Part I. Tandem Aldol-Allylation Reactions Promoted
`by Strained Silacycles
`
`Part II. Design and Synthesis of Modified Fluorescent
`
`Nucleotides for DNA Sequencing by Synthesis
`
`Qinglin Meng
`
`Submitted in partial fulfillment of
`
`the requirements for the degree of Doctor of Philosophy
`
`in the Graduate School ofArts and Sciences
`
`COLUMBIA UNIVERSITY
`
`2006
`
`Page a
`
`Illumina Ex. 1086
`IPR Petition - USP 10,435,742
`
`

`

`UMI Number: 3237290
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`Page b
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`©2006
`
`Qinglin Meng
`
`All Rights Reserved
`
`Page c
`
`

`

`ABSTRACT
`
`Part
`
`I.
`
`Tandem Aldol-Allylation Reactions Promoted by Strained
`
`Silacycles
`
`Part II. Design and Synthesis of Modified Fluorescent Nucleotides for
`
`DNA Sequencing by Synthesis
`
`Qinglin Meng
`
`The first part of this thesis presents the tandem aldol-allylation reactions promoted by
`
`strained 1,3-dioxa-2-silacyclopentane rings. Our studies have proven that both the
`
`aldehyde- and ketone-derived allylenolsilanes could react with aldehydes smoothly in the
`
`absence of catalysts to afford homoallylic I,3-diols with high diastereoselectivity. Pinacol
`
`was employed to constitute the strained 1,3-dioxa-2-silacyclopentane ring as an effective
`
`platform to activate the reactivity of silane reagents due to the effect of strain-release
`
`Lewis acidity. The tandem aldol-allylation reactions proceed via a cyclic transition state
`
`with a six-membered chair-like conformation (type 1 allylation). Homoallylic 1,3-diols
`
`with up to four stereocenters can be generated using tandem aldol-allylation reactions in
`
`one step conveniently and rapidly, which has become an important method to construct
`
`1,3-diol fragments for the total synthesis of natural products.
`
`The second part of this thesis describes the design and synthesis of both photocleavable
`
`Page d
`
`

`

`and chemically cleavable 3' modified fluorescent nucleotides. Four 3' allyl modified
`
`nucleoside triphosphates (3' -O-allyl-dNTP-NH2) were synthesized from readily available
`
`chemicals in reasonable yields after which modified fluorescent nucleotides were
`
`prepared via coupling reactions of these nucleoside triphosphates with corresponding
`
`fluorescent dyes. These fluorescent nucleotides have been applied for DNA sequencing
`
`by synthesis both in solution phase and on a glass chip and have proven to be good
`
`reversible terminators for DNA SBS. They could be accurately incorporated into a
`
`growing DNA strand in the DNA polymerase reaction and the 3' capping group could be
`
`cleaved conveniently in aqueous palladium (H)-phosphine solution after fluorophore
`
`detection. This valuable approach has offered an alternative DNA analysis method to
`
`overcome the disadvantages and limitations of conventional electrophoresis-based
`
`sequencing methods.
`
`Page e
`
`

`

`Table of Contents
`
`Part I. Tandem Aldol-Allylation Reactions Promoted by Strained Silacycles
`
`Chapter 1.
`
`Introduction
`
`References
`
`2
`
`11
`
`Chapter 2. Tandem Aldol-Allylation Reactions Promoted by a Strained 1,3,2-
`
`Dioxasilolane Cycle
`
`2.1 Tandem aldol-allylation reactions using aldehyde-derived allylenolsilanes
`
`2.2 Tandem aldol-allylation reactions using ketone-derived allylenolsilanes
`
`2.3 Discussions on tandem aldol-allylation reactions of allylenolsilanes
`
`2.4 Summary and Outlook
`
`2.5 Experimental section
`
`References
`
`13
`
`.14
`
`21
`
`.32
`
`38
`
`39
`
`63
`
`Part II. Design and Synthesis of Modified Fluorescent Nucleotides for
`
`DNA Sequencing by Synthesis
`
`Chapter 1.
`
`Introduction to DNA Sequencing by Synthesis
`
`1.1 Structures and properties of DNA, nucleotides and nuc1eosides
`
`66
`
`67
`
`

`

`1.2 Sanger dideoxy DNA sequencing
`
`1.3 DNA sequencing by synthesis
`
`1.4 DNApyrosequencing
`
`1.5 DNA sequencing using mass spectrometry
`
`1.6 DNA sequencing by nanopore
`
`References
`
`ii
`
`71
`
`73
`
`76
`
`80
`
`82
`
`85
`
`Chapter 2. Design and Synthesis of Modified Fluorescent Nucleotides for DNA
`
`Sequencing by Synthesis
`
`2.1 Background
`
`2.2 Design of modified fluorescent nucleotides for DNA SBS
`
`2.3 Synthesis of 3' allyl modified nucleoside triphosphates (1, 2, 3 and 4)
`
`87
`
`87
`
`96
`
`102
`
`2.3.1 Synthesis of 3'-O-allyl-7-deaza-7-(3-aminoprop-l-ynyl)-2'-deoxyadenosine-5'-
`
`triphosphate 1
`
`102
`
`2.3.2 Synthesis of 3'-O-allyl-7-deaza-7-(3-aminoprop-l-ynyl)-2'-deoxyguanosine-5'-
`
`triphosphate 2
`
`108
`
`2.3.3 Synthesis of 3'-O-allyl-5-(3-aminoprop-l-ynyl)-2'-deoxycytidine-5' -triphosphate
`
`3
`
`118
`
`2.3.4 Synthesis of 3'-O-allyl-5-(3-aminoprop-l-ynyl)-2'-deoxyuridine-5' -triphosphate
`
`4
`
`2.4 Synthesis of cleavable linkers
`
`120
`
`121
`
`

