Diastereoselective synthesis of isochromans via the Cu(ii)-catalysed intramolecular Michael-type trapping of oxonium ylides

Article abstract of DOI:10.1039/C8CC06390G

A highly diastereoselective approach for the rapid construction of an isochroman skeleton was achieved by the copper(ii)-catalyzed transformation of alcohol-tethered enones and diazo compounds. This transformation was proposed to proceed through the intramolecular Michael-type trapping of an in situ generated oxonium ylide intermediate. The copper(ii) catalyst may play a dual role in catalyzing diazo decomposition as well as activating the enone unit. With this method, a series of 3,4-substituted isochromans were obtained with excellent diastereoselectivities under very mild reaction conditions.

Full text of DOI:10.1039/C8CC06390G

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Diastereoselective synthesis of isochromans via
the Cu(II)-catalysed intramolecular Michael-type
trapping of oxonium ylides†
Cite this: Chem. Commun., 2018,
54, 12650
Received 6th August 2018,
Accepted 10th October 2018
Gopi Krishna Reddy Alavala,a Farrukh Sajjad,a Taoda Shi,a Zhenghui Kang,a
ab
Mingliang Ma,a Dong Xing *a and Wenhao Hu
*
DOI: 10.1039/c8cc06390g
rsc.li/chemcomm
A highly diastereoselective approach for the rapid construction of with carbonyl electrophiles is predominant due to a wide choice
an isochroman skeleton was achieved by the copper(II)-catalyzed of activating catalysts. In view of the high efficiency of this
transformation of alcohol-tethered enones and diazo compounds. strategy, a novel reaction design by incorporating new types of
This transformation was proposed to proceed through the intra- electrophilic units, as well as developing more efficient catalytic
molecular Michael-type trapping of an in situ generated oxonium systems to allow for the rapid construction of heterocycles with
ylide intermediate. The copper(II) catalyst may play a dual role structural diversity, is highly sought after.
in catalyzing diazo decomposition as well as activating the enone
Isochroman cores constitute the framework of a variety of
unit. With this method, a series of 3,4-substituted isochromans bioactive natural products.10 Examples include penicisochromans
were obtained with excellent diastereoselectivities under very mild D and E from Penicillium PSUF40,11a pergillin from Aspergillus
reaction conditions.
ustus,11b blapsin B from Blaps japanensis,11c and tezettine from
Pancratium maritimiim (Scheme 1C).11d As a result, different
The synthesis of heterocycles has drawn a large amount of atten- approaches have been developed for the synthesis of isochroman
tion in organic chemistry due to their abundance in a majority of skeletons.12 As a result of our continuous research efforts
natural products and drugs.1 Achieving heterocyclic cores through in designing new metal carbene-involved transformations for
multiple bond formation in a single step has always been in great
demand owing to its highly step-economic features.2 Over the past
decade, in situ trapping of active intermediates derived from metal
carbenes has been developed into a powerful strategy for different
types of Multi-Component Reactions (MCR).3–8 In this context, by
applying this interception strategy in an intramolecular manner
starting from alcohol or amine substrates tethered with electro-
philic units, an array of diazo-involved cyclization reactions
has been developed to effectively construct different types
of heterocyclic skeleton (Scheme 1A).9 Among them, expensive
rhodium catalysts are essential for metal carbene formation, and
co-catalysts are generally required for the activation of the electro-
philic unit to enable the trapping process, and aldol-type trapping
a Shanghai Engineering Research Center of Molecular Therapeutics and New Drug
Development, School of Chemistry and Molecular Engineering, East China Normal
University, 3663 North Zhongshan Rd., Shanghai, 200062, China.
E-mail: dxing@sat.ecnu.edu.cn
b School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006,
China. E-mail: huwh9@mail.sysu.edu.cn
† Electronic supplementary information (ESI) available: Information regarding
materials and methods and characterization data of compounds from this study.
Scheme 1 Heterocycle synthesis by the intramolecular trapping of onium
ylides and the design for the rapid construction of isochromans.
