Aldol Reaction/condensation

Reaction of a alpha-hydrogen containing carbonyl group with an enolate of an  aldehyde or ketone in the presence of suitable base or acid is called aldol reaction (aldol addtion) and the product is called aldol (beta-hydroxyaldehyde) or beta-hydroxyketone. 

While the followed dehydration reaction produce a congugate enone and these both reaction (aldol reaction and dehydration) is called aldol condensation

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1P29: Conclusion

In conclusion, we have summarized here aldol reactions and strategies which are used in synthesis of bioorganic and medicinally important compounds.Further finding related to aldol condensation and reactions are compiling and published later.
Thank you for your interest. We are welcomed your correction and modification.
For reading start from older post 1P1   

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1P28: z) Design, synthesis and in vitro testing of α-methylacyl-CoA racemase inhibitors

The enzyme α-methylacyl-CoA racemase (AMACR) is overexpressed in prostate, colon, and other cancers and has been partially validated as a potential therapeutic target by siRNA knockdown of the AMACR gene. Analogs of the natural substrate branched chain α-methylacyl coenzyme A esters, possessing one or more β-fluorine atoms, have been synthesized using Wittig, conjugate addition and asymmetric aldol reactions and found to be reversible competitive inhibitors. The CoA esters were made from the racemic acids and tested as diastereoisomeric mixtures. For the synthesis of compounds 171 and 173, A. J. Carnell et al.⁶⁸ employed an Evans asymmetric aldol reaction to have control over absolute and relative stereochemistry of the 2-methyl and 3-fluoro substituents (Scheme 28). Thus, asymmetric aldol reaction between the boron enolate derived from oxazolidinone 167 and the tetradecanal afforded the syn aldol product 168 as a single isomer.

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68. A. J. Carnell, I. Hale, S. Denis, R. J. A. Wanders, W. B. Isaacs, B. A.  Wilson, and S. Ferdinandusse, J. Med. Chem.,2007, 50, 2700.
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1P27: y) Synthesis of highly potent benzodiazepine γ-secretase inhibitors

I. Churcher et al.⁶⁵ designed novel benzodiazepine containing γ-secretase inhibitors for potent use in Alzheimer’s diseases. A syn combination of α-alkyl or aryl β-hydroxy or hydroxyl methyl substituents was shown to give highly potent compounds. Initially the introduction of a hydroxyl group into the β-position of the hydrocinnamide side chain was investigated. In the case where the α-substituent was methyl, this was carried out using the Evans oxazolidinone chiral auxiliary methodology⁶⁶ to yield the syn- or anti-aldol adduct with eitherabsolute stereochemistry. Coupling to the known, homochiral benzodiazepine⁶⁷ (155) yielded the desired amides (151-154) as shown in Scheme 27a.

Functionalization of syn-aldol (151) was possible to yield adducts (156-159); alternatively, oxidation of 151 gave the β-keto amide (160) (exclusively in the keto form in CDCl₃ solution) as a mixture of diastereomers. Treatment with the appropriate hydroxylamine yielded the oximes (161) and (162), again as mixtures of isomers. When the above route was applied to the preparation of α-4-fluorophenyl-substituted aldol analogues, significant retro-aldol reaction was observed at the LiOH/ H₂O₂-mediated auxiliary cleavage step, necessitating the use of a silyl protecting group. This modification allowed the preparation of the desired syn isomers 163-166 as outlined in Scheme 27b.

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65. I. Churcher, S. Williams, S. Kerrad, T. Harrison, J. L. Castro, M. S. Shearman, H. D. Lewis, E. E. Clarke, J. D. J. Wrigley, D. Beher, Y. S. Tang, and W. Liu, J. Med. Chem., 2003, 46,  2275.

