SYNTHESIS, CHARACTERIZATION, AND APPLICATIONS OF CHIRAL AMINO
ACID DERIVED PYRROLINES
A Dissertation Presented to The Graduate Faculty of The University of Akron
In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy
Daniel P. Jackson May, 2015 SYNTHESIS, CHARACTERIZATION, AND APPLICATIONS OF CHIRAL AMINO
ACID DERIVED PYRROLINES
Daniel P. Jackson Dissertation
Approved: Accepted:
______Advisor Department Chair Dr. Michael J. Taschner Dr. Kim C. Calvo
______Committee Member Dean of the College Dr. Claire A. Tessier Dr. Chand Midha
______Committee Member Interim Dean of the Graduate Dr. Wiley J. Youngs School Dr. Rex D. Ramsier
______Committee Member Date Dr. David A. Modarelli
______Committee Member Dr. Bi-min Zhang Newby
ii ABSTRACT
Many alkaloids, those usually containing a pyrroldiine ring, exist in many natural products and are often used in organocatalysis. Synthetic chemists have thus taken advantage of various pyrroline intermediates in order to achieve target molecules. This dissertation will describe a logical approach to the syntheses of tropane alkaloid analogues and polyhydroxylated pyrrolidines. The latter poises an interesting model for developing chiral auxiliaries for enantioselective reactions.
Chapter I of this work provides a brief overview into the pyrrolidine alkaloids and explains the significance of various pyrroline intermediates. The 3- pyrroline system is appealing because the placement of the π-bond allows for further functionilzation to a meso pyrrolidine diol, which will be useful in catalysis later.
Chapter II then describes the progression of organocatalysis with a focus on carbon-carbon bonding forming reactions with allylsilanes and carbonyl reductions with boranes. The former reaction is a modification of the Hosomi-
Sakurai reaction and utilizes the alkaloids derived in chapter I to make silacycles, where coordination of the electrophile causes a conformational change to allow selective allylation to occur. The latter reaction also utilizes the previous
iii alkaloids to generate the corresponding boracyle to transfer a hydride towards electrophiles.
Chapter III highlights the attempts of utilizting amino acid derived 3- pyrroline intermediates towards the syntheses of several natural product analogues. A foundation was laid for these target molecules, which would then be further investigated for biological activity and potentially serve as useful chiral auxiliaries in asymmetric synthesis.
iv DEDICATION
I would like to dedicate this dissertation to my family, as you all are the most important people in my life. My parents, Stanley and Gail Jackson, have sacrificed everything to allow me to grow into the man I am today. I could not thank you both more than anything in the world and I will do my best to be as good of a parent to my children. My siblings, Heather, Meredith, Claudia, and
David, you all were always there as role models in helping me interpret what is right from wrong. My in-laws, James and Renee Jones, you have been very supportive and an inspiration to me during my graduate career. I cannot thank you enough for the opportunities you have provided for my continued success.
My brothers that have stuck with me for eight long years through college, may we continue an everlasting bond that will never break. Our pillars wiil continue to define my character and everything that I embody. My children, Daylen and
Ariel, have made me develop an unbelievable level of efficiency. I would never sacrifice our time and I love you both more than anything. You are my motivation. Last but not least, my wife Lindsey, I could write a book about how much I love you and what you mean to me. You have helped keep me on track, been a perfect mother to our children, and set aside your career so that I could
v accomplish my dream. Your smile is as bright as a million suns and I thank you for pole vaulting into my life!
vi ACKNOWLEDGEMENTS
I would like to acknowledge Dr. Taschner first and foremost for being an outstanding mentor over the course of my graduate career. His guidance has enabled me to gain a whole new appreciation of all areas chemistry through analyzing problems from multiple perspectives. Dr. Taschner was faced with the option of retiring, yet, chose to stay for another five years to continue his passion of teaching to mentor one last student. He was always there when I needed him and always had an answer to help calm me down when I was unsure of myself.
In his role as interim department chair, he provided the opportunity to begin teaching laboratory sections as the instructor of record to provide the necessary experience for further teaching opportunities. I will truly never forget what he has done for my family and I wish him the best in his new journey ahead.
I would also like to acknowledge my committee members, Dr. Claire
Tessier, Dr. Wiley Youngs, Dr. David Modarelli, and Dr. Bi-min Zhang Newby for their assistance in the prepartion of this dissertation. I would like to thank the
University of Akron Chemistry department faculty and staff for their guidance. A special thanks to the NMR staff for helping me gain a better understanding of the
vii various instrumentation. Lastly, I would like to thank the front office administration, Nancy and Jean, for their help and support over the years.
viii TABLE OF CONTENTS
Page
LIST OF TABLES ...... xi
LIST OF FIGURES ...... xii
LIST OF SCHEMES ...... xiv
TABLE OF ABBREVIATIONS ...... xviii
CHAPTER
I. INTRODUCTION TO PYRROLIDINE ALKALOIDS...... 1 1.1 Alkaloids ...... 1 1.2 Pharmacology of PAs ...... 5
1.3 Tropane Alkaloids ...... 8 1.4 Polyhydroxylated Pyrrolidines...... 13 1.5 Pyrroline Intermediates...... 21 II. ALKALOIDS IN ORGANOCATALYSIS ...... 32 2.1 Early Organocatalysis...... 32 2.2 Impact of Proline in Modern Organocatalysis ...... 34 2.3 Asymmetric Allylic Alkylation...... 40 2.4 Hosomi-Sakurai Reaction ...... 45 2.5 Boron Hydride Donor Reagents...... 50
III. SYNTHESES OF 3-PYRROLINES AND DERIVATIVES ...... 57 3.1 Direct Addition of Amino Ester to Ditosyl Acetonide ...... 57
ix 3.2 Alkene Metathesis of N,N-Diallylamino Ester ...... 62 3.3 Direct Addition of Dihaloalkene...... 63 3.4 Mosher Ester Analysis ...... 67 3.5 Syntheses of TA analogues...... 70 3.6 Syntheses of PHP analogues ...... 74 3.7 Syntheses of Silacycles ...... 75 3.8 Syntheses of Boracycles...... 78 IV. CONCLUSIONS ...... 80 V. EXPERIMENTAL SECTION...... 83 5.1 General Experimental Methods ...... 83 5.2 Syntheses of Amino Acid Methyl Ester Hydrochlorides...... 84 5.3 3-Pyrroline synthesis via direct addition to ditosylacetonide...... 88 5.4 3-Pyrroline synthesis via alkene metathesis...... 91 5.5 3-Pyrroline synthesis via direct addition of cis-1,4-dichloro-2-butene.92 5.6 Mosher Ester Analysis ...... 96 5.7 Syntheses of amino acid derived PHPs from 3-pyrrolines...... 98 5.8 Synthesis of amino acid derived silacycle from 3-pyrrolines...... 102 5.9 Synthesis of amino acid derived boracycle from 3-pyrrolines...... 103 REFERENCES ...... 104
APPENDIX...... 111
x LIST OF TABLES Table Page
1. Amino acid methyl ester synthesis with thionyl chloride/methanol ...... 58 2. Amino acid methyl ester synthesis with chlorotrimethylsilane/methanol...59 3. Direct addition of amino ester and dihaloalkene to form 3-pyrroline...... 64 4. Syntheses of amino acid methyl ester pyrrolines via direct addition to a dihaloalkene in the presence of sodium carbonate in refluxing acetonitrile ...... 67
xi LIST OF FIGURES Figure Page 1. Morphine is a natural plant alkaloid found in opium and contains a ring structure and nitrogen heteroatom...... 1 2. Examples of alkaloids existing as the free-base (pyrrolidine), a salt (ethanolamine hydrochloride), as the N-oxide (4-methylmorpholine-N- oxide), and from amino acids (retronecine) ...... 2 3. Epibatidine is an alkaloid secreted through the skin by the poison dart frog as a defense mechanism...... 3 4. Compounds isolated by the French chemists Pelletier and Caventou provided a solid foundation for the studying of alkaloid chemistry...... 4 5. Structural comparison of pyrrolidine and pyrrole ...... 4 6. Some tetrapyrroles involved in biological processes include bilirubin, porphyrin, and corrin ...... 5 7. Some PAs resemble the neurotransmitter acetylcholine and inhibit the signaling system ...... 6 8. Structure of some PAs found in nature...... 7 9. Tropane alkaloids atropine, scopolamine, and hyoscyamine ...... 8 10. Structure of cocaine and procaine ...... 12 11. Aza- analogs of furanose and pyranose sugars ...... 14 12. Structures of some PHPs and the glycosidases inhibited...... 14 13. Rare class of PHPs with aryl group in the 2-position of the pyrrolidine ring eliciting both antibiotic and hypotensive activity in animals ...... 18 14. Three isomers of the pyrroline moiety used as synthons for biological scaffolds...... 22 15. Proposed TS by Hajos of proline catalyzing the formation of the Wieland- Miescher ketone...... 36
xii 16. Zimmerman Traxler model of the Aldol reaction with Lewis acid additives to give cyclic TS ...... 38 17. Acyclic TS model explaining the diastereoselectivity of the Hosomi- Sakurai reaction...... 46 18. TS showing the stereoselectivity of the hexacoordinate silicon in the Zimmerman-Traxler model...... 47 19. Coordination of incoming electrophile to alleviate ring strain of the silacyclobutane ...... 48 20. Felkin model for the reduction of carbonyl compounds ...... 53 21. The orientation of the ditosylates farthest away from the acetonide posing an issue with nucleophilic attack of bulky nucleophile ...... 61 22. 1H-NMR analyzing both Mosher esters of the reduced Leucine-3-pyrroline ...... 70 23. Amino acid derived TA mimics from 3-pyrrolines...... 71 24. First and second generation silacycle derived from amino ester 3- pyrrolines ...... 76
xiii LIST OF SCHEMES Scheme Page 1. Biosynthesis of most tropane alkaloids stem from L-ornithine to form tropinone ...... 8 2. The first synthesis of tropinone by Willstatter ...... 10 3. Robinson’s one pot synthesis of tropinone ...... 11 4. Willstatter’s synthesis of cocaine ...... 12 5. Total synthesis of (+)-cocaine utilizing L-proline as a chiral auxiliary ...... 13 6. Total synthesis of (-)-cocaine invoking ring closing metathesis...... 13 7. Preparation of 2,5-anhydro-2,5-imino-D-mannitol and 2,5-anhydro-2,5- imino-D-glucitol from 5-keto-D-fructose via reductive amination ...... 15 8. Synthesis of glycosidase inhibitor 1,4-dideoxy-1,4-imino-D-ribitol from 2,3- O-isopropylidene-D-ribofuranose...... 16 9. Examples of protecting group free protocols in the syntheses of some PHPs...... 17 10. Synthesis of (-)-Codonopsinine starting from D-alanine ...... 18 11. Synthesis of (-)-Codonopsinine starting from L-xylose ...... 19 12. PHP synthesis exploiting the imine moiety of the 1-pyrroline intermediate ...... 20 13. Retrosynthesis of a PHP involving a 3-pyrroline intermediate formed via Witting reaction ...... 20 14. PHP synthesis via 3-pyrroline intermediate ...... 21 15. Synthesis of 2-pyrrolines from ant venom involving cyclopropanes and primary amines ...... 23 16. Direct amination of dihaloalkene to yield 3-pyrroline ...... 24 17. Delepine reaction used to synthesis 3-pyrrolines from cis-2-butene-1,4- dichloride and hexamethylenetetramine ...... 24 xiv 18. Dissolving metal reduction with lithium in liquid ammonia partially reduces electron poor pyrroles into 3-pyrrolines...... 25 19. Dissolving metal reduction with zinc in acidic media partially reduces electron rich pyrroles into 3-pyrrolines ...... 25 20. Retro-Diels Alder approach to 3-pyrrolines...... 26 21. Syntheses of 3-pyrrolines via retro-Aldol and retro-Dieckmann reactions 27 22. Lithiated methoxyallenes with imines in the presence of silver to generate 3-pyrroline rings ...... 28 23. Novel approach to 3-pyrrolines via carbene chemistry...... 29 24. Oxidation of 1-benzyl-3-hydroxymethyl-3-pyrroline by pyridinium dichromate yielding to give 3-formyl-3-pyrrole instead of 3-formyl-3- pyrroline ...... 30 25. Proposed mechanism for the transformation of 3-pyrroline to pyrrole in the presence of an oxidant...... 31 26. First organocatalytic carbon-carbon bond forming reaction...... 33 27. Methanolysis of phenylmethyl ketene using cinchona alkaloid as organocatalyst...... 34 28. Synthesis of an enamine via a secondary amine and carbonyl compound to give more nucleophilic version of an enolate...... 35 29. Intramolecular Aldol addition catalyzed by L-proline...... 36 30. Aldol addition/condensation and the Michael addition...... 37 31. Accepted mechanism of the proline-catalyzed Aldol reaction...... 40 32. AAA forming a π-allylpalladium complex reacting with a stabilized nucleophile...... 41 33. Organometallic mechanism of oxidative addtion and reductive elimination of the π-allylpalladium complex as in electrophile ...... 42 34. Organometallic mechanism for the bis-pi-allylpalladium system utilized as a nucleophile...... 43 35. Basic AAA in in the proposed Zimmerman-Traxler TS, chelated with an organometallic reagent ...... 44 36. Hosomi-Sakurai reaction...... 45
xv 37. Pentacoordinate silicates used in the Hosomi-Sakurai reaction...... 47 38. Pseudoephedrine silacycle formation and allylation of various aldehydes ...... 49 39. Mechanism of the pseudoephedrine catalyzed AAA ...... 50 40. Mechanism of borohydride and aluminum hydride reductions...... 51
41. Chelation control with triacetoxyborohydride with β-hydroxy ketones ...... 52 42. The Selectride series increase steric demand and give different facial selectivity compared to borohydride ...... 53 43. Diborane reduction mechanism ...... 54 44. Enantioselective reduction of ketones with chloroboranes ...... 54 45. Catalytic enantioselective reduction of ketones with oxazaborolidines.....55 46. Catalytic cycle of of reduction with oxazaborolidine...... 55 47. Synthesis of 1,4-ditosyl-2,3-acetonide...... 60 48. Direct addition of amino ester to 1,4-ditosyl-2,3-acetonide failed to give the desired pyrrolidine acetonide...... 60 49. Tetrahydrofuran ring formation due to the proximity of one hydroxyl to the mesylate...... 62 50. Alkene metathesis to cyclize the diallylamino ester to give the 3-pyrroline ...... 63 51. Microwave-assisted direct addition of amino ester and dihaloalkene to form 3-pyrrolines ...... 65 52. Attempted synthesis of cis-1,4-dibromo--2-butene ...... 66 53. Chiral derivitizing agents to deduce chemical racemization ...... 68
54. Syntheses of the Mosher esters from the Leucine-3-pyrroline ...... 69
55. Retrosynthesis of TA analog...... 71
56. Synthesis of the Geissman-Waiss lactone from an N-acetyl-3-pyrroline derivative...... 72
57. Synthesis of TAs via iodolactonization...... 73
xvi 58. Iodoetherification of amino acid derived 3-pyrroline alcohols ...... 74 59. Syntheses of PHP analogs from amino ester 3-pyrrolines ...... 75 60. Syntheses of amino acid derived silacycles from allyltrichlorosilane and pyrrolidine diol/triol ...... 77 61. Synthesis and reactivity of possible boracycle for the catalytic enantioselective reduction of prochiral ketones ...... 78 62. Mosher ester analysis of 1-phenylethanol ...... 79
xvii TABLE OF ABBREVIATIONS
AAA Asymmetric allylic alkylations
AcOH Acetic acid
Ac2O Acetic anhydride AcCl Acetyl chloride
AD-mix (DHQD)2PHAL Asymmetric dihydroxylation dihydroquinidine adduct with phthalazine
AIBN 2,2’-Azoisobutyronitrile
Boc2O Di-tert-butyldicarbonate
Bz2O Benzoic anhydride BzCl Benzoyl chloride
COPD Chronic obstructive pulmonary disease
Cbz-Cl Benzyl chloroformate
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
DDQ 2,3-dichloro-5,6-dicyano-1,4- benzoquinone
DMAP N,N-dimethylaminopyridine
DMF N,N-dimethylformamide
2,2-DMP 2,2-Dimethoxypropane
DMSO Dimethyl sulfoxide
EDC N-(3-dimethylaminopropyl)-N’- ethylcarbodiimide hydrochloride
xviii ee Enantiomeric excess
EWG Electron withdrawing group
GPCR G-protein coupled receptor
(Ipc)2BCl B-Chlorodiisopinocampheylborane MAOS Microwave assisted organic synthesis m-CPBA m-Chloroperoxybenzoic acid
MsCl Methanesulfonyl chloride
MW Microwave
NaHMDS Sodium hexamethyldisilazide
NCS N-chlorosuccinimide
NMO N-Methylmorpholine-N-oxide
NMPO N-methylputrescine oxidase
P5C 1-Pyrroline-5-carboxylic acid
PAs Pyrrolidine alkaloids
PHPs Polyhydroxyl pyrrolidines
PMBBr p-Methoxybenzyl bromide
PNMT Putrescine N-methyl transferase
Pyr. Pyridine
RCM Ring closing metathesis
Red-Al Sodium bis(2- methoxyethoxy)aluminum hydride
SOCl2 Thionyl chloride TAs Tropane alkaloids
TBDMSOTf tert-Butyldimethylsilyltriflate
TFA Trifluoroacetic acid
TFAA Trifluoroacetic anhydride
xix THF Tetrahydrofuran
TMSCl Trimethylsilylchloride
TPP Triphenylphosphine
Tol Toluene
TsCl 4-Toluenesulfonyl chloride
TsOH Tosic acid
xx CHAPTER I
INTRODUCTION TO PYRROLIDINE ALKALOIDS
1.1 Alkaloids
Alkaloids are naturally occurring compounds, many of which contain the pyrrolidine nucleus, that are commonly found in plants and possess medicinal qualities.1 The name was coined from Carle Meissner in 1819 and stems from the Latin root “alkali-like” after it was found that these compounds reacted with common mineral acids. Alkaloids contain at least one basic nitrogen atom and it is usually bound within a ring system as shown in Figure 1.
