Asymmetric ortholithiation of amides by conformationally mediated chiral memory: An enantioselective route to naphtho- and benzofuranones

Article abstract of DOI:10.1055/s-2005-871554

An enantiomerically pure sulfinyl group ortho to an aromatic amide imposes absolute stereochemistry on the conformation of its Ar-CO axis. Sulfoxide-lithium exchange followed by addition to an aldehyde relays the chirality of the amide axis to the new hyd

Full text of DOI:10.1055/s-2005-871554

1716
LETTER
Asymmetric Ortholithiation of Amides by Conformationally Mediated Chiral
Memory: An Enantioselective Route to Naphtho- and Benzofuranones
C
hira
l
Me
o
mor
y
in the
A
n
symmetric
Synthesis
o
t
f
Benzo
h
furanones an Clayden,*a Christopher C. Stimson,a Martine Keenanb
a
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Fax +44(161)2754939; E-mail: clayden@man.ac.uk
b
Eli Lilly & Co. Ltd., Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK
Received 15 April 2005
Andersen.13 Lithiation of the tertiary amides 1 with s-
BuLi in THF14 gave ortholithiated amides 2 which reacted
with (1R, 2S, 5R, SS)-(–)-menthyl toluenesulfinate 315
(Scheme 1) to yield sulfoxides 4.7 Two alternative proto-
Abstract: An enantiomerically pure sulfinyl group ortho to an aro-
matic amide imposes absolute stereochemistry on the conformation
of its Ar–CO axis. Sulfoxide–lithium exchange followed by addi-
tion to an aldehyde relays the chirality of the amide axis to the new
hydroxyl-bearing stereogenic centre with good stereochemical fi- cols were employed: initially the sulfinate was added to
delity. Lactonisation of the hydroxyamide gives naphthofuranones
the lithiated amide (‘Method A’). Products of high ee
and benzofuranones, including the fungal metabolite isoochracein,
but with substrate-dependent stereoselectivity.
were obtained with this method when the amide was rela-
tively hindered (4a,b,d were all formed in > 95% ee). In
other cases, however, this method gave less than complete
enantiospecificity: in the case of 4e the product was race-
Key words: chiral memory, amide, sulfoxide, directed metallation,
benzofuranone
mic. Reasoning that ee at the sulfoxide centre was being
eroded by multiple invertive substitution at sulfur by the
excess nucleophile,16 we repeated these reactions using
Method B, in which the ortholithiated amide was added
by cannula to a two-fold excess of the sulfinate. The
enantiomeric excesses of 4c and 4e were dramatically im-
proved, and using 10 equivalents of sulfinate increased
the ee of 4e from 0% (by Method A) to 92% (Table 1,
Method B, entries 7–9).
Ortholithiation is a powerful method for the regioselective
functionalisation of an aromatic ring,1 but attempts to use
it to introduce ortho-substituents enantioselectively by,
for example, using chiral metallation directing groups,
have generally failed.2 Chiral versions of several classes
of metallation directing groups3 – including amides,4
oxazolines,5 hydrazides,6 sulfonamides,7 and sulfoxides8
– have all been examined, but only the last two have been
able to show good, though substrate-dependent, levels of
diastereoselectivity on addition to prochiral electrophiles.
We have reported that an aromatic tertiary amide group,
which may possess a stereogenic Ar–CO axis,9 is capable
of directing the diastereoselective formation of a new
hydroxyl-bearing centre via ortholithiation and reaction
with an aldehyde.10 In this paper we report the extension
of this work to the synthesis of enantiomerically enriched
alcohols by using the conformation of a slowly-rotating
amide Ar–CO axis to store a record of the configuration
of a pre-existing stereogenic centre, with its stereo-
chemistry later being regenerated in the guise of an enan-
tiomerically enriched chiral alcohol.
