aber: Asymmeny 242013) 553-542 ELSEVIER journal homepag: Content lists available at SeiVerse ScienceDirect, Tetrahedron: Asymmetry & www-elsevier.com/locateste Additive-controlled regioselective direct asymmetric aldol reaction of hydroxyacetone and aldehyde Ling-yan Liu, Bing Wang, Yunna Zhu, Wei-xing Chang, Jing Li* 1 of lemente Ogee Chis, Nan University, Wein Reed, Nankt District Tee 30071, P Chine ‘stzaceraiy simple dipeptide derivative Wo prepared fom proline and valine has been developed for the dizect asymmetric aldol reaction of hydrexyacetone and various aldehydes with moderate to hi Yields and high enantoselectivities, More importantly, this regioselective reaction could be easly regulated by changing the additives inthe presence ofthe same organocatalyst Tb, to afford the normal 1 2diol adducts and the distavoured 14-diol products. respectively ina highly regioselective fashion. A possible react mechanism has also been propose, © 2013 Elsevier Lid llrightsreserved 1. Introduction Since the first report of the protine.catalyzed direct asymmetric aldol reaction,’ many organocatalysts have been designed and syn- thesized in order to improve the catalyst reactivity, the enantiose- lectivity, and the substrate scope Since then, the organocatalysis reaction has been rapidly developed over the last few decades. In this field, the use of hydroxyacetone as a donor in organocatalyzed direct aldol reactions, which generate polyoxygenated compounds, chiral 12-diols or 1,4-diols, which are common structural motifs found in a vast array of natural and biologically active molecules, has been the subject of increasing research and is still regarded HO, 40" basinal dexamethasone TF Garresponcing author. Te: +96 222350 5051/1430. mal déresesilngyanBnanka ede (Li) hingPnankaieda. Ly o857-a6)8 se iter © 2015 Elsevier Led Al gs reserved as an interesting synthetic challenge (Fig. 1)? So far, high levels of enantioselectivity have been achieved for both the syn and anti products by utilizing chiral catalysts derived from primary and sec- ‘ondary amines including multipeptides or prolinamides.* Despite ‘hese important advances, some limitations stl exist. For example, aldol reaction donors are limited to the protected hydroxy- and ihydroxy-acetones. The development of stereoselective organo- catalysts for direct aldol reactions with unprotected hydroxyke- tones still remains an important goal because of enantio- and chemoselectivity issues. In addition, it should be noted that this reaction between an hydroxyacetone and an aldehyde usually fives a 1,2-diol product and hardly any 1.4-diol compound whichey ti et a Terhedon: Aymmety 24 (203) 533-542 © cooe: owe (Sh AY scO0E! " q Ny N 8 4 on 8 gute 2 Two orsanocstyste wed to ctae the resction of hydronacetane and alehvée tard the dstivored 14nd prod in Gone eports is the disfavored product. That is why that there are so few reports ‘on the construction of the adverse 1,4-diol product. To the best of our knowledge, only Gong et al have reported on the formation of this unfavorable product up to date, They used a small peptide (Fig. 2, A) as an efficent catalyst for the asymmetric direct aldol reactions of hydroxyacetone with aldehydes to afford ‘the chiral 14-diols, which are the disfavored products in similar aldol reactions catalyzed by either aldolases or 1-proline, that were ‘obtained in high yields and enantioselectivites in aqueous media.” They also developed another more efficient organocatalyst (Fig. 2 B), prepared from (2R3K)-diethyl 2-amino-3-hydroxy succinate ‘and L-proline, which showed superior stereo- and regio-control for the reaction compared to the small peptides. In the presence ‘of 20-30 mol of this organocatalyst B, excellent enantioselectiv- ities ranging from 91% ta 99% and high regioselectiviies were observed for the otherwise disfavored products (1,4-dials) from the direct aldol reactions of hydroxyacetone with 2 broad range of aldehydes* ‘Our research group also reported on the asymmetric aldol reac- tion of acetone or cyclohexanone and aldehydes catalyzed by the prolinethioamides derived ftom i-proline and valine.” On the basis of Gong's research results, we reasoned that our prolinethioa- ides may also act as efficient catalysts for the asymmetric direct aldol reaction of hydroxyacetone and aldehydes. Thus, in order to ‘explore the application ofthese prolinethioamide catalysts further, ‘we herein tepott on the aldol reaction donor to encompass hhydroxyacetone. 