Celastraceae sesquiterpenoids: biological activity and synthesis

Plant extracts of the Celastraceae have been used for centuries throughout South America and China as insect repellents and insecticides in traditional agriculture, and also for the treatment of a plethora of medical ailments from stomach complaints and fever to rheumatoid arthritis and cancer. Many of the medicinally interesting properties associated with these crude preparations have now been attributed to a large family of highly oxygenated sesquiterpenoids based on a tricyclic dihydroagarofuran skeleton. In this article, the structural diversity and range of biological activities associated with this intriguing class of natural products are examined with a view to stimulating interest in their total synthesis. Existing synthetic endeavours towards their synthesis are also evaluated.     

Synthesis of novel D-seco-taxoids derived from 1-deoxybaccatin VI

New D-seco-taxoids were synthesized from 1-deoxybaccatin VI and their structures were confirmed by 1HNMR, 13CNMR, ESIMS and X-ray crystallography. The key step of the synthesis involved the opening of the oxetane ring under acid and basic conditions in order to obtain new multidrug resistance (MDR) reversal agents and new synthetic precursors of paclitaxel analogues.     

The First Efficient Approach from α-(-)-Santonin to Dihydroagarofuran Sesquiterpene

The naturally occurring dihydroagarofuran compounds have been demonstrated to show some important bioactive activities, such as insect antifeedant, antitumor activities.¹ Synthetic research of this kind of compounds have been attracting the increasing interest of organic chemists. Because a total synthesis of polyol skeleton involved too many steps,² our synthetic efforts are focusing on search for a short and efficient approach and thus, we begin with readily available α-(-)-santonin(1). The creative key steps include generation of C₅-OH, the stereochemical reversion at C-7 and the cyclization of tetrahydrofuran. A successful approach is shown in the following scheme.     

Total synthesis of bryostatins: the development of methodology for the atom-economic and stereoselective synthesis of the ring C subunit

Bryostatins, a family of structurally complicated macrolides, exhibit an exceptional range of biological activities. The limited availability and structural complexity of these molecules makes development of an efficient total synthesis particularly important. This article describes our initial efforts towards the total synthesis of bryostatins, in which chemoselective and atom-economical methods for the stereoselective assembly of the ring C subunit were developed. A Pd-catalyzed tandem alkyne-alkyne coupling/6-endo-dig cyclization sequence was explored and successfully pursued in the synthesis of a dihydropyran ring system. Elaboration of this methodology ultimately led to a concise synthesis of the ring C subunit of bryostatins.     

Antitumor Sesquiterpenes from Euonymus nanoides

The isolation, structure elucidation, and antitumor activity of four new sesquiterpene polyol esters, i.e., of 6α,13‐bis(acetyloxy)‐9β‐(cinnamoyloxy)‐1β‐(furan‐3‐ylcarbonyl)oxy]‐4α‐hydroxy‐β‐dihydroagarofuran ( 1 ), 13‐(acetyloxy)‐9β‐(benzoyloxy)‐4α‐hydroxy‐1β,6α‐bis[(2‐methylbutanoyl)oxy]‐β‐dihydroagarofuran ( 2 ), 1β,6α,13‐ tri(acetyloxy)‐9β‐(cinnamoyloxy)‐4α‐hydroxy‐β‐dihydroagarofuran ( 3 ), and 6α,13‐bis(acetyloxy)‐9β‐(benzoyloxy)‐4α‐hydroxy‐1β‐[(2‐methylbutanoyl)oxy]‐β‐dihydroagarofuran ( 4 ), and of five known sesquiterpene polyol esters 5 – 9 from the seed oil of Euonymus nanoides Loes. are reported (β‐dihydroagarofuran=octahydro‐2,2,5a,9‐tetramethyl‐2H‐3,9a‐methano‐1‐benzoxepin).     

Total Synthesis of (−)‐Nakadomarin A

A highly efficient 12‐step synthesis of the marine alkaloid (?)‐nakadomarin A has been accomplished. The key advanced intermediate, a tetracyclic ketone derivative, was constructed in just seven steps using a sequence that includes an asymmetric Pauson–Khand reaction, an Overman rearrangement reaction, a ring‐closing metathesis reaction, and an amination reaction. Late introduction of the furan ring during the synthesis of (?)‐nakadomarin A means that the key tetracyclic ketone derivative has the potential to serve as an advanced intermediate for the synthesis of related marine alkaloids.     

Efficient route to 2H-1,3-oxazines through ring expansion of isoxazoles by rhodium carbenoids

Studies related to the total synthesis of elisabethin C led to the discovery of a rhodium-catalyzed cascade sequence involving isoxazole ring expansion and a [4+3] cycloaddition. The scope of the isoxazole ring expansion was explored, resulting in the synthesis of a range of 2H-1,3-oxazines in 47-96% yield.     

