Bioinspired Synthesis of Chiral 3,4-Dihydropyranones via S-to-O Acyl

Feb 27, 2018 - (5) However, in biological systems, S-to-O acyl-transfer reactions are among the most ... α-keto ester 2a with various DTMs 1a–e, ca...
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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Bioinspired Synthesis of Chiral 3,4-Dihydropyranones via S‑to‑O Acyl-Transfer Reactions Hui Jin,† Juyeol Lee,† Hu Shi,†,‡ Jin Yong Lee,† Eun Jeong Yoo,§ Choong Eui Song,† and Do Hyun Ryu*,† †

Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China § Department of Chemistry, Kangwon National University, Chuncheon 24341, Korea ‡

S Supporting Information *

ABSTRACT: A bioinspired synthesis of chiral 3,4-dihydropyranones via S-to-O acyl-transfer reactions is described. Asymmetric Michael addition−lactonization reactions of β,γ-unsaturated α-keto esters with thioesters are catalyzed by proline-derived urea, providing 3,4-dihydropyranones and spiro-3,4-dihydrocoumarin-fused 3′,4′-dihydropyranones in high yield (up to 94%) with excellent stereoselectivities (up to >20:1 dr, 99% ee) under catalyst loadings as low as 1 mol %.

P

Scheme 1. Bioinspired Synthesis of Chiral 3,4Dihydropyranones

yranones and their hydro derivatives are found in many natural products and pharmaceuticals possessing various biological activities.1 The importance of the structural core has encouraged the development of numerous catalytic reactions for the synthesis of chiral 3,4-dihydropyranones.2 Among the different types of strategies for the synthesis of 3,4dihydropyranones, organocatalytic Michael addition−lactonizations of α,β-unsaturated ketone with mild acylating agents have proven quite powerful.2g,h As acylating agents, thioesters have been widely used for amide bond formation in peptide and protein synthesis via S-toN acyl-transfer processes.3 In contrast, S-to-O acyl-transfer reactions have received relatively little attention in organic synthesis. Generally, S-to-O acyl-transfer reactions are carried out under basic conditions4 or in the presence of thiophilic metal cations, including Hg(II), Ag(I), Cu(I), and Cu(II).5 However, in biological systems, S-to-O acyl-transfer reactions are among the most important for ester synthesis.6 In nature, most pyranones are synthesized via the polyketide pathways in which S-to-O acyl-transfer processes play key roles.7 For example, biosynthesis of antibiotic myxopyronin A occurs by means of two steps (Scheme 1, eq 1):7b first, two acyl carrier protein (ACP)-tethered chains are interconnected by means of a Claisen-like condensation reaction catalyzed by ketosynthase (KS), forming a β,δ-diketothioester polyketide product, and then the keto−enol tautomerism of the polyketide intermediate, followed by an S-to-O acyl-transfer process, facilitates lactonization to afford myxopyronin A. Recently, our group has developed highly efficient asymmetric Michael addition reactions of nitroolefins with dithiomalonates catalyzed by proline-derived urea catalyst © XXXX American Chemical Society

PU.8 Enlightened by these findings, we became interested in whether dithiomalonates (DTMs) 1 can be interconnected with β,γ-unsaturated α-keto esters 2 through asymmetric Michael addition to form δ-ketothioester intermediates 3 that then undergo biomimetic lactonization to afford chiral 3,4dihydropyranones (Scheme 1, eq 2). Herein, we disclose the first examples of bioinspired synthesis of chiral 3,4-dihydropyranones through low-loading organocatalytic Michael addition−lactonization reaction cascades of β,γ-unsaturated α-keto esters with thioesters. A series Received: January 30, 2018

A

DOI: 10.1021/acs.orglett.8b00331 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters of seldom reported 3-unsubstituted 3,4-dihydropyranones were synthesized in high yields and ee.2b,d,j Moreover, spiro-3,4dihydrocoumarin-fused 3′,4′-dihydropyranones 7 (Scheme 2) with adjacent quaternary and tertiary stereocenters can be obtained in excellent stereoselectivities by means of this method.

