Enantioselective carbolithiation of cinnamyl acetals. New access to chiral disubstituted cyclopropanes

Full text of DOI:10.1021/jo9705172

4898
J . Org. Chem. 1997, 62, 4898-4899
Sch em e 1
En a n tioselective Ca r bolith ia tion of
Cin n a m yl Aceta ls. New Access to Ch ir a l
Disu bstitu ted Cyclop r op a n es
Stephanie Norsikian, Ilane Marek,*
J ean-Franc¸ois Poisson, and J ean F. Normant*
decided to examine different chiral ligands8 but none of
them provided enantioselectivities as high as (-)-
sparteine. So, we investigated this problem following a
different approach. Indeed, recent theoretical studies by
Houk9 and Bailey10 reveal that the initial step for the
intermolecular as well as intramolecular carbometalation
is an energetically favorable coordination of the lithium
atom with the π-system,11 which serves to establish the
geometry of the system prior the addition to occur. Thus,
in order to promote this initial π-chelation, we decided
to increase the association between the organolithium
and the functional group of the substrate to enforce the
proximity effect (called complex induced proximity ef-
fects,12 CIPE). So, we have prepared the dimethyl
acetal13 of the (E)-cinnamyl alcohol and studied the
enantioselective carbolithiation, in the presence of (-)-
sparteine, as described in Scheme 1.
Addition of the substrate to a solution of various alkyl
lithiums in hexane (or cumene) in the presence of 1 equiv
of (-)-sparteine14 leads, after hydrolysis, to the corre-
sponding carbometalated products in good yield. After
deprotection of the acetal moieties, the alcohols were
obtained in very good enantiomeric excesses as deter-
mined according to Alexakis and Mangeney15 (see Table
1). The use of the acetal allows the reaction to proceed
at -50 °C instead of 0 °C for the carbolithiation of the
corresponding alcohol.7 Primary (in the absence (entries
1-3) or in the presence7 (entry 5) of lithium salts)) and
secondary organolithiums (entry 4) undergo enantiose-
lective carbolithiations in the presence of 1 equiv of (-)-
sparteine in hexane (or in cumene) via this simple
method. The results summarized in Table 1 show also
that addition to this cinnamyl acetal in the presence of
a catalytic amount of (-)-sparteine (10%) also leads to
good enantiomeric excess (entries 6, 8, and 9), even with
1% of chiral ligand (entry 7), whatever the nature of the
alkyllithium used (primary or secondary). Moreover, the
product itself is not an enantioselective catalyst16 since
the hydrolysis of the reaction mixture after only 30%
conversion leads to the same enantiomeric excess.
With the chiral benzylic organolithium in hand (before
hydrolysis), we then studied its reaction with an in-
Laboratoire de Chimie des Organoe´le´ments, Universite´ P. et
M. Curie, associe´ au CNRS URA 473, 4 Place J ussieu,
75252 Paris Cedex 05, France
Received March 21, 1997
The addition of an organometallic reagent to an un-
activated olefin is generally difficult to control since such
an addition may lead to polymerization of the olefin1
unless the final organometallic adduct is stabilized2 or
differs markedly from the starting one.3 Indeed, since
the initial work of Wittig,4 who showed that the presence
of a donor group in the proximity of the double bond of
the alkene promotes the carbolithiation reaction,2 the
stereochemical outcome of the addition of alkyllithiums
(and the reactivity of the new carbon metal bond as
stereogenic center) to substituted allylic alcohols were
investigated.2,5 However, enantioselective carbometala-
tion reactions are still scarce, although actively studied
by different groups,6 due to the difficulty for enantiofacial
differentiation of an unactivated alkene. In this context,
we have recently described a new asymmetric carbo-
lithiation of cinnamyl derivatives in the presence of (-)-
sparteine, which leads to the corresponding carbometa-
lated product in 66-80% enantiomeric excess.7 In a
search to increase these enantiomeric excesses, we
(1) (a) Ziegler, K.; Gellert, H. G. Liebigs Ann. Chem. 1950, 567, 195.
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Dimmel, D. R.; Huang, S. J . Org. Chem. 1973, 38, 2756.
(3) For the synthesis and reactivity of sp3 organogembismetallic via
a carbometalation reaction, see: Marek, I.; Normant, J . F. Chem. Rev.
1996, 96, 3241.
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G. W.; Veefkind, A. H.; Graaf, W. L.; Bickelhaupt, F. Liebigs Ann.
Chem. 1967, 706, 47. (c) Veefkind, A. H.; Bickelhaupt, F.; Klumpp, G.
W. Recl. Trav. Chim. Pays-Bas 1969, 88, 1058. (d) Veefkind, A. H.;
Schaaf, J . V. D.; Bickelhaupt, F.; Klumpp, G. W. J . Chem. Soc., Chem.
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1978, 1873.