CCDC 1849633. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c8cc06390g
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heterocycle synthesis, an efficient method for the synthesis of FeTPPCl showed no catalytic activity at all (Table 1, entry 3),
3,4-substituted isochromans starting from alcohol-tethered and the use of Cu(CH3CN)4PF6 was promising, yielding the
enones and diazo compounds via a transition metal-catalyzed desired cyclization product 3a in 60% yield with excellent
cyclization process could be envisioned (Scheme 1B). The diastereoselectivity and the undesired O–H insertion product
intramolecular Michael-type trapping of an in situ generated was not observed (Table 1, entry 4). Several other copper
oxonium ylide intermediate derived from metal carbene is catalysts were then tested. The reaction did not proceed when
anticipated to fulfill such a process. To achieve this goal, several CuCl was used (Table 1, entry 5). It was promising to find that
difficulties need to be considered: (1) the in situ generated the much cheaper CuSO4 salt also catalysed this reaction, albeit
oxonium ylide intermediate may undergo rapid 1,2-proton with a reduced efficiency (Table 1, entry 6). The reaction
transfer before it can be intercepted by the tethered enone efficiency was further improved by employing Cu(OTf)2 as
unit;3 (2) an intramolecular oxo-Michael addition of the the catalyst (Table 1, entry 7). Different solvents were then
alcohol-tethered enone under metal catalysis may occur to screened, and CH2Cl2 was proven to be the most optimal. With
afford isobenzofurans;13 (3) Michael-type trapping of oxonium other types of halogenated solvents such as DCE and CHCl3,
ylide intermediates with enones is difficult owing to their this transformation was less effective and the undesired oxo-
relatively low electrophilic features compared with carbonyl Michael addition product 5 derived from 1a was observed
compounds.14 Herein, we report our recent results on a (Table 1, entries 8 and 9). Toluene and EtOAc also gave poor
copper-catalyzed cyclization reaction between alcohol-tethered yields of 3a (Table 1, entries 10 and 11). When the reaction
enones and diazo compounds for the efficient construction of temperature was raised to 40 1C, 3a was obtained exclusively in
isochroman derivatives.
78% yield and the stereoselectivity remained excellent (Table 1,
Initially, an alcohol-tethered enone 1a was chosen as the entry 12). Increasing the amount of 2a was helpful for suppres-
model substrate to react with methyl phenyldiazoacetate 2a by sing the formation of 5 and therefore further improved the
employing different metal catalysts. When 1 mol% of Rh2(OAc)4 yield of 3a to 81% (Table 1, entry 13). The absence of a copper
was employed, the desired cyclization product 3a was obtained catalyst led to no consumption of both starting materials,
in 21% yield with good diastereoselectivity, as well as the O–H indicating its indispensable role for the current transformation
insertion product 4 in 65% yield (Table 1, entry 1). Realizing (Table 1, entry 14).
that Rh(II) might be too reactive for the O–H insertion pathway,
With the optimized reaction conditions in hand, the substrate
several other types of metal catalyst were tested. Among them, scope was investigated (Scheme 2). First, a series of aryl diazo
[Pd(allyl)Cl]2 showed a similar catalytic effect (Table 1, entry 2), esters bearing different substituents on the aryl ring were tested.
Different halogen substituents including F, Cl and Br could be
tolerated regardless of their electronic effects, yielding the corres-
Table 1 Condition optimizationa
ponding isochroman products in good yields (3b–3e and 3j).
Several diazo esters bearing electron-donating substituents on
the aryl ring, including those bearing bis- and tris-substituents,
also underwent the desired cyclization to afford the isochroman
products in moderate to good yields (3g–3i, 3k and 3l). Substrates
bearing electronically distinct substituents on the aryl rings of
the enone unit were then investigated. The electronic features
of the different substituents showed less impact, and the
corresponding cyclization products were obtained in moderate
to good yields (3n–3t). Alkyl substituents on the enone unit
were also tolerated, affording the isochroman product in
moderate yield (3u). Substrates with secondary alcohol units
also worked well to give the corresponding cyclization product
in good yield (3v) with a 1 : 1 dr. It is worth mentioning that all
of the isochroman products showed excellent diastereoselec-
tivities to yield the cyclization products as single diastereomers
except for 3v, which showed a 1 : 1 dr. This transformation is
currently limited to the use of donor/acceptor type aryldiazo-
acetates as the diazo source, and a number of other types of
diazo compounds all failed to give the desired cyclization
product.15 Replacing the enone unit with other types of
Michael acceptor, such as ester or cyano groups, also failed
Yield of
Yields of
Entry Catalyst
Solvent
3ab (%) d.r. of 3ac 4/5b (%)
d
1
2
3
Rh2(OAc)4
CH2Cl2
CH2Cl2
CH2Cl2
21
34
90 : 10
90 : 10
—
95 : 5
—
95 : 5
95 : 5
95 : 5
95 : 5
95 : 5
95 : 5
95 : 5
95 : 5
—
65/o5
51/o5
o5/o5
o5/o5
o5/o5
o5/o5
15/o5
o5/10
o5/20
o5/o5
o5/o5
o5/5
e
[Pd(allyl)Cl]2
FeTPPCl
o5
4
5
6
7
8
9
10
11
12 f
13 f,g
14 f,g
Cu(CH3CN)4PF6 CH2Cl2
60
CuCl
CuSO4
CH2Cl2
CH2Cl2
CH2Cl2
DCE
o5
35
63
51
44
25
16
78
81
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
—
CHCl3
Toluene
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
o5/o5
o5/o5
o5
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (10 mol%), to produce the corresponding cyclization product.15 Finally,
a
b
4 Å MS (150 mg), solvent (2.5 mL), r.t., 12 h. Isolated yields; ‘‘o5%’’
the structure and stereochemistry of the products were
unambiguously confirmed by the single crystal X-ray analysis
of 3a, which was concluded to be syn. The analogous
means the product was not observed by 1H NMR of crude mixture.
