I would like to thank my committee members, Professors John Bercaw, Greg Fu, and the chair of my committee, Professor Brian Stoltz. I must also thank the Natural Sciences and Engineering Research Council (NSERC) of Canada for a graduate fellowship and the NIH for financial support. I also have to thank Blake Daniels, the freshman I started working with on the Prince project.
In addition to the Reisman lab, I also have to thank the other friends I've made at Caltech, including Dr.
Ray Crystallography Report Relevant to Chapter 4
Introduction
The pyrroloindoline motif (marked in red, Figure 1a) constitutes the core heterocyclic motif of a diverse structural class of natural products. These compounds have been shown to exhibit remarkable biological activities in a wide range of pharmacological screens, including anticancer, 1,2 antibacterial, 3 anti-inflammatory4, and cholinesterase inhibition activities.5 The all-carbon C3a quaternary center found in many of these compounds include a wide variety of substituents. The inherent challenge of preparing such structures, combined with their promising medicinal value, has led to the development of a variety of methods for their synthesis.6-8.
This chapter provides an overview of strategies for the preparation of the pyrroloindoline motif in the context of total natural product synthesis.
Pyrroloindoline Synthesis via Oxindoles
The total synthesis of idiospermulin was completed by hydrogenation to saturated sulfonamide, reduction of the oxindole carbonyl with Red-Al, and treatment with excess sodium in ammonia. The Trost laboratory has developed a molybdenum-catalyzed asymmetric allylic alkylation (AAA reaction) of 3-alkyloxindoles to furnish oxindoles with quaternary all-carbon stereocenters C3.10 The Mo-catalyzed AAA reaction involves metal precoordination followed by nucleophilic reduction in elimination. , unlike the palladium-catalyzed process in which the nucleophile directly attacks the π-allyl from. Indeed, high enantioselectivities were observed with ligand 27 derived from trans -1,2-diaminocyclohexane; in the proposed model for enantiodiscrimination, the favored approach minimizes steric congestion between the ligand and the oxindole enolate as the C terminus of the enolate moves toward the π-allyl.
In the alternative approach, the bulk of the oxindole clashes sterically with the ligand during bond formation.
Pyrroloindoline Synthesis via C3 Functionalization/Cyclization
The optimal conditions for the Mo-catalyzed AAA reaction were applied to a formal total synthesis of (–)-physostigmine ( Figure 3b ). The MacMillan laboratory has completed a total synthesis of the Strychnos alkaloid minfiensine ( 4 ) using an enantioselective organocatalytic Diels–Alder/amine cyclization cascade to construct the pyrroloindoline core ( Figure 9 ). Condensation of the secondary amine catalyst 60 with propynal generates an iminium ion with the acetylenic group directed away from the bulky t -butyl substituent of the catalyst.
Thus, total syntheses of these natural products are particularly suitable for asymmetric catalysis, as each enantiomer of the required pyrroloindoline building block can be achieved by choosing the appropriate enantiomer of the catalyst.
Concluding Remarks
Chapter 2 describes the development of a (R)-BINOLSnCl4-catalyzed formal (3 + 2) cycloaddition to directly prepare enantio-enriched pyrroloindolines from 3-substituted indoles and 2-amidoacrylates. Nocardioazine B (75) was obtained by coupling differentially protected pyrroloindoline building blocks endo-73 and exo-69 with BOP-Cl.
Notes and References
Lindsay Repka.1 At the beginning of our efforts in this area, there were only two such methods for the direct preparation of pyrroloindolines from indole precursors: MacMillan's organocatalytic addition-cyclization of tryptamines with α,β-unsaturated aldehydes,2 and palladium catalyzed by Trost. C3-allylation of 3-substituted indoles.3. This chapter describes the development of a new approach for the enantioselective preparation of pyrroloindolines, using a formal (3 + 2) catalyzed (R)-BINOL•SnCl4 cycloaddition of 3-substituted indoles and 2-amidoacrylates. This reaction is tolerant of various substitution patterns and includes the necessary C2 substitution for advancement to pyrroloindoline diketopiperazine natural products.
Parts of this chapter are taken from published studies (see references 7 and 19) and the supporting information found therein.
Development of a Formal (3 + 2) Cycloaddition
Attempts to improve the enantioselectivity of the formal (3 + 2) cycloaddition began with an investigation of the temperature effects. The formal (3 + 2) cycloaddition between 1,3-dimethylindole (89) and benzyltrifluoroacetamidoacrylate (71) is amenable to in situ NMR monitoring, as it is homogeneous over the course of the reaction. In the course of the reaction, resonances corresponding to an indole-acrylate adduct grow; however, these peaks do not correspond to the pyrroloindoline product.
