Studies towards complex bridged alkaloids: regio- and stereocontrolled enolate chemistry of 2,5-diketopiperazines

Available online at www.sciencedirect.com

Tetrahedron 64 (2008) 3713e3735

www.elsevier.com/locate/tet

Studies towards complex bridged alkaloids: regio- and

stereocontrolled enolate chemistry of 2,5-diketopiperazines

,y

*

Mark Pichowicz, Nigel S. Simpkins , Alexander J. Blake, Claire Wilson

School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, UK

Received 21 November 2007; received in revised form 22 January 2008; accepted 7 February 2008

Available online 9 February 2008

Abstract

The substitution of symmetrical N-protected diketopiperazines (DKPs) via enolate intermediates has been studied. The enolate reactions were

highly diastereocontrolled, leading to enantiopure DKP products if chiral amino acid precursors were employed, and giving racemic products,

starting with centrosymmetric DKPs, even when a chiral lithium amide base was used to generate the lithium enolate. With unsymmetrical DKPs

derived from proline and either alanine, phenylalanine or valine, the enolate substitution occurred with high regio- and stereoselectivity on the

proline residue. This enabled the synthesis of substituted DKPs that could be cyclised via cationic processes to give the bicyclo[2.2.2]diaza-

octane core structure present in paraherquamide and stephacidin natural products.

Keywords: Diketopiperazine; Cationic cyclisation; Stephacidin; Paraherquamide

1. Introduction

In parallel to these activities, the medicinal chemistry com-

munity has identiﬁed the DKP motif as a privileged structure

for drug development, including diversity-orientated synthesis,

and resin-bound and combinatorial library approaches.⁵This

chemistry has already unearthed diverse bioactive DKPs, for

example, as oxytocin antagonists, ligands for G-protein-cou-

pled receptors and as potential inhibitors of calpain.⁶The

role of small peptides, including DKPs, may be particularly

signiﬁcant in the latter area as these compounds have been

identiﬁed as important in bacterial quorum sensing and cross

talk.⁷

Finally, the DKP motif is proving to be versatile as a probe

for crystal engineering, for example, the propensity of DKPs

to form extended macromolecular arrays in the solid state en-

ables the predictable formation of planar or non-planar ‘tape’

structures.⁸

With this background it is clear that the development of

methods for the formation and selective manipulation of

DKPs is an important topic of considerable current interest.

We became interested in two closely related areas of DKP

chemistry that rely upon substitution of preformed DKPs using

metal enolates. In the ﬁrst project we wanted to explore the

chemistry of simple, symmetrical trans-disubstituted DKPs

The 2,5-diketopiperazine (DKP) motif has emerged as an

important core structure in natural product chemistry, medici-

nal chemistry and crystal engineering.¹Natural products that

incorporate DKPs range in complexity from cyclodipeptides

like brevianamide F (1), through members of the trypostatin

family, such as spirotryprostatin B (2), to the immensely com-

plex alkaloid stephacidin B (3).^2e4

The more complex members of these families pose signif-

icant synthetic challenges, and many research groups have

been interested in the development of new synthetic methods

and strategies to enable access to such compounds. In many

cases these efforts have been driven by the interesting biolog-

ical activities of the natural products, for example, the very po-

tent and selective, antitumour activities associated with the

stephacidins.

* Corresponding author.

E-mail address: n.simpkins@bham.ac.uk (N.S. Simpkins).

y

Present address: School of Chemistry, The University of Birmingham,

Edgbaston, Birmingham B15 2TT, UK.

doi:10.1016/j.tet.2008.02.020

3714

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

HO

N

O

H

N

H

O

NH

O

N

O

N

H

HN

H

N

H

N

O

H

N

O

+

N

O

OC

N

H

-

O

H

N

1 brevianamide F

2 spirotryprostatin B

3 stephacidin B

O

of general structure 4. These compounds are centrosymmetric

and so are potential substrates for asymmetric synthesis by

enantiotopic group differentiation, for example, enantioselec-

tive enolisation using a chiral lithium amide base.⁹In the

event, we also explored analogous enolate chemistry using

the enantiopure cis-disubstituted DKP series.

