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DOI: 10.1055/s-0032-1316604
Asymmetric Aldol Reactions of Heterocyclic Dienolsilanes and α,β-Unsaturated Carbonyl Derived Dienolsilanes
Publication History
Received: 17 April 2012
Accepted after revision: 11 June 2012
Publication Date:
23 July 2012 (online)
Abstract
The enantioselective aldol reaction has drawn considerable attention for its atom economy. Numerous metal-catalyzed and organocatalytic asymmetric aldol methods for dienolsilanes (1,3-dienyloxysilane-based systems) have been developed during the past decade. The main aim of this review is to present recent developments in asymmetric aldol reactions with aldehyde-, ketone-, and amide-derived dienolsilanes, and heterocyclic α,β-unsaturated ester derived dienolsilanes, which have found considerable application in the synthesis of natural products and bioactive chemicals.
1 Introduction
2 Heterocyclic Dienolsilanes
2.1 Organometallic Catalysts
2.2 Organocatalysts
3 α,β-Unsaturated Carbonyl Derived Dienolsilanes
3.1 Aldehyde- and Ketone-Derived Dienolsilanes
3.2 Amide-Derived Dienolsilanes
4 Conclusions
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Key words
aldol reaction - asymmetric catalysis - silyloxy dienes - heterocycles - α,β-unsaturated carbonylIntroduction
The highly atom-economical aldol reaction is a well-known C–C bond-forming reaction in chemical synthesis. However, one key problem of the vinylogous aldol reaction is site selectivity; the addition of a nucleophilic dienolate to a carbonyl group may generate a mixture of both α- and γ-addition products (Scheme [1]).




One strategy that provides γ-site selectivity is to use silyl dienolates as nucleophiles in Lewis acid promoted aldol additions. In particular, the vinylogous aldol reaction of α,β-unsaturated dienolsilanes provides rapid access to polyketide derivatives, such as δ-hydroxy-β-keto esters and α,β-unsaturated δ-hydroxy carbonyl compounds, which paves the way for polyol unit formation, a motif commonly found in many natural products. Another challenge is the need to perform these reactions asymmetrically, because most bioactive molecules and natural products have one or more stereogenic centers. Numerous enantioselective aldol-type reactions have been developed in recent years, these include the use of chiral ligands and Lewis acid catalysts. A variety of efficient Lewis acid catalysts, such as titanium, copper, and chromium, have been introduced for this reaction.[1] [2] [3] Recently, Alcaide and Almendros,[ 4a ] Kalesse,[ 4b ] and Trost and Brindle[ 4c ] detailed the development of metal- and organo-based catalytic asymmetric aldol methodologies. The review by Trost and Brindle[ 4c ] emphasized the simple organocatalyst proline and other catalysts with good catalytic activities. Casiraghi and co-workers[ 5 ] reported vinylogous nucleophilic substrates, including acyclic and heterocyclic dienolsilanes, applied in the total synthesis of bioactive natural products from 2000 to 2010. In the same year, a review by Pansare et al. described recent progress in organocatalytic vinylogous aldol reactions.[ 6 ] These authoritative reviews directed the reader to those works on asymmetric vinylogous aldol reactions.
Although acyclic dienolsilanes 1 and 2 were the first α,β-unsaturated ester derived dienolsilanes used in vinylogous aldol reactions, in recent years the use of heterocyclic dienoxysilanes has instead been explored in the synthesis of related polyketide compound. These new heterocyclic α,β-unsaturated dienolsilanes and α,β-unsaturated carbonyl derived dienolsilanes are useful in the synthesis of many bioactive natural products and complex synthetic intermediates. Casiraghi and co-workers[ 5 ] have reviewed dienolsilanes derived from α,β-unsaturated esters in asymmetric aldol reactions; this short review focuses on recent developments in asymmetric aldol reactions with heterocyclic α,β-unsaturated ester derived dienolsilanes 5–8 (Figure [1]), and aldehyde-, ketone-, and amide-derived dienolsilanes 9–12 (Figure [2]).




