Thesis
Reference
Catalyst-controlled diastereoselective isomerization of optically active primary allylic alcohols
GUILLEMIN, Julien
Abstract
Le but de cette thèse a été l'investigation de l'isomérisation diastereosélective d'alcools allyliques primaires chiraux, ainsi que leur synthèse. Dans la première partie de ce travail de recherche, deux voies de synthèse différentes ont été mises au point pour l'obtention d'alcools allyliques primaires énantioenrichis. L'approche stéréoconstructive repose sur l'installation de la stéréochimie du carbon C-(4) par l'hydrogénation enantiosélective d'un alcène fonctionnalisé. Tandis que l'approche stéréorétentive se base sur le couplage croisé d'un produit commercial déjà énantiopur et d'un autre fragment. Des alcools allyliques primaires hautement énantioenrichis et géométriquement purs ont été synthétisés. Quatre catégories de substrats ont ainsi été développés. Dans la dernière décennie, l'isomérisation énantiosélective d'alcools allyliques primaires a été largement étudiée par différents groupes de recherches. Cependant, très peu d'exemples décrivent l'isomérisation diastéréosélective d'alcools allyliques primaires chiraux. La seconde partie de ce travail de [...]
GUILLEMIN, Julien. Catalyst-controlled diastereoselective isomerization of optically active primary allylic alcohols. Thèse de doctorat : Univ. Genève, 2018, no. Sc. 5276
URN : urn:nbn:ch:unige-1122794
DOI : 10.13097/archive-ouverte/unige:112279
Available at:
http://archive-ouverte.unige.ch/unige:112279
Disclaimer: layout of this document may differ from the published version.
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Catalyst-Controlled Diastereoselective Isomerization of Optically Active Primary Allylic Alcohols
THÈSE
présentée à la Faculté des sciences de l’Université de Genève pour obtenir le grade de Docteur ès sciences, mention chimie
par
Julien GUILLEMIN
de
Issy-les-Moulineaux (France)
Thèse N° 5276
GENÈVE 2018
Département de chimie organique Professeur Clément Mazet
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The results reported in this manuscript were part of my Ph.D work carried out in the laboratories of Prof. Clément Mazet in the Organic Chemistry Department at the University of Geneva.
I am extremely grateful to my supervisor for giving me the opportunity to be a member of his group for the last four years. Thank you for your time, advices and guidance. I would also like to thank the members of my thesis committee Dr. Amalia Isabel Poblador-Bahamonde (University of Geneva, Switzerland) and Prof. Jean-François Poisson (Université Grenoble Aples, France) for all the time dedicated in the evaluation of this thesis.
Dr. Gaël Tran helped me significantly writing this manuscript, and I cannot be more grateful for that. Thank you again for your advice and your honesty regarding the corrections and the feedback you provided me. I would like also to thank Daniele Fiorito for helpful suggestions while writing this manuscript.
I want to thank my past and present colleagues in the department and also the entire Mazet group. Kenji Caprice is acknowledged for being my best “buddy” in here; your arrival in the department changed everything. I cannot thank you enough for that. Along the same line, I would like to thank Dominic Hoch who has been such an inspiring friend when he was in the department. Thank you Gustavo Borrajo-Calleja for your help, support and the nice (scientific or not) discussions we had within the last 2 years. Many thanks to Ciro Romano and Daniele Fiorito for the scientific discussions we had during the last 4 years, and also the good laughs shared.
Many thanks to the most recent members in the Mazet group: Michele Garbo, Yangbin Liu, Dr. Gaël Tran and Camille Desfeux. We overlapped few months only, but it was nice to work by your sides and shared some good times with you.
Marion Pupier is acknowledged for the amazing work she is doing maintaining the NMR facilities for us to always work in the best conditions.
Sonia, Candolfi, Stéphane Rosset and Rifanul Miah are acknowledged for their constant support during the last 4 years and their contagious optimism.
I would like also to thank Dr. Elena Cardenal-Muñoz who supported me in the best ways possible since I started to write this manuscript.
Finally, but not least, I would like to thank the persons who believed in me since the beginning when I did not: Anne Courteix, Dr. Virginie Béreau, Julien Vache and mostly my beloved mother and sister.
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°C : celsius degree Ad : adamantyl Ar : aryl
Atm : atmosphere
BArF : tetrakis[3,5bis(trifluoromethyl)phenyl]borate BINAP : 2,2′-bis(diphenylphosphino)-1,1′-
binaphthalene Bn : benzyl Bz : benzoyl
Boc : tert-butyloxycarbonyl cat. : catalytic
CH2Cl2 : dichloromethane CH3CN : acetonitrile COD : 1,5-cyclooctadiene Conv. : conversion Cp : cyclopentadienyl Cy : cyclohexyl
d.r. : diastereomeric ratio
dba : trans,trans-dibenzylideneacetone DBU : 1,8-diazabicyclo[5.4.0]undec-7-ene DCE : 1,2-dichloroethane
DCM : dichloromethane DFT : density functional theory
DIOP : 2,3-O-isopropylidene-2,3-dihydroxy-1,4- bis(diphenylphosphino)butane
DIBAL-H : diisobutylaluminium hydride DifluorPhos : (2,2,2',2'-tetrafluoro-[4,4'- bibenzo[d][1,3]dioxole]-5,5'-
diyl)bis(diphenylphosphane) DMF : N,N-dimethylformamide DMSO : dimethyl sulfoxide
DTBM-SEGPHOS : 5,5′-bis[di(3,5-di-tert-butyl-4- methoxyphenyl)phosphino]-4,4′-bi-1,3-
benzodioxole
ee : enantiomeric excess es : enantiospecifity ent : enantiomer equiv. : equivalent Et : ethyl
Et3N : triethylamine EtOH : ethanol
GBL : gamma butyrolactone h : hours
HPLC: high-performance liquid chromatography Hz : hertz
i-Pr = iso-propyl IR : infrared
J : coupling constant
K : kelvin
KHMDS : potassium bis(trimethylsilyl)amide KOH : potassium hydroxide KOt-Bu: potassium tert-butoxide LFER : linear free-energy relationship LiHMDS : lithium bis(trimethylsilyl)amide m : multiplet
Me : methyl mg : milligram min : minute mmol : millimole Ms : mesyl MW : microwave nd : not determined
NHC : N-heterocyclic carbene NMR : nuclear magnetic resonance NOESY : nuclear overhauser effect spectroscopy
o-Tol : ortho-tolyl
OTBS : tert-butyldimethylsilyl ether OTBDPS : tert-butyldiphenylsilyl ether PAA : primary allylic alcohol
Ph : phenyl
PMB : para-methoxybenzyl ppm : parts per million Pr : propyl
p-Tol : p-tolyl
R : generic organic fragment rH : hydrodynamic radius rx : crystallographic radius s : singlet
t : triplet
TBDMS : tert-butyldimethylsilyl TBDPS : tert-butyldiphenylsilyle TBS : tert-butyldimethylsilyl t-Bu : tert-butyl
t-BuLi : tert-butyl lithium Tf : triflate
TFA : trifluoroacetic acid THF : tetrahydrofuran TIPS : triisopropylsilyl TMS : trimethylsilyl Tol : tolyl
TON : turnover number Ts : tosyl
X : generic halide
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Le but de cette thèse a été l’investigation de l’isomérisation diastereosélective d’alcools allyliques primaires chiraux, ainsi que leur synthèse.
