Research Collection
Doctoral Thesis
Novel approach to spiro-pyrrolidine-oxindoles and its application to the synthesis of (±)-horsfiline and (-)-spirotryprostatin B
Author(s): Marti, Christiane
Publication Date: 2003
Permanent Link: https://doi.org/10.3929/ethz-a-004489068
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ETH Library
Diss. ETH No. 15001
Novel Approach to Spiro-Pyrrolidine-Oxindoles and its Application to the Synthesis of (±)-Horsfiline and (–)-Spirotryprostatin B
A dissertation submitted to the SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZÜRICH
for the degree of Doctor of Natural Sciences
Presented by
Christiane MARTI
Dipl. Ing. ECPM Strasbourg born 25. August 1972 in Stuttgart, Germany
Accepted on the recommendation of Prof. Dr. Erick M. Carreira, examiner Prof. Dr. Hans-Jürg Borschberg, co-examiner
Karin, Gerhard und Thomas in grosser Dankbarkeit gewidmet
Und ist schon jemals ein Ziegel so vom Dach gefallen, wie es das Gesetz vorschreibt? Niemals! Nicht einmal im Laboratorium zeigen sich die Dinge so wie sie sollen. Sie weichen regellos nach allen Richtungen davon ab, und es ist einigermaβen eine Fiktion, daβ wir das als Fehler der Ausführung ansehen und in der Mitte einen wahren Wert vermuten.
Robert Musil
Acknowledgements
My dissertation at ETH was a real learning experience that was enjoyable most of the time. Any successes during this time are also due to substantial support from others. I therefore express my deepest thanks to:
Prof. Dr. Erick M. Carreira ― I benefited his guidance and support throughout the course of my thesis. He was always open for scientific discussions, has an endless supply of ideas, and allowed me the freedom to decide the direction of the project. At times when I was willing to give up; he somehow found a way of motivating me to reach the final goal.
Prof. Dr. Hans-Jürg Borschberg ― He accepted the co-examination of my thesis and his interest in this work led to a thoroughly corrected manuscript.
Alec Fettes ― He read and corrected my manuscript and thereby substantially improved this thesis not only in grammar and spelling, but also with clever suggestions on the presentation of the content.
Christian Fischer ― His diploma work presents a noteworthy contribution to this thesis. His enthusiastic working attitude and his conscientious but efficient preparative work impressed me deeply.
Brigitte Brandenberg, Philipp Zumbrunnen and Prof. Dr. Bernhard Jaun ― The spectra from the NMR-service had always a wonderful appearance, even when I only submitted the tiniest amounts. Without help interpreting some of the spectral data, I would have been lost.
Rolf Häflinger, Oswald Greter, Oliver Scheidegger and Dr. Walter Amrein ― They measured my MS spectra and answered all associated questions.
Volker Gramlich and Paul Seiler ― They both solved X-ray crystal structures relevant to this project and had the time to discuss their results with me in detail.
The members of the ETH staff responsible for ‘Schalter’, ‘Glaswäscherei’, ‘Entsorgung’ are gratefully acknowledged for prompt service always accompanied with a smile and a friendly word.
The students in the OCP1 synthesized multigram quantities of my starting material.
The Carreira group is acknowledged for creating an overall pleasant working atmosphere. My special thanks go to:
Claudia Dörfler and Franziska Peyer ― They solved every administrative problem and did all the paperwork. Also they always had an open ear for problems of the group and its individuals.
Jeffrey Bode, Alec Fettes, Dieter Muri, Tobias Ritter ― They have all been more than just co-workers, lab-mates or ‘Settlers’ but real friends. Jeff is a wonderful person and a brilliant chemist. His suggestions on my project were always very helpful. Alec and I went a long way together (St Gallen-Zürich, Sola Duo, 8 h 15 min). His suggestions on my chemistry decided the success of this project. Didi and Tobi are real sportsman and I enjoyed playing volley and squash with them or having them chase me though the forest (jogging), up the mountains (hiking in summer) und down the hills (skiing in winter).
Roger Fässler, Patrick Aschwanden, Jürg Oetiker and Stephan Schnidrig ― They where always in a good mood and made the atmosphere in the lab an enjoyable one. Aschi is the best PC-expert and was always solving my problems with ‘this stupid computer’.
My friends outside of the Carreira group also contributed significantly to this thesis by encouraging me whenever it was necessary. My special thanks go to Anja Schürch, Sibylle Steimen and Ulee Speicher, but also to my friends back in Germany and France
and from Volley KSOe.
Many thanks go also to my family for their support and love.
Last but not least: Thomas, I thank you very much for you support and love and for standing at my side all the time. Without you, I would not have made it.
Publications and Presentations
Alec Fettes, Christiane Marti and Erick M. Carreira “Catalytic Asymmetric Aldol Reactions” Org. Reactions, manuscript in preparation.
Christiane Marti and Erick M. Carreira “Total Synthesis of (–)-Spirotryprostatin B, Synthesis and Related Studies” manuscript in preparation.
Christiane Marti and Erick M. Carreira “Construction of Spiro[Pyrrolidine-3,3’-Oxindoles] ― Recent Applications to the Synthesis of Oxindole Alkaloids” Eur. J. Org. Chem. manuscript submitted.
Christiane Meyers and Erick M. Carreira “Total Synthesis of (–)-Spirotryprostatin B” Angew. Chem. Int. Ed. in press.
Christian Fischer, Christiane Meyers and Erick M. Carreira “Efficient Synthesis of (±)-Horsfiline through the MgI2-Catalysed Ring-Expansion Reaction of a Spiro[cyclopropane-1,3’-indol]-2’-one” Helv. Chim. Acta 2000, 83, 1175.
Phil B. Alper, Christiane Meyers, Andreas Lerchner, Dionicio R. Siegel and Erick M. Carreira ”Facile, Novel Methodology for the Synthesis of Spiro[pyrrolidin-3,3’-oxindoles]: Catalyzed Ring-Expansion Reactions of Cyclopropanes by Aldimines” Angew. Chem. Int. Ed. 1999, 38, 3186.
Christiane Meyers, Phil B. Alper, Christian Fischer and Erick M. Carreira “Novel Methodology for the Synthesis of Spiro-Oxindoles” Poster presentation; Bayer Informationstage, Bayer AG (Germany), July 2000.
Christiane Meyers, Phil B. Alper and Erick M. Carreira “Novel Methodology for the Synthesis of Pyrrolidine-spiro-Oxindole Ring Systems” Poster presentation; Drug Discovery, Pfizer (UK), September 1999
Abstract
The spiro-pyrrolidine-oxindole ring system is a recurring structural element that has been identified in a number of cytostatic alkaloids. These spiro-fused ring systems embody stereochemical and structural complexities that continue to challenge the synthetic chemist. In this thesis the development of a novel approach to spiro-pyrrolidine-oxindoles by MgI2-catalyzed ring-expansion reaction of spiro-cyclopropyl-oxindole I and a number of N-alkyl- as well as N-aryl-sulfonyl aldimines II is presented (Scheme A).
MgI2 acts as a bifunctional catalyst: R' MgI2 (10-20 mol%), N THF nucleophilic R I N O R' N O activation Bn N Bn I III Mg activation by R N O I Lewis acid II major diastereomer Bn ca. 80:20
Scheme A: Ring expansion of spiro-cyclopropyl-oxindole I with aldimines II catalyzed by MgI2.
MgI2 acts as a bifunctional catalyst wherein the Lewis-acidic metal and the nucleophilic counterion operate in synergy. The resulting spiro-pyrrolidine-oxindole ring systems III were obtained in good yields and with high diastereoselectivities.
MeO MeO NMe MeO NMe MgI2 (5.5 mol%), THF 83 % 41 % N O N O overall N O Bn Me Bn H N IV horsfiline MeN NMe V
Scheme B: Synthesis of (±)-horsfiline.
Our interest in the class of spiro-pyrrolidine-oxindole natural products as well as the scope of the ring-expansion reaction led us to apply this method in the synthesis of horsfiline and spirotryprostatin B. The synthetic route to (±)-horsfiline demonstrates the use of 1,3,5-trimethyl-1,3,5-triazine (V) as an equivalent for N-methylmethanimine under
the conditions of the ring-expansion reaction. The synthesis afforded (±)-horsfiline in 41% yield over 5 steps via N-benzyl-spiro-cyclopropyl-oxindole (IV) (Scheme B).
In order to access the spirotryprostatin B core in a straightforward fashion, we could establish that C9-substituted (spirotryprostatin numbering) spiro-pyrrolidine-oxindole derivative VIII can be obtained in good yield from substituted cyclopropane VI and imine VII.
The diastereomer distribution favors VIII possessing the required C3–C18 anti- relationship (6:1). The corresponding syn-diastereomers were found to be converted to VIII by refluxing in acetic acid. Resolution is achieved by peptide coupling with N-Boc-
L-proline chloride to furnish IX.
MeHC MeHC MeHC O 9 O BocN N MgI2, THF HN 18 N HN N + 3 H N O O H TIPS
VI VII TIPS TIPS VIII IX AcOH, ∆ + isomers
O CO2Me CO2Me O N O BocN Julia-Kociensky O BocN olefination HN 3 N HN N HN N H 18 H H O O O Me Me O Me Me spirotryprostatin B XI X
Scheme C: Total synthesis of (–)-spirotryprostatin B.
Introduction of the prenyl side chain was accomplished by olefination of aldehyde XII by Julia–Kocieńsky reaction to give XI, although similar transformations proved difficult in earlier syntheses. Intermediate XI was then converted to spirotryprostatin B (Scheme C). The synthetic sequence was performed in 16 steps (3.4% overall yield) and is a powerful demonstration of the utility of the ring-expansion method.
Zusammenfassung
Das Spiro-Pyrrolidin-Oxindol Ringsystem ist ein Strukturelement, welches in einigen zytostatisch wirkenden Alkaloiden identifiziert wurde. Die stereochemische und strukturelle Komplexität dieser Systeme machen Spiro-Pyrrolidin-Oxindole zu attraktiven Zielmolekülen für den organischen Synthetiker. Diese Abhandlung beschreibt
die Entwicklung einer neuartigen Methode, die über eine MgI2-katalysierte Ring- Erweiterungs-Reaktion von Spiro-Cyclopropyl-Oxindol I mit verschiedenen N-Alkyl- bzw N-Aryl-Sulfonyl-Aldiminen II zu Spiro-Pyrrolidin-Oxindolen führt (Schema A).
MgI2, ein Katalysator mit synergetischem Aktivierungsmuster: R' MgI2 (10-20 mol%), N THF nucleophile R I N O R' N O Aktivierung Bn N Bn I III Mg Lewis Säure R N O I Aktivierung II bevorzugtes Bn Diastereomer ca. (80:20)
Schema A: MgI2-katalysierte Ring-Erweiterung von Spiro-Cyclopropyl-Oxindol I mit Aldiminen II.
MgI2 konnte als wirksamer Katalysator identifiziert werden, in dem die Lewis-Acidität des Metallzentrums (MgII) und die Nukleophilie des Gegenions (I−) synergetisch zu wirken scheinen. Die Spiro-Pyrrolidin-Oxindole III wurden in guten Ausbeuten und mit hoher Diastereoselektivität erhalten.
MeO MeO NMe MeO NMe MgI2 (5.5 mol%), THF 83% 41 % N O N O N O Bn Me Bn Gesamt- H N ausbeute IV Horsfiline MeN NMe V
Schema B: Synthese von (±)-Horsfilin.
Unser allgemeines Interesse an Naturstoffen aus der Klasse der Spiro-Pyrrolidin- Oxindole, sowie die Anwendungsbreite der von uns entwickelten Methode führten zur
Verwendung der MgI2-katalysierten Ringerweiterungsreaktion in den Synthesen der Alkaloide Horsfilin und Spirotryprostatin B.
In der Synthese von (±)-Horsfilin konnte die Eignung von 1,3,5-Trimethyl-1,3,5-triazin (V) als synthetisches Äquivalent für N-Methyl-Methanimin unter den Bedingungen der Ringerweiterungsreaktion bewiesen werden. (±)-Horsfilin wurde in 41% Ausbeute in 5 Stufen über N-Benzyl-Spiro-Cyclopropyl-Oxindol (IV) als Zwischenstufe erhalten (Schema B).
Um das Gerüst von Spirotryprostatin B in effizienter Weise aufzubauen, muss ein Spiro- Pyrrolidin-Oxindol mit einem Substituent in der 9-Position (Spirotryprostatin Nummerierung) zugänglich sein. Wir konnten zeigen, dass das Spiro-Pyrrolidin-Oxindol- Derivat VIII in guter Ausbeute durch Verknüpfung von Cyclopropan VI und Imin VII erhalten werden kann.
Das Diastereomerenverhältnis begünstigt VIII (Verhältnis 6:1) mit der benötigten relativen anti-Orientierung an den Zentren C3 und C18. Die entsprechenden syn- Diastereomere konnten durch Behandlung mit kochender Essigsäure in VIII überführt
werden. Die Umsetzung mit N-Boc geschütztem L-Prolin-Chlorid erlaubt eine Trennung der Diastereomere und führt zu IX.
MeHC MeHC MeHC O 9 O BocN N MgI2, THF HN 18 N HN N + 3 H N O O H TIPS
VI VII TIPS TIPS VIII IX AcOH, ∆ + Isomere
O CO2Me CO2Me O N O BocN Julia-Kociensky O BocN Olefinierung HN 3 N HN N HN N H 18 H H O O O Me Me O Me Me spirotryprostatin B XI X
Schema C: Totalsynthese von (–)-Spirotryprostatin B.
Die Prenyl-Seitenkette konnte durch eine Julia–Kocieńsky Reaktion des Aldehyds X eingeführt werden, obwohl ähnliche Olefinierungsreaktionen in früheren Synthesen Probleme bereiteten. Aus der Zwischenstufe XI wurde Spirotryprostatin B erhalten (Schema C). Spirotryprostatin B wurde in 16 Stufen und 3.4% Gesamtausbeute erhalten. Diese Synthese ist Beweis für die Eignung unserer Ring-Erweiterungs-Reaktion zur Synthese komplexer Naturstoffe.
Abbreviation List
T [α]D specific rotation at the sodium D line at temperature T Å angström Ac acetyl AIBN 2,2’-azo-iso-butyronitrile aq aqueous atm atmosphere Bn benzyl bp boiling point Boc tert-butyl carbamate BOP benzotriazol-1-yloxitris(dimethylamino)phosphonium hexafluoro- phosphate BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphinic chloride br broad Bu butyl c concentration °C degree centigrade ca. circa calcd calculated cat. catalytic Cbz carbobenzyloxycarbonyl cm centimeter COSY correlated spectroscopy Cp cyclopentadiene δ NMR chemical shift in ppm downfield from a standard d day d doublet dba (E,E)-dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DEAD diethyl azodicarboxylate decomp. decomposition DEI desorption electron impact ionization DHQ-CLB dihydrochinine-(4-chlorobenzoylether) (DHQ)2PHAL dihydrochinine-(1,4-phthalazinediether) DMA N,N-dimethyl acetamide DMAP 4-N,N-dimethylamino pyridine DMDO dimethyl dioxirane DME 1,2-dimethoxyethane DMF N,N-dimethyl formamide DMSO dimethyl sulfoxide DNBA 1,3-dimethyl barbituric acid
DPPA diphenylphosphoryl azide ∆ reflux ∆∆E difference in heat of formation EI electron impact ionization equiv equivalent Et ethyl EWG electron withdrawing group FAB fast atom bombardment ionization g gram Glu glutamic acid h hour HMBC heteronuclear multiple-bond correlation HMDS 1,1,1,3,3,3-hexamethyldisilazane HMQC heteronuclear multiple quantum coherence HPLC high-performance liquid chromatography HR high resolution Hz herz IC50 incapacitating concentration 50 IR infrared spectrum J coupling constant J joule kcal kilocalorie L liter LDA lithium di-iso-propyl amide LHMDS lithium 1,1,1,3,3,3-hexamethyldisilazane m meta m multiplet m milli M molarity M mega MALDI matrix assisted laser desorption ionization mCPBA 3-chloroperbenzoic acid Me methyl MIC maximum inhibitory concentration min minute mol moles mp melting point MS mass spectrometry MS molecular sieves µ micro N normality NBS N-bromosuccine imide NCS N-chlorosuccine imide NMO N-methylmorpholine N-oxide NOE nuclear Overhauser effect
o ortho org. organic p para PFG pulse field gradient PG protecting group Ph phenyl PMP 1,2,2,6,6-pentamethylpiperidine ppm parts per million Pr propyl psi pounds per square inch Py pyridine q quartet quint quintett R substituent Rf retention factor RT room temperature s singlet s second s sec sat. saturated SEM 2-(trimethylsilyl)ethoxymethyl t triplet TBAF tetra-n-butylammonium fluoride TBS tert-butyldimethylsilyl TDA-1 tris[2-(2-methoxyethoxy)-ethyl]amine Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TIPS tri-iso-propyl TLC thin layer chromatography TMS trimethylsilyl Tol tolyl Troc 2,2,2-trichloroethoxycarbonyl Ts 4-methylphenylsulfonyl UV ultraviolet vs. versus WSC 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
Table of Contents 1
I. Table of Contents
II. Introduction...... 5
1. Alkaloids...... 5
2. Oxindole Alkaloids...... 7
III. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles...... 11
1. Existing Methods for the Synthesis of Spiro-Pyrrolidine-Oxindoles ...... 11
1.1. Oxidative Rearrangement Reactions...... 11
1.2. Intramolecular Mannich Reactions...... 18
1.3. Dipolar Cycloaddition Reactions...... 19
1.4. Intramolecular Heck Reactions...... 21
1.5. Radical Cyclization Reactions ...... 23
1.6. Asymmetric Nitroolefination...... 25
1.7. Rearrangement of [(N-Aziridinomethylthiomethylene]-2-oxindoles ...... 25
2. Novel Approach to the Synthesis of Spiro-Pyrrolidine-Oxindoles...... 26
2.1. Retrosynthetic Analysis...... 26
2.2. MgI2-Catalyzed Ring-Expansion Reaction of Spiro-Cyclopropyl-Oxindoles with Aldimines...... 29
2.2.1. Initial Results...... 29 2 Table of Contents
2.2.2. Optimization and Scope of the Ring-Expansion Reaction ...... 31
2.2.3. Mechanistic Aspects...... 38
2.2.4. Conclusion ...... 41
IV. The Synthesis of (±)-Horsfiline ...... 42
1. Introduction...... 42
1.1. Isolation...... 42
1.2. Synthetic Approaches...... 43
1.2.1. Jones’ and Wilkinson’s Synthesis of (±)-Horsfiline...... 43
1.2.2. Laronze’s Syntheses of (±)-Horsfiline...... 44
1.2.3. Borschberg’s Approach to (+)- and (–)-Horsfiline ...... 45
1.2.4. Palmisano’s Route to (–)-Horsfiline ...... 46
1.2.5. Fuji’s Synthesis of (–)-Horsfiline ...... 48
2. Synthesis of (±)-Horsfiline by MgI2-Catalyzed Ring-Expansion Reaction of Spiro-Cyclopropyl-Oxindole and 1,3,5-Trimethyl-1,3,5-Triazinane ...... 49
3. Conclusion ...... 51
V. The Total Synthesis of (–)-Spirotryprostatin B...... 52
1. Introduction...... 52
1.1. Isolation and Biological Activity...... 52
1.2. Synthetic Approaches...... 55
1.2.1. Danishefsky’s Route to Spirotryprostatin A...... 55 Table of Contents 3
1.2.2. Williams’s Synthesis of Spirotryprostatin B...... 58
1.2.3. Ganesan’s Approach to Spirotryprostatin B ...... 60
1.2.4. Danishefsky’s Synthesis of Spirotryprostatin B ...... 62
1.2.5. Overman’s Approach to Spirotryprostatin B ...... 63
1.2.6. Fuji’s Route to Spirotryprostatin B...... 65
2. Synthesis of (–)-Spirotryprostatin B Employing the MgI2-Catalyzed Ring- Expansion Reaction ...... 67
2.1. Retrosynthetic Analysis...... 67
2.2. Initial Studies ...... 69
2.2.1. Regioselectivity...... 69
2.2.2. Substituent at the Spiro-Cyclopropyl-Oxindole Suitable for Ring Expansion ..... 71
2.2.3. Identification of a Suitable Imine for the Ring Expansion ...... 77
2.2.4. Optimization of the Key Step ...... 78
2.3. Synthesis of Spirotryprostatin B from Intermediate 323 ...... 83
2.4. Synthesis of Spirotryprostatin B from Intermediate 324 ...... 97
2.5. Synthesis of Spirotryprostatin B from Intermediate 326 ...... 98
3. Conclusion ...... 101
VI. Conclusion and Outlook...... 103
VII. Experimental Part...... 105
1. General methods ...... 105 4 Table of Contents
2. Preparation of Useful Reagents and Buffers...... 108
3. MgI2-Catalyzed Ring-Expansion Reaction of Spiro-Cyclopropyl-Oxindoles with Aldimines...... 110
4. Synthesis of (±)-Horsfiline by MgI2-Catalyzed Ring-Expansion Reaction of Spiro-Cyclopropyl-Oxindole and 1,3,5-Trimethyl-1,3,5-Triazinane ...... 136
5. Synthesis of (–)-Spirotryprostatin B Employing the MgI2-Catalyzed Ring- Expansion Reaction ...... 141
5.1. Synthesis of Spirotryprostatin B from Intermediate 323 ...... 165
5.2. Synthesis of Spirotryprostatin B from Intermediate 324 ...... 183
5.3. Synthesis of Spirotryprostatin B from Intermediate 326 ...... 186
Curriculum Vitae...... 195 Introduction 5
II. Introduction
1. Alkaloids
The first alkaloid obtained in pure form was morphine, which was isolated from opium by Sertürner in 1806. The product was commercialized by Merck and was the first medicine sold with a purity guaranty in 1822. In 1819, Meissner introduced the term alkaloid for nitrogen-containing substances of vegetable origin as a description of their basic (alkaline) character. Soon enough, the definition had to be adjusted, as alkaloids were also discovered in animals, for example in insects and amphibians. Today, alkaloids are defined as nitrogen-containing substances originating from vegetable and animal origin. Some classes of compounds that match this definition are not considered alkaloids, namely amino acids, peptides and nucleotides.1
amino acids biogenic amines glutamic acid GABA ornithin putrescine secondary metabolites lysin cadaverine polyketides NH phenylalanine phenylethylamine shikimate metabolites 3 tyrosine tyramine terpenes/steroids tryptophane tryptamine histidine histamine
alkaloids pseudo alkaloids
Figure 1: Biogenesis of alkaloids in plants
[1] Hesse, M. Alkaloidchemie; Thieme: Stuttgart, 1978; Vol. B9. 6 Introduction
Plants produce alkaloids from amino acids by enzymatic decarboxylation to the corresponding biogenic amines, which subsequently undergo condensation with secondary metabolites such as polyketides, shikimate metabolites, terpenes and steroids to form alkaloids. The condensation products of secondary metabolites with ammonia as nitrogen source instead of an amine are referred to as pseudo alkaloids.
The classification of alkaloids is rather difficult because of their enormous structural diversity and, according to the context, a different mode of classification can be useful, for example biogenesis, structural relationship, botanical origin or spectroscopic criteria (chromophore for UV spectroscopy, ring skeleton for MS). These classification systems are generally not exclusive. The most useful classification for the organic chemist is made on the basis of the nitrogen containing substructure: 2
- heterocyclic alkaloids
- alkaloids with exocyclic nitrogen and aliphatic amines
- putrescin, spermidin and spermine alkaloids
- peptide alkaloids
- terpene and steroid alkaloids
[2] Hesse, M. Alkaloide, Fluch oder Segen der Natur?; Verlag Helvetica Chimia Acta, Wiley-VCH: Weinheim, 2000. Introduction 7
2. Oxindole Alkaloids
The oxindole alkaloids are a subclass of the indole alkaloids, a family of heterocyclic alkaloids. Indole alkaloids comprise alkaloids that contain the indole chromophor (1) itself, or a structural element derived from indole like 2-8 (Figure 2).
N N N R R indole (1) dihydroindole (2) indolenine (3)
O
N N O N R R R 3-oxindole 2-oxindole (5) carbazole (6) pseudoindoxyl (4)
N N N N R R β-carboline (7) γ-carboline (8)
Figure 2: Structural motifs of some indole alkaloids.
Historically, the first four oxindole alkaloids (9-12) were found in the roots of Gelsemium sempervirens, and are classified as Gelsemium species. Additional oxindoles were isolated from Aspidosperma, Mitragyna, Ourouparia, Rauwolfia and Vinca.3 These alkaloids possess the same basic framework derived from tryptamine and secologanine (13), a C10 unit of terpenoid origin, and can be further classified into two substructural classes: the tetracyclic secoyohimbane (or corynantheidine) type (e.g. rhynchophylline (14)) and the pentacyclic heteroyohimbane (or ajmalicine) type (e.g. formosanine (15)). Other types of oxindole alkaloids could be isolated, exemplified by (–)-horsfiline (16)4, spirotryprostatin B (17)5, strychnofoline (18)6 and (+)-paraherquamide B (19)7,8
[3] Bindra, J. S. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1973; Vol. 14, pp 84-121. [4] Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. J. Org. Chem. 1991, 56, 6527-6530. [5] Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832-835. [6] Angenot, L. Plantes médicales et phytothérapie 1978, 12, 123. [7] Ondeyka, J. G.; Goegelman, R. T.; Schaeffer, J. M.; Kelemen, L.; Zitano, L. J. Antibiot. 1990, 43, 1375-1379. [8] Banks, R. M.; Blanchflower, S. E.; Everett, J. R.; Manger, B. R.; Reading, C. J. Antibiot. 1997, 50, 840-846. 8 Introduction
(Figure 3). The secoyohimbane and heteroyohimbane alkaloids, that comprise a large group of natural products, can be classified as normal, pseudo, allo and epiallo on the basis of their configuration at C3 relative to C20 (numbering of heteroyohimboid alkaloids). Additional classification is based on the configuration at C7 of the spiro- pyrrolidine-oxindole moiety and comprises the two possible isomers A and B (Table 1).8
O CHO R O H OGlu NMe HN H RN N Et O MeO C O MeO O 2 R = H: gelsemine (9) R = H: gelsemicine (11) secologanine (13) R = OMe: gelsevirine (10) R = OMe: gelsedine (12)
Me H N H Me N Me N R R OMe H MeO H O H H H N O N O CO Me H MeO2C H 2 N O H
rychnophylline (14) formosanine (15) (-)-horsfiline (16) secoyohimbane sceletton heteroyohimbane sceletton tetracyclic oxindol alkaloids pentacyclic oxindol alkaloids
Me Me O O O N N N N O O HN HN N H H O Me H HN H MeN N O O Me Me Me Me OH spirotryprostatin B (17) strychnofoline (18) (+)-paraherquamide B (19)
Figure 3: Some oxindole alkaloids.
Configuration C3-H C20-H C7 normal α β A or B pseudo β β A or B 20 R' C N allo α α A or B 7 D OMe 3 R A B H epiallo β α A or B N O H MeO2C
Table 1: Configuration terminology for oxindole alkaloids: α: H below C/D plane, β: H above C/D plane, A = (S), B = (R).
In the normal/pseudo series, no oxindole alkaloid with pseudo configuration has been isolated so far. In the allo/epiallo series, the allo configuration is more abundant than its Introduction 9
epiallo counterpart. Biogenetic studies suggest that the biosynthesis of spiro-pyrrolidine- oxindoles occurs via oxidation of the corresponding tetrahydro-β-carboline 20. The thereby created spiro-center possesses either (R)- (B-series, 22) or (S)- (A-series, 21) configuration. Both forms can be equilibrated in vitro through the ring-opened form 23 (Scheme 1).9
NR [O] S NR R' N N O H H R' 20 21
[O]
NR R NR R' R' N O N O H H 22 23
Scheme 1: Biosynthesis of oxindoles from tetrahydro-β-carbolines and isomerization.
In nature, oxindole alkaloids often occur as pairs of interconvertible isomers (e.g. rhynchophylline (14) and isorychnophylline, which is 7-epi-rhynchophylline). This observation can be explained by the same isomerization mechanism, which was noticed as early as 1959 and independently elucidated by two research groups. Wenkert and Marion both proposed a retro-Mannich reaction involving the open-ring intermediate 23.10,11 Kinetic studies of the isomerization in the series of tetracyclic oxindole alkaloids were performed by Laus and revealed that the reaction is a pseudo-first-order process.12 It could be shown that refluxing each of the isomers independently in pyridine or acetic anhydride led to the same equilibrium mixture wherein one of the isomers is favored.11 Hendrickson noted that the predominant isomer is also the less basic one. In equilibration studies with yohimbine oxindoles, the stronger base was predominant after treatment with
[9] Brown, R. T. In Heterocyclic Compounds; Saxon, J. E., Ed.; Wiley Interscience: New York, 1983; Vol. 25, Part 4, pp 85-97. [10] Wenkert, E.; Udelhofen, J. H.; Bhattacharyya, N. K. J. Am. Chem. Soc. 1959, 81, 3763-3768. [11] Seaton, J. C.; Nair, M. D.; Edwards, O. E.; Marion, L. Can. J. Chem. 1960, 38, 1035-1042. [12] Laus, G. J. Chem. Soc. Perkin Trans. 2 1998, 315-317. 10 Introduction
acid, whereas the weaker base predominated after refluxing in pyridine. Only in one structure could the conjugate acid be stabilized by hydrogen bonding to the oxindole carbonyl. The free base is apparently destabilized by electrostatic repulsion of the 13 carbonyl group and the lone pair of Nb (Figure 4).
predominant in acidic media predominant in basic media
O H HN N N HN
O possiblility of minimal electrostatic hydrogen bonding repulsion
Figure 4: Stabilization of yohimbine oxindoles in different media.
[13] Yeoh, G. B.; Chan, K. C.; Morsingh, F. Rev. Pure and Appl. Chem. 1967, 49-66. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 11
III. Novel Methodology for the Synthesis of Spiro- Pyrrolidine-Oxindoles
1. Existing Methods for the Synthesis of Spiro-Pyrrolidine- Oxindoles
1.1. Oxidative Rearrangement Reactions
First studies in the oxindole series were based on the structural relationship of oxindoles and their tetrahydro-β-carboline counterpart. An early study by Taylor revealed that rhynchophylline (14) can be obtained from dihydrocorynantheine (24) by a three-step procedure by oxidative rearrangement (Scheme 2),14 and a general relationship between indole alkaloids and their oxindole analogues was postulated by Shavel and Zinnes.15
H N Et N N a - c OMe H H H H Et H H N O H MeO2C OMe MeO2C 14 24
Scheme 2: a) tBuOCl; b) KOH/MeOH; c) H2O/AcOH.
Later experiments showed that the chloro-indolenine intermediate 26, upon heating in acetic acid, undergoes rearrangement to a C3 (indole numbering) epimeric mixture 27/28, without pronounced preference for either of the two epimers.
Furthermore, it was found that chlorination of the indole ring yielded a mixture of α- and β-chloro derivatives 26, obtained from tetrahydro-β-carboline 25, and that only the major α-chloro-isomer undergoes rearrangement in refluxing methanol to provide a rapidly
[14] Finch, N.; Taylor, W. I. J. Am. Chem. Soc. 1962, 84, 3871-3877. [15] Shavel, J.; Zinnes, H. J. Am. Chem. Soc. 1962, 84, 1320-1321. 12 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
equilibrating mixture of 29 and 30 (Scheme 3).16 Extensive studies and computational analyses by Borschberg and Acklin on the oxidative rearrangement of yohimbane-type alkaloids suggest that the α-chloro-isomers undergo rearrangement much faster than the β-chloro-isomers and are thus to a great extent protected from side-reactions observed with the β-chloro compounds.17,18
N R' N R' 33 + R R b N O N O Cl H H a 27 28 N N R' R' N N R' R' H c N N R R 33 25 26 R + R N OMe N OMe
29 30
Scheme 3: a) tBuOCl, RT; b) H2O/AcOH; ∆ c) MeOH, ∆.
Martin expanded the method to the oxidation of indoles, where Nb is incorporated in a D-ring lactam. The critical ring contraction was achieved by addition of silver perchlorate and led ultimately to pteropodine (34) (Scheme 4).19
X
A C N N B N O H Me H Me N H a, b e H H D Me H H O H H O H O N O CO Me N O CO Me H 2 H 2 MeO2C 34 32: X = O 31 c, d 33:X=H2
Scheme 4: a) tBuOCl, RT; b) AgClO4, aq MeOH/HClO4, RT; c) AlH3, RT;
d) NaBH4, RT; e) AcOH, ∆.
[16] Awang, D. V. C.; Vincent, A.; Kindack, D. Can. J. Chem. 1984, 62, 2667-2675. [17] Stahl, R.; Borschberg, H. J.; Acklin, P. Helv. Chim. Acta 1996, 79, 1361-1378. [18] Another approach to intermediates of the general structure 26 from 1,2,3,4-tetrahydro-9-hydroxy-β-carboline is described by Somei: Somei, M.; Noguchi, K.; Yamagami, R.; Kawada, Y.; Yamada, K.; Yamada, F. Heterocycles 2000, 53, 7-10. [19] Martin, S. F.; Mortimore, M. Tetrahedron Lett. 1990, 31, 4557-4560. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 13
Cook and co-workers discovered that tetracycle 36 and its N-benzyl-protected derivative 35 led to two isomeric oxindole products 37 and 38 stereospecifically upon reaction with tBuOCl/NEt3, followed by treatment with acetic acid. Simply the absence or presence of the N-benzyl protecting group allows access alsonisine- or voachalotine- related oxindole alkaloids respectively. It is believed that the diastereoselection is of steric origin (Scheme 20 5). The starting material 35 is accessible from D-(+)-tryptophane by asymmetric Pictet– Spengler reaction.21,22
Bn H N O O less b, c NBn NH voachalotine N hindered H H H O oxindole H N O 35 Ph N H 37 a O
H O NH b, c NH NH more alstonisine series N hindered H alkaloids H O N O H 36 HN 38
Scheme 5: a) 5% HCl in EtOH, H2, Pd/C, RT; b) tBuOCl/NEt3, RT; c) AcOH, MeOH, ∆.
Among the possible strategies for assembly of the oxindole core, the use of the Pictet– Spengler reaction (Scheme 6) later followed by an oxidation/rearrangement sequence found widespread use over the years.
[20] Yu, P.; Cook, J. M. Tetrahedron Lett. 1997, 38, 8799-8802. [21] Pictet, A.; Spengler, T. Ber. 1911, 44, 2030. [22] Yu, P.; Wang, T.; Yu, F. X.; Cook, J. M. Tetrahedron Lett. 1997, 38, 6819-6822. 14 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
CO2Me CO2Me NH O 2 + NH R N [H+] R N H R' H R' 39 40 41
+ H+, -H O 2 -H+
CO2Me CO2Me N H NH R N R N H H H R' R'
Scheme 6: Pictet–Spengler reaction.
Reaction of tryptophane derivative 39 with an aldehyde 40 usually leads to tetrahydro-β- carboline 41 as the cis-product is favored at the kinetic level.23,24 Alternatively, the tetrahydro-β-carboline can also be prepared from tryptophane by a Bischler–Napieralski reaction, although this sequence has been shown to lead to racemization.25
N-bromo succinimide as oxidant is frequently used instead of tBuOCl and was employed in the synthesis of (+)-elacomine (42)26 and (–)-horsfiline (16)27 by Borschberg, in Danishefsky’s synthesis of spirotryprostatin A (43),28,25 in Ganesan’s route to spirotryprostatin B (17)29 and also in the synthesis of paraherquamide B (19)30 by Williams (Scheme 7).
[23] Harrison, D. M.; Sharma, R. B. Tetrahedron Lett. 1986, 27, 521-524. [24] Kodato, S.; Nakagawa, M.; Hongu, M.; Kawate, T.; Hino, T. Tetrahedron 1988, 44, 359-377. [25] Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem. Soc. 1999, 121, 2147-2155. [26] Pellegrini, C.; Weber, M.; Borschberg, H. J. Helv. Chim. Acta 1996, 79, 151-168. [27] Pellegrini, C.; Strässler, C.; Weber, M.; Borschberg, H. J. Tetrahedron: Asymmetry 1994, 5, 1979-1992. [28] Edmondson, S. D.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1998, 37, 1138-1140. [29] Wang, H. S.; Ganesan, A. J. Org. Chem. 2000, 65, 4685-4693. [30] Cushing, T. D.; SanzCervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 1996, 118, 557-579. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 15
CO2Me R X O CO2Me CO2Me CO2Me a) 'X ', THF HN NR'' + NR'' NR'' HN NR'' R N b) AcOH, H2O R N H H O R' O R' H R' R R'
O H O N O HN N HN NH H O Me Me MeO MeO Me Me (+)-elacomine (42) spirotryprostatin A (43)
Scheme 7: Oxidative rearrangement induced by a halogenating agent employed for the total synthesis of natural products.
Not only halogenating agents, but also other oxidants are useful reagents to convert tetrahydro-β-carbolines into spiro-oxindoles. For this type of conversion, Pb(OAc)4 has first been investigated by Taylor in 1963,31 and employed by Bodo to confirm the 4 structure of (±)-horsfiline ((±)-16) by oxidation of the Nb-methyl-tetrahydro-β-carboline.
Pb(OAc)4 was also used by Borschberg in a model study for the synthesis of 26 + (+)-elacomine (42). The tetrahydro-β-carboline 44 reacts with Pb(OAc)3 to afford iminium species 45, which undergoes rearrangement to 46, leading to oxindole 47 (Scheme 8).
AcO Pb(OAc)2 NR'' NR''
Pb(OAc)3 OAc NR'' NR'' R' R' R N R N R N OAc R N O H H H H R' R' 44 45 46 47
Scheme 8: Spiro-rearrangement employing Pb(OAc)4.
[31] Finch, N.; Hsu, I. H. C.; Gemenden, C. W.; Taylor, W. I. J. Am. Chem. Soc. 1963, 85, 1520-1523. 16 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
HO O O H H Cl H a b CO2Me CO2Me N N N MeO N MeO N MeO N H H
gardnerine (48) Me 49 Me 50 Me
c d
O H O O Cl H Cl H
CO2Me O CO2Me N N HN MeO N MeO N MeO N O Me H H OMe 51 52 Me 55 Me
H O OH O O
N CO2Me CO2Me H OH S N R N MeO N O H Me H 56 MeO N OMe Me MeO N O Me H 54 53
Scheme 9: a) ClCO2Me, MgO, THF/H2O, RT; b) tBuOCl, NEt3, CH2Cl2, RT;
c) NaOMe, MeOH, RT; d) AcOH, H2O, MeOH, RT.
Another way to access spiro-oxindoles from tetrahydro-β-carbolines employs OsO4. In
1989, Sakai introduced OsO4 as reagent for the spiro-rearrangement following mechanistic considerations for the selective formation of Na-demethoxyhumantenirine (55) from gardnerine (48). He observed that spiro-rearrangement of 50 afforded either (S)-isomer 53 or (R)-isomer 54, when 50 was treated with sodium methylate or acetic acid, respectively. He concluded that the methoxide approaches 50 from the less hindered face, anti to the bridged ether linkage, giving rise to transition state 51 that will ultimately rearrange to (S)-isomer 53. On the other hand, 50 can react with water in aqueous acidic media to form 52. After chloride elimination, rearrangement to (R)-isomer 54 is predominantly observed (Scheme 9).32 Following this observation, the authors speculated that a product similar to 51 could be obtained from the attack of 49 by OsO4 that would then lead to the desired (S)-isomer selectively by pinacol-type rearrangement. Following
[32] Takayama, H.; Masubuchi, K.; Kitajima, M.; Aimi, N.; Sakai, S. Tetrahedron 1989, 45, 1327-1336. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 17
this OsO4-rearrangement procedure, Sakai also converted gardnerine (48) to 33 Na-demethoxy-11-methoxy-(19R)-hydroxygelselegine (56).
O O O HO O Os H NBn OsO4, O NMe NaHSO aq O NMe MeN O 3 O O THF, ∆ N N N O BnN Me Ph Ph 57 58 60
Bn N O
OsO4, ligand O NaHSO3 aq OH MeN O O MeN O O Os O H THF, RT L N O BnN O BnN Me
59 61
Scheme 10: Pinaccol rearrangement using OsO4.
Sakai’s work was followed up by Cook, who used OsO4 to access the alstonisine oxindole series (Scheme 10). He showed that OsO4 reacts with tetrahydro-β-carboline 57 selectively to furnish 60. The osmium is probably first complexed to the piperidine nitrogen and then osmylation occurs intramolecularly from the convex face of the substrate to furnish 58. The concave face is osmylated by the use of bulky ligands such as cinchona alkaloid derivatives DHQ-CLB and (DHQ)2PHAL yielding 59 that ultimately leads to 61 after hydrolysis.34,35
A study of the rearrangement of indole derivatives with DMDO was carried out by Foote.36 He observed that indole derivatives 62 can be oxidized to the corresponding epoxides 63 at low temperature. Rearrangement occurs at ambient temperature to furnish
[33] Takayama, H.; Kitajima, M.; Ogata, K.; Sakai, S. J. Org. Chem. 1992, 57, 4583-4584. [34] Peterson, A. C.; Cook, J. M. Tetrahedron Lett. 1994, 35, 2651-2654. [35] Peterson, A. C.; Cook, J. M. J. Org. Chem. 1995, 60, 120-129. [36] Zhang, X. J.; Foote, C. S. J. Am. Chem. Soc. 1993, 115, 8867-8868. For a related process, see: Adam, W.; Lévrai, A.; Mérour J.-Y.; Nemes, C.; Patonay, T. Synthesis 1997, 268-270. 18 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
oxindoles 64 (Scheme 11). This method has not yet found application in the synthesis of oxindole natural products.
R R R a) b) Me O N Me N Me N O COMe COMe COMe 62 63 64
Scheme 11: a) DMDO, acetone, CH2Cl2, –78 °C; b) 5 h, RT.
1.2. Intramolecular Mannich Reactions
The spiro-pyrrolidine-oxindole core can also be introduced by intramolecular Mannich reaction from precursors such as 65, available from tryptamine-derrived oxindole. By this method, the total synthesis of a mixture of (±)-rhynchophyllol and (±)-isorhynchophyllol (66) was achieved by van Tamelen in 1969 (Scheme 12).37
NH N Et N Et a) HCl N O NaIO4 O OH H Et b) NaBH4 N O N O HO H H H 65 HO 66
Scheme 12: Intramolecular Mannich reaction.
Ban and Oishi employed the Mannich reaction to elucidate the stereochemistry of (±)-rhynchophylline and (±)-isorhynchophylline. Comparison of the IR spectra of oxindoles 67 and 68 with rhynchophyllane obtained by degradation of rhynchophylline revealed that the relative stereochemistry of the ethyl substituents on the piperidine ring in both natural products corresponds to structure 67 (Scheme 13).38
[37] van Tamelen, E. E.; Yardley, J. P.; Miyano, M.; Hinshaw Jr., W. B. J. Am. Chem. Soc. 1969, 91, 7333-7338. [38] Ban, Y.; Oishi, T. Chem. Pharm. Bull. 1963, 11, 451-460. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 19
Cl CHO H Et H H Et Et N
Et H N O Me 67
NH3 N O Me Cl H N Et
Et Cl H CHO N O H Me Et 68 H Et
Scheme 13: Synthesis of rhynchophyllane by Mannich reaction.
The Mannich approach found application in the synthesis of a number of spiro-oxindole alkaloids for example (±)-formosanine ((±)-15),39 salacin,40 and spirotryprostatin B (17),41 as well as a range of unnatural spiro-oxindoles.42,43
1.3. Dipolar Cycloaddition Reactions
Palmisano was the first to successfully introduce 1,3-dipolar cycloadditions as a method for a completely different, clearly non-biomimetical approach to the spiro-pyrrolidine- oxindole skeleton in his synthesis of (–)-horsfiline (16) (Scheme 14).44 The N-methyl- azomethine ylide is generated in situ from sarcosine and formaldehyde. The synthesis of (±)-16 was achieved using the ethyl ester (R = Et), whereas asymmetric synthesis of (–)- horsfiline was possible through the use of a chiral auxiliary (R = (–)-menthyl).
[39] Winterfeldt.E; Gaskell, A. J.; Korth, T.; Radunz, H. E.; Walkowiak, M. Chem. Ber. Recl. 1969, 102, 3558-3572. [40] Ponglux, D.; Wongseripipatana, S.; Aimi, N.; Nishimura, M.; Ishikawa, M.; Sada, H.; Haginiwa, J.; Sakai, S. Chem. Pharm. Bull. 1990, 38, 573-575. [41] von Nussbaum, F.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2000, 39, 2175-2178. [42] Jansen, A. B. A.; Richards, C. G. Tetrahedron 1965, 21, 1327-1331. [43] Rosenmund, P.; Hosseini-Merescht, M.; Bub, C. Liebigs Ann. Chem. 1994, 151-158. [44] Palmisano, G.; Annunziata, R.; Papeo, G.; Sisti, M. Tetrahedron: Asymmetry 1996, 7, 1-4. 20 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
RO2C NMe RO C 2 (+)-16 MeO MeO NMe R = Et
N O 3 Å MS, N O 16 H toluene, ∆ H R = (-)-menthyl 69
Scheme 14: Synthesis of horsfiline by 1,3-dipolar cycloaddition.
In his subsequent work, the [2+3]-cycloaddition with chiral auxiliaries was employed in a more straightforward process on aromatic acrylates, the ester functionality being ultimately incorporated into the indole core (Scheme 15).45
NMe NMe MeO MeO CO2R* CO2R* 16 a b NO2 NO2 Ph R =
Scheme 15: a) sarcosine, (CH2O)n, 3 Å MS, toluene, ∆; b) H2, 10% Pd/C, MeOH.
Tõke successfully employed structurally more complex azomethine ylides in a study aiming at the synthesis of different oxindole structures.46 In order to access spiro- pyrrolidine-oxindoles without necessity for reductive cleavage of the electron- withdrawing group (for example the ester functionality present in 69); Brown showed that 3-methylideneindolin-2-one obtained from flash vacuum pyrolysis of the acetate of 3-hydroxy-3-methylindolin-2-one can also serve as dienophile in the 1,3-dipolar cycloadditions. The azomethine ylides were obtained from silylated amino nitriles by treatment with silver fluoride.47 One of the most outstanding applications of this methodology is found in the synthesis of spirotryprostatin B (17) by Williams (Scheme 16). He employed chiral azomethine ylide 71, which is prepared by addition of
[45] Cravotto, G.; Giovenzani, G. B.; Pilati, T.; Sisti, M.; Palmisano, G. J. Org. Chem. 2001, 66, 8447-8453. [46] Nyerges, M.; Gajdics, L.; Szöllõsy, A.; Tõke, L. Synlett 1999, 111-113. [47] Bell, S. E. V.; Brown, R. F. C.; Eastwood, F. W.; Horvath, J. M. Aust. J. Chem. 2000, 53, 183-190. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 21
3-methoxy-3-methyl-1-butanal to 5,6-diphenylmorpholine-2-one. Reaction with oxindole 70 led to cycloadduct 72 in 82% yield.48,49
Ph Ph MeO Me O EtO2C Ph Me N Ph a O O O H + N CO Et N O O HN 2 H Me 70 MeO 71 Me 72
Scheme 16: a) 3 Å MS, toluene, RT.
One example of a pathway, in which the azomethine ylide is prepared by decarboxylative condensation of an isatin derivative 73 with an α-amino acid 74 is displayed in Scheme 17. trans-Chalcones (75) were used as dipolarophiles. Following this scheme, Fokas synthesized a library of 26,500 spiro[pyrrolidine-2,3’-oxindoles] of general structure 76.50
R4 3 R4 O R R3 R4 N N Ph 1 R R3 a + R1 R1 Ph N O N CO2H H N O O R2 N O O R2 R2 73 74 Ph Ph 75 76
Scheme 17: a) dioxane/H2O, 80 Æ 90 °C.
1.4. Intramolecular Heck Reactions
The use of the Heck reaction for the synthesis of the spiro-oxindole core was pioneered by Overman. He showed that amides like 77, in the presence of Pd(OAc)2 and PPh3, undergo intramolecular cyclization in high yields (Scheme 18).51
[48] Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666-5667. [49] Sebahar, P. R.; Osada, H.; Usui, T.; Williams, R. M. Tetrahedron 2002, 58, 6311-6322. [50] Fokas, D.; Ryan, W. J.; Casebier, D. S.; Coffen, D. L. Tetrahedron Lett. 1998, 39, 2235-2238. [51] Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4130-4133. 22 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
O O NMe N a Me Br 77
Scheme 18: a) Pd(OAc)2 (1 mol%), PPh3 (4 mol%), AgNO3, NEt3 (2.0 equiv),
CH3CN, ∆.
Further investigations in this intramolecular Heck reaction revealed an interesting aspect. The reaction can lead to an excess of the (R)- or the (S)-isomer when it is catalyzed by an (R)-(+)-BINAP palladium complex, depending on the reaction conditions.52 It was found that addition of a silver phosphate leads to the (S)-spiro-oxindole, whereas the opposite enantiomer is obtained in the presence of PMP as base.53 Overman suggests a ‘cationic’ pathway for the silver salt mediated reaction and a ‘neutral’ pathway in the presence of a base.54 However, this mechanistic suggestions could not account for the striking differences in the stereochemical outcome under different conditions. The intramolecular Heck reaction was used by Overman in the total syntheses of (±)-gelsemine ((±)-9) (Scheme 19).55 A similar sequence was also employed by Hiemstra in the synthesis of gelsedine (12).56,57
I MOM O O N N a MOM (+)-9 OMe RN RN OMe Br Br (11:1)
Scheme 19: a) [Pd2(dba)3]·CHCl3, AgNO3, NEt3, THF, ∆.
