Parallel kinetic resolution of tert-butyl (RS)-6-alkyl-cyclohex-1-ene-carboxylates for the asymmetric synthesis of 6-alkyl-substituted cishexacin derivatives

Article abstract of DOI:10.1016/j.tetasy.2008.11.019

Excellent levels of enantiorecognition are displayed by tert-butyl (RS)-6-n-alkyl-cyclohex-1-ene-carboxylates in mutual kinetic resolutions with lithium (RS)-N-benzyl-N-(α-methylbenzyl)amide. Therefore a 50:50 pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide and lithium (R)-N-3,4-dimethoxybenzyl-N-(α-methylbenzyl)amide allows their efficient parallel kinetic resolution, affording differentially protected 6-n-alkyl-cishexacin derivatives in high yield and >95% de. N-Debenzylation and ester hydrolysis give access to the corresponding homochiral 6-n-alkyl-substituted cishexacin derivatives.

Full text of DOI:10.1016/j.tetasy.2008.11.019

Tetrahedron: Asymmetry 19 (2008) 2870–2881
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Parallel kinetic resolution of tert-butyl (RS)-6-alkyl-cyclohex-1-ene-carboxylates
for the asymmetric synthesis of 6-alkyl-substituted cishexacin derivatives
*
Stephen G. Davies , Matthew J. Durbin, Scott J. S. Hartman, Ai Matsuno, Paul M. Roberts, Angela J. Russell,
Andrew D. Smith, James E. Thomson, Steven M. Toms
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:
Excellent levels of enantiorecognition are displayed by tert-butyl (RS)-6-n-alkyl-cyclohex-1-ene-carbox-
Received 16 October 2008
Accepted 21 November 2008
Available online 12 January 2009
ylates in mutual kinetic resolutions with lithium (RS)-N-benzyl-N-(
50:50 pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-( -methylbenzyl)amide and lithium (R)-
N-3,4-dimethoxybenzyl-N-( -methylbenzyl)amide allows their efficient parallel kinetic resolution,
a-methylbenzyl)amide. Therefore a
a
a
affording differentially protected 6-n-alkyl-cishexacin derivatives in high yield and >95% de. N-Debenzy-
lation and ester hydrolysis give access to the corresponding homochiral 6-n-alkyl-substituted cishexacin
derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
by chromatography due to the differing polarities of the N-benzyl
and N-3,4-dimethoxybenzyl protecting groups (Scheme 1).
There has been considerable interest in the secondary structural
characteristics of short (typically fewer than eight residues) oligo-
mers comprising b-amino acids.1 Within this arena, oligomers of
the diastereoisomers of the simple cyclic b-amino acids, 2-ami-
no-cyclopentane-carboxylic acids (cispentacin and transpentacin)
and 2-amino-cyclohexane-carboxylic acids (cishexacin and trans-
hexacin) have been shown to adopt well-defined secondary struc-
tures in solution and in the solid state.2,3 In order to enhance the
structural diversity of monomeric cispentacin and transpentacin
derivatives available for both secondary structural2 and bioactivity
studies,4 we recently reported the efficient kinetic and parallel
kinetic resolution of a range of 3-alkyl-, 3-oxy- and 5-alkyl-substi-
tuted cyclopent-1-ene-carboxylates,5 utilising the conjugate
addition of either homochiral or a pseudoenantiomeric mixture
of homochiral lithium amides,6 respectively, for the asymmetric
synthesis of the corresponding homochiral 3- and 5-substituted
cispentacin and transpentacin derivatives. In these systems, high
levels of substrate bias for conjugate addition anti to the 3- or
5-substituent, coupled with the exceptionally high facial prefer-
ences of lithium amides 1 and 2,7 allowed highly selective resolu-
tions to be achieved. High levels of facial selectivity upon kinetic
protonation of the intermediate enolates, anti to the newly
installed nitrogen substituent,5,8 allowed ready access to single
diastereoisomers of both enantiomeric series of 3- or 5-substituted
2-amino-cyclopentane-carboxylates, which were easily separable
We wished to extend this versatile protocol to encompass the
synthesis of substituted cishexacin derivatives, via parallel kinetic
resolution of a substituted tert-butyl cyclohex-1-ene-carboxylate
upon treatment with a 50:50 mixture of pseudoenantiomeric lith-
ium amides, and report herein our investigations within this area
concerning the preparation of 6-substituted cishexacin derivatives.
2. Results and discussion
When investigating parallel kinetic resolutions,5d–h we have
promulgated the idea that it is prudent to follow a strategy of first
evaluating the level of substrate control—in this system through
the addition of an achiral lithium amide to the racemic a,b-unsat-
urated ester. In cases where high levels of substrate control are ob-
served, the conjugate addition of a racemic lithium amide to the
racemic
a,b-unsaturated ester (mutual kinetic resolution) may
then be performed, allowing the selectivity factor E to be directly
determined in the absence of deleterious mass action effects.9 Hav-
ing established the maximum levels of enantiorecognition attain-
able, parallel kinetic resolution utilising the conjugate addition of
a 50:50 mixture of the pseudoenantiomeric, homochiral lithium
amides, lithium (S)-N-benzyl-N-(
a
-methylbenzyl)amide
1
and
lithium (R)-N-3,4-dimethoxybenzyl-N-(a-methylbenzyl)amide 2
can be performed.
2.1. Preparation of 6-alkyl-cyclohex-1-ene-carboxylates
The synthesis of a range of tert-butyl 6-alkyl-cyclohex-1-ene
carboxylates 6–11 was accomplished from glutaraldehyde.5f,10
* Corresponding author. Fax: +44 1865 275633.
E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.11.019

S. G. Davies et al. / Tetrahedron: Asymmetry 19 (2008) 2870–2881
2871
OMe
Ph
OMe
Ph
N
Li
(S)-1
Ph
R
OMe
CO2tBu
Ph
N
Ph
+
N
(i)
OMe
CO2tBu
CO2tBu
R
R = C(SPh)3, Ph
Pr, tBu, mesityl
i
R
Ph
N
Product A
Product B
Li
(R)-2
>98% de
>98% de
Ratio A:B = 50:50
-methylbenzyl)amide (S)-1, lithium (R)-N-3,4-dimethoxybenzyl-N-(
Scheme 1. Reagents and conditions: (i) lithium (S)-N-benzyl-N-(
ꢁ78 °C, 2 h, then NH4Cl (satd, aq).
a
a
-methylbenzyl)amide (R)-2, THF,
Under optimised conditions, treatment of glutaraldehyde with tert-
butyl diethylphosphonoacetate in a biphasic 7 M aq K2CO3/DCM
mixture in the presence of AliquatÒ 336 gave a mixture of cyclic
the major diastereoisomeric b,c-unsaturated ester 16 was tenta-
tively assigned as syn by analogy with a related system (vide infra).
Chromatographic purification gave 14 in 80% yield and >95% de.
The relative configuration within 14 was assigned by 3J 1H NMR
coupling constant analysis, assuming that in solution 14 adopts a
chair conformation which places the bulky N,N-dibenzylamino
substituent in an equatorial position. Conjugate addition of lithium
a,b-unsaturated ester 3 and diester 4. Separation by chromatogra-
phy gave 4 in 5% yield as a single diastereoisomer, and 3 as a mix-
ture with AliquatÒ 336. This mixture was treated with acetic
anhydride, with subsequent purification giving acetate 5 in 16%
yield over two steps from glutaraldehyde. Copper-mediated Grig-
nard alkylation of 5 allowed access to a range of tert-butyl 6-al-
kyl-cyclohex-1-ene carboxylates 6–11 (Scheme 2).
N-benzyl-N-isopropylamide 13 to
ceeded in >95% de, to give b-amino ester 15, but was accompanied
by 15% of competing -deprotonation to give a 60:40 mixture of
syn-16 and anti-17. Chromatography gave an 85:15 mixture of b-
amino ester 15 and the products of -deprotonation (syn-16 and
a,b-unsaturated ester 6 also pro-
c
c
anti-17). The relative all-syn configuration within b-amino ester
15 was assigned on the basis of 3J 1H NMR coupling constant anal-
ysis (Scheme 3).
CO2tBu
OH
CHO
CHO
CO2tBu
CO2tBu
(i)
+
Ph
3
4, 5%, >98% de
Ph
CO2tBu
Ph
N
(i)
(ii)
N
Li
12
CO2tBu
Me
Ph
CO2tBu
CO2tBu
R
Me
(ii)
(iii)
6
Ph
14, 80%, >95% de
OAc
N
6, R = Me, 76%
7, R = Et, 87%
8, R = Bn, 86%
9, R = Ph, 80%
10, R = iPr, 70%
11, R = tBu, 83%
5, 16%
Li
over 2 steps
13
Ph
N
+
+
CO2tBu
Me
CO 2tBu
CO2tBu
Scheme 2. Reagents and conditions: (i) (EtO)2POCH2CO2tBu, K2CO3 (7 M, aq),
AliquatÒ 336, DCM, rt, 72 h; (ii) Ac2O, Et3N, DMAP, DCM, rt, 16 h; (iii) RMgCl, CuI,
THF, ꢁ78 °C to rt, 1 h.
Me
syn-16
Me
-17
anti
15, >95% de
Ratio of conjugate addition:γ-deprotonation = 85:15
2.2. Evaluation of substrate control
Scheme 3. Reagents and conditions: (i) lithium dibenzylamide 12 (4 equiv), THF,
ꢁ78 °C, 3 h, then NH4Cl (satd, aq); (ii) lithium N-benzyl-N-isopropylamide 13
(4 equiv), THF, ꢁ78 °C, 3 h, then NH4Cl (satd, aq).
With 6-alkyl-cyclohex-1-ene-carboxylates 6–11 in hand, the
inherent levels of substrate diastereofacial control were evaluated
via the conjugate addition of achiral lithium amides. Lithium di-
benzylamide 125b,c,e,g,h,11 and lithium N-benzyl-N-isopropylamide
135g,h were investigated, the latter being employed as it has been
previously shown by us to very closely mimic the reactivity of lith-
Having demonstrated that the 6-methyl-substituent within 6
offers excellent levels of substrate control upon conjugate addition
of both lithium dibenzylamide 12 and lithium N-benzyl-N-isopro-
pylamide 13, the addition of lithium N-benzyl-N-isopropylamide
ium N-benzyl-N-(
lithium dibenzylamide 12 to 6-methyl-substituted
rated ester 6 gave b-amino ester 14 as a single diastereoisomer
(>95% de)12 and trace amounts (<5%) of b,
-unsaturated esters
syn-16 and anti-17 (in the ratio of 60:40), which arise from
deprotonation of ,b-unsaturated ester 6 by the lithium amide,
rather than conjugate addition. The relative configuration within
a-methylbenzyl)amide 1. Conjugate addition of
13 to the range of 6-substituted
a,b-unsaturated esters 7–11 was
a
,b-unsatu-
investigated. Addition to 6-ethyl 7 and 6-benzyl 8 gave, in each
case, the corresponding b-amino esters 18 and 19 in >95% de, along
with ꢀ10% of the corresponding syn- and anti-diastereoisomers of
c
c
-
the b,c-unsaturated ester products of c-deprotonation 20–23.
a
Chromatography gave 18 and 19 in 77% and 83% yields, respec-

