Reversal diastereoselectivity in the benzylation of phosphonopropanoamides

Article abstract of DOI:10.1080/10426507.2010.522638

A convenient and efficient preparation of phosphonopropanoamides bearing (S)-1-(1'- naphthyl)ethylamine, (S)-3,3-dimethyl-2-butylamine, and (S)-2-amine-3-methylbutane in good yield has been achieved. The stereochemical outcome of the asymmetric benzylatio

Full text of DOI:10.1080/10426507.2010.522638

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Reversal Diastereoselectivity in the
Benzylation of Phosphonopropanoamides
Javier Cervantes-González a , Selene Lagunas-Rivera a & Mario
Ordóñez a
a Centro de Investigaciones Químicas , Universidad Autónoma del
Estado de Morelos , Cuernavaca , Mor. , México
Published online: 25 Apr 2011.
To cite this article: Javier Cervantes-González , Selene Lagunas-Rivera & Mario Ordóñez (2011)
Reversal Diastereoselectivity in the Benzylation of Phosphonopropanoamides, Phosphorus, Sulfur, and
Silicon and the Related Elements, 186:4, 707-711, DOI: 10.1080/10426507.2010.522638
To link to this article: http://dx.doi.org/10.1080/10426507.2010.522638
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Phosphorus, Sulfur, and Silicon, 186:707–711, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.522638
REVERSAL DIASTEREOSELECTIVITY IN THE
BENZYLATION OF PHOSPHONOPROPANOAMIDES
Javier Cervantes-Gonza´lez, Selene Lagunas-Rivera,
and Mario Ordo´n˜ez
Centro de Investigaciones Qu´ımicas, Universidad Auto´noma del Estado
de Morelos, Cuernavaca, Mor., Me´xico
A convenient and efficient preparation of phosphonopropanoamides bearing (S)-1-(1ꢁ-
naphthyl)ethylamine, (S)-3,3-dimethyl-2-butylamine, and (S)-2-amine-3-methylbutane in
good yield has been achieved. The stereochemical outcome of the asymmetric benzylation
reaction of their enolates changes dramatically with the LDA equivalents used. The enolization
of the phosphopropanoamides with LDA (2 equiv.) followed by the reaction with benzyl bromide
gives rise to the (R,S) quaternary phosphonoamides, whereas the (S,S) diastereoisomer can
be obtained by enolization with LDA (≥2.5 equiv.) followed by the addition of benzyl bromide.
This method provides access to both diastereoisomers changing only the base equivalents.
Keywords Aminophosphonates; diastereoselective benzylation; phosphonoamides; quaternary
stereocenter; reversal diastereoselectivity
INTRODUCTION
Optically active α-aminophosphonic acids are analogues of α-amino acids in which
the planar carboxylic acid group (CO2H) is replaced by a sterically more demanding
tetrahedral phosphonic acid group (PO3H2). This class of compounds is currently at-
tracting interest in the organic and medicinal chemistry, as well as in agriculture, due to
their important biological and pharmacological properties.1 Due to the tetrahedral config-
uration at phosphorus, α-aminophosphonic acids act as stable analogues of the unstable
tetrahedral–carbon transition-state in peptide hydrolysis, and therefore act as enzyme in-
hibitors.2 Many natural and synthetic α-aminophosphonic acids, α-aminophosphonates,
and phosphonopeptides have potential applications, e.g., as anti-HIV,3 antibacterial,4 an-
tibiotic,5 anticancer,6 antitumor,7 and antiviral agents.8 Furthermore, in agrochemistry, a
number of α-aminophosphonic acids and derivatives are used as fungicidal9 and herbicidal
agents.10
The utility of the α-aminophosphonic acids and their peptidic derivatives as biolog-
ical tools and chemical applications has stimulated during the last 35 years the need for
Received 20 August 2010; accepted 3 September 2010.
This work was carried out with the financial support of CONACYT-MEXICO (Project 62271), and (in part)
by CONACYT-MEXICO-INDIA (Bilateral Project J110.501/2006).
Address correspondence to Mario Ordo´n˜ez, Centro de Investigaciones Qu´ımicas, Universidad Auto´noma
del Estado de Morelos, Av. Universidad 1001, 62209 Cuernavaca, Mor., Me´xico. E-mail: palacios@ciq.uaem.mx
707

