Transformation of Arylmethylamines into α-Aminophosphonic Acids via Metalated Phosphoramidates: Rearrangement of Partly Configurationally Stable N-Phosphorylated α-Aminocarbanions

Article abstract of DOI:10.1021/jo000585f

N-Benzyl phosphoramidate was protected at nitrogen with a TMS, p-toluenesulfonyl, Boc, lithium carboxylate, or diethoxyphosphinyl group and metalated with s-BuLi or LDA at -78 °C at the benzylic carbon. For the latter three protecting groups, the intermediate α-amino(phenylmethyl)-lithiums isomerized to N-protected α-aminophosphonates (phosphoramidate-aminophosphonate rearrangement). (R)-N-[1-²H₁]Phenylmethyl phosphoramidate in combination with Boc or (EtO)₂P-(O) was used to demonstrate that metalation occurs with a high primary kinetic isotope effect (k_H/k_D 13-50) and migration of the diethoxyphosphinyl group with retention of configuration at carbon. Furthermore, the short-lived carbanion lithium pairs are partly configurationally stable as the aminophosphonates formed with the two protecting groups have enantiomeric excesses of 79 and 24%, respectively. When homochiral lithium amides derived from (R)-N-isopropyl-1-phenylethylamine and (R,R)-N,N-di(1-phenylethyl)amine were used to induce a phosphoramidate-aminophosphonate rearrangement, chiral nonracemic α-aminophosphonates were formed (ee 26-35%). Three racemic aminophosphonates were deprotected with hot 6 M HCl and purified by ion-exchange chromatography on Dowex 50W,H⁺ to exemplify the transformation of phenyl-, p-tolyl-, and (1′-naphthyl)methylamine into aminophosphonic acids via lithiated phosphoramidates.

Full text of DOI:10.1021/jo000585f

J . Org. Chem. 2000, 65, 6121-6131
6121
Tr a n sfor m a tion of Ar ylm eth yla m in es in to r-Am in op h osp h on ic
Acid s via Meta la ted P h osp h or a m id a tes: Rea r r a n gem en t of P a r tly
Con figu r a tion a lly Sta ble N-P h osp h or yla ted r-Am in oca r ba n ion s
Friedrich Hammerschmidt* and Martin Hanbauer
Institut fu¨r Organische Chemie der Universita¨t Wien,Wa¨hringerstrasse 38, A-1090 Wien, Austria
frha@felix.orc.univie.ac.at
Received April 17, 2000
N-Benzyl phosphoramidate was protected at nitrogen with a TMS, p-toluenesulfonyl, Boc, lithium
carboxylate, or diethoxyphosphinyl group and metalated with s-BuLi or LDA at -78 °C at the
benzylic carbon. For the latter three protecting groups, the intermediate R-amino(phenylmethyl)-
lithiums isomerized to N-protected R-aminophosphonates (phosphoramidate-aminophosphonate
rearrangement). (R)-N-[1-2H1]Phenylmethyl phosphoramidate in combination with Boc or (EtO)2P-
(O) was used to demonstrate that metalation occurs with a high primary kinetic isotope effect
(kH/kD 13-50) and migration of the diethoxyphosphinyl group with retention of configuration at
carbon. Furthermore, the short-lived carbanion lithium pairs are partly configurationally stable
as the aminophosphonates formed with the two protecting groups have enantiomeric excesses of
79 and 24%, respectively. When homochiral lithium amides derived from (R)-N-isopropyl-1-
phenylethylamine and (R,R)-N,N-di(1-phenylethyl)amine were used to induce a phosphoramidate-
aminophosphonate rearrangement, chiral nonracemic R-aminophosphonates were formed (ee 26-
35%). Three racemic aminophosphonates were deprotected with hot 6 M HCl and purified by ion-
exchange chromatography on Dowex 50W,H+ to exemplify the transformation of phenyl-, p-tolyl-,
and (1′-naphthyl)methylamine into aminophosphonic acids via lithiated phosphoramidates.
In tr od u ction
phites to homochiral imines,7 acyliminium ions8 and
nitrones,9 alkylation of R-lithiated homochiral imines
derived from R-aminomethylphosphonic acid10 and the
transformation of chiral, nonracemic R-hydroxyphospho-
nates11 via R-azidophosphonates.
R-Aminophosphonic acids serve as surrogates for R-ami-
no acids, which play an important role in biological
systems. The phosphonic acid group is considered to be
an isosteric replacement for the carboxyl group. It also
mimics the tetrahedral intermediate of reactions of
carboxylic acid derivatives. Therefore, racemic and chiral,
nonracemic phosphonic acid1 analogues of proteinogenic
and nonproteinogenic amino acids and peptides contain-
ing them have been prepared and tested for a variety of
biological effects.2 Recently, R-aminobenzylphosphonic
acids were found to be potent inhibitors of human
prostatic acid phosphatase.3 (R)-Phosphatyrosine (phos-
phonic acid analogue of L-tyrosine) occurs naturally as a
component of two hypotensive tripeptides.4
Despite the widespread interest in aminophosphonic
acids, the number of available methods is still limited.
The more general methods for the synthesis of chiral,
nonracemic R-aminophosphonic acids, except chemical1a
and enzymatic5 resolution, are the enantioselective ad-
dition of phosphites to achiral imines,6 addition of phos-
We have been interested in the phosphate-phospho-
nate rearrangement and its reverse process for some time
(Scheme 1).12 Phosphates of general structure 1 with R1
being Ar or, as found recently, alkyl and a suitable
protecting group R2 at phosphorus are metalated to give
short-lived, configurationally stable R-oxyalkyllithium
compounds (()-2. They isomerize by migration of the
dialkoxyphosphinyl group from oxygen to carbon to give
phosphonates (()-3 and on workup R-hydroxyphospho-
nates (()-4. This reaction is related to the Brook rear-
rangement.13 We reasoned that by replacing oxygen by
(6) Gro¨ger, H.; Saida, Y.; Sasai, H.; Yamaguchi, K.; Martens, J .;
Shibasaki, M. J . Am. Chem. Soc. 1998, 120, 3089-3103.
(7) Smith, A. B., III; Yager, K. M.; Taylor, C. M. J . Am. Chem. Soc.
1995, 117, 10879-10888.
(8) Seebach, D.; Charczuk, R.; Gerber, C.; Renaud, P. Helv. Chim.
Acta 1989, 72, 401-425.
(9) Huber, R.; Knierzinger, A.; Obrecht, J .-P.; Vasella, A. Helv. Chim.
Acta, 1985, 68, 1730-1747. Huber, R.; Vasella, A. Helv. Chim. Acta
1987, 70, 1461-1476.
* To whom correspondence should be addressed. Fax: (internat.)
+43-1-4277-9521. Tel: +43-1-4277-52105.
(1) Reviews: (a) Dhawan, B.; Redmore, D. Phosphorus Sulfur 1987,
32, 119-144.; (b) Kukhar, V. P.; Soloshonok, V. A.; Solodenko, V. A.
Phosphorus, Sulfur, Silicon Relat. Elem. 1994, 92, 239-264.
(2) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur, Silicon Relat. Elem.
1991, 63, 193-215.
(3) Beers, S. A.; Schwender, C. F.; Loughney, D. A.; Malloy, E.;
Demarest, K.; J ordan, J . Bioorg. Med. Chem. 1996, 4, 1693-1701.
(4) Kase, H.; Yamato, M.; Koguchi, T.; Okachi, R.; Kasai, M.;
Shirahata, K., Kawamoto, I.; Shuto, K.; Karasawa, A.; Deguchi, T.;
Nakayama, K. Eur. Pat. Appl. EP 0 061 172 A1, 1982; Chem. Abstr.
1983, 98, 107793.
(10) Song, Y.; Niederer, D.; Lane-Bell, P. M.; Lam, L. K. P.; Crawley,
S.; Palcic, M. M.; Pickard, M. A.; Pruess, D. L.; Vederas, J . C. J . Org.
Chem. 1994, 59, 5784-5793. Groth, U.; Richter, L.; Scho¨llkopf, U.
Tetrahedron Lett. 1992, 48, 117-122. Hanessian, S.; Bennani, Y. L.
Tetrahedron Lett. 1990, 31, 6465-6465.
(11) Hammerschmidt, F.; Wuggenig, F. Tetrahedron: Asymmetry
1999, 10, 1709-1721. Gajda, T. Tetrahedron: Asymmetry 1994, 5,
1965-1972. Meier, C.; Laux, W. H. G.; Bats, J . W. Liebigs Ann. 1995,
1963-1979.
(12) Hammerschmidt, F.; Schmidt, S. Eur. J . Org. Chem. 1999,
3511-3518.
(13) Review: Brook, A. Acc. Chem. Res. 1974, 7, 77-84. Hoffmann,
R.; Bru¨ckner, R. Chem. Ber. 1992, 125, 2731-2739.
(5) Solodenko, V. A.; Kasheva, T. N.; Kukhar, V. P.; Kozlova, E. V.;
Mironenko, D. A.; Svedas, V. K. Tetrahedron 1991, 47, 3989-3998.
10.1021/jo000585f CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/25/2000

6122 J . Org. Chem., Vol. 65, No. 19, 2000
Hammerschmidt and Hanbauer
Sch em e 1
Sch em e 3
Sch em e 2
Sch em e 4
aminophosphonate rearragement, which they call ami-
nophosphonate-amidophosphate rearrangement. One is
given in Scheme 3. The intermediate R-aminobisphos-
phonate (()-13 isomerizes to R-aminophosphonate (()-
10f. Migration of the phosphinyl group generates a
carbanionic species that is stabilized by a phenyl and a
phosphonate group and protonated to furnish (()-10f. To
study the feasibility of the phosphoramidate-aminophos-
phonate rearrangement, we selected in the first place
benzylamine (5) to ease deprotonation, Et for R and six
different protecting groups for PG (see Scheme 2).
