UflHBUseful HBr-elimination of vicinal dibromides having ... · UflHBUseful HBr-elimination of...
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U f lHB li i ti f ii l dib id h i dj tO f ti l Useful HBr elimination of vicinal dibromides having an adjacent O functional group: Useful HBr-elimination of vicinal dibromides having an adjacent O-functional group: Useful HBr elimination of vicinal dibromides having an adjacent O functional group: A li ti i t ti d t l d t th i Applications in one pot reaction and natural product synthesis Applications in one-pot reaction and natural product synthesis Applications in one pot reaction and natural product synthesis Noriki Kutsumura * Akito Kiriseko and Takao Saito* Noriki Kutsumura,* Akito Kiriseko, and Takao Saito* Noriki Kutsumura , Akito Kiriseko, and Takao Saito Department of Chemistry Faculty of Science Tokyo University of Science Kagurazaka 1 3 Shinjuku ku Tokyo 162 8601 Japan Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan O O CO Me OH regioselective elimination ref. 1 ref. 3 CO 2 Me OH regioselective elimination major minor O O O major minor O O O O O O C C b d Br " ild b " (1 2 i ) O (±) Unsaturated ester ref 1a O (±) 12 Hydroxytremetone ref 1a OH R 3 Me O C–C bond Br R 3 2 R 3 "mild base" (1–2 equiv) (±)- , -Unsaturated ester ref. 1a (±)-12-Hydroxytremetone ref. 1a OH (+) Tanikolide R 2 R 3 f or mation easily prepared disubstituted R 2 R R 2 Br R (no name natural product) (Bitalin A) (+)-Tanikolide R 2 allyl alcohol derivatives R O Tetr ahedr on Lett. 2004 , 45, 8273. allyl alcohol derivatives Br OR 1 OR 1 O Bul l . Chem. Soc. Jpn. 2005 , 78, 1549. OR 1 R 5 Slide No.6 Br R 3 OR 1 OR Tot al Synt heses of OAc Bul l . Chem. Soc. Jpn. 2005 , 78, 1549. R one pot gishi O ref 2 Br R 2 R Tot al Synt heses of N t l P d t OAc one-pot thr ee step sequence Negish (+) Heteroplexisolide E br omine ref. 2 Nat ur al Pr oduct s thr ee-step sequence (+)-Heteroplexisolide E br omine dditi OR 1 3 "mild base" O R 4 addition Slide No.8–10 OR R 2 R 3 (±) 12 Acetoxytremetone ref. 1a R 4 3 rd f 1 R 2 (±)-12-Acetoxytremetone O R 3 Br S hi 1 st Pyr HBr ref. 1 Use of one pot regioselective DBU TBAF (5 i ) O R 5 R 2 R 3 2 R 3 Br Sonogashira 1 st Pyr.-HBr 3 Use of one-pot regioselective N i hi li OR 1 DBU or TBAF (5 equiv) O R 5 R 2 R 3 R 2 Negishi coupling O O 1 R 2 R 3 d Slid N 5 f 2 O O O O OR 1 R OR 1 R 5 2 nd DBU Slide No.5 two-step elimination ref. 2 O OH OR 1 OR R 5 S highly regio and stereoselective nC 12 H 25 OH OR 1 R 5 Suzuki highly regio- and stereoselective HO nC 12 H 25 uki r egioselective Slide No.3–4 synthesis of trisubstituted alkenes mild base: 2 equiv. of NaOAc, NaOPiv, iPr 2 NEt, K 2 CO 3 HO T li li B ( ) (R R) S i f B ref 2 OH elimination Slide No.3 4 mild base: 2 equiv. of NaOAc, NaOPiv, iPr 2 NEt, K 2 CO 3 1 i f DBU DBN DABCO TBAF ref 4 Tulipalin B (–)-(R,R)-Sapinofuranone B ref. 2 OH 1 equiv. of DBU, DBN, DABCO, TBAF ref.4 Heter ocycl es 2004 , 63, 2349. ( )-Muricatacin ref. 2b 4 One pot reaction is of great significance from Slide No.7 (–)-Muricatacin R 4 One-pot reaction is of great significance from ref. 1 (regioselective elimination) ref. 3 (Accounts) One-pot method for chemoselective bromination of allyl alcohol derivatives both economical and ecological points !! ref. 1 (regioselective elimination) ( ) Oh i T Ni hi S * Ch L tt 2004 33 1084 ref. 3 (Accounts) ( ) Oh i T K N Ni hi S * J S h O Ch J 2008 66 139 2 R 3 and sequential C–C bond formation in same pot have been developed U f O R i (a) Ohgiya, T.; Nishiyama, S.