Intramolecular formal aza-[3 + 3] cycloaddition approach to indoloquinolizidine alkaloids. A stereoselective total synthesis of (+/-)-tangutorine

[reaction: see text] A 19-step stereoselective total synthesis of (+/-)-tangutorine is described here. The total synthesis features an intramolecular aza-[3 + 3] formal cycloaddition strategy and also a Heck coupling for constructing the C2-C3 bond. This work provides a novel approach toward the indoloquinolizidine family of alkaloids.     

Utilization of a Michael addition: dipolar cycloaddition cascade for the synthesis of (+/-)-cylindricine C

A new approach to the marine alkaloid (+/-)-cylindricine C has been devised. The key element of the synthesis consists of a Michael addition/dipolar cycloaddition cascade between 2,3-bis(phenylsulfonyl)-1,3-butadiene and 9-triisopropylsilanyloxy-non-1-en-5-one oxime. The resulting cycloadduct was converted into (+/-)-cylindricine C by a sequence of reactions including a reductive cyclization, intramolecular enolate alkylation, and conjugate addition to introduce the n-hexyl side chain.     

A cycloaddition cascade approach to the total synthesis of (-)-FR182877

An asymmetric synthesis of the cytotoxic natural product, (-)-FR182877 (1), has been achieved. Chirality for the entire structure was established using two (4R)-4-benzyl-2-oxazolidinone-mediated boron aldol reactions. A 19-membered macrocarbocycle was synthesized by the coupling of two fragments using a regioselective Suzuki coupling (17 + 23 --> 26; 84%) and macrocyclization of a beta-keto ester (30 --> 31; 77%). Oxidation of 31 triggered a sequence of stereoselective transannular Diels-Alder reactions (32 -->34; 63%) forming four new rings and seven new stereocenters in the pivotal construction event. This pentacyclic intermediate was subsequently transformed to (-)-FR182877. Semiempirical calculations of the transannular Diels-Alder cycloaddition cascade were carried out to determine the origins of asymmetric induction.     

A total synthesis of (+/-)-alpha-cyclopiazonic acid using a cationic cascade

The indolic terpene alkaloid alpha-cyclopiazonic acid has been prepared in 11 steps from indole-4-methanol; the key step is a carbocationic cascade, terminated by a 4-nitrosulfonamide group and initiated by benzylic carbocation formation directly from the intermediate , which gives the tetracyclic product in 74% yield.     

Application of the Rh(II) cyclization/cycloaddition cascade for the total synthesis of (+/-)-aspidophytine

[Structure: see text] A new strategy for the synthesis of (+/-)-aspidophytine has been developed and is based on a Rh(II)-catalyzed cyclization/dipolar cycloaddition sequence. The resulting [3+2]-cycloadduct undergoes an efficient Lewis acid mediated cascade that rapidly provides the complete skeleton of aspidophytine. The synthesis also features a mild decarbomethoxylation reaction.     

A new synthetic approach to the bicyclo[5.3.1]undecane ring system in taxanes

The bicyclo[5.3.1]undecane derivative 19, which was referred to the A,b ring system of taxane diterpenes, was synthesized by a base-induced fragmentation reaction of the tricyclic diol monomesylate 18 derived highly stereoselectively from 5-methyl-1,3-cyclohexadione.     

A 4+3 cycloaddition approach to the synthesis of (+/-)-sterpurene

A synthesis of the sesquiterpene sterpurene is presented. Key steps include a 4+3 cycloaddition reaction and a quasi-Favorskii rearrangement. [reaction--see text]     

Formal total synthesis of (+/-)-gamma-lycorane and (+/-)-1-deoxylycorine using the [4+2]-cycloaddition/rearrangement cascade of furanyl carbamates

The total syntheses of gamma-lycorane and (+/-)-1-deoxylycorine were accomplished using an intramolecular Diels-Alder cycloaddition of a furanyl carbamate as the key step. The initially formed [4+2]-cycloadduct undergoes nitrogen-assisted ring opening followed by deprotonation/reprotonation of the resulting zwitterion to give a rearranged hexahydroindolinone. The stereochemical outcome of the IMDAF cycloaddition has the side arm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. The key intermediate used in both syntheses corresponds to hexahydroindolinone 20. Removal of the t-Boc group in 20 followed by reaction with 6-iodobenzo[1,3]dioxole-5-carbonyl chloride afforded enamide 22. Treatment of this compound with Pd(OAc)(2) employing the Jeffrey modification of the Heck reaction provided the galanthan tetracycle 24 in good yield. Compound 24 was subsequently converted into (+/-)-gamma-lycorane using a four-step procedure to establish the cis-B,C-ring junction. A radical-based cyclization of the related enamide 33 was used for the synthesis of 1-deoxylycorine. Heating a benzene solution of 33 with AIBN and n-Bu(3)SnH at reflux gave the tetracyclic compound 38 possessing the requisite trans fusion between rings B and C in good yield. After hydrolysis and oxidation of 38 to 40, an oxidative decarboxylation reaction was used to provide the C(2)(-)C(3)(-)C(12) allylic alcohol unit characteristic of the lycorine alkaloids. The resulting enone was eventually transformed into (+/-)-1-deoxylycorine via known synthetic intermediates.     

The N-hydroxymethyl group for stereoselective conjugate addition: application to the synthesis of (-)-statine

[reaction: see text] Efficient synthesis of enantiomerically pure (-)-statine was achieved with the stereoselective intramolecular conjugate addition of the hydroxyl group tethered to the amino group of a configurationally stable N-Boc-L-leucinal derivative.     

