Stereoselective hydroazidation of amino enones: Synthesis of the ritonavir/lopinavir core

Article abstract of DOI:10.1021/ol0524104

(Chemical Equation Presented) The base-catalyzed hydroazidation of α′-amino α,β-unsaturated ketones with in situ generated hydrazoic acid was found to proceed with high stereoselectivity in favor of the syn product. The stereoselectivity is controlled by

Full text of DOI:10.1021/ol0524104

ORGANIC
LETTERS
2006
Vol. 8, No. 1
51-54
Stereoselective Hydroazidation of Amino
Enones: Synthesis of the Ritonavir/
Lopinavir Core
Ilaria Adamo, Fabio Benedetti,* Federico Berti, and Pietro Campaner
Department of Chemical Sciences, UniVersity of Trieste, Via Giorgieri 1,
I-34127 Trieste, Italy
benedett@units.it
Received October 5, 2005
ABSTRACT
The base-catalyzed hydroazidation of r′-amino
r,â-unsaturated ketones with in situ generated hydrazoic acid was found to proceed with high
stereoselectivity in favor of the syn product. The stereoselectivity is controlled by the configuration of the enone and syn/anti ratios up to 7:1
were obtained with secondary and tertiary amines at low temperature. By this route the diamino alcohol core of HIV-PR inhibitors ritonavir and
lopinavir was synthesized in 37% yield from phenylalanine.
The conjugate addition of a nitrogen nucleophile to an R,â-
unsaturated carbonyl compound (the aza-Michael reaction)
is a classical synthetic method, giving access to important
classes of compounds, such as â-amino acids1 and ketones,2
â-lactams,3 and 1,3-amino alcohols.4 A variety of nitrogen
compounds can be used as nucleophiles in this reaction,
including aliphatic and aromatic amines, lithium amides,
hydroxylamines, oximes, carbamates, and other nitrogen
donors.1-5 For the introduction of a primary amino group,
azide offers several advantages over other nucleophiles as
this reagent is simple and inexpensive and does not require
catalysts due to its high reactivity, and the conversion of
the product into primary amine is relatively atom economic
and can be carried out with a variety of reducing agents and
conditions.6 The hydroazidation of R,â-unsaturated com-
pounds has been carried out with hydrazoic acid,7 but this
highly toxic and explosive reagent can be replaced by safer
azide donors8 or, alternatively, can be generated in situ from
trimethylsilyl azide (TMSN3) and a carboxylic acid.9
Asymmetric aza-Michael reactions have recently attracted
much attention, and stereoselection has been achieved with
chiral catalysts5 and by asymmetric induction from chiral
reagents or auxiliaries.10 In this communication we report
on the hydroazidation of amino acid derived R,â-unsaturated
ketones to give â-azido carbonyl compounds in which the
(6) (a) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.,
Int. Ed. 2005, 44, 5188-5240. (b) Scriven, E. F. V.; Turnbull, K. Chem
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(1) (a) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. BiodiVersity
2004, 1, 1111-1239. (b) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-
8035. (c) Sharma, G. V. M.; Reddy, V. G.; Chander, A. S.; Reddy, K. R.
Tetrahedron: Asymmetry 2002, 13, 21-24. (d) Taillefumier, C.; Lakhrissi,
Y.; Lakhrissi, M.; Chapleur, Y. Tetrahedron: Asymmetry 2002, 13, 1707-
1711. (e) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 117-128.
(2) (a) Bartoli, G.; Bartolacci, M.; Giuliani, A.; Marcantoni, E.; Mas-
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S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4, 1319-1322. (c) Xu, L.
W.; Xia, C. G. Tetrahedron Lett. 2004, 45, 4507-4510.
(3) Caracciolo Torchiarolo, G.; D’Onofrio, F.; Margarita, R.; Parlanti,
L.; Piancatelli, G.; Bella, M. Tetrahedron 1998, 54, 15657-15666.
(4) (a) Kolarovic, A.; Berkes, D. A.; Baran, P.; Povazanec, F. Tetrahedron
Lett. 2005, 46, 975-978. (b) Takashiro, E.; Nakamura, Y.; Miyamoto, S.;
Ozawa, Y.; Sugiyama, A.; Fujimoto, K. Bioorg. Med. Chem. 1999, 7, 2105-
2114.
(7) (a) Lakshmipathi, P.; Rama Rao, A. V. Tetrahedron Lett. 1997, 38,
2551-2552. (b) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999,
121, 8959-8960.
(8) Chung, B. Y.; Park, Y. S.; Cho, I. S.; Hyun, B. C. Bull. Korean
Chem. Soc. 1988, 9, 269-270.
(9) (a) Guerin, D. J.; Horstmann, T. E.; Miller, S. J. Org. Lett. 1999, 1,
1107-1109. (b) Horstmann, T. E.; Guerin, D. J.; Miller, S. J. Angew. Chem.,
Int. Ed. 2000, 39, 3635-3638. (c) Guerin, D. J.; Miller, S. J. J. Am. Chem.
Soc. 2002, 124, 2134-2136.
(10) See, for example: (a) Prieto, A.; Fernandez, R.; Lassaletta, J. M.;
Vazquez, J.; Alvarez, E. Tetrahedron 2005, 61, 4609-4613. (b) Etxebarria,
J.; Vicario, J. L.; Badia, D.; Carrillo, L. J. Org. Chem. 2004, 69, 2588-
2590. (c) Molteni, M.; Volonterio, A.; Zanda, M. Org. Lett. 2003, 5, 3887-
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D.; Muller, S. F.; Raabe, G.; Runsink, J. Eur. J. Org. Chem. 2000, 879-892.
(5) (a) Xu, L. W.; Xia, C. G. Eur. J. Org. Chem. 2005, 633. (b) Hultzsch,
K. C. AdV. Synth. Catal. 2005, 347, 367-391.
10.1021/ol0524104 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/03/2005

