The Synthesis of P-Chiral Amino Acid-Derived Phosphonamidic Anhydrides

Article abstract of DOI:10.1021/jo000631b

The synthesis of an array of P-chiral amino acid-derived phosphonamidic anhydrides is described. These anhydrides are prepared by condensation of allylated amino acids 19-22 with methyl- or vinylphosphonic dichlorides 23 or 24 to produce three diastereomeric anhydrides 4-11a-c in good to excellent yields. The mechanistic issues concerning anhydride formation are discussed and supported by experimental results. Vinylphosphonamidic anhydrides 8-11 are further derivatized via the ring-closing metathesis (RCM) reaction to yield amino acid-derived bicyclic phosphonamidic anhydrides.

Full text of DOI:10.1021/jo000631b

J . Org. Chem. 2000, 65, 4721-4728
4721
Th e Syn th esis of P -Ch ir a l Am in o Acid -Der ived P h osp h on a m id ic
An h yd r id es
Kevin T. Sprott and Paul R. Hanson*
Department of Chemistry, 2010 Malott Hall, University of Kansas, Lawrence, Kansas 66045-2506
phanson@ukans.edu
Received April 25, 2000
The synthesis of an array of P-chiral amino acid-derived phosphonamidic anhydrides is described.
These anhydrides are prepared by condensation of allylated amino acids 19-22 with methyl- or
vinylphosphonic dichlorides 23 or 24 to produce three diastereomeric anhydrides 4-11a -c in good
to excellent yields. The mechanistic issues concerning anhydride formation are discussed and
supported by experimental results. Vinylphosphonamidic anhydrides 8-11 are further derivatized
via the ring-closing metathesis (RCM) reaction to yield amino acid-derived bicyclic phosphonamidic
anhydrides.
Sch em e 1
In tr od u ction
Anhydrides and their derivatives have a rich history
both in terms of their synthetic utility as well as their
biological relevance.1 Anhydrides are widely known to
serve as potent inhibitors of a variety of enzymes,2 with
a number of anhydrides recently being reported as potent
in-activators of various serine proteases.3 Pyrophosphonic
acid 1 (Scheme 1) and related analogues are a class of
phosphorus-based anhydrides that have gained enormous
attention over the last 50 years for their ability to serve
as potent inhibitors of osteoclastic bone resorption and,
therefore, have therapeutic value as osteoporotic agents.4
Bisphosphonates,5 synthetic non-hydrolyzable P-C-P
analogues of pyrophosphates, are thus far the most
effective agents developed for inhibiting osteoclastic bone
re-sorption. As a result of the pioneering work of Fleisch,6
these agents have become the primary players in the
fight against osteoporosis, with Alendronate (2) now on
the market.7 Bisphosphonic acids have also proven to be
powerful inhibitors of squalene synthase,8 a crucial
enzyme in the role of cholesterol biosynthesis. Current
efforts in this area are focused on the development of
diverse pyrophosphate analogues in hopes of improving
their therapeutic profiles.9
Schrader first reported a multitude of unique pyro-
phosphates during his initial work on phosphorus based
insecticides.10 A class of compounds that we have begun
to study are the nitrogen containing phosphonamidic
anhydrides 3. Since the initial report of these anhy-
drides,11 an array of analogues have been studied,12 many
of which possess an assortment of chemical and biological
attributes including plant regulation,13 metal chelation,14
and anti-cholinesterase activity. As part of our program
* To whom correspondence should be addressed. Tel: (785) 864-
3094. Fax: (785) 864-5396. http://www.chem.ukans.edu/phansongroup/.
(1) ) (a) Tarbell, D. S. Accounts Chem. Res. 1969, 2, 296-300. (b)
Soai, K. Yuki Gosei Kagaku Kyokaishi 1987, 45, 1148-56. (c) Martin,
A. A.; Barnikow, G. Z. Chem. 1987, 27, 90-95. (d) Eberson, L.; Nyberg,
K. Encycl. Electrochem. Elem. 1978, 12, 261-328.
(2) (a) Karibian, D.; J ones, C.; Gertler, A.; Dorrington, K. J .;
Hofmann, T. Biochemistry 1974, 13, 2891-2897. (b) Hampton, A.;
Harper, P. J . Arch. Biochem. Biophys. 1971, 143, 340-341. (c)
Yamaguchi, M.; Hatefi, Y. Arch. Biochem. Biophys. 1985, 243, 20-27.
(d) Takahashi, K. J . Biochem. 1977, 81, 641-646. (e) Moulin, A.;
Fourneron, J .-D.; Pie´roni, G.; Verger, R. Biochemistry 1989, 28, 6340-
6346. (f) Hampton, A.; Harper, P. J .; Sasaki, T.; Howgate, P.; Preston,
R. K. Biochem. Biophys. Res. Commun. 1975, 65, 945-950.
(3) (a) Iijima, K.; Katada, J .; Hayashi, Y. Biorg. Med. Chem. Lett.
1999, 9, 413-418. (b) Moorman, A. R.; Abeles, R. H. J . Am. Chem.
Soc. 1982, 104, 6785-6786. (c) Baek, D.-J .; Reed, P. E.; Daniels, S. B.;
Katzenellenbogen, J . A. Biochemistry 1990, 29, 4305-4311. (d) Gelb,
M. H.; Abeles, R. H. J . Med. Chem. 1986, 29, 585-589. (e) Ito, K.;
Igarashi, K.; Muramatsu, M.; Harada, T.; Hayashi, Y.; Katada, J .; Uno,
I. Biochem. Biophys. Res. Commun. 1997, 240, 850-855.
(6) a) Fleisch, H. A.; Russell, R. G. G.; Francis, M. D. Science 1969,
165, 1262-1264. (b) Francis, M. D.; Russell, R. G. G.; Fleisch, H. A.
Science 1969, 165, 1264-1266.
