Spirotryprostatin B

Chembox new
Name = Spirotryprostatin B
ImageFile = SpirotryprostatinB.png ImageName = Spirotryptostatin B
Section2 = Chembox Properties
Formula = C₂₁H₂₁N₃O₃
MolarMass = 363.41 g/mol

Spirotryprostatin B is an indolic alkaloid found in the "Aspergillus fumigatus" fungus. Spirotryprostatin B and several other indolic alkaloids (including Spirotryprostatin A, as well as other tryprostatins and cyclotryprostatins) have been found to have anti-mitotic properties, and as such they have become of great interest as anti-cancer drugsRef|Cui. Because of this, the total syntheses of these compounds is a major pursuit of organic chemists, and a number of different syntheses have been published in the chemical literature.

The first total synthesis was accomplished in 2000 by the Danishefsky group at Columbia UniversityRef|Danishefsky, with a number of other syntheses following shortly thereafter by WilliamsRef|Williams, GanesanRef|Ganesan, FujiRef|Fuji, CarreiraRef|Carreira, HorneRef|Horne, OvermanRef|Overman, and most recently TrostRef|Trost.

From a synthetic point of view, the most challenging structural features of the molecule are the C3 spirocyclic ring juncture and the adjacent prenyl-substituted carbon. Approaches toward preparing the skeleton of spirotryprostatin B have varied considerably.

Danishefsky spirotryprostatin B synthesis:

In the Danishefsky synthesis, an amine derived from tryptophan was condensed with an aldehyde, triggering a Mannich-type reaction wherein the pendant oxindole acted as a nucleophile toward the intermediate iminium species.

Williams spirotryprostatin B synthesis:

The synthesis by the Williams group utilized a 3-component coupling reaction. A secondary amine was combined with an aldehyde to form an intermediate azomethine ylide, which underwent a 1,3-dipolar cycloaddition with an unsaturated oxindole also present in the reaction mixture.

Ganesan spirotryprostatin B synthesis:

Ganesan made use of a biomimetic strategy in his synthesis of spirotryprostatin B. An indole was treated with "N"-bromosuccinimide to trigger an oxidative rearrangement, forming the quaternary stereocenter in a diastereoselective manner.

Fuji spirotryprostatin B synthesis:

In the synthesis developed by the Fuji group, the stereochemistry at the spirocyclic carbon was established by a nitroolefination reaction. An oxindole with pendant prenyl group was reacted with a nitroolefin bearing a chiral leaving group.

Carreira spirotryprostatin B synthesis:

The Carreira group made use of a magnesium iodide promoted annulation reaction in their approach toward spirotryprostatin B. An oxindole bearing a cyclopropane was reacted with an imine in the presence of the magnesium iodide, triggering the ring-expansion reaction.

Horne spirotryprostatin B synthesis:

Horne's synthesis of spirotryprostatin B also made use of a Mannich-type process, wherein a chloro-indole served as the pro-nucleophile. The cyclization was triggered by treating the pendant imine with the acyl chloride derived from proline. The resulting iminium species was attacked by the chloro-indole, forming the spirocyclic bond.

Overman spirotryprostatin B synthesis:

The Overman group utilized a Heck reaction to prepare the molecule. An iodo-aniline with a tethered alkene was subjected to palladium catalysis. The intermediate palladium-allyl species was intercepted by the pendant amide nitrogen to generate the prenyl stereocenter in the same reaction.

Trost spirotryprostatin B synthesis:

In the synthesis developed by the Trost group, the stereochemistry at the spirocyclic ring juncture is established by a decarboxylation-prenylation sequence, reminiscent of the Carroll reaction. Here, a prenyl ester serves as both the nucleophile and electrophile precursor. Upon treatment with a chiral palladium catalyst the prenyl group ionizes and decarboxylates. The resulting ion pair subsequently recombines to generate the prenylated product. Notably, double bond migration occurs and the prenyl group is attacked at the oxindole carbon.

References

#Note|Cuicite journal
author = Cui, CB "et al"
title = Spirotryprostatin B, a novel mammalian cell cycle inhibitor produced by Aspergillus fumigatus
journal = J. Antibiot.
volume = 49
issue =
pages = 832–835
date = 1996
pmid = 8823522
#Note|Danishefskycite journal
author = von Nussbaum, F; Danishefsky, SJ
title = A Rapid Total Synthesis of Spirotryprostatin B: Proof of Its Relative and Absolute Stereochemistry
journal = Angew. Chem. Int. Ed.
volume = 39
issue = 12
pages = 2175–2178
date = 2000
doi = 10.1002/1521-3773(20000616)39:12<2175::AID-ANIE2175>3.0.CO;2-J
doilabel = 10.1002/1521-3773(20000616)39:122175::AID-ANIE21753.0.CO;2-J
#Note|Williamscite journal
author = Sebahar, PR; Williams, RM
title = The Asymmetric Total Synthesis of (+)- and (-)-Spirotryprostatin B
journal = J. Am. Chem. Soc.
volume = 122
issue = 23
pages = 5666–5667
date = 2000
doi = 10.1021/ja001133n
#Note|Ganesancite journal
author = Wang, H; Ganesan, A
title = A Biomimetic Total Synthesis of (-)-Spirotryprostatin B and Related Studies
journal = J. Org. Chem.
volume = 65
issue = 15
pages = 4685–4693
date = 2000
doi = 10.1021/jo000306o
#Note|Fujicite journal
author = Bagul, TD "et al"
title = Total Synthesis of Spirotryprostatin B via Asymmetric Nitroolefination
journal = Org. Lett.
volume = 4
issue = 2
pages = 249–251
date = 2002
doi = 10.1021/ol016999s
#Note|Carreiracite journal
author = Meyers, C; Carreira, EM
title = Total Synthesis of (-)-Spirotryprostatin B
journal = Angew. Chem. Int. Ed.
volume = 42
issue = 6
pages = 694–696
date = 2003
doi = 10.1002/anie.200390192
#Note|Hornecite journal
author = Miyake, FY "et al"
title = Preparation and Synthetic Applications of 2-Halotryptophan Methyl Esters: Synthesis of Spirotryprostatin B
journal = Angew. Chem. Int. Ed.
volume = 43
issue = 40
pages = 5357–5360
date = 2004
doi = 10.1002/anie.200460419
#Note|Overmancite journal
author = Overman, LE; Rosen, MD
title = Total Synthesis of (-)-Spirotryprostatin B and Three Stereoisomers
journal = Angew. Chem. Int. Ed.
volume = 39
issue = 24
pages = 4596–4599
date = 2000
doi = 10.1002/1521-3773(20001215)39:24<4596::AID-ANIE4596>3.0.CO;2-F
doilabel = 10.1002/1521-3773(20001215)39:244596::AID-ANIE45963.0.CO;2-F
#Note|Trostcite journal
author = Trost, BM; Stiles, DT
title = Total Synthesis of Spirotryprostatin B via Diastereoselective Prenylation
journal = Org. Lett.
volume = 9
issue = 15
pages = 2763–2766
date = 2007
doi = 10.1021/ol070971k