Asymmetric synthesis of β-substituted Baylis-Hillman products via lithium amide conjugate addition

Article abstract of DOI:10.1016/j.tet.2007.05.015

A three-step protocol for the asymmetric synthesis of a range of β-substituted Baylis-Hillman products has been developed. This procedure involves the diastereoselective conjugate addition of lithium (R)-N-methyl-N-(α-methylbenzyl)amide to an α,β-unsatura

Full text of DOI:10.1016/j.tet.2007.05.015

Tetrahedron 63 (2007) 7036–7046
Asymmetric synthesis of b-substituted Baylis–Hillman products
via lithium amide conjugate addition
*
Alexander Chernega, Stephen G. Davies, Dirk. L. Elend, Christian A. P. Smethurst,
Paul M. Roberts, Andrew D. Smith and G. Darren Smyth
Department of Organic Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Received 5 February 2007; revised 19 April 2007; accepted 3 May 2007
Available online 8 May 2007
Abstract—A three-step protocol for the asymmetric synthesis of a range of b-substituted Baylis–Hillman products has been developed. This
procedure involves the diastereoselective conjugate addition of lithium (R)-N-methyl-N-(a-methylbenzyl)amide to an a,b-unsaturated ester to
generate an N-protected b-amino ester in high de. Subsequent asymmetric aldol reaction via deprotonation with LDA, transmetallation with
B(OMe)3 and addition of an aldehyde gives a range of syn-aldol products in moderate to high de. Purification of the syn-aldol products to
homogeneity followed by tandem N-oxidation and Cope elimination gives the desired b-substituted Baylis–Hillman products in good yield
and high de and ee.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives of cinchona alkaloids11 all showing some suc-
cess. For example, amine 4 promotes the coupling of acryl-
Carbon–carbon bond forming reactions are of fundamental
importance in organic chemistry, with a plethora of stoi-
cheiometric and catalytic methods having been developed
for use in synthesis. Among these different strategies, the
condensation of an aldehyde and an acrylate ester catalysed
by a tertiary amine1 or phosphine2 to afford a-methylene-b-
hydroxy-esters (commonly known as the Morita–Baylis–
Hillman reaction) has been exploited widely.3 These com-
pounds have proven to be useful synthetic intermediates,
often used to provide practical synthons in stereoselective
synthesis.4 As this efficient reaction produces polyfunctional
chiral molecules in a single step, various endeavours seeking
to develop asymmetric versions of this reaction to afford al-
lylic alcohols in enantiomerically enriched form have been
reported. In principle, asymmetry in the Morita–Baylis–
Hillman reaction may be induced through the use of a chiral
source in any or all of the reaction components. For instance,
chiral acrylates have been widely used, with menthyl,5 car-
bohydrate6 and pyrazolidinone7 derived auxiliaries giving
reasonable to high levels of stereocontrol. The first highly
enantioselective approach in this area was that of Leahy
et al., who reported asymmetric Baylis–Hillman reactions
using a derivative of Oppolzer’s camphor sultam auxiliary
1, which generated 2 in >99% ee upon treatment with
DABCO and propanaldehyde.8 Chiral amines have also been
evaluated as catalysts for the asymmetric Baylis–Hillman
reaction, with DABCO derivatives,9 pyrrolizidines10 and
ate 5 with a range of aldehydes in up to 99% ee;12
a
strategy that has been used in natural product synthesis.13
Chiral phosphines have also been used to promote efficient
catalysis.14 Furthermore, a range of chiral aldehydes have
been used to induce stereoselectivity,15 with enantiomeri-
cally pure azetidine carboxaldehydes such as 7 undergoing
highly selective Baylis–Hillman reactions with methyl vinyl
ketone and DABCO (Fig. 1).16 A double diastereoselective
Baylis–Hillman variant that uses a chiral carbohydrate
O
O
DABCO
EtCHO
MeOH
CSA
O
OH
CO2Me
O
N
Et
S
O
O
Et
Et
1
2, 98%
>99% e.e.
3, 85%
OH
N
4
O
OH
O
(10 mol%)
iBuCHO
O
iBu
OCH(CF3)2
OCH(CF3)2
N
6, 51%, 99% e.e
5
4
O
O
HO
PhO
O
CHO
PhO
O
H
N
DABCO
MeCN
-70 °C
N
7
8, 80%, >97% d.e.
* Corresponding author. E-mail: steve.davies@chem.ox.ac.uk
Figure 1. Asymmetric Baylis–Hillman reactions.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.015

A. Chernega et al. / Tetrahedron 63 (2007) 7036–7046
7037
derived acrylate and an enantiomerically pure aldehyde has
also been reported.17
2. Results and discussion
2.1. Model studies: preparation of (E)- and
(Z)-10-hydroxyethyl-3-alkyl-prop-2-enoates
Although efficient, these approaches are restricted to the
use of b-unsubstituted acrylate components, generating
a-methylene-b-hydroxy compounds. Methods for the prep-
aration of b-substituted Baylis–Hillman products have
been reported, although examples are limited. Racemic
b-substituted Baylis–Hillman products may be prepared
from a-silyl-alkenoates but with low levels of (E)/(Z)
stereocontrol,18 whilst hydroalumination of b-propiolates
in the presence of HMPA and subsequent reaction with an
aldehyde gives the desired products with high (Z)-stereo-
control.19 Enantiomerically enriched b-substituted Baylis–
Hillman products may be prepared by a-functionalisation
of chiral a,b-unsaturated sulfoxides with aldehydes,20 and
through the reaction of silyl allenolates with aldehydes cat-
alysed by a chiral oxazaborolidine,21 although the synthetic
generality of these procedures has yet to be demonstrated. In
order to address this structural limitation, we became inter-
ested in the development of methodology that is capable
of the stereoselective synthesis of enantiomerically pure
b-substituted Baylis–Hillman products. Previous investiga-
tions from this laboratory have demonstrated that the
conjugate addition of homochiral lithium amides derived
from a-methylbenzylamine to a,b-unsaturated esters allows
the asymmetric synthesis of b-amino acid derivatives in high
de22 and it was proposed that this methodology could be
used as the cornerstone of a three-step strategy for the
asymmetric synthesis of b-substituted Baylis–Hillman prod-
ucts. This protocol would involve the diastereoselective
conjugate addition of lithium (R)-N-methyl-N-(a-methyl-
benzyl)amide23 to an a,b-unsaturated ester to generate ste-
reoselectively the corresponding b-amino ester. Subsequent
asymmetric aldol reaction and tandem N-oxidation and
Cope elimination would generate the desired b-substituted
Baylis–Hillman products. As the Cope elimination is known
to proceed via a stereospecific syn-elimination24 the relative
configuration of C(2) and C(3) within the aldol products will
determine the formation of the corresponding (E)- or (Z)-
b-substituted Baylis–Hillman products (Fig. 2). We report
herein our full investigations in this area, part of which has
been communicated previously.25
Initial studies concentrated on the application of this pro-
posed three-step methodology to enable the synthetic
equivalent of coupling an a,b-unsaturated ester (tert-butyl
cinnamate and tert-butyl crotonate) with acetaldehyde.
Thus, conjugate addition of lithium (R)-N-methyl-N-(a-
methylbenzyl)amide 9 (>98% ee)26 to tert-butyl cinnamate
and tert-butyl crotonate gave the corresponding b-amino es-
ters (3S,aR)-10 and (3R,aR)-11 in 88 and >98% de, respec-
tively.27 The configuration at C(3) within b-amino esters 10
and 11 was assigned by analogy to the transition state model
previously developed for the addition of this class of lithium
amide to a,b-unsaturated esters.28 Exhaustive chromato-
graphy did not enhance the diastereomeric excess of 10,
which was thus isolated in 94% yield and 88% de, whilst
chromatography allowed the isolation of 11 in 84% yield
and in >98% de (Scheme 1).
(i)
Me
t
CO2 Bu
Me
Ph
N
R
Ph
N
Li
t
CO2 Bu
R
R = Ph, Me
10, R = Ph, 94%, 88% d.e.
11, R = Me, 84%, >98% d.e.
(R)-9
Scheme 1. Reagents and conditions: (i) (R)-9 (1.6 equiv), THF, ꢀ78 ꢁC.
b-Amino esters 10 and 11 were next subjected to an asym-
metric boron aldol reaction. Previous investigations within
this area have demonstrated that lithium (Z)- and (E)-b-amino
enolates (generated from conjugate addition of a lithium
amide to an a,b-unsaturated ester, and deprotonation of a
b-amino ester, respectively) offer stereodivergent reaction
manifolds upon reaction with aldehydes;29 however, the
use of trimethylborate to transmetallate the lithium (E)-eno-
late offers high levels of C(2)–C(10) syn-selectivity,30 and
therefore this protocol was applied to b-amino esters 10
and 11. Deprotonation of 10and 11 with LDA to form the cor-
responding lithium (E)-enolate was followed by the addition
of B(OMe)3 before the addition of acetaldehyde, giving the
crude aldol products. Very high levels of diastereoselectivity
were observed upon aldol reaction of the cinnamate derived
b-amino ester (3S,aR)-10 in this protocol, furnishing a 93:7
mixture of diastereoisomers, with the major diastereoiso-
meric aldol product purified to homogeneity by flash chroma-
tography, giving (2S,3S,10R,aR)-12 in 76% yield. Reaction of
b-amino ester (3R,aR)-11 under identical conditions showed
lower levels of diastereoselectivity, furnishing a 78:22
mixture of diastereoisomers. Purification to homogeneity
by chromatography allowed the isolation of the separable
diastereoisomers (2S,3R,10R,aR)-13 and (2R,3R,10S,aR)-14
in 76% combined yield (Scheme 2).
