Ligand control and asymmetric Michael reactions of enantioenriched configurationally stable N-Boc anilino benzylic and allylic organolithium species

Full text of DOI:10.1021/ja972333a

J. Am. Chem. Soc. 1997, 119, 10537-10538
10537
Communications to the Editor
respectively.2,6 In the absence of a ligand or with tetrameth-
ylethylenediamine (TMEDA) as the ligand, the 1,2-adduct 3 is
obtained in a 1:1 diastereomeric ratio in 77 and 88% yields,
respectively. In the presence of N′,N′,N,N-tetraethylethylene-
Ligand Control and Asymmetric Michael Reactions
of Enantioenriched Configurationally Stable N-Boc
Anilino Benzylic and Allylic Organolithium Species
Yong Sun Park, Gerald A. Weisenburger, and Peter Beak*
Department of Chemistry
UniVersity of Illinois at UrbanasChampaign
Urbana, Illinois 61801
ReceiVed July 14, 1997
Reactions in which the formation of a new carbon-carbon
bond provides two stereogenic centers with high enantioselec-
tivity are of special interest for asymmetric synthesis. We report
chiral ligand controlled Michael additions of organolithium
species in which both termini of the new bond are formed with
high levels of enantioselectivity.1 This work is based on our
discoveries that the regiochemistry of 1,2- vs 1,4-addition of
an R-lithio-N-Boc benzylic and allylic aniline derivative can
be ligand controlled and that the corresponding enantioenriched
configurationally stable benzylic and allylic organolithiums,
which are ligated to (-)-sparteine, give Michael addition
products with high enantiointegrities.2 Conjugate additions
which have been reported to give high enantioenrichments at
adjoining â- and γ-carbons are chiral ligand controlled additions
of enolates and chiral auxiliary controlled additions of phosphine
oxide, phosphonamide, phosphonate, oxazaphosphorinane 2-ox-
ide, or sulfoximine allyl carbanions.3 Chiral ligand and chiral
auxillary controlled Michael additions which provide high
enantioenrichments at â- or γ- carbons in diastereoselective
diamine (TEEDA), 3 and 4 are obtained in 45 and 31% yields,
respectively. With N′,N′,N,N-tetramethyl-1,3-propanediamine
(TMPDA) as the ligand, the yields of 3 and 4 are 38 and 41%.
Reaction in the presence of N,N-dibutylbispidine (DBB), a
ligand which was chosen because of its similarity to (-)-
sparteine, provides the 1,4-adduct 4 in 72% yield.7 In the
presence of (-)-sparteine (5), 2 reacts with 2-cyclohexenone
to provide 4 in 70% yield. The formation of 1,2- or 1,4-addition
products from 2-cyclohexenone and 2/L clearly can be con-
,4
8
trolled by selection of the ligand.
Reactions of the configurationally stable enantioenriched
benzylic lithiated intermediate (R)-2/5, conveniently generated
by lithiation of 1 with n-BuLi/5 in toluene, with 2-cyclohex-
enone, 2-cyclopentenone, and 2-butenone and trimethylsilyl
chloride (TMSCl) give the highly enantioenriched products
5
conjugate additions have been reported.
Lithiation of N-Boc-N-(p-methoxyphenyl)benzylamine (1)
with 1.1 equiv of n-BuLi/L complex in ether at -78 °C affords
the dipole-stabilized carbanion 2/L which reacts with 2-cyclo-
hexenone to give the 1,2- and/or 1,4-addition products 3 and 4,
(
S,S)-4, (S,S)-7, and (S)-8 with >99:1 diastereoselectivities (dr)
and >95:5 enantioselectivities in yields of 82, 86, and 63%,
respectively. If trimethyltin chloride is used as the electrophile
(1) For reviews of stereoselective Michael additions, see; Leonard, J.
Contemp. Org. Synth. 1994, 1, 387. Tomioka, K.; Koga, K. Asymmetric
Synthesis; Morrison, J. D. Ed.; Academic Press: New York, 1993; Vol. 2,
Part A, Chapter 7. Perlmutter, P. ConjugatiVe Addition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1992. Lee, V. J. In ComprehensiVe
Organic Syntheses; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1
991; Vol. 4, Chapter 1.2. Oare, D. A.; Heathcock, C. H.; Topics in
Stereochemistry; Eliel, E. L., Wilen, S. H., Eds; John Wiley & Sons, Inc.:
New York, 1991; Vol 20, p 87 and references cited therein.
