Stereocontrolled synthesis and alkylation of cyclic β-amino esters: Asymmetric synthesis of a (-)-sparteine surrogate

Article abstract of DOI:10.1039/b712503h

A convenient method for the stereoselective synthesis of cyclic β-amino esters from an iodo αβ-unsaturated ester and α-methylbenzylamine is described. Subsequent enolate generation and alkylation proceeds with complete stereocontrol, with the two stereogenic centres working together. In this way, a functionalised piperidine suitable for alkaloid natural product synthesis was prepared. The usefulness of the methodology is exemplified with the concise synthesis of a (-)-sparteine surrogate. The Royal Society of Chemistry.

Full text of DOI:10.1039/b712503h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereocontrolled synthesis and alkylation of cyclic b-amino esters: asymmetric
synthesis of a (−)-sparteine surrogate†‡
Jean-Paul R. Hermet,a Aure´lien Viterisi,a Jonathan M. Wright,a Matthew J. McGrath,a Peter O’Brien,*a
a
Adrian C. Whitwood§ and John Gildayb
Received 14th August 2007, Accepted 20th September 2007
First published as an Advance Article on the web 2nd October 2007
DOI: 10.1039/b712503h
A convenient method for the stereoselective synthesis of cyclic b-amino esters from an iodo
ab-unsaturated ester and a-methylbenzylamine is described. Subsequent enolate generation and
alkylation proceeds with complete stereocontrol, with the two stereogenic centres working together. In
this way, a functionalised piperidine suitable for alkaloid natural product synthesis was prepared. The
usefulness of the methodology is exemplified with the concise synthesis of a (−)-sparteine surrogate.
Introduction
The piperidine structural motif is a common feature of numer-
ous biologically active pharmaceutical compounds and natural
products. As a result, the development of new methods for the
asymmetric synthesis of chiral piperidines is an important topic
that continues to capture the imagination of synthetic chemists.1
With this in mind, our group has an ongoing interest in the
preparation of cyclic b-amino esters 1 and their stereoselective
alkylation to amino esters anti-2 (Scheme 1).2,3 A number of
research groups have shown that the conversion of amino esters
1 → anti-2 is a particularly useful reaction for alkaloid natural
product synthesis and successful total syntheses of (+)- and (−)-
Scheme 1
lupinine,4,5 (−)-stelettamide B6 and ( )-thermopsine7 have been
pipecolic esters,9 conjugate addition of chiral amine derivatives
to ab-unsaturated esters and subsequent cyclisation,2,10,11 SN2
displacement–cyclisation of ab-unsaturated esters using a chiral
amine,3,12 stereoselective allylation of a chiral iminium ion6 and
hydrogenation of enamide esters using a chiral auxiliary13,14 or
chiral catalyst.15
successfully reported in recent times. In this paper, we report
a simple method for the preparation of either enantiomer of
cyclic b-amino esters 1 together with a study of the stereoselective
alkylation of amino esters 1 → anti-2 where R1 = a-methylbenzyl.
The usefulness of this methodology is demonstrated with the
concise synthesis of a (−)-sparteine surrogate.
Previous research in our group has led to the development of
two different approaches for the asymmetric synthesis of cyclic
b-amino esters: (i) conjugate addition of chiral lithium amides to
ab-unsaturated esters followed by N-deprotection and cyclisation2
and (ii) SN2 displacement of an iodo-substituted ab-unsaturated
ester using a chiral amine and concomitant cyclisation.3 Of these
two methods for synthesising cyclic b-amino esters 1, our preferred
approach, which we have now optimised, is the diastereoselective
Bunce-style16 SN2 substitution-cyclisation of iodo-ab-unsaturated
ester 3 and (S)-a-methylbenzylamine to amino esters (R,S)-
4 and (S,S)-4 (Scheme 2). The required iodo ester 3 can be
readily prepared in gram quantities from 5-chloropentanol via
Swern oxidation,17 Horner–Wadsworth–Emmons reaction18 and
Finkelstein reaction16 (84% yield over 3 steps, see Supporting
Information†). The initial conditions examined for the cycli-
sation process involved refluxing of iodo ester 3 and (S)-a-
methylbenzylamine in EtOH for 16 hours. This gave a 65 : 35
mixture of diastereomeric amino esters (R,S)-4 and (S,S)-4.3
However, we have recently found that carrying out the reaction
in DMF at room temperature for 64 hours (due to a slower
cyclisation step at this temperature) led to slightly improved
Results and discussion
Stereoselective synthesis of cyclic b-amino esters
Due to the importance of cyclic b-amino esters 1 in natural product
synthesis, it is not surprising to find that several approaches
for their asymmetric synthesis have been developed. These in-
clude chemical4 and enzymatic resolutions,8 homologation of
aDepartment of Chemistry, University of York, Heslington, York, YO10
5DD, UK. E-mail: paob1@york.ac.uk; Fax: +44 1904 432516; Tel: +44
1904 432535
bAstraZeneca, Process R & D, Avlon Works, Severn Road, Hallen, Bristol,
BS10 7ZE, UK
† Electronic supplementary information (ESI) available: Additional
experimental procedures (synthesis of iodo ester
bromomethyl)acrylate and proof of relative stereochemistry of alkylation
reactions). See DOI: 10.1039/b712503h
‡ CCDC reference number 623452. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b712503h
3 and ethyl (a-
§ Author to whom correspondence regarding the X-ray crystal structure
should be addressed.
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Scheme 3 Reagents and conditions: i, Pd(OH)2/C, NH4+HCO2−, EtOH,
reflux, 90 min; ii, Boc2O, Et3N, CH2Cl2, rt, 16 h.
(R,S)-5 was similarly deprotected to amine (R)-6 (86% yield).
An alternative N-deprotection method using reaction with a-
chloroethyl chloroformate was lower yielding.
Stereoselective alkylation of cyclic b-amino esters
Next, we studied the stereoselectivity of the alkylation of enolates
derived from the cyclic b-amino esters. The anti-stereoselective
alkylation of enolates generated from amino esters such as (R,S)-
4 was first reported by Lhommet et al. in 1999.20 Since enolate
alkylations of (R,S)-4 show better stereoselectivity than similar
reactions of N-Boc amino esters such as (R)- or (S)-7,4,6 we
speculated that the two stereogenic centres in amino ester (R,S)-
4 were working together to produce high stereoselectivity. To
specifically probe this, the stereoselectivity of enolate alkylation
of diastereomeric amino esters (R,S)-4 and (S,S)-4 was studied;
additionally, we included the achiral N-benzyl group (amino ester
12) as part of this study.
Scheme
2 Reagents and conditions: i, (S)-a-methylbenzylamine or
(S)-(1-naphthyl)ethylamine, Et3N, DMF, rt, 64 h.
stereoselectivity. In this way, a 75 : 25 mixture of (R,S)-4 and
(S,S)-4 was produced from which we isolated a 68% yield of amino
ester (R,S)-4 after chromatography.19 Using the same conditions,
a 63% yield of amino ester (R,S)-5 was obtained using (S)-(1-
naphthyl)ethylamine (Scheme 2).
In order to rationalise the preferred formation of amino esters
(R,S)-4/5 over (S,S)-4/5, we devised the following model (Fig. 1).
Bunce et al. have already shown that the reaction of benzylamine
with iodo ester 3 proceeds via intermolecular SN2 substitution
of the iodide followed by intramolecular conjugate addition of
the amine onto the ab-unsaturated ester.16 It is reasonable to
assume that the same mechanistic pathway occurs with (S)-a-
methylbenzylamine and (S)-(1-naphthyl)ethylamine and this has
allowed us to construct two preferred conformations A and B
for cyclisation to (R,S)-4/5 and (S,S)-4/5 respectively (Fig. 1).
In both A and B, the hydrogen of the chiral amine occupies the
most sterically hindered “inside” position. The major products
(R,S)-4/5 arise via A in which the sterically larger aryl (Ar) group
minimises its steric clash with the axial hydrogen on the carbon
labelled with a *. Thus, better stereoselectivity is obtained with the
more sterically demanding 1-naphthyl substituent.
Alkylations of amino esters (R,S)-4, (S,S)-4 ◦and 12 were carried
out by deprotonation using LHMDS at −78 C and subsequent
reaction with benzyl bromide or methyl iodide (Scheme 4). The
ratio of diastereomeric alkylation products was determined from
1
the H NMR spectra of the crude products; the yields quoted
are of single diastereomers (8/9) or of mixtures of diastere-
omeric adducts (10/11/13/14) after chromatography. Further
Fig. 1 Model to explain the sense of induction in the SN2 substitution–in-
tramolecular cyclisation of iodo ester 3.
