A concise asymmetric synthesis of torcetrapib

Article abstract of DOI:10.1021/jo071031g

(Chemical Equation Presented) Optically active torcetrapib was synthesized in seven steps from achiral precursors without the need for protecting groups, utilizing an enantioselective aza-Michael reaction to achieve asymmetry.

Full text of DOI:10.1021/jo071031g

A Concise Asymmetric Synthesis of Torcetrapib
Meritxell Guino´, Pim Huat Phua, Jean-Claude Caille,‡ and
King Kuok (Mimi) Hii*
Department of Chemistry, Imperial College London, Exhibition
Road, South Kensington, London SW7 2AZ, United Kingdom
mimi.hii@imperial.ac.uk
FIGURE 1. Structure of torcetrapib.
ReceiVed May 21, 2007
SCHEME 1. Published Asymmetric (Retrosynthetic) Route
to Torcetrapib
Optically active torcetrapib was synthesized in seven steps
from achiral precursors without the need for protecting
groups, utilizing an enantioselective aza-Michael reaction to
achieve asymmetry.
Hailed at one stage as “one of the most important drugs of our
generation”, it was to be the first CETP inhibitor to be developed
commercially, to be used in combination with a statin for the
treatment of CHD. However, despite a great deal of optimism
and anticipation, drug development was halted during late stages
of a Phase III clinical trial in December 2006, due to increased
risk of patient death. Clinical trial data subsequently revealed
that the combination therapy not only failed to inhibit the onset
of atherosclerosis but also appeared to elevate blood pressure,
despite significant improvements in lowering LDL-C and
increasing HDL-C levels.4 This unexpected result raised several
questions on the role of LDL-C and HDL-C on atherosclerosis
and the future of CETP inhibitors as therapeutic drugs. At the
time of writing, it is not clear whether the failure of the clinical
trial was due to specific toxicity or mechanism of action.5
Coronary heart disease (CHD) is caused by the build up of
fatty plaques in the coronary arteries (atherosclerosis), which
restricts blood flow to the heart. In the last few decades, it has
fast become the leading cause of death in many developed
countries, largely as a result of poor diet and lifestyle choices
adopted by an increasingly affluent society.
