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And Iodolactonization, and Cycloetherification

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And Iodolactonization, and Cycloetherification Lewis base catalysis of bromo- and iodolactonization, SPECIAL FEATURE and cycloetherification Scott E. Denmark1 and Matthew T. Burk Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, IL 61801 Edited by Eric N. Jacobsen, Harvard University, Cambridge, MA, and approved July 13, 2010 (received for review April 17, 2010) Lewis base catalyzed bromo- and iodolactonization reactions have been developed and the effects of catalyst structure on rate and cyclization selectivity have been systematically explored. The effects of substrate structure on halolactonization reactions and the interaction of those effects with the effects of catalyst Fig. 1. General scheme of halocyclization reactions. structure have been investigated, leading to synthetically useful improvements in cyclization selectivity. The knowledge acquired was applied to the development of Lewis base catalyzed bromo- properties of chiral Lewis base catalysts from those of readily and iodocycloetherification reactions. The ability of some of the available achiral analogs is highly desirable. surveyed catalysts to influence the cyclization selectivity of Halolactonization and cycloetherification reactions can pro- halolactonization reactions demonstrates their presence in the duce either of two constitutional isomers, arising from cyclization transition structure of the product-determining cyclization step. in an exo or endo fashion (24). The ratio of the two isomers is This observation implies that chiral derivatives of these catalysts influenced largely by the substrate, the identity of the halogen, have the potential to provide enantioenriched products regardless and the choice of reaction conditions. Under conditions wherein of the rates or mechanisms of halonium ion racemization. the halonium ion is undergoing rapid exchange, the product- determining step must also be the stereochemistry-determining CHEMISTRY halocyclofunctionalization ∣ halogenation step. Therefore, the ratio of constitutional isomers produced in the presence of an achiral Lewis base catalyst serves as an in- lectrophilic halocyclizations of olefins, in which electrophilic dicator of the presence of the catalyst in the stereo-determining Ehalonium ions are generated from olefins and opened intra- transition structure. This knowledge would allow the search for molecularly by nucleophilic functional groups (Fig. 1), are versa- an enantioselective catalyst to focus on classes of compound tile synthetic transformations with proven applications to the whose presence in and capacity to influence the relevant transi- synthesis of biologically relevant molecules (1–6). The develop- tion state structure has been demonstrated. ment of catalytic enantioselective halocyclization methods is a In this paper we report a systematic investigation into the topic of increasing interest in synthetic organic chemistry, one influence of Lewis base catalysts on the rate and constitutional site selectivity in bromo- and iodo- lactonization reactions. that presents unique challenges and opportunities for various endo exo paradigms of catalysis in addition to the obvious importance The changes in the ratio of 6- to 5- cyclization products induced by the presence of a wide range of achiral Lewis base and utility of this transformation. To date, only a few notable suc- catalysts provides evidence for the presence of the Lewis base cesses have been reported; these include the use of chiral Ti-salen in the site-selectivity-determining step, whereas in situ IR mon- complexes in iodoetherification (7) and cinchonidinium phase- itoring provides comparative rate data. These findings are then transfer catalysts in iodolactonization (8). Recently, modified applied to the development of Lewis base catalysis of bromo- Cinchona alkaloids have been successfully employed in catalytic and iodo-etherification reactions. enantioselective chlorolactonization (9), as well as a catalytic enantioselective bromolactonization of 1,3-eneynes via conjugate Results opening of achiral bromonium ions (10–15*). The program to evaluate the feasibility of Lewis base catalysis of Careful mechanistic studies by Brown and coworkers and from halofunctionalization of isolated double bonds would involve these laboratories identified a serious obstacle to the develop- electrophilic bromine and iodine sources (halosuccinimides) in ment of catalytic enantioselective iodination and bromination conjunction with unsaturated carboxylic acids and alcohols. For methods, namely the propensity of iodonium and bromonium the initial survey of Lewis bases, 5-phenyl-4-pentenoic acid (1a) ions (but not chloronium ions) to undergo degenerate halogen was chosen as the test substrate and a standard experimental pro- exchange with olefins (Fig. 2) (16–19). This process racemizes cedure was adopted. All reactions were run in dichloromethane the halonium ions at rates that can compete with nucleophilic at 0.15 M in substrate with 1.2 equivalent (equiv) of electrophile capture. Chiral