Stereoselective Synthesis of Dienyl-Carboxylate Building Blocks: Formal Synthesis of Inthomycin C

Abstract

A direct synthesis of stereodefined halodienes is reported. Those key building blocks enable a concise access to polyenic products, as demonstrated in a modular synthesis of Inthomycin C.

Dienyl carboxylate and carbinol subunits are fundamental structural scaffolds present in various natural products¹ (Figure 1). Through simple modifications in the diene substitution pattern and olefin geometry, Nature is able to access remarkable structural diversity. Such functionalized conjugated dienes are conventionally built from simple mono-olefinic fragments² through, e.g., cross-coupling,^3,4 metathesis⁵ or olefination reactions.⁶ Controlling the configuration of the double bond arrays generated during such transformations represents a major challenge.

Figure 1.

Examples of natural products containing a dienyl-carboxylate or –carbinol moiety.

The use of stereodefined mono-olefinic fragments as building blocks for cross-coupling reactions leading to the di- or polyenyl frameworks of interest is a strategy that has gained prominence.⁷ An elegant example of such a tactic is the development by Burke of an assembly of so-called MIDA-boronate building blocks, that allow the deployment of iterative cross-couplings en route to polyenic natural products.⁸ Nevertheless, the syntheses of the basic mono-olefinic fragments are typically multi-step and mandate the introduction of a halide and organometallic residue in each fragment. We report herein a strategy for the direct preparation of dienyl carboxylate building blocks that significantly streamlines the total synthesis of polyene natural products.^9,10,11

During our studies on allylic alkylation of lactone 1a,¹² we have discovered an unexpected halide ring-opening relying on the use of alkali halide salts. As shown in Scheme 1(a-b), clean ring-opening of lactone 1a with either NaI or LiBr provides almost exclusively trans-halocyclobutenes 2a-b in quantitative yields. Furthermore, nucleophilic chlorination of 1a with HCl selectively affords cis-chlorocyclobutene 2c with similar efficiency (Scheme 1c).

Scheme 1.

Direct synthesis of halocyclobutenes and their ring-opening reactions.

These thermally stable halocyclobutenes and their ester or amide derivatives are prone to 4π-electrocyclic conrotatory ring opening^13,14 upon heating. Surprisingly, the iodocyclobutene 2a and derivatives undergo productive ring-opening leading to a mixture of diene geometrical isomers.^15,16 In contrast, 2b and the brominated carboxylate analogues thereof afford the (E,E)-halodienes 4a-d cleanly upon refluxing in THF.¹⁷ In complementary fashion, the cis-4-chlorocyclobut-2-ene carboxylic acid 2c¹⁸ can be readily derivatized and unravelled to deliver the (Z,E)-dienyl carboxylates 5a-d (Scheme 1c).

In order to determine the factors controlling the reactivity and stereoselectivity of the ring openings of 2a-c, we modeled these 4π-electrocyclic ring opening reactions computationally.¹⁹ Computations indicate that the electrocyclic ring opening reactions of the disubstituted cyclobutenes 2a-c are all exergonic and thus irreversible with a ΔG_rxn ranging from −11 kcal/mol for 2b and 2c to −14 kcal/mol for 2a. The high temperatures required for the ring openings of 2a-c are consistent with the computed free energy barriers (~30 kcal/mol). The transition structures for the ring opening of 2a, 2b, and 2c are shown in Figure 2.²⁰

Figure 2.

Lowest energy conrotatory transition structures for the ring opening of 2a, 2b, and 2c. ΔH‡ and ΔG‡ are given in red below the corresponding transition structure. The enthalpy and free energy values in blue are the differences between the disfavored (not shown) and preferred transition states. Energies are given in kcal/mol.

Donors like iodide stabilize the transition state by interacting with the transition state LUMO.²¹ The iodide substituent is a weaker donor than chloride or bromide, explaining a 10-fold difference in the rate of reaction of 2a and 2b.

The stereochemical outcomes of the electrocyclic reactions of 2b-c are in agreement with the model regarding torquoselectivity of 4π-electrocyclic ring opening of cyclobutenes.¹⁶ In the ring opening of halocyclobutenes, strong n donors rotate outward in order to maximize orbital overlap between the high energy, nonbonding orbital of the donor and the transition state LUMO (σ*).²² Indeed, computations show that the conrotatory transition state of ring opening in which the halide rotates outward is 13-14 kcal/mol lower in energy than the alternative where the halide rotates inward (Figure 2). Conversely, strong acceptors, like aldehydes, tend to rotate inward in order to maximize overlap of their relatively low energy acceptor orbital with the transition state HOMO (σ).

