some new insight and applications in enantioselective ... · enantioselective synthesis ischia...
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Dieter Hoppe, Organisch-Chemisches Institut, WWU Munster
(- )-Sparteine-mediated deprotonations
Some new insight and applications inenantioselective synthesis
Ischia Advanced School of Organic Chemistry (IASOC) 2004
September 18 - 23, Ischia Porto (Napoli, Italy)
D. Hoppe, Universitat Munster
Outline
~ Asymmetric Deprotonation of Alkyl Carbamates
~ Synthesis of (- )-Slaframine
~ Asymmetric Deprotonation of Allyl Carbamates
~ Enantioselective Homoaldol Reaction
~ Enantioselective Cycloalkylation
~ Synthesis of (- )-Kainic Acid
~ Homoenolate Reagents by Asymmetric y-Deprotonation
~ Cyclopropane Synthesis via Carbamoyl Migration
D. Hoppe, Universitat Munster 2
Recent Reviews
D. Hoppe, T. Hense, Angew. Chem. 1997, 109,2376; /nt. Ed. Eng/. 1997,36,2282.
A. Basu, S. Thayumanavan, Angew. Chem. /nt. Ed. 2002, 41, 717.
D. Hoppe, F. Marr, M. BrOggemann, in Organolithiums in Enantiose/ectiveSynthesis (Ed. D. M. Hodgson), Topics in Organometallic Chemistry, Voi 5,2003,61-138.P. Beak, T. A. Johnson, D. D. Kim, S. H. Lim, ibid, 139.Further contributions in this volume by: D. M. Hodgson, B. Goldfuss, T.Toru, J. Clayden, J. F. Normant.
D. Hoppe, G. Christoph, "Asymmetric deprotonation with a/ky/lithium-(-)-sparteine", in The Chemistry of Organolithium Compounds (Eds. Z.Rappoport, I. Marek), in Patai Series The Chemistry of Functiona/ Groups,p. 1055-1164, Wiley, 2004.
D. Hoppe, Universitat MOnster 3
Kinetic Control by Selection between Enantiotopic Protons
HR EI..~ EI+
@' S ""'OCby ~
o =
;X::)(N~.."..LoJ~ ,.
Cby
+ s-BuLi/(-)-sparteine
~S/kR - 50:~
D. Hoppe, F. Hintze, P. Tebben, Angew. Chem. 1990, 102, 1457; Int. Ed. 1990, 29, 1422.Mechanism of deprotonation: E.-U. WOrthwein, K. Behrens, D. Hoppe, Chem. Eur. J. 1999, 5, 3459.
D. Hoppe, Universitat MOnster 4
Total Synthesis ot (-)-Slatramine tram (S)-Glutamic Acid
1. Retrosynthetic Scheme
:dJ~ OAc
7 : 1
N 2
H2N 6 5 3
==>~
FGI's(- )-Slaframine
OCb'
==>
x
Key Intermediate 1
~....-Removepro-S-H-1andpro-S-H-5
H
Hm~ ~:~'
l NCbO
Hm~ ~:~'
;:' .. N :CbO '.:
(L. Padeken)
D. Hoppe, Universitat Munster 5
~
Key Intermediate 2
==>
OCb'
~ : H: '6
H .6 NH2. ~H2l. / ACbO CH2 =ti;) IH2C-X X
~x
[:';0
H2C=0
~o o
HO~OHNH2
(S)-Glutamic Acid
Total Synthesis ot (-)-Slatramine trom (S)-Glutamic Acid
2. Highly Diastereoselective Disubstitution of a N,N-Dibenzyl-(S)-glutamindiol Dicarbamate
o
~o 6 standard steps
HO ..OH .. ..
NH2 60%
R' N
2 FO
y" "O
~i--O V ,BF3'OEt~- 0Jl-NR2 66%
NBn2
O
O~OMe
::0o~NBn2
DIBAL-H, THF.
d.r.> 98:2
I O~s HR H t;:;"\ O X. s-BuLi,Et20, -78"C,
A ~ $ R ~)l ~ (-)-sparteine..N O O N OI \ / Internai
/'... NBn2 ~ stereocontrol..
(L. Padeken)
D. Hoppe, Universitat Munster 6
Cb Cby
~s ;:HR ~CbO - OCby
NBn2
1. s-BuLi, 6-)-sparteine"2. CI-C-°'ii
56%
d.r. > 97:3Externalstereocontrol
98%
HO, HO~
CbO~OCbYNBn2
Key Intermediate1
Total Synthesis of (-)-Slaframine from (S)-Glutamic Acid
3. Bicyclizationand Final Steps
HO
~HO -
CbO ~ OCby
NBn2
1. H2/Pd-C2. (BochN.
OH1. 5N HCIIMeOH
cb:
2. NaOH, !::J. =.87% ", N
CbO"
H OTr1.Swern
£0=
2. H2NOH -...N~ N~OH
D. Hoppe, Universitat MOnster
1. MsCIIEt3N,CH2CI2 OCbHO 2. TFA,CH2CI2
cb- Y~o § 3. K2C03,MeOH,!::J. §: .
