Catalytic enantioselective synthesis of quaternary carbon stereocentres

Abstract

Quaternary carbon stereocentres-carbon atoms to which four distinct carbon substituents are attached-are common features of molecules found in nature. However, before recent advances in chemical catalysis, there were few methods of constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for the synthesis of single stereoisomers of such organic molecules. This progress now makes it possible to incorporate quaternary stereocentres selectively in many organic molecules that are useful in medicine, agriculture and potentially other areas such as flavouring, fragrances and materials.

Figure 1. Quaternary stereocenters are important structural features of many biologically active molecules as exemplified by the natural products cortisone and morphine

a, Structures of the steroid cortisone and opioid morphine with their quaternary stereocenters highlighted. Me, methyl. b, Steric congestion, which presents a formidable challenge for chemical synthesis of molecules containing quaternary stereocenters, is illustrated in the molecular models of morphine, particularly in the space-filling model on the right in which its sterically congested quaternary center is barely visible at the end of the pointing arrow.

Figure 2. The use of catalytic enantioselective Diels–Alder reactions to synthesize natural products containing quaternary stereocenters

ee, enantiomeric excess. a, A bimolecular Diels–Alder reaction promoted by iminium ion activation forms intermediate 1 in the first step of a cascade sequence generating tetracyclic product 2. This product contains the quaternary stereocenter and four rings common to several groups of indole alkaloids and was employed to complete enantioselective total syntheses of various indole alkaloids, including (−)-minovincine (3), (−)-akuammicine (4), and (−)-strychnine (5). Boc, tert-butoxycarbonyl; Me, methyl; PMB, p-methoxybenzyl; p-TsOH, p-toluenesulfonic acid; t-Bu, tert-butyl; TBA, tribromoacetic acid. b, An iron-bisoxazoline catalyzed bimolecular Diels–Alder reaction forms product 9 whose quaternary stereocenter subsequently controlled the elaboration of the two additional quaternary stereocenters of ent-hyperforin (10). TIPS, triisopropylsilyl; Et, ethyl; MS, molecular sieves. c, Oxazaborolidinium-catalyzed intramolecular Diels–Alder reaction to form the 11-membered ring and quaternary stereocenter of palominol (14). Tf, trifluorosulfonyl; TIPS, triisopropylsilyl; Ph, phenyl.

Figure 3. Examples of other catalytic enantioselective cycloaddition reactions used to prepare products containing quaternary stereocenters

ee, enantiomeric excess. a, The synthesis of a cyclopentene-fused indoline by a formal [3+2]-cycloaddition of 1,3-dimethylindole and a vinyl diazoester using a rhodium catalyst. This reaction is suggested to take place in a stepwise fashion via dipolar intermediate 15. Me, methyl; Ph, phenyl. b, The [3+2]-cycloaddition of a Pd-trimethylenemethane intermediate generated from allylic acetate 17 to form a tetracyclic intermediate in the total synthesis of (−)-marcfortine C. MOM, methoxymethyl; TMS, trimethylsilyl; Ac, acetate; dba, dibenzylideneacetone; Ph, phenyl. c, Enantioselective synthesis of 1,4-cycloheptadiene 23 from triene 20 and vinyl diazoester 21. The first step in this sequence is Rh-catalyzed cyclopropanation of the terminal double bond of the acyclic triene to form divinyl cyclopropane 22, which upon in situ Cope rearrangement generates 23 and its quaternary stereocenter. Product 23 was employed in the total synthesis of the diterpenoid (−)-5-epi-vibsanin E. Me, methyl; TBS, tert-butyldimethylsilyl.

