Síntese assimétrica do (+)- e do (-)-mutisiantol e obtenção de 1-tetralóis opticamente...

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GRAZIELA GALLEGO BIANCO

“Síntese assimétrica do (

−

)- e do (+)- mutisiantol e obtenção de 1-tetralóis opticamente ativos”

Tese apresentada ao Instituto de Química

da Universidade de São Paulo para obtenção do

Título de Doutor em

Química Orgânica

Aprovado em: ____________

Banca Examinadora

Prof. Dr.

_______________________________________________________

Instituição: _______________________________________________________

Assinatura: _______________________________________________________

Prof. Dr.

_______________________________________________________

Instituição: _______________________________________________________

Assinatura: _______________________________________________________

Prof. Dr.

_______________________________________________________

Instituição: _______________________________________________________

Assinatura: _______________________________________________________

Prof. Dr.

_______________________________________________________

Instituição: _______________________________________________________

Assinatura: _______________________________________________________

Prof. Dr.

_______________________________________________________

Instituição: _______________________________________________________

Assinatura: _______________________________________________________

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(15)

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D% *

MeO

MeO OMe

18

19 MeO

O 16

1. redução

2. eliminação contração de anel

3 etapas HO

(18)

:0

:0*0 !−−−−#$ !"#$ % &

:0*0*0 E , % &

" $ 0#0#7 8 $$ /& _# _" _{$ "} _5B6

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# # # 9 $ ^ "" 897 T ; # " 8 "

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# "4 5 6/ " # " # # $ $ " " " K 7

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# $"L$ ; >" 5K . / 1 F ) 0 . /

1 F ) 06/ 8 $ 9" $ # K < >"

(19)

D% 8

MeO

18

MeO

O

(R)-16

HO

(+)-mutisiantol

MeO

MeO OMe

19

MeO

O

20 H 21

desproteção Wittig hidrólise

contração

de anel 1. redução2. eliminação (R)

# " $ " K $ # >" $ 5.6 *2 9 " < $ 5.6 5B6

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D% :&*'

OHC

O

(R)

(R)-(+)-citronelal (+)-laevigatina

; 7 $" $ $" # " 5B6 " $ 7 $

" "; # $ Y 7 K < T ? [ /&*& _# _$" ₉ _$" _$;"

(20)

D% 6&*&

OAc

O

1,5 eq. em massa PPL, 0,1M tampão fosfato,

pH=7, ta, 48 h

OAc

O O

OH

+

96% ee 44% 95% ee

47%

(±)-83 (−)-84 (−)-83

(S)

(R)

$ K $" Y 9 " "; $" $ $" # # " 7 #

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$ $" R " $" K $" " < 7 # 7 # " 34

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$" > # K $ M >" $ 5B6 " $" 5 T A6/

D% 7

MeO

O MeO

MeO

OH O

(CF3CO)2O, CF3CO2H

OAc

O

OH MeO

O anidrido

succínico, AlCl3

Zn(Hg), HCl/H2O

2-metil-anisol 11 12

13

NaBH₄, MeOH

OH MeO

85

OAc MeO

Ac₂O, Et₃N

KMnO4, MgSO4.7H2O

acetona

86

(±)-87

Resolução cinética

enzimática MeO

O OAc

(S)-87

+ MeO

O OH

(21)

# " >" $ 34 33 $ $" $" $ T # $ Y

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D% 2

MeO

O OAc

(S)-87

K2CO3,

MeOH MeO

O OH

(S)-88

TsCl,

piridina MeO

O OTs

(S)-89

MeO

O (R)-16

Me2CuLi

MeO

O OH

(R)-88

TsCl,

piridina MeO

O OTs

(R)-89

MeO

O (S)-16

Me2CuLi

" " "; $ # " $ > $ $" R " $" 7 >

" $ $9 > " 7 K < T 4 5.6 5 6 33 #

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(22)

9" * " $ $ $ /&' _{" 4} _** ₉ _> _" _M

< $ " 4 7 4 " $ 5 $ F

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9 0 / 4 *8 9 H 9" $" # 4

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5 T C6/ " " # Y4 " K " $ " " /+7 &'

D% 4

OH O

O MeO

OH O MeO

Zn(Hg), HCl(conc.)

H2O, tolueno,

2 dias, refluxo

11 12

83% 97%

O MeO

13

3,7eq. (CF3CO)2O,

1 eq. CF3CO2H,

10 min

" " $ *: 9 < > " 1:H(. : 9 $ $ " "

37 O'X $ $" / 7 " " 37 9 > " M " $

;" " " $ 5 ") 67 $ # $ = 121 " $ # $ 5!. 6

" / " " 32 9 >" OAX $ $" 5 T +6/ 0

> $< 32 9 < " < $ $ F " # ? [ /7&*& _T _{9 <}

0 # $ $ " # "4 5Q.$ =6 $ " " $ 7 4 9 "

$; 8 #" 8 " 5. =/C:* 6/ 0" " " # > 4" 7

# 9 " # < " $ 9 < $ 4 / 9 "

8 K # # " 7 T 9 K " $ >" " $ /

$ $" $ >" # " 0 " " $ 349 )'X7 K M # $ #

> / 0" 9 9 " $ $ K # F

" $ 4 $" 9 " / $ 9 < T #

(23)

D% 3

O MeO

13

OAc MeO

O 5,5 eq. KMnO4,

2,5 eq. MgSO4.7H2O Acetona/H2O (3:1),

0 °C-ta, 2 h

86

87 2 eq. NaBH4 THF/MeOH, 0 °C-ta,

N2, 2 h.

