privileged scaffolds in synthesis: 2,5-piperazinediones as templates for the preparation of...

6902 Chem. Soc. Rev., 2012, 41, 6902–6915 This journal is c The Royal Society of Chemistry 2012

Cite this: Chem. Soc. Rev., 2012, 41, 6902–6915

Privileged scaffolds in synthesis: 2,5-piperazinediones as templates for the

preparation of structurally diverse heterocycles

Juan F. Gonzalez, Irene Ortın, Elena de la Cuesta and J. Carlos Menendez*

Received 25th April 2012

DOI: 10.1039/c2cs35158g

2,5-Piperazinediones (2,5-diketopiperazines, DKPs) can be viewed as privileged building blocks

for the synthesis of heterocyclic systems. This tutorial review aims at underscoring the large

number and structural variety of nitrogen heterocycles that are available by suitable manipulation

of DKP starting materials, including many bioactive compounds and natural products.

1. Introduction

Privileged structures, which can be defined as single molecular

frameworks able to provide ligands for diverse receptors,

are a powerful and effective tool used in Medicinal Chemistry

for the discovery of novel biologically active molecules.1 We

propose that this concept can be extended to the field of

Organic Synthesis, where certain types of molecules can be

considered as ideally poised to provide access to structurally

varied frameworks. These molecules are, therefore, ideal starting

materials for synthesis.

The use of small molecules to regulate protein activity by

direct interaction is a powerful tool for the study of biological

systems. Traditionally, biological systems have been studied

by genetic approaches based on the generation of random

mutations, followed by screening in search for a specific

phenotype. An alternative approach, large collections of small

molecules can be employed to study the roles of specific

proteins in biological pathways. This ‘‘chemical genetic’’

approach depends on the ability of synthetic chemistry to

provide rapid access to structurally diverse and complex small

molecules which, in a more general context, is essential for the

generation of new hit and lead compounds to aid the process

of discovery of new bioactive compounds in the pharmaceu-

tical and agrochemical industries. These needs have led to the

development of a new synthetic philosophy called diversity-

oriented synthesis (DOS), which differs from the usual target-

oriented synthesis in that its focus is on the generation of

maximum structural diversity and complexity in the minimum

number of steps. Simple, polyfunctional molecules are ideal

starting materials for synthesis and are particularly important

in diversity-oriented synthesis (DOS), which aims at providing

Departamento de Quımica Organica y Farmaceutica, Facultad deFarmacia, Universidad Complutense, 28040 Madrid, Spain.E-mail: [email protected]; Fax: +34 91 3941822;Tel: +34 91 3941840

Juan F. Gonzalez

Juan F. Gonzalez grew up inSalamanca (Spain). Heobtained a degree in Chemistryat Universidad de Salamancaand a PhD at the Departmentof Organic and MedicinalChemistry at UniversidadComplutense (UCM), underthe supervision of CarmenAvendano, in 2005. He thenworked as a PostdoctoralFellow at Strathclyde Univer-sity (UK) with William J.Kerr (2007–2008), afterwhich he joined the School ofPharmacy in UCM as an

academic staff member. He is currently a member of theMenendez group, doing research on the use of multicomponentreactions to obtain novel heterocyclic compounds, aimed atdiversity-oriented synthesis and medicinal chemistry.

Irene Ortın

Irene Ortın grew up in Madrid(Spain), and obtained adegree in Pharmacy at Univer-sidad Complutense, Madrid(UCM). She earned her PhDat the Department of Organicand Medicinal Chemistry atthe School of Pharmacy inUCM in 2010, working onthe total synthesis of saframycinand analogues under the super-vision of Carmen Avendanoand Elena de la Cuesta.She spent some months as avisiting scientist in the labora-tory of Dr A. Ganesan, at

Southampton University (2008). Currently, she is working asa Postdoctoral Marie-Curie Fellow in the Darren Dixongroup at Oxford University (UK), working on bifunctionalorganocatalysis.

Chem Soc Rev Dynamic Article Links

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This journal is c The Royal Society of Chemistry 2012 Chem. Soc. Rev., 2012, 41, 6902–6915 6903

quick access to libraries of molecules with an emphasis on

skeletal diversity.2

The purpose of this tutorial review is to show that 2,5-

piperazinediones (2,5-diketopiperazines, DKPs) can be con-

sidered as privileged starting materials for the preparation of

heterocycles. This is a key field of Organic Synthesis, since

heterocycles are essential materials in the functioning of any

developed society,3 and in particular in the search for new

bioactive compounds since they provide about 60% of

compounds in use or in the pipeline of the pharmaceutical

and agrochemical industries, among others.

DKPs are the simplest cyclic peptides, consisting of two

amino acids, and can be easily obtained in enantiomerically

pure form by a variety of methods.4 Despite their simplicity,

their combination of chirality and high functional density

renders them attractive synthetic starting materials. The

applications of DKPs to the synthesis of some specific hetero-

cyclic systems have been reviewed, although not recently,5–8

and a rather dated general overview of the reactivity of

2,5-piperazinediones is also available.9

2. Synthetic methods involving reactions at DKP

carbonyls

We will first discuss the preparation of heterocyclic systems

through manipulation of DKP systems based on the reactivity

of their carbonyl groups. The main challenge in this type of

transformations normally lies in the need to distinguish both

carbonyl groups in order to achieve regioselective transformations.

