Asymmetric syntheses of 3,4-syn- and 3,4-anti-3-substituted-4- aminopiperidin-2-ones: Application to the asymmetric synthesis of (+)-(3S,4R)-cisapride

Article abstract of DOI:10.1016/j.tet.2011.12.084

The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl) amide to δ-(N-allylamino)-α,β-unsaturated esters, followed by N-deallylation and cyclisation of the resultant β,δ-diamino esters, gives the corresponding 4-aminopiperidin-2-ones as single diastereoisomers (>99:1 dr). Subsequent deprotonation with LiHMDS and functionalisation of the resultant lithium enolate gives 3,4-anti-3-substituted-4-aminopiperidin-2-ones in >99:1 dr. Alternatively, in situ oxidation of the intermediate lithium (Z)-β-amino enolates formed upon conjugate addition gives α-hydroxy-β,δ-diamino esters, which after N-deallylation and cyclisation gives the corresponding 3,4-syn-3-hydroxy-4-aminopiperidin-2-ones in >99:1 dr. The utility of this methodology was successfully demonstrated in a concise asymmetric synthesis of the gastroprokinetic agent (+)-(3S,4R)- cisapride {(+)-(3S,4R)-N(1)-[3′-(4″-fluorophenoxy)propyl]-3-methoxy- 4-(2?-methoxy-4?-amino-5?-chlorobenzamido)piperidine} in nine steps from commercially available starting materials with an overall yield of 19%.

Full text of DOI:10.1016/j.tet.2011.12.084

Tetrahedron 68 (2012) 3263e3275
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric syntheses of 3,4-syn- and 3,4-anti-3-substituted-4-aminopiperidin-
2-ones: application to the asymmetric synthesis of (þ)-(3S,4R)-cisapride
*
Stephen G. Davies , Rosemary Huckvale, James A. Lee, Thomas J.A. Lorkin, Paul M. Roberts,
James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 October 2011
Received in revised form 13 December 2011
Accepted 29 December 2011
Available online 3 January 2012
The conjugate addition of lithium (R)-N-benzyl-N-(
saturated esters, followed by N-deallylation and cyclisation of the resultant b,d-diamino esters, gives the
corresponding 4-aminopiperidin-2-ones as single diastereoisomers (>99:1 dr). Subsequent deprotonation
with LiHMDS and functionalisation of the resultant lithium enolate gives 3,4-anti-3-substituted-4-
aminopiperidin-2-ones in >99:1 dr. Alternatively, in situ oxidation of the intermediate lithium (Z)-
a
-methylbenzyl)amide to
d
-(N-allylamino)-
a,b-un-
b-
amino enolates formed upon conjugate addition gives -hydroxy- -diamino esters, which after N-
a
b,d
Keywords:
Lithium amide
Conjugate addition
4-Aminopiperidin-2-one
4-Aminopiperidine
(þ)-(3S,4R)-Cisapride
deallylation and cyclisation gives the corresponding 3,4-syn-3-hydroxy-4-aminopiperidin-2-ones in
>99:1 dr. The utility of this methodology was successfully demonstrated in a concise asymmetric synthesis
of the gastroprokinetic agent (þ)-(3S,4R)-cisapride {(þ)-(3S,4R)-N(1)-[30-(400-fluorophenoxy)propyl]-
3-methoxy-4-(2000-methoxy-4000-amino-5000-chlorobenzamido)piperidine} in nine steps from commercially
available starting materials with an overall yield of 19%.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
b
-amino esters and their derivatives.10 This methodology has found
numerous applications, including the total syntheses of natural
products,11 molecular recognition phenomena12 and resolution
protocols,13 and has been reviewed.14 As part of our ongoing research
programme in this area we became interested in the application of
this methodology for the preparation of enantiopure azacyclic
scaffolds. We have previously demonstrated the asymmetric
3-Substituted-4-aminopiperidines are important targets in or-
ganic synthesis as they are common building blocks for potential
therapeutic agents.1 For example, trans-3,4-disubstituted piperi-
dine 1 has recently been found to have anti-fungal activity,2 dihy-
droxylated piperidine 2 is a potential building block for HIV
protease inhibitors,3 and cis-3-methylfentanyl 3 and (3R,4S,20S)-
ohmefentanyl 4 are derivatives of the analgesic fentanyl,4 with both
having greatly increased potency compared to fentanyl itself
(Fig. 1).
A key point to address in any synthetic route to enantiopure
piperidines is the construction of the azacyclic skeleton in such
a manner to enable the desired substitution pattern to be in-
troduced stereoselectively. A large variety of different methods
exist to achieve this goal, including the reduction of pyridines,5
ring-closing metathesis,6 aza-Diels-Alder reactions7 and via intra-
molecular aza-Michael additions,8 and the synthesis of piperidines
has been extensively reviewed.9
Previous investigations from our laboratory have demonstrated
that the conjugate addition of enantiopure secondary lithium amides
(derived from a-methylbenzylamine) to a,b-unsaturated esters rep-
resents a general and efficient synthetic protocol for the synthesis of
Fig. 1. Biologically active 3-substituted-4-aminopiperidines 1e4.
* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.084

3264
S.G. Davies et al. / Tetrahedron 68 (2012) 3263e3275
syntheses of 3,4-anti- and 3,4-syn-3-methoxy-4-aminopyrrolidines
11 and 18 via conjugate addition of lithium (S)-N-methyl-N-(
Me
N
Me
a-
Ph
Bn
N
methylbenzyl)amide (S)-12 to methyl 4-(N-allyl-N-benzylamino)
CO2Me
CO2Me
but-2-enoate 5.15,16 For the preparation of 3,4-anti-substituted pyr-
Ph
(i)
(ii)
O
rolidine 11, b-amino ester 6 was formed via conjugate addition of (S)-
N
N
N
Bn
12 to 5 followed by treatment with satd aq NH4Cl, which gave 6 in 91%
yield and >99:1 dr. N-Deallylation of 6 and subsequent cyclisation
was achieved with Pd(PPh3)4 and N,N-dimethyl barbituric acid
(DMBA) as an allyl cation scavenger, followed by treatment of the
Bn
6, 91%, >99:1 dr
7, 89%, >99:1 dr
5
(iii)
Me
resultant b,g-diamino ester with SiO2 to induce cyclisation to give
Me
Me
4-aminopyrrolidin-2-one 7 in 89% yield and >99:1 dr. Deprotonation
of 7 with lithium tetramethylpiperidide (LiTMP), followed by enolate
oxidation upon treatment with (þ)-camphorsulfonyloxaziridine
[(þ)-CSO] 1317 gave 3,4-anti-3-hydroxy-4-aminopyrrolidin-2-one 8
in 86% yield and >99:1 dr. Sequential O-methylation of 8, reduction
of 9 with LiAlH4, and hydrogenolysis of 10 gave 3,4-anti-3-methoxy-
4-(N-methylamino)pyrrolidine 11 (which was isolated as the corre-
sponding TsOH salt) in 65% overall yield from 8. The complementary
synthesis of 3,4-syn-3-methoxy-4-aminopyrrolidine 18 proceeds via
conjugate addition of (S)-12 to 5 and in situ oxidation of the in-
N
OMe
N
OMe
N
OH
(v)
(iv)
Ph
Ph
Ph
O
O
N
N
N
Bn
Bn
Bn
10, 94%, >99:1 dr
9, 95%, >99:1 dr
8, 86%, >99:1 dr
(vi)
Me
HN
OMe
termediate lithium (Z)-
b
-amino enolate with (þ)-CSO 13 to give
Me
N
S
Ph
N
Li
a
-hydroxy- -amino ester 14 in 92% yield and >99:1 dr. Sequential
b
O
O2
O-methylation of 14, N-deallylation of 15, and cyclisation gave
pyrrolidin-2-one 16 in 41% yield over two steps. Reduction of 16
with LiAlH4, and subsequent hydrogenolysis of 17 gave 3,4-syn-3-
methoxy-4-(N-methylamino)pyrrolidine 18 (which was isolated as
the corresponding HCl salt) in 84% yield from 16 (Scheme 1).
We envisaged that this approach could also be used for the syn-
thesis of 3,4-syn- and 3,4-anti-3-substituted-4-aminopiperidines
N
H
•2TsOH
(S)-12
(+)-CSO 13
11•2TsOH, 73%, >99:1 dr
Me
OH
Me
Ph
Bn
N
Ph
Bn
N
(iv)
(vii)
CO2Me
CO2Me
CO2Me
OMe
from d-amino-a,b-unsaturated esters and delineate herein our full
investigations within this area. Part of this work has been commu-
N
N
N
Bn
nicated previously.18
14, 92%, >99:1 dr
15, 62%, >99:1 dr
5
2. Results and discussion
(ii)
2.1. Asymmetric synthesis of 3-substituted-4-aminopiperidin-
2-ones
Me
HN
Me
N
Me
N
OMe
OMe
OMe
O
A
range of N,N-diprotected
23e25 was required for the synthesis of 3-substituted-4-
aminopiperidin-2-ones; the nature of the -amino protecting
groups within 23e25 were chosen to provide orthogonal or com-
plementary protection to the -amino substituent that would be
d-amino-a,b-unsaturated esters
(viii)
(v)
Ph
Ph
d
N
N
N
•2HCl
H
Bn
Bn
b
18•2HCl, 84%, >99:1 dr
17, quant, >99:1 dr
16, 66%, >99:1 dr
introduced upon conjugate addition of the lithium amide reagent.
Scheme 1. Reagents and conditions: (i) lithium (S)-N-methyl-N-(a-methylbenzyl)
ꢀ
Using a one-pot procedure developed by Chesney and Marko for the
amide (S)-12, THF, ꢀ78 ꢁC, 2 h; (ii) Pd(PPh3)4, DMBA, CH2Cl2, rt, 16 h then SiO2, CH2Cl2;
(iii) LiTMP, THF, ꢀ78 ꢁC, 2 h then (þ)-CSO 13, THF, ꢀ78 ꢁC to rt, 16 h; (iv) NaH, THF, 0 ꢁC,
1 h then MeI, 0 ꢁC to rt, 12 h; (v) LiAlH4, THF, reflux, 12 h; (vi) H2 (5 atm), Pd(OH)2/C,
synthesis of an analogous
gate addition of amines 19e21 to acrolein and Wittig olefination of
the in situ formed
-amino aldehydes20 with tert-butyl (triphenyl-
phosphoranylidene)acetate 22 gave -unsaturated esters 23e25 in
d-amino-a,b
-unsaturated ester,19 conju-
MeOH, 48 h then TsOH; (vii) lithium (S)-N-methyl-N-(a-methylbenzyl)amide (S)-12,
b
THF, ꢀ78 ꢁC, 2 h then (þ)-CSO 13, ꢀ78 ꢁC to rt, 12 h; (viii) H2 (5 atm), Pd(OH)2/C,
a,b
MeOH, 48 h then HCl.
68e91% yield, and in >99:1 dr in each case (Scheme 2).21 The (E)-
configurations within 23e25 were confidently assigned from the
diagnostic values of the olefinic coupling constants (23: J2,3¼15.7 Hz;
24: J2,3¼15.7 Hz; 25: J2,3¼15.5 Hz).
R1
R1
(i)
NH
R2
N
R2
O
With
gate addition of lithium (R)-N-benzyl-(N-
3222 to 23e25 was undertaken and gave, after treatment of the re-
action mixture with satd aq NH4Cl, -amino esters 26e28 as single
diastereoisomers (>99:1 dr) in 52e88% isolated yield. The absolute
(R,R)-configurations within -amino esters 26e28 were initially
d-amino-a,b-unsaturated esters 23e25 in hand, the conju-
a-methylbenzyl)amide (R)-
19, R1 = R2 = allyl
20, R1 = allyl, R2 = Bn
21, R1 = R2 = Bn
t
Ph3P
CO2 Bu
b
(ii)
22
b
t
R1
CO2 Bu
assigned by reference to the transition state mnemonic developed by
us to rationalise the diastereofacial selectivity of this class of lithium
amide reagents upon conjugate addition.23 The synthesis of 3,4-syn-
3-substituted-4-aminopiperidin-2-ones from 23e25 required the
stereoselective introduction of the C(3)-substituent prior to cyclisa-
tion, which could be performed via either a ‘tandem’ or a ‘stepwise’
conjugate addition/enolate functionalisation protocol.17c By analogy
N
R2
23, R1 = R2 = allyl, 72%, >99:1 dr
24, R1 = allyl, R2 = Bn, 91%, >99:1 dr
25, R1 = R2 = Bn, 68%, >99:1 dr
Scheme 2. Reagents and conditions: (i) acrolein, DBU, THF, ꢀ15 ꢁC, 40 min;
t
(ii) Ph3P]CHCO2 Bu 22, ꢀ15 ꢁC to rt, 16 h.

