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PERSPECTIVE www.rsc.org/obc | Organic & Biomolecular Chemistry

Chiral BINOL-derived phosphoric acids: privileged Brønsted acid
organocatalysts for C–C bond formation reactions
Alexandru Zamfir, Sebastian Schenker, Matthias Freund and Svetlana B. Tsogoeva*
Received 4th June 2010, Accepted 27th July 2010
DOI: 10.1039/c0ob00209g

BINOL-derived phosphoric acids have emerged during the last five years as powerful chiral Brønsted
acid catalysts in many enantioselective processes. The most successful transformations carried out with
Published on 06 September 2010 on http://pubs.rsc.org | doi:10.1039/C0OB00209G

chiral BINOL phosphates include C–C bond formation reactions. The recent advances have been
reviewed in this article with a focus being placed on hydrocyanations, aldol-type, Mannich,
Friedel–Crafts, aza-ene-type, Diels–Alder, as well as cascade and multi-component reactions.
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1 Introduction type reactions3,4a and aza-Friedel–Crafts alkylation,4b the devel-
opment of novel BINOL phosphate-catalyzed reactions has been
The development of stereospecific C–C bond-forming reactions is continuously studied and enabled great progress in recent years.5
of utmost importance in the field of synthetic organic chemistry. Several research groups reported the application of BINOL
Especially evident in pharmaceutical and natural product syn- phosphates in numerous highly enantioselective transformations.
thesis, enantioselective reactions are important for introduction In most cases the key aspect of catalysis is the bifunctional
of chiral centers throughout a bioactive compound. There are character (Brønsted acid/Lewis base) of the phosphoric acid
many proven enantioselective methods utilized in natural product moiety.5b
synthesis. In particular, enzymatic processes and transition metal- In this Perspective, we attempt to offer an overview of enan-
based catalysis have garnered much attention. tioselective C–C bond formation reactions catalyzed by chiral
Over the recent years, asymmetric organocatalysis has emerged BINOL-derived phosphoric acids published after 2006 through
as a new exciting and environmentally friendly methodology to the beginning of 2010. Specifically, this article is focused
in organic chemistry, complementing bio- and metal-catalysis.1 on hydrocyanations, aldol-type, Mannich, Friedel–Crafts, aza-
Increasing attention has been paid to asymmetric organocatalytic ene-type, Diels–Alder, as well as cascade and multi-component
reactions via hydrogen bonding activation and/or Brønsted acid reactions.
activation of carbonyl compounds and imines.2 In particular, the
use of chiral phosphoric acids for the synthesis of optically active
2 Hydrocyanations
compounds has become a new and exciting area of contemporary
synthetic organic chemistry. The addition of hydrogen cyanide to imines and/or ketones
Since the pioneering studies of the groups of Akiyama3 and constitutes one of the most direct and practical methods
Terada4 in 2004 on the application of chiral BINOL-derived for the synthesis of a-amino acids, tertiary cyanohydrins and
phosphoric acids as powerful Brønsted acid catalysts in Mannich- derivatives.6
Rueping and Azap7 employed the axially chiral phosphoric
Department of Chemistry and Pharmacy, Chair of Organic Chemistry acid 1 (Fig. 1) for the enantioselective hydrocyanation of imines
I, University of Erlangen-Nuremberg, Henkestrasse 42, 91054 Erlangen, derived from aromatic aldehydes (Scheme 1a). The authors directly
Germany. E-mail: tsogoeva@chemie.uni-erlangen.de used HCN and isolated the respective amino nitriles in moderate

Alexandru Zamfir was born in Sebastian Schenker was born in
Bucharest, 1982. He studied Augsburg, in 1984. He received
chemistry at Göttingen Univer- his B.Sc and M.Sc degrees in
sity where he finished with a Molecular Science from the Uni-
Diploma in 2007. The same versity of Erlangen- Nuremberg.
year he began his graduate Since 2008 he has been in the
studies at Erlangen-Nürnberg Tsogoeva research group, working
University under the supervi- on DFT and ab initio simulations
sion of Prof. Svetlana Tsogoeva. of organocatalytic C–C-bond for-
His research includes binaphthyl- mation reactions in collaboration
derived Brønsted and Lewis acids with Prof. Tim Clark.
for diverse organocatalytic reac-
tions.
Alexandru Zamfir Sebastian Schenker

This journal is © The Royal Society of Chemistry 2010 Org. Biomol. Chem.

