DIOLS, POLYKETIDESAND BIOLOGICALLY ACTIVE COMPOUNDS

OH

OHOH

AMPHIDINOL 3

Antifungal

o

OH OH

Ph

STRICTIFOLIONE

Antifungal o

OH OH

PASSIFLORICINE A

Antifungal

~

OH OHOH °yO

NH2

HOSCYTOPHYCIN

O Antifunga/,potential therapeutic value for

the treatment of drug-resistant cancers

DISCODERMOLIDE

Immunosuppressiveanticancer

HO I I l '. IOH OH OH OH OH OH

OH

I

OH OHH02C...... ....À.A .A.

,OH \\OH

OH OH

OH OH )..,/ \rI

ZINCOPHORIN

Antibacterial

. ...CHON

IMe

OH

AMPHIDINOL 3

HO .-OH OH OH

OHOH

OH.OH

~

PMBO~\~H c:>PMBO~H C:>PMBO~OR OR OR O OR O OR

I I ''H I

PMBO .OR OR OR O

ALL YL TIT ANA TION

QM""'O rM

.,~Ph

Ph... 'lo Ph

Ph 'lo Oo_I.. -

~..

~M9C~

QCI1i 0 Ph OH !h )M

.'~ MH.. HCI

Ph .. PhPh'h Ph'h

Ph . . O Ph . O + CpTICI.0-1- 0-1-~ ~

~ ~TADDOL

Duthaler, R. O J. Am. Chem. Soc. 1992, 114,2321-2336

o *Ti OH

RJlH(R,R) . R

O *TiOH

RJlH(5,5) . :

R

1

PMBO~HO

Q:h...O ,Ph

9'1 ~PhPh"~O

Ph --!.-O .'.:,

SYNTHESIS OF THE C1-C14 FRAGMENT OF AMPHIDINOL 3

(R,R)-TI* . 1

PMBO~

OH 42 -03

80%

. 1

PMBO~HOR O

1- TBDMSCI

90%ee >98%

5 Sleps ~t 36%

(EtOhP(O)O.17 atoms

(EtOhOP,,-/C02Ete

~ ~ 6 H 1-Dibal-H ~ ~6 OEt

PMBO. ... PMBO .. 4 .OR o 2-Mn02 OR 4 O65%

.

,

~~HPMBO : - t'I.. A -I? Il

cm OR OR 12 O

CROSS-MET ATHESIS REACTION

~pri~iPr

~ Ph

(CFahOC".Mo ~ 1I ~Me(CFahOC Me

~CN

"MeSN

yNMeS

PhCI" IRu

CI' I

PCYa

o~OR

o~H

"MesN NMes

CI,..rCI~ I =o--(

O 'I ~

O -~ R

1 h 6?? ~

PMBO~CHO I >PMBO~ + ~CHOOH OH

R + EWG=M

REWG.

r=M -- -,r EWG

R)

RM-

1\MesN NMes

Ch..!

c'~lh

-{-u

CROSS-MET A THESIS REACTION ~\~\~HPMBO ~ - I ~ - l' 12 Il

OR OR OR O

PMBO CHOCat

PMBOCHO+ .OH CH2CI2 OH

25°C, 36 h 75% EIZ= 50/1

PMBO C02EtCat

PMBOC02Et+ .OH CH2CI2 OH

25°C, 36 h 70% EIZ = 50/1

~ OH

CHEMOSELECTIVITY.

2HO -

OH OH OH OH OH OH

2 ~ 6 (8,8)-1 6PMBO~CHO . PMBO .

OH 86% OH OH

EIZ= 50/1

~CHO 6

X . PMBO :

"Ru" OH OH

QI.

~ 11"'10 ,Ph

9 ~?I ~PhPh..t?O

Ph O -f...........

I ~CHO

+ "Ru"

40% 35%

f\MesN NMes

CIl..!C"lh-<.-{J

PMBO~CHO +OH OHC~CHO

OH

~~ OH

CHEMOSELECTIVITY

.

2HO -

OH OH OH OH OH OH

PMBO~OH

.. PMBO .OH OH

AC20

Pyr. PMBO .

OAc OAc95%

I"RU"

63%t ~CHO 3eq

PMBO .OAc OAc OAc

!"RU"

60%~CHO 3eq

PMBO .OAc OAc OAc

(S,5)-1AC20,Pyr

80%PMBO .

OAc OAc.

