AN ABSTRACT OF THE THESIS OF Heath Eugene Giesbrecht for the degree of Master of Science in Chemistry on June 19, 2008. Title: Broadening the Scope of the Modified-Julia Reaction: A Mild and Stereoselective Method for the Synthesis of (Z)-Configurated α,βUnsaturated Lactones Abstract approved: Paul R. Blakemore An intramolecular variant of the modified-Julia olefination was demonstrated by the synthesis of α,β-unsaturated lactones in a mild and (Z)-selective fashion. The lynchpin reagent (benzothiazol-2-sulfonyl) acetic acid was synthesized in a straightforward fashion in 86% overall yield from commercially available 2-mercaptobenzothiazole via conversion to ethyl (benzothiazol-2-ylthio)acetate by base mediated alkylation with ethyl chloroactetate; saponification of the ester to (1,3benzothiazol-2-ylthio)acetic acid; and, oxidation by ammonium molybdate and H2O2 to afford the key sulfonyl acid reagent. Through the use of an efficient dicyclohexylcarbodiimide coupling reaction, the acetic acid derivative was condensed with a series of ω-alkenyl carbinols to form the corresponding ω-alkenyl (benzothiazol-2sulfonyl)acetates in moderate to excellent yields (60 – 94%). The esters were then subjected to ozonolysis conditions (O3 in CH2Cl2) and, after subsequent reduction of the ozonide with dimethyl sulfide, the carboxaldehyde intermediates were immediately subjected to 1,8diazabicycloundec-7-ene in CH2Cl2 (-78 °C to rt) to effect cyclic alkene formation. Successful production of the α,β-unsaturated lactones was observed for a variety of ring sizes (7, 12, 13, and 19) in moderate yields (30 – 45%), but comparable to other methods for lactone synthesis. Aldol condensation products resulting from the elimination of H2O from the putative anti-β-alkoxy-benzothiazol-sulfones intermediates were also obtained from the smaller rings sizes, albeit in low yields (2 – 4%). The reaction conditions proved to be ideal for these simple substrates. Significantly, biasing factors such as Thorpe-Ingold effects were not required to aid macrocyclic lactone formation. The targeted α,βunsaturated lactones were generated stereoselectively with predominantly (Z)-configuration (Z:E ≥ 85:15) in all cases examined. © Copyright by Heath Eugene Giesbrecht June 19, 2008 All Rights Reserved Broadening the Scope of the Modified-Julia Reaction: A Mild and Stereoselective Method for the Synthesis of (Z)Configurated α,β-Unsaturated Lactones by Heath Eugene Giesbrecht A THESIS submitted to Oregon State University in partial fulfillment of the requirements for the degree of Master of Science Presented June 19, 2008 Commencement June 2009 Master of Science thesis of Heath Eugene Giesbrecht presented on June 19, 2008 APPROVED: Major Professor, Representing Chemistry Chair of the Department of Chemistry Dean of the Graduate School I understand that my thesis will become part of the permanent collection of Oregon State University libraries. My signature below authorizes release of my thesis to any reader upon request Heath Eugene Giesbrecht, Author ACKNOWLEDGEMENTS The author would like to express his sincere appreciation to the following people. I would first like to thank my advisor Prof. Paul R. Blakemore for his support and guidance in both my chemistry and other studies during my stay in Corvallis. Dr. Jeff Morre for his mass spectroscopic services while at Oregon State University. Dr. Rodger Kohnert for his time and assistance with NMR analysis and instruction. All of the professors who took the time to teach me organic chemistry as well as other subjects during my time at the university. All of my colleagues in the Blakemore Research Group for both challenging and inspiring me during these four years. Tartar Foundation for summer funding. Oregon State University for all the lasting friendships that I have made during my time here. Lastly, I would sincerely like to thank those in the Chemistry Department who stuck by me through the difficult times and always believed in my abilities even when I would question them. TABLE OF CONTENTS Page 1 Synthesis of α,β-Unsaturated Lactones Using Previously Employed Methods……………………. 1.1 The Modified-Julia-Kocienski Olefination: Early Development, Mechanistic Consideration, and Applications………….... 3 Stereoselective Synthesis of α,β-Unsaturated Esters and Amides via Intermolecular Modified-Julia Olefination………………….. 15 Recent Applications of the Modified-Julia Olefination………………………………….. 17 Overview of Projected Study……………….. 22 Synthesis of (Benzothiazol-2-sulfonyl) Acetates…… 24 1.2 1.3 1.4 2 2.1 Initial Routes to Proposed (Benzothiazol2-sulfonyl) Acetate Intermediates…………… 24 Synthesis of (Benzothiazol-2-sulfonyl) acetic acid……………………………………. 28 DCC Coupling of (Benzothiazol-2-sulfonyl) acetic acid with ω-Alkenyl Carbinols………... 30 2.4 Direct Synthesis of ω-Alkenyl Carbinols…….. 30 2.5 Synthesis of (Benzothiazol-2-sulfonyl) acetate Esters Using DCC Coupling………………….. 33 α,β-Unsaturated Lactone Formation………………….. 35 3.1 Ozonolysis of ω-Alkenyl Sulfonyl Esters…….. 35 3.2 Modified-Julia Reacton of ω-Carboxaldehyde Sulfonyl Esters………………………………… 38 Conclusion…………………………………………….. 44 2.2 2.3 3 4 1 TABLE OF CONTENTS (Continued) Page 5 Experimental……………………………………….... 45 6 References………………………………………........ 78 Bibliography……………………………………………….. 83 Appendix…………………………………………………… 88 LIST OF FIGURES Figure 1. 2. 3. Page Examples of natural products containing α,β–unsaturated lactones…..……………………………………………… 2 Aromatic activators commonly used in the modified-Julia reaction………………………………………………….. 14 Readily synthesized esters from DCC coupling………… 34 LIST OF TABLES Table 1. 2. 3. Page Influence of counterion and solvent in the stereochemical course of the coupling reaction………………………….. 6 E-selectivity exhibited for unsaturated (aromatic) aldehydes ………………………………………………… 11 Aldehyde substituent effect on stereoselectivity of alkene geometry………………………………………………….. 17 LIST OF SCHEMES Scheme Page 1. The modified-Julia olefination with (BT) sulfones……… 4 2. Self-condensation of BT sulfones leading to dimerization 5 3. Reaction type (a) exemplified…………………………… 6 4. Stereoselective elimination of β-alkoxy-BT-sulfone intermediates……………………………………………… 8 5. Mechanism explaining stereochemical outcome of modified-Julia reaction…………………………………… 9 6. Cross-over adduct formation……………………………… 10 7. Substrate dependence in the synthesis of Rapamycin…….. 12 8. Effect of the heterocyclic activator on the yields of α,β-unsaturated esters…………………………………….. 15 9. Stereoselective synthesis of fluorinated olefins…………... 18 10. Additive effect of MgBr2 on alkene geometry……………. 19 11. Synthesis of substituted exoglycals using the modified-Julia reaction…………………………………… 19 12. Synthesis of vinyl ethers with the modified-Julia reaction.. 20 13. Synthesis of α,β-unsaturated Weinreb amides from BT-sulfones………………………………………………. 21 14. First published example of an intramolecular modified-Julia reaction…………………………………… 22 15. Schematic representation of proposed study……………… 22 16. Alkylation of 2-mercaptobenzothiazole…………………... 25 LIST OF SCHEMES (Continued) Scheme Page 17. Thermodynamic transesterification of BT-sulfide ……… 26 18. Attempts to prepare lynchpin reagent 78 from ester 83…. 26 19. Mechanism for the formation of purple betaine pigment 91……………………………………………….. 28 20. Synthesis of key reagent 78 by oxidation of thioether 88... 29 21. Facile decarboxylation of the lynchpin reagent in high dielectric constant solvents………………………………. 30 22. General scheme for ester formation……………………… 30 23. Grignard reaction for synthesis of 2° aryl alcohol……….. 31 24. Pentenol 107 synthesis from dimethyl malonate 103……. 32 25. Reduction of undecenoic acid…………………………… 32 26. Synthesis of ethereal alcohol 113………………………… 33 27. Initial ester formation through DCC coupling…………… 34 28. General two-step ozonolysis/lactonization protocol……… 35 29. Differences in product distribution due to solvent effects... 36 30. Reduction of ozonide……………………………………... 37 31. 7-membered lactone formation…………………………… 39 32. 12-membered α,β-unsaturated lactone formation………... 40 33. 13-membered α,β-unsaturated lactone formation………... 41 34. 19-membered ethereal α,β-unsaturated lactone formation.. 41 LIST OF SCHEMES (Continued) Scheme 35. Elimination of labile substrate ………………………….. Page 42 This thesis is dedicated to every individual who has, throughout my life, inspired me to dream, think, learn, do, teach and especially write. I dedicate this specifically to my loved ones, family and friends: to those with whom I can share this occasion, but also to those whom I will encounter later in existence. You have been my ultimate motivation. Broadening the Scope of the Modified-Julia Reaction: A Mild and Stereoselective Method for the Synthesis of (Z)Configurated α,β -Unsaturated Lactones 1. Synthesis of α,β -Unsaturated Lactones Using Previously Employed Methods At present, few generally stereoselective synthesis of applicable methods exist for the α,β-unsaturated lactones, especially macrocyclic examples. These include, but are not limited to, methods where the ring closure comes from intramolecular esterification (i.e., lactonization)1, others where the alkene is the point of metathesis2, and other common alkenation reactions3 most often the Horner-WadsworthEmmons reaction4 as well as a variety of other methods5. Some natural products contain α,β-unsaturated lactones include rhizoxin D6, dactdyolide7, (+)-latrunculin A8, callystatin A9, (+)-digitoxigenin10, and phorboxazole A11 (Figure 1). 2 O O O O O O O O O HO O O O O H HN O N OH S O O 2 Dactylolide 1 Rhizoxin D 3 O (+)-Latrunculin A O O O H H HO OH O OH H 5 (+)-Digitoxigenin 4 Callystatin A OH O N O Br OMe O MeO O N O OH OH O O O 6 Phorboxazole A Figure 1. Examples of natural products containing α,β–unsaturated lactones Many of the protocols used to generate unsaturated lactones involve harsh conditions not amicable to advanced substrates, or else lengthy syntheses are needed to arrive at the desired substrates necessary for lactone formation. In many of these approaches, the selectivity for the alkene formation lies toward the more stable (E)-isomer and very few known methods return the (Z)-isomer as the major product. This thesis describes a novel, convenient way to construct (Z)-configurated α,β– unsaturated lactones via the modified-Julia alkenation under so called “Barbier-type” conditions12. 3 1.1 The Modified-Julia-Kocienski Olefination: Early Development, Mechanistic Consideration, and Applications The modified-Julia olefination13 allows for the single-step synthesis of alkenes from carbonyl compounds and heterocyclic sulfones via a novel condensation process. The direct synthesis of olefins employing heterocyclic sulfones was initially described by Sylvestre Julia in 1991 (Scheme 1). The reaction commences with the metallation/deprotonation of an aryl alkyl benzothiazol-2-yl sulfone 7, the resulting anion 8 acts as the nucleophilic partner in the reaction manifold. This species subsequently condenses with a carbonyl compound 9 forming a transient β-alkoxysulfone intermediate 10. The alkoxide continues along the reaction pathway, attacking in an intramolecular fashion the electrophilic C=N bond of the benzothiazole (BT) portion of the molecule. The series of consecutive reactions results in a putative spirocyclic intermediate 11 that selectively breaks down via an overall Smiles rearrangement14 affording the alkene 14 together with loss of sulfur dioxide 15 and elimination of metallated benzothiazolone 13. 