123. - Jonathan Clayden

LETTER 873
Addition of Lithiated Tertiary Aromatic Amides to Epoxides and Aziridines:
Asymmetric Synthesis of (S)-(+)-Mellein
Asymmetric Jonathan Synthesis of (S)-(+)-Mellein Clayden,* a Christopher C. Stimson, a Madeleine Helliwell, a Martine Keenanb c School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Fax +44(161)2754939; E-mail: clayden@man.ac.uk
d Eli Lilly & Co. Ltd., Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK
Received 12 January 2006
Abstract: Addition of ortholithiated or laterally lithiated amides to
epoxides or aziridines provides, in some cases stereoselectively,
products which may cyclise to yield benzopyranones in good enantiomeric
excess.
Key words: lithiation, directed metallation, synthesis, epoxide,
benzopyranone, isochromanone
The synthesis of benzo-fused lactones via lithiation of an
aromatic precursor 1 (typically an amide or oxazoline) and
addition to carbonyl compound, followed by lactonisation,
is a useful route to benzofuranones 2 and benzopyranones.
3 We have shown 4 that asymmetry may be
introduced into the synthesis of benzofuranones by such a
sequence by ‘chiral memory’, 5 exploiting the axially
chiral conformation of a tertiary amide group 6 to relay the
stereochemistry of a sulfoxide precursor to the stereogenic
centre of benzofuranone and naphthofuranone products.
X
Y
X
Y
O
O
1
Z
Z
NR 1 2
NR 1 2
5
1. s-BuLi
2. BF3·OBu2
R 2
HCl (2 M)
dioxane
Scheme 1 Addition of lithiated amides to epoxides and lactonisation
Racemic benzopyranones (3,4-dihydroisocoumarins) 4
have been made by the route 1 → 5 → 3 → 4: lateral lithiation
of an amide, addition to an aldehyde or ketone, and
lactonisation of the resulting alcohol, 7,8 but metamorphosis
of this route into an asymmetric synthesis of benzopy-
SYNLETT 2006, No. 6, pp 0873–087604.04.2006
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939043; Art ID: D01006ST
© Georg Thieme Verlag Stuttgart · New York
X
Y
O
O
R2 R3 O
2 X
NR1 2
R2 Z anti-3
+
R2 NR1 2
R 3
OH
OH
R
Y
syn-3
Z
conformers (X = H)
or atropisomers (X ≠ H)
3
X
Y
O O R3 Z
4
R 2
ranones 4 is complicated by the inconvenient fact that
laterally lithiated derivatives of atropisomeric amides 5
racemise rapidly even at low temperature. 9,10 An alternative
organolithium addition, of an epoxide 2 to the
ortholithiated derivative of amide 1, offers a complementary
synthesis of alcohols 3, and hence lactones 4. 11 In this
communication we report the synthesis of benzopyranones
in racemic and in enantiomerically enriched form
[including the natural product (S)-(+)-mellein] using either
the epoxide 2 or a chiral derivative of amide 1 as the
source of asymmetry.
Tertiary aromatic amides 1a–d were lithiated with sec-butyllithium
and added to a range of cyclic and acyclic
achiral epoxides 2a–e) in the presence of boron trifluoride
dibutyl etherate. 12 Table 1 shows the results of these additions.
Moderate to good yields of the alcohols 3 were obtained.