Me
Ph
N
t
CO2 Bu
R
Aldol
reaction
Me
H
Me
H
Ph
N
Ph
CO2 Bu +
N
t
t
CO2 Bu
R
R
OH
OH
R'
R'
H
H
N-oxidation and
Cope elimination
N-oxidation and
Cope elimination
In order to establish unambiguously the relative configura-
tion of the two new stereogenic centres formed during the
aldol protocol, the major diastereoisomeric b-amino aldol
products 12 and 13 were converted into the corresponding
acetonides. Reduction of 12 and 13 with LiAlH4 in THF
and treatment of the resulting diols 15 and 16 with 2,2-dime-
thoxypropane and camphorsulfonic acid (CSA) in acetone
R
t
CO2 Bu
t
R
CO2 Bu
OH
R'
R'
OH
H
H
Figure 2. Proposed route to b-substituted Baylis–Hillman products.

7038
A. Chernega et al. / Tetrahedron 63 (2007) 7036–7046
Me
Ph
N
t
CO2 Bu
R
10, R = Ph, 88% d.e.
11, R = Me, >98% d.e.
d.r. 93:7 (R = Ph)
d.r. 78:22 (R = Me)
(i)
Me
H
Me
H
Ph
N
Ph
N
t
t
+
CO2 Bu
CO2 Bu
R
R
Me
OH
Me
OH
H
H
syn-major
syn-minor
12, R = Ph, 76%
13, R = Me, 56%
14, R = Me, 20%
Scheme 2. Reagents and conditions: (i) LDA (3 equiv), THF, ꢀ78 to 0 ꢁC,
Me
H
Ph
N
then B(OMe)3, then MeCHO.
Ph
O
gave the acetonides 17 and 18 in good yield. In each case,
analysis of the coupling constants in the 1H NMR spectra al-
lowed the assignment of axial and equatorial relationships
between the ring protons, with 1,3-diaxial relationships con-
firmed through NOE difference analysis as demonstrated for
18 (Scheme 3). This analysis confirmed the expected syn-
selectivity for the aldol reaction, consistent with the predicted
configurations of the major diastereoisomeric b-amino ester
aldol products 12 and 13.
Me
O
H
17
Figure 3. Chem 3D representation of the X-ray crystal structure of 17 (some
H atoms were removed for clarity).
Me
H
Me
H
Ph
Me
Me
N
Ph
Me
Me
N
(i)
t
CO2 Bu
OH
OH
OH
Me
H
Me
H
H
14
H
Ph
N
Ph
N
(i)
19, quant
t
CO2 Bu
R
R
OH
(ii)
Me
OH
Me
OH
H
H
15, R = Ph, 58%
16, R = Me, quant
12, R = Ph
13, R = Me
Me
H
nOe 3.4%
Ph
Me
Me
N
(ii)
J 3.6 Hz
J 5.5 Hz
O
H
Me
H
O
Me
H
H
Ph
N
Me
Me
O
H
20, 96%
O
R
O
J 3.7 Hz
H
Scheme 4. Reagents and conditions: (i) LiAlH4, THF, 0 ꢁC to rt.
18
R2N
Me
NR2 = N-benzyl-N-α-methylbenzyl
Me
O
H
H
17, R = Ph, 93%
18, R = Me, 96%
(2S,3R,10S,aR) absolute configuration assigned from the
known (R)-a-methylbenzyl fragment (Fig. 4).
Scheme 3. Reagents and conditions: (i) LiAlH4, THF, 0 ꢁC to rt; (ii) 2,2-di-
methoxypropane, acetone, CSA.
Having established unambiguously the stereoselectivity of
the aldol reactions of b-amino esters 10 and 11 with acet-
aldehyde, the tandem N-oxidation and Cope elimination of
the b-amino aldol products 12–14 to the desired b-phenyl
or b-methyl Baylis–Hillman products were investigated.
Stereospecific syn-elimination from 12 and 13 was predicted
to give rise to the corresponding (E)-b-substituted Baylis–
Hillman products, while 14 was anticipated to yield the
corresponding (Z)-b-substituted product. As expected, treat-
ment of the syn-aldol products 12 and 13 with mCPBA in
CHCl3 resulted in the formation of the desired products
(2E,10R)-21 and (2E,10R)-22 as single diastereoisomers in
74 and 58% isolated yield, respectively. Further application
of this methodology to the aldol product 14 gave the corre-
sponding (Z)-b-methyl Baylis–Hillman product 23 in 59%
Single crystal X-ray analysis of 17 allowed unambiguous
confirmation of the relative configuration, with the absolute
(4R,5R,10S,aR) configuration assigned relative to the known
(R)-a-methylbenzyl fragment (Fig. 3).
In a similar fashion, reduction of minor diastereoisomeric b-
amino aldol product 14 in the crotonate derived series with
LiAlH4 gave the diol 19 in quantitative yield. Elaboration
of 19 to the acetonide 20 and subsequent 1H NMR spectro-
scopic analysis also confirmed the syn-configuration within
14 (Scheme 4).
X-ray crystallographic analysis of 19 allowed unambigu-
ous assignment of the relative configuration, with the

A. Chernega et al. / Tetrahedron 63 (2007) 7036–7046
7039
observed upon reaction of the boron (E)-enolate derived
from 11 with benzaldehyde, and with the boron (E)-enolate
of 24 with acetaldehyde. In each of these cases, three diaste-
reoisomers were observed by 1H NMR spectroscopic
analysis of the crude reaction product, with the major dia-
stereoisomer purified to homogeneity in each case and
assigned the syn-configuration by analogy to that previously
proven unambiguously (Scheme 6).
Me
H
Me
H
Me
H
Ph
Me
N
Ph
N
Ph
N
(i)
Me
t
t
CO2 Bu
Ph
N
+
CO2 Bu
OH
R
R
t
CO2 Bu
R
Me
OH
OH
OH
R'
R'
H
H
H
19
β-Amino ester
10, 11, 24
Major aldol product
25-29
Other diastereoisomer(s)
Figure 4. Chem 3D representation of the X-ray crystal structure of 19 (some
H atoms were removed for clarity).
Major aldol
β-Amino ester
product
R'
R
d.r.
Yield %a
10
10
10
11
Ph
Ph
Ph
Me
25
26
27
28
Ph
iPr
93:7
85:15
65
66
66
54
69
yield. 1H NMR NOE difference experiments were indicative
of the assigned alkene configurations within (2E,10R)-21,
(2E,10R)-22 and (2Z,10S)-23. The ee of 21 was determined
to be >99% by chiral HPLC analysis31 and comparison
with an authentic scalemic sample,32 indicating that the N-
oxidation protocol proceeds without epimerisation of the
C(10) stereogenic centre. Although the ee of Baylis–Hillman
products 22 and 23 could not be unambiguously determined,
similar high levels of enantiomeric excess are assumed due
to their isolation as single diastereoisomers, and their forma-
tion from single diastereoisomers of enantiomerically pure
aldol products 13 and 14 (Scheme 5).
tBu
Ph
Me
71:29
46:38:16
60:30:10
24 (E)-MeCH=CH 29
Scheme 6. Reagents and conditions: (i) LDA (3 equiv), THF, ꢀ78 to 0 ꢁC,
then B(OMe)3, then R0CHO. [aCombined isolated yield of all diastereoiso-
mers.]
With a range of homogenous syn-aldol products 25–29 in
hand, their conversion to the corresponding b-substituted
Baylis–Hillman products was investigated. Treatment of
aldol products 25–29 with mCPBA gave, in each case, the
corresponding (E)-b-substituted Baylis–Hillman products
30–34 in good (59–70%) yield and in >95% de. The (E)-con-
figuration within 30–34 was identified by NOE difference
NMR spectroscopic analysis, consistent with the assigned
configuration of the aldol precursors and syn-elimination
during the Cope elimination. The ee of 30 was unambigu-
ously established as >99% by HPLC analysis,34 although
the ees of 31–34 could not be unambiguously identified either
via derivatisation, chiral shift or HPLC analysis. However,
the isolation of 26–29 as essentially single diastereoisomers
(>95% de) allows an ee of >98% (consistent with the >98%
ee of the N-methyl-N-(a-methylbenzyl)amine used to initiate
the conjugate addition reaction) to be assumed (Scheme 7).
Me
H
t
CO2 Bu
Ph
N
R
(i)
t
CO2 Bu
R
Me
OH
H
Me
OH
H
12, R = Ph, >98% d.e.
13, R = Me, >98% d.e.
21, R = Ph, 74%, >99% e.e
22, R = Me, 58%
Me
Me
H
Ph
Me
Me
N
t
CO2 Bu
(i)
t
CO2 Bu
Me
OH
H
OH
H
Me
H
t
14, >98% d.e.
23, 59%
CO2 Bu
Ph
N
R
(i)
t
CO2 Bu
R
Scheme 5. Reagents and conditions: (i) mCPBA, CHCl3, rt.
OH
R'
H
OH
R'
2.2. Preparation of a range of (E)-10-hydroxyalkyl-3-
alkyl-prop-2-enoates
H
25-29
30-34
Aldol
product
25
R
R'
Product Yield % d.e.
Having demonstrated the utility of this methodology for
the synthesis of model (E)- and (Z)-b-substituted Baylis–
Hillman products, the generality of this three-step protocol
was probed. Aldol reaction of b-amino esters (3S,aR)-10,
(3R,aR)-11 and the known b-amino ester (3R,4E,aR)-2423a
with a range of aldehydes was therefore evaluated. Aldol
reaction of the boron (E)-enolate derived from 10 with benz-
aldehyde, iso-butyraldehyde and pivaldehyde gave aldol
products 25–27 with high to reasonable levels of stereoselec-
tivity (93:7, 85:15 and 71:29, respectively), with the major
syn-diastereoisomer33 purified to homogeneity in each
case. Markedly lower levels of diastereoselectivity were
Ph
Ph
Ph
Me
Ph
30
31
32
33
34
63
66
59
62
70
>95
>95
>95
>95
>95
i
26
Pr
t
27
Bu
Ph
Me
28
29 (E)-MeCH=CH
Scheme 7. Reagents and conditions: (i) mCPBA, CHCl3, rt.
3. Conclusion
A three-step protocol for the diastereoselective synthesis of
b-substituted Baylis–Hillman products has been developed,

7040
A. Chernega et al. / Tetrahedron 63 (2007) 7036–7046
involving conjugate addition of lithium (R)-N-methyl-N-(a-
methylbenzyl)amide to an a,b-unsaturated ester, followed
by asymmetric aldol reaction and subsequent tandem N-oxi-
dation and Cope elimination. The aldol reactions proceed
with moderate to good levels of diastereoselectivity and
the generality of this protocol towards a range of a,b-unsat-
urated esters and aldehydes has been demonstrated. The fur-
ther application of this methodology for natural product
synthesis is currently underway within this laboratory.
