Chemoenzymatic synthesis of a tachykinin NK-2 antagonist

Article abstract of DOI:10.1016/S0040-4020(01)00796-7

A non-peptide tachykinin antagonist has been synthesized in a short and efficient four step sequence starting from a chiral enol acetate, which was obtained in enantiomerically pure form by resolution using a lipase catalysed transesterification reaction. The biotransformation was optimized in terms of solvent, temperature and immobilization method used. Oxidative cleavage of the (+)-enol acetate to give the key aldehyde ester intermediate could be achieved indirectly by oxidative rearrangement to an enone followed by Baeyer-Villiger oxidation and ring opening, or by epoxidation, rearrangement and oxidative cleavage or most directly by ozonolysis. X-Ray crystallographic analysis of a camphanic ester derivative of an ester alcohol confirmed that the absolute configuration of the enol acetate was (S).

Full text of DOI:10.1016/S0040-4020(01)00796-7

TETRAHEDRON
Pergamon
Tetrahedron 57 12001) 8193±8202
Chemoenzymatic synthesis of a tachykinin NK-2 antagonist
Graham Allan,a Andrew J. Carnell,a,p Maria Luisa Escudero Hernandeza and Alan Pettmanb
aDepartment of Chemistry, Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK
bDepartment of Process Research and Development, P®zer Ltd, Sandwich, Kent CT13 9NJ, UK
Received 8 June 2001; revised 2 July 2001; accepted 26 July 2001
AbstractÐA non-peptide tachykinin antagonist has been synthesized in a short and ef®cient four step sequence starting from a chiral enol
acetate, which was obtained in enantiomerically pure form by resolution using a lipase catalysed transesteri®cation reaction. The bio-
transformation was optimized in terms of solvent, temperature and immobilization method used. Oxidative cleavage of the 11)-enol acetate
to give the key aldehyde ester intermediate could be achieved indirectly by oxidative rearrangement to an enone followed by Baeyer±Villiger
oxidation and ring opening, or by epoxidation, rearrangement and oxidative cleavage or most directly by ozonolysis. X-Ray crystallographic
analysis of a camphanic ester derivative of an ester alcohol con®rmed that the absolute con®guration of the enol acetate was 1S). q 2001
Published by Elsevier Science Ltd.
1. Introduction
progress, methods to achieve this type of transformation
which are amenable to scale-up using commercially avail-
able catalysts that can operate at ambient temperature are
required.
The desymmetrization of prochiral ketones to obtain chiral
enolates or lactones has become an important method in
asymmetric synthesis. Chiral lithium amides have been
employed by Koga,1 Simpkins2 and others for the deproto-
nation of 4-substituted cyclohexanones and prochiral
bicyclic ketones.3 However, in order to achieve high
selectivity, specialised chiral amines may be required and
the reactions are run at low temperatures 12788C or
21008C) under anhydrous conditions. The chiral silyl enol
ethers that result from enolate trapping can provide a handle
for maintaining the newly introduced asymmetry by
oxidative cleavage or electrophilic addition. Asymmetric
Baeyer±Villiger reactions can be carried out using mono-
oxygenase enzymes4 and asymmetric copper and platinum
catalysts5,6 but suffer from low substrate concentrations and
moderate enantioselectivities, respectively. Despite recent
We recently reported the use of a lipase enzyme for the
effective desymmetrization of prochiral ketone 4-cyano-4-
13,4-dichlorophenyl)cyclohexanone 1 1Scheme 1).7,8 The
racemic enol acetate 2 derived from ketone 1 was
resolved using Amano Pseudomonas ¯uorescens lipase
1PFL) to give unreacted enantiomerically pure 1100% ee)
1S)-enol acetate 2 and recovered ketone 1, the product of
the lipase transesteri®cation. Unlike most enzyme kinetic
resolutions this reaction has the advantage that the prochiral
ketone can be chemically recycled leading to greater
than 50% yields of enantiopure enol ester after several
cycles, constituting a desymmetrization of the prochiral
ketone.
Scheme 1. Reagents and conditions: 1i) Pseudomonas ¯uorescens lipase, THF, nBuOH; 1ii) isopropenyl acetate, pTsOH.
Keywords: enol acetate; NK-2antagonist; lipase; enone; ozonolysis.
Corresponding author. Tel.: 144-0-151-794-3531; fax: 144-0-151-794-3588; e-mail: acarnell@liv.ac.uk
p
0040±4020/01/$ - see front matter q 2001 Published by Elsevier Science Ltd.
PII: S0040-4020101)00796-7

8194
G. Allan et al. / Tetrahedron 57 02001) 8193±8202
The sensoneuropeptide tachykinins, which include
substance P and neurokinins A and B, are distributed in
the peripheral and central nervous systems and are known
to be involved in neurologic in¯ammation, pain trans-
mission and bronchoconstriction.9 The effects of these
tachykinins are mediated through the activation of NK-1,
NK-2and NK-3 receptors and new antagonists are being
sought as a means of controlling pain and in¯ammation.
P®zer have developed a class of non-peptidic neurokinin
NK-2antagonists generally consisting of an 1 S)-4-aryl-4-
dialkylaminoethyl-N-alkyl d-lactams such as structure 3
1Scheme 2).10
obtain an enone with no loss of enantiomeric purity and so
envisaged making enone 8 in the same way.13
Unfortunately the prochiral ketone 1 was not a substrate for
cyclohexanone
monooxygenase,
2,5-diketocamphane
monooxygenase 1MO1) or 3,4,4-trimethylcyclopent-2-
enone acetic acid monooxygenase 1MO2), enzymes
known to give chiral lactones from prochiral or racemic
cyclohexanones.4,14 We therefore focussed our attention
on the alternative route involving the optically pure enol
acetate 2 as the starting material.
2.1. Optimization of the biotransformation for the
preparation of (S)-(1)-2
We now report full details of the optimization of the
biotransformation of the enol ester 2 and the synthesis of
a representative member of this class of tachykinin NK-2
antagonists.
In an attempt to ensure that we had found optimum condi-
tions for the biotransformation we screened a range of
enzymes, varied the solvent and reaction temperature and
examined a range of immobilisation methods. Our initial
screen in toluene and THF identi®ed eight lipases.8
Reactions in toluene were generally faster than those in
THF but selectivity was lower. Pseudomonas ¯uorescens
lipase was the best enzyme in terms of reaction rate and
selectivity giving the enol acetate 2 in .99% ee after
70% conversion in 8.5 h 1Eˆ15) in THF. The same reaction
in toluene gave an E value of 6.5. The PFL reaction was then
carried out in a range of solvents 1Table 1). THF turned out
to be the optimal solvent with E values ranging from 1 in
phosphate buffer to 15 for THF.
