Total Synthesis and Structure Revision of Didemnaketal B

Didemnaketal B, a structurally complex spiroacetal that exhibits potent HIV‐1 protease inhibitory activity, was originally discovered by Faulkner and his colleagues from the ascidian Didemnum sp. collected at Palau. Its absolute configuration was proposed on the basis of degradation/derivatization experiments of the authentic sample. However, our total synthesis of the proposed structure of didemnaketal B questioned the stereochemical assignment made by Faulkner et al. Here we describe in detail our first total synthesis of the proposed structure 2 of didemnaketal B, which features 1) a convergent synthesis of the C7–C21 spiroacetal domain by means of a strategy exploiting Suzuki–Miyaura coupling, 2) an Evans syn‐aldol reaction and a vinylogous Mukaiyama aldol reaction for the assembly of the C1–C7 acyclic domain, and 3) a Nozaki–Hiyama–Kishi reaction for the construction of the C21–C28 side chain domain. The NMR spectroscopic discrepancies observed between synthetic 2 and the authentic sample as well as careful inspection of the Faulkner’s stereochemical assignment led us to postulate that the absolute configuration of the C10–C20 domain of 2 has been erroneously assigned. Accordingly, the total synthesis of the revised structure 65 was achieved to show that the NMR spectroscopic properties of synthetic 65 were in good agreement with those of the authentic sample. Furthermore, application of the phenylglycine methyl ester (PGME) method to the C7–C21 spiroacetal domain enabled us to establish the absolute configuration of didemnaketal B.     

Formal Total Synthesis of (−)‐Apicularen A by a Strategy Based on Ring‐Closing Metathesis and Transannular Cyclization

A formal synthesis of (?)‐apicularen A, a potent antitumor agent with unique biological properties, has been completed in a 15‐step sequence starting from a known, enantiomerically pure hydroxyepoxide, which was generated by using the Jacobsen hydrolytic‐kinetic‐resolution methodology. The 12‐membered macrocyclic lactone in the target was constructed by ring‐closing metathesis, and the trans‐tetrahydropyran ring system was created through the transannular etherification of a hydroxyalkene.     

Modular Total Synthesis of Rhizopodin: A Highly Potent G‐Actin Dimerizing Macrolide

A highly convergent total synthesis of the potent polyketide macrolide rhizopodin has been achieved in 29 steps by employing a concise strategy that exploits the molecule′s C₂ symmetry. Notable features of this convergent approach include a rapid assembly of the macrocycle through a site‐directed sequential cross‐coupling strategy and the bidirectional attachment of the side chains by means of Horner–Wadsworth–Emmons (HWE) coupling reactions. During the course of this endeavor, scalable routes for synthesis of three main building blocks of similar complexity were developed that allowed for their stereocontrolled construction. This modular route will be amenable to the development of syntheses of other analogues of rhizopodin.     

Total Synthesis of (−)‐Glaucocalyxin A

A practically useful method for the formation of the highly oxygenated bicyclo[3.2.1]octane ring system through Mn(OAc)₃‐mediated radical cyclization of alkynyl ketones was developed, which opens up a new avenue for the total synthesis of a number of highly oxidized diterpenoids. Application of this method enabled the first total synthesis of (?)‐glaucocalyxin A. Other salient features of the synthesis include a highly enantioselective conjugate addition/acylation cascade reaction, a Yamamoto aldol reaction, and an intramolecular Diels–Alder reaction to assemble the A/B ring system.     

Synthesis of Each Enantiomer of Rocaglamide by Means of a Palladium(0)‐Catalyzed Nazarov‐Type Cyclization

A recently reported Pd⁰‐catalyzed asymmetric Nazarov‐type cyclization has been successfully applied in the key step of the first catalytic asymmetric total synthesis of (?)‐rocaglamide (natural) and (+)‐rocaglamide. The stereochemistry at the C3 position that controls the stereochemistry of all other stereocenters is determined in the cyclization step. This versatile and modular synthesis proceeds from simple reagents.     

Total Synthesis of (+)‐Minfiensine: Construction of the Tetracyclic Core Structure by an Asymmetric Cascade Cyclization

A new method for one‐step construction of the tetracyclic core structure of the indole alkaloid (+)‐minfiensine was developed utilizing a palladium‐catalyzed asymmetric indole dearomatization/iminium cyclization cascade. An efficient total synthesis of (+)‐minfiensine was realized using this strategy. The present method enables access to the common core structure of a series of monoterpene indole alkaloids, such as vincorine, echitamine, and aspidosphylline A.     

Total Synthesis of (±)‐Strictamine

The total synthesis of strictamine has been achieved in nine steps from a known enol triflate. Characteristic features of our approach included: a) creation of a C7 all‐carbon quaternary stereocenter at an early synthetic stage; b) use of an N,N‐dimethyl tertiary amine as a surrogate of the primary amine for the rapid build‐up of a functionalized 2‐azabicyclo[3,3,1]nonan‐9‐one skeleton (achieved by using a reaction sequence of α‐bromination of the ketone, followed by a stereoconvergent intramolecular nucleophilic substitution reaction); and c) a late‐stage construction of the indolenine unit.     

