N-Heterocyclic Carbene-Catalyzed Aldol ... - ACS Publications

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N‑Heterocyclic Carbene-Catalyzed Aldol-Lactonization of Ketoacids via Dynamic Kinetic Resolution Santigopal Mondal,†,§ Subrata Mukherjee,†,§ Tamal Kanti Das,†,§ Rajesh Gonnade,‡ and Akkattu T. Biju*,†,§ †

Organic Chemistry Division, ‡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: N-Heterocyclic carbene (NHC)-catalyzed enantioselective aldol lactonization of acyclic ketoacids, proceeding via dynamic kinetic resolution, is presented. The carbene generated from the chiral aminoindanol-derived triazolium salt in the presence of LiCl was the key for the success of this transformation. The reaction allowed the diastereoselective and enantioselective synthesis of cyclopentane-fused β-lactones having three contiguous stereocenters. The reaction products are shown to undergo substrate-controlled β-lactone opening in the presence of amines to afford succinimide derivatives with four contiguous stereocenters. KEYWORDS: N-heterocyclic carbenes, organocatalysis, aldol lactonization, β-lactones, DKR strategies, ketoacids

N

Scheme 1. Aldol Lactonization of Ketoacids for the Synthesis of β-Lactones

-Heterocyclic carbene (NHC) organocatalysis has emerged as a powerful synthetic strategy for the enantioselective construction of carbocycles and heterocycles as well as acyclic molecules, which are medicinally and biologically important.1 Despite these advances in asymmetric catalysis, NHC-catalyzed transformations proceeding via dynamic kinetic resolution (DKR) has been relatively less explored.2 In 2012, the Scheidt group demonstrated an unprecedented intramolecular NHC-catalyzed DKR of various α-substituted β-ketoesters for the synthesis of functionalized βlactones and cyclopentenes.3 This seminal report paved the way for employing DKR strategies in NHC catalysis. Subsequently, the Johnson group reported the NHC-catalyzed enantioselective cross-benzoin reaction and the homoenolate annulation with activated carbonyls using the DKR strategy.4,5 Moreover, the Wang group uncovered the DKR for the synthesis of δlactones via a cooperative NHC/Lewis acid catalysis,6 and the DKR of 6-hydroxy pyranones using an enantioselective redox esterification strategy.7 Very recently, the Chi group disclosed the NHC-catalyzed DKR of α,α-disubstituted carboxylic esters.8 Herein, we report the NHC-catalyzed aldol-lactonization of ketoacids proceeding via the DKR strategy, and the reaction resulted in the diastereoselective and enantioselective synthesis of cyclopentane-fused β-lactones. The aldol lactonization of ketoacids catalyzed by nucleophiles is one of the convenient and straightforward methods for the synthesis of functionalized β-lactones.9 In 2010, the Romo group reported the enantioselective aldol lactonization of ketoacids, using Birman’s homobenzotetramisole derivative10 as the organocatalyst (see Scheme 1, eq 1).11 We envisaged the NHC-organocatalyzed aldol lactonization of racemic acyclic ketoacids for the enantioselective synthesis of cyclopentane© XXXX American Chemical Society

fused β-lactones proceeding via the DKR strategy (Scheme 1, eq 2). This bis-cyclization reaction proceeds via the generation of NHC-bound chiral azolium enolate intermediate,12 which is formed by the reaction of carboxylic acid moiety through in situ activation in the presence of a coupling reagent. The azolium enolate intermediate cyclizes with the tethered keto group through aldol β-lactonization sequence to form β-lactone containing three contiguous stereocenters.3,13 The present study was initiated by the treatment of the ketoacid 1a with the triazolium salt 314 in the presence of the peptide coupling reagent 2-(7-aza-1H-benzotriazole-1-yl)1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) Received: March 1, 2017 Revised: May 6, 2017

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ACS Catalysis and Cs2CO3 as the base. Interestingly, under these conditions, the cyclopentane-fused β-lactone 2a was formed in 83% yield, dr = 2:1, and er = 93:7 (Table 1, entry 1). [Here, dr represents

Scheme 2. Substrate Scope of the Aldol Lactonization Reactiona

Table 1. Optimization of the Reaction Conditionsa

entry

variation of the standard conditionsa

yield of 2ab

dr of 2ac

er of 2ad

1 2 3 4 5 6 7 8 9 10 11 12 13 14

none PivCl, instead of HATU CDI, instead of HATU Na2CO3, instead of Cs2CO3 KOt-Bu, instead of Cs2CO3 DABCO, instead of Cs2CO3 toluene, instead of THF DME, instead of THF CH2Cl2, instead of THF 50 mol % Sc(OTf)3 additive 50 mol % AcOH additive 50 mol % LiBr additive 50 mol % LiCl additive 50 mol % LiCl, 15 mol % of 3, CH2Cl2, instead of THF