90%

OH MeO

85

3 eq. Ac2O, Et3N DMAP, ta, 30 min

95%

96%

# >" $ 5±6 34 " " $;" $< 4" 9 $ 7

$9 4 " /

;" $ " " < # < # $8 $"

; " 9 7 T # 5 6 T 5 67 " < $

9 " $4 T / ! " 9 7 " " K $ $ $" 8 $ F

$ " " N > " " # " 9 <

$ 4 / " " $ 34 N 9 > " M $4 # " 9

$ T 5β 0" $ 6/ # " < $ F $ " "

" $ H & 9 >" /

OAc MeO

O (S)-87

OAc MeO

O

+

(24)

>" # N # " # 7 9 $ 4 < 8

; " 347 $ Q* ) . :/ 4 N 33 9 >" +CX

$ $" 7 " T O/

D% 5

1,5 eq. K₂CO₃ , MeOH/H₂O ta, 15 min

OAc MeO

OH MeO

O O

87 88

87%

9 # K >" # " 49 T $ $" R

4 N 33 # K4 $ F " " / $" $" 7 $

" " $< 4" 7 # " # " # > > K $

T 5 " 9 4 9 " $4 T 6/

? [ /&*& _{9 <} _{" "} _{" N " #} _$< ₇ _{> 7} _& ₃

# 5 67 # 5 6 # 4 7 $ T 8

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" " # $ /

# # 9 $ 8 K $" # > < > " " 7 Y4 T

T 7 " # 9 9 " 5#:_C6/ # K $" " " 9

" $ " 7 K < T " " < K / $" $" 7 $

" # 7 " # " # # " / 1 $" # " $ 7

9 " / $ " 9 0 5!. 6 9 " < 7 > < 9 8 7

$ " " / K $ $< > 8 $ < / H <

# $8 $" " $ T " " $ $" K " #

$Y " $ $ T / > K T $ $" R

8 K T T " " $" $ 7 9 $" # / "

(25)

/ E% 80 " $;" $< 4" " 0 " " $ 5±6 34/

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$ $" ; O+X/ ?4 # K 9 K 4 5−6 337 # " 8 7

9 $ 4 K " <4 " " 7 K < T $ T $ 8 K

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$9 $" K " F #" 5aαb!6/ # " 8

$< 4" K < 7 $ # K >" 4 5−6 33 "; OCX T $

" # $ 5+ 6 9 # 5 T &'6/

OAc

O MeO

(−)-87

O MeO

(−)-88

(26)

D% *9

OAc

O MeO

(±)-87

OAc

O MeO

(−)-87 +

O MeO

(−)-88 OH

1,5 eq. K2CO3 MeOH/H2O,

15 min, ta

OAc

O MeO

(+)-87 O

MeO

(+)-88 OH 3 eq. Ac2O, Et3N,

DMAP, 30 min 1,5 eq. em massa PPL

tampão fosfato, 27 °C, pH=7

A (2 dias) 39%, 80% ee 37%, 98% ee

B (8 dias) 43%, 97% ee 38%, 97% ee

A 80% ee 98% ee

B 97% ee 97% ee

$9 F > " 5−6 5B6 337 > # " K " " 7

$ 9 " $ / $ $ $ $" " K # " >

< # ? [ /&*& _# ₄ ₅₋_{6 5}_.₆ ₃₆ _# _{" "} ₅₋_{6 5 6} _3: _" _>;

# K $ $" 5K T =67 ; # K T $9 F

> " # 4 5−6 33 # " " 5−6 34 K % 5.6 5−6 33 5 6 5−6 347

$ /

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(27)

/ E% :0 " " 0 " " $ 5B6 34 # K $ $" 4 5−6 33/

# $ " # 7 9 # K >" " $" 5−6 T $" 5B6 33 > $

0 $ $" ; $ $" T K )C =CX #

$ $" R 7 " T $ " 9 " # # $"

;" " $" /

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# 0 " # >" $ # " " 35 ;" # # "

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&&6/

D% **

MeO

OH

O

MeO

OTs

O

Me2CuLi MeO

O TsCl,

piridina

(−−−−)-88 (R)-89 (S)-16

OAc

O MeO

(+)-87

OAc

O MeO

(28)

" # " $ 9 /&*= _# _$" _$9 _{K T} _K _$" _{' c}

# &G 8 / # $8 " < $ " 9 5 !67

> K T # " # 9 / d # " $" $" T

" 9 $ ; $4 T # # $8 $" "

7 # # " #F K M " # " K / " $

$ " $" # 7 # $ # " 49 > K K # "

$ 9 7 > K K " >; " # " / # >

" < 7 " $ # # " # " $ $ 9

# Y / )' 8 7 $ 33 9 $" # / H < 0"

# " > " # K # K $" > K T >"

$ K $" $9 M # / - $ K 0" 9 T 9 < $

8 K $ $8 /

$4 # ! # " > " " " # " 7 K $

" T # " 8 K # " / # " $" " K # 9 #

" 9 " # U" '5 >" K " $ # 0 7 Y # "

$ # $" 9 /

K " " " # $" 7&*A _{$ T} ₄ ₃₃ _> _" _M

*7A T/ 1 " $ 7 " < $ # # $ 5! 6 !. / "

9 $ " 9 " 7 # >" K " # 0 $" $" #

/

# " " $ " K K " $" " < # T L$

# > # # " # F # " 7 "4K T "

# $" $ " # / # T $ 4 33 0 " # >

" 5 $ " " 6 $ " $" $ < 7 9 $ $ # "

(29)

MeO

OH 90

/ E% 60 0 # ># " T # >" " $" " K " 33/

$" $" 7 # $" " " " 7 # " 59 $ 9

> K $ $4 . &_:/ _$ _{8 # "} _T _{7 " K <7}

# K " 4 > $< 9 9 7 $ T $

" " $ 9 # K $ $" $ $8 " > " > " " "

" # / K 7 $" 7 " " $ # $" α " " 247 #

4 > $< /

4 24 9 9 $" >" # := α " " $ 227 T ;

5 T &*6/

D% *8

O

66

1 eq. NaBH4, MeOH/THF

0 °C-ta, 2 h

97%

OH

67

$" 7 " " # $" T Y4 8 K < #

4 337 1 # $ / # $8 $" # ! $ K 9

$ K # " 7 $ $" $" 7 # 0" 7 # $ # " " # " 9

# /

! K $ $ # $" 9 9 " 7 # 0 # 7 K

(30)

' & *0 $ F # $ " " " K " 24/

OH

67

TsCl, condições

OTs

6 & 7 .