(i) LHMDS, THF, -78 °C

(ii) R-X

NP

P = paramethoxybenzyl

(PMB)

PN

R

O

7 >90% de

6

Scheme 1. Davies’ method for stereoselective alkylation of DKPs.

O

H

N

NP

R

and introducing substituents in a stepwise manner. Commer-

cially available glycine anhydride 8 was doubly protected to

give bis-PMB derivative 9, Scheme 2. Alkylation of this com-

pound to give 10 proved straightforward, although a subse-

quent second allylation provided only moderate yields of the

desired product 11a. A simple solution was to treat 9 with

2 equiv of base, followed by excess alkylating agent, which

immediately provided trans-diallylated DKP 11a in very

good yield, accompanied by only small quantities of tris-

and tetra-alkylated product, Scheme 2.

R

PN

R

O

4 P = protection

5 P = protection

In the second project we were interested in probing the re-

gio- and stereochemical outcome of enolisationesubstitution

of unsymmetrical DKPs incorporating proline, i.e., 5. The ob-

jective of this project was to make available intermediates that

could be further transformed towards complex natural product

targets (and analogues), such as the aforementioned

stephacidins.

Herein we describe the results of these studies, which have

uncovered some useful results that should ﬁnd signiﬁcant fu-

ture application in the synthesis of highly substituted DKPs.

This proved to be a rather convenient method to access

these compounds and three other members of the family

were also prepared by this one-pot procedure. This process

must involve sequential enolisationesubstitution steps, since

a bis-enolate would have anti-aromatic character.

As expected from the precedent set by the Davies work,¹⁰

we obtained only the trans-disubstituted products, despite the

less encumbered nature of the intermediates in the case of

2. Result and discussion

i

11aec, compared to the established Pr substituted system.

Although the stereochemistry of 11aed was expected to be

2.1. Synthesis and substitution of symmetrically substituted

DKPs

1

as shown, we secured these assignments by comparison of H

NMR data with the much better known cis-isomers (vide in-

fra), and also obtained an X-ray structure determination for

bis-allyl DKP 11a, Figure 1.

The structure conﬁrms our assignment and also shows the

highly symmetrical pattern of nitrogen and carbon substituents

that occupy positions alternately above and below the planar-

ised DKP ring.

With a selection of trans-substituted DKPs available we

then set about testing them in enolate alkylation chemistry.

In contemporaneous studies with the corresponding cis-

DKPs (vide infra), we established that the usual lithium bases,

including LDA and LHMDS, were ineffectual for this type of

enolisation. In all cases, quenching with a range of electro-

philes, including attempted deuterium incorporation using

D₂O, MeOD or AcOD, gave only recovered starting material.

In fact, for 11d, which has a bulky ⁱPr group (and also a PMB

substituent) on each face of the DKP ring, we were unable to

ﬁnd conditions for effective enolate formation, even using very

For the synthesis of symmetrical trans-disubstituted DKPs

4 we ﬁrst considered access by cyclisation of a stereodeﬁned

dipeptide or via equilibration of the, much better known, cis-

substituted DKPs. Neither of these approaches appeared at-

tractive, due to either the longwinded nature of the synthesis

or the difﬁculties of separating mixtures of cis and trans iso-

mers. Instead, we chose to prepare the desired compounds

by alkylation of the parent cyclo[GlyeGly] in appropriately

N-protected form. This part of our work was inﬂuenced by

the ﬁndings of Davies and co-workers, who had shown that

the cyclo[ValeGly] derivative 6 underwent highly trans-selec-

tive enolate substitution reactions to give 7, Scheme 1.¹⁰

The high levels of diastereocontrol achieved were shown to

be due to a relay effect that depended on the use of bulky

benzyl type protection (especially N-PMB) on the ring nitro-

gen atoms. We expected that analogous chemistry would be

possible, starting from a doubly protected cyclo[GlyeGly]

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

3715

O

(i) LHMDS (1 equiv)

THF, -10 °C

(ii) allyl bromide

NPMB

PMBN

O

NH

NaH, PMBCl

DMF, 0 °C

NPMB

10 67%

HN

PMBN

O

(i) LHMDS (2 equiv)

