LETTER
Titanium-Mediated Cyclopropanation of w-Alkenoic Diesters
2741
Oi-Pr
HO
O
Oi-Pr
O
N
i-PrOOC
BnN
i-PrOOC
N
Oi-Pr
Bn
Ti(Oi-Pr)2
E (–39.71 kcal⋅mol–1
O
c
C
O
12
c
C6H11MgCl
10
)
14 (53%) (cis/trans = 20:80)
E(cis)– E(trans) = +2.19 kcal⋅mol–1
Ti(Oi-Pr)2
Ti(Oi-Pr)4
i-PrO
O
N
Bn
Bn
O
Oi-Pr
O
N
d
d
i-PrOOC
HO
Oi-Pr
D (0.0 kcal⋅mol–1
)
NBn
(i-PrO)2Ti
F (-46.19 kcal⋅mol–1
)
13
E(cis) – E(trans) = –0.75 kcal⋅mol–1
)
Figure 2
with Et2O (30 mL) and the filtrate was dried over MgSO4.
After evaporation of the solvents, the residue was purified by
column chromatography.
ing the literature, such 3-azabicyclo[3.1.0]hexan-1-ol
skeleton was only observed in the cyclopropanol 8.
The predicted and observed good diastereoselectivity (cis/
trans = 20:80) determined by two-dimensional NOESY
NMR spectroscopy) should allow one to develop a scope
of applications using this methodology.
(6) Ethyl 1-Hydroxybicyclo[3.1.0]hexan-3-carboxylate (5a)
1H NMR (250 MHz, CDCl3): d = 4.22 (q, J = 7.0 Hz, 2 H,
cis), 4.11 (q, J = 7.0 Hz, 2 H, trans), 2.96 (t, J = 10.0 Hz, 1
H, trans), 2.95 (t, J = 10.0 Hz, 1 H, cis), 2.61 (dd, J = 5.0,
13.0 Hz, 1 H, cis), 2.60 (dd, J = 5.0, 13.0 Hz, 1 H, trans),
2.25–2.50 (m, 8 H), 2.00 (d, J = 5.0, 13.0 Hz, 1 H, cis), 1.99
(d, J = 5.0, 13.0 Hz, 1 H, trans), 1.18–1.30 (m, 2 H), 0.93 (t,
J = 6.7 Hz, 3 H, cis), 0.90 (t, J = 6.7 Hz, 3 H, trans), 0.58 (dd,
J = 4.5, 6.0 Hz, 1 H, trans), 0.47 (dd, J = 4.5, 6.0 Hz, 1 H,
cis). 13C NMR (50 MHz, CDCl3): d = 176.1 (cis), 175.1
(trans), 63.7 (cis), 62.6 (trans), 60.5, 40.7 (cis), 40.0 (trans),
36.4 (trans), 35.9 (cis), 30.6 (trans), 28.2 (cis), 23.8 (cis),
20.6 (trans), 17.1, 13.9 (trans), 13.1 (cis). IR (neat): 3384,
2938, 2872, 1731 cm–1. MS (EI, cis isomer): m/z (%) = 170
(24) [M+], 128 (93), 100 (100), 97 (38), 55 (44). MS (EI,
trans isomer): m/z (%) = 170 (14) [M+], 97 (100), 69 (26), 55
(30), 41 (24). HRMS (cis isomer): m/z calcd for C9H14O3:
170.0942; found: 170.0944. HRMS (trans isomer): m/z
calcd for C9H14O3: 170.0942; found: 170.0946.
In summary, we have explored a new domain of compet-
itive reactions in the Kulinkovich cyclopropanation. The
calculations can provide a useful and convenient tool for
understanding and for the search for the improvement of
selectivities in such reactions. Moreover, pyrrolidinones
constitute a versatile framework in the construction of
elaborated biologically or pharmacologically active sub-
stances. Our sequence represents an original and very ef-
ficient approach towards these compounds possessing
exploitable functional groups and we are currently devot-
ing our efforts towards synthetic application.