* Chem. Lett. 2004 , 33, 1084. (a) Ohgiya, T.; Kutsumura, N.; Nishiyama, S.* J. Synth. Or g. Chem., Jpn. 2008 , 66, 139. R 2 R and sequential C–C bond formation in same pot have been developed. Use f or One-pot React i on f 2 (fi t t t l th i f (+) h t l i lid E) (b) Kutsumura N *; Iijima M ; Toguchi S ; Saito T * Chem Lett 2011 40 1231 (b) Ohgiya T *; Kutsumuram N ; Nishiyama S * Synl ett 2008 3091 ref. 2 (first total synthesis of (+)-heteroplexisolide E) ( t l t t l t h i ) (b) Kutsumura, N. ; Iijima, M.; Toguchi, S.; Saito, T. Chem. Lett. 2011 , 40, 1231. (b) Ohgiya, T. ; Kutsumuram N.; Nishiyama, S. Synl ett 2008 , 3091. OR 1 R 5 ref. 1 (one-pot bromination and sequential Sonogashira coupling) (a) Kutsumura N *; Kiriseko A ; Saito T * Tetr ahedr on Lett 2012 53 3274 ( not onl y t ot al synt hesi s) ref. 2 (two-step elimination) ref. 4 (TBAF-promoted regioselective and two-step elimination) OR R 5 ref. 1 (one pot bromination and sequential Sonogashira coupling) K t N * Ni K S it T * O L tt 2010 12 3316 M t R d A ti l J l 2010 (a) Kutsumura, N. ; Kiriseko, A.; Saito, T. Tetr ahedr on Lett. 2012 , 53, 3274. (b) K t N * Ki i k A S it T * H t l 2012 86 i (a) Kutsumura N ; Yokoyama T ; Ohgiya T ; Nishiyama S * Tet r ahedr on Lett 2006 47 4133 (a) Kutsumura N *; Kubokawa K ; Saito T * Synl ett 2010 2717 ; Most Accessed Articles Nov 2010 Kutsumura, N.*; Niwa, K.; Saito, T.* Or g. Lett. 2010 , 12, 3316.; Most Read Articles, Jul. 2010. (b) Kutsumura, N.*; Kiriseko, A.; Saito, T.* Heter ocycl es 2012 , 86, in press. (a) Kutsumura, N.; Yokoyama, T.; Ohgiya, T.; Nishiyama, S. Tet r ahedr on Lett. 2006 , 47, 4133. (a) Kutsumura, N. ; Kubokawa, K.; Saito, T. Synl ett 2010 , 2717.; Most Accessed Articles, Nov. 2010. (b) Yokoyama, T.; Kutsumura, N.; Ohgiya, T.; Nishiyama, S.* Bul l . Chem. Soc. Jpn. 2007 , 80, 578. (b) Kutsumura, N.*; Kubokawa, K.; Saito, T.* Synthesi s 2011 , 2377. (Invited Special Issue); Most Accessed Articles, Aug.–Sep. 2011. Method B: 4 Method A: M th d A Method B: R 4 Method A: Br i) Pyr.-HBr 3 Method A: 3 Br Br NO 2 Br B B ii) DBU i) Pyr.-HBr 3 iii) alkyne (1 5 equiv) B B ii) DBU i) Pyr.-HBr 3 iii) Me Zn M 2 Br R 3 ii) DBU (3.1 equiv) 3 (1.1 equiv) R 5 R 2 R 3 2 R 3 Br O Br Br NO 2 Br Br Br R 3 Br R 3 (1 1 equiv) 2 R 3 3 (1 1 equiv) iii) alkyne (1.5 equiv) CuI (0 1 equiv) Br R 3 Br R 3 ii) DBU (3 1 equiv) 2 R 3 i) Pyr. HBr 3 (1 1 equiv) iii) Me 2 Zn (4 0 equiv) R 3 Me R 2 R R 5 R 2 R 2 R 5 O O Br O Br R 2 R R 2 R (1.1 equiv) R 2 R (1.1 equiv) CuI (0.1 equiv) 3 Br R 2 R 3 R 2 R 3 (3.1 equiv) R 2 R (1.1 equiv) (4.0 equiv) R 2 R 3 (CH Cl) i l ti O OTIPS Br R R K CO R 2 R 3 Br R R R OR 1 (CH 2 Cl) 2 OR 1 OR 1 R 5 Br r egioselective nPr OTIPS OR 1 OR 1 OR 1 K 2 CO 3 PdCl 2 (PPh 3 ) 2 R 2 OR 1 OR 1 OR 1 CH 3 CN PEPPSI TM -IPr OR 1 OR OR R Br elimination or CH 3 CN nPr NO 2 O OR 1 OR 1 OR (1.1 equiv) (5 mol%) OR 1 OR 1 OR 3 (5 mol%) OR 1 2 A 100% (>99/1) A 87% (31/1) A : 69% (10/1) A 92% (18/1) (CH 2 Cl) 2 Et 3 N (2.0 equiv) OR 1 CH 3 CN-THF Method A: A mixture of s.m. (1.0 equiv) and Pyr.