Investigation of a flexible enantiospecific approach to aziridines

Article abstract of DOI:10.1021/jo7023637

(Chemical Equation Presented) A flexible approach to functionalized and enantioenriched aziridines has been developed from an intermediate aziridinylmethyl tosylate. This protocol features a Cu-catalyzed Grignard substitution reaction that allows a range of functionalized organic fragments to be incorporated. Moreover, a convenient one-pot procedure is outlined that allows the trityl group to be exchanged for a range of common N-protecting groups.

Full text of DOI:10.1021/jo7023637

of this methodology is the availability of enantiopure aziridine
starting materials; however, our substrates to-date have been
limited to those that are accessible from commercial R-amino
acid sources. Accordingly, we sought to develop a flexible route
to enantiopure 2-substituted aziridines that would allow a range
of groups to be incorporated from a single late-stage intermedi-
ate, while providing a means for flexibility in N-protecting group
incorporation.
Investigation of a Flexible Enantiospecific
Approach to Aziridines
Clare E. Jamookeeah,† Christopher D. Beadle,‡
Richard F. W. Jackson,† and Joseph P. A. Harrity*,†
Department of Chemistry, UniVersity of Sheffield, Sheffield,
S3 7HF, United Kingdom, and Eli Lilly and Company Ltd,
Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey,
GU20 6PH, United Kingdom
A survey of the literature revealed some useful manifestations
of this general concept. Specifically, De Kimpe demonstrated
that N-Ts aziridinylmethyl bromides underwent smooth substitu-
tion with Li2CuCNR2 and R2CuLi (R ) Me, Bu),7 while
Bergmeier demonstrated that enantiopure Ts-protected aziridi-
nylmethyl tosylates underwent substitution with dialkylcuprates
via a ring opening-cyclization mechanism.8 This study also
highlighted that the reaction was unsuccessful for Ph- and
vinylmetal species and that the products could be prone to
further addition. Sweeney et al. showed that similar chemistry
could be carried out using diphenylphosphoryl- (Dpp) in place
of Ts-groups. Furthermore, the employment of Grignard reagents
provided the opportunity to use substoichiometric quantitites
of Cu-salts.9 These studies also confirmed that the substitution
proceeded via initial ring opening of the aziridine. Finally, De
Kimpe has demonstrated that dialkylcuprates react with N-alkyl
aziridinylmethyl bromides, although 2-3 equiv of the cuprate
are required and only alkyl- and Ph-groups may be transferred.10
In this case, direct substitution is more likely although this was
not confirmed. For the purposes of employing this strategy as
a general method to access enantiopure functionalized aziridines
for further elaboration, we wanted to establish a general protocol
that allowed the use of functionalized organometallic species.
Furthermore, we opted to utilize a trityl protecting group in order
to discourage competing ring opening processes and to facilitate
the introduction of various activating groups at the aziridine
N-atom at a late stage (Scheme 1).
j.harrity@sheffield.ac.uk
ReceiVed NoVember 1, 2007
A flexible approach to functionalized and enantioenriched
aziridines has been developed from an intermediate aziridi-
nylmethyl tosylate. This protocol features a Cu-catalyzed
Grignard substitution reaction that allows a range of func-
tionalized organic fragments to be incorporated. Moreover,
a convenient one-pot procedure is outlined that allows the
trityl group to be exchanged for a range of common
N-protecting groups.
Aziridines are extremely useful building blocks in organic
synthesis because of their ability to function as reactive
electrophilic substrates.1 They undergo a large number of
nucleophilic ring-opening processes, often with excellent control
of regio- and stereoselectivity. Accordingly, a great many
methods have been developed for the preparation of these
compounds in enantioenriched form, including asymmetric
catalytic aziridination,2 kinetic resolution,3 stereoselective aziri-
dine functionalization,4 and enantiospecific synthesis from
R-amino acids.5 Recent work in this department has focused
on the exploitation of aziridines in [3 + 3] annulation processes
for the stereoselective synthesis of piperidines.6 A prerequisite
SCHEME 1. Functionalization of Enantiopure Tr-Protected
Aziridine
Our studies began by developing a practical synthesis of
enantiopure tosylate 2. Accordingly, 1 was prepared in four steps
from commercial (S)-serine methyl ester hydrochloride accord-
ing to literature procedures11 and converted into tosylate 2 under
standard conditions in high yield (Scheme 2).
