CHAPTER 3. base O N R R = C 5 H 11 OTHP. OBn. OBn. Ti(OiPr) 4, D-( )-DET t-buooh, MS 4Å 20 C, 4 d MOMO. OBn + MOMO OMOM MOMO OH

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1 Chpter 3 1 CPTER 3 1. The produt is the ldehyde, nd the mehnism is nlogous to the DMS-sed oxidtions disussed in Setion 3.2.C. resonle mehnism is shown. Pyridine -oxide ttks the romomethyl moiety vi n S 2 mehnism. Upon heting, pyridine -oxide (or eventully the pyridine y-produt) removes the hydrogen, s shown, with displement of pyridine (the leving group) to generte the ldehyde. This is relted to DMS oxidtions of lohols in tht leving group is tthed to the oxygen in, mking the -hydrogen suseptile to removl y se. See J. rg. Chem., 1999, 64, R R = C 5 11 TP se R R 2. These regents re used for the Shrpless symmetri epoxidtion. Using the Shrpless model shown, ( )-DET will deliver the epoxide oxygen from the front of the (R)-enntiomer of the remi lohol to give the epoxide shown. Sine the (S)-enntiomer is mismthed for this hirl dditive, it will ret muh slower so it is possile to onvert the (R)-enntiomer to the epoxide while the (S)-enntiomer does not ret. Therefore, the uthors in the ited pper isolted the unreted enntiopure lohol for use in their synthesis. This proess is lled kineti resolution. MM Bn Ti(iPr) 4, D-( )-DET t-bu, MS 4Å 20 C, 4 d MM Bn + MM Bn see Synthesis, 1993, 615 vi "" D-( )-DET MM Bn 3. () This retion is tken from J. m. Chem. So., 2002, 124, The epoxidtion must tke ple from the top fe, s the moleule is drwn, to give the proper stereohemistry of the lohol unit. The lohol is formed y removl of the ketone -hydrogen with the se (DBU - se. 2.9.), formtion of the C=C unit nd opening the epoxide ring. The stereohemistry of epoxidtion is diserned from the model (C=C lkene rons nd B re mrked. It is not ompletely ovious from the model tht the top fe is less hindered euse of the methyl group, ut the fused five-memered rings re somewht pukered, nd this loks pproh of the ulky met-

2 2 rgni Synthesis Solutions Mnul hloroperoxyenzoi id from the ottom. rememer tht the trnsition stte for this epoxidtion is rther ulky (se. 3.4.C). B 1. mp, C 2 Cl 2 2. DBU B () This is Beyer-Villiger rerrngement, nd the ron est le to er positive hrge is the one tht migrtes. The tertiry ridgehed ron therefore migrtes in preferene to the primry ron. () xidtion of phenol with Fremy's slt shows preferene for the pr quinone. The reson is formtion of the intermedite r-(s 3 K) 2. This rther ulky sustituent shows less steri hindrne with the oxygen in the pr position thn it does in the ortho position. Relief of steri hindrne therefore drives this retion to give the pr intermedite nd, therey, the pr quinone. (d) In generl, lkenes ering eletron withdrwing groups ret slower thn simple lkenes. There is lso steri effet tht my ly role, sine dihydroxyltion usully ours t the less sterilly hindered site. See J. m. Chem. So., 1999, 121, () In this retion, the tive regent is the hydroperoxide nion ( ). Conjugte ddition to the, unsturted ronyl ours from the fe of the moleule opposite the methyl groups in order to minimize steri hindrne. The resulting enolte nion ttks the eletrophili oxygen to generte n epoxide, with loss of hydroxyl. Steri hindrne with the methyl groups dittes delivery of from the ottom fe of the moleule, nd the retion proeeds with high distereoseletivity for the produt shown. too hindered

3 Chpter 3 3 () The regents will indue is hydroxyltion of the lkene. s drwn, the regent will e delivered from the less sterilly hindered exo fe to give the mjor produt. The primry soure of this steri hindrne is the hydrogen ridging ether unit on the ottom side of the ring, whih interts with ny regent pprohing from tht fe. In simple iylo[2.2.1]heptene, out 20-30% delivery of regent from the endo fe is ommon, ut here the ridging ether effetively prevents this. t s 4, M, q TF 10 C RT see Synthesis, 1996, 219 () The mjor produt desried in J. m. Chem. So., 2002, 124, 9726 is the diol shown. There my e neighoring group effet involving the llyli lohol unit to diret the dihydroxyltion vi pth 1. Inspetion of the model suggests tht the top fe is less hindered, nd tht pproh to rons /B (pth 1) my e somewht less hindered thn pproh to rons C/D (pth 2). It is likely tht the regioseletivity rises from omintion pth 1 eing less hindered nd the neighoring group ssistne provided y the llyli. 2 1 D C B s 4 69% C D B (d) In this retion, the presene of the hydroxyl group might e expeted to provide neighoring group effet, pling the epoxy-oxygen syn to the. quik look t the 3D model, however, shows tht the onformtion of the 8-memered ring ples the more or less t right ngles to the -ond so one fe is not fvored over the other vi oordintion. This retion is dominted y steri effet, nd the top fe () is less hindered, leding to the stereohemistry shown MCPB, C 2 Cl 2 74% see J. rg. Chem., 2000, 65, 9129

