Asymmetric synthesis of cyclic β-amino acids and cyclic amines via sequential diastereoselective conjugate addition and ring closing metathesis

Article abstract of DOI:10.1016/S0040-4020(03)00411-3

Diastereoselective conjugate addition of lithium (S)-N-allyl-N-α-methylbenzylamide to a range of α,β-unsaturated esters followed by ring closing metathesis is used to afford efficiently a range of substituted cyclic β-amino esters in high d.e. Alternatively, conjugate addition to α,β-unsaturated Weinreb amides, functional group conversion and ring closing metathesis affords cyclic amines in high d.e. The further application of this methodology to the synthesis of a range of carbocyclic β-amino esters via conjugate addition, enolate alkylation and ring closing metathesis is also described. Application of this methodology affords, after deprotection, (S)-homoproline, (S)-homopipecolic acid, (S)-coniine and (1S,2S)-trans-pentacin.

Full text of DOI:10.1016/S0040-4020(03)00411-3

Tetrahedron 59 (2003) 3253–3265
Asymmetric synthesis of cyclic b-amino acids and cyclic amines
via sequential diastereoselective conjugate addition
and ring closing metathesis
†
b
b
Ann M. Chippindale,a Stephen G. Davies,b Keiji Iwamoto, Richard M. Parkin,
,
,
*
Christian A. P. Smethurst,b Andrew D. Smithb and Humberto Rodriguez-Sollab
aChemical Crystallography Laboratory, University of Oxford, 9 Parks Road, Oxford OX1 3PD, UK
bThe Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 23 January 2003; revised 18 February 2003; accepted 14 March 2003
Abstract—Diastereoselective conjugate addition of lithium (S)-N-allyl-N-a-methylbenzylamide to a range of a,b-unsaturated esters
followed by ring closing metathesis is used to afford efficiently a range of substituted cyclic b-amino esters in high d.e. Alternatively,
conjugate addition to a,b-unsaturated Weinreb amides, functional group conversion and ring closing metathesis affords cyclic amines in high
d.e. The further application of this methodology to the synthesis of a range of carbocyclic b-amino esters via conjugate addition, enolate
alkylation and ring closing metathesis is also described. Application of this methodology affords, after deprotection, (S)-homoproline,
(S)-homopipecolic acid, (S)-coniine and (1S,2S)-trans-pentacin. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
an increase in steric bulk affect markedly the ring closure
(Fig. 1).
The metal-catalysed exchange of the alkylidene groups of
two olefins has attracted enormous attention in the last
decade,1 predominantly since the pioneering studies of
Schrock2 and Grubbs,3 who detailed the first synthetic
applications of the general functional group tolerant
molybdenum and ruthenium based alkylidene complexes
PhC(Me)2CHvMovN[2,6-(iPr)2C6H3]{[OCMe(CF3)2]2}
and PhCHvRu(PCy3)2Cl2 1, respectively. The stability and
reactivity of such complexes has allowed ring closing
metathesis to be used widely within organic synthesis,4 with
specific application to the synthesis of a range of nitrogen
containing heterocyclic compounds,5 alkaloids6 and amino
acid derivatives7 being well documented.8 These studies
have demonstrated that the efficiency of a given metathesis
reaction is highly dependent upon the environment around
the reaction centre, particularly if a chelating or co-ordi-
nating substituent is in close proximity to one of the CvC
double bonds undergoing reaction. For instance, both
Rutjes9 and Maier10 have shown that the efficacy of ring
closing metathesis of N-containing substrates 2–4 and 5–7
with Grubbs catalyst 1 is highly dependent upon the nature
of the N-protecting groups. Changes in both the confor-
mational and basic character of the nitrogen atom, as well as
Previous investigations from our laboratory have shown that
lithium (R)-N-allyl-N-a-methylbenzylamide 8 undergoes
highly diastereoselective conjugate addition reactions to
a,b-unsaturated esters to give tertiary b-amino esters with
high levels of predictable diastereoselectivity.11 Differential
Keywords: lithium amide; conjugate addition; ring closing metathesis.
*
Corresponding author. Tel.: þ44-1865-275695; fax: þ44-1865-275633;
e-mail: steve.davies@chem.ox.ac.uk
Current address: School of Chemistry, University of Reading,
Whiteknights, Reading RG6 6AD, UK.
†
Figure 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00411-3

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A. M. Chippindale et al. / Tetrahedron 59 (2003) 3253–3265
Scheme 2. Reagents and conditions: (i) (S)-8, THF, 2788C.
To evaluate this methodology, conjugate addition of lithium
amide (S)-8 to both (E,E)-tert-butyl hexa-2,4-dieneoate 10
and (E)-tert-butyl penta-2,4-dieneoate 11 gave N-allyl
b-amino esters (3R,aS,4E)-1217 and (3R,aS)-13 in 78 and
62% yield, respectively, and in .95% d.e. in each case. In a
similar fashion, conjugate addition of lithium amide (S)-8
to (E,E)-methyl heptan-2,5-dieneoate 14 gave (3S,5E,aS)-
methyl 3-(N-allyl-N-a-methylbenzylamino)hept-5-enoate
15 in 69% yield and .95% d.e. (Scheme 2).
Scheme 1. Reagents and conditions: (i) (R)-8, THF, 2788C; (ii) Pd(PPh3)4,
DCM, N,N-dimethylbarbituric acid; (iii) (Cbz)2O, DCM; (iv) I2, DCM, 08C;
(v) NaN3, DMF; (vi). H2, Pd/C; (vii). 5N, HCl, K.
Having prepared homochiral dienes via conjugate addition
of lithium N-allyl amide (S)-8 to a,b-unsaturated acceptors,
the use of a,b-unsaturated Weinreb amides in this protocol
was probed. It was envisaged that conjugate addition,
combined with subsequent amide functional group con-
version would enable an alternative and facile synthesis of
dienes for ring closing metathesis. To test the viability of
this procedure, conjugate addition of lithium amide (S)-8 to
(E)-N-methoxy-N-methyl 4-methyl-pent-2-eneamide 16 or
(E)-N-methoxy-N-methyl hex-2-eneamide 17 gave b-amino
esters (3R,aS)-18 and (3S,aS)-19 in 63 and 65% yield,
respectively, and in .95% d.e. in each case. Reduction of
b-amino Weinreb amides (3R,aS)-18 and (3S,aS)-19 with
DIBAL-H and treatment of the crude reaction mixture with
sodamide and triphenylphosphonium methylbromide
afforded (4R,aS)-20 and (4S,aS)-21 in 64 and 62% yield,
respectively (Scheme 3).
N-deprotection via deallylation through either rhodium12 or
palladium catalysis13 allows further functionalisation, as
demonstrated by the synthesis of the key b-amino acid 9 of
Sperabillin B and D (Scheme 1).14
As a further application of this versatile methodology, we
report herein upon the scope of the diastereoselective
conjugate addition of lithium amide (S)-8 for the formation
of a range of homochiral dienes. Application of this
methodology enables the limitations of alkene substitution
and ring size upon the efficiency of ring closing metathesis
to be evaluated via the synthesis of a range of heterocyclic
and carbocyclic derivatives. Part of this work has been
communicated previously.15
2. Results and discussion
2.1. Preparation of homochiral dienes via conjugate
addition of lithium (S)-N-allyl-N-a-methylbenzylamide
to a,b-unsaturated acceptors
Initial investigations were directed toward the synthesis of a
range of homochiral dienes via conjugate addition of
lithium amide (S)-8 to a variety of a,b-unsaturated
acceptors, in which direct functionalisation of the N-allyl
group of lithium amide (S)-8 could be achieved via ring
closing metathesis (Fig. 2).16
Scheme 3. Reagents and conditions: (i) (S)-8, THF, 2788C; (ii) DIBAL-H,
THF, 2788C; (iii) Ph3PCH3Br, NaNH2, DCM, 08C to rt.
Figure 2.

A. M. Chippindale et al. / Tetrahedron 59 (2003) 3253–3265
3255
catalyst produced a mixture of secondary amines, which
were separable by column chromatography, providing the
major diastereoisomer of a-allylated b-amino ester anti-24
in 77% yield and .95% d.e. from 22, and furnishing the
major diastereoisomer anti-25 in 56% yield and .95% d.e.,
and the minor diastereomer syn-26 in 22% yield and .95%
d.e. from 23. As previous investigations have shown that
unprotected amines may have a deleterious effect upon the
efficiency of ring closing metathesis,9,10 b-amino esters 24
and 25 were Z-protected, furnishing carbamates 27 and 28,
respectively, while the minor diastereoisomer syn-26 was
subjected to ester deprotection and cyclisation using Ohno’s
conditions,19 giving the dieneyl b-lactam 29 in 92% yield
(Scheme 4).
In a similar manner, tandem conjugate addition of lithium
(S)-N-benzyl-N-a-methylbenzylamide to (E)-tert-butyl
4-methyl-penta-2,4-dieneoate 30 and alkylation with allyl
bromide gave a 1.1:1 mixture of anti- to syn-diastereo-
isomers which differed in configuration at C(2), from which
the major diastereoisomer anti-31 was isolated in 36% yield
as a single diastereoisomer by column chromatography and
recrystallisation (Scheme 5). The relative anti-configuration
within b-amino ester 31 was confirmed by X-ray crystal-
lographic analysis, with the absolute (2S,3R,aS)-configu-
ration confirmed relative to the known configuration of the
N-a-methylbenzyl group (Fig. 3).
2.3. Ring closing metathesis of homochiral dienes
Having prepared a range of homochiral dienes, their
susceptibility to ring closing metathesis was investigated,
initially concentrating upon treatment of b-amino esters 12
and 13 with Grubbs’ ruthenium alkylidene catalyst
PhCHvRu(PCy3)2Cl2 1. Each furnished the desired N-a-
methylbenzyl-protected pyrrolidine b-amino ester (2R,aS)-
32 in comparable 77 and 76% yields respectively, and as a
single diastereoisomer in each case, indicating that no
epimerisation had taken place during the ring closing
metathesis protocol. Alternative ring closing metathesis
Scheme 4. Reagents and conditions: (i) LDA, THF, 2788C; then allyl
bromide, 2788C to rt; (ii) LDA, THF, 2788C; then 1-bromopent-4-ene,
2788C to rt; (iii) (PPh3)3RhCl, MeCN/H2O, K; (iv) (Cbz)2O; (v) TFA,
DCM (1:1), rt; (vi) (PyS)2, MeCN, PPh3, K.
2.2. Preparation of homochiral dienes via conjugate
addition/alkylation
A strategy for the synthesis of dienes involving enolate
alkylation was next probed, with deprotonation of N-allyl
b-amino ester (3R,aS)-12 with LDA and alkylation with
allyl bromide giving an inseparable mixture of anti- and
syn-diastereoisomers 22 in 75% d.e. and 99% yield.
Similarly, alkylation of b-amino ester (3R,aS)-12 with
1-bromopent-4-ene gave an inseparable mixture of anti- and
syn-diastereoisomers 23 in 21% d.e. and 92% yield. In each
case the anti-configuration of the major diastereoisomer was
assigned by analogy to the selectivity previously reported
for alkylation of b-amino enolates.18 N-Deallylation of the
mixtures of diastereoisomers 22 and 23 with Wilkinson’s
Scheme 5. Reagents and conditions: (i) lithium (S)-N-benzyl-N-a-
methylbenzylamide, THF, 2788C; (ii) allyl bromide (1.5 equiv.).
Figure 3. Chem 3D representation of the X-ray crystal structure of
(2S,3R,aS)-31.

