Asymmetric alkylation of dimethoxyphosphoryl-N-[1-(S)-α-methyl- benzyl]acetamide enolates. Synthesis of both stereoisomers from the same source of chirality by changing the equivalents of LDA

Article abstract of DOI:10.1039/b416616g

A new methodology has been developed for the synthesis of both stereoisomers from a single chiral source. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b416616g

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Asymmetric alkylation of dimethoxyphosphoryl-N-[1-(S)-a-methyl-
benzyl]acetamide enolates. Synthesis of both stereoisomers from the
same source of chirality by changing the equivalents of LDA{
Mario Ordo´n˜ez,*a Eugenio Herna´ndez-Ferna´ndez,a Janet Xahuentitlaa and Carlos Cativielab
Received (in Corvallis, OR, USA) 2nd November 2004, Accepted 1st December 2004
First published as an Advance Article on the web 19th January 2005
DOI: 10.1039/b416616g
principal product; similar results were obtained when LDA (1.5–
2.0 equiv.) was used.
A new methodology has been developed for the synthesis of
both stereoisomers from a single chiral source.
In view of the unsatisfactory results for the mono-methylation
reaction of (S)-2, we decided to carried out the deprotonation with
another base. Thus, the alkylation of (S)-2 with methyl iodide
using lithium bis(trimethylsilyl)amide (2.1 equiv.) as base at 278 uC
in THF, affords exclusively the monomethylated product 3 in
good yield and with a diastereoselectivity 47 : 53 (Scheme 1).
In order to induce the construction of quaternary carbon
centers, we carried out the introduction of the second alkyl group
employing the lithium enolate generated by treatment of 3 with
different equivalents of LDA.
Development of stereoselective reactions is one of the most
important topics in modern synthetic chemistry, where the
synthesis of both stereoisomers of a chiral compound is a very
important topic in asymmetric synthesis. To attain this goal,
traditional methods require the use of both chiral auxiliaries to
obtain the stereoisomers with opposite configurations. However,
due to the lack of its naturally occurring counterpart or equivalent
of some chiral auxiliaries, this process is not
a general
methodology. For this reason, the synthesis of either of the two
possible stereoisomers in high optical purity derived from the same
source of chirality is an attractive tool.
The results collected in Table 1 show that the enolization of 3
with freshly prepared lithium diisopropylamide (2.0 equiv., 278 uC
for 1 h) in THF, followed by the addition of benzyl bromide
(1.1 equiv., 278 uC for 1 h), afforded the a,a-disubstituted
b-phosphonoamides (R,S)-4 and (S,S)-5 in good chemical yield
and with a diastereoselectivity (90 : 10) with a predominance of
diastereomer (R,S)-4 as a colorless oil (entry 3). On the other hand,
when the enolate of the amide 3 was generated with freshly
prepared lithium diisopropylamide (2.5 equiv., 278 uC for 1 h),
followed by the addition of benzyl bromide, also led to the
a,a-disubstituted b-phosphonoamides (R,S)-4 and (S,S)-5 in good
chemical yield and with a moderate diastereoselectivity (20 : 80),
but now with a predominance of diastereomer (S,S)-5, as a
crystalline solid (entry 6). Identicals results were obtained with 3
and 4 equiv. of LDA (entries 8, 10). Additionally, the addition of
lithium chloride (3 or 6 equiv.) to the reaction did not improve the
diastereoselectivity, entries 4 and 7.
To the best of our knowledge, only a few synthetic approaches
have been used to obtain both individual stereoisomers via
alkylation of enolates with high optical purity from a single chiral
source. The strategies involve the systematic examination of
base,1,2 electrophiles3 and addition of additives,2,4 but there is no
report for the preparation of the two possible stereoisomers using
the same chiral auxiliary by changing the equivalents of base.
On the other hand, the efficient synthesis of optically pure
a-aminophosphonic acids is one of the most important topics in
organic chemistry.5 Although various chiral a-aminophosphonic
acids have been prepared with high enantiomeric excess by
stoichiometric or catalytic asymmetric reaction, only a few
examples of stereoselective synthesis of a-aminophosphonic acids,
bearing a quaternary chiral a-carbon atom, have been, to the best
of our knowledge, reported.6
As part of our program to obtain aminophosphonic acids,7
herein we wish to report the synthesis of both quaternary
diastereomers (R,S)-4 and (S,S)-5 in good diastereoselectivity
from b-phosphonoamide 3 bearing (S)-a-methylbenzylamine as
single inductor of the chirality,8 where the stereochemistry was
strongly influenced by the number of equivalents of LDA used.
The starting b-phosphonoamide 3 was synthesized in two steps
from amide 1. Thus the Arbuzov reaction9 of trimethylphosphite
with the amide (S)-1 at 100 uC affords the dimethoxyphosphoryl-
N-[(S)-a-methylbenzyl]acetamide [(S)-2] in quantitative yield.
Enolization of (S)-2 with lithium diisopropylamide (2.1 equiv.,
278 uC for 1 h) in THF, followed by the addition of methyl iodide
(excess, 278 uC for 1 h), led to the a,a-dimethylated compound as
1
The diastereomeric excesses were determined by means of H
and 31P NMR. In fact, the signals in 31P NMR for diastereomer
{ Electronic supplementary information (ESI) available: Experimental.
See http://www.rsc.org/suppdata/cc/b4/b416616g/
*palacios@buzon.uaem.mx
Scheme 1
1336 | Chem. Commun., 2005, 1336–1338
This journal is ß The Royal Society of Chemistry 2005

