An Efficient Synthesis of a Hydroxyethylamine (HEA) Isostere and Its α-Aminophosphonate and Phosphoramidate Derivatives as Potential Anti-HIV Agents

Article abstract of DOI:10.1002/cmdc.201200271

HIV protease is a promising drug target for AIDS therapy, and several potent HIV-1 protease inhibitors have been reported to date. Although existing inhibitors exhibit high selectivity, they have also been associated with severe side effects and the possi

Full text of DOI:10.1002/cmdc.201200271

MED
DOI: 10.1002/cmdc.201200271
An Efficient Synthesis of a Hydroxyethylamine (HEA)
Isostere and Its a-Aminophosphonate and
Phosphoramidate Derivatives as Potential Anti-HIV Agents
Asish K. Bhattacharya,*[a] Kalpeshkumar C. Rana,[a] Christophe Pannecouque,[b] and
Eric De Clercq[b]
Dedicated to Dr. Arvind A. Natu (IISER-Pune) on the occasion of his 65th birthday
HIV protease is a promising drug target for AIDS therapy, and
several potent HIV-1 protease inhibitors have been reported to
date. Although existing inhibitors exhibit high selectivity, they
have also been associated with severe side effects and the pos-
sible emergence of therapeutic resistance. As HIV protease
cleaves the peptide bond via a tetrahedral intermediate, vari-
ous transition-state models such as hydroxyethylamine (HEA)
have been designed. We therefore pursued an efficient synthe-
sis of an HEA isostere; this was performed with a novel one-
pot reduction–transimination–reduction reaction sequence as
a key step. a-Aminophosphonate and phosphoramidate deriv-
atives of the HEA isostere were designed and synthesized, and
all of the synthesized derivatives were assayed for their anti-
HIV activities against wild-type and mutant HIV strains. Phos-
phoramidate derivative 15a was found to be the most active
of all synthesized compounds against the IIIB and RES056
strains. As phosphonates are known to exhibit physiological
stability, good cell permeability, and other promising pharma-
cokinetic characteristics, our newly synthesized compounds
have the potential as alternatives to existing therapeutics and
diagnostics.
Introduction
Acquired immune deficiency syndrome (AIDS) is a disease of
the human immune system caused by the human immunode-
ficiency virus (HIV). AIDS has become a pandemic which is es-
calating at an alarming rate.[1] UNAIDS and WHO estimate that
25 million people have died due to AIDS since its first report. It
was estimated that about 34 million people were found to be
living with HIV/AIDS, 2.7 million people were newly infected,
and approximately 1.8 million died due to this disease in 2010
alone.[2]
HIV protease has been found to be one of several potential
drug targets for AIDS therapy.[3a] Inhibition of HIV protease
leads to the formation of immature noninfectious virions.[3b]
Several potent HIV-1 protease inhibitors have been report-
ed,[4,5] and there are presently many clinically approved pro-
tease inhibitors (Figure 1). Although the existing inhibitors are
highly selective, they are also reported to possess side effects
such as lipodystrophy, hyperlipidemia, insulin resistance,[1h,6]
and emergence of resistant mutants upon prolonged use.[7]
HIV proteases are very important for the life cycle of HIV,
which possesses a C2-symmetric homodimeric structure that
selectively cleaves the Phe-Pro (Tyr-Pro) moiety of the virus
protein.[8] Inhibition of HIV protease is a well-known strategy
for the development of new anti-HIV agents.[3,4] HIV protease
cleaves the peptide bond via a tetrahedral intermediate,
during which water plays an important role.[9,10] Various inhibi-
tors have been designed based on this transition-state, known
as transition-state analogues.[5] Based on this concept of transi-
tion-state analogues, different substrate models were de-
Figure 1. Clinically approved HIV protease inhibitors.
[a] Dr. A. K. Bhattacharya, Dr. K. C. Rana
Division of Organic Chemistry, CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune-411 008 (India)
E-mail: ak.bhattacharya@ncl.res.in
[b] Prof. Dr. C. Pannecouque, Prof. Dr. E. De Clercq
Rega Institute for Medical Research, Katholieke Universiteit Leuven
Minderbroedersstraat 10, 3000 Leuven (Belgium)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201200271.
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signed. Such substrate models consist of hydroxyethylamine
(HEA) 6, statine 7, norstatine 8, diamino mono-ol 9, diamino
diol 10, diamino alcohol 11, hydroxyethylene 12, and dihy-
droxyethylene isosteres 13 (Figure 2).[8]
amine. The epoxide 17 could then be prepared by the epoxi-
dation of olefin 18 which, in turn, can be obtained from corre-
sponding aldehyde 19 using a Tebbe methylenation reaction
(Scheme 1). On the other hand, a-aminophosphonate deriva-
tives 14a–e and phosphoramidate derivatives 15a–b could be
synthesized from the corresponding amine 20, which could be
obtained from 16 as depicted in Scheme 2.
Scheme 1. Retrosynthesis of HEA isostere 16.
Figure 2. Substrate models for HIV protease inhibitors.
Of these substrate models, hydroxyethylamine (HEA) 6 is an
attractive motif due to its low molecular weight and its use as
the central core of several anti-HIV drugs, such as amprenavir
4 (Figure 1).[5,8] We opined that replacement of the P2 pocket
group of the inhibitor with aminophosphonate/phosphorami-
date could result in more potent inhibitors, as phosphonates
are known to be stable under physiological conditions, do not
react with enzymes like cholinesterase (thus decreasing their
toxicity), show good cell permeability, and increase cellular ac-
cumulation and retention of drug compounds, thus improving
their therapeutic and diagnostic value.[11] Several methods
have been reported for the synthesis of HEA isostere 16;[8]
however, these methods suffer from one or more drawbacks
such as low overall yields, lengthy steps, and use of hazardous
reagents such as lithium metal. In continuation of our interest
in the design and synthesis of aminophosphonates as novel
protease inhibitors,[12] we report herein an efficient synthesis of
16 and its aminophosphonate derivatives 14a–e and phos-
phoramidate derivatives 15a–b (Figure 3), with the expectation
Scheme 2. Retrosynthesis of aminophosphonate 14 and phosphoramidate
15 derivatives of the HEA isostere.
We envisaged phenylalanine 21 as the starting material for
the synthesis of compound 17 (Scheme 3). First, phenylalanine
21 was benzylated and subsequently reduced to dibenzyl-phe-
nylalanol 22, which was oxidized using Swern oxidation condi-
tions to form aldehyde 19.[13] Aldehyde 19 was subjected to
Tebbe methylenation[14] to furnish olefin 18 in 63% yield. Reac-
tion of olefin 18 with m-CPBA did not give the corresponding
epoxide 17, but it furnished a rearranged product which was
Figure 3. Designed aminophosphonate and phosphoramidate derivatives of
the HEA isostere.
that aminophosphonate/phosphoramidate will find its place in
the P2 pocket of the enzyme and, therefore, derivatives 14 and
15 could serve as potent anti-HIV agents.
Results and Discussion
Scheme 3. Reagents and conditions: a) NaOH, K2CO3, H2O, BnBr, reflux, 3 h;
b) LAH, Et2O, 08C, overnight, 60% after two steps; c) (COCl)2, DMSO, CH2Cl2,
ꢀ78!08C, Et3N, 1 h, 98%; d) Tebbe reagent, THF, 08C, 30 min, 63%; e) m-
CPBA, 08C, CH2Cl2.
Retrosynthetically, the synthesis of HEA isostere 16 could be
accomplished by the opening of epoxide 17 with isobutyl
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identified as 23 (60%) by its spectral data. The formation of re-
arranged product 23 could be due to the fact that olefin 18 is
a tertiary amine which undergoes N-oxidation reaction fol-
lowed by a Meisenheimer rearrangement[15] (Scheme 4).
Scheme 4. Meisenheimer rearrangement.
Scheme 7. Reagents and conditions: a) TMSCN, BF3·Et2O, CH2Cl2, ꢀ208C, 2 h,
80%; b) LAH, THF, 08C, 1 h, 60%; c) NiCl2·6H2O, NaBH4, MeOH, 08C, 1 h,
50%.
To access the desired epoxide 17, we decided to change the
protecting group strategy for the amine group. Therefore, we
thought that a carboxybenzyl (Cbz) group could be effective
as a protecting group instead of a dibenzyl group. We began
our synthesis by LAH reduction of phenylalanine 21 to amino
alcohol 24, followed by Cbz protection[16] to furnish compound
25. Compound 25 was then subjected to Swern oxidation to
yield amino aldehyde 26. Unfortunately, reaction of aldehyde
26 with Tebbe reagent[14] resulted in the formation of a com-
plex mixture. This could be attributed to the instability of
amino aldehydes and the reactive nature of the Tebbe reagent
(Scheme 5).
cating that the stereochemistries in compound 27a and 27b
are (S,S) and (R,R), respectively, which is in accordance with
published data.[18] The cyanohydrin 27a, having the desired
stereochemistry, was subjected to LAH reduction at 08C; how-
ever, decyanated alcohol 22 was obtained as a major product
(60%). Finally, synthesis of compound 28 was achieved by the
reduction of cyanohydrin 27a by in situ-generated nickel
boride,[19] albeit in moderate yield. In order to achieve the syn-
thesis of desired isostere 16, two other subsequent reactions
on compound 28, namely imine formation with isobutyralde-
hyde followed by reduction of imine with NaBH4, would be re-
quired. As compound 28 was obtained in 50% yield, and two
further reactions needed to be performed for the ultimate syn-
thesis of isostere 16, this route was found to be not lucrative
enough and, therefore, we decided to develop a one-pot
method.
Scheme 5. Reagents and conditions: a) LAH, THF, 08C!reflux, 73%; b) CBZ-
Cl, Bi(NO3)3·5H2O, MeOH, 30 min, 90%; c) (COCl)2, DMSO, ꢀ78!08C, Et3N,
1 h, 82%; d) Tebbe reagent.