CbO OCby 59% "", Nt NH CbO (X-Ray)BUO~
~ Total yield (from glutamic acid): 14%
92%
TrCI cO~ OTr
., -
CbO"'" N
DIBAL-H
93%. ~Tr
HO"",~~J
1. Pt02/H2in EtOH/HCI
2. AC20/Pyridine~90%
~AC
ArJiNA.,~.JShelf stable form of
(-)-Slaframine
(L. Padeken)
7
Enantioselective Homoaldol Reaction of (E}-Crotyl Carbamate
l:~;l~n-BuLi/(-)-sparteine.pentane,cyclohexane,
-78°Cv
Cb
):)CbOM
..
I M = Ti(OiprhH20 ~ M=H
(62-95%, 90-94% ee)
~O of-
~ T/: l,O.- d
ROCb YRCHO..
R = alkyl, aryl
~
!
Ti(dPr)4Inversion
~Ti(Oiprh(IIIHOCb
D. Hoppe, Universitat MOnster
O. Zschage, Angew. Chem. 1989, 101,67; H. Paulsen, C. Graeve, Synthesis 1996,141.
8
(S)-1-Lithiocrotyl Carbamate - Conversion into an Air- and Water-Stable, Chiral Boron Homoenolate Reagent
1.Ti(Oipr)42. BU3SnCI- ~
BU3Sri OCb
80%,88%ee
TsI
CN)-CIN\Ts .
CHzClz
TS,
~r) \OCb Ts
Direct Conversion:Racemization: ... ...
~. ........... ~lj<OCb
8 (R)-10%, 85% ee
!RCHOtoluene, 60°C
OH 48-72 h
R~CH3 OCb
1. HCI/HzO2. pinacol
product can be purified by LCon SiOz without precautions
yield: 60-90%, 85% ee,ZIE> 94:6
Synthesis 2004, in presso
D. Hoppe,UniversitatMunster
(E. Beckmann)
9
X-Ray Structure of [(CH3hSi(CHhOC(O)NiPr2Li(Sparteine)]
M. Marsch, K. Harms, O. Zschage, D. Hoppe, G. Boche*, Angew. Chem. 1991, 103,338-339.
D. Hoppe,UniversitatMunster 10
Configurational Stability of Lithiated 3,3-Disubstituted AllylCarbamates
s-BuLi, r\
~ R ,Hs (-)-sparteine ~Li . ~ iMe3
$ : Me3SICI.. - ..O~ ~~~ s O~ R O~
Geranyl-Cb (E) * -70. lo -40.0
in situ 41%,82% ee15 min, -78°C 47%,73% ee240 min, -78°C 85%, 16% ee
s-BuLi, .
~~(-)-sparteine
~ Me3SICI.. ..
toluene
nllHs CbO s""(Q) CbO R SiMe3CbO HR
Neryl-Cb (Z) @ = Li .H-sparteine in situ 43%, 76% ee15 min, -78°C 75%,69% ee240 min, -78°C 87%,12% ee
. No torsion of allylic double bond
. Medium configurational stability of the stereogenic center
(W. Zeng)11
Conclusions
D. Hoppe, Universitat MOnster
Enantioselective Homoaldol Reaction of (1-Cycloalkenyl)methylCarbamates
.~2,P<v I. J)
~,c2iJ5
~16
>-l'~~
./C16 '1-- ,.,
'~,. ., N CJ,f;..{d2
~' Ì) .. O1S d--\, p.- .,',
.
,
~C
.
1
.
2 ".r.
.,
C
.
14 -'~.I,
C23'
~ C13'~ V',
ClI' ~,. C,
8 '( C81 {),-' ""~.J~1O C9.
.
'.
~'..:)
~ ','r:-o-iL 01''Cf«{ ,
'-
~O' ,- C6,.~.g" C2
~'~ ~(R. Frohlich) c.. Br
Eur. J. Org. Chem. 2002,414-427.
..