To demonstrate the usefulness of the cyclisation methodology, it
was necessary to develop suitable conditions for N-deprotection of
the a-methylbenzyl chiral auxiliary. In our hands, the most useful
procedure involved transfer hydrogenolysis using Pd(OH)2/C and
ammonium formate (Scheme 3). Thus, under these conditions,
amino ester (R,S)-4 was converted into amine (R)-6 (>95 : 5 er
by chiral shift NMR spectroscopy) in 84% yield after distillation.
Subsequent Boc-protection delivered N-Boc protected amino ester
(R)-7 in 89% yield. Alternatively, N-Boc protected amino ester (R)-
7 could be directly prepared in 82% yield from (R,S)-4 without
isolation of the intermediate amine. The naphthylamino ester
Scheme 4 Reagents and conditions: i, (a) LHMDS, −78 ◦C, THF, 1 h;
(b) PhCH2Br or MeI.
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chromatography of the benzylated adducts 10 led to a 48% yield
of the major diastereomer which was identified as (S,S,S)-10
by X-ray crystallography (Fig. 2). A series of N-deprotections
and NMR spectroscopic correlations (detailed in the Supporting
Information†) enabled assignment of the stereochemistry of all
of the benzyl adducts and the methyl adducts were assigned by
analogy.
Fig. 3 Structures of (−)-sparteine and the (+)- and (−)-sparteine
surrogates.
(−)-cytisine.22 Work from our group has demonstrated that the
(+)-sparteine surrogate behaves in an enantiocomplementary fash-
ion in a wide range of reactions.23 In addition, other groups have
utilised the (+)-sparteine surrogate in syntheses of P-stereogenic
phosphine boranes, chiral diarylmethanes and (−)-kainic acid.24
In recent work, we have shown that sec-butyllithium complexes of
the (+)-sparteine surrogate are not only more reactive than their
(−)sparteine counterparts but also more effective in asymmetric
catalysis using sub-stoichiometric amounts of chiral diamine
ligands.25 As a result, the development of an efficient route to
the (−)-sparteine surrogate is currently of much importance. This
is exacerbated by the fact that the previous asymmetric routes for
the preparation of the (−)-sparteine surrogate are either long or
low yielding.26
Our retrosynthetic analysis of the (−)-sparteine surrogate is
shown in Scheme 5. It was envisaged that bis-lactam 15 would be a
suitable precursor to the (−)-sparteine surrogate. Disconnection of
the amides in bis-lactam 15 reveals a bis-b-amino ester 16 which
we anticipated disconnecting in two different ways. In the first
strategy, a chiral b-amino ester enolate 17 would be reacted with
Michael acceptor 18. By analogy with the highly anti-selective
enolate alkylations shown in Scheme 4, it was hoped that such a
Michael reaction would proceed with high anti-stereoselectivity.
Fig. 2 X-Ray crystal structure of anti-10.
As shown in Scheme 4, alkylation of amino ester (R,S)-4
proceeded with complete anti-stereoselectivity (as reported earlier
by Lhommet et al.20) to give adducts (R,R,S)-8 and (R,R,S)-
9.21 This was clearly the situation in which the two stereogenic
centres worked together since the analogous reactions with amino
ester (S,S)-4 generated 60 : 40 mixtures of diastereomeric adducts
10 and 11. Removal of the stereogenic centre on the N-alkyl
substituent restored high anti-stereoselectivity as shown by the
alkylations of amino ester 12 which proceeded in ≥90 : 10
diastereoselectivity. Thus, for alkylations of enolates derived from
cyclic b-amino esters, good levels of stereocontrol (∼90 : 10
diastereoselectivity) can be obtained using N-benzyl- or N-Boc-
protection4,6 but complete stereoselectivity (>98 : 2) requires the
use of the appropriately configured N-a-methylbenzyl substituent.
Such a pronounced difference with enolate alkylations of the
two diastereomers is significant since stereoselective routes to
amino esters such as (S,S)-4 via the conjugate addition of chiral
lithium amides to ab-unsaturated esters (followed by cyclisation)
have already been established by ourselves2 and Davies and co-
workers.11
Concise total synthesis of a (−)-sparteine surrogate
In order to demonstrate the usefulness of the synthesis and alky-
lation of cyclic b-amino esters such as (R,S)-4, we elected to carry
out the asymmetric synthesis of a (−)-sparteine surrogate (Fig. 3).
The intention was to use our new methodology to complete the
synthesis in significantly fewer steps than the previously published
asymmetric routes.
Due to the lack of availability of (+)-sparteine, we have been
actively engaged in the search for a chiral ligand that behaves as
the enantiomer of naturally occurring (−)-sparteine. Our efforts
culminated with the disclosure in 2002 of a suitable (+)-sparteine
surrogate which could be readily synthesised in three steps from
Scheme 5
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For stereocontrol at the more remote stereogenic centre, we
planned using a chiral auxiliary attached to the amine in the
Michael acceptor, as precedented in methodology developed by
a group at Pfizer for the synthesis of structurally related b-amino
acid derivatives.27 In the event, this strategy was flawed as we were
unable to bring about reaction of the enolate 17 with Michael
acceptor 18 under a range of conditions.
Thus, the second strategy (Scheme 5) was eventually adopted.
Here, the plan was to introduce an amino substituent by conjugate
addition to the ab-unsaturated ester functionality in amino ester
19. Amino ester 19 would itself be generated by stereoselective
alkylation chiral b-amino ester enolate 17 using an appropriate
a-bromomethyl acrylate. Originally, we had hoped to achieve
stereocontrol in the amine conjugate addition reaction using a
Davies-style chiral lithium amide nucleophile but no products were
obtained from any of our attempts. In the end, however, we had to
accept a stereorandom incorporation of this amino functionality
(vide infra).
Our five-step synthesis of the (−)-sparteine surrogate using the
second strategy from Scheme 5 is summarised in Scheme 6. Thus,
reaction of (S)-a-methylbenzylamine with iodo ester 3 under the
optimised conditions (Et3N, DMF, room temperature, 64 hours)
gave a 68% yield of cyclic b-amino ester (R,S)-4 after chromatog-
raphy. Next, enolate formation and stereoselective alkylation with
ethyl (a-bromomethyl)acrylate proceeded efficiently to give a single
diastereomeric alkylated b-amino ester 20 in 93% yield. The second
amino functionality in the (−)-sparteine surrogate was introduced
using conjugate addition of N-methyl hydroxylamine to the ab-
unsaturated ester.28 The reaction was high yielding (85% yield of
21) but, unsurprisingly, there was no stereocontrol at the newly-
formed stereogenic centre and an inseparable 50 : 50 mixture of
diastereomers was generated. All our attempts to introduce chiral
lithium amides or simple amines in conjugate addition reactions
with 20 were unsuccessful.
Our intention was to carry out transfer hydrogenolysis of 21
using Pd(OH)2/C and ammonium formate with a view to cleaving
both the N-a-methylbenzyl and N–O bonds. If successful, this
should facilitate double lactamisation to generate the required
bis-lactam 15. Only one of the diastereomeric hydroxylamines 21
possesses the correct relative stereochemistry for bis-lactamisation
and we were thus delighted to observe formation of the desired bis-
lactam 15 which was isolated in 48% yield after chromatography.
Another product was isolated from this reaction and it was
eventually identified as a single diastereomer of enamine ester
22 (34% isolated yield).29 The formation of enamine ester 22
was unexpected and presumably proceeds via N-a-methylbenzyl
cleavage and cyclisation of the unprotected amine onto an imine
(that could form by, for example, elimination of the hydroxyl group
from the hydroxylamine). Subsequent elimination of the amine
would then give the enamine ester. The relative stereochemistry of
enamine ester 22 has not been unequivocally proven but is assumed
to be as shown in Scheme 6 based on the relative stereochemistry
of 21.
