Synthesis of a new ligand for metal assembly to a selective receptor

Article abstract of DOI:10.1021/jo9804590

Diarylphosphinic acid 2, bearing two ethylenediamine groups, was designed with the aim of assembly to form a hydrophobic cavity upon binding to metals. The new ligand was prepared in optically active form from phenylalanine by an efficient sequence which required chromatography only for the P-C bond forming steps. Versatile intermediates in the synthesis are described. Complexes of this ligand with Zn²⁺ were shown to bind closely related aromatic guests bearing anionic tethered groups with 1000-fold discrimination. Diarylphosphinic acid 2, bearing two ethylenediamine groups, was designed with the aim of assembly to form a hydrophobic cavity upon binding to metals. The new ligand was prepared in optically active form from phenylalanine by an efficient sequence which required chromatography only for the P-C bond forming steps. Versatile intermediates in the synthesis are described. Complexes of this ligand with Zn²⁺ were shown to bind closely related aromatic guests bearing anionic tethered groups with 1000-fold discrimination.

Full text of DOI:10.1021/jo9804590

1784
J . Org. Chem. 1999, 64, 1784-1788
Articles
Syn th esis of a New Liga n d for Meta l Assem bly to a Selective
Recep tor
Alan W. Schwabacher,* Andrei D. Stefanescu,1 and Atiq ur Rehman
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201
Received March 10, 1998
Diarylphosphinic acid 2, bearing two ethylenediamine groups, was designed with the aim of
assembly to form a hydrophobic cavity upon binding to metals. The new ligand was prepared in
optically active form from phenylalanine by an efficient sequence which required chromatography
only for the P-C bond forming steps. Versatile intermediates in the synthesis are described.
Complexes of this ligand with Zn2+ were shown to bind closely related aromatic guests bearing
anionic tethered groups with 1000-fold discrimination.
In tr od u ction
Binding selectivity is the distinctive feature of biologi-
cal receptors and catalysts that provides their most
valued properties.2 High selectivity results from the
cooperation of multiple binding interactions.3 The study
of simple synthetic binding sites has led to useful
materials4 and to improvements in our understanding of
noncovalent binding events.5 These synthetic host mol-
ecules are generally less selective in binding to multi-
functional organic guests than are antibodies, because
of current limitations in design and preparation of large
concave molecules with appropriately oriented interact-
ing groups. Self-assembly, the formation at equilibrium
of a well-defined ordered structure, provides an effective
route to large structures.6 Self-assembled structures
capable of binding a substrate are of particular interest.7-10
We have reported the synthesis of a bis amino acid
which self-assembles in the presence of Co2+ to form
complex 1 (Figure 1), forming a cavity that binds hydro-
F igu r e 1.
phobic guests.9 Guest molecules that bear tethered car-
boxylate anions bind less strongly than their neutral
analogues to the anionic complex, except for certain
guests that bind more strongly.10,11 These guests are able
to bind such that the carboxylate can ligate the metal.
The cooperation of the hydrophobic and polar binding
interactions leads to significant selectivity for those
guests that fit well. Our analysis suggests that this
receptor very effectively juxtaposes the two types of
binding sites.10,11 Its limitations derive from the ex-
tremely weak binding of carboxylate to metal.
(1) Current address: MEMC Electronic Materials, St. Peters, MO
63376.
(2) Fersht, A. Enzyme Structure and Function, 2nd ed.; W. H.
Freeman: New York, 1985.
(3) J encks, W. P. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 4046-4050.
(4) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley,
A. J . M.; McCoy, C. P.; Rademacher, J . T.; Rice, T. E. Chem. Rev. 1997,
97, 7, 1515-1566. Bell, T. W.; Hou, Z.; Luo, Y.; Drew, M. G. B.;
Chapoteau, E.; Czech, B. P.; Kumar, A. Science 1995, 269, 671-674.
(5) Ma, J . C.; Dougherty, D. A. Chem. Rev. 1997, 97, 1303-1324.
Lehn, J .-M. Angew. Chem., Int. Ed. Engl. 1990, 29, 1304-1319.
Walliman, P.; Marti, T.; Furer, A.; Diederich, F. Chem. Rev. 1997, 97,
1567-1608. Diederich, F. Cyclophanes; Royal Society of Chemistry:
Cambridge, 1991; Vol. 2. Schmidtchen, F.; Berger, M. Chem. Rev. 1997,
97, 1609-1646.
(6) Zeng, F.; Zimmerman, S. C. Chem. Rev. 1997, 97, 1681-1712.
Lindsey, J . S. New J . Chem. 1991, 15, 153-180. Seto, C. T.; Whitesides,
G. M. J . Am. Chem. Soc. 1993, 115, 905-916. Lehn, J .-M.; Mascal,
M.; DeCian, A.; Fischer, J . J . Chem. Soc., Chem. Commun. 1990, 479-
481.
