Bronsted acid-catalyzed desymmetrization of meso-aziridines

Article abstract of DOI:10.1021/ja0751779

The enantioselective ring-opening of meso-aziridines with azide nucleophiles proceeded in the presence of a catalytic amount of a chiral phosphoric acid catalyst. The reaction affords the formation of the products in excellent yield and enantioselectivity. Preliminary mechanistic studies indicate that the active catalytic species is a chiral silane that is generated in situ. Copyright

Full text of DOI:10.1021/ja0751779

Published on Web 09/18/2007
Brønsted Acid-Catalyzed Desymmetrization of meso-Aziridines
Emily B. Rowland, Gerald B. Rowland, Edwin Rivera-Otero,§ and Jon C. Antilla*
Department of Chemistry, UniVersity of South Florida, 4202 East Fowler AVenue CHE 205A,
Tampa, Florida 33620
Received July 11, 2007; E-mail: jantilla@cas.usf.edu
The vicinal diamine structural moiety is a privileged framework
in organic chemistry.1 Vicinal diamines have been used extensively
as chiral auxiliaries and chiral ligands. Chiral vicinal diamines can
also be found in anticancer agents and anti-influenza drugs, as well
as many other biologically active compounds. Researchers have
developed many methods for the synthesis of these diamines.1 One
of the most direct methods for their synthesis is the ring-opening
of aziridines with nitrogen nucleophiles.2 While many of these
existing strategies have been successful, the development of
catalytic, enantioselective methods for the opening of meso-
aziridines has been much less studied. In 1999, Jacobsen and co-
workers reported the first enantioselective ring-opening of meso-
aziridines with azidotrimethylsilane using a chiral chromium
complex.3 Recently, Shibasaki and co-workers have reported the
use of chiral yttrium complexes for the desymmetrization of meso-
azirdines in route to the synthesis of Tamiflu.4 In this communica-
tion, we report the first example of a Brønsted acid-catalyzed
enantioselective ring-opening of meso-aziridines as well as pre-
liminary investigations into the mechanism of such reactions.
Organocatalysis, the use of small, chiral organic molecules as
enantioselective catalysts, has been a fruitful area of research for
the past decade.5 In 2004, the research groups of Akiyama6 and
Terada7 independently reported that phosphoric acids derived from
BINOL could be used as enantioselective catalysts. Since the first
report, our group, as well as other groups, has shown that chiral
phosphoric acids are versatile catalysts for the addition of various
nucleophiles to imines.8 List and co-workers have demonstrated
that amine salts of chiral phosphoric acids could be used for the
asymmetric reduction of enones10 and the dynamic kinetic resolution
of racemic aldehydes.11 Chiral phosphoric acids as mediators for
the enantioselective desymmetrization of meso-aziridines would
represent a new and powerful utilization of such catalysts as the
potential activation involves a non-imine-based electrophile.Our
initial investigation into the desymmetrization of meso- aziridines
involved studying the effect of substitution on the nitrogen atom
of the aziridine with PA-1 as the catalyst (Table 1). The screening
of both Cbz and BOC protecting groups on the nitrogen resulted
in the formation of the product as the racemate in moderate yield
(entries 1, 2). However, to our delight a 4-nitrobenzoyl-substituted
imine resulted in the formation of the product in good yield and
moderate enantioselectivity (entry 3). Corresponding substitution
with a 3,5-dinitrobenzoyl group on the nitrogen (entries 6-8)
provided for the desired product in an excellent yield and moderate
ee. Our ideal conditions in terms of yield and enantioselectivity
required the use of a bis-(3,5-trifluoromethyl)benzoyl group as a
substituent (entries 9-10). However, the use of this substituent
generally resulted in longer reaction times. Solvent studies revealed
that the use of 1,2-dichloroethane resulted in the formation of the
product in the highest yield and enantioselectivity.
Figure 1. VAPOL and VANOL phosphoric acids.
Table 1. Optimization of Reaction Conditionsf
a General Procedure: molar ratio of 1/2 ) 1:1.5 in 0.5 mL of solvent.
b Isolated yield. c Determined by chiral HPLC analysis. d Reaction performed
using a molar ratio of 1/2 ) 1.5:1. e Catalyst derived from (S)-VAPOL
resulted in a reversal of the retention time for the major enantiomer of 3 as
judged by chiral HPLC (see SI). f DCM ) dichloromethane, DCE ) 1,2-
dichloroethane.
We next turned our attention to the variation of the aziridine
(Table 2). Using the optimized reaction conditions, PA-2 derived
from the VANOL framework proved to be a comparable catalyst
