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Multi-Step Organic Synthesis

A Guide Through Experiments


Nicolas Bogliotti and Roba Moumné






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Dedicated to Lina and Juliette

In memory of Constant Bogliotti


This book is a collection of problems in organic chemistry finding its origin between 2010 and 2015 at École normale supérieure Paris-Saclay (at that time École normale supérieure de Cachan).

In the context of students’ preparation for a competitive national examination in Chemistry (Agrégation de Sciences Physiques, option Chimie), giving access to teaching positions in French higher education institutions, a number of exercises dealing with multistep syntheses of natural products and active pharmaceutical ingredients were created from chemical research literature.

After extensive selection, adjustment, and modification, part of the original material is compiled in this volume. It is completed by exercises related to the field of chemical biology, which we consider an essential branch of chemical education, taught at Université Pierre et Marie Curie.

Besides its initial purpose, this work reflects to some extent a common practice in organic chemistry research laboratories, often on the occasion of group seminars, which is going through multistep synthesis with questions related to synthetic strategies, reaction conditions, and transformation mechanisms. In this respect, several excellent titles are available and are listed in the section “Further Reading.”

While we tried to inject some of this essence in our book, our objective was also to provide a broad readership, not necessarily specialized in organic chemistry, an accessible set of problems in multistep synthesis, including experimental aspects, which are not extensively covered by current offers available on the market. The “self-studying” nature of this book indeed allows the reader to be assisted by a number of indications such as detailed textual description of the operating conditions (rate and order of reagents addition), macroscopic observations (color change, gas evolution, formation of a precipitate, increase in temperature, etc.), workup procedures (neutralization, extraction, etc.), as well as selected characteristic spectroscopic or spectrometric data of the products (infrared vibrations, 1H-NMR and 13C-NMR, mass spectrometry, etc.). Elucidation of molecular structure is thereby seen as a puzzle to be solved by aggregating available pieces. This vision of chemistry as essentially a game and a source of intellectual stimulation, shared by many of our colleagues, is worth being put forward, especially in the present troubled times when “societal impact” tend to constitute the quasi-exclusive input and justification for scientific research.

We stress that our book aims to be a practice medium adapted from published syntheses, not a strictly authentic description thereof. Indeed we chose to favor pedagogy over authenticity when we estimated that part of the original research article was not completely suited for teaching purposes. For example, while we enforced to keep intact the “spirit” of the initial work, we also took the freedom to slightly modify reaction conditions or synthetic routes and add expected characteristic spectroscopic data when missing in the original article, in order to create a story which, although not entirely real, remains mostly plausible. These modifications are listed as footnotes throughout the book. As teachers, we see such a choice as a requirement to render state-of-the-art syntheses overall accessible to nonexperts; while as researchers, we are convinced that students need to be in contact as early as possible with the practice of chemistry as it is performed in research laboratories.

In the first part, Chapters 1–5 describe short syntheses, with the longest linear sequences below five steps, which are well suited to emphasize the understanding of operating conditions and workup procedures. Process-scale syntheses of active pharmaceutical ingredients are especially represented, shedding light on common practices of the chemical industry that are often unknown (or unsuitable) to academic laboratories. Then, Chapter 6, presenting the total synthesis of a complex biologically active macrolide, might appear as uncommon in the sense that only a few chemical structures are mentioned (mostly starting materials, by-products, and target compounds). Rather, a number of indications are given in a textual form. Such a presentation, which somehow parallels the ability of some chemists to precisely define complex molecular structure by merely employing appropriate words, undoubtedly requires effort to maintain a sufficient level of mental representation. Chapters 7–10 deal with the synthesis of photochromic and fluorescent molecules, whose properties either allow the control of reactivity with light or the monitoring of enzyme activity in a biological context. Some general aspects of structure–property relation are included. Chapters 11–14 report synthetic approaches toward various natural products. Although slightly more “classical” in their form, as compared to other problems in the book, they highlight the detours, surprises, and dead ends commonly faced in total synthesis. Finally, given the growing interest for education at the chemistry/biology interface and the key role played by chemists in understanding living systems at the molecular scale, Chapters 15 and 16 are dedicated to the chemical synthesis of relevant bioactive compounds and study of their biological activities, with emphasis on the relation between tridimensional structure and function.

We express our warmest thanks to the reader paying attention to this book and our words, and also to our past and present students, colleagues, and mentors, for their input on this work.

