Asymmetric synthesis and applications of β-amino Weinreb amides: Asymmetric synthesis of (S)-coniine

Article abstract of DOI:10.1039/b402531h

Conjugate addition of lithium (S)-N-benzyl-N-a-methylbenzylamide to a range of α,β-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The β-amino Weinreb amide products may be transformed into β-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes β-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral δ-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.

Full text of DOI:10.1039/b402531h

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Asymmetric synthesis and applications of ꢀ-amino Weinreb
amides: asymmetric synthesis of (S )-coniine
Anthony J. Burke, Stephen G. Davies,* A. Christopher Garner, Tom D. McCarthy,
Paul M. Roberts, Andrew D. Smith, Humberto Rodriguez-Solla and Richard J. Vickers
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, UK OX1 3TA. E-mail: steve.davies@chem.ox.ac.uk
Received 19th February 2004, Accepted 22nd March 2004
First published as an Advance Article on the web 5th April 2004
Conjugate addition of lithium (S)-N-benzyl-N-α-methylbenzylamide to a range of α,β-unsaturated Weinreb
amides proceeds with high levels of diastereoselectivity (>95% de). The β-amino Weinreb amide products may be
transformed into β-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes
β-amino aldehydes. Trapping of the aldehyde via Wadsworth–Emmons reaction and subsequent manipulation offers
an efficient route to homochiral δ-amino acid derivatives and 2-substituted piperidines. The application of this
methodology for the synthesis of (S)-coniine is demonstrated.
nature of these reactions suggests that the enolates of Weinreb
amides prepared in this way are completely stable under the
reaction conditions (Scheme 1).
Introduction
N-protected α-amino aldehydes and ketones have been widely
used as building blocks in natural product synthesis,1 and are
attractive chiral synthons for the preparation of amino sugars,2
amino acids3 and pyrrolidines.4 In contrast, their β-amino
analogues have received much less attention, with relatively few
reports of the asymmetric synthesis of homochiral β-amino
aldehydes and ketones. Approaches toward these synthetic tar-
gets include the oxidation of γ-amino alcohols5 and the select-
ive reduction of N-protected-β-amino esters,6,7 although their
inherent instability8 has precluded a general method for their
synthesis.9 Previous investigations from this laboratory have
shown that the highly diastereoselective conjugate addition of
Scheme 1 Reagents and conditions: (i) (S)-1, THF, Ϫ78 ЊC then
NH4Cl(aq).
homochiral lithium amides derived from α-methylbenzylamine
to a range of α,β-unsaturated esters and subsequent N-depro-
tection offers an efficient route to the asymmetric synthesis of
The absolute configuration of the C(3) stereogenic centre
β-amino acids and derivatives.10 In order to apply this method-
of β-amino Weinreb amides 5–7 was assigned in each case by
ology to the asymmetric synthesis of β-amino aldehydes and
analogy with the model previously developed to explain the
ketones, we investigated whether β-amino Weinreb amides11
stereoselectivity observed during addition of lithium amide
would provide β-amino aldehydes and ketones via reaction with
(S)-1 to α,β-unsaturated acceptors.16 This assignment was con-
hydride and organometallic reagents. We report herein our
firmed by the synthesis of an authentic sample of ent-5 from the
investigations within this area, utilising the conjugate addition
known β-amino ester 8, the absolute configuration of which has
of lithium (S)-N-benzyl-N-α-methylbenzylamide (S)-1 to a
previously been confirmed by its conversion to β-phenylalanine
range of α,β-unsaturated Weinreb amides and subsequent
(Scheme 2).17
transformations. Part of this work has been communicated
previously.12
Results and discussion
Preparation of ꢀ-amino aldehydes and ketones
Initial studies concentrated upon the susceptibility of α,β-
unsaturated N-methoxy-N-methylamides toward conjugate
additions of lithium (S)-N-α-methylbenzyl-N-benzylamide 1.
The suitability of this lithium amide methodology for conjugate
addition to α,β-unsaturated N-methoxy-N-methylamides is not
immediately apparent, as Weinreb amides have been shown to
decompose upon exposure to highly basic reagents, presumably
due to the instability of their enolates.13 Furthermore, only
limited examples of enolate formation from Weinreb amides
have been demonstrated,14 as they are known to be unstable
with respect to a retro-ene process to eliminate formalde-
hyde.15 However conjugate addition of (S)-1 to α,β-unsaturated
Weinreb amides 2–4 furnished β-amino Weinreb amides 5–7 in
>95% de and in uniformly excellent (>90%) isolated yield. The
Scheme 2 Reagents and conditions: (i) TFA, DCM (1 : 1), rt;
(ii) (MeO)MeNHؒHCl, DCC/DMAP, NEt3, rt.
With the range of β-amino N-methoxy-N-methyl amides 5–7
in hand, their conversion to β-amino ketones was investigated.
Thus, treatment of β-amino amide (3R,αS)-5 with PhMgBr
utilising the reaction conditions previously developed by
Weinreb and Nahm11 gave the expected β-amino ketone
(3R,αS)-9 in 84% yield. Similar treatment of the β-amino
amides (3S,αS)-6 and (3R,αS)-7 with MeMgBr enabled the
preparation of β-amino ketones (4S,αS)-10 and (4R,αS)-11
respectively in good yields (Scheme 3).
Attention next focused on the possibility of direct reduction
of β-amino amides 5–7 to the corresponding β-amino alde-
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 3 8 7 – 1 3 9 4
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Scheme 3 Reagents and conditions: (i) R’MgBr (3eq.), THF, 0 ЊC to rt.
hydes, which could then be used as key intermediates for the
synthesis of δ-amino acid derivatives or 2-substituted piper-
idines after synthetic manipulation. In a model study, the
treatment of 3-phenyl β-amino amide (3R,αS)-5 with DIBAL-
H in THF at Ϫ78 ЊC and subsequent protic work-up showed,
by 1H NMR spectroscopic analysis, that the reaction had
proceeded to good conversion, furnishing the N,N-protected
β-amino aldehyde 12.18 Attempts to obtain analytically pure
β-amino aldehyde 12 via chromatographic purification on silica
led to amine elimination, consistent with the well documented
instability of β-amino aldehydes (Scheme 4).8
Scheme 5 Reagents and conditions: (i) DIBAL-H, hexanes, THF,
0 ЊC then acetone, sat. C4H4KNaO6(aq).(Rochelle salt); (ii) (EtO)2-
POCH2CO2 Bu, n-BuLi, THF, Ϫ78 ЊC to rt; (iii) H2 (5atm), Pd(OH)2 on
t
C, MeOH.
Application to the asymmetric synthesis of piperidines
The combination of this conjugate addition and DIBAL-H/
Wadsworth–Emmons methodology was extended further for
the asymmetric synthesis of homochiral δ-lactams and 2-alkyl-
piperidines.21 Treatment of β-amino amides 5–7 with DIBAL-
H and reaction of the crude reaction mixture with the lithium
anion of triethylphosphonoacetate gave the separable ethyl
δ-amino α,β-unsaturated esters (E)-24 : (Z)-25, (E)-26 : (Z)-27
and (E)-28 : (Z)-29 respectively in high yields (85–90%) and
with high diastereoselectivity. Concurrent hydrogenation and
hydrogenolysis of (E)-24, (E)-26 and (E)-28, and treatment of
the resulting mixture in toluene at reflux gave δ-lactams 30–32
in high yields. Reduction of δ-lactams 30–32 with LiAlH4 gave,
after treatment with HCl in Et2O and purification, (R)-2-
phenylpiperidine hydrochloride 33 {[α]2D3 Ϫ2.8 (c = 1.0, MeOH),
lit.22 [α]2D3 Ϫ3.1 (c = 1.0, MeOH)}, (S)-2-methylpiperidine
hydrochloride {(S)-pipecoline hydrochloride} 34 {[α]2D3 Ϫ3.6
(c = 1.1, EtOH); lit.23 ent [α]2D3 ϩ4.0 (c = 2, EtOH)} and (R)-2-
iso-propylpiperidine hydrochloride 35 (Scheme 6).
Scheme 4 Reagents and conditions: (i) DIBAL-H, THF, Ϫ78 ЊC;
(ii) SiO2 chromatography.
The possibility of trapping the intermediate aldehyde 12 in
situ with a Wadsworth–Emmons reagent to generate the corre-
sponding α,β-unsaturated ester was next considered. Attempts
at
a tandem “one-pot” DIBAL-H/Wadsworth–Emmons
approach resulted in only the formation of the aldehyde by 1H
NMR spectroscopic analysis, indicating that the aluminium
complex formed during reduction was stable under the reaction
conditions, presumably only furnishing aldehyde 12 upon protic
work-up. Investigations therefore focused on a stepwise
approach to this transformation, forming first the β-amino
aldehydes 12–1419 by reduction of β-amino amides 5–7 with
DIBAL-H, followed by protic work-up and subsequent
Wadsworth–Emmons reaction. Application of this protocol to
β-amino Weinreb amide 5 gave excellent conversion to the
required N,N-protected tert-butyl δ-amino α,β-unsaturated
esters (E)-15 : (Z)-16 in an 89 : 11 ratio.20 Purification allowed
isolation of the separable diastereoisomeric products (E)-15
and (Z)-16 in 83% and 2% yield respectively (85% overall).
Similar treatment of β-amino Weinreb amides 6 and 7 gave the
tert-butyl δ-amino α,β-unsaturated esters (E)-17 : (Z)-18 and
(E)-19 : (Z)-20 respectively with high diasteroselectivity, fur-
nishing the separable (E)- and (Z)-diastereoisomers in high
yields after chromatography. Subsequent hydrogenolysis and
hydrogenation of (E)-15, (E)-17 and (E)-19 gave the δ-amino
acid tert-butyl esters 21–23 in 94–98% yield and >95% ee
respectively, as determined by chemical derivatisation with both
Scheme 6 Reagents and conditions: (i) DIBAL-H, hexanes, THF,
0 ЊC then acetone, sat. C4H4KNaO6(aq). (Rochelle salt); (ii) (EtO)2-
POCH2CO2Et, n-BuLi, THF, Ϫ78 ЊC to rt; (iii) H2 5 atm, Pd(OH)2 on
C, MeOH; then PhMe, ∆; (iv) LiAlH4, Et2O, ∆ then HCl.