R

NPMB

R

THF, -10 °C

(ii) R-X (excess)

-78 °C to RT

PMBN

9 90%

8

O

11a R = allyl 75%

11b R = benzyl 60%

11c R = Et 32%

11d R = i-Pr 53%

Scheme 2. A convenient access to symmetrical trans-disubstituted DKPs.

lithium enolate.^10bThis problem was solved by swapping to

the corresponding potassium enolates. In our case it appears

that enolate formation is the problematic step and that the

use of a bis-lithium amide, which is probably less aggregated

(and so more reactive) than a normal lithium amide, is

uniquely effective. In each case only a single diastereomer

was isolated, the assignments initially being based mainly on

the precedent shown in Scheme 1, although further evidence

was garnered later on (vide infra).

The alkylation of DKPs 11aec was then attempted using

a number of chiral bases, including 14e17, and also by use

of the s-BuLiesparteine combination.

Figure 1. X-ray structure of DKP 11a. Atoms bearing the sufﬁx A are related

to their unsufﬁxed equivalents by the symmetry operation (1ex, 1ey, 1ez).

strong bases such as NaH or n-BuLi. We then discovered that

the simple bis-lithium amide base 12 enabled reasonably efﬁ-

cient substitution of 11aec, Table 1.

Ph

N

Ph

N

Me

Me Me

Me

Ph

Me

Ph

Me

Ph

N

Li

Ph

N

Li

X

These studies were not fully optimised, since our objective

was to effect an asymmetric variant of this type of reaction by

means of a chiral base. The origins of the unique effectiveness

of the bis-lithium amide base in these reactions (and in many

others, vide infra), compared to ordinary lithium amides, are

not entirely clear. Davies also recently reported difﬁculties

with the use of lithium bases for substitutions of disubstituted

DKPs but this was ascribed to poor reactivity of the hindered

14

15

16 X = H

17 X = Li

As found using achiral bases, no effective substitution

could be achieved with simple (mono) lithium amides 14e16.

In contrast, the bis-lithium amide base 17 delivered high yields

of alkylation product, for example, benzylation of 11a gave

13a in 90% yield, but the enantiomeric excess of this product

was shown to be only 8%. The antipode of base 17 gave the

same level of induction but in the opposite sense.

This was a great disappointment to us and it did not prove

possible to achieve higher levels of induction using any of the

DKPs 11aec, or by using additives (like LiCl)¹¹or by in situ

trapping procedures with carbon or silicon electrophiles

(Me₃SiCl trapping did not give a stable product). Similarly,

the s-BuLiesparteine reagent gave only racemic material

from attempted desymmetrisations of DKPs.

At this point we had to abandon our efforts to effect a novel

asymmetric synthesis using chiral bases. However, we had

demonstrated highly diastereoselective access to DKPs with

structures 13aeg and it became clear that some of these types

of compound were potentially of further interest, and that

some could undergo additional useful transformation, for

Table 1

Alkylation of DKPs 11 to give 13 as racemates

O

(i)

R

BnN

Li

NBn

Li

12

NPMB

R

PMBN

R¹

R

THF, -78 °C

(ii) R¹-X

O

11

rac-13

Starting DKP

R

R¹eX

Product DKP

Yield (%)

11a

11b

11c

Allyl

Bn

BnBr

EtI

13a

13b

13c

13d

13e

13f

76

41

49

69

37

61

72

PhSSPh

Allyl Br

EtI

Bn

PhSSPh

BnBr

Et

13g

3716

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

Table 2

Alkylation of DKPs 22a and 22b to give 13 in enantiomerically pure form

example, ring-closing metathesis of 13a gave bridged DKP 18

in good yield, Scheme 3.¹²

O

(i)

R

BnN

Li

NBn

Li

12

NPMB

R

O

PMBN

R¹

R

THF, -78 °C

NPMB

Grubbs' type II Ru

toluene, 70 °C

O

PMBN

O

PMBN

(ii) R¹-X

O

Bn

N

PMB

O

Ph

22

13

R¹eX

Product DKP

Yield (%)

rac-13a

18 92%

Starting DKP

R

22a

22c

a

Bn

Me

Allyl Br

EtI

13d

13e

13f

91

99

96^a

98

84

47

81

91

76

91

Scheme 3. Metathesis route to a bridged DKP.

