Thione-Based Auxiliaries in Organic Synthesis

Transcription

1 Thione-Based Auxiliaries in rganic ynthesis C 2 An Evans Group Evening eminar Wade Downey Friday, March 1, title 2/28/02 6:46 PM

2 Thione-Based Auxiliaries in rganic ynthesis Thiazolidinethione xazolidinethione eminar cope 1. Auxiliary synthesis 2. alf-reduction 3. Amine acylation 4. Aldol-type reactions 5. Iminium additions 6. ther reactions a. Claisen condensation b. Diels-Alder c. earrangements d. elenylation e. eductive coupling f. otochemistry elevant eviews: Fujita, E.; agao, Y. Adv. eterocycl. Chem. 1989, 45,1-36. Mukaiyama, T.; Kobayashi,. rg. eact. 1994, 46, scope 3/2/02 10:49 AM

3 Auxiliary ynthesis K, 5 equiv C C, 16 h % 1 a 2 C 3, 1.5 equiv C C, 15 min % Le Corre, M. J. rg. Chem. 1995, 60, Cl 2 C=, Et 3 C 2 Cl 2 95% Thiones were acylated easily with Et 3 and the appropriate acid chloride. Crimmins, M. J. rg. Chem. 2001, 66, Auxiliary ynthesis 3/2/02 10:54 AM

4 alf-eduction: Mukaiyama 1.2 equiv DIBAL, C Yield (%) C 2 C 2 C 2 C 3 C 2 C() C 2 C 2 C 2 Br(C 2 ) 9 C 2 C=C i-bu i-bu Al Proposed intermediate Comparable yields with tri-t-butoxyaluminum hydride Mukaiyama, T. Chem. Lett. 1977, Mukaiyama, T. Bull. Chem. oc. Jpn. 1979, 52, Mukaiyama reduction 3/2/02 10:54 AM

5 alf-eduction: agao and Fujita 20% DIBAL in hexane C 2 Cl 2, hexane, C Yield (%) (C 2 ) 3 C 2 (C 2 ) 7 C 2 (C 2 ) 13 C 2 C=C Yields are comparable to Mukaiyama's. DIBAL was "injected dropwise onto a yellow solution... until the original yellow colour of the reaction medium vanished." Full reduction with ab 4 proceeded with >90% yields. agao, Y.; Fujita, E. J. Chem. oc., Chem. Commun. 1978, agao, Y.; Fujita, E. J. Chem. oc., Perkin Trans , agao reduction 2/28/02 2:42 PM

6 Aminolysis: agao and Fujita C C 2 Cl C t Yield (%) 2 Butyl Cy 4-C 6 4 Bn C 3 (C 2 ) 4 1 min 5 min 6 d 8 min 1 min imilar aminolyses were successful for other -acylated thiones (aryl, alkyl, unsaturated). "tirring was continued until the original yellow color of the solution disappeared." min 7 d 3 min a 95 b + Proposed Transition tate a) solvent = TF b) solvent = Et-TF agao, Y.; Fujita, E. Tetrahedron Lett. 1980, 21, agao aminolysis 1 2/28/02 6:35 PM

7 Macrolactamization: agao and Fujita n 2 2 C 2 Cl 2 n + dimer n Monomer Yield (%) Dimer Yield (%) (C 2 ) 2 (C 2 ) 4 (C 2 ) 6 (C 2 ) 6 (C 2 ) 3 (C 2 ) 4 (C 2 ) 3 (C 2 ) This process has been to applied to the total synthesis of codonocarpine, lunarine, and lunaridine. 06-agao aminolysis 2 2/28/02 2:49 PM agao, Y.; Fujita, E. Tetrahedron Lett. 1980, 21, agao, Y.; Fujita, E. Chem. Lett. 1980, Fujita, E. Pure Appl. Chem. 1981, 53, agao, Y.; Fujita, E. J. Chem. oc., Chem. Commun. 1981, agao, Y.; Fujita, E. eterocycles 1981, 15,

