ChemInform Abstract: HIGH DIASTEROSELECTION IN THE CLAISEN REARRANGEMENT OF ENANTIOMERICALLY PURE BUTYROLACTONES

1983 ◽  
Vol 14 (2) ◽  
Author(s):  
F. E. ZIEGLER ◽  
J. K. THOTTATHIL
Keyword(s):  
Claisen Rearrangement ◽  
Enantiomerically Pure

C-O Ring Containing Natural Products: Paeonilactone B (Taylor), Deoxymonate B (de la Pradilla), Sanguiin H-5 (Spring), Solandelactone A (White), Spirastrellolide A (Paterson)

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Oxidative Coupling ◽  
Claisen Rearrangement ◽  
Cyclic Carbonate ◽  
Membered Ring ◽  
State University ◽  
Enantiomerically Pure ◽  
University Of Cambridge ◽  
Spirastrellolide A ◽  
The University ◽  
Oregon State University

Richard J. K. Taylor of the University of York has developed (Angew. Chem. Int. Ed. 2008, 47, 1935) the diasteroselective intramolecular Michael cyclization of phosphonates such as 2. Quenching of the cyclized product with paraformaldehyde delivered ( + )-Paeonilactone B 3. Roberto Fernández de la Pradilla of the CSIC, Madrid established (Tetrahedron Lett. 2008, 49, 4167) the diastereoselective intramolecular hetero Michael addition of alcohols to enantiomerically-pure acyclic sulfoxides such as 4 to give the allylic sulfoxide 5. Mislow-Evans rearrangement converted 5 into 6, the enantiomerically-pure core of Ethyl Deoxymonate B 7. The ellagitannins, represented by 10, are single atropisomers around the biphenyl linkage. David R. Spring of the University of Cambridge found (Organic Lett. 2008, 10, 2593) that the chiral constraint of the carbohydrate backbone of 9 directed the absolute sense of the oxidative coupling of the mixed cuprate derived from 9, leading to Sanguiin H-5 10 with high diastereomeric control. A key challenge in the synthesis of the solandelactones, exemplified by 14, is the stereocontrolled construction of the unsaturated eight-membered ring lactone. James D. White of Oregon State University found (J. Org. Chem. 2008, 73, 4139) an elegant solution to this problem, by exposure of the cyclic carbonate 11 to the Petasis reagent, to give 12. Subsequent Claisen rearrangement delivered the eight-membered ring lactone, at the same time installing the ring alkene of Solandelactone E 14. AD-mix usually proceeds with only modest enantiocontrol with terminal alkenes. None the less, Ian Paterson, also of the University of Cambridge, observed (Angew. Chem. Int. Ed. 2008, 47, 3016, Angew. Chem. Int. Ed. 2008, 47, 3021) that bis-dihydroxylation of the diene 17 proceeded to give, after acid-mediated cyclization, the bis-spiro ketal core 18 of Spirastrellolide A Methyl Ester 19 with high diastereocontrol.

The Carreira Synthesis of (+)-Daphmanidin E

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Claisen Rearrangement ◽  
Primary Alcohol ◽  
Selective Reduction ◽  
Catalytic Amount ◽  
Rat Aorta ◽  
Compact Structure ◽  
Enantiomerically Pure ◽  
Claisen Rearrangements ◽  
Cu Catalyst ◽  
Aldol Addition

(+)-Daphmanidin E 3, isolated from the leaves of Daphniphyllum teijsmanni, shows moderate vasorelaxant activity on the rat aorta. Considering the curiously compact structure of 3, Erick M. Carreira of ETH Zürich chose (Angew. Chem. Int. Ed. 2011, 50, 11501) to start the synthesis from the enantiomerically pure bicyclic diketone 2. The mono enolate of 2 was readily prepared, but the steric bulk of the ketal of 4 was needed to direct the subsequent hydroboration. Indeed, the alkene of 5 was so congested that excess BH3 at elevated temperature was required. Under those conditions, the esters were also partially reduced, so the reduction was completed with Dibal to deliver the crystalline triol 6. After protection of the alcohols, the remaining carbon atoms of 3 were added by sequential Claisen rearrangements. O-Alkylation with 7 delivered 8, which rearranged with 10:1 diastereoselectivity. After O-allylation, the second Claisen rearrangement led to 9 as the only isolable product. Selective hydroboration of 9 led to 10, which was deprotected, then dehydrated following the Grieco protocol. Functional group manipulation of 11 led to the aldehyde 12, which was condensed with nitromethane to give 13. Direct conjugate addition to 13 gave at best a 1:3 preference for the wrong diastereomer. With a chiral Cu catalyst, this was improved to 5:1 in favor of the desired diastereomer. Ozonolysis of 14 followed by selective reduction of the aldehyde gave the primary alcohol, which was carried onto the iodide. Elimination with DBU then delivered 15, setting the stage for the key intramolecular bond connection. After extensive exploration, it was found that irradiation of 15 in the presence of a catalytic amount of a cobaloxime catalyst and a stoichiometric amount of Hünig’s base gave clean cyclization to 16. The last carbocyclic ring of (+)-daphmanidin E 3 was closed by intramolecular aldol addition of the aldehyde of 17 to the ketone, followed by dehydration. The seemingly simple intramolecular imine formation to prepare the natural product, initially elusive, was effected by heating the ammonium salt in ethanol. The Co-catalyzed cyclization of 15 to 16 is particularly striking.

