THE UTILIZATION OF SULFINIMINES (N-SULFINYL IMINES) IN
THE ASYMMETRIC SYNTHESIS OF SUBSTITUTED
PYRROLIDINES
A Dissertation
Submitted to the
Temple University Graduate Board
In Partial Fulfillment
of the Requirements for the Degree
DOCTOR OF PHILOSOPHY
By
Kerisha Andrea Bowen
May 2009
ABSTRACT
The Utilization of Sulfinimines (N-Sulfinyl Imines) Towards
the Sythesis of Nitrogen Containing Compounds
By Kerisha A. Bowen
Doctor of Philosophy
Temple University, 2009
Doctoral Advisory Committee Chair: Professor Franklin A. Davis, Ph.D.
The objective of this research was the development of new methods for the asymmetric synthesis of nitrogen containing compounds. As one part of this goal, 3,4- dihydroxyprolines and their derivatives were prepared from sulfinimines (N-sulfinyl imines). During this project new methods were developed for asymmetric hydroxylation and decarboxylation of 3-oxo-2-carboxylate pyrroldines. The application of this new methodology was realized by the total synthesis of the α- and β-glycosidases inhibitor
(+)-lentginosine.
It was also found that electrophiles regioselectively add to the 4-position of 3-oxo-2- carboxylate-5-substituted pyrrolidines. The addition is accomplished through lithium diisopropyl amide generation of the pyrrolidine dianion. This addition was also compatible with 3-oxo-2-phosophono-5-substituted pyrroldines. Furthermore air oxidation of these pyrrolidines give the corresponding pyrroles. This procedure represents the first general preparation procedure for 2-phonopyrroles, which have been examined as HIV protease inhibitors.
ii
A range of β-amino carbonyl compounds were prepared from N-sulfinyl β-amino
Weinreb amides in a concise and efficient procedure. A general method for the preparation of a variety of β-amino carbonyl compounds arose from the addition of an assortment of organometallic reagents to the Weinreb amides. The N-sulfinl β-amino
Weinreb amides are prepared by reaction of the potassium enolate of N-methoxy-N- methylacetamide with sulfinimines or lithium N,O-dimethylhydroxylamine with N- sulfinyl β-amino esters.
iii
ACKNOWLEDGEMENTS
I have so many people to thank for all of my successes at Temple University. While there are many that I want to mention by name, please know that there are countless people who have helped and supported me in my studies. Although it would be impossible for me to mention everyone by name, I would like to express my gratitude to all of them.
First, I would like to thank my “Father in Chemistry” my research advisor Dr.
Franklin A. Davis. His help and guidance in my life has gone beyond just the traditional role of professor and has truly stepped into the realm of fatherhood. From my first year at Temple, Dr. Davis took time out of his busy schedule to help me with my classes and made sure that I understood the theory of Organic mechanisms. As the years past, Dr.
Davis became a friend and confidante. As a true father would, he challenged me to be best person that I could possibly be. Although, I may have questioned his methods along the way, the person that I am now appreciates who he was then.
I would also like to thank my graduate committee members Dr. John R. Williams,
Dr. Scott Sieburth, and Dr. Madeleine Joullié. All of whom have supported along the way. Dr. Joullié who I have known the longest, has been a great mentor and role model.
She is an inspiration, and I am blessed to have worked with her. Dr. Williams, who also served as one of my instructors, taught me the importance of mechanisms and I have adopted his grading methods in my own personal teaching career. Finally, Dr. Sieburth, who not only served as an excellent instructor, but also a much needed comic relief. I have not only enjoyed the conversations that we have had, but also the many posters
iv
outside of his office. Although, he may not get the recognition that he deserves for all that he does behind the scenes, I would like to say that I am thankful for him. Other faculty that should be recognized include Dr. Alfred Findeisen for his dedicated service as the Organic chemistry class coordinator and Dr. Charles DeBrosse, without whom
Organic synthesis would not be credible at Temple University. My gratitude also goes to
Dr. Grant Krow, Dr. David Dalton, and Dr. Rodrigo Andrade for their continued support.
The Temple University chemistry department staff also deserve much thanks because without them the building would not function. Regina Shapiro, the departments trusted business manager, who was there to help solve most of my dilemmas. Bobbi
Johnson, who year after year, arranged my teaching schedule. Jeanette Ford, the department’s purchasing administer, who made sure I had all of the reagents and materials that I need to complete my reactions and who was able to figure out the chaotic solvent system maintenance forms. Jason Pfeffer and Regee Neely the graduate secretaries who were in charge of my graduate file and contracts. I would like to thank,
Reverend George McCurdy for his inspirational words and friendship throughout the years. I would like to take time to thank the late Mr. Warren Muir, who was responsible for the department’s stockroom. Warren was a great friend and mentor, and the department has not been the same since he left.
I have a lot of respect and gratitude to my colleagues. Particularly, Dr. Ramachandar
Tokalo and Dr. Junyi Zhang who served as postdoctoral fellows in the Davis research group and who mentored my laboratory training. My friends in the Davis group Dr.
Yongzhong Wu, Dr. Bin Yang, Dr. Jeffrey Melamed, Dr. He Xu, Dr. Minsoo Song, Dr.
Jianghe Deng, Mr. Yinxing Li, Ms. Danyang Li, Mr. Yanfeng Zhang, Mr. Hui Qiu, Mr.
v
Paul Gaspari, Mr. Naresh Theddu, Mr. Venkata Velvadapu, Mr. Narendra Gaddiraja, and
Mr. Peng Xu. I would want to especially recognize my lab mate Ms. Jing Chai, who has become a valued friend. Also, I would like to thank my many friends throughout the chemistry department. A large amount of my thanks and gratitude go to my friend and undergraduate lab partner Mr. GorDan Tyson Reeves for his friendship and in particular his assistance with my mass spectra data collection; your help is very much appreciated.
To the people who have watched me grow up, I am forever grateful. My church family at Shiloh Baptist church, who have supported me throughout the years both spiritually and financially, thank you. My friends, who have grown with me, your companionship is very much appreciated. I have a lot of love to give to my large but close family. I have lost some of them on this journey, but I will always remember them in my heart. To my brother, Keville Bowen, who has put up with me since birth, thank you for everything that you have done. Finally, my mother, Marjorie Bowen, you are an inspiration, and you have set a perfect example of what people can accomplish if they focus. I realize that the road that we traveled to get to this point in life was rough, but we did it together, and as you always say “no one can take away your education.”
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TABLE OF CONTENTS
Page
ABSTRACT……………………………………………………………………………...ii
ACKNOWLEDGEMENTS…………………………………………………………….iv
LIST OF TABLES………………………………………………………………………xi
LIST OF FIGURES……………………………………………………………………xiii
LIST OF ABBREVIATIONS...... xiv
CHAPTER
1. SYNTHESIS OF 3-OXO-2-CARBOXYLATE-PYRROLIDINES AND
PYRROLIDINE DERIVATIVES
1.1 Introduction……………………………………………………………………...1
1.2 Functionalization of Pyrrolidines………………………………………………..2
1.2.1 Introduction of an Ester into a Pyrrolidine Ring……….....……………2
1.2.2 C-3 Oxidations of Pyrrolidines……………...…...…………………….3
1.3 Cyclization of Vicinal Tricarbonyls………………………………..……………6
1.4 Dieckmann Condensation of 3-[(Carbonyl)methylamino]propanoates……..…14
1.5 Metal Catalyzed NH Insertion Reactions of α-Diazo-β-ketoesters……………18
1.5.1 Copper Catalyzed Cyclizations……………………………………….19
1.5.2 Rhodium Catalyzed Reactions………………………………………..22
2. SYNTHESIS AND UTILIZATION OF SULFINIMINES (N-SULFINYL
IMINES) AS CHIRAL IMINE BUILIDING BLOCKS
vii
2.1 Introduction………………………………………………………………….…25
2.2 Present Study…………………………………………………………………...33
2.2.1 Previous Syntheses of 3,4-Dihydroxyprolines………………………..34
2.2.2 Synthesis of (2R)-3,4-Dihydroxyproline Isomers………………...... 36
2.2.2.1 Decarboxylation of 3-Oxo-2-carboxylate Pyrrolidines………….38
2.2.2.2 Additions to C-2 of 2-Phenyl-4-oxo Pyrrolidine………...…...….43
2.2.3 Synthesis of (+)-Lentiginosine……………………….……………….50
2.2.3.1 Previous Syntheses of (+)-Lentiginosine……...…………………51
2.2.3.2 Total Synthesis of (+)-Lentiginosine...……………….………….53
2.2.4 Conclusion...... 58
3. SYNTHESIS OF POLYSUBSTITUTED PYRROLES FROM SULFINIMINES
(N-SULFINYL IMINES)
3.1 Introduction...... 59
3.2 Present Study...... 63
3.2.1 Synthesis of Racemic 2-Carboxy and 2-Phosphonopyrrolidines...... 64
3.2.2 Synthesis of 4-Substituted-3-oxo-2,5-disubstituted Pyrolidines...... 67
3.2.3 Aromatization of 3-Oxo Pyrrolidines to Pyrroles...... 71
3.2.4 Conclusion...... 76
4. ASYMMETRIC SYNTHESIS OF β-AMINO CARBONYL COMPOUNDS
WITH N-SULFINYL β-AMINO WEINREB AMIDES
4.1 Introduction...... 77
4.2 Present Study...... 82
4.2.1 Synthesis of β-Amino Weinreb Amides from Sulfinimines...... 82
viii
4.2.2 Synthesis of N-Sulfinyl β-Amino Aldehydes and Ketones...... 86
4.2.3 Conclusion……………………………………………………………88
5. EXPERIMENTAL SECTION…………………………………………………….89
REFERENCES………………………………...………………………………………150
ix
x
LIST OF TABLES
Table 1.1: Generation of 3-oxo-2-carboxyl pyrrolidines 8 from common oxidizing
reagents ………………………………………………….………………….4
Table 1.2: Reaction of 20 with Primary Amines ………………………………………9
Table 1.3: Reaction of substituted alkenyl tricarbonyl electrophile 42……….………13
Table 1.4: Dieckmann cyclization of oxazolidine 69…………………………………18
Table 1.5: Examination of the Scope of the Stevens [1,2] Rearrangement…………...21
Table 2.1: Decarboxylation conditions of Pyrrolidine (R)-167……………………….43
Table 2.2: Formation of (2S,3S)-171 from C-2 Addition of Davis’ Oxaziridine (-)-170
to (R)-155………………………………………………………………….45
Table 2.3: Transformations of (2S,3S)-173…………………………………………...46
Table 2.4: Conversion of (2S,3S,4R)-174 to (2R,3S,4R)-179…………………………47
Table 3.1: Rh2(OAc)4 Mediated Aromatization of 240 to Pyrrole 243……………….63
Table 3.2: Synthesis of 3-Oxo-5-Substituted Pyrrolidine-2-Carboxylates...... 65
Table 3.3: Synthesis of 3-Oxo-5-Substituted Pyrrolidine-2-Phosphonates...... 66
Table 3.4: Reaction of Electrophiles with the Dianions of 252 and 256...... 69
Table 3.5: Regioselective Electrophilic Additions to 1,3-Dicarbonyl Dianions...... 70
Table 3.6: Aromatization of Pyrrolidine 267 to Pyrrole 268...... 71
Table 3.7: Aromatization of Substituted Pyrrolidines to Pyrroles 272 and 273...... 74
Table 4.1: Reaction of Lithium Hexyne with Amino Acid Derivatives...... 79
Table 4.2: Preparation of 1,2-Diketones from 292...... 80
xi
Table 4.3: Synthesis of β-Amino Weinreb Amides 304 and 306 from Sulfinimines and
N-Methoxy-N-methylacetamides...... 84
Table 4.4: Synthesis of β-Amino Weinreb Amides 304 and 306 from N-Sulfinyl β-
Amino Methyl Esters and Lithium N,O-Dimethylhydroxyamine...... 85
Table 4.5: Synthesis of N-Sulfinyl β-Amino Aldehydes and Ketones from β-Amino
Weinreb Amides and Organometallic Reagents…………………………..87
xii
LIST OF FIGURES
Figure 1.1: General Structure of Pyrrolidines and Pyrrolidine Derivatives…………….1
Figure 1.2: Products of 3-Oxo-2-carboxylate Pyrrolidine Reactions…………………...1
Figure 1.3: Vicinal Polyketones…………………………………………………………7
Figure 1.4: Metal Catalysts Used for NH Insertion Reactions………………………...19
Figure 2.1: Stereodirecting Effect of the Sulfinyl Auxilary…………………………...26
Figure 2.2: Sulfinimine Mediated Asymmetric Transformations……………………...26
Figure 2.3: p-Toluenesulfinyl Aldimines and Ketimines………………………………28
Figure 2.4: tert-Butylsulfinyl Aldimines and Ketimines……………………………….29
Figure 2.5: (2R,4S,5R)-119 Derived sulfinamides……………………...……………...31
Figure 2.6: Some Polyhydroxylated Indolizidine Metabolites…………………………51
Figure 3.1 The Structure of Pyrrrole...... 59
Figure 4.1: Reactions of N-Sulfinyl Weinreb Amides with Organometallic Reagents..86
xiii
LIST OF ABBREVIATIONS
Abbreviation Name
Ac Acetyl
Acac Acetylacetonate
AIBN azo-bis-isobutyronitrile
BINAP 9-Borabicyclo[3.3.1]nonane
Bn Benzyl
Boc tert-Butyoxycarbony
Bu n-Butyl
Bz Benzoyl cat. Catalytic
Cbz Carbobenzyloxy oC Temperature in degrees Centigrade
2D Two-dimensional
3D Three-dimensional
DABCO 1,4-Diazobicyclo[2.2.2]octane d Days
DCC 1,3-Dicyclohexylcarbodiimide
DDQ 2,3-Diclohor-5,6-dicyano-1,4-benzoquinone
% de Percent diasteromeric excess
DEA Diethylamine
DEAD Diethylazodicarboxylate
xiv
DIBAL-H Diisobutylaluminum hydride
DMAP 4-Dimethylaminopyridine
DMF N,N’-Dimethylformamide
DMS Dimethyl sulfide
DMSO Dimethyl sulfoxide
% ee Percent enantiomeric excess
Et Ethyl
EDA Ethylenediamine
EDTA Ethylenediaminetetraacetic acid
Equiv Equivalent(s)
GC Gas chromatography h Hour(s) hυ Irradiation with light
HMPA Hexamethylphosphoramide
HMPT Hexamethylphosphorus triamide
HOMO Highest occupied molecular orbital
HPLC High performance liquid chromatography i-Pr Isopropyl
IR Infrared spectroscopy
LDA Lithium diisopropylamide
LiHMDS Lithium hexamethyl disilazide
LUMO Lowest unoccupied molecular orbital m-CPBA meta-Chloroperbenzoic acid
xv
Me Methyl min Minute(s)
MOM Methoxymethyl
Ms Methanesulfonyl
NBS N-Bromosuccinimide
NCS N-Chlorosuccinimide
NIS N-Iodosuccinimide
NMO N-Methylmorpholine N-oxide
PCC Pyridinium chlorochromate
PDC Pyridinium dichromate
Ph Phenyl
PhH Benzene
PhMe Toluene
Pr n-Propyl
Quant Quantitative yield s-Bu sec-Butyl s-BuLi sec-Butyllithium s Seconds
TBAF Tetrabutylammonium fluoride
TBDMS tert-Butyldimethylsilyl t-Bu tert-Butyl
TEMPO Tetramethylpiperidinyloxy free radical
TFA Trifluoroacetic acid
xvi
TFAA Trifluoroacetic anhydride
Tf(OTf) Triflate
THF Tetrahydrofuran
TMS Trimethylsilyl
Tol Tolyl
Xc Chiral auxillary
xvii CHAPTER 1
SYNTHESIS OF 3-OXO-2-CARBOXYLATE 5-PYRROLIDINES
1.1 Introduction
Pyrrolidines are five membered nitrogen heterocyclic systems that are found in many alkaloids and pharmaceuticals.1,2 Also, pyrrolidines serve as building blocks for the synthesis of more complex alkaloids including indolizine and pyrrolizidine ring systems (Fig. 1.1).3,4 The range of biological activities of the later is impressive. 3-Oxo-
2-carboxylate pyrrolidines have gained sufficient synthetic interest due to the versatility of the reactions they undergo. For instance, they are capable of decarboxylation, substitution, and aromatization to pyrroles (Fig. 1.2).
N N R N H
Pyrrolidine Pyrrolizidine Indolizidine Proline (R = CO2H)
Figure 1.1: General Structure of Pyrrolidines and Pyrrolidine Derivatives
O O R3 O OH
OR1 OR1 OR1 N N N N R2 O R2 R2 O R2 O
3-Oxo-2-carboxy Decarboxylation Addition Aromatization pyrrolidine product product product
Figure 1.2: Products of 3-Oxo-2-carboxylate Pyrrolidine Reactions
1 In general, four methods have been practiced in the synthesis of these unique structures. The first method involves introduction of an ester or oxidation of an alcohol on a pyrrolidine ring. Another method that is utilized is the reaction of amines with α,β- dione esters, which are referred to as tricarbonyl esters and their derivatives. The
Dieckmann condensation of 3-[(carbonyl)methylamino]propanoates is another way of producing these functionalized pyrroldines. Probably the most common method used for their formation is intramolecular metal catalyzed NH insertion reaction of δ-amino-α- diazo-β-keto esters. All of these methods will be discussed in detail.
1.2 Functionalization of pyrrolidines
Pyrrolidines that do not posses the 3-oxo-2-carboxylate functionality can be transformed into these types of compounds through two general methods: esterification and oxidation of an alcohol. Several approaches including the Swern and Dess-Martin oxidation have been employed in the conversion of these pyrrolidines. In addition imine hydrolysis and methylene oxidation have been used.
1.2.1 Introduction of an ester into a pyrrolidine ring
The only example of forming a 3-oxo-2-carboxylate pyrrolidine through esterification was reported by Page and coworkers.5,6 They applied this approach to the synthesis of (+)-lactacystin 6, a microbial metabolite that was isolated from the culture broth of a Streptomyces species.7 The condensation reaction of N-benzyl glycine ethyl ester (1) and benzyl malonyl chloride gave 3-oxo propanoate 2 (Scheme 1.1). Propanoate
2 underwent tetrabutylammonium fluoride promoted Dieckmann cyclization and
2 electrophilic subsitution to give 3.5 The ester moiety was introduced by subjecting the lithium enolate of 3 to methyl cyanoformate or Mander’s reagent to produce 5. 8 It was noted that the use of lithium diispropyl amide (LDA), sodium hydride (NaH), lithium tert-butoxide (LiOt-Bu), or potassium tert-butoxide (KOt-Bu) resulted in only the O- acylation product.5
O O CO Bn O 2 BnO C TBAF, Et2O, rt 2 Bn BnO Cl N CO2Et H pyridine, DMAP, O N CO2Et MeI, THF, rt 24h O N CH2Cl2, rt 24 h Bn 53% Bn 83%
1 2 3
LiHMDS
OH O OLi BnO2C BnO2C NCCO2Me OH O CO Me O N N 2 75% O N CO2H Bn Bn Bn
6 5 4 (+)-Lactacystin
Scheme 1.1
1.2.2 C-3 oxidations of pyrrolidines
The most common method for converting a pyrrolidine into a 3-oxo-2-carboxylate pyrrolidine is through oxidation of an alcohol to a ketone (Scheme 1.2). Rapoport used the Dess-Martin periodinane (DMP) to oxidize the alcohol in 7a to give 8a (Table 1.1, entry 1).9-11 Hydroxy methyl azabicyclo[2.2.1]heptan-2-ol 7b was transformed to bridged 3-oxo 2-carboxy pyrrolidine 8b with the Jones reagent.12 In steps toward the total synthesis of KSM-2690 B, a β-lactone in a class of compounds that exhibit
3 antimicrobial activity against several Gram-positive bacteria and cytotoxic activity against human ladder carcinoma, Donohoe and co-workers utilized the Swern oxidation to form 3-oxo-2-carboxylate pyrrolidine 8c.13-15
OH O [O] R2 R2 R3 1 3 1 N R R N CO2R PG PG
1 2 3 1 2 3 7a: R =CO2t-Bu, R ,R = -CH2CH2- 8a: R =CO2t-Bu, R ,R = CH2CH2- 1 2 3 1 2 3 7b: R =CH2OH, R ,R =-CH2CH2- 8b: R =CO2H, R ,R =-CH2CH2- 1 2 3 1 2 3 7c: R =CO2Et, R =(R)-CH(Me)BOM, R =H 8c: R =CO2Et, R =(R)-CH(Me)BOM, R =H
Scheme 1.2
Table 1.1 Generation of 3-oxo-2-carboxyl pyrrolidines 8 from common oxidizing reagents. entry alcohol oxidizing reagent(s) % isolated yield of 8
9-11 1 7a AcO OAc 78 I OAc
O
12 2 7b CrO3 and aq. H2SO4 90
13-15 3 7c (COCl)2, DMSO then Et3N 95
Oxidation of alcohols is not the only method of introducing a 3-oxo group in a pyrrolidine ring. In steps toward the total synthesis of (+)-duocarmycin A (13), a naturally occurring potent antitumor antibiotic, imine hydrolysis introduced the oxo group to the indoline ring (Scheme 1.3).16-18 The imine functionality of 10 was formed
4 by LDA promoted condensation of 9.16 Once this ring was formed the oxazolidinone chiral auxillary was removed by methanolysis to give 3-imine 2-carboxy indoline 11.
Finally imine hydrolysis with p-toluenesulfonic acid (TsOH) provided 3-oxo-2- carboxylate pyrrolidine 12, which was later converted to natural product 13.
OTBDMS OTBDMS OTBDMS
HN HN i-Pr NC N c N N CH3 Boc X OC Boc MeO2C Boc LDA, THF LiOCH3 O N H C N H3C N 3 N 84% O O Boc OBn 78% Boc OBn Boc OBn
9 10 11
TsOH 80% CO2Me O H C 3 OTBDMS HN O H3C N N CH3 O OCH3 MeO2C Boc Me O N O N OCH 3 Boc OBn O OCH3 Xc 13 12
Scheme 1.3
An alternative route to 3-oxo 2-carboxy pyrrolidines is oxidation of a 3-methylene unit. This procedure was utilized in the synthesis of (+)-lactacystin (17), a metabolite isolated from Streptomyces sp. OM-6519 broth that exhibits neurotrophic activity
(Scheme 1.4).7,19,20 Treatment of α-ethynyl substituted serine 14 with tributyl tin hydride
(Bu3SnH) and azobisisobutyronitrile (AIBN) gave a 2:1 inseparable mixture of 3- methylene 2-carboxy pyrrolidine epimers 15a and 15b. As attempts to epimerize 15a to
15b were unsuccessful, both pyrrolidines were subjected to ozonolysis producing 16a and
5 16b in the expected 2:1 ratio. Separation of the epimers was achieved by conversion of the stereocenter to a sulfide with S-methyl p-toluenesulfonothioate (p-
CH3C6H4SO2SCH3), and the sulfide was removed diastereoselectively with Raney nickel.
CH3 CH3 Br CH3 Bu3SnH, AIBN MeO2C + MeO2C MeO2C O O N O toluene, reflux N N H H H OTBS 70% (2:1 inseparable mixture) OTBS OTBS
14 15a 15b major minor
o 1. O3, MeOH, -78 C o 2. Me2S, -78 C to rt 75% (2:1 inseparable mixture)
NHAc HO C HO CH O CH 2 O 3 O CH3 3
MeO C + MeO2C S O 2 O N N O N H H H OTBS OH OTBS
17 16a 16b (+)-Lactacystin
Scheme 1.4
1.3 Cyclization of Vicinal Tricarbonyls
Vicinal tricarbonyl compounds were first introduced in 1890 when de Neufville and von Pechmann reported the synthesis of diphenyl triketone (Fig. 1.3).21 The following year, Abenius and Soderbaum published their synthesis of diphenyl tetraketone.22 In 1901, Sachs and Barshall described a synthesis for dimethyl triketone, the first aliphatic vicinal trione.23 There are several methods of preparing these compounds, but they are commonly prepared from β-dicarbonyl ketones.24,25 Wasserman
6 has established the method of cyclizing 1,2,3-tricarbonyl systems into pyrrolidines and pyrroles.25-36
O O O O O O Ph Ph Ph Ph H3C CH3 O O O O
Diphenyl triketone Diphenyl tetraketone Dimethyl triketone
Figure 1.3: Vicinal Polyketones
Phosphorus ylide 18 was oxidized to tricarbonyl 19 by singlet oxygen generated from bisacenaphthalenethiophene (BANT) and molecular oxygen (Scheme 1.5).
Decarboxylation of 6-chloro-2,3-dioxohexanoate 19 gave vinyl tricarbonyl 20.35 This vinyl tricarbonyl reacted with commercially available 3,4-dimethoxybenzeneethanamine
21 to form the 3-oxo 2-carboxy-2-hydroxy pyrrolidine 22. The cyclization occured as a result of both nucleophilic attack at the central carbonyl carbon and Micheal addition at the vinylic position of 20. Treatment of 22 with mildly acidic silica gel or boron trifluoride gave 70% of pyrrole 24, and indolizidine 25 is formed in 41% by the reaction of 22 with phosphoric trichloride.35 These transformations are thought to go through common intermediate 23, which has not been isolated.
7 PPh3 O O Cl Ot-Bu O2, h!, BANT Cl Ot-Bu HCO3Na Ot-Bu
O O O O 60% (over two steps) O O
18 19 20
OMe NH2 OMe MeO 21 N acid MeO OH MeO MeO 24 N N MeO O MeO O t-BuO2C t-BuO2C OH MeO POCl3 N 23 22 MeO t-BuO2C O
25
Scheme 1.5
To determine the versatility of this procedure, other functionalized indolizidines were prepared (Table 1.1).36 Initially, cis- and trans-5-methoxy-4-pentene-1-amine added to the tricarbonyl 20 to give pyrrololidine 26, which was immediately carried on to indolizidine aldehyde 27a in 45% and 20% yield, respectively (Table 1.1, entries 1 and
2). Similarly, reaction of 20 with trans-4-(trimethylsilyl)-3-butene-1-amine lead to a
42% overall yield of indolizidine 27b, however cis-4-(trimethylsilyl)-3-butene-1-amine aromatized to hydroxypyrrole 28 (Table 1.1, entries 3 and 4). This phenomenon was explained by Overman, who concluded that trans-vinylsilanes add preferentially to iminium ions presumably to enhance the hyperconjugative stabilization of the intermediate carbonium ion.37,38 Notably a propargylsilane underwent rapid conversion to indolizidine allene 27c in preference to the competing protodesilylation (Table 1.1, entry 5). The formation of fused N-methyl pyrrole 27d in 90% yield confirmed that the
8 efficiency of this intramolecular cyclization is dependent upon the electron density of the
π-system.
O O OH O OH CO2t-Bu 1 2 Ot-Bu NH2R additive R CO t-Bu N CO2t-Bu N + N 2 R1 R1 O O R3
20 26 27a: R2=CHO, R3=H 28 2 3 27b: R =SiMe3, R =(+) 2 3 27c: R =-C=CH2, R =H 27d: R2,R3=N-methyl pyrrole
Scheme 1.6
Table 1.2 Reaction of 20 with Primary Amines36
entry primary amine additive product % isolated yielda O 1 NH2 OMe SiO2 45 CO2t-Bu CHO N
27a
2 OMe 20
NH2
b 3 SiMe3 TFA O 42 CO2t-Bu SiMe3 H2N N
27b
c 4 Me3Si OH
H N Me Si 2 3 N CO2t-Bu
28
9 NH2 O 5 Et2O.BF3 CO2t-Bu 64 CH C 2 SiMe3 N
27c
NH O 6 2 SiO2 90 N CO2t-Bu Me N N Me 27d a % Isolated yields represents overall yield from 20. b The indolizine cation underwent a silyl elimination, so the isolated yield is the yield of the elimination product. c The pyrrole 28 was isolated in “a small amount” with no nominal figure given for the isolated yield.
Vicinyl tricarbonyl 20 undergoes cyclization with diamines to give cyclic diamines.28,30,31 A typical example of this reaction is shown by the cyclization of 20 and
2-(aminomethyl)benzeneamine (29).30 Quinoline 32 was obtained in 68% yield by treating 20 with amine 29 in the presence of silica gel. When the silica gel was removed, carbinolamine intermediate 30 is isolated. The formation of quinoline 32 was proposed to go through iminium 31.
10 O NH N Ot-Bu 2 + NH NH2 O O 2 O HO CO2t-Bu
20 29 30
N N
N (68%) NH2 O H O t-BuO2C CO2t-Bu
32 31
Scheme 1.7
Alternatively, 20 reacted as a dieneophile in a Diels-Alder reaction with trans-1-
N-acylamino-1,3-diene 33 (Scheme 1.8).26 The Diels-Alder cycloaddition intermediate
34 cyclized at the expected central carbonyl carbon to give 35 in 87% yield. Acetylenic ester 36 also undergoes the Diels-Alder reaction when treated with 3,5-dienoate 37 forming Diels-Alder adduct 38 (Scheme 1.9). Intramolecular attack of the central carbonyl followed by dehydration produces 40, which was aromatized to corresponding indole 41 upon reaction with dichloro dicyano quinone (DDQ).
