Asymmetric synthesis of 4-amino-γ-butyrolactones via lithium amide conjugate addition

Article abstract of DOI:10.1016/j.tet.2007.03.026

Upon treatment with homochiral lithium (R)-N-benzyl-N-(α-methylbenzyl)amide, γ-benzyloxy but-2-enoates undergo competitive conjugate addition and γ-deprotonation, while γ-tert-butyldimethylsilyloxy but-2-enoates undergo exclusive conjugate addition. Treatment of γ-benzyloxy or γ-tert-butyldimethylsilyloxy but-2-enamides with lithium (R)-N-benzyl-N-(α-methylbenzyl)amide furnishes exclusively the γ-benzyloxy- or γ-tert-butyldimethylsilyloxy-β-amino amide products of conjugate addition in high de. The γ-tert-butyldimethylsilyloxy-β-amino butanoate products of conjugate addition readily undergo O-desilylation and concomitant cyclisation to furnish 4-[N-benzyl-N-(α-methylbenzyl)amino]-γ-butyrolactone, which may be stereoselectively functionalised via deprotonation and alkylation?to give the corresponding trans-3-alkyl-4-amino-γ-butyrolactones. Alternatively, stereoselective alkylation of γ-benzyloxy- or γ-tert-butyldimethylsilyloxy-β-amino butanoates and butanamides through enolate formation and alkylation following a tandem (via the (Z)-lithium enolate) or stepwise (via the (E)-lithium enolate) protocol gives a range of separable syn- and anti-α-alkyl-β-amino esters and amides. O-Silyl deprotection of the syn- and anti-α-alkyl-β-amino butanoates with TBAF and concomitant cyclisation provide trans-3-alkyl-4-amino-γ-butyrolactones, consistent with epimerisation to the thermodynamically favoured trans-lactone occurring upon deprotection.

Full text of DOI:10.1016/j.tet.2007.03.026

Tetrahedron 63 (2007) 5855–5872
Asymmetric synthesis of 4-amino-g-butyrolactones via lithium
amide conjugate addition
b
Elin Abraham,a Jason W. B. Cooke,a Stephen G. Davies,a, Alan Naylor,
*
Rebecca L. Nicholson,a Paul. D. Pricea and Andrew D. Smitha
aDepartment of Organic Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
bDepartment of Medicinal Chemistry, Neurology and Gastrointestinal Diseases Centre of Excellence for Drug Discovery,
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 15 January 2007; revised 27 February 2007; accepted 2 March 2007
Available online 12 March 2007
Abstract—Upon treatment with homochiral lithium (R)-N-benzyl-N-(a-methylbenzyl)amide, g-benzyloxy but-2-enoates undergo compet-
itive conjugate addition and g-deprotonation, while g-tert-butyldimethylsilyloxy but-2-enoates undergo exclusive conjugate addition. Treat-
ment of g-benzyloxy or g-tert-butyldimethylsilyloxy but-2-enamides with lithium (R)-N-benzyl-N-(a-methylbenzyl)amide furnishes
exclusively the g-benzyloxy- or g-tert-butyldimethylsilyloxy-b-amino amide products of conjugate addition in high de. The g-tert-butyldi-
methylsilyloxy-b-amino butanoate products of conjugate addition readily undergo O-desilylation and concomitant cyclisation to furnish
4-[N-benzyl-N-(a-methylbenzyl)amino]-g-butyrolactone, which may be stereoselectively functionalised via deprotonation and alkylation to
give the corresponding trans-3-alkyl-4-amino-g-butyrolactones. Alternatively, stereoselective alkylation of g-benzyloxy- or g-tert-butyldi-
methylsilyloxy-b-amino butanoates and butanamides through enolate formation and alkylation following a tandem (via the (Z)-lithium eno-
late) or stepwise (via the (E)-lithium enolate) protocol gives a range of separable syn- and anti-a-alkyl-b-amino esters and amides. O-Silyl
deprotection of the syn- and anti-a-alkyl-b-amino butanoates with TBAF and concomitant cyclisation provide trans-3-alkyl-4-amino-g-
butyrolactones, consistent with epimerisation to the thermodynamically favoured trans-lactone occurring upon deprotection.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Previous investigations from this laboratory have shown that
the conjugate addition of homochiral lithium amides derived
from a-methylbenzylamine to a,b-unsaturated esters may be
used for the asymmetric synthesis of b-amino acid deriva-
tives.14 Furthermore, functionalisation of the (Z)-b-amino
enolate arising from conjugate addition, or the (E)-b-amino
enolate arising from deprotonation of the corresponding
b-amino ester, gives preferentially the corresponding anti-
stereoisomer with moderate to high stereoselectivity
(Fig. 1).15 This general and versatile methodology has been
applied to a number of total syntheses,16 and as part of our ex-
isting research portfolio directed towards the de novo asym-
metric synthesis of monosaccharides and amino sugars, we
outline herein the scope of this methodology for the asym-
metric synthesis of a range of 4-amino-g-butyrolactones.
Enantiomerically pure 4-amino-g-butyrolactones are widely
recognised as valuable synthetic tools within organic synthe-
sis. These versatile intermediates have been used as key
synthetic building blocks for the preparation of a wide range
of functionality including aziridines,1 oxazolidinones,2 b-
lactams,3 tetrahydroindoles4 andhighlyfunctionalized amino
acids.5 The vast majority of routes to this highly desirable
class of compound are derived from chiral pool materials,
with routes to the parent 4-amino-g-butyrolactones having
been demonstrated from aspartic acid,6 asparagine7 and ami-
nocarnitine,8 while the 4-amino-5-methyl-g-butyrolactone
framework has been synthesised from threonine.9 Only
limited stereoselective routes to the 4-amino-g-butyrolac-
tone skeleton have been demonstrated, with tandem radical
addition–cyclisation reactions of oxime ethers,10 nucleo-
philic addition to tert-butanesulfinyl a-alkoxyaldimines,11
the use of chiral auxiliaries,12 and chemoenzymatic synthe-
sis13 all having shown promise for the preparation of this
valuable motif.
It was envisaged that conjugate addition of homochiral lith-
ium N-benzyl-N-(a-methylbenzyl)amide 1 to a range of
g-benzyloxy and g-tert-butyldimethylsilyloxy but-2-enoates
and but-2-enamides 2 would give the corresponding b-amino
esters 3 with high stereoselectivity. Subsequent O-deprotec-
tion of 3 and concomitant intramolecular cyclisation would
generate 4-amino-g-butyrolactone 4, which could be readily
alkylated at C(2) via enolate formation, to generate 6.
* Corresponding author. E-mail: steve.davies@chem.ox.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.026

5856
E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
under Masamune–Roush conditions,17 to afford (E)-8 as the
Ph
Ph
sole product in 90% yield and >98% de after purification.
A range of g-tert-butyldimethylsilyloxy but-2-enoates was
also prepared, with ethyl 4-(tert-butyldimethylsilyloxy)but-
2-enoate 9 readily prepared by borane reduction of monoethyl
fumarate and subsequent silylation with TBDMSCl, giving
(E)-9 in 33% overall yield. Alternatively, treatment of alde-
hyde 1018 with either methyl or tert-butyl diethylphosphono-
acetate under Masamune–Roush conditions afforded (E)-11
and (E)-12, respectively, in >98% de in each case and in
good yield (Scheme 1).
Ph
N
Li
Li
1
Ph
Me
N
O
CO2Me
"Tandem"
Me
OMe
(Z)-enolate
MeI
Ph
Ph
Ph
N
Ph
CO2Me
N
CO2Me
Me
syn
Me
Me
Me
anti
(i)
Tandem: anti:syn 55:45
Stepwise: anti:syn 83:17
Br
CO2Me
BnO
BnO
CO2Me
7, 57%
MeI
Ph
(ii)
t
CO2 Bu
BnO
CHO
Ph
8, 90%
LDA
"Stepwise"
Ph
Me
N
OMe
O
Ph
Me
N
(iii)
Li
CO2Et
CO2Me
TBDMSO
TBDMSO
TBDMSO
CO2Et
HO2C
(E)-enolate
9, 33%
11, 41%
12, 67%
Figure 1. Diastereoselective alkylation of b-amino crotonates.
(iv)
(ii)
CO2Me
TBDMSO
CHO
Alternatively, tandem conjugate addition and enolate alkyl-
ation to give 5, followed by O-deprotection and cyclisation
would also generate the 3-substituted-4-amino-g-butyrolac-
tone 6 (Fig. 2).
t
10
CO2 Bu
Scheme 1. Reagents and conditions: (i) Ag2O, BnOH, CaSO4, DCM; (ii)
tert-butyl diethylphosphonoacetate, LiCl, iPr2NEt, MeCN, rt, 48 h;
(iii) BH3, THF, ꢀ10 ꢁC to rt, then TBDMSCl, Et3N, DCM, rt; (iv) methyl
diethylphosphonoacetate, LiCl, iPr2NEt, MeCN, rt, 48 h.
Ph
Ph
Ph
N
O-Deprotection
and
Ph
COX
N
Li
The behaviour of g-benzyloxy butenoates 7 and 8 upon
reaction with homochiral lithium N-benzyl-N-(a-methylben-
zyl)amide 1 was evaluated. Addition of lithium amide (R)-1
to g-benzyloxy methyl ester 7 gave a 44:56 mixture of methyl
(Z)-4-benzyloxybut-3-enoate (Z)-13 (arising from g-depro-
tonation) and b-amino ester 14 in >98% de (arising from
conjugate addition). Chromatographic purification gave
(Z)-13 in 42% yield and b-amino ester 14 in 47% yield and
>98% de. Treatment of g-benzyloxy tert-butyl ester 8 with
lithium amide (R)-1 gave a 50:50 mixture of products arising
from g-deprotonation [(Z)-15/(E)-16, 88:12] and conjugate
addition (17, >98% de). Purification gave a partially separa-
ble mixture of (Z)-15 and (E)-16 in 41% combined yield, and
b-amino ester 15 in 42% yield and >98% de (Scheme 2).
These product distributions indicate that g-deprotonation
competes effectively with conjugate addition in the reaction
of g-benzyloxy butenoates 7 and 8 with lithium amide (R)-1.
The predominance of the (Z)-olefins 13 and 15 from the g-de-
protonation manifold of 7 and 8 with lithium amide (R)-1 is
consistent with previous observations concerning the stereo-
chemical consequence of enoate deprotonation reactions.19
Addition of lithium amide (R)-1 to g-tert-butyldimethylsilyl-
oxy butenoates 9, 11 and 12 gave, in each case, a crude reac-
tion product containing exclusively the desired b-amino
esters 18–20 in >98% de, which were isolated in 60–76%
yield. No sign of the b,g-unsaturated ester products of g-de-
protonation was noted in the crude reaction product in each
case. The configuration at the b-centre within b-amino esters
(3S,aR)-14 and (3S,aR)-17–20 was assigned by analogy with
established models developed to explain the stereoselectivity
observed during addition of lithium amide 1 to a,b-unsatu-
rated esters.20
Ph
N
1
cyclisation
COX
Ph
Conjugate
addition
OP
2
3
OP
X = OR, NR2
P = Bn, TBDMS
O
O
4
X = OR, NR2
P = Bn, TBDMS
Enolate
alkylation
Tandem conjugate
addition and
enolate
Ph
Ph
O-Deprotection
alkylation
and
R3
Ph
N
cyclisation
N
COX
Ph
OP R3
O
O
5
6
X = OR, NR2
P = Bn, TBDMS
Figure 2. Proposed stereoselective route to 4-amino-g-butyrolactones.
2. Results and discussion
2.1. Lithium amide conjugate addition to g-benzyloxy
and g-tert-butyldimethylsilyloxy but-2-enoates and
but-2-enamides
Initial studies concentrated upon the preparation of a range
of (E)-g-benzyloxy and (E)-g-tert-butyldimethylsilyloxy
but-2-enoates. Methyl (E)-4-benzyloxybut-2-enoate 7 was
prepared in 57% yield via the Ag2O promoted bromide dis-
placement from commercially available methyl 4-bromocrot-
onate with benzyl alcohol. The corresponding tert-butyl ester
was prepared from benzyloxyacetaldehyde via olefination

E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
5857
Ph
Ph
(i)
O
BnO
CO2R
+
BnO
CO2R
Ph
BnO
N
Ph
BnO
N
O
(i)
BnO
CO2R
N
N
R = Me, (Z)-13, 45%
14, R = Me, 47%, >98% d.e.
7, R = Me
t
t
t
29, 89%, >95% d.e.
R = Bu, (Z)-15:(E)-16,
17, R = Bu, 42%, >98% d.e.
27
8, R = Bu
88:12, 41% overall
Ph
Ph
O
Ph
TBDMSO
N
O
(i)
(i)
TBDMSO
TBDMSO
CO2R
N
Ph
TBDMSO
N
N
CO2R
30, 53%, >95% d.e.
9, R = Et
18, 72%, R = Et, >98% d.e.
19, 60%, R = Me, >98% d.e.
28
11, R = Me
t
t
20, 76%, R = Bu, >98% d.e.
Scheme 4. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(a-methyl-
benzyl)amide 1, THF, ꢀ78 ꢁC, 2 h.
12, R = Bu
Scheme 2. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(a-methyl-
benzyl)amide 1, THF, ꢀ78 ꢁC, 2 h.
Having demonstrated that g-tert-butyldimethylsilyloxy
butenoates 9, 11 and 12 disfavour g-deprotonation upon
reaction with lithium amide (R)-1, the product distribution
upon conjugate addition to a g-benzyloxy- and g-tert-butyl-
dimethylsilyloxy butenamide was investigated. The desired
g-benzyloxy and g-tert-butyldimethylsilyloxy amides 27
and 28 were therefore prepared, via a multistep synthetic
scheme from the known lactone 21. Heating lactone 21
with pyrrolidine gave alcohol 22, which was subsequently
O-protected, giving the O-benzyl and O-TBDMS butena-
mides 23 and 24, respectively. Heating 23 and 24 in vacuo
induced a retro-Diels–Alder reaction and provided (Z)-a,b-
unsaturated amides 25 and 26 (J2,3 11.7 Hz) in excellent
yield, with photolysis in the presence of a catalytic amount
of diphenyldisulfide promoting isomerisation to the corre-
sponding (E)-a,b-unsaturated amides 27 (J2,3 15.0 Hz) and
28 (J2,3 15.2 Hz) in good yield (Scheme 3).21
butyldimethylsilyloxy butenoates and butenamides inhibit
g-deprotonation. However, while g-benzyloxy butenamides
promote conjugate addition exclusively, g-benzyloxy but-
enoates undergo competitive conjugate addition and g-
deprotonation. A simple model may be used to explain these
product distributions. Assuming that lithium amideconjugate
addition requires initial binding of the carbonyl functionality
of the a,b-unsaturated acceptor via lithium co-ordination, the
increased electron donating ability of the amide relative to the
ester will result in the amide carbonyl being a far better ligand
for the lithium amide than the ester carbonyl, thus promoting
the conjugate addition manifold over g-deprotonation in the
butenamide system. Competitive binding by the g-benzyloxy
substituent to the lithium amide favours g-deprotonation;
however, such binding is precluded in both g-tert-butyldi-
methylsilyloxy butenoates and butenamides.
2.2. Diastereoselective alkylation of lithium (Z)- and (E)-
enolates of g-tert-butyldimethylsilyloxy-b-amino
butanoates
O
O
O
OH
OP
(i)
(ii) or (iii)
O
N
N
b-Amino enolate elaboration following conjugate addition
was next investigated, as it was envisaged that subsequent
deprotection and cyclisation to the corresponding lactone
would offer an attractive route to functionalized 4-amino-
g-butyrolactones. Conjugate addition lithium amide (R)-1
to tert-butyl ester 12 and methylation of the resulting (Z)-
enolate22 gave a partially separable 50:50 mixture of the
syn- and anti-diastereoisomers 31/32, which were isolated
in 50% combined yield. Conjugate addition of lithium amide
(R)-1 to ethyl or methyl esters 9 and 11 and enolate methyl-
ation gave a 60:40 mixture of the partially separable syn- and
anti-diastereoisomers 33/34 and 35/36, respectively, in 53
and 49% yield. The generality of this tandem conjugate
addition–alkylation approach was also investigated, with
conjugate addition of lithium amide (R)-1 to ethyl ester 9
and alkylation with benzyl bromide and allyl bromide
giving a 71:29 and 77:23 mixture of the corresponding
syn- and anti-diastereoisomers, 37/38 and 39/40, respec-
tively, which were partially separable by chromatography,
giving 37/38 and 39/40 in 52 and 55% combined isolated
yields (Scheme 5).
O
21
O
O
22
(ii). 23, P=Bn, 96%
(iii). 24, P=TBDMS, 93%
(iv)
PO
O
O
(v)
PO
N
N
27, P=Bn, 72%
28, P=TBDMS, 60%
25, P=Bn, 99%
26, P=TBDMS, 81%
Scheme 3. Reagents and conditions: (i) pyrrolidine, 65 ꢁC then recrystalli-
sation; (ii) KH, THF, ꢀ70 ꢁC then BnBr, ꢀ78 ꢁC to rt; (iii) TBDMSCl,
NEt3, DCM, rt; (iv) reflux; (v) diphenyldisulfide, benzene/hexane (1:1), hv.
In contrast to the mixture of products observed upon conju-
gate addition of lithium amide (R)-1 to g-benzyloxy bute-
noates 7 and 8, addition of lithium amide (R)-1 to both the
g-benzyloxy and g-tert-butyldimethylsilyloxy amides 27
and 28 gave exclusively the b-amino amide products from
conjugate addition in >95% de in each case. Chromato-
graphic purification gave 29 and 30 in 89 and 53% yield,
respectively (Scheme 4).
An alternative, stepwise approach to enolate functionalisa-
tion was next investigated. Deprotonation of ethyl and
methyl b-amino esters 18 and 19, respectively, with LDA
and subsequent alkylation of the in situ formed lithium
Analysis of the product distributions arising from these
conjugate addition reactions indicates that g-tert-