HO
O H
N HO
1
Figure 1: Morphine is a natural plant alkaloid found in opium and contains a ring structure and nitrogen heteroatom.
1 Alkaloids can exist in the form of the free base, as salts, or as N-oxides shown in Figure 2. They also tend to be low molecular weight, colorless, and crystalline solids with a bitter taste. True alkaloids are those where the basic nitrogen atom originates from an amino acid. In the case of some amino acids, this adds a level of complexity to the molecule by introducing a chirality center to the alkaloid. Notable amino acids used in the biosyntheses of most alkaloids include lysine, arginine, ornithine, phenylalanine, tryptophan, and histidine.
- O HO CH2OH H H N N+ HO H Cl O NH2
2 3 4 5
Figure 2: Examples of alkaloids existing as the free-base (pyrrolidine), a salt (ethanolamine hydrochloride), as the N-oxide (4-methylmorpholine-N-oxide), and from amino acids (retronecine).
Alkaloids are mainly found in plants but have increasingly been found within animals, insects, marine organisms, and microorganisms. Epibatidine
(Figure 3) is a poisonous alkaloid found in the skin of the poison dart frog and is known to be a potent analgesic. Plants and animals use alkaloids often as defense mechanisms to avoid being eaten or disturbed or as signals such as in use of pheromones as a form of communication.
2 H Cl N N
6
Figure 3: Epibatidine is an alkaloid secreted through the skin by the poison dart frog as a defense mechanism.
In the early 1800s, French chemists Pelletier and Caventou isolated many alkaloids such as caffeine, strychnine, brucine, cinchonine, and quinine as shown in Figure 4.1 The cinchona alkaloids from the cinchona bark native to tropical forests in South America were the most significant alkaloids isolated. Quinine
(Figure 4) is one of the cinchona alkaloids found to possess anti-malarial properties. It was used for over 100 years as a therapeutic until other drugs finally took over. Alkaloids found in nature can be localized within a region or dispersed throughout an entire organism. Extraction is often easily performed in the appropriate media under acidic or basic conditions. These structures were typically studied through product degradation and revealed many principles of chemistry used today in analyzing the carbon, hydrogen, oxygen, and nitrogen composition of a given compound. These discoveries led to the isolation of many alkaloids that are routinely used in synthesis and drug design today.
3 O N N H H N N H O H H H O N N H H N O O N O
O O 7 8 9
N N OH OH
O
N N
10 11
Figure 4: Compounds isolated by the French chemists Pelletier and Caventou provided a solid foundation for the studying of alkaloid chemistry.
Of the many alkaloids found in nature, the pyrrolidine alkaloids (PAs) represent a family of compounds widely found in plants.1 Pyrrolidine, or tetrahydropyrrole, is the fully saturated version of the aromatic molecule pyrrole shown in Figure 5.
H H N N
12 13
Figure 5: Structural comparison of pyrrolidine and pyrrole.
4 Pyrrole compounds are not as common in nature when compared to other alkaloids, but have a widespread significance in several important organic systems and pharmaceuticals.2 Tetrapyrroles, for example, are a class of compounds consisting of four pyrrole moieties bound together, either cyclic or acyclic, with a carbon linker and play a vital role in many biological processes such as photosynthesis and respiration.3 Some important tetrapyrroles include bilirubinoids, porphyrins, and corrins, as shown in Figure 6. Hereinafter, this dissertation will focus primarily on the structures and functionalities of the PAs.
HOOC COOH
N N N H H O N N O NH HN NH N N
14 15 16
Figure 6: Some tetrapyrroles involved in biological processes include bilirubin, porphyrin, and corrin.
1.2 Pharmacology of PAs The PAs originate mainly in the plant families Splanaceae,
Convolvulaceae, and Erthryoxycaeae and their properties of being toxic, euphoric, and hallucinogenic have been well studied and documented.1 They have been known to interfere with neurons transferring across the synapse, affecting the central nervous system by mimicking, facilitating, or antagonizing 5 normal biological processes. For example, some of the PAs have a strong resemblance to the neurotransmitter acetylcholine (Figure 7). Acetylcholine serves the purpose of transmitting impulses between nerves in the brain and neuromuscular junctions. Thus, these particular alkaloids act as an acetylcholine agent and block it from entering the nervous system, disabling the transmission of impulses.
O N O
17
Figure 7: Some PAs resemble the neurotransmitter acetylcholine and inhibit the signaling system.
Pyrrolidine alkaloids have been shown to affect the muscarinic and nicotinic acetycholine receptors within an organism. The muscarinic acetylcholine receptor is a G-protein coupled receptor (GPCR) located in the parasympathetic, sympathetic, and central nervous systems.4,5 Hindering this process modulates several physiological functions such as smooth muscle contraction, heart rate, and bronchial and salivary secretions. The nicotinic acetylcholine receptor is also a GPCR similar to the muscarinic receptors except that it contains ion channels to mitigate the flow of sodium and potassium within a cell. These receptors trigger their effects through the binding of not only acetylcholine but also muscarine and nicotine respectively. Nicotine (Figure 8) is one of many PAs and was isolated in 1809 from tobacco within the plant family 6 Solanaceae.1 Structurally it has a methyl group bound to the nitrogen atom of the pyrrolidine and an aromatic heterocycle in the 2-position on the ring, a rarity of
PAs. One of its original purposes was to cure several diseases and help those with cardiovascular illnesses. Later it was found that nicotine was an acetylcholine antagonist and it tends to cause long-term harm towards the body.
Other PAs, including hygrine and cuscohygrine (Figure 8) isolated from coca leaves, also show biological activity and serve as precursors for other alkaloids.1
N O O N N N N
18 19 20
Figure 8: Structure of some PAs found in nature.
Other important PAs include the tropane alkaloids (TAs) and polyhydroxylated pyrrolidine (PHPs) compounds, which represent the majority of this class of alkaloids. Their structures are key to their functionalities and their physiological effects allow plants to possess potent pharmacological properties such as muscle relaxers, analgesics, stimulants, and anesthetics.1 The biosyntheses of these compounds also display key intermediates useful in the total syntheses of natural products.
7 1.3 Tropane Alkaloids A popular class of the PAs includes the TAs, some of which are shown in
Figure 9. These alkaloids are mostly derived from the amino acids ornithine and lysine with acetate or malonate derivatives shown in Scheme 1. These alkaloids are bicyclic and are well known to inhibit the activities of the parasympathetic nervous system, being acetylcholine antagonists and are responsible for vasodiliation, heart rate manipulation, pupil constriction, and the stimulation of secretions.1,6, 7
N N N H OH H OH H OH O O O O
O O O
21 22 23
Figure 9: Tropane alkaloids atropine, scopolamine, and hyoscyamine
O -CO2 PNMT NH2 NH2 H2N OH H N N 2 H NH2 NMPO 24 25 26
N O O N -CO2 N O O SCoA N H
30 29 28 27
Scheme 1: Biosynthesis of most tropane alkaloids stem from L-ornithine to form tropinone.
8 Atropine, scopolamine, and hyoscyamine are examples of TAs that act as muscarinic acetylcholine receptor antagonists seen in Figure 9. Drugs targeting these receptors have shown a significant impact in the treatment of asthma, chronic obstructive pulmonary disease (COPD), Alzheimer’s disease, schizophrenia, and Parkinson’s disease.7,8,9
Most of the TAs can be synthesized easily from tropinone (scheme 1).
Richard Willstatter was a pioneer in plant natural products for which he received a Nobel Prize in 1915. He first synthesized tropinone in 1901 with an overall low percent yield (0.75%) as shown in Scheme 2.10 The penultimate step in this elaborate synthesis was the transformation of the seven-membered ring to the bicyclic scaffold via an SN2 reaction in step 14. This led to several of the aforementioned alkaloids with the tropane core.
9 O NH2 NMe2 7. MeI 1. NH2OH 3. MeI 5. Br2 8. Ag2O 9. Br 2. Na/EtOH 4. Ag2O 6. Me NH 2 2 quinoline
31 32 33 34
Me2N Br 19. HBr 15. NaOH Br 10. HBr MeN Me2N 20. H2SO4 16. KI 14. Δ 11. Me2NH
21. CrO 17. AgCl 12. Na/EtOH 3 Br 18. Δ Br 13. Br2
38 37 36 35 MeN
O
39
Scheme 2: The first synthesis of tropinone by Willstatter.
Sir Robert Robinson was able to accomplish the synthesis with a single step transformation with a much higher yield shown in Scheme 3.11 The one pot synthesis earned Robinson the Nobel Prize in 1947 through illustration of the biosynthesis of many tropane alkaloids. This scheme took advantage of the reactivity within the simple starting materials, causing a chain reaction to ultimately lead to the favorable bicyclic structure. The key feature of this methodology employs the Mannich reaction where an aldehyde is converted to an imminium ion to react with an enolizable carbonyl compound. The reaction is driven to completion thermodynamically from the losses of water and carbon dioxide through the course of ring formation. Within this scheme lies the exploitation of a cyclic imminium species, or pyrroline intermediate, which has
10 been utilized in modern synthetic schemes in the syntheses of complex molecules.
Ca2+ O OH Cl CO2 MeNH2•HCl proton O O O Ca Co H 2 3 transfer NMe OH
H HO OH H2O -H2O, -CO2 50 h 42% CO2 O
40 41 42 43
CO2 MeN MeHN -CO2 CO2 N OH O O Me
39 45 44
Scheme 3: Robinson’s one pot synthesis of tropinone.
Cocaine (Figure 10) is another notorious TA derived from tropinone. It was first obtained from Peru, Bolivia, and Colombia and was often chewed.
Friedrich Wohler isolated the compound in 1862, and Karl Koller discovered its anesthetic properties in 1882.1 Cocaine has served as a useful model to synthesize targets that are more stable and have less toxic effects to be used clinically. The use of cocaine as a topical anesthetic led to the synthesis of procaine (Figure 10), which is still being used today in modern dentistry.
11 O MeO C 2 N MeN O O
O H2N
46 47
Figure 10: Structure of cocaine and procaine
Willstatter first accomplished the synthesis of cocaine (Scheme 4) in his analysis of the TAs in 1923.12 He elucidated the structure of cocaine through analyzing the degradation byproducts leading back to the tropinone core.
O OH O OMe O OMe
Na/EtOH Na/Hg MeN MeN MeN MeN OH CO2 O O O (Bz)2O
39 48 49 50
O OMe O OMe
MeHN MeN O recrystallize O + D-tartrate
O basify O
51 52
Scheme 4: Willstatter’s synthesis of cocaine
Two later approaches to synthesizing (+)-cocaine and (-)-cocaine follow procedures by Pearson and Hu, respectively.13,14 These methodologies provide increased selectivities and yields while using modern synthetic techniques such as enamine organocatalysis and alkene metathesis, as highlighted in Schemes 5 and 6, to achieve the bicyclic structure.
12 OHC Boc CHO CHO CO2Me N L-proline BocN OH MeN OBz PhCH3
53 54 55
Scheme 5: Total synthesis of (+)-cocaine utilizing L-proline as a chiral auxiliary.
Boc CO Me BocN 2 N RCM MeN OBz
56 57 46
Scheme 6: Total synthesis of (-)-cocaine invoking ring closing metathesis.
1.4 Polyhydroxylated Pyrrolidines Polyhydroxylated pyrrolidines (PHPs) or azasugars have been of considerable interest to chemists and biologists because of their biological role as sugar mimics.15 Azasugars are the carbohydrate analogs where the oxygen of the furan and pyran rings has been substituted with a nitrogen atom to generate pyrrolidine and piperdine rings respectively (Figure 11). The significance of these inhibitors lies in their ability to disrupt protein processes resulting in various applications as antiviral, anti-diabetic, anticancer, antibiotic agents, and in lysosomal storage disorder.16 These mimics can strongly bind carbohydrate receptors and penetrate the cell membrane with the possibility of chaperoning other molecules across as well.
13 CH OH CH OH CH OH H CH OH 2 O 2 2 N 2 H H H H H H H H OH OH OH OH
58 59 vs
CH OH CH OH 2 2 H H O OH H N OH H H OH H OH H OH H OH H H OH H OH
60 61
Figure 11: Aza- analogs of furanose and pyranose sugars
Glycosidases are enzymes that catalyze the hydrolysis of glycosidic bonds in complex carbohydrates. The smaller sugars are then further broken down and used metabolically by the organism. PHPs shown in Figure 12 are known to mimic some glycosidases, therefore inhibiting several processes involving carbohydrates.13
HO OH HO OH HN OH HO OH H3C N CH2OH N CH2OH H H
62 63 64
Figure 12: Structures of some PHPs and the glycosidases inhibited
14 A broad range of synthetic methodologies has been invoked to synthesize these interesting targets. Direct preparation of PHPs 2,5-anhydro-2,5-imino-D- mannitol and 2,5-anhydro-2,5-imino-D-glucitol from 5-keto-D-fructose (Scheme
7) came through reductive amination developed by Reitz and Baxter by following the Paulsen synthesis.17,18
CH2Ph H PhCH NH O O 2 2 N N NaBH CN HOH2C CH2OH H2 HOH2C CH2OH HOH2C CH2OH 3 MeOH, 68% Pd(OH)2/C HO OH HO OH HO OH
65 66 67
Scheme 7: Preparation of 2,5-anhydro-2,5-imino-D-mannitol and 2,5- anhydro-2,5-imino-D-glucitol from 5-keto-D-fructose via reductive amination.
Rao, et. al. developed an approach to several of the main glycosidase inhibitors derived from D-ribose.19 Scheme 8 portrays 1,4-dideoxy-1,4-imino-D- ribitol as an example.
15 Cbz O OH O NHBn OH NHBn Cbz-Cl, OH NBn HO BnNH2, MeOH HO LiAlH4, THF HO NaHCO3, MeOH HO 4 Å mol. sieves 0 °C to rt 0 °C to rt, 2 h O O reflux O O O O O O
68 69 70 71
Ac2O, pyridine H O Cbz 1. MsCl, Et N N 3 cat. DMAP NBn cat. DMAP, CH Cl Cbz 10% Pd/C, H , MeOH 2 2 OH 0 °C, 30 min HO 2 0 °C to rt, 20 min NBn AcO HO OH 6 N HCl, 12 h O O 2. K2CO3, MeOH 0 °C to rt, 1 h O O
74 73 72
Scheme 8: Synthesis of glycosidase inhibitor 1,4-dideoxy-1,4-imino-D-ribitol from 2,3-O-isopropylidene-D-ribofuranose.
Some PHPs have even been synthesized via protecting group free routes
(Scheme 9) that involve the formation of the heterocycle through amino alkene interaction.20, 21
16 NH CuO t-Bu-Xantphos (15 mol%) N MeOH-p-xylene (1:1) HO OH 140 °C, 72 h HO OH
75 76
1% AcCl O Zn, EtOH O O OMe NH (aq.) NH OH in MeOH OMe PPh3, I2 I 3 2 HO HO rt, 15 min imidazole, 18 h NaCNBH3 HO OH HO HO reflux, 18 h
77 78 79 80
O I2, NaHCO3 OH O H O H 2 N NaOH, EtOH N rt, 18 h reflux, 2 h HO HO
82 81
Scheme 9: Examples of protecting group free protocols in the syntheses of some PHPs
Codonopsinine and codonopsine (Figure 13) are two interesting PHPs isolated from Codonopsis clematidea in 1969 and have displayed antibiotic and hypotensive activities in animal tests.22 Short, efficient syntheses of these molecules were developed by Rao, et. al. where the starting material utilizes the chirality of the amino acid D-alanine, as shown in Scheme 10.
