Collective Total Syntheses of Atisane‐Type Diterpenes and Atisine‐Type Diterpenoid Alkaloids: (±)‐Spiramilactone B, (±)‐Spiraminol, (±)‐Dihydroajaconine,and (±)‐Spiramines C and D

The first total syntheses of the architecturally complex atisane‐type diterpenes and biogenetically related atisine‐type diterpenoid alkaloids (±)‐spiramilactone B, (±)‐spiraminol, (±)‐dihydroajaconine, and (±)‐spiramines C and D are reported. Highlights of the synthesis include a late‐stage biomimetic transformation of spiramilactone B, a facile formal lactone migration from the pentacyclic skeleton of spiramilactone E, a highly efficient and diastereoselective 1,7‐enyne cycloisomerization to construct the functionalized tetracyclic atisane skeleton, and a tandem retro‐Diels–Alder/intramolecular Diels–Alder sequence to achieve the tricyclo[6.2.2.0] ring system.     

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 Biomimetic Synthesis of (±)‐Basiliolide B

A highly diastereoselective and practical biomimetic total synthesis of (±)‐basiliolide B has been achieved through the study of the two proposed biosynthetic pathways (O‐methylation and O‐acylation) for the unprecedented 7‐methoxy‐4,5‐dihydro‐3H‐oxepin‐2‐one (C ring). The synthesis featured a cyclopropanation/ring opening strategy for establishing the stereogenic centers at C8 and C9, a biomimetic 2‐pyrone Diels–Alder cycloaddition for the synthesis of the ABD ring system, and finally a highly efficient biomimetic intramolecular O‐acylation for the C ring formation. This result provides an important perspective on the biosynthetic origin of the unprecedented 7‐membered acyl ketene acetal moiety of the C ring.     

Total Syntheses of (±)‐Fawcettimine, (±)‐Fawcettidine, (±)‐Lycoflexine,and (±)‐Lycoposerramine‐Q

The total syntheses of four fawcettimine‐related Lycopodium alkaloids, (±)‐fawcettimine, (±)‐fawcettidine, (±)‐lycoposerramine‐Q, and (±)‐lycoflexine, were completed in a highly stereoselective manner. The Pauson–Khand reaction of 4‐methylidene‐6‐siloxyoct‐1‐en‐7‐yne followed by regio‐ and stereoselective hydrogenation led to the short‐step preparation of the bicyclo[4.3.0]nonenone intermediate bearing a methyl group with the required stereochemistry. The subsequent chemical manipulation of the bicyclic compound afforded the 6‐5‐9‐membered tricyclic dioxo compound, which was then transformed into the four targeted alkaloids in an alternative and more efficient fashion.     

Photochemistry of Tricyclo[5.2.2.02,6]undeca‐4,10‐dien‐8‐ones: An Efficient General Route to Substituted Linear Triquinanes from 2‐Methoxyphenols. Total Synthesis of (±)‐Δ9(12)‐Capnellene

An efficient and short entry to polyfunctionalized linear triquinanes from 2‐methoxyphenols is described by utilizing the following chemistry. The Diels–Alder reactions of masked o‐benzoquinones, derived from 2‐methoxyphenols, with cyclopentadiene afford tricyclo[5.2.2.0^2,6]undeca‐4,10‐dien‐8‐ones. Photochemical oxa‐di‐π‐methane (ODPM) rearrangements and 1,3‐acyl shifts of the Diels–Alder adducts are investigated. The ODPM‐rearranged products are further converted to linear triquinanes by using an O‐stannyl ketyl fragmentation. Application of this efficient strategy to the total synthesis of (±)‐Δ⁹⁽¹²⁾‐capnellene was accomplished from 2‐methoxy‐4‐methylphenol in nine steps with 20 % overall yield.     

Diastereoselective Total Syntheses of (±)‐Caseabalansin A and (±)‐18‐Epicaseabalansin A via Intramolecular Robinson‐type Annulation

Highly diastereoselective total syntheses of (±)‐caseabalansin A ( 1 ) and (±)‐18‐epicaseabalansin A ( 2 ) are described in this paper. We revealed that the intramolecular Robinson‐type annulation of an alkynone was effective in the stereocontrolled construction of the bicyclic skeleton of 1 and 2 . Further transformation of the resulting enone, including diastereoselective reduction by LiAlH(OtBu)₃, hydroxy‐group‐directed hydrogenation, cyclization to form the cyclic acetal moiety, and introduction of a side chain by a C(sp³)?C(sp³) Stille coupling reaction, resulted in the total syntheses of (±)‐ 1 and (±)‐ 2 .     

