Enantioselective chemoenzymatic synthesis of trans-aziridines

Article abstract of DOI:10.1021/jo901548t

(Chemical Equation Presented) A straightforward, five-step procedure for the synthesis of enantiomerically pure 2,3-disubstituted trans-aziridines has been developed starting from commercially available aldehydes. Hydroxynitrile lyase-mediated cyanohydrin

Full text of DOI:10.1021/jo901548t

pubs.acs.org/joc
extensive research has concentrated on synthesizing deriva-
Enantioselective Chemoenzymatic Synthesis of
trans-Aziridines
tives of these natural products with increased potency.9,10
The ability of aziridines to undergo regio- and stereose-
lective ring-opening reactions, as well as ring expansions,
provides direct access to structural motifs and renders them
attractive building blocks in organic synthesis. They have
been applied in the total synthesis of natural products
including alkaloids,11 amino sugars,12 amino acids,13 and
lactam antibiotics, such as (þ)-thienamycin.14 Other appli-
cations are found in asymmetric synthesis, where chiral
aziridines have been utilized both as ligands and auxiliaries.
Among these reactions are the asymmetric dihydroxylation
of alkenes15 and the enantioselective addition of dialkylzinc
to various aliphatic and aromatic aldehydes.16
Bas Ritzen, Matthijs C. M. van Oers, Floris L. van Delft, and
Floris P. J. T. Rutjes*
Institute for Molecules and Materials, Radboud University
Nijmegen, Heyendaalseweg 135, NL-6525 AJ Nijmegen,
The Netherlands
f.rutjes@science.ru.nl
Received July 17, 2009
As a consequence, the development of efficient synthetic
routes to aziridines has been an important subject of inves-
tigation over the past decades. Two of the most fundamental
pathways involve the metal-catalyzed addition of nitrenes to
alkenes17 and the addition of ylides to imines.18 Although
frequently applied in the past, both methods lack full stereo-
control over the outcome of the reaction and often require
harsh conditions or the use of expensive catalysts. Other
known methods for the synthesis of aziridines include addi-
tion of metal carbenoids to imines,19,20 addition across
azirines21 and addition of carbenes to imines.22 Further-
more, alkenes can readily be transformed into aziridines
via cyclic sulfates, obtained from asymmetric dihydroxyla-
tion products and via epoxides, generated by application of
the Sharpless asymmetric epoxidation.23 However, the oldest
and conceptually perhaps most obvious synthesis of aziri-
dines utilizes 1,2-amino alcohols as precursors. In 1935,
Wenker already demonstrated that addition of sulfuric acid
to amino alcohols at elevated temperatures can yield enan-
tiopure aziridines.24 Direct ring closure of amino alcohols to
provide aziridines is known to be difficult, and previous
reports show only moderate yields.25 Better results are
obtained when the hydroxyl group is converted into a
A straightforward, five-step procedure for the synthesis
of enantiomerically pure 2,3-disubstituted trans-aziri-
dines has been developed starting from commercially
available aldehydes. Hydroxynitrile lyase-mediated cyano-
hydrin formation provided cyanohydrins in excellent
enantioselectivities and good yields. Subsequent forma-
tion of diastereomerically pure anti-amino alcohols via a
one-pot Grignard addition-reduction sequence, CuII-
catalyzed diazotransfer, and triphenylphosphine-media-
ted reductive cyclization provided the corresponding
trans-aziridines in good yields and excellent diastereos-
electivities.
Since the first synthesis by Gabriel in 1888,1 aziridines
have gained increasing interest in organic synthesis and
medicinal chemistry.2-4 Aziridines are highly reactive but,
nevertheless, occur in several natural products exhibiting
potent biological activity. For instance, mitomycins A-C,
together with porfiromycin and mitiromycin, represent an
important class of naturally occurring mitosanes, first iso-
lated from soil extracts of Streptomyces versticillatus.5 These
mitosanes6 display both antibiotic and antitumor activity,
the latter resulting from their ability to cross-link DNA.
Structure-activity relationships7,8 have identified the azirid-
ine ring as being essential for such antitumor activity and
(10) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron 1997, 53,
10229–10238.