R
R
R
R
N
N
O
O
sec-BuLi,
X
Y
X
Y
Li
THF, –78 °C
Method A: 3 (1.1 equiv)
added to 2
1
2
Method B: 2
added to 3 (2.0 equiv)
+
S
O
p-Tol
O
3
R
R
N
R
R
N
O
O
X
S
X
Y
S
p-Tol
O
p-Tol
O
Several classes of stereogenic centre have proved to be
capable of imposing an orientational preference upon a
nearby amide group,11 but for the purpose of this work we
required a chiral substituent removable at a temperature
low enough to allow the amide to retain its axial confor-
mation. A sulfinyl group appears to fit this requirement
perfectly.12
Y
anti-4
syn-4
Scheme 1 Synthesis of enantiomerically enriched amidosulfoxides
NMR indicated that the amidosulfoxides adopt a single
diastereoisomeric conformation, to the limit of detection
(>95:5), about their Ar–CO axis (which in related com-
pounds is sufficiently labile to equilibrate rapidly to the
more stable of the two possible axial conformations). The
preferred orientation of the amide group adjacent to a
sulfoxide has previously been shown to be anti, with an
(S)-sulfoxide stereogenic centre inducing P stereo-
chemistry at the amide axis.17
We therefore made a range of enantiomerically pure or
enriched amidosulfoxides 4, following the method of
SYNLETT 2005, No. 11, pp 1716–1720
0
7
.0
7
.2
0
0
5
Advanced online publication: 27.06.2005
DOI: 10.1055/s-2005-871554; Art ID: D09905ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chiral Memory in the Asymmetric Synthesis of Benzofuranones
1717
Table 1 Amidosulfoxides by Ortholithiation
Entry
Starting material
R =
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Et
X =
Y =
Method
Yield anti-4 (%)
ee anti-4 (%)
1
2
1a
1b
1c
1c
1d
1e
1e
1e
1f
Benzoa
MeO
A
A
A
B
A
A
B
Bc
B
B
74
62
48
83
56
65
60
55
55
86
> 95b
> 95
70b
> 95
96
MeO
H
4
MeO
5
MeO
H
6
i-Pr3SiO
Benzoa
Benzoa
Benzoa
Me2N
H
H
7
0b
8
Et
88
9
Et
92
10
11
Et
H
H
72
1g
i-Pr
> 95
a 1-Naphthamide.
b Previously reported in ref.7 but ee not determined.
c With 10 equiv sulfinate 3.
The amidosulfoxides anti-4 were submitted to sulfoxide-
lithium exchange12 by treatment with t-BuLi (3.0 equiv).
A reaction temperature of –90 °C was employed to mini-
mise Ar–CO rotation after formation of the presumed
enantiomerically enriched organolithium M-2. After two
minutes (the minimum time consistent with complete sub-
stitution of the sulfinyl group) an aldehyde electrophile
was added. The product was quenched with water and
kept cool and the results are shown in Scheme 2 and
Table 2.
N
N
RCHO,
–90 °C
t-BuLi (3.0 equiv),
THF, –90 °C
O
O
X
Y
S
X
Y
Li
p-Tol
O
2 min
then NH4Cl
anti-4
M-2
N
N
O
OH
O
OH
X
X
Y
+
R
R
The diastereoselectivities obtained were high – typically
10:1 or better18 – with the major product in all cases being
the syn-diastereoisomer. Chiral HPLC indicated that the
enantiomeric excess of this major syn-diastereoisomer
was also typically high, in the region of 90–95% (entries
1–6).19 Given that the only stereogenic centre in the
Y
syn-5
anti-5
Scheme 2 Chiral memory in additions to aldehydes
Table 2 Additions to Aldehydes
Entry
Starting materiala X =
Y =
R =
Et
Product, yield (%)
5a, 94
syn-5:anti-5
93:7
ee of syn-5
1
2
3
4
5
6
7
4a
4a
4a
4b
4b
4c
4g
Benzob
88
93
> 95
96
93
95
0
Benzo
Benzo
MeO
MeO
MeO
H
i-Pr
Ph
5b, 79
95:5
5c, 88
90:10
MeO
MeO
H
c-Hx
Ph(CH2)2
Et
5d, 46
> 85:15
> 90:10
95:5
5e, 59
5f, 89
H
Ph
5g, 89
60:40c
a All starting materials > 95% ee.
b 1-Naphthamide.
c Thermodynamically-controlled ratio of interconverting conformers.
