Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Dec 21;83(24):15110-15117.
doi: 10.1021/acs.joc.8b02378. Epub 2018 Dec 3.

Total Synthesis of the Ortho-Hydroxylated Protoberberines ( S)-Govaniadine, ( S)-Caseamine, and ( S)-Clarkeanidine via a Solvent-Directed Pictet-Spengler Reaction

Affiliations

Total Synthesis of the Ortho-Hydroxylated Protoberberines ( S)-Govaniadine, ( S)-Caseamine, and ( S)-Clarkeanidine via a Solvent-Directed Pictet-Spengler Reaction

Brendan Horst et al. J Org Chem. .

Abstract

The common para regioselectivity in Pictet-Spengler reactions with dopamine derivatives is redirected to the ortho position by a simple change of solvents. In combination with a chiral auxiliary on nitrogen, this ortho-selective Pictet-Spengler produced the 1-benzyltetrahydroisoquinoline alkaloids ( S)-crassifoline and ( S)-norcrassifoline and the bioactive 1,2-dioxygenated tetrahydroprotoberberine alkaloids ( S)-govaniadine, ( S)-caseamine, and ( S)-clarkeanidine with high enantiopurity. Ortho/para ratios up to 89:19 and diastereomeric ratios up to 85:15 were obtained during formation of the B-ring. The general applicability of this solvent-directed regioselectivity was demonstrated with a second Pictet-Spengler reaction as required for C-ring formation of caseamine (o/p = 14:86 in trifluoroethanol) and clarkeanidine (o/p = 86:14 in toluene).

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
General biocatalytic Pictet–Spengler reactions and some examples of alkaloids based on the 7,8-dioxygenated tetrahydroisoquinoline structure.
Scheme 1
Scheme 1. Ortho-Selective Pictet–Spengler Reaction toward the Javaberine Synthesis (ref (7a))
Scheme 2
Scheme 2. Ortho and Para Product Formation: Activation of the Enamine Intermediate in Aprotic and Protic Solvents
Scheme 3
Scheme 3. Synthesis of Govaniadine
Scheme 4
Scheme 4. Synthesis of Caseamine and Clarkeanide via Norcrassifoline
Scheme 5
Scheme 5. Ortho vs Para Selectivity in Tetrahydroberberine Synthesis

Similar articles

Cited by

References

    1. Stöckigt J.; Antonchick A. P.; Wu F.; Waldmann H. The Pictet–Spengler Reaction in Nature and in Organic Chemistry. Angew. Chem., Int. Ed. 2011, 50, 8538–8564. 10.1002/anie.201008071. - DOI - PubMed
    2. Hagel J. M.; Facchini P. J. Benzylisoquinoline Alkaloid Metabolism: a Century of Discovery and a Brave New World. Plant Cell Physiol. 2013, 54, 647–672. 10.1093/pcp/pct020. - DOI - PubMed
    3. Beaudoin A. W.; Facchini P. J. Benzylisoquinoline Alkaloid Biosynthesis in Opium Poppy. Planta 2014, 240, 19–32. 10.1007/s00425-014-2056-8. - DOI - PubMed
    1. Reviews on tetrahydroisoquinoline synthesis:

    2. Chrzanowska M.; Grajewska A.; Rozwadowska M. D. Asymmetric Synthesis of Isoquinoline Alkaloids: 2004–2015. Chem. Rev. 2016, 116, 12369–12465. 10.1021/acs.chemrev.6b00315. - DOI - PubMed
    3. Chrzanowska M.; Rozwadowska M. D. Asymmetric Synthesis of Isoquinoline Alkaloids. Chem. Rev. 2004, 104, 3341–3370. 10.1021/cr030692k. - DOI - PubMed
    4. Bentley K. W. β-Phenylethylamines and the Isoquinoline Alkaloids. Nat. Prod. Rep. 2006, 23, 444–463. 10.1039/B509523A. - DOI - PubMed
    5. See also:

    6. Lipp A.; Ferenc D.; Gütz C.; Geffe M.; Vierengel N.; Schollmeyer D.; Schäfer H. J.; Waldvogel S. R.; Opatz T. A Regio- and Diastereoselective Anodic Aryl-Aryl Coupling in the Biomimetic Total Synthesis of (−)-Thebaine. Angew. Chem., Int. Ed. 2018, 57, 11055–11059. 10.1002/anie.201803887. - DOI - PubMed
    1. Qing Z.-X.; Yang P.; Tang Q.; Cheng P.; Liu X.-B.; Zheng Y. J.; Liu Y.-S.; Zeng J.-G. Isoquinoline Alkaloids and Their Antiviral, Antibacterial, and Antifungal Activities and Structure-activity Relationship. Curr. Org. Chem. 2017, 21, 1920–1934. 10.2174/1385272821666170207114214. - DOI
    1. Rodrigues J. A. R.; Abramovitch R. A.; de Sousa J. D. F.; Leiva G. C. Diastereoselective Synthesis of Cularine Alkaloids via Enium Ions and an Easy Entry to Isoquinolines by Aza-Wittig Electrocyclic Ring Closure. J. Org. Chem. 2004, 69, 2920–2928. 10.1021/jo030287t. - DOI - PubMed
    2. Kametani T.; Nakano T.; Shishido K.; Fukumoto K. J. Chem. Soc. C 1971, 3350–3354. 10.1039/j39710003350. - DOI
    1. Müller M. J.; Zenk M. H. Early Precursors in the Biosynthesis of Cularine-type Benzylisoquinoline Alkaloids. J. Chem. Soc., Chem. Commun. 1993, 73–75. 10.1039/C39930000073. - DOI
    2. Müller M. J.; Zenk M. H. The Biosynthesis of the Cularine Alkaloids. Liebigs Ann. 1993, 1993, 557–563. 10.1002/jlac.199319930191. - DOI