Directed reductive amination of β-hydroxy-ketones: Convergent assembly of the ritonavir/lopinavir core

Article abstract of DOI:10.1021/ol062715y

(Chemical Equation Presented) An efficient procedure for the directed reductive amination of β-hydroxy-ketones (3) for the stereoselective preparation of 1,3-syn-amino alcohols (6) is reported. The operationally simple protocol uses Ti(ⁱOPr)

Full text of DOI:10.1021/ol062715y

ORGANIC
LETTERS
2007
Vol. 9, No. 2
267-270
Directed Reductive Amination of
-Hydroxy-ketones: Convergent
Assembly of the Ritonavir/Lopinavir
â
Core
Dirk Menche,* Fatih Arikan, Jun Li, and Sven Rudolph
Gesellschaft fu¨r Biotechnologische Forschung mbH (recently renamed to
Helmholtz-Zentrum fu¨r Infektionsforschung GmbH), Medizinische Chemie,
Mascheroder Weg 1, D-38124 Braunschweig, Germany
dirk.menche@helmholtz-hzi.de
Received November 7, 2006
ABSTRACT
An efficient procedure for the directed reductive amination of
â-hydroxy-ketones (3) for the stereoselective preparation of 1,3-syn-amino
alcohols (6) is reported. The operationally simple protocol uses Ti(iOPr)4 for coordination of the intermediate imino alcohol (5) and PMHS as
the reducing agent. The method was expanded to an asymmetric aldol reductive amination sequence to allow a highly convergent synthesis
of the hydroxy-amine core of the HIV-protease inhibitors ritonavir and lopinavir.
The chiral 1,3-amino alcohol functionality presents a key
element in many bioactive structures, and its synthesis is a
high priority from the perspective of medicinal chemistry
and drug discovery.1,2 The direct reductive amination of a
carbonyl in a one-pot fashion with an amine and a reducing
agent is recognized as a very important, direct, and thus
synthetically economical means to synthesize chiral amines.3,4
However, despite this importance, so far, only few examples
of asymmetric versions have been described.5,6 In particular,
the development of substrate-controlled direct asymmetric
reductive aminations presents an important research goal.7,8
Herein, we report the design, synthetic development, and
application of a procedure for the direct reductive amination
of â-hydroxy ketones to give in an operationally simple
(3) For reviews, see: (a) Martens, J. Methods of Organic Chemistry
(Houben-Weyl); Georg Thieme Verlag: Stuttgart, 1995; Vol. E21d, p 4199.
(b) Baxter, E. W.; Reitz, A. B. Organic Reactions; Wiley: New York, 2002;
Vol. 59, p 1. (c) Gomez, S.; Peters, J. A.; Maschmeyer, T. AdV. Synth.
Catal. 2002, 344, 1037.
