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Synopsis SYNOPSIS The thesis entitled “Utilization of the nucleophilic potential of the sulfinyl group for the stereoselective synthesis of (+)–zoapatanol, stereotriads from cyclopropylcarbinols and enantioselective synthesis of tamiflu” consists of three chapters. Chapter-I Total Synthesis of (+)-(2’S,3’R)-Zoapatanol In this chapter a brief account of the applications of sulfoxides in asymmetric synthesis, an account of the work carried out by various research groups toward the synthesis of (+)zoapatanol and an elaborate account of the present work is described. Zoapatanol 1 is among the many diterpenoid oxepanes isolated from the leaves of the plant Montanoa tomentosa. Investigators have suggested a potential use of zoapatanol and its bicyclic analogs as anti–fertility agents. Due to its biological activity and novel structure several groups have disclosed the total synthesis of racemic and natural zoapatanol. The issues to be addressed in an efficient synthesis of zoapatanol include, a) the stereocontrolled preparation of the oxepane ring, b) the geometrical isomerism of the allylic system and c) the relative and absolute stereochemistry of the two stereogenic centers on the ring. Figure 1 OR' HO R 3' 2' O O 1 2 3 4 R = (CH3)2C=CHCH2-, R' = H Zoapatanol R = (CH3)2CHC(CH3)=CH-, R' = H Montanol R = H2C=C(CH3)CH(CH3)CH2-, R' = H Tomentanol R = (CH3)2C(OH)CH=CH-, R' = Ac Tomentol By retrosynthetic analysis (Scheme 1) 1 was envisioned to be derived from retron 5 by oxidation of the primary hydroxyl to an acid followed by prenyllithium addition. The oxepane 5 was envisaged to be obtained by a Williamson-type ether synthesis from 6. Compound 6 was envisioned to be obtained by a B-alkyl Suzuki reaction of the organoborane derived from terminal alkene 7 with the iodoalkene 8. The triol derivative 7 was envisaged to be obtained from -hydroxy sulfoxide 9. The iodo compound 8 can be obtained from propargylic alcohol 10. 1 Synopsis Scheme 1 HO P'O OH PO O O OP' O 5 1 PO OP P'O PO OP OP' OP' OH 6 I OP' 8 7 X P, P' =Protecting group X = Leaving group O S Tol OPMB OH HO 10 OP 9 The synthesis commenced with the reaction of 9-BBN dimer with PMB ether 14 to afford the trialkylborane that was subjected to Suzuki-cross coupling with (Z)-vinyl triflate 17 in the presence of Pd(PPh3)4 and K3PO4 to furnish the α,β-unsaturated ester 15. The compound 14 obtained from propionic acid 11 in three steps and (Z)-vinyl triflate 17 was obtained from ethyl acetoacetate 16 following procedures reported in the literature. Scheme 2 LAH, THF, 0 oC-rt NaH, DIPA, nBuLi, THF COOH 11 COOH Allylbromide, 0 0C-rt, 4 h, 93% 12 13 O 9-BBN-H, THF, 0 oC NaH, PMB-Br, TBAI, THF OH 12 h, 91% OEt OPMB OPMB o 0 C-rt, 92% 14 O O 17, K3PO4, Pd(PPh3)4, 1.4-Dioxane, 85 oC, 8h, 74% 15 NaH, DCM, Tf2O OEt 0 oC-rt, 2h, 89% 16 TfO OEt O 17 The addition of lithium anion of (R)-methyl p-tolyl sulfoxide to unsaturated ester 15 in THF at 0 oC afforded -keto sulfoxide 18. Diastereoselective reduction of the keto carbonyl in 18 using DIBAL-H in THF exploiting the sulfinyl group as an intramolecular chiral auxiliary yielded the -hydroxy sulfoxide 9 (dr >95:<5), which on treatment with freshly recrystallized Nbromosuccinimide (NBS) afforded bromohydrin 19 as a single isomer regio- and stereoselectively. To transform bromohydrin 19 to alkene 7 it was required to replace the 2 Synopsis bromine by hydroxy group with inversion of configuration. This called for the chemoselective participation of the secondary hydroxyl group in epoxide formation which on treatment with NaHg would