Luận án tiến sĩ: Target and diversity-oriented synthesis using epoxyquinoid scaffolds

Mehta’s Synthesis of PanepophenanthrinConclusion Experimental Section Stereocontrolled Synthesis of a Complex Library via Elaboration of Angular Epoxyquinol Scaffolds 2.1 2.2 Introductio

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Copyright 2006 by Lei, Xiaoguang

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my wife Jing Zhou, and to my parents #89 and 4E

iv

First and foremost, I would like very much to thank my research advisor, ProfessorJohn A Porco, Jr for his great mentorship, faithful support and constant encouragementtoward my Ph D studies John’s contagious enthusiasm for synthetic organic chemistry

motivated me to embark on my scientific career in his research group, and his continuous

pursuit for creative and independent thoughts as well as his diligent purposefulness forovercoming challenges in the scientific research has been inspiring me for my career as asynthetic chemist It has been a privilege to work under his instruction and it definitelyhas been one of the most precious memories in my life

I am very grateful to Professor James S Panek for his helpful suggestions on my

manuscripts, and his critical reading of this dissertation I would also like to thank

Professor Scott S Schaus, Professor John K Snyder, and Professor Sean J Elliot forvaluable advice and suggestions

I would like to thank Professor Michael Y Sherman (School of Medicine, BostonUniversity) and his group member Nava Zaarur for their collaborative efforts toward thebiological evaluations of our chemical libraries I would also like to thank Dr GuillaumeCottarel (Cellicon Biotechnologies Inc.) for the helpful discussions and collaborations I

am very grateful to our friends Dr Emil Lobkovsky (Comell University) for x-ray crystal

structure analysis, Professor Richard P Johnson (University of New Hampshire) for

assistance with Spartan calculations, and Professor Philip J Proteau (Oregon State

University) for providing authentic kinamycin D

tremendous support and sharing the most memorable time with me in Porco Laboratory.

I wish them the best in their future careers

I would also like to thank all of the Porco group and CMLD members, Dr Aaron

Beeler, Dr A Jeevanandam, Dr Ping Lan, Dr Adam Yeager, Dr Nicolas Rabasso, Dr

Sarathy Kesavan, Dr Sivaraman Dandapani, Dr Andreas Heutling, Dr Eamon Comer,

Dr Jean-Charles Marie, Dr Xiang Wang, Dr Dawn Troast, Yongbo Hu, Jianglong Zhu,Sujata Bardhan, Chong Han, Baudouin Gerard, Andrew Germain, Bill Phillips, DaniSolano, Andrew Kleinke, Ji Qi, Suwei Dong, Stephen Scully, Gerry Kagan, Huan Cong,Qiang Zhang, Dayle Acyuilano, Jiayi Yuan, Tony Ling, Terry Huang, Jamie Ryan,Nicholas Grigoriadis, Dan Bruggemeyer, Winnie Ong and Gina Min for making thePorco lab and CMLD wonderful places to conduct my Ph.D research

I would like to thank Dr Jonathan Lee, Dr Michael Creech and Chris Singletonfor NMR and MS assistance, Alicia Downey, Katinka Csigi, Elaine Early, Mike Gooley,Charles Alongi, Paul Ferrari, Aruna Jain and Matthew Vigneau for their kind help

Finally, I want to express my sincere thanks and deepest love to my wife Jing

vi

(Order No )

XIAOGUANG LEI

Boston University Graduate School of Arts and Sciences, 2007

Major Professor: John A Porco, Jr., Professor of Chemistry

A complex, stereochemically well-defined chemical library with distinct skeletal

frameworks has been achieved via elaboration of angular epoxyquinol scaffolds The keystrategy involved highly stereocontrolled [4+2] Diels-Alder cycloaddition of chiral,nonracemic epoxyquinol dienes to generate the scaffolds Further scaffold diversificationinvolved hydrogenation, epimerization, dehydration, and condensation of the carbonylfunctionality with alkoxyamine and carbazate building blocks The overall processafforded 244 highly complex and functionalized compounds Preliminary biological

vii

The first enantioselective total synthesis of the complex diazobenzofluorenenatural product (-)-kinamycin C has been accomplished The synthesis relies on ahydroxyl-directed, asymmetric nucleophilic epoxidation process to establish the desiredstereochemistry of the complex and highly functionalized D-ring subunit Additional keyreactions include Stille cross coupling, intramolecular Friedel-Crafts annulation, and latestage diazo formation.

