Highly diastereoselective multicomponent cascade reactions: Efficient synthesis of functionalized 1-indanols

Article abstract of DOI:10.1002/anie.201208391

Trapped: A Michael-aldol-type cascade reaction including the trapping of an oxonium ylide through a delayed proton shift leads to the formation of multiple stereocenters in a mild one-pot synthesis. Enantiomerically pure indanol derivatives with four ster

Full text of DOI:10.1002/anie.201208391

Angewandte
Chemie
DOI: 10.1002/anie.201208391
Domino Reactions
Highly Diastereoselective Multicomponent Cascade Reactions:
Efficient Synthesis of Functionalized 1-Indanols**
Jun Jiang, Xiaoyu Guan, Shunying Liu, Baiyan Ren, Xiaochu Ma, Xin Guo, Fengping Lv,
Xiang Wu, and Wenhao Hu*
The rapid formation of complex molecules from simple
materials constitutes a great challenge in modern organic
chemistry and drug discovery.[1] Multicomponent reactions
(MCRs) provide a highly efficient approach for the prepara-
tion of polyfunctional molecules from simple starting materi-
als in an operationally simple and atom-economical manner.[2]
Cascade or domino reactions represent a powerful chemical
tool to build rather complex molecules, for example, complex
ring systems that bear multiple stereogenic centers in an
efficient and highly stereoselective manner.[3] However, in
most cases, multiple steps are required to form precursors for
cascade or domino reactions.[4] The combination of multi-
Scheme 1. Design of new cascade or domino reactions of successive
component reactions and cascade processes in one system
would enable the preparation of multifunctional, highly
complex ring systems in the least number of synthetic steps.[5]
It is well known that protic oxonium ylide A, which can be
generated in situ from a diazo compound and an alcohol, will
trapping active intermediates through delayed proton transfer. E1,
E2 =electrophiles or electrophilic groups.
We first considered the second trapping process as a step
in an intramolecular cascade reaction. In our approach, we
used key precursor 3, which bears bifunctional electrophilic
groups, that is, formyl and enone moieties, and which was used
by Baba and co-workers[10] as a starting material in their
cascade reactions, as the third component to trap the oxonium
ylide. Precursor 3 was easily prepared by condensation of
ortho-phthalaldehyde with the corresponding Wittig reagent,
and obtained in good yield (70–85%). Two possible reaction
pathways are involved in the trapping process of the alcoholic
oxonium ylide (Scheme 2). First, the enone functionality may
trap the oxonium ylide to form the corresponding zwitterionic
intermediate, followed by an intramolecular Aldol-type
reaction to afford functionalized indanol derivatives (path-
way A). Alternatively, the oxonium ylide may first be trapped
by the formyl group, followed by an aza-Michael addition that
À
easily lead to a traditional O H insertion product through an
extremely fast [1,2]-proton-transfer process (Scheme 1, path
a).[6] Excitingly, we were recently able to trap the in situ
generated protic oxonium ylide A by electrophiles or electro-
philic groups to form intermediate B and, followed by
a “delayed proton transfer”, to build complex molecules
with multifunctional groups (Scheme 1, path b).[7] Using this
strategy, polyfunctional bioactive molecules can be rapidly
formed through this method.[8] The chemoselectivity and
stereoselectivity of the desired reaction can be well con-
trolled, especially by applying cooperative catalysis.[9]
In the course of our studies, we were interested to find out
whether the protic zwitterionic intermediate B can be trapped
by additional electrophiles or electrophilic groups prior to the
“delayed proton transfer” process. The additional trapping
process will provide an opportunity to discover new trans-
formations to generate a more diversified structural motif in
one step (Scheme 1, path c). Owing to the involvement of the
additional trapping process, this strategy may also be used to
rationally design new multicomponent cascade reactions.
[*] J. Jiang, X.-Y. Guan, S.-Y. Liu, B.-Y. Ren, X.-C. Ma, X. Guo, F.-P. Lv,
X. Wu, Prof. W.-H. Hu
Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development
East China Normal University
Shanghai, 200062 (China)
E-mail: whu@chem.ecnu.edu.cn
[**] We greatly thank NSFC (nos 21125209 and 20932003) and MOST
(2011CB808600) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208391.
Scheme 2. Two main possible reaction pathways of trapping oxonium
ylide by 3. L=ligand.
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Table 1: Optimization of reaction conditions for the cascade reaction.[a]
leads to 1,3-dihydroisobenzofuran derivatives (pathway B).