suffer reductive elimination to yield alkene 7 (P = P1 = H). In the event, treatment of bromohydrin 19 with K2CO3 in methanol or acetonitrile yielded epoxide 21 via participation of the tertiary hydroxy group and none of the expected epoxide 20 via participation of the secondary hydroxy group. Further, attempts to protect both the hydroxy groups and subsequently deprotect to reveal the secondary hydroxy group did not meet with success. Therefore the hydroxy sulfoxide 9 was protected as its TBS ether 22 Scheme 4. Scheme 3 O OEt OPMB Tol Tol Me Tol LDA, THF, -40-0 oC, 55% 15 O S O S O S O DIBAL-H, THF OPMB 18 NBS, H2O, Toluene OH OPMB Tol rt, 2 h, 76% X Tol OH K2CO3, MeOH rt, 2 h, (or) K2CO3, AcCN rt, 12 h PMBO O Tol OH OH PMBO OH OP 20 O S O S Br 19 9 O S 1 h, -78 oC, 81% PMBO 7 OH O 21 PMBO Treatment of silyl ether 22 with freshly recrystallized N-bromosuccinimide (NBS) in toluene at ambient temperature in the presence of water afforded bromohydrin 23 as a single regio- and stereoisomer. The tertiary hydroxy group in bromohydrin 23 was protected as an acetal 24 by treatment with ethyl vinyl ether in the presence of cat CSA in CH2Cl2. Treatment of 24 with TBAF afforded 1,2–diol derivative 26 via three transformations in one pot including silyl deprotection followed by epoxide formation under basic conditions and further – elimination. 3 Synopsis Scheme 4 Tol O S OH TBS-Cl, Imidazole OPMB Tol DCM, 1 h, rt, 93% O S OPMB rt, 2 h, 76% 22 9 Tol O S NBS, H2O, Toluene OTBS OTBSOH Cat CSA, Br O Tol O S OTBSOEE 0 oC, 1 h, 88% PMBO PMBO Br 24 23 O TBAF, THF rt, 30 min, 86% Tol PMBO O S Tol OEE H O S OEE OH PMBO 26 25 Oxidation of vinyl sulfoxide 26 using mCPBA in CH2Cl2 afforded the sulfone 27 that on treatment with Mg-Hg in methanol afforded terminal alkene 28. Protection of hydroxy group as its acetate yielded compound 7, Scheme 5. Scheme 5 Tol O S O S Tol O OEE mCPBA, DCM OH PMBO 0 oC-rt, 30 min, 92% OEE OH Mg, HgCl2, MeOH PMBO 0 oC-rt, 4 h, 76% 27 26 OEE OEE Ac2O, Et3N, cat DMAP, DCM OH 28 PMBO 0 oC-rt, 1 h, 94% OAc 7 PMBO The iodo alkene 8 was prepared as detailed here under. Monoprotection of the commercially available diol 10 as its silyl ether using sodium hydride and TBS-Cl in THF afforded 29. Propargylic alcohol on treatment with Red-Al in THF followed by quenching the intermediate with iodine in THF afforded iodo compound 30 that on acetylation furnished iodo alkene 8. 4 Synopsis Scheme 6 HO TBS-Cl, NaH, THF OH 10 TBSO 0 C-rt, 14 h, 72% H I Red-Al, THF, I2 HO o Ac2O, Et3N, Cat DMAP, DCM OH 29 OTBS TBSO H I 0 oC-rt, 1 h, 97% 30 -78 oC, 2 h, 78% OAc 8 Hydroboration of alkene 7 with 9-BBN dimer in THF afforded organoborane intermediate 31 that was coupled with iodo compound 8 using Suzuki reaction in the presence of K3PO4 and Pd(PPh3)4 in 1,4-dioxane to furnish trisubstituted alkene 32 with concomitant deprotection of acetal group under reaction conditions (Scheme 7). The primary TBS ether in 32 was selectively deprotected using catalytic amount of PPTS in methanol to furnish the diol 6. With the diol 6 becoming available the stage was set to attempt the crucial Williamson-type ether reaction. Thus treatment of 6 with triflic anhydride in the presence 2,6-lutidine in CH2Cl2 afforded the oxepane 5 cleanly (Scheme 7). The 4-methoxybenzyl group of compound 5 was deprotected with the use of DDQ in aq dichloromethane to afford the alcohol 33. Scheme 7 OEE OEE 9-BBN, THF OAc PMBO TBSO H NBB OAc 3 h, 0 oC 7 I PMBO OAc 8 31 OAc OAc K3PO4, Pd(PPh3)4, 1,4-dioxane OH 8 h, 85 oC, 66% rt, 30 min, 86% OTBS OAc OH cat PPTS, MeOH PMBO OH OAc 6 32 AcO PMBO AcO OAc Tf2O, 2,6-Lutidine