Organocatalysis Episode 9 pot

2002 7 First Highly Enantioselective Brønsted Acid Catalyzed Strecker Reaction: Use of C-Nucleophiles in Chiral Ion Pair Catalysis The hydrocyanation of imines, the Strecker reaction, is

Scheme 3 Enantioselective synthesis of diepi-pumiliotoxin-C; (a) EtOH,

50 °C, 12 h, then 140 °C, 2 h; (Bohlmann and Rahtz 1957; Bagley et al 2002)

(b) 5 Mol % (S)-3f, 2 (4 equiv.) at 50 °C in benzene; (c) (Sklenicka et al 2002)

7 First Highly Enantioselective Brønsted Acid Catalyzed Strecker Reaction: Use of C-Nucleophiles in Chiral Ion Pair Catalysis

The hydrocyanation of imines, the Strecker reaction, is considered themost practical and direct route toα-amino acids (Strecker 1850) Con-sequently, various attempts to develop asymmetric Strecker reactionshave been made (for reviews, see: Gröger 2003; Yet 2001; Spino 2004)

In addition to metal-catalyzed hydrocyanations using chiral metal lysts (Al catalysts: Sigman and Jacobsen 1998a; Takamura et al 2000;Krueger et al 1999; Byrne et al 2000; Josephsohn et al 2001; Ishitani

cata-et al 1998; Kobayashi and Ishitani 2000; Chavarot cata-et al 2001; sumoto et al 2003), promising metal-free, enantioselective variants ofthis reaction have recently been disclosed These processes are based onchiral guanidines (Corey and Grogan 1999), ureas and thioureas (Sig-man and Jacobsen 1998b; Sigman et al 2000; Vachal and Jacobsen2000; Vachal and Jacobsen 2002; Wenzel et al 2003; Tsogoeva et al

Ma-2005), bis-N-oxides [for the application of stoichiometric amounts of

bis(N-oxides), see: Liu et al 2001; Jiao et al 2003] and ammonium

Fig 8 Proposed catalytic cycle for the asymmetric hydrocyanation

salts (Huang and Corey 2004) The importance of the Strecker tion and the resulting products prompted us to examine a new chiralBrønsted acid catalyst for this important transformation (Rueping et al.2006e) Based on the above described Brønsted acid catalyzed trans-

reac-fer hydrogenations using BINOL-phosphate catalysts 5, we reasoned that activation of imine 20 by catalytic protonation would generate the iminium ion A, a chiral ion pair which would subsequently undergo ad- dition of HCN to give the desired amino nitrile 21 and the regenerated Brønsted acid 5 (Fig 8).

Hence, initial explorations concentrated on varying the chiralBINOL-phosphate as well as reaction parameters including differentprotected imines, cyanide sources, catalyst loadings, temperatures, andconcentrations From these experiments the best results, with respect

to yield and selectivity, were obtained with benzyl-protected aldimines

and HCN at –40 °C using 10 mol% of catalyst 5b.

With the optimized conditions in hand we explored the scope of theBrønsted acid catalyzed hydrocyanation of various imines (Table 8)

In general, high enantioselectivities and good isolated yields of several

aromatic and heteroaromatic, N-benzyl- and N-paramethoxy-benzyl

protected amino nitriles, bearing either electron-withdrawing or tron-donating groups are obtained These products are important pre-cursors for the synthesis of amino acids and diamines Hence, in order

elec-Table 8 Scope of the asymmetric BINOL-phosphate catalyzed Strecker

aIsolated yields of the corresponding acetamide after chromatography

bEnantioselectivities were determined by HPLC analysis

to demonstrate the preparation of these compounds we used established

procedures to afford the p-methoxyphenyl glycine (Sigman et al 2000)

and the corresponding diamine (Scheme 4; Hassan et al 1998).The organocatalytic hydrocyanation of imines provides direct access

to a diverse range of aromatic amino nitriles and the correspondingamino acids and diamines in highest enantioselectivities The use of

Scheme 4 Transformation of amino nitriles in amino acids and diamines: a)

65% H2SO4, b) HCl conc., c) H2/Pd-C, d) LiAlH4

BINOL-phosphates as efficient Brønsted acid catalysts in the elective Strecker reaction shows that C-nucleophiles can be applied inthe chiral ion-pair catalysis procedure This, in turn, not only increasesthe diversity of possible transformations of this catalyst but also showsthe great potential chiral Brønsted acids in asymmetric catalysis

enantios-8 Asymmetric Brønsted Acid Catalyzed

Imino-Azaenamine

Reaction

The possibility of using C-nucleophiles in chiral ion pair catalysisencouraged us to investigate an enantioselective Brønsted acid catalyzedimino ene reaction (Rueping et al 2007a; Scheme 5) The reactionconsists of a new BINOL-phosphate catalyzed addition of methylene-

hydrazines 22 to N-Boc-protected aldimines 23 to afford chiral

amino-hydrazones 24.

