and Enantioselective Dienylation of p‑Quinone Methides Enabled by

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Highly Regio- and Enantioselective Dienylation of p‑Quinone Methides Enabled by an Organocatalyzed Isomerization/Addition Cascade of Allenoates De Wang,*,†,‡ Ze-Feng Song,† Wei-Jia Wang,† and Tao Xu*,†,‡

Org. Lett. Downloaded from pubs.acs.org by NOTTINGHAM TRENT UNIV on 05/18/19. For personal use only.

†

Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China ‡ Laboratory for Marine Drugs and Bioproducts & Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China S Supporting Information *

ABSTRACT: A novel catalytic asymmetric dienylation of para-quinone methides with allenoates has been developed. Under mild conditions catalyzed by (R)-SITCP, various dienylated bisarylmethides were obtained in moderate to good yields (up to 82% yield) and excellent enantioselectivities (90−98% ees). The efficacy and robustness were demonstrated by 27 examples of chiral dienylation products. A plausible mechanism, which involved 1,2 H-shift and umpolung of allenoates, was proposed based on deuterium labeling experiments and previous reports.

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arbon−carbon bond formation occupies a key role in synthetic organic chemistry due to its significance in the construction of pharmaceutically and materially important molecules. One of the unique methods for catalytic asymmetric C−C bond formation is 1,6-conjugate addition with paraquinone methides (p-QMs).1 Although different nucleophiles have been employed to effect this asymmetric conversion, the diene-type neucleophile has never been reported to undergo such transformation, not to mention in a catalytic asymmetric fashion. The challenges of dienylation are 3-fold: (1) controlling cis/trans isomerization during diene formation is nontrivial; (2) there have been limited methods generating geometrically specific diene nucleophiles;2 and (3) no asymmetric organocatalytic dienylation has been reported using allenoates and p-QMs, hitherto. In contrast, transitionmetal-mediated/-catalyzed asymmetric dienylation with in situ generated metal diene species had been reported (Figure 1A). In 2005, Walsh and co-workers conquered the problem of asymmetric dienylation of aldehydes/ketones using Zn-diene as the nucleophile and the chiral Lewis acid achieving enantioenriched alcohols with 42∼94% ees.3a Then Krische (2006)3b and Mikami (2009)3c reported dienylation of activated aldehydes with rhodapentacyclodienes (two examples with 88∼89% ees) and dienylsilane/chiral palladium complexes (91∼99% ees), respectively. It is interesting to note that organocatalyzed asymmetric dienylation has long been a less investigated area,3d and asymmetric control of dienylation is still a challenging problem for organocatalysis. © XXXX American Chemical Society

Figure 1. Design of organocatalytic asymmetric dienylation based on allenoates and p-QMs.

Substituted allenoates are widely employed as 1C∼4C synthons in various cycloaddition and allenylation transformations.4 A seminal discovery from the Trost group demonstrated that PPh3-catalyzed isomerization of allenoates Received: March 29, 2019

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DOI: 10.1021/acs.orglett.9b01110 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Selected Condition Optimizationa