1
homochiral and racemic Mosher’s acid chlorides and H and
19F NMR spectroscopic analysis of the resulting amides
(Scheme 5).
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To demonstrate further the utility of this methodology in
natural product synthesis, this procedure was applied to the
asymmetric synthesis of (S)-2-propylpiperidine [(S)-coniine],24
an alkaloid known to have potent neurotoxic effects.25 Conju-
gate addition of (S)-1 to (E)-N-methoxy-N-methyl hex-2-
enamide 36 furnished (3S,αS)-N-methoxy-N-methyl 3-(N-ben-
zyl-N-α-methylbenzylamino)-hexanamide 37 in 96% yield and
in >95% de. Subsequent DIBAL-H/Wadsworth–Emmons reac-
tion using triethylphosphonoacetate gave a separable 90 : 10
mixture of (E)-38 and (Z)-39 in 80% and 5% yield respectively
(85% combined yield), with hydrogenation and hydrogenolysis,
followed by heating in toluene to promote cyclisation, affording
(S)-6-propylpiperidin-2-one5 40 in 98% yield. Reduction with
LiAlH4 gave, after treatment with HCl in Et2O, (S)-coniine as
its hydrochloride salt 41 with specific rotation {[α]2D3 ϩ9.1 (c =
0.6, EtOH), lit.26 [α]2D3 ϩ9.4 (c = 0.3, EtOH)} and spectroscopic
data in excellent agreement with the literature (Scheme 7).
nitrogen via standard vacuum line techniques. All glassware was
flame-dried and allowed to cool under vacuum. THF and Et2O
were distilled under an atmosphere of dry nitrogen from
sodium benzophenone ketyl. Water was distilled. n-BuLi was
used as a 2.5 M solution in hexanes (Aldrich). PhMgBr and
MeMgBr were used as 3.0 M solutions in Et2O (Aldrich).
DIBAL-H was used as a 1.0 M solution in hexanes (Aldrich).
LiAlH4 was used as a 1.0 M solution in THF (Aldrich). All
other solvents and reagents were used as supplied (Analytical or
HPLC grade), without prior purification. All reactions were
dried with MgSO4. Thin layer chromatography was performed
on aluminium sheets coated with 60 F254 silica. Sheets were
visualised using iodine, UV light or 1% aqueous KMnO4 solu-
tion. Column chromatography was performed on Kieselgel 60
silica. Nuclear magnetic resonance spectra were recorded on
either a Bruker DPX 400 spectrometer (1H: 400 MHz and 13C:
100 MHz) or a Bruker DPX 200 spectrometer (1H: 200 MHz
and 13C: 50 MHz) in the deuterated solvent stated. Residual
signals from the solvents were used as an internal reference. All
chemical shifts (δ) are quoted in ppm and coupling constants
(J) in Hz. In all cases the reaction diastereoselectivity was
1
assessed by peak integration of the H NMR spectrum of the
crude reaction mixture. Infrared spectra (νmax) were recorded on
a Perkin-Elmer 1750 IR Fourier Transform spectrophotometer
using either a thin film on NaCl plates (film) or a KBr disc
(KBr) as stated. Only the characteristic peaks are quoted in
cmϪ1. Low-resolution mass spectra (m/z) were recorded on
either a VG MassLab 20–250 spectrometer or a Micromass
Platform
1 spectrometer. High-resolution mass spectra
(HRMS) were recorded on either a Micromass Autospec 500
OAT spectrometer or a Waters 2790 Micromass LCT electro-
spray ionisation mass spectrometer. Techniques used were
chemical ionisation (CI), atmospheric pressure chemical ionis-
ation (APCI) and electrospray ionisation (ESI) using partial
purification by HPLC with methanol : acetonitrile : water
(40 : 40 : 20) as eluent. Optical rotations were recorded on a
Perkin-Elmer 241 polarimeter with a water-jacketed 10 cm cell
and specific rotations are given in units of 10Ϫ1 deg cm2 gϪ1.
Concentrations are quoted in g per 100 mL. Melting points
were recorded on a Leica VMTG Galen III apparatus and are
uncorrected. Elemental analyses were performed by the micro-
analysis service of Inorganic Chemistry Laboratory, Oxford.
General procedure 1 for the preparation of ꢀ-amino Weinreb
amides
Scheme
7
Reagents and conditions: (i) (S)-1, THF, Ϫ78 ЊC;
(ii) DIBAL-H, hexanes, THF, 0 ЊC then acetone, sat. C4H4KNaO6(aq).
(Rochelle salt); (iii) (EtO)2POCH2CO2Et, n-BuLi, THF, Ϫ78 ЊC;
(iv) H2, Pd(OH)2/C, MeOH then PhMe, ∆; (v) LiAlH4, Et2O, ∆ then
HCl, Et2O.
n-BuLi was added dropwise via syringe to a stirred solution of
(S)-N-benzyl-N-α-methylbenzylamine in THF at Ϫ78 ЊC. After
thirty minutes a solution of the α,β-unsaturated Weinreb amide
in THF at Ϫ78 ЊC was added dropwise via cannula. After a
further two hours the reaction mixture was quenched with
saturated aqueous NH4Cl solution and allowed to warm to rt.
The organic phase was separated and the aqueous phase was
extracted three times with Et2O. The combined organic extracts
were dried, filtered, and concentrated in vacuo. The residue was
suspended in 10% aqueous citric acid solution and extracted
three times with DCM. The combined organic extracts were
washed with saturated aqueous NaHCO3 solution, dried, fil-
tered, and concentrated in vacuo. The residue was then purified
via column chromatography.
Conclusions
In conclusion, conjugate addition of homochiral lithium
N-benzyl-N-α-methylbenzylamide to a range of α,β-unsatur-
ated Weinreb amides proceeds efficiently with high diastereo-
selectivity to generate the β-amino Weinreb amides. Subsequent
transformation to the corresponding β-amino ketone or
β-amino aldehyde can be achieved readily by treatment with
suitable organometallic reagents. Trapping of the β-amino
aldehyde with a lithiated phosphonate furnishes α,β-unsatur-
ated-δ-amino esters, which are viable precursors for δ-amino
acid derivatives and 2-substituted piperidines. The further
application of this methodology for the synthesis of polyamino
natural products and polysubstituted homochiral piperidines is
currently under investigation in our laboratory.
General procedure 2 for the preparation of ꢀ-amino ketones
The Grignard reagent was added dropwise via syringe to a stirred
solution of the β-amino Weinreb amide in THF at Ϫ78 ЊC. The
reaction mixture was allowed to warm to rt over twelve hours
before being quenched with saturated aqueous NH4Cl solution.
The organic phase was separated and the aqueous phase was
extracted three times with Et2O. The combined organic extracts
were dried, filtered, and concentrated in vacuo. The residue was
then purified via column chromatography.
Experimental
General
All reactions involving organometallic or other moisture sensi-
tive reagents were performed under an atmosphere of dry
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 3 8 7 – 1 3 9 4
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General procedure 3 for the preparation of ꢁ,ꢀ-unsaturated-ꢂ-
amino esters
51.0, 56.8, 59.1, 61.0, 126.6, 126.8, 127.1, 127.9, 128.0, 128.1,
128.2, 128.3, 128.5, 142.1, 142.8, 144.3, 172.5; m/z (APCI) 403
ϩ
(MHϩ, 100%), 299 (76), 105 (32); HRMS (ESI) C26H31N2O2
DIBAL-H was added dropwise via syringe to a stirred solution
of the β-amino Weinreb amide in THF at 0 ЊC. After thirty
minutes the reaction mixture was quenched with acetone and
cannulated into stirred, degassed, saturated aqueous sodium
potassium tartrate solution at 0 ЊC. After a further thirty min-
utes the organic phase was separated and the aqueous phase
was extracted three times with DCM. The combined organic
extracts were dried, filtered, and concentrated in vacuo. The
residue was dissolved immediately in THF and cooled to
Ϫ78 ЊC before a solution of the Wadsworth–Emmons reagent,
prepared by addition of n-BuLi to a solution of the requisite
phosphonate in THF at Ϫ78 ЊC and stirred for thirty minutes,
was added dropwise via cannula. The reaction mixture was
allowed to warm to rt over four hours before being quenched
with saturated aqueous NH4Cl solution. The organic phase was
separated and the aqueous phase was extracted three times with
Et2O. The combined organic extracts were dried, filtered, and
concentrated in vacuo. The residue was then purified via column
chromatography.
requires 403.2386; found 403.2384.
(3S,ꢁS )-N-Methoxy-N-methyl 3-(NЈ-benzyl-NЈ-ꢁ-methyl-
benzylamino)butanamide 6
Following general procedure 1, n-BuLi (28.8 mL, 72.1 mmol),
(S)-N-benzyl-N-α-methylbenzylamine (15.6 mL, 74.4 mmol) in
THF (50 mL), and α,β-unsaturated Weinreb amide 3 (6.00 g,
46.5 mmol) in THF (20 mL) gave, after purification via column
chromatography (pentane : Et2O 10 : 1), the title compound 6 as
a colourless oil (15.2 g, 96%, >95% de); C21H28N2O2 requires C,
74.1; H, 8.3; N, 8.2%; found C, 73.8; H, 8.5; N, 8.1%; [α]2D2 Ϫ29.1
(c = 1.1, CHCl3); νmax (film) 1657 (C᎐O); δ (400 MHz, CDCl )
᎐
H
3
1.19 (3H, d, J = 6.7, C(4)H3), 1.40 (3H, d, J = 7.0, C(α)Me),
2.32–2.44 (2H, m, C(2)H2), 3.09 (3H, s, NCH3), 3.41 (3H, s,
OCH3), 3.52–3.59 (1H, m, C(3)H ), 3.81 (2H, ABq, JAB=14.8,
NЈCH2), 3.95 (1H, q, J = 7.0, C(α)H ), 7.21–7.51 (10H, m, Ph);
δC (100 MHz, CDCl3) 18.4, 18.7, 32.0, 37.2, 49.3, 49.8, 58.0,
60.9, 126.5, 126.6, 127.8, 127.9, 128.0, 128.2, 142.2, 144.6,
173.2; m/z (APCI) 341 (MHϩ, 100%), 237 (89), 105 (42); HRMS
(ESI) C21H29N2O2ϩ requires 341.2229; found 341.2216.
