An Asymmetric, Catalytic (4 + 3) Cycloaddition Reaction of

Letter pubs.acs.org/OrgLett

An Asymmetric, Catalytic (4 + 3) Cycloaddition Reaction of Cyclopentenyl Oxyallylic Cations Michael Topinka,† Kerstin Zawatzky,‡ Charles L. Barnes,† Christopher J. Welch,‡,§ and Michael Harmata*,† †

Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri 65211, United States Merck Research Laboratories, Rahway, New Jersey 07065, United States

‡

S Supporting Information *

ABSTRACT: Treatment of 2-tosyloxycyclopentanone with substituted furans in the presence of a chiral amino alcohol catalyst and K2HPO4 results in the formation of (4 + 3) cycloaddition products with enantioselectivities that exceed 90% in certain cases.

T

Scheme 2. The First Asymmetric, Catalytic (4 + 3) Cycloaddition Reaction

he (4 + 3) cycloaddition reaction is electronically equivalent to the Diels−Alder reaction. In the former, an allylic cation reacts as a dienophile with a diene to produce a seven-membered ring.1 As shown in Scheme 1, depending on the Scheme 1. (4 + 3) Cycloaddition Reaction

methodology was used by Sun, Lin, and co-workers to synthesize a number of natural products.7 They also established that the stereochemical outcome of the reaction is not that which would have been predicted by MacMillan’s model for the Diels−Alder reaction. We corroborated these conclusions through computational analysis of the reaction.8 Hsung later reported a reaction in which an allene oxide is opened by a copper/chiral ligand complex to form a cation that reacts with dienes to afford cycloadducts in good yields with excellent enantioselectivity.9 Our current work was inspired by a report from the MacMillan group detailing the activation of 2-tosyloxycyclopentanone (9) using a combination of a chiral amino alcohol and K2HPO4, in which indoles were used to trap the putative oxyallylic cation intermediate with excellent enantioselectivity.10 Our initial goal

nature of the Z group in the allylic cation, the species formed can evolve into, inter alia, a ketone (e.g., Z = alkoxy or oxyanion) or an alkene (e.g., Z = CH2TMS). The prevalence of sevenmembered rings in natural products that possess important biological activity has continued to provide motivation for exploration of chemistry directed toward the facile synthesis of seven-membered rings.2 Furthermore, the ability to transform (4 + 3) cycloadducts into complex structures not containing sevenmembered rings adds to the interest in further developing the methodology.3 While diastereoselective (4 + 3) cycloadditions employing chiral allylic cations have been explored,4 asymmetric catalytic versions of this chemistry are rare. We reported the first asymmetric, catalytic (4 + 3) cycloaddition reaction in 2003.5 Inspired by MacMillan’s work on the Diels−Alder reactions of chiral iminium ions,6 we reacted amine 2 with dienal 1 in the presence of 2,5-dimethylfuran (3) to afford 4 in 64% yield (Scheme 2). This compound was stereochemically characterized as pyrrole 5 (94.5:5.5 er). The © 2017 American Chemical Society