2. Results and discussion The eiret aldol reaction of hydroxyacetone with 4-nitrobenzal- etyde was fist selected as 2 model for catalyst screening and evaluation. A series of chiral protinamide catalysts were symthe- sized and examined in this reaction (Fig. 3)? The results ate listed in Table 1, Ie was found that both aldol adducts 4a and Sa could be generated in the presence of all of the proliamides Ta-1g in DMSO, with benzoic acid as an additive 7 t» except for chiral catalysts 1a and 1g (Table 1, entries 2-6) In the case of organocatalyst 1a, only the single 1.2-diol product was ‘obtained with high yield and moderate enantioselecivity (yield 9%, ee 50X) (entry 1), When using the chiral small organic mole- cule 1g with a terminal hydroxy group as the catalyst, this reaction became sluggish and produced only a trace amount ofthe 1.2-diol product (yield <10%) (entry 7). This demonstrated that the terminal hydroxy group of the prolinethioamide was disfavored for this reaction in our protocol, Overall, this eaction generally gave the usual 12-diol adduct 4a as the major product and simultaneously generated the minor 1,44diol compound Sa. In addition, we observed that prolinethioamide catalysts exhibited better enanti- selectivities than those ofthe corresponding prolinamide (entries 1 and 2, entries 5 and 6). With respect to the reaction yield and enantioselectivity, we finally chose organocatalyst 1b as the best candidate, ‘With the optimal chiral small organic molecule catalyst in hand, ‘we then performed screening experiments regarding solvents in order to further improve the regioselectvity and enantioselectivity of this asymmetric aldol reaction. {As shown in Table 2, this reaction could afford the 1.2-diol 4a as the major product with high enantioselectivity in DMSO (Table 2, entry 1), When changing to the non-coordinating solvent CHCl, or DMF, the yield of the reaction product 4a was increased (0 90% or 85%, but the enantioselectivity slightly decreased (entries 2 and 3). Moreover, expanding to the other aromatic aldehydes in a solvent of CHCl, of DMF, both the reaction regioselectivity and enantioselectivity decreased sharply. Using strongly polar sol- Vents, such as CH,CN and CHNO,, especially for CHyNO;, afforded the 1.2-diol product 4a with largely improved yields 85%, although with decreased enantioselecivities (entries 4 and 5). In the case of 4 non-polar solvent, such as toluene, the I,2-diol product could be ‘obtained with moderate enantioselectivity and good regioselectiv- ity (Table 2, entry 6), This reaction could give the 1,2-tiol product ‘with high (86%) yield but very low enantioselectivity (ee 20%) lunder neat conditions (entry 7). Based on Gong's report on the regioselectivity of the aldol reaction of hydroxyacetone and an te 1on 0 5 Q Joe +f noeatasts 2 By “ & ae oo ma we * Procedures 2 be, te DMSO solvent (05h 2017 of erganectayt, 20 el ¥ of Beale a0 and Iydronjactone (TTT mg 13 mmol Sequi) were aedee ‘ver anyérous magnesium sullate, tere, concentrated and the resiue was chromatographed by sca gel t give the pure diel product “soled yl 4 the ee was dled by HPLC wig a eal stalonary plas (De! Capa AD-H 0 AS) The Slvet eet on te eect asymmetric aa ec hdorycstone with 4nirebenzalehye ctalaed by the dipeptide erative 1b . 5 : Joo. "2 OW’ f 20 mol% PhCOOH ON’ : : “ * n emmy ~ 73 “ = = % ‘The e was dteined by HPLC wt ache statlonry plas (Daiee! Capa AD-H 0 AS) aldehyde controlled by water in the presence of multipeptide those of Gong’s work. The reaction catalyzed by our dipeptide erivatives, we also attempted to employ water or a THF/H,O derivative hardly ran in aqueous media of THE/H,0 mixture sol- mixture as the solvent under the standatd reaction conditions. vents with only twace amounts of 1,2-diol product (entries 8 and Consequently, this reaction gave completely diferent results from 9). The reason for this remains unclear. To further confirm whether26 i et ol Terhedon: Asyrmety 24 (203) 538-52 the water did play a role in the reaction of hydroxyacetone and 4-nitrobenzaldebyde, we examined the DMSO/H,0 combination system. Consequently, we observed that this reaction proceeded smoothly and afforded the corresponding. 