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!"##$%&$' %)*"&+),% -). /012&$. 34

56789:; 4

"#$%&'( )*+ ,)'- -.(,)/-'- *0 &1'(* &2'3-4 -,&5,'(6 +',) (&,75&% $5*%'(/4 +*58-9

"#$%&'( ,)/ -,/5/*-/%/2,':',. *0 /&2) -,/$ &0,/5 ,)/ 0'5-,9

NH

CO2HN

  CO2Me

R

OO

NH3

N

NHO

O

H

HO   R

CF3CO2H

N

NHO

OH

R

H2

Pd

N

NHO

OH

H R

H

H2O

NH

CO2H

HO2C   NH2

H R

+

 

5".2)%$ )- &0$ 2.)<*$=

; -'1$%/ /#/52'-/ '( ,)/ 25/&,'*( *0 & (/+ -,/5/*6/('2 2/(,5/ :'& & 2.2%'2

'(,/51/3'&,/9

!"##$%&$' %)*"&+),

<*,)'(6 /#2','(6 )&$$/(- 7(,'% ,)/ ).35*6/(&,'*( -,/$9 =)/

-,/5/*-/%/2,':',. *0 ,)/ 5/&2,'*( +',) &11*('& '- '(,/5/-,'(6 >7, (*, *0

&(. 2*(-/?7/(2/ &- ,)&, -,/5/*2)/1'-,5. 3'-&$$/&5- '( ,)/ /%'1'(&,'*(9

=)'- 6':/- ,)/ ! @/(*(/ &- /#$/2,/3 -'(2/ ,)/ &%8/(/ &(3 ,)/ 2&5>*(.%

65*7$ &5/ '( ,)/ -&1/ $%&(/9

AB

!  =)'- 1/,)*3 +&- '(:/(,/3 >. C9

D9 C.25*0, &(3 E9 F9 G//4 "# %&'(#

)*+#, %&'(# %*((-.#4 BHIJ4 HKK9

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L*%7,'*(- 0*5 O)&$,/5 AB Y ;-.11/,5'2 -.(,)/-'- ? 

!"##$%&$' %)*"&+),

Z*7 1//3 ,* &-8[ +)'2) '- ,)/ 0'5-, 2)'5&% '(,/51/3'&,/V O&( ', >/

2*(:/('/(,%. 5/-*%:/3V D'%% ,)/ 2)'5&%',. -75:':/ -7>-/?7/(, -,/$-V =)/

0'5-, '(,/51/3'&,/ '- 2)'5&% >7, ', /(*%'T/- :/5. 5/&3'%. &(3 ,)/ /(*% '-

&2)'5&%4 -* ,)&,\- (* 6**39 =)/ -/2*(3 '(,/51/3'&,/ '- 2)'5&% >7, ', )&-

,)5// 2)'5&% 2/(,5/- &(3 ,)/-/ &5/ /:'3/(,%. (*, 2*(,5*%%/39 D/ +*7%3

)&:/ ,* -/$&5&,/ ,)/ 3'&-,/5/*'-*1/5- >/0*5/ 5/-*%7,'*( &(3 ,)&, +*7%3

>/ & +&-,/ *0 ,'1/ &(3 1&,/5'&% -'(2/ &%% *0 ,)/1 6':/ ,)/ (/#,

'(,/51/3'&,/ &(.+&.9

O

Ph

O O

Ph

OH

chiral   achiral

HN OH

Ph

OH

H

three

chiral

centres

 

=)/ (/#, '(,/51/3'&,/4 ,)/ &1'(* &%2*)*% '- '3/&%[ ', )&- *(%. *(/

2)'5&% 2/(,5/ &(3 ,)&, '- (*, &00/2,/3 >. ,)/ %&-, 5/&2,'*(9 W, )&- ,+*

])&(3%/-\ 0*5 5/-*%7,'*( Y ,)/ &1'(/ &(3 ,)/ &%2*)*%9 D/ 1'6), 1&8/ &

-&%, +',) ,&5,&5'2 &2'3 *5 &( /-,/5 *0 ,)/ &%2*)*% +',) -*1/ 2)'5&% &2'39

;%,/5(&,':/%. +/ 2*7%3 5/-*%:/ ,&T&3*%/(/ ',-/%0[ ', -,'%% )&- &( &1'(*

65*7$ &(3 +/ 2*7%3 0*51 & -&%, +',) & -7',&>%/ &2'39

56789:; ?

