Enantioselective Total Synthesis of (+)‐Plumisclerin A

The first and enantioselective total synthesis of (+)‐plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring‐formation protocol was adopted to generate the characteristic tricycle[4.3.1.0^1,5]decane and trans‐fused dihyrdopyran moiety. Scalable enantioselective La^III‐catalyzed Michael reaction, palladium(0)‐catalyzed carbonylation and SmI₂‐mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D‐ring system having six continuous stereogenic centers and two all‐carbon quaternary centers. The trans‐fused dihyrdopyran moiety with an exo side‐chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)‐plumisclerin A.     

Synthesis of (+)‐13‐Stemarene and (+)‐18‐Deoxystemarin: Expeditious Preparation of the Key 6‐exo‐Hydroxybicyclo[2.2.2]octan‐2‐one Ethylene Dithioacetal

An expeditious preparation of the 6‐exo‐hydroxybicyclo[2.2.2]octan‐2‐one ethylene dithioacetal 2b , a key intermediate in the synthesis of (+)‐13‐stemarene ( 4 ) and (+)‐18‐deoxystemarin ( 5 ) is described. Compound 2b was obtained as the major product by equilibrating the endo rich mixture of 6‐hydroxybicyclo[2.2.2]octan‐2‐one ethylene dithioacetals 2 with TsOH in benzene at reflux, easily available from the corresponding hydroxy ketones 9 . The model experiments which preceeded the above transformation, not previously described in the literature, are also presented.     

A Concise Total Synthesis of (+)‐Tetrabenazine and (+)‐α‐Dihydrotetrabenazine

Highly concise asymmetric total syntheses of (+)‐tetrabenazine ( 1 ), a drug for the treatment of chorea associated with Huntington’s disease, and of (+)‐α‐dihydrotetrabenazine ( 2 ), an active metabolite of 1 , have been accomplished. Our synthetic route features a trans‐selective enol etherification, followed by an unprecedented cation‐dependent aza‐Claisen rearrangement to establish the carbon framework and two stereogenic centers of tetrabenazine. The syntheses consist of seven steps (34 % overall yield) for (+)‐ 2 and eight steps (22 % overall yield) for (+)‐ 1 .     

Stereoselective Synthesis of (−)‐(1R,1′R,5′R,7′R)‐1‐Hydroxy‐exo‐brevicomin and (+)‐exo‐Brevicomin from 3,4,6‐Tri‐O‐acetyl‐D‐glucal

Stereoselective syntheses of (?)‐(1R,1′R,5′R,7′R)‐1‐hydroxy‐exo‐brevicomin ( 1 ) and (+)‐exo‐brevicomin ( 2 ) were accomplished from 3,4,6‐tri‐O‐acetyl‐D ‐glucal ( 5 ; Schemes 2 and 3). Chemoselective reduction, Grignard reaction, Barton? McCombie deoxygenation, and ketalization were used as key steps.     

The Synthesis and Chemistry of 1,3‐Bridged Polycyclic Cyclopropenes: 8‐Oxatricyclo[3.2.1.02,4]octa‐2,6‐dienes

Three 1,3‐bridged polycyclic cyclopropenes, exo‐8‐oxatricyclo[3.2.1.0^2,4]octa‐2,6‐diene ( 10 ), endo‐8‐oxatricyclo[3.2.1.0^2,4]octa‐2,6‐diene ( 11 ), and exo‐6,7‐benzo‐1,5‐diphenyl‐8‐oxatricyclo[3.2.1.0^2,4]octa‐2,6‐diene ( 12 ), have been synthesized by elimination of 2‐chloro‐3‐trimethylsilyl‐8‐oxatricyclo[3.2.1.0^2,4]‐oct‐6‐enes, 17 , 18 and 30 , which were generated from 1‐chloro‐3‐trimethylsilylcyclopropene with furan and diphenylisobenzofuran. We have demonstrated a facile route to synthesize the highly strained 1,3‐fused polycyclic cyclopropenes, 10 , 11 , and 12 . The stereochemistry of the Diels‐Alder reactions of cyclopropene 16 with furan and DPIBF are different. Cyclopropene 16 was treated with furan to form exo‐exo and endo‐exo adducts (5:2) and treated with DPIBF to generate an exo‐exo adduct. Compounds 10 , 11 and 12 undergo isomerization reactions to form benzaldehyde and phenyl 4‐phenyl‐[1]naphthyl ketone to release strain energies via diradical mechanisms.     