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E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
TBDMSO
CO2R
The relative syn- and anti-configurations within the C(2)-
9, R = Et
methylated b-amino methyl esters 33 and 34 were next
established through conversion to the corresponding b-lac-
tams. As a model system for this transformation, b-amino
methyl ester 19 was selectively monodebenzylated with
CAN to furnish b-amino ester 41,23 with subsequent treat-
ment of 41 with MeMgBr giving the b-lactam 42 in 97%
yield. Following this protocol, syn diastereoisomer 35 gave
the cis-b-lactam 44 (J2,3 5.6 Hz), and anti diastereoisomer
36 gave the trans-b-lactam 46 (J2,3 2.1 Hz) (Scheme 7).
The stereodivergent preference for the syn stereoisomer
in the tandem conjugate addition–methylation protocol and
the anti-stereoisomer in the stepwise procedure is consistent
with alkylation proceeding via the corresponding lithium (Z)-
and (E)-enolates, respectively. However, the preferential syn
alkylation in the tandem procedure contrasts the known anti
preference for the tandem conjugate addition–methylation
of methyl crotonate,15 indicating that the stereoselectivity
of tandem b-amino enolate alkylations is highly dependent
upon the nature of the substituent at C(4).
11, R = Me
t
12, R = Bu
(i)
Ph
Ph
R'
Ph
TBDMSO
N
Ph
N
+
CO2R
R'
TBDMSO
CO2R
a
syn
R'
anti
R
syn:anti
Yield %
t
Bu
Me
Me
Me
Bn
31:32 50:50
33:34 60:40
35:36 60:40
37:38 71:29
39:40 77:23
50%
54%
49%
52%
55%
Et
Me
Et
Et
allyl
Scheme 5. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(a-methyl-
benzyl)amide 1, THF, ꢀ78 ꢁC, 2 h, then R0X, ꢀ78 ꢁC to rt. [aCombined
yield of both diastereoisomers.]
(E)-enolate22 with methyl iodide gave a 25:75 and 29:71
mixture of the corresponding syn- and anti-diastereoisomers
33/34 and 35/36, respectively, and in quantitative yield in
each case (Scheme 6).
In the amide series, tandem conjugate addition of lithium
amide (R)-1 to g-tert-butyldimethylsilyloxy butenamide 28
and enolate alkylation with methyl iodide, benzyl bromide
or allyl bromide gave a 66:34, 86:14 and 80:20 mixture of
the corresponding syn- and anti-a-methyl-, a-benzyl- and
a-allyl-b-amino butanamides 47–52 (Scheme 8). Following
the stepwise protocol, treatment of b-amino amide (3R,aR)-
30 with LDA and alkylation of the resultant enolate with MeI
gave a 65:35 mixture of syn-47/anti-48 in quantitative yield.
The syn-preference for the tandem alkylation within the
butanamide series was assigned by analogy to that observed
in the corresponding butanoates. The comparable selectiv-
ities arising from the tandem (66:34 syn/anti) and stepwise
(65:35 syn/anti) methylation reactions in this series can
be ascribed to the intermediacy of a common lithium (Z)-
b-amino amide enolate in both protocols, in contrast to the
stereodivergent enolate formation in the butanoate series.
Ph
Ph
N
TBDMSO
CO2R
18, R = Et
19, R = Me
(i)
Ph
Ph
Ph
TBDMSO
N
Ph
TBDMSO
N
+
CO2R
Me
CO2R
Me
syn
anti
Yield %a
R
syn:anti
Et
33:34 25:75
35:36 29:71
quant
Previous investigations from this laboratory have demon-
strated that the conjugate addition of lithium amide (R)-1
to a range of a,b-unsaturated esters and subsequent in situ
oxidation of the thus formed enolate with the chiral oxidant
Me
quant
Scheme 6. Reagents and conditions: (i) LDA, THF, ꢀ78 ꢁC, then MeI,
ꢀ78 ꢁC to rt. [aCombined yield of both diastereoisomers.]
Ph
O
(ii)
(i)
Ph
N
Ph
NH
Ph
TBDMSO
N
TBDMSO
CO2Me
CO2Me
TBDMSO
41, 60%
42, 97%
19
Ph
Ph
TBDMSO
NH
O
(ii)
(i)
(i)
Ph
TBDMSO
N
Ph
TBDMSO
cis-44, 73%
N
CO2Me
CO2Me
Me
43, 62%
Me
Me
syn-35
J
3,4 5.6 Hz
Ph
O
Ph
TBDMSO
NH
(ii)
Ph
TBDMSO
N
Ph
N
CO2Me
CO2Me
Me
TBDMSO
Me
Me
45, 62%
trans-46, 73
3,4 2.1 Hz
anti-36
J
Scheme 7. Reagents and conditions: (i) CAN (2.1 equiv), MeCN/H2O (5:1), rt; (ii) MeMgBr, Et2O, 0 ꢁC.

E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
5859
Ph
Ph
Bz
O
(i)
HN
Ph
TBDMSO
N
O
Ph
BnO
N
TBDMSO
BzO
CO2Me
N
CO2Me
N
28
30
14, >98% d.e.
54, 47%, >95% d.e.
Stepwise
Tandem
(ii)
(ii)
(i)
Bz
Ph
Ph
HN
Ph
TBDMSO
N
O
Ph
TBDMSO
N
O
+
O
O
N
R
N
55, 83%, >95% d.e.
R
anti
syn
Ph
Yield %a
72%
Ph
Procedure
Tandem
Stepwise
Tandem
Tandem
R
syn:anti
Me
Me
Bn
47:48 66:34
47:48 65:35
49:50 86:14
51:52 80:20
(iii)
N
quant
65%
Ph
TBDMSO
N
Ph
CO2Et
allyl
54%
O
O
18, >98% d.e.
4, 77%, >95% d.e.
Scheme 8. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(a-methyl-
benzyl)amide 1, THF, ꢀ78 ꢁC, 2 h, then RX, ꢀ78 ꢁC to rt; (ii) LDA, THF,
ꢀ78 ꢁC, 30 min, then RX, ꢀ78 ꢁC to rt.
Scheme 10. Reagents and conditions: (i) Pd/C, AcOH, 50 ꢁC, H2 (4 atm),
then PhCOCl, pyridine, DCM, 0 ꢁC to rt; (ii) LiOH, MeOH, rt, then TFA/
DCM (1:5), rt; (iii) TBAF, THF, rt.
(ꢀ)-(camphorsulfonyl)oxaziridine (CSO) proceeds with
high anti-selectivity.24 Following this procedure, conjugate
addition of lithium amide (S)-1 to 11 and subsequent oxida-
tion with (+)-CSO gave anti-a-hydroxy-b-amino ester 53 as
a single diastereoisomer in 78% isolated yield after chroma-
tography (Scheme 9).
dimethylated lactone 59. The trans configuration within
monomethyl lactone 56 was subsequently confirmed unam-
biguously (vide infra), and is consistent with the established
trans alkylation of 4-amino-g-butyrolactones derived from
aspartic acid.26 Furthermore, an authentic sample of di-
methylated lactone 59 was readily prepared by treatment
of lactone 4 with excess KHMDS and methyl iodide, giving
59 in 64% yield (Scheme 11).27 In an analogous manner,
benzylation and allylation of lactone 4 was achieved, with
authentic samples of the dibenzylated and diallylated lac-
tones 60 and 61 prepared for spectroscopic comparison.
Treatment of 4 with KHMDS and addition of benzyl bro-
mide or allyl bromide gave, at 78 and 73% conversion,
respectively, an 86:14 and 75:25 mixture of the correspond-
ing trans monoalkylated lactones 57 and 58 in >95% de28
and the dialkylated lactones 60 and 61, consistent with
high diastereoselectivity being observed for monoalkylation
of lactone 4 trans to the adjacent C(3)-amino substituent.29
Ph
(i)
Ph
TBDMSO
N
TBDMSO
CO2Me
CO2Me
OH
53, 78%, >98% d.e.
11
Scheme 9. Reagents and conditions: (i) lithium (S)-N-benzyl-N-(a-methyl-
benzyl)amide 1, THF, ꢀ78 ꢁC, 2 h, then (+)-CSO, ꢀ78 ꢁC to rt, 12 h.
2.3. Synthesis of 3-alkyl-4-amino-g-butyrolactones
With a range of g-benzyloxy- and g-tert-butyldimethylsilyl-
oxy-b-amino butanoates and butanamides in hand, their
conversion to the corresponding 4-amino-g-butyrolactones
was investigated. The assigned configuration at C(3) arising
from conjugate addition within the simple b-amino esters
was confirmed unambiguously through the conversion of
g-benzyloxy-b-amino ester 14 into the known N-protected-
g-butyrolactone 55. Hydrogenolysis of b-amino ester 14,
followed by treatment with benzoyl chloride and pyridine
gave dibenzoyl b-amino ester 54, with subsequent selective
O-benzoyl deprotection giving 4-(N-benzoylamino)-g-
butyrolactone 55 in 83% yield after purification, with com-
parable spectroscopic properties to those reported in the
literature {[a]D21 ꢀ100.8 (c 0.4, CHCl3); lit.25 [a]2D0 ꢀ97.0
(c 1.4, CHCl3)}. As an alternative route to the 4-amino-
g-butyrolactone framework, treatment of g-tert-butyl-
dimethylsilyloxy-b-amino ester 18 with TBAF gave the
lactone 4 in 77% yield (Scheme 10).
(ii) Dialkylation reaction
R = Me, 64%
R = Bn, 69%
R = allyl, 70%
Ph
Ph
Ph
(i)
R
R
N
N
N
+
R
Ph
Ph
Ph
O
O
O
O
O
O
4, >95% d.e.
56, R = Me, >95% d.e.
57, R = Bn, >95% d.e.
58, R = allyl, >95% d.e.
59, R = Me, >95% d.e.
60, R = Bn, >95% d.e.
61, R = allyl, >95% d.e.
(i) Monoalkylation reaction
R = Me, 80% conversion, 56:59, 92:8
R = Bn, 78% conversion, 57:60, 86:14
R = allyl, 73% conversion, 58:61, 75:25
Scheme 11. Reagents and conditions: (i) KHMDS (1.2 equiv), THF, ꢀ78 ꢁC
then RX (excess); (ii) KHMDS (5.0 equiv), THF, ꢀ78 ꢁC then RX (excess).
The stereoselective functionalisation of the lactone 4 via
a deprotonation–alkylation strategy was next examined.
Treatment of 4 with KHMDS (1.2 equiv), followed by an
excess of methyl iodide gave, at 80% conversion, a 92:8 mix-
ture of trans monomethylated lactone 56 (>95% de) and
The relative configurations within a-methyl-b-amino esters
33–36, and lactone 56, were next correlated to the known

5860
E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
Ph
4-(N-benzoylamino)-g-butyrolactone 62. Treatment of a
29:71 mixture of the syn- and anti-a-methyl-b-amino ethyl
esters 33 and 34, respectively, or homogeneous syn- or anti-
a-methyl-b-amino methyl esters 35 or 36 (>95% de), with
TBAF gave, in all cases, a single diastereoisomeric lactone
56, identical to that arising from the stereoselective methyla-
tion of lactone 4, in good to excellent yield after chromato-
graphic purification. Hydrogenolysis of 56, and treatment of
the resulting primary amine with benzoyl chloride and pyri-
dine, gave the known N-benzoyl lactone 62, with comparable
spectroscopic properties to those reported in the literature
(Scheme 12).25 The isolation of a single lactone 4 from the
mixture of syn-33 and anti-34, and each of the diastereoiso-
merically pure b-amino butanoates syn-35 and anti-36, is
consistent with a mechanism involving initial desilylation
andlactonisationupontreatmentwithTBAF, withsubsequent
epimerization occurring under the basic reaction conditions
to give the thermodynamically favoured trans-lactone 56.30
Ph
(ii) or (iii)
OMe
Ph
TBDMSO
N
O
OH
N
Ph
O
O
OH
53, >95% d.e.
cis-63, >95% d.e.
(i)
(i)
Ph
Ph
OH
OH
N
N
+
Ph
Ph
O
O
O
O
cis-63:trans-64 70:30
Scheme 13. Reagents and conditions: (i) TBAF, THF, rt; (ii) TBAF, AcOH,
THF, rt; (iii) I2, MeOH, rt.
syn-b-amino amide 47 with aq HF promoted desilylation
to give the alcohol 65, which cyclised to lactone 56 upon at-
tempted chromatographic purification on silica; treatment
of 65 with aq HCl also facilitated cyclisation, giving trans-
lactone 56 in 89% yield. In a one-pot procedure, treatment
of amide 47 with KF and aq HCl gave lactone 56 directly
in 80% isolated yield, whilst treatment of amides 49 and
51 with a mixture of aq HF and HCl gave the corresponding
trans-lactones directly, in good yield (Scheme 14). Mean-
while, treatment of the anti-b-amino amide 48 with TBAF
gave exclusively the alcohol anti-66, which was amenable
to chromatographic purification upon silica. Attempts to
force the cyclisation reaction to 67 by heating in aq HCl re-
sulted in extensive decomposition (Scheme 14). While acid
catalysis seems necessary to promote cyclisation of syn-65
to give the trans-lactone 56, it seems that steric hindrance
in the formation of the cis-lactone 67 from anti-66 precludes
lactonisation. Indeed, treatment of a 50:50 mixture of syn-
47/anti-48 with HF and filtration through silica gave
a 50:50 mixture of lactone 56:alcohol 66. These studies
also indicate that epimerisation and interconversion of the
anti- and syn-amides 65 and 66 under the reaction conditions
do not occur (Scheme 14).
Lactonisation of the anti-2-hydroxy-3-amino ester 53 was
next investigated. Treatment of 53 with TBAF gave
a 70:30 mixture of the separable lactones cis-63/trans-64
in 40 and 24% isolated yields, presumably due to lactonisa-
tion and partial epimerization under the basic conditions of
the reaction. In an attempt to mediate the basicity of
TBAF, anti-2-hydroxy-3-amino ester 53 was treated with
TBAF in AcOH,31 giving a single lactone 63 in 76% isolated
yield and >95% de, while the same transformation could
also be achieved by treatment of 53 with I2 in MeOH.32 Fur-
thermore, treatment of cis-lactone 63 with TBAF gave a
70:30 mixture of 63/64, consistent with partial epimerization
of cis-lactone 63 to the trans-lactone 64 under the deprotec-
tion conditions. The preference for the cis-lactone 63 in this
case may be due to hydrogen bonding between the amino
and alcohol functionalities, which is presumably only signif-
icant in the cis diastereoisomer 63 (Scheme 13).
This O-deprotection and lactonisation protocol was sub-
sequently investigated in the amide series. Treatment of
In conclusion, upon reaction with homochiral lithium
amides, g-benzyloxy butenoates undergo competitive g-
deprotonation and conjugate addition, while g-tert-butyldi-
methylsilyloxy butenoates undergo exclusive conjugate
addition in high de. In contrast, treatment of g-benzyloxy
or g-tert-butyldimethylsilyloxy butenamides with lithium
amide 1 yields exclusively the b-amino amide products of
conjugate addition in high de. g-tert-Butyldimethylsilyl-
oxy-b-amino butanoates readily undergo O-deprotection
upon exposure to TBAF, giving the corresponding 4-amino-
g-butyrolactone, which may be stereoselectively alkylated
to give the corresponding trans-3-alkyl-4-amino-g-butyro-
lactones. Alternatively, stereoselective alkylation of g-tert-
butyldimethylsilyloxy-b-amino butanoates and butanamides
following a tandem or stepwise protocol furnishes a range of
separable syn- and anti-a-alkyl-b-amino butanoates and
butanamides with modest stereoselectivities. O-Silyl depro-
tection of these syn- and anti-a-alkyl-b-amino butanoates
with TBAF and concomitant cyclisation provide trans-3-
alkyl-4-amino-g-butyrolactones, consistent with epimerisa-
tion occurring upon deprotection. The further application
of these protocols to the syntheses of natural products and
amino sugars is currently underway in the laboratory.
Ph
Ph
Ph
TBDMSO
N
Ph
TBDMSO
N
CO2Me
CO2Me
Me
Me
syn-35
anti-36
(i), quant
(i)
quant
Me
Ph
Ph
(i)
Ph
TBDMSO
N
N
CO2Et
71%
Ph
O
O
Me
syn-33:anti-34 71:29
56, >95% d.e.
(ii)
58%
Bz
HN
Me
O
O
62
Scheme 12. Reagents and conditions: (i) TBAF, THF, rt; (ii) H2, Pd/C,
AcOH then BzCl, pyridine.

