Solutions Manual for MODERN ORGANIC SYNTHESIS: An Introduction Michael H. Nantz, University of Louisville Hasan Palandoken Western Kentucky University George S. Zwiefel University of California, Davis W.H. Freeman and Company ‘New YorkISBN 13: 97807167-7494-5, ISBN 10: 0-7167-7494-1 (© 2006 by W. H, Freeman and Company All rights reserved Printed in the United Sates of America First printing W. H, Freeman and Company 41 Madison Avenue [New York, NY 10010 Houndaulls, Basingstoke RG21 GXS, England vwoywrwhfreeman.comContents Preface iv CHAPTER. SYNTHETIC DESIGN Il CHAPTER 2, STEREOCHEMICAL CONSIDERATIONS IN PLANNING ‘SYNTHESES 2 CHAPTER 3. THE CONCEPT OF PROTECTING FUNCTIONAL GROUPS 40 CHAPTER 4. FUNCTIONAL GROUP TRANSFORMATIONS: OXIDATION AND REDUCTION 55 CHAPTER 5. FUNCTIONAL GROUP TRANSFORMATIONS: "THE CHEMISTRY OF CARDON-CARBON x-BONDS AND RELATED REACTIONS CHAPTER 6, FORMATION OF CARBON-CARBON SINGLE BONDS VIA ENOLATE ANIONS: 107 CHAPTER 7. FORMATION OF CARBON-CARBON BONDS VIA ORGANOMETALLIC REAGENTS 136 CHAPTER 8, FORMATION OF CARHON-CARHON #-BONDS 165 CHAPTER 9, SYNTHESES OF CARBOCYCLIC SYSTEMS 186Preface How docs an organic chemist go about synthesizing a desired molecule? The goal of this Solutions Manual is not only to provide you with the “correct” answers to end-of- chapter problems, but also fo give you the opportunity to develop a methodical approach to symthesizing @ given target molecule using the tools and concepts covered in Modern Organic Synthesis: An Introduction. ‘We assume that th student is well acquainted with the basic concepts of organic chemistry taught atthe sophomore level, The introductory chapters provide step-by-step solutions to illustrate how a problem is broken down to smaller problems and solved. Later chapters assume the student is well versed in the concepts covered inthe previous chapters; however, the key steps involved in the solutions are highlighted. Throughout the manual, literature references are provided for problems that have been inspired by “real” world examples. ‘To assimilate synthetic methodologies and to integrate them into @ synthetic design requires actual problem solving and not merely looking at the text. Only by ‘writing the answer do we pay attention to details such as proper choice of reagents, ‘reaction conditions, mechanistic implications, and so forth. Thus its important that you refer tothe Solutions Manual only ater you have made a real effort to solve the problem, ‘or simply to verify that your approach is the same as or even Better than the one presented inthe manual. We are grateful to the Chemistry 131 students at UC Davis and especially 10 the tesching assistants of the course for their suggestions and contributions to the development of the problem sts. ‘Michael Nantz, Hasan Palandoken and George Zweifel, Tune 2006‘ABBREVIATIONS he. sey cate DMs ety ie Piven fo sic DMSO ollie PN tanta BN 2 nbioluroile DS. eet ety PTS oni fdas ce enatome ce lennon [Athenee “ “selene FP ci miro Bo eat IeProcomcl eT Boag EWG een viene ep fing er qa ih SUN Shoat ATmaRe FO fol pop rr Upbeat 9 Bn ent ‘ new Penn og atten i esi REN Raney ice (aly te. oti on MPN peameyipgponie Witgpe) BPs ciety HQ. Apogee REM ont oa ne) hy, ‘be ‘mete Bronce TX odoesbenele a Re Ant bi ett Indo amie (@-hosyeoxy) fr