r - IASOC · Cossy, J.j Blanchard, N.jMeyer,C. Eur.J. Org. Chem. 2001,339. ... OBz : 'HQBr....
Transcript of r - IASOC · Cossy, J.j Blanchard, N.jMeyer,C. Eur.J. Org. Chem. 2001,339. ... OBz : 'HQBr....
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
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
ELI-LILLY (USA)