Investigations on New Strategies for the Facile Synthesis of Polyfunctionalized Phosphinates: Phosphinopeptide Analogues of Glutathionylspermidine

Article abstract of DOI:10.1021/jo971318l

Three possible methods for the facile synthesis of functionalized phosphinates, including the core of complex phosphinopeptide analogues of glutathionylspermidine, were explored. Among these methods, the three-component condensation reaction involving ben

Full text of DOI:10.1021/jo971318l

502
J . Org. Chem. 1998, 63, 502-509
In vestiga tion s on New Str a tegies for th e F a cile Syn th esis of
P olyfu n ction a lized P h osp h in a tes: P h osp h in op ep tid e An a logu es of
Glu ta th ion ylsp er m id in e
Shoujun Chen and J ames K. Coward*
Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, and
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109
Received J uly 18, 1997
Three possible methods for the facile synthesis of functionalized phosphinates, including the core
of complex phosphinopeptide analogues of glutathionylspermidine, were explored. Among these
methods, the three-component condensation reaction involving benzyl carbamate, an aldehyde, and
a functionalized or nonfunctionalized phosphonite can afford a variety of protected R-aminophos-
phinates. However, polyamine-containing R-(aminomethylene)phosphinates can be obtained only
by the acid-catalyzed Pudovik-Abramov-type reaction of a polyamine-containing phosphonite with
a tritylamine-derived Schiff base. Thus, despite its hydrolytic lability, a Tfa-protected polyamine-
containing phosphonite reacts smoothly with tritylmethanimine and affords the corresponding
phosphinate, a key intermediate for the synthesis of complex phosphinopeptide inhibitors of
glutathionylspermidine synthetase. Elaboration of this intermediate via selective deprotection and
coupling to a protected dipeptide provided an alanine-containing phosphinate analogue of
glutathionylspermidine. The limitations and scope of the three explored methods are discussed.
In tr od u ction
ing from the attack of spermidine on the putative acyl
phosphate (Figure 1). We have recently published the
synthesis of phosphonate and phosphonamidate ana-
logues of Gsp8 and have described their inhibition of the
target enzyme, a bifunctional Gsp synthetase/amidase.8,9
Similarly, the corresponding phosphinates (2) would be
attractive synthetic targets as potential specific inhibitors
of Gsp synthetase. Compounds of this type appear to
have an advantage over the corresponding phosphonate
and phosphonamidate, both in terms of chemical stability
and biochemical properties. Thus, 2 could be phospho-
rylated by the enzyme in the presence of ATP; i.e., 2 f
3, as in the case of several other structurally similar
phosphinates.10-15 Phosphorylated phosphinates derived
from 2 should act as potent and specific inhibitors of Gsp
synthetase by closely mimicking the proposed tetrahedral
intermediate 1. Substrate specificity of the enzyme Gsp
synthetase has been investigated, and it was found that
while the glutamate and glycine residues of GSH are
essential for recognition by Gsp synthetase, the cysteine
residue can be replaced by other amino acids; e.g.,
alanine.6,9,16 On the basis of these observations, we
designed the corresponding phosphinate analogues (2a -
Recently, a conjugate of glutathione (GSH) and sper-
midine (SPD), namely N1,N8-bisglutathionylspermidine
(trypanothione, TSH), has been found in parasites of the
genera Trypanosoma and Leishmania and functions in
a similar way as does GSH in mammalian cells.1 Be-
cause TSH is found uniquely in parasites, and since GSH
reductase in the host mammalian cells does not act on
TSH as a substrate, the biosynthesis of TSH is an ideal
target for trypanocidal drug design.2,3 The de novo
biosynthetic pathway of TSH has been elucidated,3 and
the last two steps of this pathway, i.e., the formation of
TSH from GSH (eq 1), are especially attractive for drug
design. Since GSH is essential to host mammalian cells
for oxidative defense, we desire to inhibit TSH biosyn-
thesis while keeping GSH biosynthesis unaffected. Iso-
lated from Escherichia coli4,5 or Crithidia fasciculata,6,7
an ATP-dependent ligase called glutathionylspermidine
(Gsp) synthetase catalyzes the first of the two final steps
of TSH biosynthesis.
(8) Chen, S.; Lin, C.-H.; Kwon, D. S.; Walsh, C. T.; Coward, J . K. J .
Med. Chem. 1997, 40, 3842-3850.
(9) Kwon, D. S.; Lin, C.-H.; Chen, S.; Coward, J . K.; Walsh, C. T.;
Bollinger, J . M., J r. J . Biol. Chem. 1997, 272, 2429-2436.
(10) Colanduoni, J . A.; Villafranca, J . J . Bioorg. Chem. 1986, 14,
163-169.
The Gsp synthetase-catalyzed reaction probably in-
volves formation of a tetrahedral intermediate (1) result-
(11) Duncan, K.; Walsh, C. T. Biochemistry 1988, 27, 3709-3714.
(12) Logusch, E. W.; Walker, D. M.; McDonald, J . F.; Franz, J . E.
Biochemistry 1990, 29, 366-372.
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A. Science 1985, 227, 1485-1487.
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(3) Fairlamb, A. H. Annu. Rev. Microbiol. 1992, 46, 695-729.
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Walsh, C. T. J . Biol. Chem. 1995, 270, 14031-14041.
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Protein Sci. 1992, 1, 874-883.
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Ye, Q. Z.; Walsh, C. T. Biochemistry 1990, 29, 5767-5775.
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439-443.
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12059-12060.
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Haemers, A.; Fairlamb, A. H. Mol. Biochem. Parasit. 1997, 84, 25-
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S0022-3263(97)01318-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

Synthesis of Polyfunctionalized Phosphinates
J . Org. Chem., Vol. 63, No. 3, 1998 503
F igu r e 1. Postulated tetrahedral intermediate and proposed inhibitors for GSPS-catalyzed reaction.
c) as potential inhibitors of Gsp synthetase. In the
present studies, we have investigated methods for the
facile synthesis of core phosphinic acid building blocks
leading to the desired targets 2 and report the synthesis
of the first such inhibitor, an alanine-containing ana-
logue, 2a .
component condensation, Michaelis-Becker, and Pudo-
vik-Abramov reactions.
Resu lts a n d Discu ssion
The three-component condensation (TCC) reaction
involving an amide functionality, an aldehyde or a
ketone, and a trivalent phosphorus compound was first
reported by Birum22 in 1974 and was subsequently
extended by Oleksyszyn et al.23-26 for the synthesis of
R-aminophosphonic acids or R-aminophosphinic acids.
Because the free aminophenylphosphonic acids are un-
suitable for peptide coupling,27,28 facile and direct meth-
ods for the synthesis of protected R-aminophosphonic
acids and phosphonopeptides were developed by Yuan
and co-workers.29-32 This type of reaction was also
extended for the asymmetric synthesis of R-aminophos-
phonic acids.33,34 However, there is no precedent for the
direct use of phosphonous acids or alkylphosphonites,
especially functionalized alkylphosphonites, in this type
A general method for the synthesis of R-aminophos-
phonous acids was reported by Baylis in 1984.17 Reaction
of the protected R-aminophosphonous acids or esters with
a variety of Michael acceptors can afford diverse phos-
phinates and has been used in the synthesis of potent
inhibitors of several ligase and protease enzymes as noted
above.15,18-20 However, this approach is not suitable for
synthesis of the phosphinates of interest in our current
research. First, the structures of intermediates in the
synthetic approach to our targets do not contain a
Michael acceptor. Second, the yield of a key intermediate
R-(aminomethyl)phosphonous acid, required in this ap-
proach, is extremely low (6%).17 Although an improved
procedure for the synthesis of this precursor was reported
recently,21 its use in the synthesis of the highly function-
alized phosphinates of interest in this research would
involve a series of protection-reprotection steps. We
wished to synthesize a variety of protected R-aminophos-
phinates in a more direct manner. As outlined in Figure
2, three alternative routes were proposed for the synthe-
sis of the core phosphinates. These include the three-
(22) Birum, G. H. J . Org. Chem. 1974, 39, 209-212.