4 O O2 S N R1 base H S O2 S Smiles 1 R2 9 H addition R O rearrangement 2 R N O R2 S S O2 R1 11 N N O 2 O R R1 S O S 12 R1 8 S 10 N S 7 N O2 S O elimination S + 13 R2 + 1 14 R SO2 15 Scheme 1. The modified-Julia olefination with (BT) sulfones The reaction is dependent on the relative electrophilicity of the BT moiety. Due to this limitation, a non-nucleophilic base must be used for the deprotonation step, thus avoiding attack on the heterocycle. Unfortunately, in practice, when deprotonation occurs the resulting anion 17 itself becomes a good nucleophile, and owing to the donoracceptor nature of the BT heterocyle, self-condensation resulting in homocoupled species 19 can occur (Scheme 2). Reverse addition (sulfone to the base) does nothing to circumvent this problem. Of course, this alternative pathway necessarily decreases the overall yield of the desired reaction. Using “Barbier-type” conditions in which both the BTsulfone and the aldehyde are added together and subsequently subjected to the action of the base can avert this “dimerization”. This protocol considerably enhances the chemoselectivity of the reaction due to the 5 higher relative electrophilicity of the aldehyde over the BT-sulfone in a self-condensation mechanism15. Barbier-conditions typically lead to yields that are 10-40% higher in the case of simple sulfones, but when joining together complex substrates, such conditions may be intolerable. acceptor O2 S N LDA (1.1 eq), THF, -78 °C S O2 S N S 16 16 Li 17 donor Li SO2Me N S SO2BT 18 -MeSO2Li N O2 S N S S 19 Scheme 2. Self-condensation of BT sulfones leading to dimerization The stereochemical outcome of the one-pot Julia reaction is substrate controlled, but can also be influenced by reaction conditions. Julia first systematically studied the effect of structure of both the BT-sulfone and substrate on product distribution. These reactions can be broken down into three distinct types: (a) R1 and R2 are saturated (see Scheme 1), (b) the R1 is unsaturated (i.e., stabilized sulfone anion) and R2 is saturated, and (c) R1 is saturated and R2 is unsaturated15. Reactions performed under Barbier conditions, with THF as the solvent and LDA as the base, showed no stereochemical bias when saturated alkyl-BT-sulfones were 6 metallated in the presence of saturated aldehydes to yield the 1,2disubstitued alkene products (Scheme 3). nC BT O2 S 20 8H17CHO, LDA, THF, nC -78 °C to rt 8H17 21 48%, E:Z = 49:51 Scheme 3. Reaction type (a) exemplified15 Later studies16 revealed that some stereocontrol is achievable depending on the reaction conditions. The solvent polarity and counter ion were, in some instances, shown to affect the E:Z ratio of the resulting products. For example, in the reaction between the 2-(pentylsulfonyl)benzothiazole 22 and cyclohexane carboxaldehyde, moderate trans selectivity was observed when the solvent polarity was increased from toluene to DME and the trend was further enhanced when the counterion was changed from Li+ to K+ (Table 1). SO2BT (a) (Me2Si)2NM (b) cC6H11CHO 22 E:Z (23) M Li Na K 23 Reaction Solvent Toluene Et2O THF DME 50:50 54:46 54:46 49:51 50:50 51:49 66:34 62:38 54:46 70:30 75:25 76:24 Table 1. Influence of counterion and solvent in the stereochemical course of the coupling reaction 7 The geometry of the resulting alkene mixture depends on the diastereoselectivity of the initial addition of the BT moiety to the carbonyl compound. To gain insight into the mechanism, a series of base-mediated elimination studies was performed on both the syn- and anti-diastereomers of β-alkoxy-BT-sulfones17. These were made diastereomerically pure15,17 via the base mediated opening of stereodefined epoxides by heterocylic thiols followed by subsequent sulfur oxidation. In cases where R and R’ bore saturated alkyl chains, both isomers underwent antiperiplanar elimination of the electrofuge and nucleofuge in the final step, with the syn-isomer 24 reacting much faster and selectively producing the (Z)-olefin 25 (Scheme 4). The anti-isomer 26 produced the (E)-alkene 27 in a much slower reaction with a diminished overall yield. Therefore, the poor E:Z selectivity in the simple examples of the modified Julia reaction can be directly attributed to the fact that there is little diastereocontrol during the initial addition of the nucleophile to the aldehyde, reflecting the relative concentrations of the syn:anti β-alkoxy-BT-sulfone intermediates present in the reaction mixture. 8 nC 6H13 SO2BT nC H 6 13 TBAF (10 eq), THF nC H 6 13 OTBS 6H13 SO2BT nC H 6 13 25 92% TBAF (10 eq), THF OTBS 26 Scheme 4. 6H13 0 to -18 °C, 18 h 24 nC nC Stereoselective 0 to -18 °C, 18 h elimination nC nC 6H13 6H13 27 56% of β-alkoxy-BT-sulfone intermediates The observed stereochemical outcome, yield, and reaction rate can be rationalized by the substituents R and R’ being in an anti-arrangement during spirocyclization of the syn-diastereomer 34, but destabilized in the anti-diastereomer 30 due to the substituents being forced into a gauche/eclipsed conformation 31 (Scheme 5). 9 O R anti BT slow R' SO2 S O2S 30 R O S R O2 28 R' O H H H R' R -SO2 trans 32 33 H 31 destabilizing gauche to eclipsed interactions O BT R' -BTO- 29 R syn H SO 2 BTO R' BT R N R' SO2 fast S N R O2S O BTO H H 34 R' R R' SO 2 H H 36 -BTO- R R' -SO2 cis 37 35 Scheme 5. Mechanism explaining stereochemical outcome of modifiedJulia reaction When investigating the reactions of stabilized-metallated BT-sulfones with non-conjugated aliphatic aldehydes, it was observed that the reactions tend to give moderate selectivity of the cis over the trans olefin to be formed. This drift of stereocontrol was routinely noted in cases where prenyl- or benzyl-BT-sulfones were used. Where this loss was observed, equilibration between the hydroxysulfones was proposed to be the cause of the erosion of selectivity. The components of the reaction are able to add and then fragment into the resonance stabilized αmetallated sulfones 28 and the aldehyde 29 followed by the re-addition to the more rapidly forming syn-isomer 34 of the β-alkoxy-BT-sulfone intermediate. 10 The retroaddition/readdition pathway is therefore attained by metallated BT-sulfones containing unsaturated substituents (type (b)). The energy barrier for the anti-isomer 30 of the β-alkoxy-BT-sulfone intermediate to spirocyclize is evidently higher than for the analogous process from the syn-isomer during the Smiles rearrangement. This is presumably due to the gauche/eclipsed interaction of the substituents R and R’ in the spirocyclization step. As previously described, the syn-diastereomer 34 does react with an increased rate over the anti-diastereomer 30 thus resulting in the observed product distribution. Giving further credence to this mechanistic pathway, formation of a cross-over adduct 41 was observed from the reaction between the metallated anti-β-hydroxybenzyl-BT-sulfone 38 with nitrobenzaldehyde 39 (Scheme 6). CHO NO2 OH Ph Ph O2S 38 BT O2N 39 Ph LDA, THF -78 °C to rt Ph 40 40%, E:Z = 98:2 Ph 41 60%, E:Z = 98:2 Scheme 6. Cross-over adduct formation While stabilized metallated sulfones have a tendency to give cis alkenes in reactions with simple aliphatic aldehydes; the situation is more complex in other cases. For example, the reactions of stabilizedmetallated benzyl-BT-sulfones with α-branched aliphatic aldehydes give (E)-configurated alkenes almost exclusively. This type of trans 11 selectivity has been observed when using more complex aldehydes during total synthesis efforts. The final types of reactions originally investigated by Julia (type (c)) involve the synthesis of conjugated 1,2-disubstituted alkenes from saturated BT-sulfones and unsaturated aldehydes (Table 2). This class of reactions is the most synthetically useful due to the high degree of (E)olefin selectivity obtained. The best stereoselectivity was observed in the reaction between simple BT-sulfones and stabilized, electron rich aromatic aldehydes 43, although more complex BT-sulfones also gave rise to similar results15. CHO SO2BT 42 R R 43 44 LDA, THF -78 °C to rt alkene R yield E:Z X Y Z OMe H Cl 98% 68% 51% 99:1 94:6 77:23 Table 2. E-selectivity exhibited for unsaturated (aromatic) aldehydes The first application of the modified-Julia reaction in a total synthesis was reported in 1996 by Kocienski and co-workers18 who used it to synthesize the triene portion of rapamycin via both type (b) and type (c) reactions (Scheme 7). Using LiHMDS as the base to deprotonate benzothiazolyl sulfone 46, the metallated BT-sulfone was then 12 condensed with aldehyde 45 giving a 68% yield of alkenes in a 19:1 E:Z ratio. They also observed the substrate dependence of the reaction with the reaction when aldehyde 48 was condensed with BT-sulfone 49, opposite olefin geometry was preferred (Z:E = 2.4:1) in a 75% yield. This second reaction exemplifies that stabilized BT-sulfone anions have a preferential tendency to give (Z)-configurated products. OTBS S S O OMe BT CHO H S O2 45 46 M MN(SiMe3)2, THF, -78 °C to rt S S O E:Z [C21-C22] yield 47 Li Na 68% 21% 95:5 78:22 OTBS OMe 20 H 19 22 21 47 M MN(SiMe3)2, THF, -78 °C to rt E:Z [C19-C20] yield 47 Li Na K 75% 21% ---- 29:71 43:57 18:82 OTBS S S O OMe BT CHO H 48 S O2 49 Scheme 7. Substrate dependence in the synthesis of Rapamycin Also in 1996, while performing a model study of the modified-Julia olefination for their total synthesis of the natural product (+)-U- 13 10630519, Charette et al., carried out a series of investigations which confirmed the importance of solvent, temperature, and counter ion on the alkene ratio. They found that varying these parameters had a profound effect on the resulting E:Z ratio (Table 3). TIPSO N S O2 S 52 base 50 TIPSO O TIPSO H 53 51 Conditions E:Z NaHMDS, THF NaHMDS, DME NaHMDS, DMF KHMDS, THF KHMDS, toluene NaHMDS, Et2O NaHMDS, toluene NaHMDS, CH2Cl2 1.1:1 2.4:1 3.5:1 1.2:1 1:3.7 1:7.7 1:10 1:10 Table 3. Solvent effect on E:Z ratio The modified-Julia olefination was first described using BT-sulfones, but has since been extended to other heteroaryl sulfones. In fact, any aryl unit that may support a Smiles rearrangement can potentially be employed in Julia olefination chemistry, and many other such activators have now been investigated. Julia himself discovered that pyridine and pyrimidine heterocyclic sulfones could also mediate the olefination15,17. From the pyridine series, Julia was able to isolate the 2-pyridyl-βhydroxysulfone intermediates from the reaction mixtures, thus giving more validity to the proposed mechanism. Later, Kocienski extended the 14 library of heteroarenes that were able to perform the reaction to 1isoquinolinoyl, 1-methyl-2-imiazoyl, 4-methyl-2-imidazoyl, 4-methyl-1, 2, 4-triazol-3-yl, and 1-phenyl-1H-tetrazol-5-yl16. More recently, nonheterocyclic aromatics have been used, for example bis- trifluoromethylphenyl20 and hexachlorophenyl21 to affect the modifiedJulia reaction (Figure 2). N N N N N N N N N N N S BT N N N PYR CF3 R PT R = Ph F3C BTFP TBT R = tBu Figure 2. Aromatic activators commonly used in the modified-Julia reaction Since its discovery by Julia, the modified-Julia alkenation reaction has become one of the more commonly used tools for advanced fragment linkage in target-directed synthesis22. 