Synthesis of a tetrahydropyran NK1 receptor antagonist via asymmetric conjugate addition

Article abstract of DOI:10.1021/jo0504161

Two asymmetric syntheses of the NK₁ receptor antagonist 1-[2-(R)-{1-(R)-[3,5-bis(trifluoromethyl)-phenyl]ethoxy}-3-(R)-(3, 4-difluorophenyl)-4-(R)-tetrahydro-2H-pyran-4-ylmethyl]-3-(R) -methylpiperidine-3-carboxylic acid (1) were developed. In

Full text of DOI:10.1021/jo0504161

Synthesis of a Tetrahydropyran NK1 Receptor Antagonist via
Asymmetric Conjugate Addition
Mark A. Huffman,* Jacqueline H. Smitrovich, Jonathan D. Rosen, Genevie`ve N. Boice,
Chuanxing Qu, Todd D. Nelson, and James M. McNamara
Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065
mark_huffman@merck.com
Received March 4, 2005
Two asymmetric syntheses of the NK1 receptor antagonist 1-[2-(R)-{1-(R)-[3,5-bis(trifluoromethyl)-
phenyl]ethoxy}-3-(R)-(3,4-difluorophenyl)-4-(R)-tetrahydro-2H-pyran-4-ylmethyl]-3-(R)-methylpi-
peridine-3-carboxylic acid (1) were developed. In both routes, the core tetrahydropyran stereo-
chemistry was established by asymmetric conjugate addition to an R,â-unsaturated ester (6), using
an amide of the chiral auxiliary pseudoephedrine. Selective ester reduction then allowed formation
of lactone 2 with the thermodynamically preferred trans geometry. The chiral ether side chain (3)
was attached by stereoselective acetal substitution. In the first route, the chiral piperidine ester
fragment was installed at the end by N-alkylation. In the shorter second synthesis, this piece was
appended to the Michael acceptor at the beginning.
Introduction
compound, an efficient and practical synthesis was
required that would allow the preparation of kilogram
quantities. Conceptually, 1 can be broken into three
fragments, a trans-disubstituted lactone 2, the chiral
benzylic alcohol 3, and the chiral piperidine fragment 4
(Scheme 1). An acetal formation related to glycosidation
chemistry should join 2 and 3, and N-alkylation would
attach 4.
Short syntheses of enantiopure fragments 3 and 4 were
already established,5,6 so the focus was on identifying an
efficient method to prepare the core lactone 2. In a
previous synthesis of an analogue to 1, the analogous
lactone was assembled via an SN2 reaction between the
The neurokinin-1 (NK1) receptor preferentially binds
the tachykinin substance P, and this pathway plays an
important role in the response to stressful and inflam-
matory stimuli.1 An NK1 receptor antagonist, as part of
combination therapy, has been shown to prevent acute
and delayed chemotherapy-induced nausea and vomit-
ing.2 The development of new NK1 antagonists remains
an active area of pharmaceutical research.3
The tetrahydropyran 1 was identified as a potent and
selective antagonist of NK1.4 To further study this
(1) For selected reviews see: (a) Otsuka, M.; Yoshioka, K. Physiol.
Rev. 1993, 73, 229-308. (b) MacLean, S. Med. Res. Rev. 1996, 16, 297-
317.
(2) Navari, R. M.; Reinhardt, R. R.; Gralla, R. J.; Kris, M. G.;
Hesketh, P. J.; Khojasteh, A.; Kindler, H.; Grote, T. H.; Pendergrass,
K.; Grunberg, S. M.; Carides, A. D.; Gertz, B. J. N. Engl. J. Med. 1999,
340, 190-195.
(3) For recent examples see: (a) Seto, S.; Tanioka, A.; Ikeda, M.;
Izawa, S. Bioorg. Med. Chem. Lett. 2005, 15, 1485-1488. (b) Ishichi,
Y.; Ikeura, Y.; Natsugari, H. Tetrahedron 2004, 60, 4481-4490. (c)
Albert, J. S.; Ohnmacht, C.; Bernstein, P. R.; Rumsey, W. L.; Aharony,
D.; Alelyunas, Y.; Russell, D. J.; Potts, W.; Sherwood, S. A.; Shen, L.;
Dedinas, R. F.; Palmer, W. E.; Russel, K. J. Med. Chem. 2004, 47, 519-
529. (d) Reichard, G. A.; Stengone, C.; Paliwal, S.; Mergelsberg, I.;
Majmundar, S.; Wang, C.; Tiberi, R.; McPhail, A. T.; Piwinski, J. J.;
Shih, N.-Y. Org. Lett. 2003, 5, 4249-4251.