E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
Ph Ph
5861
Ph
R
Ph
Ph
TBDMSO
N
O
(i)
R=Me HO
(v)
Ph
N
O
Ph
HO
N
O
Ph
TBDMSO
N
O
N
N
N
N
Me
syn-65
Me
Me
anti-48
R=Me, syn-47
R = Bn, syn-49
R = allyl, syn-51
anti-66, 89%
(ii)
(ii)
Ph
N
Ph
(iii) or (iv)
R
Me
N
Ph
Ph
O
O
O
O
67
(i, ii). R=Me, 56, 89% (2 steps)
(iii). R = Me, 56, 80%
(iv). R = Bn, 57, 83%
(iv). R = allyl, 58, 93%
Scheme 14. Reagents and conditions: (i) HF (aq), rt; (ii) HCl (aq), rt; (iii) KF, HCl (aq), rt; (iv) HF (aq), HCl (aq), rt; (v) TBAF, THF, rt.
3. Experimental
3.1. General experimental
3.1.1. Methyl (E)-4-(benzyloxy)but-2-enoate 7. To a solu-
tion of (E)-methyl 4-bromo-2-butenonate (4.0 g,
22.3 mmol) in benzyl alcohol (20 mL) were added silver(I)
oxide (6.20 g, 27.0 mmol) and calcium sulfate (13.0 g).
The suspension was stirred in the dark, at 60 ꢁC for 48 h
before diluting with DCM and filtering through CeliteÒ.
Fractional distillation gave 7 as a pale yellow oil (2.6 g,
57%); C12H14O3 requires C, 69.9; H, 6.8%; found C, 69.9;
H, 7.1%; bp 112–116 ꢁC (0.3 mmHg); nmax (film) 1719; dH
(500 MHz, CDCl3) 3.76 (3H, s, OMe), 4.20 (2H, dd, J 2.0,
4.3, C(4)H2), 4.58 (2H, s, OCH2Ph), 6.15 (1H, dt, J 15.7,
2.0, C(2)H), 7.00 (1H, dt, J 15.7, 4.3, C(3)H), 7.31–7.39
(5H, m, Ph); dC (125 MHz, CDCl3) 51.5, 68.5, 72.7,
121.0, 127.7, 127.9, 128.6, 137.9, 144.8, 167.0; m/z (CI+)
224 ([M+NH4]+, 17%), 207 (15), 91 (100).
All manipulations of organometallic and air or moisture
sensitive reagents were performed under an atmosphere of
dry nitrogen with deoxygenated solvents and using standard
vacuum line and Schlenk tube techniques.33 THF was
distilled from sodium benzophenone ketyl, and DCM from
calcium hydride, under nitrogen. Toluene was dried by
standing over sodium wire and hexanes were distilled before
use. Benzyl bromide and allyl bromide were distilled from
calcium hydride, while methyl iodide was dried over
calcium sulfate (DrieriteÔ), prior to use. BuLi was used as
a solution in hexanes and KHMDS as a solution in toluene.
Photolysis was carried out using a Hanovia 125 W mercury
vapour lamp with a Pyrex filter. All organic solutions were
dried over MgSO4. Silica gel chromatography was carried
out on Kieselgel 60 according to the guidelines of Still.34
Thin layer chromatography was carried out using Camlab
Polygram SIL G/UV254, with a 0.25 mm coating of silica
gel containing fluorescent indicator UV254. Plates were
visualised using UV light, iodine, or potassium permanga-
nate. Melting points were determined using a Gallenkamp
apparatus and are uncorrected. Optical rotations were
recorded on a Perkin–Elmer 241 polarimeter. Elemental
analyses were performed by the analytical department of
the Inorganic Chemistry Laboratory, University of Oxford.
Infrared spectra were recorded in 0.1 mm solution cells
on a Perkin–Elmer 781 spectrophotometer. Selected charac-
teristic peaks are reported in cmꢀ1. NMR spectra were re-
corded on Bruker AM 250, WH 300, AV 400 or AM 500
instruments. The field was locked by external referencing
to the relevant deuteron resonance. Coupling constants are
given in hertz. Materials of sufficient volatility were ana-
lysed by GC–MS using a Hewlett Packard 5890A gas chro-
matograph, fitted with an SGE column (12QC3/BP1-0.5 or
25QC3/BP1-0.5) and coupled to a TRIO 1 mass spectrome-
ter running in CI+ (NH3) mode. Other mass spectra were re-
corded using a VG MASSLAB VG 20-250 CI+ (NH3) for
low-resolution samples and a VG MICROMASS ZAB-1F
with electron impact for high-resolution samples.
3.1.2. tert-Butyl (E)-4-(benzyloxy)but-2-enoate 8. Aque-
ous H2SO4 (2 M, 20 mL) was added dropwise to a stirred
solution of benzyloxyacetaldehyde diethyl acetal (1.05 g,
4.7 mmol) in Et2O (50 mL). The reaction mixture was
stirred for a further 12 h, then the mixture was partitioned
and the aqueous phase extracted with Et2O (3ꢂ20 mL).
The combined organic extracts were dried, filtered and con-
centrated in vacuo. The residue was redissolved in MeCN
(20 mL) and tert-butyl diethylphosphonoacetate (1.24 g,
4.90 mmol), LiCl (1.40 g, 31.5 mmol) and iPr2NEt
(0.59 mL, 3.48 mmol) were added in one portion. The
reaction mixture was stirred for a further 48 h and then
quenched by the addition of H2O (5 mL), the organic
layer was separated and the aqueous phase was extracted
with EtOAc (3ꢂ20 mL). The combined organic extracts
were dried, filtered and concentrated in vacuo. Purification
via column chromatography (eluent 30–40 ꢁC petrol/Et2O
10:1) gave 8 as a colourless oil (1.06 g, 90%); nmax (film)
1714; dH (400 MHz, CDCl3) 1.50 (9H, s, CMe3), 4.17
(2H, dd, J 4.5, 2.0, C(4)H2), 4.57 (2H, s, OCH2Ph), 6.05
(1H, dt, J 15.9, 2.0, C(2)H), 6.89 (1H, dt, J 15.9, 4.5,
C(3)H), 7.29–7.39 (5H, m, Ph); dC (100 MHz, CDCl3)
28.1, 68.7, 72.7, 80.4, 123.3, 127.6, 127.8, 128.5,
137.8, 142.9, 165.6; m/z (CI+) 249 ([M+H]+, 100%);
HRMS (CI+) C15H21O+3 ([M+H]+) requires 249.1491; found
249.1479.

5862
E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
3.1.3. Ethyl (E)-4-(tert-butyldimethylsilyloxy)but-2-
enoate 9. Borane (1.0 M in THF, 40.0 mL, 40.0 mmol)
was added dropwise to a stirred solution of monoethyl fuma-
rate (5.76 g, 40.0 mmol) in THF (20 mL) at ꢀ10 ꢁC. Stirring
was continued for a further 10 h during which time the solu-
tion was allowed to warm to 20 ꢁC, the reaction was
quenched with 50% aq AcOH (30 mL) and concentrated in
vacuo. The slurry was poured into satd aq NaHCO3
(100 mL), extracted with EtOAc (2ꢂ50 mL), and the com-
bined organic extracts dried and concentrated in vacuo.
The residue was redissolved in DCM (100 mL) and treated
with TBDMSCl (6.50 g, 43.0 mmol) and Et3N (6.62 mL,
47.6 mmol). After 55 h at 20 ꢁC the reaction mixture was
poured into H2O (100 mL) and the organic layer washed se-
quentially with 0.1 M aq HCl (100 mL) and satd aq NaHCO3
(100 mL). The organic layer was dried, filtered through
a short plug of silica and the solvent evaporated. Distillation
gave the title compound 9 as a colourless oil (3.24 g, 33%);
bp 88 ꢁC (0.3 mmHg); nmax (film) 1713, 1662; dH (500 MHz,
CDCl3) 0.09 (6H, s, SiMe2), 0.93 (9H, s, SiCMe3), 1.31 (3H,
t, J 7.2, CO2CH2Me), 4.21 (2H, q, J 7.2, CO2CH2), 4.35 (2H,
dd, J 3.4, 2.3, C(4)H2), 6.10 (1H, dt, J 15.4, 2.3, C(2)H), 7.01
(1H, dt, J 15.4, 3.4, C(3)H); dC (125 MHz, CDCl3) ꢀ5.7,
14.1, 18.2, 25.7, 60.2, 62.1, 119.7, 147.6, 166.9; m/z (CI+)
262 ([M+NH4]+, 60%), 245 (100), 187 (36); HRMS (CI+)
C8H15O3Si ([MꢀC4H8]+) requires 187.0790; found
187.0791.
column chromatography (eluent 30–40 ꢁC petrol/Et2O
60:1) gave 12 as a colourless oil (4.0 g, 41%); nmax (film)
1727, 1664; dH (400 MHz, CDCl3) 0.09 (6H, s, SiMe2),
0.93 (9H, s, SiCMe3), 3.75 (3H, s, OMe), 4.34 (2H, dd, J
3.4, 2.4, C(4)H2), 6.12 (1H, dt, J 15.4, 2.4, C(2)H), 7.01
(1H, dt, J 15.4, 3.4, C(3)H); dC (100 MHz, CDCl3) ꢀ5.5,
18.3, 25.8, 51.5, 62.1, 119.1, 147.7, 167.1; HRMS
(CI+) C11H23O3Si+ ([M+H]+) requires 231.1416; found
231.1417.
3.1.5. tert-Butyl (E)-4-(tert-butyldimethylsilyloxy)but-
t
anoate 12. (EtO)2P(O)CH2CO2 Bu (5.74 g, 22.8 mmol),
LiCl (5.39 g, 127 mmol) and iPr2NEt (2.77 mL, 17.1 mmol)
were added to a stirred solution of 10 (3.3 g, 19.0 mmol) in
MeCN (40 mL). The reaction mixture was stirred for 48 h
and then quenched by the addition of H2O (5 mL). The
organic layer was separated and the aqueous layer was
extracted with EtOAc (40 mL). The combined organic
extracts were dried and concentrated in vacuo. Purification
via flash column chromatography (eluent 30–40 ꢁC petrol/
Et2O 60:1) gave 12 as a colourless oil (2.17 g, 67%); Rf
0.2 (30–40 ꢁC petrol/Et2O 60:1); nmax (film) 1717, 1661;
dH (400 MHz, CDCl3) 0.06 (6H, s, SiMe2), 0.90 (9H, s,
SiCMe3), 1.46 (9H, s, OCMe3), 4.29 (2H, dd, J 3.5, 2.3,
C(4)H2), 5.97 (1H, dt, J 15.4, 2.3, C(2)H), 6.86 (1H, dt,
J 15.4, 3.5, C(3)H); dC (100 MHz, CDCl3) ꢀ5.5, 18.3,
25.8, 28.1, 62.1, 80.1, 121.4, 146.0, 166.0; HRMS (CI+)
C14H28O3Si+ ([M]+) requires 272.1808; found 272.1808.
3.1.4. Methyl (E)-4-(tert-butyldimethylsilyloxy)but-
anoate 11. TBDMSCl (6.62 g, 48 mmol) was added in one
portion to a stirred solution of but-2-ene-1,4-diol (2.14 g,
24 mmol), imidazole (2.99 g, 24 mmol) and DMAP
(50 mg) in DCM (50 mL) at rt. After stirring for 12 h, the re-
action mixture was concentrated in vacuo, the residue was
dissolved in Et2O (50 mL) and washed with 1 M aq HCl
(50 mL), dried and concentrated in vacuo to give 1,4-
di-(tert-butyldimethylsilyloxy)but-2-ene as a colourless oil
that was used without purification (7.63 g, quant); dH
(400 MHz, CDCl3) 0.07 (12H, s, 2ꢂSiMe2), 0.90 (18H, s,
2ꢂSiCMe3), 4.24 (4H, dd, J 2.7, 0.7, C(1)H2, C(4)H2),
5.56 (2H, td, J 2.7, 0.7, C(2)H, C(3)H).
3.2. General procedure 1 for lithium amide conjugate
addition
BuLi (2.5 M in hexanes, 1.55 equiv) was added dropwise via
syringe to a stirred solution of (R)-N-benzyl-N-(a-methyl-
benzyl)amine (1.6 equiv) in THF at ꢀ78 ꢁC. After stirring
for 30 min a solution of the requisite a,b-unsaturated car-
bonyl compound (1.0 equiv) in THF at ꢀ78 ꢁC was added
dropwise via cannula. After stirring for a further 2 h at
ꢀ78 ꢁC the reaction mixture was quenched with satd aq
NH4Cl and allowed to warm to rt over 15 min. The reaction
mixture was concentrated in vacuo and the residue was par-
titioned between DCM and 10% aq citric acid. The organic
layer was separated and the aqueous layer was extracted
twice with DCM. The combined organic extracts were
washed sequentially with satd aq NaHCO3 and brine, dried
and concentrated in vacuo.
O3 was bubbled through a stirred solution of 1,4-di-(tert-
butyldimethylsilyloxy)but-2-ene (7.63 g, 24 mmol) in DCM
(50 mL) at ꢀ78 ꢁC until the solution turned blue. O2 was
then bubbled through the solution until it turned colourless.
DMS (10 mL) was added dropwise via syringe and the reac-
tion mixture stirred for 12 h. The reaction mixture was con-
centrated in vacuo, the residue was redissolved in Et2O
(50 mL) and washed with H2O (50 mL), dried and concen-
trated in vacuo to give 10 as a colourless oil that was used
without purification (7.37 g, 88%); dH (400 MHz, CDCl3)
0.08 (6H, s, SiMe2), 0.90 (6H, s, SiCMe3), 4.17–4.21 (2H,
m, C(2)H2), 9.67–9.69 (1H, m, C(1)H).
3.2.1. Methyl (3S,aR)-3-[N-benzyl-N-(a-methylbenzyl)-
amino]-4-benzyloxybutanoate 14. BuLi (2.5 M in hexanes,
1.51 mL, 3.77 mmol), (R)-N-benzyl-N-(a-methylbenzyl)-
amine (822 mg, 3.89 mmol) in THF (40 mL) and 7 (500 mg,
2.43 mmol) in THF (20 mL) were reacted according to gen-
eral procedure 1 and gave a 44:56 mixture of (Z)-13/14.
Chromatography (eluent 30–40 ꢁC petrol/DCM 1:1) gave
(Z)-13 as a colourless oil (first to elute, 212 mg, 42%) and
14 (second to elute, 472 mg, 47%) as a pale yellow oil.
(EtO)2P(O)CH2CO2Me (10.8 g, 52 mmol), LiCl (10 g,
236 mmol) and iPr2NEt (4.43 mL, 34 mmol) were added to
a stirred solution of 10 (7.37 g, 42.4 mmol) in MeCN
(50 mL). The reaction mixture was stirred for 48 h and
then quenched by the addition of H2O (5 mL). The organic
layer was separated and the aqueous layer was extracted
with EtOAc (50 mL). The combined organic extracts were
dried and concentrated in vacuo. Purification via flash
Data for (Z)-13: Rf 0.54 (30–40 ꢁC petrol/DCM 1:1); nmax
(film) 1739, 1669; dH (400 MHz, CDCl3) 3.20 (2H, dd,
J 7.1, 1.6, C(2)H2), 3.69 (3H, s, OMe), 4.60–4.65 (1H, m,
C(3)H), 4.83 (2H, s, OCH2), 6.19 (1H, dt, J 6.2, 1.6,
C(4)H), 7.29–7.39 (5H, m, Ph); dC (100 MHz, CDCl3)
29.7, 51.9, 73.8, 98.6, 127.3, 128.0, 128.5, 137.3, 172.7,

E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
5863
200.0; m/z (CI+) 207 ([M+H]+, 100%); HRMS (CI+)
(eluent 30–40 ꢁC petrol/DCM 2:1) gave 18 as a colourless
oil (268 mg, 72%); C27H41NO3Si requires C, 71.2; H, 9.1;
N, 3.1%; found C, 71.0; H, 9.35; N, 3.0%; [a]2D3 ꢀ7.9 (c
2.0, CHCl3); nmax (film) 1729; dH (500 MHz, CDCl3) 0.02
(6H, s, SiMe2), 0.88 (9H, s, SiCMe3), 1.19 (3H, t, J 7.2,
CO2CH2Me), 1.38 (3H, d, J 6.9, C(a)Me), 2.19 (2H, dd, J
15.0, 5.5, C(2)HA), 2.36 (1H, dd, J 15.0, 7.7, C(2)HB),
3.49–4.09 (8H, m, C(3)H, C(4)H2, C(a)H, CO2CH2Me,
NCH2), 7.19–7.42 (10H, m, Ph); dC (125 MHz, CDCl3)
ꢀ5.7, 14.0, 18.2, 18.7, 25.8, 34.4, 50.8, 55.5, 57.8, 60.1,
65.1, 126.8, 127.0, 128.1, 128.3, 128.4, 128.5, 142.0, 144.0,
173.0; m/z (CI+) 456 ([M+H]+, 100%), 310 (60), 206 (38).
C12H15O3 ([M+H]+) requires 207.1021; found 207.1024.
Data for 14: C27H31NO3 requires C, 77.7; H, 7.5; N, 3.35%;
found C, 77.6; H, 7.8; N, 3.1%; [a]2D2 ꢀ14.5 (c 1.0, EtOH);
nmax (film) 1731; dH (500 MHz, CDCl3) 1.38 (3H, d, J 6.9,
C(a)Me), 2.26 (1H, dd, J 14.7, 5.6, C(2)HA), 2.39 (1H, dd,
J 14.7, 7.4, C(2)HB), 3.49 (3H, s, OMe), 3.46–3.85 (5H,
m, C(3)H, NCH2), 3.94 (1H, q, J 6.9, C(a)H), 4.47 (2H, s,
OCH2Ph), 7.20–7.40 (15H, m, Ph); dC (125 MHz, CDCl3)
18.3, 35.2, 50.6, 51.4, 53.8, 57.7, 72.5, 73.2, 127.0, 127.1,
127.8, 128.1, 128.4, 128.6, 138.7, 141.7, 143.8, 173.2; m/z
(CI+) 418 ([M+H]+, 19%), 212 (82), 196 (33), 105 (27), 91
(100).
3.2.4. Methyl (3S,aR)-3-[N-benzyl-N-(a-methylbenzyl)-
amino]-4-(tert-butyldimethylsilyloxy)butanoate 19. BuLi
(2.5 M in hexanes, 0.96 mL, 2.02 mmol), (R)-N-benzyl-
N-(a-methylbenzyl)amine (0.44 g, 2.08 mmol) in THF
(20 mL) and 11 (0.30 g, 1.30 mmol) in THF (10 mL) were
reacted according to general procedure 1. Chromatography
(eluent 30–40 ꢁC petrol/DCM 2:1) gave 19 as a colourless
oil (344 mg, 60%); Rf 0.21 (30–40 ꢁC petrol/Et2O 20:1);
[a]1D8 ꢀ10.6 (c 1.0, CHCl3); nmax (film) 1739; dH
(400 MHz, CDCl3) 0.02 (3H, s, SiMeA), 0.03 (3H, s, SiMeB),
0.88 (9H, s, SiCMe3), 1.38 (3H, d, J 6.8, C(a)Me), 2.22 (1H,
dd, J 15.0, 5.8, C(2)HA), 2.38 (1H, dd, J 15.0, 7.9, C(2)HB),
3.48–3.56 (1H, m, C(4)HA), 3.55 (3H, s, OMe), 3.58–3.79
(3H, m, C(3)H, C(4)HB, NCHA), 3.84 (1H, d, J 14.7,
NCHB), 3.94 (1H, q, J 6.8, C(a)H), 7.18–7.43 (10H, m,
Ph); dC (100 MHz, CDCl3) ꢀ5.6, 18.2, 18.5, 25.9, 34.4,
50.7, 51.3, 55.4, 57.6, 65.0, 126.6, 126.7, 127.8, 128.0,
128.1, 128.3, 141.5, 143.7, 173.0; m/z (ESI+) 442
([M+H]+, 100%); HRMS (ESI+) C26H40NO3Si ([M+H]+)
requires 442.2776; found 442.2777.
3.2.2. tert-Butyl(3S,aR)-3-[N-benzyl-N-(a-methylbenzyl)-
amino]-4-benzyloxybutanoate 17. BuLi (2.5 M in hexanes,
0.83 mL, 2.08 mmol), (R)-N-benzyl-N-(a-methylbenzyl)-
amine (452 mg, 2.14 mmol) in THF (20 mL) and 8 (330
mg, 1.34 mmol) in THF (10 mL) were reacted according
to general procedure 1 and gave a 44:6:50 mixture of (Z)-
15/(E)-16/17. Chromatography (eluent 30–40 ꢁC petrol/
DCM 2:1) gave (Z)-15 as a colourless oil (first to elute,
109 mg, 33%), a 27:73 mixture of (Z)-15/(E)-16 as a clear
colourless oil (second to elute, 27 mg, 8%) and 17 as
a pale yellow oil (third to elute, 256 mg, 42%).
Data for (Z)-15: Rf 0.2 (30–40 ꢁC petrol/DCM 2:1); nmax
(film) 1732, 1669; dH (400 MHz, CDCl3) 1.46 (9H, s,
CMe3), 3.11 (2H, dd, J 7.1, 1.6, C(2)H2), 4.59–4.64 (1H,
m, C(3)H), 4.82 (2H, s, OCH2Ph), 6.16 (1H, dt, J 6.3, 1.6,
C(4)H), 7.29–7.39 (5H, m, Ph); dC (100 MHz, CDCl3)
28.1, 31.1, 73.7, 80.3, 99.4, 127.9, 127.9, 128.5, 137.4,
146.3, 171.6; m/z (CI+) 249 ([M+H]+, 25%), 193 (100);
HRMS (CI+) C15H21O3 ([M+H]+) requires 249.1491; found
249.1486.
3.2.5. tert-Butyl (3S,aR)-3-[N-benzyl-N-(a-methylbenzyl)-
amino]-4-(tert-butyldimethylsilyloxy)butanoate 20. BuLi
(2.5 M in hexanes, 0.46 mL, 1.14 mmol), (R)-N-benzyl-N-
(a-methylbenzyl)amine (248 mg, 1.17 mmol) in THF
(20 mL) and 12 (200 mg, 0.73 mmol) in THF (10 mL)
were reacted according to general procedure 1. Chromato-
graphy (eluent 30–40 ꢁC petrol/Et2O 100:1) gave 20 as a col-
ourless oil (269 mg, 76%); [a]2D3 ꢀ13.7 (c 1.0, CHCl3); nmax
(film) 1728; dH (400 MHz, CDCl3) 0.02 (3H, s, SiMeA), 0.03
(3H, s, SiMeB), 0.89 (9H, s, SiCMe3), 1.37 (3H, d, J 7.0,
C(a)Me), 1.42 (9H, s, CMe3), 2.06 (1H, dd, J 15.3, 4.5,
C(2)HA), 2.27 (1H, dd, J 15.1, 8.3, C(2)HB), 3.47–3.52
(1H, m, C(3)H), 3.59–3.72 (3H, m, C(4)H2, NCHA), 3.88
(1H, d, J 14.9, NCHB), 3.93 (1H, q, J 7.0, C(a)H), 7.20–
7.41 (10H, m, Ph); dC (100 MHz, CDCl3) ꢀ5.6 ꢀ5.5,
18.3, 19.5, 25.8, 25.9, 35.1, 50.8, 55.5, 58.3, 64.8, 79.9,
126.4, 126.7, 127.8, 128.0, 128.1, 128.2, 142.1, 143.9,
171.9; m/z (ESI+) 484 ([M+H]+, 100%); HRMS (ESI+)
C29H45NO3Si ([M+H]+) requires 484.3247; found 484.3229.
Data for (E)-16: Rf 0.14 (30–40 ꢁC petrol/DCM 2:1); dH
(400 MHz, CDCl3) 1.45 (9H, s, CMe3), 2.87 (2H, dd,
J 7.5, 1.2, C(2)H2), 4.77 (2H, s, OCH2Ph), 4.97 (1H, dt,
J 12.7, 7.5, C(3)H), 6.45 (1H, dt, J 12.7, 1.2, C(4)H),
7.29–7.41 (5H, m, Ph).
Data for 17: Rf 0.06 (30–40 ꢁC petrol/DCM 2:1); [a]2D4 ꢀ72.9
(c 0.8, CHCl3); nmax (film) 1727; dH (400 MHz, CDCl3) 1.37
(3H, d, J 7.1, C(a)Me), 1.39 (9H, s, CMe3), 2.11 (1H, dd, J
15.0, 4.6, C(2)HA), 2.25 (1H, dd, J 15.0, 8.5, C(2)HB),
3.46 (1H, dd, J 9.6, 6.0, C(4)HA), 3.60 (1H, dd, J 9.6, 6.0,
C(4)HB), 3.65 (1H, d, J 15.0, NCHA), 3.68–3.74 (1H, m,
C(3)H), 3.83 (1H, d, J 15.0, NCHB), 3.90–3.95 (1H, m,
C(a)H), 4.47 (2H, OCH2Ph), 7.21–7.39 (15H, m, Ph); dC
(100 MHz, CDCl3) 15.3, 28.0, 36.1, 50.7, 53.7, 58.4, 72.4,
73.0, 80.0, 126.5, 126.8, 127.4, 127.5, 127.8, 128.0, 128.1,
128.2, 128.3, 138.6, 141.8, 143.6, 171.7; m/z (ESI+) 460
([M+H]+, 100%); HRMS (ESI+) C30H38NO3 ([M+H]+) re-
quires 460.2852; found 460.2848.
3.2.6. (1S,2S,3S,4R)-{3-(Hydroxymethyl)-7-oxabicy-
clo[2.2.1]hept-5-en-2-yl}(pyrrolidin-10-yl)methanone 22.
A solution of 21 (7.48 g, 49.2 mmol) in pyrrolidine
(10 mL, 120 mmol) was heated at 65 ꢁC (6 h) before cooling
and evaporation of excess pyrrolidine. The resulting oil was
crystallised by the addition of acetone, and the resultant solid
recrystallised from acetone to give 22 as pale brown crystals
(4.99 g, 45%) that were used without further purification.
Filtration of an EtOAc/EtOH (1:1) solution through a short
3.2.3. Ethyl (3S,aR)-3-[N-benzyl-N-(a-methylbenzyl)-
amino]-4-(tert-butyldimethylsilyloxy)butanoate 18. BuLi
(2.5 M in hexanes, 0.51 mL, 1.27 mmol), (R)-N-benzyl-N-
(a-methylbenzyl)amine (277 mg, 1.31 mmol) in THF
(20 mL) and 9 (200 mg, 0.82 mmol) in THF (10 mL) were
reacted according to general procedure 1. Chromatography

