Atropisomeric amides: Stereoselective enolate chemistry and enantioselective synthesis via a new SmI2-mediated reduction

Article abstract of DOI:10.1039/a901154d

The use of certain types of atropisomeric amides, incorporating an N-MEM-ortho-tert-bityariume group, for stereoselective reactions, has been explored. Enolate reactions of these systems are highly diastereocontrolled, and enantiomerically enriched starting materials can be obtained, starting from lactic acid, via a new SmI2 mediated reduction process.

Full text of DOI:10.1039/a901154d

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Atropisomeric amides: stereoselective enolate chemistry and
enantioselective synthesis via a new SmI2-mediated reduction
Adam D. Hughes, David A. Price and Nigel S. Simpkins*
School of Chemistry, The University of Nottingham, University Park, Nottingham,
UK NG7 2RD
Received (in Cambridge) 1st February 1999, Accepted 23rd March 1999
The use of certain types of atropisomeric amides, incorporating an N-MEM-ortho-tert-butylaniline group, for
stereoselective reactions, has been explored. Enolate reactions of these systems are highly diastereocontrolled,
and enantiomerically enriched starting materials can be obtained, starting from lactic acid, via a new SmI2
mediated reduction process.
substituent R, as described in our initial communication in this
Introduction
area, vide infra.2
In 1994 a report from Curran’s group described the powerful
stereodirecting potential of certain types of axially twisted
amides.1 For example, atropisomeric amide 1 was shown to
undergo a cycloaddition reaction with a nitrile oxide to give
product 2, rather than 3, with excellent levels of diastereo-
control, Scheme 1. In such reactions the formation of products
In addition to the question of diastereocontrol in this type
of reaction is the issue of availability of the starting atrop-
isomeric amides in enantiomerically enriched form. Although
we managed to acquire small amounts of enantiomerically
enriched atropisomeric amide by means of a rather inefficient
kinetic resolution procedure, it was Taguchi and co-workers
who first described an effective access to these compounds via a
chiral pool approach.3,4 For example, they were able to prepare
(ϩ)-6 in 96% ee, starting from (S)-O-acetyllactic acid, and
also demonstrated further highly stereocontrolled chemistry
of these compounds, such as an iodine-activated Diels–Alder
cycloaddition to generate 7, Scheme 3.
O
Me
N
tBu
tBu
O
O
H
1
N
N
PhCNO
tBu
I2, AcOEt
tBu
O
O
Me
Me
Ph
Ph
N
N
+
tBu
tBu
O
O
(+)-6 (96% ee)
7 (87%)
N
N
Scheme 3
tBu
tBu
>97 : 3
Our contemporaneous studies of the chiral pool approach to
these atropisomeric amides followed a similar strategy, and
unearthed a new samarium-mediated reduction reaction.5 In
this paper we provide full details of this work, along with the
previous studies of enolate alkylation and aldol reaction.
3
2
Scheme 1
having stereogenic centres is controlled by the chiral aryl-C–N
axis in the starting material. Radical reactions with these amide
systems, and also with related cyclic imides, were also found to
proceed with good selectivity.
Our own interest in this area lay in the possibility of using
this type of stereocontrol in reactions of enolates, for example
the diastereocontrolled alkylation of 4 to give 5, Scheme 2.
This type of reaction posed special problems, which we were
able to solve only by careful choice of the additional nitrogen
Enolate chemistry with racemic atropisomeric amides
Our initial experiments involved alkylation reactions of the
lithium enolate derived from anilide 8 by treatment with
LDA. These reactions gave the desired products 9 in good
chemical yield but with very modest diastereoselectivities of
around 2–4:1 (Scheme 4). Since with a bulky amide such as
O
O
Y
O
Y
O
R
N
LDA, THF
R–X
R
N
N
LDA, THF
N
tBu
tBu
R
tBu
E
tBu
electrophile
(E+)
8 Y = Me
10 Y = MEM
9 Y = Me
11 Y = MEM
4
5
Scheme 2
Scheme 4
J. Chem. Soc., Perkin Trans. 1, 1999, 1295–1304
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Table 1 Yields and diastereoselectivities in enolate reactions of amide
8 the (Z)-enolate should be efficiently formed, we attributed
this poor level of selectivity to the possibility of rotation
around the amide C–N bond in the intermediate enolate,
as illustrated by 12. An obvious approach to controlling the
10
Electrophile
PhCH2Br
Yield 11 (%)
Diastereomer ratio
83
82
89
69
84
25:1
15:1
H2C᎐CHCH2Br
᎐
O
Li
EtI
15:1
PhCH᎐CHCH2Cl
>25:1a
>25:1a
᎐
OH
O
O
O
Me
PhSSO2Ph
MEM
tBu
LiO
N
N
N
a Only one diastereomer observed by NMR spectroscopy.
R
tBu
tBu
Me
Table 2 Yields and diastereoselectivities in aldol reactions of amide 10
12
13
14
Aldehyde
Yield 14 (%)a
Me
PhCHO
87
85
89
87
86
tBu
N
O
H
OH
O
Me2CHCHO
C6H11CHO
Me3CCHO
EtCHO
O
O
R
tBu
Li
O
N
R
H
Me MEM
a The syn-aldol product only was observed, all atropselectivities >25:1.
15
16
conformation of such enolates would be to introduce a metal
co-ordinating group Y into the N-substituent. Initial attempts,
using imide type derivatives with Y = Boc or COtBu were
unrewarding, these compounds not forming enolates, but in
the latter case acting as an acylating agent. We turned instead
to the N-MEM derivative 10, which we hoped might fix the
conformation of the enolate by co-ordination, as shown in 13.
Pleasingly, the enolate reactions of 10, with simple electro-
philes, such as alkyl halides, proved much more stereoselective
than those involving 8, Table 1.
In each case we assumed that the major product was 11, corre-
sponding to reaction on the face of the enolate not shielded by
the ortho-tert-butyl group, which is consistent with all of the
literature chemistry, and with our later findings, vide infra.
NMR spectra of the crude products were very clean, and in
each case we were able to identify the minor diastereoisomer by
thermal atropisomerisation. For example, elevated temperature
NMR studies showed that the isomer ratio of 11 (R = Bn)
changed from 25:1 to only 2:1 after warming to 95 ЊC for
65 minutes.
nuisance since it interfered with NMR analysis of the product
ratios. Although we were reasonably confident that we could
identify minor conformers by running NMR spectra in dif-
ferent solvents, we double-checked the initial selectivity figures
by HPLC and found good agreement (i.e. there was at least a
25:1 ratio of isomers in every case).
Having demonstrated useful levels of diastereocontrol in
preliminary enolate reactions of atropisomeric amides, the next
immediate problem related to the release of chiral products
from the anilide. A major disadvantage of these systems is
the reluctance of the sterically hindered anilide to under-
go hydrolysis to the corresponding carboxylic acid. Despite
extensive efforts, involving the screening of many types of
conditions we were unable to achieve this type of conversion.
Curran has also commented upon this deficiency, and has
examined alternative derivatives in which one of the methyls
of the tert-butyl group is replaced by a trialkylsilyloxy group.
Unfortunately, although these compounds show improved
hydrolytic behaviour, the aryl C–N rotational barrier is
somewhat reduced, leading to easier racemisation, and the
compounds also seem to react with a lower degree of selectivity.
Instead, we demonstrated that release of chiral compounds
is possible by reductive means, for example conversion of 11
into 17, using either LiAlH4 or LAB (lithium amidotrihydro-
borate),8 and conversion of the aldol product 14 (R = Ph) into
diol 18, Scheme 5.
We also examined the aldol reactions of 10, involving
addition of achiral aldehydes to the lithium enolate in THF,
Table 2.
With a range of bulky or branched chain aldehydes, and even
with propanal, the aldol products 14 were obtained with very
good diastereoselectivity. The lability of the MEM group in
the starting amide 10 precluded the use of alternative aldol
strategies, involving the use of TiCl4 or Bu2BOTf.6 We antici-
pated that the major aldol product would be the syn-isomer 14
resulting from reaction of a (Z)-lithium enolate, via a transition
state such as 15, in which the bulky ortho-tert-butyl group in
the enolate is orientated away from the approaching aldehyde.
This expectation was confirmed following a single crystal
X-ray structure determination for the product 14 (R = Ph)
from reaction with benzaldehyde, as revealed in our initial
communication.2
A problem with determining the degree of stereoselectivity
in these aldol reactions was the presence of additional con-
formers, compared to simple alkylations. Although we could
reasonably assign the atropselectivities indicated (i.e. with
respect to the anilide aryl C–N axis), the NMR spectra of the
aldol products also showed additional minor signals attributed
to amide C–N rotamers (E/Z rotamers), e.g. 16. This problem
has been discussed by Curran in a recent full paper in which he
explores the conformational aspects of a wide range of anilides,
and in which he coins the term “prochiral auxiliary” to describe
this approach to asymmetric synthesis.7 In our case, the
presence of minor (Z)-conformers in the products was a
O
MEM
N
OH
(i) (80%)
tBu
or (ii) (73%)
Ph
Ph
(±)17
11 R = Bn
OH
O
OH
MEM
(i)
N
Ph
tBu
OH
Ph
(68%)
Me
Me
(±) 18
14 R = Ph
Scheme 5 Reagents and conditions: (i) LiAlH4, THF, room temp.; (ii)
LAB, THF, room temp.
In the first case we have repeated the cleavage with enantio-
merically enriched material (vide infra) and demonstrated
little or no loss in enantiomeric purity. In the case of 18 our
observation of a single stereoisomer again indicates that
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product epimerisation is not a problem. If desired it should be
possible to oxidise such compounds to give the corresponding
aldehydes or carboxylic acid derivatives.
A final area of exploration involved examining the corre-
sponding reactions of homologues of 10, namely the phenethyl
derivative 19 and the isobutyl variant 20. Unfortunately the
good results). Anilide 23 was then N-alkylated with MEMCl
in order to install the required MEM group, which furnished
the two separable atropisomeric products 24a and 24b. At this
point it was not possible to assign the relative stereochemistry
of the aryl-C–N axis, which was deduced following subsequent
transformations.
