Phosphonate diester and phosphonamide synthesis. Reaction coordinate analysis by 31P NMR spectroscopy: Identification of pyrophosphonate anhydrides and highly reactive phosphonylammonium salts

Article abstract of DOI:10.1021/ja962465o

A series of phosphonochloridates was prepared from the corresponding phosphonate monoesters, and their reactions with alcohols, amines, and the bisnucleophile 4-aminobutan-1-ol have been investigated using ³¹P NMR spectroscopy. In the conversion of phosphonate monoesters to phosphonochloridates via the addition of thionyl chloride or oxalyl chloride, pyrophosphonate anhydrides were found to be formed readily as byproducts. The anhydrides reacted readily with alcohols, but more slowly than the corresponding phosphonochloridates, and only sluggishly, if at all, with amines. Therefore, when phosphonamides are prepared, anhydride formation must be suppressed. This is accomplished when the monoester is added to the chloridating agent. Unhindered phosphonochloridates reacted predominantly with the amino function of 4-aminobutan-1-ol to furnish the phosphonamidates, whereas a sterically hindered phosphonochloridate demonstrated a preference for O-coupling. This result indictes that the energy gained during P-O bond formation surmounts the kinetic barrier resulting from steric hindrance more effectively than formation of the weaker P-N bond. Importantly, treatment of the phosphonochloridates with tertiary amines prior to addition of the nucleophile resulted in the formation of hitherto unrecognized phosphonylating agents, which we formulated as phosphonyltrialkylammonium salts. The latter, unlike the anhydrides, are more reactive than the phosphonochloridates toward both alcohols and amines, affording improved yields of phosphonate esters and amides. These improved yields are not obtained when triethylamine is added simultaneously with the nucleophile merely to neutralize acid rather than as a deliberate step to generate the phosphonyltrialkylammonium salts. Use of these novel phosphonylating agents proceeded without concomitant racemization at stereogenic centers α to phosphorous. Interestingly, reaction of even an unhindered phosphonyltriethylammonium salt with 4-aminobutan-1-ol favored O-phosphonylation over N-phosphonylation by a factor of 8, demonstrating that both the charge transfer in the transition state and steric hindrance affect the propensity for P-O vis a vis P-N bond formation. In marked contrast, simultaneous addition of this bisnucleophile and triethylamine, like coupling in the absence of tertiary amine, afforded the phosphonate and phosphonamide in nearly equal amounts.

Full text of DOI:10.1021/ja962465o

J. Am. Chem. Soc. 1997, 119, 8177-8190
8177
Phosphonate Diester and Phosphonamide Synthesis. Reaction
31
Coordinate Analysis by P NMR Spectroscopy: Identification
of Pyrophosphonate Anhydrides and Highly Reactive
Phosphonylammonium Salts1
Ralph Hirschmann,* Kraig M. Yager,2a Carol M. Taylor,2b Jason Witherington,2c
Paul A. Sprengeler,2a Barton W. Phillips, William Moore,† and Amos B. Smith, III*
Contribution from the Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104, and Protein Chemistry Laboratory, Department of
Pathology and Laboratory Medicine, Medical School of the UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
ReceiVed July 17, 1996X
Abstract: A series of phosphonochloridates was prepared from the corresponding phosphonate monoesters, and their
reactions with alcohols, amines, and the bisnucleophile 4-aminobutan-1-ol have been investigated using 31P NMR
spectroscopy. In the conversion of phosphonate monoesters to phosphonochloridates via the addition of thionyl
chloride or oxalyl chloride, pyrophosphonate anhydrides were found to be formed readily as byproducts. The
anhydrides reacted readily with alcohols, but more slowly than the corresponding phosphonochloridates, and only
sluggishly, if at all, with amines. Therefore, when phosphonamides are prepared, anhydride formation must be
suppressed. This is accomplished when the monoester is added to the chloridating agent. Unhindered phospho-
nochloridates reacted predominantly with the amino function of 4-aminobutan-1-ol to furnish the phosphonamidates,
whereas a sterically hindered phosphonochloridate demonstrated a preference for O-coupling. This result indictes
that the energy gained during P-O bond formation surmounts the kinetic barrier resulting from steric hindrance
more effectively than formation of the weaker P-N bond. Importantly, treatment of the phosphonochloridates with
tertiary amines prior to addition of the nucleophile resulted in the formation of hitherto unrecognized phosphonylating
agents, which we formulated as phosphonyltrialkylammonium salts. The latter, unlike the anhydrides, are more
reactive than the phosphonochloridates toward both alcohols and amines, affording improved yields of phosphonate
esters and amides. These improVed yields are not obtained when triethylamine is added simultaneously with the
nucleophile merely to neutralize acid rather than as a deliberate step to generate the phosphonyltrialkylammonium
salts. Use of these novel phosphonylating agents proceeded without concomitant racemization at stereogenic centers
R to phosphorous. Interestingly, reaction of even an unhindered phosphonyltriethylammonium salt with 4-aminobutan-
1-ol favored O-phosphonylation over N-phosphonylation by a factor of 8, demonstrating that both the charge transfer
in the transition state and steric hindrance affect the propensity for P-O Vis a Vis P-N bond formation. In marked
contrast, simultaneous addition of this bisnucleophile and triethylamine, like coupling in the absence of tertiary
amine, afforded the phosphonate and phosphonamide in nearly equal amounts.
Organophosphorus(V) derivatives are stable surrogates of
high-energy tetrahedral transition states common to many
enzyme-catalyzed reactions and thus are useful both in the
elucidation of enzyme mechanisms and as enzyme inhibitors.3
Such transition state analogs have been exploited as potent
inhibitors of serine and aspartic acid proteases such as chymot-
rypsin,4 pepsin,5 and HIV protease6 and of the metalloproteases
carboxypeptidase A,7 angiotensin-converting enzyme,8 thermol-
ysin,9 leucine aminopeptidase,10 endothelin converting enzyme,11
and human collagenase.12 Similarly, class C â-lactamase,13
HMG-CoA reductase,14 and D-alanyl-D-alanine ligase15 are
effectively inhibited by P(V)-based transition state analogs. Also
of interest is the fact that several phosphonopeptides have shown
potent antibacterial activity.16 More recently the transition state
† Medical School of the University of Pennsylvania.
X Abstract published in AdVance ACS Abstracts, August 15, 1997.
(1) A preliminary account of this work has been published, see:
Hirschmann, R.; Yager, K. M.; Taylor, C. M.; Moore, W.; Sprengeler, P.
A.; Witherington, J.; Phillips, B. W.; Smith, A. B., III. J. Am. Chem. Soc.
1995, 117, 6370.
(2) Current address: (a) Arris Pharmaceutical Corporation, 385 Oyster
Point Boulevard, Suite 4, South San Francisco, CA 94080. (b) University
of Auckland, Private Bag 92019, Auckland, New Zealand. (c) SmithKline
Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue,
Harlow, Essex, CM19 5AW, U.K.
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654. (b) Hanson, J. E.; Kaplan, A. P.; Bartlett, P. A. Biochemistry 1989,
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Patchett, A. A.; Ulm, E. H.; Vassil, T. C. Proc. Natl. Acad. Sci. U.S.A.
1982, 79, 2176. (b) Elliott, R. L.; Marks, N.; Berg, M. J.; Portoghese, P. S.
J. Med. Chem. 1985, 28, 1208.
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Kolbert, A. C.; Drewry, D. H.; Bartlett, P. A.; Oas, T. G.; Griffin, R. G.
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S0002-7863(96)02465-1 CCC: $14.00 © 1997 American Chemical Society

8178 J. Am. Chem. Soc., Vol. 119, No. 35, 1997
Hirschmann et al.
analog concept of Pauling3 has been successfully applied to
hapten design, giving rise to antibodies catalyzing diverse
reactions,17 including the recently reported formation of dipep-
tides18 and of larger peptides.18c Because of their important,
diverse chemical and biological properties, we report herein new
understanding of the chemistry relating to the synthesis of
phosphonate esters and phosphonamides.1
Background. Generally, phosphonate esters and phospho-
namides are prepared by the reaction of phosphonochloridates
or phosphonodichloridates19 with alcohols or amines respec-
tively, as typified in Scheme 1. Monochloridates have been
prepared by reaction of phosphonate diesters with 1 equiv of
phosphorus pentachloride,20 by treatment of monoesters with
thionyl chloride or oxalyl chloride,21 and by oxidative chlorina-
tion of phosphinate esters with carbon tetrachloride.22 The
phosphonochloridate strategy has also been extended to the solid
phosphonate diesters using mixed BOP-phosphonate esters,25
di-p-nitrophenyl phosphonate esters,26 and modified Mitsunobu27
reactions. Our interest in the synthesis of complex phosphonate
esters and amides stems from a continuing program to design
and synthesize haptens (e.g., 4 and 5) for the generation of
catalytic antibodies possessing peptide ligase activity as reported
by Hirschmann, Benkovic, and Smith and their collaborators18a,b
and by Jacobsen and Schultz18c (Scheme 1).18a,b
Although several publications have alluded to the instability
of phosphonamides at acidic and even physiological pH,22,28
Janda and co-workers6a observed less than 2% decomposition
of a phosphonamide at pH 3.5 after 1 week,29 encouraging us
to undertake the preparation of 4. However, efforts to couple
D-tryptophanamide (8) with phosphonochloridate 7 failed to
yield the desired phosphonamide 10 even in the presence of
silver ion (see below). Attempts to couple monoester (-)-6
with 8 using a variety of condensing reagents such as diphenyl
phosphorylazide and BOP reagents were also unsuccessful. We
were able, however, to couple chloridate 7 with (R)-(+)-â-
indolyllactamide 930 in the presence of silver ion31,32 to afford
phosphonate diester (+)-11 in yields that initially varied
unpredictably from 0 to 32%, but could be improved to a
reproducible 40% via the new procedure described herein.33
Phosphonate diester (+)-11 was subsequently converted into
hapten 5, which generated useful catalytic antibodies.18a,b
Scheme 1
31P NMR Analysis of Phosphonochloridate Formation. In
order to provide some insight into the observed preference for
alcoholysis of the activated phosphonate monoesters, we studied
the formation and subsequent reactions of phosphonochloridates
using 31P NMR. To simplify the study, we chose 16 and 18 as
substrates, because the resulting stereogenic center at phosphorus
would result in enantiomers rather than diastereomers, simplify-
ing spectral interpretation. Treatment of diethyl (phthalimi-
domethyl)phosphonate (13),19b obtained either commercially or
by bromination (PBr3, 140 °C, 1 h) of N-(hydroxymethyl)-
phthalimide (12) and subsequent Arbuzov reaction [P(OEt)3,
120 °C, 1 h] with hydrazine hydrate (EtOH, 25 °C, 72 h),
provided diethyl (aminomethyl)phosphonate (14). Because of
(20) (a) Yamauchi, K.; Kinoshita, M.; Imoto, M. Bull. Chem. Soc. Jpn.
1972, 45, 2528. (b) Yamauchi, K.; Kinoshita, M.; Imoto, M. Bull. Chem.
Soc. Jpn. 1972, 45, 2531. (c) Hariharan, M.; Chaberek, S.; Martell, A. E.
Synth. Commun. 1973, 3, 375. (d) Yamauchi, K.; Mitsuda, Y.; Kinoshita,
M. Bull. Chem. Soc. Jpn. 1975, 48, 3285.
(21) (a) Lamden, L. A.; Bartlett, P. A. Biochem. Biophys. Res. Commun.
1983, 22, 4618. (b) Hoffmann, M. Synthesis 1986, 557. (c) Malachowski,
W. P.; Coward, J. K. J. Org. Chem. 1994, 59, 7616. (d) Malachowski, W.
P.; Coward, J. K. J. Org. Chem. 1994, 59, 7625.
(22) Sampson, N. S.; Bartlett, P. A. J. Org. Chem. 1988, 53, 4500.
(23) Maffre-Lafon, D.; Escale, R.; Dumy, P.; Vidal, J.-P.; Girard, J.-P.
Tetrahedron Lett. 1994, 35, 4097.
phase synthesis of phosphonopeptides.23 In addition, the
synthesis of phosphonopeptides from hydroxybenzotriazole
esters and phosphonochloridates exploiting silver ion catalysis
has been reported,24 as have methods for preparing complex
(24) Musiol, H.-J.; Grams, F.; Rudolph-Bohner, S.; Moroder, L. J. Org.
Chem. 1994, 59, 6144.
(25) Campagne, J.-M.; Coste, J.; Jouin, P. Tetrahedron Lett. 1993, 34,
6743.
(26) Tawfik, D. S.; Eshhar, Z.; Bentolila, A.; Green, B. S. Synthesis 1993,
968.
(27) (a) Campbell, D. A.; Bermak, J. C. J. Org. Chem. 1994, 59, 658.
(b) Campbell, D. A. J. Org. Chem. 1992, 57, 6331.
(28) (a) Hariharan, M.; Motekaitis, R. J.; Martell, A. E. J. Org. Chem.
1975, 40, 470. (b) Yamauchi, K.; Ohtsuki, S.; Kinoshita, M. J. Org. Chem.
1984, 49, 1158. (c) Rahil, J.; Haake, P. J. Am. Chem. Soc. 1981, 103, 1723.
(29) While the stability of phosphonamides is thus not a major concern,
the lack of (or minimal) double-bond character of the P-N bond of
phosphonamides negates a potential plus of phosphonamide haptens over
their diester counterparts.
(30) (a) Larcheveˆque, M.; Petit, Y. Tetrahedron Lett. 1987, 23, 1993.
(b) Larcheveˆque, M.; Petit, Y. Bull. Chim. Soc. Fr. 1989, 130. (c) Entzeroth,
M.; Kunczik, T.; Jaenicke, L. Liebigs Ann. Chem. 1983, 226.
(31) (a) Takimoto, S.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1976, 49, 2335. (b) Tung, R. D.; Dhaon, M. K.; Rich, D.
H. J. Org. Chem. 1986, 51, 3350.
(14) Robl, J. A.; Duncan, L. A.; Pluscec, J.; Karanewsky, D. S.; Gordon,
E. M.; Ciosek, C. P., Jr.; Rich, L. C.; Dehmel, V. C.; Slusarchyk, D. A.;
Harrity, T. W.; Obrien, K. A. J. Med. Chem. 1991, 34, 2804.
(15) Parsons, W. H.; Patchett, A. A.; Bull, H. G.; Schoen, W. R.; Taub,
D.; Davidson, J.; Combs, P. L.; Springer, J. P.; Gadebusch, H.; Weissberger,
B.; Valiant, M. E.; Mellin, T. N.; Busch, R. D. J. Med. Chem. 1988, 31,
1772.
(16) Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassall, C. H.; Holmes,
S. W.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P. S. Nature 1978, 272, 56.
(17) For comprehensive reviews, see: (a) Lerner, R. A.; Benkovic, S.
J.; Schultz, P. G. Science 1991, 252, 659. (b) Benkovic, S. J. Annu. ReV.
Biochem. 1992, 61, 29. (c) Lerner, R. A. Acc. Chem. Res. 1993, 26, 391.
(18) (a) Hirschmann, R.; Smith, A. B., III; Taylor, C. M.; Benkovic, P.
A.; Taylor, S. D.; Yager, K. M.; Sprengeler, P. A.; Benkovic, S. J. Science
1994, 265, 234. (b) Jacobsen, J. R.; Schultz, P. G. Proc. Natl. Acad. Sci.
U.S.A. 1994, 91, 5888. (c) Smithrud, D. B.; Benkovic, P. A.; Benkovic, S.
J.; Taylor, C. M.; Yager, K. M.; Witherington, J.; Phillips, B. W.; Sprengeler,
P. A.; Smith, A. B., III; Hirschmann, R. J. Am. Chem. Soc. 1997, 119, 278.
(19) (a) Rogers, R. S. Tetrahedron Lett. 1992, 33, 7473. (b) Denmark,
S. E.; Chen, C.-T. J. Org. Chem. 1994, 59, 2922. (c) For aromatic amine-
catalyzed couplings of phosphonodichloridates, see: Doak, G. O.; Freedman,
L. D. J. Am. Chem. Soc. 1954, 76, 1621.
(32) Independently, Moroder and co-workers also reported the beneficial
effects of silver ion on the formation of complex phosphonate diesters.24
(33) Smith, A. B., III; Taylor, C. M.; Benkovic, S. J.; Hirschmann, R.
Tetrahedron Lett. 1994, 35, 6853.