In addition, the modest diastereoselectivity leads to lower isolated yields of the pure exo diastereomer.
Concluding Remarks
It is proposed that this reaction occurs via a highly face-selective catalyst-directed protonation and that cyclization of the resulting iminium intermediate occurs only by workup. The implications of these experiments have resulted in the reoptimization of the conditions for this reaction to provide higher levels of selectivity. The mechanistic proposal has led to the development of other methods for indole alkaloid synthesis, including a tandem conjugate addition/enantioselective protonation reaction to generate tryptophan derivatives,§ a conjugate addition/in situ reduction to give indolin amino acid derivatives (Chapter 2), and a conjugate addition/asymmetric protonation/ Prins cyclization reaction (Chapter 3).
In addition, this reaction has been used to prepare the core pyrroloindoline motifs in the enantioselective total synthesis of the natural products (–)-lansai B20 and (+)-nocardioazine A.21** Additional related research within the Reisman laboratory is focused on improving mechanistic understanding of the formal (3 + 2) cycloaddition reaction, application of the asymmetric protonation strategy to new methods and synthesis of pyrroloindoline natural products.
Experimental Section
The crude residue was purified by flash chromatography (20→35% ethyl acetate/hexanes) to give 53.0 mg (77% yield) of 94 in a 6:1 ratio of diastereomers (as determined by 1H NMR analysis of the purified product). The crude residue was purified by flash chromatography (5→8% ethyl acetate/hexanes) to give 54 mg (86% yield) of 96 in a 4:1 ratio of diastereomers (determined by NMR analysis of the crude reaction mixture). The crude residue was purified by flash chromatography (5→10% ethyl acetate/hexanes) to give 83.1 mg (93% yield) of 98a in a 3:1 ratio of diastereomers (as determined by HPLC analysis of the purified product).
The crude residue was purified by flash chromatography (5→12% ethyl acetate/hexanes) to give 53.0 mg (61% yield) of 98b in a 3:1 diastereomer ratio (as determined by 1 H NMR analysis of the purified product). The crude residue was purified by flash chromatography (5→15% ethyl acetate/hexanes) to give 72.9 mg (84% yield) of 98c in a 5:1 diastereomer ratio (as determined by 1H NMR analysis of the purified product). The crude residue was purified by flash chromatography (0→5% ethyl acetate/hexanes) to give 50 mg (51% yield) of 98d in a 3:1 diastereomer ratio (as determined by 1H NMR analysis of the pure product).
The crude residue was purified by flash chromatography (0→10% ethyl acetate/hexanes) to afford 78.3 mg (91% yield) of 98e in a 4:1 ratio of diastereomers (determined by 1H NMR analysis of the purified product). The crude residue was purified by flash chromatography (0→5% ethyl acetate/hexanes) to afford 61 mg (54% yield) of 98f in a 6:1 ratio of diastereomers (determined by 1H NMR analysis of the purified product). The crude residue was purified by flash chromatography (5→20% ethyl acetate/hexanes) to afford 60 mg (65% yield) of 98g in a >18:1 ratio of diastereomers (determined by 1H NMR analysis of the pure product) .
The crude residue was purified by flash chromatography (5→20% ethyl acetate/hexanes) to give 81 mg (80% yield) of 98h in a 4:1 ratio of diastereomers (as determined by 1H NMR analysis of the crude reaction mixture). The crude residue was purified by flash chromatography (0→10% ethyl acetate/hexanes) to give 79.7 mg (90% yield) of 72 in a 3:1 ratio of diastereomers (determined by SFC analysis of the purified products, prior to diastereomer separation ). The crude residue was purified by flash chromatography (0→20% ethyl acetate/hexanes) to give 10.7 mg (18% yield) of 98i in an 8:1 diastereomer ratio (as determined by NMR analysis of the pure product).
The crude residue was purified by flash chromatography (5→25% ethyl acetate/hexanes) to afford 48.1 mg (68% yield) of 110d (major diastereomer only).