the same university. has been successfully employed by the group of Feng10 for the cyanation of ketimines. Org.b-diamino carboxylic acids. Germany. thus shifting the nature of catalysis from Brønsted acid to Lewis acid organocatalysis. for a postdoctoral project. a professor of organic chemistry In 2004.org | doi:10. In January 2002 she was appointed a first junior pro- in aqueous systems. Published on 06 September 2010 on http://pubs. at the University of Erlangen. The sodium salt of unsubstituted binaphthyl phosphoric acid (BPA). This rare example of a cyanation of C N bonds catalyzed by a Lewis acid. Tsogoeva has been Deggendorf. which can serve as valuable precursors for natural products or pharmaceuticals. Similar to their For a synthetic pathway to a.9 leading to synthetically valuable tertiary cyanohydrins. organo-autocatalysis. especially peptides search scientist. The actually active catalyst is proposed to be an in situ formed O-silylated BINOL-phosphate. His research 2000 she joined the Degussa AG Matthias Freund mainly focuses on asymmetric Svetlana B. Scheme 1 3 Aldol-type and related reactions The aldol-type reactions. he worked in the born in 1973. In July Nürnberg. are among the most commonly (85–99%). asymmetric oxidations with non-heme iron complexes. has been conducted in up to 95% yield and up to 93% ee. Biomol. namely isolated as formamides. to synthe. she moved Y receptor. fessor in Germany at the Georg-August-University of Göttingen. Germany. previous report. our group reported the first organocatalytic enantioselective route for the conversion of readily prepared and air stable aliphatic hydrazones to synthetically valuable a-hydrazinonitriles (Scheme 1e). Then. generated in situ from a Brønsted acid. She was Until 2006. View Article Online The group of Ishihara used the same strategy for the cya- nation of ketones. Regensburg University. acid 4 as organocatalyst for the addition of nitroalkanes to the Matthias Freund was born in Svetlana B.11 The BINOL phosphate 3- Downloaded by Ball State University on 12/05/2013 18:54:09. in 1978. as well as nitroaldol. since February 2007. Germany. catalyzed Strecker-type reaction provided a new practical and direct route to a-hydrazino acids of synthetic and biological importance. showing best results for Li+ as a counterion (up to 99% yield and 86% ee. Petersburg State University. he received his diploma at the Friedrich-Alexander-Uni- degree in Chemistry from the versity of Erlangen-Nuremberg. This journal is © The Royal Society of Chemistry 2010 . Rueping’s group8 further employed catalyst 1 for the applied C–C bond forming reactions.1039/C0OB00209G Very recently. because available binaphthyl phosphate is used to generate quaternary carbon centers (Scheme 1d). aza-nitroaldol and to high yields (53–97%) and good to high enantioselectivities Robinson annulation reactions. Salts of phosphoric acid 2 were used. Scheme 1c). as well as synthesis of natural product hybrids for medicinal chemistry.12 The versatility of these enantioselective hydrocyanation of ketimines derived from aryl reactions stem from their utility in constructing chiral building methyl ketones (Scheme 1b). where she completed her doctoral size ligands for the Neuropetide thesis in 1998. The reaction is remarkable.rsc. In 2007 he joined to the Johann Wolfgang Goethe- the group of Professor Tsogoeva University Frankfurt am Main. Chem. the enantioselectivity is steered by the formation Rueping and coworkers13 developed the axially chiral phosphoric of a chiral ion pair between the catalyst and the imine. Her research is currently focused on asymmetric organocatalysis. The products of this reaction were blocks for the synthesis of structurally complex molecules. Tsogoeva Fine Chemicals Division as a re- organocatalysis mediated by small molecules. studied chemistry at group of Professor Buschauer at St. High yields and selectivities were obtained in the presence of para butyl-ortho-adamantyl phenol (PBAP) as an additive. amino acids bearing a quaternary stereocenter.

Chem. Downloaded by Ball State University on 12/05/2013 18:54:09. 1 Org. Published on 06 September 2010 on http://pubs.1039/C0OB00209G This journal is © The Royal Society of Chemistry 2010 Fig. View Article Online . Biomol.org | doi:10.rsc.

