Atroposelective attack of nucleophiles and electrophiles on 2-acyI-l-naphthamides and their enolates

Article abstract of DOI:10.1039/b000668h

Organolithiums, Grignard reagents and borohydride reducing agents attack 2-acyl-l-naphthamides to give tertiary and secondary alcohols with high or complete atroposelectivity. High levels of stereoselectivity can also be obtained in the alkylations of eno

Full text of DOI:10.1039/b000668h

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Atroposelective attack of nucleophiles and electrophiles on
2-acyl-1-naphthamides and their enolates
Jonathan Clayden,* Neil Westlund, Roy L. Beddoes and Madeleine Helliwell
Department of Chemistry, University of Manchester, Oxford Rd., Manchester, UK M13 9PL
Received (in Cambridge, UK) 24th January 2000, Accepted 10th March 2000
1
Organolithiums, Grignard reagents and borohydride reducing agents attack 2-acyl-1-naphthamides to give tertiary
and secondary alcohols with high or complete atroposelectivity. High levels of stereoselectivity can also be obtained
in the alkylations of enolates derived from the same ketones, though the low barrier to thermal epimerisation of the
product ketones prevents accurate determination of the kinetic stereoselectivity of the alkylation. The direction of
attack in both cases is controlled by the perpendicular conformation of the aromatic amide substituent, whose NR2
group shields one face of the ketone.
N-naphthylpyrimidine analogues of flavines32,33 and phenyl-
Introduction
pyridine analogues of NADH.34,35
In 2-substituted and 2,6-disubstituted tertiary benzamides the
We reviewed the atroposelective reactions of non-biaryl
aromatic ring and the planar, conjugated amide group lie more
atropisomers in 1997,36 and since then there have been further
or less perpendicular.1 Provided the benzene ring is unsym-
reports that rotational restriction in anilides and maleimides
metrically substituted, this conformation is chiral, and with a
exerts stereocontrol over enolate alkylations,37–39 aldol reac-
sufficiently large barrier to rotation about the Ar–CO bond the
tions,37 radical additions,40,41 and cycloadditions.40–43
enantiomeric conformers become atropisomers and the com-
In this paper and the two which follow we describe our stud-
ies into the use of a conformationally fixed amide substituent to
control the stereochemistry at new chiral centres by influencing
the direction in which reagents attack carbonyl groups (and
their derivatives) attached to the aromatic ring. We show that
the reactions of 1 may generally be explained by a model (Fig.
pounds are resolvable.2–5 We recently published our work on the
structural features necessary for conformational stability in
tertiary aromatic amides, particularly 2-substituted tertiary
naphthamides 1.6
The chirality inherent in the Ar–CO bond means that
hindered tertiary 1-naphthamides bearing chiral substituents
1) in which the perpendicular arrangement of the amide pres-
may exist as two diastereoisomers, and we have described the
ents the two faces of the naphthalene ring, and any substituents
diastereoselective synthesis of 2-(1-hydroxyalkyl)-1-naphth-
attached to the ring, with two very different steric environ-
ments. One face of the ring is sheltered by the nitrogen’s alkyl
amides by addition of ortholithiated 1-naphthamides to alde-
hydes.1,7 The level of diastereoselectivity in these reactions, in
substituents while the other is much more exposed to attack
which the stereogenic axis and the stereogenic centre are both
since the approach of a reagent is hindered only by the carbonyl
formed in the same step, reached about 90:10.
The use of axial chirality to control relative stereochemistry
oxygen atom. This paper will discuss nucleophilic attack on
2-acyl-1-naphthamides44 and electrophilic attack on their
has received rather less attention than its use (in the form of
enolates.45 The next paper46 will discuss 2-formyl-1-naphth-
chiral ligands) to control absolute stereochemistry.8 In the
amides and their derivatives, and will highlight the role of
biaryl series, binaphthyls9 have been used as chiral auxiliaries
metal–carbonyl coordination in their reactions, and the third
to control enolate alkylation,10–14 conjugate additions to
paper47 will discuss the stereoselective reactions of 8-acyl-1-
α,β-unsaturated carbonyl compounds,14–16 nucleophilic attack
naphthamides.
on aldehydes or ketones,17–22 intramolecular pinacol reac-
tions,23–25 cycloadditions,26 atroposelective formation of a
Synthesis of 2-acyl-1-naphthamides
second biaryl axis,27,28 and desymmetrisation of prochiral
anhydrides.29 Atroposelective reactions of the aromatic rings
To investigate the ability of the amide to direct attack on sub-
stituents attached to the naphthalene ring, we needed a range
of ketones 2–4. Each ketone was made by ortholithiation of
the parent N,N-dialkyl-1-naphthamide 5, 7 or 9 with s-BuLi,48
addition of the organolithium to an aldehyde RCHO,1 and
Jones oxidation of the resulting diastereoisomeric mixtures of
alcohols 6, 8 or 10 (Scheme 1).49
themselves, generating central chirality from axial chirality,
have been observed in the nucleophilic attack of fluoride on
an oxidised biphenyl derivative,30 in the deprotonation/
protonation of naphthylfluorenes,31 and in the oxidations of
Additions of organometallics to 2-acyl-1-naphthamides
Ketones 3b and 3f were each treated with methyllithium and
with methylmagnesium bromide. The tertiary alcohols 11 and
12 were isolated as single atropisomeric diastereoisomers in
excellent yield (Scheme 2). Analytical HPLC of the crude reac-
tion mixtures showed that in each case the diastereoselectivity
was >99:1. The sense of the selectivity was independent of the
metal: both MeLi and MeMgBr gave identical products.
Fig. 1 The directing influence of the amide group.
DOI: 10.1039/b000668h
J. Chem. Soc., Perkin Trans. 1, 2000, 1351–1361
This journal is © The Royal Society of Chemistry 2000
1351

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Fig. 2 X-Ray crystal structure of 13.
Scheme
2
Diastereoselective attack by nucleophiles on 2-acyl-
naphthamides: (i) MeMgBr, THF, Et2O, Ϫ78 ЊC; (ii) MeLi, THF, Et2O,
Ϫ78 ЊC; (iii) EtMgBr, THF, Et2O, Ϫ78 ЊC.
in a position to reduce the ketones 2–4 to the corresponding
alcohols using some nucleophilic hydride equivalents (Scheme
3). This enabled us to test the effect on the stereoselectivity of
varying the size of (a) the nucleophile and (b) the nitrogen’s two
alkyl substituents. Table 1 shows the result of treating the
ketones with each of three reducing agents of increasing steric
bulk: NaBH4, LiEt3BH and Li(s-Bu)3BH. The crude reaction
products were stored at Ϫ18 ЊC and analysed by HPLC to
determine product ratios. Yields in every case were essentially
quantitative.
Scheme 1 Synthesis of 2-acylnaphthamides: (i) s-BuLi, Ϫ78 ЊC, THF,
30 min; (ii) RCHO, Ϫ78 to Ϫ20 ЊC, 30 min; (iii) CrO3, H2SO4, H2O,
acetate, 0–20 ЊC, 70 min; (iv) t-BuLi, Ϫ78 ЊC, THF, 30 min.
The anti diastereoisomer is always the major product. In
order to clarify the origin of the diastereoselectivity of these
and other reactions of ketones 2–4 we determined the X-ray
crystal structure of ketone 3e (Fig. 3). The crystal structure
shows clearly the perpendicular arrangement of the amide and
The tertiary alcohol 13, which is diastereoisomeric with 11,
was made by a complementary route from the methyl ketone 3a
and ethylmagnesium bromide. Alcohol 13 was isolated in 96%
yield, and analytical HPLC of the crude reaction mixture again
showed >99:1 diastereoselectivity. The stereochemistry of 13
(and therefore also 11) was determined by an X-ray crystal
structure, shown in Fig. 2, and we assume that 12 is formed with
the same sense of diastereoselectivity. Although bond rotation
about Ar–CO should interconvert 11 and 13, the barrier to
rotation provided by the fully substituted carbon atom at the
2-position is very high, and 11 and 13 could not be made to
interconvert even by heating in toluene at 55 ЊC for 28 h (more
vigorous conditions led to decomposition).
the ring: the dihedral angle between the amide C᎐O and the
᎐
C1–C2 bond of the naphthalene ring is 96Њ. It also indicates
that the C2–C(᎐O) bond adopts an approximately s-cis con-
᎐
formation, maximising conjugation with the ring while avoiding
severe steric interactions between Ph and the amide. It is clear
that the two faces of the ketone in this conformation are
presented with very different steric environments: the amide’s
bulky NR2 group blocks one face, leaving the other open to
attack by nucleophiles. Exclusive attack from the face opposite
the amide’s NR2 group leads to the stereochemistry of 11–13,
and preferential attack from this face accounts for the anti
stereochemistry of the major diastereoisomers of 6, 8 and 10.
Coordination of the nucleophiles’ metal counter-ion to the
basic amide carbonyl group may also play a part in controlling
stereoselectivity.
Nucleophilic reductions of 2-acyl-1-naphthamides
We had already made the pairs of diastereoisomeric alcohols 6,
8 and 10 using the additions to aldehydes summarised in
Scheme 1, and had assigned their stereochemistry by a combin-
ation of crystallographic and NMR techniques.1 We were now
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Table 1 Stereoselective reduction of ketones 2, 3 and 4
Starting
materials
2 ϩ NaBH4
anti-6:syn-6
79:21
3 ϩ NaBH4
anti-8:syn-8
2 ϩ LiEt3BH
anti-6:syn-6
83:17
3 ϩ LiEt3BH
anti-8:syn-8
93:7
4 ϩ LiEt3BH
anti-10:syn-10
>99:1
3 ϩ Li(s-Bu)3BH
anti-8:syn-8
86:14
R =
a
Me
82:18
87:13a
80:20
86:14
89:11
95:5
b
c
d
e
Et
n-C5H11
i-Pr
86:14
81:19
87:13
86:14
88:12
87:13
89:11
97:3
93:7
98:2
92:8
—
—
—
89:11
—
—
Ph
140:1
>99:1
—
a Reaction carried out at Ϫ40 ЊC.
thalene ring and the amide substituents. For 2a–2d and 3a–3d
there is rather little variation in selectivity between substituents,
but the diaryl ketones 3e and to some extent 2e are reduced with
significantly greater selectivity.
