Asymmetric construction of quaternary carbon centers by regio- and enantiocontrolled allylzincation

Article abstract of DOI:10.1021/ol005892m

(equation presented) An allylic zinc reagent bearing a chiral bisoxazoline ligand adds to a substituted cyclopropenone acetal to produce an optically active cyclopropanone acetal possessing a quaternary chiral center in high yield with 97.8-99.8% ee. The

Full text of DOI:10.1021/ol005892m

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2193-2196
Asymmetric Construction of Quaternary
Carbon Centers by Regio- and
Enantiocontrolled Allylzincation†
Masaharu Nakamura, Toshihiro Inoue, Akihito Sato, and Eiichi Nakamura*
Department of Chemistry, The UniVersity of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
nakamura@chem.s.u-tokyo.ac.jp
Received April 4, 2000
ABSTRACT
An allylic zinc reagent bearing a chiral bisoxazoline ligand adds to a substituted cyclopropenone acetal to produce an optically active
cyclopropanone acetal possessing a quaternary chiral center in high yield with 97.8−99.8% ee. The steric effects of the bulky bisoxazoline
ligand overwhelm the regioselectivity inherent to the electronic property of the olefinic acceptor. High pressure exerts favorable effects on the
reaction rate without affecting the high enantio- or regioselectivity.
The enantioselective addition of an organometallic reagent
to a trisubstituted sp2 carbon atom of a substituted olefin is
Scheme 1. 1,4-Addition and Carbometalation for
Enantioselective Construction of a Quaternary Chiral Centera
a prime candidate for a method for straightforward construc-
tion of a quaternary chiral carbon center.1 Enantioselective
conjugate addition of an organometallic reagent to a â,â-
disubstituted R,â-unsaturated carbonyl compound, a seem-
ingly ideal methodology, has thus far failed to serve such a
purpose (Scheme 1, route a).2 We report herein the first
example of enantioselective construction of a quaternary
chiral center through a ligand-controlled carbometalation
reaction (Scheme 1, route b). A particularly noteworthy
finding was that the regioselectivity of the carbometalation
inherent to the nature of the olefinic acceptor can be entirely
reversed by the use of a bulky chiral ligand in place of a
halide ligand on the metal atom.
a RM ) organometallic reagent; L* ) chiral ligand; R′ ) alkyl,
aryl, Me3Si, Me3Ge, Me3Sn; R′′ ) H.
An allylic zinc reagent possessing an anionic bisoxazoline
(BOX) ligand (2-5) can be prepared in situ as shown in
Scheme 2 and undergoes various types of enantioselective
additions,3 among which the addition to nonsubstituted
cyclopropenone acetal (CPA) 1a served as a prototype for
the present studies.4 The product of the carbometalation
† This paper is dedicated to Prof. Jose Barluenga of Universidad de
Oviedo on the occasion of his 60th birthday.
(1) For reviews, see: (a) Martin, S. F. Tetrahedron 1980, 36, 419-460.
(b) Fuji, K. Chem ReV. 1993, 93, 2037-2066 (c) Corey, E. J.; Guzman-
Perez, A. Angew. Chem., Int. Ed. 1998, 37, 389-401.
(2) For reviews, see: (a) Rossiter, B. E. Swingle, N. M. Chem. ReV.
1992, 92, 771-806. Organozinc addition: (b) Soai, K.; Shibata, T. In
Organozinc Reagents. A Practical Approach; Knochel, P., Jones, P., Eds.;
Oxford University Press: New York, 1999; Chapter 12.5.
(3) (a) Nakamura, M.; Hirai, A.; Sogi, M.; Nakamura, E. J. Am. Chem.
Soc. 1998, 120, 5846-5847. (b) Nakamura, M.: Hirai, A.; Nakamura, E.
J. Am. Chem. Soc. 1996, 118, 8489-8490. (c) Hanessian, S.; Yang, R.-Y.
Tetrahedron Lett. 1996, 52, 8997-9000.
10.1021/ol005892m CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/28/2000