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671. (b) Marumoto, S.; Kuwajima, I. Chem. Lett. 1992, 1421. (c)
Marumoto, S.; Kuwajima, I. J . Am. Chem. Soc. 1993, 115, 9021. (d)
Klein, S.; Marek, I.; Normant, J . F. J . Org. Chem. 1994, 59, 2925.
(6) Asymmetric carbocupration of cyclopropene: (a) Isaka, M.;
Nakamura, E. J . Am. Chem. Soc. 1990, 112, 7428. Asymmetric
allylzincation of cyclopropene: (b) Kubota, K.; Nakamura, M.; Isaka,
M.; Nakamura, E. J . Am. Chem. Soc. 1993, 115, 5879. (c) Nakamura,
M.; Arai, M.; Nakamura, E. J . Am. Chem. Soc. 1995, 117, 1179.
Zirconium-catalyzed asymmetric ethylmagnesiation: (d) Morken, J .
P.; Didiuk, M. T.; Hoveyda, A. H. J . Am. Chem. Soc. 1993, 115, 6997.
(e) Hoveyda, A. H.; Morken, J . P. J . Org. Chem. 1993, 58, 4237. (f)
Morken, J . P.; Didiuk, M. T.; Visser, M. S.; Hoveyda, A. H. J . Am.
Chem. Soc. 1996, 116, 3123. (g) Visser, M. S.; Heron, N. M.; Didiuk,
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(h) Bell, L.; Whitby, R. J .; J ones, R. V. H.; Standen, M. C. H.
Tetrahedron Lett. 1996, 37, 7139. Zirconium-catalyzed asymmetric
alkylalumination: (i) Kondakov, D. Y.; Neghishi, E. I. J . Am. Chem.
Soc. 1995, 117, 10771. (j) Kondakov, D. Y.; Neghishi, E. I. J . Am. Chem.
Soc. 1996, 118, 1577 Asymmetric ring opening of an oxabicyclic
compound: (k) Lautens, M.; Gajda, C.; Chiu, P. J . Chem. Soc., Chem.
Commun. 1993, 1193. Intramolecular carbolithiation: (l) Coldham, I.;
Hufton, R.; Snowden, D. J . J . Am. Chem. Soc. 1996, 118, 5322. (m)
Krief, A.; Bousbaa, J . Synlett 1996, 1007. (n) Asymmetric carbometa-
lation of zincated hydrazones to cyclopropene: Nakamura, E.; Kubota,
K. J . Org. Chem. 1997, 62, 792.
(8) The synthesis and the enantioselectivities of these different
ligands will be reported in due course.
(9) Houk, K. N.; Rondan, N. G.; Schleyer, P.v.R.; Kaufmann, E.;
Clark, T. J . Am. Chem. Soc. 1985, 107, 2821.
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Rossi, K.; Thiel, Y.; Wiberg, K. B. J . Am. Chem. Soc. 1991, 113, 5720.
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1972, 94, 8260. (c) Dolzine, T. W.; Oliver, J . P. J . Organomet. Chem.
1974, 78, 165. (d) St. Denis, J .; Oliver, J . P.; Smart, J . B.; Dolzine, T.
W. J . Organomet. Chem. 1974, 78, 165.
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(13) Klug, A. F.; Untch, K. G.; Fried, J . H. J . Am. Chem. Soc. 1972,
94, 7827.
(14) For a recent review on the use of (-)-sparteine in asymetric
syntheses, see: Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552 and references cited
therein.
(15) (a) Alexakis, A.; Frutos, J . C.; Mutti, S.; Mangeney, P. J . Org.
Chem. 1994, 59, 3326. (b) Alexakis, A.; Mutti, S.; Mangeney, P. J . Org.
Chem. 1992, 57, 1224.
(7) Klein, S.; Marek, I.; Poisson, J . F.; Normant, J . F. J . Am. Chem.
Soc. 1995, 117, 8853.
(16) For a highlight see: Bolm, C.; Bienewald, F.; Seger, A. Angew.
Chem. Int. Ed. Engl. 1996, 35, 1657 and references cited therein.
S0022-3263(97)00517-3 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 15, 1997 4899
Ta ble 1
Ta ble 2
(-)-sparteine
yieldc eed
solvent (%) (%)
(-)-sparteine
entrya
RLi
n-BuLi
n-BuLi
HexLi
alcohol
(equiv)b
entrya
RLi
cyclopropane
(equiv)b
solvent yieldc (%)
1
2
3
4
5
6
7
8
9
2
2
3
4
5
2
2
3
4
1
1
1
1
cumene 72
hexane 77
cumene 70
cumene 80
cumene 50
95
94
94
90
90
92
85
92
92
1
2
3
4
n-BuLi
n-BuLi
s-BuLid
HexLi
6
6
7
8
1
cumene
hexane
hexane
hexane
60
61
66
59
0.1
0.1
0.1
s-BuLie
HeptLi, LiBrf
n-BuLi
n-BuLi
HexLi
1
a
After the carbometalation reaction, the mixture is rapidly
0.1
0.01
0.1
0.1
hexane
hexane
hexane
hexane
67
50
65
77
b
warmed to room temperature. Based on the cinnamyl substrate.
c Based on pure isolated product and calculated from the cinnamyl
d
substrate. As a mixture of two diastereomers from the use of
s-BuLie
s-BuLi.
a
The reactions were carried out by addition of the substrate to
b
the RLi-sparteine mixture at -50 °C. Based on the cinnamyl
Sch em e 3
substrate. c Based on pure isolated product, after deprotection of
d
the acetal (yield of the deprotection >95%). ee was determined
by 31P NMR.15 e As a mixture of two diastereomers from the use
f
of s-BuLi. The organolithium reagents were prepared in Et2O,
and the addition was carried out in cumene, see ref 7.
