Double asymmetric induction as a mechanistic probe: The doubly diastereoselective conjugate addition of enantiopure lithium amides to enantiopure α,β-unsaturated esters and enantiopure α,β-unsaturated hydroxamates

Article abstract of DOI:10.1016/j.tet.2011.05.102

The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(α-methylbenzyl)amide to a range of enantiopure α,β-unsaturated esters [derived from Corey's 8-phenylmenthol chiral auxiliary] and enantiopure α,β-unsaturated hydroxamates [derived from our 'chiral Weinreb amide' auxiliary (S)-N-1-(1′-naphthyl)ethyl-O-tert- butylhydroxylamine] has been used as a mechanistic probe to determine the reactive conformations of these acceptors.

Full text of DOI:10.1016/j.tet.2011.05.102

Tetrahedron 67 (2011) 6382e6403
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Double asymmetric induction as a mechanistic probe: the doubly
diastereoselective conjugate addition of enantiopure lithium amides to
enantiopure
a,b-unsaturated esters and enantiopure a,b-unsaturated
hydroxamates
*
Stephen G. Davies , James A. Lee, Paul M. Roberts, James E. Thomson, Jingda Yin
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 March 2011
Received in revised form 12 May 2011
Accepted 23 May 2011
Available online 30 May 2011
The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(a-methyl-
benzyl)amide to a range of enantiopure
a
,b
-unsaturated esters [derived from Corey’s 8-phenylmenthol
chiral auxiliary] and enantiopure
a,b-unsaturated hydroxamates [derived from our ‘chiral Weinreb
amide’ auxiliary (S)-N-1-(10-naphthyl)ethyl-O-tert-butylhydroxylamine] has been used as a mechanistic
probe to determine the reactive conformations of these acceptors.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Lithium amide
Conjugate addition
Chiral auxiliary
Doubly diastereoselective
1. Introduction
diastereoselective ‘matched’ reaction pairing. These data, in
combination with the well established diastereofacial preference
Previous investigations from this laboratory have demonstrated
that the conjugate addition of enantiopure secondary lithium
observed upon addition of lithium N-benzyl-N-(
a-methylbenzyl)
amide 1 to achiral
a,b
-unsaturated esters and amides,1 allowed the
amides (derived from
esters represents a general and efficient synthetic protocol for the
synthesis of
-amino esters and their derivatives.1 This methodology
a
-methylbenzylamine) to
a
,
b
-unsaturated
anti-s-cis form of N-enoyl oxazolidin-2-one 2 to be identified as the
reactive conformation (Fig. 1).
We envisaged that double asymmetric induction could be
further exploited as a mechanistic probe to elucidate the reactive
conformation of other chiral a,b-unsaturated carbonyl compounds
upon conjugate addition. We proposed to investigate the dia-
stereoselectivity elicited upon conjugate addition of the antipodes
b
has found numerous applications, including the total syntheses
of natural products,2 molecular recognition phenomena3 and
resolution protocols4 and has been reviewed.5 For instance, we have
recently elaborated the use of double asymmetric induction as
a mechanistic probe to elucidate the reactive conformation of
enantiopure N-enoyl oxazolidin-2-ones upon the conjugate addition
of an enantiopure lithium amide.5,6 In this study, the doubly
diastereoselective conjugate additions of the antipodes of lithium
of lithium N-benzyl-N-(a-methylbenzyl)amide 1 to enantiopure
a,b-unsaturated carbonyl compounds, such as ester 5 [derived from
Corey’s 8-phenylmenthol chiral auxiliary 67] and hydroxamate 7
[derived from our ‘chiral Weinreb amide’ auxiliary (S)-N-1-(10-
naphthyl)ethyl-O-tert-butylhydroxylamine 88] (Fig. 2). We report
herein our findings within this area.
N-benzyl-N-(a-methylbenzyl)amide 1 to a range of enantiopure
N-enoyl oxazolidin-2-ones were investigated. For example, the
conjugate addition of (R)-1 to N-enoyl oxazolidin-2-one 2 gave 3
with relatively low diastereoselectivity (83:17 dr) representing
the doubly diastereoselective ‘mismatched’ pairing of chiral
reagents, whereas the corresponding addition of (S)-1 gave 4 as
a single diastereoisomer (>99:1 dr) representing the doubly
2. Results and discussion
2.1. Conjugate additions to chiral a,b-unsaturated esters
Corey’s 8-phenylmethol auxiliary 8 has shown considerable
versatility in synthesis9 and found use in, for example, nucleophilic
addition reactions,10 cycloadditions,11 intermolecular ene reactions,12
* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.102

S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
anti-s-cis reactive
6383
Ph
Ph
conformation
Ph
Ph
Bn
Ph
N
Li
(R)-1
Ph
N
Li
(S)-1
O
O
O
N
O
O
Ph
N
Ph
N
O
O
Ph
H
Ph
3, 83:17 dr
N
O
Ph
4, >99:1 dr
N
O
"mismatched"
"matched"
2
Bn
Bn
Reagent control
Substrate control
Fig. 1. The doubly diastereoselective conjugate addition of the antipodes of lithium N-benzyl-N-(a-methylbenzyl)amide 1 to enantiopure N-enoyl oxazolidin-2-one 2 in the
anti-s-cis reactive conformation.
8-Phenylmenthyl crotonate 9 and 8-phenylmenthyl cinnamate
18 were selected as model substrates for this investigation and were
therefore synthesised by coupling the requisite acid chlorides and
8-phenylmenthol 6. Thus, auxiliary 6 was prepared on a >10 g scale
in 36%overallyield from(þ)-(R)-pulegone21 according toa literature
procedure.22 Subsequent treatment of 6 with cinnamoyl chloride in
O
O
R
O
N
HO
6
5
Ph
Ph
€
the presence of Hunig’s base gave 18 in 56% isolated yield. However,
treatment of 6 with crotonoyl chloride under the same conditions
HN
OtBu
1-Nap
gave
isolated; subsequent isomerisation of 19 upon treatment with DBU
gave -unsaturated ester 9 in 65% yield and >99:1 dr (Scheme 2).
b,g-unsaturated ester 19 in 90% yield as the only product
R
1-Nap
OtBu
8
7
a,b
Fig. 2. Enantiopure a,b-unsaturated esters 5 [derived from Corey’s 8-phenylmenthol
chiral auxiliary 6] and enantiopure
a,b-unsaturated hydroxamates 7 [derived from
(S)-N-1-(10-naphthyl)ethyl-O-tert-butylhydroxylamine 8]. [1-Nap¼1-naphthyl].
(i)
O
oxidation reactions,13 reduction reactions,14 rearrangement
processes,15 photochemical/radical reactions16 and as a resolving
Ph
HO
O
agent.17
a,b-Unsaturated esters of this chiral alcohol have also
Ph
O
Ph
shown application as substrates in diastereoselective conjugate
addition reactions.18 One notable example reported by d’Angelo
and Maddaluno, however, describes the high pressure induced
18, 56%
6
(i)
conjugate addition of primary amines to chiral
a,b-unsaturated
esters, such as 9.19 The authors report that whilst moderate levels
of diastereoselectivity were obtained upon conjugate addition
of primary amines to 9 it is noteworthy that ‘the double diastereo-
differentiation phenomenon was not observed’ upon addition of
(ii)
O
O
Me
O
either (R)- or (S)-
finding is consistent with the poor diastereoselectivity observed
upon thermal addition of (S)- -methylbenzylamine 10 to methyl
crotonate, which has been reported to give a 54:46 epimeric
mixture of
-amino esters.20 In contrast, the conjugate addition of
a-methylbenzylamine 10 to 9 (Scheme 1). This
Ph
Ph
9, 65%, >99:1 dr
19, 90%
a
Scheme 2. Reagents and conditions: (i) RCOCl, iPr2NEt, THF, rt, 18 h; (ii) DBU, THF,
rt, 18 h.
b
secondary lithium amides, such as lithium N-benzyl-N-(a-methyl-
1H NMR spectroscopic analysis of 8-phenylmenthyl
saturated esters 9 and 18 and the corresponding methyl esters
suggests that the phenyl group of the auxiliary effectively shields
one face of the olefin.23 There are four conformations of an
a,b-un-
benzyl)amide 1 to a range of achiral
a,b
-unsaturated esters at ꢀ78 ꢁC
in THF has consistently been shown to proceed with extremely high
levels of diastereoselectivity (typically >95:5 dr).5 We therefore
proposed to use this reaction to identify the reactive conformations of
8-phenylmenthyl a,b-unsaturated esters upon the conjugate addition
of a lithium amide using the tool of double asymmetric induction.
8-phenylmenthyl
a,b-unsaturated ester where this shielding is
possible: two s-cis conformations 20A and 20B, and two s-trans
conformations 20C and 20D (Fig. 3).24 Upon conjugate addition, the
same product would arise from attack on the least hindered face of
both conformations 20A and 20D, and the other diastereoisomer
would result from attack on the least hindered face of both con-
formations 20B and 20C. Several enolate trapping studies following
the conjugate addition of lithium amides to both chiral6b and
R
(i)
O
NH
O
Me
O
Me
O
Ph
Ph
achiral25 substrates have concluded that the lithium (Z)-
b-amino
12-17
9
enolate arises from conjugate addition to the acceptor in an s-cis
reactive conformation. Assuming that these findings are consistent
with the conjugate addition of a lithium amide to 8-phenylmenthyl
a,b-unsaturated esters 9 and 18, either conformation 20A or 20B
will be the reactive conformation upon conjugate addition.
The doubly diastereoselective conjugate addition of both anti-
combined
RNH2
R
products dr yield (%)
(R)-10 (R)-CHMePh 12:13 75:25
(S)-10 (S)-CHMePh 14:15 80:20
60
60
90
11
Bn
16:17 80:20
Scheme 1. Reagents and conditions: (i) RNH2, MeOH, 15 kbar, 50 ꢁC, 24 h.
podes of lithium N-benzyl-N-(a-methylbenzyl)amide 1 to 9 and 18

6384
S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
O
O
O
R
O
R
O
20A
20B
O
O
O
R
R
20C
20D
Fig. 4. X-ray crystal structure of (3S,10R,20S,50R,
aS)-23 (some H atoms are omitted for
Fig. 3. Possible conformations of 20: s-cis 20A and 20B, and s-trans 20C and 20D.
clarity).
were next investigated. Thus, the conjugate additions of (S)-1 to
both 9 and 18 proceeded with high diastereoselectivity giving
23 and 24 in 98:2 and 95:5 dr, respectively; in both cases the
major diastereoisomeric products were isolated as single
diastereoisomers (>99:1 dr) after chromatographic purification.
Again, the configurations at C(3) within
were established unambiguously by a separate chemical synthesis
in each case. -Amino esters (R,R)-25 and (3S, R)-26 [obtained
from the conjugate addition of lithium amide (R)-1 to tert-butyl
crotonate and tert-butyl cinnamate, respectively]26 were treated
with TFA to give the corresponding carboxylic acids, which were
coupled with Corey’s auxiliary 6 via the intermediacy of the
corresponding acid chlorides. The spectroscopic properties, including
b-amino esters 29 and 30
b
a
The configurations at C(3) within
unambiguously established by a separate chemical synthesis in
each case: -amino esters (S,S)-25 and (3R, S)-26 [obtained
b-amino esters 23 and 24 were
b
a
from the conjugate addition of lithium amide (S)-1 to tert-butyl
crotonate and tert-butyl cinnamate, respectively]1a,26 were
treated with TFA to give the corresponding carboxylic acids, which
were coupled with Corey’s auxiliary 6 via the intermediacy of the
corresponding acid chlorides. The spectroscopic properties, including
specific rotation values, of the samples of b-amino esters 29 and 30
prepared in this manner were identical to the major diastereoisomers
arising from the conjugate addition of lithium amide (R)-1 to 9 and
18, providing unequivocal evidence of the sense of stereoinduction
observed in these reaction pairings (Scheme 4). The conjugate
additions of (S)-1 to both 9 and 18 therefore represent the doubly
diastereoselective ‘matched’ reaction pairings, and the conjugate
additions of (R)-1 to both 9 and 18 proceeded under the dominant
stereocontrol of the lithium amide reagent representing the doubly
diastereoselective ‘mismatched’ reaction pairings.
specific rotation values, of the samples of b-amino esters 23 and 24
prepared in this manner were identical to the major diastereoisomers
arising from the conjugate addition of lithium amide (S)-1 to 9 and
18, providing unequivocal evidence of the sense of stereoinduction
observed in these reactions (Scheme 3). Furthermore, the relative
configuration within 23 was also unambiguously assigned by
single crystal X-ray diffraction analysis,27 with the absolute
(3S,10R,20S,50R,
a
S)-configuration assigned relative to the known
Ph
configurations of both the (þ)-(R)-pulegone derived auxiliary 6
(i)
O
Ph
N
OLi
and the (S)-
a
-methylbenzyl stereocentre (Fig. 4).
R
O
R
O
Ph
Ph
(i)
Ph
O
Ph
N
OLi
9, R = Me
27, R = Me
28, R = Ph
18, R = Ph
R
O
R
O
R = Me, 88:12 dr
R = Ph, 83:17 dr
Ph
Ph
9, R = Me
21
, R = Me
, R = Ph
Ph
N
Ph
18, R = Ph
22
(ii), (iii)
R = Me, 98:2 dr
R = Ph, 95:5 dr
Ph
Ph
N
O
CO2tBu
R
R
O
Ph
N
Ph
(R,R)-25, R = Me, >99:1 dr
(3S, R)-26, R = Ph, >99:1 dr
29, R = Me, >99:1 dr
(i). 20%,a (ii). 46%
30, R = Ph, >99:1 dr
(i). 18%,a (ii). 55%
Ph
α
(ii)
Ph
Ph
N
O
t
CO2 Bu
R
R
O
Scheme 4. Reagents and conditions: (i) (R)-1, THF, ꢀ78 ꢁC, 2 h; (ii) TFA/CH2Cl2
(v/v 1:1), rt, 2 h, then (COCl)2, DMF, CH2Cl2, 0 ꢁC to rt, 1 h; (iii) 6, CH2Cl2, rt, 18 h [a
mixed fractions were also isolated, see Ref. 28].
(S,S)-25, R = Me, >99:1 dr
(3R, S)-26, R = Ph, >99:1 dr
, R = Me, >99:1 dr
23
Ph
α
(i). 71%, (ii). 61%
24, R = Ph, >99:1 dr
(i). 62%, (ii). 55%
In addition, the conjugate additions of achiral lithium dibenzyl-
amide 3129 and lithium N-isopropyl-N-benzylamide 324aec to these
substrates were also conducted to assess the extent of substrate
control in these systems. The conjugate additions of both achiral
lithium amides 31 and 32 to both 9 and 18 proceeded with the same
sense of stereoinduction and modest levels of diastereoselectivity
(up to 80:20 dr). In the case of addition of these lithium amides to
9 the major diastereoisomers were isolated in >99:1 dr, although
Scheme 3. Reagents and conditions: (i) (S)-1, THF, ꢀ78 ꢁC, 2 h; (ii) TFA/CH2Cl2
(v/v 1:1), rt, 2 h, then (COCl)2, DMF, CH2Cl2, 0 ꢁC to rt, 1 h then 6, CH2Cl2, rt, 18 h.
Upon conjugate addition of (R)-1 to both 9 and 18 lower levels
of diastereoselectivity were observed, giving 29 and 30 as the
major products in 88:12 and 83:17 dr, respectively; in both cases
the major diastereoisomeric products were isolated as single
diastereoisomers (>99:1 dr) after chromatographic purification.28

S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
6385
R2
R1
Bn
R2
R1
Bn
(i)
O
N
O
N
O
+
R1
O
O
O
Ph
Ph
Ph
A
B
9, R1 = Me
18, R1 = Ph
yield
of A (%)
yield
crude dr
(A:B)
Michael
lithium
amide
acceptor
R1
R2
A
B
of B (%)
9
9
31
32
Me Bn
Me iPr
33
34
37
38
78:22
72:28
25 (>99:1 dr) 10 (63:37 dr)
9a (>99:1 dr)
--
18
18
31
32
Ph
Ph
Bn
iPr
35
36
39
40
65:35
80:20
85 (65:35 dr)
78 (80:20 dr)
--
--
Scheme 5. Reagents and conditions: (i) LiNR2Bn, THF, ꢀ78 ꢁC, 2 h [a a mixed fraction was also isolated, see Ref. 30].
the addition products derived from 18 proved to be inseparable
and were therefore isolated as mixtures of C(3)-epimers
(Scheme 5).30
the stereodirecting phenyl group of the auxiliary in conformation
20B, although these data do not discount the possibility that
the formation of 29 and 30 may occur via preferential addition
of (R)-1 to 9 and 18 in an alternative conformation (Fig. 6).
In order to assign the configurations within
b-amino esters
33e40 the stereochemical outcomes of these reactions were next
correlated with the products arising from conjugate addition of
lithium amides (S)-1 and (R)-1 to 9 and 18. Thus, the N-benzyl and
2.3. Conjugate additions to chiral
hydroxamates
a,b-unsaturated
N-a-methylbenzyl groups within b-amino esters 23, 24, 29 and 30
were removed via hydrogenolysis in the presence of Pearlman’s
catalyst [Pd(OH)2/C] to give 41e44 in 61e98% yield as single
We have previously established that the alkylations of enolates
derived from N-1-(10-naphthyl)ethyl-O-tert-butylhydroxamates, such
as 49 proceed with high levels of diastereoselectivity (>95:5 dr) to
diastereoisomers (>99:1 dr) in each case.
b-Amino esters 41e44
were then treated with BnBr in the presence of K2CO3 at 100 ꢁC to
give access tothecorrespondingenantiopure a-stereogenicaldehydes
provide authentic samples of the N,N-dibenzyl substituted
esters 33, 35, 37 and 39 in 86e95% yield and >99:1 dr.
b
-amino
or ketones 52 in >95:5 er following treatment of the intermediate
hydroxamates 51 with either LiAlH4 or MeLi.8a,c A combination of
evidence gained through experimental observations (including
modification of the auxiliary structure), physical measurements, and
molecular mechanics calculations, was found to validate a ‘chiral
relay’31 mechanism, which was proposed to rationalise the observed
stereochemical outcome in these reactions.8b It was shown that
deprotonation of 49 with KHMDS leads to a non-chelated (Z)-enolate
50 with the oxygen atoms adopting an anti-periplanar conformation.
The configuration of the N-1-(10-naphthyl)ethyl group dictates the
position of the O-tert-butyl group and the configuration adopted by
the pyramidal nitrogen atom. Subsequentenolate alkylation occurs on
the face anti to both the O-tert-butyl group (steric control) and N-lone
pair (stereoelectronic control). Based on these alkylation studies we
b-Amino
esters 41e44 were also subjected to
a reductive alkylation
procedure to give single diastereoisomers of the N-isopropyl
substituted analogues 45e48 in 62e83% yield and >99:1 dr. Finally,
treatment of 45e48 with BnBr provided access to authentic samples
of the N-isopropyl-N-benzyl substituted b-amino esters 34, 36, 38
and 40 in 75e90% yield and >99:1 dr (Scheme 6). Furthermore, the
relative configuration within 33 was also unambiguously assigned
by single crystal X-ray diffraction analysis,27 with the absolute
(3S,10R,20S,50R)-configuration assigned relative to the known
configuration of the (þ)-(R)-pulegone derived auxiliary 6 (Fig. 5).
2.2. The origins of diastereoselectivity observed upon
conjugate addition to 8-phenylmenthyl
esters
a
,
b-unsaturated
envisaged that a,b-unsaturated hydroxamates 7 [derived from our
‘chiral Weinreb amide’ auxiliary (S)-N-1-(10-naphthyl)ethyl-O-tert-
butylhydroxylamine 8] may undergo conjugate addition reactions
Considering the double asymmetric induction observed upon
addition of the antipodes of lithium N-benzyl-N-( -methylbenzyl)
with high levels of diastereocontrol at the
proposed to evaluate this hypothesis upon the conjugate addition
of 31, 32 and the antipodes of 1 to -unsaturated hydroxamates 7,
and also use the tool of double asymmetric induction to identify the
reactive conformation of 7 in this case (Fig. 7).
b-position. We therefore
a
amide 1 to both 9 and 18, in the ‘matched’ cases conjugate addition
of (S)-1 to 9 results in the preferential formation of 23 in 98:2 dr,
and addition of (S)-1 to 18 results in the preferential formation of 24
in 95:5 dr. In the ‘mismatched’ cases, conjugate addition of (R)-1 to
9 results in the formation of 29 in 88:12 dr, and the addition of (R)-1
to 18 results in the formation of 30 in 83:17 dr. These empirical
‘matched’ and ‘mismatched’ product distributions cannot be
achieved if the reaction were to proceed through s-cis conformation
20A, but is consistent with addition of lithium amides (S)-1 and
(R)-1 to 9 and 18 in s-cis conformation 20B. In this model, the
preferential addition of lithium amide (S)-1 to the back face of the
double bond as drawn within 20B (reagent control) coincides with
addition opposite to the bulky stereodirecting group of the
auxiliary (substrate control), and is consistent with the formation
of 23 and 24 in the ‘matched’ reactions. The formation of 29 and
30 as the major diastereoisomers in the ‘mismatched’ cases may
occur via approach of the lithium amide (R)-1 on the same face as
a,b
Enantiopure
a,b-unsaturated hydroxamates 54 and 55 were
prepared in 88 and 94% yield by reaction of (S)-N-1-(10-naphthyl)
ethyl-O-tert-butylhydroxylamine 8 with crotonyl and cinnamoyl
chlorides, respectively (Scheme 7). The 1H and 13C NMR spectra of 54
and 55 were indicative of these compounds being rotameric in CDCl3
at rt; however, 1H NMR spectroscopic analysis of both 54 and 55 at
343 K in PhMe-d8 revealed that peak coalescence had occurred.
The solid state conformations of 54 and 55 were also investigated
by single crystal X-ray diffraction (Fig. 8).27 In both cases the con-
formation of the ‘chiral Weinreb amide’ auxiliary was found to be
consistent with our previous observations concerning this class of
hydroxamates,32 i.e., that the oxygen atoms adopt an anti-periplanar
conformation, the O-tert-butyl group is approximately perpendicular
to this plane, the nitrogen atom is pyramidalized, and the nitrogen