OAc DDQ, DCM:H2O (19:1) O DCM, -78 oC, 6 h, 68% OPMB 0 oC,30 min, 91% 5 O OH 33 Oxidation of the alcohol 33 using TEMPO in the presence of PhI(OAc)2 in aq acetonitrile afforded the acid 34. Following the precedent of Chen, reaction of prenyl lithium with acid 34 in a mixture of THF and ether afforded (+)-zoapatanol in only 40% yield. In an attempt to improve the yield the acid was converted to Weinreb amide 35 by treatment with MeNHOMe.HCl, iPr2NEt and EDCI in CH2Cl2. Reaction of prenyl lithium with Weinreb amide 35 in a mixture of 5 Synopsis THF and diethyl ether (1:1) at -78 oC furnished the (+)-zoapatanol by concomitant deprotection of both acetyl groups in 72% yield. The yield was much better using Weinreb amide. Scheme 8 AcO OAc AcO PhI(OAc)2, TEMPO, aq CH3CN OH HO O rt, 4 h, 93% O O 33 AcO H MeNOMe.HCl, EDCI, cat DMAP iPr2NEt, DCM, Me 0 oC-rt, 12 h, 82% OMe N O O 35 34 HO Li AcO OAc THF:Ether (1:1) -78-0 oC, 2 h, 72% OH O O 1 In conclusion, a short stereoselective efficient synthesis of zoapatanol (2.8% overall yield in 20 steps) was achieved. The key steps include the stereo– and regioselective functionalization of a trisubstituted alkene to create a quaternary stereogenic center, a B–alkyl Suzuki coupling reaction to create trisubstituted alkenes stereoselectively. Another interesting feature of the synthesis is the one-pot transformation of compound 24 to 26. Also the methodology can be applied in the synthesis of other oxepane diterpenoids and analogs of zoapatanol. Chapter-II Regio- and stereoselective cyclopropylcarbinols activated preparation by of mercuric stereotriads and tetrads from trifluoroacetate via sulfinyl group participation. This chapter deals with the preparation of stereotriads and tetrads consisting of alternating hydroxyl and methyl groups from cyclopropylcarbinols. Alternating hydroxy and methyl substituted subunits are a characteristic feature of polypropionate derived natural products. The importance of these natural products as antibiotics, antifungals, antitumors, antiparasitics and immunosuppressants together with their structural and stereochemical complexity has led to the design and development of several unique methodologies to prepare these structures. A common strategy has been the disconnection of the polypropionate chain into smaller subunits containing alternating methyl and hydroxy groups and uniting them by coupling reactions. In an abiding interest in utilizing the sulfinyl group as an intramolecular nucleophile, the oxymercuration–demercuration of cyclopropylcarbinols was investigated with the aim of obtaining products possessing alternating hydroxy and methyl groups as observed in 6 Synopsis polypropionate derived natural products. This chapter includes the regio- and stereospecific opening of cyclopropylcarbinols by an intramolecular sulfinyl group promoted by mercuric trifluoroacetate to furnish stereotriads and stereotetrad, Scheme 9. Scheme 9 Tol O S OH 1. Hg(OCOCF3)2, HgO, 1.2-DCE R2 3 R 2. Aq KBr 3. nBu3SnH, cat Et3B, O2, DCM R1 Tol O S OHHO 2 R R3 R1 The cyclopropylcarbinols were prepared from the corresponding allylic alcohols using the Furukawa’s protocol. The trans di- and trisubstituted allylic alcohols were prepared as depicted in Scheme 10. The -keto sulfoxides 38 a-d were prepared by reaction of the lithium anion of the (S)-methyl-p-tolylsulfoxide 36 with trans unsaturated esters 37 a-d following the protocol reported by Solladie and co-workers. Scheme 10 O Tol O S 36 R1 LDA,THF EtO Me 2 R R 37 a-d -40 oC-0 oC Tol O S R1 O DIBAL-H R 38 a-d a: R = R1 = H, R2 = CH2Ph b: R = R1 = H, R2 = OBn c: R = Me, R1 = H, R2 = (CH2)4Me d: R = H, R1 = Me, R2 = OBn R 2 ZnCl2, THF Tol O S OH R R1 R2 39 a-d (E)--Hydroxy-,-unsaturated sulfoxides 39 a-d were prepared by diastereoselective reduction of ketones 38 a-d respectively using DIBAL-H in the presence of ZnCl2 in THF with (>95:<5) diastereoselectivity, Scheme 10. The cis disubstituted allylic alcohols were prepared by selective reduction of propargylic alcohols. The aldehyde 40 upon subjecting to the Corey–Fuchs reaction afforded dibromo compound 41, that on further treatment with nBuLi in THF and quenching with acetaldehyde provided an inseparable mixture of propargylic alcohols 42 & 43 in equimolar amounts. The propargylic alcohols 45 & 46 were prepared as an epimeric mixture in equimolar proportion and good yield by condensing the lithium anion of the sulfoxide 36 with the aldehyde 44, Scheme 12. 7 Synopsis Scheme 11 Ph S H O 40 Ph Ph Br S 0 oC, 1h, 95% S Ph 42 Tol CBr4, TPP, DCM S 43 OH OH LDA, THF + Me 44 36 -78 oC, 1h, 80% Br 41 O O S n-BuLi, CH3CHO, THF ( )Me 5 Tol -40--78 oC, 1h, 86% O S O S OH Tol 46 ( ) 5 45 OH ( ) 5 The inseparable mixture of propargylic alcohols 42 & 43 were subjected to reduction with nickel boride to afford an equimolar ratio of separable allylic alcohols 47 & 48. In a similar fashion propargylic alcohols 45 & 46 were also transformed into an equimolar ratio of separable allylic alcohols 49 & 50. Scheme 12 Ph OH S Ni(OAc)2.4H2O, NaBH4, 42 & 43 Tol O S Ph Ethanol, Ethylenediamine rt, 8h, 85% OH Ph Ni(OAc)2.4H2O, NaBH4, O S Tol Ethanol, Ethylenediamine rt, 8h, 89% ( ) 5 S 47 OH 45 & 46 OH S 48 OH ( ) 5 Tol O S 49 OH ( ) 5 50 The epimeric inseparable mixture of sulfoxides 51 & 52 were prepared by subjecting both the sulfides 47 & 48 to treatment with mCPBA in CH2Cl2 Scheme 13. Scheme 13 OH Ph S OH Ph Ph O S 1h, 92% 47 S mCPBA, CH2Cl2, -40 oC 51 o mCPBA, CH2Cl2, -40 C 1h, 90% 48 8 OH Ph O S OH 52 Synopsis Preparation of cyclopropylcarbinols. Cyclopropylcarbinols 53-60 were prepared from the corresponding allylic carbinols using Furukawa’s protocol in yields ranging from 83-92%, Scheme 14. Scheme 14 O S Tol OH R1 R2 Tol DCM, 0 oC - rt R 39 a-d O S Et2Zn, CH2I2, 1,2-DME R1 OH R2 R 53-56 R1, R2 = H, Me R3 = alkyl, OBn Isomeric cyclopropylcarbinols were prepared by oxidation followed by diastereoselective reduction of some cyclopropylcarbinols to study the influence of relative stereochemistry of sulfoxide and carbinol centre on product formation. Thus cyclopropylcarbinols 53, 55-58 were converted to cyclopropylketones 61-65 under mild conditions by treatment with Dess-Martin periodinane (DMP) in CH2Cl2 in good yield, Scheme 15. Scheme 15 Tol O S OH R1 R2 R 53, 55, 56 Tol O S OH DMP, DCM 0 oC - rt, 30 min Tol O S R2 R 61-63 R1, R2 = H, Me R3 = alkyl, OBn DMP, DCM 0 oC - rt, 30 min, 89% R1 O Tol O S O 57 Tol O S OH 64 DMP, DCM 0 oC - rt, 30 min, 91% Tol O S O 65 58 Diastereoselective reduction of ketones 61-63 & 65 using DIBAL–H in THF yielded cyclopropylcarbinols 66-68 & 70. In a similar manner diastereoselective reduction of 64 using DIBAL-H in the presence of anhydrous ZnCl2 furnished alcohol 69. 