Total Synthesis of (−)‐Merochlorin A

The first asymmetric total synthesis of the meroterpenoid (?)‐merochlorin A is described. The route features enantiospecific gold‐catalyzed tandem 1,3‐acyloxy migration/Nazarov/aldol reaction sequence to furnish the bicyclo[3.3.0]octane core in a single step from a linear propargylic 1,3‐enyne aldehyde. After completion of the central skeleton by reductive enol lactone rearrangement, late stage Diels–Alder cycloaddition/aromatization sequence installed the resorcinol. An additional salient feature of the synthesis is the assignment of the absolute configuration, which had not been determined previously.     

Vicinal Dianion of Triethyl Ethanetricarboxylate: Syntheses of (±)‐Lichesterinic Acid, (±)‐Phaseolinic Acid, (±)‐Nephromopsinic Acid, (±)‐Rocellaric Acid,and (±)‐Dihydroprotolichesterinic Acid

The vicinal dianion 2 derived from triethyl ethanetricarboxylate reacted regioselectively with aldehydes and ketones at C(β) to provide paraconic acid derivatives 5a – f in moderate to high yields as mixtures of diastereoisomers. The paraconic acid derivatives 5e and 5f were utilized as the starting materials for the syntheses of (±)‐lichesterinic acid ( 12 ), (±)‐phaseolinic acid ( 13 ), (±)‐nephromopsinic acid ( 14 ), (±)‐rocellaric acid ( 15 ), and (±)‐dihydroprotolichesterinic acid ( 16 ).     

A Bioinspired Synthesis of (±)‐Rubrobramide, (±)‐Flavipucine,and (±)‐Isoflavipucine

A biomimetic synthesis of naturally occurring lactams rubrobramide, flavipucine, and isoflavipucine is described. The key step is a regioselective Darzens reaction between isobutyl glyoxal and an α‐bromo‐β‐ketoamide. The construction of the core tricyclic ring system of rubrobramide was achieved by a cascade reaction in a single step from an α,β‐epoxy‐γ‐lactam. Furthermore, the absolute configuration of naturally occurring (+)‐rubrobramide was determined by vibrational circular dichroism. (±)‐Flavipucine and (±)‐isoflavipucine were synthesized from an epoxyimide, which was prepared by reaction of isobutyl glyoxal with a protected α‐bromo‐β‐ketoamide. Deprotection of the epoxyimide and formation of the pyridone ring gave (±)‐flavipucine, which was converted into (±)‐isoflavipucine by thermal isomerization.     

Pentafulvene for the Synthesis of Complex Natural Products: Total Syntheses of (±)‐Pallambins A and B

The first total syntheses of pallambins A and B are enabled by the use of pentafulvene in an unprecedented Diels–Alder reaction. After elaboration of the adduct through chemoselective cyclopropanation, strategic C? H insertion affords the dense tetracyclic core of the natural products. 1,3‐Dipolar cycloaddition and palladium(II)‐catalyzed alkoxycarbonylation were leveraged for the construction of the hexacyclic scaffold en route to both natural products.     

Biomimetic Total Synthesis of (±)‐Homodimericin A

A biomimetic total synthesis of racemic homodimericin A was achieved in seven steps, including two cascade reactions. Aqueous buffer solutions are found to help both the oxidative dimerization cascade and the intramolecular Diels–Alder cascade. This synthetic sequence validates key steps in the biogenetic proposal of homodimericin A.     

A Bioinspired Synthesis of (±)‐Rubrobramide, (±)‐Flavipucine,and (±)‐Isoflavipucine

A biomimetic synthesis of naturally occurring lactams rubrobramide, flavipucine, and isoflavipucine is described. The key step is a regioselective Darzens reaction between isobutyl glyoxal and an α‐bromo‐β‐ketoamide. The construction of the core tricyclic ring system of rubrobramide was achieved by a cascade reaction in a single step from an α,β‐epoxy‐γ‐lactam. Furthermore, the absolute configuration of naturally occurring (+)‐rubrobramide was determined by vibrational circular dichroism. (±)‐Flavipucine and (±)‐isoflavipucine were synthesized from an epoxyimide, which was prepared by reaction of isobutyl glyoxal with a protected α‐bromo‐β‐ketoamide. Deprotection of the epoxyimide and formation of the pyridone ring gave (±)‐flavipucine, which was converted into (±)‐isoflavipucine by thermal isomerization.     