(11) Nakagawa, M.; Kawahara, M. Org. Lett. 2000, 2, 953–955.
(12) Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.; Pineschi, M.
Tetrahedron: Asymmetry 1996, 7, 779–786.
(13) Davis, F. A.; Deng, J.; Zhang, Y.; Haltiwanger, R. C. Tetrahedron
2002, 58, 7135–7143.
(14) Tanner, D.; Somfai, P. Tetrahedron Lett. 1987, 28, 1211–1214.
(15) Tanner, D.; Harden, A.; Johansson, F.; Wyatt, P.; Andersson, P. G.
Acta Chem. Scand. 1996, 89, 2357–2364.
(16) Lawrence, C. F.; Nayak, S. K.; Thijs, L.; Zwanenburg, B. Synlett
1999, 1571–1572.
(17) Atkinson, R. S. Tetrahedron 1999, 55, 1519–1559.
(18) Ochiai, M.; Kitagawa, Y. Tetrahedron Lett. 1998, 39, 5569–5570.
(19) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chem., Int. Ed.
1995, 34, 676–678.
(20) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518–
4521.
(1) Gabriel, S. Ber. Dtsch. Chem. Ges. 1888, 21, 1049–1049.
(2) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247–258.
(3) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2007, 107,
2080–2135.
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(4) Gansauer, A. Angew. Chem., Int. Ed. 2006, 45, 5733.
(5) Lefemine, D. V.; Dann, M.; Barbatschi, F.; Hausmann, W. K.;
Zbinovsky, V.; Monnikendam, P.; Adam, J.; Bohonos, N. J. Am. Chem.
Soc. 1962, 84, 3184–3185.
(6) Kasai, M.; Kono, M. Synlett 1992, 778–790.
(7) Tomasz, M. Chem. Biol. 1995, 2, 575–579.
(8) Han, I.; Kohn, H. J. Org. Chem. 1991, 56, 4648–4653.
(9) Kinoshita, S.; Uzu, K.; Nakano, K.; Shimizu, M.; Takahashi, T.;
Matsui, M. J. Med. Chem. 1971, 14, 103–109.
(21) Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J. Am.
Chem. Soc. 1996, 118, 8491–8492.
(22) Deyrup, J. A.; Greenwald, R. B. J. Am. Chem. Soc. 1965, 87, 4538–
4545.
(23) Lohray, B. B.; Gao, Y.; Sharpless, K. B. Tetrahedron Lett. 1989, 30,
2623–2626.
(24) Wenker, H. J. Am. Chem. Soc. 1935, 57, 2328–2328.
(25) Davis, F. A.; McCoull, W. Synthesis 2000, 1347–1365.
7548 J. Org. Chem. 2009, 74, 7548–7551
Published on Web 09/10/2009
DOI: 10.1021/jo901548t
r
2009 American Chemical Society

Ritzen et al.
JOCNote
SCHEME 1. Retrosynthetic Route to Aziridines
TABLE 1. HNL-Mediated Cyanohydrin Formation and Protection
powerful leaving group, thus inducing an intramolecular
displacement reaction. Several methods are described and
extensive investigations of this reaction showed that aziri-
dines can be isolated in high yield and stereoselectivity.26,27
Inspired by these results and the relevance of these mole-
cules we set out to investigate a new and readily applicable
catalytic pathway for the synthesis of enantiomerically pure
trans-aziridines. Our approach is outlined retrosynthetically
in Scheme 1. We envisioned that the aziridine skeleton could
arise via a direct closure of the aforementioned 1,2-amino
alcohols, which would occur in a stereoselective manner.
Furthermore, we hypothesized that optically active cyano-
hydrins could be used as strategic synthons for the synthesis
of the amino alcohols, exploiting the electrophilicity of the
cyano group toward stereoselective addition of organome-
tallic reagents. Finally, chemoenzymatic cyanohydrin for-
mation was envisioned to provide these precursors in high
ee using aldehydes as substrates.
entry
R1
enzyme product yield (%)a ee (%) config.