4 4 rgni Synthesis Solutions Mnul (e) In the first retion, the mild Dess-Mrtin proedure onverts the llyli lohol unit to onjugted ketone. In the seond step, the D-mix- delivers dihydroxyltion from the top fe to give the diol shown, with high distereoseletivity nd enntioseletivity. Using the Shrpless model, D-mix- should deliver the hydroxyls from the ottom ut in tht model, ottom is reltive to the methyl groups t the llyli position. Therefore, delivery opposite the methyl groups leds to the stereohemistry shown. This sequene is tke from Lee's synthesis of mphidinolide B1 (see referene). Si 2 t-bu PMB SiiPr 3 Si 2 t-bu Si 2 t-bu SiiPr 3 Si 2 t-bu? PMB Si 2 t-bu SiiPr 3 Si 2 t-bu? PMB () Dess-Mrtin periodinne, pyridine, C 2 Cl 2 () D-mix-, S 2 2, q t-bu see Tetrhedron Lett., 2000, 41, These three retions involve Shrpless symmetri epoxidtion. The model in Figure 3.2 is used to predit delivery of the regent from the re or si fe. t-bu, ( )-DET Ti(i-Pr) 4, C 2 Cl 2 see J. rg. Chem., 2000, 65, 1738 () When oriented ording to Figure 3.2, ( ) trtrte delivers from the ottom fe to give the epoxide with the stereohemistry shown. () Using the sme model from Figure 3.2, the llyli lohol is ligned s shown, nd ( )-trtrte should pproh from the k for est seletivity. This would led to the stereohemistry shown with the epoxy unit to the rer nd the methyl projeted to the front. otie tht the llyli ette unit ws not epoxidized under these onditions, only the llyli lohol unit.

5 Chpter 3 5 t-bu, ( )-DET Ti(iPr) 4, C 2 Cl 2 see Tetrhedron Lett., 2000, 41, 2181 ( )-trtrte () Using the model from Figure 3.2, the orienttion of the llyli lohol using ( )-DIPT delivers the oxygen from the ottom, s shown. The smller ethyl group is on tht fe, nd the epoxide shown is generted with good stereoseletivity. ( )-trtrte 6. The mjor produts of eh retion re shown in the following sequene. Si 2 t-bu Si 2 t-bu?? Si 2 t-bu? Si 2 t-bu () enzoyl hloride (), + () I 4 J. m. Chem. So., 1999, 121, 5589 ()??? () BuLi, ether-dms ; I () 3 ; P 3 () PDC, DMF () J. rg. Chem., 2000, 65, 3738

6 6 rgni Synthesis Solutions Mnul 7. This sequene is tken from J. m. Chem. So., 2002, 124, Swern oxidtion (3.2.C.i) gives the ketone, whih elimintes the tosyl group in the presene of triethylmine (vi removl of the idi -hydrogen with onomitnt loss f the tosyl) to give the onjugted ketone. n internl onjugte ddition of the pyrrole unit (lso see 9.7.) leds to the oserved produt. Tol 2 S 2 2 Et 3 DMS, (CCl) 2 67% Tol 2 S 2 2 Ts The initil retion is the expeted oxidtion of the enzyli lohol to the ldehyde. This is suseptile to ttk y the pendnt unit, to form protonted hemietl, nd loss of the proton gives the hemi-etl. If the unit is oxidized further with Mn 2 tht is still present, the oserved ltone is otined. + Mn 2 Mn 2 Mn 2, C 2 Cl 2 C + see eteroyles, 1996, 42, 589 2% 98%

7 Chpter () Si 2 t-bu PMB Si 2 t-bu PMB B () rg. Lett. 2002, 4, 443 () (i-pr) 3 Si J. rg. Chem., 2003, 68, 4215 (d) J. rg. Chem., 2002, 67, 2566 Si 2 t-bu (e) rg. Lett., 2002, 4, 19 (f) J. rg. Chem., 2003, 68, 1030 (g) PMB PMB - p-methoxyenzoyl J. m. Chem. So., 2002, 124, 5654 Si 3 (h) C 2 t-bu see J. m. Chem. So., 1999, 121, 9574 (i) C C J. rg. Chem., 2003, 68, 1242 (j) Cl see J. Chem. So., Perkin Trns 1, 1993, 1095 (k) C (l) C (m) 2 M e see J. m. Chem. So., 1979, 101, 4400 J. rg. Chem., 2003, 68, 7428 Tetrhedron,2003, 59, 9239