1.2-diol adduct with increased yield and decreased enantioselectivity compared to ‘when using pure DMSO as solvent (entry 10). In addition, when ‘employing the hydrophilic ionic liquid BrnimBFs, which possesses 4 strong polarity and is environmentally benign, the 1,2-diol adduct could be generated in high yield, but the enantioselectivity, ‘was lower (entry 11). However. this reaction gave the 1,2-diol product with a sharply decreased yield and enantioselectivity ‘when carried out ina solvent system of BmimBF, and water (entry 12)-Allof the above results indicated that water was unsuitable for this reaction using our methodology. The catalyst loading and reaction temperature usually have an important influence on the asymmetric reaction yield and enanti- ‘selectivity. Thus, we adjusted the amount of organocatalyst 1b under the standard procedure. When increasing the amount of prolinethioamide 1b {rom 20 mol % to 30 mol %, the 1,2-diol was ‘obtained with excellent yield (95%), although the enantioselectivi- ‘ty was slightly decreased (Table 3, entries 1 and 2). Decreasing the “organacatalyst loading to 10mol % or 5 mol, led to decreasing, yields and sharply decreased enantioselectivties (entries 3 and 4). The reaction temperature was also tested, Good regiaselectivity ‘was produced with the single 1.2-diol compound being obtained with up to 90% yield but moderate enantioselectivity at room temperature (entry 5)- Generally, lowering the temperature is favorable for improving the reaction enantioselectivty. However, no improved results were observed at -20°C (entry 6). In view of these results, we adopted the following reaction condition as the optimal protocol: 20mol % amount of catalyst 1b, O°C and DMSO solvent ‘Although benzoic acd is usually used as an additive in asym- metric aldol reactions which can accelerate the formation of an ‘mine or transformation to an enamine via the interaction of the ‘catalyst and ketone, the fine tuning of the additive may have an important impact on the reaction yield and enantioselectivity Hence, additives were also investigated seriously. As shown in ‘Table 4, this reaction gave similar regioselectivities and total yields in the presence or absence of benzoic acid with a slightly decreased enantioselectivity in the latter ease (entries 1 and 2). When using 2-hydroxy benzoic acid as the additive, only 1,2-dil product 4a ‘was obtained with 85x yield and 89% enantiomeric excess (Table 4 entry 3), However. the results were completely different with the ‘major product 1,4-diol Sa (yield 50%, ee 90%) and minor 1,2-tiol 4a (yield 27%, e¢ 65%) in the case of 4-hydroxybenzoic acid (entry 4), Further adjusting of the acidity ofthe aditives, such as phthalic acid, phenol, 2-hydroxyphenol or even chiral (R)-BINOL and so on, fia not improve on the results obtained (Table 4, entries 5-8). ‘When using a stronger acid, such as CF;COOH or CH,COOH, the reaction hatdly proceeded, This reaction fegioselecivity was thor oughly eversed and afforded most of the 1,4-diol Sa with up to 93% ee and only trace amounts of the usual 1.2-diol 4a (entry 8) when employing neutral Al,0, 2s the auxiliary. This observation encouraged us to further fine tune the Al,0;. Unfortunately, adopt- ing activated AlO, treated by water, this reaction gave similar results to those of unactivated Al,O; (entry 10). Considering the possible effect of the whole reaction system pk, value on the reac- tion, we attempted to use basic AlO3, However, while the regiose- lectivity decreased slightly, the enantioselectivity of 1,4-tiol increased to 98% (entry 11).This indicated thatthe acid-base prop- erty of the AO, had a certain influence on the reaction regioselec- tivity. On the other hand, we assumed that the steric hinderance of ‘AlO, may also have a dominant role on the reaction regioselectiv= ity due to the larger mesh latice structure of Al,05. With these factors in mind, other metal oxides, such as SiO,, ZnO, MgO and C20 and so on, wete also examined in the feaction of bydroxyace- tone and 4-nitrobenzaldehyde under the standard procedure. All reactions proceeded smoothly