(4) More recent examples are described in: (a) Apodaca, R.; Xiao, W.
Org. Lett. 2001, 3, 1745. (b) Allegretti, M.; Berdini, V.; Candida Cesra,
M.; Curti, R.; Nicolini, L.; Topai, A. Tetrahedron Lett. 2001, 42, 4257. (c)
Gross, T.; Seayad, A. M.; Ahmad, M.; Beller, M. Org. Lett. 2002, 4, 2055.
(d) Miriyala, B.; Bhattacharyya, S.; Williamson, J. S. Tetrahedron 2004,
60, 1463. (e) Itoh, T.; Nagata, K.; Miyazaki, M.; Ishikawa, H.; Kurihara,
A.; Ohsawa, A. Tetrahedron 2004, 60, 6649. (f) Menche, D.; Hassfeld, J.;
Li, J.; Menche, G.; Ritter, A.; Rudolph, S. Org. Lett. 2006, 8, 741.
(5) For a review of direct asymmetric reductive aminations, see: Tararov,
V. I.; Bo¨rner, A. Synlett 2005, 203.
(6) For auxiliary-mediated variants, see: (a) Blaser, H.-U.; Buser, H.-
P.; Jalett, H. P.; Pugin, B.; Spindler, F. Synlett 1999, 867. (b) Kadyrov, R.;
Riermeier, T. H. Angew. Chem., Int. Ed. 2003, 42, 5472. (c) Tararov, V. I.;
Kadyrov, R.; Riermeier, T. H.; Fischer, C.; Bo¨rner, A. AdV. Synth. Catal.
2004, 346, 561. (d) Chi, Y. X.; Zhou, Y. G.; Zhang, X. M. J. Org. Chem.
2003, 68, 4120. (e) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2006, 128, 84.
(1) For examples of bioactive 1,3-amino alcohols, see: (a) Wang, Y.-
F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am. Chem. Soc. 1982, 104, 6465.
(b) Benz, G.; Henning, R.; Stasch, J.-P. Angew. Chem., Int. Ed. 1991, 30,
1702. (c) Boyd, S. A.; Fung, A. K. L.; Baker, W. R.; Mantei, R. A.; Armiger,
Y.-L.; Stein, H. H.; Cohen, J.; Egan, D. A.; Barlow, J. L.; Klinghofer, V.;
Verburg, K. M.; Martin, D. L.; Young, G. A.; Polakowski, J. S.; Hoffman,
D. J.; Garren, K. W.; Perun, T. J.; Kleinert, H. D. J. Med. Chem. 1992, 35,
1735. (d) Jacobi, P. A.; Murphree, S.; Rupprecht, F.; Zheng, W. J. Org.
Chem. 1996, 61, 2413. (e) Steinmetz, H.; Glaser, N.; Herdtweck, E.; Sasse,
F.; Reichenbach, H.; Ho¨fle, G. Angew. Chem., Int. Ed. 2004, 43, 4888.
(2) For previous approaches to the chiral 1,3-amino alcohol functionality,
which are however not as short and convergent as the one described herein,
see: (a) Pilli, R. A.; Russowsky, D.; Dias, L. C. Chem. Commun. 1987,
14, 1053. (b) Pilli, R. A.; Russowsky, D.; Dias, L. C. J. Chem. Soc., Perkin
Trans. 1 1990, 1213. (c) Ghosh, A. K.; Bilcer, G.; Schiltz, G. Synthesis
2001, 2203. (d) Keck, G. E.; Truong, A. P. Org. Lett. 2002, 4, 3131. (e)
Benedetti, F.; Berti, F.; Norbedo, S. J. Org. Chem. 2002, 67, 8635. (f)
Adamo, I.; Benedetti, F.; Berti, F.; Campaner, P. Org. Lett. 2006, 8, 51.
10.1021/ol062715y CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/23/2006

