Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of α,β-Unsaturated Aldehydes

doi:10.3390/molecules24183412

Review

. 2019 Sep 19;24(18):3412.

doi: 10.3390/molecules24183412.

Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of α,β-Unsaturated Aldehydes

Zhonglei Wang^{1

2}

Affiliations

¹ School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China. wangzl16@tsinghua.org.cn.
² School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. wangzl16@tsinghua.org.cn.

PMID: 31546876
PMCID: PMC6767148
DOI: 10.3390/molecules24183412

Review

Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of α,β-Unsaturated Aldehydes

Zhonglei Wang. Molecules. 2019.

. 2019 Sep 19;24(18):3412.

doi: 10.3390/molecules24183412.

Author

Zhonglei Wang^{1

2}

Affiliations

¹ School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China. wangzl16@tsinghua.org.cn.
² School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China. wangzl16@tsinghua.org.cn.

PMID: 31546876
PMCID: PMC6767148
DOI: 10.3390/molecules24183412

Abstract

Chirality is one of the most important attributes for its presence in a vast majority of bioactive natural products and pharmaceuticals. Asymmetric organocatalysis methods have emerged as a powerful methodology for the construction of highly enantioenriched structural skeletons of the target molecules. Due to their extensive application of organocatalysis in the total synthesis of bioactive molecules and some of them have been used in the industrial synthesis of drugs have attracted increasing interests from chemists. Among the chiral organocatalysts, chiral secondary amines (MacMillan's catalyst and Jorgensen's catalyst) have been especially considered attractive strategies because of their impressive efficiency. Herein, we outline advances in the asymmetric total synthesis of natural products and relevant drugs by using the strategy of chiral secondary amine catalyzed reactions of α,β-unsaturated aldehydes in the last eighteen years.

Keywords: asymmetric total synthesis; bioactive natural products; chiral secondary amines; pharmaceuticals; α,β-unsaturated aldehydes.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

**Scheme 1**
Chiral secondary amines and iminium catalytic cycle.

**Scheme 2**
Total synthesis (+)-curcuphenol.

**Scheme 3**
Total synthesis of (+)-tolterodine.

**Scheme 4**
Total synthesis of (+)-BMS-594726 and COX-2 inhibitor.

**Scheme 5**
Total synthesis of (+)-frondosin B.

**Scheme 6**
Total synthesis of (−)-rhazinal, (−)-rhazinilam, and (−)-leuconolam.

**Scheme 7**
Total synthesis of (-)-flustramine B.

**Scheme 8**
Total synthesis of (−)-diazonamide A.

**Scheme 9**
Total synthesis of thailanstatins A-C and spliceostatin D.

**Scheme 10**
Total synthesis of (+)-conicol.

**Scheme 11**
Total synthesis of α-tocopherol.

**Scheme 12**
Total synthesis of (+)-dactylolide.

**Scheme 13**
Total synthesis of (+)-sedamine, (+)-allosedamine, (+)-coniine, (−)-homoproline, (−)-homopipecolic acid, and (−)-pelletierine.

