Asymmetric Hetero-Ene Reactions of Trimethylsilyl Enol Ethers Catalyzed by Tridentate Schiff Base Chromium(III) Complexes

Article abstract of DOI:10.1002/anie.200351591

A concerted ene reaction between silyl enol ethers and simple aldehydes is catalyzed by chiral (Schiff base) Cr^III complexes with high stereoselectivity (see scheme). This method leads directly to enantioenriched β-hydroxy silyl enol ether deri

Full text of DOI:10.1002/anie.200351591

Angewandte
Chemie
Hetero-Ene Reaction
Asymmetric Hetero-Ene Reactions of
Trimethylsilyl Enol Ethers Catalyzed by
Tridentate Schiff Base Chromium(iii)
Complexes**
Rebecca T. Ruck and Eric N. Jacobsen*
Asymmetric hetero-ene reactions between aldehydes and
enol ethers provide convenient access to a wide variety of
chiral b-hydroxycarbonyl derivatives from stable, readily
available precursors. Recently, we demonstrated that the
tridentate Schiff base chromium(iii) complex 1 catalyzes
hetero-ene reactions between 2-methoxypropene and benz-
aldehyde derivatives to provide the corresponding b-aryl b-
hydroxymethylenol ether products in high enantioselectivities
and yields.[1] Promisingreactivity and enantioselectivity were
also uncovered in reactions of 2-trimethylsilyloxyproprene
with aromatic aldehydes to generate highly enantioenriched
b-hydroxytrimethylsilyl enol ether products (Scheme 1).
Scheme 1. TIPS=triisopropylsilyl, TMS=trimethylsilyl.
None of the corresponding b-silyloxyketone products attrib-
utable to Mukaiyama aldol pathways were detected in the
latter case, suggesting a concerted pericyclic reaction mech-
anism.[2] Intrigued by the potential of this unusual silyl enol
ether ene methodology,[3] we have investigated it more deeply
and discovered it to be far more broadly applicable than the
correspondingalkyl enol ether methodology first reported.
[*] Prof. E. N. Jacobsen, R. T. Ruck
Department of Chemistry and Chemical Biology
Harvard University
Cambridge, MA 02138 (USA)
Fax: (+1)617-496-1880
E-mail: jacobsen@chemistry.harvard.edu
[**] This workwas supported by the NIH (GM-59316) and by a
predoctoral fellowship from the National Science Foundation and
an graduate fellowship from the ACS Division of Organic Chemistry
sponsored by Albany Molecular Research, Inc. to R.T.R.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 4771 –4774
DOI: 10.1002/anie.200351591
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We report here its successful application to highly enantio-
selective and diastereoselective reactions of prochiral and
chiral aliphatic aldehydes.
Aliphatic aldehydes 4a–f proved to be excellent sub-
strates for enantioselective hetero-ene reactions catalyzed by
CrIII complex 2, undergoing reaction with 2-trimethylsilyloxy-
propene to generate the b-hydroxytrimethylsilyl enol ether
products 6a–f in high yields and enantioselectivities (Table 1).
serve as useful substrates for doubly diastereoselective ene
reactions to generate monoprotected syn- or anti-1,3-diols.
Enantiopure 3-hydroxybutyraldehyde derivatives 7a and 7b
were both subjected to ene reactions with 2-trimethylsilyloxy-
propene (5), and the selectivities obtained with each enan-
tiomer of catalyst 2 were compared with those generated with
the achiral variant 8 (Scheme 2, Table 2). Achiral catalyst 8
Table 1: Hetero-ene reactions between aliphatic aldehydes and 2-trime-
thylsilyloxypropene [Eq. (1)].[a,b]
Product
R
t [h]
Yield [%][c]
ee [%]
6a
6b
6c
6d
6e
6 f
nPr
iPr
iBu
65
72
72
72
20
40
87
83
77
47[f]
90
87
89[e]
90[e]
87[e]
93[e]
93[g]
90[g]
cyclopropyl
TBDPSOCH2CH2
TBDPSOCH2CH2CH2
[d]
[d]
Scheme 2.
[a] Reactions were carried out with 1.0 mmol of aldehyde, ~4 mmol of 5
(480 mL of 93–94% purity), 0.05 mmol of 2 (28.4 mg), powdered 4-Š
molecular sieves (400 mg), and DIPEA (25 mL) at 48C. [b] Absolute
stereochemistry was determined by hydrolysis of 6c to the b-hydroxy-
ketone and comparison of the optical rotation to the known literature
value.[5] [c] Net yield of crude product contaminated with residual catalyst
(see text). [d] TBDPS=tert-butyldiphenylsilyl. [e] Enantiomeric excess
was determined by hydrolysis to the b-hydroxyketone and analysis by
chiral GC (g-TA) or HPLC (Whelk-01). [f] This reaction proceeded only to
55% conv. of substrate. [g] Enantiomeric excess determined for the TMS
enol ether, which was analyzed by chiral HPLC on a Whelk-01 column.