11 Me O O O Me O Me OH Ot-Bu ! + CO t-Bu CO t-Bu NH 2 N 2 O O PhH O NH O Me Si O 3 Me3Si SiMe3
20 33 34 35
Scheme 1.8
EtO2C EtO2C EtO2C O O O O O ! NHn-Bu OH Ot-Bu + Ot-Bu PhH 2,6-di-t-butylphenol N CO2t-Bu O 57% O CH2Cl2 n-Bu
36 37 38 39
57%
EtO2C EtO2C OH OH
DDQ CO2t-Bu CO2t-Bu N N 77% n-Bu n-Bu
41 40
Scheme 1.9
The scope of this methodology was expanded to include chiral vicinal tricarbonyl electrophiles. Here it was found that protected amino acid 42 cyclized with primary amines to 3-oxo-2-carboxylate-2-hydroxy pyrrolidine 43, which aromatized to pyrrole 44 with silica gel (Scheme 1.10, Table 1.3). Reactions of 42 with electron rich amine sources, such as the one described in entry 3 give competing aromatization and intramolecular cyclization products 44c and 45.
12 O O O OH 1 MeO C NH2R SiO2 2 OBn OH 2 2 CO Bn R N CO Bn R N 2 NBoc2 O 2 R1 R1
42 43 44
Scheme 1.10
Table 1.3 Reaction of substituted alkenyl tricarbonyl electrophile 4226
1 entry NH2R product and % isolated yield
1 OH O NH2 MeO N CO2Bn NBoc2 Bn
44a (47%)
2 OH O NH2 MeO N CO2Bn MeO NBoc2
OMe 44b (64%)
NBoc 3 OH 2 O CO2Me NH2 MeO N CO2Bn N N NBoc2 + H N H O BnO C HN 2
44c 45 (28%) (19%)
13 1.4 Dieckmann Condensation of 3-[(Carbonyl)methylamino]propanoates
The Dieckmann condensation, named for German chemist Walter Dieckmann, is a based catalyzed cyclization of 1,6- or 1,7-diesters into cyclic β-ketoesters, and is commonly referred to as the intramolecular Claisen condensation (Scheme 1.11). The mechanism involves nucleophilic acyl substitution of an ester group by the enolate ion of the second ester. This method is also compatible with heterocyclic β-ketoesters.39-45
Campaigne, Shutske, and Payne reported one of the first examples of the Dieckmann cyclization for the formation of a 3-oxo-2-carboxy pyrrolidine in their synthesis of 55
(Scheme 1.12).46
O
R3 OR1 O O O O base 48 OR1 OR1 R3 OR1 2 2 R2 R R
46 47 49
Claisen Condensation Reaction
O OR O CO2R base CO2R CO2R CO2R OR OR O O 50 51 52 53
Dickmann Cyclization
Scheme 1.11
14
EtO C O EtO2C CO2Et 2 NaOH
N CO2Et 75% N CO2Et Me Me N N
54 55
Scheme 1.12
Half-thiol diesters have been used in Dieckmann condensation reactions to control regioselectivity in diesters that otherwise would have hydrogens with similar acidity. A good example is that described in Scheme 1.13. The half-thiol diester 58 was formed by the Michael addition of ethyl 2-aminoacetate (57) to S-ethyl prop-2-enethioate (56).47
Thioester 58 was then treated with sodium hydride, which removed the hydrogen alpha to the nitrogen giving pyrrolidine 59 exclusively.
O O O COSEt H N NaH + 2 OEt SEt N CO2Et CO Et EtO2C THF N 2 77% CO2Et
56 57 58 59
Scheme 1.13
The half-thiol diester Dieckmann cyclization was utilized in the synthesis of the
3-oxo 2-carboxy pyrrolidine unit of carbapenem system (+)-64 (Scheme 1.15).48 This four step sequence started with the cycloaddition of azetidinone (+)-60 with siloxydiene
61 to give carbeacephem (+)-62. Treatment of (+)-62 with ozone opened the cyclohexene ring to produce carboxylic acid (+)-63, which was converted to (+)-64
15 through a coupling reaction with dipyridyldisulfide. The sodium enolate of (+)-64 underwent a regioselective Dieckmann condensation to form the 3-oxo 2-carboxy pyrrolidine of (+)-65. Again the enolate was not formed at the thioester. As was observed in the cyclization reactions of tricarbonyl compounds, stereocontrol did not occur in the formation of the pyrrolidine.
OTBS OTBS OTBS OAc OTBS OTBS O3/MeOH OH ZnCl2 Ac2O, Et3N NH + N N O O 65% O 85% O
CO2Me
(+)-60 61 (+)-62 (+)-63
N S S N
94%
OTBS OTBS S N O NaHMDS N N O O 65% O CO2Me CO2Me
(+)-65 (+)-64
Scheme 1.14
Efforts were made to perform the Dieckmann condensation asymmetrically. One of the first attempts involved the conversion of 4,4-dimethyl-1,3-oxazolidine-2-thione
(DMOT) 66 to ester 68.49 This ester was of particular interest due to the bulkiness of the
DMOT unit. Upon exposure to 2 equivalents of NaHMDS, 67 cyclized to 68 in 60% yield. The authors noted that crude 68 was isolated with the stereochemistry shown in
16 Scheme 1.15, but attempts to purify the product resulted in substantial epimerization of the ester.
OTBS OTBS OTBS O O O N Br N O NaHMDS O NH O S N O S N O (80%) O (60%) O O O O O
66 67 68
Scheme 1.15
Chiral oxazolidine 69 was treated with NaOMe to give regioselective Dieckmann condensation products 70 and 71, which can not be separated from its tautomer 72
(Scheme 1.16).50 As demonstrated in Table 1.4, substitution of R prevents the formation of 70 to give exclusively 71 and its tautomer 72. As 71 and 72 were inseparable, the mixture in which R is a methyl group was coupled with enantiomerically pure (S)-(-)-α- methoxy-α-trifluoromethylphenylacetic acid to form the Mosher ester of 72.51 Mosher
19 esters exhibit distinct F NMR signals for the CF3 groups, and analysis of 71 showed that it is formed with the stereochemistry indicated in Scheme 1.16 at an e.e. of 96%.50
R CO2Et EtO2C OH R O R OH O CO2Me CO2Me CO Me N NaOMe 2 O N + O N O N Me3C O O O O Me3C Me3C Me3C
69 70 71 72
Scheme 1.16
17
Table 1.4 Dieckmann cyclization of oxazolidine 6950
entry R % isolated yield of 70 % isolated yield of 71 and
72
1 H 12 64
2 Me --- 96
3 Ph --- 73
1.5 Metal catalyzed NH insertion reactions of α-diazo-β-keto esters
The most common preparation of enantiopure 3-oxo-2-carboxylate pyrrolidines is the copper or rhodium catalyzed NH insertion reactions of α-diazo-β-keto-δ-amino esters. Rhodium(II) [Rh2(OCOC7H15)4] was the first reported catalyst for this methodology. 52 It was later found that the more economic copper(II) acetylacetone or rhodium(II) acetate catalyst are equally effective (Fig. 1.4).
18 Me Me O O Rh O O Me O O Me Cu Me O O Me O O Rh O O Me Me
Copper (II) acetylacetonate Rhodium(II) acetate Cu(acac)2 Rh2(OAc)4
Figure 1.4: Metal Catalysts Used for NH Insertion Reactions
1.5.1 Copper catalyzed cyclizations
In general, copper catalyzed ring closures proceed by the Stevens rearrangement, which is characterized by the conversion of intermediate ammonium salts to amines through a 1,2-rearrangement.53,54 Scheme 1.17 illustrates an example of this procedure.55
Here (R)-(-)-5-phenylmorpholin-2-one (73) was coupled with ethyl 2-diazo-3-keto-pent-
4-enoate (74) to give (-)-75. Treatment of (-)-75 with Cu(acac)2 leads to aziridinium ylides 77a and 77b that are thought to go through intermediates 76a and 76b. Transfer of the carbon alpha to the carbonyl in the lactone to the C-2 position of the pyrrolidine gives a racemic mixture of 78. By comparison, reaction of 75 with Rh2(OAc)4 gave a complex mixture of products with 78 being the minor product. In a separate report, it was found that the more substituted lactam (+)-79 undergoes the same rearrangement to give (+)-82
56 as a single diastereomer (Scheme 1.18). Again reaction of (+)-79 with Rh2(OAc)4 gave a mixture of products with (+)-82 as the minor product, and pyrrolidines 78 and 82 are reported to be formed in quantitative yield.
19 O O
O O O O Ph N O O CH2Cl2, rt + OEt Ph N 80% OEt H N2 N2 (R)-(-)-73 74 (-)-75
Cu(acac)2
O O O Ph O Ph N N O N O O O LnM O OEt Ph O EtO CO Et O 2
(-)-78 77a 76a
EtO O O O O O EtO MLn O Ph Ph N N N Ph O O CO Et O O O 2 (+)-78 77b 76b
Scheme 1.17
Ph O O O O O Ph Ph Ph Ph O Ph N O O N O N Ph Cu(acac)2 N O O OEt LnM O O OEt O Ph N EtO CO Et 2 O 2
(+)-79 80 81 (+)-82
Scheme 1.18
To determine the effect of the heterocyclic ring size on the stereochemistry of the rearrangement both isoindolines and tetrahydroisoquinolines were examined in the copper catalyzed NH insertion reaction. In these studies, β-ketoester 83 was cyclized to tetrahydroisoquinolines or benzazepine 85 in good yields (Scheme 1.19). However a 1:1
20 mixture diastereomers was observed.57 A separate study found that cyclization of ester
86 also produced a 1:1 mixture of enantiomers 87a and 87b (Scheme 1.20). In contrast, aziridinium ylide 88 underwent an asymmetric Stevens rearrangement to form 90 as a single diastereomer (Scheme 1.21).58 The selectivity of this reaction is probably due to the stereochemical demands required for the 2 + 2 cyclization of intermediate 89.
n n n O O Cu(acac)2 N N OEt N
N2 R R R EtO C EtO2C 2 O
83 84 85
Scheme 1.19
Table 1.5 Examination of the Scope of the Stevens [1,2] Rearrangement57 entry n R product % isolated yield of 85
1 0 H 85a 68
2 1 85b 73
3 Me 85c 77
4 CH=CHCH3 85d 77
21 N MentO2C O MentO2C O O Cu(acac)2 N + N O O
N2
86 87a 87b
Scheme 1.20
Ph O H O CO2Et EtO C Cu(acac)2 CO2Et 2 N Ph Ph N N 21% O N 2 Ph Ph Ph
88 89 90
Scheme 1.21
1.5.2 Rhodium catalyzed cyclizations
Rhodium catalyzed NH insertion reactions of δ-amino-β-ketoesters were first reported in 1980. Since this time it has become one of the most widely used means of generating 3-oxo 2-carboxy pyrrolidines.52 Treatment of α-diazo-δ-amino-β-ketoester 94 with a catalytic amount of Rh2(OAc)4 gives 85% of 92 as a single isomer (Scheme 1.22).
Alternatively, photolysis of 94 produces a 1:9 ratio of 92 and 93. The Rh2(OAc)4 catalyst was selected because it was previously described as a good diazo insertion catalyst in the
. 59 synthesis of alcohols compared to RhCl3 H2O and RhCl(PPh3)3. This method was also applied to the more substituted lactam 94 in the asymmetric synthesis of carbapenem
95.60-62 Subsequently, a broad range of enantiopure carbapenems, which are a class of β- lactams that are powerful antibiotics and chemotherapeutic agents, have been prepared by
22 63-72 this strategy. The Rh2(OAc)4 catalyzed cyclization was found to be compatible with the formation of 4- and 6-membered nitrogen heterocycles.73,74
N2 CO CHPh 2 2 h! or O CO CHPh NH O N + N 2 2 O Rh2(OAc)4 O O CO2CHPh2 O
91 92 93
1 3 1 R R N2 R R3 R2 CO PNB R2 2 Rh2(OAc)4 O NH O N O O CO2PNB
94a, R1 = H, R2 = Me, R3 = Me 95 94b, R1 = OH, R2 = Me, R3 = H 1 2 3 94c, R = OH, R = CO2Me, R = H
Scheme 1.22
An early example of the use of Rh2(OAc)4 for monocyclic 3-oxo-2-carboxylate pyrrolidines is found in the synthesis of the antihypertensive drug enalapril 98, which is
75 sold commercially as Vasotec . The Rh2(OAc)4 promoted NH insertion reaction of 96 to 97 gave a 95:5 mixture of C-2 enantiomers with 97 being the major product (Scheme
1.23). Additionally, Davis and coworkers applied this method to the asymmetric synthesis of several pyrrolidines including the potent antifungal and antibiotic agent (+)- preussin (106).76-78 They found that the rhodium catalyst was not compatible with sulfur.77 It was deemed necessary to convert N-sulfinyl α-diazo-β-ketoester (+)-99 to N-
Boc amine (-)-100, which readily formed pyrrolidine (-)-102 with Rh2(OAc)4 (Scheme
1.24). It was later discovered that this method worked with alkyl derivatives of (-)-100.78
23 An excellent illustration of this is the recent total synthesis of (+)-preussin 106 (Scheme
1.25).76
O O NHBoc O Rh2(OAc)4 EtO CO2t-Bu EtO C CO t-Bu CO H 85% 2 N 2 N 2 N2 H Boc EtO C N 2 O Me Bn
96 97 98 Enalapril
Scheme 1.23
O Boc S 1. TFA NH O O O p-Tolyl NH O O 2. Boc2O/Et3N Rh2(OAc)4 Ph OMe Ph OMe 90% 94% Ph N CO2Me N2 N2 Boc
(+)-99 (-)-100 (-)-101
Scheme 1.24
O Boc S 1. TFA NH O O p-Tolyl NH O O 2. Boc2O/Et3N n-C5H11 OMe n-C5H11 OMe N2 N2
(-)-103 (+)-104
Rh2(OAc)4
OH O
Ph CO Me n-C9H19 N n-C9H19 N 2 Me Boc
106 (+)-105 (+)-Preussin
Scheme 1.25
24 CHAPTER 2
SYNTHESIS AND UTILIZATION OF SULFINIMINES (N-SULFINYL IMINES)
AS CHIRAL IMINE BUILDING BLOCKS
2.1 Introduction
Sulfinimines (N-sulfinyl imines) 107 are versatile chiral imine building blocks that are characterized by their sulfur stereogenic center. This sulfinyl auxillary exerts powerful stereodirecting effects in addition of enolates and organometallic reagents to both enolizable and nonenolizable sulfinimines with high asymmetric induction (Figure
2.1).79 Furthermore the sulfinyl group hinders epimerization of the newly created stereocenter in the sulfinamide product 108 by stabilizing anions at nitrogen and can act as a protecting group. In contrast to other imine N-auxillaries, the sulfinyl group is easily removed under comparatively mild conditions. The utility of sulfinimines 107 in highly diastereoselective asymmetric syntheses of amine derivatives has been demonstrated and is the subject of several reviews.80-84 Since their inception sulfinimes have been transformed into a number of biologically relevant structural units including α- and β- amino acids, α- and β-amino phosphonates, isoquinolines, syn- and anti- diamino esters, aziridine carboxylates, and aziridine phosphonates (Fig. 2.2).80,84-86
25 Lewis Base O R2 Site 2 2 O R Z M Z H R 1 S * 3 Z 1 S 3 R N * R * 3 Stereogenic R N R Z = H, alkyl, aryl, H H2N R ' Center RCHCO2R , CN etc. 108 109 Lewis Base Sulfinamide Primary Amine Activating Site Groups 107 Sulfinimine (N-Sulfinyl Imine)
Figure 2.1 Stereodirecting effect of the sulfinyl auxiliary
R1 O R1 2 O CH2 O CN R R S R N S p-Tolyl N R p-Tolyl N R2 Et2AlCN CN H ' H "-Amino Ketones R !-Amino Acids Isoquinolines O 1 O R1 2 O R R2 R R CH2 S CO2Me R3 S p-Tolyl N p-Tolyl N P(OR)2 H O O H R3 M O (RO)2 P "-Amino Acids OMe !-Amino Phosphonates O R1 R3 R2 N S 2 O 1 2 2 R COOMe R R p-Tolyl N R O M O M Br S CO2Et 1 3 p-Tolyl N Sulfinimine R N R H OEt OMe NR2 (N-Sulfinyl Imine) S syn- and anti-2,3- O p-Tolyl O Diamino Esters 3 Aziridine Carboxylates S R R P(OR)2 1 S O O R X S R R2 P(OR)2 p-Tolyl N H 1 3 S S R N R S p-Tolyl O !-Amino Aldehyde and Aziridine Phosphonates Ketones
Figure 2.2 Sulfinimine Mediated Asymmetric Transformations
Davis and co-workers pioneered the asymmetric synthesis of (S)-p- toluenesulfinimine 112 by elaboration of Andersen’s menthyl ester 110.87,88 Their initial preparation described in method A involves direct conversion of the Andersen reagent
110 by treatment with 1.5 equivalents of LiHMDS followed by 2 equivalents of an
26 aldehyde or ketone under dehydrating conditions to give an aldimine or ketimine (S)-112
(Scheme 2.1).88 Later a second two-pot method (method B) proved to give higher yields of enantiopure sulfinimines because it avoided the unwanted aldol reactions caused by reaction of the aldol with excess LiHMDS.87 This procedure arose from the isolation of sulfinamide (S)-111 by protonating the SN2 product formed by the reaction of LiHMDS and 110.87 Enantiopure sulfinimine (S)-112 results from treatment of (S)-111 with an
87,89 aldehyde or ketone in the presence of a Lewis acidic dehydrating agent Ti(OEt)4.
Some of the aldimine and ketimine products prepared by the Davis group are given in
Figure 2.3.87,89
O S 1. LiHMDS p-Tolyl O 2. RCHO, CsF one-pot (method A) (S)-110 O H(R') 1. LiHMDS S p-Tolyl N R 2. Sat. NH4Cl (87%) (S)-112
O RCHO or RC(O)R' S p-Tolyl NH2 Ti(OEt)4 two-pot (method B) (S)-111
Scheme 2.1
27 O H O Me O Me S S S p-Tolyl N Ph p-Tolyl N Ph p-Tolyl N n-Bu
(S)-112a (S)-112b (S)-112c (76%) (62%) (40%)
O H O H O H S S O S p-Tolyl N p-Tolyl N p-Tolyl N Me
N (S)-112d (S)-112e (S)-112f (80%) (68%) (60%)
O H O H O H S S S p-Tolyl N p-Tolyl N Me p-Tolyl N t-Bu
Ph (S)-112g (S)-112h (S)-112i (87%) (93%) (60%)
Figure 2.3 p-Toluenesulfinyl Aldimines and Ketimines
Later Ellman and co-workers prepared the tert-butylsulfinimine from the asymmetric oxidation of di-tert-butyl disulfide (113) using hydrogen peroxide and vanadyl acetylacetonate [VO(acac)2] to give tert-butanethiosulfinate (S)-115 (Scheme
2.2).90-92 Addition of lithium amide in ammonia provided the (R)-tert-butanesulfinamide
(116), which can be separated in its enantiomerically pure form by crystallization. The tert-butylsulfinimine (R)-117 was generated according to Davis’s procedure, and a list of sample tert-butyl aldimines or ketimines are shown in Figure 2.4. The tert-butyl sulfinamide (R)-116 is distinguished from the p-toluenesulfinamide (112a) by its increased nucleophilicity and steric hinderance caused by the tert-butyl group.90-92
28 O O slow addition of H2O2 1. LiNH2, NH3, S t-Bu S t-Bu o S t-Bu S VO(acac)2 (0.50 mol%), t-Bu S THF, -78 C t-Bu NH2 (S)-114 (0.50 mol%) 2. crystalization 113 acetone (S)-115 (65% overall yield, (R)-116 0oC, 20 h >99% ee) (98%, 86% ee) RCHO, CuSO4 or RC(O)R', Ti(OEt)4 t-Bu H N OH O (H)R' S t-Bu OH t-Bu N R
t-Bu (R)-117 (S)-114
Scheme 2.2
O H O Me O Me S S S t-Bu N Ph t-Bu N Ph t-Bu N i-Bu
(R)-117a (R)-117b (R)-117c (91%) (89%) (88%)
O H O H O H S S O S Ph t-Bu N t-Bu N t-Bu N
N (R)-117d (R)-117e (R)-117f (100%) (82%) (79%)
O H O Me O S OTBS S OTBS S t-Bu N t-Bu N t-Bu N
(R)-117g (R)-117h (R)-117i (96%) (63%) (91%)
Figure 2.4 tert-Butylsulfinyl Aldimines and Ketimines
Senanayake and co-workers reasoned that the introduction of a more bulky R1 group to sulfinimine 107 would increase the diastereoselectivity of the addition of organometallic reagents.93 They developed a general procedure for the synthesis of a variety of sulfinamides from inexpensive and readily available (R,S)-N-tosyl-
29 norephedrine (118) (Scheme 2.3). The hypothesis behind the use of (R,S)-118 was the ability of the N-tosyl group to strengthen the S-N bond in N-tosyl-4-methyl-5-phenyl-
1,2,3-oxathiazolidine-2-oxide (TMPOO, 119), while weakening the S-O bond in the compound.94 They determined that oxathiazolidine oxide (2R,4S,5R)-119 was a common pathway to both R- and S- sulfinamide 120. As shown in Figure 2.5 this procedure has produced an assortment of sulfinamides, which are readily converted to sulfinimines via
Davis’ protocol.
O Ts SOCl2, Py S Ts 1. RMgX O HO HN o O N THF, -78 C 2. LiNH2, NH3 S R NH2 Ph Me >90% Ph Me (>99% de)
(R,S)-118 (2R,4S,5R)-119 (S)-120 (R)-TMPOO
1. LiNH2, NH3 2. RMgX
O S R NH2
(R)-120
Scheme 2.3
30 O O O S S S NH2 NH2 NH2
(R)-116 (81%, 75% ee) (R)-111 (77%, 10% ee) (R)-120a (85%,68% ee) (S)-116 (89%, 99%ee) (S)-111 (83%, 99%ee) (S)-120a (80%, 99%ee)
O O O S S S NH2 NH2 NH2
(R)-120b (81%, 75% ee) (R)-120c (77%,10% ee) (R)-120d (85%, 68% ee) (S)-120b (90%, 99%ee) (S)-120c (87%, 99% ee) (S)-120d (80%, 99% ee)
O O S S NH2 NH2
(S)-120e (90%, 99% ee) (R)-120f (80%, 94% ee)
Figure 2.5. (2R,4S,5R)-119 derived sulfinamides
Recently, both Ruano’s and Kazlauskas’ research groups reported protocols for the production of racemic sulfinamides.95,96 Ruano and his colleagues were able to get quantitative (±)-methyl p-toluenesulfinate (122) from the N-bromosuccinimide promoted oxidation of commercially available p-tolyl disulfide (121). Sulfinate 122 was converted to sulfinamide 111 by LiHMDS. Like Ruano, Kazlauskas reported a procedure for the synthesis of racemic tert-butyl sulfinamide (116) that began from a disulfide.96 In this alternative method, meta-chloroperbenzoic acid (m-CPBA) was used as the oxidizing agent, and the sulfur-sulfur bond was broken by the conversion of the thiosulfate into sulfinyl chloride 124.97,98 Amination was performed by the addition of ammonium hydroxide (NH4OH) to give sulfinamide 116 in 21% overall yield.
31
O O NBS, MeOH LiHMDS S p-Tolyl S S p-Tolyl S p-Tolyl OMe p-Tolyl NH quant 75% 2
121 (±)-122 (±)-111
Scheme 2.4
1. m-CPBA O O 2. SO Cl NH OH S t-Bu 2 2 S 4 S t-Bu S t-Bu Cl t-Bu NH (20% overall yield) 2
123 (±)-124 (±)-116
Scheme 2.5
Additionally, Kazlauskas reported the racemic synthesis of seven other sulfinamides from their sulfinyl chlorides, which were generated by two general methods.
The first approach was the formation of the sulfinyl chloride 126 by reaction of sulfinate
125 with oxalyl chloride (Scheme 2.6).96 Addition of ammonium hydroxide gave 56% and 59% of sulfinamides 111 and 127a, respectively. Alternatively, Kazlauskas followed the sulfinyl chloride preparation procedure reported by Klunder and Sharpless.99 This transformation involves the reduction of sulfonyl chloride 128 to 126 by oxidation of trimethyl phosphite [P(OMe)3] to trimethyl phosphone. Aminiation in this case was achieved by the introduction of LiHMDS followed by protonation with NH4Cl.
32 O O O S (ClCO)2 NH4OH R ONa S S R Cl R NH2
125a R = p-tolyl 126 111 R = p-tolyl 125b R = Ph 127a R = Ph
Scheme 2.6
O 1. LiHMDS O P(OMe) 2. NH Cl RSO Cl 3 S 4 S 2 R Cl R NH EtOH 2
128 126 127
a, R = Ph; b, R = p-ClPh; c, R = p-MeOPh; d, R = 2,4,6-MePh; e, R = 1-naphthyl; f, R = 2,4,6-i-PrPh; g, R = t-Bu
Scheme 2.7
2.2 Present Study
The major objective of this present study is to utilize enantiopure sulfinimines for the synthesis of biologically relevant pyrrolidines. The plan to accomplish this goal involves: (i) utilizing sulfinimine chemistry to create a new protocol for the asymmetric synthesis of 4-oxo-2-substituted pyrrolidines, which allows for various functional groups to occupy the 2-position and (ii) devising a method for the stereocontrolled hydroxylation at the 3-position of pyrrolidine 130 (Scheme 2.8). Chemical manipulation of 130 will allow for the synthesis of a variety of functionized pyrrolidine diols. Enantiopure pyrroldine diols are vital structural units in compounds that are useful in the treatment of cancer, HIV, and other diseases.100-111
33 O O HO OH 3 S 4 R1 N R2 2 2 R2 R N 5 N H H 1
129 130 131
Scheme 2.8
2.2.1 Previous Syntheses of 3,4-Dihydroxyprolines
The most common synthetic strategy for the synthesis of 3,4-dihydroxyprolines involves the conversion of aldopentoses, monosacharides composed of five carbon atoms with an aldehyde.112-120 An example of this method is given in Scheme 2.9. Here
(2R,3R,4R)-lyxose (132) was cyclized to a lactone and protected with triphenylmethane to afford 59% of 133.118 The diols in lactone 133 were silated to 134, and the ring was opened by NaBH4 to give 135. The diols of 135 were converted to mesylates, and pyrrolidine 137 was formed in 79% by heating 136 with benzylamine.
1. Br2, K2CO3, H2O O OH 2. Ph3CCl, pyridine O O TBDMSCl O O DMAP, 80oC OCPh3 DMF, imidazole OCPh3 H OH (59% over 2 steps) (88%) OH OH HO OH TBSO OTBS
(2R,3R,4R)-132 (2R,3S,4S)-133 (2R,3S,4S)-134
NaBH4, CeCl3 MeOH (98%)
TBSO OTBS
PhCH2NH2 OTBS CH3SO2Cl, OTBS o OCPh3 85 C, 60 h pyridine, DMAP N MsO OCPh3 HO OCPh3 (79%) (74%) Ph TBSO OMs TBSO OH
(2S,3S,4S)-137 (2S,3R,4S)-136 (2S,3S,4S)-135
Scheme 2.9
34 The benzyl group of 137 was removed by hydrogenation, and the free amine was then protected with fluorenylmethyl chloroformate (Scheme 2.10).118 Concentrated formic acid in acetonitrile cleaved the trityl ester of 138 forming 139 in 71% yield. This step proved to be problematic as these conditions could also cleave the silyl esters.121
The Swern oxidation followed by sodium chlorite oxidation gave protected 3,4- dihydroxyproline 141. Removal of the protecting groups afforded a 59% yield of 142.
1. H , Pd/C TBSO OTBS 2 TBSO OTBS TBSO OTBS 2. FmocCl, Et3N toluene HCO2H, MeCN OCPh3 OCPh3 OH N (65%) N (71%) N Fmoc Fmoc Ph
(2S,3S,4S)-137 (2S,3S,4S)-138 (2R,3S,4S)-139
(COCl)2, DMSO Et3N, CH2Cl2 (96%)
1. TBAF, THF HO OH TBSO OTBS TBSO OTBS 2. MeOH/dioxane/ NaClO2, NaOH (15:4:1) KH2PO4, C6H10 OH OH O N (59%) N (93%) N H O O Fmoc Fmoc
(2S,3S,4S)-142 (2R,3S,4S)-141 (2S,3S,4S)-140
Scheme 2.10
Another common approach toward the synthesis of cis-3,4-dihydroxyprolines involves asymmetric dihydroxylation of a 3,4-dehydropyrrolidine.122-124 Ring closing metathesis is applied in the formation of dehydropyrrolidine 144.124 Asymmetric dihydroxylation adds cis-diols anti to the 2-furyl group giving 145 as a single isomer.
The 3,4-alcohols of 145 were converted to an acetonide, and the 2-furan was oxidized to
35 a carboxylic acid and esterified to 147. Reduction of the ester followed by deprotection gave 149.
HO OH Cat. OsO4, NMO Grubbs I t-BuOH, THF, H2O O O O N (92%) N (92%) N Boc Boc Boc
(S)-143 (S)-144 (2R,3R,4S)-145
2,2-DMP, cat. p-TSA CH2Cl2 (83%)
1. cat. RuO , NaIO O O O O 2 4 O O t-BuOH, MeCN, CCl4 DiBAL-H Et2O 2. CH2N2, Et2O OMe O N (80%) N (82%) N Boc OH Boc O Boc
(2R,3R,4S)-148 (2S,3R,4S)-147 (2R,3R,4S)-146
1. 80% aq. TFA 2. aq. HCl (75%)
HO OH
N H OH
(2R,3R,4S)-149
Scheme 2.11
2.2.2 Synthesis of (2R)-3,4-dihydroxyproline isomers
The current strategy for the synthesis of all stereoisomers of 3,4- dihydroxypyrrolidines from common building block 130 involves employment of Davis’s methodology for sulinimine derived proline derivative (R)-101.77 In this approach, it was found that the sodium enolate of methyl acetate adds to the C=N bond in phenyl sulfinimine (SS)-112 to give 84% of β-amino ester (SS,R)-150 in greater than 97%ee
36 (Scheme 2.12). A second equivalent of the enolate yields pentanoate (SS,R)-151, which can be converted to α-diazo (SS,R)-99 with 4-carboxy benzenesulfonazide (4-CBSA).