Received: June 23, 2017 Published: July 25, 2017 4106

DOI: 10.1021/acs.orglett.7b01868 Org. Lett. 2017, 19, 4106−4109

Letter

Organic Letters

destroyed upon substitution of an alkyl group at the 3-position of the furan (Table 1, entries 4 and 5). Using tetrahydrobenzofuran as a diene mitigated this effect only slightly, affording an er of 57.5:42.5 (Table 2, entry 6). We thought that incorporation of an aryl group at the 2position of the furan might increase interactions between the diene and the catalyst and lead to increased enantioselectivity.12 Whether this reasoning is valid remains to be seen, but 2phenylfuran afforded cycloadduct 12g in 60% yield with an er of 91.5:8.5 (Table 2, entry 7). Moving the phenyl group farther from the furan ring increased the yield of cycloadduct dramatically but also resulted in much lower enantioselectivity (Table 2, entries 8 and 9). The two halogenated furans we examined displayed interesting behavior. 2-Chlorofuran afforded a cycloadduct in fair yield with reasonable enantioselectivity (Table 2, entry 10). The surprise, for which we have as yet no good explanation, is that 2-bromofuran gave racemic cycloadduct (Table 2, entry 11). This reaction is reproducible. While we suspected that the cycloaddition might be reversible, limited efforts to establish reversibility have proven negative, and we are continuing to examine this substrate. Finally, 3-bromofuran afforded a cycloadduct in good yield but with poor enantioselectivity (Table 2, entry 12). The results that are most exciting are those that involve furans substituted at the 2-position with atoms from the chalcogen group. Excellent yields and excellent enantioselectivies were observed for 2-phenylthiofuran and various congeners (Table 2, entries 13−15). The same was true for 2-phenylselenofuran (Table 2, entry 16). Furan 11q also gave a cycloadduct in high yield, although the enantioselectivity dropped slightly relative to systems bearing only a monocyclic aryl ring on the sulfur atom (Table 2, entry 17). Replacing the phenyl ring in 11m with a cyclohexyl group led to a large drop in yield and a smaller drop in enantioselectivity (Table 2, entry 18). This supports the idea that aryl groups interact with the catalyst in some way to promote the cycloaddition reaction, especially with respect to yield. As expected from the preceding results, 2-thiomethylfuran afforded the cycloadduct in fair yield with very low enantioselectivity (Table 2, entry 19). Interestingly, while cycloadduct 12l was formed with low enantioselectivity, 12t was formed in very good yield and with an excellent er (94.5:5.5; Table 2, entry 20), indicating that substituents like the 2-phenylthio group are key to both the yield and enantioselectivity in this process. Finally, placing that phenylthio group at the 3-position of the furan was deleterious, giving a cycloadduct with only a low er in 59% yield (Table 2, entry 21). There are many mechanistic questions associated with this reaction. According to the model proposed by MacMillan for the attack of indoles on an oxyallylic cyclopentenyl cation complexed to an amino alcohol like 3, a single carbon, highlighted in Figure 1, is preferred for attack by the nucleophile, and the facial selectivity is determined by a π-stacking interaction between the oxyallylic cation and one of the naphthyl rings of the catalyst. The model is reliably predictive in MacMillan’s chemistry. The approach of a 2-substituted furan to the oxyallylic cation consistent with this analysis is shown in Figure 1b. Cycloadducts 12m and 12p were recrystallized to enantiomeric purity, and their structures and absolute stereochemistries were determined by X-ray analysis (anomalous dispersion). The structures of all of the other cycloadducts derived from 2-substituted furans were

was to use the same chemistry to see whether it could be parlayed into an asymmetric (4 + 3) cycloaddition reaction. While little optimization was performed, we did investigate several variables in a preliminary fashion. The results are shown in Table 1. Table 1. Optimization of the Cycloaddition

entry

modificationsa

1 2 3

none 4 equiv of H2O; 5 equiv of K2HPO4 4 equiv of H2O; 5 equiv of K2HPO4; 10 (30 mol %) 2 equiv of 2-Me-furanb 4 equiv of TFE sans H2Ob 2-Cl-cyclopentanoneb C6H6 solventb C6H5CF3 solventb without 10b catalyst, no K2HPO4b no H2Ob

4 5 6 7 8 9 10 11

time (h)

yield (%)

130 130 95

43 55 55

74:26 74:26 74:26

95 105 236 85 115 95 95 95

54 57 42 50 58 0 7 40

74:26 63.5:36.5 66.5:33.5 66:34 64.5:35.5 n.d.d n.d. 74:26

erc

a

Changes to standard reaction conditions. bThese entries include the modifications of entry 3. cEstablished via GC analysis using a JWCyclosil column. dNot determined.