2.1. Reactions involving nucleophilic attacks onto DKP

carbonyls

Cleavage of the DKP ring via hydrolysis or alcoholysis is

normally performed under acidic conditions. This cleavage

can be achieved in a regioselective fashion if both lactam units

in the piperazinedione ring can be differentiated, and this has

led to interesting synthetic applications. Thus, it has been

recently reported that compounds 2, readily available from an

aldol-type reaction between o-nitrobenzaldehydes and N,N0-

diacetyl-2,5 diketopiperazinediones 1, can be efficiently trans-

formed into homochiral o-nitroaryl pyruvylamino esters 3 by

acid-promoted alcoholysis, both under conventional and

microwave-assisted conditions. The side chain of these inter-

mediates was transformed into an indole ring by reductive

cyclization to yield compounds 4, whose N-(indole-2-carbonyl)

substituent makes them interesting as potential components of

peptidomimetics (Scheme 1).10

Interestingly, compounds 5, the regioisomers of 3 bearing

the nitro group at the m- or p-positions, afforded excellent

yields of para- or meta-2,6-diazacyclophanes (6a,b) when

their catalytic hydrogenation was performed under high

dilution conditions and using ethyl acetate as solvent

(Scheme 2).11

Another way to achieve regioselectivity in the cleavage of

the diketopiperazine ring is based on the differentiation of the

two carbonyls by transformation of one of them into an imide.

For instance, compound 7 could be opened both by N- and

O-nucleophiles to give the chiral peptidic pyrrolidines 8, with-

out any racemization being detected (Scheme 3).12

The electrophilic character of the carbonyl group of the

DKP rings has also been exploited for the synthesis of

compounds containing the pyrazino[2,1-b]quinazoline frame-

work, including several natural products. The quinazoline

moieties in these compounds were prepared from 1,3-dialkyl-

N-(o-azidobenzoyl)piperazine-2,5-diones 9 via sequential

Staudinger/intramolecular aza-Wittig reactions. These trans-

formations were performed under thermal conditions by

treating compounds 9 with tributylphosphine, yielding moderate

Elena de la Cuesta

Elena de la Cuesta Eloseguiwas born in San Sebastian(Spain) in 1953. She studiedPharmacy at UniversidadComplutense in Madrid(UCM), where she obtainedher degree in 1975 and herPhD in 1981 under theguidance of Professor PalomaBallesteros. After postdoctoralstays at the Junta de EnergıaNuclear (Division deIsotopos), in Madrid, withDr Barrachina, and EcolePolytechnique, Palaiseau, withProfessor Francois Mathey,

she joined the Department of Organic and PharmaceuticalChemistry at UCM, where she was promoted to ProfessorTitular in 1984 and to Full Professor in 2010. Her currentinterests are in the area of the synthesis of heterocyclic naturalproduct analogues with potential biological activity.

J. Carlos Menendez

Jose Carlos Menendez wasborn in Madrid and obtaineddegrees in Pharmacy andChemistry, followed by aPh. D. in Pharmacy fromUCM. After a postdoctoralstay at the group of ProfessorSteven Ley at ImperialCollege, he returned as aProfessor Titular to theOrganic and MedicinalChemistry Department atUCM, where he has pursuedhis career ever since, havingobtained recently (2010) hisAccreditation as a Full

Professor. His research interests deal mostly with syntheticwork related to the development of new antitumour drugs andligands of prion protein. Other projects pursued in his groupplace emphasis on the development of new synthetic methodo-logy, including work on CAN as a catalyst for synthesis and onnew domino and multicomponent reactions for the preparationof biologically relevant compounds. He is a CorrespondingMember of the Spanish Royal Academy of Pharmacy and hasbeen a Visiting Professor at Aix-Marseille III University.

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to good yields of the heterocyclic compounds 10, which included

some natural products such as ent-fumiquinazoline G (Scheme 4a).7

This reaction was also employed by Danishefsky to transform

the fused DKP 11 into ardeemin 12, a natural MDR reversor,13

as shown in Scheme 4b.