(4) Owen, S. N.; Seward, E. M.; Swain, C. J.; Williams, B. J. U.S.
Patent 6,458,830 B1, 2001.
(5) (a) Brands, K. M. J.; Payack, J. F.; Rosen, J. D.; Nelson, T. D.;
Candelario, A.; Huffman, M. A.; Zhao, M.; Li, J.; Craig, B.; Song, Z.;
Tschaen, D. M.; Hansen, K.; Devine, P. N.; Pye, P. J.; Rossen, K.;
Dormer, P.; Reamer, R. A.; Welch, C. J.; Mathre, D.; Tsou, N. N.;
McNamara, J. M.; Reider, P. J. J. Am. Chem. Soc. 2003, 125, 2129-
2135. (b) Hansen, K. B.; Chilenski, J. R.; Desmond, R.; Devine, P. N.;
Grabowski, E. J. J.; Heid, R.; Kubryk, M.; Mathre, D. J.; Varsolona,
R. Tetrahedron: Asymmetry 2003, 14, 3581-3587.
(6) 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.
10.1021/jo0504161 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/29/2005
J. Org. Chem. 2005, 70, 4409-4413
4409

Huffman et al.
SCHEME 1
SCHEME 2
chosen because of our previous experience that it pro-
vided crystalline intermediates in a related series of
compounds.6 Selective reduction of 10 to primary alcohol
11 was best accomplished with LAH below -30 °C. The
stereoisomeric mixture of alcohols could then be cyclized
to cis and trans lactones with a strong acid such as
hydrochloric, p-toluenesulfonic, or methanesulfonic acid.
Treatment of the lactones with catalytic DBU gave an
equilibrium 94:6 trans/cis ratio, in which the trans
lactone (12) ee was 87%.
dianion of phenylacetic acid and an enantiopure second-
ary tosylate 5, followed by oxygen deprotection and
lactonization.6 While practical, this route was lengthy
since the synthesis of 5 required five steps including a
kinetic resolution. In striving for a shorter overall route,
we decided to try to access 2 through an asymmetric
conjugate addition reaction to a Michael acceptor 6.
Lactone Synthesis. Although (R,R)-lactone 12 was
crystalline, isolation in pure form from the crude mixture
proved to be difficult. A more successful approach was
to achieve chemical and stereoisomeric purification by
isolation of crystalline Michael adduct 10, crystallized in
56% yield and 97.6% de from toluene/heptane.
From isolated 10, reduction with LAH gave a single
isomer of hydroxy amide 11. Lactonization to 12 could
be accomplished with anhydrous HCl, allowing for simple
recovery of the crystallized pseudoephedrine HCl salt.
However, HCl delivered 12 as a mixture with the cis
lactone that required epimerization with DBU. The use
of methanesulfonic acid for the cyclization minimized cis
lactone formation and 12 could be crystallized from
isopropyl acetate/heptane in 78% yield from 10 and 99.8%
ee.
Acetal Formation. Having prepared the lactone, the
next problem was stereoselective installation of the (R)-
bis(trifluoromethyl)phenylethyl ether side chain. Reduc-
tion of 12 to lactol 13 could be done with DIBALH at -30
°C, or more conveniently with lithium tri-tert-butoxy-
aluminohydride at 0 °C (Scheme 3). The interconverting
mixture of anomers crystallized as all-trans-13 from
toluene/hexanes. The glycosidation-like substitution reac-
tion to give acetal 16 requires activation of the lactol.
Several ester and imidate activations were tried. The best
method was formation of the p-nitrobenzoates 14, as an
un-isolated trans/cis mixture, followed by BF3-catalyzed
substitution at -30 °C, to give 16 in 94:6 2,3-trans/2,3-
cis selectivity. The high kinetic stereoselectivity is be-
lieved to be a steric result in which the bulky secondary
alcohol adds trans to the aryl substituent in the di-
pseudoaxial oxocarbenium intermediate 15. If the reac-
Results and Discussion
Asymmetric Michael Addition. Conjugate addition
of an amide derivative of 3,4-difluorophenylacetic acid
to an R,â-unsaturated ester 6 was expected to give an
amido ester. Selective reduction of the ester group to a
primary alcohol should allow formation of the six-
membered-ring lactone 2 with expulsion of the amine
from the amide moiety. We knew that a cis/trans mixture
of lactones could be epimerized to primarily the desired
trans-6 so the kinetic stereochemistry at the aryl-bearing
enolate R-carbon was not critical. Several amine chiral
auxiliaries were evaluated for their ability to control
facial selectivity on the Michael acceptor, as determined
by ee measurement after conversion to the crude trans
lactone.7 From these experiments, (R,R)-pseudoephedrine
amide 8 was chosen.