Biomimetic Total Syntheses of (−)‐Leucoridines A and C through the Dimerization of (−)‐Dihydrovalparicine

Concise biomimetic syntheses of the Strychnos‐Strychnos‐type bis‐indole alkaloids (?)‐leucoridine A ( 1 ) and C ( 2 ) were accomplished through the biomimetic dimerization of (?)‐dihydrovalparicine ( 3 ). En route to 3 , the known alkaloids (+)‐geissoschizoline ( 8 ) and (?)‐dehydrogeissoschizoline ( 10 ) were also prepared. DFT calculations were employed to elucidate the mechanism, which favors a stepwise aza‐Michael/spirocyclization sequence over the alternate hetero‐Diels–Alder cycloaddition reaction.     

Asymmetric Synthesis of Both Enantiomers of Protected 5‐Hydroxynorvaline by Hetero‐Diels‐Alder Addition of ethyl 2‐Nitrosoacrylate to (R)‐ and (S)‐1‐Phenylbutyl Vinyl Ether

Both enantiomers of protected 5‐hydroxynorvaline were prepared by hetero‐Diels‐Alder addition of ethyl 2‐nitrosoacrylate to readily available (R)‐ and (S)‐1‐phenylbutyl vinyl ether and a further three‐step manipulation. Attempted synthesis of (±)‐vigabatrin from protected (±)‐5‐hydroxynorvaline was unsuccessful.     

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.     

Total Synthesis of (±)‐Eusiderin G and (±)‐Eusiderin M

(±)‐Eusiderin G and (±)‐Eusiderin M were first synthesized from pyrogallol, in which the Claisen Rearrangement was used to afford two important C₆‐C₃ units.     

Total Synthesis of (-)-Kaerophyllin,(-)-Hinokinin and (±)-Isohinokinin

Kaerophyllin (1) ,hinokinin (2 )andtheiranalogue isohinokinin (3)belongtothedibenzylbutyrolactone lig nans .Kaerophyllin (1)wasisolatedfromtherootofspot tedcowparsley (ChaerophyllummaculatumWilld .) 1andhinokinin (2 )wasisolatedfromtheheartwoodofLiboce drusformosanaFlorin .2 AccordingtoMacRaeandTow ers ,3afivememberedlactoneringandamethylenedioxylgroupwereimportantstructuralcharacteristicswhichcon tributetotheactivityoflignansasantitumoragents .More over ,anunsaturateddoublebondbetweenC3—…     

Facile Synthesis of (±)‐Parahigginone Methyl Ether and (±)‐Curcuphenol

Using Grinard coupling as a key step, a facile synthetic approach to (±)‐parahigginone methyl ether 1 and (±)‐curcuphenol 2 has been achieved by five steps with 42.3% and 58.6% overall yield, respectively.     

Total Synthesis of (±)‐Integrifolin

The total synthesis of (±)‐integrifolin has been achieved for the first time through the stereoselective preparation of the bicyclo[5.3.0]decane skeleton based on the tungsten‐catalyzed cyclization of acyclic trienynes under photoirradiation conditions. Further key transformations of the cyclized product are the Tamao oxidation through cyclic silyl ether, the introduction of two oxygen functionalities by the oxidation of the diene and the construction of three exo‐methylene moieties.     

Asymmetric Total Synthesis of (−)‐Maoecrystal V

The asymmetric total synthesis of (?)‐maoecrystal V, a novel cytotoxic pentacyclic ent‐kaurane diterpene, has been accomplished. Key steps of the current strategy involve an early‐stage semipinacol rearrangement reaction for the construction of the C10 quaternary stereocenter, a rhodium‐catalyzed intramolecular O?H insertion reaction, and a sequential Wessely oxidative dearomatization/intramolecular Diels–Alder reaction to forge the pentacyclic framework of maoecrystal V.