Both 1-indanol derivates and 1,3-dihydroisobenzofuran deriv-
atives are found in natural products and many biologically
active and pharmaceutically important molecules.[11]
We started our investigations by employing compound 3a
to trap the oxonium ylide that was generated in situ in the
reaction of methyl phenyldiazoacetate 1a and benzyl alcohol
2a in the presence of a transition-metal catalyst. Cu(OTf)2
was the best catalyst for the Michael-type trapping of
oxonium ylides by enones as electrophilic trapping agents,[12]
and was thus first employed to catalyze this reaction. No
desired product, but a significant amount of side-product
Entry
Catalyst
T [8C]
Yield[b] [%]
d.r.[c]
1[d]
2
Cu(OTf)2
40
RT
RT
RT
–
–
[Rh2(OAc)4]
[Cu(hfaa)2]
[RuCl2(C10H14)]
72
45
68
>20:1
>20:1
>20:1
3[d]
4[d]
[a] Unless otherwise noted, all reactions were carried out by addition of
1a (0.24 mmol) in DCE (1 mL) to a mixture of 2 mol% of Rh2(OAc)4, 2a
(0.24 mmol), 3a (0.2 mmol), and 4 ꢀ MS (0.1 g) in 2 mL of DCE under
an argon atmosphere for 1 h. [b] Determined by 1H NMR analysis.
[c] Yields of isolated product 4 after purification by column chromato-
graphy. [d] Catalyst loading: 10 mol%. Bn=benzyl, DCE=1,2-dichloro-
ethane, hfaa=hexafluoroacetylacetone, Tf=trifluoromethanesulfonyl.
À
from O H insertion was observed (Table 1, entry 1). When
[Rh2(OAc)4] was used as the catalyst instead of Cu(OTf)2, the
reaction went smoothly via pathway A to give product 4a of
a Michael-aldol-type reaction in 72% yield with a d.r. > 20:1
(Table 1, entry 2). Even though we discovered that oxonium
ylides can be successfully trapped by aldehydes,[7b,9a] keto-
nes[7a] and imines,[7c,9a–c] only a few examples have been
reported of the use of enones as electrophiles to trap
oxonium ylides.[12,13] The preference of pathway A
Table 2: Cascade reactions of diazo compounds with alcohols and bifunctional
substrates 3.[a]
over pathway B under the present reaction condi-
tions is possibly due to the second intramolecular
Aldol-type trapping process, which is the driving
force that facilitates the first trapping process. As
a result, polyfunctional complex molecules with four
new bonds and a new ring system were rapidly
generated through this one-pot cascade reaction.
In order to optimize the reaction conditions,
additional catalysts were surveyed. Complexes [Cu-
(hfaa)2] and [RuCl2(C10H14)] also gave the desired
product 4a in 45% and 68% yield, respectively
(Table 1, entries 3 and 4). The effect of solvents and
the reaction temperature was also investigated (see
the Supporting Information), and the best result was
obtained when the reaction was conducted in DCE
at room temperature (Table 1, entry 2).
Under the optimized reaction conditions, this
three-component cascade process showed a broad
tolerance toward various substituents on the aryl
group next to the enone moiety (Table 2, entries 1–
9). The process was also tolerant toward other
alcohols, including bulky alcohols (Table 2,
entries 10–13), and other diazo compounds
(Table 2, entries 14–17). In all cases, the ability to
control the formation of four new stereogenic
centers enabled the synthesis of diverse 1-indanols
Ent.
Ar1 (1)
R (2)
Ar2(3)
Yield[b] [%]
1
2
3
4
5
6
7
8
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
Ph (3a)
72 (4a)
66 (4b)
64 (4c)
75 (4d)
61 (4e)
60 (4 f)
81 (4g)
83 (4h)
75 (4i)
67 (4j)
65 (4k)
70 (4l)
65 (4m)
61 (4n)
71 (4o)
72 (4p)
78 (4q)
pFC6H4 (3b)
pClC6H4 (3c)
mClC6H4 (3d)
oClC6H4 (3e)
pNO2C6H4 (3 f)
pCH3C6H4 (3g)
pCH3OC6H4 (3h)
2-furyl (3i)
pFC6H4 (3b)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
9
Bn (2a)
10
11
12
13
14
15
16
17
CH3 (2b)
CH3CH2 (2c)
(CH3)2CH (2d)
9-anthryl-CH2 (2e)
Bn (2a)
Bn (2a)
Bn (2a)
Bn (2a)
Ph (1a)
mBrC6H4 (1b)
pBrC6H4 (1c)
pCH3C6H4 (1d)
pCH3OC6H4 (1e)
For footnotes, see Table 1.
in good yields and excellent stereoselectivity (d.r. > 20:1). The
formation of multiple new stereogenic centers in one
operation is still very challenging in modern organic chemis-
try. Although various organocatalytic methods have been
reported for the formation of multiple stereogenic centers in
one-pot reactions,[3e,14] this multicomponent cascade reaction
represents a new strategy to build multifunctional ring
systems with four contiguous stereogenic centers, including
one quaternary stereocenter, in a mild, rapid, and efficient
way from simple precursors.
tion with one equivalent each of methyl phenyldiazoacetate
1a, benzyl alcohol 2a, benzaldehyde 5, and chalcone 6, and
a catalytic amount of [Rh2(OAc)4] in DCE (Scheme 3). Four-
component products (10 or 11), which would have resulted
from an intermolecular Michael-aldol-type reaction or from
an aldol-aza-Michael reaction, were not formed (see the
Supporting Information, Table S1). Interestingly, the product
resulting from the trapping of the oxonium ylide by benzal-
dehyde 5 was not observed, either. Instead, the reaction just
À
gave main product 7 from O H insertion in 47% yield,
To expand the cascade trapping process to intermolecular
reactions, we conducted a four-component competitive reac-
product 8 from epoxidation of benzaldehyde in 15% yield,
and product 9 from a Michael-type trapping of the oxonium
2
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Scheme 3. Intermolecular four-component competitive reaction.