1
2
3
4
5
Ph
4-BrC6H4
3-piperonyl (R)-HNL
2-furanyl
4-butenyl
(S)-HNL
(R)-HNL
3
4
5
6
7
90
79
81
70
67
>99b
>99c
>99b
>99c
>99d
(S)
(R)
(R)
(S)e
(R)
(R)-HNL
(R)-HNL
aIsolated yield after chromatography. bDetermined by GC analysis.
cDetermined by HPLC analysis. dDetermined by derivatization with
Mosher’s acid chloride and comparison with the diastereomeric esters
prepared from their racemic counterparts. eThe stereochemical arrange-
ment is as expected for the (R)-HNL; however, due to priority changes
following the Cahn-Ingold-Prelog rules, the product has the (S)-config-
uration.
smoothly afforded the metallo imine, as was monitored by
mass analysis. Dry methanol was added to destroy the excess
of Grignard reagent and to protonate the primary imine anion
intermediate. In situ reduction by adding an excess of NaBH4
took place in a diastereoselective fashion according to Cram’s
chelation model, affording 8 in 92% yield with excellent
diastereoselectivity of 99% (entry 1, Table 2). Pleased with
these results, we applied the one-pot reaction sequence on
cyanohydrins 3-7 by using various Grignard reagents. Grat-
ifyingly, the desired anti-amino alcohols 9-17 could be iso-
lated in reasonable to good yields. In the case of entry 3, the
addition of 3-chlorophenylmagnesium bromide proceeded
muchslower andproducedonly21%of alcohol10. Prolonged
stirring or other attempts to improve the yield led to consider-
able side product formation. It seems conceivable that steric
interactions play a more decisive role in this reaction. Addi-
tionally, we were pleased to find that in all cases the dr of the
reaction sequence was >95%, except for entry 10, which
showed a significantly lower dr of 72% as compared to the
aromatic cyanohydrins. This discrepancy is presumably
caused by the decreased size of the butenyl side chain of the
cyanohydrin, resulting in a smaller difference between both
diastereofaces. Synthetic efforts to react cyanohydrin 7 with
aliphatic Grignard reagents provided the desired amino alco-
hols in rather poor dr. For this reason we decided to focus on
the synthesis of the aromatic amino alcohols.
In a first attempt to cyclize the amino alcohols to the
corresponding aziridines, simultaneous nosylation of both
the alcohol and amino functionality was investigated. Var-
ious reaction conditions were explored but unfortunately
this approach afforded only mixtures of N-sulfonylated
product with small amounts of the desired precursor. With
this precursor in hand, however, we continued with the base-
catalyzed cyclization. Much to our surprise, all efforts to
cyclize this precursor failed, even after prolonged reaction
times. Heating of the reaction mixture up to 50 °C to force
any cyclization merely led to formation of side products.
Considering these results, we concluded that direct ring
closure of the free amino alcohol using Mitsunobu-type
conditions might be more successful. Subjection of the amino
alcohol to PPh3 in combination with either DEAD or DIAD
in various solvents, however, did not result in any reaction
Inspired by previous work from the group of Effenberger28-30
and due to our own general interest in the synthesis and
application of chiral cyanohydrins,31 the first step in our
envisioned route was realized via hydroxynitrile lyase
(HNL)-mediated cyanohydrin formation. Hydroxynitrile
lyases are designed by nature to convert cyanohydrins into
the corresponding aldehydes and hydrogen cyanide, which
are used by some plants as a defense mechanism. By using a
two-phase system of water and methyl tert-butyl ether
(MTBE) and a large excess of HCN, however, the equilibria
can be directed to the cyanohydrins.32 Starting from five
different aldehydes and using (R)-selective HNL from Pru-
nus amygdalus (PaHNL) and (S)-selective HNL from Hevea
brasiliensis (HbHNL) as catalysts yielded the corresponding
hydroxynitriles 2 as the crude products. Subsequent protec-
tion of the hydroxyl group (TBSCl, DMAP, imidazole) to
prevent racemization and regeneration of the aldehyde,
provided cyanohydrins 3-7 in high yield, and excellent
enantiomeric excess (Table 1).