Hydrazones have proven to be important synthetic intermediates thatcan be readily derivatized to many useful chiral blocks, including ami-no-aldehydes, amino-nitriles, or diamines without any racemization(Scheme 6; Pareja et al 1999; Enders et al 1999; Enders and Schubert1984; Diez et al 1998, 1999; review: Job et al 2002)

Scheme 5 Brønsted acid catalyzed imino aza-enamine reaction

Scheme 6 Useful derivatizations of chiral amino hydrazones

Given the value of these products we decided to develop an elective Brønsted acid catalyzed synthesis of amino hydrazones Op-

enantios-timization of the reaction showed that N-Boc protected aldimines 23

in combination with the pyrrolidine-derived hydrazine 22a gave yields of amino-hydrazones 24 With regard to the chiral Brønsted acid catalysts used, the use of octahydro-BINOL-phosphate 5c resulted in

good-the best enantioselectivities The results are summarized in Table 9 In

general, a series of N-Boc-protected aldimines bearing

electron-with-drawing or electron-donating groups could be applied in the lective aza enamine reaction resulting in the corresponding hydrazones

enantiose-24a–h in good isolated yields and with the so far highest

enantioselec-tivities (77%–90% ee) The mild reaction conditions of this metal-free

process, together with the operational simplicity and practicability, der this approach not only a useful procedure for the synthesis of op-tically active aminohydrazones but additionally, it further expands the

ren-Table 9 Scope of the asymmetric BINOL-phosphate imino-azaenamine

aIsolated yields after chromatography

bEnantioselectivities were determined by HPLC analysis

cAfter one recrystallization from hexane-dichloromethane

repertoire of enantioselective BINOL-phosphate catalyzed tions using C-nucleophiles

transforma-9 Development of the First Brønsted Acid Assisted Enantioselective Brønsted Acid Catalyzed Direct Mannich Reaction

Mannich reactions represent one of the most important methods forthe preparation of natural products and biologically active nitrogen-containing compounds, includingβ-amino acids, aldehydes and ketones(for reviews: Kobayashi and Ishitani 1999; Kleinmann 1991; Arend

et al 1998; Arend 1999; Cordova 2004) Consequently, various tioselective variants of the Mannich reaction have been reported How-ever, most of the protocols focused on reactions of aldimines with pre-formed enolate equivalents (Fujieda et al 1997; Ishitani et al 1997;Kobayashi et al 1998, 2002; Ishitani et al 2000; Hagiwara et al 1998;Fujii et al 1999; Ferraris et al 1998a,b, 1999, 2002) Hence, the de-velopment of a direct catalytic enantioselective Mannich reaction ofprior unmodified carbonyl donors would be desirable, as it prevents thenecessity of enolate preformation, isolation and purification (Yamasaki

enan-et al 1999a,b; Matsunaga enan-et al 2003; Trost and Terrell 2003; Juhl enan-et al.2001; Bernardi et al 2003; Hamashima et al 2005)

Based on our previously developed Brønsted acid catalyzed reactions(for selected references: see Rueping et al 2005a,b, 2006a–e, 2007a),

we assumed that a direct reaction of an aromatic ketone 25 and aldimine

26 should lead to the desired β-amino ketone 27 (Fig 9).

Fig 9 Catalytic cycle for direct Brønsted acid catalyzed Mannich reaction

In the first step of this reaction a proton transfer from the chiral

Brøn-sted acid 5 to the aldimine 26 will result in the formation of a chiral ion-pair which is now activated to react with the nucleophile 25a The

subsequent Mannich reaction will then result in the corresponding

β-amino ketone 27 The fundamental requirement for the successful

de-velopment of such a Brønsted acid assisted, asymmetric Brønsted acidcatalyzed direct Mannich reaction (Rueping et al 2007b) must be that

the achiral Brønsted acid BH is not able to activate the aldimine 26.

Following this concept we were able to develop the first direct Mannichreaction of acetophenone and derivatives with aldimines to obtain thecorrespondingβ-amino ketones in excellent enantioselectivities giventhat there is no alternative procedure which results in these products insuch an efficient manner (Rueping et al 2007b) For instance, direct

Mannich reaction of 25 with 26a resulted in the desired amino ketone

27a with 86% ee (Scheme 7).

