The Cobalt Way to Angucyclinones: Asymmetric Total Synthesis of the Antibiotics (+)‐Rubiginone B2, (−)‐Tetrangomycin,and (−)‐8‐O‐Methyltetrangomycin

A cobalt(I)‐mediated convergent and asymmetric total synthesis of angucyclinones with an aromatic B ring has been developed. In the course of our research, we synthesized three naturally occurring anguclinone derivatives, namely, (+)‐rubiginone B₂ ( 1 ), (?)‐8‐O‐methyltetrangomycin ( 2 ), and (?)‐tetrangomycin ( 3 ). By combining 3‐hydroxybenzoic acid, 3‐methoxybenzoic acid, citronellal, and geraniol as starting materials in a convergent way, we were able to synthesize chiral triyne chains, which were cyclized with [CpCo(C₂H₄)₂] (Cp=cyclopentadienyl) by means of an intramolecular [2+2+2] cycloaddition to their corresponding tetrahydrobenzo[a]anthracenes. Successive oxidation and deprotection steps led to the above‐mentioned natural products 1 – 3 .     

Enantioselective Synthesis of (−)‐(R)‐Cordiachromene and (−)‐(R)‐Dictyochromenol Utilizing Intramolecular SNAr Reaction

A simple and efficient enantioselective synthesis of chromene, (?)‐(R)‐cordiachromene ( 1 ), and (?)‐(R)‐dictyochromenol ( 2 ) has been accomplished. This convergent synthesis utilizes intramolecular S_NAr reaction for the formation of chroman ring, and Seebach's method of ‘self‐reproduction of chirality’ should establish the (R)‐configuration of the C(2) side chain as key steps.     

Synthesis of the Spermidine Alkaloids (−)‐(2R,3R)‐ and (−)‐(2R,3S)‐3‐Hydroxycelacinnine: Macrocyclization with Oxirane‐Ring Opening and Inversion via Cyclic Sulfamidates

The two epimers (?)‐ 1a and (?)‐ 1b of the macrocyclic lactam alkaloid 3‐hydroxycelacinnine with the (2R,3R) and (2R,3S) absolute configurations, respectively, were synthesized by an alternative route involving macrocyclization with the regio‐ and stereoselective oxirane‐ring opening by the terminal amino group (Schemes 2 and 6). Properly N‐protected chiral trans‐oxirane precursors provided (2R,3R)‐macrocycles after a one‐pot deprotection‐macrocyclization step under moderate dilution (0.005–0.01M ). The best yields (65–85%) were achieved with trifluoroacetyl protection. Macrocyclization of the corresponding cis‐oxiranes was unsuccessful for steric reasons. Inversion at OH? C(3) via nucleophilic displacement of the cyclic sulfamidate derivative with NaNO₂ led to (2R,3S)‐macrocycles. The synthesized (?)‐(2R,3S)‐3‐hydroxycelacinnine ((?)‐ 1b ) was identical to the natural alkaloid.     

Enantioselective Access to (−)‐Ambrox® Starting from β‐Farnesene

Starting from inexpensive (E)‐β‐farnesene ( 1 ), an eight‐step enantioselective synthesis of the olfactively precious Ambrox^® ((?)‐ 2a ) has been performed. The crucial step is the catalytic asymmetric isomerization of (2E,6E)‐N,N‐diethylfarnesylamine ( 3 ) to the corresponding enamine (?)‐(R,E)‐ 4a , applying Takasago's well‐known industrial methodology. The resulting dihydrofarnesal ((+)‐(R)‐ 5 ) (90% yield, 96% ee), obtained after in situ hydrolysis (AcOH, H₂O), was then cyclized under catalytic SnCl₄ conditions, via its corresponding unreported enol acetate (?)‐(R)‐ 4b , to afford trans‐decalenic aldehyde (+)‐ 6a . Subsequent transformations furnished bicyclic ketone (?)‐ 8a and unsaturated nitrile (+)‐ 11 , both reported as intermediates to access to (?)‐ 2a .     

Catalytic Asymmetric Total Synthesis of (−)‐Galanthamine and (−)‐Lycoramine

The catalytic asymmetric total syntheses of (?)‐galanthamine ( 1 ) and (?)‐lycoramine ( 2 ) have been achieved by using a conceptually new strategy featuring two metal‐catalyzed reactions as the key steps. A new method for the construction of 3,4‐fused benzofurans has been developed through a palladium‐catalyzed intramolecular Larock annulation reaction, which was successfully applied to the construction of the ABD tricyclic skeleton of 1 and 2 . To achieve the asymmetric synthesis of 1 and 2 , a Sc^III/N,N′‐dioxide complex was used to catalyze the enantioselective conjugate addition of 3‐alkyl‐substituted benzofuranone to methyl vinyl ketone for the construction of a chiral quaternary carbon center.     