´
J. CERVANTES-GONZALEZ ET AL.
708
chemists to develop new methodologies for their synthesis, in racemic or enantiomeri-
cally pure form.11 In this context, several protocols for efficient asymmetric synthesis of
α-aminophosphonic acids and derivatives have emerged in recent years, especially taking
into account that biological activity of these depends on the absolute configuration of the
stereogenic α-carbon to the phosphorus atom.12 All these procedures can be classified into
(1) enantio- and diastereoselective hydrophosphonylation of imines (Pudovik reaction);
(2) the classical Kabachnik–Fields reaction, an enantio- and diastereoselective three com-
ponent reaction (aldehyde, amine, and dialkyl phosphite); (3) diastereoselective alkylation
of phosphoglycinates derivatives, (4) diastereoselective amination of phosphonates; (5) chi-
ral pool processes; (6) catalytic asymmetric hydrogenation of dehydroaminophosphonates;
(7) resolution process; and (8) by convergent synthetic strategy.13 However, the method-
ologies described above generally are not useful for the synthesis of quaternary α-
aminophosphonic acids.
With the purpose of establishing a methodology for the synthesis of quaternary α-
and β-aminophosphonic acids with a high stereoselectivity derived from the same source of
chirality, recently we carried out the benzylation of the phosphonopropanoamide 3a bearing
(S)-α-methylbenzylamine as an chiral auxiliary, and found reversal diastereoselectivity
by changing only the lithium bases equivalents (such as LDA, LiHMDS, LTMP, and n-
BuLi), whereas when using NaHMDS and KHMDS, reversal diastereoselectivity was not
observed.14 In this article, we report the results of the synthesis and diastereoselective
benzylation of the phosphonopropanoamides 3b–d bearing (S)-1-(1ꢁ-naphthyl)ethylamine,
(S)-3,3-dimethyl-2-butylamine, and (S)-2-amine-3-methylbutane as chiral auxiliaries.
RESULTS AND DISCUSSION
The starting phosphonopropanoamides 3a–d used in this study were easily prepared
in good yield from 2-bromopropionyl bromide employing the protocol developed in our
laboratory.15 Thus, the treatment of commercially available 2-bromopropionyl bromide
with the chiral (S)-amines 1b–d in the presence of K2CO3 at room temperature gave the
diastereoisomeric mixture of α-bromopropanoamides 2b–d in excellent yield,16 which by
reaction with trimethyl phosphite at 140◦C afforded the phosphonopropanoamides 3b–d in
good yields (Scheme 1).16 The reaction of diastereoisomerically pure 2a–d with trimethyl
phosphite at 140◦C provided the phosphonopropanoamides 3a–d with 50:50 diastereoiso-
meric ratio (dr), which can be explained by enolization of the α-carbon to the phosphorus
atom. Similar results were obtained at 100–130◦C, but under these conditions the reaction
not was complete.
O
Me
Me
O
O
Me
O
(MeO)3P
140 o
K2CO3
Br
(MeO)2P
Br
N
H
N
H
R
R
H2N
+
R
C
Br
CH2Cl2/H2O
Me
Me
Me
1a; R = Ph
2a; R = Ph, 96%
3a; R = Ph, 81%
1b;R = 1-Naphthyl
1c; R = i-Pr
2b; R = 1-Naphthyl, 98%
2c; R = i-Pr, 82%
3b; R = 1-Naphthyl, 72%
3c; R = i-Pr, 69%
1d; R = t-Bu
2d; R = t-Bu, 95%
3d; R = t-Bu, 75%
Scheme 1

