Asymmetric synthesis of piperidines and octahydroindolizines using a one-pot ring-closure/N-debenzylation procedure

Article abstract of DOI:10.1016/j.tet.2011.09.038

The conjugate addition of an enantiopure lithium amide to a ζ-hydroxy-α,β-unsaturated ester followed by a one-pot ring-closure/N-debenzylation protocol has been used in the asymmetric syntheses of (S)-coniine and (R)-δ-coniceine (isolated as the corresponding hydrochloride salts), and (R,R)-1-(hydroxymethyl)octahydroindolizine (the bicyclic fragment of stellettamides A-C).

Full text of DOI:10.1016/j.tet.2011.09.038

Tetrahedron 67 (2011) 9975e9992
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of piperidines and octahydroindolizines using a one-pot
ring-closure/N-debenzylation procedure
*
Stephen G. Davies , Ai M. Fletcher, Deri G. Hughes, James A. Lee, Paul D. Price, Paul M. Roberts,
Angela J. Russell, Andrew D. Smith, James E. Thomson, Oliver M.H. Williams
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 1 August 2011
Received in revised form 9 September 2011
Accepted 12 September 2011
Available online 17 September 2011
The conjugate addition of an enantiopure lithium amide to a z-hydroxy-a,b-unsaturated ester followed
by a one-pot ring-closure/N-debenzylation protocol has been used in the asymmetric syntheses of (S)-
coniine and (R)- -coniceine (isolated as the corresponding hydrochloride salts), and (R,R)-1-(hydrox-
ymethyl)octahydroindolizine (the bicyclic fragment of stellettamides AeC).
Ó 2011 Elsevier Ltd. All rights reserved.
d
Dedicated to Professor Gilbert Stork on the
occasion of his 90th birthday
Keywords:
Lithium amide
Asymmetric synthesis
Piperidines
Coniine
d-Coniceine
1. Introduction
The piperidine skeleton is one of the most common ring systems
found in alkaloid natural products. The structures of (þ)-coniine 1,
(þ)-carpamic acid 2, (þ)-norsedamine 3 and (þ)-deoxynojirimycin
4, for example, are representative of this class of natural products
(Fig. 1). Many enantiopure piperidines exhibit potent biological
activity,1 and the broad range of biological activities exhibited by
these compounds has meant they have been common targets for
synthetic chemists.2 A key point to address in any synthetic route to
enantiopure piperidines is the construction of the azacyclic skele-
ton in such a manner to enable the desired substitution pattern to
be introduced stereoselectively. A large variety of different methods
exist to achieve this goal, including the reduction of pyridines,1c,3
ring-closing metathesis4 and aza-DielseAlder reactions,5 and the
synthesis of piperidines has been extensively reviewed.6
Fig. 1. Piperidine alkaloids 1e4.
protocol for the synthesis of b
-amino esters and their derivatives.7
Previous investigations from our laboratory have demonstrated
that the conjugate addition of numerous enantiopure secondary
This methodology has found numerous applications, including the
total syntheses of natural products,8 molecular recognition phe-
nomena9 and resolution protocols,10 and has been reviewed.11 As
part of our ongoing research programme in this area we became
interested in the application of this methodology for the prepara-
tion of enantiopure piperidines and their derivatives and envisaged
three approaches towards the piperidine motif: (i) via ring-closing
lithium amides (derived from
a-methylbenzylamine) to a,b-un-
saturated esters represents a general and efficient synthetic
* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G.
Davies).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.038

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S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
metathesis of a 4-(N-allylamino)alk-1-ene, (ii) via the intra-
molecular conjugate addition of lithiated -(N- -methyl-
benzylamino)- -unsaturated ester and (iii) via cyclisation of a
halo-
-amino ester.12 We have previously reported the application
of the first of these strategies in the synthesis of (S)-coniine 1 via
the conjugate addition of lithium (S)-N-allyl-N-( -methylbenzyl)-
amide 5 to -unsaturated hydroxamate 6, followed by ring-
closing metathesis of and tandem hydrogenation/hydro-
achieved, relative to the standard stepwise experimental pro-
tocol, indicating that alternative processes, such as 1,2-addition
or g-deprotonation of the a,b-unsaturated ester by BuLi do not
interfere with the conjugate addition reaction. It was therefore
envisaged that this approach could be applicable to the diaster-
eoselective syntheses of azacyclic scaffolds such as 2-substituted
pyrrolidines, piperidines and azapanes from the corresponding
a
z
a
a
,b
z
-
b
a
a,b
7
lithiated
esters.
3
z
- or
h
-(N-
a
-methylbenzylamino)- -unsaturated
a
,
b
genolysis of the resultant tetrahydropyridine 8 (Scheme 1).8a The
outcomes of our investigations into the other two strategies are
delineated herein; part of this work has been communicated
previously.13
For our third strategy (cyclisation of a
z
-halo-b-amino ester to
give enantiopure piperidine scaffolds) we envisaged that a one-pot
procedure may be employed via an intramolecular SN2-type dis-
placement of the halide by the amino substituent with concomitant
loss of the N-
we have recently reported that iodoamination of 13 upon treat-
ment with I2 occurs with in situ loss of the N- -methylbenzyl
a-methylbenzyl group. In support of this hypothesis,
a
protecting group. The reaction presumably proceeds via reversible
iodonium formation and cyclisation to give quaternary ammonium
ion 15 that undergoes preferential loss of the N-
cation, which is then trapped by acetonitrile in a Ritter reaction to
give racemic N- -methylbenzylacetamide (RS)-17 in 72% yield, in
a-methylbenzyl
a
addition to pyrrolidine 16, which was isolated in 63% yield and
>99:1 dr.18 Within a similar area, O’Brien et al. have shown that
z-chloro substituted secondary amino ester 18 undergoes an
intramolecular SN2-type displacement to give piperidine 12 in 70%
yield (Scheme 3).12b
Ph
Ph
O
Scheme 1. Reagents and conditions: (i) THF, ꢀ78 ꢁC, 2 h; (ii) DIBAL-H, THF, ꢀ78 ꢁC,
30 min; (iii) NaNH2, [Ph3PCH3]þ[Br]ꢀ, CH2Cl2, ꢀ40 ꢁC to rt, 4 h; (iv) RuCl2(]CHPh)(PCy3)2,
CH2Cl2, reflux, 12 h; (v) Pd/C, H2 (5 atm), MeOH, rt, 24 h then HCl.
t
Ph
I
CO2 Bu
Ph
N
N
(i)
t
CO2 Bu
O
O
O
Within the area of intramolecular conjugate additions, dia-
stereoselective ‘thermal’ additions have previously been reported
for the synthesis of piperidines.14 For example, O’Brien et al. have
13, >99:1 dr
14
reported that reaction of (R)-
a-methylbenzylamine with z-iodo-
a,b
-unsaturated ester 9 gave a 65:35 mixture of piperidines 11
Ph
O
Ph
O
and 12, which were isolated in 45 and 24% yield, respectively
t
t
Ph
CO2 Bu
I
CO2 Bu
(Scheme 2).15 We envisaged that kinetically controlled cyclisation
N
N
O
of a lithiated z-(N-a-methylbenzylamino)-a,b-unsaturated ester
I
+
would provide superior diastereoselectivity relative to the intra-
molecular ‘thermal’ additions described above as lithium chela-
tion, present in intermolecular lithium amide conjugate
additions,16 should rigidify the transition state for conjugate ad-
dition. We have recently reported a one-pot lithium amide con-
jugate addition protocol,7b,17 which involves treating a pre-mixed
Ph
N
H
Me
O
O
(RS)-17, 72%
16, 63%, >99:1 dr
15
solution of N-benzyl-N-(a-methylbenzyl)amine (1.1 equiv) and
-unsaturated ester (1.0 equiv) in THF at ꢀ78 ꢁC
Ph
NH
the requisite
a
,
b
with BuLi (1.05 equiv).7b Similar levels of reaction efficiency were
CO2Et
(ii)
N
Ph
CO2Et
12, 70%
Cl
18
Scheme 3. Reagents and conditions: (i) I2, NaHCO3, MeCN, rt, 20 h; (ii) K2CO3, NaI,
EtOH, reflux, 16 h.
2. Results and discussion
2.1. Intramolecular lithium amide conjugate addition
The strategy involving intramolecular conjugate addition of
a lithiated z-(N-a-methylbenzylamino)-a,b-unsaturated ester was
investigated first. Substrates 28e30 were prepared from the cor-
responding lactones 19e21 via one-pot reduction with DIBAL-H
followed by in situ WadswortheEmmons olefination. Oxidation
Scheme 2. Reagents and conditions: (i) (R)-a-methylbenzylamine, Et3N, EtOH, reflux,
16 h.

S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
9977
of the resultant
gave aldehydes 25e27 in good yield. Subsequent reductive ami-
nation of 25e27 with (R)-N-benzyl-N-( -methylbenzyl)amine and
NaBH(OAc)3, followed by chemoselective N-debenzylation of the
corresponding tertiary amines using 3.0 equiv of CAN,19 gave 28, 29
and 30 in 23, 64 and 44% yield, respectively (Scheme 4).
u
-hydroxy-
a
,
b
-unsaturated esters 22e24 with IBX
that the cyclisation precursors 36 could either be accessed directly
from the conjugate addition of an enantiopure lithium amide 39 to
a
z
-halo-
of -hydroxy-
esters 38 can be readily produced via the addition of a lithium
a
,
b
-unsaturated esters 37 (route A) or via the intermediacy
z
b
-amino esters 38 (route B). -Hydroxy- -amino
z
b
amide 39 to
z
-hydroxy-
a
,b
-unsaturated ester 23 (Fig. 2).
Ph
Ph
Ar
N
Li
39
Ar
N
+
R
N
t
t
CO2 Bu
Route A
CO2 Bu
t
CO2 Bu
X
X
35
36, X = Cl, Br, I
37, X = Cl, Br, I
Route B
Ph
Ph
N
Ar
N
Li
+
39
Ar
t
t
CO2 Bu
CO2 Bu
Scheme 4. Reagents and conditions: (i) BuLi, tert-butyl diethylphosphonoacetate,
DIBAL-H, THF, ꢀ78 ꢁC to rt, 16 h; (ii) IBX, DMSO, rt, 16 h; (iii) NaBH(OAc)3, (R)-N-benzyl-
OH
OH
N-(a
-methylbenzyl)amine, THF, 16 h; (iv) CAN, MeCN/H2O (v/v 5:1), rt, 16 h. [aIsolated
38
23
in 85:15 dr [(E):(Z)]; all other compounds were isolated as single diastereoisomers
(>99:1 dr)].
Fig. 2. Retrosynthetic analysis of enantiopure piperidine 35.
Initial investigations focused upon the conjugate addition of
enantiopure lithium amides to -halo substituted -unsaturated
esters 40e42 (route A, Fig. 2), with subsequent cyclisation of the re-
sultant -halo- -amino esters via the proposed N-debenzylation
strategy. The desired -iodo-, -bromo- and -chloro- -unsaturated
With substrates 28e30 in hand, the intramolecular lithium
amide conjugate addition reactions were attempted. Treating 28
with 1.0 equiv of BuLi resulted in clean cyclisation to give an in-
separable 75:25 mixture of pyrrolidines 31 and 32, respectively, in
93% combined yield.20 Treatment of 29 with 1.0 equiv of BuLi
produced a complex mixture of products containing a 50:50 ratio of
piperidines 33 and 34, respectively, as the major components.21
Purification of this mixture allowed isolation of 33 in 15% yield
and 34 in 32% yield, as single diastereoisomers (>99:1 dr) in each
case (Scheme 5). Treating 30 with 1.0 equiv of BuLi gave a complex
mixture of unidentifiable products, presumably arising due to in-
termolecular conjugate addition, consistent with a slower rate of
cyclisation for the corresponding seven-membered ring. The ap-
parent lack of diastereoselectivity in this intramolecular case is
presumably due to an inability of the lithium amide to adopt the
correct geometry for the usual transition state for intermolecular
conjugate addition.16
z
a,b
z
b
z
z
z
a,b
esters 40e42 were easily synthesised from tert-butyl 7-hydroxyhept-
2-enoate 23 using standard procedures (Scheme 6).12a,22
Scheme 6. Reagents and conditions: (i) PPh3, imidazole, I2, PhMe/MeCN (v/v 4:1),
65 ꢁC, 2 h; (ii) PPh3, CBr4, CH2Cl2, 0 ꢁC to rt, 1 h; (iii) SOCl2, pyridine, 50 ꢁC, 6 h.
Addition of lithium (R)-N-benzyl-N-(
4323 to
-iodo substituted 40 gave exclusively the known trans-
hexacin derivative 44,24 resulting from intramolecular displace-
ment of the pendant -iodo substituent by the intermediate lithium
-amino enolate, in 58% yield and >99:1 dr. Conjugate addition of
a-methylbenzyl)amide (R)-
z
z
b
(R)-43 to
z
-bromo substituted 41 resulted in formation of an in-
-bromo- -amino ester 45, re-
spectively, both as single diastereoisomers (>99:1 dr), consistent
with the decreased reactivity of the -bromo group towards SN2-
type displacement reactions. Addition of (R)-43 to -chloro
substituted 42, however, gave exclusively the desired -chloro-
separable 56:44 mixture of 44 and
z
b
z
z
z
b-
amino ester 46 (>99:1 dr), which was isolated in 76% yield and
>99:1 dr after chromatographic purification (Scheme 7).
Attempted cyclisation of 46 with in situ N-debenzylation, which
involved heating a solution of 46 in MeCN at 80 ꢁC for 16 h, un-
fortunately returned only starting material, even in the presence of
Scheme 5. Reagents and conditions: (i) BuLi, THF, ꢀ78 ꢁC, 2 h.
2.2. Cyclisation with concomitant N-debenzylation
1.5 equiv of AgBF4. As the z-iodo- and z-bromo-substituted a,b-
unsaturated esters were proving incompatible with the proposed
synthetic route (due to the lability of iodide and bromide groups),
In our third strategy for the synthesis of enantiopure piperidine
scaffolds (cyclisation of a
z
-halo-b-amino ester), it was anticipated
and the cyclisation of the z-chloro-substrate was not efficacious,