reaction is a cyclopropanone acetal (6) which serves as a
useful synthon for organic synthesis.4a,5 For this reaction to
generate a quaternary carbon center, it needs first to react
with a substituted cyclopropene6 (1b-f) and then to react
regioselectively to afford 6 rather than 7 (Scheme 2). To
Table 1. Enantioselective Allylzincation of Substituted CPA
1b and 1c
Scheme 2. Addition of Chiral Allylic Zinc Reagent to
Substituted CPA
a Slight excess (1.1-1.2 equiv) of allylic zinc reagent was used. b A:
the reaction was carried out at 25 °C under atmospheric pressure. B: the
reaction was carried out at 25 °C under high pressure (1 GPa). c The other
regioisomers was not detected by GLC analysis. d Isolated yield. e Deter-
mined by GLC analysis of the product obtained by hydrogeation of the
terminal olefinic bond unless otherwise noted. The peak due to the
enantiomeric product could not be detected in the cases where a > mark is
used, and the ee data refers to the detection limit under the analytical
1
conditions employed. f Determined by H NMR analysis after conversion
to MTPA derivatives.
2-phenyl-substituted CPA 1c with 2 gave exclusively the
allylation product 6c (R2 ) H) with >99.6% ee (entry 5).
An asymmetrically substituted allylic nucleophile such as
prenyl zinc reagent 5 contains two sites of potential reactivity.
To our pleasant surprise, this reagent reacted with 2-ethyl-
CPA 1b to afford the most sterically congested product 6
(R1 ) C2H5, R2 ) CH3). The reaction was slow but took
place with 100% regioselectivity with respect to both the
allylic (SE′) and the olefinic groups. In addition, the enan-
tioselection was complete (>99.5% ee, entry 6). The SE′
reactivity of the allylic zinc reagent suggests the participation
of a σ-allylic metal species in the reaction as predicted by
theoretical calculations.8
We found that high pressure (conditions B in Table 1)9
accelerates the allylzincation reaction and significantly
improves the product yield without affecting the high
enantioselectivity.10 Under a pressure of 10 kbar (1 GPa),
the reactions of 2 with 1b and 1c were complete within 12
h at 25 °C and quantitatively afforded 6b (R1 ) C2H5, R2 )
H and R1 ) C6H5, R2 ) H) in >98% ee (entries 7 and 8).
Even the reaction of 1b with prenyl reagent 5 took place
smoothly to give the congested product 6b (R2 ) CH3) in
93% yield with >99.5% ee (entry 9). The high pressure did
not significantly affect the enantioselectivity and regiose-
lectivity. This observation, along with the syn-addition
mode,11 supports the concerted nature of the allylzincation
of olefins.8
this end, we examined substituted CPA bearing various
Group 14 R1 subsituents (1d-f) for the addition of a chiral
and achiral allylic zinc reagent.
The reaction of the 2-ethyl- or 2-phenyl-substituted CPA
(1b or 1c) was slow but 100% regioselective, favoring the
formation of 6 regardless of the allylzinc reagent employed.
It proceeded in such a manner that the carbon nucleophile
added to the more substituted olefinic carbon to generate a
more stable anionic product (Scheme 2 and Table 1). The
regioselectivity conforms to the general rule proposed for
substituted alkynes.7
Allylzincation reactions of 2-ethylcyclopropenone acetal
1b5 were examined first. Addition of allylzinc bromide
proceeded sluggishly under ambient conditions (conditions
A: 25 °C, atmospheric pressure) to afford the single
regioisomer 6b (R2 ) H) in 45% yield (entry 1). The chiral
allylic zinc reagent 2 that bears a phenyl-substituted bis-
oxazoline ligand also reacted sluggishly to give the same
regioisomer, 6b (R2 ) H), in moderate yield. When the R
group on the chiral ligand was changed from phenyl to tert-
butyl (3) and isopropyl (4), the reaction slowed and the
enantioselectivity dropped (entries 3 and 4). Allylation of
(4) (a) Nakamura, M.; Arai, M.; Nakamura, E. J. Am. Chem. Soc. 1995,
117, 1179-1180. (b) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem.
Soc. 2000, 122, 978-979
(5) Isaka, M.; Nakamura, E. J. Am. Chem. Soc. 1990, 112, 7428-7430.
(6) Such substituted cyclopropenone acetals are readily available from
1,3-dichloroacetone on a large scale. Isaka, M.; Ejiri, S.; Nakamura, E.
Tetrahedron 1992, 48, 2045-2057.
(7) Nakamura, E.; Miyachi, Y.; Koga, N.; Morokuma, K. J. Am. Chem.
Soc. 1992, 114, 6686-6692. See also: Hirai, A.; Nakamura, M.; Nakamura,
E. J. Am. Chem. Soc. 1999, 121, 8665-8666 and references cited therein.
(8) Nakamura, M.; Nakamura, E. Computational Studies on Diastereo-
and Enantioselectivities of Allylmetalation of Cyclopropenone Acetals. In
Electronic Conference Heterocyclic Chemistry; Rzepa, H. S., Snyder, J.,
Leach, C., Eds.; Royal Society of Chemistry: London, 1997; ISBN 0-85404-
894-4. See also: Kubota, K.; Mori, S.; Nakamura, M.; Nakamura, E. J.
Am. Chem. Soc. 1998, 120, 13334-13341.
2194
Org. Lett., Vol. 2, No. 15, 2000