2. Results and discussion
Our original retrosynthesis of the lactam 3 involved, as the
®nal step, reductive cyclisation11 of the nitrile ester 4 which
would be made by reductive amination of aldehyde 5. This
aldehyde would be derived by ring opening and oxidation of
the lactone 6 which we envisaged could be made by asym-
metric Baeyer±Villiger oxidation of the cyclohexanone 1
using a monooxygenase enzyme.4 Alternatively the enol
lactone 7 might be accessible from the enone 8 by regio-
selective Baeyer±Villiger oxidation according to a similar
transformation reported by Schultz.12 This would present
the correct aldehyde oxidation state for subsequent
reductive amination.
Immobilisation of enzymes can provide advantages such as
increased activity and selectivity and can also facilitate
downstream processing. We had previously shown that the
rate and enantioselectivity of Humicola lipase in hexane,
when used for the transesteri®cation of enol acetates derived
from prochiral oxabicyclic [3.2.1] ketones, was greatly
improved by prior adsorption of the enzyme onto ¯ash
We had previously used Tsuji's bimetallic oxidative
rearrangement of an enantiomerically pure enol acetate to
Scheme 2.

G. Allan et al. / Tetrahedron 57 02001) 8193±8202
8195
Table 1. Variation in selectivity of PFL catalysed transesteri®cation of
substrate 2 with solvent
of enol ether 9 with PhSeCl followed by oxidative elimina-
tion with H2O2 afforded the enone 8 in 52% yield over 2
steps. Evans et al. reported the formation of a,b-unsaturated
ketones from the corresponding triisopropyl silyl enol ethers
by direct dehydrogenation using ceric ammonium nitrate at
08C in DMF.17 We subjected the TMS enol ether 9 to these
conditions but this gave a low 16%) yield of the enone 8,
perhaps owing to the lability of the TMS group under these
conditions. Increasing the size of the groups on silicon gave
a progressive increase in yield 128% for TBDMS and 32%
for iPr3Si) but yields for the formation of the silyl enol ether
substrates were progressively worse with an increase in size
of the silane. Overall, we found Tsuji's oxidative rearrange-
ment to be the highest yielding, but the success of this
transformation was highly dependent on the purity of the
reagents used.
Solvent
Time 1h)
Conversion 1%)
ee 1%)
E
THF
3.5
2.5
4
4
1
70
41
7294
5261
66
.99
48
15
9
EtOAc
Dioxane
Toluene
Et2O
7
6.5
85
6
CH3CN
Hexane
Buffer
6.5
6.5
2.5
5253
55
56
5
5.7
0
1
1
silica.15,16 Use of silica adsorbed PFL in THF gave no
improvement in enantioselectivity and reaction times were
considerably longer 19 days for 20% conversion cf. 3.5 h for
70% conversion with freeze dried non-adsorbed enzyme).
Covalent attachment of PFL to the polymer Eupergit C gave
more encouraging results in that, although enantio-
selectivity was unaffected, the rate was increased 12.5 h
for 68% conversion cf. 3.5 h with non-immobilised enzyme)
and the immobilised enzyme could be easily removed and
re-used with no noticable loss in activity. It was decided to
carry out the large-scale biotransformations to obtain
the material required for the synthesis using Eupergit
C-immobilised PFL in THF with n-BuOH at room tempera-
ture for the transesteri®cation. The reaction was carried out
on 10 g of racemic enol aceate 2 to yield, after chromato-
graphy, 2.8 g 128% yield) of enol acetate 11)-1S)-2 of high
enantiomeric excess.
For the conversion of the enol acetate 2 to the ester aldehyde
5 three approaches were tried 1Scheme 4). Enone 8 under-
went regioselective Baeyer±Villiger oxidation with pertri-
¯uoroacetic acid prepared in situ, according to the
procedure reported by Schultz whereby tri¯uoroacetic
anhydride is reacted with urea±hydrogen peroxide in
dichloromethane in the presence of sodium hydrogen
phosphate.12
Under these conditions the enol lactone 7 produced is stable
and could be isolated in 80% yield. The enol lactone 7 could
be ring opened using basic methanol to provide the aldehyde
ester 5 in 60% yield. Alternatively, epoxidation of the enol
acetate followed by rearrangement and oxidative cleavage
gave the same aldehyde ester 5 in lower overall yield.
Finally, much more direct was the ozonolysis of enol acetate
2 in methanol/dichloromethane to give, after reductive
workup with DMS or Ph3P, the aldehyde ester 5 in 62%
yield. Although the yield was disappointing, it was repro-
ducible and the directness of this method was preferable to
the other approaches. In order to con®rm the suspected
1S)-con®guration of the 4-position of the enol acetate 11)-
2 we converted the aldehyde 12)-5 into the crystalline
camphanic ester derivative 13 via alcohol 12 shown in
Scheme 5. Crystallisation of the ester 13 from propan-2-ol
gave crystals suitable for X-ray analysis.7 By reference to
2.2. Synthesis of the NK-2 antagonist 3
For the synthesis of the enone 8 directly from enol acetate 2
we found Tsuji's method capricious in that, although yields
of 65% were obtainable, they were dif®cult to reproduce.
We therefore considered three alternative procedures
1Scheme 3). Firstly, treatment of the enol acetate 2 with
methyl lithium and phenyl selenyl chloride followed by
oxidative elimination with H2O2 gave enone 8 in a poor
35% yield. The TMS enol ether 9 could be made in 66%
yield by treatment of the enol acetate 2 with methyl lithium
followed by trimethyl silyl chloride. Subsequent treatment
Scheme 3. Reagents and conditions: 1i) MeLi, THF, TMSCl 157%); 1ii) PhSeCl, DCM then H2O2 152%); 1iii) CAM, DMF, 08C; 1iv) Pd1OAc)2, MeOSnBu3,
allyl methyl carbonate, MeCN 165%); 1v) MeLi, THF, PhSeCl, 08C then H2O2 135%).

8196
G. Allan et al. / Tetrahedron 57 02001) 8193±8202
Scheme 4. Reagents and conditions: 1i) Pd1OAc)2, dppe, MeOSnBu3, allyl methyl carbonate, MeCN 165%); 1ii) UHP, 1CF3CO)2O, Na2HPO4 DCM 180%); 1iii)
MeOH, K2CO3 160%); 1iv) MCPBA, Na2HPO4, DCM 172%); 1v) CHCl3, CH3CO2H 174%); 1vi) NaIO4, MeOH 158%); 1vii) O3, MeOH, DCM then Ph3P 162%).
the 101S) camphanyl moiety the absolute con®guration of
the cyano substituted center was determined to be 1S),
thus con®rming the con®guration of the enol acetate 11)-
2 as 1S) required for the synthesis of the NK-2antagonist 3.
genation conditions 1Pd-C/H2) was not successful. The
presence of the triethylamine used to release the free
azetidine amine from its hydrochloride salt or the resultant
triethylamine hydrochloride may have poisoned the
palladium catalyst. However, prior formation of the imine
between 14 and 12)-5 in THF in the presence of triethyl-
amine followed by reduction with sodium triacetoxyboro-
hydride afforded the intermediate 12)-15 in 91% overall
yield. The reductive cyclization of 12)-15 to give lactam
To complete the synthesis of the NK-2antagonist 3 required
reductive amination of the aldehyde 12)-5 ester followed by
lactam formation and N-benzylation. Reductive amination
with morpholinoazetidine18 hydrochloride 14 under hydro-
Scheme 5. Reagents and conditions: 1i) NaB1OAc)3H, AcOH, ,208C 172%); 1ii) 12)-11S)-camphanic acid chloride, DMAP, Et3N, DCM 183%).