Spiroacetal biosynthesis: (+/-)-1,7-dioxaspiro[5.5]undecane in Bactrocera cacuminata and Bactrocera oleae (Olive Fruit Fly)

[reaction: see text] A biosynthetic scheme rationalizing the formation of (+/-)-1,7-dioxaspiro[5.5]undecane (5) in the fruit fly species Bactrocera cacuminata and Bactrocera oleae (olive fruit fly) is presented. Incorporation studies with deuterium-labeled keto aldehyde (10), 1,5-nonanediol (11), and 1,5,9-nonanetriol (12), and our previous finding that both oxygen atoms of 5 originate from dioxygen, are strongly evidentiary. The racemic condition of the natural spiroacetal 5 is accounted for, and inter alia, it is demonstrated that dihydropyran (18) is not an important intermediate en route to 5.     

Intramolecular michael addition reaction to chiral vinylic sulfoxides. An enantioselective synthesis of (R)- and (S)-1,7-dioxaspiro[5.5]undecane

(R)- and (S)-1,7-Dioxaspiro[5.5]undecane ((R)-1 and (S)-1), sex pheromone of an olive fly, was each stereoselectively synthesized using an intramolecular Michael addition of hydroxyl group to a chiral vinylic sulfoxide moiety as an asymmetric induction step.     

The formal total synthesis of (+/-)-strychnine via a cobalt-mediated [2 + 2 + 2]cycloaddition

A short, highly convergent total synthesis of racemic isostrychnine, and thus strychnine, has been completed. The route involves 14 steps in the longest linear sequence and is highlighted by a cobalt-mediated [2 + 2 + 2]cycloaddition of an alkynylindole nucleus to acetylene.     

A stereoselective route toward polyhydoxylated piperidines. A total synthesis of (+/-)-deoxymannojirimycin

[reaction: see text] A chemo- and stereoselective palladium-catalyzed amination of silylated butenediol dicarbonates has allowed for the introduction of a glycine moiety to obtain a desired functionalized epoxysilane. A stereoselective aldolization then delivered the piperidine ring which may be used as a precursor for the synthesis of a variety of polyhydroxylated azasugars. This efficient approach has been illustrated by the synthesis of 1-deoxymannojirimycin including a stereoselective reduction with LAH and a Tamao-Fleming oxidation of a C-SiMe(2)Ph bond.     

Highly stereoselective synthesis of the indolo[2,3-a]quinolizine ring system and application to indole natural product synthesis

We report a novel, facile and highly stereoselective approach to the indolo[2,3-a]quinolizine ring system from a readily available, non-racemic chiral template. We demonstrate the potential for application of this methodology to natural product synthesis through conversion of the template to a simple indole alkaloid with high enantiomeric purity.     

Total synthesis of (+/-)-strychnine via a [4 + 2]-cycloaddition/rearrangement cascade

A new strategy for the synthesis of the Strychnos alkaloid (+/-)-strychnine has been developed and is based on an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran. The critical D-ring was assembled by an intramolecular palladium-catalyzed enolate-driven cross-coupling of an N-tethered vinyl iodide. [reaction: see text].     

Formal [3 + 3] cycloaddition approach to chromenes and chromanes. Concise total syntheses of (+/-)-rhododaurichromanic acids A and B and methyl (+/-)-daurichromenic ester

[reaction: see text] Total syntheses of (+/-)-rhododaurichromanic acids A and B and methyl (+/-)-daurichromenic ester are described here. Despite the complex appearances of these compounds, their syntheses are completed in six steps with a 15% overall yield as a mixture by featuring our formal oxa-[3 + 3] cycloaddition methodology.     

Total synthesis of (+/-)-jamtine using a thionium/N-acyliminium ion cascade

[reaction: see text] The first total synthesis of (+/-)-jamtine (4), a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties, is described. The key step involves a tandem thionium/N-acyliminium ion cyclization from enamido sulfoxide 13. The cascade process takes place with high diastereoselectivity and in excellent yield.     

Transannular dipolar cycloaddition as an approach towards the synthesis of the core ring system of the sarain alkaloids

Intramolecular transannular dipolar cycloaddition was investigated as a key step in a synthetic approach to the core of the sarain alkaloids; although the use of an azomethine ylide was unsuccessful with the chosen aldehyde substrate, cycloaddition with a nitrone did give the alternative regioisomeric bridged cycloadduct.     

Studies on the synthesis of (+/-)-stenine: a combined intramolecular [4 + 2]-cycloaddition/rearrangement cascade

Several cyclic 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMSTF) with beta-alkoxy-gamma-dithiane lactams. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). The resulting oxa-bridge cycloadducts underwent a subsequent 1,2-methylthio shift to form tricyclic lactams in high yield. Furan 9, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. Conformational effects imposed by the placement of a carbonyl group within the tether, combined with a rotational bias about the C(2)-N bond, enhances the rate of the IMDAF reaction of the seven-ring system so that it occurs readily at 25 degrees C. The feasibility of using the cascade sequence in the context of a total synthesis of the Stemona alkaloid (+/-)-stenine was explored. The eventual synthesis of (+/-)-stenine was carried out by an intramolecular Diels-Alder reaction of a 2-amido-5-methylthio-substituted furan containing a trans-pent-3-enoic acid methyl ester side chain in order to create the desired azepinoindole skeleton. This was followed by a series of reductions to set the syn-anti stereochemical relationship at the incipient ring fusion sites present in stenine. All six stereocenters at the azepinoindole core were derived in high stereoselectivity from the functionality present in the rearranged cycloadduct 10. Compound 10 was converted to stenine in 11 additional steps via a sequence that features a Crabtree's-catalyst directed hydrogenation, iodolactonization, and a Keck allylation.