The sulfinyl group in (SS,R)-99 was easily cleaved with TFA in methanol to give sulfinate
122, and the deprotected amine was reprotected with Boc2O in the presence of catalytic
DMAP. The pyrrolidine (R)-101 resulted from the Rh2(OAc)4 promoted NH insertion of
(R)-100. However, Davis and co-workers observed a 85:15 mixture of cis:trans isomers of the (R)-101 in solution, which changed to a 60:40 isomer mixture upon chromatographic purification. Structural determination of 101 was proved by NOE and
NOESY experiments on (2S,3R,5R)-153, which was isolated from reduction of 101 followed by deprotection of (R)-152.
O O O H CH3CO2Me S CH3CO2Me S S NaHMDS p-Tolyl NH O NaHMDS p-Tolyl NH O O p-Tolyl N Ph o Ph OMe o Ph OMe -78 C, Et2O -78 C,THF (84%, >97% de) (87%)
(SS)-112a (SS,R)-150 (SS,R)-151
4-N3SO2C6H4CO2H Et3N, MeCN (91%)
O O Boc 1. TFA/MeOH S Rh2(OAc)4 NH O O 2. Boc2O, Et3N, p-Tolyl NH O O Ph CO Me DCM DMAP, TFA N 2 Ph OMe Ph OMe (94%) (90%) Boc N2 N2
(R)-101 (R)-100 (SS,R)-99
NaBH4/MeOH (85%)
OH OH TFA, DCM Ph N CO2Me (73%) Ph N CO2Me H Boc
(R)-152 (2S,3R,5R)-153
Scheme 2.12
37 2.2.2.1 Decarboxylation of 3-oxo-2-carboxylate pyrrolidines
It was found necessary to develop a protocol for the decarboxylation of (R)-101 to obtain the desired pyrrolidine builiding block 155. It was observed that treatment of (R)-
101 with two molar equivalents of LiOH in THF/H2O (5:2) gave carboxylic acid (R)-154 in 67% isolated yield (Scheme 2.13).125,126 The carboxylic acid was characterized by the disappearance of the two proton peaks at δ 3.80 and 3.82 in the 1H NMR that were representative of the methyl ester, and was confirmed by a broad O-H stretch at 3304 cm-
1 in the IR. Carboxylic acid (R)-154 was heated to 90 oC to give 75% of 4-oxo-2-phenyl pyrrolidine (R)-155. The spectral data collected for (R)-155 is consisted with the values reported by Wang and co-workers.127
O O O LiOH !, PhMe Ph N CO2Me rt, 8 h Ph N CO2H (75%) Ph N Boc (67%) Boc Boc
(R)-101 (R)-154 (R)-155
Scheme 2.13
The decarboxylation method described in Scheme 2.13 was also tested with the benzyloxycarbonyl (Cbz) protected pyrrolidine (R)-158 to explore the compatibility of the methodology. The introduction of the Cbz-protecting group was achieved by two
77 pathways (Scheme 2.14). The first involve the desulfination of (SS,R)-151 followed by
DMAP catalyzed reaction of the newly freed amine with benzyl chloroformate (CbzCl) to give (R)-156. The transformation was confirmed by the disappearance of the sulfinyl methyl peak at δ 2.38 in the 1H NMR and the emergence of two new peaks at δ 5.25 and
38 5.74, which are representative of the methylene portion of the benzyl carbamate. Diazo transfer of (R)-156 with 4-CBSA allowed for 83% of (R)-157. Alternatively, Cbz- protected diazo amide (R)-157 can be realized from sulfinylamide (SS,R)-99 by removal of the sulfinyl auxillary followed by Cbz protection of the free amine. Treatment of (R)-
157 with Rh2(OAc)4 produced a 96% yield of 2,3,5-trisubstituted pyrrolidine (R)-158
(Scheme 2.15). The LiOH promoted decarboxylation of (R)-158 gave only a 17% yield of 2-phenyl-4-oxo pyrrolidine (R)-159, which is an overall yield of 9% from (SS,R)-150.
O 1. TFA S p-Tolyl NH O O 2. Et3N, CbzCl, Cbz DMAP NH O O Ph OMe (77%) Ph OMe
(SS,R)-151 (R)-156
4-CBSA, Et3N (83%)
O 1. TFA S p-Tolyl NH O O 2. Et3N, CbzCl, Cbz DMAP NH O O Ph OMe (87%) Ph OMe N 2 N2
(SS,R)-99 (R)-157
Scheme 2.14
O O Cbz Rh2(OAc)4 1. LiOH NH O O DCM 2. 90oC, PhH Ph OMe (96%) Ph N CO2Me (17%) Ph N N2 Cbz Cbz (R)-157 (R)-158 (R)-159
Scheme 2.15
39 As the LiOH driven decarboxylation of (R)-158 did not prove to be profitable, a second strategy was developed which sought to replace the methyl ester with a tert-butyl ester. This approach was adopted because previous reports have shown that the tert-butyl ester is easily removed under acidic conditions and the Cbz-group does not cleave under these conditions.128,129 Introduction of the tert-butyl ester was achieved by the addition of the sodium enoate of tert-butyl acetate to amide (SS,R)-150 (Scheme 2.16). Diazo transfer of (SS,R)-160 gives 96% of (SS,R)-161, which undergoes desulfination and carbamate formation yielding 97% of (R)-163. Alternatively, (R)-163 is formed by first introducing the Cbz-group to (R)-160, and then performing the diazo transfer. The
Rh2(OAc)4 promoted NH transfer of (R)-163 resulted in 86% of pyrrolidine (R)-164
(Scheme 2.17). The decarboxylation of (R)-164 with 20 molar equivalents of TFA in
DCM at room temperature produced 93% of (R)-159. This alternative decarboxylation procedure increased the overall yield from 9% to 64%.
O O O S CH3CO2t-Bu S 4-CBSA S p-Tolyl NH O p-Tolyl NH O O p-Tolyl NH O O NaHMDS Et3N, MeCN Ph OMe -78oC,THF Ph Ot-Bu (96%) Ph Ot-Bu (86%) N2
(SS,R)-150 (SS,R)-160 (SS,R)-161
1. TFA/MeOH 1. TFA/MeOH 2.CbzCl, Et N, 3 2.CbzCl, Et3N, DMAP, THF DMAP, THF (96%) (97%)
Cbz 4-CBSA Cbz NH O O NH O O Et3N, MeCN Ph Ot-Bu (83%) Ph Ot-Bu N2 (R)-162 (R)-163
Scheme 2.16
40
O O Cbz Rh2(OAc)4 TFA NH O O DCM DCM, rt Ph Ph Ot-Bu (86%) Ph N CO2t-Bu (93%) N N2 Cbz Cbz (R)-163 (R)-164 (R)-159
Scheme 2.17
Following the successful transformation of (R)-164 to (R)-159, attempts were made to selectively remove the tert-butyl ester of (R)-167 in the presence of a Boc- protecting group (Scheme 2.17). To complete this task (SS,R)-160 was converted to Boc- amide (R)-165, and was then subjected to diazo transfer (Scheme 2.18). As shown in
Schemes 2.14 and 2.16, sulfinamide (SS,R)-161 can go directly to (R)-166 by acidic cleavage of the auxillary and immediate Boc protection of the free amine. Cyclization of
(R)-166 gives 89% of pyrrolidine (R)-167.
O 1. TFA/MeOH S 2.Boc2O, Et3N, Boc p-Tolyl NH O O DMAP, THF NH O O Ph Ot-Bu (90%) Ph Ot-Bu
(SS,R)-160 (R)-165
4-CBSA Et3N, MeCN (73%)
O 1. TFA/MeOH S 2.Boc O, Et N, Boc Rh (OAc) O p-Tolyl NH O O 2 3 2 4 DMAP, THF NH O O DCM Ph Ot-Bu (70%) Ph Ot-Bu (89%) Ph N CO2t-Bu N2 N2 Boc
(SS,R)-161 (R)-166 (R)-167
Scheme 2.18
41
Previous reports have shown that it is possible to cleave an N-Boc protecting group and a tert-butyl ester independent of each other. Rapport demonstrated that 500 mol % of 1 M HCl in ethyl acetate (EtOAc) would selectively cleave the N-Boc protecting group of both primary and secondary amines in the presence of a t-butyl
130 ester. Also, Wu and colleagues found that ZnBr2 converted a tert-butyl ester into a carboxylic acid without affecting primary N-Boc amines.131 Later, Marcantoni’s research group achieved the same transformation with cerium(III) chloride heptahydrate.132 The reaction conditions supplied by Wu and Marcantoni were applied to pyrrolidine (R)-167, and the results are described in Table 2.1 (Scheme 2.19). It was observed that these conditions were not a practical means to getting (R)-155. Instead mixtures of (R)-155,
168, and (R)-169 were obtained. Pyrrolidine (R)-155 is distinguished from pyrrolidine
168 by the presence of rotamers. The 1H NMR of 168 shows a broad NH peak at 2.03 ppm and a single 9 H peak at 1.39 ppm. In contrast, the 1H NMR of (R)-155 shows two 9
H peaks at 1.27 ppm and 1.32 ppm with no broad NH peaks. The selectivity of the decarboxylation did not improve with CeCl3. The proposed mechanism of the conversion of (R)-167 to (R)-155 involves the coordination of the metal with the ester oxygen atoms.
This complex activates the carbonyl for water hydrolysis to a carboxylic acid. Although the acid intermediate was not isolated in this reaction, Wu and Marcantoni were both able to observe the carboxylic acid in the 1H NMR.
42 O Boc Rh2(OAc)4 NH O O DCM O Ph Ot-Bu (89%) Ph N N2 O O O
(R)-166 (R)-167
conditions
O O O
+ + Ph N Ph N CO2t-Bu Ph N H H Boc
(R)-169 168 (R)-155
Scheme 2.19
Table 2.1 Decarboxylation conditions of Pyrrolidine (R)-167131,132
% isolated yield entry conditions (R)-155 168 (R)-169
1 ZnBr2 (5 equiv.) 12 13 60
2 ZnBr2 (3 equiv.) 13 20 52
3 ZnBr2 (1 equiv.) 18 27 36
. 4 CeCl3 7H2O (1.5 equiv.) 15 15 45
NaI (1.3 equiv.)
2.2.2.2 Additions to C-2 of 2-phenyl-4-oxo pyrrolidine
One of the pivotal steps in the proposed construction of 3,4-dihydoxyproline is the regioselective hydroxylation of (R)-155 and (R)-159. In order to prove the utility of
43 the 2-substituted-4-oxo pyrrolidine building block, it must be able to undergo both regio- and stereoselective addition of electrophiles. Precedent shows that base removal of a C-3 proton of pyrrolidine (R)-159 can allow for electrophilic addition at this site.133 The aprotic oxidizing (-)-reagent [(8,8-dichlorocamphoryl)sulfonyl]-oxaziridine [(-)-170] was employed as an electrophile to introduce the hydroxy group (Scheme 2.20). This reagent was used for its availability and because its bulkiness is expected to direct oxidation anti to the phenyl group at C-1.134-136 Hydroxy pyrrolidine (R)-172 is achieved in 42% and
63% yield with n-butyllithium and LDA acting as the base in THF (Table 2.1, entries 1 and 2). The yield is raised to 91% with LDA in a 1:10 solvent mixture of ion stabilizer hexamethylphosphoramide (HMPA) and THF (entry 3). Appling this protocol to (R)-155 gives 67% of 3-hydroxy-4-oxo-pyrrolidine (R)-173 (Scheme 2.21).
1. base O 2. (-)-170 HO O Cl 3. HCl Cl N Ph Ph N N S O Cbz Cbz O2
(R)-159 (2S,3S)-171 (-)-170
Scheme 2.20
1. LDA O 2. (-)-170 HO O 3. HCl Ph Ph N HMPA/THF N Boc (67%) Boc
(R)-155 (2S,3S)-172
Scheme 2.21
44 Table 2.2 Formation of (2S,3S)-171 from C-2 Addition of Davis’ Oxaziridine (-)-170 to
(R)-155
Entry Base Solvent % Isolated Yield of
(2S,3S)-171
1 n-BuLi THF 42
2 LDA THF 63
3 LDA HMPA/THF (1:10) 91
The C-2 hydroxy C-3 oxo pyrrolidine 173 proved to be a viable means to the four stereoisomers of 3,4-dihydroxy pyrrolidines (Scheme 2.22). Reduction of the oxo group with NaBH4 allowed for a nearly quantitative yield of 3,4-cis pyrrolidine diol 174 (Table
2.2, entries 1 and 2).137 Conversely, the 3,4-trans diol 175 is accessible from reduction of
(2S,3S)-173 with tetramethylammonium triacetoxyborohydride [Me4NHB(OAc)3]
(entries 3 and 4). This borohydride is presumed to go through a B-OH coordination, which directs stereoselective reduction of the ketone.138 As shown in entries 5 and 6, attempts were made to generate 175 with NaBH4/CeCl3 and ZnBH4, however these gave
3:1 and 4:1 ratios of inseparable mixtures of 175 and 174, respectively.137,139
Alternatively, pyrrolidine 173 is able to undergo Mitsunobu stereochemical inversion to give 2,3-cis pyrrolidine 176 (entries 7 and 8).140 The configuration of all of these transformations were confirmed by 1H NMR comparison with literature reports.141 The pyrroldine cis-174 is distinguished from trans-175 by its coupling constant of 13 Hz compared the 10 Hz coupling constant of the latter.
45
HO O HO OH HO OH AcO O conditions Ph N Ph N Ph N Ph N PG PG PG PG
(2S,3S)-173 (2S,3S,4R)-174 (2S,3S,4S)-175 (2S,3R)-176 a PG = Boc b PG = Cbz
Scheme 2.22
Table 2.3 Transformations of (2S,3S)-173
Entry Protecting Group Conditions Result % Yield
1 Boc NaBH4, MeOH 174a 98
2 Cbz 174b 93
3 Boc Me4NBH(OAc)3, 175a 77
AcOH/MeCN
4 Cbz 175b 73
5 NaBH4/CeCl3, 174b:175b (1:3) 90
MeOH
6 ZnBH4, THF 174b:175b (1:4) 98
7 Boc PPh3, DIAD, AcOH 176a 73
8 Cbz 176b 70
The transformation of 3,4-cis pyrrolidine 174 to dihydroxyproline (2R,3S,4R)-179 began with the formation of acetonide 177 (Scheme 2.23).124 The isopropylidine ketal
46 protecting group was desirable because of its stability in the subsequent aryl oxidation.
The conversion of 177a to carboxylic acid 178a is known and is well documented.124,142-
145 Efforts to oxidize 177b to 178b were less successful giving 33% of the carboxylic acid (Table 2.3). This is most likely due the presence of a second phenyl group.
Deprotection of 178a resulted in 75% of (2R,3S,4R)-179, and spectral data collected for the 3,4-dihydroxyproline was identical to reported values.120
HO OH O O 2,2-DMP, p-TSA Ph N (76-82%) Ph N PG PG
(2S,3S,4R)-174 (2S,3S,4R)-177 a = Boc b = Cbz NaIO4 (15 equiv.) . RuCl3 H2O (0.01 equiv.) CCl4/MeCN/H2O (1:1:1.5) (33-50%)
HO OH O O HCl HO HO N (75%) N H O O PG
(2R,3S,4R)-179 (2R,3S,4R)-178
Scheme 2.23
Table 2.4 Conversion of (2S,3S,4R)-174 to (2R,3S,4R)-179
Entry Protecting % Isolated Yield of % Isolated Yield of % Isolated Yield of
Group (2S,3S,4R)-177 (2R,3S,4R)-178 (2R,3S,4R)-179
1 Boc 82 50 75
2 Cbz 76 33 ---
47
The trans-dihydroxyproline (2R,3S,4S)-182 was prepared in a manner similar to that described in Scheme 2.23. Here the 3,4-diol of (2S,3S,4S)-175a was converted into acetate esters with acetic anhydride and DMAP giving 60% of (2S,3S,4S)-180 (Scheme
2.24).146 Again oxidation of the phenyl group was achieved with a catalytic amount of
RuCl3 and 5 equiv. of NaIO4 to 50% of (2R,3S,4S)-181. Both release of the diol and formation of the free amine resulted from treatment of (2R,3S,4S)-181 with acid forming
(2R,3S,4S)-182. The 1H NMR and rotation of (2R,3S,4S)-182 was consistent with literature values.147
HO OH AcO OAc
AcO2, DMAP Ph N MeCN Ph N Boc (60%) Boc (2S,3S,4S)-175a (2S,3S,4S)-181
NaIO4 RuCl3 (50%)
HO OH AcO OAc TFA/Dowex HO2C N (67%) HO2C N H Boc (2R,3S,4S)-183 (2R,3S,4S)-182
Scheme 2.24
The final two stereoisomers of 3,4-dihydroxy proline were prepared from common intermediate (2S,3R)-176a. The all cis pyrrolidine configuration resulted from reduction of (2S,3R)-176a with NaBH4, and the 3,4-trans pyrrolidine was formed by reduction with ZnBH4 (Scheme 2.25). Immediate conversion of the diols to acetate esters
48 gave 75% of (2S,3R,4S)-183 and 90% of (2S,3R,4R)-184. Both the cis- and trans- pyrrolidines were transformed into carboxylic acids (2R,3R,4S)-185 and (2R,3R,4R)-186.
As previously described in Scheme 2.24, cleavage of the diols and Boc protecting group is accomplished with acid. The spectral data obtained for (2R,3R,4S)-187 and
(2R,3R,4R)-188 are consistent with literature values.148
AcO O AcO OAc AcO OAc 1. NaBH4 or ZnBH4 2. AcO , DMAP 2 or Ph N MeCN Ph N Ph N Boc Boc Boc
(2S,3R)-176a (2S,3R,4S)-183 (2S,3R,4R)-184 (75%) (90%)
NaIO4 RuCl3
HO OH HO OH AcO OAc AcO OAc TFA/Dowex or or HO C HO C HO2C N 2 N 2 N HO2C N H H Boc Boc
(2R,3R,4R)-188 (2R,3R,4S)-187 (2R,3R,4S)-185 (2R,3R,4R)-186 (75%) (90%) (67%) (67%)
Scheme 2.25
These protocols provide a general pathway to the four stereoisomers of 3,4- dihydroxyprolines in 11 steps from (SS,R)-150 (Scheme 2.26). One advantage of this method is the benefit of a common intermediate, which avoids the current procedure of using the two enantiomers of tartaric acid and its derivatives.120,147 Also, the stereodirecting effects of the sulfinyl auxillary eliminates many of the problems that found in previous syntheses associated with introducing new chiral centers.
49 HO OH HO OH
or HO2C N HO2C N H H
(2R,3S,4R)-180 (2R,3S,4S)-182 (7%) O (3%) S p-Tolyl NH O 11 steps
Ph OMe HO OH HO OH
(SS,R)-150 or HO2C N HO2C N H H
(2R,3R,4S)-187 (2R,3R,4R)-188 (9%) (9%)
Scheme 2.26
2.2.2 Synthesis of (+)-Lentiginosine
To further demonstrate the utility of (S)-130 as a chiral building block, it was used in the total synthesis of indolizidine metabolite (+)-lentiginosine [(+)-189] (Scheme
2.27). Lentiginosine was isolated in 1990 from the leaves of Astragalus lentignosus.149
It was later found to be a selective and powerful inhibitor of α- and β-glycosidases.150 It is also structurally related to other polyhydroxylated indolizidine metabolites, such as swainsonine and castanospermine, which are being investigated as potential drugs because of their anti-HIV activity (Fig. 2.6).149,151
O HO OH
R N N H
130 (+)-(1S,2S,8aS)-189
Scheme 2.27
50
HO OH HO OH HO H H H HO HO N N N
HO OH Lentiginosine Swainsonine Castanospermine
Figure 2.6. Some polyhydroxylated indolizidine metabolites
2.2.3.1 Previous Syntheses of (+)-Lentiginosine
In general, there are two different approaches to the synthesis of the six- membered ring of lentiginosine and other related polyhydroxylated indolizidines. The first is ring closing metathesis and the second is intramolecular displacement of an activated OH group.152-163 Singh’s synthesis of (1S,2S,8aS)-189 is an example of generating the indolizidine through ring closing metathesis (Scheme 2.28).154 They started by transforming commercially available L-(+)-tartaric acid (190) to protected tetra-ol (2S,3S)-191 through a literature procedure.164 The free alcohol of (2S,3S)-191 was converted to azide (2S,3S)-192 by treating its tosylate with sodium azide.154
Homoallylic alcohol (4R,5S,6S)-193 was formed by Corey-Kim oxidation of the terminal alcohol to an aldehyde followed by chelation controlled addition of allyltributyl tin. The authors reported that they were unable to get the aldehyde from Swern, PCC, or Dess-
Martin oxidations. The pyrrolidine ring was constructed by turning (4R,5S,6S)-193 to its mesylate (4R,5S,6S)-194, and then reducing the azide to promote an SN2 cyclization.
Acrylolyl chloride was employed to give (2S,3S,4S)-196 from (2S,3S,4S)-195. Grubbs’ first generation catalyst was used to form the six membered ring of indolizidinone
51 (1S,2S,8aS)-197. Hydrogenation of (1S,2S,8aS)-197 followed by reduction of the amide gave lentiginosine (189).
1. BnBr, Bu4NI 18-crown-6 (80%) 2. LAH (88%) OH OBn 1. TsCl, Et3N OBn 3. NaH, TBSCl (90%) 2. NaN3, CO2H OH N3 HO2C TBSO TBSO (60%) OH OBn OBn
(2S,3S)-190 (2S,3S)-191 (2S,3S)-192 diisopropyl D-tartaric acid 1. TBAF (95%) 2. NCS, Me2S 3. SnCl4, Allyl tributyl tin (70% over 2 steps)
BnO OBn OMs OBn OH OBn LiAlH4 MsCl, Et3N N3 N3 N (68%) (92%) H OBn OBn
(2S,3S,4S)-195 (4R,5S,6S)-194 (4R,5S,6S)-193
O
Cl
Et3N (85%)
BnO OBn BnO OBn HO OH 1. 10% Pd/C, H2 Grubbs 1 2. LiAlH4 N (86%) N (97%, 7% overall) N
O O
(2S,3S,4S)-196 (1S,2S,8aS)-197 (1S,2S,8aS)-189
Scheme 2.28
Petrini’s synthesis of (+)-lentiginosine (189) is an illustration of ring closure through reaction with an activated alcohol (Scheme 2.29).152 Nitrone (3S,4S)-199 was prepared in five steps using a literature procedure and starting with (2R,3R)-198.165-167
Addition of 4-(phenylmethoxy)butylmagnesium bromide to (3S,4S)-199 produced a 95:5 mixture of (2S,3S,4S)-200.152 Reduction of the hydroxylamine with Raney Ni catalyst
52 followed by debenzylation gave 76% of amino alcohol (2S,3S,4S)-201. Activation of the alcohol with Ph3P led to the intramolecular SN2 ring closure forming 88% of (1S,2S,8aS)-
202. The removal of the methoxymethyl groups resulted in 91% of (1S,2S,8aS)-189.
1. BnNH2 2. NaBH4, BF3 3. CH2(OMe)2, P2O5 HO CO H 4. H /Pd(OH) MOMO OMOM MOMO OMOM 2 2 2 MgBr 5. H2O2, SeO2 BnO
HO CO2H (33% over 5 steps) N (82%) N OBn O OH
(2R,3R)-191 (3S,4S)-199 (2S,3S,4S)-200 (L-tartaric acid)
1. H2, Raney-Ni 2. HCONH4, Pd/C (76%)
HO OH MOMO OMOM MOMO OMOM Ph3P, HCl, MeOH CCl4, Et3N N (91% 17% overall) N (88%) N OH H
(1S,2S,8aS)-189 (1S,2S,8aS)-202 (2S,3S,4S)-201
Scheme 2.29
2.2.3.2 Total Synthesis of (+)-Lentiginosine
The strategy for the sulfinimine derived synthesis of (+)-lentiginosine (189) starts with breaking the carbon-nitrogen bond of the piperidine portion of the indolizidine to give a protected 3,4-trans-dihydroxy pyrrolidine 203 (Scheme 2.30). The plan for ring formation involves the reaction of the nitrogen with an activated alcohol. This diol could be derived from reduction of a 3-hydroxy-4-oxo-pyrrolidine 204. It was found that employing this method pyrrolidine 205 must be prepared from sulfinimine 206.
53 HO OH PGO OPG HO O
N N N H H OR OR
(+)-189 203 204
O O S p-Tolyl N N RO H OR
206 205
Scheme 2.30
One aldehyde that seemed to satisfy the criteria needed for this synthetic strategy was 5-(benzyloxy)pentanal (208). Oxidiation of 5-benzyloxy-1-pentanol (207) was done
168 with pyridinium chlorochromate (PCC) (Scheme 2.31). Sulfinimine (SS)-209 is generated in 88% with Davis’s protocol, and was converted into mono ester (SS,S)-210 by reaction with the sodium enolate of methyl acetate.125 Treatment of 210 with the enolate of tert-butyl acetate gives 75% of (SS,S)-211. The tert-butyl ester was desirable due to its easy removal during the decarboxylation step. Sulfinamide (SS,S)-211 is converted to
Cbz-amide (S)-212, and then subjected to diazo transfer to give (S)-201. The Rh2(OAc)4 promoted NH insertion of (S)-213 produces 83% of pyrrolidine (2S,5S)-214.
54 O PCC (S)-112 S BnO OH BnO O p-Tol N (64%) Ti(OEt)4 (88%) BnO
207 208 (SS)-209
MeOAc NaHMDS (70%)
O O Cbz S S NH O O p-Tol NH O O t-BuOAc p-Tol NH O 1.TFA NaHMDS Ot-Bu Ot-Bu OMe 2. CbzCl,DMAP (75%) OBn Et3N OBn OBn (67%)
(S)-212 (SS,S)-211 (SS,S)-210
4-CBSA Et3N (71%)
Cbz NH O O O Rh2(OAc)4 BnO Ot-Bu BnO N CO t-Bu N (83%) 2 2 Cbz
(S)-213 (2S,5S)-214
Scheme 2.31
Decarboxylation of (2S,5S)-214 with 20 equiv. of TFA resulted in 87% of 2- substituted-4-oxo pyrrolidine building block (S)-215 (Scheme 2.32). This chiral precusor was treated with LDA and Davis’s oxaziridine (-)-170 to give 80% of alcohol (2S,3S)-
216. Reduction of (2S,3S)-216 with Me4NBH(OAc)3 afforded 73% of trans-3,4- pyrrolidine diol (2S,3S,4S)-217. The alcohols of (2S,3S,4S)-217 were converted into acetate esters to allow for selective removal of the protecting groups. Pyrrolidine
(2S,3S,4S)-218 was hydrogenated to simultaneously cleave both the Bn and Cbz groups
55 forming 80% of (2S,3S,4S)-219. The piperidine ring formed as a result of PPh3 promoted intramolecular displacement of an activated OH, and release of acetate esters yield 60% of (+)-lentiginosine (189).152 The 1H NMR and 13C NMR of (+)-189 is consistent with reported values of (+)-lentiginosine. However the experimental rotation obtained was
20 20 152,154,169,170 [α] D = +2.1, and the literature value for the rotation is [α] D = +2.8. The reason for the inconsistency with the observed rotation is unknown. There are some discrepancies in the reported rotation of (+)-189. 152,154,169,170 Yoda, who reported the
20 first synthesis of the alkaloid, obtained an observed rotation of only [α] D = +0.19, but it was later attributed to some diastereomeric impurites.169 Also Petrini had an
20 20 experimental rotation of [α] D = +2.8, while Singh found a rotation of [α] D =
+4.5.152,154
56 O O 1. LDA HO O 2. (-)-170 TFA 3. HCl
BnO N CO2t-Bu (87%) BnO N (80%) BnO N Cbz Cbz Cbz
(2S,5S)-214 (S)-215 (2S,3S)-216
Me4NBH(OAc)3 (73%)
AcO OAc AcO OAc HO OH AcO, Et3N H2, Pd/C DMAP HO N (80%) BnO N (89%) BnO N H Cbz Cbz
(2S,3S,4S)-219 (2S,3S,4S)-218 (2S,3S,4S)-217
1. PPh3, CCl4, NEt3 2. TFA (60%, 3% over 17 steps)
HO OH
N
(+)-(1S,2S,8aS)-189
Scheme 2.32
In total (+)-189 was formed in 3% overall yield in 17 steps. The described synthesis does not give (+)-189 in as great of yield as some of the previously reported syntheses.152-156,158 However, it has the potential to be a general pathway to a broad range of natural and unnatural derivatives of (+)-lentiginosine. These derivatives could provide insight into the structure activity relationship of this alkaloid.
57 2.2.4 Conclusion
In summary, a method has been devised for the synthesis of pyrrolidine building block 130. This building block is remarkable due to its ability to access all of the cis and trans isomers of 3,4-dihydroxyprolines. This approach improves on previous syntheses of these systems as it allows for construction of pyrrolidines from one common intermediate. Further this building block was successfully used in the synthesis of (+)- lentiginosine, and also could be used in the synthesis of its enantiomers.