G. Allan et al. / Tetrahedron 57 02001) 8193±8202
8197
Scheme 6. Reagents and conditions: 1i) 1a) 114), THF, Et3N, rt, 1b) NaB1OAc)3H, Et3N 191%); 1ii) H2, Raney Ni, MeOH, 458C 197%); 1iii) KH, 3-
methoxybenzylbromide, DMF,18-C-6, 08C, 128%).
11)-16 was acheived in 97% yield using hydrogenation and
Raney Nickel. Fortunately, no dechlorination of the
aromatic ring was observed under these conditions. Lactam
16 underwent N-benzylation to furnish the target NK-2
antagonist 11)-3 in 28% yield 1Scheme 6).
and chemically recycled, thus providing greater than 50%
yield of the chiral enol ester over several cycles. We are
currently developing an in situ method for this recycling
which will be reported elsewhere.
In attempts to improve this step we used valerolactam as a
model substrate. This underwent benzylation cleanly with
3-methoxybenzyl bromide or chloride using KOH/DMSO/
10% H2O or NaOH/18-crown-6/DMF in yields of 75 and
72%, respectively. However, when these conditions were
applied to the lactam 16, low yields resulted. The morpho-
linoazetidine group may undergo N-benzylation and the
resulting alkylammonium species may not be ef®cient
alkyl donors or may undergo ring cleavage leading to
more polar products.
3. Experimental
3.1. General
Elemental analysis, NMR spectra, infrared spectra, mass
spectra and accurate mass measurements were obtained
and recorded were recorded as previously described.19 Melt-
ing points were taken on a gallemkamp melting point
apparatus and are uncorrected. Optical rotations [a]D
1concentration in g/100 mL, solvent) were recorded on an
Optical Activity A1000 polarimeter at 589 nm. GC analysis
was performed on a DANI 3800 gas chromatograph
equipped with an Altech Econo-Cap SE-30 column.
Samples were prepared as 5±10% solutions in EtOAc and
were analysed at temperatures between 150 and 3008C.
HPLC analysis was performed on a Waters 2690 separations
module equipped with a Daicel Chiralpak AD or Chiracel
OJ column. Samples were recorded using a Waters 996
photodiode array detector. Integration was performed
using Waters Millenium32 software.
In summary, the enantiomerically pure 1S)-enol acetate 2
was obtained by enantioselective transesteri®cation with
Pseudomonas ¯uorescens lipase under optimized condi-
tions. The enol acetate was converted to enone 8 using
Tsuji's conditions with no loss of enantiomeric purity and
subsequent Baeyer±Villiger oxidation gave regioselective
oxygen insertion towards the alkene, giving the enol lactone
7. Ozonolysis of the enol acetate 2 proved to be the most
direct way to access the required ester aldehyde inter-
mediate 5 for subsequent elaboration to the target NK-2
antagonist 1S)-3 in a short and ef®cient four step synthesis.
As previously stated, the ketone product of the bio-
transformation is prochiral and can easily be separated
3.1.1. 4-Cyano-4-(30,40-dichlorophenyl)cyclohex-1-enyl
acetate 2. To a stirred solution of 4-cyano-4-130,40-dichloro-
phenyl)cyclohexanone 120 g, 75 mmol) in dry THF

8198
G. Allan et al. / Tetrahedron 57 02001) 8193±8202
1400 mL) at 2788C under argon was added LHMDS 197 mL
1M, 97 mmol). The mixture was stirred for 15 min, where-
upon acetic anhydride 110.6 mL) was added and the mixture
allowed to warm to rt for 1 h. The reaction was quenched by
the addition of ammonium chloride solution 1100 mL) and
ether was added 1200 mL). The organic layer was washed
with saturated ammonium chloride solution 13£300 mL)
and brine 13£300 mL), dried 1MgSO4) and concentrated
under reduced pressure to yield the crude product as a
yellow oil, which was puri®ed by ¯ash column chromato-
graphy on silica 1eluent 2:1 hexane/diethyl ether) to give the
title compound 2 120 g, 86%) as a white solid, mp 153±
1548C. 1Found C, 57.81; H, 4.18; N, 4.48. C15H13Cl2NO2
requires C, 58.08; H, 4.22; N, 4.52%) 1HRMS: found M1
309.0322. C15H13 35Cl2NO2 requires 309.0323); nmax1neat)
2233 1CN), 1755 1CO); dH 1300 MHz, CDCl3) 2.23 13H, s,
AcCH3), 2.23±2.67 16H, m, 2£H-3, 2£H-5 and 2£H-6),
5.46 11H, s, H-2) 7.22±7.56 13H, Ar); dC 175 MHz,
CDCl3) 20.9 1AcCH3), 24.6, 32.7, 35.4 1C-3, C-5, and
C-6), 40.0 1C-4), 110.5 1C-2), 121.5 1CN), 125.3, 128.1
and 131.1 1C-20, C-50, C-60), 132.8, 133.5 and 139.6
1C-10, C-30 and C-40), 148.1 1C-1), 169.3 1CvO); m/z 1EI)
309 13%, M1), 267 111), 70 169), 43 1100). HPLC Chiralpak
AD, RT 1R)-3 15.5 min, 1S)-3 20.9 min, eluent 100% EtOH,
¯ow rate 0.5 mL/min, l 220 nm.
1.91 mmol) at 08C. The reaction was cooled to 2788C,
trimethylsilyl chloride 1225 mg, 2.07 mmol) was added
and the mixture allowed to warm to room temperature
over 1 h. The reaction was quenched with saturated
ammonium chloride solution 120 mL), ether was added
110 mL) the organic layer was washed with water
13£10 mL), dried 1MgSO4) and the solvent was removed
in vacuo. The crude product was puri®ed by ¯ash column
chromatography on silica 1petroleum ether/diethyl ether,
7:1) to yield the product 9 1101 mg, 45%) as a white
solid. Mp 728C. 1Found C, 56.68; H, 5.63; H, 4.14; M2
339.0611. C16H19N35Cl2OSi requires C, 56.47; H, 5.63; N,
4.11%; 339.0613); nmax1®lm) 1cm21) 2238 1CN); dH
1300 MHz; CDCl3; Me4Si) 0.20 19H, s, CH3), 2.14±2.57
16H, m, H-3, H-5 and H-6), 4.89 11H, t, Jˆ2.1 Hz, H-1),
7.13 11H, dd, Joˆ8.5 Hz, Jmˆ2.2 Hz, H-60), 7.25 11H, d,
Joˆ8.5 Hz, H-50) and 7.35 11H, d, Jmˆ2.2 Hz, H-20); dC
175 MHz; CDCl3; Me4Si) 0.21 13£CH3), 27.69, 33.02 and
35.92 1C3, C5 and C6), 40.36 1C4), 100.09 1C2), 121.89
1CN), 125.37, 128.02 and 130.89 1C20, C50and C60),
132.44, 133.24 and 140.20 1C10, C30 and C40) and 150.50
1C1); m/z 1EI) 339 19%, [M]1), 142195), 127 1100), 75 138)
and 73 130).
