Synthesis of a first thiophene containing analog of the HIV protease inhibitor nelfinavir

Article abstract of DOI:10.1016/j.tetlet.2004.02.026

A stereoselective and efficient preparation of a thiophene containing intermediate 2 from ethyl 3-thienyl propenoate 4 as the core of new possible HIV protease inhibitors is described. The chiral intermediate has been successfully used for the preparation

Full text of DOI:10.1016/j.tetlet.2004.02.026

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2797–2799
Synthesis of a first thiophene containing analog of the HIV protease
inhibitor nelfinavir
Carlo Bonini,* Lucia Chiummiento, Margherita De Bonis, Maria Funicello and
Paolo Lupattelli
Dipartimento di Chimica, Universitꢀa degli Studi della Basilicata, Via N. Sauro, 85, 85100 Potenza, Italy
Received 18 January 2004; revised 4 February 2004; accepted 6 February 2004
Abstract—A stereoselective and efficient preparation of a thiophene containing intermediate 2 from ethyl 3-thienyl propenoate 4 as
the core of new possible HIV protease inhibitors is described. The chiral intermediate has been successfully used for the preparation
of the analog 1 of the potent HIV inhibitor nelfinavir.
Ó 2004 Elsevier Ltd. All rights reserved.
The effort for an efficient therapy against AIDS was
recently considerably aided by the discovery of a new
class of drugs, which were designed in order to block the
action of the so-called HIV protease (HIV-Pr), an
essential enzyme for maturation of the infectious virus.1
HIV-Pr inhibitors were transformed into drugs as pep-
tidomimetic compounds,2 while others arose by the
application of computer-assisted design.3 The transition
state structure analogs, which were found most effective
in the actual drugs in therapeutic use, are dipeptido
isosteres.4 Many of these inhibitors belong to the class of
the hydroxyethylamine (HEA) inhibitors, such as nelfi-
navir and saquinavir (see Fig. 1). There are already
many synthetic approaches to these compounds,5 which
Figure 1.
mainly focused the efforts on the synthesis of the core
HEA segment with the correct relative and absolute
stereochemistry.
Therefore we were induced to design and synthesise a
We focused our attention on nelfinavir, since it is the
only developed HIV-Pr inhibitor in therapeutic use, with
first thiophene containing HIV-Pr inhibitor analogue
such as the compound 1, illustrated in Figure 1.
sulfur containing core segment. Furthermore, to our
knowledge, no thienyl containing HIV-Pr inhibitor has
The development of a practical synthetic route to a core
so far been prepared and tested. This could probably be
intermediate such as 2 (see Scheme 1) was found to be
due to some difficulties in the introduction of the thienyl
crucial to the final preparation of 1. Furthermore, chiral
moiety in the core of the compound, although it is well
compound 2 could in turn be introduced in different
known that the thienyl group well mimics the phenyl
cores of potential HIV-Pr inhibitors. This intermediate,
group6 of phenylalanine in many peptidomimetics and,
already containing the thienyl group, could be derived
therefore, was successfully introduced in many drugs.6b;c;d
from the chiral a,b-dihydroxy ester 3, eventually
obtained by Sharpless AD procedure, from the thio-
phene acrylate 4.
Keywords: HIV-Pr inhibitors; Peptidomimetics; Hydroxyethylamine
(HEA) inhibitors; Nelfinavir analog; Thiophene; Sulfite.
According to this retrosynthetic scheme, the regio- and
stereoselective introduction of the nitrogen group on the
* Corresponding author. Tel.: +39-0971-202254; fax: +39-0971-2022-
23; e-mail: bonini@unibas.it
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.026