9978
S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
>99:1 dr from the conjugate addition of (R)-5128 to 23, was also
investigated. Iodination of 52 upon treatment with 5.0 equivof PPh3,
I2 and imidazole22b gave
-iodo- -amino ester 53 in 91% yield and
z
b
>99:1 dr. Subsequent treatment of 53 under the AgBF4 promoted
cyclisation conditions gave an 86:14 mixture of 49 and a compound
which was tentatively assigned as ,3 z-unsaturated b-amino ester 54,
although only 49 was isolated in 84% yield after purification. In-
terestingly, heating a solution of 53 in MeCN at reflux for 16 h (in the
absence of AgBF4) caused complete consumption of starting mate-
rial, to give 49 and p-methoxystyrene 55, which were isolated in 94
and 65% yield, respectively. The one-pot conversion of z-hydroxy-b-
amino ester 52 into 49 was next attempted by heating a solution of
52 in MeCN in the presence of I2, PPh3 and imidazole. Under these
conditions cyclisation and in situ N-debenzylation gave piperidine
49 in 75% isolated yield (in three steps and 35% overall yield from
valerolactone) and 55 in 33% isolated yield (Scheme 9).
d-
Scheme 7. Reagents and conditions: (i) (R)-43, THF, ꢀ78 ꢁC, 2 h then NH4Cl (satd aq).
attention turned towards our second strategy involving the syn-
thesis of
b
z-halo-b-amino esters from the corresponding z-hydroxy-
-amino esters (route B, Fig. 2). Thus, iodination22b of 4725 [pre-
pared in 66% isolated yield and >99:1 dr upon conjugate addition
of (R)-43 to 23] gave 48 in 85% isolated yield as a single di-
astereoisomer (>99:1 dr). Heating a solution of 48 in MeCN for 16 h
at reflux resulted in formation of a 48:49:3 mixture of starting
material 48, piperidine 49 and
respectively, in addition to racemic N-
(RS)-17 (resulting from Ritter reaction of the intermediate
3
z
-unsaturated
b-amino ester 50,
a
-methylbenzylacetamide
a
-
methylbenzyl cation with acetonitrile). However, repetition of this
reaction in the presence of 1.5 equiv of AgBF4 resulted in complete
consumption of starting material, giving a 63:37 mixture of 49 and
50, respectively, in addition to (RS)-17. Purification of this mixture
enabled isolation of 49 in 55% yield and >99:1 er,26 50 in 33% yield
and >99:1 dr, and (RS)-17 in 49% yield (Scheme 8). The formation of
50 in this system is consistent with silver-promoted elimination of
HI from within 48.
Scheme 9. Reagents and conditions: (i) THF, ꢀ78 ꢁC, 2 h; (ii) PPh3, imidazole, I2, PhMe/
MeCN (v/v 4:1), 65 ꢁC, 2 h; (iii) AgBF4, MeCN, 80 ꢁC, 16 h; (iv) MeCN, 80 ꢁC, 16 h; (v)
PPh3, imidazole, I2, MeCN, 80 ꢁC, 16 h. [PMP¼p-methoxyphenyl].
2.3. Asymmetric syntheses of (S)-coniine and (R)-d-coniceine
With methodology for the synthesis of piperidine 49 estab-
lished, attention was turned towards the elaboration of 49 in the
syntheses of the Hemlock alkaloids (S)-coniine 1,29,30 and (R)-
d-
coniceine 56.31 It was envisaged that (S)-coniine 1 could be
accessed via a tandem hydrogenation/hydrogenolysis of homo-
allylamine 57, which in turn could be synthesised from ester 49 via
the intermediacy of aldehyde 58. Aldehyde 58 was also selected as
a suitable precursor for the synthesis of (R)-
envisaged that chain extension of 58 would give
59, which may then undergo one-pot hydrogenolysis, imine for-
mation and in situ reduction to give (R)- -coniceine 56 (Fig. 3).
d-coniceine 56: it was
g-amino aldehyde
d
Thus, the tert-butyl ester functionality within 49 was fully re-
duced with DIBAL-H at 0 ꢁC to give alcohol 60 in 99% yield. Sub-
Scheme 8. Reagents and conditions: (i) PPh3, imidazole, I2, PhMe/MeCN (v/v 4:1),
sequent oxidation of 60 under Swern conditions gave
b-amino
65 ꢁC, 2 h; (ii) AgBF4, MeCN, 80 ꢁC, 16 h.
aldehyde 58 in quantitative yield.32 Wittig reaction of 58 with
methyl triphenylphosphonium bromide gave homoallylamine 57 in
52% yield. Tandem hydrogenation/hydrogenolysis of 57 in the
presence of Pearlman’s catalyst [Pd(OH)2/C] gave, after treatment
with HCl, (S)-coniine hydrochloride 1$HCl in 82% yield (Scheme 10).
Since it was probable that loss of the benzylic cation could be
rate-limiting,27 the corresponding N-(p-methoxy-
a-methylbenzyl)
substituted analogue 52, which was produced in 76% yield and

S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
9979
2.4. Synthesis of functionalised octahydroindolizines
Investigations into the alkylation of piperidine 49 to allow
access to more functionalised natural products, based on an indo-
lizine scaffold, were next undertaken. 1-(Hydroxymethyl)octahy-
droindolizine 62 was identified as a potential target as it possesses
the correct configuration for the heterocyclic core fragment of the
octahydroindolizine alkaloids stellettamides AeC 63e65
(Fig. 4).2d,35 Stellettamides AeC 63e65 were all isolated from ma-
rine sponges of the genus Stelleta and share the common
(1S,4S,8aR)-1-amidomethyl-N(4)-methylindolizidine architectural
motif.2d,35c Stellettamide A 63 was the first of these alkaloids iso-
lated (by Fusetani et al. in 1990) and displays antifungal and cyto-
toxic activity.35a Several total syntheses of these compounds have
recently been reported, allowing the absolute configurations within
63e65 to be established unambiguously.
Fig. 3. Retrosynthetic analyses of (S)-coniine 1 and (R)-d-coniceine 56.
The spectroscopic data for (S)-coniine hydrochloride 1$HCl were
found to be in excellent agreement with those previously reported
in the literature {mp 207e209 ꢁC; lit.33 mp 214e216 ꢁC; ½a 2D3
þ9.2
ꢂ
(c 0.3 in EtOH); lit.34
½
a 2D3
ꢂ
þ9.4 (c 0.3 in EtOH)}.
Fig. 4. The structures of stelletamides AeC 63e65, incorporating a 1-(amidomethyl)-
octahydroindolizine heterocyclic core.
Scheme 10. Reagents and conditions: (i) DIBAL-H, THF, 0 ꢁC to rt, 6 h; (ii) (COCl)2,
DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC to rt; (iii) [Ph3PMe]þ[Br]ꢀ, KOtBu, THF, 0 ꢁC to rt, 16 h; (iv)
Pd(OH)2/C (20% wt), H2 (1 atm), MeOH, rt, 48 h then HCl.
Initial investigations towards the alkylation of ester 49
employed 2.0 equiv of LiTMP and 3.0 equiv of methyl bromoacetate,
which gave 66 in 90:10 dr (70% conversion). Purification of the
crude reaction mixture gave an inseparable 77:23 mixture of 66
(98:2 dr) and starting material 49, respectively. The stereochemical
outcome of the alkylation reaction was initially assigned by analogy
For the synthesis of (R)-d-coniceine 56, chain extension of al-
dehyde 58 via a Wittig reaction with (methoxymethyl)triphenyl-
phosphonium bromide gave enol ether 61 as a 52:48 mixture of
to previous alkylations of
b
-amino enolates.15,36 Unfortunately,
geometric isomers. Hydrolysis of this mixture gave
hyde 59 in 81% yield (from 58), which upon treatment with
Pearlman’s catalyst under 1 atm of H2 gave (R)- -coniceine 56,
which was isolated as the corresponding hydrochloride salt in 94%
yield (Scheme 11).
g
-amino alde-
attempts to improve the reaction conversion by employing alter-
native bases was not successful: attempted alkylation of 49 upon
treatment with 1.5 equiv of LiHMDS and 2.0 equiv of methyl bro-
moacetate resulted in 69% conversion to 66 (86:14 dr), whereas
treatment of 49 with 2.0 equiv of LDA and 3.0 equiv of methyl
bromoacetate led to improved conversion, but with a decrease in
diastereoselectivity giving 66 in 80:20 dr (Scheme 12).
d
Scheme 11. Reagents and conditions: (i) [Ph3PCH2OMe]þ[Br]ꢀ, KOtBu, THF, 0 ꢁC to rt,
16 h; (ii) CH2Cl2/HCO2H (v/v 4:1), rt, 16 h; (iii) Pd(OH)2/C (20% wt), H2 (1 atm), MeOH,
rt, 48 h then HCl.
Scheme 12. Reagents and conditions: (i) BuLi, HTMP, BrCH2CO2Me, THF, ꢀ78 ꢁC to rt,
16 h; (ii) LiHMDS, BrCH2CO2Me, THF, ꢀ78 ꢁC to rt, 4 h; (iii) BuLi, iPr2NH, BrCH2CO2Me,
THF, ꢀ78 ꢁC to rt, 16 h.

9980
S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
Treating the 77:23 mixture of 66 (98:2 dr) and 49, respectively,
under hydrogenolysis conditions led to successful debenzylation of
66, and also partial cyclisation of secondary amino ester 67 to give
hexahydroindolizin-3-one 68.37 Complete cyclisation of 67 to 68
was achieved by heating the crude product mixture in CHCl3 for
16 h.38 Hexahydroindolizin-3-one 68 was duly obtained as a single
diastereoisomer (>99:1 dr) in 53% yield (from 49) after chro-
matographic purification (Scheme 13). The relative configuration
within 68 was then confirmed by 1H NMR NOE analysis, which
showed strong reciprocal enhancements between the C(1)H and
C(8a)H protons. With 68 in hand, it was predicted that reduction
with LiAlH4 would generate the corresponding 1-(hydroxymethyl)-
octahydroindolizine 62. Thus, tandem reduction of the amide and
ester groups within 68 with LiAlH4 gave (R,R)-1-(hydroxymethyl)-
octahydroindolizine 62 in 95% yield and >99:1 dr (Scheme 13).
t
Scheme 14. Reagents and conditions: (i) BuLi, HTMP, BrCH2CO2 Bu, THF, ꢀ78 ꢁC to rt,
16 h; (ii) 1.35 M HCl in MeOH, 60 ꢁC, 16 h; (iii) Pd(OH)2/C, H2 (1 atm), MeOH, rt, 24 h;
(iv) LiAlH4, THF, reflux, 48 h.
LiAlH4 gave 76 in quantitative yield and >99:1 dr, and conversion to
the p-nitrobenzoate derivative 77 produced crystals suitable for X-
ray diffraction analysis (Scheme 15). These crystallographic data
(Fig. 5) unambiguously established the relative configuration
within 77 (and also those within 62, 66e71, and 73e76), with the
absolute configurations assigned relative to the known diaster-
eofacial selectivity observed upon conjugate addition of an enan-
tiopure lithium amide.11
Scheme 13. Reagents and conditions: (i) Pd(OH)2/C, H2 (1 atm), MeOH, rt, 48 h;
(ii) CHCl3, reflux, 16 h; (iii) LiAlH4, THF, reflux, 16 h. [a77:23 mixture of 66 (98:2 dr)
and 49].
Both
diastereoisomers
of
1-(hydroxymethyl)octahy-
droindolizine have previously been reported,39 although some
discrepancies exist between the various spectroscopic data for
these compounds in the literature. We therefore sought to un-
ambiguously clarify these apparent discrepancies by producing
several derivatives of 62 (and the corresponding epimer) for
attempted recrystallisation and analysis by X-ray diffraction. Upon
scale-up an optimized procedure for the preparation of 62 was
developed: alkylation of 49 with tert-butyl bromoacetate gave 69 in
quantitative conversion and 90:10 dr. Subsequent trans-
esterification of 69 upon treatment with HCl in MeOH gave 70,
which upon deprotection of the N-benzyl group gave hexahy-
droindolizin-3-one 71 in >99:1 dr and 66% overall yield (three
steps). Reduction of 71 with LiAlH4 then gave 62 in quantitative
yield and >99:1 dr; this synthetic sequence was readily achieved
on a >1 g scale (Scheme 14).
Unfortunately all attempts to crystallise derivatives of 62 for
single crystal X-ray diffraction analysis were unsuccessful. How-
ever, we were able to obtain a sample of the epimeric 1-(hydrox-
ymethyl)octahydroindolizine 76 via an alternative procedure: it
was observed that alkylation of 72 (prepared previously as part of
our synthetic endeavours towards the Sedum alkaloids8h) with
methyl bromoacetate proceeded with complementary diaster-
eoselectivity to the alkylations of 49, giving an 85:15 mixture of
syn-73 and anti-74, respectively, which was isolated in 74% com-
bined yield. Treating this mixture under standard hydrogenolysis
conditions gave, after chromatographic purification, anti-75 as
a single diastereoisomer (>99:1 dr) in 78% isolated yield;40 the
spectroscopic data for 75 were clearly distinct from those of the
epimeric hexahydroindolizin-3-one 71. Treatment of 75 with
Scheme 15. Reagents and conditions: (i) NaHMDS, THF, ꢀ78 ꢁC, 30 min then
BrCH2CO2Me, ꢀ78 ꢁC to rt, 16 h; (ii) Pd(OH)2/C (50% wt), H2 (1 atm), MeOH, rt, 16 h
then NaHCO3 (satd, aq); (iii) LiAlH4, 60 ꢁC, THF, 3 days; (iv) p-NO2C6H4COCl, CH2Cl2,
Et3N, rt, 20 h. [Ar¼p-NO2C6H4].
Whilst our data are unambiguous, agree with those of Martin39e
and Pandey,39c and are broadly consistent with those of Nagao,39a it
appears that Hoffmann and Pete,39d,g have misassigned the config-
uration within their 1-(hydroxymethyl)octahydroindolizidine
product since their data are not consistent with any stereoisomer
(Table 1). Although the discrepancy in the values of the specific ro-
tations for 76 remains unexplained, the stereochemical assignments
for both our samples of (ꢀ)-(R,R)-62 and (þ)-(1S,8aR)-76 are secure.
3. Conclusion
In conclusion, a one-pot ring-closure with concomitant N-
debenzylation protocol has been developed for the synthesis of an
enantiopure piperidine scaffold. The conjugate addition of an
enantiopure lithium amide to a z-hydroxy-a,b-unsaturated ester,

S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
9981
Furthermore,
a
sample of (1S,8aR)-1-(hydroxymethyl)octahy-
droindolizine was also produced by a complementary procedure;
X-ray diffraction analysis of the corresponding p-nitrobenzoate
derivative unambiguously clarified the existing literature discrep-
ancies between the spectroscopic data for both these 1-(hydrox-
ymethyl)octahydroindolizines.
4. Experimental
4.1. General experimental
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 et al.39 Water was
purified by an ElixÒ UV-10 system. All other reagents were used as
supplied (analytical or HPLC grade) without prior purification. Or-
ganic 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.
Elementalanalyses were recordedbythe microanalysis service of
the Inorganic Chemistry Laboratory, University of Oxford, UK.
Melting points were recorded on a Gallenkamp Hot Stage apparatus
and are uncorrected. Optical rotations were recorded on a Per-
kineElmer 241 polarimeter with a water-jacketed 10 cm cell. Spe-
cific rotations arereported in 10ꢀ1 deg cm2 gꢀ1 and concentrationsin
g/100 mL. IR spectra were recorded on a Bruker Tensor 27 FT-IR
spectrometer as either a thin film on NaCl plates (film) or a KBr
Fig. 5. Chem3D representation of the X-ray crystal structure of 77 (selected H atoms
are omitted for clarity).
followed by heating a solution of the corresponding z-hydroxy-b-
amino ester in MeCN in the presence of I2, PPh3 and imidazole,
promoted cyclisation and in situ N-debenzylation to give tert-butyl
(R)-(N-benzylpiperidin-20-yl)acetate in 75% isolated yield (in three
steps and 35% overall yield from commercially available
d-valer-
olactone). Subsequently, the total asymmetric syntheses of (S)-co-
niine and (R)-
d-coniceine (isolated as the corresponding
hydrochloride
salts), and (R,R)-1-(hydroxymethyl)octahy-
droindolizine (the bicyclic core of stellettamides AeC) were ach-
ieved via elaboration of this enantiopure piperidine template.
Table 1
Spectroscopic data for 62 and 76
Authors
Pandeya
Davies
Davies
Martin
Nagao
Hoffmann and Peteb
N
N
N
N
N
N
Structure
OH
H
O
H
O
H
O
H
O
OH
(S,S)
?
Configuration
Specific Rotation Racemic
(RS,RS)-62
(R,R)-62
(1S,8aR)-76
(1RS,8aSR)-76
Racemic
CD3CN
(1R,8aS)-76
½
a 2D3
ꢂ
ꢀ35.8 (c 0.5 in EtOH) ½a D23
ꢂ
þ27.4 (c 1.0 in EtOH)
½
a 2D2
ꢂ
ꢀ53.4 (c 1.2 in EtOH) ½a D21
ꢂ ꢀ82.1 (c 1.0 in EtOH)
NMR solvent
CDCl3
CDCl3
CDCl3
CD3CN
CDCl3
CDCl3
1H NMR data
0.95e2.55 (12H) 1.13e1.37 (2H)
1.40e1.69 (3H)
1.10e1.32 (2H) 1.14e1.26 (2H) 1.13e1.20 (2H)
1.40e1.49 (1H) 1.35e1.65 (4H) 1.33e1.61 (4H)
1.50e1.65 (3H) 1.71e1.89 (4H) 1.71e1.87 (4H)
1.72e1.82 (1H) 1.91e1.98 (1H) 1.90e1.96 (1H)
1.84e2.08 (4H) 2.05 (1H)
2.15e2.20 (1H) 2.45 (OH)
1.05e2.36 (12H)
0.94e2.29 (8H)
1.74e1.87 (4H)
1.90e2.13 (3H)
3.05e3.40 (2H)
3.46 (1H)
3.86 (1H)
2.36e2.69 (4H)
3.01e3.16 (1H)
3.21e3.42 (1H)
3.58e3.68 (2H)
4.51 (1H)
2.95e3.30 (3H)
3.33e3.65 (2H)
2.05 (1H)
2.60 (1H)
2.86e2.92 (1H) 2.88e2.91 (1H)
2.80e3.38 (2HþOH)
2.26 (OH)
3.63 (2H)
3.95 (OH)
2.99e3.10 (2H) 2.94e3.02 (1H) 2.97 (1H)
3.56e3.65 (2H) 3.41e3.51 (2H) 3.41e3.49 (2H)
13C NMR data
24.2a
25.6
26.9
29.5
41.2
53.3
53.8
64.2a
64.7
39c
24.1
25.3
25.4
26.7
41.0
53.6
53.9
64.6
66.2
24.3
25.2
25.3
30.5
46.1
53.4
53.9
64.9
67.3
24.7
25.7
25.8
30.9
46.7
53.3
53.6
64.3
67.6
25.2
26.1
26.3
31.2
47.2
53.8
54.1
64.7
68.2
39e
24.3
25.2
25.4
30.4
46.1
53.1
53.4
64.6
67.4
39a
24.3
25.2
25.4
30.4
46.1
53.1
53.4
64.6
67.4
39d
Ref.
a
The authors have kindly confirmed that there is a peak missing at 24.15 ppm in their reported 13C NMR data and that the value of ‘54.17 ppm’ was reported in error. The
corrected values, as supplied by Pandey et al., are shown here.
b
The authors are confident (personal communication, N. Hoffmann) that the (1S)-configuration for their compound is correct, but the relative configuration is probably
erroneous. However, their data do not support any stereochemical assignment.