4.3. General procedure 2 for tandem N-oxidation and
Cope elimination
A solution of mCPBA (50% pure, 2 equiv) in CHCl3
(10 mL) was added to the aldol product in CHCl3 (5 mL)
and stirred at rt under nitrogen. Satd aq NaHCO3 (5 mL)
was added when no sign of starting material was apparent
by TLC and starch/KI paper. The resultant material was
extracted with DCM (2ꢂ15 mL), dried and concentrated
in vacuo.
4. Experimental
4.3.1. tert-Butyl (3S,aR)-3-[N-methyl-N-(a-methylbenz-
yl)amino]-3-phenylpropanoate 10. Following the litera-
ture procedure,35 BuLi (1.4 M in hexanes, 10.5 mL, 14.7
mmol), (R)-N-methyl-N-(a-methylbenzyl)amine (2.12 g,
15.7 mmol) in THF (20 mL) and tert-butyl cinnamate
(2.0 g, 9.8 mmol) in THF (30 mL) gave, after purification
by column chromatography (40–60 ꢁC petrol/Et2O 12:1),
10 as a clear yellow oil (3.13 g, 94%, 88% de). Found: C,
77.65; H, 8.9; N, 4.3%. C22H29NO2 requires: C, 77.8; H,
8.6; N, 4.1%. [a]D22 +33.3 (c 1.0 in CHCl3); nmax (film)
1729 (C]O); dH (500 MHz, CDCl3) 1.30 (9H, s, CMe3),
1.36 (3H, d, J 6.6, C(a)Me), 2.08 (3H, s, NMe), 2.62 (1H,
dd, J 14.3, 8.6, C(2)HA), 2.88 (1H, dd, J 14.3, 6.4,
C(2)HB), 3.66 (1H, q, J 6.6, C(a)H), 4.30 (1H, dd, J 8.6,
6.4, C(3)H), 7.19–7.37 (10H, m, Ph); dC (50 MHz, CDCl3)
16.7 (C(a)Me), 27.9 (CMe3), 33.1 (NMe), 38.5 (C(2)),
59.2, 60.9 (C(3), C(a)), 80.2 (CMe3), 126.6, 127.2 (Php),
127.4, 128.1, 128.3 (Pho, Phm), 140.9, 145.3 (Phi), 171.4
(C(1)); m/z (CI, NH3) 340 ([M+H]+, 100%).
4.1. General experimental
All reactions described as being carried out under nitrogen
were performed using standard vacuum line techniques us-
ing glassware that was flame-dried and subsequently cooled
in vacuo. THF was distilled under nitrogen from sodium
benzophenone ketyl. Butyllithium was purchased as a
1.6 M solution in hexanes and titrated against diphenylacetic
acid prior to use. Di-iso-propylamine was distilled from (and
stored over) potassium hydroxide pellets. Aldehydes were
freshly distilled before use. All other solvents and reagents
were used as supplied, without further purification. Organic
layers were dried over MgSO4. Thin layer chromatography
was performed on aluminium plates coated with 60 F254 sil-
ica. 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.
4.3.2. tert-Butyl (3R,aR)-3-[N-methyl-N-(a-methylbenz-
yl)amino]butanoate 11. Following the literature proce-
dure,35 BuLi (1.5 M in hexanes, 10.5 mL, 15.8 mmol),
(R)-N-methyl-N-(a-methylbenzyl)amine (2.3 g, 16.9 mmol)
in THF (20 mL) and tert-butyl crotonate (1.5 g, 10.5 mmol)
in THF (30 mL) gave, after purification by column chroma-
tography (eluent toluene/acetone 70:1), 11 as a clear yellow
oil (2.5 g, 84%, >98% de). Found: C, 73.6; H, 10.0; N,
5.6%. C17H27NO2 requires: C, 73.6; H, 9.8; N, 5.1%. [a]D22
ꢀ2.9 (c 1.0 in CHCl3); nmax (film) 1730 (C]O); dH
(500 MHz, CDCl3) 0.97 (3H, d, J 6.6, C(4)H3), 1.34 (3H,
d, J 6.6, C(a)Me), 1.44 (9H, s, CMe3), 2.07 (3H, s, NMe),
2.15 (1H, dd, J 13.9, 7.8, C(2)HA), 2.44 (1H, dd, J 13.9,
6.6, C(2)HB), 3.48 (1H, app sextet, J 7.0, C(3)H), 3.56 (1H,
q, J 6.6, C(a)H), 7.19–7.34 (5H, m, Ph); dC (50 MHz,
CDCl3) 14.2, 21.8 (C(4), C(a)Me), 28.1 (CMe3), 32.1
(NMe), 40.1 (C(2)), 51.2, 62.1 (C(3), C(a)), 79.8 (CMe3),
126.6 (Php), 127.2, 128.2 (Pho, Phm), 146.2 (Phi), 172.0
(C(1)); m/z (ESI+) 300 ([M+Na]+, 50%), 278 ([M+H]+,
100%).
Melting points were recorded on a Gallenkamp Hot Stage
apparatus and are uncorrected. Elemental analyses were re-
corded by the microanalysis service of the Dyson–Perrins
Laboratory, University of Oxford. Optical rotations were
recorded on a Perkin–Elmer 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 spec-
tra were recorded on a Perkin–Elmer 1750 FT spectrometer
as a KBr disc (KBr), a thin film on an NaCl plate (film) or
as a solution in CHCl3 using 1.0 mm NaCl cells (CHCl3).
Selected characteristic peaks are reported in cmꢀ1. NMR
spectra were recorded on a Bruker AC200, Bruker WH300,
Bruker AV400 or Bruker AM500 spectrometer in CDCl3.
The field was locked by external referencing to the deuteron
resonance. Mass spectra were obtained on a VG Masslab
20–250 Quadrupole instrument (CI, NH3) or a VG BIO-Q
instrument (ESI+).
4.2. General procedure 1 for aldol reaction
BuLi (3 equiv) was added dropwise to a solution of di-
iso-propylamine (3.5 equiv) in THF (20 mL) at ꢀ78 ꢁC
and warmed to 0 ꢁC for 30 min before a solution of the b-
amino ester in THF (30 mL) was added via cannula and
stirred for 2 h at 0 ꢁC under nitrogen. After recooling to
ꢀ78 ꢁC, B(OMe)3 (4 equiv) was added and the reaction mix-
ture was stirred for 30 min before the addition of freshly dis-
tilled aldehyde (excess). After 2 h, satd aq NH4Cl (5 mL)
was added and the mixture warmed to rt before being parti-
tioned between brine (50 mL) and Et2O (3ꢂ40 mL), dried
and concentrated in vacuo.
4.3.3. tert-Butyl (2S,3S,10R,aR)-2-(10-hydroxyethyl)-3-
[N-methyl-N-(a-methylbenzyl)amino]-3-phenylpropa-
noate 12. Following general procedure 1, BuLi (1.4 M in
hexanes, 3.16 mL, 4.42 mmol) and di-iso-propylamine
(0.72 mL, 5.2 mmol) in THF (60 mL), 10 (500 mg, 1.47
mmol) in THF (40 mL), B(OMe)3 (0.50 mL, 4.42 mmol)
and acetaldehyde (w1 mL, excess) gave, after purification
by column chromatography (eluent 40–60 ꢁC petrol/Et2O
2:1) 12 as a clear colourless oil (430 mg, 76%). Found: C,
75.45; H, 8.9; N, 3.6%. C24H33NO3 requires: C, 75.2; H,
8.7; N, 3.65%. [a]D22 +68.0 (c 0.95 in CHCl3); nmax (film)

A. Chernega et al. / Tetrahedron 63 (2007) 7036–7046
7041
3450 (br, O–H), 1728 (C]O); dH (300 MHz, CDCl3) 1.16
(3H, d, J 6.1, C(20)H3), 1.28 (3H, d, J 6.7, C(a)Me), 1.38
(9H, s, CMe3), 2.14 (3H, s, NMe), 3.18 (1H, dd, J 8.5, 6.4,
C(2)H), 3.84 (1H, q, J 6.7, C(a)H), 4.21 (1H, dq, J 8.5, 6.1,
C(10)H), 4.29 (1H, d, J 6.4, C(3)H), 5.88 (1H, br s, OH),
7.20–7.46 (10H, m, Ph); dC (50 MHz, CDCl3) 13.5, 21.3
(C(20), C(a)Me), 28.0 (CMe3), 34.3 (NMe), 53.4 (C(2)),
58.0, 66.7, 68.0 (C(3), C(10), C(a)), 80.0 (CMe3), 126.9
(Php), 127.6 (Pho/Phm), 128.0 (Php), 128.2, 128.3, 129.6
(Pho, Phm), 135.8, 143.4 (Phi), 171.2 (C(1)); m/z (CI, NH3)
384 ([M+H]+, 40%).
residue was purified by column chromatography (eluent
Et2O) to give 15 (47 mg, 58%) as a clear colourless oil.
Found: C, 76.7; H, 8.5; N, 4.4%. C20H27NO2 requires: C,
76.6; H, 8.7; N 4.5%. [a]2D3 +77.7 (c 1.1 in CHCl3); nmax
(film) 3369 (br, O–H); dH (300 MHz, CDCl3) 1.07 (3H, d,
J 6.5, C(20)H3), 1.41 (3H, d, J 6.6, C(a)Me), 2.04 (3H, s,
NMe), 2.50–2.58 (1H, m, C(2)H), 3.59–3.66 (2H, m,
C(1)HA, C(a)H), 3.76 (1H, app quintet, J 6.3, C(10)H),
3.88 (1H, dd, J 11.0, 3.8, C(1)HB), 4.24 (1H, d, J 8.1,
C(3)H), 4.37 (1H, br s, OH), 7.18–7.42 (10H, m, Ph); dC
(50 MHz, CDCl3) 16.2, 19.3 (C(20), C(a)Me), 34.9 (NMe),
45.2 (C(2)), 59.5 (C(a)), 62.8 (C(1)), 66.7, 67.0 (C(3),
C(10)), 127.0, 127.3, 127.8, 128.3, 128.5, 129.6 (Pho, Phm,
Php), 134.9, 143.7 (Phi); m/z (ESI+) 314 ([M+H]+, 100%).