58 CHAPTER 3
SYNTHESIS OF POLYSUBSTITUTED PYRROLES
FROM SULFINIMINES (N-SULFINYL IMINES)
3.1 Introduction
Pyrrole was first isolated from the distillation of bone material by Anderson in
1857 (Fig. 3.1).171 Since its discovery, the pyrrole unit has been found in natural dyes, pharmaceutical agents, and used in molecular optics, electronics, conducting polymers, and antibacterials (Fig. 3.1).172-177 Due to its broad utility, pyrroles have been the subject of multiple reviews, and several methods have been devised for the synthesis of these five-membered nitrogen heterocycles.178-180 The classical methods of obtaining pyrroles include the Knorr, Paal-Knorr, and Hantzch syntheses.181-183
3 2 (")
4 1 (!) N H Pyrrole (1-H pyrrole)
Figure 3.1 The Structure of Pyrrole
One of the first and most well documented synthetic strategy for pyrrole synthesis is the Paal-Knorr synthesis in which ammonia or a primary amine reacts with a 1,4- dicarbonyl compound 220 (Scheme 3.1).182,184-186 Pyrrole 223 results from two successive nucleophilic additions of the amine to the carbonyls followed by dehydration.187,188
Substituted amines can react with 2,5-dimethoxytetrahydrofuran (224) to give N- substituted pyrroles such as 225 (Scheme 3.2).189-192
59
NH3 Me Me Me Me Me Me HO OH O O PhH, reflux O OH N H2N H
220 221 222
(90%)
Me N Me H 223
Scheme 3.1
BnNH2, aq. Pyridine MeO O OMe AcOH, reflux N (quant.) Bn 224 225
Scheme 3.2
The Knorr pyrrole synthesis involves the reaction of an α-aminoketone 226 with a carbonyl compound 227 (Scheme 3.3).193,194 The α-ketoester 227 must possess both an
α-methylene group and a second activating species such as an ester. This second group must be present to aid in the condensation of the two components. The proposed mechanism suggests that the nitrogen first attacks the more electrophilic carbonyl group to give intermediate 228. Then the newly formed C-C double bond of 228 displaces the oxygen through 229 to give pyrrole 230.
60 Me O CO2Et Me O CO2Et aq. KOH, rt + NH O CO Me N CO2Me 2 2 H
226 227 228
HO Me CO2Et CO2Et Me CO Me N CO2Me (53%) N 2 H H 230 229
Scheme 3.3
The final classical method for pyrroles is the Hantzsch synthesis. This method employs an α-halocarbonyl compound 231, a β-ketoester 232, and ammonia (Scheme
3.4).195 It is believed that pyrrole 234 is formed by reaction of the amine with the β- ketoester 232 followed by nucleophilic displacement of the halogen. Ring closure is achieved by the nitrogen attacking the second carbonyl and dehydration.
Cl CO2Et Cl CO2Et aq. NH + 3 Me O O Me rt to 60oC Me O H2N Me
231 232 233 (41%)
CO2Et
Me N Me H
234
Scheme 3.4
61 Other modern methods have been employed for the synthesis of substituted pyrroles. Campaigne and Shutske were successful in their aromatization of pyrrolidine
(2S,4S,5S)-235 to pyrrole 236 with NBS (Scheme 3.5).196 More recently Zhu was able to obtain pyrrole 239 by heating diazo compound 237 (Scheme 3.6).197 In the proposed mechanism, 237 was heated to 80 oC to give intermediate pyrrolidine 238a. They claim that at high temperatures the pyrrolidine is most stable in its enol form 238b, which loses
HF forming pyrrole 239 in 91% in both cases when R is Ph and 2-furan.
EtO2C O EtO2C OH NBS, NaHCO3 Ph N CO2Et Ph N CO2Et Me Me
(2S,4S,5S)-235 236
Scheme 3.5
Ph Rh(OAc) F O F OH F OH NH O O 4 F F toluene toluene, 80 oC reflux R OEt R N CO2Et R N CO2Et (91% over two steps) R N CO2Et F F N2 Ph Ph Ph
237 238a 238b 239
R = Ph, 2-Furan
Scheme 3.6
Wang reported another example of pyrroles from α-diazocarbonyl compounds in
2006 (Scheme 3.7).198 In this aromaization, pyrrolidine 241 was not isolated, but it was believed that intermediate 241 undergoes an N-tosyl elimination to give pyrrole 242.
62 Pyrrole 242 is thought to rearrange to NH-pyrrole 243. As shown in Table 3.1, this method is compatible with both tri- and tetra-substituted pyrrolidines.
Ts 2 2 2 R O R O H R OH NH O O Rh(OAc)4 benzene, reflux 1 R OEt 1 1 O 1 R CO2Et R R CO Et 2 N N N 2 R N2 H Ts OEt 240 241 242 243
Scheme 3.7
198 Table 3.1 Rh2(OAc)4 Mediated Aromatization of 240 to Pyrrole 243
Entry R1 R2 % Isolated Yield
1 Ph H 75
2 Me 87
3 2-Furan H 91
4 i-Bu 73
3.2 Present Study
The focus of this research is the design and synthesis of tetrasubstituted pyrroles from their sulfinimine derived pyrrolidine carboxylates and phosphonates 244. This includes the regioselective addition of an electrophile to the 4-position of the pyrrolidine and an efficient method for its aromatization to the corresponding pyrrole 246. One of the benefits to this methodology is that it allows for the synthesis of a range of
63 phosphonopyrrolidines and pyrroles, which have been examined as HIV protease inhibitors.199-201 Currently, there are no general procedures for their preparation.199-203
O R3 O 3 1. LDA 3 R OH 3 4 2. R X 2 SiO2, air 2 1 2 1 2 1 R R R 5 R R R N N 1 N H PG PG
244 245 246 1 R = CO2Me or P(O)Me2
Scheme 3.8
3.2.1 Synthesis of Racemic 2-Carboxy and 2-Phosphonopyrrolidines
Racemic (±)-p-toluenesulfinamide (111) was prepared using Ruano’s procedure to form the pyrrolidines.95 The 2-carboxy pyrrolidines were made according to Davis’s method for the synthesis of chiral 2-carboxy pyrrolidines (Scheme 3.9).77 The yields and spectral data for the racemic intermediates were consistent with their asymmetric counterparts.77,78 The yields of each are shown in Table 3.2.
64 O O 1 O R CHO MeCO2Me S S p-Tolyl NH O S Ti(OEt)4 NaHMDS p-Tolyl NH2 p-Tolyl N R R OMe
(±)-111 247 248
MeCO2Me NaHMDS
O Boc Boc 1. TFA/MeOH S NH O O NH O O Et3N 2. Boc2O, Et3N p-Tolyl NH O O 4-CBSA DMAP R OMe R OMe R OMe
N2
251 250 249
Rh2(OAc)4
O
R N CO2Me Boc
252
a: R = Ph; b: R = 2-Furan; c: R = t-Bu; d: R = CH2=CH-
Scheme 3.9
Table 3.2 Synthesis of 3-Oxo-5-Substituted Pyrrolidine-2-Carboxylates
Entry R % Isolated Yield
247 248 249 250 251 252
1 Ph 83 88 85 90 81 68
2 2-Furan 94 91 84 82 76 74
3 Me3C- 85 78 85 97 82 63
4 CH2=CH- 91 73 85 92 95 87
The phosphonopyrrolidines 256 were prepared in a procedure that was reported by Davis and co-workers in 2004.204 In this protocol, treatment of β-ketoester 248 with 5
65 equivalents of lithium dimethyl methylphosphonate gives N-sulfinyl δ-amino-β- ketophosphonate 253 (Scheme 3.10). The sulfinyl auxiliary of 253 was removed by TFA and replaced with the Boc group. Conversion of 254 to α-diazo-β-ketophosphonate 255 was achieved with commercially available 4-acetamido-benzenesulfonyl azide (4-ABSA) and NaH. The azide transfer agent was changed from the previously used 4-carboxy benzenesulfonazide (4-CBSA) and Et3N due to the slow reaction time of this combination.204,205 Pyrrolidine phosphonate 256 was formed in good yields by the
Rh2(OAc)4 catalyzed NH insertion reaction of 255 (Table 3.2).
O O 1. TFA/MeOH S S 2. Boc O, Et N Boc p-Tolyl NH O p-Tolyl NH O O 2 3 NH O O CH3P(O)(OMe)2 DMAP P(OMe)2 P(OMe)2 R OMe n-BuLi, -78oC R R
248 253 254 a: R = Ph b: R = 2-Furan c: R = t-Bu NaH 4-CH3CONHPhSO2N3 d: R = CH2=CH- O Boc Rh (OAc) NH O O R N P(OMe)2 2 4 P(OMe)2 Boc O R N2 256 255
Scheme 3.10
Table 3.3 Synthesis of 3-Oxo-5-Substituted Pyrrolidine-2-Phosphonates
Entry R % Isolated Yield
253 254 255 256
1 Ph 84 90 83 67
2 2-Furan 82 97 71 67
66 3 Me3C- 80 87 85 94
4 CH2-CH- 83 87 83 85
3.2.2 Synthesis of 4-Substituted-3-oxo-2,5-disubstituted Pyrrolidines Pyrrolidines
The 3-oxo-2-carboxy pyrrolidine 252a was treated with LDA to form the 2,4- carbonyl dianion 257 (Scheme 3.11). Davis’s oxaziridine (-)-170 was added; however unlike the previously described 4-oxo-2-substituted pyrrolidines, dianion 257 failed to convert into a 4-oxo-3-hydroxy pyrrolidine. Alternatively, when chiral 3-oxo-2-carboxy pyrrolidine (2RS,5R)-101 was treated with 3 equivalents of LDA followed by 1.5 equivalents of methyl iodide 4-methyl-3-oxo-2-carboxy pyrrolidine (2RS,4S,5R)-258 was formed in 82% yield as a single regioisomer (Scheme 3.12). From these findings, it was concluded that electrophiles could be regioselectively added to the 4-position of pyrrolidines 252, and the oxaziridine (-)-170 may have been unsuccessful due to the bulkiness of the electrophile.
O O O LDA (-)-170 OMe OMe NR Ph N CO2Me Ph N Ph N Boc Boc O Boc O 252a 257a 257b
Scheme 3.11
67 Me O O 1. LDA 2. MeI Ph CO Me Ph N CO2Me (82%) N 2 Boc Boc (2RS,5R)-101 (2RS,4S,5R)-258
Scheme 3.12
In order to determine the scope of this electrophilic addition, the methyl group was introduced to the tert-butyl and 2-furan substituted carboxy pyrrolidines 252
(Scheme 3.13). Benzyl bromide was used as an alternate electrophile. The results of the additions are shown in Table 3.4 entries 1-5. Attempts to introduce the benzyl group to tert-butyl substituted pyrrolidine 252b was unsuccessful, further validating the argument that steric demands can prevent C-4 additions. This method proved to be compatible with the 2-phosphono pyrrolidine 256 (Table 3.4, entries 6-8).
2 O 1. LDA R O 2. R2X 1 1 R N CO2Me R N CO2Me Boc Boc
252 259a: R1 = Ph, R2 = Me 259b: R1 = Ph, R2 = Bn 259c: R1 = 2-Furan, R2 = Me 1 2 259d: R = Me3C, R = Me 1 2 259e: R = Me3C, R = Bn
2 O 1. LDA R O 2. R2X 1 1 R N P(OMe)2 R N P(OMe)2 Boc O Boc O
256 260a: R1 = Ph, R2 = Bn 260b: R1 = 2-Furan, R2 = Me 260c: R1 = 2-Furan, R2 = Bn
Scheme 3.13
68 Table 3.4 Reaction of Electrophiles with the Dianions of 252 and 256
Entry Pyrrolidine 252/256, R1 R2 259/260
(% Isolated Yield)
1 252a, R1 = Ph MeI 259a, R2 = Me (83)
2 BnBr 259b, R2 = Bn (79)
3 252b, R1 = 2-Furan MeI 259c, R2 = Me (88)
1 2 4 252c, R = Me3C MeI 259d, R = Me (50)
5 BnBr NRa
6 256a, R1 = Ph BnBr 260a, R2 = Bn (41)
7 256b, R1 = 2-Furan MeI 260b, R2 = Me (40)
8 BnBr 260c, R2 = Bn (70) a Starting material was recovered.
The regioselectivity of the electrophiles to the C-4 position of the carbanions of
252 and 256 is thought to be due to the lower nucleophilicity and steric hinderance of the
C-2 β-dicarbonyl anion. This substitution trend is evidenced in other 1,3-dicarbonyl systems (Scheme 3.14).206 When 261 is a methyl β-keto ester, the C-4 substitution product 263 can be obtained in 85% yield (Table 3.5, entry 1). This position is also the more nucleophilic site in β-keto amides (Table 3.5, entry 2). There is also precedent for this pattern in β-keto phosphonates (Scheme 3.15).206
69 O O O O O O 2 eq of base RX Me Z H2C Z Z R
261 262 263
Scheme 3.14
Table 3.4 Regioselective Electrophilic Additions to 1,3-Dicarbonyl Dianions206
Entry Z Base RX % Isolated Yield
1 OMe NaH/n-BuLi Me2C=CHCH2Br 85
2 N(Me)2 LDA BnCl 92
O O 1. NaH O O O O 2. BuLi RX P(OMe)2 P(OMe)2 P(OMe)2 Me H2C R
264 265 266 R = Me, n-Bu, i-Pr, Bn (65-75%)
Scheme 3.15
This general method for the synthesis of 4-substituted 3-oxo 2,5-disubstituted pyrrolidines is advantageous for a variety of reasons. First, this is a convenient pathway for tetrasubstituted 2-carboxy and 2-phosphono pyrrolidines. The latter has been examined as HIV protease inhibitors, but has few reported syntheses.199,200 These pyrrolidines could serve as potential building blocks for biologically relevant compounds.
70 3.2.3 Aromatization of 3-Oxo Pyrrolidines to Pyrroles
The first attempt to oxidize pyrrolidine 243a to pyrrole 268 involved applying
Campaigne and Shutske’s conditions to the deprotected pyrrolidine 267. They subjected their pyrrolidine to NBS and NaHCO3 for 30 min, however after 16 h only pyrrolidine
267 in the keto form 267a was obtained (Table 3.6, entry 1).196 The crude 1H NMR of
267, proved that at rt it remained in the keto form 267a for up to 4 days. It was also observed that attempts to purify 267a gave 268. After this observation, 267a was treated with silica gel in EtOAc for 5 h yielding 88% of 268 in air (Table 3.6, entry 2).
However, 267a was recovered when exposed to the same conditions under the inert gas argon (Table 3.6, entry 3). Dissolving 267a in EtOAc and leaving it vulnerable to air oxidation for 5 h resulted in no reaction (Table 3.6, entry 4). From these results, it was hypothesized that 267a needed an additive to promote the formation of 267b, and air was responsible for the aromatization of 267b to pyrrole 268. Both acid and base additives were added to the pyrrolidine in air to confirm this suggested mechanism (Table 3.6, entries 5-9).
O O O H O H TFA conditions O O Ph N CO2Me Ph N CO2Me Ph N Ph N H H H Boc OMe OMe 243a 267a 267b 268
Scheme 3.16
Table 3.6 Aromatization of Pyrrolidine 267 to Pyrrole 268
Entry Conditions Solvent % Isolated Yield
71 1 NBS/NaHCO3 (1:1.1), argon dioxane:water (9:1) NR
2 SiO2, air EtOAc 88
3 SiO2, argon NR
4 Air NR
5 TFA, air 80
6 TFA, argon NR
7 Et3N, air 33
8 Pyridine, air NR
9 Cs2CO3 20
Once it became clear that air had a substantial role in formation of the pyrrole, it was theorized that a radical reaction between 267b and molecular oxygen occurred
(Scheme 3.17). To prove this, a KI peroxide test was performed after 268 was formed using the conditions described in Table 3.6, entry 2. The test was performed by crushing a commercially available low range tablet from Orbeco Analytical Systems and adding it to the reaction flask. When peroxide is present, the it reacts with KI to produce I2, which reacts with diethyl-p-phenylenediamine to produce a pink-red color. After 5 min a red color was observed in the KI test of a 0.020 g scale of pyrrole 268.
72 OH OH H OH H O2 + HO HOO Ph CO Me Ph CO Me 2 CO Me N 2 N 2 Ph N 2 H H H
267b 269 270
O OH H HOO H2O2 + O CO Me Ph N Ph N 2 H OMe H 268 271
Scheme 3.17
These conditions were then applied to the other previously prepared carboxy and phosphonopyrrolidines to give their respective pyrroles. What is remarkable about this aromatization is that it is compatible with a variety of pyrrolidine systems (Scheme 3.18).
In most cases, the pyrroles were formed in good yield. The only case in which the yield of a 2-carboxy pyrrole was modest was 5-tert-butyl-4-methyl pyrrole 272f (Table 3.7, entry 6). The most modest 2-phosphonopyrrole was 273d (Table 3.7, entry 11). The low yields of these two pyrroles may be attributed to the bulkiness of the two groups, which may hinder the radical removal of the two hydrogens.
73 2 2 R O 1. TFA R OH 2. NaHCO3 1 3. SiO , air 1 R N CO2Me 2 R N CO2Me H Boc
243, R2 = H 272 250, R2 = Me, Bn
2 2 R O 1. TFA R OH 2. NaHCO3 1 3. SiO , air 1 R N P(OMe)2 2 R N P(OMe)2 H Boc O O
247, R2 = H 273 251, R2 = Me, Bn
Scheme 3.18
Table 3.7 Aromatization of Substituted Pyrrolidines to Pyrroles 272 and 273
Entry Pyrrolidine R1 R2 Product
(% isolated yield)
1 243b 2-Furyl H 272a (75)
2 243c Me3C 272b (81)
3 243d CH2=CH 272c (81)
4 250a Ph Me 272d (78)
5 250b Bn 272e (67)
6 250c 2-Furyl Me 272f (67)
7 250e Me3C Me 272g (50)
8 247a Ph H 273a (75)
9 247b 2-Furyl 273b (80)
10 247c Me3C 273c (61)
11 251a Ph Bn 273d (51)
74 12 251b 2-Furyl Me 273e (60)
13 251c Bn 273f (75)
In another study, it was found possible to introduce a chlorine atom at C-4 and achieve aromatization without deprotection. In order to accomplish this goal, N-sulfinyl
β-keto eser 249a was converted to N-Cbz β-keto ester 274 (Scheme 3.19). The Cbz group was employed due to its stability in acidic conditions. The ester underwent a diazo transfer followed by rhodium catalyzed NH insertion to give N-Cbz pyrrole 276.
Chlorination resulted from treatment of 276 with LDA and 0.75 equivalents of 1,3- dichloro-5,5-dimethylhydantoin (DMDCH). Unfortunately, the chlorine was eliminated when pyrrolidine 277 was treated with the standard silica gel/air aromatization conditions discussed previously giving pyrrole 278. Changing to Et3N did not alter the resulting product.
O S 1. TFA/MeOH Cbz Cbz p-Tolyl NH O O 2. CbzCl, Et3N NH O O Et3N NH O O DMAP 4-CBSA Ph OMe Ph OMe Ph OMe (77%) (83%) N2
249a 274 275
Rh2(OAc)4 (93%)
OH Cl O O
SiO2-air (82%) 1. LDA
Ph CO2Me Ph CO2Me Ph CO2Me N or Et3N (68%) N 2. O N Cl Cbz Cbz N Cbz N Cl Me 278 277 Me O 276 (53%)
75 Scheme 3.19
3.2.4 Conclusion
In summary, the dianions of 2,5-disubstituted 3-oxo pyrrolidines regioselectively undergo electrophilic substitution at C-4 position affording tetrasubstituted pyrrolidines.
This is advantageous because it allows for a general pathway for tetrasubstituted 2- carboxy and 2-phosphono pyrrolidine synthesis, which are biologically significant. Air oxidation of these pyrrolidines affords the corresponding tetrasubstituted pyrroles at room temperature without the need for a leaving group. Importantly, this methodology provides convenient access to the relatively unexplored 2-phosphonopyrroles 273 for further biological and chemical evaluation.
76 CHAPTER 4
ASYMMETRIC SYNTHESIS OF β-AMINO CARBONYL COMPOUNDS WITH
N-SULFINYL β-AMINO WEINREB AMIDES
4.1 Introduction
N-Methoxy-N-methylamide or Weinreb amides 279 were first introduced by
Nahm and Weinreb in 1981, and have since gained recognition as key synthetic building blocks.207,208 These amides have gained interest due to its accessibility and selective reactivity. The great advantage of N-methoxy-N-methylamide 279 is the formation of the stable tetrahedral intermediate 280 during nucleophilic addition (Scheme 4.1).
O Me O O M OMe R2M H+ R1 N N O R1 R2 Me Me R2 R1 279 280 281
Scheme 4.1
There are several established methods for the preparation of Weinreb amides 279 including the direct conversion of an acid chloride 282 with commercially available N,O- dimethylhydroxylamine (283) (Scheme 4.2).209 Weinreb amides can also be made from carboxylic acids and 283 with the aid of a coupling reagent such as BOP (benzotriazol-1- yloxytris[dimethylamino]-phosphonium hexafluorophosphate) or DCC
(dicyclohexylcarbodiimide) (Scheme 4.3).210 Transamination of Evans’ chiral auxillary in lactone 286 gave N-methoxy-N-methylamide 287 (Scheme 4.4).211
77 O O OMe Pyridine (2.2 eq) OMe + HN R N R Cl Me CH2Cl2 Me
282 283 279
Scheme 4.2
N O 1. Et3N O 2. BOP N - Me Me OMe PF6 OH N NH 3. MeONHMe.HCl OPH[N(Me) ] NH NH Me 2 3 Boc 4. Et3N Boc (85%) BOP 284 285
Scheme 4.3
OH O O OH O AlMe3 OMe Ph N O Ph N . Me MeONHMe HCl Me Me Me Ph
286 287
Scheme 4.3
Weinreb amides are readily transformed into ketones by treatment with Grignard reagents or organolithium reagents. Rapoport and co-workers compared the reactivity of lithium acetylides with various amino acid derivatives and found that the N-alkoxy derivatives gave exclusively the ynone 290 with no evidence of alcohol 291 formation
(Scheme 4.4, Table 4.1).212 The ynone product is attributed to the tetrahedral intermediate that is formed through coordination of the lithium ion to both the N-methoxy and carboxyl oxygents. It was shown that N,N’-dimethoxy-N,N’-dimethylethanediamide
(292) produces 1,2-diketones 293 with treatment by excess organolithium or Grignard
78 reagents (Scheme 4.5).213 It was observed that organolithium reagents with both electron- donating and electron-withdrawing groups were more efficient in the synthesis of diketone 293 (Table 4.2).
O O OH Me Me Me X + + Li NHCO2Et NHCO2Et NHCO2Et
288 289 290 291
Scheme 4.4
Table 4.1 Reaction of Lithium Hexyne with Amino Acid Derivatives212
Entry X Ratio % Isolated Yield of
290
1 OH No reaction
2 Cl (100% 291) (48% 291)
3 -N(Me)OMe >100:1 84
4 O >100:1 88 N
O 5 N Ratio not determined 74
OMe O O O N Me Excess RM R R Me Me N R + N M = Li, MgBr O OMe O O OMe
292 293 294
79 Scheme 4.5
Table 4.2 Preparation of 1,2-Diketones from 292213
Entry Reagent Mol Equiv. % Isolated Yield of % Isolated Yield of
293 294
1 PhMgBr 4 62 21
2 PhLi 5 76 2
3 4-MePhMgBr 5 48 48
4 4-MePhLi 6 86 4
5 4-ClPhMgBr 5 0 17
6 4-ClPhLi 4 66 9
Another characteristic of Weinreb amides is that they give aldehydes when treated with reducing agents such as LAH or DiBAL-H. In the initial studies of the limitations of Weinreb amides, it was shown that N-methoxy-N-methylbenzamide (295) was reduced to benzaldehyde (296) with excess reducing agents (Scheme 4.6).207 It was also found that reduction with the bulkier DiBAL-H reagent proceeded more selectively. Sibi and
Sharma found that treatment of α-oxo-Weinreb amide 297 with excess NaBH4 gives 1,2- diol 298.214
O O OMe excess H- Ph N Ph H Me LAH (67%) DiBAL-H (71%) 295 296
80 Scheme 4.6
O OH Ph OMe NaBH4 Ph N (92%) O Me OH 297 298
Scheme 4.7
Weinreb amides do not form the tetrahedral intermediate upon treatment with strong bases such as LDA. Graham and Scholz were the first to report this phenomenon.215 They observed that treatment of N-methoxy-N-methylamide 299 with 2 equivalents of LDA reduced it to amide 300. They were able to determine that this reduction occurs through an E2 elimination by subjecting the Weinreb amide of pivolic acid (301) to the same conditions. This study proved that an enolate was not formed during the reduction.
O O MeO OMe LDA MeO N NH Me Me
299 300
Scheme 4.8
H N O H2C O O O N NH + H H Me Me
301 302 303
Scheme 4.9
81 4.2 Present Study
The goal of this research is the design of a general method for the asymmetric synthesis of diverse β-amino aldehydes and ketones from sulfinimine-derived N-sulfinyl
β-amino Weinreb amides. Chiral β-amino carbonyl compounds are important chiral building blocks in the asymmetric syntheses of biologically significant nitrogen- containing molecules, which include β-amino acids and 1,3-amino alcohols.216-224 The current method of preparing β-amino aldehydes and ketones is limited to the substitution of the ketone and can undergo self-condensation or β-elimination.225-227 A strategy to solve this problem is the synthesis of β-amino aldehydes and ketones (SS,R)-305 from sulfinimine-derived N-sulfinyl β-amino Weinreb amides (SS,R)-304. It is believed that the sulfinyl auxillary will provide suitable N-protection to prevent self-condensation or β- elimination of the amino group.
O O O H S S p-Tolyl NH O p-Tolyl NH O S R'M p-Tolyl N R OMe R N R R' Me
(S)-112 (SS,R)-304 (SS,R)-305
Scheme 4.10
4.2.1 Synthesis of β-Amino Weinreb Amides from Sulfinimines
The enolate of commercially available N-methoxy-N-methylacetamide adds to the
C=N bond of sulfinimines (S)-112 and (S)-117 to give the corresponding N-sulfinyl β- amino Weinreb amides (SS,R)-304 and (SS,R)-306 respectively (Scheme 4.11). Better yield and higher diastereoselectivity was observed with the potassium enolate of N-
82 methoxy-N-methylacetamide in THF (Table 4.3, entries 1-5). Also, the p-toluenesulfinyl imines (S)-112 had higher diastereoselectivity compared to the tert-butyl sulfinimine (S)-
117. Although high selectivity was achieved in many of the examples, entries 3 (R2 =
2 2 Ph), 6 (R = p-CF3Ph), and 7 (R =Me) had maximum de’s of 70%, 54%, and 84% respectively. A second approach to N-sulfinyl β-amino Weinreb amides 304 and 306 was treating methyl N-sulfinyl β-amino carboxylates 307 and 308 with 5 equivalents of lithium N,O-dimethylhydroxyamine (Scheme 4.12). When fewer equivalents of
LiN(OMe)Me were used the reaction was incomplete (Table 4.4, entry 2). This approach was beneficial because the absolute stereochemistry of the amine is unaffected by the transformation.
O-M+ O OMe O H N S R1 NH O 1 S 2 Me R N R OMe R2 N Me
1 1 (S)-112: (R = p-Tolyl) (SS,R)-304: (R = p-Tolyl) 1 1 (S)-117: (R - t-Bu) (SS,R)-306: (R - t-Bu)
Scheme 4.11
Table 4.3 Synthesis of β-Amino Weinreb Amides 304 and 306 from Sulfinimines and N-
Methoxy-N-methylacetamides228
Entry Sulfinimine R2 Base (solvent) Weinreb dr (% de)a % yieldc
amide
1 112a Ph LiHMDS (THF) 304a 79:21 (58)b
83 2 NaHMDS 82:18 (64)
(THF)
3 KHMDS (THF) 85:15 (70) 65d
4 KHMDS 51:49 (2)
(PhMe)
5 KHMDS (Et2O) 54:46 (8)
e 6 112j p-CF3Ph KHMDS (THF) 304b 77:23 (54)
7 112h Me KHMDS (THF) 304c 92:8 (84) 52
8 112k n-Pr KHMDS (THF) 304d 99:1 (98) 68
9 112i t-Bu KHMDS (THF) 304e 99:1 (98) 68
10 112l Cl-(CH2)4- KHMDS (THF) 304f 99:1 (98) 76
11 112f E-Me- KHMDS (THF) 304g 99:1 (98) 82
CH=CH-
12 117a Ph KHMDS (THF) 306a 52:48 (4)e
13 117b n-Pr KHMDS (THF) 306b 86:14 (72)e
14 117k t-Bu KHMDS (THF) 306c 88:12 (76)e aDetermined by 1H NMR of the crude reaction mixture unless otherwise noted. bEstimated by isolation of the two diastereoisomers. cIsolated yield of major diastereoisomer. dIsolated by fractional crystallization. eInseparable mixture of diastereoisomers.