(23) Oleksyszyn, J .; Subotkowska, L.; Mastalerz, P. Synthesis 1979,
985-986.
(24) Oleksyszyn, J .; Tyka, R.; Mastalerz, P. Synthesis 1978, 479-
480.
(25) Oleksyszyn, J .; Gruszecka, E. Tetrahedron Lett. 1981, 22, 3537-
3540.
(26) Oleksyszyn, J . J . Prakt. Chem. 1987, 329, 19-28.
(27) Kafarski, P.; Lejczak, B.; Mastalerz, P. Can. J . Chem. 1982,
60, 3081-3084.
(17) Baylis, E. K.; Campbell, C. D.; Dingwall, J . G. J . Chem. Soc.,
Perkin Trans. 1 1984, 2845-2853.
(18) J ira´cek, J .; Yiotakis, A.; Vincent, B.; Lecoq, A.; Nicolaou, A.;
Checler, F.; Dive, V. J . Biol. Chem. 1995, 270, 21701-21706.
(19) Ellsworth, B. A.; Tom, N. J .; Bartlett, P. A. Chem. Biol. 1996,
3, 37-44.
(20) Tanner, M. E.; Vaganay, S.; van Heijenoort, J .; Blanot, D. J .
Org. Chem. 1996, 61, 1756-1760.
(21) J iao, X.-Y.; Verbruggen, C.; Borloo, M.; Bollaert, W.; De Groot,
A.; Dommissee, R.; Haemers, A. Synthesis 1994, 23-24.
(28) Kafarski, P.; Lejczak, B.; Mastalerz, P.; Dus, D.; Radzikowski,
C. J . Med. Chem. 1985, 28, 1555-1558.
(29) Yuan, C.; Qi, Y. Synthesis 1986, 821.
(30) Yuan, C.; Wang, G. Synthesis 1990, 256.
(31) Yuan, C.; Wang, G.; Chen, S. Synthesis 1990, 522-524.
(32) Yuan, C.; Chen, S. Synthesis 1992, 1124-1128.
(33) Huber, J . W., III; Gilmore, W. F. Tetrahedron Lett. 1979, 33,
3049-3052.
(34) Chung, S.-K.; Kang, D.-H. Tetrahedron Asymmetry 1996, 7, 21-
24.

504 J . Org. Chem., Vol. 63, No. 3, 1998
Chen and Coward
F igu r e 2. Retrosynthetic pathway for phosphinates.
Sch em e 1
of reaction. We envisioned that a variety of functional-
ized alkylphosphonites may also participate in this type
of reaction and afford the functionalized R-aminophos-
phinates suitable for our target synthesis. As described
briefly in a previous communication,35 this condensation
can be realized under very mild conditions (AcCl, rt) and
affords a small molecular library of R-aminophosphinates
(eq 2). These phosphinates are not only useful for our
Having established a convenient method for the syn-
thesis of protected R-aminophosphinic acids using the
TCC reaction, we sought to use this method for the
synthesis of the polyamine-containing phosphinic acids
required in our target synthesis. Starting from the
natural polyamine, putrescine (7), the polyamine-con-
taining phosphonous acid 10 and its ethyl ester 11
bearing various protective groups were synthesized as
shown in Scheme 1. The Michaelis-Arbuzov reaction of
936 with bis(trimethylsilyl) hydrogen phosphonite (BTH)
was effected by a slight modification of a recently
published procedure.40 At elevated temperature (105 °C,
toluene), 9 reacted smoothly with BTH to give the desired
(35) Chen, S.; Coward, J . K. Tetrahedron Lett. 1996, 37, 4335-4338.
(36) Substituted 1,4-diaminobutanes 9 were synthesized by the
monoacylation (9a ) or monotosylation (9b,c) of 1,4-diaminobutane with
trifluoroacetic anhydride or tosyl chloride.37 The remaining free amino
group was then protected by reaction with di-tert-butyl dicarbonate
or N-(ethoxycarbonyl)phthalimide to give the orthogonally protected
1,4-diaminobutane, 8. Alkylation of 8 with 1,4-diodobutane was effected
in the presence of NaH.38,39
(37) Crombie, L.; J arrett, S. R. M. J . Chem. Soc., Perkin Trans. 1
1992, 3179-3183.
(38) Lakanen, J . R. Ph.D. Thesis, The University of Michigan, Ann
Arbor, MI, J anuary 1994.
(39) Nordlander, J . E.; Catalane, D. B.; Eberlein, T. H.; Farkas, L.
V.; Howe, R. S.; Stevens, R. M.; Tripoulas, N. A. Tetrahedron Lett. 1978,
50, 4987-4990.
current research but are also potential building blocks
for a variety of phosphinic peptides for use in inhibition
studies of many ligase or protease enzymes.

Synthesis of Polyfunctionalized Phosphinates
J . Org. Chem., Vol. 63, No. 3, 1998 505
Sch em e 2
phosphonous acid 10 in satisfactory yields. Conversion
of 10 to the ethyl esters 11 was achieved in the usual
manner by using DCC41 as the coupling reagent. Of the
two ethyl phosphonites (11a and 11c) synthesized, the
Tfa derivative 11a was found to be extremely susceptible
to hydrolysis; i.e., 11a was converted completely to 10
when standing exposed to air at rt for several days. In
contrast, the tosyl-protected phosphonite 11c was very
stable; no detectable hydrolysis was found upon standing
at rt exposed to air for over 6 months. With the
polyamine-containing phosphonous acid 10 and ethyl
phosphonite 11 in hand, use of the TCC reaction for the
synthesis of polyamine-containing phosphinates was
investigated. Unfortunately, neither 10 nor 11 would
react with ZNH2 and formaldehyde to give the polyamine-
containing R-aminomethanephosphinic acid, a key inter-
mediate in our target synthesis.
Our attention then turned to the Michaelis-Becker
reaction strategy (Scheme 2). Reaction of (bromometh-
yl)phthalimide 12 with BTH did not proceed as reported
for this type of alkylation reaction.40 Instead of the
desired phosphonous acid 13, the corresponding sym-
metric phosphinate 16a was obtained when equimolar
amounts of 12 and BTH were mixed in CH2Cl2 at 0 °C to
rt. This appears to be the result of a double Arbuzov
reaction of the bromide with BTH.42,43 A similar observa-
tion was also mentioned by Grobelny.44 We found that
the proportion of the products 13 and 16a can be
controlled by manipulating the relative amount of start-
ing material 12 and BTH used. When a 1:4 ratio of 12:
BTH was employed, the desired product 13 was obtained
as the major product but the separation of 13 from the
bis-alkylation product, 16a , proved to be problematic. The
mixture was therefore treated directly with diazomethane
to give the corresponding methyl esters 14 and 16b,
which were then separated easily by silica gel chroma-
tography. Unfortunately, treatment of 14 with 9b under
various Michaelis-Becker conditions; e.g., KH or NaH45,46
and sodium bis(trimethylsilyl)amide,47 failed to form any
trace of the desired phosphinate. Instead, the starting
material, phosphonite 14, was found to decompose under
these conditions. Since it is known that methyl esters
of phosphonous acids are very susceptible to hydrolysis,48
13 was converted to the more stable ethyl ester by
treatment with EtOH/EDC.49 The resultant ethyl ester
15 also failed to react with 9b under Michaelis-Becker
conditions. Similar problems have been encountered
using the Michaelis-Becker reaction for the synthesis
of complex phosphonates.50
The Pudovik-Abramov reaction has been used widely
for the synthesis of phosphonates from dialkyl or trialkyl
phosphites and carbonyl compounds.45 Because of the
mild conditions employed for the removal of a trityl
group, Soroka first synthesized trityl-protected R-ami-
nophosphonates from dialkyl phosphites and tritylamine-
derived Schiff bases by slight modification of the existing
literature procedure.51 The use of a functionalized phos-
phonite such as 11a or 11c in Soroka’s procedure should
afford the core phosphinate for our target synthesis.