Dans la première partie de ce travail de recherche, deux voies de synthèse différentes ont été mises au point pour l’obtention d’alcools allyliques primaires énantioenrichis. L’approche stéréoconstructive repose sur l’installation de la stéréochimie du carbon C-(4) par l’hydrogénation enantiosélective d’un alcène fonctionnalisé. Tandis que l’approche stéréorétentive se base sur le couplage croisé d’un produit commercial déjà énantiopur et d’un autre fragment. Des alcools allyliques primaires hautement énantioenrichis et géométriquement purs ont été synthétisés. Quatre catégories de substrats ont ainsi été développés.
Dans la dernière décennie, l’isomérisation énantiosélective d’alcools allyliques primaires a été largement étudiée par différents groupes de recherches. Cependant, très peu d’exemples décrivent l’isomérisation diastéréosélective d’alcools allyliques primaires chiraux.
La seconde partie de ce travail de recherche s’est focalisé sur cet aspect. Les alcools allyliques primaires énantioenrichis synthétisés ont été évalué dans l’isomérisation diastéréoselective catalysée par l’iridium. Aussi bien des aldéhydes anti- que cis- comportant des stéréocentres vicinaux tertiaires ont été isolés avec d’excellents rapports diastéréomériques et d’excellents excès énantiomériques. L’influence du profil de substitutions des alcools allyliques primaires dans cette réaction a également été étudiée.
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Finalement, des études préliminaires pour la synthèse de ϒ-butyrolactones ont été conduites. Inspiré par des précédents présents dans la littérature, l’isomérisation d’alcools allyliques primaires chiraux portant une fonction alcool non-protégée a été réalisée pour l’obtention de lactones. Ces résultats encourageant motivent l’intention de synthétiser des ϒ- butyrolactones énantioenrichis via une isomérisation stéréodivergente, un concept déjà validé dans l’historique de recherche du groupe Mazet.
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The aim of this thesis work has been the investigation of diastereoselective isomerization of chiral primary allylic alcohols and their synthesis.
In the first part of this thesis, two types of synthetic routes were developed in order to access optically active allylic alcohols with high levels of enantioenrichment. The stereoconstructive approach relies on the installation of stereochemistry at C-(4) by the asymmetric hydrogenation of a functionalized olefin. The stereoretentive approach is based on enantiopure starting materials where building blocks will be linked via cross-coupling reaction. Geometrically pure enantioenriched primary allylic alcohols were obtained with high level of enantioenrichment in practical yields. Four different types of substrate class were developed.
In the last decade enantioselective isomerization of primary allylic alcohols has been extensively studied by different groups. However, only few examples of diastereoselective isomerization of chiral allylic alcohols have been reported so far. As a second part of this thesis work, the synthesized optically active primary allylic alcohols were evaluated in Ir- catalyzed diastereoselective isomerization. Both anti- and syn-aldehydes bearing vicinal tertiary stereocenters were successfully synthesized with excellent diastereomeric ratios and perfect enantiomeric excesses. The substitution pattern influence was also investigated in this transformation.
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Finally, preliminary investigations were conducted to synthesis ϒ-butyrolactones, which are highly valuable for their potent biological activities. Inspired by literature precedents, successful isomerization of chiral primary allylic alcohols bearing adjacent free hydroxyl group performed to deliver the desired lactone. The feasibility of a stereodivergent isomerization on racemic mixtures being already achieved within the group, the synthesis of enantioriched lactones was about to be conducted.
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Table of Content
1. General Introduction ... 1
1.1 Transition metal-catalyzed isomerization of primary and secondary allylic alcohols... 2
1.1.1 Enantioselective isomerization ... 3
1.1.1.1 Ruthenium ... 3
1.1.1.2 Rhodium ... 7
1.1.1.3 Palladium ... 11
1.1.1.4 Iridium ... 13
1.2 Transition metal-catalyzed diastereoselective isomerization of primary allylic alcohols ... 21
1.2.1 Relevant examples ... 21
1.2.1 Ir-catalyzed diastereoselective isomerization of primary allylic alcohols ... 24
1.2.2 Catalyst-directed diastereoselective isomerization of allylic alcohols for the stereoselective construction of C-(20) in steroid side chains ... 26
1.3 Catalyst-controlled diastereoselective reactions ... 28
1.3.1 Double diastereocontrol ... 28
1.3.1.1 Principle ... 28
1.3.1.2 Predominant substrate-control ... 30
1.3.1.3 Predominant catalyst-control ... 33
1.4 Objectives ... 37
1.5 References ... 40
2. Preparation of Enantioenriched Primary Allylic Alcohols ... 45
2.1 Stereoconstructive approach: installation of C-(4) stereochemistry ... 46
2.1.1 Chemoselective and enantioselective hydrogenation of chalcones ... 46
2.1.2 Horner–Wadsworth–Emmons olefination ... 47
2.2 Stereoretentive route via cross-coupling reactions: study case of Naproxen and Mandelic acid derivatives ... 51
2.2.1 Synthesis of -ketoester ... 51
2.2.2 Access to enantioenriched enoates via cross-coupling reactions ... 53
2.3 Conclusions ... 56
2.4 References ... 56
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3. Catalyst-Controlled Diastereoselective Isomerization of Primary Allylic Alcohols for The
Construction of Vicinal Tertiary Stereocenters ... 57
3.1 Introduction ... 57
3.1.1 Approach to access vicinal tertiary stereogenic carbone centers ... 57
3.1.2 Conformational preferences of allylic systems: allylic 1,2-strain versus allylic 1,3-strain ... 58
3.2 Results and discussion ... 62
3.2.1 Substitution pattern influence of 103 ... 63
3.2.1.1 Substrate class I: alkyl/alkyl ... 63
3.2.1.2 Substrate class II: alkyl/aryl ... 68
3.2.1.3 Substrate class III: aryl/aryl ... 73
3.2.1.4 Summary ... 74
3.2.2 Influence of a benzylic character at C-(4) ... 76
3.2.2.1 Naproxen derivatives ... 76
3.2.2.2 Substrate class IV: influence of an heteroatom in place of R2 ... 81
3.3 Conclusions ... 86
3.4 References ... 87
4. Stereodivergent Reaction on Racemic Mixture ... 89
4.1 Introduction ... 89
4.1.1 Principle ... 89
4.1.2 Selected examples... 90
4.2 Stereodivergent isomerization on racemic mixture... 92
4.3 Access to ϒ-butyrolactones ... 93
4.3.1 Relevant precedent in literature ... 93
4.3.2 Feasibility of ϒ-butyrolactones synthesis via stereodivergent isomerization of primary allylic alcohols: preliminary investigations ... 94
4.4 Discussion and perspectives ... 95
4.5 References ... 96
5. General Conclusion and Perspectives ... 99
5.1 Conclusions ... 99
5.2 Perspectives ... 101
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6. Experimental Section ... 103
6.1 General Information... 103
6.2 Preparation of Enantioenriched Primary Allylic Alcohols ... 105
6.2.1 Stereoconstructive approach ... 105
6.2.1.1 General procedure for enantioselective hydrogenation of chalcones 109 ... 105
6.2.1.2 General procedure for the preparation of 103e-h ... 108
6.2.1.3 Representative procedure for the enantiomer separation of 103e-h by semi-preparative HPLC ... 113
6.2.2 Stereoretentive approach ... 127
6.2.2.1 Procedures for the preparation of -ketoesters 113a-b ... 127
6.2.2.2 Stereoselective synthesis of enol tosylates 112 ... 128
6.2.2.3 Procedures for the preparation of primary allylic alcohols 103 via Negishi cross-coupling... 131
6.3 Catalyst-Controlled Diastereoselective Isomerization of Primary Allylic Alcohols for The Construction of Vicinal Tertiary Stereocenters ... 142
6.3.1 General procedure for the isomerization of 103e-j catalyzed by 39 ... 142
6.3.2 General procedure for the isomerization of 103e-jb catalyzed by 43 ... 143
6.3.3 Representative procedure for the isomerization of 103ja catalyzed by 43 ... 144
6.3.4 Characterization of aldehydes 103... 145
6.3.5 Characterization of alcohols 161-162... 147
6.4 Stereodivergent Reaction on Racemic Mixture ... 161
6.4.1 General procedure for the synthesis of rac-103la-b... 161
6.4.2 Representative procedure for the isomerization of rac-103la-b catalyzed by 39 ... 163
6.5 Table of X-ray crystallography ... 164
6.5.1 X-ray data and structure refinement of (R)-108d ... 164
6.6 References ... 165
1
1. General Introduction
Allylic alcohols are valuable precursors to various enantio- and diastereoselective transition metal-catalyzed transformations such as cyclopropanation,1 allylic substitution,2 epoxidation3, dihydroxylation,3e,4 hydroboration,5 hydrogenation6 and isomerization7 (Scheme 1.1).