S.G. Davies et al. / Tetrahedron 68 (2012) 3263e3275
3265
to our synthesis of 3,4-syn-substituted pyrrolidine 18, the ‘tandem’
lithium amide conjugate addition of (R)-32 to 23, and subsequent in
36 being assigned relative to the known configuration of the (R)-
-methylbenzyl stereogenic centre (Fig. 2).27 This analysis also
allowed the assigned absolute (R,R,R)-configuration within
hydroxy- -amino ester 30 and the absolute (R,R)-configurations
within 27 and 34 to be unambiguously confirmed. The absolute
(R,R)-configurations within 26 and 33, and the absolute (R,R,R)-
configurations within 29 and 35 were therefore assigned by
analogy.
a
situ oxidation of the intermediate lithium (Z)-
b
-amino enolate24
a-
with (ꢀ)-CSO 13, was attempted first. Conjugate addition of (R)-32
to 23 followed by treatment with (ꢀ)-CSO 13 gave 29 in 68% isolated
yield and >99:1 dr. These conditions were then successfully applied
to substrates 24 and 25 to give 30 and 31 in 42 and 33% yield, re-
spectively, and >99:1 dr in both cases (Scheme 3).25 The absolute
(R,R,R)-configurations within 29e31 were assigned by analogy to the
well established stereochemical outcome of this anti-amino-
hydroxylation protocol.17a,c,26
b
Scheme 4. Reagents and conditions: (i) Pd(PPh3)4, DMBA, CH2Cl2, 35 ꢁC, 3 h; (ii)
PhCO2H, toluene, 80 ꢁC, 16 h.
Scheme 3. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(a-methylbenzyl)
amide (R)-32, THF, ꢀ78 ꢁC, 2 h then NH4Cl (satd aq); (ii) lithium (R)-N-benzyl-N-(
a-
methylbenzyl)amide (R)-32, THF, ꢀ78 ꢁC, 2 h then (ꢀ)-CSO 13, ꢀ78 ꢁC to rt, 16 h.
[a26 was also isolated in 7% yield; b27 was also isolated in 36% yield; c28 was also
isolated in 47% yield].
The attempted formation of
conjugate addition of (R)-32 to 23e25 and in situ alkylation of the
intermediate lithium (Z)-
-amino enolates24 with either MeI or
tert-butyl bromoacetate (using our previously reported protocol24c
was not successful, as the intermediate lithium (Z)- -amino eno-
a-alkyl-b-amino esters via ‘tandem’
b
)
b
lates proved inert to alkylation giving complex mixtures of prod-
ucts within which only 26e28 could be identified. A ‘stepwise’
protocol was therefore investigated whereby deprotonation of
26e28 with LDA was followed by addition of either MeI or tert-
butyl bromoacetate. However, the intermediate lithium (E)-
b-
amino enolates24 derived from
b,d-diamino esters 26e28 also
Fig. 2. Chem 3D representation of the single crystal X-ray diffraction structure of 36
(selected H atoms are omitted for clarity).
proved inert to alkylation under these conditions. Our synthetic
endeavours therefore focussed upon the N-deprotection and cyc-
lisation of
hydrogenolysis of
in the presence of Pearlman’s catalyst [Pd(OH)2/C] gave poor mass
return. N-Deallylation of -amino esters 26 and 27, however, upon
b
-amino esters 26e31. Unfortunately, attempted
It was anticipated that alkylation of enolates derived from
4-aminopiperidin-2-one 34 would give predominantly 3,4-anti-3-
alkyl-4-aminopiperidin-2-ones as a result of alkylation on the
d
-(N,N-dibenzylamino)- -amino esters 28 and 31
b
b
face opposite the bulky C(4)-N-benzyl-N-(a-methylbenzyl)amino
treatment with Pd(PPh3)4 (0.01 equiv per allyl group) and DMBA
(3.0 equiv per allyl group),15 was successful although attempts to
isolate the intermediate amines gave poor mass return. The crude
reaction mixture obtained from deallylation of 26 was therefore
dissolved in toluene and the resultant solution was treated with
PhCO2H (0.1 equiv) and heated at 80 ꢁC for 16 h, which gave 4-
aminopiperidin-2-one 33 in 77% yield (over two steps) and >99:1
dr. This procedure was subsequently applied to 27, 29 and 30, using
either 0.05 or 0.1 equiv of PhCO2H, to give the corresponding 4-
aminopiperidin-2-ones 34e36 as single diastereoisomers (>99:1
dr) in 47e69% isolated yield (Scheme 4). The relative configuration
within 36 was unambiguously established by single crystal X-ray
diffraction analysis, with the absolute (R,R,R)-configuration within
substituent. A variety of strong bases have previously been used in
t
the alkylation of piperidin-2-ones, including BuLi,28 LiTMP15 and
LDA.29 However, treatment of 4-aminopiperidin-2-one 34 with
either LiTMP (1.5 equiv), LDA (1.5 equiv), or KHMDS (2.0 equiv),
followed by treatment of the resultant enolate with MeI (3.0 equiv)
gave returned starting material exclusively. The use of either
NaHMDS (2.0 equiv) or LiHMDS (1.5 equiv) as the base, however,
gave 3,4-anti-3-methyl-4-aminopiperidin-2-one 37 in >99:1 dr,
although the reaction conversions were very low (10 and 26%
conversion, respectively). Increasing the equivalents of LiHMDS
was found to significantly increase the reaction conversion and
under optimised conditions the use of 3.0 equiv of LiHMDS was
found to give quantitative conversion to 37 (>99:1 dr), which was

3266
S.G. Davies et al. / Tetrahedron 68 (2012) 3263e3275
isolated in 67% yield after chromatographic purification
(Scheme 5). No evidence of dialkylation was noted in the 1H NMR
spectrum of the crude reaction mixture. The relative configuration
within 37 was unambiguously assigned by single crystal X-ray
diffraction analysis, with the absolute (3S,4R,aR)-configuration
within 37 assigned from the known configuration of the (R)-
a
-
methylbenzyl stereogenic centre (Fig. 3).27 This optimised pro-
cedure was also applied to the alkylation of 34 with tert-butyl
bromoacetate, although only 20% conversion to 38 (80:20 dr) was
noted in this case; after purification 38 was isolated in 12% yield
and >99:1 dr. The configuration at C(3) within 38 was assigned by
analogy to that unambiguously established for 37 upon alkylation
with MeI.
Scheme 6. Reagents and conditions: (i) LiHMDS, THF, ꢀ78 ꢁC, 1 h then (þ)-CSO 13,
ꢀ78 ꢁC to rt, 16 h; (ii) LiHMDS, THF, ꢀ78 ꢁC, 1 h then (ꢀ)-CSO 13, ꢀ78 ꢁC to rt, 16 h; (iii)
PPh3, DEAD, p-nitrobenzoic acid, THF, 0 ꢁC, 6 h; (iv) K2CO3, MeOH, rt, 16 h.
Although the alkylation/enolate oxidation of these substrates
proved to be somewhat troublesome, this strategy readily provided
access to both 3,4-syn- and 3,4-anti-3-hydroxy-4-aminopiperidin-
2-ones 36 and 39 in >99:1 dr. We therefore sought to demonstrate
the utility of this protocol in the asymmetric synthesis of a 3-
substituted-4-aminopiperidine, and selected (þ)-(3S,4R)-cisapride
as a suitable target.
2.2. Asymmetric synthesis of (D)-(3S,4R)-cisapride
(ꢂ)-(RS,SR)-Cisapride {(ꢂ)-(RS,SR)-N(1)-[30-(400-fluorophenoxy)-
propyl]-3-methoxy-4-(2000-methoxy-4000-amino-5000-chlorobenzamido)-
piperidine} 40 is a gastroprokinetic agent31 that was developed by
Janssen Pharmaceutica in the 1980s32 (Fig. 4). The racemate was
marketed (from 1993 onwards) under the trade name PropulsidÒ as
a treatment for gastroesophageal reflux disease,33 although it has
also beenused successfully in the treatmentof othergastrointestinal
diseases such as chronic bowel constipation and irritable bowel
syndrome.34 However, the adverse gastrointestinal (e.g., abdominal
pain and diarrhoea) and cardiovascular effects associated with tak-
ing this medication can be severe.35 Between 1993 and 1999 there
were 341 cases of cardiac dysrhythmia attributed to the use of
PropulsidÒ, as well as 80 reported deaths, which ultimatelyled tothe
voluntary withdrawal of the drug from market in the USA in 2000,
pending further research.36 It has been reported that administration
of the (þ)-(3S,4R)-eutomer substantially reduces the adverse effects
associated with the racemate,37 and the biological screening of
compoundsrelated tocisapride 40is still an activearea ofresearch.38
As such, there is continued interest in the development of methods
to enable the efficient syntheses of analogues of cisapride 40.
Scheme 5. Reagents and conditions: (i) LiHMDS, ꢀ78 ꢁC,
1 h, then MeI or
t
BrCH2CO2 Bu, THF, ꢀ78 ꢁC to rt, 16 h.
Fig. 3. Chem 3D representation of the single crystal X-ray diffraction structure of 37
(selected H atoms are omitted for clarity).
The corresponding 3,4-anti-3-hydroxy-4-aminopiperidin-2-one
39 was produced upon treatment of 34 with LiHMDS (3.0 equiv),
followed by oxidation of the intermediate lithium enolate with either
(þ)- or (ꢀ)-CSO 13, which gave 15 and 47% conversion to 39,30 which
was isolated as a single diastereoisomer (>99:1 dr) in 5 and 37% yield,
respectively (Scheme 6). Therelative3,4-anti-configurationwithin39
was initially assigned by analogy to the stereochemical outcome of
enolate alkylation. The diagnostic 1H NMR 3J coupling constants
observed between the C(3)H and C(4)H protons, however, were
supportive of this assignment (for 3,4-syn-3-substituted-4-
Fig. 4. Structure of (þ)-(3S,4R)-cisapride 40.
It was envisaged that the asymmetric synthesis of (þ)-(3S,4R)-
cisapride 4039,40 could be achieved from the corresponding 3-
hydroxy-4-aminopiperidin-2-one, which in turn could be derived
from N-[3-(40-fluorophenoxy)propyl]-N-allylamine 42. Secondary
amine 42 was therefore produced by treatment of commercially
available 1-(40-fluorophenoxy)-3-bromopropane 41 with allyl-
amine, which gave 42 in 87% yield.41 Subsequent conversion of 42
3
aminopiperidin-2-ones 35 and 36, J3,4¼6.0e6.3 Hz; for 3,4-anti-3-
3
substituted-4-aminopiperidin-2-ones 37e39, J3,4¼10.1e11.0 Hz).
into
a,
b
-unsaturated ester 44 was achieved (following the pro-
Furthermore, an authentic sample of 3,4-anti-39 was prepared via
Mitsunobu reaction of 3,4-syn-36 upon treatment with PPh3, DEAD
and p-nitrobenzoic acid, followed by transesterification of the re-
sultant p-nitrobenzoate ester. The sample so produced
displayed identical spectroscopic data to the sample of 3,4-anti-39
which was prepared by oxidation of the enolate derived from 34
(Scheme 6).
19
ꢀ
cedure of Chesney and Marko) by conjugate addition of 42 to
acrolein at ꢀ15 ꢁC to give
b-amino aldehyde 43 that was trapped by
in situ Wittig reaction with tert-butyl (triphenylphosphor-
anylidene)acetate 22 to give a 77:23 mixture of (E) and (Z) geo-
metric isomers. Purification gave diastereoisomerically pure (E)-44
(J2,3¼16.2 Hz) in 70% yield (Scheme 7).

S.G. Davies et al. / Tetrahedron 68 (2012) 3263e3275
3267
acid 51 was achieved via treatment of 51 with ethyl chloroformate
and Et3N, followed by addition of 50 to the reaction flask.32,42
Chromatographic purification of the crude reaction mixture gave
(þ)-(3S,4R)-cisapride 40 in 64% isolated yield over the two steps and
>99:1 dr (Scheme 9). This sample of cisapride 40 displayed identical
spectroscopic data to those of an authentic sample. The total
asymmetric synthesis of (þ)-(3S,4R)-cisapride 40 from commercially
available starting materials was therefore achieved in nine steps
with an overall yield of 19%. This synthetic strategy can be applied to
the preparation of either enantiomer of cisapride 40, and should be
readily amenable to diversification.
Scheme 7. Reagents and conditions: (i) allylamine, K2CO3, NaI, THF, 45 ꢁC, 16 h; (ii)
t
acrolein, DBU, THF, ꢀ15 ꢁC, 40 min; (iii) Ph3P]CHCO2 Bu 22, THF, ꢀ15 ꢁC to rt, 16 h.
Diastereoselective conjugate addition of lithium amide (R)-32 to
a
,b
-unsaturated ester 44 was followed by in situ enolate oxidation
upon treatment with (ꢀ)-CSO 13 to give -hydroxy- -amino ester
a
b
45 as a single diastereoisomer (>99:1 dr), which was isolated in
64% yield and >99:1 dr after chromatographic purification. The
absolute (R,R,R)-configuration within 45 was again assigned by
analogy to the well established stereochemical outcome of our
aminohydroxylation process.17a,c Following the previously opti-
mised procedures, N-deallylation of 45 and subsequent cyclisation
of 46 to give the corresponding 3-hydroxy-4-aminopiperidin-2-
one 47 was achieved by sequential treatment with Pd(PPh3)4 in
the presence of DMBA, followed by heating a solution of the crude
reaction mixture in toluene at 80 ꢁC in the presence of PhCO2H
(0.05 equiv). After chromatographic purification, 3,4-syn-3-
hydroxy-4-aminopiperidine-2-one 47 was isolated in 99% yield
over the two steps and in >99:1 dr (Scheme 8).
Scheme 9. Reagents and conditions: (i) NaH, THF, 0 ꢁC, 1 h, then MeI, 0 ꢁC to rt, 16 h;
(ii) LiAlH4, THF, 60 ꢁC, 16 h; (iii) H2, Pd(OH)2/C, MeOH, rt, 16 h; (iv) 51, ClCO2Et, Et3N,
THF, rt, 16 h.
Scheme 8. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(a-methylbenzyl)
Fig. 5. Chem 3D representation of the single crystal X-ray diffraction structure of 49
(selected H atoms are omitted for clarity).
amide (R)-32, THF, ꢀ78 ꢁC, 2 h, then (ꢀ)-CSO 13, ꢀ78 ꢁC to rt, 12 h; (ii) Pd(PPh3)4,
DMBA, CH2Cl2, 35 ꢁC, 3 h; (iii) PhCO2H, toluene, 80 ꢁC, 16 h.
O-Methylation of 47 was achieved upon sequential treatment
with NaH then MeI, which gave 48 in 77% isolated yield and >99:1
dr. Subsequent reduction of 48 with LiAlH4 in THF at reflux gave 3,4-
syn-3-methoxy-4-aminopiperidine 49 in 99% isolated yield
(Scheme 9). The relative configuration within 49 was unambiguously
assigned by single crystal X-ray diffraction analysis, with the abso-
3. Conclusion
The conjugate addition of lithium (R)-N-benzyl-(N-
benzyl)amide to -(N-allylamino)- -unsaturated esters, followed
by N-deallylation and cyclisation of the resultant -diamino es-
ters, gives the corresponding 4-aminopiperidin-2-ones as single
diastereoisomers (>99:1 dr). Subsequent deprotonation with
LiHMDS and functionalisation of the resultant lithium enolate gives
3,4-anti-3-substituted-4-aminopiperidin-2-ones in >99:1 dr. Al-
a-methyl-
d
a,b
b,d
lute (3S,4R,aR)-configuration within 49 being assigned from the
known configuration of the (R)-
a-methylbenzyl stereogenic centre
(Fig. 5).27 Hydrogenolytic N-debenzylation of 49 in the presence of
Pearlman’s catalyst [Pd(OH)2/C] gave primary amine 50, and sub-
sequent coupling of 50 with 2-methoxy-4-amino-5-chlorobenzoic
ternatively, in situ oxidation of the intermediate lithium (Z)-
amino enolates formed upon conjugate addition gives -hydroxy-
b-
a