0 &7A T/ 1 7 # $ 7 ' A c 7 )' 8 &/24 #[

*/ 1 5 6

:* /

"/ =

#

/ *7' T/ 1 7 # $ 7 ' A c 7 *= 87 *5 6 &/ 1 #[

*/24 #[

:* /

"/ =

#

8 )7' T/ 1 ") 7 *5 67 ' c 7 *= 8 &/24 ")

*/ 1 5 6

:* #

9 )7' T/ 1 7 A T/ ") 7 :* *7 " 7 &' 8 &/24 :* *

*/ 1 :* *

/ "/ #

$ >" K N0 " $ $8 " $" " K 7 K $9 8 K

$" $ $ $ T / " < # " T 7

$8 $" 7 ; # K 9 " / 8 0 $ 5* 9 " < " " /

$ F $ # " " 9 T Y4 " " $"

# " " 24/ # " " " < &7A T 1 # $ # * ' c /

# 0" # $K K " # $ # 9 "

> / # $ " # " 9 # 7 $ K $" 7 $9 M

# / $ " " " < # $" 9 $ # $ " #

$ * # )' 8 # 0" 7 T $K K 4

&'X # " # $ / ! " K <7 # " " 58 9 >" GAX

(31)

D% *:

92 91

OH OTs

1,5 eq. TsCl, piridina, 0 °C, 30 h

65%

- K < >" # " " 58 " $ 8 $ F

$ 7 " " # $" 4 33 $" / $4 # !

" T # " # T $" 9 / # )' 8 9

$" # 7 8 K $ $ " # " $ # " 49 / 0"

9 < $ F " < /

" $" " K # # " $" 9 < " < $ $

" 49 " # U" 'V7 # " $ $ " 5 * )6 9 " $4 /

-" < $ $ # T " # " $" K $"

# $ > 0 / " 9 " # K " # # " 7

# ; # # " $ #R < 7 $ T 9 F

8 8 K # " 7 Y $4 . &_: _{" K T} _# _# _"

" # / " $" " K # " 7 # # # " K 9 < 7

" #R / 9 F # 8 $4 " T

# " >" # " " 4 33/ $ $" 9

# " 759 5:7 $9 # $" $ T &=/

D% *6

OH

O MeO

OH MeO

OTs MeO

+ 1,5 eq. TsCl, piridina,

30 h

(32)

> $< 56/ # $" " $ " $ # 4 " $ 9R$

5 1 67 " $ K $" A X " > " 8 0 8 "

5 */G:* 67 " / $ $" >" # # " " 9

0 $" 7 O'X7 " # $ " 5 T &A6/

D% *7&*G

92 91

OH p-TsOH, 5 mol% CoCl2.6H2O OTs ClCH2CH2Cl, refluxo (~80 °C)

1 h

95%

HO _p_{-TsOH, 5 mol% CoCl} TsO

2.6H2O ClCH2CH2Cl, refluxo (~80 °C)

1,5 h

88%

95 94

$ >" K N0 " $ " $" " K 7 " < $ K

# $" 8 0 $ 5*/ > $ $8 4 > $< $ "

" " 7 " " "; $ # > " $" $" $" / ! F 9 < 7

" < $ A X " " &' X/ # " " # $ "

# " 9 # $ $ CX # " " 58 9 >" # " N

/ $9 < $" 7 $ $ # < " >" # @ [ /&*G

$ $ " " >" $ " $" " K " 24 337

" T # " Y " Y 9 $ $" 7 K < T

# # > K $ K # " # T $ < $4 # !/

; 7 " # " K > " $" $ "4K $ $ F # $ 0" 7

T 9 < T 7 K 8 K > " " # " " # 4 K " $

" # " # # " Y ># " $

(33)

$ $ 9 $9 $" $ >" $ " " 357

# # " " $ " K T # # K > " " 8 0 > $<

33# # " 7 # $ " " $ Y *2 ;" /

:0*080:0 - & () H& & ' G & 24

# $ " M " " > K T $ $e 4 > $< 7

T $ 7 # " $ 9 $ # $ $" " /

$ 0 # " /

8 /&** _" _# _K _{" $ 9} ₄ _{> $<}

" # " * # " $ $" ;" 5B6 " $ /

" "; # " > $" " T > " " $ " $

; # $ Y # $ # $" 5B6 " $" / T &G " " #

> " " < / @ $" T " $9 T "

# $" # >" $ " 9 < 9 7 K M $ " >

# " / " 9 " < # 9 # ;K $ " # > " " /

D% *2&**

HO H

OR O

Cl Cl

1,1 eq. MsCl, 1,5 eq. Et3N

CH2Cl2

(banho de gelo e sal), 15 min

MsO H

OR O

Cl Cl

Ph

OR O

Cl Cl 2 eq. Ph2CuCNLi2,

Et2O, -50 a -25 °C,

18 h e 5,5 h a ta

97% 70%

$ /7&*C _" _> _{>" $} _{" 7} _" _{# #}

(34)

D% *4&*C

1,1 eq. MsCl, 1,5 eq. Et₃N, CH₂Cl₂, −20 ºC a ta

10 min

HO MsO

rendimento não determinado

" /7&*+ _" _> _{>" $} _{# "} ₈ _$ _{# "}

" 7 " < ; 4 7 $" $ > $< 5 T &+6/

D% *3&*+

1,2 eq. MsCl, 1,2 eq. Et3N, 0 °C, CH2Cl2,

30 min

OH OMs

H3CO

HO

H3CO

MsO

1 eq. CaCl2,

DMSO, ta, 3 h Cl

82%

Cl H3CO

MsO 95%

1,2 eq. MsCl, 1,2 eq. Et3N, 0 °C-ta, CH2Cl2,

4 h

83%

58%

1 eq. CaCl2, DMSO, ta, 48 h

! K /&*O _$ _$" _;" _{5B6 $} _{" $} _{" K;} _*

" > $< / @ $ " 7 $ " $" 7 T > " " ; $ $ > " " 7

# 0 # $ $" $ " " T " > $< 9 $ $"

/ d # " $" # > T " $ ;

(35)

D% *5&*O

OH

1. MsCl, Et3N, THF, -20 °C 2. 20 eq. NH2CH3 3. HCl, Et2O O

Cl Cl

K-Selectride , THF, -10 °C

Cl

Cl Cl Cl

NHCH3.HCl

(+)-indatralina

93% 67%

> $ $9 F 7 " $" >" " 4 337 #

# " $ " " K; * # " / -" < 4 24

7 Y4 T 7 $" " 0 # $ $" 7 # $ 4

> $< $ $" 5K T &O6/

# " " $ " $ " < &7* T/ . 7 &7* T/ ")

" $ 5 T *' 46/ # ' c 9 # $8

" K; !/ # & 8 # > K 9 # "