Before the synthesis of the desired polyfunctionalized
phosphinates was initiated, studies were done to optimize
the reaction conditions using a model reaction. Thus, a
simple phosphonite, ethyl phenylphosphonite (18), was
subjected to the reaction with the imine, 17, under the
reported conditions (toluene, 100 °C, 4 h).51 However,
no trace of addition product could be detected after
prolonged time (24 h). Many other conditions previously
employed for this type of reaction such as KF/18-C-6/
CH3CN,52 NaOMe/MeOH,15,20 and a silylphosphorus re-
agent53 were also evaluated but none gave satisfactory
results. Finally, when catalytic amounts of a Lewis acid
such as boron trifluoride were added, the reaction was
successfully effected in hot toluene and gave the desired
phosphinate product 19 in 82% yield. Satisfactory yields
could also be obtained from the analogous reaction
involving functionalized phosphonites such as 15, 11a ,
and 11c to provide 20-22, respectively (eq 3). It should
be noted that boron trifluoride in catalytic amounts is
(40) Boyd, E. A.; Regan, A. C.; J ames, K. Tetrahedron Lett. 1994,
35, 4223-4226.
(47) Berkowitz, D. B.; Sloss, D. G. J . Org. Chem. 1995, 60, 7047-
7050.
(48) Baylis, K. E. Tetrahedron Lett. 1995, 36, 9389-9392.
(49) Malachowski, W. P.; Coward, J . K. J . Org. Chem. 1994, 59,
7625-7634.
(41) Karanewsky, D. S.; Badia, M. C. Tetrahedron Lett. 1986, 27,
1751-1754.
(42) Montchamp, J .-L.; Tian, F.; Frost, J . W. J . Org. Chem. 1995,
60, 6076-6081.
(43) Kurdyumova, N. R.; Ragulin, V. V.; Tsvetkov, E. N. Russ. J .
Gen. Chem. (Engl. Transl.) 1994, 64, 380-383.
(44) Grobelny, D. Synth. Commun. 1989, 19, 1177-1180.
(45) Engel, R. In The Synthesis of Carbon-Phosphorous Bonds; CRC
Press, Inc.: Boca Raton, FL, 1988; pp 77-137.
(46) Martin, M. T.; Angeles, T. S.; Sugasawara, R.; Aman, N. I.;
Napper, A. D.; Darsley, M. J .; Sanchez, R. I.; Booth, P.; Titmas, R. C.
J . Am. Chem. Soc. 1994, 116, 6508-6512.
(50) Anderson, G. T.; Alexander, M. D.; Taylor, S. D.; Smithrud, D.
B.; Benkovic, S. J .; Weinreb, S. M. J . Org. Chem. 1996, 61, 125-132.
(51) Soroka, M.; Zygmunt, J . Synthesis 1988, 370-372 and refer-
ences therein.
(52) Texier-Boullet, F.; Lequitte, M. Tetrahedron Lett. 1986, 27,
3515-3516.
(53) Evans, D. A.; Hurst, K. M.; Takacs, J . M. J . Am. Chem. Soc.
1978, 100, 3467-3477.

506 J . Org. Chem., Vol. 63, No. 3, 1998
Chen and Coward
Sch em e 3a
a
Z ) carbobenzyloxy.
essential for this reaction; using either stoichiometric or
excess boron trifluoride results in drastically decreased
yields.
synthesis of 2a , a potent, slow-binding inhibitor (Ki ) 3.2
µM, Ki* ) 7.8 nM) of Gsp synthetase.54
Exp er im en ta l Section
Gen er a l Meth od s. Standard analytical and solvent puri-
fication methods have been described previously.8 19F NMR
spectra were obtained on a Bruker 300 spectrometer at 282
MHz; chemical shift data are reported in reference to TFA. J
values are reported in Hz. N-(Trifluoroacetyl)-1,4-diaminobu-
tane37 and the N-tritylimine 1751 were prepared according to
known procedures. “Usual workup” refers to dissolving the
concentrated reaction mixture in EtOAc followed by washing
with 5% citric acid, 5% NaHCO3 solution, and brine, followed
by drying (Na2SO4) and removal of EtOAc.
Meth yl [[N-(Ben zyloxyca r bon yl)a m in o]m eth yl]p h os-
p h in ic a cid (6a , R1 ) R2 ) H). A mixture of benzyl
carbamate (160 mg, 1.05 mmol) and formaldehyde (90 mg of
37% aqueous solution, 1.1 mmol) in AcCl (5 mL) was stirred
at 0 °C for 30 min. Adamantanamine methylphosphonite 4a
(240 mg, 1.0 mmol) was then added. The resultant suspension
was then stirred at rt for 6 h. Volatile components were then
removed under reduced pressure, and the residue was parti-
tioned between 5% NaHCO3 (45 mL) and Et2O (30 mL). The
aqueous layer was separated and acidified with 6 N HCl to
pH 2 and then extracted with EtOAc (4 × 30 mL). The
combined EtOAc extracts were dried (Na2SO4), and solvent was
removed to afford 0.17 g (67%) of the crude product 6a as a
powder, crystallized from EtOAc/hexane: mp 123-125 °C; 1H
NMR (CDCl3) δ 1.38 (d, 3H, J ) 14.1), 3.47 (d, 2H, J ) 6.3),
5.03 (s, 2H), 5.54 (br, 1H), 7.25 (s, 5H), 11.65 (br, 1H); 13C NMR
δ 156.6, 136.3, 128.8, 128.5, 128.4, 67.5, 40.8 (d, J ) 104), 12.8
(d, J ) 95.6); 31P NMR δ 50.6; MS (FAB) m/z 244 (MH+, 100),
177 (3), 154 (3), 136 (4); HRMS (FAB) calcd for C10H14NO4PH
Unlike the aforementioned TCC reaction that can be
applied to a variety of both aliphatic and aromatic
aldehydes, this last method is not very successful with
an aromatic aldehyde; e.g., trying to extend this reaction
to a Schiff base derived from tritylamine and benzalde-
hyde was unsatisfactory. However, in the case of more
complex phosphonites such as the polyamine-containing
phosphonites 11a and 11c, this modified Pudovik-
Abramov method is required. Combination of these two
methodologies is therefore capable of providing many
structural variants of protected R-aminophosphinates for
different purposes. Thus, compound 6a can be easily
obtained by the TCC method and is the core phosphinate
for synthesis of a nonpolyamine-containing phosphinate
for enzyme inhibition studies.54 Compounds 21 and 22,
obtained by the Pudovik-Abramov method, contain the
core phosphinate required for the successful synthesis of
the complex polyamine-containing phosphinate inhibitors
2a -c.
(MH+) 244.0739, found 244.0728. Anal. Calcd for C10H14
-
NO4P: C, 49.39; H, 5.80; N, 5.76. Found: C, 49.75; H, 5.75;
N, 5.80.
