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.