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S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
Ph
Ph
(i)
(ii)
Ph
N
O
NH2
O
Ph
N
O
R
O
R
O
R
O
Ph
Ph
Ph
23, R = Me, >99:1 dr
24, R = Ph, >99:1 dr
41, R = Me, 76%a
33, R = Me, 95%a
42, R = Ph, 61%a
35, R = Ph, 88%a
(iii)
Ph
NH
O
(ii)
N
O
R
O
R
O
Ph
Ph
45, R = Me, 73%a
34, R = Me, 90%a
46, R = Ph, 62%a
36, R = Ph, 83%a
Ph
Ph
(i)
(ii)
Ph
N
O
NH2
O
Ph
N
O
R
O
R
O
R
O
Ph
Ph
Ph
29, R = Me, >99:1 dr
30, R = Ph, >99:1 dr
43, R = Me, 98%a
37, R = Me, 86%a
44, R = Ph, 65%a
39, R = Ph, 90%a
(iii)
Ph
NH
O
(ii)
N
O
R
O
Me
O
Ph
Ph
47, R = Me, 83%a
38, R = Me, 75%a
48, R = Ph, 75%a
40, R = Ph, 80%a
Scheme 6. Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C, MeOH, AcOH, rt, 18 h; (ii) BnBr, K2CO3, 100 ꢁC, 7 h; (iii) acetone, NaBH3CN, MeOH, rt, 18 h [a isolated in >99:1 dr].
be the doubly diastereoselective ‘matched’ reaction pairing with
nucleophilic attack preferentially occurring on the face anti to both
the O-tert-butyl group and N-lone pair.
The conjugate addition of lithium dibenzylamide 31, lithium
N-isopropyl-N-benzylamide 32 and the antipodes of lithium N-benzyl-
N-(a-methylbenzyl)amide 1 to a,b-unsaturated hydroxamates 54 and
55 were next undertaken. The addition of lithium amide (R)-1 to both
54 and 55 gave, ineachcase, thecorrespondingb-amino hydroxamates
56 and 60 in >95:5 dr,33 representing the doubly diastereoselective
‘matched’ reaction pairings. The levels of diastereoselectivity observed
upon conjugate addition of lithium (S)-N-benzyl-N-(a-methylbenzyl)
amide (S)-1 to 54 and 55 were much lower, representing the doubly
diastereoselective ‘mismatched’ reaction pairings. In the case of the
C(3)-methyl substituted a,b-unsaturated hydroxamate 54 the conju-
gate addition of (S)-1 proceeded under the predominant stereocontrol
of the lithium amide giving a mixture of 57 and 65 in 25:75 dr,
respectively. Upon purification of the crude reaction mixture it was
possible to enrich the diastereoisomeric purity of the major product
giving 65 in 46% yield and 90:10 dr. In the case of the C(3)-phenyl
Fig. 5. X-ray crystal structure of (3S,10R,20S,50R)-33 (some H atoms are omitted for
clarity).
substituted
a,b-unsaturated hydroxamate 55 conjugate addition
lone-pair lies syn-periplanar to the O-tert-butyl group. It is notable
that these structures also bear a striking resemblance tothat proposed
for enolate 50. Assuming that 54 and 55 adopt similar conformations
in solution it may therefore be reasoned that their reactive
conformations upon conjugate addition are similar also. In this case
the conjugate addition of lithium amide (R)-1 would be predicted to
of (S)-1 gave a 60:40 mixture of 61 and 69, respectively; in this case
the major diastereoisomer 61 was isolated in 18% yield and 85:15 dr.34
The conjugate additions of the achiral lithium amides 31 and 32 to
a,b-unsaturated hydroxamates 54 and 55 all proceeded with the same
sense of stereoinduction and with modest levels of diastereoselectivity
(ꢂ70:30 dr) to give 58, 59, 62 and 63 as the major products. In these

S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
6387
Ph
O
Ph
N
Predict
"mismatched"
Predict
"matched"
R
O
Not observed! X
Observed
"matched"
Ph
23, R = Me, 98:2 dr
24, R = Ph, 95:5 dr
Ph
Ph
Ph
N
Li
Ph
N
Li
(S)-1
(S)-1
reagent control
(attack from front face)
O
substrate control
(attack from front face)
O
R
O
R
O
reagent control
(attack from back face)
substrate control
(attack from back face)
20B
20A
Ph
Ph
Ph
N
Li
Ph
N
Li
(R)-1
(R)-1
Ph
Predict
Predict
"matched"
"mismatched"
O
Ph
N
X
Not observed!
Observed
"mismatched"
R
O
Ph
29, R = Me, 88:12 dr
30, R = Ph, 83:17 dr
Fig. 6. Model to rationalise the observed ‘matched’ and ‘mismatched’ double asymmetric induction; given the observed ‘matched’ and ‘mismatched’ reaction pairings, the reactive
conformation cannot be 20A.
O
(i)
X
R'
Me
O
HN
Ot
1-Nap
R
N
OtBu
1-Nap
R
O
N
KHMDS
H
1-Nap
R
H
Bu
N
1-Nap
O
tBu
54, R = Me, 88%
55, R = Ph, 94%
OtBu
8
enolate
formation
49
50
Scheme 7. Reagentsandconditions:(i)RCH¼CHCOCl,CH2Cl2,rt,18 h[1-Nap¼1-naphthyl].
alkylation favoured
anti to tert
-butyl group
and N-lone pair
O
O
LiAlH4
case, thereby also confirming the assigned configurations within 57,
or MeMgBr
R
R
61, 64 and 68: both enantiomers of
hydrolysedwithTFAthentheresultantcarboxylicacidswerecoupled
with (S)-N-1-(10-naphthyl)ethyl-O-tert-butylhydroxylamine
to
b-amino esters 25 and 26 were
R''
N
OtBu
1-Nap
(R'' = H, Me)
R'
R'
8
52, 95:5 er
51, >95:5 dr
giveauthenticsamples of56, 60, 65and69assinglediastereoisomers
(>95:5 dr), although the overall yields obtained in the coupling step
were relatively low. The spectroscopic properties, including specific
rotation values, of the samples of 56, 60, 65 and 69 prepared in this
manner were consistent with the major diastereoisomers35 arising
from the conjugate addition of lithium amides (R)-1 and (S)-1 to
Ph
Ph
Ph
N
Li
1
O
Ph
N
O
a,b-unsaturated hydroxamates 54 and 55, providing unequivocal
R
N
OtBu
1-Nap
R
N
OtBu
1-Nap
doubly
diasteroselective
"matched" reaction
pairing?
evidence of the sense of stereoinduction observed in these reaction
pairings (Scheme 9). Furthermore, the relative configuration within
56 was unambiguously assigned by single crystal X-ray diffraction
7
53
analysis,27 with the absolute (3R,1’S,
aR)-configuration assigned
Fig. 7. Alkylation of chiral hydroxamates 49 and the doubly diastereoselective
conjugate addition of the antipodes of
[1-Nap¼1-naphthyl].
relative to the known configurations of both the (R)-
a
-methylbenzyl
1 to a,b-unsaturated hydroxamates 7.
stereocentre and the (S)-N-1-(10-naphthyl)ethyl-O-tert-butylhy-
droxylamine 8 derived ‘chiral Weinreb amide’ auxiliary (Fig. 9).
Authentic samples of the products arising from the conjugate
addition of 31 and 32 to
were produced by conversion of (R,R)-25 and (3S,
corresponding enantiopure N,N-dibenzyl substituted derivatives 58
and 62 and N-isopropyl-N-benzyl substituted derivatives 59 and 63,
although the yields of the coupling steps were again found to be
a
,
b
-unsaturated hydroxamates 54 and 55
cases, separation of the diastereoisomeric products could not be
achieved upon purification, even after exhaustive flash column
chromatography (Scheme 8).
The configurations at C(3) within 56, 60, 65 and 69 were
established unambiguously by a separate chemical synthesis in each
aR)-26 into the

6388
S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
Fig. 8. X-ray crystal structures of (a) 54 and (c) 55 (some H atoms are omitted for clarity). [1-Nap¼1-naphthyl].
R2
R1
Bn
R2
Bn
(i)
O
N
O
N
O
+
R1
N
1-Nap
N
1-Nap R1
N
1-Nap
OtBu
OtBu
OtBu
54, R1 = Me
A
B
55, R1 = Ph
yield
of A (%)
yield
conv crude dr
(%) (A:B)
Michael lithium
acceptor amide
1
R
2
R
A
B
of B (%)
54
54
54
54
( )-1 Me ( )-CHMePh 56 64 quant >95:5 81 (>95:5 dr)
--
R
R
(S)-1 Me (S)-CHMePh 57 65
91
83
83
25:75
--
46a (90:10 dr)
31
32
Me
Me
Bn
iPr
58 66
59 67
80:20 66 (80:20 dr)
80:20 70 (80:20 dr)
--
--
55
55
55
55
(R)-1 Ph (R)-CHMePh 60 68
( )-1 Ph ( )-CHMePh 61 69
94
90
92
65
>95:5 80 (>95:5 dr)
60:40 18a (85:15 dr)
70:30 62 (70:30 dr)
80:20 60 (80:20 dr)
--
--
--
--
S
S
31
32
Ph
Ph
Bn
62 70
63 71
iPr
a
Scheme 8. Reagents and conditions: (i) LiNR2Bn, THF, ꢀ78 ꢁC, 2 h [1-Nap¼1-naphthyl; mixed fractions were also isolated, see Ref. 34].
Ph
Ph
Ph
N
Ph
N
O
(i), (ii)
CO2tBu
R
R
N
1-Nap
OtBu
(R,R)-25, R = Me, >99:1 dr
56, R = Me, 16%, >95:5 dr
60, R = Ph, 10%, >95:5 dr
)
R
α
(3S,
-26, R = Ph, >99:1 dr
Ph
Ph
Ph
N
Ph
N
O
(i), (ii)
t
CO2 Bu
R
R
N
1-Nap
OtBu
(S,S)-25, R = Me, >99:1 dr
65, R = Me, 15%, >95:5 dr
69, R = Ph, 12%, >95:5 dr
α
(3R, S)-26, R = Ph, >99:1 dr
Fig. 9. X-ray crystal structure of (3R,10S,
[1-Nap¼1-naphthyl].
aR)-56 (some H atoms are omitted for clarity).
Scheme 9. Reagents and conditions: (i) TFA/CH2Cl2 (v/v 1:1), rt, 2 h; (ii) (COCl)2, DMF,
CH2Cl2, rt, 1 h then (S)-8$(þ)-CSA, CH2Cl2, 16 h [1-Nap¼1-naphthyl].
relatively poor.36 The spectroscopic properties, including specific
rotation values, of the samples of 58, 59, 62 and 63 prepared in this
manner were consistent with the majordiastereoisomers arisingfrom
the conjugate addition of lithium amides 31 and 32to a,b-unsaturated
hydroxamates 54 and 55, providingunequivocalevidence of the sense
reaction of (S)-1 with 54 and 55 proceeded with much poorer levels
of diastereoselectivity (25:75 and 60:40 dr, respectively) and
represents the ‘mismatched’ reaction pairings. These empirical
‘matched’ and ‘mismatched’ product distributions are consistent
with the preferential addition of lithium amide (R)-1 to the top face
of the double bond (reagent control) as drawn within s-cis reactive
conformation 72, which coincides with addition opposite to the
stereodirecting tert-butyl group and N-lone pair within the auxiliary
(substrate control). The poor diastereoselectivity observed in the
‘mismatched’ cases may occur via approach of lithium amide (S)-1
on the same face as the stereodirecting tert-butyl group of the
auxiliary, although these data do not discount the possibility that
preferential addition of (S)-1 to 54 and 55 proceeds via an
of stereoinduction observed in these reactions (Scheme 10).
2.4. The origins of diastereoselectivity observed upon conjugate
addition to a,b-unsaturated hydroxamates
As predicted, the conjugate addition of (R)-1 to enantiopure
a,b-unsaturated hydroxamates 54 and 55 proceeded with high
diastereoselectivity (>95:5 dr in each case) and represents the
doubly diastereoselective ‘matched’ reaction pairings, whereas
alternative conformation of the
a,b-unsaturated hydroxamate.

S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
6389
diastereoselective ‘matched’ cases the known diastereofacial
preference exerted by lithium N-benzyl-N-( -methylbenzyl)amide
Ph
Ph
a
(i), (ii), (iii)
then (iv)
Ph
N
Ph
N
O
was found to be in accord with conjugate addition to the face
opposite to the stereodirecting groups within these auxiliaries
(i.e., the phenyl group within Corey’s 8-phenylmenthol auxiliary
and both the tert-butyl group and N-lone pair within our ‘chiral
Weinreb amide’ auxiliary).
t
CO2 Bu
R
R
N
OtBu
1-Nap
(R,R)-25, R = Me, >99:1 dr
(3S,αR)-26, R = Ph, >99:1 dr
58, R = Me, 4%, >95:5 dr
62, R = Ph, 5%, >95:5 dr
Ph
Ph
4. Experimental
(i), (v), (ii),
(iii) then (iv)
Ph
N
N
O
t
4.1. General experimental
CO2 Bu
R
R
N
1-Nap
OtBu
All reactions involving organometallic or other moisture-sensitive
reagents were carried out under a nitrogen or argon atmosphere
using standard vacuum line techniques and glassware that was flame
dried and cooled under nitrogen before use. Solvents were dried
according to the procedure outlined by Grubbs and co-workers.37
(R,R)-25, R = Me, >99:1 dr
(3S,αR)-26, R = Ph, >99:1 dr
59, R = Me, 5%, >95:5 dr
63, R = Ph, 6%, >95:5 dr
Scheme 10. Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C, MeOH, rt, 36 h; (ii)
BnBr, K2CO3, 100 ꢁC, 7 h; (iii) TFA/CH2Cl2 (v/v 1:1), rt, 2 h; (iv) (COCl)2, DMF, CH2Cl2,
0
ꢁC to rt, 1 h then (S)-8$(þ)-CSA, K2CO3, CH2Cl2, 18 h; (v) acetone, NaBH3CN, MeOH, rt,
i
Water was purified by an ElixÒ UV-10 system. PrOH was distilled
16 h [1-Nap¼1-naphthyl].
from CaO. BuLi was purchased from SigmaeAldrich (as solution in
hexanes) and titrated against diphenylacetic acid before use. All other
reagents were used as supplied (analytical or HPLC grade) without
prior purification. Organic layers were dried over MgSO4. Thin layer
chromatography was performed on aluminium plates coated with 60
F254 silica. Plates were visualised using UV light (254 nm), iodine, 1%
aq KMnO4, or 10% ethanolic phosphomolybdic acid. Flash column
chromatography was performed on Kieselgel 60 silica.
Melting points were recorded on a Gallenkamp Hot Stage
apparatus. Optical rotations were recorded on a PerkineElmer 241
polarimeter with a water-jacketed 10 cm cell. Specific rotations
are reported in 10ꢀ1 deg cm2 gꢀ1 and concentrations in g/100 mL.
IR spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer
as either a thin film on NaCl plates (film) or a KBr disc (KBr), as
stated. Selected characteristic peaks are reported in cmꢀ1. NMR
spectra were recorded on Bruker Avance spectrometers in the
deuterated solvent stated. Spectra were recorded at rt unless
otherwise stated. The field was locked by external referencing to
the relevant deuteron resonance. Low-resolution mass spectra
were recorded on either a VG MassLab 20e250 or a Micromass
Platform 1 spectrometer. Accurate mass measurements were run
on either a Bruker MicroTOF internally calibrated with polyalanine,
or a Micromass GCT instrument fitted with a Scientific Glass
Instruments BPX5 column (15 mꢃ0.25 mm) using amyl acetate as
a lock mass.
These findings are consistent with our previous observations con-
cerningthealkylationof theofenolatesderivedfrom N-1-(10-naphthyl)
ethyl-O-tert-butylhydroxamates8 in that a ‘chiral relay’31 mechanism
may be proposed to rationalise the observed stereochemical out-
come of the reaction: theconfiguration of theN-1-(10-naphthyl)ethyl
group dictates the position of the O-tert-butyl group and also
the configuration adopted by the pyramidal nitrogen atom. A fully
staggered arrangement is adopted in which minimisation of steric
interactions between the C(10)-methyl and O-tert-butyl groups leaves
the C(10)-hydrogen and carbonyl oxygen atoms eclipsing, minimising
syn-pentane interactions. Minimisation of lone pairelone pair
repulsion controls the configuration of the pyramidal nitrogen atom;
the doubly diastereoselective ‘matched’ conjugate addition of (R)-1
then occurs on the opposite face to both the nitrogen lone-pair and
the bulky O-tert-butyl group (Fig. 10).
syn-pentane
interaction
minimised
conjugate addition
on opposite face to
tert-butyl group
Ph
Ph
(R)-1
N
Li
and nitrogen lone pair
R
Me
Me
O
O
O
H
tBu
1-Nap
R
N
1-Nap
H
O
syn-pentane
interaction
minimised
tBu
72
4.2. General procedure 1: conjugate addition of lithium amide
Fig. 10. A ‘chiral relay’ mechanism in the doubly diastereoselective conjugate addition
of (R)-1 to 54 (R¼Me) and 55 (R¼Ph). [1-Nap¼1-naphthyl].
BuLi (1.6 equiv) was added to a solution of the requisite amine
(2.0 equiv) in THF at ꢀ78 ꢁC. After 30 min, a solution of the requisite
substrate (1.0 equiv) in THF at ꢀ78 ꢁC was added dropwise via
cannula. After a further 2 h, satd aq NH4Cl was added and the
reaction mixture was allowed to warm to rt before being con-
centrated in vacuo. 10% aq Citric acid solution was then added
and the resultant mixture was extracted with three portions
of CH2Cl2. The combined organic extracts were washed with satd
aq NaHCO3 and brine, then dried and concentrated in vacuo.
3. Conclusion
In conclusion, the doubly diastereoselective conjugate additions
of the antipodes of lithium N-benzyl-N-(a-methylbenzyl)amide to
a range of enantiopure -unsaturated esters and enantiopure a,b-
a
,b
unsaturated hydroxamates have been used as a mechanistic probe
to determine the reactive conformations in these systems. In all
cases, conjugate addition occurs with the a,b-unsaturated carbonyl
compounds adopting s-cis reactive conformations. High levels of
diastereoselectivity (ꢂ95:5 dr) were observed in the doubly
diastereoselective ‘matched’ reaction pairings. In all but one case
the dominant stereocontrolling element in the ‘mismatched’
reaction pairings was found to be the lithium amide reagent.
Intermediate levels of diastereoselectivity were observed upon
conjugate addition of achiral lithium amides, providing an indication
of the level of substrate control in these systems. In the doubly
4.3. General procedure 2: deprotection with TFA
A solution of the requisite substrate in TFA/CH2Cl2 (v/v 1:1) was
stirred at 0 ꢁC for 5 min. The reaction mixture was then allowed to
warm to rt over 2 h then concentrated in vacuo. In the case of
tertiary amino ester starting materials, the residue was dissolved in
CH2Cl2 and the resultant solution was washed with satd aq
NaHCO3, then dried and concentrated in vacuo.