reactions. For most halogen-phenyl. showed yields up to 99% and ee values of up isolated products. For the complete reaction yields chiral environment. Furthermore. The cases.6¢ positions and 2. very good regioselectivity and good to very good enantioselectivities (80– enantioselectivity (up to 97%).4-dione. up to Akiyama’s group could show that the N-aryl group plays a crucial ten days. Remarkably.18 The reaction proceeds with moderate to good yields and enantioselectivities (Scheme 3b). the reaction The first application of chiral BINOL phosphate catalysis to can also be carried out in a two step one pot reaction without an asymmetric Mannich process is dated back to 2004. Acetic acid shifts the keto–enol equilibrium of up to 66% and ee values of up to 99% were observed. An a-methyl group already leads to reduced yields. enantiose- hydroxy-a-amino acid derivatives having a quaternary stereogenic lective vinylogous Mukaiyama–Mannich reactions of acyclic silyl center at the a-carbon atom in a highly enantio.6-(i-Pr)3 C6 H2 in Downloaded by Ball State University on 12/05/2013 18:54:09. the authors 10 mol% loading (Scheme 2b). 90%. This mechanism Terada et al. for the most cases. Similarly. is shifted towards Terada demonstrates the direct Mannich reaction of N-Boc the nitronate. the yield is 80–94%. View Article Online N-PMP a-iminoester. the enol. Scheme 4a). equilibrium. The reaction shows remarkable syn unsaturated carboxylic esters in high yields (up to 94%).17 In the best an alcoholic solvent mixture to allow temperatures of -30 ◦ C.org | doi:10. results of this reaction were rationalized by DFT calculations. which are useful for 4-(MeO)C6 H4 does the yield significantly drop to 66%. catalyzed by a BINOL organocatalysis has been presented: the reaction proceeds between phosphoric acid-derived catalyst. the actual reactive species (Scheme 2a). when decrease in yield or enantioselectivity. acetophenone reacted with different N-aryl aldimines to of 3-buten-2-one with diverse substituted indanone derivatives. A catalytic cycle is proposed.rsc. Sickert and Schneider21 reported the first catalytic. ether by a chiral phosphoric acid catalyst 5.O-acetals. Rueping and coworkers20 disclosed for the first time an enan- tioselective Brønsted acid-catalyzed direct Mannich reaction of Scheme 2 acetophenone with aldimines (Scheme 3d).b- elective manner (Scheme 2c). Akiyama3 and Terada4 independently disclosed the potential of where the key step might be an iminium ion–BINOL phosphate BINOL phosphate catalysis in the Mannich and/or Mannich-type complex. which is in favor of the former. enamines with pentane-2. the imine role in the formation of the typical double H-bond interaction might be protonated and therefore is activated for the addition. The reaction between the TBS-substituted 4 Mannich and Mannich-type reactions dienolate and PMP-derived aryl aldimines has a high tolerance concerning the aryl group. R1 intermediates for further elaboration to other valuable products. describe the vinylogous Mannich reaction of aldimines with 2-trimethylsiloxyfuran catalyzed by a BINOL Published on 06 September 2010 on http://pubs. The best catalyst he found is a BINOL-derivative substituted by iodine in the 6. This journal is © The Royal Society of Chemistry 2010 .1039/C0OB00209G phosphoric acid derivative.3¢ positions (Scheme 3c). Biomol.or Z-isomer of the enecarbamate is used. The reaction is R-selective and allows a broad scope of alkylenamines with one H in a-position. Akiyama et al. acetophenone more to the reactive part. which allows phosphoric acid derivatives to catalyze in an in a chiral environment. Mechanistically it was suggested that the chiral to 83%. A drawback might be the long reaction times necessary. hetero-aryl Asymmetric Mannich reactions are among the most powerful and alkyl-phenyl-derived substrates. reported the Robinson annulation-type reaction acid. diastereoselectivities of >99 : 1 and enantioselectivities of reaction shows good to excellent yields and high enantioselec- up to 96% ee and yields of up to 99% can be achieved. In terms of enantioselectivity it plays no role if the E. Akiyama employed his reaction for the synthesis of g-butenilide derivatives. the corresponding Mannich products in low to moderate yields catalyzed by two chiral phosphoric acids 5 and 6 at only 2– (22–53%) and good ee values (56–86%). complete selectivity (up to 50 : 1 dr) and. The tivities for a number of aryl substituted imines (Scheme 4b).and diastereos.3¢-substituted BINOL phos- phoric acid derivatives.4. In the presence of the catalyst. the Michael did not give information about the absolute configuration in the addition reaction. Schneider reported another vinylogous Mannich Another Mannich-type reaction through chiral BINOL-based reaction of vinylketene silyl N. yield decreases. dienolates and imines to furnish highly valuable d-amino a. the nitroalkane–nitronate enantioselective fashion. pattern. which provides b. the 3. Org.22 The reaction is carried out in aldimines and ketene silyl acetals (Scheme 3a). Ab initio calculations let him assume activation via a 9-membered ring interaction pattern between the reactant and the catalyst. only tools for preparing b-amino carbonyl compounds.14 The first step. In combination with the second reaction. They employed 3.16 can also be an alkyl group like t-Bu. developed the direct aldol-type reaction of is supported by the fact that no reaction was observed without azlactones with an oxocarbenium ion15 via protonation of a vinyl acetic acid. However. Brønsted acid activates the imine by forming an ion pair in a but enantioselectivities increase.19 They were able to achieve up to quantitative yields and 99% ee with comparably low catalyst loadings of 5%. in which a chiral and an achiral Brønsted acid assisted synergistically. In the presence of the combination of axially chiral phosphoric acid 8 and acetic Akiyama et al. Chem.

27 phosphoric acid (catalyst 12) was used. Ishihara. First obtained in excellent chemical yields and enantioselectivities. Chem. Furthermore. purification on silica gel. Also remarkably. Terada and co-workers first employed a chiral phos- a mechanism in which the reactive imine is built in situ and can be phoric acid to promote the F–C alkylation of 2-methoxyfuran activated by the Brønsted functionality of the catalyst.25 Being aware that binaphthyl phosphoric acids are the reaction times are mostly kept below 1 h. The authors proposed In 2004. While moderate selectivities have This journal is © The Royal Society of Chemistry 2010 Org.24 The reaction uses transformations.3-diamines.b- Studying the Mannich reaction of aldimines with acetylacetone. Scheme 3 Schneider reported a procedure of a BINOL-phosphoric acid he arrived at the surprising finding that calcium salts of catalyst derivative catalyzed Mukayama-Mannich reaction (Scheme 4c– 28 gave similar results to the previously published work4a obtained f). Both the system with chiral can be employed as key step in the five step total synthesis of (S).26 one of the oldest organic been developed in the group of J.28 Using catalyst 14. while the with N-Boc aldimines. the asymmetric Friedel–Crafts alkylation of indoles with a.23 The reaction shows excellent yield and enantioselectivities under the same conditions where the involvement of Brønsted acid over a wide range of substrates (14 examples with yield >90%. phosphoric acid and the system with calcium salts are used for a anabasine with 92% ee.1039/C0OB00209G Downloaded by Ball State University on 12/05/2013 18:54:09. conditions to achieve a yield of 96% and 92% ee at a low catalyst loading of 3 mol%. Biomol. when the catalyst 28 19 examples with ee >90%). and the products (furan-2-ylamines) were enecarbamate coordinates at the basic site of the catalyst. Zhu. Ishihara decided to investigate whether Zhou and He29 used a H8 -BINOL-derived catalyst (12) for such compounds could have catalytic activity in known reactions. . View Article Online Published on 06 September 2010 on http://pubs.-L. a H8 -binaphthyl-derivative of the the way to the discovery of new asymmetric F–C reactions. The reaction can be carried out as was washed with 2 M HCl after purification on silica gel to ensure two-component as well as three-component reaction. poor yields were observed and the opposite An optimized procedure for the Mukaiyama–Mannich reaction enantiomer was obtained in excess. excellent enantioselectiv- An intriguing study has been carried out in the group of ities of beyond 99% are observed (Scheme 5a). You. the absence of salts. catalyst 28 itself was implied.4b an aminoether is built that is reduced without further purification The F–C reaction of indoles with imines is investigated by the with NaBH3 CN. process for the synthesis of versatile building blocks of biologically The reaction shows high yields and excellent enantioselectivities active compounds.org | doi:10. The total yield over five reaction steps was 5 Friedel–Crafts-type reactions 55%. unsaturated aromatic ketones. thus leading to anti-1. the results being summarized in Scheme 4h. The field of organocatalysis has recently paved (Scheme 4g). The yields are high: readily neutralized to alkali or earth-alkali metal salts even upon mostly above 80%. A multicomponent enantioselective Mannich reaction has The Friedel–Crafts (F–C) alkylation. Schneider’s group optimized the reaction series of substrates. group of S.rsc. represents an important C–C bond-forming enecarbamates as nucleophiles. As a catalyst.