Scheme 1.1 Access to valuable compounds from allylic alcohols
1 a) H. Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev. 2003, 103, 977–1050; b) A. B.
Charette, C. Molinaro, C. Brochu, J. Am. Chem. Soc. 2001, 123, 12168–12175; c) S. R. Goudreau, A. B. Charette, J. Am. Chem. Soc. 2009, 15633–15635; A. Voituriez, L. E. Zimmer, A. B. Charette; J.
Org. Chem. 2010, 75, 1244–1250; E. Lévesque, S. R. Goudreau, A. B. Charette, Org. Lett. 2014, 16, 1490–1493
2 a) B. Sundararaju, M. Achard, C. Bruneau, Chem. Soc. Rev. 2012, 41, 4467–4483; b) N. A. Butt, W.
Zhang, Chem. Soc. Rev. 2015, 44, 7929–7967
3 a) R. A. Johnson, B. K. Sharpless, In Catalytic Asymmetric Synthesis; 2nd ed., I. Ojima, Ed., Wiley- VCH: New York, 2000, 231−285; b) T. Katsuki, Synlett 2003, 281–297; c) Comprehensive Asymmetric Catalysis, E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds. Springer: Berlin, 1999; d) Name Reactions, Jie Jack Li, Ed. Springer-Verlag Berlin Heidelberg. 2010; e) K. Matsumoto, T. Katsuki, Comprehensive Chirality 2012, 5, 69–117
4 a) C. Prévost, Compt. Rend. 1933, 196, 1129–1131; b) H. C. Kolb, M. S. Van Nieuwenhze, K. B.
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1795; d) D. J. Mergott, Woodward cis-dihydroxylation. In Name Reactions for Functional Group Transformations; J. J. Li, E. J. Corey, Eds., John Wiley & Sons: Hoboken, NJ, 2007, pp 327−332.
5 a) D. A. Evans, G. C. Fu, A. H. Hoveyda, J. Am. Chem. Soc. 1988, 110, 6917–6918; b) K. Burgess, M. J. Ohlmeyer J. Org. Chem. 1988, 53, 5178; c) K. Burgess, M. J. Ohlmeyer Chem. Rev., 1991, 91, 1179–1191; d) D. A. Evans, G. C. Fu, A. H. Hoveyda, J. Am. Chem. Soc. 1992, 114, 6671–6679;
6 a) S. Inoue, M. Osada, K. Koyano, H. Takaya, R. Noyori Chem. Lett. 1985, 1007–1008; b) R. Noyori, Angew. Chem. Int. Ed. 2002, 41, 2008–2022; c) S. J. Roseblade, A. Pfaltz Acc. Chem. Res. 2007, 40, 1402–1411; d) Y. Zhu, K. Burgess Acc. Chem. Res. 2012, 45, 1623–1636; e) J.-Q. Li, J. Liu, S.
Krajangsri, N. Chumnanvej, T. Singh, P. G. Andersson, ACS Catal. 2016, 6, 8342−8349
7 a) R. Uma, C. Crévisy, R. Grée, Chem. Rev. 2003, 103, 27–51; b) L. Mantilli, C. Mazet, Chem. Lett.
2011, 40, 341–344; c) D. Cahard, S. Gaillard, J.-L. Renaud, Tetrahedron Lett. 2015, 56, 6159–6169
2
In the past twenty years, isomerization of primary and secondary allylic alcohols has become an attractive redox-economical process to access the corresponding aldehydes and ketones.7c Numerous transition metals catalyze this reaction, where platinum metals were used with more noticeable success to asymmetric isomerization of primary and secondary allylic alcohols.7
1.1 Transition metal-catalyzed isomerization of primary and secondary allylic alcohols
Three dominant mechanisms have been proposed to rationalize this reaction, which deeply depend on the nature of the catalyst and the reaction conditions7a,c (Scheme 1.2).
Scheme 1.2 The three main mechanisms proposed for metal-catalyzed isomerization reactions
The metal hydridre mechanism occurs usually in acidic medium, where the allylic alcohol first -coordinates with a metal hydride complex, generated in-situ or ex-situ. Consecutive migratory insertion of the alkene into the metal hydride bond generates the key metal-alkyl
3
species. Subsequent β-hydride elimination furnishes a η2-enol metal hydride intermediate, and decomplexation releases the free enol and the metal hydride catalyst which can reengage into the catalytic cycle. Finally, tautomerization of the enol yields the corresponding carbonyl compound.
The -allyl mechanism starts as well with -coordination with the metal complex, commonly in neutral conditions. Oxidative addition of the metal into a C-H bond of the allylic alcohol occurs to form a -allyl-metal hydride intermediate, which generates a η2-enol metal complex after reductive elimination. Final decoordination provides the metal catalyst as well as the free enol, which will tautomerize to generate the corresponding carbonyl compound.
The intramolecular 1,3-hydrogen shift mechanism is relevant under basic conditions, where deprotonation of the allylic alcohol results in the formation of a metal-alkoxide complex. Subsequent β-hydride elimination furnishes an enal-metal hydride intermediate.