-HBr 3 (1.1 equiv) in solvent was stirred at rt. A : 100% (>99/1) A : 87% (31/1) A : 69% (10/1) A : 92% (18/1) (CH 2 Cl) 2 Et 3 N (2.0 equiv) rt CH 3 CN THF R 1 acyl, phenyl 60 ºC Method A: A mixture of s.m. (1.0 equiv) and Pyr. HBr 3 (1.1 equiv) in solvent was stirred at rt. DBU (3 1 equiv) was added to the mixture at 0 ºC and the reaction system was B : 95% (>99/1) B : 78% (28/1) B : 60% (12/1) B : 89% (17/1) R 1 acyl rt 60 ºC DBU (3.1 equiv) was added to the mixture at 0 C and the reaction system was then heated to 60 ºC R acyl then heated to 60 ºC. NO 2 nPen tBu nPen Ph tBu Me Br Br NO 2 OMe Br NO 2 nPen tBu nPen Ph tBu Me Br O Br OMe O 2 M M OMe M Cl O Method B: i) Pyr.-HBr 3 Br Br O O O Me Me Me ii) DBU (1 1 equiv) Method B: 3 (1 1 equiv) Br R 3 R 3 Br R 3 O Br O O O O ii) DBU (1.1 equiv) (1.1 equiv) R 2 R R 5 R 2 R R 5 R 2 R O Br O O O O O O O O O OMe K CO i l ti R R A : 90% (>99/1) A : 91% (49/1) O O O 76% 80% 81% 48% (Me Zn 6 equiv) OMe K 2 CO 3 (1 1 equiv) r egioselective OR 1 Br OR 1 R 5 OR 1 A : 90% (>99/1) B 93% ( 99/1) A : 91% (49/1) B 92% (40/1) A : 92% (20/1) A : 91% (>99/1) 76% 80% 81% 48% (Me 2 Zn, 6 equiv) (1.1 equiv) elimination OR 1 Br OR R 5 OR B : 93% (>99/1) B : 92% (40/1) A : 92% (20/1) A : 91% (>99/1) OMe OMe OMe Me OMe (CH 2 Cl) 2 O 84% OMe 94% 93% 81% OMe 91% OMe Me M Me OMe 2 2 or CH 3 CN O NO Cl 84% 94% tB 93% 81% 91% O Me Me or CH 3 CN O Br NO 2 Br Cl tBu OTBDPS nPr O Method B: A mixture of s.m. (1.0 equiv), Pyr.-HBr 3 (1.1 equiv), and K 2 CO 3 (1.1 equiv) in solvent Br Br Br O Br nPen OTBDPS nPr 3 2 3 was stirred at rt. DBU (1.1 equiv) was added to the mixture at 0 ºC and the reaction Br O O OPMB O OMe nPen was stirred at rt. DBU (1.1 equiv) was added to the mixture at 0 C and the reaction system was then heated to 60 ºC Br OPMB O O 81% OMe 84% 82% nPen system was then heated to 60 C. OPMB O O O O 81% 84% O 82% A 94% (57/1) O O O OPMB O Me Bromine addition Tr ans addition A : 94% (57/1) A : 34% (8/1) B : 90% (20/1) B : 90% (15/1) OPMB P OPMB tBu tBu Me Me O Me Bromine addition Tr ans addition B : 94% (21/1) A : 34% (8/1) : 90% (20/1) B : 90% (15/1) OPMB nPr NO tBu tBu OTBDPS OPMB P O OPMB DBU-Promoted elimination Regioselective tr ans elimination 82% 77% NO 2 28% 70% OTBDPS OPMB nPr Me 82% 77% 28% 70% Me Kutsumura N *; Niwa K ; Saito T * Or g Lett 2010 12 3316 Kutsumura N *; Niwa K ; Saito T * Or g Lett 2010 12 3316 Kutsumura N *; Niwa K ; Saito T * Or g Lett 2010 12 3316 OPMB Kutsumura, N. ; Niwa, K.; Saito, T. Or g. Lett. 2010 , 12, 3316. M t R d A ti l J l 2010 Kutsumura, N. ; Niwa, K.; Saito, T. Or g. Lett. 2010 , 12, 3316. M t R d A ti l J l 2010 Kutsumura, N. ; Niwa, K.; Saito, T. Or g. Lett. 2010 , 12, 3316. M t R d A ti l J l 2010 79% 88% 87% (Me 2 Zn, 6 equiv) 74% Most Read Articles, Jul. 2010. Most Read Articles, Jul. 2010. Most Read Articles, Jul. 2010. 79% 88% 87% (Me 2 Zn, 6 equiv) 74% Method B: R 4 Pyr -HBr Me 2 Zn (6.0 equiv) Method B: R 4 O Pyr.-HBr 3 (1 1 equiv) O B DBU (3 1 equiv) O 2 PEPPSI TM -IPr O O Br Br Br ii) DBU i) Pyr.