With the key aziridine intermediate in hand, we turned our
attention to the Cu-catalyzed alkylation chemistry (Table 1).
As outlined in entries 1 and 2, alkyl Grignard reagents 3 and
4 substituted in high yield as expected, although the yield
† University of Sheffield.
Eli Lilly and Company Ltd.
(1) For reviews on aziridine chemistry see: (a) McCoull, W.; Davis, F.
A. Synthesis 2000, 1347. (b) Sweeney, J. B. Chem. Soc. ReV. 2002, 31,
247. (c) Hu, X. E. Tetrahedron 2004, 60, 2701. (d) Yudin, A. Aziridines
and Epoxides in Organic Synthesis; Wiley-VCH.: Weinheim, Germany,
2006.
‡
(2) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905.
(3) Kim, S. K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2004, 43, 3952.
(4) Hodgson, D. M.; Humphreys, P. G.; Ward, J. G. Org. Lett. 2005, 7,
1153.
(5) Craig, D.; Berry, M. B. Synlett 1992, 41.
(7) D’hooghe, M.; Kerkaert, I.; Rottiers, M.; De Kimpe, N. Tetrahedron
2004, 60, 3637.
(6) (a) Hedley, S. J.; Moran, W. J.; Prenzel, A. H. G. P.; Price, D. A.;
Harrity, J. P. A. Synlett 2001, 1596. (b) Hedley, S. J.; Moran, W. J.; Price,
D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286. (c) Moran, W. J.;
Goodenough, K. M.; Raubo, P.; Harrity, J. P. A. Org. Lett. 2003, 5, 3427.
(d) Goodenough, K. M.; Moran, W. J.; Raubo, P.; Harrity, J. P. A. J. Org.
Chem. 2005, 70, 207. (e) Goodenough, K. M.; Raubo, P.; Harrity, J. P. A.
Org. Lett 2005, 7, 2993. (f) Pattenden, L. C.; Wybrow, R. A. J.; Smith, S.
A.; Harrity, J. P. A. Org. Lett. 2006, 8, 3089. (g) Provoost, O. Y.; Hedley,
S. J.; Hazelwood, A. J.; Harrity, J. P. A. Tetrahedron Lett. 2006, 47, 331.
(8) (a) Bergmeier, S. C.; Punit, P. S. J. Org. Chem. 1997, 62, 2671. (b)
Lapinsky, D. J.; Bergmeier, S. C. Tetrahedron Lett. 2001, 42, 8583.
(9) Sweeney, J. B.; Cantrill, A. A. Tetrahedron 2003, 59, 3677.
(10) (a) D’hooghe, M.; De Kimpe, N. Synlett 2004, 271. (b) D’hooghe,
M.; Rottiers, M.; Jolie, R.; De Kimpe, N. Synlett 2005, 931.
(11) (a) Baldwin, J. E.; Spivey, A. C.; Schofield, C. J.; Sweeney, J. B.
Tetrahedron 1993, 49, 6309. (b) Bosche, U.; Nubbermeyer, U. Tetrahedron
1999, 55, 6883.
10.1021/jo7023637 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/08/2008
1128
J. Org. Chem. 2008, 73, 1128-1130

SCHEME 2. Synthesis of Tr-Protected Aziridine
Intermediatea
opening to the allylamine 19 (76%) and none of the desired
product 12.13
a Reagents and conditions: (a) TsCl, Et3N, cat. DMAP, CH2Cl2, rt, 16
h; 92%.
We next turned our attention to the conversion of the N-Tr
moiety into alternative protecting groups that activate the
aziridine to ring opening reactions. The traditional two-step
deprotection-protection protocol could give rise to volatility
problems when low molecular weight substrates were employed
so we sought a one-pot procedure that would allow a range of
activating groups to be introduced at nitrogen. We carried out
our investigations on substrate 13 and our results are highlighted
in Table 2.
TABLE 1. Cu-Catalyzed Alkylation Reactions
TABLE 2. One-Pot Deprotection-Alkylation
a Conditions: Grignard was added to a THF solution of aziridine and
Cu-catalyst at - 78 °C and the reaction warmed to room temperature before
stirring for 16 h. b 50 mol % of CuBr‚DMS employed in this case. DMS:
dimethyl sulfide.