for the desymmetrization of the meso-aziridine derived from
cyclohexane as PA-1 (entries 1, 2). However, the use of PA-2 for
ring-opening an aziridine derived from 1,4-cyclohexadiene resulted
in the formation of the product in much lower yield than using
PA-1 but with similar enantioselectivity (entries 3, 4). Azide
addition to a cycloheptane aziridine resulted in the formation of
the ring-opened product in excellent enantioselectivity but with a
decrease in the yield of the product (entry 5). Heating this reaction
to 60 °C resulted in the formation of the product in excellent yield
and moderate selectivity (entry 6). The reaction time for both
reactions is much longer than the time required for the ring-opening
of the cyclohexane aziridine. Various aziridines derived from
cycloalkanes resulted in the formation of the ring-opened product
in good yield and enantioselectivity. Aziridines containing acyclic
aliphatic and aryl substituents resulted in the formation of the
product in excellent yield and with good enantioselectivity (entries
§ University of South Florida Interdisciplinary Nuclear Magnetic Resonance
Facility.
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J. AM. CHEM. SOC. 2007, 129, 12084-12085
10.1021/ja0751779 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Proposed Mechanism of the Organocatalytic
Table 2. Variation of Aziridine Substrate
Desymmetrization of meso-Aziridines
chiral silane that is generated in situ by the reaction of the chiral
phosphoric acid with azidotrimethylsilane. Future work will include
extension of the substrate scope and theoretical and experimental
studies into the mechanism of this and related transformations.
Acknowledgment. We thank the Petroleum Research Fund for
financial support (PRF 45899-G1). We are also grateful to Ted
Gauthier (HRMS, NSF-CRIF:MU #0443611) of USF.
Supporting Information Available: Experimental procedures,
characterization, chiral HPLC conditions, and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
a General conditions: molar ratio of 1/2 ) 1.5:1. b Isolated yield.
c Enantioselectivity determined by HPLC analysis. d Molar ratio of 1/2 )
1:2. e Reaction performed at 60 °C.
References
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9 and 10). Heterocyclic aziridines could also be employed in the
ring-opening reaction. The use of an aziridine derived from 2,5-
dihydrofuran resulted in a drastic decrease in yield of the product,
with the balance of mass attributed primarily to unreacted starting
material (entry 11).
Preliminary studies into the mechanism of the organocatalytic
desymmetrization of meso-aziridines indicate that the presence of
the trimethylsilyl group is required for the formation of the ring-
opened product. It has long been known that compounds containing
an amide, sulfoxide, or a PdO double bond can activate silane
compounds into donating a nucleophile.12 The reaction of the
aziridine with tetrabutylammonium azide and NaN3 in the presence
of the phosphoric acid resulted in no reaction. Notable is the fact
that the reaction does not occur with azidotrimethylsilane in the
absence of the phosphoric acid. However, the use of NaN3 in the
presence of trimethylsilyl chloride resulted in the formation of the
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1
product in moderate yield. Preliminary H NMR studies indicate
the presence of a new compound containing proton signals
indicative of the formation of the new TMS-containing compound
6. This evidence leads us to speculate that the reaction occurs by
the mechanism shown in Scheme 1. The first step of the reaction
involves the formation of the active catalyst by displacement of
the azide. The resulting chiral silane 4 then activates the aziridine
by means of coordinating to the carbonyl functionality of the
aziridine, resulting in the formation of 5. Species 5 then undergoes
attack by the azide nucleophiles, resulting in 6 and the reformation
of PA. Compound 6 readily decomposes on silica gel to form
product 3.
(10) (a) Mayer, S.; List, B. Angew. Chem. Int. Ed. 2006, 45, 4193. (b) Martin,
N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368.
(11) Hoffman, S.; Nicoletti, M.; List, B. J. Am. Chem. Soc. 2006, 128, 13074.
(12) For an excellent review on the activation of silanes, see: Denmark, S.
E.; Heemstra, J. R.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682.
In conclusion, we report the first organocatalytic desymmetri-
zation of meso-aziridines using chiral phosphoric acids derived from
VAPOL and VANOL. The active catalytic species appears to be a
JA0751779
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J. AM. CHEM. SOC. VOL. 129, NO. 40, 2007 12085