Expeditious synthesis of novel NK1 antagonists based on a 1,2,4-trisubstituted cyclohexane

Article abstract of DOI:10.1016/j.tetlet.2005.12.067

A stereoselective asymmetric route to novel potent NK₁ antagonists based on a 1,2,4-trisubstituted cyclohexane core is discussed.

Full text of DOI:10.1016/j.tetlet.2005.12.067

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1295–1298
Expeditious synthesis of novel NK1 antagonists based on a
1,2,4-trisubstituted cyclohexane
Olivier Dirat,* Jason M. Elliott, Richard A. Jelley, A. Brian Jones and Michael Reader
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre,
Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
Received 12 October 2005; revised 6 December 2005; accepted 14 December 2005
Available online 10 January 2006
Abstract—A stereoselective asymmetric route to novel potent NK1 antagonists based on a 1,2,4-trisubstituted cyclohexane core is
discussed.
Ó 2005 Elsevier Ltd. All rights reserved.
The utility of neurokinin-1 receptor (NK1R) antagonists
for the treatment of chemotherapy-induced emesis has
now been established; Aprepitant (EmendÒ) 1 is cur-
rently the only commercially available drug in this
class.1 At one time, the 2,3-cis relationship seen in
Aprepitant was believed to be essential for binding to
the NK1R, however, a number of compounds with
trans–trans 1,2,3-trisubstituted five-2 (exemplified by 2)
and six-3 membered rings, with subnanomolar affinities,
have been reported since. Herein, we report the dis-
covery of potent NK1R antagonists based on a 1,2,4-tri-
substituted cyclohexane (exemplified by 3), and two
asymmetric routes to this core.
CF3
CF3
CF3
CF3
O
N
O
O
O
NH
HN
H
N
N
N
F
O
F
N
HN
1
2
CF3
CF3
O
The need for an efficient and scalable synthesis of the
key ketone 4 led us to investigate two routes. The first
route started from the chiral pool and used a diastereo-
selective 1,4-addition onto 7, followed by O-alkylation
of 5 with 6 resulting in inversion of configuration. The
second route started with a-arylation of 8 followed by
an asymmetric reduction of the ketone to yield 5
(Scheme 1).
N
N
N
F
3
metallic species (organolithium, Grignard), copper
sources (Li2Cu(CN)thienyl,5 CuBr, CuI, CuCN), Lewis
acid (none, BF3ÆOEt2) and solvents (Et2O, THF).
Although most of these combinations did not give a
satisfactory yield for the transformation (significant
1,2-addition was observed), gratifyingly a 92% yield of
the trans-isomer 10 was obtained using 4-fluorophenyl-
lithium and CuCN in THF. The deprotection of 10
was more problematic than expected, as TBAF in
THF gave multiple degradation products. TBAF buf-
fered with AcOH in THF avoided degradation but at
the expense of a very long reaction time. A practical
Our initial approach for the synthesis of 4 is shown in
Scheme 2. The a,b-unsaturated ketone 9 was obtained
in six steps from quinic acid in 15% yield and required
only one column chromatography.4 Numerous condi-
tions were tested to perform a diastereoselective 1,4-
addition onto 9 using various combinations of organo-
Keywords: NK1; Asymmetric synthesis; Triazole; a-Arylation.
*
Corresponding author. Tel.: +44 1279440307; fax: +44 1279440390;
e-mail: olivier_dirat@merck.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.067