`

`2.4.1 Synthesis of chemically cleavable allyl linker 5
`
`2.4.2 Synthesis of photocleavable linker 65
`
`2.5 Synthesis of fluorescent nucleotides 73, 77, 81, 85, 86, 87, 88, 89
`
`iii
`
`123
`
`124
`
`125
`
`2.6 Confirmation of allyl position in the modified nucleoside molecules: O-allyl or
`
`N-allyl.
`
`2.7 Experimental section
`
`References
`
`129
`
`131
`
`159
`
`Chapter 3. Application of Modified Fluorescent Nucleotides
`
`as Reversible
`
`Terminators for DNA Sequencing by Synthesis
`
`3.1 Survey of methods to cleave 3' allyl group and allyl linker moiety
`
`162
`
`162
`
`3.2 Application of photocleavable modified fluorescent nucleotides as
`
`reversible
`
`terminators for DNA sequencing by synthesis
`
`167
`
`3.3 Application of photocleavable modified fluorescent nucleotides as
`
`reversible
`
`terminators for DNA sequencing on a glass chip
`
`172
`
`3.4 Application of chemically cleavable modified fluorescent nucleotides as reversible
`
`terminators for DNA sequencing by synthesis
`
`175
`
`3.5 Proposed photocleavage and deallylation mechanisms of modified fluorescent
`
`nucleotides in DNA sequencing by synthesis
`
`3.6 Experimental section
`
`References
`
`183
`
`185
`
`190
`
`

`

`Chapter 4. Summary and Outlook
`
`Appendix:
`
`IH and l3C NMR Spectra
`
`Part I
`
`Part II
`
`iv
`
`192
`
`195
`
`196
`
`247
`
`

`

`List of Schemes, Figures and Tables
`
`v
`
`Part 1.
`
`Chapter 1.
`
`Introduction
`
`Scheme 1-1. Noncatalyzed aldol addition reactions of silacyclobutanes with aldehydes...4
`
`Scheme 1-2. Noncatalyzed allylation reactions of silacyclobutanes with aldehydes and
`
`ketones
`
`'"
`
`'"
`
`5
`
`Scheme 1-3. Noncatalyzed allylation reactions of allylic silacycles with aldehyde
`
`reported by Kira
`
`7
`
`Scheme 1-4. Noncatalyzed allylation reaction of an allylic silane containing a strained
`
`I,3-dioxa-2-silacyclopentane ring with benzaldehyde by Xiaolun Wang
`
`Figure 1-1. Examples of some polyketides containing 1,3-diol fragment
`
`Figure 1-2. Lewis acidity of silicon is enhanced by the strained silacyclobutane ring
`
`Figure 1-3. Classification of allylation reactions proposed by Denmark
`
`8
`
`2
`
`6
`
`9
`
`Chapter 2.
`
`Tandem Aldol-Allylation Reactions Promoted by a Strained
`
`1,3,2-Dioxasilolane Cycle
`
`Scheme 2-1. Tandem aldol-allylation reactions of allylenolsilanes with dimethylacetals
`
`promoted by Lewis acids
`
`13
`
`Scheme 2-2. Noncatalyzed tandem aldol-allylation reactions of allylenolsilane 4
`
`containing a strained 1,3-dioxa-2-silacyclopentane ring with aldehydes by Xiaolun
`
`

`

`Wang
`
`vi
`
`15
`
`Scheme 2-3. Synthesis of allylenolsilanes 8 and 9 containing a strained 1,3-dioxa-2(cid:173)
`
`silacyclopentane cycle,
`
`their noncatalyzed tandem aldol-allylation reactions with
`
`aldehyde, and stereochemical confirmation of the major tandem products 11 and 12 ... .. 17
`
`Scheme 2-4. Xiaolun Wang and Andrew J. Nation's work on noncatalyzed tandem
`
`aldol-allylation reaction of substituted allylenolsilanes 15-19 with cyclohexane-
`
`carboxaldehyde
`
`21
`
`Scheme 2-5. Synthesis of acetone-derived allylenolsilane 25, its noncatalyzed tandem
`
`aldol-allylation reaction with aldehyde, and stereochemical confirmation of tandem
`
`products 27
`
`23
`
`Scheme 2-6. Synthesis of acetone-derived allylenolsilanes 33-36 with methyl-substituted
`
`allyl groups
`
`25
`
`Scheme 2-7. Noncatalyzed tandem aldol-allylation reactions of allylenolsilanes 33-36
`
`with cyclohexanecarboxaldehyde
`
`Scheme 2-8. Stereochemical confirmation of the major tandem products 45- 48
`
`27
`
`28
`
`Scheme 2-9. Synthesis of allylenolsilanes 54 and 55,
`
`their noncatalyzed tandem
`
`aldol-allylation reactions with aldehyde, and stereochemical confirmation of tandem
`
`products 58 and 59
`
`Scheme 2-10. Reaction pathways of 55 with aldehyde to form 59a, 59b and 60
`
`30
`
`31
`
`Scheme 2-11. Attempted synthesis of 63-68 and noncatalyzed tandem aldol-allylation
`
`reactions of 68 with aldehydes
`
`36
`
`