83 83 20:1, but the product was racemic (entry 6 in Table 1). The screening of different solvents revealed better reactivity affording 2a in >82% yield, but the dr and er values were not improving with variation in solvents (entries 7−9 in Table 1). At this stage, we considered the use of various additives. The addition of Sc(OTf)3 and AcOH improved the dr, but provided less reactivity (entries 10 and 11 in Table 1). The use of LiBr improved the reactivity, but the dr was 1:1 (entry 12 in Table 1). Employing LiCl as the additive afforded 2a in 68% yield, 5:1 dr, and 94:6 er (entry 13 in Table 1).15 Finally, performing the reaction in CH2Cl2 using 50 mol % of LiCl and 15 mol % of 3 furnished 2a in 70% yield, dr = 10:1, and er = 95:5 (entry 14 in Table 1).16 These were the best reaction conditions identified for this transformation. With the reaction conditions in hand, we then examined the substrate scope of aldol β-lactonization reaction (Scheme 2).

a

General reaction conditions: 1 (0.50 mmol), 3 (15 mol %), HATU (1.5 equiv), LiCl (50 mol %), Cs2CO3 (1.5 equiv), CH2Cl2 (7.0 mL), 25 °C, and 24 h. The diastereomers are separable by column chromatography and are given as combined yields of both diastereomers. The dr value was determined by 1H NMR spectroscopy of crude reaction mixture, and the er value was determined by HPLC analysis on a chiral column. bThe reaction was performed on a 0.25 mmol scale.

The parent system worked well and a series of electronreleasing and electron-withdrawing groups on the aryl ring at the α-keto moiety in 1 are well-tolerated and, in all cases, the cyclopentane-fused β-lactone was formed with good yield, diastereoselectivity, and enantioselectivity (2a−2h). It is noteworthy that the −CF3-substituted substrate resulted in the formation of the β-lactone 2g in 71% yield, dr > 20:1, and er = 93:7. Moreover, substrates with sterically different alkoxycarbonyl groups at the β-position of the carboxylic acid moiety readily underwent smooth β-lactonization, affording the desired products 2i−2k with good yield, enantioselectivity, and excellent diastereoselectivity. In addition, this annulation reaction is not limited to methyl ketones, but instead other alkyl ketones also worked well to furnish the functionalized βlactones in moderate yields (2l, 2m). When the α-aryl keto moiety in 1 was replaced with α-alkyl functionality, the diastereoselectivity dropped to dr = 2:1, while maintaining good reactivity and enantioselectivity (2n, 2o). 3996

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conditions forms the ketene intermediate D, which, upon reaction with NHC, forms the NHC-enolate C. The intramolecular aldol reaction of enolate C could provide the cyclopentane intermediate E, which, upon β-lactonization, affords the cyclopentane-fused β-lactone 2 with the regeneration of the NHC catalyst. It is also conceivable that the cyclopentane alkoxide E adds to the azolium moiety (instead of β-lactonization) to generate the spirolactone intermediate, as proposed by Scheidt and co-workers,3b followed by ring contraction and carbene elimination, results in the formation of 2. The intermediates C and C′ are in rapid equilibrium, because of the basic reaction conditions employed. It is likely that the major diastereomer 2 will be formed from C, where the aryl group R is in pseudo-axial orientation. This conformation is more favorable than C′, which can lead to the minor diastereomer 2′ via the azolium intermediate E′. This may be because of the destabilization effect in C′, which is due to the interaction of the aryl (R) and the alkyl (R1) groups. Interestingly, when the reaction was performed using NaCl (50 mol %) as the additive, the two diastereomers 2a and 2a′ are formed in yields of 43% and 41%, respectively (see eq 3).