8 Desymmetrization: agao and Fujita 2 C C u, solvent, C 2 Cl 2 u u olvent Yield (%) 2 C C 2 2 C 2 Cl 2 69 Br Et t-bu Et TF TF TF Proposed Model: First nucleophile attacks least favored hindered of four carbonyl faces. Dipole-minimized structure supported by crystal structure Initial amide product isolable (74% yield, 10:1 dr) 07-agao desymmetrization 1 2/28/02 7:35 PM agao, Y.; Fujita, E. J. Am. Chem. oc. 1982, 104, agao, Y.; Fujita, E. J. rg. Chem. 1983, 48, agao, Y.; Fujita, E. Tetrahedron 1984, 40,

9 Aminolysis: agao and Fujita Kinetic esolution of acemic Amines (C 2 ) 14 C equiv C 2 Cl (C 2 ) 14 + ee's typically 25 60% yield of amides >90% agao, Y.; Fujita, E. Tetrahedron Lett. 1982, 23, Absolute tructure Determination of Amines 2 equiv (C 2 ) 14 C C 2 Cl 2 * C 2 (C 2 ) (C 2 ) 14 otation of recovered thione starting material indicates absolute structure of starting amine. 08-agao resolution 2/27/02 12:44 PM agao, Y.; Fujita, E. Tetrahedron Lett. 1982, 23,

10 Thiazolidinethione Adduct Derivatization ab 4 83% DIBAL 69% Bn 2 79% Bn i-bu TE TETf 100% i-bu Imidazole 79% () Cl Imidazole 77% Crimmins, M. rg. Lett. 2000, 2, Thione elaboration 2/28/02 7:36 PM

11 Aldol: Mukaiyama 1. n(tf) 2, -Ethylpiperidine (EP) 1 C 2 Cl 2, 78 C, 20 min 2. 2 C, 78 C, 15 min Yield (%) syn:anti BnC 2 BnC 2 BnC 2 BnC :1 32:1 32:1 32:1 32:1 Prior to this report, Mukaiyama had used these enolization conditions extensively for crossed aldols of ketones. dr's were determined by 13 C M. 10-Mukaiyama ach aldol 2/28/02 7:13 PM Mukaiyama, T. Chem. Lett. 1982,

12 ther Enolates: Mukaiyama 1. n(tf) 2, EP C 2 Cl 2, 78 C, 30 min C, temp Yield (%) syn:anti ( 78 C) Cbz(Bn) ( 40 C) Boc(Bn) ( 40 C) BnC 2 C=C 2 Pentyl BnC 2 Pentyl BnC 2 Pentyl :3 5:1 1:1 2:1 6:1 9:1 19:1 19:1 19:1 9:1 19:1 19:1 19:1 19:1 o elimination products were observed. o mention of results with chiral ligand This methodology was employed in the total synthesis of (±)-thienamycin. Mukaiyama, T. Chem. Lett. 1985, Mukaiyama methoxy aldol 2/27/02 1:04 PM

13 Aldol: Mukaiyama 1. n(tf) 2, EP C 2 Cl 2, 78 C, 20 min C, 95 C, 15 min Yield (%) ee (%) BnC 2 Et Pentyl Cy Absolute stereochemistry proven only for benzaldehyde adduct Prior to this report, the "Mukaiyama Ligand" had been used for enantioselective crossed aldols and ketone homoaldols. Mukaiyama, T. Chem. Lett. 1983, Mukaiyama ch ac aldol 2/28/02 2:54 PM

14 Pyruvate Aldol: Mukaiyama 1. n(tf) 2, EP C 2 Cl 2, 78 C, 30 min C 2, 2 4 h i-bu 2 C(C 2 ) 2 Yield (%) ee (%) Previous aldol ligand afforded only 18% ee. A scan of ligands showed the 1-naphthyl moiety to be superior to cyclohexyl, phenyl, 2,6-xylyl, and 2-naphthyl. ee's determined by use of chiral shift reagent Mukaiyama, T. Chem. Lett. 1983, Mukaiyama pyruv aldol 3/1/02 11:20 AM

15 Aldol: Mukaiyama 1. n(tf) 2, EP Bn C 2 Cl 2, 78 C, 20 min 2. C, 78 C, 3 h Bn L* Yield (%) syn:anti ee (%) BnC 2 Pentyl Cy BnC 2 Pentyl Cy none :3 3:1 1.6:1 3:1 1.3:1 1:4 1:7 1:10 1:4.9 1: = TMEDA as ligand resulted in diastereoselectivity similar to that induced by the chiral ligand. ote that even in the absence of ligand, C is anti selective. 14-Mukaiyama Bn aldol 2/27/02 12:59 PM Mukaiyama, T. Chem. Lett. 1984,