4.3.4. tert-Butyl (2S,3R,10R,aR)- and (2R,3R,10S,aR)-2-
(10-hydroxyethyl)-3-[N-methyl-N-(a-methylbenzyl)ami-
no]butanoate (2S,3R,10R,aR)-13 and (2R,3R,10S,aR)-14.
Following general procedure 1, BuLi (1.5 M in hexanes,
7.2 mL, 10.8 mmol) and di-iso-propylamine (1.77 mL,
12.6 mmol) in THF (100 mL), 11 (1.0 g, 3.60 mmol) in
THF (50 mL), B(OMe)3 (1.22 mL, 10.8 mmol) and acetal-
dehyde (w2 mL, excess) gave, after purification by column
chromatography (eluent 40–60 ꢁC petrol/Et2O 7:1 then
toluene/acetone 40:1), 13 and 14 (875 mg, 76% combined
yield).
4.3.6. (2R,3R,10R,aR)-2-(10-Hydroxyethyl)-3-[N-methyl-
N-(a-methylbenzyl)amino]butan-1-ol 16. LiAlH4 (1.0 M
in THF, 2.5 mL, 2.5 mmol) was added to a stirred solution
of 13 (500 mg, 1.55 mmol) in THF (50 mL) at 0 ꢁC and
warmed to rt for 15 h before the dropwise addition of water
(0.5 mL). EtOAc (15 mL) was added and the mixture was
stirred for 3 h before being filtered through Celite, dried
and concentrated in vacuo. The residue was purified by
column chromatography (eluent 40–60 ꢁC petrol/Et2O 4:1)
to give 16 as a clear colourless oil (389 mg, quant); nmax
(film) 3364 (br, O–H); dH (300 MHz, CDCl3) 1.01 (3H, d,
J 6.7, C(4)H3), 1.16 (3H, d, J 6.4, C(20)H), 1.40 (3H, d, J
6.7, C(a)Me), 1.92–1.97 (1H, m, C(2)H), 2.03 (3H, s,
NMe), 3.28 (1H, m, C(3)H), 3.73–3.83 (2H, m, C(1)HA,
C(a)H), 3.92–4.03 (2H, m, C(1)HB, C(10)H), 7.22–7.34
(5H, m, Ph); dC (50 MHz, CDCl3) 11.0 (C(a)Me), 18.9,
19.1 (C(4), C(20)), 33.0 (NMe), 47.8, 56.3, 61.2, 67.4
(C(2), C(3), C(10), C(a)), 63.2 (C(1)), 127.2, 127.5, 128.5
(Pho, Phm, Php), 143.8 (Phi); m/z (CI, NH3) 252 ([M+H]+,
100%); HRMS (CI, NH3) found: 252.1964; C15H26NO2+
([M+H]+) requires: 252.1964.
First to elute: 14 as a clear colourless oil (229 mg, 20%).
Found: C, 71.1; H, 10.0; N, 4.55%. C19H31NO3 requires:
C, 71.0; H, 9.7; N, 4.4%. [a]2D2 +9.3 (c 1.0 in CHCl3); nmax
(film) 3190 (br, O–H), 1722 (C]O); dH (500 MHz,
CDCl3) 0.91 (3H, d, J 6.5, C(4)H3), 1.18 (3H, d, J 6.1,
C(20)H3), 1.47 (9H, s, CMe3), 1.47 (3H, d, J 6.6, C(a)Me),
1.98 (3H, s, NMe), 2.32 (1H, dd, J 10.7, 9.3, C(2)H), 3.62
(1H, q, J 6.6, C(a)H), 3.73 (1H, dq, J 10.7, 6.5, C(3)H),
4.13 (1H, dq, J 9.3, 6.1, C(10)H), 7.23–7.33 (5H, m, Ph),
7.93 (1H, br s, OH); dC (50 MHz, CDCl3) 10.2, 21.4, 21.5
(C(4)H3, C(20)H3, C(a)Me), 28.0 (CMe3), 32.7 (NMe),
56.2, 56.9, 62.8, 71.2 (C(2), C(3), C(10), C(a)), 81.0
(CMe3), 127.1, 127.4, 128.7 (Pho, Phm, Php), 143.8 (Phi),
172.1 (C(1)); m/z (CI, NH3) 322 ([M+H]+, 100%).
4.3.7. (4R,5R,10S,aR)-2,2,4-Trimethyl-5-{10-[N-methyl-
N-(a-methylbenzyl)amino]benzyl}-1,3-dioxane 17. A so-
lution of 2,2-dimethoxypropane and acetone (1:1, 10 mL)
was added to a mixture of 15 (40 mg, 0.13 mmol) and (+)-
CSA (2 mg), and heated at reflux for 8 h. Na2CO3 was added
until neutral pH was reached, and the mixture filtered, dried
and concentrated in vacuo. Purification by column chroma-
tography (eluent 40–60 ꢁC petrol/Et2O 5:1) and recrystallisa-
tion (40–60 ꢁC petrol/Et2O) gave 17 as white plates (42 mg,
93%). Found: C, 78.1; H, 8.6; N, 3.7%. C23H31NO2 requires:
C, 78.15; H, 8.8; N 4.0%. Mp 138–143 ꢁC; [a]D26 +43.4 (c 1.3
in CHCl3); dH (500 MHz, CDCl3) 0.65 (3H, d, J 6.8,
C(4)Me), 1.52 (6H, s, C(2)Me2), 1.60 (3H, d, J 6.4,
C(a)Me), 1.72 (3H, s, NMe), 2.27 (1H, app dq, J 10.7, 3.1,
C(5)H), 3.27 (1H, q, J 6.4, C(a)H), 4.05 (1H, dd, J 11.1,
3.1, C(6)HA), 4.28 (1H, qd, J 6.8, 3.0, C(4)H), 4.48 (1H,
dd, J 11.1, 3.3, C(6)HB), 4.72 (1H, d, J 10.7, C(10)H),
7.18–7.38 (10H, m, Ph); dC (125 MHz, CDCl3) 20.6, 21.0,
22.6, 29.1 (C(2)Me2, C(4)Me, C(a)Me), 34.6 (NMe), 38.5
(C(5)), 55.9, 61.4 (C(10), C(a)), 62.5 (C(6)), 68.3 (C(4)),
98.6 (C(2)), 126.5, 126.8, 127.3, 127.8, 128.2, 129.2 (Pho,
Phm, Php), 137.3, 147.0 (Phi); m/z (ESI+) 354 ([M+H]+,
100%).
Second to elute: 13 as a clear yellow oil (646 mg, 56%).
Found: C, 70.9; H, 9.6; N, 4.4%. C19H31NO3 requires: C,
71.0; H, 9.7; N, 4.4%. [a]2D2 ꢀ7.9 (c 1.0 in CHCl3); nmax
(film) 3436 (br, O–H), 1727 (C]O); dH (500 MHz,
CDCl3) 1.25 (6H, overlapping 2ꢂ3H d, C(4)H3, C(20)H3),
1.38 (3H, d, J 6.9, C(a)Me), 1.49 (9H, s, CMe3), 2.11 (3H,
s, NMe), 2.83 (1H, dd, J 9.3, 4.4, C(3)H), 3.19 (1H, qd, J
6.6, 4.4, C(3)H), 4.20–4.29 (2H, m, C(10)H, C(a)H), 6.36
(1H, br s, OH), 7.24–7.35 (5H, m, Ph); dC (50 MHz,
CDCl3) 12.8, 14.7, 22.0 (C(4), C(20), C(a)Me), 28.1
(CMe3), 32.5 (NMe), 53.4, 57.1, 57.5, 66.0 (C(2), C(3),
C(10), C(a)), 80.7 (CMe3), 127.1, 128.1 (Pho, Phm, Php),
141.4 (Phi), 172.0 (C(1)); m/z (CI, NH3) 322 ([M+H]+,
80%).
4.3.5. (2R,3S,10R,aR)-2-(10-Hydroxyethyl)-3-[N-methyl-
N-(a-methylbenzyl)amino]-3-phenylpropan-1-ol 15. A
solution of 12 (100 mg, 0.26 mmol) in THF (5 mL) was
added to a suspension of LiAlH4 (100 mg, 2.50 mmol) in
THF (5 mL) and stirred at rt for 24 h, before the sequential
dropwise addition of water (0.5 mL), 1 M aq NaOH
(0.1 mL) and more water (0.5 mL). EtOAc (15 mL) was
added and the mixture was stirred for 3 h before being fil-
tered through Celite, dried and concentrated in vacuo. The
4.3.7.1. X-ray crystal structure determination for 17.
Data were collected using an Enraf–Nonius CAD4

7042
A. Chernega et al. / Tetrahedron 63 (2007) 7036–7046
diffractometer with graphite monochromated Cu Ka radia-
tion using standard procedures at rt. The structure was solved
by direct methods, all non-hydrogen atoms were refined with
anisotropic thermal parameters. Hydrogen atoms were
added at idealised positions. The structure was refined using
CRYSTALS.36
CDCl3) 9.7 (C(4)), 21.2 (C(a)Me), 21.8 (C(20)), 32.7
(NMe), 47.9 (C(2)), 55.1 (C(3)), 61.0 (C(1)), 62.6 (C(a)),
70.3 (C(10)), 127.2, 128.6 (Pho, Phm, Php), 144.4 (Phi);
m/z (CI, NH3) 252 ([M+H]+, 100%).