`

`vii
`
`Scheme 2-12. Synthesis of an acetone-derived allylenolsilane 71 and its noncatalyzed
`
`tandem aldol-allylation reaction with benaldehyde by Xiaolun Wang et ai
`
`37
`
`Figure 2-1. Rychnovsky's empirical method using l3C NMR spectra to assign the
`
`stereochemistry of syn- and anti-1,3-diol acetonides due to their different stable
`
`conformations
`
`19
`
`Figure 2-2. Design of a ketone-derived allylenolsilane and the suggested tandem
`
`aldol-allylation reaction with aldehyde
`
`22
`
`Figure 2-3. Proposed tandem aldol-allylation transition state of allylenolsilanes 25, 33-36
`
`with aldehyde to produce syn-1,3-diols as major products
`
`33
`
`Figure 2-4. Proposed tandem aldol-allylation transition state of allylenolsilanes 54 and
`
`55 with aldehyde to produce 1,3-diols 58 and 59 as preferred products
`
`34
`
`Part II.
`
`Chapter 1.
`
`Introduction to DNA Sequencing by Synthesis
`
`Scheme 1-1. The process of the DNA polymerase reaction: the hydroxyl group on the 3'
`
`end of the primer is necessary for the incorporation of the next nucleotide
`
`70
`
`Scheme 1-2. Schematic illustration of Sanger dideoxy DNA sequencing by four dNTP's
`
`and four fluorescent dye-labeled ddNTP's to obtain the sequence of the primer
`
`72
`
`Scheme 1-3. Schematic process of DNA pyrosequencing in the presence of enzymes
`
`78
`
`Scheme 1-4. Schematic illustration of photocleavable mass-tagged nucleotides for DNA
`
`sequencing using mass spectrometry
`
`81
`
`

`

`viii
`
`Figure 1-1. Names and structures of the four 2'-deoxyribonucleoside 5'-triphosphates
`
`(dNTP's)
`
`Figure 1-2. Watson-Crick base pairing of double-stranded DNA
`
`67
`
`68
`
`Figure 1-3. Possible labeling sites of fluorescent dyes on the nucleoside triphosphate
`
`molecule
`
`76
`
`Figure 1-4. A nucleic acid stretch passes through a nanopore by the applied electric field
`
`(left) and electronic signatures are generated as a result (right)
`
`83
`
`Chapter 2. Design and Synthesis of Modified Fluorescent Nucleotides for DNA
`
`Sequencing by Synthesis
`
`Scheme 2-1. Designed molecular model of fluorescent nucleotide and proposed
`
`sequencing cycle using these modified nucleotides
`
`91
`
`Scheme 2-2. Massive parallel DNA sequencing chip using modified fluorescent
`
`nucleotides
`
`92
`
`Scheme 2-3. An entire sequencing cycle using photocleavable fluorescent 3'-O-allyl-
`
`dUTP-PC-Bodipy-FL-510 nucleotide as a reversible terminator for DNA SBS
`
`95
`
`Scheme 2-4. Design of modified photocleavable fluorescent nucleotides for DNA
`
`SBS
`
`97
`
`Scheme 2-5. Application of a chemically cleavable fluorescent 3'-O-allyl-dGTP-allyl-
`
`Bodipy-FL-510 nucleotide as a reversible terminator for DNA SBS
`
`.1 00
`
`Scheme 2-6. Design of modified chemically cleavable fluorescent nucleotides for DNA
`
`

`

`SBS
`
`Scheme 2-7. Milton's synthetic strategy of 1..
`
`Scheme 2-8. Synthetic routes of6 from 13
`
`Scheme 2-9. Our synthesis of 1 from 13
`
`Scheme 2-10. Milton's synthetic strategy of2
`
`Scheme 2-11. Synthetic route of21 from 25
`
`Scheme 2-12. Alternative synthetic route of 21 from 29
`
`Scheme 2-13. Our first attempted synthesis of 37 from 25
`
`Scheme 2-14. Attempted synthetic route toward 2 from 36
`
`Scheme 2-15. Another attempted synthetic route toward 2 from 36
`
`Scheme 2-16. Our final synthesis of24 from 43
`
`Scheme 2-17. Complete synthetic route of 2 from 25
`
`Scheme 2-18. Milton's synthetic strategy of 3
`
`Scheme 2-19. Milton's synthetic strategy of 4
`
`Scheme 2-20. Synthetic strategy of 4 in our previous work
`
`'"
`
`Scheme 2-21. Our modified synthetic route of 4 from 52
`
`Scheme 2-22. Synthesis of allyl linker 5
`
`Scheme 2-23. Synthesis of photocleavable linker 65
`
`IX
`
`101
`
`102
`
`103
`
`104
`
`108
`
`109
`
`111
`
`112
`
`114
`
`115
`
`116
`
`11 7
`
`118
`
`120
`
`121
`
`122
`
`124
`
`125
`
`Scheme 2-24. Synthesis of3'-O-allyl-dNTP-allyl-Dyes 73, 77, 81 and 85
`
`126-127
`
`Scheme 2-25. Synthesis of3'-O-allyl-dNTP-PC-Dyes 86-89
`
`128
`
`Figure 2-1. A transition state complex of DNA template, primer, DNA polymerase and a
`
`