34 High yields and ee values ranging broad scope of N-Boc benzimine derivatives (Scheme 5c).32 The reaction is synthetically valuable because quarternary car- bon centres are being built.and Z isomers yield the same product in a test reaction. indolylglycine was afforded in 98% ee. a set of substrates is tested which gave excellent yields and high enantioselectivities. This journal is © The Royal Society of Chemistry 2010 . Scheme 5 in E/Z-mixtures does not play a role. Only from 86% for Nps-protected (S)-indolylglycine to 88% for Trs- a few indole derivatives have been tested and also show high protected (R)-indolylglycine were observed.rsc. View Article Online Published on 06 September 2010 on http://pubs. The enantioselective F–C alkylation of substituted indoles with nitrostyrene catalyzed by a chiral BINOL-based phosphoric acid Scheme 4 is described. Both the E. The key step of the proposed mechanism is depicted in Scheme 6a. enantioselectivities.31 The reaction works for a the stereochemical integrity of the a-carbon atom and (S)- scope of substituted indoles and alkyl. the silylated axially chiral phophoric acid Org. the advantage of the method lies in the use of only (Scheme 6b). Boc-enamines.org | doi:10.-L. On a preparative scale. Tritylsulfenyl. Chem.5% ee and 71% yield was obtained by Terada et al.or phenyl-substituted N.and 2-nitrophenylsulfenyl-substituted glyoxyl phoric acid catalyst is reported. a sign that the enamine–ketimine equilibrium is part of the mecha- nism. a F–C product with 99. Removal of the Nps catalyzed by a BINOL-based chiral monophosphoric acid 5 via protecting group under mild acidic conditions did not affect activation of electron-rich alkenes.30 The achieved yields are mostly imines were used in chiral phosphoric acid catalyzed F–C reactions very good and enantioselectivities are remarkably high for a with indole (Scheme 6c).1039/C0OB00209G Downloaded by Ball State University on 12/05/2013 18:54:09. no reaction occurred. After finding the proper reaction conditions. demonstrated the enantioselective F–C reaction crystallization from the reaction mixture. the reaction is proposed to proceed via an imine intermediate. Thus. As the catalyst. of the reaction is the choice of the right molecular sieve. The reaction proceeds throughout with moderate Antilla and coworkers35 developed an organocatalytic version to good yield and remarkably constant high enantioselectivity of enantioselective Friedel–Crafts reactions between pyrroles and (Scheme 5d). It has been reported that a crucial point in the course 2 mol% organocatalysts (Scheme 5b). Biomol.33 Itoh and Akiyama were able to achieve up to quantitative yield and high enantioselectivities of up to 94% ee been obtained. Whether the enamine is present as single isomer or imines. When the reaction with N- methylated reactants was tested. The best A highly enantioselective 1. Q.2-aza-Friedel–Crafts reaction of results are achieved with 3 Å molecular sieves. Zhou describes the Brønsted acid-catalyzed enantios- elective F–C reaction between indoles and a-aryl enamides. indole with aromatic imines using a BINOL-derived monophos.