An Efficient Synthesis of a Potential (−)‐Reserpine Intermediate from (−)‐Shikimic Acid of the Chiral Pool

A highly stereoselective route to the polysubstituted chiral octahydrobenzofuran 12 , a potential synthon for the E‐ring core in the (?)‐reserpine synthesis, is described. The α‐bromo acetal 11 was obtained from inexpensive (?)‐shikimic acid ( 3 ) through a series of highly stereoselective chemical reactions (Scheme). Et₃B/Bu₃SnH‐Mediated intramolecular radical cyclization of 11 led to compound 12 with the required configuration.     

Total Synthesis of (−)‐Isoschizogamine

The total synthesis of (?)‐isoschizogamine was accomplished, featuring the construction of the quaternary carbon center by the modified Johnson–Claisen rearrangement in basic media and the facile assembly of the key tetracyclic quinolone intermediate through a cascade cyclization. The characteristic cyclic aminal was constructed by late‐stage C?H functionalization at the position adjacent to the lactam nitrogen using a combination of CrO₃ and nBu₄NIO₄ and subsequent Bi(OTf)₃‐mediated cyclization.     

Total Synthesis of (−)‐Cleistenolide

An efficient and short total synthesis of (?)‐cleistenolide ( 1 ) from D ‐mannitol with an overall yield of 23.6% is described. The chiron approach for the synthesis of (?)‐cleistenolide involves a one‐C‐atom Wittig olefination, a selective allylic triethylsilyl protection, and a Grubbs‐catalyzed ring‐closure‐metathesis (RCM) reaction as the key steps.     

Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (?)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO₄)₂‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (?)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.     

Divergent Total Syntheses of (−)‐Daphnilongeranin B and (−)‐Daphenylline

(?)‐Daphnilongeranin B and (?)‐daphenylline are two hexacyclic Daphniphyllum alkaloids, each containing a complex cagelike backbone. Described herein are the first asymmetric total synthesis of (?)‐daphnilongeranin B and a bioinspired synthesis of (?)‐daphenylline with an unusual E ring embedded in a cagelike framework. The key features include an intermolecular [3+2] cycloaddition, a late‐stage aldol cyclization to install the F ring of daphnilongeranin B, and a bioinspired cationic rearrangement leading to the tetrasubstituted benzene ring of daphenylline.     

Indole‐Diterpene Synthetic Studies: Total Synthesis of (−)‐21‐Isopentenylpaxilline

An efficient, stereocontrolled total synthesis of the complex indole‐diterpene alkaloid (?)‐21‐isopentenylpaxilline ( 1 ) has been achieved. Key elements of the synthesis include the stereocontrolled construction of the advanced eastern hemisphere (?)‐ 68 , involving a highly efficient union of the eastern and western fragments (?)‐ 68 and 5 exploiting our 2‐substituted indole synthesis, application of the Negishi π cycloalkylation tactic as a new, potentially general protocol for the construction of ring C, and the fragmentation of a β,γ‐epoxy ketone to introduce the tertiary OH group at C(13) in the indole diterpene skeleton.     

Total Synthesis of Marine Eicosanoid (−)‐Hybridalactone

(?)‐Hybridalactone ( 1 ) is a marine eicosanoid isolated from the red alga Laurencia hybrida. This natural product contains cyclopropane, cyclopentane, 13‐membered macrolactone and epoxide ring systems incorporating seven stereogenic centers. Moreover, this compound has an acid‐labile skipped Z,Z‐diene motif. In this paper, we report on the total synthesis of (?)‐hybridalactone ( 1 ). The unique eicosanoid (?)‐hybridalactone ( 1 ) was synthesized starting from optically active γ‐butyrolactone 2 in a linear sequence comprising 21 steps with an overall yield of 21.9 %. A key step in the synthesis of (?)‐hybridalactone ( 1 ) is the methyl phenylsulfonylacetate‐mediated one‐pot synthesis of the cis‐cyclopropane‐γ‐lactone derivative. This reaction provided an efficient and stereoselective access to cis‐cyclopropane‐γ‐lactone 12 . Further elaboration of the latter compounds through desulfonylation, epoxidation, oxidation, Wittig olefination and Shiina macrolactonization afforded (?)‐hybridalactone.     

