Asymmetric cyclization of achiral olefinic organolithiums controlled by a stereogenic lithium intramolecular carbolithiation in the presence of (-)- sparteine [12]

Full text of DOI:10.1021/ja000471l

J. Am. Chem. Soc. 2000, 122, 6787-6788
6787
bidentate ligand. It occurred to us that, on this basis, it might be
possible to effect enantiofacially selective cycloisomerization of
an achiral olefinic organolithium by simply conducting the
isomerization of the achiral substrate in the presence of such a
chiral ligand. In light of the elegant pioneering studies by Normant
and Marek, demonstrating the ability of the lupine alkaloid (-)-
sparteine (1) to promote enantioselective intermolecular carbo-
lithiation,9 this readily available, chiral diamine was chosen for
exploratory investigation. As demonstrated by the results of model
studies presented below, conducting the cyclization of achiral
olefinic organolithiums in the presence of stoichiometric amounts
of 1 renders the isomerization enantioselective.
The 2-(N,N-diallylamino)phenyllithium (2) substrate, which is
known to afford high yields of 3-substituted indolines upon 5-exo
cyclization and trapping with an electrophile,4 was selected as a
representative model to assess the possibility of effecting enan-
tioselective ring closure of an achiral organolithium. Aryllithium
2 was prepared in virtually quantitative yield, as previously
described,4b by treatment of 0.1 M solutions of N,N-diallyl-2-
bromoaniline (3), typically (vide infra) in dry n-pentane-diethyl
ether (9:1 by vol), with 2.2 molar equiv of t-BuLi at -78 °C.10
Asymmetric cyclization of 2 was easily accomplished, as il-
lustrated in Scheme 1, by addition of 2.2 equiv of dry, oxygen-
Asymmetric Cyclization of Achiral Olefinic
Organolithiums Controlled by a Stereogenic
Lithium: Intramolecular Carbolithiation in the
Presence of (-)-Sparteine
William F. Bailey* and Michael J. Mealy
Department of Chemistry, The UniVersity of Connecticut
Storrs, Connecticut 06269-3060
ReceiVed February 4, 2000
The cycloisomerization of olefinic organolithiums provides a
regiospecific and highly diastereoselective route to functionalized
carbocyclic and heterocyclic systems.1-4 Molecular orbital cal-
culations indicate the stereochemical course of these formally
anionic cyclizations5 is a consequence of a fairly rigid transition
state for the process in which the lithium atom is coordinated to
the remote π-bond.3 Indeed, the ground-state structure of arche-
typal 5-hexenyllithium (shown below) resembles a chairlike
arrangement in which the lithium atom at C(1) is coordinated to
the C(5)-C(6) π-bond.3,6 Calculations further suggest that the
cycloisomerization of 5-hexenyllithium (and, by analogy, other
unsaturated organolithiums) should proceed with complete reten-
tion of configuration at the lithium-bearing C(1) position by syn-
addition to the π-bond.3 This later prediction has been confirmed
experimentally by the groups of Hoppe and Nakai7 and the
stereoselectivity of the ring closure has been exploited in several
recent reports detailing the asymmetric cyclization of chiral
5-hexenyllithiums that possess a stereogenic carbanionic center.2k,7,8
Scheme 1
On the assumption that the internally coordinated lithium atom
of an unsaturated organolithium has two additional sites available
for ligation, the lithium atom of an achiral substrate is rendered
stereogenic upon complexation in an η2-fashion with a chiral,
free (-)-sparteine (1) to the -78 °C solution and allowing the
resulting mixture to warm and stand at various temperatures for
1-1.5 h prior to quench with MeOH. The enantiomeric purity of
the resulting (R)-(-)-1-allyl-3-methylindoline (4)11 was assayed
directly by CSP HPLC on a Chiralcel-OD column as detailed in
the Supporting Information. The results of these experiments,
summarized in Table 1, demonstrate that the (-)-sparteine-
mediated cyclization of 2 is indeed highly enantioselective.