vill

CHAPTER 1 Total Synthesis of (+)-Panepophenanthrin

CHAPTER 2

1.11.2

Total Synthesis of (+)-Panepophenanthrin

A Synthesis of the Chiral, Non-racemic

Bromo-epoxyketone Scaffold

B Completion of (+)-Panepophenanthrin Synthesis

C Mechanistic Studies for Diels-Alder Dimerization

Other Syntheses of Panepophenanthrin

A Baldwin’s Synthesis of Panepophenanthrin

B Mehta’s Synthesis of PanepophenanthrinConclusion

Experimental Section

Stereocontrolled Synthesis of a Complex Library via

Elaboration of Angular Epoxyquinol Scaffolds

2.1

2.2

Introduction

Methodology Development for Library Synthesis

A Synthesis of Epoxyquinol Scaffolds

B Further Elaboration of Angular Scaffolds

CHAPTER 3

D Library Design2.3 Synthesis of a Polymer-supported Anthracene as a

Dienophile Scavenger

A Introduction

B Synthesis of the First-generation Resin

C Synthesis of the Second-generation Resin

D Scope and Limitations

E Application of the Second-generation ScavengerResin

2.4 Parallel Synthesis of Angular Epoxyquinol Scaffolds

2.5 Streamlined Synthesis of Advanced Scaffolds2.6 Library Synthesis

2.7 Analysis of Library Members2.8 Preliminary Biological Evaluation2.9 Conclusion

the Kinamycins3.3 First Retrosynthetic Analysis for Kinamycin C3.4 Asymmetric Synthesis of Kinamycin C

3.5 Conclusion3.6 Experimental Section

Table 2.1

Table 2.2

Dienophile Sequestration Using Anthracene Resin P5

Syntheses of Flavonoid Diels-Alder Cycloadducts

Xil

59

62

Relative Energies for the Intermediates in the Two Pathsfor Diels-Alder Dimerization

B3LYP/6-31G*-optimized Transition-state for the Formation

of PanepophenanthrinRationalization for the Unsuccessful Dimerization of syn-monomer 20

Proton Alignment for EnolizationPrenylflavonoid Diels-Alder Natural ProductsAngular Epoxyquinol Scaffolds

Representative Library MembersRepresentative Natural Products with 6-6-5 Ring SystemsInhibition of induction of Hsp72 by angular compounds A1,A3, A6, A7, A8 and A9 (3.0 uM concentration)

Revised Retrosynthetic Analysis for Kinamycin CProposed Mechanism for Intramolecular Friedel-CraftsAnnulation and Regioselective MOM Deprotection

Summary for the Previously Reported Diazo Formations

Overview of the Asymmetric Total Synthesis of Kinamycin C

Revised Synthesis for Panepophenanthrin

Possible Mechanisms For the Diels-Alder DimerizationSynthesis of New Diels-Alder Dimers

Thermolysis of Hemiacetal-bridged (1) and Nonbridged (24)

Baldwin’s Synthesis of Panepophenanthrin

Mehta’s Synthesis of Panepophenanthrin

Target and Diversity-oriented Synthesis Using Epoxyketone

ScaffoldsSynthesis of Maleimide-derived Angular Epoxyquinol

Scaffolds

Synthesis of a Urazole-containing, Angular Epoxyquinol

ScaffoldHydroxyl-directed Diels-Alder CycloadditionElaboration of an Angular Epoxyquinol ScaffoldHydrogenation of Cycloadduct 20

Hydrogenation and Attempted Epimerization of the Urazole

Parallel Synthesis of Maleimide-derived, Angular EpoxyquinolScaffolds

Synthesis of Urazole-containing ScaffoldsSynthesis of Advanced Scaffolds

Asymmetric Nucleophilic Epoxidation

Attempted Condensation of Compound 47

End Game for Kinamycin C

acetic anhydride2,6-di-tert-butyl-4-methylphenolbenzyl

t-butyl carbonate or t-butyl carbamatebutyl

concentrationcalculatedcatalytic

chemical ionization

centimetercorrelation spectroscopyconcentrated

conversionmeta-chloroperoxybenzoic acidchemical shift

trans, trans-dibenzylidene acetone1,8-diazabicyclo[5,4,0]undec-7-enedichloromethane