Currently, statins constitute one of the most effective classes
of drugs prescribed for the treatment of CHD, by reducing levels
of low-density lipoprotein cholesterol (LDL-C, “bad” choles-
terol) through the inhibition of an enzyme known as HMG-
CoA reductase. However, in recent years, adverse side effects
of statins are starting to emerge.1 Coupled with the expiry of
patent protection for several highly commercially successful
statins, there is a drive to develop drugs that can inhibit or
prevent atherosclerosis via novel mechanisms.2 In this context,
the story of torcetrapib (1, Figure 1) has been followed with a
great deal of interest, both by the pharmaceutical industry and
the media.The core structure of torcetrapib consists of a
tetrahydroquinoline with stereogenic centers at C-2 and C-4,
occupied by ethyl and N-benzylcarbamate substituents, respec-
tively. An inhibitor of the cholesteryl ester transfer protein
(CETP), it can boost the level of high-density lipoprotein
cholesterol (HDL-C, “good” cholesterol) and lower LDL-C.3
Preparative routes for compound 1 were first disclosed by
its inventors in the patent literature6 and subsequently in two
journal articles.7 In one of these reports, the tetrahydroquinoline
ring was constructed by a stereospecific ring cyclization of an
acyl immonium ion, generated from the N-arylated amino acid
derivative 2a (Scheme 1). Asymmetric synthesis of this key
(4) (a) Nissen, S. E.; Tardif, J.-C.; Nicholls, S. J.; Revkin, J. H.; Shear,
C. L.; Duggan, W. T.; Ruzyllo, W.; Bachinsky, W. B.; Lasala, G. P.; Tuzcu,
E. M. New Engl. J. Med. 2007, 356, 1304. (b) Kastelein, J. J. P.; van Leuven,
S. I.; Burgess, L.; Evans, G. W.; Kuivenhoven, J. A.; Barter, P. J.; Revkin,
J. H.; Grobbee, D. E.; Riley, W. A.; Shear, C. L.; Duggan, W. T.; Bots, M.
L. New Engl. J. Med. 2007, 356, 1620-1630.
(5) Nissen, S. E.; Tardif, J.; Nicholls, S. J.; Revkin, J. H.; Shear, C. L.;
Duggan, W. T.; Ruzyllo, W.; Bachinsky, W. B.; Lasala, G. P.; Tuzcu, E.
M. New Engl. J. Med. 2007, 356, 1304.
‡ PPG Fine Chemicals, Z. I. la Croix Cadeau, B.P. 79, 49242 Avrille´ Cedex,
France.
(1) Ravnskov, U.; Rosch, P. J.; Sutter, M. C.; Houston, M. C. Br. Med.
(6) (a) Damon, D. B.; Dugger, R. W. Eur. Pat. Appl. EP1125929, 2001
and US Patent 6,313,142, 2001. (b) Damon, D. B.; Dugger, R. W.; Scott,
R. W. US Patent 6,689,897, 2004.
J. 2006, 332, 1330.
(2) Kidd, J. Nat. ReV. Drug DiscoVery 2006, 5, 813.
(3) Brousseau, M. E.; Schaefer, E. J.; Wolfe, M. L.; Bloedon, L. T.;
Digenio, A. G.; Clark, R. W.; Mancuso, J. P.; Rader, D. J. New Engl. J.
Med. 2004, 350, 1505.
(7) (a) Damon, D. B.; Dugger, R. W.; Magnus-Aryitey, G.; Ruggeri, R.
B.; Wester, R. T.; Tu, M.; Abramov Y. Org. Process Res. DeV. 2006, 10,
464-471. (b) Damon, D. B.; Dugger, R. W.; Hubbs, S. E.; Scott, J. M.;
Scott, R. W. Org. Process Res. DeV. 2006, 10, 472-480.
10.1021/jo071031g CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/11/2007
6290
J. Org. Chem. 2007, 72, 6290-6293

SCHEME 2. Synthesis of Michael Acceptors
SCHEME 3. Chiral Ligand Screening
SCHEME 4. Preparation of Optically Active N-Arylated â-Amino Acid Derivatives 2a and 2b under Optimized Reaction
Conditions
intermediate was achieved in seven steps from (R)-2-aminobu-
tanol, involving the use of protecting groups and substantial
functional group conversions.
the presence of different ligands. Six chiral diphosphines were
chosen (Scheme 3), which were previously shown to induce
high enantioselectivity in analogous aza-Michael reactions.9
Initially, reactions were conducted using a protocol described
before: The palladium catalyst was formed in situ by stirring
Pd(OTf)2‚2H2O and a slight excess of the diphosphine ligand
for 1 h, whereupon a deeply colored (orange-red) solution was
generated. At 5 mol % catalyst loading, 1 equiv of the aniline
was exposed to an excess of the alkene substrate (1.5 equiv) at
room temperature in toluene. Under these conditions, the
addition product (S)-2a was obtained with high enantioselec-
tivities of between 81 and 85%, even though the reactions were
sluggish, achieving no more than 56% conversion in 3 days.
Among these, BINAP and P-Phos10 offered considerably higher
yields than the others.
Herein, we will describe an asymmetric synthesis of the
intermediate 2a in just four steps from achiral precursors, using
an enantioselective aza-Michael reaction developed in our
laboratory.8 Following our previously described methodology,
Michael acceptors 4a and 4b were prepared in high yields in
three steps (Scheme 2): a neat mixture of chloroacetyl chloride
and the requisite alkyl carbamate was heated to yield the
R-chlorocarbamate, which was subjected to an Arbuzov reaction
with triethylphosphite to give phosphonate esters 3a and 3b.