Phosphonate Diester and Phosphonamide Synthesis
J. Am. Chem. Soc., Vol. 119, No. 35, 1997 8179
its instability, the crude amine 14 was converted directly to the
stable N-carbobenzyloxy (Cbz) derivative 15 (CbzCl, Et3N, CH2-
Cl2, 0 f 25 °C, 15 h) in 87% yield from 13. Basic hydrolysis6a
(2 M NaOH, 25 °C, 24 h) afforded 16 in 43% yield (Scheme
2).
24.2 or 23.9 ppm, which were assigned to carbamate rotamers
on the basis of temperature-dependent 31P NMR studies (revers-
ible coalescence observed at 325K). Indeed, similar minor
rotamers were observed in the spectra of all phosphorus-
containing compounds described herein. Treatment of either
16 or 18 (0.05 M, CDCl3) with thionyl chloride led, within 30
min, to their complete consumption, as revealed by 31P NMR
(spectra b and d) (Figure 1). In addition to the expected
phosphonochloridates 19 (spectrum b; 35.6 ppm, R ) Cbz) and
20 (spectrum d; 35.7 ppm, R ) Fmoc), a pair of upfield singlets
(byproducts) at 16.4 and 16.1 ppm (R ) Cbz) or 16.5 and 16.2
ppm (R ) Fmoc) were also observed.
Scheme 2
The upfield byproducts proved to be active phosphonylating
agents, as shown by the fact that on addition of benzyl alcohol
(5 equiv, 32 °C) both of the phosphonochloridates and the new
upfield intermediates were consumed, affording the mixed
diesters 21 and 22 (23.6 ppm for both compounds) as the major
products (Scheme 4). In contrast, treatment of a similar mixture
with benzylamine (5 equiv, 32 °C) led to selective reaction of
the phosphonochloridates, furnishing the benzyl phosphona-
mides 23 and 24 (27.2 ppm for both compounds), but leaving
the upfield signals unchanged (Figure 2).
Alternatively, protection of amine 14 as its (fluorenyl-
methoxy)carbonyl (Fmoc) carbamate (FmocCl, Et3N, tol, 25 °C)
and subsequent hydrolysis of the resulting diester 17 afforded
monoester 18 in 35% overall yield (Scheme 3).
The above alcoholysis and aminolysis experiments demon-
strated that the upfield byproducts are less reactive than
Scheme 4
Scheme 3
The 31P NMR spectra (202.5 MHz, 0.05 M, CDCl3) of the
starting materials, the monoesters 16 (spectrum a) and 18
(spectrum c, respectively) (Figure 1), displayed major resonances
at 24.8 and 24.9 ppm (relative to 85% H3PO4, external standard).
Each resonance was accompanied by a minor upfield signal at
phosphonochloridates 19 and 20 and that even the latter couple
less readily with benzylamine than with benzyl alcohol. This
result, which is in marked contrast to the well-known greater
reactivity of amines compared to alcohols toward activated
carboxylic acids, serves as a reminder that a comparison of the
relative reactivity of two or more nucleophiles depends on the
electrophile.34
Structure of the Upfield Byproducts. We had initially
considered the possibility that at least one of the upfield signals
might correspond to the mixed P-O-S anhydride 25, which
might then react with chloride ion to generate the phospho-
nochloridate (Scheme 5). However, the fact that the same
upfield signals appear in the 31P NMR spectra when 18 is treated
with oxalyl chloride or oxalyl bromide disproved this interpreta-
tion, since one would expect the mixed P-O-C (26 and 27)
and P-O-S anhydrides 25 to be spectroscopically distinct.
It was attractive to attribute the appearance of two upfield
phosphorus resonances for each byproduct to the presence of
diastereomeric phosphorus atoms; this in turn strongly suggested
the formation of pyrophosphonate anhydride diastereomers:
(34) (a) Bruice, T. C.; Benkovic, S. J. In Bioorganic Mechanisms; W.
A. Benjamin, Inc.: New York, 1966; Vol. 1, pp 42-43. (b) Drago, R. S.;
Wong, N.; Ferris, D. C. J. Am. Chem. Soc. 1991, 113, 1970.
(35) Greenhalgh, R.; Heggie, R. M.; Weinberger, M. A. Can. J. Chem.
1970, 48, 1351.
(36) (a) Toy, A. D. F. J. Am. Chem. Soc. 1948, 70, 3882. (b) For the
synthesis of pyrophosphate anhydrides with thionyl chloride and other acyl
halides, see: Mason, H. S.; Todd, A. R. J. Chem. Soc. 1951, 2267. Corby,
N. S.; Kenner, G. W.; Todd, A. R. J. Chem. Soc. 1952, 1234.
Figure 1. 31P NMR spectra: (a) Cbz-protected monoester 16; (b)
phosphonochloridate 19; (c) Fmoc-protected monoester 18; (d) phospho-
nochloridate 20.

8180 J. Am. Chem. Soc., Vol. 119, No. 35, 1997
Hirschmann et al.
via condensation of an alkylphosphonic acid with an electro-
philic phosphorus species.27b
A plausible mechanism for the formation of pyrophosphonate
anhydrides is illustrated for a generic monoester 33 and
phosphonochloridate 34 in Scheme 6 (eq 1). When 33 is mixed
with the chlorinating agent, there is partial conversion to
phosphonochloridate 34. Suprisingly, 34 competes effectively
Scheme 6
Figure 2. 31P NMR spectra: (a) Fmoc-protected monoester 18; (b)
phosphonochloridate 20 and upfield byproducts; (c) reaction of line b
with benzyl alcohol (5 equiv); (d) reaction of a mixture similar to line
b with benzylamine (5 equiv).
Scheme 5
with the chlorinating agents for 33, to give a mixture also
containing the diastereomeric anhydrides 35. The 31P NMR
spectrum supports this interpretation since the relative amount
of anhydride formed is initially very high and decreases with
time. As expected, addition of monoester to a solution of thionyl
chloride suppresses the formation of the anhydrides, the
chlorinating agent now always being present in excess. As
shown below, this procedure should be employed especially
when the nucleophile is an amine. A reviewer of the initial
communication kindly suggested an alternative explanation, Viz.,
that monoester 33 is in competition with chloride ion for the
mixed P-O-S anhydride 36, leading to phosphonochloridate
as illustrated in Scheme 6 (eq 2). This suggestion is attractive
because monoester concentration is high at the beginning of
the reaction and chloride ion concentration is low. However,
pretreatment of monoester 16 with an excess of tert-butylam-
monium chloride (10 equiv), ensuring a high initial chloride
ion concentration, does not affect the ratio of anhydrides and
phosphonochloridates and therefore argues against this mech-
anism. Although we do not exclude the possibility that some
of the anhydride arises via the pathway suggested by the referee,
taken together our observations support a mechanism in which
the anhydrides arise preponderantly via successful competition
by the phosphonochloridates with the chlorinating agent for
monoester.
meso-29 and meso-31, and (R,R)- and (S,S)-30 and -32
Figure 3).
Although phosphonic acid anhydrides have been described
in the literature,35,36they have not been reported as side products
of phosphonochloridate preparation. It has, however, been
reported that the conversion of phosphinic acids to phosphinic
chlorides with phosgene proceeds via pyrophosphinic anhy-
drides, the latter being converted to the halide with additional
phosgene.37 In addition, Bartlett and co-workers concluded, on
both chemical and spectral grounds, that the active phospho-
nylating agent in the dicyclohexylcarbodiimide (DCC)-mediated
couplings of phosphonate monoesters is the corresponding
pyrophosphonate anhydride.4 Similarly, Campbell had reported
the formation of a pyrophosphonate anhydride as a byproduct
To provide additional support for the structures assigned to
the pyrophosphonate anhydrides 29-32, the Cbz-protected
monoester 16 was added to a solution of thionyl chloride (3
equiv, 32 °C, 1 h, evaporation at e1 mmHg) furnishing
primarily phosphonochloridate 19, accompanied by a small
amount of the symmetrical anhydrides 29 and 30 (Figure 4,
spectrum a). Addition of 1 equiv of the Fmoc-protected
monoester 18 generated indeed the diastereomeric unsym-
(37) Phosphorus; An Outline of its Chemistry, Biochemistry and Technol-
ogy; Corbridge, D. E. C., Ed.; Studies in Inorganic Chemistry 10; Elsevier:
New York, 1990; p 340.
Figure 3.

Phosphonate Diester and Phosphonamide Synthesis
J. Am. Chem. Soc., Vol. 119, No. 35, 1997 8181
Table 1
metrical anhydrides 38 (16.5 and 16.2 ppm; line b). A reciprocal
experiment was performed by treatment of the Fmoc-protected
phosphonochloridate 20 with 16, which led to an analogous
mixture of three pyrophosphonate anhydrides. The elemental
compositions of the anhydrides were confirmed by electrospray
mass spectroscopy, yielding molecular ions corresponding to
the sodium-complexed symmetrical anhydrides 29 and 31 (R
) Cbz, m/z calcd 550.4, found 550.8; R ) Fmoc, m/z calcd
726.7, found 726.8) and the unsymmetrical anhydride 38 (R )
Cbz, Fmoc, m/z calcd 639.5, found 638.9).
furnished diacid 46, which was converted to the dichloridate
[(COCl)2, DMF, CH2Cl2] and allowed to react with p-nitroben-
zyl alcohol. Hydrolysis of the resulting diester using sodium
iodide in acetone afforded monoester 47 in 43% overall yield
from 46. The coupling of monoester 47 with D-tryptophan
methyl ester was attempted three times; only a trace amount of
what was believed to be the desired product (48) was ever
obtained.
Scheme 7
Figure 4. 31P NMR spectra: (a) phosphonochloridate 19 and sym-
metrical anhydrides 29 and 30; (b) reaction of line a with monoester
18 giving unsymmetrical anhydrides 38 and unreacted 19; (c) reaction
of line b with triethylamine affording 76 (Vide infra) and unreacted
38; (d) reaction of line c with benzyl alcohol (5 equiv) to give diester
21 and unreacted 38.
To the best of our knowledge, the ability of phosphonochlo-
rides to compete effectively with reagents such as thionyl
chloride and oxalyl chloride for phosphonic acids has not been
appreciated in the prior literature. This surprising observation
has important synthetic consequences, because the resulting
anhydrides differ significantly in their reactivity from the
phosphonochloridates, reacting slower with alcohols and not at
all with amines. When phosphonamide formation is desired,
formation of anhydrides must be suppressed.
The Role of Steric Factors. The center undergoing nucleo-
philic attack during coupling is markedly more hindered in (-)-7
than in 19. Methanol reacted with chloridate 7 to give the mixed
ester 39 in near quantitative yield. Indeed, as shown in Table
1, most alcohols gave very good yields of mixed diesters, and
even tert-butyl alcohol gave 41 in 48% yield. Importantly, this
latter result shows that steric hindrance alone is not likely to be
responsible for the failure of 7 to react with D-tryptophanamide.38
We also investigated the reactivity of chloridate 51 in which
the p-nitrobenzyl ester is replaced by the less-hindered ethyl
ester (Scheme 8). Chloridate 51 was prepared by carbamoy-
lation of amine 4940 to afford Cbz-protected ester 50, which
was converted directly to 51 by heating at reflux in acetone
with sodium iodide followed by chlorination [(COCl)2]. The
resulting chloridate 51 reacted smoothly with methanol to give
To gain a better understanding of the role of steric factors,
we investigated a series of electrophiles that were intermediate
in steric hindrance between 19 and 7. We first studied the
Fmoc-protected p-nitrobenzyl monoester 47, which lacks the
R-cyclohexyl substituent of 7 (Scheme 7). Dimethyl (amino-
methyl)phosphonate (44)39 was dephthalylated followed by
reprotection with FmocCl to furnish 45. Acid hydrolysis then
(38) Notably (()-methyl â-indolyllactate,30 unlike tryptophol, failed to
furnish 43 under the standard reaction conditions (ROH, 2 equiv, CH2Cl2,
25 °C, 3 h). This difference may in part reflect reduced nucleophilicity as
a result of hydrogen bonding between the hydroxyl and the C-terminal
carboxyl moiety.
(39) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36,
1379.