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C. Bonini et al. / Tetrahedron Letters 45 (2004) 2797–2799
Scheme 1. Retrosynthetic analysis for compound 2.
diol 3 was recognised as the key step of the overall
sequence.
As outlined in Scheme 2, the synthesis of compound 2
started from commercial thienyl aldehyde 5, which was
transformed into the ethyl 3-thienylpropenoate ester 4,
almost quantitatively (95% yield) by Horner–Emmons
olefination. The Sharpless AD7 was successfully per-
formed on 4, as developed by our procedure on thio-
phene acrylates,8 with indeed improved yields (66%) and
excellent ee (>98%) of the final diol 3.9
Scheme 3. Synthesis of nelfinavir analog 1. Reaction conditions: (a)
BH3ÆSMe2, NaBH4, THF, MeOH, 3 h, rt; (b) MesSO2Cl, Pyr, CH2Cl,
0 °C, 22 h; (c) K2CO3, PHIQ, i-PrOH, 50 °C, 21 h; (d) H2, Pd/C,
MeOH, 3 h, rt; (e) 3-Acetoxy-2-methyl bezoic acid, DCC, DMAP,
CH2Cl2, 2h, rt; (f) Na, MeOH, 1 h rt.
In order to properly introduce the nitrogen functional-
ity, the diol 3 was first transformed into the sulfite 6.10
Then, to avoid possible thiophene ring oxidation, the
azido group was directly introduced by sodium azide on
compound 6,11 without the previous oxidation to the
usually used cyclic sulfate, as usually performed on
analog substrates.10a The reaction proceeded smoothly
regio- and stereoselectively, without the isolation of the
intermediate acyclic sulfite, affording the target azido
alcohol 2,12 in good overall yield (70% in two steps). It is
noteworthy that, in similar nucleophilic substitution of
azido group for the HIV-Pr inhibitor synthesis,5 the
reaction was always performed on the corresponding
cyclic sulfate, with one more step required for the syn-
thesis.
other approaches.14 The direct reduction of ester 2, to
obtain azido diol 7, was achieved with satisfactory result
(90% yield) using BH3ÆSMe2 and catalytic NaBH4, a
system known to perform chemoselective reductions on
a-hydroxy esters.15 Then, the regioselective activation of
the primary hydroxyl group to compound 8 was
smoothly performed with the more hindered mesit-
ylenesulfonyl chloride (70% yield), instead of the tosyl
derivative (50% yield).
Then, the first amino side chain, was easily introduced
8
with the commercially available16
We decided to use this chiral precursor in order to
perform the total synthesis of an analog of already used
HIV-Pr inhibitors and we focused our efforts on the
compound 1, which is a structural analog of the thienyl
containing nelfinavir.
by treating
[3S-(3a,4ab,8ab)]-N-(tert-butyl)decahydro-3-isoquinoline
carboxamide (PHIQ), so that we obtained azido alcohol
9 (80% yield) without isolation of possible intermediate
epoxide. The azido group in compound 9 was finally
reduced via catalytic hydrogenation, affording amino
alcohol 10 in high yield (91%).
In Scheme 3, the synthesis of 1, starting from azido
alcohol 2, was reported. After several attempts on the
preliminary reduction of the azido group,13 we decided
to proceed with the synthesis in the presence of the
unprotected azido alcohol, which actually resulted in a
more straightforward synthetic sequence avoiding pro-
tection and deprotection manipulation, as described in
The synthesis was completed with the amide bond for-
mation, by a condensation between 10 and 3-acetoxy-2-
methyl benzoic acid, which gave the protected com-
pound 11 (66% yield).
The deprotection of the phenol group with Na/MeOH,
afforded the target compound 1ꢀ in 81% yield.
ꢀ
())(3S,4aS,8aS,20R,30R)-2-[20-hydroxy-30-(3-hydroxy-2-methyl-benzo-
ylamino)-30-(thiophen-2-yl)-propyl]-decahydro-isoquinoline-3-carb-
20
D
oxylic acid tert-butylamide (1) ½aꢀ )2 7 c( 0.6, EtOAc); 1H NMR
(500 MHz, CDCl3) d 7.26–7.24 (m, 1H), 7.13–7.12 (m, 1H), 7.05–7.02
(m, 1H), 6.99–6.98 (m, 2H), 6.90–6.85 (m, 2H), 6.05 (br s, 1H), 5.47–
5.43 (m, 1H), 4.22–4.19 (m, 1H), 2.68–1.20 (m, 19H), 2.14 (s, 3H),
1.34 (s, 9H); 13C NMR (125 MHz, CDCl3) d 174.0, 169.8, 155.1,
140.2, 137.9, 127.3, 126.8, 126.7, 125.8, 122.6, 119.0, 116.9, 71.2, 70.1,
60.0, 59.4, 53.1, 51.5, 35.9, 33.4, 30.9, 30.7, 28.8, 26.2, 25.9, 21.1, 12.6.
Anal. Calcd for C29H41N3O4S: C, 66.00; H, 7.83. Found: C, 66.03; H,
7.82.
Scheme 2. Reaction conditions: (a) NaH 60%, (EtO)2POCH2CO2Et,
toluene, rt; (b) AD mix-b, [DHQD]2PHAL, MeSO2NH2, H2O/
t-BuOH, 0–15 °C, 15 h; (c) SOCl2, Pyr, CH2Cl2, 0 °C, 15 h; (d) NaN3,
DMF/CH3CN, 15 °C, 15 h.

C. Bonini et al. / Tetrahedron Letters 45 (2004) 2797–2799
2799
syntheses of drugs see: (b) Zhang, A.; Zhou, G.; Rong,
S.-B.; Johnson, K. M.; Zang, M.; Kozikowski, A. P.
Bioorg. Med. Chem. Lett. 2002, 12, 993–995; (c) Uckun, F.
M.; Pendergrass, S.; Maher, D.; Zhu, D.; Tuel-Ahlgren,
L.; Mao, C.; Venkatachalam, T. K. Bioorg. Med. Chem.
Lett. 1999, 9, 3411–3416; (d) Corral, C.; Lissavetzky, J.;
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J. A. M.; Sanchez-Mateo, C. C. Bioorg. Med. Chem. 1999,
7, 1349–1359.
In conclusion, the main features and novelties of this
work are: (i) the original synthesis of a novel chiral
intermediate as HEA core, via Sharpless AD and highly
regioselective introduction of the azido group; (ii) the
manipulation of the chiral azido alcohol 2 without
protection–deprotection sequence; (iii) the complete
preparation of the first thiophene containing analog of
an HIV-Pr inhibitor. The application of this sequence
for the preparation of similar and novel analogs is cur-
rently under intensive investigation.
7. (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547; for most recent review
ꢀ
see: (b) Marko, I. E.; Svendsen, J. S. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 2,
pp 713–787.
Acknowledgements
8. Bonini, C.; DꢁAuria, M.; Fedeli, P. Tetrahedron Lett. 2002,
43, 3813–3815.
9. By a slight modification of the experimental conditions
(2.4 mol % of (DHQD)2PHAL) the overall yield was
improved from 55%8 up to 66%, the ee being superior to
98% (by HPLC on Chiralcel OJ-H column).
The authors gratefully acknowledge MIUR (Ministry of
Instruction, University and Research-Rome) for finan-
cial support (Project FIRB: RBNE017F8N).
10. (a) Nymann, K.; Svendsen, J. S. Acta Chem. Scand. 1994,
48, 183–186; (b) Byun, H. S.; He, L.; Bittman, R.
Tetrahedron 2000, 56, 7051–7091.
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