268 CHIMIA 2011, 65, No. 4 Laureates: Awards and Honors, SCS Fall Meeting 2010 doi:10.2533/chimia.2011.268 Chimia 65 (2011) 268–270 © Schweizerische Chemische Gesellschaft Asymmetric Intramolecular Diels-Alder Reactions of Trienals Catalyzed by Chiral Ruthenium Lewis Acids

Sirinporn Thamapipol§ and E. Peter Kündig*

§SCS DSM Prize for best poster

Abstract: Chiral single-point binding ruthenium Lewis acid catalysts [Ru(acetone)((S,S)-BIPHOP-F)(Cp)][SbF6]

((S,S)-1a) and [Ru(acetone)((S,S)-BIPHOP-F)(indenyl)][SbF6] ((S,S)-1b) efficiently catalyze intramolecular Diels- Alder (IMDA) reactions of trienals under mild conditions to afford the endo cycloaddition products as the major products in good yields with high diastereo- and enantioselectivities. Keywords: Asymmetric IMDA reaction · Chiral catalyst · Diels-Alder · Lewis acid · Ruthenium

Cycloaddition reactions with their poten- Fig. 1. Single-point - - binding chiral Ru tial for a high degree of stereo- and regio- SbF6 SbF6 control are arguably the most versatile Lewis acid catalysts. + + processes for the construction of five- and (C F ) Ru (C F ) Ru 6 5 2P O 6 5 2P O six-membered rings. Spectacular asym- O P(C F ) O P(C F ) metric versions have been achieved by 6 5 2 6 5 2 Ph O Ph O using chiral Lewis acid catalysts.[1] Our (S,S)-1a (S,S)-1b studies in this area focused on one-point Ph Ph binding chiral ruthenium Lewis acids (1a and 1b) that are based on structurally Scheme 1. Single-point binding chiral Ru Lewis acid catalysts well-defined monocationic half-sandwich 1. (S,S)-BIPHOP-F, reflux, 20 h complexes that incorporate a C2-symmet- ric perfluoroaryl phosphinite ligand. This heptane, 2. CHI3, acetone, reflux, 24 h ligand enforces the appropriate chiral en- Ru3(CO)12 reflux, 2 h OC Ru H vironment around the coordination site 70% and it also offsets the donor properties of CO the cyclopentadienyl- and indenyl-ligands - (Fig. 1). The chiral, electron-poor ligand SbF6 contributes to the Lewis acidity of these + (C6F5)2P Ru (C6F5)2P Ru complexes, and together with the aromatic I AgSbF6, CH2Cl2 O O O arene, generate a chiral binding site that is P(C6F5)2 P(C6F5)2 acetone, rt, 90 min O ideal for the activation of a,b-unsaturated Ph O Ph carbonyl compounds. (S(S,S,S))--1a1a Ph quant. Ph

Scheme 2. Synthesis of [Ru(acetone)((S,S)-BIPHOP-F)(Cp)][SbF6] (1a) Scheme 1. Synthesis of [Ru(acetone)((S,S)-BIPHOP-F)(Cp)][SbF6] (1a).

The synthesis of the stable iodoruthe- furnished Lewis acid 1b as shown in nium complex was achieved in a ‘one pot’ Scheme 2.[2b]

procedure from [Ru3(CO)12]. Significant to These mild chiral Lewis acids proved the success was the hydride-labilizing ef- to be excellent catalysts for intermolecular fect, which enabled CO substitution in the Diels-Alder (DA) reactions of various di- [2] [3] in situ formed [RuCp(CO)2H]. Heating at enes with enals and enones, 1,3-dipolar reflux in acetone in the presence of iodo- cycloadditions of enals with nitrones[4] and form afforded the chiral Ru-iodo complex, of enals with nitrile oxides[4b,5] as shown in *Correspondence: Prof. E. P. Kündig and halide abstraction by AgSbF generat- Scheme 3. The 1,4-addition of thiophenols University of Geneva 6 [2a] Department of Chemistry ed Lewis acid 1a as shown in Scheme 1. to enones could also be carried out using Quai Ernest Ansermet 30 Catalyst 1b was synthesized via ligand these catalysts.[6] Representative examples 1211 Geneva 4 exchange in [Ru(Cl)(indenyl)(PPh ) ] with are shown in Scheme 4. Tel.: +41 22 379 60 93 3 2 Fax: +41 22 379 32 15 BIPHOP-F to afford [Ru(BIPHOP-F)(Cl) We have established details of the mode E-mail: [email protected] (indenyl)]. Halide abstraction with AgSbF6 of action of these catalysts, notably the role Laureates: Awards and Honors, SCS Fall Meeting 2010 CHIMIA 2011, 65, No. 4 269