Figure 4. Catalytic enantioselective polyene cyclizations to construct polycyclic products having quaternary stereocenters

ee, enantiomeric excess. a, The use of a protic acid catalyst for the cyclization of an aryl diene to form two rings and one quaternary stereocenter. i-Bu, isobutyl; t-Bu, tert-butyl; BINOL, 1,1′-bi-2-naphthol. b, The iridium-catalyzed cyclization of a triene alcohol to construct the trans-decalin core 25 of the labdane diterpenoid (+)-asperolide C (26). The first step in this cascade cyclization is the generation of a η³-allyliridium cation from the allylic alcohol fragment of 24. PMB, p-methoxybenzyl; TMS, trimethylsilyl; cod, 1,5-cyclooctadiene; Tf, trifluorosulfonyl. c, The gold-catalyzed cyclization of an aryl dienyne to form three rings and two quaternary stereocenters of tetracyclic product 28. Et, ethyl; Me, methyl; t-Bu, tert-butyl. d The rhodium-catalyzed cyclization of dienyne 30 to form bridged azatricyclic product 32. This reaction is suggested to take place via metallacyclic intermediate 31, which undergoes alkene insertion and reductive elimination to furnish product 32. Ts, p-toluenesulfonyl; tol-BINAP, 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthalene; cod, 1,5-cyclooctadiene; L, ligand. e, The cyclization of tetraene aldehyde 33 in the presence of an imidazolone catalyst and a Cu(II) oxidant to form five rings and four quaternary stereocenters of hexacyclic product 35. This novel reaction is suggested to proceed by single-electron oxidation of the initially formed iminium ion intermediate to generate 34, which undergoes a series of 6-endo radical cyclizations to eventually give product 35. The nitrile substituents are incorporated to disfavor 5-endo cyclizations in the formation of the second and fourth rings. Me, methyl; Tf, trifluorosulfonyl; TFA, trifluoroacetic acid; NaTFA, sodium trifluoroacetate; i-Pr, isopropyl; DME, 1,2-dimethoxyethane.

Figure 5. Transition metal-catalyzed insertion reactions that form quaternary stereocenters

ee, enantiomeric excess. a, The enantioselective intramolecular Heck cyclization of dienyl triflate 36 to form 1,4-diene intermediate 37, which upon exposure to excess trifluoroacetic acid provided tetracyclic product 38 in route to the indole alkaloid (+)-minfiensine (39). The use of PHOX ligand 40 was critical in achieving both high stereoinduction and preventing isomerization of the initially formed product 37 to the conjugated 1,3-diene regioisomer. Boc, tert-butoxycarbonyl; Me, methyl; Tf, trifluorosulfonyl; Ac, acetyl; TFA, trifluoroacetic acid. b, The intramolecular nickel-catalyzed arylcyanation of a tethered double bond to form indane 41. DME, 1,2-dimethoxyethane; Ph, phenyl; t-Bu, tert-butyl. c, The palladium-catalyzed cyclization/dearomatization of aryl(naphthyl)amine 42 to form tetracyclic product 43. This reaction is suggested to occur via a six-membered palladacyclic intermediate that undergoes reductive elimination to form generate product 43. Ph, phenyl; dba, dibenzylideneacetone; t-Bu, tert-butyl; THF, tetrahydrofuran; Me, methyl; Cy, cyclohexyl. d, The rhodium-catalyzed conversion of alkenyl benzocyclobutanone 45 to tricyclic ether 47. This transformation is believed to occur by initial insertion of rhodium into the C–C bond to form acylrhodium intermediate 46, which in the enantiodetermining step undergoes intramolecular carboacylation of the tethered alkene to form product 47. cod, 1,5-cyclooctadiene; L, ligand; Me, methyl; t-Bu, tert-butyl. e, The bimolecular Heck-type addition of an arylboronic acid to the trisubstituted double bond of 49 to form ketone product 52. This rare example of a bimolecular alkene insertion to form a quaternary stereocenter is suggested to occur by initial enantioselective carbopalladation of the alkene to generate intermediate 50, which undergoes sequential β-hydride eliminations/migratory insertions along the alkyl chain to form alkene complex 51 and then the ketone product. Ts, p-toluenesulfonyl; Tf, trifluorosulfonyl; Me, methyl; MS, molecular sieves; DMF, N,N-dimethylformamide; t-Bu, tert-butyl.