9982
S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
disc (KBr), as stated. 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 in-
strument fitted with a Scientific Glass Instruments BPX5 column
(15 mꢃ0.25 mm) using amyl acetate as a lock mass.
(30 mL), then dried and concentrated in vacuo to give 23 (96:4 dr
[(E)/(Z)]). Purification via flash column chromatography (eluent
30e40 ꢁC petrol:Et2O, 2:1) gave 23 as a colourless oil (3.78 g, 62%,
>99:1 dr [(E)/(Z)]);41 dH (400 MHz, CDCl3) 1.48 (9H, s, CMe3),
1.55e1.65 (4H, m, C(5)H2, C(6)H2), 2.18e2.25 (2H, app dq, J 6.9, 1.4,
C(4)H2), 3.66 (2H, t, J 6.6, C(7)H2), 5.75 (1H, d, J 15.6, C(2)H), 6.85
(1H, dt, J 15.6, 6.9, C(3)H).
4.2.3. tert-Butyl (E)-8-hydroxyoct-2-enoate 24.
H
O
t
4.2. General procedure: lithium amide conjugate addition
u
B
CO2
BuLi was added dropwise to a stirred solution of the requisite
BuLi (3.89 mL, 9.72 mmol) was added dropwise to a solution of tert-
butyl diethylphosphonoacetate (2.43 g, 8.76 mmol) in THF (15 mL)
at ꢀ78 ꢁC. The resultant solution was stirred for 30 min at ꢀ78 ꢁC
then a solution of 21 (1.00 g, 8.76 mmol) in THF (5 mL) at ꢀ78 ꢁC
was added via cannula followed by the dropwise addition of DIBAL-
H (1.0 M in THF, 8.58 mL, 8.58 mmol). The reaction mixture was
allowed to warm to rt over 16 h, then satd aq sodium potassium
tartrate (5 mL) was added. The reaction mixture was then parti-
tioned between EtOAc (30 mL) and 0.5 M aq HCl (30 mL). The or-
ganic layer was washed with satd aq K2CO3 (30 mL) and brine
(30 mL), then dried and concentrated in vacuo to give 24 (92:8 dr
[(E)/(Z)]). Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 1:0; increased to 30e40 ꢁC petrol/Et2O, 2:1)
gave 24 as a colourless oil (500 mg, 23%, 85:15 dr [(E)/(Z)]); nmax
(film) 3413 (OeH), 1715 (C]O), 1652 (C]C); dH (400 MHz, CDCl3)
1.36e1.53 (4H, m, C(5)H2, C(6)H2), 1.48 (9H, s, CMe3), 1.54e1.62 (2H,
m, C(7)H2), 2.15e2.22 (2H, app dq, J 6.9, 1.3, C(4)H2), 3.65 (2H, t, J
6.6, C(8)H2), 5.74 (1H, d, J 15.5, C(2)H), 6.85 (1H, dt, J 15.5, 6.9, C(3)
H); dC (100 MHz, CDCl3) 25.3, 27.9 (C(5), C(6)), 28.1 (CMe3), 32.0
(C(4)), 32.5 (C(7)), 62.8 (C(8)), 80.1 (CMe3), 123.1 (C(2)), 147.8 (C(3)),
166.2 (C(1)); m/z (CIþ) 232 ([MþNH4]þ, 100%); HRMS (CIþ)
C12H26NO3þ ([MþNH4]þ) requires 232.1907; found 232.1920.
amine in the THF at ꢀ78 ꢁC. After 30 min, a solution of the requisite
a,b-unsaturated ester in THF was added via cannula. The reaction
mixture was stirred at ꢀ78 ꢁC for 2 h and then satd aq NH4Cl was
added. The resultant mixture was concentrated in vacuo and
extracted with three portions of Et2O. The combined organic ex-
tracts were dried and concentrated in vacuo. The residue was dis-
solved in CH2Cl2, the resultant solution was washed with 10% aq
citric acid, satd aq NaHCO3 and brine, then dried and concentrated
in vacuo.
4.2.1. tert-Butyl (E)-6-hydroxyhex-2-enoate 22.
H
O
t
u
B
CO2
BuLi (45.5 mL, 113.3 mmol) was added dropwise to a solution of
tert-butyl diethylphosphonoacetate (28.3 g, 112 mmol) in THF
(50 mL) at ꢀ78 ꢁC. The resultant solution was stirred for 30 min at
ꢀ78 ꢁC then a solution of 19 (8.78 g, 102 mmol) in THF (25 mL) at
ꢀ78 ꢁC was added via cannula followed by the dropwise addition of
DIBAL-H (1.0 M in THF, 100 mL, 100 mmol). The reaction mixture
was allowed to warm to rt over 16 h, then satd aq sodium potas-
sium tartrate (5 mL) was added. The reaction mixture was parti-
tioned between EtOAc (30 mL) and 0.5 M aq HCl (30 mL). The
organic layer was washed with satd aq K2CO3 (30 mL) and brine
(30 mL), then dried and concentrated in vacuo to give 22 (98:2 dr
[(E)/(Z)]). Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 2:1) gave 22 as a colourless oil (2.67 g, 14%,
>99:1 dr [(E)/(Z)]);25 nmax (film) 3428 (OeH),1715 (C]O),1653 (C]
C); dH (400 MHz, CDCl3) 1.48 (9H, s, CMe3), 1.69e1.76 (2H, m, C(5)
H2), 2.24e2.31 (2H, app dq, J 6.9, 1.3, C(4)H2), 3.67 (2H, dt, J 6.6, 1.3,
C(6)H2), 5.74 (1H, d, J 15.2, C(2)H), 6.87 (1H, dt, J 15.2, 6.9, C(3)H); dC
(100 MHz, CDCl3) 28.1 (CMe3), 28.3 (C(5)), 31.0 (C(4)), 62.0 (C(6)),
82.5 (CMe3), 123.5 (C(2)), 147.0 (C(3)), 173.1 (C(1)); m/z (CIþ) 187
([MþH]þ,100%); HRMS (CIþ) C10H19O3þ ([MþH]þ) requires 187.1329;
found 187.1335.
4.2.4. tert-Butyl (E)-6-oxohex-2-enoate 25.
O
t
u
B
CO2
IBX (2.26 g, 8.06 mmol) was added to a solution of 22 (500 mg,
0.269 mmol, >99:1 dr [(E)/(Z)]) in DMSO (10 mL) and the resultant
mixture was stirred at rt for 16 h. Et2O (50 mL) was then added and
the organic layer was washed with H2O (4ꢃ40 mL). The organic
layer was then dried and concentrated in vacuo to give 25 as
a colourless oil (494 mg, quant, >99:1 dr [(E)/(Z)]);25 dH (400 MHz,
CDCl3) 1.48 (9H, s, CMe3), 2.48e2.54 (2H, app q, J 6.9, C(4)H2), 2.63
(2H, dt, J 6.9, 0.9, C(5)H2), 5.78 (1H, dt, J 15.7, 1.1, C(2)H), 6.84 (1H, dt,
J 15.7, 6.9, C(3)H), 9.80 (1H, app s, C(6)H).
4.2.2. tert-Butyl (E)-7-hydroxyhept-2-enoate 23.
4.2.5. tert-Butyl (E)-7-oxohept-2-enoate 26.
H
O
O
t
t
u
B
CO2
u
B
CO2
BuLi (13.6 mL, 34.0 mmol) was added dropwise to a solution of tert-
butyl diethylphosphonoacetate (8.49 g, 33.7 mmol) in THF (20 mL)
at ꢀ78 ꢁC. The resultant solution was stirred for 30 min at ꢀ78 ꢁC
then a solution of 20 (3.06 g, 30.6 mmol) in THF (10 mL) at ꢀ78 ꢁC
was added via cannula followed by the dropwise addition of DIBAL-
H (1.0 M in THF, 30.0 mL, 30.0 mmol). The reaction mixture was
allowed to warm to rt over 16 h, then satd aq sodium potassium
tartrate (5 mL) was added. The reaction mixture was then parti-
tioned between EtOAc (30 mL) and 0.5 M aq HCl (30 mL). The or-
ganic layer was washed with satd aq K2CO3 (30 mL) and brine
IBX (420 mg, 1.50 mmol) was added to a solution of 23 (100 mg,
0.50 mmol, >99:1 dr [(E)/(Z)]) in DMSO (2 mL) and the resultant
mixture was stirred at rt for 16 h. Et2O (15 mL) was then added and
the organic layer was washed with H2O (4ꢃ25 mL). The organic
layer was then dried and concentrated in vacuo to give 26 as
a colourless oil (99 mg, quant, >99:1 dr [(E)/(Z)]);42 dH (400 MHz,
CDCl3) 1.48 (9H, s, CMe3), 1.77e1.85 (2H, app quintet, J 7.0, C(5)H2),
2.20e2.26 (2H, app dq, J 7.0, 1.5, C(4)H2), 2.49 (2H, dt, J 7.0, 1.3, C(6)
H2), 5.77 (1H, dt, J 15.6, 1.5, C(2)H), 6.82 (1H, dt, J 15.6, 7.0, C(3)H),
9.79 (1H, t, J 1.3, C(7)H).

S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
9983
4.2.6. tert-Butyl (E)-8-oxooct-2-enoate 27.
29.8 (C(4)), 47.1 (C(6)), 58.3 (C(
a
)), 80.0 (CMe3), 123.2 (C(2)), 126.5,
128.4, 126.9 (o,m,p-Ph), 145.8 (i-Ph), 147.5 (C(3)), 166.1 (C(1)); m/z
O
þ
(ESIþ) 290 ([MþH]þ, 100%); HRMS (ESIþ) C18H28NO2 ([MþH]þ)
t
requires 290.2115; found 290.2117.
u
B
CO2
4.2.8. tert-Butyl (E,R)-7-[N-(
29.
a
-methylbenzyl)amino]hept-2-enoate
IBX (687 mg, 2.45 mmol) was added to a solution of 24 (175 mg,
0.818 mmol, 85:15 dr [(E)/(Z)]) in DMSO (5.0 mL) and the resultant
mixture was stirred at rt for 16 h. Et2O (30 mL) was then added and
the organic layer was washed with H2O (4ꢃ20 mL). The organic
layer was then dried and concentrated in vacuo to give 27 as
a colourless oil (123 mg, 71%, 85:15 dr [(E)/(Z)]); nmax (film) 1714
(C]O),1653 (C]C); dH (400 MHz, CDCl3) 1.47e1.53 (2H, m, C(5)H2),
1.48 (9H, s, CMe3), 1.61e1.70 (2H, m, C(6)H2), 2.16e2.23 (2H, m, C(4)
H2), 2.45 (2H, dt, J 7.2, 1.3, C(7)H2), 5.74 (1H, td, J 15.6, 1.5, C(2)H),
6.82 (1H, td, J 15.6, 6.9, C(3)H), 9.76 (1H, app s, C(8)H); dC (100 MHz,
CDCl3) 21.5 (C(6)), 27.5 (C(5)), 28.1 (CMe3), 31.7 (C(4)), 48.6 (C(7)),
80.1 (CMe3), 123.4 (C(2)), 147.0 (C(3)), 166.0 (C(1)), 202.2 (C(8)); m/z
(CIþ) 230 ([MþNH4]þ, 100%); HRMS (CIþ) C12H24NO3þ ([MþNH4]þ)
requires 230.1751; found 230.1748.
N
Ph
H
t
u
B
CO2
Step 1: NaBH(OAc)3 (3.31 g, 15.6 mmol) was added to a solution of
(R)-N-benzyl-N-( -methylbenzyl)amine (3.30 g, 15.6 mmol) and 26
a
(2.06 g, 10.4 mmol, >99:1 dr [(E)/(Z)]) in THF (40 mL) and the re-
sultant solution was stirred at rt for 16 h. 1.0 M aq NaOH (10 mL)
was then added and the aqueous layer was extracted with EtOAc
(40 mL). The combined organic layers were then dried and con-
centrated in vacuo. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 15:1) gave tert-butyl (E,R)-7-[N-
4.2.7. tert-Butyl
(E,R)-6-[N-(a-methylbenzyl)amino]hex-2-enoate
benzyl-N-(a-methylbenzyl)amino]hept-2-enoate as a pale yellow
28.
oil (3.22 g, 79%, >99:1 dr [(E)/(Z)]); C26H35NO2 requires C, 79.35; H,
Ph
9.0; N, 3.6%; found C, 79.2; H, 8.6; N, 3.5%; ½a D21
þ18.9 (c 1.2 in
ꢂ
CHCl3); nmax (film) 1715 (C]O); dH (400 MHz, CDCl3) 1.39 (3H, d, J
NH
6.8, C(a)Me), 1.41e1.49 (4H, m, C(5)H2, C(6)H2), 1.51 (9H, s, CMe3),
2.00e2.06 (2H, app q, J 6.9, C(4)H2), 2.31e2.40 (1H, m, C(7)HA),
2.48e2.57 (1H, m, C(7)HB), 3.51 (1H, d, J 14.0, NCHAHBPh), 3.59 (1H,
t
u
B
CO2
d, J 14.0, NCHAHBPh), 3.93 (1H, q, J 6.8, C(
C(2)H), 6.82 (1H, dt, J 15.6, 6.9, C(3)H), 7.22e7.43 (10H, m, 2ꢃPh); dC
(100 MHz, CDCl3) 14.8 (C( )Me), 25.6, 26.9 (C(5), C(6)), 28.2 (CMe3),
31.7 (C(4)), 48.7 (C(7)), 54.4 (NCH2Ph), 57.7 (C( )), 79.9 (CMe3),
122.9 (C(2)), 126.6, 127.9, 128.0, 128.1, 128.5 (o,m,p-Ph), 140.9, 143.8
(i-Ph), 148.0 (C(3)), 166.2 (C(1)); m/z (ESIþ) 394 ([MþH]þ, 100%).
Step 2: CAN (1.06 g, 1.91 mmol) was added to a solution of tert-
a)H), 5.69 (1H, d, J 15.6,
Step 1: NaBH(OAc)3 (854 mg, 4.03 mmol) was added to a solution of
(R)-N-benzyl-N-( -methylbenzyl)amine (851 mg, 4.03 mmol) and
a
a
25 (495 mg, 2.69 mmol, >99:1 dr [(E)/(Z)]) in THF (10 mL) and the
resultant solution was stirred at rt for 16 h. 1.0 M aq NaOH (10 mL)
was then added and the aqueous layer was extracted with EtOAc
(40 mL). The combined organic layers were then dried and con-
centrated in vacuo. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 15:1) gave tert-butyl (E,R)-6-[N-ben-
a
butyl (E,R)-7-[N-benzyl-N-(a-methylbenzyl)amino]hept-2-enoate
(250 mg, 0.64 mmol, >99:1 dr [(E)/(Z)]) in MeCN/H2O (v/v 5:1,
10 mL) and the resultant mixture was stirred at rt for 16 h. The
reaction mixture was then diluted with Et2O (20 mL), satd aq
NaHCO3 was added (20 mL), and stirring was continued for a fur-
ther 30 min. The aqueous layer was extracted with Et2O
(2ꢃ20 mL) and the combined organic extracts were dried and
concentrated in vacuo. Purification via flash column chromatog-
raphy (gradient elution, 0/30% Et2O in 30e40 ꢁC petrol) gave 29
zyl-N-(a-methylbenzyl)amino]hex-2-enoate as a colourless oil
(282 mg, 28%, >99:1 dr [(E)/(Z)]); C25H33NO2 requires C, 79.1; H, 8.8;
N, 3.7%; found C, 79.1; H, 8.8; N, 3.5%; ½a D23
ꢂ
þ29.9 (c 1.0 in CHCl3); nmax
(film) 1713 (C]O); dH (400 MHz, CDCl3) 1.40 (3H, d, J 6.8, C(
a
)Me),
1.50 (9H, s, CMe3), 1.54e1.63 (2H, m, C(5)H2), 2.02e2.19 (2H, app q, J
7.2, C(4)H2), 2.34e2.42 (1H, m, C(6)HA), 2.53e2.60 (1H, m, C(6)HB),
3.53 (1H, d, J 14.0, NCHAHBPh), 3.60 (1H, d, J 14.0, NCHAHBPh), 3.93
(1H, q, J 6.8, C(
7.2, C(3)H), 7.22e7.44 (10H, m, 2ꢃPh); dC (100 MHz, CDCl3) 14.9 (C(
Me), 26.0 (C(5)), 28.2 (CMe3), 29.7 (C(4)), 48.7 (C(6)), 54.5 (NCH2Ph),
57.8 (C( )), 79.9 (CMe3), 122.9 (C(2)), 126.7, 127.9, 128.0, 128.2, 128.6
a)H), 5.65 (1H, dd, J 15.6,1.2, C(2)H), 6.79 (1H, dt, J 15.6,
as a colourless oil (157 mg, 81%, >99:1 dr [(E)/(Z)]); ½a D21
þ64.8 (c
ꢂ
a)
1.0 in CHCl3); nmax (film) 3382 (NeH), 1714 (C]O), 1652 (C]C); dH
(400 MHz, CDCl3) 1.36 (3H, d, J 6.6, C(a)Me), 1.41e1.52 (4H, m, C(5)
a
H2, C(6)H2), 1.48 (9H, s, CMe3), 2.11e2.17 (2H, app q, J 6.9, C(4)H2),
2.38e2.45 (1H, m, C(7)HA), 2.47e2.49 (1H, m, C(7)HB), 3.75 (1H, q,
(2ꢃo,m,p-Ph), 140.8, 143.6 (2ꢃi-Ph), 147.9 (C(3)), 166.1 (C(1)); m/z
(ESIþ) 380 ([MþH]þ, 100%).
J 6.6, C(
H), 7.23e7.36 (5H, m, Ph); dC (100 MHz, CDCl3) 24.3 (C(
(C(5)), 28.1 (CMe3), 29.8 (C(6)), 31.8 (C(4)), 47.5 (C(7)), 58.4 (C(
a
)H), 5.72 (1H, d, J 15.6, C(2)H), 6.83 (1H, dt, J 15.6, 6.9, C(3)
)Me), 25.8
)),
Step 2: CAN (568 mg, 1.04 mmol) was added to a solution of tert-
butyl (E,R)-6-[N-benzyl-N-(a-methylbenzyl)amino]hex-2-enoate
a
a
(131 mg, 0.35 mmol, >99:1 dr [(E)/(Z)]) in MeCN/H2O (v/v 5:1,
6 mL) and the resultant mixture was stirred at rt for 16 h. The re-
action mixture was then diluted with Et2O (20 mL), satd aq NaHCO3
was added (20 mL), and stirring was continued for a further 30 min.
The aqueous layer was extracted with Et2O (2ꢃ20 mL) and the
combined organic extracts were dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution,
0/30% Et2O in 30e40 ꢁC petrol) gave 28 as a yellow oil (83 mg,
80.0 (CMe3), 123.2 (C(2)), 126.5, 128.4, 126.8 (o,m,p-Ph), 145.7 (i-
Ph), 147.6 (C(3)), 166.1 (C(1)); m/z (ESIþ) 304 ([MþH]þ, 100%);
þ
HRMS (ESIþ) C19H30NO2 ([MþH]þ) requires 304.2271; found
304.2283.
4.2.9. tert-Butyl (E,R)-8-[N-(a-methylbenzyl)amino]oct-2-enoate 30.
Ph
83%, >99:1 dr [(E)/(Z)]); ½a D23
þ39.5 (c 1.0 in CHCl3); nmax (film)
ꢂ
3375 (NeH), 1714 (C]O), 1653 (C]C); dH (400 MHz, CDCl3) 1.37
NH
(3H, d, J 6.6, C(
2.16e2.26 (2H, app q, J 6.9, C(4)H2), 2.43e2.49 (1H, m, C(6)HA),
2.43e2.49 (1H, m, C(6)HB), 3.77 (1H, q, J 6.6, C( )H), 5.74 (1H, dt, J
15.8, 1.6, C(2)H), 6.84 (1H, dt, J 15.8, 6.9, C(3)H), 7.24e7.37 (5H, m,
Ph); dC (100 MHz, CDCl3) 24.4 (C( )Me), 28.1 (CMe3), 28.7 (C(5)),
a)Me), 1.50 (9H, s, CMe3), 1.59e1.66 (2H, m, C(5)H2),
t
u
B
CO2
a
Step 1: NaBH(OAc)3 (134 mg, 0.63 mmol) was added to a solution of
(R)-N-benzyl-N-( -methylbenzyl)amine (133 mg, 0.63 mmol) and
a
a