manner 1,3-syn-amino alcohols. Furthermore, the efficiency
of this method was expanded to an asymmetric aldol
reductive amination sequence for the rapid assembly of the
hydroxy-amine core of the pharmaceutically used9 HIV-
protease inhibitors ritonavir (1)10 and lopinavir (2)11 (Figure
1).
a Zimmerman-Traxler-type transition state (5), where R2
adopts an equatorial position, leading to the desired 1,3-syn
product. It should be noted that this synthetic design relies
on selective activation of imine 4 as one of the intermediates
in the reductive amination of carbonyls.5,6c
To test our notion for such a directed C-N bond
formation, the amination of hydroxy-ketone 7 was studied
with para-anisidine (8), which may be readily cleaved under
oxidative conditions (see below), in the presence of various
Lewis acids and hydride reagents. Representative results are
summarized in Table 1. Although various conditions12 (e.g.,
Table 1. Directed Reductive Amination of â-Hydroxy-ketone
7a
Figure 1. 1,3-syn-Amino alcohol functionality: a key element of
the HIV-protease inhibitors ritonavir (1) and lopinavir (2).
As outlined in Scheme 1, the 1,3-amino alcohol function-
ality may be obtained in a retro-synthetic sense by reductive
dr
yield
entry
MLn
H-
LiBH4
NaBH4
Hantzsch
ester
NaCNBH3
Hantzsch
ester
NaBH4
NaBH4
conditions
THF, rt
THF, rt
toluene,
60 °C
THF, rt
toluene,
60 °C
9/10b [%]c
1
2
3
NiCl2
ZnCl2
Sc(OTf)3
-
78:22
-
<5
27
<5
d
Scheme 1. Synthetic Concept for Accessing 1,3-syn-Amino
4
5
HOAc
83:17
52:48
22
14
Alcohols by Directed Reductive Amination
thiouread
6
7
8
9
10
11
Ti(iOPr)4
Ti(OEt)4
THF, rt
THF, rt
THF, rt
THF, rt
THF, rt
CH3CN,
81:19
70:30
82:18
80:20
83:17
89:11
45
32
16
28
66
81
Ti(Binol)(iOPr)2 NaBH4
TiCl(iOPr)3
Ti(iOPr)4
NaBH4
PMHS
PMHS
Ti(iOPr)4
(1.4 equiv)
(2.2 equiv)
-20 °C, 48 h
a
Typical reaction conditions: 24 h on a 1 mmol scale with 1.25 equiv
of Lewis acid (MLn), 2 equiv of reducing agent (H-), and 2 equiv of amine
b
8. Ratio was determined by RP-HPLC (Nucleosil 100-5 C18) (see
c
d
Supporting Information). Isolated yield after flash chromatography.
Reaction was run with 0.2 equiv of Lewis acid in the presence of 5 Å MS.
PMP: para-methoxy-phenyl.
amination of hydroxy-ketone 3, itself readily available by
aldol coupling. To access the 1,3-syn array 6, a chelation-
controlled intermolecular reduction was envisioned. As the
intermediate imino alcohol 4 was expected to strongly
coordinate to Lewis acids, reduction should then proceed in
entries 1-5) failed to give the desired amino alcohols in
preparatively useful yields, leading mainly to retro-aldol
processes (entries 1, 2, and 4), elimination (entry 3), or low
conversion (entry 5), the best results in the first screen were
obtained with the reagent combination Ti(iOPr)4/NaBH4
(entry 6) giving the desired amine 9 in promising yield and
(7) Asymmetric aminations of cyclic ketones have been reported: (a)
Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah,
R. D. J. Org. Chem. 1996, 61, 3849. (b) Williams, G. D.; Pike, R. A.;
Wade, C. E.; Wills, M. Org. Lett. 2003, 5, 4227. (c) Nugent, T. C.;
Seemayer, R. Org. Process Res. DeV. 2006, 10, 142. (d) Enders, D.; Paleek,
J.; Grondal, C. Chem. Commun. 2006, 655.
(8) Asymmetric reductive aminations with chiral amines are reported
by: Nugent, T. C.; Ghosh, A. K.; Wakchaure, V. N.; Mohanty, R. R. AdV.
Synth. Catal. 2006, 348, 1289.
(11) 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.
(9) (a) Abbenante, G.; Fairlie, D. P. Med. Chem. 2005, 1, 71. (b) Kaplan,
S. S.; Hicks, C. B. Expert Opin. Pharmacother. 2005, 6, 1573.
(10) 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.
(12) For related conditions for direct reductive aminations of carbonyls,
see: (a) entry 1, ref 4a. (b) Entry 2: Bhattacharyya, S. Synth. Commun.
1997, 27, 4265. (c) Entry 3: ref 4e. (d) Entry 4: Borch, R. F.; Bernstein,
M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897. (e) Entry 5: ref 4f.
(f) Entry 6: Bhattacharyya, S.; Neidigh, K. A.; Avery, M. A.; Williamson,
J. S. Synlett 1999, 1781.
268
Org. Lett., Vol. 9, No. 2, 2007

