fluoride ion induced stereoselective functionalization of ... · fluoride ion induced...
TRANSCRIPT
Fluoride ion induced stereoselective functionalizationof heterosubstituted silyl derivatives
Dipartimento di Chimica Organica, Polo Scientifico, Via della Lastruccia, 1350019 Sesto Fiorentino (Firenze)
c-c bond formation through organosilanes
Q Conventional carbanions ArCH£ l R-CH=CH-CH£
~Eb E+ .-~S
'~'-..::IIf' -Me3SiFF Me3 I
I. Fleming, J. Dunogues, R. Smithers Org. Reactions, 37, 57 (1989)
Q Non conventional carbanions(Umpolung)
o
RJJ-
o
~ R'-XR S
. F-
IMe3..
o
~R'R
Synthesis, 647 (1989)
Easy transfer of silylated nucleophiles ontothiocarbonyl compounds
Z = Ph, CH=CH2 Ali carbon chains
~CH2-SiMe3
5
R)lR'
F -J~R R'
Synlett, 1992,880TetrahedronLett., 1994,35,161J. Org. ChenL,1996,61,7174..
Z = PhS, PhSe a - Heterosubstituted
Isilanes
Eur. J. Org. ChenL,2000,2171
(/nversion of the regiochemistry )
Easy access to more versatile intermediates
Reactivity of the C-Si bond
CF31 + CH3LiEt20
..-78°C [CF3Li] .. [CF2] ..
F2C=CF2
Burton, D.J., Yang, Z.-Y., Tetrahedron, 1992,48,1897
CF3SiMe3 +
°
ARIR
F- ..F3CXoSiMe3
R R'
Surya Prakash, G.H., Yudin, A.K. Che.m Rev.1997,97,757
('ì R-Li.
[ Q] ~ ('ìS S e S
'-/ 111 Sy~ F-~ E1.RLi ('ì ~+2. TMSCI SyS
SiMe3N.H. Andersen et al.,Tetrahedron, 37, 4069 (1981)
r'1SyS
SiMe3..
[
?.]
RCHO ...(ì5 5
RXOH
F-
Possible use OJ diJJerent heterosubstituted silylatednucleophiles ?
x= S, N, Sn, Se
nSyX
SiMe3
X = S, N, P, o
RSyX-R'SiMe3
Acyclic a - heterodisubstitutedorganosilanes
2-Trimethy/si/y/-1 ,3-disubstitutedheterocyc/es
Synthesis 0/ mixed organometalZic silylatednucleophiles
PhSe,/SnR3
(s-BuhNLiPhse'e LiEf)
PhSe,/SnR3
e LiEf)v . PhSeySnR3
E+ . ER.W. Hoffrnan et al., Tetrahedron Lett., 31,7419 (1990)
..PhsexsnBU3Ar OH
59-68%
Phse, 1. LDA .2. BU3SnCI
SiMe3PhSeySnBu3
SiMe3
ArCHO
TBAF,0.1 eq., THF
111
Ph/se SnR3eA.Degl'Innocenti, A. Capperucci, T. Nocentini, Tetrahedron, in press
Synthetic equivalent Or not easilyobtainable carbanions
A. Degl'Innocenti, A. Capperucci, T. Nocentini, Tetrahedron, in press
PhSeySnR3PhSe"""SnR3
SiMe3- e
o I
Ph7dH
p::xsnR3 ojPh '-': OHS H
59%
snR3TBAF0.1 eq
PhseXsnR3THF .... OH-78°C -> r.t. S
Ph OH
61% 68%
Fluoride ion induced intramolecular functionalization:synthesis of dihydrobenzothiophen- and dihydrobenzofuran
systems
Possible use of different heterosubstituted silylatednucleophiles ?
x= S, N, Sn, Se
/\SyX
SiMe3
X =S, N, P, O
RSyX-R'SiMe3
Acyclic a - heterodisubstitutedorganosilanes
2-Trimethy/si/y/-1 ,3-disubstitutedheterocyc/es
eco OH
O'SH
I F- 0:J:J0Js,O"
S "'S I
eco Me3S j',J...SI Y = 81%S
Me3SiAci
d.e. = 84%
ecoI OHOH
s,OF- 0:J:J0J
Me3SiAO. S "'0 I
Y = 81%d.e. = 43%
O + PhSyCI C(°OHI F-.
