Reactions of Iminium Ions with Michael Acceptors through

Asymmetric Synthesis DOI:10.1002/ange.200604715Reactions of Iminium Ions with Michael Acceptors through a Morita–Baylis–Hillman-Type Reaction:Enantiocontrol and Applications in Synthesis**

Eddie L.Myers,Johannes G.de Vries,and Varinder K.Aggarwal*

a -Functionalization of alkenes activated by electron-with-drawing groups (EWGs)encompass an important C àC bond-forming strategy in organic synthesis,and can be realized in one of three ways:a)metal-catalyzed functionalization of a -halogeno [1]or a -metallo substrates;[2]b)a vinylogous enoli-zation,a -alkylation,and isomerization sequence;[3]or c)nucleophilic catalysis:the Rauhut–Currier and Morita–Baylis–Hillman (MBH)reactions.[4]The MBH transforma-tion (Scheme 1),[5]which is traditionally effected by catalytic amounts of a tertiary amine or phosphine and uses an aldehyde as the terminal electrophile,has become more recently a powerful synthetic tool with the increased scope in Michael acceptors (for example,vinyl sulfones [6a]and acryl-amides [6])and electrophiles (for example,halides,[7a,b]epox-ides,[7c]allyl carbonates,[7d]acetals,[7e–h]and aryl cation equiv-alents [7i]).A class of electrophile that has received little attention is N-acyl iminium ions [8]which would lead to biologically important and highly functionalized

b ’-amido-a ,b -unsaturated carbonyl compounds.[9]Herein,we describe our success in employing this class of substrates and also in rendering the reaction asymmetric.

Initial investigations focused on the pyrrolidine 1(PG =Cbz,m =1;Scheme 1)and reaction conditions in which a combination of a Lewis acid (to form the iminium ion electrophile)and a weak Lewis base (to form the enolate nucleophile)were used.[10]The standard Lewis bases for the

MBH reaction (phosphines and amines)were ineffective with

BF 3·OEt 2:use of PPh 3resulted in a stable phosphine–iminium

ion adduct [11]presumably because of the poor leaving group

ability of the phosphine,[12]and pyridine caused dimerization

of the pyrrolidine presumably through base-promoted enam-

ine formation and subsequent attack on a second iminium

ion.[13]In contrast,sulfides proved effective:treatment of a

solution of pyrrolidine 1and methyl vinyl ketone (MVK)with

BF 3·OEt 2and SMe 2,[10a]followed by treatment of the resultant

crude mixture with DBU,resulted in the isolation of the

MBH-type adduct 2a in 30%yield.Other Lewis acid/Lewis base combinations were then investigated,namely TiCl 4,[10c,14]TiCl 4/SMe 2,[10b,15]Et 2Al-I,[16]and TMSOTf/SMe 2.[7f,g]The

latter combination was found to be optimum and provided

adducts 2a –m ;in good to excellent yield (Table 1).With these

conditions,the scope of the alkene was exceptionally broad and encompassed enones,both acyclic (entry 1)and cyclic (entries 2and 3),enals including acrolein (entries 4and 5),and S -ethyl propenethiolate [17](entry 6).Methyl acrylate (entry 7)was only moderately successful since the dimeriza-tion of pyrrolidine 1was again observed as a competing process.

The scope of the N,O-acetal was also explored (Table 1).

The piperidine analogue of 1gave adducts in good to

excellent yield (entries 8and 9).With this substrate,the temperature had to be maintained below à608C since dimerization of the N,O-acetal was extremely facile at higher temperatures.[13]The Boc (entries 10and 11)and tosyl analogues (entries 12and 13)of 1also gave good to excellent yields of adducts.

