Stereoselective synthesis of a potent human NK1 receptor antagonist via acyl-Claisen rearrangement

Article abstract of DOI:10.1055/s-2006-932489

Stereoselective synthesis of the tetrahydropyran derivative 1 is reported. Diastereoselective acyl-Claisen rearrangement was employed for formation of C3 and C4 chiral centres on the tetrahydropyran ring. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-932489

600
LETTER
Stereoselective Synthesis of a Potent Human NK1 Receptor Antagonist via
Acyl-Claisen Rearrangement
S
tereoselectiv
i
S
ynth
o
esis of
a
Pot
t
H
umranN 1
K
R
ecep
R
tor
A
ntagonist aubo,*a Claudio Giuliano,b Alastair W. Hill,a Ian T. Huscroft,a Clare London,a Austin Reeve,a
Eileen M. Seward,a Christopher G. Swain,a Janusz J. Kulagowskia
a
Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, CM20 2QR, UK
Fax +44(1279)440187; E-mail: piotr_raubo@merck.com
b
Department of Pharmacology, Istituto di Ricerche di Biologia Molecolare (IRBM) P. Angeletti, Merck Research Laboratories, Rome,
Italy
Received 1 December 2005
This work is dedicated to Professor Jerzy Wicha on the occasion of his 70th birthday.
CF3
CF3
Abstract: Stereoselective synthesis of the tetrahydropyran deriva-
tive 1 is reported. Diastereoselective acyl-Claisen rearrangement
was employed for formation of C3 and C4 chiral centres on the
tetrahydropyran ring.
CF3
CF3
O
O
N
O
Key words: acyl-Claisen rearrangement, asymmetric synthesis,
total synthesis, stereoselectivity, NK1 receptors
O
N
N
F
F
HN
O
Neurokinin-1 (NK1) receptor antagonists are of continu-
ing interest since the natural ligand for the NK1 receptor –
Substance P – has been implicated in the pathophysiology
of a wide range of disease conditions including neurogen-
ic inflammation, transmission of pain, emesis and depres-
sion.1,2 Recently, the Merck NK1 antagonist, aprepitant
(Emend®), has been approved for the prevention of acute
and delayed chemotherapy-induced nausea and vomiting
(Figure 1). Since 1991, when the first non-peptidic antag-
onist was reported,3 numerous selective and structurally
diverse NK1 ligands have been identified and subsequent-
ly developed.1,4 Recently, syntheses of trans,trans-substi-
tuted tetrahydropyran derivatives have been described.4g,h
In the search for selective hNK1 receptor antagonists, we
were interested in examining 3,4,5-trans,trans-trisub-
stituted tetrahydropyran derivatives. Compound 1 was
identified for synthesis and biological evaluation.
NH
Emend®
1
O
OH
Figure 1
In this communication, we report our approaches to the
stereoselective synthesis of a 3,4,5-trisubstituted tetra-
hydropyran 1, a potent NK1 receptor antagonist.
Conceptually, 1 can be disconnected into two fragments,
a trans lactone 2 and the chiral spiropiperidine 3
(Scheme 1).
We envisaged that the optically pure trans lactone 2
would be accessible from the chiral allyl ester 4 through
the diastereoselective Ireland–Clasien rearrangement5
and subsequent lactonisation of the resulting hydroxy
acid. In turn, 4 could be assembled from commercially
CF3
Ar
O
Ar
Ar
O
O
OH
RO
O
CF3
O
O
Br
5
6
O
O
O
O
N
MeO2C
2
F
RO
F
4
F
F
7
1
NH
8
O
O
OH
3
OH
Scheme 1 Ar = 3,5-bis(trifluoromethyl)phenyl
SYNLETT 2006, No. 4, pp 0600–0604
0
2.
0
3.
2
0
0
6
Advanced online publication: 20.02.2006
DOI: 10.1055/s-2006-932489; Art ID: D36205ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Synthesis of a Potent Human NK1 Receptor Antagonist
601
50% overall yields.6 The hydroxy group in 12 and 12a was
protected as a tert-butyldimethylsilyl ether and the ester
reduced using DIBAL-H to give Z-allylic alcohols 13 and
13a in 86% yield. Finally, the standard coupling of the
alcohol 13a with the acid 9 provided the allylic ester 14 in
86% yield. The Ireland–Claisen rearrangement of the
lithium enolate of 14 in the presence of trimethylsilyl
chloride yielded a mixture of isomeric acids that were
converted to methyl esters on treatment with trimethyl-
CF3
CF3
a, b
O
CF3
CF3
O
c
OH
6
X
9 X = OH
10 X = Cl
Scheme 2 Reagents and conditions: a) tert-butyl bromoacetate,
NaH, THF, 90%; b) TFA, CH2Cl2, 56%; c) (COCl)2, CH2Cl2, cat.