Deprotonation of 8 with 2 equiv of LHMDS in the
presence of TMEDA followed by the addition of acceptor
9 at -70 °C gave a mixture of amido esters in which the
anti-(R,R) isomer 10 was the major product (Scheme 2).7
The p-methoxyphenyl (PMP) protecting group on 9 was
(7) Smitrovich, J. H.; Boice, G. N.; Qu, C.; DiMichele, L.; Nelson, T.
D.; Huffman, M. A.; Murry, J.; McNamara, J.; Reider, P. J. Org. Lett.
2002, 4, 1963-1966.
4410 J. Org. Chem., Vol. 70, No. 11, 2005

Synthesis of an NK1 Receptor Antagonist
SCHEME 3
SCHEME 5
hydrolysis of the ethyl ester followed by crystallization
of the salt with methanesulfonic acid. The overall yield
was 25% from 3,4-difluorophenylacetic acid.
SCHEME 4
Second Generation Route. In considering possible
shorter syntheses, we noted that installing the chiral
piperidine fragment 4 at the beginning might eliminate
three steps involved in the protecting group chemistry.
It was expected, however, that carrying the aminoester
through the entire synthesis would present challenges.
The ethyl ester group would need to survive reductions
of both the Michael adduct and the lactone as well as
the lactone formation step. The tertiary amine might
complicate lactonization and Lewis acid-catalyzed acetal
formation.
Lactone Synthesis. Preparation of the chiral Michael
acceptor 19 was done by reaction of piperidine 4 (as the
di-p-toluoyl-D-tartaric acid salt from the resolution) with
ethyl bromocrotonate (Scheme 5). The product was puri-
fied by crystallization of the tosylate salt, then converted
to the free base before use.
Reaction of pseudoephedrine amide 8 with 19 under
the previously used conditions gave results that were
disappointing with respect to both yield and stereoselec-
tivity. Fortunately, addition of lithium chloride (5 equiv)
to the reaction mixture gave dramatically improved
results, with 20 being formed in 95% yield and 92% de.9
Although addition to acceptor 19 occurred from the re
face as before, with LiCl the syn product was now formed.
Attempted use of LAH for the reduction of 20 was not
selective, with both ethyl esters apparently undergoing
some reduction. Lithium tri-sec-butylborohydride, on the
other hand, was selective. It seems that the adjacent
quaternary center protects the nipecotate ester from
reaction with this bulky reducing agent. The hydroxy-
amide 21 was isolated in 79% yield by crystallization.
Acid-mediated cyclization of syn-hydroxy-amide 21 was
slow, requiring 5 days at 60 °C, while the minor anti
component in crude samples lactonized quickly. The
lactone was formed in a trans/cis ratio of 85:15. After
removal of pseudoephedrine by chromatography, the
tion mixture is warmed before quenching, the product
epimerizes to a lower thermodynamic ratio of 75:25.
Completion of the Synthesis. While trans,trans-16
is a solid, it could not be isolated in high yield without
chromatography. Instead, the crude reaction mixture was
taken forward. Reaction with CAN cleaved the PMP
protecting group to give 17, which was also not isolated
(Scheme 4). The primary alcohol was activated with
benzenesulfonyl chloride and DABCO,8 and the chiral
piperidine fragment was then installed via N-alkylation.
Addition of water to the acetonitrile reaction mixture
directly crystallized 18 in high diastereomeric and chemi-
cal purity. The yield was 80% from the last isolated
intermediate, lactol 13. The synthesis was completed by
(8) Hartung, J.; Hu¨nig, S.; Kneuer, R.; Schwarz, M.; Wenner, H.
Synthesis 1997, 1433-1438.
(9) Smitrovich, J. H.; DiMichele, L.; Qu, C.; Boice, G. N.; Nelson, T.
D.; Huffman, M. A.; Murry, J. J. Org. Chem. 2004, 69, 1903-1908.