A facile approach for the construction of the oxetane ring from 5α-acyloxy-Δ~(4(20)) - taxoids

An oxetane ring can be constructed from 5α-acyloxy-Δ4(20)-taxoids. Hie facile intramolecular acyl migration from 5- to 20-position under slightly basic conditions enabled the construction of the oxetane ring in a convenient short cut, whereas the acyl migration from 2- to 20-position left the 2-hydroxyl accessible to a later benzoylation. An unexpected five-mem-bered 4-O, 20- O sulfite ring was formed in the attempted construction of the oxetane ring with 5α-triflate as a leaving group. After the construction of the oxetane ring, treatment with strong base LiHMDS and acetyl chloride gave the expected 4-O-acetate while treatment with acetic anhydride and DMAP gave a 4-O-acetoacetate.     

Short and Divergent Total Synthesis of (+)‐Machaeriol B, (+)‐Machaeriol D, (+)‐Δ8‐THC,and Analogues

Short and highly efficient stereoselective syntheses provide machaeriols and cannabinoids in a divergent approach starting from a common precursor, commercially available (S)‐perillic acid. Key features of the novel strategy are a stereospecific palladium‐catalyzed decarboxylative arylation and a one‐pot sequence comprising a stereoselective hydroboration followed by oxidation or reduction of the corresponding intermediary boranes. The divergent approach is convincingly demonstrated by the five‐step syntheses of (+)‐machaeriol B, (+)‐machaeriol D, and related analogues, and the four‐step synthesis of (+)‐Δ⁸‐THC and an analogue.     

Competitive Gold‐Promoted Meyer–Schuster and oxy‐Cope Rearrangements of 3‐Acyloxy‐1,5‐enynes: Selective Catalysis for the Synthesis of (+)‐(S)‐γ‐Ionone and (−)‐(2S,6 R)‐cis‐γ‐Irone

We report a simple, highly stereoselective synthesis of (+)‐(S)‐γ‐ionone and (‐)‐(2S,6R)‐cis‐γ‐irone, two characteristic and precious odorants; the latter compound is a constituent of the essential oil obtained from iris rhizomes. Of general interest in this approach are the photoisomerization of an endo trisubstituted cyclohexene double bond to an exo vinyl group and the installation of the enone side chain through a [(NHC)Au^I]‐catalyzed Meyer–Schuster‐like rearrangement. This required a careful investigation of the mechanism of the gold‐catalyzed reaction and a judicious selection of reaction conditions. In fact, it was found that the Meyer–Schuster reaction may compete with the oxy‐Cope rearrangement. Gold‐based catalytic systems can promote either reaction selectively. In the present system, the mononuclear gold complex [Au(IPr)Cl], in combination with the silver salt AgSbF₆ in 100:1 butan‐2‐one/H₂O, proved to efficiently promote the Meyer–Schuster rearrangement of propargylic benzoates, whereas the digold catalyst [{Au(IPr)}₂(μ‐OH)][BF₄] in anhydrous dichloromethane selectively promoted the oxy‐Cope rearrangement of propargylic alcohols.     

The Absolute Configuration of (+)‐Ethyl cis‐1‐Benzyl‐3‐hydroxypiperidine‐4‐carboxylate and (+)‐4‐Ethyl 1‐Methyl cis‐3‐Hydroxypiperidine‐1,4‐dicarboxylate; a Revision

Discrepancies between chiroptical data from the literature and our determination of the structure of the title compounds (+)‐ 5 and (+)‐ 9a were resolved by an unambiguous assignment of their absolute configuration. Accordingly, the dextrorotatory cis‐3‐hydroxy esters have (3R,4R)‐ and the laevorotatory enantiomers (3S,4S)‐configuration. The final evidences were demonstrated on both enantiomers (+)‐ and (?)‐ 5 by biological reduction of 4 by bakers' yeast and stereoselective [Ru^II(binap)]‐catalyzed hydrogenations of 4 (Scheme 2), by the application of the NMR Mosher method on (+)‐ and (?)‐ 5 (Scheme 3), as well as by the transformation of (+)‐ 5 into a common derivative and chiroptical correlation (Scheme 4).     