Furthermore, we wanted to determine the configurational
stability of a N-phosphorylated R-aminolithium com-
pound 7 and the stereochemistry of the rearrangement
at carbon. Finally, we hoped to get chiral, nonracemic
R-aminophosphonates by use of homochiral bases.
a protected nitrogen, it might be possible to prepare
R-aminophosphonates. The proposed sequence starts with
a primary amine 5 which is transformed into phospho-
ramidate 6 (Scheme 2). Metalation with a strong lithium
base generates N-phosphorylated R-aminolithium com-
pound (()-7, which rearranges to lithiated R-aminophos-
phonate (()-9 and gives R-aminophosphonate (()-10 on
workup. In analogy to the phosphate-phosphonate
rerrangement, we propose the term phosphoramidate-
aminophosphonate rearrangement for this isomerization,
which so far has not been reported in the literature. The
intermediates (()-7 are a new class of R-aminolithium
compounds14 having attracted much attention during the
last years.
Resu lts a n d Discu ssion
Tr im eth ylsilyl a s P r otectin g Gr ou p . Phosphora-
midate 14 was prepared in high yield from benzylamine
(5) and diethyl chlorophosphate (Scheme 4). Phosphora-
midate 1416 was used to test the various protecting
groups for the rearrangement. The trimethylsilyl group,
Pudovik and Zimin give in a review a few rare
examples for the retro-reaction of the phosphoramidate-
(15) Pudovik, A. N.; Zimin, M. G. Pure Appl. Chem. 1980, 52, 989-
(14) Reviews: Gawley, R. E. Current Org. Chem. 1997, 1, 71-97.
Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y. S.; Thayumanavan, S.
Acc. Chem. Res. 1996, 29, 552-560.
1011.
(16) Willeit, A.; Mu¨ller, E. P.; Peringer, P. Helv. Chim. Acta 1983,
66, 2467-2480.

Transformation of Arylmethylamines into R-Aminophosphonic Acids
J . Org. Chem., Vol. 65, No. 19, 2000 6123
Sch em e 5
Sch em e 7
Sch em e 6
Sch em e 8
Sch em e 9
which can be manipulated easily, was introduced by
silylation of the lithiated phosphoramidate with TMSCl.
Because of the anticipated instability of the N-silylated
phosphoamidate 6a toward aqueous workup, it was not
isolated. Instead, the reaction mixture was recooled to
-78 °C and s-BuLi was added. The C-silylated phospho-
ramidate (()-16 was isolated in 80% overall yield for both
steps. This result proves unambiguously that metalation
of the N-silylated phosphoramidate generates an R-ami-
nocarbanionic species (()-7a in which the silyl group
migrates exclusively in preference to the phosphinyl
group (retro-aza-Brook rearrangement).17 A similar reac-
tion was found for Boc derivative 17 by Voyer and
Barberis (Scheme 5).18 The strong electron-withdrawing
p-toluenesulfonyl group is ideally suited to both acidify
the hydrogens R to nitrogen and to stabilize the negative
charge on nitrogen after migration of phosphorus was
tested next.
Sch em e 10
p-Tolu en esu lfon yl a s P r otectin g Gr ou p . The N-
tosyl amide 6b was prepared easily from phosphorami-
date 14 according to Scheme 6. Treatment of 6b with 2.4
equiv of n-BuLi/TMEDA produced phosphoramidate (()-
21 in 73% yield. Its formation starts very likely with the
generation of imine 19 by elimination (E2 or E1cB) of
p-toluenesulfinate from 6b. Excess n-BuLi adds to the
CdN bond to give lithiated phosphoramidate (()-20,
which is protonated on workup. s-BuLi gives an analo-
gous product in 54% yield having complex NMR spectra
as a 1:1 mixture of two diastereomers is formed. When
the trifluoromethylsulfonyl group was substituted for the
p-toluenesulfonyl group, the product pattern did not
change. LDA did not effect elimination of p-toluenesulfi-
nate, but metalation of the p-tolyl ring ortho to the
sulfonyl group (Scheme 7). A 1,4-migration of phosphorus
and protonation furnished crystalline sulfonamide 22.
Boc a s P r otectin g Gr ou p . Two entries to N-Boc-
protected phosphoramidate 6c were developed (Scheme
8). First, benzylamine (5) was protected with (Boc)2O/
Et3N19 in dichloromethane followed by phosphorylation
of the lithiated N-Boc amine. Second, the two steps were
interchanged, which gave a better overall yield. Possibly,
the lithiated carbamate was phosphorylated not only at
nitrogen but to a small extent also at oxygen (Scheme
9). The sensitive enol phosphate 24 hydrolyzed on workup
to regenerate the starting material. We have no evidence
for a 1,3-phosphinyl shift in 6c20 to give enol phosphate
24.
The rearrangement of phosphoramidate 6c with 1.5
equiv of s-BuLi/TMEDA was a smooth reaction (Scheme
10). It was finished in 30 min in diethyl ether and
furnished R-aminophosphonate (()-10c21 in 77% yield.
(19) Kanazawa, A. M.; Correa, A.; Denis, J .-N.; Luche, M. J .; Greene,
A. E. J . Org. Chem. 1993, 58, 255-257.
(20) Zwierzak, A.; Pilichowska, S. Synthesis 1982, 920-924.
(21) Genet, J . P.; Mallart, S.; Greck, C.; Piveteau, E. Tetrahedron
Lett. 1991, 32, 2359-2362.
(17) Honda, T.; Mori, M. J . Org. Chem. 1996, 61, 1196-1197.
(18) Barberis, N.; Voyer, N. Tetrahedron Lett. 1998, 39, 6807-6810.

6124 J . Org. Chem., Vol. 65, No. 19, 2000
Hammerschmidt and Hanbauer
Sch em e 12
Sch em e 11
Sch em e 13
The introduction of the Boc group and the phosphora-
midate-aminophosphonate rearrangement can also be
carried out as a one-pot reaction in 70% overall yield.
P iva loyl a s P r otectin g Gr ou p . The satisfying results
with the Boc group induced us to study also the pivaloyl
group as protecting group. When pivalamide 2522 was
treated with s-BuLi and diethyl chlorophosphate, or when
phosphoramidate 14 was treated with LDA and then
Piv2O, only pivalamide 25 was isolated (Scheme 11). This
finding can be explained by assuming that in the first
case the desired product 6d isomerized to the presumably
thermodynamically more stable enol phosphate 26, which
is hydrolyzed on aqueous workup. In the second case, the
lithiated pivalamide is phosphorylated at oxygen. To
circumvent the possible rearrangement of the N-pivaloyl
phosphoramidate 6d at room temperature, Piv2O was
added to the metalated phosporamidate. The reaction
mixture was kept at -78 °C for 1.5 h before the addition
of s-BuLi to induce the phosphoramidate-aminophospho-
nate rearrangement. Unfortunately, no aminophoshonate
could be detected, which is possibly caused by an N to O
migration of the phosphinyl group in the N-pivaloyl
phosphoramidate 6d even at -78 °C.
Ca r boxyl a s P r otectin g Gr ou p . Katritzky et al.
found that carboxylation of lithiated benzyl alcohol and
benzylamine can be used to facilitate metalation R to the
heteroatom.23 We also tried this method, because the
unprotected amino group is formed immediately on
workup (Scheme 12).
The lithiated phosphoramidate was carboxylated by
simply replacing the argon atmosphere by CO2 and
allowing the reaction mixture to warm to room temper-
ature. The solvent and excess CO2 were removed in vacuo
(0.3 mm). The solid lithium salt 6e of the carbamidic acid
was dissolved in diethyl ether and treated with s-BuLi
at -78 °C. Addition of acetic acid and extractive workup
furnished the aminophosphonate (()-2724 in 47% yield,
which was not optimized.
Sch em e 14
phorylation of the lithiated phosphoramidate with diethyl
chlorophosphate gave bisphosphoramidate 6f 6 in 72%
yield (Scheme 13). It was rearranged under the standard
conditions (diethyl ether, s-BuLi/TMEDA, -78 °C) in 70%
yield to the highly polar aminophosphonate (()-10f.26
From the five protecting groups tested the Boc group
is best, because it can be handled very easily. In practice,
a phosphoramidate of an arylmethylamine can be N-
protected with Boc, metalated, and rearranged in a one-
pot sequence. The crude product of the N-Boc R-amino-
phosphonate can be deprotected in refluxing 6 M HCl to
give R-aminophosphonic acid as will be shown later.
Con figu r a tion a l Sta bility of N-P h osp h or yla ted
r-Am in o(p h en ylm eth yl)lith iu m a n d Ster eoch em is-
tr y of Its P h osp h or a m id a te-Am in op h osp h on a te
Rea r r a n gem en t a t Ca r bon . The phosphoramidates
derived from homochiral R-deuteriobenzylamine with a
Boc or a diethoxyphosphinyl group at nitrogen were
prepared (Scheme 14). The first one was obtained from
deuterated phenylmethanol (S)-28,27 which was con-
verted to phosphoramidate (R)-[1-2H1]6c by a Mitsunobu
reaction using Ph3P/DEAD/N-Boc phosphoramidate 29.28
Dieth oxyp h osp h in yl Gr ou p a s P r otectin g Gr ou p .
At last, a second diethoxyphosphinyl group was placed
on the nitrogen to test it as a protecting group. Phos-
(25) Naumann, C.; Kocis, P. Phosphorus, Sulfur, Silicon Relat. Elem.
1994, 91, 169-178.
(26) Zimin, M. G.; Dvoinishnikova, T. A.; Konovalova, I. V.; Pudovik,
A. N. Izv. Akad. Nauk. SSSR Ser. Khim. 1978, 499-500; Chem. Abstr.
1978, 88, 190978n.