XVIH

HIV human immunodeficiency virus

HMBC heteronuclear multiple bond correlation

HMDS hexamethyldisilazide

HMQC heteronuclear multiple quantum coherence

HOMO highest occupied molecular orbital

HPLC high performance liquid chromatography

HRMS high resolution mass spectroscopy

Hz hertz

IC50 inhibitory concentration 50%

XIX

low resolution mass spectroscopy

lowest occupied molecular orbital

sodium bis(trimethylsilyl)amidenucleus factor

nanomolarnuclear magnetic resonance

nuclear Overhauser effectphenyl

XX

tetrahydrofuranthin layer chromatographytrityl (Ph3C)

ultraviolet

microwave

XXI

Total Synthesis of (+)-Panepophenanthrin

1.1 Introduction to (+)-Panepophenanthrin

The ubiquitin-proteasome pathway plays an important role in the regulation of

several diverse cellular processes including cell division, signal transduction, apoptosis,

receptor-mediated endocytosis, and gene transcription regulation.' The majority of

proteins destined for degradation are associated by the attachment of multiple ubiquitinmolecules which provide a recognition signal for the 26S proteasome

Ubiquitination of proteins requires the sequential action of three major enzymes,the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-

protein ligase (E3) (Figure 1.1) Free ubiquitin, a 76 amino acid linear peptide cannot beattached to the target protein by the native ligase Ubiquitin must be activated byubiquitin-activating enzyme E1 in an ATP-dependent manner and then transferred to aubiquitin-conjugating enzyme E2 Activation of ubiquitin begins with formation ofubiquitin-adenylate from ATP and the COOH-terminus of the ubiquitin, freeing theinorganic pyrophosphate Ubiquitin-adenylate is then non-covalently attached to the El.Next, ubiquitin forms a thioester with the active cysteine site of E1, thus freeing AMP Inthis way, each E1 enzyme could be loaded with two ubiquitin molecules in the form of

target proteins with the help of different E3 ligases It has been shown that abnormalubiquitination-mediated protein degradation may be associated with human cancers,

inflammation, and neurodegenerative disease.” Small molecule ubiquitination inhibitors

may thus serve as both molecular probes of major cellular networks as well as potential

3

therapeutic agents for human diseases

Figure 1.1 Ubiquitination Pathways

products produced by Diels-Alder dimerization, ’ including torreyanic acid (2)°® and

epoxyquinols A (3) and B (4)° (Figure 1.2).

Figure 1.2 Panepophenanthrin and Related Epoxyquinoid Natural Produts

3 epoxyquinol A 4 epoxyquinol B

Panepophenanthrin was tested by treatment with recombinant human E1 andbiotinylated ubiquitin The in vitro ICso value was determined to be 17.0 pg/mL.However, no significant inhibitory effect of panepophenanthrin was observed in intact

cells up to a concentration of 50 ug/mL, presumably due to reaction of the compoundwith intracellular thiols

1.2 Retrosynthetic Plan for Panepophenanthrin

Our retrosynthetic route for panepophenanthrin is depicted in Figure 1.3 Dimer 1may be derived from hemiacetal formation of hydroxy ketone precursor 5 The

and coworkers.'” The x-ray crystal structure of 1 also shows the close proximity of thetertiary alcohol and ketone which should substantially favor formation of a hemiacetalbridge '' In principle, hemiacetal formation may precede intramolecular [4+2]

cycloaddition !“ Open form precursor 5 may be derived from exo-Diels Alder dimerization (exo with respect to the carbonyl substituent)'? of epoxyquinol monomer 6,

the conjugated diene isomer of the natural product panepoxydon 7.'* Recent reports byShotwell and coworkers have documented the facile rearrangement of 7 to conjugatedisomers such as 6 under mildly acidic conditions.'*? Epoxyquinol diene monomer 6 may

be derived from transformations of chiral, nonracemic epoxy ketone 8, including a

Heck-type coupling to install the dienol Compound 8 may be prepared in either antipode using

tartrate-mediated asymmetric nucleophilic epoxidation ' of a quinone monoketal

A Synthesis of the Chiral, Non-racemic Bromo-epoxyketone Scaffolds

The synthesis of epoxyquinol diene monomer 6 was initiated by hypervalent iodine

7 of the readily available monomethoxy hydroquinone 9 !° to afford oxidation '

dimethoxyketal 10 (Scheme 1.1) Transketalization of 10 with 1, 3-propanediol using

Pirrung’s conditions!’ afforded 1,3-dioxane 11 which was found to be a suitable substrate

for nucleophilic epoxidation Tartrate-mediated nucleophilic epoxidation of 11 usingNaHMDS as base cleanly produced epoxy ketone 8 (80 % yield, 95 % ee) The absolutestereochemistry of 8 was confirmed by single x-ray crystal structure analysis (Scheme1.1)

Scheme 1.1 Synthesis of Chiral, Non-racemic Bromo-epoxyketone Scaffolds

OMe OMe ‘aMeO._-OMe §1,3-Propanediol Oo 0

3 steos Br Phl(OAC);, Br BFa.Et,O Br

oer ———>~ ——— >

92% MeOH, DME, rt, 2h , 75%9 rt, 1h , 96% oe

OH OH 10 0 110

oO .O PhạCOOH (3.5 equiv.),

X-ray Br NaHMDS (3.0 equiv.),

` = O L-DIPT (1.2 equiv.),

€ 8 0.1 Min toluene, -55°C , 48h

O 80% (95% e.e.)