8182 J. Am. Chem. Soc., Vol. 119, No. 35, 1997
Hirschmann et al.
a quantitative yield of the mixed diester 52, but again no
Scheme 10
coupling was observed with D-tryptophan methyl ester.
Scheme 8
Because the aminolysis conditions used by us are more
vigorous than those employed in peptide synthesis, we consid-
ered that the failure to obtain the desired coupling products
might be due to premature loss of the Fmoc protecting group.
However, when the chloridate 20 was allowed to react with
either benzyl alcohol or benzylamine under identical conditions
(5 equiv of nucleophile, 25 °C, 0.5 h), the expected diester 22
and phosphonamide 24 were obtained in 89 and 64% yield
(Scheme 9), respectively.
agents on their reaction with oxygen and amine nucleophiles.35,43
Their results are briefly summarized. Employing ethanolamine
as a bisnucleophile to measure alcoholysis vs. aminolysis of
activated phosphylating agents, they interpreted their results in
terms of the semiempirical treatment of Hudson,44 which
assumes that for small charge transfer in the transition state there
is a preference for easily polarizable nucleophiles (amino), but
as the charge transfer in the transition state increases, the energy
obtained from bond formation becomes more important and a
faster reaction is observed with less easily polarizable nucleo-
philes (hydroxyl). This is consistent with the fact that the P-O
bond is ca. 20 kcal stronger than the P-N bond.45-48 Green-
halgh concluded, therefore, that when the leaving group of the
phosphylating agent is kept constant, the preference for the less-
polarizable nucleophile increases in the series from phospho-
rodiamides to phosphinates. When the leaving group is varied
within the series, O-phosphylation is observed in the order Cl
< pyro anhydride < CN < F. Thus, chloro compounds
represent a region of the reactivity curve where maximum
selectivity for the more polarizable amino functionality should
be expected, suggesting that the chlorophosphonate should have
optimized the formation of the phosphonamide.
Scheme 9
Taken together, our results suggest that the reasons for the
failure of chloridate 7 to couple with derivatives of D-tryptophan
are complex and not due solely to steric hindrance generated
by the cyclohexyl or the p-nitrobenzyl substituents nor to the
instability of the Fmoc protecting group. We therefore inves-
tigated more fully the effect of changes in the nucleophiles on
the coupling reactions.
The results of Greenhalgh and co-workers were fundamental
to understanding the reactivity patterns of unhindered phosphy-
lating agents, but their studies did not address steric hindrance.
We extended Greenhalgh’s studies via the addition of a
bisnucleophile to sterically diverse chloridates. When n-
pentanol was allowed to react with chloridate 7, the diester (+)-
56 was obtained in good yield (70%) (Scheme 11). When
chloridate 7 was treated with 4-aminobutan-1-ol (3 equiv, CH2-
The Role of Electronic and Steric Properties of the
Nucleophile. Treatment of chloridate 19 with anhydrous
methanol afforded mixed diester 53 in quantitative yield
(Scheme 10). Similarly, treatment of chloridate 19 with benzyl
alcohol furnished 21 in 86% yield. In contrast, chloridate 19
gave the phosphonamide 23 in 69% yield, and the coupling of
19 with the more hindered D-tryptophan methyl ester afforded
54 in only 40% yield. To ensure that the lower yields obtained
in the aminolyses were not due to acid-catalyzed hydrolysis of
the products, we avoided acidic conditions via the procedure
of Patel41 and Biller,42 using N,N-diethyltrimethylsilylamine for
phosphonochloridate generation. When this protocol [Et2-
NSiMe3, CH2Cl2, (COCl)2, DMF (cat.)] was employed, the
coupling of 16 with 8 provided 55 in only a slightly improved
yield of 52%.
(43) Greenhalgh, R.; Weinberger, M. A. Can. J. Chem. 1967, 45, 495.
(44) Hudson, R. F. Chimia 1962, 16, 173. (b) Hudson, R. F. Structure
and Mechanisms in Organophosphorus Chemistry; Academic: London,
1965.
(45) Hartley, S. B.; Holmes, W. S.; Jacques, J. K.; Mole, M. F.;
McCoubrey, J. C. Quart. ReV. Loundon 1963, 17, 216.
(46) Earlier, Dostrovsky and Halmann47 and Hudson and Keay48
established that alcoholysis and aminolysis of phosphonochloridates proceed
by the same mechanism involving an SN2 process in which the rate-
determining step involves approach of the nucleophile to the electrophilic
phosphorus center. These workers had also shown that basicity of the
nucleophile, steric hindrance, and the relative energies of the bonds formed
and broken influence the rate-determining step.
In two important publications, Greenhalgh and co-workers
provided analyses of the effects of the structure of phosphylating
(40) Yager, K. M.; Taylor, C. M.; Smith, A. B., III. J. Am. Chem. Soc.
1994, 116, 9377.
(41) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron Lett.
1990, 39, 5591.
(42) Biller, S. A.; Forster, C. Tetrahedron 1990, 46, 6645.
(47) (a) Dostrovsky, I.; Halmann, M. J. Chem. Soc. 1953, 511. (b)
Dostrovsky, I.; Halmann, M. J. Chem. Soc. 1953, 516.
(48) Hudson, R. F.; Keay, L. J. Chem. Soc. 1960, 1859.

Phosphonate Diester and Phosphonamide Synthesis
J. Am. Chem. Soc., Vol. 119, No. 35, 1997 8183
Cl2, 25 °C, 3 h), three products were isolated. The major
product 57 was highly polar and gave a positive ninhydrin test
indicating the presence of a free amine. Because 57 was too
polar to be purified by flash chromatography and decomposed
during RP-HPLC, it was characterized as the acetylated deriva-
tive 59. Compound 59 was also prepared by coupling 7 with
N-acetyl-4-aminobutan-1-ol in 68% yield. The two minor
products, phosphonamides 58 and 60, were formed in trace
(<5%) amounts. Structure assignments are based on mass
spectrometry and 31P NMR analysis and are made by analogy
with the model system 16 (Vide infra).
not be resolved in the 31P NMR spectrum. It is reasonable to
assume that the 31P chemical shift of 57 would be similar to
that of 59, since acetylation of the nitrogen six bonds away from
phosphorus would be expected to have only a minor effect. As
is demonstrated in spectrum e of Figure 5, O-coupling pre-
dominates in the reaction of chloridate 7 with 4-aminobutan-
1-ol. This observation is consistent with our results described
above (i.e., coupling with a large number of alcohols, but little
or no coupling with hindered amines). Importantly, this result
is inconsistent with the hypothesis of Greenhalgh that the
chlorophosphonate should optimize phosphonamide formation.
4-Aminobutan-1-ol was also allowed to react with the
unhindered chloridate 19 as shown in Scheme 12. Significantly,
the ratio of the three products was different from that observed
for chloridate 7: with 19, N-coupling predominates (Figure 6;
spectrum e), whereas treatment of chloridate 7 with 4-aminobu-
tan-1-ol led to selective O-coupling.
Scheme 11
Scheme 12
The 31P NMR spectra (202.5 MHz) of monoester (-)-6
(spectrum a) and 58-60 (spectra b, c and d, respectively) are
shown in Figure 5. Compounds 57-59 exist as mixtures of
two diastereomers and 60 as four diastereomers which could
In accord with Greenhalgh’s studies, these results indicate
that unhindered phosphonochloridates, such as 19, exhibit a
preference for more polarizable nucleophiles (amines). How-
ever, our results with the more-hindered phosphonochloridate
7 clearly illustrate that steric factors must also be considered.
Successful coupling between sterically hindered partners requires
surmounting a large energy barrier as the reactants approach in
the transition state. We surmise that the energy gained as the
stronger phosphonate P-O bond forms (g20 kcal per mol more
stable than a P-N bond), reduces this barrier enough to facilitate
coupling with alcohol 9. In coupling with amine 8, too little
bond energy is gained as the weaker P-N bond forms to
overcome the steric repulsion, and decomposition of chloridate
7 occurs more rapidly than coupling with the amine. Conse-
quently, when preparing complex phosphonates and phospho-
namides, the sterics of the phospylating agent must be consid-
ered along with its polarizablity in determining relative preference
for amine vs. alcohol nucleophiles.
By the same logic, the greater stability of the P-O bond
should also lower the thermodynamic energy of product
phosphonate 11 relative to phosphonamide 10, but our failure
to observe formation of 10 prevents any conclusions based on
thermodynamic control. Nonetheless, experiements with the
simple phosphonamide 23 failed to reveal any signs of revers-
ibility.
While these experiments were in progress, we explored an
alternate explanation for the fact that we could generate 11 but
not 10. It is a well-known fact that N-acylated and even
urethane-protected amino acids and peptides undergo cyclization
by tertiary amines to form oxazolones,49 which are themselves
reactive acylating agents (c.f., 65 to 66, Scheme 13, eq 1). We
hypothesized that the lack of amine coupling with chloridate 7
might be due to analogous cyclization of 7 to give the
Figure 5. 31P NMR spectra: (a) monoester (-)-6; (b) phosphonamide
58; (c) phosphonate ester 59; (d) bisadduct 60; (e) reaction of
phosphonochloridate 7 with 4-aminobutan-1-ol; (e) reaction of phospho-
nochloridate 7 with 4-aminobutan-1-ol and triethylamine.
(49) Benoiton, N. L. in The Peptides; Udenfriend, S., Meienhofer, J.,
Eds.; Academic Press: San Diego, CA, 1983; Vol. 5, Chapter 4.

8184 J. Am. Chem. Soc., Vol. 119, No. 35, 1997
Hirschmann et al.
of phosphinyl azide 74 to tetrazole phosphinic acid 75 (Scheme
14).52
Scheme 14
However, as will be shown below, cyclization does not occur
when R-aminophosphonochloridates are allowed to react with
amines.
Reaction of Phosphonochloridates with Tertiary Amines.
Formation of a Novel Reactive Species. In the hope of
generating an oxaphospholine, the phosphonochloridate 16,
containing some of the diastereomeric anhydrides, was allowed
to react with triethylamine. This resulted in the conversion of
16 into a new species displaying a dramatic downfield shift of
the 31P NMR resonance (44.7 ppm); the anhydrides remained
unchanged (see Figure 4). We propose that the product
corresponding to the low-field resonance is not the anticipated
oxazaphospholine (c.f., 67, Scheme 14), but rather phospho-
nyltriethylammonium salt 76 (Scheme 15).53,54 Our assignment
Figure 6. 31P NMR spectra: (a) monoester 16; (b) phosphonamide
61; (c) phosphonate ester 62; (d) bisadduct 64; (e) reaction of
phosphonochloridate 19 with 4-aminobutan-1-ol; (f) reaction of phospho-
nochloridate 19 with 4-aminobutan-1-ol and triethylamine.
Scheme 15
oxazaphospholine 67. Oxazaphospholines such as 70 and 71,
substituted at the R-position, had been prepared previously by
alternate routes.50,51 Indeed, 70 was reported to undergo ethanol-
induced ring opening to afford the diethyl ester, but not to react
with aniline. We speculated, therefore, that oxazaphospholines
might similarly react with alcohols to furnish the diester (68)
but fail to undergo a similar ring opening phosphonylation of
amines (Scheme 13, eq 2).
Additionally, Bartlett and Acher have proposed such a
heterocycle as an undetected intermediate in the rearrangement
is based upon the following considerations. The IR spectrum
of 70 displays a characteristic absorption at 1625 cm-1 (CdN),
which is absent in the spectrum of 76. Moreover, the reported
31P NMR chemical shifts of 70 and 71 (23 and 24.6 ppm,
respectively) are considerably upfield of the observed 44.7 ppm
resonance. The “P-ketene” 77 and trigonal bipyramidal (TBP)
species 78 were considered as alternate structures for the new
reactive intermediate. The former possibility has been ruled
out (Vide infra), while the TBP structure (78), although not
rigorously excluded, seems unlikely in light of both the known
lability of phosphorus derivatives with this ligand array
(phosphorus pentahalides excluded) and their proclivity toward
reorganization to the more stable tetrahedral coordination
Scheme 13
(50) Korenchenko, O. V.; Aksinenko, A. Y.; Sokolov, V. B.; Martynov,
I. V. Heteroatom Chem. 1992, 3, 147.
(51) (a) Drach, B. S.; Lobanov, O. P. J. Gen. Chem. USSR 1974, 44,
2730. (b) Lobanov, O. P.; Drach, B. S. J. Gen. Chem. USSR 1982, 52, 980.
(52) Bartlett, P. A.; Acher, F. Bull. Soc. Chim. Fr. 1986, 771.
(53) A structure analogous to 76 was proposed by Mucha et al. for a
compound which displayed a 31P shift at 15.3 ppm; however, our earlier
results suggest that this species is actually the anhydride: Mucha, A.;
Kafarski, P.; Plenat, F.; Cristau, H.-J. Tetrahedron 1994, 50, 12743.
(54) Yamazaki and co-workers have proposed that an acyloxy N-
phosphonium salt with pyridine was formed an intermediate in an Arbuzov
reaction but the species was uncharacterized: Yamazaki, N.; Niwano, M.;
Kawabata, J.; Higashi, F. Tetrahedron 1975, 31, 665.

