Enantioselective catalytic carbonyl-ene cyclization reactions

Article abstract of DOI:10.1002/anie.200704439

(Chemical Equation Presented) Intramolecular ene reactions of simple alkenyl aldehydes are catalyzed by a chiral (Schiff base)Cr^III complex with high enantio-and diastereoselectivity, affording densely functionalized heterocyclic or carbocyclic products (see scheme for example). Desymmetrizations of alkenyl dialdehydes and bis(alkenyl) aldehydes are also achieved.

Full text of DOI:10.1002/anie.200704439

Angewandte
Chemie
DOI: 10.1002/anie.200704439
Cyclizations
Enantioselective Catalytic Carbonyl–Ene Cyclization Reactions**
Melissa L. Grachan, Matthew T. Tudge, and Eric. N. Jacobsen*
The carbonyl–ene reaction is a synthetically important
method of generating homoallylic alcohols with concomitant
carbon–carbon bond formation.[1–3] Substantial effort has
been directed toward developing catalytic enantioselective
variants, and several notable advances have been made.[3–9]
However, most systems identified to date are limited to highly
electrophilic aldehyde substrates bearing strongly electron-
withdrawing substituents or Lewis basic substituents that
allow two-point binding to the catalyst.[4,5,9] Recently, our
group discovered that CrIII complexes of tridentate Schiff
base ligands (1) promote enantioselective hetero-ene reac-
tions between electron rich enol ethers and electronically
unactivated aldehydes (Scheme 1).[6b,c] We became interested
erate stereochemically complex cyclic structures in a straight-
forward manner. Herein, we report carbonyl–ene cyclization
reactions of a variety of alkenyl aldehydes promoted by
catalyst 1c, resulting in the highly diastereo- and enantiose-
lective formation of a diverse range of heterocyclic and
carbocylic products.
Until now, only very limited success has been reported for
intramolecular ene reactions induced by chiral cata-
lysts.[2,3,7–10] Yamamoto and co-workers discovered the first
examples that were promoted by more than stoichiometric
amounts of a Zn/binol complex (binol = 2,2’-dihydroxy-1,1’-
binapthyl).[7] Subsequently, Mikami and co-workers demon-
strated that a TiIV/binol system is an effective catalyst for the
enantio- and diastereoselective cyclization of a limited range
of alkenyl aldehydes.[8] More recently, Yang and co-workers
reported the highly enantioselective cyclization of pyruvate
derivatives catalyzed by a CuII/bisoxazoline complex to
generate functionalized cyclopentanes.[9]
Evaluation of a series of Schiff base complexes of type 1 in
the ene cyclization of model substrate 2a led to identification
of complex 1c as the optimal catalyst; the product was
obtained as a 4.5:1 ratio of diastereomers and in good
enantiomeric excess (Scheme 2). However, product 3a was
Scheme 2. Preliminary result.
Scheme 1. (Schiff base)CrIII-catalyzed enantioselective intermolecular
hetero-ene reactions.TMS=trimethylsilyl, TBDPS=tert-butyldiphenyl-
silyl, TIPS=triisopropylsilyl.
generated in variable yields as a result of competing enoliza-
tion and poorly stereoselective aldol pathways. Undesired
side reactions were avoided through the use of a,a-disub-
stituted aldehydes as substrates.[11] Thus, treatment of alkenyl
aldehyde 2b with 0.8 mol% catalyst 1c at 48C resulted in a
reproducible, highly diastereo- and enantioselective carbon-
yl–ene cyclization to yield tetrahydrofuran 3b as a volatile oil
in greater than 30:1 d.r., 93 % ee, and 77% yield (Table 1,
entry 1).
in developing an intramolecular variant of this reaction,
motivated in part by the possibility that the entropic
advantage conferred to such transformations might allow
simultaneous use of both unactivated olefins and aldehydes.