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A. M. Chippindale et al. / Tetrahedron 59 (2003) 3253–3265
Scheme 6. Reagents and conditions: (i) 4 mol% RuCl2(vCHPh)(PCy3)2,
DCM, K, 12 h.
catalysts showed lower reactivity upon reaction with
b-amino ester 12, the Nugent20 catalyst failing to generate
any of the desired b-amino ester 32, while treatment
with the Schrock catalyst PhC(Me)2CHvMovN[2,6-
(iPr)2C6H3]{[OCMe(CF3)2]2}2 produced 60% conversion
to 32. Grubbs’ ruthenium alkylidene catalyst 1 was there-
fore used in all further studies, with b-amino ester 15
furnishing the piperidine b-amino ester (2S,aS)-33 in 49%
yield and in .95% d.e., while treatment of dienes (4R,aS)-
20 and (4S,aS)-21 provided the cyclic amines 34 and 35 in
78 and 92% yield, respectively, and in .95% d.e. in each
case (Scheme 6).
Scheme 7. Reagents and conditions: (i) 4 mol% RuCl2(vCHPh)(PCy3)2,
DCM, K, 12 h.
systems, methodology for the efficient deprotection of the
products of ring closing metathesis was desired. Deprotec-
tion of b-amino ester 33 to (S)-homopipecolic acid 4122 was
the initial target of these studies, with N-deprotection via
catalytic hydrogenation affording b-amino ester 40 in 93%
1
yield and .95% e.e. (as shown by H NMR spectroscopic
analysis in the presence of (R)-2,2,2-trifluoro-1-(9-anthryl)-
ethanol and comparison with an authentic racemic standard)
indicating that racemisation does not occur under the
hydrogenolytic reaction conditions. Subsequent ester
hydrolysis and ion exchange chromatography gave
(S)-homopipecolic acid 41 {[a]2D6¼þ24.0 (c 0.87, H2O);
lit.23 [a]D¼þ22.1 (c 0.6, H2O)} in 92% yield (Scheme 8).
Having demonstrated the use of Grubbs’ alkylidene catalyst
for the synthesis of N-protected heterocyclic amino acids
and amines, application to the synthesis of carbocyclic
b-amino ester derivatives was attempted. Treatment of N-Z
b-amino esters 27 and 28 with 4 mol% catalyst 1 proceeded
efficiently, giving the desired five and seven-membered
cyclic b-amino esters 36 and 37 in 85 and 78% yield,
respectively, and as single diastereoisomers in each case.
Treatment of b-lactam 29 with alkylidene 1 similarly
proceeded efficiently, giving the bicyclic b-lactam template
38 in 93% yield as a single diastereoisomer, although
attempted ring closure of b-amino ester 31 proved difficult
to drive to completion, furnishing the desired b-amino ester
template 39 in 35% yield at 50% conversion, even after
addition of further catalyst. Similar results 0regarding the
efficiency of ring closing metathesis of 1,1 -alkenes with
catalyst 1 have been noted in the literature (Scheme 7).21
Deprotection of b-amino ester (2R,aS)-32 to (S)-homopro-
line 4424 was successfully achieved via alkene hydrogen-
ation with Wilkinson’s catalyst, furnishing N-a-methyl-
benzyl b-amino ester 42 in 86% yield and as a single
2.4. Deprotection: synthesis of (S)-homopipecolic acid,
(S)-homoproline, (S)-coniine and (1S,2S)-trans-pentacin
hydrochloride
Having demonstrated that the combination of lithium amide
conjugate addition and ring closing metathesis allows
access to a diverse range of heterocyclic and carbocyclic
Scheme 8. Reagents and conditions: (i) 2 M HCl; (ii) Dowex 50WX8-200.

A. M. Chippindale et al. / Tetrahedron 59 (2003) 3253–3265
3257
3. Conclusion
A strategy involving diastereoselective conjugate addition
of lithium (S)-N-allyl-N-a-methylbenzylamide to an a,b-
unsaturated ester or amide, followed by ring closing
metathesis has been successfully developed. Application
of this protocol allows the asymmetric synthesis of the
amine (S)-coniine 45, the heterocyclic b-amino acids
(S)-homoproline 44 and (S)-homopipecolic acid 41, and
carbocyclic (1S,2S)-trans-pentacin 46. Further applications
of the diastereoselective conjugate addition of homochiral
lithium amides, coupled with ring closing metathesis for
the asymmetric synthesis of a variety of natural products are
currently underway within our laboratory.
4. Experimental
Scheme 9. Reagents and conditions: (i) (PPh3)3RhCl, H2 (2 atm), MeCN,
rt; (ii) Pd(OH)2 on C, H2 (1 atm), MeOH–H2O–AcOH (40:4:1), rt; (iii) HCl
(aq) then Dowex 50WX8-200.
4.1. General experimental
All reactions involving moisture sensitive reagents were
performed under an atmosphere of dry nitrogen or argon via
standard vacuum line techniques. All glassware was flame-
dried and allowed to cool under vacuum. THF was distilled
under an atmosphere of dry nitrogen from sodium
benzophenone ketyl. Water was distilled. BuLi was used
as a solution in hexanes (Aldrich) at the molarity stated.
PhCHvRu(PCy3)2Cl2 was used as supplied (Lancaster). All
other solvents and reagents were used as supplied
(Analytical or HPLC grade), without prior purification.
All reactions were dried with MgSO4. Thin layer chroma-
tography was performed on aluminium sheets coated with
60 F254 silica. Sheets were visualised using iodine, UV light
or 1% aqueous KMnO4 solution. Flash column chroma-
tography was performed on Kieselgel 60 silica or neutral
alumina. Nuclear magnetic resonance spectra were recorded
on either a Bruker AMX 500 spectrometer (1H: 500 MHz
and 13C: 126 MHz), Bruker DPX 400 spectrometer (1H:
400 MHz and 13C: 100 MHz) or a Bruker DPX 200
spectrometer (13C: 50 MHz) in the deuterated solvent
stated. Residual signals from the solvents were used as an
internal reference. All chemical shifts (d) are quoted in ppm
and coupling constants (J) in Hz. In all cases the reaction
diastereoselectivity was assessed by peak integration of the
1H NMR spectrum of the crude reaction mixture. Infrared
spectra (nmax) 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 cm21. 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. Specific optical
rotations were recorded on a Perkin–Elmer 241 polarimeter
with a water-jacketed 10 cm cell and are given in units of
1021 deg cm2 g21. Concentrations are quoted in g/100 mL.
Melting points were recorded on a Leica VMTG Galen III
apparatus and are uncorrected. Elemental analyses were
performed by the microanalysis service of the Dyson Perrins
Laboratory, Oxford or the Inorganic Chemistry Laboratory,
Oxford.
diastereoisomer in .95% e.e.25 N-benzyl deprotection via
hydrogenolysis furnished b-amino ester 43 in 92% yield,
with ester hydrolysis affording (S)-homoproline 44
{[a]2D3¼þ3.4 (c 1.0, H2O); lit.26[a]D25¼þ4.0 (c 1.0, H2O)}
in excellent yield after purification by ion exchange
chromatography (Scheme 9).
Further applications of this hydrogenolytic deprotection
were demonstrated via the synthesis of (S)-coniine 45,27
a
simple cyclic alkaloid from conium-maculatum (poison
hemlock),28 and (1S,2S)-trans-pentacin 46, oligomers of
which show secondary structure in both solution and the
solid state.29 Thus, hydrogenation of N-protected cyclic
amine 35 and treatment with HCl, furnished (S)-coniine
hydrochloride 45 in 95% yield, with specific rotation
{[a]2D1¼þ8.3 (c 0.7, EtOH); lit, [a]2D5¼þ9.4 (c 0.32,
EtOH);30 [a]2D5¼þ8.1 (c 0.6, EtOH)31} and spectroscopic
properties consistent with those of the literature. Similarly,
exhaustive hydrogenation and ester hydrolysis of b-amino
ester 36 afforded trans-pentacin hydrochloride 46 as a single
diastereoisomer with spectroscopic properties consistent
with those of the literature {[a]D¼þ46.4 (c 1.04, H2O),
lit.32 ent [a]D¼250.7 (c 0.75, H2O)} (Scheme 10).33
Scheme 10. Reagents and conditions: (i) 10% Pd/C, H2 (5 atm), MeOH, rt;
then HCl.