(7) Shinkai, I.; Ohta, Y. Bioorg. Med. Chem. 1996, 4, 3-4.
(8) (a) Amin, D.; Cornell, S. A.; Gustafson, S. K.; Needle, S. J .;
Ullrich, J . W.; Bilder, G. E.; Perrone, M. H. J . Lipid Res. 1992, 33,
1657-1663. (b) Ciosek, C. P.; Magnin, D. R.; Harrity, T. W.; Logan, J .
V. H.; Dickson, J . K.; Gordon, E. M.; Hamilton, K. A.; J olibois, K. G.;
Kunselman, L. K.; Lawrence, R. M.; Mookhtiar, K. A.; Rich, L. C.;
Slusarchyk, D. A.; Sulsky, R. B.; Biller, S. A. J . Biol. Chem. 1993, 268,
24832-24837. (c) Magnin, D. R.; Biller, S. A.; Dickson, J . K.; Logan,
J . V.; Lawrence, R. M.; Chen, Y.; Sulsky, R. B.; Ciosek, C. P.; Harrity,
T. W.; J olibois, K. G.; Kunselman, L. K.; Rich, L. C.; Slusarchyk, D. A.
J . Med. Chem. 1995, 38, 2596-2605.
(4) (a) Sato, M. Grese, T. A.; Dodge, J . A.; Bryant, H. U.; Turner, C.
H. J . Med. Chem. 1999, 42, 1-24. (b) Zimolo, Z.; Wesolowski, G.; Rodan,
G. A. J . Clin. Invest. 1995, 96, 2277-2283.
(5) (a) Russell, R. G. G. Clin. Endocrinol. 1982, 2, 114-124. (b)
Fleisch, H. Bone Miner. Res. 1983, 1, 319-357. (c) Sunberg, R. J .;
Ebetino, F. H.; Mosher, C. T.; Roof, C. F. Chemtech 1991, 21, 304-
309. (d) Russell, R. G. G.; Rogers, M. J . Bone 1999, 25, 97-106. (e)
Shoemaker, L. J . Pedatrics 1999, 134, 264-267. (f) Teronen, O.;
Heikkila, P.; Konttinen, Y. T.; Laitinen, M.; Salo, T.; Hanemaaijer,
R.; Teronen, A.; Maisi, P.; Sorsa, T. Ann. N. Y. Acad. Sci. 1999, 878,
453-465.
(9) Recently, novel clodronic acid dianhydrides have been shown to
be bioreversible prodrugs of clodronate: (a) Ahlmark, M.; Vepsa¨la¨inen,
J .; Taipale, H.; Niemi, R.; J a¨rvinen, T. J . Med. Chem. 1999, 42, 1473-
1476. (b) Hurst, M.; Noble, S. Drugs Aging 1999, 15, 143-167. (c) See
also ref 8.
(10) Schrader, G. Die Entwicklung neuer insektizider Phosphorsa¨ure-
Ester; Verlag Chemie, GmbH.: Germany, 1963.
(11) J oesten, M. D.; Chen, Y. T. Inorg. Chem. 1972, 11, 429-431.
10.1021/jo000631b CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/06/2000

4722 J . Org. Chem., Vol. 65, No. 15, 2000
Sprott and Hanson
Sch em e 2
Sch em e 3
followed by ring-closing metathesis (Scheme 3). However,
repeated attempts at the bis-allylation of the phospho-
namide 16 failed. We next attempted to couple 2.0
equivalents of the R-branched allylated amino acids
19-2219 with the methyl- or vinylphosphonic dichlorides
23 or 24 (Scheme 4). However, repeated attempts at this
coupling resulted only in mono-amination to yield two
diastereomeric phosphonamidic chloridates 25-32P SS
and 25-32P RS (Scheme 4). This result is presumable due
to steric factors which prevent the bis-coupling of two
secondary R-branched amino acids with methyl phospho-
nic dichloride.20 These P-chiral diastereomers are re-
markably stable, and can be isolated and purified by SiO2
column chromatography in near quantitative yields. The
chloridates are consistently formed in an approximate
1:1 ratio as determined by 31P NMR, regardless of the
amino acid/phosphonic dichloride combination. Upon
standing at ambient temperature, these intermediate
chloridates 25-32 dimerize over a period of 4 days as
monitored by 31P NMR. After water workup, this protocol
(method A) yields three diastereomeric phosphonamidic
anhydrides: a pseudo-meso isomer 4-11c, and a pair of
C2-symmetric diastereomers 4-11a , and 4-11b as
aimed at the development of structurally diverse phos-
phorus- and sulfur-based compounds,15 we herein report
a concise strategy into a new class of P-chiral amino acid-
derived phosphonamidic anhydrides 4-15 (Scheme 2).
These compounds, containing two stereogenic phosphorus
atoms, exist as a pair of C2-symmetric diastereomers and
a single pseudo-meso diastereomer.16 In this initial
report, we discuss the convenient synthesis of a multitude
of amino acid-based phosphonamidic anhydrides 4-15
(Scheme 2) and provide a mechanistic overview for their
formation. We feel that this approach provides ample
opportunity into the development of potentially useful,
chiral, nonracemic phosphonamidic anhydrides.
Resu lts a n d Discu ssion
1
assayed by 31P NMR (Table 1), H NMR, 13C NMR, and
In our continuing effort to synthesize novel P-hetero-
cycles,15 we have targeted a number of cyclic phosphorus
containing motifs which can be accessed via the ring-
closing metathesis (RCM) reaction (Scheme 3). Recently
we reported a similar RCM strategy as a facile method
to prepare amino acid-derived C2-symmetric cyclic sul-
famides.17 Our initial attempts to prepare the cyclic
phosphonamide 18 in a similar manner focused on the
bis-allylation of the phosphonamide 1618 to derive 17
mass spectral analysis. Typical yields of the anhydrides
in this original recipe range from 40 to 80%, with the
remainder as hydrolyzed phosphonamidic acid.