For the introduction of the second stereogenic center we
used an elegant method developed by Brussee et al.,33 which
relied on a tandem Grignard addition-NaBH4 reduction
sequence providing the desired compounds in high yield and
excellent diastereoselectivity. Thus, addition of phenylmagne-
sium bromide to cyanohydrin 3 in diethyl ether at 0 °C
(26) Pfister, J. R. Synthesis 1984, 969–970.
(27) Kametani, T.; Kigawa, Y.; Ihara, M. Tetrahedron 1979, 35, 313–316.
(28) Effenberger, F.; Ziegler, T.; Forster, S. Angew. Chem., Int. Ed. 1987,
26, 458–460.
(29) Effenberger, F.; Stelzer, U. Tetrahedron: Asymmetry 1995, 6, 283–
286.
€
(30) Effenberger, F.; Forster, S.; Wajant, H. Curr. Opin. Biotechnol. 2000,
11, 532–539.
(31) Wijdeven, M. A.; Wijtmans, R.; van den Berg, R. J. F.; Noorduin,
W.; Schoemaker, H. E.; Sonke, T.; van Delft, F. L.; Blaauw, R. H.; Fitch,
R. W.; Spande, T. F.; Daly, J. W.; Rutjes, F. P. J. T. Org. Lett. 2008, 10, 4001–
4003.
(32) Fechter, M. H.; Griengl, H. Enzyme catalysis in organic synthesis;
Wiley-VCH: Weinheim, 2002; Vol. 2.
(33) Brussee, J.; Dofferhoff, F.; Kruse, C. G.; Gen, A. Tetrahedron 1990,
46, 1653–1658.
J. Org. Chem. Vol. 74, No. 19, 2009 7549

Ritzen et al.
JOCNote
TABLE 2. Grignard Addition, Reduction, and Diazotransfer
TABLE 3. Desilylation and Ring Closure
yielda (%)/
amino yielda (%)/ azido yielda
entry s.m.
R
R1
product
drb (%)
config.
entry s.m.
R1
alcohol
drb (%)
alcohol (%) config.
1
2
3
4
5
6
7
8
9
10
18 Ph
Ph
29
30
31
32
33
34
35
36
37
38
60/99
47/99
89/99
51/99
73/99
(R,R)
(R,R)
(R,R)
(R,R)
(S,S)
(S,S)
1
2
3
4
5
6
7
8
9
10
3
3
3
3
4
4
6
6
5
7
Ph
8
9
92/99
70/99
21/99
64/95
51/99
49/99
52/99
53/99
91/99
52/72
18
19
20
21
22
23
24
25
26
27
99 (S,R)
93 (S,R)
99 (S,R)
91 (S,R)
87 (R,S)
76 (R,S)
66 (S,S)
64 (S,S)
90 (R,S)
76 (R,S)
19 Ph
20 Ph
21 Ph
22 4-BrC6H4
23 4-BrC6H4
24 2-furanyl
25 2-furanyl
4-FC6H4
3-ClC6H4
Allyl
4-FC6H4
4-MeOC6H4
4-FC6H4
4-MeOC6H4
4-FC6H4
3-ClC6H4
allyl
4-FC6H4
4-MeOC6H4
4-FC6H4
4-MeOC6H4
4-MeOC6H4
Ph
10
11
12
13
14
15
16
17
53/99
c
c
26 3-piperonyl 4-MeOC6H4
27 4-butenyl Ph
54/99
46/99
(S,S)
(S,S)
aIsolated yield after chromatography. bDetermined by 1H NMR
aIsolated yield after chromatography. bDetermined by 1H NMR
analysis of the crude product.
analysis of the crude product. cProduct decomposed during reaction.
this decreased the reaction rate dramatically but did not
improve the yield.
despite literature precedent on similar substrates.26,34
A
modified synthetic route involving protection of the nitrogen
atom to enhance the Mitsunobu reaction would be less
attractive since this requires an additional deprotection step
to afford the unprotected aziridine. Consequently, an alter-
native approach was conceptualized involving the introduc-
tion of an azide functionality. The conditions for the CuII-
catalyzed diazotransfer reaction were based on a comparison
between two different literature procedures, namely, with
imidazole-1-sulfonyl azide35 and triflic azide36,37 as reagents.