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A. M. Chippindale et al. / Tetrahedron 59 (2003) 3253–3265
4.2. Representative procedure 1
gel, (5% Et2O/40–60 petrol) 13 as a clear pale yellow oil
(2.9 g, 69%); [a]D23¼þ6.4 (c 1.3, CHCl3), nmax/cm21 (film)
1728 s(CvO); dH (CDCl3, 500 MHz), 7.34–7.20 (5H,
m, Ph), 5.91–5.81 (1H, m, NCH2CHCH2), 5.48–5.37 (2H,
m, C(5)H, C(6)H), 5.17–5.13 (1H, dd, J¼15.5, 1.7 Hz,
NCH2CHCHH), 5.07–5.04 (1H, dd, J¼10.1, 1.7 Hz,
NCH2CHCHH), 4.02–3.97 (1H, q, J¼6.8 Hz, C(a)H),
3.57 (3H, s, OMe), 3.45–3.38 (1H, m, C(3)H), 3.26–3.21
(1H, dd, J¼15.2, 6.2 Hz, NCHHCHCH2), 3.19–3.13 (1H,
dd, J¼15.2, 6.2 Hz, NCHHCHCH2), 2.32–2.21 (3H, m,
C(2)H2 and C(4)HA), 2.02–1.95 (1H, m, C(4)HB), 1.68–
1.66 (3H, d, J¼5.3 Hz, C(7)H3), 1.40–1.38 (3H, d, J¼
6.9 Hz, C(a)Me); dC (CDCl3, 50 MHz), 173.5 (CO), 145.1
(Phipso), 139.2, (NCH2CH), 129.0 (C(5)H), 128.2, 127.8
(Pho-,m-), 127.2, 126.8 (Php-, C(6)H), 115.7 (NCH2CHCH2),
57.8 (C(a)H), 55.5 (C(3)H), 51.3 (OMe), 48.9 (NCH2),
37.4, 35.8 (C(2)H2, C(4)H2), 19.4 (C(a)Me), 17.9 (C(7)H3);
HRMS, C19H27NO2 requires 302.2120, found 302.2119.
To a solution of b-amino ester (6 mmol) in DCM (200 mL)
was added ruthenium alkylidene 1 (0.25 mmol, 4 mol%)
under argon flow and stirred at reflux under argon for 12 h.
The solution was concentrated in vacuo and purified by
column chromatography.
4.2.1. (3R,4E,aS)-Methyl 3-(N-allyl-N-a-methylbenzyl-
amino)-hept-4-enoate 12. Following the literature pro-
cedure,34
(S)-N-allyl-N-a-methylbenzylamine
(3.0 g,
18.5 mmol) in THF (30 mL), n-BuLi (1.63 M, 10.5 mL,
17.0 mmol) and 10 (2.0 g, 14.2 mmol) in THF (10 mL)
gave, after purification by column chromatography on silica
gel, (5% Et2O/40–60 petrol), 12 as clear pale yellow oil
(2.9 g, 69%); [a]D23¼þ6.4 (c 1.32, CHCl3), nmax/cm21 (film)
1728 s(CvO); dH (CDCl3, 500 MHz), 7.34–7.20 (5H, m,
Ph), 5.91–5.81 (1H, m, NCH2CHCHA), 5.48–5.37 (2H,
m, C(5)HvC(6)H), 5.15 (1H, dd, J¼15.5, 1.7 Hz, NCH2
CHCHB), 5.05 (1H, dd, J¼10.1, 1.6 Hz, NCH2CHCH2),
4.00 (1H, q, J¼6.8 Hz, C(a)H), 3.57 (3H, s, OMe), 3.45–
3.38 (1H, m, C(3)H), 3.23 (1H, dd, J¼15.2, 6.2 Hz,
NCHHCHCH2), 3.16 (1H, dd, J¼15.2, 6.2 Hz,
NCHHCHCH2), 2.32–2.21 (3H, m, C(2)H2 and C(4)HA),
2.02–1.95 (1H, m, C(4)HB), 1.67 (3H, d, J¼5.3 Hz,
C(7)H3), 1.39 (3H, d, J¼6.8 Hz, C(a)Me); dC (CDCl3,
126 MHz), 173.1 (CO), 144.8 (Phipso), 138.8 (NCH2CH),
128.7, 128.0, 127.6, 126.9, 126.6 (Ph and C(5)HvC(6)H),
115.5 (NCH2CHCH2), 57.8 (OMe), 55.5 (C(a)H), 51.2
(C(3)H), 48.9 (NCH2), 37.4 (C(2)H2), 35.8 (C(4)H2), 19.4
(C(7)H3), 18.8 (C(a)Me); m/z (APCIþ), 316 (MHþ, 100%),
260 (MHþ2C4H8, 55%); HRMS, C20H30NO2 requires
316.2277, found 316.2274.
4.2.4. (E)-N-Methoxy-N-methyl 4-methyl-pent-2-enamide
16. Isobutyraldehyde (0.50 mL, 5.51 mmol) was added to a
solution of N-methoxy-N-methyl-2-(triphenylphosphoranyl-
idene) acetamide (2.00 g, 5.51 mmol) in DCM (20 mL) was
and stirred at rt for 24 h before concentration in vacuo and
purification by column chromatography on silica gel, (5%
Et2O–pentane) to afford 16 as a pale yellow oil (0.80 g,
92%); nmax/cm21 (film) 1664, 1637 s(CvO); dH (CDCl3,
400 MHz), 6.88 (1H, dd, J¼15.5, 6.9 Hz, C(3)H), 6.28 (1H,
d, J¼15.5 Hz, C(2)H), 3.64 (3H, s, OMe), 3.17 (3H, s,
NMe), 2.45–2.40 (1H, m, Me2CH), 1.02–1.00 (6H, d, J¼
6.8 Hz, Me2CH); dC (CDCl3, 126 MHz), 167.2 (CO), 153.9
(C(3)H), 115.8 (C(2)H), 61.5 (OMe), 32.2 (Me2CH), 31.1
(NMe), 21.4 (Me2CH); m/z (APCIþ), 158 (MHþ, 100%);
HRMS, C8H16NO2 requires 158.1181, found: 158.1187.
4.2.2. (3R,aS)-tert-Butyl 3-(N-allyl-N-a-methylbenzyl-
amino)-pent-4-enoate 13. Following the literature pro-
4.2.5. (E)-N-Methoxy-N-methyl hex-2-enamide 17.
Butyraldehyde (0.81 mL, 9.05 mmol) was added to a
solution of N-methoxy-N-methyl 2-(triphenylphosphoranyl-
idene) acetamide (3.3 g, 9.05 mmol) in DCM (20 mL) and
stirred at rt for 12 h before concentration in vacuo.
Purification by column chromatography on silica gel, (5%
Et2O/40–60 petrol) gave 17 (0.68 g, 48%) as a colourless
oil and as single diastereoisomer; nmax/cm21 (film) 1663
s(CvO), 1635 (CvC); dH (CDCl3, 200 MHz), 6.99–6.85
(1H, m, C(3)H), 6.35 (1H, dt, J¼15.5, 1.4 Hz, C(2)H), 3.65
(3H, s, OMe), 3.19 (3H, s, NMe), 2.22–2.11 (2H, m,
C(4)H2), 1.54–1.36 (2H, m, C(5)H2), 0.92–0.85 (3H, m,
C(6)H3); dC (CDCl3, 50 MHz), 167.0 (CO), 147.6 (C(3)H),
118.7 (C(2)H), 61.5 (OMe), 34.4 (C(4)H2), 32.2 (NMe),
21.5 (C(5)H2), 13.6 (C(6)H3); m/z (APCIþ), 158 (MHþ,
100%); HRMS, C8H16NO2 requires 158.1181, found
158.1188.
cedure,34
(S)-N-allyl-N-a-methylbenzylamine
(4.5 g,
28.2 mmol) in THF (40 mL), n-BuLi (1.60 M, 16.4 mL,
26.3 mmol) and 11 (2.9 g, 18.8 mmol) in THF (25 mL)
gave, after purification by column chromatography on
silica gel, (5% Et2O/40–60 petrol) 13 as a clear pale yellow
oil (3.65 g, 62%); [a]2D6¼þ8.3 (c 1.04, CHCl3); nmax/cm21
(film) 1730 s(CvO); dH (CDCl3, 500 MHz), 7.42–7.21
(5H, m, Ph), 5.96–5.79 (2H, m, NCH2CHCH2 and C(4)H),
5.18–5.03 (4H, m, NCH2CHCH2 and C(5)H2), 4.06 (1H, q,
J¼6.8 Hz, C(a)H), 3.98–3.93 (1H, m, C(3)H), 3.18 (2H,
app d, J¼6.2 Hz, NCH2), 2.45 (1H, dd, J¼14.5, 6.5 Hz,
C(2)HA), 2.34 (1H, dd, J¼14.5, 8.2 Hz, C(2)HB), 1.48 (9H,
s, C(CH3)3), 1.42 (3H, d, J¼6.8 Hz, C(a)Me); dC (CDCl3,
126 MHz), 171.1 (CO2), 144.9 (Phipso), 138.8, 138.1 (C(4)H
and NCH2CH), 128.0, 127.7, 126.6 (Ph), 115.8, 115.6
(C(5)H2 and NCH2CHCH2), 79.9 (C(CH3)3), 57.5, 57.3
(C(a)H and NCHCH2), 49.6 (NCH2), 38.9 (C(2)H2), 28.0
(C(CH3)3), 18.8 (C(a)Me); m/z (APCIþ), 316 (MHþ,
100%), 260 (MHþ2C4H8, 55%); HRMS, C20H30NO2
requires 316.2277, found 316.2274.
4.2.6. (3R,aS)-N-Methoxy-N-methyl 3-(N-allyl-N-a-
methylbenzylamino)-4-methyl-pentanamide 18. Follow-
ing the literature procedure,34 (S)-N-allyl-N-a-methyl-
benzylamine (1.14 g, 7.1 mmol) in THF (30 mL), n-BuLi
(1.60 M, 4.1 mL, 6.6 mmol) and 16 (795 mg, 5.1 mmol) in
THF (5 mL) gave, after purification by column chroma-
tography on silica gel, (20% Et2O/40–60 petrol), 18 as a
pale yellow oil (1.0 g, 63%); [a]2D3¼þ8.0 (c 1.1, CHCl3);
4.2.3. (3S,5E,aS)-Methyl 3-(N-allyl-N-a-methylbenzyl-
amino)hept-5-enoate 15. Following the literature pro-
cedure,34
(S)-N-allyl-N-a-methylbenzylamine
(3.0 g,
18.5 mmol) in THF (30 mL), n-BuLi (1.63 M, 10.5 mL,
17.1 mmol) and 11 (2.0 g, 14.2 mmol) in THF (10 mL)
gave, after purification by column chromatography on silica
n
max/cm21 (film) 1664 s(CvO); dH (CDCl3, 500 MHz),
7.33–7.16 (5H, m, Ph), 5.94–5.86 (1H, m, NCH2CHCH2),