2872
S. G. Davies et al. / Tetrahedron: Asymmetry 19 (2008) 2870–2881
Ph
CO2tBu
CO2tBu
R
CO2tBu
N
+
(i)
CO2tBu
R
R
R
syn
anti
R = Et, syn-20:anti-21 83:17
R = Bn, sy n-22:anti-23 91:9
7, R = Et
8, R = Bn
18, R = Et, 77%, >95% de
19, R = Bn, 83%, >95% de
Scheme 4. Reagents and conditions: (i) lithium N-benzyl-N-isopropylamide 13 (4 equiv), THF, ꢁ78 °C, 3 h, then NH4Cl (satd, aq).
tively. 3J1H NMR coupling constant analysis facilitated the assign-
ment of the relative 1,2-syn-1,6-syn-configuration within 18 and
19 (Scheme 4).
Attempted conjugate addition of lithium N-benzyl-N-isopro-
pylamide 13 to 6-phenyl 9, 6-isopropyl 10 or 6-tert-butyl 11 gave
mixtures comprising starting material, the corresponding 1,4-addi-
tion products 24–26 (>95% de) and the diastereoisomers of the cor-
substituent showing complete diastereofacial control, with pref-
erential addition of the lithium amide occurring syn to the stereo-
controlling 6-alkyl substituent. This predilection presumably
arises due to minimisation of 1,2-strain between the ester group
and adjacent C(6)-alkyl group, forcing the latter into a pseudo-ax-
ial position of a half-chair conformation 33. Favoured axial attack
of lithium amides 12 and 13 and subsequent protonation anti to
the amino group5,8 afford the all syn product. In the case of 9–
responding b,c-unsaturated esters 27–32, in varying ratios. In the
case of 6-tert-butyl-substituted b,
c
-unsaturated esters 31 and 32,
11, however, the bulkier,
block the syn face of the
a
-branched substituents presumably
3J 1H NMR coupling constant analysis allowed assignment of the
relative syn-configuration of the major diastereoisomer 31 and
the relative anti-configuration of the minor diastereoisomer 32,
assuming in both cases that a half-chair conformation is adopted
with the tert-butyl group occupying a pseudoequatorial site. The
a,b-unsaturated ester, thus retarding
the conjugate addition reaction. Alignment of the pseudoaxial
CꢁH -bond of C(3) with the -system of the ,b-unsaturated es-
ter in conformation 33 accounts for the alternative, ready
r
p
a
c-
deprotonation reaction occurring in this system. Kinetic proton-
ation of the intermediate dienolate anti to the 6-alkyl group ac-
counts for the modest preference for formation of the syn-
relative syn-configuration of the major diastereoisomeric b,c-
unsaturated esters 16, 20, 22, 27 and 29 were therefore tentatively
assigned by analogy. In an attempt to favour the conjugate addition
diastereoisomer of the corresponding b,c-unsaturated ester
reaction of lithium N-benzyl-N-isopropylamide 13 to
a
,b-unsatu-
(Fig. 1).
rated esters 9–11, iterative experiments involving changes to reac-
tion times, concentration and equivalents of lithium amide were
performed, but yielded similar results. Due to the substantial com-
Having demonstrated that tert-butyl 6-alkyl-cyclohex-1-ene-
carboxylates 6–8 demonstrate very high levels of substrate con-
trol upon conjugate addition of lithium N-benzyl-N-isopropyla-
mide 13, the mutual kinetic resolution of 6–8 with lithium (RS)-
peting formation of b,c-unsaturated esters 27–32 in these cases, it
was envisaged that these substrates would not be amenable to fur-
ther investigation into their mutual or parallel kinetic resolution
(Scheme 5).
N-benzyl-N-(a-methybenzyl)amide (RS)-1 was next investigated
in order to determine the maximum value of the stereoselectivity
factor E.9
CO2tBu
2.3. Mutual kinetic resolution
R
In mutual kinetic resolutions, mass action effects are negated
and the selectivity factor E is independent of the reaction conver-
sion, and is equivalent to the ratio of products.9 The conjugate
addition of racemic lithium amide (RS)-1 to 6-methyl 6 was ini-
tially investigated and, after quenching with satd aq NH4Cl, b-ami-
no ester 34 was formed in >95% de, consistent with E >40.9 The
conjugate addition reaction was accompanied by trace amounts
(<5%) of competing c-deprotonation leading to b,c-unsaturated es-
ters syn-16 and anti-17 (in the ratio 60:40). Purification by flash
chromatography gave b-amino ester 34 in 85% isolated yield and
9, R = Ph
10, R = iPr
11, R = tBu
Ph
(i)
N
+
+
CO2tBu
R
CO2tBu
R
CO2tBu
R
Product B
>95% de (Scheme 6). The relative (1RS,2SR,6RS,aSR)-configuration
within 34 was unambiguously established by single crystal X-ray
crystallographic analysis (Fig. 2). This analysis also confirmed that
Product C
syn-β,γ-unsaturated
ester
Product A
anti-β,γ-unsaturated
ester
β-amino ester
24, R = Ph
25, R = iPr
26, R = tBu
27, R = Ph
29, R = iPr
31, R = tBu
28, R = Ph
30, R = iPr
32, R = tBu
the relative configurations of the C(2) and N-
reocentres were consistent with the diastereofacial preference of
both the chiral lithium amide 1 (reagent) and the chiral ,b-unsat-
a-methylbenzyl ste-
a
ratio
R
conversion %
A:B:C
urated ester 6 (substrate). The mutual kinetic resolutions of 6-
ethyl 7 and 6-benzyl 8 with lithium amide (RS)-1 were investi-
gated and gave, in each case, single diastereoisomeric b-amino es-
ter products 35 and 36, respectively (>95% de, consistent with E
Ph
iPr
tBu
100
74
78:13:9
41:35:24
13:70:17
56
>40),9 and the b,
c
-unsaturated esters 20–23 (<5% in both cases).
Chromatography gave 35 and 36 in good yield (Scheme 6). In each
case, the relative configuration [(1RS,2SR,6RS, SR)-35 and (1RS,
Scheme 5. Reagents and conditions: (i) lithium N-benzyl-N-isopropylamide 13
(4 equiv), THF, ꢁ78 °C, 3 h, then NH4Cl (satd, aq).
a
The b-amino ester products 14, 15, 18 and 19 formed upon
conjugate addition of lithium amides 12 and 13 to
rated esters 6–8 are consistent, in each case, with the 6-alkyl
2SR,6SR,aSR)-36] was assigned by analogy to that unambiguously
proven for b-amino ester 34; 3J 1H NMR coupling constant analyses
of 35 and 36 were supportive of these assignments for the C(1),
a,b-unsatu-

S. G. Davies et al. / Tetrahedron: Asymmetry 19 (2008) 2870–2881
2873
H+
conjugate
H
H+
γ-deprotonation
addition
LiO
tBuO2C
C(3)
tBuO
R
tBuO
LiO
R
NR2
R
LiNR2
protonation
protonation
axial attack
favoured
anti to amino
anti to C (6) alkyl
group favoured
group favoured
33
NH4Cl
NH4Cl
R
CO2tBu
tBuO2C
R
NR2
t
NR2
BuO2C
all-syn diastereoisomer
R
syn-diastereoisomer
Figure 1. Mnemonic depicting lithium amide conjugate addition to and c-deprotonation of 6-alkyl-cyclohex-1-enecarboxylates 6–11.
Ph
bond coplanar with the carbonyl bond, which necessarily orien-
tates the relevant orbital systems orthogonal. This conformation
is displayed within the X-ray crystal structure of 34, and these
observations are consistent with the outcome of attempted epi-
merisation reactions in a related cyclopentane-derived system.5g,h
In order to verify that the stereochemical outcome observed in
CO2tBu
Ph
N
(i)
CO2tBu
R
R
the mutual kinetic resolution of
a,b-unsaturated esters 6–8 with
6, R = Me
7, R = Et
8, R = Bn
34, R = Me, 85%, >95% de
35, R = Et, 76%, >95% de
36, R = Bn, 84%, >95% de
lithium amide (RS)-1 was identical to that observed upon sub-
strate-directed addition of lithium N-benzyl-N-isopropylamide
13 to 6–8, the configurations within b-amino esters 15 and 34
were correlated. Thus, hydrogenolysis of 15 (as an 85:15 mixture
of 15:[16+17]) mediated by Pearlman’s catalyst gave N-isopropyl
b-amino ester 37 in >95% de. Hydrogenolysis of 34 in a MeOH/
acetone mixture promoted concomitant N-debenzylation and
reductive amination to give 37 in >95% de (Scheme 7).
Scheme 6. Reagents and conditions: (i) lithium (RS)-N-benzyl-N-(
zyl)amide (RS)-1 (4 equiv) THF, ꢁ78 °C, 3 h, then NH4Cl (satd, aq).
a-methylben-
Ph
Ph
N
CO2tBu
Me
Ph
Ph
NH
N
Ph
(ii)
N
(i)
34
t
t
t
CO2 Bu
CO2 Bu
CO2 Bu
Me
Me
Me
37, >95% de
78% from 15
94% from 34
34, >95% de
15, >95% de
Scheme 7. Reagents and conditions: (i) H2 (1 atm), Pd(OH)2/C, MeOH, rt, 24 h; (ii)
H2 (1 atm), Pd(OH)2/C, MeOH/acetone (9:1), rt, 24 h.
The results of these mutual kinetic resolutions demonstrate
that excellent levels of enantiorecognition are shown between
cyclic
a,b-unsaturated esters 6–8 and lithium N-benzyl-N-(a-
methylbenzyl)amide 1 (E >40 in each case),9 implying that their
kinetic or parallel kinetic resolution via this conjugate addition
protocol may be achieved. Although the development of an effi-
cient kinetic resolution protocol would allow for the preparation
of homochiral 6-substituted cishexacin derivatives, the experi-
mental conditions for such a procedure must be carefully con-
trolled, and may vary from substrate to substrate, in order that
the reaction is stopped at ca. 50% conversion. Subsequent studies
therefore focused on the development of a more robust parallel
kinetic resolution protocol, employing a pseudoenantiomeric mix-
ture of lithium amides, which has the advantage of negating the
detrimental effects of mass action and, thus, potentially allowing
a more facile experimental protocol.
Figure 2. Chem 3D representation of the X-ray crystal structure of 34 (some H
atoms removed for clarity).
C(2) and C(6) stereogenic centres of the cycohexane ring. The
conversion of b-amino ester 1,2-syn-1,6-syn-34 into the corre-
sponding 1,2-anti-1,6-anti diastereoisomer upon base-catalysed
epimerisation of the C(1)-stereocentre was next investigated.
However, treatment of 34 with KOtBu at rt returned only starting
material. Even under more forcing conditions (10 equiv of base at
reflux for several days), no trace of epimerisation was observed.
Treatment of 34 with NaH followed by CD3OD returned only
starting material (i.e., no trace of D incorporation), suggesting
that deprotonation was not occurring. This may be due to the fa-
2.4. Parallel kinetic resolution
In order to effect parallel kinetic resolution,
a,b-unsaturated es-
voured solution-phase conformation of 34 placing the
a-CꢁH
r-
ters 6–8 were treated with a 50:50 mixture of lithium (S)-N-ben-

