Marco Luparia

Catalytic Asymmetric Diastereodivergent Deracemization

Your wish is my command: Deracemization is a powerful strategy wherein a racemate is converted into a 100 % yield of a single enantiopure product. A new concept in catalytic deracemization is presented, in which a racemate with n stereogenic elements can be selectively converted into each one of 2(m) (m = number of chiral centers of the product) different enantiopure products, by simple tuning of the reaction conditions.

Gold-Catalyzed Synthesis of Furans and Furanones from Sulfur Ylides

Scheme 1 reveals a notable incidence of 3-carboxy-functionalized polysubstituted furans in the natural product cores, including furofuranone and -pyranone moieties (such as in angelone). Herein we report a simple and flexible gold-catalyzed synthesis of densely functionalized 3-carboxyfuran derivatives that hinges on a key cross-coupling between sulfonium ylides and alkynes. We further disclose an intriguing reactivity switch that allows the synthesis of furanones containing a quaternary center as well as computational data on the mechanism of these transformations. Initial studies focused on the alkynyl sulfonium ylide 1a, readily available by direct ylide transfer to the corresponding ketoester. Exposure of this compound to diverse gold(I) promoters led to sharply contrasting results (see the Supporting Information for details), and it was found that the simple combination of commercially available PPh3AuCl and AgSbF6 led to quantitative conversion into the furofuranone 2a at room temperature within 3 h. We then examined the scope of this simple yet highly effective procedure for the intramolecular preparation of bicyclic furans. Importantly, all the alkynyl sulfonium ylides employed as substrates could be readily accessed by direct ylide transfer in very high yields according to our previously reported procedure. Their stability towards chromatography and recrystallization along with their crystallinity renders them easily handled substrates for subsequent transformations. As shown in Table 1, a variety of bicyclofurans could be readily prepared by simply stirring the ylide precursors in the presence of the gold catalyst at room temperature. Importantly, the preparation of the furopyranone 2 i (Table 1, entry 9) required slightly modified conditions and the use of a different, more electron-poor phosphine, once again suggesting that less facile cyclizations of sulfonium ylides onto alkynes may be favored by the use of more electrondeficient gold(I) species. Various alkyl and aryl moieties were tolerated by the procedure, and furopyrrolones such as 2k could also be prepared by employing an amide-tethered alkyne. All-carbon tethers are also suitable for this transformation (Table 1, entry 12). To the best of our knowledge, this constitutes the first intramolecular synthesis of furans from stabilized sulfonium ylides. We then turned our interest to an intermolecular version of the same reaction. The double stabilization of our sulfonium ylides made some optimization of this process necessary, and some key results obtained are compiled in Scheme 2. The use of tBuXPhos as a ligand was required to obtain synthetically useful yields of product 5 a, particularly with regard to preventing excessive polymerization of phenylacetylene (4a ; Scheme 2a). The very high regioselectivity of this reaction is noteworthy, as only trace amounts of other regioisomers could be detected. Additionally, and in complementary fashion to the recent elegant report by Skyrdstrup et al. employing singly stabilized sulfonium ylides, we Scheme 1. Selected examples of natural products containing a furan core.

Diastereodivergent De-epimerization in Catalytic Asymmetric Allylic Alkylation

Diastereomers made to order: In an unprecedented ligand-controlled process a racemic mixture of four stereoisomers can be converted with high selectivity into each one of the diastereomers of the product, at will (see scheme). The mechanism of this deracemization of epimers, that is, a de-epimerization, was also studied.

From Stereodefined Cyclobutenes to Dienes: Total Syntheses of Ieodomycin D and the Southern Fragment of Macrolactin A

A copper-promoted flexible synthesis of cyclobutenes carrying simple alkyl chains, enabling even the most hindered nucleophiles to be employed, has been developed. The versatility of this approach was exemplified by a short total synthesis of ieodomycin D and a straightforward preparation of the southeastern fragment of macrolactin A. The latter features a late-stage, double cyclobutene electrocyclic ring opening that directly delivers a bis-diene of defined geometry.