Removal of the trityl group was carried out using standard
TFA deprotection conditions14 whereupon the solution was
basified by addition of triethylamine. The addition of TsCl then
allowed 20 to be isolated in high yield (entry 1). Moreover,
chiral HPLC analysis for 20 indicated >99% ee and optical
rotation data showed this compound to have (R)-configuration15
confirming that the Grignard substitution had taken place
through direct displacement to give the aziridine with retention
of absolute configuration. In the context of the reactions outlined
in Table 1, these data provide evidence for direct substitution
rather than addition at the aziridine followed by cyclization.
Finally, addition of appropriate reagents for p-methoxybenze-
nesulfonyl- (PMBS), Cbz-, and Dpp-protection proceeded
smoothly to give the corresponding products 20-23 in good
yield (entries 2-4). Notably, in the reaction indicated in entry
1, we found that the acid quench could be carried out with less
expensive NH4OH (22 equiv). Subsequent addition of Et3N (3
equiv) and TsCl (1.2 equiv) provided 20 in 72% yield.
dropped somewhat when employing allylmagnesium bromide
5 (entry 3). The incorporation of aryl groups proceeded smoothly
(entries 4 and 5) as did more functionalized reagents 8 and 9
(entries 6 and 7).
Some additional noteworthy observations made during this
study were the following: (1) The potential for heteroatom
centered displacements was demonstrated by the incorporation
of azide. Specifically, 17 was formed in excellent yield upon
heating 2 with NaN3 in DMF. (2) Addition of butyl- and
allylmagnesium bromide to 2 in the absence of Cu-catalyst
resulted in recovery of starting material. In contrast, around 50%
conversion of 2 to 15 was observed upon addition of the Bu¨chi
1
Grignard 8 (16 h; as judged by 250 MHz H NMR spectros-
copy).12 (3) The corresponding aziridinylmethyl bromide 18
appears to be significantly less reactive than the tosylate 2. Cu-
catalyzed addition of the Bu¨chi Grignard 8 provided a 23% yield
of 15 after 16 h with the majority of remaining material
consisting of starting aziridine 18. Moreover, reaction of
allylmagnesium bromide with 18 resulted in reductive ring
(13) Elimination appears to be promoted by allyl Grignard, indeed, 19
was also observed as the major byproduct when the tosylate 2 was employed
(Table 1, entry 3). These observations mirror those made by De Kimpe
and co-workers in their studies.10b
(12) The Bu¨chi Grignard reagent 8 has been proposed to exist as a
dialkylmagnesium species that can undergo transformations more typical
of an organocuprate. For example, 8 can undergo conjugate addition to
enones in the absence of Cu-catalysts: Sworin, M; Neumann, W. L.
Tetrahedron Lett. 1987, 28, 3217.
(14) Righi, P.; Scardovi, N.; Marotta, E.; ten Holte, P.; Zwanenburg, B.
Org. Lett. 2002, 4, 497.
(15) Optical rotation data for (S)-20 ([R]25D +17.8 (c 1.82, CHCl3)) shows
the opposite sign to that observed in our sample: [R]22 -20.0 (c 1.00,
D
CHCl3). Alonso, A. A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455.
J. Org. Chem, Vol. 73, No. 3, 2008 1129

SCHEME 3. Synthesis and Functionalization of
Tr-Protected Aziridine 21a
cm-1) 3057 (w), 1597 (s), 1490 (s), 1480 (s) 1365 (m); HRMS
(EI) m/z (M+) calcd for C29H27NO3S 469.1712, found 469.1708.