17 HO OH HO OH
OCH3 N N OCH3 OCH3
83 84
Figure 13: Rare class of PHPs with aryl group in the 2-position of the pyrrolidine ring eliciting both antibiotic and hypotensive activity in animals
1. LiAlH4, THF 1. (COCl)2, DMSO O OsO4 O 0 °C to reflux, 10 h H3C CH2Cl2, -78 °C H3C AD-mix-(DHQD)2PHAL H3C OH OH 2. p-OMeC H COCHPPh CH3SO2NH2, NaHCO3 2. Cbz-Cl, NaOH, THF NHCbz 6 4 3 NHCbz NH OMe 2 CH2Cl2, rt t-BuOH:H2O, 0 °C
85 86 87
AcO OAc OAc OAc OH O 1. NaBH4, MeOH H3C H3C LiAlH4, THF TFA, CH2Cl2 0 °C - rt, 30 min H3C N CbzN OAc CbzN OH 0 C - rt, 4 h 0 - 60 °C, 5 h OMe ° H OMe 2. Ac2O, CH2Cl2 H OMe Cbz Et3N, 0 °C - rt, 16 h
90 89 88
HO OH
H3C N OMe CH3
83
Scheme 10: Synthesis of (-)-Codonopsinine starting from D-alanine
The intrigue with this class of compounds lies in the arrangements of the contiguous stereocenters about the pyrrolidine ring causing the various biological activities. To achieve this complex configuration, carbohydrates were initial targets due to their pre-existing stereochemistry, flexible functionalization and chemical manipulation, and the availability of the starting sugars shown in
Scheme 11.23 18 O O O O OH 1. Acetone/H+ TsCl, Et3N O LiAlH4 O HO O OH OTs 2. 0.1 N HCl CH2Cl2, 0 °C THF, 0 °C PMBBr O O O HO OH OH OH OH NaH, THF 91 92 93 94 N O S OPMB S O O O OHCO HO O NaHMDS NaIO4 60% aq. AcOH OHC HO O OCHO THF, -78 °C MeOH-H2O OPMB cat. H2SO4 OPMB NaBH4 OMe OPMB MeOH 98 97 96 95
OPMB OPMB OH 1. TPP, Benzene, H O, 40 °C 1. MsCl, Et3N, 0 °C ZrCl4 2 OH N3 N3 OMe 2. NaN3, DMF, 70 °C OMe MeCN OMe 2. (Boc)2O Et3N 99 100 101
HO OH red-Al HO OH HO OH OH toluene, reflux + m-CPBA N N N CH2Cl2, 0 °C NHBoc OMe OMe OMe OMe CH3 Boc Boc
83 104 (9:1) 103 102
Scheme 11: Synthesis of (-)-Codonopsinine starting from L-xylose
Another interesting method of achieving these target compounds arises
from the use of pyrroline intermediates. The syntheses presented earlier
(Schemes 5 and 6) by Pearson and Hu both invoked the pyrrolinium intermediate
to synthesize the target molecule cocaine. Davis, et. al. exploited the reactivity of
the pyrrolinium system to install extending carbon chains irreversibly when
analyzing diverse carbohydrate-processing enzyme probes (Scheme 12).24 This
method starts with a 3-pyrroline derivative to form the diol functionality in the 3,4-
positions leading to the 1-pyrroline species.
19 Cbz H H Cbz 1. C6H5CH2OCOCl N N N TBDMSOTf, pyr. CH Cl N NCS NaOH, toluene 2 M H2SO4 2 2 H , Pd/C, MeOH Et2O 2. mCPBA, CH2Cl2 Et2O 2 O HO OH TBDMSO OTBDMS
105 OMe 106 OMe 107 108
Cl H H N TFA(aq) N p-MeOBnMgCl N DBU N
THF Et2O HO OH TBDMSO OTBDMS TBDMSO OTBDMS TBDMSO OTBDMS
112 111 110 109 Scheme 12: PHP synthesis exploiting the imine moiety of the 1-pyrroline intermediate
An alternative to imines in achieving PHPs utilizes enantiomerically pure 3-
pyrrolines derived from amino acids. A retrosynthetic analysis shows the 5-
membered ring heterocycle of the PHP can be closed via the Wittig reaction
(Scheme 13) done by Hewson and Burley.25
OH O H HO PPh3 HOH C HOH C N HOH2C N 2 N 2 SO2Ph SO2Ph SO2Ph
113 114 115
HO O O
HOH C NH HOH2C NH 2 SO Ph SO2Ph 2
117 116
Scheme 13: Retrosynthesis of a PHP involving a 3-pyrroline intermediate formed via Witting reaction
20 The amino acid was easily converted to a ketone by addition of methyl lithium followed by the addition of the viny phosphonium salt to yield the 3-pyrroline 114
(Scheme 14). A PHP was yielded after osmylation (or epoxidation) followed by
N-deprotection.
O O CH Li 1. NaH OsO HOH C 3 4 2 HOH2C HOH C OH 2. 2 N Me NO H H PPh3 3 NHSO2Ph NHSO2Ph SO2Ph
117 116 114 OH HO
HOH2C N
SO2Ph
113
Scheme 14: PHP synthesis via 3-pyrroline intermediate
1.5 Pyrroline Intermediates Pyrrolines, or dihydropyrroles, are useful synthons for the preparation of novel biologically important compounds containing the pyrrolidine skeleton highlighted in Figure 14. 1-Pyrroline systems are imines and are generally synthesized under mild conditions. They also have similar reactivity to their aldehyde and ketone analogues in the preparation of more complex molecules. 1-Pyrrolines have been utilized in a number reaction schemes in order to synthesize interesting heterocycles including porphyrin and corrin systems.26,27 These compounds usually involve the formation of a 1-pyrrolinium species, which is susceptible to nucleophilic attack in the 2-position (Scheme 3). 1-Pyrroline-5-
21 carboxylic acid (P5C) represents one of the more important dihyrdropyrroles because of its role in glutamate metabolism, arginine degradation, and proline biosynthesis and degradation (Figure 14).28,29
H H N N N
118 119 105 H Boc N N HO2C HOH2C N O CO2H
120 121 122
Figure 14: Three isomers of the pyrroline moiety used as synthons for biological scaffolds
Dihydropyrroles have also been isolated from ant venom used as a defensive compound to ward off predators.30 They were synthesized from the reaction of cyclopropane rings with primary amines to yield the pyrrolines shown in Scheme
15. This methodology provides access to functionalized pyrrole rings or pyrrolidine rings if a reduction occurs over oxidation. 2-Pyrrolines, though not as common as 1-pyrrolines, have led to the study of other heterocyclic systems including the syntheses of carbapenem β-lactam antibiotics 130-132 (Figure
14).31
22 O O R3 = vinyl BrH2C CH2Br + R2 OR1
123 124
O O R4 R3 = Ph O O R4 NH2 Me2S Br + N R2 OR1 R3 R2 R2 OR1 Ph R3 CO2R1 125 124
R = alkyl 127-129 130-132 O O 3 Ph3PH2C CHR3 + Br R2 OR1
126 124
Scheme 15: Synthesis of 2-pyrrolines from ant venom involving cyclopropanes and primary amines
Generally, 3-pyrrolines are rather limited in scope but they offer an appealing route to the formation of pyrroles via oxidation, the formation of pyrrolidines through reduction, and functionalized pyrrolidines in the 2,5- and/or 3,4-positions
32 often leading towards a C2-symmetric species seen in catalysis. Iminoribitol derivatives represent a class of purine nucleoside hydrolase inhibitors synthesized from 3-pyrrolines (Figure 14) to build a PHP scaffold.33 One straightforward method of synthesizing 3-pyrrolines follows the direct amination of a dihaloalkene.34 Using primary amines led to the possible formation of spiro compounds (Scheme 16) along with the desired 3-pyrroline products.
23 Ph PhNH2 N
134
Et2 Et2NH N Cl Cl Cl
135 133 H NH N N Cl 3 +
105 136
Scheme 16: Direct amination of dihaloalkene to yield 3-pyrroline
The Delepine reaction, highlighted in Scheme 17, shows a method by which the ammonia is introduced through substitution of one of the halogens of the dihaloalkene with hexamethylenetetramine. This then causes the intramolecular cyclization to afford the free pyrroline.35
Cl N CH3Cl reflux, 4h N EtOH/conc. HCl (11:2) Cl Cl + N N Cl N N N N rt, 18 h
133 137 138
H 2.5 eq K2CO3 N EtOH Cl NH3 Cl rt, 2 h, reflux, 1.5 h
105 139
Scheme 17: Delepine reaction used to synthesis 3-pyrrolines from cis-2- butene-1,4-dichloride and hexamethylenetetramine
24 A method for functionalized 3-pyrrolines involves the partial reduction of pyrrole under dissolving metal conditions. Donohoe’s approach to the synthesis of the pyrrolidine alkaloid epiaustraline (Scheme 18) utilizes the Birch reduction and required an electron-withdrawing group to be present in the 2-position to obtain the desired product.36
Boc Boc N Li, NH , -78 C N N MeO2C CO2Me 3 ° MeO2C CO2Me HOH2C H isoprene, NH4Cl HO OH
140 141 142
Scheme 18: Dissolving metal reduction with lithium in liquid ammonia partially reduces electron poor pyrroles into 3-pyrrolines
Knorr and Rabe first reported another dissolving metal reduction of pyrrole where electron-rich substituents where placed in the 2,5-positions (Scheme 19) to allow the transformation to occur.37
H H N Zn N HCl
143 144
Scheme 19: Dissolving metal reduction with zinc in acidic media partially reduces electron rich pyrroles into 3-pyrrolines.
25 3-Pyrrolines have also been synthesized via forming bicyclic rings systems.
These reactions take advantage of first performing a Diels-Alder reaction to generate the ring, subsequent chemical transformations, and a retrocyclization process to liberate the desired 3-pyrroline. Anderson was able to take N- methylmaleimide in the presence of furan to give the adduct in Scheme 20.38
This adduct underwent lithium aluminum hydride reduction of the amides to give the amine followed by a retro Diels-Alder to give the 3-pyrroline. The advantage of this route is that it yields an unsubstituted 3-pyrroline, which is not commonly seen. Also, the substitutent bound to the nitrogen atom was not electron deficient.
O O benzene O LiAlH + 4 Δ O O + N O reflux N N N O O 145 146 147 148 149 146
Scheme 20: Retro-Diels Alder approach to 3-pyrrolines
Robina, et. al. exploited the strain in bridgehead substituted bicyclo[2.2.1]hept-2-ene systems to generate stereoselective 3-pyrrolines
(Scheme 21).39 Here, pyrrole is used as the diene with an acetylene as the dienophile. Usually pyrrole does not participate in Diels-Alder reactions unless a carbamate is present to decrease its aromatic character. Following the formation of the bicyclo[2.2.1]heptadiene is the conjugate addition of diethylamine to the
26 vinyl sulfone, elimination of HBr to give an enamine intermediate, followed by acid hydrolysis of the enamine to give the ketone. These products can then be further manipulated via retro-Aldol or retro-Dieckmann reactions to give the 2,5- disubstituted 3-pyrrolines.
Boc Boc Br Boc N N N Toluene, 90 °C Br Et3N/Et2NH, MeCN, rt + O 10% HCl Ts Ts Ts
150 151 152 153
Boc Boc N N Boc N O LiBH4, THF, -78 °C NaOMe cat. CHO retro-Aldol Ts OH MeOH, rt rac Ts Ts
153 154 155
Boc N Boc N O AcOH cat. CO2Me retro-Dieckman Ts MeOH, rt, 1 h Ts
153 156
Scheme 21: Syntheses of 3-pyrrolines via retro-Aldol and retro-Dieckmann reactions
Intramolecular cyclization of α-amino allenes in the presence of small amounts of silver acetate is another route to generate 3-pyrrolines. This reaction starts by taking lithiated methoxyallenes and reacting them with an N-tosyl imine shown in Scheme 22.40 This route was of interest due to the ability to generate electron rich pyrrole derivatives to be used to make polypyrroles such as
27 porphyrins and to synthesize scaffolds of other various pyrrolidine alkaloids.41,42
α-Amino allenes have been thoroughly explored using other heavy metals to efficiently catalyze the reaction.43
Ph 1. N OMe OMe OMe OMe n-BuLi Ts 0.27 eq. AgNO3 C C C -40 - -20 C H THF, -40 °C Li ° Ph acetone, rt N Ph 2. H2O H N Ts Ts
157 158 159 160
Scheme 22: Lithiated methoxyallenes with imines in the presence of silver to generate 3-pyrroline rings
Several novel approaches to 3-pyrrolines involve carbene chemistry utilizing olefin metathesis (Scheme 23) and C-H insertions.44 3-Pyrrolines have been proven to aid in the syntheses of complex molecules by minimizing steps and being performed under relatively mild conditions.
28 R CO2Me R CO2Me PCy3 N Grubbs I N Cl Ru Cl CH Cl , 40 °C Ph 2 2 PCy3 Grubbs I
161 162
Ph Ph Grubbs I N N 1,4-benzoquinone CD2Cl2, 40 °C, 24 h
163 134
R H R Br Br 1 1 1. 1,5 C-H R1 R2 N R N R NHX 2. KHMDS insertion 2 2 X X alkylidene carbene
164 165 166
Scheme 23: Novel approach to 3-pyrrolines via carbene chemistry
One drawback often seen when synthesizing 3-pyrrolines is the oxidation to the pyrrole byproduct. This transformation has been studied and found that certain oxidants added to the system will complete the conversion shown in
Scheme 24.32
29 CH2Ph N PDC Major OHC
168 CH2Ph N
HOH2C CH2Ph 167 N ClCOCOCl Major DMSO OHC Et3N 169
Scheme 24: Oxidation of 1-benzyl-3-hydroxymethyl-3-pyrroline by pyridinium dichromate yielding to give 3-formyl-3-pyrrole instead of 3-formyl-3-pyrroline
Other oxidants used to achieve the pyrrole also include 2,3-dichloro-5,6- dicyano-1,4-benzoquinone (DDQ), chloranil, manganese dioxide, palladium on carbon, and sulfur. However, 3-formyl-3-pyrroline was obtained under Swern oxidation conditions (dimethyl sulfoxide/trifluoracetic anhydride/triethylamine).
This side reaction becomes highly important when trying to manipulate a pyrroline to functionalize the heterocycle and make a useful intermediate. A protocol from Verpoort, et. al. describes synthesizing a pyrroline ring via alkene metathesis and purposely aromatizing it using similar oxidants to achieve the pyrrole.32 Scheme 25 highlights a proposed mechanism of oxidation using chloranil as the oxidant.
30 171 173
R2 R2
N H H N 2 R2 R R1 R1 Grubbs' II N O O N R1 Cl Cl Cl Cl R1
170 Cl Cl Cl Cl 175 O O
172 174
Scheme 25: Proposed mechanism for the transformation of 3-pyrroline to pyrrole in the presence of an oxidant
Synthetic chemists have continued studying TAs and PHPs as they elicit significant biological activities. One objective of this dissertation involves synthesizing targets closely resembling these alkaloids as they may provide a new class of attractive compounds exacting similar responses within biological systems.
31 CHAPTER II
ALKALOIDS IN ORGANOCATALYSIS
2.1 Early Organocatalysis Asymmetric organocatalysis utilizes chiral organic molecules to synthesize stereodefined products from a variety of chemical transformations in the absence of a metal atom. These molecules predominately contain the heteroatoms of oxygen, sulfur, nitrogen, and phosphorus to accerlerate chemical reactions.
There are several advantages of using an organocatalyst including their availability, low cost, low toxicity, insensitivity to moisture in the atmosphere, and ease of recovery upon reaction completion with minimal waste. Over the last two decades, organocatalysts have been developed to compete with enzyme and organometallic catalysis. This methodology becomes important when trying to avoid biological methods that are often too specific or in performing metal free synthesis. Alkaloids were the initial target molecules as organocatalysts because they were easily isolated from nature.45
During the mid 1800s, Louis Pasteur discovered the first asymmetric reaction by doing kinetic resolution studies and found that the organism
32 Penicillium glauca destroyed one of the enantiomers of a racemic ammonium tartrate solution. He later found various organic molcules, such as the cinchona alkaloids, that underwent the same reaction.35 Georg Bredig later reexamined the findings of Pasteur under non-enzymatic conditions in order to decipher the cause of such selectivity. These studies fortunately led to the discovery of the first organocatalyzed carbon-carbon bond forming reaction by taking benzaldehyde in the presence of hydrogen cyanide gas and a chiral alkaloid to give a cyanohydrin (Scheme 26) albeit in <10% ee (enantiomeric excess).
O OH HCN H CN < 10% ee
176 177
OCH3
OH OCH3 N H N N H OH N
178 179
Scheme 26: First organocatalytic carbon-carbon bond forming reaction
The cinchona alkaloids function by forming a pocket being held together by ionic interactions, hydrogen bonding, or both. Quinine (Scheme 24), for example, shows three important structural features of these organocatalysts.
They have a chiral center that is flanked by a tertiary nitrogen atom, which aids in the hydrogen bonding interactions and also a bulky backbone with the quinoline
33 core. The transition state model shows how loosely or tightly bound the compound is with the catalyst, thus rationalizing the ee values. It wasn’t until the
1960s that useful enantioselectivies were achieved by using these organocatalysts. This was seen in the reaction of methanol adding across ketenes shown in Scheme 27.46 It became evident that this was an interesting methodology for generating stereocenters, competing with transition metal and enzymatic catalysis.