3.3.2. 4-Cyano-4-(3,4-dichlorophenyl)cyclohex-2-enone
8. Method A: To a solution of 4-cyano-4-130,40-dichloro-
phenyl)cyclohex-1-enyl acetate 2 1150 mg, 0.4 mmol) in
dry CH3CN 15 mL) was added palladium acetate 16.7 mg,
0.03 mmol), bis1diphenylphosphino)ethane 112mg, 0.03
mmol) and allylmethylcarbonate 10.07 mL, 0.62mmol)
and the mixture was stirred for 30 min at room temperature.
Tributyltin methoxide 10.03 mL, 0.12mmol) was then
added and the mixture heated under re¯ux for 18 h. The
solution was ®ltered through celite and dichloromethane
115 mL) was added. The organic layer was washed with
saturated ammonium chloride solution 13£15 mL), dried
1MgSO4) and the solvent removed in vacuo. The crude
product was puri®ed by ¯ash column chromatography on
silica 1hexane followed by diethyl ether/hexane, 1:1) to
yield the product 8 177.4 mg, 65%) as a colourless oil. Rf
1ethyl acetate/hexane, 1:1) 0.62. 1Found M1 265.0065.
C13H935Cl2NO requires 265.0061); nmax1®lm) 1cm21) 2239
1CN), 1693 1CvO); dH 1300 MHz; CDCl3; Me4Si) 2.13±
2.86 14H, m, H-5 and H-6), 6.33 11H, d, Jˆ9.9 Hz, H-3),
6.80 11H, d, Jˆ9.9 Hz, H-2) and 7.24±7.54 13H, m, Ar-H);
dC 175 MHz; CDCl3; Me4Si) 34.65 and 37.63 1C5 and C6),
42.25 1C4), 118.41 1CN), 125.48, 128.31 and 131.52 1C20,
C50 and C60), 132.49 1C30), 133.73 and 134.03 1C30 and
C40), 137.91 1C10), 143.61 1C2) and 195.22 1C1); m/z 1EI)
265 144%, [M]1), 237 182), 202 123), 267 132), 239 157)and
174 1100).
3.2. Typicalbiotransformation protocol
To a solution of enol acetate 2 1100 mg, 0.41 mmol) in dry
THF 110 mL) at 308C was added n-BuOH 10.046 mL,
0.50 mmol) and lipase from Pseudomonas ¯uorescens
130 mg). The solution was stirred for 3.5 h, until 65%
conversion to ketone was observed by GC, whereupon the
mixture was ®ltered through a celite pad and the enzyme
washed with diethyl ether. The ®ltrate was concentrated
under reduced pressure to give the crude product as a yellow
solid which was puri®ed by ¯ash column chromatography
on silica 1eluent 5:1 petrol/ethyl acetate) to give the enantio-
merically pure 1.99% ee) enol acetate 2 129 mg, 29%)as a
white crystalline solid, mp 148±1508C.
3.3. Scale-up biotransformation procedure
The enol acetate 2 110 g, 32.4 mmol), Pseudomonas
¯uorescens lipase, Amano 18 g) and n-BuOH 15.21 mL,
64.7 mmol) were stirred in THF at room temperature for
9.5 h whereupon HPLC 1Chiralpak AD) indicated 100%
ee for the enol acetate. RT 1R)-2 15.5 min, 1S)-2 20.9 min,
eluant 100% EtOH, 0.5 mL/min. The solution was ®ltered
through a glass sinter funnel, the residual enzyme washed
with tetrahydrofuran and the solvent removed by evapora-
tion under reduced pressure. The crude residue was puri®ed
by ¯ash column chromatography 1eluent 1:2diethyl ether/
petroleum ether) to give the ketone 17 g) and the 1S)-enol
acetate 3 12.8 g, 28%, .99% ee) as a white solid, mp 148±
1508C, [a]Dˆ111.5 1cˆ1.74 in CHCl3). Other analytical
data as reported above.
Method B: A solution of phenylselenyl chloride 1100 mg,
0.53 mmol) in dichloromethane 13 mL) was added to a stir-
red solution of silyl enol ether 9 1100 mg, 0.29 mmol) in
dichloromethane 13 mL) at 2788C. After 10 min the
mixture was warmed to room temperature and dichloro-
methane 130 mL) was added. The solution was washed
with a saturated solution of sodium hydrogen carbonate
12£25 mL) and a saturated solution of sodium chloride
12£25 mL). The organic layer was dried 1MgSO4) and
the solvent removed in vacuo. The a-phenylselenide
was isolated from the crude. 1Found M1 418.9733.
3.3.1. 4-Cyano-4-(3,4-dichlorophenyl)-1-(trimethylsilyl-
oxy) cyclohexene 9. A solution of 4-cyano-4-130,40-
dichlorophenyl)cyclohex-1-enyl acetate
0.83 mmol) in THF 110 mL) was added to a solution of
1.4 methyl lithium in diethyl ether 11.36 mL,
2
1200 mg,
M

G. Allan et al. / Tetrahedron 57 02001) 8193±8202
8199
C19H1535Cl2NO76Se requires 418.9723); nmax1®lm) 1cm21
)
layers where combined and washed with lithium chloride
solution 13£25 mL). The crude product was puri®ed by ¯ash
column chromatography on silica to yield the product 8
150 mg, 32%) whose spectral data was consistent with
those previously observed.
2238 1CN), 1719 1CvO); dH 1300 MHz; CDCl3; Me4Si)
2.16±3.08 16H, m, H-3, H-5 and H-6), 4.61 11H, dd, Jˆ6,
7.2 Hz, H-2), 7.21±7.60 18H, m, Ar-H); dC 175 MHz;
CDCl3; Me4Si) 37.38, 38.38 and 45.28 1C3, C5 and C6),
44.34 1C4), 48.76 1C2), 120.08 1CN), 1020 4.91, 128.55 and
131.30 1C20, C50 and C60), 126.55 1C1 ), 127.72, 129.59
and 135.19 1C200, C300, C400, C500 and C600), 133.32, 133.75
and 137.94 1C10, C30 and C40) and 203.24 1CvO); m/z 1EI)
3.3.3. 5-Cyano-5-(30,40-dichlorophenyl)-4,5-dihydro-3H-
oxepin-2-one 7. 4-Cyano-4-130,40-dichlorophenyl)cyclo-
hex-2-enone 8 154 mg, 0.20 mmol) and urea hydrogen per-
oxide 1100 mg, 2.0 mmol) were dissolved in
dichloromethane 15 mL) with sodium hydrogen phosphate
1259 mg, 1.8 mmol) under nitrogen. The mixture was
cooled to 08C and the tri¯uoroacetic anyhydride 10.07 mL,
0.5 mmol) was added. Urea hydrogen peroxide 150 mg,
1.0 mmol) and tri¯uoroacetic anhydride 10.07 mL,
0.5 mmol) were added. The mixture was stirred at room
temperature for 12h and then quenched with saturated
aqueous sodium hydrogen carbonate and extracted with
dichloromethane 13£50 mL). The organic layer was dried
1MgSO4), ®ltered and the solvent removed in vacuo. The
product was obtained as colourless oil 7 140 mg, 80%).