16 Aldol: agao and Fujita 1 1. n(tf) 2, EP C 2 Cl 2, 50 C, 3 h equiv 2 C, 78 C, 20 min 1 2 on-evans syn! 1 2 dr Isolated Yield (%) Pr 3.2:1 4.5:1 8:1 10:1 5: Tf n 2 Chelated transition-state structure predicts "on-evans" selectivity. 1 Enolization conditions from Mukaiyama Proposed Transition tate Mukaiyama also postulates a chelated transition state for his racemic tin-mediated aldol. agao, Y.; Fujita, E. J. Chem. oc., Chem. Commun. 1985, agao aldol 1 3/2/02 11:06 AM

17 Acetate Aldol: agao and Fujita 1 1. n(tf) 2, EP C 2 Cl 2, 50 C, 3 h 2. 2 C, 50 C, 4 h Et Et Et 2 dr 13:1 33:1 8:1 36:1 13:1 Total Yield (%) ote the change to thiazolidinethione auxiliary. A footnote suggests that saturated aldehydes are just as selective. 1.2 equiv n(tf) 2 and 1.2 equiv EP were optimal. Excess base led to dehydration products. Excess n(tf) 2 led to lower yields, presumably due to aldehyde polymerization. o mention of propionates agao, Y.; Fujita, E. J. rg. Chem. 1986, 51, agao ac aldol 3/2/02 10:56 AM

18 Aldol: agao equiv n(tf) equiv EP TF, 50 C, 3 h equiv, TF, 50 C, 2 h 3. 5% Cl dr Yield (%) tarting lactone is an aldehyde precursor: Et Pr 99:1 99:1 66:1 99:1 99:1 99: C Aldol 4-acetoxy lactone is unreactive under the reaction conditions. Lactonization occurs during the acid workup. agao, Y. J. rg. Chem. 1989, 54, agao aldol-lactone 2/28/02 7:37 PM

19 δ-lactone: agao equiv n(tf) equiv EP C 2 Cl 2, 40 C, 2 h equiv 2 C, 40 C, 1 h 3. K 2 C 3, DMF, rt, 1 h 1 2 X c 1 2 (Bn)Cbz s-bu exyl Yield (%) Tf n Tf 1 ationale: 18-agao d-lactone 2/28/02 7:37 PM Initial aldol adduct cyclizes under K 2 C 3 /DMF conditions. All product lactones were "optically pure" by PLC and 1 M. tarting material recovered in 5-32% yield In order to avoid steric repulsion between 1 and the isopropyl group, n may coordinate as shown. Dipole-minimized conformation based upon crystal structure agao, Y. Chem. Lett 1992,

20 Aldol: Miller X 1. Bu 2 BTf, 2 Et 1 C 2 Cl 2, 0 C, 30 min equiv 2 C, 78 0 C C 2 X 1 C 2 2 X 1 2 Yield (%) dr Et Et Pr n(tf) 2 afforded "Evans-syn" aldol adducts, unlike the agao/fujita results! Absolute stereochemistry was proven by optical rotation of methanolysis products. dr is calculated from the ee reported by Miller for the methanolysis products. o oxidative workup is required. 19-Miller aldol 1 3/2/02 11:03 AM 66:1 66:1 24:1 99:1 99:1 99:1 99:1 siao, C.; Miller, M. Tetrahedron Lett. 1985, 26, siao, C.; Miller, M. J. rg. Chem. 1987, 52, C 2 L Proposed Transition tate B L

21 Aldol: Miller 1. Bu 2 BTf, 2 Et 1 C 2 Cl 2, 0 C, 30 min 2. 2 C, 78 0 C C 2 1 C C Yield (%) dr Et i() 2 exyl 58 99:1 Boc 73 D The Miller system appears to be compatible with functionalized aldehydes and enolates. C 2 C=C 2 C 28 D Miller, M., Tetrahedron 1990, 46, Boyd,.; siao, C. J. rg. Chem. 1991, 56, Miller, M., Tetrahedron Lett. 1991, 32, Miller aldol apps 2/23/02 1:33 PM