66. D. A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc., 1982, 104, 1737.
67. P. J. Reider, P. Davis, D. L. Hughes, E. J. J. Grabowski, J. Org. Chem., 1987, 52, 955.
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1P26: x) Synthesis of vanillin ethers from 4-(bromomethyl) coumarins as anti-inflammatory agents

M. Ghate et al.⁶⁴ treated 4-(Bromomethyl) coumarins (145) with vanillins, (146) give the corresponding ethers (147), which underwent Knovenagel condensation with ethyl cyanoacetate resulting in the formation of ethers (149) contain an active methylene group and the ortho carbonyl group. Ethers (149), when refluxed in alcoholic potassium carbonate underwent an intramolecular aldol reaction leading to the formation of 4-(7’-methoxy 2’-benzo[b]furanyl)coumarins (150) and the aryloxymethyl Coumarin (148) with p-formyl group were found to be most active as shown in scheme 26.

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64. M. Ghate, D. Manohar, V. Kulkarni, R. Shobha, and S. Y. Kattimani, Eur. J. Med. Chem., 2003, 38, 297.
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1P25: w) Vasodilating and antiarrhythmic activity of heteryl lactones

 L. Leite et al.⁶³ prepared a new series of unsaturated γ- and δ-lactones with pyridyl, quinolyl and nitrophenyl substituents (143, 144), synthesized by the condensation of unsaturated methyl lactones with heteryl aldehyde or nitrobenzaldehyde in the base-catalysed aldol reaction. The antiarrhythmic, vasodilating and cardiotonic activities of the synthesized compounds have been studied in vivo and ex vivo. 3-cyano-5,5-dimethyl-4-[4'-(4-pyridyl)-1',3'-butadienyl)]-2(5H)furanone (143e) displayed a significant vasodilating activity. The antiarrhythmic activity of this compound was higher, but its toxicity lowers than that of the procainamide reference drug. Five-membered lactones, particularly 3-cyano-4-(4-pyridylvinyl)-5,5-dimethyl-2(5H)-furanone (143c), exhibited a remarkable cardiotonic activity. The replacement of a pyridyl substituent by a nitrophenyl group in the pyranone derivative did not change the cardiovascular activity and toxicity as shown in scheme 25.

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63. L. Leite, D. Jansone, M. Veveris, H. Cirule, Y. Popelis, G. Melikyan, A. Avetisyan, and E. Lukevics, Eur. J. Med. Chem., 1999, 34, 859.
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1P24: v) Asymmetric aldol condensation as a route to polypropionate derived pheromones

J. P. DiBattista and F. X. Webster⁶¹ developed a new route for polypropionate derived pheromones using asymmetric aldol condensation as the key step for the synthesies of 129 and 134 as shown in scheme 24a and 24b following the procedure of Evans.⁶²

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61. J. P. DiBattista, and F. X. Webster, Bioorg. Med. Chem., 1996, 4, 423.

62. D. A. Evans, R. L. Dow, T. L. Shih, J. M. Takas, and R. Zahler, J. Am. Chem. Soc., 1990, 112, 5290.
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1P23: u) Synthesis of 2, 5-linked pyrrolinones

A. B. Smith, III et al.⁶⁰ constructed a novalpeptide scaffold for β-strand/sheet and related secondary peptide structural mimics are described. The scaffold, consisting of a repeating array of 2, 5, 5-trisubsttuted pyrrolinone (enaminone) units punctuated with appropriate amino side chains, is conceptually related to their previously successful 3, 5-linked polypyrrolinone non-peptidepeptidomimetic scaffold. Construction of the 2, 5, 5-trisubstituted pyrrolinone ring system proceeds via intramolecular condensation of an N-protected amino dione. The latter is prepared from a protected α-amino ketons and aldehyde via an aldol-oxidation reaction sequence as shown in scheme 23.

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60. A. B. Smith, III, S. T. Knight, P. A. Sprengeler, and R. Hirschmann Bioorg. Med. Chem., 1996, 4, 1021.