Synlett 2005, No. 11, 1716–1720 © Thieme Stuttgart · New York

1718
J. Clayden et al.
LETTER
starting material is destroyed before the aldehyde is
added, the most likely explanation for this result is that the
axial conformation of the amide has mediated the transfer
of stereochemical information from the old sulfoxide cen-
tre to the new hydroxyl-bearing centre. The fact that a
substituent ortho to the amide (in addition to the sulfinyl
group) is essential for any level of asymmetry in the
product supports this hypothesis: compound 4g (entry 7)
lacks this substituent and in this case the lithiated amide
‘forgets’ the stereochemistry of the sulfoxide as a result of
fast bond rotation.20,21
N
O
O
O
OH
conditions
R
R
syn-5a–c
6a–c
N
O
7
Slow rotation has been invoked as the controlling feature
in other ‘chiral memory’ sequences, most notably the
asymmetric alkylation reactions of amino acids developed
by Kawabata and Fuji,22 where the orientation of a car-
bamate group stores a record of a stereogenic centre
which is destroyed by enolisation and then recreated faith-
fully, controlled by the carbamate conformation, in a sub-
sequent alkylation. Both this method and the one we now
describe are special cases of the phenomenon described
by Seebach as ‘self-regeneration of stereocentres’:23 in his
pioneering work, the configuration of a temporary stereo-
genic centre was employed as the mediator of chiral mem-
ory. The linking feature of all chiral memory sequences is
the formation, under thermodynamic control, of a tempo-
rary stereochemical feature, which is no longer present in
the final product of the sequence.
Scheme 3 Ring-closure to enantiomerically enriched naphtho-
furanones
ways to some degree retentive, suggesting that the princi-
pal mechanism for cyclisation is nucleophilic substitution
at the amide carbonyl group rather than SN1-style dis-
placement of the hydroxyl group by the nucleophilic
amide oxygen atom (Figure 1).25
N
N
–
–
OH
O
O
R
R
retention
retention/inversion?
In order to convert them to useful chiral products, and to
bring the chiral memory sequence to completion, we
sought to lactonise the alcohols 5a–c to naphthofuranones
6 (Scheme 3).24 However, protic and Lewis acids convert-
ed the hydroxyamide 5a to only poor yields of 6a
(Table 3, entries 1–3 give some examples) and pose the
risk of rapid racemisation via carbocationic intermediates.
We therefore turned to more neutral conditions, and found
by chance that by heating the alcohols 5 with sodium p-
toluenesulfinate, or, better, sodium or potassium acetate in
refluxing xylene, gave good yields of the naphthofura-
nones 6 (entries 4–7) The cyclisation varied in the degree
of its stereospecificity, although interestingly it was al-
Figure 1 Mechanisms for lactonisation
With a small, aliphatic R substituent (entry 4), ee was pre-
served intact in the product. However, with a more bulky
or an aryl substituent (entries 5 and 6), selectivity was
significantly lower, presumably because of competitive
cyclisation via an invertive or non-stereospecific substitu-
tion of the hydroxyl group by the amide carbonyl group.
Using KOAc, cyclisation of 5f gave 6f (Scheme 4 and
Table 3 entry 7) which was deprotected with BBr3 to
yield the simple fungal metabolite isoorchracein26 in 50%
yield, but unfortunately with only 11% ee as a result of
Table 3 Cyclisation to Yield Naphtho- and Benzofuranones 6
Entry
Starting material, ee (%)
R =
Et
Conditionsa
Product
6a
Yield
ee (%)
–
b
1
2
3
4
5
6
7
5a, n/d
5a, n/d
5a, 88
5a, 88
5b, 93
5c, >95
5f, 95
A
B
C
D
D
D
D
–
Et
6a
Traceb
25
–
Et
6a
88
89
73
17
83
Et
6a
72
i-Pr
Ph
Et
6b
70
6c
70
6f
75
a Conditions: A: MeSO3H, toluene, D; B: PPTS, xylene, D; C: silica, toluene, D; D: KOAc, xylene, D.
b Significant quantities of elimination product 7 formed.
