Letter pubs.acs.org/OrgLett
Organocatalytic Enantioselective Vinylogous Michael-Aldol Cascade for the Synthesis of Spirocyclic Compounds Santigopal Mondal,†,§ Subrata Mukherjee,†,§ Santhivardhana Reddy Yetra,†,§ Rajesh G. Gonnade,‡ and Akkattu T. Biju*,†,§,∥ †
Organic Chemistry Division and ‡Centre for Material Characterization, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune 411008, India § Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India S Supporting Information *
ABSTRACT: Enantioselective synthesis of pyrazolone-fused spirocyclohexenols by the secondary amine-catalyzed cascade reaction of α,β-unsaturated aldehydes with α-arylidene pyrazolinones is reported. This formal [3 + 3] organocascade reaction proceeds through a vinylogous Michael-aldol sequence to furnish the spiroheterocycles with three stereocenters including an allcarbon quaternary center in good yields and selectivities. The catalytic generation of α,β-unsaturated iminium ions from enals and tandem dienolate/enolate formation from pyrazolinones are the key for the success of this spiroannulation reaction.
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Scheme 1. Organocascade Catalysis Initiated by Iminium Ion Activation
rganocatalytic enantioselective transformations involving cascade/domino processes constitute one of the powerful synthetic strategies for the rapid construction of complex molecules containing multiple stereocenters in an operationally simple procedure.1 These one-pot operations usually reduce labor and waste as well as allow the use of readily available starting materials.2 Moreover, sensitive/labile intermediates can be efficiently employed in cascade catalysis. In many of the secondary amine-catalyzed cascade reactions, a catalytically generated α,β-unsaturated iminium ion formed from α,βunsaturated aldehyde or ketone and the chiral catalyst will be intercepted at the β-position by a nucleophile followed by the subsequent addition of electrophile at the α-position (Scheme 1, eq 1).3 The Michael-aldol cascade processes are one of the important modes of reactivity in this category, which has been widely employed for the synthesis of functionalized alcohols.3 The synthetic potential of the organocascade catalysis has been extended to vinylogous reactivity,4 which can be achieved either by the use of vinylogous enolate-type nucleophile or by the generation of catalyst-bound vinylogous enamine intermediates (dienamines).5 In 2013, Tian and Melchiorre reported an elegant vinylogous organocascade catalysis for the enantioselective synthesis of spirocyclic oxindoles by the primary amine-catalyzed reaction of β-substituted cyclic dienones with oxindoles (eq 2).6 Another vinylogous reaction that has received considerable attention recently is the vinylogous Michael addition to various electrophiles.7 Over the past decade, vinylogous Michael reaction has been extensively explored using silyl dienolates, butyrolactones, lactams, enones, α,α-dicyanoalkenes, and 3-alkylidene oxindoles as vinylogous Michael donors.8 © XXXX American Chemical Society
In spite of the developments in vinylogous Michael addition reactions, the organocascade involving vinylogous Michael reaction has received limited attention compared to the one involving Michael reaction.9 Herein, we report a secondary Received: July 9, 2017
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DOI: 10.1021/acs.orglett.7b02085 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
organocascade reaction, we envisaged using various Brønsted acid additives. Interestingly, the use of 1.0 equiv of BzOH as additive improved the yield to 89% and ee to 97%, maintaining the 5:1 dr (entry 7).13 The use of trifluoroacetic acid (TFA) was not beneficial in this spiroannulation (entry 8). The use of 1.0 equiv of AcOH as additive slightly improved the dr and ee (entry 9). Finally, with the use of 5.0 equiv of AcOH, the spiro compound 3a was isolated in 94% yield, 10:1 dr, and 98% ee (entry 10).14 Regarding the substrate scope of this reaction, we first examined the tolerance of various α,β-unsaturated aldehydes under the optimized conditions (Scheme 2). A series of enals
amine-catalyzed organocascade involving vinylogous Michaelaldol sequence for the diastereoselective and enantioselective synthesis of pyrazolone-fused spirocyclohexenols by the reaction of α,β-unsaturated aldehydes with α-arylidene pyrazolinones (eq 3).10 This all-carbon formal [3 + 3] annulation proceeds under mild reaction conditions to afford the spiroheterocycles with three stereocenters including an all-carbon quaternary center in good yields. We have recently employed α-arylidene pyrazolinones as bisnucleophiles for the tandem generation of dienolate/enolate under basic conditions and the subsequent interception with chiral α,β-unsaturated acylazoliums generated under N-heterocyclic carbene catalysis.11a These reactions afforded spirocyclohexadienones in good yields and high ee values. Inspired by this work, we envisioned that the tandem dienolate/enolate generated from pyrazolinones could be intercepted with catalytically generated α,β-unsaturated iminium ions, and if successful, this could result in the synthesis of spirocyclohexenols with multiple stereocenters. With this background information, the present studies were initiated by treating 3-(4methoxyphenyl)propenal 1a with α-arylidene pyrazolinone 2a in the presence of the secondary amine catalyst 412 in CH2Cl2 at 30 °C. To our delight, under these conditions, the spirocyclohexenol 3a was formed in 23% yield and 5:1 dr and 94% ee (Table 1, entry 1). Compared to the catalyst 4, the use of TMS-protected diphenyl prolinol 5 and L-proline 6 showed better reactivity but very poor enantioselectivity (entries 2 and 3). A rapid solvent screening indicated that CH3CN and CHCl3 resulted in comparable results (entries 4 and 5), but the reaction returned only traces of 3a when performed in 1,4-dioxane (entry 6). In order to improve the reactivity and selectivity of this
Scheme 2. Scope of the α,β-Unsaturated Aldehydesa
Table 1. Optimization of the Reaction Conditionsa
a
For the conditions, see the Supporting Information. bStructure and stereochemistry confirmed by X-ray analysis.
entry
variation of the standard conditionsa
yield (%) of 3ab
dr of 3ac
ee of 3ad
1 2 3 4 5 6 7 8 9 10
none 5 instead of 4 6 instead of 4 CH3CN instead of CH2Cl2 CHCl3 instead of CH2Cl2 1,4-dioxane instead of CH2Cl2 1.0 equiv of BzOH additive 1.0 equiv of TFA additive 1.0 equiv of AcOH additive 5.0 equiv of AcOH additive
23 82 46 26 25