2.2. Synthetic sequences initiated by the formation of DKP

lactim ethers

The generation of iminoethers derived from DKPs has been

used to enhance the electrophilic properties of their carbonyl

groups. For example, treatment of 13 with triethyloxonium

tetrafluoroborate (Meerwein’s salt) afforded lactim ether 14,

whose Von Niementowsky-type cyclocondensation with

anthranilic acid at high temperature afforded the hexacyclic

compound 15, closely related to the ardeemins (Scheme 5a).14

The step leading to the quinazolidinone ring was subsequently

shown to be improved under microwave irradiation condi-

tions. This protocol was employed to generate a variety of

heterocyclic frameworks as exemplified in Scheme 5b by the

synthesis of pentacyclic compound 17, which arises from a

double cyclocondensation.15 Not unexpectedly, when the

starting diketopiperazine had two lactam units it was not

possible to achieve regioselectivity at the lactim ether

formation stage, even when employing the more hindered

O-tert-butylsilyl lactim ethers.16

DKP lactim ethers are also obvious precursors for the

preparation of pyrazine natural products including methoxy-

pyrazines (MP) and asymmetric mono- and disubstituted

pyrazines such as 2-isobutyl-3-methoxypyrazine (IBMP),

2-isopropyl-3-methoxy pyrazine (IPMP), 2-sec-butyl-3-

methoxypyrazine (SBMP) and 2-isobutyl-3-methoxypyrazine

(IBMP), which are of interest because they have been identi-

fied in a wide range of materials from vegetal origin and, in

particular, are known to be responsible for the green, herbac-

eous, or vegetative characteristic aromas of Sauvignon blanc

Scheme 2 Preparation of 2,6-diazacyclophanes from ring-opening

products of DKPs.

Scheme 3 Regioselective opening of a N-carbamoylated DKP.

Scheme 4 Synthesis of pyrazino[2,1-b]quinazoline frameworks using

intramolecular aza-Wittig reactions from DKPs.

Scheme 1 Synthesis of 2-acylindoles from 3-arylmethylene-2,5-

diketopiperazines.

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and Cabernet Sauvignon wines. Several syntheses of methoxy-

pyrazines using as starting materials DKPs or related com-

pounds have been described in the literature.17 In the same line,

an elegant synthesis-guided structure revision of the sarcodonin

natural product family has been reported, involving the con-

struction of a hydroxypyrazine from a DKP.18

2.3. Synthetic methods involving the reduction of DKP

carbonyl groups

Piperazine structural fragments are present in a surprisingly

large number of pharmacologically active compounds, and

bridged bicyclic piperazine structures are also found in natural

and synthetic bioactive compounds. These considerations have

made the development of synthetic methodologies to obtain

conformationally fixed piperazine analogues an attractive

goal. In many cases, these compounds have been prepared

by reduction of the carbonyl groups of DKP derivatives to

methylenes, normally using lithium aluminium hydride. One

example of this strategy is shown in Scheme 6, which exem-

plifies the preparation of derivatives of the 6,8-diazabicyclo-

[3.2.2]nonane, which were of interest as high-affinity ligands of

the s receptor. Compound 18 was prepared in five steps from

(S)-glutamic acid and cyclized by a Dieckmann reaction with

LiHMDS as base, involving trapping of the intermediate with

chlorotrimethylsilane to form stereoselectively the mixed

methyl/silyl acetal 19 to shift the equilibria towards the

formation of the bicyclic system. An exchange of protecting

group via intermediate ketone 20 followed by lithium aluminium

hydride reduction and deprotection afforded the target com-

pound 21 (Scheme 6).19 A similar route allowed the prepara-

tion of 7,9-diazabicyclo[4.2.2]decanes.20,21

Several natural products contain a 14-membered para- and

meta-cyclophane diaryl ether structural subunit. A recent

formal synthesis of the antifungal antibiotic piperazinomycin,

the simplest of these compounds, relies on the full reduction of

a 2,5-piperazinedione. As shown in Scheme 7, compound 23

was prepared from 22 via an intramolecular O-arylation of a

phenol with an arylboronic acid, and was subsequently trans-

formed into the natural product 24 using a previously reported

reduction with borane, followed by O-demethylation.22

Many other relevant compounds have been obtained by

complete reduction of both carbonyl groups in suitable diketo-

piperazine precursors. Among them, we will mention as

illustrative examples the chiral tertiary amines 25, developed

as asymmetric catalysts for the Baylis–Hillman reaction,23 and

also polycyclic compounds 26, which were prepared in the

course of a pharmacophore search for allosteric ligands of the

muscarinic M2 receptor24 (Scheme 8).

The reduction of the DKP carbonyl groups has been

observed to follow unexpected courses in some substrates.

One example is summarized in Scheme 9, which summarizes

the results obtained in the reaction of compound 27 with

lithium aluminium hydride, which was followed by N-Boc

protection of the crude to facilitate product isolation and

subsequent acid deprotection. While the reaction in ether

afforded solely the expected 7,10-diazabicyclo[4.2.2]dec-3-ene

Scheme 5 Synthesis of pyrazino[2,1-b]quinazolines by cycloconden-

sations of DKP lactim ethers with anthranilic acid.

Scheme 6 Synthesis of 6,8-diazabicyclo[3.2.2]nonanes based on the

Dieckmann cyclization of a DKP derivative.

Scheme 7 Total synthesis of the antibiotic piperazinomycin, includ-

ing the reduction of both carbonyls of a DKP by borane.