stereoselectivity is efficiently controlled by the remote stereo-
center present on the substrate (1,4-asymmetric induction).
Our first attempt to hydroazidate ketone 3 with diethyla-
luminum azide7 was frustrating, as this reaction failed to give
any recognizable product, while the corresponding N,N-
dibenzyl compound 5 (Scheme 2) underwent a [3 + 2]
Scheme 2
cycloaddition with the same reagent followed by an Al-
promoted hydride shift and reductive elimination of diben-
zylamine, giving the triazole 6.17
Recently, the â-azidation of R,â-unsaturated carbonyl
compounds with a 1:1 mixture of acetic acid and TMSN3 as
the azide source and a catalytic amount of a tertiary amine
has been reported by Miller and co-workers.9a Under these
conditions, with tertiary or secondary amines such as
triethylamine, diisopropylamine, or DBU, the ketone 3 was
completely converted into products (Table 1). However, no
Our interest in this reaction arose in connection with
studies on the synthesis of dipeptide isosteres and peptido-
mimetic protease inhibitors.11 Recently, considerable interest
has developed in the 1,4-diamino 2-hydroxybutane scaffold
1 as core unit of peptidomimetic inhibitors of HIV-protease.12
In particular, compound 1a, a mimic of the Phe-Phe dipep-
tide, is the central element of Ritonavir13 and Lopinavir,14
two potent inhibitors of HIV-PR, currently used in the
treatment of AIDS.15
Table 1. Catalysts for Azide Addition to Enone 3
Our original approach to 1a was based on the retro-
synthetic analysis shown in Scheme 1. The pivotal R,â-
Scheme 1
unsaturated ketone 3, readily obtained from L-phenylala-
nine,16 was transformed into epoxyalcohol 2 in two steps;
however, conversion of 2 into 1a required seven steps.10b
We reasoned that this approach would be considerably
shortened if the enone 3 could be directly hydroazidated to
give the azido ketone 4 in a stereocontrolled way: conversion
of 4 to 1a would then be straightforward.
1
a By 400 MHz H NMR. b Amine: 0.05 equiv.
(11) (a) Benedetti, F.; Berti, F.; Garau, G.; Martinuzzi, I.; Norbedo, S.
Eur. J. Org. Chem. 2003, 1973-1982. (b) Benedetti, F.; Berti, F.; Norbedo,
S. J. Org. Chem. 2002, 67, 8635-8643. (c) Tossi, A.; Bonin, I.; Antcheva,
N.; Norbedo, S.; Benedetti, F.; Miertus, S.; Nair, A. C.; Maliar, T.; Del
Bello, F.; Palu`, G.; Romeo, D. Eur. J. Biochem. 2000, 267, 1715-1722.
(12) (a) Babine, R. E.; Bender, S. L. Chem. ReV. 1997, 97, 1359-1472.
(b) Brik, A.; Wong, C. H. Org. Biomol. Chem. 2003, 1, 5-14.
stereoselectivity was observed, as a 1:1 mixture of syn and
anti diastereoisomers 4a and 4b was formed (Table 1; entries
1-3). Decreasing the basicity (entries 4-6 and 8) and the
amount of the catalyst (entries 9 and 10), resulted in an
increase of the selectivity in favor of the syn isomer 4a. The
52
Org. Lett., Vol. 8, No. 1, 2006