Determined by 1H NMR of crude mixture. 1 mol%. 2 mol%.
c
f
d
e
g
Reaction at 40 1C. 2a (0.5 mmol).
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To shed light on the mechanism of this transformation, two
control experiments were conducted. First, the O–H insertion
product 4 derived from 1a and 2a was subjected to standard
reaction conditions, but the cyclization product 3a was not
observed even after 24 h (eqn (1)). This result indicated that a
stepwise pathway involving an O–H insertion followed by an
intramolecular Michael reaction is unlikely for the current
transformation. On the other hand, the oxo-Michael adduct 5
from 1a was allowed to react with 2a under standard reaction
conditions, and 3a was also not observed (eqn (2)). This result
indicated that 5 was not the intermediate for the formation of
3a. Moreover, the absence of a copper catalyst showed no
consumption of 1a (the formation of 5 can only be achieved
when in the presence of a copper catalyst, eqn (3)), indicating
that the copper catalyst may play a dual role in catalyzing diazo
decomposition as well as activating the enone unit in the
following Michael addition.
Based on these results and the precedent reports, a plausible
mechanism was proposed (Scheme 3). Diazoacetate 2a was first
converted into copper carbene A, which then reacted with 1a to
afford oxonium ylide B. This oxonium ylide could be further
isomerized into its more stable enolate form C. The O–H
insertion product 4 was generated via 1,2-proton transfer with
this active intermediate (path A). On the other hand, in the
presence of a tethered enone unit, intramolecular Michael-type
trapping of intermediate C would occur to afford the cyclization
product 3a (path B). To rationalize the excellent diastereoselec-
tivity observed for this transformation, a transition state for
the intramolecular Michael-type trapping step was proposed.
Intramolecular hydrogen-bonding between the oxygen atom on
the enolated ylide and the proton derived from the benzyl
alcohol may play a key role in pushing the enone unit away,
to therefore generate the syn-product preferentially (Scheme 3).
To further illustrate the practical applicability of this protocol,
a gram-scale reaction was conducted. With 5 mol% of loaded
catalyst, 4.2 mmol of 1a underwent the desired cyclization to
provide 1.2 g of 3a in 71% yield (Scheme 4a). To establish the
Scheme 2 Substrate scope.
isochroman products were assigned the same configuration
as 3a (Scheme 2, X-ray of 3a).16
(1)
(2)
(3)
Scheme 3 Proposed mechanism and explanation of the stereochemistry.
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3 For selected reviews, see: (a) X. Guo and W. Hu, Acc. Chem. Res.,
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Scheme 4 Gram-scale synthesis of 3a and its synthetic applications.
synthetic significance of this transformation, the isochroman
product 3a was transformed into different analogues (Scheme 4b).
Thus, simple hydrolysis resulted in carboxylic acid 6 in excellent
yield.17 Fischer-indole synthesis afforded the indole substituted
isochroman 7 in moderate yield and the diastereoselectivity was
completely maintained.18 Furthermore, reduction followed by
FeCl3-mediated regioselective annulation resulted in a tetracyclic
molecule 8 bearing 3 stereocenters in good yield with high
diastereoselectivity.19
In conclusion, we have developed a highly diastereoselective
approach for the synthesis of 3,4-substituted isochromans by the
copper(II)-catalyzed cyclization reaction of alcohol-tethered
enones and diazo compounds. This transformation was
proposed to proceed through the intramolecular Michael-type
trapping of an in situ generated oxonium ylide intermediate. The
less expensive copper(II) catalyst played a key role in carbene
formation, enone activation and selectivity control in this trans-
formation. Further application of this strategy to the construc-
tion of heterocycles with structural diversity is in progress.
Financial support from the National Natural Science Foun-
dation of China (21332003, 21772043) is greatly acknowledged.
We also thank the financial support from the Guangdong
Innovative and Entrepreneurial Research Team Program
(No. 2016ZT06Y337).
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Conflicts of interest
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There are no conflicts to declare.
15 For details, see the ESI†.
16 CCDC 1849633 (3a)†.
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