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1P22: t) Synthesis of sialyl Lewis x mimetics as selectin inhibitors by enzymatic aldol condensation reactions

C.-C. Lin et al.⁵⁶ prepared several D-mannosyl phosphate/phosphonate derivatives have been enzymatically prepared as sialyl Lewis x tetrasaccharide mimics, which showed strong-to-moderate inhibition against E-, P-, and L-selectins. The synthesis of these mimics is very straight forward; mannosyl aldehyde derivatives are condensed with dihydroxyacetone phosphate (DHAP) in the presence of a DHAP-dependent aldolase to provide mannosyl phosphates. According to C.-C. Lin et al. in their preliminary work⁵⁷ reported that mannosyl phosphates 115 and 116 are good inhibitors of P- and L-selectins. Molecular modeling showed that both 115 and 116 overlap well with the active conformations of SLe^x. In this paper present the detailed synthesis of 115 and 116 and related structures using enzymatic aldol condensation, and analysis of those structures as inhibitors of the three selectins. As shown in Scheme 22a, O- and C-mannosyl aldehydes were chosen as aldolase substrates because D-mannose has been successfully used as the L-fucose equivalent in the design of SLe^x mimetics.⁵⁸ The aldol condensation of the aldehyde with dihydroxyacetone phosphate (DHAP) and the corresponding phosphonate (C-DHAP) using different DHAP-dependent aldolases generates two hydroxyl groups which they postulate to mimic the 4- and 6-hydroxy groups of the galactose moiety, and the phosphate/phosphonate group which mimics the carboxylate negative charge. This strategy creates two new stereogenic centers for use to screen for the best mimic of the galactose residue and is flexible enough to furnish a number of derivatives while keeping the other essential groups in appropriate spatial distance and orientation (see 3-7, Scheme 22b). In addition, the 6-position of the sugar moiety can be changed to hydrophobic functional groups which are expected to increase the binding activity with E- and P- selectin.^{57, 59}

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56. C.-C. Lin, F. Morís-Varas, G. Weitz-Schmidt, and C.-H. Wonga, Bioorg. Med. Chem., 1999, 7, 425.

57. C.-H. Wong, M.-V. Francisco, S.-C. Hung, T.-G. Marron, C.-C. Lin, K. W. Gong, and G. Weitz-Schmidt, J. Am. Chem. Soc., 1997, 119, 8152.

58. (a) B. Dupré, H. Bui, I. L. Scott, R. V. Market, K. M. Keller, P. J. Beck, and T. P. Kogan, Bioorg. Med. Chem. Lett., 1996, 6, 569. (b) T. G. Marron, T. J. Woltering, G. Weitz-Schmidt, and C.-H. Wong, Tetrahedron Lett., 1996, 37, 9037. (c) K. Hiruma, T. Kayimoto, G. Weitz-Schmidt, I. Ollmann, and C.-H. Wong, J. Am. Chem. Soc., 1996, 118, 9265.

59. (a) J. Y. Ramphal, M. Hiroshige, B. Lou, J. J. Gaudino, M. Hayashi, S. M. Chen, L. C. Chiang, F. C. A. Gaeta, and S. A. DeFrees, J. Med. Chem., 1996, 39, 1357. (b) M. Hayashi, T. Tanaka, M. Itoh, and H. Miyauchi, J. Org. Chem., 1996, 61,2938.
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1P21: s) Synthesis of chaetomellic acids and analogues

S. B. Singh et al.⁵⁵ synthesized chaetomellic acids which are a class of alkyl dicarboxylic acids that were isolated from Chaetomella acutiseta using starting step as aldol condensation. Chaetomellic acids are potent and highly specific farnesyl-pyrophosphate (FPP) mimic inhibitors of Ras farnesyl-protein transferase. The synthetic strategy of chaetomellic acids involved a biomimetic-type aldol condensation of the appropriate fatty acid ester with pyruvate followed by elimination of an equivalent of water and hydrolysis of the ester groups. Aldol condensations (Scheme 21) of the appropriate fatty acid esters with methylpyruvate would give an aldol product that would have the carbon skeleton of chaetomellic acids. The aldol reactions in the standard conditions, addition of methylpyruvate to enolate, resulted in very poor yields due to the insolubility of the enolate at -78^oC. This problem could not be circumvented by raising the temperature due to the base catalyzed polymerization of methyl pyruvate at room temperature. However, performing the aldol reaction in the reverse order easily overcame this problem. The reaction of lithium diisopropylamide with methyl palmitate gave an enolate that was slowly added to the cooled (-78^oC) solution of methylpyruvate. This gave a 1:1 diastereomeric mixture of aldol products 113a and 114a in greater than 80% yield (Scheme 21). The aldol reaction of methyl oleate with methyl pyruvate was performed in a similar manner to give a 1:1 diastereomeric mixture of 113b and 114b with a greater than 80% yield. Operationally this reaction was easier due to the increased solubility of the unsaturated enolate at lower temperature. A similar reaction of methyl myristate with methyl pyruvate gave 113c and 114.

