Enantio- and diastereoselective catalytic alkylation reactions with aziridines

Article abstract of DOI:10.1021/ja8036965

The first asymmetric phase transfer catalyzed alkylation reaction of a range of carbon acids with N-sulfonyl aziridines is reported. When 10 mol % of a cinchona derived quaternary ammonium salt was employed as the catalyst under mildly basic conditions, N

Full text of DOI:10.1021/ja8036965

Published on Web 07/11/2008
Enantio- and Diastereoselective Catalytic Alkylation Reactions with Aziridines
Thomas A. Moss,† David R. Fenwick,‡ and Darren J. Dixon*,†
School of Chemistry, The UniVersity of Manchester, Oxford Road, Manchester M13 9PL, U.K., and Pfizer Global
Research & DeVelopment, Ramsgate Road, Sandwich, Kent CT13 9NJ, U.K.
Received May 18, 2008; E-mail: darren.dixon@man.ac.uk
Scheme 1. Enantio- and Diastereoselective Aziridine Alkylation
The enantioselective construction of γ-amino butyric acid derivatives
from simple starting materials via asymmetric catalysis provides convenient
access to a range of structurally diverse natural products, pharmaceutical
compounds, and potential building blocks for γ-peptides and foldamer
chemistry. To this end, developments in the field of enantioselective
Michael additions of carbonyl compounds to nitroolefins have been
significant with highly enantioselective examples known to both nitro-
ethylene and ꢀ-substituted nitroolefins.1,2
We recognized a complementary, synthetically powerful and as yet
unreported route to these compounds could involve a catalytic enantiose-
lective alkylation reaction of a carbon acid with a protected amino ethylene
synthon,3 such as an N-protected aziridine.4 Furthermore, such a reaction
would install directly a protected amino group and allow γ-substituents
to be incorporated into the produced γ-amino acid backbone. Attracted
by the simplicity of the approach and the synthetic potential of the
methodology, we began our investigations.
Pathways
Table 1. Preliminary Studies into the Enantioselective Alkylation of
tert-Butyl Indanone Carboxylate 1a with Aziridine Electrophiles
Herein we report a direct enantioselective catalytic alkylation reaction
of methine pronucleophiles (Scheme 1) with N-sulfonyl aziridines leading
to products containing the amino ethylene group attached to a stereogenic
quaternary carbon (R1R2R3CCH2CH2NHP) in high enantiomeric excess.
Extension of the work to include diastereoselective variants is also
described.
entry
R
catalyst
conditionsa
convb 48 h eec
%
1
2
3
4
5
6
7
8
9
Mes
Mes
Mes
Mes
4a
4b
4f
rt, CH2Cl2
rt, CH2Cl2
BEMP (10%), rt
50% aq Cs2CO3, rt
50% aq Cs2CO3, 0 °C
50% aq Cs2CO3, 0 °C
50% aq Cs2CO3, 0 °C
50% aq Cs2CO3, 0 °C
50% aq Cs2CO3, -20 °C
50% aq K2HPO4, -20 °C
15
10
10
6
Preliminary studies using tert-butyl indanone carboxylate 1a as a
representative pronucleophile and N-mesitylene sulfonyl aziridine5 2a were
performed (Table 1). Initially, bifunctional cinchona catalysts 4a and b
(entries 1 and 2) were screened for activity in dichloromethane as solvent.
At room temperature, the reaction was prohibitively slow (15 and 10%
conversion after 48 h), giving the alkylation adduct in low enantioselectivity
(10 and 6%, respectively), leading us to conclude that N-sulfonyl protected
aziridines were unsuitable electrophiles for these bifunctional organocata-
lysts. To address the need for enhanced reactivity, we screened various
phase transfer catalysts (4c-f) and base combinations.6–8 Phase transfer
catalysis has previously been employed in conjunction with the phospho-
rine base, BEMP.9 Accordingly, in an initial proof of concept, we found
indanone adduct 3a was afforded in an encouraging 33% ee when 10
mol % of phase transfer catalyst 4f10 was employed with 10 mol % of
BEMP (entry 3). Anticipating a prevalent background reaction would
operate under these conditions,5 we turned to a 50% aqueous solution of
Cs2CO3 as the base. Gratifyingly, the alkylation adduct was formed in
91% ee, although the reaction was slow (35% conversion after 48 h, entry
4). A versatile feature of aziridine chemistry is that the reactivity of the
electrophile can be tuned by judicious choice of nitrogen protecting group.