2874
S. G. Davies et al. / Tetrahedron: Asymmetry 19 (2008) 2870–2881
zyl-N-(
a-methylbenzyl)amide (S)-1 (2 equiv) and lithium (R)-N-
OMe
3,4-dimethoxybenzyl-N-(
a
-methylbenzyl)amide (R)-2 (2 equiv)
OMe
in THF at ꢁ78 °C, followed by quenching with satd aq NH4Cl, to give,
in each case, a 50:50 mixture of two diastereoisomeric products 34–
36 and 38–40 (derived from conjugate addition of (S)-1 and (R)-2,
respectively)13 in >95% de, consistent with the complementary
selectivities of the two pseudoenantiomeric lithium amides, with E
>40.9 In each case, the diastereoisomeric b-amino ester products
were easily separated by flash column chromatography due to the
disparate polarities of the N-benzyl and N-3,4-dimethoxybenzyl
groups. b-Amino esters 34–36 were spectroscopically identical to
(i)
Ph
N
Ph
NH
CO2tBu
Me
CO2tBu
Me
38
41, 66%,
>95% de
>95% de
the products of mutual kinetic resolution of
a,b-unsaturated esters
(ii)
6–8 with lithium (RS)-N-benzyl-N-( -methylbenzyl)amide 1. The
a
relative all-syn configuration around the cyclohexane ring within
38–40 was assigned on the basis of 3J 1H NMR coupling constant
analyses, and the absolute configuration at C(2) was assigned, in
each case, by reference to the transition state mnemonic developed
to rationalise the very high facial bias of this class of lithium amides,7
and by analogy to the X-ray crystal structure of 34 (Scheme 8).
NH2•HCl
NH2
CO2H
(iii)
CO2tBu
Me
Me
(1S,2R,6 S)-43
(1S,2 R,6S)-42
84%, >95% de
88%, >95% de
2.5. N-Deprotection: synthesis of 6-substituted cishexacin
Ph
N
OMe
OMe
Ph
(ii)
NH2
CO2tBu
CO2tBu
Ph
Me
Me
CO2tBu
34
>95% de
(1R,2S,6R)-42
Ph
N
Ph
N
(i)
91%, >95% de
+
CO2tBu
R
CO2tBu
R
(iii)
R
NH2•HCl
6, R = Me
7, R = Et
8, R = Bn
34, R = Me, 37%
35, R = Et, 45%
36, R =Bn, 41%
38, R = Me, 41%
39, R = Et, 40%
40, R = Bn, 38%
CO2H
Scheme 8. Reagents and conditions: (i) lithium (S)-N-benzyl-N-(
a
-methylben-
-methylben-
Me
zyl)amide (2 equiv), lithium (R)-N-3,4-dimethoxybenzyl-N-(
1
a
(1R,2S,6R)-43
zyl)amide (R)-2 (2 equiv), THF, ꢁ78 °C, 3 h, then NH4Cl (satd, aq). All compounds
92%, >95% de
were isolated in > 95% de.
Scheme 9. Reagents and conditions: (i) DDQ, DCM/H2O (5:1), rt, 48 h; (ii) H2
(1 atm), Pd(OH)2/C, MeOH, rt, 24 h; (iii) TFA/DCM (1:1), rt, 16 h then HCl, Et2O.
derivatives
In order to demonstrate the utility of this methodology for
the synthesis of substituted cishexacin derivatives, a representa-
tive series of deprotection steps to give the free amino acid was
undertaken with 6-methyl-substituted b-amino esters 34 and
38. Hydrogenolysis of homochiral 34, resulting from conjugate
addition of lithium (S)-N-benzyl-N-(a-methylbenzyl)amide 1 in
the parallel kinetic resolution protocol, furnished primary b-ami-
no ester (1R,2S,6R)-42 in >95% de, consistent with our previous
reports that hydrogenolysis of N-benzyl-N-a-methylbenzyl pro-
3. Conclusion
tert-Butyl (RS)-6-alkyl-cyclohex-1-ene-carboxylates that pos-
sess a 6-alkyl substituent which is not
levels of enantiorecognition in mutual kinetic resolutions with lith-
ium (RS)-N-benzyl-N-( -methylbenzyl)amide. Parallel kinetic reso-
lution of tert-butyl 6-n-alkyl-cyclohexene-1-carboxylates using a
pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-( -methyl-
benzyl)amide and lithium (R)-N-3,4-dimethoxybenzyl-N-( -meth-
ylbenzyl)amide furnishes the corresponding pseudoenantiomeric
tert-butyl 2-amino-6-n-alkyl-cyclohexane-carboxylates, which are
easily separable by chromatography. Subsequent N-deprotection
followed by ester hydrolysis affords the enantiomeric (1R,2S,6R)-
and (1S,2R,6S)-6-methyl-cishexacin derivatives in high diastereo-
isomeric purity.
a-branched display excellent
a
a
a
tected b-amino esters proceeds with no loss of stereochemical
integrity.14 Meanwhile, treatment of homochiral b-amino ester
38 (from conjugate addition of lithium (R)-N-3,4-dimethyoxy-
benzyl-N-(
tive cleavage of the N-3,4-dimethoxybenzyl group was followed
by hydrogenolytic removal of the N- -methylbenzyl group to
a-methylbenzyl)amide 2) with DDQ to effect oxida-
a
give the enantiomeric primary b-amino ester (1S,2R,6S)-42 in
>95% de {for (1R,2S,6R)-42, ½a D25
¼ ꢁ3:7 (c 1.0 in CHCl3); for
ꢂ
(1S,2R,6S)-42, ½a D25
¼ þ1:2 (c 1.0 in CHCl3)}. Subsequent ester
ꢂ
4. Experimental
hydrolysis upon treatment with TFA gave the corresponding b-
amino acids in >95% de in each case, which were isolated as
the hydrochloride salts (1R,2S,6R)-43 and (1S,2R,6S)-43 due to
4.1. General experimental
their increased solubility {for (1R,2S,6R)-43, ½a D25
¼ ꢁ2:0 (c 1.0
ꢂ
All reactions involving organometallic or other moisture-sen-
sitive reagents were carried out under a nitrogen or argon atmo-
sphere using standard vacuum line techniques and glassware
in 1 M HCl); for (1S,2R,6S)-43, ½a D25
¼ þ1:8 (c 1.0 in 1 M HCl)}
ꢂ
(Scheme 9).

S. G. Davies et al. / Tetrahedron: Asymmetry 19 (2008) 2870–2881
2875
that was flame dried and cooled under nitrogen before use. Sol-
vents were dried according to the procedure outlined by Grubbs
and co-workers.15 Water was purified by an ElixÒ UV-10 system.
All other solvents and 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 vis-
ualised using UV light (254 nm), iodine, 1% aq KMnO4, or 10%
ethanolic phosphomolybdic acid. Flash column chromatography
was performed on Kieselgel 60 silica on a glass column, or on
a Biotage SP4 flash column chromatography platform. Melting
points were recorded on a Gallenkamp Hot Stage apparatus
and are uncorrected. Optical rotations were recorded on a Per-
kin–Elmer 241 polarimeter with a water-jacketed 10 cm cell.
Specific rotations are reported in 10ꢁ1 deg cm2 gꢁ1 and concen-
trations in g/100 mL. IR spectra were recorded on 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 cmꢁ1. NMR spectra were recorded on Bruker Avance
spectrometers in the deuterated solvent stated. The field was
locked by external referencing to the relevant deuteron reso-
nance. Chemical shifts (d) are reported in ppm and coupling con-
stants (J) in Hz. Low-resolution mass spectra were recorded on
either a VG MassLab 20-250 or a Micromass Platform 1 spec-
trometer. Accurate mass measurements were run on either a
Bruker MicroTOF internally calibrated with polyalanine, or a
Micromass GCT instrument fitted with a Scientific Glass Instru-
ments BPX5 column (15 m ꢃ 0.25 mm) using amyl acetate as a
lock mass.
H2 was bubbled through the solution and the atmosphere of
the reaction vessel was saturated with H2 (1 atm). After 24 h,
the reaction mixture was filtered through CeliteÒ (eluent
MeOH) and concentrated in vacuo. The crude mixture was dis-
solved in Et2O and washed sequentially with satd aq NaHCO3
and brine, dried and concentrated in vacuo to give the desired
product.
4.5. General procedure 4: hydrolysis of b-amino esters
TFA was added dropwise to the requisite b-amino ester in DCM
at 0 °C (TFA/DCM, 1:1). The solution was vigorously stirred for 16 h
at rt then concentrated in vacuo. HCl (2 M in Et2O) and MeOH were
added to the crude reaction mixture which was then stirred for
30 min and concentrated in vacuo. The residue was partitioned be-
tween Et2O and H2O, the layers were separated and the aqueous
layer was concentrated to a volume of ꢀ0.5 mL. Purification via
ion-exchange chromatography (DowexÒ 50WX8-200 resin, eluent
1 M aq NH4OH) gave the free b-amino acid. Addition of HCl (2 M
in Et2O) and concentration in vacuo gave the b-amino acid hydro-
chloride salt.
4.6. tert-Butyl (RS)-6-acetoxy-cyclohex-1-ene-carboxylate 5
CO2tBu
OAc
4.2. General procedure 1: Grignard addition to tert-butyl (RS)-6-
acetoxy-cyclohex-1-ene-carboxylate 5
tert-Butyl diethylphosphonoacetate (41.8 g, 166 mmol) was
added in one portion to a vigorously stirred biphasic system of
50% aq glutaraldehyde (30.0 mL, 166 mmol), 7 M aq K2CO3
(47.0 mL, 332 mmol) and AliquatÒ 336 (100 mL) in DCM
(100 mL) at rt. After 72 h the mixture was filtered through Cel-
iteÒ (eluent DCM), the layers were separated and the organic
layer was washed with brine (100 mL), dried and concentrated
in vacuo. Purification via flash column chromatography (gradient
elution, eluent 30–40 °C petrol/Et2O, 19:1, increased to 30–40 °C
petrol/Et2O, 9:1) gave 3 as a viscous orange oil (contaminated
with AliquatÒ 336), which was used without further purification.
CuI (0.05 equiv) was added in one portion to a solution of 5
(1 equiv) in THF (0.4 M) at ꢁ78 °C. After 5 min the appropriate
Grignard reagent (1.5 equiv) was added dropwise and the mix-
ture allowed to warm to rt over 1 h. The reaction was quenched
with satd aq NH4Cl, the layers were separated and the aqueous
layer was extracted with Et2O. The combined organic layers
were washed with brine, dried and concentrated in vacuo. Puri-
fication via flash column chromatography gave the desired
product.
Further elution gave di-tert-butyl nona-2,7-dieneoate
4 as a
white solid (2.3 g, 5%);16 dH (400 MHz, CDCl3) 1.47 (9H, s,
CMe3), 1.60 (2H, quintet, J 7.4, C(5)H2), 2.19 (4H, app qd, J 7.4,
1.4, C(4)H2, C(6)H2) 5,74 (2H, d, J 15.6, C(2)H, C(8)H), 6.81 (2H,
dt, J 15.6, 7.4, C(3)H, C(5)H).
4.3. General procedure 2: lithium amide conjugate addition to
a,b-unsaturated esters
BuLi (3.95 equiv) was added dropwise to a stirred solution of
the requisite amine(s) (4 equiv) in THF at ꢁ78 °C. After 30 min, a
solution of the requisite ,b-unsaturated ester (1 equiv) in THF
(overall concentration of ,b-unsaturated ester = 0.1 M) at
Ac2O (27.7 mL, 293 mmol) was added dropwise to a stirred
solution of 3 (11.6 g, ꢀ58.6 mmol), Et3N (8.9 mL, 87.9 mmol)
and DMAP (30 mg) in DCM (30 mL) at rt. After 16 h the mix-
ture was diluted with DCM (50 mL), washed sequentially with
satd aq NaHCO3 (2 ꢃ 50 mL) and brine (50 mL), dried and con-
centrated in vacuo. Purification via flash column chromatogra-
phy (eluent 30–40 °C petrol/Et2O, 9:1) gave 5 as a colourless
oil (6.3 g, 16% from glutaraldehyde over 2 steps); mmax (film)
2977 (C–H), 1738 (C@O), 1714 (C@O), 1369, 1167, 929; dH
(400 MHz, CDCl3) 1.45 (9H, s, CMe3), 1.60–1.66 (3H, m, C(4)H2,
C(5)HA), 1.91–1.96 (1H, m, C(5)HB), 2.03 (3H, s, COMe), 2.07–
2.18 (1H, m, C(3)HA), 2.29–2.38 (1H, m, C(3)HB), 5.70 (1H, app
br s, C(6)H), 7.18 (1H, dd, J 5.0, 2.8, C(2)H); dC (100 MHz, CDCl3)
16.6 (C(4)), 21.3 (COMe), 25.7 (C(3)), 28.0 (CMe3), 28.1 (C(5)),
a
a
ꢁ78 °C was added via cannula and the reaction mixture was
stirred for a further 3 h before the addition of satd aq NH4Cl
solution. The organic layer was separated and the aqueous layer
was extracted three times with Et2O. The combined organic
layers were washed sequentially with 10% aq citric acid, satd
aq NaHCO3 and brine, before being dried and concentrated in
vacuo. Purification via flash column chromatography gave the
desired product.
4.4. General procedure 3: hydrogenolysis of N-benzyl protected
b-amino esters
t-
64.8 (C(6)), 80.5 (CMe3), 130.2 (C(1)), 144.4 (C(2)), 165.1 (CO2
Pd(OH)2/C (50% w/w to substrate) was added to a vigor-
ously stirred solution of the requisite N-benzyl protected
b-amino ester in degassed MeOH (0.1 M) at rt under argon.
Bu), 170.1 (COMe); m/z (ESI+) 503 ([2M+Na]+, 100%); HRMS
(ESI+) C13H20NaO4
263.1252.
([M+Na]+) requires 263.1254; found
þ