22 Aldol: Yan 1. TiCl 4, 2 Et C 2 Cl 2, 0 C, 20 min 2. 1:1 TiCl 4 C (1.5 2 equiv) 78 C, 2 h Yield (%) dr Pr C=C :1 99:1 99:1 50:1 Corresponding oxazolidinones, under the same conditions, afforded ~1:1 mixture of epimers at the α-carbon. Boron enolates yield Evans syn products in high dr. Lithium enolates yield on-evans syn products (dr = 2-9:1). A subsequent paper showed that aldehyde-ticl 4 complex was unnecessary for on-evans syn selectivity. 21-Yan aldol 1 2/27/02 1:21 PM Proposed Transition tate Yan, T. Tetrahedron Lett. 1991, 32, Yan, T. Tetrahedron Lett. 1993, 34, Yan, T. J. Am. Chem. oc. 1993, 115, Ti Cl Cl Cl

23 Acetate Aldol: Yan 1. Lewis Acid, 2 Et C 2 Cl 2, 0 C, 25 min 2. C, 78 C, 2 h + A B Lewis Acid Yield (%) A:B Bu 2 BTf Pr C=C :3 1:3 1:12 1:3 The authors propose that the 9-BB-mediated aldol proceeds through a boat-like transition state, whereas the Bu 2 BTf reaction occurs via the usual chair. 9-BB(Tf) TiCl 4 Pr C=C Pr C=C :1 7:1 99:1 6:1 10:1 19:1 13:1 16:1 The titanium-mediated reaction is believed to proceed via a chelated transition state. Boron enolates of the corresponding oxazolidinone auxiliary show the same trend: Bu 2 BTf affords Evans syn, and 9-BB(Tf) affords non-evans syn, although diastereoselectivity is modest (2-3:1). Yan, T. J. rg. Chem. 1994, 59, Yan, T. J. rg. Chem. 1995, 60, Yan acetate aldol 2/28/02 7:26 PM

24 Bromoacetate Aldol: Yan 1. TiCl 4, 2 Et C 2 Cl 2, 0 C, 10 min 2. Br 2, Et, 78 C 3. C, 78 C, 1.5 h Br Yield (%) dr C=C Pr :1 99:1 99:1 99:1 dr determined by 400 Mz 1 M Epoxide Formation: X c Br 1. Et 3, 2, C 3 C 2. K 2 C 3, C =, 79% = C=C, 86% = Pr, 83% =, 82% Yan, T. Tetrahedron Lett. 1999, 40, Yan, T. Tetrahedron: Asymmetry 1999, 10, Yan bromoacetate aldol 3/1/02 11:22 AM

25 Aldol: Crimmins 1. 1 equiv TiCl 4, sparteine, 0 C equiv C, 0 C, 1 h Bn 1 Bn TiCl 4 Isolated Yield (%) 1. 2 equiv TiCl 4, Et, 0 C C, 78 C, 1 h 1:2 Bn 2 Et C=C C 2 =C Et C=Ca C 2 =C 1 equiv 2 equiv :1 32:1 36:1 37:1 90:1 1:22 1:19 1:41 1:18 1:99 M experiments suggest that a different enolate species forms upon addition of second equivalent of TiCl 4. unig's base or TMEDA in the place of sparteine resulted in lower yields (50-60%) but similar selectivity. The chirality of sparteine was shown to have no impact on diastereoselectivity. a) eaction at 78 C 24-Crimmins aldol 1 3/2/02 10:59 AM Crimmins, M.; King, B.; Tabet, E. J. Am. Chem. oc. 1997, 119,

26 Aldol: Crimmins 1. TiCl 4, 1 equiv sparteine, 0 C equiv C, 0 C, 1 h Bn 1 Bn 1. TiCl 4, 2 equiv sparteine, 0 C equiv C, 0 C, 1 h Bn 2 base Yield (%) 1:2 1 equiv 2 equiv i-bu C=C C 2 =C i-bu C=C C 2 =C :1 19:1 41:1 18:1 142:1 1:44 1:32 1:36 1:37 1:90 Use of 2 Et as base resulted in lower selectivity (typically 10:1). Use of TMEDA in the place of sparteine caused no significant change in selectivity, but lowered yields ~10%. Changes in Lewis acid stoichiometry had no effect on diastereoselectivity. 25-Crimmins Aldol 2 3/2/02 11:00 AM Crimmins, M. rg. Lett. 2000, 2,