# 2
Heterocyclic Dienolsilanes
2.1Organometallic Catalysts
Heterocyclic dienolsilanes including furan-, thiophene-, and pyrrole-based five-membered d4 nucleophiles have been explored over the last 20 years. A number of great achievements in highly diastereocontrolled syntheses were made via the Mukaiyama-type aldol reaction using these dienolsilanes. Casiraghi and co-workers[ 5 ] have summarized vinylogous aldol methodology and its applications using heterocyclic dienolsilanes. Recent asymmetric aldol reactions with these cyclic dienolates by organometallic catalysts are summarized in this review.
Katsuki et al.[ 7 ] developed a vinylogous Mukaiyama aldol reaction between benzaldehyde (13) and 2-(trimethylsilyloxy)furan (5) with chromium and chiral ligand complex 15 in 2003 (Scheme [2]). Protic cosolvents such as water and propan-2-ol were essential for high selectivity. Propan-2-ol was proven to be superior to water; syn-14 formed in 86% yield and 93% ee using 2.5 mol% catalyst of catalyst 15 in propan-2-ol. The authors believed that the protic solvent suppressed retroaldolization in the conversion of the aldolate into the butenolide syn-14.


More recently, Bolm et al.[ 8 ] developed a copper-catalyzed asymmetric vinylogous Mukaiyama aldol reaction. Using 10 mol% of the C 1-symmetric aminosulfoximine ligand 18 and copper(II) triflate, a variety of catalytic asymmetric aldol reactions were carried out with furan-, thiophene-, and pyrrole-based nucleophiles and ketonic electrophiles, for example 2-(trimethylsilyloxy)furan (5) and methyl pyruvate (16) afforded the γ-butenolide 17 (Scheme [3]). Among the heterocyclic nucleophiles examined, 2-(trimethylsilyloxy)furan (5) and 1-methyl-2-(trimethylsilyloxy)pyrrole were the most favorable giving products with high yields and excellent selectivities. Notably, a microwave-accelerated stereoselective Mukaiyama aldol reaction was first reported. Moderate enantiomeric excess (51%) and good diastereomeric excess (91%) values were achieved in tetrahydrofuran under microwave irradiation.[ 8 ]


To expand the scope of the Mukaiyama aldol reaction of 2-(trimethylsilyloxy)furan (5), in 2001 Meshram et al.[ 9 ] demonstrated the catalytic Mukaiyama aldol reactions of 2-(trimethylsilyloxy)furan (5) with isatin (19) in the presence of lanthanum(III) triflate (Scheme [4]). Isatins substituted in the 5-, 6-, and 7-positions resulted in good selectivities, while 4-substituted isatins were less selective because of steric hindrance; reduced selectivities were observed when the isatin nitrogen was substituted with an ethyl or benzyl group.


Excellent progress has been made in the total synthesis of natural products with polyketide frameworks using Mukaiyama aldol reactions. Heterocyclic dienolsilanes, as nucleophilic dienolates, have been comprehensively applied in asymmetric aldol reactions. In 2007, Evans et al.[ 10 ] described a practical total synthesis of (+)-azaspiracid-1 (27) in 2.7% overall yield (Scheme [5]). The key E-I ring fragment 25 was obtained in 13 steps from N-phenylglyoxamide (22) and 3-methyl-2-(trimethylsilyloxy)furan (21). The asymmetric aldol reaction was catalyzed by a Sn2+ complex 28, instead of the traditional copper complex, with 97% ee. After hydrogenation, protection, lactone reduction, silylation, deprotection, and seven other reactions, the C27–C34 fragment 25 was attained in 27% overall yield. The A–D aldehyde 26 was also synthesized and the fragments 25 and 26 were successfully combined to give the natural product (+)-azaspiracid-1 (27) in four further steps.