5864
E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
plug of silica (Rf 0.50), followed by recrystallisation from
acetone gave an analytically pure sample of 22 as colourless
crystals; mp 130–131 ꢁC (dec); C12H17NO3 requires C, 64.5;
H, 7.7; N, 6.3%; found C, 64.4; H, 7.7; N, 6.3%; nmax (KBr)
3625, 1628; dH (500 MHz, CDCl3) 1.73–2.07 (4H, m,
N(CH2CH2)2), 2.14 (1H, dt, J 8.5, 5.9, CHCH2OH), 2.56
(1H, d, J 8.5, CHCON), 3.37–3.70 (6H, m, CH2OH,
N(CH2CH2)2), 5.03 (1H, s, OCH), 5.12 (1H, s, OCH), 6.44
(2H, AB system, JAB 6.1, CH]CH); dC (125 MHz, CDCl3)
24.1, 25.8, 42.1, 44.5, 45.7, 46.6, 61.8, 79.2, 80.1, 136.5,
136.6, 171.4; m/z (CI+) 224 ([M+H]+, 10%), 156 (100).
crystallised on standing (1.37 g, 98%); mp 39–41 ꢁC;
C15H19NO2 requires C, 73.4; H, 7.8; N, 5.7%; found C,
73.4; H, 7.8; N, 5.4%; nmax (KBr) 1656, 1610; dH
(500 MHz, CDCl3) 1.82–2.01 (4H, m, N(CH2CH2)2),
3.45–3.51 (4H, m, N(CH2CH2)2), 4.55 (2H, s, OCH2Ph),
4.68 (2H, dd, J 4.9, 2.2, C(4)H2), 6.04 (1H, dt, J 11.7, 2.2,
C(2)H), 6.23 (1H, dt, J 11.7, 4.9, C(3)H), 7.28–7.37 (5H,
m, Ph); dC (125 MHz, CDCl3) 24.1, 25.9, 45.3, 46.7, 68.8,
72.7, 120.9, 127.6, 127.9, 128.4, 138.3, 143.2, 165.0; m/z
(CI+) 246 ([M+H]+, 100%), 140 (65), 91 (28).
3.2.10. (Z)-1-(Pyrrolidin-10-yl)-4-(tert-butyldimethylsilyl-
oxy)but-2-en-1-one 26. Compound 24 (5.00 g, 14.8 mmol)
was pyrolysed under vacuum with a hot air gun for 5 min and
the residue distilled to give 26 as a pale yellow oil (3.25 g,
81%); C14H27NO2Si requires C, 62.4; H, 10.1; N, 5.2%;
found C, 62.5; H, 10.2; N, 5.0%; bp 140 ꢁC (0.3 mmHg);
nmax (film) 1651, 1608; dH (400 MHz, CDCl3) 0.04 (6H,
s, SiMe2), 0.87 (9H, s, SiCMe3), 1.79–1.98 (4H, m,
N(CH2CH2)2), 3.42–3.48 (4H, m, N(CH2CH2)2), 4.75 (2H,
dd, J 4.7, 2.3, C(4)H2), 5.92 (1H, dt, J 11.7, 2.3, C(2)H),
6.13 (1H, dt, J 11.7, 4.7, C(3)H); dC (125 MHz, CDCl3)
ꢀ5.5, 18.1, 24.2, 26.0, 25.8, 45.3, 46.7, 61.9, 119.2, 147.5,
165.2; m/z (CI+) 269 ([M]+, 8%), 212 (100), 73 (25).
3.2.7. (1S,2S,3S,4R)-{3-(Benzyloxymethyl)-7-oxabicy-
clo[2.2.1]hept-5-en-2-yl}(pyrrolidin-10-yl)methanone 23.
Potassium hydride (1.26 g of a 35% dispersion in mineral
oil, 11.0 mmol) was washed with hexane (2ꢂ5 mL) and sus-
pended in THF (40 mL) at ꢀ70 ꢁC. To this was added a solu-
tion of the alcohol 22 (1.96 g, 8.80 mmol) in THF (50 mL),
followed by BnBr (1.15 mL, 9.70 mmol) and the mixture
stirred for 2 h at ꢀ70 ꢁC and overnight (18 h) at 20 ꢁC.
The reaction mixture was filtered through a plug of silica,
eluting with EtOAc and evaporation of the solvent gave 23
as a pale yellow oil, which crystallised on standing (2.64 g,
96%). Chromatography (eluent EtOAc) and recrystallisation
from PhMe/hexane (1:2) gave an analytically pure sample;
mp 106–108 ꢁC; C19H23NO3 requires C, 72.8; H, 7.4; N,
4.5%; found C, 72.9; H, 7.6; N, 4.3%; nmax (KBr) 1631; dH
(500 MHz, CDCl3) 1.64–1.88 (4H, m, N(CH2CH2)2), 2.23
(1H, td, J 8.7, 5.8, CHCH2OBn), 2.50 (1H, d, J 8.7,
CHCON), 3.27–3.51 (6H, m, CH2OBn, N(CH2CH2)2),
4.43, 4.54 (2H, AB system, JAB 11.6, OCH2Ph), 4.96 (1H,
s, OCH), 5.15 (1H, s, OCH), 6.42 (2H, AB system, JAB
5.8, CH]CH), 7.28–7.35 (5H, m, Ph); dC (125 MHz,
CDCl3) 24.0, 25.6, 40.4, 44.3, 45.6, 46.4, 70.4, 73.2, 79.6,
80.3, 127.7, 127.9, 128.4, 136.2, 136.8, 138.3, 170.7; m/z
(CI+) 314 ([M+H]+, 2%), 246 (100), 154 (25), 91 (16).
3.2.11. (E)-1-(Pyrrolidin-10-yl)-4-benzyloxybut-2-en-1-
one 27. A solution of 25 (1.13 g, 4.63 mmol) and diphenyl-
disulfide (50 mg, 0.23 mmol) in benzene/hexane (1:1,
100 mL) was photolysed at 25 ꢁC for 5 h. Filtration of the
solution through CeliteÒ and evaporation of the solvent
gave a yellow oil. Chromatography (eluent EtOAc/hexane
2:1) and recrystallisation (Et2O/pentane) gave 27 as a white
solid (820 mg, 72%); Rf 0.16 (EtOAc/hexane 2:1);
C15H19NO2 requires C, 73.4; H, 7.8; N, 5.7%; found C,
73.7; H, 8.05; N, 5.65%; mp 34 ꢁC; nmax (KBr) 1667,
1607; dH (500 MHz, CDCl3) 1.84–2.02 (4H, m,
N(CH2CH2)2), 3.55 (4H, t, J 6.8, N(CH2CH2)2), 4.21 (2H,
dd, J 2.0, 4.2, C(4)H2), 4.59 (2H, s, OCH2Ph), 6.44 (1H,
dt, J 15.2, 2.0, C(2)H), 6.96 (1H, dt, J 15.2, 4.2, C(3)H),
7.29–7.38 (5H, m, Ph); dC (125 MHz, CDCl3) 24.3, 26.1,
45.9, 46.6, 69.2, 72.7, 121.7, 127.7, 127.8, 128.5, 138.1,
140.8, 164.4; m/z (CI+) 246 ([M+H]+, 100%).
3.2.8. (1S,2S,3S,4R)-{3-(tert-Butyldimethylsilyloxy-
methyl)-7-oxabicyclo[2.2.1]hept-5-en-2-yl}(pyrrolidin-
10-yl)methanone 24. To a solution of the alcohol 22 (3.70 g,
16.6 mmol) in DCM (60 mL) were added TBDMSCl
(2.76 g, 18.3 mmol) and Et3N (2.77 mL, 19.9 mmol) and
the mixture stirred at 20 ꢁC for 48 h. The reaction mixture
was extracted sequentially with H2O (100 mL), 0.1 M aq
HCl (100 mL) and satd aq NaHCO3 (100 mL), dried and
concentrated in vacuo to give 24 as a yellow oil (5.19 g,
93%) that was used without further purification. Chromato-
graphy (eluent Et2O) gave an analytically pure sample; Rf
0.12 (Et2O); C18H31NO3Si requires C, 64.05; H, 9.3; N,
4.15%; found C, 63.8; H, 9.5; N, 4.1%; nmax (film) 1632;
dH (500 MHz, CDCl3) 0.04 (3H, s, SiMeA), 0.06 (3H, s,
SiMeB), 0.89 (9H, s, SiCMe3), 1.81–2.11 (5H, m,
N(CH2CH2)2, CHCH2OSi), 2.46 (1H, d, J 8.6, CHCON),
3.33–3.58 (6H, m, CH2OSi, N(CH2CH2)2), 4.96 (1H, s,
OCH), 5.14 (1H, s, OCH), 6.41 (2H, s, CH]CH); dC
(125 MHz, CDCl3) ꢀ5.6, 18.0, 24.1, 25.8, 25.7, 42.4, 44.2,
45.5, 46.4, 62.8, 78.9, 80.0, 136.2, 136.7, 170.5; m/z (CI+)
338 ([M+H]+, 3%), 270 (100), 212 (60), 138 (20).
3.2.12. (E)-1-(Pyrrolidin-10-yl)-4-(tert-butyldimethylsilyl-
oxy)but-2-en-1-one 28. A solution of 26(2.32 g, 8.59 mmol)
and diphenyldisulfide (94 mg, 0.43 mmol) in hexane
(100 mL) was photolysed at 25 ꢁC for 4 h. Filtration of the
solution through CeliteÒ and evaporation of the solvent
gave a yellow oil. Chromatography (eluent EtOAc/hexane
2:1) and distillation gave 28 as a low-melting solid (1.39 g,
60%); Rf 0.37 (EtOAc/hexane 2:1); C14H27NO2Si requires
C, 62.4; H, 10.1; N, 5.2%; found C, 62.3; H, 10.0; N,
5.05%; bp 170 ꢁC (0.5 mmHg); nmax (film) 1667, 1605; dH
(500 MHz, CDCl3) 0.09(6H, s, SiMe2), 0.94(9H, s, SiCMe3),
1.84–2.03 (4H, m, N(CH2CH2)2), 3.54 (4H, t, J 6.8,
N(CH2CH2)2), 4.36 (2H, dd, J 3.1, 2.4, SiOCH2), 6.42 (1H,
dt, J 15.0, 2.2, C(2)H), 6.97 (1H, dt, J 15.0, 3.3, C(3)H); dC
(125 MHz, CDCl3) ꢀ5.6, 18.1, 24.1, 25.9, 25.7, 45.7, 46.4,
62.4, 119.8,144.1,164.9;m/z(CI+)269([M]+, 1%),212(100).
3.2.9. (Z)-1-(Pyrrolidin-10-yl)-4-(benzyloxy)but-2-ene-1-
one 25. Compound 23 (1.78 g, 5.69 mmol) was pyrolysed
under vacuum with a hot air gun for 5 min and the residue
distilled (bp 190 ꢁC/0.5 mmHg) to give 25 as an oil, which
3.2.13. (3S,aR)-1-(Pyrrolidin-10-yl)-3-[N-benzyl-N-(a-
methylbenzyl)amino]-4-benzyloxybutan-1-one 29. BuLi
(2.5 M in hexanes, 0.38 mL, 0.95 mmol), (R)-N-benzyl-N-