the axially chiral silylated phosphoric acid 18 served as the a catalyst. which furnished the products in good to very good yield and ee (Scheme 7c). different aromatic N-benzoyl imines were found to be suitable for the reaction with N-methyl pyrrole and furnished the corresponding products in very good yields and good to very good ee. The provides a practical route to useful b-aminoimine derivatives reaction seems to be tolerant concerning the aryl groups of the which can be readily transformed to 1. With respect to variations of the donor. phosphoric acid. According to these pyrroles with nitroolefins using binaphthyl-based phosphoric acid calculations.b).and core-substituted pyrroles.org | doi:10. fluorinated groups are needed to avoid bisalkylation 19. The yield of this reaction is reported to In 2006 Terada et al. The present method ketones and perfluoroethyl-aryl ketones can be employed. the observed selectivities remained the nitro function of the nitroolefin while the Brønsted acidic site moderate (Scheme 7f).rsc.39 BINOL mechanism the bifunctional character of the binaphthyl-based phosphate 29 has been used as catalyst with a loading of 5 mol%. In this case the acidic function can coordinate While the yields were high. View Article Online Published on 06 September 2010 on http://pubs. ketone. also difluorometyl-aryl well for a broad scope of arylaldimines. This journal is © The Royal Society of Chemistry 2010 Org. as these furnished the products in moderate to very good yield and ee. the enantioselectivity drops to <70% while the reaction chiral BINOL phosphoric acid 19 achieving throughout very good rate increases and the yield remains good. the authors studied different N. . Chem. which were also more or less suitable in the reaction with the imine. Biomol. the reaction reactions. A direct and efficient Brønsted acid-promoted arylation of 6 Reactions of enecarbamates: aza-ene-type. As the authors investigated variations of the acceptor.40 well with a series of substituted indoles. The authors suggest as an explanation of the reaction methanes has been developed in the group of S.37 A wide range of substrates has been tested. enantioselectivity (Scheme 8a). If substituted pyrroles are The reaction can be performed at extremely low loading of a employed.3-diamine derivatives. The reaction was shown to work Instead of trifluoromethyl-aryl ketones.1039/C0OB00209G Downloaded by Ball State University on 12/05/2013 18:54:09. developed a highly efficient enantioselective be 52–99% for the reported substrates. showing overall very high yields and high enantioselectivity A Friedel–Crafts reaction leading to asymmetrical triaryl- (Scheme 7d).-L. thus bringing the two molecules in reactivity range. DFT calculations have been carried out to investigate The group of You investigated the Friedel–Crafts alkylation of the charge distribution in the products. The reaction runs very aza-ene-type reaction of N-benzoylimines with enecarbamates. can coordinate with the NH of the pyrrole. Scheme 6 18 was employed (Scheme 7a. trifluoromethyl ketones has been developed38 providing good to self-coupling excellent enantioselectivities from (76 to 99% ee) for indoles as aromates (Scheme 7e). The group of Antilla36 developed a method for the enantiose- lective addition of N-benzyl indoles to N-benzoyl imines derived Scheme 7 from aromatic aldehydes. You.

catalyzed by H8 -BINOL derivative 12 (Scheme 10c). This method is applicable to not only aromatic hemiaminal ethers but also to aliphatic hemiaminal ethers to give the corresponding product in good to high enantioselectivity (up to 97% ee). in a single step. 7 Diels–Alder and related cycloadditions The enantioselective Diels–Alder reaction is one of the most Scheme 8 important and powerful reactions for the synthesis of complex Published on 06 September 2010 on http://pubs. The corresponding products have been isolated in (Scheme 10b). selectivity and Asymmetric catalysis in the Diels–Alder reaction has also been ee was strongly dependant on the substitution pattern of the realized using chiral Brønsted-acid catalysts. enecarbamate.46 The reaction can be significantly improved up to >99% ee and their application for the synthesis of versatile through the addition of an achiral Brønsted acid additive. indicating that the phosphoryl oxygen of is still one of the most challenging tasks in organic chem.44 Downloaded by Ball State University on 12/05/2013 18:54:09. The same authors carried out hybrid DFT (vinyl ethers) to form tetrahydroquinoline derivatives with high to B3LYP/6-31G** calculations on the proposed double H-bond excellent enantioselectivity (up to 97%. with which they were able to rationalize the catalyzed by chiral phosphoric acid 19 are applicable for linear as observed selectivity. etaldehyde anion equivalent through the activation of hemiami. Chem. It provides access to chiral carbocyclic compounds Terada and co-workers further demonstrated a highly enantio.d). As a result. 19 might form a hydrogen bond with the hydrogen of the imine istry. This journal is © The Royal Society of Chemistry 2010 . The reactions interaction pattern. Terada’s group43 reported an enantioselective two-carbon ho. catalyzed asymmetric direct aza-hetero-Diels–Alder reaction. well as cyclic vinyl ethers. The synthetic building blocks—b-methyl-b-aminoketones—has been best additive tested was acetic acid concerning the enhancement demonstrated (Scheme 9b).org | doi:10. extensive research effort has been and diastereoselective aza-ene-type reaction of glyoxylate with dedicated to the development of chiral catalysts for highly stereo- enecarbamates catalyzed by a chiral BINOL-based phosphoric and regioselective versions of the transformation. those bearing nitrogen or another heteroatom. Recently our group42 reported the enantioselective BINOL OH moiety.41 The achievable yield. high enantioselectivity.47 Good Scheme 9 Org. Biomol.rsc.3-diamine derivatives. acid 20 (Scheme 8b). The same group reported the aza-Diels–Alder reaction be- bearing a N-atom. of ee. (E)-Enecarbamates where shown to perform much Akiyama et al.1039/C0OB00209G molecules. N-aryl group of aldimines was found to be essential for attaining and in particular. View Article Online nal ethers by the chiral phosphoric acid catalysts 9 and 21 (Scheme 9c. The method provides access to enantioenriched 1.45 have developed an inverse electron-demand better—mostly 99% ee and good diastereoselectivities—than the aza-Diels–Alder reaction of aldimines with electron-rich alkenes respective (Z)-isomers. phosphate 3-catalyzed formation of a quaternary carbon center. Gong and co-workers described the first chiral Brønsted acid- mologation method using enecarbamate derivatives as an ac. which are potentially useful synthetic intermediates. Scheme 10a). The presence of the OH moiety on the The enantioselective construction of quaternary carbon centers. through the self-coupling reaction of enamides tween arylimines and Danishefsky’s diene using 5 as a catalyst (Scheme 9a).