2876
S. G. Davies et al. / Tetrahedron: Asymmetry 19 (2008) 2870–2881
4.7. tert-Butyl (RS)-6-methyl-cyclohex-1-ene-carboxylate 6
4.10. tert-Butyl (RS)-6-phenyl-cyclohex-1-ene-carboxylate 9
CO2tBu
CO2tBu
Me
Ph
Following General Procedure 1,
5
(1.0 g, 4.16 mmol), CuI
Following General Procedure 1, 5 (200 mg, 0.83 mmol), CuI
(8 mg, 0.04 mmol) and phenylmagnesium chloride (2 M in THF,
0.62 mL, 1.25 mmol) in THF (0.5 mL) gave, after purification via
flash column chromatography (gradient elution, eluent 30–40 °C
petrol/Et2O, 49:1, increased to 30–40 °C petrol/Et2O, 24:1), 9 as a
colourless oil (173 mg, 80%); mmax (film) 2933, 1710 (C@O), 1367,
1254, 1168; dH (400 MHz, CDCl3) 1.23 (9H, s, CMe3), 1.50–1.59
(2H, m, C(4)H2), 1.68–1.75 (1H, m, C(5)HA), 1.91–2.00 (1H, m,
C(5)HB), 2.18–2.37 (2H, m, C(3)H2), 3.83 (1H, app br s, C(6)H),
7.13–7.20 (4H, m, C(2)H, Ph), 7.27 (2H, app t, J 7.5, Ph); dC
(100 MHz, CDCl3) 17.8 (C(4)), 25.9 (C(3)), 27.8 (CMe3), 31.8 (C(5)),
40.3 (C(6)), 79.9 (CMe3), 125.7 (p-Ph), 127.7, 128.0 (o-Ph, m-Ph),
(21 mg, 0.11 mmol) and methylmagnesium chloride (2.3 M in
THF, 2.7 mL, 6.21 mmol) in THF (10 mL) gave, after purification
via flash column chromatography (gradient elution, eluent 30–
40 °C petrol/Et2O, 49:1, increased to 30–40 °C petrol/Et2O,
24:1), 6 as a colourless oil (680 mg, 76%); mmax (film) 2933,
2871, 1706 (C@O), 1644, 1455, 1366, 1170; dH (400 MHz, CDCl3)
1.06 (3H, d, J 6.8, C(6)Me), 1.48 (9H, s, J 7.1, CMe3), 1.45–1.69
(4H, m, C(4)H2, C(5)H2), 2.01–2.21 (2H, m, C(3)H2), 2.50–2.66
(1H, m, C(6)H), 6.80 (1H, app t, J 4.0, C(2)H); dC (100 MHz, CDCl3)
17.4 (C(4)), 20.2 (C(6)Me), 25.9 (C(3)), 27.8 (C(6)), 28.1 (CMe3),
29.7 (C(5)), 79.8 (CMe3), 136.9 (C(1)), 138.0 (C(2)), 167.0 (CO2
tBu); HRMS (FI+) C12H20O2 ([M]+) requires 196.1458; found
133.8 (C(1)), 140.1 (C(2)), 145.8 (i-Ph), 166.6 (CO2 Bu); m/z (ESI+)
t
þ
534 ([2M+NH4]+, 100%); HRMS (ESI+) C17H22NaO4 ([M+Na]+) re-
þ
196.1461.
quires 281.1512; found 281.1510.
4.8. tert-Butyl (RS)-6-ethyl-cyclohex-1-ene-carboxylate 7
4.11. tert-Butyl (RS)-6-isopropyl-cyclohex-1-ene-carboxylate 10
CO2tBu
CO2tBu
Et
iPr
Following General Procedure 1, 5 (500 mg, 2.08 mmol), CuI
(9.9 mg, 0.052 mmol) and ethylmagnesium chloride (2.0 M in
THF, 1.6 mL, 3.2 mmol) in THF (5 mL) gave, after purification
via flash column chromatography (gradient elution, eluent 30–
40 °C petrol/Et2O, 49:1, increased to 30–40 °C petrol/Et2O,
24:1), 7 as a colourless oil (380 mg, 87%); mmax (film) 3004,
2964, 1706 (C@O), 1640; dH (400 MHz, CDCl3) 0.90 (3H, t, J
8.0, C(6)CH2Me), 1.22–1.24 (1H, m, C(6)CHAHBMe), 1.47 (9H, s,
CMe3), 1.54–1.57 (4H, m, C(4)HA, C(5)H2, C(6)CHAHBMe), 1.68–
1.72 (1H, m, C(4)HB), 2.09–2.13 (2H, m, C(3)H2), 2.38–2.40 (1H,
m, C(6)H), 6.80 (1H, app t, J 4.0, C(2)H); dC (100 MHz, CDCl3)
12.3 (C(6)CH2Me), 17.3 (C(5)), 25.0 (C(4)), 25.8 (C(3)), 26.4
Following General Procedure 1, 5 (200 mg, 0.22 mmol), CuI
(8 mg, 0.04 mmol) and isopropylmagnesium chloride (2 M in
THF, 0.62 mL, 1.25 mmol) in THF (0.5 mL) gave, after purification
via flash column chromatography (gradient elution, eluent 30–
40 °C petrol/Et2O, 49:1, increased to 30–40 °C petrol/Et2O, 24:1),
10 as a colourless oil (130 mg, 70%); mmax (film) 2961, 1708
(C@O), 1367, 1171, 1071; dH (400 MHz, CDCl3) 0.83 (3H, d, J 6.8,
MeCHMe), 0.90 (3H, d, J 6.8, MeCHMe), 1.48 (9H, s, CMe3), 1.48–
1.54 (2H, m, C(4)HA, C(5)HA), 1.61–1.70 (2H, m, C(4)HB, C(5)HB),
1.90 (1H, app septet, J 6.8 CHMe2), 2.09–2.14 (2H, m, C(3)H2),
2.42–2.48 (1H, m, C(6)H), 6.76 (1H, app t, J 3.8, C(2)H); dC
(100 MHz, CDCl3) 18.7 (C(4)), 19.2, 21.0 (CHMe2), 23.3 (C(5)), 25.6
(C(3)), 28.1 (CMe3), 30.5 (CHMe2), 38.6 (C(6)), 79.7 (CMe3), 136.4
(C(6)CH2Me), 28.1 (CMe3), 34.4 (C(6)), 79.7 (CMe3), 136.4 (C(1)),
t
138.0 (C(2)), 167.1 (CO2 Bu); HRMS (FI+) C13H22O2 ([M]+) re-
þ
(C(1)), 137.9 (C(2)), 168.1 (CO2 Bu); HRMS (FI+) C14H24O2 ([M]+)
t
þ
quires 210.1614; found 210.1622.
requires 224.1771; found 224.1779.
4.9. tert-Butyl (RS)-6-benzyl-cyclohex-1-ene-1-carboxylate 8
4.12. tert-Butyl (RS)-6-tert-butyl-cyclohex-1-ene-carboxylate
11
CO2tBu
CO2tBu
tBu
Bn
Following General Procedure 1,
5 (1.0 g, 4.16 mmol), CuI
(21 mg, 0.11 mmol) and benzylmagnesium chloride (2 M in
THF, 3.1 mL, 6.24 mmol) in THF (10 mL) gave, after purification
via flash column chromatography (gradient elution, eluent 30–
40 °C petrol/Et2O, 49:1, increased to 30–40 °C petrol/Et2O,
24:1), 8 as a colourless oil (972 mg, 86%); mmax (film) 3003,
2976, 1702 (C@O), 1366, 1249; dH (400 MHz, CDCl3) 1.35–1.38
(1H, m, C(5)HA), 1.56 (9H, s, CMe3), 1.58–1.69 (3H, m, C(4)H2,
C(5)HB), 2.15–2.29 (2H, m, C(3)H2), 2.39 (1H, dd, J 13.1, 7.8,
C(6)CHAHBPh), 2.84–2.86 (1H, m, C(6)H), 3.02 (1H, dd, J 13.1,
3.8, C(6)CHAHBPh), 6.93 (1H, app t, J 3.8, C(2)H), 7.15–7.33 (5H,
m, Ph); dC (100 MHz, CDCl3) 16.8 (C(4)), 24.3 (C(5)), 25.9 (C(3)),
28.2 (CMe3), 35.0 (C(6)), 39.5 (C(6)CH2Ph), 80.0 (CMe3), 125.8
Following General Procedure 1, 5 (200 mg, 0.83 mmol), CuI
(8 mg, 0.04 mmol) and tert-butylmagnesium chloride (2 M in
THF, 0.62 mL, 1.25 mmol) in THF (0.5 mL) gave, after purification
via flash column chromatography (gradient elution, eluent 30–
40 °C petrol/Et2O, 49:1, increased to 30–40 °C petrol/Et2O, 24:1),
11 as a colourless oil (164 mg, 83%); mmax (film) 2967, 1710
(C@O), 1366, 1251, 1169; dH (400 MHz, CDCl3) 0.91 (9H, s,
C(6)CMe3), 1.45–1.57 (2H, m, C(4)HA, C(5)HA), 1.48 (9H, s, OCMe3),
1.70–1.79 (1H, m, C(4)HB), 1.80–1.88 (1H, m, C(5)HB), 2.08–2.14
(2H, m, C(3)H2), 2.59–2.64 (1H, m, C(6)H), 6.70 (1H, app t, J 4.2,
C(2)H); dC (100 MHz, CDCl3) 19.5 (C(4)), 24.2 (C(5)), 24.7 (C(3)),
28.0 (OCMe3), 29.1 (C(6)CMe3), 35.6 (C(6)CMe3), 41.2 (C(6)), 79.7
(p-Ph), 128.2, 128.3 (o-Ph, m-Ph), 135.5 (C(1)), 139.2 (C(2)),
t
(OCMe3), 135.7 (C(1)), 138.1 (C(2)), 169.8 (CO2 Bu); HRMS (FI+)
t
141.3 (i-Ph), 166.7 (CO2 Bu); HRMS (FI+) C18H24O2 ([M]+) re-
þ
C15H26O2 ([M]+) requires 238.1927; found 238.1934.
þ
quires 272.1771; found 272.1775.