-HBr 3 iii) (HO) 2 B R 4 O O (1.1 equiv) CH CN t O Br DBU (3.1 equiv) 60 ºC O PEPPSI IPr (10 l%) O O Br Br R 3 Br R 3 (1.1 equiv) R 2 R 3 3 (1.1 equiv) iii) (3 0 equiv) R O CH 3 CN, rt O 60 ºC O (10 mol%) O O Br R 2 R R 2 R (1.1 equiv) R 2 (1.1 equiv) (3.0 equiv) R 3 O O O Pd-Catalyzed M M + K 2 CO 3 Pd(PPh ) (10 mol%) R 2 R 3 O Pd-Catalyzed Hydr ogenolysis Br Br 87% in one pot Me Me + OR 1 OR 1 OR 1 K 2 CO 3 (1 1 equiv) Pd(PPh 3 ) 4 (10 mol%) K CO (7 0 i ) R O O O Aldol Reaction Hydr ogenolysis OPMB OPMB OPMB 87% in one-pot Br OR OR CH CN (1.1 equiv) K 2 CO 3 (7.0 equiv) OR 1 O OPMB OPMB OPMB Br O O CH 3 CN DMF-H 2 O OR 1 O O 2 1 100 ºC Me CHO S N 2 product S N 2' products R 1 benzyl 100 C O O HO PMBO CHO S N 2 product S N 2 products (ca 6 : 4 mixture) O O PMBO O O O (ca. 6 : 4 mixture) (+) Heteroplexisolide E O 1. LDA, / THF O NO Cl ref 1 (+)-Heteroplexisolide E O O 2 Ac 2 O py DMAP rt i) DDQ / CH 2 Cl 2 -H 2 O nBu 3 SnH (1.1 eq.) NO 2 Cl R 4 ref. 1 O R i l ti Known O O 2. Ac 2 O, py., DMAP, rt ;then DBU / (CH Cl) 70 ºC i) DDQ / CH 2 Cl 2 H 2 O ii) PPTS acetone 50 ºC nBu 3 SnH (1.1 eq.) Pd(PPh 3 ) 4 (5 mol%) iii) (2.0 equiv) KF B R Isolation: from Heter opl exi s mi cocephal a O Regioselective Known P d O Me ;then DBU / (CH 2 Cl) 2 , 70 C ii) PPTS, acetone, 50 C Pd(PPh 3 ) 4 (5 mol%) toluene 100 ºC 10 min KF 3 B Activity: unknown O Negishi Coupling Pr ocedur e M Me toluene, 100 ºC, 10 min. PEPPSI TM -IPr (3 mol%) Activity: unknown O Me OPMB O 86% 2 steps 90% in one-pot 98% 2 steps PEPPSI IPr (3 mol%) K 2 CO 3 (5 0 equiv) OH OPMB OPMB O O 86%, 2 steps 90% in one-pot 98%, 2 steps Pd(OCOCF ) [ ] D 20 +74.0 (c 0.38, MeOH) K 2 CO 3 (5.0 equiv) MeOH 75 ºC 3 steps OH OPMB O O O Pd(OCOCF 3 ) 2 D lit [ ] D 20 +15 6 (c 0 27 MeOH) OPMB OPMB OPMB MeOH, 75 ºC OPMB PMBO 3 steps O O (10 mol%) lit. [ ] D +15.6 (c 0.27, MeOH) PMBO Commer cially O O toluene, 100 ºC, 10 h 86% 67% 65% 67% Et Chir al Building Block ref. 2 Commer cially Available Cl Et Chir al Building Block ref. 2 Available + (+)-Heteroplexisolide E Cl O O B O 94% NO CBr 4 , PPh 3 O O Br O 94% NO 2 ref. 1 CH 2 Cl 2 , rt O O O O O as a single pr oduct ! S Fan X ; Zi J ; Zhu C ; Xu W ; Cheng W ; Yang S ; Guo Y ; Shi J * J Nat Pr od 2009 72 1184 2 2 M M + O O ref. S OPMB OBn Fan, X.; Zi, J.; Zhu, C.; Xu, W.; Cheng, W.; Yang, S.; Guo, Y.; Shi, J.* J. Nat . Pr od. 2009 , 72, 1184. Me Me + Me (+)-Heteroplexisolide E OPMB OBn ref. 2 Br OH (8 : 1 mixture) OBn OPMB OPMB 75% OPMB 56% ref. 2 ( ) Zh L M t D R * O L tt 2003 5 3475 Br OH 75% 56% (a) Zhu, L.; Mootoo, D. R.* Or g. Lett. 2003 , 5, 3475. O O O ref. 72% 63% 70% 82% (b) Kutsumura N ; Yokoyama T ; Ohgiya T ; Nishiyama S * Tetr ahedr on Lett 2006 47 4133 S 2 product S 2' products (a) Kutsumura N *; Kiriseko A ; Saito T * Tetr ahedr on Lett 2012 53 3274 72% 63% 70% 82% (b) Kutsumura, N.; Yokoyama, T.; Ohgiya, T.; Nishiyama, S. Tetr ahedr on Lett. 2006 , 47, 4133. ( ) Y k T K t N Oh i T Ni hi S * B l l Ch S J 2007 80 578 S N 2 product S N 2 products (a) Kutsumura, N.*; Kiriseko, A.; Saito, T.* Tetr ahedr on Lett. 2012 , 53, 3274. (c) Yokoyama, T.; Kutsumura, N.; Ohgiya, T.; Nishiyama, S.* Bul l . Chem. Soc. Jpn. 2007 , 80, 578. (ca. 6 : 4 mixture) (b) Kutsumura, N.*; Kiriseko, A.; Saito, T.* Heter ocycl es 2012 , 86, in press. Thi k tl tdb th S k Si tifi R hG tf Th J Si S it This work was partly supported by the Sasakawa Scientific Research Grant from The Japan Science Society. This work was partly supported by the Sasakawa Scientific Research Grant from The Japan Science Society.