# T $" / # ) 8 )' $ " # " #

$ 9 $" # # 4 / 1 0" 9

< > 0 " # " 7 " < $ F # K $" 9 / : K "

9 " > 8 " # " > 0 &' c 7 # $ # $" # "

K $" 7 # ; " # $" 9 " " $ K " $9 F >" $

" " /

# $4 . &_: _# _{" > " #R} _> _K _" _"

# " 7 # " " 4 " # " 7 T 9 $" 9

$ # " 52/

(36)

< $" $" / K $" # " # $" 9 5 9 $ 88

" 526 " K; $4 . &:7 $9 " $ T *'/

D% 89

OH

Condição A ou B

Cl

+

67 96 22

A) 1,2 eq. MsCl, 1,2 eq. Et3N, CH2Cl2, 0 °C, 3 h 30 min

B) 1,7 eq. MsCl, 2,2 eq. Et3N, CH2Cl2, 0 °C, 2 h 30 min

OH

67 +

6 1 3

8 1,5 0,5

: :

>" $ # " 8 $ # $ " K; 9

" 7 $" " # % 9 " " ;7 $" 7

> " > " " # 8 $ " / - 9 $" 8 $ " ; T $

" $ 9 7 # 0 # 7 &)'₇ _H&)&

*&*+/ $" 7 $4 . &:

# " " $9 9 # " OG/

H A # $" 0# $ # " . &_{:7 $} _# _> _K

" # " A7*O ## 7 9 $" # $" 8 N$ : :> 5+ >_)7) :<6

# " 52/ " $ $ " " 8 N$ 9 $ / 8 N$ :

9 $ 88 # $" # " # " G7== ## 7 9 $" # $" "

: 5+ _ O7= :<6 : 5+ _&7G :<6 $ " e " # $" / $

" 8 N$ 9 $ 7 : 7 " >; ; # " # " G7'& ## 9 $"

# $" : 5+ _ O7= :<6 : 5+ _=7G :<6/ =7CA ## # # >

# $ $ # " $ > $ " # " 7 4 247 > K T

(37)

/ E% 70 0# $ # " . &_{: 5)'' .:<6} _" _# _" ₈₈ ₅₂_/

H G # $" # " # " 527 $ > K # $

&GG $" $ G7&A &G+ $" $ &7OC/ !

# " # 7 $ > $ L$ " K $" )A )C _; _{)%&7 #}

$ T # " $9 # $ # " / $ 7 " >; 7

T # > &)& 9 M # 4" /

Cl

96

Ha Hb

Hb

22

H_c H_d

H_e He

Cl

96

(38)

> K $ $ 9 # " 5 T *&6 $ "

T 84 > 7 T K M " " $ # " $ 7 $

: ") /

D% 8*

S

O O

Cl H

H H

NEt3

S

O O

Cl H

H

-Cl

-NHEt3 _S

O O

R O H

S

O O

CH2 O R

H

R O Ms

$" $" 7 " T " K " " $ > " " / " " T

# 7 # $ # $" 7 # $8 T " $ T **/&)*7 &))

$ $8 5 6 8 K 9 # " " 9 " T

# " $ # " 52/ $ $8 5>67 # 8 K "

# " $ $" " " $ # " $ # " 247 $ 4 # " $ 7 T

9 " T # $ " 7 > $ 4 /

D% 88

OH

MsCl, Et3N

OMs

Cl

-Cl

67 96

caminho (a):

caminho (b):

OH

67

OH2

- Et3N

96 Cl

-Cl Et3NH

# # $"L$ " # > : 7 T # Y

(39)

> ; K $" # K " # $ : $ $ / $" $" 7

# $ " 4 # " # > $ /

:4 $ " " $ " > >" $ # " $ " $" " K

9 " 7 " /&)*7 &)= ₇&)* ₄ _{> $<}

; $K " $ # " K " 7 " T *)/

D% 8:&)*

MsCl, piridina, CH2Cl2

X

Z Y OH

X

Z Y

Cl

> $ " >" $ " " " > $ $

" $" " K >" $ # " /

:0*08060 - %' % () ! 8# ; I & & & 25

? $ /&)A _# _K _{> " "} ₈ ₀ _G _{" 0 " "} ₄₄ _#

" e$ " # 7 K $ M " " $ 63/ " " < " 9 9 "

5546 # " $ 9 4 > # 7 7 > " " $ #

" " K; # " # $"

$ / $ $" >" $ # " 5COX6 9 # $"

$ 5G+X6 5 T *=6/ d # " $" $" T " " $" # #

# " K " 4 447 # ; >" K # $ 8 $ 9" $ # $ $" 7

(40)

D% 86&)A

OH

77 MeO

48 MeO

n-BuLi; ClPO(OEt)2 (97) THF, -78 °C

MeMgBr ou Me2Cu(CN)Li2

Grignard: 68% Cuprato: 79%

$ $ " $ 9 < 7 T ; 0 " $" Y # $ 7

8 $ > " " 7 " " # # " 7 " < $

" # / $ Y # " " " 37 < $;" $< 4" 7

7 > " " 8 0 $ # $" " # ? $ /&)A _T`N$ ₇

< 0 > $< " " $ *7 9 $ # $" Y4 "

# $" 5±6 " $" 7+ $ $ " " $ 8 K *2 #" $" " K

5 T *A6/

D% 87

MeO

O (R)-16

OH MeO

(±)-85

Resolução cinética enzimática

OH MeO

(S)-85

OAc MeO

(R)-86

+

Procedimento descrito por Jung e col.

