Bis , cyclization

In the synthesis of morphine, bis-cyclization of the octahydroisoqtiinolinc precursor 171 by the intramolecular Heck reaction proceeds using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the rr-allylpalladium intermediate 172, which attacks the phenol intramolecularly to form the benzofuran ring (see Section 1.1.1.3). Based on this method, elegant total syntheses of (-)- and (+ )-dihydrocodei-none and (-)- and ( + )-morphine (173) have been achieved[141]. 

The tandem intramolecular conjugate addition to 99 followed by an intramolecular alkylation reaction leads to a bis-cyclized product in good yield (equation 80)66. 

Overman and co-workers have reported Mannich bis-cyclizations (carboxylate-terminated iV-acyliminium ion bis-cyclizations Scheme 56) and employed these in the total synthesis of (—)-ajmalicine <1995JA9139>. 

Tetrahydrobis(benzofuran) is produced by a tandem cyclization reaction from the bis-vinyl ether on reaction with catalytic quantities of rhodium(l) salts in the presence of electron-rich phosphine ligands <20030L1301>. Thus, employing 10mol% of [RhCl(coe)2]2 with 20mol% of a dicyclohexyl ferrocenyl phosphine ligand produces the bis-cyclized product (coe = cyclooctene Equation 67). 

Recent efforts in the area of Friedel-Crafts alkylations have focused on the direct introduction of alkyl groups bearing functionalities, and on intramolecular alkylative cycliz-ations. The cyclization of the 2-substituted thiophene (55) to (56) has been achieved in 65% yield (80JOC3159). Similarly, the 3-substituted thiophene (57) has been cyclized to the isomeric (58). In both cases, detosylation of the product was achieved by treatment with diisobutylaluminum hydride (DIBAL). An elegant bis-cyclization of the diene (59) to the octahydrodibenzothiophene (60) has been reported (70CJC2587). 

In contrast to carbenes, nitrene attacks only the carbon and never the sulfur atom of thiophene the only exception to this is discussed in Section 3.14.3.5. Unsubstituted thieno[3,2-/>]pyrrole and thieno[2,3-6]pyrrole have been prepared by thermolysis of the corresponding vinyl azides (Scheme 68) (81IJC(B)27l). A bis-cyclization of this type has also been reported (73CR(C)(277)1149>. Similarly, in the benzo[Z>jthiophene series the nitrene (252), generated either by thermolysis of the azide or by P(OEt)3 induced deoxygenation of the nitro compound, gives only the condensed indole (253) (79AG(E)900). 

Haloacetamides (56) react with potassium thiocyanate (57) to give 2-thiocyanatoacetamides (58), which cyclize in proton-donor solvents to the 2-imino-4-thiazolidinones (59) [Eq. (17)].83 Similarly, 5-nitro-2-fur-aldehyde chloroacetylhydrazone and 57 give 2-imino-3-(5-nitrofurfurylidene-amino)-4-thiazolidinone.84 Bis-cyclizations have also been successfully accomplished.85... 

A new stereocontrolled synthetic route to the potent proteasome inhibitor omuralide 46 has been developed from methyl pyroglutamate <07JOC10108>. The development of a new convertible isocyanide, indole-isocyanide, for ready access to pyroglutamic acids has culminated in the formal total synthesis of omuralide featuring a stereocontrolled Ugi reaction <07OL3631>. A novel enantioselective total synthesis of 20S proteasome inhibitor salinosporamide A 47 included, as a key feature, an intramolecular aldol cyclization <07OL2289>. A concise total synthesis of ( )-salinosporamide A, ( )-cinnabaramide A, and derivatives via a bis-cyclization process has been documented <07OL2143>. The... 

Bis-Cyclization-Anion Capture Processes Allenyl Starter Species... 

Propargylic carbonates are valuable substrates in Pd(0)-catalyzed processes. Their chemistry differs mechanistically from that of simple alkynes in that they form allenyl palladium species. We and others have shown these versatile intermediates can serve a double function as both starter and terminating species in bis-cyclization-anion capture cascades A typical example is the process 45 46, which generates azabicyclo [3.1.0] hexanes (Scheme 5.6.12) in good yield. ... 

We have provided numerous examples that show that these bis-cyclization-anion capture processes are diastereoselective. For example, 47a, b in the presence of Pd(0) and 2-thienyl tri-n-butylstannane in THF at 60 °C for 2-A h afford 48 and 49 as single diastereomers (Scheme 5.6.13). ... 

Bis-cyclization processes can be engineered to deliver linear or angularly fused systems (Scheme 5.6.15) or spirocycles. 

Scheme 5.6.15 Strategies for bis-cyclization-anion capture with aryl halide starter species...

Typical examples of bis-cyclization anion capture processes forming fused and spirocyclic rings, triggered by aryliodide species, are shown in Scheme 5.6.16. Thus, enamide 50 reacts with Af-SEM-indolyl stannane in the presence of Pd(0) to afford a 5 1 diastereomer mixture of 51 and 52 in 74% yield, whilst 53 reacts with 2-pyridyltri- -butyltin in the presence of Pd(0) to afford 54a as a single diastereoisomer. ... 

Scheme 5.6.16 Stereochemical outcome of bis-cyclization-organnostannane-capture cascades...

None specified Model proposed cobalta-cycle intermediates of bi-cyclization of substrate 138... 