PhSSPh

PhCHO

NCCO₂Et

Allyl Br

EtI

At this stage it appeared worthwhile to establish access to

compounds of generic formula 13 by the chiral pool approach,

starting from readily available amino acid precursors. Starting

from the proteinogenic amino acids, this approach places

obvious limitations on the starting substituents R in 13 but

should furnish useful DKP building blocks.

We probed this idea in a limited way, starting from enantio-

merically pure DKPs prepared in a conventional fashion,

Scheme 4.¹³

13h

13i

13j

13k

13l

PhSSPh

NCCO₂Et

MeI

13m

13n

13o

BnBr

Product formed as 1:1 mixture of diastereomers at new carbinol centre.

Both the intermediates N-Boc dipeptides 21 and the NeH

DKPs corresponding to 22 (not shown) are well known

for these series of compunds, and the ﬁnal protected DKPs

22 were quite distinct from the trans-substituted counterparts

11 prepared previously.¹⁴The ﬁnal protection was best

carried out by slow addition of a suspension NaH in DMF

to a mixture of NeH DKP and 4-methoxybenzyl chloride.

In our hands, this method proved more effective than the pub-

lished protocol for avoiding DKP epimerisation to give the

trans-compounds.¹⁵In the case of 22b we also checked for

any sign of racemisation during N-protection by deprotecting

using ceric ammonium nitrate, which furnished a sample

of NeH DKP with the identical speciﬁc rotation as seen

initially.

In subsequent enolisation chemistry we found that the va-

line derived DKP 22b, rather like the trans-isomer 11d, would

not undergo effective deprotonationesubstitution using a num-

ber of bases, including LDA, LHMDS, LiH, MeLi, n-BuLi and

base 12. We focused instead on the alanine and phenylalanine

derived systems and found that either n-BuLi or base 12 gave

the expected products. Alkylationesubstitution chemistry was

then carried out using these two DKPs and a range of electro-

philes, Table 2.

the excellent yields seen for alkylation, sulfenylation, aldol

and acylation for this compound. As before, we observed for-

mation of only a single diastereomer in each case, which is to

be expected since both series of reactions proceed via the same

enolate (albeit racemic for Table 1 and enantiomerically pure

for Table 2).

Initially, reactions of the alanine derived DKP 22c proved

problematic due to the formation of over-alkylated DKP by-

products, along with starting DKP. At ﬁrst sight this outcome

might appear as a consequence of using a bis-lithium amide

(and thus excess base), but the use of less base simply resulted

in the recovery of larger quantities of starting DKP. We pro-

posed that the problem was due to intermolecular proton

exchange between ﬁrst alkylated DKP and the enolate of the

starting DKP (perhaps within an aggregate). The more highly

substituted DKP enolate would be expected to be less aggre-

gated than the parent, and so more reactive in alkylations.

This problem was alleviated by running the reactions with

22c substantially more dilute (with respect to DKP) than the

other systems, and increasing the equivalents of available

alkylating agent.

Chiral ylidenepiperazine diones are intermediates of estab-

lished synthetic utility, since they undergo a range of stereo-

controlled addition reactions to give DKPs.¹⁶Since we had

prepared two sulfur substituted DKPs, 13f and 13l, we chose

Enolate reactions of the phenylalanine derived DKP 22a

were optimised compared to the rather preliminary studies

of the corresponding trans-DKP 11b, which is reﬂected in

R

O

(i) HCO₂H

HCl-H₂N

+

CO₂Me

CO₂H

R

EDCI, Et₃N

CH₂Cl₂, 0 °C

(ii) 2-butanol-toluene

reflux

H

N

19

NPMB

R

CO₂Me

BocHN

PMBN

(iii) NaH, PMBCl

DMF, 0 °C

R

O

R

O

BocHN

20

21a R = Bn (86%)

21b R = i-Pr (81%)

21c R = Me (88%)

22a R = Bn (42%)

22b R = i-Pr (37%)

22c R = Me (46%)

Scheme 4. Synthesis of enantiopure DKPs.