General procedure 4 for the preparation of ꢂ-amino esters
Pd(OH)2/C was added to a vigorously stirred solution of the
requisite tert-butyl α,β-unsaturated-δ-amino ester in degassed
MeOH at rt and placed under a hydrogen atmosphere (5 atm).
After twenty-four hours the reaction mixture was filtered
through Celite® (eluent MeOH) and the filtrate was concen-
trated in vacuo.
(3R,ꢁS )-N-Methoxy-N-methyl 3-(NЈ-benzyl-NЈ-ꢁ-methyl-
benzylamino)-4-methylpentanamide 7
Following general procedure 1, n-BuLi (23.7 mL, 59.2 mmol),
(S)-N-benzyl-N-α-methylbenzylamine (12.8 mL, 61.1 mmol) in
THF (50 mL), and α,β-unsaturated Weinreb amide 4 (6.00 g,
38.2 mmol) in THF (20 mL) gave, after purification via column
chromatography (pentane : Et2O 10 : 1), the title compound 7 as
a colourless oil (13.4 g, 95%, >95% de); C23H32N2O2 requires C,
75.0; H, 8.8; N, 7.6%; found C, 74.9; H, 9.1; N, 7.6%; [α]2D2 Ϫ37.4
General procedure 5 for the preparation of piperidin-2-ones
Pd(OH)2/C was added to a vigorously stirred solution of the
requisite ethyl α,β-unsaturated-δ-amino ester in degassed
MeOH at rt and placed under a hydrogen atmosphere (5 atm).
After twenty-four hours the reaction mixture was filtered
through Celite® (eluent MeOH) and the filtrate was concen-
trated in vacuo. The residue was dissolved in toluene and
refluxed for twelve hours before being concentrated in vacuo.
The residue was then purified via column chromatography.
(c = 1.0, CHCl3); νmax (film) 1667 (C᎐O); δ (400 MHz, CDCl )
᎐
H
3
0.93, 1.15 (2 × 3H, d, J = 6.7, CH(CH3)2), 1.47 (3H, d, J = 7.1,
C(α)Me), 1.71–1.82 (2H, m, CH(CH3)2, C(2)HA), 2.37–2.43
(1H, br m, C(2)HB), 3.11 (3H, s, NCH3), 3.44 (3H, s, OCH3),
3.51–3.55 (1H, m, C(3)H ), 3.59 (1H, d, J = 15.0, NЈCHA), 3.83
(1H, q, J = 7.1, C(α)H ), 3.89 (1H, d, J = 15.0, NЈCHB), 7.23–
7.56 (10H, m, Ph); δC (100 MHz, CDCl3) 19.8, 20.0, 20.8, 31.6,
32.4, 32.8, 51.4, 56.7, 57.6, 60.9, 126.6, 126.8, 127.9, 128.0,
128.2, 128.3, 141.6, 142.1, 173.9; m/z (APCI) 369 (MHϩ, 100%)
General procedure 6 for the preparation of piperidine
hydrochlorides
ϩ
265 (43), 105 (24); HRMS (ESI) C23H33N2O2 requires
369.2542; found 369.2542.
LiAlH4 was added dropwise via syringe to a stirred solution of
the requisite piperidin-2-one in Et2O at 0 ЊC. The reaction mix-
ture was refluxed for twelve hours before being quenched with
2 M aqueous KOH solution. The organic phase was separated
and the aqueous phase was extracted three times with Et2O.
The combined organic extracts were dried, filtered, and poured
into saturated ethereal HCl solution at 0 ЊC before being con-
centrated in vacuo. The residue was then purified via column
chromatography.
(3R,ꢁS )-3-(N-Benzyl-N-ꢁ-methylbenzylamino)-1,3-diphenyl-
propan-1-one 9
Following general procedure 2, PhMgBr (0.3 mL, 0.90 mmol)
and β-amino Weinreb amide 5 (180 mg, 0.45 mmol) in THF
(10 mL) gave, after purification by column chromatography
(pentane : Et2O 4 : 1), the title compound 9 as a colourless oil
(158 mg, 84%); C30H29NO requires C, 85.9; H, 7.0; N, 3.3%;
found C, 86.2; H, 6.8; N, 3.6%; [α]2D2 Ϫ2.0 (c = 0.9, CHCl3);
(3R,ꢁS )-N-Methoxy-N-methyl 3-(NЈ-benzyl-NЈ-ꢁ-methyl-
benzylamino)-3-phenylpropanamide 5
νmax (film) 1684 (C᎐O); δ (200 MHz, CDCl3) 1.34 (3H, d,
᎐
H
J = 6.9, C(α)Me), 3.09 (1H, dd, J = 16.7, J = 4.6, C(2)HA), 3.35
(1H, dd, J = 16.7, J = 9.1, C(2)HB), 3.78 (2H, ABq, JAB=14.7,
NCH2), 4.05 (1H, q, J = 6.9, C(α)H ), 4.78 (1H, dd, J = 9.1,
J = 4.6, C(3)H ), 7.16–7.66 (20H, m, Ph); δC (50 MHz, CDCl3)
15.9, 41.4, 50.9, 56.7, 58.3, 126.6, 126.8, 127.0, 127.2, 127.9,
128.1, 128.2, 128.4, 128.8, 129.0, 132.8, 136.9, 141.2, 141.6,
142.4, 143.9, 198.4; m/z (CI) 420 (MHϩ, 22%), 212 (100), 209
(79), 105 (30).
Following general procedure 1, n-BuLi (19.5 mL, 48.7 mmol),
(S)-N-benzyl-N-α-methylbenzylamine (10.5 mL, 50.3 mmol) in
THF (50 mL), and α,β-unsaturated Weinreb amide 2 (6.00 g,
31.4 mmol) in THF (20 mL) gave, after purification via column
chromatography (pentane : Et2O 10 : 1), the title compound 5 as
a colourless oil (11.6 g, 92%, >95% de); C26H30N2O2 requires C,
77.6; H, 7.5; N, 7.0%; found C, 77.4; H, 7.2; N, 7.4%; [α]2D2 Ϫ23.8
(c = 1.1, CHCl3); νmax (film) 1662 (C᎐O); δ (400 MHz, CDCl )
᎐
H
3
(4S,ꢁS )-4-(N-Benzyl-N-ꢁ-methylbenzylamino)pentan-2-one 10
1.39 (3H, d, J = 6.9, C(α)Me), 2.63 (1H, dd, J = 15.5, J = 4.5,
C(2)HA), 2.94–2.98 (1H, br m, C(2)HB), 3.04 (3H, s, NCH3),
3.36 (3H, s, OCH3), 3.84 (2H, ABq, JAB=15.5, NЈCH2), 4.11
(1H, q, J = 6.9, C(α)H ), 4.70 (1H, dd, J = 9.8, J = 4.5, C(3)H ),
7.23–7.56 (15H, m, Ph); δC (100 MHz, CDCl3) 15.6, 32.0, 35.1,
Following general procedure 2, MeMgBr (0.4 mL, 1.06 mmol)
and β-amino Weinreb amide 6 (180 mg, 0.53 mmol) in THF
(10 mL) gave, after purification via column chromatography
(pentane : Et2O 4 : 1), the title compound 10 as a colourless oil
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 3 8 7 – 1 3 9 4
1390

View Article Online
(138 mg, 88%); C20H25NO requires C, 81.3; H, 8.5; N, 4.7%;
126.9, 127.0, 127.6, 127.8, 128.0, 128.3, 128.5, 128.6, 140.5,
142.3, 145.4, 193.8.
found C, 81.2; H, 8.7; N, 4.5%; [α]2D2 Ϫ20.0 (c = 1.0, CHCl3);
νmax (film) 1684 (C᎐O); δ (200 MHz, CDCl3) 1.14 (3H, d,
᎐
H
J = 6.6, C(5)H3), 1.37 (3H, d, J = 6.9, C(α)Me), 1.76 (3H, s,
C(1)H3), 2.20 (1H, dd, J = 15.0, J = 8.0, C(3)HA), 2.42 (1H, dd,
J = 15.0, J = 5.4, C(3)HB), 3.42–3.59 (1H, m, C(4)H ), 3.72 (2H,
ABq, JAB=14.8, NCH2), 3.88 (1H, q, J = 6.9, C(α)H ), 7.18–7.46
(10H, m, Ph); δC (50 MHz, CDCl3) 17.6, 18.9, 29.6, 48.5, 49.0,
49.6, 57.5, 126.7, 126.8, 127.8, 128.1, 128.2, 128.4, 141.6, 143.9,
208.3; m/z (CI) 296 (MHϩ, 13%), 212 (100), 105 (10), 85 (11).