Enantioselective Total Synthesis of (+)‐Jungermatrobrunin A

A concise and enantioselective total synthesis of (+)‐jungermatrobrunin A ( 1 ), which features a unique bicyclo[3.2.1]octene ring skeleton with an unprecedented peroxide bridge, was accomplished in 13 steps by making use of a late‐stage visible‐light‐mediated Schenck ene reaction of (?)‐1α,6α‐diacetoxyjungermannenone C ( 2 ). Along the way, a UV‐light‐induced bicyclo[3.2.1]octene ring rearrangement afforded (+)‐12‐hydroxy‐1α,6α‐diacetoxy‐ent‐kaura‐9(11),16‐dien‐15‐one ( 4 ). These divergent photo‐induced skeletal rearrangements support a possible biogenetic relationship between (+)‐ 1 , (?)‐ 2 , and (+)‐ 4 .     

Enantioselective Catalysis Coupled with Stereodivergent Cyclization Strategies Enables Rapid Syntheses of (+)‐Limaspermidine and (+)‐Kopsihainanine A

Enantioselective Pd‐catalyzed allylic alkylations of dihydropyrido[1,2‐a ]indolone (DHPI) substrates were used to construct the C20‐quaternary stereocenters of multiple monoterpene indole alkaloids. Stereodivergent Pictet–Spengler and Bischler–Napieralski cyclization/reduction cascades furnish the cis‐ and trans ‐fused azadecalin subunits present in Aspidosperma and Kopsia alkaloids, respectively, en route to highly efficient syntheses of (+)‐limaspermidine and (+)‐kopsihainanine A.     

Studies towards the Synthesis of (+)-Dictyoxetane

The dolabellane-type diterpene dictyoxetane represents a significant challenge to synthetic organic chemistry. Methodology directed towards the total synthesis of naturally occurring (+)-dictyoxetane is reported. Catalytic asymmetric synthesis of the trans-hydrindane ring system is achieved through chemoselective deoxygenation of the Hajos-Parrish ketone. An alternative to the Garst-Spencer furan annulation is developed for the synthesis of a 2,5-dimethyl, tetrasubstituted furan, employing a tandem 5-exo-dig alcohol to alkyne cyclisation/aromatisation reaction as a key step. The (4+3) cycloaddition reaction of an oxyallyl cation with a tetrasubstituted furan is established on a cyclohexanone-derived model system, and a range of related (4+3) cycloadditions investigated on a homochiral, trans-hydrindane-fused furan, where regio- and diastereoselectivity is required for the natural product synthesis. In an alternative (4+2) Diels-Alder approach, a C₂-symmetric vinyl sulfoxide-based chiral ketene equivalent is used to prepare oxanorbornenes with the same oxygen bridge stereochemistry found in the 2,7-dioxatricyclo[4.2.1.0^3,8]nonane ring system of the natural product.     

1‐Acetyl‐3′‐(4‐bromophenyl)‐3′‐chlorospiro[3H‐indole‐3,2′‐oxetan]‐2(1H)‐one

In the title compound, C₁₈H₁₃BrClNO₃, the heterocyclic ring of the indole is distorted from planarity towards an envelope conformation. The orientations of the indole, oxetane, chloro and bromo­phenyl substituents are conditioned by the sp³ states of the spiro‐junction and the Cl‐attached C atoms.     