J. Org. Chem, Vol. 70, No. 11, 2005 4411

Huffman et al.
polyethylene sheets. In the NMR spectra of amide compounds,
the separated signals of minor rotamers are indicated with
an asterisk.
SCHEME 6
(E)-1-(3-Ethoxycarbonylallyl)-3-(R)-methylpiperidine-
3-carboxylic Acid Ethyl Ester (19). To a suspension of (R)-
ethyl-3-methylpiperidine-3-carboxylate di-p-toluoyl-D-tartaric
acid salt6 (1.82 g, 5.0 mmol) and diisopropylethylamine (2.18
mL, 12.5 mmol) in acetonitrile (18 mL) at 0 °C was added
ethyl-4-bromocrotonate (0.688 mL, 5.0 mmol) over 5 min. After
3 h at 0 °C, the solution was partitioned between aq Na2CO3
and toluene, and the organic layer was washed with aq 10%
NH4Cl followed by water. p-Toluenesulfonic acid monohydrate
(0.904 g, 4.75 mmol) was added and the solution was evapo-
rated to dryness. The tosylate salt was crystallized from
isopropyl acetate, giving 1.86 g (4.1 mmol, 82%). White solid;
mp 92.8-93.5; 1H NMR (400 MHz, CD3OD) δ 7.72 (d, J ) 8.1
Hz, 2H), 7.25 (d, J ) 8.1 Hz, 1H), 6.91 (ddd, J ) 15.7, 7.6, 6.0
Hz, 1H), 6.32 (d, J ) 15.7 Hz, 1H), 4.30-4.26 (m, 4H), 4.04-
3.90 (m, 2H), 3.73 (br d, J ) 12.5 Hz, 1H), 3.45 (br d, J ) 12.1
Hz, 1H), 3.01 (td, J ) 12.5, 2.7 Hz, 1H), 2.86 (d, J ) 12.6 Hz,
1H), 2.38 (s, 3H), 2.22 (br d, J ) 13.4 Hz, 1H), 1.91 (m, 1H),
1.67 (m, 1H), 1.54 (td, J ) 13.5, 3.6 Hz, 1H), 1.30 (t, J ) 7.1
Hz, 3H), 1.29 (t, J ) 7.1 Hz, 3H), 1.24 (s, 3H); 13C NMR (100
MHz, CD3OD) δ 176.2, 166.3, 143.8, 141.8, 135.6, 131.0, 130.0,
127.1, 63.3, 62.2, 58.7, 58.6, 54.5, 44.0, 32.6, 24.2, 22.2, 21.5,
14.6, 14.4; IR 3456, 1725, 1664 cm-1. Anal. Calcd for C22H33-
NO7S: C, 58.00; H, 7.30; N, 3.07. Found: C, 57.94; H, 7.30;
N, 3.03.
trans isomer 22 was crystallized in 81% yield in the
presence of DBU to epimerize the cis isomer.
Completion of the Synthesis. Attempted reduction
of 22 with lithium tri-sec-butylborohydride suffered from
apparent overreduction of the lactone. On the other hand,
reaction with lithium tri-tert-butoxyaluminohydride was
clean, with no overreduction and no reduction of the ethyl
ester group observed (Scheme 6). The lactol was obtained
as an oil that contained a mixture of anomers. Attempted
acylations with p-nitrobenzoyl chloride gave several
unidentified byproducts, but clean activation was achieved
with p-nitrobenzoic acid, EDC, and catalytic DMAP.
BF3 was not an effective catalyst for substitution of 24.
Catalytic BF3 was inactivated by the amine, and over-
stoichiometric quantities gave decomposition. On the
other hand HBF4 (1.2 equiv, -40 °C) induced clean
substitution to a 91:9 ratio of 2,3-trans/2,3-cis isomers.
As before, trans,trans-acetal 18 could be isolated in high
purity by crystallization from acetonitrile/water. The
yield from lactone 22, the last isolated intermediate, was
82%, and at this point the original synthesis was inter-
cepted. The overall yield of 1 in this formal total synthesis
was 45% from 3,4-difluorophenylacetic acid.
1-[3-(S)-(3,4-Difluorophenyl)-2-(R)-ethoxycarbonyl-
methyl-3-{N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N-
methylcarbamoyl}propyl]-3-(R)-methylpiperidine-3-car-
boxylic Acid Ethyl Ester (20). A suspension of amide 8 (1.00
g, 3.13 mmol) and LiCl (0.66 g, 15.65 mmol) in THF (2 mL)
was sparged with nitrogen, then cooled to 0 °C. LHMDS (1.0
M in THF, 6.26 mL, 6.26 mmol) was added dropwise. After 30
min at 0 °C the solution was cooled to -20 °C and 19 (free
base, 0.938 g, 3.31 mmol) was added. After 30 min at -20 °C,
the reaction was quenched with aq 30% NH4Cl and EtOAc was
added. The organic layer was separated and washed with
water and brine, dried over MgSO4, and concentrated in vacuo.