84 O O
1 S 1 S R NH O LiN(OMe)Me R NH O OMe R2 OMe R2 N Me
1 1 (SS,R)-307: (R = p-Tolyl) (SS,R)-304: (R = p-Tolyl) 1 1 (SS,R)-308: (R - t-Bu) (SS,R)-306: (R - t-Bu)
Scheme 4.12
Table 4.4 Synthesis of β-Amino Weinreb Amides 304 and 306 from N-Sulfinyl β-Amino
Methyl Esters and Lithium N,O-Dimethylhydroxyamine
Entry β-amino R2 equiv. of Weinreb % isolated
ester LiN(OMe)Me Amide yield
1 307a Ph 5 304a 78
2 3 61
3 307b p-CF3Ph 5 304b 54
4 307c Me 5 304c 66
5 307e t-Bu 5 304e 68
6 307g E-MeCH=CH- 5 304g 82
7 308a Ph 5 306a 79
4.2.2 Synthesis of N-Sulfinyl β-Amino Aldehydes and Ketones
Sulfinyl β-amino Weinreb amides 304 react with various organometallic reagents to give good-to-excellent yields of the corresponding N-sulfinyl β-amino aldehydes and ketones (Figure 4.1, Table 4.5). In these transformations it was found necessary to have
85 excess organometallic reagent, usually 5 equivalents (entries 2 and 3). It is suspected that the sulfinyl NH proton is removed before reaction at the N-methoxy-N-methyl amide site.
In general, Grignard reagents gave better yields when compared to organo lithium reagents (entries 2 and 4, also 5 and 6). All attempts get (SS,R)-99 by treating 304a with the lithium enolate of methyl acetate were unsuccessful, however β−keto phosphonate
314 was synthesized by addition of the lithium enolate of dimethyl methyl phosphonate
(entries 9 and 10).
O O O S S S p-Tolyl NH O p-Tolyl NH O p-Tolyl NH O
R H R Me Ph n-Bu
(SS,R)-309a: R = Ph (84%) (SS,R)-310a: R = Ph (92%) (SS,R)-311 (88%) (SS,R)-309b: R = t-Bu (70%) (SS,R)-310b: R = p-CF3Ph (63%) - - (SS,R)-310c: R = Cl (CH2)4 (77%)
O O O S S S p-Tolyl NH O p-Tolyl NH O p-Tolyl NH O O
R Ph Ph Ph OMe Me (SS,R)-312a: R = Ph (84%) (SS,R)-313: (84%) (SS,R)-99 (0%) (SS,R)-312b: R = t-Bu (88%)
O S p-Tolyl NH O O P(OMe) Ph 2
(SS,R)-314 (88%)
Figure 4.1 Reactions of N-Sulfinyl Weinreb Amides with Organometallic Reagents
86
Table 4.5 Synthesis of N-Sulfinyl β-Amino Aldehydes and Ketones from β-Amino
Weinreb Amides and Organometallic Reagents
Entry Weinreb amide (R) Reagent (equiv) Product % Isolated
yield
1 304a (Ph) DiBAL-H (5) 309a 84
2 MeMgBr (5) 310a 92
3 MeMgBr (3) 67
4 MeLi (5) 60
5 PhMgBr (5) 312a 84
6 PhLi (5) 49
7 n-BuLi (8) 311 88
8 MeC≡CMgBr (5) 313 84
9 CH3CO2Me/LiHMDS (5) 99 0
10 CH3P(O)(OMe)2/n-BuLi 314 88
(2)
11 304b (p-CF3Ph) MeMgBr (5) 310b 63
12 304e (t-Bu) DiBAL-H (5) 309b 70
13 PhMgCl (5) 312b 88
87 4.2.3 Conclusion
In conclusion, new and general methodology has been introduced for the asymmetric synthesis of N-sulfinyl β-amino Weinreb amides. Through this pathway the synthesis of Weinreb amides was achieved by addition of the potassium enolate to a sulfimine or addition of the lithium enolate of N,O-dimethylhydroxyamine to N-sulfinyl
β-amino esters. It was observed that p-toluenesulfinyl imines 112 gave better yields and higher selectivies compared to the tert-butylsulfinyl imines 117. The newly generated
Weinreb amides react with a variety of organometallic agents to transform to N-sulfinyl
β-amino aldehydes and ketones, which are valuable chiral building blocks for the asymmetric synthesis of biologically relevant nitrogen-containing compounds.
88 CHAPTER 5
EXPERIMENTAL SECTION
General Methods
Reagents and solvents were purchased from Sigma-Aldrich Company or Acros
Organics and used without additional purification unless otherwise noted. Glassware was oven-dried at 120 oC and cooled to ambient temperature in desiccators prior to use.
Reactions involving sensitive substances and/or requiring anhydrous reaction conditions were performed under argon atmosphere. Reagent grade tetrahydrofuran (THF), diethyl ether (Et2O), toluene (PhMe), and methylene chloride (CH2Cl2) were purified by filtration on a Glass Contour Solvent Dispensing System. Column chromatography was performed on silica gel, Merck grade 60 (230-400 mesh). Analytical and preparative thin-layer chromatography was performed on precoated silica gel plates (250 and 1000 microns) purchased from Analtech Inc. TLC plates were visualized with UV, in an iodine chamber, or with ninhydrin unless otherwise noted.
Melting points were recorded on a Mel-Temp apparatus and are uncorrected.
Optical rotations were measured on a Perkin-Elmer 341 polarimeter. Infrared spectra were recorded on a Perkin-Elmer 1600 FTIR spectrometer using NaCl plates for liquid
1 13 and KBr disc for solids. H and C NMR spectra were obtained in CDCl3 or CD3OD
1 solution and were referenced to TMS (0.00 ppm), CHCl3 (7.26 ppm for H NMR and
77.36 for 13C NMR), methanol (3.35 ppm for 1H NMR and 49.86 ppm for 13C NMR) using GE Omega 500 MHz, Bruker 400 MHz, or Varian 300 MHz NMR spectrometer.
31 P NMR spectra were obtained in CDCl3 solution and referenced externally to 85%
89 H3PO4. High resolution mass spectra were collected at the Department of Chemistry,
Drexel University, Philadelphia, PA.
Methyl (SS,R)-(+)-2-diazo-3-oxo-5-(p-toluenesulfinylamino)-5-phenylpentanoate
(99),77 methyl (R)-(+)-2-diazo-3-oxo-5-(tert-butoxycarbonylamino)-5-phenylpentanoate
(100),78 methyl (2RS)-N-(tert-butyloxycarbonyl)-3-oxo-5-phenylpyrrolidine-2- carboxylate (101),77 (S)-(+)-p-toluenesulfinamide (111),87 (±)-p-toluenesulfinamide
(111),95 (S)-(+)-N-(benzylidene)-p-toluenesulfinamide (112a),88 (±)-N-(2-furan-2-yl)-p-
87 87 toluenesulfinamide (112e), (±)-N-(tert-butyl)-p-toluesulfinamide (112i), (SS)-(+)-N-p-
229 (trifluoromethylbenzylidene)-p-toluenesulfinamide (112j), methyl (SS,R)-(+)-N-(p-
230 toluenesulfinyl)-3-amino-3-phenylpropanoate (150), methyl (SS,R)-(+)-5-phenyl-3-
231 oxo-5-(p-toluenesulfinylamino)-pentanoate (151), (SS,S)-(+)-tert-butyl-3-oxo-5-N-(p- toluenesulfinylamino)-9-benzyloxynonanoate (211)125 were prepared according to literature procedures.
Methyl-(±)-N-(p-toluenesulfinyl)-3-phenylpropanoate (248a),230 methyl-(+)-4,4- dimethyl-N-(p-toluenesulfinyl)-3-aminopentanoate (249c),78 methyl-(+)-3-oxo-5-(p- tolunesulfinyl)-pent-4-enoate (249d),232 methyl-(+)-3-oxo-5-(p-toluenesulfinylamino)-5- phenylpentanoate (249a),231 methyl-(+)-3-oxo-5-(tert-butoxyloxycarbonylamino)-5- phenylpentanoate (250a),77 methyl-(+)-5-(tert-butoxycarbonyl)-6,6-dimethyl-3- oxoheptanoate (250c),78 methyl-(+)-2-diazo-3-oxo-5-(tert-butyloxycarbonylamino)-5- phenylpentanoate (251a),77 methyl-(+)-2-diazo-6,6-dimethyl-3-oxo-N-(tert- butoxycarbonyl)-5-aminoheptanoate (251c),78 methyl-(+)-N-(tert-butyloxycarbonyl)-3- oxo-5-phenylpyrrolidine-2-carboxylate (252a),77 dimethyl-(-)-2-oxo-4-(p- toluenesulfinylamino)-4-phenylbutylphosphonate (253a),204 dimethyl-(-)-N-(tert-
90 butoxycarbonyl)-3-oxo-5-tert-butylpyrrolidine-2-phosphonate (254c),204 dimethyl-(+)-2- oxo-N-(tert-butoxycarbonyl)-4-amino-4-phenylbutylphosphonate (254a)204 dimethyl (-)-
2-oxo-N-(tert-butoxycarbonyl)-4-amino-5,5-dimethylhexylphosphonate (254c),204 dimethyl-(+)-1-diazo-2-oxo-N-(tert-butoxycarbonyl)-4-amino-4-phenylbutylphosphonate
(255a),204 (+)-diazo-2-oxo-N-(tert-butoxycarbonyl)-4-amino-5,5- dimethylhexylphosphonate (255c),204 dimethyl-(+)-N-(tert-butoxycarbonyl)-3-oxo-5- phenylpyrrolidine-2-phosphonate (256a),204 dimethyl-(-)-N-(tert-butoxycarbonyl)-3-oxo-
5-tert-butylpyrrolidine-2-phosphonate (256c)204 were previously synthesized as enantiomerically and diastereomerically pure compounds. The racemic forms of these materials exhibited identical physical and spectral properties when compared to their optically active counterparts.
CHAPTER 2: SYNTHESIS AND UTILIZATION OF SULFINIMINES (N-
SULFINYL IMINES) AS CHIRAL IMINE BUILDING BLOCKS
O
Ph N CO2H Boc (R)-154
(5R)-(+)-1-(tert-butoxycarbonyl)-3-oxo-5-phenylpyrrolidine-2-carboxylic acid
(154). In an oven-dried, 25-mL, single-neck, round-bottom flask equipped with a stirring bar, rubber septum, and argon balloon was placed (2RS)-N-(tert-butyloxycarbonyl)-3- oxo-5-phenylpyrrolidine-2-carboxylate (101, 0.029 g, 0.09 mmol) and LiOH (0.008 g,
0.09 mmol) in THF (2 mL) and H2O (0.8 mL). The solution was stirred at rt for 8 h. The
91 organic phase was extracted with CH2Cl2 (2 x 5 mL), dried (Na2SO4), and concentrated.
20 Preparatory TLC (20% EtOAc/hexanes) afforded 0.018 g (67%) of a viscous oil; [α]D =
-1 1 + 43.6 (c = 0.79); IR (neat) 3304, 2989, 1746, 1716 cm ; H NMR (CDCl3) δ 1.26 (s, 9
H); 2.91-3.09 (m, 2 H), 5.11 (m, 1 H), 5.37 (m, 1 H), 7.21-7.40 (m, 5 H); 28.1, 29.6, 46.2,
53.6, 58.1, 81.2, 125.7, 127.4, 128.6, 154.0, 174.2, 201.1. HRMS calcd for
C16H19NO5Na (M + Na) 328.1161. Found 328.1169.
O
Ph N Boc (R)-155
(2R)-(+)-(N-tert-Butoxycarbonyl)- 4-oxo-2-phenylpyrrolidine (155). In an oven-dried, 25-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (R)-154 (0.024 g, 0.08 mmol) in anhydrous toluene (10 mL). The solution was refluxed for 16 h, H2O (2 mL) was added, and the solution was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), and concentrated. Preparative TLC
20 (30% EtOAc/hexanes) afforded 0.005 g (75%) of (R)-155 as an oil; [α]D = + 6.52 (c =
-1 1 0.64); IR (neat) 2980, 2931, 1760, 1695, 1401, 1154 cm ; H NMR (CDCl3) δ 1.26 (s, 9
H); 2.53-2.61 (m, 1 H); 3.07-3.21 (m, 1 H), 3.88-4.13 (m, 2 H); 5.37 (br, s, 1 H); 7.19-
13 7.40 (m, 5 H); C NMR (CDCl3) δ 28.1, 29.6, 46.1, 53.1, 57.6, 80.5, 125.3, 127.4, 128.7,
153.8. HRMS calcd for C15H19NO3Na (M + Na) 284.1263. Found 284.1259.
92 Cbz NH O O
Ph OMe (R)-156
Methyl (5R)-(+)-3-oxo-5-(N-benzyloxycarbonylamino)-5-phenylpentanoate
(156). In an oven-dried, 250-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed methyl (SS,R)-(+)-5- phenyl-3-oxo-5-(p-toluenesulfinylamino)-pentanoate (151, 0.383 g, 1.06 mmol) in anhydrous methanol (50 mL). The solution was cooled to 0 oC, and TFA (0.4 mL, 5.2 mmol) was added. The reaction mixture was stirred for 1 h, concentrated, and anhydrous
o THF (50 mL) was added. The solution was cooled to 0 C, Et3N (0.84 mL, 5.7 mmol),
DMAP (0.122 g, 1.0 mmol), and benzyl chloroformate (0.2 mL, 1.42 mmol) were added.
The solution was warmed to rt, and after 8 h, H2O (5 mL) was added. The solution was extracted with EtOAc (3 x 20 mL), and the combined organic phases were washed with brine (20 mL), dried (Na2SO4), and concentrated. Flash chromatography (30%
o 20 EtOAc/hexanes) afforded 0.291 g (77%) of a white solid, mp 82-84 C; [α]D = + 3.36 (c
-1 1 = 1.37); IR (neat) 3314, 1747, 1716, 1688 cm ; H NMR (CDCl3) δ 3.07 (d, J = 5.4, 1
H), 3.13 (d, J = 6.5, 1 H), 3.40 (s, 2 H), 3.69 (s, 3 H); 5.05-5.13 (m, 1 H), 5.15-5.22 (m, 1
13 H), 5.61-5.73 (m, 2 H); 7.22-7.60 (m, 10 H); C NMR (CDCl3) δ 48.6, 49.8, 51.7, 52.8,
67.3, 126.5, 128.1, 128.7, 129.1, 129.2, 136.7, 141.1, 155.9, 167.6, 200.9. HRMS calcd for C20H21NO5Na (M + Na) 378.1317. Found 378.1314.
93 Cbz NH O O
Ph OMe
N2 (R)-157
Methyl (5R)-(+)-2-diazo-3-oxo-5-(N-benzyloxycarbonylamino)-5- phenylpentanoate (157). In an oven-dried, 100-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (R)-
156 (0.448 g, 1.26 mmol) in anhydrous CH3CN (50 mL). The reaction mixture was
o cooled to 0 C, 4-carboxybenzensulfonazide (4-CBSA) (0.315 g, 1.39 mmol) and Et3N
(0.52 mL, 3.78 mmol) were added, and the solution was warmed to rt. After stirring for 4 h, H2O (10 mL) was added and the solution was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (3 x 10 mL), dried (Na2SO4), and concentrated. Flash chromatography (20% EtOAc/hexanes) afforded 0.400 g (83%) of
o 20 (R)-157 as a white solid, mp 110-112 C; [α]D = + 3.33 (c = 1.35); IR (neat) 3312,
-1 1 2923, 2138, 1720, 1654 cm ; H NMR (CDCl3) δ 3.33-3.36 (m, 1 H), 3.44 (dd, J = 15.0,
15.5, 1 H); 3.83 (s, 3 H); 5.08 (dd, J = 21.5, 21.0, 2 H); 5.25-5.26 (m, 1 H), 5.74-5.75 (m,
13 1 H) 7.27-7.35 (m, 10 H); C NMR (CDCl3) δ 30.1, 46.1, 52.3, 52.7, 67.2, 126.5, 127.9,
128.4, 128.7, 128.8, 129.0, 136.8, 141.7, 155.9, 162.1, 190.4. HRMS calcd for
C20H19N3O5Na (M + H) 404.1226. Found 404.1222.
O
Ph N CO2Me Cbz (R)-158
94 Methyl (2RS,5R)-(+)-(N-benzyloxycarbonyl)-3-oxo-5-phenylpyrrolidine-2- carboxylate (158). In an oven-dried, 25-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (R)-
157 (0.018 g, 0.05 mmol) and Rh2(OAc)4 (0.04 g, 0.01 mmol) in CH2Cl2 (2 mL). After stirring for 8 h at 35 oC, the solution was concentrated, and flash chromatography (20%
20 EtOAc/Hexanes) afforded 0.018 g (0.05 mmol) of (R)-158 as a clear oil; [α]D = + 6.22
-1 1 (c = 0.84); IR (neat) 3256, 1772, 1747, 1700, 1391, 1159 cm ; H NMR (CDCl3) δ 2.57
(m, 1 H), 3.16 (d, J = 16 Hz, 1 H), 3.86 (s, 3 H), 4.59 (m, 1 H), 5.01 (m, 2 H), 7.12-7.16
13 (m, 8 H), 7.21-7.23 (d, J = 10 Hz, 2 H); C NMR (CDCl3) δ 45.8, 46.8, 52.5, 67.9, 68.0,
83.6, 12.8, 126.0, 126.5, 126.8, 127.3, 127.9, 128.2, 128.4, 129.3, 130.0, 142.4, 143.1,
154.9, 165.1, 203.6, 204.0. HRMS calcd for C20H19NO5Na (M + Na) 376.1161. Found
376.1159.
O
Ph N Cbz (R)-159
(2R)-(-)-(N-benzyloxycarbonyl)-4-oxo-2-phenylpyrrolidine (159) from (R)-
158. In an oven-dried, 25-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (R)-158 (0.014 g,
0.04 mmol) and LiOH (0.003 g, 0.08 mmol) in anhydrous THF (2 mL) and H2O (0.8 mL). The mixture was allowed to stir at rt for 8 h. The organic phase was extracted with
CH2Cl2 (2 x 5 mL) and concentrated. The residue was dissolved in anhydrous PhMe (10
95 mL). The solution was refluxed for 16 h, H2O (2 mL) was added, and the solution was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine
5 mL, dried and concentrated. Preparative TLC (30% EtOAc/hexanes) afforded 0.002 g
20 -1 (17%) of an oil; [α]D = + 2.97 (c = 0.58); IR (neat) 3256, 1747, 1700, 1391, 1159 cm ;
1 H NMR (CDCl3) δ 2.54 (m, 1 H), 3.15 (d, J = 16 Hz, 1 H), 4.09-4.12 (m, 2 H), 4.59 (m,
13 1 H), 5.01 (m, 2 H), 7.12-7.16 (m, 8 H), 7.21-7.23 (d, J = 10 Hz, 2 H); C NMR (CDCl3)
δ 45.8, 52.4, 67.8, 68.2, 126.4, 126.5, 126.8, 127.3, 127.8, 128.1, 128.4, 129.3, 130.0,
142.2, 154.7, 165.1, 203.4. HRMS calcd for C18H18NO3 (M + H) 296.1287. Found
296.1283.
O
Ph N Cbz (R)-159
Methyl (-)-(N-benzyloxycarbonyl)-3-oxo-5-phenylpyrrolidine (159) from (R)-
164. In an oven-dried, 25-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (R)-164 (0.776 g,
1.96 mmol) in CH2Cl2 (50 mL). The solution was stirred at rt, and TFA (3.1 mL, 40.24 mmol) was added. After 8 h, H2O (1 mL) was added and the solution was extracted with
CH2Cl2 (3 x 20 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), and concentrated. Flash chromatography (70% EtOAc/hexanes) afforded 0.539 g (93%) of an oil. The physical properties are identical with those of (R)-
159, prepared from (R)-158 (see above).
96
O S p-Tolyl NH O O
Ph Ot-Bu (SS,R)-160
tert-Butyl (SS,R)-(+)-5-phenyl-3-oxo-5-(p-toluenesulfinylamino)pentanoate
(160). In an oven-dried, 300-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed NaHMDS (6.40 mL,
6.40 mmol) and tert-butyl acetate (0.9 mL, 6.38 mmol) in THF (10 mL). The solution
o was cooled to -78 C for 1 h, and methyl (SS,R)-(+)-N-(p-toluenesulfinyl)-3-amino-3- phenylpropanoate (150, 0.504 g, 1.59 mmol) in THF (20 mL) was added. After 4 h, sat.
NH4Cl (3 mL) was added and the solution was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (3 x 10 mL), dried (Na2SO4) and concentrated. Flash chromatography (30% EtOAc/hexanes) afforded 0.546 g (86%) of
20 (SS,R)-160 as a yellow oil; [α]D = + 48.6 (c = 1.79); IR (neat) 3179, 2979, 2927, 1738
-1 1 cm ; H NMR (CDCl3) δ 1.41 (s, 9 H), 2.41 (s, 3 H), 3.10-3.12 (m, 2 H), 3.26 (s, 2 H),
4.90-4.92 (m, 2 H), 7.26-7.43 (m, 7 H), 7.57-7.59 (d, J = 8.0, 2 H); 13C NMR δ 21.7,
28.3, 50.3, 54.7, 82.6, 125.7, 127.8, 128.4, 129.2, 140.8, 141.8, 142.7, 166.2, 201.5.
HRMS calcd for C22H27NO4S (M + Na) 424.1559. Found 424.1566.
O S p-Tolyl NH O O
Ph Ot-Bu
N2 (SS,R)-161
97 tert-Butyl (SS,R)-(+)-2-diazo-3-oxo-5-(N-toluenesulfinylamino)-5- phenylpentanoate (161). In an oven-dried, 300-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed
(SS,R)-160 (1.401 g, 3.49 mmol) in anhydrous CH3CN (100 mL). The reaction mixture
o was cooled to 0 C, and 4-CBSA (0.915 g, 4.03 mmol) and Et3N (1.5 mL, 10.76 mmol) were added. The reaction mixture was warmed to rt, and after 4 h H2O (10 mL) was added, and the solution was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), and concentrated. Flash chromatography (30% EtOAc/hexanes) afforded 1.432 g (96%) of (SS,R)-161 as a yellow
20 -1 1 oil; [α]D = + 65.2 (c = 1.64); IR (neat) 3199, 2979, 2926, 2134, 1710, 1650 cm ; H
NMR (CDCl3) δ 1.49 (s, 9 H), 2.41 (s, 3 H), 3.25-3.30 (m, 1 H), 3.42-3.46 (m, 1 H), 4.93-
4.94 (m, 1 H), 5.05-5.06 (m, 1 H), 7.27-7.47 (m, 7 H), 7.57-7.59 (d, J = 10.0, 2 H); 13C
NMR δ 21.7, 28.6, 47.6, 55.2, 83.8, 125.8, 127.7, 128.2, 129.0, 129.9, 141.4, 141.6,
142.8, 160.6, 191.0. HRMS calcd for C22H25N3O4S (M + Na) 450.1463. Found
450.1476.
Cbz NH O O
Ph Ot-Bu (R)-162
tert-Butyl (5R)-(+)-3-oxo-5-(N-benzyloxycarbonylamino)-5-phenylpentanoate
(162). In an oven-dried, 300-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (SS,R)-160 (1.927 g,
4.80 mmol) in anhydrous methanol (100 mL). The solution was cooled to 0oC, and TFA
(1.9 mL, 25.1 mmol) was added. After stirring for 1 h, the mixture was concentrated.
98 o The residue was dissolved in THF (100 mL), cooled to 0 C, and Et3N (4.2 mL, 30.1 mmol), DMAP (0.611 g, 5.00 mmol), and benzyl chloroformate (0.9 mL, 6.46 mmol) were added. After warming to rt, the solution was stirred for 5 h and quenched by addition of saturated NH4Cl (10 mL). Water (20 mL) was added, the solution was extracted with EtOAc (3 x 30 mL), and the combined organic phases were washed with brine (20 mL), dried (Na2SO4), and concentrated. Flash chromatography (20%
o 20 EtOAc/hexanes) afforded 0.994 g (96%) of a white solid, mp 64-66 C; [α]D = + 4.17 (c
-1 1 = 0.63); IR (neat) 3314, 1748, 1716, 1689 cm ; H NMR (CDCl3) δ 1.40 (s, 9 H), 3.08
(d, J = 5.5, 1 H), 3.15 (d, J = 6.5, 1 H), 3.41 (s, 2 H), 5.11 (m, 1 H), 5.59 (br s, 2 H), 7.21-
13 7.59 (m, 10 H); C NMR (CDCl3) δ 28.6, 45.9, 50.1, 52.5, 65.8, 84.0, 126.5, 128.1,
128.5, 129.1, 129.2, 136.6, 141.1, 155.8, 167.6, 200.8. HRMS calcd for C23H27NO5Na
(M + Na) 420.1787. Found 420.1784.
Cbz NH O O
Ph Ot-Bu
N2 (R)-163
tert-Butyl (5R)-(+)-2-diazo-3-oxo-5-(N-benzyloxycarbonylamino)-5- phenylpentanoate (163) from (R)-162. In an oven-dried, 300-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (R)-162 (1.051 g, 2.65 mmol) in anhydrous CH3CN (100 mL). The reaction mixture was cooled to 0 oC, 4-carboxybenzensulfonazide (4-CBSA) (0.650 g,
2.86 mmol) and Et3N (1.1 mL, 7.89 mmol) were added, and the solution was warmed to
99 rt. After stirring for 4 h, H2O (10 mL) was added and the solution was extracted with
EtOAc (3 x 20 mL). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), and concentrated. Flash chromatography (10% EtOAc/hexanes)
o 20 afforded 0.914 g (83%) of a white solid, mp 51-53 C; [α]D = + 6.15 (c = 0.52); IR
-1 1 (neat) 3350, 2978, 2134, 1711, 1649 cm ; H NMR (CDCl3) δ 1.51 (s, 9 H), 3.20-3.31
(m, 1 H), 3.49-3.53 (m, 1 H), 5.04 (dd, J = 28.0, 28.5, 1 H), 5.19-5.28 (m, 1 H), 5.83-5.92
13 (m, 1 H) 7.25-7.38 (m, 8 H), 7.59-7.61 (d, J = 9.5, 2 H); C NMR (CDCl3) δ 28.6, 45.8,
52.5, 67.1, 70.1, 83.9, 126.6, 127.8, 128.4, 128.8, 128.9, 130.1, 130.9, 141.9, 155.9,
160.9, 190.9. HRMS calcd for C23H25N3O5 (M + Na) 446.1692. Found 446.1691.
Cbz NH O O
Ph Ot-Bu
N2 (R)-163
tert-Butyl (5R)-(+)-2-diazo-3-oxo-5-(N-benzyloxycarbonylamino)-5- phenylpentanoate (163) from (R)-161. In an oven-dried, 50-mL, single-necked, round- bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (SS,R)-161 (0.083 g, 0.19 mmol) in anhydrous methanol (8 mL). The solution was cooled to 0 oC, and TFA (0.1 mL, 1.3 mmol) was added. After stirring for 1 h, the mixture was concentrated. The residue was dissolved in THF (10 mL), cooled to 0 oC, and Et3N (0.2 mL, 1.43 mmol), DMAP (0.053 g, 0.44 mmol), and benzyl chloroformate
(0.05 mL, 0.36 mmol) were added. After warming to rt, the solution was stirred for 5 h and quenched by addition of saturated NH4Cl (0.5 mL). Water (1 mL) was added, the solution was extracted with EtOAc (3 x 10 mL), and the combined organic phases were
100 washed with brine (1 mL), dried (Na2SO4), and concentrated. Flash chromatography
(30% EtOAc/hexanes) afforded 0.078 g (97%) of a white solid. The physical properties are identical with those of (R)-163 prepared from (R)-162 (see above).
O
Ph N CO2t-Bu Cbz (R)-164
tert-Butyl (2RS,5R)-(+)-(N-benzyloxycarbonyl)-3-oxo-5-phenylpyrrolidine-2- carboxylate (164). In an oven-dried, 100-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (R)-
163 (0.357 g, 0.84 mmol) and Rh2(OAc)4 (0.037 g, 0.08 mmol) in CH2Cl2 (40 mL) and the reaction mixture was warmed to 35oC. After stirring for 8 h at this temperature, the solution was concentrated. Flash chromatography (20% EtOAc/Hexanes) afforded 0.285
20 g (0.72 mmol) of (R)-161 as a clear oil; [α]D = + 4.8 (c = 0.39); IR (neat) 3107, 2979,
-1 1 1746, 1716 cm ; H NMR (CDCl3) δ 1.39 (s, 9 H), 2.61 (d, J = 18.2 Hz, 1 H), 2.63 (m, 1
H), 3.52-3.56 (m, 1 H), 4.61-4.69 (br s, 1 H), 5.81-5.89 (br s, 2 H), 7.25-7.37 (m, 8 H),
13 7.58-7.61 (d, J = 9.6, 2 H); C NMR (CDCl3) δ 28.6, 48.6, 55.6, 67.1, 77.6, 83.8, 126.6,
127.8, 128.4, 128.8, 128.9, 130.1, 130.8, 141.8, 156.0, 169.0, 204.7. HRMS calcd for
C23H25NO5Na (M + Na) 418.1630. Found 418.1624.
Boc NH O O
Ph Ot-Bu (R)-165
101 tert-Butyl (5R)-(-)-3-oxo-5-(N-tert-butoxycarbonylamino)-5-phenylpentanoate
(165). In an oven-dried, 100-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (SS,R)-160 (0.275 g,
0.64 mmol) in anhydrous methanol (10 mL). The solution was cooled to 0 oC, and TFA
(0.3 mL, 3.25 mmol) was added. The reaction mixture was stirred for 1 h, concentrated,
o and anhydrous THF (10 mL) was added. The solution was cooled to 0 C, Et3N (0.6 mL,
3.95 mmol), DMAP (0.024 g, 0.19 mmol), and Boc2O (0.211 mL, 0.97 mmol) were added, and the solution was warmed to rt. After 8 h, H2O (1 mL) was added and the solution was extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), and concentrated. Flash chromatography
o 20 (20% EtOAc/hexanes) afforded 0.209 g (90%) of a white solid, mp 85-86 C; [α]D = -
-1 1 17.2 (c = 0.48); IR (neat) 3281, 2963, 1746, 1718 cm ; H NMR (CDCl3) δ 1.39 (s, 9 H),
1.40 (s, 9 H), 3.09 (d, J = 5.6 Hz, 1 H), 3.15 (d, J = 6.5 Hz, 1 H), 3.40 (s, 2 H), 4.63 (d, J
13 = 8.5 Hz, 1 H), 5.01 (br s, 1 H), 7.11-7.21 (m, 5 H); C NMR (CDCl3) δ 28.6, 28.7, 50.1,
52.8, 65.7, 81.8, 83.8, 126.4, 128.1, 141.1, 141.6, 156.0, 168.1. HRMS calcd for
C20H29NO5Na (M + Na) 386.1943. Found 386.1939.