An Atom-Economical and Stereoselective Domino Synthesis of Functionalised Dienes

Open sesame: A direct synthesis of functionalised and stereodefined dienes, relying on a domino allylic alkylation/electrocyclic ring-opening sequence, is reported. This method allows concise access to doubly vinylogous esters. A further systematic study of ring-opening rates of carbon-substituted cyclobutenes allowed the design of substrates amenable to sequential pericyclic reactions (see scheme).

Regio- and Enantioselective Cyclobutene Allylations

Catalytic asymmetric allylation of lactone 1 with allyl boronates leads to functionalized cyclobutenes in high regio- and stereoselectivity.

Enantioselective Synthesis and Olfactory Evaluation of 13‐Alkyl‐Substituted α‐Ionones

To study the influence of the steric bulk of the substituents at C(5) on the olfactory characteristics of α‐ionone, the (S)‐antipodes of compounds 8–10 were synthesized starting from (S)‐α‐cyclogeraniol (14a). The latter was available in useful preparative yield with 95% ee by enantioselective lipase‐PS‐mediated acetylation of the racemic mixture. Key step in the conversion of 14a to 8–10 was an SN2′‐type reaction of an organocuprate on the allylic phosphate 20, which appears to be a general method for the introduction of an alkyl substituent at the cyclohexene CC bond of ionones. Olfactory evaluation showed that, compared to the parent (S)‐α‐ionone (1), the odor strength and fragrance facets of the three analogues 8–10 are significantly influenced by the bulkiness of the substituent at C(13), giving further evidence that hydrophobic interactions of this group play a significant role in the chemoreception of ionones. In particular, the odor of the ethyl derivative 8 was found to be significantly stronger than that of the parent (S)‐α‐ionone (1).

Enantioselective Synthesis and Olfactory Evaluation of Bicyclic α- and γ-Ionone Derivatives: The 3D Arrangement of Key Molecular Features Relevant to the Violet Odor of Ionones

Violet smelling ionones 1-3, occurring in the headspace of different flowers, are well-known perfumery raw materials. With the goal to recognize the still ill-defined spatial arrangement of structural features relevant to the binding of ionones to olfactory G-protein coupled receptors, through B3LYP/6-31G(d) modeling studies we identified bicyclic compounds 7-9 as conformationally constrained 13-alkyl-substituted analogues of monocyclic alpha- and gamma-ionones. They were thus synthesized to evaluate the olfactory properties. The enantioselective syntheses of 7-9 entailed two common key steps: (i) a Diels-Alder reaction to construct the octalinic core and (ii) a Julia-Lythgoe olefination to install the alpha,beta-enone side chain. The odor thresholds of synthetic 7 and 9 were significantly lower than the corresponding parent ionones, and 9 showed the lowest threshold value among violet-smelling odorants examined so far. Modeling studies suggested a nearly identical spatial orientation of key hydrophobic and polar moieties of compounds 1, 3, and 4-9. Presumably, interaction of these moieties with ionone olfactory receptors (ORs) triggers a similar receptor code that is ultimately interpreted by the human brain as a pleasant woody-violet smell. These results open the way to studies aimed at identifying and modeling complementary binding sites on alpha-helical domains of ionone receptor proteins.

Direct synthesis of stereodefined and functionalized dienes as valuable building blocks.

We have reported a direct and stereoselective synthesis of functionalized dienoic carboxylates from the simple bicyclic lactone 1. The use of oxygen- or nitrogen-based nucleophiles in a domino allylic alkylation/4π-electrocyclic ring opening affords reliable access to dienes with interesting functionalities. Alternatively, halide substitution offers synthesis of other classes of functionalized dienoic acids. Herein, we demonstrate the utility of such dienoic products as key building blocks in various transformations as well as natural product synthesis.