More significant is the change in stereoselectivity on
changing N-substituents. With LiBHEt3, N(CHPr2)2 ketones 4
were reduced with complete anti selectivity, Ni-Pr2 ketones 3
were reduced with >90:10 selectivity, while NEt2 ketones 2 were
reduced with 80:20–90:10 selectivity. The results with the
smaller NaBH4 are less consistent. Clearly, in general, larger
N-substituents block more effectively the more hindered face of
the ketone, though in view of the complete selectivity obtained
in the reactions of Ni-Pr2 ketones 3 with alkyllithium and
Grignard reagents it is surprising that as much as 10–20% of
the syn isomer is formed. The dependence of selectivity on the
N-substituent could also be a conformational effect, attribut-
able to slight changes in the angle at which the ketone is
attacked.
LiBHEt3 was the most stereoselective reducing agent we
tried. The less bulky NaBH4 performed less well in almost all
cases, and stereoselectivity was not improved by using the even
more hindered LiBH(s-Bu)3. For high stereoselectivity, the
choice of reagent is more important than the choice of
N-substituent, and although N(CHPr2)2 ketones 4 exhibit the
highest levels of selectivity, they are the most inconvenient to
make.1
Fig. 3 X-Ray crystal structure of 3e.
Enolate alkylations of 2-acyl-1-naphthamides
Among the most successful and widely used stereoselective
reactions are the alkylations of chiral enolates,50 and Simpkins
has employed the atroposelective alkylation of enolates derived
from rotationally restricted anilides in a chiral auxiliary
strategy.37,38,51 We found that the lithium enolate of ketone 3b
was too unreactive to be alkylated by BnBr (Table 2, entry 1),
but that the sodium enolates of 3b and 3f, made by treating the
ketone with NaHMDS at Ϫ78 ЊC, could be alkylated with MeI
or BnBr in 1–2 h at room temperature, and gave 82–87% yields
of the alkylated ketones 14–16 as mixtures of atropisomers
(Scheme 4 and Table 2, entries 2–4).
Because of the danger of epimerising the products at this
temperature, a point discussed further below, we turned to the
even more reactive potassium enolates, formed with KHMDS
at Ϫ78 ЊC, to get alkylation at or below 0 ЊC. The potassium
enolate of 3f was alkylated with MeI at Ϫ78 ЊC, and a cold
aqueous work-up of the reaction gave the atropisomeric
products in a rather disappointing 67:33 ratio (entry 7). The
reaction of the potassium enolate of 3f with BnBr was too slow
to give product at Ϫ78 ЊC, but a 75:25 ratio of benzylated
ketones was obtained after alkylation at 0 ЊC for 30 min, along
with 6% of 18, the product of O-alkylation (entry 6). Similarly,
the potassium enolate of 4f gave a 95:5 ratio of diastereo-
isomers with BnBr at 0 ЊC (entry 8). The potassium enolate
of 3b reacted with BnBr at room temperature to give a 58:42
mixture of diastereoisomers (entry 5).
Scheme 3 Stereoselective reduction of ketones 2–4: (i) NaBH4, EtOH,
0 ЊC; (ii) LiBHEt3, THF, 0 ЊC; (iii) Li(s-Bu)3BH, THF, 0 ЊC.
The difference in selectivity between reductions of ketones
2–4 bearing different R groups may be due to fine tuning of the
reactive conformation: changing R may affect by a few degrees
the angle of attack of the reducing agent relative to the naph-
J. Chem. Soc., Perkin Trans. 1, 2000, 1351–1361
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Table 2 Stereoselective alkylation of ketone enolates
Starting
ketone
Alkylatinga
agent
Yield
(%)
Ratioa
syn:anti
Thermodynamic
Entry
Base
Temp./ЊC
Product
ratiob syn:anti
1
2
3
4
5
6
7
8
3b
3b
3f
3f
3b
3f
3f
4f
LDA
BnBr
BnBr
BnBr
MeI
BnBr
BnBr
MeI
20
20
20
20
20
0
—
14
15
16
14
15
16
17
0
—
—
—
—
58:42
75:25
67:33
95:5
—
—
—
—
58:42
25:75
48:52
17:83
NaHMDS
NaHMDS
NaHMDS
KHMDS
KHMDS
KHMDS
KHMDS
85
82c
87
83
84d
71
Ϫ78
BnBr
0
83
a By NMR. b Ratio after standing in ether for several days at 20 ЊC. c With a trace of enol ether 18. d Also isolated 6% of enol ether 18.
rotation is typical of atropisomers bearing trigonal blocking
substituents.52 The otherwise comparable secondary alcohols 6
and 8 have half-lives for epimerisation at 20 ЊC measured in
weeks, and the epimerisation of tertiary alcohols 11 and 13
could not be observed at 55 ЊC (half life at 20 ЊC >4 years).6
It appears therefore that with sodium enolates the rate of
product epimerisation approaches the rate of alkylation, and
we expect any reaction carried out at 20 ЊC to give a product
ratio significantly affected by epimerisation during the alkyl-
ation. To investigate whether the alkylations of the potassium
enolates were under purely kinetic control we allowed the prod-
uct mixtures to stand in solution in ether at 20 ЊC for 3–7 days
(see final column of Table 2). In three cases (entries 6–8) the
product mixture attained a thermodynamic equilibrium in
which the minor product from the initial reaction mixture con-
stituted the major component. Only the alkylation of 3b to give
14, which had been carried out at 20 ЊC (entry 5), maintained
the same ratio of products, which presumably therefore does
not represent the kinetic selectivity of the reaction.
We can therefore be sure that the ratios observed directly
from the reactions at Ϫ78 ЊC or 0 ЊC are not purely under
thermodynamic control: while some epimerisation may have
taken place during reaction or work-up, the major kinetic
product is in each case the opposite diastereoisomer from the
major thermodynamic product. Nonetheless, only in the alkyl-
ation of 4f at 0 ЊC to give 17 (entry 8) may we be certain of
having isolated close to the kinetic product mixture, which must
contain at least 95% syn-17.
We expect high levels of kinetic stereocontrol only from a
geometrically pure intermediate, and silylating the potassium
enolates of 3b and 3f with Me3SiCl at Ϫ78 ЊC indeed gave the
silyl enol ethers 19 and 20 as single geometrical isomers, which
we presume to have Z stereochemistry (Scheme 5).
Scheme 4 Alkylation of enolates: (i) base, Ϫ78 ЊC (see Table 2); (ii)
BnBr; (iii) MeI.
The poor stereoselectivities observed in most of these reac-
tions may be, at least in part, a consequence of the low barrier
to epimerisation (by Ar–CO rotation†) of the products. The
atropisomeric diastereoisomers of 14 and 16 were separable by
HPLC, but isolation of pure samples of the diastereoisomers
was hampered by rapid epimerisation. By cooling the HPLC
column and eluent, it was possible to obtain a sample of 16
enriched to 78:22 syn:anti. Using published methods,6 we
determined a value of 96.8 kJ molϪ1 for ∆G‡epim, the barrier to
Scheme 5 O-Silylation of potassium enolates: (i) KHMDS, Ϫ78 ЊC;
(ii) Me3SiCl, Ϫ78 ЊC.
We were unable to prove unambiguously the stereochemistry
of the enolate alkylation products. In an attempt to obtain a
crystalline compound for X-ray crystal structure analysis, we
reduced with LiBHEt3 the 17:83 mixture of atropisomers
obtained from the epimerisation of 17. Only two products 21
and 22 were formed, and we assume that, like the reductions of
4a and 4e, the stereoselectivity of the reaction is controlled
entirely by the amide axis, and that each product diastereo-
isomer arises from a single starting material diastereoisomer
epimerisation, of syn-16. Assuming constancy of ∆G‡
with
epim
temperature,6 this corresponds to a half-life for the epimeris-
ation of about 3 h at 20 ЊC, or 2 days at 0 ЊC. Rapid bond
† In the racemic series it is impossible to distinguish between an epimer
produced by Ar–CO rotation and one produced by unselective alkyl-
ation. In the enantiomerically pure series, of course, the epimers arising
in each case would be enantiomeric.
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HPLC was carried out on a Waters Z Module (10 cm by 8 mm,
packed SiO2 stationary phase) at a pressure of 200 lb inϪ2 at
room temperature using a Waters 510 pump with the flow rate
at 2.0 ml minϪ1. Detection was at 280 nm using a Perkin-Elmer
LC 480 Auto Scan Diode Array detector. Preparative HPLC
was carried out on a Dynamax-60A column at a pressure of
0.15 kPa at room temperature using a Gilson 305 Pump with
flow rate at 15.0 ml minϪ1. Detection was at 280 nm using a
Gilson 115 UV Detector. Ether refers to diethyl ether; petrol
refers to petroleum ether (bp 40–60 ЊC). J values are in Hz.
Barriers to racemisation or epimerisation of 3b, 6a, 6e, 8a, 8b,
8e, 13 and 16 have been published elsewhere.6
Fig. 4 Stereoselective alkylation of 4f.
2-Acetyl-N,N-diethyl-1-naphthamide 2a
A stock solution of oxidising agent was prepared by dissolving
CrO3 (2.5 g) in 20% sulfuric acid. The mixture of diastereoiso-
meric alcohols 6a1 (219 mg, 0.81 mmol) was dissolved in acet-
one (8 ml) and the solution was cooled to 0 ЊC. The CrO3 solu-
tion (0.8 ml) was added, and the orange mixture was stirred for
40 min at 0 ЊC and 30 min at room temperature. The reaction
mixture was poured into saturated NaHCO3 solution (50 ml)
and extracted with EtOAc (20 ml × 4). The combined organic
extracts were washed with water (50 ml), dried (MgSO4) and
concentrated under reduced pressure to afford the ketone 2a
(218 mg, 100%), as a white solid which was used without further
purification. Rf (EtOAc) 0.45; νmax(film)/cmϪ1 3015, 1687, 1619;
δH(200 MHz, CDCl3) 8.0–7.8 (4 H, m, ArH), 7.7–7.5 (2 H, m,
ArH), 3.85 (1 H, dq, J 14 and 7, NCHAHBMe), 3.65 (1 H, dq,
J 14 and 7, NCHAHBMe), 3.02 (2 H, q, J 7, NCH2Me), 2.69 (3
H, s, MeCO), 1.44 (3 H, t, J 7, NCH2Me) and 0.90 (3 H, t, J 7,
NCH2Me); δC(75 MHz, CDCl3) 199.0, 169.5, 136.5, 135.1,
131.1, 129.7, 128.7, 128.4, 128.0, 127.6, 126.9, 124.9, 42.8, 38.7,
28.6, 13.3 and 12.3; m/z (CI) 270 (100%, M ϩ Hϩ) and 197
(73%, M Ϫ NEt2) (Found: Mϩ, 269.1412. C17H19NO2 requires
M, 269.1416).
