DOI: 10.1002/chem.200801892 Enantioselective Organocatalytic Conjugate Addition of Aldehydes to Vinyl Sulfones and Vinyl Phosphonates as Challenging Michael Acceptors Sarah Sulzer-Moss,[a] Alexandre Alexakis,*[a] Jiri Mareda,[a] Guillaume Bollot,[a] Gerald Bernardinelli,[b] and Yaroslav Filinchuk[c] Abstract: Chiral amines with a pyrrolidine framework catalyze the enantioselective conjugate addition of a broad range of aldehydes to various vinyl sulfones and vinyl phosphonates in high yields and with enantioselectivities up to > 99 % ee. This novel process provides synthetically useful chiral g-gem-sulfonyl or phosphonyl aldehydes which can be widely functionalized with retention of the enantiomeric excess. Mechanistic insights including DFT calculations are explored in detail. Introduction Besides transition-metal complexes and enzymes, organocatalysis is now well-recognized as a powerful tool for the preparation of optically active compounds.[1, 2] The pioneering reports of the proline intermolecular aldol reaction[3] and iminium ion catalysis concept[4] set the stage for an explosion of aminocatalysis over the last few years. Chiral secondary amines have proven to be effective aminocatalysts by covalently activating the carbonyl partners either via nucleophilic enamine or electrophilic iminium species.[5] Among the wide variety of methods available, the asymmetric conjugate addition (ACA) catalyzed by pyrrolidine analogues is of considerable importance for stereoselective C C bond forming reactions.[6] Direct Michael addition of carbonyl donors via enamine activation represents a particularly attractive route, affording versatile functionalized adducts in an atom-economical manner. Several electron-withdrawing groups on the Michael acceptor, including nitro,[7, 8] car[a] S. Sulzer-Moss, Prof. A. Alexakis, Dr. J. Mareda, G. Bollot Department of Organic Chemistry, University of Geneva 30 Quai Ernest Ansermet, 1211 Geneva (Switzerland) Fax: (+ 41) 22-379-3215 E-mail: alexandre.alexakis@unige.ch Keywords: aldehydes · amines · asymmetric synthesis · Michael addition · organocatalysis bonyl,[7f, 9] and ester,[7i, 10] groups, have been successfully exploited in aminocatalysis. Nevertheless, expanding the scope of Michael acceptors still remains an important challenge. In this context, after developing efficient 2,2’-bipyrrolidine and 3,3’-bimorpholine derivatives for ACA of aldehydes and ketones to nitroolefins,[8] we focused on less extensively explored vinyl sulfones and vinyl phosphonates due to their easy access from commercial sources and their potential for offering highly tunable chiral intermediates. In the past, considerable efforts have been devoted to the development of ACA to vinyl sulfones.[11, 12] Although the reaction of preformed enamines with vinyl sulfones has been known for some time,[13] only sporadic examples lead to enantioenriched adducts,[14] and the use of organocatalysis in this area remains elusive.[15] Moreover, despite the great interest in vinyl phosphonates,[16] few reports describe the formation of chiral g-phosphonate carbonyl compounds through ACA.[17] With a view to generalizing the scope of pyrrolidine-based catalysis, we have recently communicated the first enantioselective organocatalytic conjugate addition of aldehydes to vinyl sulfones[18] and to vinyl phosphonates[19] (Scheme 1). Herein, we describe improved conditions and catalysts for these ACA, which result in higher yields and enantioselec- [b] Dr. G. Bernardinelli Laboratoire de Cristallographie, University of Geneva 24 Quai Ernest Ansermet, 1211 Geneva (Switzerland) [c] Dr. Y. Filinchuk Swiss-Norwegian Beam Lines, ESRF, BP-220 6, rue Jules Horowitz, 38043 Grenoble (France) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200801892. 3204 Scheme 1. ACA of aldehydes to vinyl sulfones and vinyl phosphonates catalyzed by chiral amines.  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2009, 15, 3204 – 3220 FULL PAPER tivities for a broad range of aldehydes. In addition, the synthetic utility of optically active Michael adducts as useful chiral synthons is exemplified by various functionalizations. We also present mechanistic insights including DFT calculations for the N-iPr-(2S,2’S)-bipyrrolidine (iPBP) catalyst. Results and Discussion The vinyl sulfones and vinyl phosphonates used for this study are compiled in Figure 1. Some of these compounds (1, 2, 3, 6) were purchased from commercial suppliers; others (4, 5, 7) were prepared according to literature procedures (see Supporting Information).[20–22] sion was achieved in 30 minutes with vinyl bisACHTUNGRE(sulfone) 4 in moderate yield (entry 4). This suggested that the reactivity of pyrrolidine-catalyzed conjugate addition of aldehydes requires geminal bisACHTUNGRE(sulfonyl) groups on the olefin. In view of the investigation of the diastereoselectivity of the reaction, we were interested in b-substituted vinyl bisACHTUNGRE(sulfones). Owing to difficulties in the synthesis of b-alkyl vinyl bisACHTUNGRE(sulfones) due to their propensity to isomerize into the more stable allylic bisACHTUNGRE(sulfone),[23] we opted for grafting a phenyl appendage at the b-position through a modified Knoevenagel procedure.[24] Surprisingly, under pyrrolidine catalysis, b-phenyl bisACHTUNGRE(sulfone) 5 underwent a retro-Knoevenagel reaction, releasing bis(phenylsulfonyl)methane anion 16 which reacted with isovaleraldehyde 8 a to give allylic bisACHTUNGRE(sulfone) 14 after suitable isomerization (Table 1, entry 5, Scheme 2). Figure 1. Vinyl sulfones 1–5 and vinyl phosphonates 6, 7 studied. Scheme 2. Mechanism of formation of allylic bisACHTUNGRE(sulfone) 14. Reactivity—mono-activated vs bis-activated vinyl sulfones: At the outset of our studies, we evaluated the reactivity of vinyl sulfones 1–5 towards catalytic conjugate addition. Isovaleraldehyde 8 a was selected as our model substrate due to its low tendency to do a self-aldol reaction and 25 mol % of pyrrolidine was used as the organocatalyst (Table 1). A large excess of aldehyde (10 equiv) was employed to force an equilibrium to favor the Michael adduct. Inspired by our previous work on nitroolefins,[8] chloroform was used as the solvent. No or scarcely any reaction occurred with mono-activated vinyl sulfones 1–3 (entries 1–3) whereas complete conver- We therefore focused our attention on vinyl bisACHTUNGRE(sulfone) 4 and performed an extensive screen of reaction conditions. Table 1. Reactivity of vinyl sulfones 1–5. Entry Vinyl sulfone t Product Conv.