Various aromatic and one conjugated aldehyde hydrazones. catalyzed by the chiral phosphoric acid This journal is © The Royal Society of Chemistry 2010 Org. The second step is an aza-Cope rearrangement in a chiral environment.d). application of chiral BINOL phosphates to this type enantioselectivities (up to 87%) and yields (up to 86%) have of transformation opened up a promising new frontier in organic been reported for the reaction of aromatic aldimines with cyclo. The first one is from the appropriate hydrazine and ketone (Scheme 11b).rsc. hexenone. yet only a relatively small scope of halogen.48 This reaction leads to synthetically valuable 2.51 In particular.49 Dihydropyrans are achieved by a hetero-Diels–Alder reaction between glyoxylate and 2-tert-butyl dimethylsiloxy or 1-methoxy butadienes (Scheme 11c. Biomol. Terada et al. were suitable in the reaction with the homoallylic amine.1039/C0OB00209G Rearrangements involving carbon–carbon or carbon–heteroatom migrations performed in an enantioselective manner are important reactions because they lead to optically active compounds with Downloaded by Ball State University on 12/05/2013 18:54:09. reported a highly anti. catalyzed by BINOL-derived catalyst 2. . corresponding products were isolated in moderate to good yield tivities. Rueping and co-workers52 reported an interesting CN-substituted phenylimines has been studied.b-unsaturated aryl (Scheme 12). 8 Rearrangements Published on 06 September 2010 on http://pubs. a second variant of the reaction was tested in which the (up to 87%) and in good to high ees (up to 94% ee).and anti-selective dihydropyran synthesis. developed the first enantio. Also the formation of an iminium salt with a chiral anion. methyl and Recently. The pyrazolines (Scheme 11a).and enantioselective synthesis of b-amino alcohols through the aza-Petasis–Ferrier Scheme 11 rearrangement reaction. except for when long linear alkyl groups were used (R = n-C5 H11 ). synthesis. catalyzed by the axially chiral Brønsted acid 22 on an intramolecular electrocyclization of a. In detail.50 Within the recent years various enantioselective rearrangement Scheme 10 reactions by asymmetric organocatalysis have been reported.org | doi:10. The reaction was found to proceed with excellent enantioselectivities (up to 99%) and mostly good yields and excellent diastereoselectivities (up to 95 : 5 anti/syn) over the whole substrate scope. the yields and selectivities were high. Chem. Scheme 12 Terada et al. After obtaining high yields and selec. molecular frameworks not easily accessible by other approaches. method for the organocatalytic enantioselective aminoallylation The group of List investigated the activity of catalyst 13 of aldehydes. the hydrazone has been built and used without the need of purification authors suggest two key steps in the mechanism. The release of steric strain (two phenyl substituents) is the driving force here. View Article Online here.

enantioselective one-pot multicomponent conclusion that the reactants are activated by two molecules of the reactions.1039/C0OB00209G Downloaded by Ball State University on 12/05/2013 18:54:09. The reac- tion is carried out as sequence starting from racemic hemiaminal allyl ethers which are isomerized to the vinyl ethers by Ni-catalysis (Scheme 13b).and phenyl-substituted hemiaminal ethers. Acyclic ketones perform slightly worse with yields of 42–69% and enantioselectivities of 78–80% ee Furthermore. for a one-pot entry to piperidine derivatives.58 reported a catalytic asymmetric 1. Scheme 15a).54 allowing and ee (63%. For cyclic ketones. yields of 74– Scheme 15 97% and enantioselectivities of up to 98% were reported with catalyst 24 (Scheme 14b). The has been reported (Scheme 15b). Enantioselectivities are remarkably high yield varies from moderate to high. The reaction proceeds with moderate to good yields (up to 86%) and mostly very good enantioselectivities (88–97%) in the presence of catalyst 24.59 that enables diastereo. Diastereoselectivities where also shown to be very good Scheme 13 (up to 20 : 1 dr). Recently.rsc. Chem. an aromatic pri- Terada and co-workers57 have developed an efficient and highly mary amine and a 1. the same research group has reported the organocatalytic enantioselective aza-Petasis–Ferrier reaction of hemiamial vinyl ethers. Biomol. In mechanistic studies. A broad scope of aryl-aldehydes can be used as reactants. a urea or thiourea. View Article Online 5 (Scheme 13a).4-dihydropyridines with high enantioselectivity acid catalyst 25.org | doi:10. featuring a chiral monophosphoric arylsubstituted 1. The performance of the reaction reaction allows the formation and control over three stereogenic is remarkably constant over a large range of examples. are very promising protocols for synthesis. The same group developed the chiral Brønsted acid-catalyzed three- component direct Mannich reaction. the enantioselectivity is mostly (up to 99% ee) throughout a broad substrate scope of N-Boc. clization reaction between a cinnamaldehyde. >80% ee. which allow easy access to complex molecules from catalyst. While the centres at the same time. One of them is the chiral phosphoric acid-catalyzed version (Scheme 14a). while achieving high levels of ee of the catalyst and the product is observed.53 The reaction works with alkyl-. an asymmetric catalytic three-component cy- (Scheme 14c). Scheme 14 aldimines. Subsequently. a nonlinear effect between the starting materials and catalysts. Published on 06 September 2010 on http://pubs.and phenyl-substituted hemiaminal ethers. Gong et al. amino esters and 9 Cascade and multi-component reactions anilines into chiral imidazolidines with high levels of enantiose- lectivity (up to 98% ee. The same authors also known as domino or tandem reactions) have become the emi- tested cyclopropanecarbaldehyde leading to a decrease in yield nent new strategy in contemporary organic synthesis. Also. Org. Gong and coworkers55 reported different methods to carry out the Biginelli reaction (known as a three-component condensation reaction between an aldehyde. Throughout the substrate spectrum mostly excellent ees (up to 99%) and good yields (up to 87%) have been observed. asymmetric organocatalytic cascade reactions (also out with a broad scope of arylaldehydes.3-dicarbonyl compound. This journal is © The Royal Society of Chemistry 2010 . The reaction can be carried Since recently. and an easily enolizable carbonyl compound). readily available precursors. The reaction can be carried out with urea and thiourea and several acetoacetic acid esters. The reaction has been reported for several alkyl- substituted as well as benzyl.3-dipolar cycloaddition that directly assembles aldehydes.and enantioselective tandem aza-ene-type/cyclization the straightforward synthesis of enantiomerically enriched 4- cascade reaction (Scheme 14d). benzyl. 30% ee) but an increase in diastereoselectivity to increasingly rapid access to structural complexity from simple >100 : 1.56 which performs well with both cyclic and acyclic ketones. leading to the enantiocontrol.