ten pe oceangeyt lenis die hneaile ADA pe * soon ergoiee B52 moteane ‘isowopylanie SAB Step ae Gin emplogentong KHIMDS satu ‘poscaon (COL enim eemetyide Stent eae Oncaea Leslie. ti SE rma yebony ©. ‘yeep ar ube ‘nett Ci ocamphlose wed LAK ont lamin ee ‘ineny ADCO. —naiee(222hetme LDA sapopytamise wi tyme DENA. LSdiaabeyel(4s0) LIMBS. Hien The onsen ee a DBL asoabaeabeyeS40)———ACPBA anaemia TES ehyla once Meson ma Thane Leiden MEM 2-neoryetboymetyl TFA tot i Dog Aetna mele TTEAA een aye itbenmanane MO. TH ey &, seer ens moni ot TP teanyoprn DEAD. at wnnetonyite Meno etanemleey) Thx. they CHM.) DET, et se MS. aoeear sees TS pron Ditty RaShgdo 2H pan MVE ami a one TDMEDA NDA sty IAD —liaopops emsoboqiae NDS. atremowecnne ‘edanine DIBA Hlieterysninmhyige NCS. ederim IMS noone IPT. aieprey tate RMON ‘MST ines DMAP -dimelamineyine Moxie ‘iowonebareatonse MDO—sinetsxiane NMP ent maiioe TRAP ot peymanion DME. aborgetiane OC, psi lero ‘een DMP Nslineigomeniée FDC. bom Tana igen) DMP. Dewi godine RG preci gp te tn (ptlenrly) DMPC NDP aimayeoplnees Phony 2 estCHAPTER 1 Synthetic Design Overview Chapter 1 focuses on how to design and execute the synthesis ofa variety of target molecules (TM) using the tools and strategies you encountered in ‘Modern Organic Synthesis: An Introduction. Problem 1 (Functional Group Interconversions) introduces how to recognize precursors of Key functional groups present in a target molecule. Problem 2 (Uimpoling) highlights the use of carbonyl group polarity reversal, an important synthetic tool. Problem 3 (Retrosyathetic Analysis) stresses approaches to disassembling a target molecule into simpler fragments and ultimately into starting materials. Problem 4 (Synthesis) provides the opportunity to put into practice these concepis by designing protocols for the syntheses of various target ‘molecules. Key Concepts Retrosynthetic analysis Synthetic equivalent (SE) Functional group interconversion (FGI) Carbony! group polarity reversal (Umpotung)2 + Chapter Syatati Design SOLUTIONS TO CHAPTER 1 PROBLEMS ‘The more challenging problems are identified by an asterisk (*). 1, Functional Group Interconversion. Show how each ofthe following, ‘compounds can be prepared from the given starting material CXCH} OH —= EIO,C(CH.ICN Solution: Fis in this problem: 41. Primary (1) a choi to ety! ester 2.12 aloorol tonite Q 0° 4c), 1, DHP_, cat. T20H, by CHCHAOM Fe ES EIOACICH AON SEE EIOCICH:ACN 2.603 aso. 23, EI0H, cat, HeS0g Step 1 ‘The 1° alcohol is protected with dihydropyran (DHP). Step2a Reaction of an alkyl chloride with magnesium (Mg) provides the corresponding Grignard reagent (conversion of an electrophilic carbon to a nucleophile carbon). Step2b Reaction of a Grignard reagent with catbon dioxide affords the carboxslic acid Step3_ Fischer esterification (teaction ofa carboxylic acid with excess alcoho! and a strong acid catalyst) Step4 The 1° alcohol is converted to a good leaving group (losylate) for the ensuing displacement reaction (Step 5) Step 5 Sq2 displacement ofthe tosylate group with eyanide anion provides the ™. FI in this probe Carbonic ae to 1° amiSolon to Chapter Problems * 3 OW 200% C08 ay cre seo sure” CF ‘30. H, HzO S haot 0 Step 1 Carboxylic acid is converted to an acyl chloride with thionyl chloride (SOCI, or oxalyl ehoride ((CO).Ch}. Step2 Reaction ofthe acyl chloride with ammonia (NHs) affords the amide. Step 3a Reduction of the amide with lithium aluminum hydride (LiAIH,) provides the TM, Steps 3b+e Workup protocol O > Cha ms Solution: Fale in this problem: fi Alkane toast 2! Alene ta higher carbon homolog (2k 3. Unarcat, OH ‘Hp, EIOH, eat BOT ‘omy BY 2,94 NaHCO Step 1 Conversion ofthe alkene to the epoxide Step 2a Epoxide opening proceeds via Sx2 displacement to give the trans- adduct Step 2b Workup protocol Step 3 Semi-hydrogenation of the tiple bond with Lindlar’s catalyst gives the Qralkene. Step4 Conversion of the aleohol to the acetate with acetyl chloride (CH,C(O}CI or AcCh provides the TM. “ON = ONY4+ Chapter Syatheie Design Solution: FI inthis problem: Che-carbon hemaogaton ofa terminal double bond to a terminal souorated carbon one ENB, Carnes, OO” Frecne” Orn.) “tee = OnWe 5 ‘Step 1 Hydroboration-oxidation yields the 1° aleaho Step2_ Oxidation with pyridinium chlorochromate (PCC) affords the aldehyde Step3 Wittig reaction provides the TM. (Note: The ylide reagent is prepared by treating PhyP with CDsI to obtain PhsP*CDy and followed by deprotonation with n-BuLi.) 2. alcoho to carboxylic a0 9 se Kn,THF,0°0 AL DHP cat Ht 3b. PhCH BF vm HOLTON gata HET HOY OTP “Trego oh Be NaOH HO bt Saaaton Step | 1° aleohol at C3) is protected as its tetrahydropyranyl (THP) ether, Step 2a Reduction of the carboxylic acid with lithium aluminum hydride (LiAIH, affords the aleobol. Step 2b Workup protacol. Stcp 3 Williamson ether synthesis provides the C(1) benzyl ether. Step4 THP hydrolysis at CG). Step 5 _ Jones oxidation produces the TM in 55% overall yield Reference: MeGuitk, . Collum, D.B. J. Org. Chem. 1984, 49, 843,Solutions to Caper 1 Problems + § 1a. UAH, THE 3.NalOs THRO aes ib. NaOH, HO, CR Rada MeOH, 0 “2M; MeOH 4.0105, H:80s H SSCS ON oy 6 & Gaon | — 6 a Lact (wemiaceta) Step 1a Reduction of the lactone with lithium aluminum hydride LiAIM, provides the diol Step tls Workup protocol Step 2 THP hydrolysis affords the trol with C(1), C(2) and C(4) bearing the hydroxyl groups. ‘Step 3 Oxidative cleavage of the 1,2-dio! (C(1)-C(2)] with sodium periodate (NalO,) gives the aldehyde at CQ). Step 4 Acidic media of Jones oxidation allows the in-situ formation of the lactol (a hemiacetal), whieh i then oxidized to the lactone (TM). 1 Fora similar synthesis, see Takano, S; Tamura, N.; Ogasavvar, K. Chem. Soc, Chem, Comms. 1981, 155. 2. Umpolung. Show how each of the following compounds can be prepared from the given starting material using either a formyl or an acyl anion equivalent in the synthetic scheme, wow —e (=6 + Chapter 1 Sythe Desi Ja. mbubi, THR HS 2. Bul, THF, OD ESSE oA) See Swe yo Wer HO Step 1b Selective Sy2 displacement ofthe iodide (beter leaving group than chloride) Step 2. Intraolecl isplacement of the chloride Solution: on AAS AK scion uty 274 1 Weor Retype rescson ‘erage reaction iromatanopK = 10 Note that the deprotonation of the strong acid nitromethane (pK, = 10) is secomplished using the relatively weak base sodium methoxide (NaOMe), 9 CICHe(CHy}y CHC (CHL CH —P CHy(CHabCICH.dCt ‘Solution:Solaion to Chapter Prblens #7 ac uo eee IS Sher umes EIOH,quinotne ° Reference: For an analogous synthesis, see Smith, R. Gi; Daves, Jt, G. Ds