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derivative 28, it was found that it could be diverted towards

the generation of compound 29 as the major product by

changes in the reaction medium. This 1,2-bond migration of

the olefin-bearing bridge was proposed to be driven by relief of

ring strain in compounds 28, since they were found to be

highly strained in the solid state and showed atypical bond

angles in which the alkenyl, allylic, and bridgehead carbons

are in a planar orientation. The transformation of 28 into 29

was promoted by polar solvents and additives, being optimal

for the THF-HMPA combination, possibly because they

stabilize one or more relevant polar transition states.25

As shown in the previous examples, the usual reagents for

reducing the DKP carbonyls to methylenes are lithium alumi-

nium hydride or diborane. These very potent reducing agents

are not suitable for some types of substrates, such as those that

have structural moieties prone to hydrogenolysis. For these

cases, a milder method has been developed that involves the

transformation of the lactam moieties into thiolactams, which

allows the use of catalytic hydrogenation for the reduction

step. This thionation-hydrogenation protocol has been

employed to obtain compounds 32 from 30 without cleavage

of the bond between the benzylic carbon and the oxazolidi-

none oxygen atom to give 31. This was the only reaction

course observed upon treatment of 30 with lithium aluminium

hydride (Scheme 10).26

Selective activation of one of the lactam carbonyl groups as

an electrophile is possible via its partial reduction to an

hemiaminal followed by transformation of the latter into an

iminium species in the presence of acid. The best method to

achieve this selective reduction has been found to be based on

the activation of one of the carbonyls by its transformation

into a carbamate-derived imide, which allows its reduction to

an hemiaminal employing mild reagents such as sodium boro-

hydride under acidic conditions. Several nitrogen substituents,

including CO2Me, CO2iPr, CO2

tBu (Boc) and CO2CH2Ph

(Cbz), have been employed for this purpose.12 Similarly,

several acidic conditions have been employed to induce the

generation of an iminium cation at a subsequent stage.

A systematic study of the synthesis of 2,6-bridged piperazin-

3-ones based on the intramolecular trapping of theN-acyliminium

ions thus generated with p-nucleophilic groups contained in a

C-2 side chain has been published. Thus, selective reduction of

the DKP carbonyl belonging to a mixed imide system in

compound 33 afforded the unstable hemiaminal 34, whose

exposure to acid afforded the bridged compounds 36, pre-

sumably via the acyliminium intermediates 35 (Scheme 11).27

This type of chemistry has been widely employed for the

construction of the bridge in the framework of tetrahydro-

isoquinoline alkaloids of the saframycin–ecteinascidin families,

which are very attractive synthetic targets because of their

antitumor and antimicrobial activities.28

In one case where the acyliminium-based approach failed,

the chemoselective reduction of one of the DKP carbonyls

could still be used to direct the desired cyclization. Thus,

the intermediate arising from the partial reduction of the

carbamate-activated DKP carbonyl in compound 37 was

subjected to elimination conditions that gave the cyclic

enamide 38. This sets the stage for an intramolecular Heck

reaction that afforded the tricyclic compound 39, which was

employed by Fukuyama as a key intermediate in his total

synthesis of the polycyclic antitumour marine alkaloid ectei-

nascidin 743 (Scheme 12).29

3. Syntheses of heterocycles involving reactions at

the DKP nitrogens

Synthetic routes that include the creation of a N–C bond at

one of the DKP nitrogens are very common and involve different

methodologies such as N-alkylation with alkyl halides or acetals,

metal-catalyzed cross coupling reaction with allenes and

Mannich reaction with amines in the presence of formaldehyde,

among others. In this Section, we will focus on reactions

Scheme 8 Other examples of the full reduction of DKP systems.

Scheme 9 Migration of the olefin-bearing bridge in the lithium

aluminium hydride reduction of bridged DKP 27.

Scheme 10 A thionation-hydrogenation protocol for the reduction of

a DKP without hydrogenolysis of a benzylic C–O bond.

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comprising an N-alkylation or arylation step and leading to

structurally diverse polyheterocycles containing DKP ring systems.

3.1. Methods involving alkylation at the DKP nitrogen

The pyrazino[1,2-b]isoquinoline-1,4-dione tricyclic core of

many tetrahydroisoquinoline antitumor antibiotics can be

readily accessed from readily available 1-acetyl-3-arylmethyl-

piperazine-2,5-diones 40, which are transformed into the

corresponding bis-(O-trimethylsilyl)lactims in order to increase

their N-nucleophilicity. Subsequent addition of aliphatic or

aromatic dialkyl acetals in the presence of trimethylsilyl triflate

as a Lewis acid gave 41 as a diastereoisomeric mixture, and

these intermediates, when exposed to p-toluenesulfonic acid,

afforded the tricyclic compounds 42 in good yields (Scheme 13).30

In subsequent work, a one-pot N-alkylation/cyclization pro-

cedure was developed that allowed the preparation of com-

pounds 42 from 40 in good yields, using trimethylsilyl triflate

as the promoter for both steps. However, the one-pot protocol

had the shortcoming that it required the use of stoichiometric

amounts of the expensive trimethylsilyl triflate.

In the course of related work, it was discovered that planned

Pictet–Spengler reactions of diketopiperazine 43 gave the

1,3-benzoxazepine derivative 45 instead of the expected fused

isoquinoline, presumably by attack of the ortho-methoxy

group onto the exocyclic N-acyliminium cation 44 followed

by O-demethylation and N-deacetylation (Scheme 14).31

(�)-Spirotryprostatin B (47) is a fungal metabolite with

antimitotic properties that has been a popular target for total

synthesis since its isolation from Aspergillus fumigatus.

