Stereoselective Addition of Dimethyl Thiophosphite to Imines

Article abstract of DOI:10.1021/jo035707t

Dimethyl thiophosphite (DMTP) was synthesized from dimethyl phosphite, and the diastereoselective addition of DMTP to benzaldimines bearing chiral auxiliary groups was examined. Yields of the product α -aminophosphonothionates ranged from 17% to 75% after chromatography. The addition of DMTP to the benzaldimine derived from (S)-phenylglycinol afforded the highest diastereoselectivity (83:17), whereas addition of DMTP to the benzaldimine derived from threonine methyl ester and alanine methyl ester were far less diastereoselective, affording 38:62 and 61:39 ratios, respectively. Addition of DMTP to the benzaldimine derived from (R)-α-methylbenzylamine (78:22) and (S)-serine methyl ester (73:27) were intermediate in selectivity. DMTP addition to the imines formed between serine methyl ester and acetaldehyde and isobutyraldehyde gave 55:45 and 70:30 ratios, respectively, with the diastereoselectivity corresponding roughly to the size of the α-alkyl group. The stereochemistry of the newly formed α-stereocenters resulting from the addition of DMTP to (S)- and (R)-phenylglycinol benzaldimines was confirmed by conversion of the product α-aminophosphonothionates to the known enantiomers of phosphonophenylglycine.

Full text of DOI:10.1021/jo035707t

Ster eoselective Ad d ition of Dim eth yl Th iop h osp h ite to Im in es
Pakamas Tongcharoensirikul,† Alirica I. Suarez,†,‡ Troy Voelker,§ and
Charles M. Thompson*,†,§
Department of Biomedical and Pharmaceutical Sciences and Department of Chemistry, The University of
Montana, Missoula, Montana 59812, and Facultad de Farmacia, Universidad Central de Venezuela,
Caracas, Venezuela
charles.thompson@umontana.edu
Received November 20, 2003
Dimethyl thiophosphite (DMTP) was synthesized from dimethyl phosphite, and the diastereose-
lective addition of DMTP to benzaldimines bearing chiral auxiliary groups was examined. Yields
of the product R-aminophosphonothionates ranged from 17% to 75% after chromatography. The
addition of DMTP to the benzaldimine derived from (S)-phenylglycinol afforded the highest
diastereoselectivity (83:17), whereas addition of DMTP to the benzaldimine derived from threonine
methyl ester and alanine methyl ester were far less diastereoselective, affording 38:62 and 61:39
ratios, respectively. Addition of DMTP to the benzaldimine derived from (R)-R-methylbenzylamine
(78:22) and (S)-serine methyl ester (73:27) were intermediate in selectivity. DMTP addition to the
imines formed between serine methyl ester and acetaldehyde and isobutyraldehyde gave 55:45
and 70:30 ratios, respectively, with the diastereoselectivity corresponding roughly to the size of
the R-alkyl group. The stereochemistry of the newly formed R-stereocenters resulting from the
addition of DMTP to (S)- and (R)-phenylglycinol benzaldimines was confirmed by conversion of
the product R-aminophosphonothionates to the known enantiomers of phosphonophenylglycine.
In tr od u ction
(S,R)-Alafosfalin and (R)-phospholeucine are R-amino-
phosphonic acids (APAs), a class of R-amino acid isosteres
in which the carboxylic acid group has been replaced by
a phosphonic acid group (Figure 1). Like natural amino
acids, the biological activity of APAs correlates with the
stereochemistry at the R-carbon center. For example,
(S,R)-alafosfalin shows higher antibacterial activity than
any of its other diastereomers,1 and (R)-phospholeucine
is a more potent inhibitor of leucine aminopeptidase than
the S enantiomer.2,3
F IGURE 1. Structures of alafosfalin and (R)-phospholeucine.
theses of the corresponding phosphonothionate analogues
of APAs, the R-aminophosphonothioic acids (APTAs;
To incorporate the desired configuration at the R-center
of R-aminophosphonic acids, a number of approaches
have been devised.4-11 In many of these synthetic strate-
gies, the P-C bond and R-chiral center are formed by
asymmetric addition of a phosphite to an imine. The
resulting enantioenriched R-aminophosphonate is gener-
ally converted to the APA following straightforward
synthetic manipulations.
(4) Aimakov, O. A.; Erzhanov, K. B.; Mastryukova, T. A. Russ. Chem.
Bull. 1999, 48, 1792-1794.
(5) (a) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J . Org. Chem.