(7) Linton, B.; Hamilton, A. D. Chem. Rev. 1997, 97, 1668-1680.
Conn, M. M.; Rebek, J . Chem. Rev. 1997, 97, 1647-1668.
(8) Maverick, A. V.; Ivie, M. L.; Waggenspack, J . H.; Fronczeck, F.
R. Inorg. Chem. 1990, 29, 2403. Baldes, R.; Schneider, H. J . Angew.
Chem., Int. Ed. Engl. 1995, 34, 321-323. Schneider, H.-J .; Ruf, D.
Angew. Chem., Int. Ed. Engl. 1990, 29, 1159-1160. Fujita, M.; Aoyagi,
M.; Ibukuro, F.; Ogura, K.; Yamaguchi, K. J . Am. Chem. Soc. 1998,
120, 611-612. Rivera, J . M.; Mart´ın, T.; J r., J . R. Science 1998, 279,
Therefore, we decided to prepare a new ligand with a
modified structure to allow a more positive metal center.
Compound 2 retains the diarylphosphinate hydrophobic
concavity appropriate for binding aromatic compounds
from water, with its hydrophilic convex surface to prevent
aggregation. Ethylenediamine groups, rather than amino
acids of 13, ligate metal without neutralizing the positive
charge. The more positive metal center and overall
complex should better bind an anionic ligand. In this
1021-1023.; Kuroda, Y.; Kawashima, A.; Hayashi, Y.; Ogoshi, H. J .
Am. Chem. Soc. 1997, 119, 4929-4933. J ones, M. W.; Gupta, N.;
Schepartz, A.; Thorpe, H. H. Inorg. Chem. 1992, 31, 1308-1310. Cole,
K. L.; Farran, M. A.; Deshayes, K. Tetrahedron Lett. 1992, 33, 599-
602.
(9) Schwabacher, A. W.; Lee, J .; Lei, H. J . Am. Chem. Soc. 1992,
114, 7597-7598.
(10) Lee, J .; Schwabacher, A. W. J . Am. Chem. Soc. 1994, 116, 8382-
8383.
(11) Schwabacher, A. W.; Lee, J . Manuscript in preparation.
10.1021/jo9804590 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/02/1999

Synthesis of a New Ligand for Metal Assembly
J . Org. Chem., Vol. 64, No. 6, 1999 1785
F igu r e 3.
of 6 allowed to stand in the presence of ammonia in
methanol for 20 times the usual reaction time, followed
by acylation of the crude mixture with Boc-L-alanine.
Amide 6 was reduced using borane THF complex,
conveniently prepared by treating sodium borohydride
with iodine in THF.13 At reflux in THF, amide reduction
is frequently accompanied by partial cleavage of iodine
from the aryl group. This iodine cleavage is not simply a
function of temperature: at reflux even in toluene/THF,
sometimes amide reduction went without iodine cleavage.
Chloroform solvent showed no advantages over THF, and
amide reduction did not proceed in dichloromethane.
Iodine cleavage was neither caused nor consistently
prevented by intentional addition or careful exclusion of
air or light, control of heating or quench rate, or washing
of glassware with aqua regia to remove transition-metal
contaminants. Though high temperature did not consis-
tently cause iodine cleavage, lower temperature did
consistently prevent it; at room temperature the reaction
proceeded slowly but gave amine free of detectable iodine
cleavage product. Diamine was isolated as Boc-protected
derivative 7, crystallized in 88% yield. This sequence
readily yields decagram amounts of analytically pure 7
from phenylalanine with no chromatography.
F igu r e 2. Self-assembly of 2 to form host 3.
Sch em e 1. Syn th esis of Liga n d 2
Protected diamine 7 was coupled to tert-Butyl phos-
phinate 8 by the Pd-catalyzed procedure we have de-
scribed.14 tert-Butyl phosphinate rather than methyl
phosphinate was used because the methyl analogue of 9
is difficult to separate from minor side products and the
tert-butyl protecting group is more conveniently removed
at the end of the sequence. tert-Butyl phosphinate is more
stable than methyl phosphinate but reacts substantially
more slowly. Thus tert-butyl phosphinate must be free
of methyl phosphinate from which it is prepared.14
It is most effective to couple iodide 7 with an excess of
tert-butyl phosphinate in the presence of Pd(PPh3)2Cl2,
cleanly producing monoarylphosphinate 9 because phos-
phinate decomposition products couple more slowly than
does 8. Compound 9 is freed of excess 8 and converted to
diarylphosphinate 10 by reaction with iodide 7, again
under palladium catalysis.
paper we describe the preparation of 2 (Figure 2) and
demonstrate that its metal complexes bind organic
guests.