Boc NH O O
Ph Ot-Bu
N2 (R)-166
tert-Butyl (5R)-(-)-2-diazo-3-oxo-5-(N-tert-butoxycarbonylamino)-5- phenylpentanoate (166) (from 165). In an oven-dried, 100-mL, single-necked, round- bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (R)-165 (0.173 g, 0.48 mmol) anhydrous CH3CN (40 mL). The reaction
102 o mixture was cooled to 0 C, and 4-CBSA (0.120 g, 0.53 mmol) and Et3N (0.2 mL, 1.43 mmol) were added. The reaction mixture was warmed to rt, and after 4 h, H2O (1 mL) was added and the solution was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (1 mL), dried (Na2SO4), and concentrated. Flash chromatography (30% EtOAc/hexanes) afforded 0.136 g (73%) of a white solid, mp
o 20 -1 1 61 C; [α]D = - 17.4 (c = 0.51); IR (neat) 2963, 2142, 1718, 1699 cm ; H NMR
(CDCl3) δ 1.41 (s, 9 H), 1.50 (s, 9 H), 3.23 (m, 1 H), 3.48 (m, 1 H), 5.01 (dd, J = 10.6,
13 11.0, 1 H), 5.23 (m, 1 H), 7.22-7.34 (m, 5 H); C NMR (CDCl3) δ 28.6, 28.7, 45.8, 52.3,
83.9, 84.0, 126.6, 126.7, 127.9, 128.3, 141.8, 156.0, 160.1, 190.7. HRMS calcd for
C20H27N3O5Na (M + Na) 412.1848. Found 412.1842.
Boc NH O O
Ph Ot-Bu
N2 (R)-166
tert-Butyl (+)-2-diazo-3-oxo-5-(N-tert-butoxycarbonylamino)-5- phenylpentanoate (166) (from 161). In an oven-dried, 50-mL, single-necked, round- bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (SS,R)-161 (0.134 g, 0.31 mmol) in anhydrous methanol (5 mL). The solution was cooled to 0oC, and TFA (0.1 mL, 1.30 mmol) was added. After stirring for 1 h, the mixture was concentrated. The residue was dissolved in THF (10 mL), cooled to 0oC, and Et3N (0.3 mL, 2.15 mmol), DMAP (0.008 g, 0.07 mmol), and Boc2O (0.101 g, 0.47 mmol) were added. After warming to rt, the solution was stirred for 5 h and quenched by addition of saturated NH4Cl (0.5 mL). Water (0.5 mL) was added, the solution was extracted with EtOAc (3 x 5 mL), and the combined organic phases were washed with
103 brine (1 mL), dried (Na2SO4), and concentrated. Flash chromatography (20%
EtOAc/hexanes) afforded 0.092 g (70%) of a white solid. The physical properties are identical with those of (R)-166 prepared from (R)-165 (see above).
O
Ph N CO2t-Bu Boc (R)-167
tert-Butyl (2RS,5R)-(-)-N-(tert-butoxycarbonyl)-3-oxo-5-phenylpyrrolidine-2- carboxylate (167). In an oven-dried, 300-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (R)-
166 (0.511 g, 1.31 mmol) and Rh2(OAc)4 (0.058 g, 0.13 mmol) in CH2Cl2 (50 mL), and the reaction mixture was warmed to 35 oC. After stirring for 8 h at this temperature the solution was concentrated. Flash chromatography (10% EtOAc/hexanes) afforded 0.422
20 -1 1 g (89%) of an oil; [α]D = - 109.2 (c = 0.84); IR (neat) 3101, 2961, 1746, 1718 cm ; H
NMR (CDCl3) δ 1.39 (s, 9 H), 1.41 (s, 9 H), 2.58 (d, J = 18.0 Hz, 1 H), 2.63 (m, 1 H),
13 3.53-3.56 (m, H), 4.63-4.72 (br s, 1 H), 7.12-7.21 (m, 5 H); C NMR (CDCl3) δ 28.7,
28.8, 48.6, 55.3, 66.7, 81.8, 83.8, 125.8, 127.7, 128.2, 155.9, 167.3, 204.5. HRMS calcd for C20H27NO5Na (M + Na) 384.1787. Found 384.1789.
HO O
Ph N Cbz (2S,3S)-171
104 (2S,3S)-(+)-(N-Benzyloxycarbonyl)-3-hydroxy-4-oxo-2-phenylpyrrolidine
(171). In an oven-dried, 100-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (R)-159 (0.272 g,
0.92 mmol) in THF (20 mL) and HMPA (2 mL). The reaction flask was cooled to -78 oC, and LDA (0.80 mL, 1.6 mmol, in THF) was added. The solution was stirred for 1 h at which time (-)-8,8-dichlorocamphorsulfonyl oxaziridine (Davis’ oxaziridine, 170)
(0.531 g, 1.78 mmol) was added. After stirring at -78 oC for 2 h, the solution was quenched with 20% aq. HCl (10 mL) and warmed to rt. Sodium thiosulfate (5 mL) was added, and the solution was extracted with Et2O (3 x 10 mL). The combined organic phases were washed with water (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. Flash chromatography (20% EtOAc/hexanes) afforded 0.260 g (91%) of a
o 20 white solid, mp 103-104 C; [α]D = 4.7 (c = 0.29); IR (neat) 3284 (br), 2959, 1738,
-1 1 1716 cm ; H NMR (CDCl3) δ 3.73 (br s, 1 H), 4.06 (m, 1 H), 4.17 (m, 1 H), 4.79 (m, 1
H), 5.09 (m, 1 H), 5.86 (br s, 2 H), 7.06-7.19 (m, 8 H), 7.25-7.27 (d, J = 10.0 Hz, 2 H);
13 C NMR (CDCl3) δ 51.9, 56.2, 67.2, 96.1, 127.1, 127.2, 127.6, 127.9, 128.5, 128.8,
140.9, 141.6, 156.1, 207.1. HRMS calcd for C18H17NO4Na (M + Na) 334.1055. Found
334.1052.
HO O
Ph N Boc (2S,3S)-172
(2S,3S)-(-)-(N-tert-Butoxycarbonyl)-3-hydroxy-4-oxo-2-phenylpyrrolidine
(172). In an oven-dried, 100-mL, single-necked, round-bottom flask equipped with a
105 magnetic stirring bar, rubber septum, and argon balloon was placed (R)-155 (0.024 g,
0.09 mmol) in THF (5 mL) and HMPA (0.5 mL). The reaction flask was cooled to -78 oC, and LDA (0.09 mL, 0.09 mmol, in THF) was added. The solution was stirred for 1 h at which time (-)-170 (0.074 g, 0.25 mmol) was added. After stirring at -78 oC for 2 h, the solution was quenched with 20% aq. HCl (2 mL) and warmed to rt. Sodium thiosulfate (1 mL) was added, and the solution was extracted with Et2O (3 x 5 mL). The combined organic phases were washed with water (1 mL) and brine (1 mL), dried
(Na2SO4), and concentrated. Flash chromatography (20% EtOAc/hexanes) afforded
20 0.008 g (67%) of an oil; [α]D = -6.3 (c = 0.37); IR (neat) 3291 (br), 2976, 1741, 1718;
1 H NMR (CDCl3) δ 1.39 (s, 9 H), 3.71 (br s, 1 H), 4.04 (m, 1 H), 4.14 (m, 1 H), 4.68 (m,
13 1 H), 5.10 (m, 1 H), 7.07-7.18 (m, 5 H); C NMR (CDCl3) δ 28.8, 55.7, 66.9, 81.7, 95.9,
127.1, 127.2, 127.9, 128.5, 129.1, 155.9, 206.9. HRMS calcd for C15H20NO4 (M + H)
278.1392. Found 278.1386.
HO OH
Ph N Boc (2S,3S,4R)-174a
(2S,3S,4R)-(-)-(N-tert-Butoxycarbonyl) 3,4-dihydroxy-2-phenylpyrrolidine
(174a). In an oven dried, 100-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (2S,3S)-172 (0.241 g,
0.87 mmol) in anhydrous methanol (30 mL). The reaction flask was cooled to -78 oC, and NaBH4 (0.130 g, 3.48 mmol) was added, and the solution was warmed to rt. After stirring for 1 h, H2O (3 mL) was added, and the solution was extracted with EtOAc (3 x
106 10 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), and concentrated. Flash chromatography (20% EtOAc/hexanes) afforded 0.240 g (0.86
20 1 mmol) of an oil; [α]D = -38.1 (c = 0.44); IR (neat) 3296 (br), 2975, 1741; H NMR
(CDCl3) δ 1.39 (s, 9 H), 3.65 (dd, J = 13.0, 13.2, 1 H), 3.82 (br s, 2 H), 4.59 (m, 1 H),
13 4.97 (m, 1 H), 7.14-7.32 (m, 5 H); C NMR (CDCl3) δ 28.7, 49.3, 56.0, 76.1, 77.0, 81.8,
127.0, 127.8, 127.9, 128.4, 128.4, 156.0. HRMS calcd for C15H22NO4 (M + H) 280.1549.
Found 280.1546.
HO OH
Ph N Cbz (2S,3S,4R)-174b
(2S,3S,4R)-(+)-(N-Benzyloxycarbonyl) 3,4-dihydroxy-2-phenylpyrrolidine
(174b). In an oven dried, 50-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (2S,3S)-171 (0.057 g,
0.18 mmol) in anhydrous methanol (15 mL). The reaction flask was cooled to -78 oC, and NaBH4 (0.027 g, 0.72 mmol) was added, and the solution was warmed to rt. After stirring for 1 h, H2O (1 mL) was added, and the solution was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (1 mL), dried (Na2SO4), and concentrated. Flash chromatography (20% EtOAc/hexanes) afforded 0.053 g (0.17
20 -1 1 mmol) of an oil; [α]D = 53.6 (c = 0.62); IR (neat) 3286 (br), 2961, 1738 cm ; H NMR
(CDCl3) δ 3.69-3.98 (m, 2 H), 4.08 (dd, J = 13.1, 13.2 Hz, 1 H), 4.62 (m, 1 H), 4.91 (m, 1
13 H), 7.23-7.35 (m, 10 H); C NMR (CDCl3) δ 50.1, 56.4, 67.1, 76.9, 77.5, 127.3, 127.0,
107 127.2, 127.7, 127.8, 128.4, 128.9, 129.0, 156.1. HRMS calcd for C18H19NO4Na (M +
Na) 336.1212. Found 336.1215.
HO OH
Ph N Boc (2S,3S,4S)-175a
(2S,3S,4S)-(-)-(N-tert-Butoxycarbonyl) 3,4-dihydroxy-2-phenylpyrrolidine
(175a). In an oven dried, 100-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (2S,3S)-172 (0.119 g,
0.43 mmol) in MeCN (10 mL) and acetic acid (10 mL). The reaction flask was cooled to
o -40 C, and tetramethylammonium borane triacetate [Me4NBH(OAc)3] (3.168 mg, 12.04 mmol) was added. The reaction mixture was stirred at this temperature for 15 h, quenched with 0.5 N aq. sodium potassium tartrate (2 mL). The solvent was diluted with
CH2Cl2 and washed with aq. NaHCO3 solution (3 x 10 mL). The solution was extracted with CH2Cl2, and the combined organic phases were washed with aq. NaHCO3 solution
(5 mL), H2O (5 mL), brine (5 mL), dried (Na2SO4), and concentrated. Flash chromatography (EtOAc:hexanes:MeOH 20:80:10) afforded 0.092 g (77%) of an oil;
20 -1 1 [α]D = 56.1 (c = 0.29); IR (neat) 3296 (br), 2974, 1742 cm ; H NMR (CDCl3) δ 1.40
(s, 9 H), 2.08 (br s, 2 H), 3.37 (dd, J = 10.3, 10.5 Hz, 1 H), 4.08-4.11 (m, 2 H), 4.62 (m, 1
13 H), 5.08 (m, 1 H), 7.06-7.17 (m, 5 H); C NMR (CDCl3) δ 28.8, 49.4, 56.2, 75.9, 77.2,
81.7, 127.0, 127.8, 127.9, 128.5, 128.9. HRMS calcd for C15H22NO4 (M + H) 280.1549.
Found 280.1546.
108 HO OH
Ph N Cbz (2S,3S,4S)-175b
(2S,3S,4S)-(-)-(N-Benzyloxycarbonyl) 3,4-dihydroxy-2-phenylpyrrolidine
(175b). In an oven dried, 50-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (2S,3S)-171 (0.043 g,
0.14 mmol) in MeCN (5 mL) and acetic acid (5 mL). The reaction flask was cooled to -
o 40 C, and tetramethylammonium borane triacetate [Me4NBH(OAc)3] (1.031 mg, 3.92 mmol) was added. The reaction mixture was stirred at this temperature for 15 h, quenched with 0.5 N aq. sodium potassium tartrate (1 mL). The solvent was diluted with
CH2Cl2 and washed with aq. NaHCO3 solution (3 x 5 mL). The solution was extracted with CH2Cl2, and the combined organic phases were washed with aq. NaHCO3 solution
(2 mL), H2O (2 mL), brine (2 mL), dried (Na2SO4), and concentrated. Flash chromatography (EtOAc:hexanes:MeOH 20:80:10) afforded 0.031 g (73%) of an oil;
20 1 [α]D 73.2 (c = 0.61); IR (neat) 3279, 2961, 1737, 1716; H NMR (CDCl3) δ 3.47 (dd, J
= 10.5, 10.6, 1 H), 3.75 (br s, 2 H), 4.06 (m, 1 H), 4.19 (m, 1 H), 4.63 (m, 1 H), 5.12 (m,
1 H), 5.89 (s, 2 H), 7.07 (d, J = 8.6, 1 H), 7.19-7.25 (m, 5 H), 7.27-7.30 (m, 4 H); 13C
NMR (CDCl3) δ 50.4, 51.9, 67.1, 75.6, 79.1, 127.1, 127.2, 127.6, 127.9, 128.5, 128.8,
141.6, 141.8, 156.1. HRMS calcd for C18H19NO4Na (M+Na) 336.1212. Found
336.1209.
109 O O
Ph N Boc (2S,3S,4R)-177a
(2S,3S,4R)-N-tert-Butoxycarbonyl-3,4-dihydroxy-2-phenylpyrrolidine
Isopropylidene Acetal 177a. In an oven dried, 50-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed
(2S,3S,4R)-174a (0.112 g, 0.40 mmol), 2,2-dimethyoxypropane (0.1 mL, 0.81 mmol), and p-toluenesulfonic acid monohydrate (0.010 g, 0.05 mmol) in acetone (5 mL). After stirring at rt for 3 h, the reaction mixture was concentrated. Flash chromatography (15%
o 20 EtOAc/Hexanes) afforded 0.105 g (82%) of a white solid, mp 98-99 C. [α]D 49.02 (c
-1 1 1.6, CHCl3); IR (neat) 2982, 1702, 1601 cm ; H NMR (CDCl3) δ 1.28 (s, 3H), 1.34 (s,
3H), 1.39 (s, 9H), 3.66 (m, 1 H), 4.01 (d, J = 8.6 Hz, 1H), 4.70 (d, J = 5.3 Hz, 1H), 4.76
13 (m, 1H), 5.13 (m, 1H), 7.16-7.36 (m, 5H); C NMR (CDCl3) δ 25.2, 27.1, 28.3, 52.8,
67.4, 78.8, 78.9, 87.5, 112.1, 125.8, 127.2, 128.7, 140.4, 154.5. HRMS calcd for
C18H26NO4 (M+H) 320.1862. Found 320.1861.
O O
Ph N Cbz (2S,3S,4R)-177b
(2S,3S,4R)- N-Benzyloxycarbonyl-3,4-dihydroxy-2-phenylpyrrolidine
Isopropylidene Acetal 177b. In an oven dried, 50-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed
110 (2S,3S,4R)-174b (0.097 g, 0.31 mmol), 2,2-dimethyoxypropane (0.1 mL, 0.81 mmol), and p-toluenesulfonic acid monohydrate (0.010 g, 0.05 mmol) in acetone (5 mL). After stirring at rt for 3 h, the reaction mixture was concentrated. Flash chromatography (15%
o 20 EtOAc/Hexanes) afforded 0.083 g (76%) of a white solid, mp 106-107 C. [α]D 82.6 (c
-1 1 = 0.59); IR (neat) 2986, 1701, 1604 cm ; H NMR (CDCl3) δ 1.29 (s, 3H), 1.33 (s, 3 H),
3.97 (m, 1 H), 4.06 (m, 1 H), 4.53 (m, 1 H), 4.77 (m, 1 H), 5.36 (m, 1 H), 5.88 (s, 2 H),
13 7.18-7.32 (m, 10 H); C NMR (CDCl3) δ 25.4, 27.7, 50.4, 51.9, 67.1, 75.9, 79.3, 127.1,
127.2, 127.6, 127.9, 128.5, 128.8, 141.6, 141.8, 156.1. HRMS calcd for C21H24NO4
(M+H) 354.1705. Found 354.1699.
O O
HO2C N Boc (2R,3S,4R)-178a
(2R,3S,4R)-N-tert-Butoxycarbonyl-3,4-dihydroxyproline Isopropylidene
Acetal (178a). In an oven dried, 50-mL, two-necked round-bottom flask equipped with a magnetic stirring bar and argon balloon was placed 177a (0.089 g, 0.28 mmol), carbon tetrachloride (2 mL), acetonitrile (2 mL), water (4 mL), and sodium bicarbonate (0.393 mg, 4.68 mmol). After stirring for 15 min., sodium periodate (0.960 g, 4.48 mmol) was added. After stirring for 15 min, ruthenium trichloride hydrate (0.006 g, 0.03 mmol) was
o added. After stirring for 48 h, the reaction mixture was cooled to 0 C and Et2O (3 mL) was added. The solution was extracted with Et2O (3 x 3 mL), and the combined organic phases were washed with H2O (1 mL), brine (1 mL), dried (Na2SO4), and concentrated.
Flash chromatography (20% MeOH/CH2Cl2) afforded 0.040 g (50%) of a colorless oil;
111 20 -1 1 [α]D +43.7 (c = 0.08); IR (neat) 3436, 1745, 1582 cm ; H NMR (CDCl3) δ 1.27 (s,
3H), 1.34 (s, 3H), 1.40 (s, 9H), 3.79 (m, 2H), 4.41 (m, 1 H), 4.75 (m, 1H); 13C NMR
(CDCl3) δ 25.2, 26.7, 28.5, 52.3, 66.9, 80.3, 81.6, 82.4, 111.7, 154.1, 172.3. HRMS calcd for C13H22NO6 (M+H) 288.1447. Found 288.1441.
AcO OAc
Ph N Boc (2S,3S,4S)-181
(2S,3S,4S) N-(tert-Butoxycarbony)-3,4-bis(acetoxy)-2-phenylpyrrolidine
(181). In an oven dried, 50-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (2S,3S,4S)-175a
(0.140 g, 0.50 mmol) in anhydrous CH2Cl2 (6 mL). The reaction mixture was cooled to 0 oC and DMAP (0.067 g, 0.56 mmol) and (0.19 mL, 2.0 mmol) was added. After stirring for 1 h, H2O (0.5 mL) was added, and the solution was extracted with EtOAc (3 x 5 mL).
The combined organic phases were washed with brine (1 mL), dried (Na2SO4), and concentrated. Flash chromatography (20% EtOAc/hexanes) afforded 0.109 g (60%) of a
o 20 1 white solid m.p. 134-135 C; [α]D +28.9 (c = 0.33); IR (neat) 3003, 1749, 1236; H
NMR (CDCl3) δ 1.39 (s, 9H), 2.03 (s, 3H), 2.12 (s, 3H), 3.47 (m, 1H), 4.08-4.11 (m, 2H),
13 4.67 (m, 1H), 5.09 (m, 1H), 7.12-7.18 (m, 5H); C NMR (CDCl3) d 21.2, 22.4, 28.8,
49.4, 56.2, 75.9, 77.2, 81.7, 127.0, 127.8, 127.9, 128.5, 128.9. HRMS calcd for
C19H26NO6 (M+H) 364.1760. Found 364.1762.
112 AcO OAc
HO2C N Boc (2R,3S,4S)-182
(2R,3S,4S)-N-(tert-Butoxycarbonyl)-3,4-bis(acetoxy)pyrrolidine-2-carboxylic acid (182). In an oven dried, 50-mL, two-necked round-bottom flask equipped with a magnetic stirring bar and argon balloon was placed (2S,3S,4S)-181 (0.076 g, 0.21 mmol), carbon tetrachloride (2 mL), acetonitrile (2 mL), water (4 mL), and sodium bicarbonate
(0.393 mg, 4.68 mmol). After stirring for 15 min., sodium periodate (0.960 g, 4.48 mmol) was added. After stirring for 15 min, ruthenium trichloride hydrate (0.006 g, 0.03 mmol) was added. After stirring for 48 h, the reaction mixture was cooled to 0 oC and
Et2O (3 mL) was added. The solution was extracted with Et2O (3 x 3 mL), and the combined organic phases were washed with H2O (1 mL), brine (1 mL), dried (Na2SO4), and concentrated. Flash chromatography (20% MeOH/CH2Cl2) afforded 0.035 g (50%)
o 20 of a colorless oil; white solid; m.p. 157-158 C; [α]D +23.1 (c = 0.49); IR (neat) 3517,
1 3256, 1747; H NMR (CDCl3) δ 1.40 (s, 1H), 2.03 (s, 3H), 2.12 (s, 3H), 3.46 (m, 1H),
13 3.52 (m, 1H), 4.01 (m, 1H), 4.21 (d, J = 3.8, 1H), 4.56 (m, 1H); C NMR (CDCl3) δ
21.2, 22.4, 28.5, 51.7, 68.7, 74.9, 80.1, 170.1, 170.3, 172.1, 172.3. HRMS calcd for
C14H22NO8 (M+H) 332.1345. Found 332.1347.
HO OH
HO2C N H
(2R,3S,4S)-183
113 (2R,3S,4S)-3,4-Dihydroxyproline (183). In an oven dried, 25-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (2R,3S,4S)-182 (0.109 g, 0.33 mmol) in 80% aqueous TFA (10 mL).
After stirring for 2 h at rt, the mixture was poured into a Dowex 50WX8 ion-exchange column and was sequentially eluted with MeOH (30 mL), H2O (30 mL), and 10%
o 20 NH4OH (50 mL) to give 0.038 g (67%) of a white solid; m.p. 240-242 C. [α]D +16.1 (c
-1 1 = 0.52); IR (neat) 3517, 3256, 1617, 1577 cm ; H NMR (CDCl3/D2O) δ 3.44 (d, J =
12.8 Hz, 1H), 3.56 (dd, J = 12.8, 3.6, 1 H), 4.02 (m, 1H), 4.25 (d, J = 3.8 Hz, 1H), 4.50
13 (m, 1H); C NMR (CDCl3) δ 51.8, 68.4, 74.7, 80.0, 172.1. HRMS calcd for C5H10NO4
(M+H) 148.0610. Found 148.0612.
HO OH
HO2C N H
(2R,3R,4S)-187
(2R,3R,4S)-3,4-Dihydroxyproline (187). In an oven dried, 25-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (2R,3R,4S)-185 (0.152 g, 0.46 mmol) in 80% aqueous TFA (10 mL).
After stirring for 2 h at rt, the mixture was poured into a Dowex 50WX8 ion-exchange column and was sequentially eluted with MeOH (30 mL), H2O (30 mL), and 10%
20 NH4OH (50 mL) to give 0.072 g (90%) of a white solid; [α]D +54.6 (c = 0.49); IR
-1 1 (neat) 3512, 3254, 1618, 1577 cm ; H NMR (CDCl3/D2O) δ 3.09 (dd, J = 11.2, 8.7 Hz,
13 1H), 3.42 (dd, J=11.2, 7.6 Hz, 1H), 4.03 (d, J = 34.0 Hz, 1H); C NMR (CDCl3) δ 47.2,
64.8, 70.3, 71.4, 170.9. HRMS calcd for C5H10NO4 (M+H) 148.0610. Found 148.0608.
114
HO OH
HO2C N H
(2R,3R,4R)-188
(2R,3R,4R)-3,4-Dihydroxyproline (188). In an oven dried, 25-mL, single- necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (2R,3R,4R)-186 (0.080 g, 0.24 mmol) in 80% aqueous TFA (8 mL). After stirring for 2 h at rt, the mixture was poured into a Dowex 50WX8 ion- exchange column and was sequentially eluted with MeOH (30 mL), H2O (30 mL), and
20 10% NH4OH (50 mL) to give 0.031 g (75%) of a white solid; [α]D +16.9 (c = 0.23); IR
-1 1 (neat) 3512, 3254, 1618, 1577 cm ; H NMR (CDCl3/D2O) δ 3.16 (d, J = 12.6 Hz, 1H),
3.55 (m, 1H), 4.23 (d, J = 3.6, 1H), 4.29 (d, J = 8.0, 1H), 4.37 (m, 1H); 13C NMR
(CDCl3/D2O) δ 51.5, 65.7, 75.4, 76.2, 171.5. HRMS calcd for C5H10NO4 (M+H)
148.0610. Found 148.0606.
AcO OAc
HO N H
(2S,3S,4S)-219
(2S,3S,4S)-2-(4-Hydroxybutyl)-3,4-bis(acetoxy)pyrrolidine (219). In an oven dried, 50-mL, two-necked round-bottom flask equipped with a magnetic stirring bar and argon balloon was placed (2S,3S,4S)-218 (0.097 g, 0.20 mmol) in MeOH (10 mL) and
10% Pd on carbon (0.030 g) was added. The mixture was refluxed for 2 h and cooled to rt. The catalyst was removed by filtration through a Celite column and washed with
115 MeOH. Flash chromatography (80:19:1 CHCl3/MeOH/NH4OH) afforded 0.041 g (80%)
20 -1 1 of a clear gel, [α]D -12.9 (c 0.48); IR (neat) 3300, 1738 cm ; H NMR (CDCl3) δ 1.42-
1.74 (m, 6H), 2.04 (s, 3H), 2.13 (s, 3H), 3.52-3.67 (m, 2 H), 3.73 (m, 1H), 4.05 (m, 1H),
13 4.69 (m, 2H); C NMR (CDCl3) δ 20.8, 21.2, 22.4, 29.6, 32.3, 51.2, 64.1, 80.5, 81.6,
171.3, 172.0. HRMS calcd for C12H22NO5 (M+H) 260.1498. Found 260.1496.
HO OH
N
(1S,2S,8aS)-189
(1S,2S,8aS)-(+)-Lentiginosine (189). In an oven dried, 25-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed (2S,3S,4S)-219 (0.022 g, 0.06 mmol) in DMF (2 mL) and Ph3P (0.035 g, 0.12 mmol), CCl4 (0.01 mL, 0.12 mmol), and Et3N (0.02 mL, 0.14 mmol) were added.
The reaction mixture was stirred for 4 h, concentrated, and anhydrous THF (2 mL) was added. The solution was cooled to 0 oC, and TFA (0.02 mL, 0.27 mmol) was added.
After 1 h, H2O (0.5 mL) was added and the solution was extracted with EtOAc (3 x 3 mL). The combined organic phases were washed with brine (2 mL), dried (Na2SO4), and concentrated. Flash chromatography [(65:25:9:1) hexane/EtOAc/EtOH/30%NH4OH]
o 20 1 afforded g (60%) of a white solid; mp 106-107 C; [α]D 2.1 (c 0.26); H NMR (CDCl3)
δ 1.12-1.79 (m, 5H), 1.82-2.02 (m, 2H), 2.06 (dd, J = 11.3, 2.9 Hz, 1H), 2.60 (dd, J =
11.4, 7.4 Hz, 1H), 2.80 (dd, J = 11.4, 2.0 Hz, 1H), 2.91 (dd, J = 11.2, 2.0, 1H), 3.59 (dd, J
13 = 8.8, 4.0 Hz, 1H), 4.02-4.05 (m, 1H); C NMR (CDCl3) δ 25.1, 25.8, 29.7, 54.7, 62.9,
74.6, 77.8, 85.2. HRMS calcd for C8H16NO2 (M+H) 158.1181. Found 158.1178.
