Formation of Scalemic Aziridines via the Nucleophilic Opening of Aziridines

Full text of DOI:10.1021/jo962307f

J . Org. Chem. 1997, 62, 2671-2674
2671
Sch em e 1
F or m a tion of Sca lem ic Azir id in es via th e
Nu cleop h ilic Op en in g of Azir id in es
Stephen C. Bergmeier* and Punit P. Seth
Division of Medicinal Chemistry, College of Pharmacy,
The Ohio State University, Columbus, Ohio 43210
Received December 10, 1996
In tr od u ction
As part of our work in the preparation of aziridine-
allylsilanes1 we had need of a method for the preparation
of simple monosubstituted, scalemic aziridines such as
1. The preparation of scalemic aziridines has been well
covered in a number of reviews.2 Two methods seemed
particularly well suited for the preparation of the types
of aziridines needed for our work. First, an amino acid
can be converted into a substituted aziridine.3 The use
of amino acids, however, is quite limiting as to the
identity of R. Second, the aziridination of an olefin with
PhIdNTs and a copper catalyst has been shown to be
useful in some cases.4 While this method can be ex-
tremely useful, again the choice of R can be limited. For
example, other olefins in the molecule can be a problem,
and optimal yields are only obtained with cyclic or
strained olefins.
Sch em e 2
NH Cl
3
Our plan (Scheme 1) was to prepare the aziridine 2
and to examine the reactivity of this molecule with a
variety of organometallic reagents. The reaction of the
aziridine ring with cuprates, organolithium reagents, and
Grignard reagents is well known.5 We were not certain
where nucleophilic attack would take place with an
* To whom correspondence should be addressed. Telephone: 614-
292-5499. E-mail: bergmeier.1@osu.edu.
aziridine such as 2, and a variety of products are possible.
If nucleophilic attack takes place at the tosyl ester, (S)-1
would be the result. We had hoped that attack would
take place on the aziridine ring and lead to intermediate
3, which would then recyclize to form aziridine (R)-1. A
similar strategy has been used in reactions of glycidyl
tosylate.6 In that case, when glycidyl tosylate was
reacted with heteroatom nucleophiles, displacement of
the tosylate was observed to be the major reaction
pathway. Reaction of glycidal tosylate with organome-
tallic reagents, however, gave products resulting from
exclusive epoxide ring opening. In our case, such a
strategy would allow the preparation of a number of
monosubstituted aziridines from a single aziridine pre-
cursor. The preparation of the precursor aziridine 10,
in optically pure form from (R)-serine is well known.7
(1) Bergmeier, S. C.; Seth, P. P. Tetrahedron Lett. 1995, 36, 3793.
(2) For exhaustive discussions of the synthesis and reactions of
aziridines see: (a) Aziridines, Azirines and Fused-ring Derivatives.
Padwa, A.; Woolhouse, A. D. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984;
Vol. 7; Lwowski, W., Ed., pp 80-93. (b) Aziridines. Deyrup, J . A. In
The Chemistry of Heterocyclic Compounds; Weissberger, A., Taylor,
E. C., Eds.; Wiley: New York, 1983; Vol. 42; Hassner, A., Ed., pp 11-
83. (c) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (d)
Kametani, T.; Honda, T. Adv. Heterocycl. Chem. 1986, 39, 181.
(3) For some examples of the synthesis of chiral nonracemic aziri-
dines from amino acids see: (a) Bergmeier, S. C.; Lee, W. K.; Rapoport,
H. J . Org. Chem. 1993, 58, 5019 and references therein. (b) Baldwin,
J . E.; Farthing, C. N.; Russell, A. T.; Schofield, C.; Spivey, A. C.
Tetrahedron Lett. 1996, 37, 3761. (c) Osborn, H. M. I.; Cantril, A. A.;
Sweeney, J . B. Tetrahedron Lett. 1994, 35, 3159. (d) Ho, M.; Chung, J .
K. K.; Tang, N. Tetrahedron Lett. 1993, 34, 6513. (e) Berry, M. B.;
Craig, D. Synlett, 1992, 41. Also see ref 7 and references cited therein.
(4) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J . Am. Chem. Soc.
1994, 116, 2742. (b) Li, Z.; Conser, K. R.; J acobsen, E. N. J . Am. Chem.
Soc. 1993, 115, 5326. (c) O’Conner, K. J .; Wey, S. C.; Burrows, C. J .
Tetrahedron Lett. 1992, 33, 1001.
Resu lts a n d Discu ssion
(5) For examples of reactions of aziridines with, Grignard reagents
see: (a) Chakraborty, T. K.; Hussain, K. A.; Thippeswamy, D.