Daterman, GE. J. Org. Chem. 1975, 40, 1593. “a. oo Solution: 2 ae als] Heche yea ‘OMe (.2-sston preva inbta atten EA) E rshanoyis ct wna ae eat 18, TMSCN, Znlp 2 winkd fr ioe A 1 eth coate re Af eof Chee ay te CE recente) ~~ Ca menonron ‘OH 4b. NaHCO, 9 secrets. MeOH Lx A cong |_HO AAA cote eet by " -eyanohydrin, unstable to base+ Chapter 1 Synthetic Devon Step3b The resonance-stabilized enolate anion reacts both chemo- and regio- selectively: iodide displacement occurs in preference to 1,2-addition; alkylation occurs eto the nitile moiety Reference: For an analogous synthesis, ee Kang, 8. H; Lee, H.S. Tetrahedron Lett. 1998, 36, 6713, 3. Retrosynthetic Analysis — One-Step Disconnections. For each of the following compounds, suggest a one-step disconnection, Use FGIs as needed, Show charge patteras, the synthons, and the corresponding synthetic ‘equivalents * aay 3 (man Reroomtti eas ASS 5 APY. ayy, 0+ ot © Do tat ora at os ss Smet sou © Dy Bead | ND Sa, stone am Bi BEiee Lewis acid-eatalyzed (SnCl,) ring opening of the epoxide is regioselective, placing the nucleophile atthe more substituted carbon, Reference: Pearce, G. T; Gore, W. By Silverstein, R.M. J. Org. Chem, 1976, 41,2191.Solutions to Chaper | Problems * 9 ; aphe = y eee ° aphe avy hee iL whe eH HO (workup) v “ Me 5 are orm OF 3 7 + 2mengee Co mer Ma" OH > ‘MeO2C " ‘cyclohexene = Diels-Alder ransiom ‘The 3° allylic alcohol isnot well suited as a dienophile (bulky, acid-sensitive). A better choice is methyl acrylate (electron-leficieat alkene). Addition of MeMgBr to the ester afer cycloaddition Furishes the 3° aleohol moiety.0 + Chapter Syotietic Design Synthesis: o le Me 4.meoee Dataterrescion (sHepineo! Conte wekos Me the = a singeral Retrosynthetic analysis: yen > “yt 8 acon sro “oo : : an Sint meer ar srs ar TH8 oo singel 50% Reference: Denniff, P; Macleod, 1 Whiting, D. A. J. Chem, Soe., Perkin Trans. 1981, 82,Soluions to Chaper | Prolews #11 Retrsyhetic ani: ° ° 4 hy an wy <“ Vv - E10" HIN, 2 >XE cos > ‘S o = s00S¢ An eres gu \Gebiainthe dosed cargo patom confuse sektion Synthesis ° B00 wok ae co keto ester ar condensation of two esters (Dieckmann condensation) ofthe ethyl ester provides the B-koto carboxylic acid ion of the carboxylic acid (Note: This requires a keto Step Inramote Step 2 Saponiia Step3_Decarboxy group) Retrosynthetie analysis: ° ° Fl COS 8 CO = CON ei : :12 + Chapter 1 Syntstic Design ndered halide. Thus, the alkyation approach (shown below) isnot a sterically recommended. Care Oe, 4. Synthesis. Outline a retrosynthetc scheme for cach of the following target molecules using the indicated starting material. Show (I) the analysis (Gncluding FGI, synthons, and synthetic equivalents) and (2) the synthesis of each TM, oO” Retrosynhetc analysis: Foked or - Oe 1 3-chetone Loe, Ae) A Be) a owe on o u = BAN gy BN c0se) OMe One Dyse)Soluion to Chaper 1 Problems * 13 Synthesis @ ‘eile, gna OANA, on moe, y 2. Nal asoe, ow we Frcs rate rr Step 1 Phenol (pK,=10) deprotonation and alkylation gives B. Step2_ Conversion of the alkyl bromide to the corresponding alkyl iodide (Finkelstein reaction). Step3 Alkylation of the 1,3 ketone enolate A provides the TM. Reference: For a similar synthesis, soe Diana, G. D. Salvador, U, J