At this point we required a deoxygenation reaction in order
to convert each of the diastereomeric amides 24 into the corre-
sponding enantiomeric products 10. It was anticipated that a
direct deoxygenation should be possible using SmI2, which has
been used extensively in such reactions, but mainly involving
α-heteroketones.10 A search of the literature revealed a dearth
of such amide reductions and established that SmI2 had not
been previously applied to amide deoxygenation.11 Initial reac-
tions of amides 24 with SmI2 under standard conditions were
somewhat sluggish, and only by adopting the recently reported
protocol, involving addition of LiCl to the reaction mixture,
were acceptable yields obtained.12 This new reaction, the scope
of which is outlined in more detail below, allowed us to isolate
the required enantiomeric atropisomers 10 in good yield. The
enantiomeric excess of these compounds proved difficult to
determine, but was established to be у93% following con-
version to the corresponding α-methylated compounds 25. The
absolute configurations shown were deduced following further
transformations, vide infra. At this point it is appropriate to
compare our route with that of the Taguchi group, who also
used this type of approach to access anilides such as 6. Their
sequence involved combining 22 with 26, furnishing directly the
mixture of atropisomers, of which 27 was the major isomer,
Scheme 7.
O
O
MEM
tBu
MEM
tBu
Ph
N
N
rac-19
rac-20
enolate chemistry of these compounds was more complicated
than for 10, with 19 proving difficult to alkylate cleanly (giving
starting material–product mixtures) and the E/Z rotamer
complications discussed above being far more evident for
products from 20. At this point we chose to concentrate activity
in the complementary area of work aimed at the synthesis of
non-racemic anilides.
A chiral pool approach to non-racemic atropisomeric
anilides
Although there are several conceivable approaches to our
atropisomeric anilides in non-racemic form, including asym-
metric synthesis and biocatalysis methods, we chose to con-
centrate on a method which would supply both enantiomers in
highly enantiomerically enriched form. The route adopted is
shown in Scheme 6, and involves manipulation of commercially
O
HN
O
N
O
O
O
tBu
tBu
(i)
(ii)
H
OAc
EDC
OH
N
OH
OH
+
tBu
(90%)
(82%)
OAc
AcO
CH2Cl2
OH
21
OAc
27 (56%)
22
26
(–)-23
(–)-22
Scheme 7
(iii)
It can be seen that this result differs somewhat from our
experience in that 27 corresponds to 24b, which we obtained as
the minor isomer. That such differences in ratios are observed
is not in the least surprising, given the different nitrogen
substituents present, and also the different types of reaction
in which the chiral C–N axis is established (amide coupling
in the case of 26, amide N-alkylation for 24). We were denied
the possibility of accessing amides 24 by an amide coupling
analogous to that shown in Scheme 7 by the instability of the
required N-MEM aniline. Conversion of 27 into 6 required
acetate hydrolysis, alcohol activation by formation of the
mesylate, selenide displacement and selenoxide syn-elimination.
With highly enantiomerically enriched atropisomeric amides
10 in hand, we were able to repeat some of the chemistry
illustrated earlier in Scheme 5 to access non-racemic products.
In particular, we took each of the enantiomers (ϩ)- and (Ϫ)-10
and carried out benzylation followed by reductive removal
of the auxiliary to give the primary alcohols (Ϫ)- and (ϩ)-17
respectively, as shown in Scheme 8.
Since the absolute configurations of these alcohol products
are well established in the literature,13 we were able to assign the
configuration of the asymmetric carbon centre in the precursor
amides 11, and hence infer the configuration of the aryl
C–N axis to be as shown in 10, 11 and 24. Comparison of
optical rotation data also indicated that the optical purity of
these compounds (ca. 93%) correlated well with the established
enantiomeric excess of the precursor amides 10.
O
O
MEM
tBu
MEM
tBu
N
N
X
+
X
(–)-24b (X = OAc, 25%)
(–)-10 (X = H, 73%)
(+)-24a (X = OAc, 41%)
(+)-10 (X = H, 65%)
(iv)
(iv)
O
MEM
N
tBu
25 (either enantiomer)
Scheme 6 Reagents and conditions: (i) AcCl, AcOH; (ii) EDCؒHCl,
CH2Cl2; (iii) NaH, THF, 0 ЊC then MEMCl; (iv) Sml2 (4 equiv.), LiCl
(12 equiv.), THF, room temp.
available -(ϩ)-lactic acid 21 (ca. 98% ee) in what amounts to a
resolution procedure.
Acetylation of 21 gave the O-acetyl derivative 22, which was
then coupled with 2-tert-butylaniline using established peptide
coupling techniques.9 We found the yields of anilide 23 to be
modest using many methods, the use of 3-ethyl-1-[3-(dimethyl-
amino)propyl]carbodiimide hydrochloride (EDCؒHCl) giving
the best results (in related work the pyBOP reagent also gave
One additional aspect of this chemistry which was briefly
explored is illustrated in Scheme 9. By a sequence analogous to
that shown in Scheme 6 for the O-acetyl series, we were also able
J. Chem. Soc., Perkin Trans. 1, 1999, 1295–1304
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O
O
required that this is not a particularly facile process. Never-
MEM
tBu
MEM
tBu
theless, the reaction seems fairly general for different types of
tertiary amide, and effects the removal of α-bromo, α-acetoxy
and α-benzyloxy functions. In general we found it necessary to
add LiCl to the reactions (Method A), although entries 4–6
show that debromination is rather more facile, and works well
enough with SmI2 alone (Method B). Debromination of a
secondary amide is facile (entry 6), but other secondary amides
gave either very poor yields of product (entry 9) or no reduction
at all (entry 10). In the latter case only the hydroxy amide
resulting from acetate cleavage was obtained (52%).
N
N
OH
(i)
(ii)
Ph
83%
49%
Ph
(+)-10
(–)-10
(+)-11 R = Bn
(–)-11 R = Bn
(–)-17
(+)-17
(i)
(ii)
80%
60%
Scheme 8 Reagents and conditions: (i) LDA, THF, PhCH2Br; (ii)
LiAlH4, THF.
O
O
Conclusions
MEM
tBu
MEM
tBu
LDA
R–X
N
N
Although several groups have now established the credibility of
a chiral C–N axis as a stereocontrolling element for asymmetric
synthesis a number of problems with this approach remain to
be solved. Foremost amongst these is the need to establish more
direct and efficient entries to the chiral amides (and imides,
etc.) in enantiomerically pure form; clearly the chiral pool
approach described above is not ideal. Other considerations
include the development of alternative motifs for the chiral
axis, which will allow easier manipulation of chiral products. If
these types of difficulty can be overcome then the application of
the “prochiral auxiliary” method to a wider range of reactions
may become an attractive area for future exploration.
BnO
BnO R
28
29
Scheme 9
to prepare the corresponding O-benzyl compounds, including
28 (as a separate atropisomer). It appeared possible that this
compound could be alkylated stereoselectively via the corres-
ponding enolate, which would give rise to amide derivatives
of general structure 29. This process would amount to a
novel version of the “self-replication of chirality” principle,
developed extensively by Seebach and co-workers,14 and would
allow the preparation of chiral α-alkoxy carboxylic acids
and related products. Unfortunately, under a variety of con-
ditions, we were unable to effect efficient enolate formation and
alkylation. This problem is no doubt related to the difficulty we
experienced in hydrolysing substituted amides 11, and is due
to the highly hindered nature of such systems.
Experimental
General procedures
Melting points were determined on a Reichert Hot Stage
apparatus and are uncorrected. Infrared spectra were recorded
using a Perkin-Elmer 1600 series FTIR spectrophotometer as
either sample solutions in chloroform or films. High resolution
mass spectra were acquired on a VG Micromass 70E or AEI
MS-902 mass spectrometer using electron impact (EI), chemical
ionization (CI) or fast atom bombardment (FAB) using meta-
nitrobenzyl alcohol (NBA) as the matrix. Microanalytical data
were obtained on a Perkin-Elmer 240B elemental analyser.
Optical rotations were recorded using a JASCO DIP-370
digital polarimeter. Proton NMR spectra were recorded on a
Bruker WM 250 (250 MHz), a Bruker AM 400 (400 MHz), a
Bruker DRX 500 (500 MHz) or a JEOL EX-270 (270 MHz)
spectrometer either at ambient temperature or 333 K. The
chemical shifts were recorded relative to an internal tetra-
methylsilane standard. All coupling constants, J, are reported
in Hertz and abbreviations used are s - singlet, d - doublet, t
- triplet, q - quartet, m - multiplet, dd - double doublet etc.,
also br s - broad singlet, br d - broad doublet etc. The ratio of
isomer mixtures were determined using 1H NMR spectroscopy.
Carbon-13 NMR spectra were either recorded on a JEOL EX
270 (68 MHz) spectrometer or a Bruker AM 400 (100 MHz)
at ambient temperature. The multiplicities indicated were
obtained using a DEPT sequence. Proton and carbon assign-
A new SmI2-mediated reduction of á-functionalised
amides
Since the type of amide deoxygenation described above
appeared rather rare, and the application of SmI2 to such amide
reduction was unprecedented,15 we applied the new method to
a range of other amides, according to Scheme 10, as shown
in Table 3.
The reductions have not been fully optimised, and it is clear
from the extended reaction time of at least 24 hours that is
O
O
R
R'
Method A or B
R
R'
N
N
X
R"
R"
A - SmI2 (4 equiv.), LiCl (12 equiv.), THF
B - SmI2 (4 equiv.), THF
Scheme 10
Table 3 SmI2 Reduction of amides
Entry
R
RЈ
RЉa
X
Methodb
Product
Yield (%)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
CH2Ph
CH2Ph
CH2Ph
CH2Ph
Me
MEM
Me
Me
Me
H
Ph
Ar
Ar
Ar
Ph
Ar
Et
OAc
OBn
OBn
Br
Br
Br
OAc
OAc
OAc
OAc
A
A
A
B
B
B
A
A
A
A
30
10
31
31
30
32
33
34
35
36
85
69
50
57
72
72
69
60
13
0c
Et
RЈ/RЉ = pyrrolidine
H
H
CH2Ph
tBu
10
a Ar = 2-tert-butylphenyl. b See Experimental section for descriptions of Methods A and B. c No reduction observed, see text.
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ments were frequently assisted by obtaining 1H–1H COSY and
1H–13C COSY spectra, which were recorded on a JEOL EX 270
spectrometer. Reaction progress was monitored by thin layer
chromatography (TLC) using Merck silica gel 60 F254 precoated
plates which were visualised with ultraviolet light and
developed by staining with either basic potassium per-
manganate solution or acidic ammonium molybdate().