Intramolecular conjugate addition to the enal generates a -oxa-allyl-metal complex.
Terminal protonation releases the metal catalyst as well as the free enol which forms the corresponding carbonyl compound upon tautomerization.
Labelling experiments and DFT calculations support the above mechanisms. However, experimental evidences are rare and all previous attempts to isolate and identify putative catalytic intermediates have been unsuccessful.
In the following discussion, major achievements obtained with ruthenium, rhodium, palladium and iridium complexes in enantioselective isomerization will be discussed in a chronological order. Less common examples of diastereoselective isomerization will be commented next.
1.1.1 Enantioselective isomerization
1.1.1.1 Ruthenium
In 1989, a first attempt to isomerize enantioselectively nerol with a ruthenium complex was made by Süss-Fink and co-workers with an enantiomeric excess of 12%.8 Building on this precedent, Salzer and co-workers prepared various chiral ruthenium complexes and evaluated them in the isomerization of nerol and geraniol.9 Citronellal was obtained in low to high yields, but in very low enantiomeric excesses (13-19% ee).
In 2012, Sowa and co-workers reported the asymmetric reduction of primary allylic alcohols to saturated alcohols via a tandem process of asymmetric isomerization/transfer
8 G. Süss-Fink, T. Jenke, H. Heitz, A. M. Pellinghelli, A. Tiripicchio, J. Organomet. Chem. 1989, 379, 311–323
9 A. Doppiu, A. Salzer, Eur. J. Inorg. Chem. 2004, 2244–2252
4
hydrogenation catalyzed by the {RuCl2(COD)}n–Tol-binap system or [RuCl(p-cymene)(Tol- binap)]Cl.10 Geraniol derivatives were reduced with high enantioselectivity, but this process could not selectively give the chiral aldehydes 3. Ruthenium hydride species, formed in situ, catalyzed both the isomerization and the reduction (Scheme 1.3).
Scheme 1.3 Over-reduction observed with ruthenium catalysts
In 2013, Ohkuma and co-workers reported an efficient enantioselective isomerization of primary allylic alcohols into the corresponding aldehydes catalyzed by the well-defined [RuCl2(o-Tol-Binap)(dbapen)] 5 in ethanol at room temperature.11 Citronellal 3a was obtained in good yields with perfect stereoselectivity from geraniol (E)-1a and nerol (Z)-1a, using only 0.5 mol% of 5. Deuterium-labelling experiments supported an intramolecular 1,3-hydrogen shift mechanism.
Scheme 1.4 Enantioselective isomerization of primary allylic alcohols catalyzed by a Ru-catalyst (Ohkuma)
In 2005, Ikariya reported the first example of enantioselective isomerization of secondary allylic alcohols 6a-b,12 which are scarce in the literature. The half-sandwich [Cp*Ru(P–N)]
complex 8, in which the P–N ligand derived from (L)-proline, was able to furnish the corresponding ketones 7a-b in good yields with enantiomeric excesses ranging from 62% to 74%. Racemic sec-allylic alcohols with (E)- and (Z)-geometry led to ketones with opposite absolute configurations as a result of a dynamic kinetic resolution (DKR). Once again, mechanistic investigations supported an intramolecular 1,3-hydrogen shift mechanism (Scheme 1.5).
10 R. Wu, M. G. Beauchamps, J. M. Laquidara, J. R. Sowa, Angew. Chem. Int. Ed. 2012, 51, 2106–
2110
11 N. Arai, K. Sato, K. Azuma, T. Ohkuma, Angew. Chem. Int. Ed. 2013, 52, 7500–7504
12 M. Ito, S. Kitahara, T. Ikariya, J. Am. Chem. Soc. 2005, 127, 6172–6173.
5
Scheme 1.5 Enantioselective isomerization of racemic secondary allylic alcohols catalyzed by a Ru-catalyst (Ikariya)
In 2012, Cahard and co-workers reported a ruthemium-catalyzed enantiospecific isomerization of secondary trifluoromethylated allylic alcohols 11a-e.13 They reported a new approach to prepare enantioenriched carbonyl compounds featuring a β-trifluoromethylated stereogenic carbon center. The protocol is notable for its simplicity of execution and high enantiospecificity. They also described a unique example of chemo- and enantioselective transfer hydrogenation of β-CF3-α,β-unsaturated enones 10a-e. Experimental evidences supported an intramolecular suprafacial enantiospecific 1,3-hydrogen transfer (Scheme 1.6).
13 V. Bizet, X. Pannecoucke, J.-L. Renaud, D. Cahard, Angew. Chem., Int. Ed. 2012, 51, 6467–6470
6
Scheme 1.6 Enantiospecific isomerization of fluorinated secondary allylic alcohols catalyzed by a Ru-catalyst (Cahard)
7 1.1.1.2 Rhodium
In 1976, Botteghi and Giacomelli reported the very first attempt to isomerize primary allylic alcohols 1b-c into the corresponding aldehydes 3b-c using [HRh(CO)(PPh3)3] 16 as precatalyst with (–)-DIOP 17.14 Poor enantiomeric excesses were measured by optical rotation (Scheme 1.7).
Scheme 1.7 First enantioselective isomerization of primary allylic alcohols catalyzed by a Rh-catalyst (Botteghi and Giacomelli)
In the late 1980s, Noyori reported the asymmetric isomerization of allylamines 18 to optically active enamines 19 with excellent enantiomeric excesses (> 95% ee), using a cationic binap-rhodium(I) complex 20.15 This work led to a collaboration with the Takasago Company in Japan, and culminated with its implementation for the ton-scale synthesis of (–)-menthol 21. To date, this effort is still perceived as a landmark contribution in asymmetric homogeneous catalysis to date (Scheme 1.8).
14 C. Botteghi, G. Giacomelli, Gazz. Chim. Ital. 1976, 106, 1131–1134
15 a) K. Tani, T. Yamagata, S. Otsuka, S. Akutagawa, H. Kumobayashi, T. Taketomi, H. Takaya, A.
Miyashita, R. Noyori, J. Chem. Soc., Chem. Commun., 1982, 600–601; b) K. Tani, T. Yamagata, S.
Akutagawa, H. Kumobayashi, T. Taketomi, H. Takaya, A. Miyashita, R. Noyori, S. Otsuka, J. Am.
Chem. Soc. 1984, 106, 5208–5217; c) S. Inoue, H. Takaya, K. Tani, S. Otsuka, T. Sato, R. Noyori, J.
Am. Chem. Soc. 1990, 112, 4897–4905
8
Scheme 1.8 Enantioselective isomerization of allylic amines, to access (R)-citronellal for the synthesis of (–)- menthol (Noyori)
Tani applied the same protocol to isomerize allylic alcohols 1a,d.16 Both primary and secondary allylic alcohols showed good reactivity, although lower enantioinduction was observed (Scheme 1.9).
