This article was published as part of the

Rapid Formation of Molecular Complexity in Organic Synthesis issue

Reviewing the latest advances in reaction development and

complex, target-directed synthesis

Guest Editors Professors Erik J. Sorensen and Huw M. L. Davies

Please take a look at the issue 11 table of contents to access

other reviews in this themed issue

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Enantioselective catalysis and complexity generation from allenoatesw

Bryan J. Cowen and Scott J. Miller*

Received 1st June 2009

First published as an Advance Article on the web 24th July 2009

DOI: 10.1039/b816700c

Lewis base catalysis of reactions with allenoates using phosphine and amine nucleophiles has

emerged as a key platform for the generation of molecular complexity. Investigations in this area

have established a range of suitable coupling partners for allenoates, including electron-deficient

olefins, imines, and aldehydes. This tutorial review will describe these methodologies, with a

special emphasis on recent work regarding asymmetric reactions using chiral Lewis base catalysts.

1. Introduction

The development of new methods for chemo-, regio-, and

stereoselective chemical bond formation is a primary focus in

the field of organic synthesis. Such methods enable construction

of the molecular frameworks encountered in compounds of

interest in pharmacology and materials science settings, inter alia.

As targets for chemical synthesis are often diverse in structure,

general methods to synthesize an array of unique compounds

are desirable, if not also elusive. The importance of the

generation of a variety of molecular scaffolds in a rapid,

atom-economical fashion has been prominently displayed by

the recent progress in the area of diversity-oriented synthesis

(DOS).1 This review will describe synthetic methods for

diversity and complexity generation employing Lewis base-

catalyzed reactions of allenoate (a-allenic ester) substrates.

The evolution of these methods into asymmetric variants for

enantioselective catalysis will also be addressed.

Lewis base catalysis, often classified as nucleophilic catalysis,

remains an active and dynamic area of interest for synthetic

chemists. Small-molecule electron-pair donors (Lewis bases)

are effective catalysts for a range of synthetic transformations.

The development of chiral Lewis bases for asymmetric

catalysis has resulted in a myriad of chiral catalysts for

enantioselective reactions, as well as expanded conceptual

frameworks in the broader field of catalysis.2 Phosphine and

amine-based catalysts, bearing non-bonding electron pairs, are

commonly employed in these transformations. Phosphines,

while traditionally utilized primarily as ligands for transition-

metal processes, have recently become attractive as nucleophilic

catalysts.3 Naturally-occurring alkaloids (e.g., the cinchona

family)4 and a-amino acids (e.g., L-proline),5 as well as

synthetic amines, have now been widely applied in studies of

asymmetric catalysis.6 This review focuses on phosphines and

amines as Lewis base catalysts in the reactions of allenoates.

Allenoates are an attractive substrate class for Lewis base

catalysis due to their facile preparation7 and diverse reactivity.

As illustrated in Fig. 1, addition of a Lewis base to the

electrophilic, sp-hybridized, b-carbon of an a-allenic ester (1)

results in the generation of a zwitterionic enolate-like inter-

mediate. The nature of this zwitterion may be depicted in

several ways, which include anion localization at the a-carbonor g-carbon or delocalized, as a 1,3-dipole. Consideration of

these resonance structures is useful in understanding the

modes of reactivity of allenoates upon exposure to different

Department of Chemistry, Yale University, 225 Prospect Street,New Haven, CT 06520-8107, USA. E-mail: scott.miller@yale.edu;Fax: +1-203-436-4900; Tel: +1-203-432-9885w Part of the rapid formation of molecular complexity in organicsynthesis themed issue.

Bryan J. Cowen

Bryan J. Cowen was born inSuffern, NY (USA), in 1981.He received his BS inchemistry from BinghamtonUniversity in 2004, where heparticipated in research inthe laboratories of ProfessorSusan L. Bane. His graduateresearch with Professor ScottJ. Miller, starting at BostonCollege and currently atYale University, involves thedevelopment of catalyticenantioselective reactions withallenoates. Upon completionof his PhD degree from Yale,

he will join the laboratories of Professor David Y. Gin at theMemorial Sloan-Kettering Cancer Center in New York City.

Scott J. Miller

Scott J. Miller was born inBuffalo, NY (USA), in 1966.He received his BA andPhD degrees from HarvardUniversity under the guidanceof David A. Evans. Followingpostdoctoral studies withRobert H. Grubbs at Caltech,he joined the faculty at BostonCollege in 1996. In 2006, hebegan an appointment in theDepartment of Chemistry atYale University. His researchinterests are in the areasof synthesis, catalysis andchemical biology.

3102 | Chem. Soc. Rev., 2009, 38, 3102–3116 This journal is �c The Royal Society of Chemistry 2009

TUTORIAL REVIEW www.rsc.org/csr | Chemical Society Reviews

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Lewis base catalysts in the presence of electrophilic-coupling

partners. As will be evident from the examples presented

herein, this zwitterionic intermediate may undergo a variety

of transformations, including cycloadditions, general base-

mediated reactions, and processes mechanistically related to

the Morita–Baylis–Hillman8 and Rauhut–Currier reactions.9

2. Phosphine-catalyzed reactions with allenoates

2.1 Cycloadditions of electron-deficient olefins with achiral

phosphine catalysts

a-Allenic esters were first utilized as substrates for phosphine-

promoted coupling reactions in the pioneering work of Zhang

and Lu in 1995.10 It was found that treatment of ethyl

2,3-butadienoate (1a) with electron-deficient olefins such as

ethyl acrylate (2), in the presence of substoichiometric (10 mol%)

triphenylphosphine (PPh3), resulted in a formal [3 + 2]-

cycloaddition reaction (Scheme 1). Regioisomeric cyclopentene

products 3a and 3c were isolated in 76% combined yield

(75 : 25, 3a : 3c). Interestingly, the more nucleophilic tributyl-

phosphine (PBu3) catalyst resulted in a faster reaction rate but

a lower isolated yield (66%) of products (75 : 25, 3a : 3c). Thelower yield is attributed to dimerization of 2 as a competing

side reaction when PBu3 is employed as the catalyst.

In addition to acrylates, methyl vinyl ketone, acrylonitrile,

diethyl fumarate (4), and diethyl maleate (5) were shown as

competent substrates for the cycloaddition. Reactions with 4

and 5 were stereospecific furnishing products trans-6 and cis-6,

respectively (Scheme 2).