(2Z,5S,ꢁS )- and (2E,5S,ꢁS )-tert-butyl 5-(N-benzyl-N-ꢁ-
methylbenzylamino)-hex-2-enoate (Z )-18 and (E )-17
Following general procedure 3, DIBAL-H (29.4 mL, 29.4
mmol), β-amino Weinreb amide 6 (5.00 g, 14.7 mmol) in THF
(20 mL), n-BuLi (7.1 mL, 17.6 mmol) and tert-butyl di-
ethylphosphonoacetate (4.1 mL, 17.6 mmol) in THF (10 mL)
gave, after purification and separation via column chromato-
graphy (pentane : Et2O 80 : 1), gave (Z)-18 (0.11 g, 2%) as a
colourless oil; [α]2D5 Ϫ86.7 (c = 0.6, CHCl3), νmax (film) 1712
(4R,ꢁS )-4-(N-Benzyl-N-ꢁ-methylbenzylamino)-5-methylhexan-
2-one 11
(C᎐O), 1652 (C᎐C); δ (400 MHz, CDCl ) 1.12 (3H, d, J = 6.6,
᎐
᎐
H
3
Following general procedure 2, MeMgBr (0.3 mL, 0.98 mmol)
and β-amino Weinreb amide 7 (180 mg, 0.49 mmol) in THF
(10 mL) gave, after purification via column chromatography
(pentane : Et2O 4 : 1), the title compound 11 as a colourless oil
(89 mg, 56%); C22H29NO requires C, 81.7; H, 9.0; N, 4.3%;
found C, 81.6; H, 8.8; N, 4.6%; [α]2D2 Ϫ27.1 (c = 2.0, CHCl3);
C(6)H3), 1.35 (3H, d, J = 6.9, C(α)Me), 1.45 (9H, s, C(CH3)3),
2.51–2.59 (1H, m, C(4)HA), 2.78–2.86 (1H, m, C(4)HB), 2.91–
2.96 (1H, m, C(5)H ), 3.75 (2H, ABq, JAB=14.2, NCH2), 3.97
(1H, q, J = 6.9, C(α)H ), 5.59 (1H, d, J = 11.4, C(2)H ), 5.83 (1H,
app dt, J = 11.4, J = 6.6, C(3)H ), 7.18–7.39 (10H, m, Ph);
δC (100 MHz, CDCl3) 16.5, 18.1, 28.2, 33.7, 49.4, 52.1, 56.7,
79.8, 121.3, 126.5, 126.6, 127.8, 127.9, 128.1, 128.5, 142.0,
144.9, 148.2, 172.3; m/z (APCIϩ) 380 (MHϩ, 38%), 276 (47), 105
νmax (film) 2963 (C–H), 1717 (C᎐O); δ (200 MHz, CDCl ) 0.81,
᎐
H
3
1.13 (2 × 3H, d, J = 6.7, CH(CH3)2), 1.42 (3H, d, J = 7.1,
C(α)Me), 1.61–1.68 (1H, m, CH(CH3)2), 1.85 (3H, s, C(1)H3),
2.17–2.25 (2H, m, C(3)H2), 3.37–3.41 (1H, m, C(4)H ), 3.53
(1H, d, J = 14.9, NCHA), 3.76 (1H, d, J = 14.9, NCHB), 3.77
(1H, q, J = 7.1, C(α)H ), 7.22–7.50 (10H, m, Ph); δC (50 MHz,
CDCl3) 19.6, 19.7, 20.8, 29.8, 32.5, 44.0, 51.3, 55.7, 57.2, 126.6,
126.9, 127.9, 128.0, 128.2, 128.3, 141.3, 141.5, 207.2; m/z (CI)
324 (MHϩ, 12%), 212 (100), 112 (14), 105 (23).
ϩ
(100); HRMS (ESI) C25H34NO2 requires 380.2590; found
380.2592; further elution gave (E)-17 (4.59 g, 82%) as a colour-
less oil; [α]2D3 Ϫ31.4 (c = 1.0, CHCl3); νmax (film) 1711 (C᎐O),
᎐
1649 (C᎐C); δ (400 MHz, CDCl ) 1.14 (3H, d, J = 6.6, C(6)H ),
᎐
H
3
3
1.38 (3H, d, J = 6.9, C(α)Me), 1.54 (9H, s, C(CH3)3), 2.00–2.20
(1H, m, C(4)HA), 2.28–2.35 (1H, m, C(4)HB), 3.01–3.06 (1H, m,
C(5)H ), 3.79 (2H, ABq, JAB=14.6, NCH2), 3.98 (1H, q, J = 6.9,
C(α)H ), 5.65 (1H, d, J = 15.5, C(2)H ), 6.71 (1H, app dt,
J = 15.5, J = 7.8, C(3)H ), 7.24–7.49 (10H, m, Ph); δC (100 MHz,
CDCl3) 17.6, 18.3, 28.2, 37.3, 49.6, 51.8, 57.3, 79.9, 123.9,
126.5, 126.6, 127.8, 128.0, 128.2, 128.3, 141.9, 144.6, 146.7,
165.9; m/z (APCI) 380 (MHϩ, 32%), 276 (26), 105 (100); HRMS
(ESI) C25H34NO2ϩ requires 380.2590; found 380.2601.
NMR data for intermediate (3S,αS)-3-(N-benzyl-N-α-
methylbenzylamino)butanal 13: δH (200 MHz, CDCl3) 1.13
(3H, d, J = 6.7, C(4)H3), 1.40 (3H, d, J = 6.9, C(α)Me), 2.12 (1H,
ddd, J = 16.4, J = 7.8, J = 2.0, C(2)HA), 2.34–2.52 (1H, m,
C(2)HB), 3.49–3.66 (1H, m, C(3)H ), 3.72 (2H, ABq, JAB=14.5,
NCH2), 3.90 (1H, q, J = 6.9, C(α)H ), 7.12–7.40 (10H, m, Ph),
9.08–9.13 (1H, m, CHO); δH (50 MHz, CDCl3) 15.4, 18.3, 47.1,
48.9, 49.2, 56.4, 126.7, 126.9, 127.7, 127.9, 128.2, 128.5, 140.8,
143.8, 203.0.
(2Z,5R,ꢁS )- and (2E,5R,ꢁS )-tert-butyl 5-(N-benzyl-N-ꢁ-
methylbenzylamino)-5-phenylpent-2-enoate (Z )-16 and (E )-15
Following general procedure 3, DIBAL-H (24.9 mL, 24.9
mmol), β-amino Weinreb amide 5 (5.00 g, 12.4 mmol) in THF
(20 mL), n-BuLi (6.0 mL, 14.9 mmol) and tert-butyl di-
ethylphosphonoacetate (3.5 mL, 14.9 mmol) in THF (10 mL)
gave, after purification and separation via column chromato-
graphy (pentane : Et2O 80 : 1), (Z)-16 (0.11 g, 2%) as a colour-
less oil; [α]2D3 Ϫ8.8 (c = 0.5, CHCl ); ν (film) 1711 (C᎐O), 1638
᎐
3
max
(C᎐C); δ (400 MHz, CDCl3) 1.06 (3H, d, J = 6.9, C(α)Me),
᎐
H
1.48 (9H, s, C(CH3)3), 3.00–3.08 (1H, m, C(4)HA), 3.29–3.37
(1H, m, C(4)HB), 3.80 (2H, ABq, JAB=14.5, NCH2), 3.90 (1H,
dd, J = 8.5, J = 7.1, C(5)H ), 4.16 (1H, q, J = 6.9, C(α)H ), 5.62
(1H, d, J = 11.6, C(2)H ), 5.85 (1H, app dt, J = 11.6, J = 7.0,
C(3)H ), 7.18–7.48 (15H, m, Ph); δC (100 MHz, CDCl3) 16.1,
28.1, 29.7, 50.4, 56.5, 61.8, 80.0, 121.9, 125.5, 126.5, 126.6,
127.0, 127.8, 128.1, 128.3, 128.4, 128.6, 141.7, 141.8, 145.0,
147.0, 166.0; m/z (APCI) 442 (MHϩ, 54%), 338 (12), 105 (100);
(2Z,5R,ꢁS )- and (2E,5R,ꢁS )-tert-butyl 5-(N-benzyl-N-ꢁ-
methylbenzylamino)-6-methylhept-2-enoate (Z )-20 and (E )-19
Following general procedure 3, DIBAL-H (27.2 mL, 27.2
mmol), β-amino Weinreb amide 7 (5.00 g, 13.6 mmol) in THF
(20 mL), n-BuLi (6.5 mL, 16.3 mmol) and tert-butyl di-
ethylphosphonoacetate (3.8 mL, 16.3 mmol) in THF (10 mL)
gave, after purification and separation via column chromato-
graphy (pentane : Et2O 80 : 1), (Z)-20 (0.12 g, 2%) as a colour-
ϩ
HRMS (ESI) C30H36NO2 requires 442.2746; found 442.2754;
further elution gave (E)-15 (4.57 g, 83%) as a colourless oil; [α]2D3
Ϫ20.3 (c = 1.0, CHCl3); νmax (film) 1712 (C᎐O), 1652 (C᎐C);
᎐
᎐
δH (400 MHz, CDCl3) 1.18 (3H, d, J = 6.9, C(α)Me), 1.53 (9H, s,
C(CH3)3), 2.49–2.57 (1H, m, C(4)HA), 2.69–2.77 (1H, m,
C(4)HB), 3.78 (1H, d, J = 14.5, NCHA), 3.90 (1H, d, J = 14.5,
NCHB), 4.01 (1H, dd, J = 8.7, J = 6.3, C(5)H ), 4.15 (1H, q,
J = 6.9, C(α)H ), 5.65 (1H, d, J = 15.5, C(2)H ), 6.72 (1H, app dt,
J = 15.5, J = 7.1, C(3)H ), 7.24–7.53 (15H, m, Ph); δC (100 MHz,
CDCl3) 15.6, 28.2, 34.7, 50.6, 56.3, 61.6, 79.9, 124.3, 126.7,
126.8, 127.2, 127.7, 127.8, 128.2, 128.3, 128.4, 128.8, 141.4,
141.7, 144.5, 145.9, 165.8; m/z (APCI) 442 (MHϩ, 12%), 338
less oil; [α]2D5 Ϫ35.7 (c = 0.3, CHCl3); νmax (film) 1714 (C᎐O),
᎐
1636 (C᎐C); δ (400 MHz, CDCl ) 0.92, 1.00 (2 × 3H, d, J = 6.8,
᎐
H
CH(CH3)2), 1.32 (3H, d, J =3 6.8, C(α)Me), 1.46 (9H, s,
C(CH3)3), 1.79–1.83 (1H, m, CH(CH3)2), 2.26–2.30 (1H, m,
C(4)HA), 2.57–2.62 (1H, m, C(5)H ), 2.80–2.84 (1H, m,
C(4)HB), 3.72 (1H, d, J = 15.2, NCHA), 3.86 (1H, q, J = 6.8,
C(α)H ), 3.90 (1H, d, J = 15.2, NCHB), 5.54 (1H, d, J = 11.5,
C(2)H ), 5.84 (1H, app dt, J = 11.5, J = 5.8, C(3)H ), 7.21–7.47
(10H, m, Ph); δC (100 MHz, CDCl3) 19.9, 20.3, 20.9, 28.1, 28.2,
31.9, 51.6, 58.4, 62.3, 79.7, 120.5, 126.3, 126.7, 127.8, 127.9,
128.0, 128.1, 142.1, 143.6, 149.4, 166.0; m/z (APCI) 408 (MHϩ,
ϩ
(10), 105 (100); HRMS (ESI) C30H36NO2 requires 442.2746;
found 442.2735.
