Unprotected Amino Aldehydes in Organic Synthesis

304 Pages·2010·20.78 MB·English

Unprotected Amino Aldehydes in Organic Synthesis
by
Ryan Matthew Hili
A thesis submitted in conformity with the requirements
for the degree of Doctor of Philosophy
Graduate Department of Chemistry
University of Toronto
© Copyright by Ryan Matthew Hili, 2010
Unprotected amino aldehydes in organic synthesis
Ryan Matthew Hili
Doctor of Philosophy
Graduate Department of Chemistry
University of Toronto
2010

Abstract

In 1908, H. Emil Fisher attempted to prepare glycinal, an unprotected amino aldehyde, which he
found to be inherently unstable and prone to polymerization. This instability arises from the
propensity of amines to condense with aldehydes. Accordingly, amino aldehydes require
protection of the amine functional group. On the contrary, aziridines do not condense with
aldehydes; the aziridine ring-strain precludes the formation of an iminium ion. Predicated upon
this orthogonal reactivity, a stable class of unprotected amino aldehydes has been prepared, and
an in-depth investigation into their chemical reactivity has been undertaken.1,2 Reactions
designed to utilize both their nucleophilic (amine) and electrophilic (aldehyde) centres have
demonstrated their capacity to forge multiple bonds in a single transformation, and have been
implemented in the synthesis of complex heterocycles and cyclic peptides.
ii
Scheme 1. Selected transformations involving unprotected amino aldehydes

(1) Publications: a) Hili, R., Yudin, A. K. “Making carbon-nitrogen bonds in biological and
chemical synthesis” Nature Chem. Biol. 2006, 2, 284-287. b) Hili, R.; Yudin, A. K.
“Readily available unprotected amino aldehydes” J. Am. Chem. Soc. 2006, 128, 14772-
14773. c) Yudin, A. K., Hili, R. “Overcoming the demons of protecting groups with
amphoteric molecules” Chem. Eur. J. 2007, 13, 6538-6542. d) Hili, R.; Yudin, A. K.
“Amphoteric amino aldehydes enable rapid assembly of unprotected amino alcohols”
Angew. Chem. Int Ed. 2008, 47, 4188-4191. e) Hili, R.; Baktharaman, S.; Yudin, A. K.
“Synthesis of chiral amines using α-amino aldehydes” Eur. J. Org. Chem. 2008, 31, 5201
– 5213. f) Baktharaman, S.; Hili, R.; Yudin, A. K. “Amino carbonyl compounds in
organic synthesis’’ Aldrichimica Acta, 2008, 41, 109 – 119. g) Hili, R.; Yudin, A. K.
“Amphoteric amino aldehyde re-route the aza-Michael reaction” J. Am. Chem. Soc. 2009,
131, 16404 – 16406. h) Hili, R.; Yudin, A. K. “Macrocyclization of linear peptides
enabled by amphoteric amino aldehydes” submitted 2009.
(2) Patents: a) Yudin, A. K.; Hili, R. “Unprotected amino aldehydes and applications for
same” WO patent No. 2008046232. b) Yudin, A. K.; Hili, R. “Cyclic Peptide Synthesis
using Unprotected Amino Aldehydes” US provisional patent No. 61160571.