Representative Procedure for Cu-Catalyzed Grignard Sub-
stitution: (R)-2-Pentyl-1-tritylaziridine (10). To a solution of 2
(0.1 g, 0.213 mmol, 1 equiv) and CuBr‚DMS (11 mg, 0.05 mmol,
0.25 equiv) in THF (1.3 mL) was added freshly prepared butyl-
magnesium bromide solution in THF (titrated to 0.55 M, 0.77 mL,
0.426 mmol, 2 equiv) at -78 °C. The resulting solution was stirred
at -78 °C for 15 min and allowed to warm to rt overnight. The
reaction mixture was quenched with water, poured onto brine, and
extracted with ethyl acetate. The combined organic extracts were
dried over MgSO4 and concentrated in vacuo. Flash chromatography
(5:1, petroleum ether:EtOAc) provided 10 as a clear oil (65 mg,
86%). [R]22D -19.4 (c 1.00, CHCl3). 1H NMR (250 MHz, CDCl3)
δ 0.84 (3H, t, J ) 6.5 Hz), 1.02 (1H, d, J ) 6.0 Hz), 1.10-1.25
(8H, m), 1.55 (1H, d, J ) 3.5 Hz), 1.87 (1H, m), 7.19-7.51 (15H,
m); 13C NMR (62.9 MHz, CDCl3) δ 14.0, 22.6, 26.6, 26.7, 31.8,
a Reagents and conditions: (a) (i) Swern. (ii) MeLi, THF, -78 °C to rt,
1 h; 87% over two steps. (b) TsCl, Et3N, cat. DMAP, 4 d; 81%. (c) NaN3,
DMF, 60 °C, 16 h; 72%. (d) (i) PhMgBr, 25% CuBr‚DMS, THF, -78 °C
to rt, 16 h. (ii) TFA, CHCl3, MeOH (3:1), -78 °C to rt, 4 h. (iii) Et3N,
TsCl, 16 h; 54% over three steps.
32.8, 33.0, 72.1, 126.5, 127.3, 129.6, 145.0; FTIR (film, υmax cm-1
)
3056 (w), 2927 (w), 1596 (s), 1489 (s), 1447 (m); HRMS (EI) m/z
(M+) calcd for C26H29N 355.2300, found 355.2288.
In an effort to develop the chemistry to include more heavily
substituted systems, we investigated the synthesis and alkylation
of a secondary tosylate analogue 25. As outlined in Scheme 3,
oxidation of 1 followed by addition of MeLi provided a 4:1
mixture of diastereomeric alcohols 24 that were tosylated in
good yield. A diastereomerically enriched (20:1 dr) sample of
25 was generated by recrystallization from hexane/ethyl acetate.
Azide substitution of 25 took place in good yield and with clean
inversion to provide 26. Moreover, Cu-catalyzed substitution
with PhMgBr was also successful; however, the nonpolar nature
of the product resulted in inefficient chromatographic purifica-
tion. We therefore subjected the crude material to the one-pot
deprotection-protection protocol and were pleased to isolate
27 in 54% yield over the three steps.16
Synthesis of (S)-2-(Azidomethyl)-1-tritylaziridine (17). To a
solution of 2 (0.25 g, 0.532 mmol, 1 equiv) in DMF (1.8 mL) was
added sodium azide (0.17 g, 2.66 mmol, 5 equiv) at rt. The solution
was heated to 60 °C and left overnight. Upon cooling, diethyl ether
was added to the solution and the reaction was quenched with brine.
The organic extracts were washed with water, dried over MgSO4,
and concentrated in vacuo. Flash chromatography (5:1 petroleum
ether:EtOAc) provided 17 as a pale yellow oil (0.175 g, 97%). [R]23
D
1
-12.0 (c 1.67, CHCl3). H NMR (250 MHz, CDCl3) δ 1.17 (1H,
d, J ) 6.0 Hz), 1.48 (1H, m), 1.82 (1H, d, J ) 3.0 Hz), 3.48 (2H,
d, J ) 5.0 Hz), 7.16-7.35 (9 H, m), 7.52 (6 H, d, J ) 7.0 Hz); 13
C
NMR (62.9 MHz, CDCl3) δ 25.5, 31.6, 53.6, 74.0, 126.8, 127.6,
129.4, 144.2; FTIR (film, υmax cm-1) 3057 (w) 2923 (m), 2852
(m), 2096 (s), 1596 (m), 1487 (m); HRMS (EI) m/z (M+) calcd for
C22H20N4 340.1688, found 340.1685.
In summary, we report a simple and practical route to a range
of enantioenriched aziridines through the Cu-catalyzed substitu-
tion of a readily available aziridinylmethyl tosylate 2. Moreover,
we have developed a one-pot procedure for the conversion of
the product N-trityl aziridines to a range of more activated
substrates that could be further employed as electrophilic
reagents.