BENZYLATION OF PHOSPHONOPROPANOAMIDES
709
Table 1 Benzylation of phosphonopropanoamides 3a–d
O
O
O
Me
O
Me
Me
O
O
1. LDA
(MeO)2P
+
(MeO)2P
(MeO)2P
THF, –78 oC
2. BnBr
N
H
R
N
H
N
H
R
R
Bn
Me
Me
Bn
Me
3a-d
(R,S)-4a-d
(S,S)-5a-d
Entry
R
LDA (equiv.)
Yield (%)
(R,S)-4: (S,S)-5a
1
2
3
4
5
6
7
8
Ph
Ph
1-Naphtyl
1-Naphtyl
i-Pr
i-Pr
t-Bu
t-Bu
2.0
2.5
2.0
2.5
2.0
2.5
2.0
2.5
77
83
73
77
71
79
73
75
90:10b
20:80b
91:9
31:69
75:25
40:60
89:11
18:82
a(R,S)-4:(S,S)-5 ratio was determined by 31P NMR at 81 MHz in the crude product.
bThese results were described in Ref. 13b.
In accordance with our preliminary investigations,14 the benzylation reaction of phos-
phonopropanoamides 3b–d was carried out using freshly prepared LDA (2.0 and 2.5 equiv.)
in dry THF at −78◦C. The results are summarized in Table 1.
With the phosphonopropanoamides 3b–d in hand, the compound 3b was treated with
freshly prepared LDA (2.0 equiv.) in dry THF at −78◦C followed by the addition of benzyl
bromide (1.0 equiv), obtaining the quaternary α,α-disubstituted phosphonoamides (R,S)-4b
and (S,S)-5b in 73% yield and 91:9 dr, with a predominance of (R,S)-4b diastereoisomer
(Table 1, entry 3). However, when 3b was treated with LDA (2.5 equiv.) at −78◦C followed
by the addition of benzyl bromide, the reaction afforded the phosphonoamides (R,S)-4b and
(S,S)-5b in 77% yield and 31:69 dr, with a predominance of (S,S)-5b diastereoisomer (Table
1, entry 4). These results revealed that the benzylation step is quite sensitive to LDA equiv-
alents used in the enolization. Initially, we anticipated that the diastereoselectivity could be
increased as the size of the aryl group increased from phenyl to 1-naphthyl in the phospho-
propanoamides 3a and 3b, respectively; however, experimentally the diastereoselectivity
was similar in both cases (Table 1, entries 1–4).17
These results are explained assuming that the enolates 6a,b derived by deprotonation
of 3a and 3b with LDA (2.0 equiv.) adopt the same conformation, which is in accordance
with the precedent in the literature and is favored by the coordination C C O Li O P,18
and where the orientation of the C H bond in the methylbenzyl or methyl-1-naphthyl chiral
fragments towards the oxygen atom. Therefore, the relative size of these groups determines
the preferred direction of benzyl bromide addition. In this arrangement, effectively the
phenyl and 1-naphthyl groups block the re face of the enolates 6a,b towards the benzylation,
and the addition of benzyl bromide would occur from the same face of the methyl group
(si face), providing the (R,S)-4a and (R,S)-4b diastereoisomers, respectively, as principal
product. On the other hand, the addition of LDA 0.5 to 2.0 equivalents more to 6a,b gave the
enolates 7a,b, where we propose that one additional molecule of LDA is coordinated with
C C O and N Li fragments, and the orientation of the C H bond in the methylbenzyl
or methyl-1-naphthyl chiral fragments is directed towards C C bond in the enolates 7a,b,
and the phenyl and 1-naphthyl groups now blocks the si face of enolates 7a,b; the addition

´
710
J. CERVANTES-GONZALEZ ET AL.
Li
O
Me
O
O
H
O
(MeO)2P
si
(MeO)2P
N
H
N
Li
Me
Bn
Me
Me
BnBr
(R,S)-4a,b; major
Z-enolates 6a,b
LDA
(0.5-2.0 eq)
BnBr
Li
N
Li
O
Me
O
N
Li
O
O
H
(MeO)2P
(MeO)2P
N
H
re
Me
Bn
Me
Me
(S,S)-5a,b; major
Z-enolates 7a,b
Figure 1 Mechanism proposed for the benzylation of 3a and 3b.
of benzyl bromide occurs by the re face, giving the (S,S)-5a and (S,S)-5b diastereoisomers,
respectively, as major product (Figure 1).
Having established a highly efficient procedure for the benzylation of the phosphono-
propanoamides 3a,b bearing (S)-α-methylbenzylamine and (S)-1-(1ꢁ-naphthyl)ethylamine
with reversal diastereoselectivity, we turned our attention to the benzylation of the phospho-
noamides 3c,d bearing (S)-3,3-dimethyl-2-butylamine and (S)-2-amine-3-methylbutane as
a chiral auxiliaries, and found that the benzylated phosphonoamides (R,S)-4c,d were ob-
tained as principal diastereoisomers 75:25 and 89:11 dr, respectively (Table 1, entries 5 and
7), when LDA (2.0 equiv.) were used in the enolization, whereas when using LDA (≥2.5
equiv), the (S,S)-5c,d diastereoisomers were obtained as major product (Table 1, entries 6
and 8).
CONCLUSION
Reversal diastereoselectivity in the benzylation of the phosphopropanoamides 3a–d
is strongly dependent of LDA equivalents used in the enolization, which can be attributed to
effects of the aggregation states of the enolates. This methodology provides access to both
diastereoisomers from the same source of chirality, changing only the LDA equivalents.
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