This methodology has recently been extended to a palladium catalyzed bis-cyclization in which the furan ring is formed directly C.Y. Hong and L.E. Overman, Tetrahedron Lett., 35, (1994), 3453. 

Grigg has extended his cyclization-anion capture protocol for a variety of mono- and bis-cyclizations in which organoboron derivatives function as anion capture agents <97T11803>. Thus, as an example of a 5-exo trig monocyclization utilizing an alkene as the terminating species, the iodide 68 afforded the arylated indoline 69. 

Balme, G. and Bouyssi, D. (1991) Total synthesis of the triquinane marine sesquiterpene ( )A 02) capneUene using apaUadium-catalyzed bis-cyclization step. Tetrahedron, 50,403-14. 

Pd-catalysed bis-cyclization of l-ene-6,ll-diynes (19) with bis(pinacolato)diboron affords homoallylic alkylboronates (20), which indicates a cascade reaction, where the final transmetallation of bis(pinacolato)diboron is faster than a possible -hydride elimination process. ... 

This Pd-catalyzed cascade bis-cyclization reaction can also be applied to trans linear substrates 40 and 41. It was possible to effect either 5-exo or 6-endo cyclizalion selectively by an appropriate choice of the electron-withdrawing substituents of the nucleophile, as illustrated in Scheme 20. Ero-cyclizations were observed when sterically encumbered nucleophiles were employed. Cyclopentanes were obtained as a result of steric interactions between the nucleophile and one of the allylic hydrogens of the linear substrate. Endo-cyclizations leading to trani-octahydrophenanthrene were the only reactions observed when less sterically demanding nucleophiles were employed. Notably, these cyclizations proceed in a completely stereoselective trans manner. Attack of the carbon nucleophile onto a double bond electrophilicaUy activated by the palladium species results in a trans configuration of the fused ring junction. This stereochemistry is defined by that of the double bond in the initial substrate the relative configuration of compound 42 or 43 is hereby controlled. 

This one-step synthesis of tricyclic systems has also been extended to provide a synthetic strategy for both cis- and tra 5 -hexahydro-l//-benz[/]indene starting from a common acetylenic precursor (44) (Scheme 21). Hydrogenation of 44 over Lindlar s catalyst gave 45. This compound would then be involved in a Pd-catalyzed cascade process, resulting in a bis-cyclization reaction. This reaction, performed in THF, at 55 °C, with potassium t-butoxide and 5% Pd(dppe) led to the exclusive formation of trans-hexa-hydro-l//-benz[/]indene. The stereochemical control of this reaction may be explained if it were to pass through a transition state in which the benzylic substituent lies in a pseudoequatorial orientation. 

The palladium-catalyzed cyclization of acyclic polyenes to form polycyclic systems (eq 40) constitutes a very powerful further development of the above method. cr-Alkylpalladium intermediates, produced in an intramolecular Heck reaction, can be efficiently trapped by neighboring aUcenes to give bis-cyclization products of either spiro or fused geometry. The second cyclization also produces a [Pg.463]

Brevicomin (20), a pheromone of a bark beetle, is a member of a small group of cyclic ketals which have been in vogue as targets in recent years (see below). A neat synthesis of ( )-e/i /o-brevicomin has been published in which a key step is the PdCl2-CuCl2-catalysed bis-cyclization of the olefin diol (21). 

Hong, C. Y. Overman, L. E. "Preparation of Opium Alkaioids by Paiiadium Cataiyzed Bis-Cyclizations. Formai Totai Synthesis of Morphine" Tetrahedron Lett. 1994, 35, 3453, Aiso see Hong, C. Y. Kado, N. Overman, L. E. "Asymmetric Synthesis of Either Enantiomer of Opium Alkaloids and Morphinans. Total Synthesis of (-)- and (+)-Dihydrooodeinone and (-)- and (+)-Morphine" J. Am. Chem. Soc. 1993, 115,11028-11029. Heerdlng, E. A. Hong, C. Y. Kado, N. Look, G. C. Overman, L. E. "Simple Method for Controlling Stereoseleotion in Mannich Cyclization Reactions of Aldehydes" J. Org. Chem. 1993, 58, 6847-6948. 

The double-cyclization cascade was also reported by the same group (Scheme 19.79) [ 149]. The bis- and mono-aminomethylated pyrroloindoles/dipyrrolopyridines 294 and 295 (X = CH/N) were obtained selectively by a controlled Mannich type of reaction-cyclization of4,6-diethynyl-l,3-phenylenediamine (X = CH) or its pyridine congener (X = N) 293 with paraformaldehyde and secondary amines. Treatment of 293 with Cul and EtsN without using Mannich-type reactions furnishes a high-yielding bis-cyclization of terminal alkynes to give 296. 

Nguyen, H., Ma, G., and Romo, D. (2010) A -strain enabled retention of chirality during bis-cyclization of 3-ketoamides total synthesis of (-)-salinosporamide A and (-)-homosalinosporamide A. Chem. Commun., 4803-4805. 

Inuki, S., Yoshimitsu, Y., Oishi, S., Fujii, N., and Ohno, H. (2009) Ring-contraction/stereoselective functionalization cascade Total synthesis of pachastrissamine (jaspine B) through palladium-catalyzed bis-cyclization of bromoallenes. Org. Lett., 11, 4478-4481. 

---