Five bicyclo[3.3.0]octa‐2,6‐dienes

A series of five compounds containing the bicyclo[3.3.0]octa‐2,6‐diene skeleton are described, namely tetramethyl cis,cis‐3,7‐dihydroxybicyclo[3.3.0]octa‐2,6‐diene‐2,4‐exo,6,8‐exo‐tetracarboxylate, C₁₆H₁₈O₁₀, (I), tetramethyl cis,cis‐3,7‐dihydroxy‐1,5‐dimethylbicyclo[3.3.0]octa‐2,6‐diene‐2,4‐exo,6,8‐exo‐tetracarboxylate, C₁₈H₂₂O₁₀, (II), tetramethyl cis,cis‐3,7‐dimethoxybicyclo[3.3.0]octa‐2,6‐diene‐2,4‐exo,6,8‐exo‐tetracarboxylate, C₁₈H₂₂O₁₀, (III), tetramethyl cis,cis‐3,7‐dimethoxy‐1,5‐dimethylbicyclo[3.3.0]octa‐2,6‐diene‐2,4‐exo,6,8‐exo‐tetracarboxylate, C₂₀H₂₆O₁₀, (IV), and tetramethyl cis,cis‐3,7‐diacetoxybicyclo[3.3.0]octa‐2,6‐diene‐2,4‐exo,6,8‐exo‐tetracarboxylate, C₂₀H₂₂O₁₂, (V). The bicyclic core is substituted in all cases at positions 2, 4, 6 and 8 with methoxycarbonyl groups and additionally at positions 3 and 7 with hydroxy [in (I) and (II)], methoxy [in (III) and (IV)] or acetoxy [in (V)] groups. The conformations of the methoxycarbonyl groups at positions 2 and 4 are exo for all five compounds. Each C₅ ring of the bicyclic skeleton is almost planar, but the rings are not coplanar, with dihedral angles of 54.93 (7), 69.85 (5), 64.07 (4), 80.74 (5) and 66.91 (7)° for (I)–(V), respectively, and the bicyclooctadiene system adopts a butterfly‐like conformation. Strong intramolecular hydrogen bonds exist between the –OH and C=O groups in (I) and (II), with O...O distances of 2.660 (2) and 2.672 (2) Å in (I), and 2.653 (2) and 2.635 (2) Å in (II). The molecular packing is stabilized by weaker C—H...O(=C) interactions, leading to dimers in (I)–(III) and to a chain structure in (V). The structure series presented in this article shows how the geometry of the cycloocta‐2,6‐diene skeleton changes upon substitution in different positions and, consequently, how the packing is modified, although the intermolecular interactions are basically the same across the series.     

Five 2‐aryl‐substituted tetrahydro‐1,4‐epoxy‐1‐benzazepines: isolated molecules and hydrogen‐bonded chains and sheets

(2SR,4RS)‐2‐exo‐Phenyl‐2,3,4,5‐tetrahydro‐1H‐1,4‐epoxy‐1‐benzazepine, C₁₆H₁₅NO, (I), (2SR,4RS)‐2‐exo‐(4‐chlorophenyl)‐2,3,4,5‐tetrahydro‐1H‐1,4‐epoxy‐1‐benzazepine, C₁₆H₁₄ClNO, (II), and (2SR,4RS)‐2‐exo‐(3‐methylphenyl)‐2,3,4,5‐tetrahydro‐1H‐1,4‐epoxy‐1‐benzazepine, C₁₇H₁₇NO, (III), all crystallize with Z′ = 2, in the space groups Cc, P2₁/n and P2₁/c, respectively. In each of (II) and (III), the conformations of the two independent molecules are significantly different. The molecules in (I) are linked by C—H...π(arene) hydrogen bonds to form two independent chains, each containing only one type of molecule. The molecules in (II) are linked into sheets by a combination of C—H...O, C—H...(N,O) and C—H...π(arene) hydrogen bonds, all of which link pairs of molecules related by inversion, while in (III), the molecules are linked into sheets by a combination of C—H...N, C—H...O and C—H...π(arene) hydrogen bonds. There are no direction‐specific intermolecular interactions of any kind in the structure of (2SR,4RS)‐7‐bromo‐2‐exo‐phenyl‐2,3,4,5‐tetrahydro‐1H‐1,4‐epoxy‐1‐benzazepine, C₁₆H₁₄BrNO, (IV), but in the structure of (2SR,4RS)‐2‐exo‐(4‐bromophenyl)‐7‐chloro‐2,3,4,5‐tetrahydro‐1H‐1,4‐epoxy‐1‐benzazepine, C₁₆H₁₃BrClNO, (V), a combination of one C—H...N hydrogen bond and one C—H...O hydrogen bond links the molecules into sheets of alternating centrosymmetric R²₂(14) and R⁶₆(22) rings. Comparisons are made with the structures of a number of related compounds.     