The asymmetric Mukaiyama aldol reaction has successfully been extended to a (silyloxy)pyrrole. Casiraghi and co-workers[ 11 ] developed an alternative asymmetric route for indolizidine 31, an important core structure of many marine natural products (Scheme [6]). Tin(IV) chloride catalyzed diastereocontrolled vinylogous Mukaiyama aldol reaction of the nucleophilic pyrrole 7 to the glyceraldehyde 29 gave the chiral building block lactam 30 in high yield. The classical ene-ene ring-closing-metathesis reaction for assembling heterocyclic systems was used to install the bicyclic indolizidine skeleton 31 in 19.5% yield.
# 2.2
Organocatalysts
The vinylogous Mukaiyama aldol reaction has become a common method for stereoselective adaptation in natural product synthesis by metal-based catalysts in excellent yield. Over the past decade, organocatalysis has become an attractive option for Mukaiyama aldol reactions because of its exceptionally mild conditions. Kalesse[ 4b ] and Pansare and Paul[ 6 ] reviewed the development on boron- and bisphosphoramide-based organocatalysts, two major catalytic systems for Mukaiyama aldol reactions. A brief summary of recent advances in bisphosphoramide- and cinchona-based organocatalysts for Mukaiyama aldol reactions of heterocyclic dienolsilanes is presented in this section.
In 2010, Casiraghi and co-workers[ 12 ] reported enantioselective Mukaiyama aldol reactions of pyrrole- 7 and furan-based dienolsilanes 6 with aromatic and heteroaromatic aldehydes for a butenolide-like framework.[ 12 ] A series of representative catalysts with potential to be effective for asymmetric Mukaiyama aldol reactions were screened, and the bisphosphoramide 34 was found to give the aldol products in high yield and enantioselectivity. Using the catalyst 34 (3 mol%) and silicon tetrachloride (1.1 equiv) in dichloromethane and tetrahydrofuran at –78 °C, adduct 32 was obtained from 2-(tert-butyldimethylsilyloxy)furan (6) and benzaldehyde (13) in 95% yield and 54% de (Scheme [7]). When applied to pyrrole-based dienolsilane 7 and benzaldehyde (13), the reaction proceeded to give 33 in 97% yield and 99% de. Using other aromatic and heteroaromatic aldehydes, the corresponding lactams or lactones were also obtained in excellent yields and good or excellent enantioselectivities.




Casiraghi and co-workers[ 13 ] expanded the scope of furan-based dienolsilane nucleophiles for asymmetric Mukaiyama aldol reactions by extending the double bond system of the furan.[ 13 ] Bisvinylogous and hypervinylogous Mukaiyama aldol reactions of furan-based silyloxy polyenes with good or excellent enantiocontrol were developed for the first time. The first model compound, 2-(tert-butyldimethylsilyloxy)-5-vinylfuran (36) was readily obtained from acetaldehyde (35) and 2-(tert-butyldimethylsilyloxy)furan (6) in three steps with 63% yield. After the Mukaiyama aldol reaction between 4-bromobenzaldehyde (37) and 36 in the presence of organocatalyst bisphosphoramide 34, silicon tetrachloride, and diisopropylethylamine, a single ε-regioisomer butenolide 38 was obtained in 96% ee (Scheme [8]). Decreased yields and chemoselectivities were observed when the 5-vinyl-2-silyloxyfuran 36 was replaced with a further extended reactant 39 or 41 due to the presence of multinucleophilic sites, although excellent stereoselectivity was still obtained. The Mukaiyama aldol reactions of hyperextended pentaene 41 and 4-bromobenzaldehyde (37) afforded the expected hypervinylogous aldol adduct 42 in 42% yield as a mixture of 5Z/2′E/4′E and other isomers (>98:2 er for both).


Although significant progress has been made in the development of asymmetric catalysts for vinylogous aldol reactions between heterocyclic dienolsilanes and aromatic aldehydes, the asymmetric vinylogous aldol reaction of aliphatic aldehydes remains challenging. In 2010, Deng et al.[ 14 ] reported an enantioselective aldol reaction of benzaldehyde (13) and 2-(trimethylsilyloxy)furan (5) with a cinchona alkaloid carboxylate ammonium salt 45 as a difunctional chiral catalyst, which was prepared using a thiourea-amine and trifluoroacetic acid (Scheme [9]). This catalytic method tolerated variations in both furans and aldehydes. Good enantioselectivities were obtained in aldol reactions of 2-(silyloxy)furans and aliphatic aldehydes. For example, the corresponding anti-adduct was attained in 82:18 dr to 78:22 dr and 80–84% ee with heptanal or hexanal under optimized conditions. Remarkably, the cinchona alkaloid salt 45 was also suitable for the reaction of sterically hindered furans, for example 2-ethyl-5-(trimethylsilyloxy)furan (43) reacted with benzaldehyde (13) to give anti-44 with 95:5 dr and 81% ee.


In 2010, Wang et al. reported the use of bifunctional alkaloid thiourea catalysts in vinylogous Mukaiyama aldol reactions for the important building blocks γ-substituted butenolides, which are useful in the synthesis of natural active products.[ 15 ]
The organocatalyst 50 was found to be favorable for vinylogous aldol reactions and provided high enantioselectivity and diastereoselectivity in a series of screenings. Remarkably, both electron-donating and -withdrawing substituted groups in the aromatic aldehyde afforded high enantioselectivies. Reaction of 2-(trimethylsilyloxy)furan (5) with 4-nitrobenzaldehyde (46) or 4-methylbenzaldehyde (48) gave the corresponding vinylogous Mukaiyama products anti-47 and anti-49 with 91% and 88% ee, respectively (Scheme [10]).