Zalay, E. $3; Carabateas, P. M.; Williams, G. L} Collins, J. C. Med. Chem. 1971, 20, 757 ». ° wth © tom é én é o 8 Cpeyrenoptonn (ential coping) Retrosynthetc analysis: an we On = On ° age) . B > eAYyRewoo > RO Bonde GH * Reasons Unpatng "COnH ° a Cromer 4 LA + mmscticome <= LY Wow 8 we cise) ‘COR14 + Chapter Syatatie Design Synthesis: 10. UDA THE 2.8. tower ey Sonor tS BA Xoo = 38 oH. MeOH ‘coon omar ome S89 4:66, cr > CHC A en MeOH, HO oY O<) Step 1a Deprotonation using the non-nucleophilc base LDA avoids 1,2-additon to thealdchyde C. Step 1b. Note that the -OH group of the alkyl iodide substrate A. must be protected prior to alkylation, Step2 Wittig reaction, Step3 Ester saponification and acidification, which also cleaves the acid- sensitive THP group. Step4 Head-o-til esterifications of two hydroxy acid substrates give the bis lactone. Step 5 Removal ofthe dthiane provides the TM. Reference: For an analogous synthesis, see Seebach, D.; Seuring, B.; Kalinowski, 1-O.; Lubosh, W; Renger, B. Angew. Chem. Int. Ed 1977, 16, 268 SOE om ASalwionsa Chapter | Pblens © 18 Retrosyntetic analysis: im_h0H + AKAD? Sn Eagon = formatdonye ro ee DR ONO ties u Me 2A on " 1 ral 2m E 2 ier econo se 8 Synthesise ta, nPrtighr (2 00) 2.Per, Ma Br £00 Bey owe TentnD Ae (wort) 2. Mg, YO Ess Ma oHOH 30.4" HO week Step3 The reaction ofa tertiary Grignard reagent witha hindered ketone may result in reduction andior enolizaton of the Ketone. However, in the present example, the use of formaldehyde (an excellent electrophile) circumvents these side reactions. DOA toe ey16 + Chapter Syotetic Design Retrosynihetic analysis: ase) 266 Yrat Ye my . Ama Bay se ewe) Synths ta. tg £0 Oe 0 am, Bue A, Py 4 cleat 8 ee ™ Meo NN HME ton CS oN a of vatun (vanguitzet)Solations o Chapter 1 Problems + 17 Retrosynthetie analysis: ‘Tp canara am oa 1 or. a ee i or Ae DISE) EAS = electophitic Ph sracsisalt, —} as) oten cise) Synthesis: Nie 1.14010) iw 2eCATn, g BAL ay a zt Ho” baat > Ze naoHe 0 Step 1 Reaction of CH,C(O)CI with D affords the amide (weak activator compared to an amine), which should circumvent multiple substitutions in Step 2a. Step 2a. Elecirophilic aromatic substitution oceurs orth to the amide. Step 2b Workup. Step2c_ Hydrolysis ofthe amide provides B. Siep3 Reaction of the 2° amine (ofthe aromatic ring B) withthe ethyl ester forms the amide while the reaction ofthe 1° amine (of glycine A) with the carbonyl group forms the imine. Referene + For an analogous synthesis, see Gates, M. J. Org. Chem, 1980, 45, 1675,18 + Chapter Syntbetie Design £ Synthesis: a ty Be LO] 2 cos 2 oe Pe 5 Hea TH wa © 73% 7 Hh 48. Bult ok 5, HgCla, Hg OH oO ‘OH EE won GH HO Step2 Conversion ofthe 1° alcohol othe 1° alkyl bromide. Reference: Sharma, A.; Iyer, P; Gamre, 8; Chattopadhyay, S. Synthesis 2004, 1037,Solon to Chapter 1 Poblame * 18 Ho . om OH (GHg,cr, 7° Retrosynthetic analysis: ne 4 FN on 2S GH CHacHy GH Gnayors I, gee ren ASE) ° (CHabeCHs, 69) Ure Fa HONS Eo” On Gdors (CHaWcls c Fat wit action) Ho HO NNO engPacticHeols e ° Synthesis: ‘pnporycHicy” a.taciiteg, gee! gPOHA(CH 60), eto nat dso i 3 MA ooo ~ ° Cowu, TH ® se HEH aoe HCN, H.0. Step 1 The diol E must be protected (acetal, in this example) for the Wittig reaction to proceed. The Wittig reagent is prepared from the ‘phosphonium jdide using sodium