1Found 281.0005. C13H935Cl2NO2 requires 281.0010);
37
429 10.4%, 2£ Cl and 82Se [M]1), 427 13, 35Cl, 37Cl and
82Se [M]1), 425 112, 35Cl, 37Cl and 79Se [M]1), 423 119,
35
35
2£ Cl and 79Se [M]1), 42119, 2£ Cl and 78Se [M]1), 420
13, 2£ Cl and 77Se [M]1), 419 13, 2£ Cl and 76Se [M]1),
268 113), 266 121), 158 120), 155 120), 140 118), 77 128) and
55 1100). The crude was dissolved in dichloromethane
110 mL) and cooled to 2408C, hydrogen peroxide
10.2mL) was added and the mixture was warmed to room
temperature and stirred over 2h. Dichloromethane 120 mL)
was added and the mixture was washed with a saturated
solution of sodium hydrogen carbonate 12£25 mL) and a
saturated solution of sodium chloride 12£25 mL). The
organic layer was dried 1MgSO4) and the solvent removed
in vacuo. Flash column chromatography on silica 1diethyl
ether/hexane, 1:1) yielded the product 8 140 mg, 52%)
whose spectral data was consistent with that previously
observed.
35
35
n
max1®lm) 1cm21
)
2240 1CN), 1771 1CvO); dH
1300 MHz; CDCl3; Me4Si) 2.22 11H, m, Hax-4), 2.54 11H,
m, Hax-3), 2.89±3.08 12H, m, Heq-3 and Heq-4), 5.10 11H,
dd, Jˆ7.7, 1.6 Hz, H-4), 6.51 11H, d, Jˆ7.7 Hz, H-3), 7.30
11H, dd, Joˆ8.4 Hz, Jmˆ2.3 Hz, H-60), 7.35 11H, d,
Joˆ8.4 Hz, H-50) and 7.58 11H, d, Jmˆ2.3 Hz, H-20); dC
175 MHz, CDCl3; Me4Si) 31.36 and 34.29 1C6 and C7),
46.52 1C5), 109.29 1C3), 119.70 1CN), 125.40, 128.25,
and 131.44 1C20, C50 and C60), 133.73, 134.00 and 138.00
1C10, C30 and C40), 140.64 1C4) and 168.77 1CO); m/z 1EI)
Method C: 4-Cyano-4-13,4-dichlorophenyl)cyclohexanone
1 12.5 g, 7.5 mmol) was dissolved in THF 130 mL) and the
solution was cooled to 2788C under N2. A solution of 1M
LiHMDS in THF 110 mL, 10.0 mmol) was added and the
mixture stirred for 10 min. TIPSCl 13 mL, 14.0 mmol) was
added and the mixture left to warm to room temperature
over 1 h. The reaction was quenched with saturated
NaHCO3 solution 170 mL) and the product extracted with
diethyl ether 13£70 mL). The organic layers were combined
and dried 1MgSO4) and the solvent removed in vacuo. The
residue was puri®ed by ¯ash column chromatography on
silica 1petroleum ether/diethyl ether, 7:1) to yield the
product TIPS enol ether 11.2g, 37%) as a white solid.
1Found M1 423.1547. C22H31N35Cl2OSi requires
423.1552); nmax1®lm) 1cm21) 2238 1CN); dH 1300 MHz;
CDCl3; Me4Si) 0.99±1.53 121H, m, 3£CH1CH3)2), 2.15±
2.20 16H, m, H-3, H-5 and H-6), 4.88 11H, m, H-2), 7.35
11H, dd, Joˆ8.5 Hz, Jmˆ2.1 Hz, H-60), 7.47 11H, d,
Joˆ8.5 Hz, H-50) and 7.57 11H, d, Jmˆ2.1 Hz, H-20); dC
175 MHz; CDCl3; Me4Si) 12.60 13£CH1CH3)2), 17.95
13£CH1CH3)2), 27.61, 33.04 and 36.00 1C3, C5 and C6),
40.27 1C4), 98.73 1C2), 122.05 1CN), 125.41, 128.07 and
130.91 1C20, C50 and C60), 132.43 and 133.26 1C30 and
C40), 140.37 1C10) and 150.74 1C1); m/z 1EI) 427 11%,
35
281 11, 2£ Cl [M]1), 255 117), 253 128), 190 111), 84 122)
and 55 1100).
3.3.4. 4-Cyano-1,2-epoxy-4-(30,40-dichlorophenyl)cyclo-
hexylacetate 10. 4-Cyano-4-130,40-dichlorophenyl)cyclo-
hex-1-enyl acetate 2 154 mg, 0.17 mmol) and sodium
hydrogen phosphate 1101 mg, 0.7 mmol) were dissolved in
dichloromethane 110 mL), the mixture was cooled to 08C
and m-chloroperbenzoic acid 1247 mg, 1.4 mmol) was
added. The reaction was left to warm to room temperature.
The reaction was quenched with water 130 mL) and
extracted with dichloromethane 13£50 mL), dried
1MgSO4) and the solvent removed in vacuo. The product
10 was isolated as a white solid as an inseparable mixture of
diastereoisomers 141 mg, 72%). For the major diastereo-
isomer 1Found M2 325.0277; C15H13N35Cl2O3 requires
325.0272); nmax1®lm) 1cm21) 2238 1CN), 1755 1CvO);
dH 1300 MHz; CDCl3; Me4Si) 1.89±2.81 16H, m, H-3,
H-5 and H-6), 2.11 13H, s, CH3), 3.50 11H, d, Jˆ4.8 Hz,
H-2), 7.29 11H, dd, Joˆ8.5 Hz, Jmˆ2.4 Hz, H-60), 7.48 11H,
d, Joˆ8.5 Hz, H-50) and 7.55 11H, d, Jmˆ2.4 Hz, H-20); dC
175 MHz; CDCl3; Me4Si) 21.02 1CH3), 24.76, 30.25 and
37.33 1C3, C5 and C6), 39.92 1C4), 55.20 1C2), 81.14
1C1), 120.78 1CN), 124.96, 127.81 and 131.18 1C20, C50
and C60), 132.93 and 133.56 1C30 and C40), 139.55 1C10)
and 169.10 1CvO); m/z 1EI) 325 11%, [M]1), 199 113), 197
127), 55 118) and 43 1100, CH3CO).
