The semi-pinacol rearrangement of homochiral epoxyalcohols catalysed by rare earth triflates

Article abstract of DOI:10.1039/b101838h

α,β-Epoxy ketones, prepared using the polyleucine catalysed asymmetric epoxidation of enones, can be converted into α-substituted β-hydroxy ketones via carbonyl alkylation with Grignard reagents followed by ytterbium triflate catalysed semi-pinacol rearrangement of the resulting epoxyalcohols.

Full text of DOI:10.1039/b101838h

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The semi-pinacol rearrangement of homochiral epoxyalcohols
catalysed by rare earth triflates
a
b
a
a
Jamie F. Bickley, Bernhardt Hauer, Paula C. A. Pena, Stanley M. Roberts*
a
and John Skidmore
1
a
Department of Chemistry, University of Liverpool, Liverpool, UK L69 7ZD.
E-mail: smrsm@liv.ac.uk
BASF AG, ZHF B9, D67056, Ludwigshafen, Germany
b
Received (in Cambridge, UK) 27th February 2001, Accepted 10th April 2001
First published as an Advance Article on the web 1st May 2001
ꢀ
,ꢁ-Epoxy ketones, prepared using the polyleucine
case of some of our substrates, prompted an investigation into
the utility of rare earth triflates as catalysts for epoxyalcohol
semi-pinacol rearrangements.
catalysed asymmetric epoxidation of enones, can be
converted into ꢀ-substituted ꢁ-hydroxy ketones via
carbonyl alkylation with Grignard reagents followed by
ytterbium triflate catalysed semi-pinacol rearrangement of
the resulting epoxyalcohols.
A number of trans-β-alkylenones were prepared in order to
provide substrates for developing the alkylation–rearrangement
methodology. The β-ethylenone 3 was prepared via a Wittig
reaction between propionaldehyde and benzoylmethylene
triphenylphosphorane and the β-benzylenone 5 was synthesised
Polyamino acids, such as polyleucine, are able to catalyse the
asymmetric epoxidation of α,β-unsaturated enones 1 by basic
H O , a transformation known as the Juliá–Colonna reaction
15
as previously described. The γ-benzyloxyenone 4 was pre-
pared by application of chemistry previously utilised for the
2
2
16
1
ethyloxy-substituted analogue. Thus, 2-benzyloxyethanol was
oxidised under Swern conditions and the resulting aldehyde was
treated with benzoylmethylene triphenylphosphorane to afford
the desired enone 4 in 38% yield over the two steps.
(
Scheme 1). To date, most of the epoxides 2 prepared have been
3
Oxidation of the β-ethylenone 3 under biphasic conditions,
using urea–H O and DBU in THF, catalysed by silica-
2
2
17
Ϫ1
immobilised poly--leucine (416 mg mmol enone), gave the
epoxide 6 in 64% yield and 60% ee after 17 hours (Scheme 2).
Scheme 1 Reagents and conditions: (a) urea–H O , DBU, poly--
leucine or SiO –poly--leucine, THF, rt.
2
2
2
1
2
of the type R = aryl or alkyl and R = aryl or vinyl, for which
2
ees are generally >80%. The first part of this communication
shows that enones 1 where R = aryl and R = alkyl can also
be epoxidised with good stereocontrol, under the previously
1
2
3
described biphasic reaction conditions.
Grignard reagents add to the carbonyl group of α,β-
epoxyketones in a highly stereoselective manner; diastereo-
selectivities >99 : 1 in favour of the product of Cram-chelate
addition are typically observed in the generation of the tertiary
4
alcohols. Such enantiomerically enriched epoxyalcohols have,
in the past, been formed by a less efficient, five-step Sharp-
less asymmetric epoxidation–oxidation–alkylation–oxidation–
5,6
alkylation strategy. It has been shown that when treated with
stoichiometric quantities of certain Lewis acids such epoxy-
alcohols undergo a semi-pinacol rearrangement to afford
5
6–8
aldols. A range of Lewis acids including TiCl , BF ؒOEt ,
4
3
2
7
9
alumina and SnCl has been used to this effect. The corre-
4
sponding silyl ethers exhibit similar reactivity when treated
1
0
5
10
with BF ؒOEt , TiCl4 and SnCl . In the case of less reactive
3
2
4
6
10
substrates, Ti(i-PrO) Cl2 and Ti(i-PrO) Cl have been used.