Finally, LiAlH4 reduction of both lactam units in bis-lactam
15 led to the efficient formation of the (−)-sparteine surrogate
{[a]D −29.6 (c 1.0 in EtOH) ([a]D +26.5 (c 1.0 in EtOH)
for the (+)-sparteine surrogate26b)}, isolated in 68% yield after
Kugelrohr distillation. This five-step synthesis of the (−)-sparteine
surrogate from iodo ester 3 is the most efficient (17.5% overall
yield) and shortest synthesis to date. The generation of the
mixture of diastereomeric hydroxylamines 21 and their subsequent
transformation into two products, 22 and 15, which then need to
be separated have thus far precluded synthesis on a multi-gram
scale.
Conclusion
To summarise, we have developed a convenient chiral auxiliary-
mediated cyclisation method for the preparation of cyclic b-amino
esters (R,S)-4. Furthermore, we have exemplified the synthetic
utility of the stereoselective alkylation of amino esters such as
(R,S)-4 with the shortest synthesis of the (−)-sparteine surrogate.
We hope that the methodology reported herein will be of use
to those involved in the asymmetric synthesis of piperidinyl-
containing natural products and pharmaceutical candidates.
Experimental
General
Water is distilled water. Et2O and THF were freshly distilled from
benzophenone ketyl whereas CH2Cl2 was freshly distilled from
CaH2. Petrol refers to the fraction of petroleum ether with a
boiling point range of 40–60 ◦C. All reactions were carried out
under O2-free N2 or Ar using oven-dried and/or flame dried
glassware. Flash column chromatography was carried out using
Fluka silica gel 60 (0.035–0.070 mm particle size). Thin layer
chromatography was carried out using Merck F254 alumina-backed
silica plates. Proton (270 MHz or 400 MHz) and carbon (67.9
Scheme 6 Reagents and conditions: i, (S)-a-methylbenzylamine, Et3N,
DMF, rt, 64 h; ii, (a) LHMDS, −78 ◦C, THF,
1 h; (b) ethyl
(a-bromomethyl)acrylate; iii, MeHNOH·HCl, Et3N, CH2Cl2, rt, 64 h; iv,
Pd(OH)2/C, NH4+HCO2−, EtOH, reflux, 16 h; v, LiAlH4, THF, reflux,
16 h.
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or 100.6 MHz) NMR spectra were recorded using an internal
deuterium lock. All samples were recorded in CDCl3. Chemical
shifts are quoted in parts per million and referenced to CHCl3
(7.27). Carbon NMR spectra were recorded with broadband
proton decoupling and were assigned using DEPT experiments.
Infra-red spectra were recorded on an FT-IR spectrometer. Optical
rotations were recorded at room temperature (20 ◦C) and [a]D
measurements are given in units of 10−1 deg cm2 g−1. For Ku¨gelrohr
distillation, the temperatures quoted correspond to the oven tem-
peratures.
Ethyl {(2R)-1-[(1S)-1-(1-naphthyl)ethyl]piperidin-2-yl}acetate
(R,S)-5 and ethyl {(2S)-1-[(1S)-1-(1-naphthyl)ethyl]piperidin-
2-yl}acetate (S,S)-5
Using the general procedure for cyclisation, (S)-(1-naphthyl)-
ethylamine (0.32 mL, 1.95 mmol), iodoester 3 (500 mg, 1.77 mmol)
and Et3N (0.21 mL, 1.95 mmol) in DMF (10 mL) gave the
1
crude product which contained an 85 : 15 mixture (by H NMR
spectroscopy) of amino esters (R,S)-5 and (S,S)-5. Purification by
flash chromatography with petrol–EtOAc (9 : 1) as eluent gave
amino ester (R,S)-5 (365 mg, 63%) as a pale yellow oil, [a]D −84.2
(c 1.0 in CHCl3); RF(9 : 1 petrol–EtOAc) 0.25; IR (CDCl3): 1720
−1
1
=
(C O) cm ; H NMR (400 MHz, CDCl3) d: 8.49 (br s, 1H), 7.89–
7.84 (m, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.66 (br d, J = 6.0 Hz,
1H), 7.52–7.43 (m, 3H), 4.49–4.36 (m, 1H), 4.25–4.13 (m, 2H),
3.73–3.69 (m, 1H), 2.79 (dd, J = 13.5, 3.5 Hz, 1H), 2.68 (dd, J =
13.5, 10.0 Hz, 1H), 2.40 (dt, J = 12.0, 4.5 Hz, 1H), 2.25 (ddd,
J = 12.0, 10.0, 3.0 Hz, 1H), 1.92–1.84 (m, 1H), 1.69–1.64 (m, 1H),
1.59–1.26 (m, 4H), 1.49 (d, J = 6.5 Hz, 3H), 1.31 (t, J = 7.0 Hz,
General procedure for cyclisation of iodoester
A solution of chiral amine (3.85 mmol), iodoester 3 (1.00 g,
3.50 mmol) and Et3N (3.85 mmol) in DMF (20 mL) under N2 was
stirred at rt for 64 h. Water (20 mL) and Et2O (20 mL) were added
and the two layers were separated. The aqueous layer was extracted
with Et2O (2 × 20 mL) and the combined organic extracts were
dried (MgSO4) and evaporated under reduced pressure to give the
crude product.
3H); 13C NMR (100.6 MHz, CDCl3) d: 173.3 (C O), 141.4 (ipso-
=
Ar), 134.0 (ipso-Ar), 131.6 (ipso-Ar), 128.6 (Ar), 127.1 (Ar), 125.4
(Ar), 125.2 (Ar), 125.1 (Ar), 124.6 (Ar), 124.0 (Ar), 60.3 (CH2),
57.0 (br, CH), 52.1 (CH), 45.1 (CH2), 30.6 (CH2), 29.7 (CH2), 25.7
(CH2), 20.2 (CH2), 18.1 (Me), 14.2 (Me); MS (CI, NH3) m/z 326
[(M + H)+, 100], 238 (10); HRMS (CI, NH3) m/z [M + H]+ calcd
for C21H27NO2, 326.2120; found, 326.2125 and amino ester (S,S)-5
(40 mg, 7%) as a pale yellow oil, [a]D +5.5 (c 0.75 in CHCl3); RF(9 :
Ethyl {(2R)-1-[(1S)-1-phenylethyl]piperidin-2-yl}acetate (R,S)-4
and ethyl {(2S)-1-[(1S)-1-phenylethyl]piperidin-2-yl}acetate
(S,S)-4
Using the general procedure for cyclisation, (S)-a-methylbenzyl-
amine (0.5 mL, 3.85 mmol), iodoester 3 (1.00 g, 3.5 mmol)
and Et3N (0.55 mL, 3.85 mmol) in DMF (20 mL) gave the
−1
1
=
1 petrol–EtOAc) 0.15; IR (CDCl3): 1720 (C O) cm ; H NMR
(400 MHz, CDCl3) d: 8.57–8.54 (m, 1H), 7.87–7.82 (m, 1H), 7.73
(d, J = 8.0 Hz, 1H), 7.57–7.54 (m, 1H), 7.50–7.39 (m, 3H), 4.44
(q, J = 6.5 Hz, 1H), 3.95 (q, J = 7.5 Hz, 2H), 3.47–3.41 (m, 1H),
2.92 (dt, J = 13.0, 3.0 Hz, 1H), 2.71 (dd, J = 13.5, 5.0 Hz, 1H),
2.54 (dt, J = 13.0, 2.5 Hz, 1H), 2.50 (dd, J = 13.5, 9.0 Hz, 1H),
1.77–1.25 (m, 6H), 1.49 (d, J = 6.5 Hz, 3H), 1.08 (t, J = 7.5 Hz,
1
crude product which contained a 75 : 25 mixture (by H NMR
spectroscopy) of amino esters (R,S)-4 and (S,S)-4. Purification by
flash chromatography with petrol–EtOAc (9 : 1) as eluent gave
amino ester (R,S)-4 (720 mg, 68%) as a pale yellow oil, [a]D −36.1
(c 1.0 in CHCl3); RF(9 : 1 petrol–EtOAc) 0.3; IR (CDCl3): 1730
3H); 13C NMR (100.6 MHz, CDCl3) d: 173.1 (C O), 141.3 (ipso-
=
−1
1
=
(C O) cm ; H NMR (400 MHz, CDCl3) d: 7.38 (dd, J = 8.0,
1.5 Hz, 2H), 7.30 (td, J = 8.0, 1.5 Hz, 2H), 7.22 (tt, J = 8.0, 1.5 Hz,
1H), 4.20–4.12 (m, 2H), 3.70 (q, J = 6.5 Hz, 1H), 3.51 (dq, J = 9.0,
4.5 Hz, 1H), 2.63–2.52 (m, 2H), 2.32 (dt, J = 12.0, 5.0 Hz, 1H),
2.21 (ddd, J = 12.0, 9.0, 4.0 Hz, 1H), 1.82–1.74 (m, 1H), 1.63–
1.52 (m, 2H), 1.50–1.36 (m, 3H), 1.31 (d, J = 6.5 Hz, 3H), 1.27 (t,
Ar), 134.2 (ipso-Ar), 131.5 (ipso-Ar), 128.7 (Ar), 127.2 (Ar), 125.5
(Ar), 125.2 (Ar), 125.15 (Ar), 124.9 (Ar), 124.4 (Ar), 60.0 (CH2),
58.3 (CH), 51.9 (CH), 42.7 (CH2), 31.4 (CH2), 27.7 (CH2), 24.6
(CH2), 21.0 (Me), 19.2 (CH2), 14.0 (Me); MS (CI, NH3) m/z 326
[(M + H)+, 100], 238 (30); HRMS (CI, NH3) m/z [M + H]+ calcd
for C21H27NO2, 326.2120; found, 326.2122.