`

`x
`
`2',3' -dideoxycytidine triphosphate (ddCTP) in the DNA polymerase reaction established
`
`by H. Pelletier et al. The left figure illustrates the incorporation process of ddCTP onto
`
`the 3' end of the primer catalyzed by Mg2+ and polymerase active residues. The right
`
`figure shows the steric interaction of polymerase active residues with ddCTP in the
`
`presence of primer and template
`
`88
`
`Figure 2-2. Structures of
`
`the four photocleavable fluorescent nucleotides and
`
`photocleavage of the 2-nitrobenzyllinker by near-UV irradiation
`
`94
`
`Figure 2-3. Coupling constants of selected fi-anomers of 2' -deoxy-D-ribofuranosyl-
`
`purines
`
`106
`
`Figure 2-4. Coupling constants of selected a-anomers of 2' -deoxy-D-ribofuranosyl-
`
`purines
`
`Figure 2-5. Substituent effect on the iodination site of 7-deazaguanine
`
`Figure 2-6. l3C NMR chemical shifts of selected allyl compounds
`
`Table 2-1. Incorporation analysis of modified nucleotides by DNA polymerases
`
`Table 2-2.
`
`Influence of cycle efficiency on sequencing read length
`
`106
`
`110
`
`130
`
`89
`
`98
`
`Chapter 3. Application of Modified Fluorescent Nucleotides as Reversible
`
`Terminators for DNA Sequencing by Synthesis
`
`Scheme 3-1. Milton's method to cleave a 3' allyl group using an aqueous palladium (11)-
`
`phosphine system
`
`164
`
`Scheme 3-2. Genet's method to cleave an allyl group from allyl esters, allyl carbonates or
`
`

`

`allyl carbamates using an aqueous palladium-phosphine system
`
`Xl
`
`164
`
`Scheme 3-3. Thayumanavan's strategy to cleave an allyl group from allyl esters and allyl
`
`carbamates using a palladium (0) catalyst
`
`165
`
`Scheme 3-4. Smith's cleavage of an allyl group by palladium (II) chloride in acetic acid
`
`and sodium acetate
`
`'"
`
`165
`
`Scheme 3-5. Extension with 3'-O-allyl dNTP-PC-Dye on a DNA template
`
`170-171
`
`Scheme 3-6. Illustrative description of immobilizing a DNA template on a glass chip via.
`
`a copper (I)-catalyzed 1,3-dipolar cycloaddition reaction
`
`173
`
`Scheme 3-7. Extension with 3'-O-allyl dGTP-allyl-Bodipy-FL-510 90 on a repeat C
`
`template
`
`178
`
`Scheme 3-8. Extension with 3'-O-allyl dNTP-PC-Dye on a DNA template
`
`.l81-182
`
`Scheme 3-9. Photolysis mechanism of 2-nitrobenzyllinker moiety
`
`183
`
`Scheme 3-10. Proposed mechanism of cleaving allyl groups from allyl ethers and allyl
`
`carbamates in aqueous palladium-phosphine solution
`
`184
`
`Figure 3-1. Structures of fluorescent 3'-O-allyl-dNTP-PC-Dye nucleotides 86-89
`
`168
`
`Figure 3-2. Application of photocleavable modified fluorescent 3'-O-allyl-dNTP-PC-
`
`Dye nucleotides 86~89 for DNA sequencing by synthesis on a glass chip
`
`175
`
`Figure 3-3. Structures of fluorescent 3'-O-allyl-dNTP-allyl-Dye nucleotides 73, 77, 81
`
`and 85
`
`179
`
`Table 3-1. Deallylation of3'-O-allylthymidine by Na2PdC14 and TPPTS in water....... 166
`
`

`

`xii
`
`Acknowledgements
`
`The first part of this thesis was finished under the guidance of Professor James L.
`
`Leighton. Here I would like to thank him for his great support and instruction to me as
`
`well as his knowledge and professionalism during the years I was working in his group. It
`
`was my pleasure to work together with Xiaolun Wang, Andrew Nation and Nicholas Perl
`
`in this tandem aldol-allylation project. I appreciate their intelligence and motivation so
`
`much. I also want to express my gratitude to Dr. Katsumi Kubota, Christopher Hamblett
`
`and other members in the Leighton group, for all their help.
`
`The second part of this thesis was finished under the guidance of Professor Jingyue Ju
`
`and Professor Nicholas J. TUITO. I would like to express my most sincere gratitude and
`
`appreciation for their guidance and support. Their enthusiasm and professionalism in
`
`science will inspire me all my life. Dr. James J. Russo gave me very helpful suggestions
`
`on my thesis. lowe special thanks to Dr. Xiaopeng Bai, who gave me so much help in
`
`every aspect since I joined this group. We worked together on the triphosphate
`
`preparation and he also worked on the HPLC purification of fluorescent nucleotides.
`
`Xiaopeng and Shenglong Zhang prepared the fluorescent 3'-O-allyl-dNTP-PC-Dye
`
`nucleotides. Dye Hyun Kim, Dr. Hameer Ruparel, Dr. Lanrong Bi, Dr. Xiaoxu Li, Dr.
`
`Zengmin Li, Dr. Mong Marma and Shundi Shi worked on the biological evaluation of the
`
`fluorescent nucleotides in Chapter 3 of Part II. I also appreciate the great help and
`
`