[a] [%] Yield[b] [%] 1 2 3 4 5 1 2 3 4 5 4d 4d 4d 30 min 30 min 7a 8a 9a 10 a 14[c] 0 0 < 10 100 100 – – – 53 – [a] Determined by 1H NMR of the crude material. [b] Isolated yields after purification by column chromatography on silica gel. [c] For the formation of 14, see Scheme 2. Chem. Eur. J. 2009, 15, 3204 – 3220 ACA of aldehydes to vinyl sulfones—Optimization of reaction conditions: The modest yield obtained previously (53 %, Table 1, entry 4) could be explained by the formation of tetrasulfone by-product 17, arising from 1,4-addition of bis(phenylsulfonyl)methane anion 16, generated in situ, to vinyl bisACHTUNGRE(sulfone) 4 (Table 2 and Section on Mechanistic Insights) (Table 1, entry 4 vs Table 2, entry 1). Moreover, the sensitivity of g-sulfonyl aldehyde 12 a also accounts for the precedent modest yield. Indeed, purification on silica gel (53 % yield) gave unsatisfactory results whereas a significant improvement was observed by using Florisil (75 % yield) Table 1, entry 4 vs Table 2, entry 1). The stereochemical outcome was next examined by testing a range of pyrrolidine-core organocatalysts for the Michael reaction of isovaleraldehyde 8 a with vinyl bisACHTUNGRE(sulfone) 4, with the results summarized in Table 2. We first found that decreasing the temperature to 60 8C gave higher enantioselectivity (entries 2–3 vs entry 4). It was also apparent that the selectivity of 2,2’-bipyrrolidine derivatives 18 a–f relies on the steric hindrance of the tertiary amine (entries 4–9). Either a primary group on the nitrogen such as N-Bn 18 c (entry 6) and N-Me 18 d (entry 7) or a too bulky group such as N-cHex 18 b (entry 5) and N-3-pentyl 18 e (entry 8) were revealed to be unselective. Surprisingly, hydrochloride salt 18 f did not catalyze the reaction (entry 9). Moreover, the smaller the group, the higher the quantity of by-product 17. Significantly, the proportion of tetrasulfone 17 becomes lower as the substituent becomes bulkier. Actually, the most interesting result from the 2,2’-bipyrrolidine  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 3205 A. Alexakis et al. Table 2. ACA of isovaleraldehyde 8 a to vinyl bisACHTUNGRE(sulfone) 4; catalyst screening. Table 2. (Continued) Entry Catalyst 14 Entry Catalyst Reaction condi- Conv.[a] [%] tion Yield[b] [%] ee[c] [%] 1 RT, 30 min 100 75 (19)[d] – 2 RT, 30 min 100 65 (18)[d] 57 3 30 8C, 1 h 100 62 (16)[d] 63 4 60 8C, 2 h 100 71 (13)[d] 75 5 60 8C, 2 h 100 43 (17)[d] 58 6 60 8C, 2 h 100 27 (31)[d] 45 7 60 8C, 2 h 100 23 (50)[d] 54 8 60 8C, 2 h 100 69 (6)[d] 47 9 60 8C, 2 h 0 – – 10 60 8C, 2 h 100 79 (0)[d] 55 11[e] 60 8C, 2 h 100 25 (4)[d] 19 12 60 8C, 2 h 100 38 (2)[d] 53 13[e] 60 8C, 2 h n.d.[f] n.d.[f] n.d.[f] 3206 www.chemeurj.org Reaction condi- Conv.[a] [%] tion 60 8C, 2 h 0 Yield[b] [%] ee[c] [%] – – [a] Determined by 1H NMR on the crude material. [b] Isolated yields after purification by column chromatography on Florisil. [c] ee values were determined by SFC. [d] Proportion of tetrasulfone by-product 17 determined by 1H NMR of the crude material. [e] The reaction was sluggish and led to many by-products. [f] Not determined. derivatives was obtained with the secondary iPr group 18 a (71 % yield, 75 % ee) (entry 4). Replacement of the bicyclic five-membered ring by a six-membered ring prevented the formation of tetrasulfone 17 which improved the yield from 71 to 79 % but also decreased the enantioselectivity (entry 4 vs 10). Interestingly, mono-substituted pyrrolidinylmethyl diamines 18 h, and 18 i provided only traces of by-product 17 which stems from their low tendency to add to vinyl bisACHTUNGRE(sulfone) 4 (entries 11–12). However, diamines 18 h and 18 i gave Michael adduct 12 a in low yield (entries 11–12). In this series, the tertiary amine had to be composed of a morpholine moiety to achieve good enantioselectivity (entry 11 vs entry 12). Moreover, neither l-proline nor diphenylprolinol 18 j afforded the desired Michael adduct 12 a (entries 13– 14). From these results, iPBP 18 a was found to be the best catalyst for the reaction (Table 2, entry 4). Influence of the solvent as well as catalyst loading were next evaluated (Table 3). Chlorinated solvent (CHCl3, CH2Cl2) achieved the highest yields and enantioselectivities (entries 1–3). The use of anhydrous CHCl3 decreased the amount of by-product 17 with respect to purum CHCl3 (entry 2 vs entry 1). All other solvents tested were rather disappointing. No conversion was obtained with anhydrous CH3CN (entry 5), whilst MeOH (entry 4) or anhydrous THF (entry 6) provided lower yields and ee values in comparison to anhydrous CHCl3 which gave the best results (entry 2). It should be emphasized that the enantioselectivity and chemical yield including proportion of by-product 15 depends on the catalyst loading. The greater the quantity of iPBP 18 a employed, the better the enantioselectivity and the yield (entries 2, 7–11). Hence, 25 mol % of iPBP 18 a in CHCl3 was the best compromise with regard to selectivity and reactivity (entry 2). Other experiments concerning the concentration of aldehyde 8 a and sequence of reagent addition were conducted (Table 4). As widely described,[1, 2] the larger the concentration of aldehyde, the cleaner the reaction and the better the enantioselectivity (entry 1 vs entries 3–4). The excess of aldehyde forces an equilibrium favouring the Michael adduct, and consequently restricting side reactions. The requirement of a large excess of aldehyde was confirmed by the slow addition of isovaleraldehyde 8 a which led to many by-products (entry 2). Finally, the slow addition of vinyl bisACHTUNGRE(sulfone) 4  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2009, 15, 3204 – 3220 Enantioselective Organocatalysis FULL PAPER Table 3. Effect of solvent and catalyst loading. Entry Catalyst loading [mol %] [c] 1 2[e] 3 4 5 6 7 8 9 10 11 25 25 25 25 25 25 5 10 15 30 40 Solvent T [8C] CHCl3 CHCl3 CH2Cl2 MeOH CH3CN THF CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 60 60 78 60 45 78 60 60 60 60 60 Table 4. Effect of aldehyde concentration and sequence of reagent addition. ee[b] [%] Yield[a] [%] [d] 71 (18) 71 (13)[d] 50 (23)[d] 65 (18)[d] n.d.[f] 15 (19)[d] 15 (4)[d] 40 (13)[d] 68 (11)[d] 70 (19)[d] 70 (20)[d] 75 75 66 35 n.d.[f] 15 34 34 52 75 80 [a] Isolated yields after purification by column chromatography on Florisil. [b] ees were determined by chiral SFC. [c] Purum CHCl3 without prior purification. [d] Proportion of tetrasulfone by-product 17 determined by 1H NMR of the crude material. [e] CHCl3 extra dry, with molecular sieves, filtered over basic alumina. [f] Not determined. suppressed the formation of by-product 17, but with a decrease of enantiomeric excess (entry 5). Entry 1 2[d] 3 4 5[f] Equivalent aldehyde 8 a 10 10 2 5 10 Yield[a] [%] [c] 71 (13) n.d.[e] 43 (33)[c] 53 (25)[c] 78 (0)[c] ee[b] [%] 75 n.d.[e] 45 58 63 [a] Isolated yields after purification by column chromatography on Florisil. [b] ees were determined by chiral SFC. [c] Proportion of tetrasulfone by-product 17 determined by 1H NMR of the crude material. [d] Slow addition of isovaleraldehyde 8 a (1 h30). [e] Not determined (sluggish reaction). [f] Slow addition of vinyl bisACHTUNGRE(sulfone) 4 (1 h 30 min). organocatalyst led to a,a-dimethyl-g,g-sulfonyl aldehyde 12 f in good yield (entry 6). The differentiation between methyl and ethyl in 3-methylbutyraldehyde 8 g was obviously not enough to provide good stereocontrol (entry 7). Finally, 2phenylpropionaldehyde 8 h reacted very slowly with no selectivity, probably due to the enolizable benzylic protons under basic catalysis (entry 8). Improved conditions and catalyst for ACA of aldehydes to ACA of aldehydes to vinyl sulfones catalyzed by iPBP— vinyl sulfones—Diphenylprolinol silyl ether: Although we Scope of aldehydes: With the optimized conditions in hand have demonstrated the efficiency of the first organocatalytic for iPBP 18 a catalyst, we next enlarged the scope of the reACA of aldehydes to vinyl sulfones in terms of yield and reaction with a variety of aldehydes (Table 5). Overall, the activity, the previous set of reaction conditions was substrate asymmetric induction depended on