N-(Tr iflu or oa cet yl)-N′-p h t h a loyl-1,4-d ia m in ob u t a n e
(8a ). A solution of N-Tfa-1,4-diaminobutane (3.4 g, 15.4
mmol), N-(ethoxycarbonyl)phthalimide (4.06 g, 18.5 mmol),
and Et3N (5.3 mL) in dry THF (120 mL) was refluxed for 12
As outlined in Scheme 3, culmination of this building
block strategy for the construction of potent inhibitors
of glutathionylspermidine synthetase is illustrated by the
(54) Chen, S.; Lin, C.-H.; Walsh, C. T.; Coward, J . K. Bioorg. Med.
Chem. Lett. 1997, 7, 505-510.

Synthesis of Polyfunctionalized Phosphinates
J . Org. Chem., Vol. 63, No. 3, 1998 507
h. The volatile components were then removed under reduced
pressure, and the residue was dissolved in EtOAc (150 mL),
washed with 5% citric acid and brine, and dried over sodium
sulfate. Removal of the solvents afforded a solid that was
crystallized from a mixture of CHCl3 and hexane; 4.5 g (93%)
of the product was obtained as a white solid: Rf 0.35 (hexane/
EtOAc, 2:1); mp 146-147 °C; 1H NMR (CDCl3) δ 1.61-69 (m,
2H), 1.70-1.80 (m, 2H), 3.39-3.47 (m, 2H), 3.73 (t, 2H, J )
7), 6.81 (b, 1H), 7.70-7.79 (m, 2H), 7.81-7.88 (m, 2H); 13C
NMR (CDCl3) δ 168.7, 157.7, 134.3, 132.1, 123.5, 39.7, 37.3,
yellow oil: 1H NMR (CDCl3) δ 1.56-1.85 (m, 8H), 3.21 (t, 2H,
J ) 9.5), 3.35-3.52 (m, 4H), 3.73 (t, 2H, J ) 9.1), 7.70-7.79
(m, 2H), 7.80-7.91 (m, 2H); 13C NMR (CDCl3) δ 168.0, 155.4
(q, J ) 34.3 Hz), 134.4, 131.6, 123.0, 116.5 (q, J ) 289 Hz),
46.6, 46.0, 45.3, 37.0, 36.9, 30.1, 29.8, 29.1, 27.3, 25.5, 25.2,
25.0, 23.6, 18.2, 7.9, 7.7; 19F NMR (CDCl3) δ 7.58, 7.54; MS
(CI/CH4) m/z 497 (MH+, 100), 371 (23), 369 (16), 273 (59);
HRMS (CI/CH4) calcd for C18H20F3IN2O3H (MH+) 497.0549,
found 497.0555. Anal. Calcd for C18H20F3IN2O3: C, 43.56; H,
4.07; N, 5.65. Found: C, 43.72; H, 4.04; N, 5.62.
26.2, 26.1; 19F NMR (CDCl3) δ 0.06. Anal. Calcd for C14H13
-
N-Tosyl-N-(4-iodobu tyl)-N′-Boc-1,4-diam in obu tan e (9b)
F3N2O3‚0.4H2O: C, 52.30; H, 4.33; N, 8.71. Found: C, 52.45;
H, 4.33; N, 8.85.
was obtained in a similar manner with a yield of 64%: IR
(neat) ν 3355, 1707, 1159 cm-1 1H NMR (CDCl3) δ 1.48 (s,
;
N-(ter t-Bu t oxyca r b on yl)-N′-t osyl-1,4-d ia m in ob u t a n e
(8b). A stirred solution of N-tosyl-1,4-diaminobutane (5.8 g,
25.4 mmol), obtained as described below for the synthesis of
8c, and di-tert-butyl dicarbonate (5.55 g, 25.4 mmol) in dry
CH2Cl2 (50 mL) was heated to reflux for 4 h. After removal of
the volatile components, the product was crystallized from
hexane to afford 8.1 g (93%) of 8b as a white solid: mp 84-86
9H), 1.49-1.65 (m, 6H), 1.75-1.84 (m, 2H), 2.43 (s, 3H), 3.07-
3.15 (m, 6H), 3.20 (t, 2H, J ) 7), 4.51 (br, 1H), 7.32 (d, 2H, J
) 5), 7.75 (d, 2H, J ) 8); 13C NMR (CDCl3) δ 156.1, 143.3,
136.8, 129.8, 127.2, 79.2, 48.3, 47.4, 40.1, 30.4, 29.6, 28.6, 27.4,
26.2, 21.6, 6.2; MS (FAB) m/z 525 (MH+, 1.6), 425 (16), 243
(100), 154 (20).
N-Tosyl-N-(4-iod ob u t yl)-N′-p h t h a loyl-1,4-d ia m in ob u -
ta n e (9c) was obtained in 64% yield in a similar manner: mp
1
°C (hexane); IR (KBr) ν 3285, 1688 cm-1; H NMR (CDCl3) δ
1.43 (s, 9H), 1.48-1.54 (m, 4H), 2.43 (s, 3H), 2.86-2.95 (m,
2H), 3.00-3.12 (m, 2H), 4.55 (br, 1H), 4.83 (br, 1H), 7.31 (d,
2H, J ) 8), 7.74 (d, 2H, J ) 8); 13C NMR (CDCl3) δ 143.5, 137.0,
129.9, 127.2, 79.9, 42.8, 40.0, 28.6, 27.3, 26.8, 21.7.
93-94 °C; IR (KCl) ν 1712 cm-1 1H NMR (CDCl3) δ 1.54-
;
1.75 (m, 6H), 1.75-1.90 (m, 2H), 2.40 (s, 3H), 3.10-3.20 (m,
6H), 3.69 (t, 2H, J ) 6), 7.28 (d, 2H, J ) 8), 7.62-7.78 (m,
4H), 7.82-7.88 (m, 2H); 13C NMR (CDCl3) δ 168.5, 143.4, 136.8,
134.2, 132.2, 129.8, 127.2, 123.4, 48.1, 47.5, 37.4, 30.4, 29.6,
26.2, 25.9, 21.6, 6.3. Anal. Calcd for C23H27IN2O4S: C, 49.82;
H, 4.92; N, 5.05. Found: C, 50.40; H, 5.14; N, 5.00.
N-Tosyl-N′-p h th a loyl-1, 4-d ia m in obu ta n e (8c). A solu-
tion of TsCl (3.16 g, 16 mmol) in dry THF (15 mL) was added
dropwise to a stirred solution of putrescine 7 (2 mL, 20 mmol)
and NMM (2.23 mL, 20 mmol) in THF (20 mL) over a period
of 2 h. The volatile components were removed under reduced
pressure, and the residue was partitioned between 5% NaH-
CO3 and CH2Cl2 (40 mL each). The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2
(2 × 30 mL). Combined CH2Cl2 solutions were dried (Na2SO4)
and concentrated to afford an oil that was extracted with 1 N
HCl (2 × 20 mL), and precipitated material was filtered off.
The filtrate was extracted with Et2O (2 × 40 mL) and was
then basified (pH 11) by the addition of ammonium hydroxide
(29%) and extracted with CH2Cl2 (4 × 40 mL). The CH2Cl2
extracts were combined and dried over sodium sulfate. Re-
moval of the solvent afforded 2.3 g (61%) of N-tosyl-1,4-
diaminobutane as an amorphous powder: mp 65-68 °C; IR
(CDCl3) ν 3363, 3290, 3055, 1322, 1155 cm-1; 1H NMR (CDCl3)
δ 1.38-1.50 (m, 2H), 1.50-1.60 (m, 2H), 2.62-2.69 (m, 2H),
[4-[N-(Tr iflu or oa cetyl)-N-(4-p h th a lim id obu tyl)a m in o]-
bu tyl]p h osp h on ou s Acid (10a ). A mixture of ammonium
hypophosphite55 (1.86 g, 22.4 mmol) and HMDS (4.74 mL, 22.4
mmol) was stirred at 110 °C under argon for 1.5 h. Toluene
(70 mL) was then added via a syringe followed by the addition
of 9a (2.20 g, 4.4 mmol) in toluene (40 mL). After being stirred
at 105-108 °C overnight, the mixture was cooled naturally to
rt and quenched with AcOH (4 mL) and MeOH (20 mL).
