Decarboxylation of allylic β-ketoesters

Transcription

1 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 Decarboxylation of allylic β-ketoesters Indicate the mechanism of the following transformation: d 2 dba mol% h mol% TF, rt d 0 L n d 0 L n d II L n C 2 Tsuji Acc. Chem. es (20) 140. d II L n

2 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 Allylic carbonates h d 2 dba mol% h mol% TF, rt h 90% C 2 C 2 note: no external base is needed 2 C C 2 C 2 h h h 3 h L n d II L n d II L n d II h 3 Chemoselectivity: allylic carbonates are more reactive towards d mediated oxidative addition than allylic acetates. Ac C 2 C 2 d 2 dba mol% h mol% TF, rt Ac 77% C 2 no product corresponding to attack at the allylic acetate was observed. lefin geometry: anti/syn isomerization of the π-allyl intermediate occurs at a faster rate than nucleophilic attack. neryl acetate (Z) C 2 C 2 d 2 dba mol% h mol% TF, rt 54%, (52:48 E/Z) C 2 Tsuji TL 1982 (23) review: Tsuji Acc. Chem. es (20) 140.

3 M.C. White Chem 253 π-allyl chemistry Week of ovember 8, 2004 Difunctional allylic alkylating agents ationalize the formation of different products. In each case indicate the intermediates. C 2 C 3 C 2 d 2 dba 3 /dppe 5 mol% TF, 50 o C C 2 C 2 C 3 A C2C3 2 C C 2 C 2 a (C C 2 3 C) 2 W(C) 4 25 mol% bpy 25 mol%, TF, o C C 2 C 3 B C 2 C 2 C 2 C 2 C 2 C 3 C 2 C 2 C 2 C 2 C 2 C 2 A d II L n 2 C C 2 2 C C 2 C 2 C 2 C 2 C 3 B d II L n Trost JACS 1987 (109) 2176.

4 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 π-trimethylenemethane cyclizations C 2 C 3 Si 3 Ac (h 3 ) 4 d DE TF C 2 C 3 51 % yield Si 3 h 2 d (0) h 2 Si 3 Ac Silicon-carbon bond weakened by the proximal positive charge C 6 11 C 3 Ac d h 2 h 2 d h 2 h 2 palladium π-trimethylenemethane complex C 6 11 C 3 C 6 11 d h 2 h 2 d h 2 h 2 d h 2 h 2 C 2 C 3 C 6 11 C 2 C 3 Trost ACIEE 1986 (25) 1. The geometry of (E)-olefins is retained in the products, suggesting that the mechanism is concerted ([32]) that the mechanism is stepwise but collapse of the intermediate enolate is faster than σ-bond rotation. (Z)-olefins give mixtures of syn and anti products; this argues that the mechanism for π-trimethylenemethane cyclizations is in fact stepwise.

5 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 Carbon and oxygen spirocycles: Ac Ac cis-fused decalin systems: 2 C C 2 = E C 2 Et C 2 C 2 Et d(h 3 ) 4 7 mol% a, TF, 65 o C d(h 3 ) 4 7 mol% a, TF, 65 o C L n (Ac)d II Cyclizations E E 66% C 2 C 2 Et C 2 Et >99% note that attack at the least sterically hindered position results in a bridgehead olefin: C 2 Godleski JC 1982 (47) 383. d d 2 dba 3 /h 3 cat 2 dba 3 /h 3 cat a, TF, 65 o a, TF, 65 C o C Ac C 2 E C 2 E Ac 75%, >98% cis complements the obinson annulation >98% cis approach which generally leads to Backvall TL 1989 (30) 617. trans-fused rings. review on cyclizations: Trost ACIEE 1989 (28) Macrocyclizations occur readily. egioselectivity favors substitution at the least sterically hindered carbon, particularly when bulky nucleophiles are used. 2 C C 2 E E TES TES TES TMS TES 3 C d 2 dba 3 10 mol% -tbu TF, 40 o C, 12h 80% t-bu C 3 C 19-membered ring formation 3 C 3 TMS Sorenson JACS 2002 (124) ()-F182877