15 1.2 Stereoselective Synthesis of α,β -Unsaturated Esters and Amides via Intermolecular Modified-Julia Olefination In 2005, Blakemore et al., extended the modified-Julia methodology to the synthesis of α,β-unsaturated esters23 by condensing a novel BTsulfone reagent, ethyl (benzothiazol-2-ylsulfonyl)acetate (55) with various aldehydes. The construction of the key reagents in the study was a two-step straightforward synthesis of the BT- (55), PT- (56), and TBT(57) sulfones from the parent heterocycle. Act SH 54 (a) EtO2CCH2Cl (1.2 eq), K2CO3, acetone, 56 °C, 20h Act (b) (NH4)6Mo7O24 (5 mol%), aq. H2O2 (4 eq), EtOH, 0 °C to rt, 40 h 55 56 57 PhCHO (1 eq), DBU (2eq), CH2Cl2, rt, 16 h O2 S O OEt Act Yield BT PT TBT 71% 57% 35% O Ph OEt 58 Act Yield BT PT TBT 63% 5% 0% Scheme 8. Effect of the heterocyclic activator on the yields of α,βunsaturated esters These reagents were then subjected to the reaction conditions previously employed for the modified-Julia reaction (NaHMDS, THF, -78 °C to 0°C) in order to assess their ability to participate in the alkenation. 16 Unfortunately, none of the reagents reacted significantly with benzaldehyde under these reaction conditions. The low reactivity was not wholly unexpected because of the highly stabilized nature of the sulfone metallate in this case. However, at elevated temperature (THF, reflux) trans-ethyl cinnamate 58 was produced in a 62% yield (E:Z > 98:2). The PT- and TBT-sulfones produced little, if any, product when subjected to the same conditions. Various bases were then evaluated to perform the reaction at lower temperatures, with the researchers settling on 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) and anhydrous LiCl. When reacting under these conditions, product 58 was recovered in a 21% yield after 20h. Removal of the LiCl from the reaction conditions improved the yield to 45%. Once less harsh conditions were identified, the reaction solvent was varied in order to improve yields. Attempting to use a variety of solvents in the olefination reaction, it was observed that the ideal medium was dichloromethane where the overall yield was improved to 88% at 23 °C with DBU as the base (E:Z = 96:4). Ethyl (benzothiazol-2-ylsulfonyl)acetate (55) was then deprotonated with DBU in the presence of a number of aldehydes, most giving good to moderate yields under the optimized conditions (Table 3). When the BT-sufone 55 was subjected to the reaction conditions and subsequently aryl aldehydes were added to the mixture, the expected (E)-olefin was 17 preferentially produced when these stabilized aldehydes were used. This was especially the case when electron deficient aldehydes were used. The trans stereoselectivity was shown to erode when electron rich aryl aldehyde substrates were incorporated. The stereoselectivity was completely reversed when non-stabilized aliphatic aldehydes were condensed with the key reagent thus selectively producing the (Z)-alkene geometry. This type of selectivity was expected on the basis of earlier studies with stabilized sulfone anions (i.e., type (b) reactions, see above). BT O2 S O O OEt 55 (2 eq) H R O DBU (2 eq) CH2Cl2, rt, 16h R 59 Aldehyde 4-(NO2)C6H4CHO 2,6-Cl2C6H3CHO 4-(MeO)C6H4CHO nC H CHO 5 11 Citronellal OEt 60 Yield (%) E:Z 89% 83% 93% 41% 64% >98:2 >98:2 92:8 19:81 30:70 Table 3. Aldehyde substituent effect on stereoselectivity of alkene geometry 1.3 Recent Applications of the Modified-Julia Olefination Since the last major review24, the modified-Julia olefination has been used to access a diverse array of alkenyl functional groups. Of these, some of the more interesting examples include the synthesis of fluorinated alkene derivatives25,26. These have been shown to be useful building blocks for the synthesis of biologically active compounds, 18 selective enzyme inhibitors, and pharmaceutical precursors27. Zajc et al. showed that vinyl fluorides could be prepared by condensation of a metallated α-fluoro-BT-sulfone with an appropriate aldehyde or ketone25. They found that they could affect the stereochemical outcome of the reaction by varying the reaction conditions. The yields from alkyl, aryl, and allyl aldehydes were all excellent (87-100%) as were the yields of substrates with ketone functionalities. Again, it was found that the stereochemical outcome was affected by varying the reaction conditions (Scheme 9). (E : Z = 1 : 11.9) F LiHMDS, O2 S N S 61 Ph DMF-DMPU (1:1), -78 °C Ph 63 F CHO 62 Ph LiHMDS, F THF, -78 °C (E : Z = 2.2 : 1) 64 Scheme 9. Stereoselective synthesis of fluorinated olefins In a natural extension of the aforementioned experiments26, Lequeux et al. were able to synthesize flouroalkenoates 66 and 67 stereoselectively from the fluoroalkyl-BT-sulfones 65 and the corresponding aldehyde (Scheme 10). They observed that the olefin geometry was highly affected by the reaction conditions, including base, temperature, and additives. The olefination was observed to be most selective with DBU as the base at -78 to 20 °C over 2 h. 19 F CO2Et DBU H O2S N S CO2Et R RCHO F DBU, 65 F MgBr2 R CO2Et H yield Z:E Ph- none MgBr2 72% 71% 44:56 92:8 nC none MgBr2 57% 87% 31:69 88:12 8H17- (Z) 67 additive R (E) 66 Scheme 10. Additive effect of MgBr2 on alkene geometry Another more recent application28 using BT-sulfones in the modifiedJulia olefination is the synthesis of enol ethers 70 from lactones 69 constructing tri- and tetrasubstituted exogycals (Scheme 11). O2S R1 O N S n O OR 68 69 LiHMDS, -78 °C, then DBU (28-77%), E-selective R2 O n 3 OR R 70 Scheme 11. Synthesis of substituted exoglycals using the modified-Julia reaction This reaction is unique in that it is necessary to use DBU as an additive to promote the elimination from the hemiacetal arising from the condensation 68 and 69. 20 Vinyl ethers are another functional group easily accessed by the modified-Julia alkenation29. In 2003, Berthelette et al. accessed these substrates that are useful in reactions such as Diels-Alder30, Claisen rearrangements31, and aldehyde homologations32. The reaction conditions are significantly more mild than conventional vinyl ether syntheses. Both aldehydes and ketones are substrates that can be easily used in the reaction (Scheme 12). The one limitation of this current methodology is that the stereoselectivity of the reaction is extremely poor with the ratio of E:Z isomers usually being approximately equal in all examples. O2 S N O S LiHMDS, O R1 R2 R3 THF, -78 °C 45-90% 72 O R2 R1 R3 R1, R2 = aryl, alkyl R3 = aryl, akyl, benzyl 73 71 Scheme 12. Synthesis of vinyl ethers with the modified-Julia reaction α,β-Unsaturated N-methoxy-N-methyl amides have also been synthesized with similar methodology33. In 2006, Manjunath et al. synthesized a number of these α,β-unsaturated Weinreb amides34 from the corresponding aldehydes and the BT-sulfone 74 using NaH in THF (Scheme 13). 21 O2 S N S 74 O N O O NaH, THF, RCHO 44-72% R R = aryl, alkyl, sugar N O 75 Scheme 13. Synthesis of α,β-unsaturated Weinreb amides from BTsulfones Aïssa published an interesting report35 on improved conditions for use of the modified-Julia olefination to perform the methylenation of aldehydes and ketones. In this series of experiments, TBT-sulfones 76 were used exclusively to execute the synthesis. Under two different protocols, Barbier-type conditions were employed using (a) NaHMDS at -78 °C, or (b) Cs2CO3 at 70 °C in THF, to return good to excellent yields when using one or the other of the new methodologies. During this notable work, the first examples of intramolecular modified-Julia olefination were achieved (Scheme 14). Aïssa shows three examples of this cyclic variant with a BT-sulfone-ω-aldehyde 76 as the substrate and 1,4dioxane as the solvent. The best results were observed when the substrates were added over 15 h by slow-addition syringe pump to a dioxane/DMF solvent mixture at 100 °C. The modest yields encountered when working with the larger rings, Aïssa claims, are an entropy issue counteracting their formation due to the fact no inherently favorable conformation effect is established in the architecture of the substrates. 22 EtO2C N N O2 S CO2Et Cs2CO3, n O EtO2C dioxane/DMF, 100 °C N N CO2Et n 76 n yield 1 2 8 91% 32% 56% (E : Z) 0 : 100 1:1 2:1 77 Scheme 14. First published example of an intramolecular modified-Julia reaction 1.4 Overview of Projected Study Cognizant of the widespread occurrence of α,β-unsaturated lactones 81 in a variety of bioactive natural product molecules, and the growing scope of the modified-Julia reaction, we elected to study an intramolecular variant of the process directed at this important class of ester. Requisite ω-sulfonyl carboxaldehydes 80 for the projected study were envisioned to arise from ω-alkenyl alcohols 79 and sulfonyl acid 78 via esterification and ozonolysis reactions (Scheme 15). N HO O O2 S OH n 79 O2 S N S O O S 80 78 base O yield? stereochemistry? intramolecular Julia-olefination O n 81 Scheme 15. Schematic representation of proposed study CHO n 23 The study was divided into three phases. The first phase consisted of the development of an efficient synthesis of the “lynch-pin” sulfonyl acid 78. This was followed by the study of the esterification reactions from 78, and finally the in situ generation of ω-sulfonyl carboxaldehydes 80 and subsequent olefination. investigation of intramolecular modified-Julia 24 2. Synthesis of (Benzothiazol-2-sulfonyl)acetates The three routes which were proposed to be investigated that could lead to the target compounds, BT-sulfonyl acetates, are (a) the thermal transesterification of 55 using excess alcohol as the solvent; (b) the carbodiimide coupling reaction of sulfide acid 89 and various ω-alkenyl carbinols; and (c) the synthesis of (benzothiazol-2-sulfonyl)acetic acid36 (78) and the subsequent coupling of the various ω-alkenyl carbinols with this reagent. All of the paths were pursued in the course of this research. 2.1 Initial Routes to Proposed (Benzothiazol-2-sulfonyl)acetate Intermediates Commencing with the condensation of 2-mercaptobenzothiazole (81) with ethyl chloroacetate (82) under mild basic conditions, this straightforward reaction produced the resulting ester 83 in a quantitative yield. An alternate synthetic route was pursued by reacting 81 with methyl bromoacetate (84) under the same conditions giving ester 85 in a quantitative yield (Scheme 16). 25 O Cl N SH S O Br N SH 81 O 84 OMe K2CO3, acetone, 56 °C, 19h, 100% S N OEt S K2CO3, acetone, 56 °C, 19h, 100% 81 S 82 OEt 83 O S N OMe S 85 Scheme 16. Alkylation of 2-mercaptobenzothiazole Base promoted thermal transesterification of the ethyl ester 86 with ωunsaturated straight-chain primary alcohols was then examined (Scheme 17). The reaction conditions for this protocol, though they give the desired ester, were deemed inefficient and inappropriate for potential future applications using complex alcohol substrates. This was due to a number of drawbacks to the transesterification protocol. First, the ωunsaturated alcohol 87 was used as the solvent in a 3 equivalent excess. Since the alcohol in the reaction will usually be the more advanced intermediate, using it as the solvent is not advantageous. Also, the reaction conditions are relatively harsh because of the high temperatures; many advanced interemediates may not be able to withstand the media. Finally, only primary alcohols were shown to be able to effect efficient transesterification. All attempts to perform the reaction with 2° or 3° alcohols failed. Due to these obvious detriments a new pathway to arrive at the desired esters was explored. 