Insoluble materials were removed by filtration through a layer
of Celite, and the filtrate was concentrated under reduced
pressure. The resultant oily residue was partitioned between
CH2Cl2 (150 mL) and concentrated hydrochloric acid (40 mL).
The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (2 × 40 mL). The combined organic
layers were dried (NaSO4), and removal of solvent afforded
1.29 g (67%) of the crude product 10a as an oil that was used
for the synthesis of 11a . A small portion was purified by
2.88-2.95 (m, 2H), 7.29 (d, 2H, J ) 8), 7.74 (d, 2H, J ) 8); 13
C
NMR (CDCl3) δ 143.2, 138.4, 129.8, 127.2, 43.3, 41.6, 30.8, 27.7,
DEAE ion-exchange chromatography (0.1
M NH4OAc/
21.7.
MeOH): 1H NMR (CDCl3) δ 1.55-1.95 (m, 10H), 3.35-3.49
(m, 4H), 3.71 (t, 2H, J ) 6.4), 7.11 (d, 1H, J ) 543), 7.68-7.80
(m, 2H), 7.81-7.92 (m, 2H), 9.65-9.82 (br, 1H); 19F NMR
(CDCl3) δ 7.11, 7.06; 31P NMR (CDCl3) δ 37.5, 36.9; MS (FAB)
m/z 435 (MH+, 100), 401 (13), 268 (25), 121 (17). Anal. Calcd
for C18H22F3N2O5P‚H2O: C, 47.78; H, 5.36; N, 6.19. Found:
47.79; H, 5.15; N, 6.10.
A solution of N-tosyl-1,4-diaminobutane (5.55 g, 24 mmol),
obtained as described above, N-(ethoxylcarbonyl)phthalimide
(5.55 g, 25 mmol), and Et3N (4.9 mL) in dry THF (150 mL)
was heated at reflux temperature for 4 h. The volatile
components were then removed under reduced pressure, and
the residue was dissolved in EtOAc (200 mL), washed with
5% citric acid and brine, and dried over sodium sulfate.
Removal of the solvents afforded a solid that was crystallized
from a mixture of EtOAc and hexane; 7.0 g (78%) of the product
8c was obtained as a white powder: mp 128-129 °C; IR (KBr)
[4-[N -T o s y l-N -(4-p h t h a lim id o b u t y l)a m in o ]b u t y l]-
p h osp h on ou s Acid (10c). In a two-necked round-bottom
flask equipped with a refluxing condenser were placed am-
monium hypophosphite (0.39 g, 4.7 mmol) and HMDS (1 mL,
4.7 mmol). The stirred mixture was heated to 110 °C under
dry N2 for 2 h. Toluene (8 mL) was then added through a
syringe followed by the addition of a solution of 9c (0.52 g,
0.94 mmol) in dry toluene (8 mL). The mixture was stirred
at 105 °C for 24 h. The reaction was then quenched by the
addition of methanol (4 mL) and AcOH (0.5 mL) at rt. After
removal of the solvents and volatile materials, the residue was
dissolved in CH2Cl2 (60 mL) and washed with 6 N HCl (10
mL). The organic layer was dried (Na2SO4) and concentrated
under reduced pressure. The crude product was purified by
ion-exchange chromatography on a DEAE column eluting with
0.1 M ammonium acetate in MeOH to afford 0.32 g (70%) of
the product as a hygroscopic solid: 1H NMR (CDCl3) δ 1.40-
1.62 (m, 10H), 2.36 (s, 3H), 3.20-3.14 (m, 4H), 3.62 (t, 2H, J
ν 3289, 1770, 1712 cm-1 1H NMR (CDCl3) δ 1.48-1.56 (m,
;
2H), 1.65-1.74 (m, 2H), 2.41 (s, 3H), 2.95-3.02 (m, 2H), 3.65
(t, 2H, J ) 7), 4.52 (t, 1H, J ) 6), 7.29 (d, 2H, J ) 10), 7.68-
7.76 (m, 4H), 7.82-7.88 (m, 2H); 13C NMR (CDCl3) δ 168.5,
143.4, 138.0, 134.1, 132.0, 129.8, 127.1, 123.2, 42.6, 37.3, 26.8,
25.8, 21.6.
N-(Tr iflu or oa cet yl)-N-(4-iod o)b u t yl-N′-p h t h a loyl-1,4-
d ia m in obu ta n e (9a ). To a suspension of KH (1.42 g, 12.4
mmol) in dry THF (60 mL) was added 8a (3.0 g, 9.55 mmol)
slowly at 0 °C under a dry atmosphere of N2. Crown ether
18-C-6 (0.25 g) was then added followed by the addition of 1,4-
diiodobutane (11.9 g, 36.2 mmol) at 0 °C. The mixture was
stirred overnight at rt and then was quenched by the addition
of AcOH (5 mL) and MeOH until a clear solution was obtained
(ca. 20 mL). This solution was concentrated under reduced
pressure. After usual workup and column chromatography
on silica gel (gradient elution from 100% hexane to 67% hexane
in EtOAc), 2.6 g (55%) of the product was obtained as a light
(55) Boyd, E. A.; Regan, A. C.; J ames, K. Tetrahedron Lett. 1992,
33, 813-816.

508 J . Org. Chem., Vol. 63, No. 3, 1998
Chen and Coward
) 6), 7.00 (d, 1H, J ) 501), 7.23 (d, 2H, J ) 8), 7.62 (d, 2H, J
) 8), 7.65-7.77 (m, 2H), 7.88-7.85 (m, 2H); 13C NMR (CDCl3)
δ 168.5, 143.3, 136.8, 134.2, 132.2, 129.9, 127.3, 123.4, 48.3,
48.1, 37.5, 31.3 (d, J ) 91), 30.0 (d, J ) 15), 26.1, 25.9, 21.6,
19.2; 31P NMR (CDCl3) δ 28.3; MS (FAB) m/z 493 (MH+, 100),
479 (30), 160 (40), 337 (40); HRMS (FAB) calcd for C23H29N2O6-
PSH 493.1562, found 493.1562.