to 1,3-conjugated dienes was very inspiring. 5 It was hypothesized that substituted allenotes could serve as potential precursors for dienylation as 4C components. We postulated that using chiral phosphine-catalyzed allenoate isomerization to generate nucleophilic zwitterionic intermediates, if trapped by p-QMs via 1,6-conjugate addition, would represent a unique strategy for asymmetric dienylation (Figure 1C). As simple as it seems, several key questions must be addressed: (a) allenoate homocoupling through cycloaddition and isomerization;6 (b) regioselective control between δ-carbon and αcarbon of the in situ generated zwitterionic intermediate; and (c) different reaction pathways with p-QMs such as 1,4addition and/or cycloaddition (Figure 1C).1 Our studies toward this cascade transformation started from optimization of p-QM 1a and benzyl allenote 2a as model substrates with both phosphine- and nitrogen-based catalysts. We were delighted to find that PPh3 yielded desired δ-carbonselective dienylation product (2E,4Z)-2a in a 72% yield (Table 1, entry 1) compared to none when using DABCO as catalyst (entry 2). The product 2a showed a 2E,4Z geometrical selectivity (dr > 20:1) based on 1H NMR analysis. These results indicated chiral phosphines (CPs) would potentially serve as an asymmetric source for enantioselective dienylation. To our disappointment, mono-PPh3 mimics CP1 and CP2 providing nothing but Trost type (Figure 1B) diene 4a. It was found that this isomerization pathway was inherent and consumed most of the allenoates (vide infra). On the other hand, chiral bisphosphines CP3 provided an inspiring 37% ee albeit with 26% yield of 3a. A further screening of chiral bisphosphine ligands (CP4∼8) was carried out (entries 6− 10), showing only low to moderate enantioselectivities (13∼50% ee) and relatively low yields (19∼37%). Only allenoate isomerization product 4a was isolated.5 The identification of SDP ligand (CP9) stimulated our curiosity when observing 4% yield but 55% ee (entry 11). It was speculated that bisphosphine accelerated the isomerization process due to its two phosphine atoms, while the spiro skeleton of the ligand might be a privileged backbone. Following this idea, it was finally found that monophosphine (R)-SITCP (CP10) dramatically increased both yield (67%) and ee (73%) to a decent level (entry 12, for complete optimization, see Tables S1 and S2 in the Supporting Information).7 Anhydrous molecular sieves (73% yield, 77% ee) and low temperature (65% yield, 82% ee) both were found to slightly benefit the reaction enantioselectivity (entries 13 and 14), if not the efficiency as well. When phenyl allenote (2b) was used as substrates, a satisfying 93% ee was observed, although 30% of 3b was isolated (entry 15). An X-ray crystallography was conducted, establishing the (S,2Z,4E)configuration for 3a (Table 1, X-ray structure). The competitive diene formation was attributed to be the cause of low efficiency, thus double equivalents of allenotes 2b were employed (48% yield, 92% ee, entry 16). To our delight, the reaction yield could further be elevated to 69% yield with 93% ee through dilution of the reaction (entry 17). With optimal conditions in hand, the substrate scope was investigated using 1a and a variety of allenoates 2 (Scheme 1). It was found that electronic variation of the R3 substituent did not affect the enantioselectivities (91∼96% ees for 3b∼3e) as much, compared to yields. The asymmetric dienylation slightly favors electro-withdrawing substituents on R3, as Br-phenyl (3d) and F-phenyl (3e) products showed increased yields (81% and 70%, respectively) compared to 62% yields of Me-

a

All reactions were run with 10 mol % of catalyst on 0.1 mmol with a ratio of 1a/2a= 1/1.2 at the indicated temperature for 12 h unless otherwise noted. bIsolated yield of 3a unless otherwise noted. cee was determined by chiral HPLC. dOnly 4 was detected. eThe reaction was run for 48 h. f2b was used, and yields indicated isolation yields of 3b instead. gDouble the amount of 2b (0.2 mmol) was used. hThe reaction was run at diluted concentration (0.025 M).

phenyl (3c) substituted products. No obvious para-substituent effect was observed based on the above results. When altering the Ar group on the ester functional groups, it was concluded that electron-rich aromatic groups always lead to good enantioselective control (93∼98% ees for 3f∼3h) but moderate yields (62∼47% yields for 3f∼3h). The reaction with Cl-phenyl ester 2i was very complex as significant decomposition was observed, yet high enantioselectivity was achieved (27% yield, 94% ee for 3i). In addition to allenaotes, the p-QM substrate scope was also explored using 2b as the coupling partner (Scheme 2). First, electronic alteration of the R group was performed by synthesizing a variety of para-substituted p-QMs (1b∼1i). We were delighted to see that enantioselectivities were well B

DOI: 10.1021/acs.orglett.9b01110 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 1. Exploration of Allenoate Scopea−c

Scheme 2. Exploration of the p-QMs Scopea−c

a

All reaction were run with 10 mol % of CP10 on 0.1 mmol with a ratio of 1a/2 = 1/2 in 4 mL of toluene and stirring for 48 h at 0 °C unless otherwise noted. bIsolated yield. cee was determined by chiral HPLC. a

All reactions were run with 10 mol % of CP10 on 0.1 mmol with a ratio of 1/2b = 1/2 in 4 mL of toluene and stirring for 48 h at 0 °C unless otherwise noted. bIsolated yield. cee was determined by chiral HPLC. dEthyl ester (−CO2Et) allenote instead of phenyl ester (−CO2Ph) for product 5o′.