27 Aldol: Crimmins Bn L 4 Ti X c Evans syn Bn L 4 Ti TiCl 4 or AgbF 6 Chloride emoval -thylpyrrolidinone or sparteine Ligand Addition Bn Ti Cl Cl Cl X c on-evans syn Bn Ti Cl Cl Cl 26-Crimmins T 3/1/02 11:29 AM Crimmins, M. J. Am. Chem. oc. 1997, 119, Crimmins, M. rg. Lett. 2000, 2, Crimmins, M. J. rg. Chem. 2001, 66,

28 Acetal Addition: Urpi and omea 1. TiCl 4, 2 Et C 2 Cl 2, 0 C 2., Lewis Acid, 40 C Lewis Acid T ( C) Isolated Yield (%) dr Cl n BF 3 Et 2 ncl C ClC C 6 4 Pr i-bu :1 4.3:1 10:1 6:1 13:1 12:1 7:1 Ti econd Lewis acid necessary to activate acetal Less reactive aldehydes require higher temperatures and the stronger ncl 4. Proposed Transition tate Urpi, F.; omea, P. rg. Lett. 2001, 3, Urpi acetal 1 3/2/02 11:07 AM

29 Acetal Addition: Urpi and omea 1. TiCl 4, 2 Et C 2 Cl 2, 0 C 2., Lewis Acid, temperature L.A. T ( C) Isolated Yield (%) dr Cl n BF 3 Et 2 ncl C ClC 6 4 Pr i-bu :1 13:1 7:1 3:1 3:1 4:1 2.4:1 Ti Yields are very similar to propionate case. Compared to the propionate cases, selectivity is similar for BF 3, worse for ncl 4. Proposed Transition tate Urpi, F.; omea, P. Tetrahedron Lett. 2001, 42, Urpi acetal 2 2/28/02 7:41 PM

30 Aldol: Evans Bn 1 1. cat. MgBr 2 Et 2, Et 3 2 C, TMCl, EtAc Cl, TF Bn Mol % Catalyst Isolated Yield (%) dr 4-C C :1 19:1 19:1 L L Et Allyl Bn i-bu C=C C=C() 2-naphthyl C 2 =C() :1 19:1 7:1 7:1 10:1 13:1 8:1 19:1 Mg L L Bn Proposed Transition tate TMCl is necessary to turn over the catalytic cycle. Aliphatic aldehydes are unreactive or self-condense. 29-Evans aldol 2/28/02 6:37 PM Evans, D.; Downey, C.; haw, J.; Tedrow, J. rg. Lett., accepted.

31 The Aldol Comparison Lewis Acid Base / Ac? Yield (%) dr Major Diastereomer Mukaiyama n(tf) 2 EP nly ~20:1 agao/fujita n(tf) 2 EP o Yes ~8:1 ~25:1 on-evans syn on-evans syn Miller Bu 2 BTf 2 Et both o ~20:1 Evans syn Yan Crimmins Urpi Evans TiCl 4 Bu 2 BTf 9-BB(Tf) TiCl 4 TiCl 4 MgBr 2 Et 2 2 Et sparteine 2 Et Et 3 Yes o nly o o Yes o ~50:1 ~20:1 ~20:1 ~25:1 ~25:1 ~8:1 ~15:1 on-evans syn Evans syn Either syn Either syn on-evans anti Evans anti Mukaiyama: stoichiometric chiral ligand agao/fujita: applied to many syntheses Miller: ester substituent on auxiliary Yan: camphor-based auxiliary Crimmins: either syn diastereomer Urpi: anti addition to dimethyl acetals Evans: anti selective, mild Lewis acid 30-aldol comparison 3/1/02 11:30 AM