Because the latter reaction gave the highest yield (near
quantitative) for the conversion of 8 to the corresponding
azido alcohol 18, we decided to conduct all diazotransfer
reactions under these conditions. Thus, subjection of the
amino alcohols 9-17 under the aforementioned conditions,
afforded the azido alcohols 19-27 in good yields (64-99%).
With the anti-azido alcohols in hand, the stage was set for
the synthesis of the trans-aziridines (Table 3). Deprotection
with TBAF in THF resulted in clean conversion into the
corresponding free azido alcohols, which could be used after
a simple extraction, but without further purification in
a phosphine-mediated Staudinger-type ring closure.38-40
Performing the cyclization in THF or DMF at elevated
temperatures (70-90 °C) in combination with trimethylphos-
phine initially led to poor conversion into the desired trans-
aziridine. A more rewarding result was obtained by stirring
the anti-azido alcohols in the presence of triphenylphosphine
in refluxing acetonitrile. Much to our satisfaction, the azir-
idines 29-34, 37, and 38 could be isolated in moderate
to good yields (46-89%). In an attempt to avoid the
tedious purification of triphenylphosphine oxide, polymer-
bound triphenylphosphine was also used. As anticipated,
Unfortunately, in the case of entries 7 and 8, no product
could be isolated. Although mass spectrometry of the reac-
tion mixture showed formation of the intermediate oxaza-
phospholidine and a product with the expected mass, we
were unable to isolate the desired aziridines. A suitable
mechanistic explanation is lacking, although a partial answer
may lie in the electron-donating capacity of the furanyl
substituent.
Furthermore, we proved by using chiral HPLC analysis of
acetylated 29 that no (partial) racemization had taken place
during the whole sequence. Optical rotation measurements
were compared to literature values and proved the formation
of the trans-substituted aziridine 29.41
Conclusions
In summary, a novel and straightforward procedure has
been developed that allows for the synthesis of unprotected
trans-aziridines starting from commercially available alde-
hydes. The key step in this relatively mild sequence involves
chemoenzymatic enantioselective HNL-mediated cyanohy-
drin formation. We also demonstrated that the correspond-
ing anti-amino alcohols could be synthesized in good yields
and excellent diastereoselectivities. The last two steps in the
sequence, diazotransfer and phosphine-mediated ring clo-
sure, produced the target aziridines in high yield and en-
antiomeric purity.
Experimental Section
(S)-2-(tert-Butyldimethylsilyloxy)-2-phenylacetonitrile (3). A
solution of benzaldehyde (500 mg, 4.71 mmol) in MTBE (40 mL)
was added to a cooled (0 °C) solution of KCN (3.07 g, 47.1 mmol,
10 equiv) in citrate buffer (40 mL, pH=5.0). After addition of
(S)-HNL (800 μL), the reaction mixture was stirred at 0 °C for
1.5 h and quenched with 5 M HCl (5 mL), causing the enzyme to
precipitate. The precipitate was filtrated over a glass funnel filled
with cotton. The filtrate was extracted with CH2Cl2 (3 ꢀ 50 mL)
and the organic layers were combined, dried (Na2SO4), and
(34) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 6267–6270.
(35) Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797–3800.
(36) Cavender, C. J.; Shiner, V. J. J. Org. Chem. 2002, 37, 3567–3569.
(37) Nyffeler, P. T.; Liang, C. H.; Koeller, K. M.; Wong, C. H. J. Am.
Chem. Soc. 2002, 124, 10773–10778.
ꢀ
(38) Ramon, R.; Alonso, M.; Riera, A. Tetrahedron: Asymmetry 2007, 18,
2797–2802.
(39) Tanner, D.; Birgersson, C.; Gogoll, A.; Luthman, K. Tetrahedron
1994, 50, 9797–9824.
ꢀ
(41) Arroyo, Y.; Meana, A.; Rodrı
´
M. A.; Garcıa-Ruano, J. L. Tetrahedron 2006, 62, 8525–8532.
´
guez, J. F.; Santos, M.; Sanz-Tejedor,
€
(40) Pochlauer, P.; Muller, E. P. Helv. Chim. Acta 1984, 67, 1238–1247.