but afforded the products with low regioselectvity and low enantioselectivity (entries 12-15) In addition, we also attempted to introduce other bulky additives, such a P-cycladextrin, diatomite and Cr,0, and so on; the reaction produced the major disfavored 1,4-diol and minor 1.2-diol. The 1.4/1.2-diol ratios were 2:1, 1.2:1 and 1.3:1, respectively. This far= ther confirmed our hypothesis that the steric hinderance of the additive plays a key role Based on the above results, we concluded that this reaction could be selectively triggered by only changing the additives from i ¥ Ooty coome ote one ° on x oH » . Ate dle i on omemmcoon ON ow marae 2 ® “ se 12a prot shots oa Say ar = or "a “The eas determined by HPLC ings eral stationary pave Dae! Chialpak AD o AS‘The leret adie: employed in he direct asymmetric alglrescton of hyéryacetone with nitabenalehyae 20 mals Ob Mon ° woo FS Soa § on 20moN% adciive ON : » “ « : com Boo s * ‘ ? no, sno-opcoon 9 on Smeue ote eae on sa | de OnN’ f ee Scheme 1 A reloselecive aldo section of hydenyaclone and -ntrobenaledivde 2-hydroxybenzoic acid to aluminum oxide and catalyzed by the same organocatalyst Tb at 0°C in DMSO solvent (Scheme 1), To better understand the scope and limitations of our catalyst systems, some aromatic aldehydes were chosen as aldol acceptors in the presence of salicylic aid or AO), respectively (Tables 5 and 6).As shown in Table 5 it ean be seen that the favored 1,2-diols 4 were mainly obtained with high yields and high diastereoselectiv- ities as well as excellent enantioselectivities when using the salicylic acid as an additive, Upon closer inspection of these data, we observed that the aromatic aldehydes with strong electron- ‘withdrawing substituents were better substrates than their unsub- stituted counterpart in terms of reactivity and stereoselectivity (Table , entries 1-8 vs 8) For example, for the 4-nitro, 2-triluore- ‘methyl and 4-cyanobenzaldehyde substrates, only single 1.2-diols products were obtained (entries 1, 5 and 6) under the standard procedure, Furthermore, excellent enantioselectivity was obtained (up to 98% forthe 2-tifluoromethyl benzaldehyde). In comparison, for the other substituted benzaldehydes, there were small amount of 14-diols obtained except fr the major 1,2-diols (Table 5, entries 2-4 and 7-8). Similarly, adopting AlO; as an auxiliary, the above substrates were also examined in the asymmetric aldol reaction with hyrox-ne te a Terhedon:Ayrmety 24203) 533-52 rors smote it £ YY cooks 3 y ono . ners Fon-GcooR by ong oe 2 3 am Sina) sy a ra Ta Fas 7 ocere in a be he DMSO solvent [OS mi mel wiganocayst Hh onel salle wa and hyonyacione (111g 1S mae, Seu) were added sequentally The ceacion mintre was cole to 0°C and then the azomate aleve substrates (0.25 mmo. equ) were a@ to hs reaction system Which Ws falawed by TLC Aer complein-stursted aqueous Nil we added fo quench the rescion which wa extaced with yl asa tee ties (2 10m) ied vet isolated yl «te eieereaceletvity wa determined by HNMR specrorcopy The ee as determined by HPLC wing 4 eal stationary pase (aie Capa AD. or AS, Tjian these valu ayes atypia inte eso hmino de zo ners AAW coote ° ow y OH Oo ToHo jb A OH . sy af . monet aso, CA oH DMSO, 0°C-t 2 : Sion Aen 7 Ta a Ta aa mana ma a Teal i ‘completion, saturated aqueous NHI was added to quench the reaction, which was extracted with ethyl acetate thee times (3 « 10 ded over anhydrous magnesium “Te twas determined by HPLC sng aia statlonary phase (Dae Chitalpak ADH a AS ‘acetone under the optimal protocol. As a result, we obtained the to the salicylic acid additive, this kind of reaction regioselectivity, main disfavored 1,4-diols with high or excellent enantioselectivi- was relatively poor. All reactions afforded a certain amount of ties but with moderate or high yields in all substrates. Compared the favored 1.2-diols. With regard to the nitro-substitured benzal-I "0 9 37 6 Figure 4 the 'H NMR spectrum In DMSOMt, (A: hydroxyacetone, 8 etanectalYst 1B, C hyeoxvactone = ehydes, 2-nitrobenzaldehyde resulted in the lowest yield and fegioselectivity compared to -nitro and 4-nitrobenzaldehyde (entries 2 vs 1 and 3). In addition, the reaction gave the approxi- ‘mate yields of 1,4-dil (yield 55%) and 1,2-diol (yield 37%) when using