(2) We have reported the 1,4-addition of (R)-2/5 to acrolein in the
presence of (-)-sparteine: Park, Y. S.; Beak, P. J. Org. Chem. 1997, 62,
1
574. For conjugate additions by allyl organolithiums to cinnamaldehyde
controlled by a sterically encompassing aluminum phenolate, see: Ooi, T.;
Kondo, Y.; Maruoka, K. Angew. Chem., Int. Ed. Engl. 1997, 36, 1183.
(3) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay, T.;
Simson, M.; Seebach, D. Synthesis 1993, 1271. Yasudo, K.; Shindo, M.;
Koga, K. Tetrahedron Lett. 1997, 38, 3531.
(4) Haynes, R. K.; Stokes, J. P.; Hambley, T. W. J. Chem. Soc., Chem.
Commun. 1991, 58. Hanessian, S.; Gomtsyan, A.; Payne, A.; Herve, Y.;
Beaudoin, S. J. Org. Chem. 1993, 58, 5032. Tanaka, K.; Ohta, Y.; Fuji, K.
J. Org. Chem. 1995, 60, 8036. Pyne, S. P.; Dong, Z.; Skelton, B. W.; White
A. H. J. Org. Chem. 1997, 62, 2337.
(5) For cases of chiral ligand control, see: Tomioka, K.; Sudani, Y.;
Shinmi, Y.; Koga, K. Chem. Lett. 1985, 329. Conn, R. S. E.; Lovell, A.
V.; Karady, S.; Weinstock, L. M. J. Org. Chem. 1986, 51, 4710. Tomioka,
K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989, 111, 8266. Sasai, H.;
Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 1571. Yamaguchi,
M.; Shiraishi, T.; Igarashi, Y.; Hirama, M. Tetrahedron Lett. 1994, 35, 8233.
Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520.
Kumamoto, T.; Auki, S.; Nakajama, M.; Koga, K. Tetrahedron: Asymmetry
and the product (S)-6 is allowed to react with n-BuLi/(-)-
sparteine followed by 2-cyclopentanone and TMSCl, (R,R)-7
1
994, 5, 1431. Inagaki, K.; Nozaki, K.; Takaya, H. Synlett. 1997, 119. For
cases of chiral auxiliary control, see: Hua, D. H.; Venkataraman, S.; Coulter,
M. J.; Sinai-Zingde, G. J. Org. Chem. 1987, 52, 719. Hua, D. H.; Chan-
Yu-King, R.; McKie, J. A.; Myer, L. J. Am. Chem. Soc. 1987, 111, 5026.
Meyers, A. I.; Shipman, M. J. Org. Chem. 1991, 56, 7098. Denmark, S.
E.; Kim, J. H. J. Org. Chem. 1995, 60, 7535.
(6) Park, Y. S.; Boys, M. L.; Beak, P. J. Am. Chem. Soc. 1996, 118,
3757. For diastereoselective addition of 2 to an imine, see: Kise, N.;
Kashiwagi, K.; Watanabe, M.; Yoshida, J. J. Org. Chem. 1996, 61, 428.
S0002-7863(97)02333-0 CCC: $14.00 © 1997 American Chemical Society

10538 J. Am. Chem. Soc., Vol. 119, No. 43, 1997
Communications to the Editor
is obtained with a 98:2 er in 61% overall yield.2,6 In the absence
of TMSCl, the yields of the enantioenriched products decrease
significantly. The absolute configuration of (S,S)-7 was
assigned by X-ray crystallography of a (1S)-camphorsulfanamide
derivative of deprotected (S,S)-7. The absolute configurations
of 4 and 8 are assigned by analogy to (S,S)-7.
2-cyclopentenone as the electrophile and (R)-2/5, the product
(S,S,R)-16 is obtained in 81% yield with 93:7 dr and 95:5 er. A
one-pot reaction beginning with 2-cyclopentenone and alkylation
of the intermediate silyl enol ether of (S,S)-7 with methyl iodide
gives (S,S,R)-16 in 53% yield with 96:4 er and 94:6 dr.12
Treatment of (S,R)-14 with lithium diisopropylamide (LDA)
9
The methodology is applicable to configurationally stable
10
R-lithio allylic aniline derivatives. Treatment of N-Boc-N-
(p-methoxyphenyl)cinnamylamine (9) with 1.1 equiv of n-
BuLi/5 to provide (R)-10/5 followed by addition of the Michael
acceptors, 5,6-dihydro-2H-pyran-2-one or 2(5H)-furanone, along
with TMSCl affords products (S,R)-13 and (S,R)-14 with
8
9:11 and 96:4 diastereoselectivities with 96:4 and 97:3
enantioselectivities, respectively. The diastereomers of (S,R)-
followed by addition of methyl iodide affords (S,R,R)-17 in 61%
yield with 97:3 er and 90:10 dr. Treatment of the major
diastereomer of 17 with LDA followed by the addition of allyl
bromide provides (S,R,R)-18 diastereospecifically in 51% yield
1
2
with 97:3 er.