MeO

(R)-15

Oxidação benzílica (ref 8)

# > $ " " 7 $ " " T 5 # & 7

9 7 > < 6 # " < $ " # $;" $< 4"

(41)

# K 8 $< 4" " " " 4 / 7

< " 4 37 " < $ 8 0 $ 7 K $" 7 " " K $ 7

$" $" /

# " 37 32 " K # $ K $ 9 N 7 # " $" 7 # $

< $Y F T # >" # F N / 9 # K <

> # $ $" R 4 377 # K $ F $ "

" " / ; 7 " " N 32 # $" > # #

> K $ " H C/

/ E% 40 " " " 32 N /

7 $" 7 # " # $;" 5±6 37 / " "

K $ 9 " < 0 5= T/6/ 9 # $8 # ! $

Y4 9 # K > K 9 # " Y 5B6 32/ 9 $" #

$" $ A'X " # " 7 9 $ $ " " 5B6 37 +GX

" " 5B6 32 OOX 5 T *G 6/ # # " 9 < " K;

OAc MeO

(+)-86

OAc MeO

(−)-86

(42)

# " $; " $ 84 $ " " " #" 7 T # "

" $ $9 > " 7 $ $" $" 7 $9 # $" $ T

*G ; > $ $ $" " K # " > " " /

D% 82

OH

CALB, hexano, 32 °C

OAc OAc

+

OH

(±)-85 (+)-85

49%, >86% ee

48%, >98% ee

(+)-86 38%, >99% ee

47%, >99% ee

MeO 4 eq. MeO MeO

OAc

(−)-86 98% ee

MeO

Ac2O, Et3N DMAP [α]D27 +36,9 [α]D27 +106,6

[α]D27−96,9 A) 2 h e 40 min, ta

B) 4 h, 32 °C

T 9 # K $ 0 $ $" ; 4 5B6 377 $K

" " " 9 $ 4 7 K < T $ $" R 4 $ #

# $ T / H + # $" 5 6 " " " 5B6 32

>" 5>6 " " 5−6 32 >" # " 4

(43)

/ E% 305 6 " " " 5B6 32 >" $;" $< 4" 5±6

37Z 5>6 " " " 5−6 32 # K $ $" K " < 4 5B6 37

" $" /

! $" > $ " >" $ " " T ; # K

>" $ $ $" N 4 37 > $ 0 $ $" ; " K; "

;" 7 $ " $" " K > " " /

! " < # " # < " " " /

8 C " 0 " " 257 # # > " " $" W . $ #

4 37 $" / " " 25 9 >" # # $ $" " " $ 237

7 > " . : 5 T *C6/

D% 84

O MeO

OH MeO

2,8 eq. NaBH₄, MeOH, 2 h,

0 °C-ta

OAc MeO

(+)-86

5 6

OAc MeO

(−)-86

(44)

H $ 4 # # $" 9 9 54/ 1 # " ; 7 # ; $

" K # $ K $ > " # # # " 0 "

9 9 53 5 5 6 )6 * T/ " $ ;" " 7 > $ 7 ' c 7 $9

# $" $ T *+/&)G

D% 83

P O

Cl Cl

Cl

2 eq. EtOH, Et₂O 0 °C por 3 h, ta por 1 h

P O

EtO Cl

OEt

98 97

+ 2 HCl_(g) 50%

> 0 K : 5 6 9 ># " 9 " >" $

# " 54/ " $ $ ; $ $" $" M " $ 7 9 $

9 # " $ " 9 9 " " " 9 9 " / " # " 9 $"

' c 7 # T > : 5 6$ 9 " K / # $ # # > $9 $" 9

" # " > " / " ; $ 4 # " ># "

" " > : 5 67 ; " K $" / $ $" >" # " 54 9

> 0 5A'X67 # # " $ " F $ " K T $ 4 /

" $ # T &*' c 7 # 54 " $ 9 > "L$

" K 7 T $ #R $" 9 /

> " " 25 $" " N # % # # # " 7

# # 0 " 9 9 " /

7 # K $" 7 9 " $ 9 # > 1:H $ 9

$ " $" $ / 7 8 K . " " −C+ c

$ $ M 9 # " / # . > K " "

K $ " $ e $ / # # 0 $ " $

4 25 & T/ −C+ c 1:H $ / # )' $ 4 "

9 " $ 9 > $ $ $" K # " " < $ L$ / #

(45)

# 0" 7 # " > " 9 > " M $4 . &_{:7 $} _#R

$ " " # $ " # " 9 9 " 555 T *O6/

D% 85

MeO

OH

69

i. 1 eq. n-BuLi

ii. 5 eq. Me2CuCNLi2

iii.15 eq. ClP(O)OEt2 (97) MeO

OH

69

+ MeO

O

99

P OEt OEt

Mistura 1:4

O

! $4 # !7 # $" $" $ 8 K " # "

$ $ 7 $ # " . &_: _{$ " "} _{# #} _&%=

" " 25 9 9 " 55/

9 # " 55 # 7 # ; K " 8 K

> " " # " / < " " $" " K 7 $ K $K " $

$" 7 # ; " >" $ " /

# " . &_: _# _{" > "} _" _T _$" _{$ 9} _{" K}

" 9 9 " / " $" " K # 9 " K; $ " 49 9 $

" # 0 # " 7 $ T # $ # " " # " #R

# /

H O # $" 0# $ # " . &_: _# _" _{> " /}

> K $ 9 $" 8 N$ : 5 " # " A7== A7=+ ## 6 9 9 "

557 T # 8 N$ :> $ 4" 9 9 / 1 >; > K

(46)

/ E% 50 0# $ # " . &_{: 5)'' .:<6} _{# "} ₅₅ ₂₅_/

$ $ T # " 55 ; >" 7 $ 84 > " " 7 # $ T

$ 9 $ " K $ # / > # " $" " < " K

# N$ # 7 " " $" $ $ 9 " $ " K 7

$9 # $" " >; " # ? $ /&)A

# # $" $ 9 < $ $K $ $ 4

" 9 >" " $" $" / F 9 " 7 $ T

$" $ 9 $ $" $" 4 " WC+ c / "

$ 9 " $ 9 # > T $" $8 " 9 9 " K 1:H7

" >; WC+ c / " 9 $" " # " "; $

" # " > $" $ # &* 8/ 9 # $8 # ! 9

$ K # " #R > K /

# 0" 7 " # 0 # " 9 >" / - " $" " K

# 9 # $ " 49 " # U" 'V 9 9 " 7 $ 9 # K

# $ $" 9 $ $8 # " / 1 $" < "

# $" " K < 7 # ; /

! K " $ " K 7 > $ K " $ " K # >" $

*28 T /

MeO

HO _H_c

69

MeO O P O EtO

EtO Ha

Hb

(47)

:0*08070 - ' %() & *2 F

$ $ $ >Y " K >" $ " " $ *2 K 7 " " ";

