First synthesis of (+)-alpha- and (+)-gamma-polypodatetraenes

First synthesis of (+)-alpha-polypodatetraene (1) and (+)-gamma-polypodatetraene (2) was achieved from (+)-albicanol (6) and (-)-drimenol (8), respectively. The absolute structure of natural (+)-2 was established to be (5S,9S,10S)-polypoda-7,13(E),17(E),21-tetraene.     

Asymmetric total syntheses of (+)-cheimonophyllon e and (+)-cheimonophyllal

The highly enantiocontrolled total syntheses of natural (+)-cheimonophyllon E (5) and (+)-cheimonophyllal (6), biologically intriguing oxygenated bisabolane-type sesquiterpenoids, have been completed. The present synthetic strategy featured the use of an asymmetric aldol-type reaction for preparing in the first synthetic step an optically active 6-C-substituted 3-methyl-2-cyclohexenone derivative. Thus, a Mukaiyama aldol reaction of 1-methyl-3-silyloxy-1,3-cyclohexadiene 31 with alpha,beta-unsaturated aldehyde 11 in the presence of a chiral (acyloxy)borane (CAB)-type Yamamoto catalyst 33 proceeded with high levels of both diastereo- and enantioselectivities. The predominant aldol adduct, syn-9, was transformed into gamma,delta-epoxy allylic alcohol 8 by a nine-step sequence, including the substrate-controlled 1,2-reduction of enone, syn-12, also the epoxidation of allylic alcohol 15. Epoxy-alcohol 8 underwent 5-exo-cyclization in a high regioselective manner under acidic conditions to produce a bicyclic key intermediate (+)-7, which was eventually efficiently converted to (+)-cheimonophyllon E (5) or (+)-cheimonophyllal (6).     

Determination of the absolute structure of (+)-akaterpin

We describe the total synthesis and structural determination of (+)-akaterpin (1), an inhibitor of phosphatidylinositol-specific phospholipase C (PI-PLC). The key features of the synthetic strategy include the resolution of β,γ-unsaturated ketone (±)-2a with chiral sulfoximine 6. The absolute stereochemistry was determined by comparison of the specific optical rotation data of (+)-1 and (-)-1 with that of natural akaterpin.     

光学纯反式-(+)-水合蒎醇的新方法合成

以3,5-二羟基-4-甲基苯甲酸甲酯为原料,通过7步反应,高产率地合成了反式-(+)-水合蒎醇[(+)-1],其结构通过IR,MS和NMR等技术进行了确认,该化合物的光学纯度e.e.高达99%.     

Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinonide

The first enantioselective total synthesis of (-)-triptolide (1), (-)-triptonide (2), (+)-triptophenolide (3), and (+)-triptoquinonide (4) was completed. The key step involves lanthanide triflate-catalyzed oxidative radical cyclization of (+)-8-phenylmenthyl ester 30 mediated by Mn(OAc)3, providing intermediate 31 with good chemical yield (77%) and excellent diastereoselectivity (dr 38:1). (+)-Triptophenolide methyl ether (5) was then prepared in > 99% enantiomeric excess (> 99% ee), and readily converted to natural products 1-4. In addition, transition state models were proposed to explain the opposite chiral induction observed in the oxidative radical cyclization reactions of chiral beta-keto esters 17 (without an alpha-substituent) and 17a (with an alpha-chloro substituent).     

Total synthesis of pancratistatin relying on the [3,3]-sigmatropic rearrangement

A new total synthesis of the antitumor alkaloid, pancratistatin (1), has been accomplished from readily available starting materials. Claisen rearrangement of the racemic dihydropyranethylene 17 was employed to construct the A and C rings with the appropriate stereochemistry. In addition, the Ireland-Claisen rearrangement of the enantiomerically pure 9 followed by ring-closing metathesis provided the important intermediate 24, thus implying that our approach could yield the enantioselective synthesis of (+)-pancratistatin. With the appropriately functionalized cyclohexene 24, stereo- and regiocontrolled functional group interchanges, such as iodolactonization, dihydroxylations, and a cyclic sulfate elimination reaction, facilitated the production of the target natural product.     

Total synthesis of (+)-grandifloracin by iron complexation of a microbial arene oxidation product

(+)-Grandifloracin was synthesized from sodium benzoate by means of a dearomatizing dihydroxylation that proceeds with unusual regioselectivity. Iron diene complexes formed from the arene oxidation product permit the use of otherwise inaccessible transformations. The synthetic material was shown to be antipodal to the natural product, thus determining the absolute configuration of grandifloracin for the first time.     