The proposed mechanism for the cycloaddition reaction

begins with nucleophilic addition of the phosphine to the

b-carbon of the allenoate 1a (Scheme 3). This generates the

zwitterionic enolate intermediate which may be represented by

7a or 7c. Cycloaddition of 7a with acrylate 2 is then proposed

to generate ylide 8a while cycloaddition of 7c with 2 generates

ylide 8c. Proton transfer provides enolates 9a and 9c which

undergo elimination of the catalyst and deliver regioisomeric

cyclopentenes 3a and 3c.Lu and co-workers then expanded the cycloaddition

methodology to include exocyclic olefin substrates.11 The utility

of this advance was demonstrated in a later disclosure for use

in the synthesis of (�)-hinesol (10; Scheme 4).12 A reaction

between allenoate 1b and chiral, non-racemic exomethylene

(+)-11 with 10 mol% PBu3 as the catalyst provided spirocyclic

product 12 as a single regioisomer in 63% yield and a 94 : 6

diastereomer ratio (dr). The high diastereoselectivity was

attributed to approach of the zwitterionic intermediate from

Fig. 1 The Lewis base–allenoate zwitterionic intermediate.

Scheme 1 [3 + 2]-Cycloaddition between allenoate 1a and ethyl

acrylate (2).

Scheme 2 Stereospecific [3 + 2]-cycloaddition with diethyl fumarate

(4) and maleate (5).

Scheme 3 Proposed mechanism for allenoate–acrylate [3 + 2]-

cycloaddition.

Scheme 4 [3 + 2]-Cycloaddition in the synthesis of (�)-hinesol (10).

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the opposite face of the b-methyl substituent. The formation

of the g-regioisomer is suppressed by destabilizing steric

interactions between the bulky t-Bu ester of the allenoate

and the carbocycle substrate. The synthesis of 10 was then

completed in five subsequent steps.

Another application of this annulation in the context

of target-oriented synthesis was reported by Pyne and

co-workers.13 In this study, a phosphine-catalyzed [3 + 2]-

cycloaddition is utilized in the preparation of cyclopentenyl

L-glutamate analogs. It was found that the stereochemical

outcome of cycloadditions with allenoates bearing g-substituentsdepended on the nature of the substituent. For example,

phenyl-substituted allenoate (�)-13 reacts with exomethylene

14 under PPh3 catalysis to provide 15 in 78% yield (Scheme 5).

However, when methyl-substituted allenoate (�)-16 is subjected

to 14 under the same conditions cycloadduct 17 is produced in

38% yield. Product 17 forms with the opposite configuration

at the newly formed tertiary stereocenter as compared with 15.

This is rationalized by analysis of transition states 18 and 19

leading to products 15 and 17, respectively. In transition state

18, the bulky phenyl substituent prefers a trans-relationship to

the triphenylphosphonium moiety of the zwitterion, whereas

in 19 the smaller methyl substituent may accommodate

a cis-relationship. This cis-stereoisomer 19 benefits from

minimization of steric interactions between the methyl sub-

stituent and the N-benzoyl protecting group of substrate 14

during cycloaddition. Heterocycles 15 and 17 were then

carried forward to amino acids 20 and 21, respectively, the

latter of which was found to be an agonist of the mGlu2

receptor with an EC50 value of 158 mM. These studies also

presaged the development of enantioselective reactions that

take advantage of the putative erasure of the axis of chirality

upon reaction of the allenoate with Lewis base catalysts

(see Section 2.2).

A report further expanding the substrate scope of the

[3 + 2]-cycloadditions to include b-substituted olefins

was disclosed by the groups of Lu and Zhang in 2006.14

Specifically, the reaction of highly activated 2-benzylidene-

malononitrile with allenoate 1a using catalytic PPh3 provided

the expected cycloadduct as a single regioisomer. Prior to this

work, only diethyl fumarate and maleate were effective

b-substituted olefin substrates (see Scheme 2). The method

was developed into a one-pot procedure with generation of

2-benzylidenemalononitriles (22) in situ from reaction of aryl

aldehydes (23) and malononitrile (24) under PPh3 catalysis,

followed by slow addition of allenoate 1a (Scheme 6).

Although substrates derived from aliphatic aldehydes did

not participate in the reaction, high yields (up to 86%) of a

variety of aryl-substituted products 25 were obtained.

Recently, the same research groups reported that b-disubstituted alkylidenemalononitriles participated in a different

reaction pathway than the monosubstituted analogs upon

exposure to allene 1a and PPh3.15 Treatment of 1a with 26

and PPh3 (10 mol%) in refluxing toluene delivered products of

type 27 in moderate to high yields (50–82%; Scheme 7). The

structures of these cyclopentenes reveal that the allenic

ester serves as the two carbon coupling partner as opposed

to its usual role as the three carbon fragment in the formal

[3 + 2]-cycloaddition. Isotopic labeling studies helped to

support the reaction mechanism depicted in Scheme 7. It is

proposed that zwitterionic intermediate 7a acts as a general

base to generate carbanion 28 from substrate 29. Nucleophilic

addition to vinylphosphonium intermediate 30 would then

provide ylide 31. Proton transfer and phosphine elimination

generates 32 which, after deprotonation mediated by 7a, ispoised for intramolecular ring closure providing the observed

product 34. As predicted by the mechanism, this methodology

thus requires allylic protons on substrate 26 to generate

carbanion 28.

Tran and Kwon have studied 2-benzylidenemalononitriles

(22) in cycloaddition reactions with a-substituted allenoate 35

Scheme 5 Stereodivergent cycloadditions with g-substituted allenoates.

Scheme 6 [3 + 2]-Cycloadditions of 2-benzylidenemalononitriles

(22).

Scheme 7 [3 + 2]-Cycloadditions with disubstituted malononitriles.

3104 | Chem. Soc. Rev., 2009, 38, 3102–3116 This journal is �c The Royal Society of Chemistry 2009

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(Scheme 8).16 In these cases, regioselectivity was dependent on

the choice of phosphine Lewis base employed in the reaction.

For example, hexamethylphosphorous triamide (P(NMe2)3)

catalyzes the formation of 36 (86–98% yield), while P(4-FC6H4)3provides regioisomer 37 (80–93% yield). Notably, these cyclo-

hexene products result from formal [4 + 2]-cycloadditions

between allenoate 35 and malononitrile 22.

Mechanistically, the regiodivergent [4 + 2]-cycloaddition

reactions begin with zwitterion formation. This is followed by

either g-addition to the arylidene (pathway A) or proton

transfer (pathway B) to generate ylide 38 (Scheme 9A). It is

proposed that electron-deficient phosphines (e.g., P(4-FC6H4)3)

stabilize ylide 38 and therefore promote pathway B. Conversely,

the b0-protons of the P(NMe2)3–35 zwitterion are less acidic

disfavoring formation of ylide 38 and thus promoting pathway A.