A. M. Chippindale et al. / Tetrahedron 59 (2003) 3253–3265
3259
5.24 (1H, dd, J¼17.3, 1.4 Hz, NCH2CHCHH), 5.10 (1H, dd,
J¼10.1, 1.4 Hz, NCH2CHCHH), 3.94 (1H, q, J¼7.1 Hz,
C(a)H), 3.43 (3H, s, OMe), 3.33 (1H, app. dt, J¼8.2, 3.1 Hz,
NCHCH2), 3.27–3.23 (1H, m, NCHH), 3.11–3.06 (1H, m,
NCHH), 3.08 (3H, s, NMe), 2.35–2.30 (1H, m, C(2)HA),
1.91 (1H, dd, J¼16.4, 2.8 Hz, C(2)HB), 1.71–1.64 (1H, m,
C(4)H), 1.44 (3H, d, J¼7.1 Hz, C(a)Me), 1.01 and 0.84
(2£3H, d, J¼6.7 Hz, Me2CH); dC (CDCl3, 126 MHz), 173.8
(CO), 143.4 (Phipso), 139.0 (NCH2CHCH2), 128.0, 127.8,
126.4 (Ph), 115.0 (NCH2CHCH2), 60.6 (OMe), 58.1, 57.8
(C(a)H and C(3)H), 49.6 (NCH2), 32.7 (NMe), 32.2
(C(4)H), 31.6 (C(2)H2), 20.5, 20.3, 19.6 (C(a)Me and
C(4)Me2); m/z (CIþ, NH3), 319 (MHþ, 100%); HRMS,
C19H31N2O2 requires 319.2386, found, 319.2395.
4.7 Hz, C(4)H), 1.99–1.89 (2H, m, C(3)H2), 1.78–1.71
(1H, m, C(5)H), 1.38 (3H, d, J¼6.9 Hz, C(a)Me), 0.95
(3H, d, J¼6.8 Hz, C(5)Me), 0.89–0.88 (3H, d, J¼6.7 Hz,
C(5)Me); dC (CDCl3, 126 MHz), 144.9 (Phipso), 140.0
(NCH2CHCH2), 138.8 (C(2)H), 128.0, 127.9, 126.6 (Ph),
114.8 (NCH2CHCH2), 114.6 (C(1)H2), 62.5 (C(a)H), 59.4
(C(4)H), 50.2 (NCH2CHCH2), 33.6 (C(2)H2), 31.8 (C(5)H),
21.5 (C(a)Me), 20.9, 20.4 (C(5)Me2); m/z (CIþ, NH3), 258
(MHþ, 100%), 216 (M2C3H5, 73%); HRMS, C18H28N
requires 258.2222, found, 258.2227.
4.2.9. (4S,aS)-4-N-Allyl-N-a-methylbenzylamino-hept-
1-ene 21. DIBAL-H (1.5 M in toluene; 1.53 mL,
2.30 mmol) was added to a solution of 19 (365 mg,
1.15 mmol) in THF (20 mL) at 2788C and stirred for 3 h
before the addition of acetone (2 mL). The solution was
added via cannula into a saturated solution of sodium
potassium tartrate (20 mL) and then extracted into Et2O
(2£100 mL), dried, and concentrated in vacuo. The crude
product was added to a solution of phosphonium bromide/
sodamide (744 mg, 2.30 mmol) in DCM (10 mL) at 2408C
and warmed to rt over 12 h before the addition of pH 7
buffer (1 mL), concentrated in vacuo, partitioned between
DCM (2£100 mL) and water (30 mL), dried and concen-
trated in vacuo. Purification by column chromatography on
silica gel, (5% Et2O/40–60 petrol) gave 21 as a clear pale
yellow oil (184 mg, 62%); [a]2D3¼29.3 (c 1.49, CHCl3);
4.2.7. (3S,aS)-N-Methoxy-N-methyl 3-(N-allyl-N-a-methyl-
benzylamino)-hexanamide 19. Following the literature
procedure,34 (S)-N-allyl-N-a-methylbenzylamine (746 mg,
4.64 mmol) in THF (20 mL), n-BuLi (2.50 M; 1.7 mL,
4.35 mmol) and 17 (455 mg, 2.9 mmol) in THF (5 mL)
gave, after purification by column chromatography on silica
gel, (5% EtOAc/40–60 petrol), 19 as a clear pale yellow oil
(595 mg, 65%); [a]2D3¼27.5 (c 2.09, CHCl3); nmax/cm21
(film) 1654 s(CvO); dH (CDCl3, 500 MHz), 7.36–7.20
(5H, m, Ph), 5.97–5.89 (1H, m, NCH2CHCH2), 5.16 (1H,
dd, J¼17.2, 1.4 Hz, NCH2CHCHH), 5.11 (1H, app d,
J¼10.1 Hz, NCH2CHCHH), 4.03–4.02 (1H, m, C(a)H),
3.46 (3H, s, OMe), 3.53–3.46 (1H, m, C(3)H) 3.35 (1H, dd,
J¼15.2, 4.3 Hz, NCHH), 3.21–3.16 (1H, m, NCHH), 3.09
(3H, s, NMe), 2.30–2.13 (2H, m, C(2)H2), 1.46 (3H, d,
J¼6.7 Hz, C(a)Me), 1.51–1.45, 1.33–1.26 (4H, m, C(4)H2
and C(5)H2), 0.88 (3H, t, J¼7.1 Hz, C(6)H3); dC
(CDCl3, 126 MHz), 173.3 (CO), 143.7 (Phipso), 138.4
(NCH2CHCH2), 128.1, 127.9, 126.9 (Ph), 116.0 (NCH2
CHCH2), 60.9, 58.6 (C(a)H and OMe), 54.1 (C(3)H), 49.1
(NCH2), 35.5 (C(2)H2CO), 33.8 (C(4)H2), 32.0 (NMe), 29.7
(C(5)H2), 20.0 (C(a)Me), 14.1 (C(6)H3); m/z (CIþ, NH3),
320 (MHþ, 100%); HRMS, C19H31N2O2 requires 319.2386,
found, 319.2383.
n
max/cm21 (film) 1639 s(CvC); dH (CDCl3, 400 MHz),
7.40–7.25 (5H, m, Ph), 5.98–5.90 (1H, m, NCH2CHCH2),
5.69–5.61 (1H, m, C(2)H), 5.25 (1H, ddd, J¼17.2, 3.5,
1.8 Hz, NCH2CHCHH), 5.10 (1H, ddd, J¼10.2, 3.5, 1.8 Hz,
NCH2CHCHH), 4.93–4.89 (2H, m, C(1)H2), 4.02 (1H, q,
J¼6.9 Hz, C(a)H), 3.36–3.31 (1H, m, NCHH), 3.20–3.15
(1H, m, NCHH), 2.74–2.68 (1H, m, C(4)H), 2.07–2.01
(1H, m, C(3)HA), 1.88–1.82 (1H, m, C(3)HB), 1.58–1.49,
1.44–1.24 (4H, m, C(5)H2 and C(6)H2), 1.41 (3H, d,
J¼6.9 Hz, C(a)Me), 0.91–0.88 (3H, t, J¼7.2 Hz, C(7)H3);
dC (CDCl3, 126 MHz), 145.3 (Phipso), 140.0 (NCH2
CHCH2), 137.8 (C(2)H), 128.0, 127.7, 126.5 (Ph), 115.2
(NCH2CHCH2), 114.7 (C(1)H2), 58.4 (C(a)H), 57.2
(C(4)H), 48.7 (NCH2), 35.7 (C(3)H2), 34.6 (C(5)H2), 20.7
(C(a)Me), 20.2 (C(6)H2), 14.3 (C(7)H3); m/z (CIþ, NH3),
258 (MHþ, 30%); HRMS, C18H28N requires 258.2222,
found 258.2223.
4.2.8. (4R,aS)-4-N-Allyl-N-a-methylbenzylamino-5-
methyl-hex-1-ene 20. DIBAL-H (1.5 M in toluene;
0.28 mL, 0.42 mmol) was added to a solution of 18
(66 mg, 0.208 mmol) in THF (3 mL) at 2788C and stirred
for 3 h before the addition of acetone (1 mL). The solution
was added via cannula into a saturated solution of sodium
potassium tartrate (5 mL) and then extracted into Et2O
(50 mL), dried, and concentrated in vacuo. The crude
product was added to a solution of phosphonium bromide/
sodamide (135 mg, 0.415 mmol) in DCM (3 mL) at 08C and
warmed to rt over 18 h before the addition of pH7 buffer
(1 mL), concentrated in vacuo, partitioned between DCM
(2£100 mL) and water (30 mL), dried and concentrated in
vacuo. Purification on silica gel, (10% Et2O/40–60 petrol)
gave 20 as a yellow oil (34 mg, 64% (2 steps); [a]D¼216.4
(c 1.53, CHCl3);nmax/cm21 (film) 1638 s(CvC); dH
(CDCl3, 500 MHz), 7.34–7.22 (5H, m, Ph), 5.96–5.88
(1H, m, NCH2CHCH2), 5.67 (1H, ddt, J¼18.3, 8.9, 7.1 Hz,
C(2)H), 5.22 (1H, ddd, J¼17.3, 3.5, 1.8 Hz, NCH2
CHCHH), 5.06 (1H, ddd, J¼10.2, 3.5, 1.8 Hz, NCH2
CHCHH), 4.88–4.84 (2H, m, C(1)H2), 3.97 (1H, q,
J¼6.9 Hz, C(a)H), 3.32–3.27 (1H, m, NCHH), 3.19–3.15
(1H, dd, J¼15.9, 6.9 Hz, NCHH), 2.50 (1H, app dt, J¼7.1,
4.2.10. syn-(2R,3S,4E)- and anti-(2S,3S,4E)-tert-Butyl
2-allyl-3-(N-allyl-N-a-methylbenzylamino)-hex-4-enoate
22. LDA (2.0 M, 3.94 mL, 7.87 mmol) was added to a
solution of 12 (1.73 g, 5.25 mmol) in THF and stirred for
30 min before the addition of allyl bromide (2.27 mL,
26.3 mmol) and allowed to warm to rt over 12 h. After
concentration in vacuo, the residue was partitioned between
DCM (100 mL) and water (25 mL), dried, and concentrated
in vacuo. Purification by column chromatography on silica
gel, (10% Et2O/40–60 petrol) afforded 22 (1.92 g, 99%)
as a pale yellow oil and as a mixture of diastereoisomers
(d.e. 75%); (data for major diastereoisomer as minor dia-
stereoisomer obscured); nmax/cm21 (film) 1728 s(CvO); dH
(CDCl3, 500 MHz), 7.39–7.19 (5H, m, Ph), 5.88–5.71 (2H,
m, NCH2CHCH2 and C(20)H), 5.54 (1H, dq, J¼15.3,
6.4 Hz, C(5)H), 5.38 (1H, ddd, J¼15.3, 9.9, 1.4 Hz,
C(4)H), 5.11–4.96 (4H, m, NCH2CHCH2 and C(30)H2),
4.04 (1H, q, J¼6.7 Hz, C(a)H), 3.56 (1H, app t, J¼10.3 Hz,

3260
A. M. Chippindale et al. / Tetrahedron 59 (2003) 3253–3265
C(3)H), 3.25 (1H, dd, J¼14.8, 5.1 Hz, NCHH), 3.12 (1H,
dd, J¼14.8, 7.8 Hz, NCHH), 2.69–2.61 (1H, m, C(2)H),
2.23–2.18 (1H, m, C(10)HA), 2.13–2.06 (1H, m, C(10)HB),
1.77 (3H, dd, J¼6.4, 1.4 Hz, C(6)H3), 1.74 (3H, d, J¼
6.7 Hz, C(a)Me), 1.47 (9H, s, C(CH3)3); dC (CDCl3,
126 MHz), 173.6 (CO), 145.5 (Phipso), 138.7, 135.6,
129.4, 128.3, 127.8, 127.6, 126.2 (NCH2CHCH2, C(20)H,
C(4)H, C(5)H and Ph), 116.1, 115.1 (NCH2CHCH2 and
C(30)H2), 79.9 (C(CH3)3), 63.1 (C(a)H), 57.2 (C(3)H), 50.0
(NCH2), 49.7 (C(2)H), 35.3 (C(10)H2), 28.1 (C(CH3)3), 18.8
(C(6)H3), 17.9 (C(a)Me); m/z (APCIþ), 370 (MHþ, 100%);
HRMS, C24H36NO2 requires 370.2746, found 370.2738.
J¼15.2, 6.5 Hz, C(5)H), 5.11–5.01 (3H, m, C(4)H and
C(30)H2), 3.81 (1H, q, J¼6.4 Hz, C(a)H), 3.28–3.25 (1H,
m, C(3)H), 2.33–2.26 (3H, m, C(10)H2 and C(2)H), 1.71
(3H, dd, J¼6.4, 1.5 Hz, C(6)H3), 1.50 (9H, s, C(CH3)3),
1.28 (3H, d, J¼6.4 Hz, C(a)Me); dC (CDCl3, 126 MHz),
173.4 (CO), 146.7 (Phipso), 135.8, 131.6, 128.1, 126.6
(C(4)H, C(5)H, C(20)H and Ph), 116.1 (C(30)H2), 79.9
(C(CH3)3), 60.0 (C(a)H), 54.3 (C(3)H), 51.9 (C(2)H), 34.0
(C(10)H2), 28.1 (C(CH3)3), 22.4 (C(6)H3), 17.6 (C(a)Me);
m/z (APCIþ), 330 (MHþ, 73%), 274 (MHþ2C4H8, 100%);
C21H32NO2 requires 330.2433, found 330.2430.
4.2.13. syn-(2R,10S,4E,aS)-tert-Butyl 2-(10-{N-a-methyl-
benzylamino}-but-2-enyl)-hept-6-enoate 25 and anti-(2S,
10S,4E,aS)-tert-butyl 2-(10-{N-a-methylbenzylamino}-
but-2-enyl)-hept-6-enoate 26. RhCl(PPh3)3 (0.14 g,
0.15 mmol) was added to a refluxing solution of 23 (1.2 g,
3.0 mmol) in MeCN–H2O (85:15, 20 mL) and refluxed for
2 h whilst solvent was continuously replaced and azeotropic
removal of propanal was effected. After concentration in
vacuo, the residue was purified by column chromatography
on silica gel, (3% Et2O/40–60 petrol), to afford the major
diastereomer anti-25 (603 mg, 56%) and the minor
diastereoisomer syn-26 (0.240 g, 22%) as colourless oils;
data for major diastereoisomer anti-25; [a]2D6¼287.3 (c
1.02, CHCl3); nmax/cm21 (film) 1728 s(CvO); dH (CDCl3,
500 MHz), 7.33–7.20 (5H, m, Ph), 5.81 (1H, ddt, J¼17.0,
10.3, 6.9 Hz, C(6)H), 5.500(1H, dq, J¼15.2, 6.4 Hz, C(30)H),
5.06–4.96 (3H, m, C(2 )H and C(7)H2), 3.80 (1H, q,
J¼6.4 Hz, C(a)H), 3.22 (1H, app t, J¼9.0 Hz, C(10)H),
2.20–2.16 (1H, m, C(2)H), 2.10–2.00 (2H, m, C(5)H2),
1.70 (3H, dd, J¼6.4, 1.6 Hz, C(40)H3), 1.56–1.36 (4H, m,
C(3)H2, C(4)H2), 1.51 (9H, s, C(CH3)3), 1.26 (3H, d, J¼
6.4 Hz, C(a)Me); dC (CDCl3, 126 MHz), 174.2 (CO), 146.8
(Phipso), 138.5, 131.8, 128.1, 127.9, 126.6 (C(20)H, C(30)H,
C(6)H and Ph), 114.4 (C(7)H2), 79.8 (C(CH3)3), 60.4
(C(a)H), 54.3 (C(10)H), 52.3 (C(2)H), 33.5 (C(5)H2), 29.0,
26.6 (C(4)H2, C(3)H2), 28.1 (C(CH3)3), 22.5 (C(40)H3),
17.6 (C(a)Me); m/z (APCIþ), 358 (MHþ, 100%), 302
(MHþ2C4H8 80%); HRMS, C23H36NO2 requires 358.2746,
found 358.2752; data for minor diastereoisomer anti-26;
[a]2D3¼241.5 (c 0.40, CHCl3); nmax/cm21 (film) 1728
s(CvO); dH (CDCl3, 500 MHz), 7.36–7.21 (5H, m, Ph),
5.79 (1H, ddt, J¼15.6, 10.3, 6.7 Hz, C(6)H), 5.48 (1H, dq,
J¼15.2, 6.4 Hz, C(30)H), 5.28 (1H, ddd, J¼15.6, 8.5,
1.6 Hz, C(7)HA), 5.02–4.93 (2H, m, C(20)H and C(7)HB),
3.88 (1H, q, J¼6.4 Hz, C(a)H), 3.11 (1H, dd, J¼6.5, 2.0 Hz,
C(10)H), 2.41–2.37 (1H, m, C(2)H), 2.06–2.02 (2H, m,
C(5)H2), 1.66 (3H, dd, 6.4, 1.5 Hz, C(40)H3), 1.70–1.25
(4H, m, C(3)H2, C(4)H2), 1.45 (9H, s, C(CH3)3), 1.29 (3H,
d, J¼6.4 Hz, C(a)Me); dC (CDCl3, 126 MHz), 173.7 (CO),
146.4 (Phipso), 138.7, 131.0, 128.3, 127.6, 126.7, 126.6
(C(20)H, C(30)H, C(6)H and Ph), 114.4 (C(7)H2), 80.2
(C(CH3)3), 60.5 (C(a)H), 54.3 (C(10)H), 50.5 (C(2)H), 33.6
(C(50)H2), 28.7, 26.9 (C(4)H2, C(3)H2), 28.2 (C(CH3)3), 23.3
(C(4 )H3), 17.7 (C(a)Me); m/z (CIþ, NH3), 358 (MHþ,
100%), 302 (MHþ2C4H8 22%); HRMS, C23H36NO2
requires 358.2746, found 358.2761.
4.2.11. syn-(2R,10S,4E,aS)- and anti-(2S,10S,4E,aS)-tert-
butyl 2-(10-{N-allyl-N-a-methylbenzylamino}-but-2-enyl)-
hept-6-enoate 23. LDA (2.0 M, 3.8 mL, 7.60 mmol) was
added to a solution of 12 (1.66 g, 5.06 mmol) in THF
(50 mL) and stirred for 30 min before the addition of
5-bromopentene (1.20 mL, 10.1 mmol) and allowed to
warm to rt over 12 h. After concentration in vacuo, the
residue was partitioned between DCM (100 mL) and water
(25 mL), dried, and concentrated in vacuo. Purification by
column chromatography on silica gel, (1–3% Et2O/40–60
petrol), 23 as clear pale yellow oil (1.35 g, 92%) and as a
mixture of diastereoisomers; data for major diastereoisomer
anti-(2S,10S,4E,aS)-23; nmax/cm21 (film) 1727 s(CvO); dH
(CDCl3, 400 MHz), 7.37–7.16 (5H, m, Ph), 5.82–5.72 (2H,
m, C(6)H and NCH2CHCH2), 5.48, 5.31 (2H, m, CHvCH),
5.04–4.91 (4H, m, NCH2CHCH2, C(7)H2), 4.00 (1H, q, J¼
6.7 Hz, C(a)H), 3.50 (1H, app t, J¼10.3 Hz, C(10)H), 3.22
(1H, m, NCHH), 3.09 (1H, dd, J¼14.8, 7.8 Hz, NCHH),
2.53–2.51 (1H, m, C(2)H), 2.08–1.96 (2H, m, C(5)H2),
1.76–1.74 (3H, dd, J¼6.3, 1.3 Hz, C(40)H3), 1.60–1.21
(4H, m, C(3)H2, C(4)H2), 1.49 (9H, s, C(CH3)3), 1.35 (3H,
d, J¼6.7 Hz, C(a)Me); dC (CDCl3, 100 MHz), 174.5 (CO),
145.6 (Phipso), 138.9, 138.6 (C(6)H, NCH2CHCH2), 129.1,
128.5, 128.4, 128.3, 127.8 (C(20)H, C(30)H and Ph), 115.0,
114.3 (C(7)H2, NCH2CHCH2), 79.7 (C(CH3)3), 63.3
(C(a)H), 57.2 (C(10)H), 50.1 (NCH2), 49.7 (C(2)H), 33.5
(C(50)H2), 30.3, 26.5 (C(4)H2, C(3)H2), 28.2 (C(CH3)3), 19.0
(C(4 )H3), 18.0 (C(a)Me); m/z (APCIþ), 398 (MHþ, 100%),
342 (MHþ2C4H8, 25%); HRMS, C26H40NO2 requires
398.3059, found 398.30061; selected data for minor dia-
stereoisomer syn-(2R,1 S,4E)-23; nmax/cm21 (film) 1728
s(CvO); dH (CDCl3, 400 MHz), 2.42–2.33 (1H, m,
C(20)H), 1.71 (3H, d, J¼4.5 Hz, C(40)H3), 1.40 (9H, s,
C(CH3)3); dC (CDCl3, 100 MHz), 174.4 (CO), 145.4
(Phipso), 138.8, 138.5 (C(6)H, NCH2CHCH2), 116.0, 114.2
(C(7)H2, NCH2CHCH2), 80.1 (C(CH3)3), 61.7 (C(a)H),
56.3 (C(10)H), 50.3 (NCH2), 28.1 (C(CH3)3).
4.2.12. (2S,3S,4E,aS)-tert-Butyl 2-allyl-3-(N-a-methyl-
benzylamino)-hex-4-enoate 24. RhCl(PPh3)3 (0.22 g,
0.23 mmol) was added to a refluxing solution of 22
(1.72 g, 4.64 mmol) in a MeCN–H2O (85:15, 20 mL) and
refluxed for 2 h whilst solvent was continuously replaced
and azeotropic removal of propanal was effected. After
concentration in vacuo, the residue was purified by column
chromatography on silica gel, (3% Et2O/40–60 petrol), to
afford 24 as clear pale yellow oil (1.18 g, 77%) and as a
4.2.14. (2S,3S,4E,aS)-tert-Butyl 2-allyl-3-(N-a-methyl-
single diastereoisomer; [a]2D3¼266.2 (c 1.20, CHCl3); nmax
/
benzylamino)-N-benzyloxycarbonyl-hex-4-enoate 27.
Dibenzyl dicarbonate (1.10 g, 3.80 mmol) was added to 24
(0.47 g, 1.27 mmol) and stirred under high vacuum for 18 h
cm21 (film) 1728 s(CvO); dH (CDCl3, 500 MHz), 7.34–
7.20 (5H, m, Ph), 5.84–5.75 (1H, m, C(20)H), 5.53 (1H, dq,