NMR data for intermediate (3R,αS)-3-(N-benzyl-N-α-
methylbenzylamino)-5-phenylpropanal 12: δH (200 MHz,
CDCl3) 1.14 (3H, d, J = 6.9, C(α)Me), 2.61 (1H, ddd, J = 16.2,
J = 7.5, J = 1.8, C(2)HA), 2.85 (1H, ddd, J = 16.2, J = 7.7, J = 3.0,
C(2)HB), 3.66 (1H, d, J = 14.0, NCHA), 3.83 (1H, d, J = 14.0,
NCHB), 4.06 (1H, q, J = 6.9, C(α)H ), 4.49–4.57 (1H, m,
C(3)H ), 7.22–7.61 (15H, m, Ph), 9.37 (1H, dd, J = 3.0. J = 1.8,
CHO); δC (50 MHz, CDCl3) 18.9, 25.6, 53.5, 57.4, 67.9, 126.7,
ϩ
13%), 304 (21), 105 (100); HRMS (ESI) C27H38NO2 requires
408.2903; found 408.2905; further elution gave (E)-19 (4.68 g,
85%) as a colourless oils; [α]2D5 Ϫ5.1 (c = 1.5, CHCl3), νmax (film)
1713 (C᎐O), 1649 (C᎐C); δ (400 MHz, CDCl ) 0.99, 1.01 (2 ×
᎐
᎐
H
3
3H, d, J = 6.9, CH(CH3)2), 1.35 (3H, d, J = 6.9, C(α)Me), 1.52
(9H, s, C(CH3)3), 1.80–1.91 (2H, m, C(4)HA, CH(CH3)2), 2.03–
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 3 8 7 – 1 3 9 4
1391

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2.11 (1H, m, C(4)HB), 2.73–2.77 (1H, m, C(5)H ), 3.69 (1H, d,
J = 15.2, NCHA), 3.85 (1H, q, J = 6.9, C(α)H ), 3.90 (1H, d,
J = 15.2, NCHB), 5.53 (1H, d, J = 15.4, C(2)H ), 6.70 (1H, app
dt, J = 15.4. J = 6.6, C(3)H ), 7.26–7.52 (10H, m, Ph); δC (100
MHz, CDCl3) 19.9, 20.4, 21.0, 28.2, 31.5, 32.0, 51.9, 58.2, 60.8,
80.0, 123.4, 126.6, 127.0, 128.0, 128.1, 128.2, 128.3, 141.7,
142.9, 147.8, 166.1; m/z (APCI) 408 (MHϩ, 26%), 304 (37), 105
(Z)-25 (0.08 g, 5%) as a colourless oil; [α]2D5 Ϫ8.0 (c = 1.0,
CHCl3); νmax (film) 1715 (C᎐O), 1640 (C᎐C); δ (400 MHz,
᎐
᎐
H
CDCl3) 1.08 (3H, d, J = 6.8, C(α)Me), 1.28 (3H, t, J = 7.1,
OCH2CH3), 2.96–3.05 (1H, m, C(4)HA), 3.31–3.39 (1H, m,
C(4)HB), 3.80 (2H, ABq, JAB=14.5, NCH2), 3.92 (1H, dd,
J = 8.7, J = 6.8, C(5)H ), 4.14 (1H, q, J = 6.8, C(α)H ), 4.15 (2H,
q, J = 7.1, OCH2CH3), 5.68 (1H, d, J = 11.5, C(2)H ), 5.92 (1H,
app dt, J = 11.5, J = 4.5, C(3)H ), 7.17–7.47 (15H, m, Ph);
δC (100 MHz, CDCl3) 14.3, 15.7, 31.1, 50.4, 56.4, 59.8, 62.1,
120.1, 126.5, 127.1, 127.2, 127.8, 128.0, 128.1, 128.2, 128.5,
128.8, 141.7, 141.8, 144.9, 148.4, 166.4; m/z (APCI) 414 (MHϩ,
ϩ
(100); HRMS (ESI) C27H38NO2 requires 408.2903; found
408.2906.
NMR data for intermediate (3R,αS)-3-(N-benzyl-N-α-
methylbenzylamino)-4-methylpentanal 14: δH (200 MHz,
CDCl3) 0.85, 1.15 (2 × 3H, d, J = 6.7, CH(CH3)2), 1.43 (3H, d, J
= 7.1, C(α)Me), 1.71–1.78 (1H, m, CH(CH3)2), 1.90–2.01 (1H,
m, C(2)HA), 2.22 (1H, ddd, J = 17.0, J = 8.0, J = 2.6, C(2)HB),
3.25–3.35 (1H, m, C(3)H ), 3.60 (1H, d, J = 14.7, NCHA), 3.80
(1H, d, J = 14.7, NCHB), 3.85 (1H, q, J = 7.1, C(α)H ), 7.24–7.52
(10H, m, Ph), 9.40–9.41 (1H, m, CHO); δC (50 MHz, CDCl3)
19.3, 20.1, 21.2, 32.1, 44.3, 51.2, 56.0, 57.2, 126.8, 127.2, 127.9,
128.0, 128.2, 128.4, 140.9, 141.6, 202.0.
ϩ
14%), 310 (52), 105 (100); HRMS (ESI) C28H32NO2 requires
414.2433; found 414.2428; further elution gave (E)-24 (1.25 g,
81%) as a colourless oil; [α]2D5 Ϫ22.7 (c = 1.0, CHCl3); νmax (film)
1718 (C᎐O), 1653 (C᎐C); δ (400 MHz, CDCl3) 1.15 (3H, d,
᎐
᎐
H
J = 6.8, C(α)Me), 1.27 (3H, t, J = 7.1, OCH2CH3), 2.49–2.57
(1H, m, C(4)HA), 2.63–2.70 (1H, m, C(4)HB), 3.78 (2H, ABq,
JAB=14.7, NCH2), 3.97 (1H, dd, J = 9.1, J = 6.1, C(5)H ), 4.09
(1H, q, J = 6.8, C(α)H ), 4.14 (2H, q, J = 7.1, OCH2CH3), 5.65
(1H, d, J = 15.6, C(2)H ), 6.72 (1H, app dt, J = 15.6, J = 7.2,
C(3)H ), 7.19–7.49 (15H, m, Ph); δC (100 MHz, CDCl3) 14.2,
15.7, 34.7, 50.6, 56.3, 60.1, 61.6, 122.6, 126.6, 126.8, 127.2,
127.8, 128.1, 128.2, 128.3, 128.5, 128.6, 141.3, 141.4, 144.4,
147.0, 166.3; m/z (APCI) 414 (MHϩ, 12%), 310 (47), 105 (100);
HRMS (ESI) C28H32NO2ϩ requires 414.2433; found 414.2443.
(R)-tert-Butyl 5-amino-5-phenylpentanoate 21
Following general procedure 4, Pd(OH)2/C (250 mg), tert-butyl
α,β-unsaturated-δ-amino ester (E)-15 (500 mg) in MeOH
(5 mL), and H2 (5 atm) gave the title compound 21 as a colour-
less amorphous solid (264 mg, 94%); mp 136–138 ЊC; [α]2D2
Ϫ25.5 (c = 0.5, CHCl3); νmax (KBr) 3410 (N-H), 1725 (C᎐O);
᎐
(2Z,5S,ꢁS )- and (2E,5S,ꢁS )-ethyl 5-(N-benzyl-N-ꢁ-methyl-
benzylamino)hex-2-enoate (Z )-27 and (E )-26
δH (400 MHz, CD3OD) 1.44 (9H, s, C(CH3)3), overlapping
1.38–1.54 (1H, m, C(3)HA), 1.55–1.60 (1H, m, C(3)HB), 1.99–
2.07 (2H, m, C(4)H2), 2.23–2.30 (2H, m, C(2)H2), 4.28 (1H, dd,
J = 9.1, J = 6.2, C(5)H ), 7.45–7.52 (5H, m, Ph); δC (100 MHz,
CD3OD) 22.8, 28.7, 35.1, 35.9, 57.1, 82.1, 128.9, 130.8, 130.9,
138.4, 174.5; m/z (CI) 250 (MHϩ, 100%), 194 (46); HRMS (CI)
C15H24NO2ϩ requires 250.1807; found 250.1809.
Following general procedure 3, DIBAL-H (8.8 mL, 8.82 mmol),
β-amino Weinreb amide 6 (1.50 g, 4.41 mmol) in THF (10 mL),
n-BuLi (2.1 mL, 5.29 mmol) and triethylphosphonoacetate (1.1
mL, 5.29 mmol) in THF (5 mL) gave, after purification and
separation via column chromatography (pentane : Et2O 80 : 1),
(Z)-27 (0.14 g, 9%) as a colourless oil; [α]2D5 Ϫ90.7 (c = 0.9,
(S )-tert-Butyl 5-aminohexanoate 22
CHCl3); νmax (film) 1716 (C᎐O), 1642 (C᎐C); δ (400 MHz,
᎐ ᎐
H
CDCl3) 1.14 (3H, d, J = 6.7, C(6)H3), 1.28 (3H, t, J = 7.2,
OCH2CH3), 1.37 (3H, d, J = 6.9, C(α)Me), 2.59–2.67 (1H, m,
C(4)HA), 2.80–2.88 (1H, m, C(4)HB), 2.95–3.01 (1H, m,
C(5)H ), 3.78 (2H, ABq, JAB=14.4, NCH2), 4.00 (1H, q, J = 6.9,
C(α)H ), 4.14 (2H, q, J = 7.2, OCH2CH3), 5.69 (1H, d, J = 11.6,
C(2)H ), 5.97 (1H, app dt, J = 11.6, J = 7.2, C(3)H ), 7.20–7.49
(10H, m, Ph); δC (100 MHz, CDCl3) 14.3, 16.5, 18.1, 34.0, 49.4,
52.1, 56.8, 59.7, 119.5, 126.5, 126.6, 127.7, 127.9, 128.1, 128.5,
141.9, 144.9, 149.7, 166.6; m/z (APCI) 352 (MHϩ, 28%), 248
Following general procedure 4, Pd(OH)2/C (250 mg), tert-butyl
α,β-unsaturated-δ-amino ester (E)-17 (500 mg) in MeOH
(5 mL), and H2 (5 atm) gave the title compound 22 as a colour-
less amorphous solid (241 mg, 98%); mp 98–100 ЊC; [α]2D4 Ϫ1.5
(c = 0.9, CHCl3); νmax (KBr) 3410 (N-H), 1729 (C᎐O); δ (400
᎐
H
MHz, CD3OD) 1.12 (3H, d, J = 6.6, C(6)H3), 1.47 (9H, s,
C(CH3)3) overlapping 1.34–1.48 (2H, m, C(4)H2), 1.59–1.67
(2H, m, C(3)H2), 2.26 (2H, app t, J = 7.2, C(2)H2), 2.89–2.97
(1H, m, C(5)H ); δC (100 MHz, CD3OD) 22.8, 23.2, 28.8, 36.7,
39.5, 48.1, 81.9, 175.2; m/z (CI) 188 (MHϩ, 100%), 132 (32);
HRMS (CI) C10H22NO2ϩ requires 188.1651; found 188.1655.