I...TI.. o Ph~~' rPh

Ph'~OPh 0-1-

~

"MesN NMes

CI. YRu

CI. I "=h-<~

6 Steps, Overall yield of 17.5%

::Dcn -<

:J:

Z

l=o

J:J

-IIl

:J:

»m

J:J

'<cn - cn

J:J

O " .....

lJn

w I C - O r- cn

:J:

I

l.

or--

oo

I.t.

.o

:J:

......

o.I

"tI

J:J

J:J

"tI:

::r:::

r

SYNTHESIS OF 1,3-DIOLS

.9H OH

O OH ; ;11 l (R,R)-Ti.#' ~XR

H"'" rr.XR /' n" (S,S~

OH OH

~XR "

O OH

~ XR (R,R)-Ti

~ . XR. ~H "-"her, -78°C "85%

OS04' Nal04

ether, H20

O OH O OH (R,R)

r;/Ti

~ (S,S)-Ti ~ Os04,Na104 ~XR. XR . XRH "ether, -78°C ~ "ether, H20 H "~ OH OH

87% (S,S)-T, ~XR~ Il ~ I ~ "

9H OH

~XR "

XR = OBz, OTr, CH2Ar"=1,2, " ~Ji..O ,Ph

~ 9~ -r-PhPh"~"O

Ph O~.."

~Ji..O ,Ph~ 9 -~Ph

Ph"~OPh ~--'-O .::

de>95%

(R,R)-Ti (S,S)-Ti

o

o XI

JJ O s:

- + - I Cf)

-I :o - (') -I - "T1

O ....

- O z mlJ

£ "ti

:J'

"ti

:J'

"ti

:J'

o

"ti

:J'

:J:

LJ=

J

" /o :J

:

"ti

:J'

o/

XI

-I -,.:

o

"'to

:J:

SYNTHESIS OF (+)-STRICTIFOLIONE

o

Ph~H(5,5)- Ti*

..Et20, -78 °C

83%

OH. 1) OS04, NMO

..

OH OH

Ph~Ph~Nal04

2) (R,R)-Ti*

76%

X OH X O

Ph 84% H

92%1 Acryloyl Chloride

, iPrNEt2O

X oVPh

Cat.GI X O. OO

CH2CI2 -82% Ph

~I.

~I"ro Ph

~"ct rPh

Phr~9Ph o-!-.-

I DMP,Acetone

95%t CSA, 25 °C

AcroleinX

Ph~.

Cat HCH2CI2,rt

70%

HCI

O

OH OH

Ph

..MeOH87%

9 Steps, 23%overallyield

PCY3I

G = Ch Ru "':'\CI., Ph

PCY3

1'\

MeSNyNMeSH= ChRU

~CI.,O 'I ~--\ -

H02C1

ZINCOPHORIN AND ITS METHYL ESTER

Isolated in 1984 from a straln of Streptomyces griseus

High afflnity for Zn(lI) and Mg(lI) catlonZincophorin and Its calcium salt = Strong antlbacterlal properties agalnst Gram-posltlve bacterla

The ammonium and sodlum salts = antlcoccldal activlty agalnst Eimeriatenella In chicken embryos

One total synthesis: Danishefsky et al. J. Am. Chem. Soc., 1987, 109, 1572

25

Antiviral activity with reducedceli toxicity compare to the free acld

RETROSYNTHETIC ANAL YSIS

~~

...' OH OH 9HH02C - * \..;...

1 ~ H O H ~ 9 ~ 11 ;~3. ..'- - - -- - - -"\. OH~c=) Me02~~oMh 12

ALDOLISATION i H H:5 !C1-C12 FRAGMENT

25

~ CROTYLMETAl

ZINCOPHORIN

("l..."

R~Y~~~OP QE

(l ..."

Me02cYto4o1 : H H:': -\

INTRAMOLECULAR ELECTROPHILIC RING OPENINGC1-C9 FRAGMENT

+

25

~

C13-C25 FRAGMENT

INTRAMOLECULAR OXYMERCURA TIONOF CYCLOPROPYLCARBINOLS

HA - OBn

'Hoc"N~Hg2+

1) Hg(CI04)2NaHC~, hexane-. <;1~

~è! l. ."oBn+HgBr

Inversion

2) KBr, 1120

79%

~"..