The Zakarian Synthesis of ( + )-Pinnatoxin A

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Claisen Rearrangement ◽  
Aldol Condensation ◽  
Primary Alcohol ◽  
Allylic Alcohol ◽  
University Of California ◽  
Santa Barbara ◽  
Enantiomerically Pure ◽  
Calcium Channel Activator ◽  
The University ◽  
Nabh4 Reduction

( + )-Pinnatoxin A 3, isolated from the shellfish Pinna muricata, is thought to be a calcium channel activator. A key transformation in the synthesis of 3 reported (J. Am. Chem. Soc . 2008, 130, 3774) by Armen Zakarian, now at the University of California, Santa Barbara, was the diastereoselective Claisen rearrangement of 1 to 2. The alcohol portion of ester 1 was derived from the aldehyde 4, prepared from D-ribose. The absolute configuration of the secondary allylic alcohol was established by chiral amino alcohol catalyzed addition of diethyl zinc to the unsaturated aldehyde 5. The acid portion of the ester 1 was prepared from (S)-citronellic acid, by way of the Evans imide 7. Methylation proceeded with high diasterocontrol, to give 8. Functional group manipulation provided the imide 9. Alkylation then led to 10, again with high diastereocontrol. In each case, care had to be taken in the further processing of the α-chiral acyl oxazolidinones. Direct NaBH4 reduction of 8 delivered the primary alcohol. To prepare the acid 10, the alkylated acyl oxazolidinone was hydrolyzed with alkaline hydrogen peroxide. On exposure of the ester 1 to the enantiomerically-pure base 11, rearrangement proceeded with high diastereocontrol, to give the acid 2. This outcome suggests that deprotonation proceeded to give the single geometric form of the enolate, that was then trapped to give specifically the ketene silyl acetal 12. This elegant approach is dependent on both the ester 1 and the base 11 being enantiomerically pure. The carbocyclic ring of pinnatoxin A 3 was assembled by intramolecular aldol condensation of the dialdehyde 11. This outcome was remarkable, in that 11 is readily epimerizable, and might also be susceptible to β-elimination. Note that the while the diol corresponding to 11 could be readily oxidized to 11 under Swern conditions, attempts to oxidize the corresponding hydroxy aldehyde were not fruitful.

A First Generation Chemoenzymatic Synthesis of (+)-Galanthamine

2010 ◽  
Vol 63 (10) ◽  
pp. 1437 ◽  
Author(s):  
Martin G. Banwell ◽  
Xinghua Ma ◽  
Ochitha P. Karunaratne ◽  
Anthony C. Willis
Keyword(s):  
Total Synthesis ◽  
First Generation ◽  
Claisen Rearrangement ◽  
Starting Material ◽  
Chemoenzymatic Synthesis ◽  
Quaternary Carbon ◽  
Enantiomerically Pure ◽  
Rearrangement Reaction

A total synthesis of (+)-galanthamine [(+)-1] has been achieved using the readily available and enantiomerically pure metabolite 2 as starting material. The quaternary carbon centre (C8a) associated with target 1 was constructed using the Eschenmoser–Claisen rearrangement reaction.