Liquid chromatography was performed using forced flow (flash
chromatography) with the indicated solvent system on Fluka
silica gel 60 (220–440 mesh).
Organic solvents and reagents were dried from the following
as required: THF and Et2O (sodium–benzophenone ketyl),
methanol (from magnesium methoxide onto 3 Å molecular
sieves), CH2Cl2 and chlorotrimethylsilane (calcium hydride).
Petroleum ether refers to light petroleum (bp 40–60 ЊC) which
was distilled prior to use. All other reagents were used as
received from commercial suppliers unless otherwise stated.
Typical procedure for enolate reactions of 10: benzylation of 10
to give (Ra*,2S*)-N-(2-tert-butylphenyl)-N-(2-methoxyethoxy-
methyl)-2-methyl-3-phenylpropionamide 11 (R ؍ Bn)
nBuLi (0.81 ml of a 1.60 M solution in hexanes, 1.30 mmol) was
added in one portion to a stirred solution of diisopropylamine
(0.20 ml, 1.50 mmol) in THF (10 ml) at Ϫ78 ЊC, under an
atmosphere of nitrogen, followed by warming to 0 ЊC for 15
min. To the resulting solution of LDA at Ϫ78 ЊC, a solution of
the anilide (293 mg, 1.00 mmol) in THF (1 ml) was added
dropwise. After 30 min benzyl bromide (0.24 ml, 2.00 mmol)
was added in one portion and the reaction mixture stirred for
30 min at Ϫ78 ЊC, followed by addition of saturated aqueous
NaHCO3 (2.5 ml) and then warming to room temperature. The
reaction mixture was extracted with Et2O (3 × 30 ml), the com-
bined organic extracts were washed with saturated aqueous
NaHCO3 (10 ml), brine (30 ml), dried (MgSO4) and evaporated
under reduced pressure. The resulting yellow oil was purified by
column chromatography (20% EtOAc–light petroleum) to yield
the title compound as a pale yellow oil (340 mg, 0.89 mmol,
89%) (Found: C, 75.41; H, 9.01; N, 3.53. C24H33NO3 requires C,
75.16; H, 8.67; N, 3.65%); νmax (CHCl3)/cmϪ1 2931, 1657, 1602,
1488, 1364, 1099, 908; δH (250 MHz, CDCl3) 0.98 (3H, t, J 6.1,
CH3CH), 1.32 (9H, s, (CH3)3C), 2.48 (2H, m, PhCH2), 3.05
(1H, m, CH3CH), 3.38 (3H, s, CH3O), 3.55 (2H, m, CH2OCH3),
3.81 (2H, m, NCH2OCH2), 4.39 (1H, d, J 10.0, NCH2O), 5.82
(1H, d, J 10.0, NCH2O), 6.76 (2H, m, ArH), 7.02 (1H, dd,
J 7.8, 1.5, ArH), 7.15 (4H, m, ArH), 7.37 (1H, ddd, J 7.8, 7.8,
1.5, ArH), 7.56 (1H, dd, J 7.8, 1.5, ArH); δC (68 MHz, CDCl3)
15.3 (CH3), 32.3 (CH3), 36.1 (C), 39.6 (CH), 40.5 (CH2), 58.8
(CH3), 68.9 (CH2), 71.8 (CH2), 78.4 (CH2), 126.1 (CH), 126.7
(CH), 128.0 (CH), 128.6 (CH), 128.9 (CH), 129.8 (CH), 132.5
Synthesis of N-2-tert-butylphenyl-N-(2-methoxyethoxymethyl)-
propionamide 10
(i) N-(2-tert-Butylphenyl)propionamide. Propionyl chloride
(4.00 g, 43.23 mmol) was added dropwise to a stirred solution
of 2-tert-butylaniline (7.10 g, 47.55 mmol) and NaOH (1.90 g,
47.55 mmol), in Et2O (200 ml) and water (200 ml) at 0 ЊC,
followed by warming to room temperature for 2 h. The reaction
mixture was poured onto 2 M NaOH (50 ml) and extracted
with Et2O (3 × 50 ml), the combined organic extracts were
washed with brine (50 ml), dried (MgSO4) and evaporated
under reduced pressure. The resulting white solid was recrystal-
lised from light petroleum to give the desired amide as a white
crystalline solid (7.88 g, 38.38 mmol, 89%), mp 119–120 ЊC
(Found: C, 76.24; H, 9.40; N, 6.67. C13H19NO requires C, 76.10;
H, 9.26; N, 6.83%); νmax (CHCl3)/cmϪ1 3467, 1681, 1578, 1493,
1365, 1293, 1091; δH (270 MHz, CDCl3) 1.28 (3H, t, J 7.3,
CH3CH2), 1.40 (9H, s, (CH3)3C), 2.42 (2H, q, J 7.3, CH3CH2),
7.21 (3H, m, ArH and NH), 7.38 (1H, d, J 7.3, ArH), 7.54
(1H, d, J 7.3, ArH); δC (68 MHz, CDCl3) 9.6 (CH3), 30.4 (CH2),
30.6 (CH3), 34.5 (C), 126.1 (CH), 126.4 (CH), 126.5 (CH),
(CH), 138.3 (C), 139.1 (C), 145.9 (C), 177.8 (C᎐O); m/z (EI) 326
᎐
(Mϩ Ϫ tBu, 97%), 250 (10), 162 (20), 146 (42), 119 (45), 89
(100).
Allylation of 10 to give (Ra*,2S*)-N-(2-tert-butylphenyl)-N-(2-
methoxyethoxymethyl)-2-methylpent-4-enamide 11 (R ؍ allyl).
Reaction of 10 according to the procedure described above gave
a crude product as a pale yellow oil, which was purified by flash
column chromatography (20% EtOAc–light petroleum) to give
the title compound as a colourless oil (250 mg, 75%) (Found:
C, 71.95; H, 9.74; N, 4.08. C20H31NO3 requires C, 72.04; H,
9.37; N, 4.20%); νmax (film)/cmϪ1 2971, 1666, 1598, 1488, 1088,
914, 733; δH (400 MHz, CDCl3) 1.04 (3H, d, J 6.5, CH3CH),
1.31 (9H, s, (CH3)3C), 2.18 (1H, m, CH3CH), 2.34 (2H, m,
128.6 (CH), 135.1 (C), 143.1 (C), 172.2 (C᎐O); m/z (EI) 205
᎐
(Mϩ, 55%), 148 (100), 134 (100), 106 (24), 91 (23).
(ii) N-2-tert-Butylphenyl-N-(2-methoxyethoxymethyl)propion-
amide 10. To a stirred suspension of NaH (1.22 g of a 60%
dispersion in oil, 30.39 mmol) in THF (10 ml) at 0 ЊC, under
an atmosphere of nitrogen, was added dropwise a solution of
the anilide prepared as described above (2.08 g, 10.13 mmol) in
THF (10 ml), with vigorous evolution of hydrogen. After 15
min MEMCl (2.89 ml, 25.33 mmol) was added in one portion
and the reaction mixture was stirred at 0 ЊC for 1 h. MeOH
(5 ml) was then cautiously added and the reaction mixture
poured onto water (50 ml) and extracted with EtOAc (3 ×
50 ml). The combined organic extracts were dried (MgSO4)
and evaporated under reduced pressure to yield a pale yellow oil
that was subsequently purified by bulb to bulb distillation
(160 ЊC/1 mmHg) to give 10 as a pale yellow oil (2.61 g, 8.90
mmol, 88%); νmax (film)/cmϪ1 2967, 1673, 1598, 1488, 1242,
1081, 761; δH (400 MHz, CDCl3) 1.06 (3H, t, J 7.4, CH3CH2),
1.32 (9H, s, (CH3)3C), 2.03 (2H, m, CH3CH2), 3.38 (3H, s,
CH3O), 3.56 (2H, m, CH2OCH3), 3.77 (1H, ddd, J 9.1, 5.6,
3.4, NCH2OCH2), 3.85 (1H, ddd, J 9.1, 5.6, 3.4, NCH2OCH2),
4.36 (1H, d, J 10.0, NCH2O), 5.81 (1H, d, J 10.0, NCH2O),
7.12 (1H, d, J 7.7, ArH), 7.22 (1H, dd, J 7.7, 7.7, ArH), 7.33
(1H, dd, J 7.7, 7.7, ArH), 7.54 (1H, d, J 7.7, ArH); δC (68 MHz,
CDCl3) 8.9 (CH3), 28.6 (CH2), 32.0 (CH3), 35.9 (C), 58.8 (CH3),
68.8 (CH2), 71.7 (CH2), 78.2 (CH2), 126.8 (CH), 128.5 (CH),
CH CH᎐CH ), 3.34 (3H, s, CH O), 3.55 (2H, m, CH OCH ),
᎐
2
2
3
2
3
3.76 (1H, ddd, J 9.1, 5.6, 3.4, NCH2OCH2), 3.88 (1H, ddd,
J 9.1, 5.6, 3.4, NCH2OCH2), 4.36 (1H, d, J 10.0, NCH2O), 4.92
(2H, m, CH CH᎐CH ), 5.51 (1H, m, CH CH᎐CH ), 5.80
᎐
᎐
2
2
2
2
(1H, d, J 10.0, NCH2O), 7.30 (3H, m, ArH), 7.53 (1H, d, J 7.8,
ArH); δC (68 MHz, CDCl3) 15.1 (CH3), 32.2 (CH3), 36.9 (C),
38.5 (CH2), 58.7 (CH3), 68.8 (CH2), 71.7 (CH2), 78.2 (CH2),
116.7 (CH2), 128.4 (CH), 128.5 (CH), 129.6 (CH), 132.4 (CH),
135.1 (CH), 138.3 (CH), 145.6 (C), 177.7 (C᎐O); m/z (EI)
᎐
276 (Mϩ Ϫ tBu, 100%), 258 (10), 228 (18), 178 (23), 162 (71),
146 (98).