Tetrahedron, 1995, 51, 3873. (b) Pacewicka, K. O.; Zwierzak, A.
Synthesis 1996, 333. (c) Ezquerra, J .; Pedregal, C.; Lamas, C.; Alvarez,
P.; Vaquero, J . J . Tetrahedron Lett. 1996, 37, 683, also see ref 3b.
Reactions of organocuprates with aziridines: (d) Dureault, A.; Tranche-
pain, I.; Depezay, J . J . Org. Chem. 1989, 54, 5324. (e) Ibuka, T.; Nakai,
K.; Habshita, H.; Fujii, N.; Garrido, F.; Mann, A.; Chounan, Y.
Yamamoto, Y. Tetrahedron Lett. 1993, 34, 7421. (f) Baldwin, J . E.;
Spivey, A. C.; Schofield, C.; Sweeney, J . B. Tetrahedron 1993, 49, 6309.
(g) Tanner, D.; He, H. M.; Somfai, P. Tetrahedron 1992, 48, 6069. (h)
Tanner, D.; He, H. M. Tetrahedron 1992, 48, 6079. Reactions of Wittig
reagents with aziridines: (i) Baldwin, J . E.; Adlington, R. M.; Robinson,
N. G. J . Chem. Soc., Chem. Commun. 1987, 153. (j) Baumann, T.;
Buchholz, B.; Stamm, H. Synthesis 1995, 44. Reactions of sulfur ylides
with aziridines: (k) Nadir, U. K.; Arora, A. J . Chem. Soc., Perkin Trans.
1995, 44. Indole (l) Kozikowski, A. P.; Sato, K. Tetrahedron Lett. 1989,
31, 4073. (m) Dubois, L.; Mehta, A.; Tourette, E.; Dodd, R. H. J . Org.
Chem. 1994, 59, 434. Reactions of dithianes with aziridines: (n)
Osborn, H. M. I.; Sweeney, J . B.; Howson, B. Synlett 1993, 675.
Reactions of enolates with aziridines: (o) Lygo, B. Synlett 1993, 764.
(p) Berry, M. B.; Craig, D.; J ones, P. S. Synlett 1993, 513, also see ref
3a.
The preparation of aziridine 10 was carried out as
shown in Scheme 2. The readily available (S)-serine was
esterified and tosylated, and the free hydroxyl was
protected as a tert-butyldimethylsilyl ether. Reduction
of the methyl ester was most efficiently carried out with
lithium borohydride to produce 7.8 The aziridine ring
was then formed via a Mitsunobu reaction.9 Desilylation
of 8 yields aziridine 9 in 44% overall yield from (S)-serine.
Tosylation produces the desired N-tosyl,O-tosylaziridine
10.
(6) Klunder, J . M.; Onami, T.; Sharpless, K. B. J . Org. Chem. 1989,
54, 1295.
(7) Fujii, N.; Nakai. K.; Habashita H.; Hotta, H.; Tamamura, T.;
Otaka. A.; Ibuka, T. Chem. Pharm. Bull. 1994, 42, 2241.
(8) Wipf, P.; Fritch, P. C. J . Org. Chem. 1994, 59, 4875.
(9) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Huges, D. L. The
Mitsunobu Reaction. In Organic Reactions; Paquette, L., Ed.; J ohn
Wiley & Sons, Inc: New York, 1992; Vol. 42, p 335.
S0022-3263(96)02307-9 CCC: $14.00 © 1997 American Chemical Society

2672 J . Org. Chem., Vol. 62, No. 8, 1997
Notes
Sch em e 3
Sch em e 5
Sch em e 4
Sch em e 6
We were pleased to find that the reaction of 10 with
n-Bu2CuLi gave only a single product (11a ) in good yield
(Scheme 3). As 11a could have either the S or R
configuration, or a mixture of the two, the absolute
stereochemistry needed to be determined. In order to
unambiguously assign the absolute stereochemistry, the
aziridine 11a with the R configuration was prepared by
an alternate route (Scheme 4). Starting from aziridine
8, reaction with n-Bu2CuLi gave a single ring-opened
product 12. Desilylation and aziridine formation via a
Mitsunobu reaction gave 11a with the R configuration.
This compound was identical with respect to optical
rotation with 11a prepared via the single-step aziridine
opening/aziridine reformation reaction.
NH Cl
3
Further proof of the stereochemical integrity of 11a
was desired. For this purpose, the enantiomer of 11a ,
aziridine 23, was prepared from the aziridine tosylate
22. A number of routes which could lead us to 22 from
(S)-serine were examined (Scheme 5). The aziridine ester
14 was prepared from 5 via a Mitsunobu reaction.
