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V. K.; Fang, G. Y.; Charmant, J. P. H.; Meek, G. Org. Lett. 2003, 5, 1757.
18. A single example of the Simmons-Smith cyclopropanation of an allylic amine
had previously been reported prior to 1993, although no experimental details
were provided, see: Perraud, R.; Arnaud, P. Bull. Soc. Chim. Fr. 1968, 1540.
19. Aggarwal, V. K.; Fang, G. Y.; Meek, G. Org. Lett. 2003, 5, 4417.
20. Katagiri, T.; Iguchi, N.; Kawate, T.; Takahashi, S.; Uneyama, K. Tetrahedron:
Asymmetry 2006, 17, 1157.
21. For cyclopropanation studies, see: (a) Davies, S. G.; Ling, K. B.; Roberts, P. M.;
Russell, A. J.; Thomson, J. E. Chem. Commun. 2007, 4029; (b) Csatayová, K.;
Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Org. Lett.
2010, 12, 3152.
22. For epoxidation studies, see: (a) Aciro, C.; Claridge, T. D. W.; Davies, S. G.;
Roberts, P. M.; Russell, A. J.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751; (b)
Aciro, C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.
Org. Biomol. Chem. 2008, 6, 3762; (c) Bond, C. W.; Cresswell, A. J.; Davies, S. G.;
Fletcher, A. M.; Kurosawa, W.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Smith, A.
D.; Thomson, J. E. J. Org. Chem. 2009, 74, 6735; (d) Bagal, S. K.; Davies, S. G.; Lee,
J. A.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Thomson, J. E. Org. Lett. 2010, 12,
136.
36. Meier, H.; Antony-Mayer, C.; Schulz-Popitz, C.; Zerban, G. Liebigs Ann. Chem.
1987, 12, 1087.
37. For the anti-selective epoxidation of cis-cyclooct-2-en-1-ol, see: (a) Itoh, T.;
Kaneda, K.; Teranishi, S. J. Chem. Soc., Chem. Commun. 1976, 421; (b) Cope, A. C.;
Keough, A. H.; Peterson, P. E.; Simmons, H. E.; Wood, G. W. J. Am. Chem. Soc.
1957, 79, 3900.
38. For a discussion of the conformation of cyclooctane derivatives, such as cis-
cyclooctene see: Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981.
39. Crystallographic data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 733890, see also Ref. 22c.
40. Poulter, C. D.; Friedrich, E. C.; Winstein, S. J. Am. Chem. Soc. 1969, 91, 6892.
41. Molander, G. A.; Harring, L. S. J. Org. Chem. 1989, 54, 3525.
42. Leong, M. K.; Mastryukov, V. S.; Boggs, J. E. J. Mol. Struct. 1998, 445, 149.
43. Crystallographic data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 733888, see also Ref. 22c.
44. Abraham, R. J.; Castellazzi, I.; Sancassan, F.; Smith, T. A. D. J. Chem. Soc., Perkin
Trans. 2 1999, 99.
45.
a-Benzotriazolyl substituted amine 22 was prepared on a multigram (>20 g)
scale in 87% yield by condensation of benzaldehyde with dibenzylamine and
benzotriazole. The corresponding reaction with isobutyraldehyde gave 23 in
81% yield, also on a >20 g scale, according to the procedure detailed in: Ka-
trizky, A. R.; Nair, S. K.; Qiu, Q. Synthesis 2002, 199.
23. For aziridination studies, see: Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A.
J.; Thomson, J. E.; Woods, P. A. Tetrahedron 2010, 66, 6806.
24. Allylic amine 8 was prepared according to the procedure detailed in Ref.
22a.
25. (a) Wittig, G.; Schwarzenbach, K. Angew. Chem. 1959, 20, 652; (b) Furukawa, J.;
Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53.
26. Denmark, S.; O’Connor, S. P. J. Org. Chem. 1997, 62, 3390.
27. As determined by peak integration of the 1H NMR spectrum of the crude re-
action mixture.
28. Attempts at N-methylation of 9 with either MeI or MeOTf were not successful,
even at elevated temperatures.
29. Alternative (iodomethyl)zinc acetate reagents were also screened, although it
was found that the yield of syn-9 increased with the reactivity of the carbenoid
used [CH3CO2ZnCH2I, <10%; CH2ClCO2ZnCH2I, 62%; CHCl2CO2ZnCH2I, 89%;
CCl3CO2ZnCH2I, 66%; CF3CO2ZnCH2I, 92%].
30. Extended reaction times led to lower yields of the desired cyclopropane
product syn-9 [1 h, 92%; 6 h, 71%; 12 h, 64%].
46. In the cyclopropanation of (Z)-24 (91:9 dr) and (Z)-26 (96:4 dr), the di-
astereoisomeric purity of the starting material was maintained in the products.
Additionally, the observed minor diastereoisomer from the reaction of (Z)-24
matched the major product from the cyclopropanation of (E)-29 by 1H NMR
spectroscopic analysis.
47. In each case the syn-configurations of the major diastereoisomers were ten-
tatively assigned assuming N-directed cyclopropanation via a conformation,
which minimises 1,2-allylic strain.
48. For studies on a related system, see: Ezzitouni, A.; Russ, P.; Marquez, V. E. J. Org.
Chem. 1997, 62, 4870.
49. Coote, S. C.; O’Brien, P.; Whitwood, A. C. Org. Biomol. Chem. 2008, 6, 4299.
50. Crystallographic data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 644843; see also Ref. 21a.
51. The cyclopropanation of an allylic carbamate was first reported in 1972. The
reaction of ethyl (RS)-cyclohex-2-en-1-ylcarbamate under SimmonseSmith
conditions was reported to give the syn-diastereoisomer in 75e95% yield,
see: Tardella, P. A.; Pellacani, L.; DiStazio, G. Gazz. Chim. Ital. 1972, 102, 822.