J = 7.0 Hz, 3H); 13C NMR (67.9 MHz, CDCl3) d: 173.1 (C O),
=
146.1 (ipso-Ph), 128.0 (Ph), 127.2 (Ph), 126.4 (Ph), 60.2 (CH2),
59.2 (C), 52.3 (CH), 44.9 (CH2), 32.0 (CH2), 29.9 (CH2), 25.6
(CH2), 20.7 (Me), 17.7 (CH2), 14.1 (Me); MS (CI, NH3) m/z 276
[(M + H)+, 100], 188 (80), 172 (40), 105 (50); HRMS (CI, NH3)
m/z [M + H]+ calcd for C17H25NO2, 276.1964; found, 276.1967
and amino ester (S,S)-4 (240 mg, 23%) as a pale yellow oil, [a]D
−6.5 (c 1.0 in CHCl3); RF(9:1 petrol–EtOAc) 0.15; IR (film): 1730
(R)-Ethyl piperidin-2-ylacetate (R)-6
A suspension of 20% Pd(OH)2 on C (35 mg, 0.04 mmol), amino
+
−
ester (R,S)-4 (200 mg, 0.74 mmol) and NH4 HCO2 (140 mg,
2.22 mmol) in EtOH (2 mL) was stirred and heated at reflux
under N2 for 90 min. After being allowed to cool to rt, the solids
were removed by filtration through Celite and washed with Et2O
(50 mL). Then, 2 M NH4OH(aq) (10 mL) was added to the filtrate
and the two layers were separated. The aqueous layer was extracted
with Et2O (3 × 20 mL) and the combined organic extracts were
dried (MgSO4) and evaporated under reduced pressure to give
the crude product as a colourless oil. Purification by Ku¨gelrohr
distillation gave amine (R)-6 (104 mg, 84%, >90% ee by NMR
spectroscopy in the presence of 7.0 equiv. (S)-2,2,2-trifluoro-1-
(9-anthryl)ethanol) as a colourless oil, bp 80–85 ◦C/2.0 mmHg
(lit.,26b 85–90 ◦C/1.5 mmHg); [a]D −10.8 (c 1.0 in CHCl3); RF(9 :
−1
1
=
(C O) cm ; H NMR (400 MHz, CDCl3) d: 7.37–7.27 (m, 4H),
7.25–7.20 (m, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.84 (q, J = 6.5 Hz,
1H), 3.51 (dq, J = 9.0, 4.5 Hz, 1H), 2.69 (dd, J = 14.0, 4.5 Hz,
1H), 2.63–2.51 (m, 2H), 2.45 (dd, J = 14.0, 9.0 Hz, 1H), 1.71–
1.38 (m, 6H), 1.34 (d, J = 6.5 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H);
13
=
C NMR (67.9 MHz, CDCl3) d: 172.9 (C O), 144.8 (ipso-Ph),
128.1 (Ph), 127.3 (Ph), 126.6 (Ph), 60.0 (CH2), 59.0 (CH), 52.6
(CH), 43.4 (CH2), 32.7 (CH2), 28.9 (CH2), 24.9 (CH2), 21.2 (Me),
20.1 (CH2), 14.1 (Me); MS (EI) m/z 275 [M+, 20], 260 (65), 105
(100); HRMS (EI) m/z M+ calcd for C17H25NO2, 275.1885; found,
275.1884.
1
1 CH2Cl2–MeOH) 0.2; H NMR (400 MHz, CDCl3) d: 4.08 (q,
3618 | Org. Biomol. Chem., 2007, 5, 3614–3622
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J = 7.0 Hz, 2H), 3.04–2.95 (m, 1H), 2.90–2.81 (m, 1H), 2.60 (td,
J = 11.5, 3.0 Hz, 1H), 2.33–2.28 (m, 2H), 2.10 (br s, 1H), 1.75–1.64
(m, 1H), 1.58–1.46 (m, 2H), 1.40–1.27 (m, 2H), 1.23 (t, J = 7.0 Hz,
3H), 1.21–1.12 (m, 1H). Spectroscopic data consistent with that
reported in the literature.26b
126.5 (Ph), 125.9 (Ph), 60.2 (CH2), 58.9 (CH), 55.4 (CH), 49.0
(CH), 44.1 (CH2), 31.9 (CH2), 25.1 (CH2), 24.1 (CH2), 23.3 (CH2),
14.1 (Me), 12.7 (Me); MS (CI, NH3) m/z 366 [(M + H)+, 100], 188
(40). The optical rotation of benzylated amino ester (R,R,S)-8 was
erroneously reported with a positive sign.20
(R)-tert-Butyl 2-(2-ethoxy-2-oxoethyl)piperidin-1-carboxylate
(R)-7
Ethyl (2R)-{(2R)-1-[(1S)-1-phenylethyl]piperidin-2-yl}propionate
(R,R,S)-9
A solution of Boc2O (421 mg, 1.93 mmol) in CH2Cl2 (6 mL) was
added dropwise to a stirred solution of amine (R)-6 (150 mg,
0.88 mmol) and Et3N (1.22 mL, 8.80 mmol) in CH2Cl2 (6 mL) at
rt under N2. The resulting solution was stirred at rt for 16 h. Then,
2 M HCl(aq) (5 mL) was added and the two layers were separated.
The organic layer was washed with brine (2 × 5 mL) and water
(5 mL), dried (MgSO4) and evaporated under reduced pressure
to give the crude product. Purification by flash chromatography
with petrol–EtOAc (3 : 1) as eluent gave N-Boc amino ester (R)-7
(212 mg, 89%) as a colourless oil, [a]D +7.4 (c 1.0 in CHCl3); RF(3 :
1 CH2Cl2–MeOH) 0.45; 1H NMR (400 MHz, CDCl3) d: 4.72–4.62
(m, 1H), 4.09 (q, J = 7.0 Hz, 2H), 4.00–3.91 (m, 1H), 2.76 (br
t, J = 13.0 Hz, 1H), 2.55 (dd, J = 14.0, 7.5 Hz, 1H), 2.50 (dd,
J = 14.0, 8.0 Hz, 1H), 1.67–1.47 (m, 6H), 1.43 (s, 9H), 1.23 (t,
J = 7.0 Hz, 3H), 1.21–1.12 (m, 1H). Spectroscopic data consistent
with that reported in the literature.30
Using the general procedure for alkylation, amino ester (R,S)-4
(250 mg, 0.90 mmol), LHMDS (1.28 mL of a 1.06 M solution
in THF, 1.30 mmol) and MeI (85 lL, 1.36 mmol) in THF
1
(6 mL) gave the crude product as a single diastereomer (by H
NMR spectroscopy). Purification by flash chromatography with
petrol–EtOAc–Et3N (90 : 10 : 1) as eluent gave methylated amino
ester (R,R,S)-9 (224 mg, 88%) as a colourless oil, [a]D −12.2 (c
1.1 in CH2Cl2); RF(9 : 1 petrol–EtOAc) 0.3; IR (CHCl3): 1725
−1
1
=
(C O) cm ; H NMR (400 MHz, CDCl3) d: 7.41 (d, J = 7.5 Hz,
2H), 7.30 (t, J = 7.5 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 4.26–4.05
(m, 3H), 3.07 (quintet, J = 7.0 Hz, 1H), 2.93–2.85 (m, 1H), 2.60
(ddd, J = 12.0, 6.0, 3.5 Hz, 1H), 2.33 (ddd, J = 12.0, 9.0, 3.0 Hz,
1H), 1.78–1.20 (m, 6H), 1.32 (d, J = 6.5 Hz, 3H), 1.26 (t, J =
7.0 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H); 13C NMR (100.6 MHz,
=
CDCl3) d: 175.4 (C O), 144.7 (ipso-Ph), 127.9 (Ph), 127.5 (Ph),
126.3 (Ph), 60.2 (CH2), 58.8 (CH), 54.9 (CH), 44.3 (CH2), 40.1
(CH), 24.7 (CH2), 24.6 (CH2), 23.5 (CH2), 14.2 (Me), 12.0 (Me),
10.6 (Me); MS (CI, NH3) m/z 290 [(M + H)+, 100], 188 (20);
HRMS (CI, NH3) m/z [M + H]+ calcd for C18H27NO2, 290.2120;
found, 290.2121. The optical rotation of benzylated amino ester
(R,R,S)-9 was erroneously reported with a positive sign.20
General procedure for alkylation of amino esters
LHMDS (1.06 M solution in THF, 1.30 mmol) was added
dropwise to a stirred solution of the amino ester (250 mg,
0.90 mmol) in THF (6 mL) at −78 ◦C under N2. After stirring
at −78 ◦C for 1 h, the alkyl halide (1.30 mmol) was added
dropwise. The resulting solution was allowed to warm to rt over
4 h and stirred at rt for 12 h. Then, the solvent was evaporated
under reducedpressure. The residue was partitionedbetweenwater
(10 mL) and 1 : 1 Et2O–CH2Cl2 (10 mL). The two layers were
separated and the aqueous layer was extracted with Et2O–CH2Cl2
(3 × 10 mL). The combined organic layers were dried (MgSO4)
and evaporated under reduced pressure to give the crude product
as a yellow oil.