The epoxide openings were, as expected, reliably stereospecific
with regard to the two new stereogenic centres
in 3a–e, formed by invertive substitution of the symmetrical
epoxide. However, kinetic stereoselectivity with regard
to the amide axis was not high. 13 Only 3e was formed
with any remarkable atropisomeric diastereoselectivity,
and our tentative general assignment of anti stereochemistry
(see Scheme 1) to the major atropisomeric diastereomer
is based on the crystal structure of anti-3a¢
(Figure 1). 14 Additions of lithiated amides 1a¢ and 1e to
chiral epoxides 2f and 2g similarly lacked diastereoselec-
Figure 1 X-ray crystal structure of anti-3a¢

874 J. Clayden et al. LETTER
Table 1 Benzopyranones via Addition of Lithiated Amides to Epoxides
Entry 1 R 1 X Y Z 2 R 2 R 3 3 Yield (%)anti:syn a 4 Yield (%)
1 1a Et MeO H H 2a (CH 2) 4 3a 40 70:30 4a 70
2 1a¢ i-Pr MeO H H 2a (CH 2) 4 3a¢ 89 80:20 b – c –
3 1b Et NMe 2 H H 2b (CH 2) 3 3b 62 70:30 4b 78
4 1b Et NMe 2 H H 2c CH 2OCH 2 3c 43 70:30 – c –
5 1c Et MeO MeO H 2d d Me Me 3d 64 50:50 4d 25
6 1c Et MeO MeO H 2e d Ph Ph – – – 4e e 26
7 1d i-Pr Benzo f H 2a (CH 2) 4 3e 30 93:7 – c –
8 1e Et H H Cl 2f H Me 3f 33 50:50 g,h 4f 78
9 1a¢ i-Pr MeO H H 2g H Et 3g 65 60:40 i – c –
a Ratio of atropisomeric diastereomers determined by NMR. Stereochemistry of major diastereomer not definitively assigned.
b Stereochemistry of major diastereomer assigned from X-ray crystal structure (Figure 1).
c Failed to lactonise.
d cis-Epoxide.
e Lactone isolated directly from addition reaction even before treatment with acid.
f 1-Naphthamide.
g Diastereomeric conformers.
h Anti relationship between side-chain stereogenic centres.
i Ratio of 95:5 after crystallisation.
tivity, though, intriguingly, allowing the 60:40 mixture of
diastereomers of 3g to crystallise improved the ratio to
>95:5. In 3f, the product ratio is that of an equilibrating
mixture of conformers, since steric hindrance around the
amide axis is insufficient to allow 3f to exist as separable
atropisomers. 6
The diethyl amido alcohols (as diastereomeric mixtures)
3a,b,d,f were lactonised7 to give single diastereomers of
benzopyranones 4 in generally good yield. More hindered
diisopropylamides 3a¢,e,g, along with 3c, failed to lactonise
under these conditions, and 4d was formed in only
25% yield. Lactone 4f was formed directly in the addition
reaction even without treatment with acid.
By using chiral and enantiomerically pure epoxides it
should be possible to synthesise enantiomerically pure
benzopyranones, 12 a class of molecules which includes a
number of important natural products. 15 We took the 2-silyloxybenzamide
1f, ortholithiated it and treated it with
(S)-(+)-propylene oxide 2f to yield a mixture of diastereomers
of alcohol 3h. Lactonisation under acid conditions
resulted in cyclisation and deprotection to give
fungal metabolite (S)-(+)-mellein (4h, Scheme 2). 16
Treatment of the same ortholithiated derivative of amide
1f with cis-2,3-dimethyloxirane 2d gave the racemic
alcohols 3i, which cyclised with deprotection to yield
the deshydroxymethyl derivative 4i of gamahorin17 in
racemic form.
The introduction of asymmetry into this last reaction via
the epoxide is of course impossible due to the epoxide’s
symmetry. We therefore investigated whether it would be
possible to use atropisomeric and enantiomerically pure
Synlett 2006, No. 6, 873–876 © Thieme Stuttgart · New York
ortholithiated amides, which we have shown may be made
from 2-sulfinylamides by sulfoxide–lithium exchange 18 to
desymmetrise a meso-epoxide. We took the two sulfinylamides,
which had been made by Andersen’s method 19
from (1R,2S,5R,S S)-(–)-menthyl p-toluenesulfinate, 20 and
added them to cyclohexene oxide at –78 °C (Scheme 3).