We then chose to apply this methodology to the synthesis of the necine base (+)-heliotridine (Scheme 2).[18]Pyrrolidine 3was prepared from (S )-malic acid using the procedure of

Speckamp and co-workers.[19]Although the employment of

the above methodologies failed to provide MBH-type adduct 4,it was found that treatment of a solution of 3and methyl acrylate in CH 3CN with the combination of TMSOTf,BF 3·OEt 2[20]and SMe 2gave the required adduct 4in 85%yield,albeit as a mixture of diastereomers in favor of the

trans Scheme 1.The Morita–Baylis–Hillman reaction and our proposed study.Cbz =benzyloxycarbonyl,DBU =1,8-diazabicyclo[5.4.0]undec-7-ene,TMS =trimethylsilyl,PG =protecting group.[*]Dr.E.L.Myers,Prof.Dr.V.K.Aggarwal School of Chemistry University of Bristol Cantock’s Close,Bristol BS81TS (UK)Fax:(+44)117-929-8611E-mail:v.aggarwal@ae330da8dd88d0d232d46a11 Prof.J.G.de Vries

DSM Pharmaceutical Products Advanced Synthesis,Catalysis &Development P.O.Box 18,6160MD Geleen (The Netherlands)[**]We thank Dr.J.P.H.Charmant and S.Saithong for X-ray analysis.We thank DSM and the EPSRC for financial support and Merck for unrestricted research support.V.K.A.thanks the Royal Society for a Wolfson Research Merit

Award.Supporting information for this article is available on the WWW under ae330da8dd88d0d232d46a11 or from the author.Angewandte Chemie

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isomer.However,all attempts to bring about ring-closing metathesis (RCM)of diene 4failed,with isomerization of the allyl moiety to the enamide the only transformation observed.[21]An alternative route to the necine base was then devised in which metathesis precedes the MBH-type reaction.Cross-metathesis of 3with acrolein was achieved using the Grubbs–Hoveyda catalyst,and subsequent MBH-type ring closure was effected using the conditions developed for the acyclic transformation.[8]Ultimately,bicyclic aldehyde 6was isolated as an inseparable mixture of epimers.Multisite reduction to the requisite oxidation state was achieved by

heating a solution of 6in THF with LiAlH 4to reflux to give

(+)-heliotridine in 38%yield.The unnatural isomer (à)-retronecine (7)was also isolated in 12%yield.Whilst the structure of the natural product is relatively simple,its synthesis has prompted us to develop alternative reaction conditions for more demanding substrates,and the problems encountered with the RCM step clearly demonstrate the superiority of the MBH ring closure in this context.

To render the reaction asymmetric,enantiomerically pure chiral sulfide was used in place of SMe 2(Table 2).Using the camphor sulfonic acid derivative,sulfide 8,which was

designed and synthesized within our research group for use in chemistry based on sulfonium ylides,[22]gave adducts in good yield and with high ee values (Table 2,entries 3and 4).Sulfide 8,was easily recoverable (>90%yield)by column chromatography of the crude mixtures.

It was found that piperidine-based rather than pyrroli-dine-based N,O-acetals (Table 2,entries 5and 6versus 1and 2),and Boc rather than Cbz carbamate (Table 2,entries 3and 4versus 1and 2)provided MBH-type adducts with improved ee values.When the acyclic enone MVK was employed,the corresponding adduct 2a was obtained with a low ee value (8%).The absolute stereochemistry of 2k was determined to be S by synthesis,crystallization,and X-ray analysis of the camphor sulfonamide derivative;the remaining adducts were assigned by analogy.

The origin of the high asymmetric induction is intriguing.Low-temperature NMR studies of a solution of cyclohex-enone,sulfide 8,and TMSOTf in CD 2Cl 2at à908C revealed a mixture of diastereomeric b -sulfonium silyl enol ethers 9a and 9b in an unassigned ratio of 2:1as the predominant species (Scheme 3).[23]On warming the mixture to à108C in increments of 208C,the equilibrium shifted in favor of starting material 8;[24]at à308C only starting material was detected.On recooling to à908C,the 2:1mixture of b -sulfonium silyl enol ethers was formed again.This reveals that the silyl enol ethers 9a and 9b are formed reversibly and,at the reaction temperature,are in dynamic equilibrium with the

Table 1:Synthesis of MBH-type adducts 2a –m

.