52. SimmonseSmith cyclopropanations of similar systems have been reported;
for the cyclopropanation of an allylic carbamate, see: (a) Pilar de Frutos, M.;
Fernández, M. D.; Fernández-Alvarez, E.; Bernabé, M. Tetrahedron Lett. 1991,
32, 541; (b) Newombe, N. J.; Simpkins, N. S. J. Chem. Soc., Chem. Commun.
1995, 831; (c) Mohapatra, D. K. J. Chem. Soc., Perkin Trans. 1 2001, 1851; (d)
Pietruszka, J.; Witt, A.; Frey, W. Eur. J. Org. Chem. 2003, 68, 3219. For the cy-
clopropanation of an allylic amide, see: (e) For the cyclopropanation of an
allylic phosphonamide, see: Russ, P.; Ezzitouni, A.; Marquez, V. E. Tetrahedron
Lett. 1997, 38, 723; Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc.
2003, 125, 761.
31. 4,4-Diphenylcyclohex-1-ene 12 was synthesised in two steps from commer-
cially available enone 84 in 74% overall yield. N,N-Dibenzyl cyclohexylamine 13
was synthesised by benzylation of cyclohexylamine 86 to give 13 in 84% yield,
according to the procedure detailed in: Ju, Y.; Varma, R. S. Green Chem. 2004, 6,
219.
NHTs
O
N
(i)
(ii)
Ph Ph
84
Ph Ph
85, 99%
Ph Ph
12, 75%
0
53. Substrates 59e61 were prepared in 57e83% yield via the Bi(OTf)3-catalysed SN
substitution of cyclohex-2-enol 46 with a range of carbamates, see: Qin, H.;
Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2007, 46, 409.
54. (a) McBriar, M. D.; Guzik, H.; Xu, R.; Paruchova, J.; Li, S.; Palani, A.; Clader, J. W.;
Greenlee, W. J.; Hawes, B. E.; Kowalski, T. J.; O’Neill, K.; Spar, B.; Weig, B. J. Med.
Chem. 2005, 48, 2274; (b) McBriar, M. D.; Guzik, H.; Shapiro, S.; Xu, R.; Par-
uchova, J.; Clader, J. W.; O’Neill, K.; Hawes, B.; Sorota, S.; Margulis, M.; Tucker,
K.; Weston, D. J.; Cox, K. Bioorg. Med. Chem. Lett. 2006, 16, 4262; (c) Kowalski, T.
J.; Spar, B. D.; Weig, B.; Farley, C.; Cook, J.; Ghibaudi, L.; Fried, S.; O’Neill, K.; Del
Vecchio, R. A.; McBriar, M.; Guzik, H.; Clader, J.; Hawes, B. E.; Hwa, J. Eur. J.
Pharmacol. 2006, 535, 182; (d) Kanuma, K.; Omodera, K.; Nishiguchi, M.; Fu-
nakoshi, T.; Chaki, S.; Nagase, Y.; Iida, I.; Yamaguchi, J.; Semple, G.; Tran, T.-A.;
Sekiguchi, Y. Bioorg. Med. Chem. 2006, 14, 3307; (e) McBriar, M. D.; Guzik, H.;
Shapiro, S.; Paruchova, J.; Xu, R.; Palani, A.; Clader, J. W.; Cox, K.; Greenlee, W. J.;
Hawes, B. E.; Kowalski, T. J.; O’Neill, K.; Spar, B. D.; Weig, B.; Weston, D. J.; Farley,
C.; Cook, J. J. Med. Chem. 2006, 49, 2294.
NH2
NBn2
(iii)
86
13, 84%
Reagents and conditions: (i) TsNHNH2, MeOH/PhMe (2:1), rt, 16 h; (ii) catechol
borane, CHCl3, 0 ꢀC to rt, 2 h then NaOAc$H2O, 60 ꢀC, 1 h; (iii) BnBr, NaOH (0.5 M
aq), 80 ꢀC, 30 min.
32. It is known that external ligands, such as DME, significantly reduce the rate of
reaction of the WittigeFurukawa reagent [Zn(CH2I)2]. See: Denmark, S. E.;
Edwards, J. P.; Wilson, S. R. J. Am. Chem. Soc. 1992, 114, 2592.
33. Transition state 15 is analogous to the corresponding proposed transition states
for the cyclopropanation of allylic alcohols with zinc carbenoid reagents, see:
(a) Wittig, G.; Wingler, F. Chem. Ber. 1964, 97, 2146; (b) Nakamura, M.; Hirai, A.;
Nakamura, E. J. Am. Chem. Soc. 2003, 125, 2341; (c) Blanchard, E. P.; Simmons,
H. E. J. Am. Chem. Soc. 1964, 86, 1337.
55. As in the previous mechanistic investigations concerning the cyclopropanation
of N,N-dibenzyl protected allylic amine 8, the use of cyclohexene as an external
olefin to mimic the cyclopropanation of allylic carbamate 61 was not practical
due to its relatively high volatility (bp 83 ꢀC).
56. Carbamate 77 was readily synthesised from cyclohexylamine 86 in 99% yield by
reaction with benzyl chloroformate.
34. Allylic amines 16e18 were prepared according to the procedures detailed in
Ref. 22c.
57. The relative configuration within syn-80 was established by single crystal X-ray
analysis. Crystallographic data (excluding structure factors) have been
35. Several instances of syn-selective osmylation and epoxidation reactions of 3-
substituted cyclopentenes which proceed in the absence of any obvious