Purification by column chromatography (10:90 to 40:60 EtOAc/
hexanes) gave 20 in 92% de (1.79 g, 2.97 mmol, 95%). Colorless
oil; 1H NMR (400 MHz, CD3CN 3:2 rotamer ratio) δ 7.42-7.07
(m, 8H), 7.03-6.93* (m, 2H), 4.64* (m, 1H), 4.62 (d, J ) 6.0
Hz, 1H), 4.58 (br s, 1H), 4.28* (br s, 1H), 4.47* (dd, J ) 9.2,
3.2 Hz, 1H), 4.13 (dd, J ) 6.4, 2.8 Hz, 1H), 4.10 (d, J ) 7.6 Hz,
1H), 4.05 (q, J ) 7.2 Hz, 2H), 3.90* (d, J ) 8.4 Hz, 1H), 3.86
(q, J ) 7.2 Hz, 2H), 2.82* (s, 3H), 2.79 (m, 2H), 2.76 (s, 3H),
2.64 (m, 1H), 2.32-2.22 (m, 2H), 2.11-2.04 (m, 2H), 2.02 (d,
J ) 5.6 Hz, 2H), 1.96 (s, 1H), 1.90 (m, 1H), 1.53 (m, 2H), 1.20
(t, J ) 7.2 Hz, 3H), 1.17* (t, J ) 7.2 Hz, 3H), 1.10 (t, J ) 7.2
Hz, 3H), 1.08 (s, 3H), 1.07* (s, 3H), 0.97* (d, J ) 6.8 Hz, 3H),
0.93 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.7,
176.5*, 174.2, 173.2*, 172.9, 171.0*, 150.3 (dd, JCF ) 248.2,
12.8 Hz), 149.6 (dd, JCF ) 248.2, 12.8 Hz), 142.0, 141.4*, 134.1-
(dd, JCF ) 4.8, 4.0 Hz), 128.5*, 128.2, 127.6, 126.8*, 126.5,
125.1 (m), 118.5* (d, JCF ) 17.7 Hz), 117.9 (d, JCF ) 17.7 Hz),
117.2 (d, JCF ) 17.7 Hz), 116.8* (d, JCF ) 17.7 Hz), 75.9, 75.1*,
62.4, 60.3*, 60.2, 60.1*, 60.0, 59.2, 58.3, 54.3, 53.7*, 48.1, 47.6*,
43.6, 43.4*, 37.3*, 36.4, 34.2, 33.8*, 33.4, 33.3*, 27.2*, 24.4,
23.6, 23.1*, 20.9*, 15.5*, 14.21, 14.18, 14.14 (2C); IR 3411,
1725, 1624, 1514 cm-1. Anal. Calcd for C33H44F2NO6: C, 65.76;
H, 7.36; N, 4.65. Found: C, 65.70; H, 7.45; N, 4.31.
Conclusion
Two efficient syntheses of NK1 antagonist 1 were
developed. Both approaches rely on asymmetric Michael
addition of a pseudoephedrine amide enolate combined
with diastereoselective acetal formation to establish the
tetrahydropyran core stereochemistry. The second ap-
proach avoids protecting group manipulations by incor-
porating the piperidine ester fragment into the Michael
acceptor and carrying it through the entire synthesis.