Phosphonate Diester and Phosphonamide Synthesis
J. Am. Chem. Soc., Vol. 119, No. 35, 1997 8185
environment.55 Though quaternary ammonium salts have been
suggested as intermediates in acyl phosphonate couplings, this
is the first conclusive identification of such a species.
afford phosphonate diester (+)-11 in yields that varied unpre-
dictably from 0 to 32%.57 As we had hoped, conversion of
phosphonochloridate 7 to the phosphonyltriethylammonium
intermediate 79 prior to the addition of silver cyanide repro-
ducibly furnished diester (+)-11 in 40% yield (Scheme 16).58
Addition of triethylamine after the addition of 9 and silver
cyanide gave yields below 10%. Thus, our protocol both
improved the yield of (+)-11 over the conventional procedure
and made the reaction reproducible. Unfortunately, 79 failed
to form the desired phosphonamide 10 even in the presence of
silver ion, as demonstrated by 31P NMR studies. This result is
consistent with the phophonyltriethylammonium species’ prefer-
ence for oxygen over amine nucleophiles.
Importantly, intermediate 76 reacted more rapidly with benzyl
alcohol than phosphonochloridate 19, although both afforded
the mixed diester 21 in high yield. The increased reactivity of
76 relative to 19 was even more pronounced in the coupling
with amines. When a 1:1 mixture of 76 and 16, generated with
0.5 equiv of triethylamine, was treated with a limiting amount
of benzylamine, the amine reacted exclusively with 76 to give
23 (X ) NH), with no detectable consumption of the phospho-
nochloridate as indicated by 31P NMR.
Intermediate 76 also displayed a markedly greater affinity
for alcohols than did phosponocloridate 19. As mentioned
above, treatment of 19 with 4-aminobutan-1-ol led to a 1.5-
fold preference for N-coupling (Figure 6). In striking contrast,
when 19 is allowed to first react with 1 equiv of triethylamine
to generate 76, and then allowed to react with 4-amino-1-
butanol, O-coupling dominates over N-coupling by a factor of
8, as evidenced by RP-HPLC and 31P NMR (Figure 6f). Such
a change in selectivity indicates a shift to greater charge transfer
in the transition state. The strong preference for coupling with
O suggests that formation of 76 is the procedure of choice for
preparation of phosphonate esters.
Scheme 16
In many conventional phosphonate syntheses, triethylamine
is added along with the nucleophile as an acid scavenger. The
suggestion has been made,56 in response to our previous
publication,1 that intermediate 76 could be the actual intermedi-
ate for all such couplings. However, we believe that the
experimental results cited in the previous paper and those
reported in this paper favor the view that, in such conventional
procedures, the triethylamine acts only as an acid scavenger.
For example in several 31P NMR experiments in which the
nucleophile and triethylamine were added simultaneously to the
chloridate 19, no evidence for the formation of 76 was seen,
nor were any noticeable changes in reaction rates or product
composition in comparison to reactions carried out in the
absence of triethylamine. On the other hand, as reported
previously, both yields and reaction rates were improved when
19 was allowed to react first with triethylamine, generating 76.
The marked difference in selectivity between phosphonochlo-
ridate 19 and phosphonyltriethylammonium species 76 toward
the bisnucleophile 4-aminobutan-1-ol allowed us to address this
question directly. In couplings with this bisnucleophile, 19
displayed a 1.5-fold preference for N-coupling, while 76
displayed an 8-fold preference for O-coupling. Therefore, the
product ratio of a conventional coupling procedure in which
the bisnucleophile and triethylamine are added simultaneously
will reveal which species is the reaction intermediate. As we
anticipated, treatment of chloridate 19 with a mixture of
4-aminobutan-1-ol and 1 equiv of triethylamine yielded a 1.2:1
mixture of N-coupled to O-coupled products, as determined by
RP-HPLC. Thus, simultaneous addition of a tertiary amine had
no effect on the coupling ratio to within expeimental error. These
results demonstrate that while 76 may play a minor role in this
system during a conventional coupling, the triethylamine acts
primarily as an acid scavenger. Thus, the phosphonyltriethy-
lammonium species 76 must be preformed to affect the outcome
of the reactions.
Despite the increased reactivity of 76 toward both alcohols
and amines, the R-carbon of the phosphonylammonium species
is not prone to racemization, as is evidenced by the formation
of only two diastereomers of (+)-11 (diastereomeric at phos-
phorus) in the coupling of 79 with 9. Moreover, enantiomeric
purity is retained upon an aqueous quench of 79; a result that
also rules out formation of 77. Additional support derives from
the observation that deuterium is not incorporated (2H NMR,
HRMS) at the R-center during coupling reactions of 76 with
excess benzylamine-N,N-d2. We have also observed the forma-
tion of phosphonylammonium salts of 19 with other tertiary
amines including diisopropylethylamine, N-methyl piperidine,
N-methyl-2,6-tetramethylpiperidine, 4-(dimethylamino)pyridine
(DMAP), and Dabco, but not with pyridine or 2,6-lutidine.
Reaction of 19 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
lead to decomposition.19c,59-61
Summary. We have demonstrated that pyrophosphonate
anhydrides are readily formed in the preparation of phospho-
nochloridates from phosphonate monoesters with thionyl chlo-
ride and oxalyl chloride and that these anhydrides are less-
reactive toward nucleophiles, particularly toward amines than
(57) Smith, A. B., III; Taylor, C. M.; Benkovic, S. J.; Hirschmann, R.
Tetrahedron Lett. 1994, 35, 6853.
(58) Numerous attempts to employ 31P NMR to probe the effects of silver
ion have not, to date, been enlightening. There are no obvious changes in
the 31P NMR spectrum of 77 after treatment with silver cyanide at room
temperature, and heating in the absence of a nucleophile leads to
decomposition as evidenced by a complex upfield region in the 31P NMR
spectrum.
(59) Since the standard protocol for phosphonopeptide (amide) formation
involves the addition of tertiary amines to convert the amine salt to the
free base, an excess of tertiary amine in these cases would be expected to
form a phosphonylammonium salt.53 1H-Tetrazole-assisted phosphonate
diester synthesis from phosphonodichloridates has been reported.60 In
particular reaction of phosphonodichloridates with 1H-tetrazole leads
sequentially and selectively to the replacement of the chloride substituents
with two different alcohols to give the product mixed diesters in good yield.
This reaction was not, however, studied with alkylamine nucleophiles.
Amine-catalyzed coupling and hydrolysis of phosphate derivatives is also
well-known;61 here, 1H NMR and IR spectroscopic evidence for N-
phosphorylated adducts has been provided.51b To our knowledge, however,
the presumed P-N adducts in many studies have not been identified.62
(60) Zhao, K.; Landry, D. W. Tetrahedron 1993, 49, 363.
Eager to exploit the increased reactivity of the triethylam-
monium salts, we returned to the synthesis of hapten (+)-5.
Previously, we had observed coupling of chloridate 7 with (R)-
(+)-â-indolyllactamide (9)30 in the presence of silver ion to
(55) Van Wazer, J. R. Phosphorus and its Compounds; Interscience
Publishers: New York, 1964; Vol. 1, Chapter 3, pp 74-75.
(56) Fernandez, M. F.; Vlaar, C. P.; Fan, H.; Liu, Y.; Froczek, F. R.;
Hammer, R. P. J. Org. Chem. 1995, 60, 7390.

8186 J. Am. Chem. Soc., Vol. 119, No. 35, 1997
Hirschmann et al.
dimethylformamide (6 µl, 0.010 mmol) and oxalyl chloride (13 µL,
0.147 mmol) were added. The mixture was stirred for 0.5 h at 0 °C,
diluted with benzene (5 mL), and concentrated. The residue was
redissolved in benzene (2 mL) and treated with Et3N (20 µL, 0.147
mmol) followed by silver cyanide (29 mg, 0.217 mmol). After 5 min
at room temperature, (R)-â-indolyllactamide (9) (22.4 mg, 0.011 mmol)
was introduced, and the mixture was heated at reflux for 2 h, cooled
to room temperature, filtered and concentrated. Flash chromatography
(2% MeOH/CH2Cl2) gave diesters 11 (19.8 mg, 37% yield) as a white
solid. The diastereomers were separated by RP-HPLC. For the minor
the corresponding phosphonochloridates. Unlike their carboxy-
lic acid counterparts, the phosphonochloridates do not cyclize
to oxazaphospholines upon treatment with a tertiary amine, but
afford instead the hitherto unrecognized phosphonylammonium
salts. These phosphonylammonium salts are highly reactive
phosphonylating agents, superior to phosphonochloridates, af-
fording higher yields of phosphonate esters and amides.62 These
improVed yields are not obtained when triethylamine is added
merely to neutralize acid rather than as a deliberate step to
generate the phosphonyltrialkylammonium salts.63 We have also
shown that the phosphonochloridates differ markedly in their
reactivities toward amines and alcohols. The preference for
oxygen- vs. nitrogen-coupling varies and depends on both the
steric and electronic environment surrounding the electrophilic
phosphorus center and the structure of the nucleophile. For
example, with the chloridate derived from acid 47 or chloridates
7 and 51, the steric congestion imparted by the cyclohexyl and/
or p-nitrobenzyl groups hindered, and in many cases precluded,
formation of phosphonamides. Our results indicate that suc-
cessful coupling of phosphonochloridate 7 with hindered
alcohols was due largely to the added strength of the forming
P-O ester bond. On the other hand, when steric requirements
of the phosphonochloridate are less demanding (i.e., 19 and 20),
phosphonamide formation tends to dominate. Alteration of the
electronic properties of the electrophilic phosphorous center by
conversion of phosphonochloridates into the phosphonylam-
monium salts resulted in a dramatic increase in oxygen
selectivity, as demonstrated in coupling reactions with the
bisnucleophile 4-aminobutan-1-ol.
diastereomer: amorphous white solid (4.5 mg); [R]25 +15° (c 0.47,
D
EtOH); IR (CHCl3) 3480 (m), 3430 (w), 3005 (m), 2930 (s), 2860 (m),
1710 (br, s), 1610 (w), 1525 (s), 1455 (m), 1350 (s), 1320 (w), 1290
(m), 1230 (m), 1010 (s), 955 (m), 855 (m) cm-1; 1H NMR (500 MHz,
CDCl3) δ 8.06 (d, J ) 8.5 Hz, 2 H), 7.96 (br s, 1 H), 7.78 (dd, J ) 7.5,
2.0 Hz, 2 H), 7.60 (d, J ) 7.9 Hz, 2 H), 7.53 (dd, J ) 10.8, 7.6 Hz, 1
H), 7.40 (t, J ) 7.5 Hz, 2 H), 7.33 (d, J ) 8.5 Hz, 2 H), 7.28 (t, J )
7.5 Hz, 1 H), 7.25 (d, J ) 7.9 Hz, 1 H), 7.15 (t, J ) 7.5 Hz, 1 H), 7.08
(t, J ) 7.5 Hz, 1 H), 7.00 (d, J ) 1.8 Hz, 1 H), 6.12 (br s, 1 H), 5.54
(br s, 1 H), 5.11-4.90 (m, 3 H), 4.60 (dd, J ) 10.8, 6.0 Hz, 1 H), 4.35
(dd, J ) 10.8, 6.0 Hz, 1 H), 4.12 (t, J ) 6.0 Hz, 1 H), 3.95 (ddd, J )
18.5, 10.7, 4.5 Hz, 1 H), 3.33 (m, 2 H), 1.85-0.65 (m, 11 H); 13C
NMR (125 MHz, CDCl3) δ 171.8, 156.1, 147.8, 143.6, 143.5, 142.7,
141.4, 141.3, 135.9, 128.1, 127.9, 127.8, 127.5, 127.2, 127.1, 124.8,
124.6, 123.7, 122.3, 120.1, 120.0, 119.8, 118.7, 111.2, 109.3, 66.8 (d,
JCP ) 7 Hz), 66.6, 53.3 (d, JCP ) 154 Hz), 47.2, 38.1, 38.0, 30.4, 30.3,
29.7, 29.2, 27.8, 25.8, 25.7, 25.6; high-resolution mass spectrum (CI,
NH3) m/z 737.2740 [(M + H)+; calcd for C40H42N4O8P 737.2740].
For the major diastereomer: amphous white solid (15 mg); [R]25
D
+25° (c 0.44, EtOH); IR (CHCl3) 3420 (w), 3000 (m), 2950 (s), 2930
(s), 2860 (m), 1720 (s), 1605 (w), 1520 (w), 1505 (w), 1455 (m), 1345
1
(m), 1250 (s), 1125 (s), 1035 (s), 855 (w), 550 (w) cm-1; H NMR
(500 MHz, CDCl3) δ 8.08 (d, J ) 8.7 Hz, 2 H), 7.84 (dd, J ) 19.0,
7.5 Hz, 2 H), 7.58 (d, J ) 17.7, 7.4 Hz, 2 H), 7.55-7.30 (m, 10 H),
7.03 (ddd, J ) 7.9, 5.2, 2.5 Hz, 1 H), 6.76 (d, J ) 2.2 Hz, 1 H), 6.71
(br s, 1 H), 5.50 (br s, 1 H), 4.93 (m, 1 H), 4.82 (dd, J ) 12.8, 7.1 Hz,
1 H), 4.71 (dd, J ) 11.0, 5.3 Hz, 1 H), 4.67 (dd, J ) 12.9, 6.9 Hz, 1
H), 4.44 (dd, J ) 10.9, 5.1 Hz, 1 H), 4.18 (t, J ) 5.1 Hz, 1 H), 4.13
(d, J ) 10.5 Hz, 1 H), 3.81 (ddd, J ) 17.5, 11.0, 6.2 Hz, 1 H), 3.39 (d,
J ) 15.0 Hz, 1 H), 3.18 (dd, J ) 15.0, 9.2 Hz, 1 H), 1.71-0.40 (m, 11
H); 13C NMR (125 MHz, CDCl3) δ 172.0, 156.2, 147.7, 143.9, 143.5,
142.6, 142.5, 141.5, 141.3, 135.7, 128.1, 127.9, 127.7, 127.3, 124.9,
124.6, 123.7, 122.8, 122.4, 120.2, 120.1, 119.9, 118.6, 111.3, 110.0,
66.5, 66.0, 52.8 (d, JCP ) 151 Hz), 47.4, 38.0, 30.4, 30.3, 29.0, 28.1,
28.0, 25.8, 25.7; high-resolution mass spectrum (CI, CH4) m/z 614.2343
[(M-p-NO2C6H4)+; calcd for C34H37N3O6P 614.2420].
Experimental Section
Materials and Methods. Except as otherwise indicated, reactions
were carried out under argon with dry, freshly distilled solvents, in
glassware flame-dried under vacuum, with magnetic stirring. Tetrahy-
drofuran (THF) and diethyl ether were distilled from sodium and
benzophenone. Benzene was distilled from sodium. Dichloromethane,
triethylamine, and benzylamine were distilled from calcium hydride.
Thionyl chloride and oxalyl chloride were distilled immediately prior
to use.
All reactions were monitored by thin-layer chromatography (TLC)
using 0.25 mm E. Merck precoated silica gel plates. Flash chroma-
tography was performed with E. Merck silica gel 60 (particle size
0.040-0.063 mm). Yields refer to chromatographically and spectro-
scopically pure compounds, except as noted.
Proton, carbon-13, and phosphorus-31 NMR spectra were recorded
on a Bruker AM-500 spectrometer. Proton and 13C chemical shifts
are reported in δ values relative to internal tetramethylsilane. Phosphorus-
31 spectra were acquired with broad-band proton decoupling; shifts
are reported in δ values relative to external 85% phosphoric acid.
Optical rotations were measured with a Perkin-Elmer Model 241
polarimeter. High-resolution mass spectra were obtained with a VG
Micromass 70/70H or VG ZAB-E spectrometer.
Phthalimide (13). A mixture of N-(hydroxymethyl)phthalimide (12)
(31.46 g, 0.180 mol) and phosphorus tribromide (48.45 g, 0.180 mol)
was heated at 140 °C for 1 h. The homogeneous orange solution was
cooled to room temperature and poured into ice water, and the resultant
pale yellow crystals were collected by filtration, dried over P2O5 under
vacuum (<1 mmHg), and recrystallized from CHCl3-hexanes (1:1)
to give N-(bromomethyl)phthalimide (34.4 g, 80% yield) as colorless
needles: mp 148-150 °C (lit.19b 149-150 °C);64,65 IR (CHCl3) 3050
(w), 1790 (s), 1730 (s), 1470 (m), 1425 (s), 1385 (s), 1350 (s), 1305
1
(m), 1065 (s), 915 (s), 705 (w), 590 (m) cm-1; H NMR (500 MHz,
CDCl3) δ 7.94-7.30 (m, 4 H), 5.50 (s, 2 H); 13C NMR (125 MHz,
CDCl3) δ 165.6, 134.7, 131.8, 123.9, 31.2; high-resolution mass
spectrum (CI, NH3) m/z 239.9638 [(M + H)+; calcd for C9H7NO2Br
239.9660].
Microanalyses were performed by Robertson Labs, Madison, N.J.
Phosphonate Diesters 11. A solution of monoester (-)-6 (40.0
mg, 0.073 mmol) in CH2Cl2 (2 mL) was cooled to 0 °C, and dry
(61) (a) Wagner-Jauregg, T.; Hackley, B. E., Jr. J. Am. Chem. Soc. 1953,
75, 2125. (b) Jencks, W. P.; Gilchrist, M. J. Am. Chem. Soc. 1965, 87,
3199. (c) Kirby, A. J.; Jencks, W. P. J. Am. Chem. Soc. 1965, 87, 3209. (d)
Kirby, A. J.; Jencks, W. P. J. Am. Chem. Soc. 1965, 87, 3217. (e) Kirby,
A. J.; Varvoglis, A. G. J. Am. Chem. Soc. 1967, 89, 415. (f) Jameson, G.
W.; Lawlor, J. M. J. Chem. Soc. B 1970, 53. (g) Wakselman, M.; Guibe´-
Jampel, E. Tetrahedron Lett. 1970, 1521. (h) Ho¨fle, G.; Steglich, W.;
Vorbru¨ggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569. (i) Kirby, A.
J.; Varvoglis, A. G. J. Chem. Soc. B 1968, 135.
(62) Studies are underway in our laboratory which will explore the
synthetic potential and mechanistic aspects of the phosphonylammonium
salts more fully.
(63) Attempts to monitor the simultaneous addition of a nucleophile and
triethylamine to chloridates employing 31P NMR could not be carried out
because the triethylammonium salts are converted instananeously to product
on addition of the nucleophile.
The bromide and triethyl phosphite (27.69 g, 0.170 mol) were heated
at 120 °C; the ethyl bromide byproduct was collected via a distillation
apparatus. After 1 h, the mixture was cooled to room temperature and
diluted with CHCl3 (100 mL). The solution was washed with water
(3 × 100 mL), dried (CaSO4), and concentrated to give a yellow solid.
Crystallization from hexanes-Et2O (1:1) gave 13 (40.12 g, 81% yield)
as colorless needles: mp 67-68 °C (lit.20b 67 °C); IR (CHCl3) 3000
(w), 1780 (m), 1730 (s), 1405 (m), 1395 (m), 1310 (w), 1240 (m),
1
1060 (m), 1020 (m), 975 (w), 905 (w) cm-1; H NMR (500 MHz,
CDCl3) δ 7.9-7.7 (m, 4 H), 4.22 (dd, JHP ) 14.0 Hz, JHH ) 7.0 Hz,
(64) Davidson, S. K.; Phillips, G. W.; Martin, S. F. Org. Synth. 1987,
65, 119.
(65) Pucher, G. W.; Johnson, T. B. J. Am. Chem. Soc. 1922, 44, 817.