We recently developed an optimized method (method
B) which consistently leads to higher yields. A represen-
tative example of this new procedure applied to any of
the phosphonamidic chloridates 25-32 was as follows:
a single diastereomeric mixture of neat phosphonamidic
chloridates 30P SS and 30P RS was cooled to 0° and
exposed neat to 3.5 equivalents of triethylamine in an
inert atmosphere. The reaction mixture was heated to
50° and monitored by TLC until disappearance of the
phosphonamidic chloridates (typical reaction time is 30
min). The mixture was partitioned between EtOAc and
water to cleanly yield the three diastereomeric anhy-
(12) (a) Healy, J . D.; Shaw, R. A.; Smith, B. C.; Thakur, C. P.; Wood,
M. J . Chem. Soc., Dalton Trans. 1974, 12, 1286-1290. (b) Duddeck
H.; Lecht, R. Phosphorus Sulfur 1987, 29, 169-178. (c) Breker, J .;
Schmutzler, R. Chem. Ber. 1990, 123, 1307-1312. (d) Harger, M. J .
P.; Sreedharan-Menon, R. J . Chem. Soc., Perkin Trans. 1 1994, 3261-
3267.
(13) Hofer, W.; Klaus, L. German Patent, Application: DE 74-
2420627 740427.
(14) (a) J oesten, M. D. Inorg. Chem. 1967, 6, 1598-1599. (b)
Lannert, K. P.; J oesten, M. D. Inorg. Chem. 1968, 7, 2048-2051. (c)
Prysak, M. F.; J oesten, M. D. Inorg. Chem. 1969, 8, 1455-1458. (d)
Lannert, K. P.; J oesten, M. D. Inorg. Chem. 1969, 8, 1775-1777. (e)
Prysak, M. F.; J oesten, M. D. Inorg. Chim. Acta 1970, 4, 383-389. (f)
J oesten, M. D.; Smith, H. E.; Vix, V. A. J . Chem. Soc., Chem. Commun.
1973, 18-19.
(15) (a) Hanson, P. R.; Stoianova, D. S. Org. Lett. 2000, 2, 1769-
1772. (b) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett. 1998, 39,
3939-3942. (c) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett. 1999,
3297-3300. (d) Hanson, P. R.; Sprott, K. T.; Wrobleski, A. D.
Tetrahedron Lett., 1999, 40, 1455-1458.
(17) (a) Dougherty, J . M.; Probst, D. A.; Robinson, R. E.; Moore, J .
D.; Klein, T. A.; Snelgrove, K. A.; Hanson, P. R. Tetrahedron 2000,
manuscript accepted for publication. (b) Additional results related to
the synthesis of seven-membered cyclic sulfamides via RCM strategies
are currently the topic of a manuscript submitted for publication.
(18) Amino acids have previously been coupled to phosphonic
dichlorides, see: (a) Koizumi, T.; Amitani, H.; Yoshii, E. Tetrahedron
Lett. 1978, 3741-3742. (b) Koizumi, T.; Kobayashi, Y.; Amitani, H.;
Yoshii, E. J . Org. Chem. 1977, 42, 3459-3460.
(19) Rutjes, F. P. J . T.; Schoemaker, H. E. Tetrahedron Lett. 1997,
38, 677-680.
(16) We have designated the term "pseudo-meso" to the diastereomer
which contains an unlike-relationship between the two stereogenic
phosphorus atoms in the optically active compounds 4-15c. The pair
of C2-symmetric diastereomers contain a like-relationship between the
two stereogenic phosphorus atoms in the optically active compounds
4-15a ,b.
(20) (a) Sprott, K. T.; Hanson, P. R. Abstract of Paper, 219th
National Meeting of the American Chemical Society, San Francisco,
CA.; Amercan Chemical Society: Washington, DC, 2000; ORGN 825.
(b) Additional results related to the synthesis of seven-membered
P-heterocycles via RCM strategies are currently the topic of
a
manuscript submitted for publication.

Amino Acid-Derived Phosphonamidic Anhydrides
J . Org. Chem., Vol. 65, No. 15, 2000 4723
Sch em e 4
Ta ble 1. 31P NMR Reson a n ces for th e C2-sym m etr ic P h osp h on a m id ic An h yd r id es 4-11a ,b a n d th e P seu d o-Meso
P h osp h on a m id ic An h yd r id es 4-11c
d/l pair
(%)
pseudo-meso
Pdt
R1
R2
CH3
yield (%)
58a
entry
31P δ
entry
(%)
27
31P δ (J , Hz)
4
CH3
4a b
31
29.47
29.41
30.14
29.88
30.10
29.36
30.20
29.94
16.70
16.69
17.46
16.80
17.56
16.98
17.22
16.87
4c
28.95 (34.4)
28.94 (34.4)
29.19 (35.5)
28.41 (35.5)
28.96 (36.7)
28.12 (36.7)
29.19 (35.4)
28.41 (35.4)
16.40 (34.5)
16.25 (34.5)
16.48 (37.5)
15.78 (37.5)
15.90
5
6
CH2CHMe2
CH2Ph
CH3
82b
72a
49a
5a b
6a b
7a b
8a b
9a b
10a b
11a b
53
23
43
20
39
28
44
5c
29
26
20
31
42
27
40
CH3
6c
7
CHMe2
CH3
CH3
63a
51a
7c
8
CHdCH2
CHdCH2
CHdCH2
CHdCH2
8c
9
CH2CHMe2
CH2Ph
52a
81b
55a
9c
10
11
10c
11c
CHMe2
84a
16.32 (35.9)
15.98 (35.9)
a
Method A. bMethod B.