A different catalyst is preferred for this second coupling
step. When triphenylphosphine is used as the ligand for
palladium, a side product is formed which was tentatively
assigned structure 11 on the basis of 1H NMR, 31P NMR,
and MS data (Figure 3). Presumably the unsubstituted
phenyl group is derived from triphenylphosphine. Ex-
change of aryl groups on Pd with those of a phosphine
ligand is known.15 However, in other cross-coupling
reactions of aryl iodide with methyl phosphinate or
methyl arylphosphinate, we have not previously observed
Resu lts a n d Discu ssion
Syn th esis of Liga n d 2. The synthesis of ligand 2 is
outlined in Scheme 1. Iodination of phenylalanine, fol-
lowed by esterification with SOCl2 in methanol, was
carried out as we have described,12 with minor improve-
ments. Compounds 4 and 5 are difficult to separate from
contaminating diiodophenyl derivatives, sometimes pro-
duced by overiodination. Ester 5 was converted to amide
6 by treatment with ammonia in methanol. Amide 6 is
easily crystallized, so that samples of iodophenylalanine
that have been overiodinated will produce pure 6.
The enantiomeric purity of 6 was confirmed by HPLC.
Less than <0.5% epimerization was observed in a sample
(13) McKennon, M. J .; Meyers, A. I. J . Org. Chem. 1993, 58, 3568-
3571.
(14) Schwabacher, A. W.; Stefanescu, A. D. Tetrahedron Lett. 1996,
37, 425-428.
(15) Morita, D. K.; Stille, J . K.; Norton, J . R. J . Am. Chem. Soc. 1995,
117, 8576-8581. Kwang-Cheng, K.; Cheng, C. J . Am. Chem. Soc. 1991,
113, 6313-6315.
(12) Lei, H.; Stoakes, M. S.; Herath, K. P. B.; Lee, J .; Schwabacher,
A. W. J . Org. Chem. 1994, 59, 4206-4210.

1786 J . Org. Chem., Vol. 64, No. 6, 1999
Schwabacher et al.
Ta ble 1. Dissocia tion Con sta n ts of 1- a n d 2-Su bstitu ted
Na p h th a len e Gu ests fr om Hosts 1 a n d 3
guest
KD (M-1
)
naphthyl
substituent
host 1
host 3b
-
14- 1-OCH2CO2- (1.65 ( 0.52) × 10-4 a (2.01 ( 0.50) × 10-3
15- 2-OCH2CO2
(1.1 ( 0.20) × 10-2 a
(6.1 ( 3.0) × 10-3
-
16- 1-CH2CO2-
(1.02 ( 0.13) × 10-3 a (1.05 ( 0. 33) × 10-2
17- 2-CH2CO2
(2.85 ( 0.70) × 10-3 a (8.58 ( 2.13) × 10-3
2-
18- 1-OPO3
19- 2-OPO3
(7.4 ( 2.2) × 10-3 b
(3.9 ( 3.0) × 10-3 b
<1 × 10-5
2-
(2.52 ( 0.68) × 10-4
a
b
From ref 10. Present work.
presumed to be of 2:2 stoichiometry and is represented
as 3 without direct evidence. It appears to have largely
one composition over the concentration range investi-
gated here: NMR and CD spectra of 3 change only in
intensity between 10-3 and 10-5 M. Structural charac-
terization of the metal complex was deferred in favor of
binding characterization.
F igu r e 4. Titration of 9.1 × 10-4 M 2 with Zn2+ in 100 mM
pD 9 borate in D2O. This is well above the Kd. A linear change
in chemical shift with added Zn2+ is seen in all signals
(including the aromatic signals off scale of this graph) leveling
off upon reaching a 1:1 ratio. Assignments based on COSY and
NOESY spectra: ArCHbHeCHa(NH2)CHcHdNH2.
This complex binds aromatic guests. Complex 3 (Zn2+
and 2) in pD 9 borate/D2O was titrated with various
anionic naphthalene derivatives. Changes were observed
such side products.10,12,14,16 tert-Butyl ester 9, while
desirable in many ways, couples slowly enough that
phenyl exchange is a problem. (p-Me2NC6H4)3P as a
ligand for palladium catalyst allows clean formation of
10, uncontaminated by 11. Presumably this is because
oxidative addition of Pd0 into the Ar-P bond is slower
with the more electron-rich aryl group.
1
in the chemical shifts of all resonances of the H NMR
spectrum of 3.
All shifts were simultaneously fit by multidimensional
nonlinear least squares to obtain dissociation constants
shown in Table 1.
Titrations to determine affinity were carried out at host
concentrations below the Kd. In the case of 1-naphthyl
phosphate, binding is sufficiently strong that only an
upper limit for the Kd can be determined, since solutions
dilute enough to cause dissociation are not easily studied.
However, titrations of 3 with 1-naphthyl phosphate
clearly indicate a strong binding in a 1:1 ratio. The
complexation-induced shifts are consistent with the
proposed binding orientation.