Paris, France
January 2017

Nicolas Bogliotti
Roba Moumné

List of Abbreviations

AA amino acid
Ac acetyl
ACE-Cl α-chloroethyl chloroformate
AIBN azobisisobutyronitrile
All allyl
aq. aqueous
Ar or ar aryl or aromatic
Arg arginine
Asp aspartic acid
atm atmosphere
a.u. arbitrary unit
9-BBN 9-borabicyclo[3.3.1]nonane
BINOL 1,1′-bi-2-naphtol
Bip biphenylalanine
Bn benzyl
Boc tert-butoxycarbonyl
br broad
C cystein
ca. circa
CAN ceric ammonium nitrate
cat. catalyst or catalytic
Cbz carboxybenzyl
CBC covalent bond classification
CDI carbonyldiimidazole
Cha cyclohexylalanine
ClF 4-chlorophenylalanine
COD 1,5-cyclooctadiene
conv. conversion
Cy cyclohexyl
D aspartic acid
d doublet
DAADH D-amino acid dehydrogenase
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC N-N′-dicyclohexylcarbodiimide
dd doublet of doublets
de diastereoisomeric excess
D-Glu D-glucose
dr diastereoisomeric ratio
DIAD diisopropyl azodicarboxylate
DIBAL-H diisobutylaluminium hydride
DIC N-N′-diisopropylcarbodiimide
DIPEA N,N-diisopropylethylamine
DMA dimethylacetamide
DMAP 4-dimethylaminopyridine
DMBA 1,3-dimethylbarbituric acid
DMF dimethylformamide
E glutamic acid
F phenylalanine
e electron
EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
ee enantiomeric excess
equiv. equivalent
G glycine
GDH glucose dehydrogenase
Gly glycine
h hour
5-HT 5-hydroxytryptamine
HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
HBTU 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate
Hfe homophenylalanine
HFIP hexafluoroisopropanol
HMPA hexamethylphosphoramide
HOAt 1-hydroxy-7-azabenzotriazole
HOBt N-hydroxybenzotriazole
HPLC high performance liquid chromatography
HRMS high resolution mass spectrometry
KHMDS potassium bis(trimethylsilyl)amide
m multiplet
IPAc isopropyl acetate
K lysine
L leucine
Leu leucine
LiHMDS lithium bis(trimethylsilyl)amide
liq. liquid
Lys lysine
m-CPBA meta-chloroperoxybenzoic acid
MEK methyl ethyl ketone
Mes mesityl
MIBK methyl isobutyl ketone
MIC minimal inhibitory concentration
MIO 4-methylideneimidazole-5-one
MS molecular sieves
Ms mesyl
1-Nal 1-naphtylalanine
2-Nal 2-naphtylalanine
NADH nicotinamide adenine dinucleotide
NADPH nicotinamide adenine dinucleotide phosphate
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
NHS N-hydroxysuccinimide
NIR near infrared
Nle norleucine
NMM N-methylmorpholine
NMO N-methylmorpholine N-oxide
NMP N-methyl-2-pyrrolidone
NMR nuclear magnetic resonance
Np naphtyl
P proline
p d-proline
Pro proline
pro d-proline
PAL phenylalanine ammonia lyase
Pbf 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl
PBS phosphate-buffered saline
PEG polyethylene glycol
PG protecting group
PG-I protegrin I
PLP pyridoxal 5′-phosphate
PMB 4-methoxybenzyl
Pmc 2,2,5,7,8-pentamethyl-chromane-6-sulfonyl
P(o-Tol)3 tri(ortho-tolyl)phosphine
Pp 2-phenyl-2-propyl
PTSA para-toluenesulfonic acid
Ph phenyl
Phe phenylalanine
Phg phenylglycine
Q glutamine
q quartet
quant. quantitative
R arginine
rt room temperature
Rf retardation factor
RFU relative fluorescence unit
s singlet or second
SMO Smoothened
soln. solution
Su succinimide
t triplet
TBAF tetra-n-butylammonium fluoride
TBME tert-butyl methyl ether
TBS tert-butyldimethylsilyl
TBDPS tert-butyldiphenylsilyl
TEMPO 2,2,6,6-tetramethylpiperidinyloxy
Tf trifluoromethanesulfonyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin-layer chromatography
TMEDA tetramethylethylenediamine
TMS trimethylsilyl
Tol tolyl
Ts 4-toluenesulfonyl
TSTU 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate
Tyr tyrosine
UV ultraviolet
V valine
Val valine
vis visible
vs versus
v/v volume by volume
W tryptophane
w/w weight by weight
Y tyrosine