F igu r e 1. (1H decoupled 31P spectrum) 31P NMR analysis of crude vinylphosphonamidic chloridates 30-P RS and 30-P RS before
water workup using method A.
drides 9a-c. Subsequent column chromatography yielded
the corresponding pseudo-meso compound 9c and the pair
of diastereomers 9a ,b (the individual diastereomers 9a ,b
were difficult to separate from each other). Yields in this
improved procedure were typically greater than 80%. All
of the anhydrides 4-11a -c were slowly hydrolyzed in
the presence of moisture, but were stable indefinitely in
a number of solvents including chloroform, methylene
chloride and DMSO.
We have relied heavily on 31P NMR analysis (Table 1)
in attempts to deduce the mechanism of anhydride
formation. As seen in Figure 1 (and Table 1), initial
formation of the leucine-derived phosphonamidic chlori-
dates 30-P RS and 30-P RS is indicated by the appearance
of two downfield singlets (R2 ) CHdCH2, ∼37-38 ppm;
when R2 ) CH3, ∼47-48 ppm). Upon heating, formation
of phosphonamidic anhydrides 9a -c occur, leading to
variable ratios of all three diastereomers as evident by

4724 J . Org. Chem., Vol. 65, No. 15, 2000
Sprott and Hanson
F igu r e 2. (1H decoupled 31P spectrum) 31P NMR analysis of crude vinylphosphonamidic anhydrides 9a -c after water workup
using method A.
the appearance of two singlets (C2-symmetric diastere-
omers, 9a ,b ) and a pair of doublets (pseudo-meso, 9c)
between 15 and 18 ppm. (Figure 2).
Anhydride formation appears to occur in a nonste-
reospecific manner, since subjecting each individual
chloridate diastereomer to the improved reaction condi-
tions yields the same three diastereomeric anhydrides.
Given that the starting chloridate was a single diaste-
reomer of either “like” SPS or “unlike” SPR configurations,
and that the resulting anhydrides contain both “like” and
“unlike” diastereo-relationships, the displacement at
phosphorus is not stereoselective. The ratios seen in
anhydride formation were typically inconsistent (∼1-3:
1-3 of pseudo-meso to diastereomeric C2-symmetric pair).
The nature of the proposed reaction mechanism undoubt-
edly allows for this inconsistency during anhydride
formation.
We have yet to observe 31P NMR peaks corresponding
to the intermediate phosphonimidic cations 33 or 34.
Attempts to detect these intermediates were made by
monitoring the reaction by 31P NMR over a period of
several days. As shown in Figure 3, the dimerization of
a mixture of the diastereomeric valine-derived phospho-
namidic chloridates 28 (∼1:1 mixture of 28P RS and
28P SS), under anhydrous conditions in CDCl3/Et3N,
smoothly progresses over time to yield a pair of C2-
symmetric diastereomers 7a ,b (two singlets) and a single
pseudo-meso isomer 7c (pair of doublets). Careful analy-
sis of this spectra shows the presence of two very small,
unaccountable, peaks at ∼45.4 ppm (0-20% completion)
and 35.9 ppm (>50% completion). Other than these
peaks, the reaction appears to proceed cleanly from
starting chloridate to product. It is also worth noting that
the 31P NMR resonance corresponding to the valine
phosphonamidic acid is also not present. We feel that this
spectroscopic evidence indicates that our proposed mech-
anism goes through three short-lived reactive intermedi-
ates (33-35) which may have low relative abundance.
Although it may be argued that this reaction cannot
proceed past intermediates 33 and 34 under anhydrous
conditions, adventitious amounts of water must be
present to account for the above observations. We have
repeated this experiment several times and have ob-
served the same result each time.
Mech a n istic Issu es
Thus far, mechanistic studies pertaining to the forma-
tion of phosphonamidic anhydrides have been limited in
the literature. Harger and co-workers have identified
various phosphonamidic anhydrides in their eloquent
mechanistic studies of base-induced rearrangements of
N-phosphinoylhydroxylamine derivatives.21 In addition,
Smith, Hirschmann and co-workers have recently ad-
dressed mechanistic issues involved in pyrophosphonate
anhydride formation associated with their efforts to
synthesize phosphonopeptides.22 While any detailed
mechanistic discussion requires further investigation, a
reasonable hypothesis for the formation of anhydrides
4-11 is depicted in Scheme 5. We propose a mechanism
that involves nucleophilic participation from the nitrogen
of a phosphonamidic chloridate molecule (25-32) to
directly couple with another phosphonamidic chloridate
molecule (25-32) (Scheme 5). This is in contrast to
another plausible mechanism involving direct coupling
of a phosphonamidic acid molecule (hydrolyzed 25-32)
with another phosphonamidic chloridate molecule
(25-32). The proposed mechanism involves two inter-
mediate trigonal bipyramidal-containing transition states
33 and 35, rather than a stereocontrolled direct displace-
ment via an SN2-like transition state. The nonstereospe-
cific addition of water to the phosphoniminium species
34 generates the second trigonal bipyramidal transition
state 35 which collapses to yield the 3 diastereomeric
anhydrides 4-11a -c.
(21) (a) Harger, M. J . P.; Sreedharan-Menon, R. Chem. Commun.
1996, 7, 867-868. (b) Harger, M. J . P.; Sreedharan-Menon, R. J . Chem.
Soc., Perkin Trans. 2 1999, 159-164. (c) Harger, M. J . P. Chem.
Commun. 1997, 8, 403-404. (d) Harger, M. J . P. J . Chem. Res., Synop.
1996, 110-111. (e) See also ref 12d.
(22) Hirschmann, R.; Yager, K. M.; Taylor, C. M.; Witherington, J .;
Sprengeler, P. A.; Phillips, B. W.; Moore, W.; Smith, A. B., III. J . Am.
Chem. Soc. 1997, 119, 8177-8190.