One-pot reduction–transimination–reduction
Hence, we once again changed our synthetic strategy and
postulated that our target compound (HEA isostere 16) could
be synthesized from cyanohydrin 27a which, in turn, can be
accessed from aldehyde 19 (Scheme 6). Aldehyde 19 was sub-
In a one-pot reduction–transimination–reduction approach,
the cyano group is initially reduced by DIBAL-H at ꢀ788C, fol-
lowed by reaction with methanolic ammonium bromide which
converts iminium aluminum complex into the free NꢀH imine.
This primary imine is then converted into a more stable secon-
dary imine by a transimination reaction.[20] Afterward, reduction
of the secondary imine with NaBH4 is carried out in the same
pot to furnish the secondary amine. We decided to carry out
synthesis of isostere 16 following this approach. We began our
synthesis with the TBS protection of cyanohydrin 27a by treat-
ing it with TBSCl to furnish compound 29. The reduction–tran-
simination–reduction reaction was employed on protected cya-
nohydrin 29 (Scheme 8) obtaining amine 30 in good yield
(75%). The TBS group was deprotected with TBAF in THF solu-
tion (1m) to furnish desired isostere 16. Thus, we were success-
ful in developing a one-pot reduction–transimination–reduc-
tion approach for the synthesis of isostere 16. This isostere
was then subjected to N-sulfonylation[4m] with aqueous sodium
carbonate in dichloromethane to afford compound 31 which,
upon benzyl deprotection with Pd(OH)2/C and H2, furnished
free amine 20 (Scheme 9).
Scheme 6. Alternative retrosynthesis of HEA isostere 16.
jected to Lewis acid-catalyzed cyanohydrin formation using
TMSCN and BF3·Et2O to furnish 27a as the major diastereomer
(Scheme 7).[17] The stereochemistries of compounds 27a and
27b were confirmed by their spectral data. In compound 27a,
the proton of CHOH appearing at d=3.98 ppm (d) showed
a coupling constant of 5.4 Hz while that of 27b (d=4.25 ppm,
d) exhibited a higher coupling constant (8.1 Hz), thereby indi-
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Scheme 8. Reagents and conditions: a) TBSCl, Imidazole, CH2Cl2, RT, over-
night, 93%. b) DIBAL-H, Et2O, ꢀ788C, 3 h; c) NH4Br in MeOH; d) isobutyl
amine, 3 h; e) NaBH4, 75% in four steps; f) TBAF, THF, 85%.
Figure 4. ORTEP diagram of compound 36.[22]
Synthesis of a-aminophosphonate and phosphoramidate
derivatives of the HEA isostere
Having accomplished the synthesis of HEA isostere 16 and free
amine 20, we set out on our next aim to synthesize its a-ami-
nophosphonate and phosphoramidate derivatives. We carried
out a Kabachnik–Fields reaction of the amine with piperonal
by following known methods[23] that included catalytic systems
such as TaCl5, InCl3, and Mg(ClO4)2 under various reaction con-
ditions. However, none of the reported methods gave the cor-
responding product 14a. The reactions were limited with
regard to the formation of imine, and unreacted starting mate-
rials (~60%) were recovered even when the reaction was con-
tinued beyond 24 h. We then turned to one of our recently de-
veloped methods for the synthesis of a-aminophosphona-
tes.[12c] When the reaction was repeated in the presence of Am-
berlite-IR120 (acidic) under neat reaction conditions, traces of
product formation were observed after 24 h. We carried out
the same reaction under microwave irradiation, and corre-
sponding product 14a was obtained in good yield within
1 min as an inseparable diastereomeric mixture (Scheme 11).
Scheme 9. Reagents and conditions: a) 4-Methoxysulfonylchloride, CH2Cl2,
Na2CO3(aq), 3 h, 71%; b) Pd(OH)2/C, H2, 1 atm, overnight, 85%.
Confirmation of the stereochemistry of HEA isosteres 16
and 36
The spectral data for HEA isostere 16 were compared with
published values,[21] and were found to be in good agreement
with the reported data. This clearly proved that the stereocen-
ter of the hydroxy group was a-oriented. Moreover, when the
similar sets of reactions were performed on minor diastereo-
mer 27b, as depicted in Scheme 10, compound 36 was ob-
tained as a crystalline solid. X-ray crystal structure analysis[22] of
compound 36 unambiguously proved the b-orientation of the
hydroxy group (Figure 4). This indirectly proves that the hy-
droxy group of isomer 20 is a-oriented.
Scheme 11. Reagents and conditions: a) RCHO, diethyl phosphite, Amberlite-
IR120 (acidic), MWI, 53%.
Most of the catalytic systems reported for the Kabachnik–
Fields reaction use aromatic aldehydes and aromatic amines;
there are very few reports for the reaction of aromatic alde-
hydes and aliphatic amines.[24] Hence, we proposed that Am-
berlite-IR120 under microwave irradiation[12c] would be a good
alternative for the synthesis of a-aminophosphonate deriva-
Scheme 10. Reagents and conditions: a) TBDMSCl, imidazole, CH2Cl2, RT, over-
night, 85%; b) DIBAL-H, Et2O, ꢀ788C, 3 h; c) NH4Br in MeOH; d) isobutyl
amine, 3 h; e) NaBH4, overnight, 78% in four steps; f) TBAF, THF, 81%; (g) 4-
methoxysulfonylchloride, CH2Cl2, Na2CO3(aq), 3 h, 83%; h) Pd(OH)2/C, H2,
1 atm, overnight, 80%.
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Scheme 12. Reagents and conditions: a) Amberlite-IR120 (acidic), MWI.
tives of isostere 16 using Kabachnik–Fields reaction
(Scheme 12).
Scheme 15. Reagents and conditions: a) DEP or DBP, CCl4, K2CO3, CH2Cl2.
Free amine 20 was treated with diverse aldehydes and di-
ethylphosphite under microwave irradiation in the presence of
Amberlite-IR120 as a solid catalyst to furnish corresponding a-
aminophosphonates 14a–e as mixtures of diastereomers
(Scheme 13). However, these diastereomers were found to be
inseparable by column chromatography as well as by prepara-
tive thin layer chromatography. Thus, the diastereomeric ratio
Biological activity
All synthesized a-aminophosphonate and phosphoramidate
derivatives of HEA (14a–e and 41a–e) and (15a–b), respective-
ly, were assayed for biological activity against wild-type HIV-
1 strain IIIB and HIV-2 strain ROD, along with the double
mutant strains RES056 (K103N + Y181C), according to the MTT
method in MT-4 cells.[26] The results of the bioassay of all the
compounds expressed as IC50, CC50, and SI (selectivity index)
values are summarized in Table 1. Drugs currently used in clini-
cal treatment of HIV-1 infection, DDN/DDC and DMP266, were
used as controls.
1
was calculated from H NMR spectral data.
Table 1. Bioassay of our synthesized compounds against HIV-1 in MT-4
cells.
[b]
[c]
Compd
Strain[a]
IC50 [mgmLꢀ1
]
CC50 [mgmLꢀ1
]
SI[d]
<1
14a
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
RES056
ROD
IIIB
RES056
IIIB
>13.20
>13.20
>2.47
>2.47
>14.24
>14.24
>11.52
>11.52
>13.25
>13.25
>13.73
>13.73
>4.94
>4.94
>3.94
>3.94
>13.68
>13.68
>13.93
>13.93
7.77
13.20
13.20
2.47
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
8
14b
14c
14d
14e
41a
41b
41c
41d
41e
15a
Scheme 13. Reagents and conditions: a) RCHO, diethyl phosphite, MWI, Am-
berlite-IR120 (acidic).
2.47
14.24
14.24
11.52
11.52
13.25
13.25
13.73
13.73
4.94
Similarly, a-aminophosphonate derivatives of HEA isostere
41a–e having a b-oriented hydroxy group were also synthe-
sized from amine 36 by employing the above-mentioned
method (Scheme 14). In addition to a-aminophosphonate de-
rivatives, we decided to synthesize phosphoramidate deriva-
tives 15a–b. Amine 20 was subjected to Atherton–Todd[25] re-
action conditions (Scheme 15) with diethylphosphite or dibu-
tylphosphite to furnish the desired phosphoramidate deriva-
tives 15a–b.
4.94
3.94
3.94
13.68
13.68
13.93
13.93
64.50
64.50
64.50
13.08
13.08
0.04
7.40
9
>64.50
>13.08
>13.08
0.37
<1
<1
<1
>55
>41
>1133
>12
15b
DDN/DDC
DMP266
ROD
IIIB
RES056
0.49
0.0018
0.17
0.16
0.0001
0.01
[a] IIIB: wild-type HIV-1; ROD: HIV-2; RES056: double mutant (K103N+
Y181C). [b] IC50: compound concentration required to effect 50% protec-
tion of MT-4 cells against HIV-induced cytotoxicity as determined by MTT
assay. [c] CC50: concentration required to decrease the viability of mock-
infected cells by 50% as determined by MTT assay. [d] Selectivity index
(CC50/IC50).
Scheme 14. Reagents and conditions: a) RCHO, diethyl phosphite, MWI, Am-
berlite-IR120 (acidic).
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gel using EtOAc/petroleum ether (PE) (2:98) as eluent to furnish
olefin 18 as a colorless syrup (205 mg, 63%): Rf =0.65 (EtOAc/PE,
1:9); [a]20D = +17.6 (c=1 in CHCl3); IR (CHCl3): n˜ =3063, 3024,
The results summarized in Table 1 indicate that phosphora-
midate derivative 15a was the most active amongst all the
synthesized compounds against the IIIB and RES056 strains. In-
terestingly, compound 15a was inactive against HIV-2; it was
found to be active against HIV-1 and double mutant strain
RES056 with IC50 values of 7.77 and 7.40 mgmLꢀ1 and selectivity
factors of 8 and 9, respectively. The synthesized a-amino-
phosphonate derivatives of HEA (14a–e and 41a–e) did not
show any significant activity against HIV-1 (IIIB) or HIV-2 (ROD),
with IC50 values greater than the corresponding CC50 values,
rendering SI values less than 1.