Scheme 1.9 Enantioselective isomerization of primary allylic alcohols catalyzed by a [Rh(BINAP)] catalyst (Tani)
16 S. Otsuka, K. Tani, Synthesis 1991, 9, 665–680
9
Later, Chapuis and co-workers at Firmenich SA, concluded that BINAP gave the optimal results after performing systematic screening of numerous privileged chiral ligands for the Rh-catalyzed asymmetric isomerization of several primary allylic alcohols. Up to 61% ee and 51% ee were obtained for geraniol (E)-1a and nerol (Z)-1a respectively.17
The real breakthrough in the rhodium-catalyzed asymmetric isomerization of primary allylic alcohols came from Fu and co-workers in 2000.18 They discovered that the combination of a cationic rhodium(I) precusors 26 and a chiral-planar phosphaferrocene 23 could catalyze the enantioselective isomerization of primary allylic alcohols (Z)-1d-h in moderate to good yields and unprecedented enantioselectivities (Scheme 1.10).
Despite this formidable achievement, their system is thwarted with several practical limitations. Not only catalyst 24 has to be freshly prepared for every reaction, but its activation is also relatively tedious. Under nitrogen atmosphere, a solution containing 23 in THF is added dropwise to a stirred suspension of 26 in THF, followed by filtration. After three vacuum/H2-refill cycles, the solution is stirred for 1 h. Another filtration and subsequent concentration of the filtrate offers the bis-solvato active species 25, which can be finally engaged in the isomerization reaction.
Scheme 1.10 First efficient enantioselective isomerization of primary allylic alcohols catalyzed by a Rh-catalyst (Fu)
17 C. Chapuis, M. Barthe, J.-Y. de Saint Laumer, Helv. Chim. Acta 2001, 84, 230–242.
18 K. Tanaka, S. Qiao, M. Tobisu, M. M.-C. Lo, G. C. Fu, J. Am. Chem. Soc. 2000, 122, 9870–9871
10
Under these conditions, it was found that the selectivity was dependent on the counterion, the solvent, but not on the temperature. It is important to highlight that this reaction is stereospecific as (Z)- and (E)-1e gave aldehydes 3e of opposite absolute configuration. In 2001, after further ligand engineering the Fu group improved the method to isomerize both geometrically pure (E)- and (Z)- primary allylic alcohols 1 with enhanced reactivity and enantioselectivity.19 Extensive mechanistic studies supported a intramolecular 1,3-hydrogen shift mechanism (Scheme 1.11).
Nevertheless, the harsh reaction conditions and the difficult accessibility of the ligand prevented dissemination of this work into the synthetic community.
Scheme 1.11 Scope and mechanistic studies of enantioselective isomerization of primary allylic alcohols (Fu)
In 2017, Zhao and co-workers reported the first efficient method to isomerize secondary allylic alcohols with high enantioselectivities, using a chiral-rhodium(I) complex with a catalytic amount of silver carbonate acting as a base.20 They could enantioselectively isomerize both acyclic (29) and cyclic (31,33) racemic secondary allylic alcohols in moderate to excellent yields. As typically observed under basic conditions, mechanistic studies were in support of a 1,3-hydrogen shift mechanism (Scheme 1.12).
19 K. Tanaka, G. C. Fu, J. Org. Chem. 2001, 66, 8177–8186
20 L. Tang-Lin, T. W. Ng, Y. Zhao J. Am. Chem. Soc. 2017, 139, 3643−3646
11
Scheme 1.12 Scope and mechanistic studies of the enantioselective isomerization of racemic secondary allylic alcohols catalyzed by a Rh-catalyst (Zhao)
1.1.1.3 Palladium
As part of their program on isomerization reactions21-22 catalyzed by metal-hydride complexes, in 2014 Mazet and co-workers reported a general palladium precatalyst for the isomerization of allylic, homoallylic and alkenyl alcohols.23 Detailed mechanistic studies including isotopic labelling, crossover experiments and computational studies are in favor of a decoordinative chain-walking process involving iterative migratory insertion/β-H elimination sequences (Scheme 1.13).
Enantioselective isomerization of allylic alcohol 1h and homoallylic alcohol 1i was also disclosed affording moderate enantioinduction. When enantioenriched citronellol derivatives
21 D. J. Vyas, E. Larionov, C. Besnard, L. Guénée, C. Mazet, J. Am. Chem. Soc. 2013, 135, 6177–
6183
22 H. Li, C. Mazet, Acc. Chem. Res. 2016, 49, 1232−1241
23 E. Larionov, L. Lin, L. Guénée, C. Mazet, J. Am. Chem. Soc. 2014, 136, 16882–16894
12
1j-k were subjected to isomerization, complete racemization was observed, thus supporting a decoordinative chain-walking process.
Scheme 1.13 Scope and mechanistic studies of enantioselective isomerization of primary homo- and allylic alcohols (Mazet)
Other groups have been involved on related systems where an olefin is isomerized and the refunctionalization of an alcohol (primary or secondary) into a carbonyl derivative constitutes the driving-force of the process. Nonetheless, as the triggering event differs from the initial hydrometallation involved in the isomerizations described in this introduction, they will not be
13
described herein. Of note, based on mechanistic investigations, it was generally found that the isomerization can also be coordinative or partially decoordinative.24
1.1.1.4 Iridium
The use of iridium in homogeneous catalysis raised interest in the community when Crabtree and Stork independently showed its specific ability to coordinate to highly substituted olefins in the context of hydrogenation of unfunctionalized olefins.25
In iridium-catalyzed hydrogenation of alkenes, early examples are present in the literature where isomerization is a competing process.26 In 1982, Crabtree stated: “some olefin isomerization accompanies hydrogenation. This must arise by -elimination.”27
At the same period of time, Felkin28 and Shin29 reported isomerization of primary and secondary allylic alcohols using iridium complexes. In 2002, their work was featured in the novel synthesis of the F-ring building block in the total synthesis of Halichondrin B 38 (Scheme 1.14).30
Scheme 1.14 Isomerization of a primary allylic alcohol in the total synthesis of Halichondrin B (Burke)
24 For related studies on similar systems: a) E. Weissberger, A. Stockis, Bull. Soc. Chim. Belg. 1980, 89, 281–287; b) T.-S. Mei, H. H. Patel, M. S. Sigman, Nature 2014, 508, 340–344; c) S. Singh, J.
Bruffaerts, A. Vasseur, I. Marek, Nat. Commun. 2017, 8, 14200; d) F. Juliá-Hernández, T. Moragas, J.
Cornella, R. Martin, Nature 2017, 545, 84–88
25 Iridium catalysis, P. G. Andersson, Ed. Springer-Verlag Berlin Heidelberg 2011
26 a) R. H. Crabtree, M. W. Davis, Organometallics 1983, 2, 681–682; b) G. Stork, D. Kahne, J. Am.
Chem. Soc. 1983, 105, 1072–1073
27 R. H. Crabtree, P. C. Demou, D. Eden, J. M. Mihelcic, C. A. Parnell, J. M. Quirk, G. E. Morris, J.
Am. Chem. Soc. 1982, Vol. 104, No. 25, 6995–7001
28 D. Baudry, M. Ephritikhine, H. Felkin, Nouv. J. Chem. 1978, 2, 355–356.
29 a) C. S. Chin, J. Park, C. Kim, S. Y. Lee, J. H. Shin, J. B. Kim, Catal. Lett. 1988, 1, 203–206; b) C.