Following arylidene addition, both pathways proceed to their

respective products through sequential proton transfers,

6-endo cyclization, and catalyst extrusion. With regard to

substrate scope, the reaction is tolerant of substituents at the

b0-position of the allenoate (39) in reactions with 40, generating

products 41 in high yields (77–98%) and dr’s (up to 10 : 1;

Scheme 9B). Interestingly, only one regioisomer is formed

(through pathway A) with b0-substituted allenic ester substrates,

regardless of the nature of the phosphine catalyst.

Another striking contribution to this field from the Kwon

laboratory revealed the development of an intramolecular

cycloaddition process with substrates of type 42 and 43

(Scheme 10).17 When the electron-withdrawing group

(EWG) attached to the olefin is an ester (e.g., CO2Et, 42),

catalytic PBu3 is effective at promoting the desired [3 + 2]-

cycloaddition to deliver products 44 in high yields (70–98%) as

single diastereomers. Using substrate 43, with EWG = NO2,

although PBu3 does not catalyze a productive cyclization, the

substantially less nucleophilic tris(p-fluorophenyl)-phosphine

delivers nitronate product 45 in 62% yield. This product was

subsequently exploited in 1,3-dipolar cycloadditions with a

variety of dipolarophiles to provide structurally complex

heterocycles 46 (83–97% yield).

Endocyclic olefins have also been applied in the Lu reaction.

For example, Ishar and co-workers reported that 3-formyl-

chromones (47) undergo efficient cycloadditions with allenic

ester 1a and PPh3 (14 mol%) in refluxing benzene

(Scheme 11).18 The formyl group is lost during the reaction

delivering product 48 as a single regio- and diastereoisomer in

good yield (72–74%).

A synthetic application of allenoate cyloadditions with

endocyclic olefins which addressed key stereochemical issues

was recently reported by Garcıa Ruano and co-workers.19 In

their study, chiral non-racemic 5-ethoxy-3-sulfinylfuranones

were employed in reactions with g-substituted and unsubstituted

allenoates. Regio- and diastereoselective reactions were

observed for the cycloaddition of 1a with either 49 or 50 using

catalytic PPh3 to produce bicyclic lactones 51 and 52,

respectively (Scheme 12; 51: 96% yield; 52: 75% yield). The

relative stereochemical outcome is rationalized by the zwitterionic

intermediate approaching the substrate anti to the 5-ethoxy

group. An additional stereocenter is selectively installed in

reactions of 49 or 50 with allenoate (�)-16 and PPh3 as the

catalyst. Although yields are modest (53: 47%; 54: 24%),

high endo–exo selectivity (432 : 1) is observed in the

process delivering chiral, optically pure products containing

Scheme 8 [4 + 2]-Cycloadditions of a-substituted allenoate 35

and 22.

Scheme 9 Mechanism and scope of the [4 + 2]-cycloaddition

between a-substituted allenoates (39) and arylidenes (40).

Scheme 10 Intramolecular cycloaddition reactions.

Scheme 11 [3 + 2]-Cycloadditions of 3-formylchromones (47).

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four stereogenic centers. It is noteworthy that substrates

analogous to 49/50 lacking a C3-sulfinyl substituent react with

low endo–exo selectivity (2 : 1; not shown). Thus, the authors

propose that products 53/54 arise from ring closure of inter-

mediate 55 as opposed to the sterically encumbered 56.

Jones and Krische very recently applied a phosphine-

catalyzed [3 + 2]-cycloaddition of an endocyclic olefin in

the total synthesis of the natural product, (+)-geniposide

(57; Scheme 13).20 Applied early in the synthesis, the annulation

between 1a and optically pure substrate 58 using 10 mol%

PPh3 proceeds in 63% yield with complete regio- and diastereo-

control. The product 59 is then elaborated to 57 in ten steps.

Chiral substrate 58 was prepared by kinetic resolution through

palladium-catalyzed allylic substitution.

2.2 Enantioselective cycloadditions of electron-deficient olefins

A pioneering enantioselective allenoate cycloaddition reaction

was reported shortly after Lu’s original disclosure. In this

work, Zhang et al. studied a variety of chiral phosphines in

annulations between a-allenic esters and acrylate substrates.21

Structurally rigid P-chiral phosphabicyclo[2.2.1]heptane catalysts

provided cyclopentene products with the highest levels of

enantioselectivity. The optimized conditions employed 10 mol%

chiral phosphine catalyst 60a in the reaction between allenoate

1a and isobutyl acrylate 61 at 0 1C in toluene (Scheme 14). The

cyclopentene product 62 was isolated as a single regioisomer in

88% yield with 93% enantiomeric excess (ee). Lower levels of

regio- and enantioselectivity were observed in reactions using

acrylates with smaller ester substituents (e.g., Me, Et).

Following Zhang’s work, almost a decade passed before

there were any further reports of enantioselective cycloadditions

of this type with electron-deficient olefins. Wilson and Fu then

revealed their findings with binaphthyl-derived phosphine

catalyst 63 in reactions with b-substituted enones and allenoates

(Scheme 15).22 Treatment of 1a with chalcone substrates 64

and 10 mol% phosphine 63 furnishes cyclopentene products

65a and 65c with two contiguous stereogenic centers in good

yields (39�74%) with high regio- (up to 420 : 1, 65c : 65a)and enantiocontrol (up to 90% ee). Surprisingly, regioselection

differs in this system as compared to the PPh3-catalyzed

acrylate cycloadditions. The major product (65c) in this

case results from addition of the g-centered anion of the

zwitterion to the enone. It was also demonstrated that dienones

such as 66 undergo a single enantioselective cycloaddition to

give spirocyclic product 67 in 81% yield and 89% ee using

phosphine 63.

Cowen and Miller then reported enantioselective allenoate–

enone cycloadditions using an amino acid-based phosphine

catalyst.23 Gilbertson and co-workers had previously shown

that phosphine-embedded peptides were efficient chiral ligands

in enantioselective metal-catalyzed reactions such as allylic

alkylations.24 Additionally, their group studied the synthesis

and structure of these phosphine-containing amino acids and

peptides in great detail;25 however, their exploitation as

nucleophiles had not been previously reported in the literature.

Thus, treatment of allenic ester 1c with tetralone-derived

exomethylene substrate 68 and 10 mol% protected diphenyl-

phosphinylalanine (69) at �25 1C in toluene gave product 70

as a single regioisomer in 95% yield with 80% ee (Scheme 16).