Phosphonate Diester and Phosphonamide Synthesis
J. Am. Chem. Soc., Vol. 119, No. 35, 1997 8187
4 H), 4.12 (d, J ) 11.4 Hz, 2 H), 1.34 (t, J ) 7.0 Hz, 6 H); 13C NMR
3250 (w), 3000 (m), 1725 (s), 1515 (s), 1460 (m), 1410 (m), 1305
(m), 1250 (s), 1195 (m), 1145 (m), 1095 (m), 1070 (m), 1035 (s), 960
(125 MHz, CDCl3) δ 166.4, 133.8, 131.5, 123.0, 62.3, 32.9 (d, JCP
)
1
156 Hz), 15.9; high-resolution mass spectrum (CI, NH3) m/z 298.0871
(s), 910 (w), 880 (w), 690 (m) cm-1; H NMR (500 MHz, CDCl3) δ
[(M + H)+; calcd for C13H16NO5P 298.0844].
7.35-7.22 (m, 10 H), 5.77 (br s, 1 H), 5.07 (d, J ) 5.1 Hz, 2 H),
4.13-4.00 (m, 3 H), 3.92 (m, 1 H), 3.68 (ddd, J ) 15.8, 10.5, 6.0 Hz,
1 H), 3.45 (ddd, J ) 15.8, 10.8, 5.1 Hz, 1 H), 3.34 (dd, J ) 16.8, 7.0
Hz, 1 H), 1.22 (t, J ) 7.1 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
156.2, 139.6, 136.3, 128.5, 128.1, 128.0, 127.3, 127.2, 67.0, 60.6 (d,
JCP ) 7 Hz), 44.6, 37.9 (d, JCP ) 145 Hz), 16.3 (d, JCP ) 6 Hz); 31P
NMR (202.5 MHz, CDCl3) δ 27.2; high-resolution mass spectrum (CI,
CH4) m/z 363.1472 [(M + H)+; calcd for C18H24N2O4P 363.1474].
Anal. Calcd for C18H23N2O4P: C, 59.66; H, 6.40; N, 7.73. Found:
C, 59.86; H, 6.33; N, 7.59.
Diester (17). Following the procedure described above for 15, amine
14 was prepared from 13 (7.0 g, 0.024 mol) and hydrazine hydrate
(1.26 g, 0.025 mol) in absolute ethanol (47 mL). A solution of
fluorenylmethyl chloroformate (6.7 g, 0.026 mol) in toluene (20 mL)
was cooled to 0 °C, and a solution of crude amine 14 in toluene (40
mL) was added via a pressure-equalizing addition funnel over 30 min.
After an additional 30 min, the solution was treated dropwise with Et3N
(4.9 mL, 0.035 mol), warmed to room temperature, and stirred for 9 h.
The mixture was then diluted with CH2Cl2 (10 mL), filtered, and
concentrated. Flash chromatography (5% MeOH-CH2Cl2) furnished
17 (3.08 g, 33% yield) as a pale yellow oil: IR (CHCl3) 3420 (w),
3000 (m), 1725 (s), 1510 (m), 1445 (w), 1305 (m), 1240 (s), 1145 (w),
1025 (s), 970 (m), 795 (w) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.78
(d, J ) 7.5 Hz, 2 H), 7.62 (d, J ) 7.6 Hz, 2 H), 7.42 (t, J ) 7.4 Hz,
2 H), 7.32 (t, J ) 7.4 Hz, 2 H), 5.27 (br s, 1 H), 4.40 (d, J ) 7.0 Hz,
2 H), 4.25 (t, J ) 6.9 Hz, 1 H), 4.17 (m, 4 H), 3.66 (dd, JHP ) 10.1
Hz, JHH ) 5.9 Hz, 2 H), 1.35 (t, J ) 7.0 Hz, 6 H); 13C NMR (125
MHz, CDCl3) δ 156.2, 143.8, 141.3, 134.1, 127.8, 127.1, 125.0, 123.5,
120.0, 67.3, 62.6 (d, JCP ) 6.9 Hz, 2 C), 47.2, 36.7 (d, JCP ) 158 Hz),
16.4 (d, JCP ) 5.7 Hz, 2 C); high-resolution mass spectrum (CI, CH4)
m/z 390.1467 [(M + H)+; calcd for C20H25NO5P 390.1470].
Diester (15). A solution of phthalimide 13 (13.74 g, 0.046 mol) in
absolute ethanol (90 mL) was treated with hydrazine hydrate (2.43 g,
0.049 mol) and stirred at ambient temperature for 3.5 days. The white
phthalyl hydrazide precipitate was removed by vacuum filtration, and
the filtrate was concentrated at reduced pressure without heating to
provide primary amine 14 as a pale yellow oil. Without purificataion,
14 was dissolved in CHCl3 (155 mL), and the solution was cooled to
0 °C, treated with benzyl chloroformate (8.67 g, 0.051 mol) and Et3N
(7.02 g, 0.069 mol), warmed to room temperature, and stirred for 15
h. The resultant mixture was diluted with CH2Cl2 (100 mL), washed
with 2 N aqueous H2SO4 (2 × 170 mL), dried (MgSO4), filtered, and
concentrated to furnish 15 (12.11 g, 87% yield) as a pale yellow, viscous
oil: IR (CHCl3) 3450 (m), 3000 (s), 1725 (s), 1515 (s), 1450 (w), 1390
(w), 1305 (m), 1240 (s), 1150 (m), 1025 (s), 975 (s), 820 (w), 690 (w)
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.34 (m, 5 H), 5.35 (br s, 1 H),
5.12 (s, 2 H), 4.11 (q, J ) 7.3 Hz, 4 H), 3.61 (dd, JHP ) 11.2 Hz, JHH
) 6.0 Hz, 2 H), 1.29 (t, J ) 7.1 Hz, 6 H); 13C NMR (125 MHz, CDCl3)
δ 156.1, 136.2, 128.4, 128.1, 128.0, 123.4, 102.2, 67.1, 32.5, 36.6 (d,
JCP ) 157 Hz), 16.3; high-resolution mass spectrum (CI, NH3) m/z
302.1133 [(M + H)+; calcd for C13H21NO5P 302.1157].
Anal. Calcd for C13H20NO5P: C, 51.83; H, 6.69. Found: C, 51.92;
H, 6.79.
Monoester (16). A mixture of diester 15 (5.32 g, 0.018 mol) and
2 N aqueous NaOH (30 mL) was stirred vigorously for 18 h at ambient
temperature and then washed with CH2Cl2 (2 × 70 mL) and acidified
with 2 N H2SO4 (85 mL). The resultant solution was extracted with
CH2Cl2 (160 mL) and EtOAc (2 × 160 mL), and the combined organic
solutions were dried (MgSO4), filtered, and concentrated to give the
crude product (4.74 g, 100% yield) as a white solid. Crystallization
from hot benzene afforded 16 (2.03 g, 43% yield) as white needles:
mp 101-103 °C; IR (CHCl3) 2990 (w), 1732 (s), 1510 (m), 1450 (w),
1305 (w), 1230 (m), 1145 (m), 1044 (s), 995 (m) cm-1; 1H NMR (500
MHz, CDCl3) δ 7.78 (br s, 1 H), 7.33 (s, 5 H), 5.11 (s, 2 H), 4.10 (p,
J ) 7.2 Hz, 2 H), 3.61 (d, J ) 11.5 Hz, 2 H), 1.28 (t, J ) 7.0 Hz, 3
H); 13C NMR (125 MHz, CDCl3) δ 156.3, 136.1, 128.5, 128.2, 128.1,
67.3, 62.7, 37.0 (d, JCP ) 159 Hz), 16.2; 31P NMR (202.5 MHz, CDCl3)
δ 24.8; high-resolution mass spectrum (CI, NH3) m/z 274.0829 [(M +
H)+; calcd for C11H17NO5P 274.0844].
Monoester (18). Sodium iodide (200 mg, 1.33 mmol) was added
to a solution of diester 17 in acetone (8 mL), and the resultant mixture
was heated at reflux for 48 h, cooled, and concentrated. The concentrate
was diluted with water (50 mL) and washed with EtOAc (2 × 50 mL).
The aqueous layer was then acidified to pH with 2 N H2SO4 and
extracted with EtOAc (3 × 50 mL), and the combined extracts were
dried (MgSO4), filtered, and concentrated. Flash chromatography (25%
MeOH-CHCl3) gave 18 (168 mg, 35% yield) as a colorless foam: IR
(CHCl3) 3420 (br, w), 3000 (br, w), 1725 (s), 1510 (m), 1450 (w),
Anal. Calcd for C11H16NO5P: C, 48.35; H, 5.90; N, 5.13. Found:
C, 48.16; H, 5.94; N, 5.03.
1
1310 (w), 1230 (m), 1035 (s), 800 (w) cm-1; H NMR (500 MHz,
CDCl3) δ 9.09 (br s, 1 H), 7.77 (d, J ) 7.5 Hz, 2 H), 7.60 (d, J ) 7.5
Hz, 2 H), 7.41 (t, J ) 7.3 Hz, 2 H), 7.31 (t, J ) 7.3 Hz, 2 H), 5.40 (br
s, 1 H), 4.43 (d, J ) 6.9 Hz, 2 H), 4.23 (t, J ) 6.6 Hz, 1 H), 4.16 (p,
J ) 7.2 Hz, 2 H), 3.67 (d, JHP ) 11.4 Hz, 2 H), 1.35 (qd, JHH ) 7.0,
JHP ) 2.7 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 156.2, 143.7, 141.3,
127.7, 127.1, 125.1, 120.0, 67.4, 62.7, 47.1, 37.1 (d, JCP ) 157 Hz),
16.3 (d, JCP ) 7 Hz); 31P NMR (202.5 MHz, CDCl3) δ 24.2; high-
resolution mass spectrum (CI, CH4) m/z 361.1168 [(M + H)+; calcd
for C18H21NO5P 361.1157.
Phosphonate [(()-22]. Following the procedure described above
for 21, chloridation of 18 (31.4 mg, 0.087 mmol) with thionyl chloride
(11.4 mg, 0.096 mmol) followed by reaction with Et3N (13.3 µL, 0.208
mmol) and benzyl alcohol (46.9 mg, 0.434 mmol) furnished (()-22
(35.0 mg, 89% yield) as a colorless oil after flash chromatography (50%
EtOAc-hexanes): IR (CHCl3) 3440 (m), 3220 (m), 3000 (br, w), 1725
(s), 1515 (s), 1450 (m), 1310 (m), 1240 (s), 1150 (m), 1025 (m), 910
(s), 710 (m) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J ) 7.5 Hz,
2 H), 7.60 (d, J ) 7.5 Hz, 2 H), 7.45-7.30 (m, 9 H), 5.17 (br s, 1 H),
5.13 (d, JHP ) 8.6 Hz, 2 H), 4.41 (d, J ) 6.8 Hz, 2 H), 4.22 (t, J) 7.1
Hz, 1 H), 4.13 (m, 2 H), 3.66 (dd, JHP ) 11.1 Hz, JHH ) 8.0 Hz, 2 H),
1.31 (t, J ) 7.1 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 156.2, 143.8,
141.3, 136.0, 128.7, 128.6, 128.1, 127.8, 127.1, 125.0, 120.0, 68.0 (d,
JCP ) 6.2 Hz), 67.3, 62.7 (d, JCP ) 5.5 Hz), 47.1, 36.9 (d, JCP ) 158
Hz), 16.3 (d, JCP ) 5.8 Hz); 31P NMR (202.5 MHz, CDCl3) δ 23.6;
high-resolution mass spectrum (CI, CH4) m/z 452.1621 [(M + H)+;
calcd for C25H27NO5P 452.1626].
Benzyl Ethyl [(N-Benzyloxycarbonyl)aminomethyl]phosphonate
[(()-21]. At ambient temperature, a solution of monoester 16 (66 mg,
0.242 mmol) in CH2Cl2 (1.9 mL) was treated with thionyl chloride (53
µL, 0.725 mmol). After 30 min, the mixture was concentrated and
the resultant opaque oil was exposed to high vacuum (e1 mmHg) for
3 h. The crude chloridate (()-19 was dissolved in CH2Cl2 (1.9 mL),
Et3N (37 µL, 0.266 mmol) and then benzyl alcohol (125 µL, 1.208
mmol) were added, and the solution was stirred for 45 min. Concentra-
tion and flash chromatography (33% hexanes/EtOAc) afforded (()-21
(71.1 mg, 81% yield) as a colorless oil: IR (CHCl3) 3460 (m), 3000
(m), 1735 (s), 1520 (s), 1460 (w), 1315 (m), 1240 (s), 1150 (m), 1020
1
(s), 695 (m) cm-1; H NMR (500 MHz, CDCl3) δ 7.31 (m, 10 H),
5.08 (s, 2 H), 5.06 (d, JHP ) 9 Hz, 2 H), 4.05 (m, 2 H), 3.62 (dd, JHP
) 11.2 Hz, JHH ) 6.1 Hz, 2 H), 1.25 (t, J ) 7.1 Hz, 3 H); 13C NMR
(125 MHz, CDCl3) δ 159.9, 136.2, 135.9, 128.7, 128.6, 128.5, 128.3,
128.1, 128.0, 68.0 (d, JCP ) 7 Hz), 67.3, 62.7, (d, JCP ) 7 Hz), 36.8
(JCP ) 157 Hz), 16.3 (d, JCP ) 6 Hz); 31P NMR (202.5 MHz, CDCl3)
δ 23.6; high-resolution mass spectrum (CI, CH4) m/z 364.1318 [(M +
H)+; calcd for C18H23NO5P 364.1315].
Anal. Calcd for C18H22NO5P: C, 59.50; H, 6.10; N, 3.85. Found:
C, 59.59; H, 5.99; N, 3.74.
Phosphonamide [(()-23]. Following the procedure described above
for 21, chloridate 19 was prepared from monoester 16 (51.6 mg, 0.189
mmol) and thionyl chloride (41.0 µL, 0.567 mmol) in CH2Cl2 (1.5 mL).
The crude chloridate was dissolved in CH2Cl2 (1.5 mL), Et3N (29 µL,
0.208 mmol) and then benzylamine (103 µL, 0.944 mmol) were added,
and the solution was stirred for 1 h at ambient temperature. Concentra-
tion and flash chromatography (7.5% MeOH/CH2Cl2) afforded (()-23
(57.9 mg, 85% yield) as a pale yellow wax: IR (CHCl3) 3420 (w),
Phosphonamide [(()-24]. Following the procedure described above
for 21, chloridation of 18 (33.0 mg, 0.091 mmol) with thionyl chloride
(11.9 mg, 0.100 mmol) followed by reaction with benzylamine (48.9