Table 1. Reactive Performance of Various DTMs in the Michael Addition−Lactonization Reaction Sequence

Scheme 2. Michael Addition-Lactonization Reactions of 2 with S-Phenyl-2-oxochroman-3-carbothioates 6a

entry

R

1

3, yield (%),a ee (%)b

4, yield (%)a

5, yield (%),a ee (%)b

1d 2d 3 4 5 6i

ethyl n-propyl phenyl 4-ClC6H4 4-MeOC6H4 phenyl

1a 1b 1c 1d 1e 1c

3a, 45, 85 3b, 43, 82 NDf NDf NDf NDf

e e 4a,d 95 4b,d 90 4c,d 97 e

e e 5a,g 72, 88 5a,g 65, 82 5a,h 67, 92 5a, 89, 89

a

Isolated yield. bDetermined by HPLC analysis. cDetermined by 1H NMR spectroscopy of the crude reaction mixture. dThe reaction was carried out with 1 (0.1 mmol), 2a (0.25 mmol), and PU (10 mol %) in 1 mL of MTBE. eNot determined. fNot detected. gTo a solution of 4 in CH3CN (1 mL) were added H2O, 1,10-phenanthroline, and CuCl2, and the mixture was refluxed for 1 h. hThe reaction mixture was refluxed for 2 h. iOne-pot reaction.

Furthermore, a one-pot process using starting materials 1c and 2a to form product 5a was investigated (Table 1, entry 6). Compared to the step-by-step method (Table 1, entry 3), the one-pot reaction produced 5a in the higher yield of 89% with similar enantiomeric purity (Table 1, entry 6). The developed one-pot reaction was further optimized. At first, bifunctional organocatalysts PTU, PU, epi-PU, and PSQA were screened (Table 2, entries 1−4);8 among these, PU provided the best result, affording product 5a in 89% yield with 89% ee (Table 2, entry 2). Among the solvents tested (MTBE, CH2Cl2, toluene, and PhCl), toluene was the most suitable (Table 2, entries 5−7). Lowering the catalyst loading to 5 mol % had little effect upon yield or ee (Table 2, entry 8). Further reduction of catalyst loading to 2 mol % yielded 5a with the same ee of 90% (Table 2, entry 9), although a longer reaction time was needed. Gratifyingly, lowering the reaction temperature to 0 °C at 5 mol % catalyst loading improved the ee to 93% (Table 2, entry 10). With the optimized reaction conditions in hand, we examined the substrate scope of the reactions between DTM 1c and various β,γ-unsaturated α-keto esters 2 (Table 3). Regardless of the electronic properties of the substituents of the aromatic substrates 2 (Table 3, entries 1−10), products 5 were obtained with high yields of 71−94% and high ee of 90−94%. When the R1 group of 2 was changed to the ethyl group (Table 3, entry 11), the rate of the reaction was decreased significantly in a reaction carried out with 10 mol % of PU at rt, affording product 5k with a low yield of 54% and 86% ee. In contrast, when the R1 group was changed to the PMB group, the reaction proceeded smoothly under standard conditions, affording product 5l with 78% yield and 87% ee (Table 3, entry 12). Aliphatic β,γ-unsaturated α-keto esters also performed well in the reaction (Table 3, entries 13 and 14). However, when the R2 group was a secondary cyclohexyl group,

a

The reactions were carried out with 6 (0.1 mmol), 2 (0.25 mmol), and PU (1 mol %) in chlorobenzene (0.5 mL) at rt for 1−5 h.

Initially, we investigated the expected reactions of β,γunsaturated α-keto ester 2a with various DTMs 1a−e, catalyzed by 10 mol % of PU. As listed in Table 1, when aliphatic DTMs 1a and 1b (Table 1, entries 1 and 2) were employed, only the corresponding Michael adducts 3 were isolated in good ee, and the desired tandem lactonization did not occur under the reaction conditions used. Gratifyingly, when the aromatic DTMs 1c−e (Table 1, entries 3−5) were used, the sequential lactonization reactions proceeded well, affording the lactonized product 4 with trans configurations as single diastereomers,9 and the Michael adducts 3 were not detected in the reaction process. However, ee values of products 4 cannot be determined by HPLC owing to the easy degradation of 4 in HPLC columns; rather, chemoselective decarboxylation reaction of thioester group of 4 was carried out to provide 3unsubstituted 3,4-dihydropyranone 5a, the ee of which could be determined. After various conditions were examined, a hydrolysis−decarboxylation reaction of thioester group of 4a catalyzed by 10 mol % of Cu(II)-phenanthroline complex efficiently afforded 3-unsubstituted 3,4-dihydropyranones 5a in 72% yield with 88% ee (Table 1, entry 3).10 Under the same conditions, chloro-substituted lactone 4b afforded 5a in 65% yield with 82% ee (Table 1, entry 4), and methoxy-substituted lactone 4c provided 5a in 67% yield with 92% ee in 2 h. B