Scheme 6 Reduction of alkylated ketones: (i) LiBHEt3, 0 ЊC, THF.
(Scheme 6). Unfortunately, while both of the alcohols 21 and 22
were solids, neither gave crystals of sufficiently high quality for
X-ray analysis.
We were able to make a tentative assignment of stereo-
chemistry from the fact that the more thermodynamically stable
atropisomer is in each case the minor product of enolate alkyl-
ation. 350 Conformations of 17 were minimised in a Monte
Carlo conformational search (Macromodel 4.5/MM2*):‡ of the
12 lowest energy conformers only one (the fifth most stable,
at 9.7 kJ molϪ1 above the global minimum) had syn relative
stereochemistry. Similarly, of 100 conformations of 15 found by
a Monte Carlo search, the three most stable had syn relative
stereochemistry, and the most stable anti conformer lay 7.6 kJ
molϪ1 above the global minimum. We conclude that anti-17 and
anti-15 are more stable than their syn epimers, and that the
major products of the alkylations have syn stereochemistry,
presumably arising from attack of the electrophile on the less
hindered face of the cis enolate in the conformation shown
(for 4f) in Fig. 4. Rationalising the degree of stereoselectivity is
impossible because it is not clear how much the lower selec-
tivities obtained with 3 reflect a lower level of kinetic stereo-
control and how much simply a greater propensity to epimerise
at the reaction temperature.
Ketone 4f is the only compound in which the amide axis
is demonstrably able to control enolate alkylation. The
N(CHPr2)2 amides 4 illustrate well the power of a suitably
substituted amide axis to control stereoselectivity: they can be
both alkylated and reduced highly stereoselectively; the enolate
alkylation product can usefully be thermally epimerised to give
the other diastereoisomer, and each of these two diastereo-
isomers can be reduced to a single alcohol. However, the low
yields in the synthesis of 9 and 4, and the lack of crystallinity in
the derivatives of 5, have meant that we have used 7 and its
derivatives for most subsequent work.
N,N-Diethyl-2-propanoyl-1-naphthamide 2b
In the same way, the alcohols 6b1 (390 mg, 1.37 mmol) gave
the ketone 2b (348 mg, 90%) as a white solid which was used
without further purification. νmax(film)/cmϪ1 2990, 1689, 1619;
δH(200 MHz, CDCl3) 8.0–7.8 (4 H, m, ArH), 7.6–7.4 (2 H, m,
ArH), 3.75 (2 H, ABX3 m, NCH2Me), 3.15–2.85 (4 H, m,
NCH2Me and MeCH2CO), 1.42 (3 H, t, J 7, NCH2Me), 1.20
(3 H, t, J 7, MeCH2CO) and 0.88 (3 H, t, J 7, NCH2Me);
δC(75 MHz, CDCl3) 202.0, 169.6, 136.2, 134.9, 131.5, 129.7,
128.6, 128.2, 128.0, 127.5, 127.2, 126.7, 124.3, 43.0, 38.8, 34.0,
13.3, 12.5 and 8.2; m/z (CI) 284 (90%, M ϩ Hϩ), 211 (80%,
M Ϫ NEt2) and 72 (100%, NEt2ϩ) (Found: Mϩ, 283.1566.
C18H21NO2 requires M, 283.1572).
N,N-Diethyl-2-hexanoyl-1-naphthamide 2c
In the same way, the alcohols 6c1 (140 mg, 0.43 mmol) gave a
crude product which was purified by flash chromatography
(eluting with 2:1 petrol–EtOAc) the ketone 2c (112 mg, 80%) as
a white solid. Rf (2:1 petrol–EtOAc) 0.36; νmax(film)/cmϪ1 3013,
2968, 1688, 1620; δH(200 MHz, CDCl3) 8.0–7.8 (4 H, m, ArH),
7.6–7.5 (2 H, m, ArH), 3.75 (2 H, ABX3 m, NCH2Me), 3.0 (4 H,
m, NCH2Me and CH2CO), 1.72 (2 H, m, CH2CH2CO), 1.40
(3 H, t, J 7, NCH2Me), 1.35 (4 H, m, MeCH2CH2) and 0.92
(6 H, t, J 7, NCH2Me and MeCH2CH2); δC(75 MHz, CDCl3)
201.8, 169.5, 136.2, 134.9, 131.8, 129.7, 128.6, 128.2, 128.0,
127.5, 126.7, 124.4, 43.0, 40.8, 38.7, 31.5, 24.0, 22.5, 14.0, 13.3
and 12.5; m/z (CI) 326 (100%, M ϩ Hϩ) and 253 (65%,
M Ϫ NEt2) (Found: Mϩ, 325.2045. C21H27NO2 requires M,
325.2042).
Experimental
Flash chromatography refers to chromatography carried out on
silica by the method of Still, Kahn and Mitra.54 Analytical
‡ The Monte Carlo search was carried out using the MM2* force-
field in Macromodel 4.5,53 using a G3 Macintosh with X-windows
emulation of a Silicon Graphics workstation. Seven (15) or fifteen (17)
rotatable bonds were selected, and the Polak–Ribière method was used
to minimise the energy of each conformation.
N,N-Diethyl-2-(2-methylpropanoyl)-1-naphthamide 2d
In the same way, the alcohols 6d1 (498 mg, 1.66 mmol) gave the
ketone 2d (399 mg, 80%) as a waxy solid. Rf (1:1 petrol–EtOAc)
J. Chem. Soc., Perkin Trans. 1, 2000, 1351–1361
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0.47; νmax(film)/cmϪ1 3010, 2978, 1688, 1619; δH(200 MHz,
CDCl3) 8.0–7.8 (3 H, m, ArH), 7.75 (1 H, d, J 9, ArH), 7.6–7.5
(2 H, m, ArH), 3.72 (2 H, ABX3 m, JAX = JBX = 7, NCH2Me),
3.49 (1 H, septet, J 7, CHMe2), 3.04 (2 H, q, J 7, NCH2Me),
1.40 (3 H, t, J 7, NCH2Me), 1.23 (3 H, d, J 7, CHMeAMeB), 1.18
(3 H, d, J 7, CHMeAMeB) and 0.91 (3 H, t, J 7, NCH2Me);
δC(75 MHz, CDCl3) 206.3, 169.4, 136.3, 134.7, 132.0, 130.0,
128.5, 128.05, 128.0, 127.5, 126.6, 124.1, 43.1, 38.8, 37.7, 18.8,
18.6, 13.4 and 12.6; m/z (CI) 298 (80%, M ϩ Hϩ) and 225
(100%, M Ϫ NEt2) (Found: Mϩ, 297.1723. C19H23NO2 requires
M, 297.1729).
20.8, 20.1, 20.0 and 14.0; m/z (CI) 354 (70%, M ϩ Hϩ), 253
(75%) and 100 (100%) (Found: Mϩ, 353.2348. C23H31NO2
requires M, 325.2355).
N,N-Diisopropyl-2-(2-methylpropanoyl)-1-naphthamide 3d
In the same way, the alcohols 8d1 (750 mg, 2.25 mmol) gave the
ketone 3d (663 mg, 88%) as a white solid. νmax(film)/cmϪ1 3016,
2978, 1688, 1621; δH(200 MHz, CDCl3) 8.0 (1 H, m, ArH), 7.85
(2 H, m, ArH), 7.72 (1 H, d, J 9, ArH), 7.6–7.5 (2 H, m, ArH),
3.59 (1 H, septet, J 7), 3.51 (1 H, septet, J 7), 3.39 (1 H, septet,
J 7, CHMe2 × 3), 1.76 (3 H, d, J 7, NCHMeAMeB), 1.72 (3 H,
d, J 7, NCHMeAMeB), 1.23 (3 H, d, J 7, COCHMeAMeB),
1.19 (3 H, d, J 7, COCHMeAMeB), 1.13 (3 H, d, J 7, NCH-
MeAMeB) and 0.93 (3 H, d, J 7, NCHMeAMeB); δC(75 MHz,
CDCl3) 206.4, 168.8, 136.7, 134.7, 131.7, 129.8, 128.0, 127.95,
127.9, 127.2, 126.6, 124.3, 51.3, 46.1, 37.9, 20.9, 20.7, 20.0,
19.9, 18.7 and 18.6; m/z (CI) 328 (60%, M ϩ Hϩ), 225 (90%)
and 100 (100%) (Found: Mϩ, 325.2034. C19H23NO2 requires M,
325.2042).
2-Benzoyl-N,N-diethyl-1-naphthamide 2e
In the same way, the alcohols 6e1 (525 mg, 1.4 mmol) gave the
ketone 2e (435 mg, 83%) as a gum. Rf (4:1 petrol–EtOAc) 0.25;
νmax(film)/cmϪ1 3007, 1661, 1620; δH(200 MHz, CDCl3) 8.0–7.4
(11 H, m, ArH), 3.76 (1 H, dq, J 14 and 7, NCHAHBMe), 3.48
(1 H, dq, J 14 and 7, NCHAHBMe), 3.18 (2 H, q, J 7, NCH2-
Me), 1.26 (3 H, t, J 7, NCH2Me), 1.23 (3 H, d, J 7, CHMeAMeB)
and 0.98 (3 H, t, J 7, NCH2Me); δC(75 MHz, CDCl3) 197.0,
168.5, 137.3, 136.3, 134.4, 133.1, 130.4, 129.6, 128.3, 128.2,
127.9, 127.8, 127.6, 127.2, 126.3, 125.6, 43.4, 38.7, 13.5 and
12.5; m/z (CI) 332 (40%, M ϩ Hϩ) and 259 (100%, M Ϫ NEt2)
(Found: Mϩ, 331.1568. C19H23NO2 requires M, 331.1572).