A. M. Chippindale et al. / Tetrahedron 59 (2003) 3253–3265
3261
before purification by column chromatography on silica gel,
(3–6% Et2O/40–60 petrol) to afford 27 as a colourless oil
(0.50 g, 85%); [a]2D3¼29.4 (c 1.17, CHCl3); nmax/cm21
(film) 1722 (CO), 1698 (NCO); dH (d8 toluene, 500 MHz, at
908C), 7.35–6.96 (10H, m, Ph), 5.83–5.69 (2H, m, C(20)H
and C(30)HA), 5.34 (1H, dq, J¼19.3, 6.5 Hz, C(5)H), 5.05
(1H, d, J¼12.3 Hz, N(CvO)OCHA), 4.92 (1H, d, J¼
12.3 Hz, N(CvO)OCHB), 4.98–4.89 (2H, m, C(30)HB and
C(4)H), 4.62 (1H, q, J¼7.0 Hz, C(a)H), 4.03 (1H, app. t,
J¼9.5 Hz, C(3)H), 3.32 (1H, dt, J¼9.9, 4.1 Hz, C(2)H),
2.29–2.11 (2H, m, C(10)H2), 1.69 (3H, d, J¼7.1 Hz,
C(a)Me), 1.46 (3H, dd, J¼6.5, 1.7 Hz, C(6)H3), 1.35 (9H,
s, C(CH3)3); dC (CDCl3, 126 MHz), 173.3 (CO), 155.1
(NCO), 141.9, 136.3 (Phipso), 134.7 (C(20)H), 130.7, 130.3,
128.0, 127.8, 127.7, 127.5, 127.2, 126.5 (C(4)H, C(5)H,
Ph), 116.4 (C(30)H2), 80.3 (C(CH3)3), 66.4 (OCH2Ph), 60.1
(C(a)H), 48.2 (C(3)H), 35.4 (C(10)H2), (C(2)H), 28.0
(C(CH3)3), 18.8 (C(6)H3), 17.5 (C(a)Me); m/z (CIþ, NH3),
464 (MHþ, 10%); HRMS, C29H38NO4 requires 464.2801,
found 464.2783.
CHvCH2), 5.63 (1H, dq, J¼15.2, 6.5 Hz, MeCHvCH),
5.44 (1H, ddd, J¼15.2, 9.5, 1.5 Hz, MeCHvCH), 5.02–
4.90 (3H, m, CHvCH2 and C(a)H), 3.87 (1H, dd, J¼9.4,
5.4 Hz, C(4)H), 3.08–3.03 (1H, m, C(3)H), 1.71 (3H,
dd, J¼6.5, 1.5 Hz, MeCHvCH), 1.69–1.62 (2H, m,
C(3)HCH2CH2CH2), 1.55 (3H, d, 7.2 Hz, C(a)Me), 1.52–
1.36 (4H, m, C(3)HCH2CH2); dC (CDCl3, 100 MHz), 170.0
(CO), 140.5 (Phipso), 138.4 (CHvCH2), 131.0, 128.5,
128.2, 127.4, 127.2 (MeCHvCH and Ph), 114.7
(CHvCH2), 56.8 (C(a)H), 53.2 (C(4)H), 51.4 (C(3)H),
33.5 (C(3)HCH2CH2CH2), 26.7, 24.9 (C(3)HCH2CH2CH2),
19.4 (MeCHvCH), 17.8 (C(a)Me); m/z (APCIþ), 284
(MHþ, 100%); HRMS, C19H26NO requires 284.2014, found
284.2002.
4.2.17. (E)-tert-Butyl 4-methylpenta-2,4-dienoate 30.
Methacrolein (6 mL, 62.1 mmol) was added dropwise to a
solution of tert-butyl triphenylphosphoranylideneacetate
t
(25.7 g, 68.3 mmol) in BuOH (50 mL) and stirred at rt for
16 h before the addition of water (20 mL) and Et2O
(2£50 mL), dried, filtered and concentrated in vacuo to
give the crude product. Purification by column chroma-
tography on silica gel, (2% Et2O/pentane) gave 31 (3.54 g,
42%) as an oil which was stored at 2258C under N2 to
prevent polymerisation; nmax (film) 1712 (CvO), 1632
(CvC), 1607 (CvC), 1151 (C–O); dH (CDCl3, 400 MHz)
7.27 (1H, d, J¼15.8 Hz, C(3)H), 5.81 (1H, d, J¼15.8 Hz,
C(2)H), 5.33 (1H, br s, C(5)HB), 5.31 (1H, br s, C(5)HA),
1.88 (3, s, C(4)Me), 1.51 (9H, s, C(CH3)3); dC (CDCl3,
50 MHz) 146.2, 140.8 (C(2), (C(1)), 135.3 (C(4)), 123.8
(C(5)), 120.8 (C(3)), 80.3 (C(CH3)3), 28.0 (C(CH3)3), 18.0
(C(4)Me); m/z (CIþ, NH3) 186 (MNHþ4 , 86%), 169 (MHþ,
100); HRMS C10H17O2 requires 169.1230, found 169.1231.
4.2.15. (2S,10S,4E,aS)-tert-Butyl 2-(10-{N-benzyloxycarbo-
nyl-N-a-methylbenzylamino}-but-2-enyl)-hept-6-enoate
28. Dibenzyl dicarbonate (0.94 g, 3.28 mmol) was added to
anti-25 (0.54 g, 1.50 mmol) and stirred under high vacuum
for 18 h before purification by column chromatography on
silica gel, (2–10% Et2O/40–60 petrol) to afford 28 as a
colourless oil (177 mg, 24%); [a]2D3¼211.1 (c 1.18,
CHCl3); nmax/cm21 (film) 1723 s(CO2), 1698 s(NCO2); dH
(d8 toluene, 500 MHz, at 908C), 7.37–6.96 (10H, m, Ph),
5.82 (1H, ddd, J¼15.4, 9.1, 1.7 Hz, C(20)H), 5.69 (1H, ddt,
J¼17.0, 10.3, 6.6 Hz, C(6)H), 5.34 (1H, dq, J¼15.4, 6.4 Hz,
C(30)H), 5.04 (1H, AB, J¼12.3 Hz, OCHA), 4.93 (1H, AB,
J¼12.3 Hz, OCHB), 4.95–4.87 (2H, m, C(7)H2), 4.61 (1H,
q, J¼7.0 Hz, C(a)H), 4.02 (1H, app t, J¼9.0 Hz, C(10)H),
3.30–3.24 (1H, m, C(2)H), 2.04–1.88 (2H, m, C(5)H2),
1.71 (3H, d, J¼7.0 Hz, C(a)Me), 1.48 (3H, dd, 6.4, 1.7 Hz,
C(40)H3), 1.51–1.48 (4H, m, C(3)H2, C(4)H2), 1.37 (9H, s,
C(CH3)3); dC (CDCl3, 126 MHz), 174.4 (CO), 155.3
(NCO), 142.1, 136.5 (Phipso), 138.4, 130.2, 128.4, 128.2,
128.0, 127.8, 127.7, 127.5, 126.7 (C(20)H, C(30)H, C(6)H
and Ph), 114.4 (C(7)H2), 80.4 (C(CH3)3), 66.6 (OCH2), 60.3
(C(a)H), 48.5 (C(10)H), (CHCO2),35 33.3 (C(5)H2), 30.7,
26.2 (C(4)H2, C(3)H2), 28.2 (C(CH3)3), 18.9 (C(a)Me),
17.7 (C(40)H2); m/z (CIþ, NH3), 492 (MHþ, 40%); HRMS,
C31H42NO4 requires 492.3114, found 492.3120.
4.2.18. (2S,3R,aS)-tert-Butyl 2-(prop-2-enyl)-3-(N-benzyl-
N-a-methylbenzylamino)-4-methylpent-4-enoate
31.
Following the literature procedure,18 (S)-N-benzyl-N-a-
methylbenzylamine (3.0 g, 14.3 mmol) in THF (20 mL),
n-BuLi (1.6 M, 18.7 mL, 13.9 mmol) and 30 (2.0 g,
11.9 mmol) in THF (5 mL) gave, after addition of allyl
bromide (1.5 mL, 17.8 mmol) and purification by column
chromatography on silica gel, (2% Et2O/pentane) and
recrystallisation (Et2O/pentane), 31 as a white solid (1.8 g,
36%). Found, C, 79.9; H, 8.8; N, 3.2%; C28H37NO2
requires: C, 80.15; H, 8.9; N, 3.35%; mp 62–638C;
[a]2D3¼237.0 (c 0.2, CHCl3); nmax (KBr) 1720 (CvO),
1642 (CvC), 1604 (CvC), 1164 (C–O); dH (CDCl3,
400 MHz) 7.18–7.37 (10H, m, Ph), 5.60 (1H, m,
C(2)HCH2CHvCHH), 5.02 (1H, br s, C(5)HB), 4.97 (1H,
d, J¼17.0 Hz, C(2)HCH2CHvCHH), 4.92 (1H, d, J¼
10.1 Hz, C(2)HCH2CHvCHH), 4.77 (1H, br s, C(5)HA),
4.14 (1H, q, J¼6.9 Hz, C(a)H), 3.81, 4.09 (2H, AB, J¼
14.5 Hz, NCH2Ph), 3.51 (1H, d, J¼10.6 Hz, C(3)H), 2.76
(1H, dt, J¼10.6, 4.2 Hz, C(2)H), 1.98–2.05 (2H, m,
C(2)HCH2), 1.77 (3H, s, C(4)Me), 1.45 (9H, s,
OC(CH3)3), 1.38 (3H, d, J¼6.9 Hz, C(a)Me); dC (CDCl3,
50 MHz) 174.1 (CO), 143.5, 144.6 (Phipso), 141.6 (C(4)),
135.8 (C(2)HCH2CHvCH2), 126.7, 127.9, 128.0, 128.5
and 128.9 (Pho-,m-,p-), 116.5, 116.6 (C(5)H2, C(2)HCH2
CHvCH2), 80.6 (OC(CH3)3), 65.3 (C(a)H), 57.8 (C(3)),
50.9 (NCH2Ph), 47.9 (C(2)), 35.3 (C(2)CH2), 28.1
(C(CH3)3), 21.4 (C(a)Me), 16.0 (C(4)Me); m/z (APCIþ)
420 (MHþ, 100%).
4.2.16. (3R,4S,aS,10E)-1-N-a-Methylbenzylamino-3-
(pent-4-enyl)-4-(prop-1-enyl)-azetadin-2-one 29. TFA
(2 cm3) was added to 26 (52 mg, 0.146 mmol) and stirred
at rt for 3 h before concentration in vacuo and the residue
partitioned between ethyl acetate (2£15 cm3) and a
saturated aqueous solution of sodium bicarbonate
(10 cm3). The organic phases were combined, dried and
concentrated in vacuo to afforded the crude carboxylic acid
which was dissolved in MeCN (3 cm3) and added to a
mixture of PPh3 (46 mg, 0.175 mmol) and dipyridyl
disulphide (38 mg, 0.175 mmol) and heated for 12 h.
Removal of the volatiles in vacuo and purification of the
residue by column chromatography on silica gel gave 29 as
a colourless oil (38 mg, 92%); [a]2D4¼þ43.4 (c 0.38,
CHCl3); nmax/cm21 (film) 1745 s(CvO); dH (CDCl3,
400 MHz), 7.37–7.25 (5H, m, Ph), 5.82–5.72 (1H, m,

