S-acyl-2-thioethyl aryl phosphotriester derivatives as mononucleotide prodrugs

Article abstract of DOI:10.1021/jm000996o

The synthesis and biological activities of phosphotriester derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT) bearing a phenyl group or L-tyrosinyl residues are reported. The target compounds were obtained via either P^V or P^III che

Full text of DOI:10.1021/jm000996o

4570
J . Med. Chem. 2000, 43, 4570-4574
S-Acyl-2-th ioeth yl Ar yl P h osp h otr iester Der iva tives a s Mon on u cleotid e
P r od r u gs
Nathalie Schlienger, Suzanne Peyrottes, Tarek Kassem, J ean-Louis Imbach, Gilles Gosselin,
Anne-Marie Aubertin,† and Christian Pe´rigaud*
UMR 5625 CNRS-UM II, Universite´ Montpellier II, cc 008, place E. Bataillon, 34095 Montpellier Cedex 05, France, and
Laboratoire de Virologie de la Faculte´ de Me´decine, Unite´ 74 I.N.S.E.R.M., Universite´ L. Pasteur, 3, rue Koeberle´,
67000 Strasbourg, France
Received May 29, 2000
The synthesis and biological activities of phosphotriester derivatives of 3′-azido-2′,3′-dideox-
ythymidine (AZT) bearing a phenyl group or L-tyrosinyl residues are reported. The target
compounds were obtained via either PV or PIII chemistry from the appropriate aryl precursors.
All the derivatives were evaluated for their in vitro anti-HIV activity, and they appeared to be
potent inhibitors of HIV-1 replication in various cell culture experiments, with EC50 values
between the micro- and nanomolar range. Furthermore, compounds incorporating an amino-
and/or acid-substituted tyrosinyl residue demonstrated significant anti-HIV effects in thymidine
kinase-deficient (TK-) cells showing their ability to act as mononucleotide prodrugs. The
proposed decomposition process of these mixed mononucleoside aryl phosphotriesters may
involve esterase activation followed by phosphodiesterase hydrolysis.
In tr od u ction
stability of the resulting bis(SATE) phosphotriester
derivatives but may have precluded the conversion of
the resulting mono(SATE) phosphodiester due to inap-
propriate kinetic parameters (second step, Scheme 1).
Therefore, we decided to evaluate the potential of a new
series of mixed phosphotriesters incorporating only one
SATE chain and a different protecting group on the
phosphorus atom, the latter being able to be hydrolyzed
by another enzymatic system than esterases.
Among the compounds approved in the treatment of
AIDS disease, 2′,3′-dideoxynucleoside analogues (ddN)
represent an important class of potent inhibitors of the
HIV reverse transcriptase.1,2 Nevertheless, those ddN
analogues need to be metabolized to their corresponding
5′-triphosphates (ddNTP) through the action of several
intracellular kinases. In many cases, the rate-limiting
step for the conversion of the ddN analogue to its active
metabolite (ddNTP) is the formation of the 5′-mono-
nucleotide from the nucleoside analogue.3 To overcome
this dependence of ddN upon nucleoside kinase activa-
tion, various research groups have focused their atten-
tion on the study of monophosphorylated prodrugs,
namely pronucleotides.4-7 Such pronucleotides should
be able, after intracellular hydrolysis, to give rise to the
delivery of 5′-mononucleotides, which could be further
metabolized to their corresponding ddNTP analogues in
a nucleoside kinase-nondependent way.