dimsylate, NaCH;S(O)CHS, Step2 Mild acid hydrolysis of the acetonide prevents acid-induced isomet- ization ofthe (Z)-alkene. Step3 Selective tosyltion ofthe 1° alcohol Step 4 DBU (1,8-diazabieyelo(S4.0}undee-7-ene), a bulky, non-nucleophilic nitrogen base, is used to form the epoxide, Step Sa Under basic conditions, the epoxide ring opening proceeds at the less substituted carbon (compare to Problem 38). Step Sb Workup protocol. Reference: Corey, E. 1; Kang, 1. J. Am. Chem, Soe. 981, 103, 4618,Ho. ho consider he 0 pes) ‘symmory 1 H Hom eg HOu! Fgl > > HO" H 1 be ase) 1. Dine . Wear teor sel au, of Pa Unig THF aha 2a. Etre A >I et XD see 1 MeOH, HzO. Step 2b+e Workup protocol Reference: For an analogous synthesis, see Khanapure, . P; Naja, N;; Manna, 8.3 Yang, J-I; Rokach, J. J Org. Chem. 1995, 60, 7548,Solutions © Chapter 1 Problems * 21 “Oo Retrosynthetic analysis: otros Unootng " sore f 7 mr + ee 2. Ager ‘eg (ea) Aion wot Sito a Sep! ideo psponacs oft ae wal eleton of tees (Homer-Wadsworth-Emmons modification of the Wittig reaction). Steps2+3. The euprate-mediatedI,4-addition and subsequent Lemicux-Johnson oxidation of a vinyl’ group are excellent procedures for the introduction of the f-formy/ group. Step4 Intramolecular aldol condensation provides the TM. Reference: For the synthetic sequence applied to a similar TM, see Corey, E. J; Smith 1G, J. Am. Chem. Soc. 1979, 101, 1038.CHAPTER 2 Stereochemical Considerations in Planning Syntheses Overview CChaptet 2 focuses on conformational analysis as a tool for assessing the relative reactivity and stereochemistry of eyelie compounds Problems 1-3 emphasize the three dimensional representation of various cyclic molecules and evaluation of their energies by the A, G, and U parameters In Problems 4-6, we apply conformational analysis to predict the reactivity of carbocyclic systems toward various reagents and to gather information regarding the preferred stereochemical course of the corresponding reactions. Further examples of applications of conformational analysis in organic synthesis are incomporated in Problems 7-9, Key Concepts + Conformational analysis + Corey and Feiner’s A, G, and U energy parameters + Al? strainSoltionse Chapter 2 Problems * 23 SOLUTIONS TO CHAPTER 2 PROBLEMS ‘The more challenging problems are identified by an asterisk (*. |. Draw the chair o the half-chair conformations (where applicable) for each of the molecules shown below and determine the corresponding E, and AE, values, Use the A, G, and U Values of Table 2.3 and assume 0.7 keal’mol for Mell Al2 strain Me ier A 0 Me A Me Mo Me “oH “we ir Me Me Me a b. © a Me, Me age Host 9 7 ‘OE Ho™ ‘ome s Me ws " Me "ite £ & Me 4 per H — w OF oy LD 4 Pr Me a 5 a 1 aie OH Inerstone: S| dO one 12-ciequatorial OH Pr fo 13nd bPr At Ep =Une+Uou+ 1/2 (Ane + Aon) + Are 184094 12.8409) "21 6.15 keal/mol Bi Ep = Gon + Gir =02 +08 = 1.0 kcalmol ABiy= 615-10 = 5.15 kcal/molter 2 Steeochemical Consideration in Planing Syatheses : oe ere = Me. : Me H Me ° wo 13-al Mo 1H Interactions: 213 1S-dantal Ke /H (cyclohexanone 5ystern) two 13-lanal 4 ‘ne 1:2dlauatorlal Me Mo Bp = Ane +2/3 (Ave) =18+28 (1.8) = 30 kealimal = Aint Gue* Gus =21F04 +08 = 29 kealimal ABD= 0-29 = 0.1 kealimol 7 oO Me ag te a a, 1 Mo Me ae Me Me 8 a ‘one AY? strain Me /H Interactions: two.A"? sain MoH ‘ne 1--caxial Me / Mo ALE = Une Ute +A? Melt = 1818407 =4.3 kealimol ABD = 43-14 = 29 kcal/molSolution to Chaper2 Problems + 25 ‘We Me . = ow Me H Mer ue L , : eee eee econ acne: $0 lee SS rg A: Ep Inte * Ue 1/2 (Ame) pant eee B: Ep ~2(Gue+ Gy) + A'? Melt (04404) +07 =2.3 kealimol AB = 45-23 = 22 kealimol Ms ty] Ho: Me = 0° = Me Mé Ho a 2 1a Me OME erie Interactions: Oe 43lanal OMe fone {2cloquateial Me /OH ‘ne 1-donel OHH Une + ome + 1/2 (Arte + Aome + Aon) =18409 121840909) ' keal/mol AE Ep * Awe t Guet Gow = 18404402 4 keal/mol 45-24 = 21 keal/mol26 + Chapter 2 SucsochemialConsideton in Planing Syntheses ; = = 5 ; CO = EAD = ee te aw "i mete get 4 ‘Me, Hs oo Me ; ; ee eeeeret A seam ee iandarann Si seneeoue Aust Une ncaa * 12 (Ane + Anca 18+ 18+ 184+ 12 (1.8 + 1.8) =72 kcal/mol AEp = 72-27 = 45 kealimolSolutions o Chapter? Problems © 27 Brace: fo 1, 3ladal CUt)-Mo Interactions: one 12-dequatrial CU -OH/CIB}CHy Bove: ‘wo 13-lawa O(1}.08174 one # 2dequatoria Ctaytte CiS}-CHe ‘ase + Gon * Gri on + Gs + Gans ‘ono 1,-ciawalC{6)-CHe/H fone 13-ciwalC(1}CHa seface: ‘wo 13-axal O(8)-CHy fone 13axal CCH, J Broa? V2 Anon, Brant 1 hn, ASE ~ Awe + Gow + Grey + Anes * 1/2 (Anca) = 184024044 18+ 12 (18) 5.1 kcal/mol Aon + Guue+ Great + Anca + 1/2 (Ancis) =09+04+04+18+12 (18) 44 keal/mol Ep AED= 51-4428 + Chapter 2Stecochemicl Consideration in Planing Syatboses : = ee ae sca amas -diaxial C(2)-OEt/H ttre LOPY ot Tis + Uo #8 Ast 12 Roe Fhe ; , : ne ae ae Siler eetconremen Interactions: C1 Chip H ‘one 1,3-diaxial C(2}-O8t/ ‘one 1S! {8)-CHe/H ‘one 1 Scan Cs}-CH oes Unce.t 1 Roe #112 ncn 12 Ano Az Ep = Une + Uoer + 12 (Ay) + 12 (Aon) + Aner 18409412 (1.8) +1209) +18 85 keal/mol ite + Grex, + Uosr+ Unen, + 1/2 (Aon) + 1/2 (Anes) * 12 (Ancn,) 4+04+0.9+ 18+ 1/2 (0.9) + 1/2 (1.8) + 12(18) = 4.4 kealmol Ep ABD = 585~5.75 = 0.10 keal/molSolutions to Chaper 2 Problems + 29 2, Draw the most stable conformation for each of the compounds shown below. You do not need to compute the E, and AF values. Solution: We A seo moo : ; oot, A? we ES " H » Me erates oH Me. 4 x We TH0 Sh mom == oO [ Notts i? a ‘OH Ht 4h Mon Bis the more stable conformer.0 + Chapter 2 Stereochemiea Consideration in Planing Synthese ‘rans-antitrans; each rng is inthe chai conformation, a 8- b > a 5. Given below are the observed « :§ epoxide ratios from epoxidations of the 0,0-2cetals > §Sacetals + Deoxygenations «0Satins Chap ens = A SOLUTIONS TO CHAPTER 3 PROBLEMS “The more challenging problems are Kentied by an asterisk (*. 1. Reagents. Give the ttre ofthe major products (A-G) expected rom the following reactions, Assume standard aqueous workup conditions are used for product isolation. ont. TBscL In, CeCe a DMF I8CIOR gone HO OH 2. NalOy, CHCl lege excons Solution: on 1. TBsaL ° imi, CeCe one -e-cen HO OH 2 Naldy CHCl ores A 0% Step 1 To obtain the monosilylation product, a large excess of the starting trol is used, Step 2. Vieinal diol cleavage. Reference: Paterson, 1; Delgado, O.; Florence, G. J; Lyothien, 1; O°Brien, Ms ‘Scott, Pz Sereinig, N. J. Org. Chem. 2005, 70, 150 ole 1. ToC py . gyg 2 HEGBH, THE Solution: Ce He O b. ‘Step 1. Conversion of the 2 aleoho! to the comesponding tosylate (a good leaving group), Step 2 Displacement of the tosylate with