1296
O. Dirat et al. / Tetrahedron Letters 47 (2006) 1295–1298
CF3
CF3
CF3
LG
6
OH
OP
CF3
O
1'
O
O
4
3
O
F
O
5
8
7
F
4 [3R,4S,4(1'R)]
O
O
O
Scheme 1. Retrosynthetic analysis.
using TFA in wet DCM gave the desired key ketone
OH
6 steps4
15%
48 in 11 steps and 4% overall yield.
OTBS
OH
OH
HO2C
O
This original approach has the advantage of being ster-
eoselective and reliable, but the length and the yield of
the sequence made it impractical for speedy delivery
of 4 in large quantities (>50 g). Accordingly, a shorter
synthesis of 5 was developed starting from the cheap
commercially available ketone 8 (Scheme 3). Using
Buchwald’s a-arylation conditions,9 14 was synthesized
in 70% yield on a 100 g scale. This racemic ketone was
reduced asymmetrically using Corey’s CBS oxazaboro-
lidine giving a 1/1 ratio of cis/trans diastereoisomers
by NMR (isolated yields: 5, 45%; 15, 38%) in modest
ee for the desired trans isomer 5 (54%) and good ee
for the cis isomer (86%).10,11 The next step of the
sequence (i.e., the preparation of 4) installed in a new
chiral centre with excellent stereoselectivity. Using
enantioimpure (54% ee) 5 in this reaction created a mix-
ture of diastereoisomers, which could be easily separated
by column chromatography to yield a single stereoiso-
OH
9
Quinic acid
i
OH
OR
iii
O
O
O
F
F
5
10 R = TBS
11 R = H
ii
CF3
iv
CF3
O
CCl3
NH
12
CF3
CF3
O
CF3
v
CF3
O
i
O
O
O
O
O
O
O
O
O
F
8
14
F
F
13
4
Scheme 2. Reagents and conditions: (i) 1-bromo-4-fluorobenzene, n-
BuLi, CuCN, THF, À78 to À40 °C, 92%; (ii) TFA, DCM, rt, 76%; (iii)
ethylene glycol, CSA, PhMe, D, 91%; (iv) 12, HBF4, DCE, DCM,
hexanes, À18 °C, 50%; (v) TFA, H2O, DCM, rt, 72%.
ii
OH
OH
O
O
O
O
F
F
solution was the use of TFA in DCM, which gave 76%
of the alcohol 11 in 1 h. Direct O-alkylation of 11 with
trichloroimidate 126 in the presence of a small amount
of tetrafluoroboric acid gave only traces of 4 and mostly
unreacted alcohol, but the same reaction conditions
applied to the protected ketone 5 produced the desired
stereoisomer 13 in 50% yield.7 A simple deprotection
5
15
54% ee
86% ee
Scheme 3. Reagents and conditions: (i) 1-bromo-4-fluorobenzene,
Pd2(dba)3 (1 mol %), Xantphos (2 mol %), NaOt-Bu, THF, D, 70%; (ii)
(R)-2-methyl-CBS-oxazaborolidine, BH3ÆDMS, PhMe, À40 to À6 °C,
5 45%, 15 38%.