4.3.9.1. X-ray crystal structure determination for 19.
Data were collected using an Enraf–Nonius k-CCD diffrac-
tometer with graphite monochromated Mo Ka radiation us-
ing standard procedures at 190 K. The structure was solved
by direct methods, all non-hydrogen atoms were refined
with anisotropic thermal parameters. Hydrogen atoms
were added at idealised positions. The structure was refined
using CRYSTALS.36
X-ray crystal structure data for 17 [C23H31NO2]: M¼353.51,
˚
monoclinic, space group P 1 21 1, a¼7.0424(9) A, b¼
3
ꢁ
˚
˚
˚
9.548(1) A, c¼15.797(2) A, b¼97.84(1) , V¼1052.3A ,
Z¼2, m¼5.1 cmꢀ1, colourless block, crystal dimensions¼
0.2ꢂ0.3ꢂ0.3 mm3. A total of 2125 unique reflections were
measured for 1<q<70 and 1801 reflections were used in
the refinement. The final parameters were wR2¼0.030 and
R1¼0.028 [I>3s(I)]. Crystallographic data (excluding struc-
tural factors) have been deposited at the Cambridge Crystal-
lographic Data Centre as supplementary publication number
CCDC 634751. 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].
X-ray crystal structure data for 19 [C15H25NO2]: M¼251.37,
˚
orthorhombic, space group P 21 21 21, a¼7.1930(1) A,
3
˚
˚
˚
b¼9.3005(2) A, c¼22.3709(5) A, V¼1496.58(5) A , Z¼4,
m¼0.073 mmꢀ1, colourless plate, crystal dimensions¼0.2ꢂ
0.2ꢂ0.4 mm3. A total of 2001 unique reflections were mea-
sured for 0<q<30 and 1811 reflections were used in the
refinement. The final parameters were wR2¼0.043 and
R1¼0.041 [I>3s(I)]. Crystallographic data (excluding struc-
tural factors) have been deposited at the Cambridge Crystal-
lographic Data Centre as supplementary publication number
CCDC 634752. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [fax: +44(0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
4.3.8. (4R,5R,10R,aR)-2,2,4-Trimethyl-5-{10-[N-methyl-
N-(a-methylbenzyl)amino]ethyl}-1,3-dioxane 18. A solu-
tion of 2,2-dimethoxypropane (0.3 mL) in acetone (10 mL)
was added to a mixture of 16 (300 mg, 1.2 mmol), (+)-
CSA (140 mg) and CuSO4 (100 mg, 0.63 mmol) and stirred
for 5 days at rt. Na2CO3 was added until neutral pH was
reached, and the mixture was filtered, dried and concentrated
in vacuo. Purification by column chromatography (eluent
40–60 ꢁC petrol/Et2O 10:1) gave 18 as a clear oil (340 mg,
96%). [a]2D5 +2.7 (c 1.0 in CHCl3); nmax (film) 2974
(C–H), 1453, 1378; dH (400 MHz, CDCl3) 0.97 (3H, d, J
6.5, C(20)H3), 1.28 (3H, d, J 6.9, C(4)Me), 1.33 (3H, d, J
6.6, C(a)Me), 1.45, 1.46 (2ꢂ3H, s, C(2)Me2), 1.67 (1H, m,
C(5)H), 1.88 (3H, s, NMe), 3.44 (1H, dq, J 10.1, 6.5,
C(10)H), 3.54 (1H, q, J 6.6, C(a)H), 3.92 (1H, dd, J 11.4,
3.7, C(6)HA), 4.17 (1H, dd, J 11.4, 5.2, C(6)HB), 4.28 (1H,
qd, J 6.9, 3.6, C(4)H), 7.18–7.35 (5H, m, Ph); dC
(100 MHz, CDCl3) 11.6 (C(20)), 19.9 (C(4)Me), 22.1
(C(a)Me), 23.2, 28.4 (C(2)Me2), 33.0 (NMe), 42.6 (C(5)),
48.4 (C(10)), 62.0 (C(6)), 62.4 (C(a)Me), 68.6 (C(4)), 98.2
(C(2)), 126.5, 127.2, 128.2 (Pho, Phm, Php), 147.2 (Phi);
m/z (CI, NH3) 292 ([M+H]+, 100%); HRMS (CI, NH3)
found: 292.2276; C18H30NO+2 ([M+H]+) requires: 292.2277.
4.3.10. (4S,5S,10R,aR)-2,2,4-Trimethyl-5-{10-[N-methyl-
N-(a-methylbenzyl)amino]ethyl}-1,3-dioxane 20. A solu-
tion of 2,2-dimethoxypropane (0.3 mL) in acetone (5 mL)
was added to a mixture of 19 (300 mg, 1.2 mmol), (+)-
CSA (140 mg) and CuSO4 (100 mg, 0.63 mmol) and stirred
for 5 days at rt. Na2CO3 was added until neutral pH was
reached, and the mixture was filtered, dried and concentrated
in vacuo. Purification by column chromatography (eluent
40–60 ꢁC petrol/Et2O 10:1) gave 20 (340 mg, 96%) as a clear
oil. [a]2D5 +6.6 (c 1.0 in CHCl3); nmax (film) 2988 (C–H),
1454, 1378, 1197; dH (400 MHz, CDCl3) 1.05 (3H, d, J
6.9, C(20)H3), 1.34 (3H, d, J 6.7, C(4)Me), 1.41 (3H, d, J
6.6, C(a)Me), 1.42, 1.45 (2ꢂ3H, s, C(2)Me2), 1.65 (1H, m,
C(5)H), 1.98 (3H, s, NMe), 3.43 (1H, app quintet, J 6.9,
C(10)H), 3.67 (1H, q, J 6.6, C(a)H), 3.92 (2H, app d, J 3.8,
C(6)H2), 4.27 (1H, dq, J 6.7, 3.4, C(4)H), 7.20–7.33 (5H,
m, Ph); dC (100 MHz, CDCl3) 10.6 (C(20)), 19.3 (C(4)Me),
20.3 (C(a)Me), 21.8, 28.8 (C(2)Me2), 33.1 (NMe), 40.0
(C(5)), 50.4 (C(10)), 61.8 (C(6)), 62.0 (C(a)Me), 68.9
(C(4)), 98.0 (C(2)), 126.5, 127.3, 128.2 (Pho, Phm, Php),
145.1 (Phi); m/z (CI, NH3) 292 ([M+H]+, 100%); HRMS
(CI, NH3) found: 292.2274; C18H30NO+2 ([M+H]+) requires:
292.2277.
4.3.9. (2S,3S,10R,aR)-2-(10-Hydroxyethyl)-3-[N-methyl-
N-(a-methylbenzyl)amino]butan-1-ol 19. LiAlH4 (1.0 M
in THF, 2.5 mL, 2.5 mmol) was added to a stirred solution
of 14 (500 mg, 1.55 mmol) in THF (5 mL) at 0 ꢁC and
warmed to rt for 15 h before the dropwise addition of water
(0.5 mL). EtOAc (15 mL) was added and the mixture was
stirred for 3 h before being filtered through Celite, dried
and concentrated in vacuo to give 19 as a white solid
(389 mg, quant). Found: C, 71.6; H, 10.1; N, 5.6%.
C15H25NO2 requires: C, 71.7; H, 10.0; N, 5.6%. [a]D25
+27.8 (c 1.0 in CHCl3); nmax (film) 3367 (br, O–H); dH
(400 MHz, CDCl3) 1.05 (3H, d, J 6.6, C(4)H3), 1.31 (3H,
d, J 6.1, C(20)H3), 1.45 (3H, d, J 6.7, C(a)Me), 1.50 (1H,
m, C(2)H), 1.75 (1H, br, OH), 1.96 (3H, s, NMe), 3.64
(1H, q, J 6.7, C(a)H), 3.68–3.75 (2H, m, C(1)HA, C(3)H),
3.85 (1H, dd, J 11.6, 2.9, C(1)HB), 4.21 (1H, dq, J 9.0,
6.1, C(10)H), 7.20–7.33 (5H, m, Ph); dC (100 MHz,
4.3.11. tert-Butyl (2E,10R)-2-(10-hydroxyethyl)-3-phenyl-
prop-2-enoate 21. Following general procedure 2, mCPBA
(0.18 g, 0.52 mmol) in CHCl3 (5 mL) was added to 12
(100 mg, 0.26 mmol) in CHCl3 (5 mL) and the reaction
was quenched after 1 h. Purification by column chromato-
graphy (eluent 40–60 ꢁC petrol/Et2O 12:1) gave 21 as a clear
colourless oil (48 mg, 74%, >99% ee). Found: C, 72.4; H,
8.35%. C15H20O3 requires: C, 72.55; H, 8.1%. [a]2D2 +93.7
(c 0.75 in CHCl3); nmax (film) 3500 (br, O–H), 1688
(C]O); dH (500 MHz, CDCl3) 1.52 (3H, d, J 6.6,

A. Chernega et al. / Tetrahedron 63 (2007) 7036–7046
7043
C(20)H3), 1.59 (9H, s, CMe3), 3.64 (1H, d, J 11.2, OH), 4.84
(1H, dq, J 11.2, 6.6, C(10)H), 7.27–7.41 (5H, m, Ph), 7.55
(1H, s, C(3)H); dC (125 MHz, CDCl3) 23.3 (C(20)), 28.2
(CMe3), 65.0 (C(10)), 82.0 (CMe3), 128.4, 129.0, 129.1
(Pho, Phm, Php), 134.8, 136.0 (C(2), Phi), 138.7 (C(3)),
167.1 (C(1)); m/z (CI, NH3) 249 ([M+H]+, 8%), 210
([MꢀC4H8+NH4]+, 100%); HRMS (CI, NH3) found:
210.1130; C11H16NO+3 [MꢀC4H8+NH4]+ requires:
210.1131.
73.5 (C(2), C(3), C(10), C(a)), 80.8 (CMe3), 126.9, 127.5,
127.6, 127.8, 128.1, 128.2, 128.4, 129.6 (Pho, Phm, Php),
135.8, 142.3, 142.6 (Phi), 170.0 (C(1)); m/z (CI, NH3) 446
([M+H]+, 70%).
Second to elute: a mixture of diastereoisomers as a colourless
oil (201 mg, 31%).