Overman was able to expand this method to the synthesis of spiro-pyrrolidine-oxindoles. The η3-allylpalladium species resulting from the Heck insertion can be trapped by a
[52] Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57, 4571-4572. [53] Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477-6487. [54] Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488-6499. [55] a) Earley, W. G.; Oh, T.; Overman, L. E. Tetrahedron Lett. 1988, 29, 3785-3788. b) Madin, A.; O'Donnell, C. J.; Oh, T. B.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38, 2934-2936. [56] van Henegouwen, W. G. B.; Fieseler, R. M.; Rutjes, F.; Hiemstra, H. Angew. Chem. Int. Ed. 1999, 38, 2214-2217. [57] van Henegouwen, W. G. B.; Fieseler, R. M.; Rutjes, F.; Hiemstra, H. J. Org. Chem. 2000, 65, 8317-8325. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 23
tethered nitrogen nucleophile. This sequence of two palladium-catalyzed reactions was applied to the synthesis of spirotryprostatin B (17) (Scheme 20).58
H O O O N Me O N NH N O Me SEMN HN O Pd2(dba)3 CHCl3, H SEMN O N H P(oTol)3, KOAc, Me THF, 70 °C O N O Me Me SEM I PdL2I Me
Scheme 20: Intramoleular Heck reaction and trapping of the η3-allylpalladium species.
1.5. Radical Cyclization Reactions
Radical cyclization has also proved successful for the construction of the spiro- pyrrolidine-oxindole nucleus. Jones showed that precursors like 78, in the presence of nBu3SnH and catalytic amounts of AIBN, afford the 5-exo-cyclization product 79 as major product (Scheme 21).59,60 This general method found application in the synthesis of (±)-horsfiline ((±)-16).61
R' R' N R'N N MeO Br MeO MeO a
N O N O N O R R R 78 79
Scheme 21: a) Bu3SnH, AIBN, toluene, ∆.
A very similar approach by Cossy also led to the spiro-oxindole skeleton (Scheme 22).62
[58] Overman, L. E.; Rosen, M. D. Angew. Chem. Int. Ed. 2000, 39, 4596-4599. [59] Jones, K.; Ho, T. C. T.; Wilkinson, J. Tetrahedron Lett. 1995, 36, 6743-6744. [60] Escolano, C.; Jones, K. Tetrahedron Lett. 2000, 41, 8951-8955. [61] Jones, K.; Wilkinson, J. J. Chem. Soc.-Chem. Commun. 1992, 1767-1769. [62] Cossy, J.; Cases, M.; Pardo, D. G. Tetrahedron Lett. 1998, 39, 2331-2332. 24 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
BocN NBoc a
N O N O I O OMe O OMe
Scheme 22: a) Bu3SnH, AIBN, benzene, ∆.
Another interesting approach by Jones ultimately led to oxindoles with a higher degree of substitution at the pyrrolidine part. In this tandem radical sequence, the aryl radical 80 undergoes [1,5]-hydrogen atom abstraction to 81, which cyclizes intramolecularly to the 3-position of the 2-cyanoindol with formation of 82. Radical 82 is reduced in situ with 63 nBu3SnH to 83. Oxidation yields the spiro-pyrrolidine-oxindole 84 (Scheme 23).
R R R
N N N a Br O O O N CN N CN N CN Me Me Me 80 81
O O O
NBn NBn NBn b R R R N O N CN N CN Me Me Me
84 83 82
Scheme 23: a) Bu3SnH, AIBN, toluene, ∆; b) KOtBu, O2, THF, RT.
An approach, relying on the effective preparartion of hindered spiro-oxindoles by photolysis of 1-(1-alkenyl)benzotriazoles via radical intermediates has been developed by Pleynet for the synthesis of gelsemine (9).64
[63] Hilton, S. T.; Ho, T. C. T.; Pljevaljcic, G.; Jones, K. Org. Lett. 2000, 2, 2639-2641. [64] Pleynet, D. P. M.; Dutton, J. K.; Johnson, A. P. Abstr. Pap. Am. Chem. Soc. 1999, 217, ORGN 538. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 25
1.6. Asymmetric Nitroolefination
Asymmetric nitoolefination proved a powerful tool for the efficient introduction of the spiro-center in spiro-pyrrolidine-oxindoles. Fuji showed that the enolate of 85, upon treatment with chiral nitroenamine 86, gives the corresponding quaternary compounds 87 in high yields and enantioselectivities.65
Me Me Me Ph Me MeO Ph MeO N a + OMe NO2 16 N O N O Bn Bn NO2 85 86 87
Scheme 24: a) nBuLi, 86, THF, –78 °C.
This method was among others applied to the synthesis of (–)-horsfiline (16)66 and spirotryprostatin B (17).67
1.7. Rearrangement of [(N-Aziridinomethylthiomethylene]-2-oxindoles
N-Vinylaziridines were shown to undergo facile iodide ion induced rearrangement to 2-methylthio-3,3-substituted pyrrolidines. This general method can be applied to the synthesis of spiro-oxindoles 91 from 90, easily accessible from 89 by reaction with aziridine (Scheme 25).68
MeS MeS MeS N R' SMe a R' N b R'
N O N O N O R R R 89 90 91
Scheme 25: a) aziridine, THF, RT; b) KI, acetone, RT.
[65] Fuji, K.; Kawabata, T.; Ohmori, T.; Node, M. Synlett 1995, 367-368. [66] Lakshmaiah, G.; Kawabata, T.; Shang, M. H.; Fuji, K. J. Org. Chem. 1999, 64, 1699-1704. [67] Bagul, T. D.; Lakshmaiah, G.; Kawabata, T.; Fuji, K. Org. Lett. 2002, 4, 249-251. [68] Kumar, U. K. S.; Ila, H.; Junjappa, H. Org. Lett. 2001, 3, 4193-4196. 26 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
2. Novel Approach to the Synthesis of Spiro-Pyrrolidine- Oxindoles
2.1. Retrosynthetic Analysis
The Carreira-group envisioned a very direct, alternate bond-construction strategy to spiro-pyrrolidine-oxindole ring systems. In our retrosynthetic analysis, 91 is disconnected to cyclopropane 95 and aldimine 93 (Scheme 26). As depicted for synthon 92, the charge- affinity pattern of the cyclopropane complements that of an aldimine. This strategy would not only present an alternative to existing methods, but also allow for efficient late-stage coupling of two functionalized fragments in a convergent fashion.
R1 R1 N N R2 R2 N O N O R R 91 92 93
X
R1 N + N O N OM R2 R R 95 94 93
Scheme 26: Our retrosynthetic analysis for the efficient assembly of the spiro- pyrrolidine-oxindole core.
The charge-affinity pattern of cyclopropanes, when substituted with electron-withdrawing groups, is manifest in their well-known reactivity as homo-Michael acceptors. The introduction of this 1,5-version of the classical Michael reaction is due to Bone and Perkin69 and represents an Umpolung.70 Generally, doubly activated cyclopropanes are
[69] Bone, W. A.; Perkin, W. H. J. Chem. Soc. 1895, 67, 108-119. [70] Seebach, D. Angew. Chem. Int. Ed. Engl. 1979, 18, 239-258. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 27
required for attack by a nucleophile, bearing two geminal electron-withdrawing groups such as esters or cyano groups. In most cases, the more substituted (hindered) carbon is attacked by the nucleophile.71 Pioneering work by Danishefsky had established the participation of doubly activated cyclopropanes in tandem reactions resulting in ring formation (Scheme 27).72
CO2Me CO Me O 2 a CO2Me CO Me NH N 2 N 2 CO2Me O O
Scheme 27: a) hydrazine/MeOH, ∆.
Intramolecular attack renders these activated cyclopropanes more prone to the cleavage of a C–C single bond. Stork was the first to employ intramolecular nucleophilic ring opening of Lewis acid activated cyclopropyl ketones73 and this concept of an electrophile-assisted nucleophilic attack was later on confirmed by the work of Corey and Balason74 (Scheme 28).
Me O Me Me a Me Me O H O Me E E
Scheme 28: SnCl4, benzene, ∆.
Some monoactivated cyclopropanes are also opened upon intermolecular nucleophilic attack; however, these cyclopropanes are generally found in ring systems which render
[71] a) Danishefsky, S. Accounts Chem. Res. 1979, 12, 66-72. b) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165-198. [72] a) Danishefsky, S.; Dynak, J. J. Org. Chem. 1974, 39, 1979-1980. b) Danishefsky, S.; Dynak, J.; Hatch, E.; Yamamoto, M. J. Am. Chem. Soc. 1974, 96, 1256-1259. c) Danishefsky, S.; Etheredge, S. J.; Dynak, J.; McCurry, P. J. Org. Chem. 1974, 39, 2658-2659. d) Danishefsky, S.; Dynak, J. Tetrahedron Lett. 1975, 79-80. [73] a) Stork, G.; Marx, M. J. Am. Chem. Soc. 1969, 91, 2371-2373. b) Stork, G.; Gregson, M. J. Am. Chem. Soc. 1969, 91, 2373-2374. c) Stork, G.; Grieco, P. A. J. Am. Chem. Soc. 1969, 91, 2407-2408. d) Stork, G.; Grieco, P. A. Tetrahedron Lett. 1971, 1807-1810. [74] Corey, E. J.; Balanson, R. D. Tetrahedron Lett. 1973, 34, 3153-3156. 28 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
them particularly strained or occur with strong nucleophiles such as metal selenides.75 Nickel-catalyzed additions of organolaluminums are also known with monoactivated cyclopropanes.76 Singly activated cyclopropyl ketones undergo ring opening in reactions with trimethylsilyl halides, reagents combining a potent, oxophilic electrophile with the attacking nucleophile (Scheme 29).77
O ab Me Me Me I I OTMS O
via: O E
Me Nu
Scheme 29: a) TMSI (1.2 equiv), CCl4; b) H2O.
Our strategy as depicted in Scheme 26, page 26 necessitates nucleophilic ring opening of a singly activated ring system by a weakly nucleophilic aldimine. We speculated that the use of a catalyst exhibiting dual electrophilic and nucleophilic activation would enable the desired reaction, provided competitive intramolecular cyclization (via O–alkylation) is precluded. In this regard, the selection of a Lewis acidic metal possessing nucleophilic counterions could efficiently lead to ring-opened products 94, which possess the same reactivity pattern as synthon 92.78
[75] Smith III, A. B.; Scarborough Jr., R. M. Tetrahedron Lett. 1978, 19, 1649-1652. [76] Bagnell, L.; Meisters, A.; Mole, T. Aust. J. Chem. 1975, 28, 821-824. [77] a) Miller, R. D.; McKean, D. R. J. Org. Chem. 1981, 46, 2412-2414. b) Dieter, R. K.; Pounds, S. J. Org. Chem. 1982, 47, 3174-3177. [78] For a discussion on charge affinity patterns and retrosynthesis see: Evans, D. A.; Andrews, G. C. Accounts Chem. Res. 1974, 7, 147-155. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 29
2.2. MgI2-Catalyzed Ring-Expansion Reaction of Spiro-Cyclopropyl- Oxindoles with Aldimines
2.2.1. Initial Results79
In order to test our hypothesis, initial studies with spiro-cyclopropyl-oxindole 99 and cyclic imine trimer 101 were carried out. Both starting materials of the reaction are easily obtained from commercially available products and were chosen as a simple model for the construction of tetracyclic oxindole alkaloids.
O O acb
N O 90%N O 65% N O 85% N O H Bn Bn Bn 96 97 98 99
Scheme 30: a) NaH, BnBr, DMF, RT; b) N2H4·H2O, ∆; c) NaH,
BrCH2-CH2Br, DMF, RT.
Spiro-cyclopropyl-N-benzyl-oxindole (99) was synthesized from isatin (96) in three steps. Protection of the amide nitrogen to 97, followed by Wolff–Kishner reduction afforded N-benzyl oxindole (98), which was alkylated to spiro-cyclopropyl-oxindole 99 by deprotonation and reaction with 1,2-dibromo ethane (Scheme 30).80,81 The cyclic imine precursor 101 was prepared from piperidine (100) in two steps (Scheme 31).82
H N a, b N N N
40% N 3 100 101
Scheme 31: a) NCS, Et2O; b) KOH, EtOH.
[79] Initial results leading to the development of the MgI2 catalyzed Ring-Expansion Reaction of spiro-cyclopropyl- oxindoles with imines were obtained by Dionicio R. Siegel. [80] Kishner, N. Russ. Phys. Chem. Soc. 1911, 43, 582-586. [81] Crestini, C.; Saladino, R. Syn. Commun. 1994, 24, 2835-2841. [82] Claxton, G. P.; Allen, L.; Grisar, J. M. Org. Synth., Coll. Vol. VI 1988, 968-969. 30 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
Initially, the reaction of spiro-cyclopropyl derivative 99 with imine trimer 101 in the presence of a number of metal salts, for example Mg(OTf)2, ZnI2, Zn(OTf)2, LiI, was investigated. The first notable result was obtained with MgBr2·Et2O. The desired products
102 and 103 were obtained in 13% yield upon treatment with 1.5 equivalents MgBr2·Et2O in refluxing THF (Scheme 32).
N N N MgBr2 Et2O (1.5 equiv) + + THF, ∆, 2 d N O 3 N O N O Bn 13% Bn Bn 99 101 102 103 major diastereomer
Scheme 32: First successful ring expansion of spiro-cyclopropyl-oxindole 99 with imine trimer 101.
At higher temperatures (in refluxing m-xylene), the reaction was catalytic in Lewis acid, showing complete conversion using 30 mol% MgBr2·Et2O. These conditions required the addition of DMA (one equivalent with respect to the catalyst) to the reaction mixture in order to solubilize the catalyst. The two diastereomeric products 102 and 103 were separated by flash column chromatography and analyzed separately. Both diaseteromers slowly isomerize by retro-Mannich/Mannich reaction upon standing at ambient temperature (see Scheme 1, page 9).
Interestingly, the ring-expansion reaction could also be conducted with imines possessing an N-aryl-sulfonyl protecting group. Spiro-cyclopropyl-oxindole 99 leads to spiro- pyrrolidine-oxindole 105 upon MgBr2·Et2O-catalyzed reaction with N-benzylidene- benzenesulfonamide (104) (Scheme 33). The observation that the reaction with this much weaker nucleophile was found to be even faster hints at an interesting mechanistic duality.
N SO2Ph
PhO2S MgBr2 Et2O (30 mol%) + N Ph DMA (30 mol%), m-xylene, ∆ N O N O Bn Ph Bn 99 104 105
Scheme 33: Ring expansion of spiro-cyclopropyl-oxindole 99 with benzylidene-N-sulfonamide 104. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 31
2.2.2. Optimization and Scope of the Ring-Expansion Reaction
Further improvement was achieved by addition of nBu4NI to the reaction mixture. The reaction of spiro-oxindole 99 with benzylidene-N-sulfonamide 104 was used to optimize the reaction conditions and resulted in the adoption of 10 mol% MgI2, in THF at 60 °C as standard conditions (Table 2).83
Lewis-Acid Additive Solvent Solubilizer Temperature Time Conversion MgBr ·Et O DMA 2 2 none m-xylene 135 °C 20 h 70% (30 mol%) (30 mol%) MgBr ·Et O DMA 2 2 Bu NI m-xylene 135 °C 2 h 100% (30 mol%) 4 (30 mol%) DMA none Bu NI m-xylene 135 °C 20 h 0% 4 (30 mol%) MgI 2 none THF none 60 °C 2 h 100% (10 mol%)
Table 2: Optimization of the ring-expansion reaction.
The addition of nBu4NI led to considerable rate acceleration, which prompted us to switch to MgI2 as a catalyst. The reaction rate was high even at lower temperatures, allowing for the use of THF as solvent. This change to a more polar solvent obviated the use of DMA.
In order to explore the scope of the reaction, a variety of N-aliphatic imines 106 were screened. To obtain reasonable reaction times, the standard conditions were modified and the reactions were run in a sealed tube at 80 °C (Scheme 34, Table 3)
N R' R' MgI2 (10 mol%) + N R THF, 80°C, sealed tube N O N O Bn R Bn 99 106 107 R' = aliphatic
Scheme 34: Ring expansion with N-aliphatic imines 106.
[83] Optimization of the reaction conditions and the reactions of 99 with N-aliphatic aldimines 106 were conducted by Phil B. Alper. 32 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
Aliphatic Products: Diastereomer Entry Time Yield imines major diastereomer/minor diastereomer ratio
N N N 1 19 h 86 : 14 68% 3 N O N O 101 Bn Bn 102 103
N N N 2 21 h Et Et 91 : 9 55% Et N O N O 108 Bn Bn 109 110
N N N 3 20 h iPr iPr 80 : 20 83% iPr N O N O 111 Bn Bn 112 113
N N N 4 2 h Ph Ph 79 : 21 99% Ph N O N O 114 Bn Bn 115 116
nBu nBu nBu N N N 5 2 h Ph Ph 81 : 19 98% Ph N O N O 117 Bn Bn 118 119
Table 3: Ring expansion with N-aliphatic imines 106.
The configuration of the products of type 107 was assigned by 1H NMR correlation to the major product of entry 5, for which a crystal structure had been obtained.
Imine trimers can be successfully employed in the reaction and act as an imine precursor or surrogate (entry 1). The reaction with enolizable imines results in prolonged reaction times (entry 1–3) and in a decrease in yield (entry 2), but steric bulk at the α-position seems to be favorable (entry 3).
Next, we turned our investigations to the ring-expansion reaction of 99 with substituted methylidene-N-arylsulfonamides 123. The substituted methylidene-N-arylsulfonamides are conveniently prepared by reaction of the dialkyl acetals 120 with aryl-sulfonamides Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 33
121 in the absence of solvent (Scheme 35).84 The condensation yields a solid that can be conveniently purified by recrystallization. Yields are generally moderate (between 44 and 75%) with exception of 149 (12%).
O O S H N Ar 2 O O OR' 121 S N Ar R'O R 160 °C, -2R'OH R 122 120 R' = Me R' = Et
Scheme 35: Preparation of substituted methylidene-N-arylsulfonamides 122.
With the N-tosyl-protected imines 123 in hand, we focused on the exploration of the reaction scope (Scheme 36, Table 4)
NTs NTs MgI2 (10 mol%) + R THF, 60 °C N O R N O Bn Bn 99 123
Scheme 36: Ring expansion with N-tosyl-protected imines 123.
N-tosyl- Products: Diastereomer Entry protected Time Yield major diastereomer/minor diastereomer ratio imines
NTs NTs NTs
1 Ph 8 h Ph Ph 91 : 9 97% N O N O 124 Bn Bn 125 126
NTs Me NTs NTs Me Me 2 8 h 98 : 2 89% N O N O Bn Bn 127 128 129
NTs NTs NTs 3 34 h 64 : 36 96% Me N O N O Bn Bn 130 131 Me 132 Me
[84] Albrecht, R.; Kresze, G.; Mlakar, B. Chem. Ber. Recl. 1964, 97, 483-489. 34 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
NTs Br NTs NTs Br Br 4 19 h 98 : 2 82% N O N O Bn Bn 133 134 135
NTs NTs NTs 5 22 h 82 : 18 92% N O N O Br Bn Bn 136 137 Br 138 Br
NTs NTs NTs 6 18 h 84 : 16 97% N O N O CF3 Bn Bn 139 140 141 CF3 CF3
NTs NTs NTs 7 50 h 67 : 33 75% N O N O OMe Bn Bn 142 143 OMe 144 OMe
NTs NTs NTs 8 4 h 85 : 15 97% O N O O N O O Bn Bn 145 146 147
NTs NTs NTs 9 20 h 74 : 26 62% Ph N O N O Bn Ph Bn Ph 148 149 150
NTs NTs NTs Me Me 10 96 h Me 52 : 48 55% Ph N O N O Bn Ph Bn Ph 151 152 153
NTs NTs NTs 11 4 h 98 : 2 77% TIPS N O N O 154 Bn TIPS Bn TIPS 155 156
Table 4: Ring expansion with N-tosyl-protected imines 123.
In the series with N-tosyl-imines derived from aromatic aldehydes (entries 1–8), the unsubstituted systems react fast and give rise to good diastereoselectivities (entries 1 and 8). With exception of entry 2, the rate of the reaction is decreased by both electron- withdrawing and electron-donating substituents. However, it can be observed that Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 35
electron-withdrawing substituents are more favorable than electron-donating ones in the para-position (for example entry 6 vs. entry 7 or entry 5 vs. entry 3). Better diastereoselectivities are generally observed with ortho-substituents on the aromatic ring (entries 2 and 4). Cinnamaldehyde-derived imines are also suitable reaction partners even though the products are obtained in lower yields and with lower diastereoselectivities (entries 9 and 10). The reaction with the imine derived from TIPS-protected propynal is very fast (entry 11).
In order to obtain higher levels of diastereoselectivity, we decided to change the bulkyness of the N-protecting group of the imines. Therefore the imines 157–159 were prepared according to the general protocol (Figure 5). These imines are derived p-methylbenzaldehyde, as N-tosyl-imine 130 (see Scheme 35, page 33) derived from this aldehyde led to low diastereoselectivity (64:36) in the ring expansion (entry 3,Table 4, page 34).
O O i-Pr O O Me O O S S Me S N N N
i-Pr i-Pr Me Me Me 157 Me 158 Me 159 Me
Figure 5: Sterically demanding N-(4-methyl-benzylidene)-sulfonamides.
Only 157 could be employed in the ring-expansion reaction, imines 158 and 159 being probably too sterically demanding. As a result, the products of the ring expansion with 99 were obtained in 83% combined yield with significant increase in diastereoselectivity (89:11) as compared to entry 3 (64:36) (Scheme 37). 36 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
O O O O S S O O N N S MgI (10 mol%) N 2 + THF, 60 °C + N O N O N O Bn Bn Bn 83% Me Me 99 157 Me 160 161 89:11
Scheme 37: Ring expansion of 99 with N-(4-methyl-benzylidene)- (naphthalene)-sulfonamide 157.
In order to further expand the scope of our ring-expansion reaction, we next turned to the use of other reaction partners for 99. The reaction can also be performed using aldehydes instead of aldimines, leading to the formation of spiro-fused tetrahydrofuran derivatives. The reaction of 99 with p-trifluoromethyl-benzaldehyde (162) affords oxolane 163 (Scheme 38).
O O MgI2 (10 mol%) + THF,100 °C, sealed tube N O N O Bn CF3 Bn 19% CF 99 162 163 3
Scheme 38: Ring expansion of 99 with aldehyde 162.
The use of tosylamid 165 derived from ethyl glyoxylate (164) in the reaction with 99 led to a surprise. Instead of the expected ring-expansion product 166, we obtained the product of the aromatic-substitution reaction 167, unambiguously characterized by X-ray crystallographic analysis (Scheme 39, Figure 6).85 Reactions of that type are known and generally use the N,O-(glyoxylate-hemiacetal) in the presence of a strong acid.86 Only one reference for such a reaction of electron-rich aromatic compounds with glyoxylate- derived imines has been reported.87
[85] CCDC 199468 contains the supplementary crystallographic data for 167. This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]). [86] Ben-Ishai, D.; Sataty, I.; Bernstein, Z. Tetrahedron 1976, 32, 1571-1573. [87] Saaby, S.; Fang, X. M.; Gathergood, N.; Jorgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 4114-4116. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 37
NTs
R N O Bn NTs 166 + OEt MgI2 (7.6 mol%) N O THF, 60 °C Bn O O OEt 99 165 TsHN toluene N O ∆, 3 d Bn 167 NTs O C + OEt O O 164
Scheme 39: Reaction of 99 with glyoxylate-derived N-tosyl-protected imine 165.
Figure 6: ORTEP drawing of 167. 38 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
Isocyanates are also able to react with cyclopropyl-oxindole 99, giving rise to pyrrolidinones 168 (Scheme 40). In the context of these investigations, it was shown that deprotection of the tosyl group can be accomplished with Na/naphthalene in good yield.88
N R NH R MgI2 (1 equiv) Na / naphthalene N O O + N O C THF, 100 °C N O THF,-100 °C N O Bn Bn H O 90% 99 168 R = Ts
Scheme 40: Ring expansion of 130 with isocyanates.
The reaction can also be performed with other monoactivated cyclopropanes. A lead result was obtained when cyclopropanecarboxylic acid diphenylamid 169 was employed in the ring expansion with benzylidene-N-benzenesulfonamid (104), giving two diastereomers of the desired pyrrolidine 170 (Scheme 41).
O Ph N O MgI (1 equiv) 2 PhO2S 2 + N DMA, xylene, ∆ Ph NPh2 N Ph SO2Ph 169 104 170
Scheme 41: Synthesis of substituted pyrrolidenes from cyclopropancarboxylic acid diphenylamid (169).
2.2.3. Mechanistic Aspects
Even though we have not yet undertaken detailed kinetic studies for this ring-expansion reaction, we are able to draw some conclusions from the observations made with different imine substrates. The hypothesized mechanistic pathway is depicted in Scheme 42.
[88] This study was undertaken by Andreas Lerchner during his diploma work. Lerchner A. Diploma Thesis, ETH Zürich, 1999. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 39
R N R' N R MgI2 R' N OMgI N O Bn Bn R 172 174 N + MgI2 acts as a R' N O I bifunctional catalyst: Bn I 99 N R Nucleophilic I R' Activation
MgI2 N OMgI N O Bn Bn Mg Activation by N O I Lewis Acid I 171 173 Bn
N O Bn 175
Scheme 42: Possible mechanistic pathways for the ring-expansion reaction.
The cyclopropane could be opened by one of the two potential nucleophiles present in the reaction mixture: (i) I- giving rise to enolate 171 or (ii) the imine nitrogen leading directly to enolate 172. We have evidence that the first intermediate of the ring-expansion reaction is enolate 171. If 172 was the first intermediate, it would be doubtful that the reaction could proceed with N-aryl-sulfonyl-protected imines, as those are poor nucleophiles. The pathway via intermediate 171 could also be responsible for the fact that the more nucleophilic iodide accelerates the reaction significantly as compared to bromide and that with Mg(OTf)2, no reaction is observed (Table 5). Finally, we were able to isolate 3-(2-iodo-ethyl)-N-benzyl-oxindole (175) as a by-product (characterized by 1H NMR and high resolution MALDI-MS) in a reaction wherein the imine decomposed. This compound is the keto form of enolate 171 after aqueous workup. From intermediate 171, two possible pathways are depicted in Scheme 42. A nucleophilic imine could attack intermediate 171 giving rise to 172. In this reaction the rate acceleration of iodide vs. bromide could again be manifest, iodide being the better leaving group (Table 5). From 172, the final product 174 is obtained by cyclization of the iminium species, similar as for the retro-Mannich reaction depicted in Scheme 1. This might be the pathway for N-alkyl- imines. On the other hand, with more electrophilic imines like N-aryl-sulfonyl-protected imines, the reaction is likely to proceed through adduct 173, that could close to 174 by N-alkylation. 40 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles
Leaving-Group Nucleophilic The leaving-group reactivity is defined as the Reactivity Constant ratio kX/kBr and values for the reaction of (nMeI values) - Cl- 0.0024 4.37 EtX with EtO as nucleophile are given. The nucleophilic constant is defined as: Br- 1.0 5.79 k(MeI + Nuc) I- 1.9 7.42 n = log k(MeI + MeOH)
Table 5: Leaving-group reactivities and nucleophilic constants for halogen anions.
Considering these results, it can be concluded that MgI2 acts as a bifunctional catalyst where both the Lewis acidic metal center (Mg(II)) and the nucleophilic counter ion (I–) have to operate in synergy to enable successful ring expansion.89
The ring closure of iminium 172 to 174 is a disfavored 5-endo-trig cyclization process and deserves comment.90 Baldwin has studied the cyclization behavior of hydroxyl enones to furanones and discovered that nucleophilic ring closure by conjugate addition to a neutral enone is an unfavored process forming five-membered cycles; the products could not be formed. However, under acidic conditions, cyclization is possible and this result is explained by the reduction of rotational barriers around the C−C bond of the enone resulting from enone protonation to 176.91 Intermediate 172 could also undergo ring closure by contribution of its resonance structure. Alternatively, as in the mechanism for the formation of cyclic acetals, the ring closure of 172 could be catalyzed by a nucleophile (e.g. I-) and proceed via 177 as a 5-exo-tet process (Figure 7).92 A couple of examples for disfavored 5-endo-trig cyclization reactions are known in literature for the formation of pyrrolidines and tetrahydrofuranes.93,94
[89] MgI2 is a very efficient catalyst in Diels-Alder reactions and aldol additions. This is due to the efficient - dissociation of I from L2MgI2 (L is a solvent molecule). Corey, E. J.; Li, W. D.; Reichard, G. A. J. Am. Chem. Soc. 1998, 120, 2330-2336. [90] Baldwin, J. E. J. Chem. Soc. Chem. Commun. 1976, 734-736. [91] Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org. Chem. 1977, 42, 3846-3852. [92] Johnson, D. D. Acc. Chem. Res 1996, 26, 476-482. [93] a) Grigg, R.; Kemp, J.; Malone, J.; Tangthongkum, A. J. Chem. Soc. Chem. Commun. 1980, 648-650. b) Auvray, P.; Knochel, P.; Normant, J. F. Tetrahedron Lett. 1985, 26, 4455-4458. Padwa, A.; Norman, B. H. J. Org. Chem. 1990, 55, 4801-4807. c) Jones, A. D.; Knight, D. W. Chem. Commun. 1996, 915-916. d) Berry, M. B.; Craig, D.; Jones, P. S.; Rowlands, G. J. Chem. Commun. 1997, 2141-2142. e) Craig, D.; Jones, P. S.; Rowlands, G. J. Synlett 1997, 1423-1425. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles 41
H O OH R R N N Me Me R' R' Me Me OH OH N OMgI N OMgI Bn Bn 176 172
R R N N R' I O R OH O OH I R R' O R O R N O MgI N O MgI Bn Bn H H 172 177 5-endo-trig 5-exo-tet 5-endo-trig 5-exo-tet
Figure 7: Explanations for possible 5-endo-trig cyclization.
2.2.4. Conclusion
The MgI2-catalyzed ring-expansion reaction gives access to the spiro-pyrrolidine- oxindole ring systems. This motif is a key structural feature in a number of natural products and can be rapidly assembled from easily available starting materials. The reaction proceeds with useful levels of diastereoselectivity and high yields. The dual
Lewis acidic and nucleophilic activity of MgI2 enables successful ring expansion of a monoactivated cyclopropane. This reaction provides a useful tool for the synthesis of complex natural products.
f) Dell'Erba, C.; Mugnoli, A.; Novi, M.; Pani, M.; Petrillo, G.; Tavani, C. Eur. J. Org. Chem. 2000, 903-912. g) Chang, K. T.; Jang, K. C.; Park, H. Y.; Kim, Y. K.; Park, K. H.; Lee, W. S. Heterocycles 2001, 55, 1173-1179. [94] a) Craig, D.; Smith, A. M. Tetrahedron Lett. 1992, 33, 695-698. b) Craig, D.; Ikin, N. J.; Mathews, N.; Smith, A. M. Tetrahedron Lett. 1995, 36, 7531-7534. c) Craig, D.; Ikin, N. J.; Mathews, N.; Smith, A. M. Tetrahedron 1999, 55, 13471-13494. 42 The Synthesis of (±)-Horsfiline
IV. The Synthesis of (±)-Horsfiline
1. Introduction
(–)-Horsfiline (16) is one of the structurally simpler oxindole alkaloids found in nature. It was isolated in 1991 by Bodo and co-workers from the Malaysian tree Horsfieldia superba (Figure 8), an important source of medicinal extracts and snuffs in the local medicine.95
Figure 8: The Malaysian tree Horsfieldia superba.
1.1. Isolation
(–)-Horsfiline was found together with two achiral metabolites 178 and 179, and the two- step conversion of 178 into (±)-16 by oxidative rearrangement supported the structural assignment for 16. The absolute configuration of (–)-horsfiline was not known at that time (Scheme 43).
[95] See [4], page 7. The Synthesis of (±)-Horsfiline 43
MeO NMe MeO MeO
NMe N N O N N Me Me H H H (-)-horsfiline (16) 178 179
a, b
MeO NMe
N O H (+)-16
Scheme 43: Alkaloids from Horsfieldia superba. a) Pb(OAc)4, CH2Cl2, RT; b)
MeOH/H2O/AcOH, ∆.
Horsfiline has proven an ideal target to test new methods for the general synthesis of spiro-oxindoles. Several groups have gotten involved in the synthesis of horsfiline. The first syntheses yielded racemic horsfiline ((±)-16).
1.2. Synthetic Approaches
1.2.1. Jones’ and Wilkinson’s Synthesis of (±)-Horsfiline
The synthetic route by Jones and Wilkinson is based on a radical reaction as key step. The precursor for the radical cyclization 182 was prepared from 2-bromo-4-methoxy- aniline and 181, available from Cbz-protected glycine ethyl ester (180) in a multistep sequence. Protection of the indole nitrogen proved important, as radical cyclization of unprotected 182 led only to reduction and transient TMS-protection led to considerable amounts of the undesired product from 6-endo cyclization. (±)-Horsfiline is obtained after deprotection of 183 and treatment of 184 under Eschweiler–Clarke conditions (Scheme 44).96
[96] See [61], page 23. 44 The Synthesis of (±)-Horsfiline
EtO2C O EtO2C OH EtO2C HO2C CO2Et a bc,de
NHCbz 87%N 85%N 53% N 89% N Cbz Cbz Cbz Cbz 180 181
f,g 79%
NCbz NCbz NCbz MeO j MeO Br h MeO Br
70% 94% N O N O N O SEM SEM H 183 182
MeO NH MeO NMe k,l m
68% N O 75% N O H H 184 (+)-horsfiline ((+)-16)
Scheme 44: a) ethyl acrylate, Na, toluene; b) NaBH3CN, MeOH; c) BzCl,
DMAP, Py; d) DBU, toluene, ∆; e) KOH, dioxane/H2O, 45 °C; f) NEt3, SOCl2¸ DME, 0 °C; g) 2-bromo-4-methoxy-aniline, Hünig’s base, DME; h) KH, THF,
SEMCl; j) Bu3SnH, AIBN (cat.), toluene, ∆; k) Bu4NF, DMF/ethylenediamine,
80 °C; l) H2, Pd/C, EtOH; m) HCO2H, HCHO, ∆.
1.2.2. Laronze’s Syntheses of (±)-Horsfiline
Laronze’s syntheses of horsfiline follow two different strategies, an oxidative rearrangement of tetrahydro-β-carboline and a spiro-cyclization of tryptamine-oxindole with formaldehyde. The oxidative rearrangement pathway yielded (±)-horsfiline in 52% overall yield from tetrahydro-β-carboline 185 via non isolable chloroindolenine 186. Side-products from the rearrangement reaction can be further converted into desired
(±)-horsfiline ((±)-16). The alternative route from the 5-methoxy-Nb-methyl-tryptamine (187), via oxo-tryptamine derivative 188 led to (±)-horsfiline in 35% overall yield (Scheme 45).97
[97] Bascop, S. I.; Sapi, J.; Laronze, J. Y.; Levy, J. Heterocycles 1994, 38, 725-732. The Synthesis of (±)-Horsfiline 45
Cl MeO MeO Route A: NMe a NMe overall yield = 52% N N H 185 186 b
MeO Cl MeO NMe MeO NMe c d
N N OMe N O H N Me (+)-horsfiline ((+)-16)
f
MeO MeO e Route B: NHMe NHMe overall yield = 35% N N O H H 187 188
Scheme 45: a) tBuOCl, NEt3, CH2Cl2; b) NaOH, MeOH/H2O, 70 °C; c)
NaOMe, MeOH, ∆; d) pTsOH/H2O, toluene, ∆; e) DMSO, 37% aq HCl, 80 °C;
f) (CH2O)n, AcOH, ∆.
1.2.3. Borschberg’s Approach to (+)- and (–)-Horsfiline
The first investigations towards the elucidation of the absolute configuration of horsfiline were undertaken by Borschberg. The plan was to use of a chiral tetrahydro-β-carboline derived from 5-methoxy-L-tryptophane (189) that would give rise to two diastereomers after oxidative rearrangement. Those could, after separation, be reduced to the two enantiomers of the horsfiline core. Following this strategy, both (+)- and (–)-horsfiline could theoretically be accessed from a common intermediate. In practice, different substituents at the piperidine nitrogen led to significant preferences for formation of one diastereomer over the other in the rearrangement. It was therefore preferable to access spiro-oxindole 191 from Boc-derivative 190, and 193 from N-methyl derivative 192. NOE experiments allowed for the structural assignments of the relative stereochemistry of 191 and 193 and thus of the absolute configuration of their reduced counterparts 16 46 The Synthesis of (±)-Horsfiline
and (+)-16. In the meantime, the absolute (R)-configuration was also determined by X-ray crystallographic analysis (Scheme 46).98
CO2Me
MeO CO Me MeO NMe MeO NMe 2 g,d,e,h j,k NBoc N 37% N O 49% N O H H H 190 191 (-)-horsfiline (16) a-c 77%
HO CO2H
NH Cl N 3 H 189
a-f CO Me 68% 2 NMe NMe MeO CO2Me MeO MeO g l,m NMe N 50%N O 66% N O H H H 192 193 (+)-horsfiline ((+)-16)
Scheme 46: a) 1.38% aq CH2O, MeOH, ∆, then TMSCl, MeOH, ∆;
b) (Boc)2O, NEt3, THF/H2O; c) TMSCHN2, Hünig’s base, MeCN/MeOH;
d) TMSCl, 4-MeC6H4OMe, MeOH, ∆; e) 1.38% aq CH2O, NaBH3CN, AcOH;
f) NEt3, THF, ∆; g) NBS, AcOH, THF/H2O; h) MeOH/2 N HCl aq, ∆;
j) (i) NEt3, MeOH, (ii) (CF3CO)2O, dioxane, Py; k) NaBH4, EtOH, Py, 40°C;
l) 1 N NaOH, MeOH; m) ClCO2CH2CHMe2, NMO, then 2-mercaptopyridine-
N-oxide, Me3CSH, hν.
1.2.4. Palmisano’s Route to (–)-Horsfiline
Another synthetic approach taking advantage of a 1,3-dipolar cycloaddition reaction was employed by Palmisano. He was able to access (–)-16 in five steps from enantiopure dipolarophile 195, which was obtained by Wittig olefination of 5-methoxy-isatin (194). Dipolar cycloaddition with N-methyl azomethine yilde prepared in situ from formaldehyde and sarcosine, yielded 196, and its C3 epimer. Hydrolysis of the ester and formal decarboxylation afforded (–)-horsfiline 16 (Scheme 47).99
[98] See [27], page 14. [99] See [44], page 19. The Synthesis of (±)-Horsfiline 47
RO2C RO2C MeO O MeO NMe MeO NMe abMeO 3 c,d,e 76 % 41 % 65% N O N O N O N O H Me H H H 194 195 196 (-)-horsfiline (16)
H N CO H = R sarcosine = Me 2 Me Me (-)-menthyl
Scheme 47: a) (5R)-menthyl(triphenylphosphoranylidene)acetate, diglyme, ∆;
b) sarcosine, (CH2O)n, toluene, ∆; c) powdered KOH, 18-crown-6 (cat.), THF,
then Dowex 50W × 8; d) DCC, DMAP, 2-mercaptopyridine-N-oxide, CH2Cl2;
e) Bu3SnH, AIBN (cat.), toluene, ∆.
Palmisano carefully revised his approach and concluded that a chiral precursor like 199 would still bear the electron-withdrawing ester group required for the 1,3-dipolar cycloaddition. In contrast to his first-generation synthesis, this ester group could be incorporated in the spiro-oxindole core instead of being reduced to the hydrocarbon stage. The chiral cycloaddition precursor 199 was obtained by esterification of 197 with Whitesells’ (1S,2R)-2-phenyl-1-cyclohexanol (198). 1,3-dipolar cycloaddition afforded 200 in high yield and diastereoselectivity. Ester-cleavage and reduction of the nitro group, followed by spontaneous intramolecular lactam formation led to (–)-horsfiline (16).
MeO abcMeO MeO MeO CN CO2Me CO2Me 55% 85% 76% NO2 NO2 NO2 NO2 d 80%
NMe NMe MeO g MeO f MeO e MeO CO2R* CO2H CO2R* 78% Ph N O 95% NO 78% NO2 NO2 H 2 200 199 HO 197 (-)-horsfiline (16) 86% de 198
Scheme 48: a) (4-ClC6H4)OCH2CN, tBuOK, DMF, –10 °C; b) MeOH, TMSCl;
c) (CH2O)n, K2CO3, TDA-1, toluene, 85 °C; d) 2 M NaOH, ∆, then pH 1, 0 °C;
e) 198, DCC, HOBt, DMAP, CH2Cl2, ∆; f) sarcosine, (CH2O)n, 3 Å MS,
toluene, ∆; g) H2, 10% Pd/C, MeOH. 48 The Synthesis of (±)-Horsfiline
1.2.5. Fuji’s Synthesis of (–)-Horsfiline
Fuji’s synthesis of (–)-horsfiline 16 is characterized by early introduction of the chiral quaternary center by asymmetric nitroolefination of oxindole 201 with 86. Regioselective introduction of the aromatic methoxy group is noteworthy (202 Æ 203). In spite of the successful implementation of these key steps, the overall synthesis is rendered awkward by multitudes of functional group interconversions (Scheme 49).100
Me Me Me Me Me Me ab c NO2 NO2 N O 60% N O 65% N O 97% N O Bn Bn Bn Bn Ph Ph 201 OMe d N 87% NO2 86 Me Me OH Me Me
f e NHCbz NHCbz 70% 83% CO2H N O N O N O Bn Bn Bn
g 96%
NCbz MeO NCbz MeO NMe hj,k
N O 61% N O 71% N O Bn Bn H (-)-horsfiline (16) 202 203
Scheme 49: a) nBuLi, THF, BrCH2CH=C(CH2)2; b) nBuLi, Et2O, 86;
c) NaBH4, dioxane/MeOH; d) NaNO2, AcOH/DMSO; e) NEt3, DPPA, toluene,
BnOH; f) (i) O3, EtOH, –78 °C, Me2S, (ii) NaBH4, MeOH; g) (i) MsCl, NEt3,
CH2Cl2, (ii) NaH, THF; h) (i) Pb(CF3CO2)4, CF3CO2H, (ii) NaH, THF, MeI;
j) (i) Pd/C H2, MeOH, (ii) HCHO, NaBH3CN, AcOH; k) Li/NH3.
[100] See [66], page 25. The Synthesis of (±)-Horsfiline 49
2. Synthesis of (±)-Horsfiline by MgI2-Catalyzed Ring- Expansion Reaction of Spiro-Cyclopropyl-Oxindole and 1,3,5- Trimethyl-1,3,5-Triazinane 101
In order to evaluate the applicability of the MgI2-catalyzed ring-expansion reaction for the synthesis of natural products, (±)-horsfiline ((±)-16) represents an ideal target. In view of this, (±)-16 should be accessible from spiro-3-cyclopropyl-(5-methoxy-oxindole) 204 and aldimine 205 derived from methylamine and formaldehyde (Scheme 50).102
MeO
N O R 204 MeO NMe + Me N O Me N H N (+)-horsfiline ((+)-16) MeN NMe 205 206
Scheme 50: Retrosynthetic analysis.
In the context of this analysis, the major issue to be addressed was whether the triazinane 206 could be used in the ring-expansion reaction. For that reason, the reaction of spiro- cyclopropyl-oxindole 99 with 206 was our first reaction in the synthetic approach to (±)- horsfiline. Even though higher temperatures were required for successful conversion, the
MgI2-catalyzed ring expansion proceeded smoothly. Best yields of 207 were obtained with one equivalent of 206 (three equivalents of ‘imine’) (Scheme 51).
Me THF, MgI2 (5 mol%),125 °C, NMe N 20 h, sealed tube + MeN NMe N O 97% N O Bn Bn 99 206 207
Scheme 51: Successful ring expansion of 99 with triazinane 206.
[101] The synthesis of (±)-horsfiline was carried out by Christian Fischer during his diploma work. Fischer C. Diploma Thesis, ETH Zürich, 2000. [102] Aldimines with sterically small substituents generally form trimers. 50 The Synthesis of (±)-Horsfiline
The conversion of triazinane 206 to N-methyl methanimine has been reported to take place at temperatures above 250 °C, under conditions of flash vacuum pyrolysis.103 These conditions are considerably harsher than the conditions for the formation of 207. Two mechanistic pathways are plausible for this ring-expansion reaction (Scheme 52).
Me N Me N NMe 205
N OMgI N O Bn Bn
I 209 207
MgI2
N O N OMgI Bn Bn Me Me 99 171 N NMe N NMe
N N Me Me Me N OMgI N OMgI N Bn Bn 208 MeN NMe 206
Scheme 52: Plausible mechanistic pathways for the formation of 207.
Intermediate 171 can either react with N-methyl methanimine (205) to form 209, or directly with 1,3,5-trimethyl-1,3,5-triazinane (206) giving rise to ammonium 208. The latter could then undergo fragmentation to 209, from which desired product 207 is obtained. At present there is no clear evidence for either one of the proposed pathways.
Having solved the key issue, the synthesis of (±)-horsfiline was tackled. The synthetic route started with the N-benzylation of commercially available 5-methoxyisatin (194) to yield 210 as a crystalline, red solid. The corresponding oxindole 211 was obtained by Wolff–Kishner reduction.104 The sodium enolate of 211 cleanly provided spiro- cyclopropyl-oxindole 212 by cyclization with 1,2-dibromoethane. This set the stage for the key step of our synthesis of (±)-horsfiline ((±)-16): the cyclopropane- fragmentation/ring-expansion reaction. Treatment of 213 with 1,3,5-trimethy-1,3,5-
[103] Bibas, H.; Koch, R.; Wentrup, C. J. Org. Chem. 1998, 63, 2619-2626. [104] See [80], page 29. The Synthesis of (±)-Horsfiline 51
triazinane (206) and 5.5 mol% MgI2 in THF at 125 °C in a sealed tube furnished desired spiro-pyrrolidine-oxindole 213 in 83% yield. Removal of the N-benzyl protecting group was achieved by dissolving-metal reduction (Na/NH3) and afforded (±)-horsfiline ((±)-16) in 91% yield (Scheme 53).
O O MeO abMeO MeO
74% 91% N O N O N O H Bn Bn 194 210 211
c
81%
NMe NMe MeO e MeO d MeO
91% 83% N O N O N O Bn Bn Bn (+)-16 213 212
Scheme 53: a) NaH, BnBr, DMF; b) N2H4·H2O, ∆; c) 1,2-dibromoethane, NaH,
DMF; d) MgI2 (5.5 mol%), 1,3,5-trimethy-1,3,5-triazinane (206), THF, 125 °C,
sealed tube; e) Na/NH3, –78 °C.
3. Conclusion
The short synthesis of (±)-horsfiline (five steps from commercially available material,
41% overall yield) demonstrates, for the first time, the viability of the MgI2-catalyzed ring-expansion reaction as a method for the synthesis of spiro-pyrrolidine-oxindole alkaloids. In the context of this synthesis, the utility of 1,3,5-trimethy-1,3,5-triazinane
(206) to serve as an efficient surrogate in the MgI2-catalyzed ring expansion could be demonstrated. 52 The Total Synthesis of (–)-Spirotryprostatin B
V. The Total Synthesis of (–)-Spirotryprostatin B
1. Introduction
1.1. Isolation and Biological Activity
In 1996, Osada and co-workers reported the isolation of spirotryprostatin A (43), together with spirotryprostatin B (17), from the fermentation of Asperguillus fumigatus BM939 (Figure 9).105
Figure 9: The fungus Asperguillus fumigatus.
The fungus was cultured in 400 L of fermentation medium (glucose 3%, soluble starch
2%, soybean meal, 2%, K2HPO4 0.5%, MgSO4·7H2O 0.05%, adjusted at pH 6.5 before sterilization, containing 0.05% of CA-123 and 0.05% of KM-68 antifoam) at 28 °C for 66 h at a 200 L min-1 aeration rate. Filtration of the broth yielded a filtrate and a filtercake. The latter was extracted with aqueous acetone; the acetone was removed by evaporation in vacuo and the remaining aqueous phase was combined with the filtrate. This combined aqueous phase was repeatedly extracted with ethyl acetate. The solvent was evaporated in vacuo to yield 1.2 L of an oily extract, which was further purified as depicted in Figure 10 leading to 1.2 mg of 43 and 11 mg of 17.
[105] a) Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651-12666. b) See [5], page 7. The Total Synthesis of (–)-Spirotryprostatin B 53
oily n-hexane solution n-hexane solution residue 1.2 L residue residue
solution CHCl3 residue CHCl3 H2O aq O layer org. N O layer HN N H O Me repeated n-hexane/CHCl3 Me HPLC 10:90 17 11 mg column active chromatography extract 66 g O repeated CHCl3/MeOH H HPLC 99:1 O N HN N H O Me MeO Me 43 1.2 mg
Figure 10: Isolation procedure for 43 and 17.
