Catalytic asymmetric aziridination with arylborate catalysts derived from VAPOL and VANOL ligands

Article abstract of DOI:10.1002/1521-3773(20001215)39:24<4518::AID-ANIE4518>3.0.CO;2-J

The asymmetric induction is essentially identical for a range of substrates when the VAPOL and VANOL (see picture; but not 1,1′-binaphth-2-ol (BINOL)) ligands were employed in asymmetric aziridinations catalyzed by triphenylborate (90-98% ee). The synthetic utility of these catalysts is illustrated in a synthesis of L-3,4-dihydroxyphenyl-alanine (L-DOPA).

Full text of DOI:10.1002/1521-3773(20001215)39:24<4518::AID-ANIE4518>3.0.CO;2-J

COMMUNICATIONS
structures of the Group 1 complexes of ;S)-[;Ph;Me)-
[3] R. Pi, W. Bauer, P. v. R. Schleyer, J. Organomet. Chem. 1986, 306, C1ꢁ
L. Lochmann, D. Lim, J. Organomet. Chem. 1971, 28, 153.
CH);PhCH )NH] reveal the amido ligand adopts a ªbutterfly
2
[
4] Alkyl/alkoxide: S. Harder, A. Streitweiser, Angew. Chem. 1993, 105,
108ꢁ Angew. Chem. Int. Ed. Engl. 1993, 32, 1066ꢁ M. Marsch, K.
in flightº configuration in which the phenyl groups are almost
perpendicular to each other,[8] and as such can be viewed as
having significant steric bulk with the charge concentrated on
1
Harms, L. Lochmann, G. Boche, Angew. Chem. 1990, 102, 334, Angew.
Chem. Int. Ed. Engl. 1990, 29, 308ꢁ amide/enolate: P. G. Williard, M. J.
Hintze, J. Am. Chem. Soc. 1990, 112, 8602ꢁ P. G. Williard, M. J. Hintze,
J. Am. Chem. Soc. 1987, 109, 5539ꢁ enolate/alkoxide: P. G. Williard,
G. J. MacEwan, J. Am. Chem. Soc. 1989, 111, 7 67 1.
À
the N ion. This is less likely to give stable mixed-anion
complexes, and can be contrasted to [{[PhN;H)] ;tBuO)Li-
2
NaK ´ ;tmen) } ] and [{;MeOPh)N;H)} ;tBuO)NaLi ], both of
2
2
2
2
[5] K. W. Henderson, D. S. Walther, P. G. Williard, J. Am. Chem. Soc.
1995, 117, 8680.
which are derived from primary amines.
[
[
[
6] F. M. Mackenzie, R. E. Mulvey, W. Clegg, L. Horsburgh, J. Am. Chem.
Soc. 1996, 118, 4721.
7] R. Holland, J. C. Jeffrey, C. A. Russell, J. Chem. Soc. Dalton Trans.
1999, 3331.
8] P. C. Andrews, P. J. Duggan, G. D. Fallon, T. D. McCarthy, A. C. Peatt,
J. Chem. Soc. Dalton Trans. 2000, 1937.
Experimental Section
1
: ;S)-a-;Ph;Me)CH);PhCH
a chilled ;À788C) suspension of tBuOK ;15mmol, 1.55 g) in hexane
20 mL). nBuLi ;5.5 mmol, 3.2 mL, 1.6m in hexane) was added dropwise
2
)NH ;5 mmol, 1.05 g) was added dropwise to
[9] P. C. Andrews, D. R. Armstrong, D. R. Baker, R. E. Mulvey, W. Clegg,
L. Horsburgh, P. A. OꢂNeill, D. Reed, Organometallics 1995, 14, 427ꢁ
P. C. Andrews, D. R. Armstrong, R. E. Mulvey, D. Reed, J. Organo-
met. Chem. 1990, 386, 287ꢁ P. C. Andrews, D. R. Armstrong, R. E.
Mulvey, D. Reed, J. Am. Chem. Soc. 1988, 110, 5235.