32 Iminium Addition: agao and Fujita 1.4 equiv equiv n(tf) equiv. EP TF, 78 C, 3 h 2. Ac, TF, 0 C 1 1 dr Total Yield (%) Bn Bn ()Cbz 19:1 "10 50:1" 32:1 32:1 32:1 24:1 99:1 82 "75-85" eactions complete within 30 min Acetate and propionate nucleophiles were enolized at 50 C. Yield of propionate adducts not specified 31-agao imine addn 1 2/28/02 7:29 PM agao, Y.; Fujita, E. J. Am. Chem. oc. 1986,108, agao, Y.; Fujita, E. J. Chem. oc., Chem. Commun. 1986,

33 Iminium Addition: agao and Fujita m Cl 1. 2 equiv n(tf) 2, 2.2 equiv EP TF, 78 C, 3 h equiv Ac n, TF, 0 C m Cl n m n dr 66:1 28:1 39:1 28:1 Total Yield (%) X c Further Elaboration: Alkaloids n LA 0 C reflux n m eactions complete within 2 h m Cl 44 69% agao, Y.; Fujita, E. J. Am. Chem. oc. 1988,110, agao imine addn 2 2/28/02 7:41 PM

34 Iminium Addition: agao 1.4 equiv equiv n(tf) equiv EP TF, 78 C, 3 h TM Ac, TF, 0 C 2 1 TM 1 dr Yield (%) Et 2 9:1 10:1 4:1 6: Matched case required for synthetically useful selectivity electivity much lower than for unsubstituted azetidinones. agao, Y. J. rg. Chem. 1992, 57, agao chiral imine 2/28/02 7:29 PM

35 Iminium Addition: agao equiv n(tf) equiv EP TF, 78 C, 30 min equiv., TF, 0 C, 2 h Ac dr a Isolated Yield (%) purified dr b C 6 11 Bn 1:1 3.6:1 1.6:1 1.6: :1 4.9:1 6:1 Why this turnover to anti selectivity? a) dr = major : Σ minor b) dr of chromatographically purified product agao, Y. Tetrahedron Lett. 1988,47, agao me iminium 2/28/02 7:30 PM

36 Iminium Addition: agao Cyclic Acyclic n Tf n Tf yn Anti agao, Y. Tetrahedron Lett. 1988,47, agao imine model 3/2/02 11:19 AM

37 Crossed Claisen: agao Li, MPA, TF, 78 C 2., 15 min C 6 4 Bu Bu t-bu t-bu t-bu Yield (%) ee (%) Ar Isobutyrylthione behaved analogously in both yield and selectivity. Proposed Transition tate MPA, aromatic 1 appear to be essential for high selectivity. 36-agao Claisen 2/28/02 2:57 PM Large 2 led to decreased yields. agao, Y. J. rg. Chem., 1988, 53,

38 Dieckmann Annulation: agao and Fujita Initial bservation: C 2 2 equiv K TF, rt, 10 h 69%, 96% ee K ationale: C 2 C 2 eaction was later repeated with a methyl ester in the place of the thioester. 37-agao Dieckmann 1 2/28/02 7:44 PM agao, Y., Fujita, E. Chem. Lett. 1987, agao, Y. J. rg. Chem., 1988, 53,

39 Pyrone ynthesis: agao TB n(tf) 2, EP C 2 Cl 2, 40 C, 2 h 63% Tf Tf n n Tf 38-agao pyrone 2/28/02 7:42 PM agao, Y. Chem. Lett 1992,

40 Diels-Alder: Evans 10 mol% Cu(Tf) 2, 11 mol% L* C 2 Cl 2 CEt L* Isolated Yield (%) endo:exo 96:4 92:8 84:16 endo ee (%) CEt :7 92:8 90: L* = 3 C C 1 3 Thiones react at lower temperatures than oxazolidinones (typically 40 C instead of 20 C). Thiones and oxazolidinones react comparably with Cu(II)box. With the bisimine ligand, however, thiones exhibit much better endo:exo selectivity (done typically 2 4:1). Ar Ar 2 (Ar = 2,6-Cl 2 ) 39-Evans DA 2/28/02 7:32 PM Evans, D.; Miller,.; Lectka, T. J. Am. Chem. oc. 1993, 115, Evans, D.; Lectka, T.; Miller,. Tetrahedron Lett. 1993, 34,