Several features of the data summarized in Table 1 are worthy
of note. Not surprisingly, the cyclization is more enantioselective
at lower temperatures (Table 1, cf. entries 1, 3, and 4); at
temperatures below ∼-40 °C the isomerization is too slow to
be of practical value (Table 1, entry 10). Solvent has a very
dramatic effect on the enantioselectivity of the ring closure: while
solvent systems composed of hydrocarbon-diethyl ether (Table
1, entries 3-5 and 7), pure hydrocarbon (Table 1, entry 2), or
pure ether (Table 1, entry 8) are equally effective media for the
cycloisomerization, the use of THF as solvent is to be avoided
since it leads to virtually racemic product (Table 1, entry 9).12 It
should also be noted that at least 2 molar equiv of 1 must be
(1) For a review, see: Bailey, W. F.; Ovaska, T. V. In AdVances in Detailed
Reaction Mechanisms; Coxon, J. M., Ed.; JAI Press: Greenwich, CT, 1994;
Vol. 3, Mechanisms of Importance in Synthesis, pp 251-273.
(2) For leading references, see: (a) Bailey, W. F.; Patricia, J. J.; DelGobbo,
V. C.; Jarret, R. M.; Okarma, P. J. J. Org. Chem. 1985, 50, 1999. (b) Bailey,
W. F.; Nurmi, T. T.; Patricia, J. J.; Wang, W. J. Am. Chem. Soc. 1987, 109,
9, 2442. (c) Chamberlin, A. R.; Bloom, S. H.; Cervini, L. A.; Fotsch, C. H.
J. Am. Chem. Soc. 1988, 110, 4788. (d) Bailey, W. F.; Rossi, K. J. Am. Chem.
Soc. 1989, 111, 765. (e) Bailey, W. F.; Khanolkar, A. D. J. Org. Chem. 1990,
55, 6058. (f) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K. V. J. Am. Chem.
Soc. 1992, 114, 8053. (g) Cooke, M. P., Jr. J. Org. Chem. 1992, 57, 1495 and
references therein. (h) Lautens, M.; Kumanovic, S. J. Am. Chem. Soc. 1995,
117, 1954. (i) Bailey, W. F.; Jiang, X.-L.; McLeod, C. E. J. Org. Chem. 1995,
60, 7791. (j) Krief, A.; Kenda, B.; Remacle, B. Tetrahedron 1996, 52, 7435
and references therein. (k) Coldham, I.; Hufton, R.; Snowden, D. J. J. Am.
Chem. Soc. 1996, 118, 5322.
(3) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaska, T. V.; Rossi,
K.; Thiel, Y.; Wiberg, K. B. J. Am. Chem. Soc. 1991, 113, 5720.
(4) (a) Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1996, 61, 2594. (b)
Bailey, W. F.; Jiang, X.-L. J. Org. Chem. 1996, 61, 2596. (c) Bailey, W. F.;
Carson, M. W. Tetrahedron Lett. 1997, 38, 1329.
(5) It is important to note that the lithium atom is intimately involved in
the cycloisomerization of unsaturated organolithiums: 5-hexenyllithium is
unique among the 5-hexenylalkalis in it ability to undergo facile cyclization.
See: Bailey, W. F.; Punzalan, E. R. J. Am. Chem. Soc. 1994, 116, 6577.
(6) Intramolecular coordination of the lithium atom with the remote π-bond
in the ground state of 5-hexenyllithium has been experimentally confirmed.
See: Ro¨lle, T.; Hoffmann, R. W. J. Chem. Soc., Perkin Trans. 2 1995, 1953.
(7) (a) Woltering, M. J.; Fro¨hlich, R.; Hoppe, D. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1764. (b) Tomooka, K.; Komine, N.; Nakai, T. Tetrahedron
Lett. 1997, 38, 8939.
(9) (a) Klein, S.; Marek, I.; Poisson, J.-F.; Normant, J.-F. J. Am. Chem.