E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
5865
(a-methylbenzyl)amine (206 mg, 0.98 mmol) in THF
(20 mL) and 27 (150 mg, 0.61 mmol) in THF (10 mL)
were reacted according to general procedure 1. Chromato-
graphy (eluent EtOAc/hexane 3:2) gave 27 as a colourless
oil (248 mg, 89%); Rf 0.29 (EtOAc/hexane 3:2);
C30H36N2O2$HCl requires C, 73.1; H, 7.6; N, 5.7%; found
C, 73.1; H, 7.7; N, 5.6%; [a]2D1 ꢀ0.2 (c 1.2, CHCl3); nmax
(film) 1621; dH (500 MHz, CDCl3) 1.41 (3H, d, J 6.9,
C(a)Me), 1.69–1.77 (4H, m, N(CH2CH2)2), 2.12 (1H, dd, J
14.8, 5.1, C(2)HA), 2.39 (1H, dd, J 14.8, 8.2, C(2)HB),
2.91–3.40 (4H, m, N(CH2CH2)2), 3.60 (1H, dd, J 9.6, 5.4,
C(4)HA), 3.71 (1H, dd, J 9.6, 5.6, C(4)HB), 3.76–3.81 (1H,
m, C(3)H), 3.79 (1H, d, J 15.0, NCHA), 3.96 (1H, d, J
15.0, NCHB), 3.99 (1H, q, J 6.9, C(a)H), 4.49 (2H, AB sys-
tem, JAB 11.9, OCH2Ph), 7.20–7.46 (15H, m, Ph); dC
(125 MHz, CDCl3) 18.6, 24.1, 25.8, 34.9, 45.4, 46.3, 50.8,
53.1, 57.9, 73.0, 126.7, 126.8, 127.5, 127.6, 128.2, 128.4,
138.9, 142.2, 144.3, 170.4; m/z (CI+) 457 ([M+H]+, 100%).
butyldimethylsilyloxy)butanoate 31 and 32. BuLi (2.5 M
inhexanes, 0.46 mL, 1.14 mmol),(R)-N-benzyl-N-(a-methyl-
benzyl)amine (248 mg, 1.17 mmol) in THF (20 mL), 12
(200 mg, 0.73 mmol) in THF (10 mL) and MeI (0.23 mL,
3.67 mmol) were reacted according to general procedure 2
and gave a 50:50 mixture of 31:32. Chromatography (eluent
30–40 ꢁC petrol/Et2O 100:1) gave 31 as a colourless oil (first
to elute, 56.8 mg, 16%), a mixed fraction containing 31 and
32 as a colourless oil (second to elute, 88 mg, 24%), and 32
as a colourless oil (third to elute, contaminated withw12%
20, 34.8 mg).
Data for 31: [a]D27 +0.3 (c 1.0, CHCl3); nmax (film) 1725; dH
(400 MHz, CDCl3) 0.09 (3H, s, SiMeA), 0.12 (3H, s, SiMeB),
0.92 (3H, d, J 7.0, C(2)Me), 0.97 (9H, s, SiCMe3), 1.41
(OCMe3), 1.44 (3H, d, J 7.0, C(a)Me), 2.51–2.58 (1H, m,
C(2)H), 3.01–3.05 (1H, m, C(3)H), 3.82–3.87 (2H, m,
C(4)H2), 3.91 (1H, d, J 14.1, NCHA), 4.05 (1H, d, J 14.1,
NCHB), 4.13 (1H, q, J 6.8, C(a)H), 7.19–7.36 (10H, m,
Ph); dC (100 MHz, CDCl3) ꢀ5.6, ꢀ5.5, 16.6, 16.7, 18.2,
26.0, 28.0, 41.2, 51.6, 56.9, 59.7, 62.7, 79.7, 126.5, 127.9,
128.0, 128.9, 129.0, 141.6, 145.0, 175.8; m/z (ESI+) 498
([M+H]+, 100%); HRMS (ESI+) C30H48NO3Si ([M+H]+)
requires 498.3403; found 498.3414.
3.2.14. (3S,aR)-1-(Pyrrolidin-10-yl)-3-[N-benzyl-N-
(a-methylbenzyl)amino]-4-(tert-butyldimethylsilyloxy)-
butan-1-one 30. BuLi (2.5 M in hexanes, 0.43 mL, 1.07
mmol), (R)-N-benzyl-N-(a-methylbenzyl)amine (233 mg,
1.10 mmol) in THF (20 mL) and 28 (187 mg, 0.69 mmol)
in THF (10 mL) were reacted according to general proce-
dure 1. Chromatography (eluent EtOAc/hexane 2:1) gave
30 as a colourless oil (177 mg, 54%); Rf 0.29 (EtOAc/hexane
2:1); C29H44N2O2Si requires C, 72.45; H, 9.2; N, 5.8%;
found C, 72.5; H, 9.5; N, 5.6%; [a]2D1 +8.4 (c 2.0, CHCl3);
nmax (film) 1641; dH (500 MHz, CDCl3) 0.01 (3H, s, SiMeA),
0.03 (3H, s, SiMeB), 0.87 (9H, s, SiCMe3), 1.39 (3H, d, J 6.9,
C(a)Me), 1.74–1.78 (4H, m, N(CH2CH2)2), 2.07 (1H, dd, J
15.0, 5.5, C(2)HA), 2.38 (1H, dd, J 15.0, 7.6, C(2)HB),
2.93–3.41 (4H, m, N(CH2CH2)2), 3.52–3.58 (1H, m,
C(3)H), 3.68 (2H, dd, J 10.0, 5.1, C(4)H2), 3.77 (1H, dd, J
10.0, 5.6, C(4)H2), 3.79 (1H, d, J 14.9, NCHA), 3.94 (1H,
d, J 14.9, NCHB), 3.98 (1H, q, J 7.0, C(a)H), 7.17–7.47
(10H, m, Ph); dC (125 MHz, CDCl3) ꢀ5.7, 18.0, 18.7,
24.1, 25.8, 25.8, 34.3, 45.4, 46.2, 50.8, 54.7, 57.8, 65.3,
126.6, 126.7, 128.0, 128.1, 128.2, 128.4, 142.4, 144.5,
170.6; m/z (CI+) 481 ([M+H]+, 100%), 375 (48), 335 (35),
231 (36), 105 (23), 91 (25).
Data for 32: nmax (film) 1727; dH (400 MHz, CDCl3) 0.06
(3H, s, SiMeA), 0.07 (3H, s, SiMeB), 0.92 (9H, s, SiCMe3),
1.01 (3H, d, J 6.9, C(2)Me), 1.37 (3H, d, J 7.0, C(a)Me),
1.46 (OCMe3), 2.65–2.73 (1H, m, C(2)H), 3.22–3.26 (1H,
m, C(3)H), 3.72–3.80 (3H, m, C(4)H2, NCHA), 4.03 (1H,
d, J 14.6, NCHB), 4.13 (1H, q, J 6.7, C(a)H), 7.17–7.34
(10H, m, Ph); dC (100 MHz, CDCl3) ꢀ5.8, ꢀ5.6, 14.9,
18.0, 18.1, 25.9, 28.1, 42.5, 51.2, 59.2, 61.0, 62.2,
79.6, 126.3, 126.4, 127.7, 128.0, 128.8, 142.0, 144.7,
175.5; m/z (ESI+) 498 ([M+H]+, 100%); HRMS
(ESI+) C30H48NO3Si ([M+H]+) requires 498.3403; found
498.3399.
3.3.2. Ethyl (2S,3S,aR)- and ethyl-(2R,3S,aR)-3-[N-ben-
zyl-N-(a-methylbenzyl)amino]-4-(tert-butyldimethylsilyl-
oxy)-2-methylbutanoate 33 and 34. Tandem procedure:
BuLi (2.5 M in hexanes, 0.94 mL, 2.34 mmol), (R)-N-
benzyl-N-(a-methylbenzyl)amine (511 mg, 2.42 mmol) in
THF (20 mL), 9 (368 mg, 1.51 mmol) in THF (10 mL) and
MeI (0.14 mL, 2.17 mmol) were reacted according to
general procedure 2 and gave a 60:40 mixture of 33:34.
Chromatography (eluent hexane/EtOAc 20:1) gave 33 as
a colourless oil (first to elute, 207 mg, 30%) and 36 as a
colourless oil (second to elute, 138 mg, 19%).
3.3. General procedure 2 for tandem lithium amide
conjugate addition and enolate alkylation
BuLi (2.5 M in hexanes, 1.55 equiv) was added dropwise via
syringe to a stirred solution of (R)-N-benzyl-N-(a-methyl-
benzyl)amine (1.6 equiv) in THF at ꢀ78 ꢁC. After stirring
for 30 min a solution of the requisite a,b-unsaturated car-
bonyl compound (1.0 equiv) in THF at ꢀ78 ꢁC was added
dropwise via cannula. After stirring for a further 2 h at
ꢀ78 ꢁC the reaction mixture was quenched with the requi-
site electrophile and allowed to warm to rt over 12 h. The re-
action mixture was concentrated in vacuo and the residue
was partitioned between DCM and 10% aq citric acid. The
organic layer was separated and the aqueous layer was ex-
tracted twice with DCM. The combined organic extracts
were washed sequentially with satd aq NaHCO3 and brine,
dried and concentrated in vacuo.
Data for 33: Rf 0.34 (hexane/EtOAc 20:1); [a]2D3 ꢀ6.5 (c 1.7,
CHCl3); C28H43NO3Si requires C, 71.6; H, 9.2; N, 3.0%;
found C, 71.95; H, 9.4; N, 2.9%; nmax (film) 1722; dH
(500 MHz, CDCl3) 0.04 (3H, s, SiMeA), 0.08 (3H, s, SiMeB),
0.92 (9H, s, SiCMe3), 0.93 (3H, obsc d, C(2)Me), 1.20 (3H, t,
J 7.2, OCH2Me), 1.41 (3H, d, J 6.8, C(a)Me), 2.66 (1H, dq,
J 9.5, 7.0, C(2)H), 2.98–3.04 (1H, m, C(3)H), 3.79–4.13
(7H, m, C(4)H2, C(a), OCH2Me), 7.17–7.34 (10H, m, Ph);
dC (125 MHz, CDCl3) ꢀ5.9, ꢀ5.8, 14.0, 15.8, 16.2, 18.1,
25.8, 40.2, 51.4, 56.8, 59.7, 60.0, 62.5, 126.8,
126.9, 128.0, 128.2, 128.3, 129.2, 141.6, 144.9, 176.6; m/z
(ESI+) 470 ([M+H]+, 46%), 324 (100), 220 (38), 105 (46),
91 (70).
3.3.1. tert-Butyl (2R,3S,aR)- and tert-butyl (2S,3S,aR)-2-
methyl-3-[N-benzyl-N-(a-methylbenzyl)amino]-4-(tert-

5866
E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
Data for 34: Rf 0.29 (hexane/EtOAc 20:1); [a]2D0 ꢀ16.8 (c
1.3, CHCl3); C28H43NO3Si requires C, 71.6; H, 9.2; N,
3.0%; found C, 71.7; H, 9.5; N, 2.9%; nmax (film) 1723; dH
(500 MHz, CDCl3) 0.07 (3H, s, SiMeA), 0.09 (3H, s, SiMeB),
0.92 (9H, s, SiCMe3), 1.03 (3H, d, J 6.9, C(2)Me), 1.14 (3H,
t, J 7.1, OCH2Me), 1.38 (3H, d, J 6.9, C(a)Me), 2.85 (1H, dq,
J 9.4, 6.9, C(2)H), 3.12–3.20 (1H, m, C(3)H), 3.73–4.11
(7H, m, C(4)H2, C(a)H, OCH2Me), 7.17–7.36 (10H, m,
Ph); dC (125 MHz, CDCl3) ꢀ5.9, ꢀ5.8, 13.9, 14.7, 16.5,
18.1, 25.8, 41.2, 51.3, 57.5, 60.0, 60.6, 61.3, 126.6, 126.8,
128.0, 128.2, 128.3, 129.2, 141.6, 144.9, 176.2; m/z (ESI+)
470 ([M+H]+, 52%), 324 (100), 220 (38), 105 (43), 91 (71).
100%); HRMS (ESI+) C27H42NO3Si ([M+H]+) requires
456.2934; found 456.2917.
Stepwise procedure: BuLi (0.14 mL, 0.34 mmol) was added
dropwise to a solution of di-iso-propylamine (36.1 mg,
0.36 mmol) in THF (5 mL) at 0 ꢁC. After 1 h the LDA solu-
tion was added to a solution of 19 (75.0 mg, 0.17 mmol) in
THF (5 mL) at ꢀ78 ꢁC. The reaction mixture was stirred
for 2 h before being quenched with MeI (0.06 mL,
0.85 mmol), then after 3 h at ꢀ78 ꢁC the reaction was al-
lowed to warm slowly to rt overnight. The resultant solution
was poured into brine (25 mL), extracted with Et2O (3ꢂ
25 mL), dried and concentrated in vacuo to give a 25:75
mixture of 35/36 as a pale yellow oil (80 mg, quant).
Stepwise procedure: BuLi (0.79 mL, 1.0 mmol) was added
dropwise to a solution of di-iso-propylamine (106 mg,
1.05 mmol) in THF (5 mL) at 0 ꢁC. After 1 h the LDA solu-
tion was added to a solution of 18 (228 mg, 0.50 mmol) in
THF (5 mL) at ꢀ78 ꢁC. The reaction mixture was stirred
for 2 h before being quenched with MeI (156 mL,
2.50 mmol), then after 3 h at ꢀ78 ꢁC the reaction was al-
lowed to warm slowly to rt overnight (18 h). The resultant
solution was poured into brine (25 mL), extracted with
Et2O (3ꢂ25 mL), dried and concentrated in vacuo to give
a 25:75 mixture of 35/36 as a pale yellow oil (245 mg,
quant).
3.3.4. Ethyl (2S,3S,aR)-2-benzyl-3-[N-benzyl-N-(a-meth-
ylbenzyl)amino]-4-(tert-butyldimethylsilyloxy)butanoate
37. BuLi (2.5 M in hexanes, 0.84 mL, 2.09 mmol), (R)-N-
benzyl-N-(a-methylbenzyl)amine (456 mg, 2.16 mmol) in
THF (20 mL), 9 (329 mg, 1.35 mmol) in THF (10 mL) and
BnBr (0.64 mL, 5.4 mmol) were reacted according to
general procedure 2 and gave a 71:29 mixture of 37/38.
Chromatography (eluent hexane/EtOAc 20:1) gave 37 as
a colourless oil (first to elute, 60 mg, 8%), and a mixture
of 37 and 38 as a colourless oil (second to elute, 332 mg,
44%).
3.3.3. Methyl (2S,3S,aR)- and methyl (2R,3S,aR)-2-
methyl-3-[N-benzyl-N-(a-methylbenzyl)amino]-4-(tert-
butyldimethylsilyloxy)butanoate 35 and 36. Tandem
procedure: BuLi (2.5 M in hexanes, 0.27 mL, 0.67 mmol),
(R)-N-benzyl-N-(a-methylbenzyl)amine (147 mg, 0.70
mmol) in THF (20 mL), 11 (100 mg, 0.43 mmol) in THF
(10 mL) and MeI (0.14 mL, 2.17 mmol) were reacted ac-
cording to general procedure 2 and gave a 16:53:31 mixture
of 19/35/36. Chromatography (eluent 30–40 ꢁC petrol/Et2O
200:1) gave 35 as a colourless oil (first to elute, 58.4 mg,
30%), and 36 as a colourless oil (second to elute, contami-
nated withw23% 19, 61.4 mg).
Data for 37: Rf 0.36 (hexane/EtOAc 20:1); [a]2D1 +32.6 (c 1.4,
CHCl3); C34H47NO3Si requires C, 74.8; H, 8.7; N, 2.6%;
found C, 74.7; H, 8.3; N, 3.0%; nmax (film) 1720; dH
(500 MHz, CDCl3) 0.06 (3H, s, SiMeA), 0.09 (3H, s, SiMeB),
0.87 (3H, t, J 7.1, OCH2Me), 0.94 (9H, s, SiCMe3), 1.47 (3H,
d, J 6.8, C(a)Me), 2.13 (1H, dd, J 13.5, 11.9, C(2)CHA), 2.76
(1H, ddd, J 13.5, 9.4, 4.0, C(2)H), 3.10–3.20 (2H, m, C(3)H,
C(2)CHB), 3.45–4.19 (7H, m, C(4)H2, C(a)H, OCH2Me),
6.87–7.42 (15H, m, Ph); dC (125 MHz, CDCl3) ꢀ5.8,
ꢀ5.7, 13.8, 16.6, 18.2, 26.0, 37.4, 49.3, 51.7, 57.5, 59.8,
59.9, 62.7, 126.1, 127.0, 128.3, 128.4, 128.5, 129.1, 129.3,
140.3, 141.6, 145.2, 175.1; m/z (ESI+) 546 ([M+H]+,
100%), 400 (56), 302 (75), 181 (87), 91 (65).
Data for 35: [a]D21 ꢀ10.5 (c 1.2, CHCl3); vmax (film) 1736,
1603; dH (400 MHz, CDCl3) 0.05 (3H, s, SiMeA), 0.09
(3H, s, SiMeB), 0.93 (9H, s, SiCMe3), 0.94 (3H, obsc d,
C(2)Me), 1.42 (3H, d, J 6.9, C(a)Me), 2.63–2.73 (1H, m,
C(2)H), 3.00–3.04 (1H, m, C(3)H), 3.57 (3H, s, OMe),
3.81 (1H, d, J 14.2, NCHA), 3.82–3.90 (2H, m, C(4)H2),
4.04 (1H, d, J 14.1, NCHB), 4.10 (1H, q, J 6.8, C(a)H),
7.19–7.35 (10H, m, Ph); dC (125 MHz, CDCl3) ꢀ5.9,
ꢀ5.8, 15.7, 16.0, 18.1, 25.7, 40.1, 51.1, 51.2, 56.7, 59.6,
62.3, 126.5, 126.6, 127.8, 127.9, 128.0, 128.8, 141.2, 144.5,
176.5; m/z (ESI+) 456 ([M+H]+, 100%); HRMS (ESI+)
C27H42NO3Si ([M+H]+) requires 456.2934; found 456.2934.
3.3.5. Ethyl (2S,3S,aR)-2-allyl-3-[N-benzyl-N-(a-methyl-
benzyl)amino]-4-(tert-butyldimethylsilyloxy)butanoate
39. BuLi (2.5 M in hexanes, 0.82 mL, 2.06 mmol), (R)-N-
benzyl-N-(a-methylbenzyl)amine (450 mg, 2.13 mmol) in
THF (20 mL), 9 (325 mg, 1.33 mmol) in THF (10 mL) and
allyl bromide (0.23 mL, 2.66 mmol) were reacted according
to general procedure 2 and gave a 77:23 mixture of 39/40.
Chromatography (eluent hexane/EtOAc 25:1) gave 39 as
a colourless oil (first to elute, 194 mg, 30%), and a mixture
of 39 and 40 as a colourless oil (second to elute, 165 mg,
25%).
Data for 36: vmax (film) 1738; dH (500 MHz, CDCl3) 0.08
(3H, s, SiMeA), 0.10 (3H, s, SiMeB), 0.92 (9H, s, SiCMe3),
1.03 (3H, d, J 7.0, C(2)Me), 1.39 (3H, d, J 7.0, C(a)Me),
2.89–2.95 (1H, m, C(2)H), 3.13 (1H, ddd, J 9.5, 4.3, 3.3,
C(3)H), 3.45 (3H, s, OMe), 3.77 (1H, d, J 14.5, NCHA),
3.77–3.81 (1H, obsc dd, C(4)HA), 3.90 (1H, dd, J 10.8,
3.0, C(4)HB), 4.06 (1H, d, J 14.5, NCHB), 4.10 (1H, q,
J 7.0, C(a)H), 7.17–7.36 (10H, m, Ph); dC (125 MHz,
CDCl3) ꢀ5.4, ꢀ5.2, 15.2, 16.6, 18.6, 26.3, 41.6, 51.6,
51.7, 57.6, 61.0, 61.7, 126.8, 127.0, 128.2, 128.4, 128.5,
129.4, 141.6, 145.0, 176.6; m/z (ESI+) 456 ([M+H]+,
Data for 39: Rf 0.28 (hexane/EtOAc 25:1); [a]2D0 +11.0 (c 1.1,
CHCl3); C30H45NO3Si requires C, 72.7; H, 9.15; N, 2.9%;
found C, 72.4; H, 9.2; N, 2.6%; nmax (film) 1721; dH
(500 MHz, CDCl3) 0.06 (3H, s, SiMeA), 0.08 (3H, s, SiMeB),
0.93 (9H, s, SiCMe3), 1.18 (3H, t, J 7.1, OCH2Me), 1.43 (3H,
d, J 6.9, C(a)Me), 1.75–1.86 (1H, m, C(2)CHA), 2.45–2.61
(2H, m, C(2)H, C(2)CHB), 3.03–3.09 (1H, m, C(3)H),
3.78–4.13 (7H, m, C(4)H2, C(a)H, OCH2Me), 4.80–4.86
(2H, m, CH]CH2), 5.37–5.50 (1H, m, CH]CH2), 7.19–
7.33 (10H, m, Ph); dC (125 MHz, CDCl3) ꢀ5.9, 14.2, 16.3,