Scheme 7 Direct Brønsted acid catalyzed enantioselective Mannich reaction

A special feature of this reaction is the effective interplay of an ral and a chiral Brønsted acid, which simultaneously—in a coopera-tive fashion—activate the carbonyl donor and the aldimine acceptor,thereby forming the desired enantioenrichedβ-amino ketones withoutthe necessity of enolate preformation Based on the successful appli-cation of this new concept of dual Brønsted acid catalyzed activation

achi-we decided to extend this procedure to other carbonyl donors such ascyclohexenone

10 Cooperative Co-Catalysis: The Effective Interplay

of Two Brønsted Acids in the Enantioselective

Synthesis of Isoquinuclidines

Isoquinuclidines 28 (aza-bicyclo [2.2.2]octanes) consist of N-bicyclic

structures which are the structural element of numerous natural curring alkaloids with interesting biological properties (Sundberg andSmith 2002) Furthermore, these products can be readily converted tothe biologically active pipecolic acids (Krow et al 1982, 1999; Holmes

oc-et al 1985) A roc-etrosynthoc-etic analysis shows that these isoquinuclidines

28 can be prepared from imines 29 and cyclohexenone 30 (Babu and

Perumal 1998; Shi and Xu 2001; Sunden et al 2005)

From previous work we assumed that an asymmetric Brønsted acidcatalyzed reaction should enable the formation of these valuable prod-

ucts Our concept, based on the direct reaction between aldimine 29 and cyclohexenone 30, includes the simultaneous, double Brønsted acid cat- alyzed activation of an electrophile (by a chiral Brønsted acid *BH 5)

and a nucleophile (by an achiral Brønsted acid BH) whereby both vation processes behave co-operatively and, through effective interplay,result in the desired product (Fig 10) However, the fundamental re-quirement for the successful development of such a Brønsted acid as-sisted, asymmetric Brønsted acid catalyzed reaction process must be

acti-that the achiral Brønsted acid BH is not able to activate the aldimine 29.

Hence, the initial reactions were conducted using BINOL-phosphate

5 in combination with various achiral Brønsted acids, including

pro-tonated pyridine derivatives, alcohols and acids Best ities were observed with the addition of carbonic acids, phenol and

enantioselectiv-hexafluoro isopropanol which provided the isoquinuclidines 28 with

up to 88% ee Further explorations concentrated on varying the

re-action parameters including different protected imines, catalyst

load-Fig 10 Co-operative asymmetric Brønsted acid catalyzed synthesis of

isoquin-uclidines

ings, temperature, and concentration From these experiments the best

results were obtained when chiral BINOL-phosphates 5d or 5e were

used together with co-catalyst acetic acid in toluene Under these mized conditions various aldimines were applied in the double Brønstedacid catalyzed enantioselective synthesis of isoquinuclidines (Table 10)

opti-In general isoquinuclidines, with both aromatic as well as matic residues bearing electron-withdrawing and electron-donating sub-stituents could be isolated in good yields and with high enantiomeric

heteroaro-ratios, whereby the exo:endo ratio of the products was between 1:3 and

1:9

With regard to the reaction mechanism, we assume that our new, covalent, enantioselective Brønsted acid catalyzed synthesis of isoquin-uclidines comprises two part reactions whereby subsequent Mannichand aza-Michael reactions are the key steps [Fig 11; examples of such

non-a stepwise non-addition–cycliznon-ation mechnon-anism hnon-ave been reported enon-arlierfor the reaction of silylenol ethers with aldimines (Birkinshaw et al.1988; Kobayashi et al 1995; Hermitage et al 2004)] In the first step,analogous to our previous reported ion pair catalysis (Rueping et al.2005a,b, 2006a–e, 2007a), a proton transfer from the chiral Brønsted

acid 5 to the aldimine occurs and the chiral ion pair A is formed which

is now activated to react with the nucleophile The dienol 30a, ing as a nucleophile, is formed from cyclohexenone 30 in the presence

function-Table 10 Scope of the double Brønsted acid catalyzed Mannich–Michael

reac-tion

of the second achiral Bronsted acid BH, the acetic acid, via an

accel-erated adjustment of the keto-enol-equilibrium (The rate-determiningstep of the reaction is presumably the dienol formation, as no consider-able conversion was observed without the addition of achiral Brønsted

acid.) The subsequent Mannich reaction provides the adduct B, an

ex-ceptionally reactive Michael acceptor, which leads directly to the

corre-sponding isoquinuclidine 28 as well as the regenerated chiral phosphate 5.

