Polarity Inversion of Donor-Acceptor Cyclopropanes: Disubstituted δ-Lactones via Enantioselective Iridium Catalysis

Abstract

The coupling of carbonyl electrophiles at the donor position of donor-acceptor cyclopropanes is described, representing an inversion of polarity with respect to conventional reactivity modes displayed by these reagents. Specifically, upon exposure of donor-acceptor cyclopropanes to alcohols in the presence of a cyclometallated iridium catalyst modified by (S)-BINAP, catalytic C-C coupling occurs to provide enantiomerically enriched products of carbonyl allylation. Identical products are obtained upon isopropanol mediated transfer hydrogenation of donor-acceptor cyclopropanes in the presence of aldehydes. The reaction products are directly transformed to cis-4,5-disubstituted δ-lactones.

Cyclopropanes are useful synthetic building blocks for organic synthesis due to their multifaceted reactivity and relative ease of preparation.¹ Donor-acceptor (D-A) cyclopropanes are a particularly useful subset capable of reacting with diverse partners upon exposure to the proper kinetic trigger.² All polar reactions of D-A cyclopropanes involve nucleophilic trapping at the donor site and electrophilic trapping at the acceptor site, as illustrated in stereoselective syntheses of five and six-membered ring products (Figure 1a,b).³ Although inversion or umpolung of these polarity patterns would increase the diversity of products accessible from D-A cyclopropanes, such reactivity remains elusive (Figure 1a,d).⁴ Here, we report that exposure of donor-acceptor cyclopropanes to cyclometallated iridium catalysts results in the umpolung of D-A cyclopropanes, resulting in electrophilic trapping at the donor site, as illustrated by the enantioselective C-C coupling of D-A cyclopropanes and carbonyl electrophiles to furnish δ-lactones.

Figure 1.

Lewis acid and transition metal activation D-A cyclopropane methods of activation.

The reaction of D-A cyclopropanes with transition metals to form electrophilic π-allyl intermediates is an established mode of reactivity used to prepare carbo- and heterocyclic products (Figure 1c).⁵ While the generation of nucleophilic π-allyls from D-A cyclopropanes is unknown (Figure 1d),⁴ the feasibility of umpoled carbonyl additions involving D-A cyclopropanes is suggested by recently developed reductive couplings of allylic carboxylates to carbonyl partners catalyzed by ortho-cyclometallated iridium C,O-benzoates.^6,7 A unique feature of such iridium catalyzed carbonyl allylations resides in the use of alcohols as terminal reductants, allowing highly enantioselective carbonyl addition from the alcohol or aldehyde oxidation level in the absence of stoichiometric metallic reagents. Although similar capabilities may be envisioned for corresponding D-A cyclopropane-mediated processes, π-allyl generation requires a malonic ester moiety to function as an efficient nucleofuge for oxidative addition,⁷ which at the onset of these studies had not been demonstrated for iridium. Further, as reported by one of the present authors,^5d under the conditions of palladium catalysis, D-A cyclopropanes and aldehydes combine by way of π-allyl intermediates to form tetrahydrofurans (conceptualized in Figure 1c). Thus, the proposed umpoled process must compete with an efficient π-allyl mediated transformation involving identical reactants, rendering the outcome of this endeavor uncertain.

Vinylcyclopropane 1a is prepared directly from the commercial reagents dimethyl malonate and (E)-1,4-dibromobut-2-ene.^5d In preliminary experiments, vinylcyclopropane 1a (200 mol%) and benzyl alcohol 2a (100 mol%) were exposed to the chromatographically isolated π-allyliridium complex (R)-I (5 mol%) at 50 °C under conditions effective for related crotylations employing α-methyl allyl acetate.^7d Gratifyingly, the desired adduct 4a formed as a single regioisomer with nearly complete levels of diastereo- and enantioselectivity, although the isolated yield was modest (Table 1, entry 1). The diastereoselectivity observed in the formation of 4a is amplified by competing base-catalyzed lactonization arising predominantly from the minor diastereomer. As all atoms in vinylcyclopropane 1a and alcohol 2a appear in the product, it was postulated that exogenous base may be unnecessary and, in fact, may impede reaction. While upon omission of K₃PO₄ adduct 4a is not formed (Table 1, entry 2), a decreased loading of K₃PO₄ (5 mol%) dramatically improved the isolated yield of 4a (Table 1, entry 3). Upon a slight increase in temperature (Table 1, entry 5) and decrease in the loading of vinylcyclopropane 1, adduct 4a was produced in 84% isolated yield with good levels of diastereoselectivity and excellent levels of enantioselectivity (Table 1, entry 6).