Table 2: Doubly diastereoselective ene reactions.
Aldehyde
Catalyst
9:10[a]
Conv. [%][b]
7a
7a
7a
7b
7b
7b
8
2.8:1
n.d.
92
92
n.d.
51
91
(R,S)-2
(S,R)-2
8
(R,S)-2
(S,R)-2
>46:1
1:14.4
1:2.6
3.8:1
1:>160
[a] Syn:anti ratios were determined by GC analysis. [b] Conversions
1
determined by H NMR spectroscopy; n.d.=not determined.
Catalysts 1 and 2 afforded similar enantioselectivities, but
rates were 1.5–2 times faster with the more soluble complex 2.
Reactions were conducted under solvent-free conditions in
the presence of 4-Š molecular sieves, with 2-trimethylsilyl-
oxypropene and aldehyde in a 4:1 molar ratio. Addition of
provided a modest 2.8:1 diastereoselectivity in the ene
reaction between 7a and 5, favoringthe enantiopure syn-
diol derivative 9a. This substrate-based selectivity was
enhanced to a significant extent with “matched” catalyst
(1R,2S)-2 (> 46:1). The “mismatched” catalyst (1S,2R)-2
provided a synthetically useful diastereoselectivity of 14.4:1
in favor of the enantiopure anti-diol derivative 10a. The
substrate-induced selectivity with the bulkier aldehyde 7b
reversed to favor anti-diol derivative 10b in a 2.6:1 ratio. The
now-“matched” catalyst (1S,2R)-2 provided a > 160:1 d.r. in
favor of the anti product 10b, whereas “mismatched” catalyst
(1R,2S)-2 afforded a modest 3.8:1 selectivity favoringthe syn
isomer 9b. Thus, the highly selective generation of either syn-
or anti-1,3-diol derivatives was possible through appropriate
choice of catalyst enantiomer and silyl protectinggroup.
The crude b-hydroxytrimethylsilylenol ether products
were obtained by filtration of the reaction mixtures through
Celite to remove the 4-Š molecular sieves followed by
concentration in vacuo.[7] Analysis of the brown residue by
1H NMR spectroscopy indicated the presence of ene adduct
as the only diamagnetic component. Yields were calculated
substoichiometric
amounts
of
diisopropylethylamine
(DIPEA) served to inhibit an unselective pathway promoted,
most likely, by trace amounts of Brønsted acid associated to
the catalyst.[4] The b-hydroxytrimethylsilyl enol ether prod-
ucts were unreactive as ene partners under the reaction
conditions.
The enantioselectivity and rate of the ene reactions
displayed little dependence on the steric properties of the
aldehydes, except in the extreme case of pivalaldehyde, which
proved almost completely unreactive. Butyraldehyde (4a)
underwent catalyst-induced trimerization under standard
reaction conditions, but this could be avoided by slow
addition of 4a to a solution of the other reaction components,
with no deleterious effect on enantioselectivity or reaction
rate. Reaction of b- or g-silyloxy-substituted aldehydes (4e,
4 f) proceeded with similar enantioselectivities but measur-
ably faster rates than the unfunctionalized counterparts.[6]
The high reactivity and enantioselectivity observed with
aldehyde 4e suggested that chiral b-silyloxyaldehydes might
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assumingthat the crude product retains 100% of the catalyst
by subtractingthe mass of catalyst 2 used from the mass of
crude product obtained. Purification by chromatography led
to significant losses due to product decomposition, and clean
products were obtained by flash chromatography in only ca.
35% yield.[8] However, we found that the crude mixture of
catalyst and product could be employed in a variety of useful
transformations. For example, crude b-hydroxytrimethylsilyl
enol ether 6e was protected as the tert-butyldimethylsilyl
(TBS) ether,[9] and then a Mukaiyama aldol reaction was
carried out with isobutyraldehyde in the presence of BF3·OEt2
to generate enantiopure adduct 11 in 83% yield over three
between aromatic or aliphatic aldehydes and silyl enol ether
derivatives to generate b-hydroxytrimethylsilyl enol ethers in
high enantioselectivities and yields. Current efforts are
directed toward elucidation of the mechanism of this process
and toward synthetic extensions and applications of this
promisingmethodology.
Received: April 7, 2003 [Z51591]
Published Online: September 23, 2003
Keywords: aldehydes · asymmetric catalysis · chromium · ene
.
reaction · Schiff bases
steps and
a
59:41 syn/anti ratio of diastereomers
(Scheme 3).[10]
[1] R. T. Ruck, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124,
2882 – 2883.
[2] The hetero-Diels–Alder reactions reported usinga
similar catalyst also appear to proceed by a concerted
mechanism: a) A. G. Dosseter, T. F. Jamison, E. N.