Synlett 2005, No. 11, 1716–1720 © Thieme Stuttgart · New York

LETTER
Chiral Memory in the Asymmetric Synthesis of Benzofuranones
1719
(R)-3-Ethyl-7-methoxyisobenzofuran-1(3H)-one [(R)-(+)-
isoochracein] (8).
racemisation during the deprotection step. Nonetheless,
this represents the first synthesis of 8 with any enantio-
selectivity and (subject to the limits of our certainty about
the stereospecificity of the cyclisation25) confirms that the
natural product, which is laevorotatory, has the S con-
figuration.26
Boron tribromide (0.83 mL of a 1 M solution in CH2Cl2, 0.83 mmol)
was added dropwise to a solution of lactone 6f in CH2Cl2 (3 mL) at
r.t. After 3 h, the solution was quenched with 0.1 M aq HCl and the
mixture diluted with CH2Cl2 (15 mL), washed with sat. NH4Cl so-
lution (3 ꢀ 10 mL), dried (MgSO4) and concentrated under reduced
pressure. NMR spectrum of the crude residue showed the phenol
(90%). Flash chromatography (SiO2; petroleum ether–EtOAc,
80:20) gave the ring-opened product (50%) plus the lactone (36 mg,
47%) as white crystals, mp 80–81 °C (lit.26 mp 78–79 °C); Rf = 0.55
(70:30 petroleum ether–EtOAc); 11% ee by HPLC; [a]D +48.6 (c
0.43, CHCl3). IR: nmax = 3429 (O–H), 2972 (C–H), 1735 (C=O) cm–
1. 1H NMR (300 MHz, CDCl3): d = 1.03 (3 H, t, J = 7 Hz, CH3), 1.88
(1 H, m, CH2), 2.15 (1 H, m, CH2), 5.50 (1 H, dd, J = 4, 7 Hz, CH),
6.90 (1 H, d, J = 8 Hz, ArH), 6.92 (1 H, d, J = 8 Hz, ArH), 7.58 (1
H, t, J = 8 Hz, ArH), 7.82 (1 H, br s, OH). 13C NMR (75 MHz,
CDCl3): d = 9.1, 27.8, 84.1, 111.6, 113.4, 115.6, 137.1, 150.3,
O
O
N
O
OH
KOAc,
RO
MeO
xylene, ∆
(+)-6f (R = Me) 75%, 83% ee
(+)-8 (R = H)
BBr3
syn-5f
ent-isoochracein
50%, 11% ee
Scheme 4 Synthesis of ent-isoochracein
+
156.8, 172.5. MS (CI): m/z (%) = 196 (100) [M + NH4 ], 179 (30)
[M + H]. HRMS: m/z calcd for C10H10O3 [M]: 178.0624. Found
[M+]: 178.0621.
In summary, we have shown that a transiently chiral
Ar–CO axis in an ortholithiated amide may mediate the
transfer of chirality from a sulfoxide to a hydroxyl-bear-
ing centre, providing a route to enantiomerically enriched
benzofuranones, useful compounds lacking more direct
synthetic approaches.
Acknowledgment
We are grateful to Eli Lilly and the EPSRC for support of this work.
References
(1) (a) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979,
26, 1. (b) Snieckus, V. Chem. Rev. 1990, 90, 879.
(c) Clayden, J. Organolithiums: Selectivity for Synthesis;
Pergamon: Oxford, 2002. (d) Clayden, J. In Chemistry of
Organolithium Compounds; Rappoport, Z.; Marek, I., Eds.;
Wiley: Chichester, 2004, 495–646.
(2) This is true only for uncomplexed aromatic rings: in the
ferrocene and arenechromiumtricarbonyl series, chiral
ortho-directing groups are a highly effective way of
introducing planar chirality; for a discussion, see: Clayden,
J. In Organolithiums in Enantioselective Synthesis;
Hodgson, D. M., Ed.; Springer: New York, 2003, 251–286.
(3) Pollet, P.; Turck, A.; Plé, N.; Quéguiner, G. J. Org. Chem.
