H,
CH3); 13C-NMR (CD3OD): 175.4 (OꢁCꢀO), 171.8
(CH3CO), 138.3, 137.6, 129.1, 129.0, 128.4, 128.3,
4.4.1. NaOMe
Sodium methoxide (25 wt.% solution in MeOH, 0.15
ml, 0.27 mmol) was added dropwise to a solution of 4
(65.3 mg, 0.27 mmol) in MeOH (2 ml) at 0 °C. The
mixture was stirred at r.t. until gas evolution ceased,
1
126.7, 126.6, 51.5, 50.3 (d, J=104 Hz, PCN), 41.5,
39.5, 32.9, 28.2 (d, 1J=90 Hz, PCCCO), 21.2; 31P-
NMR (CD3OD): 52.8, 52.4.

220
X. Liu et al. / Journal of Organometallic Chemistry 646 (2002) 212–222
The reaction mixture (on a scale of 0.84 mmol) was
heated at above 115 °C for 6–8 h. The rearrangement
was removed under vacuum, the residue was dissolved
in MeOH (4 ml) and purified on preparative HPLC.
Two diastereomers were separated as twin peaks and
collected, respectively.
product 13b (146.3 mg, 0.36 mmol, 67%) was separated.
1
MS (ESI): m/z 404.3 [M+1]; H-NMR (CD3OD): l
7.16–7.30 (m, 10H, 2Ph), 4.52 (m, 1H, PCHN), 3.60
(ss, 3H, OCH3), 3.15–3.26 (m, 1H, CHCO), 2.73–3.15
(m, 4H, 2PhCH2), 1.80–2.30 (m, 2H, PCH2CCO), 1.79
(ss, 3H, CH3); 13C-NMR (CD3OD): 175.6 (OꢁCꢀO),
171.8 (CH3CO), 138.1, 137.6, 129.0, 128.9, 128.4, 128.3,
128.2, 126.6, 126.5, 57.2, 51.2, 50.3 (d, 1J=104 Hz,
1
16a(S, S): MS (ESI): m/z 549.1 [M+1]; H-NMR
(CD3OD): l 7.20–7.38 (m, 15H, 3Ph), 4.54 (m, 1H,
NCH), 4.08 (m, 2H, OCH2); 4.00 (m, 1H, CHCO), 3.33
(m, 2H, NCH2Ph); 2.70–2.90 (m, 4H, 2PhCH2), 2.04 (s,
3H, CH3), 1.90–2.00 (m, 2H, PCH2); 13C-NMR
(CD3OD): 175.2 (OꢁCꢀN), 172.0 (CH3ꢀCꢁO), 153.9
(NꢀCOO), 138.4, 136.2, 129.5, 129.3, 129.2, 129.0,
128.7, 128.4, 128.3, 126.9, 126.7, 126.5, 66.2, 56.0, 50.8
1
PCN), 41.5, 39.8, 32.9, 28.3 (d, J=90 Hz, PCCCO),
21.1, 17.2; 31P-NMR (CD3OD): 52.7, 52.3.
4.5. Studies of asymmetric Michael addition reactions
with (S)-(−)-4-benzyl-2-oxazolidinone or
(S)-(−)-4-diphenylmethyl-2-oxazolidinone
1
1
(d, J=106 Hz, NCP), 39.4, 37.2, 33.1, 28.4 (d, J=
100 Hz, PCC), 21.3; 31P-NMR (CD3OD): 53.1, 52.1;
Analytical HPLC tR=13.56 min.