ϩ
(90), 105 (100); HRMS (ESI) C23H30NO2 requires 352.2277;
found 352.2285; further elution gave (E)-26 (1.25 g, 81%) as a
colourless oil; [α]2D5 Ϫ30.4 (c = 1.1, CHCl3); νmax (film) 1718
(C᎐O), 1652 (C᎐C); δ (400 MHz, CDCl ) 1.15 (3H, d, J = 7.1,
᎐
᎐
H
3
(R)-tert-Butyl 5-amino-6-methylheptanoate 23
C(6)H3), 1.34 (3H, t, J = 7.2, OCH2CH3), 1.38 (3H, d, J = 6.8,
C(α)Me), 2.02–2.10 (1H, m, C(4)HA), 2.29–2.36 (1H, m,
C(4)HB), 3.02–3.07 (1H, m, C(5)H ), 3.80 (2H, ABq, JAB=14.7,
NCH2), 3.98 (1H, q, J = 6.8, C(α)H ), 4.23 (2H, q, J = 7.2,
OCH2CH3), 5.72 (1H, d, J = 15.4, C(2)H ), 6.78 (1H, app dt,
J = 15.4, J = 7.8, C(3)H ), 7.24–7.49 (10H, m, Ph); δC (100 MHz,
CDCl3) 14.3, 17.4, 18.3, 37.5, 50.0, 51.8, 57.4, 60.1, 122.1,
126.6, 126.7, 127.6, 127.9, 128.0, 128.2, 141.8, 144.5, 148.0,
166.5; m/z (APCI) 352 (MHϩ, 11%), 248 (88), 105 (100); HRMS
(ESI) C23H30NO2ϩ requires 352.2277; found 352.2282.
Following general procedure 4, Pd(OH)2/C (250 mg), tert-butyl
α,β-unsaturated-δ-amino ester (E)-19 (500 mg) in MeOH
(5 mL), and H2 (5 atm) gave the title compound 23 as a colour-
less amorphous solid (255 mg, 97%); mp 92–94 ЊC; [α]2D4 ϩ3.3
(c = 0.7, CHCl3); νmax (KBr) 3410 (N-H), 1727 (C᎐O); δ (400
᎐
H
MHz, CD3OD) 1.02, 1.04 (2 × 3H, d, J = 6.9, CH(CH3)2), 1.47
(9H, s, C(CH3)3), 1.57–1.77 (4H, m, C(3)H2, C(4)H2), 1.93–2.05
(1H, m, CH(CH3)2), 2.32–2.35 (2H, m, C(2)H2), 3.04–3.08 (1H,
m, C(5)H ); δC (100 MHz, CD3OD) 17.1, 17.3, 20.9, 27.6, 29.1,
30.2, 34.7, 57.2, 80.7, 173.3; m/z (CI) 216 (MHϩ, 100%), 160
ϩ
(42); HRMS (CI) C12H26NO2 requires 216.1964; found
(2Z,5R,ꢁS )- and (2E,5R,ꢁS )-ethyl 5-(N-benzyl-N-ꢁ-methyl-
benzylamino)-6-methylhept-2-enoate (Z )-29 and (E )-28
216.1953.
Following general procedure 3, DIBAL-H (8.2 mL, 8.15 mmol),
β-amino Weinreb amide 7 (1.50 g, 4.08 mmol) in THF (10 mL),
n-BuLi (2.0 mL, 4.89 mmol) and triethylphosphonoacetate
(1.0 mL, 4.89 mmol) in THF (5 mL) gave, after purification and
separation via column chromatography (pentane : Et2O 80 : 1),
(Z)-29 (0.05 g, 3%) as a colourless oil; [α]2D5 Ϫ55.0 (c = 0.3,
(2Z,5R,ꢁS )- and (2E,5R,ꢁS )-ethyl 5-(N-benzyl-N-ꢁ-methyl-
benzylamino)-5-phenylpent-2-enoate (Z )-25 and (E )-24
Following general procedure 3, DIBAL-H (7.5 mL, 7.46 mmol),
β-amino Weinreb amide 5 (1.50 g, 3.73 mmol) in THF (10 mL),
n-BuLi (1.8 mL, 4.48 mmol) and triethylphosphonoacetate
(0.9 mL, 4.48 mmol) in THF (5 mL) gave, after purification and
separation via column chromatography (pentane : Et2O 80 : 1),
CHCl3), νmax (film) 1718 (C᎐O), 1654 (C᎐C); δ (400 MHz,
᎐
᎐
H
CDCl3) 0.91, 1.01 (2 × 3H, d, J = 6.7, CH(CH3)2), 1.27 (3H, t,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 3 8 7 – 1 3 9 4
1392

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J = 7.1, OCH2CH3), 1.32 (3H, d, J = 7.0, C(α)Me), 1.75–1.87
(1H, m, CH(CH3)2), 2.23–2.31 (1H, m, C(4)HA), 2.58–2.64 (1H,
m, C(5)H ), 2.82–2.91 (1H, m, C(4)HB), 3.71 (1H, d, J = 15.4,
NCHA), 3.86 (1H, q, J = 7.0, C(α)H ), 3.89 (1H, d, J = 15.4,
NCHB), 4.13 (2H, q, J = 7.1, OCH2CH3), 5.62 (1H, d, J = 11.5,
C(2)H ), 5.95 (1H, app dt, J = 11.5, J = 6.8, C(3)H ), 7.20–7.53
(10H, m, Ph); δC (100 MHz, CDCl3) 14.2, 19.9, 20.3, 20.9, 28.4,
31.9, 51.6, 58.3, 59.6, 62.2, 118.7, 126.3, 126.7, 127.8, 127.9,
128.0, 128.1, 142.0, 143.6, 150.9, 166.4; m/z (APCI) 380 (MHϩ,
(MHϩ, 100%); HRMS (ESI) C8H16NOϩ requires 142.1232;
found 142.1233.
(R)-2-Phenylpiperidine hydrochloride 33
Following general procedure 6, LiAlH4 (0.9 mL, 0.86 mmol) and
piperidin-2-one 30 (50 mg, 0.29 mmol) in Et2O (5 mL) gave,
after purification via column chromatography (DCM : MeOH
20 : 1), the title compound 33 as a colourless amorphous solid
(53 mg, 95%); mp 195–197 ЊC; [α]2D3 Ϫ2.8 (c = 1.0, MeOH), lit.22
[α]2D3 Ϫ3.1 (c = 1.0, MeOH)}; δH (400 MHz, CDCl3) 1.46–1.56
ϩ
13%), 276 (86), 105 (100); HRMS (ESI) C25H34NO2 requires
380.2590; found 380.2587; further elution gave (E)-28 (1.27 g,
(1H, m, C(4)HA
), 1.66–1.70 (1H, m, C(5)HA), 1.91–2.17 (4H, m,
82%) as a colourless oil; [α]2D5 Ϫ9.1 (c = 1.4, CHCl3); νmax (film)
C(3)H2, C(4)HB, C(5)HB), 2.64–2.72 (1H, m, C(6)HA), 2.99–
3.03 (1H, m, C(6)HB), 3.85–3.88 (1H, m, C(2)H ), 7.27–7.58
1718 (C᎐O), 1649 (C᎐C); δ (400 MHz, CDCl3) 0.98, 1.01
᎐
᎐
H
(2 × 3H, d, J = 6.8, CH(CH3)2), 1.32 (3H, t, J = 7.1, OCH2CH3),
1.35 (3H, d, J = 7.1, C(α)Me), 1.78–1.92 (2H, m, C(4)HA,
CH(CH3)2), 2.04–2.12 (1H, m, C(4)HB), 2.74–2.78 (1H, m,
C(5)H ), 3.69 (1H, d, J = 15.4, NCHA), 3.86 (1H, q, J = 7.1,
C(α)H ), 3.89 (1H, d, J = 15.4, NCHB), 4.20 (2H, q, J = 7.1,
OCH2CH3), 5.60 (1H, d, J = 15.9, C(2)H ), 6.78 (1H, app dt,
J = 15.9, J = 6.9, C(3)H ), 7.26–7.51 (10H, m, Ph); δC (100 MHz,
CDCl3) 14.3, 20.0, 20.3, 21.0, 31.6, 32.1, 51.9, 58.1, 60.1, 60.8,
121.7, 126.5, 127.1, 127.9, 128.0, 128.2, 128.3, 141.6, 142.9,
149.1, 166.6; m/z (APCI) 380 (MHϩ, 11%), 276 (59), 105 (100);
HRMS (ESI) C25H34NO2ϩ requires 380.2590; found 380.2595.
ϩ
(5H, m, Ph), 9.40 (2H, br s, NH2 ).
(S )-2-Methylpiperidine hydrochloride 34
Following general procedure 6, LiAlH4 (1.3 mL, 1.33 mmol) and
piperidin-2-one 31 (50 mg, 0.44 mmol) in Et2O (5 mL) gave,
after purification via column chromatography (DCM : MeOH
20 : 1), the title compound 34 as a colourless amorphous solid
(54 mg, 90%); mp 195–197 ЊC; [α]2D3 Ϫ3.6 (c = 1.1, EtOH), lit.23
ent. [α]2D3 ϩ4.0 (c = 2, EtOH)}; δH (400 MHz, CDCl3) 1.32–1.99
(9H, m, C(2)HCH3, C(3)H2, C(4)H2, C(5)H2), 2.81–2.86 (1H,
m, C(6)HA), 3.10–3.13 (1H, m, C(2)H ), 3.41–3.45 (1H, m,
(R)-6-Phenylpiperidin-2-one 3027
ϩ
C(6)HB), 9.18, 9.56 (2 × 1H, br s, NH2 ).