Third to elute: a minor diastereoisomer, contaminated with
w5% of an unknown impurity, as a colourless oil (20 mg,
3%); selected data: nmax (film) 3446 (br, O–H), 1707
(C]O); dH (500 MHz, CDCl3) 0.76 (9H, s, CMe3), 1.78
(3H, d, J 6.4, C(a)Me), 1.96 (3H, s, NMe), 3.36 (1H, dd, J
11.2, 9.2, C(2)H), 3.42 (1H, q, J 6.4 C(a)H), 4.98 (1H, d, J
11.2, C(3)H), 5.15 (1H, d, J 9.2, C(10)H), 7.21–7.48 (15H,
m, Ph); dC (125 MHz, CDCl3) 22.0 (C(a)Me), 27.0
(CMe3), 35.4 (NMe), 54.1, 62.2, 65.2, 79.1 (C(2), C(3),
C(10), C(a)), 80.4 (CMe3), 127.2, 127.3, 127.4, 127.5,
127.8, 127.9, 128.0, 129.0, 130.0 (Pho, Phm, Php), 133.1,
141.6, 144.0 (Phi), 172.4 (C(1)); m/z (CI, NH3) 446
([M+H]+, 10%).
4.3.12. tert-Butyl (2E,10R)-2-(10-hydroxyethyl)but-2-
enoate 22. Following general procedure 2, mCPBA
(129 mg, 0.37 mmol) in CHCl3 (5 mL) was added to 13
(60 mg, 0.19 mmol) in CHCl3 (5 mL) and the reaction was
quenched after 90 min. Purification by column chromato-
graphy (eluent 40–60 ꢁC petrol/Et2O 12:1) gave 22 (21 mg,
58%) as a colourless oil. Found: C, 64.75; H, 10.0%.
C10H18O3 requires: C, 64.5; H, 9.7%. [a]2D2 +31.7 (c 1.1 in
CHCl3); nmax (CHCl3) 3526 (br, O–H), 1684 (C]O); dH
(500 MHz, CDCl3) 1.44 (3H, d, J 6.6, C(20)H3), 1.56 (9H,
s, CMe3), 1.84 (3H, d, J 7.3, C(4)H3), 3.80 (1H, d, J 10.9,
OH), 4.74 (1H, dq, J 10.9, 6.6, C(10)H), 6.72 (1H, q, J 7.3,
C(3)H); dC (125 MHz, CDCl3) 13.5, 23.2 (C(4), C(20)),
28.2 (CMe3), 64.7 (C(10)), 81.3 (CMe3), 136.1 (C(2)),
136.6 (C(3)), 166.7 (C(1)); m/z (CI, NH3) 204 ([M+NH4]+,
10%), 187 ([M+H]+, 100%).
4.3.15. tert-Butyl (2S,3S,10S,aR)-2-(10-hydroxy-20-meth-
yl)propyl-3-[N-methyl-N-(a-methylbenzyl)amino]-3-
phenylpropanoate 26. Following general procedure 1,
BuLi (1.5 M in hexanes, 3.0 mL, 4.42 mmol) and di-iso-
propylamine (0.68 mL, 5.15 mmol) in THF (15 mL), 10
(500 mg, 1.47 mmol) in THF (15 mL), B(OMe)3 (0.66 mL,
5.9 mmol) and iso-butyraldehyde (1.35 mL, 14.7 mmol)
gave, after purification by column chromatography (eluent
40–60 ꢁC petrol/Et2O 7:1 then toluene/acetone 40:1), two
partially separable diastereoisomeric products (396 mg, 66%
combined yield).
4.3.13. tert-Butyl (2Z,10S)-2-(10-hydroxyethyl)but-2-
enoate 23. Following general procedure 2, mCPBA
(644 mg, 1.87 mmol) in CHCl3 (5 mL) was added to 14
(200 mg, 0.62 mmol) in CHCl3 (5 mL) and the reaction
was quenched after 2 h. Purification by column chromato-
graphy (eluent 40–60 ꢁC petrol/Et2O 12:1) gave 23 (68 mg,
59%) as a colourless oil. Found: C, 64.3; H, 9.9%.
C10H18O3 requires: C, 64.5; H, 9.7%. [a]2D2 ꢀ7.4 (c 1.4 in
CHCl3); nmax (CHCl3) 3601 (br, O–H), 1687 (C]O); dH
(300 MHz, CDCl3) 1.34 (3H, d, J 6.4, C(20)H3), 1.54 (9H,
s, CMe3), 1.95 (3H, d, J 7.1, C(4)H3), 2.81 (1H, br s, OH),
4.43 (1H, m, C(10)H), 6.12 (1H, q, J 7.1, C(3)H); dC
(50 MHz, CDCl3) 15.3, 22.3 (C(4), C(20)), 28.3 (CMe3),
70.1 (C(10)), 81.6 (CMe3), 134.6 (C(3)), 137.1 (C(2)),
167.2 (C(1)); m/z (CI, NH3) 187 ([M+H]+, 100%).
First to elute: a minor diastereoisomer as a colourless oil
(18 mg, 3%). [a]D22 +41.9 (c 0.4 in CHCl3); nmax (film)
3420 (br, O–H), 1703 (C]O); dH (500 MHz, CDCl3) 0.90
(3H, d, C(20)MeA), 0.93 (3H, d, C(20)MeB), 1.50 (3H, d,
J 6.4, C(a)Me), 1.57 (9H, s, CMe3), 1.51–1.62 (1H, m,
C(20)H), 1.97 (3H, s, NMe), 2.69 (1H, m, C(10)H), 3.20
(1H, q, J 6.4, C(a)H), 3.35 (1H, dd, J 11.8, 2.2, C(2)H),
3.40 (1H, d, J 11.0, OH), 4.91 (1H, d, J 11.8, C(3)H),
7.16–7.52 (10H, m, Ph); dC (50 MHz, CDCl3) 19.0, 20.0
(C(20)Me2), 21.9 (C(a)Me), 28.3 (CMe3), 34.1, 35.1 (C(20),
NMe), 50.0, 61.4, 62.3, 75.8 (C(2), C(3), C(10), C(a)), 81.3
(CMe3), 126.6, 127.4, 127.5, 128.0, 128.1, 129.4 (Pho,
Phm, Php), 134.7, 146.2 (Phi), 174.3 (C(1)); m/z (ESI+)
412 ([M+H]+, 100%).
4.3.14. tert-Butyl (2S,3S,10S,aR)-2-(10-hydroxybenzyl)-3-
[N-methyl-N-(a-methylbenzyl)amino]-3-phenylpropa-
noate 25. Following general procedure 1, BuLi (1.5 M in
hexanes, 3.0 mL, 4.42 mmol) and di-iso-propylamine
(0.68 mL, 5.15 mmol) in THF (15 mL), 10 (500 mg, 1.47
mmol) in THF (15 mL), B(OMe)3 (0.66 mL, 5.9 mmol)
and benzaldehyde (1.5 mL, 14.7 mmol) gave, after purifica-
tion by column chromatography (eluent 40–60 ꢁC petrol/Et2O
8:1), two partially separable diastereoisomeric products
(424 mg, 65% combined yield).
Second to elute: a mixture of diastereoisomers as a colourless
oil (131 mg, 22%).
Third to elute: 26 as a colourless oil (248 mg, 41%). Found:
C, 75.9; H, 8.8; N, 3.2%. C26H37NO3 requires: C, 75.9; H,
9.1; N, 3.4%. [a]D22 +45.2 (c 0.25 in CHCl3); nmax (film)
3587 (br, O–H), 1723 (C]O); dH (500 MHz, CDCl3) 0.94
(3H, d, C(20)MeA), 0.98 (3H, d, C(20)MeB), 1.25 (3H, d, J
6.7, C(a)Me), 1.32 (9H, s, CMe3), 1.52–1.60 (1H, m,
C(20)), 2.19 (3H, s, NMe), 3.31 (1H, dd, J 9.9, 5.4, C(2)H),
3.90 (1H, q, J 6.7, C(a)H), 4.04 (1H, dd, J 9.9, 2.7,
C(10)H), 4.25 (1H, d, J 5.4, C(3)H), 6.23 (1H, br s, OH),
7.21–7.52 (10H, m, Ph); dC (125 MHz, CDCl3) 11.0, 15.2
(C(20)Me2), 20.3 (C(a)Me), 27.9 (CMe3), 31.4 (C(20)), 34.2
First to elute: 25 as a colourless oil (203 mg, 31%). Found:
C, 78.0; H, 7.7; N, 3.0%. C29H35NO3 requires: C, 78.2; H,
7.9; N, 3.1%. [a]D22 +68.0 (c 0.95 in CHCl3); nmax (film)
3568 (br, O–H), 1729 (C]O); dH (500 MHz, CDCl3) 1.12
(9H, s, CMe3), 1.29 (3H, d, J 6.8, C(a)Me), 2.33 (3H, s,
NMe), 3.62 (1H, dd, J 9.8, 5.2, C(2)H), 4.08 (1H, q, J 6.8,
C(a)H), 4.35 (1H, d, J 5.2, C(3)H), 5.21 (1H, d, J 9.8,
C(10)H), 7.21–7.58 (15H, m, Ph); dC (125 MHz, CDCl3)
11.2 (C(a)Me), 27.5 (CMe3), 34.3 (NMe), 53.1, 57.1, 70.2,

7044
A. Chernega et al. / Tetrahedron 63 (2007) 7036–7046
(NMe), 49.0, 57.2, 70.0, 74.2 (C(2), C(3), C(10), C(a)), 80.7
(CMe3), 126.9, 127.7, 128.1, 128.2, 128.4, 129.7 (Pho, Phm,
Php), 136.3, 142.7 (Phi), 171.0 (C(1)); m/z (CI, NH3) 412
([M+H]+, 20%).