26 HO O S N O 87 (3 eq) OEt K2CO3, neat, 50 °C, 21 h 65% S 83 S N O S 88 Scheme 17. Thermodynamic transesterification of BT-sulfide Proceeding with the knowledge of how to synthesize ethyl (benzothiazole-2-sulfonyl)acetate (55), the key reagent in the synthesis of α,β-unsaturated esters from previous work23, the oxidation of 83 was carried out giving exclusively the oxidized BT-sulfonyl ester 55 in quantitative yield (Scheme 18). O2 S N O OH S 78 1.2 M NaOH, MeOH, 0 °C to rt O S N (NH4)6Mo7O24·4H2O OEt S O2 S N H2O2 EtOH, 0 °C to rt, 40 h, 100% 55 1.2 M NaOH, MeOH, 0 °C to rt 90% 1.2 M NaOH, 0 °C to rt 100% MeOH, O S O OH O N DCC, DCM, 0 °C, 5 min S OEt S 83 N O N S S 89 S 90 91 Scheme 18. Attempts to prepare lynchpin reagent 78 from ester 83 27 Unfortunately, attempts to saponify ester 55 failed due to the highly electrophilic nature of the BT-sulfonyl portion of the molecule. The only observable product was 2-methoxy-benzothiazole (90); the result of ipso substitution of a sulfinate nucleofuge, and the desired acid 78 was not an observed product (NMR). In lieu of these problems with the synthesis of the acid, another route was investigated. Starting now from the esters 83 and 85, subjection to hydrolysis conditions, 1.2 M NaOH in MeOH/H2O mixture, gave the expected thioether acid 89 as a light yellow powder after the saponification. In an attempt to employ existing procedures for ester synthesis, 88 was then subjected to dicyclohexylcarbodiimide (DCC)37 and the desired coupling partner alcohol. All attempts to prepare esters from acid 88 were unsuccessful, however, due to the formation of an insoluble purple pigment upon treatment with DCC. We believe that betaine 91 is the pigment generated in these experiments. The formation of related compounds from similar heterocyclic heterocyclic starting materials has been reported48. The likely mechanism of formation of the undesired product is illustrated in scheme 19. The increased electrophilicity of the carbonyl 28 moiety through activation of the acid by DCC induces the facile nucleophilic attack of N-atom of the heterocyle, thus allowing the intramolecular self-condensation product consisting of the undesired purple dye to be the only one observed. O S N O H S N · O N N H N O O N O O S N S 95 96 H S S 97 S N S N 94 93 HN O N · N O S 92 89 H S N O H N N O 98 S N S 91 H N H N O 98 Scheme 19. Mechanism for the formation of purple betaine pigment 91 2.2 Synthesis of (Benzothiazol-2-sulfonyl) acetic acid Since ester formation from BT-thioether acid 89 was problematic, and we wanted to avoid a transesterification route to substrates of interest we elected to synthesize sulfonyl acid 78. Saponification product 89 was 29 subjected to the typical sulfide oxidation conditions, MoVI and H2O2 in EtOH24, followed by a sodium bisulfite reductive-work up to afford the desired acid 78 in a 57% yield with the only by-product being the BTmethyl sulfone 99 formed in a 33% yield (Scheme 20). O S N S 89 (NH4)6Mo7O24·4H2O OH H2O2 EtOH, 0 °C to rt, 17 h, then Na2SO3 O2 S N O S OH O2 S N S 78 57% 99 33% Scheme 20. Synthesis of key reagent 78 by oxidation of thioether 88 The acid was found to be shelf stable at ambient temperature over months and stable under vacuum for 4 weeks. An interesting property of 78 is exhibited when dissolved into solvents with a high dielectric constant (ie. acetone, DMSO) (Scheme 21). The acid will spontaneously undergo facile decarboxylation to give 99 in a quantitative yield. The more polar the solvent, the faster the rate of decarboxylation. When followed by NMR analysis it takes 66 min for a 10 mg sample to fully decompose in dimethylsulfoxide and 22 h to fully decarboxylate when dissolved into acetone. This phenomenon is probably due to intramolecular deprotonation that could occur through a malonate-like cyclic transition state where one of the heteroatoms is the base for the acidic proton. 30 O2 S N O DMSO or Acteone OH S O2 S N S (– CO2), 100% 78 99 Scheme 21. Facile decarboxylation of the lynchpin reagent in high dielectric constant solvents 2.3 DCC Coupling of (Benzothiazol-2-sulfonyl) acetic acid with ω -Alkenyl Carbinols The synthesis of the BT-esters was a straightforward process using known methods to construct esters (Scheme 22). Although it was the first time DCC was used to create BT-esters, the methodology for DCC ester synthesis37 has been well documented on other substrates. O2 S N O OH DCC, CH2Cl2 HO n S 78 79 rt, 15 h O2 S N O O n S 100 Scheme 22. General scheme for ester formation 2.4 Direct Synthesis of ω -Alkenyl Carbinols The multi-step synthesis of the various ω-alkenyl carbinols initiated the construction of the BT-esters. The ω-alkenyl alcohols were synthesized 31 from readily available starting materials using previously reported methods. 1-Phenyl-2-buten-1-ol (102) was produced in a one-step synthesis reacting via the addition of the Grignard reagent derived from allyl bromide (101) to benzaldehyde in excellent yield38. Br 101 Mg, Et2O, then PhCHO, 99% OH 102 Scheme 23. Grignard reaction for synthesis of 2° aryl alcohol 4-Penten-1-ol (107) was assembled through a three-step procedure of known chemistry from dimethyl malonate (103) (Scheme 24). The malonate was deprotonated by the action of NaH39 and then to the resulting anion was added the electrophilic allyl bromide 101 making olefin 104. The resulting alkene was then subjected to modified-Krapcho conditions40 thereby dealkoxycarboxylating the malonate to form 105 ωalkenyl methyl ester 106 in a moderate yield. The ester was then reduced to the desired pentenol 107 by the action of LiAlH4 in excellent yield. 32 O NaH, THF 0° C to rt, 30 min; O O O O O Br 101 THF, reflux, 15 h 93% 103 O NaCl, H2O, O 104 DMSO, reflux, 62% LiAlH4, O 105 O OH THF, reflux, 94% 107 Scheme 24. Pentenol 107 synthesis from dimethyl malonate 103 10-Undecen-1-ol (109) was constructed quantitatively from the acid 108 by standard reducing conditions using LiAlH4 in diethyl ether41 (Scheme 25). LiAlH4, Et2O, O 100 % HO 108 HO 109 Scheme 25. Reduction of undecenoic acid Alkenyl ether 113 was assembled via a two-step process starting from the commercially available 9-decen-1-ol 110. Proceeding through the alkyl iodide intermediate 111 by the PPh3/imidazole42 substitution reaction exchanging the hydroxyl group for iodine. This was subsequently subjected to Williamson ether synthesis43 conditions with hexadiol 112 and gave an overall yield from the two steps at 31% (Scheme 26). 33 PPh3, OH 110 I I2 111 OH 112 HO OH O NaH, DMF, 31% 113 Scheme 26. Synthesis of ethereal alcohol 113 2.5 Synthesis of (Benzothiazol-2-sulfonyl)acetate Esters using DCC coupling Sulfonyl acid 78 proved amenable to standard carbodiimide mediated esterification and a variety of simple ω-alkenyl sulfonyl esters 100 were readily prepared from ω-alkenyl carbinols (Scheme 27). The initial substrate used in the DCC esterification for a proof of concept was the commercially available 10-decen-1-ol 87. After performing this step under standard conditions, it was discovered that the reaction gave an excellent 97% yield and the excess acid was easily removed using a NaHCO3 wash. O2 S N S 78 O HO OH 87 DCC, DCM, 0 °C to rt, 16 h 97% O2 S N O O S Scheme 27. Initial ester formation through DCC coupling 114 34 This methodology was then extended using the aforementioned ωalkenyl alcohols. All proceeded with moderate to excellent yields under similar conditions depending on the nature of the alcohol (Figure 3). O O2 S N DCC, CH2Cl2 HO OH O2 S N n 100 O O2 S N O S O O S 115 67% O2 S N O rt, 15 h 79 78 O S n S O2 S N 116 60% O O2 S N O S O O S 117 100% 114 93% O2 S N O O O S 118 94% Figure 3. Readily synthesized esters from DCC coupling The nature of the alcohol played a major role in the efficiency of ester formation. Primary alcohols were easily esterified through the carbodiimide procedure, whereas 2° and 3° alcohols gave much lower yields in relation to their 1° analogues. All of the esters proved to be extremely shelf-stable and readily available masked aldehyde substrates for use in the intramolecular synthesis of α,β-unsaturated lactones. 35 3. α,β -Unsaturated Lactone Formation The synthesis of the desired lactone products was envisioned to proceed through a two-step process commencing with ozonolysis45 of the requisite ω-alkenyl sulfonyl esters and then subsequent subjection to the previously employed reaction conditions for the intermolecular modified-Julia variant (Scheme 28). O2 S N O O n O3, CH2Cl2:MeOH, 15 min then O2 S N S O O CHO n S DMS, –78 °C to rt, 16h 80 100 DBU, CH2Cl2, O O –78 °C to rt, 15 h, n 81 Scheme 28. General two-step ozonolysis/lactonization protocol 3.1 Ozonolysis of ω -Alkenyl Sulfonyl Esters The ozonolysis reactions applied in this study were the first to be successfully demonstrated on BT-sulfone containing compounds 100. Initially, it was believed that the heterocycle might not be able to withstand the harsh conditions of the ozonolysis. Fortuitously, the aromatic benzothaizole was found to be unaffected by the typically 36 severe action of ozone in any appreciable amount. The use of simple ωalkenyl sulfonyl esters 100 gave the expected aldehydes 80 in pure form when subjected to typical ozonolysis conditions with CH2Cl2 as the common solvent for such reactions. In contrast, when the solvent was changed to a mixture of CH2Cl2:MeOH (4:1)46, conditions used to avoid the formation of ozonides and proceeding instead via more easily reduced α-alkoxy hydroperoxides, the longer chain esters continued to return the expected aldehyde products, whereas the shorter chain esters gave methyl acetals exclusively (Scheme 29). When the long chain ωalkenyl sulfonyl esters were subjected to a straight CH2Cl2 medium, the yields and purification were largely unaffected. O3, CH2Cl2:MeOH, 40 min, O2 S N then DMS, –78 °C to rt, 19 h 72% O O2 S N O O O O S 119 O S 115 O3, CH2Cl2, 10 min, then DMS, –78 °C to rt, 12 h 59% O2 S N O O O S 120 Scheme 29. Differences in product distribution due to solvent effects Conditions for the reduction of the ozonide were also investigated during the course of this research. Both dimethyl sulfide (DMS) and triphenylphosphine were able to effect the reductive-work up of the 37 trioxolane intermediates equally well, but both reductants had their drawbacks (Scheme 30). Triphenylphosphine was the faster of the two at reducing the ozonide, but it was necessary to remove the resulting triphenylphosphine oxide from the product mixture by column chromatography. DMS or PPh3, O O O R DCM, -78 to rt 121 O H R 122 Scheme 30. Reduction of ozonide DMS, alternatively, was less rapid in reducing the trioxolane intermediate at 19 hours. Nevertheless, DMS proved to be the ideal reductant due to the ease of removal of the dimethylsulfoxide (DMSO) byproduct. Simple evaporation of the excess DMS and the subsequent washing of its oxidation product DMSO out with excess H2O proved to be enough to eliminate all extraneous compounds from the mixture save the desired aldehydes. The DMS reductive-work up conditions also proved efficient by affording us the opportunity to immediately subject the labile aldehyde substrate to the cyclization conditions without the need for chromatography. This was ideal since it had previously been observed that the carboxaldehyde products would decompose readily on silica gel even during flash chromatographic methods. 38 During the developmental stages of the ozonolysis reaction, we considered it a likely possibility that the oxidation conditions may promote the subsequent alkenation due to the basicity of the reaction medium. Unfortunately, the desired cyclic lactone products were never observed by NMR or isolated through chromatographic methods. 