€
7550 J. Org. Chem. Vol. 74, No. 19, 2009

Ritzen et al.
JOCNote
concentrated in vacuo. The residue was dissolved in dry CH2Cl2
(15 mL) at 0 °C and TBSCl (781 mg, 5.18 mmol, 1.1 equiv),
imidazole (641 mg, 9.42 mmol, 2.0 equiv, dissolved in 1 mL
CH2Cl2), and DMAP (58 mg, 10 mol %) were added succes-
sively. The reaction mixture was stirred overnight at 0 °C. After
diluting the reaction mixture with H2O (15 mL) and Et2O
(15 mL), the organic layer was washed with H2O (2 ꢀ 30 mL)
and brine (2 ꢀ 30 mL). The resulting organic fraction was dried
(Na2SO4) and concentrated in vacuo. Column chromatography
(EtOAc/heptane, 1:7 f 1:1) yielded compound 3 (1.05 g, 90%)
as a colorless oil. Rf 0.65 (EtOAc/heptane, 1:3). [R]2D0 þ16.8
(c 1.05, CHCl3), ref 42. [R]2D0 þ17.5 (c 1.00, CHCl3). ee >99%
(GC, isothermic, 120 °C); Rt,1=13.90 min (S), Rt,2=14.38 min
(R).1H NMR (CDCl3, 400 MHz): δ 7.49-7.38 (m, 5H), 5.53
(s, 1H), 0.95 (s, 9H), 0.24 (s, 3H), 0.16 (s, 3H). 13C NMR (CDCl3,
75 MHz): δ 136.5, 129.2, 128.9, 126.0, 119.3, 64.0, 25.5, 18.2,
-5.1, -5.2. Data are in agreement with literature.42
(1R,2S)-2-(tert-Butyldimethylsilyloxy)-1,2-diphenylethanamine
(8). A solution of 3 (1.00 g, 4.04 mmol) in dry Et2O (30 mL)
was cooled to 0 °C and phenylmagnesium bromide (4.04 mL of a
3.0 M solution in Et2O, 12.1 mmol, 3.0 equiv) was added
dropwise. The reaction mixture was allowed to warm to rt and
stirred for 2 h, after which MeOH (30 mL) and NaBH4 (611 mg,
16.2 mmol, 4 equiv) were added. After 30 min, the mixture was
quenched with saturated aqueous NaHCO3 (60 mL) and the
product was extracted with EtOAc (3 ꢀ 60 mL). The organic
layers were combined, dried (Na2SO4) and concentrated in
vacuo. Column chromatography (EtOAc/ heptane, 1:7f1:1)
afforded pure 8 (1.19 g, 90%) as a colorless oil. Rf 0.41 (EtOAc/
heptane, 1:1). [R]2D0 þ31.6 (c 1.07, CH2Cl2). IR (ATR): 2953,
2926, 2855, 1093, 836, 699 cm-1. 1H NMR (CDCl3, 400 MHz): δ
7.30-7.19 (m, 10H), 4.64 (d, J=6.5 Hz, 1H), 4.02 (d, J=6.5 Hz,
1H), 1.37 (br s, 1H), 0.75 (s, 9H), -0.25 (s, 3H), -0.32 (s, 3H).
13C NMR (CDCl3, 75 MHz): δ 142.7, 142.0, 127.9, 127.8, 127.4,
127.2, 127.1, 80.2, 62.9, 29.7, 25.7, 18.0, -5.0, -5.7. HRMS
(ESI) m/z calcd for C20H30NOSi (M þ H)þ, 328.2097; found,
328.2103.
followed by H2O (5 mL), a solution of CuSO4 (11 mg, 10 mol %)
in MeOH (0.5 mL), and Et3N (297 μL, 2.01 mmol, 3.0 equiv).
The reaction mixture was stirred overnight at rt. Then saturated
aqueous NaHCO3 (25 mL) was added and the organic solvents
were evaporated. The aqueous residue was extracted with
EtOAc (3 ꢀ 25 mL) and the organic layers were combined,
dried (Na2SO4), and concentrated in vacuo to give a yellow oil.