2933, 2833, 2802, 1602, 1494, 1454, 1217, 1120 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d=2.75–3.01 (ABX, J=13.6 Hz, J=7.4 Hz, J=
6.2 Hz, 2H), 3.42–3.80 (AB, J=13.9 Hz, 4H), 3.32–3.43 (m, 1H), 5.00
(ddd, J=2.0 Hz, J=1.0 Hz, J=17.2 Hz, 1H), 5.22 (ddd, J=10.4 Hz,
J=0.6 Hz, J=2.0 Hz, 1H), 5.85 (ddd, J=17.2 Hz, J=10.4 Hz, J=
2.3 Hz, 1H), 7.00–7.23 ppm (m, 15H); 13C NMR (50 MHz, CDCl3): d=
38.4, 53.6, 62.2, 118.1, 125.9, 126.8, 128.1, 128.2, 128.6, 129.6, 135.9,
139.7, 140.2 ppm; MS (ESI): m/z 328.2 [M+H]+; Anal. calcd for
C24H25N: C 88.03, H 7.70, N 4.28, found: C 88.15, H 7.77, N 4.23.
(E)-N,N-Dibenzyl-O-(4-phenylbut-2-enyl)hydroxylamine (23): m-
CPBA (46 mg, 0.27 mmol) was added to a solution of alkene 18
(80 mg, 0.244 mmol) in CH2Cl2 (2 mL) at 08C. The reaction mixture
was allowed to stir at room temperature for 1 h. After completion
of the reaction (as assessed by TLC), water (5 mL) was added, and
the aqueous layer was extracted with CH2Cl2 (3ꢁ5 mL). The com-
bined organic extracts were dried over anhydrous Na2SO4 and con-
centrated in vacuo to afford the crude product, which was purified
by flash chromatography using EtOAc/PE (3:97) to furnish pure
product 23 as a colorless syrup (50 mg, 60%): Rf =0.50 (EtOAc/PE,
1:9); IR (CHCl3): n˜ =3065, 3019, 2926, 2910, 1602, 1494, 1454, 1217,
Conclusions
In summary, we have accomplished an efficient synthesis of
the HEA isostere, a substrate model for the transition-state an-
alogue of anti-HIV agents, by developing a novel one-pot re-
duction–transimination–reduction reaction sequence as a key
step. Further, a-aminophosphonate and phosphoramidate de-
rivatives of HEA isostere were designed and synthesized. The
efficacy of all synthesized a-aminophosphonate and phosphor-
amidate derivatives were assayed for their anti-HIV activities
against several strains. Phosphoramidate derivative 15a was
found to be the most active of all the synthesized compounds
against IIIB and RES056 strains.
1030 cmꢀ1 1H NMR (200 MHz, CDCl3): d=3.15 (d, J=6.7 Hz, 2H),
;
3.65 (dd, J=6.4, 6.6 Hz, 2H), 3.77 (s, 4H), 5.11–5.25 (m, 1H), 5.40–
5.54 (m, 1H), 7.00–7.31 ppm (m, 15H); 13C NMR (50 MHz, CDCl3):
d=38.8, 62.9, 74.3, 126.1, 127.1, 127.3, 128.2, 128.4, 128.6, 129.8,
133.5, 137.9, 140.1 ppm; MS (ESI): m/z 344.2 [M+H]+, 366.2 [M+
Na]+; Anal. calcd for C24H25NO: C 83.93, H 7.34, N 4.08, found: C
83.83, H 7.31, N 4.15.
Experimental Section
Hydrocyanation of aldehyde 19: A mixture of aldehyde 19
(1.97 g, 6 mmol), trimethylsilylcyanide (750 mL, 7.2 mmol) and
BF3·Et2O (1 mL, 7.2 mmol) in dry CH2Cl2 (50 mL) was stirred at
ꢀ208C for 2 h. After completion of the reaction (as assessed by
TLC), the reaction mixture was poured into water (50 mL), and the
aqueous phase was extracted with CH2Cl2 (3ꢁ50 mL). The com-
bined organic phases were washed with brine, dried over Na2SO4,
and concentrated in vacuo to yield crude product, which was chro-
matographed on silica gel using EtOAc/PE (5:95) as eluent to fur-
nish pure 27a (2.1 g, 80%) and 27b (0.21 g, 10%) as the major
and minor products, respectively.
Chemistry
General: FT-IR spectra were recorded on an FT-IR-8300 Shimadzu
spectrometer, and microanalyses were carried out on a Carlo–Erba
instrument. NMR spectra were recorded on Bruker ACF200 and
AV200 (200 MHz for H NMR and 50 MHz for 13C NMR) and AV400
1
(400 MHz for 1H NMR and 100 MHz for 13C NMR) spectrometers,
using CDCl3 as solvent. Tetramethylsilane (d=0.00 ppm) served as
an internal standard in 1H NMR and CDCl3 (d=77.0 ppm) in
13C NMR, respectively. Chemical shifts are expressed in parts per
million (ppm). In the case of NMR data for mixtures of diastereo-
mers, the peaks corresponding to one isomer are given. Mass spec-
tra were recorded on an LC–MS/MS-TOF API QSTAR PULSAR spec-
trometer, samples were introduced by an infusion method using
the electrospray ionization (ESI) technique. Optical rotations were
recorded on a JASCO P-1020 polarimeter. All other chemicals were
of analytical grade.
(2S,3S)-3-(Dibenzylamino)-2-hydroxy-4-phenylbutanenitrile
(27a): Colorless syrup (2.1 g, 80%): Rf =0.32 (EtOAc/PE, 1:9);
[a]20D = +48.4 (c=1 in CHCl3); IR (CHCl3): n˜ =3421, 3064, 3020,
2928, 2841, 2401, 1602, 1521, 1494, 1454, 1375, 1215, 1074,
1
1028 cmꢀ1; H NMR (200 MHz, CDCl3): d=2.94–3.01 (m, 1H), 3.18–
3.34 (m, 2H), 3.52 (d, J=13.1 Hz, 2H), 3.98 (d, J=5.4 Hz, 1H), 4.21
(d, J=13.1 Hz, 2H), 7.20–7.41 ppm (m, 15H); 13C NMR (50 MHz,
CDCl3): d=31.4, 54.6, 59.6, 61.1, 119.5, 127.1, 127.9, 128.9, 129.0,
129.1, 129.3, 136.8, 137.8 ppm; MS (ESI): m/z 357.3 [M+H]+, 379.3
[M+Na]+; Anal. calcd for C24H24N2O: C 80.87, H 6.79, N 7.86, found:
C 80.95, H 6.83, N 7.73.
(S)-N,N-Dibenzyl-1-phenylbut-3-en-2-amine (18): A round-bottom
flask equipped with a magnetic stirring bar and oil bubbler was
charged with titanocene dichloride (250 mg, 1.0 mmol) and flushed
with argon, then AlMe3 (2.0m in PhMe, 1 mL) was added dropwise.
The resulting dark red mixture was stirred at room temperature
with initial evolution of CH4 through the bubbler. Stirring was con-
tinued for 3 days. The flask was cooled to 08C, to which was
added a solution of 19 (329 mg, 1 mmol) in THF (4 mL). The reac-
tion was allowed to warm to room temperature, and stirring was
continued for 30 min. After completion of the reaction (as assessed
by TLC), the reaction mixture was diluted with diethyl ether
(10 mL) followed by the slow addition of aq. NaOH (1 mL) until gas
evolution ceased. Then, Na2SO4 was added to the reaction mixture,
it was filtered, and the filtrate was concentrated to give the crude
product, which was purified by column chromatography over silica
(2R,3S)-3-(Dibenzylamino)-2-hydroxy-4-phenylbutanenitrile
(27b): Colorless syrup (0.21 g, 10%): Rf =0.25 (EtOAc/PE, 1:9);
[a]20D = +47.0 (c=1 in CHCl3); IR (CHCl3): n˜ =3400, 3020, 2400,
;
1602, 1521, 1495, 1454, 1375, 1215, 1074, 1028 cmꢀ1 1H NMR
(200 MHz, CDCl3): d=2.95–3.09 (m, 2H), 3.25–3.33 (m, 1H), 3.42–
3.89 (AB, J=13.3 Hz, 4H), 4.25 (d, J=8.1 Hz, 1H), 7.15–7.40 ppm
(m, 15H); 13C NMR (50 MHz, CDCl3): d=32.4, 54.2, 61.8, 62.5, 119.2,
127.1, 127.7, 128.8, 128.9, 129.0, 129.4, 138.0, 138.1 ppm; MS (ESI):
m/z 357.3 [M+H]+, 379.3 [M+Na]+; Anal. calcd for C24H24N2O: C
80.87, H 6.79, N 7.86, found: C 80.93, H 6.59, N 7.75.
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ChemMedChem 0000, 00, 1 – 12
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These are not the final page numbers!

HEA Derivatives as Anti-HIV Agents
MED
(2S,3S)-1-Amino-3-(dibenzylamino)-4-phenylbutan-2-ol
(28):
CDCl3): d=ꢀ4.2, ꢀ3.2, 18.3, 20.7, 20.8, 26.1, 28.4, 32.6, 54.6, 54.7,
58.3, 62.0, 72.2, 125.6, 126.7, 128.1, 128.8, 129.8, 140.3, 142.0 ppm;
MS (ESI): m/z 531.8 [M+H]+, 553.8 [M+Na]+; Anal. calcd for
C34H50N2OSi: C 76.93, H 9.49, N 5.28, found: C 76.79; H 9.60; N 5.33.