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55. S. B. Singh, H. Jayasuriya, K. C. Silverman, C. A. Bonfiglio, J. M. Williamson, and R. B. Lingham, Bioorg. Med. Chem., 2000,8, 571.
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1P20: r) Synthesis and Biological Evaluations of Quinoline-based HMG-CoA Reductase Inhibitors

M. Suzuki et al.⁵⁴ synthesized a series of quinoline-based 3, 5-dihydroxyheptenoic acid derivatives  from quinolinecarboxylic acid esters by homologation, aldol condensation with ethyl acetoacetate dianion, and reduction of 3-hydroxyketone to evaluate their ability to inhibit the enzyme 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in vitro. Aldol condensation of 109 with ethyl acetoacetate dianion yielded racemic 5-hydroxy-3-ketoester (110) as shown in scheme 20.

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54. M. Suzuki, H. Iwasaki, Y. Fujikawa, M. Kitahara, M. Sakashita, and R. Sakoda, Bioorg. Med.Chem., 2001, 9, 2727.
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1P19: q) Chemical and Enzymatic Synthesis of Fructose Analogues

 L. Azéma et al.⁵¹ synthesized various D-fructose analogues modified at C-1 or C-6 positions from D-glucose as probes for import studies by the hexose transporter in parasites e. g. Trypanosoma brucei by taking advantage of the Amadori rearrangement or using the aldol condensation between dihydroxyacetone phosphate and appropriate aldehyde catalyzed by fructose 1, 6-diphosphate aldolase from rabbit muscle. Rabbit muscle aldolase (EC 4.1.2.13) reversibly catalyzes the formation of fructose 1, 6-diphosphate from two triose-phosphates: dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate. This enzyme which is rather selective towards the dihydroxyacetone phosphate structure accepts a large variety of aldehydes as substrate and is frequently in use for synthetic purposes.⁵² Thus, the expected fructofuranosides (102-105) were chemoenzymatically synthesized starting from (R)-3-azido-2-hydroxypropanal diethyl acetal (101) (Scheme 19).⁵³ Aldol condensation of 2-fold excess of aldehyde, resulting from deprotection of ketal (101), with dihydroxyacetone phosphate (formed in situ from fructose 1, 6-diphosphate) catalyzed by aldolase (1 mmol scale) gave the ketose-phosphate which was hydrolyzed in presence of acid phosphatase to yield 6-azido-6-deoxy-fructose (102) as unique reaction product. Subsequent ketalization of the azido ketose gave the corresponding methyl fructofuranoside (103) as a mixture of α- and β-forms. This compound allowed to obtain 6-amino-6-deoxy-fructose derivative (104), isolated after reductive amination, finally, sulfonylation of the ammonium salt with dansyl chloride,furnished the uorescent α- and β-methylfructofuranosides, 105a and 105b respectively. Attempts to obtain 105(a, b), through fructose derivative (107) starting from aldol condensation between dansyled (R) 3-amino-2-hydroxy-propanal diethylacetal 106 (obtained from 101) and dihydroxyacetone phosphate catalyzed by aldolase (Scheme 19) were unsuccessful. This is likely due to either the poor solubility of the aldehyde in aqueous solution or to the possible enzyme inactivation when high level of organic cosolvent was used to make the aldehyde soluble.

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51. L. Azéma, F. Bringaud, C. Blonski, J. Périé, Bioorg. Med. Chem., 2000, 8, 717.

