Asymmetric Synthesis of Natural Products

311 Pages·2012·3.73 MB·English

by  Ari M. P. Koskinen(auth.)

Asymmetric Synthesis of Natural Products
Asymmetric Synthesis of Natural Products
Second Edition
ARI M.P. KOSKINEN
Department of Chemistry, Aalto University,
School of Chemical Technology, Espoo, Finland
A John Wiley & Sons, Ltd., Publication
Thiseditionfirstpublished2012
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LibraryofCongressCataloging-in-PublicationData
Koskinen,Ari.
Asymmetricsynthesisofnaturalproducts/AriM.P.Koskinen,DepartmentofChemistry,AaltoUniversity,SchoolofChemicalTechnology,
Espoo,Finland.–Secondedition.
pagescm
Includesbibliographicalreferencesandindex.
ISBN978-1-119-97668-4(hardback) –ISBN978-1-119-97669-1(paper)
1. Naturalproducts–Synthesis.2. Asymmetry(Chemistry) I.Title.
QD415.K662012
547(cid:2).2–dc23
2012008652
AcataloguerecordforthisbookisavailablefromtheBritishLibrary.
ClothISBN:9781119976684
PaperISBN:9781119976691
Typesetin10/12TimesbyLaserwordsPrivateLimited,Chennai,India
Contents
PrefacetotheFirstEdition ix
PrefacetotheSecondEdition xi
ListofCommonAbbreviations xiii
1 Introduction 1
1.1 Some properties of natural products 4
1.2 Natural products as drugs 7
1.3 Structures of natural products 10
1.4 Asymmetric synthesis of natural products 15
1.5 Synthetic organic chemistry 17
References 20
2 Chirality, Topology, and Asymmetric Synthesis 23
2.1 The need for enantiopure compounds 34
2.2 Determination of enantiomeric purity 38
2.3 Chirality and thermodynamic principles of asymmetric induction 42
2.4 Methods for obtaining chiral compounds 44
References 52
3 Asymmetric Synthesis 55
3.1 Allylic strain 55
3.2 Reactions of the carbonyl group 59
3.2.1 Nucleophilic additions on the carbonyl carbon 59
3.2.2 Reactions at the α-carbon (enolate chemistry) 81
3.2.3 Reactions at the β-carbon of an enone 95
3.3 Reactions of olefins 99
3.3.1 Oxidation 99
References 108
4 Sugars 115
4.1 Monosaccharides 116
4.1.1 Aldoses and ketoses 116
4.1.2 Deoxy sugars 122
4.1.3 Amino sugars 122
4.1.4 Sugar alcohols 125
4.1.5 Acidic sugars 125
vi Contents
4.2 Polysaccharides 127
4.3 Glycoproteins and proteoglycans 131
4.4 Glycolipids 134
4.5 Sugar antibiotics 134
4.6 Cyclitols 138
References 142
5 Amino Acids, Peptides, and Proteins 145
5.1 Amino acids 145
5.2 Peptides and proteins 149
5.3 Enzymes and receptors 153
5.4 Chemical modifications of peptides 154
5.5 Biosynthesis of amino acids 156
5.6 Asymmetric synthesis of amino acids 160
5.6.1 α-Alkylation 162
5.6.2 Amination of ester enolates 167
5.6.3 Catalytic hydrogenation 169
5.6.4 Miscellaneous 170
5.6.5 Pepstatins 171
References 173
6 Nucleosides, Nucleotides, and Nucleic Acids 175
References 184
7 Polyketides 187
7.1 Biosynthesis 188
7.2 Fatty acids 190
7.2.1 Prostaglandins, thromboxanes, and leukotrienes 191
7.2.2 Sphingolipids 196
7.3 Polypropionates 200
7.3.1 Polyether antibiotics 200
7.3.2 Macrolides 201
7.3.3 Spiroketals 209
7.4 Aromatic polyketides 213
References 215
8 Terpenes 219
8.1 Terpenes 221
8.1.1 Monoterpenes 221
8.1.2 Sesquiterpenes 223
8.1.3 Diterpenes 228
8.1.4 Higher terpenes 230
8.2 Carotenoids 234
Contents vii
8.3 Steroids 235
8.3.1 Biosynthesis of steroids 240
8.3.2 Asymmetric synthesis of steroids 242
References 244
9 Shikimic Acid Derivatives 247
9.1 Case synthesis: Oseltamivir 251
References 254
10 Alkaloids 257
10.1 Heterocyclic alkaloids 258
10.1.1 Indole alkaloids 259
10.1.2 Pyrrolidine and tropane alkaloids 270
10.1.3 Quinoline and isoquinoline alkaloids 273
10.1.4 Izidine alkaloids 279
10.2 Alkaloids with exocyclic nitrogen 282
10.3 Polyamine alkaloids 283
10.4 Peptide alkaloids 283
10.5 Terpene alkaloids 284
References 285
Index 289
Preface to the First Edition
Thisbookisbasedonaone-semester,24hourlecturecoursegivenoverthepastsixyearsattheUniversity
ofHelsinki,Finland,UniversityofSurrey,England,andUniversityofOulu,Finland.Thecourseisintended
for senior undergraduate and beginning graduate students. It is also hoped that the book will be useful for
practicing research workers who want to refresh their knowledge on the field.