Transcript of UflHBUseful HBr-elimination of vicinal dibromides having ... · UflHBUseful HBr-elimination of...
U f l HB li i ti f i i l dib id h i dj t O f ti lUseful HBr elimination of vicinal dibromides having an adjacent O functional group:Useful HBr-elimination of vicinal dibromides having an adjacent O-functional group:Useful HBr elimination of vicinal dibromides having an adjacent O functional group:g j g pA li ti i t ti d t l d t th iApplications in one pot reaction and natural product synthesisApplications in one-pot reaction and natural product synthesisApplications in one pot reaction and natural product synthesispp p p y
Noriki Kutsumura * Akito Kiriseko and Takao Saito*Noriki Kutsumura,* Akito Kiriseko, and Takao Saito*Noriki Kutsumura, Akito Kiriseko, and Takao SaitoDepartment of Chemistry Faculty of Science Tokyo University of Science Kagurazaka 1 3 Shinjuku ku Tokyo 162 8601 JapanDepartment of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japanp y, y , y y , g , j , y , p
O OO O
CO Me OHregioselective elimination ref. 1 ref. 3 CO2Me OHregioselective elimination
major minor O O Omajor minor O OO OO
OC C b d
Br" ild b " (1 2 i )O
(±) Unsaturated esterref 1aO
(±) 12 Hydroxytremetoneref 1aOH R3Me OC–C bondBr
R32R3"mild base" (1–2 equiv) (±)- , -Unsaturated esterref. 1a (±)-12-Hydroxytremetoneref. 1aOH
(+) Tanikolide R2R3formationeasily prepared disubstitutedR2R R2Br
R(no name natural product) (Bitalin A)(+)-Tanikolide R2y p p
allyl alcohol derivativesR ( p ) ( )
OTetrahedron Lett. 2004, 45, 8273.
1
allyl alcohol derivatives
Br OR1 OR1 OBull. Chem. Soc. Jpn. 2005, 78, 1549. OR1R5Slide No.6Br
R3 OR1 ORTotal Syntheses of OAc
Bull. Chem. Soc. Jpn. 2005, 78, 1549. Rone pot gishi O ref 2
Br R2R Total Syntheses ofN t l P d t
OAc one-potthree step sequence Negish
(+) Heteroplexisolide Ebromineref. 2
Natural Products three-step sequence (+)-Heteroplexisolide Ebrominedditi Slid N 8 10
OR1 3"mild base" O R4
addition Slide No.8–10OR
R2R3(±) 12 Acetoxytremetoneref. 1a R4
3rdf 1R2 (±)-12-AcetoxytremetoneO
R3 Br S hi1st Pyr HBrref. 1
Use of one pot regioselective1DBU TBAF (5 i ) O R5 R2R3
2R3Br Sonogashira1st Pyr.-HBr3 Use of one-pot regioselectiveN i hi liOR1DBU or TBAF (5 equiv) O R5 R2
R3R2 Negishi couplingOO 1 R2R3
d Slid N 5f 2
O OO
OOR1 R
OR1R52nd DBU Slide No.5two-step elimination ref. 2 OOH OR1
ORR5S highly regio and stereoselective
nC12H25OH OR1R5Suzuki
highly regio- and stereoselective
HOnC12H25 ukiregioselective Slide No.3–4 synthesis of trisubstituted alkenes
mild base: 2 equiv. of NaOAc, NaOPiv, iPr2NEt, K2CO3HOT li li B( ) (R R) S i f Bref 2 OH elimination
Slide No.3 4mild base: 2 equiv. of NaOAc, NaOPiv, iPr2NEt, K2CO3
1 i f DBU DBN DABCO TBAF ref 4Tulipalin B(–)-(R,R)-Sapinofuranone Bref. 2 OH
1 equiv. of DBU, DBN, DABCO, TBAF ref.4Heterocycles 2004, 63, 2349.( )-Muricatacinref. 2b 4 One pot reaction is of great significance from
Slide No.7y , ,(–)-Muricatacin R4 One-pot reaction is of great significance fromref. 1 (regioselective elimination) ref. 3 (Accounts) One-pot method for chemoselective bromination of allyl alcohol derivatives both economical and ecological points !!ref. 1 (regioselective elimination)( ) Oh i T Ni hi S * Ch L tt 2004 33 1084
ref. 3 (Accounts)( ) Oh i T K N Ni hi S * J S h O Ch J 2008 66 139 2R3
p yand sequential C–C bond formation in same pot have been developedU f O R i
g p(a) Ohgiya, T.; Nishiyama, S.* Chem. Lett. 2004, 33, 1084. (a) Ohgiya, T.; Kutsumura, N.; Nishiyama, S.* J. Synth. Org. Chem., Jpn. 2008, 66, 139. R2Rand sequential C–C bond formation in same pot have been developed.Use for One-pot Reaction f 2 (fi t t t l th i f (+) h t l i lid E)(b) Kutsumura N *; Iijima M ; Toguchi S ; Saito T * Chem Lett 2011 40 1231 (b) Ohgiya T *; Kutsumuram N ; Nishiyama S * Synlett 2008 3091
p ref. 2 (first total synthesis of (+)-heteroplexisolide E)( t l t t l th i )(b) Kutsumura, N. ; Iijima, M.; Toguchi, S.; Saito, T. Chem. Lett. 2011, 40, 1231. (b) Ohgiya, T. ; Kutsumuram N.; Nishiyama, S. Synlett 2008, 3091.