3268
S.G. Davies et al. / Tetrahedron 68 (2012) 3263e3275
b
,
d
-diamino esters which, after N-deallylation and cyclisation, gives
(N(CH2CH]CH2)2), 145.8 (C(3)), 165.9 (C(1)); m/z (ESIþ) 27þ4
([MþNa]þ, 88%), 252 ([MþH]þ, 100%); HRMS (ESIþ) C15H26NO2
([MþH]þ) requires 252.1958; found 252.1955.
the corresponding 3,4-syn-3-hydroxy-4-aminopiperidin-2-ones in
>99:1 dr. The utility of this methodology was successfully dem-
onstrated in a concise asymmetric synthesis of the gastroprokinetic
agent (þ)-(3S,4R)-cisapride in nine steps from commercially
available starting materials with an overall yield of 19%.
4.2.2. tert-Butyl (E)-5-(N-allyl-N-benzylamino)pent-2-enoate 24.
4. Experimental
Acrolein (3.16 mL, 47.5 mmol) was added dropwise to a stirred
solution of DBU (72 mL, 0.48 mmol) and N-allyl-N-benzylamine 20
4.1. General experimental
(7.00 g, 47.5 mmol) in THF (20 mL) at ꢀ15 ꢁC. The reaction mixture
was stirred at ꢀ15 ꢁC for 40 min then 22 (12.8 g, 34.0 mmol) was
added portionwise and the reaction mixture was stirred at ꢀ15 ꢁC
for 20 min. The resultant mixture was allowed to warm to rt over
16 h, then concentrated in vacuo to give 24 in 94:6 dr. Purification
via flash column chromatography (eluent 30e40 ꢁC petrol/Et2O/
Et3N, 50:50:1) gave 24 as colourless oil (13.0 g, 91%, >99:1 dr); nmax
(ATR) 3064, 3028, 3005, 2977, 2931, 2802 (CeH), 1713 (C]O), 1651
(C]C), 1603 (C]C, aromatic); dH (400 MHz, CDCl3) 1.49 (9H, s,
CMe3), 2.36 (2H, app q, J 6.8, C(4)H2), 2.60 (2H, t, J 6.8, C(5)H2), 3.11
(2H, d, J 6.3, NCH2CH]CH2), 3.60 (2H, s, NCH2Ph), 5.11e5.24 (2H, m,
NCH2CH]CH2), 5.74 (1H, dt, J 15.7, 1.5, C(2)H), 5.82e5.93 (1H, m,
NCH2CH]CH2), 6.79e6.88 (1H, dt, J 15.7, 6.8, C(3)H), 7.20e7.35
(5H, m, Ph); dC (100 MHz, CDCl3) 28.2 (CMe3), 29.8 (C(4)), 51.8
(C(5)), 56.7 (NCH2CH]CH2), 58.0 (NCH2Ph), 80.0 (CMe3), 117.4
(NCH2CH]CH2), 123.8 (C(2)), 126.9 (p-Ph), 128.2, 128.8 (o,m-Ph),
135.7 (NCH2CH]CH2), 139.4 (i-Ph), 146.0 (C(3)), 165.9 (C(1)); m/z
(ESIþ) 324 ([MþNa]þ, 100%), 302 ([MþH]þ, 92%); HRMS (ESIþ)
C19H28NO2þ ([MþH]þ) requires 302.2115; found 302.2107.
Reactions involving organometallic or other moisture-sensitive
reagents were carried out under a nitrogen or argon atmosphere
using standard vacuum line techniques and glassware that was
flame dried and cooled under nitrogen before use. BuLi was pur-
chased from SigmaeAldrich (as a solution in hexanes) and titrated
against diphenylacetic acid before use. Solvents were dried
according to the procedure outlined by Grubbs and co-workers.43
Water was purified by an ElixÒ UV-10 system. All other reagents
were used as supplied without prior purification. Organic layers
were dried over MgSO4. Thin layer chromatography was performed
on aluminium plates coated with 60 F254 silica. Plates were
visualised using UV light (254 nm), iodine, 1% aq KMnO4, or 10%
ethanolic phosphomolybdic acid. Flash column chromatography
was performed on Kieselgel 60 silica.
Elemental analyses were recorded by the microanalysis service
of the London Metropolitan University, U.K. Melting points were
recorded on a Gallenkamp Hot Stage apparatus and are un-
corrected. Optical rotations were recorded on a PerkineElmer 241
polarimeter with a water-jacketed 10 cm cell. Specific rotations are
reported in 10ꢀ1 deg cm2 gꢀ1 and concentrations in g/100 mL. IR
spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer on
4.2.3. tert-Butyl (E)-5-(N,N-dibenzylamino)pent-2-enoate 25.
an ATR module. Selected characteristic peaks are reported in cmꢀ1
.
NMR spectra were recorded on Bruker Avance spectrometers in the
deuterated solvent stated. Spectra were recorded at rt. The field was
locked by external referencing to the relevant deuteron resonance.
Low-resolution mass spectra were recorded on either a VG MassLab
20e250 or a Micromass Platform 1 spectrometer. Accurate mass
measurements were run on either a Bruker MicroTOF internally
calibrated with polyalanine, or a Micromass GCT instrument fitted
with a Scientific Glass Instruments BPX5 column (15 mꢃ0.25 mm)
using amyl acetate as a lock mass.
Acrolein (1.69 mL, 25.3 mmol) was added dropwise to a stirred
solution of DBU (37
mL, 0.21 mmol) and N,N-dibenzylamine 21
(4.90 mL, 25.3 mmol) in THF (20 mL) at ꢀ15 ꢁC. The reaction
mixture was stirred at ꢀ15 ꢁC for 40 min then 22 (12.8 g,
34.0 mmol) was added portionwise and the reaction mixture was
stirred at ꢀ15 ꢁC for 20 min. The resultant mixture was allowed to
warm to rt over 16 h, then concentrated in vacuo to give 25 in 89:11
dr. Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/Et2O, 4:1) gave 25 as a yellow oil (6.07 g, 68%, >99:1 dr);
nmax (ATR) 3062, 3028, 2977, 2931, 2799 (CeH), 1710 (C]O), 1652
(C]C); dH (400 MHz, CDCl3) 1.54 (9H, s, CMe3), 2.40 (2H, app q, J 7.2,
C(4)H2), 2.60 (2H, t, J 7.2, C(5)H2), 3.61 (4H, s, N(CH2Ph)2), 5.74 (1H,
app d, J 15.5, C(2)H), 6.85 (1H, dt, J 15.5, 7.4, C(3)H), 7.22e7.41 (10H,
m, Ph); dC (100 MHz, CDCl3) 28.2 (CMe3), 29.8 (C(4)), 51.9 (C(5)),
58.2 (N(CH2Ph)2), 80.0 (CMe3), 123.8 (C(2)), 126.9 (p-Ph), 128.3,
128.7 (o,m-Ph), 139.5 (i-Ph), 146.2 (C(3)), 165.9 (C(1)); m/z (ESIþ) 37þ4
([MþNa]þ, 98%), 352 ([MþH]þ, 100%); HRMS (ESIþ) C23H30NO2
([MþH]þ) requires 352.2271; found 352.2258.
4.2. Experimental details
4.2.1. tert-Butyl (E)-5-(N,N-diallylamino)pent-2-enoate 23.
Acrolein (3.44 mL, 51.5 mmol) was added dropwise to a stirred
solution ofDBU (23 mL, 0.15 mmol) andN,N-diallylamine 19 (6.35mL,
51.5 mmol) in THF (20 mL) at ꢀ15 ꢁC. The reaction mixture was
stirred at ꢀ15 ꢁC for 40 min then 22 (19.4 g, 51.5 mmol) was added
portionwise and the reaction mixture was stirred at ꢀ15 ꢁC for
20 min. The resultant mixture was allowed to warm to rt over 16 h,
then concentrated in vacuoto give 23 in 91:9 dr. Purificationvia flash
column chromatography (eluent 30e40 ꢁC petrol/Et2O, 2:1) gave 23
as a yellow oil (2.33 g, 72%, >99:1 dr); nmax (ATR) 3077, 3006, 2978,
2931, 2806 (CeH), 1713 (C]O), 1651 (C]C); dH (400 MHz, CDCl3)
1.46 (9H, s, CMe3), 2.28e2.36 (2H, m, C(4)H2), 2.57 (2H, t, J 7.5,
C(5)H2), 3.09 (4H, d, J 6.3, N(CH2CH]CH2)2), 5.08e5.21 (4H, m,
N(CH2CH]CH2)2), 5.75 (1H, d, J 15.7, C(2)H), 5.78e5.89 (2H, m,
N(CH2CH]CH2)2), 6.81 (1H, dt, J 15.7, 7.0, C(3)H); dC (100 MHz,
CDCl3) 28.1 (CMe3), 29.6 (C(4)), 51.6 (C(5)), 56.8 (N(CH2CH]CH2)2),
80.0 (CMe3), 117.5 (N(CH2CH]CH2)2), 123.8 (C(2)), 135.5
4.2.4. tert-Butyl
(R,R)-3-[N-benzyl-N-(a-methylbenzyl)amino]-5-
(N0,N0-diallylamino)pentanoate 26.
BuLi (2.5 M, 2.80 mL, 7.00 mmol) was added dropwise to a stir-
red solution of (R)-N-benzyl-N-(a-methylbenzyl)amine (1.46 mL,
7.00 mmol) in THF (5 mL) at ꢀ78 ꢁC and the resultant mixture was