the 4-trfluoromethyl benzaldehyde (Table 6, entry 5). For the 2-CF,-CcH,CHO, the reaction yield and regioselectivity were better than values obtained for the corresponding 4-substituted substrate (entries 4 and 5). In terms of unsubstituted aldehyde, a poorly reactive benzaldehyde. although the enantiomeric excess was high (up to 962), the reaction yield was lower than any electron-withdrawing substituted benzaldehydes with only 41% for the 14-diol and 22% for the 1.2-dol (enty 9). From the results summatized in Tables 5 and 6, we found that the reaction methodology had some drawbacks at present. For instance, the substrates were limited to electron-withdrawing substituted aromatic aldehydes. For the poorly reactive substrates, the reaction results, including the regioselectivity and yield as well as the enantioselectivity were relatively poor. To the best of our knowledge. current reports on the asymmetric aldol reaction of hydroxyacetone for the construction of this disfavored 1,4-iol product are generally restricted to aromatic aldehydes with elec- tron-withdrawing substituents.® In the case of aluminum oxide as an additive, the reaction regioselectivity was only moderate and needs to be further improved upon, Despite the existing limi- tations. this protocol has advantages, such as the regioselectivity that can be easily regulated by changing the additives to afford the usual 1.2-diol or 1-4-diol. Most importantly, the organocatalyst employed is structurally simple and readily available from the natural amino acids proline and L-valine. Moreover, the reaction conditions were mild without harsh anhydrous and anaerobic environments. Hence, the operation is also very simple. 3 4 3 2 7 0 catalyst rbemzoe ac (11:1, D: hydronsace- We attempted to determine the mechanism of the direct asym- ‘metric aldol reaction of hydroxyacetone and aldehydes, using several methods. For instance, by using *H NMR spectroscopy in two cases (using the salicylic acid and aluminum oxide as addi- tives) (Fig. 4), we observed that the chemical shift of the ring CH (2) adjacent to the pyrrolidinic N atom was downfield shifted to the place of a. Moreover, the integral and shape of peak b (CH) close to the pyrrolidine N atom were changed significantly to the broad peak b’ in the presence of salicylic acid, This phenomenon can be ascribed to a strong intermolecular hydrogen-bond interac- ‘ion between the enol-enamine and the salicylic acid. However, for the ALO; additive, no obvious changes were observed in the 'H NMR. This may be due to the Al,O; insolubility in the DMSO-d. ‘We then looked at other MS spectra, but no significant results were obtained. Thus, based on the experimental results and previ- fous relevant reports."* we proposed 2 possible reaction mecha- nism as shown in Scheme 2, ‘At frst, the interaction of organocatalyst 1b and hydroxyace- tone led tothe formation of an imine cation which simultaneously automerizes with the enamine intermediate. The acid additive should be involved in the iminium-enamine equilibrium in the asymmetric aldol reaction catalyzed by proline a its derivatives and thus accelerate the reaction process and affect the enantiose- lectivty." Hence, inthe presence of the salicylic acid, the imine cat- Jon preferentially adopts the dominant configuration Ato form the enol-enamine € due to its strong hydrogen bonding interaction with the prolinethioamide 1b, thus affording the usual 1.2-diol products. Comparatively, when using Al,O, as an additive, because ofits steric hinderance it can affect the imine cation via B to then give enamine D, which was predicted to be a slightly more favor- able than the enol-enamine. to finally give 1,4-diols. In view of40 te Tetrahedron: Asyrmety 242013) 533-542 y NY -HOCsH,COOH * ~\ . . Z 4 ° on c RCHO oH 9 on 1 2dol product owe a ome getty, Cay on RHO 14-0 product Seheme 2. A posse mechanism ofthe resiseleciv ll reson of hyecanyaetane an somatic ade CGong’s report regarding the DFT for the reaction, the difference be- tween the enol-enamine and enamine isso slight that the revers- ible transformation between these two isomers results in the competitive formation of 1.2-diols and 1,4-diols. 