the steric bulk of the aldependent and ee values higher than 80 % could not be dehyde partner. Isovaleraldehyde 8 a and 2-cyclohexylacetalreached using iPBP 18 a (Table 5). With a view to improving dehyde 8 b afforded their respective adducts 12 a and 12 b in our methodology, we were interested in (S)-diphenylprolinol good yields and enantioselectivities (entry 1–2). The best asymmetric outcome was attained using bulkier 3,3-dimeTable 5. ACA of aldehydes 8 a–h to vinyl bisACHTUNGRE(sulfone) 4 catalyzed by iPBP 18 a. thylbutyraldehyde 8 c, with 80 % ee (entry 3). Linear aldehyde such as valeraldehyde 8 d produced adduct 12 d in good yield but with moderate enantiomeric excess (entry 4). Although substrate 8 e showed similar reactivity, no stereoselectivity was observed Entry Aldehyde/Product R1 R2 Reaction conditions Yield[a] [%] ee[b] [%] (entry 5). This methodology 1 8 a/12 a iPr H 60 8C, 2 h 71 75 (+)[c] was also applied to the chal71 70 (+)[c] 2 8 b/12 b cHex H 60 8C, 2 h lenging formation of quaterna3 8 c/12 c tBu H 60 8C, 2 h 78 80 (+)[c] 76 53 (+)[c] 4 8 d/12 d nPr H 60 8C, 2 h ry carbon centers with a,a-dis72 0[d] 5 8 e/12 e Me H 60 8C, 2 h ubstituted aldehydes but re6[e] 8 f/12 f Me Me RT, 1 h 73 – quired a higher temperature 7 8 g/12 g Et Me RT, 4 h 59 12 (+)[c] (RT) for complete conversion 8 8 h/12 h Ph Me RT, 7 h 14 (15)[f] 0 (entries 6–8). Thus, the reac[a] Isolated yields after purification by column chromatography on Florisil. [b] ees were determined by chiral tion of isobutyraldehyde 8 f as SFC. [c] Sign of the optical rotation. [d] ee determined on the corresponding primary alcohol 31 e. [e] Reaction nucleophile and pyrrolidine as performed with 50 mol % of pyrrolidine. [f] Conversion determined by 1H NMR of the crude material. Chem. Eur. J. 2009, 15, 3204 – 3220  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 3207 A. Alexakis et al. silyl ether 18 k for promoting ACA of isovaleraldehyde 8 a to vinyl bisACHTUNGRE(sulfone) 4 (Table 6). Indeed, catalyst 18 k was extensively explored by Jørgensen in various organocatalytic reactions,[25] and innovatively reported by Hayashi as an exceptional catalyst for the Michael reaction of aldehydes to nitroolefins.[7f] Pleasingly, (S)-diphenylprolinol silyl ether 18 k was found to induce particularly high stereocontrol for the ACA of isovaleraldehyde 6 a to vinyl bisACHTUNGRE(sulfone) 4. Thus, the Michael adduct 12 a was obtained in high yield (88 %), with excellent enantioselectivity and without the formation of tetrasulfone by-product 17 (93 % ee; Table 6, entry 1). (S)-Diphenylprolinol silyl ether 3 a was revealed to be an especially active catalyst owing to its bulky substituents. It is worth noting that (S,S)-iPBP 18 a and (S)-diphenylprolinol silyl ether 18 k afforded the same major enantiomer (+)-(S)-12 a which involves the same facial selectivity according to steric shielding (See Section on DFT Calculations). Table 6. ACA of isovaleraldehyde 8 a to vinyl bisACHTUNGRE(sulfone) 4 catalyzed by (S)-diphenylprolinol silyl ether 18 k; optimisation of reaction conditions. Yield[a] ee[b] T [8C] [%] [%] Entry Equivalent aldehyde 8 a Cat. loading [mol %] Solvent 1 10 25 CHCl3 2 3 4 5 6 10 10 10 10 10 25 25 25 25 25 7 8 9 10 10 10 10 2 10 5 1 10 hexane 60 toluene 60 toluene 78 RT CHCl3 H2O/EtOH RT (95:5) CHCl3 60 CHCl3 60 60 CHCl3 60 CHCl3 60 88 81 87 87 83 45 93 (+)[c] 87 93 92 90 72 90 89 90 89 92 91 86 89 [a] Isolated yields after purification by column chromatography on Florisil. [b] ee values were determined by chiral SFC. [c] Sign of the optical rotation. Our next task was optimize the reaction conditions for catalyst 18 k (Table 6). A short solvent survey revealed the suitability of nonpolar solvents (entries 1–3). The best results in terms of yields and enantioselectivity were achieved with both chloroform (entry 1) and toluene (entry 3). When the reaction in toluene was performed at a lower temperature ( 78 8C), no improvement was observed (entry 3 vs 4). For practical purposes, chloroform was chosen as the solvent in the subsequent studies. To our delight, the reaction in chloroform could also be carried out at room temperature with conservation of high yield and enantioselectivity (entry 1 vs 5). However, changing chloroform to a mixture of H2O/EtOH (95:5)[26] drastically decreased either yield or enantiomeric excess (entry 5 vs 6). The catalyst loading 3208 www.chemeurj.org could be reduced to 10 mol % or even to 5 mol %, without compromising both yield and enantioselectivity (entries 7– 8). Due to the fact that we were interested in performing these reactions on a large scale, it was pleasing to find that only 1 mol % of (S)-diphenylprolinol silyl ether 18 k was required to provide Michael adduct 12 a in 90 % yield and with 86 % ee (entry 9). Finally, it is worthy of note that the reaction could also be performed using only 2 equivalents of isovaleraldehyde 8 a with still high yield and ee (entry 10). To probe the scope of the improved methodology, a broad range of aldehydes was next considered (Table 7). Extensive variation in steric demands of the aldehyde substituent can be realized, affording g-gem-sulfonyl aldehydes 12 a–e, i–j in good yields (77–90 %) and with high enantioselectivities (76–98 % ee; entries 1–7). Once again, hindered aldehydes accessed the highest ee values, with up to 98 % ee for 3,3-dimethylbutyraldehyde 8 c (entries 1–3). Not only branched aldehydes (entries 1–3) but also linear aldehydes, such as valeraldehyde 8 d and propionaldehyde 8 e can also be employed to reach good enantioselectivity (entries 4–5). Interestingly, the allyl moiety can be introduced with good level of stereocontrol (entry 6). From a synthetic point of view, (Z)-undec-8-enal (8 j), bearing a cis double bond, gave the Michael adduct 12 j in good yield and with 93 % ee (entry 7). Table 7. ACA of aldehydes 8 a–e, i–j to vinyl bisACHTUNGRE(sulfone) 4 catalyzed by (S)-diphenylprolinol silyl ether 18 k. Entry Aldehyde/Product R1 Yield[a] [%] ee[b] [%] 1 2 3 4 5 6 6 a/10 a 6 b/10 b 6 c/10 c 6 d/10 d 6 e/10 e 6 i/10 i iPr cHex tBu nPr Me allyl 90 86 90 87 85 88 92 83 98 85 76 92 7 6 j/10 j 77 93 [a] Isolated yields after purification by column chromatography on Florisil. [b] ees were determined by chiral SFC. (S)-Diphenylprolinol silyl ether 18 k also proved to be an efficient catalyst for the straightforward construction of chiral quaternary carbon centers with a,a-disubstituted aldehydes (Table 8). Despite the unfruitful preliminary result with 3-methylbutyraldehyde 8 g (entry 1), we anticipated that higher differenciation between the a-substituents would provide better stereoinduction. Pleasingly, 2-phenylpropionaldehyde[27] 8 h underwent reaction with vinyl bisACHTUNGRE(sulfone) 4 in good yield and with promising enantiomeric excess de-  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2009, 15, 3204 – 3220 Enantioselective Organocatalysis FULL PAPER Table 8. ACA of aldehydes 8 g–h, k–l to vinyl bisACHTUNGRE(sulfone) 4 catalyzed by (S)-diphenylprolinol silyl ether 18 k. Entry Aldehyde/Product R1 R2 Yield[a] [%] ee[b] [%] 1 2 3 4 6 g/10 g 6 h/10 h 6 k/10 l 6 l/10 l Et Ph 1-naphthyl cHex Me Me Me Me 75 78 76 71 12 47 91 64 [a] Isolated yields after purification by column chromatography on Florisil. [b] ees were determined by chiral SFC. spite the presence of a very