2
3
Suzuki has reported a catalytic variant of the silyl protected
epoxyalcohol rearrangement using 2–5 mol% TMSI or
TMSOTf. When this work was initiated no catalytic variant
applicable to unprotected epoxyalcohols had been reported.
Scheme 2 Reagents and conditions: (a) urea–H O , DBU, SiO –poly--
2
2
2
11
leucine, THF, rt; (b) urea–H O , BEMP, SiO –poly--leucine, THF, rt;
2 2 2
(c) MeMgBr, THF, Et O, Ϫ78 ЊC; (d) PhMgBr, THF, Et O, Ϫ78 ЊC.
2 2
However, recently Tu et al. have shown that ZnBr can catalyse
2
12
such semi-pinacol rearrangements. In the second part of this
paper we show that rare earth triflates can be employed as
Lewis acid catalysts in a similar manner.
The use of 2-tert-butylimino-2-diethylamino-1,3-dimethyl-
18
perhydro-1,3,2-diazaphosphorine (BEMP) instead of DBU
allowed a sub-stoichiometric amount of base to be employed;
under optimum conditions, using 3 mol% BEMP, the epoxide
6 was obtained in 86% yield and 77–79% ee. Further reduction
in the amount of BEMP led to a significant loss in stereo-
selectivity, for example with 0.1 mol% the epoxide 6 was
generated in only 74% ee. Treatment of the enone 4 under
similar conditions (20 mol% BEMP) gave the epoxide 7 in 79%
yield and 93% ee. On the other hand, epoxidation of the enone
Rare earth triflates† have been shown to be viable altern-
atives to more conventional Lewis acids for a number of trans-
13
formations, including a variety of epoxide opening reactions.
The principal advantages of such triflates are their stability to
moisture, low toxicity, ease of handling, recyclable nature and
14
ability to function in a catalytic capacity. Poor reactivity,
under previously reported rearrangement conditions, in the
DOI: 10.1039/b101838h
J. Chem. Soc., Perkin Trans. 1, 2001, 1253–1255
This journal is © The Royal Society of Chemistry 2001
1253

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Table 1 The semi-pinacol rearrangement of 9 catalysed by various
rare earth triflates.
Catalyst
Mol% catalyst
Time
Yield (%)
Sc(OTf)3
La(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
20
20
20
15
10
5
6 h
10 h
3 h
15 h
3 days
6 days
90
90
99
97
87
87
5
proceeded in a lower yield due to the formation of a dimeric
side product, presumably via Michael addition of the anion
generated by deprotonation of one molecule of 5 to a second
molecule of the enone. However, when the reaction was per-
Fig. 1 X-Ray crystal structure of 3-hydroxy-1,2-diphenylpentan-1-
one (16). Thermal ellipsoids drawn with 50% probability.
Ϫ1
formed with additional silica supported catalyst (2 g mmol
enone) none of the dimeric material was generated, leading to
an improved yield of the epoxide 8 (75%) with an ee > 90%.‡
Treatment of the epoxyketones 6–8 with methylmagnesium
bromide or phenylmagnesium bromide furnished the corre-
sponding alcohols 9–12 in 90 to 96% yield; in each case only
2
1
parison with literature data and with an authentic sample. In
particular, a quartet at δ 3.53 (J 7 Hz), due to the benzylic
proton coupling to the methyl group, is a distinctive feature of
the spectrum and clearly excludes the possibility of having
formed 2-methyl-1-tetralone (the product of methyl group
migration and retro-aldol reaction) (Scheme 4).
1
a single diastereomer was observed in the H NMR spectrum.
The stereochemistry of the products was assigned by
comparison with a previously reported example in which the
19
configuration was determined by X-ray crystallography.