6390
S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
4.4. General procedure 3: N/O-acylation of a chiral auxiliary
with a carboxylic acid derivative
extracts were washed with satd aq NaHCO3 (80 mL) and brine
(80 mL), then dried and concentrated in vacuo to give a yellow oil
(14.0 g, 93%).
A solution of the requisite carboxylic acid (1.0e2.5 equiv) in
CH2Cl2 at 0 ꢁC was treated with (COCl)2 (1.00e5.00 equiv) and DMF
(1 drop). The reaction mixture was allowed to warm to rt over 1 h
then concentrated in vacuo. The residue was dissolved in CH2Cl2
and the resultant mixture was added to a solution of the requisite
chiral auxiliary (1.00 equiv) in CH2Cl2 at 0 ꢁC. The reaction mixture
was then allowed to warm to rt and stirred for 18 h. Satd aq NaHCO3
was then added and the resultant mixture was extracted with three
portions of CH2Cl2. The combined organic extracts were washed
with brine, then dried and concentrated in vacuo.
Step 2: The residue (14.0 g, 60.8 mmol) was dissolved in EtOH
(150 mL) and H2O (20 mL) then KOH (17.5 g, 300 mmol) was added.
The resultant mixture was heated at reflux for 3 h and concentrated
in vacuo to a volume of 50 mL. H2O (125 mL) was then added, and
the resultant mixture was saturated with NaCl and extracted with
Et2O (3ꢃ50 mL). The combined organic extracts were washed with
brine (80 mL), then dried and concentrated in vacuo to give a pale
yellow oil (13.0 g, 93%).
Step 3: The residue (13.0 g, 56.4 mmol) was dissolved in freshly
i
distilled PrOH (12.6 mL) and the resultant solution was added to
a mixture of Na (3.82 g, 164 mmol) in toluene (54 mL) at a rate as
to keep the reaction at a gentle reflux. Once the addition was
complete, the mixture was heated at reflux for 8 h and then cooled
to 0 ꢁC. The mixture was diluted with Et2O (60 mL) and poured into
water (70 mL) at 0 ꢁC. The aqueous layer was saturated with NaCl
and extracted with with Et2O (3ꢃ50 mL). The combined organic
extracts were washed with brine (50 mL), then dried and concen-
trated in vacuo. Purification via flash column chromatography
(gradient elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave 6 as
4.5. General procedure 4: hydrogenolysis with Pearlman’s
catalyst
Pd(OH)2/C (20% by weight as supplied, load 25e50% by weight of
substrate for reaction) was added to a vigorously stirred solution of
the requisite substrate in either (i) degassed EtOAc; (ii) degassed
MeOH; or (iii) degassed MeOH:AcOH (v/v 40:1), at rt. The resultant
suspension was stirred under hydrogen at either: (i) 1 atm or (ii)
5 atm, as stated, for 18e36 h. The reaction mixture was filtered
through CeliteÒ [eluent either (i) EtOAc or (ii) MeOH] and concen-
trated in vacuo. For reactions which required AcOH, the residue was
dissolved in CH2Cl2 and the resultant solution was washed with satd
aq NaHCO3 and brine, then dried and concentrated in vacuo.
a colourless oil (5.50 g, 36%, >99:1 dr); ½a D22
ꢀ26.5 (c 1.0 in EtOH);
ꢄ
{lit.7 for enantiomer ½a 2D0
þ26.3 (c 2.02 in EtOH)}; dH (400 MHz,
ꢄ
CDCl3) 0.85e1.20 (3H, m, CH2, CH) overlapping 0.87 (3H, d, J 6.5,
C(5)Me), 1.29 (3H, s, C(10)H3), 1.42 (3H, s, C(30)H3), 1.43e1.78 (4H, m,
2ꢃ CH2), 1.81e1.89 (1H, m, CH), 3.48 (1H, app td, J 10.6, 4.4, C(1)H),
7.15e7.47 (5H, m, Ph).
4.6. General procedure 5: N-benzylation of primary or
secondary amines
4.7.2. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(E)-but-2-enoate 9.
K2CO3 (10.0 equiv) was added to a stirred solution of the
requisite amine (1.0 equiv) in BnBr (10.0 equiv). The resultant
mixture was heated at 100 ꢁC for 7 h then allowed to cool to rt and
partitioned between satd aq NaHCO3 and CH2Cl2. The aqueous layer
was extracted with three portions of CH2Cl2 and the combined
organic extracts were then dried and concentrated in vacuo.
O
Me
O
Ph
i
4.7. General procedure 6: reductive amination with NaBH3CN
Step 1: Crotonoyl chloride (2.40 mL, 25.0 mmol) and Pr2NEt
(4.20 mL, 25.0 mmol) was added to a stirred solution of 6 (2.90 g,
12.5 mmol) in THF (30 mL) at 0 ꢁC. The resultant solution was
allowed to warm to rt and stirred for 18 h. The reaction mixture was
partitioned between satd aq NaHCO3 (30 mL) and CH2Cl2 (30 mL).
The aqueous layer was extracted with CH2Cl2 (3ꢃ30 mL). The
combined organic extracts were washed with brine (30 mL), then
dried and concentrated in vacuo. Purification via flash column
chromatography (gradient elution, 1%/20% Et2O in 30e40 ꢁC
Acetone (2.0 equiv) and NaBH3CN (4.0 equiv) were added
sequentially to a solution of the requisite primary amine (1.0 equiv)
in MeOH at rt. The resultant mixture was stirred at rt for 18 h then
concentrated in vacuo. The residue was partitioned between CH2Cl2
and H2O and the aqueous layer was extracted with three portions
of CH2Cl2. The combined organic extracts were then dried and
concentrated in vacuo.
petrol) gave 19 as a colourless oil (3.38 g, 90%);13
½
a 2D5
ꢄ
þ10.5 (c 1.0 in
4.7.1. (1R,2S,5R)-2-(20-Phenylpropan-20-yl)-5-methylcyclohexanol 6.
CHCl3); nmax (film) 2955, 2924 (CeH), 1730 (C]O), 1643 (C]C); dH
(400 MHz, CDCl3) 0.89 (3H, d, J 6.3, C(50)Me), 0.90e1.20 (3H, m, CH2,
CH), 1.23 (3H, s, C(100)H3), 1.33 (3H, s, C(300)H3), 1.42e2.10 (5H, m, 2ꢃ
CH2, CH), 2.43 (1H, dd, J 16.7, 6.8, C(2)HA), 2.48 (1H, dd, J 16.7, 6.8,
C(2)HB), 4.85 (1H, app td, J 10.6, 4.4, C(10)H), 5.02 (1H, dd, J 16.7, 1.3,
C(4)HA), 5.08 (1H, dd, J 10.1, 1.3, C(4)HB), 5.64e5.77 (1H, m, C(3)H),
7.10e7.35 (5H, m, Ph); dC (100 MHz, CDCl3) 22.2 (C(50)Me), 24.9
(C(300)), 26.9 (CH2), 28.9 (C(100)), 31.7 (CH), 35.0 (CH2), 39.4 (C(200)),
40.0 (CH2), 42.1 (C(2)), 50.7 (CH), 74.6 (C(10)), 118.0 (C(4)), 125.0
(C(3)), 125.4, 127.9, 130.5 (o,m,p-Ph), 151.7 (i-Ph), 170.8 (C(1)); m/þz
(ESIþ) 323 ([MþNa]þ, 100%); HRMS (ESIþ) C20H28NNaO2
([MþNa]þ) requires 323.1982; found 323.1978.
HO
Ph
Step 1: PhMgBr (3.0 M in Et2O, 26.4 mL, 78.8 mmol) was added
dropwise to a stirred solution of copper(I) bromide (1.12 g,
7.82 mmol) in Et2O (20 mL) at ꢀ20 ꢁC. After 30 min, a solution of
(R)-(þ)-pulegone (10.0 g, 65.7 mmol) in Et2O (13 mL) was added
over a period of 15 min and the resultant mixture was stirred at
ꢀ20 ꢁC for 16 h. The reaction mixture was then added to 2.0 M aq
HCl (80 mL) at 0 ꢁC and the aqueous layer was saturated with
NH4Cl and extracted with Et2O (3ꢃ80 mL). The combined organic
Step 2: DBU (5.00 mL, 33.6 mmol) was added to a stirred
solution of 19 (3.36 g, 11.2 mmol) in THF (35 mL) at rt and the
resultant solution was stirred at rt for 18 h. The reaction mixture
was then partitioned between 2.0 M aq HCl (30 mL) and CH2Cl2
(30 mL). The aqueous layer was extracted with CH2Cl2 (3ꢃ30 mL),
and the combined organic extracts were washed with brine

S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
6391
(30 mL), then dried and concentrated in vacuo. Purification via flash
column chromatography (gradient elution, 1%/20% Et2O in
30e40 ꢁC petrol) gave 9 as a colourless oil (2.20 g, 65%, >99:1 dr);
151.6 (i-Ph), 171.8 (C(1)); m/z (ESIþ) 512 ([MþH]þ, 100%); HRMS
(ESIþ) C35H46NO2þ ([MþH]þ) requires 512.3523; found 512.3520.
Method B: Following general procedure 2, a solution of (S,S)-25
(1.75 g, 4.95 mmol) in CH2Cl2 (17.0 mL) was treated with TFA
(17.0 mL) to give a white foam (1.32 g). Then, following general
procedure 3, a solution of the residue (131 mg) in CH2Cl2 (2 mL)
½
a 2D5
ꢄ
ꢀ10.0 (c 1.1 in hexane); {lit.38
½
a 2D5
ꢄ
ꢀ9.8 (c 13.1 in hexane)}; dH
(400 MHz, CDCl3) 0.91 (3H, d, J 6.5, C(50)Me), 0.95e1.27 (3H, m, CH2,
CH) overlapping 1.26 (3H, s, C(100)H3), 1.35 (3H, s, C(300)H3),
1.49e2.01 (4H, m, 2ꢃ CH2), 1.78 (3H, dd, J 7.2, 1.7, C(4)H3), 2.04e2.16
(1H, m, CH), 4.88 (1H, app td, J 10.6, 4.4, C(10)H), 5.38 (1H, dd, J 15.7,
1.7, C(2)H), 6.50 (1H, dd, J 15.7, 7.2, C(3)H), 7.14e7.48 (5H, m, Ph).
was reacted with (COCl)2 (40 mL, 0.46 mmol) and a solution of 6
(50 mg, 0.22 mmol) in CH2Cl2 (1 mL). Purification via flash column
chromatography (gradient elution, 1%/10% Et2O in 30e40 ꢁC
petrol) gave 23 as a colourless oil that crystallised upon standing
4.7.3. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(E)-3-phenylpropenoate 18.
(76 mg, 61%, >99:1 dr); mp 72e74 ꢁC; ½a D21
þ6.5 (c 1.0 in CHCl3).
ꢄ
4.7.4.1. X-ray crystal structure determination for 23. Data were
collected using a Nonius -CCD diffractometer with graphite
monochromated Mo K radiation using standard procedures at
150 K. The structure was solved by direct methods (SIR92); all non-
hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were added at idealised positions. The structure
was refined using CRYSTALS.40
O
k
a
Ph
O
Ph
iPr2NEt (289 mg, 2.37 mmol) was added in one portion to a stirred
solution of cinnamoyl chloride (358 mg, 2.15 mmol) inTHF (16 mL) at
0 ꢁC. An immediate precipitate was observed and the resultant sus-
pension was stirred for 15 min before a solution of 6 (500 mg,
2.15 mmol) in CH2Cl2 (4 mL) was added. The resultant mixture was
allowed to warm to rt and stirred for 18 h. The reaction mixture was
partitioned between satd aqNaHCO3 (10 mL) and CH2Cl2 (10 mL). The
aqueous layer was extracted with CH2Cl2 (3ꢃ10 mL). The combined
organic extracts were washed with brine (10 mL), then dried and
concentrated in vacuo. Purification via flash column chromatog-
raphy (gradient elution, 1%/20% Et2O in 30e40 ꢁC petrol) gave
X-ray crystal structure data for 23 [C35H45NO2]: M¼511.75,
ꢀ
ꢀ
triclinic, space group P1, a¼8.7141(2) A, b¼9.8528(2) A,
ꢀ
c¼10.1472(2) A,
a
¼98.8224(7)ꢁ,
b
¼111.4837(8)ꢁ,
g
¼105.3920(9)ꢁ,
3
ꢀ
V¼750.51(3) A , Z¼1,
m
¼0.069 mmꢀ1
, colourless block, crystal
dimensions¼0.17ꢃ0.21ꢃ0.24 mm3. A total of 3396 unique reflections
were measured for 5<q<27 and 2765 reflections were used in the
refinement. The final parameters were wR2¼0.067 and R1¼0.032
[I>ꢀ3.0
s
(I)]. Crystallographic data (excluding structure factors) has
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 815826. Copies of the data
can be obtained, free of charge, on application to CCDC,12 Union Road,
Cambridge, CB2 1EZ, UK [fax: þ44 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
18 as a colourless oil (436 mg, 56%, >99:1 dr); ½a D25
þ10.2 (c 2.2 in
ꢄ
CHCl3); {lit.39
½
a 2D5
ꢄ
þ9.9 (c 2.23 in CHCl3)}; dH (400 MHz, CDCl3)
0.94 (3H, d, J 6.5, C(50)Me), 0.96e1.27 (3H, m, CH2, CH), 1.29 (3H, s,
C(100)H3), 1.38 (3H, s, C(300)H3), 1.52e2.03 (4H, m, 2ꢃ CH2),
2.13e2.22 (1H, m, CH), 4.96 (1H, app td, J 10.6, 4.4, C(10)H), 5.81
(1H, d, J 16.0, C(2)H), 7.11e7.48 (11H, m, C(3)H, Ph).
4.7.5. tert-Butyl (S,S)-3-[N-benzyl-N-(a-methylbenzyl)amino]buta-
noate 25.
Ph
4.7.4. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
Ph
N
(S,S)-3-[N-benzyl-N-(
a
-methylbenzyl)amino]butanoate 23.
CO2tBu
Me
Ph
Following general procedure 1, a solution of (S)-N-benzyl-N-(a-
Ph
N
O
methylbenzyl)amine (2.38 g, 11.3 mmol) in THF (20 mL) at ꢀ78 ꢁC
was treated with BuLi (2.5 M, 5.10 mL, 10.9 mmol) and tert-butyl
crotonate (1.00 g, 7.03 mmol) to give (S,S)-25 in >99:1 dr. Purification
via flash column chromatography (gradient elution, 1%/20% Et2O
in 30e40 ꢁC petrol) gave (S,S)-25 as a pale yellow oil (2.18 g, 88%,
Me
O
Ph
>99:1 dr);1c
½
a 2D4
ꢄ
þ3.6 (c 1.0 in CHCl3); {lit.1c
½
a 2D4
ꢄ
þ3.6 (c 0.8 in
Method A: Following general procedure 1, a solution of (S)-N-
benzyl-N-( -methylbenzyl)amine (0.20 mL, 0.96 mmol) in THF
a
CHCl3)}; dH (400 MHz, CDCl3) 1.12 (3H, d, J 6.5, C(4)H3),1.34 (3H, d, J
(2 mL) at ꢀ78 ꢁC was treated with BuLi (1.6 M in hexanes, 0.48 mL,
0.77 mmol) and 9 (143 mg, 0.48 mmol, >99:1 dr) in THF (2 mL) to
give 23 in 98:2 dr. Purification via flash column chromatography
(gradient elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave 23 as
a colourless oil that crystallised upon standing (175 mg, 71%, >99:1
dr); C35H45NO2 requires C, 82.2; H, 8.9; N, 2.7%; found C, 82.3; H, 8.9;
7.0, C(
a)Me),1.39 (9H, s, CMe3), 2.02 (1H, dd, J 14.1, 9.0, C(2)HA), 2.26
(1H, dd, J 14.1, 4.8, C(2)HB), 3.39e3.48 (1H, m, C(3)H), 3.69 (2H, AB
system, JAB 15.0, NCH2Ph), 3.89 (1H, q, J 7.0, C(
m, Ph).
a)H), 7.19e7.42 (10H,
4.7.6. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
a 20
ꢁ
N, 2.7%; mp 72e74 C; ½ ꢄD þ6.4 (c 0.5 in CHCl3); nmax (KBr) 2959,
2924 (CeH), 1723 (C]O); dH (500 MHz, CDCl3) 0.79e1.12 (3H, m,
CH2, CH), 0.88 (3H, d, J 6.3, C(50)Me), 1.07 (3H, d, J 6.6, C(4)H3), 1.19
(3R,a
S)-3-[N-benzyl-N-(
a-methylbenzyl)amino]-3-phenylpropanoate
24.
Ph
(3H, s, C(100)H3), 1.25 (3H, s, C(300)H3), 1.31 (3H, d, J 6.9, C(
a)Me),
1.38e1.67 (4H, m, 2ꢃ CH2), 1.76e1.82 (1H, m, C(2)HA), 1.87 (1H, dd, J
Ph
N
O
14.5, 4.1, C(2)HB), 1.91e1.98 (1H, m, CH), 3.22e3.31 (1H, m, C(3)H),
3.61 (2H, AB system, JAB 14.8, NCH2Ph), 3.78 (1H, q, J 6.9, C(
(1H, app td, J 10.6, 4.3, C(10)H), 7.10e7.40 (15H, m, Ph); dC (125 MHz,
CDCl3) 18.5 (C(4)), 19.1 (C(
)Me), 21.8 (C(50)Me), 25.5 (C(300)), 26.6
(C(100)), 27.5 (CH2), 31.2 (CH), 34.5 (CH2), 39.0 (C(2)), 39.7 (C(200)), 41.5
(CH2), 49.7 (CH), 49.9 (NCH2Ph), 50.3 (C(3)), 58.4 (C(
)), 73.9 (C(10)),
125.0, 125.5, 126.4, 126.7, 127.6, 128.0, 128.2 (o,m,p-Ph), 142.1, 144.5,
a)H), 4.72
Ph
O
Ph
a
a
Method A: Following general procedure 1, a solution of (S)-N-
benzyl-N-( -methylbenzyl)amine (0.10 mL, 0.50 mmol) in THF
a

6392
S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
(1 mL) at ꢀ78 ꢁC was treated with BuLi (1.6 M in hexanes, 0.25 mL,
0.40 mmol) and 18 (90 mg, 0.25 mmol) in THF (1 mL) to give 24 in
95:5 dr. Purification via flash column chromatography (gradient
elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave 24 as a colourless
elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave 29 as a colourless
oil (51 mg, 20%, >99:1 dr); ½a D20
þ11.3 (c 1.0 in CHCl3); nmax (film)
ꢄ
2965, 2925 (CeH), 1723 (C]O); dH (500 MHz, CDCl3) 0.79e1.14 (3H,
m, CH2, CH), 0.86 (3H, d, J 6.3, C(50)Me), 0.98 (3H, d, J 6.6, C(4)H3),
oil (89 mg, 62%, >99:1 dr); ½a D20
ꢄ
ꢀ10.3 (c 1.0 in CHCl3); nmax (film)
1.18 (3H, s, C(100)H3), 1.23 (3H, s, C(300)H3), 1.31 (3H, d, J 6.9, C(
a)Me),
2963, 2924 (CeH), 1725 (C]O); dH (500 MHz, CDCl3) 0.57e1.03
(3H, m, CH2, CH), 0.79 (3H, d, J 6.3, C(50)Me), 1.13 (3H, s, C(100)H3),
1.38e1.69 (4H, m, 2ꢃ CH2),1.53 (1H, dd, J 14.6, 9.8, C(2)HA),1.90 (1H,
dd, J 14.6, 4.4, C(2)HB), 1.93e1.99 (1H, m, CH), 3.22e3.30 (1H, m,
1.19 (3H, s, C(300)H3), 1.21 (3H, d, J 6.9, C(
a
)Me), 1.25e1.61 (4H, m,
C(3)H), 3.58 (2H, AB system, JAB 15.1, NCH2Ph), 3.82 (1H, q, J 6.9, C(
a)
2ꢃ CH2), 1.84e1.92 (1H, m, CH), 2.26 (1H, dd, J 15.3, 5.4, C(2)HA),
H), 4.71 (1H, app td, J 10.6, 4.3, C(10)H), 7.09e7.40 (15H, m, Ph); dC
2.11 (1H, dd, J 15.3, 9.8, C(2)HB), 3.64 (2H, app s, NCH2Ph), 3.94 (1H,
(125 MHz, CDCl3) 18.4 (C(4)), 19.1 (C(a
)Me), 21.8 (C(50)Me), 25.1
q, J 6.9, C(
10.6, 4.3, C(10)H), 7.13e7.45 (20H, m, Ph); dC (125 MHz, CDCl3) 16.1
(C(
)Me), 21.7 (C(50)Me), 26.1 (C(300)), 26.7 (C(100)), 26.8 (CH2), 31.1
(CH), 34.5 (CH2), 37.7 (C(2)), 39.7 (C(200)), 41.2 (CH2), 50.2
(NCH2Ph), 50.6 (CH), 56.9 (C(
)), 59.3 (C(3)), 74.4 (C(10)), 125.1,
a
)H), 4.25 (1H, dd, J 9.8, 5.4, C(3)H), 4.62 (1H, app td, J
(C(300)), 26.5 (C(100)), 27.7 (CH2), 31.2 (CH), 34.6 (CH2), 39.2 (C(2)),
39.6 (C(200)), 41.7 (CH2), 49.7 (CH), 49.9 (NCH2Ph), 50.3 (C(3)), 58.4
a
(C(a
)), 74.1 (C(10)), 124.9, 125.3, 126.5, 126.7, 127.7, 127.9, 128.1
(o,m,p-Ph), 142.0, 144.3, 151.7 (i-Ph), 171.8 (þC(1)); m/z (ESIþ) 512
([MþH]þ, 100%); HRMS (ESIþ) C35H46NO2 ([MþH]þ) requires
512.3523; found 512.3522. Further elution gave an 85:15 mixture of
29 and its C(3)-epimer as colourless oil (128 mg, 50%). Data for the
a
125.5, 126.4, 126.7, 127.1, 127.9, 128.0, 128.3 (o,m,p-Ph), 141.5, 141.7,
144.4, 151.4 (i-Ph), 170.9 (C(1)); m/z (ESIþ) 574 ([MþH]þ, 100%);
þ
HRMS (ESIþ) C40H48NO2 ([MþH]þ) requires 574.3680; found
(3S,10R,20S,50R,
aR)-diastereoisomer: dH (500 MHz, CDCl3) [selected
574.3680. Data for the (3S,10R,20S,50R,
a
S)-diastereoisomer: dH
peaks] 0.72 (3H, d, J 6.3, C(50)Me), 0.90 (3H, d, J 6.6, C(4)H3),
3.33e3.43 (1H, m, C(3)H), 3.66 (2H, AB system, JAB 15.1, NCH2Ph),
(400 MHz, CDCl3) [selected peaks] 3.63 (2H, app s, NCH2Ph), 3.96
(1H, q, J 6.9, C( )H), 4.32e4.38 (1H, m, C(3)H), 4.69 (1H, app td, J
10.6, 4.3, C(10)H).
Method B: Following general procedure 2, a solution of (3R,
a
3.87 (1H, q, J 6.9, C(
(125 MHz, CDCl3) [selected peaks] 18.7 (C(4)), 19.4 (C(
(C(50)Me), 25.2 (C(300)), 27.1 (C(100)), 27.8 (CH2), 31.2 (CH), 34.6 (CH2),
58.7 (C(
)), 74.0 (C(10)), 141.8, 143.8, 149.9 (i-Ph), 171.9 (C(1)).
a
)H), 4.81 (1H, app td, J 10.6, 4.3, C(10)H); dC
a)Me), 22.0
aS)-
26 (1.66 g, 3.99 mmol) in CH2Cl2 (16.0 mL) was treated with TFA
(16.0 mL) to give a white foam (1.32 g). Then, following general
procedure 3, a solution of the residue (475 mg, 1.32 mmol) in
CH2Cl2 (5 mL) was reacted with (COCl)2 (0.11 mL, 1.39 mmol) and
a solution of 6 (154 mg, 0.66 mmol) in CH2Cl2 (2 mL). Purification
via flash column chromatography (gradient elution, 1%/10% Et2O
in 30e40 ꢁC petrol) gave 24 as a colourless oil (227 mg, 55%, >99:1
a
Method B: Following general procedure 2, a solution of (R,R)-25
(1.67 g, 4.72 mmol) in CH2Cl2 (16.0 mL) was treated with TFA
(16.0 mL) to give a white foam (1.36 g). Then, following general
procedure 3, a solution of the residue (131 mg, 0.44 mmol) in
CH2Cl2 (2 mL) was reacted with (COCl)2 (40 mL, 0.46 mmol) and
a solution of 6 (50 mg, 0.22 mmol) in CH2Cl2 (1 mL). Purification via
flash column chromatography (gradient elution, 1%/10% Et2O in
30e40 ꢁC petrol) gave 29 as a colourless oil (52 mg, 46%, >99:1 dr);
dr); ½a 2D2
ꢀ10.5 (c 1.1 in CHCl3).
ꢄ
4.7.7. tert-Butyl (3R,
a
S)-3-[N-benzyl-N-(
a
-methylbenzyl)amino]-3-
½
a 2D2
ꢄ
þ11.5 (c 1.1 in CHCl3).
phenylpropanoate 26.
4.7.9. tert-Butyl (R,R)-3-[N-benzyl-N-(a-methylbenzyl)amino]buta-
noate 25.
Ph
Ph
N
Ph
CO2tBu
Ph
Ph
N
CO2tBu
Following general procedure 1, a solution of (S)-N-benzyl-N-(a-
Me
methylbenzyl)amine (1.66 g, 7.84 mmol) in THF (20 mL) at ꢀ78 ꢁC
was treated with BuLi (2.5 M, 3.00 mL, 7.60 mmol) and tert-butyl
Following general procedure 1, a solution of (R)-N-benzyl-N-(a-
cinnamate (1.00 g, 4.90 mmol) to give (3R,
Purification via flash column chromatography (gradient elution,
1%/20% Et2O in 30e40 ꢁC petrol) gave (3R,
S)-26 as a pale yellow
oil (1.67 g, 84%, >99:1 dr);41 e4.2 (c 1.0 in CHCl3); {lit.41
a 2D4 a 2D3
e4.0 (c 1.0 in CHCl3)}; dH (400 MHz, CDCl3) 1.22 (9H, s, CMe3), 1.26
(3H, d, J 6.9, C( )Me), 2.48e2.56 (2H, m, C(2)H2), 3.68 (2H, app s,
a
S)-26 in >99:1 dr.
methylbenzyl)amine (5.94 g, 28.1 mmol) in THF (40 mL) at ꢀ78 ꢁC
was treated with BuLi (2.5 M, 10.9 mL, 27.3 mmol) and tert-butyl
crotonate (2.50 g, 17.6 mmol) to give (R,R)-25 in >99:1 dr.
Purification via flash column chromatography (gradient elution,
1%/20% Et2O in 30e40 ꢁC petrol) gave (R,R)-25 as a pale yellow
a
½
ꢄ
½ ꢄ
a
oil (5.60 g, 90%, >99:1 dr);1c
a 2D0
ꢀ3.7 (c 1.1 in CH2Cl2)}.
½
a 2D5
ꢄ
ꢀ3.9 (c 1.0 in CH2Cl2); {lit.1c
NCH2Ph), 4.00 (1H, q, J 6.9, C(
7.18e7.43 (15H, m, Ph).
a
)H), 4.40 (1H, dd, J 9.9, 5.4, C(3)H),
½ ꢄ
4.7.10. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(3S, R)-3-[N-benzyl-N-( -methylbenzyl)amino]-3-phenylpropanoate 30.
4.7.8. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
a
a
(R,R)-3-[N-benzyl-N-(
a-methylbenzyl)amino]butanoate 29.
Ph
Ph
Ph
N
O
Ph
N
O
Ph
O
Me
O
Ph
Ph
Method A: Following general procedure 1, a solution of (R)-N-
benzyl-N-( -methylbenzyl)amine (350 mg, 1.66 mmol) in THF
Method A: Following general procedure 1, a solution of (R)-N-
a
benzyl-N-(
a
-methylbenzyl)amine (212 mg, 1.00 mmol) in THF
(3 mL) at ꢀ78 ꢁC was treated with BuLi (2.5 M in hexanes, 0.53 mL,
1.33 mmol) and 18 (300 mg, 0.83 mmol) in THF (3 mL) to give 30 in
83:17 dr. Purification via flash column chromatography (gradient
elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave an 83:17 mixture of
(2 mL) at ꢀ78 ꢁC was treated with BuLi (2.5 M in hexanes, 0.32 mL,
0.80 mmol) and 9 (150 mg, 0.50 mmol) in THF (2 mL) to give 29 in
88:12 dr. Purification via flash column chromatography (gradient