labile proton at the a-position of the carbonyl (entry 2). Replacement of phenyl group with the bulkier 1-naphthyl group resulted in a higher enantioselectivity of 91 % ee (entry 3). By grafting cyclohexylmethyl appendages, chiral quaternary carbon center was formed in good yield and with 64 % ee (entry 4). Thus, we have demonstrated that our methodology is also suitable for chiral quaternary carbon center formation, reaching to good enantioselectivity. Consistently, higher yields and ee values were achieved with (S)-diphenylprolinol silyl ether 18 k in comparison to (S,S)-iPBP 18 a The most obvious cases were represented by propionaldehyde 8 e and 2-phenylpropionaldehyde 8 h for which (S,S)-iPBP 18 a could induce any stereoinduction whereas catalyst 18 k generated moderate to good enantioselectivities (Table 5, entry 5 vs Table 7, entry 5 and Table 5, entry 8 vs Table 8, entry 2). Citronellal 8 m was then selected as donor partner in order to examine the plausibility of kinetic resolution (Scheme 3). Racemic ( )-citronellal 8 m underwent reaction with vinyl bisACHTUNGRE(sulfone) 4 with excellent enantioselectivity with respect to the diastereomers but without significant selectivity in the kinetic resolution [dr syn/anti 40:60, Scheme 3, Equation (1)]. By performing the reaction with enantiopure (S)-citronellal 8 m, the Michael adduct (2S,3S)12 m is obtained in nearly pure form [ > 99 % ee, Scheme 3, Equation (2)].[28] It is worth noting that a higher enantioselectivity for Michael adduct (S,S)-12 m was observed when the reaction is performed with pure (S)-citronellal 8 m and (S)-18 k catalyst in comparison with racemic ( )-citronellal 8 m [Scheme 3, Equation (2) vs (1). This can be considered as a match situation between (S)-citronellal and (S)-18 k catalyst. From the result obtained with racemic ( )-citronellal 8 m, it seems that (R)-citronellal 8 m and the same catalyst does not afford as high diastereoselectivity. In this mismatch combination, the formation of the minor (R,R)-diastereomer 12 m affects the optical purity of of (S,S)-12 m obtained from (S)-citronellal 8 m. Therefore, the observed ee of (S,S)-12 m obtained from the racemic citronellal is lower than expected, and this can also explain the 40:60 diastereomeric ratio. Compound 12 m constitutes a highly useful chiral intermediate for the synthesis of natural products due to its citronellal scaffold improved by the introduction of a versatile gem-sulfonyl group.[29] ACA of aldehydes to vinyl phosphonates—Reactivity: to broaden the scope of our methodology and to confirm our hypothesis on the requirement of bis-activated Michael acceptors, vinyl phosphonates were selected as electrophilic olefins. We initially evaluated the reactivity of vinyl phosphonates 6–7 in the conjugate addition of isovaleraldehyde 8 a using pyrrolidine as catalyst (Scheme 4). As previously emphasized for vinyl sulfones, we found that the Michael reaction was only effected with vinyl bis(phosphonate) 7 (Scheme 4). No reaction occurred with vinyl mono-phosphonate 6 whereas full conversion was achieved in 1 h with vinyl bis(phosphonate) 7 (Scheme 4). Consequently, we assume that the Michael acceptor, with the exception of nitroolefins[7] and methyl vinyl ketone„[7f, 9] should bear geminal bis-electron withdrawing groups in order to enable the aminocatalytic ACA of carbonyl donors. ACA of aldehydes to vinyl phosphonates—Optimisation of reaction conditions: The stereochemical outcome of the ACA of isovaleraldehyde 8 a to vinyl bis(phosphonate) 7 was next explored with a short array of pyrrolidine-core organocatalysts (Table 9). Despite its excellent catalytic activity, iPBP 18 a led to moderate yield and low enantioselectivity no matter the temperature (entries 1–2). It is notable that vinyl bisACHTUNGRE(sulfone) 4 is more reactive than vinyl bis(phosphonate) 7 which is underlined by the lack of reactivity at 30 8C of the latter Michael acceptor (Table 5, entry 1 vs Table 9, entry 3). The reaction rate and the enantioselectivity were diScheme 3. ACA of citronellal 8 m to vinyl bisACHTUNGRE(sulfone) 4 catalyzed by (S)-diphenylprolinol silyl ether 18 k. Chem. Eur. J. 2009, 15, 3204 – 3220  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 3209 A. Alexakis et al. Scheme 4. Pyrrolidine-catalyzed conjugate addition of isovaleraldehyde 8 a to vinyl phosphonates 6–7. Comparison of reactivity. Table 9. ACA of isovaleraldehyde 8 a to vinyl bis(phosphonate) 7. Optimization of reaction conditions. Entry Catalyst[a] Reaction conditions Conv.[b] [%] Yield[c] [%] ee[d] [%] 1 CHCl3, RT, 1 h 100 71 31 2 CHCl3, 0 8C, 5 h 100 75 33 (+)[e] 3 CHCl3, 0 – – 4 CHCl3, 0 8C, 24 h 84 55 29 30 8C, 48 h minished when the isopropyl substituent in catalyst 18 a was exchanged by a methyl group in 18 d (entry 4). Although diamine 18 h catalyzed the reaction as fast as diamine 18 a, it was revealed to be unselective (entry 5). Neither l-proline nor (S)-diphenylprolinol 18 j generated the Michael adduct 20 a after 48 h (entries 6–7). Delightfully, (S)-diphenylprolinol silyl ether 18 k was found to induce particularly high stereocontrol for the ACA of isovaleraldehyde 6 a to vinyl bis(phosphonate) 7. The reaction was complete within 12 h at room temperature in the presence of 20 mol % of catalyst 18 k in CHCl3 and furnished Michael adduct 20 a in good yield (80 %) and with excellent enantioselectivity (90 % ee; entry 8). A decrease in the enantiomeric excess (from 90 to 80 % ee) was observed upon decreasing the temperature (entry 8 vs 9). Heating the reaction did not improve the enantiocontrol and decreased the yield (entry 10). Changing CHCl3 to a mixture of H2O/ EtOH (95:5) gave lower yield and selectivity (entry 8 vs 11). The catalyst loading could be reduced to 10 mol % while retaining a high level of enantioselectivity (entry 12). ACA of aldehydes to vinyl phosphonates—Scope of aldehyde: With the optimized conditions in hand (Table 9, entry 8), the generality of the reaction for various aldehydes was demonstrated, with the results summarized in Table 10. Good to high enantioselectivities were obtained with regard to the aldehyde substituent, ranging from 75–97 % ee (entry 1–5). Interestingly, phenetylaldehyde 8 n afforded equally good ee value (entry 4). Unfortunately, pent-4-enal 8 i, bearing a terminal double bond, gave the Michael adduct 20 i in moderate yield and with low enantiomeric excess (entry 6). The challenging formation of quaternary carbon center was achieved in good yield using isobutyralde- Table 10. ACA of aldehydes 8 a, c-f, h, i, n to vinyl bis(phosphonate) 7 catalyzed by (S)-diphenylprolinol silyl ether 18 k. 5 CHCl3, 0 8C, 5 h 100 70 15 6 CHCl3, RT, 48 h 0 – – 7 CHCl3, RT, 48 h 0 – – 8 CHCl3, RT, 12 h 100 80 9 10 11 CHCl3, 0 8C, 18 h CHCl3, 60 8C, 12 h H2O/EtOH (95:5), RT, 12 h CHCl3, RT, 15 h 100 100 100 82 71 49 90 (+)[e] 80 91 83 100 81 85 12 [a] Entries 1–11: 20 mol %, entry 12: 10 mol %. [b] Determined by H NMR of the crude material. [c] Isolated yields after purification by column chromatography on silica gel. [d] ees were determined by 1 H NMR on the corresponding imidazolidines 21 a–22 a derived from Michael adduct 20 a and N,N-dimethyl-1,2-diphenyl ethylene diamine (23), see Scheme 5. [e] Sign of the optical rotation. 