D. J. Dixon et al.
and extracted with EtOAc (25 mL). The organic phase was washed with
brine, dried over Na2SO4, filtered and concentrated. The resulting residue
was purified by flash column chromatography to yield the desired prod-
uct.
son, when the pseudoenantiomeric catalyst 10 f’ was used in
the synthesis of lactam 21, there was a decrease in the dia-
stereoselectivity of the reaction (d.r. 10:1), thus suggesting
that these were a mis-matched combination (see the Sup-
porting Information).[32]
General procedure for the phase-transfer catalysed sulfamidate ring
opening reaction: Solid Cs2CO3 (0.600 mmol) was added to a solution of
pro-nucleophile (0.400 mol), sulfamidate (0.420 mmol) and catalyst 10 f
(0.040 mmol) in xylene (2.0 mL) at 08C. Following completion of the re-
action (usually 16–72 h), 1N HCl (2 mL) was added and the mixture was
stirred for 10 min. CH2Cl2 (5 mL) was added and the layers were separat-
ed. The aqueous layer was extracted with CH2Cl2 (5 mL), the combined
organic phases were dried over Na2SO4, filtered and concentrated. The
resulting residue was purified by flash column chromatography to yield
the desired product.
Conclusion
In conclusion, we have developed highly efficient catalytic
and enantioselective alkylation methodologies for creating
quaternary carbon stereogenic centres attached to ethylene-
amino and propylene-amino motifs. Using commercially
available phosphazene reagents, it is possible to perform
base catalysed ring opening on a range of substrates in gen-
erally high yields. Then, through asymmetric phase-transfer
catalysis this reaction can be rendered highly enantioselec-
tive and diastereoselective. To address the need for a wider
variety of nitrogen protecting groups to be tolerated, we
then applied the reaction to the ring opening of 1,2- and 1,3-
cyclic sulfamidates with various substitution patterns and
protecting groups.[33] Manipulation of the alkylation adducts,
including spiro-cyclisation and intramolecular condensation
for the efficient synthesis of multicyclic systems has also
been demonstrated.
Acknowledgements
We gratefully acknowledge the EPSRC (studentships to T.A.M., D.M.B.,
A.F.K. and Leadership Fellowship to D.J.D.), Pfizer Global Research and
Development (studentship to T.A.M.), AstraZeneca (studentship to
D.M.B.) and GlaxoSmithKline (studentship to A.F.K.). We thank Dr.
John Ward (School of Chemistry, University of Manchester) for prelimi-
nary investigations into the synthesis of tert-butyl ester pro-nucleophiles.
We also thank Dr. M. Helliwell (School of Chemistry, University of Man-
chester) and Dr. Katherine Bogle for X-ray structure determination and
the Oxford Chemical Crystallography Service for the use of the instru-
mentation.
[1] For selected examples from our group of reactions forming quater-
nary stereocentres, see: a) A. W. Pilling, J. Boehmer, D. J. Dixon,
d) P. Jakubec, D. M. Cockfield, P. S. Hynes, E. Cleator, D. J. Dixon,
Experimental Section
General procedure for the BEMP catalysed aziridine ring opening reac-
tion: BEMP (10.4 mL, 0.036 mmol) was added to a solution of pro-nu-
ACHTUNGTRENNUNGcleoACHTUNGTRENNUNGphile (0.720 mmol) in THF (0.8 mL) and the resulting solution was
stirred at 258C for 10 minutes. The aziridine (0.360 mmol) was added and
the mixture was stirred at 258C until completion (usually 16–48 h). The
solution was concentrated and the residue was purified by flash column
chromatography to yield the desired product.
[2] For a review, see: C. M. Goodman, S. Choi, S. Shandler, W. F. De-
9267–9331; b) M. Santanu, J. Yang, S. Hoffmann, B. List, Chem.
Rev. 2007, 107, 5471–5569; c) D. Almas¸i, D. A. Alonso, C. Nꢁjera,
Tetrahedron: Asymmetry 2007, 18, 299–365; d) Y. Takemoto, H.
Miyabe, Chimia 2007, 61, 269–275.
General procedure for the phase-transfer catalysed aziridine ring opening
reaction: K2HPO4 (0.200 mmol in 35 mL H2O) was added to a solution of
pro-nucleophile (0.130 mmol), aziridine (0.160 mmol) and catalyst 10 f
(0.013 mmol) in a 9:1 toluene/CHCl3 mixture (1 mL) at À208C. Following
completion of the reaction (usually 16–72 h), CH2Cl2 (5 mL) and 1N HCl
(2 mL) were added and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (5 mL), the combined organic phases were
dried over Na2SO4, filtered and concentrated. The resulting residue was
purified by flash column chromatography to yield the desired product.
[4] For recent examples of secondary amine catalysed Michael additions
of aldehydes to nitro-olefins, see: a) Y. Chi, L. Guo, N. A. Kopf,
[5] For reviews on ring opening of aziridines, including asymmetric
General procedure for the synthesis of tert-butyl ester substituted pro-nu-
cleophiles with Boc2O (Method A): NaHMDS (2m in THF, 10 mL) was
added dropwise to a solution of carbonyl compound (10.0 mmol) in THF
(40 mL) at À788C. Following addition of base, Boc2O (10.0 mmol) in
THF (5 mL) was added and the mixture was stirred at À788C until com-
pletion (usually 0.5–3 h). The reaction was quenched with sat. aq. NH4Cl
and extracted with EtOAc (25 mL). The organic phase was washed with
brine, dried over Na2SO4, filtered and concentrated. The resulting residue
was purified by flash column chromatography to yield the desired prod-
uct.
´
2009, 48, 2082; e) S. Stankovic, M. D’hooghe, S. Catak, H. Eum, M.
Waroquier, V. V. Speybroeck, N. D. Kimpe, H.-J. Ha, Chem. Soc.
Rev. 2012, 41, 643–665.
General procedure for the synthesis of tert-butyl ester substituted inda-
none pro-nucleophiles with N-Boc pyrrole (Method B): Indanone
(5.0 mmol) was added to a suspension of NaH (10.0 mmol, 60% in min-
eral oil washed with hexane) in THF (20 mL) at RT. Following warming
to relux, N-Boc pyrrole (10.0 mmol) in THF (5 mL) was added dropwise
and the solution was further warmed to reflux until completion (usually
3–6 h). The reaction mixture was cooled to RT, quenched with 1N HCl
[6] For methodologies in aziridine synthesis, see: a) J. E. G. Kemp, in
Comprehensive Organic Synthesis, Vol. 7 (Eds.: B. M. Trost, I. Flem-
ing, L. Lwowski), Pergamon, Oxford, 1991, p. 469; b) K. M. L. Rai,
A. Hassner, Adv. Strain. Interest. Org. Mol. 2000, 8, 187–257; c) S. S.
Murphree, A. Padwa, Prog. Heterocycl. Chem. 2001, 13, 52–70;
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