of the counteranion,[2c,d] the pendulum mo- tion in the Ru(BINOP-F) fragment,[2e] the (S,S)-BIPHOP-F, toluene competition of enals and nitrones for the reflux, 1.5 h [4c] Ru (C6F5)2 Ru Lewis acid site and the preference of co- Ph3P Cl P Cl O ordination of enals and vinyl ketones to the PPh3 (S) P(C F ) [3] 84% 6 5 2 Ru-center (anti-s-trans vs syn-s-trans). Ph O To extend the application, we probed the (S) potential of (S,S)-1a and 1b in the intramo- SbF - 6 Ph lecular Diels-Alder (IMDA) reaction. The AgSbF , CH Cl + 6 2 2 (C F ) Ru study involved trienes 2 (Scheme 5) and 6 5 2P O 3–7 (Scheme 6) and the results of ­IMDA acetone, rt, 90 min O (S) P(C6F5)2 reactions of these substrates catalyzed by Ph O (S,S)-1a and 1b were investigated.[3,7,8] Tri- quant. (S) (S,S)-1b ene 2 containing a vinyl ketone dieneophile, Ph provided the highly enantiomerically en- riched bridgehead adduct 8 in good yield.[3] Scheme 3. Synthesis of [Ru(acetone)((S,S)-BIPHOP-F)(Indenyl)][SbF6] (1b) Scheme 2. Synthesis of [Ru(acetone)((S,S)-BIPHOP-F)(indenyl)][SbF6] (1b). Reflecting the lower reactivity of b-substi- tuted keto-dienophiles, triene 5 failed to re- Scheme 3. act. Trienals 3[9a,b] and 4,[9c] which were pre- O SbF - viously used in asymmetric IMDA reaction 6 O Applications. (C6F5)2 + R by Yamamoto, furnished the cycloadducts 9 P Ru O O H and 10, respectively in good yields with high ArS P(C F ) O 6 5 2 R or X H Ph enantioselectivities. The Thorpe-Ingold O O N Ph (R,R) R effect from the dimethyl malonate group O R increased the reactivity of trienals 6 and R' R R or X 7 shortening reaction times, from days to H R R hours. An X-ray structure of a derivative of N O O H 9 confirmed the tentative assignment made n Ar Me O O R O R' previously based on spectroscopic data. R R'' R R H The absolute configurations of products R'' nn == 0,11, 2 X 10, 12 and 13 were assigned by comparison R' O R' of the CD spectra of the SAMP-hydrazones to that derived from 9 (Scheme 7). Scheme 4. Applications X-ray structures of chiral Ru Lewis O acid/substrate complexes have been instru- O mental for the interpretation of observed H 100% conv. [2–6] H ref.Ref [2a]2e selectivities in cycloaddition reactions. 5 mol% (S,S)-1a, CH2Cl2, 92% yield For the IMDA reaction involving triene 3 92% ee 19 h, -20 °C, 2,6-lutidine the diene approach leading to the observed endo product 9 was modeled as shown in O Fig. 2. It is proposed that the enal dieno- 99% conv. phile (orange) coordinates to the Ru Lewis 76% yield ref.Ref [3]3 5 mol% (R,R)-1a, CH2Cl2, acid in an anti-s-trans conformation and 18 h, 22 °C, 2,6-lutidine 91% ee the diene (blue) approaches the C -Re- O a face of the enal moiety in an endo mode. O The pentafluorophenyl moiety of the (S,S)- 87% conv. BIPHOP-F ligand blocks the Si-face (Fig. ref.Ref [3]3 70% yield 2). This results in the observed product ste- 5 mol% (R,R)-1a, CH2Cl2, 87% ee reochemistry of 9. 24 h, 22 °C, 2,6-lutidine O Me SH O O Conclusion Me 100% conv. We have developed efficient one-point ref.Ref [6]6 binding Ru Lewis acid catalysts ((S,S)-1a 1-5 mol% (R,R)-1a, 95% yield 87% ee and 1b) capable to catalyze diastereo- and 24 h, -20 °C, 2,6-lutidine ArS MS 4Å, CH Cl enantioselectively not only DA reactions, 2 2 1,3-dipolar cycloadditions and Michael O Br Br additions but also IMDA reactions. This O N Me method gives access to highly enantiomer- Br H ically enriched bicyclic products of poten- ref.Ref [4a]4a N + N tial use in organic synthesis. 5 mol% (R,R)-1a, CH2Cl2, Me O CHO Me O CHO 50 h, -5 °C endo exo Acknowledgment 95 : 5 Financial support from the Swiss National 73% yield Science Foundation and the University of 97.7% ee of endo-isomer Geneva is gratefully acknowledged.