To a suspension of the mixture containing 13 and 16a (1.1
g) in MeOH (15 mL) was added a solution of diazomethane in
ether until a yellow color persisted for 5 min. The resultant
solution was stirred at rt for 1.5 h. Removal of the solvent
afforded the crude products 14 and 16b. Column chromatog-
raphy on silica gel eluting with EtOAc/MeOH (10:1) afforded
0.96 g of 14 (99% based on 13) and 0.16 g of 16b (78% based
on 16a ) as white solids. 14: Rf 0.57 (EtOAc); mp 101-102
O-Eth yl [4-[N-(Tr iflu or oa cetyl)-N-(4-p h th a lim id obu -
tyl)a m in o]bu tyl]p h osp h on ite (11a ). To a stirred solution
of 10a (1.21 g, 2.8 mmol) in THF (25 mL) and ethanol (3.0
mL) was added DMAP (36 mg) followed by DCC (0.75 g, 3.6
mmol). The mixture was stirred overnight at rt, the resultant
precipitated material was removed by filtration, and the
filtrate was concentrated under reduced pressure. After usual
workup and column chromatography on silica gel using EtOAc
as eluant, 1.0 g (76%) of the product 11a was obtained as a
syrup: 1H NMR (CDCl3) δ 1.34-1.40 (m, 3H), 1.57-1.83 (m,
10 H), 3.30-3.42 (m, 4H), 3.72 (t, 2H, J ) 6.5), 4.04-4.22 (m,
2H), 7.12 (dm, 1H, J ) 533), 7.68-7.74 (m, 2H), 7.76-7.88
(m, 2H); 13C NMR (CDCl3) δ 168.1, 156.6 (q, J ) 35.4), 134.0,
1
°C; H NMR (CDCl3) δ 3.84 (d, 3H, J ) 11.7), 4.11 (dd, 2H, J
) 2.2, 9.8), 7.4 (d, 1H, J ) 583), 7.75-7.81 (m, 2H), 7.86-7.95
(m, 2H); 13C NMR (CDCl3) δ 167.2, 134.5, 131.9, 123.8, 52.9
(d, J ) 7), 36.2 (d, J ) 99); 31P NMR (CDCl3) δ 28.1. 16b: Rf
0.47 (EtOAc); mp 198-200 °C; 1H NMR (CDCl3) δ 3.83 (dd,
3H, J ) 2, 11), 4.21-4.40 (m, 2H), 7.75-7.81 (m, 2H), 7.86-
7.93 (m, 2H); 13C NMR δ 167.4, 134.3, 132.2, 123.8, 52.5, 36.9
(d, J ) 98); 31P NMR (CDCl3) δ 39.7; MS (CI/NH3) m/z 399
(MH+, 100), 238 (28); HRMS (CI/NH3) calcd for C19H15N2O6-
PH 399.0746, found 399.0741. Anal. Calcd for C19H15N2O6P‚
0.3H2O: C, 56.52; H, 3.90; N, 6.94. Found: C, 56.80; H, 4.09;
N, 6.69.
133.9, 131.9, 123.1, 123.0, 116.5 (q, J ) 288), 62.4, 62.2, 46.9,
O-Eth yl (P h th a lim id om eth yl)p h osp h on ite (15). A so-
lution of 13 (0.30 g, 1.6 mmol), ethanol (0.5 mL), EDC (0.28 g,
1.6 mmol), and DMAP (10 mg) in CH2Cl2 (10 mL) was stirred
at rt for 12 h. After removal of the volatile components, the
crude product was purified by column chromatography on
silica gel (EtOAc) to afford 0.26 g (78%) of 15 as a powder: Rf
1
46.3, 46.2, 37.0, 36.9, 29.2 (d, J ) 14.1 Hz), 28.1 (d, J CP
)
93.6 Hz), 27.4 (d, J ) 14.6 Hz), 25.8, 25.7, 23.9, 18.0, 17.8,
16.1, 16.0; 19F NMR (CDCl3) δ 4.86; 31P NMR (CDCl3) δ 38.1,
37.4; MS (CI/CH4) m/z 463 (MH+, 100), 427 (7), 365 (13), 301
(10); HRMS (CI/CH4) calcd for C20H26F3N2O5PH 463.1610,
found 463.1600. Anal. Calcd for C20H26F3N2O5P: C, 51.95;
H, 5.68; N, 6.06. Found: C, 51.84; H, 5.66; N, 6.18.
1
0.5 (EtOAc); mp 90-92 °C; H NMR (CDCl3) δ 1.35 (t, 3H, J
) 7), 4.09 (dd, 2H, J ) 8, 11), 4.12-4.28 (m, 2H), 7.38 (dt, 1H,
J ) 2, 580), 7.75-7.84 (m, 2H), 7.87-7.95 (m, 2H); 13C NMR
δ 166.9, 135.7, 134.2, 131.5, 123.5, 62.9, 36.3 (d, J ) 100), 16.3;
31P NMR (CDCl3) δ 26.2; MS (DCI/NH3) m/z 254 (MH+, 100),
160 (5), 134 (8); HRMS (CI/NH3) calcd for C11H12NO4PH
254.0582, found 254.0590. Anal. Calcd for C11H12NO4P: C,
52.17; H, 4.79; N, 5.53. Found: C, 52.17; H, 4.88; N, 5.67.
O-Eth yl P h en yl [(N-Tr ityla m in o)m eth yl]p h osp h in a te
(19). A solution of ethyl phenylphosphonite 18 (18 mg, 0.11
mmol), 17 (29 mg, 0.11 mmol), and a drop of BF3‚Et2O in dry
toluene (8 mL) was stirred and heated to reflux for 8 h.
Removal of the volatile components followed by silica gel
column chromatography (EtOAc) afforded 39 mg (82%) of 19
O-Eth yl [4-[N-Tosyl-N-(4-p h th a lim id obu tyl)a m in o]bu -
tyl]p h osp h on ite (11c). To a stirred solution of 10c (0.3 g,
0.62 mmol), ethanol (29 mg), and DMAP (8 mg) in THF (6 mL)
was added DCC at 0 °C. The mixture was stirred at rt
overnight. Precipitate DCU was filtered off, and the filtrate
was concentrated and dissolved in EtOAc (40 mL). Some more
precipitated DCU was filtered off again, and the EtOAc
solution was washed with 5% NaHCO3 (2 × 30 mL) and brine
(30 mL). After being dried over sodium sulfate, the solvent
was removed. The resultant solid product was then recrystal-
lized from CHCl3/hexane to afford 0.26 g (81%) of the product
1
as a white powder: mp 102-105 °C; H NMR (CDCl3) δ 1.35
1
(t, 3H, J ) 7), 1.55-1.75 (m, 10H), 2.40 (s, 3H), 3.08-3.15 (m,
4H), 3.67 (t, 2H, J ) 7), 4.08-4.18 (m, 2H), 7.10 (d, 1H, J )
530), 7.28 (d, 2H, J ) 8), 7.66 (d, 2H, J ) 8), 7.70-7.75 (m,
2H), 7.82-7.89 (m, 2H); 13C NMR (CDCl3) δ 168.5, 143.4, 136.7,
134.2, 132.2, 131.4, 129.8, 128.2, 127.3, 123.7, 123.4, 122.9,
62.5 (d, J ) 6), 48.2, 48.1, 37.4, 29.7, (d, J ) 15), 28.3 (d, J )
94), 26.2, 25.9, 21.6, 18.2, 16.4 (d, J ) 6); 31P NMR (CDCl3) δ
38.6. Anal. Calcd for C25H33N2O6PS: C, 57.68; H, 6.40; N,
5.38. Found: C, 57.86; H, 6.64; N, 5.51.
as a solid: mp 114-116 °C; H NMR (CDCl3) δ 1.32 (m, 3H),
2.20 (t, 1H, J ) 7.8), 2.48-2.72 (m, 2H), 3.88-4.20 (m 2H),
7.11-7.42 (m, 15H), 7.55-7.82 (m, 2H), 7.94-8.07 (m, 2H);
13C NMR (CDCl3) δ 145.2, 132.9, 132.8, 132.7, 129.8, 129.0,
128.9, 128.4, 126.9, 71.9, 42.4 (d, J ) 117), 17.0; 31P NMR
(CDCl3) δ 41.4; MS (FAB) m/z 442 (MH+, 3.4), 243 (100), 91
(11); HRMS (FAB) calcd for C28H28NO2PH 442.1936, found
442.1913. Anal. Calcd for C28H28NO2P‚0.3H2O: C, 75.23; H,
6.46; N, 3.13. Found: C, 75.17; H, 6.56; N, 3.10.