8188 J. Am. Chem. Soc., Vol. 119, No. 35, 1997
Hirschmann et al.
mg, 0.457 mmol) furnished (()-24 (26.4 mg, 64% yield) as a pale
yellow oil after flash chromatography (gradient elution, 50% EtOAc-
hexanes to 7% MeOH-CHCl3): IR (CHCl3) 3405 (w), 3000 (m), 1720
the mixture was stirred at room temperature for 3 h. Concentration
and flash chromatography (50% EtOAc-hexanes) afforded 40 as a
mixture of diastereomers which were separated via RP-HPLC. For
(s), 1510 (m), 1450 (m), 1300 (w), 1235 (m), 1030 (m), 955 (w) cm-1
;
the minor diastereomer (15.2 mg, 17% yield): colorless oil; [R]25
D
1H NMR (500 MHz, CDCl3) δ 7.78 (d, J ) 7.5 Hz, 2 H), 7.60 (d, J )
7.2 Hz, 2 H), 7.41 (t, J ) 6.4 Hz, 2 H), 7.32 (m, 7 H), 5.48 (br s, 1 H),
4.40 (m, 2 H), 4.21 (t, J ) 6.9 Hz, 1 H), 4.15 (m, 2 H), 4.03 (p, J )
8.2 Hz, 1 H), 3.71 (p, J ) 6.3 Hz, 1 H), 3.52 (m, 1 H), 3.14 (m, 1 H),
1.73 (br s, 1 H), 1.30 (t, J ) 7.9 Hz, 3 H); 13C NMR (125 MHz, CDCl3)
δ 156.5, 143.8, 141.3, 139.6, 128.7, 128.6, 127.8, 127.4, 127.2, 127.1,
+3.1° (c 0.98, acetone); IR (CHCl3) 3415 (w), 3005 (w), 2940 (m),
2860 (w), 1725 (s), 1610 (w), 1525 (s), 1510 (s), 1450 (m), 1350 (s),
1330 (w), 1290 (m), 1230 (s), 1040 (s), 1010 (s), 1000 (s), 855 (m)
1
cm-1; H NMR (500 MHz, CDCl3) δ 8.07 (d, J ) 8.5 Hz, 2 H), 7.76
(d, J ) 7.5 Hz, 2 H), 7.53 (dd, J ) 14.4, 7.4 Hz, 2 H), 7.31 (s, 5 H),
7.40-7.20 (m, 6 H), 5.10-4.95 (m, 5 H), 4.43 (dd, J ) 10.7, 6.8 Hz,
1 H), 4.36 (dd, J ) 10.7, 6.8 Hz, 1 H), 4.20-4.14 (m, 1 H), 4.12 (t, J
) 6.5 Hz, 1 H), 1.95-1.91 (m, 5 H), 1.4-0.93 (m, 6 H); 13C NMR
(125 MHz, CDCl3) δ 156.2, 147.7, 143.7, 143.6, 143.1, 141.3, 135.8,
128.6, 128.1, 127.9, 127.8, 127.0, 124.9, 124.8, 123.7, 120.1, 120.0,
68.1 (d, JCP ) 7 Hz), 66.1 (d, JCP ) 5 Hz), 67.1, 52.8 (d, JCP ) 151
Hz), 47.2, 38.6, 30.5, 28.2, 28.1, 26.0, 25.9, 25.8; high-resolution mass
spectrum (CI, NH3) m/z 641.2457 [(M + H)+; calcd for C36H38N2O7P
641.2416]. For the major diastereomer (51.3 mg, 56% yield): colorless
oil; [R]o(25,D) +3.1° (c 0.75, acetone); IR (CHCl3) 3440 (w), 3080 (w),
3010 (m), 2940 (m), 2860 (m), 1730 (s), 1610 (w), 1530 (s), 1455
(m), 1380 (w), 1355 (s), 1320 (w), 1290 (m), 1250 (s), 1220 (s), 1110
125.1, 120.0, 67.2, 60.8 (d, JCP ) 6.5 Hz), 47.2, 44.8, 38.0 (d, JCP
)
145 Hz), 16.4 (d, JCP ) 6.0 Hz); 31P NMR (202.5 MHz, CDCl3) δ
27.2; high-resolution mass spectrum (CI, CH4) m/z 451.1779 [(M +
H)+; calcd for C25H28N2O4P 451.1786].
Phosphonamide (54). At room temperature, a solution of monoester
16 (112.3 mg, 0.411 mmol) in CH2Cl2 (0.50 mL) was treated with
thionyl chloride (58.7 mg, 0.493 mmol), and the resultant mixture was
stirred for 30 min and then concentrated. The residue was dissolved
in THF (1 mL) and added dropwise over 10 min to a solution of HCl‚D-
Trp‚OEt (99.5 mg, 0.390 mmol) and Et3N (124.8 mg, 1.23 mmol) in
CH2Cl2 (1 mL) at 0 °C. The mixture was gradually warmed to room
temperature, stirred for 2 h and concentrated. Flash chromatography
(2% MeOH-CHCl3) furnished 54 (66.6 mg, 36% yield), a mixture of
diastereomers, as a colorless oil: IR (CHCl3) 3490 (w), 3400 (w), 3000
(m), 1735 (s), 1515 (m), 1460 (w), 1420 (w), 1380 (m), 1305 (m),
1
(w), 1045 (s), 1010 (s), 860 (m), 690 (w) cm-1; H NMR (500 MHz,
CDCl3) δ 8.04 (d, J ) 8.7 Hz, 2 H), 7.75 (d, J ) 7.5 Hz, 2 H), 7.51
(dd, J ) 7.4, 0.7 Hz, 2 H), 7.31 (s, 5 H), 7.40-7.20 (m, 6 H), 5.08 (d,
J ) 9.2 Hz, 1 H), 5.07 (d, J ) 8.9 Hz, 2 H), 4.97 (d, J ) 8.0 Hz, 2 H),
4.46 (dd, J ) 10.7, 6.7 Hz, 1 H), 4.31 (dd, J ) 10.7, 6.8 Hz, 1 H),
4.20-4.15 (m, 2 H), 1.95-1.60 (m, 5 H), 1.31-1.11 (m, 6 H); 13C
NMR (125 MHz, CDCl3) δ 156.2, 147.6, 143.6, 143.5, 143.2, 143.1,
141.3, 135.7, 128.7, 128.6, 128.1, 127.7, 127.0, 124.9, 124.7, 123.6,
120.0, 119.9, 68.1 (d, JCP ) 7.0 Hz), 67.0, 66.2 (d, JCP ) 6.8 Hz), 52.7
(d, JCP ) 153 Hz), 47.1, 38.6, 38.5, 30.5, 30.4, 28.1, 28.0, 25.9, 25.8,
25.7; high-resolution mass spectrum (CI, NH3) m/z 641.2439 [(M +
H)+; calcd for C36H38N2O7P 641.2416].
1
1250 (s), 1135 (w), 1095 (w), 1040 (s), 965 (w), 910 (w) cm-1; H
NMR (500 MHz, CDCl3) δ 8.30 (br s, 1 H), 7.54 (dd, J ) 13.0, 8.0
Hz, 1 H), 7.38-7.28 (m, 6 H), 7.16 (q, J ) 7.5 Hz, 1 H), 7.10 (t, J )
7.5 Hz, 1 H), 7.01 (d, J ) 15.9 Hz, 1 H), 5.04 (m, 2 H), 4.38-4.27
(m, 1 H), 3.99-3.94 (m, 1 H), 3.83-3.71 (m, 1 H), 3.67 (s, 3 H),
3.64-3.29 (m, 3 H), 3.25 (d, J ) 6.0 Hz, 1 H), 3.17 (d, J ) 5.5 Hz,
1 H), 1.14 (q, J ) 7.1 Hz, 3 H); 13C NMR (62.9 MHz, CDCl3) δ 174.2,
173.9, 156.2, 136.2, 136.1, 128.5, 128.1, 127.5, 127.2, 123.4, 123.0,
122.2, 119.6, 118.4, 118.3, 111.4, 109.7, 67.0, 60.8, 60.7, 54.3, 54.2,
52.4, 38.5 (d, JCP ) 148 Hz), 38.2 (d, JCP ) 145 Hz), 30.4, 30.3, 29.9,
29.8, 16.2 (m): high-resolution mass spectrum (CI, NH3) m/z 474.1821
[(M + H)+; calcd for C23H29N3O6P 474.1797].
Anal. Calcd for C36H37N2O7P: C, 67.94; H, 5.82; N, 4.37. Found:
C, 66.94; H, 6.11; N, 4.19.
Phosphonate (42). A solution of monoester (-)-6 (110.1 mg, 0.200
mmol) and sodium methoxide (10.8 mg, 0.200 mmol) in MeOH (5
mL) was stirred at room temperature for 4 h and concentrated. The
residue was suspended in CH2Cl2 (2 mL), and DMF (4 drops) was
added. The mixture was then cooled to 0 °C and treated with oxalyl
chloride (30.6 mg, 0.24 mmol). After 15 min at 0 °C, a solution of
tryptophol (48.6 mg, 0.300 mmol) in CH2Cl2 (1 mL) was introduced
dropwise. The resultant mixture was stirred for 1 h at room temperature
and concentrated. Flash chromatography (3% MeOH-CH2Cl2) pro-
vided 42 (79.8 mg, 58% yield), a mixture of diastereomers, as a yellow
oil: IR (CHCl3) 3395 (w), 3335 (w), 3000 (w), 2940 (m), 2860 (w),
1725 (s), 1610 (w), 1520 (s), 1450 (m), 1350 (s), 1320 (w), 1250 (m),
Anal. Calcd for C23H28N3O6P: C, 58.35; H, 5.96. Found: C, 58.44;
H, 5.69.
Ester (39). A solution of monoester (-)-6 (37.8 mg, 0.069 mmol)
and sodium methoxide (3.7 mg, 0.069 mmol) in MeOH (1 mL) was
stirred at room temperature for 4 h, diluted with toluene (1 mL), and
concentrated. The residue was suspended in CH2Cl2 (2 mL), DMF (1
drop) was added, and the mixture was cooled to 0 °C and treated with
oxalyl chloride (10.5 mg, 0.082 mmol). After 15 min at 0 °C, MeOH
(0.5 mL) was added and the mixture was stirred at room temperature
for 3 h. Concentration and flash chromatography (67% EtOAc-
hexanes) gave 39 (40.0 mg, 96% yield), a mixture of diastereomers as
a colorless glass: IR (CHCl3) 3420 (w), 3005 (w), 2950 (m), 2865
(m), 1735 (s), 1620 (w), 1535 (s), 1520 (s), 1460 (m), 1360 (s), 1330
1
1210 (m), 1060 (m), 1010 (s), 910 (s), 860 (w) cm-1; H NMR (500
MHz, CDCl3) δ 8.20 (br s, 1 H), 7.98 (d, J ) 8.7 Hz, 2 H), 7.74 (d, J
) 7.6 Hz, 2 H), 7.54 (d, J ) 7.5 Hz, 1 H), 7.51 (d, J ) 7.6 Hz, 1 H),
7.35 (t, J ) 7.5 Hz, 2 H), 7.29-7.21 (m, 5 H), 7.15 (td, J ) 7.5, 1.0
Hz, 1 H), 7.07 (td, J ) 7.5, 0.9 Hz, 1 H), 6.95 (d, J ) 2.1 Hz, 1 H),
5.07 (d, J ) 10.7 Hz, 1 H), 4.86 (d, J ) 7.9 Hz, 2 H), 4.31 (dd, J )
7.0, 3.5 Hz, 1 H), 4.35-4.25 (m, 3 H), 4.11 (t, J ) 6.7 Hz, 1 H), 4.08
(m, 1 H), 3.09 (t, J ) 6.5 Hz, 2 H), 1.90-1.55 (m, 6 H), 1.30-0.82
(m, 5 H); 13C NMR (125 MHz, CDCl3) δ 156.2, 147.5, 143.6, 143.5,
143.3, 141.3, 136.1, 127.7, 127.6, 127.2, 126.9, 124.9, 124.7, 123.5,
122.4, 122.1, 120.0, 119.9, 119.5, 118.4, 111.2, 110.9, 66.9, 66.6 (JCP
) 7 Hz), 66.0 (JCP ) 7 Hz), 52.6 (JCP ) 154 Hz), 47.1, 38.5, 30.3,
28.0, 27.9, 26.5, 25.9, 25.8, 25.7; high-resolution mass spectrum (CI,
NH3) m/z 694.2631 [(M + H)+; calcd for C39H41N2O7P 694.2682].
Phosphonate (45). A solution of hydrazine hydrate (0.78 g, 15.5
mmol) and diester 44 (3.98 g, 14.8 mmol) in MeOH (25 mL) was stirred
at room temperature for 80 h and filtered. The filtrate was concentrated
without heating to give a yellow oil which was dissolved in toluene
(10 mL). The resultant solution was added dropwise to a solution of
fluorenylmethyl chloroformate (4.78 g, 18.5 mmol) in toluene (20 mL)
at 0 °C. The reaction mixture was then treated dropwise with Et3N
(1.87 g, 18.5 mmol), warmed to room temperature and diluted with
CH2Cl2 (5 mL). After 8 h the mixture was filtered and concentrated.
Flash chromatography (50% EtOAc-hexanes) gave 45 (1.45 g, 28%
yield) as a colorless wax: IR (CHCl3) 3450 (w), 3005 (m), 2960 (m),
1730 (s), 1510 (s), 1450 (m), 1310 (m), 1230 (s), 1150 (m), 1060 (s),
(w), 1295 (m), 1255 (s), 1175 (m), 1050 (s), 1020 (s), 865 (m) cm-1
;
1H NMR (500 MHz, CDCl3) δ 8.07 (t, J ) 8.2 Hz, 2 H), 7.75-7.65
(m, 2 H), 7.50-7.45 (m, 2 H), 7.40 (dd, J ) 8.6, 16.2 Hz, 2 H), 7.35-
7.30 (m, 2 H), 7.25-7.20 (m, 2 H), 5.1-4.9 (m, 3 H), 4.45-4.35 (m,
2 H), 4.27 (dd, J ) 6.8, 10.8 Hz, 1 H), 4.15-4.00 (m, 2 H), 3.66 (d,
J ) 10.8 Hz, 1.5 H), 3.63 (d, J ) 10.8 Hz, 1.5 H), 1.85-1.5 (m, 5 H),
1.3-0.8 (m, 6 H); 13C NMR (125 MHz, CDCl3) δ 156.1, 147.8, 147.7,
143.6, 143.5, 143.2, 143.1, 141.3, 128.0, 127.9, 127.8, 127.0, 124.9,
124.8, 124.7, 123.7, 120.1, 120.0, 67.0 (d, JCP ) 6 Hz), 66.4 (d, JCP
)
7 Hz), 66.2 (d, JCP ) 6 Hz), 53.1, 52.4 (d, JCP ) 136 Hz), 52.3 (d, JCP
) 142 Hz), 47.2, 47.1, 38.6, 38.5, 38.4, 30.5, 30.4, 30.3, 28.2, 28.1,
28.0, 26.0, 25.9, 25.8; 31P NMR (202.5 MHz, CDCl3) δ 27.4; high-
resolution mass spectrum (CI, NH3) m/z 587.1978 [(M + NH4)+; calcd
for C30H37N3O7P 587.1923].
Anal. Calcd for C30H33N2O7P: C, 63.82; H, 5.89; N, 4.96. Found:
C, 63.63; H, 5.89; N, 5.14.
Phosphonate (40). A solution of monoester (-)-6 (81.4 mg, 0.140
mmol) and sodium methoxide (7.7 mg, 0.14 mmol) in MeOH (2 mL)
was stirred at room temperature for 4 h, diluted with toluene (2 mL),
and concentrated. The residue was suspended in CH2Cl2 (2 mL), DMF
(2 drops) was added, and the mixture was cooled to 0 °C and treated
with oxalyl chloride (21.7 mg, 0.170 mmol). After 15 min at 0 °C,
benzyl alcohol (1 µL, 30.8 mg, 0.28 mmol) was added dropwise and