Structural elucidation of both compounds was possible by combined analytical methods. The molecular formulas were obtained from HR-EI-MS measurements. The IR-spectrum suggested the presence of a diketopiperazine system (amid-carbonyl absorptions at 1680 cm-1, near 1660 cm-1 and amid II band near 1550 cm-1) and a γ-lactam fused to an aromatic ring (carbonyl at 1715 cm-1) for both 43 and 17. These findings were supported by 13C NMR. Deduction of partial structures was enabled by detailed analysis of the 1H and 13C NMR spectra, with the aid of a pulse field gradient (PFG), 1H-1H COSY, PFG-HMQC and NOE difference experiments. The connectivity between these fragments could be established by PFG-HMBC. Assignment of the relative stereochemistry at C3 and C18 (spirotryprostatin numbering) was possible by NOE. The relative stereochemistry at C12 could only be determined for spirotryprostatin A (43), but it was assumed to be identical for spirotryprostatin B (17), as the biogenesis of both compounds is probably akin. The absolute stereochemistry could not be determined, but it was assumed that the spirotryprostatins are metabolites derived from L-tryptophane and
L-proline. 54 The Total Synthesis of (–)-Spirotryprostatin B
Both compounds inhibit the cell cycle in the G2/M phase. This was tested with mouse tsFT210 cells, a mutant cell line that grows normally at 32 °C, but is arrested in the G2 phase at 39 °C. Arrested cells simultaneously pass through the M phase to enter into the G1 phase upon transfer to 32 °C. The cycle progression in the presence of 43 and 17 is inhibited when the temperature-arrested cells are cooled to 32 °C. The IC50 values are 197.5 µM for 43 and 14.0 µM for 17. It is supposed that the significantly stronger inhibition activity of 17 is related to the absence of the 6-methoxy group on the oxindole ring as compared to 43. A similar observation was made for the structurally related compounds tryprostatin A (214) and B (215), among which the demethoxy derivative 215 is also more active (Figure 11). However, an influence of the C8–C9 olefin on the activity cannot be completely ruled out.
O O O H H O 8 N O 8 N 9 12 9 12 N HN 3 N HN 3 N HN H H 18 18 R N O O H H O 19 Me 19 Me Me MeO Me Me Me 17 43 214 R = OMe, tryprostatin A spirotryprostatin B spirotryprostatin A 215 R = H, tryprostatin B
Figure 11: Natural products isolated from Asperguillus fumigatus.
Spirotryprostatin B (17) also inhibits the growth of human chronic myelogenous leukemia K562 cells and human promyelocytic leukemia HL-60 cells with MIC’s of 35 µg mL-1 and 10 µg mL-1 respectively.5
The spirotryprostatin skeleton is characterized by: (i) a unique spiro-fusion to a pyrrolidine at the 3-position of the oxindole core, (ii) the annulated diketopiperazine ring and (iii) the prenyl moiety. Only a few spiro compounds that possess a diketopiperazine system and are derived from both tryptophane and proline (e.g. 216–219) are known,106 but none of them includes a spiro-system like 43 and 17. A 5-membered ring, spiro-fused to the 3-position of an indole skeleton is also present for example in the tryptoquivalines
[106] a) Birch, A. J.; Wright, J. J. Tetrahedron 1970, 26, 2329-2344. b) see [30], page 14. The Total Synthesis of (–)-Spirotryprostatin B 55
(220 and 221),107 but this ring is different to those found in the spirotryprostatins (Figure 12). The spirotryprostatins constitute the first example of a novel class of natural diketopiperazines with a unique spiro-ring skeleton.
O R Me H O H N MeH Me Me Me Me O N NH O N O N H NH O O R O H O NH N O N N N OH O N H N O Me Me O Me O Me 216 (+)-brevianamide A 217 (+)-brevianamide B 218 R = Me: (-)-marcfortine A 220 R = H: (+)-tryptoquivaline G 219 R = H: (-)-marcfortine B Me OAc H 221 R = : (+)-tryptoquivaline Me
Figure 12: Examples of spiro-fused indole alkaloids.
1.2. Synthetic Approaches
The difficulties associated with the isolation of significant quantities of 17 and 43 as well as the appealing architecture render the spirotryprostatins an interesting synthetic target. Several groups have successfully completed total syntheses of 43 and 17. Most strategies differ in the approach to the spiro-pyrrolidine-oxindole ring system.108
1.2.1. Danishefsky’s Route to Spirotryprostatin A
Danishefsky’s synthetic plan for spirotryprostatin A envisioned the construction of the spiro-pyrrolidine-oxindole system by a Pictet–Spengler reaction followed by oxidative rearrangement.109
The use of 6-methoxy-L-tryptophane methylester (222) as reaction partner in the Pictet– Spengler reaction seems straightforward. However, the proper choice of the aldehyde component for later introduction of the prenyl side chain of crucial importance. Prenyl aldehyde (230) itself was not used because initial studies had shown incompatibility with
[107] a) Yamazaki, M.; Fujimoto, H.; Okuyama, E. Tetrahedron Lett. 1976, 2861-2864. b) Yamazaki, M.; Fujimoto, H.; Okuyama, E. Chem. Pharm. Bull. 1977, 25, 2554-2560. c) Yamazaki, M.; Fujimoto, H.; Okuyama, E. Chem. Pharm. Bull. 1978, 26, 111-117. d) Yamazaki, M.; Okuyama, E.; Maebayashi, Y. Chem. Pharm. Bull. 1979, 27, 1611- 1617. see [30], page 14. [108] For a review see: Lindel, T. Nachrichten aus der Chemie 2000, 48, 1498-1501. [109] See [25] and [28], page 14. 56 The Total Synthesis of (–)-Spirotryprostatin B
the planned oxidative rearrangement. Investigations employing benzyloxyacetaldehyde (231) were undertaken on a model compound (the 6-demethoxy series). Although rearrangement proved successful, difficulties associated with the conversion of the benzyloxy group into the prenyl side chain where thwarted by the pronounced recalcitrance of the C18 aldehyde towards olefination. Finally aldehyde 223 was identified as viable precursor for incorporation of the prenyl moiety.
The cis/trans-ratio of the Pictet–Spengler reaction between 222 and 223 was not very high; therefore attempts to find a higher-yielding sequence to 224 were undertaken: Bischler–Napieralski reaction followed by reduction was used instead in the 6-demethoxy series and led to improved diastereoselectivity; unfortunately, the tetrahydro-β-carboline was obtained as a racemic mixture. Coupling of Pictet–Spengler adduct 224 with an
L-proline derivative and formation of the diketopiperazine ring were planned. Oxidative rearrangement would then lead to the desired core of spirotryprostatin A. Surprisingly, this sequence, when tested in the 6-demethoxy series, led to the wrong configuration at the spiro-center. This problem could be solved by inversion of steps.
Tetrahydro-β-carboline 224 was protected as its Boc derivative 225. Oxidative spiro- rearrangement followed by deprotection of the carbamate protecting group under standard conditions afforded 226.110 Installation of the diketopiperazine was effected by coupling with Troc-L-proline chloride (227) followed by deprotection of the Troc group with concomitant ring closure and yielded 228, bearing all carbon atoms of spirotryprostatin A. Conversion of the sulfide to the prenyl moiety by sulfoxide elimination afforded a 2.5:1 mixture of the desired target together with isomer 229. After HPLC separation, 229 could be isomerized to spirotryprostatin A (43) in 41% yield (Scheme 54).
[110] The yield of this transformation was found to be superior in the 6-demethoxy series, which is probably due to the increased susceptibility of methoxy-oxindoles to aromatic bromination. The Total Synthesis of (–)-Spirotryprostatin B 57
CO Me O 2 CO2Me CO2Me ac,dHN NH NH NR MeO N 2 50%MeO N 43% H H Me Me MeO SPh O Me SPh Me 222 SPh Me Me 226 b 224 R = H 223 85 % 225 R = Boc TrocN O Me O e,f OBn Cl Me H 68% O 230 231 227
O O O H H H O N O N O N g,h HN N HN N HN N H + 18 H H O O 80% O Me Me Me MeO MeO MeO SPh Me Me 300 229 228 spirotryprostatin A j 41%
Scheme 54: a) CF3CO2H, 4 Å MS, 223, CH2Cl2, 0 °C Æ RT; b) Boc2O,
CH3CN, NEt3, ∆; c) NBS, AcOH, H2O, THF, RT; d) TFA, CH2Cl2, RT;
e) NEt3, CH2Cl2, 227, 0 °C Æ RT; f) Zn, THF, MeOH, aq NH4Cl, RT;
g) NaIO4, H2O, MeOH, RT; h) toluene, ∆; j) RhCl3·3H2O, EtOH, ∆.
This synthesis is characterized by the rapid, biomimetic assembly of spirotryprostatin A and solves the difficulties associated with the prenyl side chain. The synthetic studies that were undertaken to enable this synthesis also led to a number of products (232-234) with significantly higher biological activity than spirotryprostatin A (43) on MCF7 and MDA MB-468 human breast cancer cell lines.111
[111] Depew, K. M.; Danishefsky, S. J.; Rosen, N.; SeppLorenzino, L. J. Am. Chem. Soc. 1996, 118, 12463-12464. 58 The Total Synthesis of (–)-Spirotryprostatin B
O H O O O N H CO Me H N O 2 O N HN N H HN N HN NBoc HN N O H H Me O O O MeO OBn OBn OBn Me 43 232 233 234
IC (M) 50 3 × 10-4 2.5 × 10-8 2 × 10-8 2 × 10-8 MCF7 cells IC (M) 50 1.1 × 10-4 1 × 10-4 4 × 10-5 8 × 10-5 MDA MB-468 cells
Figure 13: Biologically active intermediates.
1.2.2. Williams’s Synthesis of Spirotryprostatin B
Williams followed a completely different strategy in his synthesis of spirotryprostatin B. Instead of using the classical, biomimetic halohydrin to oxindole spiro-ring-forming sequence, he envisioned construction of the spiro-pyrrolidine-oxindole core by an asymmetric 1,3-dipolar cycloaddition reaction.112
It is known that azomethine ylids generated by reaction of 5,6-diphenyl-morpholin-2-one (235) with bulky aldehydes show a strong preference for the E-ylids.113 The cycloaddition of known oxindolylidene acetate 70 to the azomethine ylid generated by reaction of 5,6- diphenyl-morpholin-2-one 235 with aldehyde 236 gave rise to the key intermediate 72 via transition state 237. The relative stereochemistry 72 was proven by X-ray crystallographic analysis. Cleavage of the bibenzyl moiety afforded 238. Peptide
coupling with D-proline benzyl ester (239) was chosen. Deprotection of the benzyl ester
and closure of the cis-diketopiperazine yielded 240. This sequence with the L-proline derivative was low-yielding, probably reflecting the thermodynamic instability of the trans-diketopiperazine. Installation of the prenyl moiety was the next critical step. It turned out that the requisite C18 side chain could be obtained without production of
[112] See [48] and [49], page 21. [113] Williams, R. M.; Zhai, W. X.; Aldous, D. J.; Aldous, S. C. J. Org. Chem. 1992, 57, 6527-6532. The Total Synthesis of (–)-Spirotryprostatin B 59
double bond isomers by subjecting 240 to dehydrating conditions. Ester cleavage of 241 proved impossible under standard conditions, but could be accomplished with lithium iodide in refluxing pyridine. Decarboxylation to 12-epi-spirotryprostatin B (243) was effected using the Barton ester derived from 242. The C12 stereocenter was epimerized yielding a 2:1 mixture of spirotryprostatin B (17) and 12-epi-spirotryprostatin B (243), separable by chromatography on silica gel (Scheme 55).
Ph Ph O Ph Ph N Ph O MeO Me O Ph O Me O a Me CO2Et N + O HN EtO C MeO O 82 % O H O 2 Me CO Et Me Me HN HN 2 235 OMe 236 N O H 237 72 70
b 99 %
H H MeO Me Me O Me O H N MeO N Me N CO2H Me N Me N O O O O 18 H f O H c-e CO2Et CO Et 89 % CO Et HN HN 2 HN 2 70 % HN 238 BnO 241 240 H O S 239
N OH H O O 242 Me N N Me N O g,h O 12 O 9 j HN N H 8 32 % O HN Me
Me 243 17 spirotryprostatin B
Scheme 55: a) 3 Å MS, 70, toluene, ∆; b) H2, PdCl2, THF, EtOH, 60 psi, RT;
c) 239, BOP, NEt3, CH3CN, RT; d) H2, Pd/C, EtOH, RT; e) BOP, NEt3,
CH3CN, RT; f) TsOH (1.0 equiv), toluene, ∆; g) LiI, Py, ∆; h) DCC, DMAP,
242, BrCCl3, ∆; j) NaOMe, MeOH.
Williams’s synthesis is highlighted by the preparation of intermediate 72 in a single, high-yielding step. Four stereocenters are set in this 1,3-dipolar cycloaddition reaction, 60 The Total Synthesis of (–)-Spirotryprostatin B
three of which are incorporated in the synthetic target. The presence of the ester functionality at C8 serves as a useful handle to incorporate the C8−C9 double bond, a structural element that presents an additional challenge in spirotryprostatin B as compared to spirotryprostatin A. A useful synthetic precursor for the prenyl side chain was identified with aldehyde 236.
1.2.3. Ganesan’s Approach to Spirotryprostatin B
Wang and Ganesan wished to explore a biomimetic approach to spirotryprostatin B, focusing on the oxidative rearrangement of a tetrahydro-β-carboline, similar to Danishefsky’s route to spirotryprostatin A.114
The synthetic planning relied on a Pictet–Spengler reaction of L-tryptophane methyl ester (244) and prenal (231). In spite of the relatively poor yield, this approach is noteworthy given that, for the first time, prenal itself was used and not a saturated mask. Coupling of
245 with Fmoc-L-proline chloride (246) afforded 247 and set the stage for the crucial oxidative rearrangement without using protection and deprotection steps. Chemoselectivity issues related to the presence of the prenyl olefin were controlled by careful monitoring of the reaction and by avoiding large excesses of NBS. Compound 248 can thus be obtained in a straightforward sequence. One-step deprotection and cyclization afforded 249. From 249, selective introduction of the C8−C9 double bond could not be carried out. A mixture of compounds was obtained, among which the desired target 17 was isolated in poor 2% yield. The C9 hydroxy derivative 250 was obtained in 7% yield and could be converted to spirotryprostatin B in three steps via 251.
Compound 252 with the C12−C13 double bond in the L-proline part and the corresponding C12 hydroxy derivative 253 were obtained in larger amounts than the desired 17 (Scheme 56).
[114] See [29], page 14. Remark: The synthesis, as published, does not comprise an oxidation after selenation of compound 249, neither in the manuscript, nor in the experimental part. The Total Synthesis of (–)-Spirotryprostatin B 61
MeO C Fmoc CO Me CO Me 2 2 a 2 b N NH NH N N 2 N 32% N H H from 244 H H O Me Me O Me FmocN 244 245 Me 247 Me Me 231 Cl H O 246 c 68%
O O Fmoc MeO C N H N 2 N O 8 9 O O e d HN N HN N HN N H H H O 2% O 100% O Me Me Me
Me Me Me 17 249 248 spirotryprostatin B O g,h e H 74% 7% O N O O HN N 12 13 HO HO O N O N O Me BocN N f HN N H H Me O 70% O Me Me 252 5% from 249 Me Me 251 250 O H O N 12 HN N OH O Me
Me 253 20% from 249
Scheme 56: a) 231, HC(OMe)3; b) 246, Py, CH2Cl2, 0 °C; c) NBS,
THF/AcOH/H2O (1:1:1), 0 °C Æ RT; d) 20% piperidine in CH2Cl2, RT; e) (i)
LDA (3.8 equiv), –78 °C, (ii) PhSeBr –78 °C; f) Boc2O, DMAP, CH2Cl2, RT;
g) MsCl, NEt3, CH2Cl2, RT; h) TFA, Et3SiH, CH2Cl2, RT.
This route is characterized by the very efficient assembly of precursor 249, made possible by the direct use of prenal (231) and the introduction of the L-proline moiety prior to oxidative rearrangement avoiding the use of an amine protecting group. Severe problems were encountered in the ultimate elimination step, almost leaving the synthesis of spirotryprostatin B uncompleted. 62 The Total Synthesis of (–)-Spirotryprostatin B
1.2.4. Danishefsky’s Synthesis of Spirotryprostatin B
Danishefsky’s synthesis of spirotryprostatin B is based on a different strategy than his synthesis of spirotryprostatin A. It follows an approach to assemble the spirotryprostatin core by intramolecular Mannich reaction.115
L-Tryptophane methyl ester hydrochloride (254) was oxidized to oxindole 255 and reaction of 255 with aldehyde 231 afforded a mixture of four isomeric spiro-pyrrolidine- oxindoles 256. These compounds were not separable and the mixture was processed further by peptide coupling with N-Boc-L-proline (257) and yielded the mixture of coupling products 258.
CO2Me
NH CO2Me CO2Me a b Me NH Cl NH Cl N 3 95% N O 3 73% N O H H from 254 H Me 254 255 256 O Me
Me 231
BocN c
HO2C 68% H 257
O Boc MeO C N 2 N BocN BocN O O 8 MeO2C MeO2C 9 PhSe H H HN N HN 3 N H f,g H e N O d N O O O Me Me Me 86% Me 38% N O N O from 258 Me Me Me Me H H 17 260 259 258 spirotryprostatin B
Scheme 57: a) DMSO, 12 N aq HCl, AcOH, RT; b) 231, NEt3, 3 Å MS, Py,
0 °C Æ RT; c) 257, BOP-Cl, NEt3, CH2Cl2, , 0 °C Æ RT; d) (i) LHMDS (2.2 equiv), THF, 0 °C, (ii) PhSeCl (2.2 equiv), THF, 0 °C; e) DMDO (4.0 equiv),
THF, 0 °C; f) TFA, CH2Cl2, RT; g) NEt3, CH2Cl2, RT.
Deprotonation and reaction of lithiated 258 with phenylselenyl chloride gave rise to another mixture of products 259. Oxidative elimination of 259 proceeded readily and 260
[115] See [41], page 19. The Total Synthesis of (–)-Spirotryprostatin B 63
could be chromatographically separated from the resulting mixture in 38% yield from 258. Deprotection and closure of the diketopiperazine afforded spirotryprostatin B (17) in 86% yield (Scheme 57).
This sequence is very short and allows for large scale production of spirotryprostatin B (500 mg of the natural product per batch). However, the main product of the oxidative elimination of selenide 259 is the 3-epi-diastereomer of 260, obtained from the mixture of diastereomers. Notable is the efficient insertion of the C8−C9 double bond when the proline nitrogen is still protected as its carbamate.
1.2.5. Overman’s Approach to Spirotryprostatin B
Overman’s strategy relies on an asymmetric Heck reaction followed by trapping of an η3-allylpalladium species by a tethered nitrogen nucleophile.116
Key intermediate 262 was accessed from known allylic alcohol 261 in eight steps. Several conditions for the one-pot Heck reaction/η3-allylpalladium trapping were tested and finally best results were obtained with 10% [Pd2(dba)3]·CHCl3, 40% tri- o-tolylphosphane and excess potassium acetate in THF at 70 °C, giving a 1:1 mixture of 264 and 265 in 72% yield. Cleavage of the SEM protecting group from 264 cleanly provided spirotryprostatin B. Isomer 266 was obtained from 265. As it was not clear from the beginning if the η3-allylpalladium species would be attacked anti or syn to the metal, 267 incorporating the C3−C18 Z-olefin, was first prepared. From that intermediate, the C18 isomeric products were produced, proving the trapping of the η3-allylpalladium takes place anti to the metal (see also Scheme 20, page 23). In this first route, the stereochemical outcome of the key step could be tuned by using Pd/BINAP and excess PMP in DMA at 100 °C by employing either (R)- or (S)-BINAP to a 6:1 ratio in either way. This was not possible in the reaction with 263 as temperatures over 80 °C led to rapid isomerization of 263 to 267 in the presence of excess PMP in DMA, leading to formation of the undesired isomers (Scheme 58).
[116] See [58], page 23. 64 The Total Synthesis of (–)-Spirotryprostatin B
OH Me Me O Me a,b c-e MeO C MeO C 2 Me 2 Me N Me 94% 78% H I AcO OTBDPS 261 347 348 H O N f-h NH O 61% O O PO(OMe)2 N N 262 N k N HN H SEMN H O O 93% O O 36% H Me Me O N Me Me Me NH O Me 266 265 j 18 + 3 N O O O SEM I N N O O 263 HN N k SEMN N H H O 93% O 36% H Me Me O N Me Me NH 17 264 O Me 18 spirotryprostatin B 3 Me
N O SEM I 267
Scheme 58: a) Ac2O, Py, RT; b) (i) MgBr2·Et2O, THF, ∆; (ii) Hünig’s base, AcOH, RT; c) LiOH, MeOH, RT; d) TBDPSCl, DMAP, Py, RT; e) 2-
iodoaniline, 1-methyl-2-chloro-pyridinium iodide, NEt3, CH2Cl2, RT; f) NaH, THF, SEMCl, 0 °C Æ RT; g) TBAF, THF, RT; h) (i) Dess–Martin
periodinane, CH2Cl2, RT, (ii) 262, tBuOK, CH2Cl2, –78 °C Æ RT; j)
[Pd2(dba)3]·CHCl3, (oTol)3P, KOAc, THF, 70 °C; k) Me2AlCl, Hünig’s base,
CH2Cl2, –78 °C.
In this synthesis it could be proven that intramolecular Heck insertions into conjugated trienes can proceed with high stereoselectivity and that the obtained η3-allylpalladium species is trapped in an anti fashion with production of the spiro-pyrrolidine-oxindole ring system. The Total Synthesis of (–)-Spirotryprostatin B 65
1.2.6. Fuji’s Route to Spirotryprostatin B
Fuji’s route is dominated by the use of a chiral precursor obtained from asymmetric nitroolefination. The construction of the spiro-pyrrolidine-oxindole core by intramolecular ring closure of the nitrogen nucleophile on an allylic alcohol leading to the prenylated pyrrolidine is an innovative approach.117
Fuji’s synthesis commenced with the chiral precursor 268, obtained by asymmetric nitroolefination. Several steps had to be devoted to functional-group and oxidation-state adjustments in order to obtain precursor 269. Coupling of 269 with N-Boc-L-proline chloride (270) yielded 271 from which spiro-pyrrolidine-oxindoles 273 and 274 were accessed as a 1:1-mixture of diastereomers in a two-step sequence via 272. From 274 the synthesis of spirotryprostatin B was completed following Danishefsky’s procedure. Following these steps, the target 17 was obtained in modest yield together with 251 and 252 obtained before by Ganesan (Scheme 59).
With the use of precursor 268, the stereocenter at the C3 position is set at an early stage in the synthesis. The overall sequence devotes a number of steps for functional-group interconversions and protection/deprotection chemistry. Cyclization to the spiro- pyrrolidine-oxindole via intramolecular nucleophilic attack on a dimethylallylic carbocation presents a novel approach to the core and puts the prenyl side chain into the right position, albeit as a mixture of diastereomers. The weakness of this synthesis is the lack of stereocontrol at the C9 center. Although not present in the final product, this center controls the stereochemical outcome of the cyclization to the spiro-pyrrolidine- oxindole leading to a 1:1 mixture.
[117] See [67], page 25. 66 The Total Synthesis of (–)-Spirotryprostatin B
Me Me Me Me Me Me
CN CHO a b,c Bn N 3 NO 2 55% 44% Cbz N O N O N O H H H 268 (1:1)
d BocN 87% Cl H MeO2C MeO2C O Me Me O BocN O BocN 270 CO2Me HN HN HN HN Bn H f H e N O O Me Me Cbz 85% 69% N O OH H Me Me 272 271 269
g
23% 24% O MeO2C MeO2C O BocN O BocN O N 9 9 j HN N HN N HN N H H H O O 21% O Me Me Me
Me Me Me 273 274 17 spirotryprostatin B h h 89% 91% O O H H O N O N HN N HN N H H O O Me Me Me Me
Scheme 59: a) 20% aq TiCl3 (5.0 equiv), NH4OAc, MeOH/H2O, RT;
b) (i) BnNH2, CH2Cl2, RT, then TMSCN; c) CbzCl, NEt3, CH2Cl2, RT;
d) (i) K2CO3, MeOH, RT, then 1 M aq HCl; e) (i) Pd/C (80 wt%), HCO2H,
MeOH, RT; (ii) 270, WSC, CH2Cl2, RT; f) (i) mCPBA, CH2Cl2, 0 °C,
(ii) PhSeSePh (0.6 equiv), NaBH4, MeOH, ∆, (iii) 30% aq H2O2 (20.0 equiv),
THF, 0 °C; g) pTsOH (10 mol%), CH3CN, ∆; h) (i) 4 M HCl in dioxane, 0 °C,
(ii) NEt3, CH2Cl2, RT; j) (i) LHMDS (2.2 equiv), THF, 0 °C, (ii) PhSeCl (2.2 equiv), THF, 0 °C, (iii) DMDO (4.0 equiv), THF, 0 °C, (iv) 4 M HCl in
dioxane, 0 °C, (v) NEt3, CH2Cl2, RT. The Total Synthesis of (–)-Spirotryprostatin B 67
2. Synthesis of (–)-Spirotryprostatin B Employing the MgI2- Catalyzed Ring-Expansion Reaction
Spirotryprostatin B, a natural product of manageable size and appealing structure, presents a demanding synthetic target. With its structural features and given natural scarcity, spirotryprostatin B is one of those molecules, for which organic synthesis is able to provide significant quantities of synthetic material for further biological testing. Additionally, synthesis also opens the gate for the facile access to analogues with potentially higher biological activity and for elucidation of structure–activity relationships. These facts, and the development of the MgI2-catalyzed ring-expansion reaction for the straightforward access of spiro-pyrrolidine-oxindole ring systems, led us to tackle the total synthesis of spirotryprostatin B.
2.1. Retrosynthetic Analysis
Our approach to spirotryprostatin B was driven by our interest in the feasibility of using the MgI2-catalyzed ring-expansion reaction for the construction of spiro-pyrrolidine- oxindoles with a higher degree of substitution on the pyrrolidine ring. If a C9-substituted spiro-pyrrolidine-oxindole like 276 could be generated with our method, access to the spirotryprostatin B core could be envisioned. In this respect, it is important to note that in previous reactions of unsubstituted spiro-cyclopropyl-oxindole 99 with aldimines (Table 3, page 32 and Table 4, page 34), the major diastereomer always possessed the relative stereochemistry that is observed in spirotryprostatin B (17) at C3 and C18 (Scheme 60). 68 The Total Synthesis of (–)-Spirotryprostatin B
O 16 9 17 N O 8 16 PGN HN N 11 3 10 18 H HO2C O 11 19 Me H 275 Me 17 spirotryprostatin B
R' R'' R' 10 R'' 8 9 NPG 9 10 8 3 18 NPG 3 + R N O 18 R N O H H 277 276 278
Scheme 60: Retrosynthetic analysis of spirotryprostatin B.
The key intermediate 276 was planned to arise from ring expansion of spiro-cyclopropyl- oxindole 278 and imine 277. The substituents R, R’ and R’’ as well as the protecting group PG on the imine nitrogen have to fulfill a multitude of requirements:
• All together, they must be chosen in a way as to allow for successful ring expansion, so that intermediate 276 can be accessed. In this respect, first studies would have to focus on the regiochemistry of the cyclopropane- fragmentation/ring-expansion reaction with a substituted cyclopropyl moiety.
• Additionally, the substituent R on imine 277 should be either the prenyl moiety itself or a functionality that can be converted easily into the prenyl side chain. Considering that the prenyl moiety of spirotryprostatin B is the only side chain on the pentacyclic core, a synthesis that would allow for facile access to spirotryprostatin B analogues at a late stage would be desirable.
• The substituent R’ of 278 has to be a functionality at the carboxylic acid oxidation state or a synthetic equivalent and R’’ must allow for the implementation of the C8−C9 olefin.
The remaining portion of the molecule would arise from a suitably protected
L-proline derivative 275. The Total Synthesis of (–)-Spirotryprostatin B 69
2.2. Initial Studies
2.2.1. Regioselectivity
A study on substituent effects of the nucleophilic ring opening of activated cyclopropanes by Danishefsky showed that nucleophilic attack preferentially takes place at the most substituted carbon.118 This finding may be explained with the substantial dipolar character in the transition state of the ring opening (Figure 14).119
Me CO Et Me CO2Et Me CO2Et Me CO2Et 2 Nu Nu Me CO2Et Me CO Et Me CO Et Me CO Et 2 2 2
Figure 14: Charge separation in the transition state of cyclopropane ring opening upon nucleophilic attack.
In order to test the regiochemical outcome of the ring-expansion reaction, we chose methyl-substituted spiro-cyclopropyl-oxindole 282 as our first starting material. Reaction of 98 with known cyclic sulfate 281,120 prepared in a two-step sequence from 1,2-propanediol (279) via sulfite 280,121 afforded 282. Cyclic sulfates are useful reagents for the preparation of substituted spiro-cyclopropyl-oxindoles. Upon nucleophilic attack, cyclic sulfate 281 acts as a synthetic equivalent of an epoxide and is opened to the corresponding β-sulfate. Unlike in the epoxides case, this β-sulfate remains a powerful leaving group and can react further with the sodium enolate of 98 and undergo cyclization to cyclopropane 282 in the presence of excess of base.122
[118] Danishefsky, S.; Rovnyak, G. J. Org. Chem. 1975, 40, 114-115. [119] Chmurny, A. B.; Cram, D. J. J. Am. Chem. Soc. 1973, 95, 4237-4244. [120] a) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538-7539. b) Burgess, K.; Ho, K. K.; Ke, C. Y. J. Org. Chem. 1993, 58, 3767-3768. [121] a) Berridge, M. S.; Franceschini, M. P.; Rosenfeld, E.; Tewson, T. J. J. Org. Chem. 1990, 55, 1211-1217. b) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655-658. [122] For a review on cyclic sulfites and cyclic sulfates see: Lohray, B. B. Synthesis 1992, 1035-1052. 70 The Total Synthesis of (–)-Spirotryprostatin B
NOE Me O O H O OH a S O b S O c O O HO 92% 54% Me Me Me N O from 279 Bn 279 280 281 282 N O Bn 98
Scheme 61: a) SOCl2, CH2Cl2, 0 °C Æ ∆; b) NaIO4 (2.0 equiv), RuCl3·3H2O
(0.5 equiv), CH3CN/CCl4/H2O, RT; c) 98, NaH, DME, RT Æ ∆.
Methyl-substituted spiro-cyclopropyl-oxindole 282 is the major isomer of this reaction (16:1). The relative configuration was assigned by NOE enhancements.
Spiro-cyclopropyl-oxindole 282 and imine 124 were subjected to ring-expansion conditions. Best results (80% combined yield of ring-expansion products) were obtained when the reaction was performed neat, at 120 °C, with 10 mol% of MgI2; however separation of the isomers 283 proved difficult and therefore information on the regiochemistry of the cyclopropane-fragmentation/ring-expansion reaction was still not available (Scheme 62).
Me Me
NTs NTs MgI2 (10 mol%) + Ph Ph N O neat, 120 °C, 5 h N O Bn 80% Bn 282 124 283
Scheme 62: Ring expansion of substituted spiro-cyclopropyl-oxindole 282 with imine 124.
To solve this problem, the ring expansion with p-tosyl-isocyanate 284 was carried out. The analysis and separation of the reaction products was expected to be more facile because the product of the ring expansion with isocyanate 284 is lacking a stereocenter compared to 283. The overall yield of the reaction is not very high, about 50% of the starting material 282 was generally recovered. The products 285 and 286 correspond to the two possible diastereomers of a regioselective reaction, which were obtained in a 2:3 The Total Synthesis of (–)-Spirotryprostatin B 71
ratio. The sense of regioinduction could be unambiguously determined by X-ray crystallographic analysis of both diastereomers. (Scheme 63, Figure 15).123
Me Me Me Me MgI2 (25 mol%) NTs NTs NTs NTs THF, 100 °C, 75 h + C + sealed tube O O O N O O N O N O N O Bn 49% Bn Bn Bn 282 284 285 286 not observed (2:3)
Scheme 63: Ring expansion of substituted spiro-cyclopropyl-oxindole 282 with isocyanate 284.
Figure 15: ORTEP drawings of 285 (left) and 286 (right).
This result shows unambiguously that spiro-cyclopropyl-oxindoles are opened regioselectively under our ring-expansion conditions. This finding is in full accordance with Danishefsky’s earlier observations.
2.2.2. Substituent at the Spiro-Cyclopropyl-Oxindole Suitable for Ring Expansion
With this result in hand, we had to decide for a substituted spiro-cyclopropyl-oxindole that would allow for efficient functionality development towards the spirotryprostatin B core. In this respect, cyclopropyl derivative 290 displays attractive structural features,
[123] CCDC 199469 and CCDC 199470 contain the supplementary crystallographic data for 285 and 286 respectively. This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]). 72 The Total Synthesis of (–)-Spirotryprostatin B
bearing the requited carboxylate for the diketopiperazine ring and the methoxy-group allowing for the incorporation of the C8−C9 olefin. Synthesis of 290 was accomplished by rhodium-catalyzed cyclopropanation of acrylate 288 with diazo-oxindole 289.124 The required acrylate 288 was prepared from 2,3-dibromo-propionic acid ethyl ester (287), 125 and diazo-oxindole 289 was available in a two-step sequence ― formation of the tosyl hydrazone followed by base induced elimination ― from N-benzyl isatin (97) (Scheme 64).126
CO Me MeO 2 O N2 MeO d OMe + N O 89% N O Bn Bn 288 289 290
a b,c 36% 61%
O O Br OEt N O Bn Br 287 97
Scheme 64: a) NaOMe (3.0 equiv), MeOH, RT; b) N2H3Ts, MeOH, 60 °C;
c) NaOH, THF/H2O, RT; d) [Rh(OAc)2]2 (2 mol%), slow addition of 289, benzene, ∆.
Cyclopropane 290 was obtained as a separable mixture of two diastereomers in a ratio of 7:2. For convenience, only the major isomer was used for subsequent reactions. In order to test the feasibility of the ring-expansion reaction with 290, imine 124 was chosen as coupling partner. However, no trace of the desired product could be obtained under various reaction conditions including increased temperatures and catalyst loadings as well
[124] a) Anciaux, A. J.; Hubert, A. J.; Noels, A. F.; Petiniot, N.; Teyssie, P. J. Org. Chem. 1980, 45, 695-702. b) Doyle, M. P.; Vanleusen, D.; Tamblyn, W. H. Synthesis 1981, 787-789. c) Padwa, A.; Austin, D. J.; Price, A. T.; Weingarten, D. M. Tetrahedron 1996, 52, 3247-3260. For recent reviews see: d) Doyle, M. P. Chemical Reviews 1986, 86, 919-939. e) Ye, T.; McKervey, M. A. Chemical Reviews 1994, 94, 1091-1160. f) Doyle, M. P.; Forbes, D. C. Chemical Reviews 1998, 98, 911-935. [125] Ogata, N.; Nozakura, S.; Murahash.S Bull. Chem. Soc. Jpn. 1970, 43, 2987-2988. [126] a) Cava, M. P.; Litle, R. L.; Napier, D. R. J. Am. Chem. Soc. 1958, 80, 2257-2263. b) Creger, P. L. J. Org. Chem. 1965, 30, 3610-3613. The Total Synthesis of (–)-Spirotryprostatin B 73
as the use of Mg(OTf)2 as Lewis acid with non nucleophilic counterions, in order to obtain intermediate 291 instead of 292 (Scheme 65).
CO Me CO Me MeO 2 MeO 2 NTs NTs + Ph N O N O Bn Bn 290 124
CO Me I CO Me MeO 2 MeO 2
OTf
N OMg(OTf) N OMgI Bn Bn 291 292 possible intermediate possible intermediate with Mg(OTf)2 with MgI2
Scheme 65: Unsuccesful ring expansion with spiro-cyclopropyl-oxindole 290.
This unsuccessful outcome can be rationalized in two ways: (i) the steric hindrance at the quaternary carbon disfavors SN2 displacement and (ii) incompatibility of the dipolar character in the transition state of the ring opening with the chosen substituents (Figure 14, page 69). In order to identify a more suitable cyclopropane, several differently substituted cyclopropanes were prepared taking our hypothesis into consideration.
To reduce steric hinderance, we synthesized 294 by cyclopropanation of diethyl fumarate (293) with 289,127 and 296 by palladium-catalyzed cyclopropanation of acrylonitrile (295) with 289.128,129 These cyclopropanes failed to undergo reaction to give the ring expanded products under a variety of conditions (Scheme 66), probably due to the conflict of partial charges in the molecules with the dipolar character in the transition state during ring opening (Figure 14, page 69).
[127] Waitkus, P. A.; Sanders, E. B.; Peterson, L. I.; Griffin, G. W. J. Am. Chem. Soc. 1967, 89, 6318-6327. [128] Chang, S. J.; Shankar, B. K. R.; Shechter, H. J. Org. Chem. 1982, 47, 4226-4234. [129] A simplification of the starting materials in this way (R’’ = H) requires the implementation of the C8=C9 olefin without the installation of a masked leaving group, a problem already solved in Danishefsky’s synthesis of spirotryprostatin B. 74 The Total Synthesis of (–)-Spirotryprostatin B
NTs CO2Et EtO2C Ph EtO2C N2 124 NTs CO2Et a CO2Et + 83% Ph EtO C N O N O N O 2 Bn Bn Bn 293 289 294
NTs CN NC Ph
N2 124 NTs CN b + Ph N O 88% N O N O Bn Bn Bn 295 289 296
Scheme 66: a) toluene, ∆; b) Pd(OAc)2 (1 mol%.), neat, ∆.
Spiro-cyclopropyl-oxindole 301 was the next candidate chosen with respect to our assumptions. From a steric- and electronic point of view, 301 was believed akin to methyl-substituted spiro-cyclopropyl-oxindole 282. The preparation of protected alcohol 300 was achieved from allyl alcohol (297) in 6 steps via cyclic sulfate 299,130 using conditions similar to those described previously.131,132 Deprotection of the silyl group completed the synthesis of 301 (Scheme 67).133
OTBS OH O O e f a,b OH c,d S O OH HO OTBS O 60% 57%OTBS 42% 96% N O N O 297 298 Bn Bn 299 300 301 N O Bn 98
Scheme 67: a) TBSCl, imidazole, DMF, 0 °C; b) NMO·H2O, K2OsO4
(0.3 mol%); H2O/acetone/tBuOH, RT; c) NEt3, SOCl2, CH2Cl2, 0 °C; d) NaIO4
(2.0 equiv), RuCl3·3H2O (0.5 equiv), CH3CN/CCl4/H2O, RT; e) 98, NaH,
DME, RT Æ ∆; f) nBu4NF, THF.
[130] See [121b], page 69. [131] Ogilvie, K. K.; Hakimelahi, G. H. Carbohydr. Res. 1983, 115, 234-239. [132] Bernardi, A.; Cardani, S.; Scolastico, C.; Villa, R. Tetrahedron 1988, 44, 491-502. [133] Corey, E. J.; Venkates.A J. Am. Chem. Soc. 1972, 94, 6190-6191. The Total Synthesis of (–)-Spirotryprostatin B 75
Unfortunately, the ring-expansion reaction with 301 did not occur, and the use of the protected species 300 did not lead to any improvement (Scheme 68).
NTs OH OH Ph 124 NTs
Ph N O N O Bn Bn 301
NTs OTBS OTBS Ph 124 NTs
Ph N O N O Bn Bn 300
Scheme 68: Unsuccesful ring expansion with spiro-cyclopropyl-oxindoles 301 and 300.
The ring expansion seems intolerant of a wide range of sterically and electronically different cyclopropanes. Reevaluation of the failure to undergo ring-expansion with highly substituted 290 and the observation that the ring expansion with methyl- substituted spiro-cyclopropyl-oxindole 282 requires drastic reaction conditions, led to the following speculation: A substitution that enables or even facilitates charge separation in the transition state of cyclopropane ring opening is of utmost importance (Figure 14, page 69). In this respect, a vinyl cyclopropane should be ideally suited for ring expansion, given the stabilization of the incipient positive charge by allylic delocalization (Table 6).134,135
60 °C, acetone KI EtOH/H O 4:1 2 relative stability SN2, krel SN1, krel + −1 CH3CH2Cl 1 1 CH3CH2 0 kcal mol + −1 CH2=CHCH2Cl 33 74 CH2=CHCH2 –24 kcal mol
Table 6: Significance of resonance stabilization in allylic systems.
[134] See [118], page 69. [135] Morrison, R. T.; Boyd, R. N. Lehrbuch der Organischen Chemie; Verlag Chemie: Weinheim, 1980. 76 The Total Synthesis of (–)-Spirotryprostatin B
Furthermore, subsequent functionalization of the double bond should allow for a subsequent conversion to the C9 carboxylate (Figure 16).
EWG R' EWG R' EWG R R R R'
Figure 16: Charge separation and allylic stabilization in the transition state of cyclopropane ring opening.
In order to test our hypothesis, spiro-cyclopropyl-oxindole 303 was prepared from 289 and commercially available piperylene (302) (Scheme 69).136 In accordance with published work, the cyclopropanation proved chemoselective and occurred at the least substituted double bond. In a study on the regioselectivity of catalytic cyclopropanation of monosubstituted dienes, Doyle showed that cyclopropanation of 1-substituted dienes like piperylene takes place at the more accessible, terminal double bond with good to excellent regioselectivity in the presence of different transition-metal catalysts including 137 [Rh(OAc)2]2.
Me Me
N2 NTs a b + Me Ph N O 90% N O 47% N O Bn Bn Bn 302 NTs 289 303 304 Ph 124
Scheme 69: Synthesis of spiro-cyclopropyl-oxindole 303 and successful ring
expansion. a) [Rh(OAc)2]2 (2 mol%), slow addition of 289, benzene, ∆;
b) MgI2 (20 mol%), THF, 80 °C, sealed tube.
[136] See [124], page 72. [137] Doyle, M. P.; Dorow, R. L.; Tamblyn, W. H.; Buhro, W. E. Tetrahedron Lett. 1982, 23, 2261-2264. (These findings were confirmed by Davies: Davies, H. M. L.; Clark, T. J.; Smith, H. D. J. Org. Chem. 1991, 56, 3817-3824.) In the case of 2-substituted dienes, electronic factors associated with changes in the electrophilicities of the reactant metal carbenes proved relevant. The Total Synthesis of (–)-Spirotryprostatin B 77
Reaction of spiro-pyrrolidine-oxindole 303 with imine 124 provided 2,5-disubstituted-3- spiro-pyrrolidine 304 in 47% yield, and thus allowed for the first time for ring expansion with a suitably substituted spiro-cyclopropyl-oxindole (Scheme 69).
2.2.3. Identification of a Suitable Imine for the Ring Expansion
Having found a suitable substituent for ring expansion of spiro-cyclopropyl-oxindoles, we could address the next critical task. An imine had to be found which would allow for facile deprotection of the pyrrolidine nitrogen after ring-expansion. Additionally, the imine had to bear a functionality to enable access to the prenyl side chain.
For a straightforward approach to spirotryprostatin B, the direct introduction of the prenyl moiety by ring expansion of 303 with prenal-derived allyl imine (305) would be desirable;138 alternatively, the cyclopropane-fragmentation/ring-expansion reaction with imine 306139 would ultimately lead to a progenitor for the prenyl moiety, related to one of William’s intermediates.140 However, the use of either imine in the crucial key step did not provide any trace of the desired spiro-pyrrolidines (Scheme 70).
Me Me
N N + Me N O N O Bn Me Me Bn Me 303 305
Me Me
N N
+ Me N O Me Me N O OMe Bn OMe Bn Me 303 306
Scheme 70: Failure of the ring expansion reaction with imines 305 and 306.
[138] VanMaanen, H. L.; Kleijn, H.; Jastrzebski, J. T. B. H.; VanKoten, G. Bull. Soc. Chim. Fr. 1995, 132, 86-94. [139] Imine 306 was obtained by condensation of allylamine with known aldehyde 236: Alcaide, B.; Rodríguez- Campos, I. M.; Rodríguez-López, J.; Rodríguez-Vicente, A. J. Org. Chem. 1999, 64, 5377-5387. [140] See [48], page 21. 78 The Total Synthesis of (–)-Spirotryprostatin B
Both imines were found to polymerize under ring expansion conditions (MgI2 (10–20 mol%), THF, 80 °C, sealed tube), probably due to self condensation. The use of a non- enolizable imine should prevent this undesired side reaction. Imine 309 was chosen, as the protected alkyne was expected to serve as a viable precursor for the prenyl side chain. The imine was accessed from triisopropyl-silyl acetylene (307) in 2 steps according to Scheme 71.141 TIPS-acetylene (307) was converted to aldehyde 308 using ethyl formate as formylating agent. Condensation with allylamine afforded imine 309 in 80% yield over two steps.
O a b N TIPS 80% TIPS 307 over 2 steps TIPS 308 309
Scheme 71: a) (i) nBuLi, THF, –78 °C, (ii) ethyl formate (2.0 equiv), THF,
−78 °C; b) allyl amine, MgSO4, CH2Cl2, RT.
Imine 309 was used in the ring-expansion reaction with 303 (MgI2 (20 mol%), THF, 80 °C, sealed tube) and the desired product 310 was obtained in 56% yield as a mixture of diastereomers (Scheme 72).
Me Me
MgI2 (20 mol%) N N THF, 80 °C, 14 h + N O sealed tube N O Bn TIPS 56% Bn 303 309 310 TIPS
Scheme 72: Successful ring expansion of 303 with imine 309.
2.2.4. Optimization of the Key Step
With spiro-pyrrolidine-oxindole 310 we had obtained a lead compound that could potentially be a intermediate in the synthesis of spirotryprostatin B. Another important point left unaddressed previously, was the question whether the benzyl protecting group
[141] a) Journet, M.; Cai, D. W.; DiMichele, L. M.; Larsen, R. D. Tetrahedron Lett. 1998, 39, 6427-6428. b) see [139], page 77. The Total Synthesis of (–)-Spirotryprostatin B 79
was necessary for ring-expansion. Spiro-cyclopropyl-oxindole 313 was prepared from 96 in three steps, similar to the synthetic sequence described for the preparation of 303 (Scheme 73).
Me
O N N a NHTs b 2 c
90% 88% 71% N O N O N O N O H H H H 96 311 312 313
Scheme 73: a) N2H3Ts, MeOH, ∆; b) NaOH, H2O, RT; c) [Rh(OAc)2]2
(1 mol%), piperylene (4.0 equiv), slow addition of 312 in CH2Cl2, benzene, ∆.
The reaction of 313 with imine 309 gave spiro-pyrrolidine-oxindole 314, demonstrating that protection of the indole nitrogen was not required in the ring-expansion step.
In studies employing variable amounts of MgI2, it turned out that the amount of spiro- pyrrolidine-oxindole obtained from the reaction did never surpass the amount of MgI2 used, showing that the reaction was not catalytic in MgI2 anymore. This might be due to complexation of MgI2 by the free indole nitrogen. After careful adjustment of the reaction temperature, under optimal conditions at 75 °C with use of an excess of imine and one equivalent of MgI2 314 could be obtained in 67% yield (Scheme 74).
Me Me
MgI2 (1.0 equiv) N N THF, 75 °C, 15 h + N O sealed tube N O H TIPS 67% H 313 309 314 TIPS
Scheme 74: Ring expansion of 405 with imine 401 under optimized conditions.
80 The Total Synthesis of (–)-Spirotryprostatin B
The regioselectivity of the ring-expansion reaction deserves consideration (Scheme 75). Both 1,5- and 1,7- addition to the allyl cyclopropane could be considered to be taking place, leading to intermediates 316 and 317 respectively. Although, in general, only
1,5-addition is observed, probably related to the general prevalence of SN2 relative to
SN2’ displacement, there are exceptions to this rule, for example 1,7-addition is observed predominantly if the nucleophile is an enamine.142 In case compound 317 was obtained by 1,7-addition, it could be converted to the desired product 319 by allylic displacement to 318. It is also to be considered that the steps for the ring-expansion reaction would be reversible under thermodynamic control. As supported by semi empirical calculations, the five-membered ring product 319 is expected to be formed in this case (Figure 17).143 In a kinetically controlled reaction, again formation of the five-membered ring product 319 should be favored. Indeed, no trace of the seven-membered ring product (320) could be detected experimentally.
Nu Me Me N MgI2 R 1,7-addition N OMgI R' Me R'' N O R'' 317 320
R Nu N allylic displacement + Me R' N O R R'' R' Nu N 315 Me Me N R 1,5-addition R' MgI2 N OMgI N OMgI N O R'' R'' R'' 316 318 319 Nu = I , RN=CHR'
Scheme 75: Regioselectivity of the ring-expansion reaction with allylic spiro- cyclopropyl-oxindoles 315.
[142] a) Danishefsky, S.; Rovnyak, G. J. Chem. Soc., Chem. Commun. 1972, 820-821. b) Danishefsky, S.; Rovnyak, G. J. Chem. Soc., Chem. Commun. 1972, 821-822. [143] Calculations were performed using PC SPARTAN Pro. (PM3 semi-empirical molecular orbital calculations of the equilibrium geometry). The Total Synthesis of (–)-Spirotryprostatin B 81
Figure 17: Calculated difference in ∆Hf° between five and seven membered spiro-ring: ∆∆E = 4.7 kacl/mol in favor of five membered spiro-ring (PM3).
The value of the ring expansion as a method for the construction of the spirotryprostatin ring system depends on its diastereoselectivity (at C3 and C18 in the product). The diastereomers 314 turned out to be only partially separable by column chromatography, only 321 and 322 were obtained in pure form. Pyrrolidine 321 is the major product of the key step. All other isomers can be equilibrated with 321 when treated with acetic acid under reflux for 16 h, resulting in a 5:1 to 7:1 ratios in favor of 321 (Scheme 76).