Figure 6. Enantioselective copper-catalyzed conjugate additions to construct quaternary stereocenters

ee, enantiomeric excess. The upper segment of the Figure depicts several Cu-catalyzed conjugate additions to 3-methyl-2-cyclohexen-1-one (54) that form new quaternary stereocenters: a, The addition of an arylaluminum compound to 54 to form cyclohexanone 55. CuTC, copper(I) thiophene-2-carboxylate; Ph, phenyl; Et, ethyl. b, The addition of a trialkylaluminum compound to 54 to form cyclohexanone 56. Tf, trifluorosulfonyl; i-Bu, isobutyl; THF, tetrahydrofuran; Ph, phenyl; NHC, N-heterocyclic carbene. c, The addition of an arylzinc compound to 54 to form the enantiomer of cyclohexanone 55. Tf, trifluorosulfonyl; Ph, phenyl; Et, ethyl. d, The addition of an alkyl Grignard reagent to 54 to form 3,3-dialkylcyclohexanone 57. Tf, trifluorosulfonyl; Ph, phenyl; Et, ethyl. e, The addition of an alkylzirconium intermediate generated by hydrozirconation of 3,3-dimethyl-1-butene to 54 to form 3,3-dialkylcyclohexanone 58. Tf, trifluorosulfonyl; Cp, cyclopentadienyl; t-Bu, tert-butyl; Me, methyl. The lower segment of the Figure shows the use of two of these methods to form methyl-containing quaternary stereocenters in syntheses of a potential taxane terpenoid precursor and a dolabellane diterpenoid: f, The enantioselective copper-catalyzed conjugate addition/enolate trapping to introduce a quaternary methyl group in the construction of a taxadienone. CuTC, copper(I) thiophene-2-carboxylate; Me, methyl; THF, tetrahydrofuran; TMS, trimethylsilyl. g, The enantioselective copper-catalyzed conjugate addition/enolate trapping to introduce a quaternary methyl group in the total synthesis of clavirolide C. Tf, trifluorosulfonyl; Me, methyl; THF, tetrahydrofuran; TES, triethylsilyl.

Figure 7. Enantioselective intramolecular Stetter reaction and allylic alkylation reactions to construct quaternary stereocenters

ee, enantiomeric excess. a, The intramolecular Stetter reaction of enone aldehyde 64 catalyzed by the carbene generated from triazolium salt 66 to form 2,2-disubstituted cyclopentanone 65. KHMDS, potassium bis(trimethylsilyl)amide. b, The α-allylation of indoline aldehyde 67 with allylic alcohol 68 using the dual activity of iridium and amine catalysts. This reaction constructs the quaternary and adjacent secondary stereocenter of product 69. Boc, tert-butoxycarbonyl; cod, 1,5-cyclooctadiene; Ph, phenyl. c, The formation of 4,4-disubstituted 2,5-hexadienoic ester 72 by allylic displacement of phosphate triester 71. In this reaction, an alkenylcopper carbene complex is generated from a vinylboronate precursor. Me, methyl; pin, pinacolato; THF, tetrahydrofuran; Ph, phenyl. d, The anti-diastereoselective coupling of benzyl alcohol 74 with vinyl epoxide 75 using an iridium catalyst to give the product 76 of carbonyl tert-(hydroxy)prenylation. This reaction proceeds by the coupling of aldehyde and (E)-σ-allyliridium intermediates respectively generated in situ from the alcohol and vinyl epoxide precursors by an iridium-catalyzed redox process. Ph, phenyl.