S. Chin, J. H. Shin, C. Kim, J. Organomet. Chem. 1988, 356, 381–388
30 L. Jiang, S. D. Burke, Org. Lett. 2002, 4, 3411–3414
14
In the early 2000s, scattered examples in the literature reported isomerizations of olefin catalyzed by Crabtree’s catalyst.31 However, a general method was still missing.
In 2009, Mazet and co-workers reported an iridium-catalyzed isomerization of primary allylic alcohols 1 into the corresponding aldehydes 3 under mild conditions.32 Using Baudry’s activation protocol,32 the Pfaltz version of Crabtree’s catalyst 39 was detoured from its initial purpose in order to perform isomerization. Mechanistic studies revealed formation (in THF- d8) of two distinct cis-dihydride species 40 and 41 confirmed by multidimensional NMR experiments. Labelling and crossover experiments supported an intermolecular dihydride mechanism.
31 For examples of olefin isomerization catalyzed by Crabtree’s catalyst: a) D. Solé, X. Urbaneja, J.
Bonjoch, Org. Lett. 2005, 7, 5461–5464; b) M. Krel, J.-Y. Lallemand, C. Guillou, Synlett 2005, 13, 2043–2046; c) C. Fehr, I. Farris, Angew. Chem. Int. Ed. 2006, 45, 6904–6907;
32 L. Mantilli, C. Mazet, Tetrahedron Lett. 2009, 50, 4141–4144
15
Scheme 1.15 Scope and mechanistic studies of isomerization of primary allylic alcohol catalyzed by Pfaltz version of 39 (Mazet)
The research program in the Mazet group later focused on the enantioselective isomerization of primary allylic alcohols.22 Various chiral ligands were explored, leading to one conclusion: in order to maintain a level of reactivity similar to the one displayed by 40 and 41, a combination of an sp2 N-donor with a formal trialkylphosphine donor was necessary. Chiral phosphino-oxazolines33 appeared as suitable candidates as they exhibit great synthetic modularity. Subsequently, three different generations of chiral (P,N) ligands
33 a) G. Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336–345; b) X. Cui, K. Burgess, Chem.
Rev. 2005, 105, 3272–3296; c) M. P. Carroll, P. J. Guiry, Chem. Soc. Rev., 2014, 43, 819
16
were synthesized in practical yields from commercially available amino acids. Scheme 1.16 provides a comparative overview of their respective performances. The substrates investigated can be distinguished in two classes referring to the nature of R1 and R2 substituents of 1: aryl/alkyl and alkyl/alkyl. The distinction between large and small alkyl substituents is also featured. Despite their mechanistic differences, as the Rh-catalyzed isomerization, it is important to highlight that this reaction is also stereospecific.
The design of the 1st generation of iridium catalysts 42 was inspired by Helmchen’s phosphino-oxazoline.34,35 Good reactivity was observed as well as high enantioinduction measured. A major drawback for its synthesis was the expensive price of the two amino- acids used for the best candidate, L-tert-leucine and the non-natural D-tert-leucine (respectively 4895-.CHF/mol and 57058-.CHF/mol).36 This catalyst showed no reactivity with 1d, a substrate bearing a small alkyl substituent.
The 2nd generation of iridium-catalyst 43 was designed using the JM-Phos37 scaffold initially introduced by Burgess and co-workers.38 They demonstrated that starting from non- expensive L- and D-serine (respectively 129-.CHF/mol and 523-.CHF/mol)39 changing the synthetic route to access methylphosphono-oxazoline, they could vary the substitution pattern of the oxazoline. Reactivity was observed with alkyl/alkyl substrates 1a.
Nevertheless, 42 and 43 offered low reactivity and enantiomeric excess when submitted to substrates 1a,d. Besides, competing (E)-/(Z)- isomerization of the starting material was observed by NMR.
The 3rd generation of iridium-catalyst 44 emerged from the will of improving limitations mentioned before with the 1st and 2nd generations.39 The rationale behind its design was based on linear free energy relationships (LFER)40 between the ee values and the size of the substituents of the substrate tested.41 Homologation of the JM-Phos ligand was expected to increase the steric bulk in proximity to the reactive sites while providing enough flexibility in the structure to maintain efficient substrate binding.
34 a) J. Sprinz, G. Helmchen, Tetrahedron Lett. 1993, 34, 1769–1772; b) H. Danjo, M. Higuchi, M.
Yada, T. Imamaoto, Tetrahedron Lett. 2004, 45, 603–606
35 L. Mantilli, D. Gérard, S. Torche, C. Besnard, C. Mazet, Angew. Chem. Int. Ed. 2009, 48, 5143–
5147
36 Prices for each enantiomer of tert-leucine and serine in CHF per mol were calculated using the largest amount available from Sigma-Aldrich (July 2018)
37 (a) A. M. Porte, J. Reibenspies, K. Burgess, J. Am. Chem. Soc., 1998, 120, 9180–9187; (b) K.
Burgess, A. M. Porte, Tetrahedron: Asymmetry, 1998, 9, 2465–2469
38 L. Mantilli, C. Mazet, Chem. Commun., 2010, 46, 445–447
39 L. Mantilli, D. Gérard, S. Torche, C. Besnard, C. Mazet, Chem. Eur. J. 2010, 16, 12736–12745
40 Selected examples of LFER studies: a) J. J. Miller, M. S. Sigman, Angew. Chem. Int. Ed. 2008, 47, 771 –774; b) J. L. Gustafson, M. S. Sigman, S. J. Miller, Org. Lett. 2010, 12, 2794–2797; c) K. C.
Harper, M. S. Sigman, Science 2011, 333, 1875–1878; d) K. C. Harper, E. N. Bess, M. S. Sigman, Nat. Chem. 2012, 4, 366–374
41 K. C. Harper, M. S. Sigman, J. Org. Chem. 2013, 78, 2813−2818
17
This hypothesis was validated by the improved enantioselectivites obtained with 44.
However, the yields remained quite low in most cases. This last generation of iridium- catalysts showed significant improvement also in the isomerization of geraniol (E)-1a into (R)-citronellal 3a (2nd generation: 20% yield and 53% ee) with 49% yield and 82% ee.
When subjected to pre-catalysts 42 and 43, (Z)-1 and/or alkyl/alkyl primary allylic alcohols 1 bearing small alkyl substituents were found to be less reactive. Slight improvement was observed in the isomerization catalyzed by 44.
Scheme 1.16 Comparative performances of the best chiral Ir-catalysts of 1st, 2nd and 3rd generation (Mazet)
Mechanistic studies have been conducted using (R)-42.44 Labelling and crossover experiments strongly support an intermolecular dihydride mechanism. Using the general activation protocol, the chiral precatalyst forms two distinct cis-dihydride species 45 and 46 of general formula [(P,N)Ir(H)2(THF)2]BArF that were unequivocally characterized by multidimensional NMR.