NaBH4 (160 mg, 4.2 mmol) was added slowly to a suspension of cy-
anohydrin 27a (150 mg, 0.42 mmol) and NiCl2·6H2O (200 mg,
0.84 mmol) in MeOH (3 mL) at 08C. The reaction mixture was
stirred at room temperature for 1 h. After completion of reaction
(as assessed by TLC), aq. HCl (3n) was added until the black pre-
cipitate dissolved. The reaction mixture was evaporated to dryness
under reduced pressure. The residue was dissolved in water and
was made alkaline using aq. NaOH (1n) and the product was ex-
tracted with EtOAc (3ꢁ10 mL), dried over Na2SO4, and concentrat-
ed in vacuo to give the crude product, which was chromatograph-
ed over silica gel using EtOAc as eluent to furnish product 28 as
a colorless syrup (75 mg, 50%): Rf =0.54 (EtOAc/PE, 3:7); [a]20D = +
6.55 (c=1.1 in CHCl3); IR (CHCl3): n˜ =3350, 3019, 1602, 1495, 1453,
(2R,3S)-3-(Dibenzylamino)-1-(isobutylamino)-4-phenylbutan-2-ol
(16): TBAF in THF (1 mL, 1.0 mmol) was added to the solution of
30 (150 mg, 0.28 mmol) in THF (1 mL). The reaction mixture was
stirred at room temperature. After completion of the reaction (as
assessed by TLC), THF was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography
using EtOAc/PE (2:3) as eluent to obtain 16 as a colorless syrup
(100 mg, 85%): Rf =0.20 (EtOAc/PE, 1:9); [a]20D = +4.71 (c=1.05 in
CHCl3); IR (CHCl3): n˜ =3371, 3019, 2960, 2872, 2806, 1602, 1494,
1
1454, 1215 cmꢀ1; H NMR (200 MHz, CDCl3): d=0.86 (d, J=6.7 Hz,
1
1216 cmꢀ1; H NMR (200 MHz, CDCl3): d=2.43–2.55 (m, 1H), 2.67–
3H), 0.88 (d, J=6.6 Hz, 3H), 1.62–1.69 (m, 1H), 2.28–2.36 (m, 1H),
2.37–2.42 (m, 1H), 2.46–2.52 (m, 1H), 2.74–2.90 (m, 2H), 2.98–3.04
(m, 2H), 3.24 (bs, 2H), 3.57–3.73 (AB, J=13.9 Hz, 4H), 3.86–3.91 (m,
1H), 7.08–7.32 ppm (m, 15H); 13C NMR (50 MHz, CDCl3): d=20.5,
28.1, 32.7, 53.0, 54.6, 57.2, 62.3, 68.6, 125.8, 126.9, 128.2, 128.3,
128.9, 129.7, 139.9, 141.5 ppm; MS (ESI): m/z 417.5 [M+H]+, 439.5
[M+Na]+; Anal. calcd for C28H36N2O: C 80.73, H 8.71, N 6.72, found:
C 80.79, H 8.75, N 6.77.
2.84 (m, 2H), 2.95–3.15 (m, 1H), 3.35–3.88 (m, 4H), 3.46 (bs, 2H),
3.96–4.18 (m, 2H), 7.15–7.34 ppm (m, 15H); 13C NMR (100 MHz,
CDCl3): d=32.7, 44.9, 54.6, 61.7, 71.8, 125.8, 127.0, 128.3, 128.9,
129.6, 139.9, 141.6 ppm; MS (ESI): m/z 361.2 [M+H]+; Anal. calcd
for C24H28N2O: C 79.96, H 7.83, N 7.77, found: C 80.06, H 7.95, N
7.68.
(2S,3S)-2-(tert-Butyldimethylsilyloxy)-3-(dibenzylamino)-4-phe-
nylbutanenitrile (29): TBSCl (13 g, 85 mmol) was added to a solu-
tion of cyanohydrin 27a (20 g, 57 mmol) and imidazole (10 g,
143 mmol) in CH2Cl2 (100 mL) at 08C, and the reaction mixture was
stirred overnight at room temperature. After completion of the re-
action (as assessed by TLC), water (100 mL) was added, and the
product was extracted with CH2Cl2 (3ꢁ100 mL). The combined
CH2Cl2 layers were dried over Na2SO4 and evaporated to dryness
under reduced pressure to give the crude product, which was
chromatographed over silica gel using EtOAc/PE (5:95) as eluent to
furnish product 29 as a colorless syrup (25 g, 93%): Rf =0.53
(EtOAc/PE, 1:4); [a]20D =ꢀ34.23 (c=0.95 in CHCl3); IR (CHCl3): n˜ =
N-((2R,3S)-3-(Dibenzylamino)-2-hydroxy-4-phenylbutyl)-N-isobu-
tyl-4-methoxybenzenesulfonamide (31): A solution of Na2CO3
(81 mg, 0.77 mmol) in water (500 mL) was added to a solution of
16 (200 mg, 0.48 mmol) in CH2Cl2 (2 mL) at 08C. A solution of p-
methoxysulfonyl chloride (99 mg, 0.48 mmol) in CH2Cl2 (1 mL) was
added to this stirred solution at 08C. The reaction was allowed to
warm to room temperature. After completion of the reaction (as
assessed by TLC), water (5 mL) was added, and the product was ex-
tracted with CH2Cl2 (3ꢁ10 mL). The combined organic layers were
washed with brine (10 mL), dried over anhydrous Na2SO4, and con-
centrated in vacuo to obtain the crude product, which was chro-
matographed over silica gel using EtOAc/PE (1:9) as eluent to give
31 as a colorless syrup (200 mg, 71%): Rf =0.60 (EtOAc/PE, 1:3);
[a]20D =ꢀ1.44 (c=1.0 in MeOH); IR (CHCl3): n˜ =3479, 3019, 2966,
3063, 2955, 2858, 2357, 1602, 1494, 1469, 1369, 1263, 1122 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d=0.00 (s, 3H), 0.06 (s, 3H), 0.78 (s, 9H),
2.87–2.91 (m, 2H), 3.22–3.32 (m, 1H), 3.51–3.67 (m, 4H) 4.36 (d, J=
5.8 Hz, 1H), 7.03–7.16 ppm (m, 15H); 13C NMR (50 MHz, CDCl3): d=
ꢀ5.2, ꢀ5.0, 18.1, 25.7, 33.2, 55.0, 63.3, 63.6, 120.0, 126.5, 127.2,
128.3, 128.5, 128.8, 129.6, 139.0, 139.2 ppm; MS (ESI): m/z 471.9
[M+H]+, 493.9 [M+Na]+; Anal. calcd for C30H38N2OSi: C 76.55, H
8.14, N 5.95, found: C 76.65, H 8.20, N 5.86.
1
1597, 1496, 1215, 1153, 1028 cmꢀ1; H NMR (200 MHz, CDCl3): d=
0.84 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 1.63 (bs, 1H), 1.77–
1.82 (m, 1H), 2.65–2.95 (m, 4H), 2.99–3.08 (m, 3H), 3.60–3.76 (AB,
J=13.9 Hz, 4H), 3.87 (s, 3H), 4.07–4.17 (m, 1H), 6.92 (d, J=8.9 Hz,
2H), 7.12–7.31 (m, 15H), 7.58 ppm (d, J=8.9 Hz, 2H); 13C NMR
(50 MHz, CDCl3): d=19.9, 20.2, 27.3, 32.1, 54.6, 55.5, 55.6, 58.8,
62.4, 70.6, 114.2, 125.9, 126.9, 128.2, 128.3, 128.7, 129.5, 129.8,
130.6, 139.9, 141.0, 162.9 ppm; MS (ESI): m/z 587.5 [M+H]+, 589.5
[M+Na]+, 609.5 [M+K]+; Anal. calcd for C35H42N2O4S: C 71.64, H
7.21, N 4.77, found: C 71.74, H 7.35, N 4.83.
(2S,3S)-2-(tert-Butyldimethylsilyloxy)-3-(dibenzylamino)-4-phe-
nylbutanenitrile (30): A 1m solution of DIBAL-H in hexane (2.5 mL,
2.5 mmol) was added to a cooled solution (ꢀ788C) of cyanohydrin
29 (470 mg, 1 mmol) in dry ether (8 mL). After stirring at ꢀ788C for
3 h, NH4Br (240 mg) in dry MeOH (4 mL) was added. The cooling
bath was removed, isobutyl amine (500 mL, 5 mmol) was added,
and stirring was continued for another 3 h at room temperature.