**Scheme 14**
Total synthesis of (+)-angustureine.

**Scheme 15**
Total synthesis of (+)-cermizine D, (+)-myrtine, and (−)-lupinine.

**Scheme 16**
Total synthesis of (−)-epimyrtine and (+)-myrtine.

**Scheme 17**
Total synthesis of (−)-cocaine, (+)-cocaine, (+)-ferruginine, (−)-1-methylcocaine, and (+)-methylecgonine.

**Scheme 18**
Total synthesis of (−)-spiculisporic acid.

**Scheme 19**
Total synthesis of (−)-aromadendranediol.

**Scheme 20**
Total synthesis of (+)-hippolachnin A, (+)-gracilioethers A, E and F.

**Scheme 21**
Total synthesis of (+)-dehydrocurcumene, (+)-tumerone, and (+)-curcumene.

**Scheme 22**
Total synthesis of MK-0974, baclofen, and rolipram.

**Scheme 23**
Total synthesis of (+)-beraprost.

**Scheme 24**
Total synthesis of (−)-horsfiline, (−)-coerulescine, and estradiol methyl ether.

**Scheme 25**
Total synthesis of (+)-ricciocarpin A.

**Scheme 26**
Total synthesis of (+)-dysideaproline E.

**Scheme 27**
Total synthesis of (+)-virgatusin.

**Scheme 28**
Total synthesis of (+)-podophyllic aldehydes A–C.

**Scheme 29**
Total synthesis of (−)-pavidolide B.

**Scheme 30**
Total synthesis of (+)-hirsutellone B.

**Scheme 31**
Total synthesis of (+)-stagonolide C and (-)-aspinolide A.

**Scheme 32**
Total synthesis of trioxacarcins DC-45-A₁, A₂, A, C and D.

**Scheme 33**
Total synthesis of (-)-bacilosarcins A, B and (-)-AI-77-B.

**Scheme 34**
Total synthesis of (+)-paecilonic acid A.

**Scheme 35**
Total synthesis of (+)-hapalindole Q.

**Scheme 36**
Total synthesis of (+)-propindilactone G.

**Scheme 37**
Total synthesis of (-)-solanapyrone D and (+)-UCS1025A.

**Scheme 38**
Total synthesis of (−)-spinosyn A, amaminols A, and B.

**Scheme 39**
Total synthesis of (-)-vincorine.

**Scheme 40**
Total synthesis of cispentacin.

**Scheme 41**
Total synthesis of (-)-maremycin A.

**Scheme 42**
Total synthesis of (+)-fawcettimine.

**Scheme 43**
Total synthesis of (-)-cermizine B and (+)-lycoposerramine Z.

**Scheme 44**
Total synthesis of (−)-huperzine Q, (+)-lycopladine B, and (+)-lycopladine C.

**Scheme 45**
Total synthesis of (-)-katsumadain A.

**Scheme 46**
Total synthesis of (-)-strychnofoline.

**Scheme 47**
Total synthesis of (+)-*trans*-dihydrolycoricidine.

**Scheme 48**
Total synthesis of (+)-α-skytanthine.

**Scheme 49**
Total syntheses of eight monoterpenoid indole alkaloids.

**Scheme 50**
Total synthesis of (−)-strychnine, (+)-minfiensin and five other alkaloids.

**Scheme 51**
Total synthesis of (+)-galbulin.

**Scheme 52**
Total synthesis of (-)-kopsinine provided (-)-aspidofractine.

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Cited by

Asymmetric Synthesis of US-FDA Approved Drugs over Five Years (2016-2020): A Recapitulation of Chirality.
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Vermeeren P, Hamlin TA, Fernández I, Bickelhaupt FM. Vermeeren P, et al. Chem Sci. 2020 Jul 9;11(31):8105-8112. doi: 10.1039/d0sc02901g. Chem Sci. 2020. PMID: 34094173 Free PMC article.
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Wang Z, Wang N, Yang L, Song XQ. Wang Z, et al. Front Pharmacol. 2022 Aug 19;13:926507. doi: 10.3389/fphar.2022.926507. eCollection 2022. Front Pharmacol. 2022. PMID: 36059994 Free PMC article. Review.
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References

1. Ahrendt K.A., Borths C.J., MacMillan D.W. New strategies for organic catalysis: The first highly enantioselective organocatalytic diels—alder reaction. J. Am. Chem. Soc. 2000;122:4243–4244. doi: 10.1021/ja000092s. - DOI
1. Hayashi Y., Gotoh H., Hayashi T., Shoji M. Diphenylprolinol silyl ethers as efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes. Angew. Chem. Int. Ed. 2005;44:4212–4215. doi: 10.1002/anie.200500599. - DOI - PubMed
1. Franzén J., Marigo M., Fielenbach D., Wabnitz T.C., Kjærsgaard A., Jørgensen K.A. A general organocatalyst for direct α-functionalization of aldehydes: Stereoselective C−C, C−N, C−F, C−Br, and C−S bond-forming reactions. scope and mechanistic insights. J. Am. Chem. Soc. 2005;127:18296–18304. doi: 10.1021/ja056120u. - DOI - PubMed
1. MacMillan D.W. The advent and development of organocatalysis. Nature. 2008;455:304. doi: 10.1038/nature07367. - DOI - PubMed
1. Alemán J., Cabrera S. Applications of asymmetric organocatalysis in medicinal chemistry. Chem. Soc. Rev. 2013;42:774–793. doi: 10.1039/C2CS35380F. - DOI - PubMed

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[1] Ahrendt K.A., Borths C.J., MacMillan D.W. New strategies for organic catalysis: The first highly enantioselective organocatalytic diels—alder reaction. J. Am. Chem. Soc. 2000;122:4243–4244. doi: 10.1021/ja000092s. - DOI

[2] Ahrendt K.A., Borths C.J., MacMillan D.W. New strategies for organic catalysis: The first highly enantioselective organocatalytic diels—alder reaction. J. Am. Chem. Soc. 2000;122:4243–4244. doi: 10.1021/ja000092s. - DOI

[3] Hayashi Y., Gotoh H., Hayashi T., Shoji M. Diphenylprolinol silyl ethers as efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes. Angew. Chem. Int. Ed. 2005;44:4212–4215. doi: 10.1002/anie.200500599. - DOI - PubMed

[4] Hayashi Y., Gotoh H., Hayashi T., Shoji M. Diphenylprolinol silyl ethers as efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes. Angew. Chem. Int. Ed. 2005;44:4212–4215. doi: 10.1002/anie.200500599. - DOI - PubMed

[5] Franzén J., Marigo M., Fielenbach D., Wabnitz T.C., Kjærsgaard A., Jørgensen K.A. A general organocatalyst for direct α-functionalization of aldehydes: Stereoselective C−C, C−N, C−F, C−Br, and C−S bond-forming reactions. scope and mechanistic insights. J. Am. Chem. Soc. 2005;127:18296–18304. doi: 10.1021/ja056120u. - DOI - PubMed

[6] Franzén J., Marigo M., Fielenbach D., Wabnitz T.C., Kjærsgaard A., Jørgensen K.A. A general organocatalyst for direct α-functionalization of aldehydes: Stereoselective C−C, C−N, C−F, C−Br, and C−S bond-forming reactions. scope and mechanistic insights. J. Am. Chem. Soc. 2005;127:18296–18304. doi: 10.1021/ja056120u. - DOI - PubMed

[7] MacMillan D.W. The advent and development of organocatalysis. Nature. 2008;455:304. doi: 10.1038/nature07367. - DOI - PubMed

[8] MacMillan D.W. The advent and development of organocatalysis. Nature. 2008;455:304. doi: 10.1038/nature07367. - DOI - PubMed

[9] Alemán J., Cabrera S. Applications of asymmetric organocatalysis in medicinal chemistry. Chem. Soc. Rev. 2013;42:774–793. doi: 10.1039/C2CS35380F. - DOI - PubMed

[10] Alemán J., Cabrera S. Applications of asymmetric organocatalysis in medicinal chemistry. Chem. Soc. Rev. 2013;42:774–793. doi: 10.1039/C2CS35380F. - DOI - PubMed

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Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of α,β-Unsaturated Aldehydes

Affiliations

Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of α,β-Unsaturated Aldehydes

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Conflict of interest statement

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Conflict of interest statement

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