Common precursor strategy for the synthesis of bestatin, amprenavir intermediate and syn-4-hydroxy-5-phenyl-γ-lactam

Article abstract of DOI:10.1039/c4ra00205a

A common precursor strategy for the synthesis of bestatin hydrochloride, an anticancer agent, 1,3-diaminoalcohol, an amprenavir intermediate, and a syn-4-hydroxy-5-phenyl-γ-lactam intermediate of various bioactive molecules using an α,β-unsaturated ester as a common precursor is described. The protocol offers mild reaction conditions, good yields and excellent stereoselectivity.

Full text of DOI:10.1039/c4ra00205a

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COMMUNICATION
Common precursor strategy for the synthesis of
bestatin, amprenavir intermediate and syn-4-
hydroxy-5-phenyl-g-lactam†
Cite this: RSC Adv., 2014, 4, 17206
Brijesh Kumar,a Mushtaq A. Aga,a Abdul Rouf,a Bhahwal A. Shahb
Received 9th January 2014
Accepted 31st March 2014
a
*
and Subhash C. Taneja
DOI: 10.1039/c4ra00205a
www.rsc.org/advances
A common precursor strategy for the synthesis of bestatin hydro- medicinal leads and approved drugs.7 Furthermore, the
chloride, an anticancer agent, 1,3-diaminoalcohol, an amprenavir reduced form of g-lactams provides an access to the pyrrolidine
intermediate, and a syn-4-hydroxy-5-phenyl-g-lactam intermediate family of alkaloids.8 The relative and absolute stereochemistry
of various bioactive molecules using an a,b-unsaturated ester as a of the ring substituents, as well as their chemical nature play
common precursor is described. The protocol offers mild reaction critical roles in the biological properties of g-lactams and
conditions, good yields and excellent stereoselectivity.
analogues.9
The retro-synthetic pathway for the synthesis of bestatin (1),
di-aminoalcohol (2) and syn-g-lactam (3) from a,b-unsaturated
ester involved stereoselective aminohydroxylation of the double
bond as a key reaction step to afford b-amino-a-hydroxy acids
(AHPA), whereas the acid/ester itself can be synthesized from
phenyl acetaldehyde (Scheme 1). Bestatin and di-aminoalcohol
derivatives can be prepared from the same intermediate by
condensation with different amines while as g-butyrolactam is
synthesized by installing the aminoalcohol group at the
The vicinal aminoalcohol moiety is not only a widespread
structural motif in natural and synthetic biologically active
molecules (Fig. 1), but is also used widely as a versatile chiral
building block and a chiral catalyst/ligand in a variety of
asymmetric syntheses, such as enantioselective dialkylzinc
addition to aldehydes,1 enantioselective conjugated addition2
and pericyclic reactions.3 The importance and the need to
prepare these compounds, as well as their analogues have
dramatically increased the efforts towards the development of
newer methods for their synthesis.
In the present work, we have developed a common precursor
strategy4 for the synthesis of three vicinal aminoalcohols i.e.,
bestatin
[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-L-
leucine] (1), 1,3 diaminoalchol (amprenavir intermediate) and
syn-g-lactams. Bestatin (1) is an effective inhibitor of amino-
peptidase N (APN) for the treatment of leukaemia.5 Besides, it is
also a promising drug for the treatment of virus infections and
acute pain.6 Amprenavir is an effective therapeutic agent for the
treatment of HIV infection, approved by FDA in 1999. Later, its
phosphate ester pro-drug i.e. fosamprenavir with improved
solubility and bioavailability was approved by the FDA in
October 2003. g-Lactams or 2-oxopyrrolidines are ve-
membered ring lactams, constituting as an important structural
motifs in a variety of biologically active natural products,
aBio-organic Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal
Road, Jammu, India-180001. E-mail: sctaneja@iiim.ac.in; drsctaneja@gmail.com
bNatural Product Microbe, Indian Institute of Integrative Medicine (CSIR), Canal Road,
Jammu, India-180001
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra00205a
Fig. 1 Some bioactive aminoalcohols.
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at room temperature gave the desired product (8) in 50% yield
with desired stereoselectivity. Next, the ester (8) was hydrolyzed
using K2CO3 in methanol : water (10 : 1) to obtain the corre-
sponding acid (9) in 95% yield. The method was mild enough to
preserve stereochemical integrity during the transformation, as