a hydride asthe nucleophile. (Note: Steps + 2 representa common deoxygenation procedure for alcohots,)42 + Chapter 3 The Coney of Protecting Fnstiona Grows moe Pay Bialtee gy sume ‘oF 2,6-utidine, CHCl oe id ae Meosems, (OH NL Blige MeO:0%,_,OTBS Ch gee Ce ‘o" 2,6-tutidine, CHCly ‘Oo 2. UBH,, THE — ores 82% imi ‘Oo cd & ‘Step 1 Protection ofthe 1° alcohol in the presence of a 2° alcohol Step 2 Protection of the sterically hindered 2° alcohol requires the use of the reactive silylating reagent TBSOTT, Step 3. The milder reducing agent LiBH, was used for the reduction ofthe ester ‘moiety instead ofthe more powerful LiAIH., presumably to facilitate the ‘workup inthe presence of the aid-lbile OTr group. Step 4 Conversion ofthe resultant 1° alcohol to the corresponding ioe, Reference: Gu, Snider, B.B. Org. Lett 2003, 5, 4385, 1. HocHCHOH eat TeOH ° HWNoony Fe crise oar eo 2. sq NaHcOs Sa, Nad THF. 0°C 3b. Bn, et nuh 1. HoorecHoH CO Sette Doom Be cnyugor oa, Ook sateeoy MO 3a. NaH, THF, 0°C e orca nun Step 2b Workup protocolSoluios to Chaper Problems + 43 1. mBUNF fs) THE.O"Cton 2.(Mo0},C0~ 4. POC, CHCl, Po. cat Tn 8 PngPachesaoy 1850... Koon —aetret__g, move, NW 3. He, cat. POOH)YS 89% 6. Hp, Cal. POOH} IC i Seera oer co nau wane apace ea No 000, 950A cnn ett DT oy a hy 0 ee Oa , Boc EIOAa, st Boc fi Es P spnpeciowtin 0 * hy meee LO Gute be TE 7 r Le iS aria aor ~Y “eome Caos boo 2 aot Step 1 Deprotection of the silyl ethers, Step2 Acetonide formation Step3 Benzyl ether deprotection Step 4 PCC oxidation ofthe 1° alcohol should furnish the aldehyde; however, the authors reference below) used the Swem oxidation, Step 5 Wittig reaction. Step 6 Alkene hydrogenation (Note: Boe, -butoxycarbonyl, protecting group is stable tothe reaction conditions in Steps 1-6,) Reference: Wang, Qi; Sasaki, N. A. J. Org. Chem. 2008, 69, 4767.“#4 + Chapter The Concee of Protecting Funtonl Groups ‘ ' ‘reson, 2ettane runo_ ar 0A ae oie X 7 900, pt Toa CHCl 8. PCC, CHCl Sotuton: : 1-Tesom, 264 pmo A, Che wih cote Stee ‘come 2000, pA bate bu or bres se 9. FC. Cheb SRR ‘cOnMe 8 bres F Step I Silylation ofthe 2° alcohol Step 2 Removal of p-methoxybenzyl PMB) ether with 23-dichloro-5,6dicyano- Ind-benzoguinone (DDQ) requires 10 (present in pil 7 ue). Step 3 PCC oxidation ofthe I alcohol tothe corresponding aldehyde, Reference: Paterson, L; Delgado, 0.; Florence, G. J; Lyothier IL; O'Brien, Mz Scot, J.P Sereinig, N. J. Org. Chem. 2008, 70, 150. & 1, POC, CHCl, 0 °C Heat eaters ee ae « a TERE bao, coe ements eee se cere “A ee ee Ne ee Oe a s CHCly pers : ootSolutions to Chaper3 Problems * 45 ‘Step 5 Selective cleavage of the sterically less hindered TBS ether, Step 6 Conversion ofthe I° aleohol tothe corresponding iid. Reference: Nomura, L; Mukai, C. J. Org. Chem. 2004, 69,1803, 2. Selectivity. Show the product(s) expected forthe following transforma tions. 7 Me Me (Meo},CMoe Maho" ‘at T0H et ome on Solution: ‘ome Me Me (We0)-0Me2 Me Me 1 “eat. Ys0H4 Moz -bor WoL Mr HO nc (0%) on S Acetal formation occurs between the cis C(2)- and C(3)-OH groups rather than between the rans C(3)-and C(4)-OH groups. Reference: Gyergyei, Ks Toth, A Bajza, Ls Liptik, A. Synlett 1998, 127 ». ta.Mel 20a) the ore 4b, BPS-C1 (1.3 eq) 2. MsCl, EIN (xs), me ar onal iceqnncr Bt, orca ore” 82 ohare)