3262
A. M. Chippindale et al. / Tetrahedron 59 (2003) 3253–3265
X-Ray crystal structure data for 31. Data were collected
using an Enraf-Nonius CAD4 diffractometer with graphite
monochromated Cu Ka radiation using standard procedures
at rt. The structure was solved by direct methods (SIR92),
all non-hydrogen atoms were refined with anisotropic
thermal parameters. Hydrogen atoms were added at
idealised positions. The structure was refined using
CRYSTALS.36 Crystal data for 31 [C28H38NO2], colourless
block, M¼420.59, orthorhombic, space group P212121, a¼
(4 mg, 0.005 mmol) gave, after purification by column
chromatography, first on neutral alumina then on silica gel,
(2–10% Et2O/40–60 petrol) 34 as clear yellow oil (22 mg,
78%); [a]2D3¼22.0 (c 0.66, CHCl3); nmax/cm21 (film) 1653
w(CvC); dH (CDCl3, 500 MHz), 7.46–7.25 (5H, m, Ph),
5.80–5.75, 5.66–5.62 (2H, m, C(4)H and C(5)H), 4.09 (1H,
q, J¼6.6 Hz, C(a)H), 3.22–3.11 (2H, m, NC(6)H2), 2.45–
2.42 (1H, m, C(2)H), 2.24–2.19 (1H, m, C(3)HA), 2.09–
2.02 (1H, m, Me2CH), 1.99–1.95 (1H, m, C(3)HB), 1.36
(3H, d, J¼6.6 Hz, C(a)Me), 1.04 (3H, d, J¼6.8 Hz, MeCH),
0.91 (3H, d, J¼6.7 Hz, MeCH); dC (CDCl3, 126 MHz),
146.1 (Phipso), 128.1, 127.5, 126.4, 125.4, 124.6 (Ph, C(4)H
and C(5)H), 58.4 (C(a)H), 57.4 (C(2)H), 42.2 (C(6)H2),
27.7 (Me2CH), 22.6 (C(3)H2), 20.6 (C(a)Me), 18.9, 18.0
(Me2CH); m/z (APCIþ), 230 (MHþ, 5%), 105 (PhCHCH3,
100%); HRMS, C16H24N requires 230.1909, found 230.1911.
˚
˚
˚
9.275(1) A, b¼10.472(1) A, c¼26.912(6) A, U¼
3
˚
2613.88(1) A , Z¼4, m¼0.509, crystal dimensions
0.5£0.5£1.0 mm. A total of 3040 unique reflections were
measured for 0,u,74.33 and 2472 reflections were used in
the refinement. The final parameters were wR2¼0.0711 and
R1¼0.0572 [I.3s(I)]. Crystallographic data (excluding
structure factors) has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 197300.
4.2.22. (2S,aS)-1-N-a-Methylbenzylamino-2-propyl-1,2,
3,6-tetrahydropyridine 35. Following representative pro-
cedure 1, 21 (80 mg, 0.31 mmol) in DCM (20 mL) and 1
(10 mg, 0.012 mmol) gave, after purification by column
chromatography, first on neutral alumina then on silica gel,
(5–10% Et2O/40–60 petrol) 34 as clear yellow oil (64 mg,
91%); [a]2D3¼211.3 (c 1.9, CHCl3); nmax/cm21 (film) 1601
w(CvC); dH (CDCl3, 400 MHz), 7.44–7.26 (5H, m, Ph),
5.74–5.71 (1H, ddd, J¼9.9, 5.0, 2.4 Hz, C(4)H), 5.62–5.59
(1H, app. dd, J¼9.9, 2.4 Hz, C(5)H), 3.77–3.73 (1H, q, J¼
6.6 Hz, C(a)H), 3.18–3.15 (1H, m, C(2)H), 3.02–2.98 (1H,
app. d, J¼17.5 Hz, C(6)HA), 2.92–2.88 (1H, app. d, J¼
17.5 Hz, C(6)HB), 2.47–2.42 (1H, m, C(3)HA), 2.01–1.97
(1H, m, C(3)HB), 1.60–1.56, 1.47–1.32 (4H, m, MeCH2
CH2), 1.39–1.38 (3H, d, J¼6.6 Hz, C(a)Me), 1.01–0.98
(3H, t, J¼7.1 Hz, MeCH2); dC (CDCl3, 126 MHz), 146.3
(Phipso), 128.2, 127.4, 126.6, 125.4, 123.5 (Ph, C(4)H,
C(5)H), 60.3 (C(a)H), 51.2 (C(2)H), 45.2 (C(6)H2), 28.5
(C(3)H2), 27.8 (MeCH2CH2) 20.8 (C(a)Me), 20.1 (MeCH2
CH2), 14.4 (MeCH2); m/z (APCIþ), 230 (MHþ, 75%);
HRMS, C16H24N requires m/z 230.1910, found 230.1907.
4.2.19. (2R,aS)-tert-Butyl 1-(N-a-methylbenzylamino)-
2,5-dihydro-1H-2-pyrrolyl-acetate 32. Following repre-
sentative procedure 1, 13 (2.0 g, 6.29 mmol) in DCM
(200 mL) and ruthenium alkylidene 1 (0.20 g, 0.25 mmol)
gave, after purification by column chromatography (3–5%
Et2O/40–60 petrol), 32 (1.4 g, 77%) as a clear yellow oil;
[a]2D4¼2132.0 (c 0.99, CHCl3); nmax/cm21 (film) 1728
s(CvO); dH (CDCl3, 500 MHz), 7.36–7.22 (5H, m, Ph),
5.78–5.70 (2H, m, C(3)HvC(4)H), 4.21–4.16 (1H, m,
C(2)H), 3.88 (1H, q, J¼6.7 Hz, C(a)H), 3.64–3.60 (1H, m,
C(5)HA), 3.43–3.38 (1H, m, C(5)HB), 2.62 (1H, dd, J¼
14.5, 4.0 Hz, C(10)HA), 2.37 (1H, dd, J¼14.5, 8.9 Hz,
C(10)HB), 1.49 (9H, s, C(CH3)3), 1.46 (3H, d, J¼6.7 Hz,
C(a)Me), dC (CDCl3, 126 MHz), 171.3 (CO), 144.7
(Phipso), 130.6, 128.2, 127.3, 126.8, 126.6 (C(3)HvC(4)H
and Ph), 80.0 (C(CH3)3), 64.7 (C(1)H), 62.0 (MeCHN), 58.3
(C(3)H2), 43.0 (C(10)H2), 28.0 (C(CH3)3), 22.8 (C(a)Me);
m/z (APCIþ), 288 (MHþ, 80%), 219 (MHþ2C4H8, 100%);
HRMS, C18H26NO2 requires 288.1963, found, 288.1967.
4.2.20. (2S,aS)-Methyl 2-(N-a-methylbenzylamino)-
1,2,3,6-tetrahydro-2-pyridinyl-acetate 33. Following
representative procedure 1, 15 (1.28 g, 4.3 mmol) in DCM
(200 mL) and 1 (0.14 g, 0.17 mmol) gave, after purification
by column chromatography, first on neutral alumina then on
silica gel, (5% Et2O/40–60 petrol) 33 as clear yellow oil
(0.54 g, 49%); [a]2D5¼þ11.0 (c 1.01, CHCl3); nmax/cm21
(film) 1736 s(CvO); dH (CDCl3, 500 MHz), 7.38–7.22
(5H, m, Ph), 5.71 (2H, m, C(4)HvC(5)H), 3.63–3.54 (1H,
m, C(a)H), 3.60 (3H, s, OMe), 3.42–3.38 (1H, m, C(6)HA),
3.35–3.31 (1H, m, C(2)H), 3.00–2.95 (1H, m, C(6)HB),
2.56 (1H, dd, J¼14.2, 3.9 Hz, C(10)HA), 2.39–2.36 (1H, m,
C(3)HA), 2.33 (1H, dd, J¼14.2, 9.5 Hz, C(10)HB), 1.85–
1.80 (1H, m, C(3)HB), 1.35 (3H, d, J¼6.6 Hz, C(a)Me); dC
(CDCl3, 126 MHz), 173.6 (CO2), 145.6 (Phipso), 128.4,
127.1, 126.9, 125.2, 123.2 (C(4)HvC(5)H and Ph), 60.9
(OCH3), 51.4 (C(a)H), 49.2 (C(2)H), 44.6 (C(6)H2), 30.6
(C(10)H2), 29.1 (C(3)H2), 22.2 (C(a)Me); m/z (APCIþ), 260
(MHþ, 100); HRMS, C16H22NO2 requires 260.1651, found
260.1655.
4.2.23. (1S,2S,aS)-tert-Butyl 2-N-a-methylbenzylamino-
N-benzyloxycarbonyl-cyclopent-3-ene-1-carboxylate 36.
Following representative procedure 1, 27 (130 mg,
0.28 mmol) in DCM (22 mL) and 1 (12 mg, 0.014 mmol)
gave, after heating 1 h and purification by column
chromatography on silica gel, (5–10% Et2O/40–60 petrol),
36 as clear yellow oil (102 mg, 86%); [a]2D3¼þ68.1 (c 2.19,
CHCl3); nmax/cm21 (film) 1728 s(CO), 1694 s(NCO); dH
(d8 toluene, 500 MHz, at 908C), 7.31–6.92 (10H, m, Ph),
5.53–5.50 (1H, m, C(3)H), 5.37–5.33 (2H, m, C(2)H and
C(4)H), 4.98 (2H, s, OCH2Ph), 4.85 (1H, q, J¼7.0 Hz,
C(a)H), 3.04–3.00 (1H, m, C(1)H), 2.57–2.40 (2H, m,
C(5)H2), 1.52–1.51 (3H, d, J¼7.0 Hz, C(a)Me), 1.30 (9H,
s, C(CH3)3); dC (CDCl3, 126 MHz), 174.1 (CO), 155.8
(NCO), 142.0, 136.3 (Phipso), 132.4, 129.6, 128.2, 127.9,
127.8, 126.7, 126.6 (C(3)H, C(4)H, Ph), 80.3 (C(CH3)3),
67.0 (OCH2Ph), 67.0 (C(2)H), 53.2 (C(a)H), 47.5 (C(1)H),
36.5 (C(5)H2), 27.8 (C(CH3)3), 18.4 (C(a)Me); m/z (CIþ,
NH3), 422 (Mþ, 100%), 366 (M2C4H8, 64%); HRMS,
C26H32NO4 requires 422.2331, found 422.2321.
4.2.21. (2R,aS)-1-N-a-Methylbenzylamino-2-isopropyl-
1,2,3,6-tetrahydropyridine 34. Following representative
procedure 1, 20 (34 mg, 0.13 mmol) in DCM (9 mL) and 1
4.2.24. (1S,2S)-tert-Butyl 2-(10-{N-benzyloxycarbonyl-N-
a-methylbenzylamino}-cyclohept-3-ene-1-carboxylate
37. Following representative procedure 1, 28 (85 mg,