Surprisingly, single-amino acid catalyst 69 provided higher

enantioselectivity in the reaction than more elaborate di-, tri-,

and tetra-peptide phosphine-based sequences studied during

catalyst optimization. These reactions proved efficient for a

range of cyclic and acyclic exomethylenes. The origin of

Scheme 12 [3 + 2]-Cycloadditions with chiral endocyclic olefins 49

and 50.

Scheme 13 [3 + 2]-Cycloaddition in the synthesis of (+)-geniposide

(57).

Scheme 14 Enantioselective [3 + 2]-cycloaddition with acrylate 61.

Scheme 15 Enantioselective [3 + 2]-cycloadditions with chalcones

(64).

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enantioinduction was rationalized by consideration of trans-

ition state 71. In this system, the substrate approaches the

zwitterionic intermediate from the bottom face, opposite a

phenyl substituent on the phosphine catalyst. This intermediate

may be rigidified through a stabilizing Coulombic P+� � �O�interaction26,27 and an intramolecular hydrogen bond contact.

This study then focused on the application of g-substitutedallenic esters in the cycloaddition chemistry. It was envisioned

that if phosphine 69 generated zwitterion 72 through addition

to racemic allenoate (�)-73, then the allene axis of chirality

would be removed. Thus, if 72 then underwent an enantio-

selective cycloaddition with an enone substrate, a dynamic

kinetic asymmetric transformation might be realized

(Scheme 17). This strategy did indeed prove effective using

chalcones (74) as the enone-coupling partners, providing

products 75 as single regio- and diastereomers in high yields

(88–96%) with excellent ee’s (87–91%). Using one equivalent

of 69 ensured convenient reaction rates with the more sterically

encumbered allene.

Another class of structurally distinct chiral phosphines

capable of promoting enantioselective [3 + 2]-cycloadditions

between allenoates and enones was recently reported by

Marinetti and co-workers.28 In their approach, planar chiral

2-phospha[3]ferrocenophanes were prepared and studied in

annulations between 1a and various electron-deficient olefins.

The substrate scope consisted mainly of chalcone derivatives

(64), with products 65a and 65c emerging from reactions of 1a

with catalyst 76 in high yields (63–87%), regio- (up to420 : 1,

65c : 65a), and enantioselectivities (87–96% ee; Scheme 18A).

Ethyl acrylate (2) and diethyl fumarate (4) also participated in

highly enantioselective cycloadditions (84–90% ee) with 1a

using the planar chiral phosphine 76 (Scheme 18B). The

authors report that catalyst 76 displays good air-stability,

even though the P-center is trialkylated.

2.3 Cycloadditions of imines with achiral phosphine catalysts

Methodologies involving phosphine-promoted reactions of

allenoates are not limited to annulations with electron-deficient

olefins. Activated aldimines have also been shown to be

competent coupling partners in these types of transformations.

As such, this expands the reach of allenoate cyclizations

providing heterocyclic products in addition to the carbocycles

obtained from olefin substrates. Again, Xu and Lu pioneered

this subfield establishing that N-p-toluenesulfonyl (Ts) imines

(77) participate in formal [3 + 2]-cycloadditions with allenoate

1d using PPh3 (10 mol%) as the catalyst to provide 78 in high

yields (83–98%; Scheme 19).29 A salient feature of this work is

that these products are isolated as single regioisomers, in

contrast to the mixtures obtained when electron-deficient

olefins (e.g., ethyl acrylate) are employed. It was then shown

that facile manipulation of the products provides substituted

pyrroles (79) in two steps.

Kwon and co-workers later expanded this methodology

through the use of g-substituted allenic esters ((�)-80) in

reactions with 77 (Scheme 20).30 The best results were

obtained using more nucleophilic trialkylphosphines (vs. triaryl-

phosphines) such as PBu3 presumably to compensate for the

lower reactivity of the substituted allenoates. Product 81 was

isolated in near quantitative yield (89–499%) in most cases

with high diastereoselectivity (91 : 9–100 : 0 dr) for the cis-

isomer (trans-isomer not shown).

The Kwon laboratory then documented divergent chemo-

selectivity in similar reactions when the substitution pattern of

the allenic substrate was altered.31,32 Products resulting from a

Scheme 16 Enantioselective [3 + 2]-cycloadditions of enones with

protected a-amino acid catalyst 69.

Scheme 17 Deracemization reactions of g-substituted allenoate

(�)-73.

Scheme 18 2-Phospha[3]ferrocenophane-catalyzed enantioselective

[3 + 2]-cycloadditions with chalcones and acrylates.

Scheme 19 Formal [3 + 2]-cycloaddition with Ts-imines (77).

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formal [4 + 2]-cycloaddition were obtained from reactions of

allenoate 39 with imine 77 (Scheme 21). Again, catalytic PBu3(20 mol%) was effective in promoting annulations between

a variety of allenoates and Ts-imine substrates providing tetra-

hydropyridines (82) in excellent yields (82–99%) and dr’s

(83 : 17–98 : 2). In a subsequent report, Tran and Kwon applied

this method in the target-oriented syntheses of two naturally

occurring alkaloids, (�)-alstonerine and (�)-macroline.33

Mechanistically, this [4 + 2]-cycloaddition reaction is

rationalized by consideration of zwitterionic intermediate 83

(Scheme 22). a-Substitution of allenoate 84 is thought to deter

addition to the imine through the a-centered anion 83a and

promote g-centered anion 83c addition to the imine. This

provides intermediate 85 which undergoes a series of proton

transfers to give 86 followed by intramolecular 6-endo cyclization,

product (88) formation, and catalyst regeneration. The

authors propose that the first proton transfer step is rate-

determining, which is supported by the observation that

b0-CD3–84 participates in a much slower reaction than

b0-CH3–84. Additionally, allenoates with electron-withdrawing

substituents on the b0-carbon undergo rapid reactions, possibly

as a result of the increased acidity of the b0-protons facilitatingthe proton transfer step from 85 to 87.

2.4 Enantioselective cycloadditions of imines

The first example of an asymmetric cycloaddition between an

allenoate and an imine substrate was not reported until 2006.

In this preliminary study, Jean and Marinetti investigated the

propensity for known, readily available phosphine ligands

used in transition-metal complexes to serve as Lewis base

catalysts for formal [3 + 2]-cycloadditions.34 Among promising

phosphines, (R,R)-Et-FerroTANE (89) provided moderate

levels of enantiomeric excess (up to 60%) in reactions of

allenoates 1 with imine 90 to give 91 (36–98% conversion;

Scheme 23A). The enantioselectivity of the reaction was

improved by increasing the size of the ester group of the

allenoate, although this also decreased the reaction rate. Later

work by the same group established that the binaphthyl-

derived phosphine 63 was more enantioselective than chiral

phosphines previously screened (up to 80% ee; Scheme 23B).35

Of note is that cyclohexyl allenoate 1e gave the best reaction

rates of the allenoates investigated, providing products 92 in

high yields (60–88%).