OR1R5ref. 1 (one-pot bromination and sequential Sonogashira coupling) (a) Kutsumura N *; Kiriseko A ; Saito T * Tetrahedron Lett 2012 53 3274(not only total synthesis)ref. 2 (two-step elimination) ref. 4 (TBAF-promoted regioselective and two-step elimination) ORR5ref. 1 (one pot bromination and sequential Sonogashira coupling)
K t N * Ni K S it T * O L tt 2010 12 3316 M t R d A ti l J l 2010(a) Kutsumura, N. ; Kiriseko, A.; Saito, T. Tetrahedron Lett. 2012, 53, 3274.(b) K t N * Ki i k A S it T * H t l 2012 86 i(a) Kutsumura N ; Yokoyama T ; Ohgiya T ; Nishiyama S * Tetrahedron Lett 2006 47 4133 (a) Kutsumura N *; Kubokawa K ; Saito T * Synlett 2010 2717 ; Most Accessed Articles Nov 2010 Kutsumura, N.*; Niwa, K.; Saito, T.* Org. Lett. 2010, 12, 3316.; Most Read Articles, Jul. 2010. (b) Kutsumura, N.*; Kiriseko, A.; Saito, T.* Heterocycles 2012, 86, in press.(a) Kutsumura, N.; Yokoyama, T.; Ohgiya, T.; Nishiyama, S. Tetrahedron Lett. 2006, 47, 4133. (a) Kutsumura, N. ; Kubokawa, K.; Saito, T. Synlett 2010, 2717.; Most Accessed Articles, Nov. 2010.
(b) Yokoyama, T.; Kutsumura, N.; Ohgiya, T.; Nishiyama, S.* Bull. Chem. Soc. Jpn. 2007, 80, 578. (b) Kutsumura, N.*; Kubokawa, K.; Saito, T.* Synthesis 2011, 2377. (Invited Special Issue); Most Accessed Articles, Aug.–Sep. 2011.( ) y g y y p ( ) y ( p ) g p
Method B: 4 Method A:M th d A
Method B: R4 Method A:
Bri) Pyr.-HBr3Method A:3 Br BrNO2Br B Bii) DBUi) Pyr.-HBr3 iii) alkyne (1 5 equiv) B Bii) DBUi) Pyr.-HBr3 iii) Me2Zn M
2Br
R3 ii) DBU (3.1 equiv)) y 3(1.1 equiv)R5 R2R3
2R3BrO
BrBr
NO2Br
Br BrR3 Br
R3)(1 1 equiv)2R3
) y 3(1 1 equiv)
iii) alkyne (1.5 equiv)CuI (0 1 equiv)
BrR3 Br
R3ii) DBU
(3 1 equiv)2R3i) Pyr. HBr3(1 1 equiv)
iii) Me2Zn(4 0 equiv) R3Me
R2R ) ( q )( q )R5 R2 R2R5 OO
BrO Br R2RR2R(1.1 equiv)R2R (1.1 equiv) CuI (0.1 equiv)
3 Br R2R3R2R3(3.1 equiv)R2R (1.1 equiv) (4.0 equiv)
R2R3
(CH Cl)1 i l tiOOTIPS
Br R RK CO PdCl (PPh ) R2R3 Br R R
TMR
OR1(CH2Cl)2OR1 OR1R5Br regioselective nPrOTIPS
OR1 OR1OR1 K2CO3 PdCl2(PPh3)2 R2
OR1 OR1OR1 CH3CN PEPPSITM-IPrOR1OR ORRBr eliminationor CH3CN
nPrNO2O OR1 OR1OR (1.1 equiv) (5 mol%)
1OR1 OR1OR 3
(5 mol%) OR12
A 100% (>99/1)A 87% (31/1)A: 69% (10/1)A 92% (18/1) (CH2Cl)2( )Et3N (2.0 equiv) OR1
( )CH3CN-THF
Method A: A mixture of s.m. (1.0 equiv) and Pyr.-HBr3 (1.1 equiv) in solvent was stirred at rt. A: 100% (>99/1)A: 87% (31/1)A: 69% (10/1)A: 92% (18/1) (CH2Cl)2 Et3N (2.0 equiv)rt
CH3CN THFR1 acyl, phenyl60 ºCMethod A: A mixture of s.m. (1.0 equiv) and Pyr. HBr3 (1.1 equiv) in solvent was stirred at rt.