S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
6393
30 and its C(3)-epimer as a colourless oil (334 mg, 70%); nmax (film)
2964, 2924 (CeH), 1722 (C]O); m/z (ESIþ) 574 ([MþH]þ, 100%);
flash column chromatography (gradient elution, 1%/5% Et2O in
30e40 ꢁC petrol) gave a 37:63 mixture of 33 and 37 as a colourless
oil (83 mg, 10%); nmax (film) 2961, 2925 (CeH), 1725 (C]O); m/z
þ
HRMS (ESIþ) C40H48NO2 ([MþH]þ) requires 574.3680; found
þ
574.3680. Data for the (3R,10R,20S,50R,
a
R)-diastereoisomer: dH
(ESIþ) 498 ([MþH]þ, 100%); HRMS (ESIþ) C34H44NO2 ([MþH]þ)
(500 MHz, CDCl3) [selected peaks] 0.76 (3H, d, J 6.3, C(50)Me), 1.19
(3H, s, C(100)H3), 2.42 (2H, app d, J 7.8, C(2)H2), 3.65 (2H, AB system,
JAB 15.1, NCH2Ph), 4.22 (1H, app t, J 7.8, C(3)H); dC (125 MHz, CDCl3)
requires 498.3367; found 498.3368. Data for 37: dH (400 MHz,
CDCl3) 0.86e1.22 (3H, m, CH2, CH), 0.94 (3H, d, J 6.6, C(50)Me), 1.00
(3H, d, J 6.9, C(4)H3), 1.24 (3H, s, C(100)H3), 1.32 (3H, s, C(300)H3),
1.45e1.80 (3H, m, CH2, CH), 1.67 (1H, dd, J 14.5, 8.5, C(2)HA), 2.24
(1H, dd, J 14.5, 5.7, C(2)HB), 1.91e2.06 (2H, m, CH2), 3.02e3.31 (1H,
m, C(3)H), 3.53 (4H, AB system, JAB 13.9, N(CH2Ph)2), 4.80 (1H, app
td, J 10.6, 4.3, C(10)H), 7.14e7.46 (15H, m, Ph); dC (100 MHz, CDCl3)
14.7 (C(4)), 21.9 (C(50)Me), 24.6 (C(300)), 26.5 (CH2), 28.4 (C(100)), 31.3
(CH), 34.7 (CH2), 38.6 (CH2), 39.6 (C(200)), 41.6 (CH), 50.2 (C(2)), 50.5
(C(3)), 53.5 (N(CH2Ph)2), 74.2 (C(10)), 124.9, 125.4, 126.8, 128.0,
128.2, 128.4, 128.6, 128.8 (o,m,p-Ph), 140.1, 151.9 (i-Ph), 171.7 (C(1)).
Further elution gave 33 as a colourless oil that crystallised upon
standing (208 mg, 25%, >99:1 dr); C34H43NO2 requires C, 82.05; H,
[selected peaks] 19.3 (C(
(C(100)), 27.0 (CH2), 37.9 (C(2)), 39.7 (C(200)), 41.2 (CH2), 50.2
(NCH2Ph), 58.2 (C(
)), 59.3 (C(3)), 74.3 (C(10)), 140.4, 142.4, 144.6,
a
)Me), 21.8 (C(50)Me), 25.9 (C(300)), 26.6
a
151.4 (i-Ph), 170.9 (C(1)). Further elution gave 30 as a colourless oil
(86 mg,18%, >99:1 dr); ½a D24
þ87.8 (c 1.2 in CHCl3); nmax (film) 2964,
ꢄ
2924 (CeH), 1722 (C]O); dH (500 MHz, CDCl3) 0.51e1.06 (3H, m,
CH2, CH), 0.76 (3H, d, J 6.3, C(50)Me), 1.14 (3H, s, C(100)H3), 1.16 (3H, s,
C(300)H3), 1.26 (3H, d, J 6.9, C(
1.81e1.89 (1H, m, CH), 2.02 (1H, dd, J 14.8, 10.8, C(2)HA), 2.11 (1H,
dd, J 14.8, 3.8, C(2)HB), 3.61 (2H, AB system, JAB 15.1, NCH2Ph), 3.92
a
)Me), 1.29e1.66 (4H, m, 2ꢃ CH2),
(1H, q, J 6.9, C(
J 10.6, 4.3, C(10)H), 7.00e7.47 (20H, m, Ph); dC (125 MHz, CDCl3) 16.4
(C(
)Me), 21.7 (C(50)Me), 24.8 (C(300)), 26.5 (C(100)), 27.7 (CH2), 31.1
(CH), 34.5 (CH2), 37.0 (C(2)), 39.5 (C(200)), 41.1 (CH2), 50.3 (NCH2Ph),
50.9 (CH), 57.0 (C(
)), 59.2 (C(3)), 74.1 (C(10)), 125.0, 125.3, 125.4,
a
)H), 4.33 (1H, dd, J 10.8, 3.8, C(3)H), 4.59 (1H, app td,
8.7; N, 2.8%; found C, 82.2; H, 8.8; N, 2.7%; mp 71e72 ꢁC; ½a D24
þ12.6
ꢄ
(c 1.0 in CHCl3); nmax (KBr) 2961, 2925 (CeH), 1725 (C]O); dH
(500 MHz, CDCl3) 0.81e1.14 (3H, m, CH2, CH), 0.88 (3H, d, J 6.6, C(50)
Me), 1.03 (3H, d, J 6.9, C(4)H3), 1.20 (3H, s, C(100)H3), 1.28 (3H, s, C(300)
H3), 1.42e1.71 (3H, m, CH2, CH), 1.74 (1H, dd, J 14.5, 8.5, C(2)HA), 2.09
(1H, dd, J 14.5, 5.7, C(2)HB), 1.85e2.03 (2H, m, CH2), 3.08e3.16 (1H,
m, C(3)H), 3.46 (4H, AB system, JAB 13.9, N(CH2Ph)2), 4.76 (1H, app
td, J 10.6, 4.3, C(10)H), 7.11e7.38 (15H, m, Ph); dC (125 MHz, CDCl3)
15.1 (C(4)), 21.8 (C(50)Me), 25.0 (C(300)), 26.5 (CH2), 27.8 (C(100)), 31.3
(CH), 34.5 (CH2), 38.0 (CH2), 39.7 (C(200)), 41.6 (CH), 50.3 (C(2)), 50.5
(C(3)), 53.5 (N(CH2Ph)2), 74.0 (C(10)),124.9, 125.4, 126.7, 128.0,128.1,
128.7 (o,m,p-Ph), 140.1, 151.7 (i-Ph), 171.7 (C(1)).
a
a
126.5, 126.9, 127.1, 127.8, 127.9, 128.0, 128.1 (o,m,p-Ph), 141.6, 141.8,
143.9, 151.5 (i-Ph), 171.2 (C(1)).
Method B: Following general procedure 2, a solution of (3S,aR)-
26 (1.72 g, 4.14 mmol) in CH2Cl2 (17.0 mL) was treated with TFA
(17.0 mL) to give a white foam (1.41 g). Then, following general
procedure 3, a solution of the residue (378 mg, 1.05 mmol) in
CH2Cl2 (4 mL) was reacted with (COCl)2 (93 mL, 1.10 mmol) and
a solution of 6 (122 mg, 0.53 mmol) in CH2Cl2 (2 mL). Purification
via flash column chromatography (gradient elution, 1%/10% Et2O
in 30e40 ꢁC petrol) gave 30 as a colourless oil (176 mg, 55%, >99:1
4.7.12.1. X-ray crystal structure determination for 33. Data were
collected using a Nonius
k-CCD diffractometer with graphite
dr); ½a 2D5
ꢄ
þ88.0 (c 1.0 in CHCl3).
monochromated Mo K radiation using standard procedures at
a
150 K. The structure was solved by direct methods (SIR92); all non-
hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were added at idealised positions. The structure
was refined using CRYSTALS.40
4.7.11. tert-Butyl (3S,
aR)-3-[N-benzyl-N-(a-methylbenzyl)amino]-3-
phenylpropanoate 26.
Ph
X-ray crystal structure data for 33 [C34H43NO2]: M¼497.72,
ꢀ
ꢀ
monoclinic, space group Pꢁ21, a¼6.21350(10) A, b¼35.5431(5) A,
Ph
N
3
ꢀ
ꢀ
c¼13.2219(2) A,
b
¼91.2327(5) , V¼2919.34(8) A , Z¼4,
m
¼0.069 mmꢀ1
,
CO2tBu
colourless block, crystal dimensions¼0.10ꢃ0.14ꢃ0.15 mm3. A total
Ph
of 6339 unique reflections were measured for 5<q<27 and 4973
Following general procedure 1, a solution of (R)-N-benzyl-N-(a-
reflections were used in the refinement. The final parameters were
(I)]. Crystallographic data
methylbenzyl)amine (6.62 g, 31.3 mmol) in THF (80 mL) at ꢀ78 ꢁC
wR2¼0.251 and R1¼0.090 [I>ꢀ3.0
s
was treated with BuLi (2.5 M, 12.0 mL, 30.4 mmol) and tert-butyl
(excluding structure factors) has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number
CCDC 815827. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
[fax: þ44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
cinnamate (4.00 g, 19.6 mmol) to give (3S,aR)-26 in >99:1 dr.
Purification via flash column chromatography (gradient elution,
1%/20% Et2O in 30e40 ꢁC petrol) gave (3S,
aR)-26 as a pale yellow
oil (6.70 g, 83%, >99:1 dr);41
½
a 2D2
ꢄ
þ4.1 (c 1.0 in CHCl3); {lit.41 for
enantiomer ½a 2D3
ꢀ4.0 (c 1.0 in CHCl3)}.
ꢄ
4.7.13. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(S)-3-(N-isopropyl-N-benzylamino)butanoate 34 and (10R,20S,50R)-
20-(200-phenylpropan-200-yl)-50-methylcyclohexyl (R)-3-(N-isopropyl-
N-benzylamino)butanoate 38.
4.7.12. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(S)-3-(N,N-dibenzylamino)butanoate 33 and (10R,20S,50R)-20-(200-
phenylpropan-200-yl)-50-methylcyclohexyl (R)-3-(N,N-dibenzylamino)
butanoate 37.
Ph
Ph
Ph
Ph
Ph
N
O
Ph
N
O
N
O
N
O
Me
O
Me
O
Me
O
Me
O
Ph
Ph
33
37
Ph
Ph
34
38
Following general procedure 1,
a
solution of dibenzylamine
Following general procedure 1, a solution of N-benzyl-N-
isopropylamine (0.56 mL, 3.33 mmol) in THF (5 mL) at ꢀ78 ꢁC was
treated with BuLi (2.5 M in hexanes, 1.07 mL, 2.67 mmol) and 9
(500 mg, 1.67 mmol) in THF (5 mL) to give a 72:28 mixture of 34
(0.64 mL, 3.33 mmol) in THF (5 mL) at ꢀ78 ꢁC was treated with BuLi
(2.5 M in hexanes, 1.07 mL, 2.67 mmol) and 9 (500 mg, 1.67 mmol)
in THF (5 mL) to give a 78:22 mixture of 33 and 37. Purification via

6394
S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
and 38. Purification via flash column chromatography (gradient
elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave an 83:17 mixture
of 34 and 38 as a colourless oil (300 mg, 40%). Data for 38: dH
(500 MHz, CDCl3) 0.83e1.18 (3H, m, CH2, CH), 0.88 (3H, d, J 6.6,
C(50)Me), 0.96 (3H, d, J 6.6, C(4)H3), 0.99 (3H, d, J 6.6, NCHMeA),
1.00 (3H, d, J 6.6, NCHMeB), 1.21 (3H, s, C(100)H3), 1.30 (3H, s, C(300)
H3), 1.44e1.75 (3H, m, CH2, CH), 1.88e2.06 (2H, m, CH2), 1.60 (1H,
dd, J 14.5, 8.2, C(2)HA), 2.09 (1H, dd, J 14.5, 6.0, C(2)HB), 2.87 (1H,
septet, J 6.6, CHMe2), 3.09e3.16 (1H, m, C(3)H), 3.56 (2H, AB
system, JAB 14.8, NCH2Ph), 4.78 (1H, app td, J 10.6, 4.3, C(10)H),
7.10e7.35 (10H, m, Ph); dC (125 MHz, CDCl3) 18.1 (C(4)), 20.1, 21.0
(NCHMe2), 21.8 (C(50)Me), 24.5 (C(300)), 26.5 (CH2), 28.3 (C(100)),
31.3 (C(2)), 34.6 (CH), 39.6 (CH2), 40.9 (CH2), 41.7 (C(200)), 48.5
(CH), 48.8 (NCH2Ph), 49.3 (CHMe2), 50.3 (C(3)), 74.1 (C(10)), 124.9,
125.3, 126.3, 127.8, 128.0, 128.1 (o,m,p-Ph), 142.1, 151.9 (i-Ph), 171.9
(C(1)). Further elution gave 34 as a colourless oil (68 mg, 9%,
3.45 (4H, AB system, JAB 13.6, N(CH2Ph)2), 4.09 (1H, dd, J 9.2, 6.2,
C(3)H), 4.72 (1H, app td, J 10.6, 4.3, C(10)H), 7.10e7.42 (20H, m, Ph);
dC (100 MHz, CDCl3) 21.8 (C(50)Me), 24.6 (C(300)), 26.5 (CH2), 28.2
(C(100)), 31.2 (CH), 34.6 (CH2), 35.9 (C(2)), 39.6 (C(200)), 41.4 (CH2),
50.2 (CH), 53.8 (N(CH2Ph)2), 58.7 (C(3)), 74.3 (C(10)), 125.0, 125.4,
126.9, 127.2, 127.9, 128.2, 128.4, 128.6, 128.8 (o,m,p-Ph), 138.3, 139.8,
151.8 (i-Ph), 171.0 (C(1)).
4.7.15. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(R)-3-(N-isopropyl-N-benzylamino)-3-phenylpropanoate 36 and
(10R,20S,50R)-20-(200-phenylpropan-200-yl)-50-methylcyclohexyl (S)-3-
(N-isopropyl-N-benzylamino)-3-phenylpropanoate 40.
Ph
Ph
N
O
N
O
>99:1 dr); ½a 2D5
ꢄ
þ22.2 (c 0.5 in CHCl3); nmax (film) 2963, 2926
Ph
O
Ph
O
(CeH), 1725 (C]O); dH (500 MHz, CDCl3) 0.73e1.20 (3H, m, CH2,
CH), 0.93 (3H, d, J 6.6, C(50)Me), 0.99 (3H, d, J 6.6, C(4)H3), 1.04 (3H,
d, J 6.6, NCHMeA), 1.06 (3H, d, J 6.6, NCHMeB), 1.25 (3H, s, C(100)H3),
1.34 (3H, s, C(300)H3), 1.37e1.80 (4H, m, 2ꢃ CH2), 1.72 (1H, dd, J
14.7, 7.6, C(2)HA), 1.99 (1H, dd, J 14.7, 7.8, C(2)HB), 2.02e2.06 (1H,
m, CH), 2.86 (1H, septet, J 6.6, CHMe2), 3.28e3.38 (1H, m, C(3)H),
3.57 (2H, s, NCH2Ph), 4.85 (1H, app td, J 10.6, 4.3, C(10)H),
7.12e7.42 (10H, m, Ph); dC (125 MHz, CDCl3) 18.7 (C(4)), 20.1, 21.6
(NCHMe2), 22.3 (C(50)Me), 25.6 (C(300)), 27.0 (CH2), 28.3 (C(100)),
30.2 (C(2)), 31.7 (CH), 35.0 (CH2), 40.1 (CH2), 41.2 (C(200)), 48.8
(CH), 49.3 (NCH2Ph), 49.4 (CHMe2), 50.7 (C(3)), 74.4 (C(10)), 125.4,
125.8, 128.3, 128.6 (o,m,p-Ph), 142.5, 152.1 (i-Ph), 172.5 (C(1)); m/z
Ph
Ph
36
40
Following general procedure 1, a solution of N-benzyl-N-isopropyl-
amine (0.10 mL, 0.56 mmol) in THF (1 mL) at ꢀ78 ꢁC was treated
with BuLi (2.5 M in hexanes, 0.17 mL, 0.44 mmol) and 18 (100 mg,
0.28 mmol) in THF (1 mL) to give a 80:20 mixture of 36 and 40.
Purification via flash column chromatography (gradient elution,
1%/10% Et2O in 30e40 ꢁC petrol) gave a 80:20 mixture of 36 and
40 as a colourless oil (112 mg, 78%); nmax (film) 2961, 2925 (CeH),
1725 (C]þO); m/z (ESIþ) 512 ([MþH]þ, 100%); HRMS (ESIþ)
C35H46NO2 ([MþH]þ) requires 512.3523; found 512.3525. Data for
36: dH (400 MHz, CDCl3) 0.66e1.09 (3H, m, CH2, CH), 0.79 (3H, d, J
6.3, C(50)Me), 0.81 (3H, d, J 6.6, NCHMeA), 0.99 (3H, d, J 6.6, NCHMeB),
1.14 (3H, s, C(100)H3), 1.21 (3H, s, C(300)H3), 1.30e1.65 (4H, m, 2ꢃ CH2),
1.90e1.99 (1H, m, CH), 2.25e2.39 (2H, m, C(2)H2), 2.97 (1H, septet, J
6.6, CHMe2), 3.63 (2H, AB system, JAB 15.4, NCH2Ph), 4.11 (1H, dd, J
8.8, 6.3, C(3)H), 4.67 (1H, app td, J 10.6, 4.3, C(10)H), 7.13e7.44 (15H,
m, Ph); dC (100 MHz, CDCl3) 18.7, 21.2 (NCHMe2), 21.8 (C(50)Me), 25.5
(C(300)), 26.6 (CH2), 27.4 (C(100)), 31.1 (CH), 34.5 (C(2)), 38.8 (CH2), 39.6
(C(200)), 41.4 (CH2), 48.1 (CH), 49.2 (NCH2Ph), 50.3 (CHMe2), 59.9
(C(3)), 74.4 (C(10)), 125.1, 125.5, 126.5, 127.0, 127.9, 128.0, 128.3, 128.6,
128.7 (o,m,p-Ph), 141.6, 142.2, 151.6 (i-Ph), 171.2 (C(1)). Data for 40: dH
(400 MHz, CDCl3) 0.51e1.12 (3H, m, CH2, CH), 0.78 (3H, d, J 6.3, C(50)
Me), 0.86 (3H, d, J 6.6, NCHMeA), 1.03 (3H, d, J 6.6, NCHMeB), 1.18 (3H,
s, C(100)H3), 1.24 (3H, s, C(300)H3), 1.27e1.73 (4H, m, 2ꢃ CH2),
1.87e1.95 (1H, m, CH), 2.03 (1H, dd, J 14.4, 10.4, C(2)HA), 2.33 (1H,
dd, J 14.4, 4.8, C(2)HB), 2.96 (1H, septet, J 6.6, CHMe2), 3.66 (2H, AB
system, JAB 15.4, NCH2Ph), 4.14 (1H, dd, J 10.4, 4.8, C(3)H), 4.65 (1H,
app td, J 10.6, 4.3, C(10)H), 7.00e7.44 (15H, m, Ph); dC (100 MHz,
CDCl3) 18.8, 20.9 (NCHMe2), 21.7 (C(50)Me), 24.2 (C(300)), 26.4 (CH2),
28.3 (C(100)), 31.1 (CH), 34.5 (C(2)), 38.4 (CH2), 39.5 (C(200)), 41.2 (CH2),
48.2 (CH), 49.4 (NCH2Ph), 50.3 (CHMe2), 60.4 (C(3)), 74.9 (C(10)),
125.1, 125.5, 126.5, 126.9, 127.8, 128.0, 128.2, 128.6, 128.8 (o,m,p-Ph),
141.8, 142.2, 151.6 (i-Ph), 171.4 (C(1)).
þ
(ESIþ) 450 ([MþH]þ, 100%); HRMS (ESIþ) C30H44NO2 ([MþH]þ)
requires 450.3367; found 450.3362.
4.7.14. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(R)-3-(N,N-dibenzylamino)-3-phenylpropanoate 35 and (10R,20S,50R)-
20-(200-phenylpropan-200-yl)-50-methylcyclohexyl (S)-3-(N,N-dibenzyl-
amino)-3-phenylpropanoate 39.
Ph
Ph
Ph
N
O
Ph
N
O
Ph
O
Ph
O
Ph
Ph
35
39
Following general procedure 1,
a solution of dibenzylamine
(0.32 mL, 1.66 mmol) in THF (3 mL) at ꢀ78 ꢁC was treated with BuLi
(2.5 M in hexanes, 0.53 mL,1.33 mmol) and 18 (300 mg, 0.83 mmol)
in THF (3 mL) to give a 65:35 mixture of 35 and 39. Purification via
flash column chromatography (gradient elution, 1%/10% Et2O in
30e40 ꢁC petrol) gave a 65:35 mixture of 35 and 39 as a colourless
oil (394 mg, 85%); nmax (film) 2954, 2924 (CeH), 1725 þ(C]O); m/z
(ESIþ) 560 ([MþH]þ, 100%); HRMS (ESIþ) C39H46NO2 ([MþH]þ)
requires 560.3523; found 560.3523. Data for 35: dH (400 MHz,
CDCl3) 0.75e1.15 (3H, m, CH2, CH), 0.88 (3H, d, J 6.3, C(50)Me), 1.22
(3H, s, C(100)H3), 1.30 (3H, s, C(300)H3), 1.37e1.80 (4H, m, 2ꢃ CH2),
1.96e2.05 (1H, m, CH), 2.39e2.54 (2H, m, C(2)H2), 3.45 (4H, AB
system, JAB 13.6, N(CH2Ph)2), 4.19 (1H, app t, J 7.6, C(3)H), 4.76 (1H,
app td, J 10.6, 4.3, C(10)H), 7.12e7.45 (20H, m, Ph); dC (100 MHz,
CDCl3) 21.9 (C(50)Me), 25.4 (C(300)), 26.6 (CH2), 27.7 (C(100)), 31.2
(CH), 34.6 (CH2), 36.3 (C(2)), 39.7 (C(200)), 41.5 (CH2), 50.3 (CH), 53.8
(N(CH2Ph)2), 58.7 (C(3)), 74.5 (C(10)), 125.0, 125.5, 126.9, 127.3,
128.0, 128.2, 128.4, 128.6, 128.7, 128.8 (o,m,p-Ph), 138.1, 139.8, 151.7
(i-Ph), 171.0 (C(1)). Data for 39: dH (400 MHz, CDCl3) 0.72e1.15 (3H,
m, CH2, CH), 0.85 (3H, d, J 6.3, C(50)Me), 1.20 (3H, s, C(100)H3), 1.27
(3H, s, C(300)H3), 1.33e1.76 (4H, m, 2ꢃ CH2), 1.93e2.02 (1H, m, CH),
2.26 (1H, dd, J 14.9, 9.2, C(2)HA), 2.55 (1H, dd, J 14.9, 6.2, C(2)HB),
4.7.16. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(S)-3-aminobutanoate 41.
NH2
O
Me
O
Ph
Following general procedure 4, 23 (410 mg, 0.80 mmol) and
Pd(OH)2/C (205 mg) in EtOAc (5 mL) under H2 (5 atm) for 18 h gave
41. Purification via flash column chromatography (eluent 30e40 ꢁC
petrol (1% Et3N)/Et2O, 3:1, increased to 1:3) gave 41 as a pale yellow