Reduction of the ester using LiAlH4 resulted in decom-
position products. Reduction using LiBH4 gave only the
completely reduced product 15. Another route which was
attempted involved protection of the free hydroxyl of 7
with a trityl group. Desilyation followed by a Mitsunobu
reaction gave the trityl-protected aziridine 16. Hydro-
genation of 16 using Pd on charcoal gave a mixture of
products. The major product 17 was found to be the one
arising from hydrogenolysis of the aziridine ring.10
The method which ultimately worked is depicted in
Scheme 6. The methyl ester of (S)-serine was N-tosy-
lated, followed by tritylation of the free hydroxyl group
to provide 18. Reduction of the methyl ester and protec-
tion of the resulting alcohol with tert-butyldimethylsilyl
chloride gave 19. Removal of the trityl group proved to
be difficult. Use of palladium on activated charcoal
resulted in long reaction times and low yields of 20.
Hydrogenation using 100 wt % of Pearlman’s catalyst
provided 20 in a 33% yield (60% considering recovered
starting material). Use of more vigorous conditions
resulted in complete removal of the trityl as well as the
silyl protecting group. Detritylation using formic acid
in ether provided the desired product in only 39% yield.11
As before, the aziridine 21 was formed via a Mitsunobu
reaction of the vicinal amido alcohol. Deprotection of the
silyl group, followed by tosylation of the alcohol, produced
22. Aziridine 22 was then treated with n-Bu2CuLi to
provide 23.
(10) (a) Hwang, G. I.; Chung, J .; Lee, W. K. J . Org. Chem. 1996, 61,
6183. (b) Lin, Y.; Lee, W. K. Tetrahedron Lett. 1995, 36, 8431.
(11) Bessodes, M.; Komiotis, D.; Antonakis, K. Tetrahedron Lett.
1986, 27, 579.
(12) In a typical experiment, 3-5 mg of the aziridine and 20-30
mg of the solvating agent were dissolved in benzene-d6 (0.5-0.6 mL).
In the case of 11a and 23, the doublet at 1.05 ppm, corresponding to
one of the methylene protons on the aziridine ring, was shifted to 1.46
ppm for 23 (S enantiomer) and 1.44 ppm for 11a (R enantiomer).
The comparison of 11a and it’s enantiomer, 23, showed
clear differentiation in the 1H NMR when combined with
the chiral solvating reagent (S)- or (R)-(-)-2,2,2-trifluoro-
1-(9-anthryl)ethanol. The identification of the peaks
arising from the (S) enantiomer 23 allowed us to assign

Notes
J . Org. Chem., Vol. 62, No. 8, 1997 2673
an optical purity of >97% to the (R)-aziridine, 11a .12
Chiral shift agent (+)-Eu(hfc)3 was not as effective as the
chiral solvating reagent in resolving the two enantiomers.
Satisfied that the reaction of 10 with a cuprate would
provide 11 via a ring-opening-ring-closing sequence, we
turned our attention to the use of other organometallic
reagents. Neither n-BuLi nor n-BuMgBr provided any
of the desired product; only decomposition of 10 was seen.
We next wished to examine the use of other organo-
cuprate reagents. The cuprates derived from commer-
cially available methyllithium, hexyllithium, and [(tri-
methylsilyl)methyl]lithium gave acceptable yields of the
corresponding aziridines 11-11d (Scheme 3). When
methyl lithium was used, an additional product that we
have identified as N-tosyl-3-pentanamine was formed.
We believe that this product arises from the reaction of
Me2CuLi with the product 11b.13 Through the use of the
chiral solvating agent, the enantiomeric purity of aziri-
dines 11-11d was determined to be >97%.
We now turned our attention to the use of noncom-
mercially available organolithium reagents in this reac-
tion. To this end the known alkyl iodide 6-iodo-1-
(trimethylsilyl)-2-hexene14 was prepared starting from
3,4-dihydro-2H-pyran.15 The iodide was cleanly con-
verted to the corresponding organolithium reagent by
treating it with t-BuLi at -78 °C in Et2O.16 Treatment
of the intermediate organolithium with CuI resulted in
the formation of an insoluble cuprate which did not
provide very good yields of 11e (30-34%). This problem
was overcome by the addition of n-Bu3P17 to the reaction,
producing 11e in 75% yield.
We also attempted to prepare and use a cuprate
prepared from s-BuLi. Although this reagent did provide
us with some of the desired aziridine, this reaction was
not as clean as the reactions using the cuprates derived
from primary organolithiums. Similarly cuprates derived
from phenyllithium, vinyllithium, and vinylmagnesium
bromide only resulted in the decomposition of 10.