DBU (3 1 equiv) was added to the mixture at 0 ºC and the reaction system was B: 95% (>99/1)B: 78% (28/1)B: 60% (12/1)B: 89% (17/1) R1 acylrt y , p y60 ºC
DBU (3.1 equiv) was added to the mixture at 0 C and the reaction system wasthen heated to 60 ºC
R acylthen heated to 60 ºC. NO2 nPentBunPen Ph tBu Me
BrBr
NO2OMeBr NO2
nPentBunPen Ph tBu MeBr
OBrOMe
O2
M MOMe
MCl O
Method B: i) Pyr.-HBr3 Br BrO
OO Me Me Me
ii) DBU (1 1 equiv)Method B: ) y 3
(1 1 equiv) BrR3 R3Br
5 2R3 O BrO
O O Oii) DBU (1.1 equiv)(1.1 equiv)R2R
R5 R2RR5 R2R O BrO OOO O OO O O
OMeK CO i l ti
RRA: 90% (>99/1)A: 91% (49/1)O
OO76% 80% 81% 48% (Me Zn 6 equiv)
OMeK2CO3
(1 1 equiv)regioselective
OR1Br OR1R5OR1A: 90% (>99/1)B 93% ( 99/1)
A: 91% (49/1)B 92% (40/1)A: 92% (20/1)A: 91% (>99/1)
76% 80% 81% 48% (Me2Zn, 6 equiv)(1.1 equiv) eliminationOR1Br ORR5OR B: 93% (>99/1)B: 92% (40/1)A: 92% (20/1)A: 91% (>99/1) OMe OMe OMe MeOMe(CH2Cl)2 O 84%
OMe94%93% 81%
OMe91%
OMe MeMMe
OMe2 2
or CH3CNO
NOCl84%94%
tB93% 81% 91% OMe
OMe
or CH3CNOBr
NO2BrCl tBu OTBDPSnPrO
Method B: A mixture of s.m. (1.0 equiv), Pyr.-HBr3 (1.1 equiv), and K2CO3 (1.1 equiv) in solvent BrBrBr OBrnPenOTBDPSnPr( q ), y 3 ( q ), 2 3 ( q )
was stirred at rt. DBU (1.1 equiv) was added to the mixture at 0 ºC and the reaction BrOOOPMB O OMenPenwas stirred at rt. DBU (1.1 equiv) was added to the mixture at 0 C and the reactionsystem was then heated to 60 ºC
BrOPMB OO 81%
OMe84%82%
nPensystem was then heated to 60 C. OPMBOO
OO
81%84%O
82%
A 94% (57/1)OO O
OPMBO
MeBromine addition Trans addition A: 94% (57/1)A: 34% (8/1)B: 90% (20/1)B: 90% (15/1) OPMBP
OPMBtBu tBu Me Me O
MeBromine addition Trans addition
B: 94% (21/1)A: 34% (8/1): 90% (20/1)B: 90% (15/1) OPMBnPr
NOtBu tBu
OTBDPS OPMBPO
OPMBDBU-Promoted elimination Regioselective trans elimination
( )82%77%
NO228%70%OTBDPS OPMBnPr
Meg 82%77%28%70% Me
Kutsumura N *; Niwa K ; Saito T * Org Lett 2010 12 3316 Kutsumura N *; Niwa K ; Saito T * Org Lett 2010 12 3316 Kutsumura N *; Niwa K ; Saito T * Org Lett 2010 12 3316 OPMBKutsumura, N. ; Niwa, K.; Saito, T. Org. Lett. 2010, 12, 3316.M t R d A ti l J l 2010
Kutsumura, N. ; Niwa, K.; Saito, T. Org. Lett. 2010, 12, 3316.M t R d A ti l J l 2010
Kutsumura, N. ; Niwa, K.; Saito, T. Org. Lett. 2010, 12, 3316.M t R d A ti l J l 2010 79% 88% 87% (Me2Zn, 6 equiv)74%Most Read Articles, Jul. 2010. Most Read Articles, Jul. 2010. Most Read Articles, Jul. 2010. 79% 88% 87% (Me2Zn, 6 equiv)74%
Method B: R4 Pyr -HBr3Me2Zn (6.0 equiv)Method B: R4
OPyr.-HBr3(1 1 equiv) O
B DBU (3 1 equiv) O2 ( )
PEPPSITM-IPr O OBr
Br Brii) DBU3
i) Pyr.-HBr3 iii) (HO)2B R4O
O (1.1 equiv)CH CN t O
OBr DBU (3.1 equiv)
60 ºC OPEPPSI IPr(10 l%) O O
BrBr
R3 BrR3
)(1.1 equiv)R2R3
) y 3(1.1 equiv)
iii)(3 0 equiv)
R O CH3CN, rt O 60 ºC O (10 mol%) O OBr R2R
R2R(1.1 equiv)R2 (1.1 equiv) (3.0 equiv)R3 O O OPd-Catalyzed M M+
K2CO3 Pd(PPh ) (10 mol%) R2R3 OPd-CatalyzedHydrogenolysis Br Br 87% in one pot
Me Me+
OR1 OR1OR1 K2CO3(1 1 equiv)
Pd(PPh3)4 (10 mol%)K CO (7 0 i )