^*+ +*7%3 .*7 1&8/ /(&(,'*1/5'2&%%. /(5'2)/3 -&1$%/- *0 ,)/-/ 2*1$*7(3-Q/',)/5 /(&(,'*1/5RV

OHOH   OH

OH

OH

OH

OH

 

5".2)%$ )- &0$ 2.)<*$=

X'5-, -,/$- '( $%&(('(6 &( &-.11/,5'2 -.(,)/-'-9

!"##$%&$' %)*"&+),

=)/5/ &5/ 1&(. $*--'>%/ &(-+/5- )/5/9 D)&, +/ )&3 '( 1'(3 +&- -*1/

-*5, *0 &-.11/,5'2 U'/%-@;%3/5 5/&2,'*( 0*5 ,)/ 0'5-,4 &( &-.11/,5'2

&%3*% 0*5 ,)/ -/2*(3 *5 /%-/ *$/('(6 &( /$*#'3/ 1&3/ >. L)&5$%/--

/$*#'3&,'*(4 &-.11/,5'2 3').35*#.%&,'*( 0*5 ,)/ ,)'534 &(3 $/5)&$-

&-.11/,5'2 3').35*#.%&,'*( *0 &  /  &%8/(/ 0*5 ,)/ 0*75,)9 N0 2*75-/ .*7

!  =)'- -.(,)/-'- '- 05*1 ,)/

_$S*)( 2*1$&(. &(3 '- '( *(%. ,)/

$&,/(, %',/5&,75/ Q%&'(# 01234#4

BHKA4 4@@4 `aBB9

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3 L*%7,'*(- M&(7&% ,* &22*1$&(. N56&('2 O)/1'-,5. P/

1'6), )&:/ 7-/3 5/-*%7,'*( *5 &-.11/,5'2 ).35*6/(&,'*(4 *5 ,)/ 2)'5&%

$**%4 *5 &(. *,)/5 -,5&,/6. 05*1 2)&$,/5 AB9

ON

O   O

ON

O   O

LiBH4   OH

H

t -BuOOH(i -PrO)4Ti

D-(–)-DET

OMe3Al

OHOH   OHOH

OH

OHOsO4, K3Fe(CN)6, K2CO3

DHQD ligand

OH

OHOsO4, K3Fe(CN)6, K2CO3

DHQD ligand

Lewisacid

 

56789:; 3

W( ,)/ 0*%%*+'(6 5/&2,'*( -/?7/(2/4 ,)/ -,/5/*2)/1'-,5. *0 1&(3/%'2

&2'3 '- ,5&(-1',,/3 ,* & (/+ ).35*#.@&2'3 >. -,/5/*2)/1'2&%%.

2*(,5*%%/3 5/&2,'*(-9 E':/ 1/2)&('-1- 0*5 /&2) 5/&2,'*( &(3 -,&,/

+)/,)/5 ', '- -,/5/*-$/2'0'2 *5 -,/5/*-/%/2,':/9 N00/5 -*1/

5&,'*(&%'T&,'*( 0*5 ,)/ 25/&,'*( *0 (/+ -,/5/*6/('2 2/(,5/- '( ,)/ 0'5-,

&(3 %&-, 5/&2,'*(-9

HO2C   Ph

OH

(S -(+)-mandelicacid

t -BuCHO

O

O

O

Ph

t -Bu

1. LDA

2. PrBrO

O

O

Ph

t -Bu

H

H2O

HO2C

Ph   OH  

5".2)%$ )- &0$ 2.)<*$=

Z*75 2)&(2/ ,* /#&1'(/ &( '(6/('*7- 1/,)*3 *0 &-.11/,5'2 '(372,'*(9

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L*%7,'*(- 0*5 O)&$,/5 AB Y ;-.11/,5'2 -.(,)/-'- C 