To gain insight into the mechanism of the reaction, we have studied the kinetics of the NHC-catalyzed intramolecular cyclization of 1a, leading to the formation of 2a. The reaction proceeds very fast in the first 30 min, affording the major diastereomer 2a in 34% yield. Then, the reaction proceeds relatively slower, and after 24 h, 62% of the major diastereomer was formed.15 Stirring the reaction mixture beyond 24 h did not improve the yield of 2a. The kinetic profile of the reaction with the yield of major diastereomer against time is presented in Figure 1. The formation of the major diastereomer in 62%

Figure 1. Kinetics profile of the NHC-catalyzed aldol lactonization reaction.

sheds light on the DKR in the present case. The kinetic experiment also rules out the possibility of simple kinetic resolution operating in the β-lactonization reaction. Note that the ketoacid 1a was completely consumed under the present reaction conditions, because of the fast conversion to the HATU ester. Mechanistically, the reaction proceeds via the formation of the activated ester A by the addition of HATU to the ketoacid 1 (Scheme 3). The addition of NHC to the activated carboxylate A could generate the NHC-bound acyl azolium intermediate B, which, under basic conditions, generates the NHC-enolate C. Alternatively, it is also likely that the carboxylate A under basic

Under these conditions, the products are expected to be formed by the stereodivergent parallel kinetic resolution (PKR).17,18 The observation of PKR in the presence of NaCl is unclear at this stage. Notably, similar PKR was observed when the reaction was performed in toluene and using LiBr as the additive (Table 1). To examine the reversibility of the transformation, the PKR reaction mixture was subjected to LiCl conditions. Notably, even in the presence of LiCl, the products 2a and 2a′ are formed in 1:1 ratio, indicating no observation of DKR under these conditions. This also shows that 2a and 2a′ are not interconvertible. Next, we focused our attention on the functionalization of cyclopentane-fused β-lactones. The reaction of β-lactones with primary amines resulted in the synthesis of succinimide derivatives in high yields. For instance, treatment of 2a with 4-chlorobenzyl amine afforded the cyclopentane-fused succinimide 5a in 99% yield, dr > 20:1, and er = 95:5 (see Scheme 4). The reaction proceeds via the amine-induced ring opening of βlactones, followed by the intramolecular cyclization to one of the ester moiety. The β-lactone, having electronically different substituents at the 4-position of aryl ring, furnished the succinimides bearing four contiguous stereocenters in excellent yield and diastereoselectivity and good enantiopurity (5b−5d). Moreover, this ring expansion reaction worked well with linear and branched aliphatic amines (5e, 5f). In the case of reaction using the ethyl-ester-substituted βlactone, the structure and stereochemistry of the succinimide 5g was confirmed using single-crystal X-ray analysis (Figure 2).19 The absolute stereochemistry of the chiral centers in the β-lactones 2 (Scheme 2) were inferred in analogy with 5g. The ring-opening reactions of β-lactones were also performed. Heating 2a in toluene at 60 °C afforded the cyclopentene 6a in 95% yield and er = 93:7, proceeding via the decarboxylation (Scheme 5). Moreover, nucleophilic ringopening of 2a using methanol furnished the functionalized cyclopentanol 7a in 95% yield, dr > 20:1, and er = 94:6.

Scheme 3. Proposed Mechanism of the Reaction

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Scheme 4. Substrate-Controlled Conversion of β-Lactones to Succinimides in the Presence of Amines

Letter

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.7b00681.

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Details on experimental procedure, characterization data of all compounds, HPLC data of cyclopentane-fused βlactones and various succinimides (PDF) Single-crystal X-ray data of 5g (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Rajesh Gonnade: 0000-0002-2841-0197 Akkattu T. Biju: 0000-0002-0645-8261 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Generous financial support from Science and Engineering Research Board (SERB-DST), Government of India (Grant No.SR/S1/OC/12/2012) is gratefully acknowledged. Sa.M. and Su.M. thank UGC for the fellowship, and T.K.D. thanks CSIR for the fellowship. We thank Dr. P. R. Rajamohanan for the excellent NMR support and Dr. B. Santhakumari for the HRMS data.

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REFERENCES

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Figure 2. Crystal structure of 5g (thermal ellipsoids are shown with 50% probability).

Scheme 5. Stereoselective Functionalization to Cyclopentenes and Cyclopentanes

In conclusion, we have demonstrated the NHC-organocatalyzed aldol lactonization of acyclic ketoacids to furnish the cyclopentane-fused β-lactones having three contiguous stereocenters with moderate to good yields, diastereoselectivity, and enantioselectivity. The reaction proceeds via the DKR strategy. The NHC-bound azolium enolate generated by the addition of NHC to the activated carboxylate (ketoacid-HATU adduct) is the key intermediate in this transformation. Later, the βlactones are converted to succinimide derivatives with four contiguous stereocenters via the substrate-controlled β-lactone opening in the presence of amines. 3998

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