$";" 9 # # " 7 " T )'/ " " > $ >" $

" " $ *2 N 7 T 9 " # " $" 5±6 " $" 7 $

# $" " " /+7 &' _{" " $} _*2₇ _{# #} ₇ _{" <} _{" "}

> 9 $ 4 .' ) 3) $

5 6/&)C &)O

D% :9

MeO

O

MeO MeO

MeO

O

MeO

OH

HO i. Grignard

ii. H+_/H

2O Hidrogenação Oxidação

Biorredução

13 14 15

16 17 1

> $ " " $ *2 "4 " N F T " $" $"

" N$ Y $9 Y 9 $ / " " " O+7 &'&7 &=' _$ _T

$< # $8 $ $" R 9 " " $ 9 9 $ $ $"

;" " "L$ 9 $ T 9 # /

" " $ *27 # $ $" R 5 6 #

# 7 " T )&/ $< # e$ $ $" R

(48)

; 7 # >" " >; " " R 5 ! 6

$ $" $" $ T 7 = " & " " $ 39

$ .' 5K . / 1 F ) 06/

" 7 # K # " R " " 7

$ T $" $" 7 >" $ > $ $" R 8 $ 9" $ *3 #

" *4/

D% :*

MeO

OH

MeO

OH

MeO MeO

OH OH +

+

cis-(1S,4R)-17

(R)-16

+

(S)-16

(S) _MeO (R)

MeO

O O

(S)

(S) (R)

(R)

cis-(1R,4S)-17

trans-(1R,4R)-17

trans-(1S,4S)-17

# $ " " " K # > >

" " $ *27 $ T " " "; # 9 $ " $" $"

# 7 # " $" 7 M >" $ *2 N /

$ # # 5±6 *2 # " " " $ *: " K;

$ # *7C T/ " " $; / "; $ 9

# $8 " K; !7 # $ " " " # " 7 4

&'X 9 $ "; #: 4 / " " $ 9 " # ) 8 " # T

8 K $ 4 " 4 9 K $ M 9 $ *6/ $ $" >"

(49)

D% :8

O

MeO MeO

OH

MeO

13 14

2,7 eq. MeMgI, Et2O, 4 h, ta

HCl 10%, ta, 3 h

87%

9 $ *6 9 > " M 8 $ " " 7 " < $ ( " $

$ 7 " " K G " # :*5 6/ # "; $ 7

" $ 9 9 " # " " / $ $" >" $ "

9 O)X 5 T ))6/

D% ::

MeO

14

6 atm H_2(g), MeOH, 0,1 mol% Pd/C 10%

16 h MeO

15 93%

# 0 " # 0 > $< " " $ *7/ " Y4 9 <

$ # # T $ $" " " N " $" " < $ )7

# ; $ $" 9 # $ AAX/ 0 # " " $ " " T $ $"

0 F > $< # " ; > 0 /&=& _{$" $} ₈

$ $" " " # 9 $" 0 $" # $ " 0 7 $ " "

9 < / # $ " " " < Q.$ = $" 0 $"

# $ . =/C:* 7&*& K < T $ F $ Y4 8 K " <

# $ $ 0 > $< " " 32 K $ M " 0 " " $ 34 0 $"

$ $" 5OGX6 5K T +6/

(50)

" $4 K 9 # " # 7 Y ." !

> " $" 9 $" > K $" $" / # $ " " " # "

#R # > 7 " K; !7 T $ # " " 8 K 9

T $" T # / # 0" # 9 7 $ " " # $

" 4 *99 =)X $ $" " " $ *27 T # " Y 7

# $ &'X7 " $" & 1 > */ @ 9 T $ $" " " >"

9 " > 0 # 7 $ $ T # " *7 # " 9 7 #

" 9 # 7 # K K $" # 0 F # " /

$ > $ 8 $ $" " 7 " $" $ F

$ 9 $K " $9 " /

# $ " " # > 7 $" 7 T $T $"

" # " " $" ' c 7 $ > K K 9 # "

$ Y / 7 $ $ " $" " K 5 $" * 1 > *67 " # "

9 $" ' c T $" $" 0 $" 9 $ A7A T/ # ) T/7

9 K " 9 # " # 0 / " T $

" # " # $ " $" / > $ " $8 #

" " $ *77 9 $" # $ " " 7 # #

T 9 # " $ Y *99 9 > K / > " >"

$ " $8 > 5)'X *267 9 8 T >" $ F " $

$" &/

" " $" " K 0 *7 " < $ Q.$ = 9

" # " $ 7 K < T 9 # " # 0 ; $

> 0 " # " / T $ 9 " $" " # " 9

$ 40 7 A7A T Q.$ = $ $" /

" # " 9 $" −*' c " 9 8 >" Q.$ =% )'X *2

# )'X " # " 5 $" )6/ " $

T # # $" $" " " 7 " " $" " K 0 9

(51)

$" = " $ $ T " < 0 $" 8 " N$ 7

$ " $ " # " =/A:* Q.$ =/&=& T C T/

$" 0 $" " $ 9 0 > $ # C* 8/ # # 9 7 # $

*AX *2 9 >" *AX " # " 9 # / @ " T

$ " 49 < # # 9 9 9 " $ $ "

" < $ $ " 49 $ 7 $ " # " $" K " $

&' c /

K " " > $ $ 0 F # K # Q.$ =

" $" " < " < $ $" " " " $" 7+ _$ _$" ₀ _{$" ;}

) # $ " 4 ;" 4 # # $ /+ . $" $" 7

" 9 < # " # # T " < $ $" 4

;" 7 9 $ $ " "; C'X $ $" " " $ *2/&=*

$" A # $" $ $ $ ) 4

;" 4 ; $ # " *77 # K $" K 4 ;"

7 " # " > $" / >" K GOX *27 $ $ > K $ "

# " # 0 / " # " 9 7 Y 7 " " $" $ /

- $ " # " 5' c 6 " # $ 5f)' $6 ;

" $" $" 0 $" M $" $ " " $ *77 "

" $" 9 K 4K M 9 " " $ *27 $ T $ $" ; +'X

9 $ 5 $" G6/ " # $" 7 # " T : 5 6

*7 $ 7 " $ > $8 / ! $" K

" # " $ $" $" $" 0 $" 7 "; T " $ /

$4 ! # "; $ $" 0 $" " T " "

# " 8 K $ / 9 $" # # $ " <

(52)

' & 80 $ F $ # $ 0 > $< " " $ 5±6 *7/

MeO _MeO

O OH

+ MeO

O

15 16 100

Condições

.