Following general procedure 5, Pd(OH)2/C (250 mg), ethyl
α,β-unsaturated-δ-amino ester (E)-24 (500 mg) in MeOH
(5 mL), and H2 (5 atm) gave, after purification via column
chromatography (EtOAc : pentane 10 : 1), the title compound
30 as a colourless amorphous solid (142 mg, 67%); mp 115–
117 ЊC; [α]2D5 ϩ58.2 (c = 1.1, CHCl3); νmax (KBr) 3272 (N-H);
(R)-2-iso-Propylpiperidine hydrochloride 35
Following general procedure 6, LiAlH4 (1.1 mL, 1.06 mmol) and
piperidin-2-one 32 (50 mg, 0.35 mmol) in Et2O (5 mL) gave,
after purification via column chromatography (DCM : MeOH
20 : 1), the title compound 35 as a colourless amorphous
solid (55 mg, 95%); mp 168–170 ЊC; [α]2D4 ϩ7.5 (c = 0.5, CHCl3);
1651 (C᎐O); δ (400 MHz, CDCl ) 1.63–1.72 (1H, m, C(5)H ),
᎐
H
3
A
ϩ
1.74–1.87 (1H, m, C(4)HA), 1.88–1.98 (1H, m, C(4)HB), 2.08–
2.13 (1H, m, C(5)HB), 2.37–2.51 (2H, m, C(3)H2), 4.55 (1H, dd,
J = 8.7, J = 4.4, C(6)H ), 6.03–6.08 (1H, br m, NH ), 7.27–7.39
(5H, m, Ph); δC (100 MHz, CDCl3) 19.6, 31.3, 32.1, 57.7, 126.0,
127.9, 128.8, 142.5, 172.3; m/z (APCI) 176 (MHϩ, 100%);
HRMS (ESI) C11H14NOϩ requires 176.1075; found 176.1082.
νmax (KBr) 3400 (NH2 ); δH (400 MHz, CDCl3) 1.10 (6H, app t,
J = 7.4, CH(CH3)2), 1.37–1.47 (1H, m, C(4)HA), 1.57–1.67 (1H,
m, C(3)HA), 1.76–2.06 (4H, m, C(3)HB, C(4)HB, C(5)H2), 2.17–
2.27 (1H, m CH(CH3)2), 2.75–2.86 (2H, br m, C(2)H, C(6)HA),
ϩ
3.54–3.57 (1H, m, C(6)HB), 9.00, 9.35 (2 × 1H, br s, NH2 );
δC (100 MHz, CDCl3) 17.8, 19.7, 22.3, 22.8, 24.7, 30.8, 45.9,
63.2; m/z (EI) 127 (100%, Mϩ); HRMS (EI) C8H17Nϩ requires
127.1361; found 127.1361.
(S )-6-Methylpiperidin-2-one 3128
Following general procedure 5, Pd(OH)2/C (250 mg), ethyl
α,β-unsaturated-δ-amino ester (E)-26 (500 mg) in MeOH
(5 mL), and H2 (5 atm) gave, after purification via column
chromatography (EtOAc : pentane 10 : 1), the title compound
31 as a colourless amorphous solid (158 mg, 98%); mp 79–
81 ЊC; [α]2D5 ϩ22.7 (c = 0.3, CHCl3); νmax (KBr) 3285 (N-H), 1659
(3S,ꢁS )-N-Methoxy-N-methyl-3-(NЈ-benzyl-NЈ-ꢁ-methyl-
benzylamino)hexanamide 37
Following general procedure 1, n-BuLi (23.7 mL, 59.2 mmol),
(S)-N-benzyl-N-α-methylbenzylamine (12.8 mL, 61.1 mmol) in
THF (50 mL), and α,β-unsaturated Weinreb amide 36 (6.00 g,
38.2 mmol) in THF (20 mL) gave, after purification via column
chromatography (pentane : Et2O 10 : 1), the title compound 37
as a colourless oil (13.5 g, 96%, >95% de); [α]2D4 Ϫ41.9 (c = 1.0,
(C᎐O); δ (400 MHz, CDCl ) 1.18 (3H, d, J = 6.7, C(3)HCH ),
᎐
H
3
3
1.27–1.36 (1H, m, C(5)HA), 1.62–1.73 (1H, m, C(5)HB), 1.83–
1.91 (2H, m, C(4)H2), 2.20–2.29 (1H, m, C(3)HA), 2.32–2.40
(1H, m, C(3)HB), 3.46–3.51 (1H, m, C(6)H ), 6.46 (1H, br s,
NH ); δC (100 MHz, CDCl3) 19.8, 22.7, 30.4, 30.9, 48.7, 172.5;
m/z (APCI) 114 (MHϩ, 100%); HRMS (ESI) C6H12NOϩ
requires 114.0919; found 114.0918.
CHCl3); νmax (film) 1662 (C᎐O); δ (400 MHz, CDCl3) 0.89–
᎐
H
0.98 (3H, m, C(6)H3), 1.23–1.34 (1H, m, C(4)HA), 1.36–1.52
(2H, m, C(4)HB, C(5)HA), 1.38 (3H, d, J = 7.0, C(α)Me), 1.64–
1.71 (1H, m, C(5)HB), 1.94–1.99 (1H, m, C(2)HA), 2.18–2.25
(1H, m, C(2)HB), 3.08 (3H, s, NCH3), 3.41 (3H, s, OCH3), 3.48–
3.52 (1H, m, C(3)H ), 3.59 (1H, d, J = 14.9, NЈCHA), 3.85 (1H,
q, J = 7.0, C(α)H ), 3.88 (1H, d, J = 14.9, NЈCHB), 7.20–7.49
(10H, m, Ph); δC (100 MHz, CDCl3) 14.3, 19.9, 20.4, 33.9, 36.4,
50.2, 51.6, 52.6, 57.7, 60.8, 126.6, 126.7, 128.0, 128.1, 128.2,
128.4, 142.0, 143.2, 173.5; m/z (APCI) 369 (MHϩ, 100%), 265
(R)-6-iso-Propylpiperidin-2-one 32
Following general procedure 5, Pd(OH)2/C (250 mg), ethyl
α,β-unsaturated-δ-amino ester (E)-28 (500 mg) in MeOH
(5 mL), and H2 (5 atm) gave, after purification by column
chromatography (EtOAc : pentane 10 : 1), the title compound
32 as a colourless amorphous solid (181 mg, 97%); mp 75–
77 ЊC; [α]2D5 ϩ68.9 (c = 0.4, CHCl3); νmax (KBr) 3235 (N-H), 1660
ϩ
(26), 105 (80); HRMS (CI) C23H33N2O2 requires 369.2542;
found 369.2545.
(C᎐O); δ (400 MHz, CDCl3) 0.92, 0.94 (2 × 3H, d, J = 6.9,
᎐
H
(2Z,5S,ꢁS )- and (2E,5S,ꢁS )-Ethyl 5-(N-benzyl-N-ꢁ-methyl-
benzylamino)oct-2-enoate (Z )-39 and (E )-38
CH(CH3)2), 1.32–1.42 (1H, m, C(5)HA), 1.60–1.71 (2H, m,
C(4)HA, CH(CH3)2), 1.81–1.95 (2H, m, C(4)HB, C(5)HB), 2.21–
2.29 (1H, m, C(3)HA), 2.36–2.43 (1H, m, C(3)HB), 3.15–3.20
(1H, m, C(6)H ), 5.90 (1H, br s, NH ); δC (100 MHz, CDCl3)
17.8, 18.0, 20.0, 24.9, 31.4, 32.8, 58.7, 172.8; m/z (APCI) 142
Following general procedure 3, DIBAL-H (8.2 mL, 8.2 mmol),
β-amino Weinreb amide 37 (1.50 g, 4.08 mmol) in THF (10
mL), n-BuLi (2.0 mL, 4.89 mmol) and triethylphosphono-
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 3 8 7 – 1 3 9 4
1393

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4 H. Ina and C. Kibayashi, J. Org. Chem., 1993, 58, 52.
acetate (1.0 mL, 4.89 mmol) in THF (5 mL) gave, after purifi-
cation and separation via column chromatography (pentane :
Et2O 80 : 1), (Z)-39 (0.08 g, 5%) as a colourless oil; [α]2D2 Ϫ24.8
5 S. B. Davies and M. A. McKervey, Tetrahedron Lett., 1999, 40, 1229.
6 F. A. Davis and J. M. Szewczyk, Tetrahedron Lett., 1998, 39, 5951.
7 C. W. Jefford and J. B. Wang, Tetrahedron Lett., 1993, 34, 2911.
8 A. Chesney and I. E. Marko, Synth. Commun., 1990, 3167;
A. Chesney and I. E. Marko, Synlett, 1992, 275.
(c = 0.4, CHCl3); νmax (film) 1718 (C᎐O), 1641 (C᎐C); δ (400
᎐
᎐
H
MHz, CDCl3) 0.87 (3H, app t, J = 6.9, C(8)H3), 1.27 (3H, t,
J = 7.3, OCH2CH3), 1.33 (3H, d, J = 6.9, C(α)Me), 1.34–1.68
(4H, m, C(6)H2, C(7)H2), 2.49–2.77 (2H, m, C(4)H2), 3.71 (1H,
d, J = 14.9, NCHA), 3.84 (1H, d, J = 14.9, NCHB), 3.95 (1H, q,
J = 6.9, C(α)H ), 4.14 (2H, q, J = 7.3, OCH2CH3), 4.22 (1H, m,
C(5)H ), 5.68 (1H, d, J = 11.7, C(2)H ), 5.87–5.99 (1H, m,
C(3)H ), 7.18–7.43 (10H, m, Ph); δC (100 MHz, CDCl3) 14.3,
18.3, 20.6, 31.0, 35.0, 50.0, 57.0, 57.6, 59.6, 119.6, 126.6, 126.7,
127.9, 128.1, 128.2, 128.4, 142.2, 144.5, 150.0, 166.6; m/z
(APCI) 380 (MHϩ, 48%), 276 (93), 105 (100); HRMS (CI)
C25H34NO2ϩ requires 380.2590; found 380.2586; further elution
gave (E)-38 (1.23 g, 80%) as a colourless oil; [α]2D4 Ϫ18.6 (c = 1.2,
9 A. Dondoni and D. Perrone, Synthesis, 1993, 1162; J. L. Toujas,
E. Jost and M. Vaultier, Bull. Soc. Chim. Fr., 1997, 713.
10 (a) For instance see: S. G. Davies, O. Ichihara and I. A. S. Walters,
Synlett, 1993, 461; (b) S. G. Davies, N. M. Garrido, O. Ichihara and
I. A. S. Walters, J. Chem. Soc., Chem. Commun., 1993, 1153; (c) S. G.
Davies, M. E. Bunnage and C. J. Goodwin, J. Chem. Soc.,
Perkin Trans. 1, 1993, 1375; (d ) S. G. Davies, M. E. Bunnage and
C. J. Goodwin, Synlett, 1993, 731; (e) S. G. Davies, O. Ichihara and
I. A. S. Walters, Synlett, 1994, 117; ( f ) S. G. Davies and I. A. S.
Walters, J. Chem. Soc., Perkin Trans. 1, 1994, 1129; (g) S. G. Davies,
O. Ichihara and I. A. S. Walters, J. Chem. Soc., Perkin Trans. 1, 1994,
1141; (h) S. G. Davies, M. E. Bunnage, C. J. Goodwin and
O. Ichihara, Tetrahedron, 1994, 50, 3975; (i) S. G. Davies,
O. Ichihara, I. Lenoir and I. A. S. Walters, J. Chem. Soc., Perkin
Trans. 1, 1994, 1411; (j) S. G. Davies, M. E. Bunnage, A. N.