Entry PG m n R X Product Yield [%]1Cbz 10H CH 32a 952Cbz 11H CH 22b 963Cbz 12H CH 22c 964Cbz 10H H 2d [c]855Cbz 10CH 3H 2e [c,d]946Cbz 10H SEt 2f 907Cbz 10H OMe 2g [e]518Cbz 21H CH 22h [f]909Cbz 22H CH 22i [f]7510Boc11H CH 22j 6911Boc12H CH 22k 6012Ts 10H CH 32l [g]9013

Ts 1

H

SEt

2m [g]

90

[a]Alkene (2.0equiv),TMSOTf (2.5equiv),SMe 2(1.5equiv),CH 2Cl 2,

à788C to à208C,3h;sat.aq NaHCO 3quench.[b]DBU (1.5equiv),CH 2Cl 2,RT,10min.[c]Treatment with DBU was not required.[d]E /Z 5:1[e]Reaction was carried out at à208C for 16h;pyrrolidine dimerization was a competing pathway.[f]Temperature was kept below à608C.[g]Reaction mixture was warmed slowly from à788C to RT.Boc =tert -butoxycarbonyl,Tf =trifluoromethanesulfonyl,Ts =tosyl =toluene-4-sul-

fonyl.

Scheme 2.Synthesis of (+)-heliotridine.a)3(1equiv),methyl acrylate (3.0equiv),TMSOTf (3.0equiv),BF 3·OEt 2(3.0equiv),SMe 2

(3.0equiv),CH 3CN,RT,24h;b)acrolein (3.0equiv),Grubbs–Hoveyda cat.(2 5mol %),CH 2Cl 2,RT,12h;c)TMSOTf (3.0equiv),BF 3·OEt 2(3.0equiv),SMe 2(3.0equiv),CH 3CN,RT,3h;d)LiAlH 4(7.0equiv),THF,reflux,1h.

Table 2:Asymmetricsynthesis of MBH adduc ts.

[a]

Entry PG m n Product (R /S )Yield [%]ee [%]1Cbz 112b (S )69822Cbz 122c (S )86803Boc112j (S )75884Boc122k (S )90885Cbz 212h (S )88946

Cbz 2

2

2i (S )

49

98

[a]Alkene (2.0equiv),sulfide 8(1.5equiv),TMSOTf (2.5equiv),CH 2Cl 2,

<à608C,5h.

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Angew.Chem.2007,119,1925–1928

starting material.Thus,enantioselectivity is not determined at the stage of formation of the b -sulfonium silyl enol ethers.The origin of the enantioselectivity must therefore result from a dynamic kinetic transformation of b -sulfonium silyl enol ether 9a ,b ,in which either the major or minor isomer reacts faster,thereby allowing the remaining diastereomer to revert to starting material for repartitioning.Focusing on one of two scenarios in which 9a reacts faster,it could be envisioned to approach the iminium ion in several ways (Scheme 3).The synclinal approaches can be tentatively discounted since altering the size of the silyl moiety from trimethylsilyl to triisopropylsilyl had little impact on the ee value.Of the two remaining antiperiplanar approaches,attack on the Si face of the iminium ion would be disfavored because of nonbonding interactions between the two rings.This suggests that 9a should favor attack on the Re face of the iminium ion,thereby leading to the S enantiomer of the product as observed.This analysis still leaves open the question of why one diastereo-mer (9a /9b )is more reactive than the other,and this aspect is under further study.To conclude,we have developed a novel methodology which allows a very broad range of readily available Michael acceptors,including acrolein and acrylates,to couple with readily available iminium ions (masked as N,O-acetals)in both an inter-and intramolecular MBH-type reaction to give densely functionalized heterocycles.The process has been rendered asymmetric and high enantioselectivity has been achieved with cyclic enones.Finally,the usefulness of the methodology has been exemplified in a short synthesis of (+)-heliotridine.Received:November 20,2006Published online:February 5,2007.Keywords:C àC coupling ·Lewis acids ·Lewis bases ·Mannich reaction ·Morita–Baylis–Hillman reaction

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,2233.

Scheme 3.Model proposed to explain the origin of the enantio-selectivity.Angewandte Chemie

1927Angew.Chem.2007,119,1925–1928 2007Wiley-VCH Verlag GmbH &Co.KGaA,Weinheim angewandte.de

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of the b-iodo enolate of methyl acrylate(see Ref.[10d]),did not lead to the required adduct2g;the delivery of the ethyl rather than the enolate ligand to the iminium ion was the only process observed.

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[23]See the Supporting Information for1H NMR spectra of the low-

temperature experiments.

[24]The high sensitivity of K eq to temperature suggests an entropy

(T D S)and enthalpy(D H)term which are of a similar order of magnitude.

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