=)/ OY< >*(3 2&( >/ 2%/&:/3 5/372,':/%. >. ).35*6/(&,'*( &- ', '- &(

; @>/(T.% >*(39 =)'- +*7%3 &%-* ).35*6/(&,/ ,)/ (',5'%/ -* ,)&, 17-,

0'5-, >/ ).35*%.-/3 7-'(6 &2'3 *5 >&-/4 &- +/&8 &- $*--'>%/9 =)/ -,&5,'(6

1&,/5'&% '- (*, 5/2*:/5/3 &(3 ,)/ 2)'5&%',. '- %*-, &- ,)/ >.@$5*372, '-

S7-, /,).% >/(T/(/4 ,)/ (',5*6/( &,*1 >/'(6 ,5&(-0/55/3 ,* ,)/ $5*372,9

NH

Ph

H Me

R

CNacid or base

NH

Ph

H Me

R

HO2CH2 /Pd/C

NHR

CO2H

+

Me

Ph

 

56789:; B

"#$%&'( ,)/ -,/5/*2)/1'-,5. &(3 1/2)&('-1 '( ,)/ -.(,)/-'- *0 ,)/ 2)'5&%

&7#'%'&5. K@$)/(.%1/(,)*% 05*1 QfR@$7%/6*(/9 ;0,/5 ,)/ 5/&2,'*( +',) <& '( 5@

g5N^4 +)&, '- ,)/ 1'(*5 QBahR 2*1$*(/(, *0 ,)/ 1'#,75/V

O

R -(+)-pulegone

PhMgBrCuBr

O

Ph

KOHEtOH

reflux O

Ph

55:45 mixture 87:13 mixturewith other diastereoisomer

Nai -PrOH

toluene OH

Ph

87:13 mixturewith another diastereoisomer

ClCl

O1.

2. crystallise

3. KOHH2O, EtOH

OH

Ph

one diastereoisomer;one enantiomer

 

5".2)%$ )- &0$ 2.)<*$=

; 2*1>'(&,'*( *0 2*(0*51&,'*(&% &(&%.-'-4 -,/5/*-/%/2,':/ 5/&2,'*(-4

&(3 5/-*%7,'*( ,* 6/, & -'(6%/ /(&(,'*1/59

!"##$%&$' %)*"&+),

=)/ 0'5-, 5/&2,'*( '- & 2*(S76&,/ &33','*( ,)&, /:'3/(,%. 6*/- +',)*7,

&(. +*5,)+)'%/ -,/5/*-/%/2,':',.9 =)/ -,/5/*2)/1'-,5. '- (*, 0'#/3 '(

,)/ &33','*( >7, '( ,)/ $5*,*(&,'*( *0 ,)/ /(*%&,/ '( ,)/ +*58@7$9

"?7'%'>5&,'*( *0 ,)/ 1'#,75/ >. 5/:/5-'>%/ /(*%&,/ 0*51&,'*( +',) dN^

'( /,)&(*% 6':/- 1*-,%. ,)/ &%%@/?7&,*5'&% 2*1$*7(39

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D L*%7,'*(- M&(7&% ,* &22*1$&(. N56&('2 O)/1'-,5. P/

O   O

Ph

O

Ph

=

O

Ph

KOHEtOH

refluxO

Ph

H

Ph   Cu 

F/372,'*( >. ,)&, -1&%%/-, *0 5/&6/(,-4 &( /%/2,5*(4 6':/- ,)/ &%%@

/?7&,*5'&% $5*372,9 L'(2/ ,)/ -,/5/*2)/1'2&% 5&,'* '( ,)/ $5*372, '- ,)/

-&1/ &- '( ,)/ -,&5,'(6 1&,/5'&%- QKI[BaR4 ,)/ 5/372,'*( 17-, >/ ,*,&%%.