The Structure of 2‐[(1S)‐(+)‐10‐camphorsulfonamino]‐6‐aminopyridine in the Solid State and in Solution; Unprecedented Cocrystallization of Four Stereoisomers

The solid and solution structures of a new optically active aminopyridine compound, 2‐[(1S)‐(+)‐10‐camphorsulfonamino]‐6‐aminopyridine [(S)‐csaap], 1 , are reported. Crystal data: space group P2₁, a = 8.9729 (5), b = 10.9447 (6), c = 36.693 (2) Å, β = 96.435 (1)°, V = 3580.8 (3) ų, Z = 8, R₁ = 0.0673 and wR₂ = 0.1600 with I > 2σ(I). This chiral compound shows an unprecedented cocrystallization of four stereoisomers, which are characterized by X‐ray crystallography and NMR spectroscopy.     

A norbornenyl derivative with through‐space ketone π‐interaction

The title compound, endo,exo‐12‐oxotetra­cyclo­[6.2.1.1^3,6.0^2,7]­dodeca‐9‐en‐anti‐11‐yl p‐bromo­benzoate, C₁₉H₁₇BrO₃, con­sists of norbornene with an anti‐p‐bromo­benzoate substituent at the methano bridge and an exo‐fused norbornanone unit bonded to the ethano bridge. The spatially proximate ketone and alkene interact through space and the ketone C atom is substantially pyramidalized. Through‐space ketone π‐inter­action is probably responsible for the low solvolysis rate of the anti‐11‐chloride derivative.     

1‐[(E)‐2‐Arylethenyl]‐2,2‐diphenylcyclopropanes: Kinetics and Mechanism of Rearrangement to Cyclopentenes

Kinetic measurements for the thermal rearrangement of 2,2‐diphenyl‐1‐[(E)‐styryl]cyclopropane ( 22a ) to 3,4,4‐triphenylcyclopent‐1‐ene ( 23a ) in decalin furnished ΔH =31.0±1.2 kcal mol^?1 and ΔS =?6.0±2.6 e.u. The lowering of ΔH^≠ by 20 kcal mol^?1, compared with the rearrangement of the vinylcyclopropane parent, is ascribed to the stabilization of a transition structure (TS) with allylic diradical character. The racemization of (+)‐(S)‐ 22a proceeds with ΔH =28.2±0.8 kcal mol^?1 and ΔS =?5±2 e.u., and is at 150° 106 times faster than the rearrangement. Seven further 1‐(2‐arylethenyl)‐2,2‐diphenylcyclopropanes 22 , (E)‐ and (Z)‐isomers, were synthesized and characterized. The (E)‐compounds showed only modest substituent influence in their k_rac (at 119.4°) and k_isom (at 159.3°) values. The lack of solvent dependence of rate opposes charge separation in the TS, but a linear relation of log k_rac with log p.r.f., i.e., partial rate factors of radical phenylations of ArH, agrees with a diradical TS. The ring‐opening of the preponderant s‐trans‐conformation of 22 gives rise to the 1‐exo‐phenylallyl radical 26 that bears the diphenylethyl radical in 3‐exo‐position, and is responsible for racemization. The 1‐exo‐3‐endo‐substituted allylic diradical 27 arises from the minor s‐gauche‐conformation of 22 and is capable of closing the three‐ or the five‐membered ring, 22 or 23 , respectively. The discussion centers on the question whether the allylic diradical is an intermediate or merely a TS. Quantum‐chemical calculations by Houk et al. (1997) for the parent vinylcyclopropane reveal the lack of an intermediate. Can the conjugation of the allylic diradical with three Ph groups carve the well of an intermediate?     

Structure Determination and Total Synthesis of (+)‐16‐Hydroxy‐16,22‐dihydroapparicine

Herein, we describe the first asymmetric total synthesis and determination of the relative and absolute stereochemistry of naturally occurring 16‐hydroxy‐16,22‐dihydroapparicine. The key steps include 1) a novel phosphinimine‐mediated cascade reaction to construct the unique 1‐azabicyclo[4.2.2]decane core, including a pseudo‐aminal‐type moiety; 2) a highly stereospecific 1,2‐addition of 2‐acylindole or a methylketone through a Felkin–Anh transition state for the construction of a tetrasubstituted carbon center; and 3) an intramolecular chirality‐transferring Michael reaction of the ketoester, with neighboring‐group participation, to introduce a chiral center at C15 in the target molecule. In addition, we evaluated the antimalarial activity of synthetic (+)‐(15S,16R)‐16‐hydroxy‐16,22‐dihydroapparicine and its intermediate against chloroquine‐resistant Plasmodium falciparum (K1 strain) parasites.     

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.