Phosphonate Diester and Phosphonamide Synthesis
J. Am. Chem. Soc., Vol. 119, No. 35, 1997 8189
1
1040 (s), 720 (w) cm-1; H NMR (500 MHz, CDCl3) δ 7.74 (d, J )
MeOH (3 mL), and the mixture was stirred at room temperature for 4
h and then concentrated. The residue was dissolved in CH2Cl2 (4 mL)
containing DMF (2 drops), and the solution was cooled to 0 °C and
treated with oxalyl chloride (16.7 mg, 0.131 mmol). After 15 min at
0 °C, 1-pentanol (1 µL, 14.5 mg, 0.164 mmol) was introduced, and
the mixture was then stirred at room temperature for 3 h. Concentrated
and flash chromatography (67% hexanes-EtOAc) provided 56 (53.2
mg, 78% yield) as a mixture of diastereomers which were separated
via RP-HPLC. For the major diastereomer: colorless oil; [R]25D +4.3°
(c 0.19, MeOH); IR (CHCl3) 3440 (w), 3000 (w), 2860 (w), 1940 (m),
1725 (s), 1610 (w), 1525 (s), 1510 (s), 1465 (m), 1350 (s), 1320 (w),
1290 (m), 1240 (m), 1055 (m), 1010 (s), 990 (s), 860 (m), 755 (m)
7.4 Hz, 2 H), 7.58 (d, J ) 7.4 Hz, 2 H), 7.37 (t, J ) 7.4 Hz, 2 H), 7.28
(t, J ) 7.4 Hz, 2 H), 5.72 (br s, 1 H), 4.40 (d, J ) 6.8 Hz, 2 H), 4.19
(t, J ) 6.8 Hz, 1 H), 3.75 (d, J ) 10.7 Hz, 6 H), 3.65 (dd, J ) 10.7,
6.1 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 156.2, 143.6, 141.2,
127.6, 126.9, 124.9, 119.9, 67.1, 53.0, 47.0, 35.7 (d, JCP ) 158 Hz);
high-resolution mass spectrum (CI, NH3) m/z 362.1128 [(M + H)+;
calcd for C18H21NO5P 362.1157].
Diacid (46). A mixture of diester 45 (591.9 mg, 1.64 mmol) and
concentrated HCl (10 mL) was heated at 100 °C for 4 h with vigorous
stirring and then cooled, diluted with water (10 mL), and extracted
with EtOAc (3 × 65 mL). The combined extracts were washed with
brine, dried (MgSO4), filtered, and concentrated. RP-HPLC afforded
46 (330.2 mg, 60% yield) as a colorless solid: mp 96-102 °C (dec.);
IR (CHCl3) 3300 (s), 3400-2000 (br), 1695 (s), 1550 (s), 1450 (w),
1400 (w), 1310 (w), 1290 (m), 1170 (m), 1110 (w), 1080 (w), 1020
1
cm-1; H NMR (500 MHz, CDCl3) δ 8.12 (d, J ) 8.7 Hz, 2 H), 7.77
(d, J ) 7.6 Hz, 2 H), 7.56 (dd, J ) 10.7, 7.4 Hz, 2 H), 7.47 (d, J ) 8.7
Hz, 2 H), 7.40 (dd, J ) 12.7, 7.4 Hz, 2 H), 7.29 (m, 2 H), 5.15 (m, 2
H), 4.96 (d, J ) 10.7 Hz, 1 H), 4.45 (dd, J ) 10.7, 6.9 Hz, 1 H), 4.37
(dd, J ) 10.7, 6.9 Hz, 1 H), 4.16 (t, J ) 6.9 Hz, 1 H), 4.09 (ddd, J )
18.2, 10.7, 4.5 Hz, 1 H), 4.03 (m, 2 H), 1.89-1.59 (m, 8 H), 1.30-
1.03 (m, 9 H), 0.86 (m, 3 H); 13C NMR (125 MHz, CDCl3) δ 156.2,
147.0, 143.7, 143.6, 141.4, 128.0, 127.9, 127.0, 124.9, 124.8, 123.7,
120.1, 120.0, 67.1, 66.7 (d, JCP ) 7.7 Hz), 66.1, 52.6 (d, JCP ) 151
Hz), 47.2, 38.6, 30.6, 30.5, 30.2, 28.2, 27.6, 26.0, 25.9, 22.1, 13.9;
high-resolution mass spectrum (CI, NH3) m/z 621.2706 [(M + H)+;
calcd for C34H42N2O7P 621.2729].
(m), 1010 (m), 985 (m), 935 (m), 650 (w), 580 (w) cm-1; H NMR
1
(500 MHz, DMSO-d6) δ 7.89 (d, J ) 7.4 Hz, 2 H), 7.75 (d, J ) 7.4
Hz, 2 H), 7.48 (t, J ) 5.3 Hz, 1 H), 7.42 (t, J ) 7.4 Hz, 2 H), 7.33 (t,
J ) 7.3 Hz, 2 H), 4.26 (d, J ) 6.5 Hz, 2 H), 4.21 (t, J ) 6.5 Hz, 1 H),
3.30 (dd, J ) 11.2, 5.9 Hz, 2 H); 13C NMR (125 MHz, DMSO-d6) δ
156.2, 143.9, 140.7, 127.6, 127.1, 125.4, 120.1, 65.9, 36.6, 37.7; high-
resolution mass spectrum (CI, NH3) m/z 333.0742 [M+; calcd for C16H16-
NO5P 333.0766].
For the minor diastereomer: colorless oil; [R]25 -7.7° (c 1.19,
Monoester (47). Sodium methoxide (99.4 mg, 1.84 mmol) was
added to a solution of diacid 46 (291.9 mg, 0.88 mmol) in MeOH (5
mL), and the resultant mixture was stirred at room temperature for 4
h, diluted with toluene (2 mL), and concentrated. The residue was
suspended in CH2Cl2 (10 mL) and DMF (6 drops), and the mixture
was then cooled to 0 °C and treated with oxalyl chloride (277.9 mg,
2.19 mmol). After 15 min at 0 °C, a solution of p-nitrobenzyl alcohol
(335.3 mg, 2.19 mmol) in CH2Cl2 (2 mL) and THF (0.15 mL) was
added dropwise. The mixture was warmed to room temperature, stirred
for 15 h, and then diluted with CH2Cl2 (100 mL) and washed with
saturated aqueous NaHCO3, water, and brine (100 mL each). The
organic layer was dried (MgSO4), filtered, and concentrated. Flash
chromatography (gradient elution, 67-100% hexanes-EtOAc) fur-
nished the intermediate diester (220.5 mg, 52% yield). A solution of
the diester (111.2 mg, 0.23 mmol) in acetone (4 mL) was treated with
sodium iodide (34.5 mg, 0.23 mmol), heated at reflux for 1 h, and
then concentrated. The residue was dissolved in CH2Cl2 (100 mL),
and the solution was washed with 2 N HCl (100 mL) and brine and
concentrated. RP-HPLC gave 47 (51.6 mg, 48% yield) as an
amorphous solid: IR (CHCl3) 3460 (w), 3500-2000 (br), 1730 (s),
1615 (m), 1525 (s), 1480 (w), 1470 (w), 1455 (m), 1355 (s), 1315 (m),
1230 (br, s), 1150 (s), 1110 (w), 1050 (s), 1015 (s), 860 (m), 720 (w)
D
MeOH); IR (CHCl3) 3440 (w), 3010 (m), 2940 (s), 2870 (m), 1730
(s), 1615 (w), 1530 (s), 1480 (w), 1470 (w), 1455 (m), 1355 (s), 1320
(m), 1290 (br, s), 1250 (s), 1110 (w), 1030 (br, s), 900 (w), 860 (s),
1
560 (w) cm-1; H NMR (500 MHz, CDCl3) δ 8.11 (d, J ) 8.7 Hz, 2
H), 7.75 (d, J ) 7.5 Hz, 2 H), 7.54 (dd, J ) 15.5, 7.5 Hz, 2 H), 7.44
(d, J ) 8.7 Hz, 2 H), 7.38 (t, J ) 7.5 Hz, 2 H), 7.29-7.25 (m, 2 H),
5.14-5.03 (m, 3 H), 4.47 (dd, J ) 10.7, 6.8 Hz, 1 H), 4.31 (dd, J )
10.7, 6.8 Hz, 1 H), 4.14-3.97 (m, 6 H), 1.91-1.63 (m, 8 H), 1.33-
1.02 (m, 9 H), 0.87 (m, 3 H); 13C NMR (62.9 MHz, CDCl3) δ 156.1,
147.6, 143.5, 141.3, 127.7, 127.0, 124.9, 124.7, 123.7, 120.0, 66.9,
66.6 (d, JCP ) 7.4 Hz), 66.3 (d, JCP ) 6.5 Hz), 52.6 (d, JCP ) 153 Hz),
47.1, 38.6, 30.5, 30.3, 30.1, 30.0, 28.0, 27.9, 27.5, 26.0, 25.9, 25.8,
22.1, 13.9; high-resolution mass spectrum (CI, NH3) m/z 621.2711 [(M
+ H)+; calcd for C34H42N2O7P 621.2729].
Coupling of (-)-6 with 4-Aminobutan-1-ol. A suspension of
monoester (-)-6 (157.4 mg, 0.286 mmol) in dry MeOH (4 mL) was
treated with sodium methoxide (15.4 mg, 0.286 mmol), stirred at room
temperature under argon for 4 h, and concentrated. The residue was
dried azeotropically with benzene and dissolved in CH2Cl2 (6 mL),
and the solution was cooled to 0 °C. DMF (20 µL) was added followed
by oxalyl chloride (43.5 mg, 0.343 mmol). After 15 min at 0 °C, the
solution was concentrated, the residue was redissolved in CH2Cl2 (6
mL), and 4-aminobutan-1-ol (76.5 mg, 0.858 mmol) was introduced.
The resultant mixture was stirred at room temperature for 3 h and then
concentrated. Flash chromatography (gradient elution, 5-50% MeOH-
CH2Cl2) gave two fractions. The first contained 58 and 60, separable
by flash chromatography (gradient elution, 1-2% MeOH-CH2Cl2).
For 58: colorless oil; 31P NMR (202.5 MHz, CDCl3) δ 30.8; high-
resolution mass spectrum (FAB) m/z 622.2690 [(M + H)+; calcd for
C33H40N3O7P1 622.2682]. Analytical data for 60: colorless oil; 31P
NMR (202.5 MHz, CDCl3) δ 30.7, 26.2; high-resolution mass spectrum
(FAB) m/z 1154.4521 [(M + H)+; calcd for C62H69N5O13P2 1154.4445].
The second fraction consisted of unreacted (-)-6 and the major reaction
product 57. This mixture was dissolved in pyridine (0.5 mL) containing
acetic anhydride (0.50 mL), and the solution was stirred at room
temperature for 3 h and concentrated. Flash chromatography (2%
MeOH-CH2Cl2) furnished 59 as a colorless oil: IR (CHCl3) 3450 (w),
3005 (m), 2940 (m), 1725 (s), 1675 (m), 1530 (s), 1455 (m), 1350 (s),
1325 (w), 1290 (w), 1240 (m), 1155 (w), 1065 (s), 1030 (s), 860 (w),
1
cm-1; H NMR (500 MHz, DMSO-d6) δ 8.18 (d, J ) 8.5 Hz, 2 H),
7.89 (d, J ) 7.5 Hz, 2 H), 7.70 (m, 1 H), 7.71 (d, J ) 7.5 Hz, 2 H),
7.64 (d, J ) 8.4 Hz, 2 H), 7.41 (t, J ) 7.4 Hz, 2 H), 7.31 (t, J ) 7.4
Hz, 2 H), 5.12 (d, J ) 7.2 Hz, 2 H), 4.27 (d, J ) 7.0 Hz, 2 H), 4.19
(t, J ) 7.0 Hz, 1 H), 3.49 (dd, J ) 10.1, 6.0 Hz, 2 H); 13C NMR (125
MHz, DMSO-d6) δ 156.2, 146.9, 145.1, 143.7, 140.7, 127.8, 127.6,
127.0, 125.2, 123.3, 120.0, 65.9, 64.8 (d, JCP ) 5 Hz), 46.6, 36.9 (d,
JCP ) 155 Hz); high-resolution mass spectrum (CI, negative ion) m/z
467.1013 [(M - H)+; calcd for C23H20N2O7P 467.1008].
Diester 50. Benzyl chloroformate (260.5 mg, 1.53 mmol) was
dissolved in CH2Cl2 (2 mL) and added to a solution of amine (R)-4940
(253.8 mg, 1.02 mmol) in CH2Cl2 (5 mL) at 0 °C. The mixture was
treated with Et3N (175.2 mg, 1.73 mmol), stirred at room temperature
for 22 h and then concentrated. Flash chromatography (67% EtOAc-
hexanes) gave 50 (253.8 mg, 65% yield) as a colorless foam: IR
(CHCl3) 3440 (w), 3000 (m), 2940 (s), 2860 (m), 1725 (s), 1505 (s),
1450 (w), 1290 (m), 1230 (s), 1050 (s), 1025 (s), 970 (m), 550 (w)
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.35 (m, 5 H), 5.16 (d, J ) 12.2
Hz, 1 H), 5.11 (s, 1 H), 5.08 (d, J ) 12.2 Hz, 1 H), 4.10 (m, 5 H), 3.30
(t, J ) 7.0 Hz, 3 H), 2.00-1.00 (m, 11 H), 1.24 (t, J ) 7.0 Hz, 3 H);
13C NMR (125 MHz, CDCl3) δ 156.2, 136.3, 128.4, 128.1, 128.0, 67.1,
62.2 (d, JCP ) 7 Hz), 52.4 (d, JCP ) 153 Hz), 38.7, 38.6, 30.6, 30.5,
27.9, 26.1, 25.9, 25.8, 16.3 (d, JCP ) 5 Hz); high-resolution mass
spectrum (CI, NH3) m/z 384.1931 [(M + H)+; calcd for C19H31NO5P
384.1940].
1
560 (w) cm-1; H NMR (500 MHz, CDCl3) δ 8.16-8.13 (m, 2 H),
7.78-7.75 (m, 2 H), 7.60-7.25 (m, 8 H), 5.84-5.77 (m, 1 H), 5.45
(d, J ) 10.7 Hz, 1 H), 5.22-5.10 (m, 2 H), 4.51-4.46 (m, 1 H), 4.35-
4.29 (m, 1 H), 4.15 (t, J ) 6.3 Hz, 1 H), 4.11-4.01 (m, 3 H), 3.23-
3.18 (m, 2 H), 1.98-1.94 (s, 3 H), 1.89-1.53 (m, 9 H), 1.33-0.88
(m, 6 H); 13C NMR (62.9 MHz, CDCl3) δ 170.1, 156.3, 147.7, 143.6,
143.2, 141.3, 128.0, 127.0, 127.8, 127.0, 125.0, 124.9, 124.8, 124.7,
123.7, 120.1, 120.0, 77.2, 67.0 (d, JCP ) 9 Hz), 66.1 (d, JCP ) 7 Hz),
63.9, 52.6 (d JCP ) 151 Hz), 47.1, 39.1, 38.8, 38.6, 38.5, 38.4, 38.3,
Diester (56). Sodium methoxide (5.9 mg, 0.109 mmol) was added
to a suspension of monoester (-)-6 (60.2 mg, 0.109 mmol) in dry