37
35
2£ Cl [M]1), 425 13, 37Cl and 35Cl [M]1), 423 15, 2£ Cl
[M]1), 384 112, 2£ Cl [M2C3H7]2), 382155, 37Cl and 35Cl
37
[M2C3H7]1), 380 182, 2£ Cl [M2C3H7]1), 357 112,
35
37
2£ Cl [M2C3H7±HCN]1), 355 156, 357 112, 37Cl and
35Cl [M2C3H7±HCN]1) and 353 1100, 2£ Cl
35
[M2C3H7±HCN]1). 1NH4)2Ce1NO3)6 1724 mg, 1.32
mmol) was added to a solution of the 4-cyano-4-130,40-
dichlorophenyl)-1-1triisopropylsilyloxy)cyclohexene 1250 mg,
0.59 mmol) in DMF 16 mL) at 08C. The mixture was stirred
for 18 h and the reaction quenched with saturated sodium
hydrogen carbonate solution 125 mL). The product was
extracted with diethyl ether 13£25 mL) and the organic
3.3.5. 2-Hydroxy-4-cyano-4-(30,40-dichlorophenyl)cyclo-
hexanone 11. The 4-cyano-1,2-epoxy-4-13,4-dichloro-
phenyl)cyclohexyl acetate 10 150 mg, 0.15 mmol) was

8200
G. Allan et al. / Tetrahedron 57 02001) 8193±8202
dissolved in chloroform 110 mL) and acetic acid 10.26 mL)
and a catalytic amount of p-toluensulfonic acid 17 mg,
0.04 mmol) was added and the mixture was stirred for 2h
at room temperature. The reaction was quenched with satu-
rated aqueous sodium hydrogencarbonate solution 120 mL)
and extracted with dichloromethane 13£20 mL). The
organic layer was dried 1MgSO4) and the solvent removed
in vacuo. The residue was puri®ed by ¯ash column chroma-
tography on silica 1petroleum ether/ethyl acetate, 2:1) to
yield the product 11 132mg, 74%) as a white solid. The
product was a 5:1 mixture of diastereoisomers. For the
major isomer 1Found M1 283.0167; C13H11N35Cl2O2
requires 283.0164); nmax1®lm) 1cm21) 3438 1OH), 2238
1CN), 1727 1CvO); dH 1300 MHz; CDCl3; Me4Si) 1.97±
3.0216H, m, H-3, H-5 and H-6), 3.5211H, br, OH), 4.61
11H, q, Jˆ6.3 Hz, Hax-2), 5.59 11H, q, Jˆ6.2Hz, H eq-2),
7.28 11H, dd, Jmˆ2.2 Hz, Joˆ8.5 Hz, H-60), 7.46 11H, d,
Joˆ8.5 Hz, H-50) and 7.53 11H, d, Jmˆ2.2 Hz, H-20); dC
175 MHz; CDCl3; Me4Si) 36.09, 38.02and 42.421C3, C5
and C6), 72.12 1C2), 41.89 1C4), 120.31 1CN), 124.86,
127.69 and 131.38 1C20, C50 and C60), 133.45, 133.85 and
137.88 1C10, C30 and C40) and 207.31 1CO); m/z 1EI) 287
in methanol 13 mL) at 08C and the reaction was stirred for
18 h. The reaction was quenched with water 15 mL) and the
methanol removed in vacuo. The aqueous layer was
extracted with dichloromethane 110 mL), the organic
extracts were dried 1MgSO4) and the solvent removed in
vacuo. The crude product was puri®ed by ¯ash column
chromatography on silica 1ethyl acetate/hexane, 1:3) to
yield the product 5 120 mg, 58%) as a colourless oil
whose spectral data was consistent with the data previously
observed.
3.3.8. (S)-Methyl4-cyano-4-(3 0,40-dichlorophenyl)-6-
hydroxyhexanonoate 12. Sodium triacetoxyborohydride
1339 mg, 1.6 mmol) was added to a solution of the 12)-
ester aldehyde 5 1138 mg, 0.44 mmol) in acetic acid
120 mL) at 208C. After 2.5 h the reaction was quenched
with water 120 mL) and extracted with dichloromethane
13£30 mL). The organic layers were dried 1MgSO4), ®ltered
and the solvent was removed in vacuo. The residue was
puri®ed by ¯ash column chromatography on silica 1hexane/
ethyl acetate, 1:1) to yield the product 1S)-12 1100 mg, 72%)
as a colourless oil. 1Found M1 315.0428. C14H15NCl2O3
requires 315.0429); nmax1®lm) 1cm21) 3297 1OH), 2250
1CN), 1738 1CvO); dH 1300 MHz; CDCl3; Me4Si) 2.11±
2.55 16H, m, H-2, H-3 and H-5), 3.50±3.68 12H, m, H-6),
3.63 13H, s, CH3O), 7.28 11H, dd, Joˆ8.5 Hz, Jmˆ2.5 Hz,
H-60), 7.49 11H, d, Joˆ8.5 Hz, H-20) and 7.53 11H, d,
Jmˆ2.5 Hz, H-50); dC 175 MHz; CDCl3; Me4Si) 29.8,
35.85 and 42.69 1C2, C3 and C5), 44.76 1C4), 51.94 1C6),
59.05 1OCH3), 120.65 1CN), 125.30, 128.07 and 131.18
1C20, C50 and C60), 132.82, 133.68 and 137.27 1C30, C40
and C10) and 172.20 1CO); m/z 1EI) 315 111%, [M]1), 284
115), 239 148), 210 155), 197 166), 173 123) and 74 1100).
37
12%, 2£ Cl [M]1), 285 19, 37Cl and 35Cl [M]1), 283 115,
2£ Cl [M]1), 241 110), 226 111) and 197 1100).
35
3.3.6.
Methyl
4-cyano-(3,4-dichlorophenyl)-6-oxo-
hexanoate 5. Method A. The 4-cyano-130,40-dichloro-
phenyl)cyclohex-1-enyl acetate 2 1100 mg, 0.3 mmol) was
dissolved in methanol/dichloromethane, 1:4 110 mL). The
mixture was cooled to 2788C and O3/O2 was bubbled
through the solution. After 1 h the ¯ow of O3/O2 was
stopped and O2 was bubbled through until the solution
became
colourless.