DMF, quant.
1
silyldiazomethane (Scheme 4). H NMR analysis of the
crude mixture of esters indicated the diastereoisomeric
ratio of mixture 15a:15b:15c:15d = 2:10:1:2. To establish
relative stereochemistry of products of the rearrangement,
the mixture of esters 15a–d was converted into a mixture
of tetrahydropyrans 17a–d as outlined in Scheme 4. Iso-
mers were separated and the relative stereochemistry of
diastereoisomers was assigned by 1H NMR/NOE experi-
ments. Disappointingly, we found that the undesired trans
isomer, 17b, was a major product of this sequence.
available compounds: bromoacetate 5, (R)-1-[3,5-bis(tri-
fluoromethyl)phenyl]ethanol (6), methyl acrylate (7) and
4-fluorobenzaldehyde (8).
Chiral alcohol 6 was chosen as a starting nonracemic
building block. We assumed that the chiral benzylic cen-
tre might be a stereocontrolling element in the [3+3] sig-
matropic rearrangement and would facilitate definition of
stereochemistry of new chiral centres on the tetrahydro-
pyran ring.
Ar
Ar
O
O
O
The synthesis started with alkylation of the commercially
available R alcohol 6 with tert-butyl bromoacetate fol-
lowed by removal of the tert-butyl group providing the
acid 9 in 50% overall yield (Scheme 2).
O
MeO
O
a
b, c
Ph
Ph
14
15a–d
TBSO
TBSO
Ar
Ar
O
MeO2C
O
O
c, d
17a (3R,4S)
17b (3S,4R)
17c (3R,4R)
17d (3S,4S)
a, b
TsO
d, e
O
3
4
Br
R
R
Ph
Ph
R = F 11
R = H 11a
R = F
8
R = H 8a
16
TBSO
OH
Scheme 4 Reagents and conditions: a) LiHMDS, TMSCl, THF,
then TMS–diazomethane, Et2O, MeOH, 65%; b) DIBAL-H, CH2Cl2,
77%; c) TsCl, Et3N, DMAP, CH2Cl2, 90%; d) TBAF, THF; e) BuLi,
THF, 64% (two steps). Ar = 3,5-bis(trifluoromethyl)phenyl.
MeO2C
e, f
HO
R
TBSO
R
R = F 12
R = H 12a
R = F 13
R = H 13a
Ar
To overcome this obstacle, we turned our attention
towards the acyl-Claisen rearrangement.7 Recently, Mac-
Millan and co-workers reported an enantioselective Lewis
acid catalysed acyl-Claisen rearrangement of allylic
amines and ketenes (Scheme 5).8 Ketenes were generated
in situ from corresponding acyl chlorides.
O
O
O
g
Ph
TBSO
14
Scheme 3 Reagents and conditions: a) methyl acrylate, DABCO,
60 °C, 66–70%; b) PBr3, Et2O, 0 °C to r.t.; c) Et3N, HCO2H, MeCN,
reflux; d) concd HCl, MeOH, 62–70% (3 steps); e) TBSCl, DMF,
imidazole, quant.; f) DIBAL-H, CH2Cl2, 86%; g) 13a, 9, EDC, Et3N,
DMAP, CH2Cl2, 86%. Ar = 3,5-bis(trifluoromethyl)phenyl.