1999, 64, 4512; and references therein.
(4) Beak, P.; Tse, A.; Hawkins, J.; Chen, C.-W.; Mills, S.
Tetrahedron 1983, 39, 1983.
(5) Meyers, A. I.; Hanagan, M. A.; Trefonas, L. M.; Baker, R. J.
Tetrahedron 1983, 39, 1991.
(6) Pratt, S. A.; Goble, M. P.; Mulvaney, M. J.; Wuts, P. G. M.
Tetrahedron Lett. 2000, 41, 3559.
(7) Takahashi, H.; Tsubuki, T.; Higashiyama, K. Chem. Pharm.
Bull. 1991, 39, 260.
(8) Quesnelle, C.; Iihama, T.; Aubert, T.; Perrier, H.; Snieckus,
V. Tetrahedron Lett. 1992, 33, 2625; and ref. 3.
(9) Ahmed, A.; Bragg, R. A.; Clayden, J.; Lai, L. W.; McCarthy,
C.; Pink, J. H.; Westlund, N.; Yasin, S. A. Tetrahedron
1998, 54, 13277.
(10) (a) Bowles, P.; Clayden, J.; Helliwell, M.; McCarthy, C.;
Tomkinson, M.; Westlund, N. J. Chem. Soc., Perkin Trans.
1 1997, 2607. (b) Bowles, P.; Clayden, J.; Tomkinson, M.
Tetrahedron Lett. 1995, 36, 9219.
(11) 1-Silylethyl groups: (a) Clayden, J.; Pink, J. H.; Yasin, S. A.
Tetrahedron Lett. 1998, 39, 105. (b) Clayden, J.; Johnson,
P.; Pink, J. H.; Helliwell, M. J. Org. Chem. 2000, 65, 7033.
Proline-derived imidazolidines: (c) Clayden, J.; Lai, L. W.
Angew. Chem. Int. Ed. 1999, 38, 2556. Ephedrine-derived
oxazolidines: (d) Clayden, J.; Lai, L. W. Tetrahedron Lett.
2001, 42, 3163. (e) Clayden, J.; Lai, L. W.; Helliwell, M.
(R)-2-(1-Hydroxypropyl)-N,N-diisopropyl-6-methoxybenz-
amide (5f).
t-BuLi (4.2 mmol of a 1.4 M solution in hexane, 3 equiv) was added
dropwise to a stirred solution of sulfoxide 4c7 (522 mg, 1.40 mmol)
in dry THF (20 mL) under nitrogen at –90 °C. After 2 min, propi-
onaldehyde (0.806 mL, 11.12 mmol) was added dropwise at –90 °C
and the mixture was allowed to warm to r.t. 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 to give a residue which
was purified by flash chromatography (SiO2; petroleum ether–
EtOAc, 50:50) give the alcohol 5f (365 mg, 89%) as white crystals;
Rf = 0.26 (60:40 petroleum ether–EtOAc); >95:5 syn:anti diastere-
1
oisomers, >95% ee syn-isomer; [a]D +67.8 (c 0.33, acetone). H
NMR (300 MHz, CDCl3): d = 1.01 (3 H, t, J = 8 Hz, CH3), 1.07 (3
H, d, J = 7 Hz, CH3), 1.22 (3 H, d, J = 7 Hz, CH3), 1.60 (3 H, d, J =
7 Hz, CH3), 1.62 (3 H, d, J = 7 Hz, CH3), 1.85–2.06 (2 H, m, CH2),
3.56 (1 H, sept, J = 7 Hz, NCH), 3.74 (1 H, sept, J = 7 Hz, NCH),
3.84 (3 H, s, OCH3), 4.52 (1 H, t, J = 7 Hz, CHOH), 6.84 (1 H, d, J
= 8 Hz, ArH), 7.12 (1 H, d, J = 8 Hz, ArH), 7.35 (1 H, t, J = 8 Hz,
ArH). 13C NMR (75 MHz, CDCl3): d = 11.2, 20.5, 20.6, 20.8, 21.1,
27.3, 46.3, 51.5, 55.6, 72.4, 109.8, 118.2, 127.9, 129.8, 142.3,
155.1, 168.8. MS (CI): m/z (%) = 294 (30) [M + H], 69 (100).