`

`suggestions from Dr. Zengmin Li, Dr. Lanrong Bi, Dr. Zhiqiang Liu and other people
`
`with whom I have worked.
`
`xiii
`
`New England Biolabs is acknowledged for generously providing the 9° Nm DNA
`
`polymerase.
`
`Finally, I wish to thank my parents and family for their unselfish support over so many
`
`years. I could not have gone so far without their encouragement.
`
`lowe special gratitude to Yingmei, my fiancee. It is her love that makes me happy and
`
`helps me overcome the difficulties in my life. She has been and will always be my
`
`greatest fortune throughout my life.
`
`

`

`xiv
`
`for my parents and Yingmei
`
`

`

`Part I
`
`1
`
`Part I. Tandem Aldol-Allylation Reactions Promoted
`
`by Strained Silacycles
`
`

`

`Part I
`
`2
`
`Chapter 1.
`
`Introduction
`
`Polyketide units frequently appear in many natural products with stereocenters and
`
`constitute very important components of diverse natural products, such as rifamycin B,
`
`oleandomycin and rapamycin (Figure 1_1).1 Many of them have shown very important
`
`pharmacological activities. Development of convenient and efficient methods
`
`to
`
`synthesize stereo-controlled 1,3-diol fragments has attracted the enthusiasm of many
`
`chemists, especially in the pharmacology industry. Many methods for preparing 1,3-diol
`
`fragments with stereoselectivity have been investigated to date,
`
`including alkylation,
`
`aldol reaction,
`
`reduction or the use of homoallylic alcohols as starting material?
`
`Traditional strategies utilize stepwise transformations to construct such non-adjacent
`
`stereocenters, in which the two stereocenters are typically generated stereoselectively in
`
`separate steps. A more efficient but challenging approach for this purpose is to employ a
`
`tandem reaction strategy so that the two stereocenters can be created stereoselectively in
`
`o
`
`H,C
`
`CH,
`
`\\\\,.
`H,C
`
`,.\\\\CH3
`
`N(CH,),
`
`"""O~CH,
`
`H,C
`
`o---+~
`
`o
`rifamycin B
`
`"'1110
`CH, ~OCH
`b~OR
`oleandomycin
`CH,
`
`H,CO
`
`Q::;l
`
`o
`
`o
`
`,?'
`
`,?'
`
`,;::P'
`
`CH3
`rapamycin
`
`CH3
`
`Figure I-I. Examples of some polyketides containing l,3·diol fragment. I
`
`

`

`Part 1
`
`3
`
`a single step.3 By this concise method the target products can be produced conveniently
`
`and rapidly with higher efficacy and less effort.
`
`Since Mukaiyama reported the aldol addition reactions of silyl enol ethers with aldehydes
`
`and ketones promoted by Lewis acids over three decades ago (now named the
`
`Mukaiyama reaction),4 silyl enol ethers have proven to be powerful reagents for aldol
`
`reactions to form new carbon-carbon bonds in organic chemistry. In general Lewis acids
`
`are necessary to activate the carbonyl group of aldehydes and ketones. Since then, the
`
`scope of this kind of reaction has been extended to asymmetric aldol addition to produce
`
`chiral products under the catalysis of chiral Lewis acids. 5 Several years later, Sakurai
`
`reported the allylation reaction of allyltrimethylsilane with aldehydes and ketones
`
`promoted by Lewis acids (now known as the Sakurai-Hosomi reaction).6 Furthermore,
`
`the allylation and crotylation of carbonyl groups using silane reagents have been well
`
`developed into efficient strategies for preparing homoallylic alcohols and amines with
`
`stereochemical control;7 these are versatile synthetic intermediates for organic synthesis.
`
`In the past decades, the allylation and crotylation methods have been expanded to ketone
`
`derivatives to prepare tertiary carbinols, usually promoted by Lewis acids or bases, either
`
`catalytically or stoichiometrically.8
`
`In 1992 Myers reported noncatalyzed aldol addition reactions of enolic silacyclobutanes
`
`with aldehydes, which were accelerated by a four-membered silacyclobutane ring. 9 In
`
`

