Organocatalytic asymmetric direct Csp3 -H functionalization of ethers: A highly efficient approach to chiral spiroethers

Article abstract of DOI:10.1002/anie.201204274

Spiro compounds: An organocatalytic asymmetric method for the C sp 3=H functionalization of the α position of racemic cyclic ethers has been developed. The transformation, mediated by catalytic amounts of an imidazolidinone and strong acid, involves a tandem 1,5-hydride transfer/cyclization and provides access to a structurally diverse series of chiral spiroethers with high levels of enantioselectivity (see scheme). Copyright

Full text of DOI:10.1002/anie.201204274

Angewandte
Chemie
DOI: 10.1002/anie.201204274
Asymmetric Catalysis
À
Organocatalytic Asymmetric Direct Csp3 H Functionalization of
Ethers: A Highly Efficient Approach to Chiral Spiroethers**
Zhi-Wei Jiao, Shu-Yu Zhang, Chuan He, Yong-Qiang Tu,* Shao-Hua Wang, Fu-Min Zhang,
Yong-Qiang Zhang, and Hui Li
The asymmetric synthesis of chiral spiroethers, which are
present in numerous bioactive natural products (Figure 1)
enantioselective reaction of ethers are scarce. In 2005, Sames
and co-workers. reported that Sc(OTf)3 or BF3·Et2O could
À
initiate a direct functionalization of Csp3 H bonds of cyclic
ethers 1 to give racemic spiroethers 2’ (Scheme 1). This
Figure 1. Natural products containing a spiroether moiety.
and pharmaceuticals,[1] is an important endeavor in organic
synthesis. Tremendous efforts have been made during the past
few years toward developing methods for the synthesis of
spiroethers,[2] although of the methods developed, many
involve multiple steps and only a few are enantioselective.[2d–i]
Therefore, the development of methods that are highly
efficient, catalytic, and enantioselective is still required.
The direct and selective functionalization of inactive
À
Scheme 1. Asymmetric funtionalization of Csp3 H bonds for preparing
enantiopure spiroethers. LA=Lewis acid.
À
Csp3 H bonds is not only a significant and actively studied
subject in fundamental organic chemistry,[3] it is also becom-
ing a practical method for organic synthesis because of its
atom- and step economy.[4] Among the reported transforma-
tions, intramolecular redox processes for the direct function-
transformation proceeds through a tandem 1,5-hydride trans-
fer/cyclization redox process.[5b] These results suggested that
an asymmetric catalytic variant should be possible, a process
that would involve the conversion of a racemic mixture of
a cyclic ether into enantiomerically enriched spiroether.
Organocatalysis has emerged as an important method in
organic chemistry and it has been used to effect many
enantioselective transformations.[8] To accomplish the above
À
alization of Csp3 H bonds that are a to heteroatoms are
important for the synthesis of structurally diverse amine and
ether derivatives.[5] Furthermore, since the pioneering work of
Kim and co-workers,[6] there have many good results reported
in the area of intramolecular redox processes for the direct
À
enantioselective Csp3 H functionalization at positions a to
nitrogen atoms.[7] However, examples of the corresponding
enantioselective C H bond functionalization, we envisioned
À
that the formation of an iminium ion through the reaction
between a cyclic ether containing an a,b-unsaturated alde-
hyde group (1) and a chiral organocatalyst (R1NHR2) would
initiate a 1,5-hydride shift and that the resulting enamine and
oxocarbenium moieties would react to give chiral spiroether
2’’ (Scheme 1). Herein, we present our success toward this
goal.
Our investigation started with the use of tetrahydrofuran
1a, which contains both an a,b-unsaturated aldehyde and
a diethylmalonate moiety, as the model substrate for identi-
fying a suitable catalytic system. We envisioned that the
presence of strong acid would be required to ensure that the
iminium ion would be of sufficient electrophility for facilitat-
ing the transfer of the a-hydrogen atom from the THF moiety
of 1a. Thus the combination of a catalytic amount of
(+)-camphorsulphonic acid (CSA) and a proline-derived
[*] Z.-W. Jiao, Dr. S.-Y. Zhang, Prof. Y.-Q. Tu, Prof. S.-H. Wang,
Prof. F.-M. Zhang, Dr. Y.-Q. Zhang, H. Li
State Key Laboratory of Applied Organic Chemistry and
College of Chemistry and Chemical Engineering
Lanzhou University, Lanzhou 730000 (P.R. China)
Prof. C. He
Department of Chemistry, University of Chicago
929 East 57th Street, Chicago, IL 60637 (USA)
[**] This work was supported by the NSFC (Nos. 21072085,
20921120404, 21102061, and 20972059), MOST (“973” Program,
No. 2010CB833203), Key National S&T Program “Major New Drug
Development” of the Ministry of Health of China (2012ZX09201101-
003), and MOE (“111” Program and scholarship award for excellent
doctoral student, No. 86007).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204274.