Soc. 1995, 117, 8853. (b) Norsikian, S.; Marek, I.; Poisson, J.-F.; Normant,
J.-F. J. Org. Chem. 1997, 62, 4898. (c) For a review of enantioselective
intermolecular carbolithiation of alkenes, see: Marek, I. J. Chem. Soc., Perkin
Trans. 1 1999, 535. (d) For reviews of the use of (-)-sparteine to effect
asymmetric organolithium chemistry, see: Beak, P.; Basu, A.; Gallagher, D.
J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552 and Hoppe,
D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282.
(10) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404.
(11) Determination of the absolute configuration of (R)-(-)-1-allyl-3-
methylindoline (4) has been described: see, Kondru, R. K.; Wipf, P.; Beratan,
D. N. J. Phys. Chem. A 1999, 103, 6603.
(8) (a) Krief, A.; Bousbaa, J. Synlett 1996, 1007. (b) Tomooka, K.; Komine,
N.; Sasaki, H.; Shimizu, T.; Nakai, T. Tetrahedron Lett. 1998, 39, 9715. (c)
Oestreich, M.; Fro¨hlich, R.; Hoppe, D. J. Org. Chem. 1999, 64, 8616. (d)
Hoppe, D.; Woltering, M. J.; Oestreich, M.; Fro¨hlich, R. HelV. Chim. Acta
1999, 82, 1860.
10.1021/ja000471l CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/27/2000

6788 J. Am. Chem. Soc., Vol. 122, No. 28, 2000
Communications to the Editor
Table 1. Enantioselective Preparation of 1-Allyl-3-methylindoline
Scheme 3
(4)a
sparteine, temp, time, yield,c
entry
solvent b
molar equiv
°C
h
%
e.r.d
Woolsey and co-workers,13 is considerably less facile than are
the ring closures discussed above. For this reason, it was necessary
to allow solutions of 8 in n-pentane-diethyl ether containing 2.2
equiv of (-)-sparteine to stand for 1 h at +22 °C to effect cycli-
zation. Nonetheless, even at this relatively high temperature, the
cycloisomerization of 8 in the presence of 1 is fairly enantiose-
lective: as illustrated in Scheme 2, trapping of the (1-indanyl)meth-
yllithium product by protonation gave a 76% yield of the known14
(S)-(-)-1-methylindan (9) in 76% yield with an ee of 42%.
An alternative route to (1-indanyl)methyllithium, involving
cyclization of the styrene-tethered primary alkyllithium (10)
generated from 1-(2-iodoethyl)-2-vinylbenzene (11), was also
investigated. Not surprisingly, isomerization of 10 in n-pentane-
diethyl ether containing 2 equiv of 1 is a very rapid 5-exo process.
However, as shown in Scheme 2, the cycloisomerization, which
proceeds to completion in 3 h at -60 °C, affords essentially
racemic (ee ∼4%) 1-methylindan (9) in 69% yield. While it is
tempting to attribute the formation of racemic 9 to a competing,
rapid cyclization in the absence of ligated sparteine, control
experiments demonstrate that less than 10% of 9 is formed when
solutions of 10 are allowed to stand for 3 h at -60 °C in the
absence of 1. It would appear that the ability of (-)-sparteine to
facilitate the cyclization of an achiral organolithium such as 10
is not always sufficient to render such a process enantioselective.
Be that as it may, the cyclization of very simple substrates
may be conducted in an enantioselective fashion in the presence
of (-)-sparteine. As illustrated in Scheme 3, the unadorned vinyl-
lithium (12), derived from 2-bromo-1,6-heptadiene (13) by low-
temperature lithium-bromine exchange in n-pentane - diethyl
ether, undergoes a moderately enantioselective cyclization when
stirred at 0 °C in the presence of 2.2 molar equiv of 1 to give,
inter alia, (S)-(+)-(14) in ∼40% ee. Trapping of the organolithium
product with TMS-Cl gave (S)-(+)-15 of known absolute con-
figuration15 in 79% yield.