Amino Acid-Derived Phosphonamidic Anhydrides
J . Org. Chem., Vol. 65, No. 15, 2000 4725
F igu r e 3. (1H decoupled 31P spectrum) 31P NMR analysis of the dimerization of a mixture of the diastereomeric valine-derived
methyl phosphonamidic chloridates 28 (∼1:1 mixture of 28-P RS and 28-P RS) under anhydrous conditions in CDCl3/Et3N. The
reaction yields a pair of C2-symmetric diastereomers 7a ,b (two singlets) and a single pseudo-meso isomer 7c (pair of doublets).
Intervals at (a) 0%, (b) 20%, (c) 52%, (d) 85%, and (e) 100% indicating the percent-completion of reaction.
Sch em e 5
Sch em e 6
The mechanism that we have proposed has literature
precedence in previously reported pyrophosphate syn-
theses and two phosphonamidic anhydride syntheses (eqs
1-4, Scheme 6).14 Both of these earlier reports used the
Schrader (eq 1) or the modified Schrader (eq 3) methods
to yield the pyrophosphonate 40 or the phosphonamidic
anhydride 42. The reactions in eqs 1 and 3 were run
under inert, anhydrous conditions, and must invoke an
oxonium or iminium intermediate similar to 31 or 34 in
Scheme 5 in order to account for chloroethane formation.
In contrast, these reports also utilized the Toy (eq 2) and
Holmstedt (eq 4) methods to yield pyrophosphonate 41
or the phosphonamidic anhydride 43. In eqs 2 and 4, 0.5
equiv of water was deliberately included in order to
derive 0.5 equivalents of the corresponding phosphonic
acid in situ. This acid is then phosphonylated with the
remaining 0.5 equivalent of starting phosphonic chloride
to derive either the pyrophosphonate or phosphonamidic
anhydride, respectively.

4726 J . Org. Chem., Vol. 65, No. 15, 2000
Sprott and Hanson
Sch em e 7
F igu r e 4. (1H decoupled 31P spectrum) 31P NMR analysis of
the crude RCM reaction product 13c (pair of doublets at 33.55
and 32.38 ppm) after 30 min.
To further verify our mechanism, a simple cross-coupl-
ing experiment between the phenylalanine-derived phos-
phonamidic acid 44 and the pair of diastereomeric valine-
derived phosphonamidic chloridates 28-P SS and 28-P RS
was carried out under anhydrous conditions (Scheme 7).
As shown in Scheme 7, coupling of 2.6 equivalents of 44
with 1.0 equivalent of 28 gave an ∼3:1 ratio of the bis-
valine derived phosphonamidic anhydrides 7a -c (3 di-
astereomers) to the mixed valine-phenylalanine-derived
anhydrides 45 (4 diastereomers). We feel that this ratio
further supports our proposed mechanism since acid 44
was used in excess, and the resulting mixed phosphona-
midic anhydride 45 was still the minor product. These
results also indicate that the dimerization of chloridates
28 occurs faster than condensation of acid 44 with
chloridate 28.
magnetic stirring. Methylene chloride was purified via one of
two ways: by passage through the Solv-Tek purification
system employing activated Al2O3,23 or by distillation over
CaH2. Triethylamine was distilled from CaH2 and stored over
KOH. DMAP was purchased from Reilly Chemicals and was
not further purified. All amino acid precursors were purchased
from Advanced Chem Tech. Deuteriochloroform (CDCl3) was
purchased from Cambridge Isotope laboratories and stored
over potassium carbonate at room temperature. Mass spectra
were performed by the Mass Spectrometry Laboratory at the
University of Kansas. Flash column chromatography was
performed with Merck silica gel (EM-9385-9, 230-400 mesh).
Thin-layer chromatography was performed on silica gel 60F254
plates (EM-5715-7, Merck). Visualization of TLC spots was
effected using KMnO4 stain.
Leu cin e-Der ived Meth yl P h osp h on a m id ic Ch lor id a tes
(26P SS a n d 26P RS). To a flame-dried 100 mL round-bottom
flask under argon atmosphere was added methylphosphonic
dichloride 23 (1.0 mL, 11.04 mmol) and CH2Cl2 (20 mL). The
reaction flask was cooled to 0 °C, and Et3N (6.26 mL, 45.0
mmol) was added dropwise, followed by a catalytic amount of
DMAP (5 mol %). After stirring at 0 °C for 5 min, 0.98 equiv
of allylated leucine methyl ester 20 (2.0 g, 10.82 mmol) in CH2-
Cl2 (5 mL) was added via cannula. The reaction mixture was
refluxed and monitored by TLC. Once complete, the reaction
mixture was concentrated under reduced pressure, diluted
with EtOAc, filtered, and concentrated under reduced pres-
sure. Flash chromatography (SiO2, 3:1 Hex/EtOAc) gave 2.94
g (95%) of a light yellow oil consisting solely of the 2
diastereomeric chloridates 26P SS and 26P RS. Further chro-
matography (SiO2, 8:1 Hex/EtOAc) yielded portions of the
separated isomers for characterization.
Rin g-Closin g Meta th esis Stu d ies
We felt that the vinylphosphonamidic anhydrides 8-11
represented attractive scaffolds from which to exploit the
RCM reaction. The allylated amino acid vinylphospho-
namidic anhydrides 9-11 undergo ring closing metath-
esis using the Grubbs benzylidene catalyst to give
products 12-15 in excellent yields (>90%). Figure 4
1
shows the resulting crude H decoupled 31P spectrum of
the pseudo-meso bicyclic RCM product 13c (note the
downfield shift from the starting pseudo-meso phospho-
namidic anhydride 9c shown in Figure 2). The cyclic
phosphonamidic anhydride motifs 12-15 are currently
being investigated for both their synthetic and biological
utility.