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secondary amine 3 was tested first. When 1a was treated with
this combination of catalysts in 1,2-dichloroethane (DCE) at
308C for 5 days, the expected spiroether 2a’’ was not obtained
(Table 1, entry 1); the use of stronger acids, such as TfOH and
HClO4, in combination with either amine 3 or 4, also led to no
reaction (Table 1, entries 2–4). Given the outstanding perfor-
(80%), ee value (77%), and d.r. value (3.5:1; Table 1, entry 8)
than that of AgBF4 (Table 1, entry 7). In the presence of only
7, that is, in the absence of AgSbF6 or AgBF4, the reaction did
not proceed at all (Table 1, entry 9). Variation of the solvent
and reaction temperature (Table 1, entries 10–12) showed
that the solvent, CHCl3, and a reaction temperature of 208C
were optimal (91% ee and 5:1 d.r.; Table 1, entry 12).
Table 1: Optimization of the redox reaction of 1a.[a]
Entry Cat. Additive
Solvent
t [days] Yield [%][b]
ee [%][d]
1
2
3
4
5
6
7
8
3
3
3
4
5
6
7
7
7
7
7
7
(+)-CSA C2H4Cl2
5
5
5
5
5
5
3
3
5
3
3
4
n.r.
n.r.
n.r.
n.r.
–
–
–
–
–
TfOH
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
CH2Cl2
CHCl3
HClO4
HClO4
HClO4
HClO4
AgBF4
AgSbF6
–
AgSbF6
AgSbF6
AgSbF6
trace
72 (3.1:1)[c] 44/8
58 (1.2:1)[c] 67/20
80 (3.5:1)[c] 77/11
9
n.r.
–
10
11
12[e]
85 (3.0:1)[c] 71/7
81 (5.0:1)[c] 89/4
81 (5.0:1)[c] 91/4
CHCl3
[a] All reactions were performed using 0.1 mmol of 1a, 0.03 mmol of
catalyst in 2 mL of solvent at 308C. [b] Combined yield of diastereomers.
[c] The d.r. values were determined by 1H NMR spectroscopy prior to the
addition of Ph3P=CHCO2Et. [d] Determined by HPLC analysis. [e] The
reaction was carried out at 208C. n.r.=no reaction, TfOH=trifluoro-
methanesulfonic acid, TMS=trimethylsilyl.
mance of imidazolidinones 5 and 6 as LUMO-lowering
catalysts through iminium-ion formation,[9] we tested amines
5 and 6 in combination with HClO4 (Table 1, entries 5 and 6).
To our delight, when 1a was treated with 6 and HClO4 in
DCE at 308C for 5 days, the desired spiroether 2a was
obtained in a yield of 72% (Table 1, entry 6), albeit with a low
ee value (44%). Notably, in order to measure the ee value, the
initial aldehyde product 2’’ was subjected in situ to a Wittig
reaction to give the corresponding unsaturated ethylester
2a.[10]
The presence of a counterion that is more weakly
À
coordinating than ClO4 would lead to an iminium ion with
Scheme 2. Scope of the redox reaction. All reactions were performed using
0.1 mmol of substrate in CHCl3 (0.05m) unless noted otherwise. Yield of
diastereomers after column chromatography are given in parentheses. The
ee values of products were determined by HPLC. The d.r. values were
enhanced electrophilicity (Scheme 1), thus accelerating the
hydride shift. The weakly coordinating anions, BF4 and
À
SbF6À, have been effective for many catalytic reactions.[11]
Therefore, substrate 1a was treated with 7 (the hydrochloride
salt of 6) together with either AgBF4 or AgSbF6 (Table 1,
entries 7 and 8). Both reactions were complete within 3 days,
and the use of AgSbF6 led to the product 2a with higher yield
1
determined by H NMR spectroscopy prior to the addition of
Ph3P=CHCO2Et. The absolute configurations of major products were
determined based on X-ray crystallographic analysis.[13] [a] Reactions were
performed at 208C. [b] Reactions were performed at 08C. [c] Reaction was
performed on a 1 mmol scale. Bn=benzyl, n.d.=not determined.
2
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With optimized reaction conditions (Table 1, entry 12)
established, the scope and generality of this reaction were
investigated using various substituted tetrahydrofuran- or
tetrahydropyran-based substrates containing an a,b-unsatu-
rated aldehyde group (Scheme 2). Again, in order to measure
ee values, the initial aldehyde products were converted in situ
into their corresponding unsaturated ethylesters (2a–2l; E’ =
trans-CHCHCO2Et). Firstly, the use of substrate 1b, which
contains a dibenzylmalonate moiety, gave the product 2b with
an ee value that was similar to 2a, thus indicating that the
nature of the malonate group does not have a significant
impact on enantioselectivity. Further substitution of the THF
moiety led to enhanced enantioselectivity (2c–2i, Scheme 2).