During the same time period, Scherer and Gladysz reported

similar ee’s in analogous systems using rhenium catalyst 93

(Scheme 24).36 Although reactions are sluggish (8 days), high

yields (90–93%) of product 94 are obtained in moderate ee’s

(up to 60%).

A major advance in the development of highly enantio-

selective formal [3 + 2]-cycloadditions with imines was

reported by Fang and Jacobsen.37 This study employed

N-diphenylphosphinoyl (DPP) imines as well as Ts-imines as

the activated coupling partners in reactions with allenoates.38

DPP-imines outperformed Ts-imines in terms of enantio-

selectivity in reactions with 1a promoted by chiral, thiourea-

containing phosphine catalysts. However, reaction rates with

Scheme 20 Diastereoselective cycloadditions with g-substitutedallenoates ((�)-80) and Ts-imines (77).

Scheme 21 [4 + 2]-Cycloadditions of a-substituted allenoates (39)

with Ts-imines (77).

Scheme 22 Proposed mechanism of the [4 + 2]-cycloaddition of

a-substituted allenoate 84 with Ts-imines (77). Scheme 23 Enantioselective [3 + 2]-cycloadditions of Ts-imines (77).

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DPP-imines were significantly slower as compared to rates

with Ts-imines. This was remedied by inclusion of substoichio-

metric triethylamine (Et3N; 5 mol%) and water (20 mol%) in

the reaction medium which resulted in significantly increased

reaction rates. The rate enhancement is attributed to the

additives’ abilities to facilitate proton transfer and catalyst

regeneration steps in the reaction mechanism; a hypothesis

supported experimentally and computationally by work from

others.26c

Optimization of the phosphine-containing thiourea catalyst

led to identification of 95 as the most enantioselective of

those studied (Scheme 25). A variety of DPP-imines (96)

participated in the cyclizations with 1a providing products

97 in high yields (68–90%) and excellent ee’s (94–98%).

Catalyst loading was typically 10 mol%, but could be reduced

to 2.5 mol% in one case without compromising yield or

enantioselectivity. The authors propose a model for stereo-

induction based on transition state 98, in which the imine may

associate with the catalyst through hydrogen bonding to the

thiourea moiety. The zwitterionic enolate may then add to the

imine from the Re face in an intramolecular manner providing

the observed enantiomer of the cycloadduct.

Wurz and Fu reported an asymmetric variant of the

formal [4 + 2]-cycloadditions of Ts-imines and a-substitutedallenoates first reported by Kwon (see Section 2.3).39 A survey

of known chiral phosphine ligands identified 63 as the optimal

catalyst (Scheme 26). This phosphine, also successful in

enantioselective [3 + 2]-cycloadditions with imines (this section)

and electron-deficient olefins (Section 2.2), provides products

99 in high yields (42–99%). More pertinent to Fu’s study

was that 63 also provided significantly higher levels of ee and

dr in the cycloadditions compared to the other phosphines

screened. The fastest rates and highest enantioselectivities were

obtained using allenoates with an EWG at the b0-position(i.e., CO2Et; 100). The authors provide examples of product

derivatizations, including a diastereoselective dihydroxylation

reaction leading to piperidine 101.

2.5 Cycloadditions of aldehydes with achiral phosphine

catalysts

Aldehydes serve as another viable substrate class for phosphine-

promoted annulations with allenoates. Investigations in this

area began with work from Kwon and co-workers in 2005

(Scheme 27A).40 Treatment of allenoate 1f with aryl aldehydes

102 using PMe3 (20 mol%) did not furnish the dihydropyrroles

103 expected from a [3 + 2]-cycloaddition, but rather

dioxanylidenes 104E and 104Z (not shown). These compounds,

which incorporate two equivalents of the aldehyde-coupling

partner, are isolated in high yields (47–99%), exclusive cis-

diastereoselectivity, and high E/Z-selectivity. Acid-mediated

hydrolysis of these heterocycles leads to d-hydroxy-b-ketoestersin high yields (82–97%). Independent synthesis of 103,

followed by its subjection to the optimized reaction conditions,

demonstrated that it is not an intermediate in the formation

of 104; only unreacted 103 was recovered from this reaction

(Scheme 27B).

Scheme 24 Enantioselective [3 + 2]-cycloadditions of Ts-imines (77)

with rhenium catalyst 93.

Scheme 25 Enantioselective thiourea-catalyzed [3 + 2]-cycloadditions

of DPP-imines (96).

Scheme 26 Enantioselective [4 + 2]-cycloadditions of a-substitutedallenoate 100 with Ts-imines (77).

Scheme 27 Phosphine-catalyzed synthesis of dioxanylidenes (104)

from aldehydes (102).

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In light of these findings, the authors propose a mechanism

for the formation of 104 (Scheme 28). The zwitterionic inter-

mediate 105 engages the aldehyde through nucleophilic attack

by the g-centered anion 105c giving intermediate 106. This

oxyanion adds to another equivalent of aldehyde to provide

107 which undergoes a 6-exo cyclization providing enolate

108. Catalyst extrusion then delivers product 104. This

mechanism constitutes a unique case whereby productive

allenoate catalysis proceeds by initial addition through the

g-centered anion of zwitterion 105 to an electrophilic partner.

Kwon then expanded this methodology in an elegant

fashion by exploiting a stereochemical consequence of the

proposed reaction mechanism. If nucleophilic attack on the

aldehyde substrate occurs from the g-carbon of the zwitterion,

geometrical E/Z olefin stereochemistry is retained in the

resulting intermediate 106 (as opposed to attack from the

a-carbon where this information would be lost). Control over

the olefin geometry may arise from the relative populations

between zwitterionic Z-isomer 109c 2 109a and E-isomer

110c 2 110a (Scheme 29). It was proposed that use of a

sterically demanding phosphine catalyst would shift this

equilibrium from the electrostatically stabilized Z-isomer

109c 2 109a to the less encumbered E-isomer 110c 2 110a.If 110c was then added to an aldehyde, the resulting inter-

mediate 111 would be poised for intramolecular lactonization.