H O OBz 1 mol% cat. N C O OMe H Ph Ph N MeO 180 181 cat.
Scheme 27: Methanolysis of phenylmethyl ketene using cinchona alkaloid as organocatalyst
2.2 Impact of Proline in Modern Organocatalysis Modern organocatalytic reactions employ the use of enamine chemistry, which was discovered by Gilbert Stork in the early 1960s and is the nitrogen analog of enolate chemistry. An aldehyde or a ketone with an α-hydrogen reacts with a secondary amine to give the enamine as shown in Scheme 28. These enamines then subsequently react in a similar fashion as enolates via nucleophilic attack of the α-carbon to an electrophilic species.47 The advantage of using enamines is that they are good nucleophiles and tend to be less basic, preventing potential elimination byproducts during a reaction.
34 X RR RR O N N HX R2NH + -H2O -HX
182 183 184 185
Scheme 28: Synthesis of an enamine via a secondary amine and carbonyl compound to give more nucleophilic version of an enolate
Common electrophiles include alkyl halides, aldehydes/ketones, and α,β- unsaturated carbonyl compounds. The amines generally used for these reactions are cyclic, which provide rigidity to the nucleophile, aiding in a more direct route for nucleophilic attack. Synthetic chemists have since improved upon enamine chemistry by instilling chiral auxiliaries to influence asymmetry. A chiral auxiliary is a compound that binds to an achiral substrate to allow for enatioselectivity via a diastereoselective reaction. Chiral auxiliaries induce asymmetry by using directing groups or steric hindrance. They are later removed and recycled after the new stereocenter has been generated. By the early
1970s, two research groups independently found the use of a catalytic amount of
(S)-proline with a triketone would induce an intramolecular aldol cycliczation with high yield and selectivity shown in Scheme 29.48 Figure 15 shows a proposed transition state for the observed stereochemistry. The Wiechert group opted to synthesize the same target by ketone starting with the Michael addition followed by the aldol cyclization using a variety of D and L amino acids and found L-
Proline to be the most favorable. Proline was chosen because it was an
35 inexpensive, abundant compound that contained the pyrrolidine core, it had an asymmetric carbon, the 5-membered ring offered rigidity to the backbone, was slightly acidic, and had multiple contact points on the compound. The mechanism involved enamine formation with proline and one of the carbonyls of the triketone coupled with hydrogen bonding from the carboxylic acid and of the enol present as shown in Figure 15.
O O O L-proline O + MeCN O O HO O
186 187 188 Scheme 29: Intramolecular Aldol addition catalyzed by L-proline
O O
O N N O OH C H CO O 2
189 190
Figure 15: Proposed TS by Hajos of proline catalyzing the cyclization
The aldol condensation and Michael addition were two marquee reactions in the resurgence of organocatalysis.35 These reactions already gave high yields, but now can be carried out asymmetrically to synthesize many target
36 molecules, which seemed impossible before. The Aldol condensation is the reaction of the α carbon of an aldehyde or ketone with the carbonyl of another molecule to give a β-hydroxycarbonyl compound, which can undergo elimination to give an α,β-unsaturated carbonyl compound as shown in Scheme 30.
O O O R Aldol R OH -H O Aldol Reaction R' R' 2 R' R Addition R Δ R R' R' 191 192 193
EWG EWG base cat. EWG EWG Michael Addition + EWG EWG
194 195 196
Scheme 30: Aldol addition/condensation and the Michael addition
Stereochemical control of the aldol reaction often involves a chiral auxiliary such as oxazolidinone to give high facial selectivity. The oxazolidinones can be acylated and converted to the enolates of lithium, boron, tin, or titanium leading to the respective open, closed, or chelated transition states. Closed transition states are based on the Zimmerman-Traxler model (Figure 16) through a six membered ring chair conformation where the electrophile and the enolate are coordinated to the Lewis acid. The tighter the transition states generally lead to enhanced selectivities. The Michael addition (conjugate addition) is the
1,4-addition of a resonance stabilized carbanion (Michael donors) to activated
37 alkenes (Michael acceptors) such as α,β-unsaturated carbonyl compounds highlighted in Scheme 30. Facial selectivity with chiral auxiliaries is also seen here, as in the case of the Aldol reaction.49
3 R3 R3 R H OH O H H 2 M M R R2 O R2 O O O O R1 OM R1 R3 R1 R1 H H H R2
197 198 199
3 3 R3 R R OH O H H H M M H H O H O O 1 3 O O R1 OM R R 1 1 2 R R R 2 R2 R2 R
200 201 202
Figure 16: Zimmerman Traxler model of the Aldol reaction with Lewis acid additives to give cyclic TS
By the late 1990s, organocatalysis became trending in synthetic chemistry. This mode of catalysis offers a range of versatility by allowing the catalyst to bond covalently to the compound and using the sterics and electronics within the molecule to increase selectivity. As shown in the transition state model from Hajos, this proceeds rather more tightly than most metal mediated catalysis.35 In fact, the organocatalyst performs multiple tasks such as shown in the Hajos model. Proline uses its nitrogen atom to interact with the electrophile
38 and to hydrogen bond to the adjacent carboxylic acid. These catalysts began to invoke multiple functionalities as they evolved rendering them more useful as their synthetic scopes widened. Barbas and List, using L-proline as the organocatalyst, independently developed intermolecular variants in these addition reactions.50,51 Their mechanism for the aldol addition involved the appropriate enamine formation coupled with hydrogen bonding of the carboxylic acid to the incoming aldehyde (Scheme 31). The aldehyde is held such that the addition to the re-face is favored in the formation of the β-hydroxycarbonyl compound. Houk and Blackmond performed computational and kinetic studies respectively to support the proline catalyzed aldol reaction.52,53 Crystallographic data of proline derived enamines of vinylogous amides has also been obtained by List and is consistent with the transition state models proposed by Seebach and Eschenmoser.54 This gives insight into how the organocatalytic mechanism functions in other major reactions. The emphasis on the dual capabilites of proline initiated another resurrection to the area of organocatalysis and has expanded extensively to other carbon-carbon bond forming reactions such as the aldol condensation, Michael addition, Morita-Baylis-Hillman reaction, Aza-Henry reaction, and Mannich reaction.35
39 HN N -H2O N N H H H H RCHO O OH O O O HO HO O HO 203 204 205 206 O H R N +H O R N N H R H 2 O H R O OH OH H O OH O O OH O O O H
210 209 208 207
Scheme 31: Accepted mechanism of the proline-catalyzed Aldol reaction
2.3 Asymmetric Allylic Alkylation Asymmetric allylic alkylations (AAA) are another important area of carbon- carbon bond forming reactions that usually involve the use of a transition metal to aid in catalysis.55 Before organocatalysis gained notoriety, organometallic chemistry proved highly effective at preparing target molecules, even with low to moderate enantioselectivities. The allyl system has been investigated in the presence of palladium to provide facial selectivity (Scheme 32). The complex shields one side of the allyl system, which allows the nucleophile to approach from the opposite side. The π-allylpalladium species is active towards stabilized nucleophiles such as active methylenes, enolates, and phenols.
40 OAc Anion PdCl Anion 2 ∗∗ R R Ligand R R
211 212
Cl Pd 2 C2H5O2C CO2C2H5
PdCl2 PPh3
OAc NaCH(CO2C2H5)2
213 214 215
Scheme 32: AAA forming a π-allylpalladium complex reacting with a stabilized nucleophile
The mechanism (Scheme 33) proceeds through oxidative addition of palladium to the allylic acetate to give a η-3-π-allyl complex, which undergoes nucleophilic attack followed by reductive elimination to yield the final product.
41 R R' R R' * or * Nu Nu
222 223 L L R X Pd
decomplexation R'
L L 216 L Pd Pd L complexation R R' R R' * or * L Nu Nu L Pd 220 221 218 R X
L L ' nucleophilic Pd 217 R addition R R'
Nu ionization
L L Pd R X R'
219
Scheme 33: Organometallic mechanism of oxidative addtion and reductive elimination of the π-allylpalladium complex as in electrophile
Bis-π-allylpalladium complexes have been studied and found to reverse the electrophilic activity of the complex and allowing it to act as a nucleophile.56
This catalytic mechanism (Scheme 34) follows coordination of the electrophile with the π-allylpalladium complex followed by nucleophilic addition of the allyl group and transmetalltion to give the final product.
42 Pd O Ph3P R R R H 224 OH OSnBu3
228 227
SnBu 3 Pd O
R H 225 Pd O
R 226
Scheme 34: Organometallic mechanism for the bis-pi-allylpalladium system utilized as a nucleophile
π-allylpalladium species have thus been extensively useful in the syntheses of many biological targets and natural products.57 This newer tactic allowed for an alternative set of conditions so that organometallic catalysis could compete with the emerging organocatalytic methods being invoked at the time.
Although this catalytic process has many possible enantiodiscriminating mechanisms, it had the advantage in that it allowed for the formation of a variety of different bond types.58 Most notably, allylic alkylations were established as a well-known way of forming carbon-carbon bonds, but the lack of stereocontrol plagued organic chemists in the syntheses of enantiopure materials. Since the late 1970s, these reactions were altered by varying transition metals, changing the active organometallic reagents, changing methods of activation, and by
43 designing new ligands to provide stereoselectivity.59 It was during this period that the allyl moiety could be manipulated and used as a nucleophile to react with strong electrophiles (carbonyl related compounds) to form homoallylic alcohols or some related species stereoselectively (Scheme 35).
H OH MLn RCHO Anti MLn O R R
229 230 231
H OH MLn RCHO Syn O MLn R R
232 233 234
Scheme 35: Basic AAA in in the proposed Zimmerman-Traxler TS, chelated with an organometallic reagent
The synthetic utility of these reactions is shown by the regiospecificity of the allyl group to give exclusive carbon-carbon bond forming at the terminal carbon of the allylating agent. These compounds are locked and stabilized in a chair-like TS to allow for regiospecificity. The orientation of the incoming electrophile is significant and enters with the R group adopting a psuedoequatorial position of the cyclic transition state. Organometallic reagents such as boron, tin and silicon, follow similar chemistry where valency is
44 expanded when bound to the electrophile. With all of the substrates locked into place, diastereoselectivity is based on configuration of the alkene (cis/trans).
2.4 Hosomi-Sakurai Reaction Hosomi and Sakurai developed a method of performing the asymmetric allylic alkylation shown in Scheme 36. This pioneering reaction used allyltrimethylsilane in the presence of an electrophile, usually an aldehyde or ketone, activated by a Lewis acid.60 The reaction involves activation of the carbonyl followed by nucleophilic attack of the allylsilane in a stepwise acyclic manner. The allylsilane is a soft nucleophile and reacts with strong electrophiles.
This was practical in the syntheses of homoallylic alcohols but has been extending to generate many other products including homoallylic ethers, homoallylic amines, and γ, δ-unsaturated carbonyl compounds.61
OH TiCl4 Si ∗∗ O R H R 235 236
O TiCl4 Si O R R 235 237
Scheme 36: Hosomi-Sakurai reaction
The reactions gave moderate to good yields but stereochemistry of the final products is not consistent with the closed transition state model because
45 there is no evidence of a bond with the carbonyl oxygen and the silicon atom in the same vicinity. This poses an issue and gives low asymmetric induction by following an acyclic transition state. The reaction does show high diastereoselectivity and can be thoroughly explained using the Felkin-Ahn model shown in Figure 17.
Anti-periplanar
LA LA LA LA O O O O H CH3 H3C H H3C H H CH3 R H H R R H H R
SiR3 SiR3 SiR3 SiR3
Syn Anti
Synclinal
SiR3 SiR3 SiR3 SiR3 LA LA LA LA O O O O H H3C H H3C H R R H R H H R CH3 H CH3 H
Syn Anti
Figure 17: Acyclic TS model explaining the diastereoselectivity of the Hosomi-Sakurai reaction
Hosomi and Sakurai then synthesized pentacoordinate allylsilicates from allyltrialkoxysilane, catechol, and triethylamine to perform the allylation regioselectively (Scheme 37).62 The transition state follows the Zimmerman-
Traxler model when the electrophile coordinates to the silicon to generate a
46 hexacoordinate silicon species (Figure 18). The electrophile enters with the smaller group adopting a psuedoaxial position of the transition state and then allylation proceeds due to the increased Lewis acidity of the complex.
R' O OH R'' Catechol ∗∗ R' Si(OR) R' Si R''CHO 3 H NEt3 O HNEt3 2 R' R' R'
238 239 240
Scheme 37: Pentacoordinate silicates used in the Hosomi-Sakurai reaction
O H O Si O O O Ph
241
Figure 18: TS showing the stereoselectivity of the hexacoordinate silicon in the Zimmerman-Traxler model
Another ingenious way of increasing the Lewis acidity of silicon is through the relief of ring strain by changing the geometry about the silicon atom.63 Myers figured that since the bond angles of the silacyclobutanes were forced to be 90° degrees instead of the usual ~109° for a tetrahedron that their reactivity would increase due to ring strain. This strain is then relieved through coordination of
47 the electrophile to form the trigonal bipyramidal geometry. By virtue of relieving ring strain, the incoming electrophile is limited to where it can enter and bind with the silane shown in Figure 19. The ring cannot be physically maintained if it were to occupy two equatorial (120°) or two axial (180°) positions because these angles would not accommodate the four-membered ring.
L Si Si L R H R O
R' 2 sp3 sp p
~ 90 90
Highly strained Relaxed
Figure 19: Coordination of incoming electrophile to alleviate ring strain of the silacyclobutane
The use of silacyles then began gaining popularity and chemists like
Leighton wanted to focus on increasing the Lewis acidity of silicon-based catalysts that exhibited high enantioselectivity. He investigated 5-membered ring silacycles derived from diols, amino alcohols, and diamines.64 He used pseudoephedrine as a starting point because it was relatively inexpensive for both enantiomers and the silacycle was synthesized under mild conditions. The pseudoephedrine silacycle was able to catalyze the reaction with aldehydes in good yields and good enantioselectivities shown in Scheme 38.
48 Ph OH O OH Ph Si NEt3 RCHO + Cl3Si Cl N CH2Cl2 Tol R NH -10ºC
88% 2:1 dr 242 243 244 245
Entry Aldehyde Product Yield (%) ee (%)
O OH 80 81 Ph 245a Ph H
O OH 245b 59 78 Ph H Ph
O OH 245c Ph H Ph 84 88
Scheme 38: Pseudoephedrine silacycle formation and allylation of various aldehydes
To understand the mechanism, it is important to analyze the transition states and deduce how reactivity must occur. The first thing to note is that in order to relieve ring strain, the incoming aldehyde must come in and force either the nitrogen or oxygen in the silacycle into the axial position. This way, the ring will have the appropriate bond angle to allow the ring to coexist happily and relieve strain. For each diastereomer, there exist two sites where the aldehyde
49 can enter the system so the least sterically hindered chair transition state will give the major products shown in Scheme 39.
Ph
O Cl Si N O H
R
Cl 246a O H OH Ph Si
N HO R R H H
H 245 244a O R O Cl Si Ph N
246b
Ph
O
Si N Cl O H
R H OH O Ph Si 246c H Cl H R N H
HO R 245 O R 244b O Si Ph Cl N
246d
Scheme 39: Mechanism of the pseudoephedrine catalyzed AAA
2.5 Boron Hydride Donor Reagents Most reductions of carbonyl containing compounds with hydrides are derived from boron and aluminum.65 Lithium aluminum hydride is a strong
50 reducing agent that reacts with a variety of carbonyl containing compounds.
Sodium borohydride is a mild reducing agent that reacts rapidly with acid chlorides, aldehydes, and ketones, but other carboxylic acid derivatives react much slower rate or not at all. The advantage of being less reactivity allows solvent molecules to play a role in the mechanism in the reaction. The mechanism in Scheme 40 describes the course of the reaction through coordination of the metal to the cabonyl followed by a four membered ring transition state to transfer the hydride and form the aluminum-oxygen or boron- oxygen bond. Their difference in the two reducting agents lie in the Lewis acidity of the metals in that lithium is a stronger Lewis acid than sodium and aluminum hydride is a better donor than borohyrdide.
M H M H O H B O R H B R H H H R H R
247 248
M H M H O H Al O R H Al R H H H R H R
249 250
Scheme 40: Mechanism of borohydride and aluminum hydride reductions
51 There have been modifications of borohydride reagents to aid in chemoselectivity including the substitution of one hydride with a strongly electron withdrawing cyano substituent to reduce the nucleophilicity of the other hydrides and only react towards iminium groups.66 Other modifications involve substituting hydrides with other electron donating groups and also steric bulk to favor facial selectivity. Evans developed a stereoselective triacetoxyborohydride to favor the formation of anti 1,3-diols by chelating the borate with β-hydroxy ketones (Scheme 41).