Yields were only moderate but enantiomeric excess was
largely retained during the sulfoxide–lithium–electrophile
exchange process. Desymmetrisation of the epoxide results
from diastereoselective attack of the lithioamide on
one of the two enantiotopic termini of the epoxide, and is
represented by the anti:syn ratio of the diastereomeric
i-Pr3SiO
HO
O
NEt2
i-Pr 3SiO
1. s-BuLi
2. (+)-2f
HCl (2 M)
dioxane
O
NEt2
OH i-Pr3SiO
Scheme 2 Routes to naturally occurring benzopyranones
O
NEt2
O O
O O
1f
HO
OH
3h (1:1 anti:syn) 49% 3i (7:3 anti:syn) 42%
(+)-4h 62%
(S)-(+)-mellein
1. s-BuLi
2. 2d
HCl (2 M)
dioxane
(±)-4i 71%
(±)-deshydroxymethyl
gamahorin

LETTER Asymmetric Synthesis of (S)-(+)-Mellein 875
X
Y
Ni-Pr2
S
O p-Tol
6a (X, Y = benzo)
6b (X = OMe, Y = H)
Scheme 3 Desymmetrisation of a meso epoxide
products For 6a this selectivity was high, but for 6b it was
only 70:30. Unfortunately, 3e proved resistant to lactonisation
so this promising result was not pursued further.
Just as addition of an ortholithiated amide to an epoxide
yields a benzo-fused six-membered lactone, addition of a
laterally lithiated amide to an epoxide (Scheme 4) should
lead to a benzo-fused seven-membered lactone. Amides
X
Y
O
O
5 (Z = H)
NR 1 2
R 2
1. s-BuLi
2.
2a
1. s-BuLi
2. BF3·OBu2
Table 2 Additions of Laterally Lithiated Amides to Epoxides and
Aziridines
Entry SM R 1 X Y R 2 Z 9 Yield
(%)
Z
2a (Z = O)
8 (Z = NTs)
O
O
X
Ni-Pr2
syn:
anti
1 5a i-Pr Benzo a H O 9a 81 60:40 b
2 5b i-Pr Benzo a Me O 9b 40 50:50 c
3 5c i-Pr MeO H H O 9c 74 50:50
4 5a i-Pr Benzo a H NTs 9d 56 >95:5 d
5 5c i-Pr MeO H H NTs 9e 59 80:20 e
6 5d Et MeO H H NTs 9f 58 50:50
a 1-Naphthamide.
b Arbitrary assignment of stereochemistry.
c 2 Stereochemistry at centre bearing R assumed from precedent, see
ref. 13.
d Stereochemistry proved by X-ray crystallography. Formed in 70%
ee from 5a of 90% ee.
e Stereochemistry assigned by analogy with 9d.
Y
+
O
X
H
OH
anti-3
Ni-Pr2
H
OH
Y
syn-3
3a' (X = OMe, Y = H) 57%,
70:30 anti:syn, 85% ee anti
3e (X, Y = benzo) 30%,
93:7 anti:syn, 93% ee anti
Scheme 4 Epoxide and aziridine addition of laterally lithiated
amides
X
Y
X
Y
O
O
R2 NR1 2
H ZH
syn-9
+
R2 NR1 2
H ZH
anti-9
5a–d were lithiated and treated with epoxide 2a (Table 2,
entries 1–3). The resulting alcohol was formed in good
yield, but the lack of diastereoselectivity indicated the inability
of the amide axis to select between the enantiotopic
ends of the epoxide. Comparable additions to aziridines
were attempted21 with the aim of forming seven-membered
lactams. Results are shown in Table 2, entries 4–6,
and in the case of the most hindered amide 5a were encouraging:
a single diastereomer of the sulfonamide 9d
was formed, whose stereochemistry was proved by X-ray
crystal structure (Figure 2). 22 This reaction was repeated
with enantiomerically enriched (90% ee) 5a, treating with
s-BuLi at –90 °C for a period of only four minutes to minimise
racemisation. 9 Sulfonamide syn-9d was formed in
70% ee. However, attempts to cyclise 9d–f to a lactam
failed.