1-{2-(R)-[(S)-(3,4-Difluorophenyl){N-[(1R,2R)-2-hydroxy-
1-methyl-2-phenylethyl]-N-methylcarbamoyl}methyl]-4-
hydroxybutyl}-3-(R)-methylpiperidine-3-carboxylic Acid
Ethyl Ester (21). To a solution of 20 (1.07 g, 1.78 mmol) in
toluene (5 mL) below -20 °C was added LiB(sec-Bu)3H (6.0
mL of 1.0 M in THF, 6.0 mmol) over 15 min. The solution was
stirred 2 h at -21 °C, then carefully quenched with 30%
hydrogen peroxide (2.5 mL). CAUTION: Hydrogen gas evolu-
tion and large exotherm. The mixture was diluted with water
Experimental Section
Reaction solvents were purchased in anhydrous form or
dried over 3A molecular sieves. Reactions were carried out
under an atmosphere of dry nitrogen. Column chromatography
was carried out on silica gel (230-400 mesh). IR spectra were
recorded from thin films of neat samples on microporous
4412 J. Org. Chem., Vol. 70, No. 11, 2005

Synthesis of an NK1 Receptor Antagonist
and warmed to ambient temperature. The aqueous layer was
removed. The organic layer was washed with aq 10% Na2SO3
followed by water, then evaporated to a foam. Crystallization
from heptane/EtOAc 4:1 gave 0.792 g (1.41 mmol, 79%). White
solid; mp 117.8-118.4; 1H NMR (400 MHz, CD3OD, 3.3:1
rotamer ratio) δ 7.41-7.17 (m, 7H), 7.12 (m, 1H), 4.79 (br s,
1H), 4.65 (d, J ) 7.7 Hz, 1H), 4.50* (d, J ) 8.4 Hz, 1H), 4.27-
4.05 (m, 2H), 3.97* (d, J ) 9.2 Hz, 1H), 3.81 (d, J ) 9.5 Hz,
1H), 3.49-3.33 (m, 2H), 2.95 (s, 3H), 2.92 (br s, 2H), 2.91* (s,
3H), 2.47 (m, 1H), 2.33* (dd, J ) 12.3, 9.5 Hz, 1H), 2.23 (dd,
J ) 12.5, 9.4 Hz, 1H), 2.13-2.04 (m, 3H), 1.89 (br s, 1H), 1.63
(m, 2H), 1.53* (m, 1H), 1.41 (m, 1H), 1.26 (t, J ) 7.1 Hz, 3H),
1.29-1.13 (m, 2H), 1.24* (t, J ) 7.2 Hz, 3H), 1.15 (s, 3H), 1.13*
4.61 (d, J ) 8.3 Hz, 1H), 4.14-4.06 (m, 5H), 3.99 (ddd, J )
11.7, 4.6, 1.5 Hz, 1H), 3.66 (td, J ) 12.2, 2.0 Hz, 1H), 3.59
(ddd, J ) 11.3, 5.0, 1.5 Hz, 1H), 2.74 (br s, 2H), 2.59 (dd, J )
11.8, 2.9 Hz, 1H), 2.52 (br s, 2H), 2.39 (m, 1H), 2.18 (m, 1H),
2.10-1.80 (m, 12H), 1.80-1.41 (m, 6H), 1.35-1.27 (m, 2H),
1.25 (t, J ) 7.2 Hz, 3H), 1.23 (t, J ) 7.1 Hz, 3H), 1.09 (m, 1H),
1.041 (s, 3H), 1.037 (s, 3H); 13C NMR (100 MHz, CD3OD, both
anomers) δ 178.47, 178.45, 151.53 (dd, JCF ) 245.7, 12.6 Hz),
151.25 (dd, JCF ) 245.1, 12.6 Hz), 150.48 (dd, JCF ) 245.0, 12.8
Hz), 150.41 (dd, JCF ) 244.9, 12.7 Hz), 139.65 (dd, JCF ) 5.6,
4.0 Hz), 139.41 (dd, JCF ) 5.6, 4.0 Hz), 127.15 (dd, JCF ) 6.0,
3.2 Hz), 126.15 (m), 119.35 (d, JCF ) 17.4 Hz), 118.41 (d, JCF
) 17.3 Hz), 117.98 (d, JCF ) 17.1 Hz), 117.49 (d, J ) 16.9 Hz),
100.18, 94.63, 66.53, 65.04, 63.94, 63.53, 61.61, 60.15, 55.30,
54.80, 54.63, 53.18, 44.79, 39.84, 34.39, 34.36, 33.15, 32.68,
32.63, 32.16, 31.08, 30.26, 24.61, 24.32, 24.29, 23.85, 14.72,
(s, 3H), 1.06* (d, J ) 6.8 Hz, 3H), 0.90 (d, J ) 6.8 Hz, 3H); 13
C
NMR (100 MHz, CD3CN) δ 177.1, 176.9*, 174.6, 173.9*, 151.0
(dd, JCF ) 245.8, 12.7 Hz), 150.8* (dd, JCF ) 245, 12 Hz), 150.2
(dd, JCF ) 244.9, 12.8 Hz), 144.1, 143.5*, 137.9* (m), 136.9
(dd, JCF ) 5.3, 4.1 Hz), 129.3*, 129.1, 128.8*, 128.4, 128.2*,
127.5, 127.1* (dd, JCF ) 6.4, 3.2 Hz), 126.6 (dd, JCF ) 6.2, 3.3
Hz), 119.1* (d, JCF ) 17.7 Hz), 118.6 (d, JCF ) 17.6 Hz), 118.0
(d, JCF ) 17.1 Hz), 117.6* (d, JCF ) 17.1 Hz), 76.2, 75.3*, 64.2
(br), 63.6*, 63.1, 61.3, 61.2*, 61.1, 59.2*, 54.2, 51.7, 50.9*, 44.1,
44.0*, 39.9*, 39.0, 36.3*, 36.1, 33.1, 27.8, 24.9*, 23.8, 23.6*,
16.2*, 14.6, 14.51, 14.48*; IR 3381, 1725, 1624 cm-1. Anal.