9984
S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
27 (89 mg, 0.42 mmol, 85:15 dr [(E)/(Z)]) in THF (2 mL) and the
resultant solution was stirred at rt for 16 h. 1.0 M aq NaOH (10 mL)
was then added and the aqueous layer was extracted with EtOAc
(40 mL). The combined organic layers were then dried and con-
centrated in vacuo. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 15:1) gave tert-butyl (E,R)-8-[N-
3.73 (1H, q, J 6.7, C(
17.7 (C(
)Me), 22.8 (C(40)), 28.0 (CMe3), 30.7 (C(30)), 40.5 (C(2)), 49.3
(C(50)), 58.0 (C(20)), 60.0 (C(
)), 80.0 (CMe3), 126.8 (p-Ph), 127.6,
128.1 (o,m-Ph), 145.1 (i-Ph), 172.1 (C(1)).
a)H), 7.20e7.40 (5H, m, Ph); dC (100 MHz, CDCl3)
a
a
4.2.11. tert-Butyl (R,R)- and (20S,
peridin-20-yl]acetate 33 and 34.
a
R)-2-[N(10)-(
a-methylbenzyl)pi-
benzyl-N-(
a
-methylbenzyl)amino]oct-2-enoate as a colourless oil
(120 mg, 63%, 97:3 dr [(E)/(Z)]); ½a D20
þ19.4 (c 1.5 in CHCl3); nmax
ꢂ
(film) 1714 (C]O); dH (400 MHz, CDCl3) 1.21e1.36 (4H, m, C(5)H2,
N
Ph
N
Ph
C(6)H2), 1.39 (3H, d, J 6.8, C(a)Me), 1.42e1.48 (2H, m, C(7)H2), 1.51
(9H, s, CMe3), 2.07e2.13 (2H, app q, J 6.9, C(4)H2), 2.31e2.38 (1H, m,
C(8)HA), 2.47e2.55 (1H, m, C(8)HB), 3.52 (1H, d, J 14.0, NCHAHBPh),
t
t
u
B
u
B
CO2
CO2
33
34
3.59 (1H, d, J 14.0, NCHAHBPh), 3.93 (1H, q, J 6.8, C(
15.6, C(2)H), 6.83 (1H, dt, J 15.6, 6.9, C(3)H), 7.21e7.43 (10H, m, Ph);
dC (100 MHz, CDCl3) 14.9 (C( )Me), 26.7, 27.1, 27.8 (C(5), C(6), C(7)),
28.2 (CMe3), 32.0 (C(4)), 48.9 (C(8)), 54.4 (NCH2Ph), 57.8 (C( )), 79.9
a)H), 5.72 (1H, d, J
Method A: BuLi (0.21 mL, 0.52 mmol) was added dropwise to
a solution of 29 (157 mg, 0.520 mmol, >99:1 dr [(E)/(Z)]) in THF
(5 mL) at ꢀ78 ꢁC and the resultant mixture was stirred for 2 h at
ꢀ78 ꢁC. Satd aq NH4Cl (1 mL) was then added and the aqueous
layer was extracted with Et2O (2ꢃ5 mL). The combined organic
extracts were then dried and concentrated in vacuo to give a 50:50
mixture of 33 and 34. Purification via flash column chromatog-
raphy (eluent 30e40 ꢁC petrol/Et2O, 20:1) gave 33 as a pale yellow
oil (23 mg, 15%, >99:1 dr), and 34 as a pale yellow oil (50 mg, 32%,
>99:1 dr).
a
a
(CMe3),122.9 (C(2)),126.6,127.9,128.0,128.1,128.5 (o,m,p-Ph), 141.1,
143.9 (i-Ph), 148.0 (C(3)), 166.2 (C(1)); m/z (ESIþ) 408 ([MþH]þ,
þ
100%); HRMS (ESIþ) C27H38NO2 ([MþH]þ) requires 408.2897;
found 408.2896.
Step 2: CAN (340 mg, 0.63 mmol) was added to a solution of
tert-butyl
(E,R)-8-[N-benzyl-N-(a-methylbenzyl)amino]oct-2-
enoate (85 mg, 0.21 mmol, 97:3 dr [(E)/(Z)]) in MeCN/H2O (v/v
5:1, 3 mL) and the resultant mixture was stirred at rt for 16 h. The
reaction mixture was then diluted with Et2O (10 mL), satd aq
NaHCO3 was added (10 mL), and stirring was continued for a fur-
ther 30 min. The aqueous layer was extracted with Et2O (2ꢃ10 mL)
and the combined organic extracts were dried and concentrated in
vacuo. Purification by flash column chromatography (gradient
elution, 0/30% Et2O in 30e40 ꢁC petrol) gave 30 as a colourless
Data for 33: ½a 2D2
þ7.5 (c 1.0 in CHCl3); nmax (film) 2932 (CeH),
ꢂ
1727 (C]O); dH (400 MHz, CDCl3) 1.23e1.78 (6H, m, C(30)H2, C(40)
H2, C(50)H2), 1.35 (3H, d, J 6.5, C(
(1H, m, C(2)HA), 2.48e2.69 (3H, m, C(2)HB, C(60)H2), 3.05e3.09 (1H,
m, C(20)H), 3.82 (1H, q, J 6.5, C(
)H), 7.19e7.39 (5H, m, Ph); dC
(100 MHz, CDCl3) 20.2, 25.7, 29.0 (C(30), C(40), C(50)), 21.2 (C(
)Me),
28.0 (CMe3), 33.8 (C(2)), 43.5 (C(60)), 53.0 (C(20)), 59.0 (C(
)), 79.9
a)Me), 1.40 (9H, s, CMe3), 2.25e2.42
a
a
a
oil (55 mg, 70%, >99:1 dr [(E)/(Z)]); ½a D23
þ19.4 (c 1.5 in CHCl3);
ꢂ
(CMe3), 126.6 (p-Ph), 127.5, 128.1 (o,m-Ph), 144.5 (i-Ph), 172.4 (C(1));
m/z (ESIþ) 304 ([MþH]þ,100%); HRMS (ESIþ) C19H30NO2þ ([MþH]þ)
requires 304.2271; found 304.2283.
nmax (film) 3422 (NeH), 1714 (C]O), 1653 (C]C); dH (400 MHz,
CDCl3) 1.25e1.46 (6H, m, C(5)H2, C(6)H2, C(7)H2), 1.39 (3H, d, J 6.7,
Data for 34: ½a 2D2
ꢂ
þ31.5 (c 1.0 in CHCl3); nmax (film) 1728 (C]O);
C(
(1H, m, C(8)HA), 2.45e2.53 (1H, m, C(8)HB), 3.75 (1H, q, J 6.7, C(
H), 5.72 (1H, d, J 15.6, C(2)H), 6.83 (1H, dt, J 15.6, 6.9, C(3)H),
7.21e7.36 (5H, m, Ph); dC (100 MHz, CDCl3) 24.3 (C( )Me), 26.9,
27.9 (C(5), C(6)), 28.1 (CMe3), 29.8 (C(7)), 31.9 (C(4)), 47.7 (C(8)),
a)Me), 1.51 (9H, s, CMe3), 2.11e2.17 (2H, m, C(4)H2), 2.37e2.44
a
)
dH (400 MHz, CDCl3) 1.31 (3H, d, J 6.6, C(
a
)Me) 1.35e1.65 (5H, m,
C(30)HA, C(40)H2, C(50)H2), 1.47 (9H, s, CMe3), 1.72e1.82 (1H, m, C(30)
HB), 2.14e2.22 (1H, m, C(60)HA), 2.26e2.32 (1H, m, C(60)HB),
2.40e2.54 (2H, m, C(2)H2), 3.45e3.55 (1H, m, C(20)H), 3.67 (1H, q, J
a
58.4 (C(a)), 80.0 (CMe3), 123.0 (C(2)), 126.5, 126.8, 128.4 (o,m,p-Ph),
6.6, C(
a)H), 7.19e7.40 (5H, m, Ph); dC (100 MHz, CDCl3) 17.8 (C(a)
145.7 (i-Ph), 147.9 (C(3)), 166.1 (C(1)); m/z (ESIþ) 318 ([MþH]þ,
Me), 20.8 (C(50)), 25.9 (C(40)), 28.1 (CMe3), 30.2 (C(30)), 33.3 (C(2)),
þ
100%); HRMS (ESIþ) C20H32NO2 ([MþH]þ) requires 318.2428;
45.2 (C(60)), 52.6 (C(20)), 59.4 (C(
a)), 80.2 (CMe3), 126.5 (p-Ph), 127.3,
128.1 (o,m-Ph), 146.3 (i-Ph), 172.3 (C(1)); m/z (ESIþ) 304 ([MþH]þ,
found 318.2426.
þ
100%); HRMS (ESIþ) C19H30NO2 ([MþH]þ) requires 304.2271;
4.2.10. tert-Butyl (R,R)- and (20S,
rolidin-20-yl]acetate 31 and 32.
a
R)-2-[N(10)-(
a-methylbenzyl)pyr-
found 304.2278.
Method B: Wilkinson’s catalyst (7 mg, 0.083 mmol) was added to
a vigorously stirred solution of 78 (500 mg, 1.66 mmol, >99:1 dr) in
EtOAc (5 mL) and the resultant mixture was placed under an at-
mosphere of hydrogen (4 atm) and stirred for 12 h. The reaction
mixture was then concentrated in vacuo. Purification via flash
column chromatography (eluent pentane/Et2O, 20:1) gave 33 as
N
Ph
N
Ph
t
t
u
B
u
B
CO2
CO2
31
32
a colourless oil (462 mg, 92%, >99:1 dr); ½a D22
þ6.8 (c 1.0 in CHCl3).
ꢂ
BuLi (0.14 mL, 0.22 mmol) was added dropwise to a solution of 28
(63 mg, 0.22 mmol, >99:1 dr [(E)/(Z)]) in THF (2 mL) at ꢀ78 ꢁC and
the resultant mixture was stirred for 2 h at ꢀ78 ꢁC. Satd aq NH4Cl
(1 mL) was then added and the aqueous layer was extracted with
Et2O (2ꢃ5 mL). The combined organic extracts were then dried and
concentrated in vacuo to give a 75:25 mixture of 31 and 32. Puri-
fication via flash column chromatography (eluent 30e40 ꢁC petrol/
Et2O, 20:1) gave a 75:25 mixture of 3143 and 32 as a colourless oil
(59 mg, 93%).
4.2.12. tert-Butyl (E)-7-iodohept-2-enoate 40.
t
u
B
CO2
I
Imidazole (153 mg, 2.25 mmol), PPh3 (472 mg, 1.80 mmol) and I2
(457 mg, 1.80 mmol) were added to a solution of 23 (300 mg,
1.50 mmol, >99:1 dr [(E)/(Z)]) in PhMe/MeCN (v/v 4:1, 10 mL). The
resultant mixture was stirred for 2 h at 65 ꢁC and was then allowed
to cool to rt. The reaction mixture was diluted with Et2O (50 mL)
and was sequentially washed with satd aq Na2S2O3 (20 mL), H2O
(10 mL) and brine (10 mL), then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30e40 ꢁC
Data for mixture: m/z (ESIþ) 290 ([MþH]þ, 100%); HRMS (ESIþ)
þ
C18H28NO2 ([MþH]þ) requires 290.2115; found 290.2119.
Data for 32: dH (400 MHz, CDCl3) 1.38 (3H, d, J 6.7, C(a)Me), 1.41
(9H, s, CMe3), 1.54e1.78 (4H, m, C(30)H2, C(40)H2), 2.04 (1H, dd, J
14.3, 9.8, C(2)HA), 2.23 (1H, dd, J 14.3, 3.3, C(2)HB), 2.45e2.53 (1H,
m, C(50)HA), 2.68e2.75 (1H, m, C(50)HB), 3.24e3.31 (1H, m, C(20)H),