A mechanistic proposal for tartate-mediated nucleophilic epoxidations 1s shown in

Figure 1.4, and is based on our group’s previously proposed transition state model.”

The asymmetric induction and counterion dependency may be explained by preferentialformation of sodium-L-diisopropyl tartrate (Na-L-DIPT) complex (inset, Figure 1.4) in

membered ring hydrogen-bonded tartrate conformers ”°

complexes may then promote formation of two different epoxide enantiomers byhydrogen bond activation of the dienone and face-selective conjugate addition of a

peroxide anion.”! In this case, the substrate likely binds in an orientation such that thebulky bromine atom is positioned in the convex face of the chelated complex Finally,

this positioning of the substrate results in addition of the peroxide anion from the a-face

of the dienone

Figure 1.4 Mechanistic Proposal of Tartrate-Mediated Asymmetric Nucleophilic

Epoxidation of Quinone Monoketal 6

convex face [ Mẹ EPh; ì

Me—{ o-ơ

° ° HH» OHH

NaoO-o Me

/ Me inset

PhạC

B Completion of (+)-Panepophenanthrin Synthesis

Advancement of 8 to epoxyquinol monomer 6 is shown in Scheme 1.2 Attempted

chelation-controlled reduction (e.g DIBAL-H * or Zn(BHy4)2 7 ) led to poordiastereoselectivity (1:1) In contrast, reduction of 8 with Super-Hydride (LiBHEt;)

cleanly afforded syn-epoxy alcohol 12 which was subsequently converted to anti

diastereomer 13 by a Mitsunobu protocol” (80 %, two steps) Silylation of the secondary

alcohol afforded 14 which was subjected to Heck-type coupling with

2-methyl-3-buten-2-was confirmed to be identical to natural panepophenanthrin by 'H and °C NMR, mass

spectrum, [a]p, and TLC Rf values in three solvent systems

Scheme 1.2 Synthesis of (+)-Panepophenanthrin

C) 0 4 AL Spo 0% HF eas oH 1 6 : CHAON-CH,Cly, 8 CH,Cly, rt, 1h

to allylic cation 16 which may react with the carbonyl of another monomer to produce the

tethered intermediate 17.°° Intramolecular ionic-Diels Alder reaction of 17 to 18 followed

by addition of water anti to the epoxide would directly afford 1

HO O30 HF- CHẠCN eS H ` | MỸ ^ZMe a o——> Me o> Q

was allowed to stand at 25 °C without solvent (24 h, 80 %) The reaction was conducted

effectively in both standard laboratory glassware and Teflon vials, which supports theidea that an ionic Diels-Alder process is not strictly required for [4+2] dimerization.Subsequent experiments also revealed that syn-epoxyquinol monomer 20 (Scheme 1.4,inset) did not undergo Diels-Alder dimerization under conditions reported for anti isomer

6 (neat, rt) Examination of models (not shown) indicates that the endo transition statesmay be disfavored due to dipole repulsion of the carbonyls on each monomer Therefore,

of syn-monomer 20, two secondary hydroxyl groups have steric interactions to preventthe successful [4+2] Diels-Alder cycloaddition In exo transition state B, the stericinteractions are seemingly avoided A more detailed explanation for this dimerizationbased on mechanistic data is presented in Section C, Figure 1.7.