The reaction mixture was cooled in an ice bath, and NaBH4 (74 mg,
2 mmol) was added in three portions, then the mixture was stirred
overnight at room temperature. Water (20 mL) was added, and the
product was extracted with diethyl ether (3ꢁ25 mL). The com-
bined ether layers were dried over anhydrous Na2SO4 and concen-
trated to furnish the crude product, which was chromatographed
using EtOAc/PE (5:95) to afford product 30 as a colorless syrup
(398 mg, 75%): Rf =0.40 (EtOAc/PE, 1:9); [a]20D =ꢀ10.95 (c=1.0 in
CHCl3); IR (CHCl3): n˜ =3063, 3018, 2955, 2856, 1602, 1494, 1454,
N-((2R,3S)-3-Amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-me-
thoxybenzenesulfonamide (20):
A mixture of 31 (500 mg,
0.85 mmol) and a catalytic amount of Pd(OH)2 in MeOH (5 mL)
were subjected to hydrogenation at 1 atm for 24 h at room tem-
perature. The reaction mixture was filtered through Celite, and the
filtrate was concentrated in vacuo. The residue was purified by
silica gel column chromatography using a mixture of PE/EtOAc
(3:7) to furnish 20 as a colorless syrup (293 mg, 85%): Rf =0.10
(EtOAc/PE, 1:3); [a]20D = +16.28 (c=0.90 in CHCl3); IR (CHCl3): n˜ =
1
3479, 3018, 2968, 1597, 1496, 1334, 1261, 1215, 1153 cmꢀ1; H NMR
(200 MHz, CDCl3): d=0.88 (d, J=6.7 Hz, 3H), 0.92 (d, J=6.6 Hz,
3H), 1.82–1.96 (m, 1H), 2.48–2.54 (m, 1H), 2.81–3.03 (m, 3H), 3.07–
3.35 (m, 3H), 3.73–3.76 (m, 1H), 3.86 (s, 3H), 6.98 (d, J=8.9 Hz,
2H), 7.19–7.32 (m, 5H), 7.75 ppm (d, J=8.9 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=19.9, 20.2, 39.1, 52.6, 55.6, 55.7, 58.5, 73.1,
114.3, 126.4, 128.6, 129.3, 129.5, 130.3, 138.9, 162.9 ppm; MS (ESI):
1
1361, 1255, 1215, 1120 cmꢀ1; H NMR (200 MHz, CDCl3): d=0.00 (s,
3H), 0.01 (s, 3H), 0.67 (d, J=6.6 Hz, 3H), 0.69 (d, J=6.7 Hz, 3H),
0.80 (s, 9H), 1.32–1.52 (m, 1H), 2.03–2.21 (m, 2H), 2.43–2.48 (m,
2H), 2.68–2.89 (m, 2H), 3.01–3.09 (m, 1H), 3.47–3.65 (AB, J=8.2 Hz,
4H), 3.95–4.02 (m, 1H), 7.01–7.12 ppm (m, 15H); 13C NMR (50 MHz,
ChemMedChem 0000, 00, 1 – 12
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. K. Bhattacharya et al.
MED
m/z 407.4 [M+H]+, 429.4 [M+Na]+; Anal. calcd for C21H30N2O4S: C
62.04, H 7.44, N 6.89, found: C 62.09, H 7.53, N, 6.79.
N-((2S,3S)-3-Amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-me-
thoxybenzenesulfonamide (36): Title compound 36 was prepared
starting from the compound 35, as per the procedure outlined for
the preparation of 20, as a colorless solid (80%): Rf =0.10 (EtOAc/
PE, 1:3); mp: 148–1498C; [a]20D =ꢀ3.84 (c=1.0 in CHCl3); IR
(CHCl3): n˜ =3396, 3018, 2969, 1597, 1496, 1334, 1261, 1217,
(2R,3S)-2-(tert-Butyldimethylsilyloxy)-3-(dibenzylamino)-4-phe-
nylbutanenitrile (32): Title compound 32 was prepared starting
from cyanohydrin 27b, as per the procedure outlined for the prep-
aration of protected cyanohydrin 29, as a colorless syrup (85%):
Rf =0.45 (EtOAc/PE, 1:4); [a]20D =ꢀ13.9 (c=1.0 in CHCl3); IR (CHCl3):
n˜ =3021, 2959, 2931, 2859, 2401, 1602, 1471, 1495, 1454, 1364,
1155 cmꢀ1 1H NMR (200 MHz, CDCl3): d=0.78 (d, J=6.7 Hz, 3H),
;
0.80 (d, J=6.6 Hz, 3H), 1.61–1.75 (m, 1H), 2.37 (bs, 3H), 2.67–2.74
(m, 2H), 2.84–2.96 (m, 3H), 3.25–3.32 (m, 2H), 3.57–3.64 (m, 1H),
3.85 (s, 3H), 6.96 (d, J=8.8 Hz, 2H), 7.20–7.30 (m, 5H), 7.72 ppm (d,
J=8.8 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=19.9, 20.1, 27.4, 40.6,
52.7, 53.5, 55.6, 58.7, 70.1, 114.3, 126.5, 128.6, 129.4, 130.4, 138.6,
162.9 ppm; MS (ESI): m/z 407.4 [M+H]+, 429.4 [M+Na]+; Anal.
calcd for C21H30N2O4S: C 62.04, H 7.44, N 6.89, found: C 62.15, H
7.52, N 6.73.
1
1257, 1216, 1108 cmꢀ1; H NMR (200 MHz, CDCl3): d=0.00 (s, 3H),
0.13 (s, 3H), 0.85 (s, 9H), 2.95–3.10 (m, 3H), 3.53–3.68 (m, 3H),
4.05–4.12 (m, 1H), 4.37–4.38 (m, 1H), 7.08–7.35 ppm (m, 15H);
13C NMR (50 MHz, CDCl3): d=ꢀ5.4, ꢀ5.1, 18.1, 25.6, 30.8, 55.3, 62,4,
64.7, 119.8, 127.1, 128.3, 128.6, 128.8, 128.9, 129.3, 138.9,
139.3 ppm; MS (ESI): m/z 471.9 [M+H]+, 493.9 [M+Na]+, 509.8
[M+K]+; Anal. calcd for C30H38N2OSi: C 76.55, H 8.14, N 5.95,
found: C 76.49, H 8.28, N 6.10.
General experimental procedure for the synthesis of a-amino-
phosphonates: The corresponding aldehyde (1 mmol), amine 20
or 36 (1 mmol), diethylphosphite (1 mmol), and Amberlite-IR120
(100 mg) were combined in a Pyrex test tube and exposed to mi-
crowave irradiation (Kenstar OM-9918C; 2450 MHz, 2350 W). After
completion of the reaction (as assessed by TLC), the reaction mix-
ture was cooled, and CH2Cl2 (25 mL) was added. The catalyst was
removed from the reaction mixture by filtration, and the filtrate
was concentrated under vacuum. The residue was chromatograph-
ed over silica gel column (100–200 mesh) and eluted with PE/
EtOAc (2:3 to 3:2) to afford the corresponding pure a-amino-
phosphonates.
(2R,3S)-2-(tert-Butyldimethylsilyloxy)-3-(dibenzylamino)-4-phe-
nylbutanenitrile (33): Title compound 33 was prepared starting
from the protected cyanohydrin 32, as per the procedure outlined
for the preparation of compound 30, as a colorless syrup (78%):
Rf =0.35 (EtOAc/PE, 1:9); [a]20D = +6.79 (c=1.2 in CHCl3); IR
1
(CHCl3): n˜ =3020, 2955, 1602, 1495, 1454, 1362, 1216 cmꢀ1; H NMR
(200 MHz, CDCl3): d=ꢀ0.06 (s, 3H), 0.00 (s, 3H), 0.66 (t, J=6.8,
7.2 Hz, 6H), 0.84 (s, 9H), 1.29–1.36 (m, 1H), 1.87–2.10 (m, 2H),
2.45–2.54 (m, 1H), 2.91–3.01 (m, 3H), 3.07–3.15 (m, 1H), 3.39 (d,
J=13.4 Hz, 2H), 3.66–3.74 (m, 1H), 4.11 (d, J=13.4 Hz, 2H), 7.18–
7.28 ppm (m, 15H); 13C NMR (50 MHz, CDCl3): d=ꢀ4.6, ꢀ3.9, 18.2,
20.6, 20.7, 26.1, 28.5, 30.8, 52.7, 55.9, 57.3, 59.9, 73.2, 125.9, 126.8,
128.2, 128.4, 129.2, 129.4, 140.8, 141.2 ppm; MS (ESI): m/z 531.8
[M+H]+, 553.8 [M+Na]+; Anal. calcd for C34H50N2OSi: C 76.93, H
9.49, N 5.28, found: C 76.85, H 9.54, N 5.24.
Diethyl (S)-benzo[d][1,3]dioxol-5-yl-((2S,3R)-3-hydroxy-4-(N-iso-
butyl-4-methoxyphenylsulfonamido)-1-phenylbutan-2-ylamino)-
methylphosphonate (14a): Product was isolated as a 1:5 diaste-
reomeric mixture; only peaks corresponding to the major isomer
are given. Colorless syrup (53%): Rf =0.70 (EtOAc); IR (CHCl3): n˜ =
1
3340, 3022, 2400, 1598, 1494, 1440, 1300, 1210, 1150 cmꢀ1; H NMR
(2S,3S)-3-(Dibenzylamino)-1-(isobutylamino)-4-phenylbutan-2-ol
(34): Title compound 34 was prepared starting from the com-
pound 33, as per the procedure outlined for the preparation of
compound 16, as a colorless syrup (81%): Rf =0.15 (EtOAc/PE, 1:9);
[a]20D = +8.88 (c=0.90 in CHCl3); IR (CHCl3): n˜ =3683, 3338, 3019,
(400 MHz, CDCl3): d=0.83 (d, J=6.5 Hz, 3H), 0.85 (d, J=6.8 Hz,
3
3
3H), 1.14 (t, JPH =7.0 Hz, 3H), 1.24 (t, JPH =7.3 Hz, 3H), 1.69–1.76
(m, 1H), 2.70–2.75 (m, 1H), 2.81–2.82 (m, 2H), 2.89–2.91 (m, 1H),
2.93–2.97 (m, 1H), 3.07–3.22 (m 2H), 3.51–3.55 (m, 1H), 3.71–3.98
2
(m, 4H), 3.89 (s, 3H), 3.96 (d, JPH =19.6 Hz, 1H), 5.97 (s, 2H), 6.73–
1
2958, 1602, 1521, 1495, 1454, 1216 cmꢀ1; H NMR (200 MHz, CDCl3):
6.74 (m, 2H), 6.85 (m, 1H), 6.99 (d, J=9.0 Hz, 2H), 7.23–7.34 (m,
5H), 7.68 ppm (d, J=9.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=
16.3 (d, 3JPC =5.9 Hz), 16.4 (d, 3JPC =5.9 Hz), 19.8, 20.1, 27.2, 35.1,
d=0.82 (d, J=6.7 Hz, 6H), 1.56–1.62 (m, 1H), 2.12–2.46 (m, 4H),
2.76–3.12 (m, 3H), 3.40 (d, J=13.4 Hz, 2H), 3.64–3.68 (m, 1H), 3.99
(d, J=13.4 Hz, 2H), 7.14–7.34 ppm (m, 15H); 13C NMR (50 MHz,
CDCl3): d=20.6, 28.5, 31.8, 53.4, 54.4, 57.9, 61.8, 69.7, 126.2, 127.2,
128.4, 128.5, 129.1, 129.4, 139.9, 140.4 ppm; MS (ESI): m/z 417.5
[M+H]+, 439.5 [M+Na]+; Anal. calcd for C28H36N2O: C 80.73, H
8.71, N 6.72, found: C 80.81, H 8.65, N 6.81.