Leu cin e-d er ived m eth yl p h osp h on a m id ic ch lor id a te
(26P SS or 26P RS, top Rf): TLC Rf ) 0.39 (1:1 Hex/EtOAc);
[R]25 ) -42.3° (c ) 2.44, CHCl3); FTIR 1742, 1445, 1368, 1240
1
(PdO) cm-1; H NMR (400 MHz, CDCl3) δ 5.78 (dddd, 16.9,
10.2, 6.5, 6.5 Hz, 1H), 5.22 (dd, J ) 17.2, 1.2 Hz, 1H), 5.14 (d,
J ) 10.1 Hz, 1H), 4.40 (ddd, J HP ) 12.1 Hz, J HH ) 7.5, 7.5 Hz,
1H), 3.75-3.67 (m, 2H), 3.68 (s, 3H), 1.96 (d, J HP ) 16.3 Hz,
3H), 1.70 (dd, J ) 7.3, 6.3 Hz, 2H), 1.65-1.52 (m, 1H), 0.91
(d, J ) 6.4 Hz, 3H), 0.90 (d, J ) 6.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 172.37, 134.68 (d, J CP ) 3.0 Hz), 118.04, 55.87,
52.05, 47.16 (d, J CP ) 4.5 Hz), 38.49 (d, J CP ) 5.7 Hz), 24.52,
22.65 (d, J CP ) 118.9 Hz), 22.65, 21.53; 31P NMR (162 MHz,
CDCl3) δ 48.02; HRMS calcd for C11H23ClNO3P (M + H)+
required 282.1026, found 282.1049.
Con clu sion
In conclusion, the rapid assembly of these structurally
diverse amino acid-derived phosphonamidic anhydrides
and their subsequent RCM reactions have been demon-
strated. When coupled with the therapeutic potential of
anhydrides, pyrophosphates, bisphosphonates, and their
derivatives, these compounds represent an exciting new
class of phosphorus compounds. We are currently target-
ing a number of derivatives of the amino acid analogues
presented herein and are assaying them for biological
activity. These efforts will be reported in due course.
Leu cin e-d er ived m eth yl p h osp h on a m id ic ch lor id a te
(26P RS or 26P SS, bottom Rf): TLC Rf ) 0.38 (1:1 Hex/
EtOAc); [R]25 ) -13.1° (c ) 1.44, CHCl3); FTIR 1742, 1440,
1
1373, 1245 (PdO) cm-1; H NMR (400 MHz, CDCl3) δ 5.81-
5.69 (m, 1H), 5.20-5.08 (m, 2H), 4.51 (ddd, J HP ) 9.2 Hz,
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out in flame-
or oven-dried glassware under an argon atmosphere with
(23) Grubbs, R. H.; Rosen, R. K.; Timmers, F. J . Organometallics
1996, 15, 1518-1520.

Amino Acid-Derived Phosphonamidic Anhydrides
J . Org. Chem., Vol. 65, No. 15, 2000 4727
J HH ) 6.2, 6.2 Hz, 1H), 3.76-3.66 (m, 2H), 3.62 (s, 3H), 1.98
(d, J HP ) 16.0 Hz, 3H), 1.73-1.64 (m, 2H), 1.64-1.51 (m, 1H),
0.89 (d, J ) 6.3 Hz, 3H), 0.88 (d, J ) 6.5 Hz, 3H); 13C NMR
Leu cin e-Der ived Vin ylp h osp h on a m id ic An h yd r id es
(9a -c). In a procedure similar to that used for the preparation
of the methyl anhydrides 5a -c (method B), a mixture of the
diastereomeric vinylchloridates 30P SS and 30P RS (355 mg,
1.21 mmol) was subjected to the conditions of method B. Flash
chromatography (SiO2, 1:1 Hex/EtOAc) afforded 135 mg (42%)
of the pseudo-meso diastereomer 9c and 126 mg (39%) of an
inseparable mixture of C2-symmetric diastereomers 9a and 9b,
both as colorless oils.
(100 MHz, CDCl3) δ 172.56 (d, J CP ) 6.2 Hz), 134.08 (d, J CP
2.8 Hz), 118.06, 55.35 (d, J CP ) 2.0 Hz), 51.97, 46.47 (d, J CP
5.1 Hz), 37.14 (d, J CP ) 2.1 Hz), 24.31, 22.80, 22.28 (d, J CP
)
)
)
117.3 Hz), 21.20; 31P NMR (162 MHz, CDCl3) δ 47.98; HRMS
calcd for C11H23ClNO3P (M + H)+ required 282.1026, found
282.1047.
P seu d o-m eso leu cin e-d er ived vin ylp h osp h on a m id ic
a n h yd r id e (9c): TLC Rf ) 0.68 (EtOAc); [R]25 ) -15.59° (c
) 0.68, CHCl3); FTIR 1740, 1649, 1461, 1438, 1387, 1207 (Pd
Leu cin e-Der ived Meth yl P h osp h on a m id ic An h yd r id es
(5a -c) (Meth od B). To a neat solution of a mixture of
diastereomeric leucine phosphonamidic chloridates 26P RS and
26P SS (260 mg, 0.92 mmol) at 0 °C was added Et3N (450 µL,
3.22 mmol). The mixture was heated at 45 °C and monitored
by TLC and 31P NMR. The resulting salty slurry was diluted
with EtOAc (10 mL) and filtered (10 mL) and concentrated
under reduced pressure to yield 236 mg (quantitative) of a
mixture of the 3 diastereomeric anhydrides as a yellow oil.
Flash chromatography (SiO2, 1:1 Hex/EtOAc) afforded 46 mg
(20%) of the pseudo-meso diastereomer 5c, and 132 mg (56%)
of a mixture of C2-symmetric diastereomers 5a and 5b. The
mixture was comprised of 16 mg (7%) of a single C2-symmetric
diastereomer 5a or 5b, 104 mg (44%) of a mixture of C2-
symmetric diastereomers 5a and 5b, and 12 mg (5%) of a
sample of C2-symmetric diastereomer 5b or 5a at 90% purity,
all as colorless oils.