Representative Procedure for the Deprotection and Repro-
tection of Tritylaziridines. (R)-2-Benzyl-1-tosylaziridine (20).15
To a solution of 13 (0.1 g, 0.27 mmol, 1 equiv) in a mixture of
chloroform (1.5 mL) and methanol (0.5 mL) was added trifluoro-
acetic acid (0.616 mL, 7.99 mmol, 30 equiv) at -78 °C. The
solution was stirred at -78 °C for 15 min then allowed to warm to
0 °C for 4 h upon which triethylamine (1.23 mL, 8.79 mmol, 33
equiv) was added to the solution at 0 °C. After 10 min, a solution
of tosyl chloride (61 mg, 0.32 mmol, 1.2 equiv) in chloroform (0.5
mL) was added via cannula and the mixture was stirred overnight
at 0 °C. NaHCO3 solution was added and the solution was extracted
with chloroform. The organic extracts were dried over MgSO4 and
concentrated in vacuo and the product purified by flash chroma-
tography (5:1 petroleum ether:EtOAc) to provide 20 as a colorless
solid (63 mg, 81%). Mp 92-94 °C. [R]22D -20.0 (c 1.00, CHCl3).
1H NMR (250 MHz, CDCl3) δ 2.15 (1H, d, J ) 4.5 Hz), 2.42 (3H,
s), 2.67 (1H, dd, J ) 15.0, 7.0 Hz) 2.72 (1H, d, J ) 7.0 Hz), 2.80
(1H, d, J ) 15.0, 5.0 Hz), 2.89-3.00 (1H, m), 7.01-7.18 (5H, m),
7.20 (2H, d, J ) 8.0 Hz), 7.67 (2H, d, J ) 8.0 Hz); 13C NMR
(62.9 MHz, CDCl3) δ 21.6, 32.8, 37.5, 41.2, 126.5, 127.9, 128.4,
128.7, 129.6, 134.9, 137.0, 144.3.
Experimental Section
(S)-(1-Tritylaziridin-2-yl)methyl 4-Methylbenzenesulfonate
(2). To a solution of (S)-(1-tritylaziridin-2-yl)-methanol (1, 1.94 g,
6.15 mmol, 1 equiv)11b in CH2Cl2 (31 mL) were added triethylamine
(0.94 mL, 6.77 mmol, 1.1 equiv), tosyl chloride (1.30 g, 6.77 mmol,
1.1 equiv), and DMAP (0.08 g, 0.62 mmol, 0.1 equiv) at 0 °C.
The solution was left to warm to rt overnight, washed with NaHCO3,
and extracted with CH2Cl2. The organic extracts were dried over
MgSO4 and concentrated in vacuo to provide 2 as a pale yellow
solid (2.65 g, 92%). Mp 82-84 °C. [R]23D -33.0 (c 1.00, CHCl3).
1H NMR (250 MHz, CDCl3) δ 1.04 (1H, d, J ) 6.0 Hz), 1.43 (1H,
m), 1.62 (1H, d, J ) 2.5 Hz), 2.39 (3H, s), 4.06 (1H, dd, J ) 10.5,
5.5 Hz), 4.32 (1H, dd, J ) 10.5, 5.5 Hz), 7.14-7.68 (19H, m); 13
C
NMR (62.9 MHz, CDCl3) δ 21.1, 25.5, 30.5, 72.5, 73.8, 126.8,
Acknowledgment. We are grateful to the EPSRC and Eli
Lilly and Company Ltd for financial support.
127.5, 127.9, 129.3, 129.9, 133.2, 144.0, 144.7; FTIR (film, υmax
(16) The stereochemistry of compounds 25, 26, and 27 has been
elucidated by X-ray crystallography. CCDC 659299, CCDC 659300, and
CCDC 661089 contain the supplementary crystallographic data for 25, 26,
and 27, respectively. This data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax
(+44) 1223-336-033; or request@ccdc.cam.ac.uk).
Supporting Information Available: Experimental procedures,
1H /13C NMR spectra for selected compounds, and X-ray data for
compounds 25, 26, and 27. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO7023637
1130 J. Org. Chem., Vol. 73, No. 3, 2008