In particular, the use of a spirocyclic substrate led to the
corresponding product with an ee value of 96% (2i;
Scheme 2). In addition, substrates having a gem-dialkyl
group at the C5 atom of the THF ring reacted faster. As
a result, for these types of substrates, the reaction temper-
ature could be lowered from 208C to 08C and good yields and
high levels of enantioselectivity were obtained (2g–2i;
Scheme 2). This increase in rate could be due to the
electron-donating character of the C5 substituents.[12] To
further expand the substrate scope, tetrahydropyran-based
substrates were examined; good yields and high levels of
enantioselectivity were obtained (Scheme 2, 2j–2l). To eval-
uate the synthetic utility of this transformation, a reaction was
conducted on a larger scale: when 1 mmol of substrate 1b
(438 mg) was subjected to the reaction conditions (room
temperature), product 2b was obtained with similar yield
(75%) and similar levels of selectivity (91% ee, 4.4:1 d.r.) in
comparison to those obtained in a reaction of smaller scale
(Scheme 2).
Scheme 3. Proposed mechanism of the redox reaction.
Owing to the steric interaction of the bulky tert-butyl group,[14]
the E enamine is formed preferentially upon 1,5-hydride
transfer of intermediate 8, and exists in two possible con-
formers 9 and 10. Because of the repulsion of dipoles of the
cyclic-oxocarbenium-ion and enamine moieties in conformer
9, we believe that 10 is the more favored conformer.
Conformer 10 then undergoes intramolecular C C bond
formation to afford, after Wittig reaction, (2S, 6R)-2a as the
major product.
À
In conclusion, a novel organocatalytic enantioselective
À
Csp3 H functionalization of the a position of ethers was
developed. A series of chiral spiroethers with various
substituents and ring sizes were prepared from racemic
ethers with good to high levels of enantioselectivity. This
transformation is efficient, economic, tolerant of the presence
of bulky substituents, and proceeds under mild reaction
conditions. Further studies on this type of catalytic enantio-
selective transformation and synthetic applications are under-
way.
The absolute configuration of 2a (2S, 6R) was determined
by X-ray crystallographic analysis of its derivative 5a
(Figure 2).[13] Based on the above results, a plausible mech-
anism is proposed (Scheme 3). First, substrate 1 reacts with 7
under acid catalysis to form the iminium-ion intermediate 8.
Experimental Section
To a flame dried round-bottom flask were added CHCl3 (1 mL),
catalyst 7 (10.5 mg, slightly more than 0.03 mmol, 0.3 equiv),[15]
AgSbF6 (10.3 mg, 0.03 mmol, 0.3 equiv) under argon. The mixture
was stirred for 2 h at room temperature and then a solution of
substrate 1 (0.1 mmol) in CHCl3 (1 mL) was added at 208C. The
reaction was monitored by TLC analysis. After completion, Ph3P =
CHCO2Et (62.6 mg, 6.0 equiv) was added in one portion under argon
and the mixture was warmed to 308C. After completion, the reaction
mixture was purified directly by column chromatography on silica gel
eluting with petroleum ether/ethyl acetate (15:1) to afford 2.
Received: June 1, 2012
Published online: && &&, &&&&
À
Keywords: 1,5-hydride shift · asymmetric catalysis · C
H bond functionalization · organocatalysis · spiro compounds
Figure 2. X-Ray crystallographic analysis of enantiopure 5a. Thermal
ellipsoids are shown at 30% probability.
.
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4
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[13] CCDC 883142 (5a) contains the supplementary crystallographic
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[15] To ensure there was no excess AgSbF6, which could lead to the
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an additional 1 mg of catalyst 7 was added to the mixture.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Catalysis
Z.-W. Jiao, S.-Y. Zhang, C. He, Y.-Q. Tu,*
S.-H. Wang, F.-M. Zhang, Y.-Q. Zhang,
H. Li
&&&& — &&&&
À
Organocatalytic Asymmetric Direct Csp3
H Functionalization of Ethers: A Highly
Efficient Approach to Chiral Spiroethers
Spiro compounds: An organocatalytic
strong acid, involves a tandem 1,5-hy-
dride transfer/cyclization and provides
access to a structurally diverse series of
chiral spiroethers with high levels of
enantioselectivity (see scheme).
À
asymmetric method for the Csp3 H func-
tionalization of the a position of racemic
cyclic ethers has been developed. The
transformation, mediated by catalytic
amounts of an imidazolidinone and
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!