Sch em e 2
whereas the benzylic carbon is free to epimerize19 and to
promote the formation of the thermodynamically more
stable trans cyclopropane.5 According to this, the optical
purities of the trans cyclopropanes thus obtained20 are
considered to be the same as those of the linear acetals
described in Table 1.
In order to prove this enantioselection and the absolute
configuration, the cyclopropane 6 was derivatized into a
known product according to Scheme 3.
The 1(R)-phenyl-2(R)-butylcyclopropane (6) was first
oxidized21 into the corresponding acid 9 in 81% yield. The
esterification followed by the reduction of the resulting
ester leads to the 2(R)-butyl-1(R)-cyclopropylmethanol
(10), known in the literature,22 and the purity of the
chiral disubstituted cyclopropanol (93% ee) was deter-
mined by NMR by the use of chiral derivating agents.15
The same sequence was performed on the cyclopropane
6, generated in the presence of a catalytic amount of (-)-
sparteine, and the same enantiomeric excess was ob-
tained for 10.
tramolecular electrophile, namely the acetal moiety.
Indeed, when the chelating moiety is a dimethyl-
methoxymethyl ether, the formed benzylic organolithium
species is not stabilized but becomes thermally labile,17
when the reaction mixture is simply warmed to room
temperature and leads to a pure chiral trans disubsti-
tuted cyclopropane,18 via an internal nucleophilic sub-
stitution, as described in Scheme 2 and Table 2.
In conclusion, the use of the dimethyl acetal of the (E)-
cinnamyl alcohol allows a high enantioselective carbo-
lithiation in the presence of a catalytic amount of (-)-
sparteine to give, after hydrolysis at low temperature,
the corresponding alkylated product in 90-95% ee. By
warming the reaction mixture to room temperature, this
benzylic organolithium intermediate undergoes a 1,3-
elimination to give the chiral disubstituted cyclopropane
in 90-93% ee.
The alkyl and phenyl groups in these cyclopropanes
are anti to each other and may result from a W-shaped
transition state.19 Indeed, in this transformation, the
initially formed stereogenic center C-R is invariant,
when established during the carbolithiation reaction step,
(17) The formation of cyclopropane by 1,3-elimination between an
organogembismetallic and a methoxymethyl ether was already de-
scribed: (a) Marek, I.; Beruben, D.; Normant, J . F. Tetrahedron Lett.
1995, 36, 3695. (b) Beruben, D.; Marek, I.; Normant, J . F.; Platzer, N.
J . Org. Chem. 1995, 60, 2488. (c) Beruben, D.; Marek, I.; Normant, J .
F.; Platzer, N. Tetrahedron Lett. 1993, 34, 7575.
Su p p or tin g In for m a tion Ava ila ble: Typical experimen-
(18) For some representative formations of chiral cyclopropanes,
see: (a) Charette, A. B.; Marcoux, J . F. Synlett 1995, 1197 and
references cited therein. (b) Salau¨n, J . Chem. Rev. 1989, 89, 1247. (c)
Romo, D.; Meyers, A. I. J . Org. Chem. 1992, 57, 6265. (d) Davies, H.
M. L.; Huby, N. J . S.; Cantrell, W. R., J r.; Olive, J . L. J . Am. Chem.
Soc. 1993, 115, 9468. (e) Doyle, M. P. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993; Chapter
3. (f) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339. (g) Evans, D. A.; Woerpel,
K. A.; Scott, M. J . Angew. Chem., Int. Ed. Engl. 1992, 31, 430. (h)
Denmark, S. E.; O’Connor, S. P. J . Org. Chem. 1997, 62, 584.
(19) Krief, A.; Hobe, M. Tetrahedron Lett. 1992, 33, 6529.
tal procedures and spectral data of products (10 pages).
J O9705172
(20) For a previous report on the synthesis of chiral cyclopropane
mediated by a stoichiometric amount of (-)-sparteine see: Paetow, M.;
Kotthaus, M.; Grehl, M.; Fro¨lich, R.; Hoppe, D. Synlett 1994, 1034.
(21) Carlsen, H. J .; Katsuki, T.; Martin, V. S. Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936.
(22) Imai, T.; Mineta, H.; Nishida, S. J . Org. Chem. 1991, 55, 4986.