The co-eluting fraction was submitted to Pd-catalyzed cleavage of the allyl protecting group with N-DNBA as allyl scavenger.144,145 The products of this high-yielding deprotection step turned out to be separable by column chromatography (Scheme 76). Assignment of the relative stereochemistry at C3, C18 and C9 for compounds 321-325 was possible by NOE enhancements between the protons at C18, C9 and C4.
The olefin geometry of 321, 323 and 324 was assigned by analysis of the 1H NMR chemical shift for the allylic proton at C9, which is found at higher field for cis-olefins as compared to trans-olefins.146 Pyrrolidines 323 and 324 can be directly compared, as according to NOE enhancements, the relative stereochemical arrangement of the substituents on the pyrrolidine ring is identical. For compound 321, no direct comparison
[144] Pd(PPh3)4 was prepared in situ from [Pd2dba3]·CHCl3 (6 mol% Pd) and PPh3 (18 mol%) in CH2Cl2. Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. J. Organomet. Chem. 1974, 65, 253-266. [145] Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem. 1993, 58, 6109-6113. [146] Martin, G. J.; Martin, M. L.; Lefevre, F.; Naulet, N. Org. Mag. Res. 1972, 4, 121-129. 82 The Total Synthesis of (–)-Spirotryprostatin B
was possible, but the assignment was made as the C9 proton signal was found at very high field (Table 7).
b
Me Me Me
9 4 O 9 9 4 N 3 HN 3 N 3 mixed 18 ++HN N column 18 18 fraction O N O chromato- 4 H graphy TIPS 314 TIPS TIPS 321 322 32% 4% 32%
a 91%
Me Me Me Me
4 O 9 O 99O 9
HN 3 HN 33HN 3 NH NH NH HN NH 18 18 18 18 4 44O
TIPS TIPS TIPS TIPS 326 323 324 325 86% 60% 13% 18%
Scheme 76: a) [Pd2dba3]·CHCl3 (3 mol%), PPh3 (18 mol%), N-DNBA
(3.0 equiv), CH2Cl2, 30 °C; b) AcOH, ∆.
Compound Solvent δ (cis-olefin) δ (trans-olefin) ∆δ(H)
Me-CH=CHCl-Me CCl4 4.84 4.47 0.37
Me-CH=CH(OH)-Me CCl4 4.55 4.12 0.43
Me-CH=CH(OMe)-Me CCl4 4.05 3.57 0.48
Me-CH=CH(NEt2)-Me CCl4 3.57 3.20 0.37
321 CHCl3 3.41
323 CHCl3 4.22 0.40 324 CHCl3 4.62
Table 7: Chemical shifts for the allylic proton at C9 for 321, 323 and 324 in comparison to literature values. The Total Synthesis of (–)-Spirotryprostatin B 83
The stereochemical outcome of the ring-expansion reaction of 313 with 309 was found to be in favor of the desired 3,18-syn-products in a ratio of 6:1. The stereocenter at C9 is not of crucial importance, as it will be removed later on. The synthesis of spirotryprostatin B could now be envisaged. Towards that goal, we envisioned to carry out the synthesis of spirotryprostatin B from all suitable intermediates 323, 324 and 326. We commenced with the synthesis from intermediate 323.
2.3. Synthesis of Spirotryprostatin B from Intermediate 323
Me Me
N N 2 a b 71% 68% N O N O N O H H H N 312 313 314 TIPS 309 TIPS
Me Me c Me 50% O O O HN NH HN NH HN NH + +
TIPS TIPS TIPS 323 324 326 (4:1:5)
Scheme 77: a) [Rh(OAc)2]2 (1 mol%), piperylene (4.0 equiv), slow addition of
312 in CH2Cl2, benzene, ∆; b) MgI2 (1.0 equiv), THF, 75 °C; c) Pd(PPh3)4
(3 mol%), N-DNBA (3.0 equiv), CH2Cl2, 30 °C.
Intermediate 323 could be obtained in multigram quantities from 312 (Scheme 77, synthesis described in the previous paragraph). In the ensuing synthetic sequence, amide coupling of 323 and N-Boc-L-proline with concomitant resolution of the racemic material was anticipated. Best results were obtained when 323 was treated with N-Boc-L-proline 84 The Total Synthesis of (–)-Spirotryprostatin B
147 chloride (270). Acid chloride 270 was prepared in situ from N-Boc-L-proline (257) with Vilsmeier–Haack reagent from DMF and oxalyl chloride in the presence of pyridine.148 The products 327 and 328 were obtained as a 1:1 mixture and could be readily separated by column chromatography on silica gel leading to enantiomerically pure 327 in 45% yield (Scheme 78).
Me Me Me Boc Boc O O N N b HN NH HN N + HN N 90% H H O O O BocN TIPS Cl TIPS TIPS 323 H 327 328 O (1:1) 270
BocN a HO H O 257
Scheme 78: a) DMF, oxalyl chloride, Py, 257, CH2Cl2, 0 °C; b) 270, (4.0
equiv), NEt3, CH2Cl2, 0 °C Æ RT.
Correlation of the C12 stereocenter to the stereocenters of the spiro-pyrrolidine-oxindole core for 327 and 328 is not possible by spectroscopic means. Fortunately, suitable crystals for X-ray crystallographic analysis were obtained from 327 allowing for assignment of structure 327 and, therefore, of 328 as well (Figure 18).149
[147] Buschmann, H.; Scharf, H. D. Synthesis 1988, 827-830. [148] Stadler, P. A. Helv. Chim. Acta 1978, 61, 1675-1681. [149] CCDC 196803 contains the supplementary crystallographic data for 327. This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]). The Total Synthesis of (–)-Spirotryprostatin B 85
Figure 18: ORTEP drawing of 327.
From 327, cleavage of the olefin followed by oxidation-state adjustments was planned and would lead to the C9 carboxylate, required for later installation of the diketopiperazine ring. When 327 was submitted to standard dihydroxylation conditions 150 (OsO4 (4 mol%), NMO·H2O), diol 329 was obtained. Cleavage of diol 329 by
Pb(OAc)4 was carried out without prior purification and cleanly afforded aldehyde 330 in 97% yield over two steps.151 Subsequent oxidation of aldehyde 330 to the corresponding acid 331 following Lindgrens’ procedure152,153 and conversion to methyl ester 332 with diazomethane afforded 332.154 Removal of the TIPS-protecting group was accomplished in quantitative yield with TBAF in THF.155 For the large scale conversion of 327 into 333, it is noteworthy that all five steps (a–e) can be carried out without purification of any intermediate (329–332) in 80% overall yield (Scheme 79).
[150] VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973-1976. [151] Rubottom, G. M. Oxidation in Organic Chemistry; Academic Press: New York, 1982. [152] Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888-890.
[153] An interesting alternative to obtain 418 directly from 413 through OsO4-promoted catalytic oxidative cleavage was tested, but only traces of the desired material was obtained, making this direct method incompatible with the traditional three-step sequence. Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002, 124, 3824-3825.
[154] CH2N2 was prepared from N-methyl-N’-nitro-N-nitrosoguanidine and was used as an etheral solution. Fales, H. M.; Jaouni, T. M.; Babashak, J. F. Anal. Chem. 1973, 45, 2302-2303. [155] Pattenden, G.; Robertson, G. M. Tetrahedron Lett. 1986, 27, 399-402. 86 The Total Synthesis of (–)-Spirotryprostatin B
Me Me Boc HO Boc O Boc OH O N O N O N ab HN N HN N HN N H H 97% H O O O over 2 steps
TIPS TIPS TIPS 327 329 330 80% overall yield a-e without purification c of any intermediate
Boc Boc Boc MeO2C MeO2C HO2C O N O N O N HN N e HN N d HN N H H H O 99% O 89% O over 2 steps
TIPS TIPS 333 332 331
Scheme 79: a) OsO4 (4 mol%), NMO·H2O (1.2 equiv), THF/tBuOH/H2O, RT;
b) Pb(OAc)4, EtOAc, RT; c) NaClO2 (10.0 equiv), 2-methy-2-butene, pH 3.6
buffer, tBuOH, RT; d) CH2N2, Et2O, RT; e) TBAF (1.2 equiv), THF, RT.
At this stage of the synthesis, conversion of alkyne side chain into the prenyl moiety was planned. If this conversion was successful, the opportunity would be available for introduction of the endocyclic olefin and closure of the diketopiperazine to yield spirotryprostatin B.
Theoretically, conversion of the C19−C20 alkyne into the corresponding aldehyde by hydrogenation followed by oxidative olefin cleavage would set the stage for aldehyde olefination. However, as shown in Danishefsky’s elegant study en route to spirotryprostatin A, the closely related aldehyde 334 proved amazingly recalcitrant to a variety of olefination procedures.156 This led us to test alternative methods for the conversion of alkynyl side chain in 333 into the prenyl moiety (Scheme 80).
[156] See [25], page 14. The Total Synthesis of (–)-Spirotryprostatin B 87
CO2Me CO2Me O O HN NTs HN NTs olefination Me O procedures Me 334
Scheme 80: Recalcitrance of 334 to olefination procedures.
Aldehyde 335 should result from hydroboration of 333 followed by oxidative workup. Conversion to the prenyl side chain to give 336 was planned by a sequence involving methyl-Grignard-addition/oxidation/methyl-Grignard-addition/dehydration. Hydroboration of alkyne 333 with dicyclohexyl borane followed by treatment with 157 NaOH/H2O2 was carried out. However, starting material was reisolated when 1–2 equivalents of borane were used and decomposition of the starting material was observed with larger excess of reagent (Scheme 81).
Boc Boc Boc MeO2C MeO2C MeO2C O N O N a) MeMgX O N b) [O] HN N HN N HN N H H H O O c) MeMgX O hydroboration d) -H O oxidative 2 R workup O R' 333 335
Scheme 81: Failure of the hydroboration reaction of 333.
Another reaction sequence that would allow installation of the prenyl moiety in the most direct fashion is semihydrogenation of alkyne 333 to olefin 337, followed by cross metathesis. Towards this end, hydrogenation of 333 catalyzed by Pd/BaSO4 (Rosenmund catalyst) poisoned with quinoline yielded olefin 337 in 90% yield.158 The cross- metathesis reaction using the second generation Grubbs’ catalyst in either refluxing
[157] a) Pelter, A. ; Smith, K.; Brown, H. C. Borane Reagents; Academic Press: New York, 1988. b) Marshall, J. A.; Johns, B. A. J. Org. Chem. 2000, 65, 1501-1510. [158] a) Rosenmund, K.W. Chem. Ber. 1918, 51, 585-593. b) Rao, A. V. R.; Reddy, S. P.; Reddy, E. R. J. Org. Chem. 1986, 51, 4158-4159. In this reference, Pd/BaSO4 is misleadingly called Lindlar’s catalyst ― which is Pd/CaCO3/PbO ― in the experimental part. c) Initial trials were undertaken using Lindlar’s catalyst, however, only recovered starting material 333 was isolated under standard conditions. Lindlar, H. Helv. Chim. Acta 1952, 35, 446- 456. 88 The Total Synthesis of (–)-Spirotryprostatin B
CH2Cl2 or in toluene at 75 °C with 2-methyl-2-butene as cross coupling partner did not lead to conversion of the starting material to 336.159
Boc Boc Boc MeO2C MeO2C MeO2C O N O N O N a Mes N N Mes HN N HN N HN N H 90% H H Cl O O cross O Ru metathesis Me Cl Ph PCy3 Me second generation 333 337 336 Grubbs' catalyst
Scheme 82: a) H2 (1 atm), quinoline (0.5 equiv), Pd/BaSO4 (33 wt%), EtOH, RT.
In order not to lose more precious material to find a valuable entry to 336, we decided to use a model compound for further studies. Compound 155 was one of the products obtained from coupling of spiro-cyclopropyl-oxindole 99 with N-tosyl-protected imines 123 (Table 4, page 34) in our general studies of the ring-expansion reaction. This compound is available on large scale and could be easily converted to 338 by quantitative deprotection of the silyl group.160 Alkyne 338 is a valuable model, containing the terminal acetylene functionality in a structural array similar to 333. In his route to spirotryprostatin A, Danishefsky had also used an N-tosyl derivative as model compound (Scheme 80, page 87).
NTs NTs NTs NTs a b) 2 equiv MeMgX O R 100% c) -H O N O N O N O 2 N O Bn Bn Bn OMe Bn R' 155 TIPS 338 339
Scheme 83: a) TBAF (1.2 equiv), THF, RT.
Conversion to ester 339 was examined from this compound; the prenyl moiety could possibly be introduced by double methyl-Grignard addition followed by dehydration. Three procedures are known in literature that would allow for such a conversion in a 161 direct way: (i) oxidation of the alkyne with H2O2 catalyzed by MeReO3, (ii) oxidative
[159] Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751-1753. [160] See [155], page 85. [161] Zhu, Z. L.; Espenson, J. H. J. Org. Chem. 1995, 60, 7728-7732. The Total Synthesis of (–)-Spirotryprostatin B 89
rearrangement of the alkyne to the corresponding carboxylic acid by hydroxyl-(tosyloxy)- iodo-benzene followed by in situ esterification,162 (iii) reaction of lithiated alkynes with tert-butyl hydroperoxide, subsequent protonation to the ketene and solvolysis to the carboxylic acid ester.163 None of these prescriptions led to the desired ester 339; starting material was reisolated following procedures (i) and (ii), whereas decomposition was observed using conditions (iii) (Scheme 83).
NTs NTs NTs NTs a Me Me 69% N O N O N O N O Bn Bn Bn M Bn Me 338 340 Me 341
Scheme 84: a) nBuLi, MeI, THF, –78 °C Æ RT.
Our next attempt relied on the use of Schwartz’s reagent (Cp2ZrHCl), which is the reagent of choice to convert an alkyne to the corresponding alkenylzirconium species by hydrozirconation.164 Hydrometallation takes place regioselectively at the less hindered terminus. In order to use the hydrozirconation products for C–C bond forming reactions, transmetallation (often to aluminum using AlCl3) is required as the alkenyl carbon attached to zirconium in not nucleophilic enough.165 In order to convert the terminal alkyne 338 into prenylated 341, conversion to methyl-substituted alkyne 340 was achieved by lithiation followed by addition of MeI. Treatment of 340 with Schwartz’s 166 reagent, followed by treatment with AlCl3 and MeI however, did not lead to desired 341 (Scheme 84).
[162] Moriarty, R. M.; Vaid, R. K.; Duncan, M. P.; Vaid, B. K. Tetrahedron Lett. 1987, 28, 2845-2848. [163] Julia, M.; Pfeuty-Saint Jalmes, S.; Plé, K.; Verpeaux, J. N.; Hollingworth, G. Bull. Soc. Chim. Fr. 1996, 133, 15- 24. [164] Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975, 97, 679-680. [165] Carr, D. B.; Schwartz, J. J. Am. Chem. Soc. 1977, 99, 638-640. [166] Lipshutz, B. H.; Keil, R.; Ellsworth, E. L. Tetrahedron Lett. 1990, 31, 7257-7260. 90 The Total Synthesis of (–)-Spirotryprostatin B
NTs NTs NTs NTs a b c O Me Me 0-24% 26% 26% N O N O N O OH N O Bn Bn Me Bn Me 56% Bn 340 Me 342 343 based on 344 recovered 343
Scheme 85: a) Hennion’s catalyst, CH2Cl2, RT; b) MeMgI, THF, –40 °C Æ
RT; c) SOCl2, Py, –50 °C Æ RT.
Treatment of alkyne 340 with a catalytic amount of Hennion’s catalyst, a mixture of
HgOred (1.0 equiv) and BF3·Et2O (1.0 equiv) in trifluoroacetic acid (10.0 equiv), provided ketone 342.167 This reaction did not prove very reproducible and 0–24% of 342 were isolated, generally together with unreacted starting material. Treatment of 342 with methyl-Grignard reagent led to tertiary alcohol 343.168 Under dehydrating conditions, gem-disubstituted olefin 344 was obtained.169 In his synthesis of spirotryprostatin A Danishefsky had shown that the natural product can be obtained from its structural isomer
229 (Scheme 54, page 57), bearing the same side chain, by treatment with RhCl3·3H2O in refluxing EtOH. Alternatively, tertiary alcohol 343 could be methylated and eliminated according to Williams’ procedure (Scheme 55, page 59).170
Although, according to these findings, there is a possibility to convert the alkynyl side chain of 333 into the prenyl moiety, the reaction sequences proved very unreliable and low yielding and a different synthetic pathway had to be found.
[167] a) Barre, V.; Massias, F.; Uguen, D. Tetrahedron Lett. 1989, 30, 7389-7392. b) Killian, D. B.; Hennion, G. F.; Nieuwland, J. J. Am. Chem. Soc. 1936, 58, 80-81. [168] Liotta, D.; Saindane, M.; Barnum, C. J. Org. Chem. 1981, 46, 3369-3370. [169] Plate, R.; Hermkens, P. H. H.; Behm, H.; Ottenheijm, H. C. J. J. Org. Chem. 1987, 52, 560-564. [170] See [48] and [49], page 21. The Total Synthesis of (–)-Spirotryprostatin B 91
Boc Boc MeO2C MeO2C O N O N HN N HN N H H O O O R R' 345
Scheme 86: Planned olefination to access spirotryprostatin B or side-chain analogues
We decided to return to the idea of using an olefination procedure for the introduction of the prenyl side chain (Scheme 86), even though such a procedure had not been successful in an earlier synthesis (Scheme 80, page 87). Two reasons prompted us to take this decision: (i) no other reliable, short and high-yielding method is known at present, (ii) an olefination procedure would allow for facile access to spirotryprostatin B or side-chain analogues of this natural product from aldehyde 345. Investigations towards insertion of the prenyl moiety by means of olefination reactions were undertaken.
Boc Boc Boc MeO2C MeO2C MeO2C O N O N O N a b HN N HN N HN N H 88% H 87% H O O O HO O OH 337 346 345
Scheme 87: a) OsO4 (1.0 equiv), NMO·H2O (1.2 equiv), THF/tBuOH/H2O,
RT; b) Pb(OAc)4, RT.
The transformation of 337 to diol 346 was achived with OsO4/NMO·H2O in 150 THF/tBuOH/H2O with a reaction time of three days. This long reaction time suggests that the accessibility of the C19−C20 olefin of 337 is very limited. The associated difficulties with olefination processes observed by Danishefsky with aldehyde 334 (Scheme 80, page 87) might also have resulted from steric hindrance. 1H NMR spectroscopy revealed that diol 346 was formed as a single diastereomer and in contrast to all earlier intermediates, no rotamers due to the Boc group were observed (Scheme 87). 92 The Total Synthesis of (–)-Spirotryprostatin B
171 From 346, aldehyde 345 was obtained by glycol cleavage with Pb(OAc)4. With aldehyde 345 in hand ― this compound is stable at 4 °C over an extended period of time ― we next turned our attention to the critical olefination step (Scheme 87).
Among the available procedures for the olefination of sterically hindered systems, the Wittig reaction is a commonly used transformation.172 A variety of conditions were used, none of which led to the desired product 336 in pure form.173 Traces of olefination product could be observed by MS, but under all conditions we employed extensive epimerization at C18 took place and considerable amounts of 345 were decomposed (Scheme 88, Table 8).
Boc Boc MeO2C MeO2C Base Solvent Temperature Outcome O N O N nBuLi THF 0 °C Æ RT Decomposition of HN N HN N 18 H H 345, traces of product O Me O DMSO/ Me DMSO RT with correct mass O Ph3P , T NaH Me observed by MS. Me Epimerization of DMSO/ 345 base 336 PhH 60 °C reisolated 345 (86%) KH at C18. Me Ph3P I Me
Table 8, Scheme 88: Failure of Wittig reaction of 345.
Addition of iPrMgCl to aldehyde 345, followed by dehydration of the resulting alcohol was investigated. Under careful control of the amount of Grignard reagent used, conversion into alcohol 347 was achieved without epimerization at C18 in 97% yield.174 Various conditions for the direct dehydration of 347 were examined, but none provided the desired product 336 (Scheme 89, Table 9).175,176
[171] See [151], page 85. [172] Wittig, G.; Schöllkopf, U. Ber. 1954, 87, 1318-1330. [173] a) Asaoka, M.; Shima, K.; Fujii, N.; Takei, H. Tetrahedron 1988, 44, 4757-4766. b) Oppolzer, W.; Wylie, R. D. Helv. Chim. Acta 1980, 63, 1198-1203. [174] Williams, L.; Zhang, Z. D.; Shao, F.; Carroll, P. J.; Joullié, M. M. Tetrahedron 1996, 52, 11673-11694. corrigendum: Williams, L.; Zhang, Z. D.; Shao, F.; Carroll, P. J.; Joullié, M. M. Tetrahedron 1997, 53, 1923-1923. [175] a) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2339-2342. b) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327-4329. c) Dolle, R. E.; Schmidt, S. J.; Erhard, K. F.; Kruse, L. I. J. Am. Chem. Soc. 1989, 111, 278- 284. The Total Synthesis of (–)-Spirotryprostatin B 93
Boc Boc Boc MeO2C MeO2C MeO2C O N O N O N a HN N HN N HN N 18 H 97% H H O O dehydrating- O O RO Me agent Me Table 8 Me Me
345 XY, base 347 R = H 336 Table 9 348 R = X Ph Ph Ph Ph S CF F3C O O 3 F3C CF3 Martin sulfurane
Scheme 89: a) iPrMgCl (2.2 equiv), Et2O, –78 °C Æ RT.
Dehydrating agent Solvent Temperature Outcome Martin sulfurane CH Cl –20 °C Æ RT (2.0-5.0 equiv) 2 2 347 POCl3 (2.0 equiv) Py/CH2Cl2 0 °C Æ RT
Table 9: Reaction conditions employed for direct dehydration of 347.
The use of a two-step procedure also failed due to recalcitrance of 347 to convert to 348 (X = Tf or Ts) (Scheme 89, Table 10).177
XY Base Solvent Temperature Outcome
Tf2O Py CH2Cl2 0 °C Æ RT 2,6-di-tert-butyl-4- Tf O CH Cl 0 °C Æ RT 2 methyl-pyridine 2 2 347 TsCl DMAP CH2Cl2 RT
TsCl Py Py RT
Table 10: Reaction conditions employed for conversion of 347 to 348.
We next turned our attention to the Julia–Lythgoe olefination, as this three-step sequence has proven to be a valuable method for the generation of highly substituted olefins.178
[176] a) Mehta, G.; Murthy, A. N.; Reddy, D. S.; Reddy, A. V. J. Am. Chem. Soc. 1986, 108, 3443-3452. b) Shizuri, Y.; Yamaguchi, S.; Terada, Y.; Yamamura, S. Tetrahedron Lett. 1986, 27, 57-60. [177] a) Lefèbvre, O.; Brigaud, T.; Portella, C. J. Org. Chem. 2001, 66, 1941-1946. b) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley: New York, 1967. [178] Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 4833-4836. 94 The Total Synthesis of (–)-Spirotryprostatin B
Boc Boc Boc Boc MeO2C MeO2C MeO2C MeO2C O N O N O N O N b c d HN N HN N HN N HN N H 61% H 78% H 23% 18 H O O O O Me Me Me O O O HO AcO 345 S Me SO2Ph SO2Ph Ph Me Me Me Me 351 352 353 O 350 S a overall yield from 345: Ph O Na 11% 349 36%
Scheme 90: a) iPrI, 349 (1.5 equiv), Bu4NI, PhH/acetone/H2O, RT; b) nBuLi
(2.5 equiv), 350 (2.5 equiv), THF, –78 °C; Ac2O (1.2 equiv), DMAP
(1.2 equiv), CH2Cl2, RT; d) Na/Hg (2.5%, 130 wt%), Na2HPO4 (520 wt%), MeOH, RT.
Sulfone 350 was prepared by a liquid–liquid phase-transfer process from sodium benzene sulfinate (349).179 The Julia–Lythgoe sequence commenced with the addition of lithiated sulfone 350 to aldehyde 345 at –78 °C. Acylation of the hydroxyl group afforded 352, which was exposed to 2.5% Na/Hg in MeOH in the presence of Na2HPO4. From this set of reactions, the product 353 was obtained in 11% overall yield from aldehyde 345. Thus, olefination of aldehyde 345 proved possible; however, product 353 was found to have undergone extensive epimerization at C18 (Scheme 90).180
Given this promising result, further investigations were undertaken following the same general direction. The use of a more hindered base instead of nBuLi and replacement of the three-step procedure by a one-pot sequence would hopefully avoid epimerization at C18 (epimerization could have occurred by excess base) and improve the yield of the conversion of aldehyde 345 to 336 significantly.
The Julia–Kocieńsky reaction, a modification of the one-pot olefination reaction developed by Julia, was tested next.181,182 The required sulfone 365 was available from 354 by alkylation under Mitsunobu conditions, followed by oxidation with Oxone.182,183
[179] Crandall, J. K.; Pradat, C. J. Org. Chem. 1985, 50, 1327-1329. [180] a) McCombie, S. W.; Cox, B.; Ganguly, A. K. Tetrahedron Lett. 1991, 32, 2087-2090. b) Gurjar, M. K.; Srinivas, N. R. Tetrahedron Lett. 1991, 32, 3409-3412. [181] Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175-1178. [182] Kocieńsky, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365-366. [183] Ward, R. S.; Roberts, D. W.; Diaper, R. L. Sulfur Lett. 2000, 23, 139-144. The Total Synthesis of (–)-Spirotryprostatin B 95
Treatment of aldehyde 345 with the lithium salt of sulfone 356 (obtained by treatment of 356 with LHMDS), afforded the desired product 336 without epimerization at C18 in 78% yield. The structure of compound 336 was confirmed by X-ray crystallographic analysis (Scheme 91, Figure 19).184 The Julia–Kocieńsky reaction is normally employed for efficient introduction of disubstituted olefins with selective formation of the trans- isomers. To our knowledge, the use of this reaction for the formation of trisubstituted double bonds has not yet been the object of investigations and the known sulfone 356 has not yet been reported as reactant in a Julia–Kocieńsky reaction.185 Furthermore, even though Julia–Kocieńsky reactions with β-branched aryl sulfones (e.g. with 2-methyl- heptyl-aryl-sulfone) are known,186 the use of α-branched aryl sulfones for the synthesis of trisubstituted double bonds has not been reported.
Boc Boc MeO2C MeO2C O N O N c HN N HN N H 78% 18 H O O O Ph Me O O N Me N S Me 345 NN Me 336 356
b 85% Ph Ph N a N Me N SH N S 81% NN NN Me 354 355
Scheme 91: a) iPrOH, PPh3, DEAD, THF, RT; b) Oxone, MeOH, H2O, RT; c) 356, LHMDS, THF, -78 °C.
[184] CCDC 196804 contains the supplementary crystallographic data for 336 This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]). [185] Nirenburg, V.L.; Postovskii, I. Y. Izv. Vyssh. Uchebn. Zaved. Khim. Tekhnol. 1965, 8, 258. [186] Blakemore, P. R.; Cole, W. J.; Kocieńsky, P. J.; Morley, A. Synlett 1998, 26-28. 96 The Total Synthesis of (–)-Spirotryprostatin B
Figure 19: ORTEP drawing of 336.
From 336, the synthesis of spirotryprostatin B was completed in four steps following the Danishefsky route.187 Thus, selenylation of 336 followed by oxidation/elimination with DMDO afforded 357 (74%).188,189 Deprotection of the proline moiety and subsequent lactamization to the diketopiperazine ring led to spirotryprostatin B (2) in 74% yield (Scheme 92).
Boc Boc O MeO2C MeO2C O N O 8 N O N a,b 9 c HN HN HN N N N H H 74% H 74% O O O Me Me Me
Me Me Me 336 357 17 spirotryprostatin B
Scheme 92: a) PhSeCl, LHMDS, THF, 0 °C; b) DMDO, THF, 0 °C; c) (i)
TFA, CH2Cl2, RT; (ii) NEt3, CH2Cl2, RT.
The analytical characteristics observed (1H and 13C NMR spectra, MS, IR, optical rotation) were found to be identical to those reported in the literature for natural material.
[187] See [25], page 14. [188] Reich, H. J.; Reich, I. J.;Renga, J.M. J. Am. Chem. Soc. 1973, 95, 5813-5815. [189] Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Berichte 1991, 124, 2377-2377. The Total Synthesis of (–)-Spirotryprostatin B 97
2.4. Synthesis of Spirotryprostatin B from Intermediate 324
Intermediate 324 differs from 323 only by the geometry of the olefinic double bond. Applying identical synthetic steps as for the synthesis of spirotryprostatin B from 323, the route should lead to the common aldehyde intermediate 330 (Scheme 93).
Me
O HN NH steps
O Boc TIPS O N 323 HN N H O Me
O TIPS steps 330 HN NH
TIPS 324
Scheme 93: Common intermediate 330 should be accessible from 323 and 324.
Treatment of 324 with N-Boc-L-proline chloride (270) afforded a 1:1 mixture of chromatographically separable 358 and 359 (Scheme 94). No crystals could be grown from either of the two coupling products; structural assignment was therefore possible only after conversion of 358 to the known intermediate 330.
Me Me Boc Me Boc O O N N a HN NH HN N + HN N 79% H H O O O BocN TIPS Cl TIPS TIPS 324 H 358 359 O 1:1 270
Scheme 94: a) 270, (2.5 equiv), NEt3, CH2Cl2, 0 °C Æ RT.
98 The Total Synthesis of (–)-Spirotryprostatin B
The more polar coupling product was converted into the corresponding aldehyde via diol 360 in 75% overall yield. The analytical characteristics observed for aldehyde 330 were found to be identical to those found previously (see paragraph 2.3.). Therefore, structure 358 was assigned to this diastereomer.
OH Me Boc Me Boc O Boc OH O N O N O N ab HN N HN N HN N H H 75% H O O O over 2 steps
TIPS TIPS TIPS 358 360 330
Scheme 95: a) OsO4 (4 mol%), NMO·H2O (1.2 equiv), THF/tBuOH/H2O, RT;
b) Pb(OAc)4, RT.
2.5. Synthesis of Spirotryprostatin B from Intermediate 326
The difference between 323 and 326 concerns the relative configuration at the C9 stereocenter. This stereocenter is not present anymore in the natural product, and employment of the synthetic sequence used for the synthesis of spirotryprostatin B from 323 to 326 should result in formation of common intermediate 357 (Scheme 96).
Me
O HN NH steps
Boc MeO2C TIPS O N 323 HN N H O Me Me
Me O 357 HN NH steps
TIPS 326
Scheme 96: Common intermediate 357 should be accessible from 323 and 326. The Total Synthesis of (–)-Spirotryprostatin B 99
Coupling of 326 with N-Boc-L-proline chloride (270) afforded a mixture of products 361 and 362 not separable by column chromatography. The mixture of products was submitted to the conditions for conversion of the substituted vinyl group into the C9 methyl ester followed by removal of the TIPS protecting group (see section V 2.2.4.). All of these steps were carried out without purification of the intermediates. Compounds 363 and 364 in a 1:2 ratio resulted from this sequence as isomers separable by chromatography on silica gel. The fact that the obtained ratio is not 1:1, as previously observed, could be the result of a (partial) kinetic resolution of 326 with N-Boc-L-proline chloride (270).
Me Me Me Boc Boc
O 9 O N N a HN HN NH N + HN N 90% H H O O O BocN inseperable TIPS Cl TIPS by column TIPS 326 H 361chromatography 362 O 270 b-f 75%
Boc Boc O MeO2C MeO2C H O N N N 9 12 HN g N + HN N HN N H H H O O O 43% O O
(1:2) 363 364 365 seperable by column chromatography
Scheme 97: a) 270, (2.5 equiv), NEt3, CH2Cl2, 0 °C Æ RT; b) OsO4 (4 mol%),
NMO·H2O (1.2 equiv), THF/tBuOH/H2O, RT; c) Pb(OAc)4, RT; d) NaClO2
(10.0 equiv), 2-methyl-2-butene, pH 3.6 buffer, tBuOH, RT; e) CH2N2, Et2O,
RT; f) TBAF (1.2 equiv), THF, RT; g) (i) TFA, CH2Cl2, RT; (ii) NEt3, CH2Cl2, RT.
Assignment of the stereochemistry for 363 and 364 was not possible by X-ray crystallographic analysis, as from both compounds, no suitable crystals could be obtained. The major product 364 was treated with TFA followed by triethyl amine to yield 365. No NOE enhancements could be observed between the C9 and C12 protons, 100 The Total Synthesis of (–)-Spirotryprostatin B
indicating that the trans-diketopiperazine has been produced from 364. Although the absence of an NOE is not an absolute prove, spirotryprostatin A, a cis-diketopiperazine showed a pronounced NOE for these protons (Scheme 97).190 Assuming that our assignment of 363 is correct, we continued our synthetic route with compound 363. Following the same synthetic steps as in our earlier sequence, 363 was converted to aldehyde 367 via olefin 366. In this sequence, as compared to the C9 epimeric compounds, we observed the occurrence of 4 rotamers, probably due to restricted rotation around the N10-C11 amide bond.
Boc Boc Boc MeO2C MeO2C MeO2C O N O N O N a b,c HN N HN N HN N 11 H 98% H 63% 10 H O O O O
363 366 367
Ph Boc Boc O O MeO C MeO C N Me 2 2 N S O N O N N N Me HN N e,f HN N d H H 356 O 40% O 68% Me Me Me Me 357 368
Scheme 98: a) H2 (1 atm), quinoline (0.5 equiv), Pd/BaSO4 (33 wt%), EtOH,
RT; b) OsO4 (1.0 equiv), NMO·H2O (1.2 equiv), THF/tBuOH/H2O, RT;
c) Pb(OAc)4, RT; d) 356, LHMDS, THF, –78 °C; e) PhSeCl, LHMDS, THF, 0 °C; f) DMDO, THF, 0 °C.
The Julia–Kocieńsky reaction of aldehyde 367 to product 368 proceeded in 68% yield. From 368, the implementation of the C8−C9 double bond proved that the assumption about the isomer assignment of 363 and 364 had indeed been correct, as the isolated compound was identical to 357 (Scheme 98). This finding concludes the synthesis of spirotryprostatin B from 326.
[190] See [5], page 7. The Total Synthesis of (–)-Spirotryprostatin B 101
3. Conclusion
We have described the total synthesis of spirotryprostatin B (16 steps from 3-diazo-1,3- dihydro-indol-2-one (312) (Scheme 100). Our approach is highlighted by the rapid assembly of the spirotryprostatin core using our ring-expansion method for the synthesis of highly substituted spiro-pyrrolidine–oxindole alkaloids. The limited reactivity of aldehydes 345 and 367 towards olefination was overcome by the Kocieńsky-Julia reaction, which allows for the facile synthesis of analogues, important for elucidating structure–activity relationships. Over a sequence of several steps, no purification of intermediates is required, making our approach suitable for large scale synthesis.
Me Me Me
O N N AcOH, ∆ 2 HN N
MeO N O MeO N O N MeO N O H H H MeO 369 TIPS 309 TIPS TIPS
O Boc Boc H MeO2C MeO2C O N O N O N HN N HN N HN N H H H O O O Me Me MeO MeO MeO Me Me 43 spirotryprostatin A
Scheme 99: Suggestion for the rapid assembly of spirotryprostatin A.
The products of the key ring-expansion reaction can be equilibrated to 321 by refluxing in acetic acid (Scheme 76, page 82). The relative stereochemistry of 321 is the same as observed in spirotryprostatin A. Starting from diazo-oxindole 369,191 our method would also be ideal to quickly assemble spirotryprostatin A (43) (Scheme 99).
[191] Compound 369 could be prepared from known 6-methoxy isatin. Creger, P. L. J. Org. Chem. 1965, 30, 3610- 3613. 102 The Total Synthesis of (–)-Spirotryprostatin B
Me Me Me Me
O O O N HN NH HN NH HN NH + + N O H 314 TIPS TIPS TIPS TIPS 324 323 326 N
309 TIPS Me Me Me Boc Boc O N O N HN N HN N H H O O N O H 313 TIPS TIPS 358 327
O Boc O Boc
N2 O N O N HN N HN N N O H H H O O Boc 312 MeO2C O N TIPS TIPS HN N 330 330 H O
363
Boc Boc MeO2C MeO2C O N O N HN N HN N H H O O Me Me Me Me 357 357
O O N 3.4% HN N overall yield H from known 312 O Me
Me 17 spirotryprostatin B
Scheme 100: The total synthesis of spirotryprostatin B. Conclusion and Outlook 103
VI. Conclusion and Outlook
We have developed a novel method to access spiro-pyrrolidine-oxindoles by MgI2- catalyzed ring-expansion reaction in a highly convergent manner. The products of the ring expansion are generally obtained in good yields and high diastereoselectivities. The starting materials can be easily prepared in short synthetic sequences (1 to 3 steps) with high overall yields. This method is different from existing approaches to the spiro- pyrrolidine-oxindole core and represents a valuable alternative.
This method was successfully employed in the short and high-yielding synthesis of (±)-horsfiline ((±)-16). The use of 1,3,5-trimethyl-1,3,5-triazinane (206) to serve as an efficient N-methyl-methylene imine equivalent in the MgI2-catalyzed ring expansion was demonstrated.
In order to examine the viability of the method for the construction of spiro-pyrrolidine- oxindoles with a higher degree of substitution in the pyrrolidine ring, we employed our annulation method for the synthesis of an important key fragment in the total synthesis of spirotryprostatin B (17). The construction of highly substituted pyrrolidines (substituents at the 2,3 and 5 positions) can be well performed with proper selection of starting materials. In the synthesis of spirotryprostatin B (17), the problem of late-stage introduction of the prenyl side chain that proved difficult in earlier routes could be solved by application of the Julia–Kocieńsky olefination proceedure. The natural product was obtained in 16 steps from commercially available materials.
In the course of our investigations, initial results showed that the method can also be used for the formation of spiro-tetrahydrofuryl-oxindoles and for the general formation of substituted pyrrolidines from cyclopropyl amides. Although some of these discoveries have already been pursued by other research groups,192 the use of nucleophiles other than
[192] a) Lautens, M.; Han, W. S. J. Am. Chem. Soc. 2002, 124, 6312-6316. b) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3147-3150. c) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 4333-4336.
104 Conclusion and Outlook
imines (for example aldehydes N,N-dialkylhydrazones or carbodiimides) has not yet been examined and would allow for a more complete view of the reaction scope and present a useful method for the preparation of five-membered-ring heterocycles.
One of the next major goals along the line would be to achieve asymmetric induction in the ring expansion. Several possibilities can be aimed at: (i) the use of chiral imines ― sulfinyl imines would eventually be suitable for that purpose,193 (ii) the use of chiral ligands for Mg ― the use of BOX-type ligands could be envisioned ― hopefully resulting in a catalytic, asymmetric transformation.194
[193] Liu, G. C.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278-1284. [194] a) Corey, E. J.; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807-6810. b) Corey, E. J.; Wang, Z. Tetrahedron Lett. 1993, 34, 4001-4004. Experimental Part 105
VII. Experimental Part
1. General methods
All non-aqueous reactions were carried out using oven-dried or flame-dried glassware under a positive pressure of dry nitrogen unless otherwise noted. Tetrahydrofuran, acetonitrile, toluene, diethyl ether and methylene chloride were purified by distillation and dried by passage over activated alumina under an argon atmosphere (H2O content < 30 ppm, Karl-Fischer titration).195 Benzene was distilled from sodium/benzophenone ketyl under an atmosphere of dry nitrogen. Triethylamine and pyridine were distilled from KOH. Ethyl glyoxylate was freshly distilled from P2O5, 1,1,1,3,3,3- hexamethyldisilazane (HMDS), p-tosylisocyanate and quinoline were distilled prior to use. Methyliodide was filtered through silica gel prior to use. Potassium hydride (commercially available as a dispersion in mineral oil) was purified according to the procedure reported by Brown.196 n-Butyl lithium was titrated with sBuOH/phenanthroline.197 All other commercially available reagents were used without further purification.
Except as indicated otherwise, reactions were magnetically stirred and monitored by thin layer chromatography (TLC) using Merck Silica Gel 60 F254 plates and visualized by fluorescence quenching under UV light. In addition, TLC plates were stained using ceric ammonium molybdate or potassium permanganate stain.
Chromatographic purification of products (flash chromatography) was performed on E. Merck Silica Gel 60 (230-400 mesh) using a forced flow of eluant at 0.3-0.5 bar.198 Concentration under reduced pressure was performed by rotary evaporation at 40 °C at
[195] Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518- 1520. [196] Brown, C. A. J. Org. Chem. 1974, 39, 3913-3918. [197] Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165-168. [198] Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923. 106 Experimental Part
the appropriate pressure. Purified compounds were further dried for 12-72 h under high vacuum (0.01−0.05 Torr). Yields refer to chromatographically purified and spectroscopically pure compounds, unless otherwise stated.
Preparative thin layer chromatography was performed on pre coated plates silicat gel 60 F254 from E. Merck.
Kugelrohr distillations were performed with a Büchi Glass Oven B-580.
Radial chromatography was performed with a CycloGraph chromatodron using a 1mm –1 CaSO4-bound silica gel plate at a flow rate of 5-7 mL min .
Melting points were measured on a Büchi 510 apparatus. All melting points were measured in open capillaries and are uncorrected.
Optical rotations were measured on a Jasco DIP-1000 polarimeter operating at the T sodium D line with a 100 mm path length cell, and are reported as follows: [α]D , concentration (g/100 ml), and solvent.
NMR spectra were recorded on a Varian Gemini 200 spectrometer operating at 200 MHz for 1H acquisitions, a Varian Mercury 300 spectrometer operating at 300 MHz and 75 MHz for 1H and 13C acquisitions, respectively, or on a Bruker DRX500 spectrometer operating at 500 MHz and 125 MHz for 1H and 13C acquisitions, respectively. Chemical shifts (δ) are reported in ppm with the solvent resonance as the internal standard relative to chloroform (δ 7.26) and benzene (δ 7.15) for 1H, and chloroform (δ 77.0) and benzene (δ 128.0) for 13C. Data are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet; coupling constants in Hz. IR spectra were recorded on a Perkin Elmer Spectrum RXI FT-IR spectrophotometer. Optical rotations were measured on a Jasco DIP-1000 polarimeter operating at the sodium D line with a T 100 mm path length cell, and are reported as follows: [α]D , concentration (g/100 mL), and solvent.
IR spectra were recorded on a PerkinElmer Spectrum RXI FT-IR spectrophotometer. Absorptions are given in wavenumbers (cm–1). Experimental Part 107
Mass spectra were recorded by the MS service at ETH Zürich. EI-MS: VG-TRIBRID spectrometer; spectra were measured at 70 eV. FAB-MS: VG-ZAB2-SEQ spectrometer; spectra were determined in m-nitrobenzyl alcohol (3-NOBA) as matrix. MALDI-MS: IonSpec Ultima Fourier Transform Mass Spectrometer. Peaks are given in percent (m/z).
Elemental analyses were performed at the Mikrolabor der ETH Zürich.
High-performance liquid chromatography was performed on a Merck Hitachi (Interface D-7000, UV-Detector L-7400, Pump L-7100, column: Säulentechnik 4 mm ID column packed with 5 µm spherisorb SW silica gel). The detector wavelength was fixed at λ = 254 nm. A flow rate of 0.9 mL min–1 was used. All chromatograms were taken at ambient temperature.
Crystallographic structure determinations for 167 and 285 were performed on a Syntex
P21 diffractometer, MoKα radiation (λ = 0.71073 Å). The crystallographic structure determination for 286 was performed on a Picker-STOE diffractometer, CuKα radiation (λ = 1.5418 Å). Crystallographic structure determinations for 327 and 336 were performed on a Nonius CAD4 diffractometer, CuKα radiation (λ = 1.5418 Å). The structures were solved by direct methods199 and refined by full-matrix least-squares analysis200 including an isotropic extinction correction. All heavy atoms were refined anisotropically, H-atoms of the ordered part isotropically, whereby H-positions are based on stereochemical considerations.
[199] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. Burla, G. Polidori, M. Camalli, J. Appl. Crystallogr., 1994, 27, 435. [200] G.M. Sheldrick, 1997, SHELXL-97 Program for the Refinement of Crystal Structures. University of Goettingen, Germany. 108 Experimental Part
2. Preparation of Useful Reagents and Buffers
LHMDS, 0.330 M in THF
To a solution of HMDS (1.00 mL, 4.73 mmol, 1.00 equiv), in THF (10 mL) at −78°C was added nBuLi (1.42 M in hexanes, 3.33 mL, 4.73 mmol, 1.00 equiv). The solution was allowed to stir at 0°C for 30 min.
CH2N2, ≈ 0.4 M in Et2O
A solution of KOH (500 mg, 8.77 mmol, 3.90 equiv) in H2O (500 µL), was cooled to
0 °C and Et2O (5.6 mL) was added. To the biphasic mixture at 0 °C was added N-methyl-
N’-nitro-N-nitrosoguanidine (≈ 50% in H2O, 329 mg, 2.24 mmol, 1.00 equiv) in small portions. The yellow organic solution was decanted and used immediately.
BocProCl, 0.140 M in CH2Cl2
To a solution of DMF (103 µL, 1.38 mmol, 1.00 equiv) in CH2Cl2 (10 mL) at 0 °C was added oxalyl chloride (121 µL, 1.38 mmol, 1.00 equiv). A white precipitate was formed. Pyridine (111 µL, 1.38 mmol, 1.00 equiv) was added dropwise to the reaction mixture; the precipitate dissolved and the solution turned yellow. N-Boc-L-proline (297 mg, 1.38 mmol, 1.00 equiv) was then added to the solution. The reaction mixture was stirred at 0 °C for 30 min; this solution of N-Boc-L-proline chloride solution was used for the subsequent peptide coupling.
Rf = 0.73 (EtOAc)
Dimethyl-dioxirane, ≈ 0.09 M in acetone
In a 2 L 2-neck flask (1 exit connected to 100 mL 2-neck receiving flask with dry ice condenser), a solution of NaHCO3 (29 g) in acetone (96 mL) and H2O (127 mL) was cooled to 5–10 °C (ice-bath). Oxone (60 g) was added in 5 portions; in-between, the reaction mixture was stirred for 3 min. 3 min after the last addition, the condenser was filled with dry ice/acetone and the receiving flask was cooled with a −78 °C cooling bath. The ice-bath was removed and the solution of DMDO in acetone distilled at reduced Experimental Part 109
pressure (80–100 Torr). About 60 mL of solution were obtained. The solution is dried
(K2CO3) and stored over activated molecular sieves (3 Å) at −4 °C. pH 3.6 buffer
Solution of citric acid monohydrate (1.43 g) and Na2HPO4·12H2O (2.31 g) in H2O (98.5 mL). 110 Experimental Part
3. MgI2-Catalyzed Ring-Expansion Reaction of Spiro- Cyclopropyl-Oxindoles with Aldimines
O
N O Bn
1-benzyl isatin (97)
To a solution of isatin (20.0 g, 136 mmol, 1.00 equiv) in DMF (250 mL) was cooled to 0 °C (ice bath). NaH (60% dispersion in mineral oil, 5.71 g, 143 mmol, 1.05 equiv) was added portionwise to the orange solution. The solution changed color to deep purple. When the gas evolution stopped, benzyl bromide (26.7 g, 156 mmol, 1.16 equiv) was added slowly, whereupon the mixture turned red-brown. After 15 min, H2O (1.2 L) was introduced to precipitate the product. After filtration, the product was recrystallized from refluxing EtOH to afford 97 (28.9 g, 90%) after drying.
1 mp = 130-132 °C; H NMR (CDCl3, 200 MHz) δ 7.65 (dd, 1H, J = 7.5, 1.3 Hz), 7.50 (dt, 1H, J = 7.9, 1.7 Hz), 7.38-7.3 (m, 5H), 7.15-7.08 (m, 1H), 6.80 (d, 1H, J = 7.9 Hz), 4.96 (s, 2H).
N O Bn
1-benzyl-1,2-dihydro-indol-2-one (98)
A solution of 1-benzyl isatin (97) (26.1 g, 117 mmol) in hydrazine hydrate (125 mL) was heated to reflux till the gas evolution stopped (4 h). The color of the solution changed from orange via green to yellow during this time. The reaction mixture was allowed to cool to room temperature and the product was extracted with EtOAc (2 × 150 mL). The combined organic layers were dried (Na2SO4), filtered, and the solvent was evaporated in Experimental Part 111
vacuo. The yellow product was recrystallized from refluxing Et2O to afford 98 (17.0 g, 65%) after drying.
1 mp = 68 °C; H NMR (CDCl3, 200 MHz) δ 7.34-7.14 (m, 7H), 7.05-6.97 (m, 1H), 6.73 (d, 1H, J = 7.9 Hz), 4.93 (s, 2H), 3.64 (s, 2H).
N O Bn
1-benzyl-3-cyclopropyl-1,2-dihydro-indol-2-one (99)
A solution of 1-benzyl-indoline-2-one (98) (4.62 g, 20.1 mmol, 1.00 equiv) in DMF (20 mL) was treated with dibromoethane (4.28 g, 22.8 mmol, 1.13 equiv) and cooled in an ice/water bath. Then, NaH (1.49 g, 62.1 mmol, 3.09 equiv) was added in portions. After ~2/3 of the NaH had been added, the cooling bath was removed, and the addition was continued. After stirring at room temperature for 1 h, the reaction was quenched by addition of MeOH (5 mL). The reaction mixture was diluted with EtOAc (150 mL) and washed with water (4 × 50 mL) and brine (30 mL). The combined organic layers were dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by column chromatography (3:17Æ1:5 EtOAc/hexanes) to afford a yellow solid, which was recrystallized from toluene/cyclohexane to afford 99 (3.76 g, 73%) as a colorless solid after drying.
