Scandium-bipyridine-catalyzed enantioselective addition of alcohols and amines to meso-epoxides

Article abstract of DOI:10.1002/anie.200460786

A winning combination of metal and ligand: The catalyst formed in situ from Sc(OTf)₃ and bipyridine 1 (10 mol%) mediates the alcoholysis and aminolysis of Mieso-epoxides in high enantioselectivities and furnishes valuable chiral 1,2-diol monoethers 2 and 1,2-amino alcohols 3 as products (PMB = para-methoxybenzyl).

Full text of DOI:10.1002/anie.200460786

Angewandte
Chemie
Epoxide Ring Opening
Scandium–Bipyridine-Catalyzed Enantioselective
Addition of Alcohols and Amines to meso-
Epoxides**
Christoph Schneider,* Anakallil R. Sreekanth, and
Enzo Mai
Scheme 1. Sc(OTf)3-catalyzed alcoholysis and aminolysis of
cyclohexene oxide.
The catalytic, enantioselective ring opening of meso-epoxides
is an efficient means to convert readily available, inexpensive
bulk chemicals into chiral, 1,2-difunctionalized fine chemicals
in enantiomerically enriched form.[1] In such a process the
chiral catalyst, typically a chiral Lewis acid or Lewis base,
must differentiate between the two enantiotopic carbon
atoms of the epoxide and direct the nucleophilic addition in
a clean SN2 process to one of the epoxide termini. 1,2-Azido
alcohols,[2] 1,2-halohydrins,[3] 1,2-cyano alcohols,[4] 1,2-diol
monoesters and monoethers,[5] as well as 1,2-mercaptoalco-
hols[6] have been obtained thus far in good to excellent
enantioselectivities. Alternatively, chiral TiIII complexes have
been employed to reductively open meso-epoxides to furnish
enantiomerically enriched radical anions, which were then
trapped with either hydrogen donors or alkenes.[7] The
nucleophilic addition of amines to meso-epoxides currently
proceeds with only moderate enantioselectity in most cases;[8]
the catalytic, enantioselective addition of aliphatic alcohols to
meso-epoxides has not been reported at all to date. We report
here a novel chiral metal complex capable of catalyzing the
alcoholysis as well as aminolysis of meso-epoxides with good
yields and in part excellent enantioselectivities.
The starting point for our investigations was the observa-
tion made by Crotti and co-workers that lanthanide triflates
such as Yb(OTf)3 are effective catalysts for the aminolysis of
1,2-epoxides, presumably because they are able to exert their
exceptional Lewis acidity even under protic reaction con-
ditions.[9,10] Preliminary experiments with different metal
triflates revealed that Sc(OTf)3, in particular, is a highly
active catalyst for the alcoholysis and aminolysis of epox-
ides.[11] Thus, cyclohexene oxide reacted with methanol
(2 equiv) as well as aniline (1 equiv) in the presence of
1 mol% Sc(OTf)3 within 12 h at room temperature in CH2Cl2
to give the ring-opened products in high yields and complete
anti diastereoselectivity (Scheme 1).
2,2’-bipyridine 1 introduced by Bolm et al.[12] to be the most
promising (Scheme 2). Stirring Sc(OTf)3 and 1 (10 mol%
each) in CH2Cl2 at room temperature furnished the active
Scheme 2. Scandium–bipyridine-catalyzed alcoholysis of meso-
epoxides.
catalyst in situ, which catalyzed the ring opening of cis-
stilbene oxide (2a) with methanol (2 equiv) to give 1,2-diol
monoether 3a in good yield and with 92% ee (Scheme 2;
Table 1, entry 1). Various other alcohols were added success-
fully to 2a in good yields and very high enantioselectivities;
with para-methoxy benzyl alcohol giving the best results
(97% ee) (entries 2–5). Dichloromethane proved to be the
solvent of choice as reactions in other solvents did not yield
any product (THF, DMF, CH3CN) or gave significantly
reduced enantioselectivities (diethyl ether, toluene, metha-
nol).
Other aromatic meso-epoxides also furnished the ring-
opened products 3 f and 3g in good yields, excellent
enantioselectivities of up to 98% ee, and complete anti
diastereoselectivity (entries 6 and 7). The formation of small
amounts of the respective diastereomer was observed in some
reactions with aromatic epoxides when Sc(OTf)3 was used
alone as the catalyst, such an isomerization was completely