Moreover, intramolecular carbonyl–ene reactions often gen-
A variety of alkenyl aldehydes bearing heteroatom
substitution proved to be suitable substrates for this
method, providing access to a diverse array of substituted
heterocyclic products (Table 1). Geranyl aldehyde 2c under-
went regioselective cyclization to yield tetrahydrofuran 3c in
20:1 d.r. and 96% ee (Table 1, entry 2). Although slightly
higher catalyst loadings were required to promote the
reaction of tetrasubstituted alkene 2d, tetrahydrofuran 3d
[*] M. L. Grachan, Dr. M. T. Tudge, Prof. E. N. Jacobsen
Department of Chemistry and Chemical Biology
Harvard University, Cambridge, MA 02138 (USA)
Fax: (+1)617-496-1880
E-mail: jacobsen@chemistry.harvard.edu
[**] This work was supported by the NIH (GM-59316).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Enantioselective carbonyl–ene cyclizations.
aldehydes bearing either enantio-
topic alkene or aldehyde groups
(Table 2). Bis(alkenyl) aldehydes
proved to be superb cyclization
substrates, affording products with
a variety of structural motifs in high
Entry Aldehyde
Product
(R,S)-1c d.r.[a]
[mol%]
ee
Yield
yields
and
enantioselectivities
[%][b] [%][c]
(Table 2, entries 1–4). Aldehyde
4a, which contains prochiral prenyl
moieties, underwent cyclization to
generate a cyclopentanol ring with
three contiguous stereogenic cen-
ters in 7:1 d.r. The major diastereo-
mer of the differentially protected
diol, 5a, was isolated in 87% yield
and 99% ee (Table 2, entry 1).
Desymmetrization of aldehyde
ester 4b (Table 2, entry 2) afforded
b-hydroxy ester 5b as a single
diastereomer in 95% yield and
98% ee. The stereochemically com-
plex cyclopentane products 5a and
5b contain useful handles for fur-
ther synthetic elaboration, includ-
ing multiple olefin moieties with
distinct steric and electronic proper-
ties. Cyclization of aldehydes con-
taining prochiral terminal olefin
substituents, such as 4c and 4d, led
to formation of cyclohexanol rings
with two contiguous stereogenic
centers in high enantio- and diaste-
reoselectivity (Table 2, entries 3
and 4).
1
0.8
1
>30:1 93
77
2
3
20:1 96
94
78
5
1
>30:1 75
4
>30:1 96
96
5
6
7
5
–
–
93
94
72
88
98
2.5
2
>30:1 95
Catalyst 1c also proved to be
applicable to the desymmetrization
of dialdehyde substrates (Table 2,
entries 5–7).[10] Treatment of 6a
with 1 mol% 1c afforded cyclized
product 7a in 2.2:1 d.r. (Table 2,
entry 5). Despite the moderate dia-
stereoselectivity obtained in this
reaction, the major isomer could
[a] Ratios determined by 1H NMR spectroscopy or GC analysis of the crude reaction mixtures. The
relative stereochemistry was determined by NOE spectroscopy. [b] Determined by chiral GC or HPLC
analysis. The absolute stereochemistry of 3h was determined by X-ray crystallographic analysis of the p-
bromobenzoyl ester[13] and those of the other products were inferred from this result. [c] Yield of the
indicated diastereomer isolated after purification by column chromatography.
was obtained in high diastereoselectivity with concomitant
formation of a quaternary stereocenter (Table 1, entry 3).
Prenylated aldehyde 2e, which bears geminal diallyl substi-
tution at the a-carbon atom, was an excellent substrate,
undergoing cyclization in nearly quantitative yield and
96% ee (Table 1, entry 4). Six-membered rings resulted
from the cyclization of terminal olefin containing substrates,
such as 2 f, affording tetrahydropyran 3 f in 93% ee (Table 1,
entry 5).[12] The protected 2-hydroxycyclohexanone 3g was
generated in 93% ee by cyclization of the corresponding
protected a-ketoaldehyde 2g (Table 1, entry 6). Treatment of
a-amino aldehyde 2h with 2 mol% 1c afforded tosyl-
protected pyrrolidine 3h as a single diastereomer in 95% ee
and 98% yield (Table 1, entry 7).
be isolated after purification by column chromatography in
57% yield and 91% ee.