41 Thione-Based earrangements ncl 4, C 2 Cl 2 2 ncl 4 2 ncl 3 ncl 3 Et 4-Cl Total Yield (%) dr 50:1 50:1 50:1 7:1 3:1 eactions were conducted at 78 C except for aromatic substrates, which were warmed to room temperature. The camphor-based auxiliary was superior in both yield (typically 85%) and selectivity (by ~5%) but is more difficult to draw. eactions were 0.01 to 0.05 M in substrate. Palomo, C. J. Am. Chem. oc. 2001, 123, Palomo earr 2/28/02 7:44 PM

42 Thione-Based earrangements Aldol Product earrangement C Et C 2 Cl 2 2 C C 1 2 Propionates are unreactive. Competitive with methanolysis for hindered substrates Thermal Carbamate earrangement Adamczyk, A. Tetrahedron Lett. 1995, 36, C', C 2 Kt-Bu C' C 2 oppe, D. Chem. Ber. 1976, 109, earrangements 11/5/63 7:20 AM

43 ther eactions elenylation Bn 1. LDA, DMPU, TBCl 2. ecl, TF, C 2 Cl 2 Bn e 37% dr = 6:1 olmes, A. Tetrahedron: Asymmetry 1992, 3, Electroreductive Coupling 2 equiv X Bn e (0.1 A) Et 4 Ts, C 3 C X =, 68%, ee = 74% X =, 69%, ee = 66% Decarboxylation occurs under the reaction conditions. Kise,. J. rg. Chem. 1998, 63, olmes elenylation 2/28/02 7:45 PM

44 otochemical earrangement: akamoto 1 2 hν, C C % dr = 3: Isolable for 1 = 2 = "Impossible to determine stereochemistry" Major byproduct is deacylated thione. Endocyclic-oxygen analog gives similar results. Thiazolidinethiones and oxazolidinethiones yield solely deacylation products. 43-sakamoto 1 2/28/02 7:45 PM akamoto, M. J. Chem. oc., Perkin Trans ,

45 otochemical earrangement: akamoto hν, C 6 6 X X n rt n [2 + 2] X X n n X =, n = 2 X n Yield (%) Product structure confirmed by X-ray crystallography For X =, n = 2, product A was formed in 64% yield: A 44-sakamoto 2 2/28/02 7:45 PM akamoto, M., ishio, T. J. rg. Chem. 1992, 57,

46 otochemical earrangement: akamoto X n hν, C 6 6 rt X + n 1 2 X n X n Yield (%) tereochemistry supported by E studies Proposed mechanism is analogous to previous case sakamoto 3 2/28/02 7:33 PM akamoto, M. J. Chem oc., Perkin Trans ,

47 otochemical [2 + 2]: ishio hν, C 6 6 =, 59% =, 7% Ac imilar results for other -acyl groups in the starting material: isobutyryl, phenylacetyl, isovaleryl, hydrocinnamyl. M calculations suggest that substitution α to sulfur stabilizes the iminothietane. E/Z selectivity of the iminothietane products was not mentioned; in fact, the product in the paper is drawn as E, despite the Z-configured crystal structure featured in the text. ishio, T. J. Chem. oc., Perkin Trans , =, 0% =, 52% 46-ishio /28/02 7:46 PM

48 ummary Thioimides have been used extensively as acylating agents, especially for amide synthesis. alf-reduction of thioimides directly to aldehydes is possible. By far, the aldol is the most common reaction with thioimide auxiliaries. Yield and selectivity vary, but the best systems are viable options to the venerable oxazolidinones. Facile cleavage may be the thioimide's greatest asset. ther enolate reactions include Claisen, Dieckmann, iminium addition, and selenylation. With few exceptions, soft enolization is essential. Thiocarbonyl photochemistry may lead to multiple products. o asymmetric reactions have been reported. earrangement of aldol products and starting acylthiones is a potential danger. More complex enolates and aldehydes have been used in the context of natural product synthesis by the following groups: Crimmins, orikawa, uber, Kibayashi, Kocienski, agao/fujita, Paquette, izzacasa, omo, hiori, ulikowski, Thomas, and Urpi/Vilarrasa. 47-summary 2/28/02 7:47 PM