`

`Part I
`
`4
`
`contrast, acyclic enol silanes showed either no evidence of reaction or very sluggish
`
`reaction rates even at higher temperature for extended time (Scheme 1-1). One year later,
`
`Denmark independently released similar results on the reactivity of silacyclobutanes with
`
`aldehydes, in which he proposed a 'direct silicon group transfer' process confirmed by a
`
`crossover experiment. 10
`
`R R
`~.~
`Si
`O...............C H
`
`o
`
`ifO
`
`N.R.
`R=(CHzh
`
`R R
`~.~
`Si
`
`J:;~::
`
`H3CO
`
`"'::::::
`
`R R
`~.~
`Si
`
`0""'"
`
`........CH3
`
`0
`
`PhCHO
`
`C6D6
`
`..
`
`H3CO
`
`CH3
`
`R=CH 3
`R=(CHzh
`
`tl/z > 2 d, ISO °C
`t ll2 = 30 min, 27°C
`
`R=CH 3
`R=(CHzh
`
`Myers:
`R R
`~~
`Si
`
`6'~'
`
`PhCHO
`
`C6D6
`
`..
`
`R=CH3
`R = (CHzh
`
`8d,150oC
`tl/Z = 4d, 27°C
`
`Denmark:
`
`0""'"
`
`'t-Bu
`
`0
`
`OH
`
`<)
`~ PhCHO ~
`
`CsHs
`
`..
`
`Q__ Ph
`'-B"S~C'H'
`
`........0
`
`0"
`
`CH3
`97% yield, syn / anti = 97/3
`
`~
`~
`
`H3CO
`
`- - - -..~ H3CO
`CDCI3, 20°C
`
`CH3
`
`CH3
`E / Z= 89/11
`
`tll2 = 2.2 h
`
`94% yield, syn / anti = 95/5
`
`<)
`Jl ~
`(H3ChN' !' ....CsHs
`
`o
`
`0""'"
`
`'I-Bu
`
`CH3
`syn / anti = 9/91
`
`PhCHO
`CDCl3, r.t ..
`
`t ll2 = 0.67 h
`
`Scheme 1-1. Noncatalyzed aldol addition reactions of silacyclobutanes with aldehydes.9
`,loa
`
`In 1994 Utimoto reported noncatalyzed allylation reactions of allylic silacyclobutanes
`
`with aldehydes and a-hydroxyketones, which were also accelerated by the four-
`
`

`

`Part I
`
`5
`
`membered silacyclobutane nng (Scheme 1-2),u Allylic silanes without
`
`this four-
`
`membered ring could not react with carbonyl compounds in the absence of catalysts,
`
`although this reaction could be promoted by Lewis acids. 7 Utimoto also showed that the
`
`cyclohexyloxy silacyclobutane was even more reactive toward aldehydes as the Lewis
`
`acidity of its silicon was enhanced by the oxygen atom. The evidence indicated that it
`
`could react with a-hydroxyketones smoothly but other allylic silacyclobutanes could not.
`
`Utimoto:
`
`<>
`
`0/ 'Ph
`I
`Ph~
`
`PhCHO
`
`130°C, 12 h •
`
`I
`OH
`HCI (aq)
`CH30H' Ph~
`85% yield
`
`CH 3
`I~ PhCHO
`-16-0o-C-,2-4-h... N. R.
`
`H3C-T
`
`Ph
`
`R,
`O
`I
`PhCHO
`Si~R2----
`I
`130 °c, 24 h
`Ph
`R1 = H, R2 = n-Pr
`R} = n-Pr, R2 = H
`
`cJ
`--L1:--:,Si"
`R2 1!;0'
`
`H
`
`Ph
`
`R1
`
`"Jy~
`
`o
`
`R2 =Ph
`R1=Ph,
`R1= n·Bu, R2 =Ph
`R 1 ~ Ph,
`R2 ~ CH3
`
`HCI(oq). ""~ , '"~
`
`n-Pr
`syn
`68% yield
`66% yield
`
`syn /anti = 5/95
`syn /anti ~ 95/5
`
`n-Pr
`anti
`
`84% yield
`85% yield
`84% yield
`
`dr= >99:1
`dr= 98:2
`dr= 85:15
`
`Scheme 1-2. Noncatalyzed allylation reactions of silacyclobutanes with aldehydes and ketones, II
`
`Such high reactivity of silacyclobutanes described above has been explained as
`
`'strain-release Lewis acidity' by Denmark. 10b
`
`,12,13 As can be seen in Figure 1-2, acyclic
`
`silane has a normal C-Si-C bond angle of 109°. When it is attacked by a nucleophile, an
`
`

`

`Part I
`
`6
`
`intermediate of penta-coordinate trigonal bipyramidal (tbp) geometry will be formed in
`
`the transition state, in which the C-Si-C bond angle is 90°. In contrast, silacyclobutane
`
`has a C-Si-C bond angle of approximately 79° as C-Si bond length (0.193 nm) is longer
`
`than that of C-C (0.159 nm),14 which indicates that there is a ring strain in this molecule.
`
`In the corresponding tbp transition state, its ring strain is released. Therefore its reactivity
`
`with nucleophiles is greatly increased. Thus the silicon atom shows enhanced Lewis
`
`acidity when it is constrained in a small ring compared with the acyclic silane.
`
`CH3
`
`109°( I
`
`H
`3
`
`C./Ji."'IIR
`R1
`no strain
`
`2
`
`I
`
`I 79}-1
`Nucleophile
`>
`Si'OIII1IR2 --......;;.--l...~
`1
`I
`strain released
`R1
`
`IS"1"\\\\\
`
`I 79}-1
`R
`2
`:'R
`:
`Nu
`
`'
`
`Figure 1-2. Lewis acidity of silicon is enhanced by the strained silacyclobutane ring. 13
`
`Silacyclobutane is not the only cyclic silane that exhibits high reactivity because of
`
`strain-release Lewis acidity. In 1997 Kira described the noncatalyzed allylation reactions
`
`of allylic silacycles with aldehydes, promoted by a five-membered 1,3-dioxa-2-
`
`silacyclopentane ring derived from a tartrate ester (Scheme 1_3),15 Not long ago very
`
`similar reactions utilizing this ring were first reported by Wang, in which triethylamine or
`
`N,N-dimethylformamide was used as a promoter to form a 'chiral penta-coordinate
`
`transition state' .16 Earlier, Shanmuganathan also described allylation reactions of allylic
`
`1,3-dioxa-2-silacyclopentane with aldehydes in the presence of a Lewis acid. 17 Although
`
`