In conclusion, we have developed a novel method for
the preparation of enantiomerically pure monosubsti-
tuted aziridines via the reaction of an aziridine tosylate
with a primary organocuprate reagent. The attack of the
cuprate takes place at the least-substituted carbon of the
aziridine ring, resulting in the formation of ring-opened
intermediates. These intermediates can then undergo a
ring closure by displacement of the tosyl ester. With the
help of chiral solvating reagents, the optical purity of the
aziridines thus formed was judged to be >97%.
Exp er im en ta l Section 18
(2R)-2-[[[(4-Met h ylp h en yl)su lfon yl]oxy]m et h yl]-1-[(4-
m eth ylp h en yl)su lfon yl]a zir id in e (10). Et3N (2.9 g, 29.2
mmol) was added to a solution of 919 (13.6 g, 14.6 mmol) and
DMAP (180 mg, 1.5 mmol) in CH2Cl2 (15 mL) at 0 °C. p-
Toluenesulfonyl chloride (2.9 g, 15.3 mmol) was added to the
reaction over a period of 5 min. After the addition was complete,
the solution was warmed to rt and allowed to stir for another
90 min. The reaction was diluted with CH2Cl2 (20 mL) and
quenched by the addition of 1 M HCl (15 mL). The two layers
were separated, and the aqueous layer was extracted with CH2-
Cl2 (20 mL). The organic layers were combined, washed with
saturated NaHCO3 solution (15 mL) and brine, dried (MgSO4),
and concentrated. Chromatography (35% EtOAc in hexanes)
gave 4.28 g (75%) of 10 as a white solid. [R]D +18.7° (c 8.4,
EtOAc), 1H NMR (CDCl3, 250 MHz), δ 7.71 (d, 2H, J ) 8.35),
7.61 (d, 2H, J ) 8.37), 7.30 (m, 4H), 4.01 (dd, 1H, J ) 4.79,
11.24), 3.84 (dd, 1H, J ) 6.32, 11.18), 2.98-2.90 (m, 1H), 2.61
(d, 1H, J ) 7.07), 2.39 (s, 6H), 2.13 (d, 1H, J ) 4.28). 13C NMR
(CDCl3, 62.5 MHz) δ 145.0, 144.8, 134.4, 132.6, 129.8, 129.6,
(13) This di-opening product is seen to a small extent with all of
the organocuprate reagents (5-10%), but due to the small size of the
methylcuprate, increased amounts are seen (up to 25-30%). The
amount of di-opening product formed was reduced when the reaction
was not allowed to warm to rt and quenched at -78 °C. Warming the
reaction to rt also resulted in some loss of optical purity of the products.
The aziridines formed in this manner had ee in the range of 92-95%.
(14) Padwa, A.; Zhang, Z. J . Heterocycles 1994, 441. These workers
prepared 6-iodo-1-(trimethylsilyl)-2-hexene in six steps from butane-
diol. We prepared the iodide from the corresponding alcohol in 80%
yield by tosylation and displacement by iodide. The alcohol was
prepared by the method of Wenkert15 in 36% yield from dihydropyran
in a single step. The olefins formed by this coupling reaction predomi-
nantly have the Z configuration.
(15) (a) Wenkert, E.; Ferreira, V. F.; Michelotti, E. L.; Tingoli, M.
J . Org. Chem. 1985, 50, 719. (b) Kocien’ski, P.; Dixon, N. J .; Wadman,
S. Tetrahedron Lett. 1988, 29, 2353.
(16) (a) Bailey, W. F.; Punzalan, E. R. J . Org. Chem. 1990, 55, 5404.
(b) Negishi, E.; Swanson, D. R.; Rousset, C. J . J . Org. Chem. 1990, 55,
5406.
127.9, 127.7, 68.4, 36.6, 30.8, 21.4. Anal. Calcd for C17H19
-
NO5S2: C, 53.52; H, 5.02; N, 3.67. Found: C, 53.20; H, 4.76; N,
3.69.
Gen er a l P r oced u r e for th e P r ep a r a tion of Azir id in es
11a -d . A solution of the desired organolithium (1-1.35 mmol)
was added to a cold (-78 °C) suspension of CuI (95 mg, 0.5 mmol)
in THF (1.5 mL). The resulting solution was warmed to -40
°C and allowed to stir for 10 min after which it was cooled to
-78 °C. A solution of 10 (195 mg, 0.5 mmol), dissolved in THF
(1 mL) was added to the reaction via cannula under a positive
pressure of nitrogen. The reaction was allowed to stir at -78
°C for 60 min after which it was quenched by the addition of
saturated NH4Cl solution at -78 °C, and the aqueous solution
was extracted with EtOAc (2 × 5 mL), dried (MgSO4), and
concentrated. Chromatography gave the aziridines 11a -d .