Understanding these reactions will require further work. The
TMSCl can promote the Michael reaction and/or react with the
9
initial enolate to prevent further reactions. The inaccessability
of the lithium in the RLi/L complexes may also be important
in the regiocontrol. The 1,4-addition could be promoted because
complexation of the carbonyl of the Michael acceptor with the
substrate, which could favor 1,2-addition, is hindered by the
1
3 and (S,R)-14 are separated by chromatography providing
highly enantioenriched products. Reaction of N-Boc-N-(p-
methoxyphenyl)crotylamine (11) with 1.1 equiv of n-BuLi/5 at
-
78 °C in methyl tert-butyl ether (MTBE) affords (R)-12/5 and
13
ligand. The hypothesis that lack of complexation promotes
addition of 2-cyclohexenone affords (S,R)-15 in 62% yield with
reaction with inversion at the carbanionic carbon has been
8
0:20 dr and 98:2 er.11 The absolute configurations of (S,R)-
2,14
previously suggested.
1
1
1
3, (S,R)-14, and (S,R)-15 are assigned by analogy to (S,S)-7.
Three contiguous asymmetric centers can be generated with
high enantioselectivities by this methodology. With 2-methyl-
In summary, the choice of the ligand can provide control of
,2- vs 1,4-additions of organolithium species to R,â-unsaturated
1
carbonyl substrates. With highly enantioenriched configuration-
ally stable R-lithio benzylic and allylic amine derivatives and
(-)-sparteine, (R)-2/5, (S)-2/5, (R)-10/5, and (R)-12/5 participate
in asymmetric Michael additions to give products with high
enantioselectivities at both termini of the new â, γ bond.
The availability of either enantiomer of the organolithium
nucleophiles 2, 10, and 12, the facile subsequent conversions
of the newly installed groups, and the convenience of the
(
7) Gross, K. B.; Beak, P. J. Org. Chem. In press.
(
8) Previous reports have shown that the regiochemistry of conjugate
additions by organolithium species depends significantly on solvent and
that HMPA promotes 1,4-addition. Binns, M. R.; Haynes, R. K. J. Org.
Chem. 1981, 46, 3790. Ager, D. J.; East, M. B. J. Org. Chem. 1986, 51,
3
983. The reaction of 1 with n-BuLi and 2.0 equiv of HMPA in toluene
results in the formation of the 1,2-adduct.
(
(
(
9) Liu, H.; Cohen, T. Tetrahedron Lett. 1995, 36, 8925.
10) Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 12218.
11) The relative configuration of (S,R)-13 is the same as that for (S,S)-7
2
,6,10
methodology recommends synthetic applications.
Control
as determined by X-ray crystallography of (S,R)-13. With alkyl halides or
trimethyltin chloride as electrophiles, the organolithium species (R)-2/5 and
over additional stereogenic centers, extentions to related systems,
and elucidation of the course of the reactions are under further
(
R)-10/5 have been shown to provide products with the same absolute
1
5
10
study.
configurations. The absolute configuration of the stannane derivatives
previously provisionally assigned as (R) have determined by X-ray
crystallography to be (S).
1
0
Acknowledgment. We are grateful to the National Institutes of
Health GM-18874 for the support of this work.
(12) Analogy to previous studies, which show that the alkylations of
related cyclopentanones give products with the new groups at C-2 trans at,ob
a C-3 substituent, are used to make these stereochemical assignments.2
Supporting Information Available: Details of experimental
procedures and spectroscopic, analytical, and X-ray crystallographic
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Internet access instructions.
(13) Cohen, T.; Abraham, W. D.; Myers, M. J. Am. Chem. Soc. 1987,
1
09, 7923.
(
14) Thayumanavan, S.; Basu, A.; Beak, P. J. Am. Chem. Soc. In press.
15) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan,
(
S. Acc. Chem. Res. 1996, 29, 552. Beak, P.; Meyers, A. I. Acc. Chem. Res.
1
986, 19, 356.
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