1 mp = 103 °C; H NMR (CDCl3, 200 MHz) δ 7.33-7.26 (m, 5H), 7.15 (dt, 1H, J = 7.5, 1.3 Hz), 6.99 (dt, 1H, J = 7.5, 0.9 Hz), 6.86-6.84 (m, 1H), 6.80 (d, 1H, J = 7.8 Hz), 5.00 13 (s, 2H), 1.81 (dd, 2H, J = 7.8, 4.1 Hz), 1.56 (dd, 2H, J = 7.8, 4.1 Hz); C NMR (CDCl3, 75 MHz) δ 177.5, 136.5, 131.1, 129.0, 127.8, 127.6, 126.9, 122.3, 118.6, 11.2, 109.2, 44.2, 27.1, 19.5; IR (KBr) ν 1703, 1616, 1496, 1490, 1466, 1384, 1367, 1339, 1181, + + 1008, 948, 754, 738, 700, 457; DEI-MS: 249.1 (100 [M] ), 91.0 (100 [C7H7] ); Anal. calcd for C17H15NO: C 81.90, H 6.06, N 5.62, found: C 81.92, H 6.22, N 5.73.
112 Experimental Part
General procedure for the formation of substituted methylidene arylsulfonamides:
The aldehyde dimethyl- or diethylacetal (1.00 equiv) and the arylsulfonamide (1.00 equiv) were mixed in a round bottom flask equipped with a Dean-Stark condenser. The neat mixture was heated to 120−200 °C for 20 min. During this time MeOH or EtOH distilled off the reaction mixture. The resulting melt was allowed to cool to room temperature and the solid was recrystallized from refluxing toluene to yield the solid product.
Remark:
If the dialkylacetals were not commercially available, the dimethyl acetals were prepared by refluxing the aldehyde overnight in MeOH with HC(OMe)3 (3.00 equiv) and a catalytic amount of CSA (5 mol%). The reaction mixture was quenched by addition of
NEt3 and the volatiles were evaporated. The unpurified acetals were used for imine formation.201
NTs
Ph
N-benzylidene-p-toluenesulfonamide (124)
Reaction temperature: 160 °C, recrystallization: toluene, yield: 71%, colorless crystals.
1 mp = 106 °C; H NMR (CDCl3, 400 MHz) δ 8.98 (s, 1H), 7.81-7.50 (m, 5H), 7.88 (d, 2H, J = 8.4 Hz), 7.29 (d, 2H, J = 8.4 Hz), 2.38 (s, 3H).
[201] Becicka, B. T.; Koerwitz, F. L.; Drtina, G. J.; Baenziger, N. C.; Wiemer, D. F. J. Org. Chem. 1990, 55, 5613- 5619. Experimental Part 113
NTs Me
N-(2-methyl-benzylidene)-p-toluenesulfonamide (127)
Reaction temperature: 160-180 °C, recrystallization: Et2O, yield: 38%, colorless solid.
1 mp = 90 °C; H NMR (CDCl3, 200 MHz) δ 9.37 (s, 1H), 8.06-8.01 (m, 1H), 7.94-7.89 (m, 2H), 7.54-7.46 (m, 1H), 7.39-7.27 (m, 4H), 2.64 (s, 3H), 2.46 (s, 3H).
NTs
Me
N-(4-methyl-benzylidene)-p-toluenesulfonamide (130)
Reaction temperature: 160 °C, recrystallization: toluene, yield: 44%, colorless solid.
1 mp = 113-115 °C; H NMR (CDCl3, 200 MHz) δ 9.00 (s, 1H), 7.91-7.80 (m, 4H), 7.37-7.27 (m, 4H), 2.44 (s, 3H).
NTs Br
N-(2-bromo-benzylidene)-p-toluenesulfonamide (133)
Reaction temperature: 138 °C, recrystallization: toluene, yield: 75%, white solid.
1 mp = 104-106 °C; H NMR (CDCl3, 400 MHz) δ 9.46 (s, 1H), 8.20-8.15 (m, 1H), 13 7.95-7.91 (m, 2H), 7.71-7.67 (m, 1H), 7.50-7.37 (m, 4H), 2.47 (s, 3H); C NMR (CDCl3, 100 MHz) δ 169.1, 144.8, 135.6, 134.5, 133.7, 131.1, 130.5, 129.8, 128.8, 127.9, 21.6; IR (KBr) ν 1597, 1582, 1557, 1430, 1320, 1290, 1273, 1215, 1157, 1086, 1048, 1075, 861, 807, 787, 760, 705, 689, 657, 614, 546, 498; DEI-MS: 339.0 (0.14 [M]+), 91.0 114 Experimental Part
+ (100 [C7H7] ); Anal. calcd for C14H12BrNO2S: C 68.20, H 5.72, N 4.68, found: C 68.14, H 5.88, N 4.72.
NTs
Br
N-(4-bromo-benzylidene)-p-toluenesulfonamide (136)
Reaction temperature: 160 °C, recrystallization: toluene, yield: 75%, colorless solid.
1 mp = 193 °C; H NMR (CDCl3, 200 MHz) δ 9.01 (s, 1H), 7.93-7.91 (m, 2H), 7.84-7.79 (m, 2H), 7.69-7.64 (m, 2H), 7.40-7.36 (m, 2H), 2.47 (s, 3H).
NTs
CF3
N-(4-trifluoromethyl-benzylidene)-p-toluenesulfonamide (139)
Reaction temperature: 160 °C, recrystallization: toluene, yield: 74%, colorless solid.
1 mp = 152-153 °C; H NMR (CDCl3, 400 MHz) δ 9.08 (s, 1H), 8.05 (d, 2H, J = 8.0 Hz), 7.90 (ddd, 2H, J = 8.3, 8.3, 2.0 Hz), 7.75 (d, 2H, J = 8.3 Hz), 7.36 (ddd, 2H, J = 8.0, 8.0, 13 2.0 Hz), 2.45 (s, 3H); C NMR (CDCl3, 100 MHz) δ 168.4, 145.1, 136.0, 133.6, 135.6, 135.4, 134.5, 131.4, 130.0, 128.3, 21.7; IR (KBr) ν 1616, 1590, 1576, 1413, 1327, 1309, 1291, 1172, 1160, 1130, 1103, 1089, 1063, 1013, 873, 841, 789, 677, 644, 561, 551, 501; + + + DEI-MS: 327.1 (13.4 [M] ), 154.9 (87 [SO2-C7H7] ) 91.0 (100 [C7H7] ); Anal. calcd for
C15H12F3NO2S: C 55.04, H 3.70, N 4.28, found: C 55.09, H 3.93, N 4.33.
Experimental Part 115
NTs
OMe
N-(4-methoxy-benzylidene)-p-toluenesulfonamide (142)
Reaction temperature: 160-180 °C, recrystallization: toluene, yield: 75%, colorless solid.
1 mp = 127 °C; H NMR (CDCl3, 200 MHz) δ 8.95 (s, 1H), 7.92-7.87 (m, 4H), 7.34 (d, 2H, J = 8.3 Hz), 7.00-6.95 (m, 2H), 3.89 (s, 3H), 2.44 (s, 3H).
NTs
O
N-(furan-2-ylmethylidene)-p-toluenesulfonamide (145)
Reaction temperature: 120 °C, recrystallization: Et2O, yield: 12%, colorless solid.
1 mp = 100-102 °C; H NMR (CDCl3, 200 MHz) δ 8.83 (s, 1H), 7.91-7.85 (m, 2H), 7.76-7.75 (m, 1H), 7.37-7.32 (m, 3H), 6.66 (dd, 1H, J = 3.7, 2.1 Hz), 2.44 (s, 3H).
NTs
Ph
N-(3-phenyl-allylidene)-p-toluenesulfonamide (148)
Reaction temperature: 160 °C, recrystallization: toluene, yield: 63%, colorless solid.
1 mp = 117 °C; H NMR (CDCl3, 200 MHz) δ 8.81 (d, 1H, J = 9.1 Hz), 7.91-7.86 (m, 2H), 7.60-7.55 (m, 2H), 7.49-7.42 (m, 5H), 7.39-7.35 (m, 1H), 7.01 (dd, 1H, J = 15.8, 9.1 Hz), 2.46 (s, 3H).
116 Experimental Part
NTs Me
Ph
N-(2-methyl-3-phenyl-allylidene)-p-toluenesulfonamide (151)
Reaction temperature: 140-200 °C, recrystallization: toluene, yield: 57%, orange solid.
1 mp = 104-106 °C; H NMR (CDCl3, 400 MHz) δ 8.72 (d, 1H, J = 0.5 Hz), 7.89-7.86 13 (m, 2H), 7.51-7.36 (m, 7H), 2.44 (s, 3H), 2.17 (d, 3H, J = 1.3 Hz); C NMR (CDCl3, 100 MHz) δ 174.6, 151.3, 144.3, 135.6, 135.1, 134.9, 130.3, 129.9, 129.7, 128.7, 128.0, 21.6, 12.8; IR (KBr) ν 1615, 1595, 1557, 1439, 1409, 1323, 1315, 1305, 1281, 1209, 1154, 1087, 1021, 841, 813, 801, 793, 750, 701, 696, 680, 656, 589, 556, 532, 515, 513; DEI- + + + MS: 298.0 (0.46 [M] ), 144.0 (100 [M-SO2-C7H7] ) 91.0 (37 [C7H7] ); Anal. calcd for
C17H17NO2S: C 68.20, H 5.72, N 4.68, found: C 68.14, H 5.88, N 4.72.
NTs
TIPS
N-(3-triisopropylsilanyl-prop-2-ynylidene)-p-toluenesulfonimide (154)
Reaction temperature: 175 ˚C, Kugel-Rohr distillation (160 ˚C at 0.04 Torr), yield: 57%, colorless oil which solidifies upon standing.
1 mp = 39-44 ˚C; H NMR (CDCl3, 300 MHz,) δ 8.26 (s, 1H), 7.87-7.81 (m, 2H), 13 7.39-7.33 (m, 2H), 2.45 (s, 3H), 1.18-1.02 (m, 21H); C NMR (CDCl3, 75 MHz) δ 154.6, 145.4, 133.9, 130.0, 128.6, 113.8, 100.7, 21.6, 18.3, 10.8; IR (KBr) ν 2943, 2890, 2866, 2179, 1668, 1595, 1572, 1462, 1329, 1306, 1295, 1189, 1160, 1080, 1019, 997, 882, 818, 706, 685, 629, 552; DEI-MS: 363.1 (0.55 [M]+), 320.0 (100 [M-iPr]+), + 91.0 (75 [C7H7] ) Anal. calcd for C19H21NO2SSi C 62.76, H 8.04, N 3.85, found, C 62.75, H 7.88, N 3.83.
Experimental Part 117
O O S N
Me naphthalene-2-sulfonic acid 4-methyl-benzylideneamide (157)
Reaction temperature: 170-180 °C, recrystallization: toluene, yield: 66%, colorless crystals.
1 mp = 135 °C; H NMR (CDCl3, 300 MHz) δ 9.07 (s, 1H), 8.61-8.60 (m, 1H), 8.01-7.90 (m, 4H), 7.83 (d, 2H, J = 7.8 Hz), 7.77-7.59 (m, 2H), 7.29 (d, 2H, J = 7.8 Hz), 2.43 13 (s, 3H); C NMR (CDCl3, 75 MHz) δ 170.7, 135.5, 131.8, 130.2, 130.1, 129.8, 129.7, 129.4, 128.2, 127.8, 123.2, 22.1; IR (KBr) ν 1596, 1561, 1319, 1157, 1130, 1072, 860, + + 822, 798, 761, 655; MS (EI): 309.1 (10 [M] ), 191.0 (17 [SO2-C10H7] ), 127.0 + + (100 [C10H7] ); HiResEI-MS calcd for C18H15NSO2 [M] 309.0823, found, 309.0829.
i-Pr O O S N i-Pr i-Pr
Me
2,4,6 triisopropyl-N-(4-methyl-benzylidene)-benzenesulfonamide (158)
Reaction temperature: 140-170 °C, recrystallization: toluene, yield: 82%, colorless crystals.
1 mp = 167 °C; H NMR (CDCl3, 300 MHz) δ 8.97 (s, 1H), 7.81 (d, 2H, J = 8.1 Hz), 7.29 (d, 2H, J = 8.1 Hz), 7.19 (s, 2H), 4.35 (quint, 2H, J = 6.9 Hz), 2.90 (quint, 1H, J = 13 6.9 Hz), 2.43 (s, 3H), 1.29-1.24 (m, 18H); C NMR (CDCl3, 75 MHz) δ 168.9, 153.8, 151.4, 146.3, 131.4, 131.3, 130.5, 130.2, 124.1, 34.3, 29.8, 24.8, 23.6, 22.0; IR (KBr) ν 2957, 2867, 1594, 1561, 1459, 1423, 1360, 1309, 1255, 1228, 1153, 1038, 875, 819, 795, 765, 752, 666; MS (EI): 384.1 (0.08 [M-H]+).
118 Experimental Part
Me O O Me S N
Me Me Me Me
2,3,4,5,6 pentamethyl-N-(4-methyl-benzylidene)-benzenesulfonamide (159)
Reaction temperature: 170 °C, recrystallization: toluene, yield: 81%, colorless crystals.
1 mp = 170 °C; H NMR (CDCl3, 300 MHz) δ 9.00 (s, 1H), 7.82 (d, 2H, J = 8.1 Hz), 7.29 (d, 2H, J = 8.1 Hz), 2.63 (s, 6H), 2.43 (s, 3H), 2.29 (s, 3H), 2.25 (s, 6H); 13C NMR
(CDCl3, 75 MHz) δ 168.7, 135.8, 135.2, 131.5, 134.0, 130.1, 22.0, 19.4, 17.8, 1.0; IR (KBr) ν 1596, 1560, 1307, 1224, 1152, 1009, 870, 804, 768, 619; MS (EI): 329.1 (0.34 + + [M] ), 147.1 (37 [C11H15] ).
PhO S 2 N
Ph
N-benzylidene-benzenesulfonamid (104)
Reaction temperature: 160-200 °C, recrystallization: toluene, yield: 66%, colorless crystals.
1 mp = 81 °C; H NMR (CDCl3, 200 MHz) δ 9.44 (s, 1H), 8.09-7.84 (m, 4H), 7.72-7.46 (m, 6H). Experimental Part 119
NTs NTs
Ph Ph N O N O Bn Bn 125 126
(±)-(2'R,3R)-1'-[(4-methylphenyl)sulfonyl]-2'-phenyl-1-(phenylmethyl)spiro[indole- 3,3'-pyrrolidin]-2(1H)-one (125)
(±)-(2'R,3S)-1'-[(4-methylphenyl)sulfonyl]-2'-phenyl-1-(phenylmethyl)spiro[indole- 3,3'-pyrrolidin]-2(1H)-one (126)
(General procedure for the formation of 1’-(p-toluene-sulfonyl)-spiro-3,3’-pyrrolidine oxindoles)
A solution of 1-benzyl-spiro-3-cyclopropyl-indole-2-one (99) (100 mg, 401 µmol,
1.00 equiv), MgI2 (11.0 mg, 40.0 µmol, 10.0 mol%) and N-benzylidene-p- toluenesulfonamide (124) (135 mg, 521 µmol, 1.30 equiv) in THF (1 mL) was heated to 60 °C for 8 h. The reaction mixture was allowed to cool to room temperature. EtOAc
(1 mL) was added, followed by H2O (1 mL) and solid Na2S2O3 (a few crystals). The phases were separated; the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with H2O and brine (20 mL each), dried (Na2SO4) and filtered. After removal of the solvent in vacuo, the product was purified by column chromatography (15:85 Æ 3:7 EtOAc/hexanes) to afford a solid residue after evaporation of the solvent. The solid was dissolved in CH2Cl2 (10 mL), washed with 1 M aq NaOH and H2O (10 mL each) in order to remove toluene-4-sulfonamide and afford the product as a colorless solid after drying of the organic layer (Na2SO4), filtration and evaporation of the solvent in vacuo. Yield (both diastereomers): 198 mg (97%).
HPLC retention time: 125 (major): 13.8 min, 126 (minor): 15.2 min (2:8 EtOAc/hexanes), diastereomeric ratio: 91:9.
1 mp = 160-167 ˚C; H NMR (CDCl3, 500 MHz) δ 7.78-7.72 (m, 2H), 7.38-7.33 (m, 2H), 7.27-7.20 (m, 3H), 7.15-6.96 (m, 8H), 6.88-6.80 (m, 2H), 6.49 (d, 1H, J = 7.8 Hz), 4.94 (d, 1H, J = 15.7 Hz), 4.88 (s, 1H), 4.59 (d, 1H, J = 15.7 Hz), 4.20-4.03 (m, 1H), 3.97 13 (ddd, 1H, J = 10.8, 8.6, 4.8 Hz), 2.46 (s, 3H), 2.20-2.03 (m, 2H); C NMR (CDCl3, 120 Experimental Part
125 MHz, * denotes minor diastereomer signals) δ 176.5, 176.0*, 143.9, 143.8*, 142.8*, 142.0, 137.0, 136.5*, 135.3, 135.2*, 135.0*, 133.4, 129.7, 128.9*, 128.8*, 128.7, 128.6, 128.4, 128.3, 128.2, 127.9*, 127.8, 127.6, 127.5, 127.2*, 127.0, 126.7*, 125.3, 122.8*, 122.2, 109.2*, 108.9, 71.7*, 70.5, 60.4*, 59.8*, 59.1, 49.0*, 48.3, 43.7, 43.4*, 35.8*, 34.2, 21.6, 21.0*, 14.2*; IR (KBr) ν 3029, 2922, 2359, 2340, 1709, 1611, 1488, 1467, 1454, 1350, 1164, 1093, 1029, 971, 815, 776, 754, 727, 699, 660, 588, 575, 550; MS + + + (EI): 508.1 (0.76 [M] ), 353.1 (100 [SO2-C7H7] ), 91.0 (47 [C7H7] ); Anal. calcd for
C31H28N2O3S: C 73.20, H 5.55, N 5.51, found: C 73.05, H 5.75, N 5.46. Experimental Part 121
NTs NTs Me Me
N O N O Bn Bn 128 129
(±)-(2'R,3R)-2'-(2-methylphenyl)-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (128)
(±)-(2'R,3S)-2'-(2-methylphenyl)-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (129)
Yield: 89%; HPLC retention time: 128 (major): 15.5 min, 129 (minor): 12.8 min (2:8 EtOAc/hexanes), diastereomeric ratio: 98:2.
1 mp = 204-205 °C; H NMR (C6D6, 500 MHz) δ 7.98-7.96 (m, 2H), 7.69 (dd, 1H, J = 7.8, 0.9 Hz), 7.16-6.94 (m, 9H), 6.73 (d, 1H, J = 7.5 Hz), 6.67 (ddd, 1H, J = 7.7, 7.7, 1.2 Hz), 6.37 (ddd, 1H, J = 7.6, 7.6, 1.0 Hz), 6.23 (d, 1H, J = 7.5 Hz), 5.80-5.78 (m, 1H), 5.44 (s, 1H), 4.58 (d, 1H, J = 15.5 Hz), 4.23 (d, 1H, J = 15.5 Hz), 4.11 (ddd, 1H, J = 10.3, 9.0, 6.7 Hz), 3.85 (ddd, 1H, J = 9.0, 6.0, 2.2 Hz), 1.99 (ddd, 1H, J = 13.0, 10.3, 8.0 Hz), 1.94 13 (s, 3H), 1.66 (ddd, 1H, J = 13.0, 6.7, 2.2 Hz), 1.53 (s, 3H); C NMR (C6D6, 125 MHz) δ 178.1, 143.0, 138.7, 136.5, 136.2, 135.8, 130.2, 129.5, 129.5, 128.9, 128.7, 128.4, 128.1, 127.9, 127.6, 127.5, 127.5, 126.1, 125.4, 121.9, 108.3, 65.1, 57.1, 47.3, 43.2, 34.4, 21.3, 18.8; IR (KBr) ν 1706 (vs), 1608, 1487, 1465, 1341, 1305, 1164, 1094, 1031, 774, + + 751, 671, 658, 588, 552; DEI-MS: 522.3 (0.85 [M] ), 367.2 (100 [M-SO2-C7H7] ), 132.1 + + (55 [N=CMe-C7H7] ), 91.0 (42 [C7H7] ); Anal. calcd for C32H30N2O3S: C 73.54, H 5.79, N 5.36, found: C 73.64, H 5.93, N 5.44. 122 Experimental Part
NTs NTs
N O N O Bn Bn 131 Me 132 Me
(±)-(2'R,3R)-2'-(4-methylphenyl)-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (131)
(±)-(2'R,3S)-2'-(4-methylphenyl)-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (132)
Yield: 96%; HPLC retention time: 131 (major): 15.0 min, 132 (minor): 13.8 min (2:8 EtOAc/hexanes), diastereomeric ratio: 64:36.
1 # mp = 178 °C; H NMR (CDCl3, 500 MHz, denotes major-, * minor diastereomer signals) δ 7.74-7.71 (m, 2H#), 7.76-7.73 (m, 2H*), 7.36-6.61 (m, 4H), 7.25-6.84 (m, 23H), 6.50 (d, 1H#, J = 7.3 Hz), 6.44 (d, 1H*, J = 7.4 Hz), 6.48-6.46 (m, 1H#), 5.00 (s, 1H*), 4.99 (d, 1H*, J = 15.7 Hz), 4.97 (d, 1H#, J = 15.8 Hz), 4.78 (s, 1H#), 4.55 (d, 1H#, J = 15.8 Hz), 4.42 (ddd, 1H*, J = 11.4, 11.4, 5.7 Hz), 4.16 (d, 1H*, J = 15.7 Hz), 4.15-4.04 (m, 1H#, 1H*), 3.93 (ddd, 1H#, J = 10.8, 8.8, 4.6 Hz), 2.48 (s, 3H*), 2.46 (s, 3H#), 2.31 (s, 3H*), 2.24 (s, 3H#), 2.19-2.11 (m, 1H#, 1H*), 2.08-2.02 (m, 1H#), 1.96 13 (ddd, 1H*, J = 12.6, 11.4, 8.22 Hz); C NMR (CDCl3, 125 MHz, * denotes minor diastereomer signals) δ 176.4, 176.1*, 143.9, 143.7*, 142.8*, 142.0, 137.4, 137.3*, 135.3, 135.1*, 135.0*, 133.6, 129.7, 128.9*, 128.7, 128.6, 128.5*, 128.4, 128.4, 128.3, 128.2, 127.8, 127.5, 127.5, 127.2*, 126.9, 126.9, 126.7, 125.4, 122.8*, 122.3, 122.2*, 109.3*, 109.0, 71.6*, 70.5, 59.7*, 59.1, 49.0*, 48.3, 43.6, 43.4*, 35.7*, 34.0, 21.6, 21.6*, 21.3*, 21.2; IR (KBr) ν 1711, 1612, 1597, 1489, 1467, 1459, 1380, 1351, 1164, 1092, 1029, 1019, 816, 751, 733, 709, 698, 660, 591, 584, 572, 550, 542; DEI-MS: 522.0 (2.9 [M]+), + + + 367.0 (100 [M-SO2-C7H7] ), 132.1 (84 [N=CMe-C7H7] ), 91.0 (47 [C7H7] ); Anal. calcd for C32H30N2O3S: C 73.54, H 5.79, N 5.36, found: C 73.43, H 5.95, N 5.48. Experimental Part 123
NTs NTs Br Br
N O N O Bn Bn 134 135
(±)-(2'R,3R)-2'-(2-bromophenyl)-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (134)
(±)-(2'R,3S)-2'-(2-bromophenyl)-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (135)
Yield: 82%; HPLC retention time: 134 (major): 19.7 min, 135 (minor): 16.1 min (2:8 EtOAc/hexanes), diastereomeric ratio: 98:2.
1 mp = 204-205 °C; H NMR (CDCl3, 500 MHz) δ 7.84-7.81 (m, 3H), 7.43-7.19 (m, 9H), 7.12-7.07 (m, 1H), 7.03 (ddd, 1H, J = 7.7, 7.7, 1.1 Hz), 6.62-6.60 (m, 1H), 6.54 (ddd, 1H, J = 7.7, 7.7, 1.1 Hz), 5.74 (ddd, 1H, J = 7.7, 7.7, 1.1 Hz), 5.27 (s, 1H), 4.91 (d, 1H, J = 15.4 Hz), 4.54 (d, 1H, J = 15.4 Hz), 4.04-4.01 (m, 1H), 3.94 (ddd, 1H, J = 11.4, 8.9, 6.2 Hz), 2.47 (s, 3H), 2.38 (ddd, 1H, J = 13.1, 11.4, 7.9 Hz), 2.09 (ddd, 1H, J = 13.1, 6.2, 13 1.3 Hz); C NMR (CDCl3, 125 MHz) δ 178.0, 143.7, 143.2, 139.0, 135.8, 133.4, 132.2, 129.5, 129.2, 128.6, 128.4, 128.4, 127.8, 127.7, 127.2, 126.8, 124.4, 124.3, 121.8, 108.5, 66.8, 56.7, 47.2, 43.5, 34.4, 29.7, 21.7; IR (KBr) ν 1710, 1612, 1489, 1465, 1372, 1354, 1341, 1159, 1091, 1013, 814, 776, 751, 741, 700, 652, 587, 547; DEI-MS: 588.0 + + + (0.3 [M] ), 433.0 (100 [M-SO2-C7H7] ), 91.0 (47 [C7H7] ); Anal. calcd for
C31H27BrN2O3S: C 63.37, H 4.63, N 4.77, found: C 63.23, H 4.88, N 4.84. 124 Experimental Part
NTs NTs
N O N O Bn Bn 137 Br 138 Br
(±)-(2'R,3R)-2'-(4-bromophenyl)-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (137)
(±)-(2'R,3S)-2'-(4-bromophenyl)-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (138)
Yield: 92%; HPLC retention time: 137 (major): 19.7 min, 138 (minor): 16.8 min (2:8 EtOAc/hexanes), diastereomeric ratio: 82:12.
1 # mp = 153-154 °C; H NMR (CDCl3, 500 MHz, denotes major-, * minor diastereomer signals) δ 7.75-7.69 (m, 4H), 7.38-7.35 (m, 4H), 7.27-6.89 (m, 24H), 6.53-6.48 (m, 2H), 5.02 (s, 1H*), 4.96 (d, 1H*, J = 15.9 Hz), 4.96 (d, 1H#, J = 15.7 Hz), 4.75 (s, 1H#), 4.57 (d, 1H#, J = 15.7 Hz), 4.42 (ddd, 1H*, J = 11.5, 11.5, 5.6 Hz), 4.15 (d, 1H*, J = 15.9 Hz), 4.15-4.04 (m, 1H#, 1H*), 3.93 (ddd, 1H#, J = 11.0, 9.0, 3.9 Hz), 2.49 (s, 3H*), 2.47 # 13 (s, 3H ), 2.20-2.12 (m, 2H), 2.04-1.99 (m, 2H); C NMR (CDCl3, 125 MHz, * denotes minor diastereomer signals) δ 178.8*, 175.9, 144.2, 144.1*, 142.8*, 142.9, 135.7*, 135.6, 135.1, 134.9*, 134.8*, 132.8, 131.1, 130.7, 129.8, 129.2, 129.1*, 128.8*, 128.7, 128.2, 127.8*, 127.7, 127.5*, 126.9, 126.7, 125.2, 123.0*, 122.5, 122.2*, 121.9*, 121.8, 109.4*, 109.2, 71.0*, 70.2, 59.7*, 59.2, 49.0*, 48.5, 43.7, 43.5*, 35.8*, 34.0, 21.7; IR (KBr) ν 1710, 1612, 1488, 1466, 1385, 1368, 1351, 1338, 1176, 1160, 1097, 1033, 1010, 808, + + 753, 740, 706, 657, 589, 548; DEI-MS: 588.0 (0.7 [M] ), 433.0 (100 [M-SO2-C7H7] ), + + 196.0 (43 [N=CMe-C7H7] ), 91.0 (45 [C7H7] ); Anal. calcd for C31H27BrN2O3S: C 63.37, H 4.63, N 4.77, found: C 63.42, H 4.83, N 4.66. Experimental Part 125
NTs NTs
N O N O Bn Bn 140 141 CF3 CF3
(±)-(2'R,3R)-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'-[4- (trifluoromethyl)phenyl]spiro[indole-3,3'-pyrrolidin]-2(1H)-one (140)
(±)-(2'R,3S)-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'-[4- (trifluoromethyl)phenyl]spiro[indole-3,3'-pyrrolidin]-2(1H)-one (141)
Yield: 97%; HPLC retention time: 140 (major): 27.6 min, 141 (minor): 21.1 min (2:8 EtOAc/hexanes), diastereomeric ratio: 84:16.
1 # mp = 197 °C; H NMR (CDCl3, 500 MHz, denotes major-, * minor diastereomer signals) δ 7.74-7.71 (m, 4H), 7.39-6.95 (m, 26H), 6.88 (ddd, 1H#, J = 7.6, 7.6, 1.0 Hz), 6.54-6.50 (m, 2H*), 6.53 (d, 1H#, J = 12.9 Hz), 5.09 (s, 1H*), 4.95 (d, 1H#, J = 15.6 Hz), 4.93 (d, 1H*, J = 15.8 Hz), 4.90 (s, 1H#), 4.59 (d, 1H#, J = 15.6 Hz), 4.43 (ddd, 1H*, J = 11.5, 11.5, 5.7 Hz), 4.18 (d, 1H*, J = 15.8 Hz), 4.15-4.06 (m, 1H#, 1H*), 3.97 (ddd, 1H#, J = 11.0, 8.9, 3.9 Hz), 2.47 (s, 3H#), 2.47 (s, 3H*), 2.22-2.13 (m, 2H), 2.06-2.00 (m, 2H); 13 C NMR (CDCl3, 125 MHz, * denotes minor diastereomer signals) δ 175.9, 175.7*, 144.3, 144.2*, 141.9, 142.7*, 140.9, 135.1, 134.8*, 132.8, 130.0*, 129.9, 129.8, 129.6*, 129.2*, 128.8, 128.7, 128.6*, 128.2, 127.9, 127.8, 127.6*, 127.5*, 127.0, 126.6, 125.3*, 125.1, 124.8*, 124.5, 124.5, 124.5*, 122.5, 122.3*, 109.5*, 109.2, 70.9*, 70.2, 59.7*, 59.3, 49.0*, 48.6, 43.8, 43.5*, 36.1*, 34.3, 21.6, 21.6*; IR (KBr) ν 1711, 1615, 1488, 1466, 1375, 1370, 1353, 1340, 1328, 1160, 1112, 1068, 1029, 1016, 836, 810, 751, 744, + + 700, 657, 589, 548; DEI-MS: 576.0 (0.25 [M] ), 421.0 (100 [M-SO2-C7H7] ); Anal. calcd for C32H27F3N2O3S: C 66.65, H 4.72, N 4.86, found: C 66.47, H 4.81, N 4.66. 126 Experimental Part
NTs NTs
N O N O Bn Bn 143 OMe 144 OMe
(±)-(2'R,3R)-2'-[4-(methyloxy)phenyl]-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (143)
(±)-(2'R,3S)-2'-[4-(methyloxy)phenyl]-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (144)
Yield: 75%; HPLC retention time: 143 (major): 20.5 min, 144 (minor): 17.8 min (2:8 EtOAc/hexanes), diastereomeric ratio: 67:33.
1 # mp = 153-155 °C; H NMR (CDCl3, 500 MHz, denotes major-, * minor diastereomer signals) δ 7.75-7.72 (m, 2H*), 7.72-7.69 (m, 2H#), 7.36-7.34 (m, 4H), 7.22-6.87 (m, 22H), 6.66-6.64 (m, 1H*), 6.62-6.60 (m, 1H#), 6.45 (d, 1H#, J = 8.5 Hz), 6.48 (d, 1H*, J = 7.1 Hz), 5.00 (d, 1H*, J = 16.4 Hz), 4.97 (d, 1H#, J = 15.8 Hz), 4.98 (s, 1H*), 4.73 (s, 1H#), 4.53 (d, 1H#, J = 15.8 Hz), 4.44 (ddd, 1H*, J = 11.4, 11.4, 5.7 Hz), 4.16 (d, 1H*, J = 16.4 Hz), 4.12-4.04 (m, 2H), 3.92 (ddd, 1H#, J = 10.7, 9.0, 4.5 Hz), 3.75 (s, 3H*), 3.72 (s, 3H#), 2.48 (s, 3H*), 2.46 (s, 3H#), 2.21-2.13 (m, 2H), # 13 2.09-2.02 (m, 1H ), 2.01-1.93 (m, 1H*); C NMR (CDCl3, 125 MHz, * denotes minor diastereomer signals) δ 176.3, 176.2*, 159.3*, 159.2, 143.9, 143.7*, 142.8*, 142.0, 135.2, 135.2*, 135.0*, 133.2, 129.7, 129.7*, 128.9, 128.9*, 128.7, 128.6*, 128.5, 128.5*, 128.5*, 128.4, 128.2, 128.2*, 127.8, 127.8*, 127.5, 127.3*, 126.9, 126.7*, 125.3, 122.8*, 122.3, 122.3*, 113.3*, 113.0, 109.2*, 109.0, 71.4*, 70.3, 59.8*, 59.2, 55.1, 55.0*, 49.0*, 48.0, 43.6, 43.3*, 35.5*, 33.7, 21.6, 21.6*; IR (KBr) ν 1708, 1514, 1493, 1360, 1350, 1249, 1176, 1160, 1092, 1023, 824, 757, 699, 668, 659, 575, 543; DEI-MS: 538.1 + + + + (23 [M] ), 383.1 (100 [M-SO2-C7H7] ), 148.1 (89 [N=CMe-C7H7] ), 91.0 (42 [C7H7] );
Anal. calcd for C32H30N2O4S: C 71.35, H 5.61, N 5.20, found: C 71.24, H 5.74, N 5.18.
Experimental Part 127
NTs NTs
N O O N O O Bn Bn 146 147
(±)-(2'S,3R)-2'-furan-2-yl-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (146)
(±)-(2'S,3S)-2'-furan-2-yl-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (147)
Yield: 97%; HPLC retention time: 146 (major): 15.2 min, 147 (minor): 12.8 min (2:8 EtOAc/hexanes), diastereomeric ratio: 89:11.
1 mp = 161-162 °C; H NMR (CDCl3, 500 MHz) δ 7.75-7.72 (m, 2H), 7.33-7.07 (m, 9H), 6.84 (ddd, 1H, J = 7.6 Hz, 7.6 Hz, 1.0 Hz), 6.70-6.68 (m, 1H), 6.61 (d, 1H, J = 7.5 Hz), 6.21-6.19 (m, 1H), 6.16-6.15 (m, 1H), 4.98 (s, 1H), 4.94 (d, 1H, J = 15.7 Hz), 4.69 (d, 1H, J = 15.7 Hz), 3.95-3.92 (m, 2H), 2.44 (s, 3H), 2.35-2.28 (m, 1H) 2.18-2.11 13 (m, 1H); C NMR (CDCl3, 125 MHz) δ 176.6, 151.2, 143.6, 142.3, 141.8, 135.5, 134.3, 129.6, 128.8, 128.6, 127.9, 127.6, 127.1, 124.4, 122.5, 110.4, 109.2, 108.9, 63.2, 57.5, 47.3, 43.6, 34.5, 21.6; IR (KBr) ν 1706, 1614, 1600, 1489, 1466, 1459, 1450, 1369, 1353, 1340, 1311, 1221, 1176, 1161, 1098, 1081, 1037, 1009, 831, 815, 756, 744, 699, 661, + + 601, 588, 547, 532, 473; DEI-MS: 498.1 (4.5 [M] ), 343.1 (44 [M-SO2-C7H7] ), 108.1 + + (100 [N=CMe-C7H7] ), 91.0 (44 [C7H7] ); Anal. calcd for C29H26N2O4S: C 69.86, H 5.26, N 5.62, found: C 69.88, H 5.37, N 5.68. 128 Experimental Part
NTs NTs
N O N O Bn Ph Bn Ph 149 150
(±)-(2'R,3R)-1'-[(4-methylphenyl)sulfonyl]-2'-[(E)-2-phenylethenyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (149)
(±)-(2'R,3S)-1'-[(4-methylphenyl)sulfonyl]-2'-[(E)-2-phenylethenyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (150)
Yield: 62%; HPLC retention time: 149 (major): 17.6 min, 150 (minor): 15.1 min (2:8 EtOAc/hexanes), diastereomeric ratio: 74:16.
1 # mp = 182 °C; H NMR (CDCl3, 500 MHz, denotes major-, * minor diastereomer signals) δ 7.77-7.74 (m, 2H#), 7.75-7.72 (m, 2H*), 7.60-7.58 (m, 1H#), 7.36-7.33 (m, 2H#), 7.26-6.94 (m, 23H), 6.86-6.82 (m, 2H*), 6.82-6.78 (m, 2H#), 6.56-6.53 (m, 1H*), 6.55 (dd, 1H#, J = 7.7, 1.0 Hz), 6.41 (d, 1H#, J = 16.0 Hz), 6.17 (d, 1H*, J = 16.0 Hz), 6.03 (dd, 1H*, J = 16.0, 8.7 Hz), 5.82 (dd, 1H#, J = 16.0, 8.9 Hz), 5.16 (d, 1H#, J = 16.0 Hz), 5.12 (d, 1H*, J = 17.0 Hz), 4.54 (d, 1H*, J = 8.7 Hz), 4.47 (d, 1H*, J = 17.0 Hz), 4.41 (d, 1H#, J = 16.0 Hz), 4.17 (ddd, 1H*, J = 16.7, 9.9, 6.5 Hz), 4.09-3.99 (m, 2H), 4.03 (dd, 1H#, J = 8.9, 0.7 Hz), 3.67 (ddd, 1H#, J = 13.8, 10.5, 3.3 Hz), 2.46 (s, 3H#), 2.39 (s, 3H*), 2.35-2.29 (m, 2H), 2.18 (ddd, 1H*, J = 12.8, 9.9, 8.3 Hz), 2.02 # 13 (ddd, 1H , J = 11.3, 8.0, 3.3 Hz); C NMR (CDCl3, 125 MHz, * denotes minor diastereomer signals) δ 176.3*, 175.5, 144.1, 143.4*, 142.6*, 141.9, 136.0, 135.9*, 135.1*, 134.7, 133.0, 133.3*, 132.6, 129.8, 129.6, 129.5*, 129.4*,128.8*, 128.7, 128.6, 128.6*, 128.5, 128.4*, 128.1, 127.9, 127.9*, 127.7*, 127.4*, 127.3, 126.9, 126.8*, 126.8*, 126.5, 125.4, 125.1*, 124.5, 123.1, 123.0*, 109.6, 109.3*, 72.5*, 69.9, 58.8, 58.6*, 48.0, 43.9, 43.5*, 35.2*, 33.0, 21.6, 21.5*; IR (KBr) ν 1709, 1613, 1494, 1481, 1467, 1452, 1375, 1352, 1362, 1341, 1327, 1173, 1163, 1153, 1106, 1098, 1085, 979, 971, 749, 738, 697, 664, 610, 584, 547; DEI-MS: 534.1 (40 [M]+), 379.1 + + + (49 [M-SO2-C7H7] ), 144.1 (100 [N=CMe-CH=CH-C6H5] ), 91.0 (42 [C7H7] ); Anal. calcd for C33H30N2O3S: C 74.13, H 5.66, N 5.24, found: C 74.09, H 5.83, N 5.17. Experimental Part 129
NTs NTs Me Me N O N O Bn Ph Bn Ph 152 153
(±)-(2'R,3R)-2'-[(E)-1-methyl-2-phenylethenyl]-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (152)
(±)-(2'R,3S)-2'-[(E)-1-methyl-2-phenylethenyl]-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (153)
Yield: 55%; HPLC retention time: 152 (major): 15.3 min, 153 (minor): 11.6 min (2:8 EtOAc/hexanes), diastereomeric ratio: 52:48.
1 # mp = 143 °C; H NMR (CDCl3, 500 MHz, denotes major-, * minor diastereomer signals) δ 7.86 (d, 2H#, J = 8.2 Hz), 7.83-7.80 (m, 2H*), 7.41-6.93 (m, 29H), 6.79 (d, 1H#, J = 7.5 Hz), 6.71 (d, 1H*, J = 7.7 Hz), 6.67 (d, 1H#, J = 7.7 Hz), 5.06 (d, 1H#, J = 15.6 Hz), 5.03 (d, 1H*, J = 15.2 Hz), 4.62 (d, 1H*, J = 15.2 Hz), 4.52 (d, 1H#, J = 15.6 Hz), 4.50 (s, 1H#), 4.46 (s, 1H#), 4.19-4.11 (m, 1H#), 4.01-3.87 (m, 3H), 2.47 (s, 3H#), 2.45 (s, 3H*), 2.41-2.35 (m, 1H#), 2.10-1.81 (m, 1H#, 2H*), 1.78 (s, 3H#), 1.44 13 (s, 3H*); C NMR (CDCl3, 125 MHz, * denotes minor diastereomer signals) δ 176.9*, 175.6, 144.0*, 143.7, 142.3*, 142.2, 137.1, 137.1*, 135.5*, 135.4, 135.0, 135.0*, 129.8, 129.7*, 129.4, 129.2 , 128.8, 128.7, 128.6*, 128.2, 128.2*, 128.0, 127.9*, 127.8, 127.8*, 127.7, 127.6*, 127.5, 127.3*, 127.1, 127.0*, 126.5*, 126.4, 125.4, 125.3*, 123.4*, 122.9, 122.4, 122.3*, 109.3, 109.0*, 77.2, 75.0*, 63.9*, 58.5, 48.7*, 48.6, 44.0, 43.8*, 35.5*, 35.4, 21.7, 21.6*, 16.6*, 15.8; IR (KBr) ν 1711, 1611, 1597, 1489, 1466, 1455, 1349, 1164, 1093, 1029, 1015, 750, 731, 698, 667.9, 667.5, 588, 581, 550; DEI-MS: 548.1 + + + (2.7 [M] ), 393.1 (26 [M-SO2-C7H7] ), 158.1 (100 [N=CMe-CMe=CH-C6H5] ), 91.0 + (100 [C7H7] ); Anal. calcd for C34H32N2O3S: C 74.43, H 5.88, N 5.11, found: C 74.43, H 6.04, N 4.99. 130 Experimental Part
NTs NTs
N O N O Bn TIPS Bn TIPS 155 156
(±)-(2'S,3R)-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'-{[tris(1- methylethyl)silyl]ethynyl}spiro[indole-3,3'-pyrrolidin]-2(1H)-one (155)
(±)-(2'S,3S)-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'-{[tris(1- methylethyl)silyl]ethynyl}spiro[indole-3,3'-pyrrolidin]-2(1H)-one (156)
Yield: 77%; HPLC retention time: 155 (major): 7.8 min, 156 (minor): 15.6 min (15:85 EtOAc/hexanes), diastereomeric ratio: 98:2.
1 mp = 133-137 ˚C; H NMR (CDCl3, 300 MHz) δ 7.90-7.84 (m, 2H), 7.49-7.44 (m, 1H), 7.39-7.21 (m, 7H), 7.17 (ddd, 1H, J = 1.2, 7.8, 7.8 Hz), 7.03 (ddd, 1H, J = 0.9, 7.5, 7.5 Hz), 6.72 (d, 1H, J = 7.5 Hz), 4.93 (d, 1H, J = 15.6 Hz), 4.78 (d, 1H, J = 15.9 Hz), 4.49 (s, 1H), 3.90-3.70 (m, 2H), 2.46 (s, 3H), 2.20 (ddd, 1H, J = 9.0, 9.0, 12.5 Hz), 2.02 13 (ddd, 1H, J = 4.0, 7.2 Hz, 12.6 Hz) 0.90-0.80 (m, 21H); C NMR (CDCl3, 75 MHz) δ 175.7, 144.0, 142.3, 135.6, 134.1, 129.9, 128.9, 128.7, 128.0, 127.8, 127.3, 125.0, 123.1, 109.2, 100.6, 89.5, 58.3, 57.8, 47.6, 44.0, 34.3, 21.5, 18.2, 10.8; IR (KBr) ν 2947.1, 2863.5, 2360.2, 2343.0, 1717.0, 1611.9, 1487.5, 1466.7, 1366.8, 1352.2, 1167.1, 1092.9, 816.0, 747.7, 698.1, 681.3, 661.7, 573.3, 548.3; DEI-MS: 612.3 + + + + (2.6 [M] ), 569.3 (79 [M-iPr] ), 457.3 (100 [M-SO2-C7H7] ), 91.0 (94 [C7H7] ); Anal. calcd for C36H44N2O3SSi: C 70.55, H 7.24, N 4.57, found: C 70.53, H 7.35, N 4.76. Experimental Part 131
O O O O S S N N
+ N O N O Bn Bn 160 Me 161 Me
(±)-(2'R,3R)-2'-(4-methylphenyl)-1'-(naphthalen-2-ylsulfonyl)-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (160)
(±)-(2'R,3S)-2'-(4-methylphenyl)-1'-(naphthalen-2-ylsulfonyl)-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (161)
Yield: 83%; HPLC retention time: 160 (major): 25.4 min, 161 (minor): 23.9 min (15:85 EtOAc/hexanes), diastereomeric ratio: 89:11.
1 mp = 181°C; H NMR (CDCl3, 300 MHz) δ 8.33 (d, 2H, J = 1.5 Hz), 8.16 (d, 2H, J = 8.7 Hz), 7.95-7.93 (m, 2H), 7.85 (dd, 1H, J = 8.4 Hz, 1.9 Hz), 7.69-7.58 (m, 2H), 7.22- 6.82 (m, 12H), 6.47 (d, 1H, J = 7.5 Hz), 4.95 (d, 1H, J = 16.4 Hz), 4.90 (s, 1H), 4.52 (d, 1H, J = 16.4 Hz), 4.14-4.05 (m, 2H), 2.22 (s, 3H), 2.21-2.08 (m, 2H); 13C NMR
(CDCl3, 125 MHz) δ 176.4, 142.1, 137.5, 136.8, 135.3, 135.1, 133.7, 133.5, 129.6, 129.3, 129.2, 128.8, 128.6, 128.4, 128.0, 127.7, 127.5, 127.4, 126.9, 125.4, 123.4, 122.2, 109.0, 70.5, 59.0, 48.2, 43.6, 33.9, 21.2; IR (KBr) ν 1711, 1612, 1488, 1469, 1455, 1348, 1241, 1164, 1132, 1075, 1020, 969, 864, 817, 794, 750, 698, 657, 618, 580, 568, 547, 477; + + DEI-MS: 558.2 (3.5 [M] ), 367.2 (100 [M-SO2-C10H7] ); Anal. calcd for C35H30N2O3S: C 75.24, H 5.41, N 5.01, found: C 74.99, H 5.58, N 5.02. 132 Experimental Part
O
N O Bn CF3
2'-(4-trifluoromethylphenyl)-1-(phenylmethyl)spiro[indole-3,3'-oxolane]-2(1H)-one (163)
A solution of MgI2 (12.0 mg, 43.0 µmol, 10 mol%), oxindole 99 (107 mg, 429 µmol, 1.00 equiv) and 4-trifluoromethyl-benzaldehyde (165) (75 µL, 563 µmol, 1.31 equiv) in THF (2 mL) was placed into a sealed tube and heated to 100 °C for 20 h. The reaction mixture was allowed to cool to room temperature before being diluted with EtOAc
(2 mL) and quenched with H2O (2 mL) and a few crystals of Na2S2O3. The phases were separated and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine and H2O (30 mL each), dried (NaSO4), filtered, concentrated and purified by chromatography (95:5Æ2:8 EtOAc/hexanes) to afford a single diastereomer of desired 163 (34.0 mg, 19%) as a colorless solid.
1 mp = 156 °C; H NMR (CDCl3, 200 MHz) δ 7.47-7.43 (m, 3H), 7.29-7.08 (m, 7H), 6.59-6.55 (m, 3H), 5.25 (s, 1H), 5.02 (d, 1H, J = 15.4 Hz), 4.79 (ddd, 1H, J = 7.9, 7.9, 7.9), 4.43 (ddd, 1H, J = 7.9, 7.9, 5.8 Hz), 4.22 (d, 1H, J = 15.4 Hz), 2.71-2.63 (m, 2H); 13 C NMR (CDCl3, 75 MHz) δ 177.0, 143.6, 140.7, 135.4, 129.0, 128.8, 127.7, 126.9, 126.9, 126.2, 125.2, 125.2, 125.1, 123.1, 122.7, 109.6, 88.2, 68.6, 59.0, 43.7, 38.0; IR (KBr) ν 1707, 1610, 1490, 1470, 1368, 1322, 1174, 1159, 1123, 1109, 1066, 1016, 760, + + + 668; DEI-MS: 423.1 (12, [M] ), 249.1 (100 [M–CH(CH3)-p-CF3Ph] ), 91.0 (70 [C7H7] );
Anal. calcd for C25H20F3NO2: C 70.91, H 4.76, N 3.31, found: C 70.99, H 4.77, N 3.45. Experimental Part 133
O OEt
p-TolO S 2 N H N O Bn ethyl {[(4-methylphenyl)sulfonyl]amino}[2'-oxo-1'-(phenylmethyl)-1',2'-dihydro spiro[cyclopropane-1,3'-indol]-5'-yl]acetate (167)
To a solution of ethyl glyoxylate (164) (1.55 g, 15.2 mmol, 1.00 equiv), in toluene (15 mL) was added p-toluenesulfonyl isocyanate (2.31 mL, 15.2 mmol, 1.00 equiv). The reaction mixture was heated to reflux for 3 d and then cooled to room temperature before being concentrated to give sulfonimide 165 which was used without further purification.
