Titanocene(III)‐Catalyzed 6‐exo Versus 7‐endo Cyclizations of Epoxypolyprenes: Efficient Control and Synthesis of Versatile Terpenic Building Blocks

In this article, a complete study on the selectivity of titanocene(III) cyclization of epoxypolyprenes is presented. The requirements for the formation of six‐ or seven‐membered rings during these cyclizations are determined, taking into account the different substitution pattern in the epoxypolyprene precursor. Thus, a complete selectivity to 6‐exo or 7‐endo cyclization process has been achieved, yielding mono‐, bi‐, and even tricyclic compounds, constituting a new and efficient access to this type of derivative. Additionally, this procedure opens the possibility to prepare excellent building blocks for the synthesis of polycyclic compounds with a trisubstituted oxygenated function, which is present in several natural terpenes.     

6‐Azido‐6‐deoxy‐l‐idose as a Hetero‐Bifunctional Spacer for the Synthesis of Azido‐Containing Chemical Probes

The design of 6‐azido‐6‐deoxy‐l ‐idose for use as a hetero‐bifunctional spacer is reported. The hemiacetal at one terminus is an equivalent of an aldehyde and can react with nucleophiles, such as amino groups and electron‐rich aromatics. The azido group at the other terminus bio‐orthogonally undergoes a Hüisgen [3+2] cycloaddition with an acetylene. The idose derivative exhibited a higher level of reactivity towards oxime formation than a corresponding glucose derivative. The ¹³C NMR spectrum of the uniformly ¹³C‐labeled 6‐azido‐idose indicated that the acyclic forms of the sugar totaled 0.3 % of all the isomers, whereas those of glucose totaled 0.01 %. The larger population of the acyclic forms of the idose derivative would result in higher reactivity towards electrophilic addition in comparison with glucose derivatives. Finally, we prepared a C‐idosyl epigallocatechin gallate (EGCG) that bears an azido group through C‐glycosylation of EGCG with 6‐azido‐idose. This glycosyl form of the C‐idosyl EGCG exhibited a cytotoxicity against U266 cells that was comparable to that of EGCG. These results suggested that the EGCG derivative could be used as an effective chemical probe for the elucidation of EGCG biological functions.     

Biosynthesis of l‐4‐Chlorokynurenine,an Antidepressant Prodrug and a Non‐Proteinogenic Amino Acid Found in Lipopeptide Antibiotics

l ‐4‐Chlorokynurenine (l ‐4‐Cl‐Kyn) is a neuropharmaceutical drug candidate that is in development for the treatment of major depressive disorder. Recently, this amino acid was naturally found as a residue in the lipopeptide antibiotic taromycin. Herein, we report the unprecedented conversion of l ‐tryptophan into l ‐4‐Cl‐Kyn catalyzed by four enzymes in the taromycin biosynthetic pathway from the marine bacterium Saccharomonospora sp. CNQ‐490. We used genetic, biochemical, structural, and analytical techniques to establish l ‐4‐Cl‐Kyn biosynthesis, which is initiated by the flavin‐dependent tryptophan chlorinase Tar14 and its flavin reductase partner Tar15. This work revealed the first tryptophan 2,3‐dioxygenase (Tar13) and kynurenine formamidase (Tar16) enzymes that are selective for chlorinated substrates. The substrate scope of Tar13, Tar14, and Tar16 was examined and revealed intriguing promiscuity, thereby opening doors for the targeted engineering of these enzymes as useful biocatalysts.     

Enantiospecific Total Synthesis of (−)‐Bengamide E

Total synthesis of the polyhydroxy caprolactam amide natural product, bengamide E, is accomplished starting from tartaric acid. Key reactions in the synthesis include desymmetrization of the bis(dimethylamide) unit of tartaric acid, Zn(BH₄)₂‐mediated anti‐selective reduction, and a Horner–Wadsworth–Emmons olefination.     

Total Synthesis of (+)‐6‐epi‐Ophiobolin A

The ophiobolin sesterterpenes are notable plant pathogens which have recently elicited significant chemical and biological attention because of their intriguing carbogenic frameworks, reactive functionalities, and emerging anticancer profiles. Reported herein is a total synthesis of (+)‐6‐epi‐ophiobolin A in 14 steps, a task which addresses construction of the synthetically challenging spirocyclic tetrahydrofuran motif as well as several other key stereochemical problems. This work demonstrates a streamlined synthetic platform to complex ophiobolins leveraging disparate termination modes of a radical polycyclization cascade for divergent elaboration and functionalization.     

Synthesis of (E)‐4‐Bromo‐3‐methoxybut‐3‐en‐2‐one,the Key Fragment in the Polyhydroxylated Chain Common to Oscillariolide and Phormidolides A–C

The terminal bromomethoxydiene (BMD) moiety of the polyhydroxylated chain present in phormidolides and oscillariolides has been synthesized for first time. Several strategies for the stereoselective synthesis of the 4‐bromo‐3‐methoxybut‐3‐en‐2‐ones are described. Furthermore, a preliminary study to successfully introduce the BMD within the polyol chain and the fatty acid allowed us to corroborate the end structure of the polyol.     