H
ctoCb
..0 H~ ..,
R = 4-BrCsH4
35%, 87% eed.r. > 97:3
Many further examples
D. Hoppe, Universitat MOnster
o}-){l'O ~
Br
(J. Kristensen, M. Ozlugedik)
12
HR @ 1.n-BuLi,
eX:;:'[ T;(aiP'h]({aco
(-)-sparteineRCHO2. CITi(Oip3 ..-78°C
toluene, -78°C R OCb
y-Lactonisation of Optical Active Homoaldol Adducts
«.::b~H R-80% ee
MeOH/MeS03Hcat. Hg(OAc)z
~ ctj:e
= ~R
~Ol
C6 Cl
~~,. ~mdu~ci' b~1}o ~cn
C30l6 c~3 b~
33C3~
U C34
Br
Manyfurther examples: Synthesis 2004, in presso
D. Hoppe, Universitat MOnster
m-CPBA,BF3.OEt2
<=po= ~R
~
50-60%
o
Djo
~~Br
(M. OzlOgedik)
13
Synthesis of a 3,4-Divinylpyrrolidine via AsymmetricDeprotonation and Cycloalkylation
n-BuLiCbyO~ ~ /' ./.'o... "",CI (-)-sparteine" ~ ~N' ~ " ~
I toluenel -90°C
Ph
rN~CbY
Ptì ~'-
- LiCI
85%
PhCH2Br,CHCI3, 50°C-
54%
Li/~N~CI
O~O ~I PhNR2
. ~'-'::
rN OCby
Ptì R Id.r. = 100: O, 90% ee
Br e Ph\: ~J OCbyPh
I
D. Hoppe, Universitat MOnster
A. Deiters, B. Wibbeling, D. Hoppe, Adv. Synth. Cata/.2001, 343, 181.14
X-Ray Structure of the N,N-Dibenzylated Pyrrolidine
D. Hoppe, Universitat MOnster
(A. Deiters, B. Wibbeling)
15
Synthesis of (-)-a.-Kainic Acid
Montserrat M. Martinez, Org. Lett. 2004, in presso
D. Hoppe, Universitat MOnster 16
Retrosynthesis of (-)-a.-Kainic Acid
Cyclization Step
P.)I
HN . "-
HOOC """ COOH
~=' -(
~,. /1,-<"-{N OIBn OTBS
~
OCb
.-@CI
OTBS(-)-a-kainic acid
CI 62
~H-1 _OCb
> ~,(I111(
n-BuLiIH-sparteine N'I
Bn OTBS
Key intermediate
D. Hoppe, Universitat Munster
(M. Martinez)
18
Synthesis of Key Intermediate
1) a) NEt3,CsHsCHO, rt OHb) NaBH4 O°C,83% ~
2) NEt3,TBSCI,DMAP,89% W
~OOMe 3) LiBH4,il, 47% .. TBSO~NHHO~NH ,HCI
)2 Ph
a) Swern OX.,-78°Cb) Ph3P=CH(C02Et),
-20°C.-
75% (overall yield)
1) DIBAL-H,-78°C, 70%
2) NaH, CbCI, il, 53%..
NaHC03, CH3CN,il, 3h, 82%
Br~
9 ~OTES..
{OTES OH
/ '\ ~OTBSN
"Ph5 10
~OTES C02Et
~ ~.~OTBSN
"Ph 11
~ L:~BSN
"Ph 12,95%ee
1) TBAF, O°C,81%2) a) NEt3,MsCI, -40°C
b) LiCI, THF, rt, 71%..
-CCI LOCb
/"'~ OTBSN
"Ph
4.6% overall yield (9 steps)
13 (M. Martinez)
19D. Hoppe, Universitat Munster
Key Step: (-)-Sparteine-mediated Cycloalkylation
f
TBSO,§ 'H"
CI~N~ " 13 OCb2.2 eq n-BuLi/sp, Ph
-78°C, 1 h, toluene L.uu.u.u uu ~
,* R2N
TBSO .o A l~ "\LL. sp O~O
{ S HO ~:
O TBSO ""Li: .sPh./"'-..N~ ..., -f ...m.mm..~ .t H P
NR2 ( N"""'~CI
B a c ~ '1 ~11. - LiCI anti-SN'SE' Ph 11. - liGI
t 2. + H20 t 2. + H20
TBSO-~ - --( .$"-===\..~ TBSO-~ "
tç' "OGb OGb "",-~
OGb ~ O OCb
rN = "~ \ + N = rN "'I,Ph ) OTBS ) OTBS Ph (
Ph Ph
148 80%,d.L= 80:20 14b (M. Martinez)
20
*
D. Hoppe, Universitat Munster
Completion of the Synthesis to (-)-a.-Kainic Acid
-{ ...~~
~aGO~n OTBS
14a
MeOCOCI, Il,CICH2CH2CI.84% (2 steps)
[a]D20= -41.2 (c 0.52, CH2CI2)
t-BuLifTMEDA,MeSSMe
SMe
-1{ ..~=<
>0 aGO"~~TBSBn
15a
.