Total Synthesis of Bryostatin 8 Using an Organosilane‐Based Strategy

Convergent total synthesis of bryostatin 8 has been accomplished by an organosilane‐based strategy. The C ring is constructed stereoselectively through a geminal bis(silane)‐based [1,5]‐Brook rearrangement, and the B ring through geminal bis(silane)‐based Prins cyclization, thus efficiently joining the northern and southern parts of the molecule.     

Total Synthesis of Leucosceptroids A and B

Leucosceptroids A and B are sesterterpenoids with potent antifeedant and antifungal activities. A more efficient gram‐scale total synthesis of leucosceptroid B and the first total synthesis of leucosceptroid A are presented. The key transformations include an aldol reaction between a substituted dihydrofuranone and an (S)‐citronellal‐derived aldehyde, a SmI₂‐mediated intramolecular ketyl–olefin radical cyclization, and final‐stage alcohol oxidation.     

Asymmetric Total Synthesis of the Complex Polycyclic Xanthone FD‐594

A highly convergent approach was developed to achieve the first asymmetric and scalable total synthesis of FD‐594, a complex polycyclic xanthone natural product from Streptomyces sp. TA‐0256, in a longest linear sequence (LLS) of 20 steps. The trans‐9,10‐dihydrophenanthrene‐9,10‐diol fragment (B‐C‐D ring) was generated through a new strategy involving asymmetric dihydroxylation followed by Cu‐mediated oxidative cyclization. Late‐stage stereoselective glycosylation assembled the angular hexacyclic framework with a β‐linked 2,6‐dideoxy trisaccharide fragment.     

Formal Total Synthesis of (−)‐Taxol through Pd‐Catalyzed Eight‐Membered Carbocyclic Ring Formation

A formal total synthesis of (?)‐taxol by a convergent approach utilizing Pd‐catalyzed intramolecular alkenylation is described. Formation of the eight‐membered carbocyclic ring has been a problem in the convergent total synthesis of taxol but it was solved by the Pd‐catalyzed intramolecular alkenylation of a methyl ketone affording the cyclized product in excellent yield (97 %), indicating the high efficiency of the Pd‐catalyzed intramolecular alkenylation. Rearrangement of the epoxy benzyl ether through a 1,5‐hydride shift, generating the C3 stereogenic center and subsequently forming the C1–C2 benzylidene, was discovered and utilized in the preparation of a substrate for the Pd‐catalyzed reaction.     

Total Synthesis of Siomycin A: Completion of the Total Synthesis

The total synthesis of siomycin A ( 1 ), a representative compound of the thiostrepton family of peptide antibiotics, was achieved by incorporating the five synthetic segments A ( 2 ), B ( 3 ), C ( 4 ), D ( 5 ), and E ( 6 ). The dehydropiperidine segment A ( 2 ) was esterified with the dihydroquinoline segment C ( 4 ), and the subsequent coupling with the β‐phenylselenoalanine dipeptide segment D ( 5 ) at the segment C portion followed by lactamization between the segments A and D gave segment A‐C‐D ( 27 ). This was amidated with the pentapeptide segment B ( 3 ) at the segment A portion followed by one‐pot cyclization (between segments A and B) and elongation (with the β‐phenylselenoalanine dipeptide segment E ( 6 ) at the segment A portion), thus furnishing siomycin A ( 1 ).     

Enantioselective Total Synthesis of (+)‐Ophiobolin A

The enantioselective total synthesis of (+)‐ophiobolin A is described. This total synthesis features the construction of the spiro CD ring of (+)‐ophiobolin A through a stereoselective intramolecular Hosomi–Sakurai cyclization reaction, the joining of the A ring to the CD ring by using a reaction reported by Utimoto, and the construction of the ophiobolin eight‐membered carbocyclic ring through ring‐closing metathesis (RCM), which was performed for the first time in this study. This successful RCM reaction required the use of a substrate that contained either a benzyloxy or a methoxymethoxy group at the C5 position and either an isopropenyl group or its hydroxylated form at the C6 position.     

Convergent Assembly of the Tetracyclic Meroterpenoid (−)‐Cyclosmenospongine by a Non‐Biomimetic Polyene Cyclization

The cationic cyclization of polyenes constitutes a powerful and elegant transformation, which has been utilized by nature's biosynthetic machinery for the construction of complex polycyclic terpenoids. Previous studies by chemists to mimic this cyclization in the laboratory were limited to different modes of activation using biosynthetic‐like precursors, which accommodate only simple methyl‐derived substituents. Here we describe the development of an unprecedented and highly efficient polyene cyclization of an aryl enol ether containing substrate. The cyclization was shown to proceed in a stepwise manner to generate three rings and three consecutive stereocenters, two of which are tetrasubstituted, in a single flask. The developed transformation is of great synthetic value and has enabled the convergent assembly of the tetracyclic meroterpenoid (?)‐cyclosmenospongine.     

Total Synthesis of (−)‐Amphidinolide K

Macrolide magic : An enyne cross‐metathesis reaction of an alkynyl boronate with an alkene derivative as well as a radical cyclization reaction of a homopropargylic β‐alkoxyacrylate are the key transformations in the total synthesis of the cytotoxic macrolide (?)‐amphidinolide K.