1
3
52.8, 55.6, 58.3 (d, JPC =152.6 Hz), 58.3, 59.2 (d, JPC =13.9 Hz), 62.5
2
2
(d, JPC =7.3 Hz), 62.9 (d, JPC =7.3 Hz), 70.6, 101.1, 108.1, 109.0 (d,
3JPC =5.9 Hz), 114.2, 122.6 (d, 3JPC =7.3 Hz), 126.5, 128.5, 129.4,
129.6, 129.7, 130.4, 137.9, 147.4, 147.8, 162.8 ppm; 31P NMR
(161 MHz, CDCl3): d=23.57 ppm; MS (ESI): m/z 699.5 [M+Na]+;
Anal. calcd for C33H45N2O9PS: C 58.57, H 6.70, N 4.14, found: C
58.69, H 6.81, N 4.21.
N-((2S,3S)-3-(Dibenzylamino)-2-hydroxy-4-phenylbutyl)-N-isobu-
tyl-4-methoxybenzenesulfonamide (35): Title compound 35 was
prepared starting from the compound 34, as per the procedure
outlined for the preparation of compound 31, as a colorless syrup
(83%): Rf =0.45 (EtOAc/PE, 1:3); [a]20D = +5.0 (c=1.0 in CHCl3); IR
Diethyl ((2S,3R)-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfo-
namido)-1-phenylbutan-2-ylamino)(p-tolyl) methylphosphonate
(14b): Product was isolated as a 1:4 diastereomeric mixture; only
peaks corresponding to the major isomer are given. Colorless
syrup (40%): Rf =0.70 (EtOAc); IR (CHCl3): n˜ =3351, 3019, 1598,
(CHCl3): n˜ =3515, 3019, 2966, 1598, 1496, 1454, 1259, 1216 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d=0.68 (d, J=6.2 Hz, 6H), 1.40–1.58 (m,
1H), 2.53–2.69 (m, 3H), 2.80–2.91 (m, 1H), 2.96–3.15 (m, 2H), 3.21–
3.33 (m, 1H), 3.41 (d, J=13.4 Hz, 2H), 3.60–3.66 (m, 1H), 3.74 (bs,
1H), 3.87 (s, 3H), 4.09 (d, J=13.4 Hz, 2H), 6.93 (d, J=9.0 Hz, 2H),
7.21–7.32 (m, 15H), 7.64 ppm (d, J=9.0 Hz, 2H); 13C NMR (50 MHz,
CDCl3): d=19.8, 20.0, 27.0, 30.8, 54.8, 55.0, 55.6, 57.9, 61.9, 70.0,
114.1, 126.1, 127.1, 128.3, 128.6, 129.1, 129.3, 129.4, 131.0, 139.7,
140.2, 162.7 ppm; MS (ESI): m/z 587.5 [M+H]+, 589.5 [M+Na]+,
609.5 [M+K]+; Anal. calcd for C35H42N2O4S: C 71.64, H 7.21, N 4.77,
found: C 71.76, H 7.28, N 4.86.
1
1513, 1497, 1412, 1215, 1155, 1030 cmꢀ1; H NMR (200 MHz, CDCl3):
3
d=0.89 (d, J=6.5 Hz, 3H), 0.90 (d, J=6.4 Hz, 3H), 1.08 (t, JPH
=
7.0 Hz, 3H), 1.27 (t, 3JPH =7.3 Hz, 3H), 1.88–1.95 (m, 1H), 2.31 (s,
3H), 2.47–2.53 (m, 1H), 2.76–2.82 (m, 2H), 2.89–3.06 (m, 2H), 3.11–
3.16 (m, 1H), 3.32–3.36 (m, 1H), 3.63–3.71 (m, 1H), 3.84–4.06 (m,
4H), 3.89 (s, 3H), 3.99 (d, 2JPH =23.1 Hz, 1H), 6.64–6.67 (m, 2H),
6.93–7.06 (m, 6H), 7.25–7.28 (m, 3H), 7.75 ppm (d, J=8.9 Hz, 2H);
3
3
13C NMR (100 MHz, CDCl3): d=16.2 (d, JPC =5.9 Hz), 16.4 (d, JPC
=
5.9 Hz), 20.0, 20.1, 27.1, 34.8, 51.8, 55.6, 57.2 (d, 1JPC =158.5 Hz),
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HEA Derivatives as Anti-HIV Agents
57.9, 58.4 (d, 3JPC =15.4 Hz), 62.4 (d, 2JPC =7.3 Hz), 62.9 (d, JPC
6.6 Hz), 69.7, 114.2, 126.6, 128.0 (d, 3JPC =5.9 Hz), 128.6, 129.0,
129.4, 129.4, 131.0, 131.9, 137.4, 137.9, 162.8 ppm; 31P NMR
(161 MHz, CDCl3): d=23.55 ppm; MS (ESI): m/z 647.9 [M+H]+;
Anal. calcd for C33H47N2O7PS: C 61.28, H 7.32, N 4.33, found: C
61.37, H 7.38, N 4.26.
MED
2
=
31P NMR (202 MHz, CDCl3): d=23.70 ppm; MS (ESI): m/z 633.3 [M+
H]+; Anal. calcd for C32H45N2O7PS: C 60.74, H 7.17, N 4.43, found: C
60.79, H 7.24, N 4.35.
Diethyl benzo[d][1,3]dioxol-5-yl((2S,3S)-3-hydroxy-4-(N-isobutyl-
4-methoxyphenylsulfonamido)-1-phenylbutan-2-ylamino)me-
thylphosphonate (41a): Product was isolated as a 2:3 diastereo-
meric mixture; only peaks corresponding to the major isomer are
given. Colorless syrup (52%): Rf =0.60 (EtOAc); IR (CHCl3): n˜ =3346,
3019, 1597, 1497, 1442, 1303, 1216, 1154 cmꢀ1; H NMR (400 MHz,
CDCl3): d=0.71 (d, J=6.8 Hz, 3H), 0.74 (d, J=6.8 Hz, 3H), 1.09–1.32
(m, 6H), 1.45–1.78 (m, 1H), 2.39–2.65 (m, 2H), 2.73–2.85 (m, 3H),
2.89–3.06 (m, 1H), 3.35–3.41 (m, 1H), 3.56–3.77 (m, 1H), 3.89 (s,
Diethyl ((2S,3R)-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfo-
namido)-1-phenylbutan-2-ylamino)(4-nitrophenyl)methyl-
1
phosphonate (14c): Product was isolated as a 1:4 diastereomeric
mixture; only peaks corresponding to the major isomer are given.
Colorless syrup (38%): Rf =0.60 (EtOAc); IR (CHCl3): n˜ =3350, 3019,
2923, 1604, 1523, 1495, 1456, 1397, 1348, 1217, 1156, 1081,
1030 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=0.82 (d, J=6.6 Hz, 3H),
3H), 3.93–4.15 (m, 5H), 5.97 (s, 2H), 6.51–7.28 (m, 10H), 7.69 ppm
3
0.86 (d, J=6.6 Hz, 3H), 1.14 (t, 3JPH =7.2 Hz, 3H), 1.22 (t, JPH
=
(d, J=8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=16.4 (d, JPC
=
3
5.9 Hz), 19.7, 20.0, 27.2, 36.1, 53.9, 55.6, 57.8 (d, 1JPC =159.9 Hz),
7.2 Hz, 3H), 1.65–1.70 (m, 1H), 2.72–2.78 (m, 2H), 2.82–2.83 (m,
1H), 2.94–2.97 (m, 2H), 3.06–3.13 (m, 2H), 3.47–3.65 (m, 1H), 3.77–
58.2, 58.5 (d, 3JPC =7.3 Hz), 62.9 (d, 2JPC =7.3 Hz), 62.6 (d, JPC
=
2
2
7.3 Hz), 69.5, 101.1, 108.0, 109.2 (d, 3JPC =5.5 Hz), 114.2, 122.2 (d,
3JPC =8.8 Hz), 126.5, 128.5, 129.4, 129.5, 129.7, 130.4, 138.0, 147.4,
147.7, 162.8 ppm; 31P NMR (202 MHz, CDCl3): d=23.70 ppm; MS
(ESI): m/z 677.6 [M+H]+, 699.6 [M+Na]+; Anal. calcd for
C33H45N2O9PS: C 58.57c H 6.70, N 4.14, found: C 58.64, H 6.79, N
4.27.