By using o-(trifluoromethane)benzenesulfonyl aziridine 2b instead of 2a,
a significant enhancement in reactivity was realized; complete conversion
to the alkylation product was observed after 48 h at 0 °C (94% ee, entry
8). After screening various cinchona alkaloid derived phase transfer
catalysts (4c-f, entries 5-8), we found 4f bearing the bulky adamantoyl
ester was the most selective.10 By cooling the reaction mixture to -20
°C, a small increment in selectivity was observed (95% ee, entry 9), which
was further enhanced by using a milder 50% aqueous K2HPO4 mixture
100
35
100
80
100
100
100
100d
33
91
24
21
51
94
95
97
4f
o-CF3C6H4
o-CF3C6H4
o-CF3C6H4
o-CF3C6H4
o-CF3C6H4
4c
4d
4e
4f
4f
4f
10 o-CF3C6H
a For entries 3-10, reactions were performed in a 0.1 M solution of
9:1 toluene:CHCl3. b Determined by 1H NMR. c Determined by HPLC
analysis. d Conversion after 72 h.
as the base, furnishing the alkylation product in an impressive 97% ee
(entry 10, Table 1).
With optimal conditions established, the scope of the reaction was then
probed. High enantioselectivities were observed for a range of substituted
indanone pronucleophiles bearing bulky ester substituents (91-97% ee,
3b-e). Using the more basic Cs2CO3 (aq), tert-butyl cyclopentanone
carboxylate was also found to be a good substrate leading to the alkylated
product in high yield and enantiomeric excess (82% ee). In an extension
of this methodology, effective molecular recognition was witnessed when
a pronucleophile bearing an additional stereocenter was employed. Thus
with an excess of racemic tert-butyl 3-phenylindanone-2-carboxylate,
efficient production of 3g in high enantioselectivity (92% ee) and as a
single diastereoisomer was observed (Chart 1).
To extend the utility of the reaction, we wished to incorporate
enantiopure chiral aziridines. As regioselective ring opening usually occurs
on the less hindered carbon of the aziridine, this would allow product
substitution patterns to be obtained which would not normally be accessible
by the commonly employed ꢀ-substituted nitroolefin Michael reactions.
In an initial proof of concept, indanone 1a was treated with N-nosyl
† The University of Manchester.
‡ Pfizer Global Research & Development.
9
10076 J. AM. CHEM. SOC. 2008, 130, 10076–10077
10.1021/ja8036965 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Chart 1. Enantioselective Ring Opening of Unsubstituted Aziridines
with Phase Transfer Catalyst 4f
Scheme 2. One-Pot Alkylation/Desulfonation/Cyclization Sequence
As N-nosyl substituted sulfonamides are readily cleaved with thiols in
the presence of K2CO3(s),15 a one-pot alkylation/deprotection sequence
appeared feasible via a modification of the established conditions.
Pleasingly, with K2CO3(s) as the base and a staged addition of thiophenol,
tricyclic indanone imine 7, a product of intramolecular condensation, was
formed in good yield and high diastereomeric excess (Scheme 2).
In conclusion, we have developed the first highly enantioselective
aziridine alkylation reaction under phase transfer catalysis. Using single
enantiomer aziridines, moderate to high catalyst controlled diastereose-
lectivities can be observed. Using a N-nosyl protected aziridine allowed a
one-pot alkylation/desulfonation/cyclization sequence to diastereomerically
pure tricycle 7. Work to exploit this methodology in total synthesis is
currently underway and will be reported in due course.
a For desulfonation of 3b, see Supporting Information. b Reaction performed
at 0 °C with 50% aq Cs2CO3 as the base. c Relative stereochemical configuration
assigned by analogy.11
Acknowledgment. We gratefully acknowledge the EPSRC and
Pfizer Global Research and Development (to T.A.M.). D.J.D. would
like to thank Aurelie Alba for preliminary studies in this project.
Chart 2. Diastereoselective Ring Opening of Chiral Aziridines
5a-d with Phase Transfer Catalyst 4f
Supporting Information Available: Experimental procedures and
spectral data for compounds 2a,b, 3a-g, 4f, 6a-i, and 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) For recent reviews, see: (a) Pellissier, H. Tetrahedron 2007, 63, 9267. (b)
Santanu, M.; Yang, J.; Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471.
(c) Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2007,
18, 299. (d) Takemoto, Y.; Miyabe, H. Chimia 2007, 61, 269.
(2) For recent examples of secondary amine catalyzed Michael additions of
aldehydes to nitroolefins, see: (a) Chi, Y.; Guo, L.; Kopf, N. A.; Gellman,
S. H. J. Am. Chem. Soc. 2008, 130, 5608. (b) Wiesner, M.; Revell, J. D.;
Tonazzi, S.; Wennemers, H. J. Am. Chem. Soc. 2008, 130, 5610. (c) Garcia-
Garcia, P.; Lade´peˆche, A.; Halder, R.; List, B. Angew. Chem., Int. Ed. 2008,
47, 4719. (d) Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew.