Alkylation of 10 with EtI to give (Ra*,2S*)-N-(2-tert-
butylphenyl)-N-(2-methoxyethoxymethyl)-2-methylbutanamide
11 (R ؍ ethyl). Reaction of 10 according to the procedure
described above gave a crude product as a pale yellow oil, which
was purified by flash column chromatography (20% EtOAc–
light petroleum) to give the title compound as a colourless oil
(285 mg, 89%) (Found: C, 70.89; H, 9.92; N, 4.25. C19H31NO3
requires C, 70.99; H, 9.72; N, 4.36%); νmax (film)/cmϪ1 2966,
1667, 1489, 1089, 761; δH (400 MHz, CDCl3) 0.65 (3H, t, J 6.6,
CH3CH2), 0.99 (3H, d, J 6.5, CH3CH), 1.27 (9H, s, (CH3)3C),
1.55 (1H, m, CH3CH2), 2.05 (1H, m, CH3CH2), 3.31 (3H, s,
CH3O), 3.49 (2H, m, CH2OCH3), 3.70 (1H, ddd, J 9.0, 5.6, 3.4,
129.5 (CH), 132.3 (CH), 138.8 (C), 145.6 (C), 175.8 (C᎐O);
᎐
m/z (EI) 236 (Mϩ Ϫ tBu, 100%), 178 (18), 162 (45), 146 (38), 89
(86) (Found Mϩ Ϫ tBu, 236.1286. C17H27NO3 Ϫ tBu requires
M, 236.1287).
J. Chem. Soc., Perkin Trans. 1, 1999, 1295–1304
1299

View Article Online
NCH2OCH2), 3.80 (1H, ddd, J 9.0, 5.6, 3.4, NCH2OCH2), 4.28
(1H, d, J 10.0, NCH2O), 5.72 (1H, d, J 10.0, NCH2O), 7.12
(2H, m, ArH), 7.24 (1H, m, ArH), 7.47 (1H, d, J 7.8, ArH); δC
(68 MHz, CDCl3) 11.2 (CH3), 14.9 (CH3), 27.3 (CH2), 32.3
(CH3), 36.0 (C), 38.4 (CH2), 58.8 (CH3), 68.8 (CH2), 71.7 (CH2),
78.3 (CH2), 126.5 (CH), 128.4 (CH), 129.5 (CH), 132.4 (CH),
PhCHOH), 5.84 (1H, d, J 10.0, NCH2O), 7.30 (9H, m, ArH);
δC (68 MHz, CDCl3) 8.7 (CH3), 32.4 (CH3), 36.2 (C), 43.4 (CH),
58.9 (CH3), 69.4 (CH2), 71.9 (CH2), 72.5 (CH), 78.6 (CH2),
125.5 (CH), 126.9 (CH), 127.9 (CH), 129.0 (CH), 130.2 (CH),
132.4 (CH), 138.1 (C), 141.1 (C), 146.0 (C), 178.2 (C᎐O); m/z
᎐
(EI) 342 (Mϩ Ϫ tBu, 56%), 266 (11), 236 (39), 217 (23), 190 (9),
138.5 (C), 145.7 (C), 178.5 (C᎐O); m/z (EI) 264 (Mϩ Ϫ tBu,
146 (100).
᎐
82%), 146 (55), 89 (100), 59 (85), 57 (67).
Aldol reaction of 10 with isobutyraldehyde to give (Ra*,-
2S*,3R*)-N-(2-tert-butylphenyl)-N-(2-methoxyethoxymethyl)-3-
hydroxy-2,4-dimethylpentanamide 14 (R ؍ isopropyl). Reaction
of 10 according to the procedure described above gave a crude
product as a pale yellow oil, which was purified by column
chromatography (30% EtOAc–light petroleum) to yield the
title compound as a yellow oil (330 mg, 0.90 mmol, 85%),
bp 220 ЊC/0.3 mmHg (Found: C, 69.24; H, 9.99; N, 3.72.
C21H35NO4 requires C, 69.01; H, 9.65; N, 3.83%); νmax (CHCl3)/
cmϪ1 3447, 2928, 2874, 1640, 1598, 1488, 1459, 1364, 1093, 980;
δH (500 MHz, CDCl3) 0.28 (3H, d, J 6.6, (CH3)2CH), 0.96 (3H,
d, J 6.6, (CH3)2CH), 1.02 (3H, d, J 6.8, CH3CH), 1.34 (9H, s,
(CH3)3C), 1.52 (1H, m, (CH3)2CH), 2.62 (1H, dq, J 6.8, 1.2,
CH3CH), 3.32 (1H, dd, J 9.4, 1.2, CHOH), 3.38 (3H, s, CH3O),
3.57 (2H, m, CH2OCH3), 3.79 (1H, ddd, J 11.2, 5.6, 3.2,
NCH2OCH2), 3.90 (1H, ddd, J 11.2, 5.6, 3.2, NCH2OCH2),
4.42 (1H, d, J 10.0, NCH2O), 5.78 (1H, d, J 10.0, NCH2O), 7.18
(1H, dd, J 8.0, 1.6, ArH), 7.22 (1H, ddd, J 8.0, 7.3, 1.6, ArH),
7.33 (1H, ddd, J 8.0, 7.3, 1.6, ArH), 7.56 (1H, dd, J 8.0, 1.6,
ArH); δC (126 MHz, CDCl3) 8.4 (CH3), 17.9 (CH), 19.9 (CH3),
30.4 (CH), 32.5 (CH3), 36.2 (C), 37.9 (CH), 58.9 (CH3), 69.4
(CH2), 71.9 (CH2), 78.5 (CH2), 127.1 (CH), 128.9 (CH), 130.0
Reaction of 10 with cinnamyl chloride to give (Ra*,2S*)-N-(2-
tert-butylphenyl)-N-(2-methoxyethoxymethyl)-2-methyl-5-
phenylpent-4-enamide 11 (R ؍ cinnamyl). Reaction of 10
according to the procedure described above gave a crude prod-
uct as a pale yellow oil, which was purified by column chrom-
atography (30% EtOAc–light petroleum) to yield the title com-
pound as a yellow oil (300 mg, 0.73 mmol, 69%), bp 220 ЊC/0.3
mmHg (Found: C, 76.10; H, 8.85; N, 3.40. C26H35NO3 requires
C, 76.25; H, 8.61; N, 3.42%); νmax (film)/cmϪ1 3058, 3024, 2967,
1666, 1597, 1488, 1440, 1380, 1235, 1088, 761, 694; δH (500
MHz, CDCl3) 1.11 (3H, d, J 6.5, CH3CH), 1.33 (9H, s,
(CH3)3C), 2.21 (1H, m, CH3CH), 2.40 (1H, m, CHCH2), 2.53
(1H, m, CHCH2), 3.32 (3H, s, CH3O), 3.47 (2H, m, CH2OCH3),
3.75 (1H, ddd, J 11.1, 6.1, 3.2, NCH2OCH2), 3.84 (1H, ddd,
J 11.1, 6.1, 3.2, NCH2OCH2), 4.37 (1H, d, J 10.1, NCH2O),
5.81 (1H, d, J 10.1, NCH2O), 5.93 (1H, m, CH2CHCH), 6.29
(1H, d, J 15.7, CH2CHCH), 7.26 (8H, m, ArH), 7.55 (1H, dd,
J 8.1, 1.0, ArH); δC (68 MHz, CDCl3) 16.1 (CH3), 32.5 (CH3),
36.2 (C), 37.6 (CH), 38.3 (CH2), 58.9 (CH3), 68.9 (CH2), 71.7
(CH2), 78.4 (CH2), 125.9 (CH), 126.6 (CH), 127.1 (CH), 127.2
(CH), 128.4 (CH), 128.6 (CH), 129.9 (CH), 131.9 (CH), 132.8
(CH), 137.1 (C), 138.3 (C) 145.9 (C), 177.8 (C᎐O); m/z (EI) 409
(CH), 132.6 (CH), 138.0 (C), 145.8 (C), 179.1 (C᎐O); m/z (EI)
᎐
᎐
(Mϩ, 3%), 352 (8), 276 (100) (Found Mϩ, 409.2608. C26H35NO3
308 (Mϩ Ϫ tBu, 32%), 232 (20), 162 (29), 146 (100), 89 (24)
(Found Mϩ Ϫ tBu, 308.1852. C21H35NO4 Ϫ tBu requires M,
308.1862).
requires M, 409.2617).
Sulfenylation of 10 using PhSSO2Ph to give (Ra*,2S*)-N-
(2-tert-butylphenyl)-N-(2-methoxyethoxymethyl)-2-(phenyl-
sulfenyl)propionamide 11 (R ؍ SPh). Reaction of 10 according
to the procedure described above gave a crude product as a
pale yellow oil, which was purified by column chromatography
(30% EtOAc–light petroleum) to yield the title compound as a
yellow oil (337 mg, 84%), bp 220 ЊC/0.3 mmHg (Found: C,
68.98; H, 8.04; N, 3.71. C23H31NO3S requires C, 68.79; H, 7.78;
N, 3.49%); νmax (film)/cmϪ1 3059, 2966, 1668, 1597, 1487, 1440,
1373, 1243, 1083, 760, 692; δH (400 MHz, CDCl3) 1.31 (9H, s,
(CH3)3C), 1.37 (3H, d, J 6.7, CH3CH), 3.40 (3H, s, CH3O), 3.45
(1H, q, J 6.7, CH3CH), 3.60 (2H, m, CH2OCH3), 3.75 (1H,
ddd, J 11.1, 6.1, 3.2, NCH2OCH2), 4.05 (1H, ddd, J 11.1, 6.1,
3.2, NCH2OCH2), 4.43 (1H, d, J 10.1, NCH2O), 5.83 (1H, d,
J 10.1, NCH2O), 7.14–7.54 (9H, m, ArH); δC (68 MHz, CDCl3)
17.4 (CH3), 32.2 (CH3), 35.8 (C), 43.8 (CH), 58.8 (CH3), 68.8
(CH2), 71.7 (CH2), 78.4 (CH2), 126.6 (CH), 127.7 (CH), 128.5
(CH), 128.7 (CH), 129.0 (CH), 132.5 (C), 133.1 (CH), 133.2
Aldol reaction of 10 with pivaldehyde to give (Ra*,2S*,3R*)-
N-(2-tert-butylphenyl)-N-(2-methoxyethoxymethyl)-3-hydroxy-
2,4,4-trimethylpentanamide 14 (R ؍ tert-butyl). Reaction of
10 according to the procedure described above gave a crude
product as a pale yellow oil, which was purified by column
chromatography (35% EtOAc–light petroleum) to yield the title
compound as a pale yellow oil (330 mg, 0.87 mmol, 87%),
bp 220 ЊC/0.3 mmHg (Found: C, 69.80; H, 10.07; N, 3.56.