We have also defined conditions where these substrates
efficiently react in the absence of triarylphosphine. The
phosphine-free catalyst works well in this specific in-
stance, but in general is less effective for P-H aryl halide
cross-coupling reactions.17 For example, in the absence
of Ph3P, conversion of 7 to 8 proceeds to only about 10%
conversion.
Deprotection of 10 with aqueous HCl gave 2, isolated
as a trihydrochloride salt.
Self-assembled dicationic host 3 has a different sub-
strate binding selectivity than does dianionic host 1.
Charge is not the dominant factor: anions 14 and 15 are
not bound better by the cationic host 3 than by anionic
host 1. However host 1 shows a 67-fold preference for
1-substituted 14 over 2-substituted 15, while host 3 binds
14 only three times more strongly than 15. Substrates
16 and 17, with a shorter tether between carboxylate and
naphthalene, are each bound similarly by the two host
complexes. Dianionic 1-naphthyl phosphate 18 binds 7
times less strongly to 1 than does 1-naphthyl acetate 16
of the same tether length. The 2-substituted derivatives
17 and 19 bind to 1 with the same affinity.
In dramatic contrast, host 3 binds to 1-naphthyl
phosphate 18 at least 1000-fold more strongly than to
16 of the same tether length. This factor of 1000 is a
lower limit, since the binding of 1-naphthyl phosphate
18 is too strong to measure accurately by NMR. The
2-substituted 17 and 19 differ in their affinities for 1 by
a much smaller but still substantial factor of 34. This
preference for the dianionic substrate over the mono-
anionic one is reasonable for the cationic host, but the
range of values for the preference demonstrates that
charge is not the only factor of importance.
Bin d in g Stu d ies
Ligand 2 self-assembles in the presence of Zn2+ in 100
mM pH 9 borate buffer. Formation of complex is evident
by the shift in the 1H NMR resonances of 2. Figure 4
shows that titration of a solution of 2 in pH 9 borate with
Zn2+ causes a shift that is linear with increasing metal
concentration and then levels off after 1 equiv of metal
has been reached. This is strong evidence for a 1:1
stoichiometry, consistent with the desired 2:2 complex.
The shift demonstrates rapid exchange on an NMR time
scale between 2 and its Zn2+ complex, presumably 3, and
the linearity indicates a Kd for Zn2+ well below [2], as
anticipated for ethylenediamines.18 Organic guest binding
studies were carried out with a slight excess of 2 over
Zn2+, and [Host] is specified as [Zn2+]/2 in order to avoid
any complications in analysis due to free Zn2+. The large
shift in aliphatic signals of 2 upon association with Zn2+
,
without a substantial change in the aromatic spectral
region, is consistent with the expected metal coordination
to the ethylenediamines without coordination to the
phosphinate oxygens. The complex of Zn2+ with 2 is
(16) Lei, H.; Stoakes, M.; Schwabacher, A. W. Synthesis 1992, 1255-
1260.
(17) Herath, K. P. B. Synthesis of Arylphosphinic Acid Derivatives
as Building Blocks for Binding Sites. M.S. Thesis, Iowa State Univer-
sity, 1994.
(18) Martell, A. E.; Smith, R. M. Critical Stability Constants;
Plenum: New York, 1974.
Differences in selectivity of binding are due to overall
charge, shape-complementarity of the hydrophobic cavity
for aromatic guest substituent, affinity of metal for polar
guest substitutent, and the position of metal relative to
bound guest. This last factor we believe to be of utmost

Synthesis of a New Ligand for Metal Assembly
J . Org. Chem., Vol. 64, No. 6, 1999 1787
high vacuum to give 19.0 g (95.7%) of crude 6, pure by 1H
NMR. Recrystallization from 1 L of EtOAc gave 15.7 g (79%)
of 6, mp ) 168.0-169.5 °C.
importance to the creation of highly selective binding
sites. All of these are affected by the nature of the metal
center. Deciphering the contributions of these factors will
require further studies. This simple approach to binding
sites with multiple points of interaction clearly provides
receptors capable of subtle discrimination between guests.
1H NMR (250 MHz, CD3OD): δ 7.65 (d, J ) 8.1 Hz, 2H),
7.08 (br s, 1H), 6.99 (d, J ) 8.1 Hz, 2H), 5.46 (br s, 1H), 3.59
(dd, J ) 4.1, 9.1 Hz, 1H), 3.19 (dd, J ) 4.1, 13.7 Hz, 1H), 2.72
(dd, J ) 9.1, 13.8 Hz, 1H), 1.33 (br s, 1H). 13C NMR (DMSO-
d6, 62.9 MHz): δ 176.21, 138.70, 138.52, 131.61, 91.39, 55.70,
40.42; IR (KBr) 3358, 3266; 3033, 1687, 1593. MS (FAB, Cs,
Con clu sion s
30
glycerol): m/z 291 (M + 1; 100%). [R]D ) +9.84 (CH3OH, c
1.59). Anal. Calcd for C9H11IN2O: C, 37.26; H, 3.82; N, 9.66.