O-Meth yl (P h th a lim id om eth yl)p h osp h on ite (14) a n d
O-Meth yl Bis(p h th a lim id om eth yl)p h osp h in a te (16b). A
mixture of ammonium hypophosphite (3.15 g, 38 mmol) and
HMDS (6.16 g, 38 mmol) was stirred and heated to 120 °C
under dry N2 for 2 h. After being cooled to rt, CH2Cl2 (30 mL)
was added, and the reaction flask was then chilled in an ice
bath. A solution of bromomethyl phthalimide (2.28 g, 9.5
mmol) in dry CH2Cl2 (15 mL) was then added. The mixture
was stirred at 0 °C for 1 h and then at rt for 12 h. The mixture
was filtered through a layer of Celite into a mixture of MeOH
(6 mL) and CH2Cl2 (100 mL), and the filtrate was washed with
6 N HCl (20 mL). The aqueous layer was separated and back-
extracted with CH2Cl2 (2 × 40 mL). The combined CH2Cl2
solution was then dried (Na2SO4). Removal of solvents af-
forded 1.74 g (78% conversion) of a mixture of 13 and 16a (41:
9) as a light yellow solid. This material was used directly for
the reaction with diazomethane described below. An analyti-
cal sample of (phthalimidomethyl)phosphonous acid (13) was
obtained by precipitation from EtoAc: mp 209-211 °C; 1H
NMR (D2O) δ 3.83 (d, 2H, J ) 11), 7.17 (d, 1H, J ) 580), 7.70-
7.84 (m, 4H); 13C NMR (CDCl3) δ 166.8, 134.4, 134.3, 131.2,
123.0, 38.2 (d, J ) 97); 31P NMR (D2O) δ 16.4 (ammonium salt;
free acid δ 24 ppm vs 16a δ 38 ppm); MS (FAB) m/z 226 (MH+,
100), 153 (35), 103 (34); HRMS (DCI/NH3) calcd for C9H8NO4P
226.0269, found 226.0262. Anal. Calcd for C9H8NO4P: C,
48.01; H, 3.59; N, 6.22. Found: C, 47.99; H, 3.77; N, 6.27.
O-Eth yl [(N-(p h th a lim id om eth yl-N′-tr ityla m in o)m eth -
yl]p h osp h in a te (20) was obtained in a similar manner in
86% yield as an oil: Rf 0.7 (EtOAc); H NMR (CDCl3) δ 1.35
1
(t, 3H, J ) 7), 2.40-2.85 (m, 3H), 4.05-4.38 (m, 4H), 7.10-
7.29 (m, 9H), 7.45-7.65 (m, 6H), 7.70-7.81 (m, 2H), 7.84-
7.93 (m, 2H); 13C NMR (CDCl3) δ 167.7, 145.2, 134.6, 132.3,
62.1 (d, J ) 109), 35.0 (d, J ) 95), 16.9 (d, J ) 6); 31P NMR
(CDCl3) δ 41.2; MS (DCI/NH3) m/z 525 (MH+, 0.5), 447 (3),
243 (100); HRMS (CI/NH3) calcd for C31H29N2O4PH 525.1943,
found 525.1926.
O-Eth yl [N-(Tr iflu or oa cetyl)-N-(4-p h th a lim id obu tyl)-
4-a m in obu tyl]-[(N′-tr ityla m in o)m eth yl]p h osp h in a te (21).
To a stirred solution of 11a (1.0 g, 2.3 mmol) and 17 (0.58 g,
2.3 mmol) in dry toluene (50 mL) was added BF3‚Et2O (30 µL,
0.24 mmol), and the reaction solution was heated overnight
at reflux temperature under N2. The mixture was cooled to
rt and diluted with EtOAc (150 mL). After usual workup, the
crude product was purified by column chromatography on
silica gel (CHCl3/MeOH, 100:0 to 99:1) to afford 1.29 g (81%)
of the product as a syrup: 1H NMR (CDCl3) δ 1.26 (t, 3H, J )
7), 1.55-1.86 (m, 8H), 1.95-2.00 (m, 3H), 2.43-2.62 (m, 2H),
3.38-3.49 (m, 4H), 3.72 (t, 2H, J ) 6.2), 3.42-4.08 (m, 2H),
7.15-7.35 (m, 9H), 7.44 (d, 6H, J ) 7.5), 7.67-7.75 (m, 2H),
7.82-7.87 (m, 2H); 13C NMR (CDCl3) δ 168.43, 156.7 (q, J )
41 Hz), 144.8, 144.75, 134.2, 134.1, 134.0, 132.1, 132.0, 128.6,
128.3, 128.1, 126.8, 126.7, 123.4, 123.3, 116.6 (q, J ) 290 Hz),

Synthesis of Polyfunctionalized Phosphinates
J . Org. Chem., Vol. 63, No. 3, 1998 509
71.6, 71.5, 60.9, 60.8, 60.7, 47.2, 46.6, 46.4, 41.4 (d, 1J CP ) 102
Hz), 37.2, 37.1, 29.9 (d, 2J CP ) 13.8 Hz), 28.0 (d, J ) 14.4 Hz),
0.52 mmol), and finally DIEA (0.27 g, 2.1 mmol). The mixture
was then stirred at 0 °C for 20 min and at rt for 2 h. After
usual workup, the crude product was purified by column
chromatography on silica gel (gradient elution from 100%
CHCl3 to a mixture of CHCl3/MeOH (97:3)) to afford 0.4 g (80%)
of 25 as an oil: Rf 0.3 (3% MeOH/CHCl3); 1H NMR (320 K,
DMSO-d6) δ 1.05-1.17 (m, 6H), 1.34-1.57 (m, 8H), 1.58-1.70
(m, 2H), 1.74-1.89 (m, 1H), 1.93-2.05 (m, 1H), 2.23 (t, 2 H, J
) 7.2), 2.95-3.04 (m, 2H), 3.30-3.55 (m, 2H), 3.89-3.98 (m,
2H), 4.08-4.18 (m, 1H), 4.20-4.34 (m, 1H), 4.95-5.14 (m, 8H),
6.95-7.08 (br, 1H), 7.32 (bs, 20 H), 7.50-7.65 (br, 1H), 7.77-
7.85 (m, 1H), 7.91-8.00 (m, 1H); 13C NMR (CDCl3) δ 172.8,
172.0, 156.5, 136.7, 136.3, 135.4, 128.6, 128.5, 128.3, 128.1,
127.8, 67.2, 67.0, 66.6, 61.2, 61.1, 53.8, 48.9, 46.5, 40.7, 39.5,
36.9 (d, J ) 98.5 Hz), 32.0, 29.4 (d, J ) 72 Hz), 27.8, 27.2,
25.8, 25.4, 18.8, 18.2, 16.6; 31P NMR (DMSO-d6) δ 51.8; MS
(FAB) m/z 958 (MH+, 7), 920 (2), 119 (6), 91 (100); HRMS
(FAB) calcd for C50H64N5O12PH 958.4367, found 958.4373.
Anal. Calcd for C50H64N5O12P‚H2O: C, 61.51; H, 6.83; N, 7.18.
Found: C, 61.16; H, 6.74; N, 7.12.
1
26.7 (d, J CP ) 93 Hz), 26.0, 25.9, 25.8, 24.0, 19.1, 19.0, 18.9,
18.8, 16.8, 16.7; 31P NMR (CDCl3) δ 54.4, 54.0; MS (FAB) m/z
734 (MH+, 1.4), 656 (1.5), 243 (100), 91 (15); HRMS (FAB) calcd
for C40H43F3N3O5PH 734.2971, found 734.2935. Anal. Calcd
for C40H43F3N3O5P‚0.5H2O: C, 64.67; H, 5.98; N, 5.66.
Found: C, 64.32; H, 5.93; N, 5.58.