1 3210 www.chemeurj.org Entry Aldehyde/Product R1 R2 Yield[a] [%] ee[b] [%] 1 2 3 4 5 6 7[e] 8[f] 8 a/20 a 8 c/20 c 8 d/20 d 8 n/20 n 8 e/20 e 8 i/20 i 8 f/20 f 8 h/20 h iPr tBu nPr Bn Me allyl Me Ph H H H H H H Me Me 80 85 75 81 75 65 80 – 90 (S) (+)[c] 97 86 85[d] 75 46 – – [a] Isolated yields after purification by column chromatography on silica gel. [b] ees were determined by 1H NMR on the corresponding imidazolidines 21–22 derived from Michael adduct 20 and 23, see Scheme 5. [c] Sign of the optical rotation. [d] ee was confirmed by chiral SFC. [e] Performed with 20 mol % of pyrrolidine. [f] No conversion was observed after 48 h at RT.  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2009, 15, 3204 – 3220 Enantioselective Organocatalysis FULL PAPER hyde 8 f as nucleophile and pyrrolidine as organocatalyst (entry 7). However, phenylpropionaldehyde 8 h was not reactive enough to undergo the conjugate addition (entry 8). Determination of the ee of g-gem-phosphonate aldehydes: In view of the high molecular weight and non-UV active groups in Michael adducts 20, the optical purity could not be attributed by usual chiral separative techniques. Consequently, the enantiomeric excess of g-gem-phosphonate aldehydes 20 was determined by 1H NMR analysis through the formation of diastereomeric imidazolidine 21–22 with (R,R)-diamine 23 (Scheme 5).[30, 31] Scheme 5. Determination of the ee of g-gem-phosphonate aldehydes 20. 21 a–22 a, the 1H NMR spectrum of diastereomeric imidazolidines 24 a–25 a shows a major deshielded signal and a minor shielded one for the same benzylic proton. Consequently, we ascribed the (S) absolute configuration to the (+)-Michael adduct 20 a and the same spatial arrangement was assumed for the other products 20. Synthetic utility of g-gem-sulfonyl aldehydes and determination of their absolute configuration: the applicability of ggem-sulfonyl aldehydes as highly tunable synthons was illustrated by a variety of synthetic transformations involving the aldehyde as well as the sulfonyl groups. The large scale synthesis of the chiral Michael adduct 12 a was carried out with only 1 mol % of (S)-diphenylprolinol silyl ether 18 k with still high level of enantioselectivity (85 % ee). We first chose to selectively manipulate the aldehyde functionality. The Michael adduct (S)-12 a with 85 % ee was easily oxidized into carboxylic acid 26 a in 95 % yield after a brief KMnO4 exposure with no loss of enantioselectivity. Further transformation into methyl ester 27 a was achieved in high yield by the addition of TMSCHN2 to confirm the optical purity of 84 % ee (Scheme 7).[33] The use of (R,R)-diamine 23 for the derivatization of chiral aldehydes 20 provides 1H and 31P NMR spectra with different signals for each diastereomeric imidazolidine 21 and 22.[32] Very mild conditions are required for this transformation (Et2O, molecular sieves, room temperature) and an excess of (R,R)-diamine 23 was used to avoid kinetic resolution. The enantiomeric excess was determined on the crude diasteromeric imidazolidine mixture 21–22 to prevent the selective enrichment of one diastereoisomer. In one inScheme 7. Methyl ester derivatization of optically active of g-gem-sulfonyl aldehyde 12 a. stance, the enantiomeric excess of the Michael adduct 20 n with a phenyl moiety could be confirmed by supercritical Conversely, Baeyer–Villiger oxidation of the (S)-adduct fluid chromatography (SFC), proving the efficiency of the 12 a followed by saponification of formyl ester compound NMR spectroscopy for determination of the enantiomeric 28 a furnished secondary alcohol 29 a in high yield with perexcess. fect retention of configuration (Scheme 8).[34] We also managed to perform methylenation of aldehyde Determination of the absolute configuration g-gem-phos(S)-12 a with freshly prepared Petasis reagent[35] giving the phonate aldehydes: The absolute configuration of the vinyl derivative 30 a with conservation of the ee (Scheme 9). adduct 20 a was established by analogy with known Michael It is pertinent to note that the corresponding Wittig reagent adduct 12 a, (S)-bis(phenylsulfonyl)ethyl)-3-methylbutanal as well as Horner–Wadsworth–Emmons reagent induced (85 % ee) (Scheme 6). As for diastereomeric imidazolidines only epimerisation of aldehyde (S)-12 a, probably due to their basic propertities. Besides the obvious synthetic utility of the aldehyde moiety, we also considered the transformation of the sulfonyl groups.[36] After suitable reduction and protection of the primary alcohol 31 a as its Scheme 6. Determination of the absolute configuration of g-gem-phosphonate aldehydes 20 a (Scheme 5, R = iPr) by analogy with known g-gem-sulfonyl aldehyde 12 a. TBDMS ether 32 a with reten- Chem. Eur. J. 2009, 15, 3204 – 3220  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 3211 A. Alexakis et al. Scheme 8. Secondary alcohol derivatization of optically active of g-gem-sulfonyl aldehyde 12 a. samarium Barbier reaction gave the desired cyclobutanol 36 a in good yield as a single diastereomer although a small degree of racemisation was observed (Scheme 12). Scheme 12. Synthesis of cyclobutanol 36 a. Scheme 9. Methylenation of optically active of g-gem-sulfonyl aldehyde 12 a. Finally, we were interested in effecting bis-desulfonylation[11h,k–l] by exchanging the sulfonyl groups of primary alcohol 31 a with hydrogens (Scheme 13). Reduction with Raney Nickel[43] even with ultrasound activation led to the recovery of starting material 31 a. Only one sulfonyl group was reductively cleaved with aluminium amalgam (Al/Hg)[44] in 75 % conversion after 5 d. Seemingly, these reducing reagents were not suitable for totally removing non-activated geminal bisACHTUNGRE(sulfones). Fortunately, the bis-desulfonylation can be performed using activated magnesium turnings in MeOH.[45] Hence, alcohol 37 a was obtained in 45 % yield with no loss of enantioselectivity (74 % ee). Usefully, the S absolute configuration of the Michael adduct 12 a was determined by comparison of the optical rotation of the resulting alcohol Scheme 10. Reduction–protection and subsequent monodesulfonylation of optically active of g-gem-sulfonyl al37 a with literature.[46] It was dehyde 12 a. tion of the optical purity, freshly prepared samarium diiodide,[37, 38] efficiently mediated reductive monodesulfonylation of g-gem sulfonyl protected alcohol 32 a to give a potentially nucleophilic reagent 33 a in good yield and with 82 % ee (Scheme 10).[39] It is worth noting that the exact sequence of reagent addition is critical for the reaction. Indeed, addition of gem-sulfonyl compound 32 a to a solution of SmI2 in THF gave only partial conversion (40 %) whereas the reverse addition led to full conversion. Next, a-deprotonation of compound 33 a with KHMDS and subsequent addition of ethyl chloroformate afforded the acylated product 34 a in 74 % yield as a mixture of diastereomers (3:2) with 84 % ee (Scheme 11).[40] Chiral synthon 34 a could easily access enantioenriched valerolactone 35 a which is a ubiquitous structural intermediate in natural product synthesis.[41] We also investigated the intramolecular reductive cyclization of g-geminal bisACHTUNGRE(sulfone) aldehyde 12 a in order to obtain cyclobutanol 36 a which could be an interesting chiral building block for total synthesis.