1995, 60, 6656-6657. (b) Schlemminger, I.; Saida, Y.; Groger, H.;
Maison, W.; Durot, N.; Sasai, H.; Shibasaki, M.; Martens, J . J . Org.
Chem. 2000, 65, 4818-4825. (c) Huber, J . W., III; Gilmore, W. F.
Tetrahedron Lett. 1979, 3049-3052. (d) Tyka, R. Tetrahedron Lett.
1970, 677-680. (e) Kowalik, J .; Kupczyk-Suboikowska, L.; Mastalerz,
P. Synth. Commun. 1981, 81, 57-58. (f) Green, D.; Patel, G.; Elgendy,
S.; Baban, J . A.; Claeson, G.; Kakkar, V. V.; Deadman, J . Tetrahedron
Lett. 1993, 34, 6917-6920. (g) Hubert, C.; Oussaid, B.; Etemad-
Moghadam, G.; Koenig, M.; Garrigues, B. Synthesis 1994, 51-55. (h)
Schmidt, U.; Krause, H. W.; Oehme, G.; Michalik, M.; Fischer, C.
Chirality 1998, 10, 564-572. (i) Groger, H.; Hammer, B. Chem. Ind.
2000, 6, 943-948. (j) Sting, M.; Steglich, W. Synthesis 1990, 132-
134. (k) Soloshonok, V. A.; Belokon, Y. N.; Kuzmina, N. A.; Maleev, V.
I.; Svistunova, N. Y.; Solodenko, V. A.; Kukhar, V. P. J . Chem. Soc.,
Perkin Trans. 1 1992, 1525-1529. (l) Sawamura, M.; Ito, Y.; Hayashi,
T. Tetrahedron Lett. 1989, 30, 2247-2250. (m) Kukhar, V. P.; So-
lodenko, V. A. Usp. Khim. 1987, 56, 1504-1532. (n) J ommi, G.;
Miglierini, G.; Pagliarin, R.; Sello, G.; Sisti, M. Tetrahedron 1992, 48,
7275-7288. (o) Hanessian, S.; Bennani, Y. L. Synthesis 1994, 1272-
1274. (p) Hanessian, S.; Bennani, Y. L. Tetrahedron Lett. 1990, 31,
6465-6468. (q) Denmark, S. E.; Chatani, N.; Pansare, S. V. Tetrahe-
dron 1992, 48, 2191-2208. (r) Denmark, S. E.; Dorow, R. L. J . Org.
Chem. 1990, 55, 5926-5928. (s) Arai, T.; Bougauchi, M.; Sasai, H.;
Shibasaki, M. J . Org. Chem. 1996, 61, 2926-2927.
Despite significant progress in the preparation of
enantioenriched APAs, there have been very few syn-
* To whom correspondence should be addressed.
† Department of Biomedical and Pharmaceutical Sciences, The
University of Montana.
‡ Universidad Central de Venezuela.
§ Department of Chemistry, The University of Montana.
(1) (a) Lejczak, B.; Kafarski, P.; Sztajer, H.; Mastalerz, P. J . Med.
Chem. 1986, 29, 2212-2217. (b) Solodenko, V. A.; Kukhar, V. P.
Tetrahedron Lett. 1989, 30, 6917-6918. (c) Polyak, M. S. Antibiot. Med.
Biotekhnol. 1987, 32, 66-75.
(2) Kafarski, P.; Lejczak, B. Can. J . Chem. 1983, 61, 2425-2430.
(3) Stamper, C.; Bennett, B.; Edwards, T.; Holz, R. C.; Ringe, D.;
Petsko, G. Biochemistry 2001, 40, 7035-7046.
10.1021/jo035707t CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/27/2004
2322
J . Org. Chem. 2004, 69, 2322-2326

Addition of Dimethyl Thiophosphite to Imines
rapidly and in high yield to a variety of electrophiles
including imines.18 Adaptation of the addition of DMTP
to imines containing chiral auxiliaries (R1) would form
the R-aminophosphonothionates (6) bearing an enan-
tioenriched R-carbon center and would allow direct access
to the desired APTAs (eq 1).
F IGURE 2. General structures of R-aminophosphonothioic
acids (1) and phosphonothioate esters (2) and their possible
thiolo tautomers.