Purification by column chromatography (EtOAc/heptane, 1:7 f
1:3) afforded 18 (235 mg, 99%). Rf 0.71 (EtOAc/heptane, 1:1).
[R]2D0 -0.8 (c 0.96, CH2Cl2). IR (ATR): 2950, 2928, 2855, 2103,
1255, 1099, 838, 700 cm-1 1H NMR (CDCl3, 400 MHz): δ
.
7.30-7.21 (m, 10H), 4.71 (d, J=6.6 Hz, 1H), 4.57 (d, J=6.6 Hz,
1H), 0.74 (s, 9H), -0.22 (s, 3H), -0.29 (s, 3H). 13C NMR
(CDCl3, 75 MHz): δ 140.9, 137.0, 128.2, 128.1, 127.9, 127.3,
78.7, 72.2, 25.6, 18.0, -5.0, -5.6.
(2R,3R)-2,3-Diphenylaziridine (29). To a solution of 18 (142 mg,
0.41 mmol) in THF (4 mL) at 0 °C was added TBAF (480 μL of a
1.0 M solution in THF, 0.48 mmol, 1.2 equiv). The reaction
mixture was stirred at rt for 1 h. After quenching with saturated
aqueous NH4Cl (4 mL) the product was extracted with EtOAc
(3 ꢀ 8 mL). The resulting organic layers were combined, washed
with H2O (25 mL) and brine (25 mL), dried (Na2SO4) and
concentrated in vacuo. Then, the crude product was redissolved
in MeCN (4 mL) and PPh3 (129 mg, 0.48 mmol, 1.2 equiv) was
added. After refluxing the reaction mixture for 2 h, the solution was
allowed to cool to rt. The solvent was then evaporated and the
product was purified by column chromatography (EtOAc/hep-
tane, 1:7 f 1:2) to give pure 29 (36 mg, 60%) as a colorless oil.
Rf 0.56 (EtOAc/heptane, 1:1). [R]2D0 þ331 (c 1.27, CH2Cl2); ref 43.
[R]2D0 þ328.8 (c 1.25, CHCl3). IR (ATR): 3287, 3058, 3023, 1498,
1
1191 cm-1. H NMR (CDCl3, 400 MHz): δ 7.5-7.2 (m, 10H),
3.3-2.8 (br s, 2H), 1.6-1.2 (br s, 1H). 13C NMR (CDCl3,
75 MHz): δ 139.5, 128.6, 127.3, 125.5, 43.7. HRMS (ESI) m/z
calcd for C14H14N (M þ H)þ, 196.1126; found, 196.1115. Data are
in agreement with literature.43
Acknowledgment. The Council for Chemical Sciences of
The Netherlands Organization for Scientific Research
(NWO-CW) is gratefully acknowledged for financial sup-
port. We thank DSM Pharma Chemicals (Geleen, The
Netherlands) for providing the HNL enzymes.
(1S,2R)-2-Azido-1-(tert-butyldimethylsilyloxy)-1,2-diphenyle-
thane (18). To a solution of NaN3 (261 mg, 4.01 mmol, 6.0 equiv)
in a mixture of H2O/CH2Cl2 (4 mL, 1:1 v/v) at 0 °C, was added
Tf2O (337 μL, 2.01 mmol, 3.0 equiv). The reaction mixture was
stirred at 0 °C for 2 h. After quenching with saturated aqueous
NaHCO3, the layers were separated and the aqueous layer was
extracted with CH2Cl2 (1 ꢀ 3 mL). The organic layers were
combined to afford 5 mL of TfN3 solution. This TfN3 was then
added to a solution of 8 (219 mg, 0.67 mmol) in MeOH (15 mL),
Supporting Information Available: Experimental proce-
dures and spectroscopic and analytical data of all compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(42) Warmerdam, E. G. J. C.; Brussee, J.; Kruse, C. G.; van der Gen, A.
Tetrahedron 1993, 49, 1063–1070.
(43) Reyes, A.; Juaristi, E. Chirality 1998, 10, 95–99.
J. Org. Chem. Vol. 74, No. 19, 2009 7551