Total Synthesis of Lucidumone through Convenient One-pot Preparation of the Tetracyclic Skeleton by Claisen Rearrangement and Subsequent Intramolecular Aldol Reaction

The total synthesis of lucidumone ( 1 ), a Ganoderma meroterpenoid, was accomplished in racemic form from easily prepared 6 and 7 in 10 steps as the longest linear sequence. The synthesis was completed through one-pot preparation of the tetracyclic core skeleton by Claisen rearrangement followed by an intramolecular aldol reaction. The intramolecular aldol reaction allowed for the stereocontrolled construction of the bicyclo [2.2.2] octane skeleton fused to an indanone structure. The enantioselective total synthesis of 1 was also described via a chiral transfer strategy in the Claisen rearrangement.     

Total Synthesis of Kopsinitarine E

Kopsinitarines A–E are complex octacyclic caged Kopsia alkaloids with strained cage skeletons and a unique cyclic hemiaminal bridge that makes total synthesis challenging. Herein, we disclose the first total synthesis of kopsinitarine E. The key synthetic features include a SmI₂-mediated radical cascade cyclization and a subsequent semi-pinacol rearrangement to install the key carbocyclic skeleton, a chemoselective hydrosilyl amide reduction to construct the hemiaminal ether bridge, and an intramolecular Mannich reaction to establish the highly strained cage system.     

First Enantioselective Synthesis of Daphneticin

An enantioselective total synthesis of chiral daphneticin is reported firstly.     

(2R，3R)-和(2S，3S)-2-(4-羟基-3-甲氧基)-3-羟甲基-1，4-苯并二氧六环-6-醛的对映选择性合成

1,4-苯并二氧六环木脂素类天然产物多数具有增加胆碱乙酰化酶和抗肝毒等活性 ,其活性主要源于 1 ,4-苯并二氧六环官能团 [1] . 1 ,4-苯并二氧六环木脂素的消旋全合成已有报道 [2 ] ,但其不对称合成还是空白[3] .我们发展了一条对映选择性合成 1 ,4-苯并二氧六环木脂素的简捷有效的路线 .基于前面的工作 [4 ] ,我们发现 1 ,4-苯并二氧六环醛类衍生物是合成此类天然产物的关键中间体 ,选择 2 - (4-羟基- 3-甲氧基 ) - 3-羟甲基 - 1 ,4-苯并二氧六环 - 6-醛 (1 )作为目标分子 ,其合成路线如下 :Reagents and conditions:( ) Me OH,H2 SO4,9…     

Total synthesis of (-)-isoschizogamine

A first asymmetric total synthesis of (-)-isoschizogamine has been accomplished. Our synthesis features the facile construction of the carbon framework of the natural product through a Wagner-Meerwein rearrangement, a tandem metathesis, a stereoselective rhodium-mediated 1,4-addition of an arylboronic acid, and a ring-closing metathesis via a hemiaminal ether.     

Total Synthesis of the Proposed Structure of Neaumycin B

The total synthesis of the proposed structure of anti-glioblastoma natural product neaumycin B was achieved in 22 steps (longest linear sequence). The synthesis features HCl-mediated [6,6]-spiroketalization, a combination of Krische iridium-catalyzed crotylation, Marshall palladium-catalyzed propargylation, Fürstner nickel-catalyzed regio- and enantioselective vicinal monoprotected diol formation, Brown crotylation and asymmetric halide-aldehyde cycloaddition, so as to establish the challenging contiguous stereocenters.     

Synthetic approaches to carnegine, a simple tetrahydroisoquinoline alkaloid

The different approaches towards the total synthesis of carnegine, a simple tetrahydroisoquinoline alkaloid isolated from several Cactaceae and Chenopodiaceae as well as other plants, are presented. Emphasis is placed on the various enantioselective strategies leading to the natural product in chiral form.     

Enantioselective total syntheses of (-)-taiwaniaquinone H and (-)-taiwaniaquinol B by iridium-catalyzed borylation and palladium-catalyzed asymmetric α-arylation

We report a concise, enantioselective total synthesis of (-)-taiwaniaquinone H and the first enantioselective total synthesis of (-)-taiwaniaquinol B by a route that includes asymmetric palladium-catalyzed α-arylation of a ketone with an aryl bromide that was generated by sterically controlled halogenation via iridium-catalyzed C-H borylation. This asymmetric α-arylation creates the benzylic quaternary stereogenic center present in the taiwaniaquinoids. The synthesis was completed efficiently by developing a Lewis acid-promoted cascade to construct the [6,5,6] tricyclic core of an intermediate common to the synthesis of a number of taiwaniaquinoids. Through the preparation of these compounds, we demonstrate the utility of constructing benzylic quaternary stereogenic centers, even those lacking a carbonyl group in the α-position, by asymmetric α-arylation.     