In summary, addition of lithiated amides to epoxides and
aziridines proceeds with stereoselectivity which is highly
substrate dependent, and in certain cases yield products
which may be cyclised to benzopyranones with good
stereocontrol.
Figure 2 X-ray crystal structure of syn-9d
2-(Dimethylamino)-N,N-diethyl-6-(2-hydroxycyclopentyl)benzamide
(3b)
s-BuLi (1.2 equiv, 1.2 mmol of a 1.3 M solution in hexane) was added
dropwise to the amide 1b (325 mg, 1.48 mmol) stirring in dry
THF (20 mL) under nitrogen at –78 °C. After 30 min, cyclopentene
oxide 2b (153 mL, 1.77 mmol) was added dropwise at –78 °C followed
immediately by boron trifluoride dibutyl etherate (1.2 equiv,
1.2 mmol). The mixture was left to warm to r.t. and quenched with
sat. NH4Cl solution. The THF was removed under reduced pressure
and the mixture diluted with CH2Cl2 (50 mL), washed with sat.
NH4Cl solution (3 × 20 mL), dried (MgSO4) and concentrated under
reduced pressure. Flash chromatography (SiO2, PE–EtOAc =
50:50) gave the alcohols 3b as a 7:3 mixture of diastereomers.
Major diastereomer: yield 188 mg (42%), colourless oil; Rf = 0.39
(50:50 PE–EtOAc). 1H NMR (500 MHz, CDCl3): d = 0.81 (3 H, t,
J = 7 Hz, CH3), 1.17 (3 H, t, J = 7 Hz, CH3), 1.52 (1 H, m, CH2), 1.64–1.68 (2 H, m, CH2), 1.77 (1 H, m, CH2), 1.87 (1 H, m, CH2), 1.93 (1 H, m, CH2), 2.58 (6 H, s, NMe2), 2.59 (1 H, m, NCH2), 2.88
(1 H, m, NCH2), 3.05 (1 H, m, NCH2), 3.16 (1 H, m, NCH2), 3.72–
Synlett 2006, No. 6, 873–876 © Thieme Stuttgart · New York

876 J. Clayden et al. LETTER
3.76 (2 H, m, CH), 4.55 (1 H, br s, OH), 6.71 (1 H, d, J = 8 Hz, ArH),
6.83 (1 H, d, J = 8 Hz, ArH), 7.13 (1 H, t, J = 8 Hz, ArH). 13C NMR
(125 MHz, CDCl3): d = 13.0. 14.4, 23.8, 32.3, 35.9, 39.7, 43.4, 44.9,
51.2, 81.8, 116.5, 120.3, 129.9, 131.8, 143.0, 150.3, 172.2.
Minor diastereomer: yield 88 mg (21%), Rf = 0.30 (50:50 PE–
EtOAc). 1H NMR (500 MHz, CDCl3): d = 0.88 (3 H, t, J = 7 Hz,
CH3), 1.08 (3 H, t, J = 7 Hz, CH3), 1.37 (1 H, m, CH2), 1.44 (1 H,
m, CH2), 1.55 (1 H, m, CH2), 1.61 (1 H, m, CH2), 1.86 (1 H, m,
CH2), 2.10 (1 H, m, CH2), 2.54 (6 H, s, NMe2), 2.68 (1 H, m, CHAr),
2.90–2.94 (2 H, m, NCH2), 3.33 (1 H, m, NCH2), 3.47 (1 H, m,
NCH2), 4.11 (1 H, m, CHOH), 6.70 (1 H, d, J = 8 Hz, ArH), 6.75 (1
H, d, J = 8 Hz, ArH), 7.07 (1 H, t, J = 8 Hz, ArH). 13C NMR (125
MHz, CDCl3): d = 12.9, 13.7, 22.4, 34.5, 35.0, 36.7, 43.3, 45.1,
52.0, 80.0, 116.8, 120.6, 129.5, 133.3, 142.4, 150.7, 170.7.