116
CHAPTER 3: SYNTHESIS OF POLYSUBSTITUTED PYRROLES FROM
SULFINIMINES (N-SULFINYL IMINES)
O S p-Tolyl NH O
OMe
239a
Methyl-(±)-N-(p-toluenesulfinyl)-3-amino-3-phenylpropanoate (239a). In an oven-dried, 250-mL, three-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed NaHMDS (2.0 mL, 4.00 mmol) in
o anhydrous Et2O (10 mL). The mixture was cooled to -78 C and methyl acetate (0.35 mL,
4.41 mmol) was added. After stirring at -78oC for 1 h, (±)-(benzylidene)-p- toluenesulfinamide (238a, 0.644 g, 2.65 mmol) in anhydrous Et2O (30 mL) was added and the mixture was stirred at -78oC for 4 h. The mixture was quenched with saturated
NH4Cl (5 mL) and warmed to rt. Water (25 mL) was added and the solution was extracted with EtOAc (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried with Na2SO4, and concentrated. Flash chromatography (20%
EtOAc/Hexanes) afforded 0.728 g (88%) of a white solid, mp 79-81oC; IR (neat) 3051,
-1 1 1609, 1574, 1450, 1102, 1074 cm ; H NMR (CDCl3) δ 2.67 (s, 1 H), 2.71 (d, J = 6.8, 2
H), 3.45 (s, 3 H), 4.76 (q, J = 12.4, J = 12.8, 1 H), 4.93 (d, J = 6.0, 1 H), 7.13-7.22 (m, 3
13 H), 7.24-7.29 (m, 4 H), 7.45 (d, J = 8.0, 1 H); C NMR (CDCl3) δ 21.7, 42.4, 52.2, 55.2,
125.8, 127.6, 128.4, 129.1, 129.4, 140.9, 141.8, 142.7, 171.6; HRMS calcd for
C17H19NO3S (M + H) 318.1164. Found 318.1169.
117
O S p-Tolyl NH O O OMe
239b
Methyl-(±)-3-(2-furyl)-3-( p-toluenesulfinylamino)propanoate (239b). In an oven-dried 250-mL, three-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed NaHMDS (5.4 mL, 10.8 mmol) in
o anhydrous Et2O (20 mL). It was brought to -78 C and methyl acetate (0.9 mL, 11.35 mmol) was added. After stirring at -78oC for 1 h, (±)-N-(2-furylmethylidene)-p- toluenesulfinamide (238b, 1.680 g, 7.2 mmol) in anhydrous Et2O (30 mL) the mixture
o was stirred at -78 C for 4 h. The mixture was quenched with saturated NH4Cl (5 mL) and warmed to rt. Water (25 mL) was added and the solution was extracted with EtOAc (3 x
25 mL). The combined organic phases were washed with brine (25 mL), dried with
Na2SO4, and concentrated. Flash chromatography (20% EtOAc/80% Hexanes) afforded
1 1.495 g (91%) of an oil. IR (neat) 3423, 3225, 1747, 1716; H NMR (CDCl3) δ 2.25 (s, 3
H); 2.74-2.78 (m, 2 H); 3.48 (s, 3 H); 4.75 (m, 1 H); 4.89 (d, J = 7.6, 1 H); 6.19 (s, 2 H),
7.15 (d, J = 8, 2 H); 7.23 (s, 1 H); 7.44 (d, (J = 8, 2 H); 13C NMR δ 21.7, 39.8, 49.4, 52.2,
107.9, 110.8, 126.0, 126.4, 129.9, 141.8, 142.3, 142.7, 153.6, 171.4; HRMS calcd for C15
H18NO4S (M+H) 308.0956. Found 308.0946.
118 O S p-Tolyl NH O
OMe
239c
Methyl-(±)-4,4-dimethyl-N-(p-toluenesulfinyl)-3-aminopentanoate (239c). In an oven-dried, 250-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed NaHMDS (10.5 mL, 10.5
o mmol) in anhydrous EtO2 (30 mL). It was brought to -78 C and methyl acetate (0.85 mL,
10.72 mmol) was added. After stirring at -78oC for 1 h, N-(2,2-dimethylpropylidne)-p- toluenesulfinamide (238c, 1.563 g, 7.0 mmol) in anhydrous Et2O (30 mL) was added.
The mixture was stirred at -78oC for 4 h. The mixture was quenched with saturated
NH4Cl (5 mL) and warmed to rt. Water (25 mL) was added and the solution was extracted with EtOAc (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried with Na2SO4, and concentrated. Flash chromatography (20%
EtOAc/Hexanes) afforded 1.613 g (78%) of an oil; IR (neat) 3196, 2955, 1738 cm-1; 1H
NMR (CDCl3) δ 0.68 (s, 9 H), 2.11 (s, 3 H), 2.18-2.24 (m, 1 H), 2.41-2.46 (m, 1 H), 3.44
(s, 3 H), 4.03 (d, J = 9.6, 2 H), 6.99 (d, J = 8.0, 2 H), 7.32 (d, J = 8.0, 2 H); 13C NMR
(CDCl3) δ 21.7, 26.9, 36.0, 37.7, 52.3, 63.0, 125.6, 129.9, 141.6, 143.8, 172.8; HRMS calcd for C15H24NO3S (M+H) 298.1477. Found 298.1474.
O S p-Tolyl NH O
OMe
239d
119 Methyl-(±)-3-oxo-5-(p-toluenesulfinylamino)-pent-4-enoate (239d). In an oven-dried, 100-mL, single-necked, round bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon NaHMDS (8.4 mL, 8.4 mmol) in anhydrous THF (10 mL). The reaction mixture was cooled to -78 °C and methyl acetate
(0.7 mL, 8.82 mmol) was added. After stirring at this temperature for 1 h, (±)-N- allylidene-p-toluenesulfinamide (238d, 1.0 g 5.6mmol) in Et2O (30 mL) was added. The
o solution stirred at -78 C for 4 h, quenched wth saturated NH4Cl (10mL), and warmed to rt. Water was added and the solution was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4), and concentrated. Flash chromatography (40% EtOAc/hexane) afforded 1.49 (85%) of an oil;
-1 1 IR (neat) 3197, 1737, 815 cm ; H NMR (CDCl3) 2.26 (s, 3 H), 2.50-2.48 (m, 2 H), 3.51
(s, 3 H), 4.09-4.12 (m, 1 H), 4.70 (d, J = 9 Hz, 1 H), 5.08-5.10 (m, 1H), 5.16-5.21 (m, 1
H), 5.75-5.83 (m, 1 H), 7.16 (d, J = 10 Hz, 2 H), 7.45 (d, J = 10 Hz, 2 H); 13C NMR
(CDCl3) 21.6, 40.7, 52.0, 117.4, 125.9, 129.9, 138.1, 141.7, 142.3, 171.6. HRMS calcd. for C13H17NO3S (M+H) 268.0929. Found 268.1005.
O S p-Tolyl NH O O
OMe
240a
Methyl-(±)-3-oxo-5-(p-toluenesulfinylamino)-5-phenylpentanoate (240a). In an oven-dried, 100-mL, single necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed NaHMDS (1.90 mL, 1.90 mmol) in anhydrous THF (5 mL). The reaction mixture was cooled to -78oC and methyl
120 acetate (0.15 mL, 1.90 mmol) was added. After stirring at this temperature for 1 h, 239a
(0.245 g, 0.82 mmol) in THF (15 mL) was added. The solution was stirred at -78oC for 4 h, quenched with saturated NH4Cl (2 mL), and warmed to rt. Water (10 mL) was added and the solution was extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried with Na2SO4, and concentrated. Flash chromatography (50% EtOAc/Hexanes) afforded 0.143 g (85%) of an oil; IR (neat) 3194,
-1 1 2361, 1748, 1718, 1319, 1260, 1090, 1059 cm ; H NMR (CDCl3) δ 2.38 (s, 3 H), 3.08
(dd, J = 17.59, 55, 1 H), 3.12 (dd, J = 17.59, 6.6, 1 H); 3.34 (s, 2 H), 3.63 (s, 3 H, 492
(dd, J = 5.86, 121, 1 H), 4.99 (d, J = 5.5, 1 H), 7.21-7.42 (m, 7 H), 7.57 (d, J = 8.3, 2 H);
13 C NMR (CDCl3) δ 21.2, 49.9, 50.5, 52.2, 54.0, 125.2, 127.2, 127.9, 128.6, 129.4, 140.3,
141.2, 142.0, 167.0, 200.4; HRMS calcd for C19H21NO4S (M + Na) 382.1089. Found
382.1096.
O S p-Tolyl NH O O O OMe
240b
Methyl-(±)-5-(2-furyl)-5-(p-toluenesulfinylamino)-3-oxopentanoate (240b). In an oven-dried, 250-mL, three-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed NaHMDS (14.70 mL, 14.70 mmol) in anhydrous THF (15 mL). The reaction mixture was cooled to -78oC and methyl acetate (1.20 mL, 15.13 mmol) was added. After stirring at this temperature for 1 h,
239b (1.129 g, 3.67 mmol) in THF (35 mL) was added. The solution was stirred at -78oC for 4 h, quenched with saturated NH4Cl (5 mL), and warmed to rt. Water (10 mL) was
121 added and the solution was extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), and concentrated. Flash chromatography (50% EtOAc/Hexanes) afforded 1.077 g (84%) of an orange oil; IR
-1 1 (neat) 3423, 3224, 1748, 1716 cm ; H NMR (CDCl3) δ 2.27 (s, 3 H), 3.08 (qd, 2 H),
3.29 (s, 2 H), 3.57 (s, 3 H), 4.78-4.82 (m, 2 H), 6.13 (d, J = 8.4 Hz, 2 H), 6.26 (d, J = 8.0
13 Hz, 1 H), 7.15 (d, J = 8.4, 2 H), 7.22 (s, 1 H), 7.45 (d, J = 8.4, 2 H); C NMR (CDCl3) δ
21.7, 47.7, 49.5, 52.7, 108.2, 110.9, 126.0, 129.9, 141.8, 142.6, 153.4, 167.5, 200.5;
HRMS calcd for C17H20NO5S (M + H) 350.1062. Found 350.1059.
O S p-Tolyl NH O O
OMe
240c
Methyl-(±)-6,6-dimethyl-3-oxo-5-(p-toluenesulfinylamino) heptanoate (240c).
In an oven-dried, 250-mL, single necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed NaHMDS (3.80 mL, 3.80 mmol) in anhydrous THF (20 mL). The reaction mixture was cooled to -78oC and methyl acetate (0.30 mL, 3.78 mmol) was added. After stirring at this temperature for 1 h, 239c
(0.245 g, 0.82 mmol) in THF (30 mL) was added. The solution was stirred at -78oC for 4 h, quenched with saturated NH4Cl (5 mL) and warmed to rt. Water (20 mL) was added and the solution was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried with Na2SO4, and concentrated. Flash chromatography (50% EtOAc/Hexanes) afforded 0.234 g (84%) of a white solid, mp
122 o -1 1 86 C; IR (neat) 3197, 2961, 1744, 1718 cm ; H NMR (CDCl3) δ 0.95 (s, 9 H), 2.41 (s, 3
H), 2.82 (dd, J = 5.6, 13.6 Hz, 1 H), 2.91 (dd, J = 3.2, 13.6 Hz, 1 H), 3.57 (d, J = 12.4 Hz,
1 H), 3.59 (d, J = 12.4 Hz, 1 H), 3.73 (m, 1 H), 3.74 (s, 3 H), 4.04 (d, J = 7.6 Hz, 1 H),
13 7.28 (d, J = 6.8 Hz, 2 H), 7.57 (d, J = 6.8 Hz, 2 H); C NMR (CDCl3) δ 21.8, 26.9, 35.8,
46.0, 50.3, 52.8, 61.5, 125.7, 130.0, 141.8, 143.5, 168.3, 201.7. HRMS calcd for
C17H25NO4SNa (M + Na) 362.1410. Found 362.1402.
O S p-Tolyl NH O O
OMe
240d
Methyl-(±)-5-(p-toluenesulfinylamino)-3-oxo-hept-6-enoate (240d). In a 25- mL, single-necked, round-bottomed flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed NaHMDS (0.75 mL, 0.75 mmol) in anhydrous
THF (2 mL). The reaction mixture was cooled to -78 °C and methyl acetate (0.06 mL,
0.75 mmol) was added. After stirring at this temperature for 1 h, 239d (0.050 g, 0.187 mmol) in THF (1 mL) was added. The solution was stirred at -78oC for 4 h, quenched
with saturated aqueous NH4Cl solution (1 mL), and warmed to rt. Water (1 mL) was added and the solution was extracted with EtOAc (3 x 4 mL). The combined organic
phases were washed with brine (1 mL), dried (Na2SO4), and concentrated. Flash chromatography (40% EtOAc/hexane) afforded 0.049 g (85%) of a yellow oil; IR (neat)
-1 1 1735, 1718, 810 cm ; H NMR (CDCl3) δ 2.28 (s, 3H), 2.78-2.75 (m, 2 H), 3.29 (s, 2 H),
3.58 (s, 3 H), 4.16-4.13 (m, 1 H), 4.67 (d, J = 9 Hz, 1 H), 5.07 (m, 1 H), 5.16 (m, 1 H),
13 5.77 (m, 1 H), 7.15 (d, J = 10 Hz, 2 H), 7.43 (d, J = 10 Hz, 2 H); C NMR (CDCl3)
123 δ 21.8, 48.8, 49.7, 52.6, 53.2, 117.3, 125.9, 129.8, 138.1, 141.7, 142.3, 168.9, 200.9.
HRMS calcd for C15H19NO4S (M + H) 310.1035. Found 310.1115.
Boc NH O O
OMe
241a
Methyl-(±)-3-oxo-5-(tert-butyloxycarbonylamino)-5-phenylpentanoate (241a).
In an oven-dried, 100-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 240a (0.571 g, 1.59 mmol) in anhydrous methanol (20 mL). The solution was cooled to 0oC and TFA (0.60 mL, 7.79 mmol) was added. The mixture was stirred for 1 h, concentrated, and anhydrous THF (20
o mL) was added. The solution was cooled to 0 C, Et3N (1.30 mL, 9.33 mmol) and Boc2O
(2.40 mL, 2.40 mmol) were added, and the solution was warmed to rt. After 8 h, H2O (5 mL) was added and the solution was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried with (Na2SO4), and concentrated.
Flash chromatography (20% EtOAc/Hexanes) afforded 0.377 g (74%) of an oil; IR (neat)
-1 1 3376, 1752, 1718, 1685, 1521, 1167 cm ; H NMR (CDCl3) δ 1.41 (s, 9 H), 3.01-3.06
(m, 1 H), 3.15-3.20 (m, 1 H), 3.40 (m, 2 H), 369 (s, 3 H), 5.11 (m, 1 H), 5.37 (m, 1 H),
13 7.23-7.34 (m, 5 H); C NMR (CDCl3) δ 29.0, 49.3, 50.0, 51.6, 53.0, 80.5, 126.9, 128.2,
129.4, 141.8, 155.6, 167.9, 201.4; HRMS calcd for C17H23NO5 (M + H) 322.1654.
Found 322.1652.
124 Boc NH O O O OMe
241b
Methyl-(±)-5-(tert-butoxycarbonyl)-5-(2-furyl)-3-oxopentanoate (241b). In an oven-dried, 25-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 240b (0.097 g, 0.28 mmol) in anhydrous methanol (2 mL). The solution was cooled to 0oC and TFA (0.06 mL, 0.78 mmol) was added. The reaction mixture was stirred for 1 h, concentrated, and anhydrous
o THF (2 mL) was added. The solution was cooled to 0 C, Et3N (0.20 mL, 1.43 mmol) and
Boc2O (0.60 mL, 0.60 mmol) were added, and the solution was warmed to rt. After 8 h,
H2O (0.5 mL) was added and the solution was extracted with EtOAc (3 x 2 mL). The combined organic phases were washed with brine (2 mL), dried with (Na2SO4), and concentrated. Flash chromatography (20% EtOAc/Hexanes) afforded 0.071 g (82%) of a
-1 1 slight yellow oil; IR (neat) 3421, 3226, 1745, 1716 cm ; H NMR (CDCl3) δ 1.36 (s, 9
H), 3.07 (m, 2 H), 3.37 (s, 2 H), 3.64 (s, 3 H), 5.18 (m, 2 H), 6.18 (d, J = 8.1 Hz, 1 H),
13 6.21 (d, J = 8.0 Hz, 1 H), 7.19 (s, 1 H); C NMR (CDCl3) δ 28.5, 40.3, 47.8, 48.4, 52.6,
80.1, 106.9, 109.8, 140.5, 141.8, 156.3. HRMS calcd for C15H22NO6 (M + H) 312.1447.
Found 312.1441.
Boc NH O O
OMe
241c
125 Methyl-(±)-5-(tert-butoxycarbonyl)-6,6-dimethyl-3-oxoheptanoate (241c). In an oven-dried, 100-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 240c (0.870 g, 2.56 mmol) in anhydrous methanol (20 mL). The solution was cooled to 0oC and TFA (1.0 mL, 12.98 mmol) was added. The reaction mixture was stirred for 1 h, concentrated, and anhydrous
o THF (20 mL) was added. The solution was cooled to 0 C, Et3N (2.20 mL, 15.78 mmol) and Boc2O (3.90 mL, 3.90 mmol) were added, and the solution was warmed to rt. After 8 h, H2O (5 mL) was added and the solution was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried with (Na2SO4), and concentrated. Flash chromatography (20% EtOAc/Hexanes) afforded 0.748 g (97%) of a slight yellow oil; IR (neat) 3369, 1719, 1693 cm-1; 1H NMR δ 0.95 (s, 9 H), 1.40 (s, 9 H),
2.65 (t, J = 9.1 Hz, 1 H), 2.91 (s, 2 H), 3.28-3.36 (m, 2 H), 3.85 (s, 3 H), 4.59 (br s, 1 H);
13C NMR δ 24.4, 284, 35.1, 42.3, 48.7, 51.6, 56.6, 78.4, 155.6, 168.1, 192.1. HRMS calcd for C15H28NO5 (M + H) 302.1967. Found 302.1969.
Boc NH O O
OMe
241d
Methyl-(±)-(tert-butoxycarbonyl)-3-oxohept-6-enoate (241d). In an oven- dried, 100-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 240d (0.876 g, 3.23 mmol) in anhydrous methanol (30 mL). The solution was cooled to 0oC and TFA (1.20 mL, 15.58 mmol) was
126 added. The reaction mixture was stirred for 1 h, concentrated, and anhydrous THF (30
o mL) was added. The solution was cooled to 0 C, Et3N (2.70 mL, 19.37 mmol) and
Boc2O (4.80 mL, 4.80 mmol) were added, and the solution was warmed to rt. After 8 h,
H2O (15 mL) was added and the solution was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), and concentrated. Flash chromatography (5% EtOAc/hexanes) afforded 0.085 g (92%) of a
-1 1 yellow oil; IR (neat) 3123, 1720, 1707, 1649 cm ; H NMR (CDCl3) d 1.49 (s, 9 H), 2.90
(m, 2 H), 3.52 (s, 2 H), 3.79 (s, 3 H), 4.55 (br s, 1 H), 5.15 (m, 1 H), 5.19 (m, 1 H), 5.26
13 (m, 1 H), 5.70-5.90 (m, 1 H); C NMR (CDCl3) d 28.4, 47.5, 49.6, 52.7, 80.3, 115.7,
137.5, 155.4, 167.6, 201.2. HRMS calcd for C13H21NO5 (M + H) 272.1498. Found
272.1491.
Boc NH O O
OMe
N2 242a
Methyl-(±)-2-diazo-3-oxo-5-(tert-butyloxycarbonylamino)-5- phenylpentanoate (242a). In an oven-dried, 100-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed
241a (0.377 g, 1.17 mmol) in anhydrous CH3CN (30 mL). The reaction mixture was cooled to 0oC, and 4-carboxybenzenesulfonazide (4-CBSA) (0.293 g, 1.29 mmol) and
Et3N (0.50 mL, 3.59 mmol) were added. The reaction mixture was warmed to rt, and after 4 h H2O (10 mL) was added and the solution was extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried with
(Na2SO4), and concentrated. Flash chromatography (20% EtOAc/Hexanes) afforded
127 0.329 g (81%) of an oil; IR (neat) 3370, 2144, 1721, 1684, 1655, 1525, 1314 cm-1; 1H
NMR (CDCl3) δ 1.41 (s, 9 H), 3.63 (m, 2H), 3.85 (s, 3 H), 5.18 (m, 1 H), 5.43 (m, 1 H),
13 7.24-7.35 (m, 5 H); C NMR (CDCl3) δ 29.0, 46.9, 52.1, 53.0, 80.0, 126.8, 128.0, 129.3,
142.3, 155.8, 162.4, 190.9; HRMS calcd for C17H21N3O5 348.1559. Found 348.1557.
Boc NH O O O OMe
N2 242b
Methyl-(±)-5-(tert-butyyloxycarbonyl)-2-diazo-5-(2-furyl)-3-oxopentanoate
(242b). In an oven-dried, 25-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 241b (0.020 g, 0.06
o mmol) in anhydrous CH3CN (3 mL). The reaction mixture was cooled to 0 C, and 4-
CBSA (0.019 g, 0.09 mmol) and Et3N (0.05 mL, 0.36 mmol) were added. The reaction mixture was warmed to rt, and after 4 h H2O (0.5 mL) was added and the solution was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine
(5 mL), dried (Na2SO4), and concentrated. Flash chromatography (20% EtOAc/hexanes) afforded 0.015 g (76%) of a yellow oil; IR (neat) 3421, 3226, 1745, 1716, 1316, 1201 cm-
1 1 ; H NMR (CDCl3) δ 1.36 (s, 9 H), 3.11 (qd, 2 H), 3.68 (s, 3 H), 4.70 (m, 2 H), 6.23 (s, 1
13 H), 7.18 (m, 2 H); C NMR (CDCl3) δ 21.7, 48.5, 53.1, 106.0, 111.3, 146.1, 166.7,
201.8; HRMS calcd for C15H20N3O6 (M + H) 338.1352. Found 338.1355.
128 Boc NH O O
OMe
N2 242c
Methyl-(±)-2-diazo-6,6-dimethyl-3-oxo-N-(tert-butoxycarbonyl)-5- aminoheptanoate (242c). In an oven-dried, 100-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed
241c (0.175 g, 0.58 mmol) in anhydrous CH3CN (20 mL). The reaction mixture was
o cooled to 0 C, and 4-CBSA (0.154 g, 0.68 mmol) and Et3N (0.25 mL, 1.79 mmol) were added. The reaction mixture was warmed to rt, and after 4 h H2O (5 mL) was added and the solution was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried with (Na2SO4), and concentrated. Flash chromatography (20% EtOAc/Hexanes) afforded 0.156 g (82%) of a white solid, mp
o -1 1 76 C; IR (neat) 3371, 2131, 1719, 1690 cm ; H NMR (CDCl3) δ 0.95 (s, 9 H), 1.40 (s, 9
H), 2.64 (t, J = 9.2 Hz, 1 H), 3.24 (dd, J = 2.4, 10.6 Hz, 1 H), 3.85 (s, 3 H), 3.90 (m, 1 H),
13 4.59 (d, J = 8.4 Hz, 1 H); C NMR (CDCl3) δ 26.7, 28.7, 35.3, 42.0, 52.7, 56.7, 79.5,
156.2, 162.4, 192.1. HRMS calcd for C15H25N3O5Na (M + Na) 350.1692. Found
350.1693.
Boc NH O O
OMe
N2 242d
Methyl-(±)-5-(tert-butoxycarbonylamino)-2-diazo-3-oxohept-6-enoate (242d).
In an oven-dried, 50-mL, single-necked, round-bottom flask equipped with a magnetic
129 stirring bar, rubber septum, and argon balloon was placed 241d (0.998 g, 3.68 mmol) of
o 241d in anhydrous CH3CN (20 mL). The reaction mixture was cooled to 0 C, and 4-
CBSA (0.919 g, 4.05 mmol) and Et3N (1.53 mL, 11.0 mmol) were added. The reaction mixture was warmed to rt, and after 4 h H2O (15 mL) was added and the solution was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (15 mL), dried (Na2SO4), and concentrated. Flash chromatography (20%
EtOAc/hexanes) afforded 1.03 g (95%) of yellow oil; IR (neat) 3278, 2132, 1730, 1715,
-1 1 1653 cm ; H NMR (CDCl3) δ 1.49 (s, 9 H), 3.06 (m, 2 H), 3.8 (s, 3 H), 4.65 (br s, 1 H),
5.05 (m, 1 H), 5.13 (m, 1 H), 5.15 (m, 1 H), 5.45 (m, 1 H).; 13C NMR δ 28.6, 44.8, 49.7,
50.0, 52.6, 115.2, 138.1, 155.5, 162.0, 190.8 (C=N2 was not observed). HRMS calcd for
C13H19N3O5 (M + H) 298.1403. Found 298.1409.
O
N CO2Me Boc
243a
Methyl-(±)-N-(tert-butyloxycarbonyl)-3-oxo-5-phenylpyrrolidine-2- carboxylate (243a). In an oven-dried, 100-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 242a
(0.329 g, 0.95 mmol) and Rh2(OAc)4 (0.107 g, 0.24 mmol) in CH2Cl2 (30 mL), and the reaction mixture was warmed to 35 oC. After stirring for 8 h at this temperature, the solution was concentrated. Flash chromatography (20% EtOAc/Hexanes) afforded 0.263
-1 1 g (86%) of an oil; IR (neat) 1772, 1747, 1700, 1391, 1159 cm ; H NMR (CDCl3) δ 1.03-
1.27 (2s, 9 H), 2.56-269 (m, 1 H), 3.04-3.21 (m, 1 H), 3.63-3.79 (2s, 3 H), 4.57-4.66 (m,
130 1 H), 5.18-5.42 (m, 1 H), 7.01-7.10 (m, 1 H), 7.13-7.22 (m, 3 H), 7.38-7.51 (m, 1 H); 13C
NMR (CDCl3) δ 27.6, 45.4, 462, 52.7, 52.8, 56.6, 57.5, 66.3, 66.5, 81.0, 125.0, 125.7,
127.1, 127.3, 128.3, 128.4, 128.6, 141.8, 142.8, 152.6, 153.4, 166.0, 166.3, 166.7, 202.8,
203.6. HRMS calcd for C17H21NO5 (M + H) 320.1498. Found 320.1493.
O
O N CO2Me Boc
243b
1-tert-Butyl-2-methyl-5-(2-furyl)-3-oxopyrrolidine-1,2-dicarboxylate (243b).
In an oven-dried, 100-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 242b (0.813 g, 2.41 mmol) and
Rh2(OAc)4 (0.107 g, 0.24 mmol) in CH2Cl2 (30 mL), and the reaction mixture was warmed to 35 oC. After stirring for 8 h at this temperature the solution was concentrated.
Flash chromatography (20% EtOAc/hexanes) afforded 0.552 g (74%) of a yellow oil; IR
-1 1 (neat) 3094, 1737, 1667, 1314 cm ; H NMR (CDCl3) δ 1.17 (s, 9 H), 2.67 (m, 1 H), 3.15
(m, 1 H), 3.73 (s, 3 H), 4.72 (m, 1 H), 5.30(m, 1 H), 6.14 (s, 1 H), 7.08 (m, 2 H); 13C
NMR (CDCl3) δ 28.5, 43.1, 46.8, 51.6, 79.8, 106.1, 142.8, 155.3, 170.9, 202.1; HRMS calcd for C15H19NO6Na (M + Na) 332.1111. Found 332.1114.
O
N CO2Me Boc
243c
131 Methyl-(±)-5-tert-butyl-3-hydroxypyrrolidine-1-dicarboxylate (243c). In an oven-dried, 100-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 242c (0.156 g, 0.48 mmol) and
Rh2(OAc)4 (0.021 g, 0.05 mmol) in CH2Cl2 (20 mL), and the reaction mixture was warmed to 35oC. After stirring for 8 h at this temperature, the solution was concentrated.
Flash chromatography (20% EtOAc/Hexanes) afforded 0.091 g (63%) of a white solid, mp 117-118 oC; IR (neat) 2256, 1757, 1716 cm-1; 1H NMR δ 0.95 (s, 9 H), 1.52 (m, 1 H),
2.05-2.25 (m, 2 H), 2.10 (m, 1 H), 2.83 (t, J = 6.8 Hz, 1 H), 3.68 (d, J = 3.6 Hz, 1 H),
3.76 (s, 3 H), 4.44 (m, 1 H); 13C NMR δ 26.9, 33.2, 36.9, 52.3, 66.8, 67.1, 73.7, 172.1.
HRMS calcd for C10H19NO3 (M + H) 202.1443. Found 202.1445.
O
N CO2Me Boc
243d
1-tert-Butyl 2-methyl-3-oxo-5-vinylpyrrolidine-1,2-dicarboxylate (243d). In an oven-dried, 100-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 242d (0.055 g, 0.18 mmol) and
Rh2(OAc)4 (0.002 g, 0.01 mmol) in CH2Cl2 (2 mL), and the reaction mixture was warmed to 35 oC. After stirring for 8 h at this temperature the solution was concentrated. Flash chromatography (20% EtOAc/hexanes) afforded 0.042 g (87%) of a yellow oil; IR (neat)
-1 1 2956, 1735, 1710, 815 cm ; rotamers were observed. H NMR (CDCl3) δ 1.45 (d, J = 10
Hz, 9 H), 2.56-2.46 (m, 1 H), 3.02 (dd, J = 3.15 Hz, 1 H) 3.83 (d, J = 3.0 Hz, 3 H), 4.71
132 13 (m, 2 H), 5.26 (m, 2 H), 5.98 (m, 1 H); C NMR (CDCl3) δ 28.5, 43.2, 53.3, 55.6, 66.4,
66.6, 81.6, 81.7, 116.0, 116.8, 137.1, 137.6, 153.4, 167.1, 167.9, 203.4, 203.9. HRMS
calcd for C13H20NO5 (M + H) 271.1341. Found 271.1340.
