Total Synthesis of the Diterpenoid (+)‐Harringtonolide

Described herein is the first asymmetric total synthesis of (+)‐harringtonolide, a natural diterpenoid with an unusual tropone imbedded in a cagelike framework. The key transformations include an intramolecular Diels–Alder reaction and a rhodium‐complex‐catalyzed intramolecular [3+2] cycloaddition to install the tetracyclic core as well as a highly efficient tropone formation.     

A Chemoenzymatic and Fully Stereocontrolled Total Synthesis of the Antibacterial Natural Product (−)‐Platencin

The natural product (?)‐platencin is a potent antibacterial agent that exerts its effects through a novel mode of action. As such, it is an important lead in the development of next‐generation antibacterials that are urgently needed because of the rapidly developing resistance to current therapies. The work reported here concerns the development of a convergent and chemoenzymatic total synthesis of (?)‐platencin by methods that should provide access to a range of biologically relevant analogues. The key step involves a thermally promoted and facially selective intramolecular Diels–Alder (IMDA) cycloaddition reaction to give an adduct that embodies the tricarbocyclic core of (?)‐platencin. This adduct was elaborated over thirteen steps to the natural product. The substrate for the IMDA reaction was prepared by Stille cross‐coupling of a Z‐configured alkenylstannane with an iodinated diene obtained in an enantiomerically pure form through the whole‐cell biotransformation of iodobenzene.     

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.     

Chemoenzymatic Total Synthesis of (+)‐Galanthamine and (+)‐Narwedine from Phenethyl Acetate

The stereoselective total synthesis of unnatural (+)‐galanthamine starting from phenethyl acetate is described. Chirality was introduced via microbial dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) to the corresponding cis‐cyclohexadi–enediol, configuration of which provided the absolute stereochemistry of the ring C of (+)‐galanthamine. Intramolecular Heck cyclization was used to form the quaternary carbon and dibenzofuran functionality. The synthesis of (+)‐galanthamine was completed in a total of ten steps and an overall yield of 5.5 %. Experimental and spectral data are provided for all new compounds.     

A Sequential O‐Nitrosoaldol and Grignard Addition Process: An Enantio‐ and Diastereoselective Entry to Chiral 1,2‐Diols

Chiral 1,2‐diols have been prepared from α‐aminoxylated aldehydes or cyclohexanone and Grignard reagents with L ‐proline or its tetrazole derivative as the catalyst. The presence of the ate complex of CeCl₃?2 LiCl is essential for the high overall yields and good selectivities (see scheme; DMSO=dimethyl sulfoxide, THF=tetrahydrofuran, Tol=tolyl).

     

Total Synthesis and Determination of the Absolute Configuration of (+)‐Omaezakianol

The proof of the pudding : The first asymmetric total synthesis of the marine tetracyclic oxasqualenoid (+)‐omaezakianol features a convergent olefin cross‐metathesis between a monotetrahydrofuran fragment and a triepoxy alkene, and cascade oxacyclizations of a triepoxy alcohol to form the right‐hand three ether rings. The total synthesis proved the absolute configuration of (+)‐omaezakianol to be that shown.

     

Cyclic 1,2‐Diketones as Core Building Blocks: A Strategy for the Total Synthesis of (−)‐Terpestacin

We report a full account of our work towards the total synthesis of (?)‐terpestacin ( 1 ), a sesterterpene originally isolated from fungal strain Arthrinium sp. FA1744. Its promising anti‐HIV and anti‐cancer activity, as well as its novel structure, make terpestacin an attractive synthetic target. A strategy based on the unique reactivity of cyclic 1,2‐diketones (diosphenols) was developed and total synthesis of 1 was achieved in 20 steps, in the longest linear sequence, from commercially available 2‐hydroxy‐3‐methyl‐2‐cyclopenten‐1‐one. The key feature of our synthesis is the double usage of a “Pd AAA‐Claisen” protocol (AAA=asymmetric allylic alkylation), first in the early stages to generate the C1 quaternary center and then in the late stages to install the side chain. In addition, a rather unusual ene‐1,2‐dione moiety was synthesized and utilized as an excellent Michael acceptor to attach the C15 substituent. Several possible routes towards the total synthesis have been examined and carefully evaluated. During our exploration many interesting chemoselectivity issues have been addressed, such as a highly selective ring‐closing metathesis and a challenging oxidation of a disubstituted olefin in the presence of three trisubstiuted ones.     