Recently, Trost has disclosed a total synthesis of this alkaloid

having as the final step a cyclization that proceeded via a

trimethylaluminium-promoted allylic displacement of the

acetoxy group in compound 46 by a lactam nitrogen

(Scheme 15a).32 Overman’s total synthesis of the same natural

product involved a palladium-catalyzed domino process,

which was initiated by an intramolecular Heck reaction starting

from 48. The intermediate palladium-allyl species was intercepted

by the amide nitrogen under the same reaction conditions to

generate the spirotryprostatin framework (Scheme 15b).33

A total synthesis of tryprostatin B, a bioactive prenylindole

alkaloid related to the spirotriprostatins, involved an initial

domino process carried out in an aqueous buffer containing

magnesium nitrate that involved the intramolecular N-alkylation

of the DKP nitrogen of cyclo-(L-Trp-L-Pro) 51 with the

iminium cation generated in the C-3 alkylation of the pendant

indole ring by prenyl bromide. This reaction gave a mixture of

the pentacyclic compound 52 and the target tryprostatin B (54).

Scheme 11 Synthesis of complex heterocycles based on intra-

molecular cyclizations onto DKP-derived iminium cations.

Scheme 12 Construction of the ecteinascidin tricyclic bridged piperazine fragment from a DKP using an intramolecular Heck reaction.

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The overall yield of the route was improved by transforming 52

into the natural product. Thus, the prenyl side chain of 52 was

rearranged in the presence of trifluoroacetic acid to give com-

pound 53, which has the tryprostatin skeleton but lacks the prenyl

double bond due to its reaction with the acid. Hence, a final

elimination step by treatment of 53 with triethylamine was

required to reach tryprostatin B, which was obtained in a 32%

overall yield. Alternatively, the rearrangement could be carried out

directly, albeit in a lower overall yield, by exposure of compound

52 to ytterbium triflate, acting as a Lewis acid (Scheme 16).34 One

final point that deserves commentary is that, besides efficiently

providing the target natural product under very mild conditions,

this route suggests a possible biosynthetic pathway for the try-

prostatins, which is alternative to the previously accepted one.

3.2. Methods involving arylation at the DKP nitrogen

Several molecules containing a pyrazino[1,2-a]indole-1,4-

dione core have shown immunosuppressive and antimicrobial

activities, which has prompted interset in this ring system.

RajanBabu has developed a procedure for its synthesis based

on an intramolecular N-arylation reaction that gives access to

enantiopure tricyclic compounds 57 starting from diketo-

piperazines 55 and 56. These starting materials were in turn

prepared from cyclo-(L-Val-Gly) using Schollkopf methodo-

logy. The arylation step was based on the Fukuyama variation

of the Ullmann–Goldberg reaction and proceeded with iso-

merization of the starting material 55 (X = Br), but this did

not happen for the more hindered iodide 56 (Scheme 17a).

Piperazinedione formation and N-arylation can be achieved in

a one-pot procedure, as shown by the preparation of com-

pound 58 from the dipeptide precursor 57 (Scheme 17b).35

Buchwald conditions have also been applied to the synthesis

of fused heterocycles based on the N-arylation of DKPs. Thus,

Evano has obtained tetra-, penta- and heptacyclic compounds

(e.g. 60), in good yields and without any epimerization, from

diketopiperazines containing a 2-iodoindole pending side

chain (Scheme 18).36


the C-3 or C-6 DKP positions

4.1. Synthesis of diazabicyclic compounds

Simpkins has recently developed an entry into the malbran-

cheamide B and brevianamide B alkaloids, containing

Scheme 13 Trimethylsilyl triflate-promoted Pictet–Spengler reactions

between 3-arylmethyl DKPs and acetals.

Scheme 14 Deviation of a planned Pictet–Spengler reaction of a

3-arylmethylene DKP derivative towards the synthesis of fused 1,3-

benzoxazepines.

Scheme 15 Key steps of two total syntheses of (�)-spirotryprostatinB, based on: (a) an allylic displacement onto a DKP nitrogen; (b) a

domino Heck reaction/N-allylation process.

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2,5-diazabicyclo[2.2.2]octane structural fragments. In this

methodology, an acylimium cation was generated from diketo-

piperazines 61, using a hydroxy unit as a leaving group in the

presence of trimethylsilyl triflate. This triggered a cationic

domino process that involved trapping of the initial acyl-

iminium cation 62 by the prenyl side chain to give 63, which

was found to be in equilibrium with an alkene arising from its

deprotonation but was still able to react with the indole ring to

give an hexacyclic compound as a 4 : 1 mixture of diastereomers,

whose major component was 64a (Scheme 19). The minor

cyclization product (64b) was found to be a suitable precursor for

total syntheses of malbrancheamide B and ent-brevianamide B.37

The same ring system can be accessed by radical domino

reactions. Thus, Simpkins has reported that treatment of

precursor 65 with 10-azobis(cyclohexanecarbonitrile) (ACCN)