Found: C, 37.57; H, 3.93; N, 9.28.
We have presented an effective synthesis of the new
ligand 2. The synthesis proceeds via 7, readily prepared
in large quantities without chromatography. The dia-
magnetic Zn2+ complex of 2 is capable of binding to
naphthalene guests with substantial discrimination.
Binding selectivity contrasts with that of previous self-
assembled host complexes and is of sufficient interest to
warrant further scrutiny, the results of which will be
reported in due course.
HPLC (Beckman ultrasphere 4.5 × 150 mm C-18, 1.0 mL/
min, 30 min gradient 40 to 72% CH3OH in H2O, LL 19.19 min,
LD 19.95 min) showed <0.5% LD isomer.
(S )-N ,N ′-Di(t er t -b u t oxyca r b on yl)-1,2-d ia m in o-3-(4-
iod op h en yl)p r op a n e (7). A solution of I2 (40.0 g, 315 mmol)
in 100 mL of dry THF under N2 was added over 30 min to a
suspension of NaBH4 (15.0 g, 396 mmol) and amide 6 (15.0 g,
51.7 mmol) in 200 mL of THF with stirring on an ice bath in
the dark. The mixture was allowed to warm to room temper-
ature, sealed with a wired on septum, and stirred for 52 h
behind a blast shield. The mixture was cooled to 0 °C and
quenched by careful addition of 200 mL of CH3OH. The
solvents were removed by rotary evaporation, and the residue
was dissolved in 200 mL of CH3OH and reevaporated. Con-
centrated HCl (75 mL) was added, the resulting solution was
stirred, and after 1 h the solvent was removed by rotary
evaporation. To the solid residue was added 36 g of NaHCO3,
200 mL of H2O, 800 mL of CH3OH, and di-tert-butyl dicar-
bonate (27.0 g, 124 mmol). After 8 h of stirring at room
temperature, the mixture was filtered and concentrated by
rotary evaporation to 150 mL. Filtered solid and filtrate
residue were partitioned between 850 mL of EtOAc and 400
mL of H2O. Layers were separated, and aqueous layer was
extracted three times with 200 mL of EtOAc. The combined
organic layers were dried over Na2SO4 and filtered, and solvent
was removed by rotary evaporation and oil pump to yield 27.0
g of crude 7 which was crystallized from 500 mL of CH3CN to
yield 21.7 g (88%) of 7 as a white solid, mp ) 178-181 °C.
Chromatography (3:1 CHCl3/EtOAc) allowed isolation of 1.52
g (7.5%) of t-Boc-protected starting material.
Exp er im en ta l Section
Gen er a l P r oced u r es. Chemical shifts of 1H and 13C NMR
spectra are reported in ppm downfield of TMS in organic
solvents or DSS in D2O. 13C NMR spectra are 1H decoupled,
and phosphorus couplings are given; 31P chemical shifts are
reported versus external 85% H3PO4. Thin-layer chromatog-
raphy (TLC) was performed on 0.25 mm Merck silica gel 60-
F, and flash chromatography was on 230-400 mesh Merck
Kieselgel 60 as described.19 All chemicals were used as
obtained from commercial suppliers unless otherwise specified.
Crystalline anhydrous phosphinic acid was prepared by over-
night rotary evaporation at room temperature of 50% aqueous
phosphinic acid, evacuation at <0.05 Torr, and crystallization
at 4 °C. p-Iodophenylalanine was prepared as described.12
Substituted naphthalenes used as binding substrates were
purchased or prepared by literature procedures and used after
purity check by TLC and 1H NMR with recrystallization if
necessary. Acetonitrile was freshly distilled from P4O10. THF,
CH2Cl2, toluene, and triethylamine were freshly distilled from
CaH2. DMF and tert-butyl alcohol were dried over activated
4A molecular sieves.
1H NMR (250 MHz, CD3OD): δ 7.59 (d, J ) 8.1 Hz, 2H),
7.00 (d, J ) 8.3 Hz, 2H), 3.77 (m, 1H), 3.14 (dd, J ) 5.4, 13.7
Hz, 1H), 3.04 (dd, J ) 7.8, 13.6 Hz, 1H), 2.74 (dd, J ) 5.2,
13.8 Hz, 1H), 2.67 (dd, J ) 8.7, 13.7 Hz, 1H), 1.42 (s, 9H),
1.42 (s, 9H). 13C NMR (CDCl3, 63 MHz): δ 156.6, 155.8, 137.6,
137.4, 131.4, 91.8, 79.7, 79.6, 52.8, 44.0, 38.7, 28.4. FTIR
(KBr): 3363, 2978, 1689, 1529. MS (FAB, Cs, glycerol): m/z
p-Iod o-L-P h en yla la n in e Meth yl Ester Hyd r och lor id e
(5). SOCl2 (50 mL, 0.62 mol) was added over 20 min to 450
mL of CH3OH with stirring on an ice bath. (S)-p-Iodophenyl-
alanine acetic acid solvate (100 g, 0.285 mol) was added, the
flask was stoppered, and ice bath was removed. After 18 h
the solvents were removed by rotary evaporation, the residue
was redissolved in 400 mL of CH3OH, and the solvent was
again evaporated. Recrystallization from 250 mL of CH3OH
and 1000 mL of diethyl ether gave 93.0 g (95.8%) of 5 in two
crops having spectral properties identical to an authentic
standard.12
30
351 (M - I; 26%), 321, 295, 195 (100%), 251, 239, 195. [R]D
) -5.00 (CH3OH, c 1.94). Anal. Calcd for C19H29IN2O4: C,
37.26; H, 6.14; N, 5.88. Found: C, 48.16; H, 6.36; N, 5.88.