S.G. Davies et al. / Tetrahedron 68 (2012) 3263e3275
3269
stirred at this temperature for 30 min. A solution of 23 (1.10 g,
4.2.6. tert-Butyl
(R,R)-3-[N-benzyl-N-(
a
-methylbenzyl)amino]-5-
4.38 mmol) in THF (15 mL) at ꢀ78 ꢁC was then added dropwise. The
reaction mixture was stirred at ꢀ78 ꢁC for 2 h then satd aq NH4Cl
(2 mL) was added. The resultant mixture was diluted with Et2O
(40 mL) and washed with 10% aq citric acid (2ꢃ30 mL). The aqueous
layer was extracted with Et2O (2ꢃ40 mL) and the combined organic
extracts were washed with satd aq NaHCO3 (50 mL) and brine
(50 mL), then dried and concentrated in vacuo to give 26 in >99:1
dr. Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/Et2O/Et3N, 50:50:1) gave 26 as a yellow oil (1.67 g, 82%,
(N0,N0-dibenzylamino)pentanoate 28.
BuLi (2.5 M, 1.82 mL, 4.55 mmol) was added dropwise to
stirred solution of (R)-N-benzyl-N-( -methylbenzyl)amine
a
a
>99:1 dr); ½a 2D2
þ3.4 (c 1.2 in CHCl3); nmax (ATR) 3063, 3026, 3004,
ꢄ
(0.95 mL, 4.55 mmol) in THF (5 mL) at ꢀ78 ꢁC and the resultant
mixture was stirred at this temperature for 30 min. A solution of
25 (1.00 g, 2.85 mmol) in THF (15 mL) at ꢀ78 ꢁC was then added
dropwise. The reaction mixture was stirred at ꢀ78 ꢁC for 2 h then
satd aq NH4Cl (2 mL) was added. The resultant mixture was di-
luted with Et2O (30 mL) and washed with 10% aq citric acid
(2ꢃ20 mL). The aqueous layer was extracted with Et2O (2ꢃ30 mL)
and the combined organic extracts were washed with satd aq
NaHCO3 (100 mL) and brine (100 mL), then dried and concen-
trated in vacuo to give 28 in >99:1 dr. Purification via flash column
chromatography (eluent 30e40 ꢁC petrol/Et2O/Et3N, 80:20:1)
2971, 2930 (CeH), 1725 (C]O),1642 (C]C); dH (400 MHz, CDCl3)
1.35 (3H, d, J 6.8, C(a)Me), 1.42 (9H, s, CMe3), 1.48e1.59 (1H, m,
C(4)HA), 1.60e1.73 (1H, m, C(4)HB), 1.89e1.94 (2H, m, C(2)H2), 2.44
(1H, td, J 11.6, 5.3, C(5)HA), 2.94 (1H, td, J 11.6, 4.6, C(5)HB), 3.08 (2H,
dd, J 13.9, 6.8, N0(CHAHBCH]CH2)2), 3.18 (2H, dd, J 13.9, 6.2,
N0(CHAHBCH]CH2)2),3.33e3.39 (1H, m, C(3)H), 3.50 (1H, d, J 14.7,
NCHAHBPh), 3.72e3.86 (2H, m, NCHAHBPh, C(
(4H, m, N0(CH2CH]CH2)2), 5.83e5.97 (2H, m, N0(CH2CH]CH2)2),
7.22e7.46 (10H, m, Ph); dC (100 MHz, CDCl3) 20.2 (C( )Me), 28.1
(CMe3), 30.0 (C(4)), 37.8 (C(2)), 50.1 (NCH2Ph), 51.4 (C(5)), 52.5
a)H), 5.13e5.25
a
gave 28 as a colourless oil (838 mg, 52%, >99:1 dr); ½a D25
ꢄ
ꢀ9.0 (c
(C(3)), 56.8 (N(CH2CH]CH2)2), 58.0 (C(a)), 80.0 (CMe3), 117.9
(N0(CH2CH]CH2)2), 126.6, 127.0, 127.9, 128.1, 128.2, 128.3
(o,m,p-Ph), 135.2 (N0(CH2CH]CH2)2), 141.5,147.7 (i-Ph), 171.9 (C(1));
1.8 in CHCl3); nmax (ATR) 3061, 3027, 2971, 2930, 2798 (CeH), 1724
(C]O), 1601 (C]C); dH (400 MHz, CDCl3) 1.28 (3H, d, J 7.1, C(a)Me),
m/z (ESIþ) 463 ([MþH]þ, 100%); HRMS (ESIþ) C30H43N2O2
þ
1.46 (9H, s, CMe3), 1.62e1.71 (1H, m, C(4)HA), 1.71e1.83 (1H, m,
C(4)HB), 1.89e1.96 (2H, m, C(2)H2), 2.45 (1H, ddd, J 12.6, 10.4, 5.1,
C(5)HA), 2.95 (1H, ddd, J 12.6, 10.6, 5.1, C(5)HB), 3.32e3.41 (1H, m,
C(3)H), 3.46e3.56 (3H, m, NCHAHBPh, N0(CHAHBPh)2), 3.70e3.86
([MþH]þ) requires 463.3319; found 463.3302.
4.2.5. tert-Butyl
(R,R)-3-[N-benzyl-N-(a-methylbenzyl)amino]-5-
(N0-allyl-N0-benzylamino)pentanoate 27.
(4H, m, C(
dC (100 MHz, CDCl3) 20.2 (C(
a
)H, NCHAHBPh, N0(CHAHBPh)2), 7.24e7.47 (20H, m, Ph);
)Me), 28.1 (CMe3), 30.6 (C(4)), 37.9
a
(C(2)), 50.2 (NCH2Ph), 51.9 (C(5)), 52.8 (C(3)), 58.0 (C(a)), 58.4
(N0(CH2Ph)2), 80.0 (CMe3), 126.6, 126.8, 127.0 (p-Ph), 128.0, 128.2,
128.2, 128.3, 128.9, 129.0 (o,m-Ph), 139.9, 141.6, 142.9 (i-Ph), 172.1
þ
(C(1)); m/z (ESIþ) 563 ([MþH]þ, 100%); HRMS (ESIþ) C38H47N2O2
([MþH]þ) requires 563.3632; found 563.3628.
BuLi (2.5 M, 26.5 mL, 66.4 mmol) was added dropwise to a stirred
solution of (R)-N-benzyl-N-( -methylbenzyl)amine (13.9 mL,
4.2.7. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a-methylbenzyl)
amino]-5-(N0,N0-diallylamino)-pentanoate 29.
a
66.4 mmol) in THF (40 mL) at ꢀ78 ꢁC and the resultant mixture was
stirred at this temperature for 30 min. A solution of 24 (12.5 g,
41.5 mmol) in THF (150 mL) at ꢀ78 ꢁC was then added dropwise. The
reaction mixture was stirred at ꢀ78 ꢁC for 2 h then satd aq NH4Cl
(15 mL) was added. The resultant mixture was diluted with Et2O
(250 mL) and washed with 10% aq citric acid (2ꢃ150 mL). The
aqueous layer was extracted with Et2O (2ꢃ200 mL) and the com-
bined organic extracts were washed with satd aq NaHCO3 (500 mL)
and brine (500 mL), then dried and concentrated in vacuo to give 27
in >99:1 dr. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O/Et3N, 66:34:1) gave 27 as a colourless oil
BuLi (2.5 M,1.27 mL, 3.18 mmol) was added dropwise to a stirred
solution of (R)-N-benzyl-N-( -methylbenzyl)amine (0.66 mL,
a
3.18 mmol) in THF (10 mL) at ꢀ78 ꢁC and the resultant mixture was
stirred at this temperature for 30 min. A solution of 23 (500 mg,
1.99 mmol) in THF (10 mL) at ꢀ78 ꢁC was then added dropwise. The
reaction mixturewas stirredat ꢀ78 ꢁC for 2 hthen (ꢀ)-CSO 13 (1.19 g,
3.98 mmol) was added. The reaction mixture was allowed to warm
to rt over 16 h, H2O (5 mL) was added, then the organic layer was
dried and concentrated in vacuo to give 29 in >99:1 dr. Purification
via flash column chromatography (eluent 30e40 ꢁC petrol/Et2O, 3:1)
gave 26 as a colourless oil (64 mg, 7%, >99:1 dr). Further elution gave
(18.7 g, 88%, >99:1 dr); ½a D22
ꢀ2.9 (c 1.3 in CHCl3); nmax (ATR) 3062,
ꢄ
3027, 2975, 2930, 2801 (CeH),1723 (C]O),1643, (C]C),1602 (C]C,
aromatic); dH (400 MHz, CDCl3) 1.32 (3H, d, J 7.1, C(a)Me),1.44 (9H, s,
CMe3), 1.55e1.65 (1H, m, C(4)HA), 1.66e1.76 (1H, m, C(4)HB),
1.87e1.96 (2H, m, C(2)H2), 2.39e2.51 (1H, m, C(5)HA), 2.86e2.99
(1H, m, C(5)HB), 3.06 (1H, dd, J 13.9, 6.8, N0CHAHBCH]CH2), 3.19 (1H,
dd, J 13.9, 5.9, N0CHAHBCH]CH2), 3.32e3.42 (1H, m, C(3)H), 3.51 (1H,
d, J 14.9, NCHAHBPh), 3.53 (1H, d, J 13.5, N0CHAHBPh), 3.70 (1H, d, J
a 25
29 as a pale yellow oil (532 mg, 68%, >99:1 dr); ½ ꢄD ꢀ5.1 (c 1.0 in
13.5, N0CHAHBPh), 3.78e3.86 (2H, m, NCHAHBPh, C(
(2H, m, N0CH2CH]CH2), 5.89e6.02 (1H, m, N0CH2CH]CH2),
7.20e7.45 (15H, m, Ph); dC (100 MHz, CDCl3) 20.2 (C( )Me), 28.1
(CMe3), 30.4 (C(4)), 37.9 (C(2)), 50.1 (NCH2Ph), 51.7 (C(5)), 52.6 (C(3)),
56.9 (N0CH2CH]CH2), 58.0 (C( )Me), 58.3 (N0CH2Ph), 80.0 (CMe3),
a
)H), 5.16e5.29
CHCl3); nmax (ATR) 3502 (OeH), 3063, 3027, 2975, 2931, 2809 (CeH),
1720 (C]O); dH (400 MHz, CDCl3) 1.32 (3H, d, J 7.0, C(a)Me),1.47 (9H,
a
s, CMe3), 1.43e1.52 (1H, m, C(4)HA), 1.70e1.81 (1H, m, C(4)HB),
2.32e2.43 (1H, m, C(5)HA), 2.75e2.83 (1H, m, C(5)HB), 3.03e3.16
(4H, m, N0(CH2CH]CH2)2), 3.29 (1H, ddd, J 7.8, 5.3, 2.8, C(3)H),
3.71 (1H, d, J 15.4, NCHAHBPh), 3.87 (1H, d, J 2.8, C(2)H), 3.96 (1H, q, J
a
117.2 (N0CH2CH]CH2), 126.6, 126.8, 127.0 (p-Ph), 128.0, 128.1, 128.2,
128.3, 128.3, 129.0 (o,m-Ph), 136.1 (N0CH2CH]CH2), 139.6, 141.6,
142.8 (i-Ph), 172.0 (C(1)); m/z (ESIþ) 513 ([MþH]þ, 100%); HRMS
(ESIþ) C34H45N2O2þ ([MþH]þ) requires 513.3476; found 513.3460.
7.0, C(
N0(CH2CH]CH2)2), 5.81e5.93 (2H, m, N0(CH2CH]CH2)2), 7.21e7.51
(10H, m, Ph); dC (100 MHz, CDCl3) 19.3 (C( )Me), 25.0 (C(4)), 28.0
a)H), 4.24 (1H, d, J 15.4, NCHAHBPh), 3.13e3.21 (4H, m,
a

3270
S.G. Davies et al. / Tetrahedron 68 (2012) 3263e3275
(CMe3), 51.0 (NCH2Ph), 51.2 (C(5)), 56.7 (N0(CH2CH]CH2)2), 58.4,
58.7 (C(3), C( )), 71.6 (C(2)), 82.1 (CMe3), 117.7 (NCH2CH]CH2),
126.4, 127.0 (p-Ph), 128.1, 128.2, 128.4, 128.5 (o,m-Ph), þ135.4
(N0(CH2CH]CH2)2), 142.2, 143.2 (i-Ph), 174.2 þ(C(1)); m/z (ESI ) 479
([MþH]þ, 100%); HRMS (ESIþ) C30H43N2O3 ([MþH]þ) requires
479.3268; found 479.3250.
dr). Further elution gave 31 as a colourless oil (812 mg, 33%, >99:1
a
dr); ½a 2D5
ꢀ22.5 (c 1.0 in CHCl3); nmax (ATR) 3500 (OeH), 3062, 3027,
ꢄ
2973, 2798 (CeH),1719 (C]O),1602 (C]C, aromatic); dH (400 MHz,
CDCl3) 1.24 (3H, d, J 6.8, C(a)Me), 1.42 (9H, s, CMe3), 1.46e1.48 (1H,
m, C(4)HA), 1.83e1.94 (1H, m, C(4)HB), 2.40 (1H, ddd, J 12.7, 10.0, 5.4,
C(5)HA), 2.86 (1H, ddd, J 12.7, 10.0, 4.9, C(5)HB), 3.24 (1H, ddd, J 8.3,
4.6, 1.8, C(3)H), 3.53 (2H, d, J 13.6, N0(CHAHBPh)2), 3.67 (2H, d, J 13.6,
N0(CHAHBPh)2), 3.68 (1H, d, J 15.4, NCHAHBPh), 3.79 (1H, d, J 1.8,
4.2.8. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a-methylbenzyl)
amino]-5-(N0-allyl-N0-benzyl)pentanoate 30.
C(2)H), 3.90 (1H, q, J 6.8, C(
7.23e7.44 (20H, m, Ph); dC (100 MHz, CDCl3) 19.1 (C(
(C(4)), 28.0 (CMe3), 51.2 (C(5)), 51.8 (NCH2Ph), 57.9, 58.1 (C(2), C(3)),
58.1 (N0(CH2Ph)2), 71.3 (C(
)), 82.4 (CMe3),126.4,126.9,127.0 (p-Ph),
a)H), 4.24 (1H, d, J 15.4, NCHAHBPh),
a)Me), 25.0
a
128.1, 128.1, 128.2, 128.3, 128.9, 129.0 (o,m-Ph), 139.5, 142.1, 143.0
(i-Ph), 174.3 (C(1)); m/z (ESIþ) 579 ([MþH]þ, 100%); HRMS (ESIþ)
C38H47N2O2þ ([MþH]þ) requires 579.3581; found 579.3581.
BuLi (2.5 M, 3.18 mL, 7.96 mmol) was added dropwise to
stirred solution of (R)-N-benzyl-N-( -methylbenzyl)amine
4.2.10. (R,R)-4-[N-Benzyl-N-(a-methylbenzyl)amino]piperidin-
a
a
(1.67 mL, 7.96 mmol) in THF (15 mL) at ꢀ78 ꢁC and the resultant
mixture was stirred at this temperature for 30 min. A solution of
24 (1.50 g, 4.98 mmol) in THF (10 mL) at ꢀ78 ꢁC was then added
dropwise. The reaction mixture was stirred at ꢀ78 ꢁC for 2 h then
(ꢀ)-CSO 13 (2.98 g, 9.96 mmol) was added. The reaction mixture
was allowed to warm to rt over 16 h, H2O (5 mL) was added, then
the organic layer was dried and concentrated in vacuo to give 30
in >99:1 dr. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/EtOAc/Et3N, 100:10:1) gave 27 as a colourless oil
(925 mg, 36%, >99:1 dr). Further elution gave 30 as a colourless oil
2-one 33.
Pd(PPh3)4 (57 mg, 50 mmol) was added to a mixture of 26 (1.15 g,
2.49 mmol) and DMBA (2.33 g, 14.9 mmol) in de-gassed CH2Cl2
(50 mL) at 35 ꢁC. The reaction mixture was then stirred for 3 h at
35 ꢁC in the dark, then concentrated in vacuo. The residue was then
dissolved in toluene (50 mL) and PhCO2H (30 mg, 0.25 mmol) was
added. The resultant solution was stirred at 80 ꢁC for 16 h then 2.0 M
aq Na2CO3 (25 mL) was added and the aqueous layer was extracted
with CH2Cl2 (2ꢃ20 mL). The combined organic extracts were
washed with brine (50 mL), then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/EtOAc/Et3N, 50:50:1) gave 33 as a pale yellow oil (593 mg,
(1.10 g, 42%, >99:1 dr); ½a D25
ꢀ27.3 (c 1.0 in CHCl3); nmax (ATR)
ꢄ
3500 (OeH), 3083, 3063, 3027, 3004, 2976, 2932, 2808 (CeH),
1719 (C]O), 1601 (C]C, aromatic); dH (400 MHz, CDCl3) 1.34 (3H,
d, J 7.0, C(a)Me), 1.49 (9H, s, CMe3), 1.52e1.62 (1H, m, C(4)HA),
1.83e1.94 (1H, m, C(4)HB), 2.46 (1H, ddd, J 13.4, 8.8, 6.6, C(5)HA),
2.89 (1H, ddd, J 13.4, 8.8, 5.1, C(5)HB), 3.11 (1H, dd, J 14.2, 6.6,
N0CHAHBCH]CH2), 3.20 (1H, dd, J 14.2, 6.1, N0CHAHBCH]CH2),
3.32e3.38 (1H, m, C(3)H), 3.50 (1H, d, J 13.6, N0CHAHBPh), 3.71 (1H,
d, J 13.6, N0CHAHBPh), 3.76 (1H, d, J 15.4, NCHAHBPh), 3.90 (1H, d, J
77%, >99:1 dr); ½a D25
þ65.8 (c 1.0 in CHCl3); nmax (ATR) 3457 (NeH),
ꢄ
1.5, C(2)H), 4.00 (1H, q, J 7.0, C(a)H), 4.32 (1H, d, J 15.4, NCHAHBPh),
3026, 3016, 2970, 2947, 2868 (CeH), 1738 (C]O); dH (400 MHz,
5.21e5.30 (2H, m, N0CH2CH]CH2), 5.99 (1H, app ddt, J 17.0, 10.4,
6.4, N0CH2CH]CH2), 7.25e7.53 (15H, m, Ph); dC (100 MHz, CDCl3)
CDCl3) 1.39 (3H, d, J 6.6, C(a)Me),1.74 (1H, qd, J 12.3, 5.5, C(5)HA), 2.00
(1H, dd, J 12.3, 2.0, C(5)HB), 2.37 (2H, app d, J 8.8, C(3)H2), 3.03e3.17
(2H, m, C(4)H, C(6)HA), 3.22e3.29 (1H, m, C(6)HB), 3.79 (1H, d, J
15.0,NCHAHBPh), 3.83 (1H, d, J 15.0, NCHAHBPh), 3.99 (1H, q, J 6.6,
19.4 (C(
a
)Me), 25.1 (C(4)) 28.1 (CMe3), 51.2 (NCH2Ph), 51.5 (C(5)),
)), 71.4
56.5 (N0CH2CH]CH2), 58.1 (C(3)), 58.1 (N0CH2Ph), 58.5 (C(
a
(C(2)), 82.2 (CMe3), 117.6 (N0CH2CH]CH2), 126.5, 127.0, 127.1
(p-Ph), 128.2, 128.2, 128.2, 128.3, 128.3, 129.1 (o,m-Ph), 135þ.7
(N0CH2CH]CH2), 139.2, 142.3, 143.2 (i-Ph), 174.3 (C(1)); m/z (ESI )
529 ([MþH]þ, 100%); HRMS (ESIþ) C34H45N2O3þ ([MþH]þ) requires
529.3425; found 529.3426.
C(
CDCl3) 17.3 (C(
(NCH2Ph), 51.6 (C(4)), 57.1 (C(
a
)H), 6.13 (1H, br s, NH),7.20e7.44 (10H, m, Ph); dC (100 MHz,
a
)Me), 27.7 (C(5)), 36.0 (C(3)), 40.2 (C(6)), 49.6
a)), 126.7, 126.9 (p-Ph), 128.0, 128.1,
128.3, 128.3 (o,m-Ph), 141.3, 144.1 (i-Ph), 172.8 (C(2)); m/z (ESIþ) 947
([3MþNa]þ, 70%), 639 ([2MþNa]þ,100%), 309 ([MþH]þ, 20%); HRMS
(ESIþ) C20H25N2Oþ ([MþH]þ) requires 309.1961; found 309.1951.
4.2.9. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a-methylbenzyl)
amino]-5-(N0,N0-dibenzylamino)pentanoate 31.
4.2.11. (R,R)-N(1)-Benzyl-4-[N-benzyl-N-(a-methylbenzyl)amino]pi-
peridin-2-one 34.
BuLi (2.5 M, 2.73 mL, 6.83 mmol) was added dropwise to a stir-
red solution of (R)-N-benzyl-N-( -methylbenzyl)amine (1.43 mL,
a
6.83 mmol) in THF (10 mL) at ꢀ78 ꢁC and the resultant mixture was
stirred at this temperature for 30 min. A solution of 25 (1.50 g,
4.27 mmol) in THF (10 mL) at ꢀ78 ꢁC was then added dropwise. The
reaction mixture was stirred at ꢀ78 ꢁC for 2 h then (ꢀ)-CSO 13
(2.56 g, 8.54 mmol) was added. The reaction mixture was allowed
to warm to rt over 16 h, H2O (5 mL) was added, then the organic
layer was dried and concentrated in vacuo to give 31 in >99:1 dr.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/EtOAc, 10:1) gave 28 as a colourless oil (1.14 g, 47%, >99:1
Pd(PPh3)4 (184 mg, 0.160 mmol) was added to a mixture of 27
(8.19 g, 15.97 mmol) and DMBA (7.48 g, 47.91 mmol) in de-gassed
CH2Cl2 (80 mL) at 35 ꢁC. The reaction mixture was then stirred for
3 h at 35 ꢁC in the dark, then concentrated in vacuo. The residue was
then dissolved in toluene (80 mL) and PhCO2H (195 mg, 1.60 mmol)
was added. The resultant solution was stirred at 80 ꢁC for 16 h then
2.0 M aq Na2CO3 (50 mL) was added and the aqueous layer was
extracted with CH2Cl2 (2ꢃ50 mL). The combined organic extracts