-,/5/*-/%/2,':/9 =)/ &%%@/?7&,*5'&% 8/,*(/ 6':/- Bcch &%%@/?7&,*5'&%

&%2*)*% &(3 ,)/ 1'(*5 '-*1/5 17-, 6':/ *(/ *,)/5 3'&-,/5/*'-*1/5 Q+/

2&((*, -&. +)'2)R9

O

Ph   Ph

OH

O

Ph

OH

Ph

Nai -PrOH

toluene

Nai -PrOH

toluene

 

=)/ 1'#,75/ -,'%% )&- ,* >/ -/$&5&,/3 &(34 &- ', '- & 1'#,75/ *0

3'&-,/5/*'-*1/5-4 ', 2&( >/ -/$&5&,/3 >. $).-'2&% 1/&(-9 =)/

2)%*5*&2/,&,/ '- S7-, & 2*(:/('/(, 25.-,&%%'(/ 3/5':&,':/9

56789:; C

L766/-, -.(,)/-/- 0*5 -'(6%/ /(&(,'*1/5- *0 ,)/-/ 2*1$*7(3-9

OMe

Ot -Bu

O

OMe

OOH

HO

 

5".2)%$ )- &0$ 2.)<*$=

U/:'-'(6 .*7 *+( &-.11/,5'2 -.(,)/-/-9

!"##$%&$' %)*"&+),

=)/ 0'5-, 2*1$*7(3 '- &( /-,/5 3/5':/3 05*1 & 2.2%'2 -/2*(3&5. &%2*)*%

,)&, 2*7%3 >/ 1&3/ 05*1 ,)/ 2*55/-$*(3'(6 /(*(/ >. &-.11/,5'2

5/372,'*(9

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L*%7,'*(- 0*5 O)&$,/5 AB Y ;-.11/,5'2 -.(,)/-'- G 

OMe

Ot -Bu

O

OMe

C–O

ester

OMe

OH

OMe

OMe

O

OMeby asymmetric

 reduction  

F/372,'*( +',) O*5/.\- OCL 5/372'(6 &6/(, 6&:/ ,)/ &%2*)*% '( Hah

//9

OMe

O

OMe

BH3-THF

10% CBS

oxazaborolidine

OMe

OH

OMe

(t -BuCO)2OTM

 

=)/ -/2*(3 2*1$*7(3 2*7%3 >/ 1&3/ >. & D',,'6 5/&2,'*( +',) &

-,&>'%'T/3 .%'3 &(3 ,)/ 5/?7'5/3 3'*% &%3/).3/ 3/5':/3 05*1 &( /$*#.@

&%2*)*% &(3 )/(2/ &( &%%.%'2 &%2*)*% >. L)&5$%/-- /$*#'3&,'*(9

OOH

HO

WittigCHO

OOH

HO

Ph3P+

A B

ACHO

O   O

OH OH

Sharplessepoxidation

 

=)/ 0'5-, $&5, *0 ,)/ -.(,)/-'- 6':/- &( '(,/51/3'&,/ ,)&, )&3 >//(

7-/3 '( ,)/ -.(,)/-'- *0 ,)/ &(,'>'*,'2 1/,).1.2'(9 W( $5&2,'2/ ,)/

D',,'6 +&- 2&55'/3 *7, *( ,)/ /$*#.@&%3/).3/ &(3 ,5/&,1/(, *0 ,)/ %&-,

'(,/51/3'&,/ +',) &?7/*7- &2'3 6&2/ ,)/ ,&56/, 1*%/27%/9

OH

t -BuOOH

(i -PrO)4Ti

(+)-DET

O

OH

79% yield, >95% ee

[O]CHO

O   ylid B OO

 

!  =)'- 2*1$*7(3 +&- 7-/3 ,*

1&8/ & 2*1$*7(3 05*1 ,)/ 6'(68*

,5// >. "9 i9 O*5/. &(3 ;9 j9 E&:&%4

?'346&'@4*. A'33#4 BHKK4 >G4 aPcB9

!  L9 M&-&17(/ '3 67#4 "# 0(# %&'(#

)*+# BHIJ4 GC4 aJBP