0,0. CçCsJ0JOH SiMe3 Me3SiAs
Y =84%d.e. = 0%
Synthesis 0/ 2-trimethylsilyl-l,3-dithiolanes
nSs' /
1.n-BuLiX.
2.TMSCI
nSyS
SiMe3
Synthesis and reactivity 0/2-trimethylsilyl-1,3-dithiolane
First example of silyl mediateddithiolane transfer
n nS
y S = S' /SeSiMe3
DITHIOLANE ANION
EQUIVALENT
A. Degl'Innocenti, A. Capperucci, T. Nocentini, Tetrahedron Lett., 2001, 42, 4557
[s ]
S
. RJ(S-T. Oida, S. Tanimoto et al.,J. Chem. Soc. Perkin Trans I,
1\ n-BuLi 1715(1986)
SxS . + CH2=CH2
orLDA r -R H[RCHS] S.R. Wilson et al.tA
e*s- J. Am. Chem. Soc., 102,3577 (1980)
+ CH2=CHS J. Drg. Chem., 47, 3319 (1982)
I.. R H-
n1\ n -S SF
PhXOH
MeOySiMe3
HS SH
SyS+ Ph-CHO ..
r.t.(i-PrhEtNBrSiMe390%
79%
nS S
PhXOH
79%
~s1"'30% sJ
HOC
yv;$ H3
S :'
C'-::; OH
; s 30% Ph~S
~CHO 8::
~Br
n ' PhCHOS..S ~
OH.Br-Q-CHO
1\Sy
SiMe3t~CH:
(~1 sp: S
Il OHBr 78%
/ S fìl i~12% OH 'sysJ
83% OH
24%
~s80%sJ
H H
M~.J<::;yl-SIMe3+
PhCHO ..
J<:::H . J OH
Me r ìMe S Ph
cis-cis
F
cis-cis
+ PhCHO .. H H
;XHO Ph
Me~
Me~:S HStrans-trans
J<:::H SiMe3
Me --l.Me "7 "HS
F
trans-trans
Retention of con figurati on at C-2 on substituted dithiolanes
A. Capperucci, V. Ceré, A. Degl'Innocenti, T. Nocentini, S. Pollicino Synlett, 1447 (2002)
MetaZation 01 substituted dithianes
Functionalization occurs invariably on theequatorial position
A. Krief, L. Defrère TetrahedronLett. 1996,37, 8015.
.... -
Use of Se/Li exchange to obtain axially oriented diselenanes
Epimerisation always takes piace on dithianes
A. Krief, L. Defrère TetrahedronLett. 1996,37,8015.
R R R
fHt-BuLi
fLiE
fE. .-130°C
R =R', SeMe
tH Li E
fR fRE
fRt-BuLi X..-130°C
SeMe Li D
eH t-BuLieH
MeODeH. .Se -130°C Se Se
L... a : e = 98 : 2
-SeMe Li
H
fHt-BuLi
fHMeOD fD. ..
-130°CJ a : e =1 : 99
2-TrimethyZsi ZyZ-4,6-dimethyZ-l, 3-dithiane transfer
Stereoselective synthesis of C-2 substituted dithianes
A. Capperucci, V. Ceré, A. Degl'Innocenti, T. Nocentini, S. Pollicino Synlett, 2002, 1447
H H
-fsiMe3
-
fy°HF
+ Ph-CHO .r.t.
cisPh
cis
SiMe3
Ph'1-°H-fH
-F
S H+ Ph-CHO .r.t.
trans trans
R R' R R' R R'
RH
R'
H H HSyS °yO SyO
5 N-R
YSiMe3 SiMe3 SiMe3 SiMe3
Dithiolanes Dioxolanes Oxathiolanes Thiazolidines
Synthesis oJ 2-silylated heterocycles
R R
)--(SyO
SiMe3
D~R
>-<HS OH
n~HO NH-PG
,(°yN-PG
SiMe3
1,3-0xazoZidines1,3-0xathioZanes
HMDST: ring opening OJ epoxides ?
X.. R,
HO~
O
~R1 +R
Me3Si-S-SiMe3
+~R R1
Q 1,3-0xathiolanes as useful molecules indifferent synthetic processes
°ySR2
R2:::: R',
E. Dunach et al., TetrahedronLett., 2003,44, 853M.J. Porter et al., Chem. Commun., 2002, 346L.E. Overman et al., J. Am. Chem. Soc., 2000, 122,8672.