..,

Ho" , 06 =' . . OH1 /; H H:.. -- --

<:+ ~OBn~al_~

HgBrRétention

12 : 1

I n-BlI3SnH

70% ~ AIBN cat., THF

~OBn ~ ~OBnH3C 3 CHCH3 312 : 1

Collum,D.B.;Mohamadi,F.; Hallock,J.S.J.Am.Chem.Soc. 1983, 105,6882-6889.

~\.'o

3 "'7

RO ~ "'OH~. OPHg2+

SYNTHESIS OF THE CYCLOPROPYLCARBINOL

o O

~o0

1) TsNa

EtaN, MeCN

2) LiOH, H20

60%

~C02MeO N H

Me02C'I~I~ORh"""...Rh

~~Doyle's Catalyst

HO~"\\

6 9 BH.THF. ...= , OTBDPS H202' NaOH

dr> 98/2 91%

.O

N200

0 Slow add of the substrate

CH2CI2,reflux, 30h

90% e.e.> 95%

0.1% mol

Rh2[5(R)-MEPV]4 .... ~b= ,

Meli (2 equiv.)THF, -40°C 91%

Cossy, J.j Blanchard, N.j Meyer, C. Eur. J. Org. Chem. 2001,339.

OTBDPS

1) TBDPSCI, imidazole

H°t-DMF

...2) CHaS02CI, EtaN

DMAPCH2CI2

=...., OH

TBDPS= t-BuPh2Si- 85%

SYNTHESIS OF THE C1-C9 FRAGMENT OF ZINCOPHORIN ~~\

o .379

RO ."0 . OH- .-

~..~~\HO ~

:~~~~ OTBDMS

Et02C

~~\

1) PCC,CH2CI2 ~ .' H2,Pt02. .2) (EtOhP(O)-CH2C02Et t~~ OTBDMS AcOEt

NaH,THF 98%

75%dr > 98/2

.' OH

OBz ~

O

~ (c-HexhBCI "6°B( c-Hexh

. ."EtNMe2 OBz.HF. Pyr, THF

de > 96% (Hg) 71%

rl"~~\

EI02è ~OTBDMS. ~~.~~

I i-Bu2AIH

97% f'°luene, -7SoC

~

\\.~

~ .O :~~~ OTBDMS~

~'

.' OH OH OH6 ., ..-

H02C 3O: :I~~1:H H: : :- - - -SYNTHESIS OF THE C1-C9 FRAGMENT OF ZINCOPHORIN

OH

1) Hg(OCOCF3h

CH2CI2 t.a., ..

2) KBr, H20OBz :

OH

dr =93n

n-Bu3SnH, AIBN cat...

THF, toluene

85%

H

~'.'

O 6'

Il 3 8

" /1 O :, OH: : H H:

OBz : 'HQBr

SYNTHESIS OF THE C1-C9 FRAGMENT OF ZINCOPHORIN

: OH

1) TBDPSCIimidazoleIDMF .2) LiBH4, THF

3) NaI04/ MeOH

C1-C12-. -. ~"

O 6 .'3 9

MeO 1 .H O :. OH

: H :- -

1) TMSCHN2MeOH, Benzene.2) HF Pyridine

THF

69%

~"

O 6 .'3 9

H 1 § H O A § OTBDPS

90% (4 steps)

jNaCI02, NaH2P042-Me-2-butene

H20, t-BuOH

~"

O 6 .'3 9

HO 1 § H O A § OTBDPS- -

Cossy, J.; Blanchard, N.; Defosseux,M.; Meyer,C. Angew.Chem./nt. Ed.Eng/.2002,41,2144