This hypothesis was brought to fruition by studying different

phosphine Lewis bases in reactions with various aldehydes

and allenoates.41 In the optimized conditions, allenoate 1a is

treated with catalytic (10–30 mol%) tricyclopentylphosphine

(PCyp3) and aldehydes 112 providing substituted pyrone

products 113, not dioxanylidenes, in moderate to good

yields (34–91%; Scheme 30). It is proposed that the ethoxide

liberated from intramolecular lactonization serves as a general

base facilitating subsequent proton transfers en route to

products 113.

It was later established that yet another unique product may

be obtained from reactions of aldehydes and allenoates by

minor modifications to the reaction conditions.42 Inclusion

of an alcohol additive in reactions promoted by PMe3gave 2-alkoxy-5,6-dihydro-2-pyrones 114 (instead of either

dioxanylidenes or pyrones), along with acyclic product 115

(Scheme 31). The highest ratio of 114 to 115 was obtained

using alcohols bearing electron-withdrawing groups. It was

later discovered that PPh3 promoted the formation of 114

with complete suppression of 115 in the analogous system.

Mechanistically, it was proposed that the alcoholic additive

serves to disrupt the intramolecular Coulombic attraction

between the enolate oxyanion and phosphonium of the allene–

phosphine zwitterion proposed in stabilizing the s-trans

conformation. The low energy stereoisomer of the zwitterion

in the presence of an alcohol, as substantiated through a

Scheme 28 Proposed mechanism for the formation of dioxanylidenes

(104).

Scheme 29 Stereocontrol over the zwitterionic intermediate.

Scheme 30 Synthesis of pyrones (113) through PCyp3 catalysis.

Scheme 31 Mechanistic scenarios in phosphine-catalyzed aldehyde

additions to allenoates.

3110 | Chem. Soc. Rev., 2009, 38, 3102–3116 This journal is �c The Royal Society of Chemistry 2009

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computational study, is now s-cis, as when sterically bulky

phosphines are employed.43 Using the sterically less encumbered

PMe3 or PPh3 as the catalyst, the alkoxide liberated through

intramolecular lactonization may now add in a conjugate

fashion to the enoate, yielding the observed product 114

following b-phosphonium elimination. This oxa-Michael

reaction does not proceed when PR3 is sterically encumbered.

2.6 Umpolung additions with achiral phosphine catalysts

Up until this point, this review has been concerned with

reactions exploiting the nucleophilicity of the phosphine–

allenoate zwitterion. While this certainly encompasses most

literature examples of Lewis base catalysis with allenoates to

date, the zwitterionic enolate, upon protonation, may also

serve as a reasonable electrophile. The synthetic consequence

of such a mode of reactivity was first demonstrated by Trost

and Li.44 In this pioneering work, alkynoates were subjected to

acidic pronucleophilic substrates under phosphine catalysis to

provide products of umpolung addition to the alkynoate

(g-carbon addition vs. b-carbon addition). The analogous

reactivity using allenoates was realized by Zhang and Lu in

1995.45 When allenoate 1a was subjected to PPh3 (5 mol%)

and various carbon-based Brønsted acidic substrates, products

116 were obtained in high yields (56–87%) and E/Z selectivities

(44 : 56–497 : 3; Scheme 32). In this case, it is proposed

that zwitterionic intermediate 7a deprotonates the substrate

leading to ion pair 117. The carbanion may then add to the

g-carbon of the allenoate�phosphonium adduct generating

ylide 118. Proton transfer and subsequent catalyst elimination

provides the product 116. In addition to carbon-based pro-

nucleophiles, phenol was found to be a suitable oxygen-based

substrate for this umpolung addition. However, under the

standard reaction conditions, the less acidic benzyl alcohol

and methanol did not participate in the coupling reaction.

Their reactivity in the coupling was recaptured by adding

acetic acid to the mixture, which presumably protonated the

zwitterionic phosphine–allenoate intermediate 7a providing

the electrophilic vinylphosphonium species.

Virieux and co-workers established that nitrogen-based

pronucleophiles were also effective coupling partners.46

Imidazole, pyrrazole, triazole, and phthalimide, as well as

their benzo-analogs, were effective in umpolung additions

catalyzed by PPh3 (10 mol%) with allenoate 1a providing

products 119 in high yields (up to498%) and E/Z selectivities

(65 : 35–100 : 0; Scheme 33). Efficient reaction of azole

substrates requires their pKa values to be between ca. 8.5

and 14.5. This may be rationalized by analysis of Lu’s

proposed mechanism. For example, when phenyltetrazole

(pKa = 4.5) was employed in the reaction, only ion pair 120

was observed implying that the tetrazole anion is not

sufficiently nucleophilic to add to the vinylphosphonium. On the

other hand, when pyrrole (pKa = 17.5) was subjected to the

reaction, only oligomerization of allenoate 1a was observed. It

was postulated that the zwitterionic intermediate is not basic

enough to deprotonate pyrrole which would lead to productive

umpolung addition. A productive reaction of 2-formylpyrrole

121 with 1a, however, was realized with PBu3 (30 mol%). In

this case, a tandem umpolung addition–aldol condensation

mechanism is proposed to deliver the observed indolizine

product 122 in 57% yield.

An example of a tandem allenoate addition–umpolung

reaction sequence was recently discovered by Huang et al.47

It was shown that salicyl N-thiophosphinyl imines (123) react

with a-allenic esters to give 2,3-disubstituted dihydrobenzo-

furans 124 in 68–95% yields with phosphine catalysis

(Scheme 34). Phosphine 125 was found to be the optimal

catalyst giving 124 with exclusive cis stereoselectivity for a

variety of different salicyl imines. The authors suggest that 125

may act in a bifunctional mode as PBu3 alone provides

products in reduced yields (ca. 50%) and no stereoselectivity

(cis–trans = 1 : 1). As such, the proposed mechanism involves

initial g-addition of zwitterion 7c to the imine to give 126,

followed by subsequent proton transfers, and intramolecular

umpolung addition of phenolate 127 to give ylide 128.

A final proton transfer provides the product 124 following

b-elimination of the catalyst. The phenolic group of the

catalyst is proposed as a hydrogen bond donor stabilizing

conformer 127 and leading to the production of the cis-

stereoisomer.

Scheme 32 Phosphine-catalyzed umpolung additions. Scheme 33 Umpolung additions of azole pronucleophiles.

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Huang and co-workers then studied this process using

g-substituted allenoates (�)-129 (Scheme 35).48 This simple

change to the allenic ester led to the formation of a new

6-membered heterocyclic product. In this case, PPh3 was

superior to bifunctional catalyst 125 in reactions with salicyl

imines 123, providing chromanes 130 in high yields (78–92%)

and diastereoselectivities (cis–trans = 2 : 1–420 : 1). The

authors suggest a similar mechanism to that previously

described, with the exception that initial addition from the

zwitterion to the imine occurs from the terminal carbon atom.