ter t-Bu tyl P h osp h in a te a s a Tolu en e Solu tion (8).14
Anhydrous phosphinic acid (0.415 g, 6.3 mmol) in dry t-BuOH
(3.00 mL, 31.8 mmol) was treated under N2 at room temper-
ature with trimethyl orthoformate (2.70 mL, 24.0 mmol). After
3 h, the 31P NMR of reaction mixture diluted in CDCl3 showed
a 1.1:1 mixture of H2PO2CH3:H2PO2C(CH3)3, with no signifi-
cant side products. Et3N (0.4 mL) was added, and volatiles
were removed in vacuo. Two cycles followed the addition of
t-BuOH (3.4 mL) and the removal of volatiles in vacuo after
90 min. The residue was then dissolved in 2 mL of toluene
with 0.2 mL of Et3N and filtered through a 5 × 0.4 cm column
of basic alumina, followed by 1 mL of toluene, to yield 3.0 mL
of 0.82 M solution of 8 (37%), free of phosphorus-containing
side products by 31P NMR. The concentration of 8 was
1H NMR (CD3OD): δ 7.73 (d, J ) 6.0 Hz, 2H), 7.05 (d, J )
6.0 Hz, 2H), 4.31 (t, J ) 6.9 Hz, 1H), 3.81 (s, 3H), 3.22 (dd, J
30
) 15.0, 6.0 Hz, 1H), 3.12 (dd, J ) 15.0, 7.5 Hz, 1H). [R]D
+9.64 (CH3OH, c 2.16).
)
(S)-2-Am in o-3-(4-iod op h en yl)p r op ion a m id e (6). p-Iodo-
phenylalanine methyl ester hydrochloride (23.3 g, 68.4 mmol)
in 320 mL of CH3OH was stirred on an ice bath as ∼100 g of
NH3 was added by 90 min bubbling. The flask, sealed with a
clamped septum, was allowed to warm to 23 °C over 21 h. After
careful venting, TLC (methyl ethyl ketone:acetic acid:water
12:3:1, Rf ) 0.66) indicated completion. The residue from
careful rotary evaporation (caution: NH3 corrodes brass
aspirators) was partitioned between 350 mL of 70% saturated
NaHCO3 and 1.75 L of EtOAc and separated, and the aqueous
layer was extracted three times with 500 mL of EtOAc.
Combined organic layers were dried over Na2SO4 and filtered,
and the solvents were removed by rotary evaporation and then
1
determined by H NMR integration versus 1,3,5-trimethoxy-
benzene standard. The solution was used directly in Pd-
catalyzed coupling reactions with aryl iodides.
1H NMR (6:1 CDCl3/toluene): δ 7.10 (d, J ) 559.7 Hz, 2H),
1.47 (s, 9H); toluene and tert-BuOH resonances are also
present. 31P NMR (6:1 CDCl3/toluene): δ 4.03.
ter t-Bu t yl (4-((2S)-2,3-d i(ter t-b u t oxyca r b on yla m in o)-
p r op yl)p h en yl)p h osp h in a te (9). A suspension of iodoaryl
7 (190 mg, 4.00 × 10-4 mol), (Ph3P)2PdCl2 (14.0 mg, 2.0 × 10-5
(19) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

1788 J . Org. Chem., Vol. 64, No. 6, 1999
Schwabacher et al.
mol) in CH3CN (1.0 mL) and Et3N (0.031 mL, 2.2 × 10-4 mol)
was treated with a solution of tert-butyl phosphinate (8.2 ×
10-4 mol, added as 1.00 mL of a 0.82 M toluene solution also
0.58 M in Et3N). The reaction mixture was capped under N2
and heated in a 90 °C oil bath for 100 min. After the solvent
was removed by rotary evaporation, product was isolated by
flash chromatography (silica, 19:1 EtOAc/Et3N) as a white
solid, mp ) 56-60 °C (yield 0.142 g, 75%).