Figure 2).4,8,12-14 Phosphonothioic acids are sulfur-
containing analogues of phosphate groups that are well-
known in nucleoside chemistry and are of value because
the thiol group imparts chemical characteristics that
differ greatly from the corresponding phosphate group,
namely, nucleophilicity, metal binding, etc.15 Such novel
properties would be useful additions to phosphorus
analogues of amino acids and peptides. Further benefits
of installing a sulfur-containing ligand at phosphorus
include the production of a tautomerically nonequivalent
acid (thiono-thiolo equilibrium; Figure 2)16 and the
capability to generate a new asymmetric center at
phosphorus (in the monoester form, 2).13,14
One straightforward approach to prepare APTAs would
be to convert the phosphoryl (PdO) of an APA into a
thiophosphoryl (PdS) by use of Lawesson’s reagent or a
related thionating agent.17 Unfortunately, this route fails
because of preferred reactivity of thionating agents at the
amino group or amine protecting group.13 Displacement
of a phosphorus ester group (P-OR) by SH- (P-SH),
which would form the asymmetric APTA monoester, also
fails owing to competing dealkylation reactions at the
phosphorus ester groups. As a result, a convergent
approach in which the PdS is directly installed in the
product is needed. As noted, dialkyl phosphites (e.g.,
dimethyl phosphite, 3) add to imines (prepared from
chiral amines) with stereocontrol to afford R-aminophos-
phonates (4).6,9a,11 In previous work from this laboratory,
dimethyl thiophosphite (5; DMTP) was found to add
In this study, reactions between DMTP and imines
that vary in a chiral auxiliary group were conducted and
the diastereoselectivity was determined. Because suitably
positioned hydroxyl groups are known to influence dias-
tereocontrol,19 we specifically studied the effect of pen-
dant heteroatom groups on the diastereoselectivity of
thiophosphite addition. The mechanism and diastereo-
facial orientation of the addition reaction could be
established by conversion of a select R-aminophospho-
nothionate diastereomer product into a single enantiomer
of an R-aminophosphonic acid having known absolute
configuration.
Resu lts a n d Discu ssion
Syn th esis of Dim eth yl Th iop h osp h ite. Although
dimethyl thiophosphite (5; DMTP) has been synthesized
previously,18,20,21 specific spectral and experimental de-
tails are lacking for characterization. Dimethyl phosphite
(3; DMP) was reacted with Lawesson’s reagent (10
equiv)17 to afford 5 in 46% yield following distillation (eq
2). DMTP shows a characteristic 31P NMR downfield shift
(δ 74.8 ppm) relative to DMP (δ 11.1 ppm) with a large
J P-H coupling constant of 652 Hz.22 Monitoring for
reaction progress and completion by 31P NMR is recom-
mended since the reaction times vary despite rigorous
control of the reaction parameters. Allowing the thion-
ation reaction to proceed to greater than 95% completion
(disappearance of DMP) simplifies purification, although
unreacted DMP may be separated from DMTP by frac-
tional distillation.
(6) (a) Zon, J . Pol. J . Chem. 1981, 55, 643-646. (b) Dhawan, B.;
Redmore, D. Phosphorus, Sulfur Silicon Relat. Elem. 1987, 32, 119-
144. (c) Yuan, C.; Chen, S. Synthesis 1992, 1124-1128.
(7) (a) Hoffmann, M. Pol. J . Chem. 1978, 52, 851-856. (b) Imamoto,
T. Optically active phosphorus compounds; Dekker: New York, 1992.
(8) (a) Krzyzanowska, B. Z. Chem. 1988, 28, 335. (b) Kabachnik,
M. I.; Medved, T. Y.; Mastryukova, T. A. Dokl. Akad. Nauk S.S.S.R.
1953, 92, 959-962.
(9) (a) Lefebvre, I. M.; Evans, S. A., J r. J . Org. Chem. 1997, 62,
7532-7533. (b) Smith, A. B., III; Yager, K. M.; Taylor, C. M. J . Am.
Chem. Soc. 1995, 117, 10879-10888.
(10) Maury, C.; Royer, J .; Husson, H. P. Tetrahedron Lett. 1992,
33, 6127-6130.
A survey of the reaction of DMTP with electrophiles
(aldehydes, ketones, imines, and Michael acceptors) and
a brief relative rate study (3 vs 5) have been reported.18
Ad d ition of Dim eth yl Th iop h osp h ite to Im in es.
There are only a handful of investigations that have
(11) Yuan, C.; Li, S.; Wang, G.; Ma, Y. Phosphorus, Sulfur Silicon
Relat. Elem. 1993, 81, 27-35.
(12) (a) Kukhar, V. P.; Solodenko, V. A. Russ. Chem. Rev. 1987, 56,
859-874. (b) Suarez, A. I.; Lin, J .; Thompson, C. M. Tetrahedron 1996,
52, 6117-6124. (c) Krzyzanowska, B.; Stec, W. J . Heteroat. Chem. 1991,
2, 123-139.