iii
Acknowledgments
I would like to thank Professor Andrei Yudin for his guidance throughout the course of my
graduate career. His insatiable scientific curiosity was the impetus behind my development as a
scientist. I would also like to thank my committee members Professor Mark Taylor, Professor
Robert Batey, Professor Mark Nitz, Professor Mark Lautens, as well as my external examiner
Professor Sergey Kozmin, for their insights into my research; I am also grateful to Professor Jik
Chin for coutless scientific discussion. Furthermore, I am thankful for the opportunities to
conduct research in collaboration with the laboratories of Professor Eleftherios Diamandis,
Professor Aaron Wheeler, and Professor Travis Dudding.
I would like to acknowledge the consistent efforts of the departmental staff within the chemistry
department at the University of Toronto; I am particularly grateful for the various forms of
assistance provided by Anna Liza Villavelez and the graduate office. I would also like to thank
Dr. Timothy Burrows for his NMR guidance and his efforts in maintaining the NMR facilities,
Dr. Alan Lough for his analysis of several important X-ray crystal structures, and Alex Young
and the AIMS lab for their services in mass spectrometry.
I am grateful to the financial support from various institutional, provincial, national and
industrial sources. Several University of Toronto fellowships enabled me to focus on my
graduate research, while Ontario Graduate Scholarships and NSERC Postgraduate Doctoral
scholarships provided full financial support. The Boehringer Ingelheim Prize provided not only
financial support, but also afforded me with a unique opportunity to present my doctoral
research.
I had the pleasure of learning and practicing chemistry in a fruitful environment amongst several
talented chemists comprising the Yudin Group of past and present. I am particularily grateful to
those senior graduate students, especially Dr. Iain Watson, Dr. Larissa Krasnova, and Dr. Yu
Chen, whose guidance and instruction early in my graduate career readily enabled me with the
proper set of skills to perform independent research. I would finally like to thank my family and
friends whose various forms of support and encouragement throughout my graduate career were
greatly appreciated.
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Table of Contents
Acknowledgments ....................................................................................................................................................... iv
Table of Contents ......................................................................................................................................................... v
List of Tables ............................................................................................................................................................... ix
List of Figures .............................................................................................................................................................. x
List of Schemes .......................................................................................................................................................... xii
1 Introduction ........................................................................................................................................................ 2
1.1 Reaction between amines and aldehydes .................................................................................................... 2
1.1.1 Imine/enamine formation ....................................................................................................................... 3
1.2 α-Amino Aldehydes .................................................................................................................................... 4
1.2.1 N-Protected α-amino aldehydes............................................................................................................. 6
1.2.2 C-protected α-amino aldehydes ........................................................................................................... 11
1.2.3 Nucleophilic additions to α-amino aldehydes ...................................................................................... 13
1.3 Summary and outlook ............................................................................................................................... 30
1.4 References ................................................................................................................................................ 30
2 Synthesis of unprotected amino aldehydes .................................................................................................... 39
2.1 Aziridine structure and reactivity ............................................................................................................. 39
2.2 Synthesis of unprotected aziridine esters .................................................................................................. 42
2.2.1 From glycidic esters ............................................................................................................................. 43
2.2.2 From diol esters ................................................................................................................................... 44
2.2.3 From amino acids ................................................................................................................................ 45
2.3 Synthesis of unprotected aziridine aldehydes ........................................................................................... 47
2.3.1 DIBAL reduction of aziridine esters .................................................................................................... 47
2.3.2 Selectivity of dimerization ................................................................................................................... 49
2.3.3 Equilibrium of amino aldehydes in solution ........................................................................................ 52
2.3.4 Chemical stability ................................................................................................................................ 52
2.4 Experimental procedures .......................................................................................................................... 53
2.5 References ................................................................................................................................................ 64
3 Reactivity of unprotected amino aldehydes ................................................................................................... 69
v
3.1 Introduction .............................................................................................................................................. 69
3.2 Dissociation of amino aldehyde dimers .................................................................................................... 69
3.2.1 Solvent effects on dimer crossover ...................................................................................................... 70
3.2.2 Hemiacetalization ................................................................................................................................ 73
3.2.3 Bisulfite adduct formation ................................................................................................................... 74
3.3 Reaction with Amines ............................................................................................................................... 75
3.4 Reductive transformations ........................................................................................................................ 76
3.4.1 Reduction by borohydride reagents ..................................................................................................... 76
3.4.2 Reductive aminations ........................................................................................................................... 77
3.5 Kinetics of reductive amination ................................................................................................................ 79
3.5.1 Mechanistic pathways of reaction ........................................................................................................ 80
3.5.2 Experimental model ............................................................................................................................. 81
3.5.3 Kinetic results ...................................................................................................................................... 81
3.6 Allylation reactions .................................................................................................................................. 84
3.6.1 Reaction conditions ............................................................................................................................. 84
3.6.2 Reaction Scope .................................................................................................................................... 85
3.6.3 Dimeric Model for diastereoselectivity ............................................................................................... 86
3.6.4 One-pot synthesis of thio-amino alcohols ............................................................................................ 88
3.6.5 One-pot synthesis of bicyclic pyrrolidines .......................................................................................... 90
3.7 Amphoterism ............................................................................................................................................. 92
3.7.1 Definition ............................................................................................................................................. 92