R O O OAldol ReactionHydrogenolysisOPMB OPMB OPMB
87% in one-potBrOR OR
CH CN(1.1 equiv) K2CO3 (7.0 equiv)
OR1O OPMB OPMB OPMB Br
O OCH3CN DMF-H2O OR1 O O2
1100 ºC Me CHO SN2 product SN2' productsR1 benzyl100 CO O
HO PMBOCHO SN2 product SN2 products
(ca 6 : 4 mixture)yO O PMBO
OO O (ca. 6 : 4 mixture)
(+) Heteroplexisolide EO1. LDA, / THF
O
NO Cl ref 1(+)-Heteroplexisolide E O O
,2 Ac2O py DMAP rt i) DDQ / CH2Cl2-H2O nBu3SnH (1.1 eq.)NO2 Cl
R4ref. 1
OR i l ti Known OO2. Ac2O, py., DMAP, rt
;then DBU / (CH2Cl)2 70 ºCi) DDQ / CH2Cl2 H2Oii) PPTS acetone 50 ºC
nBu3SnH (1.1 eq.)Pd(PPh3)4 (5 mol%)iii) (2.0 equiv)KF B
RIsolation: from Heteroplexis micocephala ORegioselective Known
P dO
Me;then DBU / (CH2Cl)2, 70 C ii) PPTS, acetone, 50 C Pd(PPh3)4 (5 mol%)
toluene 100 ºC 10 minKF3B o ete op e s cocep a aActivity: unknown ONegishi Coupling Procedure
MMe toluene, 100 ºC, 10 min.
PEPPSITM-IPr (3 mol%)Activity: unknown O Me OPMBO86% 2 steps 90% in one-pot 98% 2 stepsPEPPSI IPr (3 mol%)
K2CO3 (5 0 equiv) OH OPMBOPMB
OO86%, 2 steps 90% in one-pot 98%, 2 steps
Pd(OCOCF ) [ ]D20 +74.0 (c 0.38, MeOH)K2CO3 (5.0 equiv)MeOH 75 ºC 3 steps
OH OPMB OO O
Pd(OCOCF3)2[ ]D ( , )
lit [ ]D20 +15 6 (c 0 27 MeOH)OPMB OPMB OPMB MeOH, 75 ºCOPMBPMBO
3 steps O O (10 mol%) lit. [ ]D +15.6 (c 0.27, MeOH)PMBO
Commercially O O toluene, 100 ºC, 10 h86% 67% 65% 67%
Et Chiral Building Block ref. 2Commercially
Available, ,
ClEt Chiral Building Block ref. 2 Available + (+)-Heteroplexisolide E
ClCB PPh
O OBO 94%
NO CBr4, PPh3 O OBr
O94%
NO2 ref. 1 CH2Cl2, rt O OOO O as a single product !
S Fan X ; Zi J ; Zhu C ; Xu W ; Cheng W ; Yang S ; Guo Y ; Shi J * J Nat Prod 2009 72 11842 2,
M M+O O g p
ref.SOPMBOBn
Fan, X.; Zi, J.; Zhu, C.; Xu, W.; Cheng, W.; Yang, S.; Guo, Y.; Shi, J.* J. Nat. Prod. 2009, 72, 1184. Me Me+Me (+)-Heteroplexisolide EOPMBOBn ref. 2 BrOH (8 : 1 mixture)
OBn OPMB OPMB75%
OPMB56%
ref. 2( ) Zh L M t D R * O L tt 2003 5 3475
BrOH ( )75%56% (a) Zhu, L.; Mootoo, D. R.* Org. Lett. 2003, 5, 3475. O OO ref.
72% 63% 70% 82% (b) Kutsumura N ; Yokoyama T ; Ohgiya T ; Nishiyama S * Tetrahedron Lett 2006 47 4133 SN2 product SN2' products (a) Kutsumura N *; Kiriseko A ; Saito T * Tetrahedron Lett 2012 53 327472% 63% 70% 82% (b) Kutsumura, N.; Yokoyama, T.; Ohgiya, T.; Nishiyama, S. Tetrahedron Lett. 2006, 47, 4133.( ) Y k T K t N Oh i T Ni hi S * B ll Ch S J 2007 80 578
SN2 product SN2 products (a) Kutsumura, N.*; Kiriseko, A.; Saito, T.* Tetrahedron Lett. 2012, 53, 3274.(c) Yokoyama, T.; Kutsumura, N.; Ohgiya, T.; Nishiyama, S.* Bull. Chem. Soc. Jpn. 2007, 80, 578. (ca. 6 : 4 mixture) (b) Kutsumura, N.*; Kiriseko, A.; Saito, T.* Heterocycles 2012, 86, in press.( ) , ; , ; , y , , p
Thi k tl t d b th S k S i tifi R h G t f Th J S i S i tThis work was partly supported by the Sasakawa Scientific Research Grant from The Japan Science Society.This work was partly supported by the Sasakawa Scientific Research Grant from The Japan Science Society.