E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
5867
18.1, 25.9, 35.1, 46.5, 51.4, 57.3, 58.9, 59.9, 62.5, 116.1,
127.0, 128.3, 129.2, 136.0, 141.5, 145.0, 175.1; m/z (ESI+)
496 ([M+H]+, 88%), 350 (100), 246 (55), 105 (59), 91 (53).
m, C(4)H2), 3.68 (3H, s, OMe), 3.81 (1H, q, J 6.5, C(a)H),
7.21–7.25 (1H, m, Ph), 7.29–7.32 (4H, m, Ph); dC
(125 MHz, CDCl3) ꢀ5.7, ꢀ5.6, 11.9, 18.1, 24.4, 25.7,
39.9, 51.2, 55.6, 58.1, 63.0, 126.7, 126.5, 128.2, 146.1,
176.3; m/z (ESI+) 366 ([M+H]+, 100%); HRMS (ESI+)
C20H36NO3Si ([M+H]+) requires 366.2464; found 366.2461.
3.3.6. Methyl (3S,aR)-3-(N-a-methylbenzylamino)-4-
(tert-butyldimethylsilyloxy)butanoate 41. CAN (394 mg,
0.72 mmol) was added to a solution of 19 (151 mg,
0.34 mmol) in MeCN/H2O (v/v 5:1; 6 mL) and the resultant
solution allowed to stir at rt for 2 h. Satd aq NaHCO3 and
Et2O were added, the organic layer separated and the aque-
ous layer extracted with Et2O. The combined organic
extracts were dried, filtered and concentrated in vacuo to fur-
nish the crude product. Chromatography (eluent 30–40 ꢁC
petrol/Et2O 10:1) gave 41 as a colourless oil (71.8 mg,
60%); [a]2D1 ꢀ22.3 (c 1.3, CHCl3); nmax (film) 3343, 1739,
1603; dH (500 MHz, CDCl3) ꢀ0.01 (3H, s, SiMeA), 0.00
(3H, s, SiMeB), 0.87 (9H, s, SiCMe3), 1.34 (3H, d, J 6.5,
C(a)Me), 1.89 (1H, br s, NH), 2.43–2.50 (2H, m, C(2)H2),
2.95 (1H, app quintet, J 5.3, C(3)H), 3.47–3.53 (2H, m,
C(4)H2), 3.66 (3H, s, OMe), 3.88 (1H, q, J 6.7, C(a)H),
7.21–7.25 (1H, m, Ph), 7.30–7.33 (4H, m, Ph); dC
(125 MHz, CDCl3) ꢀ5.7, ꢀ5.6, 18.1, 24.6, 25.7, 36.0, 51.2,
53.5, 55.1, 64.9, 126.7, 126.5, 128.3, 145.7, 172.7; m/z
(ESI+) 352 ([M+H]+, 100%), 248 (50); HRMS (ESI+)
C19H34NO3Si ([M+H]+) requires 352.2308; found 352.2305.
3.3.9. (3S,4S,aR)-N(1)-a-Methylbenzyl-3-methyl-4-(tert-
butyldimethylsilyloxymethyl)azetidin-2-one 44. Com-
pound 43 (28.7 mg, 0.079 mmol) was dissolved in Et2O
(2 mL) and the solution cooled to 0 ꢁC. MeMgBr (3 M in
Et2O, 0.03 mL, 0.086 mmol) was added dropwise and the re-
sultant solution stirred for 30 min at 0 ꢁC before the addition
of satd aq NH4Cl. The organic layer was separated and the
aqueous layer extracted with Et2O. The combined organic
extracts were dried and concentrated in vacuo. Chromato-
graphy (eluent 30–40 ꢁC petrol/Et2O/Et3N 50:50:1) gave
a clear, colourless oil 44 (19.0 mg, 73%); [a]2D3 +6.9 (c 0.5,
CHCl3); nmax (film) 1749; dH (500 MHz, CDCl3) 0.00 (3H,
s, SiMeA), 0.01 (3H, s, SiMeB), 0.87 (9H, s, SiCMe3), 1.21
(3H, d, J 7.4, C(3)Me), 1.62 (3H, d, J 7.1, C(a)Me), 3.17
(1H, qd, J 7.5, 5.6, C(3)H), 3.49 (1H, app q, J 5.8, C(4)H),
3.65 (1H, app d, J 0.7, C(4)CHA), 3.66 (1H, app d, J 1.3,
C(4)CHB), 4.94 (1H, q, J 7.1, C(a)H), 7.23–7.37 (5H, m,
Ph); dC (125 MHz, CDCl3) ꢀ5.7, 8.7, 18.0, 19.4, 25.7,
45.6, 51.5, 55.8, 62.4, 127.3, 127.0, 128.4, 140.5, 170.9;
m/z (ESI+) 334 ([M+H]+, 100%); HRMS (ESI+)
C19H32NO2Si ([M+H]+) requires 334.2202; found 334.2199.
3.3.7. (4S,aR)-N(1)-a-Methylbenzyl-4-(tert-butyldi-
methylsilyloxymethyl)azetidin-2-one 42. Compound 41
(35 mg, 0.100 mmol) was dissolved in Et2O (2 mL) and
the solution cooled to 0 ꢁC. MeMgBr (3 M in Et2O,
0.04 mL, 0.110 mmol) was added dropwise and the resultant
solution stirred for 30 min at 0 ꢁC before the addition of satd
aq NH4Cl. The organic layer was separated and the aqueous
layer extracted with Et2O. The combined organic extracts
were dried and concentrated in vacuo. Chromatography
(eluent 30–40 ꢁC petrol/Et2O/Et3N 50:50:1) gave 42 as a col-
ourless oil (30.9 mg, 97%); [a]2D1 ꢀ23.0 (c 0.9, CHCl3); nmax
(film) 1751; dH (500 MHz, CDCl3) 0.01 (3H, s, SiMeA), 0.02
(3H, s, SiMeB), 0.88 (9H, s, SiCMe3), 1.63 (3H, d, J 7.5,
C(a)Me), 2.64 (1H, dd, J 14.7, 2.3, C(3)HA), 2.83 (1H,
dd, J 14.4, 4.8, C(3)HB), 3.47–3.51 (1H, m, C(4)H), 3.62
(2H, app qd, J 11.0, 4.9, C(4)CH2), 4.96 (1H, q, J 6.8,
C(a)H), 7.26–7.29 (1H, m, Ph), 7.33–7.38 (4H, m, Ph); dC
(125 MHz, CDCl3) ꢀ5.8, ꢀ5.7, 18.1, 19.2, 25.6, 38.4,
51.6, 52.3, 127.4, 127.0, 128.4, 140.3, 166.7; m/z (ESI+)
352 ([M+MeOH+H]+, 100%), 320 (20); HRMS (ESI+)
C18H30NO2Si ([M+H]+) requires 320.2046; found 320.2043.
3.3.10. Methyl (2R,3S,aR)-2-methyl-3-(N-a-methylben-
zylamino)-4-(tert-butyldimethylsilyloxy)butanoate 45.
CAN (162 mg, 0.295 mmol) was added to a solution of 36
(64 mg, contaminated with w23% 19) in MeCN/H2O (v/v
5:1; 3 mL) and the resultant solution allowed to stir at rt
for 2 h. Satd aq NaHCO3 and Et2O were added, the organic
layer separated and the aqueous layer reextracted with Et2O.
The combined organic extracts were dried, filtered and con-
centrated in vacuo. Chromatography (eluent 30–40 ꢁC pet-
rol/Et2O 10:1) furnished 45 as a colourless oil (20.6 mg,
62%); [a]2D2 ꢀ18.5 (c 0.8, CHCl3); nmax (film) 3448, 3346,
1739, 1602; dH (500 MHz, CDCl3) 0.03 (3H, s, SiMeA), 0.01
(3H, s, SiMeB), 0.85 (9H, s, SiCMe3), 1.15 (3H, d, J 6.9,
C(2)Me), 1.29 (3H, d, J 6.5, C(a)Me), 1.75 (1H, br s, NH),
2.72 (1H, app quintet, J 7.1, C(2)H), 2.79–2.83 (1H, m,
C(3)H), 3.47–3.50 (2H, m, C(4)H2), 3.68 (3H, s, OMe),
3.81 (1H, q, J 6.5, C(a)H), 7.21–7.25 (1H, m, Ph), 7.29–
7.32 (4H, m, Ph); dC (125 MHz, CDCl3) ꢀ5.8, ꢀ5.7, 13.3,
18.1, 23.9, 25.7, 41.4, 51.2, 55.7, 58.5, 61.3, 126.7, 126.4,
128.2, 146.3, 176.2; m/z (ESI+) 366 ([M+H]+, 100%);
HRMS (ESI+) C20H36NO3Si ([M+H]+) requires 366.2464;
found 366.2461.
3.3.8. Methyl (2S,3S,aR)-2-methyl-3-(N-a-methylbenzyl-
amino)-4-(tert-butyldimethylsilyloxy)butanoate 43. CAN
(147 mg, 0.267 mmol) was added to a solution of 35
(58.0 mg, 0.127 mmol) in MeCN/H2O (v/v 5:1; 3 mL) and
the resultant solution allowed to stir at rt for 2 h. Satd aq
NaHCO3 and Et2O were added, the organic layer separated
and the aqueous layer extracted with Et2O. The combined or-
ganic extracts were dried, filtered and concentrated in vacuo.
Chromatography (eluent 30–40 ꢁC petrol/Et2O 10:1) gave
43 as a colourless oil (28.7 mg, 62%); [a]2D2 +34.7 (c 0.7,
CHCl3); nmax (film) 3447, 3345, 1737, 1602; dH (500 MHz,
CDCl3) ꢀ0.03 (3H, s, SiMeA), ꢀ0.01 (3H, s, SiMeB), 0.85
(9H, s, SiCMe3), 1.15 (3H, d, J 6.9, C(2)Me), 1.29 (3H, d,
J 6.5, C(a)Me), 1.75 (1H, br s, NH), 2.72 (1H, app quintet,
J 7.1, C(2)H), 2.79–2.83 (1H, m, C(3)H), 3.46–3.51 (2H,
3.3.11. (3R,4S,aR)-N(1)-a-Methylbenzyl-3-methyl-4-
(tert-butyldimethylsilyloxymethyl)azetidin-2-one 46.
Compound 45 (20.6 mg, 0.056 mmol) was dissolved in
Et2O (2 mL) and the solution cooled to 0 ꢁC. MeMgBr
(3 M in Et2O, 0.03 mL, 0.086 mmol) was added dropwise
and the resultant solution stirred for 30 min at 0 ꢁC before
the addition of satd aq NH4Cl. The organic layer was sepa-
rated and the aqueous layer extracted with Et2O. The com-
bined organic extracts were dried and concentrated in
vacuo. Chromatography (eluent 30–40 ꢁC petrol/Et2O/Et3N
50:50:1) furnished 46 as a colourless oil (13.7 mg, 73%);

5868
E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
[a]2D3 +48.7 (c 0.4, CHCl3); nmax (film) 1750; dH (500 MHz,
CDCl3) 0.01 (3H, s, SiMeA), 0.02 (3H, s, SiMeB), 0.88 (9H,
s, SiCMe3), 1.20 (3H, d, J 7.4, C(3)Me), 1.61 (3H, d, J 7.1,
C(a)Me), 2.84 (1H, qd, J 7.3, 2.1, C(3)H), 3.04 (1H, app td,
J 4.8, 2.0, C(4)H), 3.58–3.65 (2H, m, C(4)CH2), 4.99 (1H,
q, J 7.1, C(a)H), 7.26–7.35 (5H, m, Ph); dC (125 MHz,
CDCl3) ꢀ5.6, 12.6, 18.2, 19.2, 25.8, 46.4, 51.0, 60.7, 63.9,
127.5, 127.1, 128.6, 140.3, 170.6; m/z (ESI+) 334 ([M+H]+,
100%); HRMS (ESI+) C19H32NO2Si ([M+H]+) requires
334.2202; found 334.2208.
(3ꢂ25 mL), dried and concentrated in vacuo to give
a 65:35 mixture of 35/36 as a pale yellow oil (63 mg, quant).
3.3.13. (2S,3S,aR)-1-(Pyrrolidin-10-yl)-2-benzyl-3-[N-
benzyl-N-(a-methylbenzyl)amino]-4-(tert-butyldimeth-
ylsilyloxy)butan-1-one 49. BuLi (2.5 M in hexanes,
0.69 mL, 1.72 mmol), (R)-N-benzyl-N-(a-methylbenzyl)-
amine (375 mg, 1.78 mmol) in THF (20 mL), 28 (300 mg,
1.11 mmol) in THF (10 mL) and BnBr (0.90 mL,
7.57 mmol) were reacted according to general procedure 2
and gave a 86:14 mixture of 49/50. Chromatography (eluent
hexane/EtOAc 4:1) gave 49 as a colourless oil (first to elute,
57 mg, 9%) and a mixture of 49 and 50 as a colourless oil
(second to elute, 355 mg, 56%).
3.3.12. (2S,3S,aR)- and (2R,3S,aR)-1-(Pyrrolidin-10-yl)-
3-[N-benzyl-N-(a-methylbenzyl)amino]-4-(tert-butyldi-
methylsilyloxy)-2-methylbutan-1-one 47 and 48. Tandem
procedure: BuLi (2.5 M in hexanes, 0.66 mL, 1.66 mmol),
(R)-N-benzyl-N-(a-methylbenzyl)amine (362 mg, 1.71
mmol) in THF (20 mL), 28 (289 mg, 1.07 mmol) in THF
(10 mL) and MeI (0.65 mL, 10.4 mmol) were reacted ac-
cording to general procedure 2 and gave a 66:34 mixture of
47/48. Chromatography (eluent hexane/EtOAc 4:1) gave
47 as a colourless oil (first to elute, 223 mg, 42%), a mixture
of 47 and 48 as a colourless oil (second to elute, 60 mg, 11%)
and 48 as a colourless oil (third to elute, 97 mg, 19%).
Data for 49: Rf 0.12 (hexane/EtOAc 6:1); C36H50N2O2Si re-
quires C, 75.7; H, 8.8; N, 4.9%; found C, 75.4; H, 8.9; N,
4.7%; [a]2D1 +29.4 (c 1.6, CHCl3); nmax (film) 1622; dH
(500 MHz, CDCl3) 0.04 (3H, s, SiMeA), 0.07 (3H, s, SiMeB),
0.91 (9H, s, SiCMe3), 1.21–1.63 (4H, m, N(CH2CH2)2), 1.46
(3H, d, J 6.9, C(a)Me), 1.90–1.98, 2.93–3.01, 3.12–3.22
(5H, m, C(2)CHA, N(CH2CH2)2), 2.18 (1H, t, J 12.3,
C(2)CHA), 2.77 (1H, ddd, J 12.3, 9.6, 3.4, C(2)H), 3.29
(1H, ddd, J 9.6, 4.0, 3.0, C(3)H), 3.87–3.94 (3H, m,
C(4)H2, NCHAHBPh), 4.17 (1H, q, J 6.9, C(a)H), 4.24
(1H, d, J 14.4, NCHAHBPh), 6.90–7.50 (15H, m, Ph); dC
(125 MHz, CDCl3) ꢀ5.6, 16.7, 18.3, 23.9, 25.4, 26.0, 37.8,
45.1, 45.8, 47.1, 52.1, 58.5, 60.0, 62.9, 126.0, 126.9,
128.0, 128.2, 128.5, 129.1, 129.3, 140.8, 142.1, 145.1,
173.1; m/z (ESI+) 571 ([M+H]+, 100%), 465 (17), 425 (21).
Data for 47: Rf 0.12 (hexane/EtOAc 4:1); C30H46N2O2Si re-
quires C, 72.8; H, 9.4; N, 5.7%; found C, 72.9; H, 9.6; N,
5.4%; [a]2D0 +21.3 (c 1.3, CHCl3); nmax (film) 1641; dH
(500 MHz, CDCl3) 0.03 (3H, s, SiMeA), 0.07 (3H, s, SiMeB),
0.88 (3H, d, J 7.0, C(2)Me), 0.91 (9H, s, SiCMe3), 1.41 (3H,
d, J 6.9, C(a)Me), 1.73–1.91 (4H, m, N(CH2CH2)2), 2.69
(1H, dq, J 9.7, 6.9, C(2)H), 3.14–3.42 (5H, m, C(3)H,
N(CH2CH2)2), 3.80–4.13 (5H, m, C(4)H2, C(a)H, NCH2Ph),
7.15–7.39 (10H, m, Ph); dC (125 MHz, CDCl3) ꢀ5.8, 15.6,
16.0, 18.2, 24.2, 25.8, 26.0, 37.7, 45.4, 46.1, 51.9, 57.8, 59.6,
62.7, 126.7, 127.1, 128.1, 128.2, 129.1, 142.0, 145.0, 174.9;
m/z (ESI+) 495 ([M+H]+, 100%), 403 (26), 389 (49), 368
(23), 349 (63), 245 (40), 105 (23), 91 (19).
3.3.14. (2S,3S,aR)-1-(Pyrrolidin-10-yl)-2-allyl-3-[N-
benzyl-N-(a-methylbenzyl)amino]-4-(tert-butyldi-
methylsilyloxy)butan-1-one 51. BuLi (2.5 M in hexanes,
0.40 mL, 1.01 mmol), (R)-N-benzyl-N-(a-methylbenzyl)-
amine (220 mg, 1.04 mmol) in THF (20 mL), 28 (175 mg,
0.65 mmol) in THF (10 mL) and allyl bromide (0.11 mL,
1.3 mmol) were reacted according to general procedure 2
and gave a 80:20 mixture of 51/52. Chromatography (eluent
hexane/EtOAc 4:1) gave 51 as a colourless oil (first to elute,
114 mg, 34%) and a mixture of 51 and 52 as a colourless oil
(second to elute, 68 mg, 20%).
Data for 48: Rf 0.06 (hexane/EtOAc 4:1); C30H46N2O2Si re-
quires C, 72.8; H, 9.4; N, 5.7%; found C, 72.7; H, 9.5; N,
5.6%; [a]2D3 ꢀ16.4 (c 1.4, CHCl3); nmax (film) 1630; dH
(500 MHz, CDCl3) 0.05 (3H, s, SiMeA), 0.07 (3H, s, SiMeB),
0.92 (9H, s, SiCMe3), 1.02 (3H, d, J 6.9, C(2)Me), 1.42 (3H,
d, J 6.9, C(a)Me), 1.58–1.78 (4H, m, N(CH2CH2)2), 2.67–
3.49 (5H, m, C(3)H, N(CH2CH2)2), 2.85 (1H, dq, J 9.2,
6.9, C(2)H), 3.69 (1H, dd, J 10.9, 4.8, C(4)HA), 3.80 (1H,
dd, J 10.9, 2.4, C(4)HB), 3.88 (1H, d, J 15.4, NCHAHBPh),
4.09 (1H, d, J 15.4, NCHAHBPh), 4.22 (1H, q, J 6.9,
C(a)H), 7.13–7.37 (10H, m, Ph); dC (125 MHz, CDCl3)
ꢀ6.0, ꢀ5.8, 14.6, 19.2, 18.0, 24.1, 25.8, 25.8, 39.0, 45.6,
45.8, 50.8, 59.3, 60.9, 61.0, 126.3, 126.4, 127.9, 128.4,
142.3, 145.7, 174.4; m/z (ESI+) 495 ([M+H]+, 87%), 389
(38), 245 (38), 105 (63), 91 (100).
Data for 51: Rf 0.31 (hexane/EtOAc 3:1); C32H48N2O2Si re-
quires C, 73.8; H, 9.3; N, 5.4%; found C, 73.8; H, 9.5; N,
5.3%; [a]2D0 +20.7 (c 2.6, CHCl3); nmax (film) 1625; dH
(500 MHz, CDCl3) 0.07 (3H, s, SiMeA), 0.08 (3H, s, SiMeB),
0.93 (9H, s, SiCMe3), 1.43 (3H, d, J 6.9, C(a)Me), 1.65–1.93
(5H, m, C(2)CHA N(CH2CH2)2), 2.53–2.61 (2H, m, C(2)H,
C(2)CHB), 3.13–3.42 (5H, m, C(3)H, N(CH2CH2)2), 3.81–
3.91, 4.08–4.14 (5H, m, C(4)H2, C(a)H, NCH2Ph), 4.83
(1H, dd, J 9.9, 2.3, CH]CHAHB), 4.89 (1H, dd, J 17.0,
2.2, CH]CHAHB), 5.41–5.50 (1H, m, CH]CH2), 7.18–
7.37 (10H, m, Ph); dC (125 MHz, CDCl3) ꢀ5.6, 17.4,
18.2, 24.3, 25.8, 26.0, 35.7, 44.3, 45.3, 46.4, 51.9, 59.1,
59.8, 62.8, 116.2, 126.8, 126.9, 128.2, 128.3, 128.7, 128.9,
129.1, 136.7, 142.1, 145.3, 173.5; m/z (ESI+) 521
([M+H]+, 87%), 415 (41), 375 (78), 271 (43), 105 (100),
91 (72).
Stepwise procedure: BuLi (0.22 mL, 0.34 mmol) was added
dropwise to a solution of di-iso-propylamine (36.1 mg,
0.36 mmol) in THF (5 mL) at 0 ꢁC. After 1 h the LDA solu-
tion was added to a solution of 30 (55 mg, 0.11 mmol) in
THF (5 mL) at ꢀ78 ꢁC. The reaction mixture was stirred
for 2 h before being quenched with MeI (36 mL,
0.57 mmol), then after 3 h at ꢀ78 ꢁC the reaction was al-
lowed to warm slowly to rt overnight. The resultant solution
was poured into brine (25 mL), extracted with Et2O
3.3.15. Methyl (2S,3S,aS)-2-hydroxy-3-[N-benzyl-N-(a-
methylbenzyl)amino]-4-(tert-butyldimethylsilyloxy)but-
anoate 53. BuLi (2.5 M in hexanes, 2.7 mL, 6.74 mmol),