We began our studies using 2-methylfuran (11a) as the diene and 9 as the precursor to the dienophile. Under Macmillan’s conditions, using 10 as the catalyst (20 mol %) along with 2 equiv of K2HPO4 and 1 equiv H2O in C6F6 as the solvent, we obtained a 43% yield of cycloadduct (74:26 er; Table 1, entry 1). We hoped to improve this exciting result and found that the use of 5 equiv of K2HPO4 and 4 equiv of H2O improved the yield to 55%, with the enantioselectivity remaining unchanged (Table 1, entry 2). These reactions were slow, and we anticipated that increasing the amount of catalyst would increase the reaction rate. This was indeed the case (Table 1, entry 3), although there was no change in yield or enantioselectivity. While we chose to use excess diene (10 equiv) in this first study, we did find that we could use as little as 2 equiv of diene and obtain essentially the same result. Substituting a more acidic additive than water led to a decrease in enantioselectivity (Table 1, entry 5). Further, the use of 2chlorocyclopentanone led to a decrease in both yield and enantioselectivity, a possible manifestation of chloride inhibition.11 These results make sense in the context of the model one can use for rationalizing the stereochemical outcome of these reactions, as will be discussed later. With a reasonable set of reaction conditions in hand, we set out to find a diene or class of dienes that would give both high yields and high enantioselectivies in this process. The results are summarized in Table 2. Increasing the length of the substituent on the furan led to increases in yield and enantioselectivity (Table 2, entries 1−3). Interestingly, all enantioselectivity was 4107

DOI: 10.1021/acs.orglett.7b01868 Org. Lett. 2017, 19, 4106−4109

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Organic Letters Table 2. Asymmetric, Catalytic (4 + 3) Cycloaddition Reactions

Determined either by GC using a JW-Cyclosil column or by supercritical fluid chromatrography (CO2/MeOH) using a Chiracel OD-3, OJ-3, or Lux-2 column. See the Supporting Information for details.

a

of the furan (Figure 1c). This is precisely what we found, so the structure of 12l as drawn represents the absolute stereochemistry of the major isomer of this cycloadduct. In conclusion, we have discovered a new catalytic, asymmetric (4 + 3) cycloaddition reaction. The process works especially well with 2-arylchalcogenofurans, giving cycloadducts in high yields with excellent enantioselectivies. The reaction is slow, and there

assigned stereochemistry consistent with these experimental results. We were also able to purify cycloadduct 12l to enantiomeric purity. The previously mentioned model would suggest that the bromine substituent would end up on the opposing side of a pseudosymmetry plane bisecting the cycloadduct through the double bond and the carbonyl group vis-à-vis substituents on C-2 4108

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Letter

DEDICATION This paper is dedicated to Professor Paul A. Wender (Stanford) on the occasion of his 70th birthday.

Figure 1. (a) MacMillan model for interaction of cyclopentenyl oxyallylic cation and amino alcohol 3 (methyl groups removed for clarity). (b) Putative approach of a 2-substituted furan to oxyallylic cation in such a complex, looking down on the oxyallylic cation as indicated, with the naphthyl group removed. (c) As in (b) for a 3substituted furan.

is evidence to suggest that the substitution patterns that enhance the stereoselectivity also slow the reaction. This must be studied further. New results will be reported in due course.

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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.7b01868. Experimental procedures and GC, LC, and spectroscopic data (PDF) Crystallographic data for 12l (CIF) Crystallographic data for 12m (CIF) Crystallographic data for 12p (CIF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Christopher J. Welch: 0000-0002-8899-4470 Michael Harmata: 0000-0003-3894-2899 Present Address § C.J.W.: Welch Innovation, LLC, 29 Washington Drive, Cranbury, NJ 08512, USA.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the National Science Foundation (CHE1463724) for support, Professor David W. C. MacMillan (Princeton) for a gift of several chiral amino alcohols, and Halocarbon Products Corporation for a gift of trifluoroethanol. K.Z. thanks the MRL Postdoc Program. 4109

DOI: 10.1021/acs.orglett.7b01868 Org. Lett. 2017, 19, 4106−4109