1
16a(R, S): MS (ESI): m/z 549.3 [M+1]; H-NMR
4.5.1. General procedure
(CD3OD): l 7.11–7.36 (m, 15H, 3Ph), 4.58 (m, 1H,
NCH), 4.20 (m, 2H, OCH2); 3.68 (m, 1H, CHCO), 3.18
(m, 2H, NCH2Ph); 2.60–2.85 (m, 4H, 2PhCH2), 2.02 (s,
3H, CH3), 1.80–2.00 (m, 2H, PCH2); 13C-NMR
(CD3OD): 175.4 (OꢁCꢀN), 172.0 (CH3ꢀCꢁO), 154.1
(NꢀCOO), 138.2, 135.7, 129.6, 129.5, 129.0, 128.9,
128.7, 128.5, 128.4, 127.0, 126.8, 126.5, 66.5, 55.5, 50.8
To an ice-cold solution of (1-(N-Ac-amino)-2-phenyl-
ethyl)phosphonous acid (3), (2-naphthalenyl)phos-
phonous acid (5), (2-phenylethyl)phosphonous acid (6),
or H3PO2 (0.081 mmol) in anhydrous CH2Cl2 (1 ml)
were added N,N-diisopropylethylamine (63 ml, 0.36
mmol) and chlorotrimethylsilane (46 ml, 2.43 mmol)
under an Ar atmosphere. The mixture was stirred for 3
h at r.t. Then, the mixture was cooled to 0 °C, and
(S)-4-benzyl-3-(2-benzyl-prop-2-enoyl)-1,3-oxazolidin-
2-one (10a) or (S)-4-diphenylmethyl-3-(2-benzyl-prop-
2-enoyl)-1,3-oxazolidin-2-one (10b) (0.097 mmol) was
added dropwise. The solution was allowed to warm up
slowly and stirred at r.t. for 24 h. The mixture was
again cooled to 0 °C and absolute EtOH (66 ml) was
used to quench the reaction. After 30 min, the product
was isolated and the ratio of two isomers was deter-
mined with LC–MS and analytical HPLC.
1
1
(d, J=106 Hz, NCP), 39.2, 37.4, 33.0, 28.2 (d, J=
100 Hz, PCC), 21.2; 31P-NMR (CD3OD): 52.6, 52.2;
Analytical HPLC tR=14.24 min.
1
17a(S, S): MS (ESI): m/z 514.2 [M+1]; H-NMR
(CD3OD): l 7.00–8.26 (m, 17H, NaPh+2Ph), 4.56 (m,
1H, NCH), 4.18 (m, 1H, CHCO), 3.65 (m, 2H, OCH2);
2.60–3.00 (m, 4H, 2PhCH2), 1.90–2.10 (m, 2H, PCH2);
13C-NMR (CD3OD): 174.6 (OꢁCꢀN), 153.1 (NꢀCOO),
137.5, 135.1, 133.6, 130.0, 129.5, 129.3, 129.0, 128.5,
128.3, 127.9, 126.9, 126.5, 66.0, 55.8, 41.1, 38.9, 37.2,
32.7 (d, J=100 Hz, PCC), 21.2; 31P-NMR (CD3OD):
1
41.7; Analytical HPLC tR=16.82 min.
17a(R, S): MS (ESI): m/z 514.2 [M+1]; H-NMR
1
4.5.2. Racemization of 11b
The reaction mixture of Section 4.4.4 was not sub-
jected to separation after removal of solvent. Instead, it
was heated at 105–110 °C with three equivalents of
1,1,1,3,3,3-hexamethyldisilazane for 3 h, and then
cooled to r.t. The product and the ratio of two isomers
were determined with LC–MS and analytical HPLC.
(CD3Cl): l 6.90–8.23 (m, 17H, NaPh+2Ph), 4.48 (m,
1H, NCH), 4.06 (m, 1H, CHCO), 3.93 (m, 2H, OCH2);
2.50–3.00 (m, 4H, 2PhCH2), 2.04 (m, 2H, PCH2);
13C-NMR (CD3Cl): 174.2 (OꢁCꢀN), 153.6 (NꢀCOO),
137.8, 135.5, 133.4, 129.4, 128.9, 128.6, 128.5, 128.3,
128.1, 127.7, 127.0, 126.7, 126.5, 126.4, 66.0, 55.2, 39.9,
1
39.1, 37.1, 30.6 (d, J=100 Hz, PCC), 21.2; 31P-NMR
4.6. Synthesis of diastereomerically or enantiomerically
pure phosphinyl dipeptidomimetics
(CD3Cl): 40.4; Analytical HPLC tR=17.30 min.