(22) Martinez, A. G.; Alvarez, R. M.; Vilar, E. T.; Fraile, A. G.;
Hanack, M.; Subramanian, L. R. Tetrahedron Lett. 1989, 30, 581-
582.
(23) Katritzky, A. R.; Fan, W.-Q.; Akutagawa, K. Synthesis 1987,
415-417.
(24) Rogozhin, S. V.; Davankov, V. A.; Belov, Y. P. Izv. Akad. Nauk.
SSSR Ser. Khim. 1973, 955-956; Chem. Abstr. 1973, 79, 42610k.
(27) Wightman, R. H.; Staunton, J .; Battersby, A. R.; Hanson, K.
R. J . Chem. Soc., Perkin Trans. 1 1972, 2355-2364.
(28) Slusarska, E.; Zwierzak, A. Liebigs Ann. Chem. 1986, 402-
405.

Transformation of Arylmethylamines into R-Aminophosphonic Acids
J . Org. Chem., Vol. 65, No. 19, 2000 6125
Sch em e 15
Ta ble 1. P h osp h or a m id a te-Am in op h osp h on a te
Sch em e 16
Rea r r a n gem en t of (R)-[1-2H1]6c In d u ced by s-Bu Li or
LDA in Et2O or THF
entry
base (equiv)
solvent
yield
ee (%)
2H (%)
1
2
3
4
5
s-BuLi (2.0)
LDA (2.0)
s-BuLi (0.9)
LDA (0.9)
LDA (0.9)
Et2O
THF
Et2O
THF
Et2O
74
81
58
56
44
37
61
43
72
79
36a
67a
90b
98b
96b
Determined by 1H NMR spectroscopy. Determined by MS.
a
b
Sch em e 17
and nondeuterated diastereomers appeared as two quar-
tets (δ ) 3.48 and 3.37, J H,F ) 1.6 Hz) of different
intensity. Therefore, the deuterated species of the ami-
nophosphonate must in part be chiral, nonracemic.
We assume a clean inversion for the substitution process.
The deuterated phosphoramidate was metalated with 2
equiv of s-BuLi/TMEDA or LDA in diethyl ether or THF.
The resulting phosphoramidate 10c was formed in 74%
and 81% yield, respectively. (Scheme 15; only products
obtained by removal of protium are shown). The ee, the
yield, and the deuterium content (36% and 67% D) are
collected in Table 1. The enantiomeric excess was deter-
mined by derivatizing R-aminophosphonate (S)-[1-2H1]27
obtained by treating (S)-[2H]10c with TFA in dichlo-
romethane with (R)-MTPACl (Scheme 16).29 The mixture
of deuterated and nondeuterated diastereomeric amides
31 and 32 was investigated by NMR spectroscopy. The
250 MHz 1H NMR spectrum showed two very close
doublets of doublets (δ ) 5.445 and 5.461, each with J )
9.8, 20.6 Hz) of equal intensity for the two diastereomeric
PCH of 31 and 32. This is indicating that the nondeu-
terated species in the mixture is racemic. The CH3O
substituents of the (S)-MTPA groups of the deuterated
Three more experiments were carried out with (R)-[1-
2H1]6c using only 0.9 equiv of base, which caused a
significant drop in yield, but an increase of the deuterium
content to 90% (in diethyl ether as solvent) for s-BuLi
and 98% (in THF as solvent) and 96% (in diethyl ether
as solvent) for LDA (Table 1, entries 3-5). This finding
can be explained by the fact that excess base metalates
the rearranged products (R)- and (S)-[1-2H1]9c. The
dilithiated species 30 is configurationally not stable and
gives racemic, nondeuterated aminophosphonate (()-10c
on quenching with AcOH. That this is actually happening
is proven by metalation of (()-10c with 2 equiv of s-BuLi
or LDA and quenching with AcOD (Scheme 17). The
isolated aminophosphonate (()-[1-2H]10c was partly
deuterated (91% for s-BuLi, 28% for LDA) which is
formed via dilithiated species. The extent of deuteration
reflects in part the difference in the basicity between
s-BuLi and LDA.
(29) Review: Parker, D. Chem. Rev. 1991, 91, 1441-1457. Ham-
merschmidt, F.; Li, Y.-F. Tetrahedron 1994, 50, 10253-10264.

6126 J . Org. Chem., Vol. 65, No. 19, 2000
Hammerschmidt and Hanbauer
Sch em e 18
Assuming that a second lithiation does not interfere,
when 0.9 equiv of base are used, the deuterium contents
of 98% and 96% are the result of a high primary kinetic
isotope effect for metalation of the phosphoramidate (R)-
[1-2H1]6c (kH/kD g50 or 25) (see Scheme 15). The lithiated
species (S)-[1-2H1]7c can rearrange before or after the
inversion of the configuration. When no excess base is
present, (S)- and (R)-[1-2H1]9c are not metalated and end
up as (S)- and (R)-[1-2H1]10c. The ratio of the latter
reflects the ratio of (S)- and (R)-[1-2H1]7c. The drop in
ee from a maximum of 98% to 72% or 79%, respectively,
is caused by partial racemization of the intermediate
carbanion (S)-[1-2H1]7c before 1,2-migration of the phos-
phorus. With a deuterium content of 98% and 96% an ee
of 96% and 92% is possible at best, because the nondeu-
terated species generated by metalation of (R)-[1-2H1]6c
has (R)-configuration. The experimental ee value of 72%
and 79% demonstrate, that roughly 10% of the lithiated
phosphoramidate invert their configuration, independent
of the solvent used (THF, diethyl ether). This result
shows that the R-amino(phenylmethyl)lithium 7c is
nearly as configurationally stable as the R-oxy(phenyl-
methyl)lithium where only 3.5% of the molecules invert
their configuration. As the isolated R-aminophosphonate
10c is laevorotatory and therefore has (S)-configuration,
the rearrangement occurs with retention of configuration
at carbon as with the oxygen analogue [the change of
configuration from (R) to (S) is a consequence of the
change of priorities according to the rules developed by
Cahn, Prelog, and Ingold].30
The homochiral bisphosphoramidate (R)-[1-2H1]6f was
prepared as well and rearranged to study the influence
of the diethoxyphosphinyl group compared to Boc as
protecting group at nitrogen on the configurational
stability of the metalated species (Scheme 18). (S)-[1-2H1]-
Benzyl alcohol was again used as starting material. It
was transformed into (R)-[1-2H1]benzylamine [(R)-34] via
phthalimide (R)-33, which was obtained by Mitsunobu
reaction.31 Two consecutive phosphorylations furnished
bisphosphoramidate (R)-[1-2H1]6f, which was subjected
to a phosphoramidate-aminophosphonate rearrangement.
To minimze a possible C-metalation of the N-lithiated
intermediate R-aminophosphonate as given for the Boc-
protected analogue in Scheme 15, only 0.9 equiv of s-BuLi
or LDA were used. The results show that metalation
occurs with a primary kinetic isotope effect of g25 or g13.
As a small amount of second metalation is very likely,
the determined values are lower limits. Surprisingly, the
enantiomeric excesses of 4% and 24% are much lower
than the ones obtained with Boc as protecting group
(compare Scheme 16). Therefore, the intermediate meta-
lated bisphosphoramidate is configurationally less stable
than the corresponding lithiated N-Boc phoshoramidate.
Only a small portion of the molecules retain their
configuration.
Sch em e 19
R-hydroxyphosphonate (R)-3530 of g98% ee by the
sequence given in Scheme 19. When the Mitsunobu
reaction was carried out in toluene as solvent at room
temperature, azide (S)-36 was formed in high yield with
partial racemization (ee 86%) as proven by NMR spec-
troscopy of (R)-MTPA amide of (S)-27. When toluene was
replaced by a mixture of toluene/THF (4:1), the substitu-
tion was a clean inversion process and furnished an azide
with an ee g98%. The data of N-phosphorylated deriva-
tive (-)-(S)-10f of R-aminophosphonate (S)-27 were used
to assign the absolute configuration of (-)-[1-2H1]10f and
determine its enantiomeric excess. As the rearrangement
of bisphosphoramidate (R)-[1-2H1]6f produces aminophos-
phonate (S)-[1-2H]10f, the migration of the diethoxyphos-
phinyl group occurs with retention of configuration,
although partial racemization is heavily interfering.
To determine the absolute configuration and the enan-
tiomeric excess of (-)-[1-2H1]10f, we tried to deblock it
at nitrogen to correlate it with diethyl R-aminophenyl-
methylphosphonate,24 but all attempts with various
concentrations of hydrochloric acid at different temper-
atures were unsuccessful. So N-phosphorylated R-ami-
nophosphonate (-)-(S)-10f was prepared from known
(30) Hammerschmidt, F.; Hanninger, A. Chem. Ber. 1995, 128, 823-
830.
(31) Reviews: Mitsunobu, O. Synthesis 1981, 1-28. Hughes, D. L.
Organic Reactions 1992, 42, 335-656.

Transformation of Arylmethylamines into R-Aminophosphonic Acids
J . Org. Chem., Vol. 65, No. 19, 2000 6127
Sch em e 20
Sch em e 22
used instead of diethyl ether, an ee of about 24% can be
expected at best even if metalation is highly enantiose-
lective (93%, see Scheme 19). Therefore, we assume that
the major portion of the chiral, nonracemic R-aminophos-
phonate (R)-10f is formed by an enantioselective rear-
rangement. The (S)-ion pair complexed with (S,S)-N,N-
bis(1-phenylethyl)amine seems to rearrange more easily
than the (R)-ion pair complexed with the same amine.
Furthermore, the (R)-ion pair inverts its configuration
more easily than it rearranges.