(7) Molecular mechanic calculations were carried out using
Spartan 04 molecular modeling software (Wavefunction,
Inc. Irvine, CA.) with MMFF as the force field.
(8) Lecornué, F.; Ollivier, J. Chem. Commun. 2003, 584.
(9) An energy difference >3 kcal⋅mol–1 predicts a 100:0
selectivity.
Acknowledgment
This work was financially supported by the CNRS and the Univer-
sity of Paris-Sud (XI), by a grant to J.-M. G. from the Ministère de
la Jeunesse, de l’Education Nationale et de la Recherche, and a
grant to M. J. from the Fondation René Mohawad of Libanon.
(10) (a) Ito, Y.; Fujii, S.; Saegusa, T. J. Org. Chem. 1976, 41,
2073. (b) Ito, Y.; Fujii, S.; Nakatsuja, M.; Kawamoto, F.;
Saegusa, T. Org. Synth., Coll. Vol. VI; Wiley: New York,
1988, 327.
References and Notes
(1) (a) Kulinkovich, O. Russ. Chem. Bull. 2004, 53, 1065.
(b) Kulinkovich, O. Eur. J. Org. Chem. 2004, 4517.
(2) Eisenführ, A.; Arora, P. J.; Sengle, G.; Takaoka, L. R.;
Nowick, J. S.; Famulok, M. Bioorg. Med. Chem. 2003, 11,
235.
(11) Fadel, A.; Salaün, J. Tetrahedron 1985, 41, 1267.
(12) Ethyl 3-Oxo-4-cyclohexen-1-carboxylate (6)
1H NMR (250 MHz, CDCl3): d = 6.95 (dt, J = 4.2, 10.0 Hz,
1 H), 6.04 (dt, J = 1.5, 10.0 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2
H), 3.10 (m, 1 H), 2.65 (m, 4 H), 1.27 (t, J = 7.2 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 196.9, 172.8, 147.7, 129.6,
60.9, 39.6, 27.8, 21.5, 13.9. IR (neat): 3487, 2960, 1739
cm–1. MS (EI): m/z (%) = 168 (13) [M+], 137 (66), 109 (100).
HRMS: m/z calcd for C9H12O3: 170.0942; found: 170.0943.
(13) Okamoto, S.; Iwakubo, M.; Kobayashi, K.; Sato, F. J. Am.
Chem. Soc. 1997, 119, 6984.
(14) Cho, J. H.; Kim, B. M. Tetrahedron Lett. 2002, 43, 1273.
(15) Goldstein, S. W.; Overman, L. E.; Rabinowitz, M. H. J. Org.
Chem. 1992, 57, 1179.
(16) Disopropyl N-Allyl-N-benzylaspartate (10)
1H NMR (250 MHz, CDCl3): d = 7.20 (s, 5 H), 5.70–5.86 (m,
1 H), 4.95–5.34 (m, 4 H), 3.98 (t, J = 7.5 Hz, 1 H), 3.89 (d,
(3) Bergmeier, S. C.; Ismail, K. A. Synthesis 2000, 1369.
(4) Dowd, P. B.; Wilk, K. Synth. Commun. 1993, 105, 2307.
(5) General Procedure for the Intramolecular
Cyclopropanation of w-Alkenoic Diesters: To a solution
of w-alkenoic diesters (2 mmol) and titanium isopropoxide
(0.6 mL, 2 mmol, 1 equiv) in anhyd THF (6 mL) was added
over 4 h at r.t. under argon a solution of cyclohexyl-
magnesium chloride (5.1 mL, 8 mmol, 4 equiv, 1.57 M in
Et2O). After stirring for an additional hour at r.t., the dark
solution was cooled at 0 °C and Et2O (25 mL) was added.
The mixture was quenched by addition of a sat. NH4Cl (5
mL) solution and was stirred overnight at r.t. The white
precipitate was filtered off through a plug of Celite, washed
Synlett 2006, No. 17, 2739–2742 © Thieme Stuttgart · New York