(R)-2-P en tyl-N-[(4-m eth ylph en yl)su lfon yl]azir idin e (11a).
Prepared by the general procedure using n-BuLi (1 mmol, 0.43
mL of a 2.3 M solution in hexanes) to give 99 mg (74%) of 11a
as a colorless oil. Rf 0.23 (6% EtOAc in hexanes), [R]365 +18.5°
(c 3.0, EtOAc), 1H NMR (CDCl3, 250 MHz), δ 7.79 (d, 2H, J )
8.21), 7.29 (d, 2H, J ) 8.31), 2.63 (m, 1H), 2.59 (d, 1H, J ) 6.95),
2.40 (s, 3H), 2.02 (d, 1H, J ) 4.33), 1.6-1.1 (m, 8H), 0.78 (m,
3H). 13C NMR (CDCl3, 62.5 MHz) δ 144.3, 135.5, 129.5, 128.0,
40.4, 33.6, 31.2, 31.1, 26.3, 22.3, 21.5, 13.7. Anal. Calcd for
(17) O’Reilly, J . M.; Lin, J . M.; Duax, W. L.; Brueggemeier. R. W. J .
Med. Chem. 1995, 38, 2842.
(18) General methods: Thin layer chromatography (TLC) was
performed on Whatman precoated silica gel F254 aluminum foils.
Visualization was accomplished with UV light and/or phosphomolybdic
acid solution followed by heating. Purification of the reaction products
was carried out by flash column chromatography using glass column
dry packed with silica gel (230-400 mesh ASTM) according to the
method of Still.20 1H NMR spectra referenced to TMS were recorded
using a Bruker AF 250 or Bruker AF 270 model spectrometer. Data
are reported as follows: chemical shift in ppm from internal standard
tetramethylsilane on the δ scale, multiplicity (b ) broad, s ) singlet,
d ) doublet, t ) triplet, q ) quartet, and m ) multiplet), integration,
coupling constant (Hz). All reactions were carried out under an
atmosphere of nitrogen unless specified otherwise. Glassware was
flame dried under a flow of nitrogen. Tetrahydrofuran and diethyl ether
was distilled over sodium/benzophenone ketyl immediately prior to use.
Dichloromethane was distilled over CaH2 prior to use. Organolithium
reagents used for the reactions were purchased from Aldrich Chemical
Co. or prepared via the method of Negishi.16 (S)- and (R)-(-)-2,2,2-
trifluoro-1-(9-anthryl)ethanol was purchased from Aldrich Chemical
Co.
C
14H21NO2S: C, 62.88; H, 7.91; N, 5.20. Found: C, 62.86; H,
7.81; N, 5.20.
(R)-2-Eth yl-N-[(4-m eth ylp h en yl)su lfon yl]a zir id in e (11b).
Prepared by the general procedure using MeLi (1.2 mmol, 1.05
mL of a 1.14 M solution in Et2O) to give 67 mg (60%) of 11b as
a colorless oil. Rf 0.21 (6% EtOAc in hexanes), [R]365 -7.9° (c
3.2, EtOAc), 1H NMR (CDCl3, 250 MHz), δ 7.82 (d, 2H, J ) 8.35),
7.33 (d, 2H, J ) 7.96), 2.69 (m, 1H), 2.61 (d, 1H, J ) 6.97), 2.44
(s, 3H), 2.07 (d, 1H, J ) 4.48), 1.6 (m, 1H), 1.35 (m, 1H), 0.83 (t,
3H, J ) 7.42). 13C NMR (CDCl3, 62.5 MHz) δ 144.3, 135.4, 129.5,
127.9, 41.6, 33.4, 24.4, 21.5, 10.6. Anal. Calcd for C11H15NO2S:
C, 58.63; H, 6.71; N, 6.21. Found: C, 58.56; H, 6.52; N, 6.21.
(R)-2-[2-(Tr im eth ylsilyl)eth yl]-N-[(4-m eth ylp h en yl)su l-
fon yl]a zir id in e (11c). Prepared by the general procedure
using [(trimethylsilyl)methyl]lithium (1.2 mmol, 1.53 mL of a
(19) Compound 9 was prepared by the method of Fujii et al.7 These
workers prepared the S enantiomer of 9 starting from (R)-serine. We
started from natural (S)-serine to prepare compound 9 which was
identical in all respects to the enantiomer reported in ref 7 except for
the optical rotation [R]D +29.9° (c 9.9, EtOAc), which was the opposite.