DOI: 10.1021/acs.orglett.8b00331 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

substituted DTMs were not efficient substrates. The absolute configuration of 5 was determined by comparing the optical rotation data and NMR data of 5k with the literature results.2b Encouraged by these results, we next investigated the considerably more challenging reactions between S-phenyl-2oxochroman-3-carbothioates 6 and β,γ-unsaturated α-keto esters 2 to yield spiro-3,4-dihydrocoumarin-fused 3′,4′dihydropyranones 7 with adjacent quaternary and tertiary stereocenters (Scheme 2).11 Asymmetric constructions of spirocyclic chiral centers are exciting synthetic challenges.12 Due to their inherent three-dimensionality, spiro scaffolds have been increasingly employed in drug discovery.13 By means of this method, we can combine biologically interesting 3,4dihydrocoumarins 14 and 3,4-dihydropyranones together through a spiro building block. We first treated 6a with 2a under the developed conditions (5 mol % of PU, toluene, rt). To our delight, the reaction was completed in 0.5 h, and the desired product 7a was obtained in 81% yield with excellent stereoselectivity (single diastereomer, 99% ee). Further modification of the reaction conditions allowed the reaction to perform well using just 1 mol % of PU in chlorobenzene.15 It is worth mentioning that high catalyst loading (typically 20−30 mol %) is a very common drawback of organocatalytic reactions.16 We then explored the substrate scope. Various Sphenyl-2-oxachroman-3-carbothioates 6 and β,γ-unsaturated αketo esters 2 were examined, and all products were determined to be single diastereomers with excellent enantioselectivities of 98−99% ee (Scheme 2). Aliphatic substrate 2 also produced the product 7k in 72% yield with 97% ee. Additionally, a gram-scale experiment was performed with 2 mol % of PU to afford 1.20 g of 7a with 76% yield and 99% ee. The absolute configuration of 7j was determined by X-ray analysis (CCDC 1820511), and the stereochemistries of the other products 7 were assigned accordingly. To explain the high levels of stereoselectivity, we propose the following plausible mechanism (Scheme 3). The β,γ-unsatu-

Table 2. Optimization of the One-Pot Michael Addition/ Lactonization/Hydrolysis/Decarboxylation Reaction Sequencea

entry

cat. (mol %)

solvent

time (h)

yieldb (%)

eec (%)

1 2 3 4 5 6 7 8 9 10d

PTU (10) PU (10) epi-PU (10) PSQA (10) PU (10) PU (10) PU (10) PU (5) PU (2) PU (5)

MTBE MTBE MTBE MTBE CH2Cl2 PhMe PhCl PhMe PhMe PhMe

2 1 1 12 4 2 2 3 18 12

85 89 85 90 87 92 90 90 85 82

89 89 −52 83 82 90 83 90 90 93

a Unless otherwise noted, the first step of all reactions was carried out with 1 (0.1 mmol), 2 (0.25 mmol), and catalyst in 1 mL of solvent at rt. bIsolated yield. cDetermined by HPLC analysis. dThe reaction was carried out at 0 °C.

Table 3. Substrate Scope of the One-Pot Michael Addition/ Lactonization/Hydrolysis/Decarboxylation Reaction Sequencea

Scheme 3. Proposed Mechanism and Computed Relative Activation Energy (in kcal/mol) of TS-Si and TS-Re entry 1 2 3 4 5 6 7 8 9 10 11e 12 13 14

R1 Me Me Me Me Me Me Me Me Me Me Et PMB Me Me

R2 phenyl 4-FC6H4 4-ClC6H4 4-BrC6H4 3-BrC6H4 4-MeC6H4 4-MeOC6H4 2-naphthyl 2-thiophene-yl 2-furyl phenyl phenyl isobutyl cyclohexyl