(13) Thompson, C. M.; Lin, J . Tetrahedron Lett. 1996, 37, 8979-
8982.
(18) Trautmann, J .; Suarez, A. I.; Tongcharoensirikul, P.; Muth, G.
W.; Thompson, C. M. Phosphorus, Sulfur Silicon Relat. Elem. 2002,
177, 471-477.
(14) Mikolajczyk, M. Pure Appl. Chem. 1980, 52, 959-972.
(15) (a) Cieslak, J .; J ankowska, J .; Stawiski, J .; Kraszewski, A. J .
Org. Chem. 2000, 65, 7049-7054. (b) J ankowska, J .; Sobkowska, A.;
Cieslak, J .; Sobkowski, M.; Kraszewski, A.; Stawinski, J .; Shugar, D.
J . Org. Chem. 1998, 63, 8150-8156. (c) Zain, R.; Stawiski, J . J . Org.
Chem. 1996, 61, 6617-6622.
(16) Kabachnik, M. I.; Mastryukova, T. A.; Shipov, A. E.; Melent’eva,
T. A. Tetrahedron 1960, 9, 10-28.
(17) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061-5098.
(19) Smith, M. B. Organic Synthesis; McGraw-Hill: New York, 1994.
(20) Zabirov, N. G.; Cherkasov, R. A.; Pudovik, A. N. Zhurnal
Obshchei Khimit 1986, 56, 1189-1190.
(21) Shabana, R.; El-Kateb, A. A.; Osman, F. H. Chem. Ind. (London)
1984, 15, 553-554.
(22) Handbook of Phosphorus-31 Nuclear Magnetic Resonance Data;
Tebby, J . C., Ed.; CRC Press Inc: Boca Raton, FL, 1991.
J . Org. Chem, Vol. 69, No. 7, 2004 2323

Tongcharoensirikul et al.
SCHEME 1
TABLE 1. Ad d ition of Dim eth yl Th iop h osp h ite to Im in es Con ta in in g Ch ir a l Au xilia r y Gr ou p s (Sch em e 1)
products
chiral auxiliary
R
R1
R2
31Pa (δ)
yieldb (%)
31P ratioc [isolated ratio]d
9a /9b
(R)-phenylglycinol
Ph
Ph
Me
iPr
Ph
Ph
Ph
Ph
CH2OH
Me
Ph
100.5/98.1
98.4/97.3
102.6/101.9
102.9/101.4
97.8/97.2
97.2/96.8
100.5/98.1
101.6/98.9
75.5
17.0
32.7
15.0
62.4
33.6
63.4
63.8
75:25 [80:20]
53:47 [55:45]
55:45
30:70
73:27 [82:18]
38:62
10a /10b
11a /11b
12a /12b
13a /13b
14a /14b
17a /17b
18a /18b
(S)-L-alanine, methyl ester
(S)-L-serine, methyl ester
(S)-L-serine, methyl ester
(S)-L-serine, methyl ester
(2S,3R)-L-threonine, methyl ester
(S)-phenylglycinol
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Ph
CH2OH
CH2OH
CH2OH
CH(Me)OH
CH2OH
Me
83:17 [95:5]
76:24 [90:10]
(R)-R-methyl benzylamine
Ph
a
b
Relative to H3PO4 in CDCl3. Following column chromatography; total for both diastereomers. c 31P ratio based on integration of the
d
crude reaction mixture averaged from three trials. Isolated ratio represents the fractional purified amount of a single diastereomer.
reported the reactions of DMTP,4,18,23 and none have
investigated the formation of R-aminophosphonothion-
ates (6) containing asymmetric centers. DMTP is at least
100-fold more reactive than DMP toward electrophiles,
and importantly, DMTP does not undergo demethylation
as a side reaction to addition as does DMP. Because of
this enhanced reactivity, the diastereoselective addition
of DMTP to imines can be conducted under mild condi-
tions. Because a number of enantioenriched R-amino-
phosphonic acid analogues have been prepared by the
analogous addition of dialkyl phosphites to asymmetric
imines, the absolute configuration of a representative
R-amino phosphonothionate product can be determined
by conversion to a known APA by oxidation of the PdS
bond to PdO.
and they have the potential for examining the presence/
absence of a hydroxy directing group.