Ring expansive routes to quinolizidine alkaloids: formal synthesis of (-)-lasubine II

The application of two nitrogen ring expansion reactions to lasubine alkaloid synthesis is reported. The approach involves a conjugate reduction/alkylation sequence carried out on triisopropylsilyl-protected (S)-4-(-)-hydroxycyclopentenone, the formation of the quinolizidone ring system through nitrogen ring expansion, and the addition of an arylmetallic species to the resulting lactam. This work resulted in the preparation of 2-epi-lasubine II and a formal synthesis of lasubine II. [reaction: see text]     

Enantioselective total synthesis of FR900482

The development of two approaches for the enantioselective total synthesis of FR900482 is described. A precursor for the formation of the benzazocine ring was assembled effectively by a modification of the Sonogashira coupling of an aryl triflate with a chiral acetylene unit derived from tartaric acid and the subsequent novel ketone formation via conjugate addition of pyrrolidine to the o-nitrophenylacetylene derivative. The first-generation approach to the key pentacyclic intermediate of our racemic total synthesis utilizes an intramolecular Mitsunobu reaction of an omega-hydroxynitrobenzenesulfonamide to form the benzazocine ring and a stepwise sequence to construct the hydroxymethyl group at the C(7) position. The key intermediate could be synthesized in optically pure form via formation of the characteristic hydroxylamine hemiacetal and a stereoselective epoxide formation. In the second-generation approach, the N-hydroxybenzazocine ring could be constructed directly from an omega-formylnitrobenzene derivative by intramolecular reductive hydroxylamination. The crucial stereoselective hydroxymethylation and the formation of the hydroxylamine hemiacetal could be performed efficiently by a one-pot sequence. After leading to the pentacyclic key intermediate, the total synthesis of (+)-FR900482 was accomplished by a modification of our protocol established in the racemic total synthesis. Stereochemical issues involved in the hydroxymethylation at the C(7) position and formation of the hydroxylamine hemiacetal are also discussed in detail.     

The enantioselective Birch-Cope sequence for the synthesis of carbocyclic quaternary stereocenters. Application to the synthesis of (+)-mesembrine

A synthetic technique for generating carbocyclic quaternary stereocenters with exceptionally high levels of enantioselectivity is described. A sequence of three reactions, enantioselective Birch reduction-allylation, enol ether hydrolysis, and Cope rearrangement, is used to stereoselectively generate chiral quaternary centers on a 2-cyclohexen-1-one ring. The products of the sequence are 4,4-disubstituted-2-carboxamide-2-cyclohexen-1-one structures which are versatile intermediates in complex natural product synthesis. An application of the sequence to the synthesis of (+)-mesembrine illustrates the utility of these intermediates.     

Total synthesis of the cyclopeptide alkaloid abyssenine A. Application of inter- and intramolecular copper-mediated coupling reactions in organic synthesis

The first total synthesis of the 15-membered ring cyclopeptide alkaloid abyssenine A 1 has been achieved with a longest linear sequence of 15 steps. Central to the synthetic approach was an efficient copper-mediated Ullmann coupling/Claisen rearrangement sequence allowing for both ipso and ortho functionalization of aromatic iodide 4. This sequence was used for the synthesis of the aromatic core. The synthetic utility of copper-catalyzed coupling reactions was further demonstrated to install the enamide with a concomitant straightforward macrocyclization starting from acyclic alpha-amido-omega-vinyl iodide 13.     

The enantioselective synthesis of (-)-lycoramine with the Birch-Cope sequence

The first enantioselective synthesis of (-)-lycoramine has been achieved in 14 steps and 5% overall yield from the biaryl derivative 1. The synthesis applies the previously developed Birch-Cope sequence to create the key arylic quaternary stereocenter of (-)-lycoramine with excellent enantioselective control. The product of the Birch-Cope sequence, a versatile 4,4-disubstituted-2-carboxamide-2-cyclohexen-1-one, was elaborated through an intramolecular conjugate addition of a phenol to create the dihydrofuran ring. Chemoselective elaboration of the allyl group into an amide followed by a modified Pictet-Spengler reaction generated the azepine ring.     

A strategy for the synthesis of the fargenone/fargenin family of natural products: synthesis of the tricyclic core

A synthesis of the core ring structure of the fargenin/fargenone family of natural products is presented. The general strategy is based upon biosynthetic speculation and exploits a cascade reaction, which transforms a spirocyclic dienone into the core ring system via a deprotonation-oxy-Michael-Wittig olefination sequence. This study represents the first synthesis work towards this family of natural products.     