3.2 Modified-Julia Reacton of ω -Carboxaldehyde Sulfonyl Esters Due to the facile and time dependent decomposition of the ωcarboxaldehyde sulfonyl esters 100 that were produced in the previous ozonolysis step, it was decided that the crude products should be immediately subjected to the base mediated cyclization without purification. The reaction conditions used to effect the alkenation were similar to those previously employed for intermolecular modified-Julia olefination reactions23: the relatively innocuous base 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) in CH2Cl2. A variety of ring sizes were formed in the course of this research. The synthesis of small, medium, and large α,β-unsaturated lactones 81 each presented their own problems. ω-Carboxaldehyde sulfonyl ester 123 was the substrate used for the synthesis of the 7-member lactone 124 (Scheme 31). When subjected to the reaction conditions, the small ring was able to close, but it was 39 found, as was expected that the only lactone product that was formed was the (Z)-isomer 124. Though the stereoselectivity of the reaction is predicted by the fact that the both the BT-moiety 28 and the aldehyde 29 are unstabilized15, the more compelling argument for the selective nature of the reaction is due the impossibility of accommodating a trans olefin into a 7-membered ring. Interestingly, a byproduct isolated in small amounts was the aldol condensation product 125. This is most likely due to the fact that the nucleofuge and electrofuge must be in an antiperiplanar arrangement in order to properly eliminate. Due to the small ring size, the resulting steric demands disallow the anti-β-alkoxyBT-sulfone 30 intermediate the ability to rotate into the necessary antiperiplanar conformation that would enable the elimination reaction to occur. Therefore, the intermediate that would have necessarily led to the trans-isomer gives instead the resulting aldol product 125. O2 S N O O O O S O DBU (2eq), CH2Cl2, [7] O2 S N S -78 to rt, 15h O O [7] 123 124 31% E:Z = 0:100 125 4% Scheme 31. 7-membered lactone formation The next series of products obtained were of the medium/large sized 12membered α,β-unsaturated lactone and its aldol product (Scheme 32). These were derived from ester 116. This lactone had no predisposed 40 tendency due to steric constraints of ring size to preferentially afford either of the stereoisomers. Even with this stipulation, the medium size ring was observed to return the expected product distribution by giving the (Z)-isomer 37 in an 11:89 ratio, which falls in line with the previously observed results that type (b)15 intermolecular modified-Julia reactions afford cis-alkene stereoselectively. Separating and identifying the pair of olefin isomers, indicating where the alkene protons lay, and subsequent analysis of the integration values presented in the crude NMR determined the cis:trans ratio. Also of note was the unexpected formation of the aldol product 128. In this case ring size was not a factor in its formation, but it was observed in a diminished ratio as compared to the 7-membered analogue. O O2 S N S O O O O 126 DBU (2eq), CH2Cl2, O2 S N [12] S O O [12] -78 to rt, 15h 127 44% E:Z = 11:89 128 2% Scheme 32. 12-membered α,β-unsaturated lactone formation The stereoselectivity of 13-membered α,β-unsaturated lactone 130 formation was observed to be similar olefin ratio to the 12-membered situation. The product yield was not determined exactly because of isolation difficulty: the lactone 130 has a tendency to streak through the 41 entirety of the column. The (E:Z) ratio was once again determined by the integration values of the alkene protons found in the crude NMR. O N O O O2 S N S O2 S S [13] DBU (2eq), CH2Cl2, O O O O [13] -78 to rt, 15h 129 130 ~45% E:Z = 17:83 131 0% Scheme 33. 13-membered α,β-unsaturated lactone formation The large ring size 19-membered ethereal analogue of the reaction also went as expected affording the (Z)-isomer 37 from the unstabilized nature of both the aldehyde and BT-sulfone R groups. None of the aldol product was observed. O2 S N O O O O S DBU (2eq), CH2Cl2, -78 to rt, 15h 132 O O2 S N O O O S [19] [19] O O 133 40% E:Z = 15:85 134 0% Scheme 34. 19-membered ethereal α,β-unsaturated lactone formation 42 The whole of these examples indicate that the modified-Julia reaction is able to occur on even the simplest substrates that have no tendency to entropically cyclize on their own (ie. Thorpe-Ingold effect47) thus adding to the generality of the method developed. The final substrate attempted was the substituted ω-carboxaldehyde sulfonyl ester 135. The product exclusively formed was found to be trans-cinnamaldehyde 137. This is probably due to facile elimination following the deprotonation of the methylene group and promoted by the added stabilization afforded to the structure by the phenyl substituent. It is of note to recall that the reaction conditions for the lactone formation are of the most mild that could be encountered, yet none of the 6membered lactone 136 was isolated through chromatography or observed by spectroscopic analysis. O2 S N S O O O DBU (2eq), CH2Cl2, [6] Ph -78 to rt, 15h O 136 0% 135 O O H Ph 137 36% Scheme 35. Elimination of labile substrate A variety of other bases were investigated in the process of determining the ideal reaction conditions, but all proved to be ineffectual in promoting the desired cyclization. Other solvents besides dichloromethane were also examined in the course of the research, but 43 again, all gave low product yields in intractable mixtures. Nevertheless, it was noted that the alkene ratio (E:Z) was consistent with the results arising from the use of CH2Cl2 as the solvent. As expected, the varying chain lengths of the ω-carboxaldehyde sulfonyl esters 100 gave differing results based on the lactone ring size produced, but most returned modest yields of the expected (Z)-α,β-unsaturated lactone products 81. Besides the predicted outcomes of modified-Julia olefinations, cyclic adducts resulting from simple aldol condensation products were commonly also obtained. Significantly, when isomeric olefins were allowed by ring size, (Z)-configurated cyclic Julia products 37 predominated, presumably due to the type (b) reaction with unstabilized substrates. The generality of this method was also shown due to the nature of the starting materials, which contained no activating group yet still contained the ability to cyclize to the desired (Z)-lactone. Base labile substrates proved to be a liability to the universality of the reaction conditions. It was hypothesized that any 6-membered ring will not form, but instead will readily eliminate due to the entropic tendency to release SO2, CO2, benzothiazole and the conjugated aldehyde even in conditions as mild as those presented with DBU as a relatively weak base. 44 4. Conclusion Our results suggest that the modified-Julia reaction is an effective process for the synthesis of α,β-unsaturated lactones 81, but perhaps less efficient that the comparable Horner-Wadsworth-Emmons4 based approaches. In the examples studied, the cyclical nature of the initial βalkoxysulfone intermediates (30, 34) no doubt hindered spirocyclization (and the ensuing Smiles rearrangement14). Subsequent SO2 elimination, which usually requires an antiperiplanar arrangement of electrofugal and nucleofugal groups, would also be less effective (or otherwise impossible) from certain cyclic intermediates. Presumably, synthetic fragments leading to natural product molecules will have substituents to induce them to cyclize even more readily then the unsubstituted analogues, thereby the yields may well be observed to be higher when compared to those presented in this thesis. Interestingly, the examples described by Aïssa35 recently demonstrated successful intramolecular Julia alkenation under reaction conditions employing Cs2CO3 to facilitate the reaction. 45 5. Experimental Laboratory notebook reference: HG-183 O S N O S 83 C11H11NO2S2 (253.34) (NH4)6Mo7O24·4H2O (20 mol %), 30% H2O2, EtOH, 0 °C to rt, 40 h O2 S N O O S 55 C11H11NO4S2 (285.34) Ethyl (benzothiazol-2-ylsulfonyl)acetate: To a stirred solution of ethyl (1,3-benzothiazol-ylthio)acetic acid (5.0 g, 19.8 mmol) in ethanol (260 mL) at rt and solid was allowed to dissolve. To the solution was added (NH4)6Mo7O24·4H2O (4.4 g, 3.56 mmol) and suspension was cooled to 0 °C. To the reaction mixture was added 30% aq H2O2 (40 mL, 3.55 mol) in 10 mL portions over 1 min. Reaction was allowed to warm to rt and stir for 40 h. Suspension was filtered by vacuum and the filtrate was concentrated in vacuo to afford pink-white solid (5.61 g, 19.8 mmol, 100%): mp = 53-55 °C. Purity of the sample was confirmed by 1H NMR. IR (neat) 2989, 1742, 1471, 1342, 1153, 761 cm-1; 1H NMR (300MHz, CDCl3) δ 8.23 (1H, dd, J = 7.2, 1.8 Hz), 8.03 (1H, td, J = 7.0, 1.9 Hz), 7.63 (2H, td, J = 7.2, 1.5 Hz), 4.56 (2H, s), 4.17 (2H, q, 7.2 Hz), 1.17 (3H, t, 7.2 Hz) ppm; 13C NMR (75 MHz, CDCl3) δ 164.9 (0), 161.6 (0), 46 152.3 (0), 136.9 (0), 128.3 (1), 127.8 (1), 125.4 (1), 122.4 (1), 62.7 (2), 58.8 (2), 13.8 (3) ppm. Reference: 1) Blakemore, P. R.; Ho, D. K. H.; Nap, W. M. Org. Biomol. Chem. 2005, 3, 1365-8. Laboratory notebook reference: HG-196 O S N S OH (NH4)6Mo7O24·4H2O (0.10 eq), O2 S N O OH S 30% aq. H2O2, EtOH, 0 °C to rt, 17 h 89 C9H7NO2S2 (225.29) 78 C9H7NO4S2 (257.29) (Benzothiazole-2-sulfonyl)acetic acid: To a stirred solution of (benzothiazol-2-ylsulfanyl)acetic acid (20.0 g, 88.8 mmol) in EtOH (800 mL) at 0 °C was added ammonium molybdate (11.16 g, 9.03 mmol) solid and allowed for stir for 5min. To the suspension was added 30% aq. H2O2 (60 mL, 5.33 mol) in 10 mL portions over 1 min. Reaction was then allowed to warm to room temperature while stirring for 17 h. Reaction mixture was then cooled to 0 °C and solid was filtered by vacuum. **Caution: oxidants present. Saturated Na2SO3 solution at 0 °C was added until oxidants not present. Solution changed color from yellow to blue while standing. Removed the precipitate formed in the 47 reduction step by vacuum filtration. The pH of the reaction mixture was 1. Suspension was next extracted 5x using CHCl3, organic layers were then combined and washed with brine until aqueous phase was colorless. Organic layer was then dried over Na2SO4, and concentrated in vacuo while not allowing the bath to rise above room temperature to afford the white solid: mp 131-133 °C (13.0 g, 50.5 mmol, 59%). **1H NMR indicated that 5% was methyl-benzothiazole sulfone. IR (KBr) 3410 (br), 2994, 2933, 1725, 1471, 1338, 1166, 1101, 766; 1H NMR (400 MHz, d6-acetone) δ 8.31 (1H, dd, J = 7.1, 1.5 Hz), 8.24 (1H, d, J = 7.4 Hz), 7.75 (1H, td, J = 7.2, 1.3 Hz), 7.71 (1H, td, J = 7.2, 1.3 Hz), 4.81 (2H, s) ppm; 13C NMR (75 MHz, d6-acetone) 167.0 (0), 163.4 (0), 153.4 (0), 137.7 (0), 129.1 (1), 128.7 (1), 125.9 (1), 123.9 (1), 59.2 (2) ppm. Reference: Naya, A.; Kobayashi, K.; Ishikawa, M.; Ohwaki, K.; Saeki, T.; Noguchi, K.; Ohtake, N. Chem. Pharm. Bull. 2003, 51, 697-701. 