Triphenylphosphine
1125 mg,
0.48 mmol) was added to the reaction mixture and left to
stir for 18 h under nitrogen. The solvent was removed in
vacuo and the crude was puri®ed by ¯ash column chromato-
graphy on silica 1ethyl acetate/hexane, 1:1) to yield the
product as a colourless oil 5 162mg, 62%). 1Found C,
53.30; H, 4.38; N, 4.24. C14H13O3N35Cl2 requires C,
53.52; H, 4.17; N, 4.46%); nmax1®lm) 1cm21) 2241 1CN),
1730 1CO); dH 1300 MHz; CDCl3; Me4Si) 2.02±2.49 14H,
m, H-2and H-3), 3.16 12H, s, H-5), 3.61 13H, s, ±OCH 3),
7.30, 7.46 and 7.51 13H, m, H-20, H-50 and H-60) and 9.62
11H, s, H-6); dC 175 MHz; CDCl3; Me4Si) 29.57 and 35.29
1C2 and C3), 42.22 1C4), 52.01 1C5), 52.16 1CH3), 119.68
1CN), 125.38, 128.09 and 131.41 1C20, C50 and C60),
133.36, 133.97 and 136.40 1C10, C30 and C40), 171.88
1C1) and 195.68 1C6); m/z 1EI) 313 11.5%, [M]1), 298
117), 283 112), 210 1100) and 197 150).
3.3.9. (10S,3S,40R)-(2)-(40,70,70)-Trimethyl-30-oxo-20-oxa-
bicyclo[2.2.1]heptane-10-carboxylic acid 3-cyano-3-
(300,400-dichlorophenyl)-5-methoxycarbonyl-pentanyl
ester (2)-13. 1S)-Camphanyl chloride 1115 mg, 0.53 mmol)
and triethylamine 10.17 mL, 1.23 mmol) were added to a
solution of the 1S)-methyl 4-cyano-4-130,40-dichloro-
phenyl)-6-hydroxyhexanoate 12 1100 mg, 0.32mmol) in
dichloromethane 12mL). DMAP 113 mg, 0.041 mmol)
was added and the mixture was stirred at room temperature
for 2h whereupon the reaction was quenched with water
110 mL) and extracted with dichloromethane 13£10 mL).
The organic layers were combined and washed with satu-
rated sodium chloride solution 13£10 mL) and dried
1MgSO4). The solvent was removed in vacuo and the resi-
due was puri®ed by ¯ash column chromatography on silica
1hexane/ethyl acetate, 1:1) to yield the product 12)-13
1130 mg, 83%) as a white crystalline solid which was crys-
tallized from 2-propanol. Mp 143.0±144.08C; 1Found C,
58.27; H, 5.47; N, 2.77; M1 495.1219. C24H27N35Cl2O6
requires C, 58.07; H, 5.48; N, 2.82%, 495.1215);
[a]Dˆ222 1cˆ1 in chloroform); nmax1®lm) 1cm21) 2256
1CN), 1791 1CvO) and 1739.0 1CvO); dH 1300 MHz;
0
3.3.7. (R)-(2)-Methyl4-cyano-4-(3 ,40-dichlorophenyl)-
6-oxo-hexanoate 5. The title compound 1R)-12)-5
was synthesized in an identical manner to that above
using 1S)-11)-4-cyano-4-130,40-dichlorophenyl)cyclohex-1-
enyl acetate 11)-2 11.0 g, 3.2mmol) to yield, after puri®ca-
tion by ¯ash column chromatography on silica 1ethyl
acetate/hexane, 1:1), the product 1R)-12)-5 1610 mg, 60%)
as a colourless oil. [a]Dˆ27.5 1cˆ2.0 in chloroform)
whose spectral data was consistent with the data previously
observed.
CDCl3; Me4Si) 0.93 13H, s, CH3), 1.0213H, s, CH ), 1.10
3
13H, s, CH3), 1.62±2.55 110H, m, H-2, H-4, H-5, H-50and
H-60), 3.63 13H, s, CH3O), 4.13±4.30 12H, m, H-6) and
7.24±7.54 13H, m, Ar-H); dC 175 MHz; CDCl3; Me4Si)
9.63 1CH3), 16.71 12£CH3), 28.88, 29.78, 30.51, 35.90
and 38.80 1C2, C4, C5, C50 and C60), 44.84 1C3), 51.96
1CH3O), 54.24 and 54.73 1C40 and C70), 61.43 1C1), 90.81
Method B. Sodium periodate 145 mg, 0.21 mmol) was added
to a solution of the hydroxy-ketone 11 132mg, 0.14 mmol)

G. Allan et al. / Tetrahedron 57 02001) 8193±8202
8201
1C10), 120.04 1CN), 125.34, 131.51 and 133.27 1C200, C500
and C600), 133.27, 133.93 and 136.46 1C100, C300 and C400),
167.29, 171.97 and 177.85 13£CO); m/z 1EI) 497 11%, 37Cl
131.04, 133.08 and 142.66 1C10,C30 and C40) and 171.69
1CvO); m/z 1CI) 414 125%, 37Cl and 35Cl [M1H]1), 412
138, 2£ Cl [M1H]1), 380 132), 378 188), 344 139), 145
35
35
and 35Cl [M]1), 495 12, 2£ Cl [M]1), 316 12), 298 17), 210
136), 114 1100), 88 183) and 52175).
111), 136 194), 134 186) and 109 1100).
3.3.12. (5S)-(1)-5-(30,40-Dichlorophenyl)-1-(3000-methoxy-
benzyl)-5-(200-N-morpholinoazetidin ethyl)-piperidin-2-
one 3. A dispersion of 60% sodium hydride in oil 120 mg,
0.25 mmol) was washed with hexane and added to a solution
of 15S)-5-13,4-dichlorophenyl)-5-12-N-morpholinoazetidi-
nethyl)-piperidin-2-one 11)-16 170 mg, 0.17 mmol) in
DMF 11 mL) at 08C under an atmosphere of nitrogen.
18-Crown-6 10.05 mL, 0.25 mmol) was added and the
mixture was stirred for 10 min. whereupon m-methoxy-
benzyl bromide 10.02mL, 0.17 mmol) was added. The
mixture was allowed to warm to room temperature and stir-
red for 7 h. The reaction was quenched with water 15 mL)
and the product extracted with ethyl acetate 13£10 mL). The
organic layers were combined and washed with saturated
sodium chloride solution 13£20 mL) and water 13£20 mL).
The solvent was removed in vacuo, dried and the crude
product was puri®ed by ¯ash column chromatography on
silica 1dichloromethane/methanol, 9:1) to yield the title
product 1S)-11)-3 125 mg, 28%) as a colourless oil.
1Found [M1H]1 532.2133. C28H36N3O3Cl2 requires
532.2133). [a]Dˆ1421 cˆ1.5 in chloroform); nmax1®lm)
1cm21) 1633 1CvO); dH 1300 MHz; CDCl3; Me4Si) 1.34±
3.68 123H, m, CH2 and CH), 3.69 13H, s, CH3O), 4.31 11H,
d, Jˆ14 Hz, benzylic-H), 4.83 11H, d, Jˆ14 Hz, benzylic-
H), 6.75±6.86 13H, m, Ar-H), 7.03±7.04 11H, m, Ar-H),
7.22±7.30 13H, m, Ar-H); dC 1100 MHz; CDCl3; Me4Si)
28.81, 32.36 and 39.51 1C3, C4 and C100), 38.421C5),
50.18 1CH3O), 50.28, 54.25, 54.85, 55.22 and 58.43 1C6,
C200, C400, C800, C600, C1200 and C-benzylic), 55.58 1C500),
66.50 1C900 and C1100), 113.37, 114.27, 120.99 and 129.73
1C2000, C4000, C5000 and C6000), 125.61, 128.32 and 130.51 1C20,
C50and C60), 130.87, 132.04 and 142.39 1C10, C30 and C40),
138.04 1C1000), 159.95 1C3000) and 168.78 1CvO); m/z 1FAB)
3.3.10.
morpholinoazetidine-hexanoic acid methyl ester 15.