E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
5869
(S)-N-benzyl-N-(a-methylbenzyl)amine
(1.47 g,
6.96
3.3.18. (4S,aR)-4-[N-Benzyl-N-(a-methylbenzyl)amino]-
dihydrofuran-2(3H)-one 4. Compound 18 (910 mg,
2.00 mmol) in THF (5 mL) was treated with TBAF (948 mg,
3.00 mmol) and the solution stirred at 20 ꢁC (6 h). The mix-
ture was poured into satd aq NaHCO3 (50 mL), extracted
with Et2O (3ꢂ25 mL), dried and the solvent evaporated.
Chromatography (eluent hexane/EtOAc 4:1) gave 4 as a col-
ourless oil (456 mg, 77%); Rf 0.33 (hexane/EtOAc 4:1);
C19H21NO2$HCl requires C, 68.8; H, 6.7; N, 4.2%; found
C, 68.7; H, 7.0; N, 4.35%; mp (HCl salt) 90–110 ꢁC (dec);
[a]2D2 +74.7 (c 2.3, CHCl3); nmax (film) 1775; dH
(500 MHz, CDCl3) 1.41 (3H, d, J 7.0, C(a)Me), 2.21 (1H,
dd, J 18.0, 7.8, C(3)HA), 2.28 (1H, dd, J 18.0, 8.2,
C(3)HB), 3.72 (2H, AB system, JAB 14.7, NCH2Ph), 3.86–
3.97 (2H, m, C(3)H, C(a)H), 4.17 (1H, dd, J 9.4, 7.6,
C(5)HA), 4.37 (1H, dd, J 9.4, 6.6, C(5)HB), 7.24–7.41
(10H, m, Ph); dC (125 MHz, CDCl3) 16.3, 31.8, 50.5, 54.3,
57.5, 71.7, 127.5, 127.6, 127.9, 128.3, 128.7, 128.8, 140.2,
142.3, 176.6; m/z (ESI+) 296 ([M+H]+, 53%), 192 (100),
105 (22), 91 (25).
mmol) in THF (20 mL), 11 (1.0 g, 4.35 mmol) in THF
(10 mL) and (+)-CSO (4.20 g, 18.4 mmol) were reacted
according to general procedure 2. Chromatography (eluent
30–40 ꢁC petrol/Et2O 20:1) gave 53 as a colourless oil
(1.55 g, 78%); Rf 0.25 (30–40 ꢁC petrol/Et2O 20:1); [a]2D1
+25.0 (c 1.2, CHCl3); nmax (film) 3512, 1736; dH
(400 MHz, CDCl3) 0.02 (3H, s, SiMeA), 0.03 (3H, s, SiMeB),
0.88 (SiCMe3), 1.37 (3H, d, J 6.8, C(a)Me), 2.98 (1H, d, J
6.5, OH), 3.55–3.62 (1H, m, C(3)H), 3.68 (3H, s, OMe),
3.70–3.76 (1H, m, C(4)HA), 3.83 (1H, d, J 15.2, NCHB),
3.87–4.02 (3H, m, C(2)H, C(4)HB, C(a)H), 4.14 (1H, d, J
15.2, NCHB), 7.16–7.48 (10H, m, Ph); dC (100 MHz,
CDCl3) ꢀ5.6, 18.0, 18.4, 25.9, 51.5, 52.2, 57.7, 59.6, 61.8,
71.2, 126.6, 127.0, 127.9, 128.1, 128.2, 128.3, 141.6,
142.8, 174.8; m/z (ESI+) 458 ([M+H]+, 100%); HRMS
(ESI+) C26H40NO4Si ([M+H]+) requires 458.2727; found
458.2708.
3.3.16. Methyl (S)-3-(benzoylamino)-4-benzoyloxybut-
anoate 54. The hydrochloride salt of 14 (204 mg,
0.45 mmol), as a solution in acetic acid (3 mL), was treated
with palladium on charcoal (10%, 55 mg) and heated at
50 ꢁC for 24 h under an atmosphere of H2 (4 bar). The mix-
ture was filtered through CeliteÒ and the solvent evaporated.
The residue was suspended in DCM (5 mL) at 0 ꢁC and
treated with pyridine (182 mL, 2.25 mmol) and benzoyl
chloride (157 mL, 1.35 mmol). The solution was allowed
to warm to rt and stirred for 72 h before the solvent was evap-
orated. Chromatography (eluent Et2O) and recrystallisation
(EtOAc/hexane) gave 54 as fine, colourless needles
(72 mg, 47%); Rf 0.53 (Et2O); C19H19NO5 requires C,
66.85; H, 5.6; N, 4.1%; found C, 66.7; H, 5.3; N, 4.0%;
mp 145–146 ꢁC; [a]D20 +7.3 (c 0.5, CHCl3); nmax (film)
1725, 1665, 1516; dH (500 MHz, CDCl3) 2.80 (2H, dd, J
16.4, 5.8, C(2)HA), 2.87 (1H, dd, J 16.4, 4.8, C(2)HB),
3.70 (3H, s, OMe), 4.52 (1H, dd, J 11.4, 5.3, C(4)HA),
4.62 (1H, dd, J 11.4, 5.7, C(4)HB), 4.84–4.94 (1H, m,
C(3)H), 7.35 (1H, d, J 7.7, NH), 7.42–8.06 (10H, m, Ph);
dC (125 MHz, CDCl3) 35.2, 46.0, 51.9, 65.5, 127.0, 128.4,
128.6, 129.7, 131.6, 133.2, 134.2, 166.6, 166.9, 173.3; m/z
(ESI+) 342 ([M+H]+, 63%), 220 (100), 105 (45).
3.3.19. Methylation of (4S,aR)-4-[N-benzyl-N-(a-methyl-
benzyl)amino]dihydrofuran-2(3H)-one 4. To a solution of
4 (100 mg, 0.34 mmol) at ꢀ70 ꢁC was added KHMDS
(0.75 M in PhMe, 0.54 mL, 0.41 mmol) and the yellow solu-
tion stirred for 90 min before it was treated with MeI (64 mL,
1.02 mmol). The mixture was stirred at ꢀ70 ꢁC for 2.5 h and
then quenched with pH 7 phosphate buffer before being al-
lowed to warm to rt. The biphasic solution was extracted
with Et2O (3ꢂ5 mL), the combined extracts dried and the
solution filtered through a plug of silica gel. The solvent
was evaporated to give a pale yellow oil (105 mg), which
1
was analysed by H NMR spectroscopy and GC–MS, and
found to contain a mixture of 4,56 and 59 in the ratio
23:71:6.
3.3.20. (3S,4S,aR)-4-[N-Benzyl-N-(a-methylbenzyl)-
amino]-3-methyldihydrofuran-2(3H)-one 56. A mixture
of 33 and 34 (1:2.5 mixture, 235 mg, 0.50 mmol) in THF
(5 mL) was treated with TBAF (948 mg, 3.00 mmol) and
the solution stirred at 20 ꢁC (6 h). The mixture was poured
into satd aq NaHCO3 (50 mL), extracted with Et2O (3ꢂ
25 mL), dried and the solvent evaporated. Chromatography
(eluent hexane/EtOAc 4:1) gave 56 as a colourless oil
(110 mg, 71%); Rf 0.53 (hexane/EtOAc 4:1); C20H23NO2$
HCl requires C, 69.45; H, 7.0; N, 4.05%; found C, 69.7;
H, 6.7; N, 3.8%; mp (HCl salt) 170–173 ꢁC (dec); [a]D21
ꢀ38.7 (c 0.9, CHCl3); nmax (film) 1772; dH (500 MHz,
CDCl3) 1.01 (3H, d, J 7.1, C(3)Me), 1.38 (3H, d, J 6.9,
C(a)Me), 2.50 (1H, dq, J 9.7, 7.1, C(3)H), 3.35 (1H, ddd,
J 9.7, 8.2, 8.0, C(4)H), 3.81 (1H, d, J 14.4, NCHA), 3.94
(1H, d, J 14.4, NCHB), 3.99 (1H, q, J 6.9, C(a)H), 4.18
(1H, dd, J 9.2, 7.8, C(5)HA), 4.25 (1H, dd, J 9.2, 8.4,
C(5)HB), 7.24–7.43 (10H, m, Ph); dC (125 MHz, CDCl3)
13.5, 15.6, 37.0, 49.8, 57.1, 61.1, 67.7, 127.1, 127.6, 128.1,
128.4, 139.8, 142.9, 177.9; m/z (ESI+) 310 ([M+H]+, 100%),
206 (38), 105 (33), 91 (28).
3.3.17. (S)-4-(N-Benzoylamino)dihydrofuran-2(3H)-one
55. Compound 54 (18 mg, 0.053 mmol) was suspended in
MeOH (2 mL) and H2O (0.1 mL), treated with lithium hy-
droxide (45 mg, 1.06 mmol) and stirred at 20 ꢁC (18 h). Af-
ter evaporation of the solvent the residue was suspended in
DCM (5 mL) and treated with TFA (1 mL), the suspension
was stirred at 20 ꢁC (48 h) and the solvents evaporated.
The residue was treated with satd aq NaHCO3 (25 mL), ex-
tracted with EtOAc (3ꢂ15 mL), the combined extracts dried
and the solvent evaporated to give 55 as a white solid
(11.5 mg). The material was further purified by filtration
of an EtOAc solution through a plug of silica and crystalli-
sation by the addition of hexane to give 55 as fine white nee-
dles (9 mg, 83%); [a]D21 ꢀ100.8 (c 0.4, CHCl3); mp 129 ꢁC;
dH (500 MHz, CDCl3) 2.63 (1H, dd, J 18.1, 2.4, C(3)HA),
2.99 (1H, dd, J 18.1, 8.0, C(3)HB), 4.39 (1H, dd, J 9.9,
1.8, C(5)HA), 4.63 (1H, dd, J 9.9, 5.9, C(5)HB), 4.94–4.97
(1H, m, C(4)H), 6.24 (1H, br s, NH), 7.42–7.47 (2H, m,
Ph), 7.52–7.57 (1H, m, Ph), 7.79–7.82 (2H, m, Ph); m/z
206 ([M+H]+, 100%).
3.3.21. Benzylation of (4S,aR)-4-[N-benzyl-N-(a-methyl-
benzyl)amino]dihydrofuran-2(3H)-one 4. To a solution of
4 (100 mg, 0.34 mmol) at ꢀ70 ꢁC was added KHMDS
(0.75 M in PhMe, 0.54 mL, 0.41 mmol) and the yellow solu-
tion stirred for 90 min before it was treated with BnBr