Scheme 1.4 Revised Synthesis for Panepophenanthrin

C Mechanistic Studies for Diels-Alder Dimerization

We next considered alternative mechanistic possibilities for the Diels-Alderdimerization of monomer 6 (Scheme 1.5) In one case (path A), the tertiary hydroxylgroup of one monomer adds to the carbonyl group of another to generate a hemiacetalintermediate Intramolecular, inverse demand Diels-Alder reaction then affords thedimeric natural product.’ An alternative mechanism (path B) may involve transition-state

9929

hydrogen bonding”Š of the epoxyquinol monomers in a “pseudo-transannular,””’ normal

Diels-Alder cycloaddition Subsequent ring closure to a five-membered ring hemiacetalleads to 1

Scheme 1.5 Possible Mechanisms For the Diels-Alder Dimerization

To further probe the role of the tertiary hydroxyl group in Diels-Alder dimerization

of 6, we prepared an epoxyquinol monomer lacking this functionality (Scheme 1.6).Heck-type coupling of 14 with 3,3-dimethylbutene afforded 21 (80%) Treatment of 21

with TBAF produced 22 which was treated with 0.2 M HCI to effect ketal hydrolysis toform monomer 23 Epoxyquinol 23 was cleanly dimerized to 24 (neat, 24 h) Regio- andstereo-chemistry of 24 was confirmed by single x-ray crystal structure analysis of bis-para-bromobenzoate 25 Interestingly, 25 crystallized as a centrosymmetric racemate (P-

1 space group).”” Production of dimer 24 confirms that that tertiary alcohol of monomer

6 and hydrogen-bond organization is not essential for successful Diels-Alder dimerization

Acetylation of monomer 22 led to 26 which was hydrolyzed to monomer 27 This

compound also dimerized to afford 28 which was identical to material obtained byacetylation of 24 These studies support the normal [4+2] pathway (Scheme 1.5, path B)

in which Diels-Alder dimerization likely occurs first, followed by hemiacetal formation

Scheme 1.6 Synthesis of Des-hydroxyl Diels-Alder Dimers

To further understand the timing of the [4+2] dimerization and hemiacetalformation events, in collaboration with Professor Richard Johnson (University of NewHampshire) we performed computational studies by disconnecting panepophenanthrin in

a retro-[4+2] fashion and optimizing each stage at the B3LYP/6-31G* level of theory.”

Results are summarized in Figure 1.6 Initial formation of the hemiacetal link providesthe advantage of an intramolecular [4+2] reaction, but renders the dienophile much lessreactive because it is no longer an enone The predicted overall free energy barrier is 39.2kcal/mol In contrast, direct intermolecular cycloaddition of two epoxyketones proceeds

through a reactive dienophile and thus has a lower intrinsic barrier of 24.8 kcal/mol.Figure 1.7 shows the predicted transition state structure The initial stage ofintermolecular cycloaddition is slightly endothermic, and presumably reversible, buthemiacetal formation “locks” the structure and thus renders panepophenanthrin isolable.Thermolysis experiments on panepophenanthrin are consistent with these general

energetic considerations (Scheme 1.7) Heating of dimer 1 (CD3OD, 60 °C, 24 h) led torecovered starting material, whereas thermolysis of untethered dimer 24 (CD3OD, 50 °C,

12 h) led to quantitative production of a solution of monomer 23 ('H NMR).

Figure 1.6 Relative Energies for the Intermediates in the Two Paths

for Diels-Alder Dimerization

AE = B3LYP/6-31G* relative energy

AG = estimated free energy change

Scheme 1.7 Thermolysis of Hemiacetal-bridged and Nonbridged Dimers (1) and (24)

Diels-30 Examination of a Chem-3D model (Figure 1.7) for dimer 29 shows the relativedispositions of the tertiary alcohol and ketone functions may be disfavored for thehemiacetal formation

Figure 1.8 Rationalization for the Unsuccessful Dimerization of syn-monomer 20

1.4 Other Syntheses of Panepophenanthrin

A Baldwin’s Synthesis of Panepophenanthrin

In 2003, Baldwin and coworkers reported a total synthesis of racemic

panepophenanthrin.** Their overall approach to 1 is shown in Scheme 1.8 Racemic

(+)-bromoxone 31 was obtained in five steps from benzoquinone in accordance with the

previously reported procedure.*? TES protection of the secondary alcohol afforded silylether 32, which was coupled with vinylstanne 33 employing a Stille protocol to provide

the desired dienol 34 Compound 34 was found to dimerize completely to afford 35 underneat condition in 75 % overall yield Deprotection of 35 with NHạF afforded (+)-panepophenanthrin 1 in 85 % yield An asymmetric total synthesis of (+)-

panepophenanthrin was recently reported by the same group using enantiomerically pure(-)-bromoxone as the starting material.”