Diels-Alder reaction-aromatization approach toward functionalized ring C allocolchicinoids. Enantioselective total synthesis of (-)-7S-allocolchicine

Allocolchicinoids are analogues of the important antimitotic compound (-)-colchicine 1. A strategy is reported for the synthesis of ring C functionalized allocolchicinoids, which is based on a Diels-Alder reaction-aromatization sequence. This route is complementary to the previously disclosed benzannulation approach involving Fischer carbene complexes and alkynes. Dienes 12 and 14 incorporate the natural substitution pattern on ring A and undergo Diels-Alder reactions with various dienophiles. Subsequent aromatization affords the set of differently functionalized ring C allocolchicinoids 15-19, 23, and 25, with high regioselectively and in moderate to good yields. An intramolecular Diels-Alder reaction-aromatization sequence allows for access to allocolchicinoids with reversed regiochemical introduction of ring C substituents. The equilibria of the atropisomers of 15 and 19 are studied in three NMR solvents. Reactions of the dienes 12 and 14 with DMAD lead to the corresponding cycloadducts, but the subsequent aromatization is complicated. A regioselective Diels-Alder reaction-aromatization sequence is utilized as the key step in the first stereoselective total synthesis of (-)-allocolchicine 2. Asymmetric introduction of hydroxy group at C7 is achieved by the enantioselective reduction of ketone 29. The correct stereochemistry is then established by Mitsunobu inversion reaction using Zn(N(3))(2)-2Py.     

A synthesis of camptothecin

A total synthesis of camptothecin has been carried out. Central to our synthesis is the intramolecular condensation of a suitably designed ketol, which in turn was obtained from a tricyclic ABC ring synthon. A tandem reductive amination and Michael addition sequence on an unsaturated quinoline ester was employed for the assembly of the ABC skeleton.     

Total synthesis of (+/-)-haouamine A

The first total synthesis of the highly complex and potent anticancer agent haouamine A is reported through an eight-step sequence. Brevity of the sequence and complete control of chemo-, position-, and stereoselectivity (both planar and axial chirality) were possible through the invention of chemistry specifically tailored for the problems at hand, namely a cascade annulation proceeding via a hitherto unknown chemical entity for the indeno-tetrahydropyridine ring system as well as a pyrone-assisted stitching of the daunting bent-aromatic ring.     

Synthesis of polycyclic benzofused nitrogen heterocycles via a tandem ynamide benzannulation/ring-closing metathesis strategy. Application in a formal total synthesis of (+)-FR900482

A two-stage "tandem strategy" for the synthesis of benzofused nitrogen heterocycles is described that is particularly useful for the construction of systems with a high level of substitution on the benzenoid ring. The first stage in the strategy involves a benzannulation based on the reaction of cyclobutenones with ynamides. This cascade process proceeds via a sequence of four pericyclic reactions and furnishes a multiply substituted aniline derivative which can bear a variety of functionalized substituents at the position ortho to the nitrogen. In the second stage of the tandem strategy, ring-closing metathesis generates the nitrogen heterocyclic ring. This two-step sequence provides efficient access to highly substituted dihydroquinolines, benzazepines, benzazocines, and related benzofused nitrogen heterocyclic systems. The application of this chemistry in a concise formal total synthesis of the anticancer agents (+)-FR900482 and (+)-FR66979 is described.     

Synthetic studies of cyclic peptides stephanotic acid methyl ester,celogentin C,and moroidin

An account of the total synthesis of stephanotic acid methyl ester and celogentin C is presented. The present synthesis features a tandem asymmetric Michael addition/bromination sequence for the synthesis of leucine-tryptophan moiety, and an oxidative coupling reaction to form the tryptophan-imidazole linkage. Moreover, the total synthesis of moroidin had also been studied, and three different synthetic strategies for the construction of the right-hand ring of moroidin were studied.     

大环二氢沉香呋喃吡啶类生物碱的结构及活性

本文简要评述了近年来源于卫矛科植物中结构新颖的90个大环二氢沉香呋喃倍半萜吡啶类生物碱的结构类型，以及抗HIV及杀虫等生物活性。参考文献46篇。     

Construction of carbocyclic ring of indoles using ruthenium-catalyzed ring-closing olefin metathesis

The selective synthesis of substituted indoles was achieved by the ring-closing olefin metathesis (RCM)/elimination sequence or the RCM/tautomerization sequence of functionalized pyrrole precursors. The RCM/elimination sequence was also applied to double ring closure to yield a substituted carbazole.