as a radical initiator and tributyltin hydride gives compound

66, identical to 64 except for the protecting groups and

which, in view of its stereochemistry, can be considered as

a good precursor to alkaloids of the stephacidin family

(Scheme 20).38

Olefins can also be used to trap the last intermediate of the

radical cascade, as shown recently in a synthesis of the

pentacylic core of the asperparalines, again by the Simpkins

group.39 In this case, a radical domino process was initiated by

addition of thiophenol to the triple bond in the acetylene-

substituted DKP 67 in the presence of AIBN to generate a

radical that then undergoes a 1,6-intramolecular hydrogen

shift leading to the captodative-stabilized species 68. This is

followed by a new radical addition to the side chain double

bond, and finally to the double bond of the maleimide unit

Scheme 16 Synthesis of tryprostatin B based on a domino C-alkylation/

N-alkylation process followed by a prenyl isomerization/aromatization.

Scheme 17 Synthesis of fused diketopiperazines by Ullmann–Goldberg

N-arylation reactions.

Scheme 18 An intramolecular Buchwald N-arylation for the synthesis

of a fused DKP system.

Scheme 19 Synthesis of a diastereomer of the malbrancheamide B

and ent-brevianamide B framework by an ionic cyclization.

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affording compound 69 in 30% yield after its separation from

a mixture of diastereomers (Scheme 21).

We will finally mention the use of a metal-mediated oxidative

coupling of an enolate to achieve the formation of the carbon

bridge joining the C-2 and C-5 DKP positions. This is illustrated

below by the synthesis of (�)-stephacidin A developed by Baran,

which involved treatment of the cyclo-(Pro-Trp) derivative 70

with LDA and iron acetylacetonate. This reaction led to a

carbon–carbon bond forming reaction that afforded bridged

compound 71. Standard functional group manipulation

furnished 72, which upon heating at 200 1C underwent a

thermal domino process initiated by a retro-ene reaction that

removed the tert-butyl moiety of the Boc protection as a molecule

of isobutylene to give a carbamic acid that spontaneously

decarboxylated to afford an indole derivative with a free NH.

Heating then induced a formal aza ene-type reaction with

participation of the indole N–H that generated an unstable

spiroindolenine, which finally underwent a thermal 1,2-shift that

led to stephacidin A in enantiomerically pure form (Scheme 22).40

4.2. Synthesis of spirodiketopiperazines

3-Ylidenepiperazine-2,5-diones are popular starting materials

to obtain heterospiro rings at the C-3 or C-6 positions of

DKPs. One example of the application of this strategy can be

found in the work of Chain, who has studied the 1,3-dipolar

cycloadditions of nitrile oxides to 3-ylidenepiperazine-2,5-

diones, acting as dipolarophiles, to give spiroisoxazolidines.

In all cases only one regioisomer was observed, and some of

the reactions proceeded with high diastereoselectivity, as in the

example shown in Scheme 23, which afforded compound 75 as

a single diastereoisomer from mesitonitrile oxide 73 and DKP

74 (Scheme 23).41


two positions of the DKP ring

Some types of pericyclic reactions, including hetero Diels–

Alder and 1,3-dipolar cycloaddition reactions, have allowed

the construction of complex heterocyclic systems by simulta-

neous generation of two bonds at non-adjacent positions of

DKP systems.

5.1. Aza Diels–Alder reactions

Some fungal metabolites such as versicolamide B, the para-

herquamides, brevianamides and marcfortines contain as a

common core a 2,5-diazabicyclo[2.2.2]octane system. Their

biosynthesis has been proposed to arise via an intramolecular

Diels–Alder cycloaddition of an azadiene derived from a DKP

ring and an isoprene moiety. This proposal has attracted

considerably the attention of synthetic chemists, aiming at

its confirmation by the development of synthetic routes to

these alkaloids that involved such [4 + 2] cycloadditions onto

DKP systems. Thus, in a preparatory study toward the total

synthesis of alkaloids of this group, Williams studied inter-

and intramolecular aza Diels–Alder cyclizations in the cyclo-

[Pro-Gly] DKP ring as a model system. In this work, an

azadiene 77 was generated by treatment of 5-hydroxypiper-

azine-2,5-dione 76 with Boc anhydride in the presence of

DMAP. Diels–Alder reactions of 77 with several dienophiles

were examined; for instance, its treatment with dimethyl

acetylenedicarboxylate at 80 1C afforded compound 78 in an

excellent yield (Scheme 24a).42

Scheerer studied similar Diels–Alder reactions on chiral

substrates. Compound 79, readily available from L-serine, was

Scheme 20 Access to polycyclic systems related to the stephacidin

alkaloids based on a radical domino process.

Scheme 21 Synthesis of the pentacyclic core of the asperparalines

based on a radical domino process.