3.98 (m, 4H), 3.91 (s, 3H), 4.22 (d, JPH =21.7 Hz, 1H), 6.98 (d, J=
8.8 Hz, 2H); 7.21–7.34 (m, 5H), 7.46- 7.48 (m, 2H), 7.61 (d, J=
8.8 Hz, 2H), 8.18 ppm (d, J=8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3):
3
3
d=16.3 (d, JPC =5.1 Hz), 16.4 (d, JPC =5.1 Hz), 19.8, 20.1, 27.2, 36.0,
1
3
52.4, 55.6, 58.3 (d, JPC =146.7 Hz), 58.6, 59.9 (d, JPC =11.7 Hz), 62.9
(d, 2JPC =6.6 Hz), 63.1 (d, 2JPC =6.6 Hz), 71.4, 114.3, 123.4, 126.8,
128.7, 129.4, 129.4, 129.6, 129.9, 137.8, 144.5, 147.5, 163.0 ppm;
31P NMR (161 MHz, CDCl3): d=21.91 ppm; MS (ESI): m/z 700.6 [M+
Na]+; Anal. calcd for C32H44N3O9PS: C 56.71, H 6.54. N 6.20, found:
C 56.83, H 6.62, N 6.36.
Diethyl ((2S,3S)-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfo-
namido)-1-phenylbutan-2-ylamino)(p-tolyl)methylphosphonate
(41b): Product was isolated as a 3:2 diastereomeric mixture; only
peaks corresponding to the major isomer are given. Colorless
syrup (78%): Rf =0.65 (EtOAc); IR (CHCl3): n˜ =3436, 3019, 1598,
Diethyl 1-((2S,3R)-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsul-
fonamido)-1-phenylbutan-2-ylamino)-2-methylpropylphospho-
nate (14d): Product was isolated as a 1:4 diastereomeric mixture;
only peaks corresponding to the major isomer are given. Colorless
syrup (76%): Rf =0.20 (EtOAc/PE, 1:1); IR (CHCl3): n˜ =3349, 3019,
2966, 2873, 1598, 1579, 1497, 1465, 1391, 1337, 1260, 1216, 1154,
1497, 1335, 1260, 1215, 1154 cmꢀ1; H NMR (200 MHz, CDCl3): d=
1
0.67 (d, J=5.7 Hz, 3H), 0.71 (d, J=5.7 Hz, 3H), 1.16–1.32 (m, 6H),
1.40–1.75 (m, 1H), 2.33 (s, 3H), 2.39–2.70 (m 2H), 2.76–2.87 (m,
3H), 2.94–3.11 (m, 1H), 3.28–3.39 (m, 1H), 3.50–3.70 (m, 1H), 3.88
(s, 3H), 3.83–4.20 (m, 5H), 6.91–7.26 (m, 11H), 7.67 ppm (d, J=
9.1 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=16.5 (d, 3JPC =5.9 Hz),
19.7, 20.1, 21.2, 27.1, 36.1, 53.9, 55.6, 57.8 (d, JPC =151.8 Hz), 58.1,
58.5, 58.8, 62.6 (d, 2JPC =7.3 Hz), 63.0 (d, JPC =7.3 Hz), 69.4, 114.2,
126.3, 128.2, 128.5, 128.9, 129.0, 129.2, 130.5, 132.6, 137.7, 138.8,
162.8 ppm; 31P NMR (202 MHz, CDCl3): d=23.90 ppm; MS (ESI): m/z
669.6 [M+Na]+; Anal. calcd for C33H47N2O7PS: C 61.28, H 7.32, N
4.33, found: C 61.39, H 7.47, N 4.26.
1
1093, 1028 cmꢀ1; H NMR (400 MHz, CDCl3): d=0.59 (d, J=6.8 Hz,
1
3H), 0.60 (d, J=6.8 Hz, 3H), 0.90 (d, J=6.5 Hz, 3H), 0.95 (d, J=
6.5 Hz, 3H), 1.28–1.33 (m, 6H), 1.77–1.83 (m, 1H), 2.03–2.10 (m,
1H), 2.53–2.61 (m, 2H), 2.82–3.04 (m, 4H), 3.17–3.23 (m, 1H), 3.47–
3.63 (m, 1H), 3.82–3.84 (m, 1H), 3.86 (s, 3H), 3.93–4.18 (m, 4H),
6.98 (d, J=8.8 Hz, 2H), 7.23–7.34 (m, 5H), 7.78 ppm (d, J=8.8 Hz,
2
2H); 13C NMR (100 MHz, CDCl3): d=16.4 (d, 3JPC =5.9 Hz), 16.6 (d,
2
3JPC =5.9 Hz), 17.3 (d, 3JPC =2.9 Hz), 20.0, 20.1, 26.9, 29.5 (d, JPC
=
=
1
2
Diethyl ((2S,3S)-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfo-
namido)-1-phenylbutan-2-ylamino)(4-nitrophenyl)methyl-
phosphonate (41c): Product was isolated as a 3:2 diastereomeric
mixture; only peaks corresponding to the major isomer are given.
Colorless syrup (56%): Rf =0.56 (EtOAc); IR (CHCl3): n˜ =3463, 3019,
1597, 1523, 1348, 1260, 1216, 1155 cmꢀ1; H NMR (200 MHz, CDCl3):
3.7 Hz), 34.4, 51.1, 55.5, 57.2, 57.7 (d, JPC =162.1 Hz), 61.6 (d, JPC
8.1 Hz), 62.6 (d, 2JPC =10.3 Hz), 63.2 (d, 2JPC =7.3 Hz), 69.4, 114.2,
126.7, 128.7, 129.3, 129.4, 131.6, 138.6, 162.7 ppm; 31P NMR
(161 MHz, CDCl3): d=27.36 ppm; MS (ESI): m/z 621.5 [M+Na]+;
Anal. calcd for C29H47N32O7PS: C 58.17, H 7.91, N 4.68, found: C
58.28, H 7.98, N 4.77.
1
d=0.69 (m, 6H), 1.05–1.35 (m, 6H), 1.54–1.85 (m, 1H), 2.26–2.69
Diethyl ((2S,3R)-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfo-
namido)-1-phenylbutan-2-ylamino)(phenyl)methylphosphonate
(14e): Product isolated as a 1:3 diastereomeric mixture; only peaks
corresponding to the major isomer are given. Colorless syrup
(40%): Rf =0.70 (EtOAc); IR (CHCl3): n˜ =3430, 3019, 1598, 1497,
(m, 2H), 2.75–2.88 (m, 3H), 2.91–3.03 (m, 1H), 3.26–3.44 (m, 1H),
2
3.57–3.83 (m, 1H), 3.89 (s, 3H), 3.93–4.25 (m, 4H), 4.30 (d, JPH
=
21.3 Hz, 1H), 6.92–7.29 (m, 8H), 7.50–7.56 (m, 1H), 7.67 (d, J=
8.9 Hz, 2H), 8.17 ppm (d, J=8.2 Hz, 2H); 13C NMR (50 MHz, CDCl3):
3
3
d=16.3 (d, JPC =5.9 Hz), 16.5 (d, JPC =5.9 Hz), 19.7, 20.0, 27.3, 36.5,
1
1335, 1260, 1215, 1154 cmꢀ1; H NMR (200 MHz, CDCl3): d=0.80 (d,
1
2
53.9, 55.7, 57.8 (d, JPC =148.6 Hz), 58.5, 58.8, 63.0 (d, JPC =6.9 Hz),
63.2 (d, JPC =6.9 Hz), 69.5, 114.3, 123.4, 126.5, 128.6, 129.2, 129.4,
J=6.6 Hz, 3H), 0.82 (d, J=6.4 Hz, 3H), 1.07 (t, 3JPH =7.1 Hz, 3H),
1.21 (t, 3JPH =7.1 Hz, 3H), 1.61–1.76 (m, 1H), 2.66–2.76 (m, 1H),
2.78–2.86 (m, 2H), 2.90–2.91 (m, 1H), 2.94–2.97 (m, 1H), 3.05–3.23
(m, 2H), 3.48–3.54 (m, 1H), 3.63–4.05 (m, 4H), 3.88 (s, 3H), 4.05 (d,
2JPH =20.1 Hz, 1H), 6.95 (d, J=9.0 Hz, 2H), 7.20–7.30 (m, 10H),
7.64 ppm (d, J=8.8 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=16.2 (d,
2
129.8, 130.0, 138.4, 143.9, 147.6, 163.0 ppm; 31P NMR (202 MHz,
CDCl3): d=21.85 ppm; MS (ESI): m/z 700.6 [M+Na]+; Anal. calcd
for C32H44N3O9PS: C 56.71, H 6.54, N 6.20, found: C 56.78, H 6.63, N
6.32.
3
3JPC =5.9 Hz), 16.4 (d, JPC =5.9 Hz), 20.0, 20.1, 27.2, 34.9, 51.9, 55.6,
Diethyl 1-((2S,3S)-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsul-
fonamido)-1-phenylbutan-2-ylamino)-2-methylpropylphospho-
nate (41d): Product was isolated as a 1:1 diastereomeric mixture;
only peaks corresponding to the major isomer are given. Colorless
1
3
2
57.7 (d, JPC =158.1 Hz), 57.9, 58.5 (d, JPC =15.7 Hz), 62.6 (d, JPC
=
2
7.3 Hz), 63.0 (d, JPC =7.3 Hz), 69.9, 114.2, 126.6, 127.7, 127.8, 128.1,
128.3, 128.5, 128.7, 129.3, 129.4, 130.9, 135.2, 137.9, 162.8 ppm;
ChemMedChem 0000, 00, 1 – 12
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. K. Bhattacharya et al.
MED
syrup (70%): Rf =0.35 (EtOAc); IR (CHCl3): n˜ =3352, 3019, 1598,
66.2 (d, 2JPC =7.3 Hz), 72.7 (d, 3JPC =3.7 Hz), 114.3, 126.5, 128.4,
129.4, 129.9, 130.4, 138.0, 162.9 ppm; 31P NMR (161 MHz, CDCl3):
d=8.26 ppm; MS (ESI): m/z 621.5 [M+Na]+; Anal. calcd for
C29H47N2O7PS: C 58.17, H 7.91, N 4.68, found: C 58.29, H 8.05, N
4.61.