and piperidine-derived tertiary amines core with concomitant elimination of water.64 Following this approach. tetrahydro-b-carbolines under complete stereocontrol.65 The preferred catalyst was role in stabilizing the transition states. which employs the axially chiral such complex molecules. The reaction shows a good tolerance for building blocks are linked together in a Michael addition. View Article Online Published on 06 September 2010 on http://pubs. The (up to 99%). Various (up to 96%) and enantioselectivities (83–95%) were observed. namely spiro[pyrrolidin-3. retaining enantioselectivity. obtained. the coworkers60 developed an organocatalyzed cascade reaction of initial step of the lactone synthesis catalyzed by a gold compound is preformed enamines and a. the respective S-products is the ring-opening of enol-lactone by tryptamine.61 The au. isomerization to a more stable conjugated diene and protonation.4-b]indoles and catalytic three-component 1.org | doi:10. The one-pot reaction afforded high yields and of 2-alkyl-hyroxypyrans (Scheme 18c). After a further have proven to be beneficial here (Scheme 18a).3¢oxindole] derivatives. An impressive cascade reaction catalyzed by a binaphthyl using MCPBA. to this cascade. Then a cycliza. may Optimized conditions found by You and coworkers for both find application in medicinal chemistry.1039/C0OB00209G Downloaded by Ball State University on 12/05/2013 18:54:09. mechanism. to form a spirocyclic compound while completely Brønsted acid was developed by the group of Dixon and co. indoles can Gong and co-workers reported an unprecedented asymmetric be efficiently extended to tetrahydropyrano[3. The reaction was successfully tested for a number tion follows under enantioinduction from the binaphthyl-based of halogenated methylated and methoxylated arylimines and a set phosphoric acid 10. enamines were suitable for the reaction with a. In the complete process again high yields phosphoric acid 19 and the Hantzsch ester (Scheme 16). The a large number of aliphatic aldehydes. The initial thors have investigated a broad range of substrates and find high cross methathesis is catalyzed by 5 mol% of a ruthenium catalyst to very high yields and selectivities (Scheme 17a). Rueping and selectivities between 72 and 99%. It seems that p–p stacking interactions between the The group of Antilla developed the addition reaction of oxo-indole ring and the formed conjugated ester may play a major hydroxypyrans to N-acyl imines.b-unsaturated The group of Zhong63 utilized 4 to catalyze the addition of ketones. The respective products can be oxidatively coupled. found to be 16. In detail. Biomol. this cascade of reactions (Scheme 16) reaction is carried out in dry toluene and exhibits excellent yield includes the following Brønsted acid-catalyzed steps: at first. as the corresponding products were formed in moderate aliphatic aldehydes to a-isocyanoacetamides and their cyclization to very good yields (up to 89%) and in high enantioselectivities to form 5-amino oxazoles with a chiral alcohol residue. added and the true elegance of the reaction is revealed in producing dropyridines and azadecalinones.3-dipolar cycloaddition. both and enantioselectivity. The reaction proceeds in the presence workers. For (R)-16. DFT calculations have reactions involve toluene as the solvent in the presence of been also conducted in order to find clues about the reaction molecular sieves (4 Å). were obtained. Ruthenium-catalyzed cross metathesis is combined with a an enantioselective transfer hydrogenation with the Hantzsch ester Friedel–Crafts alkylation reaction in a one-pot reaction by forms the product. Considering the amine resulting adduct isomerizes and subsequently forms the cyclic functionality. This journal is © The Royal Society of Chemistry 2010 Org. Scheme 16 In an attempt to exploit biomimetic principles.rsc. The compounds while the Friedel–Crafts reaction is catalyzed by 1 (Scheme 18b). the group of You. Chem. Furthermore. morpholine. .62 The first step of the reaction depicted in Scheme 17b of only 2 mol% catalyst.b-unsaturated ketones to tetrahy.

Published on 06 September 2010 on http://pubs. Biomol.org | doi:10. Chem. Scheme 18 Scheme 17 This journal is © The Royal Society of Chemistry 2010 View Article Online . Downloaded by Ball State University on 12/05/2013 18:54:09.1039/C0OB00209G Org.rsc.