maintained (90∼95% ees for 5b∼5i), while efficiency of the reaction largely increased when electron-withdrawing substituents were introduced (63∼82% yields for 5b∼5g). The yields slightly dropped (54% and 43% for 5h and 5i) when electron-donating groups were attached to the R group. Second, exploration of steric factors affecting the asymmetric dienylation outcomes was examined with meta-Br-phenyl 1j and ortho-Br-phenyl 1k. Gratifyingly, the reaction showed good tolerance toward sterically hindered R group as the corresponding dienylation products 5j and 5k were successfully obtained with a respective 65% yield, 95% ee and 41% yield, 94% ee. Third, extended aromatic rings such as the naphthyl group were also compatible under standard reaction conditions, obtaining 5l in 62% yield and 92% ee. Heterocycles such as pyridine- and indole-containing compounds, are generally challenging substrates due to nucleophilic attack toward allenoates. In our study, 5m was successfully obtained in both good yield (75%) and high enantioselectivity (92% ee). In the meantime, four indole-containing p-QMs were synthesized (1n∼1q) and subjected to the asymmetric dienylation condition. The reaction showed high fidelity by affording 5n∼5q in decent yields (48∼63%) and excellent asymmetric control (93∼98% ees). A single crystal was obtained for dienylation product 5o′ (see Supporting Information for details).,8 Finally, three different R-stabilized p-QM 1r∼1t were also tested under standard reaction conditions. It was found that 1r and 1s were compatible under this dienylation condition, providing 5r (57% yield and 95% ee) and 5s (66% yield, 94% ee) in both moderate yields and good ee values,. The reaction of 1t, however, led to severe decomposition with no desired product isolated, suggesting bulky group stabalized p-QMs served as ideal precursors.

Further transformation application of the dienylated products can be found in the Supporting Information. To probe the mechanism of this phosphine-catalyzed isomerization/1,6-conjugate addition cascade, several control reactions were performed as summarized in Scheme 3. First, conjugated diene 4a was not a viable intermediate. The desired 3a was not detected under standard reaction conditions, while recycling starting material 1a and 4a quantitatively (Scheme 3, eq 1). A deuterated allenoate 2a-D (66% deuterium at αcarbon) was prepared and subjected to reaction conditions Scheme 3. Control Experiments and Deuterated Experiments

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Organic Letters

allenoates instead of pre-/in-situ-generated diene. A 1,2 Hshift was observed through deuterated experiments during the reaction coordinates. Further application of this methodology to drug intermediates as well as diene-bearing natural products is currently ongoing.

with 1a (Scheme 3, eq 2). The isolated deuterated product 3aD1 (51% yield) showed 18% and 28% of deuterium incorporation at the C1 and C2 position, respectively. The aromatic phenol OH was also partially deuterated but underwent D−H exchange during flash chromatography (see Supporting Information for details). This experiment indicated that a 1,2 H-shift took place from the C1 to C2 position during the dienylation process. To the best of our knowledge, this accounts for the first experimental evidence for the 1,2 H-shift process during allenoate isomerization. According to these findings and previous literature report,9 we proposed a plausible mechanism of this asymmetric dienylation reaction (Scheme 4).

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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.9b01110. Experimental procedures and spectral data (PDF) Accession Codes

Scheme 4. Proposed Mechanism

CCDC 1901049 and 1901051 contain 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 [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 Authors

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

Tao Xu: 0000-0001-5868-4407 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the “1000 Talents Plan for Young Professionals” and OUC for a startup fund, NSFC (No. U1606403 & No. U1706213), the pilot QNLMST (No.2015ASTP-ES14 & No. 2018SDKJ0403), and National Science and Technology Major Project of China (No. 2018ZX09735-004) for research grants. The project was partially funded by the Engineering Research Center for Marine Bioresources Comprehensive Utilization, SOA (MBRCU201802). T.X. is a Taishan Youth Scholar of Shandong Province. Qingdao municipal government is especially acknowledged for a grant in the “Leading Innovative Scholars” program. We thank Mr. Jian-Yu Zhang of OUC for help with X-ray crystallography.

A chiral phosphine PR3* attacked allenoate 2 generating zwitterionic intermediate I, which underwent a 1,4 H-shift process9 leading to intermediate II. The zwitterionic intermediate II diversified: (1) through delocalization isomerizing to II′ followed by 1,2 H-shift would yield diene product 4 and (2) through 1,6-conjugate addition with p-QM 1, forming aromatized intermediate III would lead to V via intermediate IV through sequential proton transfer and 1,4 H-shift. V could proceed under a similar 1,2 H-shift reaction that ultimately afforded dienylation products 3 and/or 5 and released chiral phosphine (see Supporting Information for large scale and derivatization of 3 and/or 5). In summary, we have developed the first organocatalyzed asymmetric dienylation reaction of p-QMs through a chiral phosphine-catalyzed allenoate isomerization/1,6-conjugate addition cascade. The reaction employed 10 mol % of (R)SITCP as catalyst and operated at 0 °C without any additives in a one-pot fashion. The reaction showed broad substrate scope, and 27 chiral dienylated bisarylmethides were generated in moderate to good yields (up to 82%) and excellent enantioselectivities (90∼98% ees). Mechanism study demonstrated that the asymmetric dienylation proceeded via

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REFERENCES

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