2-Benzoyl-N,N-diethyl-1-naphthamide 3e
In the same way, the alcohols 8e1 (94 mg, 0.25 mmol) gave the
ketone 3e (82 mg, 88%) as a solid. Rf (4:1 petrol–EtOAc) 0.22;
νmax(film)/cmϪ1 3016, 2978, 1664, 1625; δH(200 MHz, CDCl3)
8.05–7.4 (11 H, m, ArH), 3.63 (1 H, septet, J 7, NCHMe2), 3.53
(1 H, septet, J 7, NCHMe2), 1.69 (3 H, d, J 7, NCHMeAMeB),
1.42 (3 H, d, J 7, NCHMeAMeB), 1.20 (3 H, d, J 7, NCH-
MeAMeB) and 0.98 (3 H, d, J 7, NCHMeAMeB); δC(75 MHz,
CDCl3) 197.1, 168.0, 137.6, 136.9, 134.4, 133.0, 132.6, 130.6,
128.6, 128.2, 127.8, 127.4, 127.3, 126.4, 125.8, 51.5, 46.2, 21.0,
20.6, 20.0 and 19.8; m/z (CI) 360 (30%, M ϩ Hϩ), 259 (100%)
and 100 (85%) (Found: Mϩ, 359.1876. C24H25NO2 requires M,
359.1885).
2-Acetyl-N,N-diisopropyl-1-naphthamide 3a
In the same way, the alcohols 8a1 (386 mg, 1.29 mmol) gave the
ketone 3a (383 mg, 100%). The crude product was recrystallised
from ethanol to afford yellow prisms. Mp 184–186 ЊC (EtOH),
λmax/nm (εmax) (CH2Cl2) 252 (57654), 294 (9168), 338 (2847);
νmax(film)/cmϪ1 2976, 2935, 2904, 2875, 1690, 1621; δH(300
MHz, CDCl3) 8.06 (1 H, d, J 8, ArH), 7.88 (3 H, m, ArH), 7.60
(2 H, m, ArH), 3.66 (1 H, septet, J 6.5, NCH), 3.39 (1 H, septet,
J 6.5, NCH), 2.71 (3 H, s, COCH3), 1.81 (6 H, d, J 6.5,
2 × NCHCH3), 1.13 (3 H, d, J 6.5, NCHCH3) and 0.96 (3 H, d,
J 6.5, NCHCH3); δC(75 MHz, CDCl3) 198.8, 168.9, 137.2,
135.1, 130.4, 129.6, 128.3, 128.1, 127.9, 127.2, 126.8, 125.0,
51.3, 46.1, 28.7, 20.8, 20.7, 20.0 and 19.7; m/z (CI) 298 (100%,
M ϩ Hϩ) (Found: M ϩ Hϩ, 298.1801. C19H23NO2 requires
M ϩ H, 298.1807).
N,N-Diisopropyl-2-(3Ј-methylbutanoyl)-1-naphthamide 3f
Following our previously published method1 for the synthesis
of alcohols 8, s-butyllithium (27.0 ml of a 1.3 M solution in
hexanes, 35.2 mmol) and, 30 min later, isovaleraldehyde (6.0 ml,
5.6 mmol) were added to a solution of naphthamide 7 (6.900 g,
27.06 mmol) in THF (150 ml) at Ϫ78 ЊC. After 30 min the
mixture was warmed to Ϫ20 ЊC, quenched with saturated
aqueous ammonium chloride solution (30 ml) and worked up
as described to yield the crude alcohols 8f as an oil. Without
further purification, the crude alcohols 8f were oxidised by the
method used for 2a to yield a crude product which was
recrystallised from ethanol to give the ketone 3f (4.165 g, 45%)
as white prisms. Mp 135–136 ЊC (EtOH); νmax(film)/cmϪ1 3062,
2971, 2958, 2933, 2871, 1688, 1629; δH(300 MHz, CDCl3)
8.1–7.5 (6 H, m, ArH), 3.66 (1 H, septet, J 7, NCH), 3.43 (1 H,
septet, J 7, NCH), 2.92 (2 H, d, J 7, CH2), 2.33 (1 H, nonet, J 7,
CH2CH), 1.80 (3 H, d, J 7, NCHCH3), 1.78 (3 H, d, J 7,
NCHCH3), 1.17 (3 H, d, J 7, NCHCH3), 1.04 (3 H, d, J 6.5,
CH2CHCH3), 1.03 (3 H, d, J 6.5, CH2CHCH3) and 0.96 (3 H, d,
J 6.5, NCHCH3); δC(75 MHz, CDCl3) 201.7, 168.8, 136.8,
134.8, 131.6, 129.6, 128.0, 127.9, 127.1, 126.7, 124.4, 51.3, 49.8,
46.1, 25.2, 22.7, 22.6, 20.7, 20.6, 19.9 and 19.8; m/z (CI) 340
(100%, M ϩ Hϩ); m/z (EI) 339 (3%, Mϩ) and 49 (100%)
(Found: C, 77.85; H, 8.74; N, 4.15%. C22H29NO2 requires C,
77.9; H, 8.6; N, 4.1%).
N,N-Diisopropyl-2-propanoyl-1-naphthamide 3b
In the same way, the alcohols 8b1 (260 mg, 0.83 mmol) gave a
crude product which was recrystallised from ethanol to afford
the ketone 3b (222 mg, 86%) as pale yellow needles. Mp 170–
174 ЊC; νmax(film)/cmϪ1 2976, 2935, 2904, 2875, 1690, 1621;
δH(300 MHz, CDCl3) 7.93 (1 H, m, ArH), 7.73 (3 H, m, ArH),
7.45 (2 H, m, ArH), 3.52 (1 H, septet, J 6.5, NCH), 3.28 (1 H,
septet, J 6.5, NCH), 2.95 (2 H, m, CH2CH3), 1.68 (6 H, d, J 6.5,
2 × NCHCH3), 1.13 (3 H, t, J 7.0, CH2CH3), 1.00 (3 H, d, J 6.5,
NCHCH3) and 0.83 (3 H, d, J 6.5, NCHCH3); δC(75 MHz,
CDCl3) 201.8, 168.9, 136.7, 134.9, 130.9, 129.6, 128.1, 128.0,
127.9, 127.1, 126.7, 124.4, 51.3, 46.0, 34.0, 20.8, 20.7, 19.9, 19.8
and 8.2; m/z (CI) 312 (67%, M ϩ Hϩ) and 180 (100%) (Found:
Mϩ, 311.1881. C20H25NO2 requires M, 311.1885).
N,N-Diisopropyl-2-hexanoyl-1-naphthamide 3c
In the same way, the alcohols 8c1 (602 mg, 1.76 mmol) gave the
ketone 3c (527 mg, 88%) as a white solid. Rf (2:1 petrol–EtOAc)
0.47; νmax(film)/cmϪ1 3016, 2976, 1686, 1620; δH(200 MHz,
CDCl3) 8.05 (1 H, m, ArH), 7.8 (3 H, m, ArH), 7.6–7.5 (2 H,
m, ArH), 3.60 (1 H, septet, NCHMe2), 3.36 (1 H, septet,
NCHMe2), 2.98 (2 H, ABXY m, CH2CO), 1.75 (6 H, d, J 7,
NCHMe2), 1.73 (2 H, m, CH2CH2CO), 1.35 (4 H, m,
CH2CH2Me), 1.10 (3 H, d, J 7, NCHMeAMeB), 0.91 (3 H, d,
J 7, NCHMeAMeB) and 0.88 (3 H, t, CH2Me); δC(75 MHz,
CDCl3) 202.0, 168.9, 136.9, 135.0, 131.4, 129.8, 128.1, 128.05,
128.0, 127.2, 126.8, 124.5, 51.4, 46.2, 41.1, 31.5, 24.1, 22.5, 20.9,
2-Acetyl-N,N-bis(4-heptyl)-1-naphthamide 4a
By the method used for 2a, the alcohols 10a1 gave, after purifi-
cation by flash chromatography (2:1 petrol–EtOAc), the ketone
4a (99 mg, 63%) as a colourless oil. Rf (2:1 petrol–EtOAc) 0.40;
νmax(film)/cmϪ1 2958, 2930, 2870, 1680, 1624; δH(300 MHz,
CDCl3) 8.09 (1 H, m, ArH), 7.84 (3 H, m, ArH), 7.55 (2 H, m,
ArH), 3.00 (1 H, m, NCH), 2.80 (1 H, m, NCH), 2.68 (3 H, s,
COCH3), 2.47–2.03 (4 H, m, 2 × NCHCH2CH2CH3), 1.69–0.54
1356
J. Chem. Soc., Perkin Trans. 1, 2000, 1351–1361

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(12 H, m, 2 × NCHCH2CH2CH3 and 4 × NCHCH2CH2CH3),
1.04 (3 H, t, J 7, NCHCH2CH2CH3), 1.03 (3 H, t, J 7, NCH-
CH2CH2CH3), 0.69 (3 H, t, J 7, NCHCH2CH2CH3) and 0.37
(3 H, t, J 7, NCHCH2CH2CH3); δC(75 MHz, CDCl3) 198.3,
169.4, 136.9, 135.1, 130.4, 129.9, 128.2, 127.7, 127.7, 126.8,
124.9, 59.8, 56.9, 36.9, 35.9, 35.4, 28.8, 21.9, 21.7, 20.4, 20.0,
14.4, 14.4, 13.8 and 13.0; m/z (CI) 410 (100%, M ϩ Hϩ); m/z
(EI) 409 (13%, Mϩ) and 197 (100%) (Found: Mϩ, 409.2974.