Effects of silyl substitution of the olefin in olefin carbo-
metalation were investigated some time ago12 as well as in
recent years.13 It has been shown that a Group 14 metal
substituent, a stannyl substitutent in particular,14 not only
accelerates the carbometalation but controls the regioselec-
tivity so that the reaction generates a gem-dimetallic product
(e.g., the compound corresponding to 7 rather than 6). Thus,
the addition of allylzinc reagents to the silyl, germyl, and
stannyl CPAs (1d-f) proceeded far faster than that to the
carbon-subsituted CPAs (1b and 1c). For instance, the
addition of allylzinc bromide to the Group 14 metal deriva-
tives was complete in an hour at 0 °C at ambient pressure
and afforded the product with 80:20-95:5 selectivity favor-
ing the formation of 715 (Table 2, entries 1-3). Note that
regioselectivity has been ascribed to the predominant elec-
trostatic interaction between the Lewis acidic zinc atom and
the developing negative charge on the carbon connected to
the metal substituent (A in Scheme 3).7
Scheme 3. Regiochemistry of Allylzincation of CPAs Bearing
a Group 14 Metal Substituent
Table 2. Regio- and Enantioselective Allylzincation of
Substituted CPA (1d-f)
To our surprise, however, this intrinsic regioselectivity can
be completely reversed, favoring 6 with 94:6-98:2 selectivity
(entries 4-6), when the BOX-bearing allylzinc reagent 2
reacted with 1d-f. The enantioselectivity of the addition of
2 to 1d-f was excellent (97.8-99.8% ee), and the sense of
the selectivity was the same as that described in Table 1.
The observed regio- and enantioselectivities combined with
the transition structure (TS) obtained for the parent CPA (1a)
by the ab intio calculation8 indicate that the reaction took
place through TS B shown in Scheme 3. Because of the
presence of both the acetal and the Me3M moiety, the
electronically favored TS A′ is precluded by the steric effect
of the bulky BOX ligand.
To examine further the origin of the reversal of the
regioselectivity, we studied the reactions of allylzinc bromide
and 2 with the simple vinylstannane 8. In contrast to the
CPA cases, both reactions occurred in a manner dictated by
the electronic property of the vinylstannane and afforded the
same product 9 after hydrolysis. The results indicate that
suitable steric factors will overwhelm the electronics of the
reaction.
1
a Determined by H NMR. b Combined yield of regioisomers obtained
by isolation. c Determined by 1H NMR and HPLC analysis after conversion
to MTPA derivatives.
allylzinc bromide addition to 2-ethyl-CPA 1b was incomplete
even after 36 h at 25 °C (Table 1, entry 1). The observed
(9) The zinc reagent 2 (R ) C6H5) was prepared first. Thus, to a solution
of phenyl-substituted (R,R)-BOX (818 mg, 2.67 mmol) and 2,2′-bipyridyl
(ca. 1 mg) in dry THF (4.0 mL) was added a 1.49 M hexane solution of
BuLi (1.8 mL, 2.68 mmol) at 0 °C, and the mixture was stirred further for
20 min at 25 °C. To the mixture was added a 1.58 M THF solution of
allylzinc bromide (1.58 mL, 2.43 mmol) at 0 °C. After stirring for 20 min
at 25 °C, a solution of CPA 1c (480 mg, 2.20 mmol) in dry THF (2.67 mL)
was added at 0 °C. The reaction mixture (8.0 mL) was transferred into a
Teflon vessel under nitrogen, kept under high pressure (1 GPa) for 24 h at
25 °C, and then quenched with saturated NH4Cl (20 mL). Purification with
silica gel chromatography afforded the allylation product (R)-6c (R2 ) H)
(424 mg, 93% yield): IR (neat) 3073, 2956, 2856, 1639, 1602, 1498, 1471,
1446, 1351, 1292, 1157, 1132, 1070, 1043, 910, 700; 1H NMR (400 MHz,
CDCl3) δ 0.93 (s, 3 H), 1.07 (d, J ) 5.9 Hz, 1 H), 1.07 (s, 3 H), 1.37 (dd,
J ) 1.5, 5.9 Hz, 1 H), 2.34 (dd with shoulders, J ) 7.3, 14.7 Hz, 1 H),
2.76 (ddd, J ) 1.5, 6.4, 14.7 Hz, 1 H), 3.30 (d, J ) 11.0 Hz, 1 H), 3.35
(dd, J ) 0.97, 11.0 Hz, 1 H), 3.60 (distorted dd, J ) 0.97, 10.7 Hz, 1 H),
3.62 (distorted d, J ) 10.7 Hz, 1 H), 4.86-4.94 (m, 2 H), 5.61-5.73 (m,
1 H) 7.15-7.22 (m, 1 H) 7.27-7.31 (m, 4 H); 13C NMR (100 MHz, CDCl3)
δ 22.0, 22.1, 22.7, 30.6, 37.4, 38.6, 75.5, 76.4, 92.0, 116.3, 126.2, 127.9 (2
C), 129.2 (2 C), 135.4, 139.4; [R]20 ) 1.02 (c ) 3.9, benzene). Anal.
Calcd for C17H22O2: C, 79.03; H, 8.59. Found: C, 79.07; H, 8.83. The
R-configuration of this product was determined through an eight-step
conversion to (R)-2-methyl-2-phenylbutanoic acid.
D
(10) (a) le Noble, W. J.; Kelm, H. Angew. Chem., Int. Ed. Engl. 1980,
19, 841-946. (b) Matsumoto, K.; Sera, A.; Uchida, T. Synthesis 1985, 1-26.
(c) Matsumoto, K.; Sera, A. Synthesis 1985, 999-1027. (d) van Eldik, R.;
Asano, T.; le Noble, W. J. Chem. ReV. 1989, 89, 549-688. (e) Isaccs, N.
S. Tetrahedron 1991, 47, 8463-8497.
(11) Kubota, K.; Isaka, M.; Nakamura, M.; Nakamura, E. J. Am. Chem.
Soc. 1993, 115, 5867-5868.
In summary, we have demonstrated that an allylic zinc
reagent bearing a chiral BOX ligand adds to a substituted
Org. Lett., Vol. 2, No. 15, 2000
2195