A solution of MgI2 (6.00 mg, 21.8 µmol, 7.6 mol%), oxindole (99) (72.0 mg, 288 µmol, 1.00 equiv) and sulfonimide 165 (149 mg, 0.584 mmol, 2.00 equiv) in THF (1 mL) was heated to reflux for 18 h. The reaction mixture was allowed to cool to room temperature before being diluted with EtOAc (1 mL) and quenched with H2O (1 mL) as well as a few crystals of Na2S2O3. The phases were separated and the aqueous layer was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed with brine and H2O
(20 mL each), dried (NaSO4), filtered, concentrated and purified by chromatography (2:8
Æ 3:7 EtOAc/hexanes). The residue was dissolved in CH2Cl2 (10 mL), washed with 1 M aq NaOH and H2O (10 mL each) in order to remove toluene-4-sulfonamid and afforded pure 167 (42.0 mg, 29%) after drying of the organic layer (Na2SO4) and evaporation of the solvent in vacuo.
1 mp = 176 °C; H NMR (CDCl3, 200 MHz) δ 7.54-7.50 (m, 2H), 7.36-7.27 (m, 5H), 7.10-7.02 (m, 3H), 6.70 (d, 1H, J = 7.9), 6.59-6.58 (m, 1H), 5.60 (d, 1H, J = 7.5 Hz), 5.02 (d, 1H, J = 15.4 Hz), 4.98 (d, 1H, J = 7.5 Hz), 4.90 (d, 1H, J = 15.4 Hz), 4.15-3.87 (m, 2H), 2.33 (s, 3H), 1.78-1.76 (m, 2H), 1.52-1.37 (m, 2H), 1.10 (t, 3H, J = 7.1 Hz); 13 C NMR (CDCl3, 75 MHz) δ 177.0, 170.0, 143.3, 142.9, 137.1, 136.0, 131.5, 129.3, 129.2, 128.8, 127.7, 127.5, 127.1, 126.3, 117.1, 108.8, 62.3, 59.3, 44.2, 27.0, 21.4, 19.6, 19.6, 13.8; IR (KBr) ν 1742, 1709,1684, 1627, 1499, 1448, 1383, 1332, 1189, 1165, 1091, 1030, 1010, 712, 668, 560, 551; DEI-MS 504.2 (20 [M]+), 431.2 (100 134 Experimental Part
+ + [M−CO2Et] ), 91.0 (40 [C7H7] ); Anal. calcd for C28H28N2O5S: C 66.65, H 5.59, N 5.55, found: C 66.55, H 5.70, N 5.48.
Crystal data for 167 at 293(2) K, Mr = 504.58, monoclinic space group P2(1)c, ρcalc = 1.283 mg·cm–3, Z = 4, a = 11.985(11), b = 13.454(7), c = 16.70(2) Å, α = 90.00, β = 104.00(8), γ = 90.00°, V = 2613(4) Å3. Final R(F) = 0.0681, wR(F2) = 0.1540 for 335 parameters and 2600 reflections with I >2σ(I) and 1.75 < θ < 20.03°.
CCDC 199468 (167) contains the supplementary crystallographic data for this structure. This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]).
O
Ph2N
Ph N SO2Ph
N,N-1,2-tetraphenylpyrrolidine-3-carboxamide (170)
To MgI2 (88.0 mg, 320 µmol, 1.00 equiv), N,N-diphenyl-cyclopropane carboxamide (169) (75.0 mg, 320 µmol, 1.00 equiv) and N-benzylidene-p-toluenesulfonamide (104) (101 mg, 410 µmol, 1.30 equiv) was added a degassed solution (by passing a stream of Ar trough the solution) of DMA (29.5 µL, 320 µmol, 1.00 equiv) in m-xylene (1 mL). The reaction mixture was heated to 145 °C for 48 h, then allowed to cool to room temperature before being diluted with EtOAc (1 mL) and quenched with H2O (1 mL) as well as a few crystals of Na2S2O3. The phases were separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine and water (20 mL each), dried (NaSO4), filtered, concentrated and purified by column chromatography (1:3 EtOAc/hexanes) to afford 170 (both diastereomers).
Both residues from chromatography were dissolved in CH2Cl2 (10 mL), washed with 1 M aq NaOH and H2O (10 mL each) n order to remove benzene-sulfonamide and afforded Experimental Part 135
pure 170 (both diastereomers) (84.0 mg, 54%) after drying of the organic layer (Na2SO4) and evaporation of the solvent in vacuo.
Diastereomer 1: colorless oil, yield: 51.0 mg (33%).
1 H NMR (CDCl3, 300 MHz) δ 7.83-7.79 (m, 2H), 7.61-7.48 (m, 4H), 7.32-7.16 (m, 12H), 7.08-6.98 (m, 1H), 6.72-6.62 (m, 1H), 4.92 (d, 1H, J = 8.1 Hz), 3.78 (ddd, 1H, J = 11.0, 6.2, 5.0 Hz), 4.43 (ddd, 1H, J = 11.0, 11.0, 8.1 Hz), 3.07 (q, 1H, J = 8.1 Hz), 1.90-1.82 13 (m, 2H); C NMR (CDCl3, 75 MHz) δ 171.4, 141.3, 137.7, 133.0, 129.3, 128.8, 127.9, 126.7, 111.2, 68.4, 53.3, 49.8, 29.3; IR (KBr) ν 1738, 1669, 1594, 1490, 1447, 1377, + 1347, 1263, 1163, 1098, 761, 722, 692, 599; FAB-MS calcd for C29H26N2O3S [M+H] 483.1743, found, 483.1746.
Diastereomer 2: colorless solid, yield: 33.0 mg (21%).
1 mp = 189 °C; H NMR (CDCl3, 200 MHz) δ 7.53-7.45 (m, 4H), 7.37-7.06 (m, 14H), 6.57-6.53 (m, 2H), 4.67 (d, 1H, J = 8.3 Hz), 3.86-3.77 (m, 1H), 3.56-3.33 (m, 2H), 2.70 13 (ddd, 1H, J = 13.3, 9.5, 8.3 Hz), 2.06-1.96 (m, 1H); C NMR (CDCl3, 75 MHz) δ 169.6, 143.0, 139.0, 132.2, 130.0, 128.8, 128.8, 128.6, 128.2, 128.2, 127.1, 126.1, 110.5, 64.4, 47.8, 47.7, 27.4; IR (KBr) ν 1674, 1493, 1444, 1347, 1308, 1177, 1163, 1099, 1075,
1052, 1018, 757, 717, 710, 697, 689, 668, 602, 572; FAB-HRMS calcd for C29H26N2O3S [M+H]+ 483.1743, found, 483.1737.
I
N O Bn
1-benzyl-3-(2-iodo-ethyl)-1,3-dihydro-indol-2-one (175)
1 H NMR (CDCl3, 300 MHz) δ 7.35-7.24 (m, 6H), 7.19 (dt, 1H, J = 7.8, 1.2 Hz), 7.03 (dt, 1H, J = 7.8, 1.2 Hz), 6.74 (d, 1H, J = 7.8 Hz), 3.66 (dd, 1H, J = 6.5, 6.5 Hz), 3.49 (ddd, 1H, J = 10.0, 8.4, 6.9, Hz), 3.35 (ddd, 1H, J = 10.0, 8.4, 6.9, Hz), 2.51-2.38 + (m, 2H); HiResMALDI-MS calcd for C17H16NOI [M+H] 378.0355, found, 378.0345. 136 Experimental Part
4. Synthesis of (±)-Horsfiline by MgI2-Catalyzed Ring- Expansion Reaction of Spiro-Cyclopropyl-Oxindole and 1,3,5- Trimethyl-1,3,5-Triazinane
NMe
N O Bn
1'-methyl-1-(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (207)
A 10 mL sealable tube was charged with 1-benzyl-spiro-3-cyclopropyl-indole-2-one (99)
(100 mg, 400 µmol, 1.00 equiv) and anhydrous MgI2 (5.60 mg, 20.0 µmol, 5 mol%). The tube was sealed, evacuated and back-filled with argon. 1,3,5-Trimethylhexahydro-1,3,5- triazine (206) (56.0 µL, 400 µmol, 1.00 equiv) and THF (0.5 mL) were added and the tube sealed, before it was submerged in a preheated oil bath at 125 ºC. The reaction mixture turned pale-orange, and, after a few minutes, a colorless solid was observed to precipitate. After 20 h the reaction mixture was allowed to cool to room temperature and was then further cooled in an ice bath. H2O (1 mL), a crystal of Na2S2O3, and EtOAc (2 mL) were added whereupon more of the precipitate formed. The reaction mixture was extracted with EtOAc (2 × 20 mL), the layers were separated and the combined organic layers washed with brine, dried (Na2SO4),filtered, and concentrated in vacuo. Purification of the yellow oil by column chromatography on silica gel (4:1 EtOAc/acetone) afforded 207 (116 mg, 97%) as colorless oil of.
1 H NMR (CDCl3, 300 MHz) δ 7.46-7.43 (m, 1H), 7.35-7.17 (m, 5H), 7.17-7.12 (m, 1H), 7.06-7.01 (m, 1H), 6.72-6.69 (m, 1H), 4.92 (s, 2H), 3.14-3.07 (m, 1H), 2.93 (d, 1H, J = 9.0 Hz), 2.88 (d, 1H, J = 9.0 Hz), 2.82-2.73 (m, 1H), 2.48 (s, 3H), 2.47-2.39 (m, 1H), 13 2.17-2.08 (m, 1H); C NMR (CDCl3, 75 MHz) δ 180.4, 42.0, 135.9, 135.1, 128.8, 127.6, 127.2, 123.2, 123.0, 108.8, 66.7, 56.5, 53.2, 43.8, 41.7, 38.1; IR (KBr) ν 2944, 2836, 2789, 1707, 1603, 1496, 1456, 1436, 1359, 1346, 1303, 1282, 1176, 1030, 807, 739, 697, 668; DEI-MS: 324.1(29.9 [M+2H]+), 323.1(100.0 [M+H]+), 322.1(26.3 [M]+); Anal. calcd for C20H22N2O2: C 74.51, H 6.88, N 8.69, found: C 74.36, H 6.62, N 8.45. Experimental Part 137
MeO O
N O Bn
1-benzyl-5-methoxy-isatin (210)
5-Methoxyisatin (194) (1.00 g, 5.65 mmol, 1.00 equiv) was placed in a 2-neck flask and DMF (10 mL) was added. NaH (95%, 142 mg, 5.92 mmol, 1.05 equiv) was added portionwise to the brown solution which changed color to dark-blue. After the H2 evolution had stopped, benzyl bromide (771 µL, 6.49 mmol, 1.15 equiv) was added dropwise. The color changed back to brown-red. After stirring for 1 h at room temperature, H2O (30 mL) was added and a red sticky solid was observed to precipitate. The aqueous layer was extracted with EtOAc (8 × 40 mL), the combined organic layers were dried (Na2SO4) and filtered. The solvent was evaporated in vacuo. The remaining DMF was removed under high vacuum at 60 ºC. The red solid was purified by column chromatography on silica gel (2:1 hexane/EtOAc) and 194 (140 mg) and 210 (red solid, 1.11 g, 74%) were obtained.
1 mp = 117-118 °C; H NMR (CDCl3, 300 MHz) δ 7.37-7.31 (m, 5H), 7.16 (d, 1H, J = 2.8 Hz), 7.03 (dd, 1H, J = 8.4, 2.8 Hz), 6.68 (d, 1H, J = 8.4 Hz), 4.91 (s, 2H), 3.78 13 (s, 3H); C NMR (CDCl3, 75 MHz) δ 183.8, 158.5, 156.6, 144.6, 134.6, 129.1, 128.1, 127.4, 124.7, 118.1, 112.0, 109.6, 56.0, 44.1; IR (KBr) ν 1723, 1621, 1602, 1494, 1472, 1437, 1349, 1336, 1313, 1271, 1238, 1175, 1145, 1080, 1047, 1018, 836, 773, 695, 473; DEI-MS 269.1 (30.4, [M+2H]+), 268.1(100.0, [M+H]+), 267.0 (32.7, [M]+); Anal. calcd for C16H13NO3: C 71.90, H 4.90, N 5.24, found: C 71.84, H 5.09, N 5.25.
MeO
N O Bn
1-benzyl-5-methoxy-1,2-dihydro-indol-2-one (211)
1-Benzyl-5-methoxy-isatin (210) (702 mg, 2.63 mmol) was dissolved in hydrazine hydrate (5 mL) and the solution heated to reflux. After 45 min, the reaction mixture was 138 Experimental Part
allowed to cool to room temperature and a green-yellow oil separated. The reaction mixture was diluted with water (40 mL) and extracted with Et2O (30 mL). The organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. Product 211 (647 mg, 97%) was obtained as yellow oil and used without further purification. An analytically pure sample could be obtained by chromatography on silica gel (1:3 EtOAc/hexane).
1 H NMR (CDCl3, 300 MHz) δ 7.33-7.25 (m, 5H), 6.90-6.89 (m, 1H), 6.72-6.68 (m, 1H), 13 6.62-6.59 (m, 1H), 4.90 (s, 2H), 3.76 (s, 3H), 3.61 (s, 2H); C NMR (CDCl3, 75 MHz) δ 175.0, 156.0, 136.1, 128.8, 127.7, 127.4, 125.9, 112.2, 112.0, 109.4, 55.7, 43.7, 36.0; IR (KBr) ν 1708, 1602, 1494, 1454, 1436, 1359, 1345, 1289, 1220, 1180, 1142, 1037, 806, + 746, 705, 676, 621; HRMS-MS calcd for C16H15NO2 [M+H] 253.1103, found, 253.1104.
MeO
N O Bn
1-benzyl-3-cyclopropyl-5-methoxy -1,2-dihydro-indol-2-one (212)
An ethereal solution of 211 (402 mg, 1.59 mmol, 1.00 equiv) was concentrated in a 2-neck flask and dried under high vacuum. After the addition of DMF (2 mL) and 1,2-dibromoethane (0.150 mL, 1.70 mmol, 1.07 equiv) the reaction mixture was cooled to 0 ºC. NaH (95.0%, 114 mg, 5.75 mmol, 3.61 equiv) was added portionwise and the color of the reaction mixture turned from yellow to auburn upon addition. After 3 h, H2O (40 L) was added and the aqueous layer extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with H2O (4 × 20 mL) and brine (20 mL), dried
(Na2SO4), filtered, and the solvent was evaporated in vacuo. An auburn oil was obtained which was purified by chromatography on silica gel (1:9 Æ 1:8 EtOAc/hexane) yielding 358 mg (81%) of 212 as colorless crystals.
1 mp = 112-113 °C; H NMR (CDCl3, 300 MHz) δ 7.34-7.24 (m, 5H), 6.67 (m, 2H), 6.47-6.46 (m, 1H), 4.98 (s, 2H), 3.75 (s, 3H), 1.84-1.80 (m, 2H), 1.55-1.51 (m, 2H); 13 C NMR (CDCl3, 75 MHz) δ 177.1, 156.0, 136.4, 132.4, 128.8, 127.6, 127.4, 111.1, Experimental Part 139
111.0, 109.3, 106.1, 55.8, 44.1, 27.3, 19.4. IR (KBr) ν 3060, 3037, 3009, 2916, 2838, 1692, 1602, 1491, 1475, 1454, 1438, 1382, 1350, 1334, 1286, 1239, 1077, 1056, 1031, 1003, 954, 892, 882, 806, 745, 732, 698, 652, 596, 558, 458; DEI-MS 281.1 + + + (23.6 [M+2H] ), 280.1 (71.3 [M+H] ), 279.1 (100.0 [M] ); Anal. calcd for C18H17NO2: C 77.40, H 6.13, N 5.01, found: C 77.31, H 6.30, N 4.96.
MeO NMe
N O Bn
1'-methyl-5-(methyloxy)-1-(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (213)
A 10 mL sealable tube was charged with 212 (50.0 mg, 180 µmol, 1.00 equiv) and anhydrous MgI2 (2.50 mg, 9.00 µmol, 5 mol%). The tube was closed, evacuated and back-filled with argon. 1,3,5-trimethylhexahydro-1,3,5-triazine (26.0 µL, 180 µmol, 1.00 equiv) and THF (0.3 mL) were added and the tube sealed, before it was submerged in a preheated oil bath at 125 ºC. The reaction mixture turned pale-orange, and, after a few minutes, a colorless solid was observed to precipitate. After 60 h the reaction mixture was allowed to cool to room temperature and was then further cooled in an ice bath. H2O
(1 mL), a crystal of Na2S2O3, and EtOAc (2 mL) were added, whereupon more of the precipitate formed. The reaction mixture was extracted with EtOAc (3 × 10 mL), the layers were separated and the combined organic layers washed with brine (10 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. Purification of the yellow oil by chromatography on silica gel (4:1 EtOAc/acetone) afforded 213 (48.0 mg, 83%) as colorless oil.
1 H NMR (CDCl3, 300 MHz) δ 7.34-7.22 (m, 5H), 7.10 (d, 1H, J = 2.5 Hz), 6.67 (dd, 1H, J = 8.4, 2.5 Hz), 7.10 (d, 1H, J = 8.4 Hz), 4.89 (s, 2H), 3.77 (s, 3H), 3.14-3.07 (m, 1H), 2.96 (d, 1H, J = 9.3 Hz), 2.88 (d, 1H, J = 9.3 Hz), 2.81-2.72 (m, 1H), 2.49 (s, 3H), 13 2.47-2.39 (m, 1H), 2.18-2.08 (m, 1H); C NMR (CDCl3, 75 MHz) δ 180.3, 156.5, 138.9, 136.2, 135.5, 128.8, 127.6, 127.3, 112.1, 110.4, 109.1, 66.4, 56.6, 55.8, 53.7, 43.8, 41.8, 140 Experimental Part
38.1; IR (KBr) ν 2944, 2836, 2789, 1707, 1603, 1496, 1456, 1436, 1359, 1346, 1303, 1282, 1176, 1030, 807, 739, 697, 668; DEI-MS: 324.1 (29.9 [M+2H]+), 323.1 + + (100.0 [M+H] ), 322.1 (26.3 [M] ); Anal. calcd for C20H22N2O2: C 74.51, H 6.88, N 8.69, found: C 74.36, H 6.62, N 8.45.
MeO NMe
N O H
(±)-Horsfiline ((±)-16)
Ammonia (5 mL) was condensed at –78 °C and Na was added with vigorous stirring at −42 ºC until the blue color persisted. A solution of Spiro-pyrrolidine-oxindole 213
(32.0 mg, 100 µmol) in THF (0.5 mL) was added. After 13 min H2O (25 mL) and a small amount of NH4Cl were added. The pH of the reaction mixture was adjusted to pH 11 with
6 N aq HCl. The mixture was extracted with CH2Cl2 (6 × 20 mL) and washed with brine
(20 mL). The combined organic layers were dried (Na2SO4) and the solvent evaporated in vacuo. Recrystallization from n-hexane yielded (±)-horsfiline ((±)-16) (21.0 mg, 91%) as a colorless solid.
1 mp = 151 °C; H NMR (CDCl3, 300 MHz) δ 8.9 (br, 1H), 7.02 (d, 1H, J = 2.5 Hz), 6.82 (d, 1H, J = 8.3 Hz), 6.72 (dd, 1H, J = 8.3, 2.5 Hz), 3.79 (s, 3H), 3.04-2.97 (m, 1H), 2.89 (d,1H, J = 9.3 Hz), 2.84 (d, 1H, J = 9.3 Hz), 2.81-2.73 (m, 1H), 2.46 (s, 3H), 2.43-2.37 13 (m, 1H), 2.13-2.04 (m, 1H); C NMR (CDCl3, 75 MHz) δ 183.3, 156.3, 137.8, 133.7, 112.4, 110.3, 110.0, 66.3, 56.7, 55.8, 54.1, 41.7, 37.9; IR (KBr) ν 3173, 2785, 1702, 1638, 1619, 1602, 1480, 1442, 1319, 1279, 1258, 1229, 1210, 1183, 1161, 1138, 1058, 1036, 907, 883, 791, 681, 668, 641; DEI-MS 234.1 (20.4 [M+2H]+), 233.1 + + (100.0 [M+H] ), 232.1 (24.0 [M] ); Anal. calcd for C13H16N2O2: C 67.22, H 6.94, N 12.06, found: C 67.37, H 6.94, N 11.86. Experimental Part 141
5. Synthesis of (–)-Spirotryprostatin B Employing the MgI2- Catalyzed Ring-Expansion Reaction
O S O O Me
4-methyl-[1,3,2]dioxathiolane 2-oxide (280)
1,2-Propane diol (279) (10.0 g, 131 mmol, 1.00 equiv) was dissolved in CH2Cl2 (30 mL) and the solution was cooled to 0 °C. A solution of SOCl2 (11.8 mL, 162 mmol,
1.24 equiv) in CH2Cl2 (20 mL) was added via addition funnel over 1 h. The reaction mixture was then heated to reflux for 1 h and allowed to cool to room temperature. H2O (50 mL) was added to the reaction mixture, the layers were separated and the organic layer was washed with H2O (2 × 50 mL) and brine (30 mL), dried (Na2SO4), filtered, then the solvent was evaporated in vacuo and a colorless liquid was obtained. The unpurified sulfite 280 was used for the next step.
1 # Rf = 0.48; H NMR (CDCl3, 200 MHz, denotes major-, * minor diastereomer signals) δ 5.19-5.06 (m, 1#H),4.73 (dd, 1H#, J = 8.1, 5.8 Hz), 4.74-4.49 (m, 2H*), 4.32 (dd, 1H*, J = 9.1, 8.3 Hz), 3.90 (dd, 1H#, J = 8.1, 7.1 Hz), 1.63 (d, 3H*, J = 6.2 Hz), 1.45 (d, 3H#, J = 6.3 Hz).
O O S O O Me
4-methyl-[1,3,2]dioxathiolane 2,2-dioxide (281)
Sulfite 280 (8.00 g, 65.5 mmol, 1.00 equiv) was dissolved in CH3CN/CCl4 (1:1)
(400 mL). The solution was cooled to 0 °C. Precooled H2O (280 mL) was added to the mixture. Solid NaIO4 (27.2 g, 131 mmol, 2.00 equiv) and RuCl3·3H2O (68.0 mg, 142 Experimental Part
330 µmol, 0.5 mol%) were added in one portion. The reaction mixture was vigorously stirred for 1 h. The phases were separated and the aqueous layer was extracted with Et2O
(300 mL). The combined organic layers were dried (Na2SO4), filtered, and the solvent was evaporated in vacuo. Column chromatography (1:1 EtOAc/hexanes) afforded 281 (8.34 g, 92%) as colorless liquid.
1 Rf = 0.32; H NMR (CDCl3, 200 MHz,) δ 5.24-5.07 (m, 1H), 4.76 (dd, 1H, J = 8.7, 5.8 Hz), 4.34 (dd, 1H, J = 8.7, 8.7 Hz), 1.63 (d, 3H, J = 6.2 Hz).
Me
N O Bn
(±)-(1S,2S)-2-methyl-1'-(phenylmethyl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one (282)
Cyclic sulfate 281 (68.1 mg, 490 µmol, 1.10 equiv) was dissolved in DME (1.5 mL). NaH (95%, 54.0 mg, 1.34 mmol, 3.00 equiv) was added and to the resulting suspension, a solution of oxindole 98 (100 mg, 450 µmol, 1.00 equiv) in DME (1 mL) was slowly added. The reaction mixture was stirred at room temperature for 16 h and was then quenched by addition of H2O (1 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were dried
(Na2SO4), filtered, and the solvent was evaporated in vacuo. Column chromatography (1:19 EtOAc/hexanes) afforded 282 (64.0 mg, 54%) as a colorless oil.
1 Rf = 0.49 (1:3 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 7.33-7.25 (m, 5H), 7.12 (ddd, 1H, J = 7.8, 6.9, 2.2 Hz), 7.03-6.96 (m, 2H), 6.83-6.80 (m, 1H), 4.99 (s, 2H), 13 2.08-1.98 (m, 2H), 1.37 (d, 3H, J = 6.2 Hz), 1.37-1.33 (m, 1H); C NMR (CDCl3, 75 MHz) δ 177.3, 143.4, 136.3, 128.7, 128.4, 127.5, 127.4, 126.4, 121.5, 120.8, 109.0, 44.1, 32.0, 27.6, 26.0, 13.3; IR (KBr) ν 3055, 3004, 2984, 2924, 1705, 1613, 1487, 1466, 1453, 1431, 1396, 1386, 1370, 1352, 1186, 1103, 1034, 986, 870, 758, 735, 697; DEI-MS 263.2 + + (60 [M] ), 91.0 (100 [C7H7] ); Anal. calcd for C18H17NO: C 82.10, H 6.51, N 5.32, found: C 81.93, H 6.64, N 5.30. Experimental Part 143
Me Me
NTs NTs + O O N O N O Bn Bn 285 286
(±)-(3R,5'R)-5'-methyl-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'H- spiro[indole-3,3'-pyrrolidine]-2,2'(1H)-dione (285)
(±)-(3S,5'R)-5'-methyl-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'H- spiro[indole-3,3'-pyrrolidine]-2,2'(1H)-dione (286)
A sealable tube was charged with spiro-cyclopropyl-oxindole 282 (885 mg, 340 µmol,
1.00 equiv) and MgI2 (23.0 mg, 84.0 µmol, 25 mol%). p-Tosylisocyanate (56.3 µL, 380 µmol, 1.10 equiv) was added followed by THF (0.3 mL). The tube was sealed and heated to 100 °C for 3 d. The reaction mixture was allowed to cool to room temperature and
EtOAc (1 mL) was added, followed by H2O (1 mL) as well as solid Na2S2O3 (a crystal). The phases were separated and the aqueous layer was extracted with EtOAc (3 × 20 mL).
The combined organic layers were washed with H2O and brine (20 mL each), dried
(Na2SO4) and filtered. After removal of the solvent in vacuo, the product was purified by radial chromatography (3:17 EtOAc/hexanes) to afford the two diastereomers 285 and 286, (combined yield: 74 mg (48%)) together with unreacted 282 (45.1 mg, 51%)
Minor diastereomer 285: colorless crystals; yield: 31.0 mg (20%).
1 Rf = 0.25 (1:3 EtOAc/hexanes); mp = 162 °C; H NMR (CDCl3, 300 MHz) δ 7.98-7.93 (m, 2H), 7.35-6.99 (m, 10H), 6.68-6.64 (m, 1H), 4.83 (d, 1H, J = 15.7 Hz), 4.71 (d, 1H, J = 15.7 Hz), 2.88 (dd, 1H, J = 13.7, 7.5 Hz), 2.47-2.40 (m, 1H), 2.40 (s, 3H), 2.10 13 (dd, 2H, J = 13.0, 7.1 Hz), 1.80 (d, 3H, J = 6.2 Hz); C NMR (CDCl3, 75 MHz) δ 173.7, 169.5, 145.3, 143.1, 135.6, 134.9, 129.7, 129.5, 129.2, 128.8, 128.3, 127.7, 127.0, 123.6, 123.4, 109.8, 58.5, 54.4, 44.1, 36.9, 22.8, 21.7; IR (KBr) ν 1739, 1704, 1609, 1487, 1467, 1365, 1328, 1211, 1176, 1119, 1077, 752, 704, 668, 577, 547; DEI-MS 460.1 (8.4 [M]+), + 91.0 (100 [C7H7] ); Anal. calcd for C18H17NO: C 67.81, H 5.25, N 6.08, found: C 67.96, H 5.36, N 5.96. 144 Experimental Part
Crystal data for 285 at 293(2) K, Mr = 460.53, triclinic space group P-1, ρcalc = 1.361 mg·cm–3, Z = 2, a = 9.750(10), b = 10.807(12), c = 12.172(10) Å, α = 103.37(8), β = 95.24(8), γ = 113.10(8)°, V = 1124(2) Å3. Final R(F) = 0.0355, wR(F2) = 0.1044 for 301 parameters and 2279 reflections with I >2σ(I) and 1.76 < θ < 20.04°.
CCDC 199469 (285) contains the supplementary crystallographic data for this structure. This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]).
Major diastereomer 286: colorless crystals, yield: 43.0 mg (29%).
1 Rf = 0.23 (1:3 EtOAc/hexanes); mp = 171-173 °C; H NMR (CDCl3, 300 MHz) δ 7.99-7.95 (m, 2H), 7.35-6.95 (m, 10H), 6.67 (d, 1H, J = 7.9 Hz), 4.97 (d, 1H, J = 15.7 Hz), 4.83-4.72 (m, 1H), 4.79 (d, 1H, J = 15.7 Hz), 2.67 (dd, 1H, J = 13.3, 7.9 Hz), 13 2.42 (dd, 1H, J = 12.5, 5.0 Hz), 2.44 (s, 3H), 1.79 (d, 3H, J = 6.2 Hz); C NMR (CDCl3, 75 MHz) δ 173.8, 169.6, 145.1, 143.6, 135.0, 129.5, 129.3, 128.9, 128.8, 127.7, 127.3, 127.0, 127.0, 123.6, 123.3, 109.6, 58.3, 54.7, 43.9, 37.8, 23.9, 21.7; IR (KBr) ν 1737, 1700, 1612, 1461, 1468, 1342, 1203, 1188, 1167, 1127, 1080, 755, 668, 576, 547; + + DEI-MS 460.1 (10.4 [M] ), 91.0 (100 [C7H7] ); Anal. calcd for C18H17NO: C 67.81, H 5.25, N 6.08, found: C 67.95, H 5.29, N 5.92.
Crystal data for 286 at 293(2) K, Mr = 460.53, triclinic space group P-1, ρcalc = 1.295 mg·cm–3, Z = 4, a = 10.155(8), b = 14.690(14), c = 17.70(2) Å, α = 113.53(7), β = 101.53(7), γ = 90.01(7)°, V = 2362(4) Å3. Final R(F) = 0.0386, wR(F2) = 0.0879 for 599 parameters and 3228 reflections with I >2σ(I) and 2.79 < θ < 42.49°.
CCDC 199470 (286) contains the supplementary crystallographic data for this structure. This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]).
Experimental Part 145
N2
N O Bn
1-benzyl-3-diazo-1,3-dihydro-indol-2-one (289)
1-Benzyl-isatin (97) (1.00 g, 4.22 mmol, 1.00 equiv) was suspended in MeOH (20 mL). The suspension was heated to 60 °C, whereupon a deep-red solution was obtained. To this hot solution was added tosylhydrazine (793 mg, 4.26 mmol, 1.01 equiv) in one portion. A yellow product starts precipitating from the hot mixture. The reaction mixture was stirred at 60 °C for 18 h, and then allowed to reach room temperature. The intermediate tosylhydrazone (1.37 g, 80%) was collected by filtration and was used without further purification.
A solution of the tosylhydrazone (1.00 g, 2.47 mmol, 1.00 equiv) in THF (10 mL) was treated with a solution of NaOH (197 mg, 4.93 mmol, 2.00 equiv) in H2O (25 mL). The reaction mixture was stirred for 3 h at room temperature. EtOAc (20 mL) was added to the reaction mixture and the layers were separated The aqueous layer was ajusted to pH 7 by addition of dry-ice, and extracted with EtOAc (30 mL). The combined organic layers were dried (Na2SO4), filtered, and the solvent was evaporated in vacuo. Column chromatography (3:17 EtOAc/hexanes) afforded 289 (451 mg, 73%) as deep-orange crystals.
1 Rf = 0.55 (1:3 EtOAc/hexanes); mp = 89 °C; H NMR (300 MHz, CDCl3) δ 7.32-7.20 (m, 13 6H), 7.12-7.04 (m, 2H), 6.84-6.82 (m, 1H), 5.03 (s, 1H). C NMR (75 MHz, CDCl3) δ 136.0, 133.7, 128.8, 127.7, 127.3, 125.5, 122.2, 118.3, 116.8, 109.6, 44.3; IR (thin film) ν 2130, 1668, 1610, 1589, 1481, 14.68, 1404, 1383, 1342, 1178, 1168, 1103, 740, 697, + + + 681, 668, 636; DEI-MS 249.0 (13.5 [M] ), 193.0 (35 [M-N2-CO] ), 91.0 (100 [C7H7] );
Anal. calcd for C15H11N3O: C 72.28, H 4.45, N 16.86, found: C 72.31, H 4.57, N 16.78. 146 Experimental Part
O MeO OMe
2-methoxy-acrylic acid methyl ester (288)
NaOMe (14.5 g, 231 mmol, 3.00 equiv) was dissolved in MeOH (120 mL) and the solution was cooled to 0 °C. To this solution, 2,3 dibromo-propionic acid ethyl ester was added slowly by addition funnel. The reaction mixture was allowed to stir at room temperature for 6 d. Then the mixture was quenched and ajusted to pH 7 by addition of dry-ice. The resulting white precipitate was removed by filtration; the filtrate was diluted with CH2Cl2 (100 mL) and washed with H2O (2 × 120 mL). The organic layer was dried over Na2SO4, filtered, and the solvent was evaporated in vacuo. The remaining product was purified by distillation under reduced pressure (30 mbar) to give 288 (4.20 g, 36%) as a colorless liquid.
1 bp = 50 °C (30 mbar); H NMR (300 MHz, CDCl3) δ 5.38 (d, 1H, J = 2.9 Hz), 4.65 (d, 1H, J = 2.9 Hz), 3.84 (s, 3H), 3.68 (s, 3H).
CO Me MeO 2
N O Bn methyl 2-(methyloxy)-2'-oxo-1'-(phenylmethyl)-1',2'-dihydrospiro[cyclopropane- 1,3'-indole]-2-carboxylate (290)
In a 50 mL two-neck flask equipped with a reflux condenser and a CaCl2 drying tube was placed [Rh(OAc)2]2 (4.42 mg, 10.0 µmol, 2 mol%). Benzene (2 mL) and acrylate 288 (291 mg, 2.51 mmol, 5.00 equiv) were added and the mixture was heated to reflux. A solution of diazo-oxindole 289 (125 mg, 500 µmol, 1.00 equiv) in benzene (2 mL) was added to the refluxing mixture by syringe pump over a period of 5 h. The reaction mixture was allowed to reach room temperature and was then filtered over Celite eluting with benzene. Evaporation of the solvent yielded an orange oil. The product was purified by column chromatography (1:4 EtOAc/hexanes) to afford 290 (two diastereomers) (150 mg, 89%). Experimental Part 147
Diastereomer 1: colorless oil, yield: 34.5 mg (20%).
1 Rf = 0.26 (1:3 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 7.33-7.23 (m, 5H), 7.20-7.11 (m, 2H), 7.00 (dt, 1H, J = 7.5, 0.9 Hz), 6.77 (d, 1H, J = 7.8 Hz), 4.99 (d, 1H, J = 15.9 Hz), 4.90 (d, 1H, J = 15.9 Hz), 3.84 (s, 3H), 3.47 (s, 3H), 2.59 (d, 2H, J = 13 6.2 Hz), 2.02 (d, 2H, J = 6.2 Hz); C NMR (CDCl3, 75 MHz) δ 186.9, 164.1, 140.8, 133.6, 126.4, 125.3, 125.3, 124.9, 123.0, 120.1, 119.8, 106.7, 55.6, 50.1, 41.5, 35.7, 23.2, 11.7; IR (KBr) ν 2948, 1743, 1710, 1616, 1489, 1468, 1378, 1348, 1277, 1234, 1190, 1134, 1014, 750, 697; FAB-MS 338.0 (100 [M]+).
Diastereomer 2: colorless solid, yield: 116 mg (69%).
1 Rf = 0.20 (1:3 EtOAc/hexanes); mp = 76 °C; H NMR (CDCl3, 300 MHz) δ 7.33-7.26 (m, 5H), 7.18-7.13 (m, 2H), 6.95 (dt, 1H, J = 7.6, 1.2 Hz), 6.77 (d, 1H, J = 7.9 Hz), 5.08 (d, 1H, J = 16.1 Hz), 4.90 (d, 1H, J = 16.1 Hz), 3.76 (s, 3H), 3.53 (s, 3H), 2.54 (d, 2H, J = 13 6.2 Hz), 2.51 (d, 2H, J = 6.2 Hz); C NMR (CDCl3, 75 MHz) δ 172.0, 168.4, 143.6, 136.3, 129.0, 127.9, 127.8, 127.6, 125.5, 122.6, 122.1, 109.0, 58.8, 52.8, 44.4, 39.3, 25.4; IR (KBr) ν 1718, 1702, 1610, 1559, 1540, 1488, 1467, 1457, 1437, 1368, 1295, 1203, 1167, 1108, 1040, 751, 736; MS (MaldiTOF) 338.4 (100 [M]+).
EtO2C
CO2Et
N O Bn meso-diethyl 2'-oxo-1'-(phenylmethyl)-1',2'-dihydrospiro[cyclopropane-1,3'-indole]- 2,3-dicarboxylate (294)
A solution of diethyl fumarate (293) (62.0 mg, 361 µmol, 1.00 equiv) and diazo-oxindole 289 (108 mg, 433 µmol, 1.20 equiv) in toluene (0.5 mL) was heated to reflux for 3 d. The solvent was evaporated in vacuo and the residue was purified by column chromatography (1:4 EtOAc/hexanes) to afford 294 (118 mg, 83%) as a white solid. 148 Experimental Part
1 Rf = 0.37; H NMR (300 MHz, CDCl3) δ 7.38-7.26 (m, 6H), 7.22-7.16 (m, 1H), 7.00 (dt, 1H, J = 7.5, 0.9 Hz), 6.78 (d, 1H, J = 8.1 Hz), 5.06 (d, 1H, J = 15.6 Hz), 4.86 (d, 1H, J = 15.6 Hz), 4.27-4.09 (m, 4H), 3.33 (s, 2H), 1.28-1.21 (m, 6H); HiResMALDI-MS + calcd for C23H23NO5 [M+Na] 416.1474, found, 416.1466.
NC
N O Bn
2'-oxo-1'-(phenylmethyl)-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-carbonitrile (296)
A mixture of diazo-oxindole 289 (108 mg, 660 µmol, 1.00 equiv) and Pd(OAc)2 (1.42 mg, 6.60 µmol, 1 mol%) in acrylonitrile (295) (16.5 mL) was heated to reflux for 16 h. The solvent was evaporated in vacuo and the residue was purified by column chromatography (1:4 EtOAc/hexanes) to afford the 296 (two diastereomers) (160 mg, 80%).
Diastereomer 1: 85.0 mg (47%).
1 Rf = 0.35; H NMR (300 MHz, CDCl3) δ 7.38-7.24 (m, 6H), 7.25-7.19 (m, 1H), 7.17 (dt, 1H, J = 7.3, 0.9 Hz), 6.88 (d, 1H, J = 7.6 Hz), 5.01 (d, 1H, J = 15.3 Hz), 4.96 (d, 1H, J = 15.3 Hz), 2.52 (dd, 1H, J = 6.8, 5.0 Hz), 2.21 (dd, 1H, J = 6.8, 3.4 Hz), 1.94 (dd, 1H, J = 5.0, 3.4 Hz).
Diastereomer 2: 75.0 mg (41%).
1 Rf = 0.18; H NMR (300 MHz, CDCl3) δ 7.37-7.25 (m, 5H), 7.23 (dt, 1H, J = 7.4, 0.9 Hz), 7.22 (dt, 1H, J = 7.3, 0.8 Hz), 6.86-6.80 (m, 2H), 5.07 (d, 1H, J = 15.8 Hz), 4.98 (d, 1H, J = 15.8 Hz), 2.35 (dd, 1H, J = 6.1, 5.0 Hz), 2.26 (dd, 1H, J = 5.0, 3.3 Hz), 2.02 (dd, 1H, J = 6.1, 3.3 Hz).
Experimental Part 149
OH HO OTBS
1-(tert-butyl-dimethyl-silanyloxy)-propane-1,2-diol (298)
Allyl alcohol (297) (1.00 mL, 15.0 mmol, 1.00 equiv) was dissolved in DMF (7 mL), and the solution was cooled to 0 °C. Imidazole (1.30 g, 19.0 mmol, 1.30 equiv) was added followed by TBSCl (2.88 g, 19.0 mmol, 1.30 equiv). The reaction mixture was allowed to stir for 15 min, and was quenched by addition of H2O (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 40 mL). The combined organic layers were dried (Na2SO4), filtered, and the solvent was carefully removed to afford TBS-protected allyl alcohol.
Rf = 0.73; (1:1 EtOAc/hexanes).
To a solution of K2OsO4 (17.3 mg, 47.0 µmol, 0.3 mol%) and NMO·H2O (2.15 g, 15.9 mmol, 1.06 equiv) in a mixture of H2O/acetone/tBuOH (6:15:2, 11.5 mL) was slowly added the protected allylalcohol. The reaction mixture was stirred at room temperature for 16 h, then quenched by addition of 10% aq Na2SO4. The mixture is filtered though
Celite (eluting with CH2Cl2) and the layers of the filtrate were separated. The aqueous layer was extracted with EtOAc (2 × 15 mL) and the combined organic layers were dried
(Na2SO4) and filtered. Column chromatography (EtOAc) afforded 298 (1.86 g, 60%).
1 Rf = 0.40; H NMR (200 MHz, CDCl3) δ 3.75-3.65 (m, 5H), 2.56 (d, 1H, J = 4.6 Hz), 2.10 (d, 1H, J = 5.0 Hz), 0.93-0.91 (m, 9H), 0.10-0.09 (m, 6H).
O O S O O OTBS tert-butyl-(2,2-dioxo-2λ6-[1,3,2] dioxathiolan-4-ylmethoxy)-dimethyl-silane (299)
A solution of protected glycerol 298 (1.86 g, 9.01 mmol, 1.00 equiv) and NEt3 (4.99 mL,
36.0 mmol, 4.00 equiv) in CH2Cl2 (27 mL) was cooled to 0 °C. A solution of SOCl2
(0.98 mL, 13.5 mmol, 1.50 equiv) in CH2Cl2 (2.25 mL) was added dropwise. The 150 Experimental Part
reaction mixture was then stirred at 0 °C for 1 h and diluted with Et2O (50 mL). H2O (50 mL) was added to the reaction mixture, and the layers were separated. The organic layer was washed with H2O (2 × 50 mL) and brine (30 mL), dried (Na2SO4) and the solvent was evaporated in vacuo. The compound was filtered through a plug of silica gel eluting with 1:1 EtOAc/hexanes and a yellow oil was obtained.
A solution of the intermediate sulfite in CH3CN/CCl4 (1:1, 54 mL) was cooled to 0 °C.
Precooled H2O (40 mL) was added to the mixture. Solid NaIO4 (3.85 g, 18.0 mmol,
2.00 equiv) and RuCl3·3H2O (9.30 mg, 45.0 µmol, 0.5 mol%) were added in one portion. The reaction mixture was vigorously stirred for 1 h. The phases were separated and the aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic phases were dried (Na2SO4), filtered, and the solvent was evaporated in vacuo. Column chromatography (1:3 EtOAc/hexanes) afforded 299 (1.38 g, 57%) as colorless liquid.
1 Rf = 0.46 (1:3 EtOAc/hexanes); H NMR (CDCl3, 200 MHz) δ 4.98-4.89 (m, 1H), 4.75-4.61 (m, 2H), 3.94-3.91 (m, 2H), 0.92-0.89 (m, 9H), 0.12-0.11 (m, 6H).
OTBS
N O Bn
2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1'- (phenylmethyl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one (300)
Cyclic sulfate 299 (1.38 g, 5.14 mmol, 1.00 equiv) was dissolved in DME (20 mL) and NaH (95%, 375 mg, 15.6 mmol, 3.00 equiv) was added. A solution of oxindole 98 (1.16 g, 5.21 mmol, 1.01 equiv) in DME (10 mL) was slowly added to the suspension. The reaction mixture was stirred at room temperature for 16 h and was then quenched by addition of MeOH (3 mL), followed by H2O (30 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic phases were dried (Na2SO4), filtered, and the solvent was evaporated in vacuo. Experimental Part 151
Column chromatography (1:19 EtOAc/hexanes) afforded 300 (two diastereomers) (876 mg, 43%) along with unreacted oxindole 98 (146 mg, 13%).
Diastereomer 1: colorless oil, yield: 35.0 mg (2%).
1 Rf = 0.50 (1:3 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 7.33-7.24 (m, 5H), 7.13 (dt, 1H, J = 7.9, 1.6 Hz), 6.99 (dt, 1H, J = 6.1, 0.8 Hz), 6.83 (dd, 1H, J = 7.1, 0.8 Hz), 6.76 (d, 1H, J = 7.5 Hz), 5.06 (d, 1H, J = 15.8 Hz), 4.92 (d, 1H, J = 15.8 Hz), 4.16-4.13 (m, 2H), 2.25-2.18 (m, 1H), 1.86-1.76 (m, 1H), 0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H).
Diastereomer 2: colorless oil, yield: 841 mg (41%).
1 Rf = 0.42 (1:3 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 7.32-7.24 (m, 5H), 7.19-7.11 (m, 1H), 7.07-6.94 (m, 2H), 6.79 (d, 1H, J = 7.9 Hz), 5.07 (d, 1H, J = 15.8 Hz), 4.92 (d, 1H, J = 15.8 Hz), 4.01 (dd, 1H, J = 11.2, 5.4 Hz), 3.88 (dd, 1H, J = 11.2, 7.1 Hz), 2.32-2.21 (m, 1H), 2.05-1.95 (m, 1H), 1.64-1.55 (m, 1H), 0.81 (s, 9H), 0.03 (s, 3H), -0.02 (s, 3H).
OH
N O Bn
2-(hydroxymethyl)-1'-(phenylmethyl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one (301)
Spiro-cyclopropyl-oxindole 300 (diastereomer 2) (654 mg, 1.66 mmol, 1.00 equiv), was dissolved in THF (1 mL) and a solution of Bu4NF (1 M in THF, 4.89 mL, 4.99 mmol, 3.00 equiv) was added. The reaction mixture was stirred for 30 min at room temperature, diluted with EtOAc (15 mL) and H2O (5 mL) was added. The layers were separated and the organic layer was washed with brine (2 × 10 mL). The combined organic phases were dried (Na2SO4), filtered, and the solvent was evaporated in vacuo. Column chromatography (2:1 EtOAc/hexanes) afforded 301 (445 mg, 96%) as a colorless solid. 152 Experimental Part
1 Rf = 0.80 (1:1 EtOAc/hexanes); mp = 119 °C; H NMR (CDCl3, 300 MHz) δ 7.33-7.27 (m, 5H), 7.25-7.14 (m, 1H), 7.09-6.96 (m, 2H), 6.85-6.82 (m, 1H), 5.04 (d, 1H, J = 15.8 Hz), 4.96 (d, 1H, J = 15.8 Hz), 4.15-4.06 (m, 1H), 3.87 (dd, 1H, J = 12.5, 8.7 Hz), 2.46-2.30 (m, 1H), 2.02 (dd, 1H, J = 9.1, 4.6 Hz), 1.58 (dd, 1H, J = 7.5, 4.2 Hz); 13 C NMR (CDCl3, 75 MHz) δ 176.4, 143.3, 136.1, 128.8, 127.6, 127.3, 127.1, 122.1, 120.4, 109.4, 61.0, 44.2, 34.4, 31.0, 22.3; IR (KBr) ν 3407, 3026, 2916, 1687, 1612, 1490, 1467, 1451, 1432, 1391, 1356, 1305, 1193, 1152, 1124, 1102, 1054, 1032, 1017, + + 964, 757, 751, 736, 695, 668; DEI-MS 279.1 (43 [M] ), 235.1 (59 [M-CH2=CHOH] ), + 91.0 (100 [C7H7] ); Anal. calcd for C18H17NO2: C 77.40, H 6.13, N 5.01, found: C 77.46, H 6.10, N 5.00.
Me
N O Bn
1'-(phenylmethyl)-2-[1-prop-1-en-1-yl]spiro[cyclopropane-1,3'-indol]-2'(1'H)-one (303)
In a 3-neck flask equipped with a reflux condenser and an addition funnel was placed
[Rh(OAc)2]2 (7.2 mg, 16 µmol, 5 mol%). Benzene (5 mL) and piperylene (302) (mixture of isomers, 162 µL, 1.62 mmol, 5.00 equiv) were added and the suspension was heated to reflux. A solution of 289 (81.0 mg, 325 µmol, 1.00 equiv) in benzene (5 mL) was added over 4 h by syringe pump. The reaction mixture was allowed to cool to room temperature and filtered over Celite. The filter cake was washed with benzene. The filtrate was concentrated in vacuo and purified by column chromatography (1:7 EtOAc/hexanes) to afford 303 (mixture of isomeric products) (85.0 mg, 90%).
Fraction 1: colorless oil, yield: 8.0 mg (8%).
1 # Rf = 0.61 (1:3 EtOAc/hexanes); H NMR (CDCl3, 300 MHz, two isomers, denotes major-, * minor isomer signals) δ 7.31-7.21 (m, 10H), 7.19-7.09 (m, 2H), 7.06-6.94 Experimental Part 153
(m, 2H), 6.95-6.80 (m, 2H), 6.79-6.72 (m, 2H), 5.98-5.83 (m, 2H), 5.77-5.62 (m, 2H), 5.05-4.86 (m, 4H) 2.71 (dd, 1H*, J = 6.4, 6.4 Hz), 2.52 (dd, 1H#, J = 6.1, 6.1 Hz), 1.73 (d, 3H#, J = 5.2 Hz), 1.67 (d, 3H*, J = 5.3 Hz).
