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A Unified Total Synthesis of Isocyclocapitelline and Cyclocapitelline

A facile and concise synthesis of β-carboline alkaloids, such as (–)-isocyclocapitelline and (+)-cyclocapitelline, has been achieved from commercially available geraniol through a unified strategy. The key steps involved in this synthesis are Sharpless epoxidation, intramolecular ring opening of epoxide, Pictet-Spengler reaction, and dehydrogenative aromatization using 10% palladium/carbon in xylene under neutral conditions.


Results and Discussion
Our synthesis commenced with a familiar transformation in organic synthesis, which is Sharpless asymmetric epoxidation of the readily available monoterpene geraniol (1). The vital strategy in our synthesis is the preparation of chiral 2-((2R,5S)-5-(2-hydroxypropan-2-yl)-2-methyltetra-hydrofuran-2-yl)acetaldehyde (5a), a key intermediate in our synthesis, which was prepared by a sequence of transformations. Geraniol (1) was subjected to Sharpless epoxidation 29-31 using (d-(-)-diisopropyl tartrate, Ti(O i Pr) 4 , and tert-butyl hydroperoxide in dichloromethane (CH 2 Cl 2 ) to afford the epoxy alcohol 2 in 95% yield. The reductive opening of epoxide 2 was accomplished by using sodium bis(2-methoxyethoxy)aluminum hydride (3.5 M in toluene, 1.1 equiv.), to give the diol 3, with 90% yield. The diol 3 was further treated with metachloroperoxybenzoic acid in CH 2 Cl 2 , to afford the functionalized THF core as a mixture of diastereomers 4a and 4b in a 1:1 ratio, which was separated by column chromatography and obtained as pure compounds. Treatment of diol 3 with a chiral Shi 32 ketone A (derived from fructose) in the presence of oxone, potassium carbonate in acetonitrile and water over 8 hours gave the chiral THF core 4a as a single isomer. 22,26 Disappearance of the signal (dd) at δ 5.11 ppm and the presence of signals at δ 131.5, 121.4 ppm in the 1 H and 13 C nuclear magnetic resonance (NMR) spectra confirmed the formation of 4a and 4b from 3. The spectroscopic data of 4a are in agreement with that of the product formed with Shi ketone, which was further confirmed by its stereochemistry. Compound 4a was further oxidized to aldehyde 5 under a nitrogen atmosphere, using pyridinium chlorochromate (PCC) as an oxidant in CH 2 Cl 2 (60% yield) (Scheme 1). The characteristic triplet 1 H signal at δ 9.85 ppm and 13 C signal at δ 202.2 ppm confirmed the formation of aldehyde 5.

Coupling of Aldehyde 5a and 5b With Tryptamine (6)
Aldehyde 5a was treated with tryptamine (6) in the presence of TFA in CH 2 Cl 2 under Pictet-Spengler 33 conditions to give tetrahydrocarboline 7, which was further subjected to dehydrogenation with palladium (Pd)/carbon (C) in xylene under reflux conditions to furnish (−)-isocyclocapitelline (7a) in 75% yield over 2 steps, as shown in Scheme 2. The 1 H and 13 C NMR spectra of the synthesized product 8a were in full agreement with those of the reported natural product. 34 The specific rotation of our synthesized compound was Similarly, synthesis of (+)-cyclocapitelline (8b) was achieved from the aldehyde 5b by adopting the above reaction conditions, as shown in Scheme 3.
The 1 H and 13 C NMR spectra of the synthesized product 8b correlated with those of the reported natural product. 34 The specific rotation of our synthesized compound was [α] D 25 = +42.8 (c 0.5, CHCl 3 ), which was in agreement with the natural product 34 [α] D25 = +43 (c 0.5, CHCl 3 ).
General experimental details and spectroscopic data have been included in Supplementary Material 1.

Conclusion
In summary, we have successfully established a unified strategy for the total synthesis of Hedyotis plant alkaloids (-)-isocyclocapitelline (8a) and (+)-cyclocapitelline (8b) from readily available geraniol (1). The vital reactions involved in this approach are the Sharpless asymmetric epoxidation, reductive cleavage of epoxide, intramolecular ring opening of epoxide, and Pictet-Spengler reaction. The overall strategy is a very facile, scalable, and protection group-free synthesis, which makes it a concise synthesis.

Acknowledgment
We thank the Vice-Chancellor of Osmania University for his support.

Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

Supplemental Material
Supplemental material for this article is available online.