OAc OH O O OH OH [BH(OAc) ]- B 3 OAc R O 1 H R1 R2 R1 R2 R2
251 252 253
Scheme 41: Chelation control with triacetoxyborohydride with β-hydroxy ketones
Acyclic stereoselection is predicted based on the Felkin model of the transition state (Figure 20) where the substituent on the adjacent carbon dictates the stereochemical outcome. Stereoelectronic effects involve the interaction between the HOMO of the hydride and the LUMO of the carbonyl. Steric effects are minimized by approaching the side away from the largest substituent. Cyclic stereoselection is predicted on minimizing diaxial interactions from the approach of the nucleophile. These effects are seen in the selectride series (Scheme 42) where existing centers dictate formation of the new center.67
52 H preferred direction H M S of approach M S O R HO R L L
S, M, L = relative size of substituents
Figure 20: Felkin model for the reduction of carbonyl compounds
H H H H OH H O H H H OH H
LiAlH4, Et2, 0 °C 90 10
NaBH4, i-PrOH, 0 °C 85 15
Li s-Bu3BH 7 93
Scheme 42: The Selectride series increase steric demand and give different facial selectivity compared to borohydride
Boranes are neutral boron species that can also transfer hydrides but differ from the borohydrides in that they are electrophilic due to their empty p-orbital and therefore are Lewis acidic rendering them highly reactive. The mechanism slightly varies in that a hydride is transferred intramolecularly from the Lewis acid-base adduct (Scheme 43). Diborane is particularly useful because it is complimentary to lithium aluminum hydride by reducing the lower reactive carboxylic acid derivatives (carboxylic acids, nitriles, amides) easier than the more reactive (acid chlorides and anhydrides). 53 O O MR2 O MR2
R C H R2MH + H R R R R R
256 257 258 259
Scheme 43: Diborane reduction mechanism
Enantioselective reduction of unsymmetrical ketones with chiral boranes is a huge area of interest following previous work seeing high selectivity in using chloroboranes (Scheme 44).68 In these reactions, the hydride is transferred from the organic portion of the chloroborane, thus making an alkene and the alcohol.
High selectivities were achieved but at the cost of using often more than a stoichiometric amount of borane.
O CO2CH3 OH CO2CH3 (Ipc)2BCl Cl N Cl N
87% yield 99.5% e.e. on 260 261 2.75 scale
Scheme 44: Enantioselective reduction of ketones with chloroboranes
A more efficient approach to the problem utilizes an oxazaborolidine derived from proline that generates a Lewis acid-base complex in the presence of excess borane (Scheme 45).
54 Ph Ph BH3 N N Ph H B Ph BO 3 BO
262 263
Scheme 45: Catalytic enantioselective reduction of ketones with oxazaborolidines
The pyrrolidine core as a chiral auxiliary is employed again in another organocatalytic sequence to coordinate borane and transfer a hydride to the carbonyl, which is then allowed to regenerate the active species upon coordination to another borane species (Scheme 46).
H O Ph OBH2
R1 N R1 R2 H B Ph R2 3 BO
266
263
BH3
Ph Ph
N N R H Ph 1 H B Ph H2B 3 BO BO R1 O O R R2 2
264 265
Scheme 46: Catalytic cycle of of reduction with oxazaborolidine
55 The evolution of organocatalysis starting with proline has made huge advances in chemistry by synthesizing targets once thought impossible. The catalysts have become multifaceted by combining several modes of activation by including nucleophilic and electrophilic components to achieve high levels of asymmetry within a molecule. Another goal of this dissertation is to continue the syntheses of silacycles and boracycles for nucleophilic asymmetric allylic alklations and enantioselective reductions of unsymmetric ketones. The scope is to provide increased enantioselectivities by utilizing a chiral auxiliary to shield the electrophile and direct nucleophilic attack.
56 CHAPTER III
SYNTHESES OF 3-PYRROLINES AND DERIVATIVES
3.1 Direct Addition of Amino Ester to Ditosyl Acetonide The pyrrolidine nucleus was derived from various amino acids ranging from nonpolar, polar uncharged, and polar charged. They also range in size from being small (hydrogen) or large (tryptophan) as these physical features may be important in biological or catalytic processes. Construction of the pyrrolidine ring began with the transformation of the amino acids into their respective methyl esters shown in Table 1.
57 Table 1: Amino acid methyl ester synthesis with acetyl chloride/methanol
O O CH COCl, MeOH R 3 R OH 0 °C - reflux, 16 h OMe
NH2 NH3Cl
267a-d 268a-d
Entry R Yield (%)
268a H 60
268b CH(CH3)2 50
268c CH2CH(CH3)2 62
268d CH2Ph 80
The standard conditions for making methyl esters can be rather harsh and are not convenient when other functional groups are present as they may lead to undesireable side products. An alternative approach to the methyl ester synthesis (Table 2) involves chlorotrimethylsilane in methanol at room temperature.69 These mild conditions produce comparable yields for the amino esters.
58 Table 2: Amino acid methyl ester synthesis with chlorotrimethylsilane/methanol
O O TMSCl R R OH MeOH, rt OMe
NH2 NH3Cl 267a-j 268a-j
Entry R Yield (%)
268a H 66
268b CH(CH3)2 80
268c CH2CH(CH3)2 83
268d CH2Ph 84
268e OH 67
268f SH 90
268g (CH2)4NH3Cl 78
268h ArOH 93
268i (CH2)2SCH3 93 268j 91 N H
One route to the pyrrolidine core involved the direct addition of the amino acid methyl ester with a suitable protected diol shown in Scheme 47. The 1,4- ditosyl-2,3-acetonide adapted from Machida was synthesized in five steps shown in scheme.70
59 HO OH BzCl BzO OBz OsO4, Me3NO BzO OBz 2,2-DMP acetone CH2Cl2, Et3N acetone, TsOH 0 °C - rt HO OH
269 270 271
TsCl, Et N, DMAP Na, MeOH TsO OTs 3 HO OH BzO OBz CH2Cl2, 0 °C - rt
O O O O O O
272
274 273
Scheme 47: Synthesis of 1,4-ditosyl-2,3-acetonide
This approach was designed in an effort to minimize competing reactions by directly allowing the nucleophile and electrophile to interact and provide the desired syn relationship in the 3,4-positions. However, this method failed to give the desired product when the amino acid was introduced (Scheme 48).
O C R O MeO
Cl NH3 R OMe 268a-d N TsO OTs CH2Cl2, Et3N
O O O O
274 275a-d
Scheme 48: Direct addition of amino ester to 1,4-ditosyl-2,3-acetonide failed to give the desired pyrrolidine acetonide
60 Steric hinderance is a viable explanation as for why the reaction will not take place shown in Figure 21. The acetonide occupies one face of the electrophile and the distosylates, with free rotation, possibly occupy the other face to minimize interactions.
R O
H2N OTs OTs OMe H H H H H OTs H OTs H H O H O H O H O H
H2N R MeO
O
Figure 21: The orientation of the ditosylates farthest away from the acetonide posing an issue with nucleophilic attack of bulky nucleophile
The reaction was attempted using the mesylate in order to see if the same orientation is adopted as in the ditosylates, but the side reaction (Scheme 49) prevents the possibility of nucleophilic attack by the amino ester.
61 H H
O O OMs HO OH MsO MsCl, Et3N
CH2Cl2, 0 °C OO OO OO
273 276 277
Scheme 49: Tetrahydrofuran ring formation due to the proximity of one hydroxyl to the mesylate
3.2 Alkene Metathesis of N,N-Diallylamino Ester Alkene metathesis was explored following procedures by Yu, converting the amino esters into the N, N’-diallyl amino esters and using various Grubbs’ reagents shown in Scheme 50.71 This would generate the intermediate 3- pyrroline, which could be further transformed into the pyrrolidine core through addition, oxidation, or reduction of the pi bond. The results from these experiments never afforded the desired pyrrolines as reported in the literature.
This could potentially be due to deallylation of the amine via Grubbs’ catalyst.72
62 O O O R Br cat. I or II (5 mol%) OMe R R Ti(OiPr)4 (20 mol%) N OMe OMe NaHCO3, MeCN CH2Cl2, 40 °C NH3Cl 70 °C N
275d 278d 275d
Mes N N Mes PCyc3 Ph Ph Cl Cl Ru Ru Cl Cl PCyc3 PCyc3
I II
Scheme 50: Alkene metathesis to cyclize the diallylamino ester to give the 3-pyrroline
3.3 Direct Addition of Dihaloalkene The puzzling results from alkene metathesis forced the approach of the pyrroline ring synthesis from a different direction. Pericas, et. al was developing new heterocycles to be used in the Pauson-Khand reaction and decided upon the amino acid derived pyrrolines with similar reasoning.73 There were not many investigations into the syntheses of amino acid derived pyrrolines other than the methods explored by Yu utilizing alkene metathesis. Percias simplified the issue by directly taking the amino ester in the presence of a dihaloalkene to generate the pyrroline as shown in Table 3.
63 Table 3: Direct addition of amino ester and dihaloalkene to form 3-pyrroline
O O R R OR' OR' NH3Cl SOCl2 N HO OH Cl Cl CHCl3, pyr CH2Cl2, rt, 24 h 0 °C - rt
269 133
Entry R R' Yield (%)
52 279a CH3 Et
279b CH(CH3)2 Et 52
275c CH2CH(CH3)2 Me 84
275d CH2Ph Me 65
280a Ph Me 65
280b Me 76
N H
This reaction uses excess amino acid so that no additional base was necessary. The extra amino acid would then be filtered and recycled. The advantage of the direct addition method provides minimal steps towards construction of the 5-membered ring but the disadvantage involves the aforementioned oxidation of the 3-pyrroline ring formed over time. Reproducing these results of the direct addition for the 3-pyrroline was a complicated task at room temperature and when using conventional heating, therefore, Lineberry and
Taschner attempted the synthesis within a microwave reactor shown in Scheme
51. Microwave Assisted Organic Synthesis (MAOS) has increased since the
1990s because early experiments in domestic ovens proved to reduce reaction times, reduce side reactions, increase yields, and improve reproducibility.74
64 Traditional heating in comparison is slow and inefficient because of the thermal conductivity of the reaction vessel transferring energy into the system. The microwave vessel is made of borosilicate glass, which is microwave transparent.
This phenomenon is largely based on dielectric heating, which is dependent on the materials’ ability to absorb microwave energy and convert it to heat and describes the ability of molecules to be polarized. A solvent’s dielectric constant can be explained through dipolar polarization meaning that irradiation of a sample at microwave frequencies results in the dipoles aligning with the applied field. As the field oscillates, the dipoles realign and energy is lost in the form of heat. Microwave effects are still under much debate but these factors contribute to the explanation of reactivity. This methodology has provided the desired 3- pyrrolines, but the drawbacks of this route included the limited loading capacity within the microwave reactor and much lower yields upon purification (<10%) with increased oxidation byproducts.
O R O Cl Cl OMe R N
OMe Na2CO3, H2O MW, 80 W, 120 °C NH3 Cl
268a-d 275a-d
Scheme 51: Microwave-assisted direct addition of amino ester and dihaloalkene to form 3-pyrrolines
65 Another direct attempt in improving the syntheses of the pyrrolines attempted to utilize the more electrophilic reagent, 1,4-dibromo-2-butene, to allow the reaction to more readily occur at ambient temperatures. However, the dibromoalkene was never isolated possibly because of the proximity of the allylic alcohol to the allylic halide, cyclizing to generate the tetrahydrofuran species
(Scheme 48) similar to the dimesylate side reaction shown in Scheme 52.
Ph3PBr2 HO OH Br Br CH2Cl2, 0 °C
269 123
H H Br Ph3PBr2 O O O HO OH Br CH2Cl2, 0 °C
269 281 282 283
Scheme 52: Attempted synthesis of cis-1,4-dibromo--2-butene
This methodology was further explored in various solvents, with different bases, and varying concentrations and temperature. The optimal conditions used 1 equivalent of amino acid methyl ester hydrochloride, 1 equivalent of the cis-1,4-dichloro-2-butene , and four equivalents of sodium carbonate in refluxing acetonitrile over a period of 4 hours (Table 4). This provided the amino acid pyrrolines relatively pure and in good yields. If signs of pyrroline oxidation occurred, then column chromatography on silica afforded the desired pure product. Due to the increase in polarity of the amino acid side chains, the
66 nonpolar amino acid side chains (Val, Leu, Phe) were chosen to prevent other side reactions from occurring as well as maintaining an adequate solubility for ease of isolation in organic solvents. Preliminary data supports the formation of other amino acid 3-pyrrolines but the conditions need to be further optimized to gain access to the pure compounds.
Table 4: Syntheses of amino acid methyl ester pyrrolines via direct addition to a dihaloalkene in the presence of sodium carbonate in refluxing acetonitrile
O
R O Cl Cl OMe R N OMe Na2CO3, MeCN reflux, 4 h
NH3 Cl
268b-d 275b-d
Entry R Yield (%)
275b CH(CH3)2 66
275c CH2CH(CH3)2 57
60 275d CH2Ph
3.4 Mosher Ester Analysis Racemization is the conversion of one enantiomer of a compound to the other enantiomer by adjusting the solvent media, adjusting the temperature, and adjusting the pH. Enantiomers share similar physical and chemical properties but can be distinguished based on their optical rotations with limitations. The 67 placement of the amino acid side chain is crucial in the functionality of the chiral auxiliary to achieve high enantioselectivities. If the stereocenter racemizes, it would provide no selectivity. One method for detecting racemization is through introduction of an additional stereocenter. If the center has racemized, then this would generate a mixture of diastereomers, which have different chemical and physical properties. This is done through the syntheses of Mosher’s esters derived from primary, secondary, or tertiary alcohols and α-methoxy-α- trifluoromethylphenylacetic acid (Mosher’s acid) then analyzing their NMR
(Scheme 53).
Ph OCH3 Ph OCH3 R1 R1 2 OH HO 2 O R EDC, DMAP, CH2Cl2 R + CF3 CF3
H O H O
284 285 286 (R, S)
Ph OCH3 Ph OCH3 R2 R2 1 OH HO 1 O R EDC, DMAP, CH2Cl2 R + CF3 CF3
H O H O
284 287 288 (S, S)
•HCl Cl N EDC = N C N N N N H
Scheme 53: Chiral derivitizing agents to deduce chemical racemization
68 The Mosher esters of L-lecuine-3-pyrroline were synthesized by first performing a lithium aluminum hydride reduction of the ester to give the primary alcohol, which was subsequently reacted with each Mosher acid (Scheme 54).
By analyzing the 1H-NMR, one of the methylene protons adjacent to the oxygen of the ester resonates at 4.26 ppm for the S,S diastereomer and at 4.32 ppm for the S,R diastereomer (Figure 22). If the stereocenter were to racemize, then each diastereomer would be seen in each spectra, i.e. a peak at 4.26 ppm would be seen in the S,R spectrum and a peak at 4.32 ppm would be seen in the S,S spectrum. This evidence concludes that racemization has not occurred.
O O CF HO 3 CF3 O H3CO Ph Ph N H3CO
O
LiAlH EDC, DMAP, CH2Cl2 OMe 4 OH 290 ether, 0 °C - rt N N O
CF3 O OCH 275c 289 O N Ph 3 CF HO 3 Ph OCH3
291
Scheme 54: Syntheses of the Mosher esters from the Leucine-3-pyrroline
69 Figure 22: 1H-NMR analyzing both Mosher esters of the reduced Leucine- 3-pyrroline
3.5 Syntheses of TA analogues There are many synthetic routes to the tropane core, most notably the one pot synthesis by Robinson. Compounds of similar structure to the TAs have been synthesized in effort to also elicit biological responses of the natural alkaloids. Nortropanes, for example, are analogous to TAs with the difference lying in substitution of the methyl group upon the nitrogen atom. The amino acid
3-pyrroline provides a solid foundation in an effort to model the bicyclic structure of the TAs via intramolecular cyclization (Figure 23).
70 R
O MeN N O I N O R O I O
30 292 293
Figure 23: Amino acid derived TA mimics from 3-pyrrolines
Iodolactonization of the 3-pyrroline carboxylate shown in the retrosynthetic analysis in Scheme 55 offers a valid route to these structures.75
O
R R O O N O N I N R O I O
292 293 294
Scheme 55: Retrosynthesis of TA analog
Ester hydrolysis of the 3-pyrroline provides the carboxylate needed to form the iodolactone. This approach was adopted from Cinquin in his syntheses of many PHP derivatives. The required intermediate is a 3-pyrroline that undergoes iodolactonization to give the Geissman-Waiss lactone (Scheme 56).76 This lactone was developed as a convenient method to generate the bicyclic ring
71 structure with a nitrogen atom at the juncture for the necine family of pyrrolizidine alkaloids.77
I O O O
CN CH Cl , H SO Bu SnH 2 2 2 4 NH2 I2, THF, H2O 3 N 50 °C, 20 h N N benzene, AIBN
Ac Ac Ac
295 296 297
O O O O
6 N HCl N N H •HCl Ac
299 298
Scheme 56: Synthesis of the Geissman-Waiss lactone from an N-acetyl- 3-pyrroline derivative
The difference in the lactonization methods lie in the size of the ring generated, where 5-membered rings are often more favorable and form at a rate faster than the corresponding 6-membered rings.78 Ring closure of the desired amino acid pyrroline system (Scheme 57) should follow a favorable exo-tet cyclization to give a [3.2.1] bicyclo system versus the [3.2.0] bicyclo system of the Geissman-Waiss lactone.