5 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 5m 5n

time (h) 12 12 12 12 16 12 16 16 16 12 48 16 18 36

yieldb (%) 82 88 83 86 74 81 94 83 71 84 54 78 88 60

d

(90) (91)d

(90)d

(87)d

eec (%) 93 92 90 92 92 91 91 94 93 90 86 87 93 89

Unless otherwise noted, first step of all reactions was carried out with 1 (0.1 mmol), 2 (0.25 mmol), and PU (5 mol %) in 1 mL of toluene at 0 °C. bIsolated yield. cDetermined by HPLC analysis. dIsolated yield of 4 is given in parentheses. eThe reaction was carried out with 10 mol % of PU at rt. a

rated α-keto ester having an s-cis conformation coordinates to the urea moiety of the catalyst PU,17 with the methyl ester on the same side as the 3,5-bis(trifluoromethyl)phenyl group of PU, and the thioester is deprotonated by the tertiary amino group of N-methylpyrrolidine of PU and then activated by the protonated amino group (Scheme 3, 8). Addition of the thioester enolate to the Si face of the β,γ-unsaturated α-keto

product 5n was obtained in the lower yield of 60% over a longer reaction time (Table 3, entry 14). Unfortunately, αC

DOI: 10.1021/acs.orglett.8b00331 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Accession Codes

ester (Scheme 3, TS-Si) produces the major intermediate 9, followed by a tandem lactonization to afford the major product. An alternative approach of the thioester enolate to the Re face of the β,γ-unsaturated α-keto ester adopting an s-trans conformation (Scheme 3, TS-Re) is not favored due to unsuitable steric interactions. The proposed mechanism was further examined by DFT computational studies (Scheme 3, TS-Si, TS-Re). The addition reaction between 1a and 2a catalyzed by PU has been examined using the M06-2X/6-31G (d) (toluene) level of theory with Gaussian 16.18 The computational data reveal substantial differences (2.8 kcal/ mol) between the activation energy of the TS-Re and TS-Si transition states. This result is consistent with the experimentally observed stereoselectivities. To demonstrate the synthetic utility of this methodology, some transformations of the obtained products were carried out. First, products 4 were transformed in situ to Weinreb amides 10 in the presence of AgCF3CO2 without loss of enantiopurities (Scheme 4, eq 1). Then, formal synthesis of

CCDC 1820511 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hui Jin: 0000-0002-7154-5628 Hu Shi: 0000-0002-5466-5783 Jin Yong Lee: 0000-0003-0360-5059 Eun Jeong Yoo: 0000-0003-4027-2441 Choong Eui Song: 0000-0001-9221-6789 Do Hyun Ryu: 0000-0001-7615-4661 Notes

Scheme 4. Transformations of the Obtained Products

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIP) (No. NRF-2016R1A2B3007119, No. 2016R1A4A1011451).

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DEDICATION This paper is dedicated to Professor Elias J. Corey on the occasion of his 90th birthday. antihypercholesterolemic agent 122f,19 was carried out (Scheme 4, eq 2). The PMB protecting group of 5I was removed with TFA and then the resulting carboxylic acid was reduced with BH3DMS, yielding alcohol 11 in 40% yield (two steps), after which the synthesis of 12 could be finished, according to a previously reported method.2f In summary, we have disclosed a bioinspired synthesis of chiral 3,4-dihydropyranones by means of a low-loading organocatalytic Michael addition−lactonization strategy. Michael addition−lactonization reactions of β,γ-unsaturated αketo esters 2 with DTM 1c provide a series of 3-thioestersubstituted 3,4-dihydropyranones 4 in high yields and stereoselectivities, which can be easily transformed to 3-unsubstituted 3,4-dihydropyranones 5 or 3,4-dihydropyranones 10 bearing a Weinreb amide group with retention of their optical purities. Furthermore, biologically interesting spiro-3,4-dihydrocoumarin-fused 3′,4′-dihydropyranones 7 were also obtained in excellent stereoselectivities by means of this method. The high stereoselectivities observed were rationalized by means of DFT calculations. The value of this methodology was further demonstrated by applying it to the formal synthesis of antihypercholesterolemic agent 12.

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REFERENCES

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00331. Experimental procedures and full analytical data (PDF) D

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DOI: 10.1021/acs.orglett.8b00331 Org. Lett. XXXX, XXX, XXX−XXX