A Synthesis of (+)-Oblongolide

The absolute configuration of natural oblongolide is reassigned as (3aS,5aR,7S,9aS,9bS)-3a,5a,6,7,8,9,9a,9b-octahydro-7,9b-dimethylnaphtho[1,2-c]furan-1(3H)-one 2 by a 7-stage synthesis of its enantiomer 1 from (+)-citronellol involving a regioselective reduction and an intramolecular Diels-Alder reaction (IMDA) as the key steps. (+)-Citronellol was converted into methyl (2E,4E,10E)-(S)-(+)-11-tert-butoxycarbonyl-7-methyl-undeca-2,4,10-trienoate 7 by sequential Lemieux-Johnson oxidation, Wittig reaction, pyridinium chlorochromate oxidation, and Wadsworth-Emmons-Homer alkenation. A regioselective reduction of the methoxycarbonyl group in 7 afforded tert-butyl (2.E,8E,10E)-(S)-(+)-2,6-dimethyl-12-hydroxy-dodeca-2,8,10-trienoate 8 from which (+)-oblongolide was readily obtained via an IMDA reaction.     

β-Silyl styrene as a dienophile in the cycloaddition with 3,5-dibromo-2-pyrone for the total synthesis of (±)-pancratistatin

A new synthetic route to (±)-pancratistatin was devised utilizing β-silyl styrene as a dienophile in the cycloaddition with 3,5-dibromo-2-pyrone. The TMS group incorporated in the cycloadduct permitted a facile elimination process for the eventual installation of the C(1)-OH function. Subsequent transformations including Curtius rearrangement and Bischler-Napieralski reactions completed the total synthesis of (±)-pancratistatin.     

Total synthesis of the marine sponge metabolites (+)-rottnestol, (+)-raspailol A and (+)-raspailol B

The asymmetric syntheses of (+)-rottnestol (1) and the related marine sponge metabolites (+)-raspailols A (5) and B (6) are described. The key step in each of these sequences was a Stille coupling to form the C9-C10 sp2-sp2 bond and connect the polyene sidechains to the appropriate optically active tetrahydropyran core. For rottnestol (1), both C12 epimers were synthesised by a coupling between stannane 7 and (R)- or (S)-8 followed by acid hydrolysis which allowed for the assignment of the absolute configuration at the remote C12 stereocentre as R upon comparison of chiroptical data of the synthetic material with that reported for the natural product. In accord with this, (12R)-raspailol A (5) was synthesised from stannane 7 and sidechain 9 and this compound also compared well with the data for natural material including sign and absolute value of the specific rotation. Finally, the same C12 epimer of raspailol B (6) was secured via a union between stannane 10 and iodide 9 and this also possessed a similar rotation to that described for the natural product. Thus, all three compounds appear to possess the (12R) configuration, while that of the core tetrahydropyran ring is the same as proposed originally.     

Total synthesis of (+)-pederin. 2. Stereocontrolled synthesis of (+)-benzoylselenopederic acid and total synthesis of (+)-pederin

(+)-Benzoylselenopederic acid (1), a left half of (+)-pederin (3), was synthesized stereoselectively based on the Zn(BH₄)₂ reduction and total synthesis of (+)-pederin (3) was accomplished from 1 and the previously synthesized 2.     

Synthesis of (+)-pechueloic acid and (+)-aciphyllene. Revision of the structure of (+)-aciphyllene

1αH,7αH,10αH-Guaia-4,11-dien-3-one and its 1βH,10βH diastereomer, easily obtained from (+)-dihydrocarvone, are good starting materials for the synthesis of natural guaiane derivatives. Allylic oxidation of the 1αH,10αH isomer gave as main product its 13-hydroxy derivative and a small amount of (+)-7β-hydroxy-1αH,10αH-guaia-4,11-dien-3-one, whereas the 1βH,10βH diastereomer afforded selectively the (−)-7α-hydroxy-1βH,10βH enantiomer in excellent yield. From the 13-hydroxy derivative (+)-pechueloic acid and (+)-methyl pechueloate were synthesized. Deoxygenation at C₃ of the 1βH,10βH guaiadienone afforded a guaiadiene with the reported structure for aciphyllene but its spectral data did not agree with those reported for the natural diene. The structure of natural (+)-aciphyllene has been corrected to 1αH,7αH,10αH-guaia-4,11-diene obtained by deoxygenation of the 1αH,10αH guaiadienone.     

Total synthesis of (+)-dihydrocuscohygrine and cuscohygrine

The first enantioselective synthesis of (+)-dihydrocuscohygrine 1 and cuscohygrine 2 is presented. 1 was obtained in nine steps and 30% overall yield with a ruthenium-catalyzed tandem ring rearrangement metathesis key step starting from enantiomerically pure cycloheptene-1,3,5-triol derivative 6. The unknown absolute configuration of natural dihydrocuscohygrine 1 could be determined as (S,S)-(-). Cuscohygrine 2 was obtained by Jones oxidation of 1 in quantitative yield but unfortunately with complete epimerization.     