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considered a good starting point for this study, since it was

envisioned that the presence of a chiral tert-butyl aminal

auxiliary should induce a strong facial bias during the cyclo-

addition. Displacement of the bromine substituent by the azide

anion followed by an intramolecular Staudinger/aza-Wittig

reaction afforded compound 80, which was dehydrogenated

to 81 in the presence of DDQ. The Diels–Alder reaction of 81

with N-phenylmaleimide in refluxing toluene proceeded

uneventfully and afforded compound 82 as a single diaster-

eomer. The cycloaddition took place on the face of the DKP

opposing the tert-butyl substituent and with full endo selectivity

(Scheme 24b).43

Intramolecular versions of the Diels–Alder reaction were

also examined. Compounds 83 were treated with trimethyl-

oxonium tetrafluoroborate to give the corresponding lactim

ethers, which were transformed into 84 by oxidation with

DDQ followed by tautomerization under basic conditions.

Finally, a spontaneous intramolecular Diels–Alder reaction

of 84 yielded the tetracyclic adducts 85 (Scheme 25).42 In

subsequent work, the Williams group used this strategy for

the total synthesis of a number of alkaloids. As a representa-

tive example, we show in Scheme 26 the final step of their

synthesis of (+)-versicolamide B.44

Liebscher and coworkers have developed an alternative

strategy for reaching the diazabicyclo[2.2.2]octane system,

which employs ylidenepiperazine-2,5-diones as azadiene pre-

cursors. Thus, treatment of compounds 86 with acetyl chloride

under high pressure or with refluxing formic acid afforded

intermediate azadienes, whose subsequent reaction with dieno-

philes led to adducts 87 (Scheme 27). One-pot procedures to

achieve this transformation were also investigated, and were

applied to the preparation of several complex polycyclic

structures containing diazabicyclo[2.2.2]octane cores via inter-

and intramolecular Diels–Alder reactions.45

Bicyclic adducts related to 85 have been identified as

suitable precursors to fused heterocyclic systems. Thus, the

5-chloropyrazin-2(1H)-one azadienes 88, prepared in several

Scheme 22 Creation of a carbon bridge joining the C-2 and C-5 DKP positions by metal-mediated oxidative coupling of an enolate in the course

of a total synthesis of stephacidin A.

Scheme 23 1,3-Dipolar cycloaddition of a nitrile N-oxide to the

exocyclic double bond of a 3-ylidenepiperazine-2,5-dione.

Scheme 24 Intermolecular aza Diels–Alder reactions on DKP-

derived scaffolds.

Scheme 25 Intermolecular aza Diels–Alder reactions on a cyclo-

[Pro-Gly] scaffold.

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steps from trisubstituted DKPs, afforded fused pyridinones 89

under thermal conditions, through a Diels–Alder/retro-Diels–

Alder sequence. In some cases, pyranopyridines 90, arising

from loss of a molecule of isocyanate from the bridged

intermediate, were also isolated (Scheme 28).46

5.2. Oxa Diels–Alder reactions

The a,b-unsaturated lactam moiety of 3-methylene-2,5-piper-

azinediones has been used as the diene component in hetero

Diels–Alder reactions, and this method has been employed as

the key step of a recent total synthesis of the fungal metabolite

variecolortide A. The structure of this complex alkaloid con-

tains an anthracene moiety fused to a pyrane framework,

which is in turn linked to a diketopiperazine, generating a

spirocyclic N,O acetal. The reaction of the natural products

hydroxyviocristin and isoechinulin A at high temperature

afforded variecolortide A (92) in one step, in a domino process

that was interpreted as a sequence of a 1,5-hydrogen shift to

give 91, a [4 + 2] hetero Diels–Alder reaction and a final air-

induced dehydrogenation (Scheme 29).47

The C2–C3 bond of DKPs has also been employed as the

dienophile in Diels–Alder chemistry, although this required

increasing its electron density by transformation of the lactam

groups into a lactim. This chemistry was applied in studies

towards a total synthesis of the sarcodonin family of natural

products, which has a rather uncommon benzodioxazine core.

Scheme 26 Synthesis of (+)-versicolamide B by an intramolecular

hetero Diels–Alder reaction.

Scheme 27 Generation of 2-azadienes from 3-arylmethylene-2,5-

piperazinediones and an example of a subsequent Diels–Alder reaction.

Scheme 28 Synthesis of fused pyridines by a Diels–Alder/retro Diels–

Alder sequence from 5-chloropyrazin-2(1H)-ones.

Scheme 29 Synthesis of variecolortide A via a 1,5-hydrogen shift/oxa

Diels–Alder/dehydrogenation sequence.

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The DKP derivative 93 was transformed into the electron-rich

dihydroxipiperazine 94 by a straightforward three-step

sequence involving the initial transformation of both lactam

units into lactim ethers by exposure of the starting material to

Meerwein’s salt, followed by aromatization in the presence

of DDQ and double O-demethylation with treatment with

trimethylsilyl iodide. The hetero Diels–Alder reaction between

this compound, acting as the dienophile, and o-benzoquinone,

generated in situ by IBX oxidation of catechol, afforded

compound 95; its oxime 96 was proposed as a revised structure

for the sarcodonin core (Scheme 30).18

5.3. 1,3-Dipolar cycloadditions

Recently, Avendano has reported an approach to the core

of the alkaloids quinocarcin and lemonomicin that relies on

1,3-dipolar cycloaddition reactions for the construction of the

five-membered ring inherent to these alkaloids. The aryl-

methylene DKP derivatives 97 were transformed into com-

pounds 98 using well-known Pictet–Spengler chemistry. The

chemoselective reduction of their C-1 carbonyl group to give

an hemiaminal was followed by dehydration under thermal

conditions to generate the azomethine ylides 99, which acted

as 1,3 dipoles towards a variety of electron-poor olefins and

alkynes and gave good yields of the tetracyclic adducts 100

and 101 as the major reaction products (Scheme 31).48

5.4. Generation of 2,5-epidithio bridges

The epipolythiodiketopiperazine (ETP) alkaloids constitute an

important class of fungal metabolites with promising bioactivities,

but progress on their synthesis has been relatively sluggish

because of their complexity and lability. This subject has been

recently reviewed,49 and for this reason we will deal with it

only briefly.