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# 3
α,β-Unsaturated Carbonyl Derived Dienolsilane
Although enantioselective vinylogous aldol reactions of heterocyclic dienolsilanes were successfully investigated, little research has been conducted on the use of other α,β-unsaturated carbonyl derived dienolsilanes.
The first asymmetric vinylogous aldol reaction of ketone-derived dienolsilanes with high enantioselectivity was reported in 2004[ 16 ] where a chiral bisphosphoramide and silicon tetrachloride were used in the reactions. Recently, other α,β-unsaturated carbonyl derived dienolsilanes, such as aldehydes and amides, were also explored by several researchers.[ 5 ]
3.1Aldehyde- and Ketone-Derived Dienolsilanes
The scope of the nucleophile was extended to other acyclic α,β-unsaturated carbonyl derived dienolsilanes in 2007 by Denmark et al.[ 17 ] who reported the Lewis base catalyzed vinylogous aldol reactions of ketone-derived silyl dienol ethers. High levels of selectivity were observed in the addition of trimethylsilyl dienol ethers 51 or 9, or cyclohexenone-derived dienolate 54 to aldehydes. With the use of 0.05 mol% of bisphosphoramide 34 and 1.5 equivalents of silicon tetrachloride in dichloromethane at –78 °C for 24 hours, adduct 52 was obtained from dienolsilane 51 and benzaldehyde (13) in 80% yield and 98% ee (Scheme [11]). Under similar conditions, dienol ether 9 reacted with benzaldehyde (13) with high yield and enantioselectivity. Unlike the trimethylsilyl dienol ethers 51 or 9, the cyclic dienolate 54 did not react with aliphatic aldehydes. However, 54 provided the desired addition products in high yields and excellent diastereoselectivities with cinnamaldehyde, 1-naphthaldehyde, benzaldehyde, or 2-furaldehyde. When the same conditions were applied to 1,3-diketone-derived dienolsilanes, low selectivities were observed. In the presence of bisphosphoramide 34 or other phosphoramide analogues, the addition of bis-silyl dienol ethers prepared from 1,3-diketone to aldehydes, afforded adducts in low yields and enantioselectivities.


In 2011, Kalesse et al.[ 18 ] reported the first asymmetric vinylogous aldol reactions of aldehyde-derived dienolsilanes and aldehydes using tryptophane-derived oxazaborolidinone 58 as the catalyst in propionitrile to produce the desired aliphatic aldehyde addition products with good yields and excellent selectivities of up to 94% (Scheme [12]); moderate yields and selectivities were observed when aromatic aldehydes were used. Tryptophane-derived oxazaborolidinone 58 showed the broadest substrate spectrum, but a valine-derived oxazaborolidinone analogue yielded poor selectivities with aliphatic aldehydes.


# 3.2
Amide-Derived Dienolsilanes
To overcome the limitations of ketone-derived dienolates, such as low reactivity with aliphatic aldehydes and difficulties in isolation from the mixture of cross and extended conjugated dienolates, the highly reactive α,β-unsaturated amide derived dienol ethers of vinylogous aldol additions have been explored. In 2006, Denmark[ 19 ] reported the catalytic and enantioselective vinylogous aldol additions of α,β-unsaturated amide derived silyl ketene acetals. The enantioselectivity of these aldol reactions was highly depended on the structure of the nitrogen substituent, similar to the site selectivity of ester-derived dienolate aldol addition. The morpholine-derived silyl dienol ether 11 reacted with hydrocinnamaldehyde (59) in the presence of bisphosphoramide 34 in 80% yield and 98% ee (Scheme [13]). Notably, both aliphatic and conjugated aldehydes afforded high selectivities in this catalytic system. The morpholine derivative was also an important precursor that could be easily converted into a ketone in high yield.


When the morpholine-derived silyl dienol ether 11 was substituted by a methyl group, satisfactory enantioselectivity was also observed.[ 17 ] α-Methyl-substituted morpholine-derived dienolsilane 63 reacted with aliphatic aldehyde 59 using the bisphosphoramide catalyst 34 and silicon tetrachloride to give 64 in good yield and with exclusive γ-site selectivity and high enantioselectivity (Scheme [14]). Remarkably, the addition of β-methyl-substituted morpholine-derived dienolsilane 65 to hydrocinnamaldehyde (59) using the same catalytic system provided Z-66 with geometrical selectivity, which depended on the chiral bisphosphoramide 34.