[10] The reaction in the absence of tmen has only given, thus far, a
microcrystalline solid, which according to NMR spectroscopy appears
to be a mixture. All three possible anions are present: tBuO, amide,
and aza-allyl.
;
resulting in the formation of a bright red suspension. The reaction mixture
was stirred and allowed to warm to room temperature over 2 h during
which time the suspension darkened to a deeper red. Hexane was removed
in vacuo and THF added ;ca. 20 mL) which with gentle warming allowed
complete dissolution. The ligand tmen ;10 mmol, 1.51 mL) was added, then
the solvent was reduced in vacuo by approximately a third and the mixture
was placed in the freezer at À208C overnight. This resulted in a crop of red
needlelike crystals which were isolated and then washed with hexane. Yield
[11] D. Hoffmann, W. Bauer, F. Hampel, N. J. R. van Eikema Hommes,
P. von R. Schleyer, P. Otto, U. Pieper, D. Stalke, D. S. Wright, R.
Snaith, J. Am. Chem. Soc. 1994, 116, 528.
5
7% ;1.7g). M.p. 131 ± 132 8Cꢁ elemental analysis C31
H
48NK
3
O
4
;%)ꢁ calcd:
1
C 60.5, H 7.8, N 2.3ꢁ found: C 61.1, H 7.5, N 2.1ꢁ H NMR ;[D
8
]THF, 258C,
3
00 MHz): d ˆ 7.21 ;d, J ˆ 7.9 Hz, 2Hꢁ o-H), 6.90 ;brs, 2Hꢁ o-H), 6.81 ;t,
[12] P. C. Andrews, D. R. Armstrong, W. Clegg, F. J. Craig, L. Dunbar,
R. E. Mulvey, Chem. Commun. 1997, 319.
J ˆ 7.7 Hz, 2Hꢁm-H), 6.72 ;t, J ˆ 7.6 Hz, 2Hꢁm-H), 6.19 ;m, 2H, pꢁ PhCH),
6
4
1
.06 ;t, J ˆ 7.1 Hz, 1Hꢁp-H), 3.57;m, 4Hꢁ THF), 1.89 ;s, 3Hꢁ Me), 1.73 ;m,
13
Hꢁ THF), 0.96 ;s, 18Hꢁ tBu)ꢁ C NMR ;[D
8
]THF, 258C, 75.5 MHz): d ˆ
46.33 ;qC), 145.78 ;qC), 129.14 ;oC), 129.09 ;oC), 129.00 ;oC), 128.70
;
;
mC), 127.35 ;mC), 127.32 ;mC), 119.16 ;PhCH), 115.81 ;pC), 114.41
PhCMe), 105.75 ;pC), 37.5 ;tBu), 12.35 ;Me).
Crystallographic data for 1: Data collected on an Enraf Nonius Kappa
CCD at 123 K. Crystal mounted under oil. C31 , M
ˆ 615.01,
monoclinic, space group P2 /c ;no. 14), red acicular crystal measuring
H
48NK
3
O
4
r
Catalytic Asymmetric Aziridination with
Arylborate Catalysts Derived from VAPOL
and VANOL Ligands**
1
0
.30  0.24  0.10 mm, a ˆ 10.7096;5), b ˆ 16.4210;8), c ˆ 19.8427;9) Š,
À3
b ˆ 91.875;2)8, Vˆ 3487.7;2) Š3, Z ˆ 4,
1
calcd ˆ 1.171 gcm
,
l;MoKa) ˆ
À1
0
3
.71073 Š, m;MoKa) ˆ 4.23 cm , 42594 reflections measured, 8661 unique,
936 were observed ;I > 3.00s;I)), R ˆ 0.043, R
w
ˆ 0.051, GoF 1.30. The
Jon C. Antilla and William D. Wulff*
structure was solved by direct methods with all H atoms placed in idealized
positions ;rˆ 0.95 Š). The aza-allylic anion is disordered in the crystal, as
indicated by the occupancy of Me on C1 and C8 of 50:50. Crystallographic
data ;excluding structure factors) for the structure reported in this paper
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-147738. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB21EZ, UK ;fax: ;‡44)1223-336-033ꢁ e-mail: deposit@
ccdc.cam.ac.uk).