C27H39NO2 requires M, 409.2981).
reduced pressure at ambient temperature and the aqueous resi-
due was extracted with dichloromethane (4 × 10 ml). The com-
bined organic fractions were washed with brine (30 ml), dried
(MgSO4), filtered and concentrated under reduced pressure at
ambient temperature to afford the crude product as a brown
solid. Analytical HPLC of the crude product indicated the
presence of no more than 1% 13. Flash chromatography (4:1
petrol–EtOAc) afforded the alcohol 11 (57 mg, 86%) as a white
solid. tR 7.9 min (4:1 hexane–EtOAc); Rf 0.61 (2:1 petrol–
EtOAc); mp 146–148 ЊC (EtOAc); νmax(film)/cmϪ1 3387–3424,
1609; δH(300 MHz, CDCl3) 8.0–7.3 (6 H, m, ArH), 3.6 (2 H, m,
2 × NCH), 2.14 (1 H, dq, J 14 and 7.5, CHAHBCH3), 1.93 (1 H,
dq, J 14 and 7.5, CHAHBCH3), 1.81 (3 H, d, J 7, NCHCH3),
1.68 (3 H, d, J 7, NCHCH3), 1.64 (3 H, s, C(OH)CH3), 1.19
(3 H, d, J 6.5, NCHCH3), 1.00 (3 H, d, J 6.5, NCHCH3) and
0.97 (3 H, t, J 7.5, CH2CH3); δC(75 MHz, CDCl3) 172.7, 141.7,
131.9, 131.9, 130.1, 127.9, 127.6, 126.3, 125.8, 125.0, 124.9,
76.9, 51.4, 46.0, 35.3, 32.5, 20.3, 20.2, 19.75, 19.7 and 8.4; m/z
(CI) 328 (97%, M ϩ Hϩ) and 310 (100%, M Ϫ OH) (Found:
Mϩ, 327.2205. C21H29NO2 requires M, 327.2198).
2-Benzoyl-N,N-bis(4-heptyl)-1-naphthamide 4e
In the same way, the alcohols 10e (101 mg, 0.21 mmol) gave a
crude product which was purified by flash chromatography (3:1
petrol–EtOAc) to yield the ketone 4e (87 mg, 86%) as a waxy
white solid. νmax(film)/cmϪ1 2958, 2932, 2871, 1662, 1627;
δH(300 MHz, CDCl3) 8.09 (1 H, m, ArH), 7.88 (4 H, m, ArH),
7.57 (4 H, m, ArH), 7.44 (2 H, m, ArH), 3.70 (1 H, m, NCH),
2.87 (1 H, m, NCH), 2.29 (1 H, m, NCHCHAHBCH2CH3),
2.03–1.77 (2 H, m, NCHCH2CH2CH3), 1.61–0.57 (13 H, m,
NCHCHAHBCH2CH3, 2 × NCHCH2CH2CH3, 4 × NCHCH2-
CH2CH3), 0.99 (3 H, t, J 7.1, CH3), 0.83 (3 H, t, J 7.3, CH3),
0.73 (3 H, t, J 7.3, CH3) and 0.47 (3 H, t, J 7.4, CH3); δC(75
MHz, CDCl3) 196.6, 168.0, 137.0, 135.4, 134.5, 133.1, 132.2,
130.8, 129.9, 128.1, 127.9, 127.9, 127.7, 127.2, 126.9, 125.7,
60.2, 57.0, 36.9, 36.5, 35.7, 34.8, 21.7, 21.6, 20.5, 20.1, 14.4,
14.4, 14.0 and 13.2; m/z (CI) 472 (100%, M ϩ Hϩ); m/z (EI) 471
(4%, Mϩ) and 84 (100%) (Found: Mϩ, 471.3149. C32H41NO2
requires M, 471.3137).
In the same way, ketone 3b (58 mg, 0.19 mmol) and methyl-
lithium (0.16 ml, 0.22 mmol; 1.4 M in diethyl ether) gave a
crude product containing no more than 1% 13 by analytical
HPLC. Purification by flash chromatography on silica gel (4:1
petrol–EtOAc) afforded alcohol 11 (61 mg, 100%).
(Ra*,1ЈR*)-N,N-Diisopropyl-2-(1Ј-hydroxy-1Ј,3Ј-dimethyl-
butyl)-1-naphthamide 12
In the same way, ketone 3f (65 mg, 0.19 mmol) and methyl-
N,N-Bis(4-heptyl)-2-(3Ј-methylbutanoyl)-1-naphthamide 4f
magnesium bromide (0.08 ml, 0.23 mmol; 3 M in diethyl ether)
1
gave a crude product which H NMR showed to be a single
tert-Butyllithium (1.06 ml of a 1.7 M solution in pentane, 1.80
mmol) was added to a solution of naphthamide 91 (602 mg,
1.64 mmol) in THF (27 ml) at Ϫ78 ЊC under an atmosphere of
nitrogen and the mixture was stirred at Ϫ78 ЊC for 2 hours. The
resulting brown solution was treated with isovaleraldehyde
(0.57 ml, 4.92 mmol), stirred for 60 minutes, warmed to ambi-
ent temperature and quenched with saturated aqueous ammo-
nium chloride (10 ml). The THF was removed under reduced
pressure and the resulting aqueous suspension was extracted
with dichloromethane (4 × 15 ml). The combined organic
extracts were dried (MgSO4), filtered and concentrated under
reduced pressure to afford the crude alcohols 10f. Without fur-
ther purification, the alcohols 10f were oxidised by the method
used for 2a. Purification by flash chromatography on silica gel
(10:1 petrol–EtOAc) afforded the ketone 4f (167 mg, 23%) as
a white solid. Mp 124–125 ЊC (EtOAc); Rf 0.24 (5:1 petrol–
EtOAc); νmax(film)/cmϪ1 2957, 2932, 2870, 1687, 1624; δH(300
MHz, CDCl3) 7.98 (1 H, m, ArH), 7.9–7.8 (3 H, m, ArH), 7.6–
7.5 (2 H, m, ArH), 3.00 (1 H, br m, NCH), 2.90 (2 H, d, J 6.5,
COCH2), 2.82 (1 H, br m, NCH), 2.5–2.0 (5 H, m, 2 × NCH-
CH2CH2CH3 and CH(CH3)2), 1.72–1.14 (10 H, m, 2 × NCH-
CH2CH2CH3 and 3 × NCHCH2CH2CH3), 1.10–0.97 (12 H, m,
2 × NCHCH2CH2CH3 and CH(CH3)2), 0.71 (3 H, t, J 7,
NCH(CH2)2CH3), 0.67 (2 H, m, NCHCH2CH2CH3) and 0.22
(3 H, t, J 7.3, NCH(CH2)2CH3); δC(75 MHz, CDCl3) 201.1,
169.4, 136.3, 134.8, 131.6, 129.9, 128.1, 128.0, 127.7, 127.5,
126.7, 124.4, 59.8, 57.0, 50.0, 36.8, 36.0, 35.9, 25.0, 22.7, 22.7,
21.9, 21.7, 20.5, 20.1, 14.4, 13.8 and 13.1; m/z (CI) 452 (100%,
M ϩ Hϩ) (Found: Mϩ, 451.3453. C30H45NO2 requires M,
451.3450).
diastereoisomer. Flash chromatography (4:1 petrol–EtOAc)
afforded the alcohol 12 (59 mg, 87%) as colourless blades. Mp
120–123 ЊC (EtOAc); νmax(film)/cmϪ1 3425, 3061, 2974, 2963,
2936, 2869, 1611; δH(300 MHz, CDCl3) 7.9–7.2 (6 H, m, ArH),
3.54 (1 H, septet, J 6.5, NCH), 3.52 (1 H, septet, J 6.5, NCH),
1.98–1.44 (3 H, m, CH2CH(CH3)2), 1.69 (3 H, d, J 6.5,
NCHCH3), 1.56 (3 H, d, J 6.5, NCHCH3), 1.53 (3 H, s,
C(OH)CH3), 1.08 (3 H, d, J 6.5, NCHCH3), 0.94 (3 H, d, J 6.5,
CH2CH(CH3)CH3), 0.90 (3 H, d, J 6.5, NCHCH3) and 0.76
(3 H, d, J 6.5, CH2CH(CH3)CH3); δC(75 MHz, CDCl3) 172.7,
142.7, 131.9, 131.2, 130.1, 127.7, 127.6, 126.3, 125.8, 125.4,
124.9, 77.2, 51.4, 50.9, 46.0, 33.0, 25.3, 24.5, 24.3, 20.3, 20.2,
19.7 and 19.6; m/z (CI) 356 (63%, M ϩ Hϩ) and 338 (100%,
M Ϫ OH); m/z (EI) 355 (2%, Mϩ), 197 (81%) and 86 (100%)
(Found Mϩ, 355.2517. C23H33NO2 requires M, 355.2511).
In the same way, ketone 3f (65 mg, 0.19 mmol) and methyl-
lithium (0.14 ml, 0.23 mmol; 1.6 M in diethyl ether) gave a
crude product which contained (by 1H NMR) a single diastereo-
isomer. Purification by flash chromatography on silica gel (4:1
petrol–EtOAc) afforded alcohol 12 (61 mg, 90%).
(Ra*,1ЈS*)-N,N-Diisopropyl-2-(1Ј-hydroxy-1Ј-methylpropyl)-1-
naphthamide 13
In the same way, ketone 3a (365 mg, 1.23 mmol) and ethyl-
magnesium bromide (1.48 ml, 1.48 mmol; 1 M in solution in
THF) gave a crude product which analytical HPLC showed to
contain no more than 1% 11. Purification by flash chromato-
graphy [4:1 petrol–EtOAc] afforded the alcohol 13 (387 mg,
96%) as a white solid. tR 5.0 min (4:1 hexane–EtOAc); Rf 0.58
(2:1 petrol–EtOAc); mp 130–132 ЊC (EtOAc); λmax (εmax
)
(Ra*,1ЈR*)-N,N-Diisopropyl-2-(1Ј-hydroxy-1Ј-methylpropyl)-1-
naphthamide 11
(CH2Cl2) 232 (43780), 282 (7190); νmax(film)/cmϪ1 3630–3159,
1609; δH(300 MHz, CDCl3) 8.0–7.2 (6 H, m, ArH), 3.63 (1 H,
septet, J 7, NCH), 3.58 (1 H, septet, J 7, NCH), 3.20 (1 H, s,
OH), 2.04 (1 H, m, CHAHBCH3), 1.92 (1 H, m, CHAHBCH3),
1.80 (3 H, d, J 7, NCHCH3), 1.69 (3 H, d, J 7, NCHCH3), 1.63
(3 H, s, C(OH)CH3), 1.20 (3 H, d, J 7, NCHCH3), 0.97 (3 H, d,
J 7, NCHCH3) and 0.85 (3 H, t, J 7, CH2CH3); δC(75 MHz,
CDCl3) 172.5, 141.1, 131.9, 131.7, 129.9, 127.8, 127.6, 126.5,
Methylmagnesium bromide (0.08 ml, 0.24 mmol; 3 M in diethyl
ether) was added dropwise to a solution of ketone 3b (63 mg,
0.20 mmol) in THF (6 ml) at Ϫ78 ЊC under an atmosphere of
nitrogen. The mixture was stirred for 3 hours. Saturated ammo-
nium chloride solution (5 ml) was added, and the mixture was
warmed to ambient temperature. The THF was removed under
J. Chem. Soc., Perkin Trans. 1, 2000, 1351–1361
1357

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125.9, 125.0, 124.8, 51.3, 46.0, 37.6, 29.4, 20.3, 20.2, 19.5, 19.4
and 7.8; m/z (CI) 328 (100%, M ϩ Hϩ) and 310 (58%,
M Ϫ OH); m/z (EI) 310 (1%, M Ϫ OH) and 86 (100%) (Found
M ϩ Hϩ, 328.2275. C21H29NO2 requires M ϩ H, 328.2276).