Sch em e 21
En a n tioselective P h osp h or a m id a te-Am in op h os-
p h on a te Rea r r a n gem en t. To increase the attractive-
ness of this rearrangement, an enantioselective version
is desirable. Therefore, we conducted a few exploratory
experiments using homochiral bases for the metalation
(Scheme 20). When 6c was deprotonated with (-)-
sparteine/sBuLi32 or lithium amide33 bases such as B and
C, chiral, nonracemic aminophosphonate (R)-10c was
formed in moderate yields. As the enantiomeric excess
is at best 26% and as it is known that the intermediate
metalated species racemizes only to a small extent, the
enantioselectivity of deprotonation must be low. To ease
the determination of the enantiomeric excess of (R)-10c
by use of optical rotation, a reference sample of (S)-10c
was prepared from (S)-27 of 98% ee. For comparison the
ee of the sample of (R)-10c obtained with base C was also
determined by 1H and 31P NMR spectroscopy of the
corresponding Mosher amide to be 28% and 24%, respec-
tively.
At last bisphosphoramidate 6f was subjected to a
phosphoramidate-aminophosphonate rearrangement with
lithium (S,S)-N,N-bis(1-phenylethyl)amide in THF as
solvent (Scheme 21). Although the yield was onyl 30%,
the ee was 35%, which is significantly higher than with
the Boc-protected phosphoramidate 6c. As the intermedi-
ate N,N-bisphosphorylated R-amino(phenylmethyl)lith-
ium is configurationally less stable than the N-Boc
N-phosphorylated counterpart and additionally THF was
These findings are encouraging. As there are many
homochiral bases known, the ee can probably be in-
creased to an acceptable level.
P r ep a r a tion of (()-r-Am in o(a r ylm eth yl)p h osp h o-
n ic Acid s. To demonstrate the usefulness of the rear-
rangement for the preparation of R-aminophosphonic
acids from arylmethylamines, phosphoramidates 38a -
c, prepared in the same way as 14, were N-Boc protected
to give phosphoramidates 39a -c (Scheme 22). These
were isolated to fully characterize them and were then
subjected to the phosphoramidate-aminophosphonate
rearrangement, although the two steps can be carried out
as a one pot reaction. The reaction time was 30 min for
39a and 39b and 4 h for 39c and the yields varied from
75 to 83%. The free R-aminophosphonic acids were easily
obtained by refluxing the protected precursors (()-10c,
40a ,c with 6 M HCl, followed by purification by ion
exchange chromatography on Dowex 50W,H+. The ami-
nophosphonic acids (()-11c, 41a ,c were eluted with
water and were crystalline, high melting compounds.
They were derivatized in a buffer system with 3,5-
dinitrobenzyloxy carbonyl chloride (DNZ-Cl) or 2,4-
dinitrofluorobenzene (DNP-F) and used to evaluate their
enantioseparation by HPLC employing quinine-derived
chiral anion exchangers.34 The resolution values for the
DNZ derivatives are much higher than for the DNP
derivatives and range from 5 to 9. The ee of chiral,
nonracemic R-arylmethylphosphonic acids we are plan-
(32) Review: Hoppe, D.; Hense, T. Angew. Chem. 1997, 109, 2376-
2410; Angew. Chem., Int. Ed. Engl. 1997, 36, 2282-2316.
(33) Review: Cox, P. J .; Simpkins, N. S. Tetrahedron: Asymmetry
1991, 2, 1-26.
(34) Zarbl, E.; La¨mmerhofer, M.; Hammerschmidt, F.; Wuggenig,
F.; Hanbauer, M.; Maier, N. M.; Sajovic, L.; Lindner, W. Anal. Chim.
Acta 2000, 404, 169-177.

6128 J . Org. Chem., Vol. 65, No. 19, 2000
Hammerschmidt and Hanbauer
extracted with CH2Cl2. The combined organic layers were
washed with 0.5 M HCl, a saturated solution of NaHCO3, dried
(Na2SO4), and concentrated in vacuo. The residue was flash
chromatographed to furnish 6 or 39a -c.
ning to prepare by enantioselective metalation can thus
be determined easily. At present, we are trying to extend
the rearrangement to R-substituted arylmethyl- and
allylamines.
Rea r r a n gem en t of N-P r otected P h osp h or a m id a tes 6
a n d 39a -c (Gen er a l P r oced u r e C). s-BuLi (1.2 mL, 1.5
mmol, 1.3 M in cyclohexane) was added to a cooled (-78 °C)
and stirred solution of N-protected phosphoramidate 6 or
38a -c (1.0 mmol) and TMEDA (0.23 mL, 0.21 g, 1.5 mmol) in
dry diethyl ether (5 mL) under argon. When the starting
material was consumed (30 min for N-Boc derivatives, TLC:
2:1 hexanes/EtOAc; 3 h for bisphosphoramidate, TLC 1:8 CH2-
Cl2/EtOAc), AcOH (4 mL, 8 mmol; 2 M solution in diethyl
ether) was added. The reaction mixture was concentrated in
vacuo. After addition of water, the product was extracted four
times with CH2Cl2. The combined organic layers were washed
with water, dried (Na2SO4), and concentrated in vacuo. The
product was purified by flash chromatography.
P r epar ation an d Rear r an gem en t of N-P r otected P h os-
p h or a m id a tes 6 a n d 39a -c a s a On e-P ot P r oced u r e w ith
s-Bu Li (Gen er a l P r oced u r e D). s-BuLi (1.9 mL, 2.4 mmol,
1.3 M solution in cyclohexane) was added dropwise to a cooled
(-78 °C) and stirred solution of phosphoramidate 14 (2 mmol)
in dry diethyl ether (5 mL) under argon, followed by (Boc)2O
(0.48 g, 2.2 mmol) after 10 min. When the starting material
was consumed (about 3 h, TLC 8:1 CH2Cl2/EtOAc), TMEDA
(0.46 mL, 3 mmol) and s-BuLi (3.0 mmol) were added and
stirring was continued for 30 min. AcOH (8 mL, 16 mmol; 2
M solution in diethyl ether) was added and the mixture was
concentrated in vacuo. The isolation of the product was the
same as given in general procedure C.
Con clu sion s
We have demonstrated that arylmethylamines can be
easily transformed into N-protected phosphoramidates,
the Boc group being the best protecting group. These
derivatives of the amines are metalated by s-BuLi/
TMEDA or LDA. The R-amino(arylmethyl)lithiums isomer-
ize with retention of configuration to N-protected R-ami-
nophosphonates (phosphoramidate-aminophosphonate
rearrangement). As demostrated for the metalated spe-
cies derived from benzylamine, such carbanionic inter-
mediates are partly configurationally stable, which is
strongly influenced by the N-protecting group of the
phosphoramidate. Experiments to extend the methodol-
ogy to aliphatic amines are under way.
Exp er im en ta l Section
All starting materials were obtained from commercial
suppliers and were generally used without further purification.
Melting points were determined without correction. IR spectra
of liquid samples were measured as films between NaCl plates
or on a silicon35 disk. Spots on TLC plates were visualized by
UV and/or dipping the plate into a solution of (NH4)6Mo7O24
‚
Rea r r a n gem en t of N-P r otected P h osp h or a m id a te 6
w ith LDA or Hom och ir a l Lith iu m Am id e Ba ses (Gen er a l
P r oced u r e E). A solution of s-BuLi (1.2 mL, 1.5 mmol, 1.3 M
in cyclohexane) was added to a stirred and cooled (bath
temperature -20 °C) solution of i-Pr2NH (0.21 mL, 0.15 g, 1.5
mmol) or homochiral N-isopropyl-N-1-phenylethylamine or
N,N-bis(1-phenylethyl)amine in dry THF or diethyl ether (5
mL) under argon. After 10 min, the solution was cooled to -78
°C, and the phosphoramidate 6 (1 mmol, dissolved in 5 mL of
dry THF or diethyl ether) was added. Stirring was continued
for 30 min for N-Boc-protected phosporamidates (TLC 2:1
hexanes/EtOAc) and 3.5 h for bisphosphoramidates (TLC 1:8
CH2Cl2/EtOAc). AcOH (4 mL of a 2 M solution in diethyl ether)
was added and the reaction mixutre was concentrated in
vacuo. The workup and purification was as given in general
procedure C.
Rem ova l of Boc fr om N-Boc Am in op h osp h on a tes 10c
a n d P r ep a r a tion of Mosh er Am id es fr om r-Am in op h os-
p h on a tes 27 (Gen er a l P r oced u r e F ). A solution of N-Boc
aminophosphonate 10c (0.3 mmol) in a mixture of dry CH2Cl2
(1 mL) and CF3CO2H (1 mL) was stirred at room temperature
(3 h, TLC 10:1 CH2Cl2/MeOH). The reaction mixture was
concentrated in vacuo, and CH2Cl2, water, and concentrated
ammonia (5 drops) were added. The organic layer was sepa-
rated, and the aqueous one was extracted with CH2Cl2. The
combined organic phases were washed with water, dried (Na2-
SO4), and concentrated in vacuo. The crude product was
directly used for the preparation for the Mosher amide or was
purified by flash chromatography.
A mixture of crude R-aminophosphonate 27 (0.1 mmol) and
(R)-MTPACl (0.25 mmol) in dry Et3N (2 mL) and dry CH2Cl2
(1 mL) was stirred at room temperature (16 h, TLC 10:1 CH2-
Cl2/MeOH). Water (a few drops) was added, and the reaction
mixture was concentrated in vacuo. The residue was taken
up in CH2Cl2, washed with 2 M HCl, a saturated solution of
NaHCO3 and dried (Na2SO4). Evaporation of the solvent left
the crude product which was purified by flash chromatography.
