Phosphine-Catalyzed Enantioselective [4 + 2] Annulation of o

Letter pubs.acs.org/OrgLett

Phosphine-Catalyzed Enantioselective [4 + 2] Annulation of o‑Quinone Methides with Allene Ketones Zhen Wang,*,†,‡ Tianli Wang,‡ Weijun Yao,‡ and Yixin Lu*,‡,§ †

Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P. R. China ‡ Department of Chemistry, National University of Singapore, Singapore 117543, Singapore § National University of Singapore (Suzhou) Research Institute, Suzhou 215123, P. R. China S Supporting Information *

ABSTRACT: A phosphine-catalyzed highly enantioselective [4 + 2] annulation between ortho-quinone methides and allene ketones has been developed. The reported method led to the formation of chromane derivatives in high yields and excellent enantioselectivity. This is the first time that ortho-quinone methides are employed in phosphine-mediated cyclization reactions.

S

complexes,9 chiral scandium complexes,10 chiral amine,11,12 chiral phosphoric acid,13 chiral NHC,14 chiral squaramide,15 and chiral ammonium fluoride.16 To the best of our knowledge, the employment of o-QMs in phosphine-catalyzed cyclization reactions is unknown.17 This is somewhat surprising, given the fact that annulation reactions are arguably the most common reaction type in phosphine catalysis, and the widespread applications of o-QMs in the aforementioned cyclizations. Thus, we set out to explore the utilization of o-QMs in phosphine-mediated annulations. The projected annulation between o-QMs and allenes may lead to the construction of either a six- or seven-membered ring system, provided an efficient cyclization can be realized (Scheme 1). We first examined the reactivity of allene ester/ketone in their respective annulation with o-QM 2a. While the reaction between benzyl buta-2,3-dienoate and 2a in the presence of phosphine 1c did not yield the desired [4 + 3] cyclization product, the [4 + 2] annulation of allenone 3a and o-QM 2a

ince Lu’s seminal discovery of phosphine-catalyzed [3 + 2] annulation of allenoates with activated alkenes in 1995,1 phosphine-catalyzed cyclizations have become a common synthetic approach for the construction of ring structures.2 Among various cyclization methods, [3 + 2] cyclizations making use of allene esters and activated olefins and imines are the most well studied.3 Other modes of cyclizations have been explored to a lesser extent, among which the Kwon [4 + 2] cycloaddition4 and the Tong [4 + 1] annulation5 represent recent interesting developments. In the past few years, our group has developed a family of amino acid based bifunctional phosphines and actively investigated their applications in asymmetric phosphine catalysis.6 Very recently, we devised a novel [4 + 2] annulation by employing allene ketones as a C-2 synthon, which led to facile preparation of various optically enriched 3,4-dihydropyrans.7 It is certainly desirable to further advance this interesting cyclization mode, especially for the synthesis of biologically important and synthetically interesting molecular architectures. o-Quinone methides (o-QMs) are valuable intermediates in organic synthesis; their high reactivity and propensity to undergo rapid rearomatization make them synthetically very useful.8 In particular, o-QMs have been widely utilized for the asymmetric construction of chromanes, a class of compounds with interesting biological profiles. The [4 + 2] annulation between o-QMs and other two-carbon reaction partners represents a powerful approach for the facile construction of chromanes. In this context, asymmetric [4 + 2] annulation of oQMs have been established via metal catalysis or organic catalysis, and effective systems include chiral rhodium © 2017 American Chemical Society

Scheme 1. Phosphine-Catalyzed Annulation of o-QMs with Allenes

Received: June 24, 2017 Published: July 19, 2017 4126

DOI: 10.1021/acs.orglett.7b01936 Org. Lett. 2017, 19, 4126−4129

Letter

Organic Letters

The scope of enantioselective [4 + 2] annulation of o-QM 2a with different allene ketones was investigated (Table 2).

indeed proceeded smoothly to afford chromane 4a. We subsequently focused on the [4 + 2] annulation between allene ketone 3a and o-QM 2a and examined the catalytic effects of a range of amino acid derived bifunctional phosphines (Table 1). Among different hydrogen bond donating groups, an

Table 2. Substrate Scope of Asymmetric [4 + 2] Annulation of Allene Ketones with o-QM 2aa

Table 1. Catalyst Screening for [4 + 2] Annulation of o-QM 2a with Allenone 3aa

entry

cat.

t (h)

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11d

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1h

20 18 2 3 3 2 24 20 20 24 20

56 76 88 85 80 83 84 80 35 80 87

−74 −16 −56 −38 -85 −23 71 98 15 −4 98

entry

R1

R2

yield (%)b/4

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Me Me Me Me Me Me Et cyclohexyl C6H5 2-F-C6H4 3-Cl-C6H4 2-MeO-C6H4 3-Br-C6H4 4-Me-C6H4 4-F-C6H4 4-Cl-C6H4 2-thienyl 1-naphthyl C6H5

Bn 4-Cl-C6H4CH2 4-CO2Me-C6H4CH2 4-CF3-C6H4CH2 4-MeO-C6H4CH2 1-naphthylmethyl Me Me Me Me Me Me Me Me Me Me Me Me Et

85/4a 90/4b 91/4c 91/4d 89/4e 88/4f 70/4g 85/4h 92/4i 99/4j 83/4k 88/4l 96/4m 94/4n 91/4o 88/4p 89/4q 81/4r 87/4s

98 98 98 (S)d 98 98 98 97 97 98 97 98 97 98 97 98 97 95 (S)d 98 97

a

Reactions were performed with 2a (0.1 mmol), 3 (0.15 mmol), 4 Å molecular sieves (50 mg), and 1h (0.01 mmol) in toluene (1.0 mL). b Isolated yield. cDetermined by HPLC analysis on a chiral stationary phase. dThe absolute configuration was determined to be (S).