Lewis base catalysts have the potential to prevent and 0.05 equiv of Lewis base. The temperature was adjusted this or other racemization processes, if they remain bound to the such that the background (uncatalyzed) reaction was negligible. halonium ion until the newly created stereocenters are irreversi- A broad selection of Lewis bases was evaluated for kinetic com- bly set, thus maintaining a chiral environment regardless of exchange. Lewis base catalysis of halogenation has been reported – Author contributions: S.E.D. designed research; M.T.B. performed research; and S.E.D. in several different contexts (20 23), as have enantioselective and M.T.B. wrote the paper. halocyclization reactions promoted by stoichiometric amounts The authors declare no conflict of interest. of chiral Lewis bases (13–15), but the paucity of catalytic, enantio- This article is a PNAS Direct Submission. selective Lewis base catalyzed halogenations suggests that some *Wacker-type catalytic enantioselective bromination and chlorination have been of the aforementioned systems do not preserve the stereochemi- reported (11, 12), as have enantioselective iodination reactions using stoichiometric cal integrity of intermediates as described here. Given the signif- amounts of chiral ligands (13–15). icant effort required for the preparation of new chiral Lewis 1To whom correspondence should be addressed. E-mail: [email protected]. bases, and the structural and functional diversity of the reported This article contains supporting information online at www.pnas.org/lookup/suppl/ achiral Lewis base catalysts, a systematic means of inferring the doi:10.1073/pnas.1005296107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1005296107 PNAS Early Edition ∣ 1of6 Downloaded by guest on October 4, 2021 Table 1. Catalyst survey for Lewis base catalyzed bromolactonization t1∕2 Reaction Yield Entry Catalyst (min)* time (min)† (%)‡ 2aa∶3aa§ 1 None >180 180 13 25∶1 2 ðMe2NÞ2C¼O >180 180 36 23∶1 3 n-Bu3P¼O >180 180 47 51∶1 4 ðMe2NÞ3P¼O >180 180 15 50∶1 5Me2S¼O25609323∶1 6 ðMe2NÞ2C¼S<0.5 8717.3∶1 7Ph3P¼S<0.5 88291∶1 8 n-Bu3P¼S<0.5 88975∶1 9Cy3P¼S<0.5 87825∶1 10 ðMe2NÞ3P¼S<0.5 8873.4∶1 11 ðCH2Þ4S<0.5 88927∶1 12 Me2S 6 20 94 19∶1 13 ðPhSÞ2 >180 180 8 N/D 14 n-Bu3P¼Se <0.5 87885∶1 15 ðMe2NÞ P¼Se <0.5 8888.1∶1 Fig. 2. The racemization of halonium ions by degenerate exchange; nonde- 3 16 ðPhSeÞ 0.5–188494∶1 generacy induced by the presence of a chiral Lewis base. 2 17 n-Bu3P<0.5 57538∶1 18 ðMe2NÞ3P<0.5 8866.7∶1 petence. The optimal catalyst was then employed in a brief survey 19 Br2 <0.5 864400∶1 of olefinic substrates with varying double bond geometries and substituents. *Determined by React-IR monitoring, reactions performed on 0.2 mmol of 1a, in 1.5 mL of CH2Cl2 †Time elapsed before quenching Bromolactonization. The influence of Lewis bases on the rate ‡Determined by integration of 1H NMR signals for H-6 against 1a and cyclization selectivity in the bromolactonization of with 1;2;4;5-C6H2Cl4 internal standard N-bromosuccinimide (NBS) was evaluated first. Reaction pro- §Determined by integration of 1H NMR signals for H-6 gress was measured by the disappearance of the IR band at 967 cm−1. The yields and ratios of cyclization products 2aa and 1 3aa were assayed by H NMR integration against an internal 3.4∶1–94∶1. Highly reactive catalysts that also lead to increases in standard. the already high endo/exo selectivity included Ph3P¼S (entry 7), The results from the Lewis base survey are compiled in Table 1 n-Bu3P¼S (entry 8), n-Bu3P¼Se (entry 14), ðPhSeÞ2 (entry 16), and are organized by donor heteroatom. Under the standard re- and n-Bu3P (entry 17). Of the Lewis base catalysts surveyed, the action protocol, the mixture was homogenous and the rate of the highest endo selectivity was observed in the presence of Ph3P¼S background reaction in the absence of catalyst was insignificant and ðPhSeÞ2, but the highest overall endo selectivity was observed (entry 1). The oxygen donors ðMe2NÞ2C¼O, n-Bu3P¼O, and in the control experiment with a catalytic quantity of Br2 (entry ðMe2NÞ3P¼O (entries 2–4) were only marginally faster than 19). Substantial reductions in the ratio of 2aa to 3aa were the background rate and were still incomplete after 3 h. On observed in the presence of ðMe2NÞ2C¼S, ðMe2NÞ3P¼S, the other hand DMSO (entry 5), which could function as either ðMe2NÞ3P¼Se, and ðMe2NÞ3P, and (entries 6, 10, 15, 18, resp.). an oxygen or sulfur donor, led to complete reaction after only 1 h. Among the thiono donors an apparent correlation of increasing Gratifyingly, very high rate acceleration was observed with many steric bulk with decreasing endo/exo selectivity was noted (entries Lewis bases bearing sulfur, selenium, and phosphorus donor 6–10). atoms. The thiono containing bases (thiourea, phosphine sul- To evaluate the preparative utility of this bromolactonization, fides, or a thiophosphoramide, entries 6–10) were all indistin- the reaction of test substrate 1a was run on a 1.0 mmol scale guishably rapid (t1∕2 < 35 sec) and provided good yields of the and the cyclization products were isolated in 81% yield and a cyclization products.
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