5870
E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
(121 mL, 1.02 mmol). The mixture was stirred at ꢀ70 ꢁC for
(97 mg, 0.33 mmol) in THF (5 mL) was cooled to ꢀ70 ꢁC
and treated with KHMDS (0.75 M in PhMe, 2.19 mL,
1.64 mmol), and after 1 h the enolate was quenched with
MeI (205 mL, 3.30 mmol) and the reaction allowed to
warm slowly to 20 ꢁC over 19 h. The white suspension
was poured into satd aq NaHCO3 (25 mL), the solution
extracted with Et2O (3ꢂ15 mL) and the combined extracts
dried. Evaporation of the solvent and purification by
filtration through silica (Et2O) and recrystallisation from
EtOAc/hexane (ꢀ30 ꢁC) gave 59 as large colourless needles
(67 mg, 64%); C21H25NO2 requires C, 78.0; H, 7.8; N,
4.3%; found C, 78.0; H, 7.9; N, 4.2%; mp 140–143 ꢁC;
[a]2D1 ꢀ35.4 (c 0.7, CHCl3); nmax (KBr) 1768; dH
(500 MHz, CDCl3) 0.93 (3H, s, C(2)MeA), 1.29 (3H, s,
C(2)MeB), 1.32 (3H, d, J 6.9, C(a)Me), 3.21 (1H, dd, J
6.4, 3.2, C(4)H), 3.79 (2H, AB system, JAB 13.8, NCH2),
3.96 (1H, q, J 6.9, C(a)H), 4.37 (1H, dd, J 10.2, 3.2,
C(5)HA), 4.51 (1H, dd, J 10.2, 6.4, C(5)HB), 7.24–7.52
(10H, m, Ph); dC (125 MHz, CDCl3) 11.7, 18.9, 25.3,
41.7, 50.6, 54.9, 61.4, 66.9, 127.3, 127.7, 128.1, 128.3,
128.9, 138.9, 143.4, 182.6; m/z (ESI+) 324 ([M+H]+,
20%), 280 (34), 220 (100), 105 (29), 91 (38).
5 h and then treated as before to give a pale yellow oil
(134 mg), which was analysed by H NMR spectroscopy
1
and GC–MS, and found to contain a mixture of 4, 57 and
60 in the ratio 22:67:11.
3.3.22. (3S,4S,aR)-3-Benzyl-4-[N-benzyl-N-(a-methyl-
benzyl)amino]dihydrofuran-2(3H)-one 57. Compound
49 (160 mg, 0.28 mmol) in acetonitrile (3 mL) was treated
with 48% aq HF (0.5 mL) and 6 M aq HCl (0.5 mL) and
the solution stirred at 20 ꢁC for 10 days. The mixture was ba-
sified to pH>10 with satd aq NaHCO3, the solution extracted
with Et2O (4ꢂ4 mL) and the combined extracts dried. Chro-
matography (eluent DCM) gave 57 as a colourless oil
(90 mg, 83%); Rf 0.56 (DCM); C26H27NO2 requires C,
81.0; H, 7.1; N, 3.6%; found C, 81.1; H, 7.0; N, 3.75%;
[a]2D2 ꢀ64.3 (c 0.7, CHCl3); nmax (film) 1769; dH
(500 MHz, CDCl3) 1.29 (3H, d, J 6.9, C(a)Me), 2.66 (1H,
dd, J 13.4, 5.4, C(3)CHA), 2.93 (1H, dd, J 13.4, 4.8,
C(3)CHB), 2.84 (1H, ddd, J 6.9, 5.4, 4.9, C(3)H), 3.54
(1H, ddd, J 7.8, 6.9, 6.0, C(4)H), 3.78–3.84 (3H, m,
NCH2Ph, C(5)HA), 3.91 (1H, q, J 6.9, C(a)H), 4.19 (1H,
dd, J 9.7, 6.0, C(5)HB), 6.72–7.40 (15H, m, Ph); dC
(125 MHz, CDCl3) 15.1, 34.0, 44.7, 49.9, 57.1, 68.3,
126.9, 127.4, 127.6, 128.2, 128.6, 128.7, 128.8, 129.7,
137.6, 140.1, 143.4, 178.2; m/z (ESI+) 386 ([M+H]+,
100%), 282 (63), 105 (46), 91 (64).
3.3.26. (4S,aR)-3,3-Dibenzyl-4-[N-benzyl-N-(a-methyl-
benzyl)amino]dihydrofuran-2(3H)-one 60. Compound 4
(137 mg, 0.46 mmol) in THF (5 mL) was cooled to ꢀ70 ꢁC
and treated with KHMDS (0.75 M in PhMe, 3.72 mL,
2.79 mmol), and after 1 h the enolate was quenched with
BnBr (547 mL, 4.60 mmol) and the reaction allowed to
warm slowly to 20 ꢁC over 19 h. The white suspension
was poured into satd aq NaHCO3 (25 mL), the solution ex-
tracted with Et2O (3ꢂ15 mL) and the combined extracts
dried. Evaporation of the solvent and purification by chro-
matography (eluent hexane/EtOAc 8:1), followed by
crystallisation from Et2O/pentane (ꢀ30 ꢁC) gave 60 as a
micro-crystallinewhite solid (150 mg, 69%); Rf 0.27 (hexane/
EtOAc 8:1); C33H33NO2 requires C, 83.3; H, 7.0; N,
2.95%; found C, 83.55; H, 7.3; N, 2.8%; [a]2D0 ꢀ113.5 (c
1.0, CHCl3); mp 125–127 ꢁC; nmax (KBr) 1760; dH
(500 MHz, CDCl3) 1.20 (3H, d, J 6.9, C(a)Me), 1.99 (1H,
3.3.23. Allylation of (4S,aR)-4-[N-benzyl-N-(a-methyl-
benzyl)amino]dihydrofuran-2(3H)-one 4. To a cooled
(ꢀ70 ꢁC) solution of 4 (100 mg, 0.34 mmol) was added
KHMDS (0.75 M in PhMe, 0.55 mL, 0.41 mmol) and the
yellow solution stirred for 90 min before it was treated with
allyl bromide (88 mL, 1.02 mmol). The mixture was treated
as before to give a pale yellow oil (103 mg), which was ana-
lysed by 1H NMR spectroscopy and GC–MS, and found to
contain a mixture of 4, 58 and 61 in the ratio 30:60:20.
3.3.24. (3S,4S,aR)-3-Allyl-4-[N-benzyl-N-(a-methylben-
zyl)amino]dihydrofuran-2(3H)-one 58. Compound 51
(40 mg, 0.08 mmol) in acetonitrile (3 mL) was treated with
48% aq HF (0.5 mL) and 6 M aq HCl (0.5 mL) and the solu-
tion stood at 20 ꢁC for 10 days. The mixture was basified to
pH>10 with satd aq NaHCO3, the solution extracted with
Et2O (4ꢂ4 mL) and the combined extracts dried. Purifica-
tion by filtration through silica (Et2O) gave 58 as a colourless
oil (24 mg, 93%); C22H25NO2 requires C, 78.8; H, 7.5; N,
4.2%; found C, 78.5; H, 7.55; N, 4.3%; [a]2D2 ꢀ41.3 (c 1.2,
CHCl3); nmax (film) 1772; dH (500 MHz, CDCl3) 1.35 (3H,
d, J 6.9, C(a)Me), 2.09–2.18 (1H, m, C(3)CHA), 2.29–2.38
(2H, m, C(3)CHB), 2.61 (1H, dt, J 7.9, 5.5, C(3)H), 3.50–
3.57 (1H, m, C(4)H), 3.81 (1H, d, J 14.3, NCHA), 3.90
(1H, d, J 14.3, NCHB), 3.95 (1H, q, J 6.9, C(a)H), 4.19–
4.31 (2H, m, C(5)H2), 4.64 (1H, dd, J 17.0, 1.3,
CH]CHAHB), 4.85 (1H, d, J 10.1, CH]CHAHB), 5.34–
5.47 (1H, m, CH]CH2), 7.24–7.44 (10H, m, Ph); dC
(125 MHz, CDCl3) 15.2, 32.3, 42.8, 50.0, 57.1, 57.4, 68.1,
118.4, 127.2, 127.3, 127.8, 128.3, 128.4, 128.5, 133.2,
139.8, 143.1, 177.2; m/z (ESI+) 335 ([M+H]+, 30%), 232
(100), 212 (58), 105 (46), 91 (61).
d,
J 13.3, C(3)CHAHBPh), 2.57 (1H, d, J 13.3,
C(3)CHAHBPh), 2.70 (1H, dd, J 10.3, 7.2, C(4)H), 3.20
(1H, d, J 14.3, C(3)CHAHBPh), 3.37 (1H, d, J 14.3,
C(3)CHAHBPh), 3.65 (1H, d, J 6.5, C(5)HA), 3.77 (1H, d,
J 14.1, NCHA), 3.87 (1H, d, J 14.1, NCHB), 4.05 (1H, q, J
6.9, C(a)H), 4.14 (1H, d, J 11.5, C(5)HB), 6.75–7.55 (20H,
m, Ph); dC (125 MHz, CDCl3) 11.8, 37.9, 43.9, 49.5, 51.3,
55.9, 59.6, 66.4, 126.7, 127.5, 127.9, 128.2, 128.6, 128.9,
129.0, 129.8, 131.8, 136.5, 137.6, 138.7, 143.2, 182.0; m/z
(ESI+) 476 ([M+H]+, 67%), 372 (75), 212 (38), 108 (59),
91 (100).
3.3.27. (4S,aR)-3,3-Diallyl-4-[N-benzyl-N-(a-methylben-
zyl)amino]dihydrofuran-2(3H)-one 61. Compound
4
(129 mg, 0.44 mmol) in THF (5 mL) was cooled to ꢀ70 ꢁC
and treated with KHMDS (0.75 M in PhMe, 3.50 mL,
2.62 mmol), and after 1 h the enolate was quenched with
allyl bromide (381 mL, 4.40 mmol) and the reaction allowed
to warm slowly to 20 ꢁC over 19 h. The white suspension
was poured into satd aq NaHCO3 (25 mL), the solution
extracted with Et2O (3ꢂ15 mL) and the combined extracts
dried. Evaporation of the solvent and purification by
chromatography (eluent hexane/EtOAc 8:1), followed by
3.3.25. (4S,aR)-3,3-Dimethyl-4-[N-benzyl-N-(a-methyl-
benzyl)amino]dihydrofuran-2(3H)-one 59. Compound 4

E. Abraham et al. / Tetrahedron 63 (2007) 5855–5872
5871
crystallisation from Et2O/pentane (ꢀ30 ꢁC) gave 61 as a
micro-crystalline white solid (115 mg, 70%); Rf 0.22
(hexane/EtOAc 8:1); C25H29NO2 requires C, 80.0; H, 7.8;
N, 3.7%; found C, 80.1; H, 7.95; N, 3.55%; mp 94–95 ꢁC;
[a]2D0 ꢀ38.1 (c 0.9, CHCl3); vmax (KBr) 1765; dH
(500 MHz, CDCl3) 1.29 (3H, d, J 6.9, C(a)Me), 2.06 (2H,
d, J 7.3, C(3)CH2CH]CH2), 2.40 (1H, dd, J 14.6, 6.6,
C(3)CHA), 2.50 (1H, dd, J 14.6, 7.7, C(3)CHB), 3.47 (1H,
dd, J 6.4, 1.8, C(4)H), 3.73 (1H, d, J 13.9, NCHAHBPh),
3.85 (1H, d, J 13.9, NCHAHBPh), 3.98 (1H, q, J 6.9,
C(a)H), 4.36 (1H, dd, J 10.4, 1.8, C(5)HA), 4.54 (1H, dd,
J 10.4, 6.4, C(5)HB), 4.83–5.08 (4H, m, 2ꢂCH]CH2),
5.23–5.37 (1H, m, CH]CH2), 5.59–5.73 (1H, m,
CH¼CH2), 7.25–7.50 (10H, m, Ph); dC (125 MHz, CDCl3)
11.4, 33.9, 39.1, 47.3, 51.2, 55.4, 58.7, 66.8, 118.4, 119.6,
127.5, 127.8, 128.3, 128.7, 128.9, 131.8, 134.1, 138.7,
142.6, 180.7; m/z (ESI+) 375 ([M+H]+, 85%), 272 (100),
105 (53), 91 (78).
CDCl3) 12.4, 50.5, 55.2, 65.1, 67.3, 127.6, 127.6, 127.9,
128.6, 128.9, 129.0, 137.6, 141.7, 176.0; m/z (ESI+) 312
([M+H]+, 100%); HRMS (ESI+) C19H21NO3Na ([M+Na]+)
requires 334.1419; found 334.1418.
Data for syn-63: Rf 0.11 (30–40 ꢁC petrol/Et2O 2:1); mp 77–
78 ꢁC; [a]D22 ꢀ19.4 (c 0.7, CHCl3); nmax (KBr) 3415, 1770;
dH (400 MHz, CDCl3) 1.46 (3H, d, J 7.2, C(a)Me), 3.73
(1H, d, J 15.5, NCHA), 3.76 (1H, m, C(3)H), 3.89 (1H, d,
J 15.5, NCHB), 3.95 (1H, d, J 8.6, C(4)HA), 4.18 (1H, m,
C(a)H), 4.22 (1H, d, J 8.6, C(4)HB), 4.34 (1H, d, J 9.9,
C(2)H), 7.25–7.49 (10H, m, Ph); dC (100 MHz, CDCl3)
16.3, 50.4, 58.8, 63.3, 67.6, 69.7, 127.1, 127.3, 127.7,
128.0, 128.3, 128.5, 140.7, 142.4, 176.1; m/z (ESI+) 312
([M+H]+, 100%); HRMS (ESI+) C19H21NO3Na ([M+H]+)
requires 334.1419; found 334.1426.
Desilylation of 53 with TBAF/AcOH: A solution of TBAF/
AcOH (1.5:1, 0.16 mL, 0.16 mmol) was added to a stirred
solution of 53 (50 mg, 0.11 mmol) in THF (5 mL) at
0 ꢁC and allowed to cool to rt. After stirring for 18 h, the
reaction mixture was diluted with DCM, washed with H2O
and dried. The solvents were removed in vacuo. Chromato-
graphy (eluent 30–40 ꢁC petrol/Et2O 2:1) gave syn-63
(30 mg, 76%).
3.3.28. (3S,4S)-3-Methyl-4-(N-benzoylamino)dihydro-
furan-2(3H)-one 62. Compound 56 (100 mg, 0.32 mmol),
as a solution in acetic acid (3 mL), was stirred vigorously
with palladium on charcoal (10%, 25 mg) while being
heated at 60 ꢁC for 24 h under an atmosphere of H2
(6 bar). The mixture was filtered through Celite and the sol-
vent evaporated. The residue was dissolved in EtOH/hexane
and the hydrochloride salt precipitated by the addition of
ethereal HCl. The resultant salt was azeotroped with PhMe
(10 mL), then suspended in DCM (2 mL) and treated with
pyridine (78 mL, 0.97 mmol) and benzoyl chloride (75 mL,
0.65 mmol). The solution was stirred at 20 ꢁC for 7 days be-
fore the solvent was evaporated. Chromatography (eluent
hexane/EtOAc 1:1) gave 62 as a white solid (41 mg, 58%);
Rf 0.33 (hexane/EtOAc 1:1); C12H13NO3 requires C, 65.7;
H, 6.0; N, 6.4%; found C, 66.0; H, 5.6; N, 6.1%; mp 177–
178 ꢁC; [a]2D0 ꢀ98.8 (c 0.3, CHCl3); nmax (KBr) 1780,
1669, 1519; dH (500 MHz, CDCl3) 1.43 (3H, d, J 7.3,
C(3)Me), 2.68 (1H, quintet, J 7.4, C(3)H), 4.11 (1H, dd, J
9.3, 6.5, C(5)HA), 4.72 (1H, dd, J 9.3, 7.0, C(5)HB), 4.54–
4.64 (1H, m, C(4)H), 6.31 (1H, br s, NH), 7.45–7.59 (3H,
m, Ph), 7.76–7.79 (2H, m, Ph); dC (125 MHz, CDCl3)
13.7, 40.8, 53.8, 70.7, 127.0, 128.8, 132.2, 133.3, 167.8,
177.4; m/z (ESI+) 220 ([M+H]+, 100%).
3.3.30. (2R,3S,aR)-1-(Pyrrolidin-10-yl)-2-methyl-3-[N-
benzyl-N-(a-methylbenzyl)amino]-4-hydroxybutan-1-
one anti-66. To a THF (2 mL) solution of 48 (194 mg,
0.39 mmol) was added TBAF (186 mg, 0.60 mmol) and
the solution allowed to stand at rt for 3 days before concen-
tration in vacuo. Chromatography (eluent Et2O/EtOAc 1:1)
gave anti-66 as a viscous oil (132 mg, 89%); Rf 0.31
(Et2O/EtOAc 1:1); C24H32N2O2 requires C, 75.75; H, 8.5;
N, 7.4%; found C, 75.6; H, 8.7; N, 7.1%; [a]2D0 ꢀ62.2 (c
1.9, EtOH) for 66$HCl; nmax (film) 3250, 1603; dH
(500 MHz, CDCl3) 1.16 (3H, d, J 7.3, C(2)Me), 1.38 (3H,
d, J 7.0, C(a)Me), 1.71–1.82 (4H, m, N(CH2CH2)2), 2.22–
3.38 (4H, m, N(CH2CH2)2), 2.38 (1H, qd, J 7.3, 2.8,
C(2)H), 3.52 (1H, td, J 5.8, 2.8, C(3)H), 3.71 (1H, dd, J
10.5, 6.0, C(4)HA), 3.82–3.95 (4H, m, C(4)HB, C(a)H),
4.35 (1H, br s, OH), 7.21–7.47 (10H, m, Ph); dC
(125 MHz, CDCl3) 12.8, 16.9, 24.1, 25.7, 40.4, 45.8, 45.9,
51.3, 56.0, 56.9, 60.8, 126.9, 127.2, 128.3, 128.4, 128.7,
141.0, 143.3, 175.9; m/z (ESI+) 310 ([Mꢀ70], 49%), 212
(45), 206 (100).
3.3.29. (3S,4S,aS)- and (3R,4S,aS)-3-Hydroxy-4-[N-ben-
zyl-N-(a-methylbenzyl)amino]dihydrofuran-2(3H)-one
syn-(3S,4S,aS)-63 and anti-(3S,4S,aS)-64. Desilylation of
53 with TBAF: TBAF (1.39 mL, 1.39 mmol) was added to
a stirred solution of 53 (430 mg, 0.93 mmol) in THF
(20 mL) at 0 ꢁC and allowed to warm to rt. After stirring
for 6 h, the reaction mixture was diluted with DCM, washed
with H2O, dried and concentrated in vacuo. Chromatography
(eluent 30–40 ꢁC petrol/Et2O 2:1) gave anti-64 as a colour-
less oil (first to elute, 70 mg, 24%) and syn-63 as a white
crystalline solid (second to elute, 150 mg, 40%).
Acknowledgements
The authors wish to acknowledge GlaxoSmithKline for
financial support (J.W.B.C.) and New College, Oxford for
a Junior Research Fellowship (A.D.S.).
References and notes
Data for anti-64: Rf 0.27 (30–40 ꢁC petrol/Et2O 2:1); [a]2D2
+6.3 (c 2.1, CHCl3); nmax (film) 3441, 1776; dH (400 MHz,
CDCl3) 1.43 (3H, d, J 6.8, C(a)Me), 3.66 (1H, d, J 13.3,
NCHA), 3.70–3.77 (2H, m, C(3)H, OH), 3.81 (1H, d,
J 13.3, NCHB), 4.01 (1H, d, J 8.2, C(2)H), 4.07 (1H, q,
J 6.8, C(a)H), 4.36–4.42 (1H, m, C(4)HA), 4.53–4.59 (1H,
m, C(4)HB), 7.19–7.44 (10H, m, Ph); dC (100 MHz,
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Davies, S. G.; Epstein, S. W.; Garner, A. C.; Ichihara, O.;
Smith, A. D. Tetrahedron: Asymmetry 2002, 13, 1555.
25. McGarvey, G. J.; Williams, J. M.; Hiner, R. N.; Matsubara, Y.;
Oh, T. J. Am. Chem. Soc. 1986, 108, 4943.
26. For leading manuscripts in this area, see Refs. 6a–c.
27. Dialkylated b-amino-g-butyrolactones have been shown to be
allosteric modulators of the GABA receptor; see: Hadri, A. E.;
€
Abouabdellah, A.; Thomet, U.; Baur, R.; Furtmuller, R.; Sigel,
E.; Sieghart, W.; Dodd, R. H. J. Med. Chem. 2002, 45, 2824.
28. The 3,4-anti configuration within lactones 57 and 58 was
assigned by analogy to that unambiguously confirmed within
56.
29. For related work see: Seebach, D.; Wasmuth, D. Helv. Chim.
Acta 1980, 63, 197; Frater, G. Helv. Chim. Acta 1979, 62, 2825.
30. It seems likely that epimerization of the lactone rather than the
ester is taking place as lactones are know to be relatively acidic;
for selected examples see: Brown, J. M.; Elliott, R. L.; Griggs,
C. G.; Helmchen, G.; Nill, G. Angew. Chem., Int. Ed. Engl.
1981, 20, 890; Helmchen, G.; Nill, G.; Flockerzi, D.;
Youssef, M. S. K. Angew. Chem., Int. Ed. Engl. 1979, 18, 62;
Meyers, A. I.; Yamamoto, Y.; Mihelich, E. D.; Bell, R. A.
J. Org. Chem. 1980, 45, 2792; Seebach, D.; Jacobi, A.;
Rueping, M.; Gademann, K.; Ernst, M.; Jaun, B. Helv. Chim.
Acta 2000, 83, 2115.
31. Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1996, 118,
13095; Smith, A. B., III; Chen, S. S.-Y.; Nelson, F. C.;
Reichert, R. C.; Salvatore, B. A. J. Am. Chem. Soc. 1995,
117, 12017; Davies, S. G.; Nicholson, R. L.; Smith, A. D.
Org. Biomol. Chem. 2004, 2, 3385; Davies, S. G.; Nicholson,
R. L.; Smith, A. D. Org. Biomol. Chem. 2005, 3, 348.
32. Vaino, A. R.; Szarek, W. A. Chem. Commun. 1996, 2351.
33. Shriver, D. F. The Manipulation of Air-Sensitive Compounds;
McGraw Hill: New York, NY, 1969.
17. Blanchette, M. A.; Choy, W.; Vavis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183.
18. Aldehyde 10 was prepared on a multigram scale from but-2-
ene-1,4-diol following literature procedures; see: Enders, D.;
Schusseler, T. Synthesis 2002, 2280; Hayes, M. P.; Hatala,
P. J.; Sherer, B. A.; Tong, X.; Zanatta, N.; Borer, P. N.
Tetrahedron 2001, 57, 1515.
34. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.