On this topic, we have previously demonstrated that
the use of symmetrical mononucleoside phosphotriesters
incorporating S-acyl-2-thioethyl (SATE) groups leads to
the intracellular release of the corresponding 5′-mono-
nucleotide.8 The decomposition pathway of these bis-
(SATE) derivatives involves successively two esterase-
mediated activation steps (Scheme 1).9,10 However, the
removal of the second SATE masking group could be
considered as a rate-limiting step in this general
process.10,11 With the aim of the in vivo development of
a pronucleotide approach, we have previously reported
the effect of structural modifications of the SATE groups
on kinetic parameters involved in the release of the 5′-
mononucleotide from its corresponding prodrug.12,13 All
these structural modifications allowed to increase the
Resu lts a n d Discu ssion
The design of the described mixed phosphotriesters
is based on literature data14-16 which showed that
nucleotide phosphodiesterases, a family of ubiquitous
enzymes, have good affinity for aromatic substrates and
were able to selectively hydrolyze aryl phosphodiester
derivatives into the corresponding phosphomono-
esters.16,17 Thus, our idea was to generate intracellularly
an aryl phosphodiester by the use of an appropriate
phosphorylated precursor. This observation led us to
study, as a first model, mononucleoside aryl phospho-
triesters incorporating as the aryl substituent either a
phenyl group or a natural aromatic amino acid such as
L-tyrosine, respectively 2 and 3 (Chart 1). These pre-
liminary investigations were published as a short note
and demonstrated that the 5′-mononucleotide derivative
of AZT was released intracellularly.18 Herein, we would
like to report the entire study, i.e. synthesis and anti-
HIV-1 activity, of several aryl phosphotriesters of 3′-
azido-2′,3′-dideoxythymidine (AZT) 2-5 incorporating
one S-pivaloyl-2-thioethyl (tBuSATE) moiety and a
phenyl group or an amino acid residue derived from
L-tyrosine. The antiviral evaluations were carried out
in comparison to the previously described bis(tBuSATE)
phosphotriester derivative of AZT 1,9 as reference
pronucleotide.
* To whom correspondence should be addressed. Tel: 33(0)-
467144776. Fax: 33(0)467042029. E-mail: perigaud@univ-montp2.fr.
† Universite´ L. Pasteur.
Ch em istr y. The synthesis of the desired mixed aryl
phosphotriester derivatives could be carried out follow-
10.1021/jm000996o CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/24/2000

Brief Articles
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4571
Sch em e 1. Decomposition Pathway of Mononucleoside Bis(SATE) Phosphotriester Derivatives in Cell Extracts and
Intact Cells
Ch a r t 1. Structures of Studied Phosphotriester
Derivatives of AZT
nucleophile-sensitive functions (thioester, phosphotri-
ester). Consequently, we decided to use acid-labile
protecting groups and/or groups susceptible to being
hydrolyzed by an enzymatic system during biological
studies, to keep the integrity of the skeleton of the target
compounds. The tert-butyloxycarbonyl (tBoc) and tert-
butyl (tBu) groups were used as amino and acid protec-
tions, respectively. Concerning the acid functionality,
both tert-butyl and methyl esters of N-R-tBoc-L-tyrosine
were selected for their ability to be potentially removed
by enzymes such as esterases present in biological
media. Selective esterification of the acid in the presence
of the phenolic function was carried out from N-R-tBoc-
L-tyrosine, using N,N-dimethylformamide dineopentyl
acetal,19,20 to obtain the N-R-tBoc-L-tyrosine tert-butyl
ester 7a in good yields. The tyrosinyl precursors 7a ,b
(commercially available) were condensed in the presence
of 1H-tetrazole with the SATE phosphorobisamidite
reagent 6 obtained via a previously described proce-
dure.21 Then, the reaction of the adequate tyrosinyl
(tBuSATE) phosphoramidite intermediates 8a ,b with
AZT, followed by in situ oxidation using tert-butyl
hydroperoxide, afforded the fully protected phosphotri-
ester derivatives 4a ,b in 57% and 72% overall yields,
respectively, from 6. Treatment of compound 4a with
hydrochloric acid-saturated ethereal solution (30% in
weight) gave rise directly to the tyrosinyl (tBuSATE)
phosphotriester derivative of AZT as its hydrochloride
salt 3, in 50% yield (Scheme 2). Finally, the selective
removal of the tBoc group from 4a ,b was carried out
using trifluoroacetic acid/dichloromethane solution (10%
in volume) in time-controlled reactions, and the partially
protected entity 5a ,b could be isolated in good yields
after their conversion to the corresponding hydrochlo-
ride salts.