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

3717

to convert these into the corresponding ylidene systems via

sulfoxide syn-elimination, Scheme 5.

properties). These aspects have been probed over many years,

most notably by the Williams group, who have achieved sev-

eral total syntheses of the natural products and have also pro-

vided much detailed evidence for the biosynthesis.¹⁸

R

O

(i) mCPBA, NaHCO₃(aq)

(ii) toluene reflux

NPMB

SPh

NPMB

R

Recent additions to these families of compounds are the

aforementioned stephacidin B (3) and stephacidin A (26), po-

tent antitumour compounds produced by Aspergillus ochra-

ceus WC76466.⁴Total syntheses of stephacidins have been

described by the groups of Baran, Meyers and Williams, and

stephacidin A (26) has been demonstrated to be a viable pre-

cursor for the aforementioned stephacidin B (3) via the related

compound, avrainvillamide.^19e21Only following this syn-

thetic work, the absolute conﬁguration of the stephacidins

was assigned with certainty, the naturally occurring com-

pounds having the structures shown herein.

The biosynthetic origin of many of these compounds ap-

pears to involve modiﬁcation of brevianamide F 1 by indole

reverse-prenylation, and a subsequent intramolecular Dielse

Alder cycloaddition of the pendant prenyl group onto an

aza-diene generated by oxidation of the core diketopiperazine

(DKP). Some aspects of the proposed biosynthesis have been

realised by Williams and co-workers in their synthetic endeav-

ours.^18d,eWe became interested in an alternative access to this

type of bridged structure, which would also originate from

a simple DKP starting material, which is outlined in Scheme 6.

Following the aforementioned clariﬁcation of absolute ste-

reochemistry for the stephacidins, our proposed synthesis

would require ^D-proline, or some derived DKP, such as ent-

brevianamide F, as starting material.²²According to this

plan, regioselective enolate formation and substitution would

be employed to convert 1 (in suitably protected form) into

27, where X is a heteroatom group appropriate for the

formation of an N-acyliminium-type of cationic reactive

PMBN

O

R

13l R = H

13f R = Ph

23a R = H 70%

23b R = Ph 97%

Scheme 5. Synthesis of enantiopure ylidenepiperazine diones.

The phenylalanine derived system 23b was formed as

a mixture of geometric isomers, slightly favouring the E-iso-

mer (1.4:1), in which the alkene substituent (Ph) is orientated

away from the bulky N-PMB substituent. Although probably

of limited use in this particular context, we were to revisit

this type of sulfoxide elimination chemistry in our studies

aimed at stephacidin synthesis.

2.2. Synthesis and substitution of unsymmetrical proline

derived DKPs

As mentioned above, proline derived DKPs, or modiﬁca-

tions thereof, appear as structural motifs in a range of impor-

tant natural products, including 1e3. Of particular signiﬁcance

are members of several families of fungal metabolites, pos-

sessed of a bicyclo[2.2.2]diazaoctane core structure, which

includes the brevianamides, e.g., brevianamide B (24) and

paraherquamides, e.g., paraherquamide A (25).¹⁷

These compounds combine synthetically challenging struc-

tures, intriguing biosynthetic origins and, in many cases, potent

biological activities (especially anthelmintic and antinematodal

O

H

NH

N

O

H

O

HO

H

N

O

N

O

N

H

O

N

O

24 brevianamide B

25 paraherquamide A

26 stephacidin A

H

N

H

N

H

N

O

H

N

N-protection(s)

cation formation

X

NH

+

O

P

O

N

P

two substitutions

via enolisation

N

H

O

28

ent-brevianamide F 1

27

H

N

H

O

H

N

+

H

indole

trapping

H

prenyl

trapping

PN

H

6

O

P

O

N

P

R

N

O

29

30

31

Scheme 6. Planned cationic cascade route to complex bridged DKPs.