Upon treatment with catalyst 1c, prenylated 1,3-dialde-
hydes 6b and 6c undergo tandem ene cyclizations to yield
bicyclo[3.2.1]octanes 7b and 7c as single diastereomers in 92
and 93% ee, respectively (Table 2, entries 6 and 7). The first
ene cyclization generates a transient cyclopentane intermedi-
ate that contains an olefin and aldehyde in a 1,3-syn
orientation. This intermediate is poised to undergo a second
intramolecular ene reaction, resulting in the observed bicyclic
product (Scheme 3). Although 7b and 7c were isolated in
moderate yield, the precursor dialdehydes 6b and 6c are
accessible in only three steps from commercially available
starting materials, and the double ene cyclization imparts a
significant increase in both structural and stereochemical
complexity. In principle, bicyclo[3.2.1]octanes with a wide
Alternatively, stereochemically complex carbocycles
could be prepared by this method from achiral alkenyl
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Table 2: Desymmetrizations of bis(alkenyl) aldehydes and alkenyl dialdehydes.[a]
We anticipate that this methodol-
d.r.[b]
ee
Yield
[%][d]
ogy will prove to be enabling in a
variety of synthetic contexts.
Entry
Aldehyde
Product
(R,S)-1c
[mol%]
[%][c]
Experimental Section
1
2
2
7:1
99
98
87
95
General procedure for enantioselective
ene cyclizations catalyzed by 1c:
(3R,4R)-2,2-dimethyl-4-(prop-1-en-2-
yl)tetrahydrofuran-3-ol
(Table 1,
entry 1): Toluene (25 mL) and aldehyde
2b (0.2 mmol) were added to a cooled
(08C), stirred mixture of 4-Š molecular
sieves (40 mg) and catalyst 1c (1.6 mg,
1.6 mmol), contained in a flame-dried
0.5-dram reaction vial and under a N2
atmosphere, was added The reaction
mixture was warmed to 48C and
allowed to stir until conversion of 2b
was deemed complete by TLC
(ca. 30 h). The mixture was diluted
with 50% Et2O/hexanes (0.5 mL) and
loaded onto a silica gel column. Purifi-
cation by flash column chromatogra-
phy, eluting with 10% Et2O/hexanes,
afforded 3b (24 mg, 77%) as a volatile,
2
>30:1
3
4
5
2
1
1
>30:1
>30:1
2.2:1
97
99
91
89
99
57
1
colorless oil in > 30:1 d.r. by HNMR
spectroscopy and 93% ee by chiral GC
(g-TA, 858C isothermal, tr (minor)
19.5 min, tr (major) 27.1). Rf = 0.15
(10%
EtOAc/hexanes);
[a]2D0
=
À11.3 cm3 gÀ1 dmÀ1 (c = 0.36 gcmÀ3 in
CH2Cl2); IR (film): n˜max = 3429 (s),
2972 (s), 2934 (m), 2884 (w), 1650 (w),
1451 cmÀ1 (w); 1HNMR (500 MHz,
CDCl3) d = 5.07 (1H, br.s, CH), 4.77
(1H, brs, CH), 3.98–3.92 (2H, m,
OCH2), 3.83 (1H, app t, J = 4,
HOCH), 3.09–3.05 (1H, m, CH), 1.84
(3H, s, CH3), 1.62 (1H, d, J = 4, OH),
1.31 (3H, s, CH3), 1.22 ppm (3H, s,
CH3); 13C NMR (125.6 MHz, CDCl3)
d = 141.1, 113.8, 84.7, 76.6, 67.6, 51.1,
6
7
10
10
>30:1
>30:1
92
93
46
42
[a] Reactions were carried out in toluene (8m), in the presence of 4-ꢀ molecular sieves, and at ambient
temperature, except for entries 4 and 5, which were run at 48C. [b] Diastereomeric ratios determined by
1H NMR spectroscopy or GC analysis of the crude reaction mixtures. The relative stereochemistry was
determined by NOE spectroscopy. [c] Determined by chiral GC or HPLC analysis. [d] Yield of the
indicated diastereomer isolated after column chromatography.
27.7, 23.9, 22.7 ppm; m/z (CI, NH4+
174 [M + NH4].
)
Received: September 26, 2007
Published online: January 10, 2008
Keywords: aldehydes · asymmetric catalysis · chromium ·
.
cyclization · ene reaction
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In conclusion, catalyst 1c promotes highly diastereo- and
enantioselective carbonyl–ene cyclizations of a variety of
alkenyl aldehydes to afford densely functionalized hetero-
and carbocycles bearing up to three contiguous stereocenters.
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Communications
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[13] See the Supporting Information for X-ray crystallographic data.
[14] See the Supporting Information for substrate preparation.
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