Table 1.

Optimization of donor-acceptor cyclopropane-mediated carbonyl allylation of benzyl alcohol 2a.^a

Entry	K3PO4 mol%	H2O mol%	Temp. °C	1a mol%	Yield%	ee% (dr)
1	50	500	50	200	37	99 (>20:1)
2	0	500	50	200	0	N/A
3	5	500	50	200	81	98 (8:1)
4	5	0	50	200	0	N/A
5	5	500	60	200	84	98 (7:1)
6	5	500	60	150	84	98 (6:1)

^aYields are of material isolated by silica gel chromatography. Enantiomeric excess was determined by chiral stationary phase HPLC analysis. See Supporting Information for further details.

These latter conditions were applied to benzylic alcohols 2a and 3a, allylic alcohols 2c and 2d and aliphatic alcohol 2e. Good isolated yields of the corresponding adducts 4a–4e were observed and, in each case, good levels of diastereoselectivity were accompanied by exceptional levels of enantiocontrol (Table 2). As observed in prior studies,^6,7 an identical set of adducts 4a–4e are accessible from the aldehyde oxidation level upon use of i-PrOH (200 mol %) as the terminal reductant under otherwise identical reaction conditions. Again, good isolated yields, diastereo- and enantioselectivities were observed (Table 3). Thus, umpoled D-A cyclopropane-mediated carbonyl allylation occurs with equal facility from the alcohol or aldehyde oxidation level (Tables 2 and 3). The absolute stereochemical assignment of adducts 4a–4e is made on the basis of single crystal x-ray diffraction analysis, as described in the Supporting Information.

Table 2.

Donor-acceptor cyclopropane-mediated carbonyl allylation from the alcohol oxidation level.^a

^aAs described for Table 1.

Table 3.

Donor-acceptor cyclopropane-mediated carbonyl allylation from the aldehyde oxidation level.^a

^aAs described for Table 1.

To explore the utility of the coupling products, adducts 4a, 4b and 4e were subjected to conditions for Krapcho decarboxylation, resulting in formation of cis-4,5-disubstituted δ-lactones 5a, 5b and 5e. Notably, lactones of this type appear as substructures in natural products such as leustroducsin⁸ and phoslactomycin⁹ (Scheme 1). The range of compounds availed through this approach is expanded further through variation of the acceptor group, as in D-A cyclopropanes 1b, which incorporates a phosphonoacetate moiety. D-A cyclopropanes 1b reacts with either benzyl alcohol or benzaldehyde under standard conditions to provide adducts 6b and 6c, respectively. The methine adjacent to the acceptor groups of adducts 6b and 6c represents a third, undefined stereogenic center, requiring evaluation of diastereo- and enantioselectivity at a subsequent stage. For compound 6b, Horner-Wadsworth-Emmons reaction with paraformaldehyde occurs with concomitant saponification to provide the methylidene carboxylic acid, which upon exposure to dicyclohexylcarbodiimide (DCC) is transformed to the α-methylene glutarolactone 7. Enantiomeric excess was determined at this stage (Scheme 2).

Scheme 1.

Formation of cis-4,5-disubstituted δ-lactones 5a, 5b and 5e via Krapcho decarboxylation.a

^aConditions A: LiCl (500 mol%), 3Å MS, DMSO (1 M), 150 °C. Conditions B: NaCl (500 mol%), DMSO (0.2 M), 160 °C.

Scheme 2.

Reactions of D-A cyclopropanes 1b which incorporates a phosphonoacetate.a

^aReagents: (a) As described for Table 1 using catalyst (R)-I. (b) K₂CO₃, CH₂O, H₂O, 60 °C. (c) DCC, DMAP, CH₂Cl₂, 23 °C.

In summary, we report the first umpoled reactions of D-A cyclopropanes, as illustrated by diastereo- and enantioselective iridium catalyzed D-A cyclopropane-mediated carbonyl allylations from the alcohol or aldehyde oxidation levels. These studies open new routes to optically enriched cis-4,5-disubstituted δ-lactones. Of broader significance, identification of the structural and interactional features of the catalytic system required for polarity inversion provide a foundation for the development of related C-C coupling processes.