(20) Still, C. W.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 50, 2923.

2674 J . Org. Chem., Vol. 62, No. 8, 1997
Notes
0.78 M solution in pentane) to give 102 mg (69%) of 11c as a
colorless oil. Rf 0.27 (6% EtOAc in hexanes), [R]365 -32.7° (c
3.0, EtOAc), 1H NMR (CDCl3, 250 MHz), δ 7.78 (d, 2H, J ) 8.29),
7.28 (d, 2H, J ) 8.58), 2.69 (m, 1H), 2.55 (d, 1H, J ) 6.91), 2.39
(s, 3H), 2.01 (d, 1H, J ) 4.58), 1.39 (m, 2H), 0.36 (t, 2H, J )
8.67), -0.11 (s, 9H). 13C NMR (CDCl3, 62.5 MHz) δ 144.1, 135.3,
129.4, 127.9, 42.6, 33.7, 25.8, 21.4, 13.1, -2.1. Anal. Calcd for
at 0 °C. The reaction was allowed to stir for 4 h after which all
the solvent was removed by concentration under reduced pres-
sure to give a thick brown oil. Chromatography (10% EtOAc in
hexanes) gave 143 mg (88%) of 11a as a colorless oil. Analytical
data was identical to that reported for 11a prepared by reaction
of n-Bu
2CuLi with 10.
Meth yl O-(Tr ip h en ylm eth yl)-N-[(4-m eth ylp h en yl)su lfo-
n yl]-(S)-ser in a te (18). Et3N (6.2 mL, 45.0 mmol) was added
dropwise to a cold stirring suspension of methyl (S)-serinate
hydrochloride (3.1 g, 20.0 mmol) in CH2Cl2 (20 mL). The
suspension was stirred for 30 min at 0 °C. p-Toluensulfonyl
chloride (3.8 g, 20.0 mmol) was added to the reaction in small
portions over 10 min. After the addition was completed, the
reaction was warmed to rt and allowed to stir for 8 h. The
reaction was then cooled to 0 °C followed by a further addition
of triethylamine (4 mL, 28.0 mmol). Trityl chloride (11.1 g, 40.0
mmol) was then added to the reaction in small portions over 10
min, and the whole was stirred at rt for 10 h. The reaction was
then diluted with CH2Cl2 (40 mL) and washed successively with
1 M HCl, saturated NaHCO3 and brine, dried (MgSO4), and
concentrated. Chromatography (8% EtOAc in hexanes) provided
9.41 g (91%) of 18 as a white solid. [R]D +5.8° (c 7.9, EtOAc),
1H NMR (CDCl3, 250 MHz), δ 7.67 (d, 2H, J ) 8.30), 7.35 (m,
17H), 5.51 (d, 1H, J ) 9.18), 4.05 (m, 1H), 3.54 (s, 3H), 3.43 (dd,
1H, J ) 3.4 Hz, 9.06), 3.34 (dd, 1H, J ) 3.58, 9.07), 2.39 (s, 3H).
13C NMR (CDCl3, 62.5 MHz) δ 170.2, 143.4, 143.2, 137.2, 129.6,
128.5, 127.8, 127.2, 127.1, 86.8, 77.5, 77.0, 76.5, 64.6, 56.1, 52.4,
21.4. HRMS Calcd for C30H29NO5S 515.1767, found 515.1757.
C
14H23NO2SiS: C, 56.52; H, 7.79; N, 4.71. Found: C, 56.34; H,
7.98; N, 4.68.
(R)-2-Heptyl-N-[(4-m eth ylph en yl)su lfon yl]azir idin e (11d).
Prepared by the general procedure using n-hexyllithium (1.35
mmol, 0.75 mL of a 1.8 M solution in hexanes) to give 100 mg
1
(68%) of 11d as a colorless oil. [R]365 +23.8° (c 3.9, EtOAc), H
NMR (CDCl3, 270 MHz), δ 7.79 (d, 2H, J ) 8.29), 7.29 (d, 2H, J
) 8.07), 2.55 (m, 1H), 2.59 (d, 1H, J ) 6.97), 2.40 (s, 3H), 2.02
(d, 1H, J ) 4.48), 1.6-1.1 (m, 12H), 0.83 (t, 3H, J ) 6.68). 13C
NMR (CDCl3, 67.5 MHz) δ 144.3, 135.3, 129.5, 128.0, 40.4, 33.7,
31.6, 31.3, 29.0, 28.9, 26.7, 22.5, 21.5, 14.0. Anal. Calcd for
C
16H25NO2S: C, 65.04; H, 8.52; N, 4.74. Found: C, 64.87; H,
8.24; N, 4.74.