O
O
R1
R1
R2
Cl
NR3
R32N
OLA
R32N+
LA
B
– LA
2
R1
R2
– BHCl
R2
Having prepared the acid 9, our next problem was Scheme 5
selective preparation of Z-allyl alcohols 13 and 13a
(Scheme 3). This was accomplished by a six-step se-
We have hypothesised that having a chiral centre on the
allylic amine might invert stereoselectivity in the sigma-
tropic rearrangement. With the allylic alcohol 13a in
hand, we were in a position to test this hypothesis and
briefly investigate this substrate control in the acyl-
Claisen reaction.
quence beginning with the Baylis–Hillman reaction of
methyl acrylate and corresponding benzaldehyde (8, 8a)
followed by treatment with PBr3 in diethyl ether to afford
allyl bromides 11 and 11a.6 Displacement of bromine in
11 and 11a with formate and hydrolysis of the resulting
formic acid ester gave allylic alcohols 12 and 12a in 40–
Synlett 2006, No. 4, 600–604 © Thieme Stuttgart · New York

602
P. Raubo et al.
LETTER
Ar
We began with the synthesis of allyl amines 18a and 18b
(Scheme 6). For our studies, we selected (R)-O-methyl-
prolinol as a chiral amine and morpholine as an achiral
analogue. Thus, treatment of the alcohol 13a with meth-
anesulphonyl chloride followed by the corresponding
amine afforded 18a9 and 18b in 61–67% yield. Reaction
of the allyl amine 18a and benzyloxyacetyl chloride in the
presence of i-Pr2EtN and catalytic TiCl4–THF2 yielded a
mixture of two major syn diastereoisomers in the ratio
19a:19b = 1:1. Pleasingly, reaction of the chiral acid
chloride 10 and 18a proceeded smoothly to give a mixture
of four diastereoisomers 20a–d in the ratio
20a:20b:20c:20d = 18:3:5:2 with the major syn diastereo-
isomer 20a10 having the correct stereochemistry at C2 and
C3 centres.11 Reaction of the morpholine 18b with 10 fur-
nished with a mixture of four morpholine amides 21a–d in
the ratio 21a:21b:21c:21d = 4.2:3:1:1 showing that both
chiral centres are required for selectivity.
O
O
N
a, b
13
O
F
22
TBSO
c, d, e
Ar
Ar
O
O
f, g, h
O
O
CHO
24
F
F
23
Scheme 7 Reagents and conditions: a) MsCl, Et3N, CH2Cl2, 0 °C,
then morpholine, 64%; b) 10, cat. TiCl4–THF2, i-Pr2EtN, CH2Cl2, –70 °C
to r.t., 27%; c) p-TSA, MeOH, PhMe, 71%; d) DIBAL-H, CH2Cl2,
–78 °C, quant.; e) Et3SiH, BF3·OEt2, CH2Cl2, 93%; f) BH3·THF,
–78 °C to r.t.; then H2O2, NaOH, 81%; g) (COCl)2, DMSO, Et3N,
CH2Cl2, –60 °C to 0 °C; h) DBU (cat.), CH2Cl2, 99% (two steps).
Ar = 3,5-bis(trifluoromethyl)phenyl.
O
OR3
Ph
NR1R2
OH
R1R2N
TBSO
a
b
2
3
Ph
Ph
TBSO
TBSO
13a
18a–b
using lithium borohydride, removal of the TBS group
with tetrabutylammonium fluoride and subsequent cyclo-
etherification of the resulting triol under Mitsunobu
conditions afforded the racemic alcohol 26 in 44% overall
yield.
NR1R2
OMe
R3
19a (2R,3S)
19b (2S,3R)
19c (2R,3R)
19d (2S,3S)
Ph
Ar
Ar
18a
N
N
OMe
20a (2R,3S)
20b (2S,3R)
20c (2R,3R)
20d (2S,3S)
21a (2R,3S)
21b (2S,3R)
21c (2R,3R)
21d (2S,3S)
18a
18b
NCbz
NCbz
a, b, c
O
O
EtO2C
N
OH
25
26
Scheme 6 Reagents and conditions: a) MsCl, Et3N, CH2Cl2, 0 °C,
then R1R2NH, 61–67%; b) BnOCH2COCl or 10, cat. TiCl4–THF2, i-
Pr2EtN, CH2Cl2, –10 °C to 10 °C (58% for 20a). Ar = 3,5-bis(trifluo-
romethyl)phenyl.
d
O
NR1
R =
O
O
O
The morpholine amide 22 was prepared from the alcohol
13 in a similar way as described for 21a (Scheme 7).