Aldimines 8 and 16 (R ) Me, iPr and Ph) were
prepared by reaction between the aldehyde and amines
in the presence of 3 Å sieves. Aldimine formation progress
was evaluated by the appearance of the aldimine proton
(δ. 8.5 ppm) of the crude reaction mixture and estimated
to be greater than 95% prior to addition of DMTP.
Imine solutions were reacted with DMTP (1 equiv) for
up to 12 h at room temperature or 0 °C. The addition of
DMTP to the asymmetric imines (Scheme 1, Table 1)
underwent reaction readily and in relatively good conver-
sion as evidenced by 31P NMR. The products were
identified by the pentavalent thionate (PdS) 31P NMR
peaks near 100 ppm (Table 1).26 Despite near-quantita-
tive conversion by 31P NMR, both liquid extraction and
direct separation on silica gel led to significant loss of
material as evidenced by the large range in isolated
yields. The crude products were typically isolated by flash
chromatography following evaporation of the solvent.
Where possible, the individual diastereomers were
isolated from chromatography and the isomer ratio was
measured (Table 1). Most mixtures were preparatively
unseparable, affording only small amounts of one [major]
diastereomer that was of adequate quantity for spectro-
scopic and elemental analyses. The observed diastere-
omer ratios are not readily comparable to the correspond-
ing reaction of dialkyl phosphites with imines because
most routes to APAs have used the sterically more
discriminating diethyl phosphite or the lithio salt.9,11
Interestingly, phenylglycinol had no additional influ-
ence on the diastereomer ratio relative to R-methylben-
zylamine, whereas the presence/absence of a hydroxy
group on the amino acids did alter the diastereoselectiv-
ity. For example, changing the auxiliary from alanine to
As this study sought to preliminarily evaluate the
influence of chiral auxiliaries (7, 15) on the stereoselec-
tive addition of DMTP to imines (Scheme 1), substituents
i
attached to the imine were varied (8, 16; R ) Me, Pr,
Ph) to identify key interactions that would furnish
favorable diastereomer ratios. Benzaldehyde was chosen
due to the ease of imine formation and the need to
correlate the product diastereomer structures to (R)- and
(S)-phosphono(phenylglycine), for which absolute con-
figurations have been established.2,7,24,25 Imines of ac-
etaldehyde and isobutyraldehyde were examined to
evaluate the role of sterics on the diastereoselectivity and
the potential for these addition reactions to afford the
R-aminophosphonic acid analogues of alanine and leu-
cine. Phenylglycinol, R-methylbenzylamine, and the meth-
yl esters of alanine, serine, threonine, and cysteine were
selected because a number of comparative studies with
these amines as chiral auxiliaries have been conducted
(23) Pudovik, A. N.; Zametaeva, G. A. U.S.S.R., Classe Sci. Chim.
1952, 825-830.
(24) Glowiak, T.; Sawka-Dobrowolska, W.; Kowalik, J .; Mastalerz,
P.; Soroka, M.; Zon, J . Tetrahedron Lett. 1977, 3965-3968.
(25) Hall, C. R.; Inch, T. D. Phosphorus, Sulfur Silicon Relat. Elem.
1979, 7, 171-184.
(26) (a) Tebby, J . C. Handbook of Phosphorus-31 Nuclear Magnetic
Resonance Data; CRC Press: Boca Raton, FL, 1991. (b) Gorenstein,
D. G. Advances in Phosphorus-31 NMR; Dekker: New York, 1992.
2324 J . Org. Chem., Vol. 69, No. 7, 2004

Addition of Dimethyl Thiophosphite to Imines
SCHEME 2 a
F IGURE 3. Proposed orientation of addition of DMTP to 9a .
and 24, respectively. Dimethyl R-aminophosphonates 21
and 24 were hydrolyzed in sealed tubes (HCl, 100 °C) to
afford the (R-amino-R-phenyl)methylphosphonic acid 22
and 25 (phosphonophenylglycine) (Scheme 2) after neu-
tralization.
20
Compound 22 showed an optical rotation of [R]D
+17.3 (92% ee), and compound 25 showed an optical
rotation of [R]D20 -16.2 (80% ee). The rotation of the (R)-
phosphonophenylglycine previously correlated with an
a
(a) H2O2, 1:1 H2O/MeOH, rt, 9 h. (b) H2/Pd(OH)2, MeOH, rt.
(c) HCl, 100 °C (sealed tube), 12 h.
20
X-ray crystal structure showed an [R]D +18.0 (c 2.0, 1
serine increased the ratio from 61:39 to 73:27. Con-
versely, the use of threonine (branching at the hydroxyl
group) led to lowered diastereoselectivity, possibly the
result of compensating steric and conformational effects.