9 Synopsis Scheme 16 Tol O S R1 O R2 R 61-63 Tol O S DIBAL-H, THF Tol -78 oC, 1 h O S R1 OH R2 R 66-68 R1, R2 = H, Me R3 = alkyl, OBn O DIBAL-H, ZnCl2, THF Tol O S OH -78 oC, 1 h, 90% 69 64 Tol O S O DIBAL-H, THF Tol -78 oC, 1 h, 86% O S OH 65 70 Oxymercuration–Demercuration of Cyclopropylcarbinols Treatment of cyclopropane 57 with 2 eq of mercuric trifluoroacetate in the presence of 0.5 eq of mercuric oxide, 1.3 eq of water in 1,2-dichloroethane as the solvent in the dark overnight, afforded organomercurial 71 after treatment with aq potassium bromide. Demercuration of 71 using lithium borohydride yielded 1,3-diol 72 as the sole product. Scheme 17 XHg Tol O S OH Hg(OTFA)2, HgO 57 Tol O S OH OH HO S O H H2O, 1,2-DCE, 16 h, rt, 89% 2O Tol I LiBH4, THF, -78 oC 1 h, 85% HgBr 71 Tol O S OH 5 OH 72 While compound 71 was characterized, the organomercuric bromides resulting from other cyclopropylcarbinols were not characterized and directly subjected to demercuration using n– tributyltin hydride in the presence of catalytic amounts of triethylborane in an oxygen atmosphere. Demercuration using LiBH4 afforded trace amounts of sulfide via sulfoxide reduction, and this side reaction could be avoided using tributyltin hydride for demercuration. 10 Synopsis The results are collected in Table 1. An examination of the Table 1 reveals that the reaction is general in nature and proceeds with equal facility on di– and trisubstituted cyclopropylcarbinols. The reaction proceeds highly regioselectively and the outcome can be rationalized by the destabilizing inductive effect of the hydroxy/stabilizing inductive effect of the methyl groups. The reaction proceeds with clean inversion of configuration at the electrophilic carbon and sulfur atoms. Table-1: Mercuric Trifluoroacetate Promoted Sulfinyl Group Opening of Cyclopropylcarbinols S. No 1. O S Tol OH Tol O S OH 2. Tol 72 OH Tol O S OH 3. Tol 73 OH Tol O S OH 4. 5. Tol Tol 74 OH Tol O S O S OH 6. Tol 75 70 OH Ph Tol O S OH 7. Tol OH 78% Ph 76 OH Tol Ph O S 66 O S OH 75% 53 O S OH 82% 69 O S OH 84% 58 O S OH 85% 57 O S Yield Product Cyclopropylcarbinol OH OH Ph 73% 77 OH OBn Tol 54 O S OH OBn 78 11 OH 76% Synopsis 8. O S Tol OH ( )5 O S Tol OH OH 67 9. O S Tol 70 OH ( )5 O S Tol 10. Tol OH OBn Tol O S 56 11. Tol O S OH OH ( )5 74% 80 55 O S 72% ( )5 OH OH OBn 76% 81 OH OBn Recovery of Starting Material 68 12. Ph O S OH Recovery of Starting Material 59 13. Ph O S OH Ph O S 83% OH 82 60 BocN 14. Tol OH OH S Recovery of Starting Material Ph 83 BocN 15. Tol OH S 5 Recovery of Starting Material 84 The regio- & stereochemical outcome of the reaction of 57 with Hg(OCOCF3)2 entry 1, Table 1 can be rationalized by invoking intermediate I, resulting from 6-endo nucleophilic attack by the sulfinyl moiety on the cyclopropane ring Scheme 17. As Table 1 indicates, the reaction is general in nature and proceeds with equal facility on di– and trisubstituted cyclopropylcarbinols. The structure of diol 76, obtained from 53, was 12 Synopsis proven by X-ray crystallography. The structure of the other products were assigned based on analogy and further confirmed by 1H NMR–NOE analysis of the acetonides derived from the diols. In conclsion, a highly regio– and stereoselective synthesis of diastereomeric stereotriads and tetrads by oxymercuration–demercuration of cyclopropylcarbinols employing an intramolecular sulfinyl group as the nucleophile has been disclosed. The reaction proceeds with equal facility on di– and trisubstituted alkenes to furnish products possessing tertiary and quaternary stereogenic centres. The reaction can be considered to be complimentary to other routes to stereotriads/stereotetrads such as the two step epoxidation followed by dimethyl cuprate opening of allylic alcohols, hydroboration and hydrosilylation reactions. Chapter-III Enantioselective Synthesis of Tamiflu In this chapter a brief account of the synthesis of tamiflu by selected research groups is described followed by and an elaborate account of the present work. Oseltamivir phosphate (Tamiflu) 85, is an approved orally effective neuraminidase inhibitor used for the