Scheme 5. . Chirality induction of oxonium ylide-trapping cascade
reaction to afford 1-indanol building block bearing five stereogenic
centers.
ylide in 13% yield. In addition, compared to chalcone 6, the
trapping of oxonium ylide with 3, which contains a formyl
group in ortho position to the enone moiety, proceeded more
easily (see the Supporting Information, Table S2). All these
results indicated that the formyl moiety in precursor 3
promoted the trapping of the oxonium ylide by the enone
group, which is a synergistic effect between the formyl and
enone groups in the trapping of active intermediates A and B.
Many reaction pathways are possible in this complex
reaction system. To explore the mechanism of this cascade
reaction, deuterated methanol was used for the deuterium
labeling experiment to investigate the proton-transfer process
(Scheme 4). Diastereomerically pure 4r, which showed negli-
gible deuteration (less than 5%) at the tertiary carbon center,
was obtained in a good yield. This result suggests that in this
system the proton transfer was successfully delayed by the
additional trapping process (Scheme 2, pathway A).
diastereoselectivity.[15] In the current multicomponent cas-
cade reaction, the excellent stereoselective control may be
attributed to the congested transition state, which contains all
the three components, thus making chiral transfer from the
auxiliary to the product very effective.
The absolute configuration of 4t was established by X-ray
single-crystal analysis and comparison with the absolute
configuration of (1R,2S,5R)-menthol (Figure 1).
In conclusion, we have developed the first RhII-catalyzed
intramolecular three-component cascade Michael-aldol-type
reaction through the successive trapping of active intermedi-
ates. A delayed proton-transfer process was observed in this
Considering the great diastereoselectivity of these multi-
component cascade reactions, diazo l-menthol ester 1 f was
employed as a chiral auxiliary to prepare optically active
Figure 1. X-ray analysis of compound racemic 4t.
novel multicomponent cascade reaction. Furthermore,
a promising pathway for the introduction of chirality in this
multicomponent reaction was explored and gave optically
pure functionalized 1-indanol derivatives that contain multi-
ple chiral centers with complete stereocontrol. These results
gave an insight into the design of novel multicomponent
cascade reactions through active trapping of intermediates for
the rapid formation of complex cyclic molecules in one step.
Scheme 4. Deuterium labeling experiment for this oxonium ylide-trap-
ping cascade reaction.
products (Scheme 5). Three-component reactions of 1 f,
benzyl alcohol 2a, and bifunctional substrate 3b or 3h
proceed smoothly to give desired products 4s or 4t, respec-
tively, in good yields with excellent diastereoselectivity.
Removal of the chiral auxiliary with LiAlH4 successfully
gave the corresponding optically pure alcohol, which bears
five stereogenic centers, in moderate yield. l-Menthol is
considered one of the most convenient chiral reagents and
widely employed as chiral auxiliary in asymmetric synthesis,
however, examples have been limited to only moderate
Experimental Section
General Procedure: A flask was charged with bifunctional substrate 3
(0.20 mmol), alcohol 2 (0.24 mmol), Rh2(OAc)4 (1.0 mol%), and 4 ꢀ
molecular sieves (0.1 g) in DCE (2 mL). A solution of diazo
compound 1 (0.24 mmol) in DCE (1 mL) was added to the reaction
mixture over 1 h by a syringe pump. The reaction mixture was
purified by flash chromatography on silica gel to give pure 4.
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Received: October 18, 2012
Published online: && &&, &&&&
Keywords: cascade reactions · diastereoselectivity ·
.
multicomponent reactions · oxonium ylides · stereogenic centers
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Domino Reactions
J. Jiang, X.-Y. Guan, S.-Y. Liu, B.-Y. Ren,
X.-C. Ma, X. Guo, F.-P. Lv, X. Wu,
W.-H. Hu*
&&&& — &&&&
Highly Diastereoselective
Multicomponent Cascade Reactions:
Efficient Synthesis of Functionalized 1-
Indanols
Trapped: A Michael-aldol-type cascade
reaction including the trapping of an
oxonium ylide through a delayed proton
shift leads to the formation of multiple
stereocenters in a mild one-pot synthesis.
Enantiomerically pure indanol derivatives
with four stereocenters and a stereogenic
quaternary carbon center were easily
obtained through this method in moder-
ate to good yields.
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