3.7.2 Amphoteric molecules ......................................................................................................................... 93
3.7.3 Reactivity profile in domino processes ................................................................................................ 95
3.8 Summary and outlook ............................................................................................................................... 95
3.9 Experimental procedures .......................................................................................................................... 96
3.9.1 General procedure for reductive amination kinetics ............................................................................ 96
3.9.2 General procedure for allylation reactions ........................................................................................... 96
3.9.3 Characterization of allylic alcohols ..................................................................................................... 96
3.9.4 General procedure for thio amino alcohol synthesis ............................................................................ 98
3.9.5 Characterization of thio amino alcohols .............................................................................................. 99
3.9.6 General procedure for pyrrolidine synthesis ...................................................................................... 100
3.9.7 Characterization of pyrrolidines ........................................................................................................ 100
3.10 References .............................................................................................................................................. 101
4 Intercepted Pictet-Spengler reaction ............................................................................................................ 105
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4.1 Introduction ............................................................................................................................................ 105
4.1.1 The Pictet-Spengler reaction .............................................................................................................. 105
4.1.2 Mechanistic details ............................................................................................................................ 106
4.2 Intercepted Pictet-Spengler reaction ...................................................................................................... 107
4.2.1 Reaction development ....................................................................................................................... 107
4.2.2 Reaction scope ................................................................................................................................... 110
4.2.3 Mechanism......................................................................................................................................... 111
4.2.4 Ring-opening reactions ...................................................................................................................... 114
4.3 Summary and outlook ............................................................................................................................. 115
4.4 Experimental procedures ........................................................................................................................ 115
4.5 References .............................................................................................................................................. 120
5 Aza-Michael/aldol domino reaction .............................................................................................................. 122
5.1 Introduction ............................................................................................................................................ 122
5.1.1 Hetero-Michael/aldol reaction ........................................................................................................... 122
5.2 Aza-Michael/aldol with dimeric amino aldehydes .................................................................................. 124
5.2.1 Reaction development ....................................................................................................................... 124
5.2.2 Reaction scope ................................................................................................................................... 126
5.2.3 Mechanistic details ............................................................................................................................ 130
5.2.4 Transition state model ........................................................................................................................ 135
5.3 Summary and outlook ............................................................................................................................. 136
5.4 Experimental procedures ........................................................................................................................ 136
5.4.1 Protocol for aza-Michael/aldol reaction ............................................................................................ 136
5.4.2 Characterization of products .............................................................................................................. 137
5.5 References .............................................................................................................................................. 139
6 Intercepted Ugi reaction ................................................................................................................................ 143
6.1 Introduction ............................................................................................................................................ 143
6.1.1 The Ugi 5-centre 4-component reaction (U-5C-4CR) ....................................................................... 143
6.2 Synthesis of piperazinones ...................................................................................................................... 145
6.2.1 Reaction development ....................................................................................................................... 145
6.2.2 Reaction scope ................................................................................................................................... 146
6.2.3 Mechanism of reaction ...................................................................................................................... 150
6.2.4 Ring-opening Ugi cyclization ............................................................................................................ 151
6.2.5 Reduction of piperazinones ............................................................................................................... 153
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6.2.6 Piperazinone ring-opening reactions.................................................................................................. 154
6.3 Synthesis of cyclic peptides..................................................................................................................... 156
6.3.1 Reaction development ....................................................................................................................... 158
6.3.2 Reaction scope of macrocyclization .................................................................................................. 158
6.3.3 Reaction molarity............................................................................................................................... 163
6.3.4 Influence of substrate chirality .......................................................................................................... 166
6.3.5 Mechanism of reaction ...................................................................................................................... 167
6.3.6 Aziridine ring opening conjugations .................................................................................................. 169
6.4 Summary and outlook ............................................................................................................................. 171
6.5 Experimental procedures ........................................................................................................................ 172
6.5.1 Protocols for piperazinone synthesis ................................................................................................. 172
6.5.2 Protocols for cyclic peptide synthesis ................................................................................................ 173
6.5.3 Protocols for nucleophilic conjugation .............................................................................................. 174
6.5.4 Protocols for ring-opening coupling .................................................................................................. 175
6.5.5 Characterization of cyclic peptides .................................................................................................... 175
6.6 References .............................................................................................................................................. 180
Appendix I: 1H & 13C NMR and ESI-MS Spectra ................................................................................................ 183
Appendix II: X-ray crystallographic data ............................................................................................................. 242
Appendix III: Computational data ........................................................................................................................ 278