C22H37NO4 requires C, 69.62; H, 9.83; N, 3.66%); νmax (film)/
cmϪ1 3478, 2912, 2864, 1731, 1631, 1598, 1571, 1488, 1459,
1363, 1316; δH (500 MHz, CDCl3) 0.71 (9H, s, (CH3)3CCHOH),
1.10 (3H, d, J 6.7, CH3CH), 1.34 (9H, s, (CH3)3C), 2.72 (1H,
q, J 6.7, CH3CH), 3.38 (3H, s, CH3O), 3.47 (1H, s, CHOH),
3.56 (2H, m, CH2OCH3), 3.80 (1H, ddd, J 11.2, 6.0, 3.2,
NCH2OCH2), 3.90 (1H, ddd, J 11.2, 6.0, 3.2, NCH2OCH2),
4.40 (1H, d, J 10.0, NCH2O), 5.76 (1H, d, J 10.0, NCH2O), 7.21
(2H, m, ArH), 7.32 (1H, m, ArH), 7.56 (1H, dd, J 8.2, 1.1,
ArH); δC (68 MHz, CDCl3) 10.2 (CH3), 26.8 (CH3), 32.5 (CH3),
35.3 (C), 36.2 (C), 37.4 (CH), 58.8 (CH3), 69.3 (CH2), 71.9
(CH2), 77.2 (CH), 78.6 (CH2), 126.8 (CH), 128.8 (CH), 130.0
(CH), 137.6 (C) 145.6 (C), 173.2 (C᎐O); m/z (EI) 401 (Mϩ, 3%),
᎐
344 (54), 181 (17), 146 (14), 137 (48), 109 (20), 89 (100) (Found
Mϩ, 401.2016. C23H31NO3S requires M, 401.2025).
(CH), 132.7 (CH), 138.0 (C), 145.8 (C), 179.6 (C᎐O); m/z (EI)
᎐
Aldol reaction of 10 with benzaldehyde to give (Ra*,2S*,3R*)-
N-(2-tert-butylphenyl)-N-(2-methoxyethoxymethyl)-3-hydroxy-2-
methyl-3-phenylpropionamide 14 (R ؍ Ph). Reaction of 10
according to the procedure described above gave a crude
product as a pale yellow oil, which was purified by column
chromatography (20% EtOAc–light petroleum) to yield the
title compound as white crystals (320 mg, 0.80 mmol, 80%),
mp 79–81 ЊC (Found: C, 72.25; H, 8.62; N, 3.43. C24H33NO4
requires C, 72.15; H, 8.33; N, 3.51%); νmax (CHCl3)/cmϪ1 3494,
2929, 2861, 1640, 1488, 1458, 1364, 1101; δH (250 MHz, CDCl3)
0.90 (3H, d, J 6.8, CH3CH), 1.32 (9H, s, (CH3)3C), 2.62 (1H,
qd, J 6.8, 2.1, CH3CH), 3.33 (3H, s, CH3O), 3.55 (2H, m,
CH2OCH3), 3.75 (1H, br s, PhCHOH), 3.87 (2H, m,
NCH2OCH2), 4.46 (1H, d, J 10.0, NCH2O), 5.07 (1H, br s,
322 (Mϩ Ϫ tBu, 32%), 246 (42), 236 (15) (Found Mϩ Ϫ tBu,
322.2016. C22H37NO4 Ϫ tBu requires M, 322.2018).
Aldol reaction of 10 with cyclohexanecarbaldehyde to give
(Ra*,2R*,3R*)-N-(2-tert-butylphenyl)-N-(2-methoxyethoxy-
methyl)-3-cyclohexyl-3-hydroxy-2-methylpropionamide 14 (R ؍
cyclohexyl). Reaction of 10 according to the procedure
described above gave a crude product as a pale yellow oil, which
was purified by column chromatography (25% EtOAc–light
petroleum) to yield the title compound as a yellow oil (360 mg,
0.89 mmol, 89%), bp 220 ЊC/0.3 mmHg (Found: C, 71.27; H,
9.98; N, 3.37. C24H39NO4 requires C, 71.07; H, 9.69; N, 3.45%);
νmax (film)/cmϪ1 3454, 2924, 2851, 1642, 1598, 1488, 1442, 1363,
1233, 1091, 761; δH (500 MHz, CDCl3) 0.26 (1H, m,
1300
J. Chem. Soc., Perkin Trans. 1, 1999, 1295–1304

View Article Online
(CH2)5CH), 1.01 (3H, d, J 6.8, CH3CH), 1.16 (10H, m, (CH2)5),
1.33 (9H, s, (CH3)3C), 2.60 (1H, q, J 6.8, CH3CH), 3.38 (1H,
m, CHOH), 3.38 (3H, s, CH3O), 3.56 (2H, m, CH2OCH3), 3.79
(1H, ddd, J 11.1, 5.6, 3.1, NCH2OCH2), 3.89 (1H, ddd, J 11.1,
5.6, 3.1, NCH2OCH2), 4.41 (1H, d, J 10.2, NCH2O), 5.79 (1H,
d, J 10.2, NCH2O), 7.16 (1H, dd, J 7.7, 1.3, ArH), 7.22 (1H,
ddd, J 7.7, 7.5, 1.3, ArH), 7.33 (1H, ddd, J 7.7, 7.5, 1.3, ArH),
7.55 (1H, dd, J 7.7, 1.3, ArH); δC (126 MHz, CDCl3) 8.6 (CH3),
25.8 (CH2), 26.2 (CH2), 27.8 (CH2), 30.2 (CH2), 32.6 (CH3),
36.3 (C), 37.4 (CH), 39.8 (CH), 59.0 (CH3), 60.4 (CH2), 69.5
(CH2), 72.0 (CH2), 75.2 (CH), 78.6 (CH2), 127.2 (CH), 130.0
(CH), 131.3 (CH), 132.6 (CH), 138.1 (C), 145.9 (C), 179.2
under reduced pressure. The resulting yellow oil was purified by
flash column chromatography (50% EtOAc–light petroleum) to
give the title compound as a yellow oil (50 mg, 0.30 mmol, 68%);
νmax (CHCl3)/cmϪ1 3362, 2913, 1604, 1493, 1456; δH (500 MHz,
CDCl3) 0.84 (3H, d, J 7.0, CH3CH), 2.07 (1H, m, CH3CH),
2.39 (1H, s, CH2OH), 2.90 (1H, s, PhCHOH), 3.67 (2H, m,
CH2OH), 4.94 (1H, s, PhCHOH), 7.27 (1H, m, PhH), 7.34 (4H,
m, PhH); δC (126 MHz, CDCl3) 10.8 (CH3), 41.5 (CH), 66.5
(CH2), 76.8 (CH), 126.2 (CH), 127.3 (CH), 128.2 (CH), 142.7
(C); m/z (EI) 166 (Mϩ, 4%), 148 (19), 107 (100) (Found Mϩ,
166.0997. C10H14O2 requires M, 166.0994).
(C᎐O); m/z (EI) 236 (Mϩ, 50%), 146 (100), 113 (82), 101 (51), 89
(2S)-2-Acetoxypropionic acid (؊)-2216
᎐
(76).
To a stirred solution of (S)-lactic acid (3.68 g, 40.9 mmol) in
AcOH (11.7 ml) under an atmosphere of nitrogen, was added
acetyl chloride (8.71 ml, 122.6 mmol) slowly. The reaction
mixture was stirred for 5 h before removing AcOH and acetyl
chloride under reduced pressure. The crude oil was purified by
bulb to bulb distillation (112 ЊC/2 mmHg) to afford (Ϫ)-22 as a
colourless viscous oil (4.88 g, 36.9 mmol, 90%), [α]D23 Ϫ58 (c 6.70,
CHCl3); νmax (CHCl3)/cmϪ1 3512, 3176, 2900, 2638, 1732, 1460,
1374, 1287; δH (500 MHz, CDCl3) 1.54 (3H, d, J 7.2, CH3CH),
2.14 (3H, s, CH3CO), 5.11 (1H, q, J 7.2, CH3CH), 9.95 (1H,
br s, CO2H); δC (126 MHz, CDCl3) 16.9 (CH3), 20.7 (CH3),
68.2 (CH), 170.6 (C᎐O), 176.7 (C᎐O); m/z (FAB) 133 (MHϩ,
Aldol reaction of 10 with propanal to give (Ra*,2S*,3R*)-N-(2-
tert-butylphenyl)-N-(2-methoxyethoxymethyl)-3-hydroxy-2-
methylpentanamide 14 (R ؍ ethyl). Reaction of 10 according to
the procedure described above gave a crude product as a pale
yellow oil, which was purified by column chromatography
(25% EtOAc–light petroleum) to yield the title compound as a
pale yellow oil (150 mg, 0.43 mmol, 86%), bp 200 ЊC/4 mmHg
(Found: C, 68.19; H, 9.53; N, 3.77. C20H33NO4 requires C,
68.34; H, 9.46; N, 3.98%); νmax (film)/cmϪ1 3463, 3063, 2959,
1644, 1598, 1571, 1488, 1456, 1409, 1325, 1300; δH (250 MHz,
CDCl3) 0.61 (3H, t, J 7.1, CH3CH2), 1.03 (3H, d, J 7.1,
CH3CH), 1.34 (9H, s, (CH3)3C), 2.44 (1H, m, CH3CH), 3.38
(3H, s, CH3O), 3.56 (2H, m, CH2OCH3), 3.81 (2H, m,
NCH2OCH2), 4.41 (1H, d, J 10.0, NCH2O), 5.81 (1H, d, J 10.0,
NCH2O), 7.26 (3H, m, ArH), 7.56 (1H, dd, J 8.0, 1.4, ArH);
δC (68 MHz; CDCl3) 8.3 (CH3), 10.1 (CH3), 26.0 (CH2), 32.2
(CH3), 35.9 (C), 39.5 (CH), 58.7 (CH3), 68.8 (CH2), 71.6 (CH2),
72.3 (CH), 78.0 (CH2), 126.6 (CH), 128.8 (CH), 129.6 (CH),
᎐
᎐
13%), 120 (11) (Found MHϩ, 133.0510. C5H8O4 requires M,
133.0501).
