Computational Evidence of the Incipient Oxocarbenium Ion as a "Hidden Intermediate" During the Cyclization of Hydroxyenol Ether into Spiroketal Under Mild Acidic Condition.

The synthesis of spiroketals has gained attention because of their importance in chemical and biological reactions. Yet, the mechanistic investigation of mild acid-catalyzed spiroketalization remains elusive and less explored in the literature and speculated that such transformations may proceed through the oxocarbenium ion intermediate; however, the existence of such species in mild acid-catalyzed spiroketalization is not documented. The computational study has been performed at M06-2X/6-31+G(d) level to examine the kinetically controlled product formation for such reactions and the intrinsic reaction coordinates of 1 d suggest that the reaction proceeds via a "one-step, two-stage" mechanism with the formation of transient oxocarbenium as a "hidden intermediate" in the reaction. This study reveals that stereoelectronic interactions devoid the formation of stable oxocarbenium ion intermediate after the proton transfer transition state in the mild acid catalyzed spiroketalization process.

Total Synthesis of the Proposed Structure of Neaumycin B.

The total synthesis of the proposed structure of anti-glioblastoma natural product neaumycin B was achieved in 22 steps (longest linear sequence). The synthesis features HCl-mediated [6,6]-spiroketalization, a combination of Krische iridium-catalyzed crotylation, Marshall palladium-catalyzed propargylation, Fürstner nickel-catalyzed regio- and enantioselective vicinal monoprotected diol formation, Brown crotylation and asymmetric halide-aldehyde cycloaddition, so as to establish the challenging contiguous stereocenters.

A Mechanistically Inspired Halenium Ion Initiated Spiroketalization: Entry to Mono- and Dibromospiroketals.

Employing halenium affinity (HalA) as a guiding tool, the weak nucleophilic character of alkyl ketones was modulated by the templating effect of a tethered 2-tetrahydropyranyl(THP)-protected alcohol towards realizing a bromenium ion initiated spiroketalization cascade. Addition of ethanol aided an early termination of the cascade by scavenging the THP group after the halofunctionalization stage, furnishing monobromospiroketals. Alternatively, exclusion of ethanol from the reaction mixture biased the transient oxocarbenium towards α-deprotonation that precedes a second bromofunctionalization event thus, furnishing dibrominated spiroketals. The regio- and stereoselectivity exploited in the current methodology provides a novel and rapid access to the dibrominated spiroketal motifs exhibited by several natural products.

Bimetallic Catalytic Asymmetric Tandem Reaction of ß-Alkynyl Ketones to Synthesize 6,6-Spiroketals.

The enantioselective tandem reaction of ß,γ-unsaturated α-ketoesters with ß-alkynyl ketones was realized by a bimetallic catalytic system of achiral AuΙΙΙ salt and chiral N,N'-dioxide-MgΙΙ complex. The cycloisomerization of ß-alkynyl ketone and asymmetric intermolecular [4+2] cycloaddition with ß,γ-unsaturated α-ketoesters subsequently occurred, providing an efficient and straightforward access to chiral multifunctional 6,6-spiroketals in up to 97 % yield, 94 % ee and >19/1 d.r. Besides, a catalytic cycle was proposed based on the results of control experiments.

Zeolite-Based Organic Synthesis (ZeoBOS) of Acortatarin A: First Total Synthesis Based on Native and Metal-Doped Zeolite-Catalyzed Steps.

Similarly to polymer-supported assisted synthesis (PSAS), organic synthesis could be envisaged being performed by using zeolites, native or metal-doped, as heterogeneous catalysts. To illustrate this unprecedented Zeolite-Based Organic Synthesis (ZeoBOS), the total synthesis of acortatarin A was achieved through a novel strategy and using five out of eleven synthetic steps catalyzed by H- or metal-doped zeolites as catalysts. Notably, the formation of an yne-pyrrole intermediate with a copper-doped zeolite and the spiroketalization of an alkyne diol with a silver-doped zeolite have been developed as key steps of the synthesis.

Stereocontrolled Synthesis of Spiroketals: An Engine for Chemical and Biological Discovery.

Spiroketals are key structural motifs found in diverse natural products with compelling biological activities. However, stereocontrolled synthetic access to spiroketals, independent of their inherent thermodynamic preferences, is a classical challenge in organic synthesis that has limited in-depth biological exploration of this intriguing class. Herein, we review our laboratory's efforts to advance the glycal epoxide approach to the stereocontrolled synthesis of spiroketals via kinetically controlled spirocyclization reactions. This work has provided new synthetic methodologies with applications in both diversity- and target-oriented synthesis, fundamental insights into structure and reactivity, and efficient access to spiroketal libraries and natural products for biological evaluation.

A convergent total synthesis of the telomerase inhibitor (±)-γ-rubromycin.

The total synthesis of the human telomerase inhibitor γ-rubromycin in its racemic form was accomplished in 3.8 % overall yield. The key feature of this synthesis is an efficient acid-catalyzed spiroketalization for the construction of the spiroketal core. The required electronically well-balanced spiroketal precursor was obtained by the convergent assembly of a naphthyl-substituted aldehyde, an α-methoxyallyl-γ-silyl-substituted phosphonate as the central C3 building block, and a highly functionalized aryl Grignard reagent. Another key feature is the late-stage construction of the isocoumarin moiety and a simultaneous protodesilylation furnishing the known methyl aryl ether protected precursor of γ-rubromycin.

Pd(II)-catalyzed spiroketalization of ketoallylic diols.

A high-yielding stereoselective method for forming spiroketals from simple ketoallylic diols is reported. Employing catalytic [PdCl2(MeCN)2] in THF at 0 °C, these dehydrative cyclization reactions require only mild conditions to produce vinyl-substituted spiroketals in high yields after brief reaction times with water as the only byproduct. Using this method, the stereochemical information embedded at the nucleophile is transmitted "down-the-chain" and efficiently sets the stereochemistry at both the anomeric carbon atom and the newly formed allylic stereocenter.