Calcd for C31H42F2N2O5: C, 66.41; H, 7.55; N, 5.00. Found: C,
66.32; H, 7.47; N, 4.98.
3-(R)-Methyl-1-[2-oxo-3-(R)-(3,4-difluorophenyl)tetrahy-
dropyran-4-(R)-ylmethyl]piperidine-3-carboxylic Acid
Ethyl Ester (22). A solution of hydroxy-amide 21 (1.12 g, 2.00
mmol) and acetic acid (0.47 mL, 8.2 mmol) in toluene (11.5
mL) was stirred at 60 °C for 5 days. The reaction mixture was
quenched into aq 5% Na2CO3 and EtOAc. The layers were
separated and the organic layer was washed with 5% Na2CO3,
then evaporated. Column chromatography (40% EtOAc/hex-
anes) gave a trans/cis mixture of lactones. The trans lactone
was crystallized from 5% EtOAc/heptane. Addition of DBU
(0.0015 mL, 0.01 mmol) to epimerize the cis isomer, and partial
evaporation to remove EtOAc, gave 22 (0.642 g, 1.62 mmol,
81%). White solid; mp 79.3-80.1 °C; 1H NMR (400 MHz, CD3-
OD) δ 7.25-7.17 (m, 2H), 7.06 (m, 1H), 4.48 (m, 1H), 4.40 (m,
1H), 4.18-4.03 (m, 2H), 3.62 (d, J ) 10.4 Hz, 1H), 2.85 (br d,
J ) 10.0 Hz, 1H), 2.53 (br m, 1H), 2.36 (m, 1H), 2.19 (dd, J )
12.7, 9.2 Hz, 1H), 2.14 (m, 1H), 2.04 (dd, J ) 12.7, 4.2 Hz,
1H), 2.03-1.94 (br m, 2H), 1.89-1.78 (m, 2H), 1.57 (m, 1H),
1.47 (m, 1H), 1.22 (t, J ) 7.2 Hz, 3H), 1.10 (m, 1H), 1.06 (s,
3H); 13C NMR (100 MHz, CD3OD) δ 178.4, 175.2, 151.5 (dd,
JCF ) 246.3, 12.8 Hz), 150.9 (dd, JCF ) 246.2, 12.8 Hz), 137.4
(dd, JCF ) 5.6, 4.0 Hz), 127.0 (dd, JCF ) 6.3, 3.8 Hz), 119.4 (d,
JCF ) 17.9 Hz), 118.3 (dd, JCF ) 17.3 Hz), 69.4, 65.0, 62.9,
61.7, 54.7, 51.7, 44.9, 38.2, 34.3, 28.2, 24.7, 24.4, 14.7; IR 1728
cm-1. Anal. Calcd for C21H27F2NO4: C, 63.78; H, 6.88; N, 3.54.
Found: C, 63.60; H, 6.89; N, 3.55.
14.58; IR 3419, 1727 cm-1
.