1
2
3
4
5
6
7
8
9
n-C5H12-Et2O
n-C5H12
2.1
2.2
2.5
2.1
4.4
1.1
2.3
2.2
2.3
1.7
0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.0
78
88:12
0
-20
-40
-40
-40
-40
-40
-40
-60
80e 86:14
n-C5H12-Et2O
n-C5H12-Et2O
n-C5H12-Et2O
n-C5H12-Et2O
cumene-Et2O
Et2O
96e 89:11
69
68
93:7
92:8
4e
50
91:9
91e 89:11
86e 51:49
<4e
THF
n-C5H12-Et2O
10
a See text. b The relative proportions of n-pentane-diethyl ether and
cumene-diethyl ether were 9:1 by vol. c Isolated yields of chromato-
graphically pure product unless otherwise noted. d Enantiomeric ratio
determined by CSP HPLC. e Yield was determined by GC analysis.
Scheme 2
added to reaction mixtures to effect rapid enantioselective
cyclization of the aryllithium (Table 1, cf. entries 4-6): the
generation of 2 by lithium-bromine exchange is accompanied
by the formation of a full equiv of LiBr, and this salt effectively
removes a full equiv of the diamine ligand via preferential
complexation with 1 (a precipitate forms at low temperature).
It is of interest to note that the (-)-sparteine-mediated
cyclization of the aryllithium derived from N-allyl-N-methyl-2-
bromoaniline (5) is somewhat less enantioselective than is the
cyclization of the analogous diallyl substrate discussed above
(Scheme 1). Cycloisomerization of the aryllithium generated from
5 afforded an 88% yield of (-)-1,3-dimethylindoline (6) with an
ee of 70%. In light of the fact that cyclization of 2 under identical
conditions (Table 1, entry 4) leads to product with an ee of 86%,
it would appear that the presence of the two enantiotopic allyl
units in 2 contributes to the high enantioselectivity of the process.
The chemistry described in this preliminary report, summarized
in Schemes 1-3, demonstrates for the first time that a chiral ligand
may confer enantiofacial selectivity in cyclizations of achiral
olefinic organolithiums. This ability to discriminate between the
enantiotopic faces of an unactivated carbon-carbon π-bond
tethered to a formally carbanionic center considerably extends
the synthetic utility of anionic cyclization as a route to carbocyclic
and heterocyclic systems.
Acknowledgment. We are grateful to Professor Peter Wipf for his
help in determining the absolute configuration of 4 and to Dr. Terry
Rathman of FMC, Lithium Division, for a generous gift of t-BuLi. This
work was supported by the Connecticut Department of Economic
Development.
Supporting Information Available: Detailed experimental proce-
dures (PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
The results of a less extensive investigation of the (-)-spar-
teine-mediated isomerization of the achiral aryllithium (8) derived
from 2-bromo-1-(3-butenyl)benzene (7) are summarized in Scheme
2. The cyclization of 8, which was reported some time ago by
JA000471L
(13) (a) Ross, G. A.; Koppang, M. D.; Bartak, D. E.; Woolsey, N. F. J.
Am. Chem. Soc. 1985, 107, 6742. (b) Koppang, M. D.; Ross, G. A.; Woolsey,
N. F.; Bartak, D. E. J. Am. Chem. Soc. 1986, 108, 1441.
(14) Brewster, J. H. HelV. Chim. Acta 1982, 65, 317.
(15) Gais, H.-J.; Mu¨ller, H.; Bund, J.; Scommoda, M.; Brandt, J.; Raabe,
G. J. Am. Chem. Soc. 1995, 117, 2453.
(12) Apparently, as noted elsewhere by Collum, THF (but evidently not
diethyl ether) saturates the coordination sphere of lithium to the exclusion of
a bidentate diamine ligand such as 1: see, Collum, D. B. Acc. Chem. Res.
1992, 25, 448.