The ring opening of chiral aziridines is a potent method for
the synthesis of optically active amines.[ The driving force of
this process derives from the ring strain of the aziridine and
this can be used to extend the ring opening to a variety of
nucleophiles to produce difuncational amines with vicinal
chiral centers. Since no general method for catalytic asym-
metric aziridination exists,[ chiral aziridines have been
largely made from materials in which the chiral centers
already exist.[ Given the synthetic and strategic advantages
of asymmetric catalysis we began a program to find a chiral
catalyst for asymmetric aziridination, and recently reported
1]
2]
Received: August 10, 2000 [Z15620]
1d]
[
1] Reviews: L. Lochmann, Eur. J. Inorg. Chem. 2000, 1115 ± 1126ꢁ W.
Bauer, L. Lochmann, J. Am. Chem. Soc. 1992, 114, 7482ꢁ A. Mordini in
Advances in Carbanion Chemistry, Vol. 1 ;Ed.: V. Snieckus), JAI,
London, 1992, p. 1. Recent examples in synthesis: S. Choppin, P. Gros,
Y. Fort, Org. Lett. 2000, 2, 803ꢁ P. B. Tivoli, A. Deagostino, C.
Fenoglio, M. Mella, C. Prandi, P. Venturello, Eur. J. Org. Chem. 1999,
[
*] Prof. W. D. Wulff, J. C. Antilla
Department of Chemistry
Michigan State University
East Lansing, MI 48824
2
143ꢁ M. Schlosser, M. Kotthaus, Eur. J. Org. Chem. 1999, 459ꢁ M.
Schlosser, H. Geneste, Chem. Eur. J. 1998, 4, 1969ꢁ M. Schlosser, F.
Mongin, J. Porwisiak, W. Dmowski, H. H. Buker, N. M. M. Nibbering,
Chem. Eur. J. 1998, 4, 1281.
Fax : ;‡1)517-353-1793
E-mail: wulff@cem.msu.edu
[
2] R. E. Mulvey, Chem. Soc. Rev. 1998, 27, 339ꢁ R. S. Snaith, D. S. Wright
in Lithium Chemistry; A Theoretical and Experimental Overview
[
**] This work was supported by the National Institutes of Health and was
performed at the University of Chicago. VAPOL ˆ 2,2'-diphenyl-[3,3'-
biphenanthrene]-4,4'-diol, VANOL ˆ 3,3'-diphenyl-[2,2'-binaphtha-
lene]-1,1'-diol.
;
Eds.: A.-M. Sapse, P. von R. Schleyer), Wiley, New York, 1995,
Chap. 8, p. 227ꢁ L. Lochmann, J. Trekoval, J. Organomet. Chem. 1979,
179, 123ꢁ L. Lochmann, R. L. De, J. Trekoval, J. Organomet. Chem.
1978, 156, 307ꢁ L. Lochmann, J. Trekoval, J. Organomet. Chem. 1975,
99, 123.
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/angewandte/ or from the author.
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COMMUNICATIONS
the first catalyst that is generally applicable for a
range of substrates.[ This methodology involves
the addition of ethyl diazoacetate ;EDA) to
imines mediated by a catalyst prepared from the
3]
[4]
VAPOL ligand and the BH ´ THF complex. We
3
have since found that the success of the reaction is
dependent on the purity of the BH ´ THF com-
3
plex used to generate the catalyst. This observa-
tion led to the present report of the development
of a catalyst that is not only more reliable, but
which can be extended to previously unreactive
substrates, gives increased chemical yields, and
greatly increased diastereoselectivity while main-
taining high asymmetric inductions. It was also
found that the vaulted biaryl ligand VANOL[
is equally effective for this process whereas the
4c, 5]
1
,1'-binaphth-2-ol ;BINOL) ligand fails to give
Scheme 1. Synthesis of aziridine 3a and the catalyst 9. MX
3
ˆ triphenylborate.
significant asymmetric induction.