A. M. Chippindale et al. / Tetrahedron 59 (2003) 3253–3265
3263
0.17 mmol) in THF (11 mL) and 1 (6 mg, 0.006 mmol)
gave, after heating for 2 h and purification by column
chromatography on silica gel, (2–10% Et2O/40–60 petrol),
37 as a colourless oil (61 mg, 78%); [a]2D3¼þ30.2 (c 1.08,
CHCl3); nmax/cm21 (film) 1724 s(CO2), 1702 s(NCO2); dH
(d8 toluene, 500 MHz, at 908C), 7.40–6.96 (10H, m, Ph),
5.62–5.59 (1H, m, C(3)H), 5.48–5.43 (1H, m, C(4)H), 5.09
(1H, AB, J¼12.4 Hz, OCHA), 5.03 (1H, AB, J¼12.4 Hz,
OCHB), 4.78 (1H, q, J¼7.0 Hz, C(a)H), 4.63–4.62 (1H, m,
C(2)H), 3.16 (1H, dt, J¼9.3, 3.2 Hz, C(1)H), 1.98–1.87
(2H, m, C(7)H2), 1.98–1.87, 1.68–1.61, 1.49–1.44, 1.25–
1.18 (4H, m, C(5)H2, C(6)H2), 1.69 (3H, d, J¼7.0 Hz,
C(a)Me), 1.32 (9H, s, C(CH3)3); dC (CDCl3, 126 MHz),
174.3 (CO), 156.0 (NCO), 142.5, 137.0 (Phipso), 133.8, 128.5,
128.3, 128.1, 127.7, 127.0 (C(3)H, C(4)H and Ph), 80.1
(C(CH3)3), 66.9 (OCH2), 61.4 (C(a)H), 59.9 (C(2)H), 49.0
(C(1)H), 31.0 (C(7)H2), 28.2 (C(CH3)3), 27.0, 24.0 (C(5)H2,
C(6)H2), 19.7 (C(a)Me); m/z (CIþ, NH3), 450 (MHþ, 10%);
HRMS, C28H36NO4 requires 450.2644, found, 450.2636.
hydrogen for 18 h at 508C. The crude reaction mixture was
filtered through a plug of Celitew, and concentrated in vacuo
before purification by chromatography on silica gel, (20%
MeOH/Et2O) to give 40 as clear pale yellow oil (40 mg, 93%);
[a]2D6¼þ3.9 (c 0.64, CHCl3); nmax/cm21 (film) 1736 s(CvO);
dH (CDCl3, 500 MHz), 3.68 (3H, s, OMe), 3.13–3.10 (1H, m,
C(6)HA), 2.99–2.92 (2H, m, NH and C(2)H), 2.68 (1H, app.
dt, J¼11.9, 2.5 Hz, C(6)HB), 2.48–2.45 (2H, m, C(10)H2),
1.82–1.79, 1.68–1.61, 1.53–1.23 (6H, m, C(3)H2, C(4)H2,
C(5)H2); dC (CDCl3, 126 MHz), 172.5 (CO2), 53.2 (OMe),
51.6 (C(2)H), 46.4 (C(6)H2), 40.7 (C(10)H2), 29.7 (C(5)H2),
25.3, 24.2 (C(4)H2, C(5)H2); m/z (APCIþ), 158 (MHþ,
100%); C8H16NO2 requires 158.1181, found 158.1179.
4.2.28. (S)-Homopipecolic acid 41. Amino ester 40 (30 mg,
0.19 mmol) was refluxed in hydrochloric acid (2 M, 10 mL)
for 4 h before concentration in vacuo. The residue was
subjected to ion exchange chromatography on Dowex
50WX8-200 resin giving 41 as a pale yellow waxy oil
(25 mg, 92%); [a]D26¼þ24.0 (c 0.87, H2O), lit.23 [a]D¼
þ22.1 (c 0.6, H2O)}; nmax/cm21 (film) 1711 s(CvO); dH
(D2O, 500 MHz), 3.37–3.27 (2H, m, C(6)HA and C(2)H),
2.95–2.89 (1H, m, C(6)HB), 2.44 (2H, app d, J¼6.6 Hz,
C(10)H2), 1.85–1.77 and 1.58–1.39 (2£3H, m, C(3)H2,
C(4)H2 and C(5)H2); dC (CDCl3, 126 MHz), 177.1 (CO2),
54.4 (C(2)H), 44.7 (C(6)H2), 39.6 (C(10)H2), 28.1 (C(5)H2),
21.9, 21.5 (C(4)H2 and C(5)H2); m/z (APCIþ), 144 (MHþ,
100%); HRMS, C7H14NO2 requires 144.1025, found
144.1023.
4.2.25. (1R,7S,aS)-8-(N-a-Methylbenzylamino)-8-azabi-
cyclo[5.2.0]non-5-ene-9-one 38. Following representative
procedure 1, syn-29 (38 mg, 0.13 mmol) in DCM (10 mL)
and 1 (4 mg, 0.005 mmol) gave, after heating for 2 h and
purification by column chromatography on silica gel, (40%
Et2O/40–60 petrol), 38 as a colourless oil (30 mg, 93%);
[a]2D4¼þ10.5 (c 0.53, CHCl3); nmax/cm21 (film) 1736
s(CvO); dH (CDCl3, 400 MHz), 7.39–7.27 (5H, m, Ph),
5.61–5.54 (2H, m, C(5)H, C(6)H), 4.98 (1H, q, J¼7.2 Hz,
C(a)H), 4.17–4.15 (1H, m, C(7)H), 3.11 (1H, dt, J¼10.0,
5.3 Hz, C(1)H), 2.13–2.08 (2H, m, C(4)H2), 1.95–1.83,
1.63–1.46 (4H, m, C(2)H2, C(3)H2), 1.66 (3H, d, J¼7.2 Hz,
C(a)Me); dC (CDCl3, 126 MHz), 170.1 (CO), 140.3
(Phipso), 128.8, 128.7, 127.6, 127.0, 126.1 (C(5)H, C(6)H,
and Ph), 54.0 (C(a)H), 51.8, 51.4 (C(7)H, C(1)H), 26.6
(C(4)H2), 23.1, 20.3 (C(3)H2, C(2)H2), 19.6 (C(a)Me); m/z
(APCIþ), 242 (MHþ, 100%); HRMS, C16H20NO requires
242.1545, found 242.1543.
4.2.29. (2S,aS)-tert-Butyl 1-(N-a-methylbenzylamino)-
pyrrolidin-2-yl-acetate 42. RhCl(PPh3)3 (100 mg) was
added to a degassed solution of 32 (1.0 g, 3.5 mmol) in
benzene (5 mL) and stirred under 2 atm of H2 at rt. The
resultant mixture was filtered through Celitew, concentrated
in vacuo and purified by chromatography on silica gel, (10%
Et2O/pentane) to give 42 (865 mg, 86%) as a colourless oil;
[a]2D3¼256.1 (c 1.6, CHCl3), nmax/cm21 (CHCl3) 1727
s(CvO); dH (CDCl3, 400 MHz), 7.34–7.24 (5H, m, Ph),
3.78 (1H, q, J¼6.8 Hz, C(a)H), 3.08–3.03 (1H, m, C(2)H),
2.82–2.77 (1H, m, C(5)HA), 2.60 (1H, dd, J¼14.2, 2.6 Hz,
C(10)HA), 2.40–2.34 (1H, m, C(5)HB), 2.20 (1H, dd, J¼
14.2, 10.0 Hz, C(10)HB), 1.88–1.58 (4H, m, C(3)H2 and
C(4)H2), 1.46 (3H, d, J¼6.8 Hz, C(a)Me), 1.44 (9H, s,
C(CH3)3); dC (CDCl3, 100 MHz), 171.9 (CO2), 142.7
(Phipso), 128.0, 127.9, 126.8 (Ph), 80.0 (C(CH3)3), 60.3
(C(a)H), 57.0 (C(2)H), 49.7 (C(5)H2), 41.5 (C(10)H2), 30.6,
22.6 (C(4)H2 and C(3)H2), 28.1 (C(CH3)3), 22.1 (C(a)Me);
m/z (APCIþ), 290 (MHþ, 10%), 234 (MHþ2C4H8 100%);
HRMS, C18H28NO2 requires 290.2120, found 290.2126.
4.2.26. (1S,2R,aS)-tert-Butyl 3-methyl-2-(N-benzyl-N-a-
methylbenzylamino)-cyclopent-3-ene-1-carboxylate 39.
Following representative procedure 1, 31 (600 mg,
1.43 mmol) in DCM (200 mL) and 1 (5 mg, 0.5 mmol)
gave, after purification by column chromatography (2%
Et2O/pentane) 39 (195 mg, 35% at 50% conversion). Found:
C, 79.55; H, 8.5; N, 3.4%; C26H33NO2 requires: C, 79.75; H,
8.5; N, 3.6%; [a]D23¼þ61.4 (c 0.1, CHCl3); nmax (film) 1724
(CvO), 1144 (C–O); dH (CDCl3, 400 MHz) 7.19–7.45
(10H, m, Ph), 5.37 (1H, br s, C(4)H), 4.20 (1H, br s, C(2)H),
3.90 (1H, q, J¼6.8 Hz, C(a)H), 3.51, 3.76 (2H, AB, J¼
15.1 Hz, NCH2Ph), 2.61 (1H, m, C(1)H), 2.57 (1H, m,
C(5)HB), 2.31 (1H, m, C(5)HA), 1.82 (3H, s, C(3)Me), 1.40
(9H, s, OC(CH3)3), 1.29 (3H, d, J¼6.8 Hz, C(a)Me);
dC (CDCl3, 50 MHz) 176.1 (CO), 142.5, 144.6 (Phipso),
140.8 (C(3), 126.4, 126.8, 127.8, 128.0, 128.3 and 128.4
(Pho-,m-,p-), 125.6 (C(4)), 79.9 (OC(CH3)3), 71.0 (C(2)), 59.7
(C(a)H), 49.9 (NCH2), 42.9 (C(1)), 36.4 (C(5)), 27.9
(C(CH3)3), 22.1 (C(a)Me), 14.5 (C(3)Me); m/z (APCIþ)
392 (MHþ, 90%).
4.2.30. (S)-tert-Butyl pyrrolidin-2-yl-acetate 43. 20%
Pd(OH)2 on C (250 mg) was added to a degassed solution
of 42 (500 mg) in MeOH–H2O–acetic acid (40:4:1)
(45 mL) and stirred under 1 atm of H2 for 12 h at rt. The
crude reaction mixture was filtered through a plug of
Celitew, concentrated in vacuo, dissolved in DCM (5 mL)
and washed with sat aq. bicarbonate, dried, concentrated
and purified by chromatography on silica gel, (20% MeOH/
CHCl3) to give 43 as a pale yellow oil (295 mg, 92%);
[a]2D3¼þ1.0 (c 1.55, CHCl3), {lit.37 [a]2D7¼þ1.5 (c 0.99,
CHCl3)}; nmax/cm21 (CHCl3) 1728 s(CvO); dH (CDCl3,
500 MHz), 3.87–3.81 (1H, m, NCHCH2), 3.38–3.35 (2H,
4.2.27. (S)-Methyl piperidin-2-yl-acetate 40. 10% Pd on C
(10 mg) was added to a degassed solution of 33 (71 mg,
0.27 mmol) in MeOH (5 mL) and stirred under 5 atm of