Scheme 1.8 Baldwin’s Synthesis of Panepophenanthrin

6 TESCI o van Me °

o —— o — >|" ©

- Sere : Pd,(dba)s, AsPh; š

OH ,, OTES | toluene, 110 °C 34 OTES

B Mehta’s Synthesis of Panepophenanthrin

In 2004, Mehta and coworkers also reported an enantioselective total synthesis of(+)-panepophenanthrin.”” The main strategy for their synthesis used a retro-Diels-Alder

reaction to introduce highly functionalized quinone monoepoxide building block M5 Asshown in Scheme 1.9, the readily available Diels-Alder adduct M1 was transformed to ameso-diol intermediate, which was converted to M2 in high enantiomeric purity

employing enzymetic desymmetrization Further transformations of M2 afford enone M3

in good yield Epoxidation followed by base mediated hydroxymethylation provided M4

Retro Diels-Alder reaction of M4 cleanly afforded MS DIBAL-H reduction followed by

selective oxidation of the primary alcohol generated M6, which was further converted tothe desired monomer 6 through four additional steps Finally, the investigations also

observed that when monomer 6 was left aside without solvent for 24 h, it was fullytransformed to the dimer panepophenanthrin 1.

Scheme 1.9 Mehta’s Synthesis of Panepophenanthrin

HO H OAc

fi 1) NaBHy, CeClạ, 92% / \ 1), TBSCl, imid 85 % a 1), HạO¿, Na¿CO¿, 87 %

—>

H 2) lipasePS, vinylacetate H + 2) DBU, formalin, 85 (9) 2) KgCO3, MeOH DBU, formalin, 85 %

M 89 %, 99 % eo Mà (+) 3).PDC, 87 % for 2 steps ra80 tasở

PhạO, 240 °C

88 %

no.Me 9 1) PhsP=CHCOOMe, 91% OH ọ

1g eat h2 Öb 2) MeLi, 56 % of 1) DIBAL-H, 80% HO ————— O —=—————— O

74 % 6 3) MnOz, 74 % 2) Op, TEMPO, CuCl :

OH 4) HF-py, quant M6 ðrgs 96 % M5 6OTBS

1.5 Conclusion

In summary, the first enantioselective total synthesis of the ubiquitin-activatingenzyme inhibitor (+)-panepophenanthrin has been achieved employing tartrate-mediatedasymmetric nucleophilic epoxidation and stereoselective Diels-Alder dimerization of anepoxyquinol dienol monomer Modification of the epoxyquinol monomer leading topanepophenanthrin by substitution of a tertiary hydroxyl for a methyl group led tomechanistic insight for the critical [4+2] dimerization In addition, theoreticalcalculations of the dimerization were performed to evaluate the timing of the [4+2] Diels-Alder cycloaddition and hemiacetal formation events The calculation data provide verygood correlation with the experimental results to support that the Diels-Alderdimerization likely occurs first, followed by hemiacetal formation

1.6 Experimental Section

General Information: ‘H NMR spectra were recorded on a 400 MHz

spectrometer at ambient temperature with CDCl; as the solvent unless otherwise stated

'3C NMR spectra were recorded on a 75.0 MHz spectrometer (with complete proton

decoupling) at ambient temperature Chemical shifts are reported in parts per million

relative to chloroform ('H, 5 7.24; °C, 5 77.23) Data for 'H NMR are reported as

follows: chemical shift, integration, multiplicity (app = apparent, par obsc = partiallyobscure, ovrlp = overlapping, s = singlet, d = doublet, t = triplet, q = quartet, m =multiplet, ) and coupling constants Infrared spectra were recorded on a Nicolet Nexus

670 FT-IR spectrophotometer Low and high-resolution mass spectra were obtained inthe Boston University Mass Spectrometry Laboratory using a Finnegan MAT-90

spectrometer HRTOFMS spectra were obtained with Micromass LCT spectrometer by

Ms Qing Liao (Department of Chemistry and Chemical Biology, Harvard University)

X-ray crystal structures were obtained by Dr Emil Lobkovsky (Department of Chemistry

and Chemical Biology, Cornell University) Optical rotations were recorded on anAUTOPOL III digital polarimeter at 589 nm, and are recorded as [œ]p (concentration ingrams/100 mL solvent) Chiral HPLC analysis was performed on an Agilent 1100 series

(CHIRALCEL OD, Column No OD00CE-AI015) Analytical thin layer chromatography

was performed on 0.25 mm silica gel 60-F plates Flash chromatography was performed

using 200-400 mesh silica gel (Scientific Absorbent Incorporated) Yields refer tochromatographically and spectroscopically pure materials, unless otherwise stated Allreagents were used as supplied by Sigma-Aldrich, Fluka, and Strem Chemicals