HRMS: m/z calcd for C17H27NO3 [M]: 293.1985; found [M+]:
293.1986.
(R)-3-Ethyl-7-methoxyisobenzofuran-1(3H)-one (6f).
Amide syn-5f (290 mg, 1.09 mmol) and potassium acetate (4.0 g,
1.71 mmol) were heated at reflux for 18 h in xylene (10 mL). The
mixture was diluted with Et2O (20 mL), washed with sat. NH4Cl so-
lution (3 ꢀ 15 mL), dried (MgSO4) and concentrated under reduced
pressure. The residue which was purified by flash chromatography
(SiO2; petroleum ether–EtOAc, 80:20) to give the lactone 6f27 (185
mg, 95%) as a clear oil; Rf = 0.31 (70:30 petroleum ether–EtOAc);
83% ee by HPLC; [a]D +69.1 (c 0.11, acetone).
Synlett 2005, No. 11, 1716–1720 © Thieme Stuttgart · New York

1720
J. Clayden et al.
LETTER
absolute stereochemistry of comparable atropisomeric
amides obtained by quenching with simple, ‘non-prochiral’
electrophiles (see ref. 7h).
Tetrahedron: Asymmetry 2001, 12, 695. (f)Clayden, J.;Lai,
L. W.; Helliwell, M. Tetrahedron 2004, 60, 4399.
(g) Clayden, J.; Lund, A.; Vallverdú, L.; Helliwell, M.
Nature (London) 2004, 431, 966. Sulfinyl groups:
(h) Clayden, J.; Mitjans, D.; Youssef, L. H. J. Am. Chem.
Soc. 2002, 124, 5266. (i) Clayden, J.; Kubinski, P. M.;
Sammiceli, F.; Helliwell, M.; Diorazio, L. Tetrahedron
2004, 60, 4387.
(20) An alternative explanation, that the sulfoxide by-product of
the reaction, tert-butyl tolyl sulfoxide, which may be
generated in enantiomerically pure form, could mediate the
asymmetric formation of the new centre, seems unlikely,
given this dependence on amide structure.
(12) See ref. 7h. For further examples of sulfoxide displacement
by sulfoxide-metal exchange, see: (a) Clayden, J.
Organolithiums: Selectivity for Synthesis; Pergamon:
Oxford, 2002, Chap. 3.3.3, 142. (b) Capozzi, M. M. M.;
Cardellicchio, C.; Naso, F. Eur. J. Org. Chem. 2004, 1855;
and references therein. (c) Satoh, T.; Horiguchi, K.
Tetrahedron Lett. 1995, 36, 8235. (d) Carpintero, M.;
Nietro, I.; Fernández-Mayorales, A. J. Org. Chem. 2001, 66,
1768. (e) Milne, J. E.; Jarowicki, K.; Kocienski, P. J.;
Alonso, J. Chem. Commun. 2002, 426.
(13) Andersen, K. K. Tetrahedron Lett. 1962, 93.
(14) (a) Beak, P.; Brown, R. A. J. Org. Chem. 1977, 42, 1823.
(b) Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 34.
(c) As is usual with tertiary amides at the more sterically
encumbered end of the scale, the addition of TMEDA to
these lithiations was found to be unnecessary.
(15) A convenient synthesis of (–)-menthyl sulfinate on a 100 g
scale has been described, see: Solladié, G.; Hutt, J.; Girardin,
A. Synlett 1987, 173.
(16) A similar loss of absolute stereochemistry for this reason
plagues the analogous synthesis of ferrocenyl p-tolyl
sulfoxide. See: Riant, O.; Argouarch, G.; Guillaneux, D.;
Samuel, O.; Kagan, H. B. J. Org. Chem. 1998, 63, 3511; and
references therein.