treatment of human influenza and H5N1 avian flu. Numerous people have fallen victim to human influenza and H5N1 avian flu and it still continues to be a threat. A ready stock of Tamiflu is desirable to protect people from a future outbreak. Currently, tamiflu is manufactured from (–)-shikimic acid or (–)-quinic acid, however the limited availability of raw material, low overall yield and long synthetic sequences have propelled synthetic chemists worldwide to design alternate routes from non-natural readily available chemicals. An enantioselective synthesis of tamiflu taking advantage of the Diels–Alder reaction is described herein. Figure 2 COOEt O AcHN NH2 85 Oseltamivir By a retrosynthetic analysis, shown in Scheme 18, tamiflu 85 was envisioned to be derived from the unsaturated ketone 86 which can be obtained from the aziridine 87 by 13 Synopsis regioselective opening followed by oxidation. The aziridine 87 was envisaged to be obtained from the epoxycarbamate 88. The epoxidation was planned to be carried out stereoselectively by taking advantage of the directing ability of the precursor allylic carbamate. The carbamate itself was prepared by asymmetric palladium catalyzed reaction of allylic acetate with a nitrogen nucleophile derived from hydroxyl ester 89 with retention of configuration. The hydroxyl ester 89 can be readily obtained from cyclohexene carboxylic acid 90. Scheme 18 CO2Et O CO2Et O CO2Et CO2Et AcN AcHN O AcHN NH2.H3PO4 85 NHBoc NHBoc NHBoc 86 87 88 CO2Et COOH 90 OH 89 To begin with, to standardize reactions racemic substrates were employed. Commercially available cyclohexene carboxylic acid 90 on iodolactonization by treatment with sodium bicarbonate, iodine and KI in the presence of water afforded iodolactone 91. Iodolactone 91 was subjected to dehydroiodination using DBU as a base to yield unsaturated lactone 92. Base promoted opening of unsaturated lactone 92 with K2CO3 in ethanol furnished allylic alcohol 89 that upon treatment with acetic anhydride, triethylamine in presence of CH2Cl2 yielded acetate 93. Allylic substitution of the acetate in ester 93 using Pd2(dba)3, dppb and sodium azide in mixture of THF:H2O mixture afforded allylic azide 94 with the retention of stereochemistry. Scheme 19 O O OH I2, NaHCO3, KI, H2O rt, 6 h, 110 oC, 97% DBU, Toluene O 91 90 K2CO3, EtOH 5 h, rt, 90% 20 h, 98% I OH O O 92 N3 OAc Ac2O, Et3N, Cat. DMAP, DCM NaN3, Pd2(dba)3.CHCl3 0 oC - rt, 1 h, 96% 93 CO2Et dppb, THF:H2O (9:1) 80 oC, 6 h, 78% 14 CO2Et 89 CO2Et 94 Synopsis Azide 94 was chemoselectively reduced using Lindlar’s catalyst to afford free amine which was protected with (Boc)2O under basic conditions to afford carbamate 95. Stereoselective epoxidation directed by the carbamate moiety using mCPBA in dichloromethane furnished the epoxide 88. Epoxide 88 was converted to azido alcohol 96 by using ammonium azide in aq ethanol. The azido group in 96 was reduced to the corresponding primary amine using Pd/C in EtOAc under hydrogen atmosphere, and further converted to acetamide 97 under standard conditions. The next objective was to prepare aziridine 87 from amide 97 and subject it to regioselective opening with an oxygen nucleophile. To this end the carbinol 97 was converted to mesylate, subsequent treatment with sodium hydride furnished aziridine 87. With aziridine 87 in hand, the stage was set to carry out the crucial opening with water under Lewis acid conditions. Aziridine 87 on treatment with BF3.OEt2 in CH2Cl2 in the presence of water as the nucleophile afforded amino alcohol 97 instead of 98. Scheme 20 N3 NHBoc NHBoc 0 oC-20 oC, 91% CO2Et (Boc)2O, Et3N, DCM, rt, 1 h, 87% 94 95 CO2Et CO2Et CO2Et aq EtOH, 70 oC, 72% 88 HO H2, Pd/C, 1 h, EtOAc N3 O NHBoc NHBoc NHBoc HO NaN3, NH4Cl mCPBA, DCM H2, Pd-BaSO4, EtOAc, rt, 5 h, Ac2O, Et3N, DCM, rt, 1h, 76% 1. Ms-Cl, Et3N, DCM AcHN CO2Et 97 96 AcN 2. NaH, THF CO2Et 87 NHBoc HO AcHN BF3.OEt2, H2O, CO2Et 97 DCM, -24 oC NHBoc AcHN HO CO2Et 98 Having been unsuccessful in opening the aziridine regioselectively to secure 98, an alternate route was designed for the synthesis of tamiflu 85. The revised strategy was based on exploiting the Mitsunobu reaction to introduce the amino group with inversion of carbinol configuration. The retrosynthesis is depicted in Scheme 21. Tamiflu 85 was envisioned to be obtained by regioselective opening of aziridine 99. Compound 99 can be obtained from azido 15 Synopsis alcohol 100 which inturn was envisaged to be obtained by regioselective opening of epoxy carbamate 101. Carbamate 101 was traced to Diels-Alder adduct 103. Scheme 21 CO2Et O CO2Et CO2Et HO CO2Et O AcN AcHN N3 NH2.H3PO4 NHBoc NHBoc 85 NHBoc 101 100 99 CO2Et O O OH O 102 O 103 The synthesis of Diels-Alder adduct 103 began with (S)-pantolactone 104 that was subjected to treatment with propenoylchloride in the presence of triethylamine in anhydrous CH2Cl2 to afford acrylate ester 105. Treatment of 105 with an excess of butadiene in presence of TiCl4 in anhydrous CH2Cl2 following Helmchen’s protocol afforded the Diels-Alder adduct 103. Basic hydrolysis of Diels-Alder adduct 103 using LiOH.H2O in THF/H2O mixture yielded carboxylic acid 106. The acid 106 was subjected to iodolactonization afforded the iodolactone 107. Iodolactone 107 on dehydroiodination using DBU as a base yielded unsaturated lactone 108. Scheme 22 O Cl OH O O 104 O O DCM, -24 oC, 6 h, 85% O 105 -20 oC, 48 h, 72% O O 103 O O OH O DBU, Toluene NaHCO3, I2, KI H2O, rt, 20 h, 98% THF:H2O, rt, 26 h, 97% O O O O LiOH.H2O, O TiCl4, DCM: Hexane , Et3N 106 105 oC, 6 h, 97% I 107 108 Unsaturated lactone 108 was converted to hydroxyl ester 102 using K2CO3 in ethanol. Treatment of 102 with BocNHNS-p, TPP and DEAD in toluene afforded sulfonamide 109. The sulfonamide 109 was deprotected by treatment with 2-mercapto ethanol and DBU in acetone to afford the carbamate 110. Carbamate 110 was subjected to stereoselective epoxidation using 16 Synopsis mCPBA directed by the carbamate moiety in dichloromethane to afford the epoxide 101. Epoxide 101 on treatment with TMSN3 in the presence of Ti(OiPr)4 in benzene afforded the regioisomeric azido alcohols 100 & 111 in a 3:1 ratio respectively. Scheme 23 p-Ns O O OH K2CO3, EtOH rt, 5 h, 90% CO2Et DBU, 2-Mercaptoethanol Acetone, rt, 3 h, 90% CO2Et PPh3, Toluene, -24 oC, 6 h, 85% 102 108 109 NHBoc NHBoc mCPBA, DCM CO2Et 0 oC, 6 h, 83% NHBoc Ti-(iOPr)4, TMSN3 O NHBoc N3 HO o Benzene, 5 C-rt, 2 h, 86% CO2Et 101 110 Boc N H BocN-NS-p, DEAD HO CO2Et N3 100 CO2Et 111 : 3 1 Initially azido alcohol 100 was taken ahead. It was planned to oxidize the alcohol and dehydrogenate the resulting ketone using Nicolaou’s protocol. Thus azidoalcohol 100 on treatment with IBX (2.5 eq) in toluene/DMSO mixture afforded a complex mixture of products, Scheme 24. Attempted dehydrogenation in the presence of 4-methoxy pyridine N- oxide and IBX also failed to afford 112 cleanly. It was therefore decided to protect the azidoalcohol 100 as its trimethylsilyl ether and proceed further. NHBoc Scheme 24 N3 NHBoc N3 1. IBX , Toluene:DMSO (2:1), 75 oC, 3 h HO CO2Et 100 O CO2Et 112 o 2. IBX, MPO, DMSO, rt 2h, 70 C 3 h Complex Mixture Thus azidoalcohol 100 was subjected to treatment with trimethylsilyl chloride and triethyl