S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
6395
oil (192 mg, 76%, >99:1 dr); ½a D25
ꢄ
þ12.9 (c 2.0 in CHCl3); nmax (film)
Purification via flash column chromatography (gradient elution,
1%/10% Et2O in 30e40 ꢁC petrol) gave 35 as a colourless oil
(71 mg, 88%, >99:1 dr).
3374 (NeH), 2959, 2924 (CeH), 1723 (C]O); dH (500 MHz, CDCl3)
0.87e1.22 (3H, m, CH2, CH), 0.91 (3H, d, J 6.6, C(50)Me), 1.03 (3H, d, J
6.3, C(4)H3), 1.24 (3H, s, C(100)H3), 1.35 (3H, s, C(300)H3), 1.46e1.92
(4H, m, 2ꢃ CH2), 1.65e1.73 (2H, m, NH2), 1.74e1.82 (2H, m, C(2)H2),
2.04e2.11 (1H, m, CH), 3.10e3.19 (1H, m, C(3)H), 4.87 (1H, app td, J
10.6, 4.3, C(10)H), 7.14e7.35 (5H, m, Ph); dC (125 MHz, CDCl3) 21.8
(C(50)Me), 23.2 (C(4)), 24.2 (C(300)), 26.4 (CH2), 28.6 (C(100)), 31.3
(CH), 34.5 (CH2), 39.5 (C(200)), 41.8 (CH2), 43.7 (CH), 43.9 (C(2)), 50.2
(C(3)), 73.9 (C(10)), 124.9, 125.4, 127.9 (o,m,p-Ph), 151.7 (i-Ph), 171.þ8
(C(1)); m/z (ESIþ) 318 ([MþH]þ, 100%); HRMS (ESIþ) C20H32NO2
([MþH]þ) requires 318.2428; found 318.2428.
4.7.20. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(S)-3-(N-isopropylamino)butanoate 45.
NH
O
Me
O
Ph
4.7.17. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(R)-3-amino-3-phenylpropanoate 42.
Following general procedure 6, 41 (76 mg, 0.24 mmol), acetone
(35 L, 0.48 mmol) and NaBH3CN (60 mg, 0.96 mmol) were reacted
NH2
O
m
Ph
O
in MeOH (2 mL). Purification via flash column chromatography
(gradient elution, 1%/50% Et2O in 30e40 ꢁC petrol) gave 45 as
a colourless oil (63 mg, 73%, >99:1 dr); ½a D25
ꢄ
ꢀ2.2 (c 0.5 in CHCl3);
Ph
nmax (film)3321 (NeH), 2962, 2925 (CeH),1725 (C]O);dH (400 MHz,
CDCl3) 0.87 (3H, d, J 6.3, C(50)Me), 0.90e1.18 (3H, m, CH2, CH), 0.98
(3H, d, J 6.6, C(4)H3), 1.01 (3H, d, J 6.3, NCHMeA), 1.03 (3H, d, J 6.3,
NCHMeB),1.20 (3H, s, C(100)H3),1.31 (3H, s, C(300)H3),1.39e1.89 (4H, m,
2ꢃ CH2), 1.42e1.45 (1H, m, NH), 1.70 (1H, dd, J 15.4, 6.3, C(2)HA), 1.93
(1H, dd, J 15.4, 6.3, C(2)HB), 1.97e2.07 (1H, m, CH), 2.80 (1H, septet, J
6.3, CHMe2), 2.94e3.03 (1H, m, C(3)H), 4.82 (1H, app td, J 10.6, 4.3,
C(10)H), 7.08e7.32 (5H, m, Ph); dC (100 MHz, CDCl3) 20.6 (C(4)), 21.8
(C(50)Me), 22.8, 23.3 (NCHMe2), 24.7 (C(300)), 26.6 (CH2), 28.1 (C(100)),
29.7 (CH2), 31.3 (CH), 34.6 (CH2), 39.7 (C(200)), 41.7 (C(2)), 45.3 (CH),
47.0 (CHMe2), 50.2 (C(3)), 74.1 (C(10)), 125.0, 125.3, 128.0 (o,m,p-Ph),
150.6 (i-Ph), 171.6 (C(1)); m/z (ESIþ) 360 ([MþH]þ, 100%); HRMS
(ESIþ) C23H38NO2þ ([MþH]þ) requires 360.2897; found 360.2897.
Followinggeneralprocedure4, 24 (168 mg, 0.29 mmol)andPd(OH)2/
C (85 mg) in MeOH/AcOH (v/v 40:1, 4.1 mL) under H2 (5 atm) for 18 h
gave 42. Purification via flash column chromatography (eluent
30e40 ꢁC petrol (1% Et3N)/Et2O, 3:1, increased to 1:3) gave 42 as
a colourless oil (67 mg, 61%, >99:1 dr); ½a D25
þ42.8 (c 0.5 in CHCl3);
ꢄ
nmax (film)3385(NeH), 2955, 2923 (CeH),1722(C]O); dH (500 MHz,
CDCl3) 0.82e1.16 (3H, m, CH2, CH), 0.86 (3H, d, J 6.3, C(50)Me),1.18 (3H,
s, C(100)H3), 1.28 (3H, s, C(300)H3), 1.39e1.83 (4H, m, 2ꢃ CH2), 1.73 (2H,
br s, NH2),1.97e2.04 (1H, m, CH),1.99 (1H, dd, J 16.1, 4.4, C(2)HA), 2.15
(1H, dd, J 16.1, 9.5, C(2)HB), 4.15 (1H, dd, J 9.5, 4.4, C(3)H), 4.82 (1H, app
td, J 10.7, 4.4, C(10)H), 7.05e7.35 (10H, m, Ph);dC (125 MHz, CDCl3) 21.8
(C(50)Me), 24.6 (C(300)), 26.5 (CH2), 28.3 (C(100)), 31.3 (CH), 34.5 (CH2),
39.7 (C(200)), 41.6 (CH2), 43.8 (C(2)), 50.3 (CH), 52.2 (C(3)), 74.2 (C(10)),
125.1, 125.4, 126.3, 127.2, 128.0, 128.4 (o,m,p-Ph), 144.6, 151.5 (i-Ph),
171.4 (C(1)); m/z (ESIþ) 380 ([MþH]þ, 100%); HRMS (ESIþ)
C25H34NO2þ ([MþH]þ) requires 380.2584; found 380.2581.
4.7.21. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(R)-3-(isopropylamino)-3-phenylpropanoate 46.
4.7.18. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(S)-3-(N,N-dibenzylamino)butanoate 33.
NH
O
Ph
O
Ph
Ph
Ph
N
O
Me
O
Ph
Following general procedure 6, 42 (125 mg, 0.33 mmol), acetone
(48 L, 0.66 mmol) and NaBH3CN (83 mg, 1.32 mmol) were reacted
Following general procedure 5, 41 (100 mg, 0.31 mmol) was
reacted with K2CO3 (435 mg, 3.15 mmol) in BnBr (0.37 mL,
3.15 mmol). Purification via flash column chromatography (gradient
elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave 33 as a white solid
m
in MeOH (3 mL). Purification via flash column chromatography
(gradient elution, 1%/50% Et2O in 30e40 ꢁC petrol) gave 46 as
a colourless oil (86 mg, 62%, >99:1 dr); ½a D25
þ26.8 (c 0.5 in CHCl3);
ꢄ
(147 mg, 95%, >99:1 dr); mp 71e72 ꢁC; ½a D25
þ12.8 (c 0.5 in CHCl3).
ꢄ
nmax (film) 3407 (NeH), 2959, 2924 (CeH), 1725 (C]O); dH
(500 MHz, CDCl3) 0.80e1.15 (3H, m, CH2, CH), 0.88 (3H, d, J 6.6, C(50)
Me), 0.98 (3H, d, J 6.3, NCHMeA),1.06 (3H, d, J 6.3, NCHMeB),1.19 (3H,
s, C(100)H3),1.27 (3H, s, C(300)H3),1.39e1.72 (4H, m, 2ꢃ CH2),1.72e1.80
(1H, m, NH), 1.96e2.04 (1H, m, CH), 2.07 (1H, dd, J 15.7, 6.1, C(2)HA),
2.23 (1H, dd, J 15.7, 8.2, C(2)HB), 2.52e2.62 (1H, m, CHMe2), 4.01 (1H,
dd, J 8.2, 6.1, C(3)H), 4.80 (1H, app td, J 10.6, 4.3, C(10)H), 7.08e7.38
(10H, m, Ph); dC (125 MHz, CDCl3) 21.7 (C(50)Me), 21.9, 24.2
(NCHMe2), 25.1 (C(300)), 26.5 (CH2), 27.5 (C(100)), 31.2 (CH), 34.5 (CH2),
39.6 (C(200)), 41.6 (CH2), 43.1 (C(2)), 45.5 (CH), 50.3 (CHMe2), 56.5
(C(3)), 74.4 (C(10)), 125.1, 125.4, 127.1, 127.8, 128.4 (o,m,p-Ph), 143.1,
151.5 (i-Ph), 171.1 (C(1)); m/z (ESIþ) 422 ([MþH]þ, 100%); HRMS
(ESIþ) C28H40NO2þ ([MþH]þ) requires 422.3054; found 422.3054.
4.7.19. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(R)-3-(N,N-dibenzylamino)-3-phenylpropanoate 35.
Ph
Ph
N
O
Ph
O
Ph
Following general procedure 5, 42 (55 mg, 0.15 mmol) was reacted
with K2CO3 (200 mg, 1.45 mmol) in BnBr (0.17 mL, 1.45 mmol).

6396
S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
4.7.22. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(S)-3-(N-isopropyl-N-benzylamino)butanoate 34.
for 18 h gave 44. Purification via flash column chromatography
(eluent 30e40 ꢁC petrol (1% Et3N)/Et2O, 3:1, increased to 1:3) gave
44 as a colourless oil (81 mg, 65%, >99:1 dr); ½a D21
þ4.2 (c 2.1 in
ꢄ
Ph
CHCl3); nmax (film) 3385 (NeH), 2955, 2923 (CeH), 1722 (C]O); dH
(400 MHz, CDCl3) 0.80e1.17 (3H, m, CH2, CH), 0.86 (3H, d, J 6.3, C(50)
Me), 1.21 (3H, s, C(100)H3), 1.32 (3H, s, C(300)H3), 1.38e1.83 (4H, m, 2ꢃ
CH2), 1.60e1.77 (2H, m, NH2), 1.97e2.04 (1H, m, CH), 2.04e2.13 (2H,
m, C(2)H2), 4.11 (1H, dd, J 8.3, 5.1, C(3)H), 4.82 (1H, app td, J 10.9, 4.6,
C(10)H), 7.13e7.45 (10H, m, Ph); dC (100 MHz, CDCl3) 21.8 (C(50)Me),
24.6 (C(300)), 26.5 (CH2), 28.3 (C(100)), 31.3 (CH), 34.5 (CH2), 39.7
(C(200)), 41.6 (CH2), 44.2 (C(2)), 50.2 (CH), 52.4 (C(3)), 74.4 (C(10)),
125.1, 125.4, 126.3, 127.2, 128.0, 128.4 (o,m,p-Ph), 144.7, 151.7 (i-Ph),
171.2 (C(1þ)); m/z (ESIþ) 380 ([MþH]þ, 100%); HRMS (ESIþ)
C25H34NO2 ([MþH]þ) requires 380.2584; found 380.2581.
N
O
Me
O
Ph
Following general procedure 5, 45 (62 mg, 0.17 mmol) was
reacted with K2CO3 (238 mg, 1.72 mmol) in BnBr (0.21 mL,
1.72 mmol). Purification via flash column chromatography (gradient
elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave 34 as a colourless
oil (70 mg, 90%, >99:1 dr).
4.7.26. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(R)-3-(N,N-dibenzylamino)butanoate 37.
4.7.23. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(R)-3-(N-isopropyl-N-benzylamino)-3-phenylpropanoate 36.
Ph
Ph
Ph
N
O
N
O
Me
O
Ph
O
Ph
Ph
Following general procedure 5, 43 (86 mg, 0.27 mmol) was reacted
with K2CO3 (375 mg, 2.71 mmol) in BnBr (0.32 mL, 2.71 mmol).
Purification via flash column chromatography (gradient elution,
1%/10% Et2O in 30e40 ꢁC petrol) gave 37 as a colourless oil
(116 mg, 86%, >99:1 dr).
Following general procedure 5, 46 (67 mg, 0.16 mmol) was reacted
with K2CO3 (221 mg, 1.59 mmol) in BnBr (0.19 mL, 1.59 mmol).
Purification via flash column chromatography (gradient elution,
1%/10% Et2O in 30e40 ꢁC petrol) gave 36 as a colourless oil
(68 mg, 83%, >99:1 dr).
4.7.27. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(S)-3-(N,N-dibenzylamino)-3-phenylpropanoate 39.
4.7.24. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(R)-3-aminobutanoate 43.
Ph
Ph
N
O
NH2
O
Ph
O
Me
O
Ph
Ph
Following general procedure 5, 44 (60 mg, 0.16 mmol) was reacted
with K2CO3 (218 mg, 1.58 mmol) in BnBr (0.19 mL, 1.58 mmol).
Purification via flash column chromatography (gradient elution,
1%/10% Et2O in 30e40 ꢁC petrol) gave 39 as a colourless oil
(80 mg, 90%, >99:1 dr).
Following general procedure 4, 29 (160 mg, 0.31 mmol) and
Pd(OH)2/C (80 mg) in EtOAc (4 mL) under H2 (5 atm) for 18 h gave 43
as a colourless oil (97 mg, 98%, >99:1 dr); ½a D25
ꢀ25.0 (c 0.5 in CHCl3);
ꢄ
nmax (film) 3378 (NeH), 2957, 2924 (CeH), 1724 (C]O); dH
(400 MHz, CDCl3) 0.82e1.17 (3H, m, CH2, CH), 0.85 (3H, d, J 6.6, C(50)
Me), 0.94 (3H, d, J 6.3, C(4)H3), 1.18 (3H, s, C(100)H3), 1.30 (3H, s, C(300)
H3), 1.32e1.78 (4H, m, 2ꢃ CH2), 1.61e1.73 (2H, m, NH2), 1.79e1.90
(2H, m, C(2)H2), 1.95e2.08 (1H, m, CH), 2.97e3.10 (1H, m, C(3)H),
4.80 (1H, app td, J 10.6, 4.3, C(10)H), 7.09e7.31 (5H, m, Ph); dC
(100 MHz, CDCl3) 21.7 (C(50)Me), 23.2 (C(4)), 24.4 (C(300)), 26.5 (CH2),
28.4 (C(100)), 31.5 (CH), 34.5 (CH2), 39.7 (C(200)), 41.3 (CH2), 43.7 (CH),
44.3 (C(2)), 50.2 (C(3)), 74.5 (C(10)), 125.1, 125.5, 128.0 (o,m,p-Ph),
151.8 (i-Ph), 171.2 (C(1)); m/z (ESIþ) 318 ([MþH]þ, 100%); HRMS
(ESIþ) C20H32NO2þ ([MþH]þ) requires 318.2428; found 318.2427.
4.7.28. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(R)-3-(N-isopropylamino)butanoate 47.
NH
O
Me
O
Ph
4.7.25. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(S)-3-amino-3-phenylpropanoate 44.
Following general procedure 6, 43 (96 mg, 0.32 mmol), acetone
(47 L, 0.64 mmol) and NaBH3CN (80 mg, 1.26 mmol) were reacted
m
in MeOH (2 mL). Purification via flash column chromatography
(gradient elution, 1%/50% Et2O in 30e40 ꢁC petrol) gave 47 as
a colourless oil (95 mg, 83%, >99:1 dr); ½a D25
ꢄ
þ6.0 (c 0.5 in CHCl3);
NH2
O
nmax (film) 3320 (NeH), 2960, 2924 (CeH), 1725 (C]O); dH
(500 MHz, CDCl3) 0.88 (3H, d, J 6.3, C(50)Me), 0.90e1.18 (3H, m, CH2,
CH), 0.97 (3H, d, J 6.6, C(4)H3), 1.00 (3H, d, J 6.3, NCHMeA), 1.02 (3H,
d, J 6.3, NCHMeB), 1.22 (3H, s, C(100)H3), 1.31 (3H, s, C(300)H3),
1.39e1.89 (4H, m, 2ꢃ CH2), 1.42e1.45 (1H, m, NH), 1.71 (1H, dd, J
15.4, 6.3, C(2)HA), 2.00 (1H, dd, J 15.4, 6.3, C(2)HB), 1.97e2.07 (1H, m,
Ph
O
Ph
Following general procedure 4, 30 (189 mg, 0.33 mmol) and
Pd(OH)2/C (95 mg) in MeOH/AcOH (v/v 40:1, 4.1 mL) under H2 (5 atm)