1
1497, 1335, 1259, 1216, 1154 cmꢀ1; H NMR (500 MHz, CDCl3): d=
0.63 (d, J=6.6 Hz, 3H), 0.78 (d, J=6.6 Hz, 3H), 0.81 (d, J=6.8 Hz,
3H), 1.04 (d, 3JPH =6.8 Hz, 3H), 1.30–1.40 (m, 6H), 1.69–1.74 (m,
1H), 2.07–2.23 (m, 1H), 2.68–2.71 (m, 1H), 2.82–2.89 (m, 2H), 2.94–
3.07 (m, 2H), 3.12–3.22 (m, 2H), 3.32–3.35 (m, 1H), 3.54–3.59 (m,
1H), 3.88 (s, 3H), 4.09–4.20 (m, 4H), 6.96 (d, J=8.8 Hz, 2H), 7.22–
7.34 (m, 5H), 7.67 ppm (d, J=8.8 Hz, 2H); 13C NMR (125 MHz,
CDCl3): d=16.5 (d, 3JPC =5.5 Hz), 17.7 (d, 3JPC =2.2 Hz), 18.3 (d,
Biological assays
The anti-HIV activities and cytotoxicities of all the synthesized com-
pounds were evaluated against wild-type HIV-1 (IIIB), HIV-2 (ROD),
and double mutant (RES056) strains in MT-4 cells using the 3-(4,5-
dimethylthiazoldimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro-
mide (MTT) method.[26] Briefly, virus stocks were titrated in MT-4
cells and expressed as a 50% cell culture infective dose (CCID50
values). MT-4 cells were suspended in culture medium at 1ꢁ
105 cellsmLꢀ1 and infected with HIV at a multiplicity of infection of
0.02. Immediately after virus infection, 100 mL of the cell suspen-
sion was brought into each well of a flat-bottomed microtiter tray
containing various concentrations of the test compounds. The test
compounds were dissolved in DMSO at a concentration of 50 mm
or higher. After 4-days incubation at 378C, the number of viable
cells was determined using the MTT method. Compounds were
tested in parallel for cytotoxic effects in uninfected MT-4 cells. The
drugs currently being used in clinical treatment of HIV-1 infection,
DDN/DDC and DMP266, were used as control.
2
3JPC =2.5 Hz), 19.9, 27.2, 29.4 (d, JPC =3.6 Hz), 38.0, 53.4, 55.6, 57.9,
2
58.4 (d, 1JPC =158.9 Hz), 60.5, 61.5 (d, 2JPC =7.3 Hz), 61.5 (d, JPC
=
7.3 Hz), 67.8, 114.1, 126.4, 128.5, 129.3, 129.5, 130.7, 138.6,
162.7 ppm; 31P NMR (202 MHz, CDCl3): d=28.52 ppm; MS (ESI): m/z
621.5 [M+Na]+; Anal. calcd for C29H47N32O7PS: C 58.17, H 7.91, N
4.68, found: C 58.31, H 8.09, N 4.59.
Diethyl ((2S,3S)-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfo-
namido)-1-phenylbutan-2-ylamino)(pyridin-2-yl)methylphospho-
nate (41e): Product was isolated as a 1:1 diastereomeric mixture;
only peaks corresponding to the major isomer are given. Colorless
syrup (63%): Rf =0.40 (EtOAc); IR (CHCl3): n˜ =3379, 3019, 2931,
1
1597, 1497, 1468, 1434, 1259, 1215, 1154 cmꢀ1; H NMR (400 MHz,
CDCl3): d=0.69 (d, J=6.8 Hz, 3H), 0.78 (d, J=6.8 Hz, 3H), 1.16 (t,
3
3JPH =7.0 Hz, 3H), 1.28 (t, JPH =7.0 Hz, 3H), 1.49–1.68 (m, 1H), 2.51–
2.57 (m, 1H), 2.71–2.91 (m, 4H), 3.10–3.15 (m 1H), 3.40–3.45 (m,
1H), 3.59–3.64 (m, 1H), 3.89 (s, 3H), 3.78–4.11 (m, 4H), 4.45 (d,
2JPH =22.1 Hz, 1H), 6.98–7.00 (m, 2H), 7.10–7.23 (m, 5H), 7.44–7.54
(m, 3H), 7.77 (d, J=9.0 Hz, 2H), 8.47 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3): d=16.4 (d, 3JPC =5.9 Hz), 19.9, 20.1, 27.2, 38.7,
Acknowledgements
1
2
53.7, 55.6, 58.1, 61.8 (d, JPC =149.6 Hz), 60.9, 62.7 (d, JPC =7.3 Hz),
2
A.K.B. is grateful to the Department of Biotechnology (DBT), Gov-
ernment of India (New Dehli) for financial support. The authors
thank Dr. Rajesh Gonnade of the Centre for Material Characteri-
zation at the CSIR-National Chemical Laboratory (Pune) for his
kind help with X-ray crystallography of one of our samples. The
authors also gratefully acknowledge financial support of a Senior
Research Fellowship to K.C.R. by the Council of Scientific and In-
dustrial Research (CSIR), New Delhi.
62.8 (d, JPC =7.3 Hz), 70.1, 114.2, 122.5, 123.6, 126.2, 128.4, 129.3,
129.5, 130.7, 136.2, 138.3, 149.0, 155.7, 162.8 ppm; 31P NMR
(161 MHz, CDCl3): d=22.40 ppm; MS (ESI): m/z 656.5 [M+Na]+;
Anal. calcd for C31H44N3O7PS: C 58.75, H 7.00, N 6.63, found: C
58.68, H 7.12, N 6.49.
Diethyl (2S,3R)-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfo-
namido)-1-phenylbutan-2-ylphosphoramidate (15a): Colorless
syrup (76%): Rf =0.50 (EtOAc); [a]20D = +10.82 (c=0.6 in MeOH); IR
(CHCl3): n˜ =3281, 3020, 1689, 1604, 1542, 1497, 1456, 1395, 1335,
1
1262, 1215, 1155, 1046 cmꢀ1; H NMR (200 MHz, CDCl3): d=0.87 (d,
J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H), 1.14 (t, 3JPH =7.1 Hz, 3H),
1.18 (t, 3JPH =7.1 Hz, 3H), 1.81–1.95 (m, 1H), 2.85–2.94 (m, 3H),
3.08–3.16 (m, 2H), 3.26–3.51 (m, 3H), 3.75–3.88 (m, 4H), 3.86 (s,
3H), 4.22–4.30 (m, 1H), 6.97 (d, J=8.9 Hz, 2H); 7.23–7.31 (m, 5H),
Keywords: antiviral agents · hydroxyethylamine isosteres ·
phosphoramidates · synthesis · a-aminophosphonates
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7.73 ppm (d, J=8.9 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=16.1 (d,
3
3JPC =7.3 Hz), 16.2 (d, 3JPC =7.3 Hz), 20.0, 20.1, 27.1, 36.9 (d, JPC
=
=
2
6.2 Hz), 52.9, 55.6, 56.6, 58.3, 62.2 (d, 2JPC =5.8 Hz), 62.5 (d, JPC
5.8 Hz), 72.8 (d, 3JPC =3.3 Hz), 114.3, 126.4, 128.4, 129.4, 129.9,
130.4, 138.3, 162.9 ppm; 31P NMR (202 MHz, CDCl3): d=8.22 ppm;
MS (ESI): m/z 543.6 [M+H]+, 565.5 [M+Na]+; Anal. calcd for
C25H39N2O7PS: C 55.34, H 7.24, N 5.16, found: C 55.39, H 7.35, N
5.21.
Dibutyl (2S,3R)-3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfo-
namido)-1-phenylbutan-2-yl-phosphoramidate (15b): Colorless
syrup (61%): Rf =0.70 (EtOAc); [a]20D = +5.42 (c=0.5 in MeOH); IR
(CHCl3): n˜ =3392, 3019, 2963, 2874, 1597, 1578, 1497, 1456, 1391,
1337, 1260, 1216, 1154, 1092, 1030 cmꢀ1 1H NMR (200 MHz, CDCl3):
d=0.78–0.85 (m, 12H), 1.15–1.46 (m, 8H), 1.72–1.86 (m, 1H), 2.79–
3.06 (m, 6H), 3.18–3.27 (m, 1H), 3.40–3.49 (m, 1H), 3.61–3.76 (m,
4H), 3.79 (s, 3H), 6.91 (d, J=8.9 Hz, 2H); 7.13–7.23 (m, 5H),
7.65 ppm (d, J=8.9 Hz, 2H); 13C NMR (50 MHz, CDCl3): d=13.6,
18.7, 19.9, 20.2, 27.2, 32.2 (d, 3JPC =2.2 Hz), 32.4 (d, 3JPC =2.2 Hz),
37.2 (d, 3JPC =5.5 Hz), 53.1, 55.6, 56.4, 58.5, 66.1 (d, 2JPC =7.3 Hz),
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Published online on && &&, 0000
ChemMedChem 0000, 00, 1 – 12
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
&
11
&
ÞÞ
These are not the final page numbers!

FULL PAPERS
A. K. Bhattacharya,* K. C. Rana,
C. Pannecouque, E. De Clercq
&& – &&
An Efficient Synthesis of
a Hydroxyethylamine (HEA) Isostere
and Its a-Aminophosphonate and
Phosphoramidate Derivatives as
Potential Anti-HIV Agents
Getting there faster: Efficient synthesis
of a hydroxyethylamine (HEA) isostere
was carried out with a one-pot reduc-
tion–transimination–reduction reaction
sequence. a-Aminophosphonate and
phosphoramidate derivatives of the
HEA isostere were designed and synthe-
sized. All of the synthesized a-amino-
phosphonate and phosphoramidate de-
rivatives were assayed for their anti-HIV
activities.
&12
&
www.chemmedchem.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 12
ÝÝ
These are not the final page numbers!