[37b, 42] The intramolecular Scheme 11. Towards the synthesis of enantioenriched valerolactone 35 a. 3212 www.chemeurj.org Scheme 13. Bis-desulfonylation of alcohol 31 a; determination of the absolute configuration of g-gem-sulfonyl aldehydes 12 a. assumed that the spatial arrangement of the other Michael adducts 12 was the same. The absolute configuration of Michael adducts 12 was confirmed by X-ray analysis of carboxylic acid 26 c derived from g-gem-sulfonyl aldehyde 12 c (Figure 2). Many other synthetic transformations of Michael adducts 12 could be envisaged for the remaining aldehyde and sulfonyl groups. For instance, naphthalene-catalyzed lithiation of sulfones and the in situ reaction of the resulting organolithium with aldehydes and halogen compounds could be investigated to broaden the scope of the synthetic utility of Michael adduct 12.[38b, 47] Moreover, the presence of a double  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2009, 15, 3204 – 3220 Enantioselective Organocatalysis FULL PAPER Scheme 14. Functionalization of g-gem-phosphonate aldehyde 20 a; a new route to enantioenriched b-substituted vinyl phosphonate 40 a. Figure 2. X-ray crystal structure of (S)-carboxylic acid 26 c derived from g-gem-sulfonyl aldehyde 12 c. CCDC 662357 (26 c) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif carbon carbon bond on Michael adducts 12 i,j,m supplies new opportunities such as ozonolysis, cross-metathesis, radical cyclization[48] after appropriate transformations. clinal transition state based on Seebachs model[52] in which there are favourable electrostatic interactions between the nitrogen of the enamine and the electron-withdrawing group of the Michael acceptor. As the selectivity depends on steric hindrance, the very bulky diphenyl silyl ether moiety induced better enantioselectivity than the N-iPr-pyrrolidine moiety (93 % ee vs 75 % ee, see Table 6, entry 1 vs Table 5 entry 1). It is worth noting that (S,S)-iPBP 18 a and (S)-diphenylprolinol silyl ether 18 k afforded the same major enantiomer (+)-(S)-12 a which involves the same face selectivity due to steric shielding. The bulky group on the catalyst framework would promote the selective formation of the anti enamine and selective shielding of the Re approach. Consequently, the less hindered Si transition state is well favored compared to the Re and leads to the (S)-12 a adduct (R = iPr) (Scheme 15). Synthetic application of g-gem sulfonyl phosphonates: To illustrate the synthetic utility of this methodology, the enantioenriched g-gem-phosphonate aldehyde 20 a was easily converted into b-substituted vinyl phosphonate 40 a with no loss of enantioselectivity (Scheme 14). Reduction of compound 20 a with NaBH4 and subsequent protection of the primary alcohol 38 a with a TBDMS group affords the corresponding g-gem-phosphonate protected alcohol 39 a in high overall yield. The HWE reacScheme 15. Proposed transition state for the organocatalytic ACA of aldehydes to vinyl bisACHTUNGRE(sulfones) and vinyl tion with aqueous formaldebis(phosphonates) according to steric shielding. hyde using 50 % aqueous NaOH solution[49] provides the The origin of the selectivity in the organocatalytic ACA enantioenriched b-substituted vinyl phosphonate 40 a in high of aldehydes to vinyl sulfones has also been investigated for yield (81 %) with retention of the enantiomeric excess (90 % N-iPr-2S,2’S-bipyrrolidine (iPBP) catalyst by density funcee).[50] This new versatile building block could be involved in tional theory (DFT) using the PBE1PBE/6-31G* method[53] a variety of synthetic transformations such as ozonolysis, cycloaddition, conjugate addition or methyl ketone formawithin the Gaussian03 package.[54] tion.[16, 51] Transition-state modeling by DFT calculations: In the following preliminary account of computational modeling we Proposed transition-state model: The determination of the focus mainly on the structure of the transition states of the absolute configuration allowed us to postulate a Michael acenamine, derived from (S,S)-iPBP 18 a and 3,3-dimethyl buceptor attack from the Si face of the (E)-enamine according tyraldehyde 8 c, and vinyl sulfone 4, since their properties to steric shielding (Scheme 15).[6c, 25a] The selectivity of the can provide the best indications (leads) for understanding of organocatalytic ACA could be explained by an acyclic syn- Chem. Eur. J. 2009, 15, 3204 – 3220  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 3213 A. Alexakis et al. and 3.491 , respectively). The charge build-up on oxygen atoms in the II-TS, together with relatively short distances between the involved atoms, allow for improved electrostatic interactions. Scheme 16. Studied case for the transition state modeling by DFT calculations. During the Re approach (Figure 4), when compared to the reactant, the negative charge on the two crucial oxygen the observed selectivity (Scheme 16) (Computational methatoms decrease in the transition state V-TS with computed ods, see Supporting Information). charges for atoms O3 and O4 of 0.417 and 0.461, respecIndeed, on the reactant side the potential energy surface tively (Figure 4). In addition, the latter oxygen is further for enamines is quite complex, nevertheless the conformaapart from the enamine nitrogen (4.072 ). Such charge detional search provided five low energy minima within a 4 pletion and elongation of oxygen–nitrogen distance is in [kcal mol 1] range. All five minima belong to (E)-enamines contrast with what was observed for the attack of the Si and the lowest energy conformer corresponds to anti enamface. The optimized geometry parameters of V-TS are clearine. Although, the selective steric shielding of the Re face is ly less favorable for the electrostatic interactions between apparent, at least to a certain degree, from the optimized the enamine and sulfone moieties. At the origin of this structure of this reactant, it could not provide a full rationstructural perturbation is the steric hindrance between the ale for the observed selectivity. bulky substituent and the O4. Particularly, one of the hydroOne of the key factors that can enhance the selectivity of gens (attached to C10, see Figure 4) comes into close conthe Michael-acceptor attack of the (E)-enamine is the ability tact with this oxygen atom. This type of unfavorable interacof this system to develop the stabilizing electrostatic interaction is absent in the II-TS structure (Figure 3), setting theretions at the transition state between the nitrogen of the enby the stage for the improved electrostatic interactions and amine and sulfone oxygen atoms. For the reaction pathway providing further stabilization of the transition state for the leading to the Si-face adduct (Figure 3), our modeling reSi approach. Indeed, in the II-TS transition state, the bulky vealed a progressive increase of the negative charge on the substituent is extending its C10 C12 moiety away form the oxygen atoms. When comparing the charges between the reincoming sulfone (Figure 3). actant and transition state II-TS it increased, respectively, from 0.397 to 0.425 for O1 and from 0.409 to 0.438 for O2 (Figure 3). These two oxygen atoms are quite close and equidistant with respect to the enamine nitrogen (3.428 Figure 3. Schematic energy profile for ACA to the Si face of the (E)-enamine, together with the optimized structure (top) of the transition state. 