S.G. Davies et al. / Tetrahedron 68 (2012) 3263e3275
3271
were washed with brine (80 mL), then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/EtOAc, 75:25) gave 34 as a yellow solid (3.24 g, 53%,
with brine (30 mL), then dried and concentrated in vacuo. Purifica-
tion via flash column chromatography (eluent 30e40 ꢁC petrol/
EtOAc/Et3N, 100:25:1) gave 36 as a white solid (435 mg, 69%, >99:1
>99:1 dr); mp 74e75 ꢁC; ½a D25
ꢄ
þ51.3 (c 1.0 in CHCl3); nmax (ATR)
dr); mp 109e112 ꢁC; ½a D25
þ45.4 (c 1.0 in CHCl3); nmax (ATR) 3294
ꢄ
3084, 3061, 3028, 2969, 2931 (CeH), 1644 (C]O); dH (400 MHz,
(OeH), 3085, 3062, 3027, 2970 (CeH), 1634 (C]O); dH (400 MHz,
CDCl3) 1.42 (3H, d, J 6.7, C(
a
)Me),1.75 (1H, qd, J 12.1, 5.3, C(5)HA), 2.02
CDCl3) 1.32 (3H, d, J 6.8, C(a)Me),1.85e2.01 (2H, m, C(5)H2), 3.05e3.18
(1H, app d, J 12.1, C(5)HB), 2.55 (1H, dd, J 17.4,10.9, C(3)HA), 2.62 (1H,
dd, J 17.4, 5.8, C(3)HB), 3.01e3.22 (3H, m, C(6)H2, C(4)H), 3.83 (2H, s,
(2H, m, C(6)H2), 3.35 (1H, app dt, J 8.6, 6.9, C(4)H), 3.76 (1H, d, J 14.9,
N(1)CHAHBPh), 3.86 (1H, br s, OH), 3.89 (1H, d, J 14.9, N(1)CHAHBPh),
NCH2Ph), 4.04 (1H, q, J 6.7, C(
4.84 (1H, d, J 14.7, N(1)CHAHBPh), 7.19e7.52 (15H, m, Ph); dC
(100 MHz, CDCl3) 17.2 (C( )Me), 28.5 (C(5)), 36.9 (C(3)), 45.3 (C(6)),
49.6, 49.7 (NCH2Ph, N(1)CH2Ph), 52.0 (C(4)), 57.0 (C( )),126.8,126.9,
a
)H), 4.27 (1H, d, J 14.7, N(1)CHAHBPh),
4.06 (1H, d, J 6.3, C(3)H), 4.24 (1H, q, J 6.8, C(
NCHAHBPh), 4.76 (1H, d, J 14.7, NCHAHBPh), 7.18e7.51 (15H, m, Ph); dC
(100 MHz, CDCl3) 16.1 (C( )Me), 24.9 (C(5)), 43.6 (C(6)), 50.0
(NCH2Ph), 51.3 (N(1)CH2Ph), 54.8 (C(4)), 57.8 (C( )), 69.9 (C(3)),126.8,
a)H), 4.36 (1H, d, J 14.7,
a
a
a
a
127.4 (p-Ph), 127.5, 128.0, 128.1, 128.3, 128.4, 128.7 (o,m-Ph), 137.1,
141.5, 144.2 (i-Ph), 169.8 (C(2)); m/z (FIþ) 398 ([M]þ, 100%); HRMS
(FIþ) C27H30N2Oþ ([M]þ) requires 398.2353; found 398.2347.
127.0, 127.6 (p-Ph), 127.7, 128.2, 128.3, 128.3, 128.4, 128.7 (o,m-Ph),
136.6, 141.6, 144.0 (i-Ph), 171.8 (C(2)); m/z (ESIþ) 852 ([2MþNa]þ,
100%), 415 ([MþH]þ, 18%); HRMS (ESIþ) C27H30N2NaO2þ ([MþNa]þ)
requires 437.2199; found 437.2195.
4.2.12. (R,R,R)-3-Hydroxy-4-[N-benzyl-N-(a-methylbenzyl)amino]
piperidin-2-one 35.
4.2.14. (3S,4R,
aR)-N(1)-Benzyl-3-methyl-4-[N-benzyl-N-(a-methyl-
benzyl)amino]piperidin-2-one 37.
Pd(PPh3)4 (40 mg, 40
mmol) was added to a mixture of 29
(834 mg, 1.74 mmol) and DMBA (1.64 g, 10.45 mmol) in de-gassed
CH2Cl2 (25 mL) at 35 ꢁC. The reaction mixture was then stirred for
3 h at 35 ꢁC in the dark, then concentrated in vacuo. The residue was
then dissolved in toluene (20 mL) and PhCO2H (106 mg, 0.87 mmol)
was added. The resultant solution was stirred at 80 ꢁC for 16 h then
2.0 M aq Na2CO3 (15 mL) was added and the aqueous layer was
extracted with CH2Cl2 (2ꢃ15 mL). The combined organic extracts
were washed with brine (50 mL), then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent EtOAc/
Et3N, 100:1) gave 35 as a white solid (265 mg, 47%, >99:1 dr); mp
LiHMDS (1.0 M in toluene, 0.78 mL, 0.78 mmol) was added
dropwise to a solution of 34 (103 mg, 0.26 mmol) in THF (10 mL) at
ꢀ78 ꢁC and the resultant mixture was stirred at this temperature
for 1 h. MeI (50 mL, 0.78 mmol) was then added and the reaction
mixture was allowed to warm to rt over 16 h. Satd aq NH4Cl (1 mL)
was then added and the resultant mixture was diluted with Et2O
(25 mL) and washed with 10% aq citric acid (25 mL). The aqueous
layer was extracted with Et2O (2ꢃ25 mL) and the combined organic
extracts were washed sequentially with satd aq NaHCO3 (2ꢃ50 mL)
and brine (50 mL), then dried and concentrated in vacuo to give 37
in >99:1 dr. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 50:50) gave 37 as a white solid (72 mg, 67%,
73e77 ꢁC; ½a 2D5
þ45.5 (c 1.0 in CHCl3); nmax (ATR) 3245 (OeH), 3061,
ꢄ
3027, 2969, 2874 (CeH), 1648 (C]O); dH (400 MHz, CDCl3) 1.32 (3H,
d, J 6.8, C(a)Me),1.85e2.06 (2H, m, C(5)H2), 3.06 (1H, apptd, J 11.7, 4.1,
>99:1 dr); mp 135e137 ꢁC; ½a D25
þ2.2 (c 1.0 in CHCl3); nmax (ATR)
ꢄ
C(6)HA), 3.20 (1H, dtd, J 13.1, 5.5, 2.2, C(6)HB), 3.31 (1H, app q, J 7.3,
C(4)H), 3.71 (1H, d, J 14.2, NCHAHBPh), 3.79 (1H, d, J 14.2, NCHAHBPh),
3.86 (1H, br dd, J 6.0, 2.8, C(3)H), 4.03 (1H, br d, J 2.8, OH), 4.10 (1H, q, J
3028, 2971, 2930 (CeH), 1636 (C]O); dH (400 MHz, CDCl3) 1.07 (3H,
d, J 7.1, C(3)Me), 1.41 (3H, d, J 7.0, C(a)Me), 1.79 (1H, dddd, J 12.9, 11.5,
11.0, 5.3, C(5)HA), 2.05 (1H, app qd, J 12.9, 3.4, C(5)HB), 2.45 (1H, dq, J
10.1, 7.1, C(3)H), 2.70 (1H, ddd, J 11.5, 10.1, 3.4, C(4)H), 3.10 (1H, app
td, J 11.9, 3.8, C(6)HA), 3.16e3.23 (1H, m, C(6)HB), 3.69 (1H, d, J 13.9,
N(1)CHAHBPh), 3.85 (1H, d, J 13.9, N(1)CHAHBPh), 4.03 (1H, q, J 7.0,
6.8, C(a)H), 7.17e7.50 (10H, m, Ph); dC (100 MHz, CDCl3) 14.8
(C(
a
)Me), 24.6 (C(5)), 38.4 (C(6)), 51.4 (NCH2Ph), 54.2 (C(4)), 57.0
)), 68.7 (C(3)), 127.1, 127.1 (p-Ph), 127.6, 128.4, 128.5, 128.7 (o,m-
(C(
a
Ph), 140.8, 143.5 (i-Ph), 174.2 (C(2)); m/z (ESIþ) 671 ([2MþNa]þ,
þ
100%), 325 ([MþH]þ, 10%); HRMS (ESIþ) C20H25N2O2 ([MþH]þ)
C(
14.7, NCHAHBPh), 7.14e7.44 (15H, m, Ph); dC (100 MHz, CDCl3) 14.9
(C( )Me), 15.7 (C(3)Me), 26.9 (C(5)), 41.6 (C(3)), 45.1 (C(6)), 49.9,
50.1 (N(1)CH2Ph, NCH2Ph), 56.2 (C( )), 57.6 (C(4)), 126.8, 127.0,
a)H), 4.31 (1H, d, J 14.7, NCHAHBPh), 4.74 (1H, d, J
requires 325.1911; found 325.1913.
a
a
4.2.13. (R,R,R)-N(1)-Benzyl-3-hydroxy-4-[N-benzyl-N-(a-methyl-
127.3 (p-Ph), 127.9, 128.0, 128.1, 128.3, 128.6, 128.8 (o,m-Ph), 137.3,
140.6, 143.7 (i-Ph), 173.3 (C(2)); m/z (ESIþ) 848 ([2MþNa]þ, 100%),
435 ([MþNa]þ, 18%), 413 ([MþH]þ, 42%); HRMS (ESIþ) C28H33N2Oþ
([MþH]þ) requires 413.2587; found 413.2574.
benzyl)amino]piperidin-2-one 36.
4.2.15. (3S,4R,
benzyl-N-( -methylbenzyl)amino]piperidin-2-one 38.
a
R)-N(1)-Benzyl-3-(20-tert-butoxy-20-oxoethyl)-[N-
a
Pd(PPh3)4 (17 mg, 20 mmol) was added to a mixture of 30 (800 mg,
1.51 mmol) and DMBA (711 mg, 4.54 mmol) in de-gassed CH2Cl2
(12 mL) at 35 ꢁC. The reaction mixture was then stirred for 3 h at 35 ꢁC
in the dark, then concentrated in vacuo. The residue was then dis-
solved in toluene (20 mL) and PhCO2H (100 mg, 0.82 mmol) was
added. The resultant solution was stirred at 80 ꢁC for 16 h then 2.0 M
aq Na2CO3 (10 mL) was added and the aqueous layer was extracted
with CH2Cl2 (2ꢃ10 mL). The combined organic extracts were washed
LiHMDS (1.0 M in toluene, 0.75 mL, 0.75 mmol), was added
dropwise to a solution of 34 (100 mg, 0.25 mmol) in THF (10 mL)