Acid-catalysed TBS-group deprotection–lactonisation on
the amide 22 followed by reduction to the corresponding
lactol using DIBAL-H gave a mixture of lactols which
were reduced to the tetrahydropyran 23 using triethyl-
silane in the presence of boron trifluoride–diethyl ether
complex. Hydroboration–oxidation of the double bond in
23 furnished a 2:1 mixture of hydroxymethyl epimers in
favour of the undesired 5R epimer. This mixture was
oxidised to the aldehyde under Swern conditions and the
mixture of aldehydes was allowed to equlibrate in the
presence of catalytic 1,8-diazabicyclo[5.4.0]undec-1-ene
(DBU) in dichloromethane providing the required 5S
aldehyde 24 (de 94% by 1H NMR) in 81% yield.
OR
1 = Cbz
27
R
e
28 R1 = H
Scheme 8 Reagents and conditions: a) TBSOCH2CHO, LiHMDS,
THF, 76%; b) LiBH4, THF; then TBAF, THF, 76%; c) DEAD, Ph3P,
THF, 76%; d) RCl, Et3N, DMAP, CH2Cl2, 38%, de 98%; e) Pd/C, H2,
TFA, EtOH, quant.
Acylation of 26 with (–)-camphanic acid chloride and
subsequent crystallisation of the mixture of diasteroiso-
meric esters from methanol–water gave the ester 27 as a
white solid (38% yield, de 98%).12 Removal of the benzyl
carbamate provided the spirocyclic piperidine 28 in quan-
titative yield.
Spirocyclic piperidine 27 was prepared starting from ethyl
isonipecotate 25 (Scheme 8). Aldol condensation of
the lithium enolate of 25 with (tert-butyldimethylsilyl-
oxy)acetaldehyde followed by reduction of the diester
Finally, reductive amination of the aldehyde 24 with
piperidine 28 and sodium triacetoxyborohydride followed
by saponification of the camphanate ester furnished 113 in
Synlett 2006, No. 4, 600–604 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of a Potent Human NK1 Receptor Antagonist
603
Ridgill, M. P.; Rycroft, W.; Tsao, K.-L.; Swain, C. J. Bioorg.
Med. Chem. Lett. 2002, 12, 1759. (d) Seward, E. M.;
Carlson, E.; Harrison, T.; Haworth, K. E.; Herbert, R.;
Kelleher, F. J.; Kurtz, M. M.; Moseley, J.; Owen, S. N.;
Owens, A. P.; Sadowski, S. J.; Swain, C. J.; Williams, B. J.
Bioorg. Med. Chem. Lett. 2002, 12, 2515. (e) Williams, B.
J.; Cascieri, M. A.; Chicchi, G. G.; Harrison, T.; Owens, A.
P.; Owen, S. N.; Rupniak, N. M. J.; Tattersall, F. D.;
Williams, A.; Swain, C. J. Bioorg. Med. Chem. Lett. 2002,
12, 2719. (f) Gale, J. D.; O’Neill, B. T.; Humphrey, J. M.
Expert Opin. Ther. Pat. 2001, 11, 1837. (g) Huffman, M.
A.; Smitrovich, J. H.; Rosen, J. D.; Boice, G. N.; Qu, C.;
Nelson, T. D.; McNamara, J. M. J. Org. Chem. 2005, 70,
4409. (h) Nelson, T. D.; Rosen, J. D.; Smitrovich, J. H.;
Payack, J.; Craig, B.; Matty, L.; Huffman, M. A.;
Ar
CF3
O
O
CF3
O
CHO
O
N
F
a, b
24
NH
F
O
1
O
OR
28
OH
Scheme 9 Reagents and conditions: a) NaHB(OAc)3, DCE;
b) NaOH, MeOH–H2O, 50%. Ar = 3,5-bis(trifluoromethyl)phenyl.
McNamara, J. Org. Lett. 2005, 7, 55.
(5) (a) Pereira, S.; Srebnik, M. Aldrichimica Acta 1993, 26, 17.
(b) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron:
Asymmetry 1996, 7, 1847.
(6) Beltaief, I.; Hbaieb, S.; Besbes, R.; Amri, H.; Villieras, M.;
Villieras, J. Synthesis 1998, 1765.
(7) Gonda, J. Angew. Chem. Int. Ed. 2004, 43, 3516.
(8) (a) Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 1999, 121, 9726. (b) Yoon, T. P.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2001, 123, 2911.
(9) Experimental Procedure for the Preparation of 18a.
Methanesulphonyl chloride (0.12 mL, 1.5 mmol) was added
dropwise to an ice-bath-cooled, stirring mixture of 13a (280
mg, 1 mmol), Et3N (0.4 mL, 2.8 mmol) and CH2Cl2 (2 mL).