18
Scheme 1.17 Mechanistic studies for the enantioselective isomerization of primary allylic alcohols with 1st generation of Ir-catalyst
Supported by precedents in the literature, a mechanism involving two-point binding intermediate of the allylic alcohol was proposed (Scheme 1.18).42-43
After cyclooctadiene reduction, the active cis-dihydride species 45 and 46 bearing two vacant cis-coordination sites are generated. At this stage, coordination in a two-point binding of (E)-1 is expected. This step is critical as the conformation of the binding dictates the regioselectivity of the migratory insertion. From H, only 3,2-migratory insertion can occur.
The resulting tertiary alkyl-Ir(III) hydride I, with free-rotation between C-(2)–C-(3), will produce (Z)-1 after β-hydride elimination. From E, only 2,3-migratory insertion can occur, thus generating a less congested secondary alkyl-Ir(III) hydride F complex. The 2,3- migratory insertion is proposed to be both rate- and enantiodetermining. Under molecular hydrogen pressure, subsequent reductive elimination could be expected from both F and I.
Yet, this pathway is not operating under the experimental conditions developed for operating isomerization. Finally, β-hydride elimination generates the corresponding enol G which after decoordination and rapid tautomerization delivers the corresponding optically active aldehyde 3.
42 G. Stork, D. Kahne, J. Am. Chem. Soc. 1983, 105, 1072–1073
43 a) R. H. Crabtree, M. W. Davis, Organometallics 1983, 2, 681–682; b) R. H. Crabtree, M. W. Davis, J. Org. Chem. 1986, 51, 2655–2661
19
Scheme 1.18 Proposed catalytic cycle
In 2011, Andersson and co-workers took advantage of the milestone set up by the Mazet group to achieve isomerization of (Z)-configured primary allylic alcohols 1a,d-e,h,m-n.44 Simple ligand screening permitted to obtain the aldehydes 3a,d-e,h,m-n with moderate to good yield and high enantiomeric excess (Scheme 1.19). It is important to notice that the aminophosphono-oxazoline 47 employed differs substantially from the ones used by the Mazet group. This ligand is significantly more hindered and possesses 4 elements of chirality. The electronic properties are quite distinct because of a less donating phosphine bearing two ortho-tolyl groups linked to a 2-azabicyclo[2.2.1]heptane scaffold, which displayed reasonable activity.
44 J.-Q. Li, B. Peters, P. G. Andersson, Chem. Eur. J. 2011, 17, 11143–11145
20
Scheme 1.19 Improved Ir-catalyst for the isomerization of (Z)-configured primary allylic alcohols (Andersson)
21
1.2 Transition metal-catalyzed diastereoselective isomerization of primary allylic alcohols
1.2.1 Relevant examples
In 2006, Fehr and Farris, from Firmenich Company in Switzerland, reported the first stereoselective synthesis of Superambox 51, a powerful ambery odorant molecule.31c A key- step in their synthesis was the OH-assisted hydrogenation of a diol intermediate.
Unexpectedly, instead of hydrogenation, a diastereoselective OH-directed isomerization took place to afford the corresponding lactol 50 (Scheme 1.19).
Scheme 1.20 Synthesis of rac-Superambrox by a OH-directed diastereoselective isomerization (Fehr)
The same outcome was obtained with either Crabtree (52) or Chaudret’s catalyst (53). After optimization, both yielded isomerically pure rac-51 in 46% and 76% respectively.
In a following study, Fehr and co-workers reported the synthesis of Ambrox, an isomer of Superambrox.45 56 was preferred for practical reasons due to the performance it offered.
The synthesis of Ambrox analogs was described. For instance one arising from (–)- mintlactone 54. This particular example is quite impressive as two stereogenic centers are installed during lactolisation. Two diastereoisomers of 57 were obtained in 59% yield with a 1.5:1 dr (Scheme 1.21).
45 C. Fehr, I. Magpantay, L. Saudan, H. Sommer, Eur. J. Org. Chem. 2010, 6153-6156
22
Scheme 1.21 OH-directed diastereoselective isomerization of primary allylic alcohol (Fehr)
An isotopic analog with a carbon fully deuterated at the C-(2) position was prepared. When submitted to the reaction conditions, a product resulting from a formal 1,3-D shift was isolated. Crossover experiment supported the same mechanism pathway.
Scheme 1.22 Putative 1,3-H shift mechanism for the OH-directed diastereoselective isomerization (Fehr)
In 2017, Takemoto and co-workers reported the first total synthesis of Avenaol 62.46 A key aspect of their synthetic strategy was the formation of an all-cis cyclopropane intermediate.
Hydrogenation of a primary allylic alcohol 60 (protected or not) was first envisioned to deliver the corresponding carbonyl. Unfortunately, they observed formation of the trans-isomer as the major product. To circumvent this issue, they next considered the isomerization catalyzed by Crabtree catalyst 52. Relying on the two-point binding mechanism proposed by Mazet and co-workers,35 investigations were based on the directionality of the adjacent hydroxyl substituents present on the molecule, to internally stereocontrol the formation of the all-cis 61 versus the trans-isomer.
46 M. Yasui, R. Ota, C. Tsukano, Y. Takemoto, Nat. Comm. 2017, 8, 674
23
Substrate 60a was subjected to catalysis using 52, but no reaction occurred and the starting material was recovered in 58% yield. Presumably because of its strong ability to coordinate, the nitrile group deactivates the Ir-catalyst instead of behaving as a directing group (Scheme 1.23, Entry 1). When 60b was subjected to 52, OH-assisted diastereoselective isomerization proceeded, delivering all-cis-61b as the only product in 92% yield (Scheme 1.23, Entry 2).
However, the hydroxymethyl group on all-cis-61b could not be converted to a methyl group without opening of the cyclopropane which prevented its further use. When 60c was tested, low reactivity was observed as well as low diastereoselectivity (Scheme 1.23, Entry 3). The absence of OH-directing group resulted in competitive coordination between the –OTIPS and the –OPMB group with iridium, which lead to exclusive formation of trans-61b with use of 39 (Scheme 1.23, Entry 4). Finally, when primary allylic alcohol 60d was subjected to 52, the corresponding aldehydes 61 were obtained in 61% with a 2.7:1.0 dr (Scheme 1.23, Entry 5). Improved diastereoselectivity (10:1) was obtained when 39 was used (Scheme 1.23, Entry 6).
Scheme 1.23 First total synthesis of Avenaol via a diastereoselective isomerization of primary allylic alcohol (Takemoto)
Recently, Li and co-workers reported the first total synthesis of Septedine 65.47 In their approach, the key-installation of C-(16)-configuration is established via the iridium-catalyzed diastereoselective isomerization of a secondary allylic alcohol. Using 38 at 65 °C in THF, only decomposition of the starting material was observed (Scheme 1.24, Entry 1). When 63 was subjected to 39 in THF at 22 °C, they obtained epi-64 and 64 with 85% yield in a 1.0:1.2 dr (Scheme 1.24, Entry 2). The diastereoselectivity was improved to 1.0:3.1 by using 52
47 S. Zhou, R. Guo, P. Yang, A. Li, J. Am. Chem. Soc. 2018, ASAP (DOI: 10.1021/jacs.8b03712)
24
(Scheme 1.24, Entry 3). The reaction can be run either in toluene or THF, which gave the best result (Scheme 1.24, Entry 4). Heterogeneous catalysis was also used, but formation of 64 was accompanied by reduction of the vinyl group (Scheme 1.24, Entry 7).