Attempts to use cysteine methyl ester as auxiliary failed
because the reaction with benzaldehyde formed the
tetrahydrothiazole prior to imine formation.
DMTP was reacted with the imines of (R)- and (S)-
phenylglycinol to afford 9a /9b and 17a /17b. The NMR
data supported the formation of a 3:1 mixture of diaster-
eomers, however, the relative configuration of the newly
formed R-carbon (PRC) could not be directly assigned
because neither the products (9a /9b, 17a /17b) nor the
corresponding oxidized analogue (PdO) had known con-
figurations (diethyl R-aminophosphonic acids have had
absolute and/or relative configurations assigned24). There-
fore, to unambiguously assign the stereochemistry at the
PRC, synthetic routes were undertaken to convert 9a /
9b [from (R)-phenylglycinol] and 17a /17b [from (S)-
phenylglycinol] to the known phosphonophenylglycine
enantiomers 22 and 25 (Scheme 2).25
Oxidation of the thionates (PdS) to form the phospho-
nyl (PdO) was attempted with m-chloroperoxybenzoic
acid (m-CPBA), t-BuOOH, monoperoxyphthalic acid,
magnesium salt (MMPP),27 and H2O2. When 9a or 17a
was oxidized with m-CPBA or MMPP, significant decom-
position of the starting material was observed even when
the number of molar equivalents was limited. The
reaction did not occur at all when t-BuOOH was used,
indicating that 9a /17b might be more sterically hindered
than expected. Reacting 9a or 9b with a 50% H2O2 (5
mL) and CH3OH (5 mL) mixture for 9-12 h resulted in
29% yield of oxidized product 20 and 23 after chroma-
tography. The reaction was monitored by 31P NMR (δ 27.1
ppm) and stopped before completion to reduce the forma-
tion of several byproducts that have Rf values nearly
identical with those of the desired product. Phosphonates
N NaOH),24 thereby allowing the relative assignment of
the R configuration to the PRC of the major phosphono-
thionate isomer (9a ) formed from (R)-phenylglycinol, and
likewise, the S configuration for the PRC of the major
isomer (17a ) formed from (S)-phenylglycinol.
A second convergent synthesis was conducted to con-
firm that the mode of addition by DMTP was identical
to that of dimethyl phosphite (DMP). The benzaldimine
of (R)-phenylglycinol (8; R ) Ph, R1 ) Me, R2 ) Ph) was
reacted with DMP, resulting in a diastereomer pair of
R-aminophosphonate adducts. The diastereomers were
separated and the major product showed a 31P NMR
signal at δ 27.1 and [R]D20 -31.83 (CHCl3), which strongly
correlate with 20, the product obtained from the oxidation
of 9a (Scheme 2), indicating the expected identical mode
of addition by DMP and DMTP.
The preferred formation of the (R,R)-9a and (S,S)-17a
diastereomers may result from the fact that the ben-
zaldimine may predominantly adopt an E configuration
that reacts with DMTP on the face opposite to the larger
phenyl substituent (smaller CH2OH), resulting in the R
configuration at the new PRC center (Figure 3). A similar
orientation of addition could be operative for the methyl
aldimine (acetaldehyde), but the products would be less
diastereoselective. It is unknown whether the DMTP
protonates the imine prior to addition, which could shift
the configurational equilibrium.
The influence of the hydroxyl group on the diastereo-
selectivity was unclear. R-Methylbenzylamine yielded the
same diastereoselectivity as phenylglycinol. However,
serine showed an improved product ratio of 73:27 (for
13a /13b) as compared to 62:38 for threonine (14b/14a )
and 53:47 for alanine (10a /10b). The trend suggests that
the hydroxyl influences the mode the addition, but since
the alanine products 10a /10b were obtained in poor yield,
a strict comparison of these results is not possible. The
reason that the R-methylbenzylamine group gave near-
identical diastereoselectivity to phenylglycinol may be
due to the fact that the mode of addition to R-methyl-
benzaldimine closely resembles that attained by the
phenylglycinol aldimine and therefore affords similar
diastereoselectivity.
20
20 and 23 showed identical spectra with [R]D rotations
of -27.4 and +23.6, respectively.
Phosphonates 20 and 23 were hydrogenolyzed with Pd-
(OH)2/H2 to afford the dimethyl R-aminophosphonates 21
and 24 in 49% yield (Scheme 2), which led to a reversal
20
in the optical rotation to [R]D +25.7 and -24.2 for 21
In conclusion, DMTP adds to imines containing N-
chiral auxiliaries in good diastereoselectivity in certain
cases and in identical orientation to DMP. By use of
(27) J ackson, J . A.; Berkman, C. E.; Thompson, C. M. Tetrahedron
Lett. 1992, 33, 6061-6064.