Jacobsen, Angew. Chem. 1999, 111, 2549 – 2552;
Angew. Chem. Int. Ed. 1999, 38, 2398 – 2400; b) K.
Gademann, D. E. Chavez, E. N. Jacobsen, Angew.
Chem. 2002, 114, 3185 – 3187; Angew. Chem. Int. Ed.
2002, 41, 3059 – 3061.
Scheme 3.
[3] The lone previous example of an asymmetric silyl enol
ether ene transformation was reported by Mikami et al.
and involved reaction of 2-tert-butyldimethylsilyloxy-
propene and glyoxylate derivatives: K. Mikami, S. Matsukawa,
M. Nagashima, H. Funabashi, H. Morishima, Tetrahedron Lett.
1997, 38, 579 – 582.
More sterically hindered silyl enol ether derivatives were
also found to undergo asymmetric ene reactions, albeit with
significant limitations on the scope of useful aldehyde
substrates. While aliphatic aldehydes were unreactive in ene
reactions with trimethylsilylenol ethers derived from cyclo-
pentanone (12) or cyclohexanone (13), 2-bromobenzaldehyde
(15) underwent clean and highly stereoselective reactions
[4] The procedure for the preparation of catalysts 1–3[1] incorporates
a late-stage workup step with HCl, which is the likely source of
acidic impurities.
[5] B. List, P. Pojarliev, C. Castello, Org. Lett. 2001, 3, 573 – 576.
[6] In contrast, aldehydes bearingsilyloxy a-substituents underwent
ene reactions in good yields but low enantioselectivities. For
example, the reaction between tert-butyldiphenylsilyloxyacetal-
dehyde and 5 proceeded in a comparatively low 53% ee.
Similarly, TBSOCH2CHO underwent the hetero-ene reaction
with 2-methoxypropene in the presence of 1 in 54% ee. These
results stand in sharp contrast to those obtained in hetero-Diels–
Alder reactions with analogous CrIII catalysts, where substrates
such as TBSOCH2CHO afforded outstandingresults ( > 99% ee)
in cycloadditions with alkoxy- or silyloxydiene derivatives. See
ref. [2a], and: P. Liu, E. N. Jacobsen, J. Am. Chem. Soc. 2001, 123,
10772 – 10773.
with these enophiles in the presence of catalyst
3
(Scheme 4).[11] High anti diastereoselectivity was observed in
[7] The crude b-hydroxytrimethylsilyl enol ether products listed in
Table 1 were characterized by 1H NMR spectroscopy; the
purified b-hydroxyketone hydrolysis products were fully char-
acterized.
Scheme 4.
[8] Separation of the products from the nonpolar catalyst was
difficult and required careful chromatography. The low recovery
of the silyl enol ether products is attributable to partial
hydrolysis due to prolonged exposure to the chromatographic
support.
[9] The unprotected b-hydroxy silyl enol ethers underwent com-
petitive elimination and/or hydrolysis reactions under a variety
of Lewis acid catalyzed conditions.
[10] The stereochemical assignment is tentative and based on closely
related reactions: a) D. A. Evans, P. J. Coleman, B. Cote, J. Org.
Chem. 1997, 62, 788 – 789; b) I. Paterson, K. R. Gibson, R. M.
Oballa, Tetrahedron Lett. 1996, 37, 8585 – 8588.
[11] Electron-deficient benzaldehyde derivatives bearing ortho sub-
stituents provided the best rates and enantioselectivities in this
reaction, similar to observations made in ene reactions with 2-
methoxypropene. See ref. [1].
both reactions, indicatingthat the ene reaction of the cyclic
(E)-enol ether proceeds selectively through an endo transi-
tion state, as is the case in CrIII-catalyzed hetero-Diels–Alder
reactions.[2] Reaction of 2-bromobenzaldehyde (15a) with 1-
trimethylsilyloxycyclobutene (14) as the ene component was
also catalyzed by 3, although the product (18) was generated
with only moderate enantio- and diastereoselectivity. The
trisubstituted trimethylsilyl enol ether products displayed
increased stability toward silica gel chromatography, and their
purification and full characterization was accomplished after
simple filtration of the crude reaction mixture through a small
pad of silica gel to remove catalyst.
In summary, tridentate Schiff base chromium(iii) com-
plexes 1–3 catalyze a wide range of hetero-ene reactions
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[12] The relative stereochemistry was determined by hydrolysis of
the product to the b-hydroxyketone and comparison of the
couplingconstant between the two methine protons ( J = 9.3 Hz)
to that of the previously reported parent phenyl analogue: S. E.
Denmark, R. A. Stavenger, K.-T. Wong, Tetrahedron 1998, 54,
10389 – 10402.
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Angew. Chem. Int. Ed. 2003, 42, 4771 –4774