O-Eth yl [N-Tosyl-N-(4-p h th a lim id obu tyl)-4-a m in obu -
t yl][(N′-t r it yla m in o)m et h yl]p h osp h in a t e (22) was ob-
tained as a syrup in 70% yield in a similar way as for 21: 1H
NMR (CDCl3) δ 1.26 (t, 3H, J ) 7), 1.55-1.70 (m, 8H), 1.95-
2.95 (br, 1H), 2.38 (s, 3H), 2.40-2.52 (m, 2H), 3.05-3.20 (m,
4H), 3.68 (t, 2H, J ) 7), 3.90-4.05 (m, 2H), 7.15-7.28 (m, 11H),
7.46 (d, 6H, J ) 8), 7.64-7.75 (m, 4H), 7.78-7.88 (m, 2H); 13
C
NMR (CDCl3) δ 168.5, 144.9, 143.3, 136.9, 134.2, 132.2, 129.8,
128.7, 128.2, 127.3, 126.8, 123.4, 71.6 (d, J ) 16), 60.87 (d, J
) 6), 48.2, 41.4 (d, J ) 102), 37.4, 30.3 (d, J ) 14), 26.9 (d, J
) 92), 26.2, 25.9, 21.6, 19.1, 16.9; 31P NMR (CDCl3) δ 54.5;
MS (FAB) m/z 792 (MH+, 4), 243 (100), 165 (20), 91 (21); HRMS
(FAB) calcd for C45H50N3O6PSH 792.3236, found 792.3198.
Anal. Calcd for C45H50N3O6PS‚1.5H2O: C, 65.99; H, 6.54; N,
5.13. Found: C, 65.90; H, 6.16; N, 4.98.
[N-(4′-Am in ob u t yl)-4-a m in ob u t yl][[(γ-glu t a m yla la n i-
n yl)a m in o]m eth yl]p h osp h in ic Acid (2a ). A solution of 25
(0.35 g, 0.36 mmol) in 30% HBr/AcOH (25 mL) was stirred at
rt for 48 h. Volatile components were then removed on a
rotary evaporator with a bath temperature not exceeding 40
°C. The residue was dissolved in MeOH (20 mL), following
which propylene oxide was added dropwise to give a pH 6
solution. Solvents were removed under reduced pressure, and
the product was purified by ion-exchange chromatography on
O-Eth yl [N-(Ben zyloxyca r bon yl)-N-[4-[N′-(ben zyloxy-
ca r bon yl)a m in o]bu tyl]-4-a m in obu tyl][(N′′-tr ityla m in o)-
m eth yl]p h osp h in a te (23). A solution of 21 (1.24 g, 1.69
mmol) and hydrazine monohydrate (0.84 mL, 16.8 mmol) in
MeOH (40 mL) was stirred at rt for 48 h. Volatile materials
were then removed under reduced pressure, and the residue
was partitioned between CH2Cl2 (140 mL) and NH4OH (50
mL). The aqueous layer was separated and extracted with
CH2Cl2 (2 × 50 mL). Combined CH2Cl2 extracts were dried
(Na2SO4). Removal of solvents afforded an oil that, after being
dried in vacuo, was redissolved in dry CH2Cl2 (8 mL). DMAP
(50 mg) and DIEA (0.52 g, 4.06 mmol) were then added
followed by the addition of benzyl chloroformate (0.69 g, 4.06
mmol) at 0 °C. The mixture was then stirred at rt overnight.
Volatile components were removed under reduced pressure.
After usual workup, the crude product was purified by column
chromatography on silica gel (CHCl3 to a mixture of MeOH/
CHCl3 (99:1)) to afford 1.09 g (82%) of 23 as an oil: 1H NMR
(320 K, DMSO-d6) δ 1.16 (t, 3H, J ) 7), 1.34-1.61 (m, 8H),
1.74-1.85 (m, 2H), 2.42-2.43 (m, 2H), 2.96-3.04 (q, 2H),
3.15-3.24 (m, 4H), 3.85-3.97 (m, 2H), 5.00 (s, 2H), 5.04 (s,
2H), 6.95-7.11 (br, ca. 1H), 7.15-7.46 (m, 26H); 13C NMR
(CDCl3) δ 156.5, 156.2, 144.8, 136.9, 136.8, 128.6, 128.1, 127.9,
127.3, 126.9, 126.7, 67.0, 66.6, 60.7, 47.1, 46.7, 41.3 (d, J )
108 Hz), 40.7, 29.6, 26.9 (d, J ) 92 Hz), 27.2, 25.6, 19.0, 16.7;
31P NMR (DMSO-d6) δ 54.2; MS (FAB) m/z 776 (MH+, 1.3),
532 (1.1), 243 (100), 91 (41); HRMS (FAB) calcd for C46H54N3O6-
PH 776.3829, found 776.3837. Anal. Calcd for C46H54N3O6P‚
1.5H2O: C, 68.80; H, 7.17; N, 5.23. Found: C, 68.85; H, 6.87;
N, 5.15.
+
an AG 50W-X2 cation-exchange resin (100-200 mesh, NH4
form) eluting isocratically with 0.1 M NH4HCO3 buffer to
afford 123 mg (77%) of 2a as a hygroscopic solid: 1H NMR
(D2O) δ 1.36 (d, 3H, J ) 7.2), 1.41-1.59 (m, 4H), 1.62-1.78
(m, 6H), 2.00-2.12 (m, 2H), 2.43 (t, 2H, J ) 6.5), 2.90-3.17
(m, 6H), 3.35 (d, 2H, J ) 9.3), 3.68 (t, 1H), 4.24 (q, 1H); 13C
NMR (CD3OD) δ 176.5, 175.8, 175.1, 56.1, 51.2, 48.2, 48.1, 40.5
(d, J ) 98 Hz), 40.2, 32.9, 30.4, 28.6 (d, J ) 93 Hz), 28.3 (d, J
) 16 Hz), 26.1, 24.2, 20.1, 17.6; 31P NMR (D2O) δ 39.7; MS
(FAB) m/z 438 (MH+, 89), 155 (24), 121 (12), 89 (100); HRMS
(FAB) calcd for C17H36N5O6PH 438.2481, found 438.2482;
reversed-phase HPLC56 tR ) 7.7 min. Anal. Calcd for C17H36N5-
O7P‚0.5H2CO3‚H2O: C, 43.19; H, 8.09; N, 14.40. Found: C,
43.29; H, 7.94; N, 14.40.
Ack n ow led gm en t. Financial support from the UN-
DP/Worldbank/WHO Special Program for Research and
Training in Tropical Diseases (TDR) (ID No. 930598) is
gratefully acknowledged. We thank Ms. Carol Capelle
for careful preparation of the manuscript. We are
greatly indebted to Professor Chengye Yuan of Shanghai
Institute of Organic Chemistry for valuable advice and
Dr. Guohong Wang of Substance Abuse Tech., Inc., CA,
for helpful discussion.
O-Eth yl [N-(Ben zyloxyca r bon yl)-N-[4-[N′-(ben zyloxy-
ca r b on yl)a m in o]b u t yl]-4-a m in ob u t yl][(r-O-b en zyl-Z-γ-
glu ta m yla la n in yl)a m in o]m eth yl]p h osp h in a te (25). A so-
lution of 23 (0.4 g, 0.52 mmol) in 1 M HCl/MeOH (20 mL) was
heated to reflux for 20 min. Volatile components were then
removed under reduced pressure, and the residue, a syrup-
like semisolid, was dried in vacuo. This material was tritu-
rated with ether and the ether layer was then carefully
decanted. This process was repeated for several times. The
resultant residue was dried completely in vacuo and then was
dissolved in CH2Cl2 (25 mL) and cooled to 0 °C. To this stirred
solution were added 248 (0.23 g, 0.52 mmol), PyBOP (0.27 g,
Su p p or tin g In for m a tion Ava ila ble: NMR spectral data
of 8b,c, 9b,c, 10c, 14, and 20 (17 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O971318L
(56) Pearson, D. A.; Blanchette, M.; Baker, M. L.; Guindon, C. A.
Tetrahedron Lett. 1989, 30, 2739-2742.