Using epoxyalcohol 9, three readily available metal triflates,
Sc(OTf) , La(OTf) and Yb(OTf) , were tested as rearrange-
3
3
3
ment catalysts employing dichloromethane and acetonitrile as
solvents. Initial reactions were performed using 20 mol% of the
triflate catalysts. All three of the Lewis acids were found to
catalyse the migration of the aryl group of 9 to afford the aldol
1
3 (Scheme 3). Dichloromethane was found to be the better
Scheme 4 Reagents and conditions: (a) MeMgBr, THF, Et O, Ϫ78 ЊC;
2
(
b) Yb(OTf) (20 mol%), CH Cl , rt.
3
2
2
The mechanism of this latter reaction is under investigation.
At this point, we have established that open chain analogues
behave differently; the epoxyalcohol 21 forms the enone 22 on
treatment with rare-earth triflates (Scheme 5).
Scheme 3 Reagents and conditions: (a) Yb(OTf) (20 mol%), CH Cl ,
3
2
2
rt.
solvent, with the product proving clean enough to obviate the
need for additional purification (Table 1). The rate of reaction
catalysed by the three Lewis acids was found to decrease in
the order Yb(OTf) > Sc(OTf) > La(OTf) , with the former
Scheme 5
3
3
3
proving to be the most synthetically useful, generating the α-
phenyl-β-hydroxy ketone 13 in 99% yield after 3 hours.
Further experiments were performed in order to determine
In summary, we have demonstrated the applicability of
modified Juliá–Colonna epoxidation conditions to β-alkyl
substituted enones. The resultant epoxyketones have been
converted into aldols by Grignard addition followed by
the effect of reducing the molar percentage of Yb(OTf) . When
3
less than 15 mol% Yb(OTf) was employed the reaction took
3
semi-pinacol rearrangement catalysed by Yb(OTf) . The newly
3
three or more days to run to completion and the crude product
contained significant impurities. The optimised conditions of
developed rearrangement conditions constitute an efficient,
convenient and mild alternative to previously reported
procedures.
2
0 mol% Yb(OTf) in DCM were then applied to the enones 10,
3
1
1 and 12 with the corresponding aldols 14, 15 and 16 being
formed in 82, 100 and 97% yield respectively.
Experimental
Previous semi-pinacol rearrangements of epoxyalcohols have
been reported to proceed with inversion of stereochemistry at
the site of epoxide opening. X-Ray analysis of a single crystal
of the aldol 16 demonstrated that this is also the case in the
present study (Fig. 1).
Representative experimental procedure: (2S,3S)-3-hydroxy-1,2-
diphenylpentan-1-one (16)
To a solution of (2R,3S)-2,3-epoxy-1,1-diphenylpentan-1-ol
3
Cyclic trisubstituted enones such as trans-2-benzylidene-1-
tetralone§ can be epoxidised with good enantioselectivity under
(12) (300 mg, 1.18 mmol) in anhydrous DCM (6 cm ) was added
ytterbium() trifluoromethanesulfonate (150 mg, 0.242 mmol).
20
polyleucine catalysis. Treatment of 17, generated by such an
epoxidation, with methylmagnesium bromide gave the tertiary
alcohol 18 as expected. Unexpectedly, treatment of 18 with
The reaction mixture was stirred at room temperature for
3
4 hours after which time water (10 cm ) was added and the
3
product was extracted with diethyl ether (2 × 10 cm ). The
2
0 mol% Yb(OTf)3 in DCM furnished benzaldehyde (20)
combined ethereal extracts were dried (MgSO ) and the solvent
4
1
(
(
identified by H NMR and TLC) and an α-methyltetralone
40% yield). Analysis of the latter by H NMR spectroscopy
was removed in vacuo to afford (2S,3S)-3-hydroxy-1,2-diphen-
ylpentan-1-one (16) (290 mg, 1.14 mmol, 97%) as yellow
crystals; mp 87–88 ЊC; R [SiO ; petroleum ether (40–60)–
1
showed the material to be 1-methyl-2-tetralone (19) by com-
f
2
1
254 J. Chem. Soc., Perkin Trans. 1, 2001, 1253–1255

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diethyl ether, 1 : 1] 0.35 (Found: C, 80.0; H, 7.1. C H O
2
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17
18
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3
4
(
3 H, t, J 7.3 Hz, CH ), 1.32–1.48 (2 H, m, CH ), 2.89 (1 H, br s,
3
2
4
5
OH), 4.27 (1 H, dt, J 8.3, 3.9 Hz, C(3)H), 4.58 (1 H, d, J 8.6 Hz,
C(2)H), 7.19–7.50 (8 H, m, ArH) and 7.91–7.98 (2 H, m, ArH);
+
+
m/z (CI ) 254 ([M Ϫ H O + NH ] , 1%), 237 (6), 214 (69), 197
2
4
(
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3
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6
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X-Ray crystallography.¶ Crystallographic data were
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78.