52. (a) C.-H. Wong, F. P. Mazenod, and G. M. Whitesides, J. Org. Chem., 1983, 48, 3493; (b) M. D. Bednarski, E. S. Simon, N. Bischofberger, W.-D. Fessner, M.-J. Kim, W. Lees, T. Saito, H.  aldmann, and G. M. Whitesides, J. Am. Chem. Soc., 1989, 111, 627; (c) J. M. Gijsen, L. Qiao, W. Fitz, and C.-H. Wong, Chem Rev., 1996, 96, 443.

53. a) P. Page, C. Blonski, and J. Périé, Tetrahedron, 1996, 52, 1557. b) T. Gefflaut, C. Blonski, J. Périé, and M. Willson, Prog.Biophys. Molec. Biol., 1995, 63,301; (c) J. Périé, I. Rivére-Alric, C. Blonski, T. Gefflaut, N. Lauth de Viguerie, M. Trinquier, M. Willson, F. R. Opperdoes, and M Callens, Pharmac. Ther., 1993, 60, 347; (d) T. Gefflaut, C. Blonski, and J. Périé, Bioorg. Med. Chem. 1996, 4, 2043; (e) C. Blonski, D. De Moissac, J. Périé, and J. Sygusch, Biochem. J.,1997, 323, 71.
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1P18: p) Synthesis and antitumoral, antiviral evaluation of chiral spiropyrans

The principal aim of the presented work was to evaluate various but structure closely related classes of the chiral spiro-compounds for their cytostatic and antiviral activities. For this reason S. Raić-Malić et al.⁵⁰ synthesized and tested antiviral and antiviral activity of new spiro compound indolinospirobenzopyrans (93-95), indolinospironaphthopyrans (96-99) and indolinospironaphtho-1,4- oxazine (100) were synthesized by an aldol type of condensation of equimolar amounts of 1’,3’,3’-trimethyl-20-methyleneindoline and its 5’-substituted derivatives with 2-hydroxybenzaldehyde substituted with a nitro or methoxy group at position 6 or 7,1-hydroxy-2-naphthaldehyde, 2-hydroxy-1 naphth- aldehyde or 1-nitroso- 2-naphthol. This reaction involves nucleophilic attack of the enamine to the carbonyl or nitroso group and subsequent ring closure by intramolecular addition of the phenolic oxygen to the immonium group which gave under elimination of water the spiro-compounds (93-95, 96-99 and 100). Proof of the stereostructures of 100 was obtained by the single-crystal X-ray diffraction method. A substituted indoline ring and the benzopyran ring in 101 and the naphtho-1, 4-oxazine moiety in 100 are interconnected via the common chiral atom and positioned almost perpendicularly to each other. The five-membered 2, 3-dihydropyrrolo moiety of the indoline ring adopts an envelope conformation in both structures (Scheme 18).

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50. S. Raić-Malić, L. Tomašković, D. Mrvoš-Sermek, B. Prugovećki, M. Cetina, M. Grdiša, K. Paveliš, A. Mannschreck, J. Balzarini, E. D. Clercqf, and M. Mintasa, Bioorg.Med. Chem., 2004, 12, 1037.
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1P17: o) Synthesis of novel flavonoids using aldol condensation a key step

C. J. Bennett et al.⁴⁹ prepared novel flavonoids that combine the radical-scavenging ability of myricetin with vitamin E’s ability to embed itself in membranes. Unlike myricetin, these potential therapeutic antioxidants effectively protect vitamin E-deficient microsomes from lipid peroxidation. The flavonoid head groups are prepared by aldol condensation followed by Algar–Flynn–Oyamada (AFO) oxidation or by Baker–Venkataraman rearrangement. The alkyl tails are introduced by Suzuki or Negishi palladium-catalysed cross-coupling or by crossmetathesis catalysed by first generation Grubbs catalyst. Aldol condensation with trimethoxybenzaldehyde (79) with 80 and 81 gave chalcones (76) and 77. Similarly 82, 83, 85 and 86 is prepared and further synthesized novel flavonoids using different step (Scheme 17).