`

`Part I
`
`7
`
`Wang had assumed the activation from an external promoter enhanced the reactivity of
`
`the 1,3-dioxa-2-silacyclopentane ring, no external promoters were employed in Kira's
`
`results. Kira suggested that the allylation proceeded via a cyclic transition state in which
`
`one of the carbonyl groups in the tartrate coordinated with the silicon atom.
`
`Kira:
`
`i-Pr0
`
`/,.
`
`i-Pr02C
`
`2CXI11
`
`0\ /
`/Si~
`°
`
`R=CH3
`=Ph
`=Cl
`
`PhCHO ~OH
`....
`
`* ~
`
`toluene
`r.t., 40 h
`
`Ph
`
`76% yield, 24% ee
`80% yield, 19% ee
`93% yield, 47% ee
`
`H3CO\ /OCH 3
`
`CO
`
`H
`3
`
`li~ ----..~ N. R.
`
`PhCHO
`
`toluene
`r.t.,40h
`
`Scheme 1-3. Noncatalyzed allylation reactions of allylic silacycles with aldehyde reported by
`
`Kira. 15
`
`Xiaolun Wang in Prof. Leighton's group found that allylchlorosilane 1, with a strained
`
`1,3-dioxa-2-silacyclopentane ring, reacted with benzaldehyde smoothly in toluene at
`
`room temperature to produce a homoallylic alcohol in the absence of catalyst (Scheme
`
`1_4).18 In contrast, neither silane 2 with a six-membered ring nor acyclic silane 3 could
`
`react with benzaldehyde even at the elevated temperature of 50 °e. These experiments
`
`confinued that the high reactivity of 1 resulted from the five-membered 1,3-dioxa-2-
`
`

`

`Part I
`
`8
`
`silacyclopentane ring due to strain-release Lewis acidity. Although this five-membered
`
`ring has smaller ring strain than the four-membered silacyclobutane (O-Si-O bond angle
`
`is 96°),19 actually its Lewis acidity is further enhanced by its two electron-withdrawing
`
`oxygen atoms.
`
`Scheme 1-4. Noncatalyzed allylation reaction of an allylic silane containing a strained
`
`1,3-dioxa-2-silacyclopentane ring with benzaldehyde by Xiaolun Wang. 18
`
`Denmark classified allylation reactions of carbonyl compounds into three types on the
`
`basis of their mechanism?O As shown in Figure 1-3, type I allylation proceeds via a cyclic
`
`transition state with a six-membered chair-like conformation,
`
`in which the carbonyl
`
`group is activated by the internal metal via the six-membered ring (M = B, AI, Sn). By
`
`comparison, type II allylation in general involves an acyclic transition state, in which the
`
`carbonyl group is activated by an external Lewis acid (M = Si, Sn). In type III allylation,
`
`

`

`Part I
`
`9
`
`the (Z)-crotyl group is isomerized to the more stable (E)- via Lewis acid catalysis before
`
`the addition proceeds by a cyclic type I mechanism (M = Ti, Cr, Zr). Therefore the
`
`product stereochemistry is independent of the geometry of the starting material. The
`
`stereochemistry of type I allylation products can be predicted as follows: (E)-crotyl
`
`produces an anti-methyl product and (Z)-crotyl produces a syn-methyl product. Therefore
`
`the type I allylation reaction will potentially tend to give higher diastereoselectivity to the
`
`addition products than type II due to its tight transition state. The noncatalyzed allylation
`
`reactions reported by Utimoto and Kira both belong to type I, in which the carbonyl
`
`group was activated by the silicon with enhanced Lewis acidity.
`
`Type I: H
`
`R~O••··MLn
`R2~-R~
`1-
`R
`R1
`2
`R,
`
`M = B, AI, Sn
`
`r
`
`Type II:
`
`LAL~M~_,~
`
`R
`
`H
`
`R1
`M=Si, Sn
`
`R
`2
`
`R
`1
`
`Figure 1-3. Classification of allylation reactions proposed by Denmark,20
`
`Based on the discussion above, it can be seen that the silicon atom is a promising carrier
`
`of functional groups for both aldol addition and allylation reactions due to its high
`
`reactivity under diverse conditions. It is possible that both functional groups can be
`
`combined in one molecule via a silicon atom and therefore the aldol and allylation
`
`reactions could proceed in a consecutive manner so that a target 1,3-diol can be obtained
`
`conveniently in one step.
`
`

`

`Part I
`
`10
`
`In this part of the thesis, tandem aldol-allylation reactions using aldehyde- and ketone(cid:173)
`
`derived allylenolsilanes with aldehyde will be described and a discussion of the reaction
`
`results will be presented.
`
`

