Some new insight and applications in enantioselective ... · enantioselective synthesis Ischia...

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.


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)


~

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)


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


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


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


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


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


A. Deiters, B. Wibbeling, D. Hoppe, Adv. Synth. Cata/.2001, 343, 181.14

X-Ray Structure of the N,N-Dibenzylated Pyrrolidine


(A. Deiters, B. Wibbeling)

15

Synthesis of (-)-a.-Kainic Acid

Montserrat M. Martinez, Org. Lett. 2004, in presso


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


(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

*


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)


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.


[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)


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)


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


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).


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.


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


(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)


(R. Kalkofen)

31


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)


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


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


The Hoppe Group


Some new insight and applications in enantioselective ... · enantioselective synthesis Ischia...

Documents

Transcript of Some new insight and applications in enantioselective ... · enantioselective synthesis Ischia...