3272
S.G. Davies et al. / Tetrahedron 68 (2012) 3263e3275
atꢀ78ꢁCandtheresultantmixturewasstirredatthistemperaturefor
with Et2O (25 mL) and washed with 10% aq citric acid (25 mL). The
aqueous layer was extracted with Et2O (2ꢃ25 mL) and the combined
organic extracts were washed sequentially with satd aq NaHCO3
(2ꢃ50 mL) and brine (50 mL), then dried and concentrated in vacuo
to give a 53:47 mixture of 34 and 39. Purification via flash column
chromatography (eluent 30e40 ꢁC petrol/Et2O, 75:25) gave 39 as
a colourless oil (57 mg, 37%, >99:1 dr).
t
1 h. BrCH2CO2 Bu (0.11 mL, 0.75 mmol) was then added and the re-
action mixture was allowed to warm to rt over 16 h. Satd aq NH4Cl
(1 mL) was then added and the resultant mixture was diluted with
Et2O (25 mL) and washed with 10% aqcitric acid (25 mL). The aqueous
layer was extracted with Et2O (2ꢃ25 mL) and the combined organic
extracts were washed sequentially with satd aq NaHCO3 (2ꢃ25 mL)
and brine (25 mL), then dried and concentrated in vacuo to give 38 in
80:20 dr. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 50:50) gave 38 as a colourless oil (15 mg, 12%,
4.2.17. N-Allyl-N-[3-(40-fluorophenoxy)propyl]amine 42.
>99:1 dr); ½a 2D5
ꢀ34.5 (c 1.0 in CHCl3); nmax (ATR) 3463 (OeH), 3086,
ꢄ
3064, 3029, 2971, 2934(CeH),1724,1638(C]O);dH (400MHz,CDCl3)
1.35(9H, s,CMe3),1.44(3H,d,J6.8,C(a)Me),1.84(1H, appqd,J12.2, 5.0,
C(5)HA), 2.07 (1H, app dq, J 12.8, 3.1, C(5)HB), 2.44 (1H, dd, J 17.0, 4.4,
C(10)HA), 2.60 (1H, app dt, J 11.0, 4.4, C(3)H), 2.78 (1H, dd, J
17.0, 4.6, C(10)HB), 3.11e3.28 (3H, m, C(4)H, C(6)H2), 3.65 (1H, d, J 13.9,
N(1)CHAHBPh), 3.83 (1H, d, J 13.9, N(1)CHAHBPh), 3.99 (1H, q, J 6.8,
1-(30-Bromopropoxy)-4-fluorobenzene
41
(7.33
mL,
C(
7.17e7.33 (15H, m, Ph); dC (100 MHz, CDCl3) 14.6 (C(
28.1 (CMe3), 33.6 (C(10)), 43.4 (C(3)), 44.9 (C(6)), 49.6 (N(1)CH2Ph),
50.1 (NCH2Ph), 54.6 (C(4)), 56.1 (C( )), 79.9 (CMe3), 126.9, 127.1, 127.2
a)H), 4.46 (1H, d, J 14.8, NCHAHBPh), 4.63 (1H, d, J 14.8, NCHAHBPh),
45.3 mmol), NaI (6.79 g, 45.3 mmol) and K2CO3 (25.0 g, 181 mmol)
were sequentially added to a solution of allylamine (10.2 mL,
136 mmol) in THF (1.4 L). The reaction mixture was stirred for 16 h
at 45 ꢁC. The mixture was allowed to cool to rt then filtered
through CeliteÒ (eluent CH2Cl2) and the filtrate was concentrated
in vacuo. Purification via flash column chromatography (eluent
Et2O/Et3N, 100:1) gave N,N-di-[3-(40-fluorophenoxy)propyl]-N-
allylamine as a colourless oil (838 mg, 10%); nmax (ATR) 3075, 2932,
2874, 2809 (CeH), 1504 (C]C); dH (400 MHz, CDCl3) 1.87e1.97
(4H, m, 2ꢃ C(2)H2), 2.64 (4H, t, J 6.9, 2ꢃ C(1)H2), 3.13 (2H, d, J 6.3,
NCH2CH]CH2), 3.94 (4H, t, J 6.3, 2ꢃ C(3)H2), 5.13 (1H, dd, J 10.1,
1.5, NCH2CH]CHAHB), 5.19 (1H, dd, J 17.2, 1.5, NCH2CH]CHAHB),
5.77e5.90 (1H, m, NCH2CH]CH2), 6.75e6.82 (8H, m, Ar); dC
(100 MHz, CDCl3) 27.0 (2ꢃ C(2)), 50.0 (2ꢃ C(1)), 57.2 (NCH2CH]
CH2), 66.4 (2ꢃ C(3)), 115.3 (d, J 8.0, 2ꢃ C(20), 2ꢃ C(60)), 115.7 (d, J
23.2, 2ꢃ C(30), 2ꢃ C(50)), 117.4 (NCH2CH]CH2), 135.6 (NCH2CH]
CH2), 155.1 (d, J 1.6, 2ꢃ C(10)), 157.1 (d, J 237, 2ꢃ C(40)); m/z ESIþ
384 ([MþNa]þ, 26%), 362 ([MþH]þ, 100%); HRMS (ESIþ)
a)Me), 27.0 (C(5)),
a
(p-Ph), 127.9, 128.1, 128.1, 128.3, 128.4, 12þ8.9 (o,m-Ph), 137.3, 140.4,
143.5 (i-Ph), 171.9, 172.0 (C(2),C(20));m/z(FI )512([Mþ],100%);HRMS
(FIþ) C33H40N2O3þ ([Mþ]) requires 512.3033; found 512.3016.
4.2.16. (3S,4R,
aR)-N(1)-Benzyl-3-hydroxy-4-[N-benzyl-N-(a-methyl-
benzyl)amino]piperidin-2-one 39.
Method A: LiHMDS (1.0 M in toluene, 0.45 mL, 0.45 mmol) was
added dropwise to a solution of 34 (60 mg, 0.15 mmol) in THF
(10 mL) at ꢀ78 ꢁC and the resultant mixture was stirred at this
temperature for 1 h. (þ)-CSO 13 (103 mg, 0.45 mmol) was then
added and the reaction mixture was allowed to warm to rt over
16 h. Satd aq NH4Cl (1 mL) was then added and the resultant
mixture was diluted with Et2O (25 mL) and washed with 10% aq
citric acid (25 mL). The aqueous layer was extracted with Et2O
(2ꢃ25 mL) and the combined organic extracts were washed se-
quentially with satd aq NaHCO3 (2ꢃ25 mL) and brine (25 mL), then
dried and concentrated in vacuo to give an 85:15 mixture of 34
and 39. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 75:25) gave 39 (3 mg, 5%, >99:1 dr); nmax
(ATR) 3433 (OeH), 3084, 3060, 3027, 2970, 2931, 2868 (CeH), 1638
(C]O), 1603 (C]C, aromatic); dH (500 MHz, CDCl3) 1.38 (3H, d, J
þ
C21H26F2NO2 ([MþH]þ) requires 362.1926; found 362.1927. Fur-
ther elution gave 42 as a yellow oil (8.24 g, 87%); nmax (ATR) 3319
(NeH), 3076, 2925, 2873, 2819 (CeH), 1505 (C]C); dH (400 MHz,
CDCl3) 1.21 (1H, s, NH), 1.89e1.98 (2H, m, C(2)H2), 2.78 (2H, t, J 6.8,
C(1)H2), 3.25 (2H, d, J 6.1, NCH2CH]CH2), 3.97 (2H, t, J 6.3, C(3)H2),
5.07 (1H, dd, J 10.4, 1.8, NCH2CH]CHAHB), 5.16 (1H, dd, J 17.2, 1.8,
NCH2CH]CHAHB), 5.83e5.95 (1H, m, NCH2CH]CH2), 6.76e6.84
(2H, m, C(20)H, C(60)H), 6.89e6.98 (2H, m, C(30)H, C(50)H); dC
(100 MHz, CDCl3) 29.7 (C(2)), 46.2 (C(1)), 52.5 (NCH2CH]CH2),
66.9 (C(3)), 115.4 (d, J 8.0, C(20), C(60)), 115.6 (NCH2CH]CH2), 115.7
(d, J 23.2, C(30), C(50)), 136.9 (NCH2CH]CH2), 155.1 (d, J 1.6, C(10)),
157.1 (d, J 238, C(40)); m/z (ESIþ) 232 ([MþNa]þ, 20%), 210
([MþH]þ, 100%); HRMS (ESIþ) C12H17FNOþ ([MþH]þ) requires
210.1289; found 210.1287.
6.9, C(a)Me), 1.78 (1H, app qd, J 11.4, 6.0, C(5)HA), 1.92e2.02 (1H, m,
C(5)HB), 2.99e3.08 (2H, m, C(4)H, C(6)HA), 3.09–3.16 (1H, m,
C(6)HB), 3.60 (1H, s, OH), 3.89 (1H, d, J 15.0, N(1)CHAHBPh), 3.93 (1H,
d, J 15.0, N(1)CHAHBPh), 4.16 (1H, d, J 10.7, C(3)H), 4.26e4.33 (2H, m,
4.2.18. tert-Butyl
mino]pent-2-enoate 44.
(E)-5-[N-allyl-N-30-(400-fluorophenoxy)propyla-
C(
m, Ph); dC (125 MHz, CDCl3), 18.3 (C(
49.2 (N(1)CH2Ph), 50.2 (NCH2Ph), 57.9 (C(4)), 58.9 (C(
a
)H, NCHAHBPh), 4.71 (1H, d, J 15.0, NCHAHBPh), 7.15e7.50 (15H,
)Me), 25.8 (C(5)), 44.8 (C(6)),
)), 70.4
a
a
(C(3)), 126.8, 126.9, 127.7 (p-Ph), 127.8, 128.2, 128.2, 128.3, 128.4,
128.7 (o,m-Ph), 136.4, 141.7, 144.8 (i-Ph), 172.0 (C(2)); m/z (ESIꢀ) 413
þ
([MꢀH]ꢀ, 25%); HRMS (ESIþ) C27H30N2NaO2 ([MþNa]þ) requires
437.2199; found 437.2191.
Method B: LiHMDS (1.0 M in toluene, 1.13 mL, 1.13 mmol) was
added dropwise to a solution of 34 (150 mg, 0.38 mmol) in THF
(10 mL) at ꢀ78 ꢁC and the resultant mixture was stirred at this
temperature for 1 h. (ꢀ)-CSO 13 (338 mg,1.13 mmol) was then added
and thereaction mixturewas allowed towarm to rtover 16 h. Satd aq
NH4Cl (1 mL) was then added and the resultant mixture was diluted
Acrolein (0.95 mL, 14.1 mmol) was added dropwise to a stir-
red solution of DBU (21
mL, 0.14 mmol) and 42 (2.96 g,
14.1 mmol) in THF (10 mL) at ꢀ15 ꢁC. The reaction was stirred at
ꢀ15 ꢁC for 40 min then 22 (5.86 g, 15.6 mmol) was added por-
tionwise, and the reaction mixture was stirred at ꢀ15 ꢁC for
20 min. The resultant mixture was allowed to warm to rt over