`

`Part I
`
`11
`
`References
`
`[1] a) Khosla, C.; Gokhale, R S.; Jacobsen, 1. R; Cane, D. E. Annu. Rev. Biochem. 1999, 68,
`
`219-253.
`
`b) Khosla, C. Chem. Rev. 1997,97(7),2577-2590.
`
`[2] a) Oishi, T.; Nakata, T. Synthesis 1990, (8),635-645.
`
`b) Bode, S. E.; Wolberg, M.; Mueller,
`
`M. Synthesis 2006, (4), 557-588.
`
`[3] Zacuto, M. 1.; O'Malley, S. 1.; Leighton, 1. L. Tetrahedron 2003, 59(45), 8889-8900.
`
`b)
`
`Zacuto, M. J.; O'Malley, S. J.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124(27), 7890-7891.
`
`c) O'Malley, S. 1.; Leighton, J. L. Angew. Chem. Int. Ed 2001,40(15),2915-2917.
`
`[4] a) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1973,96(24), 7503-7509.
`
`b)
`
`Mukaiyama, T.; Banno, K.; Narasaka, K. Chem. Lett. 1973, (9), 1011-1014.
`
`[5] a) Narasaka, K. Synthesis 1991, (1), 1-11.
`
`b) Kobayashi, S.; Uchiro, H.; Fujishita, Y; Shiina,
`
`I.; Mukaiyama, T. J. Am. Chem. Soc. 1991,113(11),4247-4252.
`
`c) Furuta, K.; Maruyama,
`
`T.; Yamamoto, H. J. Am. Chem. Soc. 1991,113(3), 1041-1042.
`
`d) Parmee, E. R; Tempkin,
`
`0.; Masamune, S.; Abiko, A. J. Am. Chem. Soc. 1991, 113(24), 9365-9366.
`
`e) Kiyooka, S.;
`
`Kaneko, Y; Komura, M.; Matsuo, H.; Nakano, M. J. Org. Chem. 1991,56(7),2276-2278.
`
`[6] Hosomi, A.; Sakurai, H. Tetrahedron 1976, 17(16), 1295-1298.
`
`[7] Yamamoto, Y.; Asao, N. Chem. Rev. 1993,93(6),2207-2293.
`
`[8] For examples of allylation of ketones promoted by Lewis acids or bases, see: a) Yamasaki, S.;
`
`Fujii, K.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124(23),6536-6537.
`
`b) Cossy,1.; Lutz, F.; Alauze, V.; Meyer, C. Synlett 2002,
`
`(1), 45-48.
`
`c) Ishihara, K.;
`
`Hiraiwa, Y; Yamamoto, H. Synlett 2001, (12), 1851-1854.
`
`d) Kira, M.; Sato, K.; Sekimoto,
`
`K.; Gewald, R; Sakurai, H. Chem. Lett. 1995, (4), 281-282.
`
`e) Coppi, L.; Mordini, A.;
`
`Taddei, M. Tetrahedron Lett. 1987,28(9),969-972.
`
`[9] Myers, A. G.; Kephart, S. E.; Chen, H. J. Am. Chem. Soc. 1992,114(20),7922-7923.
`
`[10] a) Denmark, S. E.; Griedel, B. D.; Coe, D. M. J. Org. Chem. 1993, 58(5), 988-990.
`
`b)
`
`Denmark, S. E.; Griedel, B. D.; Coe, D. M.; Schnute, M. E. J. Am. Chem. Soc. 1994, 116(16),
`
`7026-7043.
`
`c) Denmark, S. E.; Griedel, B. D. J. Org. Chem. 1994,59(18),5136-5138.
`
`

`

`Part I
`
`12
`
`[11] Matsumoto, K.; Oshima, K.; Utimoto, K. J. Org. Chem. 1994,59(23), 7152-7155.
`
`[12] Denmark, S. E.; Jacobs, R. T.; Dai-Ho, G; Wilson, S. Organometallics 1990, 9(12),
`
`3015-3019.
`
`[13] Zhang, X.; Houk, K. N.; Leighton, J. L. Angew. Chem. Int. Ed. 2005,44(6),938-941.
`
`[14] Gordon, M. S.; Barton, T. J.; Nakano, H. J. Am. Chem. Soc. 1997, 119(49), 11966-11973.
`
`[15] Zhang, L. C.; Sakurai, H.; Kira, M. Chem. Lett. 1997, (2), 129-130.
`
`[16] a) Wang, Z.; Wang, D.; Sui, X. Chem. Commun. 1996, (19), 2261-2262.
`
`b) Wang, D.;
`
`Wang, Z. G; Wang, M. W.; Chen, Y J.; Liu, L.; Zhu, Y Tetrahedron: Asymm. 1999, 10(2),
`
`327-338.
`
`[17] Shanmuganathan, K.; French, L. G; Jensen, B. L. Tetrahedron: Asymm. 1994,5(5), 797-800.
`
`[18] Kinnaird, J. W. A.; Ng, P. Y; Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002,
`
`124(27),7920-7921.
`
`[19] Ohshita, J.; Sakurai, H.; Masaoka, S.; Tarnai, M.; Kunai, A.; Ishikawa, M. J. Organometallic
`
`Chem. 2001,633(1-2), 131-136.
`
`[20] Denmark, S. E.; Weber, E. J. Hel. Chim. Acta 1983, 66(6), 1655-1660.
`
`

`

`Part I
`
`13
`
`Chapter 2. Tandem Aldol-Allylation Reactions Promoted by
`
`Strained 1, 3-Dioxa-2-silacyclopentane Ring
`
`From the introduction in Chapter 1,
`
`it can be seen that
`
`the five-membered
`
`1,3-dioxa-2-silacyc1opentane ring effectively activates the reactivity of silane reagents by
`
`enhancing its Lewis acidity. One advantage of using this 1,3-dioxa-2-silacyc1opentane is
`
`that it can be easily prepared from chloro silanes and 1,2-diols in the presence of base.
`
`With chiral 1,2-diols incorporated in