established by NMR and optical rotation value.12 The coupling of
acid (9) L-leucine benzyl ester was carried out using EDC, N,N-
diisopropylethylamine and HOBt in dimethylformamide at room
temperature under nitrogen to afford the corresponding benzyl
ester (10) in 80% yield. In order to prepare the target product
bestatin hydrochloride, it required efficient deprotection of
functionalities i.e., debenzylation, followed by detosylation.
Thus, debenzylation was carried out via hydrogenation in the
presence of Pd/C under H2 atmosphere in methanol. Attempts for
detosylation using sodium naphthalenide13 proved unsuccessful.
A milder method using magnesium in dry methanol14 under
reuxing conditions for 12 h, deprotected the N-tosyl group
successfully. Finally, 6 N HCl in dioxane was used for the prep-
aration of bestatin hydrochloride. The overall yield in the
synthesis of 1 is 28% (Scheme 2). The structure of the nal
product was conrmed by NMR and the comparison with the
specic rotation values reported in the literature.15
Aer the successful accomplishment of the bestatin
synthesis, the common precursor strategy was extended to the
synthesis of the di-aminoalcohol precursor (2). The condensa-
tion of the acid (9) with isobutyl amine in the presence of EDC,
followed by the reduction of the amide (11) with lithium
aluminium hydride gave the desired intermediate 2 in 75%
yield (Scheme 3). The structure of 2 was established by NMR.16
The preparation of chiral b-hydroxy-g-lactam moiety, a
precursor of several biologically important molecules including
substituted cyclic GABA analogues has been the third synthetic
target of the present common precursor methodology. The key
step was the preparation of b,g-unsaturated ester (7) via in situ
isomerization of 6 using HWE reaction. Thus, b,g-unsaturated
ester was obtained in one step in 90% yield from phenyl acet-
aldehyde and triethyl phosphonoacetate, using sodium hydride
Scheme 1 Consolidated view of retrosynthetic pathways.
b,g-position of a b,g-unsaturated ester via double bond migra-
tion/isomerisation.
The rst step was the preparation of a,b-unsaturated ester (6)
using Horner–Wadsworth–Emmons reaction (HWE reaction),10
for the preparation of AHPA. The reaction of phenyl acetalde-
hyde (4) and triethyl phosphonoacetate (5) using a base in an
inert solvent gave a,b-unsaturated ester (6) as a major product.
As double bond migration to generate a b,g-unsaturated ester
was also observed during the reaction therefore, it was imper-
ative to study of the effect of the solvents and the bases on the
yield, and the reaction time. The reaction was optimized with
diethyl ether or THF as the solvent, affording the product in
92% and 88% yield respectively, (Table 1, entries 1 and 2). The
use of NaH made this reaction efficient, when performed with
1.2 equivalent NaH in diethyl ether–THF and it proceeded to
completion in 2 h at ambient temperature, affording the
product in high yield and stereoselectivity. The use of NaOMe
and NaOH led to lower stereoselectivity and yields (Table 1,
entries 7–9).
The next is the key step to determine the suitable method for
the preparation of chiral b-amino-a-hydroxy ester. Our initial
attempts employing different methods such as via amino halo-
genations, epoxidation etc. met with failure. However, Sharpless
aminohydroxylation11 of 6, employing chloramine-T trihydrate,
K2[OsO2(OH)4] and (DHQ)2PHAL catalyst in t-BuOH : water (1 : 1)
Table 1 Optimization of Horner–Wadsworth–Emmons reaction
Entry
Bases (1.2 eq.)
Solvents
Yieldsa (%)
1
2
3
4
5
6
7
8
9
NaH
NaH
NaH
t-BuOK
t-BuOK
t-BuOK
NaOMe
NaOMe
NaOH
Diethyl ether
THF
Benzene
Diethyl ether
THF
Benzene
Diethyl ether
Benzene
Diethyl ether
92
88
85
94
90
87
80
72
60
a
Yields of compound 6 were calculated aer purication.
Scheme 2 Synthesis of bestatin hydrochloride.
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(amprenavir intermediate) and syn-disubstituted g-lactam
using a common precursor strategy (a,b-unsaturated ester as a
common precursor). Various other bioactive aminoalcohol
molecules or intermediate may also be synthesized by using this
strategy.
Acknowledgements
The authors (BK, MAA and AR) thank UGC and CSIR, New Delhi
for the award of senior research fellowships. The authors are
declaring the institutional Publication Number IIIM/1653/2014.
Notes and references
Scheme 3 Synthesis of di-aminoalcohol precursor 2.
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