Com p lete Dep r otection of N-P r otected r-Am in op h os-
p h on a tes 10c, 40a a n d 40c To P r ep a r e R-Am in op h osp h o-
n ic Acid s 11c, 41a , a n d 41c (Gen er a l P r oced u r e G). A
stirred mixture of protected R-aminophosphonate (1 mmol) and
HCl (20 mL, 6 M) was refluxed (16 h, TLC 6:3:1 i-PrOH/H2O/
concentrated ammonia). The cold reaction mixture was con-
centrated in vacuo and the residue was dried in a vacuum
4H2O (24 g) and Ce(SO4)2‚4H2O (1 g) in 10% H2SO4 in water
(500 mL), followed by heating with a hot gun. Spots of free
aminophosphonic acids on TLC plates (silica, 6:3:1 i-PrOH/
H2O/concentrated ammonia) were visualized by dipping into
a solution of ninhydrin (32 mg) in ethanol (16 mL) containing
2,4,6-trimethylpyridine (1 mL) and AcOH (3 mL) and heating
with a hot gun. (S)-MTPACl [J PS Chimie; [R]20D +136.5 (c 5.2,
CCl4), ee >99.5%] was used for derivatization of R-aminophos-
phonates.
THF was distilled prior to use from K and diethyl ether from
LiAlH4. TMEDA and solvents were refluxed over drying agent,
distilled and stored over molecular sieve; toluene (Na; 4 Å),
pyridine (CaH2; 4 Å), CH2Cl2 (P4O10; 4 Å), MeOH (Mg; 3 Å).
Et3N p.A. was dried over KOH.
P h osp h or yla tion of Am in es w ith Dieth yl Ch lor op h os-
p h a te (Gen er a l P r oced u r e A). Diethyl chlorophosphate (2.9
mL, 3.5 g, 20 mmol) was added dropwise to a cooled (0 °C)
and stirred solution of of benzylamine (5) or arylmethylamine
37a -c (22 mmol) and triethylamine (3.4 mL, 2.4 g, 24 mmol)
in dry CH2Cl2 under argon. Stirring was continued at room
temperature until completion of reaction (3 h, TLC: 8:1 CH2-
Cl2/EtOAc). The reaction mixture was extracted with 1 M HCl
and a saturated aqueous solution of NaHCO3. The organic
phase was dried (Na2SO4) and concentrated in vacuo. The
residue was purified by bulb to bulb distillation.
P r ep a r a t ion of N-P r ot ect ed P h osp h or a m id a t es 6,
39a -c fr om P h osp h or a m id a tes 14, 38a -c (Gen er a l P r o-
ced u r e B). A solution of s-BuLi (4.6 mL, 6 mmol, 1.3 M, in
cyclohexane) was added to a stirred and cooled (bath temper-
ature -20 °C) solution of i-Pr2NH (0.84 mL, 0.61 g, 6.0 mmol)
in dry THF (10 mL) under argon. After 10 min, the solution
was cooled to -78 °C and phosphoramidate 14 or 38a -c (5.0
mmol, in 5 mL of dry THF) was added, followed by the
electrophile [Boc2O, Piv2O, p-MeC6H4SO2Cl, (CF3SO2)2O,
(EtO)2P(O)Cl, dissolved in 5 mL of dry THF] 10 min later. The
reaction mixture was allowed to warm slowly to room tem-
perature in the bath (16 h, TLC: 8:1 CH2Cl2/EtOAc for Boc,
Piv, Tos and Tf; 1:8 CH2Cl2/EtOAc for bisphosphoramidate)
and then concentrated in vacuo. Water and CH2Cl2 were added
to the residue and the mixture was shaken vigorouly. The
organic phase was separated and the aqueous phase was
(35) Mikenda, W. Vib. Spectrosc. 1992, 3, 327-330.

Transformation of Arylmethylamines into R-Aminophosphonic Acids
J . Org. Chem., Vol. 65, No. 19, 2000 6129
desiccator over KOH. The crude product was purified by ion
exchange chromatogrphy (Dowex 50W x 4, H+, 50-100 mesh),
using water as eluent. Ninhydrin positive fractions were
pooled, concentrated by rotary evaporation to a small volume
and freeze-dried to leave a sufficiently pure, crystalline product
11 or 41. The analytical sample was crystallized from water.
Dieth yl N-P h en ylm eth ylp h osp h or a m id a te (14). Ben-
zylamine (5) (2.3 mL, 2.3 g, 22 mmol) yielded according to
general procedure A 4.40 g (90%) of phosphoramidate 14 as a
colorless liquid: bp 140 °C/0.15 mm (lit.16 bp 120 °C/0.05 mm).
mmol) gave by general procedure C 0.265 g (77%) of crystalline
(()-10c: Rf 0.15 (2:1 hexanes/EtOAc); mp 119-121 °C (hex-
anes) (lit.21 mp 118-120 °C).
(()-Diet h yl
1-(Diet h oxyp h osp h in yla m in o)p h en yl-
m eth ylph osph on ate [(()-10f]. Bisphosphoramidate 6f (0.380
g, 1 mmol) furnished by general procedure C 0.267 g (70%) of
(()-10f as a colorless oil: Rf 0.08 (1:8 CH2Cl2/EtOAc); IR (Si)
1240, 1029 cm-1; 1H NMR (250.1 MHz, CDCl3) δ 0.97 (dt, J )
0.9, 7.1 Hz, 3H), 1.03 (dt, J ) 0.7, 7.1 Hz, 3H), 1.19 (dt, J )
0.9, 7.1 Hz, 3H),1.26 (dt, J ) 0.6, 7.0 Hz, 3H), 3.60 (m, 2H),
3.88 (m, 5H), 4.07 (m, 2H), 4.44 (dt, J ) 10.6, 23.2 Hz, 1H),
7.30 (m, 5H); 13C NMR (100.6 MHz, CDCl3) δ 15.66 (d, J ) 7.7
Hz), 15.98 (d, J ) 7.6 Hz), 16.06 (d, J ) 6.1 Hz), 16.32 (d, J )
6.1 Hz), 52.98 (d, J ) 154.5 Hz), 62.34 (d, J ) 4.6 Hz), 62.39
(d, J ) 5.4 Hz), 62.97 (d, J ) 6.9 Hz), 63.26 (d, J ) 6.9 Hz),
127.79 (d, J ) 6.1 Hz, 2C), 128.00 (d, J ) 3.1 Hz), 128.37 (d,
J ) 2.3 Hz, 2C), 136.69.
Diet h yl N-4-Tolu en esu lfon yl-N-p h en ylm et h ylp h os-
p h or a m id a te (6b). Phosphoramidate 14 (1.2 g, 5 mmol)
yielded according to general procedure B 1.30 g (65%) of
tosylamide 6b as a colorless oil: Rf 0.64 (8:1 CH2Cl2/EtOAc);
IR (Si) 1353, 1268, 1020 cm-1; 1H NMR (250.1 MHz, CDCl3) δ
1.21 (dt, J ) 1.1, 7.0 Hz, 6H), 2.36 (s, 3H), 3.97 (m, 4H), 4.66
(d, J ) 11.4 Hz), 7.21 (m, 5H), 7.41 (m, 2H), 7.70 (m, 2H); 13
C
Rea ction of n -Bu Li/TMEDA w ith Tosyla ted P h osp h o-
r a m id a t e 6b : (()-Diet h yl 1-P h en ylp en t ylp h osp h on a t e
[(()-21]. Phosphoramidate 6b (397 mg, 1 mmol) was treated
with n-BuLi (2.4 mmol, 1.5 mL, 1.6 M solution in hexane)/
TMEDA (0.36 mL, 279 mg, 2.4 mmol) according to general
procedure C. Flash chromatography (1:1 hexanes/EtOAc; Rf
0.16) and bulb-to-bulb distillation (130-140 °C/0.3 mm) gave
217 mg (73%) of (()-21 as a colorless oil: IR (Si) 3209, 1232,
1033 cm-1; 1H NMR (250.1 MHz, CDCl3) δ 0.80 (t, J ) 6.9 Hz,
3H), 0.97 (dt, J ) 0.9, 7.1 Hz, 3H), 1.21 (m, 4H), 1.24 (dt, J )
0.9, 7.1 Hz, 3H), 1.68 (m, 2H), 3.38 (br.t, J ) 9.3 Hz, 1H), 3.54
(m, 1H), 3.81 (m, 1H), 3.98 (m, 3H), 7.22 (m, 5H); 13C NMR
(62.9 MHz, CDCl3) δ 13.62, 15.51 (d, J ) 7.8 Hz), 15.89 (d, J
) 7.4 Hz), 22.08, 28.03, 38.59 (d, J ) 7.4 Hz), 55.86, 61.64 (d,
J ) 4.6 Hz), 61.66 (d, J ) 5.1 Hz), 126.08 (2C), 126.71, 128.06
(2C), 144.22 (d, J ) 2.8 Hz). Anal. Calcd for C15H26NO3P
(299.35): C, 60.19; H, 8.75; N, 4.68. Found: C, 60.21; H, 8.70,
N, 4.46.
NMR (100.6 MHz, CDCl3) δ 15.52 (d, J ) 7.4 Hz), 21.13, 51.60
(d, J ) 2.3 Hz), 63.81 (d, J ) 5.5 Hz), 127.32, 127.54 (2C),
127.83 (2C), 128.43 (2C), 128.89 (2C), 136.40, 136.98, 143.65.
Anal. Calcd for C18H24NO5P (397.43): C, 54.40; H, 6.09; N,
3.52. Found: C, 54.66; H, 5.98, N, 3.42.
Dieth yl N-ter t-Bu toxyca r bon yl-N-p h en ylm eth ylp h os-
p h or a m id a te (6c). Meth od 1. A solution of s-BuLi (4.6 mL,
6.0 mmol, 1.3 M in cyclohexane) was added to a cooled (bath
temperature -40 °C) solution of N-Boc benzylamine (23)19
(1.04 g, 5 mmol) in dry toluene (10 mL) under argon. Stirring
was continued for 15 min. Diethyl chlorophosphate (0.87 mL,
1.04 g, 6.0 mmol, dissolved in 5 mL of dry toluene) was added.