A catalyst prepared from VAPOL and a sample
of BH ´ THF that is greater than 98% pure gives
3
the aziridine 3a in 89% ee from the addition of ethyl
diazoacetate to the imine 1a. However, batches of BH3 ´
THF that are not so pure can lead to a catalyst with a much
improved profile: up to 98% ee, d.r. ꢀ 50:1, and improved
yields as well as a significantly reduced level of side products
triphenylborate, which gave an 81% yield of 3a in 95% ee
and with a d.r. ꢀ 50:1 in favor of the cis isomer.
A comparison of catalysts prepared from triphenylborate
and the biaryl ligands BINOL, VANOL, and VAPOL was
undertaken. The BINOL-derived catalyst gave very low
induction ;20% ee) for the addition of ethyl diazoacetate to
the imine 1a ;Table 1, entry 11) as well as significantly
reduced cis/trans selection and an increased proportion of
the noncyclized products 4 and 5. In contrast, the catalysts
prepared from the VANOL and VAPOL ligands and triphe-
nylborate were found to be essentially equally effective with
remarkably small variation between the two catalysts for all of
the substrates ;Table 2). In all other reactions that we have
previously examined the VANOL and VAPOL ligands have
always led to disparate levels of induction.[ In the present
case, the asymmetric inductions track nearly identically with
each substrate and only small differences are seen. For some
reactions slightly higher inductions were observed with the
VANOL catalyst while for others the higher induction was
;
Scheme 1). One of the impurities that we identified in the
commercially available samples of BH ´ THF, especially in
3
aged ones, was tributylborate. This observation prompted a
study of catalysts prepared from the VAPOL ligand and a
variety of borate esters, and the results are given in Table 1.
Indeed, it was found that a catalyst prepared from tributyl-
borate gave results nearly identical with the best observed
with impure BH ´ THF. Lower asymmetric induction was
3
seen with trimethyl- and triethylborate while higher induction
was seen with triisopropylborate, although the rate was much
slower with the latter. The performance of aluminum and
gallium ethoxides were far inferior to any of the borate esters,
and in the case of aluminum this may be attributed to poor
solubility. The optimal catalyst was that prepared from
4]
[
a]
Table 1. Asymmetric aziridination of imine 1a ;R ˆ Ph) with catalysts 9.
Entry
Metal complex
Catalyst
t [h]
Conver-
sion[
Yield of
cis-3a [%]
ee of
cis 3a [%]
cis:trans
of 3a
Yield of
4a [%]
Yield of
5a [%]
b]
[c]
[d]
[e]
[f]
[f]
g]
1
2
3
4
5
6
BH
BH
B;OnBu)
B;OnBu)
B;OiPr)
B;OMe)
3
3
´ THF
´ THF
9a[
9a[
9b[
9b
9c[
9d
9e
9 f
20
3
10
2
92
20
20
20
20
1
100
100
100
100
41
92
6751
16
53
58
72
71
20
74
92
±
89
91
96
96
97
91
26:1
21:1
44:1
> 50:1
> 50:1
35:1
3.2
5:1
7:1
> 50:1
17:1
11.1
15
3
6.3
5.3
2.4
5.0
1.0
2.5
g, h]
i]
3
[i, j]
3
4.8
1.3
3.6
2.3
6.0
16.2
4.3
12.6
k]
3
3
7
8
9
0
1
B;OEt)
3
30:1
Al;OEt)
Ga;OEt)
B;OPh)
B;OPh)
3
±
3
9g
9h
84
100
100
29
81
61
30
95
20
12.3
1.4
9.0
1
1
3
9h[
l]
3
3
[
a] Unless otherwise specified, all reactions were run in dichloromethane ;0.5m in the imine) with 0.1 mmol of ;S)-VAPOL at 228C with 1.1 equiv of ethyl
1
diazoacetate with respect to 1a and 10 mol% of the catalyst. [b] Determined by H NMR spectroscopy. [c] Isolated after puriifcation by chromatography on
silica gel. [d] Determined by HPLC on a Chiralcel OD-H column. [e] Ratio calculated by integration of the methine protons from the cis- and trans-
1
aziridines. [f] Determined by H NMR spectroscopy of the crude reaction mixture by integration of the signals relative to those of cis-3a. [g] BH
3
´ THF
Cl ) to
a solution of the catalyst and ethyl diazoacetate over 1 h and with stirring for an additional 1 h. [k] Catalyst prepared from 1 equiv of borate and 1 equiv of
S)-VAPOL. [l] ;S)-BINOL was used as the ligand to give 3a with the same configuration as ;S)-VAPOL.