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49. C. J. Bennett, S. T. Caldwell, D. B. McPhail, P. C. Morrice, G. G. Duthieb, and R. C. Hartleya, Bioorg.Med. Chem., 2004, 12, 2079
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1P16: n) 1, 3-Iminoketones as new synthons for the stereocontrolled preparation of useful carbapenem intermediates

Alcaide et al.⁴⁸ has been developed an efficient, totally stereoselective two-step synthesis of cis- and trans-carbapenem intermediates (72-73) based upon the reaction of N-methoxycarbonylmethyl 1, 3-iminoketones (70) with benzyloxyacetyl chloride followed by a stereocontrolled intramolecular aldol-type condensationas shown in scheme 16.

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48. B. Alcaide, J. Pẻrez-Castells, B. Sànchez-Vigo, and M. A. Sierra, Bioorg. Med. Chem. Lett., 1993, 3, 2369.
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1P15: m) Design and biological evaluation of a series of thiophene-based 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors

G. M. Coppola et al.⁴⁷ prepared a series of highly functionalized thiophene-based 3, 5-dihydroxyheptenoic acid derivatives (69) from aldehydes 64 by homologation, aldol condensation with ethyl acetoacetate dianion and stereoselective β-hydroxyketone reduction. High levels of HMG-CoA reductase inhibitory activity have been found within the series (Scheme 15).

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47. G. M. Coppola, R. E. Damon, H. Yu and R. G. Engstrom, Bioorg. Med. Chem. Lett., 1997, 7, 549.


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1P14: l) Synthesis and biological evaluations of condensed pyridine and condensed pyrimidine-based HMG-CoA reductase inhibitors

 M. Suzuki et al.⁴⁶ synthesized a series of 3,5-dihydroxyheptenoic acid derivatives containing pyrazolopyridine, isoxazolopyridine, thienopyridine, and pyrazolopyrimidine as a key scaffold from condensed pyridine and condensed pyrimidine carboxylic acid esters by homologation, aldol condensation with ethyl acetoacetate dianion, and stereoselective reduction of the 5-hydroxyketone. Several compounds in the series were found to have potent HMG-CoA reductase inhibitory activities in vitro and marked cholesterol biosynthesis inhibitory activities in vivo. Scheme 14 shows the elaboration of 3, 5-dihydroxyheptenoic acid derivatives 63(a–d) starting from 57(a–d). The Dibal reduction of 57(a–d), followed by PCC oxidation of the resulting alcohol 58(a–d) provided aldehydes 59(a–d). Homologation of 59(a–d) to propenal 47(a–d) was accomplished by utilizing cis-(2-ethoxyvinyl) lithium and subsequent hydrolysis with p-toluenesulfonic acid. An aldol condensation of 60(a–d) with the sodium/lithium dianion of ethyl acetoacetate afforded the racemic 3-keto-5-hydroxy esters 61(a–d) and further converted in 62(a-d) and than in 63(a-d).

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46. M. Suzuki, H. Iwasaki, Y. Fujikawa, M. Sakashita, M. Kitahara, and R. Sakoda, Bioorg. Med. Chem. Lett., 2001, 11, 1285
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1P13: k) Synthesis and anti-influenza virus activity of 4-guanidino-7-substituted neu5Ac2en derivatives

T. Honda et al.⁴⁵ synthesized a series of Zanamivir derivative possessing C-7 substituted glycerol side chains using enzyme-catalyzed aldol condensation as shown in scheme 13 (d and e) and evaluated in vitro inhibitory activity against influenza A virus sialidase. Furthermore, replacement of the C-7 hydroxyl group of zanamivir by small lipophilic substituents (F, OMe, OEt, N₃) improved influenza A virus plaque reduction activity.

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45. T. Honda, T. Masuda, S. Yoshida, M. Arai, Y. Kobayashi, and M. Yamashita, Bioorg. Med. Chem. Lett., 2000, 12, 1921.
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1P12: j) Sequential aldol condensation for the synthesis of new glycine antagonists

S. A. Giacobbe et al.⁴⁴ synthesized a new glycine antagonist via sequential aldol condensation-lactonization-elimination reaction using aldol condensation, a key step as shown in scheme 12. In his attempt, the Li enolate of N-phenylpyrrolidone, prepared by treatment of 50 with a stoichiometric amount of t-BuLi for 1.5 h was reacted with 49 in THF at -78 °C. Resulting in a 3/2 mixture of aldol products 51a (Z-form) and 51b (E-form) in 60% cumulative yield.