O. Dirat et al. / Tetrahedron Letters 47 (2006) 1295–1298
1297
CF3
CF3
CF3
N
N
N
N
.2HCl
viii
CF3
CF3
CF3
O
O
O
20
X
O
N
N
N
Y
F
F
F
4
i, ii, iii 16 X = H,
Y = OH
3
iv
v
vi
17 X = OH, Y = H
hNK1R IC50 : 80 pM14
18 X = NHBn, Y = H
19 X = H,
Y = NHCH2CONH2
vii
20 X = NH2, Y = H
Scheme 4. Reagents and conditions: (i) NaBH4, MeOH, 0 °C, 99%, 16/17: 6/1; (ii) (R)-2-methyl-CBS-oxaborolidine, BH3ÆDMS, PhMe, À40 to
À20 °C, 75%, 16/17: 20/1; (iii) (S)-2-methyl-CBS-oxaborolidine, BH3ÆDMS, PhMe, À40 to À20 °C, 75%, 16/17: 20/1; (iv) L-Selectride, THF, À78 °C,
80%, 16/17: 1/8; (v) BnNH2, NaBH(OAc)3, DCE, rt, 80%, 18/epi-18: 20/1; (vi) H2NCH2CONH2, NaBH3CN, MeOH, rt, 90%, 19/epi-19: 3/1; (vii) H2
(1 atm), Pd/C, AcOEt, rt, 94%; (viii) 20, TMSCl, pyridine, 110 °C, 42%.
mer. As a result, the isolated yield from the transforma-
tion was reduced from 50% when the reaction was
performed with enantiopure 5, to 36%. This new
sequence for the synthesis of 4 is now only four steps
and gave an 8% overall yield. Although this yield is only
double that of the first sequence, the shortness of the
route allowed us to process over 100 g of 4.
Acknowledgements
We thank J. Kingston for ee determinations and
G. Chicchi, M. Kurtz and K.-I. Tsao for hNK1R IC50
determinations.
References and notes
Hydride addition to ketone 4 or its imine derivatives
gave rise to some interesting observations (Scheme 4).
While, as expected, a ‘small’ hydride gave preferentially
axial attack with a 6/1 ratio (i), to our surprise, both
enantiomers of Corey’s bulky 2-methyl-CBS-oxazaboro-
lidine also gave axial attack with an improved ratio of
20/1 ((ii) and (iii)). Finally, a ‘large’ hydride (L-Select-
ride) gave, as expected, equatorial attack with an 8/1
ratio (iv). These unexpected substrate controlled reactions
((ii) and (iii)) could be explained by the coordination of
the boron reducing agent to the ether oxygen, allowing
an intramolecular axial delivery of the hydride. Hydride
additions to imine derivatives of 4 also gave rise to use-
ful selectivities. Reductive amination with benzylamine
using sodium triacetoxyborohydride gave excellent
selectivity for the axial product 18, whereas reductive
amination with glycinamide using sodium cyanoboro-
hydride gave a 3/1 ratio in favour of the equatorial
amine 19. Compound 312 was then easily obtained from
18 by hydrogenolysis and triazole formation using N,N-
dimethylformamidazine.13
1. Dando, T. M.; Perry, C. M. Drugs 2004, 64, 777–794.
2. Finke, P. E.; Maccoss, M.; Meurer, L. C.; Mills, S. G.;
Caldwell, C. G.; Chen, P.; Durette, P. L.; Hale, J.; Holson,
E.; Kopka, I.; Robichaud, A. WO9714671, Chem. Abstr.
127, 17433.
3. (a) Owen, S. N.; Seward, E. M.; Swain, C. J.; Williams, B.
J. WO20000056727, Chem. Abstr. 133, 266729; (b) Nelson,
T. D.; Rosen, J. D.; Smitrovich, J. H.; Payack, J.; Craig,
B.; Matty, L.; Huffman, M. A.; McNamara, J. Org. Lett.
2005, 7, 55–58.
4. (a) Trost, B. M.; Romero, A. G. J. Org. Chem. 1986, 51,
2332–2342; (b) Audia, J. E.; Boisvert, L.; Patten, A. D.;
Villalobos, A.; Danishefsky, S. J. J. Org. Chem. 1989, 54,
3738–3740.
5. Caprio, V.; Mann, J. J. Chem. Soc., Perkin Trans. 1 1998,
3151–3156.
6. Prepared from enantiomerically pure (S)-1-[3,5-bis(trifluo-
romethyl)phenyl]ethanol (see Ref. 2) using trichloroaceto-
nitrile and DBU in dichloromethane in a quantitative
yield.
7. Procedure: To a solution of 5 (1.7 g, 7.2 mmol) in a
mixture of dichloroethane (20 mL) and hexanes (40 mL) at
À20 °C, was added 12 (5.81 g, 14.5 mmol), followed by
tetrafluoroboric acid (0.13 mL, 0.72 mmol) and the mix-
ture was stirred at À16 °C overnight. The solvent was then
removed in vacuo and 13 (1.73 g, 3.6 mmol) was isolated
after column chromatography on silica gel with a gradient
of ethyl acetate in hexanes 1–3% in 50% yield as a single
stereoisomer. 1H NMR (500 MHz, CDCl3): d 7.66 (s, 1H);
7.21 (s, 2H); 7.00 (m, 2H); 6.85 (m, 2H); 4.42 (q,
J = 6.4 Hz, 1H); 3.96 (m, 4H); 3.23 (dt, J = 4.1, 10.3 Hz,
1H); 2.95 (m, 1H); 2.19 (m, 1H); 1.90–1.60 (m, 5H); 1.28
(d, J = 6.4 Hz, 3H). HRMS (ESI). Calcd for C24H23F7O3:
492.1535. Found: 492.1524.
In conclusion, we have developed a concise asymmetric
synthesis of the key ketone intermediate 4 using a palla-
dium-catalyzed a-arylation of 8, followed by an asym-
metric reduction of the ketone. The shorter second
route delivered large amounts of 4 (>100 g), which
enabled us to assess the in vitro and in vivo properties
of NK1R antagonists based around this structure. The
reductions of 4 and its derivatives under a variety of
conditions gave rise to some interesting and useful selec-
tivities. Compounds derived from 4 generally display
very potent hNK1R affinities, as exemplified by 3, which
is an 80 pM hNK1R14 antagonist. A full account of the
medicinal chemistry of these compounds will be given
elsewhere.
8. 1H NMR (500 MHz, CDCl3): d 7.74 (s, 1H); 7.40 (s, 2H);
7.00 (m, 2H); 6.89 (m, 2H); 4.58 (q, J = 6.4 Hz, 1H); 3.61
(m, 1H); 3.17 (m, 1H); 2.68–2.52 (m, 3H); 2.42 (m, 1H);
2.27 (m, 1H); 1.89 (m, 1H); 1.26 (d, J = 6.4 Hz, 3H). 13C
NMR (91 MHz, CDCl3): d 209.5, 163.5, 160.8, 146.5,