BINOL-The development of this so far unprecedented, double Brønsted acidcatalyzed enantioselective synthesis of various aromatic and heteroaro-

Fig 11 Conceivable catalytic cycle of the Brønsted-acid catalyzed

Mannich-aza-Michael-reaction

matic substituted isoquinuclidines demonstrates again the power of covalent Brønsted acid catalysis The special feature of this Mannich-aza-Michael reaction is the effective interplay of an achiral and a chi-ral Brønsted acid which, simultaneously in a cooperative fashion ac-tivate the enone and aldimine This enables an asymmetric reactionprocess, thereby, forming the desired isoquinuclidine products with thegeneration of three new stereocenters in a highly stereoselective manner(Rueping and Azap 2006)

non-11 Asymmetric Brønsted Acid Catalyzed Carbonyl Activation: The First Organocatalytic

Electrocyclic Reaction

Within the field of chiral ion pair catalysis only aldimines and imines had been activated so far However, we have recently been suc-cessful in the activation of both the electrophile, as well as the nucle-ophile in a new double Brønsted acid catalyzed reaction

keto-The enantioselective Brønsted acid catalyzed activation of a pure bonyl compound using a chiral BINOL-phosphate had not previouslybeen described Hence, we decided to develop such a reaction, a sofar unprecedented Brønsted acid catalyzed enantioselective Nazarov cy-clization (Rueping et al 2007c).

car-The Nazarov reaction belongs to the group of electrocyclic tions and is one of the most versatile methods for the synthesis of fivemembered rings which are the key structural element of numerous nat-ural products (for reviews on the Nazarov cyclization, see: Habermas

reac-et al 1994; Denmark 1991; Frontier and Collison 2005; Pellissier 2005;Tius 2005) Generally, the Nazarov cyclization can be catalyzed byBrønsted acids or Lewis acids However, only a few asymmetric vari-ations have been described, most of which require the use of largeamounts of chiral metal complexes [metal-catalyzed enantioselectiveNazarov reactions (Liang et al 2003; Aggarwal and Belfield 2003);asymmetric Nazarov reactions through enantioselective protonations(Liang and Trauner 2004)]

Within the above context and building on our previous results(Rueping et al 2005a,b, 2006a–e, 2007a; Rueping and Azap 2006), wedecided to examine a metal free, BINOL-phosphate catalyzed Nazarovreaction This would not only be the first example of a Brønsted acidcatalyzed, enantioselective, electrocyclic reaction but would addition-ally provide a simple and direct route to optically pure cyclopentenones.Based on our earlier work, we assumed that the catalytic protonation

of a divinylketone 31 by the BINOL-phosphate 5 would result in the formation of a cyclopentadienyl cation-phosphate anion adduct B Sub-

sequent conrotatory 4π-electrocyclization would lead to oxyallyl cation

C which, via the elimination of a proton, will form enolate D

Succes-sive protonation of this enolate should then result in the formation of

cy-clopentenone 32 and the regenerated Brønsted acid catalyst 5 (Fig 12).

At the outset of our experimental work we began by examining a able Brønsted acid catalyst for the enantioselective electrocyclization of

suit-dienone 31 While the use of BINOL-phosphates resulted in the ucts 32 in good yields, better dia- and enantioselectivities were obtained

prod-with the corresponding N-triflyl phosphoramides 33, which even at 0 °C

gave complete conversion after 10 min With the optimized conditions

in hand, we applied various dienones to the Brønsted acid catalyzed

Fig 12 Brønsted-acid catalyzed enantioselective Nazarov cyclization

enantioselective Nazarov reaction procedure (Table 11; Rueping et al.2007c) In general it was possible to successfully transfer differently

substituted dienones to the corresponding cyclopentenones 32a–h in

good yields and with excellent enantioselectivities (86%–99% ee) As

shown in Table 11, the reaction is not only applicable to the alkyl-, substituted, but also to the dialkyl-substituted dienones

aryl-The absolute configuration of the products was obtained from the

X-ray crystal structure analysis The cis-products of compound 32e

ex-hibits the (S)-configuration at both stereogenic centers This is in

agree-ment with a kinetic protonation through Brønsted acid 33.

While the newly developed Brønsted acid catalyzed Nazarov

reac-tion primarily generates the cis-cyclopentenones, the asymmetric metal catalyzed variations described so far often provide the trans-product

(Liang et al 2003; Aggarwal and Belfield 2003; Liang and Trauner2004) To demonstrate that a route to these isomers is also possible we

effectively isomerized the cyclopentenone cis-32a to the corresponding cyclopentenone trans-32a without loss of enantiomeric purity

(Scheme 8)

Table 11 Scope of the first enantioselective Brønsted acid catalyzed Nazarov

cyclization

Scheme 8 Isomerization without loss of enantioselectivities

We have developed the first enantioselective Brønsted acid catalyzedNazarov reaction This efficient method is not only the first example of

an organocatalytic electrocyclic reaction but it also provides the