(b) P. The highest yield for the reaction was 78% and the best ee 94%. selectivity. Rueping and Azap67 disclosed an organocatalytic method References for the enantioselective preparation of isoquinuclidines from imines derived from aromatic aldehydes and cyclohex-2-enone 1 For general reviews on asymmetric organocatalyis. (d) C. a more detailed mechanistic understanding of these powerful Brønsted acid catalysts is needed. 2005. Soc. according to which the catalyst and substrate interact via a double hydrogen Published on 06 September 2010 on http://pubs. Despite the notable achievements already accomplished. Jacobsen. Gröger. Dalko and L. it was possible Chiral BINOL phosphates have also been studied and applied to to raise the yield up to 97% (Scheme 19c). Int. 313.69 The reaction is applicable for a series of substituents tetrahydro-b-carbolines or tetrahydroisoquinolines. (e) H. (d) A. Tetrahedron. (f) Ed. (h) A.org | doi:10. R. Taylor and E. Catalyst 16 at the asymmetric carbon center and allows high yields and was found to promote the asymmetric Pictet–Spengler reaction of good enantioselectivities of 70–94% for the investigated substrate disubstituted tryptamines (Scheme 19a). Houk and B. 1584– a chiral ion pair. 4638– two catalyst structures (8 and 25) were reported to be suitable. 2004.. 2005.. (Scheme 19b). Science.–Eur. Int. N. 44. With respect to the chiral phosphoric acid. Moisan. to realize the full potential of BINOL-derived phosphoric acid catalysis and to pave the way to new organic transformations. Weinheim.. Int. (f) M. with a good ee of the corresponding endo-products. This journal is © The Royal Society of Chemistry 2010 Org. Org. Int. Recent developments in the BINOL phosphate-catalyzed C–C bond formation reactions have been summarized in this review article. View Article Online 10 Miscellaneous cyclizations of -30 ◦ C. While (c) K. I. J. Futatsugi. Takemoto. ketone analogues catalyzed by a chiral BINOL phosphoric acid vestigated although it has high synthetical value. Angew. using QM/QM (ONIOM: B3LYP/HF) calculations. Int. 1758–1763. Akiyama et al. 1924–1942. Massi. Ed. Chem. 2008. Bolm. The catalytic system involves the synergistic coop. Angew. the latter activates the donor by shifting the keto– 1586. (b) P. Chem. 2003. (e) B. as 4660.. Chem.. Yamamoto and K. Connon. the former activates the imine in a chiral environment. 4299–4306. Ed. 289– both generated the products in moderate to good yield and endo. 12. S. Adv. Angew. Schiffers and L. Dalko. The observed selectivities were rationalized (up to 98% yields and up to 96% ee). 2004. 2 For reviews. 2062–2064. 2005. Dondoni and A. 2005. Acc. The whole reaction can be carried out ing products in moderate to high yields and enantioselectivities in a one-pot fashion. Biomol. Chem. Enantioselective Organocatalysis. eration of an axially chiral phosphoric acid and acetic acid. one of the important features of organocatalysis is that the same catalyst may be able to catalyze various reactions with high conversions and enantioselectivities. Ed. see: (a) P. Chem. 11 Conclusions and outlook Downloaded by Ball State University on 12/05/2013 18:54:09. In a short time.68 and the optimization of the reaction conditions. 2001. 44. 5418–5427. 2006. providing solutions to challenging transformations of importance and for a wide range of substrates.. List and J. The optimized reaction is carried out in toluene at a temperature 2006.. by forming Berkessel and H. The same authors several cyclization reactions. Chem. Chem. a remarkable number of new enantioselective reactions subject to BINOL-derived Brønsted acid catalysis have been identified. 2007. Chem. Asymmetric Organocatalysis.. Pellissier.. Ed.. Ed. 2004. M. Wiley-VCH.. Without ques- tion. Angew. List. Over the past years.. Res.rsc. these BINOL phosphates have qualified themselves as “privileged” organocata- lysts and this Brønsted acid catalysis has been established as one of the key catalytic concepts in organocatalysis. Fuchibe.. 63.66 giving the correspond.. N. (h) T. 3726–3748. 3. Angew. Rantanen. Akiyama. see: (a) P.1039/C0OB00209G bonding interaction pattern. Int. reactive intermediate. spectrum (Scheme 19d–f). 9267–9331.: P. Chem. Chem... 2007. Dalko and L. 296. T. Itoh and K. (g) S. phoric acids. enol tautomerism of the cyclohex-2-enone towards the enol as the Weinheim. Ed. Schreiner. 32. the knowledge about the underlying mechanistic details is fairly limited and there are certainly several reactions still waiting to be discovered using this highly versatile methodology. 47. 45. 43. 1520–1543. Acknowledgements The authors gratefully acknowledge financial support from the Deutsche Forschungsgemeinschaft through SPP 1179 Scheme 19 “Organocatalysis” and BMBF (Project MDA 08/010). Moisan. (c) Y. J. W. When the imine was generated in situ. reported the synthesis of Hajos–Parrisch and Wieland–Miescher The asymmetric Pictet–Spengler reaction remains poorly in. 37. Angew. 5138–5175. Chem. 43.. 487–631. Rev. Int. Angew. Biomol. Zani. I. I. leading to derivative 5. Wiley-VCH. Yang. Pihko. 40. I. Undoubtedly.. J. (g) H. . Chem. carbonyl-aldimines with diazo acetate catalyzed by chiral phos- Ed. reported the aza-Darzens reaction of a. 2006.

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