S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
9985
petrol/Et2O, 10:1) gave 40 as a colourless oil (435 mg, 94%, >99:1 dr
[(E)/(Z)]);44 dH (400 MHz, CDCl3) 1.49 (9H, s, CMe3), 1.52e1.62 (2H,
m, C(5)H2), 1.81e1.90 (2H, m, C(6)H2), 2.17e2.25 (2H, m, C(4)H2),
3.20 (2H, t, J 6.9, C(7)H2), 5.76 (1H, dt, J 15.7, 1.7, C(2)H), 6.83 (1H, dt,
J 15.7, 6.8, C(3)H).
(1H, d, J 14.4, NCHAHBPh), 3.77 (1H, d, J 14.4, NCHAHBPh), 4.10 (1H, q,
J 6.9, C( )H), 7.18e7.36 (10H, m, Ph).
a
4.2.16. tert-Butyl (R,R)-3-[N-benzyl-N-(a-methylbenzyl)amino]-7-
bromoheptanoate 45.
Ph
4.2.13. tert-Butyl (E)-7-bromohept-2-enoate 41.
Ph
N
t
u
B
CO2
t
u
B
CO2
r
B
r
B
Following the general procedure, 41 (75 mg, 0.286 mmol, >99:1 dr
[(E)/(Z)]), (R)-N-benzyl-N-( -methylbenzyl)amine (124 mg,
a
Polystyrene supported PPh3 (1.0 mmol/g, 500 mg, 0.50 mmol)
was added to a solution of 23 (50 mg, 0.50 mmol, >99:1 dr [(E)/(Z)])
in CH2Cl2 (5 mL) at 0 ꢁC. A solution of CBr4 (166 mg, 0.50 mmol) in
CH2Cl2 (5 mL) was then added and the reaction mixture was stirred
at rt for 1 h then filtered, washed with H2O (10 mL), dried, and
concentrated in vacuo. Purification via flash column chromatogra-
phy (eluent 30e40 ꢁC petrol/Et2O, 50:1) gave 41 as a colourless oil
(121 mg, 92%, >99:1 dr [(E)/(Z)]);22a dH (400 MHz, CDCl3) 1.49 (9H,
s, CMe3), 1.57e1.66 (2H, m, C(5)H2), 1.85e1.93 (2H, m, C(6)H2),
2.18e2.25 (2H, m, C(4)H2), 3.42 (2H, t, J 6.7, C(7)H2), 5.76 (1H, dt, J
15.6, 1.5, C(2)H), 6.84 (1H, dt, J 15.6, 6.9, C(3)H).
0.456 mmol) and BuLi (0.28 mL, 0.44 mmol) in THF (4 mL) were
reacted to give, after purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 30:1), a 56:44 mixture of 44 (>99:1
dr) and 45 (>99:1 dr), respectively, as a colourless oil (89 mg).45
Data for mixture: m/z (ESIþ) 394 ([MþH]þ for 44, 100%), 476
([MþH]þ for 45, 20%).
Data for 45: dH (400 MHz, CDCl3) 1.00e1.85 (6H, m, C(4)H2, C(5)
H2, C(6)H2), 1.36 (3H, d, J 7.0, C(a)Me), 1.40 (9H, s, CMe3), 1.89 (1H,
dd, J 14.7, 9.6, C(2)HA), 1.99 (1H, dd, J 14.7, 3.2, C(2)HB), 3.23e3.35
(1H, m, C(3)H), 3.40 (2H, app t, J 6.4, C(7)H2), 3.51 (1H, d, J 15.0,
NCHAHBPh), 3.78e3.83 (1H, m, NCHAHBPh), 3.84 (1H, q, J 7.0, C(
7.18e7.39 (10H, m, Ph); dC (100 MHz, CDCl3) 20.6 (C( )Me), 28.1
(CMe3), 25.5, 32.4, 32.6 (C(4), C(5), C(6)), 34.0 (C(7)), 37.5 (C(2)), 50.1
(NCH2Ph), 53.7 (C(3)), 58.5 (C( )), 80.0 (CMe3), 126.5, 127.0 (p-Ph),
128.0, 128.1, 128.3, 128.9 (o,m-Ph), 141.9, 144.7 (i-Ph), 172.1 (C(1)).
a)H),
a
4.2.14. tert-Butyl (E)-7-chlorohept-2-enoate 42.
a
t
u
B
CO2
l
C
4.2.17. tert-Butyl (R,R)-3-[N-benzyl-N-(
a
-methylbenzyl)amino]-7-
chloroheptanoate 46.
Ph
SOCl2 (63 mg, 0.53 mmol) was added to pyridine (0.5 mL) at rt
then 23 (75 mg, 0.38 mmol, >99:1 dr [(E)/(Z)]) was added and the
resultant mixture was heated at 50 ꢁC for 6 h. The reaction mixture
was then allowed to cool to rt, CH2Cl2 (20 mL) and satd aq K2CO3
(10 mL) were added, and the aqueous layer was extracted with
CH2Cl2 (20 mL). The combined organic extracts were sequentially
washed with satd aq CuSO4 (2ꢃ15 mL) and H2O (15 mL), then dried
and concentrated in vacuo. Purification via flash column chroma-
tography (eluent 30e40 ꢁC petrol/Et2O, 50:1) gave 42 as a colour-
less oil (73 mg, 88%, >99:1 dr [(E)/(Z)]);12a dH (400 MHz, CDCl3) 1.49
(9H, s, CMe3), 1.57e1.67 (2H, m, C(5)H2), 1.72e1.85 (2H, m, C(6)H2),
2.18e2.25 (2H, m, C(4)H2), 3.54 (2H, t, J 6.5, C(7)H2), 5.75 (1H, dt, J
15.6, 1.6, C(2)H), 6.83 (1H, dt, J 15.6, 6.9, C(3)H).
Ph
N
t
u
CO2 B
l
C
Following the general procedure, 42 (80 mg, 0.366 mmol, >99:1 dr
[(E)/(Z)]), (R)-N-benzyl-N-( -methylbenzyl)amine (124 mg,
a
0.586 mmol) and BuLi (0.36 mL, 0.57 mmol) in THF (4.0 mL) were
reacted to give 46 in >99:1 dr. Purification via flash column chro-
matography (eluent 30e40 ꢁC petrol/Et2O, 25:1) gave 46 as a col-
ourless oil (120 mg, 76%, >99:1 dr); ½a D21
þ7.2 (c 1.0 in CHCl3); nmax
ꢂ
(film) 1724 (C]O); dH (400 MHz, CDCl3) 1.24e1.81 (6H, m, C(4)H2,
C(5)H2, C(6)H2), 1.33 (3H, d, J 7.0, C(a)Me), 1.41 (9H, s, CMe3), 1.89
(1H, dd, J 14.7, 9.6, C(2)HA), 1.99 (1H, dd, J 14.7, 3.2, C(2)HB),
3.23e3.35 (1H, m, C(3)H), 3.49e3.53 (1H, m, NCHAHBPh), 3.52 (2H,
4.2.15. tert-Butyl (R,R,R)-2-[N-benzyl-N-(a-methylbenzyl)amino]cy-
clohexane-1-carboxylate 44.
t, J 6.5, C(7)H2), 3.81 (1H, d, J 14.9, NCHAHBPh), 3.84 (1H, q, J 7.0, C(
H), 7.23e7.47 (10H, m, Ph); dC (100 MHz, CDCl3) 20.6 (C( )Me), 28.1
(CMe3), 24.1, 32.4, 32.7 (C(4), C(5), C(6)), 37.5 (C(2)), 45.1 (C(7)), 50.1
(NCH2Ph), 53.7 (C(3)), 58.5 (C( )), 80.0 (CMe3), 126, 127.0 (p-Ph),
a)
a
Ph
Ph
N
a
t
u
B
CO2
127.9, 128.1, 128.2, 128.3 (o,m-Ph), 141.9, 143.0 (i-Ph), 172.1 (C(1));
þ
m/z (ESIþ) 430 ([M(35Cl)þH]þ, 100%); HRMS (ESIþ) C26H3735ClNO2
([M(35Cl)þH]þ) requires 430.2507; found 430.2507.
4.2.18. tert-Butyl (R,R)-3-[N-benzyl-N-(
a
-methylbenzyl)amino]-7-
hydroxyheptanoate 47.
Following the general procedure, 40 (150 mg, 0.484 mmol, >99:1
dr [(E)/(Z)]), (R)-N-benzyl-N-( -methylbenzyl)amine (102 mg,
Ph
a
0.484 mmol) and BuLi (0.30 mL, 0.48 mmol) in THF (5 mL) were
reacted to give, after purification via flash column chromatography
(eluent 30e40 ꢁC petrol/Et2O, 50:1), 44 as a pale yellow oil (110 mg,
Ph
N
t
u
B
CO2
58%, >99:1 dr);52
½
a 2D0
ꢂ
ꢀ21.6 (c 0.6 in CHCl3); {lit.45
½
a 2D5
ꢂ
ꢀ29.6 (c
H
O
1.0 in CHCl3)}; dH (400 MHz, CDCl3) 1.25e1.85 (8H, m, C(3)H2, C(4)
H2, C(5)H2, C(6)H2), 1.40 (3H, d, J 6.9, C(
2.24 (1H, td, J 11.5, 3.7, C(2)H), 3.06 (1H, td, J 11.5, 3.3, C(1)H), 3.72
a)Me), 1.49 (9H, s, CMe3),
Following the general procedure, 23 (243 mg, 1.22 mmol, >99:1 dr
[(E)/(Z)]), (R)-N-benzyl-N-( -methylbenzyl)amine (667 mg,
a

9986
S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
3.16 mmol) and BuLi (1.24 mL, 3.11 mmol) in THF (20 mL) were
reacted to give 47 in >99:1 dr. Purification via flash column chro-
matography (eluent 30e40 ꢁC petrol/Et2O, 1:0; increased to
30e40 ꢁC petrol/Et2O, 2:1) gave 47 as a colourless oil (330 mg, 66%,
7.7, Ar); dC (100 MHz, CDCl3) 20.6 (C(
30.4 (C(4), C(5), C(6)), 37.5 (C(2)), 50.1 (NCH2Ph), 53.0 (C(3)), 55.2
(OMe), 57.3 (C( )), 62.6 (C(7)), 80.2 (CMe3), 113.5 (Ar), 126.7 (p-Ph),
128.2, 128.3, 128.9 (o,m-Ph, Ar), 134.8, 141.7 (i-Ph, Ar), 158.6 (Ar),
172.5 (C(1)); m/z (ESIþ) 442 ([MþH]þ, 100%); HRMS (ESIþ)
C27H40NO4þ ([MþH]þ) requires 442.2952; found 442.2950.
a)Me), 28.1 (CMe3), 29.7, 30.0,
a
>99:1 dr); ½a 2D1
ꢂ
þ9.5 (c 1.1 in CHCl3); {lit.25 for enantiomer ½a 2D5
ꢂ
ꢀ12.6 (c 1.2 in CHCl3)}; dH (400 MHz, CDCl3) 1.21e1.69 (6H, m, C(4)
H2, C(5)H2, C(6)H2), 1.33 (3H, d, J 7.0, C(a)Me), 1.40 (9H, s, CMe3), 1.88
(1H, dd, J 14.6, 9.5, C(2)HA), 1.97 (1H, dd, J 14.6, 3.4, C(2)HB),
3.27e3.34 (1H, m, C(3)H), 3.49 (1H, d, J 14.9, NCHAHBPh), 3.61 (2H, t,
4.2.21. tert-Butyl
ybenzyl)amino]-7-iodoheptanoate 53.
(3R,aR)-3-[N-benzyl-N-(a-methyl-p-methox-
J 6.4, C(7)H2), 3.79 (1H, d, J 14.9, NCHAHBPh), 3.82 (1H, q, J 7.0, C(
H), 7.22e7.45 (10H, m, Ph).
a)
Ph
PMP
N
4.2.19. tert-Butyl (R,R)-3-[N-benzyl-N-(a-methylbenzyl)amino]-7-
t
u
B
CO2
iodoheptanoate 48.
Ph
I
Ph
N
I2 (860 mg, 3.39 mmol) was added to a stirred solution of imidazole
(231 mg, 3.39 mmol), PPh3 (890 mg, 3.39 mmol) and 52 (300 mg,
0.679 mmol, >99:1 dr) in PhMe/MeCN (v/v 4:1, 25 mL) and the
resultant solution was stirred at 65 ꢁC for 16 h. The reaction mixture
was then allowed to cool to rt, diluted with Et2O (10 mL), then
sequentially washed with satd aq Na2S2O3 (15 mL), H2O (15 mL)
and brine (15 mL), before being dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution,
0/4% Et2O in 30e40 ꢁC petrol) gave 53 as a pale yellow oil
t
u
B
CO2
I
I2 (232 mg, 0.91 mmol) was added to a stirred solution of imidazole
(62 mg, 0.91 mmol), PPh3 (239 mg, 0.91 mmol) and 47 (75 mg,
0.18 mmol, >99:1 dr) in PhMe/MeCN (v/v 4:1, 7.5 mL) and the re-
sultant solution was stirred at 65 ꢁC for 16 h. The reaction mixture
was then allowed to cool to rt, diluted with Et2O (10 mL), then
sequentially washed with satd aq Na2S2O3 (15 mL), H2O (15 mL)
and brine (15 mL), then dried and concentrated in vacuo. Purifi-
cation via flash column chromatography (gradient elution, 0/4%
Et2O in 30e40 ꢁC petrol) gave 48 as a pale yellow oil (85 mg, 85%,
(340 mg, 91%, >99:1 dr); ½a D23
ꢂ
þ8.5 (c 1.0 in CHCl3); nmax (film) 1723
(C]O); dH (400 MHz, CDCl3) 1.32 (3H, d, J 7.0, C(
a
)Me), 1.34e1.51
(3H, m, C(4)H2, C(5)HA),1.42 (9H, s, CMe3),1.68e1.80 (3H, m, C(5)HB,
C(6)H2), 1.87 (1H, dd, J 14.7, 9.8, C(2)HA), 1.98 (1H, dd, J 14.7, 3.0, C(2)
HB), 3.15e3.21 (2H, m, C(7)H2), 3.25e3.32 (1H, m, C(3)H), 3.47 (1H,
d, J 15.0, NCHAHBPh), 3.75e3.82 (2H, m, NCHAHBPh, C(a)H), 3.81
(3H, s, OMe), 6.86 (2H, d, J 7.9, Ar), 7.22e7.28 (3H, m, Ph), 7.35e7.38
(2H, m, Ph), 7.43 (2H, d, J 7.9, Ar); dC (100 MHz, CDCl3) 7.2 (C(7)), 20.8
>99:1 dr); ½a 2D3
ꢂ
þ1.49 (c 1.6 in CHCl3); nmax (film) 1724 (C]O); dH
(500 MHz, CDCl3) 1.32e1.56 (3H, m, C(4)H2, C(5)HA), 1.37 (3H, d, J
7.0, C(a)Me), 1.43 (9H, s, CMe3), 1.69e1.79 (3H, m, C(5)HB, C(6)H2),
(C(a)Me), 27.9 (C(4)), 28.1 (CMe3), 32.4 (C(5)), 33.3 (C(6)), 37.6
1.91 (1H, dd, J 14.6, 9.7, C(2)HA), 2.01 (1H, dd, J 14.6, 3.1, C(2)HB),
3.15e3.20 (2H, m, C(7)H2), 3.28e3.34 (1H, m, C(3)H), 3.53 (1H, d, J
15.0, NCHAHBPh), 3.82 (1H, d, J 15.0, NCHAHBPh), 3.82 (1H, q, J 7.0,
(C(2)), 50.0 (NCH2Ph), 53.4 (C(3)), 55.2 (OMe), 57.6 (C(
a
)), 80.1
(CMe3), 113.5 (Ar), 126.6 (p-Ph), 128.1, 128.3, 128.9 (o,m-Ph, Ar),
135.1, 141.9 (i-Ph, Ar), 158.6 (Ar), 172.2 (Cþ(1)); m/z (ESIþ) 552
([MþH]þ, 100%); HRMS (ESIþ) C27H39INO3 ([MþH]þ) requires
552.1969; found 522.1975.
C(
(C(
(C(2)), 50.2 (NCH2Ph), 53.8 (C(3)), 58.6 (C(
a
a
)H), 7.26e7.48 (10H, m, Ph); dC (125 MHz, CDCl3) 7.2 (C(7)), 20.7
)Me), 27.9 (C(4)), 28.1 (CMe3), 32.4 (C(5)), 33.3 (C(6)), 37.6
)), 80.1 (CMe3), 126.6,
a
127.0 (p-Ph), 127.9, 128.1, 128.2, 128.3 (o,m-Ph), 142.0, 143.1 (i-Ph),
172.1 (C(1)); m/z (ESIþ) 522 ([MþH]þ, 100%); HRMS (ESIþ)
C26H37INO2þ ([MþH]þ) requires 522.1863; found 522.1869.
4.2.22. tert-Butyl (R)-2-[N(10)-benzylpiperidin-20-yl]acetate 49.
n
NB
t
u
B
CO2
4.2.20. tert-Butyl (R,R)-3-[N-benzyl-N-(a-methyl-p-methoxybenzyl)
amino]-7-hydroxyheptanoate 52.
Method A: A solution of 48 (65 mg, 0.125 mmol) and AgBF4 (37 mg,
0.19 mmol) in MeCN (15 mL) was heated at 80 ꢁC for 16 h. The
reaction mixture was then diluted with Et2O (20 mL) and the re-
sultant solution was washed with satd aq NaHCO3 (20 mL), then
dried and concentrated in vacuo. The residue was then filtered
through Celite (eluent Et2O) and the filtrate was concentrated in
vacuo. Purification via flash column chromatography (gradient
elution, 0/10% Et2O in 30e40 ꢁC petrol) gave 49 as a colourless oil
Ph
PMP
N
t
u
B
CO2
H
O
Following the general procedure, 23 (500 mg, 2.69 mmol, >99:1 dr
[(E)/(Z)]), (R)-N-benzyl-N-( -methyl-p-methoxybenzyl)amine
(21 mg, 55%, >99:1 er26), tert-butyl (R,R)-3-[N-benzyl-N-(
ylbenzyl)amino]hex-6-enoate 50 as a colourless oil (16 mg, 33%,
a-meth-
a
(1.69 g, 6.99 mmol) and BuLi (2.74 mL, 6.85 mmol) in THF (15 mL)
were reacted to give 52 in >99:1 dr. Purification via flash column
chromatography (gradient elution, 0/30% Et2O in 30e40 ꢁC pet-
>99:1 dr), and (RS)-N-a-methylbenzyl acetamide 17 as a colourless
oil (10 mg, 49%).
Data for 49: C18H27NO2 requires C, 74.7; H, 9.4; N, 4.8%; found: C,
rol) gave 52 as a colourless oil (770 mg, 76%, >99:1 dr); ½a D23
ꢂ
þ28.5
74.4; H, 9.3; N, 4.6%; ½a D23
þ18.6 (c 1.0 in CHCl3); nmax (film) 1729
ꢂ
(c 1.0 in CHCl3); nmax (film) 3427 (OeH), 1722 (C]O); dH (400 MHz,
(C]O); dH (400 MHz, CDCl3) 1.35e1.56 (4H, m, C(30)HA, C(40)HA,
C(50)H2), 1.45 (9H, s, CMe3), 1.59e1.67 (1H, m, C(40)HB), 2.13e2.20
(2H, m, C(30)HB, C(60)HA), 2.34 (1H, dd, J 14.5, 8.0, C(2)HA),
2.58e2.69 (2H, m, C(2)HB, C(60)HB), 2.91e2.97 (1H, m, C(20)H), 3.36
(1H, d, J 13.5, NCHAHBPh), 3.80 (1H, d, J 13.5, NCHAHBPh), 7.21e7.41
(5H, m, Ph); dC (100 MHz, CDCl3) 22.3 (C(50)), 25.3 (C(40)), 28.1
(CMe3), 31.0 (C(30)), 37.4 (C(2)), 50.7 (C(60)), 57.7 (C(20)), 58.6
CDCl3) 1.31e1.40 (1H, m, C(4)HA), 1.35 (3H, d, J 6.9, C(a)Me), 1.41
(9H, s, CMe3), 1.48e1.57 (1H, m, C(4)HB), 1.63e1.73 (1H, m, C(5)HA),
1.84e1.98 (5H, m, C(2)H2, C(5)HB, C(6)H2), 3.32e3.39 (1H, m, C(3)
H), 3.48 (1H, d, J 15.0, NCHAHBPh), 3.60 (2H, t, J 6.4, C(7)H2),
3.77e3.82 (2H, m, NCHAHBPh, C(
a)H), 3.81 (3H, s, OMe), 6.87 (2H, d,
J 7.7, Ar), 7.22e7.28 (3H, m, Ph), 7.35e7.38 (2H, m, Ph), 7.43 (2H, d, J