Meol
,R RSiMe3
.,, ' h.Br,n /\ r-<
SyNH s;:HS SH
SyS
SiMe3
I MeolBr I
DIPEA, r.t. DIPEA, r.tSiMe3
1,3- ThiazoZidines1,3-DithioZanes
I SiMe3
o
PhP
+ PhSSiMe3TBAF . OH
Ph~SPh69%
Tanabe, V., Mori, K., Voshida, V. J. Chem. Soc, Perkin 1, 1997, 671
Brittain, J., Gareau, V. Tetrahedron Lett., 1993, 34, 3363.
HMDST: ring opening 01 epoxides
Regioselective and enantioselective ring opening
O NEt3SH OSiMe3
PhP
+ Ph3Si-SH . OSiMe3 + SHPh Ph
1 eq. 7 1 87%
25 eq. 1 8 40%
OHO F
-
RJyR1Ri,<(Me3SihS ..
r.t.SH
(R1 =H,R) 50-100%
- RO F !:'
.:'+ (Me3SihS .. 1\
\\.. r.t. HS OHR'
e.e. > 98%
Generai way to obtain p-mercapto alcoholsMen 64% /0\ 71%
HS OH r\_-- Pr CI
HS OH rf.. 70%HS OH
96% Hr<:~\ / / ~ 88%~ ~HS OH
,,-08Z" (HMDST)H00H / ~~ Q tè:
78% )-\('OMe
C):°H HS OH
i 65%
('OH ~o OH SH84% SH '~:- {H MeArMe 69%
97% Cbz SH SH 72%
Ph
96% nOHHS
Extension to aziridines: synthesis 0/ amino thiols
and thiiranes ...
+ Me3Si-S-SiMe3 ..HS SH
rRRP
F-
TsIN F- TsHN SH
R+ Me3Si-S-SiMe3 . r
RTsIN F- TsHN SH
R,D+ Me3Si-S-SiMe3 .
/--J
MeOyBrSiMe3
1,3-0xathiolanes
NJ:23TCTM J ~
o ..NO #
H0/1",.\) "
- cytosine nucleoside analogue-high antiviral activity
O. Dwyer, Synlett, 1995, 1163
R
r<HS OH
R
r<SyO
SiMe370-85%
...CH2CI2,r.t., DIPEA
"S'Voe
R =CH3,H, 0...11" ~o""N~Cbz
Functional ization
of 1,3-oxathiolanes
s"
OX:H30%
1:1
S"O
lfOH1:1
35%
O
CsF"-SyO
--
SiMe3o
[}-9l/,
CsF
Easy transfer of 2-trimethylsilyl-oxathiolanes
Y°>-<OH~S Ph
52%
. PhCHOF-
)-(SyO
SiMe3
F- ,~CHO 74%
F-11U\- ~s CHO
):: ' OH S )::~~\ 78% Ph.o
~CHO. )::~
H3C
59%
Stereoconservative lunctionaZization 011,3-oxathioZanes
r<CH3 F- r<CH35'(0
. 5 O 1:1PhCHO
PhXOH5iMe3
r<CH3 F- r<CH3
SyO. 5yO 1:1
PhCHOSiMe3 PhAOH
H3COH2C" H3COH2C"Ì\ f\
°ySRCHO
°yS.SiMe3 TBAF
HOAR1 : 1
H3COH2C" H3COH2C" R=Ph, F-o-f\ RCHO f\
°ySO S.
HOXRTBAF 1 : 1SiMe3
1,3-0xathioZanes functionaZization toward thesynthesis of bioZogicaZ active moZecuZes
0"",/0 HN
O~O"-'Ph
..O ;.0""1"/N
O~O"-'Ph
.. O""I~N
O~O"-'Ph
.. O""I~ON
O~O"-'Ph
~ ASH
OH OO...II( )\-N LS
O~O"-'Ph
0- O-(S;Me3MeOyBr
J. < S .. S;Me,O O"-'Ph
OH0...,,(N LSH
O~O"-'Ph
..