S. G. Davies et al. / Tetrahedron: Asymmetry 19 (2008) 2870–2881
2877
4.13. tert-Butyl (1RS,2SR,6RS)-2-N,N-dibenzylamino-6-methyl-
4.15. tert-Butyl (1RS,2SR,6RS)-2-[N-benzyl-N-isopropylamino]-
cyclohexane-carboxylate 14
6-ethyl-cyclohexane-carboxylate 18
Ph
Ph
Ph
N
N
CO2tBu
Me
CO2tBu
Et
Following General Procedure 2, BuLi (2.2 M in hexanes,
0.46 mL, 1.00 mmol), dibenzylamine (201 mg, 1.02 mmol) in
THF (2 mL) and 6 (50 mg, 0.26 mmol) in THF (0.6 mL) gave a
95:3:2 mixture of 14:16:17. Purification via flash column chro-
matography (eluent 30–40 °C petrol/Et2O, 9:1) gave 14 as a col-
ourless oil (80 mg, 80%, >95% de); mmax (film) 3027, 2930, 1718
(C@O), 1454, 1149, 966; dH (400 MHz, CDCl3) 0.93 (3H, d, J 6.8,
C(6)Me) 1.27–1.33 (2H, m, C(4)HA, C(5)HA), 1.47 (9H, s, CMe3),
1.50–1.54 (1H, m, C(6)H), 1.64–1.70 (2H, m, C(3)HA, C(5)HB),
1.82–1.89 (1H, m, C(4)HB), 2.13–2.19 (1H, m, C(3)HB), 2.70
(1H, app dt, J 12.5, 4.4, C(2)H), 2.87 (1H, app t, J 4.4, C(1)H),
3.72 (4H, app s, N(CH2Ph)2), 7.21 (2H, t, J 7.2, Ph), 7.30 (4H,
app t, J 7.2, Ph), 7.40 (4H, d, J 7.2, Ph); dC (100 MHz, CDCl3)
19.3 (C(6)Me), 23.1 (C(3)), 25.7 (C(4)), 28.1 (CMe3), 28.8 (C(5)),
35.2 (C(6)), 49.7 (C(1)), 54.5 (N(CH2Ph)2), 60.8 (C(2)), 80.3
(CMe3), 126.6 (p-Ph), 128.1, 128.4 (o-Ph, m-Ph), 140.8 (i-Ph),
Following General Procedure 2, BuLi (2.3 M in hexanes, 1.21 mL,
2.80 mmol), N-benzyl-N-isopropylamine (420 mg, 2.84 mmol) in
THF (5 mL) and 7 (150 mg, 0.71 mmol) in THF (2 mL) gave a
94:5:1 mixture of 18:20:21. Purification via flash column chroma-
tography (eluent 30–40 °C petrol/Et2O, 49:1) gave 18 as a colour-
less oil (196 mg, 77%, >95% de); mmax (film) 3084, 2962, 2861,
1717 (C@O), 1455, 1328, 1145; dH (400 MHz, CDCl3) 0.95 (3H, d, J
6.5, C(6)CH2Me), 0.98 (3H, d, J 6.6, MeCHMe), 1.04 (3H, d, J 6.6,
MeCHMe), 1.19-1.35 (4H, m, C(4)HA, C(5)HA, C(6)CH2Me), 1.39
(9H, s, CMe3), 1.41–1.44 (1H, m, C(6)H), 1.53–1.59 (2H, m,
C(3)HA, C(5)HB), 1.81–1.88 (1H, m, C(4)HB), 2.08–2.12 (1H, m,
C(3)HB), 2.76 (1H, app dt, J 12.5, 4.3, C(2)H), 2.81 (1H, t, J 4.3,
C(1)H), 3.07 (1H, app septet, J 6.6, CHMe2), 3.76 (2H, ABq, JAB
15.6, NCH2Ph), 7.16–7.41 (5H, m, Ph); dC (100 MHz, CDCl3) 12.0
(C(6)CH2Me), 18.0, 20.3 (CHMe2), 25.7, 25.9 (C(3), C(4)), 26.6, 27.0
(C(5), C(6)CH2Me), 28.1 (CMe3), 42.8 (C(6)), 48.5 (CHMe2), 50.5
(NCH2Ph), 51.4 (C(1)), 59.3 (C(2)), 79.9 (CMe3), 126.0 (p-Ph),
t
174.1 (CO2 Bu); m/z (ESI+) 394 ([M+H]+, 100%); HRMS (ESI+)
t
C26H36NO2 ([M+H]+) requires 394.2741; found 394.2740. Data
127.2, 128.7 (o-Ph, m-Ph), 142.9 (i-Ph), 173.8 (CO2 Bu); m/z (ESI+)
þ
360 ([M+H]+, 100%); HRMS (ESI+) C23H38NO2 ([M+H]+) requires
þ
for syn-16: dH (400 MHz, CDCl3) [selected peaks] 3.04–3.09
(1H, m, C(1)H), 5.71–5.74 (1H, m, C(3)H), 5.81–5.84 (1H, m,
C(2)H). Data for anti-17: dH (400 MHz, CDCl3) [selected peaks]
3.04–3.09 (1H, m, C(1)H), 5.68–5.70 (1H, m, C(3)H), 5.84–5.87
(1H, m, C(2)H).
360.2897; found 360.2896. Data for syn-20: dH (400 MHz, CDCl3)
[selected peaks] 3.08–3.12 (1H, m, C(1)H), 5.70–5.73 (1H, m,
C(3)H), 5.83–5.86 (1H, m, C(2)H). Data for anti-21: dH (400 MHz,
CDCl3) [selected peaks] 3.08–3.12 (1H, m, C(1)H), 5.67–5.70 (1H,
m, C(3)H), 5.86–5.89 (1H, m, C(2)H).
4.14. tert-Butyl (1RS,2SR,6RS)-2-[N-benzyl-N-isopropylamino]-
6-methyl-cyclohexane-carboxylate 15
4.16. tert-Butyl (1RS,2SR,6SR)-2-[N-benzyl-N-isopropylamino]-
6-benzyl-cyclohexane-1-carboxylate 19
Ph
Ph
N
N
CO2tBu
CO2tBu
Me
Bn
Following General Procedure 2, BuLi (2.2 M in hexanes,
0.46 mL, 1.00 mmol), N-benzyl-N-isopropylamine (152 mg,
1.02 mmol) in THF (2 mL) and 6 (50 mg, 0.26 mmol) in THF
(0.6 mL) gave an 85:9:6 mixture of 15:16:17. Purification via
flash column chromatography (eluent 30–40 °C petrol/Et2O,
9:1) gave an 85:9:6 mixture of 15:16:17 colourless oil
(74 mg, 15 in >95% de); mmax (film) 2960, 1718 (C@O), 1455,
1366, 1147. Data for 15: dH (400 MHz, CDCl3) 0.94 (3H, d, J
6.6, C(6)Me), 0.97 (3H, d, J 6.6, MeCHMe), 1.03 (3H, d, J 6.6,
MeCHMe), 1.28–1.35 (2H, m, C(4)HA, C(5)HA), 1.40 (9H, s,
CMe3), 1.50–1.68 (3H, m, C(3)HA, C(5)HB, C(6)H), 1.79–1.85
(1H, m, C(4)HB), 2.03–2.09 (1H, m, C(3)HB), 2.72 (1H, app t, J
4.3, C(1)H), 2.77 (1H, app dt, J 12.5, 4.3, C(2)H), 3.08 (1H, sep-
tet, J 6.6, CHMe2), 3.76 (2H, ABq, JAB 15.5, NCH2Ph), 7.18 (1H,
app t, J 7.4, Ph), 7.27 (2H, app t, J 7.4, Ph), 7.39 (2H, app d, J
7.4, Ph); dC (100 MHz, CDCl3) 18.0 (MeCHMe), 19.6 (C(6)Me),
20.2 (MeCHMe), 25.3 (C(3)), 25.9 (C(4)), 28.1 (CMe3), 28.6
(C(5)), 35.2 (C(6)), 48.5 (CHMe2), 50.5 (NCH2), 53.5 (C(1)),
59.3 (C(2)), 80.0 (CMe3), 126.0 (p-Ph), 127.7, 127.8 (o-Ph, m-
Following General Procedure 2, BuLi (2.3 M in hexanes, 0.94 mL,
2.17 mmol), N-benzyl-N-isopropylamine 13 (327 mg, 2.20 mmol)
in THF (5 mL) and 8 (150 mg, 0.55 mmol) in THF (2 mL) gave an
89:10:1 mixture of 19:22:23. Purification via flash column chro-
matography (eluent 30–40 °C petrol/Et2O, 49:1) gave 19 as a col-
ourless oil (192 mg, 83%, >95% de); mmax (film) 2932, 1716 (C@O),
1602, 1494, 1391, 1146; dH (400 MHz, CDCl3) 0.98 (3H, d, J 6.6,
MeCHMe), 1.02 (3H, d,
J 6.6, MeCHMe), 1.16–1.19 (1H, m,
C(4)HA), 1.31–1.35 (1H, m, C(5)HA), 1.46 (9H, s, CMe3), 1.51–1.65
(2H, m, C(3)HA, C(5)HB), 1.65–1.83 (2H, m, C(4)HB, C(6)H), 2.09–
2.12 (1H, m, C(3)HB), 2.37 (1H, dd, J 13.3, 9.4, C(6)CHAHBPh),
2.77–2.80 (2H, m, C(2)H, C(6)CHAHBPh), 2.88 (1H, app t, J 3.8,
C(1)H), 3.07 (1H, app septet, J 6.6, CHMe2), 3.75 (2H, ABq, JAB
15.6, NCH2Ph), 7.18–7.23 (4H, m, Ph), 7.26–7.32 (4H, m, Ph),
7.39–7.41 (2H, app d,
J 7.3, Ph); dC (100 MHz, CDCl3) dC
(100 MHz, CDCl3) 18.1, 20.2 (CHMe2), 25.6, 25.8 (C(4), C(5)), 28.2
(CMe3), 40.8 (C(6)CH2Ph), 43.0 (C(6)), 48.5 (CHMe2), 50.5
(NCH2Ph2), 52.3 (C(1)), 59.5 (C(2)), 80.3 (CMe3), 125.9, 126.1 (p-
Ph), 127.7, 127.9, 128.2, 129.1 (o-Ph, m-Ph), 140.9, 142.9 (i-Ph),
t
Ph), 143.0 (i-Ph), 173.8 (CO2 Bu); m/z (ESI+) 346 ([M+H]+,
t
173.7 (CO2 Bu); m/z (ESI+) 422 ([M+H]+, 100%); HRMS (ESI+)
100%); HRMS (ESI+) C22H36NO2
346.2745.
([M+H]+) 346.2741; found
þ
C28H40NO2 ([M+H]+) requires 422.3054; found 422.3053. Data
þ