1298
O. Dirat et al. / Tetrahedron Letters 47 (2006) 1295–1298
137.3 (d), 131.8 (q), 129.2 (d), 126.6, 125.1, 122.0 (q), 115.8
1.5 h and the mixture was stirred for 2 h at À20 °C then
warmed to À6 °C and stirred for one additional hour.
Methanol was then added and the mixture warmed to
room temperature. Ethyl acetate and water were added
and the layers separated. The organic layer was washed
with a saturated solution of sodium bicarbonate and
brine, dried over sodium sulfate, filtered and evaporated in
vacuo. Compound 5 (24.5 g, 97 mmol) (the more polar
diastereoisomer) was isolated after column chromatogra-
phy on silica gel with a gradient of ethyl acetate in hexanes
10–20% in 45% yield as a white solid.
(d), 77.9, 75.2, 48.9, 45.2, 38.2, 28.8, 24.8. HRMS (ESI).
Calcd for C22H19F7O2: 448.1273. Found: 448.1262.
9. Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. J. Am.
Chem. Soc. 2000, 122, 1360–1370.
10. Determined by chiral HPLC (chiralpak AD-H 250
*
4.6 mm i.d. ethanol/isohexane gradient. Baseline separa-
tion rt 5.1 and 8.4 min for 5, and 4.2 and 6.9 min for 15).
11. Procedure: Compound 8 (100 g, 0.64 mol), tris(dibenzyl-
ideneacetone)dipalladium(0) (3.4 g, 3.7 mmol), xantphos
(4.7 g, 8.05 mmol), sodium t-butoxide (81 g, 0.84 mol) and
tetrahydrofuran (450 mL) were mixed and degassed by
bubbling nitrogen through the mixture for 20 min. The
mixture was heated to 80 °C under a nitrogen atmosphere,
and 1-bromo-4-fluorobenzene (64 g, 0.36 mol) was added.
After 10 h at this temperature, the mixture was cooled to
room temperature, and ethyl acetate and water were
added, the layers separated, the organic layer washed with
a saturated solution of sodium bicarbonate and brine,
dried over sodium sulfate, filtered and evaporated in
vacuo. Compound 14 (64 g, 0.26 mol) (slightly less polar
than 8) was isolated after column chromatography on
silica gel with a gradient of ethyl acetate in hexanes 10–
20% in 70% yield.
12. 1H NMR (500 MHz, CDCl3): d 8.31 (s, 2H); 7.71 (s, 1H);
7.29 (s, 2H); 6.99 (dd, J = 5.4, 8.6 Hz, 2H); 6.92 (t,
J = 8.5 Hz, 2H); 4.50 (q, J = 6.4 Hz, 1H); 4.44 (t,
J = 3.9 Hz, 1H); 3.41–3.35 (m, 1H); 2.82–2.76 (m, 1H);
2.46–2.40 (m, 1H); 2.21–2.13 (m, 2H); 2.08–2.01 (m, 1H);
1.66–1.59 (m, 2H); 1.32 (d, J = 6.4 Hz, 3H). 13C NMR
(91 MHz, CDCl3): d 163.6, 160.8, 146.3, 141.9, 136.9 (d),
131.8 (q), 129.2 (d), 126.5, 125.1, 121.9 (q), 115.8 (d), 78.1,
74.7, 51.2, 44.1, 36.3, 28.7, 26.3, 24.9. HRMS (ESI). Calcd
for C24H22F7N3ONa: 524.1549. Found: 524.1538.
13. Samano, V.; Miles, R. W.; Robins, M. J. J. Am. Chem.
Soc. 1994, 116, 9331–9332.
14. Binding affinity determined from inhibition of [125I]
substance P to the hNK1 receptor in CHO cells as an
average of two determinations. Cascieri, M. A.; Ber, E.;
Fong, T. M.; Sadowski, S.; Bansal, A.; Swain, C. J.;
Seward, E. M.; Frances, B.; Burns, D.; Strader, C. D. Mol.
Pharmacol. 1992, 42, 458–463.
To a solution of (R)-2-methyl-CBS-oxazaborolidine (1 M
in toluene) (22 mL, 22 mmol) in toluene (1 L) was added
borane dimethyl sulfide (12.4 mL, 130 mmol), and the
mixture was cooled to À40 °C. A solution of 14 (54 g,
216 mmol) in toluene (270 mL) was added dropwise over