J . Org. Chem, Vol. 69, No. 7, 2004 2325

Tongcharoensirikul et al.
toluene (10 mL) containing molecular sieves (3 Å, 0.5 g) was
added benzaldehyde (0.43 mL, 0.44 g, 4.19 mmol). After 3 h
at room temperature, the mixture was filtered through Celite,
dimethyl phosphite (0.38 mL, 0.46 g, 4.19 mmol) was added,
and the reaction was stirred for 48 h. The reaction mixture
was purified by chromatography (hexanes/Et2O/MeOH 4.25/
4.25/0.5) to give dimethyl phosphonate 20 (0.79 g, 2.34 mmol,
readily available, optically active amines, R-aminophospho-
nothionates may be prepared in good yield and high
stereoselectivity. With these findings, the synthesis of
APTAs containing a P-chiral group will be possible.
Exp er im en ta l Section
56%) as a yellowish oil: [R]25 -31.83 (c 1.99, CHCl3).10,11
D
Dim eth yl Th iop h osp h ite 5.21 A solution of 2,4-bis(4-meth-
oxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawes-
son’s reagent; 25 g, 0.062 mol) and freshly distilled dimethyl
phosphite (11 mL, 13.2 g, 0.12 mol) in benzene (88 mL) was
heated at 85-90 °C for 45 min. The reaction mixture was
cooled to room temperature, and hexane (80 mL) was added
to precipitate sulfur- and phosphorus-containing byproducts.
The reaction mixture was passed through filter paper and
Celite, and the solution was concentrated to an oil under
reduced pressure. The product, dimethyl thiophosphite 5,
distilled at 60 °C at 12-16 mM Hg (oil bath 85-95 °C) as a
colorless liquid (6.93 g, 0.055 mol, 45.8% yield): 1H NMR δ
7.64 (dd, J ) 651.7 and 3.4 Hz, 1 H), 3.69 (d, J ) 14.0 Hz, 3
Dim eth yl (R)-Am in o(p h en yl)m eth ylp h osp h on a te 21. A
solution of 20 (0.121 g, 0.36 mmol) and Pearlman’s catalyst
(0.03 g) in CH3OH (15 mL) was stirred for 12 h under H2 at
room temperature. The reaction mixture was degassed and
filtered through Celite; the solids were triturated with CH3-
OH, and evaporated to dryness. The residue was extracted
from CH2Cl2/2.5% NaHCO3 to afford crude product (0.093 g)
that was purified by column chromatography (hexanes/Et2O/
CH3OH 10:10:0.5) to afford R-aminophosphonate 21 as yel-
lowish oil (0.038 g, 0.18 mmol, 49%): TLC Rf ) 0.10 (hexanes/
Et2O/CH3OH ) 4.5:4.5:1); [R]23 ) +25.75 (c ) 1.90, CHCl3);
D
1H NMR δ 7.44-7.25 (m, 5H), 4.29 (d, J PCH ) 16.8 Hz, 1 H),
3.69 (d, J POCH ) 10.4 Hz, 3 H), 3.56 (d, J POCH ) 10.4 Hz, 3
H), 3.68 (d, J ) 14.0 Hz, 3 H); 13C NMR δ 52.3 (d, J P-OCH
10 Hz); 31P NMR δ 74.8.
)
3
3
3
H), 2.18 (br s, 2H); 13C NMR δ 137.4, 128.6, 128.0, 127.6, 127.6,
53.7 (d, J CP ) 149.6 Hz), 53.6 (d, J POCH ) 6.1 Hz), 53.5 (d,
3
Gen er a l P r oced u r e for th e Syn th esis of R-Am in o-
p h osp h on oth ioa tes. To a suspension of the amine hydro-
chloride (1 equiv) in THF (25 mL) was added TEA (1.1 equiv).
The mixture was stirred for 30 min, filtered, and evaporated
to yield the free base that was dissolved in a mixture of toluene
(10 mL) and the aldehyde (1.0 equiv). Molecular sieves (3 Å)
were added and the mixture was stirred at room temperature
for 2 h. The mixture was filtered through Celite (aliquot
showed imine formation; singlet at δ 8.42 ppm) and chilled to
0 °C, and dimethyl thiophosphite 5 (1.1 equiv) was added. The
reaction mixture was stirred at 0 °C for 48 h or until 31P NMR
showed loss of 5 and/or the sole appearance of signals at δ
97-103 ppm. The reaction mixture was evaporated to an oil
and chromatographed on silica gel (hexanes/Et2O) to afford
the product R-aminophosphonothioates.