3214 www.chemeurj.org Figure 4. Schematic energy profile for ACA to the Re face of the (E)-enamine, together with the optimized structure (top) of the transition state.  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2009, 15, 3204 – 3220 Enantioselective Organocatalysis FULL PAPER The present modeling can also be used to evaluate whether the tert-butyl substituent on the enamine can additionally be involved in the face selectivity of the vinyl sulfone addition. Indeed, for the vinyl sulfone approach to the Re face, one of the vinyl hydrogens develop two close contacts with the tert-butyl substituent. In the V-TS geometry (Figure 4), this steric hindrance translates into H····H distances of 1.966 and 2.258 . Again the analogous steric interference is less severe in the II-TS transition state of the Si face attack (Figure 3). Figure 5. ee Values (&) as a function of time, conversion: ~. The favorable and unfavorable interactions described above are reflected in clearly different energy barriers for time gave a near straight line (&) which indicates there is no the two modes of addition. Expressed in terms of relative epimerisation during the reaction. energies, the barrier for the vinyl sulfone 4 addition to the The absence of racemisation was also previously deterSi face amounts to 2.4 kcal mol 1, while the barrier for the mined by observing that the ee of aldehyde 12 a was almost Re approach is 5.3 kcal mol 1 higher. The incorporation of similar to the one of the corresponding primary alcohol 31 a the ZPE correction only marginally changes the energy pro(see Scheme 10). In accordance with Jørgensens explanatiofile. Since all stationary points of the potential energy surn,[25a] the stability of the chiral center during the reaction face were characterized by the vibrational analysis, we were could arise from the steric hindrance of the aminocatalyst able to apply the thermal corrections and compute the free (S,S)-iPBP 18 a and especially (S)-diphenylprolinol silyl energy (right column in Table 11). When comparing the free ether 18 k.[25a] This undesired pathway is generally prevented energies, the energy difference DDG between the two transibecause the formation of the bulky disubstituted enamine tion states further increased to 6.8 kcal mol 1. These prelimispecies VIII is disfavored in comparison to the iminium VII nary DFT results not only correlate well with the reported hydrolysis leading to enantioenriched Michael adduct 12 experimental results, but they also provide the rationale for (Scheme 17). This phenomenon is also in agreement with kithe origin of the observed selectivity. The modelling of the netic control. solvent effects is currently in progress. To obtain further information on the influence of kinetic control in our reaction, Michael adduct 12 a (75 % ee) was subjected to standard conditions [Scheme 18, Eq. (1)]. NeiTable 11. Relative energies and relative free energies [kcal mol 1] for ther variation of enantiomeric excess nor formation of vinyl ACA to (E)-enamines at the PBE1PBE level of theory. bisACHTUNGRE(sulfone) 4, that is, retro-addition, were observed which [a] [b] [c] DEACHTUNGRE(ZPE) DG Face Species DE corroborates our kinetic control hypothesis. This trend was Si Re I II-TS III IV V-TS VI 0.0 2.4 14.1 0.0 7.7 7.6 0.0 3.3 11.1 0.0 8.6 4.5 0.0 6.2 7.8 0.0 13.0 0.3 [a] Relative energies. [b] ZPE corrected relative energies. [c] Relative free energies at 25 8C. Mechanistic insights: In order to establish the role of (S,S)iPBP in ACA, we investigated advanced mechanistic studies on this catalytic system. The stability of the chiral center in the product is as important as its enantioselective formation. Consequently, we first conducted an epimerisation study by monitoring the enantiomeric excess as a function of time (Figure 5). Plotting the ee of the Michael adduct 12 a versus Chem. Eur. J. 2009, 15, 3204 – 3220 Scheme 17. Proposed transition state for the organocatalytic ACA of aldehydes to vinyl bisACHTUNGRE(sulfones) and vinyl bis(phosphonates) according to steric shielding.  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 3215 A. Alexakis et al. uct 17. Indeed, the introduction of (S,S)-iPBP 18 a last to the reaction mixture at 60 8C prevented the formation of tetrasulfone 17 (Figures 6 and 8). This result was experimentally confirmed and led to an increase of the chemical yield from 71 to 82 %. Unfortunately, no improvement of enantioselectivity was observed showing that the structure of the catalyst or more precisely its steric hindrance mainly governs the stereoinduction. Unfortunately, neither iminium 42 nor enamine 43 intermediates (Figure 9) were detected by these 1 H NMR experiments (Figure 6). However, the formation of the enamine intermediate 43 derived from isovaleraldehyde Scheme 18. Evaluation of kinetic control. confirmed by reacting a less hindered aldehyde such as valeraldehyde 6 d and compound 12 a which led only to the recovery of Michael adduct 12 a with no loss of enantioselectivity [Scheme 18, Eq. (2)]. NMR spectroscopy was also investigated to gain insight Figure 8. 1H NMR study: addition of (S,S)-iPBP 18 a to a mixture of isovaleraldehyde 8 a and vinyl bisACHTUNGRE(sulfone) 4. into the intermediates of the catalytic cycle. Preliminary results indicated the formation of by-product 17 in large amounts (Hb) and the addition of (S,S)-iPBP 18 a to vinyl bisACHTUNGRE(sulfone) 4 which trapped the catalyst as product 41 (Ha) (Figures 6 and 7). The reaction evolved into a 1:4 ratio of Michael adduct 12 a to by-product 17, suggesting a slow transformation of trapped catalyst 41 Figure 9. Iminium 42 and enamine 43 derived from isovaleraldehyde 8 a into the desired 1,4-adduct 12 a. and and (S,S)-iPBP 18 a. It is clear that the temperature as well as the sequence of reagent addition could influence the proportion of by-prod6 a and (S,S)-iPBP 18 a during the reaction was confirmed by ESI-MS method (see Supporting Information). Finally, we studied linear/non-linear effects in ACA of isovaleraldehyde 8 a to vinyl bisACHTUNGRE(sulfone) 4 catalyzed by (R,R)iPBP 18 a (Figure 10). Plotting the ee value of catalyst 18 a versus that of the Michael adduct 12 a gave a slight negative non-linear relationship. Diastereomeric active species are not in accordance with our transition sate model based on Figure 6. Identified compounds by NMR spectroscopy. steric shielding in which there is probably no H-bonding or aggregation in solution. No solid phase was observed excluding an explanation by physical phase behavior.[55] Appa- Figure 7. 1H NMR study: Addition of isovaleraldehyde 8 a to a mixture of vinyl bisACHTUNGRE(sulfone) 4 and (S,S)-iPBP 18 a. 3216 www.chemeurj.org Figure 10. Slight non-linear effect in the ACA of isovaleraldehyde 6 a to vinyl bisACHTUNGRE(sulfone) 4 catalyzed by (R,R)-iPBP 18 a.  