Chem., Int. Ed. 2008, 4722.
(3) For early studies using ꢀ-haloamines as electrophiles in ꢀ-ketoester
alkylations, see: Barltrop, J. A. J. Chem. Soc. 1947, 399.
(4) For reviews on ring opening of aziridines, including asymmetric methods,
see: (a) Pineschi, M. Eur. J. Org. Chem. 2006, 4979. (b) Watson, I. D. G.;
Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006, 39, 194. (c) Hu, X. E.
Tetrahedron 2004, 60, 2701.
(5) For a base-catalyzed process, see: Moss, T. A.; Alba, A.; Hepworth, D.;
Dixon, D. J. Chem Commun. 2008, 21, 2474 and references cited therein.
(6) (a) Blyumin, E. V.; Gallon, H. J.; Yudin, A. K. Org. Lett. 2007, 9, 4677.
(7) For reviews on PTC, see: (a) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed.
2007, 46, 4222. (b) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37,
518. (c) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506.
(8) For selected examples of advances in asymmetric phase transfer catalysis,
see: (a) O’Donnell, M. J.; Bennet, W. D.; Wu, S. J. Am. Chem. Soc. 1989,
111, 2353. (b) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003,
125, 5139. (c) Park, H.-G.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-
K.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-S. Angew. Chem., Int. Ed. 2002, 41,
3036. (d) Corey, E. J.; Bo, Y.; Busch-Petersen, J. J. Am. Chem. Soc. 1998,
120, 13000. (e) Bella, M.; Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem.
Soc. 2005, 127, 3670. (f) Lygo, B.; Allbutt, B.; Kirton, E. H. M. Tetrahedron
Lett. 2005, 46, 4461. (g) Ooi, T.; Fujioka, S.; Maruoka, K. J. Am. Chem.
Soc. 2004, 126, 11790.
(9) (a) O’Donnell, M. J.; Delgado, F.; Hostettler, C.; Schwesinger, R.
Tetrahedron Lett. 1998, 39, 8775. (b) Lee, Y.-J.; Lee, J.; Kim, M.-J.; Jeong,
B.-S.; Lee, J.-H.; Kim, T.-S.; Lee, J.; Ku, J.-M.; Jew, S.-S.; Park, H.-G.
Org. Lett. 2005, 7, 3207.
a The dr ) 2:1 when 4f was replaced with TBAB (10 mol %). b Relative and
absolute stereochemical configurations were determined by X-ray analysis.
aziridines bearing both small (5a, R4 ) H, R5 ) Me) and bulky (5b, R4
) H, R5 ) iPr; 5c, R4 ) iPr, R5 ) H) substituents, with 10 mol % of
phase transfer catalyst 4f in the presence of solid cesium carbonate12 (Chart
2).
(10) (a) Bernardi, L.; Lopez-Cantarero, J.; Neiss, B.; Jørgensen, K. A. J. Am.
Chem. Soc. 2007, 129, 5772. For early studies, see: (b) Corey, E. J.; Xu,
F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414. (c) Lygo, B.;
Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595.
Pleasingly, it was possible to obtain the matched enantiopure alkylation
products (6a and 6b) in high yields and high stereocontrol. In the mis-
matched case, catalyst control overrode the weak natural substrate control
and 6c was afforded in good diastereomeric excess (12:1 dr). Nosyl
substituted aziridine 5b was found to react slowly with non-indanone-
based pronucleophiles. However, reactivity was greatly enhanced when
the corresponding N-trifluoromethanesulfonyl protected aziridine13 (5d)
was employed with a range of pronucleophiles including indanones (6d),
cyclopentanones (6e), tetralones (6f) lactams (6g), and succinimides (6h,
6i), giving the products in high yields and in moderate to high diastereo-
meric ratios (9:2 to 30:1 dr).14
(11) Cui, H.-F.; Dong, K.-Y.; Zhang, G.-W.; Wang, L.; Ma, J.-A. Chem.
Commun. 2007, 22, 2284.
(12) For alkylations with chiral aziridines 5a-c, Cs2CO3 (s) or Cs2CO3 (aq) as
the base was found to be superior to the milder K2HPO4 (aq), whereas
with 5d Cs2CO3(s) was found to be optimal.
(13) For deprotection procedures, see: ProtectiVe Groups in Organic Synthesis;
Wuts, P. G. M., Greene, T. W., Eds.; Wiley: New York, 2007.
(14) Using 4f and Cs2CO3(s), good reactivity but poor diastereomeric ratios were
observed with a range of noncyclic phenyl cyanoacetate nucleophiles.
(15) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373.
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