Generation of a suitable carbanion for such an addition may

arise through a 1,4-proton transfer from the initial a-centeredanion of the allene–catalyst intermediate.

2.7 Enantioselective umpolung additions

Shortly after Lu’s report of phosphine-catalyzed umpolung

additions to allenoates, Zhang et al. developed an asymmetric

variant.49 Among chiral phosphines screened for activity

and enantioselectivity, phosphabicyclo[2.2.1]-heptanes again

provided the highest levels of enantiocontrol, similar to findings

in the [3 + 2]-cycloadditions with olefins (see Section 2.2).

Thus, a variety of carbon-based pronucleophiles react with

allenoates 1 in reactions catalyzed by 10 mol% 60b to provide

products 131 in good yields (31–80%) and moderate to high

ee’s (41–75%; Scheme 36). The inclusion of 50 mol% each of

sodium acetate and acetic acid was found to be advantageous

to the enantioselectivity of the reaction, although faster rates

were observed with their omission. The reaction was much

slower when lithium or ammonium acetate was substituted for

sodium acetate, with no significant effect on the ee of the

product.

3. Amine-catalyzed reactions with allenoates

3.1 Additions to aldehydes with achiral amine catalysts

In addition to phosphines, amines are also effective Lewis base

promoters for reactions of allenoates with various coupling

partners. Amines display markedly different reaction profiles

in these types of transformations when compared to phosphines.

While this area is arguably underdeveloped, several findings

have been reported. Rather interestingly, the first disclosure of

an amine-catalyzed process was reported prior to Lu’s 1995

publication of the phosphine-promoted cycloadditions of

olefins. Tsuboi et al. studied reactions of allenoates with

aldehydes in the presence of either 1,4-diazabicyclo[2.2.2]-

octane (DABCO) or n-butyllithium.50 Although only two

examples using DABCO were provided, coupled products

132 were obtained from reactions with aliphatic aldehydes

133 and 134 (Scheme 37) in 41% and 54% yield, respectively.

The products may arise through a DABCO-promoted Morita–

Baylis–Hillman-type reaction mechanism. These reactions

constitute the first examples of such a process with allenoates

as substrates.

Scheme 34 Synthesis of dihydrobenzofurans (124) by tandem

addition–intramolecular umpolung of salicyl imines (123).

Scheme 35 Chromane (130) synthesis through a tandem addition–

umpolung sequence.

Scheme 36 Enantioselective umpolung additions of carbon pro-

nucleophiles using P-chiral phosphine 60b.

Scheme 37 Amine-catalyzed additions to aliphatic aldehydes.

3112 | Chem. Soc. Rev., 2009, 38, 3102–3116 This journal is �c The Royal Society of Chemistry 2009

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3.2 Additions to electron-deficient olefins with achiral amine

catalysts

In addition to aldehydes, the Miller laboratory demonstrated

that electron-deficient olefins participate in amine-catalyzed

reactions with allenoates.51 A variety of a,b-unsaturated carbonyl

compounds can be coupled in high yields (50–98%) with 1a to

provide addition products 135 using 10 mol% quinuclidine

(Scheme 38). Of the amine catalysts surveyed for reactivity in

this reaction, only DABCO provided comparable efficiency to

quinuclidine. Others, including DMAP, N-methylimidazole,

and DBU, did not engender any formation of product 135.

Amazingly, the reactivity observed in this reaction is completely

divergent from what Lu documented in analogous reactions

using phosphine catalysis, and does not provide the formal

[3 + 2]-cycloadducts (see Section 2.1).

This dichotomy reflects a key difference in the reaction

mechanism when an amine is employed vs. a phosphine

(Scheme 39). In the phosphine-catalyzed pathway of enone

136 and 1a, cycloaddition gives ylide intermediate 137 which

is stabilized by the phosphonium moiety. This ylide then

undergoes proton transfer and catalyst regeneration steps to

generate spirocycle 138. In contrast, the analogous ammonium

construct does not support such an ylide structure (i.e., 137);

thus zwitterionic intermediate 139 does not cyclize but rather

undergoes a proton transfer and catalyst elimination to

provide product 140.

During extension of the substrate scope, it was established

that Morita–Baylis–Hillman adducts were suitable coupling

partners for these amine-catalyzed allenoate additions. This

prompted the development of a novel three-component coupling

reaction between acrylate 141, allenoate 1a, and various

aldehydes 112 (Scheme 40). Cyclic products 142, arising from

allenoate coupling to exomethylene 143, were obtained as

single diastereomers in high yields (60–88%).

The synthetic utility of the products generated in the amine-

catalyzed pathway was explored in a subsequent report.52 As

illustrated in Scheme 41A, products 144 containing a tert-

butoxycarbonyl (Boc) protected amine engaged in 7-endo-dig

cyclizations when exposed to trifluoroacetic acid, which, when

refluxed in acetonitrile provided azepines 145 in 82–97% yield.

Additionally, allenic materials could be heated in a sealed tube

in the presence of 2-aminothiazole to provide pyrimidone

products 146 in good yields (50–87%; Scheme 41B). Both

methodologies utilize the allenic ester moiety regenerated from

the amine-catalyzed reaction for further bond constructions.

3.3 Additions to imines with achiral amine catalysts

Another common substrate class compatible with amine

catalysis of allenoates are Ts-imines, as reported by Shi and

co-workers.53 In these cases, product formation was found toScheme 38 Amine-catalyzed coupling of a,b-unsaturated carbonyl

compounds.

Scheme 39 Divergent catalysis of phosphines and amines in allenoate

couplings with enones.

Scheme 40 Amine-catalyzed three-component couplings between

acrylate 141, allenoate 1a and aldehydes 112.

Scheme 41 Azepine (145) and pyrimidone (146) synthesis from

allenoates.

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be dependent on the nature of the amine Lewis base employed.

When 1a and 77 are subjected to catalytic DABCO (10 mol%),

azetidines 147 are formed in moderate to high yields (42–99%;

Scheme 42). Alternatively, when the same substrates are

subjected to DMAP as the substoichiometric Lewis base

promoter, dihydropyridines 148 are formed in moderate to

good yields (30–60%). Neither DBU nor Et3N provide any

reactivity in the couplings. The authors note that the inclusion

of 4 A molecular sieves was pertinent in obtaining high yields

of azetidine products.