Total Syntheses of (−)‐Conidiogenone B, (−)‐Conidiogenone,and (−)‐Conidiogenol

Cyclopianes are novel diterpenes featuring a highly strained 6/5/5/5 tetracyclic core embedded with 6–8 consecutive stereocenters. The concise total syntheses of (?)‐conidiogenone B, (?)‐conidiogenone, and (?)‐conidiogenol have been accomplished in 14–17 steps. The present work features a HAT‐mediated alkene–nitrile cyclization to access the cis‐biquinane, a Nicholas/Pauson–Khand reaction to construct the linear triquinane, and a Danheiser annulation to afford the congested angular triquinane skeleton.     

Microbial Transformation of Sesquiterpenes, (−)‐Ambrox® and (+)‐Sclareolide

The microbial transformation of (?)‐Ambrox^® ( 1 ), a perfumery sesquiterpene, by a number of fungi, by means of standard two‐stage‐fermentation technique, afforded ambrox‐1α‐ol ( 2 ), ambrox‐1α,11α‐diol ( 3 ), ambrox‐1α,6α‐diol ( 4 ), ambrox‐1α,6α,11α‐triol ( 5 ), ambrox‐3‐one ( 6 ), ambrox‐3β‐ol ( 7 ), ambrox‐3β,6β‐diol ( 8 ), 13,14,15,16‐tetranorlabdane‐3,8,12‐triol ( 9 ), and sclareolide ( 10 ) (Schemes 1 and 2). Further incubation of compound 10 with Cunninghamella elegans afforded 3‐oxosclareolide ( 11 ), 3β‐hydroxysclareolide ( 12 ), 2α‐hydroxysclareolide ( 13 ), 2α,3β‐dihydroxysclareolide ( 14 ), 1α,3β‐dihydroxysclareolide ( 15 ), and 3β‐hydroxy‐8‐episclareolide ( 16 ) (Scheme 3). Metabolites 2 – 5, 12, 13 , and 16 were found to be new compounds. The major transformations include a reaction path involving hydroxylation, ether‐bond cleavage and inversion of configuration. Metabolites 11 – 16 of sclareolide showed significant phytotoxicity (Table 1). The structures of the metabolites were characterized on the basis of spectroscopic techniques.     

Total Synthesis of (−)‐Zampanolide and Structure–Activity Relationship Studies on (−)‐Dactylolide Derivatives

A new total synthesis of the marine macrolide (?)‐zampanolide ( 1 ) and the structurally and stereochemically related non‐natural levorotatory enantiomer of (+)‐dactylolide ( 2 ), that is, ent‐ 2 , has been developed. The synthesis features a high‐yielding, selective intramolecular Horner–Wadsworth–Emmons (HWE) reaction to close the 20‐membered macrolactone ring of 1 and ent‐ 2 . The β‐keto phosphonate/aldehyde precursor for the ring‐closure reaction was obtained by esterification of a ω‐diethylphosphono carboxylic acid fragment and a secondary alcohol fragment incorporating the THP ring that is embedded in the macrocyclic core structure of 1 and ent‐ 2 . THP ring formation was accomplished through a segment coupling Prins‐type cyclization. Employing the same overall strategy, 13‐desmethylene‐ent‐ 2 as well as the monocyclic desTHP derivatives of 1 and ent‐ 2 were prepared. Synthetic 1 inhibited human cancer cell growth in vitro with nM IC₅₀ values, while ent‐ 2 , which lacks the diene‐containing hemiaminal‐linked side chain of 1 , is 25‐ to 260‐fold less active. 13‐Desmethylene‐ent‐ 2 as well as the reduced versions of ent‐ 2 and 13‐desmethylene‐ent‐ 2 all showed similar cellular activity as ent‐ 2 itself. The same activity level was attained by the monocyclic desTHP derivative of 1 . Oxidation of the aldehyde functionality of ent‐ 2 gave a carboxylic acid that was converted into the corresponding N‐hexyl amide. The latter showed only μM antiproliferative activity, thus being several hundred‐fold less potent than 1 .     

DFT‐GIAO1H NMR chemical shifts prediction for the spectral assignment and conformational analysis of the anticholinergic drugs (−)‐scopolamine and (−)‐hyoscyamine

The relatively large chemical shift differences observed in the ¹H NMR spectra of the anticholinergic drugs (?)‐scopolamine 1 and (?)‐hyoscyamine 2 measured in CDCl₃ are explained using a combination of systematic/molecular mechanics force field (MMFF) conformational searches and gas‐phase density functional theory (DFT) single point calculations, geometry optimizations and chemical shift calculations within the gauge including/invariant atomic orbital (GIAO) approximation. These calculations show that both molecules prefer a compact conformation in which the phenyl ring of the tropic ester is positioned under the tropane bicycle, clearly suggesting that the chemical shift differences are produced by the anisotropic effect of the aromatic ring. As the calculations fairly well predict these experimental differences, diastereotopic NMR signal assignments for the two studied molecules are proposed. In addition, a cursory inspection of the published ¹H and ¹³C NMR spectra of different forms of 1 and 2 in solution reveals that most of them show these diastereotopic chemical shift differences, strongly suggesting a preference for the compact conformation quite independent of the organic or aqueous nature of the solvent. Copyright © 2010 John Wiley & Sons, Ltd.     

