Ling-Min Xu

Diastereoselective Total Synthesis of (±)‐Schindilactone A

Schindilactone A (1) and structures 2–4 (Scheme 1a) are representative members of a novel group of nortriterpenoids isolated by Sun and co-workers from the plants of Schisandraceae, which have been used in China for the treatment of rheumatic lumbago and related diseases. Preliminary biological assays indicated that some of them possess biological activities for inhibiting hepatitis, tumors, and HIV-1. The synthetic challenge posed by 1 stems from the complexity of its molecular structure: a highly oxygenated framework bearing 12 stereogenic centers, eight of which are contiguous chiral centers located in the FGH tricyclic ring system, and an oxa-bridged ketal that lies within an unprecedented 7–8 fused carbocyclic core. The structural complexity together with the attractive biological activities has rendered 1 a target for synthetic studies. Herein we report our efforts on the development of synthetic methods and a strategy centered on the construction of the polycyclic ring system that allowed the first total synthesis of ( )-schindilactone A. This concise strategy opens a pathway for the syntheses of other compounds related to schindilactone A (2–4, Scheme 1a), as well as their derivatives and analogues.

Asymmetric Total Synthesis of Propindilactone G

A concise total synthesis of (+)-propindilactone G, a nortriterpenoid isolated from the stems of Schisandra propinqua var. propinqua, has been achieved for the first time. The key steps of the synthesis include an asymmetric Diels-Alder reaction, a Pauson-Khand reaction, a Pd-catalyzed reductive hydrogenolysis reaction, and an oxidative heterocoupling reaction. These reactions enabled the synthesis of (+)-propindilactone G in only 20 steps. As a consequence of our synthetic studies, the structure of (+)-propindilactone G has been revised.

Diastereoselective Total Synthesis of (±)‐Schindilactone A, Part 3: The Final Phase and Completion

The final phase for the total synthesis of (±)-schindilactone A (1) is described herein. Two independent synthetic approaches were developed that featured Pd-thiourea-catalyzed cascade carbonylative annulation reactions to construct intermediate 3 and a RCM reaction to make intermediate 4. Other important steps that enabled the completion of the synthesis included: 1) A Ag-mediated ring-expansion reaction to form vinyl bromide 17 from dibromocyclopropane 30; 2) a Pd-catalyzed coupling reaction of vinyl bromide 17 with a copper enolate to synthesize ketoester 16; 3) a RCM reaction to generate oxabicyclononenol 10 from diene 11; 4) a cyclopentenone fragment in substrate 8 was constructed through a Co-thiourea-catalyzed Pauson-Khand reaction (PKR); 5) a Dieckmann-type condensation to successfully form the A ring of schindilactone A (1). The chemistry developed for the total synthesis of schindilactone A (1) will shed light on the synthesis of other family members of schindilactone A.

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.

Diastereoselective Total Synthesis of (±)-Schindilactone A, Part 2: Construction of the Fully Functionalized CDEFGH Ring System

The successful synthesis of the highly complex model compound (2) of the CEFGH ring system of schindilactone A (1) is described. Several synthetic methodologies were developed and applied to achieve this goal, including ring-closing metathesis (RCM) and Co-thiourea-catalyzed Pauson-Khand reactions. Furthermore, two independent approaches were developed for the construction of the GH ring of model compound 2, the key steps of which included Pd-thiourea-catalyzed carbonylative annulation, methylation, and sequential RCM/oxa-Michael-addition reactions. The chemistry developed herein has provided a greater understanding of the synthesis of schindilactone A (1) and its analogous compounds of the same family.

Total synthesis of (±)-decinine via an oxidative biaryl coupling with defined axial chirality.

The total synthesis of (±)-decinine has been achieved. The key steps in the synthesis involved the formation of lasubine II via a gold catalyzed annulation of 1-(but-3-yn-1-yl)piperidine and the formation of the 12-membered ring of decinine (1) with complementary atropselectivity via a VOF3-mediated oxidative biaryl coupling reaction.

Highly Regioselective Syntheses of Substituted Triphenylenes from 1,2,4-Trisubstituted Arenes via a Co-Catalyzed Intermolecular Alkyne Cyclotrimerization

Herein, we report the development of a new method for the syntheses of substituted triphenylenes from the corresponding 1,2,4-trisubstituted arenes, which were themselves generated in a highly regioselective manner according to an intermolecular alkyne cyclotrimerization reaction that was catalyzed by a novel Co-TMTU complex. This highly regioselective reaction for the formation of 1,2,4-trisubstituted arenes will be a valuable addition to the plethora of tools already available to synthetic chemists and encourage further mechanistic studies of this important alkyne trimerization process.