Ethyl (2S)-3-phenyl-2-{(2S)-1-[(1S)-1-phenylethyl]piperidin-2-
yl}propionate anti-10 and ethyl (2R)-3-phenyl-2-{(2S)-1-[(1S)-1-
phenylethyl]piperidin-2-yl}propionate syn-10
Using the general procedure for alkylation, amino ester (S,S)-4
(199 mg, 0.72 mmol), LHMDS (1.03 mL of a 1.06 M solution
in THF, 1.09 mmol) and benzyl bromide (0.13 mL, 1.09 mmol)
in THF (6 mL) gave the crude product as a 60 : 40 mixture
of benzylated amino esters anti-10 and syn-10 (by 1H NMR
spectroscopy). Purification by flash chromatography with petrol–
EtOAc (97 : 3) as eluent gave benzylated amino ester anti-10
(127 mg, 48%) as a white solid, mp 69–71 ◦C; [a]D −44.8 (c
1.0 in CH2Cl2); RF(9 : 1 petrol–EtOAc) 0.3; IR (CHCl3): 1725
Ethyl (2R)-3-phenyl-2-{(2R)-1-[(1S)-1-phenylethyl]piperidin-
2-yl}propionate (R,R,S)-8
Using the general procedure for alkylation, amino ester (R,S)-4
(183 mg, 0.66 mmol), LHMDS (0.94 mL of a 1.06 M solution
in THF, 1.00 mmol) and benzyl bromide (0.12 mL, 1.00 mmol)
in THF (3.7 mL) gave the crude product as a single diastereomer
(by 1H NMR spectroscopy). Purification by flash chromatography
with petrol–EtOAc–Et3N (90 : 10 : 1) as eluent gave benzylated
amino ester (R,R,S)-8 (212 mg, 88%) as a colourless oil, [a]D −6.4
(c 1.0 in CH2Cl2); RF(9 : 1 petrol–EtOAc) 0.35; IR (CHCl3): 1720
−1
1
=
(C O) cm ; H NMR (270 MHz, CDCl3) d: 7.30–7.10 (10H, m),
4.13 (q, J = 6.5 Hz, 1H), 4.05 (q, J = 7.0 Hz), 3.47–3.25 (m,
2H), 2.98–2.80 (m, 3H), 2.23 (br d, J = 13.5 Hz, 1H), 1.75–1.50
(m, 6H), 1.31 (d, J = 6.5 Hz, 3H), 1.01 (t, J = 7.0 Hz, 3H); 13C
=
NMR (67.9 MHz, CDCl3) d: 174.5 (C O), 145.9 (ipso-Ph), 139.9
(ipso-Ph), 128.7 (Ph), 128.3 (Ph), 128.0 (Ph), 127.2 (Ph), 126.5
(Ph), 126.1 (Ph), 59.7 (CH2), 57.2 (CH), 55.7 (CH), 49.1 (CH),
42.9 (CH2), 35.5 (CH2), 21.7 (CH2), 21.5 (Me), 20.4 (CH2), 19.9
(CH2), 14.1 (Me); MS (CI, NH3) m/z 366 [(M + H)+, 80], 262
(20), 188 (100), 105 (10), 84 (35); HRMS (CI, NH3) m/z [M +
H]+ calcd for C24H31NO2, 366.2433; found, 366.2428, a 15 : 85
−1
1
=
(C O) cm ; H NMR (400 MHz, CDCl3) d: 7.45 (d, J = 7.5 Hz,
2H), 7.34 (t, J = 7.5 Hz, 2H), 7.28–7.10 (6H, m), 4.30 (q, J =
6.5 Hz, 1H), 4.18–3.97 (m, 2H), 3.25 (q, J = 7.0 Hz, 1H), 2.96
(d, J = 7.0 Hz, 2H), 2.94–2.88 (m, 1H), 2.68 (ddd, J = 12.5,
6.0, 3.5 Hz, 1H), 2.40 (ddd, J = 12.5, 8.5, 3.0 Hz, 1H), 1.79–1.02
1
mixture (by H NMR spectroscopy) of benzylated amino esters
(m, 6H), 1.34 (d, J = 6.5 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H);
anti-10 and syn-10 (90 mg, 34%) as a colourless oil and benzylated
amino ester syn-10 (44 mg, 16%) as a colourless oil, [a]D +2.9 (c
1.75 in CH2Cl2); RF(9 : 1 petrol–EtOAc) 0.3; IR (CHCl3): 1720
13
=
C NMR (100.6 MHz, CDCl3) d: 174.1 (C O), 144.6 (ipso-Ph),
140.9 (ipso-Ph), 128.8 (Ph), 128.3 (Ph), 128.0 (Ph), 127.6 (Ph),
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−1
1
=
(C O) cm ; H NMR (400 MHz, CDCl3) d: 7.40–7.12 (10H, m),
4.22 (q, J = 6.5 Hz, 1H), 3.98 (q, J = 7.0 Hz), 3.47–3.25 (m, 3H),
2.80 (dd, J = 13.5, 11.0 Hz, 1H), 2.78–2.67 (m, 1H), 2.40 (br d,
J = 14.5 Hz, 1H), 1.85–1.47 (m, 6H), 1.34 (d, J = 6.5 Hz, 3H),
1.04 (t, J = 7.0 Hz, 3H); 13C NMR (67.9 MHz, CDCl3) d: 175.2
(30 mL), dried (MgSO4) and evaporated under reduced pressure to
give the crude product. Purification by flash chromatography with
petrol–EtOAc (9 : 1) as eluent gave amino ester rac-12 (878 mg,
75%) as a pale yellow oil, RF(9 : 1 petrol–EtOAc) 0.35; 1H NMR
(400 MHz, CDCl3) d: 7.38–7.18 (m, 5H), 4.13 (q, J = 7.0 Hz, 2H),
3.80 (d, J = 13.5 Hz, 1H), 3.36 (d, J = 13.5 Hz, 1H), 3.01–2.93
(m, 1H, CHN), 2.71 (dd, J = 14.5, 4.5 Hz, 1H), 2.66–2.58 (m,
1H), 2.44 (dd, J = 14.5, 8.0 Hz, 1H), 2.21–2.13 (m, 1H), 1.81–
1.70 (m, 1H), 1.69–1.58 (m, 1H), 1.58–1.36 (m, 4H), 1.24 (t, J =
7.0 Hz, 3H). Spectroscopic data consistent with that reported in
the literature.16
=
(C O), 146.4 (ipso-Ph), 140.5 (ipso-Ph), 128.8 (Ph), 128.2 (Ph),
127.2 (Ph), 126.7 (Ph), 125.9 (Ph), 59.9 (CH2), 57.5 (CH), 54.8
(CH), 48.8 (CH), 42.5 (CH2), 36.9 (CH2), 22.6 (CH2), 22.4 (Me),
20.2 (CH2), 19.9 (CH2), 14.0 (Me) (one Ph resonance not resolved);
MS (CI, NH3) m/z 366 [(M + H)+, 100], 262 (20), 188 (70), 84 (30);
HRMS (CI, NH3) m/z [M + H]+ calcd for C24H31NO2, 366.2433;
found, 366.2428.