ing two strategies using PIII (phosphoramidite) or PV
(phosphate) intermediates depending on both the avail-
ability of the starting materials and the reactivity of
the intermediates. Thus, the phenyl (tBuSATE) phos-
photriester derivative of AZT 2 was obtained using PV
chemistry in a one-pot procedure.18 Another synthetic
route was chosen for the preparation of the mixed
phosphotriesters 4a ,b involving the phosphoramidite
approach. The phosphytilating agents bearing the SATE
moiety and the desired tyrosinyl residue could be
obtained from commercially available bis(diisopropyl-
amino)chlorophosphine with subsequent coupling of the
SATE chain moiety and then the aryl residue (Scheme
2). The crucial point of these syntheses was the choice
of the protecting groups borne by the amine and acid
functionalities of L-tyrosine. Indeed, the cleavage condi-
tions of such groups have to be compatible with the
stability of the final derivatives which possess base- and
An ti-HIV-1 Eva lu a tion . The inhibitory effects on the
replication of HIV-1 of the studied mixed phosphotri-
esters 2-5 were evaluated in three cell culture systems
(Table 1) in comparison to the parent nucleoside AZT
and to the reference pronucleotide 1. In human T4-
lymphoblastoid CEM-SS and MT-4 cells, all the tested
compounds appeared to be as potent as AZT, with 50%

4572 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23
Brief Articles
Sch em e 2 General Approach for the Synthesis of Aryl Phosphotriester Derivatives 3-5a
a
Reagents: (i) (CH3)2NCH[OCH2C(CH3)3]2, tBuOH, toluene; (ii) 6, 1H-tetrazole, HN(iPr)2, CH3CN; (iii) AZT, 1H-tetrazole, CH3CN,
then tBuOOH, toluene; (iv) 10% TFA, CH2Cl2, then HCl, dioxane solution; (v) 30% HCl, Et2O solution.
Ta ble 1. Anti-HIV-1 Activitya in Three Cell Culture Systems and Apparent Partition Coefficients of Mixed Aryl Phosphotriester
Derivatives 2-5 Compared to Parent Nucleoside AZT and Bis(tBuSATE) Phosphotriester Derivative 1 of AZT, as Reference
Pronucleotide
CEM-SS
MT-4
CEM/TK-
c
compd
EC50 (µM) b
CC50 (µM) c
EC50 (µM) b
CC50 (µM)
EC50 (µM) b
>100
0.45
3.5
29
CC50 (µM) c
log Papp
AZT
1
2
0.003
0.015
0.002
0.006
0.034
0.001
0.004
0.002
>1
>10
>10
>100
>1
>10
>10
>100
0.015
0.81
0.07
0.075
0.25
0.033
0.042
0.037
>1
>10
>10
>10
>1
>10
>10
>10
>100
>10
>10
>100
>1
>10
>10
>100
0.06 ( 0.003
3.73 ( 0.07
3.46 ( 0.04
0.24 ( 0.015
4.29 ( 0.16
3.48 ( 0.01
2.90 ( 0.02
2.25 ( 0.04
3
4a
4b
5a
5b
0.90
2.3
2.7
1.8
a
All data represent average values for at least three separate experiments. The variation of these results under standard operating
procedures is below (10%. EC50: effective concentration, or concentration required to inhibit the replication of HIV-1 by 50%. c CC50
cytotoxic concentration, or concentration required to reduce the viability of uninfected cells by 50%.
:
b
effective concentration (EC50) about submicromolar
concentration range. In contrast to AZT, the phenyl and
tyrosinyl (tBuSATE) phosphotriesters 2-5 exhibited
significant anti-HIV effects in thymidine kinase-defi-
cient CEM cells (CEM/TK-) with EC50 values which
were in the same range as that observed for the
pronucleotide 1. These results seem to demonstrate that
the studied mixed aryl phosphotriesters 2-5 were able
to give rise to the intracellular delivery of the 5′-
mononucleotide of AZT (AZTMP) and can be considered
as a new series of pronucleotides.
As illustrated in Table 1, the presence of lipophilic
substituents or ionizable functions borne by the aryl
phosphate protection influenced the anti-retroviral ac-
tivity of the corresponding phosphotriester derivatives
2-5 in CEM/TK- cells. For instance, the phosphotri-
ester 3 incorporating the deprotected tyrosinyl moiety
appeared to be the less active with an EC50 value of 29
µM, while the fully protected analogue 4a inhibited the
multiplication of HIV-1 at submicromolar concentration.