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2009, 15, 3204 – 3220 Enantioselective Organocatalysis FULL PAPER rently, there is neither epimerisation nor influence of the addition of the enantioenriched Michael adduct 12 a in the reaction conditions suggesting that there is no interaction between the chiral catalyst and the chiral product (see Figure 5 and Scheme 17). However, reversible trapping of the catalyst as compound 41 (Figure 6) could decrease the amount of available catalyst and consequently this phenomenon of reservoir effect would explain the observed negative nonlinear effect. Conclusion We are in the “golden age of organocatalysis”, and organocatalytic reactions are recognized as a powerful tool for the preparation of optically active compounds. The use of chiral amines such as pyrrolidine analogues for the enantioselective Michael reaction via enamine activation represents an important breakthrough in modern asymmetric synthesis. We have demonstrated the high potential of the organocatalytic ACA via enamine activation by expanding the scope of Michael acceptors. Hence, we disclosed the first intermolecular enantioselective organocatalytic conjugate addition of aldehydes to vinyl sulfones and vinyl phosphonates with high enantioselectivity. The principle of double activation through the presence of geminal electron-withdrawing groups on the olefin was demonstrated for inducing reactivity. Although 2,2’-bipyrrolidine derivatives 18 a–e proved to be interesting organocatalysts for these reactions (up to 80 % ee), a catalytic system with diphenylprolinol silyl ether 18 k is more flexible allowing the reaction to proceed without the formation of by-products in various solvents and with excellent enantioselectivity regardless of temperature, catalyst loading, the quantity of aldehyde, or nature of aldehyde (up to 99 % ee). We were also gratified to see that our methodology proceeded efficiently towards the formation of chiral quaternary carbon centers (up to 91 % ee). The determination of the absolute configuration as well as DFT calculations allowed us to postulate a Si transition state via an acyclic synclinal Seebachs model. Hence, the asymmetric induction depends on highly steric shielding involving an enamine intermediate. This novel enantioselective organocatalytic ACA led to optically active g-gem-sulfonyl aldehydes and g-gem-phosphonate aldehydes as useful tunable chiral synthons as exemplified by various functionalizations with conservation of the optical purity. Experimental Section For experimental procedures, characterizations, chiral separations, crystallographic information files (CIF) and DFT calculations, see Supporting Information. ACA of aldehydes to vinyl sulfones (General procedure 1): To a solution of 1,1-bis(benzenesulfonyl)ethylene (4; 50 mg, 0.162 mmol, 1 equiv) in dry chloroform filtered on basic alumina (1.5 mL) was added aldehyde 8 (1.62 mmol, 10 equiv) at the appropriate temperature, and then pyrrolidine (0.08 mmol, 50 mol %) or diphenylprolinol silyl ether 18 k Chem. Eur. J. 2009, 15, 3204 – 3220 (0.0162 mmol, 10 mol %). The evolution of the reaction was controlled by TLC until completion. The solution was hydrolysed with sat. aq. NH4Cl (2 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3  3 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash column chromatography on Florisil using a mixture of cyclohexane (c-Hex) and ethyl acetate (AcOEt). (2S)-Bis(phenylsulfonyl)ethyl)-3-methylbutanal (12 a): From isovaleraldehyde (8 a; 1.62 mmol, 10 equiv, 0.18 mL), 1,1-bis(benzenesulfonyl)ethylene (4; 0.162 mmol, 1 equiv, 50 mg) and 18 k (0.0162 mmol, 10 mol %, 5.3 mg) according to GP 1 (2 h, 60 8C) to give a yellow oil as crude product which is purified by column chromatography on Florisil (c-Hex/ AcOEt 2:1) to obtain a pale yellow oil (57.5 mg, 90 %). The enantiomeric excess was determined by chiral SFC (chiralcel OJ column, 2 mL min 1, 200 bar, MeOH 10 %-2–1–25 %, 30 8C, tR = 4.14 (R), 5.80 min (S)); [a]20 D = + 44.5 (c = 1.45 in CHCl3, 92 % ee); 1H NMR (400 MHz, CDCl3): d = 9.59 (s, 1 H), 7.96–7.88 (dd, J = 24.1, 7.4 Hz, 4 H), 7.73–7.67 (m, 2 H), 7.60–7.53 (m, 4 H), 4.71–4.68 (dd, J = 9.1, 3.1 Hz, 1 H), 2.94–2.90 (m, 1 H), 2.54–2.47 (m, 1 H), 2.17–2.11 (m, 2 H), 0.99 (d, J = 7.1 Hz, 3 H), 0.94 ppm (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 203.99 (1 CHO), 137.89 (1 Cquat.), 137.74 (1 Cquat.), 134.75 (1 CH), 134.57 (1 CH), 129.78 (1 CH), 129.37 (1 CH), 129.186 (1 CH), 129.14 (1 CH), 80.55 (1 CH), 54.67 (CH), 28.62 (1 CH), 21.51 (1 CH2), 19.84 (1 CH3), 19.04 ppm (1 CH3); MS (EI mode): m/z (%): 396 (1), 225 (28), 169 (12), 145 (14), 143 (25), 141 (11), 134 (13), 125 (49), 97 (15), 91 (17), 83 (19), 81 (10), 79 (12), 78 (25), 77 (100), 69 (13), 67 (10), 55 (35), 51 (35); IR (CHCl3): ñ = 3065w, 3020w, 2964w, 2928w, 2873w, 1724s, 1585m, 1448m, 1331s, 1311m, 1157s, 1079s cm 1. HRMS (ESI): m/z: calcd for C19H22O5S2 417.08046, found 417.08063 [M+Na] + . For the other Michael adducts 12 and their derivatives, see Supporting Information. ACA of aldehydes to vinyl phosphonates (General procedure 2): To a solution of tetraethyl ethylidenebis(phosphonate) (7; 100 mg, 0.33 mmol, 1 equiv) in CHCl3 (3 mL) was successively added aldehyde 8 (3.33 mmol, 10 equiv) and then pyrrolidine (0.066 mmol, 20 mol %) or 18 k (0.066 mmol, 20 mol %) at RT. The reaction was monitored by TLC until complete conversion. The reaction mixture was hydrolyzed with aq. sat. NH4Cl (2 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (2  3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel (CH2Cl2/EtOH 9:1) to afford 1,4-adduct 20. The enantiomeric excess were determined by 1H and 31P NMR on imidazolidine 21–22 which were prepared by adding successively molecular sieves and N,N-dimethyl1R,2R-diphenyl ethylene diamine (23; 25 mg, 0.103 mmol, 4 equiv) to a solution of compound 20 (10 mg, 0.025 mmol, 1 equiv) in diethyl ether (3 mL) at room temperature. After stirring overnight at room temperature, the reaction mixture was filtered over Celite, washed with diethyl ether (2  5 mL) and concentrated in vacuo to give the diastereomeric mixture of imidazolidine 21–22 (quant.). (S)-2-Isopropyl-4,4’-ethylphosphonate-butanal (20 a): Compound 20 a was prepared from 7 and isovaleraldehyde 8 a according to GP 2. After purification, compound 20 a was obtained as a pale yellow oil (102 mg, 80 %). The enantiomeric excess was determined by 1H and 31P NMR on imidazolidines 21 a–22 a derived from compound 20 a and (R,R)-diamine 23: 1 H NMR (400 MHz, C6D6): d = 4.57–4.55 (R,R,S), 4.51–4.48 ppm (R,R,R); 31P NMR (162 MHz, C6D6): d = 25.75 (R,R,S), 25.41–25.21 ppm (R,R,R). The absolute configuration of compound 20 a was established by analogy with imidazolidines 269 b–270 b derived from known Michael adduct (S)-bis(phenylsulfonyl)ethyl)-3-methylbutanal (12 a; 85 % ee) and 1 imidazolidines 24 a–25 a. [a]20 H NMR D = + 21.5 (c = 1.05 in CHCl3); (400 MHz, CDCl3): d = 9.67 (d, J = 1.52 Hz, 1 H), 4.21–4.14 (m, 8 H), 2.82–2.77 (m, 1 H), 2.51–2.21 (m, 2 H), 2.19–2.05 (m, 1 H), 1.99–1.87 (m, 1 H), 1.36–1.02 (m, 12 H), 1.00 (d, J = 10.1 Hz, 3 H), 0.98 ppm (d, J = 6.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 204.92 (1 CHO), 63.12– 62.72 (m, 4 CH2), 56.16–56.02 (m, 1 CH), 34.61 (t, 1 CH), 28.88 (1 CH), 21.62 (1 CH2), 20.10 (1 CH3), 19.53 (1 CH3), 16.61–16.55 ppm (m, 4 CH3); 31 P NMR (162 MHz, CDCl3): d = 23.41–23.12 ppm; MS (EI mode) m/z  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 3217 A. Alexakis et al. (%): 386 (2), 357 (11), 289 (119, 288 (100), 261 (32), 249 (20), 242 (15), 233 (14), 215 (17), 177 (12), 165 (10), 159 (13), 152 (51), 109 (11), 41 (12), 29 (17); HRMS (EI): m/z: calcd for C15H32O7P2 : 386.162331 and found 386.161380 [M] + . For the other Michael adducts 20 and their derivatives, see Supporting Information. 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