1
18a(S, S): MS (ESI): m/z 492.3 [M+1]; H-NMR
(CD3OD): l 7.19–7.36 (m, 15H, 3Ph), 4.54 (m, 1H,
NCH), 4.09 (m, 2H, OCH2); 3.88 (m, 1H, CHCO),
2.98–3.30 (m, 2H, Ph CH2CHN); 2.70–2.85 (m, 2H,
PhCH2), 2.44 (m, 2H, PCCH2), 2.09 (m, 2H, PCH2C)
1.83 (m, 2H, PCH2); 13C-NMR (CD3OD): 174.9
(OꢁCꢀN), 154.0 (NꢀCOO), 138.2, 136.0, 129.5, 129.2,
128.6, 128.5, 128.4, 128.0, 127.0, 126.8, 126.2, 66.1,
4.6.1. General coupling procedure
A mixture of phosphinic acid 3, 5 or 6 (0.63 mmol)
and 1,1,1,3,3,3-hexamethyldisilazane (3.2 mmol) was
heated at 110 °C for 1 h under Ar, then (S)-4-benzyl-3-
(2-benzyl-prop-2-enoyl)-1,3-oxazolidin-2-one
(10a)
(0.76 mmol) was added dropwise. The resulting mixture
was stirred at 105–110 °C for additional 3 h and
cooled to 70 °C. Absolute EtOH (1.5 ml) was added
and the mixture was cooled to r.t. slowly. The solvent
1
55.9, 40.5, 39.3, 37.1, 30.8 (d, J=101 Hz, PCCCO),
30.2, 28.5 (d, 1J=101 Hz, PCCC), 21.2; 31P-NMR
(CD3OD): 52.7; Analytical HPLC tR=16.60 min.

X. Liu et al. / Journal of Organometallic Chemistry 646 (2002) 212–222
221
21R: MS (ESI): m/z 355.2 [M+1]; 1H-NMR
(CD3OD): l 7.00–8.40 (m, 12H, Naph+Ph), 2.89 (m,
1H, CHCO), 2.68 (m, 2H, PhCH2), 2.04–2.60 (m, 2H,
PCH2); 13C-NMR (CD3OD): 174.8 (OꢁCꢀO), 138.3,
135.6, 132.8, 129.3, 129.0, 128.9, 128.6, 128.5, 128.3,
1
18a(R, S): MS (ESI): m/z 492.3 [M+1]; H-NMR
(CD3OD): l 7.11–7.50 (m, 15H, 3Ph), 4.75 (m, 1H,
NCH), 4.30 (m, 1H, CHCO), 4.18 (m, 2H, OCH2),
2.95–3.20 (m, 2H, PhCH2), 2.62–2.82 (m, 2H, PCCH2),
2.36 (m, 2H, PCCH2), 1.97 (m, 2H, PCH2C) 1.79 (m,
2H, PCH2); 13C-NMR (CD3OD): 175.2 (OꢁCꢀN), 154.4
(NꢀCOO), 138.6, 135.8, 129.5, 129.2, 128.6, 128.5,
128.0, 127.0, 126.8, 126.2, 66.4, 55.4, 40.5, 39.1, 37.3,
1
127.8, 127.0, 126.5, 126.2, 42.6, 40.0, 31.8 (d, J=104
Hz, PCC); 31P-NMR (CD3OD): 40.8; Analytical HPLC
tR=13.72 min. Anal. Calc. for C20H19O4P·0.3H2O: C,
66.78; H, 5.45. Found: C, 66.68; H, 5.49%.
1
1
30.8 (d, J=101 Hz, PCCCO), 30.2, 28.1 (d, J=101
Hz, PCCC), 21.2; 31P-NMR (CD3OD): 52.4; Analytical
HPLC tR=17.09 min.
22S: MS (ESI): m/z 333.1 [M+1]; 1H-NMR
(CD3OD): l 7.20–7.35 (m, 10H, 2Ph), 3.04 (m, 1H,
CHCO), 2.70–2.88 (m, 2H, PhCH2), 2.12–2.45 (m, 2H,
PCCH2Ph), 1.96–2.04 (m, 2H, PCH2CCO), 1.80 (m,
2H, PCH2CPh); 13C-NMR (CD3OD): 176.5 (OꢁCꢀO),
141.5, 141.3, 138.5, 129.1, 128.5, 128.4, 128.0, 126.6,
4.6.2. General hydrolysis procedure
Compounds 16, 17, or 18 (0.23 mmol) was dissolved
in anhydrous THF (3 ml) and the solution was cooled
to 0 °C. LiOH (0.69 mmol) in water (1 ml) was added.
The mixture was stirred at r.t. for 2 h, acidified with 3
N HCl to pH 1–3, and extracted with EtOAc. The
combined organic layers were concentrated, and the
residue was subjected to separation on HPLC.