Celite, evaporated to dryness, and crystallized from 2.0 mL of
H2O and 20 mL of EtOH to give 2, pure by NMR and HPLC
(85:15 H2O/CH3CN, 0.043% TFA, 4.3 mM sodium hexane-
sulfonate; 3 µm C-18 4.6 × 100 mm, 0.5 mL/min, 230 nm, Rf
) 4.7 min (100%)) except for EtOH of crystallization. Dissolu-
tion in H2O and lyophilization gave analytically pure 2 (0.317
g, 87%) free of EtOH.
1H NMR (D2O): δ 7.72 (dd, J ) 11.7, 8.1 Hz, 4H), 7.42 (dd,
J ) 8.1, 2.4 Hz, 4H), 3.78 (dq, J ) 8.7, 6.3 Hz, 2H), 3.40 (dd,
J ) 16.7, 6.3, 1H), 3.35 (dd, J ) 16.7, 6.8, 1H), 3.23 (dd, J )
14.4, 6.3, 1H), 3.04 (dd, J ) 14.4, 8.7, 1H). 13C NMR (D2O): δ
139.9, 138.6 (d, J ) 177.2 Hz), 134.4 (d, J ) 13.5 Hz), 132.2
(d, J ) 16.7 Hz), 55.2, 43.4, 38.8, 7.0. 31P NMR (D2O): δ 25.55.
IR (KBr): 3430, 2972 (br), 1606, 1508, 1403, 1205, 1044, 741
cm-1. UV (0.1 M aqueous HCl): ꢀ230 ) (2.51 ( 0.02 × 104) M-1
1H NMR (CDCl3): δ 7.72 (d, J ) 551 Hz, 1H), 7.69 (dd, J )
13.8, 7.8 Hz, 2H), 7.33 (dd, J ) 8.0, 3.1 Hz, 2H), 4.95 (br, 1H)
4.87 (br, 1H), 3.88 (br, 1H), 3.18 (br m, 2H), 2.88 (br m, 1H),
2.81 (dd, J ) 13.2, 6.8 Hz, 1H), 1.57 (s, 9H), 1.44 (s, 9H), 1.39
(s, 9H). 13C NMR (CDCl3): δ 156.7, 155.9, 142.8, 131.7 (d, J )
11.9 Hz), 129.6 (d, J ) 139.3 Hz), 129.6 (d, J ) 14.3 Hz), 83.1
(d, J ) 11.0 Hz), 79.7, 79.5, 52.6, 43.7, 39.2, 30.4 (d, J ) 4.5
Hz), 28.3 (two coincident resonances, demonstrated by HET-
COR cross-peaks to 1.44 and 1.39 1H resonances). 31P NMR
(CDCl3): diastereomers δ 15.66 and 15.70 (1H-coupled, each
dt, J ) 552, 12.3 Hz). IR (neat): 3328 (Br), 2978, 2931, 1710,
1521, 1252, 1170, 980 cm-1. MS (electrospray) (MeOH, positive
ion): m/z calcd for M+Na+ 493.2, found 493.1 (62%), calcd for
(M + K+) 509.2, found: 509.1 (62%). The diastereomeric
mixture crystallized in low yield from ether, mp ) 76-82 °C.
cm-1. [R]D ) -34.4 (H2O, c 1.84). MS (electrospray) (H2O/
30
MeOH, positive ions): M ) C18H27N4O2P calcd for [M + H+,
(M + 2H+)/2, (M + H+ + Na+)/2] 363.2, 182.6, 193.6, found
362.8 (30%), 181.8 (100%), 192.5 (43%). Negative ions: calcd
for [M - H+, 2M - H+] 361.2, 723.4, found 361.0 (16%), 723.6
(8%). MS (electrospray) (H2O/MeOH/NaOH, pH 9: positive
ions): calcd for [M + H+, (M + Na+), (M - H+ + 2Na+)] 363.2,
385.4, 407.2, found 363.4 (20%), 385.3 (25%), 406.8 (100%).
Negative ions: calcd for [M - H+] 361.2, found 361.8 (100%).
Anal. Calcd for C18H27N4O2P1‚(HCl)3‚(H2O)4: C, 39.75 H, 7.04;
N, 10.30. Found: C, 39.52; H, 7.08; N, 10.07.
29
[R]D ) -1.29 (CH3OH, c 1.76). Anal. Calcd for C23H39N2O6P:
C, 58.71; H, 8.35; N, 5.95. Found: C, 57.93; H, 8.73; N, 6.06.
(S,S)-ter t-Bu t yl
Bis(4-[2,3-Di(ter t-b u t oxyca r b on yl-
a m in o)p r op yl]p h en yl)p h osp h in a te (10). tert-Butyl mono-
arylphosphinate 9 (679 mg, 1.44 mmol), aryl iodide 7 (1.37 g,
2.87 mmol), Pd2(dibenzylideneacetone)3 (71 mg, 0.076 mmol,
0.153 mmol Pd), and 10 mL of CH3CN were mixed, and then
Et3N (2.00 mL, 14.3 mmol) was added. The reaction mixture
was sealed with a wired-on septum and heated in a 90 °C oil
bath for 14 h, and the solvent was removed by rotary
evaporation. Flash chromatography in 4:1 hexanes/EtOAc gave
unreacted 7. Elution with EtOAc and crystallization from
acetonitrile gave 10 (0.87 g, 74%), mp ) 179-181 °C.