The most common method for introducing the epidithio

bridge into diketopiperazines involves the introduction of

mercapto groups at C-2 and C-5 followed by oxidation to a

disulfide. The required thiols are in turn available from bromo

derivatives, hemiaminals or their ethers under acidic condi-

tions, via intermediate acyliminium cations. This is illustrated

in Scheme 32 by the first total synthesis of chaetocin A, a

potent inhibitor of lysine-specific histone methyltransferases,

developed by Sodeoka.50 Exposure of diketopiperazine 102 to

N-bromosuccinimide at low temperature led to its bromo-

cyclization, affording compound 103. A subsequent radical

bromination using as an initiator 2,20-azobis(4-methoxy-2,4-

dimethylvaleronitrile), also known as V-70, provided an inter-

mediate tribromide, which was immediately transformed into

hemiaminal 104 by treatment with water. The application of a

cobalt-catalyzed reductive coupling led to dimeric compound

105, which was treated with condensed hydrogen disulfide in

the presence of boron trifluoride etherate. This reaction pre-

sumably proceeded via the acyliminium species 106 and

afforded a crude material containing four thiol groups at the

desired positions, whose oxidation with iodine led finally to

the natural product 107.

6. Syntheses of heterocycles based on DKP

rearrangement reactions

Some interesting ring systems have been constructed on the

basis of transannular ring rearrangements of 2,5-piperazine-

diones. Thus, ring contraction and ring contraction/alkylation

sequences have been developed that afford racemic and chiral

pyrrolidinediones 109 from simple DKPs 108 (Scheme 33a).51

A similar strategy was used for the preparation of tricyclic

Scheme 30 Structural revision of sarcodonin based on a hetero

Diels–Alder reaction.

Scheme 31 Construction of the tetracyclic nucleus of the tetrahydro-

quinoline alkaloids quinocarcin and lemonomicin via 1,3-dipolar

cycloadditions of azomethine ylides 99.

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fused systems 111 from fused piperazinediones 110, which

are closely related to the previously mentioned compounds 98

(Scheme 33b).52

Another rearrangement reaction played a key role in a total

synthesis of the alkaloid (+)-phakellin, allowing to establish

its quaternary stereocenter in an enantioselective fashion.

Compound 112, prepared from a DKP derived from 4-hydroxy-

L-proline, was used as the starting material for the preparation

of trichloroimidate 113. An enamide-type Overman rearrange-

ment afforded compound 114, which was then transformed

into the target natural product by straightforward manipula-

tion (Scheme 34).53

Conclusions

2,5-Piperazinediones (DKPs) are simple, readily available

cyclic dipeptides that have a high density of functional groups

and are therefore suitable substrates for carrying out a

plethora of reactions. In this review, we have striven to show

that DKPs are ideal starting materials for the generation of

structural diversity and complexity in the field of heterocyclic

compounds. We have underscored the broad possibilities

offered by these starting materials by describing their applica-

tion to synthesis of a many types of bioactive compounds,

including several families of alkaloids.

Notes and references

1 For a review, see: R. W. DeSimone, K. S. Currie, S. A. Mitchell,J. W. Darrow and D. A. Pippin, Comb. Chem. High ThroughputScreening, 2004, 7, 473.

2 R. J. Spandl, G. L. Thomas, M. Dıaz Gavilan, K. M. G. O’Connelland D. R. Spring, An Introduction to Diversity-Oriented Synthesis,in ‘‘Linker Strategies in Solid-Phase Organic Synthesis’’, ed. P. J. H.Scott, 2009, Wiley, p. 241.

3 For a monograph summarizing the importance of heterocyclesfrom a chemical perspective, see: A. F. Pozharskii, A. T.Soldatenkov and A. R. Katritzky, Heterocycles in life and society:An introduction to heterocyclic chemistry, biochemistry and applica-tions, John Wiley and Sons, 2nd edn, 2011.

4 For a review of the biological activity and synthesis of diketo-piperazines, see: M. B. Martins and I. Carvalho, Tetrahedron,2007, 63, 9923.

Scheme 32 Generation of an epidithio bridge during a total synthesis of chaetocin A.

Scheme 33 Synthesis of 2,4-pyrrolidinediones by base-promoted ring

contraction of 2,5-diketopiperazines.

Scheme 34 An Overman rearrangement as the key step in a total

synthesis of (+)-phakellin.

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