48 Laboratory notebook reference: HG-181 O K2CO3 (1.2 eq), N SH O S Cl 81 C7H5NS2 (167.25) (1.2 eq) OEt 82 acetone, 56 °C, 18 h S N O S 83 C11H11NO2S2 (253.34) Ethyl (1,3-benzothiazol-2-ylthio)acetate: To a stirred solution of 2mercaptobenzothiazole (80.0 g, 0.478 mol) in acetone (1200 mL) at rt was added K2CO3 (79.6 g, 0.576 mol) all at once. The solution changed color from light to dark orange when solid was added. Suspension was allowed to stir for 15 min at rt. The suspension was then cooled to 0 °C and to this was added ethylchloroacetate (17.7 g, 54 mL, 0.144 mol) all at once. The vessel was then fitted with a condenser and set to reflux at 56 °C for 20 h. Solution color changed to yellow with a white precipitate formed. Reaction mixture was filtered by vacuum and filtrate was concentrated in vacuo to afford (121.2 g, 0.478 mol, 100%) of orange solid. A portion of the product was further purified by recrystallization using EtOAc to yield the purified ketone as an orange solid: mp 37-40 °C. Purity of the sample was confirmed by 1H NMR. IR (neat) 2984, 1738, 1462, 1428, 1299, 1157, 1002, 753 cm-1; 1H NMR (300MHz, CDCl3) δ 7.87 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 8.0 Hz), 7.44 (1H, td, J = 7.2, 1.1 Hz), 7.32 (1H, td, J = 7.3, 1.0 Hz), 4.27 (2H, q, 7.1 Hz), 4.19 (2H, s), 1.31 (3H, t, 7.1 Hz) ppm; 13 C NMR (75 MHz, 49 CDCl3) δ 168.4 (0), 164.9 (0), 153.0 (0), 135.6 (0), 126.2 (1), 124.6 (1), 121.8 (1), 121.2 (1), 63.2 (2), 35.3 (2), 14.3 (3) ppm. Laboratory notebook reference: HG-221 O K2CO3 (1.2 eq), N SH O S Br 81 C7H5NS2 (167.25) O S (1.2 eq) OMe 84 acetone, 56 °C, 18 h S N 85 C10H8NO2S2 (239.31) Methyl (1,3-benzothiazol-2-ylthio)acetate: To a stirred solution of 2mercaptobenzothiazole (20.0 g, 0.120 mol) in acetone (500 mL) at rt was added K2CO3 (19.9 g, 0.144 mol) all at once. The solution changed color from light to dark orange when solid was added. Suspension was allowed to stir for 15 min at rt. The suspension was then cooled to 0 °C and to this was added methylbromoacetate (22.0 g, 0.144 mol) all at once. The vessel was then fitted with a condenser and set to reflux at 56 °C for 18 h. Solution color changed to yellow with a white precipitate formed. Reaction mixture was filtered by vacuum and filtrate was concentrated in vacuo to afford 37.35 g of orange solid. The product was further purified by recrystallization using EtOAc to yield the purified thioether (28.48 g, 0.119 mol, 100%) as a off-white solid: mp 70-72 °C. Purity of the sample was confirmed by 1H NMR. 50 1 H NMR (300MHz, CDCl3) δ 7.86 (1H, d, J = 8.1 Hz), 7.76 (1H, dd, J = 8.0, 0.6 Hz), 7.41 (1H, td, J = 7.7, 1.2 Hz), 7.30 (1H, td, J = 7.6, 1.2 Hz), 4.20 (2H, s), 3.79 (3H, s) ppm; 13 C NMR (100 MHz, CDCl3) δ 168.7 (0), 164.5 (0), 152.7 (0), 135.4 (0), 126.0 (1), 124.4 (1), 121.6 (1), 121.0 (1), 52.8 (2), 34.7 (3) ppm. Laboratory notebook reference: HG-13 O S N S 83 C11H11NO2S2 (253.34) O HO 87 (3 eq) K2CO3 (0.5 eq), neat, 50 °C, 20.5 h O N S S O 88 C19H25NO2S2 (363.54) (Benzothiazol-2-ylsulfanyl)-acetic acid dec-9-enyl ester: To a stirred solution of (benzothiazol-2-ylsulfanyl)-acetic acid ethyl ester (5.0 g, 19.76 mmol) in 9-decen-1-ol (10.6 mL, ρ = 0.875, 9.25g, 59.25 mmol) was added K2CO3 (1.5 g, 10.85 mmol). Heat was then increased from rt to 50 °C. While stirring vigorously, the reaction was allowed to run for 20.5 h. The suspension was diluted with H2O (100 mL) and extracted using EtOAc (3x100 mL), dried (Na2SO4), and concentrated in vacuo to afford orange oil (12.28 g). Reaction mixture was further purified by column chromatography (10% EtOAc/hexanes) to yield product ester (4.70 g, 12.9 mmol, 65%) as a yellow oil. 51 IR (neat) 2927, 1738, 1640, 1429, 1002 cm-1; 1H NMR (300MHz, CDCl3) δ 7.86 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 8.0 Hz), 7.41 (1H, t, 7.4 Hz), 7.30 (1H, t, J = 7.6 Hz), 5.83 (1H, ddt, J = 16.8, 9.7, 6.9 Hz), 5.04-4.87 (2H, m), 4.21-4.31 (3H, m), 2.02 (2H, quartet, J = 6.9 Hz) ppm, 1.75-1.20 (13H, m); 13C NMR (75MHz, CDCl3) δ 167.8 (0), 164.4 (0), 152.5 (0), 138.6 (1), 135.1 (0), 125.7 (1), 124.0 (1), 121.3 (1), 120.7 (1), 113.9 (2), 65.6 (2), 34.7 (2), 33.4 (2), 28.8 (2), 28.7 (2), 28.5 (2), 28.1 (2), 25.4 (2) ppm. ; MS (FAB+) m/z 364 (M+H)+; HRMS (FAB+) m/z 364.1413 (calcd. for C19H26NO2S2: 364.1405). Laboratory notebook reference: HG-182 O S N S 83 C11H11NO2S2 (253.34) O O 1.5 M NaOH (2.7 eq), MeOH, 0 °C to rt, 19 h S N OH S 89 C9H7NO2S2 (225.29) (1,3-Benzothiazol-2-ylthio)acetic acid: To a stirred solution of ethyl (1,3-benzothiazol-ylthio)acetic acid (61.0 g, 0.241 mol) in methanol (800 mL) at 0 °C was added 1.5 M NaOH solution (430 mL, 0.645 mol) in 20 mL portions. The vessel was then fitted with a condenser and warm to rt and stir for 20 h. pH of solution was changed from 13 to 2 using 6 M HCl solution. Solution was allowed to stir for 10 min. Upon stirring color changed to yellow with a white precipitate formed. 52 Reaction mixture was filtered by vacuum and solid was the purified acid (10.2 g, 45.3 mmol). Filtrate was concentrated in vacuo to afford offwhite solid (51.0 g, 0.226 mol, 94%). A portion of the product was further purified by recrystallization using MeOH/H2O to yield the purified ketone as an off-white solid: mp 151-153 °C. Purity of both samples were confirmed by 1H NMR. IR (KBr) 2512, 1712, 1454, 1415, 1398, 1170, 1032, 748 cm-1; 1H NMR (300MHz, d6-DMSO) δ 7.92 (1H, d, J = 8.0 Hz), 7.83 (1H, d, J = 8.1 Hz), 7.53 (1H, td, J = 7.2, 1.2 Hz), 7.43 (1H, td, J = 7.0, 1.1 Hz), 4.03 (2H, s), 1.27 (1H, bs) ppm; 13C NMR (75 MHz, d6-DMSO) δ 169.23 (0), 165.9 (0), 152.5 (0), 134.7 (0), 126.4 (1), 124.5 (1), 121.8 (1), 121.1 (1), 35.0 (2) ppm. Reference: 1) Naya, A.; Kobayashi, K.; Ishikawa, M.; Ohwaki, K.; Saeki, T.; Noguchi, K.; Ohtake, N. Chem. Pharm. Bull. 2003, 51, 697-701. 53 Laboratory notebook reference: HG-184 O2 S N O O S 55 C11H11NO4S2 (285.34) 1.5 M NaOH (3eq), MeOH, rt, 15 h O N S 90 C8H7NOS (165.21) 2-Methoxybenzothiazole: To a stirred solution of ethyl (benzothiazol2-ylsulfonyl)acetate (1.00 g, 3.51 mmol) in MeOH (10 mL) at rt was added 1.5 M NaOH solution (7.0 mL, 10.5 mmol) dropwise over 5 min. Color changed from light yellow to dark yellow upon addition of base. The solution was allowed to stir for 15 h. The pH of the reaction mixture was lowered from 12 to 2 by addition of 6 M HCl (3 mL). Suspension was extracted 2x using CHCl3, organic layers were then combined and washed with brine. Organic layer was then dried over Na2SO4, and concentrated in vacuo to afford the orange oil (653 mg). Crude product was further purified by column chromatography (eluting with 20% Et2O/hexanes) to yield the benzothiazole (522 mg, 3.16 mmol, 90%) as a clear oil. IR (neat) 2936, 1600, 1540, 1443, 1258, 1220, 1068, 748 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.70 (1H, d, J = 8.3 Hz), 7.63 (1H, dd, J = 7.9, 0.8 Hz), 7.37 (1H, td, J = 7.4, 1.3 Hz), 7.23 (1H, td, J = 7.7, 1.2 Hz), 4.21 (3H, s) ppm; 13 C NMR (75 MHz, CDCl3) δ 173.3 (0), 149.2 (0), 132.0 (0), 125.9 (1), 123.4 (1), 121.2 (1), 120.8 (1), 58.4 (3) ppm. 54 Reference: Sawhney, S. N; Boykin, D. W. J. Org. Chem. 1979, 44, 1136-42. Laboratory notebook reference: HG-196 O S N S OH (NH4)6Mo7O24·4H2O (0.10 eq), O2 S N S 30% aq. H2O2, EtOH, 0 °C to rt, 17 h 89 C9H7NO2S2 (225.29) 99 C8H7NO2S2 (213.28) (Benzothiazole-2-sulfonyl)acetic acid: To a stirred solution of (benzothiazol-2-ylsulfanyl)acetic acid (20.0 g, 88.8 mmol) in EtOH (800 mL) at 0 °C was added ammonium molybdate (11.16 g, 9.03 mmol) solid and allowed for stir for 5min. To the suspension was added 30% aq. H2O2 (60 mL, 5.33 mol) in 10 mL portions over 1 min. Reaction was then allowed to warm to room temperature while stirring for 17 h. Reaction mixture was then cooled to 0 °C and solid was filtered by vacuum. **Caution: oxidants present. Saturated Na2SO3 solution at 0 °C was added until oxidants not present. Solution changed color from yellow to blue while standing. Removed the precipitate formed in the reduction step by vacuum filtration. The pH of the reaction mixture was 1. Suspension was next extracted 5x using CHCl3, organic layers were then combined and washed with brine until aqueous phase was colorless. Organic layer was then dried over Na2SO4, and concentrated in vacuo 55 while not allowing the bath to rise above room temperature to afford the white solid: mp °C (6.25 g, 29.3 mmol, 33%). 1 H NMR (300 MHz, d6-DMSO) δ 8.36 (1H, m), 7.63 (1H, d, J = 2.1 Hz), 7.71 (2H, sd, J = 7.2, 1.6 Hz), 3.59 (3H, s) ppm; 13 C NMR (75 MHz, CDCl3) δ 167.3 (0), 151.9 (0), 136.0 (0), 128.1 (1), 127.9 (1), 124.7 (1), 123.5 (1), 42.1 (3) ppm. Laboratory notebook reference: HG-49 Br Mg (3 eq), Et2O, 33 °C, 1.5 h, OH then C6H5CHO, 2 h 101 C3H5Br (120.98) 102 C10H12O (148.20) 1-Phenyl-3-buten-1-ol: A stirred suspension of Mg (7.05 g, 0.294 mol) in anhydrous Et2O (250 mL) under argon was added a solution of allyl bromide (8.30 mL, ρ = 1.43 g/mL, 11.86 g, 98.0 mmol) in anhydrous Et2O (125 mL). The solution was allowed to reflux at 33 °C for 0.5 h. Benzaldehyde was added (6.4 mL, ρ = 1.043 g/mL, 6.65 g, 62.7 mmol) dropwise over 30 min. Reaction was then allowed to stir for 2 h. Quenched reaction with solution of sat. NH4Cl and solid was then filtered by vacuum. Solution was extracted 3x using Et2O and dried over Na2SO4. Suspension was filtered by vacuum and concentrated in vacuo 56 to afford 13.63 g of clear oil. Structure and purity confirmed by 1H NMR. 1 H NMR (300MHz, CDCl3) δ 7.40-7.25 (5H, m) 5.80 (1H, ddt, J = 17.2, 10.1, 7.0 Hz), 5.21-5.11 (2H, m), 4.71 (1H, t, J = 6.5 Hz), 2.60-2.47 (2H, m), 2.41 (1H, bs, 2.65); 13 C NMR (75MHz, CDCl3) δ 143.8 (0), 134.3 (1), 127.9 (2C, 1), 127.0 (1), 125.7 (2C, 1), 117.2 (1), 73.2 (1), 43.2 (2) Laboratory notebook reference: HG-73 O NaH (1.1 eq), THF 0° C to rt, 30 min; O O O 103 C5H8O4 (132.04) O O O O Br 101 (1.1 eq) THF, reflux, 15 h 104 C8H12O4 (172.07) 2-Allyl-malonic acid dimethyl ester: A stirred suspension of NaH (4.00 g, 166.7 mmol) in anhydrous THF (170 mL) at 0° C under argon was treated dropwise with a solution of dimethyl malonate (17.3 mL, ρ = 1.153, 20.0 g, 151.6 mmol) in anhydrous THF (170 mL) over 35 min. During the addition, the temperature was not allowed to increase over 5 °C. The resulting suspension was stirred for 30 min. Solid NaH was observed to be consumed during the reaction. A solution of allyl bromide (13.8 mL, ρ = 1.469, 20.2 g, 166.8 mmol) in THF (170 mL) was added dropwise over 20 min. Reaction mixture was set to reflux for 57 15 h. During this time a white precipitate was observed to form. Solid was filtered by vacuum then filtrate was washed with H2O (2x200 mL) to remove any excess solid. Organic layer was removed, dried (Na2SO4), and filtered by vacuum. Solution was concentrated in vacuo to afford 24.36 g of yellow oil. A portion of the crude product was purified by column chromatography (eluting with 0-20% EtOAc/hexanes) to yield the alkylated ester (24.36 g, 141.6 mmol, 93%) as a colorless oil: IR (neat) 2954, 1737, 1643, 1437, 1342, 1234, 1191, 1157, 920 cm-1; 1H NMR (300MHz, CDCl3) δ 5.75 (1H, ddt, J = 17.0, 10.2, 6.9 Hz), 5.12 (1H, dq, J = 18.0, 1.4 Hz), 5.06 (1H, dq, J = 10.4, 1.1 Hz), 3.73 (6H, s), 3.47 (1H, t, J = 7.6 Hz), 2.65 (2H, t, J = 7.2 Hz); 13 C NMR (75MHz, CDCl3) δ 168 (2C, 0), 134 (2), 117 (1), 53 (2C, 6), 51 (2) 33 (1). Laboratory notebook reference: HG-80 O O O O O NaCl (1.25 eq), H2O (2.00 eq), DMSO, reflux 104 C8H12O4 (172.07) O 105 C6H10O2 (114.07) Pent-4-enoic acid methyl ester: To a stirred solution of 2-allyl-malonic acid dimethyl ester (24.34 g, 141.5 mmol) in DMSO (40 mL) at reflux (189 °C) under argon to which was added H2O (5.09 g, 283.0 mmol) and NaCl (10.34 g, 176.9 mmol) sequentially. Biphasic reaction mixture was 58 allowed to stir for 25 h then diluted with Et2O (150 mL) and the resulting solution was washed with H2O (6x100 mL). The organic phase was removed and dried (Na2SO4). Suspension was then filtered by vacuum and concentrated in vacuo to afford 14.87 g of crude yelloworange oil (Caution: product volatile). This material was then purified by distillation at atmospheric pressure to yield the methyl ester (9.98 g, 87.5 mmol, 62%) as a colorless oil: bp 96-100 °C. Purity of the sample was confirmed by 1H NMR. IR (neat) 2954, 1737, 1643, 1432, 1170, 916 cm-1; 1H NMR (300MHz, CDCl3) δ 5.83 (1H, ddt, J = 16.5, 10.5, 6.5 Hz), 5.08 (1H, dq, J = 17.5, 1.5 Hz), 5.02 (1H, dq, J = 17.5, 1.1 Hz), 3.70 (3H, s), 2.42 (4H, m) ppm; 13 C NMR (75MHz, CDCl3) δ 173.3 (0), 136.6 (1), 115.5 (2), 51.4 (3), 33.3 (2), 28.8 (2) ppm. Laboratory notebook reference: HG-81 O LiAlH4 (0.75 eq), O 105 C6H10O2 (114.07) THF, reflux OH 107 C5H10O (86.07) 4-Penten-1-ol: A stirred suspension of LiAlH4 (1.00 g, 26.3 