Stereoselective Total Synthesis of Hetisine‐type C20‐Diterpenoid Alkaloids: Spirasine IV and XI

The first total synthesis of the architecturally complex hetisine‐type heptacyclic C₂₀‐diterpenoid alkaloids (±)‐spirasine IV and XI is reported. The A/F/G/C tetracyclic skeleton with the challenging N?C6 and C14?C20 linkages was efficiently constructed by an intramolecular azomethine‐ylide‐based 1,3‐dipolar cycloaddition with unusual regioselectivity. SmI₂‐mediated free‐radical addition to the arene moiety without prior dearomatization and a stereoselective intramolecular aldol reaction further enabled rapid access to the hetisine core, providing a bicyclo[2.2.2]octane ring with a new oxygen substitution pattern.     

Organocatalytic Asymmetric 1,6‐Addition/1,4‐Addition Sequence to 2,4‐Dienals for the Synthesis of Chiral Chromans

A novel asymmetric organocatalytic 1,6‐addition/1,4‐addition sequence to 2,4‐dienals is described. Based on a 1,6‐Friedel–Crafts/1,4‐oxa‐Michael cascade, the organocatalyst directs the reaction of hydroxyarenes with a vinylogous iminium‐ion intermediate to give only one out of four possible regioisomers, thus providing optically active chromans in high yields and 94–99 % ee. Furthermore, several transformations are presented, including the formation of an optically active macrocyclic lactam. Finally, the mechanism for the novel reaction is discussed based on computational studies.     

Enantioselective Formal [4+2] Cycloadditions to 3‐Nitroindoles by Trienamine Catalysis: Synthesis of Chiral Dihydrocarbazoles

The first enantioselective formal [4+2] cycloadditions of 3‐nitroindoles are presented. By using 3‐nitroindoles in combination with an organocatalyst, chiral dihydrocarbazole scaffolds are formed in moderate to good yields (up to 87 %) and enantioselectivities (up to 97 % ee). The reaction was extended to include enantioselective [4+2] cycloadditions of 3‐nitrobenzothiophene. The reaction proceeds through a [4+2] cycloaddition/elimination cascade under mild reaction conditions. Furthermore, a diastereoselective reduction of an enantioenriched cycloadduct is presented. The mechanism of the reaction is discussed based on experimental and computational studies.     

Flexible Total Synthesis of 11‐Deoxylandomycins and Their Non‐Natural Analogues by Way of Asymmetric Metal Catalysis

A de novo first collective total synthesis of 11‐deoxylandomycins is reported. A signature step is featured by the Pd‐catalyzed asymmetric addition of alcohol to ene‐alkoxyallenes that assembles oligomeric 2,3,6‐trideoxyoligosaccharides. The unique feature of the protocol is illustrated by a flexible access to various natural 11‐deoxylandomycins as well as non‐natural analogues.     

Highly Diastereo‐ and Enantioselective Palladium‐Catalyzed [3+2] Cycloaddition of Vinyl Aziridines and α,β‐Unsaturated Ketones

A palladium‐catalyzed asymmetric [3+2] cycloaddition reaction of vinylaziridines with α,β‐unsaturated ketones, wherein the alkenes have a single activator, is realized in high diastereo‐ and enantioselectivity, thus affording 3,4‐disubstituted pyrrolidines in high yields with excellent ee values. The introduction of a methyl group at C1 of the vinyl group the vinylaziridines greatly improves the stereochemistry of the reaction. A plausible transition state is proposed.     

Stereocontrolled Synthesis of syn‐β‐Hydroxy‐α‐Amino Acids by Direct Aldolization of Pseudoephenamine Glycinamide

β‐Hydroxy‐α‐amino acids figure prominently as chiral building blocks in chemical synthesis and serve as precursors to numerous important medicines. Reported herein is a method for the synthesis of β‐hydroxy‐α‐amino acid derivatives by aldolization of pseudoephenamine glycinamide, which can be prepared from pseudoephenamine in a one‐flask protocol. Enolization of (R,R)‐ or (S,S)‐pseudoephenamine glycinamide with lithium hexamethyldisilazide in the presence of LiCl followed by addition of an aldehyde or ketone substrate affords aldol addition products that are stereochemically homologous with L ‐ or D ‐threonine, respectively. These products, which are typically solids, can be obtained in stereoisomerically pure form in yields of 55–98 %, and are readily transformed into β‐hydroxy‐α‐amino acids by mild hydrolysis or into 2‐amino‐1,3‐diols by reduction with sodium borohydride. This new chemistry greatly facilitates the construction of novel antibiotics of several different classes.     

Efficient Enantioselective Total Synthesis of (−)‐Horsfiline

A new efficient and concise enantioselective synthetic method for (?)‐horsfiline is reported. (?)‐Horsfiline could be obtained from diphenylmethyl tert‐butyl malonate in 9 steps (32 %,>99 % ee) by using the enantioselective phase‐transfer catalytic allylation (91 % ee) as the key step. This approach can be applied as a practical route for the large‐scale synthesis of spirooxindole natural products, which enables a systematic investigation of their biological activity to be performed.