Yandong Zhang

Total Synthesis of (±)-Aplykurodinone-1: Traceless Stereochemical Guidance

The total synthesis of the highly degraded steroidal natural product, aplykurodinone-1 (1), has been accomplished. Key features include a one-flask hydrolysis/retro-aldol/iodolactonization sequence to excise the C(8) hydroxymethylene functionality with retention of stereochemistry and the stereoselective installation of the C(13) methyl group through hydrogenation with homogeneous catalyst.

Stereoselective construction of an unprecedented 7-8 fused ring system in micrandilactone a by [3,3]-sigmatropic rearrangement.

The 7-8 bicyclic ring system of micrandilactone A (1) with the required stereochemistry and functional groups was constructed by a Bu3Al-promoted Claisen rearrangement. Computational studies indicated that the exocyclic vinyl ether undergoes a [3,3] sigmatropic process via a chairlike transition state to afford exclusively the Z-double bond in the newly generated 8-membered ring with a high level of chirality transfer.

Diastereoselective Total Synthesis of (+/-)-Schindilactone A, Part 1: Construction of the ABC and FGH Ring Systems and Initial Attempts to Construct the CDEF Ring System

First-generation synthetic strategies for the diastereoselective total synthesis of schindilactone A (1) are presented and methods for the synthesis of the ABC, FGH, and CDEF moieties are explored. We have established a method for the synthesis of the ABC moiety, which included both a Diels-Alder reaction and a ring-closing metathesis as the key steps. We have also developed a method for the synthesis of the FGH moiety, which involved the use of a Pauson-Khand reaction and a carbonylative annulation reaction as the key steps. Furthermore, we have achieved the construction of the central 7-8 bicyclic ring system by using a [3,3]-rearrangement as the key step. However, unfortunately, when this rearrangement reaction was applied to the construction of the more advanced CDEF moiety, the anticipated annulation reaction did not occur and the development of an alternative synthetic strategy would be required for the construction of this central core.

The Cyano Group as a Traceless Activation Group for the Intermolecular [3+2] Cycloaddition of Azomethine Ylides: A Five‐Step Synthesis of (±)‐Isoretronecanol

The cyano group was used as a traceless activation group for the [3+2] cycloaddition of azomethine ylides in a two-step process, thereby providing a highly effective approach to 5-unsubstituted pyrrolidines. The transformation includes the silver acetate catalyzed intermolecular 1,3-dipolar cycloaddition of α-iminonitriles and an unprecedented sodium borohydride induced reductive decyanation reaction. A diverse array of substrates is amenable to this transformation. The methodology was further extended to a five-step total synthesis of the pyrrolizidine natural product isoretronecanol.

Protecting-Group-Free Total Synthesis of (−)-Jiadifenolide: Development of a [4 + 1] Annulation toward Multisubstituted Tetrahydrofurans

A concise, protecting-group-free total synthesis of (-)-jiadifenolide, a synthetically challenging seco-prezizaane sesquiterpene with potent neurotrophic activity, is reported. The convergent route features a SmI2/H2O-mediated stereoselective reductive cyclization, an unprecedented formal [4 + 1] annulative tetrahydrofuran-forming reaction and programmed redox manipulations. The newly developed annulation of β-hydroxy aldehydes or ketones with lithium trimethylsilyldiazomethane provides access to a diverse array of multisubstituted tetrahydrofurans. The synthetic jiadifenolide exhibited weak cytotoxicity against five human cancer cell lines.

A Straightforward Route to Functionalized “trans-Diels–Alder” Motifs

A sequence consisting of a Lewis acid-catalyzed Diels-Alder reaction on a 2-halocyclohexenone, followed by reductive alkylation, provides a route to trans-fused octalinones bearing angular methyl groups with functionality corresponding to that which would have been possible from a trans-directed Diels-Alder reaction.

Total Synthesis of (+)-Fusarisetin A Driven by a One-Pot Four-Reaction Process.

A concise, asymmetric total synthesis of (+)-fusarisetin A, a hybrid natural product, has been achieved. A one-pot four-reaction process efficiently delivered the tetracycle 2 which served as a key intermediate for the synthesis of the title natural product and its analogues through amino acid incorporation.

Multifaceted cytoprotection by synthetic polyacetylenes inspired by the ginseng-derived natural product, panaxytriol

We describe herein the discovery of a series of panaxytriol (PXT)-derived polyacetylene small molecules with promising cytoprotective activity. In mouse xenograft models, we have demonstrated the capacity of our synthetic analogs to mitigate a range of cancer therapeutic agent-induced toxicities, including body weight loss, lethality, neurotoxicity, and hematotoxicity. Our PXT analogs have also been found to reduce radiation-induced body weight loss and lethality in mouse models. Moreover, several PXT analogs appear to exhibit moderate in vivo antiinflammatory activity as well as in vitro immunoenhancing capabilities. These compounds appear to derive their activity through induction of cancer preventive phase 2 enzymes. The studies described herein suggest that coadministration of a PXT-derived agent with cancer chemotherapeutics or radiation therapy may serve to mitigate a range of therapy-associated toxicities.

Total Synthesis of Aplydactone by a Conformationally Controlled C−H Functionalization

A concise, protecting-group-free total synthesis of the unusual brominated sesquiterpene aplydactone is described. Our synthesis features a [2+2] photocycloaddition, a Wolff ring contraction, an unusual remote C-H functionalization to establish the highly strained tetracyclic core, and a hydrogen-atom transfer (HAT) reaction to access the bromine-containing stereocenter. A finely tuned conformation of the α-diazoketone precursor is the key for the success of the late-stage transannular C-H insertion to deliver a bridged six-membered ring and a quaternary stereocenter (C6) between two quaternary carbon atoms (C1 and C7).

Cycloaddition/annulation strategies for the construction of multisubstituted pyrrolidines and their applications in natural product synthesis

Pyrrolidines are privileged substructures of numerous bioactive natural products and drugs. How to synthesize these important synthetic targets in a more efficient manner is a hot research topic. Plenty of novel strategies and methods have been developed in recent years. Among them, cycloaddition and annulation strategies are the most efficient methods for the construction of multisubstituted pyrrolidines in terms of atom economy, stereoselectivity, diversity of products, and especially, their potential for asymmetric synthesis. These advantages have been well demonstrated by their applications in the syntheses of pyrrolidine-containing alkaloids. In this review, we highlight both the reaction and strategy development and synthetic applications from 2008 to June of 2017. This review covers 1,3-dipolar cycloadditions, formal [3 + 2] cycloadditions/annulations, and other interesting cycloaddition or annulation strategies to illustrate a so-called “reaction-based” strategy for the total synthesis of related natural products.