The behavior of the (tBuSATE) tyrosinyl phosphotri-
ester 3 in total CEM cell extracts, used as mimic for
the intracellular medium, has previously been re-
ported.18 This stability study showed that such mixed
phosphotriester exerts its biological effect following a
decomposition process involving, successively, esterase
and phosphodiesterase systems. As a consequence, the
lower anti-HIV activity observed in the CEM/TK- cell
line for the zwitterionic derivative 3 could be related to
its limited ability to cross the cell membrane barrier by
passive diffusion due to its polarity (log Papp ) 0.24,
Table 1).
Comparison between anti-HIV activities in CEM/TK-
cells and apparent partition coefficients of phosphotri-

Brief Articles
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4573
then the solvent was removed in vacuo and the residue
dissolved in CH2Cl2. This solution was washed with aqueous
1 M HCl, a saturated aqueous solution of sodium bicarbonate,
and water. The organic layer was dried over Na2SO4, filtered,
and evaporated to dryness. The residue was purified by column
chromatography eluting with MeOH/CH2Cl2 (2:98, v/v). The
appropriate fractions were collected and evaporated to give
pure phosphotriester 2 (0.23 g, 80%) as a colorless oil: Rf 0.47
(MeOH/CH2Cl2 7:93).
ester derivatives 2-5 (Table 1) showed that other
factors are involved in the observed in vitro biological
effect. For example, despite marked differences in their
lipophilicity, the EC50 values for the phosphotriesters
4b and 5b are in the same range. These results
suggested that other factors such as the kinetics of
decomposition of aryl phosphotriesters (related to their
affinity for intracellular phosphodiesterases) may be
involved in the observed in vitro anti-HIV activity of
the corresponding phosphotriesters.
Nr-ter t-Bu toxyca r bon yl-L-ter t-bu toxytyr osin e (7a ). NR-
tert-Butoxycarbonyl-L-tyrosine (2.53 g, 9 mmol) was dissolved
in toluene (45 mL) and tert-butyl alcohol (127 mmol, 11.9 mL,
14 equiv) was added. The mixture was brought to reflux and
N,N-dimethylformamide dineopentyl acetal (27.2 mmol, 7.6
mL, 3 equiv) was added dropwise over 90 min. After stirring
for 3 h at reflux the solution was cooled to room temperature
and a saturated NaHCO3 solution was added. The aqueous
layer was extracted three times with CH2Cl2, the combined
organic layers were dried over Na2SO4, filtered and the solvent
removed in vacuo. Purification of the residue by column
chromatography on silica gel, eluting with a stepwise gradient
of EtOAc (0-30%) in CH2Cl2, and crystallization from n-hex-
ane/CH2Cl2 afforded title compound 7a (2.12 g) as colorless
needles, 70% yield: Rf 0.63 (MeOH/CH2Cl2 5:95); mp 112.8-
Con clu sion
The present study demonstrates that (tBuSATE) aryl
phosphotriester derivatives of AZT 2-5 are able to allow
the efficient intracellular delivery of the parent 5′-
mononucleotide and can be considered as a new series
of pronucleotides. The proposed mechanism for the
decomposition of these mixed phosphotriesters involves
successively an esterase and a phosphodiesterase hy-
drolytic step. The large number of chemical modifica-
tions which could be envisaged on the aryl moiety opens
the way to the search for antiviral mononucleotide
prodrugs with an adequate balance between aqueous
solubility, lipophilicity, and enzymatic stability in order
to envisage further in vivo pharmacological studies. In
this respect, the structural features of the aryl phos-
photriesters 5a ,b appear as promising phosphate pro-
tecting groups in view of the anti-HIV activity and
physicochemical properties of the resulting pronucle-
otides. Finally, the introduction of a tyrosinyl residue
in place of the second tBuSATE chain, such as in
phosphotriester 3, would open novel perspectives on the
specificity of 5′-mononucleotide delivery to infected cells
or tissues. We are aware that several therapeutic
agents22,23 presenting mimic structures with L-phenyl-
alanine, a natural occurring substrate for the large
neutral amino acid transporter (L-system), were able
to be recognized and actively transported by this carrier
through biological barriers. The presence of this trans-
porter on epithelium cell surfaces and its high capacity
and medium specificity properties are particularly at-
tractive compared to other nutrient carriers.24-26 Work
on this topic is currently in progress in our group.
