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meso Epoxides in Asymmetric Synthesis Enantioselective Opening by Nucleophiles in the Presence of Chiral Lewis Acids.

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meso Epoxides in Asymmetric Synthesis:
Enantioselective Opening by Nucleophiles in the Presence of Chiral Lewis Acids
By Ian Paterson* and David J. Berrisford
It is over a decade since the seminal discovery"] of the
asymmetric epoxidation of allylic alcohols catalyzed by titanium(1v) isopropoxide and tartrate esters. The utility of this
transformation is a result of many factors, not least of which
is the regio- and stereocontrol possible in the subsequent
nucleophilic substitution (opening) reactions of the derived
epoxy alcohols. Thus a reaction sequence of asymmetric
epoxidation, epoxide opening, and further functionalization
allows access to an impressive array of target molecules in
enantiomerically pure form. In contrast to the asymmetric
epoxidation, the enantioselective epoxidation of nonfunctionalized alkenes['] is only just emerging as a viable synthetic method. At present, the substrates are limited to certain cis
alkenes. A less common strategy, but one with considerable
merit, is the enantioselective opening[31of meso epoxides by
achiral nucleophiles in the presence of chiral Lewis acids
(Scheme 1 for R' = R'). The metal center of the Lewis acid
Enantioselective opening of meso epoxides by heteroatom
nucleophiles has been investigated previously. Some examples are shown in Scheme 3. Zinc tartrate (10 mol%) promotes the opening of simple epoxides with n-butyl thiol and
aniline with good enantio~electivity.~~]
Copper tartrate is
more efficient than zinc tartrate in promoting the reaction of
trimethylsilyl azide with ep~xides.'~]
Diisopinocampheylboron halides also display[61promising asymmetric induction in their reactions with epoxides to give P-halohydrins.
The reagents, derived from either (+) or (-)-a-pinene, are
used in stoichiometric quantities at very low temperatures.
In certain cases, recrystallization leads to enantiomerially
pure product. The combination of various ligands with titanium alkoxides has been e ~ p l o r e d ~ ' .with
~ ] trimethylsilyl
azide for epoxide opening. A recent refinement[81is the combination of TiCl,(OzFr), with the sterically demanding ditert-butyl tartrate. In the presence of trimethylsilyl azide and
10 mol YOof the titanium catalyst, cyclohexene oxide gives
the corresponding P-azido cyclohexanol with 62 Yo ee.
Zn tartrate
85% ee (82%)'5'
Scheme 1. Enantioselective opening of m e m epoxides (R'
= R2)
catalyst or reagent should be able to complex the epoxide
oxygen atom, and the ligand environment should allow the
discrimination of the formally enantiotopic carbon-oxygen
bonds of the epoxide by an appropriate achiral nucleophile.
Such a process leads to an enantioselective epoxide-opening
reaction. The discrimination of enantiotopic groups[3] remains relatively rare in nonenzymic asymmetric reactions.
Scheme 2 shows some examples[41of the discrimination attainable without a nucleophile-using chiral lithium amide
bases in the rearrangements of meso epoxides to allylic alcohols.
Scheme 2. P = SirBuMe,.
[*] Dr. I. Paterson, Dr. D. J. Berrisford
University Chemical Laboratory
Lensfield Road, GB-Cambridge CB2 1EW (UK)
Angew. Chem. In[. Ed. Engl. 1992, 31, N o . 9
1. TMSN3
62% ee (65%)18'
2. H*
Scheme 3. TMS
trimethylsilyl; Ipc = isopinocamphenyl; DTBT = di-tert-
The methodology describedIglrecently by W A. Nugent at
DuPont is a major advance in this area (Scheme 4). A novel
chiral zirconium Lewis acid promotes the reaction of trialkylsilyl azide with a range of meso epoxides to give the
corresponding P-azido alcohols in excellent enantiomeric excess. The catalyst is derived from zirconium tert-butoxide
and the tetradentate C,-symmetric ligand 1. This ligand is
readily available from commercial (albeit expensive) starting
materials-(S)-propene oxide and (S)-1-aminopropan-2ol-with
a high diastereomeric excess. Other epoxide/
aminoalcohol combinations may also be useful for the
preparation of other ligands with C , symmetry. In this way
the reaction can be optimized for each substrate. Furthermore, 1 is one of the few C,-symmetric ligands["- ''] that
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have been designed, synthesized, and successfully employed
in asymmetric catalysis. Other reactions[g1may be amenable
to catalysis by metal complexes with these or related chiral
ligands. The reaction of 1 with Zr(OtBu), at room temperature affords complex 2 with the loss of three equivalents of
tert-butanol. Controlled addition of water to 2 in THF affords complex 3 which may be isolated. The analyses show
that this complex contains 0.5 equivalents of tert-butanol
per equivalent of zirconium. The spectroscopic properties of
3 are complex, and the precise mechanistic details of the
catalysis will therefore be difficult to determine. The relative
rates of the reactions mediated by the precursor zirconium
alkoxide and the new chiral complexes such as 3 have not
been reported. It will be interesting to note the rate differences between the titanium and zirconium complexes with
identical ligands and to investigate the effect of the ligand
structure on the rate as well as the enantioselectivity.
lack of reactivity with highly hindered epoxides such as
cyclooctene oxide. New developments are anticipated with
the use of other nucleophiles, for example, trimethylsilyl
The work of W. A. Nugent addresses one of the major
classes of epoxides-symmetrically substituted cis epoxides.