Notes and References
LMRIV-N-me-TBStryptophol Example name: LMRIV-N-me-TBStryptophol Data collected at: indy.caltech.edu-inova500 Archive folder: /home/lrepka/vnmrsys/data Example folder: LMRIV-N-me-TBStryptophol FidFile : PROTON01 Pulse Sequence : PROTON (s2pul) Solvent: cdcl3 Data collected on: Jul 10, 2010 Temp. LMRIV-N-me-TBStryptophol2 Example name: LMRIV-N-me-TBStryptophol2 Data collected at: indy.caltech.edu-inova500 Archive folder: /home/lrepka/vnmrsys/data Example folder: LMRIV-N-me-TBStryptophol2 FidFile : CARBON01 Pulse Sequence : CARBON (s2pul) Solvent: cdcl3 Data collected on: Jul 10, 2010 Temp. JN-1-131-minordiast3 Example name: JN-1-131-minordiast3 Data collected at: indy.caltech.edu-inova500 Archive folder: /home/janeni/vnmrsys/data Example folder: JN-1-131-minordiast3 FidFile : CARBON01 Pulse Sequence : CARBON (s2pul) Solvent: cdcl3 Data collected on: August 5, 2010 Operator: janeni Relax.
JN-1-191-minordiast Sample name: JN-1-191-minordiast Data collected at: indy.caltech.edu-inova500 Archive folder: /home/janeni/vnmrsys/data Sample directory: JN-1-191-minordiast FidFile : PROTON01 Pulse sequence : PROTON (s2pul) Solvent: cdcl3 Data collected on: Jul 18, 2010 Temp. JN-1-191-minordiast Sample name: JN-1-191-minordiast Data collected at: indy.caltech.edu-inova500 Archive folder: /home/janeni/vnmrsys/data Sample directory: JN-1-191-minordiast FidFile : CARBON01 Pulse sequence : CARBON (s2pul) Solvent: cdcl3 Data collected on: Jul 18, 2010 Temp. JN-1-195-majordiast4 Sample name: JN-1-195-majordiast4 Data collected at: indy.caltech.edu-inova500 Archive folder: /home/janeni/vnmrsys/data Sample directory: JN-1-195-majordiast4 FidFile : PROTON01 Pulse sequence : PROTON (s2pul) Solvent: cdcl3 Data collected on: Jul 16, 2010 Temp.
JN-1-195-majordiast4 Sample name: JN-1-195-majordiast4 Data collected on: indy.caltech.edu-inova500 Archive directory: /home/janeni/vnmrsys/data Sample directory: JN-1-195-majordiast4 FidFile : CARBON01 Pulse sequence : CARBON (s2pul) Solvent: cdcl3 Data collected on: 16 Jul 2010 Temp. JN-1-195-minordiast Sample name: JN-1-195-minordiast Data collected on: indy.caltech.edu-inova500 Archive directory: /home/janeni/vnmrsys/data Sample directory: JN-1-195-minordiast FidFile : PROTON01 Pulse sequence : PROTON (s2pul) Solvent: cdcl3 Data collected on: 15 Jul 2010 Temp. JN-1-195-minordiast Sample name: JN-1-195-minordiast Data collected on: indy.caltech.edu-inova500 Archive directory: /home/janeni/vnmrsys/data Sample directory: JN-1-195-minordiast FidFile : CARBON01 Pulse sequence : CARBON (s2pul) Solvent: cdcl3 Data collected on: 15 Jul 2010 Temp.
JN-1-171-minordiast2 Sample name: JN-1-171-minordiast2 Data collected on: indy.caltech.edu-inova500 Archive directory: /home/janeni/vnmrsys/data Sample directory: JN-1-171-minordiast2 FidFile : CARBON01 Pulse sequence : CARBON (s2pul) Solvent: cdcl3 Data collected on: 14 Jul 2010 Temp. JN-1-215-minordiast2 Sample name: JN-1-215-minordiast2 Data collected on: indy.caltech.edu-inova500 Archive directory: /home/janeni/vnmrsys/data Sample directory: JN-1-215-minordiast2 FidFile : CARBON01 Pulse sequence : CARBON (s2pul) Solvent: cdcl3 Data collected on: 2 Aug 2010 Operator: janeni Relax. LMRIV-275 Sample name: LMRIV-275 Data collected on: siena.caltech.edu-vnmrs400 Archive directory: /home/jni/vnmrsys/data Sample directory: LMRIV-275 FidFile: CARBON01 Pulse sequence: CARBON: cdcl3 Solvent: cdcl3 Data collected on : 15 Jul 2010 Temp.
LMRIV-267-majorshigemi Example name: LMRIV-267-majorshigemi Data collected at: indy.caltech.edu-inova500 Archive folder: /home/lrepka/vnmrsys/data Example folder: LMRIV-267-majorshigemi FidFile: CARBON01 Pulse Sequence: CARBON (s2pul) Solvent : cdcl3 Data collected on: July 20, 2010 Temp.