113.0 °C (lit.29 111.3-112.8 °C); [R]D ) 8° (c ) 1.0, EtOH)
20
(lit.29 ) 19.4 (c ) 1.0, dioxane)). Anal. (C18H27NO5) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of P h osp h or a -
m id ites 8a ,b. To a solution of the appropriate tyrosinyl
precursor 7a ,b (0.50 mmol) in dry CH3CN (5 mL) containing
3 Å molecular sieve (0.5 g) were added at 0 °C phosphorodia-
midite 6 (0.29 g, 0.75 mmol, 1.5 equiv), diisopropylamine (0.14
mL, 1.00 mmol, 2 equiv) and 1-H-tetrazole (0.07 g, 1.00 mmol,
2 equiv). After stirring for 2 h at room temperature, the
reaction mixture was diluted with acid-free EtOAc, washed
with brine and water, dried with Na2SO4, filtered and con-
centrated in vacuo. Purification of the residue by flash column
chromatography on silica gel eluting with EtOAc/cyclohexane
(1:9, v/v) containing 1% of triethylamine afforded a diastereo-
isomeric mixture (1:1) of the desired phosphoramidite as a
colorless oil.
O-(Nr-ter t-Bu toxycar bon yl-L-ter t-bu toxytyr osin yl) O-(S-
p iva loyl-2-th ioeth yl) N,N-d iisop r op ylp h osp h or a m id ite
(8a ): 0.29 g, 95%; Rf 0.57 (Et3N/EtOAc/cyclohexane 1:1:8).
Anal. (C31H53N2O7PS) C, H, N.
O-(Nr-ter t-Bu toxyca r bon yl-L-m eth oxytyr osin yl) O-(S-
p iva loyl-2-th ioeth yl) N,N-d iisop r op ylp h osp h or a m id ite
(8b): 0.26 g, 87%; Rf 0.55 (Et3N/EtOAc/cyclohexane 1:1:8).
Anal. (C28H47N2O7PS) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of P h osp h otr i-
ester s 4a ,b. To a solution of AZT (0.093 g, 0.35 mmol) in dry
CH3CN (3 mL) containing 3 Å molecular sieve (0.5 g) were
added 1H-tetrazole (0.098 g, 1.40 mmol, 4 equiv) and dropwise
a solution of the appropriate phosphoramidite 8a ,b (0.42 mmol,
1.2 equiv) in dry CH3CN (1.5 mL). The mixture was stirred
for 1 h, tert-butyl hydroperoxide (0.28 mL, 0.84 mmol, 3 M in
toluene, 2.4 equiv) was added and the solution further stirred
for 1 h. The mixture was diluted with CH2Cl2 and washed
successively with aqueous Na2S2O3 (10%, w/v) and water, the
organic layer was dried over Na2SO4, filtered and evaporated
to dryness under reduced pressure. Purification of the residue
by silica gel column chromatography using a stepwise gradient
of MeOH in CH2Cl2 afforded the desired phosphotriester as a
white foam.
Exp er im en ta l Section
Gen er a l Meth od s. See ref 27.
Biologica l Meth od s. See ref 9.
P a r tition Coefficien t. The apparent partition coefficients
(log Papp) were evaluated for their distribution between 1-oc-
tanol (puriss, Fluka) and potassium phosphate buffer (0.02 M,
pH 7.2) using an adapted shake-flask technique.28
P h en yl S-P iva loyl-2-th ioeth yl 3′-Azid o-2′,3′-d id eoxy-
th ym id in -5′-yl P h osp h a te (2). S-(2-Hydroxyethyl)thiopiv-
aloate9 (2.22 g, 13.7 mmol) was coevaporated with dry THF
and the residue dissolved in the same solvent (130 mL). This
solution was cooled to -78 °C and phenyl phosphorochloridate
(2.1 mL, 14.0 mmol) was added dropwise over 10 min. The
mixture was stirred overnight, filtered and the filtrate evapo-
rated in vacuo. The residue was dissolved in dry CCl4, filtered
and concentrated to dryness under reduced pressure to afford
the phenyl S-pivaloyl-2-thioethyl phosphorochloridate (4.9 g)
which was directly used without further purification (31P NMR
in CDCl3, δ -0.60). The crude phosphorochloridate (0.52 g)
was coevaporated with dry THF and the residue dissolved in
the same solvent (5 mL). AZT (0.137 g, 0.51 mmol) was added,
followed by addition of N-methylimidazole (0.245 mL, 3.1
mmol). The mixture was stirred for 4 h at room temperature,
O-(Nr-ter t-Bu toxycar bon yl-L-ter t-bu toxytyr osin yl) O-(S-
p iva loyl-2-t h ioet h yl) 3′-a zid o-2′,3′-d eoxyt h ym id in -5′-yl
p h osp h a te (4a ): 0.22 g (76%); Rf 0.50 (MeOH/CH2Cl2 7:93).