mmol) in anhydrous Et2O (80 mL) at 0° C under argon was treated dropwise with pent-4-enoic acid methyl ester (4.00 g, 35.1 mmol) solution in anhydrous Et2O (80 mL) over 15 min at 0° C. Suspension was then 59 heated to reflux (34 °C). After 14 h, reaction was allowed to cool to rt and was quenched by adding a slurry of Na2SO4/H2O portionwise until gray color had completely disappeared. Suspension was filtered by vacuum and the layers were separated. Aqueous layer was extracted using Et2O (2x15 mL). Organic layers were combined, dried (Na2SO4), and the resulting suspension was vacuum filtered. Solution was concentrated in vacuo (Caution: product volatile). The structure and purity of the resulting alcohol (2.85 g, 33.1 mmol, 94%) was confirmed by 1H NMR. IR (neat) 3333, 2938, 2869, 1634, 1553, 1432 cm-1; 1H NMR (300MHz, CDCl3) δ 5.82 (1H, ddt, J = 17.0, 10.3, 6.9 Hz), 5.05 (1H, dq, J = 17.0, 1.6 Hz), 4.97 (1H, dq, J = 10.0, 1.0 Hz), 3.66 (2H, t, J = 6.5 Hz), 2.14 (2H, quartet, J = 6.0 Hz), 1.67 (2H, quintet, J = 7.0 Hz), 1.52 (1H, bs) ppm; 13 C NMR (75MHz, CDCl3) δ 138.4 (1), 114.9 (2), 62.2 (2), 31.8 (2), 30.1 (2). Laboratory notebook reference: HG-213 O OH LiAlH , Et O, 4 2 108 C11H20O2 (184.28) 33 °C, 16 h OH 109 C11H22O (170.29) 10-Undecen-1-ol: To a stirred flask was added LiAlH4 (1.072 g, 28.2 mmol) and diluted into Et2O (40 mL). Suspension was cooled to 0 °C 60 then the 10-undecenoic acid (4.23 g, 23.5 mmol, 2.98 mL)/Et2O (60 mL) solution was added to the mixture. The reaction was allowed to gradually heat to 33 °C, then continue reaction for 16 h. Na2SO4/H2O slurry was added to the reaction vessel until no reaction was observed. Solid was filtered by vacuum and the resulting solution was concentrated in vacuo to afford the alcohol (4.00 g, 23.5 mmol, 100%) as a clear oil: IR (neat) 3330, 2927, 2856, 1647, 1467, 1059, 912 cm-1; 1 H NMR (300MHz, CDCl3) δ 5.81 (1Η, ddt, J = 16.9, 10.3, 6.7 Hz), 5.05-4.87 (2H, m), 3.63 (2H, t, J = 6.6 Hz), 2.03 (2H, quart. J = 6.7 Hz), 1.75-0.02 (14H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 139.1 (1), 114.1 (2), 62.6 (2), 33.8 (2), 32.8 (2), 29.6 (2), 29.5 (2), 29.2 (2), 29.0 (2), 25.8 (2) ppm. **Note 2 x 2Cs overlap (10 C’s shown) Reference 1) Riedl, R.; Tappe, R.; Berkessel, A. J. Am. Chem. Soc. 1998, 120, 8894-9000. 61 Laboratory notebook reference: HG-206 N O2 S S HO O 78 OH (1.2 eq) N S DCC (1.2 eq), THF, 0 °C to rt, 19 h O2 S O O 114 C19H25NO4S2 (395.54) 87 C11H22O (156.27) (Benzothiazole-2-sulfonyl)acetic acid 9-decenyl ester: To a flame dried flask purged with argon, was added (benzothiazole-2- sulfonyl)acetic acid (6.80 g, 26.5 mmol) in THF (200 mL) and was allowed to dissolve at 0 °C. To this solution was added 9-decen-1-ol (3.93 g, 25.2 mmol, ρ = 0.843, 4.66 mL) neat dropwise over 1 min. Solution was allowed to stir at 0 °C for 10 min. To this was added N,N’dicyclohexylcarbodiimide (5.72 g, 27.7 mmol) all at once. White precipitate was observed to form shortly after addition of DCC. Mixture was allowed to warm to rt. After 19 h, the reaction was stopped. Solid DCU formed was filtered by vacuum. Concentrated solution in vacuo to afford crude product (15.84 g) as yellow oil containing white solid. 1H NMR confirmed product was present as well as DCU. Crude product was further purified by column chromatography (eluting with 10% Et2O/hexanes) to yield the ester (9.721 g, 24.57 mmol, 93%) as clear yellow oil. IR (neat) 3071, 2929, 2856, 1738, 1639, 1471, 1346, 1157, 912, 761 cm1 1 ; H NMR (300 MHz, CDCl3) δ 8.23 (1H, d, J = 8.0 Hz), 8.02 (1H, dd, 62 J = 6.9, 1.5 Hz), 7.65 (1H, td, J = 7.3, 1.4 Hz), 7.61 (1H, td, J = 7.1, 1.4 Hz), 5.81 (1H, ddt, 17.0, 10.2, 6.7 Hz), 5.04-4.89 (2H, m), 4.57 (2H, s), 4.10 (2H, t, J = 6.6 Hz), 2.03 (2H, q, J = 7.0 Hz), 1.59-1.09 (12H, m) ppm; 13 C NMR (75 MHz, CDCl3) δ 165.0 (0), 161.6 (0), 152.3 (0), 139.0 (1), 136.9 (0), 128.2 (1), 127.7 (1), 125.5 (1), 122.3 (1), 114.2 (2), 66.8 (2), 58.6 (2), 33.7 (2), 29.6 (2), 29.1 (2), 28.9 (2), 28.7 (2), 28.1 (2), 25.5 (2) ppm; MS (FAB+) m/z 396 (M+H)+; HRMS (FAB+) m/z 396.1309 (calcd. for C19H25NO4S2: 396.1303). Laboratory notebook reference: HG-59 OH N S 102 C10H12O (148.20) O2 S O 78 OH (1.2 eq) DCC (1.2 eq), THF, 0 °C to rt, 19 h N S O2 S O O 116 C19H17NO4S2 (387.47) (Benzothiazole-2-sulfonyl)acetic acid 3-phenyl-3-butenyl ester: To a flame dried flask purged with argon, was added (benzothiazole-2sulfonyl)acetic acid (416 mg, 1.62 mmol) in THF (15 mL) and was allowed to dissolve at 0 °C. To this solution was added 1-phenyl-3buten-1-ol (200 mg, 1.35 mmol) neat dropwise over 1 min. Solution was allowed to stir at 0 °C for 10 min. To this was added N,N’dicyclohexylcarbodiimide (334 mg, 1.62 mmol) all at once. White precipitate was observed to form shortly after addition of DCC. Mixture 63 was allowed to warm to rt. After 15 h, to the reaction was added the acid (278 mg) and DCC (222 mg) to ensure completion of reaction. Allowed reaction to run for 24 h. Solid DCU formed was filtered by vacuum. Concentrated solution in vacuo to afford crude product (478 mg) as yellow oil containing white solid. 1H NMR confirmed product was present as well as DCU. Crude product was further purified by column chromatography (eluting with 40% EtOAc/hexanes) to yield the ester (310 mg, 0.810 mmol, 60%) as clear yellow oil. IR (neat) 3067, 2929, 1738, 1642, 1553, 1471, 1342, 1278, 1148, 757, 731 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.22-8.16 (1H, m), 8.03-7.97 (1H, m), 7.63 (2H, td, J = 7.2, 1.5 Hz), 7.26-7.10 (5H, m), 5.76 (1H, t, J = 6.9 Hz), 5.65-5.45 (1H, m), 5.03-4.92 (2H, m), 4.60 (2H, s), 2.65-2.40 (2H, m), 1.56 (2H, s) ppm; 13 C NMR (75 MHz, CDCl3) δ 165.0 (0), 160.9 (0), 152.5 (0), 138.3 (0), 137.0 (0), 132.4 (1), 128.5 (1), 128.3 (1), 127.8 (1), 126.6 (1), 125.6 (1), 122.5 (1), 118.7 (2), 78.2 (1), 58.7 (2), 40.2 (2) ppm; MS (CI+) m/z 388; HRMS (CI+) m/z 388.06646 (calcd. for C19H17O4NS2 : 388.06435). 64 Laboratory notebook reference: HG-69 N OH 107 C5H10O (86.07) O2 S O S OH (1.2 eq) N 78 S DCC (1.2 eq), THF, 0 °C to rt, 12 h O2 S O O 115 C14H15NO4S2 (325.04) (Benzothiazole-2-sulfonyl)acetic acid 4-pentenyl ester: To a flame dried flask purged with argon, was added (benzothiazole-2- sulfonyl)acetic acid (9.39 g, 36.5 mmol) in THF (450 mL) and was allowed to dissolve at 0 °C. To this solution was added 4-penten-1-ol (2.85 g, 33.1 mmol) neat all at once. Solution was allowed to stir at 0 °C for 10 min. To this was added DCC (8.18 g, 39.7 mmol) all at once. White precipitate was observed to form shortly after addition of DCC. Mixture was allowed to warm to rt. After 12 h, the reaction was stopped. Solid DCU formed was filtered by vacuum. Concentrated solution in vacuo to afford crude product (13.65 g) as a clear light yellow oil containing white solid. 1H NMR confirmed product was present as well as DCU. Crude product was further purified by column chromatography (eluting with 25% EtOAc/hexanes) to yield the ester (7.13 g, 21.9 mmol, 66%) as clear yellow oil. IR (neat) 2933, 1742, 1638, 1342, 1153, 761 cm-1; 1H NMR (300MHz, CDCl3) δ 8.26-8.00 (1H, m), 8.06-8.20 (1H, m), 7.69-7.58 (2H, m), 5.82 (1H, ddt, J = 15.9, 9.4, 6.5 Hz), 4.98-4.88 (2H, m), 4.58 (2H, s), 4.12 (2H, t, J = 6.6 Hz), 1.97 (2H, quartet, J = 7.1 Hz), 1.68-1.55 (2H, m) 65 ppm; 13C NMR (75MHz, CDCl3) δ 165.0 (0), 161.6 (0), 152.4 (0), 136.8 (1), 128.2 (1), 127.8 (1), 125.5 (1), 122.3 (1), 115.5 (2), 66.1 (2), 58.7 (2), 29.6 (2), 27.3 (2). MS (ES) m/z 326 (M)+; HRMS (ES) m/z 326.05256 (calcd. for C14H16O4NS2 : 326.05208). Note 1: 1 Carbon not found in 13C spectrum Laboratory notebook reference: HG-215 N HO S O2 S O 78 OH (1.01 eq) DCC (1.02 eq), THF, 0 °C to rt, 20 h 109 C11H22O (170.29) N S O2 S O O 117 C20H27NO4S2 (409.56) Undec-10-enyl(1,3-benzothiazol-2-ylsulfonyl)acetate: To a flame dried flask purged with argon, was added 9-decen-1-ol (1.50 g, 8.82 mmol) neat and diluted into THF (80 mL). To this solution, was added (benzothiazole-2-sulfonyl)acetic acid (2.30 g, 8.95 mmol) and was allowed to dissolve at 0 °C. Solution was allowed to stir at 0 °C for 10 min. To this was added N,N’-dicyclohexylcarbodiimide (1.86 g, 9.01 mmol) all at once. White precipitate was observed to form shortly after addition of DCC. Mixture was allowed to warm to rt. After 20 h, the reaction was stopped. Solid DCU formed was filtered by vacuum. The mixture was cooled to 0 °C, and the solid filtered again. Ester was extracted with CH2Cl2 and then washed combined layers with sat. 66 NaHCO3 solution then brine. Dried layers over solid Na2SO4. Filtered solid and concentrated solution in vacuo to afford crude product as yellow oil (5.32 g) containing white solid. 1H NMR confirmed product was present as well as DCU. Crude product was further purified by column chromatography (eluting with 20% EtOAc/hexanes) to yield the ester (3.61 g, 8.82 mmol, 100%) as clear yellow oil. IR (neat) 2925, 2856, 1742, 1639, 1471, 1342, 1277, 1153, 908, 757 cm1 ; 1H NMR (300 MHz, CDCl3) δ 8.23 (1H, dd, J = 7.2, 1.8 Hz), 8.03 (1H, dd, J = 7.0, 1.9 Hz), 7.67 (1H, td, J = 7.2, 1.5 Hz), 7.61 (1H, td, J = 7.2, 1.5 Hz), 5.82 (1H, ddt, J = 17.0, 10.2, 6.7 Hz), 5.05-4.89 (2H, m), 4.58 (2H, s), 4.10 (2H, t, J = 6.7 Hz), 2.10-1.98 (2H, m), 1.64-1.08 (13H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 165.1 (0), 161.7 (0), 152.5 (0), 139.2 (1), 137.0 (0), 128.3 (1), 127.8 (1), 125.6 (1), 122.4 (1), 114.2 (2), 66.9 (2), 58.7 (2), 33.8 (2), 29.3 (2), 29.1 (2), 28.9 (2), 28.2 (2), 25.6 (2) ppm; MS (CI+) m/z 410 (M+H)+; HRMS (CI+) m/z 410.14698 (calcd. for C20H28NO4S2: 410.14598). *Note 2 x 2Cs overlap (18 Cs shown) 67 Laboratory notebook reference: HG-125 N 118 C16H32O2 (256.42) O 78 OH (1.2 eq) S O HO O2 S DCC (1.2 eq), THF, 0 °C to rt, 20 h O2 S N O O O S 118 C25H37NO5S2 (495.69) 9-Decenyloxy-1-hexanyl(1,3-benzothiazol-2-ylsulfonyl)acetate: To a flame dried flask purged with argon, was added 9-decenyloxy-1-hexanyl (385 mg, 1.50 mmol) and diluted into THF (10 mL). To this solution, was added (benzothiazole-2-sulfonyl)acetic acid (464 mg, 1.80 mmol) and was allowed to dissolve at 0 °C. To this was added N,N’dicyclohexylcarbodiimide (372 mg, 1.80 mmol) all at once. THF volume was increased to 25 mL. White precipitate was observed to form shortly after addition of DCC. Mixture was allowed to warm to rt. After 20 h, the reaction was stopped. Solid DCU formed was filtered by vacuum. The mixture was cooled to 0 °C, and the solid filtered again. Ester was extracted with CH2Cl2 and then washed combined layers with sat. NaHCO3 solution then brine. Dried layers over solid Na2SO4. Filtered solid and concentrated solution in vacuo to afford crude product as yellow oil (1.03 g) containing white solid. 