The mixture was stirred for 90 min and (R)-2-(methoxy-
methyl)pyrrolidine (0.2 mL, 1.6 mmol) was added. The
mixture was stirred for 2 h and poured onto a sat. aq solution
of NaHCO3. The mixture was extracted into CH2Cl2. The
organic extract was dried (Na2SO4) and concentrated. The
residue was purified on silica gel (CH2Cl2–2 M NH3 in
MeOH, 0–10%) to give the amine 18a (230 mg, 61%). 1H
NMR (360 MHz, CDCl3): d = 0.04 (6 H, s), 0.90 (9 H, s),
1.61–1.77 (3 H, m), 1.86–2.01 (1 H, m), 2.21 (1 H, q, J = 8.5
Hz), 2.67 (1 H, m), 2.95 (1 H, d, J = 13.2 Hz), 3.04 (1 H, m),
3.25 (1 H, dd, J = 7.4, 9.1 Hz), 3.35 (3 H, s), 3.46 (1 H, dd,
J = 4.5, 9.3 Hz), 3.74 (1 H, d, J = 13.1 Hz), 4.26 (2 H, s), 6.58
(1 H, s), 7.29–7.31 (5 H, m).
50% yield (Scheme 9). The tetrahydropyran 1 was tested
in the NK1 receptor binding affinity assay in vitro14 and it
was found to antagonise the human NK1 receptor with
IC50 = 0.15 nM.
In conclusion, the stereoselective synthesis of novel NK1
antagonist based upon the tetrahydropyran framework
was developed. Diastereoselectivity in the acyl-Claisen
sigmatropic rearrangement of 18a,b and 10 was investi-
gated allowing inversion of the distereoselective outcome
of Ireland–Claisen rearrangement of 14. The synthesis of
tetrahydropyran 1 was accomplished and the binding af-
finity of 1 at the human NK1 receptor was determined. The
tetrahydropyran derivative 1 exhibited excellent binding
affinity at the human NK1 (IC50 0.15 nM).
Acknowledgment
The authors would like to thank M.M. Kurtz and G.G. Chicchi at
Merck Research Laboratories (Rahway) for NK1 receptor screening
results.
(10) Experimental Procedure for the Preparation of 20a.
TiCl4–THF2 (33 mg, 0.1 mmol) was added to a stirred
mixture of 18a (375 mg, 1 mmol), i-Pr2EtN (0.3 mL, 1.7
mmol) at –10 °C followed by 10 (510 mg, 1.5 mmol). The
mixture was stirred at –10 °C for 30 min and warmed to 10
°C over 1 h. The mixture was treated with 1 M aq NaOH and
the mixture was extracted into CH2Cl2. The organic extract
was dried (Na2SO4) and concentrated. The residue (a
mixture of 20a:20b:20c:20d in the ratio 18:3:5:2) was
purified on silica gel (i-hexane–EtOAc, 5–35%) to give the
amide 20a (390 mg, 58%, 5:1 mixture of rotamers). 1H NMR
(400 MHz, CDCl3, a major rotamer): d = –0.07 (3 H, s),
–0.06 (3 H, s), 0.83 (9 H, s), 1.31 (3 H, d, J = 6.4 Hz), 1.64–
2.00 (4 H, m), 3.26 (1 H, m), 3.29 (3 H, s), 3.33 (1 H, dd,
J = 6.5, 9.3 Hz), 3.52 (1 H, m), 3.83–3.97 (3 H, m), 4.20 (1
H, m), 4.36 (1 H, d, J = 9.3 Hz), 4.55 (1 H, q, J = 6.6 Hz),
4.97 (1 H, s), 5.15 (1 H, s), 7.20–7.26 (5 H, m), 7.44 (2 H, s),
7.74 (1 H, s).
References and Notes
(1) Seward, E. M.; Swain, C. J. Expert Opin. Ther. Pat. 1999, 9,
571.
(2) Kramer, M. S.; Cutler, N.; Feighner, J.; Shrivastava, R.;
Carman, J.; Sramek, J. J.; Reines, S. A.; Liu, G.; Snavely, D.;
Wyatt-Knowles, E.; Hale, J. J.; Mills, S. G.; MacCoss, M.;
Swain, C. J.; Harrison, T.; Hill, R. G.; Hefti, F.; Scolnick, E.