3718

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

intermediate.²³Triggering of cation formation from 27 would

enable a cascade process in which sequential trapping of cation

intermediate 28 by the pendant prenyl group, and then 29 by the

indole, would give the desired polycyclic product 30. This pro-

cess appeared to promise an extremely concise access to natural

products, including 1e3, and we could be assured of the second

‘indole trapping’ step, since Williams and co-workers had pre-

viously demonstrated the viability of such a cyclisation.²⁴

Surprisingly, given the ubiquity of DKPs and their derived

with overall retention at the proline a-centre. The result is in

accord with the aforementioned results of Davies, involving

alkylation of a valine derived DKP, where the stereochemical

result was explained via enolate conformation A, Figure 2.^10a

The conformation shown was proposed to be favoured be-

cause torsional strain between the isopropyl substituent at C-3

and the N-4 group destabilises an alternative conformation

where both of these groups are pseudo-equatorial. The

pseudo-axial isopropyl group conveys a high level of facial se-

lectivity on the subsequent axial mode of enolate alkylation.

For our proline derived systems an analogous situation may

explain the results, as represented by conformation B. How-

ever, this argument is less convincing when considering rela-

tively small groups (R), particularly the alanine derived DKP

where R¼Me. In this case, the steric shielding afforded by

a methyl substituent in a 1,4-arrangement does not seem ade-

quate to explain the high selectivities generally observed.

Also, in the case of R¼Me, the argument for enforcing confor-

mation B due to 1,2-torsional strain also seems weaker, and

the alternative conformation C appears reasonable. In this

case there is a strong argument for top face alkylation based

on a well-established tendancy for various lactam enolates to

react anti to the pyramidilised nitrogen lone pair (shown).^29,30

This apparent stereoelectronic effect can result in very high fa-

cial selectivity when only rather small ring substituents are

present as conformational anchors.

For the sulfenylation reactions stereoselectivity was poor,

with ratios obtained being 1:1 in the case of 36a, 2:1 for

36b and 3.3:1 in the case of 36c, the selectivity apparently de-

pending on the size of the side chain of the acyclic amino acid

DKP component. We ascribe the loss of complete selectivity

in the sulfenylations, compared to all of the other reactions

carried out, to a longer forming bond (i.e., CeS vs CeC) in

the transition state.

Our initial assignment of relative stereochemistry of the

products 37e43 rested on the aforementioned single precedent

for alkylation of an enolate related to 36c.²⁶Fortunately, we

were able to conﬁrm this assignment by X-ray crystallography

in the case of the key prenylated compound 38b, required for

our cyclisation work, Figure 3.

systems (such as Schollkopf lactim ethers) in stereocontrolled

¨

processes,²⁵we could ﬁnd only a single report relating to the

transformation of proline derived unsymmetrical DKPs such as

1 into products with quaternary centres.²⁶Thus an exploration

of the regio- and stereocontrol in the enolate reactions of

DKPs such as 1 appeared a pre-requisite to any total synthesis

adventure. Similarly, the choice of the group ‘X’, the practical-

ities of generating the unusual type of cationic intermediate

28²⁷and the crucial stereochemical outcome at C-6 (stephaci-

din numbering) could not be taken for granted.

Herein, we describe our preliminary results towards realis-

ing this approach, in which we use model ^L-proline derived

i

DKP systems 31 (R¼Me, Bn or Pr; P¼PMB) to address the

key aspects described above.

In initial preparations of appropriate DKPs for this study,

starting from cheap amino acid precursors, we observed that

N-protection of the ring NeH in 31 (P¼H) led to signiﬁcant

epimerisation at the proline residue. Therefore, we adopted

a route that combined commercially available proline methyl-

ester with alanine, phenylalanine or valine derived partners, al-

ready incorporating the required PMB protection, Scheme 7.

Initial reductive amination was followed by double nitrogen

protection, amide coupling, N-Boc removal and thermally in-

duced cyclisation to give the desired DKPs 36aec.²⁸

We were delighted to ﬁnd that a range of electrophilic

substitution reactions could be conducted with these systems,

in a highly regio- and stereoselective fashion, through the

intermediacy of lithium enolates, generated using LiHMDS,

Table 3.