S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
6397
CH), 2.79 (1H, septet, J 6.3, CHMe2), 2.88e2.95 (1H, m, C(3)H), 4.80
(1H, app td, J 10.6, 4.3, C(10)H), 7.08e7.32 (5H, m, Ph); dC (125 MHz,
CDCl3) 20.1 (C(4)), 21.8 (C(50)Me), 22.2, 22.8 (NCHMe2), 25.2 (C(300)),
26.6 (CH2), 27.8 (C(100)), 31.0 (CH2), 31.3 (CH), 34.5 (CH2), 39.7
(C(200)), 41.8 (C(2)), 45.6 (CH), 47.2 (CHMe2), 50.3 (C(3)), 74.6 (C(10)),
125.1, 125.4, 127.9 (o,m,p-Ph), 151.5 (i-Ph), 171.4 (C(1)); m/z (ESIþ)
1%/10% Et2O in 30e40 ꢁC petrol) gave 40 as a colourless oil
(58 mg, 80%, >99:1 dr).
4.7.32. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (E)-but-2-
enamide 54.
þ
360 ([MþH]þ, 100%); HRMS (ESIþ) C23H38NO2 ([MþH]þ) requires
O
360.2897; found 360.2897.
Me
N
OtBu
4.7.29. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(S)-3-(N-isopropylamino)-3-phenylpropanoate 48.
K2CO3 (5.80 g, 42.0 mmol) and crotonoyl chloride (1.00 mL,
10.5 mmol) were added sequentially to a stirred solution of (S)-8$(þ)-
CSA8a (2.00 g, 4.20 mmol) in CH2Cl2 (40 mL) at rt. The resultant
mixture was stirred at rt for 12 h then quenched with H2O (40 mL).
The aqueous layer was extracted with CH2Cl2 (3ꢃ40 mL) and the
combined organic extracts were washed with brine (40 mL), then
dried and concentrated in vacuo. Purification via flash column chro-
matography (gradient elution, 1%/20% Et2O in 30e40 ꢁC petrol)
gave 54 as a colourless oil that crystallised upon standing (1.15 g, 88%,
>99:1 dr); C20H25NO2 requires C, 77.1; H, 8.1;N, 4.5%; found C, 77.0; H,
NH
O
Ph
O
Ph
Following general procedure 6, 44 (85 mg, 0.22 mmol), acetone
(38 L, 0.52 mmol) and NaBH3CN (65 mg, 1.04 mmol) were reacted
m
in MeOH (2 mL). Purification via flash column chromatography
8.2; N, 4.4%; mp 68e70 ꢁC; ½a D24
ꢀ87.6 (c 1.0 in CHCl3); nmax (KBr)
ꢄ
(gradient elution, 1%/50% Et2O in 30e40 ꢁC petrol) gave 48 as
2979, 2937, 2913 (CeH), 1657 (C]O), 1624 (C]C); dH (250 MHz,
PhMe-d8, 343 K) 0.69 (9H, s, CMe3),1.55 (3H, dd, J 6.7,1.5, C(4)H3),1.68
(3H, d, J 7.0, C(10)Me), 6.35e6.56 (1H, br m, C(10)H), 6.63 (1H, dq, J 15.2,
1.5, C(2)H), 7.03e7.29 (3H, m, C(3)H, Ar), 7.31e7.42 (1H, m, Ar),
7.48e7.66 (3H, m, Ar), 8.48e8.72 (1H, br m, Ar); dC (100 MHz, CDCl3)
16.2 (C(10)Me),18.4 (C(4)), 27.8 (CMe3), 55.4 (C(10)), 82.6 (CMe3),123.3
(C(2)),126.5 (C(3)),124.1,124.2,124.4,124.9,125.6,126.0,128.6,133.6,
136.4,142.9 (Ar),173.7 (C(1)); m/z (ESIþ) 334 ([MþNa]þ,100%); HRMS
(ESIþ) C20H25NNaO2þ ([MþNa]þ) requires 334.1778; found 334.1780.
a colourless oil (82 mg, 75%, >99:1 dr); ½a D25
ꢄ
e11.6 (c 1.0 in CHCl3);
nmax (film) 3426 (NeH), 2970, 2927 (CeH), 1726 (C]O); dH
(400 MHz, CDCl3) 0.73e1.14 (3H, m, CH2, CH), 0.84 (3H, d, J 6.6, C(50)
Me), 0.96 (3H, d, J 6.3, NCHMeA), 1.00 (3H, d, J 6.3, NCHMeB), 1.21
(3H, s, C(100)H3), 1.30 (3H, s, C(300)H3), 1.34e1.72 (4H, m, 2ꢃ CH2),
1.59e1.66 (1H, m, NH), 1.93e2.01 (1H, m, CH), 2.04 (1H, dd, J 15.2,
5.8, C(2)HA), 2.15 (1H, dd, J 15.2, 8.6, C(2)HB), 2.54 (1H, septet, J 6.3,
CHMe2), 3.94 (1H, dd, J 8.6, 5.8, C(3)H), 4.76 (1H, app td, J 10.6, 4.3,
C(10)H), 7.09e7.34 (10H, m, Ph); dC (100 MHz, CDCl3) 21.7 (C(50)Me),
21.9, 24.2 (NCHMe2), 25.0 (C(300)), 26.5 (CH2), 27.9 (C(100)), 31.2 (CH),
34.5 (CH2), 39.7 (C(200)), 41.5 (CH2), 43.5 (C(2)), 45.4 (CH), 50.3
(CHMe2), 56.7 (C(3)), 74.3 (C(10)), 125.1, 125.4, 127.0, 127.9, 128.3
(o,m,p-Ph), 143.3, 151.6 (i-Ph), 171.1 (C(1)); m/z (ESIþ) 422 ([MþH]þ,
4.7.32.1. X-ray crystal structure determination for 54. Data were
collected using a Nonius
k-CCD diffractometer with graphite
monochromated Mo K radiation using standard procedures at
a
150 K. The structure was solved by direct methods (SIR92); all non-
hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were added at idealised positions. The structure
was refined using CRYSTALS.40
þ
100%); HRMS (ESIþ) C28H40NO2 ([MþH]þ) requires 422.3054;
found 422.3054.
4.7.30. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(R)-3-(N-isopropyl-N-benzylamino)butanoate 38.
X-ray crystal structure data for 54 [C20H25NO2]: M¼622.85,
ꢀ
3
ꢀ
ꢀ
monoclinic, space group Pꢁ21, a¼13.1038(2) A, b¼9.7412(2) A, c¼
ꢀ
Ph
14.4605(3) A,
b
¼101.4490(9) , V¼1809.11(6) A , Z¼4,
m
¼0.073 mmꢀ1
,
colourless block, crystal dimensions¼0.16ꢃ0.19ꢃ0.21 mm3. A total
N
O
of 4332 unique reflections were measured for 5<q<27 and 4332
reflections were used in the refinement. The final parameters
(I)]. Crystallographic
Me
O
were wR2¼0.106 and R1¼0.051 [I>ꢀ3.0
s
data (excluding structure factors) has been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 815828. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: þ44 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
Ph
Following general procedure 5, 47 (76 mg, 0.21 mmol) was reacted
with K2CO3 (292 mg, 2.11 mmol) in BnBr (0.25 mL, 2.11 mmol).
Purification via flash column chromatography (gradient elution,
1%/10% Et2O in 30e40 ꢁC petrol) gave 38 as a colourless oil
(71 mg, 75%, >99:1 dr).
4.7.33. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (E)-3-phenylpro-
panamide 55.
4.7.31. (10R,20S,50R)-20-(200-Phenylpropan-200-yl)-50-methylcyclohexyl
(S)-3-(N-isopropyl-N-benzylamino)-3-phenylpropanoate 40.
O
Ph
Ph
N
OtBu
N
O
Ph
O
Ph
K2CO3 (5.80 g, 42.0 mmol) and cinnamoyl chloride (1.76 g,
10.5 mmol) were added sequentiallly to a stirred solution of
(S)-8$(þ)-CSA8a (2.00 g, 4.20 mmol) in CH2Cl2 (40 mL) at rt. The
resultant mixture was stirred at rt for 12 h then quenched with
Following general procedure 5, 48 (60 mg, 0.14 mmol) was reacted
with K2CO3 (196 mg, 1.42 mmol) in BnBr (0.17 mL, 1.42 mmol).
Purification via flash column chromatography (gradient elution,

6398
S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
H2O (40 mL). The aqueous layer was extracted with CH2Cl2
(3ꢃ40 mL) and the combined organic extracts were washed with
brine (40 mL), then dried and concentrated in vacuo. Purification
via flash column chromatography (gradient elution, 1%/20%
Et2O in 30e40 ꢁC petrol) gave 55 as a colourless oil that crys-
Method B: Following general procedure 2, a solution of (R,R)-25
(1.67 g, 4.72 mmol) in CH2Cl2 (16.0 mL) was treated with TFA
(16.0 mL) to give a white foam (1.36 g). Then, following general
procedure 3, a solution of the residue (156 mg) in CH2Cl2 (2 mL)
was reacted with (COCl)2 (0.10 mL, 1.04 mmol) and a mixture of (S)-
8$(þ)-CSA8a (100 mg, 0.21 mmol) and K2CO3 (290 mg, 2.10 mmol)
in CH2Cl2 (1 mL). Purification via flash column chromatography
(gradient elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave 56 as
a colourless oil that crystallised upon standing (18 mg, 16%, >95:5
tallised upon standing (1.47 g, 94%, >99:1 dr); mp 85e86 ꢁC; ½a D17
ꢄ
e44.5 (c 1.0 in CHCl3); nmax (KBr) 2975, 2932 (CeH), 1648 (C]O),
1623 (C]C); dH (250 MHz, PhMe-d8, 343 K) 0.73 (9H, s, CMe3),
1.73 (3H, d, J 6.7, C(10)Me), 6.47e6.64 (1H, br m, C(10)H), 7.05e7.15
(2H, m, Ar), 7.18e7.45 (7H, m, C(2)H, Ar, Ph), 7.53e7.66 (3H, m,
Ar), 7.92 (1H, d, J 15.8, C(3)H), 8.56e8.76 (1H, br m, Ar); dC
(100 MHz, CDCl3) 16.4 (C(10)Me), 27.8 (CMe3), 55.6 (C(10)), 83.1
(CMe3), 118.8 (C(2)), 126.6 (C(3)), 124.5, 124.9, 125.7, 126.1, 128.0,
128.6, 128.9, 129.9, 133.7, 135.4, 143.3 (Ar, Ph), 173.8 (C(1)); m/þz
(ESIþ) 396 ([MþNa]þ, 100%); HRMS (ESIþ) C25H27NNaO2
([MþNa]þ) requires 396.1934; found 396.1932.
dr); mp 155e158 ꢁC; ½a D25
þ33.9 (c 1.0 in CHCl3).
ꢄ
4.7.34.1. X-ray crystal structure determination for 56. Data were
collected using a Nonius -CCD diffractometer with graphite
monochromated Mo K radiation using standard procedures at
k
a
150 K. The structure was solved by direct methods (SIR92); all non-
hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were added at idealised positions. The structure
was refined using CRYSTALS.40
4.7.33.1. X-ray crystal structure determination for 55. Data were
collected using a Nonius
k
-CCD diffractometer with graphite
X-ray crystal structure data for 56 [C35H42N2O2]: M¼522.73,
ꢀ
monochromated Mo K radiation using standard procedures at
a
monoclinic, space group P21, a¼11.6903(3) A, b¼10.8507(3)
3
ꢀ
¼104.3593(14)ꢁ, V¼1494.64(7) A , Z¼2,
ꢀ
ꢀ
150 K. The structure was solved by direct methods (SIR92); all non-
hydrogen atoms were refined with anisotropic thermal parameters.
Hydrogen atoms were added at idealised positions. The structure
was refined using CRYSTALS.40
A, c¼12.1629(3) A,
b
m
¼0.071 mmꢀ1
,
colourless plate, crystal dimensions¼0.11ꢃ
0.13ꢃ0.24 mm3. A total of 3557 unique reflections were measured
for 5<q<27 and 3120 reflections were used in the refinement. The
X-ray crystal structure data for 55 [C25H27NO2]: M¼373.49,
final parameters were wR2¼0.079 and R1¼0.035 [I>e3.0
s(I)].
ꢀ
orthorhombic, space group P212121, a¼8.11180(10) A, b¼26.0315(4)
Crystallographic data (excluding structure factors) has been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 815830. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK [fax: þ44 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
3
ꢀ
¼0.076 mmꢀ1, colourless
ꢀ
ꢀ
A, c¼9.7014(2) A, V¼2048.75(6) A , Z¼4,
m
plate, crystal dimensions¼0.16ꢃ0.20ꢃ0.28 mm3. A total of 2632
unique reflections were measured for 5<q<27 and 2028 reflections
were used in the refinement. The final parameters were wR2¼0.065
and R1¼0.031 [I>e3.0
s
(I)]. Crystallographic data (excluding struc-
ture factors) has been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication number
CCDC 815829. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
[fax: þ44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
4.7.35. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (S,S)-3-[N-benzyl-
N-(a-methylbenzyl)amino]butanamide 65 and (S)-N-tert-butoxy-N-
10-(100-naphthyl)ethyl (3R,
aS)-3-[N-benzyl-N-(a-methylbenzyl)amino]
butanamide 57.
Ph
Ph
O
4.7.34. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (R,R)-3-[N-ben-
zyl-N-(
a-methylbenzyl)amino]butanamide 56.
Ph
N
O
Ph
N
Ph
Me
N
OtBu
Me
N
OtBu
Ph
N
O
65
57
Me
N
OtBu
Method A: Following general procedure 1, a solution of (S)-N-ben-
zyl-N-( -methylbenzyl)amine (101 mg, 0.48 mmol) in THF (1 mL)
a
Method A: Following general procedure 1, a solution of (R)-N-
benzyl-N-( -methylbenzyl)amine(101 mg, 0.48 mmol) inTHF (1 mL)
at ꢀ78 ꢁC was treated with BuLi (2.5 M in hexanes, 0.15 mL,
0.39 mmol) and 54 (75 mg, 0.24 mmol) in THF (1 mL) to give
a 75:25 mixture of 65 and 57. Purification via flash column
chromatography (gradient elution, 1%/10% Et2O in 30e40 ꢁC
petrol) gave a 60:40 mixture of 65 and 57 as a colourless oil (38 mg,
30%); nmax (film) 2974, 2932 (CeH), 1658 (C]O); m/z (ESIþ) 523
a
at ꢀ78 ꢁC was treated with BuLi (2.5 M in hexanes, 0.15 mL,
0.39 mmol) and 54 (75 mg, 0.24 mmol) in THF (1 mL) to give 56 in
>95:5 dr. Purification via flash column chromatography (gradient
elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave 56 as a colourless oil
that crystallised upon standing (102 mg, 81%, >95:5 dr); C35H42N2O2
requires C, 80.4; H, 8.1; N, 5.4%; found C, 80.5; H, 8.2; N, 5.3%; mp
þ
([MþH]þ, 100%); HRMS (ESIþ) C35H43N2O2 ([MþH]þ) requires
523.3319; found 523.3316. Data for 65: dH (250 MHz, PhMe-d8,
343 K) 0.62 (9H, s, CMe3), 1.15 (3H, d, J 6.4, C(10)Me), 1.33 (3H, d, J 7.0,
a 25
ꢁ
155e158 C; ½ ꢄD þ33.8 (c 0.5 in CHCl3); nmax (KBr) 2972, 2928 (CeH),
1660 (C]O); dH (250 MHz, PhMe-d8, 343 K) 0.67 (9H, s, CMe3), 1.23
C(a)Me), 1.59 (3H, d, J 6.7, C(4)H3), 2.26e2.41 (1H, br m, C(2)HA),
(3H, d, J 6.4, C(10)Me), 1.29 (3H, d, J 6.9, C(
a)Me), 1.59 (3H, d, J 7.0, C(4)
2.50e2.67 (1H, br m, C(2)HB), 3.67 (2H, AB system, JAB 14.9,
H3), 2.30e2.43 (1H, br m, C(2)HA), 2.48e2.60 (1H, br m, C(2)HB), 3.66
NCH2Ph), 3.89 (1H, q, J 7.0, C(a)H), 3.87e4.01 (1H, m, C(3)H),
(2H, AB system, JAB 14.6, NCH2Ph), 3.88 (1H, q, J 6.9, C(
a
)H), 3.80e3.90
6.15e6.35 (1H, br m, C(10)H), 6.95e7.46 (13H, m, Ar, Ph), 7.46e7.68
(3H, m, Ar, Ph), 8.35e8.50 (1H, br m, Ar); dC (125 MHz, CDCl3) 17.4
(1H, m, C(3)H), 6.12e6.26 (1H, br m, C(10)H), 6.92e7.40 (13H, m, Ar,
Ph), 7.50e7.63 (3H, m, Ar, Ph), 8.25e8.39 (1H, br m, Ar); dC (100 MHz,
(C(10)Me), 18.8 (C(
(C(
a
)Me), 19.1 (C(4)), 27.7 (CMe3), 29.7 (C(2)), 38.9
CDCl3) 14.2 (C(10)Me), 18.9 (C(
(C(2)), 39.4 (C(
a)Me), 19.4 (C(4)), 27.8 (CMe3), 29.8
a
)), 49.8 (C(3)), 50.1 (NCH2Ph), 58.4 (C(10)), 82.3 (CMe3), 124.8,
a
)), 49.7 (C(3)), 50.1 (NCH2Ph), 58.8(C(10)), 82.3(CMe3),
125.5, 126.1, 126.3, 126.5, 126.7, 127.7, 127.8, 128.1, 128.2, 128.6,
133.6, 136.2, 142.2, 144.1 (Ar, Ph), 179.5 (C(1)). Data for 57: dH
(250 MHz, PhMe-d8, 343 K) [selected peaks] 0.72 (9H, s, CMe3), 0.98
(3H, d, J 6.4, C(10)Me), 1.68 (3H, d, J 6.7, C(4)H3), 2.84e3.02 (1H, br m,
124.9, 125.5, 126.1, 126.4, 126.5, 126.7, 127.7, 128.2, 128.6, 133.6, 142.4,
144.4 (Ar, Ph), 186.0 (C(1)); m/z (ESIþ) 523 ([MþH]þ, 100%); HRMS
(ESIþ) C35H43N2O2þ ([MþH]þ) requires 523.3319; found 523.3320.

S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
6399
C(2)HB); dC (125 MHz, CDCl3) [selected peaks] 17.4 (C(10)Me),
18.4 (C(
)Me), 19.1 (C(4)), 26.6 (CMe3), 54.9 (C(10)), 82.4 (CMe3).
Further elution gave a 90:10 mixture of 65 and 57 as a colourless oil
(58 mg, 46%).
treated with BuLi (1.2 M in hexanes, 0.51 mL, 0.62 mmol) and 54
(120 mg, 0.39 mmol) in THF (1 mL) to give an 80:20 mixture of
59 and 67. Purification via flash column chromatography (gra-
dient elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave an 80:20
mixture of 59 and 67 as a colourless oil (124 mg, 70%); nmax
(film) 2972 (CeH), 1660 (C]O); m/z (ESIþ) 461 ([MþH]þ, 100%);
a
Method B: Following general procedure 2, a solution of (S,S)-25
(1.75 g, 4.95 mmol) in CH2Cl2 (17.0 mL) was treated with TFA
(17.0 mL) to give a white foam (1.32 g). Then, following general
procedure 3, a solution of the residue (156 mg) in CH2Cl2 (2 mL)
was reacted with (COCl)2 (0.10 mL, 1.04 mmol) and a mixture of
(S)-8$(þ)-CSA8a (100 mg, 0.21 mmol) and K2CO3 (290 mg,
2.10 mmol) in CH2Cl2 (1 mL). Purification via flash column chro-
matography (gradient elution, 1%/10% Et2O in 30e40 ꢁC petrol)
þ
HRMS (ESIþ) C30H41N2O2 ([MþH]þ) requires 461.3163; found
461.3158. Data for 59: dH (250 MHz, PhMe-d8, 343 K) 0.73 (9H, s,
CMe3), 0.97 (3H, d, J 6.6, NCHMeA), 0.99 (3H, d, J 6.6, NCHMeB),
1.17 (3H, d, J 6.6, C(10)Me), 1.68 (3H, d, J 6.9, C(4)H3), 2.39 (1H,
dd,
J 15.5, 8.8, C(2)HA), 2.87 (1H, dd, J 15.5, 4.0, C(2)HB),
2.91e2.97 (1H, m, CHMe2), 3.59 (2H, AB system, JAB 14.8,
NCH2Ph), 3.67e3.76 (1H, m, C(3)H), 6.19e6.36 (1H, br m, C(10)H),
6.90e7.63 (11H, m, Ar, Ph), 8.32e8.49 (1H, br m, Ar); dC
(125 MHz, CDCl3) 18.4, 18.6 (NCHMe2), 19.8 (C(10)Me), 21.0 (C(4)),
27.9 (CMe3), 29.7 (C(2)), 40.7 (CHMe2), 47.2 (C(3)), 49.3
(NCH2Ph), 54.7 (C(10)), 82.3 (CMe3), 123.2, 124.9, 125.5, 126.1,
126.3, 126.5, 128.0, 128.2, 128.6, 133.6, 142.3 (Ar, Ph), 179.7 (C(1)).
Data for 67: dH (250 MHz, PhMe-d8, 343 K) [selected peaks] 0.70
(9H, s, CMe3), 0.99 (3H, d, J 6.6, NCHMeA), 1.01 (3H, d, J 6.6,
NCHMeB), 1.12 (3H, d, J 6.6, C(10)Me), 1.65 (3H, d, J 6.9, C(4)H3),
2.62e2.71 (2H, m, C(2)H2); dC (125 MHz, CDCl3) [selected peaks]
18.5 (NCHMe2), 21.6 (C(4)), 27.6 (CMe3), 49.0 (NCH2Ph), 82.4
(CMe3).
gave 65 as a colourless oil (16 mg, 15%, >95:5 dr); ½a D25
ꢀ51.2 (c 0.5
ꢄ
in CHCl3).
4.7.36. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (R)-3-(N,N-dibenzyl-
amino)butanamide 58 and (S)-N-tert-butoxy-N-10-(100-naphthyl)ethyl
(S)-3-(N,N-dibenzylamino)butanamide 66.
Ph
Ph
Ph
N
O
Ph
N
O
Me
N
OtBu
Me
N
OtBu
58
66
4.7.38. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl
benzyl-N-( -methylbenzyl)amino]-3-phenylpropanamide 60.
(3S,aR)-3-[N-
Following general procedure 1,
a
solution of dibenzylamine
a
(0.14 mL, 0.71 mmol) in THF (1 mL) at ꢀ78 ꢁC was treated with BuLi
(1.2 M in hexanes, 0.47 mL, 0.57 mmol) and 54 (110 mg, 0.35 mmol)
in THF (1 mL) to give a 80:20 mixture of 58 and 66. Purification via
flash column chromatography (gradient elution, 1%/10% Et2O in
30e40 ꢁC petrol) gave an 80:20 mixture of 58 and 66 as a colourless
oil (119 mg, 66%); nmax (film) 2973, 2928 (CeH), 1660 þ(C]O); m/z
(ESIþ) 509 ([MþH]þ, 100%); HRMS (ESIþ) C34H41N2O2 ([MþH]þ)
requires 509.3163; found 509.3164. Data for 58: dH (500 MHz,
PhMe-d8, 343 K) 0.78 (9H, s, CMe3), 1.15 (3H, d, J 6.6, C(10)Me), 1.64
(3H, d, J 6.6, C(4)H3), 2.43 (1H, dd, J 15.1, 9.1, C(2)HA), 3.00 (1H, dd, J
15.1, 3.5, C(2)HB), 3.53 (4H, AB system, JAB 13.9, N(CH2Ph)2),
3.59e3.65 (1H, m, C(3)H), 6.19 (1H, q, J 6.6, C(10)H), 6.89e7.36 (13H,
m, Ar, Ph), 7.47e7.63 (3H, m, Ar, Ph), 8.28e8.39 (1H, br m, Ar); dC
(125 MHz, CDCl3) 14.4 (C(10)Me), 15.7 (C(4)), 27.7 (CMe3), 29.8
(C(2)), 38.1 (C(3)), 50.5 (C(10)), 53.7 (N(CH2Ph)2), 82.4 (CMe3), 124.1,
125.5, 126.2, 126.4, 126.7, 128.2, 128.5, 128.7, 129.0, 133.6, 140.3 (Ar,
Ph), 179.4 (C(1)). Data for 66: dH (500 MHz, PhMe-d8, 343 K) 0.72
(9H, s, CMe3), 1.09 (3H, d, J 6.6, C(10)Me), 1.62 (3H, d, J 6.6, C(4)H3),
2.61 (1H, dd, J 15.1, 9.1, C(2)HA), 2.85e2.90 (1H, br m, C(2)HB), 3.52
(4H, AB system, JAB 13.9, N(CH2Ph)2), 3.65e3.71 (1H, m, C(3)H), 6.19
(1H, q, J 6.6, C(10)H), 6.89e7.36 (13H, m, Ar, Ph), 7.47e7.63 (3H, m, Ar,
Ph), 8.28e8.39 (1H, br m, Ar); dC (125 MHz, CDCl3) 14.4 (C(10)Me),
18.1 (C(4)), 27.7 (CMe3), 31.8 (C(2)), 38.1 (C(3)), 50.5 (C(10)), 55.0
(N(CH2Ph)2), 82.4 (CMe3), 124.1, 125.5, 126.2, 126.4, 126.7, 128.2,
128.5, 128.7, 129.0, 133.6, 140.3 (Ar, Ph), 179.4 (C(1)).
Ph
Ph
N
O
Ph
N
OtBu
Method A: Following general procedure 1, a solution of (R)-N-
benzyl-N-( -methylbenzyl)amine (114 mg, 0.54 mmol) in THF
a
(1 mL) at ꢀ78 ꢁC was treated with BuLi (2.5 M in hexanes, 0.17 mL,
0.43 mmol) and 55 (100 mg, 0.27 mmol) in THF (1 mL) to give 60
in >95:5 dr. Purification via flash column chromatography (gra-
dient elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave 60 as a col-
ourless oil (126 mg, 80%, >95:5 dr); ½
aꢄ2D5 þ47.5 (c 1.0 in CHCl3);
nmax (film) 3060, 2965, 2934 (CeH), 1659 (C]O); dH (500 MHz,
PhMe-d8, 343 K) 0.68 (9H, s, CMe3), 1.29 (3H, d, J 6.9, C(10)Me), 1.47
(3H, d, J 6.9, C(a)Me), 2.71 (1H, br m, C(2)HA), 3.12 (1H, br m, C(2)
HB), 3.74 (2H, AB system, JAB 14.8, NCH2Ph), 4.06 (1H, q, J 6.9, C(a)
H), 4.93 (1H, dd, J 10.1, 3.8, C(3)H), 5.82e6.01 (1H, br m, C(10)H),
7.05e7.68 (21H, m, Ar, Ph), 7.91e8.05 (1H, br m, Ar); dC (100 MHz,
CDCl3) 27.3 (CMe3), 27.8 (C(10)Me), 30.9 (C(
a
)Me), 38.0 (C(2)), 51.1
(NCH2Ph), 53.4 (C(
a
)), 56.7 (C(3)), 61.6 (C(10)), 82.2 (CMe3), 125.3,
125.9, 126.2, 126.4, 126.7, 127.0, 127.8, 128.1, 128.6, 133.5, 135.3,
4.7.37. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (R)-3-(N-isopropyl-
N-benzylamino)butanamide 59 and (S)-N-tert-butoxy-N-10-(100-
naphthyl)ethyl (S)-3-(N-isopropyl-N-benzylamino)butanamide 67.
142.7, 144.3 (Ar, Ph), 176.9 (C(1)); m/z (ESIþ) 585 ([MþH]þ, 100%);
þ
HRMS (ESIþ) C40H45N2O2 ([MþH]þ) requires 585.3476; found
585.3481.
Method B: Following general procedure 2, a solution of
(3S,aR)-26 (1.72 g, 4.14 mmol) in CH2Cl2 (17.0 mL) was treated
Ph
Ph
with TFA (17.0 mL) to give a white foam (1.41 g). Then, following
general procedure 3, a solution of the residue (170 mg) in CH2Cl2
N
O
N
O
Me
N
OtBu
(2 mL) was reacted with (COCl)2 (80 mL, 0.95 mmol) and a mix-
Me
N
OtBu
ture of (S)-8$(þ)- CSA8a (90 mg, 0.19 mmol) and K2CO3 (263 mg,
1.90 mmol) in CH2Cl2 (1 mL). Purification via flash column chro-
matography (gradient elution, 1%/10% Et2O in 30e40 ꢁC petrol)
59
67
Following general procedure 1, a solution of N-benzyl-N-iso-
propylamine (0.13 mL, 0.77 mmol) in THF (1 mL) at ꢀ78 ꢁC was
gave 60 as a colourless oil (11 mg, 10%, >95:5 dr); ½a D23
þ46.9 (c 1.1
ꢄ
in CHCl3).