The (+)‐cis‐ and (+)‐trans‐Olibanic Acids: Key Odorants of Frankincense

Frankincense (olibanum) is one of the oldest aromatic materials used by humans, but the key molecular constituents contributing to its characteristic odor remained unknown. Reported herein is the discovery that (1S,2S)‐(+)‐trans‐ and (1S,2R)‐(+)‐cis‐2‐octylcyclopropyl‐1‐carboxylic acids are highly potent and substantive odorants occurring in ppm amounts in all of the frankincense samples analyzed, even those showing radically different volatile compositions. These cyclopropyl‐derived acids provide the very characteristic old churchlike endnote of the frankincense odor.     

Enantioselective Total Synthesis of 3β‐Hydroxy‐7β‐kemp‐8(9)‐en‐6‐one,a Diterpene Isolated from Higher Termites

The first total synthesis of the title diterpene was accomplished starting from the Wieland–Miescher ketone. A diastereoselective sulfa‐Michael addition enabled the generation of the delicate β,γ‐unsaturated ketone moiety, while the tetracyclic kempane skeleton was readily constructed through domino metathesis.     

Enantioselective Organocatalytic Construction of Spiroindane Derivatives by Intramolecular Friedel–Crafts‐Type 1,4‐Addition

The highly enantioselective organocatalytic construction of spiroindanes containing an all‐carbon quaternary stereocenter by intramolecular Friedel–Crafts‐type 1,4‐addition is described. The reaction was catalyzed by a cinchonidine‐based primary amine and accelerated by water and p‐bromophenol. A variety of spiro compounds containing quaternary stereocenters were obtained with excellent enantioselectivity (up to 95 % ee). The reaction was applied to the asymmetric formal synthesis of the spirocyclic natural products (?)‐cannabispirenones A and B.     

Total Synthesis of (±)‐Phomoidride D

Described herein is a synthetic strategy for the total synthesis of (±)‐phomoidride D. This highly efficient and stereoselective approach provides rapid assembly of the carbocyclic core by way of a tandem phenolic oxidation/intramolecular Diels–Alder cycloaddition. A subsequent SmI₂‐mediated cyclization cascade delivers an isotwistane intermediate poised for a Wharton fragmentation that unveils the requisite bicyclo[4.3.1]decene skeleton and sets the stage for synthesis completion.     

A Flexible Approach to Azasugars: Asymmetric Total Syntheses of (+)‐Castanospermine, (+)‐7‐Deoxy‐6‐epi‐castanospermine,and (+)‐1‐epi‐Castanospermine

The asymmetric total synthesis of natural azasugars (+)‐castanospermine, (+)‐7‐deoxy‐6‐epi‐castanospermine, and synthetic (+)‐1‐epi‐castanospermine has been accomplished in nine to ten steps from a common chiral building block (S)‐ 8 . The method features a powerful chiral relay strategy consisting of a highly diastereoselective vinylogous Mukaiyama‐type reaction with either chiral or achiral aldehydes (≥95 % de; de=diastereomeric excess) and a diastereodivergent reduction of tetramic acids, which allows formation of three continuous stereogenic centers with high diastereoselectivities. The method also provides a flexible access to structural arrays of 5‐(α‐hydroxyalkyl)tetramic acids, such as 17/34 , and 5‐(α‐hydroxyalkyl)‐4‐hydroxyl‐2‐pyrrolidinones, such as 18 and 25/35 a . The method constitutes the first realization of the challenging chiral synthons A and D and thus of the conceptually attractive retrosynthetic analysis shown in Scheme 1 in a highly enantioselective manner.     

Convergent Synthesis of (−)‐Quinocarcin Based on the Combination of Sonogashira Coupling and Gold(I)‐Catalyzed 6‐endo‐dig Hydroamination

The total synthesis of the pentacyclic tetrahydroisoquinoline alkaloid quinocarcin, which possesses intriguing structural and biological features, has been achieved through a gold(I)‐catalyzed regioselective hydroamination reaction. It is noteworthy that the regioselectivity of the intramolecular hydroamination of an unsymmetrical alkyne could be completely switched through substrate control. Other key features of this synthesis include the highly stereoselective synthesis of 2,5‐cis‐pyrrolidine through the intramolecular amination of the bromoallene and the Lewis acid mediated ring opening of dihydrobenzofuran.     

Asymmetric α‐Hydroxylation of a Lactone with Vinylogous Pyridone by Using a Guanidine–Urea Bifunctional Organocatalyst: Catalytic Enantioselective Synthesis of a Key Intermediate for (20S)‐Camptothecin Analogues

We have developed a catalytic asymmetric synthesis of (S)‐4‐ethyl‐6,6‐(ethylenedioxy)‐7,8‐dihydro‐4‐hydroxy‐1H‐pyrano[3,4‐f]indolizine‐3,10(4H)dione ( 5 a ), a synthetic intermediate for (20S)‐camptothecin analogues. A key step in this synthesis is an asymmetric α‐hydroxylation of a lactone with a vinylogous pyridone structure ( 8 a ) by using a guanidine–urea bifunctional organocatalyst. The present oxidation was successfully applied to the synthesis of C20‐modified derivatives of (+)‐C20‐desethylbenzylcamptothecin ( 13 ).