Chemoenzymatic synthesis of (+)-aspicilin from chlorobenzene

The enantiomerically pure cis-1,2-dihydrocatechol 2, which is obtained by microbial oxidation of chlorobenzene, has been converted, via intermediate 3, into the natural product (+)-aspicilin (1).     

Synthese von (+)-Abscisinsäure

Synthesis of (+)-Abscisic Acid . Starting from (4S)-4-hydroxy-2,6,6-trimethylcyclohex-2-enone ( 2 ), a short synthesis of the natural (+)-abscisic acid ((+)- 1 ) has been accomplished.     

Synthesis of (+)-galiellalactone. Absolute configuration of galiellalactone

[reaction: see text]. (+)-Galiellalactone was synthesized starting from (R)-(+)-pulegone. Natural and synthetic galiellalactone have opposite optical rotations, demonstrating that the structure of the natural product is 1a.     

General approach for the synthesis of sarpagine indole alkaloids. Enantiospecific total synthesis of (+)-vellosimine, (+)-normacusine B, (-)-alkaloid Q3, (-)-panarine, (+)-Na-methylvellosimine, and (+)-Na-methyl-16-epipericyclivine

The first total synthesis of (+)-Na-methyl-16-epipericyclivine (9) was completed [from d-(+)-tryptophan methyl ester] in an overall yield of 42% (eight reaction vessels). The optical rotation [[alpha]D +22.8 (c 0.50, CHCl3)] obtained on this material confirmed that the reported optical rotation [[alpha]D 0 (c 0.50, CHCl3)]47 was biogenetically unreasonable. The total syntheses of (+)-vellosimine, (+)-normacusine B, (-)-alkaloid Q3, (-)-panarine, and (+)-Na-methylvellosimine are also described. Moreover, a mixed sample (1:1) of synthetic (-)-panarine and natural (-)-panarine yielded only one set of signals in the 13C NMR; this indicated that the two compounds are identical and further confirmed the correct configuration of (+)-vellosimine, (+)-normacusine B, and (-)-alkaloid Q3. In this approach, the key templates, (-)-Na-H,Nb-benzyltetracyclic ketone 15a and (-)-Na-methyl,Nb-benzyltetracyclic ketone 43 were synthesized on multihundred gram scale by the asymmetric Pictet-Spengler reaction and a stereocontrolled Dieckmann cyclization via improved sequences. An intramolecular palladium (enolate-mediated) coupling reaction was employed to introduce the C(19)-C(20) E-ethylidene function in the sarpagine alkaloids for the first time in stereospecific fashion.     

Concise enantioselective total syntheses of (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine and (+)-norchelidonine by a Pd II-catalyzed ring-opening strategy

New enantioselective syntheses of the B/C hexahydrobenzo[c]phenanthridine alkaloids (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine, and (+)-norchelidonine are described. Our rapid and convergent route to this class of natural products involved the development and application of a Pd II-catalyzed asymmetric ring-opening reaction of a meso-azabicyclic alkene with an aryl boronic acid as the key step. By screening a variety of functionalized ortho-substituted aryl boronic acids, chiral ligands and reaction conditions we were able to prepare the requisite cis-1-amino-2-aryldihydronaphthalenes in high yield and in up to 90 % ee. Early attempts to complete the synthesis of (+)-homochelidonine using an N-Boc azabicyclic alkene are described in full. The successful route required a protecting group alteration followed by B ring formation and then stereoselective installation of the C-11 syn-hydroxy group by regioselective epoxide ring-opening using a hydride source. Ring-opening of the same epoxide intermediate with water ultimately led to the synthesis of (+)-chelamidine. The same strategy was then used to synthesize the other structurally similar B/C hexahydrobenzo[c]phenanthridine alkaloids, (+)-chelidonine, (+)-chelamidine, and (+)-norchelidonine.     

A concise synthesis of (+)-SCH 351448

[structure: see text] We describe a highly convergent synthetic approach to the natural product (+)-SCH 351448 (1)-a hexane-soluble heptacoordinate monosodium salt of a C(2)-symmetrical macrocyclic dilactone. Our approach implements a photochemical acylation as the key step to combine two nearly identical but orthogonal C1-C29 fragments, followed by a base-induced intramolecular acylation and deprotection to yield the natural product.     

Synthesis of Aristotelia-Type Alkaloids. Part XV. Total synthesis of (+)-hobartinol

Synthetic (+)-makomakine ( 6 ) was transformed in six steps into (+)-17R,18R)-17,18-dihydrohobartine-17,18-diol ((+)- 5 ) with an overall yield of 38% (Scheme 2). This compound was shown to be identical with natural hobartinol, a monoterpene indole alkaloid from Aristotelia australasica, originally believed to be the (17S)-epimer 1 . At the same time, the synthesis of (+)- 5 delineates the hitherto unknown absolute configuration of this metabolite.