amine in anhydrous DCM to afford the TMS ether 113 (Scheme 25). TMS ether 113 was subjected to treatment with lithium diisopropylamide in THF followed by phenylselenyl bromide to afford the selenyl compound 114. The selenyl compound 114 on treatment with hydrogen peroxide and pyridine in dicloromethane afforded an inseparable mixture of regioisomeric unsaturated esters 115 and 116 in a 2:3 ratio respectively. The mixture of unsaturated esters 115 and 116 were treated with catalytic amounts of DBU in toluene to afford the unsaturated ester 115. Unsaturated ester 115 was subjected to treatment with triphenylphosphine in toluene under Staudinger’s condition to afford aziridine 117. 17 Synopsis Scheme 25 NHBoc NHBoc NHBoc TMS-Cl, Et3N, DCM N3 LDA, PhSeBr, THF N3 TMSO CO2Et SePh CO2Et -78 oC, 30 min, 74% 0 oC, 30 min, 95% HO N3 HO CO2Et 114 113 100 NHBoc NHBoc N3 N3 H2O2, Py, DCM rt, 30 min, 76% HO 115 DBU, Toluene HO CO2Et 2 : 3 NHBoc Inseparable Mixture TPP, Toluene 105 oC, 3 h, 85% NHBoc N3 116 CO2Et 24 h, rt, 65% HO 115 CO2Et HN CO2Et 117 At this stage, the conversion of regioisomeric azido alcohol 111 to aziridine 117 was explored. Azidoalcohol 111 on treatment with trimethylsilyl chloride and triethylamine in anhydrous DCM afforded the TMS ether 118 (Scheme 26). TMS ether 118 was subjected to treatment with lithium diisopropylamide in THF followed by phenylselenyl bromide to yield 119 as the sole product. The selenyl compound 119 on treatment with hydrogen peroxide and pyridine in DCM afforded an inseparable mixture of regioisomeric unsaturated esters 120 and 121 in a 1:3 ratio respectively. The mixture was subjected to treatment with triphenylphosphine in toluene to afford the aziridines 117 and 122. These could be separated by column chromatography the aziridine 122 was isomerized using DBU to afford the required aziridine 117. Scheme 26 NHBoc NHBoc TMS-Cl, Et3N, DCM HO N3 TMSO 0 oC, 30 min, 94% CO2Et N3 CO2Et NHBoc rt, 30 min, 76% -78 oC, 30 min, 58% HO 119 NHBoc NHBoc HO N3 TPP, Toluene CO2Et N3 CO2Et 121 120 SePh CO2Et N3 118 111 H2O2, Py, DCM NHBoc HO LDA, PhSeBr, THF 1 : 3 105 oC, 3 h, 85% NHBoc HN HN 117 CO2Et 122 Separable Mixture DBU, Toluene Inseparable Mixture rt, 24 h, 58% 18 CO2Et Synopsis The aziridine 117 was protected as its acetate 99 by treatment with acetic anhydride and triethylamine in DCM, Scheme 27. The compound 99 was transformed into 123 following Shibasaki’s protocol. Thus treatment with 3-pentanol in the presence of BF3.OEt2 afforded ether 123. Finally deprotection of Boc group in 123 using trifluoroacetic acid in DCM afforded amine as its trifluoroacetate salt which on treatment with a base and then with H3PO4 in ethanol provided tamiflu 85. The physical data of 85 were in full agreement to those reported in the literature. Scheme 27 NHBoc NHBoc NHBoc Ac2O, Et3N, DCM, Cat DMAP HN CO2Et 3-Pentanol, BF3.OEt2 AcN 0 oC - rt, 30 min, 87% CO2Et 99 117 -20 oC, 30 min, 70% AcHN O CO2Et 123 NH2.H3PO4 CF3COOH, DCM, rt H3PO4, EtOH, 50 oC, 71% AcHN O CO2Et 85 In conclusion, a new stereoselective synthesis of tamiflu was achieved from (-)-cyclohexene carboxylic acid using an asymmetric Diels-Alder reaction. The regioisomeric azido alcohols 100 and 111 converged to yield the same aziridine 117. Attempts to introduce a double bond regioselectively using IBX as an oxidant following Nicoloau’s protocol afforded a complex mixture of products. The regioisomeric unsaturated esters could be prepared by selenenylation followed by elimination of selenoxide to afford isomeric esters that were isomerized to the desired product. The overall yield was 2.8%. 19