However, kinetic resolution['21 of racemic trans epoxides
may also be possible. One of the challenges stemming from
the discovery of the asymmetric catalytic epoxidation of
nonfunctionalized alkenes is the problem of regiocontrol in
the opening of unsymmetrically substituted epoxides. Here
too, the opening of epoxides mediated by chiral Lewis acids
may be useful in discriminating between the "pseudoenantiotopic" (actually diastereotopic) carbon-oxygen bonds
(Scheme 1 for R' R2) when there is little, if any, substrate
control during epoxide opening.
The Nugent reaction, just as the Sharpless asymmetric
epoxidation,"] utilizes an early transition metal alkoxide as
the catalyst precursor. This is further proof, if any is required, of the rewards of searching for new reactivity in this
area of the periodic table.
German version: Angew. Chem. 1992, 104, 1204
93% ee (86%)
I \
8% ee (79%)
8896 ee (78%)
87% ee (59%)
83% ee(6496)
2 lLZrOtBu1,
Scheme 4. Synthetic applications of zirconium complex 3. All reactions were
performed in CH,CI, at 0 "C or room temperature (48 h) with 1.04 equivalents
of trialkylsilyl azide/2 mol% CF,CO,SiMe,/X mol% 3.
The reaction is carried out by combining 3 (8 mol YO),
trimethylsilyl trifluoroacetate (2 mol YO),and a trialkylsilyl
azide with the epoxide substrate. The ee values of the 8-azido
alcohols produced are dependent on the bulk of the nucleophilic azide with isopropyldimethylsilyl azide being superior
to trimethylsilyl azide. The trimethylsilyl trifluoroacetate is
essential for the enantioselectivity. The reaction is simple to
carry out, proceeds at either room temperature or 0 "C, and
affords excellent yields. Thus the method offers an expeditious route to threo amino alcohols. One limitation is the
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[I] T. Katsuki, K. B. Sharpless. J. Am. Chem. Soc. 1980, 102, 5974; R . M.
Hanson, K. B. Sharpless, J. Org. Chem. 1986, 51, 1922; S. S. Woodard,
M. G. Finn, K. B. Sharpless, J. Am. Chem. Soc. 1991, 113, 106; M. G .
Finn, K. B. Sharpless, ibid. 1991, 113, 113.
[2] W. Zhang, J. L. Loebach, S. R. Wilson, E. N. Jacobsen, J. Am. Chem. Soc.
1990, 112, 2801; R . hie, K. Noda, Y Ito, N. Matsumoto, T. Katsuki.
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1991,56, 2296. See also: C. Bolm, Angew. Chem. 1991, 103,414; Angen.
Chem. Int. Ed. Engl. 1991, 30,403.
[3] Other examples of nonenzymatic selectiveenantiotopic group transformations: meso anhydride + lactone: K. Osakada, M. Obana. T. Ikaria, M.
Saburi, S. Yoshikawa, Tetrahedron Lett. 1981, 22, 4297; acetal -.enol: Y
Naruse, H. Yamamoto, ibid. 1986, 27, 1363; Y Narnse, T. Esaki, H. Yamamoto, ibid. 1988, 29, 1417; asymmetric hydrogenation of epoxides:
A. S. C. Chan, J. P. Coleman, J. Chem. Soc. Chem. Commun. 1991, 5 3 5 .
[4] a) J. K. Whitesell, S. W. Felman, J. O i g . Chem. 1980,45,755;b) M. Asaml,
Chem. Lett., 1984, 829; c) M. Asami, Tetrahedron Lett. 1985, 26, 5803;
d) S . K. Hendrie, J. Leonard, Tetrahedron 1987.43, 3289; e ) M . Asami, H.
Kirihara, Chem. L e f t . 1987, 389.
[5] H. Yamashita, T. Mnkaiyama, Chem. Lett. 1985, 1643; H. Yamashita, ibid.
1987, 525; Bull. SOC.Chem. Jpn. 1988, 61, 1213.
[6] N. N. Joshi, M. Srehnik, H. C. Brown, J: Am. Chem. Sac. 1988,110,6246.
(71 M. Enziane, K. I. Sutowardoyo, D. Sinou. J. Organomel. Chem. 1988,346,
C7; C. Blandy, R. Choukroun. D. Gervais, Tetrahedron Lett. 1983, 24,
[XI M. Hayashi, K. Kohmura, N. Oguni, Synlett 1991, 774.
[9] W. A. Nugent, J. Am. Chem. Soc. 1992, 114, 2168,
[lo] C. Bolm, K. B. Sharpless, Tetrahedron Lett. 1988, 29, 5101; C. Bolm,
W. M. Davis, R. L. Halterman, K. B. Sharpless, Angew. Chem. 1988, 100,
882; Angew. Chem. Int. Ed. Engl. 1988, 27, 835.
[Ill M. J. Burk, R. L. Harlow, Angew. Chem. 1990, 102, 1511; Angew. Chem.
Int. Ed. Engl. 1990, 29, 1462.
[I21 M. Asami, N. Kanemaki, Tetrahedron Lett. 1989, 30, 2125.
0570-0833192jO909-1180 $3S0+.2S/O
Angew. Chem. Int. Ed. Engl. 1992, 31, No. 9
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acid, presence, meso, chiral, asymmetric, synthesis, opening, epoxide, enantioselectivity, lewis, nucleophilic
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