S.G. Davies et al. / Tetrahedron 68 (2012) 3263e3275
3273
16 h, and then concentrated in vacuo to give 44 in 77:23 dr.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/Et2O/Et3N, 80:20:1) gave 44 as a colourless oil (3.26 g,
70%, >99:1 dr); nmax (ATR) 3077, 2977, 2932, 2811 (CeH), 1710
(C]O), 1652 (C]C); dH (400 MHz, CDCl3) 1.46 (9H, s, CMe3),
1.83e1.93 (2H, m, C(20)H2), 2.26e2.36 (2H, m, C(4)H2), 2.54e2.65
(4H, m, C(5)H2, C(10)H2), 3.10 (2H, d, J 6.3, NCH2CH]CH2), 3.94
(2H, t, J 6.3, C(30)H2), 5.11 (1H, dd, J 10.4, 1.3, NCH2CH]CHAHB),
5.17 (1H, dd, J 17.2, 1.3, NCH2CH]CHAHB), 5.74 (1H, d, J 16.2,
C(2)H), 5.77e5.87 (1H, m, NCH2CH]CH2), 6.76e6.87 (3H, m,
C(3)H, Ar), 6.90e6.98 (2H, m, Ar); dC (100 MHz, CDCl3) 27.1
(C(20)), 28.1 (CMe3), 29.8 (C(4)), 49.9, 52.2 (C(5), C(10)), 57.1
(NCH2CH]CH2), 66.5 (C(30)), 80.0 (CMe3), 115.4 (d, J 7.2, C(200),
C(600)), 115.7 (d, J 23.2, C(300), C(500)), 117.3 (NCH2CH]CH2), 123.9
(C(2)), 135.6 (NCH2CH]CH2), 145.9 (C(3)), 155.1 (d, J 1.6, C(100)),
157.1 (d, J 238, C(400)), 165.9 (C(1)); m/z (ESIþ) 386 ([MþNa]þ,
4.2.20. (R,R,R)-N(1)-[30-(400-Fluorophenoxy)propyl]-3-hydroxy-4-[N-
benzyl-N-( -methylbenzyl)amino]-piperidin-2-one 47.
a
Pd(PPh3)4 (42 mg, 0.04 mmol) was added to a mixture of 45
(2.16 g, 3.65 mmol) and DMBA (1.71 g, 11.0 mmol) in de-gassed
CH2Cl2 (40 mL) at 35 ꢁC. The reaction mixture was then stirred
for 3 h at 35 ꢁC in the dark, then concentrated in vacuo. The residue
was then dissolved in toluene (40 mL) and PhCO2H (20 mg,
0.17 mmol) was added. The resultant solution was stirred at 80 ꢁC
for 16 h then 2.0 M aq Na2CO3 (25 mL) was added and the aqueous
layer was extracted with CH2Cl2 (2ꢃ20 mL). The combined organic
extracts were washed with brine (50 mL), then dried and concen-
trated in vacuo. Purification via flash column chromatography (el-
uent 30e40 ꢁC petrol/EtOAc, 50:50) gave 47 as a yellow oil (1.72 g,
þ
27%), 364 ([MþH]þ, 100%); HRMS (ESIþ) C21H31FNO3 ([MþH]þ)
requires 364.2282; found 364.2270.
4.2.19. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a-methylbenzyl)
amino]-5-[N0-allyl-N0-30-(400-fluorophenoxy)propylamino]pentanoate
45.
99%, >99:1 dr); ½a D25
þ32.0 (c 0.91 in CHCl3); nmax (ATR) 3307
ꢄ
(OeH), 3083, 3060, 3027, 2970, 2940, 2874 (CeH), 1639 (C]O),
1627 (C]C); dH (400 MHz, CDCl3) 1.33 (3H, d, J 6.8, C(a)Me),
1.92e2.12 (4H, m, C(20)H2, C(5)H2), 3.20e3.26 (2H, m, C(6)H2), 3.34
(1H, app dt, J 8.6, 6.8, C(4)H), 3.53 (2H, t, J 7.1, C(10)H2), 3.78 (1H, d, J
14.7, NCHAHBPh), 3.82e3.91 (4H, m, NCHAHBPh, C(30)H2, OH), 3.96
(1H, dt, J 6.3, 3.3, C(3)H), 4.23 (1H, q, J 6.8, C(
C(200), C(300), C(500), C(600)), 7.20e7.50 (10H, m, Ph); dC (100 MHz,
CDCl3) 16.1 (C(
)Me), 25.0 (C(5)), 27.4 (C(20)), 44.6 (C(10)), 45.0
(C(6)), 51.2 (NCH2Ph), 54.5 (C(4)), 57.8 (C(
)), 66.0 (C(30)), 69.7
a)H), 6.71e6.98 (4H, m,
a
a
(C(3)), 115.4 (d, J 8.0, C(200), C(600)), 115.8 (d, J 23.2, C(300), C(500)),
126.9, 127.0 (p-Ph), 127.7, 128.3, 128.4, 128.4 (o,m-Ph), 141.5, 144.0
(i-Ph), 154.8 (d, J 2.4, C(100)), 157.3 (d, J 238, C(400)),þ171.7 (C(2)); dF
(470 MHz, CDCl3) þ123.9 (C(400)F); m/z (FIþ) 476 ([M] , 100%); HRMS
(FIþ) C29H33FN2O3 ([M]þ) requires 476.2470; found 476.2478.
BuLi (2.5 M,11.7 mL, 29.2 mmol) was added dropwise to a stirred
solution of (R)-N-benzyl-N-(a-methylbenzyl)amine (6.12 mL,
29.2 mmol) in THF (100 mL) at ꢀ78 ꢁC and the resultant mixture
was stirred at this temperature for 30 min. A solution of 44 (6.64 g,
18.3 mmol) in THF (80 mL) at ꢀ78 ꢁC was then added dropwise. The
reaction mixture was stirred at ꢀ78 ꢁC for 2 h then (ꢀ)-CSO 13
(10.9 g, 36.5 mmol) was added. The reaction mixture was allowed
to warm to rt over 16 h, H2O (10 mL) was added, then the organic
layer was dried and concentrated in vacuo to give 45 in >99:1 dr.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/EtOAc/Et3N, 66:34:1) gave 45 as a colourless oil (6.91 g, 64%,
4.2.21. (R,R,R)-N(1)-[30-(400-Fluorophenoxy)propyl]-3-methoxy-4-[N-
benzyl-N-(a-methylbenzyl)amino]piperidin-2-one 48.
>99:1 dr); ½a 2D5
ꢀ19.4 (c 1.0 in CHCl3); nmax (ATR) 3502 (OeH),
ꢄ
3062, 3027, 2974, 2933, 2873, 2812 (CeH), 1719 (C]O), 1601, 1505
(C]C, aromatic); dH (400 MHz, CDCl3) 1.33 (3H, d, J 6.8, C(a)Me),
A solution of 47 (1.31 g, 2.76 mmol) in THF (15 mL) was added
dropwise via cannula to a solution of NaH (60% in mineral oil,121 mg,
3.03mmol)inTHF(15mL)at0ꢁC. The reaction mixturewas allowed to
warm to rt over 1 h, then MeI (0.52 mL, 8.3 mmol) was added drop-
wise. The resulting solution was stirred at rt for 16 h then H2O (20 mL)
was carefully added. The aqueous layer was extracted with EtOAc
(2ꢃ40 mL). The combined organic layers were dried and concentrated
in vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/EtOAc, 50:50) gave 48 as a colourless oil (1.04 g, 77%,
1.47 (9H, s, CMe3), 1.44e1.54 (1H, m, C(4)HA), 1.77 (1H, dtd, J 13.5,
8.5, 5.2, C(4)HB), 1.92 (2H, tt, J 7.0, 6.6, C(20)H2), 2.39 (1H, ddd, J 13.0,
9.6, 6.3, C(5)HA), 2.63 (2H, td, J 7.0, 3.7, C(10)H2), 2.74 (1H, ddd, J 13.0,
8.8, 4.8, C(5)HB), 3.06e3.19 (2H, m, N0CH2CH]CH2), 3.28 (1H, ddd, J
7.6, 5.2, 2.5, C(3)H), 3.73 (1H, d, J 15.4, NCHAHBPh), 3.90 (1H, d, J 2.5,
C(2)H), 3.95 (2H, t, J 6.6, C(30)H2), 3.98 (1H, q, J 6.8, C(
a)H), 4.25 (1H,
d, J 15.4, NCHAHBPh), 5.13e5.24 (2H, m, N0CH2CH]CH2), 5.81e5.94
(1H, m, N0CH2CH]CH2), 6.79e7.01 (4H, m, Ar), 7.21e7.57 (10H, m,
Ph); dC (100 MHz, CDCl3) 19.4 (C(
28.0 (CMe3), 50.1 (C(10)), 51.0 (NCH2Ph), 52.0 (C(5)), 57.0
(N0CH2CH]CH2), 58.5 (C(3)), 58.8 (C(2)), 66.7 (C(30)), 71.5 (C(
)),
a
)Me), 25.1 (C(4)), 26.9 (C(20)),
>99:1 dr); ½a 2D5
þ46.8 (c 0.9 in CHCl3); nmax (ATR) 3060, 3027, 2935,
ꢄ
2827 (CeH), 1638 (C]O), 1601 (C]C, aromatic); dH (400 MHz, CDCl3)
a
82.1 (CMe3),115.4 (d, J 8.0, C(200), C(600)),115.7 (d, J 22.4, C(300), C(500)),
117.5 (N0CH2CH]CH2), 126.5, 127.0 (p-Ph), 127.9, 128.1, 128.2, 128.2
(o,m-Ph), 135.6 (N0CH2CH]CH2), 142.3, 143.3 (i-Ph), 155.2 (d, J 2.4,
C(100)), 157.1 (d, J 237, C(400)), 174.2 (C(1)); m/z (ESIþ) 591 ([MþH]þ,
1.39 (3H, d, J 6.8, C(a)Me),1.85e1.94 (1H, m, C(5)HA),1.96e2.05 (2H, m,
C(20)H2), 2.34e2.44(1H, m, C(5)HB), 2.88 (1H, app dt, J 12.4,3.3,C(4)H),
3.15e3.38 (3H, m, C(6)HA, C(6)HB, C(10)HA), 3.57 (1H, d, J 2.5, C(3)H),
3.60 (3H, s, OMe), 3.61e3.67 (1H, m, C(10)HB), 3.87e3.96 (3H, m, C(30)
þ
100%); HRMS (ESIþ) C36H48FN2O4 ([MþH]þ) requires 591.3593;
H2, NCHAHBPh), 4.10 (1H, q, J 6.8, C(a)H), 4.30 (1H, d, J 14.4, NCHAHBPh),
6.78e7.03 (4H, m, OAr), 7.20e7.54 (10H, m, Ph); dC (100 MHz, CDCl3)
found 591.3580.

3274
S.G. Davies et al. / Tetrahedron 68 (2012) 3263e3275
þ
14.4 (C(
(NCH2Ph), 54.4 (C(4)), 57.0 (C(
a
)Me), 22.7 (C(5)), 26.9 (C(20)), 43.8 (C(10)), 46.6 (C(6)), 52.0
)), 59.3 (OMe), 66.1 (C(30)), 82.9 (C(3)),
m/z (ESIþ) 283 ([MþH]þ, 50%); HRMS (ESIþ) C15H24FN2O2
a
([MþH]þ) requires 283.1816; found 283.1813.
115.4 (d, J 8.0, C(200), C(600)), 115.8 (d, J 22.4, C(300), C(500)), 126.7, 126.8,
127.5, 128.2, 128.3, 128.3 (o,m,p-Ph), 142.1, 144.3 (i-Ph), 154.9 (d, J 2.4,
C(100)), 157.3 (d, J þ238, C(400)), 168.6 (C(2)); dF (470 MHz, CDCl3) 124.0
(C(400)F); m/z (ESI ) 491 ([MþH]þ, 100%); HRMS (ESIþ) C30H36FN2O3þ
([MþH]þ) requires 491.2704; found 491.2682.
Step 2: ClCO2Et (92 mL, 0.96 mmol) was added dropwise to a so-
lution of 51 (247 mg, 0.86 mmol) and Et3N (121 mL, 0.88 mmol) in
THF (5 mL) at 0 ꢁC, and the reaction mixture was stirred for 2 h.
A solution of 50 (194 mg, 0.96 mmol) in THF (1 mL) was then added
dropwise via cannula and the reaction was allowed to warm to rt
over 16 h. The insoluble residue was filtered, and the filtrate was
concentrated in vacuo. Purification via flash column chromatogra-
phy (eluent CH2Cl2/MeOH/Et3N, 96:3:1) gave 40 as a colourless oil
4.2.22. (3S,4R,
4-[N-benzyl-N-(
a
R)-N(1)-(30-(400-Fluorophenoxy)propyl)-3-methoxy-
-methylbenzyl)amino]piperidine 49.
a
(205 mg, 64% from 49, >99:1 dr); ½a D25
þ3.3 (c 1.0 in CHCl3); nmax
ꢄ
(ATR) 3576, 3525, 3469, 3326, 3006, 2970, 2929, 2856,1738,1629; dH
(500 MHz, CDCl3) 1.79e1.92 (2H, m, C(5)H2), 1.95e2.05 (2H,
m, C(20)H2), 2.16e2.29 (2H, m, C(2)HA, C(6)HA), 2.50e2.61 (2H, m,
C(10)H2), 2.76e2.88 (1H, m, C(6)HB), 3.01e3.16 (1H, m, C(2)HB), 3.44
(3H, s, OMe), 3.44e3.47 (1H, m, C(3)H), 3.89 (3H, s, OMe), 3.93e4.01
(2H, m, C(30)H2), 4.17e4.25 (1H, m, C(4)H), 4.37 (2H, s, NH2), 6.30 (1H,
s, C(3000)H), 6.80e6.87 (2H, m, C(200)H, C(600)H), 6.93e7.00 (2H, m,
C(300)H, C(500)H), 8.11 (1H, s, C(6000)H), 8.21 (1H, d, J 8.2, CONH); dC (125
MHz, CDCl3) 26.8 (C(20)), 27.8 (C(5)), 48.0 (C(4)), 51.9 (C(6)), 53.6
(C(2)), 55.2 (C(10)), 56.0, 57.0 (2ꢃ OMe), 66.9 (C(30)), 76.7 (C(3)), 97.9
(C(3000)),111.6 (C(1000)),112.9 (C(5000)),115.4 (d, J 7.6, C(200), C(600)),115.7
(d, J 22.9, C(300), C(500)), 133.1 (C(6000)), 146.5 (C(4000)), 155.1 (d, J 1.9,
C(100)),157.2 (d, J 238, C(400)),157.5,163.þ7 (C(2000), C(1000)CONH); dF (470
MHz, CDCl3) 124.2 (C(400)F); m/z (ESI ) 466 ([M(35Cl)þH]þ, 100%);
LiAlH4 (1.0 M in THF, 4.57 mL, 4.57 mmol) was added dropwise to
a solution of 48 (747 mg, 1.52 mmol) in THF (30 mL) at 0 ꢁC. The
reaction was stirred at reflux for 16 h then cooled to 0 ꢁC and
quenched by careful addition of 2 M aq NaOH (5 mL). The reaction
mixturewas diluted with EtOAc (30 mL) and filtered through CeliteÒ
(eluent EtOAc). The filtrate was dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/EtOAc/Et3N, 50:50:1) gave 49 as a white solid (716 mg, 99%,
>99:1 dr); mp 63e67 ꢁC; ½a D25
þ50.1 (c 1.0 in CHCl3); nmax (ATR)
ꢄ
þ
HRMS (ESIþ) C23H3035ClFN3O4 ([M(35Cl)þH]þ) requires 466.1903;
3084, 3061, 3027, 2954 (CeH), 1601, 1506 (C]C, aromatic); dH
found 466.1902.
(400 MHz, CDCl3) 1.36 (3H, d, J 6.8, C(a)Me),1.60 (1H, app br d, J 11.9,
C(2)HA), 1.67 (1H, dd, J 12.5, 2.7, C(6)HA), 1.88e2.04 (3H, m, C(20)H2,
C(5)HA), 2.25 (1H, qd, J 12.5, 3.9, C(6)HB), 2.35e2.45 (1H, m, C(10)HA),
2.47e2.57 (2H, m, C(4)H, C(10)HB), 3.00 (1H, br d, J 10.4, C(5)HB), 3.08
(1H, dt, J 12.5, 2.4, C(2)HB), 3.17 (1H, s, C(3)H), 3.41 (3H, s, OMe),
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.12.084.
3.90e3.96 (3H, m, C(30)H2, NCHAHBPh), 4.11 (1H, q, J 6.8, C(
(1H, d, J 14.3, NCHAHBPh), 6.78e7.00 (4H, m, Ar), 7.18e7.51 (10H, m,
Ph); dC (100 MHz, CDCl3) 14.5 (C(
)Me), 25.8 (C(6)), 26.9 (C(20)), 51.8
(NCH2Ph), 54.1 (C(5)), 54.4 (C(2)), 55.3 (C(10)), 56.5 (C(
)), 56.8
a)H), 4.28
References and notes
a
a
1. (a) Tokuda, O.; Aikawa, T.; Ikemoto, T.; Kurimoto, I. Tetrahedron Lett. 2010, 51,
2832; (b) Campeau, L.-C.; Dolman, S. J.; Gauvreau, D.; Corley, E.; Liu, J.; Guidry,
E. N.; Ouellet, S. G.; Steinhuebel, D.; Weisel, M.; O’Shea, P. D. Org. Process Res.
Dev. 2011, 15, 1138.
(C(4)), 56.9 (OMe), 67.1 (C(30)), 80.0 (C(3)), 115.4 (d, J 8.0, C(200),
C(600)), 115.7 (d, J 22.4, C(300), C(500)), 126.3, 127.7 (p-Ph), 127.9, 128.1,
128.1, 128.5 (o,m-Ph), 142.9, 145.2 (i-Ph), 155.1 (d, J 2.4, C(100)), 157.1
(d, J 238, C(400)); dF (376 MHz, CDCl3) 124.2 (Cþ(400)F); m/z (ESIþ) 477
([MþH]þ, 100%); HRMS (ESIþ) C30H38FN2O2 ([MþH]þ) requires
477.2912; found 477.2906.
ꢀ
ꢀ
2. Boto, A.; Hernandez, R.; de Leon, Y.; Murguía, J. R.; Rodríguez-Afonso, A.
Tetrahedron Lett. 2004, 45, 6841.
ꢀ
ꢀ
~
3. Concellon, J. M.; Rivero, I. A.; Rodríguez-Solla, H.; Concellon, C.; Espana, E.;
García-Granda, S.; Díaz, M. R. J. Org. Chem. 2008, 73, 6048.
4. Higashikawa, Y.; Suzuki, S. Forensic Toxicol. 2008, 26, 1.
5. (a) Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem.
Soc. 2001, 123, 11829; (b) Glorius, F.; Spielkamp, N.; Holle, S.; Goddard, R.;
Lehmann, C. W. Angew. Chem., Int. Ed. 2004, 43, 2850.
6. (a) Taniguchi, T.; Ogasawara, K. Org. Lett. 2000, 2, 3193; (b) Schaudt, M.;
Blechert, S. J. Org. Chem. 2003, 68, 2913.
4.2.23. (3S,4R)-N(1)-[30-(400-Fluorophenoxy)propyl]-3-methoxy-4-
(2000-methoxy-4000-amino-5000-chlorobenzamido)piperidine
[(þ)-(3S,4R)-cisapride] 40.
7. (a) Hwang, Y. C.; Fowler, F. W. J. Org. Chem. 1985, 50, 2719; (b) Bailey, P. D.;
Wilson, R. D.; Brown, G. R. J. Chem. Soc., Perkin Trans. 11991, 1337; (c) Kobayashi,
S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int. Ed. 1998, 37, 979; (d) Yao, S.;
Johannsen, M.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 1998, 37,
3121; (e) Kobayashi, S.; Kusakabe, K.; Komiyama, S.; Ishitani, H. J. Org. Chem.
ꢀ
1999, 64, 4220; (f) Barluenga, J.; Aznar, F.; Ribas, C.; Valdes, C. J. Org. Chem. 1999,
64, 3736; (g) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099; (h)
Avenoza, A.; Busto, J. H.; Cativiela, C.; Corzana, F.; Peregrina, J. M.; Zurbano, M.
M. J. Org. Chem. 2002, 67, 598.
8. (a) Chen, L.-J.; Hou, D.-R. Tetrahedron: Asymmetry 2008, 19, 715; (b) Bunce, M.
A.; Peeples, C. J.; Jones, P. B. J. Org. Chem. 1992, 57, 1727; (c) Hermet, J.-P. R.;
McGrath, M. J.; O’Brien, P.; Porter, D. W.; Gilday, J. Chem. Commun. 2004, 1830.
9. For instance, see: (a) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.
1998, 633; (b) Laschat, S.; Dickner, T. Synthesis 2000, 1781; (c) Weintraub, P. M.;
Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953; (d) Buffat,
M. G. P. Tetrahedron 2004, 60, 1701; (e) Kadouri-Puchot, C.; Comesse, S. Amino
Acids 2005, 29, 101; (f) Kallstrom, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601.
10. (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2,183; (b) Davies, S. G.;
Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie, L. J.; Price, P. D.; Price Mor-
timer, A. J.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006, 17, 1793; (c)
Davies, S. G.; Garner, A. C.; Nicholson, R. L.; Osborne, J.; Roberts, P. M.; Savory, E.
D.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2009, 7, 2604; (d) Davies, S. G.;
Mujtaba, N.; Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Lett. 2009,11,1959; (e)
Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.;
Toms, S. M. Tetrahedron 2010, 66, 4604; (f) Abraham, E.; Bailey, C. W.; Claridge, T.
D. W.; Davies, S. G.; Ling, K. B.; Odell, B.; Rees, T. L.; Roberts, P. M.; Russell, A. J.;
Step 1: Pd(OH)2/C (276 mg) was added to a solution of 49
(552 mg, 1.15 mmol) in de-gassed MeOH (20 mL). The resultant
suspension was vigorously stirred under H2 (1 atm) for 16 h. The
reaction mixture was then filtered through CeliteÒ (eluent MeOH)
and the filtrate was concentrated in vacuo to give 50 as a colour-
€
€
less oil (296 mg, 91%, >99:1 dr);32
½
a 2D5
ꢄ
þ24.9 (c 1.0 in CHCl3); nmax
(ATR) 3375 (NeH), 2929, 2820 (CeH), 1600, 1505 (C]C, aromatic);
dH (400 MHz, CDCl3) 1.62e1.80 (2H, m, C(5)H2), 1.93e2.02 (2H, m,
C(20)H2), 2.10e2.31 (2H, m, C(2)HA, C(6)HA), 2.48e2.62 (2H, m,
C(10)H2), 2.70e2.80 (1H, br m, C(6)HB), 2.80e2.89 (1H, br m,
C(4)H), 2.95e3.11 (1H, br m, C(2)HB), 3.33e3.37 (1H, m, C(3)H),
3.40 (3H, s, OMe), 3.99 (2H, t, J 6.1, C(30)H2), 6.87e7.03 (4H, m, Ar);