With regards to the total synthesis of bioactive natural products, many interesting protocols have been proposed, with one involving the stereocontrolled construction of the key ring by the asymmetric vinylogous Mukaiyama aldol reaction of α,β-unsaturated amide derived dienol ethers. Detailed methodologies were authoritatively reviewed by Casiraghi and co-workers[ 5 ] in 2011. Recently, Kobayashi and co-workers[ 20 ] developed a new protocol comprising two iterative asymmetric vinylogous Mukaiyama aldol reactions and E-selective ring-closing-metathesis reaction for the first time for the synthesis of the antitumor polyketide natural product TMC-151C, which was originally isolated from the fungus Gliocladium catenulatum. As illustrated in Scheme [15], the opening move was the vinylogous Mukaiyama aldol reactions between the known chiral aldehyde 68 and l-valine-based silyl dienol ethers 67; the reaction proceeded to give 69 in good yield (91%) and high enantioselectivity (dr > 20:1) under standard conditions. The desired polychiral fragment 70 was then obtained from 69 by β-mannosylation and asymmetric crotylation in seven steps. In a parallel synthesis, vinylogous Mukaiyama aldol reactions of the same silyl dienol ethers 67 and methacrolein (71) provided the aldol adduct 72 under optimized conditions in 65% yield and greater than 20:1 diastereoselectivity. After protection and an auxiliary removal protocol, the other fragment 73 was attained. The E-selective ring-closing-metathesis reaction between 70 and 73 finally resulted in the total synthesis of the target natural product TMC-151C in three steps and 38% overall yield.