Both of these reactions can be performed without using any
solvents in one synthetic operation. Finally, the synthesis of
the R,â-unsaturated carbamates 4a and 4b was accomplished
by HWE reactions with propionaldehyde in the presence of
DBU. Analytically pure products can be obtained after recrys-
tallization.
Having identified the best-performing ligands, we optimized
the reaction. This included adjustment of reaction temperature,
dilution, catalyst loading, solvent, and substrate ratio (Supporting
Information). This led us to identify a new set of conditions
that afforded substantial improvement in reaction yield, which
was subsequently adopted to provide optically active N-arylated
â-amino acid carbamate esters (Scheme 4). Using (R)-BINAP
The addition of 4-trifluoromethylaniline to 4a, the direct
precursor of the target molecule, was examined in parallel in
(8) Hii, K. K. Pure Appl. Chem. 2006, 78, 341-349.
J. Org. Chem, Vol. 72, No. 16, 2007 6291

SCHEME 5. Final Assembly of the Target Molecule
an optically pure sample of (R)-2a (>99% ee, 100 mg) was
obtained from the mother liquor (Figure 2). Indeed, this process
of enantiomeric entrainment is highly reproducible and seems
to be independent of the initial enantiomeric excess of 2a.12
Thus, it will appear that the N-arylated â-amino acid derivative
possesses a particularly high eutectic enantiomeric excess value
in this mixed-solvent system.13 The crystallinity of the samples
was reflected by the observation of different melting points:
optically pure 2a (72-73 °C, >99% ee) has a much lower value
than a less optically active sample (109-111 °C, 37% ee).14
Optically pure intermediate (R)-2a was subsequently con-
verted to torcetrapib using published procedures (Scheme 5):7
formation of the tetrahydroquinoline heterocycle was effected
using the Lewis acid mediated reduction, with the stereochem-
istry at C-2 directing the cyclization stereospecifically to give
(2R,4S)-5 as a single diastereomer in an excellent yield.
Derivatization at N-1 was then achieved by the reaction with
ethyl chloroformate and pyridine, giving (2R,4S)-6 in a high
yield.
The final alkylation step proved to be tricky, due to
considerable steric congestion at N-2. As the reaction is quite
slow, the formation of a byproduct becomes competitive.15 In
our hands, the reaction of (2R,4S)-6 with 3,5-bis(trifluoro-
methyl)benzyl bromide using potassium tert-butoxide in dichlo-
romethane did not proceed to completion, as the presence of 6
persisted in the final reaction mixture. Hence, this remained
the only step in the synthetic sequence where column chroma-
tography was required, giving the product in a moderate yield
of 52%.16
FIGURE 2. Enantiomeric enrichment by recrystallization of optically
active 2a of 60% ee (predominantly (R)-isomer) from toluene.cyclo-
hexane: Chiral HPLC chromatograph of (a) deposited crystals (36%
ee); (b) mother liquor (>99% ee).
and (S)-P-Phos, preparative quantities of (S)- and (R)-2a can
be obtained, respectively, in good yields with ca. 90% ee
(Scheme 4). The reaction proceeded to completion more rapidly
when P-Phos was used, as the catalyst was more soluble under
these conditions. Similarly, as the benzyl carbamate 4b is
considerably more soluble than 4a, the corresponding reaction
was complete in 24 h (using the (R)-BINAP ligand), affording
the addition product (S)-2b in 79% yield and 89% ee.
Notably, the palladium catalyst appeared to be much more
efficacious when it was generated in situ, as the corresponding
reaction conducted with the isolated [(BINAP)Pd(OH2)2]2+[TfO]-
2
complex (5 mol %) resulted in much lower selectivities (68 and
75% ee for 2a and 2b, respectively).11 This is in accordance
with our earlier observation9 and attributed to the generation of
a more stable catalyst, as a slight excess of the chiral diphos-
phine ligand can be employed.