1
126.2, 41.7, 39.6, 39.4, 31.7 (d, J=90 Hz, PCCCO),
29.8 (d, 1J=91 Hz, PCCPh), 27.7; 31P-NMR (CD3OD):
52.6; Analytical HPLC tR=14.09 min. Anal. Calc. for
C18H21O4P·0.4H2O: C, 63.68; H, 6.42. Found: C, 63.62;
H, 6.31%.
22R: MS (ESI): m/z 333.1 [M+1]; 1H-NMR
(CD3OD): l 7.20–7.35 (m, 10H, 2Ph), 3.08 (m, 1H,
CHCO), 2.70–2.90 (m, 2H, PhCH2), 2.12–2.28 (m, 2H,
PCCH2Ph), 1.95–2.06 (m, 2H, PCH2CCO), 1.81 (m,
2H, PCH2CPh); 13C-NMR (CD3OD): 176.4 (OꢁCꢀO),
141.5, 141.3, 138.5, 129.1, 128.5, 128.4, 128.0, 126.6,
20S: MS (ESI): m/z 390.1 [M+1]; 1H-NMR
(CD3OD): l 7.19–7.34 (m, 10H, 10Ph), 4.48 (m, 1H,
PCHN), 3.20–3.26 (m, 1H, CHCO), 2.73–3.15 (m, 4H,
2PhCH2), 1.80–2.20 (m, 2H, PCH2CCO), 1.79 (ss, 3H,
CH3); 13C-NMR (CD3OD): 176.5 (OꢁCꢀO), 171.7
(CH3CO), 138.6, 137.6, 129.2, 128.9, 128.3, 128.2,
1
126.2, 41.7, 39.7, 39.6, 31.3 (d, J=90 Hz, PCCCO),
29.8 (d, 1J=91 Hz, PCCPh), 27.7; 31P-NMR (CD3OD):
52.7; Analytical HPLC tR=14.07 min. Anal. Calc. for
C18H21O4P·0.4H2O: C, 63.68; H, 6.42. Found: C, 63.54;
H, 6.25%.
1
127.8, 126.9, 126.5, 50.4 (d, J=104 Hz, PCN), 41.0,
39.0, 33.0, 27.6 (d, 1J=90 Hz, PCCCO), 21.1; 31P-
NMR (CD3OD): 49.1, 48.9; Analytical HPLC tR=
11.87 min. Anal. Calc. for C20H24NO5P·CH3COOH: C,
52.48; H, 4.97; N, 2.78. Found: C, 52.75; H, 5.23; N,
2.97%.
Acknowledgements
20R: MS (ESI): m/z 390.2 [M+1]; 1H-NMR
(CD3OD): l 7.15–7.38 (m, 10H, 10Ph), 4.48 (m, 1H,
PCHN), 3.20–3.26 (m, 1H, CHCO), 2.74–3.15 (m, 4H,
2PhCH2), 1.84–2.26 (m, 2H, PCH2CCO), 1.79 (ss, 3H,
CH3); 13C-NMR (CD3OD): 176.4 (OꢁCꢀO), 171.5
(CH3CO), 138.6, 137.6, 129.1, 129.0, 128.4, 128.2,
We thank Drs Andrew S. Kende and Hanqing Dong
for chemistry discussions over the course of this work.
We also thank Fred C. Wireko and Mike R. Mootz for
their work on the crystallography of 17a.
1
127.8, 126.6, 126.5, 50.4 (d, J=104 Hz, PCN), 41.4,
39.6, 33.0, 28.0 (d, 1J=90 Hz, PCCCO), 21.1; 31P-
NMR (CD3OD): 49.2, 48.9; Analytical HPLC tR=
11.93 min. Anal. Calc. for C20H24NO5P·CH3COOH: C,
52.48; H, 4.97; N, 2.78. Found: C, 52.94; H, 5.06; N,
3.14%.
References
[1] D. Obrecht, M. Altorfer, J.A. Robinson, Adv. Med. Chem. 4
(1999) 1.
[2] F.A. Etzkorn, J.M. Travins, S.A. Hart, Adv. Amino Acid
Mimetics Peptdomimetics 2 (1999) 125.