S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
9987
(NCH2Ph), 80.3 (CMe3), 126.7 (p-Ph), 128.1, 128.8 (o,m-Ph), 139.6 (i-
Ph), 172.3 (C(1)); m/z (ESIþ) 290 ([MþH]þ, 100%), 234 ([MꢀC4H8]þ,
10%).
C(1)HA), 3.90e3.98 (1H, m, C(1)HB) 4.17 (1H, d, J 12.9, NCHAHBPh),
5.09 (1H, br s, CH2OH) 7.23e7.35 (5H, m, Ph).
Data for 50: ½a 2D6
ꢂ
þ8.1 (c 0.9 in CHCl3); nmax (film) 1725 (C]O),
4.2.24. (R)-2-[N(10)-Benzylpiperidin-20-yl]ethanal 58.
1641 (C]C); dH (400 MHz, CDCl3) 1.35 (3H, d, J 7.0, C(
a
)Me), 1.41
n
NB
(9H, s, CMe3), 1.46e1.60 (2H, m, C(4)H2), 1.86e1.90 (2H, m, C(2)H2),
2.11e2.19 (1H, m, C(5)HA), 2.35e2.45 (1H, m, C(5)HB), 3.32e3.40
(1H, m, C(3)H), 3.49 (1H, d, J 15.0, NCHAHBPh), 3.79e3.82 (1H, m,
O
DMSO (0.28 mL, 4.75 mmol) was added to a solution of (COCl)2
(0.21 mL, 2.37 mmol) in CH2Cl2 (10 mL) at ꢀ78 ꢁC and the resultant
solution was stirred at ꢀ78 ꢁC for 20 min. A solution of 60 (260 mg,
1.19 mmol) in CH2Cl2 (10 mL) was then added via cannula. After
a further 20 min, NEt3 (1.0 mL, 7.12 mmol) was added and the re-
action mixture was allowed to warm to rt, stirred for 30 min, then
concentrated in vacuo. The residue was partitioned between Et2O
(20 mL) and H2O (20 mL), the aqueous layer was extracted with
Et2O (2ꢃ20 mL), and the combined organic extracts were dried and
concentrated in vacuo to give 58 as a colourless oil (258 mg, quant);
NCHAHBPh), 3.82 (1H, q, J 7.0, C(
4.99e5.05 (1H, m, C(7)HB), 5.75e5.86 (1H, m, C(6)H), 7.24e7.46
(10H, m, Ph); dC (50 MHz, CDCl3) 20.4 (C( )Me), 28.0 (CMe3), 31.2
(C(5)), 32.8 (C(4)), 37.7 (C(2)), 50.0 (NCH2Ph), 53.2 (C(3)), 58.0
(C( )), 80.0 (CMe3), 114.4 (C(7)), 126.6, 126.9 (p-Ph), 127.9, 128.1,
a)H), 4.92e4.96 (1H, m, C(7)HA),
a
a
128.3, 129.0 (o,m-Ph), 138.9 (C(6)), 141.7, 142.6 (i-Ph), 172.1 (C(1));
þ
m/z (CIþ) 394 ([MþH]þ, 100%); HRMS (CIþ) C26H35NO2 ([MþH]þ)
requires 394.2741; found 394.2742.
Method B: A solution of 53 (50 mg, 0.091 mmol) and AgBF4
(26 mg, 0.14 mmol) in MeCN (5 mL) was heated at 80 ꢁC for 16 h.
The reaction mixture was then diluted with Et2O (20 mL) and the
resultant solution was washed with satd aq NaHCO3 (20 mL) then
dried and concentrated in vacuo. The residue was then filtered
through Celite (eluent Et2O) and the filtrate was concentrated in
vacuo. Purification via flash column chromatography (gradient
elution, 0/10% Et2O in 30e40 ꢁC petrol) gave 49 as a colourless oil
½
a 2D3
ꢂ
þ8.1 (c 1.0 in CHCl3); nmax (film) 1721 (C]O); dH (500 MHz,
CDCl3) 1.41e1.56 (2H, m, C(40)HA, C(50)HA), 1.56e1.66 (2H, m, C(30)
HA, C(40)HB), 1.68e1.77 (1H, m, C(50)HB), 1.81e1.88 (2H, m, C(30)HB),
2.17e2.24 (1H, m, C(60)HA), 2.64e2.80 (3H, m, C(2)H2, C(60)HB),
3.01e3.07 (1H, m, C(20)H), 3.34 (1H, d, J 13.2, NCHAHBPh), 3.92 (1H,
d, J 13.2, NCHAHBPh), 7.26e7.38 (5H, m, Ph), 9.89 (1H, app s, C(1)H);
dC (125 MHz, CDCl3) 22.9 (C(50)), 24.9 (C(40)), 31.2 (C(30)), 45.6 (C(2)),
50.9 (C(60)), 56.0 (C(20)), 58.5 (NCH2Ph), 127.0 (p-Ph), 128.3, 128.8
(o,m-Ph), 139.2 (i-Ph), 202.4 (C(1)); m/z (FIþ) 217 ([M]þ, 100%);
HRMS (FIþ) C14H19NOþ ([M]þ) requires 217.1461; found 217.1464.
(22 mg, 84%, >99:1 er26); ½a D23
þ20.9 (c 1.0 in CHCl3).
ꢂ
Method C: A solution of 53 (1.37 g, 2.48 mmol) in MeCN (140 mL)
was heated at 80 ꢁC for 16 h. The reaction mixture was then diluted
with Et2O (20 mL) and the resultant solution was washed with satd
aq NaHCO3 (20 mL) then dried and concentrated in vacuo. The
residue was then filtered through Celite (eluent Et2O) and the fil-
trate was concentrated in vacuo. Purification via flash column
chromatography (gradient elution, 0/10% Et2O in 30e40 ꢁC pet-
rol) gave 49 as a colourless oil (667 mg, 94%, >99:1 er26), and p-
methoxystyrene 55 as a pale yellow oil (217 mg, 65%).
4.2.25. (R)-N(1)-Benzyl-2-allylpiperidine 57.
n
NB
tBuOK (116 mg, 1.04 mmol) was added portionwise to a suspension
of methyltriphenylphosphonium bromide (412 mg, 1.15 mmol) in
THF (6 mL) at 0 ꢁC and the resultant mixture was stirred at rt for
30 min. A solution of 58 (125 mg, 0.58 mmol) in THF (2 mL) was
then added dropwise. The reaction mixture was stirred at rt for 16 h
then satd aq NH4Cl (1 mL) was added. The aqueous layer was
extracted with Et2O (3ꢃ5 mL) and the combined organic extracts
were washed with brine (15 mL), then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O,15:1) gave 57 as a colourless oil (65 mg, 52%);
Data for 49: ½a 2D3
þ18.6 (c 1.0 in CHCl3).
ꢂ
Method D: Imidazole (2.11 g, 31.0 mmol), PPh3 (8.11 g,
31.0 mmol) and I2 (7.65 g, 30.1 mmol) were added to a solution of 52
(2.74 g, 6.19 mmol) in MeCN (150 mL). The resultant mixture was
stirred at 80 ꢁC for 16 h then filtered and concentrated in vacuo. The
residue was dissolved in Et2O and the resultant solution was se-
quentially washed with satd aq Na2S2O3 (20 mL), H2O (20 mL) and
brine (20 mL), then dried and concentrated in vacuo. Purification
via flash column chromatography (gradient elution, 0/10% Et2O in
30e40 ꢁC petrol) gave 49 as a colourless oil (1.35 g, 75%, >99:1
er26), and p-methoxystyrene 55 as a pale yellow oil (273 mg, 33%).
½
a 2D3
ꢂ
þ9.1 (c 0.4 in CHCl3); nmax (film) 1639 (C]C); dH (500 MHz,
Data for 49: ½a 2D3
þ22.5 (c 1.1 in CHCl3).
ꢂ
CDCl3) 1.30e1.39 (1H, m, C(4)HA),1.45e1.57 (3H, m, C(3)HA, C(5)H2),
1.66e1.75 (2H, m, C(3)HB, C(4)HB), 2.05e2.12 (1H, m, C(6)HA),
2.40e2.48 (3H, m, C(10)H2, C(2)H), 2.79 (1H, td, J 8.4, 3.9, C(6)HB),
3.29 (1H, d, J 13.3, NCHAHBPh), 4.08 (1H, d, J 13.3, NCHAHBPh),
5.09e5.15 (2H, m, C(30)H2), 5.94 (1H, tdd, J 13.6, 10.2, 6.8, C(20)H),
7.26e7.40 (5H, m, Ph); dC (125 MHz, CDCl3) 23.4 (C(5)), 25.4 (C(4)),
30.4 (C(3)), 36.2 (C(10)), 51.7 (C(6)), 57.9 (NCH2Ph), 60.2 (C(2)), 116.3
(C(30)), 126.7 (p-Ph), 128.1, 129.0 (o,m-Ph), 136.0 (C(20)), 139.6 (i-Ph);
m/z (ESIþ) 216 ([MþH]þ, 100%); HRMS (ESIþ) C15H22Nþ ([MþH]þ)
requires 216.1747; found 216.1755.
4.2.23. (R)-2-[N(10)-Benzylpiperidin-20-yl]ethanol 60.
n
NB
H
O
DIBAL-H (1.0 M in THF, 6.05 mL, 6.05 mmol) was added to a stirred
solution of 49 (350 mg, 1.21 mmol) in THF (15 mL) at 0 ꢁC. The
resultant solution was allowed to warm to rt over 6 h and was then
cooled to 0 ꢁC before H2O (5 mL) was added. The reaction mixture
was then allowed to warm to rt, 1.0 M aq KOH (10 mL) was added
and the resultant mixture was stirred at rt for 16 h. The aqueous
layer was then extracted with Et2O (2ꢃ20 mL) and the combined
organic extracts were dried and concentrated in vacuo to give 60 as
4.2.26. (S)-2-Propylpiperidine hydrochloride [(S)-coniine hydrochlo-
ride] 1$HCl.
l
C
NH2
a colourless oil (263 mg, 99%);46
a 2D3
½
a 2D5
ꢂ
þ28.6 (c 1.0 in CHCl3); {lit.47
½
ꢂ
þ28.5 (c 2.0 in CHCl3)}; dH (400 MHz, CDCl3) 1.32e1.84 (7H, m,
Pd(OH)2/C (20% w/w, 40 mg) was added to a degassed solution of 57
(50 mg, 0.23 mmol) in MeOH (3 mL) and the resultant solution was
stirred under an atmosphere of H2 (1 atm) for 48 h. The reaction
mixture was then filtered through Celite (eluent MeOH), excess
C(30)H2, C(40)H2, C(50)H2, C(2)HA), 1.91e2.00 (1H, m, C(2)HB),
2.17e2.23 (1H, m, C(60)HA), 2.71e2.77 (1H, m, C(20)H), 2.92e2.99
(1H, m, C(60)HB), 3.47 (1H, d, J 12.9, NCHAHBPh), 3.72e3.78 (1H, m,