1-[3-(R)-(3,4-Difluorophenyl)-2-(4-nitrobenzoyloxy)tet-
rahydro-2H-pyran-4-(R)-ylmethyl]-3-(R)-methylpiperidine-
3-carboxylic Acid Ethyl Ester (24). To a solution of crude
23 (theoretical 2.52 mmol from previous reaction), p-nitroben-
zoic acid (0.634 g, 3.80 mmol), and DMAP (31 mg, 0.25 mmol)
in CH2Cl2 (10 mL) at 0 °C was added EDC (0.606 g, 3.16 mmol)
in three portions. After 90 min at 0 °C, the solution was
quenched with water and partitioned between CH2Cl2 and aq
10% NH4Cl. The organic layer was washed with 1 N NaOH
and water, then evaporated to a yellow foam. The 2R/2S
diastereomer ratio was 93:7. The mixture was used in the
subsequent reaction without further purification. A small
sample of the 2R isomer was purified by column chromatog-
raphy (3.5:1 hexanes/EtOAc) and recrystallized from acetoni-
trile/water. White solid; mp 131.2-132.0 °C; 1H NMR (400
MHz, CD3CN) δ 8.22 (m, 2H), 8.04 (m, 2H), 7.29 (m, 1H), 7.16
(m, 2H), 5.87 (d, J ) 8.4 Hz, 1H), 4.14-4.05 (m, 3H), 3.81 (dd,
J ) 11.8, 2.5 Hz, 1H), 2.76 (dd, J ) 10.6, 8.5 Hz, 1H), 2.74 (br
s, 1H), 2.48 (br s, 1H), 2.21 (m, 1H), 2.11-1.95 (m, 4H), 1.90
(br m, 1H), 1.79 (br m, 1H), 1.55-1.34 (m, 3H), 1.22 (t, J )
7.1 Hz, 3H), 1.09 (m, 1H), 1.05 (s, 3H); 13C NMR (100 MHz,
CD3CN) δ 177.3, 164.0, 152.0, 151.1 (dd, JCF ) 245.6, 12.7 Hz),
150.1 (dd, JCF ) 244.8, 12.5 Hz), 137.9 (dd, JCF ) 5.6, 4.0 Hz),
135.8, 131.7, 126.2 (dd, JCF ) 6.0, 3.5 Hz), 124.7, 118.3 (d, JCF
) ∼18 Hz, partly under solvent), 118.2 (d, JCF ) 17.9 Hz), 98.9,
66.5, 64.4, 62.5, 61.0, 54.5, 51.2, 44.2, 38.7, 34.0, 30.4, 24.4,
23.9, 14.7; IR 1732 cm-1. Anal. Calcd for C28H32F2N2O7: C,
61.53; H, 5.90; N, 5.13. Found: C, 61.42; H, 5.75; N, 5.07.
1-[2-(R)-{1-(R)-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-
3-(R)-(3,4-difluorophenyl)-4-(R)-tetrahydro-2H-pyran-4-
ylmethyl]-3-(R)-methylpiperidine-3-carboxylic Acid Eth-
yl Ester (18). The crude nitrobenzoate mixture 24 (theoretical
2.52 mmol) and alcohol 3 (0.650 g, 2.52 mmol) were combined
in CH2Cl2 (14 mL) and cooled to -50 °C. HBF4 etherate (0.414
mL, 3.02 mmol) was added in one portion, and the mixture
was stirred at -40 °C. After 2.5 h, the reaction was quenched
with aq 5% Na2CO3 and warmed. The layers were separated
and the organic layer was washed once with water, then
evaporated to a pale yellow solid. The residue was recrystal-
lized from acetonitrile/water 3:1 giving a white solid. Yield was
1.31 g, 2.05 mmol, 81.5% from lactone 22.
1-[3-(R)-(3,4-Difluorophenyl)-2-hydroxytetrahydro-2H-
pyran-4-(R)-ylmethyl]-3-(R)-methylpiperidine-3-carbox-
ylic Acid Ethyl Ester (23). To a -15 °C solution of lactone
22 (1.00 g, 2.52 mmol) in THF (10 mL) was added LiAl-
(OtBu)3H (3.16 mL of 1.0 M in THF, 3.16 mmol) over 5 min.
The reaction mixture was stirred at -5 °C for 90 min, then
quenched with aqueous potassium sodium tartrate. The
mixture was extracted with ethyl acetate, and the organic layer
was washed with water and evaporated to an oil. The residue
was dissolved in ethyl acetate, filtered through a pad of silica
gel, and evaporated to an oil. The crude product was used in
the subsequent step without further purification. 1H NMR (400
MHz, CD3OD, both anomers, 1.3:1 ratio) δ 7.22 (ddd, J ) 12.3,
8.0, 2.0 Hz, 1H), 7.18-6.98 (m, 5H), 4.94 (d, J ) 2.9 Hz, 1H),
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 1, 8-14, and
16-18; 1H NMR spectra for compounds 11 and 23. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0504161
J. Org. Chem, Vol. 70, No. 11, 2005 4413