cyclopropanone acetal to generate new organometallic spe-
cies bearing a quaternary carbon center with extremely high
enantioselectivity. We have shown that high-pressure condi-
tions accelerate the carbometalation reaction without affecting
the high enantioselectivity. Interestingly, the regioselectivity
of carbometalation can be controlled by the steric effects of
the ligand on the metal atom.
Acknowledgment. This work is supported by Monbusho
and a Grant-in-Aid for Scientific Research on Priority Area
(No. 403-11166220, Molecular Physical Chemistry).
(12) (a) Buell, G. R.; Corriu, R.; Christian, G.; Spialter, L. J. Am. Chem.
Soc. 1970, 92, 7424-7428. (b) Cason, L. F.; Brooks, H. G. J. Org. Chem.
1954, 19, 1278-1282. (c) Seyferth, D.; Wada, T. Inorg. Chem. 1962, 1,
78-83. Stober, M. R.; Michael, K. W.; Speier, J. L. J. Org. Chem. 1967,
32, 2740-2744. Asymmetric synthesis: (d) Tamao, K.; Kanatani, R.;
Kumada, H. Tetrahedron Lett. 1984, 25, 1913-1916.
Supporting Information Available: Experimental pro-
cedures and physical properties of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Nakamura, E.; Kubota, K. Tetrahedron Lett. 1997, 38, 7099-7102.
(14) Nakamura, M.; Hara, K.; Sakata, G.; Nakamura, E. Org. Lett. 1999,
1, 1505-1507.
(15) The configuration of the compounds 7d-f was determined to be
trans by 1H NMR coupling analysis and is in accord with the syn-addition
mode of the carbometalation (ref 5).
OL005892M
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Org. Lett., Vol. 2, No. 15, 2000