Anal. (C35H51N6O12PS) C, H, N.
O-(Nr-ter t-Bu toxyca r bon yl-L-m eth oxytyr osin yl) O-(S-
p iva loyl-2-t h ioet h yl) 3′-a zid o-2′,3′-d eoxyt h ym id in -5′-yl
p h osp h a te (4b): 0.18 g (66%); Rf 0.40 (MeOH/CH2Cl2 5:95).
Anal. (C32H45N6O12PS) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of P h osp h otr i-
ester s 5a ,b. To a solution of the appropriate phosphotriester
4a ,b (0.06 mmol) in dry CH2Cl2 (1 mL) was added a solution

4574 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23
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of trifluoroacetic acid/CH2Cl2 (1 mL, 20%, v/v). After stirring,
the mixture was concentrated under reduced pressure. Puri-
fication of the residue by column chromatography on silica gel
eluting with a stepwise gradient of MeOH in CH2Cl2 gave the
desired phosphotriester as a white powder, after trituration
with a hydrochloric acid saturated dioxane solution, evapora-
tion and lyophilization in dioxane.
O-(L-ter t-Bu toxytyr osin yl) O-(S-p iva loyl-2-th ioeth yl)
3′-a zid o-2′,3′-d eoxyth ym id in -5′-yl p h osp h a te, h yd r och lo-
r id e (5a ): 0.034 g (65%); Rf 0.64 (MeOH/CH2Cl2 1:4). Anal.
(C30H44ClN6O10PS) C, H; N: calcd, 11.25; found, 10.78.
O-(L-Meth oxytyr osin yl) O-(S-p iva loyl-2-th ioeth yl) 3′-
a zid o-2′,3′-d eoxyth ym id in -5′-yl p h osp h a te, h yd r och lo-
r id e (5b): 0.048 g (94%); Rf 0.47 (MeOH/CH2Cl2 1:9). Anal.
(C27H38N6ClO10PS‚1.25(HCl+H2O)) C, H, N.
O-L-Tyr osin yl O-(S-P iva loyl-2-th ioeth yl) 3′-Azid o-2′,3′-
d eoxyth ym id in -5′-yl P h osp h a te, Hyd r och lor id e (3). Phos-
photriester 4a (0.07 g, 0.086 mmol) was dissolved at 0 °C in a
solution of hydrogen chloride in diethyl ether (4 mL, 30%) and
the mixture stirred at room temperature for 30 min. The
solvent was removed in vacuo and the residue subjected to
reverse-phase C18 column chromatography, eluting with a
linear gradient of MeOH in H2O (0-80%). The collected
product was dissolved in a solution of hydrogen chloride in
dioxane (2 mL, 18%) stirred for 10 min, the solvent evaporated
and the residue lyophilization in dioxane to afford the title
compound 3 (0.04 g, 68%) as a white powder: Rf 0.08 (MeOH/
CH2Cl2 1:4), 0.20 (MeOH/CH2Cl2 1.5:8.5). Anal. (C26H36ClN6O10-
PS) C, N; H: calcd, 5.25; found, 5.67.
Ack n ow led gm en t . This investigation was sup-
ported by grants from Agence Nationale de Recherches
sur le SIDA (ANRS) and Fondation pour la Recherche
Me´dicale (FRM).
Su p p or tin g In for m a tion Ava ila ble: NMR, MS, HPLC,
and UV data of the described compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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