suppressed with the chiral scandium–bipyridine complex.
Cyclic and aliphatic epoxides such as cyclohexene oxide (2d)
and cis-2-butene oxide (2e) gave rise to 1,2-diol monoethers
3h und 3i, respectively, in high yields and only moderate
enantioselectivities (entries 8 and 9).
Based upon this result we screened a number of chiral,
multidentate ligands to be attached to Sc(OTf)3 and found the
[*]Prof. Dr. C. Schneider, Dr. A. R. Sreekanth, Dipl.-Chem. E. Mai
Institut für Organische Chemie, Universität Leipzig
Johannisallee 29, 04103 Leipzig (Germany)
Fax: (+49)341-973-6599
E-mail: schneider@chemie.uni-leipzig.de
[**]This work was supported by the Deutsche Forschungsgemeinschaft
(Schn 441/3-1) and the Fonds der Chemischen Industrie. We thank
Dr. Nitin T. Patil for preliminary experiments and Prof. Dr. W. König
(Universität Hamburg) für numerous GC measurements on chiral
stationary phases.
Compounds 3 are interesting synthetic building blocks.
Thus 1,2-diol monoether 3e was converted into the PMB-
protected acyloin 4 by Swern oxidation[13] in 94% yield and
almost complete retention of configuration. Alternatively,
oxidation with ceric ammonium nitrate[14] furnished the
unprotected 1,2-diol 5 in 82% yield (Scheme 3).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 5691 –5694
DOI: 10.1002/anie.200460786
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Communications
Table 1: Results of the scandium–bipyridine-catalyzed alcoholysis of
meso-epoxides according to Scheme 2.
Entry Epoxide
Alcohol
MeOH
EtOH
Product[a]
ee
Yield
[%][b] [%][c]
1
92
96
94
95
97
81
75
80
78
82
2
3
4
5
2a
2a
2a
2a
nBuOH
allylOH
Scheme 3. Functionalization of ring-opened product as demonstrated
with 3e.
PMBOH[d]
6
MeOH
98
83
Scheme 4. Scandium–bipyridine-catalyzed aminolysis of meso-
epoxides.
marginal effects on both the enantioselecitvity (90% ee) and
yield (89%). Sterically hindered anilines such as N-methyl-
aniline maintained high yields and led to a further increase in
enantioselectivity to 97% ee (Table 2, entry 2). The ring
opening with electron-rich amines such as para-anisidine
and O-benzyl hydroxylamine proceeded with slightly dimin-
ished enantioselectivities and yielded products 6c and 6d,
which may be easily converted into free 1,2-amino alcohols
(entries 3 and 4). Aliphatic amines did not yield the desired
products presumably because they coordinate irreversibly to
the Lewis acidic Sc(OTf)3. Other aromatic epoxides reacted
with aniline in good yields and very high enantioselectivities
to furnish 1,2-amino alcohols 6e and 6 f (entries 5 and 6).
Cyclohexene oxide (2d) and cis-2-butene oxide (2e) reacted
with aniline under otherwise identical reaction conditions
with only moderate enantioselectivities, which corresponds to
the results of the alcoholysis mentioned above (entries 7 and
8).
7
MeOH
96
75
8[e]
PMBOH[d]
PMBOH[d]
54
49
90
93
9[e]
[a]The absolute configuration of the products was determined by
comparison of the rotation values with literature values or by analogy.
[b]Determined by HPLC or GC analysis on chiral stationary phases (see
the Supporting Information). [c]Yield of isolated product. [d]PMB =
para-methoxybenzyl. [e]This reaction was conducted at À208C.
Modification of the ligand struc-
ture gave first insights into structural
elements crucial for the enantioselec-
tivity of the process. Thus, using the
The optimized protocol may be directly applied to the
aminolysis of meso-epoxides (Scheme 4; Table 2). Reaction
of cis-stilbene oxide (2a) and aniline (1 equiv) in the presence
of 10 mol% each of Sc(OTf)3 and the chiral bipyridine 1
yielded 1,2-amino alcohol 6a in 95% yield und 93% ee. The
catalyst loading may be lowered to only 5 mol% with only
bis-O-methylated bipyridine
chiral ligand led to a complete loss of
enantioselectivity both in the alcohol-
ysis and aminolysis of meso-epoxides. It appears that the free
hydroxyl groups are essential for the formation of a highly
enantioselective scandium–bipyridine complex.
7
as
5692
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Angew. Chem. Int. Ed. 2004, 43, 5691 –5694