S.G. Davies et al. / Tetrahedron 68 (2012) 3263e3275
benzaldehyde and NaBH4 gave (R)-N-benzyl-N-(
3275
Smith, A. D.; Smith, L. J.; Storr, H. R.; Sweet, M. J.; Thompson, A. L.; Thomson, J. E.;
Tranter, G. E.; Watkin, D. J. Tetrahedron: Asymmetry 2010, 21, 1797; (g) Davies, S.
G.; Ichihara, O.; Roberts, P. M.; Thomson, J. E. Tetrahedron 2011, 67, 216; (h)
Abraham, E.; Claridge, T. D. W.; Davies, S. G.; Odell, B.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Smith, L. J.; Storr, H. R.; Sweet, M. J.; Thompson, A. L.; Thomson, J. E.;
Tranter, G. E.; Watkin, D. J. Tetrahedron: Asymmetry 2011, 22, 69; (i) Bagal, S. K.;
Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J. E.
Tetrahedron Lett. 2011, 52, 2216; (j) Davies, S. G.; Fletcher, A. M.; Hughes, D. G.;
Lee, J. A.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.;
Williams, O. M. H. Tetrahedron 2011, 67, 9975.
a
-methylbenzyl)amine; sub-
sequent deprotonation with BuLi in THF generated a pink solution of lithium
(R)-N-benzyl-N-( -methylbenzyl)amide (R)-32.
a
23. Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1994, 10, 1999.
24. (a) Davies, S. G.; Walker, J. C. J. Chem. Soc., Chem. Commun. 1985, 209; (b) Da-
vies, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Chem.
Commun. 1993, 1153; (c) Davies, S. G.; Walters, I. A. S. J. Chem. Soc., Perkin Trans.
1 1994, 1129; (d) Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Perkin
Trans. 11994, 1141; (e) Davies, S. G.; Foster, E. M.; McIntosh, C. R.; Roberts, P. M.;
Rosser, T. E.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2011, 22, 1035.
11. For selected examples from this laboratory, see: (a) Davies, S. G.; Kelly, R. J.;
Price Mortimer, A. J. Chem. Commun. 2003, 2132; (b) Davies, S. G.; Burke, A. J.;
Garner, A. C.; McCarthy, T. D.; Roberts, P. M.; Smith, A. D.; Rodríguez-Solla, H.;
Vickers, R. J. Org. Biomol. Chem. 2004, 2, 1387; (c) Davies, S. G.; Haggitt, J. R.;
Ichihara, O.; Kelly, R. J.; Leech, M. A.; Price Mortimer, A. J.; Roberts, P. M.; Smith,
A. D. Org. Biomol. Chem. 2004, 2, 2630; (d) Abraham, E.; Candela-Lena, J. I.;
Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.;
25. In each case samples of the corresponding
were also isolated.
a,a-diprotio-b-amino esters 26e28
26. For applications of our aminohydroxylation procedure, see: (a) Bunnage, M. E.;
Burke, A. J.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith,
A. D. Org. Biomol. Chem. 2003, 1, 3708; (b) Davies, S. G.; Nicholson, R. L.; Price,
P. D.; Roberts, P. M.; Savory, E. D.; Smith, A. D. Tetrahedron: Asymmetry 2009,
20, 758; (c) Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.
ꢀ
ꢀ
ꢀ
Sanchez-Fernandez, E. M.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry
2007, 18, 2510; (e) Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.;
Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655; (f) Abraham, E.;
Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.;
Org. Lett. 2011, 13, 1594; (d) Csatayova, K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.;
Russell, A. J.; Thomson, J. E.; Wilson, D. L. Org. Lett. 2011, 13, 2606. See also Refs.
11def.
27. Crystallographic data (excluding structure factors) for compounds 36, 37 and
49 have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 845673e845675, respectively.
Copies of these data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
28. Meyers, A. I.; Kunnen, K. B.; Still, W. C. J. Am. Chem. Soc. 1987, 109, 4405.
29. Weber, K.; Ohnmacht, U.; Gmeiner, P. J. Org. Chem. 2000, 65, 7406.
30. In both cases, 1H NMR spectroscopic analysis of the crude reaction mixture
revealed that 39 was formed in >90:10 dr, although peak overlap precluded
a more accurate determination of the reaction diastereoselectivity.
31. Georgiadis, G. T.; Markantonis-Kyroudis, S.; Triantafillidis, J. K. Ann. Gastro-
enterol. 2000, 13, 269.
32. Van Daele, G. H. P.; De Bruyn, M. F. L.; Sommen, F. M.; Janssen, M.; Van Nueten, J.
M.; Schuurkes, J. A. J.; Niemegeers, C. J. E.; Leysen, J. E. Drug Dev. Res.1986, 8, 225.
33. (a) Clin. Pharmacol. 1993, 12, 876 (News); (b) Barone, J. A.; Jessen, L. M.; Colaizzi,
J. L.; Bierman, R. H. Ann. Pharmacother. 1994, 28, 488.
34. (a) Nurko, S.; Garcia-Aranda, J. A.; Guerrero, V. Y.; Worona, L. B. J. Pediatr.
Gastroenterol. Nutr. 1996, 22, 3; (b) Cucchiara, S. J. Pediatr. Gastroenterol. Nutr.
1997, 25, 250.
35. Tonini, M.; De Ponti, F.; Di Nucci, A.; Crema, F. Aliment. Pharmacol. Ther. 1999, 13,
1585.
36. Michalets, E. L.; Williams, C. R. Clin. Pharmacokinet. 2000, 39, 49.
37. Gray, N. M.; Young, J. W. U.S. Patent 5,629,328, 1997.
38. (a) Sakaguchi, J.; Iwasaki, N.; Iwanage, Y.; Saito, T.; Takakhara, E.; Kato, H.;
Hanaoka, M. Chem. Pharm. Bull. 2001, 49, 424; (b) McKinnell, R. M.; Armstrong,
S. R.; Beattie, D. T.; Choi, S.-K.; Fatheree, P. R.; Gendron, R. A. L.; Goldblum, A.;
Humphrey, P. P.; Long, D. D.; Marquess, D. G.; Shaw, J. P.; Smith, J. A. M.; Turner,
S. D.; Vickery, R. G. J. Med. Chem. 2009, 52, 5330.
39. For previous syntheses of (ꢂ)-(RS,SR)-cisapride, see: (a) Kim, B. J.; Pyun, D. K.;
Jung, H. J.; Kwak, H. J.; Kim, J. H.; Kim, E. J.; Jeong, W. J.; Lee, C. H. Synth.
Commun. 2001, 31, 1081; (b) Cossy, J.; Molina, J. L.; Desmurs, J.-R. Tetrahedron
Lett. 2001, 42, 5713. See also Ref. 32.
ꢀ
ꢀ
Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez, E. M.; Scott, P. M.;
Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 1665; (g) Davies, S. G.;
Fletcher, A. M.; Roberts, P. M.; Smith, A. D. Tetrahedron 2009, 65, 10192; (h)
Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2011,
13, 2544; (i) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J.
Tetrahedron Lett. 2011, 52, 6477.
12. For selected examples from this laboratory, see: (a) Cailleau, T.; Cooke, J. W. B.;
Davies, S. G.; Ling, K. B.; Naylor, A.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.;
Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 3922; (b)
Davies, S. G.; Durbin, M. J.; Goddard, E. C.; Kelly, P. M.; Kurosawa, W.; Lee, J. A.;
Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Smith, A. D.
Org. Biomol. Chem. 2009, 7, 761; (c) Davies, S. G.; Lee, J. A.; Roberts, P. M.;
Thomson, J. E.; Yin, J. Tetrahedron 2011, 67, 6382; (d) Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Thomson, J. E.; Yin, J. Org. Lett. 2012, 14, 218.
13. For selected examples from this laboratory, see: (a) Davies, S. G.; Garner, A. C.;
Long, M. J. C.; Morrison, R. M.; Roberts, P. M.; Smith, A. D.; Sweet, M. J.; Withey,
J. M. Org. Biomol. Chem. 2005, 3, 2762; (b) Aye, Y.; Davies, S. G.; Garner, A. C.;
Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 2195; (c)
Abraham, E.; Davies, S. G.; Docherty, A. J.; Ling, K. B.; Roberts, P. M.; Russell, A. J.;
Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 1356; (d) Davies,
S. G.; Durbin, M. J.; Hartman, S. J. S.; Matsuno, A.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 2870.
14. Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833.
15. Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P. M.;
Rodríguez-Solla, H.; Smith, A. D. Chem. Commun. 2006, 2664.
16. Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P. M.; Smith, A.
D.; Rodríguez-Solla, H.; Thomson, J. E.; Toms, S. M. Org. Biomol. Chem. 2007, 5,
1961.
17. (a) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1994,
2385; (b) Bunnage, M. E.; Burke, A. J.; Davies, S. G.; Goodwin, C. J. Tetrahedron:
Asymmetry 1995, 6, 165; (c) Bunnage, M. E.; Chernega, A. N.; Davies, S. G.;
Goodwin, C. J. J. Chem. Soc., Perkin Trans. 1 1994, 2373.
40. For a previous formal synthesis of (þ)-(3S,4R)-cisapride, see: Shirode, N. M.;
Likhite, A. P.; Gumaste, V. K.; Rakeeb, A.; Deshmukh, A. S. Tetrahedron 2008, 64,
7191.
18. Davies, S. G.; Huckvale, R.; Lorkin, T. J. A.; Roberts, P. M.; Thomson, J. E. Tetra-
hedron: Asymmetry 2011, 22, 1591.
19. Chesney, A.; Marko, I. E. Synth. Commun. 1990, 20, 3167.
41. N,N-Di-[3-(40-fluorophenoxy)propyl]-N-allylamine (the product of N-dia-
lkylation) was also isolated from this reaction in 10% yield.
ꢀ
20. These intermediate
b-amino aldehydes are reportedly susceptible to poly-
merisation although this can be minimised by the addition of a catalytic
amount of DBU (1 mol %), the use of THF over CH2Cl2, and maintaining the
reaction temperature at ꢀ15 ꢁC, see Ref. 19.
42. See also: (a) Janssen, C. G. M.; Lenoir, H. A. C.; Thijssen, J. B. A.; Knaeps, A. G.;
Heykants, J. J. P. J. Labelled Compd. Radiopharm. 1987, 24, 1493; (b) Lee, J. S.; Oh,
Y. S.; Lim, J. K.; Yang, W. Y.; Kim, I. H.; Lee, C. W.; Chung, Y. H.; Yoon, S. J. Synth.
Commun. 1999, 29, 2547.
21. The corresponding (Z)-diastereoisomers were not isolated.
22. Enantiopure (R)-
a
-methylbenzylamine (99% ee) is commercially available.
-methylbenzylamine upon treatment with
43. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
Reductive alkylation of (R)-
a