6 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 Asymmetric functionalization via deracemization Deracemization X L n d 0 u a enantiotopic ends of a meso π-allyl intermediate. dl n b syn/anti a b u u u a dl n note that syn/anti isomerization results in an errosion in ee's. Challenge: creating an effective asymmetric environment outside the coordination sphere of the metal opposite to the chiral ligand. Solutions: ayashi's nucleophile directing tether: ayashi TL 1986 (27) Fe h 2 d 2 h 2 d h 2 faltz's electronic disymmetry. faltz ACIEE 1993 (32) 566. t-bu u The hydroxyl group on the ligand tether is thought to interact attractively with the incoming nucleophile via -bonding and direct it towards attack at one end of the π-allyl group. The stronger π-acceptor properties of phosphines vs. imines results in differential trans-effects between the two coordinating functionalities. The strong -d bond translates into a long (weaker) d-c bond trans to it. This is thought to increase the ionic nature of the bond resulting in more carbonium character at the corresponding carbon and preferential attack by the nucleophile at that site. Ar Ac Ac Ar The 1,3-diphenylallyl system favors the syn,syn isomer. Syn-anti isomerizations often lead to erosions in ee's for acyclic substrates. [Cld(η 3 -allyl)] 2 0.5mol% 1 (1 mol%), TF a [Cld(η 3 -allyl)] 2 1 mol% 2 (2.5 mol%), DMF, 65 o C a C 2 C 2 C 2 C 2 alkyl substituted 1,3 allyl's give high ee's: Ar 2 C 2 C C 2 C 2 Ar Ar = h, 97% yield, 90% ee 1-p, 40% yield, 92% ee =, 50% yield, 97% ee i-r, 96% yield, 88% ee h, 99% yield, 99% ee

7 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 Asymmetric functionalization via deracemization Challenge: creating an effective asymmetric enviroment outside the coordination sphere of the metal opposite to the chiral ligand. Solutions: chiral backbone linker linker h 2 h 2 d 3 Trost Acc. Chem. es (29) 355. Cat u - Cyclic systems: C 2 [Cld(η 3 -allyl)] 2 2.5mol% Cat C Ac C (7.5 mol%), TF C 2 Cat %Yield % ee open quadrant The primary chirality of the stereogenic centers of the backbone gets translated via the linker units into a secondary chirality at the phosphines that are closest to the d-allyl unit. The conformational bias for edge-face stacking of the phosphine phenyl groups enforces chiral "propellers" that reach out towards the allyl unit and sterically block the trajectory of nucleophilic attack from one side. The steric bulk of the diphenylphosphine units is also thought to retard the rate of syn/anti isomerization. Because the rxn is performed in nonpolar media, the u exists as an ion pair. Trost has found that the molecular recognition event depends more on the nature of the cation than of the anion that ultimately attcks the π-allyl unit. The larger the cation, the higher the ee. bulkier ammonium ion C 2 Cl 2 results in an even tighter ion pair. larger metal ion Trost JACS 1994 (116) a (C 3 ) 4 (n-c 6 13 ) 4 (n-c 6 13 ) 4 77% 88% 92% 81% 38% 41% 68% 98% in C 2 Cl 2 K Cs Cs in C 2 Cl 2 90% 76% 98% 51% 76% >99% All the ammonium cations were added as chloride salts. esults under optimal ammonium salt conditions: C 2 86% yield 96% ee C 2 99% yield 93% ee C 2 C 2 87% yield 94% ee

8 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 Asymmetric functionalization: regio-and stereoselective amination or X L n d 0 diastereomeric dl n π σ π (aka η 3 -η 1 -η 3 ) isomerization u u u u X L n d u Both a regio- and stereoselectivity challenge achiral substrate Fe h 2 h 2 C 2 h 2 6 mol% d 2 (dba) mol%, TF, 0 o C h (91:9, E/Z) note: result indicates that syn/anti isomerization is slow relative to nucleophilic attack. 87% yield 97: 3 (branched: linear) 84% ee h racemic substrate dl n C 2 50% conditions as above L n d dl n 82% h π-σ-π isomerization is fast relative to nucleophilic attack C 2 50% L n d 18% h ayashi TL 1990 (31) 1746.

9 M.C. White/M.W. Kanan Chem 253 π-allyl chemistry Week of ovember 8, 2004 Dynamic kinetic asymmetric transformation of 5-Acyloxy-2-(5)-furanone Et 3 C I 1.2 eq. Boc racemic 2.5 % d 2 dba 3, 7.5% 1 30% Bu 4 Cl, C 2 Cl 2 Et 3 C I h 2 h 2 1 Boc racemic Boc d 0 d Cl - d d Cl - Cl - via via d d Et I 3 C - Et 3 C The addition of Cl - ion is thought to accelerate the equilibration between the two -allyl diastereomers by promoting formation of an η 1 intermediate. Since the kinetic discrimination between the two reactive diastereomers is high, increasing their rate of equilibration increases the overall selectivity of the reaction. I Trost JACS 1999 (121) d 0 The ee of the product could not be directly determined, however the ee of the product of the subsequent eck cyclization was > 95%. Et I 3 C Et reductive eck 3 C 3 C > 95% ee Aflatoxin B