(2S)-N-(2-tert-Butylphenyl)-2-acetoxypropionamide (؊)-23
To a stirred solution of the acid (Ϫ)-22 (2.00 g, 15.14 mmol)
and 2-tert-butylaniline (1.51 g, 10.09 mmol) in CH2Cl2 (10 ml)
at 0 ЊC, under an atmosphere of nitrogen, was added EDCؒHCl
(2.90 g, 15.14 mmol) in one portion. The reaction mixture was
stirred at room temperature for 24 h before pouring onto water
(30 ml) and extracting with CH2Cl2 (3 × 10 ml), the combined
organics were washed with saturated aqueous NaHCO3 (3 ×
10 ml), 2 M HCl (3 × 10 ml), brine (10 ml), dried (MgSO4)
and evaporated under reduced pressure to give a white solid.
Recrystallising from EtOAc gave the title compound as white
crystals (2.18 g, 8.28 mmol, 82%), mp 107–108 ЊC; [α]D23 Ϫ33
(c 0.94, CHCl3); νmax (CHCl3)/cmϪ1 3460, 2969, 2876, 1750,
1689, 1580, 1449, 1372; δH (500 MHz, CDCl3) 1.43 (9H, s,
132.0 (CH), 137.6 (C), 145.3 (C), 180.4 (C᎐O); m/z (EI) 294
᎐
(Mϩ Ϫ tBu, 59%), 218 (54), 188 (18) (Found Mϩ Ϫ tBu,
294.1690. C20H33NO4 Ϫ tBu requires M, 294.1705).
Reduction of racemic 11 (R ؍ Bn) with LiAlH4 to give 2-methyl-
3-phenylpropan-1-ol ( )-17
To a stirred suspension of LiAlH4 (273 mg, 7.20 mmol) in THF
(40 ml) at Ϫ10 ЊC, under an atmosphere of nitrogen, was added
the anilide 11 (R = Bn) (230 mg, 0.60 mmol) in THF (15 ml).
The reaction mixture was stirred at room temperature for 24 h
before cautiously adding 2 M NaOH (10 ml) and water (10 ml).
The reaction mixture was filtered and extracted with Et2O
(3 × 30 ml), the combined organic extracts were washed with
water (3 × 10 ml), brine (20 ml), dried (MgSO4) and evaporated
under reduced pressure. The crude mixture was purified by
column chromatography (10% EtOAc–light petroleum) to
give ( )-17 as a pale yellow oil (72 mg, 0.48 mmol, 80%); νmax
(film)/cmϪ1 3332, 3084, 3061, 3025, 2919, 1603, 1494, 1453,
1378; δH (250 MHz, CDCl3) 0.90 (3H, d, J 6.7, CH3CH), 1.81
(1H, s, CH2OH), 1.93 (1H, m, CH3CH), 2.40 (1H, dd, J 13.4,
8.1, PhCH2), 2.75 (1H, dd, J 13.4, 8.1, PhCH2), 3.48 (2H, m,
CH2OH), 7.23 (5H, m, ArH); δC (126 MHz, CDCl3) 16.5 (CH3),
37.8 (CH), 39.8 (CH2), 67.7 (CH2), 125.9 (CH), 128.3 (CH),
129.2 (CH), 140.7 (C); m/z (EI) 150 (Mϩ, 25%), 132 (20), 117
(50), 92 (53), 91 (100) (Found Mϩ, 150.1045. C10H14O requires
M, 150.1045).
(CH ) C), 1.60 (3H, d, J 6.9, CH CH), 2.21 (3H, s, CH C᎐O),
᎐
3
3
3
3
5.42 (1H, q, J 6.9, CH3CH), 7.16 (1H, td, J 7.9, 1.4, ArH), 7.25
(1H, m, ArH), 7.40 (1H, dd, J 7.9, 1.4, ArH), 7.79 (1H, dd,
J 7.9, 1.4, ArH), 8.11 (1H, br s, NH); δC (126 MHz, CDCl3)
18.0 (CH3), 21.2 (CH3), 30.6 (CH3), 34.5 (C), 71.2 (CH), 126.1
(CH), 126.2 (CH), 126.6 (CH), 127.0 (CH), 134.5 (C), 141.3 (C),
168.2 (C), 168.2 (C᎐O), 170.9 (C᎐O); m/z (EI) 264 (MHϩ, 20%),
᎐
᎐
263 (100), 206 (33), 176 (68), 160 (23), 149 (97) (Found Mϩ,
263.1517. C15H21NO3 requires M, 263.1521).
N-Alkylation of (؊)-23 to give atropisomeric derivatives (Sa,2S)-
2-acetoxy-N-(2-tert-butylphenyl)-N-(2-methoxyethoxymethyl)-
propionamide (؉)-24a, and (Ra,2S)-2-acetoxy-N-(2-tert-butyl-
phenyl)-N-(2-methoxyethoxymethyl)propionamide (؊)-24b
To a stirred suspension of NaH (202 mg of a 60% dispersion
in oil, 5.05 mmol) in THF (50 ml) at 0 ЊC, under an atmosphere
of nitrogen, was added dropwise a solution of the anilide
(Ϫ)-22 (1.40 g, 5.32 mmol) in THF (3 ml), with vigorous evolu-
tion of hydrogen. After 15 min stirring at room temperature,
the reaction mixture was cooled to 0 ЊC before addition of
MEMCl (0.55 ml, 4.79 mmol) in one portion. The reaction
mixture was stirred at 0 ЊC for 1 h and then at room tem-
perature overnight. MeOH (5 ml) was then cautiously added
and the reaction mixture poured onto water (40 ml) and
extracted with EtOAc (3 × 30 ml). The combined organic
extracts were dried (MgSO4) and evaporated under reduced
Reduction of racemic 14 (R ؍ Ph) with LiAlH4 to give 2-methyl-
1-phenylpropane-1,3-diol ( )-18
To a stirred suspension of LiAlH4 (221 mg, 5.83 mmol) in THF
(35 ml) under an atmosphere of nitrogen, was added the anilide
14 (R = Ph) (174 mg, 0.44 mmol) in THF (5 ml). The reaction
mixture was stirred for 24 h before 2 M NaOH (2.5 ml) and
H2O (2.5 ml) were carefully added. The mixture was extracted
with EtOAc (3 × 20 ml), the combined organic extracts were
washed with water (20 ml), dried (MgSO4), and evaporated
J. Chem. Soc., Perkin Trans. 1, 1999, 1295–1304
1301

View Article Online
pressure to yield a yellow oil that was subsequently purified by
column chromatography (25% EtOAc–light petroleum) to give
firstly the diastereomer (Ϫ)-24b (470 mg, 1.34 mmol, 25%) as a
pale yellow oil, [α]D23 Ϫ60 (c 1.22, CHCl3); νmax (CHCl3)/cmϪ1
2938, 2881, 1738, 1674, 1489, 1456, 1370; δH (500 MHz, CDCl3)
1.28 (3H, d, J 6.5, CH3CH), 1.33 (9H, s, (CH3)3C), 2.00 (3H, s,
NaHCO3 (10 ml), brine (10 ml), dried (MgSO4), and evaporated
under reduced pressure. The resulting yellow oil was purified
by flash column chromatography (30% EtOAc–light petroleum)
and then bulb to bulb distillation (bp 220 ЊC/0.8 mmHg) to give
25 as a yellow oil (130 mg, 0.42 mmol, 84%); νmax (film)/cmϪ1
2968, 2875, 1667, 1488, 1470, 1441, 1402, 1384, 1361; δH (250
MHz, CDCl3) 1.11 (3H, d, J 3.1, (CH3)2CH), 1.14 (3H, d, J 3.1,
(CH3)2CH), 1.38 (9H, s, (CH3)3C), 2.40 (1H, m, (CH3)2CH),
3.44 (3H, s, CH3O), 3.62 (2H, m, CH2OCH3), 3.84 (1H, ddd,
J 11.1, 5.4, 3.7, NCH2OCH2), 3.93 (1H, ddd, J 11.1, 5.4, 3.7,
NCH2OCH2), 4.41 (1H, d, J 10.1, NCH2O), 5.87 (1H, d, J 10.1,
NCH2O), 7.34 (3H, m, ArH), 7.61 (1H, dd, J 7.6, 1.1, ArH);
δC (68 MHz, CDCl3) 18.3 (CH3), 20.6 (CH3), 32.3 (CH3), 36.1
(C), 58.9 (CH3), 68.9 (CH2), 71.9 (CH2), 78.3 (CH2), 126.7
(CH), 128.6 (CH), 129.6 (CH), 132.3 (CH), 138.7 (C), 145.8 (C),
CH C᎐O), 3.38 (3H, s, CH O), 3.57 (2H, m, CH OCH ), 3.77
᎐
3
3
2
3
(1H, ddd, J 11.1, 5.9, 3.3, NCH2OCH2), 3.94 (1H, ddd, J 11.1,
5.9, 3.3, NCH2OCH2), 4.44 (1H, d, J 10.1, NCH2O), 5.06 (1H,
q, J 6.5, CH3CH), 5.82 (1H, d, J 10.1, NCH2O), 7.19 (1H, m,
ArH), 7.25 (1H, dd, J 7.7, 1.5, ArH), 7.33 (1H, td, J 7.7, 1.5,
ArH), 7.54 (1H, dd, J 7.7, 1.5, ArH); δC (126 MHz, CDCl3)
15.8 (CH3), 20.8 (CH3), 32.6 (CH3), 36.3 (C), 59.1 (CH3), 67.9
(CH), 69.1 (CH2), 72.0 (CH2), 79.0 (CH2), 126.6 (CH), 129.2
(CH), 131.3 (CH), 132.8 (CH), 136.9 (C), 145.9 (C), 169.7
(C᎐O), 171.4 (C᎐O); m/z (EI) 294 (Mϩ Ϫ tBu, 50%), 263 (4)
179.4 (C᎐O); m/z (EI) 250 (Mϩ Ϫ tBu, 100%), 146 (43) (Found
᎐
᎐
᎐
(Found Mϩ Ϫ tBu, 294.1329. C19H29NO5 Ϫ tBu requires M,
294.1342), followed by (ϩ)-24a (760 mg, 2.16 mmol, 41%) as a
pale yellow oil, [α]D23 ϩ21 (c 1.36, CHCl3); νmax (CHCl3)/cmϪ1
2931, 2882, 2822, 1733, 1682, 1488, 1456, 1371; δH (500 MHz,
CDCl3) 1.32 (9H, s, (CH3)3C), 1.36 (3H, d, J 6.5, CH3CH), 2.04
Mϩ Ϫ tBu, 250.1451. C18H29NO3 Ϫ tBu requires M, 250.1443).