Angewandte
Chemie
Table 2: Results of the scandium–bipyridine-catalyzed aminolysis of meso-epoxides according to
Scheme 4.
Experimental Section
All reactions were carried out in
flame-dried flasks under nitrogen.
Representative procedure: A solution
of Sc(OTf)3 (49 mg, 0.10 mmol) and
chiral bipyridine 1 (33 mg, 0.10 mmol)
in CH2Cl2 (5 mL) was stirred for 5 min
at room temperature. Subsequently
cis-stilbene oxide (2a) (196 mg,
1.00 mmol) and para-methoxybenzyl
alcohol (275 mg, 2.00 mmol) were
added, and the solution was stirred
for 12 h at room temperature. The
solvents were evaporated in vacuo,
and the crude product was purified by
flash chromatography on silica gel
(ether/pentane 1:2) which yielded
277 mg (82%) of 1,2-diol monoether
3e as colorless crystals. HPLC analysis
(Chiralcel-OD phase, n-hexane/iso-
propanol 90:10, 1 mLminÀ1): 97% ee.
M.p. 85–868C; IR (KBr): n˜ = 3521,
3432, 2865, 1610, 1509, 1241, 1195,
Entry
Epoxide
Amine
PhNH2
Product[a]
ee [%][b]
Yield [%][c]
95 (89)[d]
1
93 (90)[d]
2
3
4
2a
2a
2a
PhNHCH3
p-anisidine
BnO-NH2
97
82
86
85
87
85
1022 cmÀ1
;
1H NMR
(300 MHz,
CDCl3): d = 3.53 (brs, 1H), 3.82 (s,
3H), 4.26 (d, J = 10.8 Hz, 1H), 4.33 (d,
J = 8.4 Hz, 1H), 4.46 (d, J = 10.8 Hz,
1H), 4.70 (d, J = 8.4 Hz, 1H), 6.89 (dd,
J = 2.1, 6.6 Hz, 2H), 7.00–7.25 ppm (m,
12H); 13C NMR (75 MHz, CDCl3): d =
55.4, 70.6, 78.7, 86.7, 114.0, 127.4, 127.8,
127.9, 128.0, 128.2, 129.7, 137.8, 139.3,
159.5 ppm; HRMS (ESI) [M+Na]+
calcd. 279.13555, found 279.13552;
[a]2D5 = À41.68 (c = 0.72, CH2Cl2).
5
PhNH2
82
76
Under otherwise identical reaction
conditions cis-stilbene oxide (2a)
(98 mg, 0.50 mmol), aniline (47 mg,
6
PhNH2
91
93
0.50 mmol),
Sc(OTf)3
(25 mg,
0.05 mmol) and bipyridine 1 (17 mg,
0.05 mmol) were allowed to react in
CH2Cl2 (2 mL), and the reaction
yielded 138 mg (95%) of 1,2-amino
alcohol 6a[8a] (93% ee, Chiralcel-OD,
7
8
PhNH2
PhNH2
54
60
96
92
n-hexane/isopropanol
85:15,
1 mLminÀ1) as colorless crystals. M.p.
100–1038C; IR (KBr): n˜ = 3545, 3406,
3031, 2879, 2846, 1601, 1498, 1450,
1427, 1319, 1034, 758, 700 cmÀ1
;
1H NMR (200 MHz, CDCl3): d = 2.75
(brs, 1H), 4.60 (d, J = 6.9 Hz, 1H), 4.76
(brs, 1H), 4.91 (d, J = 6.0 Hz, 1H,
CH), 6.60–6.64 (m, 2H), 6.72–6.78
(m, 1H), 7.16–7.19 (m, 2H), 7.26–
[a]The absolute configuration of the products was determined by comparison of the rotation values with
literature values or by analogy. [b]Determined by HPLC or GC analysis on chiral stationary phases (see
the Supporting Information). [c]Yield of isolated product. [d]Values in brackets refer to reactions
conducted with only 5 mol% catalyst.
7.40 ppm
(m,
10H);
13C NMR
(50 MHz, CDCl3): d = 64.8, 78.1,
114.2, 118.0, 126.7, 127.4, 127.6, 128.0, 128.3, 128.6, 129.1, 140.3,
140.6, 147.3 ppm; ESI-MS m/z = 601 [2M+Na+], 312 [M+Na+], 290
[M+H+]; [a]2D3 = + 48.68 (c = 0.525, CH2Cl2).
In conclusion, we have established the first catalytic,
enantioselective addition of aliphatic alcohols to meso-
epoxides employing a novel scandium–bipyridine complex
which proceeds with in part excellent enantioselectivities and
generally good yields. This same chiral catalyst improves the
enantioselectivity of the aminolysis of aromatic meso-epox-
ides substantially. Current research efforts are directed at
improving the scope of this process by ligand optimization
and gaining structural information about the scandium–
bipyridine complex.
Received: May 25, 2004
Keywords: asymmetric catalysis · epoxides · N ligands ·
.
nucleophilic addition · scandium
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