diastereoselectivity.12,13 Although this result could not be
further improved by modifying the ligand (entries 7-9), use
of polymethylhydrosiloxane as the hydride source14 gave
increased conversion and slightly improved selectivity (entry
10). After optimizing the reaction conditions (equivalents,
solvent, temperature, reaction time), the 1,3-syn-amino
alcohol 9 was obtained in good diastereoselectivity and yield
(entry 11).15
(e.g., 18) are accepted, demonstrating the general usefulness
of the protocol.15 Notably, a similar asymmetric induction
was observed also for sterically less-hindered substrates,
which may be due to steric requirements of the presumed
intermediate 5 (Scheme 1).
The starting materials in our procedure, chiral â-hydroxy-
ketones, are easily prepared by well-established asymmetric
aldol methodology, which adds to the usefulness of our
method for a rapid and general access to 1,3-syn-amino
alcohols. To demonstrate this aspect, a convergent assembly
of hydroxy-amine 24, the key building block of ritonavir
and lopinavir, was realized (Scheme 2). Our approach
As shown in Figure 2, various additional 1,3-syn-amino
Scheme 2. Asymmetric Aldol Directed Amination Sequence:
Convergent Assembly of the Hydroxy-Amine Core (24) of
Ritonavir/Lopinavir
involved a diastereoselective aldol coupling of phenylacetone
(20) with phenylalanine-derived aldehyde 21, both readily
available starting materials, and a subsequent amination of
intermediate ketone 22. Using chiral Ipc-boron-mediated
enolate methodology,16 the hydroxyl-bearing stereogenic
center of 22 was readily set up in a straightforward fashion.
In a one-pot-type sequence, this crude intermediate was then
directly submitted to our conditions of a directed amination
to give, after deprotection of the PMP group of 23, the
ritonavir/lopinavir core 24 in good yields. It should be noted
that this approach presents the shortest route to 24 reported
so far.2c,e,f
Figure 2. Selected applications of the method for the synthesis of
1,3-syn-amino alcohols with the indicated yields and diastereo-
selectivities.15
In summary, we have developed an efficient and opera-
tionally simple method for the directed reductive amination
of â-hydroxy-ketones to give 1,3-syn-hydroxy amines in
good chemical yields and diastereoselectivities. This ap-
proach presents one of the first examples of a general one-
pot directed reductive amination of acyclic ketones. The
efficiency of this protocol was demonstrated in the synthesis
of diverse amines. Furthermore, this procedure was expanded
to an asymmetric aldol reductive amination sequence,
allowing the so far shortest synthesis of the hydroxy-amine
core of the HIV-protease inhibitors ritonavir and lopinavir.
It is expected that this protocol will find applications in
medicinal chemistry and drug research and will stimulate
the development of further methods for asymmetric reductive
aminations.
alcohols were readily obtained under these conditions by
amination of the respective â-hydroxy-ketones. In all cases,
preparatively useful yields and selectivities resulted, without
the need for further adaptation of the reaction conditions for
specific substrates. In detail, aliphatic (9-15), cyclic (17),
as well as aromatic (16, 19) and heteroaromatic substrates
(13) Stereochemical assignment of 9 and 10 was based on J-based
configurational analysis and confirmed by NMR analysis of a cyclic
derivative (see Supporting Information):
(14) Chandrasekhar, S.; Reddy, C. R.; Ahmed, M. Synlett 2000, 1655.
(15) For experimental details, spectral data, HPLC traces, and copies of
NMR spectra for all new compounds, see Supporting Information.
(16) For a review on asymmetric boron-mediated aldol reactions, see:
Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
Org. Lett., Vol. 9, No. 2, 2007
269

Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie (‘Liebig-Stipendium’ to D.M.,
‘Doktorandenstipendium’ to F.A.) and the Deutsche Fors-
chungsgemeinschaft (grant ME 2765/2-1). We thank Antje
Ritter and Tatjana Arnold (both from Gesellschaft fu¨r
Biotechnologische Forschung) for technical support.
Supporting Information Available: Experimental de-
tails, spectral data, HPLC traces, and copies of NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL062715Y
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Org. Lett., Vol. 9, No. 2, 2007