~BATPhCHO
DMF
HO
O'''lll~N ~.J VO~O"-' Ph
agonist of
muscarinic M2
receptor
1,3-ThiazoZidines
NH2H
~ -N~S~\\HO~ lf ~N.../ ~
O ~OOH
,OH
çt(}OHOH
Amoxicilline Azasugars
.. {""""\SyN\\
E N+ [
{""""\
]
SyN\\
Li",'N+
{""""\
S",Nl+
1. RLi, -50°C
2. E
A. I. Meyers et al., J Am. Chem. Soc., 1984, 106, 3270
\-;l'"{""""\ O~
SyN\'( \~O
1. RLi, -78°C ..~Il'
n O~ R. E. Gawleyet al.,
SyN\( \~ Tetrahedron: Asymmetry, 2000,11,2093E O
2.E
ThiazoZidines funetionaZization
MeOyBrSiMe3
1\ 1\
HS NH2~ SyNHSiMe3
1\~ Sy
N-PG F- ~
SiMe3
1\
SXN-PGR OH
Reaetivity of N-Boe proteeted thiazoZidines
" Jlok5 N01- ç 46% 01-r---\ Jl ~ HO d.e.>95% r---\
NJlo~5 N O S
x42% ~1
70%d.e 80:20 HO
~ t:::::::7'CHO / HO Ph d.e >95%
'l ~PhCHO
CHO o 1 - 5 r---\Jlok{"\ 5t ~ S{"\N~O..-'« 
Peculiar behaviour 01 N-Cbz protected thiazoZidines:synthesis 01 bicyclic systems
o
crH~1\ oh5~::O U
~S~O
H
1\ Oh
5~::O U
o
RJlH ..F-
1\ (oh
5XNto UR 0-
~OO 654%
S:°~5 ~8%
n-oF ~ o
L 5\-1R
A. Degl'Innocenti, A. Capperucci,T. Nocentini,S.Biondi etal.,Lett.Org.Chemistry,2004, 1,55
Reactivity and stereochemistry 01 N-Cbz protected thiazoZidines~
(Js NFO 35% ~
O d.e. >95% S'J-N,:OPh O 37%
I 7hCHO d.e.O%
CHOr.t O r.t
~N25% . S'L FO
d.e.>95'YyO '" CHO
r.t~
r
iJN,:o.. 0+
\02N ~
10%d.e. >95%
/,""",,\0S
~N~O""Ph 02N-@-CHO
HO ... ....l"
N0240% 35°C
d.e. >95%~CHO
F3C~ ./ 35°C
~ ~O
Bs r;ro + SXONJ.t.O-Ph
HO"\ /. I ....
F C CF33 30% 10%d.e 20% d.e. >95%
O
r-\ JlO""'PhSyN
SiMe3
F-@-CHO..~
~}.N,:OD 045%
F d.e20%
~oOMe
~
iJs NFOO
....\ /.
MeO 50%d.e. 25%
r.t
35°C~liJ>-CHO
35°~~
Js NFOO
S,... 50%
d.e. 20%
Reactivity under BuLi conditions
hrl~S) oS N o:
'T(R) Ò~SiMea \ ~
~ ~~ ~
ri(S) O ri(S) OS N o: S N o:'r(S) { ~R) {
(R - O (S) OPh~."OH '( Ph OH '(
70 : 30
R. E. Gawley et al., Tetrahedron: Asymmetry, 2000, 11, 2093
O \-,,--,riHO NH2
SiZyZ 1,3-thiazoZidines
'-- BOC20...~LiAIH4 ~ ~
HHO N 2
77%
'--s
, O
HnN-\+ °>95'10 . ,,)-lSH
~ \-f O
O\\.-S~N-k' ~/81'10 °\
'--'"
, OHnN-k' ~>95'10 0\
KOH..
h;$çN\{O'(
a oSiMea
8:3
!
1. MeaOyBrSiMea
2. H+cat.
h
?1°'(SiMea
$I{'"""\ 1. RLi
S'" N f,o..
0'(2. CISiMe3
Ln(S) 1.RLi
S",NfO ..
0'(2.PhCHO
FunctionaZization 0/ enantiopurethiazo Zidines
~
~-tfSiMe3
~!$
ri<S) o L5 N \~
'1fR) ~SiMe3
TBAF 1 eq ..PhCHO
O°C
TBAF 1 eq ..PhCHO
O°C
~ri~
SxN1°'(Ph OH
45:55
~!$
çN\{O'(= °
Ph/'1.0H40:60
Influence 0/ the substituent positionon the reaction stereochemistry
froSIN'h
SiMe3 'f
)~N-~'PSI b
SiMe3'f==> ~~)(o'o('
HS O l'
ijHO~NH2
Synthesis 0/5-substituted enantiopure thiazoZidines
~'I>
Ì\HO NH2
BOC20~
OhHO HNi~>95%
..
hO hoS HN-k + S HN-k,.1... o-L ~ o-LMe3Si" OMe ~ Me3Si OMe ~
1 : 1
..