Ethyl (2S*)-2-phenyl-3-[(2S*)-1-benzylpiperidin-2-yl]propionate
anti-13 and ethyl (2R*)-2-phenyl-3-[(2S*)-1-benzylpiperidin-
2-yl]propionate syn-13
Crystal structure determination of ethyl (2S)-3-phenyl-2-{(2S)-1-
[(1S)-1-phenylethyl]piperidin-2-yl}propionate anti-10
Crystal data. C24H31NO2, M = 365.50, monoclinic, a =
Using the general procedure for alkylation, amino ester rac-12
(212 mg, 0.81 mmol), LHMDS (1.15 mL of a 1.06 M solution
in THF, 1.21 mmol) and benzyl bromide (0.15 mL, 1.21 mmol)
in THF (6 mL) gave the crude product as a 90 : 10 mixture
of benzylated amino esters anti-13 and syn-13 (by 1H NMR
spectroscopy). Purification by flash chromatography with petrol–
◦
˚
7.7573(6), b = 6.5351, c = 20.5605(15) A, b = 93.341(2) , U =
3
˚
1040.54(14) A , T = 115(2) K, space group P21, Z = 2, l(Mo-
Ka) = 0.073 mm−1, 7226 reflections measured, 4564 unique (Rint
=
0.0193) which were used in all calculations. The final R1 was 0.0373
(I > 2rI) and wR2 was 0.0889 (all data). CCDC reference number
623452.‡
1
EtOAc (9 : 1) as eluent gave a 90 : 10 mixture (by H NMR
spectroscopy) of benzylated amino esters anti-13 and syn-13
(269 mg, 94%) as a colourless oil, RF(9 : 1 petrol–EtOAc) 0.3;
Ethyl (2S)-{(2S)-1-[(1S)-1-phenylethyl]piperidin-2-yl}propionate
anti-11 and ethyl (2R)-{(2S)-1-[(1S)-1-phenylethyl]piperidin-
2-yl}propionate syn-11
−1
1
=
IR (CHCl3): 1730 (C O) cm ; H NMR (400 MHz, CDCl3) d:
7.35–7.10 (10H, m), 4.11–3.94 (m, 3H), 3.52 (d, J = 13.5 Hz,
0.1H), 3.45 (d, J = 13.5 Hz, 0.9H), 3.26 (ddd, J = 11.0, 7.0, 3.0,
1H), 3.00 (dd, J = 13.5, 2.5, 1H), 2.92–2.77 (m, 2H), 2.73 (td, J =
7.5, 3.5 Hz, 1H), 2.29 (ddd, J = 12.5, 9.0, 3.5, 1H), 2.16 (ddd, J =
12.5, 9.0, 3.5, 1H), 1.78–1.34 (m, 6H), 1.10 (t, J = 7.0 Hz, 2.7H),
1.03 (t, J = 7.0 Hz, 0.3H); HRMS (CI, NH3) m/z [M + H]+ calcd
for C23H29NO2, 352.2277; found, 352.2279.
Using the general procedure for alkylation, amino ester (S,S)-4
(204 mg, 0.74 mmol), LHMDS (1.05 mL of a 1.06 M solution in
THF, 1.11 mmol) and MeI (70 lL, 1.12 mmol) in THF (6 mL)
gave the crude product as a 60 : 40 mixture of methylated amino
esters anti-11 and syn-11 (by 1H NMR spectroscopy). Purification
by flash chromatography with petrol–EtOAc (95 : 5) as eluent gave
a 65 : 35 mixture (by 1H NMR spectroscopy) of methylated amino
esters anti-11 and syn-11 (172 mg, 80%) as a colourless oil, RF(9 :
Ethyl (2S*)-2-[(2S*)-1-benzylpiperidin-2-yl]propionate anti-14
and ethyl (2R*)-2-[(2S*)-1-benzylpiperidin-2-yl]propionate syn-14
−1
1
=
1 petrol–EtOAc) 0.3; IR (CHCl3): 1720 (C O) cm ; H NMR
(270 MHz, CDCl3) d: 7.34–7.16 (m, 5H), 4.21–4.06 (m, 3H), 3.28–
3.11 (m, 2H), 2.87 (ddd, J = 14.5, 11.5, 3.0, 0.65H), 2.55 (ddd,
J = 14.5, 11.5, 3.0, 0.35H), 2.30 (dt, J = 14.5, 4.5, 0.35H), 2.24
(dt, J = 14.5, 4.0, 0.65H), 1.75–1.42 (m, 6H), 1.25–1.12 (m, 6H),
1.14 (d, J = 6.5 Hz, 3H); 13C NMR (67.9 MHz, CDCl3) d: 176.7
Using the general procedure for alkylation, amino ester rac-12
(110 mg, 0.42 mmol), LHMDS (0.60 mL of a 1.06 M solution in
THF, 0.63 mmol) and MeI (39 lL, 0.63 mmol) in THF (2.5 mL)
gave the crude product as a 95 : 5 mixture of methylated amino
esters anti-14 and syn-14 (by 1H NMR spectroscopy). Purification
by flash chromatography with petrol–EtOAc (9 : 1) as eluent gave
a 95 : 5 mixture (by 1H NMR spectroscopy) of methylated amino
esters anti-14 and syn-14 (96 mg, 82%) as a colourless oil, RF(9 :
=
=
(C O), 176.2 (C O), 146.5 (ipso-Ph), 146.0 (ipso-Ph), 128.2 (Ph),
128.0 (Ph), 127.2 (Ph), 126.6 (Ph), 126.5 (Ph), 60.0 (CH2), 59.9
(CH2), 57.3 (CH), 57.1 (CH), 56.2 (CH), 55.3 (CH), 43.0 (CH2),
42.5 (CH2), 40.3 (CH), 39.7 (CH), 22.6 (CH2), 22.4 (Me), 21.6
(Me), 20.8 (CH2), 20.4 (CH2), 20.3 (CH2), 20.0 (CH2), 15.5 (Me),
14.3 (Me), 14.2 (Me), 14.0 (Me); MS (CI, NH3) m/z 290 [(M +
H)+, 100], 188 (80), 105 (20), 84 (35); HRMS (CI, NH3) m/z [M +
H]+ calcd for C18H27NO2, 290.2122; found, 290.2121.
−1
1
=
1 petrol–EtOAc) 0.35; IR (CHCl3): 1735 (C O) cm ; H NMR
(400 MHz, CDCl3) d: 7.40–7.11 (m, 5H), 4.21–4.08 (m, 2H), 3.94
(d, J = 13.5 Hz, 0.95H), 3.76 (d, J = 13.5 Hz, 0.05H), 3.33 (d, J =
13.5 Hz, 0.95H), 3.21 (d, J = 13.5 Hz, 0.05H), 3.10 (quintet, J =
7.0 Hz, 1H), 2.85 (ddd, J = 12.5, 4.5, 3.5, 1H), 2.76–2.72 (m, 1H),
2.09 (ddd, J = 12.5, 9.5, 3.0, 1H), 1.71–1.63 (m, 1H), 1.55–1.20
(m, 5H), 1.24 (t, J = 7.0 Hz, 3H), 1.15 (d, J = 7.0 Hz, 3H); HRMS
(CI, NH3) m/z [M + H]+ calcd for C17H25NO2, 276.1964; found,
276.1963.