6 . 7

*2 *99

%

0 A7A T/ Q.$ =7 *7A T/ . =/C:* 7 " $ (:* 5)%&67 ' c " 7 ) 8 &'X =)X

/ ) T/ Q.$ =7 *7A T/ . =/C:* 7 " $ ( :* 7 ' c 7 = 8 )'X *CX

8 A T/ Q.$ =7 *7A T/ . =/C:* 7 " $ ( :* 7−*' c 7 ) 8 )'X &&X )'X

9 C T/ " =/A:* ( Q.$ =7 :* *7 9 0 7 C* 8 *AX *AX

; &7) T/ )7 : 5 6( :* 5+%*67 " 7 & 8 *' $ GOX

< &7) T/ )7 : 5 6( :* 5+%*67 ' c " 7 )' $ +'X

# " < 0 > $< 7 #R # " " >

" " $ *2/

9 >" " # F N $" # "

54 *467 # K # & T/ := 9 < / # )' $7

$ 9 $ " < :* = &'X/ > K 7 " K; !7 T

4 *4 # $8 # $" $ $" 7 $ 8 $ 9" $ *3/ # #

4 *4 5 " $ # 6 9 $ *3 9 C%) 5 T )=6/ @ $"

T *2 " " $" M :=7 $ T $" T $ A T/ "

(53)

D% :6

O MeO

OH MeO

1 eq. LiAlH₄, THF ta, 30 min

+

MeO

7:3

16 17 18

" >" T " $" # " " $ *2 T $" # 4

*4 9 " 9 " 9 $ $ > # $ $" R 7 $ T 9

# K # T " " R 4 *4/ " " > 9

< $ > " H $ - 7 > 9 / ! /

$ :/ $ ! / $ ; / ./ " /

9 $ 4 .' ) 3) 9 F " #

$ T 0" " " / $ $" " F # 8 $ 9

" < # 8 " K / # " < 7 9 $ # K $"

" K 9 $ M F " # 9 0 $ /

$ [ 9 " # # 8 " " " K 7 $ 9

0 # T " " # " )* c / # $" 9 $ 7

F 9 9 " 9 $ 8 # " < " $" $ F

> " " /

$ 9 " < $ > 7 # K "

# T $ /

# # # 9 $ $ 7 F " " $ *2 9

$ / T " 9 " * 7 = 7 &' *' /

$9 < $" $ 8 K $ $8 $K " # " # # " 7 $

(54)

D% :7

MeO

OH (R)-16

+

(S)-16 (S) _MeO (R)

MeO

O O

(S)

(R)

cis-(1R,4S)-17

Aspergillus terreus

(S)-16 (R)

MeO

O

Rhizopus oryzae

Daucus carota

K " " $ " K 7 9 # < > $ " " #

$ K " "; # # # *2 8 T /

:0*08020 L E () & 1 *6

$9 " $ 0#8# 8 $ 9 $ $ 9 $ $ < 64 9

< # 9 "< /GG _{" < $} _" _{: E7 9 $} _$ _{" " $} ₆₃

0 $" $ $" > 0 $ $" ; 5K . / 1 F )

06/

$ " # # " >" K 9 $ " 8 $" M 64 5K

T )*6 9 $ # $ $ # > " " $ 4" / ! 7

$" 7 < 8 $ ;" 9 $ *6/ $" $" " 9/

$ 9 "<7 -$ K 7 $ 7 T $ $K "

" 7*/

$ $ " # $4 " " $ *7 N 7 $9 #

(55)

/ E% *90 " 9 $" M " " $ *7 N /

! " " 7&=) ₈ _$ _K _<

# A' > 7 T # $ # 0 $" A' " / $ $ " "

# 7 8 $ 9 < $ > " 9 / $ 99 $7 - . /

8 $ ;" 9 $ *6 9 < " $ $ 7 $

# $ & X 7* # * 8 " # " > $" / $4 # " > "

# T K $K T OOX 0 $ $" ; +AX

5 T )GW $ 6/ # $ *X # " " < *9* " >; 9

> K 7 # ; " " #R < # " $"

" $" / 8 $ ;" *6 # 9 " " K <

" " " # $ 5&' " 67 # # <4

$ > " / " " $ 5B6 *7 9 >" # $ # &' " $

$ F " $" $" 7 # ; 0 $ $" ; 9 CGX

5 T )G $ 67 > 0 >" A' " 5+AX 67 ; 7 &AX # "

*9*9 >" /

MeO

+ MeO

(+)-15

(56)

D% :2

O N

O P oTol

oTol Ir cat. 51:

MeO

(+)-15 pressão A ou B,

CH2Cl2 2 h, ta, 1 mol% 51

14 MeO

BArF

101 +

A) pressão de 50 atm H2(g)

B) pressão de 10 atm H2(g)

85% ee

76% ee 92% (85:15)*

MeO 1 ₂

3 4 5 6 7

8 8a

4a 9

10 11

*_{Proporção de (+)-15 para 101, determinada por CG e por RMN de}1_H.

95% (98:2)*

" " ># " *9* 9 # $4 . &:

&) _{7 "} _{>; 7} _{# "} _" _/

# " . &_: _*9* _{$ "} _{" N} _{$ "} _$" _T

*7)C ## 7 *7G= ## )7OG ## 9 $" 7 # " K $" 7 8 N$

> $ O7 &' &&/ $ > K " $ 8 N$ 4"

$" C7&) ## C7AO ## /

# " . &) _> _K _{" N} _$ _{> $} _94"

< $ > $ 4" 7 $ $ T " $4 $ " 4 /

# " > " " # # " # ># " >" 7 $

T # $ # $ M &+G 5 # " *9* ;

&+G ( 67 $ " " >; # > / @ $" T 7 $" $" 7 9 "<C'

$ 9 # " $ 8 $ ;"

8 $ 9" $ 5K . / 1 F ) 06/

- " 9 $ *6 9 $K > " 9/ 9 "<7 # T

" " 8 9 < /g _" _" _{$" " <} _# _#

(57)

" " 8 $ ;" < $ 9 " < 7

$ $" 7 T " " 57*7 747 29 >" 7 H &&67 $ T 7* Y4

8 K # $" $" $ " 5K T )G6/

P N

O

Ir

BArF

P N

O

Ir

BArF

57 60 Catalisador de Crabtree

Ir PCy3

N PF6

/ E% **0 " " " 74729 " >" /

" 9 $ > " $ 9 $ *6 M 8 $ "