~h o~
SyN1 \~
SiMe3 87 %
0,-(
+;t-N
XOS ~CHO
HO" ~I~~"""'"
TB;;---85:15 O°C
y=47'ì'o THF
O
..JlSH ..
MeOyBrSiMe3
l-~N-{~83%
~KOH
hOHS HNi~93%
singZe diastereomer
C{L ,-(
~ CHO+o'N ~S "" HO II~ ~
F~ CF3TBAF 50:50
O°C y=44%THF
~CHO~F ,-(~
+O)\-N
~S
O°C O
THF HO l''~ F
C{L r(+ ,NyO SiMe3
S CHO
,-( CJr
!
TBAFO)\-N
~S ~AF
~ CHO O°C+0 O°C I THFS ~
HO 'I. THF MeO
55:45 O r( 85:15y=45%
+;t-N~ y=57%
HO l''~ OMe
Q Retention oJ conftguration
StereoseZective intramoZecuZar functionaZization
of thiazoZidines
1\
slNHSiMe3
o
+ G(CIo... ~~
1\ -sIN -O
S. OIMe3
THF, TBAF0.5 h, r.t
...ftu:oride tOR .d8ccd .tnuaokeal8r~u.uOR
... .oIoglCtlI'- ."".stift8 co~d.s
O
çroH6HY =80%
d.e. =70%
~DMF J-Nt O R H,ç'Sr1? ~ COOH - )lNACOCI SiMe,~O O ~ ..O O
O R 1"\
)lN~NyS~O O SiMe3
R
H2NACOOH
~ OR
~o J~ACOOHO ~ODMF
1\
O R HNyS O R 1\
~ J~ACOCI SiMe3 J~~NyS~O . ~O O SiMe3
BH,N ~:OH
L-Phe
H2NLcOOH
L-AlaH'NçOH
L-Leu
Synthesis 0/ polycyclic heterocycles
THF..
O°C
o R
~~~o~J
o R r--\)lN~NyS
~SiMe3
TBAF
single diastereomer
o R r--\
~ .J... .Ny
S TBAF- - lf .~ h O O SiMe3 THF O°C
5~~o~j
Medicinal chemistry and stereoselective
Q organic synthesis Antimalaric activity
Tetrahedron: Asymmetry, 2002, 13,2727 Q J. Med. Chem., 2004, 47,000
c:::> Structural analogues oJ TadalafilJ. Med.Chem., 2003, 46, 4533
1,3-0xazoZidines
r--'\.. Chiral auxiliaries in asymmetric~ synthesis
Eur. J. Org.Chem,2004,677-685
Q Molecules with pharmaceuticalactivity
)-( + EtOyOEtHO NHBoe SnBu3
Me Ph Me~PhH BuLi 1\~ BoeN O . BoeN
Xo
Y PhCHOBU3Sn Ph OH
Colombo, L., Di Giacomo, M., Brusotti, G., Delogu, G. Tetrahedron Lett. 1994,35,2063.
Reactivity 0/ Silyl Oxazolidines
f"\H2N OH
PhCHO.//F-
1\B
G1C..N O
" OHI~
67"10
d.e >90/0
1\
BOC"NyOSiMe3
1\Bo
ox..N O
~CHO. ~ OHF- ~
58/0
d.e >95/0
'X:°"o
B:NXU OH
47/0
d.e >90/0
uu ia atllsiea
>I Development of a general and easy approach to obtain newa-heterosubstituted silylated nucleophiles
>I First example oftransfer onto electrophiles through the C-Sibond functionalization
>I Silylated heterocycles as masked heterocyclic anions
>I Stereoselective synthesis of different cyclofused heterocycliccompounds
>I Synthesis and reactivity of new a-substituted geminal stannylsilanes
BOC20MeOyBr
.. 1"\ SiMe3
I Boe-N?O°C
Boc-NH OH ..DCM
1) DIPEA2)PTSA
SiMe3
DCM
'. h...,., ."...
,
."..,.t/"
'11& .. "Ii/> ""
Antonella Capperucci
Tiziano Nocentini
Simona Biondi
Giulio Castagnoli
Irene Malesci
Arianna Cerreti