(R)-2-[7-(Tr im eth ylsilyl)h ept-5-en yl]-N-[(4-m eth ylph en yl)-
su lfon yl]a zir id in e (11e). t-BuLi (3.7 mmol, 4.16 mL of a 0.89
M solution in pentane) was added to a solution of 6-iodo-1-
(trimethylsilyl)-2-hexene14 (500 mg, 1.8 mmol) in Et2O (5 mL)
at -78 °C. The reaction was stirred at -78 °C for 10 min after
which it was warmed to rt and allowed to stir for 1 h. The
reaction was recooled to -78 °C, and a solution of CuI (119 mg,
0.63 mmol) and nBu3P (0.75 mL, 3.0 mmol) in Et2O (5 mL) was
added to the reaction via cannula. The reaction was warmed
to -40 °C for 10 min after which it was cooled to -78 °C and
allowed to stir for another 40 min. A solution of 10 (240 mg,
0.63 mmol) in THF:Et2O (1:1, 2 mL) was added to the cuprate
solution, and the reaction was stirred for another 60 min after
which it was quenched by the addition of saturated NH4Cl
solution at -78 °C. The aqueous solution was extracted with
EtOAc (2 × 5 mL), dried (MgSO4), and concentrated. Chroma-
tography (7% EtOAc in hexanes) gave 173 mg (75%) of 11e as a
colorless oil. Rf 0.26 (6% EtOAc in hexanes). [R]365 +34.0° (c
3.0, EtOAc). 1H NMR (CDCl3, 270 MHz), δ 7.79 (d, 2H, J )
8.28), 7.30 (d, 2H, J ) 8.51), 5.35 (m, 1H), 5.15 (m, 1H), 2.69
(m, 1H), 2.59 (d, 1H, J ) 6.98), 2.41 (s, 3H), 2.02 (d, 1H, J )
4.49), 1.85 (m, 2H), 1.39 (d, 2H, J ) 8.18), 1.6-1.1 (m, 6H), -0.03
(s, 9H). 13C NMR (CDCl3, 67.5 MHz) δ 144.3, 135.4, 129.5, 127.9,
127.0, 125.6, 40.3, 33.6, 31.2, 29.1, 26.7, 26.4, 21.5, 18.4, -1.8.
Anal. Calcd for C19H31NO2SiS: C, 62.42; H, 8.55; N, 3.83.
Found: C, 62.45; H, 8.51; N, 3.84.
O-(Tr ip h en ylm eth yl)-O-(ter t-Bu tyld im eth ylsilyl)-N-[(4-
m eth ylp h en yl)su lfon yl]-(S)-ser in ol (19). A solution of 18
(1.4 g, 2.7 mmol) in THF:EtOH (1:2, 12 mL) was treated with
anhydrous LiCl (340 mg, 8.1 mmol) followed by NaBH4 (300 mg,
8.1 mmol) at 0 °C. After the addition of all the NaBH4, the
reaction was warmed to rt and stirred for 6 h. The reaction was
quenched by addition of acetone (2 mL) followed by addition of
5% HCl until the reaction became clear. The solution was
extracted with Et2O (2 × 10 mL), dried (MgSO4), and concen-
trated. The crude oil was dissolved in CH2Cl2 (3 mL). DMAP
(30 mg, 0.27 mmol) and Et3N (0.64 mL, 4.6 mmol) were added
to the above solution, and the whole was cooled in an ice bath.