All the characterization data for the final compound are in
good agreement with that previously reported. In contrast to its
The Michael product can be purified by column chromatog-
raphy. Alternatively, the catalyst can be removed from the
reaction mixture by filtration through an absorbent (silica gel).
The filtrate was then evaporated to give a yellow residue, from
which compound 2a can be separated from the excess aniline
by recrystallization from toluene/cyclohexane. During this
process, we discovered that the product crystallizes preferentially
as a heterochiral conglomerate. Initially, the crude mixture (90%
ee) deposited a crop of crystals with low enantiomeric excess
(60% ee), while the mother liquor was found to contain a
substantial amount of compound 2a of extremely high optical
purity (95% ee), as verified by chiral HPLC. The process can
be repeated using the first crop of crystals (60% ee, 250 mg),
again by recrystallization from toluene/cyclohexane, to afford
a precipitate of reduced enantiopurity (37% ee, 140 mg), while
(9) Phua, P. H.; de Vries, J. G.; Hii, K. K. AdV. Synth. Catal. 2006, 348,
587-592.
(10) For applications of P-Phos in other asymmetric catalytic reactions,
see: Wu, J.; Chan, A. S. C. Acc. Chem. Res. 2006, 39, 711-720.
(11) In a recent article, 10 mol % of [(BINAP)Pd(OH2)2]2+[TfO]-2 was
required to attain a similar ee (89%) in the addition of p-CF3C6H4NH2‚
HOTf to 4a: Hamashima, Y. Chem. Pharm. Bull. 2006, 54, 1351-1364.
(12) The process was replicated three times using various samples of 2
with enantiomeric excesses between 60 and 89%. On every occasion,
samples recovered from the mother liquor were found to possess ee values
of g95%. See Experimental Section for a representative procedure.
(13) (a) For an excellent discussion of phase behavior of chiral
compounds, see: Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; John Wiley & Sons: New York; Chapters 6 and 7. (b) For a
recent report of the eutectic ee of amino acids, see: Klussmann, M.; White,
A. J. P.; Armstrong, A.; Blackmond, D. G. Angew. Chem., Int. Ed. 2006,
45, 7985-7989.
(14) Melting point recorded for a “solvent-free sample” was reported to
be 142.3-142.4 °C (ref 7b).
6292 J. Org. Chem., Vol. 72, No. 16, 2007

mixture was filtered through silica gel and evaporated. The residue
can be purified by column chromatography or by recrystallization.
The product was obtained (after column chromatography) as
predominantly the (R)-isomer in 80% yield and 91% ee.
precursors 5 and 6, torcetrapib exhibits extremely broad NMR
resonance signals even at 55 °C, particularly the N-2 substit-
uents. Full assignment of NMR data was eventually achieved
by performing COSY, HMQC, TOCSY, and HETCORR (13C-
19F) correlation experiments.