Excellent enantioselectivity was attainable regardless of the electronic nature of the aryl moiety in the R2 substituents of the allene ketones (entries 1−6). The R1 substituents of the allene ketones were also well-tolerated, ranging from aliphatic substituents to aryl groups and heteroatom aryl rings. In all the cases examined, good chemical yields and excellent enantioselectivities were obtained (entries 7−19). On the other hand, the N-acyl aminophosphine 1e offered the opposite configuration of products in good yields with good enantioselectivities (82−91% ee, entries 1−2, 9−11, 14−16; see Supporting Information for detail). The absolute configurations of the annulation products were assigned on the basis of X-ray crystal structural analysis of 4c and 4q (entries 3, 17).19 The general applicability of this [4 + 2] annulation was further investigated by examining vinyl-substituted o-QMs (Scheme 2). The optimal catalyst 1h in our earlier optimizations only led to the formation of 5a in 82% ee. We then examined dipeptide phosphine catalysts with different backbones and discovered that O-TBS-L-Thr-L-Thr-derived 1k could drastically improve the stereoselectivity of the reaction. In the presence of 1k, the [4 + 2] annulation product 5a was obtained with 99% ee. Equally excellent enantioselectivities were attainable when different vinyl-substituted o-QMs were employed for the reaction. The dipeptide phosphine 1k also efficiently catalyzed the asymmetric [4 + 2] annulation with o-QM generated in situ

a

Reactions were performed with 2a (0.05 mmol), 3a (0.075 mmol), and the catalyst (0.005 mmol) in toluene (0.5 mL). bIsolated yield. c Determined by HPLC analysis on a chiral stationary phase, the ee value of the opposite configuration is designated as minus. d4 Å molecular sieves (25.0 mg) were added.

amide containing 3,5-bistrifluoromethylbenzoyl moiety offered the best reactivity and moderate enantioselectivity (entries 1− 3). Different amino acid backbones were next tested (entries 4−6), and t-Leu-derived phosphine−amide 1e was proven to be most effective, leading to the formation of the desired chromane in 80% yield and 85% ee. Dipeptide phosphine catalysts, shown to be extremely powerful in our previous studies, were next examined. Interestingly, L-Val-L-Val-derived phosphine-amide 1g displayed the opposite sense of enantioselectivity to that of 1e, affording the desired product in good yield and 71% ee (entry 7). A series of dipeptide phosphines were prepared and examined, aiming to enhance the stereoselectivity of the reaction. A matched configuration of dipeptide phosphines is important to the stereochemical outcome, so are the hydrogen bond donating group in the second amino acid residue (entries 8−10). Under the optimized reaction conditions,18 chromane 4a was obtained in 87% yield and with 98% ee (entry 11). 4127

DOI: 10.1021/acs.orglett.7b01936 Org. Lett. 2017, 19, 4126−4129

Letter

Organic Letters

In summary, we have successfully developed the first phosphine-catalyzed [4 + 2] annulation of o-QMs, by employing allene ketones as a reaction partner. In the presence of dipeptide phosphine catalysts, biologically interesting chormane derivatives were obtained in good yields and with nearly perfect enantioselectivities. Notably, this is the first example that o-QMs have been used in phosphine-catalyzed annulation reactions. We are currently extending the utilization of o-QMs in phosphine catalysis, and our findings will be reported in due course.

Scheme 2. Substrate Scope of Asymmetric [4 + 2] Annulation of Allene Ketones with a Series of o-QMsa

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01936. Synthesis procedure, analytical details, and copies of NMR spectra and HPLC data of all the compounds (PDF) Crystallographic data for 4c (CIF) Crystallographic data for 4q (CIF)

a

The reactions were performed with 2 (0.1 mmol), 3 (0.15 mmol), 4 Å molecular sieves (50 mg), and 1k (0.01 mmol) in toluene (1.0 mL) at room temperature; yield refers to isolated yield; ee values were determined by HPLC analysis on a chiral stationary phase. bThe reaction was performed with 1h as catalyst.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected].

from 2-(tosylmethyl)phenol 6a, affording the corresponding [4 + 2] adduct in 68% yield and 97% ee (Scheme 3). A plausible mechanism is proposed in Scheme 4.

ORCID

Zhen Wang: 0000-0002-1165-2552 Weijun Yao: 0000-0001-6463-2937 Yixin Lu: 0000-0002-5730-166X

Scheme 3. Asymmetric [4 + 2] Annulation with o-QM Generated in Situa

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Z.W. acknowledges the National Natural Science Foundation of China (No. 21602023) and Chongqing Research and Frontier Technology (cstc2016jcyjA0403) for financial support; Y.L. thanks the National University of Singapore (R-143-000-599112) and the National Natural Science Foundation of China (21672158) for generous financial support.

a

The reaction was performed with 6a (0.1 mmol), 3i (0.15 mmol), K2CO3 (0.15 mmol), and 1k (0.01 mmol) in toluene (1.0 mL) at room temperature; yield refers to isolated yield; ee value was determined by HPLC analysis on a chiral stationary phase.

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Scheme 4. Proposed Mechanism

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DOI: 10.1021/acs.orglett.7b01936 Org. Lett. 2017, 19, 4126−4129