6400
S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
4.7.39. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (S,S)-3-[N-benzyl-
N-( -methylbenzyl)amino]-3-phenylpropanamide 61 and (S)-N-tert-
butoxy-N-10-(100-naphthyl)ethyl (3R,
benzyl)amino]-3-phenylpropanamide 69
.
(2.5 M in hexanes, 0.13 mL, 0.32 mmol) and 55 (75 mg,
0.20 mmol) in THF (1 mL) to give a 70:30 mixture of 62 and 70.
Purification via flash column chromatography (gradient elution,
1%/10% Et2O in 30e40 ꢁC petrol) gave a 70:30 mixture of 62 and
70 as a colourless oil (71 mg, 62%); nmax (film) 2977 (CeH), 1659
(C]O); m/z (ESIþ) 571 ([MþH]þ, 100%); HRMS (ESIþ)
a
aS)-3-[N-benzyl-N-(a-methyl-
Ph
Ph
þ
C39H43N2O2 ([MþH]þ) requires 571.3319; found 571.3316. Data
for 62: dH (250 MHz, PhMe-d8, 343 K) 0.75 (9H, s, CMe3), 1.54 (3H,
d, J 7.0, C(10)Me), 3.12e3.28 (2H, br m, C(2)H2), 3.56 (4H, AB
system, JAB 14.0, N(CH2Ph)2), 4.78 (1H, app t, J 7.3, C(3)H),
5.98e6.19 (1H, br m, C(10)H), 7.10e7.68 (21H, m, Ar, Ph),
8.05e8.22 (1H, br m, Ar); dC (100 MHz, CDCl3) 28.0 (CMe3), 36.0
(C(10)Me), 53.5 (C(10)), 54.5 (C(2)), 54.7 (N(CH2Ph)2), 54.8 (C(3)),
82.3 (CMe3), 125.5, 126.1, 126.4, 127.0, 127.2, 128.0, 128.3, 128.4,
128.8, 128.9, 133.6, 139.3, 140.1, 140.3 (Ar, Ph).42 Data for 70: dH
(250 MHz, PhMe-d8, 343 K) 0.62 (9H, s, CMe3), 1.29 (3H, d, J 7.0,
C(10)Me), 2.85e2.97 (2H, br m, C(2)H2), 3.58 (4H, AB system, JAB
13.7, N(CH2Ph)2), 4.77 (1H, app t, J 4.6, C(3)H), 6.26 (1H, q, J 7.0,
C(10)H), 7.10e7.68 (21H, m, Ar, Ph), 8.48 (1H, d, J 8.8, Ar); dC
(100 MHz, CDCl3) 29.8 (CMe3), 36.0 (C(10)Me), 53.5 (C(10)), 54.5
(C(2)), 54.7 (N(CH2Ph)2), 54.8 (C(3)), 82.3 (CMe3), 125.5, 126.1,
126.4, 127.0, 127.2, 128.0, 128.3, 128.4, 128.8, 128.9, 133.6, 139.3,
140.1, 140.3 (Ar, Ph).42
Ph
N
O
Ph
N
O
Ph
N
OtBu
Ph
N
OtBu
61
69
Following general procedure 1, a solution of (S)-N-benzyl-N-
a-methylbenzyl)amine (114 mg, 0.54 mmol) in THF (1 mL) at
(
ꢀ78 ꢁC was treated with BuLi (2.5 M in hexanes, 0.17 mL,
0.43 mmol) and 55 (100 mg, 0.27 mmol) in THF (1 mL) to give
a 60:40 mixture of 61 and 69. Purification via flash column
chromatography (gradient elution, 1%/10% Et2O in 30e40 ꢁC
petrol) gave an 85:15 mixture of 61 and 69 as a colourless oil
(28 mg, 18%); nmax (film) 2974 (CeH), 1654 (C]O); m/z (ESIþ) 585
þ
([MþH]þ, 100%); HRMS (ESIþ) C40H45N2O2 ([MþH]þ) requires
585.3476; found 585.3481. Data for 61: dH (250 MHz, PhMe-d8,
343 K) 0.71 (9H, s, CMe3), 1.27 (3H, d, J 6.7, C(10)Me), 1.48 (3H, d, J
4.7.41. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (S)-3-(N-isopropyl-
N-benzylamino)-3-phenylpropanamide 63 and (S)-N-tert-butoxy-N-
10-(100-naphthyl)ethyl (R)-3-(N-isopropyl-N-benzylamino)-3-
phenylpropanamide 71.
7.0, C(
C(2)HB), 3.74 (2H, AB system, JAB 15.2, NCH2Ph), 4.07 (1H, q, J 7.0,
C(
)H), 4.91 (1H, dd, J 9.1, 4.9, C(3)H), 5.84e6.09 (1H, br m, C(10)H),
7.04e7.71 (21H, m, Ar, Ph), 7.91e8.12 (1H, br m, Ar); dC (125 MHz,
CDCl3) 18.7 (C(10)Me), 27.5 (CMe3), 31.0 (C(
)Me), 38.0 (C(2)), 50.4
(NCH2Ph), 51.2 (C(
)), 56.4 (C(10)), 57.8 (C(3)), 82.4 (CMe3), 125.3,
a)Me), 2.91e3.09 (1H, br m, C(2)HA), 3.10e3.29 (1H, br m,
a
a
Ph
Ph
a
125.9, 126.2, 126.4, 126.7, 127.0, 127.7, 127.8, 128.0, 128.1, 128.2,
128.6, 128.8, 133.5, 141.8, 142.8, 143.9 (Ar, Ph).42 Data for 69: dH
(250 MHz, PhMe-d8, 343 K) 0.44 (9H, s, CMe3), 1.19 (3H, d, J 6.9,
N
O
N
O
Ph
N
OtBu
Ph
N
OtBu
C(10)Me), 1.33 (3H, d, J 7.0, C(
a
)Me), 2.40e2.51 (1H, br m, C(2)HA),
3.25e3.40 (1H, br m, C(2)HB), 3.70 (2H, AB system, JAB 14.9,
NCH2Ph), 4.03 (1H, q, J 7.0, C( )H), 4.95 (1H, dd, J 11.2, 3.1, C(3)H),
6.26 (1H, q, J 6.9, C(10)H), 7.04e7.62 (21H, m, Ar, Ph), 8.51 (1H, d, J
8.2, Ar); dC (125 MHz, CDCl3) 15.2 (C(10)Me), 27.5 (CMe3), 27.8 (C(
Me), 37.8 (C(2)), 51.2 (NCH2Ph), 54.0 (C(
)), 56.4 (C(3)), 61.6 (C(10)),
71
63
a
a
)
Following general procedure 1, a solution of N-benzyl-N-iso-
propylamine (67
a
m
L, 0.40 mmol) in THF (1 mL) at ꢀ78 ꢁC was
82.3 (CMe3), 124.4, 124.7, 125.6, 126.0, 126.3, 126.4, 126.7, 127.1,
127.7, 128.0, 128.1, 128.2, 128.4, 128.6, 128.9, 129.9, 132.4, 133.5,
136.3, 142.5, 144.0 (Ar, Ph).42 Further elution gave a 50:50 mixture
of 61 and 69 as a colourless oil (63 mg, 40%).
treated with BuLi (2.5 M in hexanes, 0.13 mL, 0.32 mmol) and 55
(75 mg, 0.20 mmol) in THF (1 mL) to give an 80:20 mixture of 63
and 71. Purification via flash column chromatography (gradient
elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave an 80:20 mixture
of 63 and 71 as a colourless oil (63 mg, 60%); nmax (film) 2973,
Method B: Following general procedure 2, a solution of (3R,aS)-
2930 (CeH), 1655 (C]O); m/z (ESIþ) 523 ([MþH]þ, 100%); HRMS
26 (1.66 g, 3.99 mmol) in CH2Cl2 (16.0 mL) was treated with TFA
(16.0 mL) to give a white foam (1.32 g). Then, following general
procedure 3, a solution of the residue (187 mg) in CH2Cl2 (2 mL)
was reacted with (COCl)2 (0.10 mL, 1.04 mmol) and a mixture of (S)-
8$(þ)-CSA8a (100 mg, 0.21 mmol) and K2CO3 (290 mg, 2.10 mmol)
in CH2Cl2 (1 mL). Purification via flash column chromatography
(gradient elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave 69 as
a colourless oil (15 mg, 12%, >95:5 dr).
þ
(ESIþ) C35H43N2O2
([MþH]þ) requires 523.3319; found
523.3319. Data for 63: dH (500 MHz, PhMe-d8, 343 K) 0.67 (9H, s,
CMe3), 0.86 (3H, d, J 6.6, NCHMeA), 0.97 (3H, d, J 6.4, NCHMeB),
1.49 (3H, d, J 7.0, C(10)Me), 2.90e3.10 (2H, br m, C(2)H2),
3.07e3.11 (1H, m, CHMe2), 3.66 (2H, AB system, JAB 15.2,
NCH2Ph), 4.79 (1H, app t, J 6.7, C(3)H), 5.88e6.12 (1H, br m, C(10)
H), 7.04e7.67 (16H, m, Ar, Ph), 8.57e8.75 (1H, br m, Ar); dC
(125 MHz, CDCl3) 17.3, 19.5 (NCHMe2), 21.3 (C(10)Me), 36.1 (C(2)),
27.6 (CMe3), 39.0 (CHMe2), 41.4 (C(10)), 48.7 (NCH2Ph), 54.1 (C(3)),
82.3 (CMe3), 124.5, 124.9, 125.7, 126.3, 126.5, 126.8, 127.9, 128.2,
128.6, 128.8, 130.0, 133.6, 135.4, 143.1 (Ar, Ph), 179.3 (C(1)). Data
for 71: dH (500 MHz, PhMe-d8, 343 K) 0.49 (9H, s, CMe3), 0.88
(3H, d, J 6.6, NCHMeA), 0.98 (3H, d, J 6.4, NCHMeB), 1.49 (3H, d, J
7.0, C(10)Me), 2.70e2.79 (1H, br m, C(2)HA), 3.35e3.43 (1H, br m,
C(2)HB), 3.07e3.11 (1H, m, CHMe2), 3.66 (2H, AB system, JAB 15.2,
NCH2Ph), 4.74 (1H, app t, J 6.7, C(3)H), 6.27 (1H, q, J 7.0, C(10)H),
7.04e7.67 (16H, m, Ar, Ph), 8.51 (1H, d, J 8.2, Ar); dC (125 MHz,
CDCl3) 15.2, 18.8 (NCHMe2), 21.1 (C(10)Me), 27.7 (CMe3), 29.1
(C(2)), 33.7 (CHMe2), 41.4 (C(10)), 49.6 (NCH2Ph), 62.7 (C(3)), 82.3
(CMe3), 124.5, 124.9, 125.7, 126.3, 126.5, 126.8, 127.9, 128.2, 128.6,
128.8, 130.0, 133.6, 135.4, 143.1 (Ar, Ph), 179.3 (C(1)).
4.7.40. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (S)-3-(N,N-dibenzyl-
amino)-3-phenylpropanamide 62 and (S)-N-tert-butoxy-N-10-(100-
naphthyl)ethyl (R)-3-(N,N-dibenzylamino)-3-phenylpropanamide 70.
Ph
Ph
Ph
N
O
Ph
N
O
Ph
N
OtBu
Ph
N
OtBu
62
70
Following general procedure 1, a solution of dibenzylamine
(77
m
L, 0.40 mmol) in THF (1 mL) at ꢀ78 ꢁC was treated with BuLi

S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
6401
4.7.42. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (R)-3-(N,N-dibenzyl-
amino)butanamide 58.
71%);25a mp 64e67 ꢁC; {lit.25a mp 64e66 ꢁC}; ½a 2D5
ꢄ
ꢀ78.4 (c 2.0
in CHCl3); dH (400 MHz, CDCl3) 1.34 (9H, s, CMe3), 2.72 (1H, dd, J
14.3, 8.5, C(2)HA), 3.00 (1H, dd, J 14.3, 6.8, C(2)HB), 3.50 (4H, AB
system, JAB 13.7, N(CH2Ph)2), 4.28 (1H, app t, J 7.2, C(3)H),
7.18e7.40 (15H, m, Ph).
Ph
Ph
N
O
Step 3: Following general procedure 2, a solution of tert-butyl (S)-
3-(N,N-dibenzylamino)-3-phenylpropanoate (938 mg, 2.34 mmol)
in CH2Cl2 (10.0 mL) was treated with TFA (10.0 mL) to give a white
foam (703 mg). Then, following general procedure 3, a solution of
the residue (363 mg) in CH2Cl2 (4 mL) was reacted with (COCl)2
(0.18 mL, 2.10 mmol) and a mixture of (S)-8$(þ)-CSA8a (200 mg,
0.42 mmol) and K2CO3 (580 mg, 4.20 mmol) in CH2Cl2 (2 mL).
Purification via flash column chromatography (gradient elution,
1%/10% Et2O in 30e40 ꢁC petrol) gave 62 as a colourless oil (26 mg,
10%, >95:5 dr).
Me
N
OtBu
Step 1: Following general procedure 4, (R,R)-25 (5.27 g,
14.9 mmol) and Pd(OH)2/C (1.32 g) in MeOH (50 mL) under H2
(5 atm) for 36 h gave tert-butyl (R)-3-aminobutanoate as a colour-
less oil (1.48 g, 62%);43
½
a 2D3
ꢄ
ꢀ22.0 (c 1.0 in CHCl3); {lit.43
½ ꢄ
a 2D5
ꢀ22.2 (c 0.5 in CHCl3)}; dH (400 MHz, CDCl3) 1.13 (3H, d, J 6.5, C(4)
H3), 1.46 (9H, s, CMe3), 1.85 (2H, br s, NH2), 2.23 (1H, dd, J 15.4,
8.2, C(2)HA), 2.34 (1H, dd, J 15.4, 4.8, C(2)HB), 3.31e3.40 (1H, m,
C(3)H).
4.7.44. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (R)-3-(N-isopropyl-
N-benzylamino)butanamide 59.
Step 2: Following general procedure 5, tert-butyl (R)-3-
aminobutanoate (740 mg, 4.65 mmol) was reacted with K2CO3
(6.43 g, 46.5 mmol) in BnBr (5.50 mL, 46.5 mmol). Purification via
flash column chromatography (gradient elution, 1%/20% Et2O in
30e40 ꢁC petrol) gave tert-butyl (R)-3-(N,N-dibenzylamino)butanoate
as a colourless oil that crystallised upon standing (1.02 g, 64%); mp
Ph
N
O
Me
N
42e45 ꢁC; ½a 2D5
ꢀ12.3 (c 1.0 in CHCl3); nmax (film) 2974, 2933
ꢄ
OtBu
(CeH), 1727 (C]O); dH (400 MHz, CDCl3) 1.20 (3H, d, J 6.8, C(4)H3),
1.54 (9H, s, CMe3), 2.29 (1H, dd, J 13.9, 7.8, C(2)HA), 2.70 (1H, dd, J
13.9, 6.6, C(2)HB), 3.37e3.47 (1H, m, C(3)H), 3.66 (4H, AB system,
JAB 13.6, N(CH2Ph)2), 7.25e7.58 (10H, m, Ph); dC (100 MHz, CDCl3)
14.8 (C(4)), 28.3 (CMe3), 40.1 (C(2)), 51.1 (C(3)), 53.6, 69.8
(N(CH2Ph)2), 80.1 (CMe3), 126.9, 128.2, 128.4, 128.7, 128.9, 135.4
(o,m,p-Ph), 140.2, 155.1 (i-Ph), 171.9 (C(1)); m/z (ESIþ) 340 ([MþH]þ,
Step 1: Following general procedure 6, tert-butyl (R)-3-
aminobutanoate (1.40 g, 8.79 mmol), acetone (1.29 mL,
17.6 mmol) and NaBH3CN (2.21 g, 35.2 mmol) were reacted in
MeOH (40 mL). Purification via flash column chromatography
(gradient elution, 1%/30% Et2O in 30e40 ꢁC petrol) gave tert-
þ
100%); HRMS (ESIþ) C22H30NO2 ([MþH]þ) requires 340.2271;
found 340.2270.
butyl (R)-3-(N-isopropylamino)butanoate as
a colourless oil
Step 3: Following general procedure 2, a solution of tert-butyl
(R)-3-(N,N-dibenzylamino)butanoate (600 mg, 1.77 mmol) in
CH2Cl2 (6.0 mL) was treated with TFA (6.0 mL) to give a white foam
(501 mg). Then, following general procedure 3, a solution of the
residue (298 mg) in CH2Cl2 (3 mL) was reacted with (COCl)2
(0.18 mL, 2.10 mmol) and a mixture of (S)-8$(þ)-CSA8a (200 mg,
0.42 mmol) and K2CO3 (580 mg, 4.20 mmol) in CH2Cl2 (2 mL).
Purification via flash column chromatography (gradient elution,
1%/10% Et2O in 30e40 ꢁC petrol) gave 58 as a colourless oil
(24 mg, 11%, >95:5 dr).
(1.33 g, 75%);44
½
a 2D3
ꢄ
ꢀ20.1 (c 1.0 in CHCl3); dH (400 MHz, CDCl3)
1.41 (3H, d, J 6.5, C(4)H3), 1.46 (3H, d, J 6.5, NCHMeA), 1.47 (9H, s,
CMe3), 1.48 (3H, d, J 6.5, NCHMeB), 2.70 (1H, dd, J 17.1, 6.8, C(2)HA),
2.97 (1H, dd, J 17.1, 6.1, C(2)HB), 3.33e3.44 (1H, m, NCHMe2),
3.53e3.62 (1H, m, C(3)H).
Step 2: Following general procedure 5, tert-butyl (R)-3-(N-
isopropylamino)butanoate (850 mg, 4.22 mmol) was reacted with
K2CO3 (5.83 g, 42.2 mmol) in BnBr (5.00 mL, 42.2 mmol). Purifica-
tion via flash column chromatography (gradient elution, 1%/20%
Et2O in 30e40 ꢁC petrol) gave tert-butyl (R)-3-(N-isopropyl-N-ben-
zylamino)butanoate as a colourless oil (849 mg, 69%); ½a D25
ꢀ36.7
ꢄ
4.7.43. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (S)-3-(N,N-dibenzyl-
amino)-3-phenylpropanamide 62.
(c 1.0 in CHCl3); nmax (film) 2970, 2932 (CeH), 1729 (C]O); dH
(400 MHz, CDCl3) 1.08 (3H, d, J 6.6, NCHMeA), 1.10 (3H, d, J 6.6,
NCHMeB), 1.16 (3H, d, J 6.8, C(4)H3), 1.53 (9H, s, CMe3), 2.21 (1H, dd,
J 13.9, 6.8, C(2)HA), 2.54 (1H, dd, J 13.9, 7.3, C(2)HB), 2.93e3.04 (1H,
m, NCHMe2), 3.48e3.54 (1H, m, C(3)H), 3.70 (2H, AB system, JAB
14.7, NCH2Ph), 7.22e7.48 (5H, m, Ph); dC (100 MHz, CDCl3) 18.1, 19.5
(NCHMe2), 21.3 (C(4)), 28.2 (CMe3), 42.2 (C(2)), 48.6 (NCHMe2),
49.0 (NCH2Ph), 49.6 (C(3)), 79.9 (CMe3), 127.8, 128.0, 128.3 (o,m,p-
Ph), 142.0 (i-Ph), 172.1 (C(1)); m/z (ESIþ) 292 ([MþH]þ, 100%);
Ph
Ph
N
O
Ph
N
OtBu
Step 1: Following general procedure 4, (3S,aR)-26 (6.70 g,
16.1 mmol) and Pd(OH)2/C (1.70 g) in MeOH (65 mL) under H2
þ
HRMS (ESIþ) C18H30NO2 ([MþH]þ) requires 292.2271; found
(5 atm) for 36 h gave tert-butyl (S)-3-amino-3-phenylpropanoate
292.2270.
as a colourless oil (2.48 g, 72%);26a
½
a 2D3
ꢄ
ꢀ22.0 (c 1.0 in CHCl3);
Step 3: Following general procedure 2, a solution of tert-butyl
(R)-3-(N-isopropyl-N-benzylamino)butanoate (849 mg, 2.91 mmol)
in CH2Cl2 (9.0 mL) was treated with TFA (9.0 mL) to give a white
foam (516 mg). Then, following general procedure 3, a solution of
the residue (396 mg) in CH2Cl2 (4 mL) was reacted with (COCl)2
(0.14 mL, 1.68 mmol) and a mixture of (S)-8$(þ)-CSA8a (160 mg,
0.34 mmol) and K2CO3 (470 mg, 3.40 mmol) in CH2Cl2 (4 mL).
Purification via flash column chromatography (gradient elution,
1%/10% Et2O in 30e40 ꢁC petrol) gave 59 as a colourless oil
(14 mg, 9%, >95:5 dr).
{lit.26a
½
a 2D0
ꢄ
ꢀ21.0 (c 1.0 in CHCl3)}; dH (400 MHz, CDCl3) 1.43 (9H, s,
CMe3), 1.71 (2H, br s, NH2), 2.59 (2H, d, J 7.2, C(2)H2), 4.38 (1H, app t,
J 6.8, C(3)H), 7.24e7.40 (5H, m, Ph).
Step 2: Following general procedure 5, tert-butyl (S)-3-
amino-3-phenylpropanoate (1.20 g, 5.42 mmol) was reacted
with K2CO3 (7.50 g, 54.2 mmol) in BnBr (6.46 mL, 54.2 mmol).
Purification via flash column chromatography (gradient elution,
1%/20% Et2O in 30e40 ꢁC petrol) gave tert-butyl (S)-3-(N,N-
dibenzylamino)-3-phenylpropanoate as a white solid (1.54 g,