1H NMR confirmed product was present as well as DCU. Crude product was further purified by 68 column chromatography (eluting with 12% EtOAc/hexanes) to yield the ester (700 mg, 1.41 mmol, 94%) as clear yellow oil. IR (neat) 2924, 2852, 1742, 1471, 1338, 1273, 1153, 908, 761 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.25-8.20 (1H, m), 8.05-7.98 (1H, m), 7.67 (2H, td, J = 7.1, 1.5 Hz), 5.82 (1H, ddt, J = 16.9, 10.3, 6.6 Hz), 5.054.89 (2H, m), 4.58 (2H, s), 4.10 (2H, t, J = 6.6 Hz), 2.10-1.98 (2H, m), 1.80-0.50 (24H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 165.1 (0), 161.8 (0), 152.7 (0), 139.3 (1), 137.1 (0), 128.4 (1), 127.9 (1), 125.8 (1), 122.5 (1), 114.2 (2), 67.1 (2), 58.9 (2), 33.9 (2), 29.9 (2), 29.4 (2), 28.9 (2), 29.18 (2), 29.15 (2), 29.0 (2), 28.4 (2), 25.8 (2) ppm ** 4 C’s are hidden in 13C spectrum. Laboratory notebook reference: HG-70 N S O2 S O2/O3 (XS), DCM:MeOH, -78 °C, 10 min, O O 115 C14H15NO4S2 (325.04) then, DMS (12.8 eq), 12 h to rt N S O2 S O O O 119 C15H19NO6S2 (373.07) O (Benzothiazole-2-sulfonyl)acetic acid 4,4-dimethoxy-butyl ester: To a stirred solution of (benzothiazole-2-sulfonyl)acetic acid pent-4-enyl ester (174 mg, 534 mmol) in DCM:MeOH (4 mL:1 mL) at -78 °C was bubbled through gaseous O2/O3. Reaction was allowed to stir for 40 min, until the solution turned a light-blue color. To this solution was added 69 DMS (0.5 mL, ρ=0.846, 423 mg, 6.81 mmol) and allowed to stir for 12 h. Solution was concentrated in vacuo to afford 219 mg of yellow oil. The crude material was further purified by column chromatography (eluted with 25% EtOAc/hexanes) to yield the dimethyl acetal (143 mg, 72%) as yellow oil. IR (neat) 2937, 2830, 1738, 1471, 1342, 1273, 1153, 761, 727; 1H NMR (300MHz, CDCl3) δ 8.28-8.22 (1H, m), 8.08-8.02 (1H, m), 7.71-7.60 (2H, m), 4.60 (2H, s), 4.28 (1H, t, J = 5.3 Hz), 4.17 (2H, t, J = 6.1 Hz), 3.29 (6H, s), 1.70-1.50 (4H, m) ppm. Laboratory notebook reference: HG-71 N S O2 S O3, CH2Cl2, -78 °C, 15 min, O O 115 C14H15NO4S2 (325.40) then, DMS to rt 20 h N S O2 S O O O 123 C13H13NO5S2 (327.38) 4-(1,3-Benzothiazol-2-ylsulfonyl)butanal: To a stirred flask was added (benzothiazol-2-sulfonyl)-acetic acid 4-pentenyl ester (140 mg, 426 µmol) and diluted into DCM (5 mL). Oil and was allowed to stir at rt until yellow solution was observed. Solution was then cooled to -78 °C and bubbled through gaseous O3. After 10 min solution became blue and O3 was stopped. DMS (0.5 mL, 6.81 mmol) was added and reaction mixture was allowed to warm to rt over 21 h. Solution was concentrated 70 to afford 190 mg of orange oil. Further purified by column chromatography (eluting with 50% EtOAc/hexanes) to yield the aldehyde (83 mg, 253 µmol, 59%) as a clear yellow oil: IR (neat) 3449, 2929, 2727, 1742, 1471, 1342, 1237, 1153, 766, 723 cm-1; 1H NMR (300MHz, CDCl3) δ 9.66 (1Η, t, J = 0.85 Hz), 8.24-8.19 (1H, m), 8.067.99 (1H, m), 7.70-7.57 (2H, m), 4.57 (2H, s), 4.17 (2H, t, J = 6.2 Hz), 2.45 (2H, dt, J = 0.81, 7.2 Hz), 1.98 (2H, quint, J = 6.7 Hz) ppm; 13 C NMR (100 MHz, CDCl3) δ 200.8 (1), 165.0 (0), 161.6 (0), 152.6 (0), 137.1 (0), 128.6 (1), 128.0 (1), 125.8 (1), 122.6 (1), 65.7 (2), 58.9 (2), 40.1 (2), 20.1 (2) ppm; MS (CI+) m/z 328.1 (M+H)+; HRMS (CI+) m/z 328.03145 (calcd. for C13H14NO5S2: 328.03134). Laboratory notebook reference: HG-20 O2 S N O O S 114 C19H25NO4S2 (395.54) O3, CH2Cl2:MeOH, -78 °C, 15 min, then, DMS to rt 20 h O2 S N O O S O 126 C18H23NO5S2 (397.21) 9-Oxonoyl(1,3-benzothiazol-2-ylsulfonyl)acetate: To a stirred flask was added (benzothiazol-2-sulfonyl)acetic acid 9-decenyl ester (200 mg, 510 µmol) and diluted into DCM:MeOH (4:1) (5 mL). Oil and was allowed to stir at rt until yellow solution was observed. Solution was then cooled to -78 °C and bubbled through gaseous O3. After 10 min 71 solution became blue and O3 was stopped. DMS (0.5 mL, 6.81 mmol) was added and reaction mixture was allowed to warm to rt over 21 h. Solution was concentrated to afford 249 mg of yellow oil. Further purified by column chromatography (eluting with 40% EtOAc/hexanes) to yield the aldehyde (190 mg, 478 µmol, 94%) as a clear white oil: IR (neat) 2929, 2852, 1742, 1471, 1342, 1153, 761cm-1; 1H NMR (300MHz, CDCl3) δ 9.76 (1Η, s), 8.22 (1H, d, J = 7.5 Hz), 8.03 (1H, d, J = 7.2 Hz), 7.63 (2H, ), 4.67 (2H, s), 4.18-4.03 (2H, m), 2.41 (2H, t, J = 6.7 Hz), 1.70-0.01 (12H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 202.9 (1), 171.3 (0), 165.1 (0), 161.7 (0), 152.5 (0), 137.0 (1), 128.3 (1), 127.9 (1), 122.6 (1), 65.7 (2), 58.9 (2), 40.1 (2), 20.1 (2) ppm; MS (CI+) m/z 328.1 (M+H)+; HRMS (CI+) m/z 328.03145 (calcd. for C13H14NO5S2: 328.03134). Laboratory notebook reference: HG-93 O2 S N O O DBU (2eq), CH2Cl2, O O S -78 to rt, 15h 123 C15H17NO5S2 (355.43) (Z)-6,7-Dihydro-5H-oxepin-2-one: O 124 C6H8O2 (112.13) A stirred solution of 1,8- diazabicyclo[5.4.1]undecene (353 mg, 2.32 mmol) in CH2Cl2 (10 mL) at -78 °C under argon was treated by dropwise addition with a solution of 72 4-(1,3-benzothiazol-2-ylsulfonyl)butanal (379 mg, 1.16 mmol) in CH2Cl2 (10 mL) over 15 min. After the addition the solution was allowed to warm to rt over 15 h and stir at rt for 2 h. The reaction was then quenched by the addition of 0.375 M HCl solution. Extracted organic 3x using CH2Cl2 and combined layers. Organic layers were removed, dried (Na2SO4), and filtered by vacuum. Solution was concentrated in vacuo to afford 506 mg of light yellow oil (Z:E = 100:0). Purified product using column chromatography (eluting with 0-50% EtOAc/hexanes) to yield the a,b-unsaturated lactone (40 mg, 360 mmol, 31%) as an off-white solid. **Unable to completely separate benzothiazolone side-product, yield derived from NMR analysis. 1 H NMR (300 MHz, CDCl3) δ 6.25 (1H, dt, J = 11.7, 8.8 Hz), 5.81 (1H, d, 11.7 Hz), 4.19 (2H, t, J = 5.2 Hz), 2.54 (2H, q, J = 8.0 Hz), 1.90-1.77 (2H, m) ppm. HRMS (CI+) m/z 113.06048 (calcd. for C6H9O2: 113.06026). Laboratory notebook reference: HG-136 N S O2 S O O DBU (2.0 eq), CH2Cl2, -78 °C, 14 h O O 126 C18H23NO5S2 (397.51) (Z)-Oxacyclododec-3-en-2-one: O slow addition (0.74 mL/h) to rt 127 C11H18O2 (182.26) A stirred solution of 1,8- diazabicyclo[5.4.1]undecene (67 mg, 440 mmol) in CH2Cl2 (10 mL) at -78 °C under argon was treated by slow addition (0.74 mL/h) with a 73 solution of 9-oxononyl(1,3-benzothiazol-2-ylsulfonyl)acetate (75 mg, 189 mmol) in CH2Cl2 (10 mL) over 14 h. During the addition the solution was allowed to warm to rt over 12 h and stir at rt for 2 h. The reaction was then quenched by the addition of sat. NH4Cl solution and allowed to stir for 0.5 h. Extracted organic 5x using EtOAc. Organic layers were removed, dried (Na2SO4), and filtered by vacuum. Solution was concentrated in vacuo to afford 45 mg of light yellow oil (Z:E = 89:11). Purified product using column chromatography (eluting with 012.5% EtOAc/hexanes) to yield the a,b-unsaturated lactone (15 mg, 82.3 mmol, 44%) as a white solid (mp = 58-60 °C) : IR (KBr) 2916, 2850, 1719, 1701, 1466, 1293, 1237, 830 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.18 (1H, dt, J = 11.7, 8.0 Hz), 5.74 (1H, d, 11.7 Hz), 4.17 (2H, t, J = 5.9 Hz), 2.54 (2H, q, J = 7.4 Hz), 1.67 (2H, quint., J = 11.7 Hz), 1.491.18 (8H, m), 0.94-0.77 (2H, m) ppm; 13 C NMR (75 MHz, CDCl3) δ 167.3 (0), 148.6 (1), 120.9 (1), 64.4 (2), 29.9 (2), 29.5 (2), 29.33 (2), 29.26 (2), 29.1 (2), 29.0 (2), 26.4 (2) ppm; HRMS (CI+) m/z 183.13845 (calcd. for C11H19O2: 183.13851) Reference: 1) Izbedski, J.; Pawlak, D. Synthesis 1989, 419-23. 74 Laboratory notebook reference: HG-212 O O2 S N O O3, CH2Cl2,-78 °C, 15 min, then DMS to rt, 45 min, O [13] O S 117 C20H27NO4S2 (409.56) then conc., then, DBU (2eq), CH2Cl2, -78 °C to rt, 15h 130 C12H20O2 (196.29) Oxacyclotridec-3-en-2-one: A stirred solution of undec-10-enyl(1,3benzothiazol-2-ylsulfonyl)acetate (276 mg, 0.675 mmol) in CH2Cl2:MeOH (4:1, 20 mL) was subjected to O3 for 15 min. Bubbled argon through solution for 5 min. Then DMS (0.5 mL) was added all ta once. The resulting solution was allowed to stri at -78 °C for 50 min, then warmed to rt for 45 min. Solution was concentrated in vacuo. Concentrate was then diluted into CH2Cl2 (15 mL) and cooled to – 78 °C under an argon atmosphere. To this was added 1,8- diazabicyclo[5.4.1]undecene (206 mg, 1.35 mmol) and allowed the solution to warm to rt over 3 h. Stirred solution at rt for 30 min, then the reaction was quenched by the addition of sat. NH4Cl solution and allowed to stir for 0.5 h. Extracted organic 3x using CH2Cl2, combined layers and washed with brine. Organic layers were removed, dried (Na2SO4), and filtered by vacuum. Solution was concentrated in vacuo to afford 341 mg of light yellow oil (Z:E crude = 83:17). 1H NMR (300 MHz, CDCl3) δ 6.24-6.10 (1H, m), 5.40-4.88 (1H, m), ~ 4.17, ~ 2.54, ~1.67, 1.49-1.18 (m) ppm 75 Laboratory notebook reference: HG-125 O O2 S N S O O O O O DBU (2eq), CH2Cl2, -78 to rt, 15h O 133 C17H30O3 (282.42) 132 C24H35NO6S2 (497.67) (Z)-Oxacyclotridec-3-en-2-one: diazabicyclo[5.4.1]undecene A (37 stirred mg, solution 245 of 1,8- mmol) and dimethylaminopyridine (5 mg, 41 mmol) in CH2Cl2 (3 mL) at -78 °C under argon was treated by a solution of 9-oxononyloxy-1-hexanyl(1,3benzothiazol-2-ylsulfonyl)acetate (61 mg, 123 mmol) in CH2Cl2 (5 mL) over 5 h. The solution was then allowed the solution to warm to rt over 13 h. The reaction was quenched by the addition of sat. NH4Cl solution and allowed to stir for 2 h. Extracted organic 4x using CH2Cl2, combined layers and washed with brine. Organic layers were removed, dried (Na2SO4), and filtered by vacuum. Solution was concentrated in vacuo to afford 52 mg of light yellow oil. Product was further purified by column chromatography (EtOAc/hexanes) to yield the lactone (13.1 mg, 43%) as a white solid (Z:E = 85:15). 1 H NMR (300 MHz, CDCl3) δ 6.14 (1H, dt, J = 11.6, 7.9 Hz), 5.77 (1H, d, J = 11.6 Hz), 4.17 (2H, t, J = 5.9 Hz), 2.54 (2H, t, J = 5.6 Hz), 1.80- 76 0.50 (24H, m) ppm; 13C NMR (75 MHz, CDCl3) δ 167.1 (0), 149.0 (1), 120.6 (1), 70.0 (2), 69.8 (2), 64.0 (2), 29.7 (2), 29.4 (2), 29.3 (2), 28.7 (2), 28.6 (2), 28.5 (2), 28.3 (2), 28.2 (2), 28.0 (2), 25.7 (2), 25.5 (2) ppm; Laboratory notebook reference: HG-64 O2 S N S O O DBU (1.5 eq), CH2Cl2, O Ph 137 C9H8O (132.16) 135 C11H23NO5S2 (389.45) trans-Cinnamaldehyde: H -78 to rt, 15h O A stirred solution of 1,8- diazabicyclo[5.4.1]undecene (75 mg, 492 mmol) in CH2Cl2 (10 mL) at -78 °C under argon was treated dropwise with a solution of 3-phenyl-3oxopropyl(1,3-benzothiazol-2-ylsulfonyl)acetate (131 mg, 328 mmol) in CH2Cl2 (2 mL) over 10 min. The reaction mixture was allowed to warm to rt and spin for 28 h. The reaction was then quenched by the addition of sat. NH4Cl solution and allowed to stir for 0.5 h. Extracted organic 2x using CH2Cl2. Organic layers were removed, dried (Na2SO4), and filtered by vacuum. Solution was concentrated in vacuo to afford 93 mg of light yellow oil. 1H NMR clearly confirmed cinnamaldehyde plus other byproducts. Crude product was further purified by column chromatography (eluting with 25% EtOAc/hexanes) to yield the aldehyde (15.6 mg, 118 mmol, 36%) as clear yellow oil. 77 IR (neat) 3063, 2813, 2731, 1685, 1625, 1451, 1124, 972, 749 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.71 (1H, d, J = 7.7 Hz), 7.60-7.40 (6H, m), 6.72 (1H, dd, J = 15.9, 7.7 Hz) ppm; 13 C NMR (75 MHz, CDCl3) δ 194.0 (1), 153.1 (1), 134.2 (0), 131.5 (1), 129.4 (1), 128.8 (2C, 1), 128.7 (2C, 1) ppm 78 6. References 1. (a) F. Ding, M. P. Jennings Org. Lett., 2005, 7, 2321. (b) K. Shimada, Y. Kaburagi, T. Fukuyama J. Am. Chem. Soc., 2003, 125, 4048. (c) A. B. Smith, III, I. Noda, S. W. Remiszewski, N. 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Rev. 1988, 88, 1423. 88 Appendix 1 H NMR/13C NMR Compound Spectral Data N S 55 O2 S O O 89 N S 55 O2 S O O 90 N S 78 O2 S O OH 91 N S 78 O2 S O OH 92 N S S 83 O O 93 N S S 83 O O 94 N S 85 S O O 95 N S 85 S O O 96 S N S 88 O O 97 S N S 88 O O 98 N S 89 S O OH 99 N S 89 S O OH 100 S 90 N O 101 S 90 N O 102 S 99 N O2 S 103 S 99 N O2 S 104 102 OH 105 102 OH 106 O O 104 O O 107 O O 104 O O 108 105 O O 109 105 O O 110 107 OH 111 107 OH 112 109 OH 113 109 OH 114 S N O2 S O 114 O 115 S N O2 S O 114 O 116 S N O 116 O2 S O 117 S N O 116 O2 S O 118 S N O 115 O2 S O 119 S N O 115 O2 S O 120 S N O2 S 117 O O 121 S N O2 S 117 O O 122 N S O2 S O 118 O O 123 N S O2 S O 118 O O 124 S N O2 S O 119 O O O 125 S N O2 S 123 O O O 126 S N O2 S 123 O O O 127 N S O2 S O 126 O O 128 N S O2 S O 126 O O 129 O 124 O 130 O 127 O 131 O 127 O 132 O 130 O 133 O O 133 O 134 O O 133 O 135 H O 137 Ph 136 H O 137 Ph 137