8
1
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2
22
full matrix least squares against F using all data.
9
Crystal data. C H O , M = 254.35, orthorhombic,
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2000, 2, 1193.
11 K. Suzuki, M. Miyazawa and G. Tsuchihashi, Tetrahedron Lett.,
17
18
2
a = 5.6084(7), b = 13.3595(17), c = 19.118(3) Å, U = 1432.4(4)
3
Ϫ1
Å , space group P2 2 2 , Z = 4, µ(Mo-Kα) = 0.076 mm , 9206
1
1 1
1
987, 28, 3515.
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1
2 Y. Q. Tu, C. A. Fan, S. K. Ren and A. S. C. Chan, J. Chem. Soc.,
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used in all calculations. For I ≥ 2σ(I) R = 0.0333. The final
1
2
wR(F ) was 0.0661(all data). Absolute configuration was not
1
3 (a) H. Kotsuki, M. Teraguchi, N. Shimomoto and M. Ochi,
Tetrahedron Lett., 1996, 37, 3727; (b) P. Crotti, V. Di Bussolo,
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23
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6
1
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998, 63, 5088; (d) X.-L. Hou, J. Wu, L.-X. Dai, L.-J. Xia and
Acknowledgements
We thank the Fundação para a Ciência e Tecnologia (FCT) and
BASF for funding (P. C. A. P.).
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1
1
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Notes and references
9
5, 5813.
†
‡
The IUPAC name for triflate is trifluoromethanesulfonate.
Complete resolution of the two enantiomers of 7 using chiral HPLC,
16 P. C. Ray, PhD Thesis, Liverpool, 2000.
17 T. Geller and S. M. Roberts, J. Chem. Soc., Perkin Trans. 1, 1999,
1397.
18 BEMP is often the preferred base for Juliá–Colonna epoxid-
ations; A. Burns, K.-H. Drauz, E. A. O’Connor, S. M. Roberts and
J. Skidmore, unpublished results.
19 J. F. Bickley, A. T. Gillmore, S. M. Roberts, A. Steiner and
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20 P. A. Bentley, J. F. Bickley, S. M. Roberts and A. Steiner, Tetrahedron
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chiral GC or chiral shift NMR was not achieved. The quoted ee of
>
90% is an estimate from the partly resolved HPLC analysis.
§
The IUPAC name for 1-tetralone is 3,4-dihydronaphthalen-2(1H)-
one.
¶
CCDC reference number 160661. See http://www.rsc.org/suppdata/
p1/b1/b101838h/ for crystallographic files in .cif or other electronic
format.
1
2
M. J. Porter, S. M. Roberts and J. Skidmore, Bioorg. Med. Chem.,
999, 7, 2145.
For a discussion of the different methods for epoxidising electron
deficient double bonds and a comparison of their substrate ranges
see M. J. Porter and J. Skidmore, Chem. Commun., 2000, 1215.
21 N. J. Harper and J. Raines, J. Chem. Soc. (C), 1969, 1372.
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23 H. D. Flack, Acta Crystallogr. Sect. A Fundam. Crystallogr., 1983,
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1
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