(CHCl3) 3343 (br, O–H), 1687 (C]O); dH (500 MHz,
CDCl3) 1.08 (3H, d, J 6.5, C(4)H3), 1.18 (9H, s, CMe3),
1.35 (3H, d, J 6.6, C(a)Me), 2.01 (3H, s, NMe), 2.80 (1H,
dd, J 10.9, 2.9, C(2)H), 3.56 (1H, q, J 6.6, C(a)H), 3.96
(1H, dq, J 10.9, 6.5, C(3)H), 4.46 (1H, d, J 10.5, OH),
4.86 (1H, dd, J 10.5, 2.9, C(10)H), 7.19–7.35 (10H, m,
Ph); dC (50 MHz, CDCl3) 9.3 (C(4)H3), 21.9 (C(a)Me),
27.9 (CMe3), 32.5 (NMe), 53.0, 57.9, 63.1, 71.7 (C(2),
C(3), C(10), C(a)), 81.0 (CMe3), 125.4, 126.7, 127.0,
127.5, 128.1 (Pho, Phm, Php), 142.9, 146.2 (Phi), 183.8
(C(1)); m/z (ESI+) 384 ([M+H]+, 100%).
4.3.16. tert-Butyl (2S,3S,10S,aR)-2-(10-hydroxy-20,20-di-
methyl)propyl-3-[N-methyl-N-(a-methylbenzyl)amino]-
3-phenylpropanoate 27. Following general procedure 1,
BuLi (1.5 M in hexanes, 3.0 mL, 4.42 mmol) and di-iso-
propylamine (0.68 mL, 5.15 mmol) in THF (15 mL), 10
(500 mg, 1.47 mmol) in THF (15 mL), B(OMe)3 (0.66 mL,
5.9 mmol) and pivaldehyde (1.26 mL, 14.7 mmol) gave, after
purification by column chromatography (eluent 40–60 ꢁC
petrol/Et2O 7:1 then toluene/acetone 40:1), two partially
separable diastereoisomeric products (413 mg, 66% com-
bined yield).
Second to elute: a 67:33 mixture of two minor diastereoiso-
mers A and B (166 mg, 30%); m/z (ESI+) 384 ([M+H]+,
100%).
Selected data for A: dH (500 MHz, CDCl3) 0.96 (3H, d, J 6.5,
C(4)H3), 1.11 (9H, s, CMe3), 1.56 (3H, d, J 6.6, C(a)Me),
2.11 (3H, s, NMe), 2.74 (1H, dd, J 10.8, 9.5, C(2)H), 3.60
(1H, q, J 6.6, C(a)H), 3.91 (1H, dq, J 10.8, 6.5, C(3)H),
5.00 (1H, d, J 9.5, C(10)H), 7.23–7.45 (10H, m, Ph), 8.47
(1H, br s, OH); dC (50 MHz, CDCl3) 10.5, 21.4 (C(4)H3,
C(a)Me), 27.5 (CMe3), 32.8 (NMe), 56.0, 57.3, 62.9, 78.7
(C(2), C(3), C(10), C(a)), 80.7 (CMe3), 127.4, 127.7,
127.8, 128.7 (Pho, Phm, Php), 141.5, 143.7 (Phi), 171.1
(C(1)).
First to elute: 27 as a clear colourless oil (125 mg, 20%).
Found: C, 76.0; H, 9.4; N, 3.5%. C27H39NO3 requires: C,
76.2; H, 9.2; N, 3.3%. [a]2D2 +19.7 (c 1.0 in CHCl3); nmax
(film) 3500 (br, O–H), 1740 (C]O); dH (500 MHz,
CDCl3) 0.95 (9H, s, C(20)Me3), 1.25 (3H, d, J 6.8,
C(a)Me), 1.28 (9H, s, CMe3), 2.17 (3H, s, NMe), 3.28
(1H, dd, J 10.2, 4.6, C(2)H), 4.01 (1H, q, J 6.8, C(a)H),
4.12 (1H, d, J 4.6, C(10)H), 4.13 (1H, d, J 10.2, C(3)H),
7.15–7.42 (10H, m, Ph); dC (50 MHz, CDCl3) 10.0
(C(a)Me), 26.0, 27.7 (CMe3, C(20)Me3), 33.7 (NMe), 36.7
(C(20)Me3), 46.2, 56.4, 72.2, 77.2 (C(2), C(3), C(10),
C(a)), 80.7 (CMe3), 127.0, 128.0, 128.1, 128.2, 128.4,
130.1 (Pho, Phm, Php), 136.8, 141.6 (Phi), 171.1 (C(1));
m/z (CI, NH3) 426 ([M+H]+, 50%).
Selected data for B: dH (500 MHz, CDCl3) 1.26 (9H, s,
CMe3), 1.39 (3H, d, J 6.8, C(a)Me), 1.43 (3H, d, J 6.9,
C(4)H3), 2.21 (3H, s, NMe), 3.23 (1H, dd, J 9.5, 3.9,
C(2)H), 3.29 (1H, dq, J 6.9, 3.9, C(3)H), 4.31 (1H, q, J
6.8, C(a)H), 5.17 (1H, d, J 9.5, C(10)H), 7.11 (1H, br s,
OH), 7.22–7.49 (10H, m, Ph); dC (125 MHz, CDCl3) 13.0,
14.4 (C(4)H3, C(a)Me), 27.8 (CMe3), 32.7 (NMe), 53.5,
57.5, 57.8, 72.9 (C(2), C(3), C(10), C(a)), 80.7 (CMe3),
127.1, 127.2, 127.5, 128.0, 128.2 (Pho, Phm, Php), 141.3,
143.1 (Phi), 171.2 (C(1)).
Second to elute: a mixture of diastereoisomers as a colourless
oil (288 mg, 46%).
Third to elute: a minor diastereoisomer (80% de); selected
data: nmax (film) 3436 (br, O–H), 1716 (C]O); dH
(500 MHz, CDCl3) 0.95, 1.01 (2ꢂ9H, s, CMe3, C(20)Me3),
1.66 (3H, d, J 6.4, C(a)Me), 1.91 (3H, s, NMe), 3.14–3.19
(2H, m, C(2)H, C(a)H), 4.03 (1H, d, J 9.1, C(10)H), 4.82
(1H, d, J 11.2, C(3)H), 7.14–7.38 (10H, m, Ph), 8.70 (1H,
br s, OH); dC (50 MHz, CDCl3) 21.7 (C(a)Me), 26.0
(C(20)Me3), 27.0 (CMe3), 34.9 (NMe), 36.5 (C(20)Me3),
47.3, 62.1, 64.8, 81.9 (C(2), C(3),C(10), C(a)), 80.9
(CMe3), 127.2, 127.6, 128.0, 128.7, 130.6 (Pho, Phm, Php),
131.9, 143.9 (Phi), 172.2 (C(1)); m/z (CI, NH3) 426
([M+H]+, 30%).
4.3.18. tert-Butyl (2S,3R,4E,10R,aR)-2-(10-hydroxyethyl)-
3-[N-methyl-N-(a-methylbenzyl)amino]hex-4-enoate 29.
Following general procedure 1, BuLi (1.5 M in hexanes,
3.6 mL, 5.4 mmol) and di-iso-propylamine (0.88 mL,
6.3 mmol) in THF (60 mL), 24 (547 mg, 1.80 mmol) in
THF (20 mL), B(OMe)3 (0.61 mL, 5.4 mmol) and acetalde-
hyde (w1 mL, excess) gave, after exhaustive purification by
column chromatography (eluent 40–60 ꢁC petrol/Et2O 3:1),
two diastereoisomeric products (430 mg, 69% overall).
4.3.17. tert-Butyl (2S,3R,10S,aR)-2-(10-hydroxy)benzyl-
3-[N-methyl-N-(a-methylbenzyl)amino]butanoate 28.
Following general procedure 1, BuLi (1.5 M in hexanes,
2.95 mL, 4.33 mmol) and di-iso-propylamine (0.66 mL,
5.05 mmol) in THF (15 mL), 11 (400 mg, 1.44 mmol) in
THF (15 mL), B(OMe)3 (0.64 mL, 5.8 mmol) and benzalde-
hyde (1.47 mL, 14.4 mmol) gave, after exhaustive purifica-
tion by column chromatography (eluent 40–60 ꢁC petrol/
Et2O 12:1 then 40–60 ꢁC petrol/Et2O 6:1) three partially
separable diastereoisomeric products (298 mg, 54% com-
bined yield).
First to elute: a minor diastereoisomer as a white solid
(130 mg, 21%). Found: C, 72.4; H, 9.95; N, 3.8%.
C21H33NO3 requires: C, 72.6; H, 9.6; N 4.0%. Mp 76–
78 ꢁC; [a]D21 +61.6 (c 1.4 in CHCl3); nmax (KBr) 3450 (br,
O–H), 1726 (C]O); dH (300 MHz, CDCl3) 1.20 (3H, d, J
6.0, C(20)H3), 1.40 (9H, s, CMe3), 1.47 (3H, d, J 6.5,
C(a)Me), 1.72 (3H, dd, J 6.5, 1.2, C(6)H3), 1.96 (3H, s,
NMe), 2.47 (1H, app t, J 10.0, C(2)H), 3.45 (1H, q, J 6.5,
C(a)H), 4.01 (1H, app t, J 10.0, C(3)H), 4.16 (1H, dq, J
9.3, 6.0, C(10)H), 5.38 (1H, ddq, J 15.3, 9.6, 1.2, C(4)H),
5.66 (1H, dq, J 15.3, 6.5, C(5)H), 7.20–7.32 (5H, m, Ph),
7.91 (1H, br s, OH); dC (50 MHz, CDCl3) 17.9, 21.5 (C(6),
C(20), C(a)Me), 27.9 (CMe3), 34.4 (NMe), 54.7 (C(2)),
62.5, 63.7, 71.1 (C(3), C(10), C(a)), 80.6 (CMe3), 123.6
(C(5)), 127.1, 127.2, 128.6 (Pho, Phm, Php), 131.6 (C(4)),
First to elute: 28 as a clear colourless oil (132 mg, 24%).
Found: C, 75.4; H, 8.6; N, 3.2%. C24H33NO3 requires: C,
75.2; H, 8.7; N 3.65%. [a]2D2 +39.6 (c 0.25 in CHCl3); nmax

A. Chernega et al. / Tetrahedron 63 (2007) 7036–7046
7045
144.2 (Phi), 171.2 (C(1)); m/z (CI, NH3) 348 ([M+H]+,
80%).