72 O O R R R OMe O O + N N NaOH, THF, H2O N I2, Aq. NaHCO3, THF O I N reflux R O I O
275b-d 294b-d 292b-d 293b-d
Scheme 57: Synthesis of TAs via iodolactonization
Preliminary results did not show cyclization so another attempt involved cyclizing via iodoetherification, utilizing a hydroxyl in place of the carboxylic acid as the nucleophile shown in Scheme 58. Preliminary proton NMR data supports the transformation of the vinyl protons to two separate methine protons adjacent to two electronegative atoms. The concept of cyclizing the 3-pyrroline scaffold to gain access to TA analogues is a project in its early stages and needs further development.
73 R R OH O LiAlH4 I2, NaHCO3 + N O O ether, 0 °C - rt N Et2O/H2O (5:2) I N R R I OMe 289b-d 300b-d 301b-d N
Ph Ph R R PhMgBr O Ph N Ph 275b-d OH + O ether, 0 °C - reflux I N N R I Ph Ph
302b-d 303b-d 304b-d
Scheme 58: Iodoetherification of amino acid derived 3-pyrroline alcohols
3.6 Syntheses of PHP analogues The amino acid 3-pyrroline allows for further manipulation because of the alkene and ester moieties present within the molecule. Both functional groups provide a simple one step transformation to an alcohol to generate PHP mimics.
Lithium aluminum hydride reduction of the ester portion was seen previously to give the 3-pyrroline alcohol (Scheme 54). The alkene portion of the molecule was oxidized at the 3,4-positions to give a pyrrolidine diol species shown in scheme 58. This diol represents a simple PHP similar to the glycosidase inhibitors presented earlier (Figure 13). The combination of both the oxidation of the alkene and reduction of the ester provided the pyrrolidine triols found in
Scheme 59. This methodology provides a synthetically easy route to produce many different PHPs by altering the R group of the initial amino acids. Further modification of the PHPs could be afforded by performing alternative additions to
74 the ester versus lithium aluminum hydride to add more complexity into each PHP
(Scheme 58).
R OH Entry R Yield (%) N 306d CH2Ph 24 LiAlH O O 4 ether, 0 °C - rt R R HO OH OMe OMe 306b-d N K3Fe(CN)6, K2CO3, OsO4 N
t-BuOH/H2O
Ph Ph HO OH PhMgBr R OH 275b-d 305b-d ether, 0 °C - reflux N
Entry R Yield (%)
305b 36 CH(CH3)2 HO OH
305c CH2CH(CH3)2 28 307b-d
305d CH2Ph 67
Scheme 59: Syntheses of PHP analogs from amino ester 3-pyrrolines
3.7 Syntheses of Silacycles The two generations of silacyles synthesized were based on the compounds generated from the PHP analogues shown in Scheme 58. The goal of these compounds was to selectively form carbon-carbon bonds in the syntheses of homoallylic alcohols. The first generation silacycle (Figure 24) was synthesized to determine the plausibility of the chemistry and to closely mimic the pioneering work of Leighton with his pseudoephedrine silacycle by using the amino ester pyrroldine diol. Similarities include a 5-membered ring silacycle, three strong Lewis bases bound to the silane, and some level of asymmetric induction in the catalyst. The second generation is thought to increase selectivity
75 by replacing the chlorine on the silane with another alkoxy group. The idea is that the chiral side chain will help shield one of the two available places where the aldehyde can enter and bind the silane.
R' R' O O R O O Si Si N N O Cl O R O
308b-d 309b-d
O R' R'
R OMe R O Si O
N N O
O
O Si
Cl
I Generation II Generation
Figure 24: First and second generation silacycle derived from amino ester 3-pyrrolines
Asymmetric induction using homogenous catalysts with chiral C2- symmetric ligands is a popular method in synthesis and has evolved to utilizing pyrrolidine rings.79 The aforementioned silacycles provides an example of a system with a meso framework catalyzing the formation of new carbon-carbon bonds. The first generation was attempted using phenyalanine pyrrolidine diol in the presence of allyltrichlorosilane and triethylamine (Scheme 60). 1H-NMR data 76 show several broad resonances, which can be indicative of diastereomers formed from the resulting silylation. The purpose of this first generation catalyst was to serve as a proof of concept to mimic Leighton’s pseudoephedrine silacycle and gain insight into the plausibility of this chemistry. This silacycle was then added to a solution containing benzaldehyde in chloroform at an attempt to selectively synthesize 1-phenylbutanol but only starting material was recovered upon reaction workup. The phenylalanine pyrrolidine triol was also reacted with allyltrichlorosilane and triethylamine to give the corresponding second-generation silacycle (Scheme 59). This was also subjected to reaction with benzaldehyde in chloroform to attempt the synthesis of 1-phenylbutanol and afforded similar results where starting material was obtained. The reaction conditions need to be optimized to ensure formation of the silacycle then investigations into catalysis can be further explored.
O O
Bn Bn Bn O OMe OMe OH Bn SiCl3 SiCl3 LiAlH Si N N 4 N N ether, 0 °C - rt CHCl3, Et3N, 0 °C CHCl3, Et3N, 0 °C O O
O O HO OH HO OH Si Cl
308d 305d 306d 309d
Scheme 60: Syntheses of amino acid derived silacycles from allyltrichlorosilane and pyrrolidine diol/triol
77 3.8 Syntheses of Boracycles The amino acid derived pyrrolidine triol series could provide a useful catalyst in the transformation of unsymmetric ketones to alcohols with a high level of selectivity similar to what has been shown in the oxazaborolidine catalysts.
Formation of the trialkoxyborane provides selectivity by directing the coordination of borane to the nitrogen of the pyrrolidine and carbonyl to the trialkoxyborane on the side away from the side chain from the parent amino acid. Phenylalanine pyrrolidine triol was added to a solution containing THF and borane dimethyl sulfide to generate the active boracycle in situ (Scheme 61).
Bn O OH Bn
N BH3•SMe2 B N + BH3 THF, 0 °C O O
HO OH
306d 310
O O H Ph Bn BH3 CH3 B N Ph CH3 H2BO O O 314 311 BH3
H Ph O Ph Bn CH3 O CH3 BH2 B O Bn N BH3 B O N O O O O
313 312
Scheme 61: Synthesis and reactivity of possible boracycle for the catalytic enantioselective reduction of prochiral ketones
78 Acetophenone was then added to selectively give 1-phenylethanol, where
NMR data supports the transformation of the carbonyl to the corresponding alcohol. The next step involved the syntheses of the Mosher esters to determine the absolute configuration of the newly formed stereocenter (Scheme 62). A crude analysis of the unpurified products shows resonances with similar intensities of both respective diastereomers within each others spectrum, indicating a racemic mixture was formed upon reduction.
O CF3 HO O H3CO Ph CF3 O Ph OH H3CO
EDC, DMAP, CH2Cl2 316
315 O O CF CF3 HO 3 O Ph OCH3 Ph OCH3
317
Scheme 62: Mosher ester analysis of 1-phenylethanol
79 CHAPTER IV
CONCLUSIONS
The pyrrolidine core has been extensively studied and proven to be useful in natural product synthesis, biomimicry, and catalysis. This dissertation has thoroughly explained novel synthetic approaches to this core through transformation of various amino acid derived 3-pyrroline species. The L-amino acid methyl esters highlighted in this disseration focused on the nonpolar side chains (mainly Val, Leu, and Phe). The 3-pyrrolines were synthesized via the direct halogenation of the L-amino acid methyl ester hydrochloride with the cis-
1,4-dichloro-2-butene. Enantiopurity was determined after cyclization by making the Mosher ester with the corresponding reduced L-Leucine-3-pyrroline.
The syntheses of the amino acid derived TA analogs from 3-pyrrolines provide an interesting new type of molecule to be investigated within biological systems. Given the proximity of the ester or hydroxyl in relation to the alkene in these systems should allow for the formation of a halolactone/ether to generate a
[3.2.1] bicyclic structure common to the TAs. 3-pyrrolines also provide a trivial route to the syntheses of functionalized PHPs. Osmylation of the amino ester 3- pyrrolines yield the corresponding pyrrolidine diol and upon ester reduction 80 provides a pyrrolidine triol. These pyrrolines also provided the means to represent a new organocatalyst for the Hosomi-Sakurai reaction to form carbon- carbon bonds in the syntheses of homoallylic alcohols with allylsilanes. The catalyst should function through relieving ring strain within a five-membered silicon ring by changing the geometry from tetrahedral to trigonal bipyramidal by coordinating with the incoming electrophile. The target catalysts were originated from the PHP analogs with allyltrichlorosilane. Another organocatalyst derived from the PHP analogs were a series of boracycles, those mimicking the oxazaborolidines in the enantioselective reduction of prochiral ketones.
Future research resulting from this work includes further includes first optimizing reaction conditions to provide each of the cyclic structures illustrated in this dissertation. Once the scaffold is set, the scope of the methodology can be further explored by utilizing more highly functionalized primary amines to build a library of targets to be studied in biological or catalytic processes. This technique could also provide a framework to the syntheses other alkaloids and natural products as seen with the TAs and PHPs. The 3-pyrroline intermediate may help provide access to complex molecules only seen in nature. Future endeavors into silacycle and boracycle syntheses include further modifications to the catalyst to fully understand the limitations of the reactions. These modifications include adjusting the sterics or electronics to aid in increasing the selectivity of the catalyst. The full scope of the silacycles reactions would then be examined by reacting with other carbonyl containing compounds to generate forming quaternary chiral homoallylic alcohols and chiral homoallylic amines to 81 completely give insight into the chemo-, regio-, and stereoselectively of the
Hosomi-Sakurai reaction. As for the boracycles, developing a selective catalyst for the reduction of carbonyl containing compounds may allow for more mild conditions to be employed in comparison to standard methods. Explorations into other organocatalytic reactions would be the logical next step in the evolution each catalyst.
82 CHAPTER V
EXPERIMENTAL SECTION
5.1 General Experimental Methods
Instrumentation: 1H and 13C-NMR spectra were obtained using on a Varian
Mercury 300 MHz, 400 MHz, or 500 MHz spectrometer, operating at 300 MHz
(1H)/75 MHz (13C), 400 MHz (1H)/100 mHz (13C), or 500 MHz (1H)/125 MHz (13C) respectively. Infrared (IR) spectra were obtained on a Thermo Scientific Nicolet iS5 with iD1 transmission cell and peaks were reported in wavenumbers (cm-1).
Microwave reactions were performed using a Milestone Start microwave reactor.
Melting points were obtained via a MelTemp apparatus, and are uncorrected.
Evaporation of volatiles were performed using a Büchi rotary evaporator under water aspriator pressure (~12 mm Hg).
Materials: Unless otherwise indicated, materials were obtained from commercial suppliers (Fisher Scientific, Sigma-Aldrich, and VWR International), and were used without further purification. Reactions requiring anhydrous conditions were carried out in flame dried or oven dried glassware, with cooling under N2.
83 Methylene chloride (CH2Cl2), toluene, chloroform (CHCl3), acetonitrile (CH3CN), and diethyl ether (Et2O) were dried and deoxygenated by alumina and copper columns in the Pure Solv solvent system (Innovative Technologies, Inc.). Other solvents and anhydrous reagents were dried according to established procedures by distillation from an appropriate drying agent. Methanol (MeOH) and acetone were distilled from anhydrous potassium carbonate prior to use.
Sodium carbonate and potassium carbonate were finely ground and dried in vacuum oven overnight at 120 °C, and stored in a desiccator until needed. Thin layer chromatography was performed on 0.25 mm pre-coated silica gel 60 µm F-
254 nm glass plates (SORBENT Technologies), and was visualized with either
UV irradiation or by use of the reported stain. Column chromatography was performed using silica gel 60 µm, 250-400 mesh (SORBENT Technologies).
5.2 Syntheses of Amino Acid Methyl Ester Hydrochlorides
General synthesis for amino acid methyl ester hydrochloride with acetyl
chloride in methanol
To a flame dried 100 mL round bottom flask equipped with a magnetic stirrer was added methanol (40 mL). The flask was cooled to 0 °C with an ice water bath and acetyl chloride (5.00 mL, 5.52 g, 70.3 mmols) was added slowly via a pressure-equalizing addition funnel at a rate such that the temperature did not exceed 10 °C. After the addition was complete, the amino acid (21 mmols) was added in one portion and slowly brought to reflux over a period of 18 h. The 84 reaction was cooled to room temperature and volatiles were removed under reduced pressure to give an amorphous solid that was recrystallized from acetone to give the amino acid methyl ester hydrochloride.
Valine methyl ester hydrochloride (268b)
Valine used (2.46 g, 21 mmol), 1.76 g isolated (50% yield). MP 168-171 °C. [Lit.
80 1 171-173 °C]. H-NMR (300 MHz, CD3OD) δ 3.93 (d, J = 4.6 Hz, 1H), 3.84 (s,
3H), 2.35-2.23 (m, 1H), 1.06 (dd, J = 7.0, 2.2 Hz, 6H). 13C-NMR (75 MHz,
CD3OD) δ 166.6, 57.4, 51.2, 28.7, 15.9.
Leucine methyl ester hydrochloride (268c)
Leucine used (2.75 g, 21 mmol), 2.37 g isolated (62% yield). MP 150-152 °C.
80 1 [Lit. 151-153 °C]. H-NMR (300 MHz, CDCl3) δ 8.82 (s, 3H), 4.06 (t, J = 5.7
Hz, 1H), 3.79 (s, 3H), 2.03-1.77 (m, 3H), 0.97 (d, J = 6.1 Hz, 1H). 13C-NMR (75
MHz, CDCl3) δ 170.3, 53.1, 51.9, 39.3, 24.8, 22.4, 21.9
Phenylalanine methyl ester hydrochloride (268d)
Phenylalanine used (4.53 g, 21 mmol), 3.62 g isolated (80% yield). MP 157-161
80 1 °C. [Lit. 158-162 °C]. H-NMR (400 MHz, CD3OD) δ 7.57-7.34 (m, 5H), 4.41
(td, J = 6.8, 1.5 Hz, 1H), 3.89-3.84 (m, 3H), 3.41-3.22 (m, 2H). 13C-NMR (100
MHz, CD3OD) δ 171.4, 136.4, 131.5, 131.2, 130.0, 56.2, 54.6, 38.4.
85 General synthesis for amino acid methyl ester hydrochloride with
chlorotrimethylsilane in methanol
To a flame dried 50 mL round bottom flask equipped with a magnetic stirrer was added chlorotrimethylsilane (2.00 mL, 1.71g, 15.8 mmols) and methanol (25 mL).
To this stirred solution was added the amino acid (7.88 mmols) and the solution stirred for 24 hours. Volatiles were removed under reduced pressure to give an amorphous solid that was recrystallized from acetone to give the amino acid methyl ester hydrochloride.
Valine methyl ester hydrochloride (268b)
Valine used (923 mg, 7.88 mmol), 1.06 g isolated (80% yield). MP 169-172 °C.
80 1 [Lit. 171-173 °C]. H-NMR (300 MHz, CD3OD) δ 3.93 (d, J = 4.6 Hz, 1H), 3.84
(s, 3H), 2.35-2.23 (m, 1H), 1.06 (dd, J = 7.0, 2.2 Hz, 6H). 13C-NMR (75 MHz,
CD3OD) δ 166.6, 57.4, 51.2, 28.7, 15.9.
Leucine methyl ester hydrochloride (268c)
Leucine used (1.03 g, 7.88 mmol), 1.19 g isolated (83% yield). MP 150-152 °C.
80 1 [Lit. 151-153 °C]. H-NMR (300 MHz, CDCl3) δ 8.82 (s, 3H), 4.06 (t, J = 5.7
Hz, 1H), 3.79 (s, 3H), 2.03-1.77 (m, 3H), 0.97 (d, J = 6.1 Hz, 1H). 13C-NMR (75
MHz, CDCl3) δ 170.3, 53.1, 51.9, 39.3, 24.8, 22.4, 21.9
Phenylalanine methyl ester hydrochloride (268d)
Phenylalanine used (1.30 g, 7.88 mmol), 1.43 g isolated (84% yield). MP 156-
80 1 158 °C. [Lit. 158-162 °C]. H-NMR (400 MHz, CD3OD) δ 7.57-7.34 (m, 5H), 86 4.41 (td, J = 6.8, 1.5 Hz, 1H), 3.89-3.84 (m, 3H), 3.41-3.22 (m, 2H). 13C-NMR
(100 MHz, CD3OD) δ 171.4, 136.4, 131.5, 131.2, 130.0, 56.2, 54.6, 38.4.
Tyrosine methyl ester hydrochloride (268h)
Tyrosine used (1.43 g, 7.88 mmol), 1.70 g isolated (93% yield). MP dec. 180 °C.