View Article Online
analysis of diastereomerically pure (S,S)-5.{ Although the absolute
configuration of the liquid product was not experimentally
confirmed, it is postulated to be (R) on the quaternary carbon
center.
Table 1 Benzylation of 3 with different LDA equivalents
To explain the strong influence of the number of equivalents of
LDA on the inverse diasteroselectivity in the alkylation process of
3, a model including a chelating intermediated has been proposed
(Scheme 2).
LDA
(equiv.)
LiCl
(equiv.)
Yieldb
(%)
(R,S)-4 :
(R,S)-5c
Entry
Timea
When the phosphonoamide 3 is treated with LDA (2.0 equiv.),
the enolate geometry may be Z, in accordance with the literature
precedence and favored by the coordination C–O–Li–OLP.10 The
orientation of the C–H bond of the chiral auxiliary towards the
oxygen atom and the relative size of phenyl and methyl groups
determines the preferred direction of benzyl bromide addition,11 in
this case for the re face, which leads to (R,S)-4 diastereomer
as principal product. Additionally, the reaction appears to be
operating under kinetic control, since no evidence of reversibility
was observed and the diastereoselectivity was independent of
reaction time (Table 1, entry 5). On the other hand, when 3 was
treated with LDA (¢2.5 equiv.) we propose that now the E
enolate is favored by the coordination with one lithium
diisopropylamide molecule,12 where newly the C–H bond of the
chiral auxiliary is oriented towards the oxygen atom, so the relative
size of phenyl and methyl groups determines the preferred
direction of benzyl bromide addition, in this case for the si face,
1
2
3
4
5
6
7
8
9
10
a
1.0
1.5
2.0
2.0
2.0
2.5
2.5
3.0
3.0
4.0
60 min
60 min
60 min
60 min
5 min
60 min
60 min
60 min
5 min
—
—
—
3 or 6
—
—
3 or 6
—
—
d
d
88 : 12
88 : 12
90 : 10
90 : 10
86 : 14
20 : 80
21 : 79
20 : 80
83 : 17
20 : 80
77
60
60
83
80
77
63
78
60 min
—
b
Time for the enolate generation. Chemical yield after purification
by column chromatography. Determined by 1H NMR at 400 MHz
c
and 31P NMR at 200 MHz in the crude reaction. The reaction was
not completed.
d
(S,S)-5 were more shielded (33.37 ppm) than those for the
diastereomer (R,S)-4 (33.59). The absolute configuration of the
quaternary carbon center was given by single-crystal X-ray
Scheme 2
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 1336–1338 | 1337