9988
S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
ethereal HCl was added, and the resultant mixture was concen-
trated in vacuo. Purification via flash column chromatography
(gradient elution, 0/10% MeOH in CH2Cl2) gave 1$HCl as a white
solid (30 mg, 82%, >99:1 er); mp 207e209 ꢁC; {lit.33 mp
4.2.29. tert-Butyl (R,R)-2-[N(10)-benzylpiperidin-20-yl]-4-methoxy-
4-oxobutanoate 66.
n
NB
t
u
B
CO2
214e216 ꢁC}; ½a 2D3
ꢂ
þ9.2 (c 0.3 in EtOH) {lit.34
½
a 2D3
ꢂ
þ9.4 (c 0.3 in
EtOH)}; dH (400 MHz, CDCl3) 0.94 (3H, t, J 7.3, C(30)H3), 1.36e2.04
(10H, m, C(3)H2, C(4)H2, C(5)H2, C(10)H2, C(20)H2), 2.75e2.86 (1H, m,
C(6)HA), 2.87e3.00 (1H, m, C(6)HB), 3.40e3.53 (1H, br m, C(2)H),
9.19 (1H, br s, NHA), 9.49 (1H, br s, NHB).
e
M
CO2
Method A: BuLi (0.26 mL, 0.65 mmol) was added to a stirred so-
lution of HTMP (0.12 mL, 0.70 mmol) in THF (3.0 mL) at ꢀ78 ꢁC. After
30 min the reaction mixture was allowed to warm to rt and stirred at
rt for a further 10 min, before being cooled back down to ꢀ78 ꢁC. A
solution of 49 (100 mg, 0.35 mmol) in THF (3.0 mL) at ꢀ78 ꢁC was
then added. The resultant mixture was stirred for 1 h at ꢀ78 ꢁC then
methyl bromoacetate (159 mg, 1.04 mmol) was added. The reaction
mixture was then allowed to warm to rt over 16 h, satd aq NH4Cl was
added, and the resultant mixture was extracted with EtOAc
(2ꢃ5 mL). The combined organic extracts were washed with brine
(10 mL) then dried and concentrated in vacuo to give 66 in 90:10 dr
(70% conv). Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 50:1) gave a 77:23 mixture of 66 (98:2 dr) and
recovered starting material 49 as a colourless oil (89 mg).
4.2.27. (R)-3-[N(10)-Benzylpiperidin-20-yl]propanal 59.
n
NB
O
t
Step 1: BuOK (83 mg, 0.74 mmol) was added portionwise to
a suspension of methoxymethyltriphenylphosphonium chloride
(282 mg, 0.82 mmol) in THF (4 mL) at 0 ꢁC and the resultant mix-
ture was stirred at rt for 30 min. A solution of 58 (89 mg, 0.41 mmol)
in THF (2 mL) was then added dropwise. The reaction mixture was
stirred at rt for 16 h then satd aq NH4Cl (1 mL) was added. The
aqueous layer was extracted with Et2O (3ꢃ5 mL) and the combined
organic extracts were washed with brine (15 mL), then dried and
concentrated in vacuo. Purification via flash column chromatogra-
phy (eluent 30e40 ꢁC petrol/Et2O,15:1) gave (R)-N(1)-benzyl-2-(40-
methoxybut-30-en-10-yl)piperidine 61 as a yellow oil (81 mg, 81%,
52:48 dr).
Data for 66: dH (500 MHz, CDCl3) 1.25e1.58 (5H, m, C(30)H2, C(40)
HA, C(50)H2), 1.51 (9H, s, CMe3), 1.73e1.79 (1H, m, C(40)HB), 1.98 (1H,
dt, J 11.7, 2.5, C(60)HA), 2.69e2.74 (1H, m, C(20)H), 2.77e2.81 (2H, m,
C(3)H2), 2.87e2.92 (1H, m, C(60)HB), 3.18 (1H, d, J 13.5, NCHAHBPh),
3.57e3.61 (1H, m, C(2)H), 3.70 (3H, s, OMe), 4.07 (1H, d, J 13.5,
NCHAHBPh), 7.25e7.39 (5H, m, Ph); dC (125 MHz, CDCl3) 25.5, 26.8,
28.2 (C(30), C(40), C(50)), 28.1 (CMe3), 29.2 (C(3)), 43.8 (C(2)), 51.7
(OMe), 53.0 (C(60)), 57.7 (NCH2Ph), 61.8 (C(20)), 80.9 (CMe3), 126.8
(p-Ph), 128.3, 128.8 (o,m-Ph), 139.1 (i-Ph), 172.7, 173.7 (C(1), C(4));
m/z (ESIþ) 362 ([MþH]þ, 100%), 306 ([MꢀC4H8]þ, 50%); HRMS
(ESIþ) C21H32NO4þ ([MþH]þ) requires 362.2326; found 362.2332.
Method B: LiHMDS (1.0 M in THF, 0.52 mL, 0.52 mmol) was
added to a solution of 49 (100 mg, 0.35 mmol) in THF (2.0 mL) at
ꢀ78 ꢁC and the resultant mixture was stirred at ꢀ78 ꢁC for 20 min.
Methyl bromoacetate (106 mg, 0.69 mmol) was then added, and the
reaction mixture was allowed to warm to rt over 4 h before satd aq
NH4Cl (1.0 mL) was added. The reaction mixture was then extracted
with Et2O (2ꢃ20 mL) and the combined organic extracts were se-
quentially washed with H2O (20 mL) and brine (20 mL), then dried
and concentrated in vacuo give 66 in 86:14 dr (69% conv). Purifi-
cation via flash column chromatography (eluent 30e40 ꢁC petrol/
Et2O, 50:1) gave an 83:17 mixture of 66 (97:3 dr) and recovered
starting material 49 as a colourless oil (72 mg).
Step 2: A solution of 61 (60 mg, 0.25 mmol, 52:48 dr) in CH2Cl2/
HCO2H (v/v 4:1, 5 mL) was stirred for 16 h at rt. NaHCO3 (w200 mg)
was then added until pH >11 was achieved. The aqueous layer was
then extracted with CH2Cl2 (3ꢃ15 mL) and the combined organic
extracts were dried and concentrated in vacuo to give 59 as a yellow
oil (56 mg, quant); ½a D23
þ21.1 (c 1.0 in CHCl3); nmax (film) 1724 (C]O);
ꢂ
dH (400 MHz, CDCl3) 1.30e1.57 (4H, m, C(30)H2, C(50)H2), 1.61e1.73
(2H, m, C(40)H2), 1.91e1.99 (2H, m, C(3)H2), 2.05e2.15 (1H, m, C(60)
HA), 2.37e2.46 (1H, m, C(20)H), 2.47e2.64 (2H, m, C(2)H2), 2.75e2.83
(1H, m, C(60)HB), 3.29 (1H, d, J 13.5, NCHAHBPh), 3.97 (1H, d, J 13.5,
NCHAHBPh), 7.22e7.35 (5H, m, Ph), 9.78 (1H, app s, C(1)H); dC
(100 MHz, CDCl3) 23.3 (C(40)), 23.7 (C(3)), 24.5 (C(50)), 29.4 (C(30)),
51.1 (C(2)), 51.1 (C(60)), 57.4 (C(20)), 59.4 (NCH2Ph), 126.8 (p-Ph),
128.2, 128.8 (o,m-Ph), 139.5 (i-Ph), 202.5 (C(1)); m/z (FIþ) 231 ([M]þ,
100%); HRMS (FIþ) C15H21NOþ ([M]þ) requires 231.1618; found
231.1620.
Method C: BuLi (0.33 mL, 0.83 mmol) was added to a stirred so-
lution of iPr2NH (0.12 mL, 0.85 mmol) inTHF (3.0 mL) at ꢀ78 ꢁC. After
30 min the reaction mixture was allowed to warm to rt and stirred at
rt for a further 10 min, before being cooled back down to ꢀ78 ꢁC. A
solution of 49 (123 mg, 0.43 mmol) in THF (3.0 mL) at ꢀ78 ꢁC was
then added. The resultant mixture was stirred for 1 h at ꢀ78 ꢁC then
methylbromoacetate(0.148 mL,1.28 mmol) was added. The reaction
mixture was then allowed to warm to rt over 16 h, satd aq NH4Cl was
added, and the resultant mixture was extracted with EtOAc
(2ꢃ5 mL). The combined organic extracts were washed with brine
(10 mL) then dried and concentrated in vacuo to give 66 in 80:20 dr
(85% conv). Purification via flash column chromatography (eluent
30e40 ꢁC petrol/Et2O, 50:1) gave a 92:8 mixture of 66 (95:5 dr) and
recovered starting material 49 as a colourless oil (113 mg).
4.2.28. (R)-Octahydroindolizine hydrochloride [(R)-d-coniceine hy-
drochloride] 56$HCl.
H
l
C
N
Pd(OH)2/C (20% w/w, 40 mg) was added to a degassed solution
of 59 (90 mg, 0.39 mmol) in MeOH (3 mL) and the resultant solution
was stirred under an atmosphere of H2 (1 atm) for 48 h. The re-
action mixture was then filtered through Celite (eluent MeOH),
excess ethereal HCl was added to the filtrate, and the resultant
mixture was concentrated in vacuo. Purification via flash column
chromatography (eluent CH2Cl2/MeOH, 8:1) gave 56$HCl as a white
solid (59 mg, 94%, >99:1 er); mp 175 ꢁC; ½a D23
ꢀ1.5 (c 1.0 in EtOH);
ꢂ
4.2.30. tert-Butyl (R,R)-3-oxooctahydroindolizine-1-carboxylate 68.
nmax (KBr) 3477 (NeH); dH (400 MHz, CD3OD) 1.56e2.35 (10H, m,
C(1)H2, C(2)H2, C(6)H2, C(7)H2, C(8)H2), 2.92e3.22 (3H, m, C(3)HA,
C(8a)H, C(5)HA), 3.55e3.68 (2H, m, C(3)HB, C(5)HB); dC (125 MHz,
CD3OD) 20.5, 23.5, 24.4, 29.2, 29.5 (C(1), C(2), C(6), C(7), C(8)), 52.8,
53.6 (C(3), C(5)), 68.0 (C(8a)); m/z (ESIþ) 126 ([MþH]þ, 100%);
HRMS (ESIþ) C8H16Nþ ([MþH]þ) requires 126.1277; found 126.1278.
O
N
t
u
B
CO2

S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
9989
was added, and the resultant mixture was extracted with EtOAc
(2ꢃ5 mL). The combined organic extracts were washed with brine
(10 mL) then dried and concentrated in vacuo to give 69 in 90:10 dr.
Purification via flash column chromatography (eluent 30e40 ꢁC
petrol/Et2O, 10:1) gave tert-butyl (R,R)-2-[N(10)-benzylpiperidin-20-
yl]-4-tert-butoxy-4-oxobutanoate 69 (90:10 dr) as a colourless oil
(996 mg).
Step 2: A solution of 69 in 1.35 M HCl in MeOH (15 mL) was
heated at 60 ꢁC for 16 h. The reaction mixture was allowed to cool to
rt and then concentrated in vacuo. The resulting residue was dis-
solved in CH2Cl2 (30 mL) and washed with satd aq NaHCO3 (20 mL)
and brine (20 mL), then dried and concentrated in vacuo to give
methyl (R,R)-2-[N(10)-benzylpiperidin-20-yl]-4-methoxy-4-oxobu-
tanoate 70 as a white solid (860 mg).
A 77:23 mixture of 66 (98:2 dr) and 49 (89 mg) was dissolved in
degassed MeOH (3.0 mL) and Pd(OH)2/C (20% wt, 20 mg) was added
to the resultant solution. The resultant mixture was stirred under
H2 (1 atm) for 48 h then filtered through Celite (eluent MeOH). The
filtrate was concentrated in vacuo and the residue was dissolved in
CHCl3 (3 mL). The resultant solution was heated at reflux for 16 h
then allowed to cool to rt before being concentrated in vacuo. Pu-
rification via flash column chromatography (eluent 30e40 ꢁC pet-
rol/Et2O, 1:0; increased to neat Et2O) gave 68 as a colourless oil
(44 mg, 53% from 49, >99:1 dr); ½a D23
þ27.3 (c 1.0 in CHCl3); nmax
ꢂ
(film) 1727 (C]O), 1692 (C]O); dH (400 MHz, CDCl3) 1.16e1.51 (3H,
m, C(6)H2, C(8)HA), 1.45 (9H, s, CMe3), 1.57e1.64 (1H, m, C(7)HA),
1.65e1.73 (1H, m, C(8)HB), 1.88e1.95 (1H, m, C(7)HB), 2.43 (1H, dd, J
17.3, 9.6, C(2)HA), 2.58e2.67 (1H, m, C(5)HA), 2.78 (1H, app ddd, J
17.3, 8.2, 2.3, C(2)HB), 3.19e3.26 (1H, m, C(1)H), 3.64e3.72 (1H, m,
C(8a)H), 4.10e4.17 (1H, m, C(5)HB); dC (100 MHz, CDCl3) 23.9, 24.3,
27.6 (C(6), C(7), C(8)), 28.1 (CMe3), 32.6 (C(2)), 40.7 (C(5)), 41.0
Step 3: Pd(OH)2/C (20% wt, 172 mg) was added to a solution of
70 (860 mg) in degassed MeOH (20 mL) and the resultant mixture
was stirred under H2 (1 atm) for 24 h. The reaction mixture was
then filtered through Celite (eluent MeOH) and the filtrate was
concentrated in vacuo. The residue was then dissolved in CHCl3
(3 mL) and the resultant solution was heated at reflux for 16 h. The
residue was dissolved in CH2Cl2 (30 mL) and washed with satd aq
NaHCO3 (30 mL) and brine (30 mL), then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent
30e40 ꢁC petrol/EtOAc, 1:0; increased to neat EtOAc) gave 71 as
t
(C(1)), 58.6 (C(8a)), 80.9 (CMe3), 170.4, 171.8 (C(3), CO2 Bu); m/z
(ESIþ) 298 ([MþMeCNþNH4]þ, 100%), 262 ([MþNa]þ, 5%); HRMS
(ESIþ) C13H22NO3þ ([MþH]þ) requires 240.1609; found 240.1609.
4.2.31. (R,R)-1-(Hydroxymethyl)octahydroindolizine 62.
N
a pale yellow oil (338 mg, 66% from 49, >99:1 dr); ½a D23
þ20.3 (c
ꢂ
1.0 in CHCl3); nmax (film) 1730 (C]O), 1691 (C]O); dH (400 MHz,
CDCl3) 1.12e1.24 (1H, m), 1.35e1.85 (4H, m) [C(6)HA, C(7)H2, C(8)
H2] 1.90e1.95 (1H, m, C(6)HB), 2.48e2.62 (1H, m, C(2)HA),
2.64e2.66 (1H, m, C(5)HA), 2.95e3.00 (1H, dd, J 9.5, 3.1, C(2)HB),
3.35e3.51 (1H, m, C(1)H), 3.78e3.80 (1H, m, C(8a)H) 3.80 (3H, s,
OMe), 4.15e4.20 (1H, m, C(5)HB); dC (100 MHz, CDCl3) 23.8, 24.2,
27.9 (C(6), C(7), C(8)), 32.5 (C(2)), 40.2 (C(1)), 40.7 (C(5)), 52.5
(OMe), 58.4 (C(8a)), 171.5, 171.8 (C(3), CO2Me); m/z (ESIþ) 220
([MþNa]þ, 100%); HRMS (ESIþ) C10H15NNaO3þ ([MþNa]þ) requires
220.0944; found 220.0942.
H
O
Method A: LiAlH4 (1.0 M in THF, 1.10 mL, 1.10 mmol) was added to
a stirred solution of 68 (44 mg, 0.18 mmol) in THF (4.0 mL) at 0 ꢁC.
The resultant mixture was heated at reflux for 16 h, then cooled to
0
ꢁC. 1.0 M aq KOH (5.0 mL) was then added and the resultant
mixture was stirred at rt for 2 h before being extracted with Et2O
(2ꢃ10 mL). The combined organic extracts were washed with brine
(10 mL) then dried and concentrated in vacuo to give 62 as a col-
ourless oil (27 mg, 95%, >99:1 dr);39c,d
½
a 2D3
ꢂ
ꢀ35.8 (c 0.5 in EtOH);
dH (400 MHz, CDCl3) 1.13e1.37 (2H, m),1.40e1.69 (3H, m),1.74e1.87
(4H, m), 1.90e2.13 (3H, m) [C(1)H, C(2)H2, C(3)HA, C(5)HA, C(6)H2,
C(7)H2, C(8)H2, C(8a)H], 3.05e3.40 (2H, m, C(3)HB, C(5)HB), 3.46
(1H, dd, J 10.2, 2.4, C(10)HA), 3.86 (1H, dd, J 10.2, 2.8, C(10)HB), 3.95
(1H, br s, OH); dC (100 MHz, CDCl3) 24.1, 25.3, 25.4, 26.7 (C(2), C(6),
C(7), C(8)), 41.0 (C(1)), 53.6, 53.9 (C(3), C(5)), 64.6 (C(10)), 66.2
(C(8a)); m/z (ESIþ) 156 ([MþH]þ, 100%).
4.2.33. Methyl (2S,20R, R)- and (R,R,R)-2-[N(10)-(
a a-methylbenzyl)-
10,20,50,60-tetrahydropyridin-20-yl]-4-methoxy-4-oxobutanoate
73
and 74.
N
Ph
N
Ph
e
e
e
e
M
M
CO2
CO2
Method B: LiAlH4 (1.0 M in THF, 4.20 mL, 4.20 mmol) was added
to a stirred solution of 71 (140 mg, 0.71 mmol) in THF (5 mL) at 0 ꢁC.
The resultant mixture was heated at reflux for 48 h, then cooled to
0 ꢁC.1.0 M aq KOH (1 mL) was then added and the resultant mixture
was stirred at rt for 2 h before being extracted with Et2O (2ꢃ10 mL).
The combined organic extracts were washed with brine (20 mL)
then dried and concentrated in vacuo to give 62 as a colourless oil
M
CO2
M
CO2
7
3
74
NaHMDS (1.0 M in THF, 5.78 mL, 5.78 mmol) was added to a solu-
tion of 728h (1.00 g, 3.86 mmol) in THF (38 mL) at ꢀ78 ꢁC and the
resultant mixture was stirred at ꢀ78 ꢁC for 30 min. Methyl bro-
moacetate (1.10 mL, 11.6 mmol) was then added, and the reaction
mixture was allowed to warm to rt over 16 h before H2O (10 mL)
was added. The reaction mixture was then extracted with Et2O
(2ꢃ20 mL) and the combined organic extracts were sequentially
washed with H2O (20 mL) and brine (20 mL), then dried and con-
centrated in vacuo to give an 85:15 mixture of 73 and 74. Purifi-
cation via flash column chromatography (eluent 30e40 ꢁC petrol/
Et2O, 50:1) gave an 85:15 mixture of 73 and 74 as a colourless oil
(942 mg, 74%).
(110 mg, quant, >99:1 dr); ½a D23
ꢀ35.8 (c 0.5 in EtOH).
ꢂ
4.2.32. Methyl (R,R)-3-oxooctahydroindolizine-1-carboxylate 71.
O
N
e
M
CO2
Step 1: BuLi (1.6 mL, 3.90 mmol) was added to a stirred solution of
HTMP (0.67 mL, 3.90 mmol) in THF (10 mL) at ꢀ78 ꢁC. After 30 min
the reaction mixture was allowed to warm to rt and stirred at rt for
a further 10 min, before being cooled back down to ꢀ78 ꢁC. A so-
lution of 49 (750 mg, 2.60 mmol) in THF (10 mL) at ꢀ78 ꢁC was then
added. The resultant mixture was stirred for 1 h at ꢀ78 ꢁC then
methyl bromoacetate (1.15 mL, 7.80 mmol) was added. The reaction
mixture was then allowed to warm to rt over 16 h, satd aq NH4Cl
Data for mixture: nmax (film) 3026, 2971, 2951 (CeH),1732 (C]O);
þ
m/z (ESIþ) 354 ([MþNa]þ, 100%); HRMS (ESIþ) C19H25NNaO4
([MþNa]þ) requires 354.1676; found 354.1675.
Data for 73: dH (500 MHz, CDCl3) 1.33 (3H, d, J 6.3, C(a)Me),
1.49e1.56 (1H, m, C(50)HA), 2.05e2.22 (1H, m, C(50)HB), 2.42e2.48
(1H, m, C(60)HA), 2.66e2.76 (1H, m, C(60)HB, C(3)HA), 2.99 (1H, dd, J
16.7, 5.3, C(3)HB), 3.07e3.13 (1H, m, C(2)H), 3.52e3.60 (1H, m, C(20)