Fraction 2: colorless oil, yield: 77.0 mg (82%).
1 Rf = 0.52 (1:3 EtOAc/hexanes); H NMR (CDCl3, 300 MHz, one isomer) δ 7.32-7.22 (m, 5H), 7.14 (dt, 1H, J = 1.6, 7.5 Hz), 7.02-6.90 (m, 2H), 6.80 (d, 1H, J = 7.8 Hz), 5.80 (ddd, 1H, J = 15.2, 6.5, 0.9 Hz), 5.53-5.45 (m, 1H) 5.02 (d, 1H, J = 15.9 Hz), 4.95 (d, 1H, J = 15.9 Hz), 2.70-2.62 (m, 1H), 2.09 (dd, 1H, J = 9.0, 4.7 Hz), 1.74-1.71 (m, 3H), 1.65 (dd, 1H, J = 7.6, 4.7 Hz).
Me
NTs
Ph N O Bn
1'-[(4-methylphenyl)sulfonyl]-2'-phenyl-1-(phenylmethyl)-5'-[1-prop-1-en-1- yl]spiro[indole-3,3'-pyrrolidin]-2(1H)-one (304)
A sealable tube with side inlet was charged with MgI2 (2.0 mg, 7.3 µmol, 20 mol%), imine 124 (12.2 mg, 47.0 µmol, 1.30 equiv) and cyclopropane 303 (10.5 mg, 36.0 µmol, 1.00 equiv). THF (0.1 mL) was added by syringe. The tube was sealed, placed into an oil bath at 80 °C and heated for 14 h. The reaction mixture was allowed to reach room temperature. EtOAc (4 mL) and H2O (5 mL) were added to the reaction mixture, followed by Na2S2O3 (small crystal). This biphasic mixture was stirred for 1 h, then the phases were separated and the organic phase was washed with brine (10 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. The products could only be partially separated by column chromatography (3:17 EtOAc/hexanes) and one major fraction was obtained which could be identified as the desired product of the ring expansion 314 (mixture of isomers) (9.3mg, 47%). 154 Experimental Part
1 Rf = 0.32 (1:3 EtOAc/hexanes); H NMR (CDCl3, 300 MHz, mixture of isomers, only the major one is described) δ 7.62-6.87 (m, 16H), 6.62-6.48 (m, 2H), 5.84-5.64 (m, 2H), 5.22-5.14 (m, 1H), 5.06-4.70 (m, 1H), 4.71 (d, 1H, J = 11.2 Hz), 4.24 (d, 1H, J = 11.2 Hz), 2.42 (s, 3H), 2.33-2.20 (m, 2H), 1.72-1.69 (m, 3H).
N
Me Me allyl-(3-methyl-but-2-enylidene)-amine (305)
Allyl amine (1.56 mL, 20.9 mmol, 1.00 equiv) was cooled to 0 °C and prenal (231) (2.00 mL, 20.9 mmol, 1.00 equiv) was slowly added. KOH (powdered, 200 mg) was added to the mixture. Stirring was continued for 2 h. The mixture was filtered, and the filtrate was Kugelrohr distilled (at 30 mbar) to give desired imine 305 (875mg, 34%) as colorless liquid.
1 H NMR (200 MHz, CDCl3) δ 8.20 (dt, 1H, J = 9.6, 1.3 Hz), 6.09-5.92 (m, 2H), 5.24-5.09 (m, 2H), 4.12-4.09 (m, 2H), 1.94 (s, 3H), 1.90 (s, 3H).
N
Me Me OMe allyl-(3-methoxy-3-methyl-butylidene)-amine (306)
A solution of oxalyl chloride (3.78 mL, 43.1 mmol, 1.10 equiv) in CH2Cl2 (100 mL) was cooled to –60 °C. A solution of DMSO (6.10 mL, 86.0 mmol, 2.20 equiv) in CH2Cl2 (20 mL) was slowly added and stirring was continued till the gas evolution had stopped.
A solution of 3-methoxy-3-methyl-butanol (5.00 mL, 39.1 mmol, 1.00 equiv) in CH2Cl2
(40 mL) was added and a white suspension formed. NEt3 (27.0 mL, 196 mmol, 5.00 equiv) was added and the mixture was stirred for 15 min at –60 °C and was then Experimental Part 155
allowed to reach room temperature. H2O (150 mL) was introduced. The organic layer was separated, washed with 1 M aq HCl (200 ml), sat. aq NaHCO3 (200 mL) and brine
(200 mL), dried over Na2SO4, filtered, concentrated in vacuo and distilled under reduced pressure (bp (10 mbar) = 55 °C) to yield the corresponding aldehyde (1.88 g, 41%).
To a solution of the intermediate aldehyde (520 mg, 4.48 mmol, 1.00 equiv) and allyl amine (335 µL, 4.48 mmol, 1.00 equiv) in CH2Cl2 (6 mL) was added MgSO4 (20 mg). The reaction mixture was allowed to stir at room temperature for 12 h, filtration and evaporation of the solvent afforded imine 306 (612 mg, 88%) as colorless oil which was used without further purification.
1 H NMR (300 MHz, CDCl3) δ 7.78-7.70 (m, 1H), 6.07-5.91 (m, 2H), 5.21-5.08 (m, 2H), 4.15-4.01 (m, 2H), 3.22 (s, 3H), 2.51-2.23 (m, 2H), 1.12 (s, 6H).
O
TIPS triisopropylsilanyl-propynal (308)
A solution of triisopropylsilanyl-acetylene (307) (15.0 mL, 67.5 mmol, 1.00 equiv) in
THF (100 mL) was cooled to −78 °C. nBuLi (1.60 M in hexanes, 42.2 mL, 67.5 mmol, 1.00 equiv) was added dropwise and the mixture was stirred at −78 °C for 0.5 h. A solution of ethyl formate (10.9 mL, 135 mmol, 2.00 equiv) in THF (100 mL) was added dropwise. The reaction mixture was stirred for 45 min at −78 °C, then poured onto ice- water (100 mL) containing a trace of hydroquinone and acetic acid (1 mL). The product was extracted with Et2O (2 × 200 ml); the combined organic layers were dried (Na2SO4) filtered, and concentrated in vacuo. The unpurified aldehyde 308 was used for subsequent imine formation.
1 Rf = 0.89 (1:3 EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ 9.21 (s, 1H), 1.12-1.10 (m, 21H).
156 Experimental Part
N
TIPS
Ally-(3-triisopropylsilanyl-prop-2-ynylidene)-amine (309)
A solution of triisopropylsilanyl-propynal (308) (67.5 mmol, 1.00 equiv) in CH2Cl2
(100 mL) was treated with allyl amine (5.05 mL, 67.5 mmol, 1.00 equiv) and MgSO4 (6 g) at room temperature for 9 h. The reaction mixture turned slightly orange. The
MgSO4 was filtered off and the filter cake was washed with CH2Cl2 (3 × 20 mL). The solvent was evaporated in vacuo and the product was purified by distillation under reduced pressure (0.5 mbar, 90-95 °C) to afford imine 309 (Z and E isomer) (13.4 g, 80% over two steps) as a colorless liquid.
1 Rf = 0.50, 0.38 (1:50 EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ 7.58-7.57 (m, 2H), 6.07-5.94 (m, 2H), 5.25-5.11 (m, 4H), 5.25-5.11 (m, 4H), 4.33 (dddd, 1H, J = 5.6, 1.87, 1.87, 1.87 Hz), 4.16 (dddd, 1H, J = 5.6, 1.9, 1.9, 1.3 Hz) 1.10-1.09 (m, 42H); 13C NMR
(75 MHz, CDCl3) δ 145.7, 143.7, 134.9, 134.6, 116.9, 116.0, 103.4, 101.8, 98.3, 95.1, 64.2, 58.8, 18.6, 18.6, 11.2, 11.2; IR (thin film) ν 2945, 2867, 1644, 1612, 1593, 1464, 1384, 1366, 1072, 1027, 995, 919, 883, 678; EI-MS 249.2 (1.2 [M]+), 206.1
(100 [NC-C ≡ C-TIPS]); Anal. calcd for C15H27NSi: C 72.22, H 10.91, N 5.61, found: C 72.25, H 10.84, N 5.57.
Me
N
N O Bn TIPS
1-(phenylmethyl)-5'-[1-prop-1-en-1-yl]-1'-prop-2-en-1-yl-2'-{[tris(1-methylethyl) silyl]ethynyl}spiro[indole-3,3'-pyrrolidin]-2(1H)-one (310)
A sealable tube with side inlet was charged with MgI2 (2.2 mg, 7.9 µmol, 20 mol%), and cyclopropane 303 (11.5 mg, 40.0 µmol, 1.00 equiv). Imine 309 (60 µL, 238 µmol, Experimental Part 157
6.00 equiv) was added by syringe, followed by THF (0.1 mL). The tube was sealed, placed into an oil bath at 80 °C and heated for 14 h. The reaction mixture was allowed to reach room temperature. EtOAc (4 mL) and H2O (5 mL) were added to the reaction mixture, followed by Na2S2O3 (small crystal). This biphasic mixture was stirred for 1 h, then the phases were separated and the organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give products 310. The products could only be partially separated by column chromatography (1:19 EtOAc/hexanes) and one major fraction was obtained, containing three isomers of 310 (12 mg, 56%).
1 Rf = 0.40 (1:9 EtOAc/hexanes); H NMR (CDCl3, 300 MHz, mixture of isomers, integral ratios are described) δ 7.58-7.50 (m, 1H), 7.32-7.19 (m, 5H), 7.16-7.03 (m,1H), 7.02-6.96 (m, 1H), 6.64-6.59 (m, 1H), 6.08-5.82 (m, 1.17H), 5.77-5.58 (m, 1.72H), 5.43-5.38 (m, 0.28H), 5.30-5.19 (m, 1.28H), 5.13-5.08 (m, 0.55H), 4.98-4.81 (m, 2H), 4.23 (s, 0.55H),3.93 (s, 0.28H), 3.72 (s, 0.17H), 3.63-3.40 (m, 2.45H), 3.29-3.20 (m, 0.55H), 2.56-2.48 (m, 0.28H), 2.38-2.10 (m, 1.55H), 1.90-1.82 (m, 0.17H), 1.76-1.67 (m, 3H), 1.07 (s, 5.88H), 0.98 (s, 3.57H),0.88 (s, 11.55H).
N NHTs
N O H
3-(tosyl-hydrazono)-1,3-dihydro-indol-2-one (311)
Isatin (96) (9.44 g, 64.2 mmol, 1.00 equiv) was suspended in MeOH (300 mL). The suspension was heated to reflux, whereupon a deep-red solution was obtained. To this hot solution was added tosylhydrazine (12.1 g, 64.8 mmol, 1.02 equiv) in one portion. A yellow product starts precipitating from the hot mixture. The reaction mixture was allowed to cool to room temperature and the pure tosylhydrazone 311 (18.2 g, 90%) was filtered off.
1 Rf = 0.12 (EtOAc); mp = 207 °C; H NMR (300 MHz, CD3OD) δ 7.97 (d, 2H, J = 8.09 Hz), 7.86 (d, 1H, J = 7.47 Hz), 7.41-7.35 (m, 3H), 7.11-7.06 (m, 1H), 6.91 (d, 1H, J = 7.47 Hz), 2.43 (s, 3H). 158 Experimental Part
N2
N O H
3-diazo-1,3-dihydro-indol-2-one (312)
3-Tosylhydrazone-1,3-dihydro-indol-2-one (311) (12.0 g, 38.1 mmol, 1.00 equiv) was treated with a solution of NaOH (3.04 g, 76.1 mmol, 2.00 equiv) in H2O (375 mL). The reaction mixture was stirred for 15 h in a waterbath at 50 °C, and then allowed to cool to room temperature. The reaction mixture was neutralized by addition of dry ice, whereupon diazoketone 312 (5.36 g, 88%). precipitated: The product was directly used in the subsequent reaction.
1 Rf = 0.54 (3:1 EtOAc/hexanes); mp = 168 °C (decomp.); H NMR (300 MHz, CDCl3) δ 8.69 (br, 1H,), 7.21-7.06 (m, 3H), 7.01-6.98 (m, 1H).
Me
N O H
2-[1-prop-1-en-1-yl]spiro[cyclopropane-1,3'-indol]-2'(1'H)-one (313)
In a 3-neck flask equipped with a reflux condenser and an addition funnel was placed
[Rh(OAc)2]2 (214 mg, 485 µmol, 1 mol%). Benzene (280 mL) and piperylene (mixture of isomers, 19.5 mL, 194 mmol, 4.00 equiv) were added and the suspension was heated to reflux. A solution of 312 (7.72 g, 48.5 mmol, 1.00 equiv) in CH2Cl2 (340 mL) was added over 3 h by syringe pump. The reaction mixture was allowed to cool to room temperature and the solvent was partially removed (reduced to 1/10 of its volume). The remaining suspension was filtered over Celite and the filter cake was washed with acetone. The filtrate was concentrated in vacuo and purified by column chromatography (1:3 EtOAc/hexanes) to afford 313 (mixture of isomeric products) (69.1 g, 71%). The mixture was used without further purification in the upcoming ring-expansion step. Experimental Part 159
Ring expansion of 313 with 309:
Me Me
N N + N O N O H TIPS H 313 309 314 TIPS
A sealable tube with side inlet was charged with MgI2 (5.69 g, 20.5 mmol, 1.00 equiv). A solution of cyclopropane 313 (4.08 g, 20.5 mmol, 1.00 equiv) in THF (35 mL) was added via cannula, followed by imine 309 (6.12 g, 24.4 mmol, 1.20 equiv). The tube was sealed, placed into an oil bath at 75 °C and heated for 15 h. The reaction mixture was allowed to reach room temperature. EtOAc (250 mL) and H2O (150 mL) were added to the reaction mixture, followed by Na2S2O3 (500 mg). This biphasic mixture was stirred for 3 h, then the phases were separated and the organic phase was washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo to give 314. The following products were obtained by careful column chromatography purification (4:21 EtOAc/hexanes):
Me
O HN N
TIPS
(±)-(2'R,3S,5'S)-1'-allyl-5'-[(1E)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)ethynyl]spiro- [indole-3,3'-pyrrolidin]-2(1H)-one (321)
Pale yellow solid, 2.93 g (32%).
1 Rf = 0.59 (1:3 EtOAc/hexanes); mp = 121 °C; H NMR (300 MHz, CDCl3) δ 8.84 (br, 1H), 7.50 (d, 1H, J = 7.5 Hz), 7.14 (ddd, 1H, J = 7.5, 7.5, 1.3 Hz), 7,00 (ddd, 1H, J = 7.5, 7.5, 1.3 Hz), 6.85 (d, 1H, J = 7.5 Hz), 6.04-5.91 (m, 1H), 5.74-5.60 (m, 1H), 5.46-5.37 (m, 1H), 5.24-5.20 (m, 2H), 3.83 (s, 1H), 3.59-3.37 (m, 3H), 2.50 (dd, 1H, J = 13.1, 8.1 Hz), 1.82 (dd, 1H, J = 13.7, 8.1 Hz), 1.58 (ddd, 3H, J = 8.8, 6.2, 1.3 Hz), 160 Experimental Part
13 0.83-0.82 (m, 21H); C NMR (75 MHz, CDCl3) δ 181.1, 140.4, 134.7, 132.5, 132.1, 129.1, 127.9, 125.6, 122.9, 119.6, 109.3, 103.1, 87.5, 63.1, 62.6, 56.0, 50.9, 42.2, 18.4, 17.8, 10.9; IR (thin film) ν 3207, 2942, 2864, 1712, 1618, 1471, 1337, 1234, 1171, 990, + 912, 881, 749, 673; HiResMALDI-MS calcd for C28H40N2SiO [M+H] 449.2988, found,
449.2989; Anal. calcd for C28H40N2SiO: C 74.95, H 8.98, N 6.24, found: C 74.95, H 8.89, N 6.01.
Me
HN N O
TIPS
(±)-(2'R,3R,5'R)-1'-allyl-5'-[(1E)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)ethynyl]spiro- [indole-3,3'-pyrrolidin]-2(1H)-one (322)
Pale yellow oil, 350 mg (3.8%).
1 Rf = 0.65 (1:3 EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ 7.65-7.57 (m, 3H), 7.22-7.16 (m, 1H), 7.04-6.98 (m, 1H), 6.81 (d, 1H, J = 7.5 Hz), 5.85-5.62 (m, 2H), 5.51-5.42 (m, 1H), 5.20 (d, 1H, J = 18.1), 5.00 (d, 1H, J = 10.0 Hz), 3.92 (s, 1H), 3.55-3.37 (m, 2H), 3.22 (dd, 1H, J = 13.7, 8.1 Hz), 2.70 (dd, 1H, J = 13.1, 8.7 Hz), 1.80 (dd, 1H, J = 13.1, 6.9 Hz), 1.70 (ddd, 3H, J = 11.8, 6.2, 1.3 Hz), 1.11 (s, 21H); 13C NMR
(75 MHz, CDCl3) δ 178.1, 140.0, 136.3, 136.1, 132.5, 129.0, 127.8, 124.1, 122.3, 116.8, 109.0, 99.5, 90.6, 64.3, 62.5, 55.2, 50.7, 41.6, 18.7, 17.8, 11.3; IR (thin film) ν 3207, 3082, 2942, 2865, 2159, 1716, 1620, 1471, 1332, 1234, 1176, 995, 964, 917, 883, 750, + 677; HiResMALDI-MS calcd for C28H40N2SiO [M+H] 449.2988, found, 449.2983. Experimental Part 161
Me
N
N O H TIPS mixed fraction
Co-eluting fraction
2.90 g (32%) Rf = 0.45 (1:3 EtOAc/hexanes).
Allyl-deprotection of the co-eluting fraction:
Me Me Me Me
O O N HN HN NH ++NH HN NH O N O H TIPS mixed fraction TIPS TIPS TIPS 323 324 325
To a solution of the co-eluting fraction (3.07 g, 6.85 mmol, 1.00 equiv) and NDMBA
(3.42 g, 21.9 mmol, 3.20 equiv) in CH2Cl2 (150 mL) was added a solution of freshly prepared Pd(PPh3)4 (from [Pd2dba3]·CHCl3 (212 mg, 205 µmol, 6 mol% Pd) and PPh3
(323 mg, 1.23 mmol, 18 mol%) in 20 mL CH2Cl2). The reaction mixture was stirred at
30 °C for 12 h. CH2Cl2 (350 mL) was added and the organic solution was washed with sat. aq Na2CO3 (2 × 175 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (1.5:8.5 Æ 1:4 EtOAc/hexanes) afforded: 162 Experimental Part
Me
O HN NH
TIPS
(±)-(2'R,3S,5'R)-5'-[(1E)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)ethynyl]spiro[indole- 3,3'-pyrrolidin]-2(1H)-one (323)
Pale yellow oil, 1.68 g (60%).
1 Rf = 0.71 (1:3 EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ 7.89 (br, 1H), 7.38 (d, 1H, J = 7.47 Hz), 7.23-7.18 (m, 1H), 7.06-7.01 (m, 1H), 6.87 (d, 1H, J = 7.5 Hz), 5.69-5.63 (m, 2H), 4.35 (s, 1H), 4.22 (ddd, 1H, J = 7.5, 7.5, 7.5 Hz), 2.25-2.21 (m, 2H), 1.71 13 (d, 3H, J = 5.0 Hz), 0.86-0.85 (m, 21H); C NMR (75 MHz, CDCl3) δ 179.9, 140.4, 133.0, 131.5, 128.1, 126.9, 124.5, 122.5, 109.7, 103.7, 86.6, 60.4, 59.7, 58.7, 43.2, 18.4, 17.7, 10.9; IR (thin film) ν 3209, 2942, 2864, 1715, 1684, 1621, 1472, 883, 750, 679; + HiResMALDI-MS calcd for C25H36N2SiO [M+H] 409.2675, found, 409.2674; Anal. calcd for C25H36N2SiO: C 73.48, H 8.88, N 6.85, found: C 73.29, H 8.97, N 6.66.
Me
O HN NH
TIPS
(±)-(2'R,3S,5'R)-5'-[(1Z)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)ethynyl]spiro[indole- 3,3'-pyrrolidin]-2(1H)-one (324)
Pale yellow oil, 350 mg (13%).
1 Rf = 0.53 (1:3 EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ 8.08 (br, 1H), 7.45 (d, 1H, J = 7.5 Hz), 7.24-7.19 (m, 1H), 7.07-7.02 (m, 1H), 6.88 (d, 1H, J = 7.5 Hz), 5.68-5.55 (m, 2H), 4.62 (ddd, 1H J = 8.1, 8.1, 8.1 Hz), 4.37 (s, 1H), 2.34-2.12 (m, 2H), 1.71 (d, 3H, J = 13 5.0 Hz), 1.58 (br, 1H), 0.88-0.86 (m, 21H); C NMR (75 MHz, CDCl3) δ 140.3, 132.7, Experimental Part 163
131.3, 128.2, 185.8, 124.7, 122.5, 109.5, 103.8, 86.7, 59.5, 58.9, 54.4, 43.4, 18.4, 13.4, 10.9; IR (thin film) ν 3199, 2943, 2865, 2170, 1714, 1621, 1471, 1337, 1236, 1110, 996, + 919, 883, 750, 679; HiResMALDI-MS calcd for C25H36N2SiO [M+H] 409.2675, found, 409.2676.
Me
HN NH O
TIPS
(±)-(2'R,3R,5'S)-5'-[1-prop-1-en-1-yl]-2'-[(triisopropylsilyl)ethynyl]spiro[indole-3,3'- pyrrolidin]-2(1H)-one (325)
Pale yellow solid 510 mg (18%).
1 Rf = 0.73 (1:3 EtOAc/hexanes); mp = 63 °C; H NMR (300 MHz, CDCl3) δ 9.35 (br, 1H), 7.23-7.17 (m, 2H), 7.05-7.00 (m, 1H), 6.90 (d, 1H, J = 7.5 Hz), 5.78-5.64 (m, 2H), 4.00- 3.94 (m, 2H), 2.75 (br, 1 H) 2.44-2.31 (m, 1H), 2.21-2.08 (m, 1H), 1.73 (d, 3H, J = 5.6 13 Hz), 0.89 (s, 21H); C NMR (75 MHz, CDCl3) δ 181.7, 141.6, 131.0, 130.6, 128.2, 128.0, 122.3, 122.01, 109.7, 101.8, 85.8, 62.3, 62.1, 60.2, 43.3, 18.5, 17.9, 11.1; IR (thin film) ν 3186, 2942, 2865, 2175, 1706, 1621, 1472, 1439, 1345, 1109, 968, 883, 745, 678; + HiResMALDI-MS calcd for C25H36N2SiO [M+H] 409.2675, found, 409.2677. 164 Experimental Part
Allyl-deprotection of 321:
Me
O HN NH
TIPS
(±)-(2'R,3S,5'S)-5'-[(1Z)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)ethynyl]spiro[indole- 3,3'-pyrrolidin]-2(1H)-one (326)
To a solution of 321 (1.63 g, 3.63 mmol, 1.00 equiv) and NDMBA (1.82 g, 11.6 mmol,
3.20 equiv) in CH2Cl2 (45 mL) was added a solution of freshly prepared Pd(PPh3)4 (from
[Pd2dba3]·CHCl3 (75.0 mg, 72.0 µmol, 4 mol% Pd) and PPh3 (114 mg, 436 µmol,
12 mol%) in 5 mL CH2Cl2). The reaction mixture was stirred at 30 °C for 12 h. CH2Cl2 (200 mL) was added to the reaction mixture and the organic solution was washed with sat. aq Na2CO3 (2 × 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (9:41 EtOAc/hexanes) afforded 326 (1.27 g, 86%) as a pale yellow solid.
1 Rf = 0.28 (1:3 EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ 8.37 (br, 1H), 7.35 (d, 1H, J = 7.5 Hz), 7.16 (dd, 1H, J = 7.5, 7.5 Hz), 7.00 (dd, 1H, J = 7.5, 7.5 Hz), 6.85 (d, 1H, J = 7.5 Hz), 5.79-5.51 (m, 2H), 4.21 (s, 1H), 3.95 (ddd, 1H, J = 8.1, 8.1, 8.1 Hz), 2.58 (dd, 1H, J = 13.1, 8.1 Hz), 2.18 (br, 1H), 1.88 (dd, 1H, J = 13.1, 8.1 Hz), 1.73-1.70 13 (m, 3H), 0.83-0.82 (m, 21H); C NMR (75 MHz, CDCl3) δ 181.1, 140.4, 133.5, 131.7, 127.9, 127.8, 124.4, 122.5, 109.6, 103.0, 86.9, 60.5, 60.1, 58.9, 43.9, 18.4, 17.8, 10.9; IR (thin film) ν 3212, 2943, 2865, 2176, 1713, 1621, 1472, 1340, 1235, 1112, 965, 883, 748, + 679; HiResMALDI-MS calcd for C25H36N2SiO [M+H] 409.2675, found, 409.2684. Experimental Part 165
5.1. Synthesis of Spirotryprostatin B from Intermediate 323
Coupling of 323 with N-Boc-L-proline chloride.
Me Me Me Boc Boc O O N N
HN NH HN N + HN N H H O O O
TIPS TIPS TIPS 323 327 328
To a solution of 323 (141 mg, 345 µmol, 1.00 equiv) and NEt3 (48.0 µL, 345 µmol,
1.00 equiv) in CH2Cl2 (15 mL) at 0 °C was added N-Boc-L-proline chloride (270) (0.14 M in CH2Cl2, 10.0 mL, 1.38 mmol, 4.00 equiv). The reaction mixture was allowed to warm slowly to room temperature and was stirred for 8 h. The reaction was quenched by addition of 10% aq NaHCO3 (10 mL). The phases were separated; the organic layer was washed with sat. aq NaHCO3 (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (1:3 EtOAc/hexanes) afforded:
Me Boc O N HN N H O
TIPS tert-butyl (2S)-2-({(2'R,3S,5'R)-2-oxo-5'-[(1E)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)- ethynyl]-1,2-dihydro-1'H-spiro[indole-3,3'-pyrrolidin]-1'-yl}carbonyl)pyrrolidine-1- carboxylate (327)
Colorless crystals, 94 mg (45%).
23 1 Rf = 0.63 (1:1 EtOAc/hexanes), [α]D (c 0.250, CHCl3) = +15.6; mp = 191 °C; H NMR # (300 MHz, CDCl3 denotes major-, * minor rotamer signals) δ 7.94-7.78 (m, 2H), 7.25-7.15 (m, 4H), 7.06-7.01 (m, 2H), 6.90-6.83 (m, 2H), 5.76-5.50 (m, 4H), 5.35* (s, 1H), 5.20-5.18* (m, 1H), 2.26# (s, 1H), 4.98-4.74 (m, 3H), 3.67-3.63# (m, 1H), 166 Experimental Part
3.59-3.54* (m, 1H), 3.52-3.38 (m, 2H), 2.88-2.00 (m, 10H), 1.88-1.71 (m, 5 H), 1.66-1.64* (m, 3H), 1.53* (s, 9H), 1.49-1.47# (m, 9H), 0.85-0.81 (m, 42H); 13C NMR
(75 MHz, CDCl3, * denotes minor rotamer signals) δ 179.3, 176.9*, 171.2, 170.5*, 154.5, 154.4*, 141.0, 140.6*, 133.6, 130.7*, 130.5, 128.8, 128.5*, 127.6, 127.4*, 125.6, 124.0*, 122.9*, 122.1, 110.3*, 109.9, 102.3*, 99.0, 92.0*, 87.3, 79.6, 79.2*, 60.4*, 59.6, 59.2*, 58.7*, 58.4, 58.1, 57.1, 56.6*, 46.5, 46.3*, 43.6, 39.8*, 30.1*, 29.1, 28.6*, 28.5, 23.1*, 22.8, 18.5*, 18.3, 17.8, 17.6*, 11.1, 10.9*; IR (thin film) ν 3212, 2942, 2865, 1729, 1689, 1472, 1397, 1366, 1299, 1254, 1164, 1126, 970, 919.3, 883, 750, 677; HiResMALDI-MS + calcd for C35H51N3SiO4 [M+Na] 628.3546, found, 628.3491; Anal. calcd. for
C35H51N3SiO4: C 69.38, H 8.48, N 6.94, found: C 69.40, H 8.36, N 6.92.
Crystal data for 327 at 223 K, Mr = 605.88, monoclinic space group P2(1), ρcalc = 1.116 g·cm–3, Z = 2, a = 12.642(2), b = 11.274(2), c = 13.052(4) Å, α = 90.00, β = 104.26(2), γ = 90.00°, V = 1802.9(7) Å3. Final R(F) = 0.0564, wR(F2) = 0.1601 for 464 parameters and 3015 reflections with I >2σ(I) and θ < 64.99°. The iPr3Si groups in 327 are diordered. The disorder could be resolved for the atoms C(20), C(21), C(22), C(23), and C(25), i.e., two peaks were refined with population parameters of 0.6 and 0.4, respectively. (Only one population is displayed for clarity.)
CCDC 196803 contains the supplementary crystallographic data for 327. This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]). Experimental Part 167
Me Boc N
HN N H O O
TIPS tert-butyl (2S)-2-({(2'S,3R,5'S)-2-oxo-5'-[(1E)-prop-1-en-1-yl]-2'- [(triisopropylsilyl)ethynyl]-1,2-dihydro-1'H-spiro[indole-3,3'-pyrrolidin]-1'- yl}carbonyl)pyrrolidine-1-carboxylate (328)
White solid, 94 mg (45%).
26 1 Rf = 0.50 (1:1 EtOAc/hexanes), [α]D (c 0.745, CHCl3) = −31.6; mp = 99 °C; H NMR # # (300 MHz, CDCl3 denotes major-, * minor rotamer signals) δ 7.69* (br, 1H), 7.58 (br, 1H), 7.47# (d, 1H, J = 7.5 Hz), 7.26-7.14 (m, 3H), 7.0-6.93 (m, 2H), 6.90-6.84 (m, 2H), 6.09* (ddd, 1H, J = 15.6, 8.7, 1.9 Hz), 5.76-5.59 (m, 2H), 5.52# (dd, 1H, J = 8.7, 3.7 Hz), 5.41* (ddd, 1H, J = 15.6, 7.5, 1.9 Hz), 5.17* (s, 1H), 4.97-4.86 (m, 2H), 4.86# (s, 1H), 4.55-4.48* (m, 1H), 3.65-3.36 (m, 4H), 2.69*(dd, 1H, J = 13.7, 8.7 Hz), 2.28-2.09 (m, 5H), 1.92-1.72 (m, 6 H), 1.76# (dd, 3H, J = 6.2, 1.3 Hz), 1.68* (dd, 3H, J = 6.2, 1.3 Hz), 1.47# (s, 9H), 1.42* (s, 9H), 0.96-0.95* (m, 21H), 0.83-0.82# (m, 21 H); 13 C NMR (75 MHz, CDCl3, * denotes minor rotamer signals) δ 179.0, 176.6*, 171.0, 154.3*, 154.2, 140.9, 140.4*, 133.5, 130.6, 130.4*, 128.7, 128.4*, 127.5, 127.3*, 125.5, 123.9*, 122.8*, 122.1, 110.2*, 109.8, 102.3, 99.0*, 92.0*, 87.3, 79.6, 79.2*, 59.7, 59.2, 58.7*, 58.5, 58.1*, 57.2*, 56.7, 46.6, 46.4*, 43.8, 39.9*, 30.3*, 29.2, 28.7*, 28.6, 23.2*, 22.9, 18.7*, 18.4, 17.9, 17.8*, 11.2, 11.0*; IR (thin film) ν 3214, 2943, 2866, 2175, 1728, 1702, 1676, 1622, 1472, 1401, 1366, 1241, 1164, 1126, 883, 750, 678; HiResMALDI- + MS calcd for C35H51N3SiO4 [M+Na] 628.3546, found, 628.3535. 168 Experimental Part
O Boc O N HN N H O
TIPS tert-butyl (2S)-2-({(2'R,3S,5'R)-5'-formyl-2-oxo-2'-[(triisopropylsilyl)ethynyl]-1,2- dihydro-1'H-spiro[indole-3,3'-pyrrolidin]-1'-yl}carbonyl)pyrrolidine-1-carboxylate (330)
A solution of 327 (405 mg, 668 µmol, 1.00 equiv) and NMO·H2O (108 mg, 802 µmol,
1.20 equiv) in THF/tBuOH/H2O (4:4:1, 20 mL) was stirred at room temperature for
30 min before OsO4 (4 wt% in H2O, 170 µL, 270 µmol, 4 mol%) was added. The reaction mixture was stirred at room temperature for 16 h, then quenched by addition of 2 M aq
Na2S2O3 (25 mL) and EtOAc (25 mL). The biphasic mixture was stirred for 3 h, the phases separated; the organic layer was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The unpurified product (329) was used in the subsequent reaction.
Rf = 0.67, 0.51 (3:1 EtOAc/hexanes).
To a solution of diols 329 in EtOAc (20 mL) was added Pb(OAc)4 (344 mg, 1.00 mmol, 1.50 equiv). A yellow suspension was obtained and after stirring for 10 min, the mixture was filtered through a plug of silica gel, eluting with EtOAc. Purification by column chromatography (1:1 EtOAc/hexanes) afforded 330 (385 mg, 97%) as a white solid.
26 1 Rf = 0.83 (3:1 EtOAc/hexanes), mp = 90 °C; [α]D (c 0.290, CHCl3) = +50.8; H NMR # (300 MHz, CDCl3 denotes major-, * minor rotamer signals) δ 9.64* (d, 1H, J = 2.8 Hz), 9.52# (d, 1H, J = 3.1 Hz), 8.91 (m, 2H), 7.36-7.32 (m, 2H), 7.27-7.22 (m, 2H), 7.06-6.99 (m, 2H), 6.93-6.89 (m, 2H), 5.57# (s, 1H), 5.16* (s, 1H), 4.85-4.65 (m, 4H), 3.57-3.41 (m, 4H), 2.42-2.03 (m, 10H), 1.86-1.80 (m, 2H), 1.51* (s, 9H), 1.45# (s, 9H), 0.91-0.90 13 (m, 42H); C NMR (75 MHz, CDCl3, * denotes minor rotamer signals) δ 198.7, 197.2*, 177.4*, 177.3, 174.1, 173.6*, 154.4, 153.4*, 140.6, 140.6*, 129.4*, 129.1, 128.1, 127.7*, 125.0*, 124.9, 122.5, 110.4, 101.6, 101.1*, 91.8*, 90.7, 80.49*, 79.8, 65.1, 64.8*, 60.4, 57.4, 56.5*, 47.2, 34.8*, 34.5, 31.9, 30.2, 29.7*, 28.5, 24.7, 23.2*, 18.5, 11.0; IR (thin Experimental Part 169
film) ν 3243, 2944, 2866, 1730, 1687, 1655, 1623, 1472, 1403, 1367, 1299, 1257, 1164, + 883, 752, 669; HiResMALDI-MS calcd for C33H47N3SiO5 [M+Na] 616.3183, found,
616.3158; Anal. calcd for C33H47N3SiO5: C 66.75, H 7.98, N 7.08, found: C 66.91, H 7.82, N 6.87.
Boc MeO2C O N HN N H O
TIPS methyl (2'R,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2- oxo-2'-[(triisopropylsilyl)ethynyl]-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'- carboxylate (332)
A solution of NaClO2 (73.0 mg, 808 µmol, 10.0 equiv) in pH 3.6 buffer (1.5 ml) was added to a solution of aldehyde 330 (48.0 mg, 810 µmol, 1.00 equiv) and 2-methyl-2- butene (1 mL) in tBuOH (3 mL). The reaction mixture was stirred at room temperature for 30 min; 2 M aq HCl was added (10 mL), and the product was extracted with EtOAc
(3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo; Rf = 0.08 (3:1 EtOAc/hexanes). The product 331 was dissolved in
Et2O (5 mL) and a solution of CH2N2 in Et2O (≈ 0.4 M in Et2O) was added untill the yellow color of CH2N2 persisted. The solvent was evaporated in vacuo and the product was purified by column chromatography (4:6 EtOAc/hexanes) to afford 332 (45 mg, 89%) as a white solid.
26 1 Rf = 0.81 (3:1 EtOAc/hexanes), mp = 95 °C; [α]D (c 1.525, CHCl3) = +47.7; H NMR # (300 MHz, CDCl3 denotes major-, * minor rotamer signals) δ 8.59-8.42 (m, 2H), 7.28-7.23 (m, 2H), 7.21-7.10 (m, 2H), 7.06-6.98 (m, 2H), 6.94-6.87 (m, 2H), 5.46* (s, 1H), 5.24# (s, 1H), 5.19-5.16# (m, 1H), 5.08-5.05* (m, 1H), 4.90-4.74 (m, 2H), 3.78# (s, 3H), 3.72* (s, 3H) 3.67-3.35 (m, 4H), 2.6-2.48 (m, 2H), 2.34-2.26 (m, 2H), 2.22-2.02 (m, 4H), 1.98-1.91 (m, 2H), 1.84-1.77 (m, 2H), 1.58# (s, 9H), 1.47* (s, 9H), 0.83-0.82 13 (m, 42H); C NMR (75 MHz, CDCl3, * denotes minor rotamer signals) δ 176.1*, 175.9, 170 Experimental Part
174.6*, 174.2, 171.2, 153.9, 141.1, 130.6*, 130.4, 129.3, 123.9, 123.0, 110.9, 101.0*, 100.4, 91.9, 91.2*, 80.5, 79.4*, 61.2*, 60.6*, 60.4, 59.4, 57.5, 57.3*, 52.6, 52.4*, 47.2*, 47.1, 37.1, 36.8*, 32.4, 31.5*, 28.6*, 28.4, 24.3*, 23.4, 18.4, 11.0; IR (thin film) ν 3242, 3945, 2866, 2173, 1732, 1700, 1622, 1472, 1367, 1366, 1299, 1202, 1174, 1114, 884, + 752, 679; HiResMALDI-MS calcd for C34H49N3SiO6 [M+Na] 646.3288, found,
646.3277; Anal. calcd for C34H49N3SiO6: C 65.46, H 7.92, N 6.74, found: C 65.72, H 7.98, N 6.57.
Boc MeO2C O N HN N H O
methyl (2'S,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'- ethynyl-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate (333)
To a solution of 332 (134 mg, 215 µmol, 1.00 equiv) in THF (5 mL), was added TBAF
(1.0 M in THF, 260 µL, 260 µmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 8 h, diluted with CH2Cl2, washed with sat. aq NaHCO3, dried over
Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (13:7 EtOAc/hexanes) to afford 333 (99.0 mg, 99%) as a white solid.
24 1 Rf = 0.43 (3:1 EtOAc/hexanes), mp = 97 °C; [α]D (c 1.340, CHCl3) = +24.4; H NMR # (300 MHz, CDCl3 denotes major-, * minor rotamer signals) δ 8.91-8.50 (m, 2H), 7.73-7.52 (m, 1H), 7.32-7.23 (m, 2H), 7.16-6.88 (m, 5H), 5.57* (dd, 1H, J = 9.3, 5.0 Hz), 5.36-5.36* (m, 1H), 5.15-5.14# (m, 1H), 4.99-4.91 (m, 2H), 4.84-4.74# (m, 1H), 4.36-4.27* (m, 1H), 3.77# (s, 3H), 3.73* (s, 3H) 3.70-3.36 (m, 3H), 2.93-2.70 (m, 2H), 2.60-2.51 (m, 2H), 2.39-1.78 (m, 10H), 1.58# (s, 9H), 1.46* (s, 9H); 13C NMR (75 MHz,
CDCl3, * denotes minor rotamer signals) δ 178.1*, 175.3, 173.6, 173.4*, 171.5*, 170.4, 154.4*, 153.5, 140.6*, 140.3, 129.7, 129.1, 129.0*, 128.9*, 126.2*, 123.9, 122.8, 122.4*, 110.3, 109.5*, 80.3, 79.9*, 79.4, 79.3*, 61.0*, 60.4, 58.8, 58.4*, 57.7*, 57.5, 56.1, 54.1*, 52.7*, 52.6, 47.2, 47.0*, 38.1*, 37.3, 32.5, 29.6*, 28.5*, 28.3, 24.8, 24.0*; IR (thin film) Experimental Part 171
ν 3243, 2978, 1729, 1686, 1621, 1473, 1400, 1366, 1301, 1174, 752; HiResMALDI-MS + calcd for C25H29N3O6 [M+Na] 490.1954, found, 490.1944; Anal. calcd for C25H29N3O6: C 64.23, H 6.25, N 8.99, found: C 64.18, H 6.36, N 8.90.
Boc MeO2C O N HN N H O methyl (2'S,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2- oxo-2'-vinyl-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate (337)
To a solution of 333 (20.0 mg, 430 µmol, 1.00 equiv) and quinoline (2.6 µL, 22 µmol,
0.50 equiv) in EtOH (2 mL), was added Pd/BaSO4 (6.6 mg, 33 wt%). The reaction mixture was stirred at room temperature under H2 atmosphere for 10 h. The solution was filtered over Celite and the solvent was evaporated in vacuo. The product was purified by column chromatography (7:3 EtOAc/hexanes) to afford 337 (18.0 mg, 90%) as a white solid.
24 1 Rf = 0.45 (3:1 EtOAc/hexanes), mp = 112 °C; [α]D (c 1.590, CHCl3) = −3.4; H NMR # # (300 MHz, CDCl3 denotes major-, * minor rotamer signals) δ 8.56-8.40 (m, 2H), 7.70 (d, 1H, J = 7.5 Hz), 7.30-7.19 (m, 2H), 7.15-6.99 (m, 3H), 6.94-6.85 (m, 2H), 5.57-5.24 (m, 4H), 5.14-4.99 (m, 2H), 4.92-4.78 (m, 3H), 4.72-4.61 (m, 2H), 4.33-4.29# (m, 1H), 3.79# (s, 3H), 3.78* (s, 3H) 3.67-3.35 (m, 4H), 2.64-2.52 (m, 3H), 2.42-2.09 (m, 3H), # 13 2.02-1.70 (m, 6H), 1.57* (s, 9H), 1.49 (s, 9H); C NMR (75 MHz, CDCl3, * denotes minor rotamer signals) δ 178.7, 176.5*, 174.6*, 173.9, 172.5, 171.5*, 154.9*, 153.8, 141.0, 140.9*, 135.1, 134.7*, 129.2, 128.8*, 125.9, 123.7*, 122.9*, 122.7, 119.6*, 119.4, 114.6, 111.0*, 110.1, 80.4*, 79.8, 68.9*, 68.1, 61.1*, 59.8, 59.1*, 57.8, 57.1*, 56.4, 52.9, 52.6*, 47.3, 47.0*, 38.1, 37.0*, 32.2*, 29.6, 28.6, 28.5*, 24.9, 23.4*; IR (thin film) ν 3241, 2978, 1727, 1683, 1619, 1473, 1400, 1366, 1300, 1269, 1203, 1174, 1123, 753; + HiResMALDI-MS calcd for C25H31N3O6 [M+Na] 492.2110, found, 492.2100; Anal. calcd for C25H31N3O6: C 63.95, H 6.65, N 8.95, found: C 63.74, H 6.69, N 8.87. 172 Experimental Part
NTs
N O Bn
(±)-(2'R,3R)-2'-ethynyl-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)spiro[indole- 3,3'-pyrrolidin]-2(1H)-one (338)
To a solution of 155 (14.6 mg, 24.0 µmol, 1.00 equiv) in THF (0.5 mL), was added
TBAF (1.0 M in THF, 29 µL, 29 µmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 10 h, diluted with CH2Cl2, washed with sat. aq NaHCO3, dried over
Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (1:3 EtOAc/hexanes) to afford 338 (11 mg, 100%) as colorless oil.
1 Rf = 0.57 (1:1 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 7.90-7.82 (m, 2H), 7.50-7.43 (m, 1H), 7.41-7.37 (m, 2H), 7.32-7.19 (m, 6H), 7.06 (ddd, 1H, J = 7.8, 7.8, 0.9 Hz), 6.72 (d, 1H, J = 7.5 Hz), 5.01 (d, 1H, J = 15.4 Hz), 4.76 (d, 1H, J = 15.4 Hz), 4.46 (d, 1H, J = 3.4 Hz), 3.93-3.82 (m, 1H), 3.78-3.67 (m, 1H), 2.47 (s, 3H), 2.25 (d, 1H, J = 3.4 Hz), 2.22-2.03 (m, 2H).
NTs
N O Bn Me
(±)-(2'R,3R)-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'-prop-1-yn-1- ylspiro[indole-3,3'-pyrrolidin]-2(1H)-one (340)
A solution of 338 (42.0 mg, 92.0 µmol, 1.00 equiv) in THF (2 mL), was cooled to
−78 °C. nBuLi (1.60 M in hexane, 63.0 µL, 101 µmol, 1.10 equiv) was added dropwise and the reaction mixture was stirred for 30 min. MeI (6.3 µL, 14 µmol, 1.50 equiv) was added and the reaction mixture was allowed to warm to room temperature slowly. After
12 h, H2O was added to the mixture and the product was extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Experimental Part 173
Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (7:13 EtOAc/hexanes) to afford 340 (30 mg, 69%) as colorless oil.
1 Rf = 0.57 (1:1 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 7.87-7.82 (m, 2H), 7.44-7.41 (m, 1H), 7.39-7.32 (m, 2H), 7.32-7.21 (m, 5H), 7.19-7.16 (m, 1H), 7.07-7.02 (m, 1H), 6.69 (d, 1H, J = 7.8 Hz), 5.25 (d, 1H, J = 15.7 Hz), 4.67 (d, 1H, J = 15.7 Hz), 4.46-4.39 (m, 1H), 3.89-3.80 (m, 1H), 3.76-3.68 (m, 1H), 2.46 (s, 3H), 2.26-2.06 (m, 2H), 1.54 (d, 3H, J = 2.2 Hz).
NTs O N O Bn Me
(±)-(2'R,3R)-1'-[(4-methylphenyl)sulfonyl]-2'-(2-oxopropyl)-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (342)
Preparation of Hennion’s catalyst: To a stirred, suspension of HgOred (5.0 mg, 23 µmol,
1.0 equiv) and BF3·Et2O (3.0 µL, 23 µmol, 1.0 equiv) was added CF3CO2H (17.7 µL, 231 µmol, 10.0 equiv). A colorless solution was obtained.
To an aliquot of Hennion’s catalyst (2.0 µL, 2.2 µmol, 10 mol%) was added a solution of
340 (10.5 mg, 22.3 µmol, 1.00 equiv) in CH2Cl2 (2 mL). After 5 min, NaOMe (5 mg) was added followed by H2O (0.2 mL). The layers were separated; the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (1:3 EtOAc/hexanes) to afford 342 (2.6 mg, 24%) as colorless oil.
1 Rf = 0.19 (1:3 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 7.83-7.77 (m, 2H), 7.43-7.40 (m, 2H), 7.38-7.22 (m, 6H), 7.01 (dt, 1H, J = 7.8, 0.9 Hz), 6.61 (d, 1H, J = 7.8 Hz), 6.46 (dt, 1H, J = 7.5, 0.9 Hz), 5.54 (d, 1H, J = 7.2 Hz), 4.86 (d, 1H, J = 15.6 Hz), 4.72 (d, 1H, J = 15.6 Hz), 4.24 (dd, 1H, J = 11.0, 3.1 Hz), 3.91 (ddd, 1H, J = 9.7, 7.2, 2.2 Hz), 3.60 (dd, 1H, J = 18.7, 11.0 Hz), 3.41 (ddd, 1H, J = 17.2, 10.6, 7.2 Hz), 3.23 (dd, 1H, J = 18.7, 3.1 Hz), 2.52 (s, 3H), 2.10 (s, 1H), 1.77 (ddd, 1H, J = 8.7, 6.2, 2.2 Hz). 174 Experimental Part
NTs Me N O OH Bn Me
(±)-(2'R,3R)-2'-(2-hydroxy-2-methylpropyl)-1'-[(4-methylphenyl)sulfonyl]-1- (phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (343)
A solution of 342 (56.0 mg, 114 µmol, 1.00 equiv) in THF (10 mL) was cooled to
−40 °C. MeMgI (3.0 M in Et2O, 45 µL, 140 µmol, 1.2 equiv) was added and the reaction mixture was allowed to reach room temperature over a period of 4 h. Sat. aq NH4Cl was added (15 mL). The layers were separated; the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (1:3 EtOAc/hexanes) to afford 343 (15.0 mg, 26%) as colorless oil, together with 342 (24.0 mg).
1 Rf = 0.50 (1:1 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 7.91-7.84 (m, 2H), 7.44-7.40 (m, 2H), 7.38-7.22 (m, 5H), 7.09 (dt, 1H, J = 7.5, 0.9 Hz), 6.74-6.67 (m, 1H), 6.14 (d, 1H, J = 7.7 Hz), 4.83 (s, 2H), 4.22-4.17 (m, 1H), 4.01-3.96 (m, 1H), 3.64-3.54 (m, 1H), 2.61-2.50 (m, 1H), 2.52 (s, 3H), 2.35-2.16 (m, 2H), 2.04-2.02 (m, 2H), 1.79-1.65 + (m, 1H), 1.18 (s, 3H), 0.79 (s, 3H); HiResMALDI-MS calcd for C29H32N2SO4 [M+Na] 527.1981, found, 527.1984.