# $" / " >" 9 " < $ " " # " K

51 > )6/ > K T " T # $" 8 " 9 7*

5 $" *67 T 9 " " < $ " " $ 7 > 9 *9* " $8

$ 9 " K 5&OX6/ > K " >; T " >" 5 $" &6 $

# $" > $K " # " # " / ; 7 "

" 74 29 5 $" ) =6 # $" > 0 $ $" " K 7 K $ M

" " $ 5B6 *7 # $ )=7AX A7*X 7 # " K $" 7 $ T # " *9*

(58)

' & :01 " " 7*774729 >" $ 8 $ *6/

MeO

14

2,0 mol% de catalisador, 50 atm H₂

CH₂Cl₂, 2 h, ta MeO

(+)-15 +

MeO

101

6 & = - > > >

0 >" 5=)6 & AG

/ 7* C)7A &O

8 74 )=7) )

9 29 A7* &

a b # F " $ # /

$ $Y $" " " " < # $ " 7*7 # $

K T $" '7A X *7' X 51 > =6/ > K T T $"

T $" " # 7 0 $ $" ; >" $

# # # " $ *9*/

" " >; T $ 84 9 $ " $ 9 " K $ 0

$ $" ; >" $" &7' X *7' X " 5 $" & )6/ $" $" 7

T $ $" T $" " '7A X # &7' X 0 #

A'7OX # G+7*X/

' & 60 9 " T $" " 7* $ 8 $ *6/

6 0; = - > >

0 *7' X C*7A &O7)

/ &7A X C=7& &C7G

8 &7' X G+7* **7C

9 '7A X A'7O )&7O

(59)

- $ $ " " $" K $" " < W :* * W " >; 9 $K "

51 > A6/ $" K $" 9 " $ >4 9 " 7

$ T " $ F $ 9 $" / " T 0

$ $" ; # " " $ 5B6 *7 9 $" # >" $ F

$ $ 8 K " " $" K $" 7 ; $ $ >" $ *9* 5 #

1 > A 1 > =6/

' & 70 9 " :* * " " $ >4 $ 8 $ *6/

6 = - > >

0 *7' X CO7A &)7'

/ &7A X CG7O &C7'

8 &7' X C)7G &C7+

9 '7A X A+ *C7&

$ F % A' " :*5 67 " 7 * 8/ a b # F " $ # /

" 9 " # " $" $ $ " " # ; $9 N$ #

:*/ 9 < " " K $ # 7 $ '7= X *7' X

" 7*/ " $ F − K $" 7 " # " " # − $ 9

" 51 > G6/ # > 5 $" & )6 T &'' " 0

$ $" ; >" 9 > 0 7 $ " $ T T $" '7= X " ;

$ 9 $" # >" $ > $ 0 $ $" ; / ?4 $ $" = $ " "

T " < $ *7' X 7* &'' " :* K 8 +CX7 8 "

$ "; $" / H # K # > " $ N$ $" # /

$" # # 0 $ $" ; >" $

# $" ># " *9*/ . " < $ # T $ T $" "

(60)

' & 20 9 " # :*5 6 $ 8 $ *6/

6 = - > >

0 '7= X &'' =' )G

/ '7= X A' )+ )C

8 '7= X &' *A =)

9 *7' X &'' +C7& O7*

; *7' X A' +'7) &=7A

$ F % :* *" " 7 " 7 * 8/ a b # F " $ # /

H &* # $" " " " " N " 5797 7: *986

" < $ " " 8 $ ;" *6 1 > C " $

>" $ " " $ 9 / d " $" $" # > T " 79 7:

# < $ $" R # " T K $8 $ 9 5 $" & *6/ "

7: $ " $ $" " K T " " " 7 8 $ O*X

# $ &7AX ># " *9*/

53 Ir

BArF N

Ph

O P

102 O

P N

O

Ir

BArF

50 Ir

BArF P O

Ph Ph

O

N Ph

(61)

' & 401 " " 7977: *98$ 8 $ *6/

MeO

14

2,0 mol% catalisador, 100 atm H_2(g)

CH₂Cl₂ tratado, 2 h, ta MeO

(+)-15 ou (−)-15 +

MeO

101 *

6 & > 6 ? " >

0 79 GO 5−6 *7 &7)

/ 7: O* 5−6 *7 &7A

8 *98 +* 5B6 *7 A7C

a b # F " $ # /

" $" " K " < 7: $ K " " 9 < 7 $ T

$9 N$ T $" " 9 $ / 1 > + # $" "

>" / > K T " 7:7 T $" '7A X7 K M

" " $ 5−6 *7 > $ 0 $ $" ; 5 $" )67 T $

" 7*7 T $ $ F 9 $ # $ G'X 0

$ $" ; 5B6 *7 5K 1 > A W $" =6/ > K " >; T $

'7A X # &7A X $ T $" " 7: $ # $" $"

$ 9 " K $ K >" 5 $" & )6/ $T $" T $ $

T $" " 7* 51 > A6 # K 8 $ 9 " K $ 0

$ $" ; 7 # $ A+X # CG7OX /

$" = 1 > + # # > T $ $ T $" 7: #

'7& X # " $" $ 84 8 $ 5 # $ &G7AX $K 6 K

(62)

' & 30 $9 N$ T $" " 7: $ 8 $ *6/

6 − - > & > >

0 &7A X O&7G hOO &7O

/ &7' X O&7& hOO *7A

8 '7A X +O7* hOO =7)

9 '7& X )7C &G7A +7)

$ F % &'' " :*5 67 :* *" " 7 " 7 * 8/ a b # F " $ # /

" $ T 8 $ # >" $ 5B6 *7 ;

# $" $ $" = 1 > G 5* X 7* A' " :*6/ 8 $

# >" $ 5−6 *7 ; # $" $ $" * 1 > +7 $ T T $"

# $ & X 7: 9 $ 5−6 *7 O&X / " 9 $" M 5B6 *7

5−6 *7 " # $" $ H &)/

/ E% *:0 " 5B6 5 6 *7 5−6 5.6 *7/

" " $ 5B6 *7 5−6 *7 9 $K $ # T # ;

$" $ M $" 5B6 " $" /

MeO

(+)-(S)-15

MeO