An analogous reaction using the anilide (Ϫ)-10 gave the
enantiomeric product 25 with corresponding spectroscopic
data.
HPLC analysis of samples of 25 was carried out using
a Chiralcel OD column, employing hexane–iPrOH (99:1) as
eluant. The two enantiomers showed baseline separation, with
retention times of 10.5 and 12.5 minutes.
(3H, s, CH C᎐O), 3.38 (3H, s, CH O), 3.58 (2H, m, CH OCH ),
᎐
3
3
2
3
3.78 (1H, ddd, J 11.2, 5.8, 3.4, NCH2OCH2), 3.86 (1H, ddd,
J 11.2, 5.8, 3.4, NCH2OCH2), 4.38 (1H, d, J 10.0, NCH2O),
5.11 (1H, q, J 6.5, CH3CH), 5.82 (1H, d, J 10.0, NCH2O), 7.19
(2H, m, ArH), 7.36 (1H, td, J 7.9, 1.3, ArH), 7.57 (1H, dd,
J 7.9, 1.3, ArH); δC (126 MHz, CDCl3) 18.2 (CH3), 21.0 (CH3),
32.2 (CH3), 36.3 (C), 59.0 (CH3), 68.0 (CH), 69.3 (CH2), 71.9
(CH2), 79.0 (CH2), 126.9 (CH), 129.3 (CH), 130.4 (CH), 132.7
Polarimetric data for (؉)-11, (؊)-11, (؉)-17 and (؊)-17 (see
Scheme 8)
Spectroscopic data for the conversions shown were in accord
with those for racemic materials, given above.
(CH), 137.0 (C), 146.3 (C), 169.8 (C᎐O), 172.2 (C᎐O); m/z (EI)
᎐
᎐
The sequence starting with (ϩ)-10 gave benzylated amide
(ϩ)-11, [α]D23 ϩ79 (c 0.73, CHCl3), and then alcohol (Ϫ)-17,
[α]D23 Ϫ10 (c 1.77, C6H6). Starting with (Ϫ)-10 gave benzylated
amide (Ϫ)-11, [α]D23 Ϫ80 (c 0.70, CHCl3), and then alcohol
(ϩ)-17, [α]D23 ϩ12 (c 0.5, C6H6). The literature value for (Ϫ)-17,
established to be the (S)-enantiomer is [α]DϪ11 (c 2.75, C6H6).13
294 (Mϩ Ϫ tBu, 44%), 252 (8), 221 (4) (Found Mϩ Ϫ tBu,
294.1340. C19H29NO5 Ϫ tBu requires M, 294.1342).
Typical conditions for SmI2 reduction in the presence of LiCl
(Method A in Table 3): conversion of (؉)-24a and (؊)-24b into
(؉)-10 and (؊)-10 respectively
A solution of flame-dried LiCl (1.06 g, 24.96 mmol) in THF (24
ml) was added to a solution of SmI2 in THF (40 ml), freshly
prepared from Sm metal (1.38 g, 9.15 mmol) and 1,2-
diiodoethane (2.35 g, 8.32 mmol). After 30 min, a solution
of the starting anilide (Ϫ)-24b (450 mg, 1.28 mmol) in THF
(2 ml) was added and the reaction mixture stirred for 24 h. The
reaction mixture was then poured onto saturated aqueous
Na2SO3 (50 ml) and the organics extracted with EtOAc (2 ×
50 ml), washed with saturated aqueous Na2SO3 (50 ml), brine
(50 ml), dried (MgSO4) and solvent removed under reduced
pressure. The crude oil was purified by column chromatography
(30% EtOAc–light petroleum) to give (Ϫ)-10 as a pale yellow
oil (277 mg, 0.94 mmol, 73%), [α]D23 Ϫ26 (c 1.04, CHCl3). An
analogous reaction using (ϩ)-24a gave (ϩ)-10 in 65% yield as a
pale yellow oil, [α]D23 ϩ26 (c 2.34, CHCl3). Spectroscopic data
were in accord with those obtained for the racemic material,
listed above.
Data for products of SmI2 reductions (see Table 3)
Starting amides were prepared by standard techniques,
principally utilising EDC-mediated coupling of appropriate
carboxylic acids with amine partners. The α-bromo derivatives
were made by Schotten–Baumann reactions using α-bromo-
propionyl chloride.
Reductions involving LiCl (Method A) were carried out
as indicated above for (Ϫ)-24b. For Method B see typical
procedure below.
Entry 1. Method A was used, giving a crude solid which
was purified by column chromatography (20% EtOAc–light
petroleum) to give 30 as white crystals (27 mg, 0.17 mmol,
85%), mp 55–56 ЊC (lit.,17 55–56 ЊC); νmax (CHCl3)/cmϪ1 2981,
2940, 1644, 1596, 1496, 1463, 1389; δH (500 MHz, CDCl3) 1.05
(3H, t, J 7.4, CH3CH2), 2.07 (2H, m, CH3CH2), 3.27 (3H, s,
NCH3), 7.19 (2H, m, PhH), 7.33 (1H, app t, J 7.4, PhH), 7.42
(2H, m, PhH); δC (126 MHz, CDCl3) 9.8 (CH3), 27.6 (CH2),
37.4 (CH3), 127.4 (CH), 127.8 (CH), 129.8 (CH), 144.4 (C),
Methylation of (؉)-10 and (؊)-10 for purposes of determination
of enantiomeric excess: synthesis of N-(2-tert-butylphenyl)-N-(2-
methoxyethoxymethyl)isobutyramides 25
174.0 (C᎐O); m/z (EI) 163 (Mϩ, 26%), 107 (100), 106 (37)
᎐
(Found Mϩ, 163.0997. C10H13NO requires M, 163.0997).
To a stirred solution of diisopropylamine (0.10 ml, 0.75 mmol)
in THF (5 ml) at Ϫ78 ЊC, under an atmosphere of nitrogen,
was added nBuLi (0.50 ml of a 1.3 M solution in hexanes,
0.65 mmol), followed by warming to 0 ЊC for 15 min. To the
resulting solution of LDA at Ϫ78 ЊC, a solution of the anilide
(ϩ)-10 (147 mg, 0.50 mmol) in THF (1 ml), was added drop-
wise. After 30 min MeI (0.06 ml, 1.00 mmol) was added in one
portion and the reaction mixture stirred at Ϫ78 ЊC for 30 min,
saturated aqueous NaHCO3 (2.5 ml) was then added and the
reaction mixture allowed to warm to room temperature. The
reaction mixture was extracted with EtOAc (3 × 10 ml), the
combined organic extracts were washed with saturated aqueous
Entry 2. Method A was used to give an oil which was purified
by column chromatography (20% EtOAc–light petroleum) to
give 10 as an oil (97 mg, 0.33 mmol, 69%), with spectroscopic
data identical to those listed above.
Entry 3. Method A was used, giving a crude solid which
was purified by column chromatography (15% EtOAc–light
petroleum) to give 31 as a low melting point white solid (20 mg,
0.09 mmol, 50%), νmax (CHCl3)/cmϪ1 2966, 1681, 1597, 1570,
1487, 1376, 1076; δH (400 MHz, CDCl3) 1.04 (3H, t, J 7.4,
CH3CH2), 1.37 (9H, s, (CH3)3C), 1.97 (2H, m, CH3CH2), 3.18
1302
J. Chem. Soc., Perkin Trans. 1, 1999, 1295–1304

View Article Online
(3H, s, NCH3), 6.96 (1H, dd, J 7.7, 1.5, ArH), 7.22 (1H, ddd,
J 7.7, 7.7, 1.5, ArH), 7.32 (1H, ddd, J 7.7, 7.7, 1.5, ArH), 7.54
(1H, dd, J 7.7, 1.5, ArH); δC (68 MHz, CDCl3) 9.1 (CH3), 28.1
(CH2), 31.6 (CH3), 35.6 (C), 38.5 (CH3), 127.3 (CH), 128.2
(CH), 129.1 (CH), 129.9 (CH), 141.8 (C), 146.0 (C), 174.7
(C), 137.9 (C), 172.4 (C᎐O); m/z (EI) 255 (Mϩ, 10%), 238 (7),
᎐
237 (35), 164 (11) (Found Mϩ, 255.1263. C16H17NO2 requires
M, 255.1259), followed by N-benzyl-3-phenylpropionamide,
35, as a white solid (6 mg, 0.025 mmol, 13%), mp 78–79 ЊC
(lit.,20 83–84 ЊC); νmax (CHCl3)/cmϪ1 2927, 2856, 1667, 1604,
1496, 1454; δH (500 MHz, CDCl3) 2.52 (2H, t, J 7.6, PhCH2),
3.00 (2H, t, J 7.6, PhCH2CH2), 4.40 (2H, d, J 5.7, PhCH2N),
5.60 (1H, br s, NH), 7.15 (2H, m, PhH), 7.22 (3H, m, PhH),
7.28 (5H, m, PhH); δC (126 MHz, CDCl3) 31.8 (CH2), 38.6
(CH2), 43.7 (CH2), 126.3 (CH), 127.5 (CH), 127.8 (CH), 128.5
(CH), 128.6 (CH), 128.7 (CH), 138.2 (C), 140.8 (C), 171.9
(C᎐O); m/z (EI) 162 (Mϩ Ϫ tBu, 100%) (Found Mϩ Ϫ tBu,
᎐
162.0905. C14H21NO Ϫ tBu requires M, 162.0919).
Entry 4: typical Method B. To a solution of SmI2 in THF
(15 ml), freshly prepared from Sm metal (232 mg, 1.54 mmol)
and 1,2-diiodoethane (395 mg, 1.40 mmol), was added a
solution of the starting anilide (104 mg, 0.35 mmol) in THF
(1 ml) and the reaction mixture stirred for 24 h. The reaction
mixture was then poured onto saturated aqueous Na2SO3
(40 ml) and the organics extracted with EtOAc (2 × 40 ml),
washed with saturated aqueous Na2SO3 (30 ml), brine (30 ml),
dried (MgSO4) and solvent removed under reduced pressure.