View Article Online
concentrated in vacuum. The crude product was analyzed by 1H NMR at
400 MHz and 31P NMR at 200 MHz. The diastereomeric mixture was
cleanly separated by column chromathography.
yielding the (S,S)-5 diastereomer as principal product. In this case
the reaction appears to be operating under thermodynamic
control, since the diasteroselectivity is dependent of reaction time
(Table 1, entry 9).
1 R. K. Boeckman, Jr., D. J. Boehmler and R. A. Musselman, Org. Lett.,
2001, 3, 3777.
2 C. Alvarez-Ibarra, A. G. Csaky, R. Maroto and M. L. Quiroga, J. Org.
Chem., 1995, 60, 7934.
3 A. G. Myers and L. McKinstry, J. Org. Chem., 1996, 61, 2428.
4 J. H. Smitrovich, L. DiMichele, C. Qu, G. N. Boice, T. D. Nelson,
M. A. Huffman and J. Murry, J. Org. Chem., 2004, 69, 1903; K. Ando,
Y. Takemasa, K. Tomioka and K. Koga, Tetrahedron, 1993, 49, 1579
and references cited therein.
5 Aminophosphonic and Aminophosphinic Acids: Chemistry and Biological
Activity, ed. V. P. Kukhar and H. R. Hudson, John Wiley, New York,
2000, and references cited therein.
6 F. A. Davis, S. Lee, H. Yan and D. D. Titus, Org. Lett., 2001, 3, 1757;
R. Kuwano, R. Nishio and Y. Ito, Org. Lett., 1999, 1, 837.
7 M. Ordo´n˜ez, A. Gonza´lez-Morales, C. Ruiz, R. De la Cruz-Cordero
and M. Ferna´ndez-Zertuche, Tetrahedron: Asymmetry, 2003, 14, 1775;
M. Ordo´n˜ez, A. Gonza´lez-Morales and H. Salazar-Ferna´ndez,
Tetrahedron: Asymmetry, 2004, 15, 2719.
8 Alkylation of amides bearing (S)-a-methylbenzylamine has been
reported by V. M. Gutie´rrez-Garc´ıa, H. Lo´pez-Ru´ız, G. Reyes-Rangel
and E. Juaristi, Tetrahedron, 2001, 57, 6487.
In practical terms, the chemistry described herein provides
useful methodology for the preparation of both diastereomers of
a,a-disubstituted b-phosphonoamides using the same source of
chirality, changing the equivalents of LDA. In addition, the
b-phosphonoamides (R,S)-4 and (S,S)-5 are of great interest due
to the central role of these compounds in the stereoselective
synthesis of several classes of valuable compounds, including
a- and b-aminophosphonic acids5 bearing a quaternary chiral
a-carbon atom, b-hydroxy-a-aminophosphonic acids13 and as
potential chiral ligands.14§
We wish to thank CONACYT Mexico, for financial support
via grant 41657-Q, and Dr Jose´ Luis Garc´ıa Ruano for many
friendly discussions. Also we thank M. A. Mun˜oz-Herna´ndez for
his valuable technical help for the acquisition of the X-ray
structures.
Mario Ordo´n˜ez,*a Eugenio Herna´ndez-Ferna´ndez,a Janet Xahuentitlaa
and Carlos Cativielab
9 B. A. Arbuzov, Pure Appl. Chem., 1964, 9, 307.
10 C. P. Schickli and D. Seebach, Liebigs. Ann. Chem., 1991, 655; S. Y. Lee,
C.-W. Lee and D. Y. Oh, J. Org. Chem., 1999, 64, 7017.
11 U. Scho¨llkopf, H.-H. Hausberg, M. Segal, U. Reiter, I. Hoppe,
W. Saenger and K. Lindner, Liebigs Ann. Chem., 1981, 439;
U. Scho¨llkopf, H. H. Hausberg, I. Hoppe, M. Segal and U. Reiter,
Angew. Chem., Int. Ed. Engl., 1978, 17, 117.
12 S. Liao and D. B. Collum, J. Am. Chem. Soc., 2003, 125, 15114;
Y.-J. Kim and A. Streitwieser, Org. Lett., 2002, 4, 573; X. Sun and
D. B. Collum, J. Am. Chem. Soc., 2000, 122, 2459.
aCentro de Investigaciones Qu´ımicas, Universidad Auto´noma del Estado
de Morelos, Av. Universidad 1001, 62210 Cuernavaca, Mor., Mexico.
E-mail: palacios@buzon.uaem.mx; Fax: 527773297997;
Tel: 527773297997
bDepartment of Organic Chemistry, ICMA, Universidad de
Zaragoza-CSIC, 50009 Zaragoza, Spain. Fax: 34976761210;
Tel: 34976761210
13 M. Drag, R. Latajka, E. Gumienna´-Kontecka, H. Kozlowski and
P. Kafarski, Tetrahedron: Asymmetry, 2003, 14, 1837; A. E. Wro´blewski
and D. G. Piotrowska, Tetrahedron: Asymmetry, 2002, 13, 2509;
T. Yamagishi, K. Suemune, T. Yokomatsu and S. Shibuya, Tetrahedron
Lett., 2001, 42, 5033; F. Hammerschmidt, W. Lindner, F. Wuggenig
and E. Zarbl, Tetrahedron: Asymmetry, 2000, 11, 2955.
14 M. S. Rahman, M. Oliana and K. K. Hii, Tetrahedron: Asymmetry,
2004, 15, 1835; A. M. Maj, K. M. Pietrusiewics, I. Suisse, F. Agbossou
and A. Mortreux, J. Organomet. Chem., 2001, 626, 157; A. M. Maj,
K. M. Pietrusiewicz, I. Suisse, F. Agbossou and A. Mortreux,
Tetrahedron: Asymmetry, 1999, 10, 831.
Notes and references
{ CCDC 258161. See http://www.rsc.org/suppdata/cc/b4/b416616g/ for
crystallographic data in .cif or other electronic format.
§ Typical experimental procedure for the second alkylation of 3. To a
solution of the b-phosphonoamide 3 (1 mmol) in dry THF at 278u was
added dropwise 2.0 or 2.5 equivalents of freshly preparated LDA from
freshly titrated n-buthyllithium15 and freshly distilled diisopropylamine in
dry THF. The resulting solution was stirred for 1 h at 278u. The benzyl
bromide (1.1 equiv.) was added with continuous stirring, and the mixture
reaction was stirred at 278u for 3–4 h and quenched with saturated
aqueous NH4Cl solution. The product was extracted with ethyl acetate, the
combined organic extracts were dried over anhydrous Na2SO4, filtered and
15 E. Juaristi, A. Mart´ınez-Richa, A. Garc´ıa-Rivera and J. S. Cruz-
Sa´nchez, J. Org. Chem., 1983, 48, 2603.
1338 | Chem. Commun., 2005, 1336–1338
This journal is ß The Royal Society of Chemistry 2005