SchemeScheme 4. 5Examples. Examples of reactionsreactions withwithCpRu CpRu1a 1a. Received: January 21, 2011 270 CHIMIA 2011, 65, No. 4 Laureates: Awards and Honors, SCS Fall Meeting 2010

Scheme 5. IMDA O H O reaction of triene 2 with Ru catalyst 1a. 5 mol % (R,R)-1a, CH2Cl2 2,6-lutidine, rt, 4 d

2 (R)-8 70% yield > 95% ee Scheme 6 IMDA reaction of triene 2 with Ru catalyst 1a

R2 COR R2 H R1 Z 44 Z ROC 5 mol % (S,S)-1b 3a 1 7a R Z 2,6-lutidine, CH2Cl2, rt Z H 3: R = R1 = R2 = Z = H 9: 92% yield, 84% ee, 99:1 of endo:exo 4: R = R1 = Z = H, R2 = Me 10: 85% yield, 84% ee, 81:19 of endo:exo 5: R = Me, R1 = R2 = Z = H 11: low yield and selectivity 2 1 6: R = R = H, R = Me, Z = CO2Me 12: quant., 56%84% ee, 99:1 of endo:exo 1 2 7: R = R = R = H, Z = CO2Me 13: quant., 84%56% ee, 99:1 of endo:exo Fig. 2. Modelled approach of trienal 3 Scheme 7 Asymmetric IMDA reactions catalyzed by (S,S)-1b Scheme 9 Modelled approach of trienal 3 Scheme 6. Asymmetric IMDA reactions catalyzed by (S,S)-1b (catalyst (S,S)-1a was less active, coordinated to Ru in (S,S)-1b in an anti-s-trans 7 coordinated to Ru in (S,S)-1b in an anti-s- except in(catalyst the case(S,S of triene)-1a was 4).[7]less performant, except in the case of triene 4) orientation (catalyst part taken from the X-ray trastructurens orien ofta [Ru(acetone)((tion (catalysS,tSpar)-BIPHOP-F)t taken from the X-r(indenyl)][SbFay struct]ur ((Se,S)-1bof).[2b] This[Ru( model(S,S )-BIPHOP- 6 3c Scheme 7. Synthesis F)(Crationalizesl)(Indenyl the)][ product’sSbF6] (( S,(3aR,4R,7aSS)-1b) .)-This model OMe of hydrazones 14–17. ratioconfiguration.nalizes the productʼs (3aR,4R,7aS)- N configuration. N CHO OMe 2 N 2 1 R H 1 R H R Z NH2 (SAMP) R Z o Z MgSO4, 0 C, CH2Cl2, 2 h Z H H 9: R1 = H, R2 = H, Z = H 14, (95%) 10: R1 = H, R2 = Me, Z = H 15, (96%) 1 2 12: R = Me, R = H, Z = CO2Me 16, (84%) 1 2 13: R = H, R = H, Z = CO2Me 17, (86%)

Scheme 8. Synthesis of hydrozones 14-17

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