205.4, 205.1, 168.7, 140.1, 139.8, 137.2, 136.9, 134.7, 134.6,
131.6, 131.2, 129.7, 129.6, 129.2, 129.2, 128.3, 128.2, 128.0,
127.9, 127.2, 126.6, 126.6, 126.1, 126.0, 124.0, 51.4, 51.3,
46.1, 45.3, 44.9, 38.7, 20.7, 20.7, 20.6, 20.0, 20.0, 19.9, 19.8,
16.7 and 16.0; m/z (CI) 402 (100%, M ϩ Hϩ), 401 (3%, Mϩ) and
49 (100%) (Found: Mϩ, 401.2354. C27H31NO2 requires M,
401.2355).
General procedure for the reduction of ketones with NaBH4
Sodium borohydride (17.5 mg, 0.45 mmol, 3 equiv.) was added
to a solution of the ketone (0.15 mmol) in EtOH (4.5 ml) at
0 ЊC. The mixture was stirred at 0 ЊC for 16 h. An ice-cold solu-
tion of saturated NH4Cl was added (20 ml) and the mixture
extracted with ice-cold CH2Cl2 (20 ml × 3). The combined
organic fractions were dried at 0 ЊC (Na2SO4) and a small
aliquot was removed and stored in the freezer at Ϫ18 ЊC. The
ratio of stereoisomers in this sample was analysed by HPLC
and is quoted in Table 1. The remainder of the solution was
evaporated under reduced pressure, applying no external heat-
ing, to yield a crude product in quantitative yield. Analytical
HPLC of this material showed a ratio of stereoisomers differ-
ing from that observed in the aliquot by a few percent. Com-
parison of the 1H NMR spectrum of the mixture with those of
the known1 syn and anti alcohols 6, 8 and 10 confirmed the
sense of the stereoselectivity.
(Ra*,2ЈS*)- and (Ra*,2ЈR*)-N,N-Diisopropyl-2-(2Ј-benzyl-3Ј-
methylbutanoyl)-1-naphthamide syn- and anti-15. In the same
way, ketone 3f (160 mg, 0.47 mmol), potassium hexamethyl-
disilazide (0.94 ml, 0.47 mmol; 0.5 M solution in toluene)
and benzyl bromide (0.28 ml, 2.24 mmol) gave, after 6 h at
Ϫ78 ЊC and 30 min at 0 ЊC, a crude mixture of atropisomers
1
which were inseparable by HPLC. H NMR showed that the
atropisomers were present in a ratio of ca. 3:1. Purification by
flash chromatography (4:1 petrol–EtOAc) afforded a mixture
of the ketones syn- and anti-15 (170 mg, 84%) as a white solid.
Rf (2:1 petrol–EtOAc) 0.62; νmax(film)/cmϪ1 3061, 3024, 2962,
2933, 2873, 1686, 1630; δH(300 MHz, CDCl3) 8.02 (1 H, m,
ArH), 7.82 (1 H, m, ArH), 7.71 (1 H, d, J 8.7, ArH), 7.55 (1 H,
m, ArH), 7.35 (7 H, m, ArH), 3.67 (1 Hsyn, septet, J 7, NCH),
3.60 (2 Hanti, m, NCH and COCH), 3.35 (1 H, m, NCH), 3.27
(1 Hsyn, dd, J 13.5 and 11, PhCHAHB), 3.21 (1 Hanti, m,
PhCHAHB), 2.88 (1 Hsyn, dd, J 13 and 3, PhCHAHB), 2.84
(1 Hanti, m, PhCHAHB), 2.25 (1 Hanti, m, CHCH(CH3)2), 2.15
(1 Hsyn, m, CHCH(CH3)2), 1.80 (3 Hanti, d, J 6.5, CH3), 1.79
General procedure for the reduction of ketones with LiBHEt3 or
LiBH(s-Bu3)
Lithium triethylborohydride (Superhydride) or Lithium tri-
sec-butylborohydride (L-selectride) (0.16 ml of a 1 M solu-
tion in THF, 2 equiv.) was added to a solution of the ketone
(0.08 mmol) in THF (1.6 ml) at 0 ЊC (Ϫ40 ЊC in one case, as
indicated in Table 1). The mixture was stirred at 0 ЊC for 2 h and
quenched with an ice-cold solution of NaOH in 30% aqueous
hydrogen peroxide (2.5 M in NaOH). The mixture was
extracted with ice-cold EtOAc (20 ml × 3). The remainder of
the work-up and analysis followed the procedures described
for the NaBH4 reductions, and the selectivities are quoted in
Table 1.
(3 Hsyn, d, J 6.5, CH3), 1.78 (3 Hsyn, d, J 6.5, CH3), 1.74 (3 Hanti
,
d, J 7, CH3), 1.29 (3 Hsyn, d, J 6.5, CH3), 1.13 (3 Hanti, d, J 6.5,
CH3), 1.06 (3 Hsyn, d, J 7, CH3), 1.01 (6 Hanti, d, J 7, 2 × CH3),
1.00 (3 Hsyn, d, J 6.5, CH3), 0.95 (3 Hsyn, d, J 7, CH3) and 0.90
(3 Hanti, d, J 6.5, CH3); δC(75 MHz, CDCl3) 204.4, 168.7, 168.6,
141.3, 140.7, 137.2, 136.4, 134.7, 134.5, 133.0, 131.6, 129.6,
129.5, 129.3, 129.1, 128.3, 128.1, 127.9, 127.9, 127.8, 127.5,
127.0, 126.9, 126.7, 126.6, 125.8, 125.7, 124.6, 123.9, 57.0,
56.5, 51.3, 51.1, 46.1, 46.0, 33.6, 33.1, 30.7, 30.0, 20.9, 20.8,
20.7, 20.6, 20.5, 20.5, 20.0, 19.7, 19.7, 18.9 and 18.7; m/z (CI)
430 (100%, M ϩ Hϩ) (Found: M ϩ H, 430.2751. C29H35NO2
requires M ϩ H, 430.2746).
(Ra*,2ЈS*)- and (Ra*,2ЈR*)-N,N-Diisopropyl-2-(2Ј-methyl-
3Ј-phenylpropanoyl)-1-naphthamide syn- and anti-14. A solution
of ketone 3b (121 mg, 0.39 mmol) in THF (4 ml) was added to
a solution of potassium hexamethyldisilazide (0.78 ml, 0.39
mmol; 0.5 M solution in toluene), in THF (1 ml) at Ϫ78 ЊC
under an atmosphere of nitrogen. The mixture was stirred for
30 min and the resulting yellow solution was added to a solu-
tion of benzyl bromide (0.23 ml, 1.95 mmol) in THF (2 ml) at
Ϫ78 ЊC. After 60 min the reaction was warmed to 20 ЊC and
stirred for a further 30 min. Saturated aqueous ammonium
chloride (2 ml) was added, the mixture was extracted with
dichloromethane (7 ml × 4) and the combined organic extracts
were dried (MgSO4), filtered and concentrated under reduced
pressure without external heating to afford the crude product.
Analytical HPLC (4:1 hexane–EtOAc) of the crude product
showed the atropisomers to be present in a ratio of 52:48.
Purification by flash chromatography (4:1 petrol–EtOAc)
afforded a mixture of ketones 14 (129 mg, 83%) as a white solid.
The mixture was separated by preparative HPLC (8:1 hexane–
EtOAc) to afford two samples of diastereoisomerically enriched
mixtures containing 75:25 syn-14:anti-14 and 20:80 syn-
14:anti-14. tRanti 3.9 min and tRsyn 5.0 min (4:1 hexane–EtOAc);
Rf (2:1 petrol–EtOAc) 0.59; νmax(film)/cmϪ1 3059, 3025, 2974,
2933, 2873, 1689, 1630; δH(300 MHz, CDCl3) 8.05 (1 H, m,
ArH), 7.86 (2 H, m, ArH), 7.60 (3 H, m, ArH), 7.35–7.20 (5 H,
m, Ph), 3.74 (1 H, m, COCH), 3.67 (1 H, m, NCH), 3.43 (1 H,
m, NCH), 3.28 (1 Hsyn, dd, J 13.5 and 6.5, PhCHAHB), 3.22
(1 Hanti, dd, J 14 and 4.5, PhCHAHB), 2.69 (1 Hsyn, J 14 and 8,
PhCHAHB), 2.64 (1 Hanti, dd, J 14 and 10, PhCHAHB), 1.82
(3 H, d, J 7, CH3), 1.81 (3 Hanti, d, J 7, CH3), 1.80 (3 Hsyn, d,
J 6.5, CH3), 1.80 (3 Hsyn, d, J 6.5, CH3), 1.24–1.14 (6 H, m,
2 × CH3) and 1.01–0.95 (3 H, m, CH3); δC(75 MHz, CDCl3)
Also obtained was N,N-diisopropyl-2-[(1ЈZ)-1Ј-(benzyloxy)-
3Ј-methylbut-1Ј-enyl]-1-naphthamide 18 (21 mg, 6%) as a colour-
less oil. Rf (2:1 petrol–EtOAc) 0.55; νmax(film)/cmϪ1 3239, 3063,
2974, 2932, 1721, 1629; δH(300 MHz, CDCl3) 7.84 (1 H, d, J 9,
ArH), 7.75 (1 H, m, ArH), 7.71 (1 H, d, J 8.9, ArH), 7.41 (3 H,
m, ArH), 7.30–7.10 (5 H, m, ArH), 5.03 (1 H, d, J 9, CH=CO),
4.77 (1 H, d, J 12, PhCHAHB), 4.37 (1 H, d, J 12, PhCHAHB),
3.47 (2 H, m, 2 × NCH), 2.80 (1 H, d septet, J 9 and 6.5,
CHCH(CH3)2), 1.69 (3 H, d, J 6.5, CH3), 1.50 (3 H, d, J 6.5,
CH3), 1.04 (3 H, d, J 6.5, CH3), 0.90 (3 H, d, J 6.5, CHCH-
(CH3)CH3), 0.81 (3 H, d, J 6.6, CH3) and 0.73 (3 H, d, J 6.7,
CHCH(CH3)CH3); δC(75 MHz, CDCl3) 168.8, 151.0, 137.8,
133.3, 133.2, 130.3, 129.6, 128.8, 128.0, 127.9, 127.8, 127.5,
126.7, 126.6, 126.2, 125.9, 125.7, 72.7, 50.9, 46.0, 25.4, 23.3,
22.8, 21.2, 20.6 and 20.3; m/z (CI) 430 (32%, M ϩ Hϩ) and
102 (100%) (Found: M ϩ Hϩ, 430.2750. C29H35NO2 requires
M ϩ H, 430.2746).