1R)-12)-Methyl
4-cyano-4-130,40-dichloropheyl)-6-oxo-
(4S)-(2)-Cyano-4-(30,40-dichlorophenyl)-6-N-
hexanoate 5 1180 mg, 0.57 mmol), morpholinoazetidine
hydrochloride 198 mg, 0.54 mmol) and triethyl amine
10.064 mL) were stirred in THF 110 mL) for 30 min at
room temperature under an atmosphere of nitrogen. Sodium
triacetoxyborohydride 1160 mg, 0.74 mmol) was added
followed by acetic acid 10.04 mL) and the reaction was
stirred for 3 h. The reaction was quenched with saturated
sodium hydrogen carbonate solution 15 mL) and the product
extracted with dichloromethane 13£10 mL), dried 1MgSO4)
and the solvent removed in vacuo. The crude product was
puri®ed by ¯ash column chromatography on silica
1dichloromethane/methanol, 9:1) to yield the product
12)-1S)-15 1227 mg, 91%) as a colourless oil. [a]Dˆ
217.6 1cˆ2in chloroform). 1Found [M 1H]2 440.1521.
C21H2735Cl2N3O3 requires 440.1507); nmax1®lm) 1cm21
)
2220 1CN) and 1738 1CvO); dH 1300 MHz; CDCl3;
Me4Si) 1.87±3.71 121H, m, 10£H-2, H-3, H-5, H-6, H-200,
H-300, H-400, H600, H-700, H-900 and H-1000), 3.6213H, s,
CH3O) and 7.22±7.29 13H, m, Ar-H); dC 175 MHz;
CDCl3; Me4Si) 29.86, 35.82, 38.23, 50.15, 55.11, 58.38,
66.55 1C2, C3, C5, C6, C200, C400, C600, C700, C900 and
C1000), 45.30 1C4), 51.87 1CH3), 55.521CH), 120.55 1CN),
125.28, 128.12 and 131.18 1C20, C50 and C60), 132.76,
133.66 and 137.35 1C10, C30 and C40) and 172.23 1CO);
m/z 1CI) 442185%, 37Cl and 35Cl [M1H]1), 440 1100,
35
2£ Cl [M1H] and 406 120).
3.3.11. (5S)-(1)-5-(30,40-Dichlorophenyl)-5-(200-N-morph-
olinoazetidinethyl)-piperidin-2-one
16.
12)-14S)-4-
37
Cyano-4-13,4-dichlorophenyl)-6-N-morpholinoazetidine-
hexanoic acid methyl ester 12)-15 1180 mg, 0.41 mmol)
was dissolved in methanol 120 mL) and Raney Nickel
118 mg) was added followed by NH4OH 10.10 mL). The
mixture was heated under re¯ux for 18 h under an
atmosphere of hydrogen. The solution was cooled and
®ltered through celite and the methanol was removed in
vacuo. The residue was dissolved in dichloromethane
120 mL), washed with a saturated solution of NaHCO3
13£20 mL). The solution was dried 1MgSO4) and the solvent
removed in vacuo. The residue was puri®ed by ¯ash column
chromatography on silica 1dichloromethane/methanol,
10:1) to yield the product 1S)-11)-16 1166 mg, 97%),
whose spectral data was consistent with the data previously
observed. [a]Dˆ17.21 cˆ2.2 in chloroform). 1Found
[M1H]1 412.1545. C20H2835Cl2N3O2 requires 412.1558);
535 11%, 2£ Cl [M]1), 533 11, 37Cl and 35Cl [M]1), 531 11,
2£ Cl [M]1), 121 113), 113 1100) and 98 111).
35
3.3.13. N-(3-methoxybenzyl)piperidin-2-one 18. A solu-
tion of valerolactam 17 1200 mg, 2.0 mmol) and sodium
hydride 1150 mg, 3.0 mmol) in xylene 110 mL) was heated
to re¯ux. The m-methoxybenzyl chloride 10.3 mL) in xylene
12mL) was added dropwise and mixture was heated under
re¯ux for 18 h. The reaction was quenched with water
120 mL), the xylene was removed in vacuo and the aqueous
layer was extracted with dichloromethane 13£20 mL). The
organic layers were combined, dried 1MgSO4) and the
solvent removed in vacuo. The crude product was puri®ed
by ¯ash column chromatography on silica 1petroleum ether/
ethyl acetate, 1:2) to yield the product 18 1270 mg, 62%) as
a colourless oil. 1Found M1 219.1260. C13H17NO2 requires
219.1259); nmax1®lm) 1cm21) 1644 1CvO); dH 1300 MHz;
CDCl3; Me4Si) 1.70±1.81 14H, m, H-4 and H-5), 2.42±2.46
12H, m, H-3), 3.15±3.19 12H, m, H-6), 3.76 13H, s, CH3O),
4.55 12H, s, H-benzylic), 6.76±6.80 13H, m, Ar-H) and 7.21
11H, m, Ar-H); dC 175 MHz; CDCl3; Me4Si) 21.21, 23.01
1C4 and C5), 32.24 1C3), 47.16 1C-Bn), 49.87 1C6), 55.05
1CH3), 112.71, 113.62, 120.31, 129.56, 139.01 and 159.98
1C-ar) and 169.86 1CvO); m/z 1EI) 219 171%, [M]1), 204
13, [M2CH3]1), 134 122), 122 1100), 121 157).
n
max1®lm) 1cm21) 1667 1CvO); dH 1300 MHz; CDCl3;
Me4Si) 1.57±3.70 123H, m, H-3, H-4, H-6, H-100, H-200,
H-morpholinoazetidine), 6.78 11H, br, NH), 7.14 11H, dd,
Joˆ8.4 Hz, Jmˆ2.1 Hz, H-60), 7.37 11H, d, Jmˆ2.2 Hz,
H-20) and 7.4211H, d, Joˆ8.4 Hz, H-50); dC 175 MHz;
CDCl3; Me4Si) 28.19, 32.30, 37.76, 49.98, 50.19, 54.44,
58.48 and 66.53 1C3, C4, C6, C100, C200 and CH2±morpho-
linoazetidine), 38.921C5), 55.55 1CH±morpholino-
azetidine), 125.86, 128.61 and 130.77 1C20, C50 and C60),

8202
G. Allan et al. / Tetrahedron 57 02001) 8193±8202
9. For reviews see: Maggi, C. A.; Manzini, S. Drugs Lung 1994,
Acknowledgements
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1G. A.) and to Amano Enzyme Europe Ltd for kind donation
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