Ethyl (1-benzylpiperidin-2-yl)acetate rac-12
A stirred solution of benzylamine (0.55 mL, 4.98 mmol), iodoester
3 (1.27 g, 4.49 mmol) and Et3N (0.70 mL, 4.98 mmol) in EtOH
(12.5 mL) under N2 was heated at reflux for 16 h. After being
allowed to cool to rt, the solvent was evaporated under reduced
pressure. Water (20 mL) was added and the mixture was extracted
with Et2O (2 × 30 mL). The combined organic extracts were
washed with water (30 mL), 5% Na2S2O3(aq) (30 mL) and brine
Diethyl (4R)-2-methylene-4-{(2R)-1-[(1S)-1-phenylethyl]piperidin-
2-yl}pentanedioate (R,R,S)-20
Using the general procedure for alkylation, amino ester (R,S)-4
(125 mg, 0.46 mmol), LHMDS (0.66 mL of a 1.06 M solution
3620 | Org. Biomol. Chem., 2007, 5, 3614–3622
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in THF, 0.69 mmol) and ethyl (a-bromomethyl)acrylate (134 mg,
(1R,9aR)-Diethyl 2,6,7,8,9,9a-hexahydro-1H-quinolizine-1,3-
0.69 mmol) in THF (3 mL) gave the crude product as a single
diastereomer (by H NMR spectroscopy). Purification by flash
dicarboxylate 22 and (1R,5S,11aR)-3-methyl-octahydro-1,5-
methanopyrido[1,2-a][1,5]diazocine-2,6-dione 15
1
chromatography with petrol–EtOAc (9 : 1) as eluent gave alkylated
amino ester (R,R,S)-20 (165 mg, 93%) as a colourless oil, [a]D
−10.7 (c 1.0 in CHCl3); RF(9 : 1 petrol–EtOAc) 0.25; IR (film):
A suspension of 20% Pd(OH)2 on C (20 mg, 0.02 mmol), a
50 : 50 mixture of hydroxylamines 21 (110 mg, 0.25 mmol) and
+
−
NH4 HCO2 (48 mg, 0.75 mmol) in EtOH (1 mL) was stirred
and heated at reflux under N2 for 16 h. After being allowed to
cool to rt, the solids were removed by filtration through Celite
and washed with CH2Cl2 (50 mL). Then, 2 M NH4OH(aq) (5 mL)
was added to the filtrate and the two layers were separated. The
aqueous layer was extracted with CH2Cl2 (3 × 10 mL) and the
combined organic extracts were dried (MgSO4) and evaporated
under reduced pressure to give the crude product. Purification
by flash chromatography with CH2Cl2–MeOH (50 : 1) and then
CH2Cl2–MeOH (9 : 1) as eluent gave quinolizidine 22 (24 mg,
34%) as a colourless oil, [a]D +94.4 (c 1.0 in CHCl3); RF(9 : 1
−1
1
=
1720 (C O) cm ; H NMR (400 MHz, CDCl3) d: 7.37 (br d,
J = 7.5 Hz, 2H), 7.30 (br t, J = 7.5, Hz, 2H), 7.22 (br t, J =
7.5, Hz, 1H), 6.16 (d, J = 1.0 Hz, 1H), 5.57 (d, J = 1.0 Hz, 1H),
4.28 (q, J = 6.5 Hz, 1H), 4.24–4.02 (m, 4H), 3.30 (ddd, J = 12.0,
7.0, 3.0 Hz, 1H), 2.84 (td, J = 7.0, 3.5 Hz, 1H), 2.77 (ddd, J =
13.0, 8.0, 3.5 Hz, 1H), 2.66 (br d, J = 14.5 Hz, 1H), 2.54–2.44
(m, 2H), 1.76–1.37 (m, 6H), 1.31 (d, J = 6.5 Hz, 3H), 1.24 (t, J =
7.0 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H); 13C NMR (100.6 MHz,
=
=
CDCl3) d: 173.9 (C O), 166.8 (C O), 145.0 (ipso-Ph), 138.5 (C),
127.9 (Ph), 127.6 (Ph), 126.6 (CH2), 126.4 (Ph), 60.6 (CH2), 60.1
(CH2), 58.2 (CH), 55.9 (CH), 45.6 (CH), 43.6 (CH2), 29.5 (CH2),
23.9 (CH2), 23.2 (CH2), 22.5 (CH2), 14.7 (Me), 14.2 (Me), 14.1
(Me); MS (CI, NH3) m/z 388 [(M + H)+, 100], 188 (40); HRMS
(CI, NH3) m/z [M + H]+ calcd for C23H33NO4, 388.2488; found,
388.2482.
=
=
CH2Cl2–MeOH) 0.75; IR (film): 3015, 1730 (C O), 1665 (C O),
−1
1
=
1620 (C C), 1220 cm ; H NMR (400 MHz, CDCl3) d: 7.31
(d, J = 2.0 Hz, 1H), 4.20 (q, J = 7.0 Hz, 2H), 4.15 (q, J =
7.0 Hz, 2H), 3.55–3.50 (m, 1H), 3.45–3.38 (m, 1H), 3.18 (td, J =
13.0, 3.0 Hz, 1H), 2.87 (dt, J = 12.0, 5.5 Hz, 1H), 2.62 (ddd,
J = 16.5, 5.5, 1.5 Hz, 1H), 2.40 (ddd, J = 16.5, 12.0, 2.0 Hz,
1H), 1.92–1.87 (m, 1H), 1.73–1.34 (m, 5H), 1.28 (t, J = 7.0 Hz,
3H), 1.27 (t, J = 7.0 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
(4R)-Diethyl 2-[(N-hydroxy-N-methylamino)methyl]-4-{(2R)-1-
[(1S)-1-phenylethyl]piperidin-2-yl}pentanedioate 21
=
=
d: 172.2 (C O), 168.4 (C O), 144.7 (CH), 94.9 (C), 60.7 (CH2),
59.2 (CH2), 55.7 (CH), 54.6 (CH2), 41.8 (CH), 26.5 (CH2), 25.8
(CH2), 24.6 (CH2), 19.0 (CH2), 14.7 (Me), 14.2 (Me); MS (CI,
NH3) m/z 282 [(M + H)+, 100]; HRMS (CI, NH3) m/z [M + H]+
calcd for C15H23N2O4, 282.1705; found, 282.1699 and bislactam 15
(27 mg, 48%) as a colourless oil, [a]D +41.8 (c 1.0 in CHCl3); RF(9 :
Et3N (14 lL, 0.1 mmol) was added dropwise to a stirred solution of
N-methylhydroxylamine hydrochloride (9 mg, 0.1 mmol) in THF
(2 mL) at rt under N2. After stirring for 10 min, a solution of
alkylated amino ester (R,R,S)-20 (40 mg, 0.1 mmol) was added
dropwise via a cannula and the resulting solution was stirred at rt
for 64 h. The solvent was evaporated under reduced pressure and
Et2O (5 mL) was added to the residue. The solids were removed by
filtration through a plug of silica and washed with Et2O (50 mL).
The solvent was evaporated under reduced pressure to give the
crude product. Purification by flash chromatography with petrol–
=
1 CH2Cl2–MeOH) 0.4; IR (film): 3015, 2940, 1730 (C O), 1635
−1
1
=
(C O), 1440, 1215 cm ; H NMR (400 MHz, CDCl3) d: 4.74
(ddd, J = 13.5, 4.0, 2.0 Hz, 1H), 3.51–3.40 (m, 2H), 3.38 (ddd, J =
12.0, 5.0, 3.0 Hz, 1H), 2.93 (s, 3H), 2.93–2.88 (m, 1H), 2.82–2.78
(m, 1H), 2.49 (td, J = 13.5, 3.5 Hz, 1H), 2.10–2.07 (m, 2H), 1.99–
1.92 (m, 1H), 1.87–1.83 (m, 1H), 1.73–1.68 (m, 1H), 1.40–1.20
13
=
(m, 3H); C NMR (100.6 MHz, CDCl3) d: 170.0 (C O), 168.1
1
EtOAc (3 : 1) as eluent gave a 50 : 50 mixture (by H NMR
=
(C O), 59.2 (CH), 52.8 (CH2), 42.2 (CH2), 41.7 (CH), 37.1 (CH),
spectroscopy) of hydroxylamines 21 (38 mg, 85%) as a colourless
34.0 (Me), 31.3 (CH2), 25.0 (CH2), 24.8 (CH2), 24.1 (CH2); MS
(CI, NH3) m/z 282 [(M + H)+, 100]; HRMS (CI, NH3) m/z [M +
H]+ calcd for C12H18N2O2, 223.1447; found, 223.1448.