(Ra*,2ЈR*)
and
(Ra*,2ЈS*)-N,N-Diisopropyl-2-(2Ј,3Ј-
dimethylbutanoyl)-1-naphthamide syn- and anti-16. In the same
way, ketone 3f (247 mg, 0.73 mmol) in THF (11 ml), potassium
hexamethyldisilazide (0.81 ml of a 0.5 M solution in toluene,
0.41 mmol) in THF (1 ml) and methyl iodide (0.23 ml, 3.64
mmol) gave, after 110 min at Ϫ78 ЊC, a crude product.
Analytical HPLC of the crude product showed a 67:33 ratio of
atropisomers syn-16:anti-16. Purification by flash chromato-
graphy (4:1 petrol–EtOAc) afforded a mixture of ketones 16
(102 mg, 71%) as a white solid. The mixture was separated by
preparative HPLC (6:1 hexane–EtOAc) to afford two samples
of diastereoisomerically enriched mixtures containing 74:26
anti
syn-16:anti-16 and 29:71 syn-16:anti-16 respectively. tR 5.0
1358
J. Chem. Soc., Perkin Trans. 1, 2000, 1351–1361

View Article Online
min and tRsyn 6.4 min (6:1 hexane–EtOAc); Rf 0.58 (4:1 petrol–
EtOAc); νmax(film)/cmϪ1 2968, 2932, 2914, 2873, 1686, 1629;
δH(300 MHz, CDCl3) 8.01 (1 H, m, ArH), 7.89 (2 H, m, ArH),
7.80 (1 Hsyn, d, J 8.7, ArH), 7.73 (1 Hanti, d, J 8.7, ArH), 7.58
(2 H, m, ArH), 3.65 (1 H, m, NCH), 3.44 (1 H, m, NCH), 3.34
(1 H, m, COCHCH3), 2.22 (1 Hsyn, m, CHCH(CH3)2), 2.12
(1 Hanti, m, CHCH(CH3)2), 1.80–1.70 (6 H, m, 2 × CH3), 1.25
21.6, 20.6, 20.6, 20.3, 18.7, 14.4, 13.9 and 13.4; m/z (CI) 542
(100%, M ϩ Hϩ); m/z (EI) 541 (6%, Mϩ), 86 (100%), 84 (100%)
and 49 (100%) (Found: Mϩ, 541.3920. C37H51NO2 requires M,
541.3920).
N,N-Diisopropyl-2-{(1ЈZ)-1Ј-[(trimethylsilyl)oxy]prop-1Ј-
enyl}-1-naphthamide 19. A solution of ketone 3b (255 mg, 0.82
mmol) in THF (12 ml) was added to a solution of potassium
hexamethyldisilazide (1.80 ml, 0.90 mmol; 0.5 M solution in
toluene) in THF (2 ml) at Ϫ78 ЊC under an atmosphere of
nitrogen. After 20 minutes, the resulting yellow solution was
added via a cannula to a solution of chlorotrimethylsilane (0.52
ml, 4.1 mmol), triethylamine (1.1 ml) and THF (2 ml) at Ϫ78 ЊC
to give a white suspension. After 10 minutes saturated aqueous
sodium hydrogen carbonate (2 ml) was added and the mixture
was extracted with diethyl ether (10 ml × 4). The combined
organic extracts were washed with water (20 ml) and aqueous
0.1 M citric acid (20 ml), dried (MgSO4), filtered and concen-
trated under reduced pressure to afford the silyl enol ether 19
(292 mg, 93%) as a white solid. Mp 100–101 ЊC; νmax(film)/cmϪ1
3057, 2965, 2930, 2874, 2859, 1630; δH(300 MHz, CDCl3) 7.77
(1 H, d, J 7.5, ArH), 7.66 (1 H, d, J 7, ArH), 7.62 (1 H, d, J 8.5,
(3 Hanti, d, J 6.5, CH3), 1.21 (3 Hanti, d, J 6.5, CH3), 1.16 (3 Hsyn
,
d, J 6.5, CH3), 1.15 (3 Hsyn, d, J 7, CH3), 1.05 (3 Hsyn, d, J 6.5,
CH3), 1.00 (3 Hanti, d, J 7, CH3), 0.97 (3 Hanti, d, J 6.5, CH3),
0.96 (3 Hsyn, d, J 6.5, CH3), 0.92 (3 Hsyn, d, J 6.6, CH3) and 0.90
(3 Hanti, d, J 6.6, CH3); δC(75 MHz, CDCl3) 206.8, 205.7, 168.8,
168.7, 134.6, 134.6, 132.6, 132.2, 129.7, 129.4, 128.1, 127.9,
127.8, 127.8, 127.2, 127.0, 126.6, 126.4, 124.3, 124.2, 51.4, 51.3,
49.5, 48.4, 46.2, 46.1, 30.2, 29.8, 21.6, 21.4, 20.7, 20.6, 20.5,
20.0, 19.9, 19.8, 19.8, 18.0, 17.7 and 11.9; m/z (CI) 354 (100%,
M ϩ Hϩ) (Found: M ϩ Hϩ, 354.2433. C23H31NO2 requires
M ϩ H, 354.2433).
(Ra*,2ЈR*)- and (Ra*,2ЈS*)-N,N-Bis(4-heptyl)-2-(2Ј-benzyl-
3Ј-methylbutanoyl]-1-naphthamide syn- and anti-17. In the same
way, ketone 4f (97 mg, 0.22 mmol), potassium hexamethyl-
disilazide (0.48 ml, 0.24 mmol; 0.5 M solution in toluene) and
benzyl bromide (0.13 ml, 1.08 mmol) gave, after 15 minutes at
Ϫ78 ЊC and 2 h at 0 ЊC, a crude product. Analytical HPLC
(20:1 hexane–EtOAc) showed a ratio of 95:5 syn-17:anti-17.
Purification by flash chromatography on silica gel (10:1 petrol–
EtOAc) afforded a mixture of the ketones syn- and anti-17 (97
mg, 83%) as a colourless oil (inseparable by preparative HPLC).
tR 10 min (20:1 hexane–EtOAc); νmax(film)/cmϪ1 3061, 3027,
2959, 2932, 2871, 1682, 1629; δH(300 MHz, CDCl3, peaks for
syn-17 only) 7.85 (1 H, m, ArH), 7.60 (2 H, m, ArH), 7.44 (1 H,
d, J 8.5, ArH), 7.34 (2 H, m, ArH), 7.14 (1 H, m, ArH), 7.04–
6.90 (3 H, m, ArH), 6.86 (1 H, t, J 7, ArH), 3.42 (1 H, dt, J 7.5
and 5, COCH), 2.93 (1 H, dd, J 14 and 7.5, PhCHAHB), 2.81
(1 H, m, NCH), 2.62 (1 H, dd, J 14 and 5.5, PhCHAHB), 2.59
(1 H, m, NCH), 2.20 (2 H, m, NCH(CHAHBCH2CH3)2), 2.06–
1.82 (3 H, m, NCH(CHAHBCH2CH3)2 and CH(CH3)2), 1.40–
0.93 (8 H, m, NCH(CH2CH2CH3)2 and 4 × NCHCH2CHAHB-
CH3), 0.92–0.70 (13 H, m, 4 × NCHCH2CHAHBCH3, 2 ×
NCHCH2CH2CH3 and CH(CH3)CH3), 0.74 (3 H, d, J 7,
CH(CH3)CH3), 0.48 (3 H, t, J 7, NCHCH2CH2CH3) and
0.03 (3 H, t, J 7, NCHCH2CH2CH3); δC(75 MHz, CDCl3)
204.5, 169.2, 140.5, 135.9, 134.5, 132.4, 129.7, 129.3, 128.0,
127.9, 127.8, 127.6, 127.3, 126.6, 125.6, 124.6, 59.8, 56.8,
56.4, 36.6, 36.3, 36.0, 35.7, 33.3, 29.8, 21.8, 21.7, 20.7, 20.5,
20.1, 18.9, 14.5, 14.2, 13.8 and 13.1; m/z (CI) 559 (14%,
M ϩ NH4ϩ) and 543 (100%); m/z (EI) 329 (43%, M Ϫ NR2) and
91 (100%) (Found: M ϩ NH4ϩ, 559.4239. C37H51NO2 requires
M ϩ NH4ϩ, 559.4263).
The 95:5 mixture of ketones syn- and anti-17 were dissolved
in ether. After 2 weeks in diethyl ether at ambient temperature
the solution contained 17:83 syn-17:anti-17 (by 1H NMR).