NTs Me N O Bn
(±)-(2'R,3R)-1'-[(4-methylphenyl)sulfonyl]-2'-(2-methylprop-2-en-1-yl)-1-(phenyl- methyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (344)
A solution of 343 (15.0 mg, 29.7 µmol, 1.00 equiv) in pydidine (0.2 mL) was cooled to
−50 °C. SOCl2 (4.0 µL, 50 µmol, 1.7 equiv) was added and the mixture was allowed to reach room temperature over a period of 2 h. CH2Cl2 (15 mL) was added. The layers were separated; the organic layer was washed with 1 M aq HCl (10 mL), then brine
(10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The product was Experimental Part 175
purified by column chromatography (1:4 EtOAc/hexanes) to afford 344 (3.8 mg, 26%) as colorless oil, together with 343 (6.5 mg, 56%).
1 Rf = 0.74 (1:1 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ 7.88-7.85 (m, 2H), 7.43-7.40 (m, 2H), 7.32-7.21 (m, 5H), 7.09 (dt, 1H, J = 7.8, 1.2 Hz), 6.84-6.79 (m, 1H), 6.61 (d, 1H, J = 7.8 Hz), ), 6.41 (d, 1H, J = 6.9 Hz), 5.02 (d, 1H, 15.6 Hz), 4.52 (d, 1H, 15.6 Hz), 4.32-4.27 (m, 2H), 4.21 (dt, 1H, J = 10.6, 4.4 Hz), 4.03, (ddd, 1H, J = 11.2, 9.9, 5.9 Hz), 3.77, (ddd, 1H, J = 11.2, 7.2, 4.0 Hz), 2.91-2.76 (m, 2H), 2.50 (s, 3H), 2.13 (ddd, 1H, J = 10.0, 5.9, 4.4 Hz), 1.73 (ddd, 1H, J = 12.8, 9.3, 7.2 Hz), 1.39 (s, 3H).
Boc MeO2C O N HN N H O HO OH methyl (2'R,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'- (1,2-dihydroxyethyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate (346)
A solution of 337 (17.0 mg, 36.0 µmol, 1.00 equiv) and NMO·H2O (6.0 mg, 43 µmol, 1.2 equiv) in THF/tBuOH/H2O (4:4:1, 1 mL) was stirred at room temperature for 30 min before OsO4 (4 wt% in H2O, 230 µL, 36.0 µmol, 1.00 equiv) was added. The reaction mixture was stirred at room temperature for 3 d. The reaction was quenched by addition of a 2 M aq Na2S2O3 (2 mL) and EtOAc (2 mL) was added. The biphasic mixture was stirred for 6 h. The phases were separated; the organic layer was washed with brine
(5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (3:1 EtOAc/hexanes) afforded diol 346 (16.0 mg, 88%) as colorless oil.
26 1 Rf = 0.18 (3:1 EtOAc/hexanes), [α]D (c 1.545, CHCl3) = −1.4; H NMR (300 MHz,
CDCl3) δ 8.33 (br, 1H), 7.67 (d, 1H, J = 7.5 Hz), 7.20 (ddd, 1H, J = 7.5, 7.5, 1.3 Hz), 7.03 (ddd, 1H, J = 7.5, 7.5, 1.3 Hz), 6.81 (d, 1H, J = 7.5 Hz), 5.39 (d, 1H, J = 9.3 Hz), 5.27 (d, 1H, J = 10.6 Hz), 4.52 (s, 1H), 4.34 (dd, 1H, J = 8.1, 4.4 Hz), 4.07 (ddd, 1H, J = 176 Experimental Part
8.7, 8.7, 8.7 Hz), 3.78 (s, 3H), 3.65-3.45 (m, 4H), 3.25-3.15 (m, 1H), 3.11 (dd, 1H, J = 13.7, 10.0 Hz), 2.68 (d, 1H, J = 14.9 Hz), 2.44-2.10 (m, 3H), 1.91-1.81 (m, 1H), 1.48 13 (s, 9H); C NMR (75 MHz, CDCl3,) δ 181.5, 175.7, 171.3, 155.7, 141.1, 128.8, 128.0, 127.7, 122.5, 109.8, 80.7, 71.7, 69.9, 62.1, 59.7, 58.6, 54.8, 52.8, 47.8, 38.1, 30.0, 28.5, 24.9; IR (thin film) ν 3449, 2977, 1722, 1660, 1474, 1412, 1368, 1328, 1206, 1165, 1131, + 1030, 755; HiResMALDI-MS calcd for C25H33N3O8 [M+Na] 526.2165, found, 526.2155.
Boc MeO2C O N HN N H O O methyl (2'R,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-(1- hydroxy-2-methylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'- carboxylate (345)
To a solution of diol 346 (88.0 mg, 0.175 mmol, 1.00 equiv) in EtOAc (5 mL) was added
Pb(OAc)4 (90.0 mg, 0.262 mmol, 1.50 equiv). A yellow suspension was obtained and after stirring for 10 min, the mixture was filtered through a plug of silica gel, eluting with EtOAc. Evaporation of the solvent and purification by column chromatography (3:1 EtOAc/hexanes) afforded 345 (72 mg, 87%) as a colorless oil.
24 1 Rf = 0.51 (3:1 EtOAc/hexanes), [α]D (c 0.760, CHCl3) = +16.0; H NMR (300 MHz,
CDCl3) δ 9.05 (d, 1H, J =4.7 Hz), 8.15 (br, 1H), 7.84 (d, 1H, J = 7.5 Hz), 7.23 (ddd, 1H, J = 7.5, 7.5, 0.9 Hz), 7.02 (ddd, 1H, J = 7.5, 7.5, 0.9 Hz), 6.87 (d, 1H, J = 7.5 Hz), 5.60 (dd, 1H, J = 8.4, 8.4 Hz), 4.53 (d, 1H, J = 4.7 Hz), 4.25 (dd, 1H, J = 8.1, 4.1 Hz), 3.82 (s, 3H), 3.55-3.38 (m, 2H), 2.78-2.61 (m, 2H), 2.34-1.96 (m, 3H), 1.92-1.80 (m, 1H), 1.49 13 (s, 9H); C NMR (75 MHz, CDCl3,) δ 195.0, 176.1, 173.9, 171.4, 154.5, 139.8, 129.3, 126.4, 125.4, 122.8, 110.4, 79.9, 70.3, 59.0, 56.9, 53.8, 52.9, 47.0, 40.4, 29.3, 28.4, 24.8; IR (thin film) ν 3250, 2979, 2251, 1732, 1681, 1652, 1651, 1474, 1404, 1367, 1272, + 1210, 1165, 1131, 912, 732; HiResMALDI-MS calcd for C24H29N3O7 [M+Na] 494.1903, found, 494.1907. Experimental Part 177
Boc MeO2C O N HN N H O HO Me Me methyl (2'S,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-(1- hydroxy-2-methylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'- carboxylate (347)
A solution of aldehyde 345 (10.4 mg, 22.1 µmol, 1.00 equiv) in Et2O (2 mL) was cooled to −78 °C. iPrMgCl (2.0 M in Et2O, 16 µL, 33 µmol, 1.5 equiv) was added slowly and the reaction mixture was stirred for 2 h; then the mixture was allowed to reach room temperature slowly. After 14 h, Et2O (5 mL) and sat. aq NH4Cl (5 mL) were added, the layers were separated and the organic layer was washed with brine (10 mL), dried
(Na2SO4), filtered, and the solvent was evaporated in vacuo. Purification by column chromatography (1:1 EtOAc/hexanes) afforded 347 (11.1 mg, 97%) as colorless oil.
1 Rf = 0.38 (3:1 EtOAc/hexanes); H NMR (300 MHz, CDCl3) 8.25-7.85 (br, 1H), 7.61 (d, 1H, J = 7.5 Hz), 7.26-7.21 (m, 1H), 7.09-7.04 (m, 1H), 6.85 (d, 1H, J = 7.8 Hz), 5.28 (d, 1H, J = 9.3 Hz), 4.67 (s, 1H), 4.29-4.25 (m, 1H), 4.02 (d, 1H, J = 12.1 Hz), 3.76 (s, 3H), 3.54-3.43 (m, 2H), 3.31 (dd, 1H, J = 13.1, 10.3 Hz), 3.20-3.13 (m, 1H), 2.65 (d, 1H, J = 13.1 Hz), 2.47-2.38 (m, 1H), 2.27-2.09 (m, 2H), 1.92-1.49 (m, 3H), 1.28-1.23 + (m, 9H), 0.87-0.83 (m, 6H); HiResMALDI-MS calcd for C27H37N3O7 [M+Na] 538.2529, found, 538.2510.
O O S Me Ph Me
(propane-2-sulfonyl)-benzene (350)
To a solution of sulfinate 349 (7.83 g, 47.7 mmol, 1.50 equiv) and Bu4NI (750 mg) in
H2O/acetone (4:3, 17.5 mL) was added iPrI (5.40 g, 31.8 mmol, 1.00 equiv) followed by benzene (7.5 mL). The reaction mixture was heated to reflux for 24 h, then cooled to 178 Experimental Part
room temperature and poured onto a mixture of H2O (30 mL) and EtOAc (30 mL). The layers were separated and the organic layer was washed with 1 M aq Na2S2O3 (30 mL). The solvent was evaporated to afford a colorless oil. Purification by column chromatography (3:1 EtOAc/hexanes) afforded 350 (3.13 g, 36%) as colorless oil.
1 H NMR (300 MHz, CDCl3) δ 7.92-7.87 (m, 2H), 7.70-7.62 (m, 1H), 7.59-7.56 (m, 2H),
3.19 (quint, 1H, J = 6.9 Hz), 1.30 (d, 6H, J = 6.9 Hz).
Ph N Me N S NN Me
5-(isopropylthio)-1-phenyl-1H-tetrazole (355)
To a mixture of iPrOH (79.0 µl, 1.03 mmol, 1.00 equiv), triphenylphosphine (296 mg, 1.13 mmol, 1.10 equiv) and 2-phenyl-2H-tetrazole-5-thiol (201 mg, 1.13 mmol, 1.10 equiv) in THF (12 ml) was added DEAD (178 µl, 1.13 mmol, 1.10 equiv) dropwise over 10 min. The yellow solution was stirred at room temperature for 8 h and then concentrated under reduced pressure. A mixture of pentane and EtOAc (9:1, 20 ml) was added, the suspension was filtered over Celite and the filtrate concentrated under reduced pressure. Purification by flash chromatography (1:9 EtOAc/hexanes) provided 5-(isopropylsulfanyl)-1-phenyl-1H-tetrazole (355) (183 mg, 81% yield) as a colorless oil.
1 Rf = 0.77 (1:3 EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ 7.58-7.52 (m, 5H), 4.16 (quint, 1H, J = 6.5 Hz), 1.52 (d, 6H, J = 6.5 Hz). Experimental Part 179
Ph O O N Me N S NN Me
5-(isopropylsulfonyl)-1-phenyl-1H-tetrazole (356)
To a solution of 5-(isopropylsulfanyl)-1-phenyl-1H-tetrazole (183 mg, 0.831 mmol, 1.00 equiv) in methanol (8 mL) was added an aqueous solution (8 mL) of Oxone (1.53 g, 2.49 mmol, 3.00 equiv) at room temperature. After stirring at room temperature for 2 d, the mixture was diluted with Et2O (20 mL), washed with H2O (25 mL). The layers were separated and the aqueous phase was extracted with Et2O (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (1:4 EtOAc/hexanes) provided sulfone 356 (177 mg, 85% yield) as a white solid.
1 Rf = 0.38 (1:3 EtOAc/hexanes); mp = 67 °C; H NMR (300 MHz, CDCl3) δ 7.69-7.56 (m, 5H), 4.03 (quint, 1H, J = 6.9 Hz), 1.52 (d, 6H, J = 6.9 Hz).
Boc MeO2C O N HN N H O Me Me methyl (2'S,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-(2- methylprop-1-en-1-yl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'- carboxylate (336)
To a solution of sulfone 356 (28.3 mg, 112 µmol, 2.30 equiv) in THF (0.7 mL) at −78°C was added dropwise LHMDS (0.330 M in THF, 340 µL, 120 µmol, 2.3 equiv). The yellow solution was stirred at −78°C for 30 min. This solution was added in one portion with a precooled syringe to a solution of aldehyde 345 (23.0 mg, 49.0 µmol, 1.00 equiv) in THF (0.7 mL) at −78 °C. The reaction mixture was stirred at -78°C for 3 h; then the mixture was slowly warmed to room temperature and stirred for 8 h. The reaction mixture was diluted with Et2O (10 mL) and washed with H2O (10 mL). The organic layer was 180 Experimental Part
dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (3:2 EtOAc/hexanes) to afford 336 (19 mg, 78%) as white crystals.
24 1 Rf = 0.28 (3:1 EtOAc/hexanes), [α]D (c 0.985, CHCl3) = +30.7; mp = 231 °C; H NMR # (300 MHz, CDCl3, denotes major-, * minor rotamer signals) δ 7.92 (br, 2H), 7.51-7.45 (m, 1H*), 7.38-7.17 (m, 1H#), 7.12-6.96 (m, 4H), 6.89 (d, 1H#, J = 7.5 Hz), 6.81 (d, 1H*, J = 7.5 Hz), 5.50 (t, 1H*, J = 7.8 Hz), 5.50 (d, 1H*, J = 9.7 Hz), 5.22 (d, 1H*, J = 9.7 Hz), 4.98 (t, 1H*, J = 9.0 Hz), 4.84-4.70 (m, 2H#), 4.46 (dd, 1H#, J = 8.7, 2.2 Hz), 4.29 (dd, 1H*, J = 8.1, 3.4 Hz), 3.78 (s, 3H#), 3.73 (s, 3H*), 3.70-3.50 (m, 2H), 3.45-3.34 (m, 2H), 2.70-2.53 (m, 2H), 2.35-1.72 (m, 10H), 1.72 (s, 3H#), 1.59 (s, 9H#), 1.57 # 13 (s, 9H*), 1.53 (s, 3H ), 1.53 (s, 3H*), 1.51 (s, 3H*); C NMR (75 MHz, CDCl3,) δ 176.0, 174.0, 171.2, 153.5, 139.9, 137.9, 129.5, 128.7, 123.7, 122.8, 121.4, 110.1, 80.2, 63.0, 60.7, 58.8, 57.2, 52.4, 46.8, 37.3, 32.2, 28.4, 25.9, 23.2, 18.3; IR (thin film) ν 3246, 2977, 2931, 1727, 1698, 1619, 1472, 1434, 1401, 1366, 1298, 1270, 1202, 1173, 1167, 752; + HiResMALDI-MS calcd for C27H35N3O6 [M+Na] 520.2423, found, 520.2409.
Crystal data for 336 at 193 K, Mr = 616.95, orthorhombic space group P2(1)2(1)2(1), –3 ρcalc = 1.311 g·cm , Z = 4, a = 8.9350(10), b = 13.870(2), c = 25.228(7) Å, α = 90.00, β = 90.00, γ = 90.00°, V = 3126.5(10) Å3. Final R(F) = 0.0608, wR(F2) = 0.1778 for 395 parameters and 2945 reflections with I >2σ(I) and θ < 69.98°.
CCDC 196804 (336) contains the supplementary crystallographic data for this structure. This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]). Experimental Part 181
Boc MeO2C O N HN N H O Me Me methyl (2'S,3S)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-(2- methylprop-1-en-1-yl)-2-oxo-1,1',2,2'-tetrahydrospiro[indole-3,3'-pyrrole]-5'- carboxylate (357)
To a solution of 336 (9.0 mg, 180 µmol, 1.0 equiv) in THF (1 mL) at 0 °C was added
LHMDS (0.330 M in THF, 121 µL, 400 µmol, 2.20 equiv). The solution was kept at 0 °C for 30 min and a solution of phenylselenyl chloride (7.6 mg, 400 µmol, 2.2 equiv) in THF (1 mL) was added. The reaction mixture was stirred at 0 °C for 90 min, and quenched by addition of sat. aq NaHCO3 (10 mL). The product was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The unpurified mixture was used without for the subsequent reaction.
Rf = 0.59, 0.51 (3:1 EtOAc/hexanes).
To a solution of the intermediate selenide in THF (0.5 mL) at 0 °C was added DMDO
(≈ 0.09 M in acetone, 80.0 µL, 72.0 µmol, 4.00 equiv). Stirring was continued for 3 h, the solvent was evaporated in vacuo. Column chromatography (11:9 EtOAc/hexanes) afforded 357 (6.9 mg, 74% over two steps) as a colorless oil.
25 1 Rf = 0.50 (3:1 EtOAc/hexanes), [α]D (c 0.220, CHCl3) = +42.0; H NMR (300 MHz, # CDCl3, denotes major-, * minor rotamer signals) δ 7.97-7.60 (br, 2H), 7.26-7.19 (m, 2H), 7.14-7.10 (m, 2H), 7.07-6.97 (m, 2H), 6.85 (d, 2H, J = 7.5 Hz), 5.71-5.67 (m, 2H*), 5.49-5.44 (m, 2H#), 5.31-5.23 (m, 2H), 4.52-4.48 (m, 1H*), 4.37-4.35 (m, 1H#), 3.85 (s, 3H#), 3.84 (s, 3H*), 3.68-3.55 (m, 2H), 3.47-3.29 (m, 2H), 2.18-1.65 (m, 8H), 1.58 (s, 6H), 1.50 (s, 9H#), 1.45 (s, 9H*), 1.42 (s, 3H*), 1.25 (s, 3H#); 13C NMR
(75 MHz, CDCl3,) δ 177.2, 171.7, 162.1, 153.6, 140.3, 140.0, 137.6, 129.1, 128.9, 127.5, 126.8, 122.3, 122.0, 109.8, 80.2, 65.5, 58.2, 52.6, 46.8, 31.5, 28.6, 25.4, 23.4, 18.3, 17.8; IR (thin film) ν 3248, 2977, 2932, 1732, 1694, 1619, 1472, 1400, 1366, 1260, 1228, 182 Experimental Part
+ 1164, 1126, 753; HiResMALDI-MS calcd for C27H33N3O6 [M+Na] 518.2267, found, 518.2276.
O O N HN N H O Me
Me spirotryprostatin B (17)
A solution of 357 (4.7 mg, 10 mmol, 1.0 equiv) in CH2Cl2/TFA (5:1, 0.6 mL) was stirred at room temperature for 30 min. The solvent was evaporated in vacuo and the product was dissolved in CH2Cl2 (0.5 mL), and NEt3 (5.2 µL, 38 µmol, 4.0 equiv) was added. The reaction mixture was stirred at room temperature for 4 h, and quenched by addition of sat. aq NaHCO3 (10 mL). The product was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo.
Column chromatography (75:20:8 CH2Cl2/EtOAc/iPrOH) afforded spirotryprostatin B (17) (2.6 mg, 74% over two steps) as a white solid.
26 Rf = 0.23 (75:20:8 CH2Cl2/EtOAc/i-PrOH), mp = 136 °C; [α]D (c 0.045, CHCl3) = 1 −148.8; H NMR (500 MHz, CDCl3) δ 7.53 (br, 1H), 7.24 (ddd, 1H, J = 7.6, 7.6, 1.1 Hz), 7.07 (d, 1H, J = 7.6 Hz), 7.00 (ddd, 1H, J = 7.6, 7.6, 1.1 Hz), 6.85 (d, 1H, J = 7.6 Hz), 5.78 (s, 1H), 5.43 (d, 1H, J = 8.9 Hz), 5.21 (ddd, 1H, J = 8.9, 8.9, 1.4 Hz), 4.34 (dd, 1H. J = 10.7, 6.1 Hz), 3.80 (ddd, 1H, J = 12.2, 12.2, 8.2 Hz), 3.57 (m, 1H), 2.51-2.47 (m, 1H), 2.13-2.09 (m, 1H), 2.04-1.93 (m, 2H), 1.57 (s, 3H), 1.28 (d, 3H, J = 1.2 Hz); 13C NMR
(125 MHz, CDCl3,) δ 177.8, 162.6, 155.1, 140.3, 138.4, 138.3, 129.1, 127.9, 127.3, 122.3, 120.5, 116.3, 109.8, 64.2, 61.8, 61.6, 44.9, 29.3, 25.5, 22.1, 18.3; IR (thin film) ν 3212, 2926, 1855, 1725, 1682, 1644, 1471, 1434, 1326, 1293, 1215, 1157, 1105, 753; + HiResMALDI-MS calcd for C21H21N3O3 [M+Na] 386.1481, found, 386.1478. Experimental Part 183
5.2. Synthesis of Spirotryprostatin B from Intermediate 324
Coupling of 324 with N-Boc-L-proline chloride.
Me Me Boc Me Boc O O N N
HN NH HN N + HN N H H O O O
TIPS TIPS TIPS 324 358 359
To a solution of 324 (150 mg, 367 µmol, 1.00 equiv) and NEt3 (51.0 µL, 367 µmol, 1.00 equiv) in CH2Cl2 (13 mL) at 0 °C was added N-Boc-L-proline chloride (0.140 M in
CH2Cl2, 6.70 mL, 918 µmol, 2.50 equiv). The reaction mixture was allowed to warm slowly to room temperature and stirred for 8 h. The reaction was quenched by addition of
10% aq NaHCO3 (10 mL). The phases were separated; the organic layer was washed with sat. aq NaHCO3 (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (1:3 EtOAc/hexanes) afforded:
Me Boc O N HN N H O
TIPS tert-butyl (2S)-2-({(2'R,3S,5'R)-2-oxo-5'-[(1Z)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)- ethynyl]-1,2-dihydro-1'H-spiro[indole-3,3'-pyrrolidin]-1'-yl}carbonyl)pyrrolidine-1- carboxylate (358)
White solid, 89 mg (40%).
26 Rf = 0.59 (1:1 EtOAc/hexanes), [α]D (c 0.425, CHCl3) = −4.03; mp = 86-87 °C; 1 # H NMR (300 MHz, CDCl3 denotes major-, * minor rotamer signals) δ 8.47 (br, 1H*), 8.34 (br, 1H#), 7.37-7.13 (m, 4H), 7.10-6.99 (m, 2H), 6.94-6.84 (m, 2H), 5.66-5.41 (m, 4H), 5.41 (s, 1H*), 5.25-5.13 (m, 2H), 5.14 (s, 1H#), 4.95-4.68 (m, 2H), 3.69-3.34 184 Experimental Part
(m, 4H), 2.39-1.96 (m, 8H), 1.85-1.64 (m, 10H), 1.55 (s, 9H#), 1.45 (s, 9H*), 0.82 (s, 13 42H); C NMR (75 MHz, CDCl3, * denotes minor rotamer signals) δ 176.3*, 176.2, 173.3*, 172.9, 154.1*, 153.5, 140.1, 131.6*, 130.7, 128.7, 128.4*, 127.8, 127.1*, 124.8, 124.4*, 124.2, 123.7*, 122.9, 122.8*, 110.1*, 109.9, 102.0*, 101.1, 90.8, 89.5*, 79.9, 79.2*, 58.7, 57.9*, 57.7, 56.7, 56.5*, 56.1*, 54.5*, 47.3, 40.2, 40.0*, 32.2, 30.4*, 29.8*, 29.3, 28.8, 28.5*, 24.7, 23.5*, 18.5, 13.2, 13.1*, 11.0; IR (thin film) ν 3206, 2942, 2865, 2171, 1728, 1688, 1471, 1397, 1297, 1166, 1121, 883, 768, 752, 676; HiResMALDI-MS + calcd for C35H51N3SiO4 [M+Na] 628.3546, found, 628.3535.
Me Boc N
HN N H O O
TIPS tert-butyl (2S)-2-({(2'S,3R,5'S)-2-oxo-5'-[(1Z)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)- ethynyl]-1,2-dihydro-1'H-spiro[indole-3,3'-pyrrolidin]-1'-yl}carbonyl)pyrrolidine-1- carboxylate (359)
White solid, 87mg (39%).
26 1 Rf = 0.42 (1:1 EtOAc/hexanes), [α]D (c 0.450, CHCl3) = −9.87; mp = 96 °C; H NMR # (300 MHz, CDCl3 denotes major-, * minor rotamer signals) δ 8.71 (br, 1H*), 8.57 (br, 1H#), 7.48 (d, 1H#, J = 7.5 Hz), 7.25-7.19 (m, 3H), 7.04-6.88 (m, 4H), 6.12-6.05 (m, 1H*), 5.71-5.45 (m, 3H), 5.29-5.15 (m, 2H), 5.19 (s, 1H*), 4.68-4.87 (m, 1H), 4.90 (s, 1H#), 3.68-3.36 (m, 4H), 2.70 (dd, 1H#, J = 13.1, 8.1 Hz), 2.32-2.10 (m, 5H), 2.00-1.77 (m, 7H), 1.73-1.67 (m, 6H), 1.48 (s, 9H#), 1.43 (s, 9H*), 0.96-0.95 (m, 21H*), # 13 0.85-0.82 (m, 21 H ); C NMR (75 MHz, CDCl3, * denotes minor rotamer signals) δ 178.6, 176.3*, 170.7, 170.3*, 154.2*, 154.1, 140.7, 140.3*, 133.2, 132.2*, 131.1, 130.5*, 128.7, 128.4*, 125.5, 125.5*, 124.8, 124.0*, 122.9*, 122.1, 110.1, 109.7*, 102.0, 99.0*, 91.9*, 87.3, 79.7, 79.1*, 59.1, 58.6*, 58.1, 57.0*, 56.4, 55.7*, 53.7*, 53.5, 46.5, 46.4*, 43.1, 39.3*, 30.2*, 29.7, 28.6, 28.5*, 23.3*, 22.9, 18.6, 18.4*, 13.3*, 13.0, 11.2, 11.0*; IR (thin film) ν 3208, 2942, 2865, 2171, 1728, 1704, 1676, 1621, 1472, 1399,
1366, 1265, 1166, 1125, 883, 749, 678; HiResMALDI-MS calcd for C35H51N3SiO4 [M+Na]+ 628.3546, found, 628.3536. Experimental Part 185
O Boc O N HN N H O
TIPS tert-butyl (2S)-2-({(2'R,3S,5'R)-5'-formyl-2-oxo-2'-[(triisopropylsilyl)ethynyl]-1,2- dihydro-1'H-spiro[indole-3,3'-pyrrolidin]-1'-yl}carbonyl)pyrrolidine-1-carboxylate (330)
A solution of 358 (21.6 mg, 35.7 µmol, 1.00 equiv) and NMO·H2O (5.0 mg, 43 µmol,
1.2 equiv) in THF/tBuOH/H2O (4:4:1, 1 mL) was stirred at room temperature for 30 min before OsO4 (4 wt% in H2O, 9.0 µL, 1.4 µmol, 4 mol%) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by addition of 2 M aq Na2S2O3 (2 mL) and EtOAc (5 mL) was added. The biphasic mixture was stirred for 3h. The phases were separated; the organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The mixture of isomeric products was used without further purification.
Rf = 0.16 (3:1 EtOAc/hexanes).
To a solution of diols in EtOAc (1.5 mL) was added Pb(OAc)4 (18.3 mg, 53.6 µmol, 1.50 equiv). A yellow suspension was obtained and after stirring for 10 min, the mixture was filtered through a plug of silica gel, eluting with EtOAc. Purification by column chromatography (1:1 EtOAc/hexanes) afforded 330 (18 mg, 85%) as a white solid. 186 Experimental Part
5.3. Synthesis of Spirotryprostatin B from Intermediate 326
Coupling of 326 with N-Boc-L-proline chloride.
Me Me Me Boc Boc O O N N
HN NH HN N + HN N H H O O O
inseperable TIPS TIPS by column TIPS 326 361chromatography 362
To a solution of 326 (150 mg, 367 µmol, 1.00 equiv) and NEt3 (51.0 µL, 367 µmol,
1.00 equiv) in CH2Cl2 (10 mL) at 0 °C was added N-Boc-L-proline chloride (0.140 M in
CH2Cl2, 7.00 mL, 929 µmol, 2.50 equiv). The reaction mixture was allowed to warm slowly to room temperature and stirred at room temperature for 8 h. The reaction was quenched by addition of 10% aq NaHCO3 (10 mL). The phases were separated; the organic layer was washed with sat. aq NaHCO3 (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (11:9 EtOAc/hexanes) afforded the product as a mixture of isomers 361/362 (182 mg, 82%), which were used for the following steps without further separation.
Rf = 0.15 (1:1 EtOAc/hexanes). Experimental Part 187
Transformation to 363/364
Me Me Boc Boc Boc Boc MeO2C MeO2C O N N O N N
HN N + HN N HN N + HN N H H H H O O O O O O (1:2) TIPS inseperable TIPS seperable 363 364 361by column 362 by column chromatography chromatography
Dihydroxylation and diol cleavage:
A solution of 361/362 (122 mg, 202 µmol, 1.00 equiv) and NMO·H2O (33.0 mg,
242 µmol, 1.20 equiv) in THF/tBuOH/H2O (4:4:1, 5 mL) was stirred at room temperature for 30 min before OsO4 (4 wt% in H2O, 52.0 µL, 81.0 µmol, 4 mol%) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by addition of 2 M aq Na2S2O3 (5 mL) and EtOAc (5 mL). The biphasic mixture was stirred for 3 h. The phases were separated; the organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The mixture of isomeric products was used without further purification.
Rf = 0.27 (3:1 EtOAc/hexanes).
To a solution of diols in EtOAc (10 mL) was added Pb(OAc)4 (104 mg, 303 µmol, 1.50 equiv). A yellow suspension was obtained and after stirring for 10 min, the mixture was filtered through a plug of silica gel, eluting with EtOAc. The mixture of isomeric products was used without further purification.
Rf = 0.32 (3:1 EtOAc/hexanes).
Oxidation and ester formation:
A solution of NaClO2 (182 mg, 2.01 mmol, 10.0 equiv) in pH 3.6 buffer (3.5 mL) was added to a solution of the aldehydes and 2-methyl-2-butene (2.1 mL) in tBuOH (7 mL).
The reaction mixture was stirred at room temperature for 30 min, 2 M aq HCl was added (5 mL), and the product was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. 188 Experimental Part
Rf = 0.06 (3:1 EtOAc/hexanes).
The products were dissolved in Et2O (4 mL) and a solution of CH2N2 in Et2O (≈ 0.4 M in
Et2O) was added untill the yellow color of CH2N2 persisted. The solvent was evaporated in vacuo and the unpurified products were used for the next reaction.
Rf = 0.44 (3:1 EtOAc/hexanes).
TIPS deprotection:
To a solution of the esters in THF (6 mL), was added TBAF (1.0 M in THF, 240 µL, 240 µmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 8 h, and diluted with CH2Cl2. The organic solution was washed with sat. aq NaHCO3, and dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (13:7 EtOAc/hexanes) to afford the two isomers 363 and 364 in combined yield of 72 mg (75%).
Boc MeO2C O N HN N H O
methyl (2'S,3S,5'S)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'- ethynyl-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate (363)
Colorless oil, 25 mg (26%).
26 1 Rf = 0.37 (3:1 EtOAc/hexanes), [α]D (c 0.240, CHCl3) = −8.7; H NMR (300 MHz,
CDCl3 mixture of 4 rotamers, relative integration is given) δ 8.53-8.51 (m, 0.8H), 8.42 (s, 0.07H), 8.39 (s, 0.13H), 7.64-7.54 (m, 1H), 7.34-7.20 (m, 1H), 7.13-7.01 (m, 1H), 6.93-6.88 (m, 1H), 5.50 (d, 0.08H, J = 2.3 Hz), 5.46 (d, 0.31H, J = 2.3 Hz), 5.29 (m, 0.15H), 5.15-5.03 (m, 0.8H), 4.87 (d, 0.46H, J = 2.3 Hz), 4.85-4.82 (m, 0.2H), 4.68-4.65 (m, 0.4H), 4.58-4.54 (m, 0.46H), 4.26-4.22 (m, 0.14H), 3.86 (s, 0.16H), 3.77-3.77 (m, 0.84H), 3.67-3.39 (m, 2H), 2.73 (d, 0.08H, J = 2.3 Hz), 2.70 (d, 0.46H, J = 2.3 Hz), 2.66 (d, 0.31H, J = 2.3 Hz), 2.58-2.41 (m, 1.15H), 2.39-2.06 (m, 3H), 1.98-1.74 13 (m, 2H), 1.52-1.28 (m, 9H); C NMR (75 MHz, CDCl3, mixture of rotamers) δ 178.7, Experimental Part 189
178.6, 172.3, 171.6, 171.5, 154.3, 153.7, 141.4, 141.3, 129.5, 126.2, 126.0, 125.7, 125.6, 125.4, 124.9, 122.2, 122.0, 110.2, 80.2, 80.0, 79.6, 79.5, 58.6, 58.2, 57.6 56.0, 55.5, 54.5, 53.1, 53.0, 52.5, 52.4, 47.1, 36.5, 31.5, 30.2, 28.6, 28.5, 24.3, 22.0; IR (thin film) ν 3246, 2977, 2116, 1721, 1687, 1673, 1620, 1473, 1402, 1366, 1261, 1241, 1166; + HiResMALDI-MS calcd for C25H29N3O6 [M+Na] 490.1954, found, 490.1945.
Boc MeO2C N
HN N H O O
methyl (2'R,3R,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'- ethynyl-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate (364)
Colorless solid, 46 mg (49%).
26 Rf = 0.22 (3:1 EtOAc/hexanes); mp = 142-144 °C [α]D (c 1.00, CHCl3) = +31.5; 1H NMR (300 MHz, mixture of rotamers, only the major rotamer is described) δ 8.30 (br, 1H), 7.62 (d, 1H, J = 7.1 Hz), 7.31 (dt, 1H, J = 7.8, 1.2 Hz), 7.11-7.06 (m, 1H), 6.92 (d, 1H, J = 7.5 Hz), 4.88 (dd, 1H, J = 8.1, 9.7 Hz), 4.69 (d, 1H, J = 2.2 Hz), 4.58 (dd, 1H, J = 8.4, 2.2 Hz), 3.78 (s, 3H), 3.69-3.58 (m, 1H), 3.56-3.36 (m, 1H), 2.67 (d, 1H, J = 2.2 13 Hz), 2.57-2.46 (m, 3H), 2.19-1.71 (m, 3H), 1.49 (s, 9H); C NMR (75 MHz, CDCl3, mixture of rotamers, the two major ones are described) δ179.4, 178.8, 171.8, 171.6, 171.4, 171.2, 154.2, 154.0, 141.7, 141.6, 132.1, 132.0, 129.5, 129.1, 128.6, 128.4, 125.9, 125.8, 125.4, 124.9, 122.1, 122.0, 110.3, 110.1, 80.3, 80.1, 79.7, 79.5, 78.7, 78.5, 58.4, 58.3, 57.6, 55.2, 55.1, 53.8, 53.0, 52.4, 46.9, 46.8, 40.7, 36.6, 30.0, 29.4, 28.5, 28.4, 23.4, 23.1, 14.3, 12.9; IR (thin film) ν 3233, 2977, 1716, 1621, 1473, 1403, 1364, 1331, 1262, + 1240, 1168, 1128, 754; HiResMALDI-MS calcd for C25H29N3O6 [M+Na] 490.1954, found, 490.1945. 190 Experimental Part
O H N
N HN H O O
(2R,3R,5aS,10aR)-3-ethynyl-5a,6,7,8-tetrahydro-1H,5H-spiro[dipyrrolo[1,2-a:1',2'- d]pyrazine-2,3'-indole]-2',5,10(1'H,10aH)-trione (365)
A solution of 364 (15.3 mg, 41.6 µmol, 1.00 equiv) in CH2Cl2/TFA (5:1, 2 mL) was stirred at room temperature for 30 min. The solvent was evaporated in vacuo and the product was dissolved in CH2Cl2 (1 mL), and NEt3 (22.8 µL, 166 µmol, 4.00 equiv) was added. The reaction mixture was stirred at room temperature for 4 h, and quenched by addition of sat. aq NaHCO3 (10 mL). The product was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (75:20:8 CH2Cl2/EtOAc/iPrOH) afforded 365 (6.0 mg, 43% over two steps) as a colorless oil.
23 1 Rf = 0.24 (75:20:8 CH2Cl2/EtOAc/iPrOH), [α]D (c 0.250, CHCl3) = −74.1; H NMR
(300 MHz, CDCl3) δ 8.14 (br, 1H), 7.45 (d, 1H, J = 7.6 Hz), 7.29 (ddd, 1H, J = 7.6, 7.6, 1.2 Hz), 7.08 (ddd, 1H, J = 7.6, 7.6, 1.2 Hz), 6.91 (d, 1H, J = 7.6 Hz), 5.12 (ddd, 1H, J = 11.8, 8.1, 5.6 Hz), 4.91 (d, 1H, J = 2.5 Hz), 4.22 (ddd, 1H, J = 11.8, 68.1,.2 Hz), 4.06 (ddd, 1H, J = 15.6, 9.3, 6.8 Hz), 3.30 (ddd, 1H, J = 12.5, 10.0, 5.0 Hz), 2.66 (dd, 1H, J = 13.1, 5.6 Hz), 2.58 (d, 1H, J = 2.5 Hz), 2.57-2.38 (m, 1H), 2.18-1.79 (m, 4H); 13C NMR
(125 MHz, CDCl3,) δ 179.6, 165.0, 164.4, 140.7, 129.4, 126.6, 122.7, 110.0, 109.7, 78.1, 62.7, 58.0, 54.2, 53.3, 44.5, 38.6, 28.5, 22.1, 20.6; IR (thin film) ν 3262, 2925, 2125,
1715, 1660, 1619, 1472, 1445, 1311, 1189, 755; HiResMALDI-MS calcd for C19H17N3O3 [M+Na]+ 336.1343, found, 336.1350. Experimental Part 191
Boc MeO2C O N HN N H O methyl (2'S,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2- oxo-2'-vinyl-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate (366)
To a solution of 363 (170 mg, 364 µmol, 1.00 equiv) and quinoline (22.0 µL, 182 µmol,
0.50 equiv) in EtOH (4 mL) was added Pd/BaSO4 (50 mg, 33 wt%). The reaction mixture was stirred at room temperature under H2 atmosphere for 24 h. The solution was filtered over Celite to remove the catalyst and the solvent was evaporated in vacuo. The product was purified by column chromatography (57:43 EtOAc/hexanes) to afford 366 (167 mg, 98%) as a colorless oil.
22 1 Rf = 0.32 (3:1 EtOAc/hexanes), [α]D (c 0.735, CHCl3) = −9.6; H NMR (300 MHz,
CDCl3 mixture of 4 rotamers, relative integration is given) δ 8.85-8.77 (m, 0.55H), 8.65 (s, 0.38H), 8.58 (s, 0.07H), 7.57 (d, 0.26H, J = 8.1 Hz), 7.32-7.12 (m, 1.74H), 7.09-6.85 (m, 2H), 5.99-5.84 (m, 0.68H), 5.77-5.29 (m, 2H), 5.22-5.20 (m, 0.32H), 5.14-5.03 (m, 1H), 4.95-4.83 (m, 0.55H), 4.68-4.64 (m, 0.45H), 4.58-4.55 (m, 0.15H), 4.43-4.36 (m, 0.69H), 4.29-4.22 (m, 0.16H), 3.86-3.85 (m, 0.25H), 3.87-3.86 (m, 2.57H), 3.67-3.33 (m, 2H), 2.70-2.18 (m, 2.85H), 2.11-1.74 (m, 3.15H), 1.48-1.40 (m, 9H); 13C NMR
(75 MHz, CDCl3, mixture of 4 rotamers) δ 180.5, 179.7, 179.6, 178.7, 178.5, 173.5, 173.2, 172.4, 172.3, 171.8, 171.6, 171.4, 154.3, 154.2, 153.7, 153.6, 141.5, 141.4, 136.0, 135.9, 129.4, 129.3, 129.0, 128.9, 126.2, 126.2, 126.0, 122.0, 121.8, 121.7, 119.5, 119.1, 110.3, 110.2, 80.0, 79.6, 79.4, 79.3, 65.0, 64.0, 58.6, 58.5, 58.2, 57.9, 57.6, 57.4, 57.2, 56.9, 56.2, 55.9, 55.5, 54.5, 54.0, 52.9, 52.4, 52.4, 52.3, 47.2, 47.1, 36.4, 35.9, 35.8, 32.0, 31.5, 30.7, 30.2, 29.7, 29.1, 28.5, 24.3, 23.0; IR (thin film) ν 3242, 2977, 1721, 1687, 1473, 1403, 1366, 1257, 1242, 1202, 1167, 1125, 754, 668; HiResMALDI-MS calcd for + C25H31N3O6 [M+Na] 492.2110, found, 492.2105.
192 Experimental Part
Boc MeO2C O N HN N H O O methyl (2'R,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'- formyl-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate (367)
A solution of 366 (60.0 mg, 128 µmol, 1.00 equiv) and NMO·H2O (21.0 mg, 154 µmol,
1.20 equiv) in THF/tBuOH/H2O (4:4:1, 5 mL) was stirred at room temperature for 30 min before OsO4 (4 wt% in H2O, 813 µL, 128 µmol, 1.00 equiv) was added. The reaction mixture was stirred at room temperature for 2 d. The reaction was quenched by addition of 2 M aq Na2S2O3 (5 mL) and EtOAc (5 mL). The biphasic mixture was stirred for 6 h. The phases were separated; the organic layer was washed with brine (10 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (3:2 EtOAc/hexanes) afforded the diol as colorless oil.
Rf = 0.10 (3:1 EtOAc/hexanes).
To a solution of the unpurified diol in EtOAc (5 mL) was added Pb(OAc)4 (43.0 mg, 125 µmol, 1.00 equiv). A yellow suspension was obtained, and, after stirring for 10 min, the mixture was filtered through a plug of silica gel, eluting with EtOAc. Evaporation of the solvent and purification by column chromatography (7:3 EtOAc/hexanes) afforded 367 (38 mg, 63%) as a colorless oil.
24 1 Rf = 0.49 (3:1 EtOAc/hexanes), [α]D (c 1.650, CHCl3) = −0.2; H NMR (300 MHz,
CDCl3 mixture of 4 rotamers, relative integration is given) δ 9.82-9.76 (m, 0.62H), 9.62 (d, 0.38H, J = 2.8 Hz), 9.04-8.95 (m, 0.52H), 8.83-8-69 (m, 0.48H), 7.29-7.20 (m, 1H), 7.12-6.87 (m, 3H), 5.24-4.87 (m, 1.48H), 4.83 (d, 0.18H, J = 2.8 Hz), 4.76-4.63 (m, 0.24H), 4.57-4.52 (m, 0.28H), 4.48-4.48 (m, 0.10H), 4.41-4.37 (m, 0.25H), 4.22-4.15 (m, 0.47H), 3.90 (s, 0.63H), 3.87 (s, 0.66H), 3.82-3.78 (m, 1.71H), 3.67-3.35 (m, 2H), 2.92-2.77 (m, 0.27H), 2.74-2.54 (m, 0.79H), 2.45-2.25 (m, 1.11H), 2.21-1.75 (m, 3.83H), 13 1.47-1.39 (m, 9H); C NMR (75 MHz, CDCl3, mixture of 4 rotamers) δ 197.3, 197.2, 178.2, 177.8, 173.0, 172.6, 172.0, 171.5, 154.1, 153.6, 141.0, (132.0), (131.9), 129.8, 129.5, (128.5), (128.3), 126.3, 125.5, 125.3, 124.8, 123.1, 122.7, 122.2, 110.7, 110.2, Experimental Part 193
80.4, 80.3, 79.8, 79.3, 70.2, 69.8, 69.3, 67.3, 60.0, 59.4, 58.3, 57.4, 56.4, 53.3, 53.1, 52.7, 47.0, 46.8, 40.4, 37.3, 31.2, 30.0, 29.7, 29.2, 28.5, 28.5, 24.5, 24.0, 23.3, 23.2; + HiResMALDI-MS calcd for C24H29N3O7 [M+Na] 494.1903, found, 494.1894.
Boc MeO2C O N HN N H O Me Me methyl (2'S,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-(2- methylprop-1-en-1-yl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'- carboxylate (368)
To a solution of sulfone 356 (10.6 mg, 41.9 µmol, 2.50 equiv) in THF (0.5 mL) at −78°C was added dropwise LHMDS (0.330 M in THF, 123 µL, 41.9 µmol, 2.50 equiv). The yellow solution was stirred at −78°C for 30 min. This solution was added in one portion with a precooled syringe to a solution of aldehyde 367 (7.9 mg, 17 µmol, 1.0 equiv) in THF (0.5 mL) at −78 °C. The reaction mixture was stirred at -78°C for 3 h; then the mixture was slowly warmed to room temperature and stirred for 8 h. The reaction mixture was diluted with Et2O (10 mL) and washed with H2O (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (11:9 EtOAc/hexanes) to afford 368 (5.7 mg, 68%) as a colorless oil,
26 1 Rf = 0.33 (3:1 EtOAc/hexanes), [α]D (c 0.135, CHCl3) = −0.0; H NMR (500 MHz,
CDCl3 mixture of 4 rotamers, relative integration is given) δ 7.82 (br, 1H), 7.24-7.17 (m, 1H), 7.14-7.05 (m, 1H), 7.03-6.93 (m, 1H), 6.89-6.84 (m, 1H), 5.56-5.51 (m, 0.82H), 5.44-5.34 (m, 0.32H), 5.22 (d, 0.16H, J = 9.7 Hz), 5.17 (d, 0.18H, J = 9.2 Hz), 5.11-5.06 (m, 0.82H), 4.89-4.86 (m, 0.18H), 4.81 (d, 0.52H, J = 9.3 Hz), 4.46-4.36 (m, 0.42H), 4.27-4.25 (m, 0.46H), 4.20-4.18 (m, 0.12H), 3.86 (s, 0.40H), 3.79-3.74 (m, 2.60H), 3.64-3.59 (m, 0.68H), 3.57-3.52 (m, 0.32H), 3.49-3.34 (m, 1H), 2.63-2.77 (m, 0.32H), 2.57-2.50 (m, 0.68H), 2.45-2.21 (m, 1.19H), 2.12-1.91 (m, 2.51H), 1.80-1.71 (m, 1.30H), 194 Experimental Part
1.70 (s, 1.30H), 1.70 (s, 2.06H), 1.44-1.43 (m, 9H), 1.70 (s, 0.94H), 1.70 (s, 1.03 H), 1.70 13 (d, 1.20H, J = 1.0 Hz), 1.70 (s, 0.77H); C NMR (125 MHz, CDCl3, mixture of 4 rotamers) δ 179.3, 172.9, 172.3, 153.8, 140.7, 137.1, 132.2, 132.0, 128.8, 128.5, 127.0, 126.4, 123.3, 122.8, 122.0, 121.6, 120.6, 109.4, 109.3, 79.9, 79.8, 61.7, 61.6, 58.9, 58.6, 58.5, 57.8, 57.6, 52.4, 52.3, 46.9, 36.0, 35.8, 31.3, 29.9, 29.7, 28.5, 28.5, 28.3, 25.5, 25.3, 24.1, 23.0, 17.8, 17.7; IR (thin film) ν 3227, 2976, 1724, 1695, 1624, 1468, 1401, 1366, + 1260, 1242, 1202, 1167, 1118, 755; HiResMALDI-MS calcd for C27H35N3O6 [M+Na] 520.2423, found, 520.2413.
Boc MeO2C O N HN N H O Me Me methyl (2'S,3S)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-(2- methylprop-1-en-1-yl)-2-oxo-1,1',2,2'-tetrahydrospiro[indole-3,3'-pyrrole]-5'- carboxylate (357)
To a solution of 368 (3.3 mg, 6.6 µmol, 1.0 equiv) in THF (1 mL) at 0 °C was added
LHMDS (0.330 M in THF, 76.0 µL, 25.2 µmol, 3.80 equiv). The solution was kept at 0 °C for 30 min and a solution of phenylselenyl chloride (4.8 mg, 25 µmol, 3.8 equiv) in THF (1 mL) was added. The reaction mixture was stirred at 0 °C for 90 min; and then quenched by addition of sat. aq NaHCO3 (6 mL). The product was extracted with EtOAc
(3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The mixture of isomeric products was used for elimination without further purification.
Rf = 0.59, 0.51 (3:1 EtOAc/hexanes).
To a solution of the selenide in THF (1 mL) at 0 °C was added DMDO (≈ 0.09 M in acetone, 300 µL, 265 µmol, 4.00 equiv). After stirring for 3 h, the solvent was evaporated in vacuo. Preparative TLC (3:1 EtOAc/hexanes) afforded 357 (1.3 mg, 40% over two steps) as a colorless oil. Curriculum Vitae 195
VIII. Curriculum Vitae
1972 Born on August 25, in Stuttgart, Germany.
1979-1983 Primary school in Ensheim, Germany.
1983-1992 High school in Saarbrücken, Germany.
Abitur: Scientific Maturity, July 1992.
1992-1995 Studies in Chemistry at the Universität des Saarlandes, Germany.
1995-1998 Studies in Chemistry at ECPM Strasbourg, France.
1996 Internship (6 weeks): Wacker Chemie GmbH, Burghausen, Germany.
1997 Internship (3 month): Toray Inc., Kyoto, Japan.
1998 Diploma thesis in the group of Prof. Dr. Francois Diederich, under the supervision of Laurent Ducry at the ETH Zürich.
• Studies towards the Synthesis of a New Ligand for Asymmetric Phase-Transfer Catalysis Bearing Binaphthyl and Cinchona Alkaloid Moieties.
1998-2003 Ph.D. thesis under the direction of Prof. Dr. Erick M. Carreira at the ETH Zürich.
• Novel Approach to Spiro-Pyrrolidine-Oxindoles and its Application to the Synthesis of (±)-Horsfiline and (−)-Spirotryprostatin B.
• Supervision of two diploma theses.
• Teaching assistant and head teaching assistant in the practica of organic chemistry and teaching assistant for chemistry exercises and lectures.
Zürich, January 2003 Christiane Marti