SMe-1{ .~=<
'0 aGO'~~TBSMeOOC
18a
MeS03H,MeOH,Il
55% (2 steps)
Lit.1[a]D20=-43.0 (c 1.25, CH2CI2)
D. Hoppe, Universitat Munster
IMeOOC OH
Completion of the Synthesis to (-)-a.-Kainic Acid
~
J ~-COOMe'\o ~" .
~HMeOOC19a
NOE studies at low P show:
C2/C3 ~ trans configuration
C3/C4 ~ cis configuration
(M. Martinez)
21
--J ~-COOMe~ ,'"~, .
~HMeOOC19a
1) Jones' ox.2) 40% NaOH3) Dowex 50WX-2004) Amberlite CG-50.38% overall yield
---1 ,,-COOH~ ~.'
~COOHNH
2 W. Oppolzer, K. Thirring, J. Am. Soc., 1982, 104,4978.
SMe
W o
MeS03H,MeOH,!l O.
48%(over2 steps) NIMeOOCOTBS
14b 20b
3 D. A. Campbell, M. T. Raynham, J. K. Taylor, Perkin 1,2000, 19,3194.
D. Hoppe, Universitat Munster
[a]D20 =-14.3 (c 0.40, H2O)
Lit.2 [a]D20 =-15.0 (c 0.50, H2O)
NOE studies at low Tashows:
C2IC3 ~ cis configuration
C3/C4 ~ cis configuration
[a]D20 =-28.1 (c 0.30, CHCI3)
Lit.3 [a]D20 =+32.1 (c 1.20, CHCI3)ent-20b
(M. Martinez)
22
y-Deprotonation of 1-Phenyl-1-alkenyl Carbamates
First Results
Conclusions:
I i+ Enantiotopos differentiatingy-deprotonation with n-BuLiI(- )-sparteine
ot Enantioenriched ion pairis configurationally stable
ot Configurations stili unknownat this stage
(M. Seppi)
D. Hoppe, Universitat Munster 23
Stereochemistry of Aldehyde Addition (1)
a o.::::::/Nipr2IfN..! lN"':Li o
~Inversion
.-CITi(NEt2b
o
~HBr~
.-Syn-SE'
path B
path Aanti-SE'
o
~HBr~
SCHA""
ifJBr
HO ICbO ~ PDC ..
Ph ~LP
Br
CbOO ~ IPh ~
(+)-(8)-6ent-4c (diastereomers)
(R. Kalkofen) 24D. Hoppe, Universitat Munster
*OCb
Ph--L ~:TiRf.';;;;;;:tR-:
R = NEt2. R1 =p-BrCsH4
PDC
Br
..
Ph' ~ent-4c
CbO Hs HR
oan-BuLi/(-)-sparteine CbO-78.C,toluene
. I *o
CIAoMe,&
( 78%, 78% ee
j"-B,l",-)p'""OO
-78.C,toluene
l cloM'ì:f:N
.J(" ! ..N (fN... .P:_Nipr2N''''Li
..
I 1,&,&
Configuration of the Allyllithium Intermediate
OCb
Ph --L -;;;.-/TiR7.~R~
R = NEt2, R1 = Alkyl, Aryl
:I:
c:::::>T. OCb
(Et2Nh ~ IPh ~ >
(S)-5 (S)-2a
Transmetallation Li~ Ti in ali known cases: Inversion
liII~ Lithiumintermediate 2a has (S)-configuration
c+ (- )-Sparteineln-butyllithium removesthe y-pro-Rproton
CbO
JVT \ ..~RPh~
[1] Titanation, reviews: M. T. Reetz, Organotitanium Reagents in Organic Synthesis, Springer, Berlin, 1986;.Organotitanium Chemistry": M. T. Reetz in Organometallics in Synthesis (Ed. M. Schlosser), Wiley, Chichester,
2002,817. (R. Kalkofen)
D. Hoppe, Universitat MOnster 25
Highly Stereoselective Homoaldol Reactions-4-.-
T' OCb
(Et2Nb :xAPh ~(S)-5 [ ]
*R1CH=O OCb
~Ph ~:
TI#:
R = NEt2, R1 = Alkyl, Aryl
HCICl J:3 _R1
Ph' ~ I + syn-ent-4OH
..
anti-ent-4
2o
c{H
3 ~H
4d'H
71 98:2 95 -133
~CbO 9H,"" '"
I OHb 75
77
D. Hoppe, Universitat Munster
Angew. Chem. Int. Ed. 2004, 43, 1423-1427. (R. Kalkofen)
26
Entry Aldehyde Product Yield[%] d.r. e.e. [%] [a 1"- ..
o
d'HfiY""V" 66 95:5 97 -135
Br -</
99:1 96 -73
99:1 95 -85
Enolization via abstraction of the most acidic proton.