Enantioselective Synthesis of (−)‐(19R)‐Ibogamin‐19‐ol

The first total synthesis of the natural product (?)‐(19R)‐ibogamin‐19‐ol ((?)‐ 1 ) is reported (biogenetic atom numbering). Starting with L ‐glutamic acid from the chiral pool and (2S)‐but‐3‐en‐2‐ol, the crucial aliphatic isoquinuclidine (= 2‐azabicyclo[2.2.2]octane) core containing the entire configurational information of the final target was prepared in 15 steps (overall yield: 15%). The two key steps involved a highly effective, self‐immolating chirality transfer in an Ireland–Claisen rearrangement and an intramolecular nitrone‐olefin 1,3‐dipolar cycloaddition reaction (Scheme 3). Onto this aliphatic core was grafted the aromatic moiety in the form of N(1)‐protected 1H‐indole‐3‐acetic acid by application of the dicyclohexylcarbodiimide (DCC) method (Scheme 4). Four additional steps were required to adjust the substitution pattern at C(16) and to deprotect the indole subunit for the closure of the crucial 7‐membered ring present in the targeted alkaloid family (Schemes 4 and 5). The spectral and chiroptical properties of the final product (?)‐ 1 matched the ones reported for the naturally occurring alkaloid, which had been isolated from Tabernaemonatana quadrangularis in 1980. The overall yield of the entire synthesis involving a linear string of 20 steps amounted to 1.9% (average yield per step: 82%).     

On the Reactivity of (−)‐(R)‐Carvone and (−)‐4aα,7α,7aβ‐Nepetalactone: Synthesis of New Heterocycles

The 1,3‐dipolar cycloaddition of 4‐chlorobenzonitrile oxide to the unsaturated system of (?)‐(R)‐carvone occurred exclusively at C(8) to give a new isoxazoline derivative. This derivative reacts with NH₂OH to yield a new heterocycle, observed for the first time. On the other hand, the addition of 4‐chlorobenzonitrile oxide to the unsaturated lactone (?)‐4aα,7α,7aβ‐nepetalactone gave, in a good yield, also a new heterocycle, again obtained for the first time. The terpenoid (?)‐(R)‐carvone and iridoid (?)‐4aα,7α,7aβ‐nepetalactone were isolated from Moroccan species Mentha viridis (L.) and Nepeta tuberosa (L.), respectively. The new heterocycles obtained were identified by combination of chromatographic and spectroscopic methods.     

Divergent Total Syntheses of Enmein‐Type Natural Products: (−)‐Enmein, (−)‐Isodocarpin,and (−)‐Sculponin R

Divergent total syntheses of the enmein‐type natural products (?)‐enmein, (?)‐isodocarpin, and (?)‐sculponin R have been achieved in a concise fashion. Key features of the strategy include 1) an efficient early‐stage cage formation to control succeeding diastereoselectivity, 2) a one‐pot acylation/akylation/lactonization to construct the C‐ring and C8 quarternary center, 3) a reductive alkenylation approach to construct the enmain D/E rings and 4) a flexible route to allow divergent syntheses of three natural products.     

Synthesis of (−)‐3‐Carene‐2,5‐dione via Allylic Oxidation of (+)‐3‐Carene

Activated carbon‐supported CuCl₂ (CuCl₂/AC) is a heterogeneous catalyst for the liquid‐phase selective allylic oxidation of (+)‐3‐carene with tert‐butyl hydroperoxide (TBHP) and O₂ to produce (?)‐3‐carene‐2,5‐dione. The possible reaction mechanism and the effects of different factors on the allylic oxidation were investigated. The optimal conditions are as follows: reaction temperature, 45 °C; molar ratio of CuCl₂ to (+)‐3‐carene, 1%; volume ratio of (+)‐3‐carene to TBHP, 1:3; and reaction time, 12 h. Under the optimal conditions, the conversion of (+)‐3‐carene reached 100%, whereas the selectivity for (?)‐3‐carene‐2,5‐dione reached 78%. The CuCl₂/AC catalyst was characterized via X‐ray diffraction, and the chemical structure of the target compound was identified via infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, mass spectrometry, and optical analysis.