Figure 8. Use of palladium-catalyzed asymmetric allylic alkylation reactions for constructing quaternary centers in alkaloid and terpenoid natural products

a, The regioselective prenylation of oxindole 78 upon base-promoted reaction with the η³-allylpalladium electrophile generated from a prenyl carbonate to form 79. This product was a late-stage intermediate in the enantioselective total synthesis of ent-flustramine A (80). Me, methyl; Boc, tert-butoxycarbonyl; dba, dibenzylideneacetone; TBAT, tetrabutylammonium difluorotriphenylsilicate; Ph, phenyl. b, The syn-diastereoselective diallylation of β-ketoester 82 (a mixture of racemic diastereomers) to give (R,R)-83, a pivotal intermediate in the enantioselective total synthesis of (−)-cyanthiwigin F. dmdba, bis(3,5-dimethoxybenzylidene)acetone; Ph, phenyl; t-Bu, tert-butyl.

Figure 9. Miscellaneous methods involving the union of a catalytically generated chiral carbon electrophile with a carbon nucleophile

ee, enantiomeric excess. a, The Steglich rearrangement of indole carbonate 85 in the presence of Fu’s planar-chiral catalyst 88 to give 3,3-disubstituted oxindole 86 in route to (+)-gliocladin C. Boc, tert-butoxycarbonyl; Me, methyl; THF, tetrahydrofuran. b, The copper-catalyzed β-arylation of indole 89 and concomitant cyclization to form 3a-arylpyrrolidinoindolinone 90. Me, methyl; Bn, benzyl; Tf, trifluorosulfonyl; Mes, 1,3,5-trimethylbenzene; Ph, phenyl. c, The Ni-catalyzed coupling of an indole with a 3-bromooxindole in route to (+)-perophoramidine. This reaction sets the two contiguous quaternary stereocenters of (+)-perophoramidine. OAc, acetoxy; MS, molecular sieves; THF, tetrahydrofuran; Me, methyl; Ph, phenyl.

Figure 10. Enantioselective desymmetrization reactions of precursors containing prochiral quaternary carbons

ee, enantiomeric excess. a, The ring-closing metathesis of triene 93 to give tetrahydropyridine 94 using a molybdenum catalyst. Catalytic hydrogenation of product 94 then completes a novel construction of (+)-quebrachamine (95). RCM, ring-closing metathesis; Et, ethyl. b, The gold-catalyzed ring expansion of an allenylcyclopropanol to form (R)-2-ethenyl-2-phenylcyclobutanone. Ph, phenyl; Me, methyl, xylyl, 3,5-dimethylphenyl; NaBARF, sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. c, The rhodium-catalyzed hydroacylation of cyclopropene 96 with salicyaldehyde to form cyclopropane 97. Coordination of the phenolic oxygen of salicyaldehyde and the ring strain of the cyclopropene promotes this bimolecular hydroacylation reaction. The observed diastereoselectivity is suggested to result from Rh-hydride insertion and subsequent C–C bond reductive elimination taking place preferentially from the cycloproprne face opposite the larger substituent. Me, methyl; Cy, cyclohexyl; t-Bu, tert-butyl; cod, 1,5-cyclooctadiene. d, The enantiotopic rhodium-catalyzed insertion into a C–C bond of cyclobutanone 98, followed by intramolecular insertion of the rhodium-acyl intermediate to give bridged-tricyclic ketone 99. Bn, benzyl; Me, methyl; cod, 1,5-cyclooctadiene; t-Bu, tert-butyl. e, The palladium(II)-catalyzed enantiotopic C–H activation of sodium diphenylacetate 100 templated by the carboxylate group, followed by bimolecular Heck coupling with styrene to give product 101. OAc, acetoxy; BQ, benzoquinone; Ph, phenyl; Boc, tert-butoxycarbonyl. f, The desymmetrization of a prochiral 1,4-cyclopentenone by copper-catalyzed conjugate addition of a methyl group to give chiral product 103 was the key step in the total synthesis of (+)-madindoline B. Bn, benzyl; Tf, trifluorosulfonyl; Pr, propyl; Me, methyl; Bu, butyl; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; t-Bu, tert-butyl.