2878
S. G. Davies et al. / Tetrahedron: Asymmetry 19 (2008) 2870–2881
for syn-22: dH (400 MHz, CDCl3) [selected peaks] 3.09–3.13 (1H, m,
C(1)H), 5.75–5.78 (1H, m, C(3)H), 5.84–5.87 (1H, m, C(2)H). Data
for anti-23: dH (400 MHz, CDCl3) [selected peaks] 3.09–3.13 (1H,
m, C(1)H), 5.72–5.75 (1H, m, C(3)H), 5.87–5.90 (1H, m, C(2)H).
4.20. tert-Butyl (1RS,2SR,6RS,aSR)-2-[N-benzyl-N-(a-methyl-
benzyl)amino]-6-methyl-cyclohexane-carboxylate 34
Ph
Ph
N
CO2tBu
Me
4.17. Addition of lithium N-benzyl-N-isopropylamide 13 to tert-
butyl (RS)-6-phenyl-cyclohex-1-ene-carboxylate 9
Following General Procedure 2, BuLi (2.3 M in hexanes,
0.46 mL, 1.06 mmol), N-benzyl-N-isopropylamine (163 mg,
1.09 mmol) in THF (5 mL) and 9 (176 mg, 0.68 mmol) in THF
(1.8 mL) gave a 78:13:9 mixture of 24:27:28. Purification via
flash column chromatography (eluent 30–40 °C petrol/Et2O,
49:1) gave a 78:13:9 mixture of 24:27:28 as a colourless oil
(232 mg, 24 in >95% de). Data for 24: dH (400 MHz, CDCl3) [se-
lected peaks] 3.06–3.13 (2H, m, C(1)H, CHMe2), 3.22–3.27 (1H,
m, C(2)H), 3.95 (2H, ABq, JAB 14.6, NCH2Ph); dC (100 MHz, CDCl3)
[selected peaks] 49.4 (CHMe2), 53.1 (C(2)), 53.9 (C(1)). Data for
syn-27: dH (400 MHz, CDCl3) [selected peaks] 3.42–3.47 (1H, m,
C(1)H), 5.95–5.98 (1H, m, C(3)H), 6.00–6.03 (1H, m, C(2)H); dC
(100 MHz, CDCl3) [selected peaks] 47.0 (C(1)), 124.7 (C(3)),
130.0 (C(2)). Data for anti-28: dH (400 MHz, CDCl3) [selected
peaks] 3.42–3.47 (1H, m, C(1)H), 5.92–5.95 (1H, m, C(3)H),
6.03–6.06 (1H, m, C(2)H); dC (100 MHz, CDCl3) [selected peaks]
47.0 (C(1)), 124.7 (C(3)), 130.0 (C(2)).
Following General Procedure 2, BuLi (2.3 M in hexanes, 4.45 mL,
10.3 mmol), (RS)-N-benzyl-N-( -methylbenzyl)amine (2.24 g,
a
10.6 mmol) in THF (22 mL) and 6 (519 mg, 2.65 mmol) in THF
(4.5 mL) gave a 95:3:2 mixture of 34:16:17. Purification via flash
column chromatography (gradient elution, eluent 30–40 °C pet-
rol/Et2O, 49:1, increased to 30–40 °C petrol/Et2O, 24:1) gave 34
as a white solid (923 mg, 85%, >95% de); mp 90–92 °C (DCM/pen-
tane); mmax (film) 2931, 1717 (C@O), 1453, 1367, 1150; dH
(400 MHz, CDCl3) 0.85 (3H, d, J 6.9, C(6)Me), 1.18–1.27 (2H, m,
C(4)HA, C(5)HA), 1.32 (3H, d, J 6.8, C(a)Me), 1.38–1.42 (1H, m,
C(6)H), 1.46 (9H, s, CMe3), 1.52–1.66 (2H, m, C(3)HA, C(5)HB),
1.78–1.84 (1H, m, C(4)HB), 2.09–2.19 (1H, m, C(3)HB), 2.55 (1H,
app t, J 4.4, C(1)H), 2.67–2.70 (1H, m, C(2)H), 3.82–3.95 (2H, ABq,
JAB 15.0, NCH2Ph), 4.06 (1H, q, J 6.8, C(
Ph), 7.29–7.36 (4H, m, Ph), 7.45–7.57 (4H, m, Ph); dC (100 MHz,
CDCl3) 15.4 (C( )Me), 19.4 (C(6)Me), 25.5 (C(3)), 25.8 (C(4)), 28.2
(CMe3), 28.6 (C(5)), 35.2 (C(6)), 51.0 (NCH2), 52.0 (C(1)), 56.7
(C( )), 59.7 (C(2)), 80.3 (CMe3), 126.4, 126.5 (p-Ph), 127.8, 127.9,
a)H), 7.19–7.25 (2H, m,
a
a
4.18. Addition of lithium N-benzyl-N-isopropylamide 13 to tert-
butyl (RS)-6-isopropyl-cyclohex-1-ene-carboxylate 10
t
128.0, 128.2 (o-Ph, m-Ph), 142.5, 144.6 (i-Ph), 174.1 (CO2 Bu); m/z
(ESI+) 408 ([M+H]+, 100%); HRMS (ESI+) C27H28NO2 ([M+H]+) re-
þ
quires 408.2897; found 408.2903.
Following General Procedure 2, BuLi (2.3 M in hexanes, 0.38 mL,
0.87 mmol), N-benzyl-N-isopropylamine (133 mg, 0.89 mmol) in
THF (1.5 mL) and 10 (50 mg, 0.22 mmol) in THF (0.7 mL) gave a
41:35:24 mixture of 25:29:30. Purification via flash column chro-
matography (eluent 30–40 °C petrol/Et2O, 49:1) gave a 41:35:24
mixture of 25:29:30 as a colourless oil (64 mg, 25 in >95% de). Data
for 25: dH (400 MHz, CDCl3) [selected peaks] 2.73 (1H, app dt, J
12.5, 4.1, C(2)H), 2.94 (1H, app t, J 4.1, C(1)H), 3.05 (1H, app septet,
J 6.6, CHMe2), 3.74 (2H, ABq, JAB 15.6, NCH2Ph); dC (100 MHz,
CDCl3) [selected peaks] 49.9 (C(1)), 50.6 (NCH2Ph), 59.7 (C(2)). Data
for syn-29 and anti-30: dH (400 MHz, CDCl3) [selected peaks] 3.10–
3.16 (1H, m, C(1)H), 5.64–5.70 (1H, m, C(3)H), 5.86–5.92 (1H, m,
C(2)H); dC (100 MHz, CDCl3) [selected peaks] 44.3 (C(1)), 124.7
(C(3)), 130.4 (C(2)).
4.21. X-ray crystal structure determination for 34
Data were collected using an Enraf-Nonius
ter with graphite monochromated Mo-K radiation using standard
procedures at 190 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
j-CCD diffractome-
a
(
17
positions. The structure was refined using CRYSTALS
.
X-ray crystal structure data for 34 [C27H37NO2]: M = 407.60,
ꢀ
triclinic, space group P1, a = 9.9898(1) Å, b = 10.4028(2) Å, c =
14.0324(2) Å,
a
= 107.8397(7), b = 92.5204(7)°,
c
= 116.5274(8)°,
V = 1213.70(3) Å3, Z = 2,
l
= 0.069 mmꢁ1, colourless plate, crystal
dimensions = 0.1 ꢃ 0.1 ꢃ 0.2 mm3. A total of 5514 unique reflections
were measured for 5 < h < 27 and 3618 reflections were used in the
refinement. The final parameters were wR2 = 0.047 and R1 = 0.042
4.19. Addition of lithium N-benzyl-N-isopropylamide 13 to tert-
butyl (RS)-6-tert-butyl-cyclohex-1-ene-carboxylate 11
[I > 3.0r(I)]. Crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 679351. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
Following General Procedure 2, BuLi (2.3 M in hexanes, 1.00 mL,
2.36 mmol), N-benzyl-N-isopropylamine 13 (361 mg, 2.42 mmol)
in THF (4.5 mL) and 11 (144 mg, 0.61 mmol) in THF (1.6 mL) gave
a 13:70:17 mixture of 26:31:32. Purification via flash column chro-
matography (eluent 30–40 °C petrol/Et2O, 49:1) gave a 13:70:17
mixture of 26:31:32 as a colourless oil (146 mg, 26 in >95% de).
Data for 26: dH (400 MHz, CDCl3) [selected peaks] 3.07 (1H, app
septet, J 6.6, CHMe2), 3.60 (2H, ABq, JAB 15.3, NCH2Ph). Data for
syn-31: dH (400 MHz, CDCl3) [selected peaks] 3.08–3.13 (1H, m,
C(1)H), 5.60–5.66 (1H, m, C(3)H), 5.81–5.86 (1H, m, C(2)H); dC
(100 MHz, CDCl3) 18.9, 27.0 (C(4), C(5)), 28.0, 28.1 (CMe3,
C(6)CMe3), 32.9 (CMe3), 43.9 (C(6)), 48.0 (C(1)), 80.2 (CMe3),
4.22. tert-Butyl (1RS,2SR,6RS,aSR)-2-[N-benzyl-N-(a-methyl-
benzyl)amino]-6-ethyl-cyclohexane-carboxylate 35
Ph
Ph
N
CO2tBu
Et
t
125.8 (C(3)), 130.3 (C(2)), 173.9 (CO2 Bu). Data for anti-32: dH
(400 MHz, CDCl3) [selected peaks] 2.88–2.94 (1H, m, C(1)H),
5.46–5.51 (1H, m, C(3)H), 5.87–5.91 (1H, m, C(2)H); dC (100 MHz,
CDCl3) 22.8, 25.2 (C(4), C(5)), 27.8, 28.0 (CMe3, C(6)CMe3), 33.5
(CMe3), 44.1 (C(6)), 46.1 (C(1)), 80.2 (CMe3), 125.6 (C(3)), 130.2
Following General Procedure 2, BuLi (2.3 M in hexanes,
1.22 mL, 2.80 mmol), (RS)-N-benzyl-N-( -methylbenzyl)amine
(639 mg, 2.84 mmol) in THF (5 mL) and 7 (150 mg, 0.71 mmol)
a
t
(C(2)), 175.3 (CO2 Bu).

S. G. Davies et al. / Tetrahedron: Asymmetry 19 (2008) 2870–2881
2879
in THF (2 mL) gave a 95:3:2 mixture of 35:20:21. Purification
via flash column chromatography (eluent 30–40 °C petrol/
Et2O, 99:1) gave 35 as a colourless oil (196 mg, 76%, >95%
de); mmax (film) 2968, 2933, 1714 (C@O), 1367, 1147; dH
(400 MHz, CDCl3) 0.83 (3H, t, J 7.3, CH2Me), 1.02–1.10 (1H,
m, C(6)H), 1.14–1.25 (3H, m, C(6)CH2Me, C(4)HA), 1.32 (3H, d,
(3H, d, J 6.6, C(6)Me), 0.97 (3H, d, J 6.6, MeCHMe), 1.03 (3H,
d, J 6.6, MeCHMe), 1.29–1.39 (2H, m, C(4)HA, C(5)HA), 1.46
(9H, s, CMe3), 1.55–1.62 (3H, m, C(3)HA, C(5)HB, C(6)H), 1.69–
1.74 (1H, m, C(3)HB), 1.77–1.82 (1H, m, C(4)HB), 2.71 (1H,
app dt, J 11.7, 4.5, C(2)H), 2.83 (1H, app t, J 4.5, C(1)H), 3.08
(1H, app septet,
J 6.6, CHMe2); dC (100 MHz, CDCl3) 20.0
J 6.7, C(
a
)Me), 1.46 (9H, s, CMe3), 1.48–1.65 (3H, m, C(3)HA,
(C(6)Me), 22.2, 23.8 (CHMe2), 25.1 (C(4)), 28.3 (CMe3), 28.5,
28.6 (C(3), (C(5)), 34.1 (C(6)), 43.9 (CHMe2), 50.5 (C(1)), 54.8
C(5)H2), 1.81–1.84 (1H, m, C(4)HB), 2.14–2.21 (1H, m, C(3)HB),
2.64–2.68 (2H, m, C(1)H, C(2)H), 3.87 (2H, ABq, JAB 14.9,
t
(C(2)), 80.0 (CMe3), 172.6 (CO2 Bu); m/z (ESI+) 256 ([M+H]+,
60%); HRMS (ESI+) C15H30NO2
256.2278.
([M+H]+) 356.2271; found
þ
NCH2), 4.06 (1H, q,
7.30–7.35 (4H, m, Ph), 7.51–7.62 (4H, m, Ph); dC (100 MHz,
CDCl3) 11.7 (CH2Me), 15.4 (C( )Me), 25.8 (C(5)), 25.9, 26.6,
26.7, (C(3), C(4), CH2CH3), 28.2 (CMe3), 42.6 (C(6)), 49.5
(C(1)), 51.0 (NCH2), 56.7 (C( )), 59.7 (C(2)), 80.1 (CMe3),
J
6.7, C(
a
)H), 7.19–7.26 (2H, m, Ph),
a
From 34: Pd(OH)2/C (50 mg, 50% w/w of substrate) was
added to vigorously stirred solution of 34 (100 mg,
a
a
0.25 mmol) in degassed MeOH (2.25 mL), and acetone
(0.25 mL) at rt under argon. H2 was bubbled through the solu-
tion and the atmosphere of the reaction vessel saturated with
H2 (1 atm). After 24 h, the reaction mixture was filtered through
CeliteÒ (eluent EtOAc) and washed with satd aq NaHCO3
(10 mL), dried and concentrated in vacuo to give 37 as a colour-
less oil (59 mg, 94%, >95% de).
126.3, 126.5 (p-Ph), 127.8, 127.9, 128.0, 128.1 (o-Ph, m-Ph),
t
142.6, 144.5 (i-Ph), 174.1 (CO2 Bu); m/z (CI+) 422.4 ([M+H]+,
100%); HRMS (CI+) C28H40NO2 ([M+H]+) requires 422.3054;
þ
found 422.3054.
4.23. tert-Butyl (1RS,2SR,6SR,aSR)-2-[N-benzyl-N-(a-methyl-
benzyl)amino]-6-benzyl-cyclohexane-carboxylate 36
4.25. tert-Butyl (1R,2S,6R,
amino]-6-methyl-cyclohexane-carboxylate 34 and tert-butyl
(1S,2R,6S, -methylbenzyl)-
R)-2-[N-30,40-dimethoxybenzyl-N-(
aS)-2-[N-benzyl-N-(a-methylbenzyl)-
Ph
a
a
Ph
N
amino]-6-methyl-cyclohexane-carboxylate 38
CO2tBu
Bn
OMe
OMe
Following General Procedure 2, BuLi (2.3 M in hexanes,
0.95 mL, 2.17 mmol), (RS)-N-benzyl-N-( -methylbenzyl)amine
Ph
a
(495 mg, 2.20 mmol) in THF (5 mL) and 8 (150 mg, 0.55 mmol)
in THF (2 mL) gave a 95:3:2 mixture of 36:22:23. Purification
via flash column chromatography (eluent 30–40 °C petrol/Et2O,
99:1) gave 36 as a pale yellow oil (223 mg, 84%, >95% de); mmax
(film) 2971, 2931, 1716 (C@O), 1493, 1206; dH (400 MHz, CDCl3)
Ph
N
Ph
N
+
CO2tBu
Me
CO2tBu
Me
34
38
1.12–1.17 (1H, m, C(4)HA), 1.29 (3H, d, J 6.6, C(a)Me), 1.43–1.47
(2H, m, C(5)HA, C(6)H), 1.54 (9H, s, CMe3), 1.55–1.65 (2H,
C(5)HB), 1.68–1.72 (1H, m, C(3)HA), 1.79–1.83 (1H, m, C(4)HB),
2.18 (1H, app qd, J 12.7, 3.8, C(3)HB), 2.39 (1H, dd, J 13.4, 8.1,
Following General Procedure 2, BuLi (2.2 M in hexanes,
1.39 mL, 3.02 mmol), (S)-N-benzyl-N-( -methylbenzyl)amine
(323 mg, 1.53 mmol) and (R)-N-3,4-dimethoxybenzyl-N-( -meth-
ylbenzyl)amine (415 mg, 1.53 mmol) in THF (6 mL) and
a
a
C(6)CHAHBPh), 2.56 (1H, dd,
(1H, app t, J 4.0, C(1)H), 2.66–2.70 (1H, m, C(2)H), 3.90 (2H,
ABq, JAB 18.0, NCH2Ph), 4.03 (1H, q, J 6.6, C( )H), 7.10 (2H, d, J
7.1, Ph), 7.22–7.38 (11H, m, Ph), 7.51 (2H, d, J 7.1, Ph); dC
(100 MHz, CDCl3) 16.1 (C( )Me), 25.7, 25.9, 26.1 (C(3), C(4),
C(5)), 28.5 (CMe3), 37.5 (C(6)CH2Ph), 42.8 (C(6)), 49.6 (C(1)),
51.1 (NCH2Ph), 57.1 (C( )), 60.5 (C(2)), 80.5 (CMe3), 125.9,
J 13.4, 8.1, C(6)CHAHBPh), 2.62
6
(150 mg, 0.77 mmol) in THF (1.7 mL) gave a 45:45:6:4 mixture
of 34:38:16:17. Purification via flash column chromatography
(eluent 30–40 °C petrol/Et2O, 3:1) gave 34 (116 mg, 37%, >98%
a
a
de) as a wax; ½a 2D3
¼ ꢁ92:7 (c 1.0 in CHCl3). Further elution (elu-
ꢂ
ent 30–40 °C petrol/Et2O, 1:1) gave 38 as
a colourless oil
a
(145 mg, 41%, >95% de); ½a D23
¼ þ80:9 (c 1.0 in CHCl3); mmax
ꢂ
126.4, 126.5 (p-Ph), 127.7, 128.0, 128.1, 129.0, 129.3 (o-Ph, m-
(film) 3027, 2959, 1716 (C@O), 1313, 1150; dH (400 MHz, CDCl3)
0.83 (3H, d, J 6.8, C(6)Me), 1.21–1.28 (2H, m, C(4)HA, C(5)HA),
t
Ph), 140.6, 142.7, 144.4 (i-Ph), 174.0 (CO2 Bu); m/z (CI+) 484
([M+H]+, 100%); HRMS (CI+) C33H42NO2
484.3210; found 484.3213.
([M+H]+) requires
þ
1.33 (3H, d, J 6.8, C(
s, CMe3), 1.52–1.59 (1H, m, C(5)HB), 1.60–1.67 (1H, m, C(3)HA),
1.78–1.84 (1H, m, C(4)HB), 2.15 (1H, app qd, 12.5, 3.7,
a)Me), 1.35–1.39 (1H, m, C(6)H), 1.44 (9H,
J
4.24. tert-Butyl (1RS,2SR,6RS)-2-[N-isopropylamino]-6-methyl-
cyclohexane-1-carboxylate 37
C(3)HB), 2.47 (1H, app t, J 4.2, C(1)H), 2.66 (1H, app dt, J 12.5,
4.2, C(2)H), 3.81 (2H, app s, NCH2), 3.87 (3H, s, OMe), 3.93
(3H, s, OMe), 4.02 (1H, q, J 6.8, C(a)H), 6.79 (1H, d, J 8.1,
C(50)H), 6.92 (1H, app d, J 8.1, C(60)H), 7.16 (1H, s, C(20)H), 7.21
(1H, app t, J 7.5, Ph), 7.31 (2H, app t, J 7.5, Ph), 7.47 (2H, app
NH
t
CO2Bu
d, J 7.5, Ph); dC (100 MHz, CDCl3) 14.2 (C(a)Me), 19.4 (C(6)Me),
25.3 (C(3)), 25.8 (C(4)), 28.3 (CMe3), 28.6 (C(5)), 35.1 (C(6)),
Me
50.7 (NCH2), 53.0 (C(1)), 55.9, 55.9 (OMe), 56.1 (C(a)), 59.2
(C(2)), 80.4 (CMe3), 110.5 (C(50)), 111.5 (C(20)), 120.1 (C(60)),
126.4 (p-Ph), 127.7, 127.8 (o-Ph, m-Ph), 134.8 (C(10)), 144.6 (i-
From 15: Following General Procedure 3, Pd(OH)2/C (37 mg,
50% w/w of substrate) and 15 (74 mg, ꢀ0.21 mmol) gave 37
t
Ph), 147.5 (C(40)), 148.8 (C(30)) 174.1 (CO2 Bu); m/z (ESI+) 468
([M+H]+ 100%); HRMS (ESI+) C29H42NO4 ([M+H]+) requires
þ
a
colourless oil (42 mg, 78%, >95% de); mmax (film) 2930,
1722 (C@O), 1457, 1366, 1249; dH (400 MHz, CDCl3) 0.94
468.3108; found 468.3110.