21S: MS (ESI): m/z 355.2 [M+1]; 1H-NMR
(CD3OD): l 7.00–8.40 (m, 12H, Naph+Ph), 3.02 (m,
1H, CHCO), 2.90 (m, 2H, PhCH2), 2.04–2.54 (m, 2H,
PCH2); 13C-NMR (CD3OD): 175.1 (OꢁCꢀO), 138.3,
135.6, 133.6, 129.0, 128.9, 128.3, 127.8, 126.9, 126.5,
41.7, 39.4, 31.7 (d, 1J=104 Hz, PCC); 31P-NMR
(CD3OD): 40.6; Analytical HPLC tR=13.73 min. Anal.
Calc. for C20H19O4P·2H2O: C, 61.53; H, 5.89. Found:
C, 61.41; H, 6.09%.
[3] (a) V. Dive, J. Cotton, A. Yiotakis, A. Michaud, S. Vassiliou, J.
Jiracek, G. Vazeaux, M.-T. Chauvet, P. Cuniasse, P. Corvol,
Proc. Natl. Acad. Sci. USA 96 (1999) 4330;
(b) H. Chen, F. Noble, P. Coric, M.C. Fournie-Zaluski, B.P.
Roques, Proc. Natl. Acad. Sci. USA 95 (1998) 12028.
[4] (a) D. Georgiadis, G. Vazeux, C. Llorens-Corts, A. Yiotakis, V.
Dive, Biochemistry 39 (2000) 1152;
(b) J. Jiracek, A. Yiotakis, B. Vincent, F. Checler, V. Dive, J.
Biol. Chem. 271 (1996) 19606.
[5] P.B. Morgan, J.M. Scholz, M.D. Ballinger, I.D. Zipkin, P.A.
Bartlett, J. Am. Chem. Soc. 113 (1991) 297.

222
X. Liu et al. / Journal of Organometallic Chemistry 646 (2002) 212–222
[6] E.A. Boyd, M. Corless, K. James, A.C. Regan, Tetrahedron
Lett. 31 (1990) 2933.
A.I. Albanov, B.A. Trofimov, J. Gen. Chem. USSR (Engl.
Transl.) 66 (1996) 54.
[7] A. Yiotakis, S. Vassiliou, J. Jiracek, V. Dive, J. Org. Chem. 61
(1996) 6601.
[8] M. Matziari, D. Georgiadis, D. Vincent, A. Yiotakis, Org. Lett.
3 (2001) 659.
[15] X.E. Hu, Ph.D. dissertation, Florida State University, 1992.
[16] M.J. Gallagher, J. Sussman, Phosphorus 5 (1975) 91.
[17] Hashimoto Norio, Aoyama Toyohiro, Shioiri Takayuki, Chem.
Pharm. Bull. 29 (1981) 1475.
[9] H. Chen, F. Noble, A. Mothe, H. Meudal, P. Coric, S. Danasci-
mento, B.P. Roques, P. George, M.C. Fournie-Zaluski, J. Med.
Chem. 43 (2000) 1398.
[10] (a) N. Chen, W.L. Renz, R.K. Pinschmidt Jr., US patent (1995)
5463110;
[18] T.R. Burke, D.G. Liu, Y. Gao, J. Org. Chem. 65 (2000)
6288.
[19] D.A. Evans, Aldrichim. Acta 15 (1982) 23.
[20] M.P. Sibi, P.K. Deshpande, J. Ji, Tetrahedron Lett. 36 (1995)
8965.
(b) H.J. Cristau, A. Coulombeau, A. Genevois-Borella, J.L.
Pirat, Tetrahedron Lett. 42 (2001) 4491.
[11] E.K. Baylis, C.D. Campbell, J.G. Dingwall, J. Chem. Soc.
Perkin Trans. 1 (1984) 2845.
[12] S.J. Fitch, J. Am. Chem. Soc. 86 (1964) 61.
[13] J.L. Montchamp, Y.R. Dumond, J. Am. Chem. Soc. 123 (2001)
510.
[21] Calculations were performed using the SPARTAN package from
Wavefunction, Inc. The geometry was initially optimized with
molecular mechanics calculations MMFF94, J. Comp. Chem.
(17) 1996, 490–461. The MMFF94 calculations were followed by
AM1 geometry optimization.
[22] D.A. Evans, K.M. Hurst, J.M. Takacs, J. Am. Chem. Soc. 100
(1977) 3467.
[14] S.N. Arbuzova, N.K. Gusarova, S.F. Malysheva, L. Brandsma,
[23] H. Schmidt, Chem. Ber. 81 (1948) 477.