contained less than 2% B;OnBu)
3
. [h] Catalyst prepared at 08C for 24 h. [i] 5 mol% of the catalyst. [j] Syringe pump addition of imine ;in 1 mL of CH
2
2
;
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Table 2. Asymmetric aziridination with VAPOL and VANOL catalysts prepared from B;OPh)
3
.[a]
Entry
Imine
R
Ligand
t [h]
Yield of
cis-3 [%][
ee of
cis-3 [%]
cis-:trans-3[d]
Yield of
4 [%]
Yield of
5 [%]
b]
[c]
[e]
[e]
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
1a
1b
1c
1d
Ph
;S)-VAPOL
;S)-VANOL
;S)-VAPOL
;S)-VANOL
;S)-VAPOL
;S)-VANOL
;R)-VAPOL
;S)-VANOL
;R)-VANOL
;S)-VAPOL
;S)-VAPOL
;S)-VANOL
;S)-VAPOL
;S)-VANOL
;S)-VAPOL
48
0.5
5
77[f]
85
95
96
98
98
94
91
96
97
93
> 50:1
> 50:1
> 50:1
> 50:1
40:1
> 50:1
> 50:1
> 50:1
> 50:1
> 50:1
> 50:1
> 50:1
40:1
4.4
3.3
3.4
8
11.1
6
< 1
< 1
< 1
3.8
1.7
1.0
2.2
3
7.1
4
< 1
< 1
< 1
0.3
9.2
91[
85
g]
p-BrC
6
H
4
1
o-MeC
6
H
4
14
16
20
5
16
12
20
5
69
65
85[
83
f, h]
3,4-;OAc)
2-furyl
1-naphthyl
n-propyl
2
6 3
C H
55[
8792
54[
60
i]
1e
1 f
1g
1
1
1
1
1
1
j]
91
90
91
97
94
8.3
6.79.2
< 1
< 1
< 1
1h
1i
tert-butyl
12
5
8
78
77[
74
< 1
< 1
< 1
k]
> 50:1
38:1
c-C
6
H
11
[
a] Unless otherwise specified, all reactions were run in dichloromethane containing 0.5m imine at 228C with 1.1 equiv of ethyl diazoacetate with respect to
imine 1a and 10 mol% of the catalyst. [b] Isolated after puriifcation by chromatography on silica gel. [c] Determined by HPLC on a Chiralcel OD-H column.
1
[
d] Ratio calculated by integration of the methine protons from cis- and trans-aziridines. [e] Determined by H NMR spectroscopy of the crude reaction
mixture by integration of the signals relative to those of cis-3. [f] Reaction with 2 mol% of the catalyst ;entry 1) or 2.5 mol% ;entry 7) and 1.0m of the imine.