−1
=
oil, RF(3 : 1 petrol–EtOAc) 0.2; IR (film): 1730 (C O) cm ;
1H NMR (400 MHz, CDCl3) d: 7.41–7.34 (m, 2H), 7.33–7.25
(m, 2H), 7.24–7.17 (m, 1H), 6.28 (br s, 0.5H), 5.79 (br s, 0.5H),
4.28–3.97 (m, 4.5H), 3.85 (dq, J = 11.0, 7.5 Hz, 0.5H), 3.20–
3.12 (m, 0.5H), 3.08–3.03 (m, 0.5H), 2.88–2.80 (m, 2H), 2.73–
2.55 (m, 3H), 2.60 (s, 1.5H), 2.52 (s, 1.5H), 2.42–2.36 (m, 0.5H),
2.32–2.25 (m, 0.5H), 2.04–1.85 (m, 2H), 1.68–1.58 (m, 1H), 1.50–
(1S,2S,9S)-11-Methyl-7,11-diazatricyclo[7.3.1.02,7]tridecane,
(−)-sparteine surrogate
1.05 (m, 11H), 1.20 (t, J = 7.5 Hz, 1.5H), 1.07 (t, J = 7.5 Hz,
LiAlH4 (77 mg, 2.03 mmol) was added in one portion to a stirred
so◦lution of bislactam 15 (75 mg, 0.34 mmol) in THF (1.5 mL) at
0 C under N2. The resulting suspension was stirred and heated
at reflux for 16 h. After cooling to rt, Et2O (1 mL) was added
and solid Na2SO4·H2O was added portionwise until effervescence
ceased. The resulting mixture was stirred at rt for 30 min. The
solids were removed by filtration through Celite and washed with
9 : 1 CH2Cl2–MeOH (30 mL). The filtrate was dried (MgSO4) and
the solvent evaporated under reduced pressure to give the crude
product as a yellow oil. Purification by Kugelrohr distillation gave
(−)-sparteine surrogate (44 mg, 68%) as a pale yellow oil, bp 110–
13
=
1.5H); C NMR (100.6 MHz, CDCl3) d: 175.0 (C O), 174.8
=
=
=
(C O), 174.7 (C O), 174.3 (C O), 144.5 (ipso-Ph), 144.3 (ipso-
Ph), 128.0 (Ph), 127.8 (Ph), 127.6 (Ph), 127.4 (Ph), 126.5 (Ph),
126.3 (Ph), 63.8 (CH2), 63.0 (CH2), 60.5 (CH2), 60.41 (CH2),
60.38 (CH2), 60.3 (CH2), 58.8 (CH), 55.4 (CH), 54.7 (CH), 48.78
(CH), 48.76 (CH), 44.6 (CH), 44.4 (CH), 44.2 (CH2), 44.0 (CH2),
42.8 (CH2), 42.7 (CH2), 26.5 (CH2), 25.5 (CH2), 25.3 (CH2), 24.6
(CH2), 24.3 (CH2), 23.8 (CH2), 23.5 (CH2), 23.0 (CH2), 14.2 (Me),
14.15 (Me), 14.1 (Me), 14.0 (Me), 13.9 (Me), 13.1 (Me); MS
(CI, NH3) m/z 435 [(M + H)+, 100], 188 (65), 389 (30); HRMS
(CI, NH3) m/z [M + H]+ calcd for C24H38N2O5, 435.2859; found,
435.2856.
◦
◦
115 C/0.3 mmHg (lit.,27b 95–110 C/0.8 mmHg); [a]D −29.6 (c
1.0 in EtOH) (lit.,27b [a]D +26.5 (c 1.0 in EtOH) for (+)-sparteine
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surrogate); 1H NMR (400 MHz, CDCl3) d: 3.03–2.96 (m, 2H), 2.89
(dt, J = 11.5, 2.0 Hz, 1H), 2.86–2.82 (m, 1H), 2.24 (ddd, J 11.0,
3.5, 1.5 Hz, 1H), 2.18–2.12 (m, 1H), 2.15 (s, 3H), 1.98 (dd, J = 11.5,
3.0 Hz, 1H), 1.94–1.89 (m, 1H), 1.86–1.45 (m, 11H). Spectroscopic
data consistent with that reported in the literature.27b
15 C. Pousset, R. Callens, A. Marinetti and M. Larcheveˆque, Synlett,
2004, 2766.
16 R. A. Bunce, C. J. Peeples and P. B. Jones, J. Org. Chem., 1992, 57,
1727.
17 R. W. Hoffmann, T. Sander and A. Hense, Liebigs Ann. Chem., 1993,
771.
18 M. P. Cooke and R. K. Widener, J. Org. Chem., 1989, 52, 1381.
19 Separation of the (R,S)- and (S,S)-diastereomers of 4 and 5 by
chromatography is straightforward. However, Breuning and Steiner
have reported a fractional crystallisation approach for isolation of
the methyl ester of (R,S)-4 (ref. 12). Thus, crystallisation of the salt
from (R,S)-4–(+)-CSA should allow a non-chromatographic method
for isolation of (R,S)-4.
20 S. Ledoux, J.-P. Ce´le´rier and G. Lhommet, Tetrahedron Lett., 1999, 40,
9019.
21 Adducts 8 and 9 (derived from (S)-a-methylbenzylamine) exhibited
negative optical rotation values. It appears that the optical rotation data
for 8 and 9 in the paper by Lhommet et al. (ref. 20) were erroneously
reported.
Acknowledgements
We thank AstraZeneca (J-P R H), the EPSRC (M J M), and the
University of York/Hoffmann-La Roche (J M W) for funding
and The Royal Society of Chemistry for the award of a J W T
Jones Travelling Fellowship (to PO’B) for a sabbatical stay at the
University of Geneva. We also thank Klaus Ditrich of BASF,
Germany for the kind donation of samples of (R)- and (S)-(1-
naphthyl)ethylamine.
22 M. J. Dearden, C. R. Firkin, J.-P. R. Hermet and P. O’Brien, J. Am.
Chem. Soc., 2002, 124, 11870.
23 (a) M. J. Dearden, M. J. McGrath and P. O’Brien, J. Org. Chem., 2004,
69, 5789; (b) P. O’Brien, K. B. Wiberg, W. F. Bailey, J.-P. R. Hermet
and M. J. McGrath, J. Am. Chem. Soc., 2004, 126, 15480; (c) C. Genet,
M. J. McGrath and P. O’Brien, Org. Biomol. Chem., 2006, 4, 1376.
24 (a) M. J. Johansson, L. Schwartz, M. Amedjkouh and N. Kann,
Tetrahedron: Asymmetry, 2004, 15, 3531; (b) J. A. Wilkinson, S. B.
Rossington, S. Ducki, J. Leonard and N. Hussain, Tetrahedron, 2006,
62, 1833; (c) Y. Morita, H. Tokuyama and T. Fukuyama, Org. Lett.,
2005, 7, 4337.
25 (a) M. J. McGrath and P. O’Brien, J. Am. Chem. Soc., 2005, 127, 16378;
(b) M. J. McGrath, J. L. Bilke and P. O’Brien, Chem. Commun., 2006,
2607; (c) M. J. McGrath and P. O’Brien, Synthesis, 2006, 223; (d) C.
Genet, S. J. Canipa, P. O’Brien and S. Taylor, J. Am. Chem. Soc., 2006,
128, 9336.
26 For previous syntheses of the (+)- or (−)-sparteine surrogate, see ref. 22
and (a) B. Danieli, G. Lesma, D. Passarella, P. Piacenti, A. Sacchetti,
A. Silvani and A. Virdis, Tetrahedron Lett., 2002, 4(3), 7155; (b) J.-P. R.
Hermet, D. W. Porter, M. J. Dearden, J. R. Harrison, T. Koplin, P.
O’Brien, J. Parmene, V. Tyurin, A. C. Whitwood, J. Gilday and N. M.
Smith, Org. Biomol. Chem., 2003, 1, 3977; (c) B. Danieli, G. Lesma, D.
Passarella, A. Sacchetti, A. Silvani and A. Virdis, Tetrahedron Lett.,
2005, 46, 7121; (d) A. J. Dixon, M. J. McGrath and P. O’Brien, Org.
Synth., 2006, 83, 141.
27 I. T. Barnish, M. Corless, P. J. Dunn, D. Ellis, P. W. Finn, J. D. Hardstone
and K. James, Tetrahedron Lett., 1993, 34, 1323; P. J. Dunn, M. L.
Hughes, P. M. Searle and A. S. Wood, Org. Process Res. Dev., 2003, 7,
244.
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