2880
S. G. Davies et al. / Tetrahedron: Asymmetry 19 (2008) 2870–2881
4.26. tert-Butyl (1R,2S,6R,
a
S)-2-[N-benzyl-N-(
a
-methylbenzyl)-
36:40:22:23. Purification via flash column chromatography (eluent
30–40 °C petrol/Et2O, 99:1) gave 36 as a colourless oil (117 mg, 41%,
amino]-6-ethyl-cyclohexane-carboxylate 35 and tert-butyl
(1S,2R,6S, -methylbenzyl)-
a
R)-2-[N-30,40-dimethoxybenzyl-N-(
a
>95% de); ½a 2D3
¼ ꢁ36:0 (c 1.0 in CHCl3). Further elution with (eluent
ꢂ
amino]-6-ethyl-cyclohexane-carboxylate 39
30–40 °C petrol/Et2O, 1:1) gave 40 as a colourless oil (121 mg, 38%,
>95% de); ½a 2D3
¼ þ26:5 (c 1.0 in CHCl3); mmax (film) 2933, 1715
ꢂ
OMe
(C@O), 1513, 1263, 1155; dH (400 MHz, CDCl3) 1.10–1.15 (1H, m,
OMe
C(4)HA), 1.23–1.27 (1H, m, C(5)HA), 1.30 (3H, d, J 6.7, C(a)Me),
1.43–1.48 (1H, m, C(6)H), 1.50 (9H, s, CMe3), 1.62–1.70 (2H, m,
C(3)HA, C(5)HB), 1.76–1.83 (1H, m, C(4)HB), 2.11–2.23 (1H, m,
C(3)HB), 2.34 (1H, dd, J 13.5, 8.3, CHAHBPh), 2.56 (1H, dd, J 13.5, 6.3,
CHAHBPh), 2.61–2.67 (2H, m, C(1)H, C(2)H), 3.82 (2H, ABq, JAB 14.8,
NCH2), 3.88 (3H, s, OMe), 3.92 (3H, s, OMe), 4.03 (1H, q, J 6.7,
Ph
Ph
N
Ph
N
+
CO2tBu
Et
CO2tBu
Et
C(a
)H), 6.80 (1H, d, J 8.2, C(50)H), 6.93 (1H, d, J 8.2, C(60)H), 7.07
(2H, d, J 7.2, Ph), 7.11 (1H, s, C(20)H), 7.21 (2H, app d, J 7.2, Ph), 7.27
(4H, app t, J 7.2, Ph), 7.39 (2H, app d, J 7.2, Ph); dC (100 MHz, CDCl3)
35
39
15.2 (C(a)Me), 25.7, 25.8, 26.0 (C(3), C(4), C(5)), 28.3 (CMe3), 40.3
(CH2Ph), 42.7 (C(6)), 50.6 (C(1)), 50.7 (NCH2), 55.9, 55.9 (OMe), 56.5
Following General Procedure 2, BuLi (2.2 M in hexanes, 1.70 mL,
3.70 mmol), (S)-N-benzyl-N-( -methylbenzyl)amine (429 mg,
1.90 mmol) and (R)-N-3,4-dimethoxybenzyl-N-( -methylben-
zyl)amine (514 mg, 1.90 mmol) in THF (8 mL) and 7 (200 mg,
1.19 mmol) in THF (2 mL) gave 47.5:47.5:3:2 mixture of
(C(a
)), 59.8 (C(2)), 80.5 (CMe3), 110.6 (C(50)), 111.3 (C(20)), 119.9
a
(C(60)), 125.8, 126.5 (p-Ph), 127.7, 127.9, 128.1, 129.0 (o-Ph, m-Ph),
a
134.9 (C(10)), 140.6, 144.4 (i-Ph), 147.5 (C(40)), 148.7 (C(30)) 173.9
t
(CO2 Bu); m/z (ESI+) 544 ([M+H]+ 100%); HRMS (ESI+) C35H46NO4
þ
a
([M+H]+) requires 544.3421; found 544.3422.
35:39:20:21. Purification via flash column chromatography (eluent
30–40 °C petrol/Et2O, 99:1) gave 35 as a colourless oil (182 mg, 45%,
>95% de); ½a 2D3
ꢂ
¼ ꢁ64:7 (c 1.0 in CHCl3). Further elution (eluent 30–
4.28. tert-Butyl (1S,2R,6S,aR)-2-[N-(a-methylbenzyl)amino]-6-
methyl-cyclohexane-carboxylate 41
40 °C petrol/Et2O, 1:1) gave 39 as a colourless oil (180 mg, 40%, >95%
de); ½a 2D3
¼ þ65:6 (c 1.0 in CHCl3); mmax (film) 2963, 2933, 1715
ꢂ
(C@O), 1513, 1262, 1142; dH (400 MHz, CDCl3) 0.81 (3H, d, J 7.2,
(C(6)CH2Me), 1.04–1.11 (1H, m, C(6)H), 1.13–1.21 (3H, m, C(4)HA,
Ph
NH
CO2tBu
C(6)CH2Me), 1.32 (3H, d, J 6.7, C(a)Me), 1.42–1.47 (1H, m, C(5)HA),
1.43 (9H, s, CMe3), 1.48–1.53 (1H, m, C(5)HB), 1.60–1.67 (1H, m,
C(3)HA), 1.79–1.86 (1H, m, C(4)HB), 2.19 (1H, app qd, J 12.8, 4.0,
C(3)HB), 2.58 (1H, app t, J 4.0, C(1)H), 2.64 (1H, app dt, J 12.8, 4.0,
C(2)H), 3.81 (2H, s, NCH2), 3.87 (3H, s, OMe), 3.93 (3H, s, OMe), 4.04
Me
DDQ (190 mg, 0.85 mmol) was added portionwise to a solution of
38 (190 mg, 0.40 mmol) in DCM (10 mL) and H2O (2 mL) and the
dark red mixture was stirred at rt for 48 h. Satd aq NaHCO3
(15 mL) was added, the layers were separated and the aqueous layer
was extracted with DCM (3 ꢃ 10 mL). The combined organic layers
were washed with brine (50 mL), dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30–40 °C/
Et2O, 85:15) gave 41 as a colourless oil (84 mg, 66%, >95% de);
(1H, q, J 6.7, (C(a
)H), 6.80 (1H, d, J 8.2, C(50)H), 6.93 (1H, d, J 8.2,
C(60)H), 7.13 (1H, s, C(20)H), 7.21 (1H, app t, J 7.4, Ph), 7.31 (2H, app
t, J 7.4, Ph), 7.48 (2H, app d, J 7.4, Ph); dC (100 MHz, CDCl3) 11.8
(CH2Me), 14.5 (C(a)Me), 25.8, 26.6, 26.7 (C(3), C(4), C(5)), 28.2
(CMe3), 29.7 (CH2Me), 42.6 (C(6)), 50.4 (C(1)), 50.7 (NCH2), 55.9,
55.9 (OMe), 56.2 (C(a
)), 59.4 (C(2)), 80.2 (CMe3), 110.6 (C(50)),
111.4 (C(20)), 120.0 (C(60)), 126.4 (p-Ph), 127.7, 127.8 (o-Ph, m-Ph),
t
134.9 (C(10)), 144.6 (i-Ph), 147.5 (C(40)), 148.7 (C(30)) 174.0 (CO2 Bu);
½
a 2D3
ꢂ
¼ ꢁ47:7 (c 1.0 in CHCl3); mmax (film) 3418 (N–H), 2959, 2930,
1723 (C@O), 1451, 1367; dH (400 MHz, CDCl3) 0.96 (3H, d, J 6.8,
C(6)Me), 1.12–1.19 (1H, m, C(4)HA), 1.29 (3H, d, J 6.6, C( )Me),
m/z (ESI+) 482 ([M+H]+ 100%); HRMS (ESI+) C30H44NO4þ ([M+H]+) re-
quires 482.3265; found 482.3265.
a
1.39–1.45 (3H, m, C(3)HA, C(5)HA, C(6)H), 1.52 (9H, s, CMe3), 1.55–
1.60 (1H, m, C(5)HB), 1.69–1.83 (2H, m, C(3)HB, C(4)HB), 2.41 (1H,
app dt, J 12.8, 4.9, C(2)H), 2.88 (1H, app t, J 4.9, C(1)H), 4.10 (1H, q, J
4.27. tert-Butyl (1R,2S,6S,
amino]-6-benzyl-cyclohexane-carboxylate 36 and tert-butyl
(1S,2R,6R, -methylbenzyl)-
R)-2-[N-30,40-dimethoxybenzyl-N-(
aS)-2-[N-benzyl-N-(a-methylbenzyl)-
6.6, (C(
(100 MHz, CDCl3) 19.9 (C(6)Me), 24.9 (C(4)), 25.5 (C(
(CMe3), 28.8, 28.9 (C(3), C(5)), 33.4 (C(6)), 50.0 (C(1)), 53.8 (C(
a
)H), 7.23–7.26 (1H, m, Ph), 7.31–7.35 (4H, m, Ph); dC
)Me), 28.4
)),
a
a
a
amino]-6-benzyl-cyclohexane-carboxylate 40
a
54.8 (C(2)), 80.0 (CMe3), 126.4 (p-Ph), 126.7, 128.4 (o-Ph, m-Ph),
OMe
t
146.0 (i-Ph), 172.7 (CO2 Bu); m/z (ESI+) 318 ([M+H]+ 100%); HRMS
OMe
+
(ESI+) C20H32NO2 ([M+H] ) requires 318.2428; found 318.2431.
þ
Ph
4.29. tert-Butyl (1R,2S,6R)-2-amino-6-methyl-cyclohexane-
carboxylate 42
Ph
N
Ph
N
+
CO2tBu
Bn
CO2tBu
Bn
NH2
CO2tBu
36
40
Me
Following General Procedure 3, Pd(OH)2/C (42 mg, 50% w/w of
substrate) and 34 (84 mg, 0.24 mmol) gave (1R,2S,6R)-42 as a
Following General Procedure 2, BuLi (2.2 M in hexanes, 1.06 mL,
2.30 mmol), (S)-N-benzyl-N-( -methylbenzyl)amine (264 mg,
1.18 mmol) and (R)-N-3,4-dimethoxybenzyl-N-( -methylben-
zyl)amine (319 mg, 1.18 mmol) in THF (4 mL) and 8 (160 mg,
0.59 mmol) in THF (2 mL) gave 47.5:47.5:3:2 mixture of
a
white wax (40 mg, 91%, >95% de); ½a D23
¼ ꢁ3:7 (c 1.0 in CHCl3);
ꢂ
a
mmax (film) 3374 (N–H), 2931, 1721 (C@O), 1393, 1367, 1150; dH
(400 MHz, CDCl3) 0.98 (3H, d, J 6.9, C(6)Me), 1.23–1.29 (1H, m,
a