SYNTHESIS OF THE C1-C12 FRAGMENT OF ZINCOPHORIN

~~~

o .'

MeO 1. O:.. 9 OH: H H:- -

/Q'-~Ji.,O ~Ph

~ 9' -r-PhPh"~.,O

Ph O-:L-.."

(R,R)-Ti

1) Dess-MartinPyridine, CH2CI2

2) ~Ti*(R,R)

63 % (diastereomer-anti,anti)

1) Et2CuLi (excess)Et20, -78°C

12 .2) Dess-MartinPyridine, CH2CI2

60% (4 steps)

.. MeO . .: H :- :

1) TBSOTf, 2,6-lutidineCH2CI2,-78°C

2) OS04 cat., NMO,acétoneIH20puis Na104,THFIH20

MeO . . H: H -

RETROSYNTHESIS OF THE C13-C25 FRAGMENT

o

c:::>25

-

o

YHT8S0

ChiralAllenylmétal

Addition

< I

[~.-M ]

8nO-13

OR25 .

OC22,E

QR

'0/~T8S0 I

~~

.' OH OH <,?H

H02C . ~;...O . 13

§ H H § § §

( I

25

8nO 13

OR

-y° C20> C22

CH3 DBn°:-J

9R ,«~

«O

SYNTHESIS OF THE C13-C25 FRAGMENT OF ZINCOPHORIN

MeVOMs

Pd(OAeh.PPha eat.

Et2Zn

THF, -20°C

MOMO

~-------

..[

H, zn<OMS>

]

'. --I'-""-'-'-MeChiral Allenylzine

MOMO

o

o

YHTBSOTHF, -20°C

25

..

.1) MOMCI,i-Pr2NEt

CH2CI2

2) n-BuLi, HMPT, THF

Br""""""'" o Bn

86%

OMsI

r-. Zn~ ~~(;~e ~I

TBSO~' ~.~H H H Me

Felkin-Anh Model

+ 75%

'" OH

~: ~18 :;;.'"

19

T8S0

dr > 98/2

SYNTHESIS OF THE C13-C25 FRAGMENT OF ZINCOPHORINMOMO

MOMO1) BU4NF,THF -

P\Me Li

MgBr2 (excess) .BnO

. MOMO MOMO

2) DMP, py, CH2CI2

92%Et20ITH F, -78°C

93%

o

CrjoI ~

: l"'OAc"AcO OAc

OMP

Nu HWR

Cram-chelate . )'!Y09

(,"~ Mg2+Meo-~

dr =9/1

AC20

Pyr

oCarroll-Claisen

MOMO[3,3]

~---------_.Ireland-Claisen

~-----_.

BnOMOMO

SYNTHESIS OF THE C13-C25 FRAGMENT OF ZINCOPHORIN

~o --MOMQ'!!

DMAP cat.THF, t.a.

88%

BnO

MOMO! ~

oEIZ> 96/4

MOMO~

...

yYO O

72% I A~Oa neutral

, 60°C

Me

MOM9..

LDA(2.5 éq). I /1THF yyoLiOLiO

I THF, reflux

+ 15h /'BnO 13

RMOMO

~

~'.' OH OH OH6 -

H02C 3. * ...~1. O.. 9. ~, 13: H H: : :- - - -OHSYNTHESIS OF THE C13-C25 FRAGMENT OF ZINCOPHORIN

25

MOMO25 .

o

TBSO

Me02C

1) DIBAL-H .Et2O, -78°C

2) MeS02CIi-Pr2NEt, CH2CI2,O°C

92%

1) TBSOTf, 2,6-lutidine

2) Li (excess)THF/t-BuOH

NH3liq., -33°C,. 25

3) Dess-MartinPyridine, CH2CI2

65%

MOMO*25

1) p-TSA, MeOH (2)88% I .

2) LIAIH4, THF, reflux

SYNTHESIS OF THE METHYL ESTER OF ZINCOPHORIN

16 Steps, 12%

Methyl ester of Zincophorin

12TiCI4, ;..Pr2NEt --CH2CI2,-78°C

25

11 Steps, 21 %

1) NaB~, MeOH,O°C--2) HF.pyridine, THF, 20°C

66%

-78.oC,2 hdr > 96/4(C10-C12-C13syn, syn)

70%

SYNTHESIS OF ZINCOPHORIN

o

N200

0 12% ~ Me02C1 Me02C

1

16 steps

Intramolecular Oxymercuration 01 Cyclopropylcarbinol

~ 25

70% tLiOH

H02C1 :

25

o

YHOTBS

11 steps

21%

Carroll-Claisen Rearrangement

ACKNOWLEDGMENTS~

!I~I

.

1 . ..

CENTRE NATIONAL

l!! DE LA RECHERCHE

y SCIENTIFlQUEfUI J<

f;

ES?CI

S. BOUZBOUZC. MEYER

M. DEFOSSEUXN. BLANCHARD

SPECIAL THANKS

R. DUTHALERA. HOVEYDA

FINANCIAL SUPPORTFr $ Fr $ Fr $ Fr $ Fr $ Fr $ Fr

ESPCICNRS

MREST

RHODIAPPG-SIPSY

LABORATOIRE LAFONAVENTIS

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