Chernega and C. J. Goodwin, J. Chem. Soc., Perkin Trans. 1, 1994,
2373; (k) S. G. Davies, M. E. Bunnage and C. J. Goodwin, J. Chem.
Soc., Perkin Trans. 1, 1994, 2385; (l ) S. G. Davies, A. J. Edwards and
I. A. S. Walters, Recl. Trav. Chim. Pays-Bas, 1995, 114, 175; (m) S. G.
Davies and O. Ichihara, Tetrahedron: Asymmetry, 1996, 7, 1919;
(n) S. G. Davies and D. J. Dixon, Chem. Commun., 1996, 1797;
(o) S. G. Davies and D. J. Dixon, J. Chem. Soc., Perkin Trans. 1,
1998, 2635; (p) S. G. Davies, I. Brackenridge, D. R. Fenwick,
O. Ichihara and M. E. C. Polywka, Tetrahedron, 1999, 55, 533;
(q) S. G. Davies, G. D. Smyth and A. M. Chippindale, J. Chem. Soc.,
Perkin Trans. 1, 1999, 3089.
CHCl3); νmax (film) 1719 (C᎐O), 1651 (C᎐C); δ (400 MHz,
᎐
᎐
H
CDCl3) 0.91 (3H, app t, J = 7.2, C(8)H3), 1.34 (3H, t, J = 7.3,
OCH2CH3) and 1.35 (3H, d, J = 7.1, C(α)Me) overlapping,
1.27–1.39 (2H, m, C(6)HA, C(7)HA), 1.46–1.55 (1H, m,
C(6)HB), 1.59–1.69 (1H, m, C(7)HB), 1.90–2.04 (2H, m,
C(4)H2), 2.84–2.91 (1H, m, C(5)H ), 3.66 (1H, d, J = 14.7,
NCHA), 3.88 (1H, d, J = 14.7, NCHB), 3.91 (1H, q, J = 7.1,
C(α)H ), 4.22 (2H, q, J = 7.3, OCH2CH3), 5.68 (1H, d, J = 15.5,
C(2)H ), 6.77 (1H, app dt, J = 15.5, J = 7.6, C(3)H ), 7.26–7.49
(10H, m, Ph); δC (100 MHz, CDCl3) 14.3, 19.4, 20.5, 34.6, 35.0,
50.0, 56.0, 57.6, 60.1, 122.1, 126.6, 126.9, 127.8, 128.0, 128.2,
128.3, 141.9, 143.6, 148.3, 166.6; m/z (APCI) 380 (MHϩ, 10%),
276 (29), 105 (100); HRMS (CI) C25H34NO2ϩ requires 380.2590;
found 380.2589.
11 S. Nahm and S. M. Weinreb, Tetrahedron Lett., 1981, 22, 3815.
12 S. G. Davies and T. D. McCarthy, Synlett, 1995, 700.
13 S. L. Graham and T. H. Scholtz, Tetrahedron Lett., 1990, 31, 6269.
14 The addition of a sulfoximine anion to α,β-unsaturated N-methoxy-
N-methylamides has been reported; K. E. Rodriques, Tetrahedron
Lett., 1991, 32, 1275, for the recent formation of the potassium
(S )-6-Propylpiperidin-2-one 40
Following general procedure 5, Pd(OH)2/C (250 mg), ethyl
α,β-unsaturated-δ-amino ester (E)-38 (500 mg) in MeOH
(5 mL), and H2 (5 atm) gave, after purification via column
chromatography (EtOAc : pentane 10 : 1), the title compound
40 as a colourless amorphous solid (183 mg, 98%); mp 58–
60 ЊC; [α]2D2 ϩ18.1 (c = 0.6, CHCl3), νmax (KBr) 3208 (N-H), 1665
enolate of N-methoxy-N-methylacetamide see
: F. A. Davis,
K. R. Prasad, M. B. Nolt and Y. Wu, Org. Lett., 2003, 5, 925.
15 G. E. Keck, S. F. McHardy and J. A. Murphy, Tetrahedron Lett.,
1993, 34, 6215.
16 J. F. Costello, S. G. Davies and O. Ichihara, Tetrahedron:
Asymmetry, 1994, 5, 3919.
17 S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1991, 3, 183.
18 As shown by the presence of the characteristic aldehydic proton
peak at δH 9.37.
(C᎐O); δ (400 MHz, CDCl3) 0.94 (3H, m, C(6)HCH2-
᎐
H
CH2CH3), 1.33–1.48 (6H, m, C(6)HCH2CH2CH3, C(5)H2),
1.63–1.73 (1H, m, C(4)HA), 1.85–1.94 (1H, m, C(4)HB), 2.24–
2.33 (1H, m, C(3)HA), 2.36–2.43 (1H, m, C(3)HB), 3.29–3.33
(1H, m, C(6)H ), 5.76–5.79 (1H, br m, NH ); δC (100 MHz,
CDCl3) 13.9, 18.5, 19.8, 28.5, 31.3, 39.1, 52.9, 172.3; m/z
(APCI) 142 (MHϩ, 100%); HRMS (CI) C8H15NOϩ requires
142.1232; found 142.1233.
1
19 H and 13C NMR spectroscopic data for the crude intermediate
β-amino aldehydes 12–14 is contained within the Experimental
section.
1
20 As shown by H NMR spectroscopic anlysis of the crude reaction
mixture.
21 For a related conversions of β-amino aldehydes to piperidines see
references 5 and 6.
22 A. R. Katritzky, G. Qiu, B. Yang and P. J. Steel, J. Org. Chem., 1998,
63, 6699.
23 J. M. Andrés, I. Herráiz-Sierra, R. Pedrosa and A. Pérez-Encabo,
Eur. J. Org. Chem., 2000, 1719.
(S )-2-Propylpiperidine hydrochloride [(S )-coniine
hydrochloride] 41
24 For selected asymmetric syntheses of (S)-coniine see R. S. Al-awar,
S. P. Joseph and D. L. Comins, J. Org. Chem., 1993, 58, 7732;
D. Enders and J. Tiebes, Liebigs Ann., 1993, 173; K. Hattori and
H. Yamamoto, Tetrahedron, 1993, 49, 1749; W. Oppolzer, C. G.
Bochet and E. Merrifield, Tetrahedron Lett., 1994, 35, 7015; Y. Hirai
and M. Nagatsu, Chem. Lett., 1994, 21; M. Amat, N. Llor and
J. Bosch, Tetrahedron Lett., 1994, 35, 2223; S. Fréville, J. P. Célérier,
V. M. Thuy and G. Lhommet, Tetrahedron: Asymmetry, 1995, 6,
2651; Y. H. Kim and J. Y. Choi, Tetrahedron Lett., 1996, 37, 5543;
A. B. Charette, M. Grenon, A. Lemire, M. Pourashraf and J. Martel,
J. Am. Chem. Soc., 2001, 123, 11829; T. J. Wilkinson, N. W. Stehle
and P. Beak, Org Lett., 2000, 2, 155.
Following general procedure 6, LiAlH4 (1.1 mL, 1.06 mmol) and
piperidin-2-one 40 (50 mg, 0.35 mmol) in Et2O (5 mL) gave,
after purification via column chromatography (DCM : MeOH
20 : 1), the title compound 41 as a colourless amorphous solid
(52 mg, 90%); mp 217–219 ЊC; [α]2D3 ϩ9.1 (c = 0.6, EtOH), lit.26
[α]2D3 ϩ9.4 (c = 0.3, EtOH)}; δH (400 MHz, CDCl3) 0.95 (3H, t,
J = 7.3, C(2)HCH2CH2CH3), 1.37–2.01 (10H, m, C(2)HCH2-
CH2CH3, C(3)H2, C(4)H2, C(5)H2), 2.75–2.85 (1H, m, C(6)HA),
2.90–3.00 (1H, m, C(6)HB), 3.40–3.50 (1H, m, C(2)H ), 9.18,
ϩ
9.52 (2 × 1H, br s, NH2 ).
25 D. Rizzi, C. Basile, A. Di Maggio, A. Sebastio, F. Introna Jr.,
R. Rizzi, A. Scatizzi, S. De Marco and J. E. Smialek, Nephrol., Dial.,
Transplant., 1991, 6, 939.
26 M. J. Munchhof and A. I. Meyers, J. Org. Chem., 1995, 60, 7084.
27 F. A. Davis, B. Chao, T. Fang and J. M. Szewczky, Org. Lett, 2000, 2,
1041.
References and notes
1 M. T. Reetz, Chem. Rev., 1999, 99, 1121.
2 A. Golebiowski, U. Jacobsson and J. Jurczak, Tetrahedron, 1987, 43,
3063.
3 K. E. Rittle, C. F. Homnick, G. S. Ponticello and B. E. Evans, J. Org.
Chem., 1982, 47, 3016.
28 M. Amat, N. Llor, J. Hidalgo, C. Escdano and J. Bosch, J. Org.
Chem., 2003, 68, 1919.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 3 8 7 – 1 3 9 4
1394