9990
S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
H), 3.70 (3H, s, OMe), 3.75 (3H, s, OMe), 3.79e3.84 (1H, m, C(
5.57e5.61 (1H, m, C(30)H), 5.92e5.96 (1H, m, C(40)H) 7.22e7.35 (5H,
m, Ph); dC (125 MHz, CDCl3) 19.8 (C(50)), 22.5 (C(
)Me), 35.5 (C(3)),
40.0 (C(60)), 46.4 (C(2)), 51.7 (OMe), 51.9 (OMe), 55.1 (C(20)), 58.0
(C(
)), 126.2 (p-Ph), 126.9, 128.1, 128.3 (o,m-Ph, C(30), C(40)), 145.5 (i-
a
)H),
4.2.36. (1S,8aR)-Octahydroindolizin-1-yl-methyl-4-nitrobenzoate
77.
a
N
a
Ph), 172.7, 174.7 (C(1), C(4)).
O
O
Data for 74: dH (500 MHz, CDCl3) [selected peaks] 5.65e5.70
(1H, m, C(30)H), 5.85e5.89 (1H, m, C(40)H).
4.2.34. Methyl
75.
(1S,8aR)-3-oxooctahydroindolizine-1-carboxylate
N
O2
O
p-Nitrobenzoyl chloride (298 mg, 1.61 mmol) was added to
a stirred solution of 76 (100 mg, 0.64 mmol) in CH2Cl2 (2 mL) and
NEt3 (2 mL) at rt, and the resultant solution was stirred for 20 h. The
reaction mixture was then diluted with CH2Cl2 (20 mL) and the re-
sultant solution was washed with satd aq NaHCO3 (2ꢃ20 mL) then
dried and concentrated in vacuo. Purification via flash column
chromatography (eluent Et2O) gave 77 as a yellow solid (89 mg, 46%,
N
e
M
CO2
Pd(OH)2/C (50% wt, 450 mg) was added to a solution of 73
(900 mg, 2.71 mmol, 85:15 dr) in degassed MeOH (20 mL) and the
resultant mixture was stirred under H2 (1 atm) for 16 h. The re-
action mixture was then filtered through Celite (eluent MeOH) and
the filtrate was concentrated in vacuo. The residue was then dis-
solved in CH2Cl2 (20 mL) and the resultant solution was washed
with satd aq NaHCO3 (20 mL) and brine (20 mL), then dried and
concentrated in vacuo. Purification via flash column chromatogra-
phy (eluent 30e40 ꢁC petrol/EtOAc, 1:1; increased to neat EtOAc)
>99:1 dr); mp 50e52 ꢁC; ½a D23
þ58.1 (c 1.0 in CHCl3); nmax (film) 2932
ꢂ
(CeH),1722(C]O);dH (400 MHz, CDCl3) 1.15e1.35 (2H, m),1.47e1.69
(4H, m), 1.77e1.80 (1H, m), 1.90e2.25 (5H, m), 3.03e3.08 (2H, m),
4.32e4.38 (2H, m, C(10)H2), 8.17 (2H, d, J 8.9, Ar), 8.27 (2H, d, J 8.9, Ar);
dC (100 MHz, CDCl3) 24.2, 25.2, 25.4, 30.5 (C(2), C(6), C(7), C(8)), 42.7
(C(8a)), 53.1, 53.4 (C(3), C(5)), 67.7 (C(10)), 67.8 (C(1)), 123.6, 130.6,
135.6,150.5 (Ar),164.7 (C]O); m/z (ESIþ) 305 ([MþH]þ,100%); HRMS
(ESIþ) C16H21N2O4þ ([MþH]þ) requires 305.1496; found 305.1499.
gave 75 as a colourless oil (536 mg, 78%, >99:1 dr); ½a D23
þ13.7 (c 1.0
ꢂ
in CHCl3); nmax (film) 2941 (CeH), 1733 (C]O), 1685 (C]O); dH
(400 MHz, CDCl3) 1.10e1.43 (3H, m, C(6)HA, C(7)HA, C(8)HA),
1.64e1.67 (1H, m, C(6)HB), 1.83e1.89 (1H, m, C(7)HB), 2.03e2.10
(1H, m, C(8)HB), 2.52e2.62 (3H, m, C(2)H2, C(5)HA), 2.72e2.78 (1H,
m, C(1)H), 3.46e3.51 (1H, m, C(8a)H), 3.78 (3H, s, OMe), 4.04e4.08
(1H, m, C(5)HB); dC (100 MHz, CDCl3) 23.4, 24.0 (C(6), C(7)), 32.5
(C(8)), 33.6 (C(2)), 40.0 (C(5)), 43.8 (C(1)), 52.3 (CO2Me), 59.3
(C(8a)), 170.4, 171.8 (C(3), CO2Me); m/z (ESIþ) 220 ([MþNa]þ, 100%);
4.2.36.1. X-ray crystal structure determination for (1S,8aR)-
77. Data were collected using an Oxford Diffraction SuperNova
diffractometer with graphite monochromated Cu Ka radiation us-
ing standard procedures at 150 K. The structure was solved by di-
rect methods (SIR92); all non-hydrogen atoms were refined with
anisotropic thermal parameters. Hydrogen atoms were added at
idealised positions. The structure was refined using CRYSTALS.49
X-ray crystal structure data for (1S,8aR)-77 [C16H21N2O4.5]:
þ
HRMS (ESIþ) C10H15NNaO3 ([MþNa]þ) requires 220.0944; found
ꢀ
ꢀ
M¼626.71, triclinic, space group P 1, a¼6.8943(2) A, b¼7.0698(3) A,
220.0943.
ꢀ
c¼17.9334(6) A,
a
¼99.126(3)ꢁ,
b
¼92.701(3)ꢁ,
g
¼114.185(3)ꢁ,
3
V¼781.17(5) A , Z¼2,
m
¼0.811 mmꢀ1, colourless plate, crystal
ꢀ
4.2.35. (1S,8aR)-1-(Hydroxymethyl)octahydroindolizine 76.
dimensions¼0.01ꢃ0.21ꢃ0.22 mm3. A total of 29432 reflections
N
were measured for 5<q<27 and 29,432 reflections were used in the
refinement. The final parameters were wR2¼0.098 and R1¼0.038
[I>ꢀ3.0 (I)].
s
H
O
Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 834029. Copies of these
data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif., or
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: þ44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
LiAlH4 (1.0 M in THF, 4.20 mL, 4.20 mmol) was added to a stirred
solution of 75 (140 mg, 0.71 mmol) in THF (5.0 mL) at 0 ꢁC. The
resultant mixture was heated at reflux for 3 days, then cooled to
0
ꢁC. 1.0 M aq KOH (5.0 mL) was then added and the resultant so-
lution was stirred at rt for 2 h before being extracted with Et2O
(4ꢃ10 mL). The combined organic extracts were washed with brine
(10 mL), then dried and concentrated in vacuo to give 76 as a col-
ourless oil (110 mg, quant, >99:1 dr);39a,e
½
a 2D3
ꢂ
þ27.4 (c 1.0 in
Acknowledgements
EtOH); nmax (film) 3206, 2928, 2854, 1441; dH (400 MHz, CDCl3)
1.10e1.32 (2H, m), 1.40e1.49 (1H, m), 1.50e1.65 (3H, m), 1.72e1.82
(1H, m), 1.84e2.08 (4H, m), 2.15e2.20 (1H, m) [C(1)H, C(2)H2, C(3)
HA, C(5)HA, C(6)H2, C(7)H2, C(8)H2, C(8a)H], 2.26 (1H, br s, OH),
2.99e3.10 (2H, m, C(3)HB, C(5)HB), 3.56e3.65 (2H, m, C(10)H2); dH
(400 MHz, CD3CN) 1.14e1.26 (2H, m), 1.35e1.65 (4H, m), 1.71e1.89
(4H, m) [C(1)H, C(2)H2, C(6)H2, C(7)H2, C(8)H2, C(8a)H], 1.91e1.98
(1H, m), 2.05 (1H, app q, J 8.9), 2.86e2.92 (1H, m), 2.94e3.02 (1H,
m) [C(3)H2, C(5)H2], 2.45 (1H, br s, OH), 3.41e3.51 (2H, m, C(10)
H2);48 dC (100 MHz, CDCl3) 24.3, 25.2, 25.3, 30.5 (C(2), C(6), C(7),
C(8)), 46.1 (C(1)), 53.4, 53.9 (C(3), C(5)), 64.9 (C(10)), 67.3 (C(8a)); dC
(100 MHz, CD3CN) 24.7, 25.7, 25.8, 30.9 (C(2), C(6), C(7), C(8)), 46.7
(C(1)), 53.3, 53.6 (C(3), C(5)), 64.3 (C(10)), 67.6 (C(8a));48 m/z (ESIþ)
156 ([MþH]þ, 100%); HRMS (ESIþ) C9H18NOþ ([MþH]þ) requires
156.1383; found 156.1389.
The authors would like to thank New College, Oxford for a Junior
Research Fellowship (A.D.S.), and Professors Stephen F. Martin and
Ganesh Pandey, and Dr. Norbert Hoffmann for the efficient and
useful exchange of data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.09.038.
References and notes
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aR)-configuration within the major diastereoisomer 31 was assigned by
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son’s catalyst gave an authentic sample of piperidine 32 in 92% isolated yield
and >99:1 dr.
N
Ph
( )
i
N
Ph
tBu
tBu
ꢁ
CO2
CO2
1999, 64, 4220; (f) Barluenga, J.; Aznar, F.; Ribas, C.; Valdes, C. J. Org. Chem. 1999,
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M. J. Org. Chem. 2002, 67, 598.
78, >99:1 dr
33, 92%, >99:1 dr
Reagents and conditions: (i) Rh(PPh3)3Cl (5 mol %), H2 (4 atm), EtOAc, rt, 12 h.
6. For instance, see: (a) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.
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23. Enantiopure (R)-
ductive alkylation of (R)-
dehyde and NaBH4 gave (R)-N-benzyl-N-(
deprotonation with BuLi in THF generated a pink solution of lithium (R)-N-
benzyl-N-( -methylbenzyl)amide 43.
a
-methylbenzylamine (99% ee) is commercially available. Re-
-methylbenzylamine upon treatment with benzal-
-methylbenzyl)amine; subsequent
€
€
Acids 2005, 29, 101; (f) Kallstrom, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601.
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Mortimer, A. J.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006, 17, 1793;
(c) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Savory,
E. D.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2009, 20, 758; (d)
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a
a
a
24. Holmes, A. B.; Smith, A. L.; Williams, S. F. J. Org. Chem. 1991, 56, 1393.
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26. Although the enantiomeric purity of 49 was not unambiguously determined, it
was inferred as >99:1 er from the known diastereoisomic purities of the
precurors 48, 52 and 53 (>99:1 dr in each case), consistent with the known
enantiopurity of the N-benzyl-N-(
a-methylbenzyl)amine (>99:1 er) and N-
benzyl-N-(p-methoxy- -methylbenzyl)amine (>99:1 er) used.
a
27. We have recently published the sucessful application of this strategy in the
synthesis of polysubstituted pyrrolizidines, see Ref. 7i.
28. Enantiopure (R)-p-methoxy-
available. Reductive alkylation of (R)-p-methoxy-
treatment with benzaldehyde and NaBH4 gave (R)-N-benzyl-N-(p-methoxy-
methylbenzyl)amine; subsequent deprotonation with BuLi in THF generated
a
-methylbenzylamine (99% ee) is commercially
a
-methylbenzylamine upon
a
-
a yellow solution of lithium (R)-N-benzyl-N-(p-methoxy-
a-methylbenzyl)am-
ide 51.
8. For selected examples from this laboratory, see: (a) Davies, S. G.; Iwamoto, K.;
Smethurst, C. A. P.; Smith, A. D.; Rodriguez-Solla, H. Synlett 2002, 1146; (b)
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ꢁ
ꢁ
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ꢁ
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ꢁ
ꢁ
Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez,
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b
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10. For selected examples from this laboratory, see: (a) Davies, S. G.; Garner, A. C.;
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ꢁ
~
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9992
S.G. Davies et al. / Tetrahedron 67 (2011) 9975e9992
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