Bifunctional Iminophosphorane-Catalyzed Enantioselective Nitroalkane Addition to Unactivated α,β-Unsaturated Esters**

Herein we describe the enantioselective intermolecular conjugate addition of nitroalkanes to unactivated α,β-unsaturated esters, catalyzed by a bifunctional iminophosphorane (BIMP) superbase. The transformation provides the most direct access to pharmaceutically relevant enantioenriched γ-nitroesters, utilizing feedstock chemicals, with unprecedented selectivity. The methodology exhibits a broad substrate scope, including β-(fluoro)alkyl, aryl and heteroaryl substituted electrophiles, and was successfully applied on a gram scale with reduced catalyst loading, and, additionally, catalyst recovery was carried out. The formal synthesis of a range of drug molecules, and an enantioselective synthesis of (S)-rolipram were achieved. Additionally, computational studies revealed key reaction intermediates and transition state structures, and provided rationale for high enantioselectivities, in good agreement with experimental results.     

Enantioselective Palladium‐Catalyzed Dearomative Cyclization for the Efficient Synthesis of Terpenes and Steroids

A novel enantioselective palladium‐catalyzed dearomative cyclization has been developed for the efficient construction of a series of chiral phenanthrenone derivatives bearing an all‐carbon quaternary center. The effectiveness of this method in the synthesis of terpenes and steroids was demonstrated by a highly efficient synthesis of a kaurene intermediate, the facile construction of the skeleton of the anabolic steroid boldenone, and the enantioselective total synthesis of the antimicrobial diterpene natural product (?)‐totaradiol.     

Bent π-Conjugation within a Macrocycle: Asymmetric Total Syntheses of Spirohexenolides A and B

Macrocycles with bent π-conjugation motif are extremely rare in nature and synthetically daunting and anticancer haouamines and spirohexenolides were representative of such rare natural products with synthetically challenging bent π-conjugation within a macrocycle. While the total synthesis of haouamines has been elegantly achieved, spirohexenolides remains an unmet synthetic challenge due to the highly strained bent 1,3,5-triene conjugation within C15 macrocycle. Inspired by the chemical synthesis of cycloparaphenylenes (CPPs) and haouamines, herein we devise a synthetic strategy to overcome the highly strained bent 1,3,5-triene conjugation within the macrocycle and achieve the first, asymmetric total synthesis of spirohexenolides A (>20 mg) and B (>50 mg). Our synthesis features strategic design of ring-closing metathesis (RCM) macrocyclization followed by double dehydration to achieve the C15 macrocycle with the deformed nonplanar 1,3,5-triene conjugation. In addition, we have developed a new enantioselective construction of highly functionalized spirotetronate fragment (northeast moiety) through RCM and Ireland–Claisen rearrangement. Our in vitro bioassay studies reveal that both spirohexenolides are cytotoxic against a panel of human cancer cells with IC₅₀ 1.2–13.3 μM and spirohexenolide A is consistently more potent (up to 3 times) than spirohexenolide B, suggesting the importance of alcohol for their bioactivity and for medicinal chemistry development.     

Lewis Base/Brønsted Acid Co‐catalyzed Enantioselective Sulfenylation/Semipinacol Rearrangement of Di‐ and Trisubstituted Allylic Alcohols

An enantioselective sulfenylation/semipinacol rearrangement of 1,1‐disubstituted and trisubstituted allylic alcohols was accomplished with a chiral Lewis base and a chiral Brønsted acid as cocatalysts, generating various β‐arylthio ketones bearing an all‐carbon quaternary center in moderate to excellent yields and excellent enantioselectivities. These chiral arylthio ketone products are common intermediates with many applications, for example, in the design of new chiral catalysts/ligands and the total synthesis of natural products. Computational studies (DFT calculations) were carried out to explain the enantioselectivity and the role of the chiral Brønsted acid. Additionally, the synthetic utility of this method was exemplified by an enantioselective total synthesis of (?)‐herbertene and a one‐pot synthesis of a chiral sulfoxide and sulfone.     

Straightforward α‐Amino Nitrile Synthesis Through Mo(CO)6‐Catalyzed Reductive Functionalization of Carboxamides

The selective reduction of amides into an intermediate hemiaminal catalyzed by Mo(CO)₆ together with the inexpensive and easy to handle TMDS (1,1,3,3‐tetramethyldisiloxane) as reducing agent, followed by subsequent trapping of the hemiaminal with a cyanide source, allows for the straightforward synthesis of α‐amino nitriles. The methodology presented here, displays high levels of chemoselectivity allowing for the reduction of amides in the presence of functional groups such as ketones, imines, aldehydes, and acids, which affords a simple route for the synthesis of α‐amino nitriles with a broad scope of functionalities in high yields. Furthermore, the applicability of this methodology is demonstrated by scale up experiments and by derivatization of the target compounds into synthetically interesting products. The selective cyanation is successfully applied in late stage functionalizations of amide containing drugs and prolinol derivatives.     