The basic idea of a course combining asymmetric synthesis and natural product chemistry came from
ProfessorTapioA.Haseearlyin1987whendiscussinghowbesttocoverboththefundamentalsandlatest
developments in asymmetric synthesis in a stimulating way. As natural product synthesis is the logical
field of application for asymmetric transformations, I decided to try out the concept. Over the years it has
worked well, and the course has developed into an enjoyable one, both for the students and the teacher.
For the evolution, I must thank the many students at the three universities for their helpful comments and
suggestions.
Thebookbeginswithabriefintroductiontothegeneralfieldanditsalliedapplications.Chapter2covers
thebasicthermodynamicsandterminologyaswellasprocessesforasymmetricsynthesis.Chapter3forms
the main body of the individual asymmetric reactions which are covered both in terms of theory and
applications. The rest of the book, Chapters 4 to 10, covers the individual natural product classes. I
have tried to give a brief overview of the structural varieties and biosynthetic pathways leading to these
compounds, as well as the practical (mainly pharmacological) importance of a number of representative
compounds. To keep the reading lighter, I have also included some rather amusing anecdotes from the
past.Thesynthesesoftheindividualnaturalproducttypesarecoveredwithexamples,givingsomegeneral
methods for the particular natural products. I have deliberately not included repetitions of long sequences
of reactions which are not pertinent to the subject - these can be found in the references and in recent
literature. The references are not exhaustive; quite the contrary, I have tried to keep the number as low as
possible without sacrificing the context. For all omissions of important work, or references, I express my
apologies. I will also warmly welcome all comments for possible future editions.
I wish to thank Professor Tapio A. Hase for the impetus for coming up with the course, and my
mentors Professor Mauri Lounasmaa (Helsinki University of Technology, Finland) and Professor Henry
Rapoport (University of California, Berkeley, USA) for leading me to the wonderful world of natural
product chemistry and asymmetric synthesis.
Finally, my wife Pa¨ivi, and three daughters, Tiina, Joanna and Heidi, have taken a lot of grief during
the writing process. Without their everlasting understanding and love, the whole project could not have
been accomplished.
A.M.P.K.
Preface to the Second Edition
Thesecondeditionofthisbooktookalongtimetocomeabout.Maybetoolongbutperhapsnot,sincethe
intervening time actually gave me a lot of perspective, which I try to convey to you, too. In 1992, when
thefirsteditionwasjustfinished,thechemistryscenewasverymuchdifferentfromtoday.Organometallic
chemistryhadonlyrecentlybecomeamainstreampracticeforsyntheticchemists;asymmetricsynthesiswas
still a field mainly practiced by specialists, and practically nobody talked about combinatorial chemistry.
In the analytical field, a 500MHz NMR was considered to be luxury equipment, and 2D experiments
were usually limited to COSY and NOESY spectra. This made the analysis of conformations much more
tedious than today. And of course computer modeling was still in its infancy, force field methods were
slow, cumbersome, and could only handle small molecules.
The publisher asked for a second edition quite some time ago, about 10 years ago, but honestly, I was
too busy with changes in my career. While the book project was on a back burner, asymmetric synthesis
keptdevelopingatanincreasingpace,asdidotherspecialistfieldsofchemistry.Organometallicchemistry
turnedasymmetricinabigwayinthelate1990s,andmetalcatalyzedreactionswonmanyfollowers.Inthe
1990s there was a huge thrive to combinatorialize practically everything, until the hype for combinatorial
chemistry faded as quickly as it came about. It still remains a tool, a useful one, but only one tool among
many.Methodsforstructuralanalysis,bothexperimentalandcomputational,havegivenusunprecedented
means to rationalize and predict the stereochemical outcomes of reactions. Organic molecules have been
used as catalysts for reactions at least for as long as one has written records. Organocatalysis is a term
coined between the two editions of this book, and it will be interesting to see how the concept will
eventually evolve. One thing is for sure; our increasingly comprehensive understanding of chemistry and
its adjoining fields require a new perspective in the development of new chemical reactions, which is the
core of chemistry.
This book forms the core for a continuum of two smaller lecture courses, each of a length of half a
semester, that is about six weeks each (it used to be a single full term course, but was split in two a few
years ago). Since the course is for advanced level students, I have done away with traditional tutorials,
exams,andessays,andinsteadtogetherwiththestudentsweusuallytrytodosomethingdifferentlyevery
year. Whether you use this book for teaching a course or use it to learn yourself, I strongly recommend
you to experiment with learning methods, too. Some suggestions that have been very popular, are the
following: the students should keep a learning diary and compare it with their class mates. We have
divided the students to small task groups, where in pairs, sorry, in doublets or triplets, they analyzed for
instance, the syntheses of a particular natural product from two different eras, like 40 years apart. Or they
compared the mechanistic explanations of a particular reaction based on two papers several decades apart.
