Schindilactone A

Asymmetric Total Syntheses of Hypoestin A, Albolic Acid, and Ceroplastol II.[Pubmed:35657330]

J Am Chem Soc. 2022 Jun 15;144(23):10162-10167.

The first asymmetric total synthesis of bioactive diterpenoid hypoestin A with an unprecedented [5-8-5-3] tetracyclic skeleton is accomplished in 15 steps from commercially available (R)-limonene. Furthermore, the second asymmetric total syntheses of sesterterpenoids albolic acid and ceroplastol II in 21 steps are also reported. The synthetically challenging and highly functionalized [X-8-5] (X = 5 or 7) tricarbocyclic ring systems found in hypoestin A, albolic acid, ceroplastol II, and Schindilactone A, as well as other natural products, are efficiently and directly constructed via a unique intramolecular Pauson-Khand reaction of an allene-yne. This work represents the first reported use of the Pauson-Khand reaction to access synthetically challenging eight-membered-ring systems in natural product synthesis.

The Journey of Schinortriterpenoid Total Syntheses.[Pubmed:30681828]

Acc Chem Res. 2019 Feb 19;52(2):480-491.

Plants in the Schisandraceae family are important components of the traditional Chinese herbal medicines and are often used to treat various illnesses. Therefore, these Schisandraceae plants are valuable sources for the discovery of new chemical entities for novel therapeutic development. Considerable progress has been made in the identification of bioactive and structurally novel triterpenoids from the Schisandraceae family in the past two decades. In particular, Sun and co-workers have successfully isolated over 100 nortriterpenoids from the Schisandraceae family. Some of these nortriterpenoids have strong inhibitory activities toward hepatitis, tumors, and HIV-1. However, the natural scarcity of these nortriterpenoids in the Schisandraceae plants has hampered their isolation and further biomedical development, and their biosynthesis has not been fully elucidated. It is therefore important and urgent to develop efficient and streamlined total syntheses of these medicinally important nortriterpenoids. Such syntheses will provide sufficient materials for detailed biological studies as well as new synthetic analogues and probe molecules to improve their biological functions and elucidate their mode of actions. However, because of their structural novelty and complexity, the total syntheses of these nortriterpenoid natural products present a significant challenge for synthetic chemists, despite the progress made in organic synthesis, particularly total synthesis, in the 20th century and since the beginning of the 21st century. New synthetic methodologies and strategies therefore need to be invented and developed to facilitate the total syntheses of these nortriterpenoid natural products. With this in mind, our group has spent the last 15 years, ever since the isolation of micrandilactone A (1) by Sun and co-workers in 2003 ( Sun et al. Org. Lett. 2003 , 5 , 1023 - 1026 ), working on synthetic studies with a view to developing methods and strategies for the total syntheses of schinortriterpenoids. Enabling methods such as a thiourea/Pd-catalyzed alkocycarbonylative annulation and a thiourea/Co-catalyzed Pauson-Khand reaction have been developed under these circumstances to form the key ring systems and stereocenters of these complex target molecules. These methodological advances have led us to the first total syntheses of Schindilactone A (2), lancifodilactone G acetate (6a), 19-dehydroxyarisandilactone A (9), and propindilactone G (10) with diverse structural features via a branching-oriented strategy. The chemistry developed during our total synthesis campaign has not only helped us to deal with various challenges encountered in the syntheses of the four target molecules, but has also opened up new avenues for synthesizing other naturally occurring schinortriterpenoids and their derivatives, which will likely result in molecules with improved biological functions and tool compounds to enable elucidation of their mechanism of actions or potential cellular targets. This Account highlights the chemistry evolution of our schinortriterpenoid syntheses.

Diastereoselective total synthesis of (+/-)-schindilactone a, Part 3: The final phase and completion.[Pubmed:22761030]

Chem Asian J. 2012 Oct;7(10):2341-50.

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 2: Construction of the fully functionalized CDEFGH ring system.[Pubmed:22761018]

Chem Asian J. 2012 Oct;7(10):2334-40.

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.

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.[Pubmed:22761005]

Chem Asian J. 2012 Oct;7(10):2321-33.

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.