10 M.C. White/M.W. Kanan Chem 253 π-allyl chemistry Week of ovember 8, 2004 Intramolecular asymmetric allylic alkylation in the synthesis of [2.2.2] bicycles 1 C 2 Et C 2 C 3 d 2 dba 3 2 mol % d 0 5 mol % C 2 Cl 2, rt C 2 Et C 2 Et % yield; 2 : 3 = 4.6 : 1; ee 2 = 99% d 0 = 4 possible transition states for cyclization h 2 h 2 C 2 Et 3 d d C 2 Et d 0 C 2 C 3 A decarboxylation C 2 C 2 Et d The ligand framework provides moderate diastereocontrol with excellent enantiocontrol for the major diastereomer in this cyclization, which can proceed through any of four transition states. - d C 2 Et C 2 Et pseudo-enantiomeric d C 2 Et C 2 Et Trost L C 2 Et d 0

11 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 Asymmetric functionalization: regio-and stereoselective alkylation h Ac (C 6 4 -p-cf 3 ) 2 4 mol% i-r [Ir(CD)Cl] 2 4 mol%, TF h h C 2 C 2 a C 2 C 2 2 C C 2 99% yield 95:5 (branched:linear) 91% ee Stereochemical model: C 2 Tf Ar 2 i-r Ir I S Cl h Ac Ar 2 i-r Cl Ir III S h Ac u h 3 h 3 Ir III Cl crystallographically characterized Ir III π-allyl complex h 2 C C 2 The benzylic carbon preferentially orients trans to the diarylphosphine. ationale: sterics and/or better stablization of the carbonium ion character resulting from the trans influence of Ar 2. The h substituent is also oriented trans to the oxazoline i-r substituent. ationale: sterics. elmchen TL 1997 (38) Chen M 1997 (16) 1159.

12 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 Asymmetric functionalization: regio-and stereoselective alkylation/amination recedent for using phosphoramidite ligands to effect asymmetric Ir mediated allylic substitutions: h h 1 2 Ac Ac 4 mol% [Ir(CD)Cl] 2 2 mol%, TF 2 C 2 C a h 2 C C 2 from 1: 54% yield 95:5 (branched: linear) 43% ee from 2: 92% yield 98:2 (branched:linear) 69% ee Alkylated of ()-2 (>99 % ee) gives product of 75% ee. elmchen Chem. Comm artwig explores amine nucleophiles: artwig JACS 2002 (124) ASA. h C 2 artwig notes that the branched allylic carbonate gives aminated products with low ee's. () 2 mol% [Ir(CD)Cl] 2 1 mol%, TF, 50 o C h 2 h h ( a, C, C )-3 limitations: use of the ligand diastereomer ( a, C, C )-3 gives the opposite enantiomer in diminished yield (66%) and ee (75%). h h 89% yield 98:2 (branched:linear) 94% ee h hex 88% yield 98:2 (branched:linear) 96% ee h h 91% yield 97:3 (branched:linear) 96% ee h 58% yield 96:2:2 (branched:linear:bisalkylated) 97% ee 92% yield 99:1 (branched:linear) 97% ee h 58% yield 96:2:2 (branched:linear:bisalkylated) 97% ee

13 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 Molybdenum-catalyzed asymmetric alkylations h C 2 C 3 1 h C 2 C mol% (EtC) 3 Mo(C) 3 10 mol% TF, reflux a C 2 C 3 C 2 C 3 h 2 C C 2 from 1:88% yield 32:1 (branched: linear) 99% ee from 2:70% yield 13:1 (branched: linear) 92% ee h C 2 C 2 If the reaction were proceeding via initial preferential formation of one of the two possible diastereomeric π-allylmolybdenum complexes, starting with racemic 2 would result in racemic product or the products of a kinetic resolution (max. 50% yield of enantioenriched alkylated product). Since racemic substrate gives nearly equivalent levels of ee to those observed for 1, the main pathway is thought to proceed via dynamic π σ π isomerization of the initially formed π-allylmolybdenum complexes with preferential nucleophilic attack on one of the 2 diastereomeric complexes. Synthesis of quaternary amino acids h pro-chiral allyl carbonate C 2 t-bu Trost JACS 2002 (124) h pro-chiral azlactone 15 mol% (EtC) 3 Mo(C) 3 10 mol% LiMDS TF, reflux h h C 3 K 2 C 3 83% yield of branched product 96:4 dr 99% ee h()c C 2 C 3 h solvolysis of the crude azlactone in methanol yields the protected quaternary amino acids in high yields