8 8 rgni Synthesis Solutions Mnul (n) PMB C 2 PMB = p-methoxyenzyl J. rg. Chem., 2003, 68, 7818 (o) see J. rg. Chem., 2000, 65, 9129 (p) Et Bn see J. m. Chem. So., 1987, 109, 5878 (q) Si 2 t-bu C see J. rg. Chem., 2000, 65, 3432 (r) C J. rg. Chem., 2003, 68, 7548 (s) see p 137 (Cope elimintion) t-bu 2 Si (t) see J. m. Chem. So., 1999, 121, 5087 (u) J. m. Chem. So., 2004, 126, 2194 (v) C 2 t-bu 2 C(4-2 -C 6 4 ) see J. rg. Chem., 2002, 67, 7774 C C 2 C C 2 t-bu (w) rg. Lett. 2003, 5, 3931 (x) t-bu 2 Si rg. Lett. 2002, 4, 1543 (y) Si(i-Pr) 3 ngew. Chem. Int. Ed., 2003, 42, 694 (z) () C C 2 t-bu () see Chem. Commun., 2000, 837 see Synthesis, 1998, 479 rg. Lett. 2002, 4, 909

9 Chpter 3 9 t-bu 2 Si C C 2 Et () Si 2 t-bu J. m. Chem. So., 2002, 124, (d) see rg. Lett., 2000, 2, 3177 (e) 2 C see rg. Lett., 2000, 2, In eh se one exmple of suitle synthesis is shown. In mny, perhps most, ses there re other syntheti pprohes tht re resonle. () The shortest pproh is to use the pproprite Grignrd regent with the ldehyde derived from oxidtive levge of diol, derived from hydrolysis of the strting epoxide. The Grignrd retion is disussed in Setion 8.4.C. C d () q. + () s 4, I 4 () C 2 C 2 Mg ; 2 (d) PCC () See the tul synthesis in Chem. Lett., 1979, This pertinent retions re outlined elow. 2 C 2 C 2 C 2 C d 2 C C e () 3 ; 2 2 () SCl 2 ; () B 4 ; 3 + (d) PCl 3, pyridine (e) 3 ; 2 S () It is very possile tht the hydroxy id will spontneously ylize to the ltone. The id tlysis in step d is dded s formlism sine six-memered ring ltones re somewht hrder to form thn five-memered ring ltones, whih spontneously form from hydroxy ids in virtully ll ses. Step is redution nd the funtionl group retion wheel in Chpter 1 (Figure 1.1) provides severl possile regents, inluding sodium orohydride, whih will e disussed in Setion

10 10 rgni Synthesis Solutions Mnul 2 C 2 C () K, Et () 3 ; 2 2 () B 4 ; 3 + (d) + d (d) This retion uses Beyer-Villiger rerrngement (Se. 3.6.) to set the oxygen on the ylohexne ring. Eventul oxidtion leds to the ketone tht n e onverted to its dioxolne ketl. d () MCPB () i. q K ii. q + () PCC (d) 1,2-ethnediol, t + (e) The onversion of the lohol to the lkene involves Chugev elimintion (see Se. 2.9.C.iv). ther syn elimintion methods ould e used if the lohol were onverted to nother funtionl group. d () 3 ; 2 S () B 4 ; 3 + () i. CS 2 ii. I iii. 200 C (d) MCPB (f) n E2 retion gives the lkene, llowing selenium dioxide oxidtion to the llyli lohol. xidtion to the id with PDC in DMF is followed y onversion to the id hloride nd quenhing with mmoni to give the mide. d 2 () K, Et () Se 2 () PDC, DMF (d) i. oxlyl hloride ii. 3 (g) n E2 retion gives ylohexene nd epoxidtion followed y n id-tlyzed ring opening in the presene of methnol gives 2-methoxy ylohexnol. xidtion gives the ketone nd Swern oxidtion ws used here, lthough most of the milder onditions in this hpter would suffie. d () K, Et () MCPB (), t + (d) Swern oxidtion

11 Chpter 3 11 () () () (d) C C C 2 (h) (i) () MCPB () C, DMF ; hydrolysis () i. ii. I (d) i. q ii. 3 + C 2 2 () PCl 3, pyridine () 3 ; 2 2 () i. SCl 2 ii. 2 (j) xidtion of the seondry lohol in the presene of the tertiry lohol requires mild oxidizing gent. Severl regents re ville, inluding tetrpropylperruthente nd the Dess-Mrtin regent shown. () s 4, M () Dess-Mrtin periodinne (k) Elimintion of the lohol with PCl 3 (Se. 2.8.) nd pyridine gives the lkene, nd ozonolysis leds to the methyl ketone. The finl step is Beyer-Villiger rerrngement. () PCl 3, pyridine () 3, 2 S () MCPB d e 3 (l) () MCPB () i. q K ii. q + () PCl 3, pyridine (d) MCPB (e) 3, TF (m) This diol to ketone rerrngement is the pinol rerrngement (see Se ). () s 4 ; M () +