diastereoselectivity further improved at lower temper-
atures (entries 7 and 10), and the best de (75%) was ob-
tained with 5% L-proline methyl ester, at -18 °C for 72 h
(entry 10).
Table 3. Reduction of Amino Ketone 4a
As the chiral bases brucine (entries 6 and 7) and L-proline
methyl ester (entries 8-10) proved particularly effective in
this reaction, we turned our attention to the influence of the
chirality of the amine on the stereoselectivity. Thus, we
carried out the reaction of enantiomeric enones 3 and 7
(derived from D-phenylalanine)16 with trimethylsilyl azide
in the presence of L- and D-proline methyl ester (Table 2).
entry
reagent
NaBH4
NaCNBH3
NB-enantride THF, -78 °C
L-selectride MeOH, -78 °C
conditions
yield (%) anti/syn
1
2
3
4
MeOH, 0 °C
MeOH, 0 °C
90
85
80
70
75:25
50:50
50:50
<5:95
Table 2. Hydroazidation of Enantiomeric Enones 3 and 7 with
L- and D-Proline Methyl Estera
Reduction with sodium borohydride (Table 3) gave a 3:1
mixture of anti,anti and syn,syn diamino alcohols 911b and
10.11b Sodium cyanoborohydride gave a 1:1 mixture of
diastereoisomers, and the same result was obtained with NB-
enantride, although this reagent has been reported to give
syn-reduction with similar substrates.20 The desired selectivity
was obtained with L-selectride,21 which gave exlusively the
syn,syn azido alcohol 10 (Table 3). This known compound
can finally be converted into the mono-Boc-protected di-
amine 11 by catalytic hydrogenation in 95% yield (Scheme
3).11b By this combination of stereoselective azidation and
a Conditions: TMSN3, 5 equiv; AcOH, 5 equiv; amine 0.2 equiv; CH2Cl2;
25 °C. b syn/anti ratios; by chiral HPLC.
Scheme 3
A comparison of matching substrate-base pairs (entries 1 and
4) and mismatching pairs (entries 2 and 3) shows only a
modest drop in the stereoselectivity from 5:1 to 4:1. This
clearly indicates that, with the present series of amines,18
the chirality of the catalyst has only a minor effect on the
stereoselectivity, which is chiefly controlled by the substrate
through 1,4 asymmetric induction.19
The main diastereoisomer 4a, obtained from the reaction
of enone 3 with TMSN3 (Table 1), was isolated in 70% yield
by crystallization; this compound possesses the correct
configuration to serve as a precursor of the target diamine
1a (Scheme 1). Syn (Felkin-Anh) reduction of the R-amino
carbonyl group is required for the conversion of 4a into 1a.
syn-reduction, the Boc-protected Phe-Phe isostere 11 is
available from 3 in three steps and 49% yield, a considerable
improvement over the eight steps (8% yield) previously
required.11b
(13) Kempf, D. J.; Sham, H. L.; Marsh, K. C.; Flentge, C. A.; Betebenner,