14 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 Asymmetric functionalization: prochiral nucleophile Asymmetric alkylation chiral backbone h 2 h 2 3 linker d linker open quadrant The geometric requirements of the chiral pocket created by the diphenylphosphine propellers can also effect selective nucleophilic attack of an allyl unit by one face of a prochiral nucleophile. When prochiral allyl units are used, excellent diastereoselectivities can also be achieved. X Y Z vs. Z X Y Ac [Cld(η 3 -allyl)] 2 0.5mol% 3 (1.2 mol%), tol, rt C 2 TMG (,,','-tetramethylguanidine) 86% yield 86% ee Upon deprotonation, the base used results in the cationic partner to the enolate formed. a bases gave lower ee's. [Cld(η 3 -allyl)] 2 0.5mol% 3 (1.2 mol%), tol, rt C 2 C 2 h C 2 TMG (,,','-tetramethylguanidine) 71% yield 97% ee 88% de Trost JACS (33) 7879.

15 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 Asymmetric functionalization: desymmetrization h 2 h 2 chiral backbone linker d b linker a open quadrant ath a depicts ionization of the pro- leaving group. A "clockwise" twist of the catalyst leading to ionization positions the open quadrant of the ligand over the face of the cyclopentyl allyl, thus minimizing sterically unfavorable interaction. Inversely, ionization via path b leads to severe steric interactions between the substrate and the phenyl group of the diphenylphosphine. 3 Desymmetrization of meso-biscarbamates. Ts Ts S 92% yield 85% ee d II TsC 2 - d 0 Ts Ts b Ts d 0 a Ts path b attack via sterically unfavored path b d Ts TsC 2 - When base is added (Et 3 ), the ee increases to 99%. ne rationale given by Trost to account for this dramatic increase in ee is that deprotonation of the carbamate increases the rate of intramolecular attack relative to intermolecular attack by the displaced carbamate anion. path a Trost JACS 1992 (114) Trost JC 1998 (63) S Ts d 0

16 M.C. White, Chem 253 π-allyl chemistry Week of ovember 8, 2004 Asymmetric functionalization: desymmetrization Desymmetrization via intermolecular nucleophilic attack: 2 C 2 C 68% yield 92% ee h h h h 2 h 2 6 mol% d 2 (dba) 3 2 mol% h a C 2 C 2 h h 2 h 2 6 mol% d 2 (dba) 3 2 mol% h C 2 C 2 80% yield 93% ee Trost JACS 1992 (114) "From furan to nucleosides" an example of intermolecular nucleophilic attack. Trost JACS 1996 (118) h()c Cl h h h h Cl Cl h()c C()h h 2 h 2 h 2 h 2 6 mol% 6 mol% d 2 (dba) 3 2 mol% d 2 (dba) 3 2 mol% Et 93% ee 3 Et 3 93% ee C()h h()c 2 2 C()h D-adenosine L-adenosine

17 M.C. White/Q. Chen Chem 253 π-allyl chemistry Week of ovember 8, 2004 Total synthesis of (-)-Anatoxin-a via desymmetrization Ts C 2 2.5% d 2 dba 3 CCl 3, 7.5% L C 2 Cl 2, 0 C Ts racemic L = h 2 C 2 88% ee 90% yield (-)-Anatoxin-a aka "very fast death factor" Ts C 2 dl Ts C 2 trans substituted cyclooctene did not give any cyclization product. Ts C 2 dl After initially observing slow reaction rates and low ee's with the standard bis phosphine ligands, the authors reasoned that the "chiral space" created by these standard ligands was too restrictive for the steric demands of the cyclooctenyl substrate. Alternatively, application of the less sterically demanding,-bidentate chiral ligand shown resulted in dramatic rate enhancements and good ee for the cyclization reaction. Ts C 2 dl C 3 Ts dl 3 C C 2 C 2 Trost JACS 1999 (121) 3057.

18 M.C. White Chem 253 π-allyl chemistry Week of ovember 8, 2004 Question rovide a mechanism for the following transformation. h h Ac Si 3 (h 3 ) 4 d toluene, mixture of stereoisomers