3264
A. M. Chippindale et al. / Tetrahedron 59 (2003) 3253–3265
(a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
1995, 28, 446. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413. (c) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1
1998, 371. (d) Schuster, M.; Blechert, S. Angew. Chem. Int.
Ed. Engl. 1997, 37, 2036.
m, NCH2), 3.09–3.04 (1H, dd, J¼16.9, 5.9 Hz, CHHCO),
2.77–2.72 (1H, dd, J¼16.9, 8.2 Hz, CHHCO2), 2.30–2.24
(1H, m, NCH2CH2CHH), 2.09–1.95 (2H, m, NCH2CH2),
1.74–1.67 (1H, m, NCH2CH2CHH), 1.42 (9H, s, C(CH3)3);
dC (CDCl3, 126 MHz), 169.1 (CO2), 81.7 (C(CH3)3), 55.9
(NCHCH2), 44.7 (NCH2), 37.3 (CH2CO), 30.2, 23.4
(NCHCH2 and NCH2CH2), 28.0 (C(CH3)3); m/z (APCIþ),
186 (MHþ, 10%), 130 (MHþ2C4H8 100%).
2. (a) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.;
DiMare, M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875.
(b) Bazan, G. C.; Oskam, J. H.; Cho, H.-N.; Park, L. Y.;
Schrock, R. R. J. Am. Chem. Soc. 1991, 113, 6899.
3. Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426.
4. For example see (a) Yang, Z.; He, Y.; Vourloumis, D.;
Vallberg, H.; Nicolaou, K. C. Angew. Chem. Int. Ed. Engl.
1997, 36, 166. (b) Houri, F.; Xu, Z.; Cogan, D. A.; Hoveyda,
A. H. J. Am. Chem. Soc. 1995, 117, 2943. (c) Balog, A.; Meng,
D.; Kamenecka, T.; Bertinato, P.; Su, D.-S.; Sorensen, E. J.;
Danishefsky, S. J. Angew. Chem. Int. Ed. Engl. 1996, 35, 2801.
4.2.31. (S)-Homoproline 44. HClaq (1 M, 20 mL) was
added to 43 (200 mg) and stirred at rt for 12 h before
concentration in vacuo. Purification by ion exchange
chromatography (Dowex 50WX8-200) gave 44 (134 mg,
96%) as a white solid; [a]2D3¼þ3.4 (c 1.0, H2O); lit.26
[a]2D5¼þ4.0 (c 1.0, H2O); dH (D2O, 400 MHz), 3.70–3.63
(1H, m, C(2)H), 3.23–3.13 (2H, m, C(5)H2), 2.53–2.41
(2H, m, C(10)H2), 2.12–2.03 (1H, m, C(3)HA), 1.99–1.80
(2H, m, C(4)H2), 1.60–1.50 (1H, m, C(3)HA).
¨
(d) Schinzer, D.; Limberg, A.; Bohm, O. M. Chem. Eur. J.
1996, 2, 1477. (e) For a review of macrocyclic synthesis using
RCM see Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792.
5. For the recent application of ring closing metathesis to
heterocycle synthesis see (a) Lim, S. H.; Ma, S.; Beak, P.
J. Org. Chem. 2001, 66, 9056. (b) Kumareswaran, R.; Hassner,
A. Tetrahedron: Asymmetry 2001, 12, 2269.
4.2.32. (S)-(1)-Coniine hydrochloride 45. A solution of
35 (38 mg, 0.148 mmol) in degassed MeOH (2 mL) was
hydrogenated at 5 atm over 10% palladium on carbon
(15 mg) for 12 h at rt before filtration through a pad of
Celitew eluting with Et2O. The resultant solution was cooled
to 08C and treated with HCl gas and stirred at rt for 10
minutes before concentration in vacuo. Purification by
column chromatography on silica (5% MeOH/DCM) gave
45 (23 mg, 95%) as a white solid; mp 1958C (lit.38 mp
2058C); {[a]2D1¼þ8.3 (c 0.7, EtOH); lit. [a]2D5¼þ9.4 (c
0.32, EtOH);30 [a]D25¼þ8.1 (c 0.6, EtOH)31}; dH (CDCl3,
400 MHz), 9.6–9.0 (2H, bm, NH·HCl), 3.60–3.35 (1H, bm,
C(2)H), 3.00–2.90 (1H, m, C(6)HA), 2.85–2.75 (1H, m,
C(6)HB), 2.21–1.36 (10H, m, C(3)H2, C(4)H2, C(5)H2,
C(10)H2 and C(20)H2), 1.05–0.80 (3H, bm, Me).
6. (a) Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.;
¨
Patzel, M.; Ramser, M. N.; Wagner, A. S. Tetrahedron 1996,
52, 7251. (b) Arisawa, M.; Takezawa, E.; Nishida, A.; Mori,
M.; Nakagawa, M. Synlett 1997, 1179. (c) Paolucci, C.;
Musiani, L.; Venturelli, F.; Fava, A. Synthesis 1997, 1415.
(d) Dyatkin, A. B. Tetrahedron Lett. 1997, 38, 2065. (e) White,
J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am. Chem. Soc. 1998,
120, 7359. (f) Ahn, J.-B.; Yun, C-S.; Kim, K. H.; Ha, D.-C.
J. Org. Chem. 2000, 65, 9249. (g) White, J. D.; Hrnciar, P.
J. Org. Chem. 2000, 65, 9129.
7. For representative examples see (a) Hammer, K.; Undheim, K.
Tetrahedron 1997, 53, 10603. (b) Hammer, K.; Rømming, C.;
Undheim, K. Tetrahedron 1998, 54, 10837. (c) Hammer, K.;
Undheim, K. Tetrahedron: Asymmetry 1998, 9, 2359.
(d) Clark, J. S.; Middleton, M. D. Org. Lett. 2002, 4, 765.
4.2.33. (1S,2S)-2-Aminocyclopentanecarboxylic acid
hydrochloride 46. 10% palladium on carbon (20 mg) was
added to a degassed solution of 36 (93 mg, 0.220 mmol) in
glacial acetic acid (3 mL) and hydrogenated under 5 atm of
hydrogen for 18 h at 508C. The crude reaction mixture was
filtered through Celitew, concentrated in vacuo then treated
with an ethereal solution of hydrochloric acid (20 mL). The
resulting solution was stirred for 20 min at rt before
concentration in vacuo, giving 46 (30 mg, 73%) as a white
solid; [a]2D2¼þ46.4 (c 1.04, H2O), {lit.32 [a]2D8¼250.7 (c
0.75, H2O) for enantiomer}; dH (D2O, 300 MHz), 3.79–
3.68 (1H, m, C(2)H), 2.82–2.70 (1H, m, C(1)H), 2.15–2.00,
1.81–1.50 (6H, m, (C(3)H2, C(4)H2, C(5)H2).
´ ´ `
(e) Martın, R.; Alcon, M.; Pericas, M. A.; Riera, A. J. Org.
Chem. 2002, 67, 6896.
8. For a review of the application of RCM to the synthesis of
N-containing compounds see Phillips, A. J.; Abell, A. D.
Aldrichim. Acta 1999, 32, 75.
9. Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron Lett. 1997,
38, 677.
10. Maier, M. E.; Lapeva, T. Synlett 1998, 891.
11. For previous uses of the N-allyl-N-a-methylbenzyl lithium
amide in synthesis see (a) Davies, S. G.; Hedgecock, C. J. R.;
McKenna, J. M. Tetrahedron: Asymmetry 1995, 6, 2507.
(b) Davies, S. G.; Hedgecock, C. J. R.; McKenna, J. M.
Tetrahedron: Asymmetry 1995, 6, 827. (c) Davies, S. G.;
Fenwick, D. R. Chem. Commun. 1997, 565. (d) Davies, S. G.;
Fenwick, D. R.; Ichihara, O. Tetrahedron: Asymmetry 1997, 8,
3387. (e) Davies, S. G.; Garrido, N. M.; McGee, P. A.;
Shilvock, J. P. J. Chem. Soc., Perkin Trans. 1 1999, 3105.
12. (a) Laguzza, B. C.; Ganem, B. Tetrahedron Lett. 1981, 22,
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Chem. 1973, 38, 3224. (c) Moreau, B.; Lavielle, S.; Marquet,
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Acknowledgements
The authors would like to thank the EPSRC and Oxford
Asymmetry International Plc for support (C. A. P. S)
through a CASE award, New College, Oxford for a Junior
Research Fellowship (A. D. S) and MECD (Spain) for a
postdoctoral fellowship (H. R. S.).
´
13. Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993,
58, 6109.
14. (a) Davies, S. G.; Ichihara, O. Tetrahedron Lett. 1999, 40,
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26. Busson, R.; Vanderhaeghe, H. J. Org. Chem. 1978, 43, 4438.
27. For other selected asymmetric syntheses see (a) Al-awar, R. S.;
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35. Not visualised due to spectrum broadening.
36. Watkin, D. J.; Prout, C. K.; Carruthers, J. R.; Betteridge, P. W.
CRYSTALS. Chemical Crystallography Laboratory: Oxford,
UK, 1996; issue 10.
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