80 1 [Lit. dec. 192 °C]. H-NMR (300 MHz, CD3OD) δ 7.12-7.04 (m, 2H), 6.79-6.75
(m, 2H), 4.24 (dd, J = 7.1, 6.2 Hz, 1H), 3.81 (s, 3H), 3.23-3.03 (m, 2H). 13C-NMR
(75 MHz, CD3OD) δ 173.0, 160.8, 134.3, 128.1, 119.4, 57.9, 56.1, 39.1.
Serine methyl ester hydrochloride (268e)
Serine used (828 mg, 7.88 mmol), 821 mg isolated (67% yield). MP dec. 151 °C.
80 1 [Lit. dec. 163 °C]. H-NMR (300 MHz, CD3OD) δ 4.13 (t, J = 3.9 Hz, 1H), 4.05-
13 3.89 (m, 2H), 3.85 (s, 3H). C-NMR (75 MHz, CD3OD) δ 168.6, 59.3, 54.8, 52.3.
Lysine methyl ester hydrochloride (268g)
Lysine used (1.15 g, 7.88 mmol), 1.43 g isolated (78% yield). MP dec. 192 °C.
81 1 [Lit. 210-212 °C]. H-NMR (300 MHz, CD3OD) δ 4.09 (t, J = 6.5 Hz, 1H), 3.85
(s, 3H), 2.96 (t, J = 7.6 Hz, 2H), 2.07-1.87 (m, 2H), 1.78-1.45 (m, 4H). 13C-NMR
(75 MHz, CD3OD) δ 169.8, 52.1, 38.9, 29.6, 26.7, 21.8.
87 5.3 3-Pyrroline synthesis via direct addition to ditosylacetonide
cis-1,4-Di-O-benzoyl-2-butene-1,4-diol (270) To a flame dried 2-necked 1 L round bottom flask equipped with a mechanical stirrer was added cis-2-butene-1,4-diol (7.50 mL, 8.00 g, 92 mmol), triethylamine
(38 mL, 33.3 g, 276 mmol) and methylene chloride (400 mL). The solution was cooled to 0 °C and benzoyl chloride (32 mL, 38.8 g, 276 mmol) was added via a pressure equalizing addition funnel with vigorous stirring. After addition, the reaction was allowed to slowly warm to room temperature where it continued stirring for a period of 18 h. The reaction was quenched upon the addition of ice and the mixture was washed with water (2 x 100 mL) and brine (2 x 50 mL). The organic layers were combined and dried over anhydrous sodium sulfate.
Volatiles were removed under reduced pressure and the residue was recrystallized from 95% ethanol to give 17.2 g of a solid white product (64%
1 yield). MP 56-58 °C. [Lit. dec. 60-63 °C]. H-NMR (300 MHz, CDCl3) δ 5.02 (d,
J = 4.8 Hz, 4H), 5.97 (t, J = 3.9 Hz, 2H), 7.42-7.60 (m, 8H), 8.05-8.08 (d, 2H).
13 C-NMR (75 MHz, CDCl3) δ 166.5, 133.3, 130.1, 129.8, 128.6, 128.5, 60.7. meso-1,4-Di-O-benzoyl-1,2,3,4-tetrol (271) To a 50 mL 3-necked round bottom flask equipped with a magnetic stirrer was added acetone (12 mL) and t-butanol (2 mL) along with the alkene (1.00 g, 3.38 mmol). To the stirred solution was added trimethylamine-N-oxide (472 mg, 4.25 mmol) followed by a catalytic amount of osmium tetroxide (~40 mg). Caution!
88 This corrosive reagent is a health hazard with an acute toxicity if ingested, inhaled, or encounters contact with the skin. The reaction was monitored via
TLC and upon completion was quenched with sodium dithionite (200 mg, 1.15 mmol) in water (2 mL). The reaction was diluted with ethyl acetate (30 mL) and washed with brine (2 x 10 mL). The organic layer was dried over anhydrous sodium sulfate and volatiles were removed under reduced pressure to give 645 mg (58% yield) of a white, crystalline product without further purification. MP
1 147-152 °C. H-NMR (300 MHz, CD3OD) δ 8.11-8.07 (m, 4H), 7.64-7.58 (m,
2H), 7.50-7.45 (m, 4H), 4.61 (dd, J = 11.6, 2.6 Hz, 2H), 4.48-4.42 (m, 2H), 4.05-
13 3.98 (m, 1H). C-NMR (75 MHz, CD3OD) δ 168.1, 134.1, 131.4, 130.7, 129.5,
71.1, 67.7. meso-1,4-Di-O-benzoyl-2,3-O-isopropylidenebutane-1,2,3,4-tetrol (272) To a 500 mL round bottom flask equipped with a magnetic stirrer was added the diol (3.00 g, 9.09 mmol) dissolved in 150 mL of acetone. To this solution was added 2,2-dimethoxypropane (11.2 mL, 9.47 g, 90.9 mmol) and a catalytic amount of TsOH. The reaction was monitored via TLC. Upon completion, the solution was neutralized with saturated sodium bicarbonate and excess solvent was removed under reduced pressure. The white residue was dissolved in ether
(150 mL) and washed with brine (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and volatiles were removed under reduced pressure to give 3.29 g (98% yield) of a white, fluffy solid without further purification. MP
70 1 105-107 °C. [Lit. dec. 108-109 °C]. H-NMR (300 MHz, CDCl3) δ 8.08-8.03 (m,
4H), 7.59-7.53 (m, 2H), 7.43 (q, J = 7.2 Hz, 4H), 4.62-4.45 (m, 6H), 1.53 (s, 3H), 89 13 1.43 (s, 3H). C-NMR (75 MHz, CDCl3) δ 166.7, 134.2, 130.5, 128.9, 110.4,
75.3, 63.7, 28.5, 25.7. meso-2,3-O-Isopropylidenebutane-1,2,3,4-tetrol (273) To a flame dried 3-necked round bottom flask equipped with a magnetic stirrer was added methanol (500 mL) and the solution was cooled to 0 °C. Sodium metal (586 mg, 25.5 mmol) was added to the solution followed by the acetonide
(14.99 g, 40.5 mmol). Caution! This corrosive reagent reacts violently with water. The reaction was monitored via TLC. Upon completion, the solution was neutralized with saturated ammonium chloride and volatiles were removed under reduced pressure. The residue was dilute with brine (50 mL) and extracted with chloroform (3 x 20 mL). The organic layers were combined and ether was added to precipitate a white solid. The solid was filtered and washed with ether. The ether extracts were combined and volatiles were removed under reduced pressure to give a crude oil. The oil was purified via column chromatography using 40% ethyl acetate/hexanes followed by 100% methanol to give 4.99 g
1 (76% yield) of a reddish-brown oil. H-NMR (300 MHz, CDCl3) δ 4.28-4.22 (m,
2H), 3.72 (qd, J = 10.8, 4.2 Hz, 4H), 3.47 (s, 2H), 1.42 (s, 3H), 1.33 (s, 3H). 13C-
NMR (75 MHz, CDCl3) δ 108.9, 77.5, 61.1, 28.1, 25.6. meso-2,3-O-Isopropylidene-1,4-di-O-(p-tolylsulfonyl)butane-1,2,3,4-tetrol
(274)
To a 500 mL round bottom flask equipped with a magnetic stirrer was added the diol (4.76 g, 29.4 mmol) in methylene chloride (200 mL). To the solution was added triethylamine (10.00 mL, 7.26 g, 71.7 mmol) and the solution was cooled 90 to 0 °C. Tosyl chloride (12.33 g, 64.7 mmol) and a catalytic amount of DMAP
(~200 mg) was added. The reaction was monitored via TLC and upon completion volatiles were removed under reduced pressure and the resulting residue was triturated with 10% hydrochloric acid (20 mL). The solid was collected by filtration and washed with ice cold water and recrystallized from 95% ethanol to give 10 g (73% yield) of a solid white powder. MP 111-114 °C. [Lit.
70 1 dec. 114-116 °C]. H-NMR (300 MHz, CDCl3) δ 7.76 (dd, J = 8.5, 1.9 Hz, 4H),
7.34 (d, J = 8.4 Hz, 4H), 4.29 (q, J = 4.5 Hz, 2H), 4.08-3.94 (m, 4H), 2.44 (s, 6H),
1.28 (s, 3H), 1.25 (s, 3H).
5.4 3-Pyrroline synthesis via alkene metathesis
Diallylamino acid methyl ester To a flame dried 500 mL round bottom flask equipped with a magnetic stirrer was added acetonitrile (250 mL), the amino acid (21 mmol), and sodium bicarbonate
(7.07 g, 84 mmol). Allyl bromide (4.00 mL, 5.68 g, 46.3 mmol) was added and the solution was brought to 70 °C. The reaction was monitored via TLC and upon completion volatiles were removed under reduced pressure. The residue was purified via column chromatography using 5% ethyl acetate/hexanes to give a clear, colorless oil.
91 (S)-methyl-2-N,N-diallyl-3-phenylpropanoate (278d)
Phenylalanine methyl ester hydrochloride used (4.53 g, 21 mmol), 4.09 g isolated
1 (75% yield). H-NMR (300 MHz, CDCl3) δ 7.47-7.35 (m, 5H), 5.88 (m, J = 17.2,
10.1, 7.2, 5.0 Hz, 2H), 5.37-5.26 (m, 4H), 3.91 (t, J = 7.6 Hz, 1H), 3.81 (s, 3H),
3.61-3.54 (m, 2H), 3.27 (dt, J = 14.1, 8.1 Hz, 2H), 3.10 (td, J = 14.0, 7.0 Hz, 2H).
13 C-NMR (75 MHz, CDCl3) δ 172.7, 138.3, 136.1, 129.1, 128.0, 126.0, 117.0,
63.6, 53.3, 50.9, 35.5.
5.5 3-Pyrroline synthesis via direct addition of cis-1,4-dichloro-2-butene
cis-1,4-dichloro-2-butene (133) To a flame dried 250 mL 3-necked round bottom flask equipped with a magnetic stirrer was added cis-2-butene-1,4-diol (60.0 mL, 64.2 g, 729 mmol), pyridine (3 mL), and methylene chloride (30 mL). The solution was cooled to 0 °C and thionyl chloride (150 mL, 245 g, 2.06 mol) was added dropwise from a pressure- equalizing addition funnel at a rate such that the temperature did not exceed 10
°C. Caution! This corrosive reagent reacts violently with water and liberates a toxic gas. It also has an acute toxicity if ingested, inhaled, or encounters contact with the skin. When the addition was complete, the reaction was allowed to warm to room temperature and stir for a period of 18 hours. Upon reaction completion, ice was carefully added to quench any unreacted thionyl chloride.
The solution was washed with brine (5 x 50 mL) and dried over anhydrous
92 sodium sulfate. Volatiles were removed under reduced pressure and the solution was azeotroped with toluene (3 x 75 mL). The solution was when vacuum distilled using aspirator pressure to give a 68 mL (89% yield) of a clear and
1 colorless product. BP 68-70 °C. H-NMR (300 MHz, CDCl3) δ 5.89-5.78 (m, 2H),
13 4.15-4.07 (m, 4H). C-NMR (75 MHz, CDCl3) δ 129.4, 37.9.
General synthesis for microwave-assisted syntheses of amino acid derived
3-pyrrolines
To a microwave reaction vessel equipped with a magnetic stirrer was added the amino acid (11 mmol), sodium carbonate (1.28 g, 12.1 mmol) and water (15 mL).
The solution was flushed with N2 and cis-2-butene-1,4-dichloride (1.2 mL, 1.42 g,
11 mmol) was added and the vessel was sealed and placed inside the microwave reactor. The microwave settings were 80 watts for 20 min at 123 °C.
Upon completion, the product was extracted using chloroform (5 x 20 mL) and volatiles were removed under reduced pressure to give a dark orange residue.
(S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-3-methylbutanoate (275b)
Valine methyl ester hydrochloride used (1.84 g, 11 mmol), 464 mg isolated (23%
1 yield). H-NMR (300 MHz, CDCl3) δ 5.74 (t, J = 1.7 Hz, 2H), 3.81-3.66 (m, 5H),
3.60-3.50 (m, 2H), 3.07 (d, J = 9.1 Hz, 1H), 2.13-1.90 (m, 1H), 1.03-0.90 (m, 6H).
13 C-NMR (75 MHz, CDCl3) δ 172.3, 127.0, 71.0, 55.4, 50.5, 29.4, 19.9, 19.1.
93 (S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-4-methylpentanoate (275c)
Leucine methyl ester hydrochloride used (2.00 g, 11 mmol), 694 mg isolated
1 (32% yield). H-NMR (300 MHz, CDCl3) δ 5.75 (d, J = 1.8 Hz, 2H), 3.76-3.69 (m,
5H), 3.59-3.53 (m, 2H), 3.49 (t, J = 7.5 Hz, 1H), 1.70-1.61 (m, 2H), 1.58-1.51 (m,
13 1H), 0.92 (dd, J = 11.4, 6.3 Hz, 6H). C-NMR (75 MHz, CDCl3) δ 174.2, 127.1,
62.3, 56.0, 51.1, 40.4, 25.0, 22.61, 22.53.
(S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-3-phenylpropanoate (275d)
Phenylalanine methyl ester hydrochloride used (2.16 g, 11 mmol), 967 mg
1 isolated (38% yield). H-NMR (500 MHz, CDCl3) δ 7.30-7.17 (m, 5H), 5.77 (d, J =
9.3 Hz, 2H), 3.81-3.75 (m, 2H), 3.72-3.64 (m, 2H), 3.60 (s, 3H), 3.12-3.01 (m,
13 2H). C-NMR (125 MHz, CDCl3) δ 172.8, 138.0, 129.0, 128.4, 127.1, 126.5,
66.5, 56.3, 51.2, 37.7.
General synthesis for amino acid derived 3-pyrrolines using conventional
heating
To a flame dried 10 mL round bottom flask equipped with a magnetic stirrer and
N2 inlet was added the amino adid methyl ester hydrochloride (0.472 mmol), sodium carbonate (200 mg, 1.89 mmol), and acetonitrile (5 mL). To the stirred solution was added the cis-2-butene-1,4-dichloride (50 µL, 59 mg, 0.472 mmol) and the reaction was brought to reflux for a period of 4 hours. The reaction was cooled to room temperature and the solid was filtered and washed with methanol.
Volatiles were removed under reduced pressure to give an oil that was diluted
94 with methylene chloride (5 mL) and washed with brine (2 x 3 mL). The organic layer was dried over anhydrous sodium sulfate and volatiles were removed under reduced pressure to give crude product that was purified via column chromatography in 5% ethyl acetate/hexanes.
(S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-3-methylbutanoate (275b)
Valine methyl ester hydrochloride used (79 mg, 0.472 mmol), 57 mg isolated
1 (66% yield). H-NMR (500 MHz, CDCl3) δ 5.74 (t, J = 1.7 Hz, 2H), 3.81-3.66 (m,
5H), 3.60-3.50 (m, 2H), 3.07 (d, J = 9.1 Hz, 1H), 2.13-1.90 (m, 1H), 1.03-0.90 (m,
13 6H). C-NMR (125 MHz, CDCl3) δ 172.3, 127.0, 71.0, 55.4, 50.5, 29.4, 19.9,
19.1. HRMS (ES+): C10H17NO2 m/z = calcd 183.1260, found 183.0990. IR
(film): νmax 3074, 2961, 2872, 1729, 1630, 1148.
(S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-4-methylpentanoate (275c)
Leucine methyl ester hydrochloride used (86 mg, 0.472 mmol), 53 mg isolated
1 (57% yield). H-NMR (300 MHz, CDCl3) δ 5.75 (d, J = 1.8 Hz, 2H), 3.76-3.69 (m,
5H), 3.59-3.53 (m, 2H), 3.49 (t, J = 7.5 Hz, 1H), 1.70-1.61 (m, 2H), 1.58-1.51 (m,
13 1H), 0.92 (dd, J = 11.4, 6.3 Hz, 6H). C-NMR (75 MHz, CDCl3) δ 174.2, 127.1,
62.3, 56.0, 51.1, 40.4, 25.0, 22.61, 22.53. HRMS (ES+): C11H19NO2 m/z = calcd
197.1417, found 197.1090. IR (film): νmax 3074, 2984, 2950, 2842, 1736, 1637,
1195
95 (S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-3-phenylpropanoate (275d)
Phenylalanine methyl ester hydrochloride used (102 mg, 0.472 mmol), 66 mg
1 isolated (60% yield). H-NMR (500 MHz, CDCl3) δ 7.30-7.17 (m, 5H), 5.77 (d, J
= 9.3 Hz, 2H), 3.81-3.75 (m, 2H), 3.72-3.64 (m, 2H), 3.60 (s, 3H), 3.12-3.01 (m,
13 2H). C-NMR (125 MHz, CDCl3) δ 172.8, 138.0, 129.0, 128.4, 127.1, 126.5,
66.5, 56.3, 51.2, 37.7. HRMS (ES+): C14H17NO2 m/z = calcd 231.1260, found
231.0861. IR (film): νmax 3075, 2950, 2805, 1738, 1642, 1168.
5.6 Mosher Ester Analysis
(S)-2-(2,5-dihydro-1H-pyrrol-1-yl)-4-methylpentanol (289) To a flame-dried 50 mL round bottom flask equipped with a magnetic stirrer was added ether (10 mL) and lithium aluminum hydride (443 mg, 11.66 mmols).