It is important to notice that this is the only example of diastereoselective isomerization of a secondary allylic alcohol present in the literature to date.
Scheme 1.24 First total synthesis of Septedine, via the diastereoselective isomerization of secondary allylic alcohol (Li)
1.2.1 Ir-catalyzed diastereoselective isomerization of primary allylic alcohols
After exploring the enantioselective isomerization of primary allylic alcohols, the Mazet group research program moved on more challenging investigations of diastereoselective isomerization. A preliminary study was carried out to evaluate the potential of 39 in such transformation.48 Diastereoselectivity could be assessed using streric descriptors such Charton49 and Sterimol50 parameters, both from the perspective of the catalyst and the substrates.
Susbstrates bearing various sterically demanding substituents were evaluated with 39. Once again, a correlation was observed between Charton values and the anti/syn ratio. When the
48 H. Li, C. Mazet, Org. Lett. 2013, 15, 6170–6173
49 (a) M. Charton, J. Am. Chem. Soc. 1975, 97, 1552−1556; (b) M. Charton, J. Org. Chem. 1976, 41, 2217−2220.
50 (a) A. Verloop, Drug Design, E. J. Ariens, Ed. Academic Press: New York, 1976; Vol. III, p 133; b) A. Verloop, J. Tipker, Biological Activity and Chemical Structure, J. A. Buisman, Ed. Elsevier:
Amsterdam, 1977, p 63; (c) A. Verloop, A., J. Tipker, QSAR in Drug Design and Toxicology; D. Hadzi, B. Jerman-Blazic, Eds.; Elsevier: Amsterdam, 1987, p 97. (d) A. Verloop, IUPAC Pesticide Chemistry, J. Miyamoto, Ed., Pergamon: Oxford, 1983, Vol. 1, p 339
25
steric bulk increases, up to 1:30 dr is observed in favor of the syn diastereoisomer 3og, with a sterically-demanding cyclohexyl group (Scheme 1.25, Entry 7).
Scheme 1.25 Diastereoselective isomerization of racemic primary allylic alcohols (Mazet)
A series of analogs of 39 were synthesized with sterically demanding substituents on the ortho position of the pyridine ligand 39a-c. Increasing the bulkiness on the catalyst correlated well with a decrease in the anti/syn ratio (visualized on the plot of log(dr) as a function of the Charton values; Scheme 1.26).
Scheme 1.26 Diastereoselective isomerization using Crabtree catalyst analogs (Mazet)
When 1oe was subjected to 39c formation of homoallylic alcohol 66 was observed, whereas only 3oe was obtained with 39. This might be explained by competitive 2,3-/3,2-migratory insertions. Steric clash between the bulky substituent present on the pyridine ligand and the hydroxyl group disfavor two-point binding of the catalyst, resulting in opposite regioselectivity.
26
Scheme 1.27 Regioselective isomerization of a primary allylic alcohol: competing migratory insertions (Mazet)
1.2.2 Catalyst-directed diastereoselective isomerization of allylic alcohols for the stereoselective construction of C-(20) in steroid side chains
In 2015, the Mazet group reported the stereoselective construction of C-(20) in stereoidal primary allylic alcohols by Ir-catalyzed directed diastereoselective isomerization.51 Synthetic routes to access both geometries of the primary allylic alcohols 67 were designed.
To evaluate the innate bias inspired from the steroidal scaffold, both geometrically pure primary allylic alcohols were engaged in independent isomerization reactions catalyzed by 39. Primary allylic alcohol 67a was used as model substrate.
The (E)-67a revealed high internal stereocontrol in favor of the C-20-(R)-68a with 29:1 dr (76% yield). With (R)-43, a match situation was observed and C-20-(R)-68a was obtained in 70% yield with perfect diastereoselectivity (>50:1.0). However when (S)-43 was used, low reactivity was noted as well as moderate opposite diastereoselectivity (1.0:8). The same scenario was observed with the (Z)-67a, even though significantly lower innate bias was initially measured (1.4:1.0). The high diastereoselectivities obtained were rationalized on the basis of a locked-conformation around C-(17)–C(20) observed in the solid state (X-Ray analysis) and in solution (multidimensional NMR). The Ir-catalyst can only approach the double bond from only one face due to the steric hindrance of the steroidal scaffold.
51 H. Li, C. Mazet, J. Am. Chem. Soc. 2015, 137, 10720–10727
27
When alkyl/alkyl analogs of 67 bearing either small or large alkyl substituents were engaged, homoallylic alcohols were predominantly generated.52 Overall this indicates that the isomerization reaction is not only driven by steric factors (see 69 and 70) but also by electronic factors (71), which strongly influence the regioselectivity of the migratory insertion step (N versus O) (Scheme 1.28).
Scheme 1.28 Stereospecific isomerization of steroidal allylic alcohols and limitations (Mazet)
52 Structures confirmed by X-Ray analysis; H. Li, PhD Thesis: Ir-catalyzed diastereoselective isomerization of primary allylic alcohols, 2015
28
1.3 Catalyst-controlled diastereoselective reactions
1.3.1 Double diastereocontrol
1.3.1.1 Principle
The concept of diastereoselective synthesis is based on the fact that a stereogenic center present on a given molecule can influence the formation of a neighboring stereogeonic center.3c-d,53 The development of methods where a catalyst can selectively control the formation of one or several stereogenic centers independently of a stereochemically complex environment are extremely powerful and valuable.54
In a reaction employing an enantiopure catalyst and an enantioenriched substrate, when a new stereogenic center is formed, diastereoisomers are produced. This type of transformation implies stereochemical control elements from the substrate (internal diastereocontrol) and/or from the catalyst (external diastereocontrol). These controls can either converge (match) or diverge (mismatched). External diastereocontrol is likely taking place predominantly when the inherent stereogenic centers are remote. However, if the stereogenic units are adjacent to the reactive center, internal diastereocontrol will be strong, and might override the stereocontrol of the catalyst may import.
Scheme 1.29 Diastereocontrol: external (catalyst) and internal (substrate)
For instance, when a reaction occurs between a chiral reagent A* and an achiral catalyst at ambient temperature, formation of a major product could take place in a 10:1 diastereomeric ratio. In this arbitrary case, the difference in energy between the two pathways equals 1.4 kcal/mol. In a comparable reaction, when an achiral substrate A is reacting with either enantiomer of a chiral catalyst (Cat* or ent-Cat*) similar enantiomeric ratios are observed.
53 Fundamentals of Asymmetric Catalysis, P. J. Walsh, M. C. Kozlowski, Ed., University Science Books: Sausalito, CA, 2009, Chapter 13, pp. 427–454
54 a) (a) S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem., Int. Ed. Engl. 1985, 24, 1−30; b) A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307−1370; c) J.
Mahatthananchai, A. M. Dumas, J. W. Bode, Angew. Chem., Int. Ed. 2012, 51, 10954−10990