Activation of the allylic protons.
Enantiotopos differentiation by n-BuLi/(-)-sparteine for R = Ar, or Me3Si.Enhancement of the configurational stability in five-membered chelate.
Stereospecific SE'-substitutions (with few exceptions syn).Inversion via Lirri exchange possible.
Liberation of the ketone from the enol ester (e.g. TMSOTf/Nu).
D. Hoppe, Universitat Munster 27
Cyclization of Racemic Homoaldol Products - CyclopropaneCarboxaldehydes
OH
R~ OCb
Tf2O,2,6-lutidine
~~OR
R = CH2CH2Ph 84% R = CH2CH2Ph 97%,89:11 trans/cis
R = C6H11 89% R = C6H11 97%, 98:2 trans/cis
R. E. Taylor, C. A. Risatti, C. Engelhardt, M. Schmidt Drg. Lett. 2003, 5, 1377.
D. Hoppe, Universitat Munster 28
Chiral Homoenolate Reagents via the Enol Carbamate Trick
o H H BuLi/chiralo e o EI
ArAXR
ligand
ArR
EIX
ArR.. ..
CD
t0@NePrh ePrhN
oAoo
OCb EI
D(sEIX
.. .. AAAr R 0@ Ar R @@ Ar R
Synthesis of Stereohomogeneous Cyclopropanes (1)
(S. Brandau)
2.6-lutidine
R1~.(§~ICF3S0 /0
2 ?J. RCb
e t&-CF3S02, -CbCH2CI2. Tf20
path A ~R1~a I
HO o R
oANipr2 R,~Ro
D. Hoppe. Universitat MOnster 29
Synthesis of Stereohomogeneous Cyclopropanes (2)
(S. Brandau)
2.6-lutidine
R1~.(a~CF3S0{"O O' ~
I ...1' RCb
e t&-CF3S02, -CbCH2CI2. Tf20
path A ~R1~" I
HO O R
oANipr2
I, R
R1.A- ""1(O
p,~~THF
R~,.~
Te~ }-)~ R ~
oyJNipr2
R4R -/(R. Kalkofen)
Angew. Chem. Int. Ed. 2004, in presso
D. Hoppe. Universitat MOnster 30
Stereochemistry Course of the Cyclopropane Formation
(Based on Proposal of R. E. Taylor)
D. Hoppe, Universitat MOnster
(R. Kalkofen)
31
Synthesis of Stereohomogeneous Cyclopropanes (3)
Hf7H3CH
CbO"". - e -
e (koCbR '. H o - o R- .-- " H
H - HPh Pii
1,!"(h (RPh)R 1
o
RRj\ R':AH I NaH,8 I Cb -Cb06)..
.. R1 ""'1(Pho Ph THF
o} Ph eJ Ph
oANipr2 oNipr2o
Entry Starting Material Product Yield[%] e.e. [%] d.r.
"ilPh 98 91 98:21..-:: o
2"[Ph
78 95 >98:2
"'rrPt1
3 '" '" 74 96 97:3I // OH o
CbO CH,
Pt1J'''Y1H4 HPh 58 87 >98:2
OH o
(R. Kalkofen, S. Brandau)
D. Hoppe, Universitat MOnster 32
Multiple Utilization of the Same Activating/Protecting Group
1. Activation by the carbamate group in the deprotonation step for thehomoaldol reaction
2. Oirecting of regio- and stereochemistry in the addition step
3. One-step liberation of the enolate and activation of the hydroxy groupby migration in the cyclopropane-forming step
D. Hoppe, Universitat Munster 33
Acknowledgements
To ali former and present group members
Presented results bv: X-RavOr. Roland Frohlich and his
coworkersHomoeno/atesMustafa OzlClgedikJesper KristensenMichael SeppiRainer KalkofenSven BrandauWenbin ZengEdith Beckmann
Fundina
Oeutsche Forschungsgemeinschaft,SFB 424
Fonds der Chemischen IndustrieHumboldt Foundation
NRW Graduate School of Chemistry
German-Outch Graduate KollegMinisterio de Educacion, Cultura y
Oeporte of Spain
Cycloa/ky/ationAlexander OeitersLars PadekenOr. Montserrat M. Martinez
D. Hoppe, Universitat Munster 34