D.; Green, B. E.; McDonald, E.; Vasavanonda, S.; Saldivar, A.; Wideburg,
N. E.; Kati, W. M.; Ruiz, L.; Zhao, C.; Fino, L.; Patterson, J.; Molla, A.;
Plattner, J. J.; Norbeck, D. W. J. Med. Chem. 1998, 41, 602-617.
(14) Sham, H. L.; Kempf, D. J.; Molla, A.; Marsh, K. C.; Kumar, G.
N.; Chen, C. M.; Kati, W.; Stewart, K.; Lal, R.; Hsu, A.; Betebenner, D.;
Korneyeva, M.; Vasavanonda, S.; McDonald, E.; Saldivar, A.; Wideburg,
N.; Chen, X.; Niu, P.; Park, C.; Jayanti, V.; Grabowski, B.; Granneman,
G. R.; Sun, E.; Japour, A. J.; Leonard, J. M.; Plattner, J. J.; Norbeck, D.
W. Antimicrob. Agents Chemother. 1998, 42, 3218-3224.
(15) (a) Abbenante, G.; Fairlie, D. P. Med. Chem. 2005, 1, 71-104. (b)
Kaplan, S. S.; Hicks, C. B. Expert Opin. Pharmacother. 2005, 6, 1573-
1585.
(16) Benedetti, F.; Miertus, S.; Norbedo, S.; Tossi, A.; Zlatoidzky, P. J.
Org. Chem. 1997, 62, 9348-9353 and references therein.
(17) Adamo, I.; Benedetti, F.; Berti, F.; Nardin, G.; Norbedo, S.
Tetrahedron Lett. 2003, 44, 9095-9097.
(18) See ref 9b and 9c for examples of asymmetric azidations controlled
by the amine catalyst.
In conclusion, we have shown that a good level of
stereoselectivity in the substrate-controlled hydroazidation
of R-amino enones with TMSN3/AcOH can be obtained by
a careful choice of the secondary/tertiary amine catalyst and
of the reaction conditions. Although the scope of the reaction
and its mechanism are still being investigated, particularly
for the underlying stereochemical implications, its synthetic
utility has been demonstrated by the conversion of the enone
3 into Boc-protected dipeptide isostere 11. By this route the
monoprotected core of Lopinavir and Ritonavir can be
(20) Vabeno, J.; Brisander, M.; Lejon, T.; Luthman, K. J. Org. Chem.
2002, 67, 9186-9191.
(21) Rodriguez, A. C.; Ramos, A. P.; Hawkes, G. E.; Berti, F.; Resmini,
M. Tetrahedron: Asymmetry 2004, 15, 1847-1855.
(19) Accordingly, little or no enantioselectivity was observed in the L-Pro-
OMe catalyzed hydroazidation of achiral enones.
Org. Lett., Vol. 8, No. 1, 2006
53

obtained from commercial N-Boc phenylalanine methyl ester
in only five steps and 37% yield overall, this being to date
the shortest and most efficient synthesis of this important
intermediate of the pharmaceutical industry.22
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 4a/b, 7, 8a, and
10. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL0524104
Acknowledgment. This work was supported by the
Ministry for University and Scientific Research (PRIN 2003
programme and FIRB grant RBNE017F8N).
(22) Ghosh, A. K.; Bilcer, G.; Schiltz, G. Synthesis 2001, 2203-2229.
54
Org. Lett., Vol. 8, No. 1, 2006