N-[3-(4-Trifluoromethylphenylamino)pentanoyl]methyl car-
bamate, 2a:7 White solid; purified either by column chromatog-
raphy (Rf ) 0.65, SiO2, 2% MeOH/CH2Cl2) or by recrystallization
In summary, a practical asymmetric synthesis of torcetrapib
from achiral precursors has been demonstrated. Using a Pd-
catalyzed enantioselective aza-Michael reaction as the key bond-
forming step, the overall synthesis requires only seven steps
from chloroacetyl chloride. The process is highly practical, as
it does not require the use of protecting groups. Furthermore,
all of the synthetic intermediates are crystalline solids that can
be purified by crystallization. As the stereochemistry is estab-
lished by the aza-Michael reaction, the approach is also more
convergent, thus allowing structural modifications to be easily
achieved. We envisage that the methodology is applicable for
the synthesis of structurally related 4-amino-2-alkyl-1,2,3,4-
tetrahydroquinolines, a key structural motif found in many other
pharmacologically important molecules.17
22
from toluene/cyclohexane; [R]D -10.0 (CHCl3, c ) 0.02 g/mL,
86% ee, (S)-isomer); Daicel Chiralpak AD; hexane/i-PrOH 95/5;
sample concentration ) 1 mg/mL in i-PrOH, flow rate ) 1.2 mL/
min; 254 nm, tR ) 30.5 [S-(-)-isomer] and 37.0 [R-(+)-isomer]
min; δH (400 MHz, CDCl3) 7.55 (1H, br s, NH), 7.37 (2H, d, J )
8.6 Hz, Ar-H), 6.61 (2H, d, J ) 8.6 Hz, Ar-H), 4.19 (1H, br s,
NH), 3.80-3.94 (1H, m, CHN), 3.77 (3H, s, OCH3), 3.09 (1H, dd,
J ) 16, 6.5 Hz, CH2CO), 2.97 (1H, dd, J ) 16, 5.6 Hz, CH2CO),
1.64-1.74 (2H, m, CH2CH3), 0.99 (3H, t, J ) 7.5 Hz, CH2CH3);
δC (100.6 MHz, CDCl3) 172.6 (CdO), 152.3 (C), 149.8 (CdO),
126.7 (CH), 124.9 (q, J ) 270 Hz, CF3), 118.8 (q, J ) 33 Hz,
CH), 112.3 (CH), 53.2 (CH), 51.2 (CH3), 39.8 (CH2), 27.9 (CH2),
10.4 (CH3); m/z (CI+) 319 (MH+, 100%).
Achieving Enantiopurity by Recrystallization. In a small
round-bottom flask equipped with a condenser, a sample of optically
active 2a (250 mg, 60% ee, enriched in the (R)-isomer) was
suspended in cyclohexane (8 mL) and heated to reflux. Toluene
was added dropwise to the boiling suspension via the condenser,
until complete dissolution of the solid. The solution was allowed
to cool slowly to room temperature. Crystallization was judged to
be complete after 3 h, whereupon white needle-like crystals were
collected by filtration and dried under vacuum (140 mg, 37% ee,
mp 109-111 °C). The filtrate was evaporated, and the resultant
pale yellow residue was triturated with cyclohexane to give optically
pure (R)-2a (100 mg, >99% ee, mp 72-73 °C).
Experimental Section
Representative aza-Michael Reaction (Preparative Scale): In
a three-neck round-bottom flask equipped with a stirrer bar, reflux
condenser, and nitrogen inlet, Pd(OTf)2‚2H2O (84 mg, 0.19 mmol,
5 mol %) and (S)-P-Phos (135 mg, 0.21 mmol, 5.5 mol %) were
mixed in degassed dry toluene (5 mL) at 50 °C for 40 min,
whereupon a dark red solution was formed. The catalyst mixture
was diluted by the addition of toluene (20 mL), before the addition
of substrates methyl carbamate 4a (600 mg, 3.81 mmol, 1 equiv),
(4-trifluoromethyl)aniline (720 µL, 5.7 mmol, 1.5 equiv), and a
further portion of toluene (22.5 mL). The reaction mixture was then
left to stir at 50 °C for 36 h (complete consumption of 4a was
indicated by TLC). After cooling to room temperature, the reaction
Acknowledgment. The work was supported by PPG Fine
Chemicals. We are grateful to Professor Alan Armstrong
(Imperial College) for discussions on eutectic ee’s.
Supporting Information Available: Experimental procedures
and characterization data for compounds 3a, 3b, 4a, 4b, 5, and 6.
Catalytic reaction optimization, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Resulting from the dimerization of the reactive benzyl bromide,
giving a stilbene byproduct (ArCHdCHAr). This was reported previously
in ref 7b.
(16) In the original reports (ref 7), the base was added in two portions.
Torcetrapib was obtained as a monoethanolate in 73% yield.
(17) Bazin, M.; Kuhn, C. J. Comb. Chem. 2005, 7, 302-308 and
references therein.
JO071031G
J. Org. Chem, Vol. 72, No. 16, 2007 6293