The reaction mixture was allowed to warm slowly to room
temperature and was stirred until the starting material was
consumed (16 h, TLC: 8:1 CH2Cl2/EtOAc). CH2Cl2 and a
saturated solution of NH4Cl were added. The organic phase
was separated and the aqueous one was extracted twice with
CH2Cl2. The combined organic layers were washed with 0.5
M HCl and a saturated solution of NaHCO3, dried with Na2-
SO4 and concentrated in vacuo. The residue was flash chro-
matographed to yield 0.98 g (56%) of 6c as a viscous oil; Rf
0.57 (8:1 CH2Cl2/EtOAc).
Meth od 2. Phosphoramidate 14 (1.20 g, 5 mmol) was
transformed by general procedure B into 1.33 g (78%) of 6c as
a viscous oil: IR (Si) 1720 cm-1; 1H NMR (400.1 MHz, CDCl3)
δ 1.30 (dt, J ) 1.1, 7.0 Hz, 6H), 1.48 (s, 9H), 4.05 (m, 4H),
4.74 (d, J ) 11.2 Hz), 7.31 (m, 3H), 7.45 (m, 2H); 13C NMR
(100.6 MHz, CDCl3) δ 15.95 (d, J ) 6.9 Hz), 27.94, 49.49 (d, J
) 3.8 Hz), 63.26 (d, J ) 6.1 Hz), 82.30, 127.10, 127.99 (2C),
128.13 (2C), 138.85, 153.57 (d, J ) 6.1 Hz).
N-P h en ylm eth yl-2-d ieth oxyp h osp h in yl-4-m eth ylben -
zen esu lfon a m id e (22). N-Tosyl phosphoramidate 6b (0.40
g, 1 mmol) was treated with LDA according to general
procedure E. Flash chromatography (2:1 hexanes/EtOAc, Rf
0.35) of the crude product furnished 0.27 g (68%) of 22 as
crystalline solid: mp 78-80 °C (hexanes); IR (Si) 3142, 1021
1
cm-1; H NMR (250.1 MHz, CDCl3) δ 1.33 (t, J ) 0.7, 7.1 Hz,
6H), 2.41 (s, 3H), 4.07 (d, J ) 6.2 Hz, 2H), 4.17 (m, 4H), 7.14
(m, 5H), 7.37 (br.d, J ) 8.2 Hz, 1H), 7.66 (dd, J ) 1.4, 13.9
Hz, 1H), 7.95 (br.t, J ) 6.8 Hz), 7.99 (dd, J ) 6.2, 8.2 Hz, 1H);
13C NMR (62.9 MHz, CDCl3) δ 16.00 (d, J ) 6.4 Hz), 21.10,
47.16, 63.12 (d, J ) 5.5 Hz), 126.01 (d, J ) 187.1 Hz), 127.02,
127.67 128.02 (2C), 130.31 (d, J ) 12.4 Hz), 132.36 (d, J ) 2.8
Hz), 135.08 (d, J ) 6.0 Hz), 136.46, 140.73 (d, J ) 10.1 Hz),
Tet r a et h yl N-N-P h en ylm et h ylb is(p h osp h or a m id a t e)
(6f). Phosphoramidate 14 (1.20 g, 5 mmol) was transformed
by general procedure B into 1.34 g (72%) of 6f25 as a viscous
142.12 (d, J ) 12.9 Hz). Anal. Calcd for
C18H24NO5PS
(397.43): C, 54.40; H, 6.09; N, 3.52. Found: C, 54.63; H, 6.18,
N, 3.40.
1
oil: Rf 0.24 (1:3 CH2Cl2/EtOAc); IR (Si) 1262, 1026 cm-1; H
NMR (250.1 MHz, CDCl3) δ 1.22 (dt, J ) 0.6, 7.0 Hz, 12H),
3.99 (m, 8H), 4.52 (t, J ) 13.8 Hz, 2H), 7.25 (m, 3H), 7.49 (m,
2H); 13C NMR (100.6 MHz, CDCl3) δ 15.86 (d, J ) 3.1 Hz),
15.90 (d, J ) 3.1 Hz), 50.58, 63.23 (d, J ) 2.3 Hz), 63.27 (d, J
) 2.3 Hz), 127.38, 127.88 (2C), 128.83 (2C), 138.44.
Ca r boxyla tion a n d Rea r r a n gem en t of P h osp h or a m i-
d a te 14. s-BuLi (0.88 mL, 1.14 mmol, 1.3 M, in cyclohexane)
was added to a stirred and cooled (bath temperature -78 °C)
solution of phosphoramidate 14 (0.24 g, 1 mmol) in dry diethyl
ether (5 mL). After the solution was stirred for 5 min, the argon
atmosphere was replaced by a CO2 atmosphere, the cooling
bath was removed, and stirring was continued for 20 min. The
solvent was removed at the oil pump (0.3 mm), and the flask
was filled with argon. Dry diethy ether (5 mL) was added to
the residue, followed by s-BuLi (0.96 mL, 1.2 mmol, 1.3 M in
cyclohexane) after cooling of the solution to -78 °C. When the
reaction was complete (4 h, TLC 19:1 CH2Cl2/MeOH), AcOH
(1.15 mL, 2.3 mmol, 2 M solution in diethyl ether) was added.
The solvent was removed and the residue was diluted with
CH2Cl2 and water. The organic phase was separated and the
aqueous phase was extracted with CH2Cl2. The combined
organic layers were washed with water, dried (Na2SO4) and
concentrated in vacuo. The residue was flash chromatographed
(19:1 CH2Cl2/MeOH, Rf 0.29) to yield 115 mg (47%) of (()-27
as a colorless oil: 1H NMR (250.1 MHz, CDCl3) δ 1.16 (t, J )
7.0 Hz, 3H), 1.26 (t, J ) 7.3 Hz, 3H), 1.75 (br.s, 2H), 3.85 (m,
1H), 3.96 (m, 1H), 4.03 (m, 2H), 4.24 (d, J ) 17.1 Hz, 1H),
7.28 (m, 1H), 7.34 (m, 2H), 7.44 (m, 2H).
Diet h yl N-(1-Tr im et h ylsilylp h en ylm et h yl)p h osp h or -
a m id a te (16). Phosphoramidate 14 (243 mg, 1 mmol) fur-
nished according to general procedure D, except that Boc2O
was replaced by TMSCl and that the reaction mixture was
allowed to warm slowly at the end to room temperature, 0.252
g (80%) of (()-16 as a crystalline product: mp 78-79 °C
(hexanes); IR (Si) 1232, 1033 cm-1 1H NMR (250.1 MHz,
;
CDCl3) δ -0.02 (s, 9H), 0.85 (dt, J ) 0.9, 7.1 Hz, 3H), 1.27 (dt,
J ) 0.9, 7.1 Hz, 3H), 3.11 (br dd, J ) 10.1, 13.9 Hz, 1H), 3.47
(m, 1H), 3.66 (t, J ) 10.5 Hz, 2H); 3.79 (m, 1H), 3.99 (m, 2H),
7.09 (m, 3H), 7.23 (m, 2H); 13C NMR (62.9 MHz, CDCl3) δ
-4.01, 15.40 (d, J ) 7.8 Hz), 16.03 (d, J ) 7.4 Hz), 47.80 (d, J
) 5.1 Hz), 61.90 (d, J ) 4.6 Hz), 61.99 (d, J ) 5.1 Hz), 125.32,
125.83 (2C), 127.82 (2C), 142.82. Anal. Calcd for C14H24NO3-
PSi (315.42): C, 53.31; H, 7.67; N, 4.44. Found: C, 53.60; H,
7.96, N, 4.41.
(()-Dieth yl 1-(ter t-Bu toxyca r bon yla m in o)p h en ylm eth -
ylp h osp h on a t e [(()-10c]. Phosphoramidate 6c (0.34 g, 1

6130 J . Org. Chem., Vol. 65, No. 19, 2000
Hammerschmidt and Hanbauer
(+)-Diet h yl
(R)-N-ter t-Bu t oxyca r b on yl-N-[1-2H 1]-
NMR (250.1 MHz, CDCl3) δ 1.21 (dt, J ) 0.5, 7.1 Hz, 3H), 1.26
(dt, J ) 0.5, 7.1 Hz, 3H), 4.03 (m, 4H), 4.70 (d, J ) 16.7 Hz,
1H), 7.39 (m, 5H); 13C NMR (62.9 MHz, CDCl3) δ 16.16 (d, J
) 6.0 Hz), 16.27 (d, J ) 5.5 Hz), 61.49 (d, J ) 158.1 Hz), 63.33
(d, J ) 5.1 Hz), 63.43 (d, J ) 5.5 Hz), 128.16 (d, J ) 6.0 Hz,
2C), 128.57 (d, J ) 1.8 Hz, 2C), 128.72 (d, J ) 2.8 Hz), 132.16
(d, J ) 3.7 Hz). Anal. Calcd for C11H16N3O3P (269.22): C, 49.07;
H, 5.62; N, 15.61. Found: C, 49.14; H, 5.85, N, 15.47.
p h en ylm eth ylp h osp h or a m id a te (R)-[1-2H1]6c. DEAD (0.7
mL, 0.77 g, 4.4 mmol) was added dropwise to a cooled (0 °C)
and stirred solution of Ph3P (1.15 g, 4.4 mmol), N-Boc phos-
phoramidate 2925 (1.11 g, 4.4 mmol) and (S)-2827 (0.44 g, 4.0
mmol) in dry toluene (20 mL) under argon. The cooling bath
was removed and the reaction mixture was stirred for 16 h
and then concentrated in vacuo. Hexanes (20 mL) were added
and the mixture was stirred vigorously. The crystalline solid
was removed and the mother liquor was rotary evaporated.