O) cm-1 1H NMR (400 MHz, CDCl3) δ 6.45-6.22 (m, 4H),
;
6.19-6.11 (m, 1H), 6.06-5.98 (m, 1H), 5.82-5.72 (m, 2H), 5.13
(dd, J ) 17.1, 1.2 Hz, 2H), 5.09 (dd, J ) 17.1, 1.2 Hz, 2H),
4.46-4.40 (m, 1H), 4.33 (ddd, J ) 13.2, 9.5, 5.3 Hz, 1H), 3.64
(s, 3H), 3.64-3.59 (m, 4H), 3.63 (s, 3H), 1.79-1.56 (m, 6H),
0.88 (d, J ) 6.3 Hz, 6H), 0.87 (d, J ) 6.2 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 173.44 (d, J CP ) 2.5 Hz), 173.14, 135.05,
135.05, 133.52, 133.52, 128.51 (dd, J CP ) 166.4, 8.2 Hz), 128.33
(dd, J CP ) 166.4, 9.0 Hz), 117.95, 117.68, 56.08 (d, J CP ) 3.4
Hz), 55.68 (d, J CP ) 4.3 Hz), 51.85, 51.76, 47.11 (d, J CP ) 5.2
Hz), 46.52 (d, J CP ) 5.2 Hz), 38.71 (d, J CP ) 3.6 Hz), 37.61 (d,
J CP ) 3.0 Hz), 24.32, 24.06, 22.83, 22.83, 21.50, 21.34; 31P NMR
(162 MHz, CDCl3) δ 16.48 (d, J PP ) 37.5 Hz), 15.78 (d, J PP
)
37.5 Hz); HRMS calcd for C24H43N2O7P2 (M + H)+ required
533.2546, found 533.2550.
P seu d o-m eso leu cin e-d er ived m eth yl p h osp h on a m id ic
a n h yd r id e (5c): TLC Rf ) 0.40 (EtOAc); [R]25 ) -17.06° (c
) 0.59, CHCl3); FTIR 1749, 1714, 1422, 1363, 1222 (PdO)
C2-sym m etr ic leu cin e-d er ived vin ylp h osp h on a m id ic
a n h yd r id es (9a ,b): characterized as a mixture; TLC Rf )
0.24 (EtOAc); FTIR 1741, 1642, 1613, 1469, 1438, 1370, 1233
(PdO), 1207 (PdO) cm-1; 1H NMR (400 MHz, CDCl3) δ 6.37-
6.21 (m, 8H), 6.08 (ddd, J ) 10.2, 8.6, 4.2 Hz, 2H), 5.94 (ddd,
J ) 10.2, 8.5, 4.3 Hz, 2H), 5.75-5.65 (m, 4H), 5.11-4.96 (m,
8H), 4.40-4.29 (m, 4H), 3.65-3.51 (m, 8H), 3.57 (s, 6H), 3.56
(s, 6H), 1.74-1.49 (m, 12H), 0.87-0.81 (m, 24H); 13C NMR (100
MHz, CDCl3) δ 173.05, 172.93, 135.08, 135.01, 133.92, 133.86,
128.18 (dd, J CP ) 176.8, 4.9 Hz), 127.98 (dd, J CP ) 174.9, 4.1
Hz), 117.59, 117.33, 55.67, 55.50, 51.66, 51.60, 46.62, 46.22,
38.32, 37.49, 24.17, 23.98, 22.71, 22.71, 21.13, 21.05; 31P NMR
(162 MHz, CDCl3) δ 17.46, 16.80; HRMS calcd for C24H43N2O7P2
(M + H)+ required 533.2546, found 533.2556.
1
cm-1; H NMR (400 MHz, CDCl3) δ 5.87-5.75 (m, 2H), 5.18
(dd, J ) 17.1, 1.3 Hz, 1H), 5.14 (dd, J ) 17.1, 1.3 Hz, 1H),
5.12-5.06 (m, 2H), 4.49 (ddd, J HP ) 10.7 Hz, J HH ) 10.7, 5.4
Hz, 1H), 4.34 (ddd, J HP ) 9.2 Hz, J HH ) 9.2, 5.3 Hz, 1H), 3.75-
3.58 (m, 4H), 3.68 (s, 3H), 3.66 (s, 3H), 1.83-1.60 (m, 6H), 1.74
(d, J HP ) 16.8 Hz, 3H), 1.69 (d, J HP ) 16.7 Hz, 3H), 0.92 (d, J
) 6.2 Hz, 6H), 0.91 (d, J ) 6.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 173.67 (d, J CP ) 2.2 Hz), 173.20, 135.34, 135.34,
117.77, 117.48, 56.32 (d, J CP ) 2.9 Hz), 55.93 (d, J CP ) 3.6
Hz), 51.94, 51.90, 47.24 (d, J CP ) 4.9 Hz), 46.45 (d, J CP ) 4.9
Hz), 38.98 (d, J CP ) 3.7 Hz), 37.57 (d, J CP ) 2.6 Hz), 24.51,
24.19, 22.95, 22.87, 21.51, 21.33, 15.49 (dd, J CP ) 129.5, 4.3
Hz), 14.80 (dd, J CP ) 127.7, 4.5 Hz); 31P NMR (162 MHz,
CDCl3) δ 29.19 (d, J PP ) 35.5 Hz), 28.41(d, J PP ) 35.5 Hz);
HRMS calcd for C23H43N2O7P2 (M + H)+ required 509.2546,
found 509.2545.
P seu d o-Meso Bicyclic Leu cin e-Der ived P h osp h on a -
m id ic An h yd r id e (13c). To a flame-dried 25 mL round-
bottom flask were added leucine-derived vinylphosphonamidic
anhydride 9c (88 mg, 0.165 mmol) and CH2Cl2 (15 mL). The
mixture was stirred, and the system was purged with argon
for 10 min using a gas aerating tube. The Grubbs catalyst (6.8
mg, 8 µmol) was added under argon, and the reaction was
stirred and monitored for disappearance of starting material.