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# 4
Conclusions
Continuous progress has been made in the development of the catalytic aldol reactions for enantioselective C–C bond construction for several decades. This article reviews recent developments with heterocyclic dienolsilanes and α,β-unsaturated carbonyl derived dienolsilanes in asymmetric aldol reactions. Although excellent levels of enantioselectivities have been achieved with both heterocyclic and acyclic carbonyl derived nucleophiles, the addition of these nucleophiles to a wide range of aldehydes with excellent diastereoselectivity remains an unsolved problem. Considerable effort is still required to develop conjugated multifunction group derived dienolsilanes, which are rarely employed in catalytic aldol reactions. After the issues of high catalyst loading and long reaction times have been addressed, the asymmetric aldol reaction could be of wide use in natural product, fine chemical, and pharmaceutical syntheses in industries due to its great atom economy.
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References
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- 4b Kalesse M. Top. Curr. Chem. 2005; 244: 43
- 4c Trost BM, Brindle CS. Chem. Sov. Rev. 2010; 39: 1600
- 5a For a review on asymmetric vinylogous aldol reactions, see: Casiraghi G, Battistini L, Curti C, Rassu G, Zanardi F. Chem. Rev. 2011; 111: 3076
- 5b Rassu G, Zanardi F, Battistini L, Casiraghi G. Chem. Soc. Rev. 2000; 29: 109
- 6 For a review on organocatalytic vinylogous aldol reactions, see: Pansare SV, Paul EK. Chem.–Eur. J. 2011; 17: 8770
- 7 Onitsuka Y, Matsuoka Y, Irie R, Katsuki T. Chem. Lett. 2003; 32: 974
- 8 Frings M, Atodiresei I, Wang YT, Runsink J, Raabe G, Bolm C. Chem.–Eur. J. 2010; 16: 4577
- 9 Meshram HM, Ramesh P, Reddy BC, Sridhar B, Yadav JS. Tetrahedron 2011; 67: 3150
- 10 Evans DA, Dunn TB, Kvaerno L, Beauchemin A, Raymer B, Olhava EJ, Mulder JA, Juhl M, Kagechika K, Favor DA. Angew. Chem. Int. Ed. 2007; 46: 4698
- 11 Zambrano V, Rassu G, Roggio A, Pinna L, Zanardi F, Curti C, Casiraghi G, Battistini L. Org. Biomol. Chem. 2010; 8: 1725
- 12 Curti C, Ranieri B, Battistini L, Rassu G, Zambrano V, Pelosi G, Casiraghi G, Zanardi F. Adv. Synth. Catal. 2010; 352, 2011
- 13 Curti C, Battistini L, Sartori A, Lodola A, Mor M, Rassu G, Pelosi G, Zanardi F, Casiraghi G. Org. Lett. 2011; 13: 4738
- 14 Singh RP, Foxman BM, Deng L. J. Am. Chem. Soc. 2010; 132: 9558
- 15 Zhu N, Ma BC, Zhang Y, Wang W. Adv. Synth. Catal. 2010; 352: 1291
- 16 Denmark SE, Heemstra JR. Synlett 2004; 2411
- 17 Denmark SE, Heemstra JR. J. Org. Chem. 2007; 72: 5668
- 18 Gieseler MT, Kalesse M. Org. Lett. 2011; 13: 2430
- 19 Denmark SE, Heemstra JR. J. Am. Chem. Soc. 2006; 128: 1038
For a review on organocatalytic and metal-based asymmetric aldol reactions, see:
-
References
- 1a Singer RA, Carreira EM. J. Am. Chem. Soc. 1995; 117: 12360
- 1b Kim Y, Singer RA, Carreira EM. Angew. Chem. Int. Ed. 1998; 37: 1261
- 1c Rosa MD, Acocella MR, Villano R, Soriente A, Scettri A. Tetrahedron Lett. 2003; 44: 6087
- 1d Rosa MD, Acocella MR, Rega MF, Scettri A. Tetrahedron: Asymmetry 2004; 15: 3029
- 1e Wang GW, Zhao JF, Zhou YH, Wang BM, Qu JP. J. Org. Chem. 2010; 75: 5326
- 2a Evans DA, Murry JA. J. Am. Chem. Soc. 1996; 118: 5814
- 2b Evans DA, Fitch DM, Smith TE. J. Am. Chem. Soc. 2000; 122: 10033
- 2c Tejeda BB, Bluet G, Broustal G, Campagne JM. Chem.–Eur. J. 2006; 12: 8358
- 3 Shimada Y, Matsuoka Y, Irie R, Katsuki T. Synlett 2004; 57
- 4a Alcaide B, Almendros P. Eur. J. Org. Chem. 2002; 1595
- 4b Kalesse M. Top. Curr. Chem. 2005; 244: 43
- 4c Trost BM, Brindle CS. Chem. Sov. Rev. 2010; 39: 1600
- 5a For a review on asymmetric vinylogous aldol reactions, see: Casiraghi G, Battistini L, Curti C, Rassu G, Zanardi F. Chem. Rev. 2011; 111: 3076
- 5b Rassu G, Zanardi F, Battistini L, Casiraghi G. Chem. Soc. Rev. 2000; 29: 109
- 6 For a review on organocatalytic vinylogous aldol reactions, see: Pansare SV, Paul EK. Chem.–Eur. J. 2011; 17: 8770
- 7 Onitsuka Y, Matsuoka Y, Irie R, Katsuki T. Chem. Lett. 2003; 32: 974
- 8 Frings M, Atodiresei I, Wang YT, Runsink J, Raabe G, Bolm C. Chem.–Eur. J. 2010; 16: 4577
- 9 Meshram HM, Ramesh P, Reddy BC, Sridhar B, Yadav JS. Tetrahedron 2011; 67: 3150
- 10 Evans DA, Dunn TB, Kvaerno L, Beauchemin A, Raymer B, Olhava EJ, Mulder JA, Juhl M, Kagechika K, Favor DA. Angew. Chem. Int. Ed. 2007; 46: 4698
- 11 Zambrano V, Rassu G, Roggio A, Pinna L, Zanardi F, Curti C, Casiraghi G, Battistini L. Org. Biomol. Chem. 2010; 8: 1725
- 12 Curti C, Ranieri B, Battistini L, Rassu G, Zambrano V, Pelosi G, Casiraghi G, Zanardi F. Adv. Synth. Catal. 2010; 352, 2011
- 13 Curti C, Battistini L, Sartori A, Lodola A, Mor M, Rassu G, Pelosi G, Zanardi F, Casiraghi G. Org. Lett. 2011; 13: 4738
- 14 Singh RP, Foxman BM, Deng L. J. Am. Chem. Soc. 2010; 132: 9558
- 15 Zhu N, Ma BC, Zhang Y, Wang W. Adv. Synth. Catal. 2010; 352: 1291
- 16 Denmark SE, Heemstra JR. Synlett 2004; 2411
- 17 Denmark SE, Heemstra JR. J. Org. Chem. 2007; 72: 5668
- 18 Gieseler MT, Kalesse M. Org. Lett. 2011; 13: 2430
- 19 Denmark SE, Heemstra JR. J. Am. Chem. Soc. 2006; 128: 1038
For a review on organocatalytic and metal-based asymmetric aldol reactions, see:



