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List of Tables
Table 1. Scope of dimeric amino aldehyde synthesis. ................................................................................................ 48
Table 2. Scope of reductive amination of dimeric amino aldehyde with amines. ....................................................... 78
Table 3. Scope of allylindium addition reaction. ........................................................................................................ 85
Table 4. Scope of thio amino alcohol synthesis. ......................................................................................................... 89
Table 5. Scope of bicyclic pyrrolidine synthesis......................................................................................................... 91
Table 6. Reaction optimization of the intercepted Pictet-Spengler reaction. ............................................................ 109
Table 7. Reaction scope for the intercepted Pictet-Spengler reaction. ..................................................................... 110
Table 8. Scope of the aza_Michael/aldol domino reaction.a ..................................................................................... 127
Table 9. Piperazinone synthesis by reaction of amino acid with aziridine aldehyde and isocyanide. ...................... 147
Table 10. Scope of ring-opening Ugi cyclization. .................................................................................................... 152

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List of Figures
Figure 1.1. Typical pH-rate profile observed for imine formation. .............................................................................. 4
Figure 1.2. Glucosamine hydrogen chloride and glycinal. ........................................................................................... 5
Figure 1.3. N-protected α-amino aldehydes. ................................................................................................................ 6
Figure 1.4. Stablity of the amino nitrile function in C-protected amino aldehydes. ................................................... 13
Figure 1.5. Models for nucleophilic addition to N,N-disubstituted α-amino aldehydes. ............................................ 14
Figure 1.6. Models for nucleophilic addition to N-monosubstituted α-amino aldehydes. .......................................... 14
Figure 1.7. Transition-state models for Roush allylation of the Garner aldehyde. ..................................................... 17
Figure 1.8. Proposed transition states for allylindium addition to α-amino aldehyde derivatives. ............................. 23
Figure 1.9. Proposed transition-states towards 64. ..................................................................................................... 26
Figure 2.1. Molecular model of aziridine. .................................................................................................................. 39
Figure 2.2. Representations of the Coulson-Moffitt (A) and the Walsh (B) models. ................................................. 40
Figure 2.3. Aqueous pK values for diphenylmethaneiminium, aziridinium, and piperidinium ions. ........................ 40
a
Figure 2.4. Inversion barriers at nitrogen for trimethylamine and aziridine. .............................................................. 41
Figure 2.5. Commercially available starting materials used for aziridine ester syntheses. ......................................... 43
Figure 2.6. Overall yields for aziridine reaction sequence.......................................................................................... 44
Figure 2.7. X-ray crystal structure of dimeric amino aldehyde 118. .......................................................................... 48
Figure 2.8. Calculated groundstates of homodimeric and heterodimeric amino aldehyde 118. ................................. 51
Figure 2.9. Hyperconjugation exhibited in homochiral dimer .................................................................................... 51
Figure 2.10. 1H NMR spectra of dimeric amino aldehyde 122. .................................................................................. 52
Figure 3.1. A more dynamic equilibrium represented in red. ..................................................................................... 70
Figure 3.2. ESI-MS spectrum for dimer crossover experiment in MeOH. ................................................................. 71
Figure 3.3. ESI-MS spectrum for dimer crossover experiment in TFE. ..................................................................... 71
Figure 3.4. Proposed TFE involvement in dimer dissociation. ................................................................................... 72
Figure 3.5. 1H NMR spectra for amino aldehyde dimer 133 and hemiacetal 134. ..................................................... 74
Figure 3.6. Plot of [150] (■) and [151] (▲) with respect to time in the pseudo first-order reductive amination of
dimerica amino aldehyde 150 with aniline. ....................................................................................................... 82
Figure 3.7. First-order plot of Ln{[151] -[151]} with respect to time in the pseudo first-order reductive amination
∞ t
of dimeric amino aldehyde 150 with aniline. ..................................................................................................... 83
Figure 3.8. Half-order plot of 1/ ({[151] -[151]}-0.5) with respect to time in the pseudo first-order reductive
∞ t
amination of dimeric amino aldehyde 150 with aniline. .................................................................................... 83
Figure 3.9. Calculated transition state 166 for allylindium addition reaction. ............................................................ 88
Figure 3.10. X-ray crytal structure of thio amino alcohol 174.................................................................................... 89
Figure 3.11. Examples of amphoteric molecules. ....................................................................................................... 93
Figure 3.12. Reactivity profile of amphoteric molecules in domino processes. ......................................................... 95
Figure 4.1. X-ray crystal structure of anti pentacycle 195. ....................................................................................... 108
Figure 4.2. Diastereomeric transition states forming syn and anti pentacycles. ....................................................... 114
x