The proposed mechanisms for the syntheses of 147 and 148

begin with formation of the zwitterionic allenoate–catalyst

adduct 149 analogous to phosphine-catalyzed reactions

(Scheme 43). When DABCO serves as the amine Lewis base,

g-addition to the imine provides intermediate 150 which

undergoes intramolecular ring closure to give enolate 151.

Elimination and regeneration of the amine catalyst then gives

the azetidine. Alternatively, when DMAP is employed in the

reaction, a-addition to the imine provides intermediate 152, in

which the resulting N-anion adds to another equivalent of the

imine substrate providing 153. This is followed by a proton

transfer step providing a carbanion (154) which then adds in

an intramolecular fashion to the vinyl ammonium moiety

furnishing 155. Proton transfer to give 156 and catalyst

extrusion are followed by the elimination of TsNH2 providing

the observed product. The differences between DABCO and

DMAP in these cases are intriguing but presently not well

understood.

Shi then reported an amine-catalyzed tandem reaction

sequence.54 Salicyl Ts-imine substrates (157) were transformed

into chromene products 158 in 59–95% yields (Scheme 44).

Although DABCO proved to be the most efficient Lewis base

of those screened in terms of yield, DMAP-catalyzed the

formation of the same product. DBU also provided the

product, albeit in low yield after a longer reaction time.

Phosphine catalysts only provided the [3 + 2]-cycloadducts

as may have been expected considering previous work by Lu

and co-workers (see Section 2.3).

3.4 Enantioselective additions to imines

Although the subfield of amine-catalyzed reactions of a-allenicesters is less explored than phosphine-promoted variants, a

variety of chiral, racemic products have been formed in this

manner. The successes of the studies discussed above allows

for the development of new chiral amine catalysts for use in

asymmetric variants of these, or new allenoate-coupling reactions.

In this vein, Miller and co-workers recently reported an

enantioselective coupling reaction of allenoates (1) with

imines (159) promoted by substoichiometric amine catalysts

(Scheme 45).55

As described previously, PPh3 promotes the cycloaddition

of Ts-protected imines with allenoates providing heterocycles,

160 (see Section 2.3). The catalysis is diverted to give addition

products 161, albeit in moderate yields, when the protecting

group on the imine is changed to an ethoxycarbonyl group. At

the onset of Miller’s study, it was found that pyridine catalyzes

the formation of 161 from analogous substrates regardless

of the protecting group on the imine substrate (e.g., Ts,

CO2Et, Bz). Notably, DMAP was not an efficient catalyst in

Scheme 42 Divergent behavior of DABCO and DMAP in couplings

with Ts-imines (77).

Scheme 43 Proposed mechanism for formation of azetidines (147)

and dihydropyridines (148).

Scheme 44 Amine-catalyzed transformation of salicyl Ts-imines

(157) to chromenes (158).

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this process, giving mostly decomposition of the allenoate and

low isolated yield of the desired addition product. The reaction

also proved sensitive to steric effects as 2-picoline provides a

significantly lower reaction rate than pyridine in the same

time period. Intriguingly, the alkylimidazole moiety in the

protected single-amino acid Boc-p-(methyl)-histidine provided

essentially no reactivity in the coupling reaction.

The methodology was then rendered into an asymmetric

process by incorporation of Boc-L-3-pyridylalanine (Pal) into

tetrameric peptide sequences as chiral surrogates for pyridine

(Scheme 46). This led to the identification of Boc-L-3-Pal-D-

Pro-Aib-L-Phe-NMe2 (162) as an effective chiral catalyst for

the coupling of N-acyl imines 163 with allenoate 1c providing

coupled products 164 in high yields (45–88%) and ee’s

(69–84%). In some cases, products could be obtained in near

optical purity (up to 97% ee) following a single recrystallization.

Interestingly, peptides with different stereochemical configurations

of the amino acid monomers that comprise 162 catalyze

significantly less enantioselective couplings. The peptide

sequence of 162 is thought to adopt a b-turn type II0 secondary

structure in solution in analogy to similar sequences studied in

the Miller laboratory.56

The scope of the allenic counterpart in these reactions was

then investigated. Phenyl ester 1g proved to be a highly

reactive substrate in the coupling reaction with imine 165

using 10 mol% 162. This was established in direct competition

experiments using one equivalent each of 1c, 1g, and 165 with

10 mol% 162 (Scheme 47A). Product 166 (1g–165 coupling)

was formed as the major product in a 5.5 : 1 ratio with 167

(1c–165 coupling) at room temperature (7.7 : 1, 166 : 167 at 0 1C).

This finding enabled coupling reactions with 1g to proceed

smoothly at 0 1C with a variety of imine substrates providing

phenyl ester products 168 in good yields (42–67%) and high

ee’s (up to 89%; Scheme 47B).

4. Conclusions

The field encompassing Lewis base-catalyzed reactions of

allenoates remains a fertile ground for new discoveries.

As presented in this review, structurally distinct molecular

frameworks ranging from carbocycles and heterocycles

to natural product scaffolds are assembled rapidly through

reactions of a-allenic esters and suitable coupling partners.

Minor variations to the allenoate, Lewis base, and/or coupling

partner often lead to drastic changes in the reaction outcome.

Phosphine and amine catalysts have shown markedly different

behavior in these processes. The underlying mechanistic

implications for this divergency remains the basis of intense

research. Further study of this area should provide the

synthetic community with new methods involving allenoate

couplings. Additionally, the development of chiral Lewis bases

for enantioselective processes with allenoates is emerging as an

exciting platform in asymmetric catalysis.

Acknowledgements

We are grateful to our colleagues in this area noted throughout

the references for their fine contributions to this field. We wish

to thank the US National Science Foundation (CHE-0848224)

for support of our laboratory’s work in this area.

Notes and references

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3 For reviews of Lewis base catalysis with phosphines, see:(a) L.-W. Ye, J. Zhou and Y. Tang, Chem. Soc. Rev., 2008, 37,1140; (b) J. L. Methot and W. R. Roush, Adv. Synth. Catal., 2004,346, 1035; (c) X. Lu, C. Zhang and Z. Xu, Acc. Chem. Res., 2001,34, 535.

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Scheme 45 Phosphine and amine-catalyzed reactions of allenoates (1)

with imines (159).

Scheme 46 Peptide-catalyzed enantioselective N-acyl imine (163)

coupling.

Scheme 47 Allenic phenyl ester 1g in enantioselective couplings with

N-acyl imines.

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3116 | Chem. Soc. Rev., 2009, 38, 3102–3116 This journal is �c The Royal Society of Chemistry 2009

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