The ΔΔG^‡ values of trans-substituted cyclobutenes 2a-c (13-15 kcal/mol) demonstrate the clear preference of the halide substituent for outward rotation. In the ring opening of trans-disubstituted 2a-b, both the acid²³ and the halide rotate outward, whereas in the ring opening of cis-isomer 2c the acid is forced to rotate inward in the presence of the strong chloride donor. The similarity in the barriers of the trans- and cis-disubstituted cyclobutene ring openings are in agreement with prior computational work which indicates that the acid has only a small preference for outward rotation.¹⁸

While the formation of the (E,E)-iododiene via electrocyclic reaction of 2a follows the explanation provided above, the (E,Z)-iododiene cannot be formed under thermal conditions via a pericyclic mechanism, as the reaction would have to proceed through a forbidden, disrotatory transition state.^10a Such a transition state is inaccessible due to its prohibitively high energy. Instead, this (E,Z) isomer is likely formed by subsequent isomerization of the allowed (E,E) product.

We next sought to demonstrate the synthetic utility of these dienyl-carboxylates.²⁴ Inthomycin C (Scheme 2), isolated in 1991,²⁵ was shown to reduce prostate cancer cell growth as well as to possess selective in vitro antimicrobial activity. Our retrosynthetic analysis is shown in Scheme 2, breaking the natural product down to three simple fragments 4e, 6 and 7. We envisioned that the bromo diene 4e would undergo cross coupling with a suitable organometallic partner 6 delivering a triene. Further functional group interconversion and Mukaiyama aldol reaction with silylketene acetal 7 would ultimately allow the preparation of Inthomycin C.

Scheme 2.

Retrosynthetic strategy towards Inthomycin C.

In order to obtain validation for the strategy outlined in Scheme 2, we briefly evaluated the reactivity of the stereodefined diene building blocks in cross-coupling reactions (Scheme 3).²⁶ For instance, Suzuki couplings employing aryl- and vinyl boronic acids proceeded to deliver the corresponding substituted dienoic esters 8a-d. Sonogashira reactions could be performed in good yields with silyl-, alkyl- and aryl-substituted terminal alkynes and various Stille cross-couplings were also successful.²⁷ Similarly, cross-coupling onto the (Z,E)-chloro-dienes 5b-d took place without loss of the diene geometrical configuration (Scheme 4), an important observation.²⁸ To the best of our knowledge, this is an unprecedented use of doubly vinylogous chloride esters in cross-coupling reaction.

Scheme 3.

Scope of cross-coupling reactions of (2E,4E)-5-bromo-2,4-dienoic derivatives 4c-d.

Scheme 4.

Suzuki cross-coupling of (2Z,4E)-5-chloro-dienoic derivatives 5b-d.

Armed with this knowledge, we could then confidently complete the synthesis of Inthomycin C (Scheme 5). As shown, lithium bromide smoothly opened the methyl substituted lactone 1b. As before, a single trans-cyclobutenyl bromide 2d was obtained. Further amide coupling and 4π electrocyclic ring opening afforded 2-methyl-5-bromodienoic amide 4e as a single geometrical isomer. Stille cross-coupling with vinyl stannane 6,²⁹ followed by reduction to the aldehyde 11 and organocatalytic Mukaiyama aldol reaction with silylketene acetal 7 then led to product 12 in 50% yield.³⁰ The conversion of 12 to Inthomycin C has been previously reported.³¹ This modular assembly of substituents around dienes such as 4e allows considerable flexibility in the context of total synthesis.

Scheme 5.

Modular formal synthesis of Inthomycin C.

In summary, we have reported herein a direct route to functionalised and stereodefined halodiene carboxylate building blocks, which proceeds through electrocyclic ring opening of readily available halocyclobutene precursors. Appropriate control of stereochemical information at the cyclobutene level ensures access to a suitably configured diene fragment upon ring opening. Cross coupling onto these subunits allows ready access to natural product-like polyene substructures without erosion of the geometrical purity. The utility of this strategy is showcased by a modular short formal synthesis of Inthomycin C. We are currently pursuing the application of these and related approaches to the total syntheses of diverse polyene natural products.