[
[
g] Reaction in toluene:dichloromethane ;1:1). [h] Reaction was run at 08C for 4 h and then 16 h at 228C. [i] Reaction conditions: toluene, 08C for 16 h.
j] Reaction conditions: toluene, 08C for 4 h, then 228C for 16 h. [k] Reaction conditions: toluene, 08C for 4 h, then 228C for 1 h.
observed with the VAPOL catalyst. What is remarkable is
that for both ligands and for all substrates the asymmetric
induction for all combinations falls in the range of 90 ±
98% ee. The chemical yields of 3 for each catalyst are similar
and both are generally higher that the yields observed with the
BH ´ THF complex. The reaction times indicated in Table 2
3
are not indicative of rate since the times were not optimized
and in some cases different catalyst loadings were employed.
The diastereoselectivites are very high for both catalysts but
the VANOL catalyst gave a selectivity of greater than 50:1 for
every substrate. The diastereoselectivity is one of the greatest
differences between the catalysts generated from triphenyl-
borate and the BH ´ THF complex. For example, the cis:trans
3
selectivity for the imine 1c derived from ortho-methylbenzal-
dehyde was 3:1 for the catalyst prepared from VAPOL and
[3]
the BH ´ THF complex, while it was 40:1 with the corre-
3
Scheme 2. Synthesis of l-DOPA.
sponding catalyst derived from the triphenylborate catalyst.
Another dramatic difference is that the imines prepared from
pivaldehyde and 1-naphthylaldehyde are unreactive with the
benzylic bond occurred with cleavage of the benzhydral group
to give the amino ester 10 in 72% yield. After hydrolysis of
the three ester linkages l-DOPA was obtained in 60% yield
catalyst prepared from VAPOL and BH ´ THF, whereas these
3
substrates react with similar rates using the triphenylborate
catalyst to give asymmetric inductions and chemical yields
similar to those observed for the other substrates. Finally, the
rates of the reaction could not be increased by the slow
addition of the imine with the VAPOL ± borate catalyst as was
found to be the case with the VAPOL ± borane catalyst.[
An application of the VAPOL ± triphenylborate catalyst in
the synthesis of l-3,4-dihydroxyphenylalanine ;l-DOPA) is
illustrated in Scheme 2. The reaction of imine 1d with ethyl
diazoacetate in the presence of 2.5 mol% of the catalyst
derived from ;R)-VAPOL and triphenylborate led to the
formation of the aziridine 3d in 85% yield and in 96% ee on a
multigram scale. The optical purity could be improved to
greater than 99% ee with a single crystallization of the
product from hexane:dichloromethane ;10:1ꢁ the first crop
gave 85% recovery).[ Hydrogenation of the nitrogen ±
with an optical rotation of [a] ˆ À8.08. This rotation
D
corresponds to 98% ee, and thus very little if any epimeriza-
tion occurred during the hydrolysis.[
7]
Further studies on the mechanism, scope, and synthetic
applications of this asymmetric catalytic aziridination reaction
will be reported in due course.
3]
Experimental Section
3d: ;R)-VAPOL ;174 mg, 0.323 mmol) was added to a flame-dried flask
cooled under argon and then dissolved in CH Cl ;6 mL). After the
2 2
addition of triphenylborate ;281 mg, 0.969 mmol) the mixture was heated
to 558C for 1 h and then a vacuum ;0.5 mm Hg) was applied for 30 min with
the temperature maintained at 558C. The catalyst was dissolved in CH
3.0 mL) and transferred by syringe to a 50-mL flame-dried flask which was
previously charged with a stirring bar and filled with argon. A solution of
2 2
Cl
;
6]
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imine 3d ;5.00 g, 12.9 mmol) in CH
the catalyst solution at 08C. Stirring the mixture for 10 min gave an orange
solution to which was rapidly added ethyl diazoacetate ;1.484 mL,
2
Cl
2
;10 mL) was added by syringe to
[3] J. C. Antilla, W. D. Wulff, J. Am. Chem. Soc. 1999, 121, 5099.
[4] For other applications of the VAPOL ligand, see a) J. Bao, W. D. Wulff,
A. L. Rheingold, J. Am. Chem. Soc. 1993, 115, 3814ꢁ b) J. Bao, W. D.
Wulff, Tetrahedron Lett. 1995, 36, 3321ꢁ c) J. Bao, W. D. Wulff, J. B.