The Carreira Synthesis of (–)-Dendrobine

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Claisen Rearrangement ◽  
Magnesium Bromide ◽  
Gel Chromatography ◽  
Ring Fusion ◽  
Enantiomerically Pure ◽  
Schwartz Reagent ◽  
Radical Reduction ◽  
Silica Gel Chromatography ◽  
Stereogenic Center

The tetracyclic alkaloid (–)-dendrobine 3 has at its core a cyclohexane that is substituted at each of its six positions, including one quaternary center. Erick M. Carreira of ETH Zürich chose (Angew. Chem. Int. Ed. 2012, 51, 3436) to assemble this ring by the Ireland-Claisen rearrangement of the lactone 1. The absolute configuration of the final product stemmed from the commercial enantiomerically pure acetonide 4, which was selectively converted to the Z-ester 5. Following the precedent of Costa, TBAF-mediated conjugate addition of 2-nitropropane to 5 proceeded with high diastereocontrol, to give, after free radical reduction, the ester 6, which was carried on the aldehyde 7. Exposure of the alkyne 9 to an in situ-generated Schwartz reagent followed by iodination gave 10 with 10:1 regioselectivity. It was possible to separate 10 from its regioisomer by careful silica gel chromatography. Metalation followed by the addition to 7 gave an intermediate that was conveniently debenzoylated with excess ethyl magnesium bromide to deliver the diol 11. Selective oxidation led to the lactone 1. Exposure of 1 to LDA and TMS-Cl induced rearrangement to the cyclohexene acid, which was esterified to give 2. Deprotection and oxidation then gave the enone 12. Cyclohexene construction by tethered Claisen rearrangement is a powerful transformation that has been little used in target-directed synthesis. Selective addition of pyrrolidine to the aldehyde of 12 generated an enamine, leading to an intramolecular Michael addition to the enone. This selectively gave the cis ring fusion, as expected, but the product was a mixture of epimers at the other newly formed stereogenic center. This difficulty was overcome by forming the enamine from N-methylbenzylamine. After cyclization, hydrogenation set the additional center with the expected clean stereocontrol, and also effected debenzylation to give 14. To close the last ring, the ketone 14 was brominated with the reagent 15, which was developed (Can. J. Chem. 1969, 47, 706) for the kinetic bromination of ketones. Exposure of the crude α-bromo ketone to 4-dimethylaminopyridine then effected cyclization to 16. Following the literature precedent, reduction of the ketone of 16 with NaBH4 followed by gentle warming led to (–)-dendrobine 3.

The Nicolaou Synthesis of (+)-Vannusal

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Claisen Rearrangement ◽  
Complex Structure ◽  
Relative Configuration ◽  
Enantiomerically Pure ◽  
Synthetic Strategy ◽  
Single Diastereomer ◽  
Correct Assignment ◽  
Selective Catalytic Oxidation ◽  
La Jolla ◽  
Highly Strained

The correct assignment of relative configuration for portions of a complex structure that are remote one from another can present substantial difficulties. This was brought home in the course of the synthesis of (+)-vannusal 3 described (Angew. Chem. Int. Ed. 2009, 48, 5642, 5648) by K. C. Nicolau of Scripps/La Jolla. In fact, they prepared several alternative diastereomers, including the originally assigned structure, before finally coming to 3, the spectra of which matched those of the natural product. Their synthetic strategy was based on the late-stage convergent coupling of the aldehyde 13 with the iodide 19, leading to 1. The preparation of 13 began with conjugate addition of the 1-propenyl Grignard reagent 5 to the cyclohexenone 4. Deprotection, oxidation, and acetal formation led to 6, which cyclized with high diastereocontrol to 7. Carbomethoxylation of the ketone followed by Mn(OAc)3 cyclization delivered the highly strained norbornane 8 as a single diastereomer. Condensation of the derived ketone 9 with acetone 10 followed by reduction set the three remaining ternary stereogenic centers of 13. O-Alkylation of the aldehyde 11 followed by Claisen rearrangement established the alkylated quaternary center. Functional group manipulation then converted 12 into 13. The preparation of the iodide 19 began with the diene 14. Hydroboration followed by acetylation provided the meso diol. Enzymatic hydrolysis proceeded with high enantioselectivity, giving 15. Opening of the epoxide 16 with 2-propenyl lithium gave the trans alcohol, which was converted to the requisite cis alcohol 17 by Mitsunobu esterification followed by hydrolysis. Shapiro iodination of 18 then delivered 19. The iodide 19 was enantiomerically pure, but the aldehyde 13 was racemic, so coupling of the two led to 1 and its diastereomer. The cyclization of 1 with SmI2 proceeded with remarkable diastereocontrol, to give the desired 2 directly. Deprotection and oxidation then completed the synthesis of (+)-vannusal B 3. It is noteworthy that throughout this synthesis, the radicals AZADO 20 and 1-Me-AZADO 21, developed by Yoshiharu Iwabuchi (Organic Highlights, March 8, 2010), more efficient than the traditional TEMPO, were used to effect selective catalytic oxidation.

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