O S p-Tolyl NH O O
O P(OMe)2
244b
Dimethyl-(±)-2-oxo-4-(p-toluenesulfinylamino)-4-(2-furyl)-butylphosphonate
(244b). In a 50-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed n-BuLi (2 M in cyclohexane, 2.70 mL,
5.40 mmol) in anhydrous THF (5 mL). The mixture was cooled to -78 oC and dimethyl methylphosphonate (0.60 mL, 5.61 mmol) was added. After stirring at this temperature for 1 h 239b (0.207 g, 0.67 mmol) in THF (15 mL) was added via cannula. The reaction
mixture was stirred at this temperature for 4 h, quenched with saturated NH4Cl (0.5 mL), and warmed to rt. Water (5 mL) was added and the solution was extracted with EtOAc (3
x 10 mL). The combined organic phases were washed with brine (5 mL), dried (Na2SO4), and concentrated. Flash chromatography (EtOAc) afforded a colorless oil that was subjected to Kugelrohr vacuum distillation (60 oC under 2.5 mmHg) to remove dimethyl methylphosphonate, affording 0.219 g (82%) as an orange oil; IR (neat) 3379, 3192,
-1 1 1753, 1717, 1246, 1089 cm ; H NMR (CDCl3) δ 2.32 (s, 3H), 2.85 (s, 1H), 2.89 (s, 1H),
3.65 (m, 6H), 5.15 (m, 2H), 6.11 (m, 1H), 6.23 (m, 1H), 7.24 (s, 1H), 7.29 (m, 2H), 7.37
13 (m, 2H); C NMR (CDCl3) δ 20.3, 38.5, 48.1, 50.9, 106.6, 109.5, 124.6, 125.0, 128.6,
133 31 140.5, 11.4, 201.3; P NMR (CDCl3) δ 22.06. HRMS calcd for C17H23NO6P (M+H)
400.0984. Found 400.0987.
Boc NH O O
O P(OMe)2
245b
Dimethyl-(±)-2-oxo-N-(tert-butoxycarbonyl)-4-amino-4-(2-furyl)- butylphosphonate (245b). In an oven-dried, 25-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 244b
(0.124 g, 0.31 mmol) in anhydrous methanol (5 mL). The solution was cooled to 0 oC and TFA (0.12 mL, 1.57 mmol) was added. The reaction mixture was stirred for 1 h, concentrated, and anhydrous THF (5 mL) was added. The solution was cooled to 0 oC,
Et3N (0.26 mL, 1.87 mmol) and Boc2O (0.62 mL, 0.62 mmol) were added, and the
solution was warmed to rt. After 8 h, H2O (1 mL) was added and the solution was extracted with EtOAc (3 x 2 mL). The combined organic phases were washed with brine
(2 mL), dried (Na2SO4), and concentrated. Flash chromatography (20% EtOAc/hexanes) afforded 0.108 g (97%) of a yellow oil; IR (neat) 3306, 1716, 1255, 1031 cm-1; 1H NMR
(CDCl3) δ 1.37 (s, 9H), 3.01 (m, 2H), 3.38 (s, 2H), 3.61 (m, 6H), 5.14 (m, 2H), 6.16 (m,
13 1H), 6.22 (m, 1H), 7.25 (s, 1H); C NMR (CDCl3) δ 28.7, 41.9, 50.2, 51.1, 53.3, 53.6,
13 127.7, 129.0, 141.6, 155.5, 200.2; P NMR (CDCl3) δ 23.82. HRMS calcd for
C17H27NO6P (M+H) 372.1576. Found 372.1575.
134 Boc NH O O
O P(OMe)2
N2 246b
Dimethyl-(±)-1-diazo-2-oxo-N-(tert-butoxycarbonyl)-4-amino-4-(2-furyl)- butylphosphonate (246b). In a 50-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed NaH (60% in mineral oil, 0.020 g, 0.50 mmol), which was washed by petroleum ether (2 mL). After removal of the petroleum ether by syringe, the flask was placed under vacuum for 2 min, and THF (5 mL) was added by syringe. In another 50-mL round-bottom flask were placed 245b (0.075 g, 0.24 mmol) and 4-acetamidobenzenesulfonyl azide (4-ABSA,
0.058 g, 0.24 mmol) in THF (10 mL). The solution was transferred to the 50-mL, round- bottom flask containing NaH and THF via cannula quickly at rt. After stirring for 1 h,
the reaction mixture was quenched by addition of saturated aqueous NH4Cl (0.5 mL) and
extracted with Et2O (20 mL) and EtOAc (2 x 20 mL). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), and concentrated. To the residue was added CHCl3 (5 mL), and the solution was filtered and concentrated. Flash chromatography (EtOAc) afforded 0.065 g (71%) of a yellow oil; IR (neat) 3317, 1710,
-1 1 1314, 1256 cm ; H NMR (CDCl3) δ 1.33 (s, 9H), 3.02 (m, 2H), 3.64 (d, J=12.1 Hz, 3H),
13 3.70 (d, J= 12.1 Hz, 3H), 4.74 (m, 2H), 6.24 (s, 1H), 7.17 (m, 2H); C NMR (CDCl3) δ
31 21.6, 48.6, 53.5, 106.2, 111.5, 146.7, 166.9, 202.0; P NMR (CDCl3) δ 14.32. HRMS calcd for C15H22N3O7PNa (M+Na) 410.1093. Found 410.1089.
135 O
O N P(OMe)2 Boc O
247b
Dimethyl-(±)-N-(tert-butoxycarbonyl)-3-oxo-5-(2-furyl)-pyrrolidine-2- phosphonate (247b). In an oven-dried, 25-mL, single-necked round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon were placed
246b (0.070 g, 0.18 mmol) and Rh2(OAc)4 (0.008 g, 0.02 mmol) in CH2Cl2 (5 mL), and the reaction mixture was warmed to 35 oC. After stirring for 8 h at this temperature the solution was concentrated, and flash chromatography (50% EtOAc/hexanes) afforded
0.043 g (67%) of a yellow oil; IR (neat) 1762, 1701, 1668, 1315, 1032 cm-1; 1H NMR
(CDCl3) δ 1.41 (s, 9H), 2.70 (m, 1H), 3.19 (m, 1H) 3.72 (m, 6H), 4.79 (m, 1H), 5.31 (m,
13 1H), 6.15 (s, 1H), 7.09 (m, 2H); C NMR (CDCl3) δ 28.5, 43.1, 47.6, 53.1, 62.8, 80.1,
31 105.8, 112.6, 142.6, 151.2, 154.9, 201.8; P NMR (CDCl3) δ 17.52. HRMS calcd for
C15H22NO7PNa (M+Na) 382.1032. Found 382.1027.
Me O
Ph N CO2Me Boc
250a
Methyl-(±)-N-(tert-butoxycarbonyl)-3-oxo-4-methyl-5-phenypyrrolidine-2- carboxylate (250a). In an oven-dried, 25-mL, single-necked, round bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 243a
(0.021 g, 0.06 mmol) in THF (1 mL). The reaction flask was cooled to -78 oC, and LDA
(0.20 mL, 0.20 mmol, in THF) was added. The solution was stirred for 1 h at which time
136 methyl iodide (0.01 mL, 0.16 mmol) was added. After stirring at -78 oC for 2 h, the
solution was quenched with saturated NH4Cl (0.5 mL) and warmed to rt. Water (0.5 mL) was added, and the solution was extracted with EtOAc (3 x 1 mL). The combined
organic phases were washed with brine (1 mL), dried (Na2SO4), and concentrated.
Preparative TLC (20% EtOAc/hexanes) afforded 0.017 g (83%) of a slight yellow oil; IR
-1 1 (neat) 1774, 1746, 1699, 1391, 1157 cm ; H NMR (CDCl3) δ 1.09 (2s, 9H), 2.09 (m,
3H), 3.12 (m, 1 H), 3.84 (2s, 3H), 4.72 (m, 2H), 5.51 (m, 1H), 7.04 (m, 2H), 7.24 (m,
13 2H), 7.41 (m, 1H); C NMR (CDCl3) δ 10.3, 27.8, 52.6, 64.6, 67.9, 79.5, 126.7, 128.1,
31 128.2, 129.4, 129.5, 141.9, 154.3, 166.8, 203.8; P NMR (CDCl3) δ 17.21. HRMS calcd
for C18H24NO5 (M+H) 334.1654. Found 334.1658.
Bn O
Ph N CO2Me Boc
250b
Methyl-(±)-N-(tert-butoxycarbonyl)-3-oxo-4-benzyl-5-phenylpyrrolidine-2- carboxylate (250b). In an oven-dried, 25-mL, single-necked, round bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 243a
(0.061 g, 0.19 mmol) in THF (3 mL). The reaction flask was cooled to -78 oC, and LDA
(0.60 mL, 0.60 mmol, in THF) was added. The solution was stirred for 1 h at which time benzyl bromide (0.03 mL, 0.25 mmol) was added. After stirring at -78 oC for 2 h, the
solution was quenched with saturated NH4Cl (0.5 mL) and warmed to rt. Water (1 mL) was added, and the solution was extracted with EtOAc (3 x 3 mL). The combined
organic phases were washed with brine (1 mL), dried (Na2SO4), and concentrated.
Preparative TLC (20% EtOAc/hexanes) afforded 0.061 g (79%) of a slight yellow oil; IR
137 -1 1 (neat) 1743, 1711, 1401 cm ; H NMR (CDCl3) δ 1.10 (2s, 9H), 3.40 (m, 1H), 3.85 (2s,
3H), 4.30 (m, 2H), 5.02 (m, 1H), 5.61 (m, 1H), 7.33 (m, 8H), 7.53 (m, 2H); 13C NMR
(CDCl3) δ 29.5, 32.7, 57.6, 65.3, 80.7, 128.3, 128.4, 128.5, 128.8, 129.0, 129.1, 129.2,
129.3, 141.1, 141.8, 157.4, 171.9, 202.1. HRMS calcd for C24H28NO5 (M+H) 410.1967.
Found 410.1964.
Me O
O N CO2Me Boc
250c
1-tert-Butyl-2-methyl-5-(2-furyl)-4-methyl-3-oxopyrrolidine-1,2-dicarboxylate
(250c). In an oven-dried, 25-mL, single-necked, round bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 243b (0.049 g, 0.16 mmol) in THF (3 mL). The reaction flask was cooled to -78 oC, and LDA (0.50 mL, 0.50 mmol, in THF) was added. The solution was stirred for 1 h at which time methyl iodide
(0.02 mL, 0.32 mmol) was added. After stirring at -78 oC for 2 h, the solution was
quenched with saturated NH4Cl (0.5 mL) and warmed to rt. Water (1 mL) was added, and the solution was extracted with EtOAc (3 x 3 mL). The combined organic phases
were washed with brine (1 mL), dried (Na2SO4), and concentrated. Preparative TLC
(20% EtOAc/hexanes) afforded 0.045 g (88%) of a slight yellow oil; IR (neat) 1763,
-1 1 1703, 1667, 1315, 1032 cm ; H NMR (CDCl3) δ 1.16 (d, J=5.0 Hz, 3H), 1.41 (s, 9H),
3.40 (m, 1H), 3.77 (s, 3H), 3.99 (m, 1H), 5.34 (m, 1H), 6.11 (s, 1H), 7.09 (m, 2H); 13C
NMR (CDCl3) δ 10.2, 28.3, 46.9, 52.1, 56.6, 72.5, 79.3, 106.8, 109.4, 145.1, 156.2,
172.0, 200.9. HRMS calcd for C16H22NO6 (M+H) 324.1447. Found 324.1441.
138
Me O
N CO2Me Boc
250d
Methyl-(±)-N-(tert-butoxycarbonyl)-3-oxo-4-methyl-5-(tert-butyl)pyrrolidine-
2-carboxylate (250d). In an oven-dried, 25-mL, single-necked, round bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 243c
(0.036 g, 0.12 mmol) in THF (3 mL). The reaction flask was cooled to -78 oC, and LDA
(0.40 mL, 0.40 mmol, in THF) was added. The solution was stirred for 1 h at which time methyl iodide (0.02 mL, 0.32 mmol) was added. After stirring at -78 oC for 2 h, the
solution was quenched with saturated NH4Cl (0.5 mL) and warmed to rt. Water (1 mL) was added, and the solution was extracted with EtOAc (3 x 3 mL). The combined
organic phases were washed with brine (1 mL), dried (Na2SO4), and concentrated.
Preparative TLC (20% EtOAc/hexanes) afforded 0.018 g (50%) of a slight yellow oil; IR
-1 1 (neat) 1755, 1716 cm ; H NMR (CDCl3) δ 0.95 (s, 9H), 1.21 (d, J=5.1 Hz, 3H), 1.41 (s,
13 9H), 3.25 (m, 1H), 3.89 (s, 3H), 4.19 (m, 1H), 4.71 (m, 1H); C NMR (CDCl3) δ 11.1,
26.9, 29.0, 37.5, 41.6, 53.2, 62.9, 67.4, 82.1, 156.3, 167.4, 203.9. HRMS calcd for
C16H28NO5 (M+H) 314.1967. Found 314.1958.
OH
Ph N CO2Me H 268
139 5-Phenyl-3-hydroxy-1H-pyrrole-2-carboxylic acid methyl ester (268).
Typical procedure. In an oven-dried, 25-mL, single-necked, round-bottom flask equipped with a magnetic stirring bar, rubber septum, and argon balloon was placed 243a
(0.050g, 0.16 mmol) in CH2Cl2 (5 mL), and TFA (0.06 mL, 0.79 mmol) was added. The reaction mixture was stirred at rt for 3 h, at which time aqueous saturated NaHCO3 (3 mL) and H2O (1 mL) were added. The phases were separated, the aqueous phase was extracted with CH2Cl2 (2 x 3 mL), and the combined organic phases were dried (Na2SO4) and concentrated in a 25-mL round-bottom flask. To the residue was added ca. 1 g of silica gel (0.035-0.07 mm for column chromatography pore diameter ca. 6 nm) and
EtOAc (6 mL). The suspension in the reaction flask, open to the atmosphere, was stirred for 5 h, filtered, and concentrated. Flash chromatography (20% EtOAc/hexanes) afforded
0.030 g (88%) of a white solid, mp 77-79 oC; IR (neat) 3496, 2934, 1672 cm-1; 1H NMR
(CDCl3) δ 2.56 (br, 2H), 3.81 (s, 3H), 6.17 (s, 1H), 7.30 (m, 3H), 7.44 (d, J=6.1Hz, 2H);
13 C NMR (CDCl3) δ 96.5, 103.1, 148.9, 158.2, 164.9. HRMS calcd for C12H11NO3Na
(M+Na) 240.0637. Found 240.0634.
OH
O N CO2Me H 272a
5-(2-Furyl)-3-hydroxy-1H-pyrrole-2-carboxylic acid methyl ester. Yield 75%
o -1 1 of a yellow solid, mp 128-129 C; IR (neat) 3492, 1669, 1254 cm ; H NMR (CDCl3) δ
3.01 (br, 1H), 3.82 (s, 3H), 6.12 (s, 1H), 6.24 (s, 1H), 6.48 (s, 1H), 7.25 (s, 1H), 7.89 (br ,
140 13 1H); C NMR (CDCl3) δ 51.5, 96.3, 105.2, 105.8, 110.0, 131.6, 149.4, 154.8, 157.7,
165.1. HRMS calcd for C10H9NO4Na (M+Na) 230.0429. Found 230.0422.
OH
N CO2Me H 272c
5-Vinyl-3-hydroxy-1H-pyrrole-2-carboxylate acid methyl ester (272c). Yield
81% of a white solid, mp 121-123 oC; IR (neat) 3483, 3353, 3034, 1678 cm-1; 1H NMR
(CDCl3) δ 3.27 (m, 1H), 3.88 (s, 3H), 4.21 (m, 1H), 4.71 (m, 1H), 5.70 (s, 1H), 6.33 (br,
13 2H); C NMR (CDCl3) δ 51.4, 105.9, 116.7, 121.0, 129.8, 130.1, 134.7, 154.9. HRMS
calcd for C8H9NO3Na (M+Na) 190.0480. Found 190.0471.
Me OH
Ph N CO2Me H 272d
4-Methyl-5-phenyl-3-hydroxy-1H-pyrrole-2-carboxylic acid methyl ester
(272d). Yield 78% of a white solid, mp 112-114 oC; IR (neat) 3492, 1674 cm-1; 1H NMR
(CDCl3) δ 2.59 (br, 2H), 3.69 (s, 3H), 3.84 (s, 3H), 7.27 (m, 3H), 7.42 (d, J=6.0 Hz, 2H);
13 C NMR (CDCl3) δ 9.9, 51.5, 96.5, 103.4, 120.6, 124.8, 125.3, 137.6, 148.9, 158.2,
164.9. HRMS calcd for C13H13NO3Na (M+Na) 254.0793. Found 254.0782.
Bn OH
Ph N CO2Me H 272e
141 4-Benzyl-5-phenyl-3-hydroxy-1H-pyrrole-2-carboxylic acid methyl ester
(272e). Yield 67% of a white solid, mp 115-117 oC; IR (neat) 3487, 1678 cm-1; 1H NMR
(CDCl3) δ 2.59 (br, 2H), 3.79 (s, 3H), 4.03 (s, 2H), 7.27 (m, 2H), 7.34 (m, 6H), 7.52 (m,
13 2H); C NMR (CDCl3) δ 29.3, 51.4, 120.3, 121.4, 125.6, 126.5, 126.8, 127.3, 127.9,
128.0, 128.2, 128.4, 128.5, 128.7, 128.8, 136.4. HRMS calcd for C19H18NO3 (M+H)
308.1287. Found 308.1281.
Me OH
O N CO2Me H 272f
4-Methyl-5-(2-furyl)-3-hydroxy-1H-pyrrole-2-carboxylic acid methyl ester
(272f). Yield 67% of a yellow solid, mp 132-134 oC; IR (neat) 3494, 1672, 1254 cm-1; 1H
NMR (CDCl3) δ 3.03 (br, 1H), 3.71 (s, 3H), 3.81 (s, 3H), 6.24 (s, 1H), 6.47 (s, 1H), 7.23
13 (s, 1H), 7.92 (br, 1H); C NMR (CDCl3) δ 10.1, 51.4, 96.4, 105.2, 110.0, 120.3, 131.5,
149.4, 154.9, 157.6, 164.9. HRMS calcd for C11H11NO4Na (M+Na) 244.0586. Found
244.0578.
Me OH
N CO2Me H 272g
4-Methyl-5-tert-butyl-3-hydroxy-1H-pyrrole-2-carboxylate acid methyl ester
(272g). Yield 50% of a white solid, mp 114-116 oC; IR (neat) 3480, 3326, 1679 cm-1; 1H
13 NMR (CDCl3) δ 1.27 (s, 9H), 3.69 (s, 3H), 3.86 (s, 3H), 6.49 (br, 2H); C NMR (CDCl3)
142 δ 10.0, 30.4, 33.6, 51.5, 95.3, 120.6, 149.2, 154.6, 164.4. HRMS calcd for C11H18NO3
(M+H) 212.1287. Found 212.1284.
OH
Ph N P(OMe)2 H O 273a
Dimethyl 5-phenyl-3-hydroxy-1H-pyrrole-2-phosphonate (273a). Yield 75%
-1 1 of a clear oil; IR (neat) 3256, 3026, 1716 cm ; H NMR (CDCl3) δ 3.73 (s, 3H), 3.75 (s,
13 3H), 5.59 (s, 1H), 6.53 (br, 2H), 7.24 (m, 3H), 7.45 (m, 2H); C NMR (CDCl3) δ 53.0,
31 93.4, 93.5, 95.2, 112.5, 112.9, 120.6, 125.9, 126.1, 126.7, 127.2, 133.1; P NMR (CDCl3)
δ 16.38. HRMS calcd for C12H15NO4P (M+H) 268.0739.
OH
O N P(OMe)2 H O 273b
Dimethyl 5-(2-furyl)-3-hydroxy-1H-pyrrole-2-phosphonate (273b). Yield
-1 1 80% of a yellow oil, IR (neat) 3356, 1718, 1246 cm ; H NMR (CDCl3) δ 3.72 (s, 3H),
3.75 (s, 3H), 5.63 (s, 1H), 6.12 (s, 1H), 6.42 (br, 1H), 7.20 (m, 2H), 7.87 (br, 1H); 13C
31 NMR (CDCl3) δ 53.0, 93.4, 93.5, 105.2, 105.8, 108.9, 109.0, 136.9, 156.3; P NMR
(CDCl3) δ 16.42. HRMS calcd for C10H13NO5P (M+H) 258.0531. Found 258.0533.
Bn OH
Ph N P(OMe)2 H O 273d
143 Dimethyl 4-benzyl-5-phenyl-3-hydroxy-1H-pyrrole-2-phosphonate (273d).
-1 1 Yield 51% of a clear oil; IR (neat) 3257, 3025, 1716 cm ; H NMR (CDCl3) δ 3.72 (s,
3H), 3.74 (s, 3H), 4.54 (s, 2H), 6.59 (br, 2H), 7.29 (m, 8H), 7.49 (m, 2H); 13C NMR
(CDCl3) δ 29.9, 53.0, 93.4, 93.5, 95.2, 95.3, 112.6, 118.9, 120.6, 125.8, 125.9, 126.2,
31 126.7, 127.1, 128.7, 128.8, 129.0, 129.1, 133.1, 136.4; P NMR (CDCl3) δ 17.26.
HRMS calcd for C19H21NO4P (M+H) 358.1208. Found 358.1202.
Me OH
O N P(OMe)2 H O 273e
Dimethyl 4-methyl-5-(2-furyl)-3-hydroxy-1H-pyrrole-2-phosphonate (273e).
-1 1 Yield 60% of a yellow oil; IR (neat) 3358, 1716, 1252 cm ; H NMR (CDCl3) δ 2.01 (s,
3H), 3.72 (s, 3H), 3.74 (s, 3H), 6.11 (s, 1H), 6.47 (br, 1H), 7.19 (m, 2H), 7.84 (br, 1H);
13 31 C NMR (CDCl3) δ 10.4, 53.0, 93.4, 93.5, 105.2, 108.9, 109.0, 120.4, 136.9, 156.3; P
NMR (CDCl3) δ 17.26. HRMS calcd for C11H15NO5P (M+H) 272.0688. Found
272.0689.
Bn OH
O N P(OMe)2 H O 273f
Dimethyl-4-benzyl-5-(2-furyl)-3-hydroxy-1H-pyrrole-2-phosphonate (273f).
-1 1 Yield 75% of a yellow oil; IR (neat) 3355, 1717, 1247 cm ; H NMR (CDCl3) δ 3.71 (s,
3H), 3.74 (s, 3H), 4.60 (s, 2H), 6.12 (s, 1H), 7.19 (m, 2H), 7.28 (m, 5H); 13C NMR
144 (CDCl3) δ 29.8, 53.0, 93.4, 93.5, 105.3, 109.0, 109.1, 120.6, 125.8, 128.6, 128.7, 128.9,
31 136.9, 142.7, 156.3; P NMR (CDCl3) δ 17.28. HRMS calcd for C17H19NO5P (M+H)
348.1001. Found 348.1003.
145 5.4 CHAPTER 4: ASYMMETRIC SYNTHESIS OF β-AMINO CARBONYL
COMPOUNDS WITH N-SULFINYL β-AMINO WEINREB AMIDES
O S p-Tolyl NH O OMe N Me F3C 306b
General Procedure for the Synthesis of N-Methoxy-N-methyl Acetamide (N- sulfinyl) Weinreb Amides from Sulfinimines. (SS,3S)-(+)-N-(p-Toluenesulfinyl)-3- amino-N-methoxy-N-methyl-3-(p-trifluoromethylphenyl)propionamide (306b). In an oven-dried, 25-mL, single-neck, round-bottom flask equipped with a magnetic stirring bar and argon balloon was placed KHMDS (0.39 mmol, 0.77 mL of 0.5 M solution in toluene) in anhydrous ether (5 mL). The reaction mixture was cooled to -78 oC and N- methoxy-N-methylacetamide (0.04 mL, 0.38 mmol) was added. After stirring at this temperature for 1 h, (SS)-(+)-N-p-(trifluoromethylbenzylidene)-p-toluenesulfinamide
(112j, 0.075 g, 0.24 mmol) in ether (2 mL) was added. The solution was stirred at -78 oC for 4h, quenched with saturated NH4Cl (2 mL), and warmed to rt. Water (2 mL) was added and the solution was extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (2 mL), dried (Na2SO4), and concentrated. Flash chromatography (50% EtOAc/hexanes) afforded 0.062 g (63%) of a clear viscous oil;
20 -1 1 [α]D 43.51 (c 0.37, CHCl3); IR (neat) 3229, 2923, 1636, 1326 cm ; H NMR (CDCl3) δ
2.36 (s, 3H), 2.95-2.96 (m, 2H), 3.05 (s, 3H), 3.54 (s, 3H), 4.89 (dd, J = 11.6, 12.0 Hz,
13 1H), 5.59 (d, J = 5.6 Hz, 1H), 7.24-7.26 (m, 2H), 7.54-7.59 (m, 6H); C NMR (CDCl3) δ
21.4, 29.7, 29.7, 21.9, 54.7, 61.3, 76.6, 77.0, 77.5, 125.3, 125.7, 127.8, 125.9, 127.7,
146 129.7, 141.5, 145.3, 171.4. HRMS calcd for C19H21N2O3F3SNa (M+Na) 437.1126.
Found 437.1123.
O S p-Tolyl NH O OMe Me N Me
306c
(SS,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-N-methylbutanoamide
20 (306c). Yield 66% of a clear, viscous oil; [α]D 154.8 (c 2.7, CHCl3); IR (neat) 3482,
-1 1 3220, 2970, 1652 cm ; H NMR (CDCl3) δ 1.42 (d, J=6.6 Hz, 3H), 2.42 (s, 3H), 2.67 (d,
J=5.5 Hz, 2H), 3.16 (s, 3H), 3.62 (s, 3H), 3.85 (quintet, J=6.6, 13.9 Hz, 1H), 5.06 (d,
13 J=7.6 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.61 (q, J=4.9, 8.2 Hz, 2H); C NMR (CDCl3) δ
21.8, 22.7, 40.0, 47.9, 61.6, 126.1, 129.9, 141.5, 142.6, 172.2. HRMS calcd for
C13H20N2O3SNa (M+Na) 307.1092. Found 307.1090.
O S p-Tolyl NH O OMe N Me 306d
(SS,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-N-methylhexanoamide
20 (306d). Yield 68% of a clear viscous oil (96:4 ratio of inseparable diastereomers); [α]D
1 116.7 (c 2.6, CHCl3, 92% de); IR (neat) 3231, 2958, 1652; major diastereomer H NMR
δ 0.94 (t, J = 7.5 Hz, 3H), 1.40-1.44 (m, 1H), 1.47-1.54 (m, 1H), 1.58-1.62 (m, 1H), 1.68-
1.73 (m, 1H), 2.39 (s, 3H), 2.77 (s, 2H), 3.15 (s, 3H), 3.65 (s, 3H), 3.69-3.72 (m, 1H),
4.94 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.5 Hz, 2H); major
147 13 diastereomer C NMR (CDCl3) δ 14.2, 19.9, 21.7, 32.2, 37.9, 38.3, 53.4, 61.6, 125.7,
129.8, 141.4, 143.2, 172.1. HRMS calcd for C15H24N2O3SNa (M+Na) 335.1412. Found
335.1405.
O S p-Tolyl NH O OMe N Me
306e
(SS,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-N-methoxy-N-methyl-3-tert-
o 20 butylpropionamide (306e). Yield 72% of a white solid; mp 99-101 C. [α]D 137.6 (c
-1 1 0.5, CHCl3); IR (neat) 3226 (NH), 2960, 1659, 1416, 1065 cm ; H NMR (CDCl3) δ 0.91
(s, 9H), 2.32 (s, 3H), 2.66-2.68 (m, 2H), 3.15 (s, 3H), 3.64 (m, 4H), 4.63 (d, J = 8.8 Hz,
13 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0, 2H); C NMR (CDCl3) δ 21.7, 27.0, 32.8,
34.4, 36.1, 61.8, 62.6, 63.1, 125.7, 129.9, 141.5, 144.0, 173.1. Anal Calcd for
C16H26N2O3S: C 58.87, H 8.03, N 8.58. Found C 59.02, H 8.21, N 8.28.
O S p-Tolyl NH O
Me
F3C 310b
(SS,3R)-(+)-N-(p-Toluenesulfinyl)-3-amino-1-methyl-3-(p- trifluoromethylphenyl)-1-one (310b). In an oven-dried, 25-mL, single-neck, round- bottom flask equipped with a magnetic stirring bar, and argon balloon was placed 306b
(0.032 g, 0.08 mmol) in THF (2 mL). The reaction mixture was cooled to -78 oC and methymagnesium bromide (0.13 mL, 0.39 mmol) was added. After warming to rt over 3
148 h, the reaction mixture was quenched by the addition of NH4Cl (mL). Water (mL) was added and the solution was extracted with EtOAc (3 x mL). The combined organic
phases were washed with brine (mL), dried (Na2SO4), and concentrated. Flash
20 chromatography (30% EtOAc/hexanes) afforded g (63%) of an oil; [α]D 40.93 (c 0.43);
-1 1 IR (neat) 3178, 2952, 1716, 1365 cm ; H NMR (CDCl3) δ 2.09 (s, 3 H), 2.42 (s, 3 H),
3.03-3.04 (m, 2 H), 4.93 (dd, J = 12.0, 12.0 Hz, 1 H), 5.05 (d, J = 5.5 Hz, 1 H), 7.30-7.32
13 (m, 2 H), 7.53-7.64 (m, 6 H); C NMR (CDCl3) δ 21.6, 32.2, 51.9, 55.1, 61.6, 77.0, 77.3,
77.7, 125.4, 125.5, 125.6, 126.0, 128.0, 129.9, 141.8, 145.7, 171.7. HRMS calcd for
C18H18NO2F3S (M + Na) 392.0908. Found 392.0916.
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