J 10.3, C(10)H), 4.80 (1H, d, J 10.3, OH), 7.28–7.42 (5H,
m, Ph), 7.57 (1H, s, C(3)H); dC (125 MHz, CDCl3) 26.5,
28.1 (CMe3, C(20)Me3), 37.3 (C(20)), 76.5 (C(10)), 82.1
(CMe3), 128.0, 128.5, 128.6 (Pho, Phm, Php), 133.3, 135.6
(C(2), Phi), 140.6 (C(3)), 169.5 (C(1)); m/z (CI, NH3) 291
([M+H]+, 15%), 252 ([MꢀC4H8+NH4]+, 100%).
4.3.22. tert-Butyl (2E,10R)-2-(10-hydroxybenzyl)but-2-
enoate 33. Following general procedure 2, mCPBA
(72 mg, 0.21 mmol) in CHCl3 (5 mL) was added to 29
(40 mg, 0.10 mmol) in CHCl3 (5 mL) and the reaction was
quenched after 90 min. Purification by column chromato-
graphy (eluent 40–60 ꢁC petrol/Et2O 12:1) gave 34
(16 mg, 62%) as a colourless oil.37 [a]D22 ꢀ181.5 (c 0.25 in
CHCl3); nmax (CHCl3) 1685 (C]O); dH (500 MHz,
CDCl3) 1.36 (9H, s, CMe3), 1.96 (3H, d, J 7.3, C(4)H3),
4.12 (1H, d, J 11.0, OH), 5.68 (1H, d, J 11.0, C(10)H),
6.99 (1H, q, J 7.3, C(3)H), 7.23–7.38 (5H, m, Ph); dC
(50 MHz, CDCl3) 14.1 (C(4)), 28.0 (CMe3), 69.1 (C(10)),
81.7 (CMe3), 125.2, 128.2, 126.9 (Pho, Phm, Php), 134.7,
143.2 (C(2), Phi), 139.0 (C(3)), 166.5 (C(1)).
Second to elute: 29 as a clear colourless oil (300 mg, 48%).
Found: C, 72.3; H, 9.8; N, 4.3%. C21H33NO3 requires: C,
72.6; H, 9.6; N 4.0%. [a]2D1 +10.1 (c 1.6 in CHCl3); nmax
(film) 3433 (br, O–H), 1729 (C]O); dH (300 MHz,
CDCl3) 1.23 (3H, d, J 6.0, C(20)H3), 1.28 (3H, d, J 6.7,
C(a)Me), 1.45 (9H, s, CMe3), 1.75 (3H, d, J 6.0, C(6)H3),
2.07 (3H, s, NMe), 2.81 (1H, dd, J 9.5, 4.9, C(2)H), 3.57
(1H, dd, J 9.5, 4.9, C(3)H), 4.12 (1H, q, J 6.7, C(a)H),
4.25 (1H, dq, J 9.5, 6.0, C(10)H), 5.64 (1H, dq, J 15.3, 6.5,
C(5)H), 5.76 (1H, dd, J 15.3, 9.5, C(4)H), 6.45 (1H, br s,
OH), 7.19–7.31 (5H, m, Ph); dC (50 MHz, CDCl3) 12.8,
17.8, 22.1 (C(6), C(20), C(a)Me), 28.0 (CMe3), 33.1
(NMe), 53.5 (C(2)), 57.9, 66.7, 67.1 (C(3), C(10), C(a)),
80.5 (CMe3), 126.9, 127.0, 127.9, 128.1 (C(5), Pho, Phm,
Php), 130.5 (C(4)), 142.5 (Phi), 171.0 (C(1)); m/z (ESI+)
348 ([M+H]+, 100%).
4.3.19. tert-Butyl (2E,10R)-2-(10-hydroxybenzyl)-3-phe-
nylprop-2-enoate 30. Following general procedure 2,
mCPBA (194 mg, 0.45 mmol) in CHCl3 (5 mL) was added
to 25 (100 mg, 0.22 mmol) in CHCl3 (5 mL) and the reaction
was quenched after 1 h. Purification by column chromato-
graphy (eluent 40–60 ꢁC petrol/Et2O 12:1) gave 30
(44 mg, 63%) as a colourless oil.18 [a]D22 +209.3 (c 0.6 in
CHCl3); nmax (CHCl3) 3436 (br, O–H), 1707 (C]O); dH
(500 MHz, CDCl3) 1.36 (9H, s, CMe3), 3.89 (1H, d, J
11.7, OH), 5.83 (1H, d, J 11.7, C(10)H), 7.27–7.42 (10H,
m, Ph), 7.88 (1H, s, C(3)H); dC (125 MHz, CDCl3) 27.9
(CMe3), 69.5 (C(10)), 82.2 (CMe3), 125.3, 127.0, 128.3,
128.6, 128.9, 129.1 (Pho, Phm, Php), 134.2, 134.6 (Phi),
141.1 (C(3)), 143.3 (C(2)), 166.8 (C(1)); m/z (CI, NH3)
311 ([M+H]+, 8%), 254 (100%).
4.3.23. tert-Butyl (2E,4E,10R)-2-(10-hydroxyethyl)hexa-
2,4-dienoate 34. Following general procedure 2, mCPBA
(340 mg, 0.99 mmol) in CHCl3 (8 mL) was added to 29
(171 mg, 0.49 mmol) in CHCl3 (5 mL) and the reaction
was quenched after 2 h. Purification by column chromato-
graphy (eluent 40–60 ꢁC petrol/Et2O 5:1) gave 34 as a
colourless oil (73 mg, 70%). Found: C, 68.1; H, 9.3%.
C12H20O3 requires: C, 67.9; H, 9.5%. [a]2D1 +18.2 (c 1.8 in
CHCl3); nmax (CHCl3) 3520 (br, O–H), 1675 (C]O); dH
(300 MHz, CDCl3) 1.42 (3H, d, J 6.6, C(20)H3), 1.52 (9H,
s, CMe3), 1.87 (3H, d, J 6.8, C(6)H3), 3.74 (1H, br s, OH),
4.80 (1H, br s, C(10)H), 6.13 (1H, dq, J 14.7, J 6.8,
C(5)H), 6.42 (1H, dd, J 14.7, 11.5, C(4)H), 6.98 (1H, d, J
11.5, C(3)H); dC (50 MHz, CDCl3) 18.9, 23.6 (C(6),
C(20)), 28.2 (CMe3), 65.3 (C(10)), 81.3 (CMe3), 125.9
(C(5)), 131.6 (C(2)), 138.1, 139.7 (C(3), C(4)), 167.3
(C(1)); m/z (CI, NH3) 213 ([M+H]+, 40%).
4.3.20. tert-Butyl (2E,10R)-2-(10-hydroxy-20-methyl)-
propyl-3-phenylprop-2-enoate 31. Following general pro-
cedure 2, mCPBA (209 mg, 0.49 mmol) in CHCl3 (5 mL)
was added to 26 (100 mg, 0.24 mmol) in CHCl3 (5 mL)
and the reaction was quenched after 1 h. Purification by col-
umn chromatography (eluent 40–60 ꢁC petrol/Et2O 15:1)
gave 31 (44 mg, 66%) as a colourless oil. [a]2D2 ꢀ12.8 (c
0.1 in CHCl3); nmax (CHCl3) 1685 (C]O); dH (500 MHz,
CDCl3) 0.71 (3H, d, J 6.9, C(20)MeA), 1.02 (3H, d, J 6.6,
C(20)MeB), 1.57 (9H, s, CMe3), 1.99–2.06 (1H, m,
C(20)H), 3.38 (1H, d, J 11.2, OH), 4.18 (1H, dd, J 11.2,
9.3, C(10)H), 7.31–7.41 (5H, m, Ph), 7.61 (1H, s, C(3)H);
dC (125 MHz, CDCl3) 19.5, 19.7 (C(20)Me2), 28.2 (CMe3),
33.7 (C(20)), 74.9 (C(10)), 81.9 (CMe3), 128.3, 128.5,
129.0 (Pho, Phm, Php), 135.0, 135.1 (C(2), Phi), 167.7
(C(1)); m/z (CI, NH3) 277 ([M+H]+, 10%), 238
([MꢀC4H8+NH4]+, 100%).
References and notes
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4.3.21. tert-Butyl (2E,10R)-2-(10-hydroxy-20,20-dimethyl)-
propyl-3-phenylprop-2-enoate 32. Following general pro-
cedure 2, mCPBA (132 mg, 0.31 mmol) in CHCl3 (5 mL)
was added to 27 (65 mg, 0.16 mmol) in CHCl3 (5 mL) and
the reaction was quenched after 1 h. Purification by column
chromatography (eluent 40–60 ꢁC petrol/Et2O 12:1) gave 32
(26 mg, 59%) as a colourless oil. [a]2D2 ꢀ230.7 (c 0.45 in
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31. HPLC performed using a Daicel ChiralPak OD column with
a solvent system of iso-propanol/hexanes 5:95; flow rate
1.0 mL minꢀ1; retention times: (S)-enantiomer 9 min, (R)-
enantiomer 16 min.
32. A known scalemic mixture of lithium N-methyl-N-(a-methyl-
benzyl)amide 9 (33% ee, enriched in (R)-9) was used in the
same three-step protocol (conjugate addition, aldol and Cope
elimination) to generate authentic material of 33% ee to allow
unambiguous ee determination.
33. The major diastereoisomer in each case was assigned the syn-
configuration by analogy to that unambiguously confirmed
upon aldol reaction of 10 and 11 with acetaldehyde.
34. HPLC performed using a Daicel ChiralPak OD column with
a solvent system of iso-propanol/hexanes 5:95; flow rate
1.0 mL minꢀ1; retention times: (S)-enantiomer 11 min, (R)-
enantiomer 18 min.
35. Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2,
183.
23. For selected uses of lithium N-methyl-N-(a-methylbenzyl)-
amide 9 in asymmetric synthesis, see: (a) Davies, S. G.;
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Kruchinin, D.; Roberts, P. M.; Smith, A. D.; Rodriguez-Solla,
H. Chem. Commun. 2006, 2664.
36. Watkin, D. J.; Prout, C. K.; Carruthers, J. R.; Betteridge, P. W.;
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