M.; Cascieri, M. A.; Chicchi, G. G.; Sadowski, S.; Williams,
A. R.; Hewson, L.; Smith, D.; Carlson, E. J.; Hargreaves, R.
J.; Rupniak, N. M. J. Science 1998, 281, 1640.
(3) Snider, R. M.; Constantine, J. W.; Lowe, J. A. III; Longo, K.
P.; Lebel, W. S.; Woody, H. A.; Drozda, S. E.; Desai, M. C.;
Vinick, F. J.; Spencer, R. W.; Hess, H.-J. Science 1991, 251,
435.
(4) For recent advances, see: (a) Shaw, D.; Chicchi, G. G.;
Elliott, J. M.; Kurtz, M. M.; Morrison, D.; Ridgill, M. P.;
Szeto, N.; Watt, A. P.; Williams, A. R.; Swain, C. J. Bioorg.
Med. Chem. Lett. 2001, 11, 3031. (b) Elliott, J. M.; Castro,
J. L.; Chicchi, G. G.; Cooper, L. C.; Dinnell, K.;
(11) Diastereomeric products of the acyl-Claisen reaction were
separable by flash chromatography and converted into the
corresponding lactones 17a–d as outlined in Scheme 4.
(12) Diasteromeric excess was determined by HPLC analysis.
The absolute stereochemistry of C3 centre of tetrahydro-
furan ring was determined by X-ray analysis of close
analogue of 1.
Hollingworth, G. J.; Ridgill, M. P.; Rycroft, W.; Kurtz, M.
M.; Shaw, D. E.; Swain, C. J.; Tsao, K.-L.; Yang, L. Bioorg.
Med. Chem. Lett. 2002, 12, 1755. (c) Cooper, L. C.;
Carlson, E. J.; Castro, J. L.; Chicchi, G. G.; Dinnell, K.; Di
Salvo, J.; Elliott, J. M.; Hollingworth, G. J.; Kurtz, M. M.;
Synlett 2006, No. 4, 600–604 © Thieme Stuttgart · New York

604
P. Raubo et al.
LETTER
(13) Experimental Procedure for the Preparation of 1.
Sodium triacetoxyborohydride (91 mg, 0.43 mmol) was
added to a stirred mixture of 24 (100 mg, 0.215 mmol) and
28 (73 mg, 0.216 mmol) and DCE (0.5 mL). The mixture
was stirred for 60 min and treated with a sat. aq solution of
NaHCO3 and extracted with CH2Cl2. The organic extract
was dried (Na2SO4) and concentrated. The mixture was
treated with MeOH (2 mL) and 4 M aq NaOH (0.3 mL) was
added dropwise. The mixture was stirred for 15 min, diluted
with H2O and extracted into CH2Cl2. The organic extract was
dried (Na2SO4) and concentrated. The residue was purified
on silica gel (CH2Cl2–MeOH, 0–10%) to give 1 (66 mg,
50%). 1H NMR (500 MHz, CDCl3): d = 1.30 (3 H, d, J = 6.4
Hz), 1.38–1.50 (3 H, m), 1.77 (1 H, dd, J = 3.0, 12.5 Hz),
1.81 (1 H, m), 1.97 (1 H, t, J = 10.7 Hz), 2.01–2.11 (2 H, m),
2.12–2.20 (1 H, m), 2.30 (1 H, t, J = 10.6 Hz), 2.40 (1 H, m),
3.12 (1 H, t, J = 11.5 Hz), 3.25 (1 H, t, J = 10.8 Hz), 3.42 (1
H, dt, J = 4.7, 9.8 Hz), 3.52 (1 H, AB, J = 8.6 Hz), 3.57 (1 H,
AB, J = 8.6 Hz), 3.64 (1 H, dd, J = 2.2, 10.1 Hz), 3.88 (1 H,
m), 4.01 (1 H, dd, J = 4.6, 10.1 Hz), 4.21 (1 H, dd, J = 4.5,
11.8 Hz), 4.25 (1 H, dd, J = 4.6, 11.0 Hz), 4.27 (1 H, q, J =
6.5 Hz), 6.83 (2 H, t, J = 8.9 Hz), 6.93 (2 H, m), 7.20 (2 H,
s), 7.66 (1 H, s).
(14) 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, 47, 458.
Synlett 2006, No. 4, 600–604 © Thieme Stuttgart · New York