3. Conclusion Im conclusion, we have developed a novel, structurally simple dipeptide derivative 1b, which was readily prepared from ‘commercially available and inexpensive proline and L-valine for the asymmetric ditect aldol reactions of hydroxyacetone and ‘aromatic aldehydes. Good yields and diastereoselectivities as well £2 high enantioselectvites have been achieved with 20 mol cat- lyst loading. The reaction regioselectivity could be easily regu- lated by altering the additives from salicylic acid to aluminum oxide and afforded the usual 1,2-diols and 1,4-diols. The method developed herein is the frst example and of high synthetic potential 4. Experimental 41. General HNMR and °C NMR spectra were recorded on Bruker AV 300 or Varian mercury Plus 400 using CDCI, as the solvent and TMS as the internal standard unless otherwise noted: chemical shifts are given in (ppm) and coupling constants () in Hz. The enantiomeric excess was determined by HPLC using Chitalpak AS-H and AD-H column (Daicel Chemical ind, Ltd) with n-hexane and f-propanel as eluents. Acetone was distilled from K,CO, prior to use; all other Solvents and commercially available reagents were used as received without further purification unless otherwise stated.‘Analytical thin layer chromatography (TLC) was performed using Merck 60 Fasa precoated silica gel plate. Subsequent to elution, the plates were visualized using UV radiation (254nm) on a Spectroline Model ENF-24061/F 254 nm. 42. Procedure for the preparation of the organocatalyst To a stired solution of N-Roc-t-prolin (1.25 g, 81 mmol) in CHC, EEN (1.2 ml. 871 mmo!) was added slowiy at 0°C. Ater the solution was. stirred. for 10min, isobutyl chloroformate (875 il, 667 mmol) was added dropwise tothe reaction mixture 310°C. After the solution was sttted for an additional 20 min at 0°C BUN (80 il 6.67 mmol) and valine methylester bydrochlo- fide (1.10, 6.67 mmol) were added tthe reaction mixture. The feaction mixture was then warmed up to tom temperature. Alter 3h, TIC analysis indicated complete consumption of the starting material The reaction was quenched by the addition of 1M HCL and cliluted with CHCl, The organic phase was washed with #40, brine and dried over Nas50y, filtered, and then concentated under reduced pressure, Purification was accomplished. by recrystaliztion (EtOAcjn-hexane) to. give compound (S)tere buty-2-(()-I-methoxy-3-methy/-t-axo-butan-2-ycarbamoyi)pyt- rolidine-Icarborylate (1.65 g, yield 87% white crystal). Mp 68-70°C; a? = 102.0 (1.0 ECO); HNMR (400 Miz, CDCI} 8 081 (4, 3H Jn 70 Hz}, 094 (4, 3H, J= 6.9 tz) 1.46 (s, SH. 71-180 (m, 3H), 185-199 (m, 2H, 210-225 (m, 1H) 237-3447 (m, 2H), 3.72 (5, 31), 4:36-4:44 (m, 2H) ‘A mixture of the above compound (657 mg. 2mmol) and Lawesson’s reagent (410mg. T mmol in diy THE was sted for Zivat room temperatuze and then refluxed for 05 h under argon atmosphere, After removal ofthe solvent under reduced pressure, the resulting residue was purfed by flash chromatography {hexane|EtOAc) to afford compound (S)tert-buyl 24(S)-emethe oxy-3-methyl-1-oxobutan-2-ylearbamothioylpyrralidine-I-ear= boxylate (448 mg. yield 65%, white solid. "H NMR. (400 Mia DCL} § 082-099 (m, GH}, 1.44 (5, 9H), 172-175 (m, 2H) 1.86=1.87 (m, 2H), 201 (brs, 1H), 228-2.34 (m, 1H), 345-350, {0m 210, 375 (5,31), 468-470 (m, 11, .06-5 08 (m, 1H). “The above compound (482 mg, 14 mmo) was dissolved in dry CHC, (28 ml) and then TFA (14 mL) and EQSH (055 mL) were added. After 2h, the solvent was removed, diluted with CHCl, and washed with saturated NalICO,, died over Na;S0,, filtered, and then concentrated under reduced pressure (0 give catalyst 1b (256 mg. yield 78%, yellow oi). 2 = ~536 (€ 10, CHaCh} LNMR (400 Mla, CDCl): 0841.00 (dd, 6, J=69. 108 He) 1.65-1.78 (m, 2H), 200-2.04 (m, 24), 235-238 (m, 24), 3.01 309 (em, 2H), 3.75 (5, 34), 421-426 (dd, 1H J-38, 9082), 5.12-5.14(m, 1H), 1036 (brs, 1H); °C NMR (100 Mi, CDC): 5 2059, 1712, 679, 618, 523, 475, 347, 312, 261, 188, 185: FHREMS (FSD) caled for CyHaaNO35 (Met), 245.1318. found 245.1322. 43. Typical procedure for the aldol reaction of the aldehyde ‘with hydroxyacetone catalyzed by an organocatalyst To a mixture of organocatalyst 1b (0.05 mmol) and additives (005 mmol) in DMSO (02ml), bydroxyacetone (111 mg. 15 mmol, G equiv) was added. 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