Upon completion, the reaction was concentrated under reduced
pressure, passed through a plug of silica using EtOAc, and
concentrated under reduced pressure to give a crude oil. Flash
chromatography (SiO2, 100% EtOAc) afforded the bicyclic
phosphonamidic anhydride 13c (75 mg, 96%) as a colorless oil:
TLC Rf ) 0.20 (EtOAc); [R]25 ) +11.1° (c ) 0.19, CHCl3); FTIR
C2-sym m etr ic leu cin e-d er ived m eth yl p h osp h on a m id -
ic a n h yd r id e, sin gle d ia ster eom er (5a or 5b, top Rf): TLC
Rf ) 0.22 (EtOAc); [R]25 ) -37.8° (c ) 0.32, CHCl3); FTIR 1740,
1
1437, 1387, 1241 (PdO) cm-1; H NMR (400 MHz, CDCl3) δ
5.79 (dddd, J ) 16.9, 10.2, 6.2, 6.2 Hz, 2H), 5.21 (dd, J ) 15.9,
1.2 Hz, 2H), 5.12 (dd, J ) 9.8, 0.9 Hz, 2H), 4.49-4.42 (m, 2H),
3.79-3.57 (m, 4H), 3.67 (s, 6H), 1.81-1.59 (m, 6H), 1.75 (d,
J HP ) 17.0 Hz, 6H), 0.94 (d, J ) 6.0 Hz, 6H), 0.93 (d, J ) 6.2
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 173.33, 135.59, 117.62,
56.11, 51.95, 46.95, 38.71, 24.57, 22.94, 21.31, 15.67 (dd, J CP
) 130.9, 5.6 Hz); 31P NMR (162 MHz, CDCl3) δ 29.88; HRMS
calcd for C23H43N2O7P2 (M + H)+ required 509.2546, found
509.2526.
1742, 1587, 1451, 1390, 1346, 1241 (PdO), 1199 (PdO) cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.11-7.06 (m, 1H), 7.00-6.95
(m, 1H), 6.25 (dd, J ) 30.3, 9.0 Hz, 1H), 6.12 (dd, J ) 30.2,
9.0 Hz, 1H), 4.47 (ddd, J HP ) 9.4 Hz, J HH ) 6.5, 6.5 Hz, 1H),
4.29 (ddd, J HP ) 7.2 Hz, J HH ) 7.2, 7.2 Hz, 1H), 4.17-4.06 (m,
2H), 3.76-3.67 (m, 2 H), 3.67 (s, 3H), 3.65 (s, 3H), 1.67-1.64
(m, 4H), 1.64-1.51 (m, 2H), 0.97 (d, J ) 6.3 Hz, 3H), 0.93-
C2-sym m etr ic leu cin e-d er ived m eth yl p h osp h on a m id -
ic a n h yd r id e, sin gle d ia ster eom er (5b or 5a , bottom Rf
a t 90% p u r ity): TLC Rf ) 0.22 (EtOAc); [R]25 ) -5.0° (c )
0.24, CHCl3); FTIR 1740, 1437, 1387, 1241 (PdO) cm-1 1H
;
0.90 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 173.60 (d, J CP
)
NMR (400 MHz, CDCl3) δ 5.79 (dddd, J ) 16.8, 10.1, 6.6, 6.6
Hz, 2H), 5.17 (dd, J ) 16.7, 1.3 Hz, 2H), 5.10 (dd, J ) 9.1, 1.0
Hz, 2H), 4.52-4.42 (m, 2H), 3.66-3.54 (m, 4H), 3.68 (s, 6H),
1.80 (d, J HP ) 15.8 Hz, 6H), 1.78-1.53 (m, 6H), 0.94 (d, J )
6.0 Hz, 6H), 0.93 (d, J ) 6.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 173.48, 135.13, 117.47, 55.65, 51.91, 46.35, 37.46,
24.34, 22.99, 21.21, 15.27 (dd, J CP ) 130.9, 5.6 Hz); 31P NMR
(162 MHz, CDCl3) δ 30.14; HRMS calcd for C23H43N2O7P2
(M + H)+ required 509.2546, found 509.2561.
1.2 Hz), 173.13 (d, J CP ) 1.9 Hz), 146.15 (d, J CP ) 17.0 Hz),
145.75 (d, J CP ) 17.4 Hz), 119.24 (d, J CP ) 161.9 Hz), 118.62
(dd, J CP ) 166.2, 2.9 Hz), 52.20 (d, J CP ) 4.1 Hz), 52.04 (d, J CP
) 4.5 Hz), 51.84, 51.73, 47.18 (d, J CP ) 31.8 Hz), 46.82 (d, J CP
) 31.1 Hz), 39.14 (d, J CP ) 3.4 Hz), 38.49 (d, J CP ) 3.8 Hz),
24.48, 24.47, 23.06, 22.99, 21.28, 21.07; 31P NMR (162 MHz,
CDCl3) δ 33.55 (d, J PP ) 24.0 Hz), 32.38 (d, J PP ) 24.0 Hz);
HRMS calcd for C20H35N2O7P2 (M + H)+ required 477.1919,
found 477.1911.

4728 J . Org. Chem., Vol. 65, No. 15, 2000
Sprott and Hanson
Ack n ow led gm en t. This investigation was gener-
ously supported by funds provided by the National
Institutes of Health (National Institute of General
Medical Sciences, RO1-GM58103). The authors also
thank Dr. Martha Morton and Dr. David Vander Velde
for their assistance with NMR measurements and Dr.
Todd Williams for HRMS analysis. In addition, we
thank Mei Yau for assistance with the synthesis and
characterization of the compounds contained in this
manuscript.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and spectroscopic data of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O000631B