Dominy, M. J. Fumo, E. B. Grant, A. C. Rob, M. C. Whitcomb, S.-M.
Yeung, R. L. Ostrander, A. L. Rheingold, J. Am. Chem. Soc. 1996, 118,
3392ꢁ d) D. P. Heller, D. R. Goldberg, W. D. Wulff, J. Am. Chem. Soc.
1997, 119, 10551.
1
4.2 mmol) by syringe. Some bubbling was noted after the addition. The
reaction was allowed to proceed for 6 h at 08C and then for 14 h at room
temperature ;228C). The reaction mixture was transferred to a 500-mL
flask, diluted with hexanes ;250 mL), and then the volatiles were removed
under vacuum to give the crude aziridine 3d as an off-white solid. The
1
H NMR spectrum of this material revealed 3d with cis:trans ꢀ 50:1 and
[5] The VANOL ligand was prepared according to the same procedure that
has been reported for the VAPOL ligand.[
4c]
indicated that <1% of 4d and 5d were formed. Purification of 3d by
column chromatography on silica gel with a mixture of ethyl acetate:hex-
anes ;3:7) gave aziridine 3d ;5.20 g, 11 mmol) as a white solid in 85% yield.
The optical purity of this material was determined to be 96% ee by HPLC
[6] A second crop was taken but had only approximately 90% ee.
[7] The optical rotation of an authentic sample of l-DOPAwas found to be
[a]
D
ˆ À8.28.
analysis ;OD-H column). Crystallization from hexanes:CH
2 2
Cl ;10:1,
3
00 mL) gave 3d ;4.43 g) with 99% ee. A second crop was taken but
found to be only 90% ee. Spectral data for 3d: m.p. 141 ± 1438C ;hex-
1
anes:CH
;
1
;
2
Cl
2
)ꢁ H NMR ;400 MHz, CDCl
3
): d ˆ 0.99 ;t, J ˆ 7Hz, 3H), 2.24
s, 3H), 2.25 ;s, 3H), 2.68 ;d, J ˆ 7Hz, 1H), 3.18 ;d, J ˆ 7Hz, 1H), 3.95 ;s,
H), 3.95 ;m, 2H), 7.07 ;d,J ˆ 9 Hz, 1H), 7.19 ;m, 1H), 7.28 ;m, 7 H), 7.45
13
d, J ˆ 7Hz, 2H), 7. 81 ;d, J ˆ 7Hz, 2H). C NMR ;100.6 MHz, CDCl
3
):
d ˆ 13.84, 20.64, 46.57, 47.03, 60.89, 77.49, 122.75, 122.78, 126.05, 127.18,
1
1
1
1
27.30, 127.45, 127.61, 128.55, 128.65, 133.97, 141.35, 141.57, 142.21, 167.45
68.07, 168.24ꢁ IR ;thin film) 3030 ;w), 2980 ;w), 1770 ;s), 1731 ;s),
Stereoselective Synthesis of R - and
P
À1
SP-Dithymidine Phosphorothioates via Chiral
600 cm ;m)ꢁ MS ;EI): m/z ;relative intensity): 474 ;21) [M‡1], 306 ;12),
6
95 ;10), 167;100)ꢁ m/z calcd for C28H27NO : 474.1903, found 474.1903.
Indolooxazaphosphorine Intermediates
Elemental analysis calcd for C28
H
27NO
6
: C 71.02, H 5.75, N 2.96ꢁ found: C
Cl ) taken on 99% ee
**
Derived from Tryptophan
1.23, H 5.88, N 2.94. [a]2
3
ˆ À17.38, ;C ˆ 1 from CH
7
D
2
2
material ;HPLC). Further experimental details can be found in the
Supporting Information.