Caution! This corrosive reagent reacts violently with water. The solution was cooled to 0 °C with an ice water bath and the ester (1.00 g, 5.07 mmols) diluted in ether (10 mL) was slowly added to the flask. An additional 5 mL of ether was added and the solution was brought to reflux for 3 h. The reaction was cooled to room temperature and stirred for another 12 h. The solution was cooled to 0 °C with an ice water bath and water (2 mL) was slowly added followed by 10% sodium hydroxide (2 mL) and another addition of water (2 mL). The solid was filtered and the filtrate was separated. The aqueous layer was extracted with ethyl acetate (3 x 2 mL) and the organic layers were combined and washed with 96 brine and dried over anhydrous sodium sulfate. Volatiles were removed under reduced pressure to give 652 mg (76% yield) of a colorless oil. 1H-NMR (300
MHz, CDCl3) δ 5.80 (s, 2H), 3.63-3.49 (m, 4H), 3.33 (dd, J = 10.5, 8.2 Hz, 2H),
2.92-2.78 (m, 1H), 1.58 (dq, J = 13.6, 6.8 Hz, 1H), 1.29 (quintet, J = 7.2 Hz, 2H),
13 0.93 (t, J = 7.3 Hz, 6H). C-NMR (75 MHz, CDCl3) δ 127.4, 62.4, 59.8, 54.9,
35.7, 25.2, 23.9, 22.2.
2-(2,5-dihydro-1H-pyrrol-1-yl)-2-isobutyl-α-methoxy-α- trifluoromethylphenyalacetate
To a 5 mL round bottom flask equipped with a magnetic stirrer was added the alcohol (48 mg, 0.284 mmols) and chloroform (500 µL). The solution was cooled to 0 °C with an ice water bath and EDC (109 mg, 0.567 mmols) and a catalytic amount of DMAP (~5 mg) were added. To this solution was added (S)-(-)-α- methoxy-α-(trifluoromethyl)phenylacetic acid (74 µL, 99.7 mg, 0.426 mmols) and the solution stirred on ice for a period of 4 hours. The reaction was purified on silica to give 83 mg (76% yield). The reaction was also reproduced using the same alcohol (46 mg, 0.272 mmol), EDC (104 mg, 0.544 mmol), and the enantiomer (R)-(+)-)-(-)-α-methoxy-α-(trifluoromethyl)phenylacetic acid (71 µL,
95.5 mg, 0.408 mmol) to give 64 mg (61% yield).
(S,S)-(-)-2-(2,5-dihydro-1H-pyrrol-1-yl)-2-isobutyl-α-methoxy-α- trifluoromethylphenyalacetate (290)
1 H-NMR (300 MHz, CDCl3) δ 7.56 (dd, J = 6.5, 2.6 Hz, 2H), 7.39 (tt, J = 4.8, 2.5
Hz, 3H), 5.74-5.72 (m, 2H), 4.46 (dd, J = 11.3, 6.3 Hz, 1H), 4.26 (dd, J = 11.3, 97 4.5 Hz, 1H), 3.60-3.50 (m, 7H), 3.04-2.99 (m, 1H), 1.65 (dd, J = 13.6, 6.7 Hz,
13 1H), 1.41-1.25 (m, 2H), 0.91-0.87 (m, 6H). C-NMR (75 MHz, CDCl3) δ 166.6,
132.3, 129.5, 128.3, 127.4, 125.2, 121.4, 66.7, 56.6, 55.40, 55.26, 38.1, 24.9,
19 23.0, 22.6. F-NMR (282 MHz, CDCl3) δ -74.7
(S,R)-(+)-2-(2,5-dihydro-1H-pyrrol-1-yl)-2-isobutyl-α-methoxy-α- trifluoromethylphenyalacetate (291)
1 H-NMR (300 MHz, CDCl3) δ 7.59-7.56 (m, 2H), 7.42-7.35 (m, 3H), 5.73 (s, 2H),
4.44 (dd, J = 11.4, 5.7 Hz, 1H), 4.32 (dd, J = 11.4, 4.3 Hz, 1H), 3.56-3.55 (m,
7H), 3.00 (t, J = 5.9 Hz, 1H), 1.64 (dt, J = 13.5, 6.7 Hz, 1H), 1.34-1.28 (m, 2H),
13 0.88 (t, J = 6.6 Hz, 6H). C-NMR (75 MHz, CDCl3) δ 166.6, 132.3, 129.5, 128.3,
127.40, 127.35, 125.3, 121.6, 66.5, 56.8, 55.5, 38.0, 24.9, 23.1, 22.5. 19F-NMR
(282 MHz, CDCl3) δ -74.7
5.7 Syntheses of amino acid derived PHPs from 3-pyrrolines
General synthesis for amino acid methyl ester pyrrolidine diols with NMO To a 100 mL round bottom flask equipped with a magnetic stirrer was added acetone/water (1:1, 36 mL) followed by the 3-pyrroline (1.82 mmol) and N- methylmorpholine-N-oxide (NMO) (400 µL, 451 mg, 3.85 mmol). A catalytic amount of osmium tetroxide (~25 mg) was then added and the reaction was monitored via TLC. Caution! This corrosive reagent is a health hazard with an acute toxicity if ingested, inhaled, or encounters contact with the skin. Upon 98 completion, sodium sulfite (1.00 g, 8 mmol) was added to quench the reaction and was stirred for additional h. Volatiles were removed under reduced pressure and the aqueous layer was extracted with ethyl acetate (3 x 5 mL). The organic layers were combined and washed with brine (2 x 5 mL) and dried over anhydrous sodium sulfate. Volatiles were removed under reduced pressure to give a crude oil that was purified via column chromatography in 50% ethyl acetate/hexanes to give a colorless oil.
(S)-methyl-2-(meso-3,4-dihydroxypyrrolidin-1-yl)-3-phenylpropanoate
(305d)
Phenylalanine 3-pyrroline used (421 mg, 1.82 mmol), 420 mg isolated (87%
1 yield). H-NMR (300 MHz, CDCl3) δ 7.30-7.16 (m, 5H), 4.16-4.10 (m, 2H), 3.56
(m, 4H), 3.24 (s, 1H), 3.09-2.86 (m, 5H), 2.77 (dd, J = 9.9, 3.8 Hz, 1H). 13C-NMR
(75 MHz, CDCl3) δ 173.1, 137.8, 129.0, 128.6, 126.8, 71.1, 66.2, 55.98, 55.88,
51.6, 37.2
General synthesis for amino acid methyl ester pyrrolidine diols with
potassium ferricyanide (305b-d)
To a 100 mL round bottom flask equipped with a magnetic stirrer was added water (25 mL), potassium ferricyanide (4.79 g, 14.55 mmols), and potassium carbonate (1.80 g, 13.02 mmols). The solution stirred until homogenous then t- butanol was added (20 mL). The solution was cooled to 0 °C in an ice water bath and the pyrroline (4.85 mmol in 5.00 mL t-butanol) was added. The solution
99 stirred for 20 mintues followed by the addition of a catalytic amount of osmium tetroxide (~60 mg). Caution! This corrosive reagent is a health hazard with an acute toxicity if ingested, inhaled, or encounters contact with the skin. The solution was allowed to warm to room temperature and continued to stir for a 16 h period. The reaction was quenched by the addition of sodium sulfite and stirred for an additional hour. Volatiles removed under reduced pressure to give a dark residue that was dissolved in ethyl acetate. This solution was washed with water (2 x 10 mL) and brine (2 x 10 mL) then dried over anhydrous sodium sulfate. Volatiles were removed under reduced pressure to give a residue that was purified via column chromatography on silica with 100% ethyl acetate to give the diol.
(S)-methyl-2-(meso-3,4-dihydroxypyrrolidin-1-yl)-3-methylbutanoate (305b)
Valine 3-pyrroline used (889 mg, 4.85 mmol), 295 mg isolated (28% yield). 1H-
NMR (500 MHz, CD3OD) δ 4.06 (dq, J = 15.4, 5.3 Hz, 2H), 3.70 (s, 3H), 3.10 (dd,
J = 9.6, 6.1 Hz, 1H), 2.98-2.92 (m, 2H), 2.69 (dd, J = 9.8, 4.6 Hz, 1H), 2.61 (dd, J
= 9.6, 5.1 Hz, 1H), 2.00 (ddt, J = 13.4, 9.0, 6.7 Hz, 1H), 0.99 (d, J = 6.7 Hz, 3H),
13 0.88 (d, J = 6.7 Hz, 3H). C-NMR (125 MHz, CD3OD) δ 172.5, 71.1, 70.19,
70.01, 55.2, 54.5, 49.9, 28.4, 18.7, 17.9. HRMS (ES+): C10H19NO4 m/z = calcd
217.1315, found 217.0945. IR (film): νmax 3404, 2960, 1729, 1151
(S)-methyl-2-(meso-3,4-dihydroxypyrrolidin-1-yl)-4-methylpentanoate (305c)
Leucine 3-pyrroline used (957 mg, 4.85 mmol), 404 mg isolated (36% yield). 1H-
NMR (500 MHz, CD3OD) δ 4.08 (dq, J = 14.5, 5.2 Hz, 2H), 3.71 (s, 3H), 3.36- 100 3.31 (m, 2H), 3.11 (dd, J = 9.7, 6.0 Hz, 1H), 2.97 (dd, J = 9.9, 5.8 Hz, 1H), 2.72
(dd, J = 9.9, 4.6 Hz, 1H), 2.64 (dd, J = 9.7, 5.0 Hz, 1H), 1.65-1.49 (m, 3H), 0.97-
13 0.90 (m, 6H). C-NMR (125 MHz, CD3OD) δ 173.5, 70.28, 70.20, 63.2, 55.09,
55.01, 50.4, 39.4, 24.9, 21.8, 21.2. HRMS (ES+): C11H21NO4 m/z = calcd
231.1471, found 231.1141. IR (film): νmax 3381, 2955, 2870, 1737, 1157
(S)-methyl-2-(meso-3,4-dihydroxypyrrolidin-1-yl)-3-phenylpropanoate
(305d)
Phenylalanine 3-pyrroline used (1.12 g, 4.85 mmol), 862 mg isolated (67% yield).
1 H-NMR (300 MHz, CDCl3) δ 7.30-7.16 (m, 5H), 4.16-4.10 (m, 2H), 3.56 (m, 4H),
3.24 (s, 1H), 3.09-2.86 (m, 5H), 2.77 (dd, J = 9.9, 3.8 Hz, 1H). 13C-NMR (75
MHz, CDCl3) δ 173.1, 137.8, 129.0, 128.6, 126.8, 71.1, 66.2, 55.98, 55.88, 51.6,
37.2. HRMS (ES+): C14H19NO4 m/z = calcd 265.1315, found 265.0864. IR
(film): νmax 3386, 3062, 3028, 2950, 2846, 1731, 1603, 1154.
Pyrrolidine triol To a flame dried 25 mL round bottom flask equipped with a magnetic stirrer was added THF (10 mL) and the flask was cooled to 0 °C. To this solution was added lithium aluminum hydride (74 mg, 1.94 mmol) followed by the slow addition of the pyrrolidine diol (161 mg, 0.607 mmol). Caution! This corrosive reagent reacts violently with water. The reaction was allowed to warm to room temperature where it stirred for 4 hours and was quenched with a saturated solution of sodium potassium tartrate (~1 mL). The reaction was stirred for an additional 20 minutes
101 and excess solvent was removed under reduced pressure. Ethyl acetate was added to the residue and the solid was filtered and washed with ethyl acetate (2 x 3 mL). The filtrate was dried over anhydrous potassium carbonate and volatiles were removed under reduced pressure to give the triol.
(S)-2-(meso-3,4-dihydroxypyrrolidin-1-yl)-3-phenylpropanol (306d)
1 36 mg (24% yield). H-NMR (500 MHz, CD3OD) δ 7.31-7.19 (m, 5H), 4.19 (dq, J
= 13.4, 4.9 Hz, 2H), 3.60 (dd, J = 12.0, 3.4 Hz, 2H), 3.48 (dd, J = 11.9, 5.1 Hz,
2H), 3.27 (dt, J = 10.8, 5.1 Hz, 2H), 3.04-2.95 (m, 2H), 2.80-2.75 (m, 1H). 13C-
NMR (125 MHz, CD3OD) δ 138.4, 128.9, 128.2, 126.1, 70.0, 66.4, 59.2, 55.6,
55.1, 33.1.
5.8 Synthesis of amino acid derived silacycle from 3-pyrrolines
Phenylalanine diol silacycle To a flame dried 10 mL round bottom equipped with a magnetic stirrer was added allyltrichlorosilane (140 mg, 115 µL, 0.797 mmol) and acetonitrile (3 mL).
The solution was cooled to 0 °C and sodium carbonate (113 mg, 1.06 mmol) was added followed by the diol (141 mg, 0.531 mmol). The reaction stirred over a period of 16 h and the product was filtered and washed with acetonitrile.
Volatiles were removed under reduced pressure to give an orange residue (46%) that was used without further purification.
102 5.9 Synthesis of amino acid derived boracycle from 3-pyrrolines
Phenylalanine triol boracycle
To a flame dried 25 mL round bottom flask equipped with a magnetic stirrer was added the triol (11 mg, 0.0464 mmol) dissolved in THF (1 mL). The solution was cooled to 0 °C and borane dimethyl sulfide (45 µL, 10.2M, 0.464 mmol) was added to the flask. Caution! This corrosive reagent reacts violently with water and has an acute toxicity if ingested, inhaled, or encounters contact with the skin.
The solution stirred 20 minutes and acetophenone (54 µL, 55.6 mg, 0.464 mmol) was added to the flask. The solution stirred on ice for 1 h and the reaction was warmed to room temperature. Methanol (500 µL) was added to quench excess borane and 1 N HCl (500 µL) was added to the flask. The mixture was stirred for ten minutes and volatiles were removed under reduced pressure to give a residue. This was dissolved with methylene chloride (1 mL) and washed water (2 x 1 mL) and brine (1 x 1 mL) then dried over anhydrous magnesium sulfate.
Volatiles were removed under reduced pressure to give a crude oil.
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110 APPENDIX
1H/13C/19F-NMR SPECTRA OF SELECTED COMPOUNDS
111 1H/13C-NMR spectrum of cis-1,4-dichloro-2-butene (133)
112 1H/13C-NMR spectrum of valine methyl ester hydrochloride (268b)
113 1H/13C-NMR spectrum of leucine methyl ester hydrochloride (268c)
114 1H/13C-NMR spectrum of phenylalanine methyl ester hydrochloride (268d)
115 1H/13C-NMR spectrum of (S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-3- methylbutanoate (275b)
116 1H/13C-NMR spectrum of (S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-4- methylpentanoate (275c)
117 COSY spectrum of (S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-4-methylpentanoate (275c)
118 HSQC spectrum of (S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-4-methylpentanoate (275c)
119 1H/13C-NMR spectrum of (S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-3- phenylpropanoate (275d)
120 COSY spectrum of (S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-3-phenylpropanoate (275d)
121 HSQC spectrum of (S)-methyl-2-(2,5-dihydro-1H-pyrrol-1-yl)-3-phenylpropanoate (275d)
122 1H/13C-NMR spectrum of (S)-2-(2,5-dihydro-1H-pyrrol-1-yl)-4-methylpentanol (289)
123 1H/13C/19F-NMR spectrum of (S,S)-(-)-2-(2,5-dihydro-1H-pyrrol-1-yl)-2-isobutyl-α- methoxy-α-trifluoromethylphenyalacetate (290)
124 1H/13C/19F-NMR spectrum of (S,R)-(+)-2-(2,5-dihydro-1H-pyrrol-1-yl)-2-isobutyl-α- methoxy-α-trifluoromethylphenyalacetate (291)
125 1H/13C-NMR spectrum of (S)-methyl-2-(meso-3,4-dihydroxypyrrolidin-1-yl)-3- methylbutanoate (305b)
126 COSY spectrum of (S)-methyl-2-(meso-3,4-dihydroxypyrrolidin-1-yl)-3- methylbutanoate (305b)
127 HSQC spectrum of (S)-methyl-2-(meso-3,4-dihydroxypyrrolidin-1-yl)-3- methylbutanoate (305b)
128 1H/13C-NMR spectrum of (S)-methyl-2-(meso-3,4-dihydroxypyrrolidin-1-yl)-4- methylpentanoate (305c)
129 1H/13C-NMR spectrum of (S)-methyl-2-(meso-3,4-dihydroxypyrrolidin-1-yl)-3- phenylpropanoate (305d)
130 COSY spectrum of (S)-methyl-2-(meso-3,4-dihydroxypyrrolidin-1-yl)-3- phenylpropanoate (305d)
131 1H/13C-NMR spectrum of (S)-2-(meso-3,4-dihydroxypyrrolidin-1-yl)-3- phenylpropanol (306d)
132