6402
S.G. Davies et al. / Tetrahedron 67 (2011) 6382e6403
4.7.45. (S)-N-tert-Butoxy-N-10-(100-naphthyl)ethyl (S)-3-(N-isopropyl-
N-benzylamino)-3-phenylpropanamide 63.
(g) Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Thomson, J.
E.; Toms, S. M. Tetrahedron 2010, 66, 4604; (h) Abraham, E.; Bailey, C. W.;
Claridge, T. D. W.; Davies, S. G.; Ling, K. B.; Odell, B.; Rees, T. L.; Roberts, P. M.;
Russell, A. J.; Smith, A. D.; Smith, L. J.; Storr, H. R.; Sweet, M. J.; Thompson, A. L.;
Thomson, J. E.; Tranter, G. E.; Watkin, D. J. Tetrahedron: Asymmetry 2010, 21,
1797.
Ph
N
O
2. For selected examples from this laboratory, see: (a) Bunnage, M. E.; Burke, A.
J.; Davies, S. G.; Goodwin, C. J. Tetrahedron: Asymmetry 1994, 5, 203; (b)
Davies, S. G.; Kelly, R. J.; Price Mortimer, A. J. Chem. Commun. 2003, 2132; (c)
Davies, S. G.; Burke, A. J.; Garner, A. C.; McCarthy, T. D.; Roberts, P. M.; Smith,
A. D.; Rodriguez-Solla, H.; Vickers, R. J. Org. Biomol. Chem. 2004, 2, 1387; (d)
Davies, S. G.; Haggitt, J. R.; Ichihara, O.; Kelly, R. J.; Leech, M. A.; Price Mor-
timer, A. J.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2004, 2, 2630; (e)
Abraham, E.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.;
Ph
N
OtBu
Step 1: Following general procedure 6, tert-butyl (S)-3-amino-3-
phenylpropanoate (1.00 g, 4.50 mmol), acetone (0.66 mL,
9.00 mmol) and NaBH3CN (1.13 g, 18.0 mmol) were reacted in
MeOH (30 mL). Purification via flash column chromatography
(gradient elution, 1%/30% Et2O in 30e40 ꢁC petrol) gave tert-butyl
(S)-3-(N-isopropylamino)-3-phenylpropanoate as a colourless oil
ꢁ
ꢁ
Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez, E. M.; Smith, A. D.; Thomson,
J. E. Tetrahedron: Asymmetry 2007, 18, 2510; (f) Abraham, E.; Davies, S. G.;
Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org. Biomol. Chem.
2008, 6, 1655;
(g) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.;
ꢁ
Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sanchez-
(1.12 g, 94%); ½a D25
ꢀ23.1 (c 1.0 in CHCl3); nmax (film) 3328 (NeH),
ꢄ
ꢁ
Fernandez, E. M.; Scott, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem.
2008, 6, 1665; (h) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D.
Tetrahedron 2009, 65, 10192; (i) Davies, S. G.; Hughes, D. G.; Price, P. D.;
Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.; Williams, O. M. H.
Synlett 2010, 567; (j) Davies, S. G.; Ichihara, O.; Roberts, P. M.; Thomson, J. E.
Tetrahedron 2011, 67, 216.
3. For selected examples from this laboratory, see: (a) Cailleau, T.; Cooke, J. W. B.;
Davies, S. G.; Ling, K. B.; Naylor, A.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.;
Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 3922; (b)
Davies, S. G.; Durbin, M. J.; Goddard, E. C.; Kelly, P. M.; Kurosawa, W.; Lee, J. A.;
Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Smith, A. D.
Org. Biomol. Chem. 2009, 7, 761.
4. For selected examples from this laboratory, see: (a) Davies, S. G.; Garner, A. C.;
Long, M. J. C.; Morrison, R. M.; Roberts, P. M.; Smith, A. D.; Sweet, M. J.; Withey,
J. M. Org. Biomol. Chem. 2005, 3, 2762; (b) Abraham, E.; Davies, S. G.; Docherty,
A. J.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Toms, S. M.
Tetrahedron: Asymmetry 2008, 19, 1356; (c) Davies, S. G.; Durbin, M. J.; Hartman,
S. J. S.; Matsuno, A.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.;
Toms, S. M. Tetrahedron: Asymmetry 2008, 19, 2870; (d) Aye, Y.; Davies, S. G.;
Garner, A. C.; Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem.
2008, 6, 2195.
5. Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833.
6. (a) Davies, S. G.; Hermann, G. J.; Sweet, M. J.; Smith, A. D. Chem. Commun. 2004,
1128; (b) Davies, S. G.; Fletcher, A. M.; Hermann, G. J.; Poce, G.; Roberts, P. M.;
Smith, A. D.; Sweet, M. J.; Thomson, J. E. Tetrahedron: Asymmetry 2010, 21, 1635.
7. Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908.
2968, 2932 (CeH), 1727 (C]O); dH (400 MHz, CDCl3) 0.98 (3H, d, J
6.3, NCHMeA), 1.04 (3H, d, J 6.3, NCHMeB), 1.38 (9H, s, CMe3), 1.86
(1H, br s, NH), 2.51 (1H, dd, J 15.2, 6.1, C(2)HA), 2.61 (1H, dd, J 15.2,
8.3, C(2)HB), 2.56e2.65 (1H, m, NCHMe2), 4.15 (1H, dd, J 8.3, 6.1, C(3)
H), 7.20e7.38 (5H, m, Ph); dC (100 MHz, CDCl3) 21.9, 24.2 (NCHMe2),
28.0 (CMe3), 44.7 (C(2)), 45.6 (NCHMe2), 57.0 (C(3)), 80.6 (CMe3),
127.1, 127.2, 128.4 (o,m,p-Ph), 143.1 (i-Ph), 171.0 (C(1)); m/z (ESIþ)
þ
264 ([MþH]þ, 100%); HRMS (ESIþ) C16H26NO2 ([MþH]þ) requires
264.1958; found 264.1956.
Step 2: Following general procedure 5, tert-butyl (S)-3-(N-
isopropylamino)-3-phenylpropanoate (1.12 g, 4.18 mmol) was
reacted with K2CO3 (5.25 g, 41.8 mmol) in BnBr (4.50 mL,
41.8 mmol). Purification via flash column chromatography (gradient
elution, 1%/20% Et2O in 30e40 ꢁC petrol) gave tert-butyl (S)-3-(N-
isopropyl-N-benzylamino)-3-phenylpropanoate as a colourless oil
(1.22 g, 83%); ½a D25
ꢀ17.0 (c 0.5 in CHCl3); nmax (film) 2972, 2932
ꢄ
(CeH), 1728 (C]O); dH (400 MHz, CDCl3) 0.86 (3H, d, J 6.6, NCHMeA),
1.07 (3H, d, J 6.6, NCHMeB), 1.28 (9H, s, CMe3), 2.56 (1H, dd, J 14.2, 9.5,
C(2)HA), 2.81 (1H, dd, J 14.2, 5.9, C(2)HB), 3.02e3.11 (1H, m, NCHMe2),
3.71 (2H, AB system, JAB 15.1, NCH2Ph), 4.29 (1H, dd, J 9.5, 5.9, C(3)H),
7.21e7.43 (10H, m, Ph); dC (100 MHz, CDCl3) 18.5, 21.1 (NCHMe2), 27.9
(CMe3), 40.1 (C(2)), 48.2 (NCHMe2), 49.4 (NCH2Ph), 60.5 (C(3)), 80.1
(CMe3), 126.4, 126.9, 128.0, 128.1, 128.3, 128.8 (o,m,p-Ph), 141.8, 142.2
(i-Ph), 171.3 (C(1)); m/z (ESIþ) 354 ([MþH]þ, 100%); HRMS (ESIþ)
8. (a) Chernega, A. N.; Davies, S. G.; Goodwin, C. J.; Hepworth, D.; Kurosawa, W.;
Roberts, P. M.; Thomson, J. E. Org. Lett. 2009, 11, 3254; (b) Davies, S. G.;
Goodwin, C. J.; Hepworth, D.; Roberts, P. M.; Thomson, J. E. J. Org. Chem. 2010,
75, 1214; (c) Chernega, A. N.; Davies, S. G.; Fletcher, A. M.; Goodwin, C. J.;
Hepworth, D.; Prasad, R. S.; Roberts, P. M.; Savory, E. D.; Smith, A. D.; Thomson,
J. E. Tetrahedron 2010, 66, 4167.
9. For a review, see: Whitesell, J. Chem. Rev. 1992, 92, 953.
C23H32NO2 ([MþH]þ) requires 354.2428; found 354.2427.
þ
10. For instance, see: (a) Kaneko, T.; Turner, D. L.; Newcomb, M.; Bergbreiter, D. E.
Tetrahedron Lett. 1979, 20, 103; (b) Whitesell, J. K.; Bhattacharya, A.; Henke, K. J.
Chem. Soc., Chem. Commun. 1982, 988; (c) Yamamoto, Y.; Maeda, M.; Maruyama,
K. J. Chem. Soc., Chem. Commun. 1983, 774; (d) Comins, D. L.; Goehring, R. R.;
Joseph, S. P.; O’Connor, S. J. Org. Chem. 1990, 55, 2574.
Step 3: Following general procedure 2, a solution of tert-butyl
(S)-3-(N-isopropyl-N-benzylamino)-3-phenylpropanoate (1.13 g,
4.14 mmol) in CH2Cl2 (12.0 mL) was treated with TFA (12.0 mL) to
give a white foam (1.00 g). Then, following general procedure 3,
a solution of the residue (312 mg) in CH2Cl2 (4 mL) was reacted
with (COCl)2 (0.18 mL, 2.10 mmol) and a mixture of (S)-8$(þ)-CSA8a
(200 mg, 0.42 mmol) and K2CO3 (580 mg, 4.20 mmol) in CH2Cl2
(2 mL). Purification via flash column chromatography (gradient
elution, 1%/10% Et2O in 30e40 ꢁC petrol) gave 63 as a colourless
oil (19 mg, 8%, >95:5 dr).
11. For instance, see: (a) Boeckman, R. K., Jr.; Naegely, P. C.; Arthur, S. D. J. Org. Chem.
1980, 45, 752; (b) Swindell, C. S.; Tao, M. J. Org. Chem. 1993, 58, 5889; (c) Rigby,
J. H.; Sugathapaia, P.; Heeg, M. J. J. Am. Chem. Soc. 1995, 117, 8851; (d) Serells, A.
K.; Simpson, G. W. Tetrahedron Lett. 1997, 38, 4277; (e) Oppolzer, W.; Kurth, M.;
Reichlin, D.; Chapuis, C.; Mohnhaupt, M.; Moffatt, F. Helv. Chim. Acta 1981, 64,
2802.
€
12. For instance, see: (a) Oppolzer, W.; Robbiani, C.; Battig, K. Helv. Chim. Acta 1980,
63, 2015; (b) Whitesell, J. K.; Bhattacharya, A.; Aguilar, D. A.; Henke, K. J. Chem.
Soc., Chem. Commun. 1982, 989.
13. Muniz, K.; Iesato, A.; Nieger, M. Chem.dEur. J. 2003, 9, 5581.
14. For instance, see: (a) Donohoe, T. J.; Guyo, P. M.; Helliwell, M. Tetrahedron Lett.
Acknowledgements
€
€
1999, 40, 435; (b) Sebek, M.; Holz, J.; Borner, A.; Jahnisch, K. Synlett 2009, 461.
15. For instance, see: (a) Anderson, J. C.; O’Loughlina, J. M. A.; Tornosb, J. A. Org.
Biomol. Chem. 2005, 3, 2741; (b) Tayama, E.; Kimura, H. Angew. Chem., Int. Ed.
2007, 46, 8869; (c) Tayama, E.; Orihara, K.; Kimura, H. Org. Biomol. Chem. 2008,
6, 3673.
The authors would like to thank the EPSRC and SCI-Ink for
a Dorothy Hodgkin Postgraduate Award (J.Y.).
16. For instance, see: (a) Koch, H.; Runsink, J.; Scharf, H.-D. Tetrahedron Lett. 1983,
24, 3217; (b) Little, R. D.; Moeller, K. D. J. Org. Chem. 1983, 48, 4487.
17. For instance, see: (a) Kozikowski, A. P.; Tuckmantel, W.; Liao, Y.; Manev, H.;
References and notes
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Ikonomovic, S.; Wroblewskil, J. T. J. Med. Chem. 1993, 36, 2706; (b) Kozikowski,
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1. (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183; (b) Costello, J.
F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1994, 5, 1999; (c) Davies, S.
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Mortimer, A. J.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006, 17, 1793;
(d) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Savory,
E. D.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2009, 20, 758; (e)
Davies, S. G.; Garner, A. C.; Nicholson, R. L.; Osborne, J.; Roberts, P. M.; Savory, E.
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18. For instance, see: (a) Oppolzer, W.; Loher, H. J. Helv. Chim. Acta 1981, 64, 2808;
ꢁ
(b) Barluenga, J.; Montserrat, J. M.; Florez, J.; García-Granda, S.; Martín, E.
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6403
19. d’Angelo, J.; Maddaluno, J. J. Am. Chem. Soc. 1986, 108, 8112.
20. Under these conditions the conjugate addition reaction is known to be
reversible, see: Furukawa, M.; Okawara, T.; Terawaki, Y. Chem. Pharm. Bull. 1977,
25, 1319.
30. Upon conjugate addition of 32 to 9 a mixed fraction containing an 83:17 mixture
of 34 and 38 was also isolated in 40% yield after chromatographic purification.
31. (a) Bull, S. D.; Davies, S. G.; Fox, D. J.; Garner, A. C.; Sellers, T. G. R. Pure Appl.
Chem. 1998, 70, 1501; (b) Bull, S. D.; Davies, S. G.; Fox, D. J.; Sellers, T. G. R.
Tetrahedron: Asymmetry 1998, 9, 1483; (c) Bull, S. D.; Davies, S. G.; Epstein, S. W.;
Ouzman, J. V. A. Chem. Commun. 1998, 659; (d) Bull, S. D.; Davies, S. G.; Epstein,
S. W.; Leech, M. A.; Ouzman, J. V. A. J. Chem. Soc., Perkin Trans. 1 1998, 2321; (e)
Bull, S. D.; Davies, S. G.; Garner, A. C.; Mujtaba, N. Synlett 2001, 781; (f) Bull, S.
D.; Davies, S. G.; Garner, A. C.; O’Shea, M. D. J. Chem. Soc., Perkin Trans. 1 2001,
3281; (g) Sibi, M. P.; Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc.
2001, 123, 8444; (h) Quaranta, L.; Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4,
39; (i) Corminboeuf, O.; Quaranta, L.; Renaud, P.; Liu, M.; Jasperse, C. P.; Sibi, M.
P. Chem.dEur. J. 2003, 9, 29; (j) Malkov, A. V.; Hand, J. B.; Kocovsky, P. Chem.
Commun. 2003, 1948; (k) Hitchcock, S. R.; Casper, D. M.; Vaughn, J. F.; Finefield,
J. M.; Ferrence, G. M.; Esken, J. M. J. Org. Chem. 2004, 69, 714; (l) Sibi, M. P.;
Stanley, L. M. Tetrahedron: Asymmetry 2004, 15, 3353; (m) Sibi, M. P.;
Prabagaran, N. Synlett 2004, 2421; (n) Clayden, J.; Vassiliou, N. Org. Biomol.
Chem. 2006, 4, 2667; (o) Bull, S. D.; Davies, S. G.; Epstein, S. W.; Garner, A. C.;
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Tetrahedron 2006, 62, 7911; (p) Parrott, R. W., II; Hitchcock, S. R. Tetrahedron:
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R. J. New J. Chem. 2007, 31, 486.
21. (þ)-(R)-Pulegone was purchased from the Aldrich chemical company.
22. Ort, O. Org. Synth. 1987, 65, 203.
23. A comparative study of the 1H NMR spectra for 9 and 18, and the corresponding
methyl esters 73 and 74, reveals that the peaks corresponding to the olefinic
C(2)H and C(3)H protons within both 9 and 18 are shifted upfield with respect
to the corresponding resonances in the 1H NMR spectra of 73 and 74, consistent
with the phenyl group of the auxiliary shielding one face of the olefin. [a
approximate value (ꢅ0.05 ppm) due to peak overlap].
O
O
R
O
R
OMe
9 R = Me
73 R = Me
74 R = Ph
Ph
18 R = Ph
δ
for C(2)H for C(3)H
δ
H (ppm)
H (ppm)
Ester
R
32. Crystallographic data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
numbers CCDC 733577, 745789 and 745790; see also Refs. 8a,c.
9
Me
Me
Ph
Ph
5.38
5.76
5.81
6.53
6.50
6.81
7.20a
7.73
73
18
74
33. Due to the highly rotameric nature of all the b-amino hydroxamates described
herein more accurate determinations of the reaction diastereoselectivities were
not possible.
34. In some cases mixed fractions were also obtained after purification by flash
column chromatography: following reaction of (S)-1 with 54 a 60:40 mixture
of 65 and 57 was also isolated in 30% combined yield, and following reaction of
(S)-1 with 55 a 50:50 mixture of 61 and 69 was also isolated in 40% combined
yield.
35. The conjugate addition of (S)-1 to 55 produced a 60:40 mixture of 61 and 69,
respectively. In this case the spectroscopic data for the authentic sample of 69
were consistent with the minor diastereoisomer from the conjugate addition
reaction.
36. Attempted hydrogenolysis of 56 was not successful and returned a complex
mixture of products: 1H NMR spectroscopic and mass spectrometric analyses of
the crude reaction mixture indicated the presence of products arising from
cleavage of the NeO, NeC(10) and N-benzyl bonds.
37. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
24.
A
search of the Cambridge Crystallographic Database revealed that the
structures of a range of different 8-arylmenthol -unsaturated esters all
adopt conformations similar to 20B (Fig. 3) in the solid state.
a,b
25. (a) Davies, S. G.; Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 1129; (b)
Uyehara, T.; Asao, N.; Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1989, 753; (c)
Asao, N.; Uyehara, T.; Yamamoto, Y. Tetrahedron 1990, 46, 4563; (d) Jahn, U.;
€
Muller, M.; Aussieker, S. J. Am. Chem. Soc. 2000, 122, 5212; (e) Davies, S. G.;
Foster, E. M.; McIntosh, C. R.; Roberts, P. M.; Rosser, T. E.; Smith, A. D.; Thomson,
J. E. Tetrahedron: Asymmetry, 2011, doi:10.1016/j.tetasy.2011.06.008.
26. (a) Davies, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Chem.
Commun. 1993, 1153; (b) Davies, S. G.; Dixon, D. J. Chem. Commun. 1996, 1797;
(c) Davies, S. G.; Dixon, D. J. J. Chem. Soc., Perkin Trans. 1 1998, 2635.
27. Crystallographic data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
numbers CCDC 815826(23), 815827 (33), 815828(54), 815829 (55) and 815860
(56).
28. In some cases mixed fractions were also obtained after purification by flash
column chromatography: following reaction of (R)-1 with 9 an 85:15 mixture
of 29 and its C(3)-epimer was also isolated in 50% combined yield, and
following reaction of (R)-1 with 18 an 83:17 mixture of 30 and its C(3)-epimer
was also isolated in 70% combined yield.
38. Carpita, A.; Magistris, E.; Rossi, R. Gazz. Chim. Ital. 1989, 119, 99.
39. Ye, S.; Tang, Y.; Dai, L. J. Org. Chem. 2001, 66, 5717.
40. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.; Watkin, D. J. J. Appl.
Crystallogr. 2003, 36, 1487.
41. Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.; Smith, A. D. J.
Chem. Soc., Perkin Trans. 1 2000, 22, 3765.
42. A peak corresponding to C(1) was not observed in the 13C NMR spectrum for
this compound.
29. (a) Bunnage, M. E.; Chippindale, A. M.; Davies, S. G.; Parkin, R. M.; Smith, A. D.;
Withey, J. M. Org. Biomol. Chem. 2003, 1, 3698; (b) Bunnage, M. E.; Davies, S. G.;
Parkin, R. M.; Roberts, P. M.; Smith, A. D.; Withey, J. M. Org. Biomol. Chem. 2004,
2, 3337 See also Ref. 4.
43. Davies, S. G.; Mulvaney, A. W.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry
2007, 18, 1554.
44. Hank, Z.; Bruneau, C.; Renaud, J. Synthesis 2009, 15, 2627.