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44. S. A. Giacobbe, D. Baraldi, and R. Di Fatrio,  Bioorg. Med. Chem. Lett., 1998, 8, 1689.
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1P11: i) Intramolecular aldol cyclization of L-lyxo-Hexos-5-ulose Derivatives

 G. Catelani et al.⁴¹ synthesized a new diastereoselective D-chiro-Inositol because of their biological intrest.⁴² The DBU-promoted intramolecular aldol condensation of two partially protected l-lyxo-hexos-5-ulose derivatives (39 and 40), in turn obtained starting from methyl β-D-galactopyranoside, takes place with fairly good yield and complete diastereoselectivity to give 2L-(2,3,6/4,5)-pentahydroxycyclohexanone derivatives (41 and 42). The stereoselective reduction of 41 and 41 with sodium triacetoxyborohydride leads, after catalytic debenzylation, to 47, while the sodium borohydride reduction⁴³ furnishes, with opposite stereoselectivity, a derivative of allo-inositol (48).

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41. G. Catelani, A. Corsaro, F. D’Andrea, M. Mariania, and V. Pistarà Bioorg. Med. Chem. Lett., 2002, 12, 3313.

42. M. J. Berridge, Nature, 1989, 341, 197; Billington, D. C. The Inositols Phosphates—Chemical Synthesis and Biological Significance; VCH: Weinheim, 1993.

43. P. L. Barili, G. Berti, G. Catelani, F. D’Andrea, F. De Rensis, and G. Goracci, J. Carbohydr.Chem., 1998, 17, 1167.
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1P10: h) Synthesis of versatile route to arylthiomethyl morpholine analogues of reboxetine

J. Boot et al.³⁸ worked on a novel arylthiomethyl morpholines, a potent selective norepinephrine reuptake inhibitors (NERIs) and dual serotonin/ norepinephrine reuptake inhibitors (SRI/NERIs). The target compounds were prepared using a stereochemically versatile synthesis featuring an aldol condensation as the key step. One enantiomer of the 2-methoxy-substituted analogue was found to be a potent and selective norepinephrine reuptake inhibitor, whereas the opposite enantiomer was a potent dual serotonin/norepinephrine reuptake inhibitor.Reaction between benzaldehyde and the enolate derived from readily available N-benzyl-2-morpholinone (34) gave an acceptable yield of the two diastereomeric benzylalcohols (35) and (36) in a ratio of 2.2/1 (Scheme 10).³⁹ The aldol products could be separated by chromatography on silica gel. The assignment of relative stereochemistry was based on the coupling constants between the proton at C-2 of the morpholine ring and the benzylic hydrogen. The initial assignment of the relative stereochemistry was later confirmed by X-ray crystallographic analysis.⁴⁰ Diborane-mediated reduction of the lactam gave morpholine benzyl alcohols (37) and (38) in good yield.

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38. J. Boot, M. Cases, B. P. Clark, J. Findlay, P. T. Gallagher, L. Hayhurst, T. Man, C. Montalbetti, R. E. Rathmell, H. Rudyk, M. W. Walter, M. Whatton, and V. Wood, Bioorg. Med. Chem. Lett., 2005, 15, 699.

39. A. Dobrev, L. Nechev, and K. Ivanov, Liebigs Ann. Chem., 1989, 815.

40. For details see: M. W. Walter, B. P. Clark, P. T. Gallagher, H. L. Haughton, and H. C. E. Rudyk, WO 2004017977NET assay: J. Gobel, D. L. Saussy, and A. Goetz, J. Pharmacol.Toxicol. Methods, 1999, 42, 237; SERT/DAT assay: S. Ramamoorthy, E. Giovanetti, Y. Qian, and R. Blakely, J. Biol. Chem., 1998, 273, 2458.


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