S. G. Davies et al. / Tetrahedron: Asymmetry 19 (2008) 2870–2881
2881
Gademann, K.; Guichard, G.; Hintermann, T.; Jaun, B.; Matthews, J. L.;
Schreiber, J. V. Helv. Chim. Acta 1998, 81, 932; Gung, B. W.; Zou, D. J. Org.
Chem. 1999, 64, 2176; Lee, H.-S.; Syud, F. A.; Wang, X.; Gellman, S. H. J. Am.
Chem. Soc. 2001, 123, 7721; Winkler, J. D.; Piatnitski, E. L.; Mehlmann, J.;
Kasparec, J.; Axelsen, P. H. Angew. Chem., Int. Ed. 2001, 40, 743; Raguse, T. L.; Lai,
J. R.; Gellman, S. H. Helv. Chim. Acta 2002, 85, 4154; Raguse, L.; Lai, J. R.;
Gellman, S. H. J. Am. Chem. Soc. 2003, 125, 5592; Park, J.-S.; Lee, H.-S.; Lai, J. R.;
Kim, B. M.; Gellman, S. H. J. Am. Chem. Soc. 2003, 125, 8539; Luppi, G.; Galeazzi,
R.; Garavelli, M.; Formaggio, F.; Tomasini, C. Org. Biomol. Chem. 2004, 2, 2187;
Izquierdo, S.; Kogan, M. J.; Parella, T.; Moglioni, A. G.; Branchadell, V.; Giralt, E.;
Ortuño, R. M. J. Org. Chem. 2004, 69, 5093.
C(5)HA), 1.31–1.37 (1H, m, C(4)HA), 1.46 (9H, s, CMe3), 1.55–1.69
(5H, m, C(3)HA, C(4)HB, C(6)H, NH2), 1.74–1.80 (2H, m, C(3)HB,
C(5)HB), 2.65 (1H, app t, J 4.8, C(1)H), 2.75–2.82 (1H, m, C(2)H);
dC (100 MHz, CDCl3) 19.8 (C(6)Me), 24.7 (C(5)), 28.3 (CMe3), 28.4
(C(4)), 30.5 (C(3)), 34.1 (C(6)), 52.2 (C(2)), 54.2 (C(1)), 80.3
t
+
(CMe3), 172.5 (CO2 Bu); HRMS (ESI+) C12H24NO2 ([M+H] ) requires
þ
214.1802; found 214.1800.
4.30. tert-Butyl (1S,2R,6S)-2-amino-6-methyl-cyclohexane-
carboxylate 42
2. Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1994, 116, 1054; Seebach, D.;
Overhand, M.; Kühnle, F. N. M.; Martinoni, B.; Oberer, L.; Hommel, U.; Widmer,
H. Helv. Chim. Acta 1996, 79, 913; Appella, D. H.; Christianson, L. A.; Klein, D. A.;
Powell, D. R.; Huang, X.; Barchi, J. J.; Gellman, S. H. Nature 1997, 387, 381;
Martinek, T. A.; Táth, G. K.; Vass, E.; Hollósi, M.; Fülop, F. Angew. Chem., Int. Ed.
2002, 41, 1718.
NH2
CO2tBu
3. For a review see: Fülop, F. Chem. Rev. 2001, 101, 2181.
4. Babler, J. H.; Sarussi, S. J. J. Org. Chem. 1987, 52, 3462.
Me
5. For kinetic resolution of 3-alkyl-cyclopent-1-ene-carboxylates see: (a) Bailey,
S.; Davies, S. G.; Smith, A. D.; Withey, J. M. Chem. Commun. 2002, 2910; (b)
Bunnage, M. E.; Chippindale, A. M.; Davies, S. G.; Parkin, R. M.; Smith, A. D.;
Withey, J. M. Org. Biomol. Chem. 2003, 1, 3698; (c) Bunnage, M. E.; Davies, S.
G.; Parkin, R. M.; Roberts, P. M.; Smith, A. D.; Withey, J. M. Org. Biomol.
Chem. 2004, 2, 3337; For parallel kinetic resolution of 3-alkyl-cyclopent-1-
ene-carboxylates see: (d) Davies, S. G.; Garner, A. C.; Long, M. J. C.; Smith, A.
D.; Sweet, M. J.; Withey, J. M. Org. Biomol. Chem. 2004, 2, 3355; For parallel
kinetic resolution of 3-oxy-substituted cyclopent-1-ene-carboxylates see: (e)
Aye, Y.; Davies, S. G.; Garner, A. C.; Roberts, P. M.; Smith, A. D.; Thomson, J.
E. Org. Biomol. Chem. 2008, 6, 2195; For kinetic and parallel kinetic
resolution of 5-alkyl-cyclopent-1-ene-carboxylates see: (f) Davies, S. G.;
Díez, D.; El Hammouni, M. M.; Garner, A. C.; Garrido, N. M.; Long, M. J. C.;
Morrison, R. M.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Chem. Commun.
2003, 2410; (g) Davies, S. G.; Garner, A. C.; Long, M. J. C.; Morrison, R. M.;
Roberts, P. M.; Savory, E. D.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Org.
Biomol. Chem. 2005, 3, 2762; (h) 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.
6. For a review of the conjugate addition of homochiral lithium amides see:
Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16,
2833.
7. Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1994, 5,
3919.
8. The high stereocontrol asserted upon protonation of an enolate anti to an
adjacent heteroatom is well documented; see: Zimmerman, H. E. Acc. Chem.
Res. 1987, 20, 263; Mohrig, J. E.; Rosenberg, R. E.; Apostol, J. W.; Bastienaansen,
M.; Evans, J. W.; Franklin, S. J.; Frisbie, C. D.; Fu, S. S.; Hamm, M. L.; Hirose, C. B.;
Hunstad, D. A.; James, T. L.; King, R. W.; Larson, C. J.; Latham, H. A.; Owen, D. A.;
Stein, K. A.; Warnet, R. J. Am. Chem. Soc. 1997, 119, 479; Banfi, L.; Guanti, G.
Tetrahedron: Asymmetry 1999, 10, 439; Davies, H. M. L.; Hodges, L. M.; Gregg, T.
M. J. Org. Chem. 2001, 66, 7898.
Following General Procedure 3, Pd(OH)2/C (30 mg, 50% w/w of
substrate) and 41 (62 mg, 0.20 mmol) gave (1S,2R,6S)-42 as a white
wax (37 mg, 88%, >95% de); ½a D23
¼ þ1:2 (c 1.0 in CHCl3).
ꢂ
4.31. (1R,2S,6R)-2-Amino-6-methyl-cyclohexane-carboxylic
acid hydrochloride 43
NH2
•
HCl
CO2H
Me
Following General Procedure 4, TFA (1 mL) and (1R,2S,6R)-42
(26 mg, 0.12 mmol) in DCM (1 mL), then HCl (2 M in Et2O, 1 mL)
and MeOH (1 mL) gave (1R,2S,6R)-43 as a white powder (22 mg,
92%, >95% de); mp 90–92 °C; ½a D23
¼ ꢁ2:0 (c 1.0 in 1 M aq HCl);
ꢂ
mmax (KBr) 3114 (NH3þ), 2962, 2931, 1714 (C@O), 1601, 1203; dH
(400 MHz, D2O) 0.90 (3H, d, J 7.0, C(6)Me), 1.16–1.29 (2H, m,
C(4)HA, C(5)HA), 1.31–1.38 (1H, m, C(5)HB), 1.63–1.80 (4H, m,
C(3)H2, C(4)HB, C(6)H), 2.86 (1H, app t, J 4.6, C(1)H), 3.26–3.32
(1H, m, C(2)H); dC (100 MHz, D2O) 19.3 (C(6)Me), 23.5 (C(4)), 25.5
(C(3)), 28.0 (C(5)), 33.8 (C(6)), 47.8 (C(1)), 51.7 (C(2)), 175.0
(CO2H); HRMS (FI+) C8H16NO2þ ([MꢁCl]+) requires 158.1176; found
158.1163.
9. Horeau, A. Tetrahedron 1977, 31, 1307.
10. Dambrin, V.; Villiéras, M.; Moreau, C.; Amri, H.; Toupet, L.; Villiéras, J.
Tetrahedron Lett. 1996, 37, 6323; Dambrin, V.; Villiéras, M.; Janvier, P.;
Toupet, L.; Amri, H.; Lebreton, J.; Villiéras, J. Tetrahedron 2001, 57,
2155.
4.32. (1S,2R,6S)-2-Amino-6-methyl-cyclohexane-carboxylic
acid hydrochloride 43
11. 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.
12. The presence of trace amounts (<5%) of unknown impurities precluded a more
accurate assessment of the diastereoisomeric excess value.
NH2
•
HCl
CO2H
13. The corresponding b,c-unsaturated ester products of c-deprotonation 16, 17
Me
and 20–23 were also produced during the parallel kinetic resolution reactions
(610% in each case).
14. Davies, S. G.; Garrido, N. M.; Kruchinin, D.; Ichihara, O.; Kotchie, L. J.; Price, P.
D.; Price Mortimer, A. J.; Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry
2006, 17, 1793.
Following General Procedure 4, TFA (1.5 mL) and (1S,2R,6S)-42
(30 mg, 0.14 mmol) in DCM (1.5 mL), then HCl (2 M in Et2O, 2
mL) and MeOH (2 mL) gave (1S,2R,6S)-43 as a white powder
(18 mg, 84%, >95% de); ½a D23
¼ þ1:8 (c 1.0 in 1 M aq HCl).
ꢂ
15. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
16. Davies, S. G.; Diez, D.; Dominguez, S. H.; Garrido, N. M.; Kruchinin, D.; Price, P.
D.; Smith, A. D. Org. Biomol. Chem. 2005, 3, 1284.
References
17. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.; Watkin, D. J.
CRYSTALS; Chemical Crystallography Laboratory: University of Oxford, UK,
2001.
1. For instance see: Hintermann, T.; Seebach, D. Synlett 1997, 437; Seebach, D.;
Matthews, J. L. Chem. Commun. 1997, 21, 2015; Seebach, D.; Abele, S.;