The solvent was removed under reduced pressure to yield a
colourless oil containing anti-17. tR 11.6 min (20:1 hexane–
EtOAc); νmax(film)/cmϪ1 3061, 3028, 2958, 2931, 2871, 1689,
1629; δH(300 MHz, CDCl3) 7.80 (1 H, m, ArH), 7.56 (1 H, m,
ArH), 7.45 (1 H, d, J 8.5, ArH), 7.32 (2 H, m, ArH), 7.07 (3 H,
d, J 4, ArH), 6.97 (3 H, m, ArH), 3.30 (1 H, ddd, J 11, 4.5 and 3,
COCH), 3.06 (1 H, dd, J 13 and 11, PhCHAHB), 2.86 (1 H, br
m, NCH), 2.60 (2 H, m, NCH and PhCHAHB), 2.10 (2 H, m,
2 × CHAHBCH2CH3), 1.94 (3 H, m, 2 × CHAHBCH2CH3 and
CH(CH3)2), 1.50–1.00 (8 H, m, 2 × CH2CH2CH3 and 4 ×
CH2CHAHBCH3), 0.91–0.77 (11 H, m, CH(CH3)CH3, 2 ×
CH2CH2CH3 and 2 × CH2CHAHBCH3), 0.74 (3 H, d, J 7,
CH(CH3)CH3), 0.55 (2 H, m, 2 × CH2CHAHBCH3), 0.47 (3 H,
t, J 7, CH2CH2CH3) and 0.10 (3 H, t, J 7, CH2CH2CH3); δC(75
MHz, CDCl3) 204.1, 168.9, 141.5, 136.9, 134.2, 133.1, 129.1,
128.2, 128.0, 127.7, 127.6, 127.5, 127.2, 126.5, 125.8, 123.9,
59.8, 57.4, 57.2, 36.7, 36.4, 36.0, 35.7, 33.6, 30.9, 21.9,
ArH), 7.34 (3 H, m, ArH), 5.14 (1 H, q, J 7, C᎐CHCH ), 3.44
᎐
3
(2 H, m, 2 × NCH), 1.65 (3 H, d, J 6.5, NCHCH3), 1.62 (3 H, d,
J 7, NCHCH ), 1.51 (3 H, d, J 6.5, C᎐CHCH ), 0.98 (3 H,
᎐
3
3
d, J 6.5, NCHCH3), 0.75 (3 H, d, J 6.5, NCHCH3) and 0.00
(9 H, s, SiMe3); δC(75 MHz, CDCl3) 168.8, 149.4, 133.2, 132.9,
132.6, 130.2, 127.7, 127.6, 126.6, 125.9, 125.7, 125.4, 109.2,
50.7, 45.9, 21.3, 20.5, 11.6 and 0.4; m/z (CI) 384 (65%, M ϩ Hϩ)
and 312 (100%); m/z (EI) 383 (4%, Mϩ) and 73 (100%) (Found:
Mϩ, 383.2279. C23H33NO2Si requires M, 383.2280).
N,N-Diisopropyl-2-{(1ЈZ)-3Ј-methyl-1Ј-[(trimethylsilyl)oxy]-
but-1Ј-enyl}-1-naphthamide 20. In the same way, ketone 3f (261
mg, 0.77 mmol), potassium hexamethyldisilazide (1.70 ml, 0.85
mmol; 0.5 M solution in toluene), chlorotrimethylsilane (0.49
ml, 3.85 mmol), and triethylamine (1.1 ml) gave, after purifica-
tion by flash chromatography on neutral alumina (15:1 petrol–
EtOAc) the silyl enol ether 20 (301 mg, 95%) as a sticky white
solid. Rf (15:1 petrol–EtOAc) 0.41; νmax(film)/cmϪ1 3057, 2963,
2933, 2905, 2868, 1642, 1632; δH(300 MHz, CDCl3) 7.81 (1 H,
d, J 7.5, ArH), 7.68 (1 H, m, ArH), 7.64 (1 H, d, J 8, ArH), 7.41
(1 H, d, J 8.5, ArH), 7.36 (2 H, m, ArH), 4.95 (1 H, d, J 9.5,
CHCH(CH3)2), 3.45 (2 H, m, 2 × NCH), 2.78 (1 H, d septet,
J 9.5 and 6.5, CHCH(CH3)2), 1.69 (3 H, d, J 6.5, CH3), 1.57
(3 H, d, J 6.5, CH3), 1.03 (3 H, d, J 6.5, CH3), 1.00 (3 H, d, J 6.5,
CH3), 0.96 (3 H, d, J 6.5, CH3), 0.77 (3 H, d, J 6.5, CH3) and
0.00 (9 H, s, Si(CH3)3); δC(75 MHz, CDCl3) 168.8, 146.8, 133.2,
132.8, 132.6, 130.2, 127.7, 127.5, 126.5, 126.2, 125.9, 125.7,
122.2, 50.8, 45.9, 25.4, 23.4, 22.9, 21.3, 21.2, 20.8, 20.6 and 0.4;
m/z (CI) 412 (100%, M ϩ Hϩ); m/z (EI) 411 (6%, Mϩ) and
49 (100%) (Found: Mϩ, 411.2597. C25H37NO2Si requires M,
411.2953).
(Ra*,1ЈR*,2ЈR*)- and (Ra*,1ЈR*,2ЈS*)-N,N-Bis(4-heptyl)-2-
(1Ј-hydroxy-3Ј-methyl-2Ј-(phenylmethyl)butyl)-1-naphthamide
21 and 22. By the general procedure given above, the 17:83
mixture of ketones syn- and anti-17 (66 mg, 0.12 mmol) in THF
(2 ml) were treated with LiBHEt3 (0.31 ml, 0.31 mmol; 1 M
solution in THF) to yield a crude product (64 mg, 97%) con-
taining, by analytical HPLC, two diastereoisomers 21 and 22
in a ratio of 25:75. Purification by preparative HPLC (30:1
hexane–EtOAc) gave the alcohol 21. tR 7.3 min (30:1 hexane–
EtOAc); νmax(film)/cmϪ1 3064, 3027, 3015, 2990, 2973, 2959,
2934, 2881, 1717; δH(300 MHz, CDCl3) 7.80 (1 H, m, ArH),
7.60 (1 H, m, ArH), 7.39 (2 H, m, ArH), 7.20 (2 H, m, ArH),
6.73 (1 H, m, ArH), 6.64 (4 H, m, ArH), 4.79 (1 H, dd, J 9 and
3.5, CHOH), 2.97 (2 H, m, 2 × NCH), 2.41 (2 H, d, J 5.5,
CH2Ph), 2.25 (2 H, m, CHAHBCH2CH3 and CH(OH)CH),
2.12–1.80 (3 H, m, 3 × CHAHBCH2CH3), 1.54–0.74 (26 H, m,
J. Chem. Soc., Perkin Trans. 1, 2000, 1351–1361
1359

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4 × CHAHBCH2CH3, 4 × CH2CH2CH3, CH(CH3)2, CHOH
and 2 × CH2CH2CH3), 0.69 (3 H, t, J 6.5, CH2CH2CH3) and
0.26 (3 H, t, J 7, CH2CH2CH3); δC(75 MHz, CDCl3) 169.6,
142.5, 136.4, 132.7, 128.8, 128.5, 128.3, 127.9, 127.6, 127.2,
126.0, 126.0, 125.9, 124.3, 123.7, 73.0, 59.7, 56.8, 37.1, 36.3,
35.2, 30.9, 27.6, 21.9, 21.8, 20.9, 20.4, 17.6, 14.5, 14.4, 14.0 and
13.2; m/z (CI) 544 (100%, M ϩ Hϩ); m/z (EI) 543 (3%, Mϩ), 397
(88%, M Ϫ C11H15) and 183 (100%) (Found: Mϩ, 543.4065.
C37H53NO2 requires M, 543.4076).
Acknowledgements
We are grateful to the EPSRC and Roche Discovery (Welwyn)
for a CASE award (to N. W.), to Zeneca for an unrestricted
grant, to the Royal Society for an Equipment Grant, and to
Dr Francis Wilson for helpful discussions.
References
Also obtained was the alcohol 22. tR 10.5 min (30:1 hexane–
EtOAc); νmax(film)/cmϪ1 3058, 3047, 3016, 2994, 2973, 2933,
1717; δH(300 MHz, CDCl3) 7.81 (1 H, dd, J 9 and 2, ArH), 7.70
(2 H, m, ArH), 7.52 (1 H, d, J 8.5, ArH), 7.40 (2 H, m, ArH),
7.16–7.00 (5 H, m, ArH), 5.06 (1 H, dd, J 6 and 3.5, CHOH),
2.96 (1 H, br m, NCH), 2.89 (1 H, quintet, J 6.5, NCH), 2.76
(2 H, d, J 6.5, CH2Ph), 2.40 (1 H, m, CHAHBCH2CH3), 2.23
(2 H, m, CH(OH)CH and CHAHBCH2CH3), 1.98 (2 H, m,
CH2CH2CH3), 1.60–0.80 (12 H, m, CH(CH3)2, 3 × CH2CH2-
CH3, 2 × CH2CH2CH3 and OH), 0.97 (3 H, t, J 7.5, CH2-
CH2CH3), 0.96 (3 H, t, J 7.5, CH2CH2CH3), 0.88 (3 H, d, J 6.5,
CH(CH3)CH3), 0.86 (3 H, d, J 7, CH(CH3)CH3), 0.66 (3 H,
t, J 7.5, CH2CH2CH3), 0.63 (2 H, m, CH2CH2CH3) and 0.17
(3 H, t, J 7.5, CH2CH2CH3); δC(75 MHz, CDCl3) 169.4, 142.4,
136.9, 132.9, 132.6, 129.6, 128.8, 128.3, 128.0, 127.7, 126.1,
126.0, 126.0, 125.6, 123.9, 74.5, 59.8, 56.9, 52.1, 37.0, 36.8, 36.2,
35.5, 32.6, 28.8, 21.9, 21.7, 21.1, 20.4, 20.1, 18.9, 14.4, 14.1
and 13.1; m/z (CI) 544 (100%, M ϩ Hϩ); m/z (EI) 543 (3%, Mϩ),
397 (53%, M Ϫ C11H15), 396 (29%, M Ϫ C11H16) and 183
(100%) (Found: Mϩ, 543.4059. C37H53NO2 requires M,
543.4076).
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,
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ence Fourier map corresponded to 0.24 and Ϫ0.20 e ÅϪ3
,
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7.6743(9), b = 24.817(4), c = 10.629(1) Å, β = 101.216(9)Њ,
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gave R1 = 0.051, wR2 = 0.050. The maximum and minimum
peaks on the final difference Fourier map corresponded to
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§ CCDC reference number 207/412. See http://www.rsc.org/suppdata/
p1/b0/b000668h for crystallographic files in .cif format.
1360
J. Chem. Soc., Perkin Trans. 1, 2000, 1351–1361

View Article Online
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J. Chem. Soc., Perkin Trans. 1, 2000, 1351–1361
1361