The crude solid was purified by column chromatography (20%
EtOAc–light petroleum) to give 31 (44 mg, 0.20 mmol, 57%),
identical to entry 3.
(C᎐O); m/z (EI) 240 (MHϩ, 18%), 239 (100), 148 (92) (Found
᎐
Mϩ, 239.1308. C16H17NO requires M, 239.1310).
Entry 10. Method A was used to give a crude oil that
contained none of the desired reduction product 37, but on
purification by column chromatography (30% EtOAc–light
petroleum) gave the undesired hydrolysis product (2S)-N-tert-
butyl-2-hydroxy-3-phenylpropionamide as a pale yellow oil
(25 mg, 0.11 mmol, 52%), [α]D23 Ϫ47.6 (c 1.72, CHCl3), νmax
(CHCl3)/cmϪ1 3605, 3410, 3065, 3031, 2967, 2931, 2872, 1675,
1603, 1526, 1454, 1410, 1365; δH (500 MHz, CDCl3) 1.30 (9H,
s, (CH3)3C), 2.53 (1H, d, J 5.1, OH), 2.95 (1H, dd, J 13.9, 6.4,
PhCH2), 3.13 (1H, dd, J 13.9, 6.4, PhCH2), 4.17 (1H, m,
PhCH2CH), 6.00 (1H, br s, NH), 7.26 (3H, m, PhH), 7.33
(2H, m, PhH); δC (126 MHz, CDCl3) 28.7 (CH3), 41.2 (CH2),
51.0 (C), 73.0 (CH), 127.1 (CH), 128.9 (CH), 129.7 (CH), 136.9
Entry 5. Method B was used to give a crude solid which
was purified by column chromatography (30% EtOAc–light
petroleum) to give 30 (59 mg, 0.36 mmol, 72%), identical to
entry 1.
Entry 6. Method B was used to give a crude solid which
was purified by column chromatography (30% EtOAc–light
petroleum) to give 32 as white crystals (74 mg, 0.36 mmol,
72%). For spectroscopic data, see preparation of 10.
(C), 171.6 (C᎐O); m/z (EI) 205 (Mϩ Ϫ O, 2%), 204 (15), 203
᎐
(94), 188 (17) (Found Mϩ Ϫ O, 205.1459. C13H19NO2 Ϫ O
requires M, 205.1467).
Entry 7. Method A was used to give a crude oil which
was purified by column chromatography (40% EtOAc–light
petroleum) to give 33 as a pale yellow oil (60 mg, 0.29 mmol,
69%);18 νmax (CHCl3)/cmϪ1 2937, 2876, 1650, 1488, 1455, 1383,
1363, 1312; δH (250 MHz, CDCl3) 1.10 (6H, m, (CH3CH2)2N),
2.59 (2H, m, PhCH2CH2), 2.98 (2H, t, J 7.9, PhCH2CH2), 3.22
(2H, q, J 7.1, (CH3CH2)2N), 3.38 (2H, q, J 7.1, (CH3CH2)2N),
7.24 (5H, m, PhH); δC (68 MHz, CDCl3) 13.0 (CH3), 14.2
(CH3), 31.6 (CH2), 35.1 (CH2), 40.2 (CH2), 41.9 (CH2), 126.0
Acknowledgements
We are grateful to the Engineering and Physical Sciences
Research Council (EPSRC) and Merck Sharp and Dohme
(Terlings Park, Harlow, Essex, UK CM20 2QR) for support of
D. A. P. under the CASE scheme, and we also acknowledge
EPSRC for support of A. D. H.
References
(CH), 128.4 (CH), 141.5 (C), 171.2 (C᎐O); m/z (EI) 205 (Mϩ,
᎐
48%), 204 (22), 203 (58) (Found Mϩ, 205.1461. C13H19NO
1 D. P. Curran, H. Qi, S. J. Geib and N. C. DeMello, J. Am. Chem.
Soc., 1994, 116, 3131.
2 A. D. Hughes, D. A. Price, O. Shishkin and N. S. Simpkins,
Tetrahedron Lett., 1996, 37, 7607.
requires M, 205.1467).
Entry 8. Method A was used to give a crude oil which
was purified by column chromatography (60% EtOAc–light
petroleum) to give 34 as a pale yellow oil (25 mg, 0.12 mmol,
60%);19 νmax (CHCl3)/cmϪ1 2950, 2876, 1722, 1644, 1495, 1456,
1344; δH (500 MHz, CDCl3) 1.82 (4H, m, N(CH2)4), 2.55 (2H,
t, J 7.9, PhCH2CH2), 2.97 (2H, t, J 7.9, PhCH2CH2), 3.26 (2H,
t, J 6.6, N(CH2)4), 3.45 (2H, t, J 6.6, N(CH2)4), 7.22 (5H,
m, PhH); δC (126 MHz, CDCl3) 24.2 (CH2), 25.8 (CH2), 31.0
(CH2), 36.5 (CH2), 45.5 (CH2), 46.4 (CH2), 125.8 (CH), 128.2
3 O. Kitagawa, H. Izawa, T. Taguchi and M. Shiro, Tetrahedron Lett.,
1997, 38, 4447.
4 O. Kitagawa, H. Izawa, K. Sato, A. Dobashi, T. Taguchi and
M. Shiro, J. Org. Chem., 1998, 63, 2634.
5 A. D. Hughes and N. S. Simpkins, Synlett, 1998, 967.
6 D. A. Evans, F. Urpi, T. C. Somers, J. S. Clark and M. T. Bilodeau,
J. Am. Chem. Soc., 1990, 112, 8215.
7 D. P. Curran, G. R. Hale, S. J. Geib, A. Balog, Q. B. Cass, A. L. G.
Degani, M. Z. Hernandes and L. C. G. Freitas, Tetrahedron:
Asymmetry, 1997, 8, 3955.
8 A. G. Myers, B. H. Yang and D. J. Kopecky, Tetrahedron Lett., 1996,
37, 3623.
9 M. Bodansky, Principles of Peptide Synthesis, Springer Verlag, New
York, 1984, pp. 9–58.
(CH), 141.2 (C), 170.6 (C᎐O); m/z (EI) 204 (MHϩ, 11%), 203
᎐
(86), 131 (14), 112 (100), 105 (15) (Found Mϩ, 203.1306.
C13H17NO requires M, 203.1310).
10 For reviews, see (a) G. A. Molander, Org. React., 1994, 46, 211;
(b) G. A. Molander and C. R. Harris, in Encyclopedia of Reagents
for Organic Synthesis, ed. L. A. Paquette, Wiley, 1995, vol. 6,
pp. 4428–4432; (c) G. A. Molander and C. R. Harris, Chem. Rev.,
1996, 96, 307; (d) H. B. Kagan and J. L. Namy, Tetrahedron, 1986,
42, 6573.
11 For other examples of α-deoxygenation, see (a) T. Naito, N. Kojima,
O. Miyata, I. Ninomiya, M. Inoue and M. Doi, J. Chem. Soc.,
Perkin Trans. 1, 1990, 1271; (b) N. Hirose, S. Sohda, S. Kuriyama and
S. Toyoshima, Chem. Pharm. Bull., 1973, 21, 960; (c) E. J. Enholm
and S. Jiang, Tetrahedron Lett., 1992, 33, 6069; (d) E. J. Enholm and
S. Jiang, Tetrahedron Lett., 1992, 33, 5729.
Entry 9. Method A was used to give a mixture of products
which were separated by column chromatography (40%
EtOAc–light petroleum) to give firstly the undesired hydrolysis
product, (S)-N-benzyl-2-hydroxy-3-phenylpropionamide, as a
white solid (34 mg, 0.13 mmol, 65%), mp 81–82 ЊC; [α]D23 Ϫ57.7
(c 1.15, CHCl3); νmax (CHCl3)/cmϪ1 3422, 2927, 1667, 1605,
1586, 1547, 1496, 1454; δH (500 MHz, CDCl3) 2.60 (1H, d, J 4.5,
OH), 2.93 (1H, dd, J 13.9, 6.4, PhCH2), 3.25 (1H, dd, J 13.9,
6.4, PhCH2), 4.34 (1H, m, PhCH2CH), 4.39 (1H, dd, J 14.8, 5.9,
PhCH2N), 4.46 (1H, dd, J 14.8, 5.9, PhCH2NH), 6.80 (1H, br s,
NH), 7.18 (2H, m, PhH), 7.27 (8H, m, PhH); δC (126 MHz,
CDCl3) 41.0 (CH2), 43.2 (CH2), 73.0 (CH), 127.2 (CH), 127.6
(CH), 127.9 (CH), 128.8 (CH), 128.9 (CH), 129.7 (CH), 136.7
12 J. R. Fuchs, M. L. Mitchell, M. Shabangi and R. A. Flowers II,
Tetrahedron Lett., 1997, 38, 8157.
13 H. Sacha, D. Waldmuller and M. Braun, Chem. Ber., 1994, 127,
1959.
J. Chem. Soc., Perkin Trans. 1, 1999, 1295–1304
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18 D. H. R. Barton and J. A. Ferreira, Tetrahedron, 1996, 52, 9347.
19 C. Burnell-Curty and E. J. Roskamp, Tetrahedron Lett., 1993, 34,
5193.
20 M. Yamada, S. Yahiro, T. Yamano, Y. Nakatani and G. Ourisson,
Bull. Soc. Chim. Fr., 1990, 127, 824.
14 D. Seebach, A. R. Sting and M. Hoffmann, Angew. Chem., Int. Ed.
Engl., 1996, 35, 2709.
15 For an example in which an α-oxygenated amide is the product
of a SmI2 reaction, see J. H. Rigby, A. Cavezza and M. J. Heeg,
J. Am. Chem. Soc., 1998, 120, 3664.
16 G. Cahiez and E. Metais, Tetrahedron Lett., 1995, 36, 6449.
17 K. Kato and T. Mukaiyama, Bull. Chem. Soc. Jpn., 1991, 2948.
Paper 9/01154D
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