This can be challenging, but will teach the student to read and understand old papers, where even the
structures were drawn differently! Among the favorites are student lectures, where the students mine the
literature and databases and construct their own interpretation for discussion before I preach the orthodox
teachings.Whenthestudentscomeupwithanewexplanation,theycanalsosharethemomentofcreating
new knowledge, which culminates in dissemination to their colleagues.
Isimplymustsharethewaythisbookfinallycametobefinished.In2004wehadawonderfulmeeting,
under the auspices of the EU COST actions, in the beautiful old monastery of Certosa di Pontignano near
Siena, Italy. At some point during the discussions over very palatable Tuscan wines, I said to Maurizio
xii PrefacetotheSecondEdition
and Bruno Botta that I really would love to write the second edition in Tuscany. Of course, the brothers
warmly welcomed me to Italy to take up the job. After the meeting, reality struck back, and everyday
chores kept me plodding the well-trodden paths of academic life. The dream of writing under olive trees
remained a warm joke with friends and family, and a hazy dream in my solitary moments. Things started
rolling in the summer of 2010, first verbally during the ICOS meeting in Bergen, and then later in the
autumn with a written contract ready for signature. By the end of 2010 I was committed, but the logistics
were still a complete mess, until in May 2011 when Aalto University granted me a sabbatical leave for
the end part of the year, without which the whole project would never have been finished. Olive trees,
Italy, and writing the book would turn into a dream come true. With the help of La Sapienza Professor
Bruno Botta, we managed to find a wonderful house in Tuscania, a small town in northern Lazio. The
tranquility and the atmosphere of the house provided the best surrounding imaginable for doing the job.
Waking up in the morning to the sounds of a nearby waterfall in the background and the early morning
baahs of Francesco’s sheep in the foreground. Our landlord, Francis Kuipers, a well-known composer and
musicprofessional,andhis‘assistant’IoneKerrCiccioli,madesurethatwewerecompletelysafe-mobile
phones did not pick up transmission, but the Wi-Fi was strong, so I could do all my database searches
speedily.
It was a truly rewarding experience to be able to concentrate on this project so totally without other
worries, and I hope this is also reflected in the outcome. I am greatly indebted to those who made it all
possible. First of all, all the students at Oulu University, Helsinki University of Technology, presently
Aalto University, and Helsinki University where I have given the lecture courses regularly. My students
in my research group have all contributed over the years, providing a perfect sounding board for new
ideas and insights. My colleagues both at the universities I have been affiliated with as well as my friends
around the world have all contributed to my professional development, and deserve my warmest thanks.
The first and second editions are separated by two decades, which makes this edition the second gener-
ation. On personal level, that’s what has also happened: my daughters, whom I thanked in the preface to
the first edition, have moved out, and have been replaced with Sara, and finally a boy; Mikko. They, and
my muse and lifeline Pa¨ivi have given me the strength and inspiration to finish this work.
Finally to you, my readers, I wish to convey the same message I finish my guest lectures with. When
I was flying out of the nest of my main mentor Professor Henry Rapoport of UC Berkeley, a pioneer of
asymmetric synthesis and a great protagonist for experimentation, gave me the message to be passed on:
‘Keep the Bunsen burning!’
Ari Koskinen
Karkkila February, 2012
List of Common Abbreviations
Ac acetyl
acac acetylacetonate
ACC aminocyclopropanecarboxylic acid
Ad adenosyl
AD asymmetric dihydroxylation
ADP adenosine diphosphate
AIBN azoisobutyronitrile
AMP adenosine monophosphate
n-Am n-amyl
An p-anisyl
anh. anhydrous
aq. aqueous
atm atmosphere
ATP adenosine triphosphate
9-BBN 9-borabicyclo[3.3.1]nonane
(cid:2) (cid:2)
BINAL-H 1,1-bi-2,2-naphthol – Lithium aluminum hydride complex
(cid:2) (cid:2)
BINAM 1,1-binaphthalene-2,2-diamine
(cid:2) (cid:2)
BINAP 2,2-bis(diphenylphosphino)-1,1-binaphthyl
(cid:2) (cid:2)
BINOL 1,1-bi-2,2-naphthol
(cid:2) (cid:2)
BIPHEP 2,2-bis(diphenylphosphino)- 1,1-biphenyl
BMS borane-dimethyl sulfide
Bn benzyl
Boc tert-butoxycarbonyl
BOX bisoxazoline
n-Bu n-butyl
s-Bu sec-butyl
t-Bu tert-butyl
Bz benzoyl
CAB Chiral acyloxyborolidine
CAL Candidaantarctica lipase
CAN ceric ammonium nitrate
cat catalytic amount
CB catecholborane
CBS Corey-Bakshi-Shibata
Cbz benzyloxycarbonyl (carbobenzyloxy)
CCK cholecystokinin
CD circular dichroism