Organocatalytic asymmetric total synthesis of (R)-rolipram and formal synthesis of (3S,4R)-paroxetine

An efficient enantioselective total synthesis of (R)-rolipram and an efficient enantioselective formal synthesis of (3S,4R)-paroxetine has been achieved using the highly enantioselective Michael addition of malonate nucleophiles as key steps in both cases.     

Synthesis of the 3-(3,4,5-Trimethoxyphenyl)-pyrrolidine: A New Conformationally Constrained Mescaline Analogue

The total synthesis of the 3‐(3,4,5-trimethoxyphenyl)-pyrrolidine, a new and conformationally constrained mescaline analogue, was accomplished in a concise and efficient manner. The synthetic route encompassed only 4 steps from the starting N-Cbz-3-pyrrolidine, in 46% overall yield. The route features a highly effective Heck arylation of the non-activated olefin N-Cbz-3-pyrrolidine with the 3,4,5-trimethoxybenzene diazonium tetrafluoroborate. The hemiaminal (lactamol) Heck adduct was converted to the mescaline analogue in a sequence of reactions: (a) dehydration of the intermediate hemiaminal 3 with trifluoroacetic acid anhydride, (b) hydrogenation/hydrogenolysis of the endocyclic enecarbamate 6 with H2-Pd/C, and (c) formation of the rather stable mescaline analogue in the form of a hydrochloride salt. The target molecule constitutes a new mescaline analogue with potential activity towards 5‐HT2 dopamine receptors.     

Enantioselective total synthesis of guanacastepene N using an uncommon 7-endo Heck cyclization as a pivotal step

A convergent, enantioselective total synthesis of (+)-guanacastepene N was developed that features a 7-endo Heck cyclization as the key step. In the course of this synthesis, short syntheses of the enantiomerically pure cyclopentenone and cyclohexene building blocks 5 and 6, which constitute A and C ring fragments of guanacastepene N, were developed. These fragments were linked by a challenging conjugate addition reaction that also generated the C11 quaternary carbon stereocenter. Regioselective 7-endo Heck cyclization gave rise to a tricyclic intermediate, which was elaborated to complete the first total synthesis of guanacastepene N and the second enantioselective total synthesis of a guanacastepene natural product.     

Efficient Synthesis of 2—Ethyl—A—ring Analogues of 19—Nor—1α,25—dihydroxy Vitamin D3

The novel 19-nor-1α,25-dihydroxy vitamin D3 analogues possessing an ethyl at the 2-position(4 and 5).were synthesized by coupling 25-hydroxy Windaus-Grundmann ketone derivative 20 with A-ring synthons(15 and 19)respectively.The enantioselective synthesis of substituted bicyclic[3,1,0]hexanes structure A-ring synthons,started from all-cis-3,5-dihydroxy-4-ethyl-1-(methoxycarbonyl)cyclohexane via lipase-catalyzd asymmetrization,was demonstratcd.     

Indole Editing Enabled by HFIP-Mediated Ring-Switch Reactions of 3-Amino-2-Hydroxyindolines

This work reports the novel reactivity of hemiaminal as a precursor for indole editing at the multi-site. The HFIP-promoted indole editing of indoline hemiaminals affords 2-arylindoles through a ring-switch sequence. The key to success of this transformation is to use a cyclic hemiaminal as an α-amino aldehyde surrogate under transient tautomeric control. This transformation features mild reaction conditions and good yields with broad functional group tolerance. The utility of this transformation is presented through the one-pot protocol and the synthesis of isocryptolepine.     

Concise Total Synthesis of (−)-Quinocarcin Enabled by Catalytic Enantioselective Reductive 1,3-Dipolar Cycloaddition of Secondary Amides

A concise asymmetric total synthesis of (−)-quinocarcin has been accomplished with high step economy from commercially available starting materials. A catalytic enantioselective reductive 1,3-dipolar cycloaddition reaction of N-heteroaryl secondary amides with reactive dipolarophiles using iridium/copper relay catalysis was developed to prepare the key chiral pyrrolidine intermediate with three stereocenters. This protocol features excellent regio-, exo- and enantioselectivities, broad substrate scope, and good functional group tolerance. The high efficiency was also ensured by a Rh^III-catalyzed C−H activation/cyclization and a tandem diastereoselective hydrogenation/cyclization to construct the tetrahydroisoquinoline-pyrrolidine tetracyclic core unit of quinocarcin.     

A short and efficient enantioselective route to a key intermediate for the total synthesis of forskolin

A simple route for the enantioselective synthesis of key intermediates (11 and 12) for the total synthesis of forskolin has been developed starting from acid 6 and (S)-alcohol 5. The latter is prepared by enantioselective catalytic CBS reduction of dienone 3, and is converted by an intramolecular Diels-Alder reaction to tricyclic lactone 9.