IR: nmax = 3391 (OH), 2938, 2871 and 2786 (CH), 1602 (C=O)
cm –1 . MS (CI): m/z (%) = 305 (100) [M + H]. HRMS: m/z calcd for
C18H28N2O2: 305.2224 [M]; found: 305.2223 [M + H].
(3a,9b)-6-(Dimethylamino)-1,2,3,3a-tetrahydrocyclopenta[c]isochromen-5(9bH)-one
(4b)
The amide 3b (84 mg, 0.33 mmol) was heated at 90 °C in 2 M HCl
in dioxane (3 mL) for 18 h. The mixture was cooled, diluted with
Et 2O (20 mL), washed with sat. NH 4Cl solution (3 × 20 mL), dried
(MgSO 4) and concentrated under reduced pressure. The residue was
purified by flash chromatography (SiO 2, PE–EtOAc = 80:20) to
give the lactone 4b as white crystals (50 mg, 78%), mp 86–88 °C;
R f = 0.83 (PE–EtOAc, 50:50). IR: n max = 2974 and 2955 (CH), 1713
(C=O) cm –1 . 1 H NMR (500 MHz, CDCl 3): d = 1.31 (1 H, m, CH 2),
1.65–1.81 (2 H, m, CH 2), 1.80 (1 H, m, CH 2), 1.91–1.94 (1 H, m,
CH 2), 2.04–2.10 (1 H, m, CH 2), 2.67 (1 H, m, CHAr), 2.72 (6 H, s,
NMe 2), 4.00 (1 H, m, CH), 6.33 (1 H, d, J = 8 Hz, ArH), 6.65 (1 H,
d, J = 7 Hz, ArH), 7.10 (1 H, d, J = 8 Hz, ArH). 13 C NMR (125 MHz,
CDCl 3): d = 20.5, 24.1, 28.3, 44.0, 45.1, 82.8, 112.2, 114.1, 115.1,
133.3, 145.8, 154.1, 166.1. MS (CI): m/z (%) = 232 (10) [M + H].
HRMS: m/z calcd for C 14H 17O 2N: 231.1254 [M]; found: 231.1254
[M + ].
Acknowledgment
We are grateful to the EPSRC and to Eli Lilly & Co., Ltd. for support.
References and Notes
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Synlett 2006, No. 6, 873–876 © Thieme Stuttgart · New York
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Chem. Commun. 2004, 228.
(10) Asymmetry was introduced into a comparable reaction of 2alkylbenzoate
esters by the use of a chiral lithium amide
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(11) For a comparable strategy using secondary amides, see:
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6171.
(12) A previous report had indicated lack of reactivity between
lithiated tertiary amides and epoxides in the absence of BF 3,
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P. Tetrahedron Lett. 1994, 35, 3949.
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aldehydes is in contrast stereoselective with respect to the
axis and the benzylic stereogenic centre, but non
stereoselective with regard to the relationship between the
two centers, see: Clayden, J.; Pink, J. H.; Westlund, N.;
Frampton, C. S. J. Chem. Soc., Perkin. Trans. 1 2002, 901.
(14) X-ray crystallographic data have been deposited with the
Cambridge Crystallographic Database, reference 288095.
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Asymmetry 1997, 8, 2153; and references cited therein.
(17) Koshino, H.; Yoshihara, T.; Okuno, M.; Sakamura, S.;
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(19) Andersen, K. K. Tetrahedron Lett. 1962, 93.
(20) Solladié, G.; Hutt, J.; Girardin, A. Synlett 1987, 1731.
(21) Additions of ortholithiated amides to aziridines failed even
in the presence of Lewis acids.
(22) Crystallographic data have been deposited with the
Cambridge Crystallographic database, reference 288094.