Flash chromatography (2:1 hexanes/EtOAc, Rf 0.36) gave 0.89
g (64%) of (R)-[1-2H1]6c as a colorless oil: 2H g98% (by 1H
Dieth yl (S)-1-Am in op h en ylm eth ylp h osp h on a te [(S)-
27]. A solution of (S)-36 [0.41 g, 1.5 mmol, [R]20 -35.11 (c
D
1.17, CHCl3)] and Ph3P (0.65 g, 2.5 mmol) in dry THF (10 mL)
was stirred under argon at room temperature until completion
of reaction (19 h, TLC 19:1 CH2Cl2/MeOH).37 Water (1 mL)
was added, and the mixture was refluxed for 3 h (TLC 1:8 CH2-
Cl2/EtOAc). The mixture was concentrated in vacuo. Flash
chromatography (1:8 CH2Cl2/EtOAc, Rf 0.14) of the residue
yielded 337 mg (92%) of (S)-27 as a colorless oil: [R]20D -16.30
(c 1.49, MeOH) [lit.24 [R]20D -15.60 (c 1.0, MeOH)]; when azide
NMR); [R]20 +0.36 (c 33.1, acetone); 1H NMR (250.1 MHz,
D
CDCl3) δ 1.25 (dt, J ) 0.9, 7.1 Hz, 6H), 1.43 (s, 9H), 4.01 (m,
4H), 4.68 (d, J ) 11.4 Hz, 1H), 7.26 (m, 3H), 7.39 (m, 2H); 13
C
NMR (100.6 MHz, CDCl3) δ 15.98 (d, J ) 6.9 Hz), 27.97, 49.26
(dt, J ) 3.0, 21.9 Hz), 63.28 (d, J ) 5.4 Hz), 82.32, 127.16,
128.06 (2C), 128.18 (2C), 138.81, 153.62. 31P NMR (162.0 MHz,
CDCl3) δ 3.39. Anal. Calcd for C16H25DNO5P (344.35): C, 55.81;
H + D, 7.61; N, 4.07. Found: C, 56.09; H + D, 7.60, N, 4.04.
(R)-N-[1-2H1]P h en ylm eth ylp h th a lim id e [(R)-33]. DEAD
(0.83 g, 0.75 mL, 4.8 mmol) was added dropwise to a stirred
and cooled (0 °C) solution of phthalimide (1.26 g, 4.8 mmol),
of Ph3P (1.26 g, 4.8 mmol) and (S)-28 (0.44 g, 4.0 mmol) in dry
THF (20 mL) under argon. The cooling bath was removed and
stirring was continued at room temperature (4 h, TLC: 2:1
hexanes/EtOAc). Then water (1 mL) was added and the
reaction mixture was filtered through a column of silica (60
g), eluting with CH2Cl2. The eluate was concentrated in vacuo
and the crude product was flash chromatographed (2:1 hex-
anes/EtOAc, Rf 0.42) to yield 958 mg (99%) of (R)-33 as a
crystalline product: mp 116-117 °C [lit.26 for (()-33 mp 116
°C (hexane)], g98% D (1H NMR); [R]20D +0.12 (c 8.50, acetone).
(R)-[1-2H1]P h en ylm eth yla m in e [(R)-34]. Phthalimide (S)-
33 (0.81 g, 3.3 mmol) was deprotected by a literature proce-
dure26 to yield 358 mg (100%) of (R)-34 as a yellowish oil that
was used for the next step without further purification.
Dieth yl (R)-N-[1-2H1]P h en ylm eth ylp h osp h or a m id a te
[(R)-[1-2H1]14]. Crude amine (R)-34 (0.27 g, 2.5 mmol) was
transformed using general procedure A into 452 mg (74%) of
with [R]20 +40.17 (c 1.16, CHCl3) was reduced by the same
D
procedure, an amine of [R]20D -18.72 (c 1.26, MeOH) resulted;
the 1H NMR spectrum is identical with that of (()-27.
Diet h yl
(S)-1-(Diet h oxyp h osp h in yla m in o)p h en yl-
m eth ylp h osp h on a te [(S)-10f]. Diethyl chlorophosphate (0.12
mL, 138 mg, 0.8 mmol) was added dropwise to a cooled (0 °C)
and stirred solution of (S)-27 [0.13 g, 0.53 mmol, [R]20D -16.30
(c 1.49, MeOH)] and Et3N (0.18 mL, 1.2 mmol) in dry CH2Cl2
(5 mL) under argon. The cooling bath was removed and the
mixture was refluxed (4 h, TLC 10:1 CH2Cl2/MeOH). The
cooled solution was washed with 2 M HCl and a saturated
solution of NaHCO3, dried (Na2SO4), and concentrated in
vacuo. Flash chromatography of the residue furnished 139 mg
(69%) of (S)-10f as a colorless oil: [R]20 -17.06 (c 1.08,
D
acetone); aminophosphonate (S)-27 with [R]20D -18.72 (c 1.26,
MeOH) gave (S)-10f with [R]20 -19.54 (c 0.99, acetone); the
D
spectroscopic data of (S)-10f are identical with those of (()-
10f.
Dieth yl (S)-1-(ter t-Bu toxyca r bon yla m in o)p h en ylm e-
th ylph osph on ate [(S)-10c]. R-Aminophosphonate (S)-27 (0.15
g, 0.61 mmol, ee 98%) was reacted with Et3N (2 equiv) and
Boc2O (1.1 equiv) by the procedure given for the preparation
for (S)-10f. Flash chromatography (5:1 CH2Cl2/EtOAc, Rf 0.23)
furnished 134 mg (63%) of (S)-10c as a crystalline solid: mp
(R)-[1-2H1]14 as a colorless liquid: bp 145 °C/0.2 mm; g98%
D (1H NMR); [R]20 -0.62 (c 13.96, acetone); H NMR (250.1
1
D
137-138 °C (hexanes) [lit.21 for (()-10c 118-120 °C]; [R]20
MHz, CDCl3) δ 1.27 (t, J ) 7.1 Hz, 6H), 3.02 (t, J ) 7.5, 1H),
4.03 (m, 5H), 7.28 (m, 5H); 13C NMR (100.6 MHz, CDCl3) δ
15.96 (d, J ) 6.9 Hz), 44.87 (t, J ) 20.9 Hz), 62.14 (d, J ) 5.5
Hz), 127.13 (3C), 128.34 (2C), 139.47 (d, J ) 6.0 Hz); 31P NMR
(162.0 MHz, CDCl3) δ 9.76.
D
-15.81 (c 0.96, acetone); the spectroscopic data are identical
with that of (()-10c.
Dieth yl N-(4-Meth ylp h en yl)m eth ylp h osp h or a m id a te
(38a ). Amine 37a (2.8 mL, 2.7 g, 22 mmol) yielded according
to general procedure A 4.41 g (86%) of phosphoramidate 38a
as a colorless liquid that solidified on storage at +4 °C: bp
145 °C/0.15 mm; IR (Si) 3226, 1239, 1032 cm-1; 1H NMR (400.1
MHz, CDCl3) δ 1.26 (t, J ) 7.0 Hz, 6H), 2.29 (s, 3H), 3.07 (dt,
J ) 6.5, 10.5 Hz, 1H), 4.01 (m,6H), 7.13 (AA′BB′system, 4H);
13C NMR (100.6 MHz, CDCl3) δ 16.00 (d, J ) 7.7 Hz), 20.09,
44.91, 62.12 (d, J ) 5.4 Hz), 127.13 (2C), 129.02 (2C), 136.55
(d, J ) 6.1 Hz), 136.77; 31P NMR (162.0 MHz, CDCl3) δ 9.65.
Anal. Calcd for C12H20NO3P (257.26): C, 56.03; H, 7.84; N,
5.44. Found: C, 55.79; H, 7.72, N, 5.34.
Tet r a et h yl (R)-N-[1-2H 1]P h en ylm et h ylb is(p h osp h or -
am idate) [(R)-[1-2H1]6f]. Phosphoramidate (R)-[1-2H1]14 (0.42
g, 1.7 mmol) was transformed by general procedure B into 318
mg (49%) of (R)-[1-2H1]6f as a viscous oil: Rf 0.27 (1:8 CH2-
Cl2/EtOAc); g98% 2H (1H NMR); [R]20D -0.33 (c 5.99, acetone);
1H NMR (250.1 MHz, CDCl3) δ 1.23 (dt, J ) 0.6, 7.1 Hz, 12H),
4.00 (m, 8H), 4.52 (t, J ) 13.5 Hz, 1H), 7.26 (m, 3H), 7.50 (m,
2H); 13C NMR (62.9 MHz, CDCl3) δ 15.83 (d, J ) 3.7 Hz), 15.91
(d, J ) 3.7 Hz), 50.02 (t, J ) 21.6 Hz), 63.21 (d, J ) 2.3 Hz),
63.28 (d, J ) 2.3 Hz), 127.38, 127.97 (2C), 128.83 (2C), 138.38;
31P NMR (162.0 MHz, CDCl3) δ 5.15.
Dieth yl N-(4-Meth oxyp h en yl)m eth ylp h osp h or a m id a te
(38b). Amine 37b (2.9 mL, 3.0 g, 22 mmol) yielded according
to general procedure A 4.67 g (85%) of phosphoramidate 38b
as a colorless liquid: bp 175 °C/0.15 mm; IR (Si) 3233, 1249,
Dieth yl (S)-1-Azid op h en ylm eth ylp h osp h on a te [(S)-36].