tert-Butyldimethylsilyl chloride (810 mg, 5.4 mmol) was added
to the cold solution, and the reaction was allowed to stir
overnight at rt. The mixture was then diluted with CH2Cl2 (5
mL), washed successively with 1 M HCl, saturated NaHCO3,
and brine, dried (MgSO4), and concentrated. Chromatography
(10% EtOAc in hexanes) provided 1.42 g (87%) of 19 as a white
1
Alter n ate P r epar ation of (R)-2-P en tyl-N-[(4-m eth ylph en -
yl)su lfon yl]a zir id in e (11a ). n-BuLi (1.21 mL of a 2.3 M
solution in hexanes, 2.8 mmol) was added to a suspension of
CuI (270 mg, 1.4 mmol) in THF (2.8 mL) at -40 °C. The bluish
black solution that was formed was allowed to stir at -40 °C
for 40 min. A solution of 87 in THF (1 mL) was added to the
cuprate solution, and the reaction was allowed to stir at -78 °C
for 60 min after which it was warmed to rt and stirred for
another 60 min. The reaction was quenched by the addition of
saturated NH4Cl solution (10 mL), and the aqueous layer was
extracted with EtOAc (2 × 10 mL). The organic layers were
combined, dried (MgSO4), and concentrated. Chromatography
(8% EtOAc in hexanes) gave 249 mg (86%) of 12 as a colorless
oil. 1H NMR (CDCl3, 250 MHz), δ 7.72 (d, 2H, J ) 8.31), 7.25
(d, 2H, J ) 8.15), 4.73 (d, 1H, J ) 8.29), 3.40 (dd, 1H, J ) 3.27,
9.96), 3.30 (dd, 1H, J ) 4.28, 9.95), 3.15 (m, 1 H) 1.63-1.08 (m,
8 H), 0.81 (s, 12H), -0.06 (s, 3H), -0.08 (s, 3H). 13C NMR (CDCl3,
62.5 MHz) δ 143.1, 138.6, 129.5, 127.1, 64.3, 55.1, 32.1, 31.5,
25.8, 25.2, 22.4, 21.4, 18.2, 13.8, -5.6. nBu4NF (0.8 mL of 1 M
solution in THF, 0.8 mmol) was added dropwise to an ice cold
solution of 12 (240 mg, 0.63 mmol) in THF (1.5 mL). The
solution was stirred for 1 h after which it was diluted with water
and extracted with EtOAc (2 × 5 mL). The layers were
separated, and the combined organic layers were dried (MgSO4)
and concentrated. Chromatography (3% MeOH in CHCl3) gave
180 mg (98%) of 13 as a colorless oil. 1H NMR (CDCl3, 250
MHz), δ 7.75 (d, 2H, J ) 8.18), 7.25 (d, 2H, J ) 8.36), 5.36 (m,
1H), 3.5 (m, 2H), 3.28 (m, 2H), 2.76 (m, 1 H), 2.37 (s, 3H), 1.36-
1.00 (m, 8 H), 0.73 (t, 3H, J ) 6.47). 13C NMR (CDCl3, 62.5
MHz) δ 143.3, 137.9, 129.6, 127.1, 64.8, 55.7, 31.6, 31.3, 25.1
22.3, 21.3, 13.7. Diethyl azodicarboxylate (120 mg, 0.70 mmol)
was slowly added to a stirred solution of 13 (180 mg, 0.63 mmol)
and triphenylphosphine (180 mg, 0.70 mmol) in THF (3.5 mL)
solid. [R]D +6.2° (c 3.4, EtOAc), H NMR (CDCl3, 250 MHz), δ
7.65 (d, 2H, J ) 8.27), 7.35 (m, 17H), 4.90 (d, 1H, J ) 7.61),
3.81 (dd, 1H, J ) 3.60, 9.88), 3.63 (dd, 1H, J ) 6.07, 9.86), 3.37
(m, 1H), 3.28 (dd, 1H, J ) 4.52, 8.95), 3.0 (dd, 1H, J ) 6.18,
8.97), 2.41 (s, 3H), 0.83 (s, 9H), 0.0 (d, 6H). 13C NMR (CDCl3,
62.5 MHz) δ 143.6, 143.0, 138.0, 129.5, 128.5, 127.7, 127.0, 126.9,
86.8, 62.1, 61.9, 54.6, 25.8, 21.4, 18.1, -5.6.
O-(ter t-Bu tyldim eth ylsilyl)-N-[(4-m eth ylph en yl)su lfon yl]-
(S)-ser in ol (20). A mixture of the protected diol 19 (250 mg,
0.41 mmol) and 250 mg of 20% Pd(OH)2/C in EtOAc (2 mL) was
hydrogenated at atmospheric pressure for 24 h. The reaction
mixture was then filtered through a bed of Celite and evapo-
rated. Chromatography (20% EtOAc in hexanes) gave 50 mg
(34%) of the detritylated product 20 as well as 106 mg of the
starting material 19 (43%). Analytical data was identical to that
reported in literature.7
(2S)-2-[[[(4-Met h ylp h en yl)su lfon yl]oxy]m et h yl]-1-[(4-
m eth ylp h en yl)su lfon yl]a zir id in e (22). Prepared on a 1.1
mmol scale using the same procedure for the conversion of 8 to
10. Analytical data was identical to that reported for 10 except
for [R]D -20.4° (c 3.0, EtOAc).
(S)-2-P en tyl-N-[(4-m eth ylp h en yl)su lfon yl]a zir id in e (23).
Prepared using the same procedure for the conversion of 10 to
11a . Analytical data was identical to that reported for 11a
except for [R]365 -16.6° (c 1.5, EtOAc).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 18 and 19 (4 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O962307F