Yixin Lu and George Just*
The use of phosphorothioates as DNA analogues useful in
antisense-based therapy is well established[ and led to the
development of Vitravene as the first antisense drug.[
Several other phosphorothioate oligonucleotides ;PS-Oligos)
are in clinical trials. Although Stec et al. described an elegant
Received: August 9, 2000 [Z15611]
1]
2]
[
1] a) D. Tanner, Angew. Chem. 1994, 106, 625ꢁ Angew. Chem. Int. Ed.
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Comprehensive Heterocyclic Chemistry II, Vol. 1A ;Ed.: A. Padwa),
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hensive Heterocyclic Chemistry II, Vol. 1A ;Ed.: A. Padwa), Pergamon,
Oxford, 1996, p. 61ꢁ d) J. Sweeney, H. M. I. Osborn, Tetrahedron:
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2] For previous work on catalytic asymmetric aziridinations, see a) D. A.
Evans, K. A. Woerpel, M. M. Hinman, M. M. Faul, J. Am. Chem. Soc.
[3]
oxathiaphospholane-based approach for preparing diaster-
eomerically pure phosphorothioates, it has not been used for
large-scale production of PS-Oligos, which are still used as a
6
mixture of about 10 diastereomers. The use of cyclic N-
[
acylphosphoramidites as promising monomers for the stereo-
controlled synthesis of phosphorothioates was recently re-
ported by Beaucage et al.[
1
1
1
991, 113, 726ꢁ b) R. E. Lowenthal, S. Masamune, Tetrahedron Lett.
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4]
[5]
Previously, we developed cyclic phosphoramidites such as
sugar-derived oxazaphosphorinanes,[
5b,c]
indolooxazaphos-
phorines ;a),[
5e, f]
and indoleimidazoles for the stereoselec-
[5i]
tive synthesis of PS-Oligos. Here we report on the use of
promising indolooxazaphosphorine precursors derived from
tryptophan which do not require a difficult chromatographic
separation and may form the basis of a practical process.
As demonstrated in the indolooxazaphosphorine ap-
proach,[ chiral auxiliary a led to the stereoselective synthesis
of phosphorothioate in solution. When it was applied to solid-
phase synthesis, a b-elimination caused rearrangement to give
1
1
9
1
5f]
[
*] Prof. Dr. G. Just, Dr. Y. Lu
Department of Chemistry
McGill University
8
368ꢁ q) L. Casarrubios, J. A. Perez, M. Brookhart, J. L. Templeton, J.
Org. Chem. 1996, 61, 8358ꢁ r) H.-J. Ha, K.-H. Kang, J.-M. Suh, Y.-G.
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Jorgensen, J. Chem. Soc. Perkin Trans. 1 1997, 1287ꢁ t) C. Langham, P.
Piaggio, D. Bethell, D. F. Lee, P. McMorn, P. C. Bulman Page, D. J.
Willock, C. Sly, F. E. Hancock, F. King, G. J. Hutchings, J. Chem. Soc.
Chem. Commun. 1998, 1601ꢁ u) S. Minakata, T. Andl, M. Nishimura, I.
Ryu, M. Komatsu, Angew. Chem. 1998, 110, 3596ꢁ Angew. Chem. Int.
Ed. 1998, 37, 3392ꢁ v) P. Müller, C. Baud, Y. Jacquier, Can. J. Chem.
Montreal, PQ, H3A 2K6 ;Canada)
Fax : ;‡1)514-398-3797
E-mail: just@chemistry.mcgill.ca
[
**] This work was financially supported by Natural Science and Engineer-
ing Research Council of Canada ;NSERC). We thank Nadim Saadeh
and Dr. Orval Mamer, McGill University biomedical mass spectro-
scopy unit, for recording mass spectra.
1
998, 76, 738ꢁ w) S. K. Bertilsson, L. Tedenborg, D. A. Alonso, P. G.
Andersson, Organometallics 1999, 18, 1281ꢁ x) K. Juhl, R. G. Hazell,
K. A. Jorgensen, J. Chem. Soc. Perkin Trans. 1 1999, 2293.
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/angewandte/ or from the author.
Angew. Chem. Int. Ed. 2000, 39, No. 24
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
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