Zn Com p lex of Bis[4-(2S)-2,3-d ia m in op r op yl)p h en yl]-
p h osp h in ic Acid (3). A stock solution of (2.7 mM) complex 3
was prepared by adding 0.9 equiv of anhydrous ZnSO4 in D2O
to 2 in 100 mM sodium borate in D2O. Nominal [3] ) [Zn2+]/2.
1H NMR (0.1 M borate in D2O): δ 7.662 (dd, J ) 11.0, 8.2
Hz, 8H), 7.28 (d, J ) 7.2 Hz, 8H), 3.02 (d, J ) 10.4 Hz, 4H),
2.86 (d, J ) 12.8 Hz, 8H), 2.60 (dd, J ) 12.8, 8.4 Hz, 4H) 2.31
(br, 4H).
NMR Titr a tion P r oced u r e. 1H NMR titrations were
performed at 20.0 ( 0.5 °C in 0.2 M borate buffer in D2O at
constant host concentration of ca. 10-4 M. Host was titrated
with a solution of host and guest, and all distinguishable
resonances of host and guest were fit to yield a single KD, using
multidimensional nonlinear least squares using Scientist
(MicroMath) version 2.01. Error limits are 95% confidence (s
plane).
1H NMR (CDCl3): δ 7.69 (dd, J ) 12.0, 7.8 Hz, 4H), 7.24
(dd, J ) 7.8, 2.7 Hz, 4H), 4.93 (br m, 2H), d 4.86 (br m, 2 H),
3.86 (br m, 2 H), 3.15 (br m, 4H), 2.84 (br m, 2H), 2.75 (dd, J
) 13.5 Hz, 6.9 Hz, 2H), 1.48 (s, 9H), 1.42 (s, 18H), 1.37 (s,
18H). 13C NMR (CDCl3): δ 156.7, 155.8, 141.6, 132.8 (d, J )
186.1 Hz), 131.8 (d, J ) 13.8 Hz), 129.3 (d, J ) 17.8 Hz), 83.6
(d, J ) 10.9 Hz), 79.5, 79.4, 52.6 43.7, 39.0, 30.9 (d, J ) 5.2
Hz) 28.4. 31P NMR (CDCl3): δ 26.51 (1H-coupled, quintet, J )
11.7 Hz). IR (neat): 3335 (Br), 3054, 2977, 2932, 2872, 1716,
Host resonances were fit using the following equation
∆δ
δi ) δ0i
+
max i(S - S2 - 4H G )
x
1539, 1271, 1251,1228, 1040 cm-1
. MS (electrospray)
0
0
H0
(MeOH): calcd for M + Na+ ) C42H67N4O10P1Na1 841.4, found
30
840.7 (100%). [R]D ) -4.64 (CH3OH, c 0.517). Anal. Calcd
and guest resonances were fit using the following equation
for C42H67N4O10P: C, 61.60; H, 8.25; N, 6.48. Found: C, 61.22;
H, 8.27; N, 6.68.
∆δ
δj ) δ0j
+
max j(S - S2 - 4H G )
x
0
0
When Ph3P is used in this process, an impurity tentatively
assigned as 11 is formed.
G0
1H NMR (CDCl3): δ 7.78 (dd, J ) 13, 8 Hz, 2H), 7.70 (dd, J
) 12, 8 Hz, 2H), 7.46 (m, 3H), d 7.25 (dd, J ) 9, 3 Hz, 2H),
1.50 (s, 9H), 1.42 (s, 9H), 1.36 (s, 9H). 31P NMR (CDCl3): δ
where KD ) dissociation constant, H0 ) total host added, and
G0 ) total guest added, and S ) H0 + G0 + KD, all in molarity.
26.65: MS (electrospray) (MeOH): calcd for M + Na+
)
Ack n ow led gm en t. This work was supported by
NIH Grant GM47736-02.
C
29H43N4O6P1Na1 569.3, found 569.0 (100%).
Bis[4-(2S)-2,3-d ia m in op r op yl)p h en yl]p h osp h in ic Acid
Tr ih yd r och lor id e Tetr a h yd r a te (2). tert-Butyl diarylphos-
phinate 10 (513 mg, 0.626 mmol) suspended in 8.7 mL of 9 M
HCl was stirred for 30 min at 80 °C, and then the solvents
were removed by rotary evaporation. The residue in 4 mL of
H2O was decolorized with 90 mg of charcoal, filtered through
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
2 and 3. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O9804590