(21) Attempts to extend this application of chiral memory to the
control of stereogenic centres formed by lateral lithiation
were hampered by the remarkably fast racemisation of
laterally lithiated amides. See: (a) Clayden, J.; Helliwell,
M.; Pink, J. H.; Westlund, N. J. Am. Chem. Soc. 2001, 123,
12449. (b) Clayden, J.; Pink, J. H.; Westlund, N.; Frampton,
C. S. J. Chem. Soc., Perkin Trans. 1 2002, 901. (c) See
also: Clayden, J.; Stimson, C. C.; Keenan, M.; Wheatley, A.
E. H. Chem. Commun. 2004, 228.
(22) (a) Fuji, K.; Kawabata, T. Chem.–Eur. J. 1998, 4, 373.
(b) Kawabata, T.; Chen, J.; Suzuki, H.; Nagae, Y.;
Kinoshita, T.; Chancharunee, S.; Fuji, K. Org. Lett. 2000, 2,
3883. (c) Kawabata, T.; Kawakami, S.; Majumdar, S. J. Am.
Chem. Soc. 2003, 125, 13012. (d) Kawabata, T.; Fuji, K.
Top. Stereochem. 2003, 23, 175. (e) Kawabata, T.; Öztürk,
O.; Chen, J.; Fuji, K. Chem. Commun. 2003, 162.
(23) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2709.
(24) Ortholithiation, addition to aldehydes, and lactonisation
under acid conditions is an established way of making
benzofuranones from aromatic amides: see ref. 1b and
references therein, and ref. 27.
(25) It is of course possible that chiral memory effects operate
during the cyclisation, and we cannot rule out retentive
cyclisation via a benzylic carbocation. Our confidence in the
absolute stereochemistry of the products is based upon the
fact that simple 3-alkylbenzofuranones with reported optical
rotations are laevorotatory if S and dextrorotatory if R. See:
ref. 5 and: (a) Watanabe, M.; Hashimoto, N.; Araki, S.;
Butsugan, Y. J. Org. Chem. 1992, 57, 742.
(17) See ref. 7h. The level of conformational selectivity has
recently been determined in related compounds to be of the
order of 200:1 (Clayden, J.; Helliwell, M.; Mitjans, D.;
Regan, A. C. manuscript in preparation).
(18) In our earlier work on the addition of racemic
organolithiums to aldehydes (ref. 10), we reported
somewhat lower diastereoselectivities, although those
reactions were carried out at –78 °C. Repeating some of the
earlier racemic reactions at –90 °C confirmed that it is
simply the temperature, and not the enantiomeric purity of
the organolithiums, which improves the diastereoselectivity.
Racemic ortholithiated amides are heterochiral dimers (at
least in the solid state: see Clayden, J.; Davies, R. P.;
Hendy, M. A.; Snaith, R.; Wheatley, A. E. H. Angew. Chem.
Int. Ed. 2001, 40, 1238), and some differences in reactivity
between organolithiums of different ee are therefore to be
expected.
(b) Ramachandran, P. V.; Chen, G.-M.; Brown, H. C.
Tetrahedron Lett. 1996, 37, 2205. (c) Kawasaki, T.;
Kimachi, T. Tetrahedron 1999, 55, 6847.
In a previous publication (ref. 7h) we got this wrong: we
claimed, erroneously, the opposite dependence of optical
activity on stereochemistry (though in mitigation we suggest
that the experimental section of ref. 25b invites
misinterpretation!), and the proposed cationic mechanism
for the lactonisation reported in ref. 7h is consequently
probably wrong.
(26) (–)-Isoochracein is a fungal metabolite isolated from
Hypoxylon spp. See: Anderson, J. R.; Edwards, R. L.;
Whalley, A. J. S. J. Chem. Soc., Perkin Trans. 1 1983, 2185.
(27) Anstiss, M.; Clayden, J.; Grube, A.; Youssef, L. H. Synlett
2002, 290.
(19) The major diastereoisomer was identified by comparison
with known compounds whose structure had been confirmed
by X-ray crystallography (ref. 10). Absolute stereochemistry
was deduced from the preferred orientation of amides
adjacent to enantiomerically pure sulfoxides and from the
Synlett 2005, No. 11, 1716–1720 © Thieme Stuttgart · New York