To a stirred and cooled (0 °C) solution of (R)-3530 [0.32 g, 1.3
mmol; [R]20 +37.31 (c 1.04, CHCl3)] and Ph3P (0.47 g, 1.8
D
1
1032 cm-1; H NMR (250.1 MHz, CDCl3) δ 1.26 (dt, J ) 0.7,
mmol) in a mixture of dry toluene (8 mL) and dry THF (2 mL)
under argon HN3 (1.12 mL, 1.8 mmol, 1.6 M in toluene) was
added, immediately followed by DEAD (0.29 mL, 0.32 g, 1.8
mmol). The cooling bath was removed and stirring was
continued until the reaction was finished (1 h, TLC 3:1 CH2-
Cl2/EtOAc). MeOH (0.3 mL) was added and the solvent was
removed in vacuo. Hexanes (15 mL) were added to the residue
and the mixture was stirred vigorously for 16 h. The crystalline
material was filtered off and the mother liquor was concen-
trated. Flash chromatography (8:1 CH2Cl2/EtOAc, Rf 0.38)
yielded 338 mg (96%) of (S)-36 as a colorless oil: [R]20D -40.17
(c 1.16, CHCl3); ee 98% when the reaction was carried out in
7.1 Hz, 6H), 3.01 (dt, J ) 6.3, 10.5 Hz, 1H), 3.75 (s, 3H), 4.01
(m, 6H), 7.01 (AAÅBB’ system, 4H); 13C NMR (62.9 MHz,
CDCl3) δ 16.01 (d, J ) 6.9 Hz), 44.69, 55.10, 62.13 (d, J ) 5.5
Hz), 113.76 (2C), 128.44 (2C), 131.73 (d, J ) 6.4 Hz), 158.75;
31P NMR (162.0 MHz, CDCl3) δ 9.70. Anal. Calcd for C12H20
-
NO4P (273.26): C, 52.75; H, 7.38; N, 5.13. Found: C, 52.01;
H, 7.35, N, 4.86.
Dieth yl N-(1′-Na p h th yl)m eth ylp h osp h or a m id a te (38c).
Amine 37c (3.2 mL, 3.4 g, 22 mmol) yielded according to
(36) Kim, J .-M.; Bogdan, M. A.; Mariano, P. S. J . Am. Chem. Soc.
1993, 115, 10591-10595.
(37) O¨ hler, E.; Kotzinger, S. Liebigs Ann. Chem. 1993, 269-280.
dry toluene in the same way, 146 g (47%) of (S)-36 resulted;
[R]20 -35.11 (c 1.17, CHCl3); ee 86%; IR (Si) 2104 cm-1; H
1
D

Transformation of Arylmethylamines into R-Aminophosphonic Acids
J . Org. Chem., Vol. 65, No. 19, 2000 6131
general procedure A 5.17 g (88%) of phosphoramidate 38c: bp
175 °C/0.15 mm; mp 61-63 °C; IR (Si) 3220, 1235, 1032 cm-1
(48%) of 39c as a colorless oil; Rf 0.35 (10:1 CH2Cl2/EtOAc);
1
;
IR (Si) 1723 cm-1; H NMR (250.1 MHz, CDCl3) δ 1.27 (dt, J
1H NMR (250.1 MHz, CDCl3) δ 1.28 (dt, J ) 0.7, 7.1 Hz, 6H),
3.02 (dt, J ) 6.4, 9.1 Hz, 1H), 4.04 (m, 4H), 4.54 (dd, J ) 6.9,
8.7 Hz, 2H), 7.48 (m, 4H), 7.82 (m, 2H), 8.06 (m, 1H); 13C NMR
(62.9 MHz, CDCl3) δ 16.04 (d, J ) 6.9 Hz), 43.12, 62.31 (d, J
) 5.5 Hz), 123.09, 125.24, 125.33, 125.71, 126.20, 128.12,
128.64, 130.98, 133.69, 134.84 (d, J ) 6.9 Hz); 31P NMR (162.0
MHz, CDCl3) δ 9.46. Anal. Calcd for C15H20NO4P (293.30): C,
61.43; H, 6.87; N, 4.78. Found: C, 61.33; H, 6.71, N, 4.73.
Diet h yl N-ter t-Bu t oxyca r b on yl-N-(4-m et h ylp h en yl)-
m eth ylp h osp h or a m id a te (39a ). Phosphoramidate 38a (1.30
g, 5 mmol) was transformed by general procedure B into 1.22
g (68%) of 39a as a colorless oil: Rf 0.40 (10:1 CH2Cl2/EtOAc);
) 0.9, 7.1 Hz, 6H), 1.41 (s, 9H), 4.09 (m, 4H), 5.24 (d, J ) 11.2
Hz, 2H), 7.46 (m, 4H), 7.72 (bd, J ) 7.8 Hz, 2H), 7.83 (m, 1H),
8.06 (m, 1H); 13C NMR (100.6 MHz, CDCl3) δ 16.04 (d, J ) 6.9
Hz), 27.90, 47.23, 63.65 (d, J ) 6.1 Hz), 82.48, 122.89, 123.59,
125.21, 125.44, 125.87, 127.39, 128.58, 130.79, 133.53, 133.96,
153.73 (d, J ) 6.1 Hz); 31P NMR (162.0 MHz, CDCl3) δ 3.55.
Anal. Calcd for C20H28NO5P (393.42): C, 61.06; H, 7.17; N,
3.56. Found: C, 61.34; H, 7.17, N, 3.48.
(()-1-Am in op h en ylm eth ylp h osp h on ic Acid [(()-11c].
Phosphoramidate 14 (243 mg, 1 mmol) was transformed by
general procedure D into aminophosphonate (()-10c, which
was deproteced as crude product by general procedure G: yield
124 mg (63% overall yield starting from 14) of (()-11c as a
crystalline solid; Rf 0.49, mp 279-281 °C (water) [lit.38 280-
282 °C (water/EtOH)].
(()-1-Am in o-(4-m eth ylp h en yl)m eth ylp h osp h on ic Acid
[(()-41a ]. Phosphoramidate 39a (357 mg, 1 mmol) was
transformed by general procedure C into aminophosphonate
(()-40a which was deprotected as crude product by general
procedure G; yield: 152 mg (75% overall yield starting from
39a ) of (()-41a as a crystalline solid: Rf 0.61, mp 274-276
°C (water) [lit.38 274-277 °C (water/EtOH)].
(()-1-Am in o-(1′-n a ph th yl)m eth ylph osph on ic Acid [(()-
41c]. Phosphoramidate 39c (393 mg, 1 mmol) was transformed
by general procedure C into aminophosphonate (()-40c which
was deprotected as crude product by general procedure G;
yield: 117 mg (49% overall yield starting from 39c) of (()-
41c as a crystalline solid: Rf 0.72, mp 268-270 °C (water)
[lit.39 270 °C (water/MeOH)].
1
IR (Si) 1720 cm-1; H NMR (250.1 MHz, CDCl3) δ 1.25 (dt, J
) 0.9, 7.1 Hz, 6H), 1.43 (s, 9H), 2.29 (s, 3H), 4.00 (m, 4H),
4.65 (d, J ) 11.4 Hz), 7.18 (AA′BB′ system, 4H); 13C NMR (62.9
MHz, CDCl3) δ 15.92 (d, J ) 6.9 Hz), 20.96, 27.94, 49.20 (d, J
) 3.2 Hz), 63.16 (d, J ) 5.5 Hz), 82.17, 128.05 (2C), 128.76
(2C), 135.80, 136.62, 153.55 (d, J ) 6.4 Hz). 31P NMR (162.0
MHz, CDCl3) δ 3.46. Anal. Calcd for C17H28NO5P (357.38): C,
57.13; H, 7.90; N, 3.92. Found: C, 57.16; H, 7.70, N, 3.77.
Dieth yl N-ter t-Bu toxyca r bon yl-N-(4-m eth oxyp h en yl)-
m eth ylp h osp h or a m id a te (39b). Phosphoramidate 38b (1.40
g, 5 mmol) was transformed by general procedure B into 1.41
g (75%) of 39b as a colorless oil: Rf 0.31 (10:1 CH2Cl2/EtOAc);
the analytical sample was bulb to bulb distilled, bp 185 °C/
0.2 mm; IR (Si) 1720 cm-1
1.24 (dt, J ) 0.9, 7.1 Hz, 6H), 1.43 (s, 9H), 3.75 (s, 3H), 3.97
(m, 4H), 4.62 (d, J ) 11.4 Hz), 7.08 (AA′BB′ system,. 4H); 13
;
1H NMR (250.1 MHz, CDCl3) δ
C
NMR (62.9 MHz, CDCl3) δ 15.89 (d, J ) 7.4 Hz), 27.93, 48.84
(d, J ) 3.2 Hz), 55.04, 63.07 (d, J ) 5.5 Hz), 82.12, 113.40
(2C), 129.63 (2C), 131.08, 153.52 (d, J ) 6.0 Hz); 31P NMR
(162.0 MHz, CDCl3) δ 3.42. Anal. Calcd for C17H28NO6P
(373.38): C, 54.69; H, 7.56; N, 3.75. Found: C, 54.94; H, 7.67,
N, 3.97.
Dieth yl N-ter t-Bu toxyca r bon yl-N-(1′-n a p h th yl)m eth -
ylp h osp h or a m id a te (39c). Phosphoramidate 38c (1.50 g, 5
mmol) was transformed by general procedure B into 0.94 g
Ack n ow led gm en t. We are grateful to the Fonds zur
Fo¨rderung der wissenschafltichen Forschung (project
no. P13017-CHE and 6537C).
J O000585F
(38) Lukszo, J .; Tyka, R. Synthesis 1977, 239-240.
(39) Hoffmann, H.; Fo¨rster, H. Monatsh. Chem. 1968, 99, 380-388.