8190 J. Am. Chem. Soc., Vol. 119, No. 35, 1997
Hirschmann et al.
30.6, 30.5, 30.4, 30.3, 28.2, 28.1, 27.8, 27.7, 27.5, 27.4, 26.2, 26.0,
25.9, 25.6, 23.2; 31P NMR (202.5 MHz, CDCl3) δ 26.1; high-resolution
mass spectrum (FAB) m/z 664.2753 [(M + H)+; calcd for C35H43N3O8P
664.2787].
Coupling of 16 with 4-Aminobutan-1-ol via 76. A solution of
monoester 16 (105.2 mg, 0.392 mmol) in dry MeOH (3 mL) sodium
methoxide (21.1 mg, 0.392 mmol), stirred at room temperature for 4 h
and then concentrated. The residue was dissolved in CH2Cl2 (3 mL),
the solution was cooled to 0 °C, and DMF (2 drops) and oxalyl chloride
(59.6 mg, 0.47 mmol) were introduced sequentially. After 15 min at
0 °C, toluene (1.5 mL) was added and the mixture was concentrated.
The residue was taken up in CH2Cl2 (3 mL), cooled to 0 °C, and treated
with triethylamine (TEA 43.5 mg, 0.429 mmol). After 15 min, the
reaction was warmed to room temperature and treated with 4-ami-
nobutan-1-ol (104.2 mg, 1.17 mmol). The resultant mixture was stirred
at room temperature for 1 h and concentrated. An aliquot of the crude
reaction mixture was analyzed by analytical RP-HPLC. The following
relative ratios were obtained: (()-61 (0.11), (()-62 (1.00). Flash
chromatography (gradient elution, 3-50% MeOH-CH2Cl2) afforded
(()-61 (7.0 mg, 5%) and (()-64 (12.3mg, 13%). Isolation of (()-62
as its N-acyl derivative gave (()-63 (50 mg, 35%).
Coupling of 16 with 4-Aminobutan-1-ol and Triethylamine. A
solution of monoester 16 (101.2 mg, 0.375 mmol) in dry MeOH (3
mL) sodium methoxide (20.3 mg, 0.375 mmol) was stirred at room
temperature for 4 h and then concentrated. The residue was dissolved
in CH2Cl2 (3 mL), the solution was cooled to 0 °C, and DMF (2 drops)
and oxalyl chloride (57.3 mg, 0..452 mmol) were introduced sequen-
tially. After 15 min at 0 °C, toluene (1.5 mL) was added and the
mixture was concentrated. The residue was taken up in CH2Cl2 (3
mL) and treated with a mixture of 4-aminobutan-1-ol (100.2 mg, 1.13
mmol) and TEA (41.8 mg, 0.413 mmol) in CH2Cl2 (0.5 mL), and the
resultant mixture was stirred at room temperature for 1 h and
concentrated. An aliquot of the crude reaction mixture was analyzed
by analytical RP-HPLC. The following relative ratios were obtained:
(()-61 (1.22), (()-62 (1.00). Flash chromatography (gradient elution,
3-50% MeOH-CH2Cl2) afforded (()-61 (34 mg, 23%) and
(()-64 (21 mg, 18%). Isolation of (()-62 as the N-acyl derivative
gave (()-63 (21.5 mg, 15%)
Coupling of (-)-6 with 4-(N-Acetylamino)butan-1-ol. A suspen-
sion of monoester (-)-6 (94.2 mg, 0.171 mmol) in dry MeOH (3 mL)
was treated with sodium methoxide (9.2 mg, 0.171 mmol), and the
mixture was stirred at room temperature for 4 h and then concentrated.
The residue was dried azeotropically with benzene (5 mL) and dissolved
in CH2Cl2 (4 mL). The solution was cooled to 0 °C, and DMF (2
drops) and oxalyl chloride (23.9 mg, 0.188 mmol) were sequentially
introduced. After 15 min at 0 °C, a solution of 4-(N-acetylamino)-
butan-1-ol (50.0 mg, 0.381 mmol) in CH2Cl2 (2 mL) was added, and
the mixture was stirred at room temperature for 5 h. Concentration
and flash chromatography (2% MeOH-CH2Cl2) gave 59 (77.6 mg,
68% yield), a mixture of diastereomers, as a colorless oil.
Coupling of 16 with 4-Aminobutan-1-ol. A solution of monoester
16 (63.1 mg, 0.235 mmol) in dry MeOH (2 mL) sodium methoxide
(12.7 mg, 0.235 mmol), stirred at room temperature for 4 h and then
concentrated. The residue was dissolved in CH2Cl2 (2 mL), the solution
was cooled to 0 °C, and DMF (2 drops) and oxalyl chloride (35.8 mg,
0.282 mmol) were introduced sequentially. After 15 min at 0 °C,
toluene (1 mL) was added and the mixture was concentrated. The
residue was taken up in CH2Cl2 (2 mL) and treated with 4-aminobutan-
1-ol (62.9 mg, 0.706 mmol), and the resultant mixture was stirred at
room temperature for 1 h and concentrated. An aliquot of the crude
reaction mixture was analyzed by analytical RP-HPLC. The following
relative ratios were obtained: (()-61 (1.49), (()-62 (1.00). Flash
chromatography (gradient elution, 3-50% MeOH-CH2Cl2) afforded
(()-61 (21.9 mg, 27% yield) and (()-64 (9.5 mg, 13.5% yield). For
(()-64: colorless oil; IR (CHCl3) 3470 (m), 3280 (br), 3000 (m), 1725
(s), 1515 (s), 1455 (w), 1400 (w), 1345 (w), 1305 (m), 1240 (br, s),
1150 (m), 1100 (w), 1035 (s), 970 (s), 840 (w), 690 (w), 500 (w) cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.38-7.27 (m, 10 H), 5.57 (br d, J )
2.9 Hz, 1 H), 5.41 (br s, 1 H), 5.11 (s, 2 H), 5.10 (s, 2 H), 4.15-3.97
(m, 6 H), 3.62 (m, 3 H), 3.43 (m, 1 H), 2.93 (m, 2 H), 1.65 (p, J ) 6.8
Hz, 2 H), 1.51 (p, J ) 7.0 Hz, 2 H), 1.29-1.24 (m, 6 H); 13C NMR
(125 MHz, CDCl3) δ 156.5, 156.2, 136.2, 128.4, 128.2, 128.1, 67.2,
67.1, 65.8 (d, JCP ) 6 Hz), 62.8 (d, JCP ) 6 Hz), 60.6 (d, JCP ) 6 Hz),
40.2, 37.9 (d, JCP ) 144 Hz), 36.5 (dd, JCP ) 158, 8.0 Hz), 28.1, 27.2,
16.4; 31P NMR (202.5 MHz, CDCl3) δ 23.5, 27.7; high-resolution mass
spectrum (FAB) m/z 600.2210; [(M + H)+; calcd for C26H40N3O9P2
600.2240]. For (()-61: colorless oil; IR (CHCl3) 3430 (m), 3300 (br,
m), 3000 (s), 2940 (s), 1725 (s), 1520 (s), 1460 (w), 1410 (w), 1305
(m), 1250 (br, s), 1150 (m), 1100 (m), 1040 (s), 965 (m), 910 (w), 850
Reaction Monitoring via 31P NMR Spectroscopy: A Representa-
tive Experiment. An oven-dried NMR tube was charged with
monoester 16 (10 mg, 0.037 mmol) and dry chloroform-d (0.7 mL)
under argon. Following acquisition of the 31P NMR spectrum, the
mixture was treated with a solution of freshly distilled thionyl chloride
(2 M in CDCl3, 37 µL, 0.073 mmol). The tube was shaken periodically
over 30 min, and the solution was then concentrated with a stream of
dry argon. The resultant oil was exposed to high vacuum (e1 mmHg)
for 1 h and dissolved in dry chloroform-d (0.7 mL).
A
31P NMR
spectrum was acquired, and the Fmoc monoester 18 (13 mg, 0.037
mmol) was then added. After 2.4 h, a 31P NMR spectrum showed the
presence of unreacted 18 and the anhydrides 29, 30, and 38. After
treatment of the reaction mixture with dry triethylamine (5 µL, 0.037
mmol), the NMR spectrum was consistant with formation of the
phosphonyl triethylammonium salt 76, accompanied by anhydrides 29,
30, and 38. This mixture was then allowed to react with dry benzyl
alcohol (11 µL, 0.11 mmol). After 10 min the 31P NMR spectrum
revealed complete conversion of 76 to 21 (X ) O); 29, 30, and 38 did
not react.
1
(w), 690 (w) cm-1; H NMR (500 MHz, CDCl3) δ 7.39-7.29 (m, 5
H), 5.79 (m, 1 H), 5.11 (s, 2 H), 4.10-3.97 (m, 2 H), 3.67 (ddd, J )
15.8, 10.8, 7.1 Hz, 1 H), 3.61 (t, J ) 5.7 Hz, 2 H), 3.41 (ddd, J )
15.7, 10.8, 5.0 Hz, 1 H), 3.14 (br s, 1 H), 2.92 (m, 2 H), 2.50 (br s, 1
H), 1.53 (m, 4 H), 1.28 (t, J ) 7.1 Hz, 3 H); 13C NMR (62.9 MHz,
CDCl3) δ 156.5, 136.2, 128.5, 128.1, 128.0, 67.1, 62.0, 60.4 (d, JCP
)
6 Hz), 40.5, 37.7 (d, JCP) 145 Hz), 29.4, 28.4, 28.3, 16.4, 16.3; 31P
NMR (202.5 MHz, CDCl3) δ 28.1; high-resolution mass spectrum (CI,
NH3) m/z 344.1477 [(M + H)+; calcd for C15H25N2O5P 344.1501].
For acetylation of the O-coupled adduct 63, a mixture of 64 and 62
was dissolved in pyridine (1 mL) and acetic anhydride (0.5 mL). The
resultant solution was stirred at room temperature for 1 h and
concentrated. Flash chromatography (2% MeOH-CH2Cl2) furnished
(()-63 (8.8 mg, 10% yield) as a colorless oil: IR (CHCl3) 3450 (m),
3350 (br, w), 3005 (m), 1725 (s), 1760 (s), 1515 (s), 1450 (w), 1370
Acknowledgment. Support was provided by the National
Institutes of Health (Institute of General Medical Sciences)
through grant GM-45611, by Bachem, Inc. (Torrance, CA), and
by the Merck Research Laboratories. K.M.Y. thanks the NIH
(National Cancer Institute) for a postdoctoral fellowship, and
C.M.T. acknowledges the receipt of a William Georgetti
Scholarship and a University of Pennsylvania, School of Arts
and Sciences, Dissertation Fellowship. We also thank Dr. G.
Furst and Mr. J. Dykins, Directors of the University of
Pennsylvania Spectroscopic Facilities, for assistance in obtaining
NMR spectra and high-resolution mass spectra, respectively.
1
(w), 1310 (m), 1235 (br, s), 1145 (m), 1020 (s) cm-1; H NMR (500
MHz, CDCl3) δ 7.40-7.31 (m, 5 H), 5.90 (br s, 1 H), 5.33 (m, 1 H),
5.12 (s, 2 H), 4.16-4.01 (m, 4 H), 3.63 (ddd, J ) 10.5, 6.0, 3.5 Hz, 2
H), 3.25 (q, J ) 7.0 Hz, 2 H), 1.96 (s, 3 H), 1.67 (m, 2 H), 1.57 (q, J
) 7.0 Hz, 2 H), 1.31 (t, J ) 7.0 Hz, 3 H); 13C NMR (CDCl3, 62.9
MHz) δ 170.3, 156.2, 136.1, 128.5, 128.3, 128.0, 67.2, 66.0 (d, JCP
)
7 Hz), 62.7 (d, JCP ) 6 Hz), 38.9, 36.6 (d, JCP ) 158 Hz), 27.7, 27.6,
25.5, 23.2, 16.4 (d, JCP ) 5 Hz); high-resolution mass spectrum (CI,
NH3) m/z 387.1658 [(M + H)+; calcd for C17H28N2O6P 387.1685].
JA962465O