J POCH ) 12.2 Hz); 31P NMR δ 27.5; HRMS calcd for M + H+
3
of C9H14NO3P 216.0790, found 216.0782; Anal. Calcd for
C9H214NO3P‚0.25H2O: C, 49.20; H, 6.65; N, 6.38. Found: C,
48.85; H, 6.74; N, 6.33.
(R)-P h osp h on op h en ylglycin e 22.24 A solution of 21 (0.046
g, 0.20 mmol) was dissolved in HClconc (2 mL) and heated in a
sealed tube at 100 °C for 12 h. The mixture was evaporated
to a solid white residue that was dissolved in EtOH (2 mL)
and treated with propylene oxide (10 mL), resulting in a white
precipitate. The white precipitate was isolated by centrifuga-
tion, triturated with Et2O, filtered, and dried to give 22 as a
white solid (0.025 g, 0.13 mmol, 66.8% yield): [R]23 ) +17.3
D
1
(c ) 0.52, 1 N NaOH); H NMR (D2O) δ 7.34-7.20 (m, 5H),
4.21 (d, J PCH ) 16.0 Hz, 1 H); 13C NMR (D2O) δ 134.1, 129.9,
129.6, 128.6, 54.7 (J PC ) 137.4 Hz); 31P NMR (CDCl3) δ 10.9;
HRMS calcd for M + H+ of C7H11NO3P 188.0476, found
188.0491.
O,O-Dim eth yl (R)-{[(1R)-2-Hydr oxy-1-ph en yleth yl]am i-
n o}(p h en yl)m eth ylp h osp h on a te 20. A solution of 9a (0.360
g, 0.26 mmol) in 50% H2O2 (5 mL), and CH3OH (5 mL) was
stirred at room temperature for 8-10 h (31P NMR monitoring).
The reaction was stopped with 2.5% NaHCO3 (40 mL) and
extracted with CH2Cl2 (5 × 40 mL) to afford crude 20 (0.292
g) that was chromatographed with hexanes/Et2O/CH3OH (10:
10:0.5). The phosphonate 20 was obtained as a yellowish oil
(0.104 g, 0.309 mmol, 29%): TLC Rf ) 0.14 (hexanes/Et2O/
Ack n ow led gm en t . We thank the NSF (CHE
9807469 and MCB9808372) for financial support of this
project. Support for the mass spectral facility was made
possible with grants from the NSF (EPS 9977757) and
the Murdock Trust (Vancouver, WA). P.T. thanks the
American Heart Association for a postdoctoral fellow-
ship. We also thank J eff Trautmann and Greg Muth for
additional experiments.
CH3OH ) 4.25:4.25:0.5); [R]23 ) -25.53 (c ) 1.90, CHCl3);
D
1H NMR δ 7.33-7.19 (m, 10 H), 4.10 (d, J PCH ) 18.8 Hz, 1H),
4.01-3.98 (m, 1H), 3.78-3.73 (m, 1H), 3.73 (d, J POCH ) 10.4
Hz, 3H), 3.63-3.59 (m, 1H), 3.49 (d, J POCH )10.4 H3z, 3 H),
3
3.08 (br s, 1H); 13C NMR δ 140.4, 136.2, 128.4, 128.4, 128.2,
128.2, 127.9, 127.5, 127.3, 66.1, 62.8, 62.7, 58.1 (d, J PC ) 152.6
Su p p or tin g In for m a tion Ava ila ble: Procedures and
physical data for compounds 9a /9b, 10a /10b, 11a /11b, 12a /
12b, 13a /13b, 14a /14b, 17a /17b, 18a /18b, and 25. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Hz), 53.6 (d, J POCH ) 9.2 Hz), 53.2 (d, J POCH ) 9.2 Hz); 31P
3
NMR δ 27.1; Anal.3 Calcd for C17H22NO4P: C, 60.89; H, 6.61;
N, 4.18. Found: C, 60.57; H, 6.62; N, 4.12.
Compound 20 was also prepared by the addition of dimethyl
phosphite to the benzaldimine of (R)-phenylglycinol. To a
solution of (R)-(-)-2-phenylglycinol (0.57 g, 4.19 mmol) in
J O035707T
2326 J . Org. Chem., Vol. 69, No. 7, 2004