This brief survey demonstrated that effective alkylation, ac-

ylation, aldol and sulfenylation reactions are viable in good

yields. In all cases we observed completely regioselective re-

action at the proline a-centre, which is in accord with the sin-

gle result reported previously for a cyclo[ValePro] derivative

similar to 36c.^26aThis is likely both the kinetic and thermo-

dynamic outcome.

In the case of the two benzaldehyde aldol products 43a and

43b we were initially a little surprised that single diastereo-

mers were formed. Unfortunately we were unable to determine

the stereochemistry of these compounds at the newly formed

off-template secondary alcohol centre using NOE experi-

ments, and the compounds were not crystalline. We tentatively

propose the stereochemistry shown below for these

With the exception of sulﬁdes 42aec all of the products

were isolated as single diastereomers, the reaction occurring

O

H

R

(i)

(ii)

(iv)

CO₂Me

(iii)

PMBN

Boc

N

Boc

NH₂

CO₂H

N

CO₂H

PMBHN

CO₂H

N

R

H

PMB

O

33a R = Me (46%)

33b R = Bn (88%)

33c R = ⁱPr (67%)

34a R = Me (76%)

34b R = Bn (69%)

34c R = ⁱPr (27%)

32a R = Me

32b R = Bn

32c R = ⁱPr

35a R = Me (93%)

35b R = Bn (90%)

35c R = ⁱPr (87%)

36a R = Me (94%)

36b R = Bn (84%)

36c R = ⁱPr (76%)

Scheme 7. Preparation of unsymmetrical DKPs. Reagents and conditions: (i) p-methoxybenzaldehyde, NaBH₃CN, MeOH; (ii) (Boc)₂O, ⁱPr₂NEt, 1,4-dioxaneH₂O

(1:1); (iii) L-proline methylestereHCl salt, EDCI, HOBT, Et₃N, CH₂Cl₂; (iv) HCO₂H then reﬂux in 2-butanoletoluene (xylene used for 36c).

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

3719

Table 3

Alkylation of DKPs 36aec

O

E

N

H

N

(i) LiHMDS (1.5-3.0 equiv.)

THF, -78 °C

PMBN

R

H

R

H

(ii) electrophile

36

37 - 43

DKP

Electrophile^a

Allyl bromide

Prenyl bromide

PhCH₂Br

EtI

NCCO₂Et

PhSSPh^b

PhCHO

36a

36b

36c

a

37a (51)

37b (71)

37c (73)

38a (60)

38b (82)

d

39a (62)

39b (58)

39c (83)

d

40b (56)

40c (61)

41a (83)

41b (69)

41c (55)

42a (52)

42b (60)

42c (64)

43a (63)

43b (57)

d

Values in brackets are isolated yields (%) of pure DKP product.

These products isolated as mixtures of diastereoisomers (see text).

b

LiO

4

LiO

H

N

H

5

6

LiO

N

1

R₄

PMB

N

R₁

N

O

N

O

PMB

H

3

2

O

R

A

B

C

Figure 2. Rationalisation of DKP enolate selectivity.

compounds, which we expect to arise via transition state A, in

which interactions between the proline ring and the phenyl

ring on the aldehyde are minimised in the usual type of

ZimmermaneTraxler arrangement, Figure 4.

With a model DKP system, equipped with a suitable prenyl

appendage, we required to explore the installation of a second

group X, as indicated earlier in Scheme 6, which would allow

cation formationecyclisation. Initially, we chose to carry out

sulfenylation of 38b (i.e., X¼SPh) to give 44, since this also

enabled subsequent sulfoxide syn-elimination to give exo-ben-

zylidene product 45, Scheme 8.

As seen in some of our earlier enolisation studies, the eno-

lisation of DKP 38b was unsuccessful using conventional

bases such as LDA, LiHMDS, KHMDS or n-BuLi, and we

achieved acceptable results only by employing the bis-lithiated

base 12. Deprotonation using this base, followed by addition

of diphenyl disulﬁde gave a single diastereomeric product 44

in reasonable yield. The formation of a single diastereomer

in this reaction was unexpected (especially bearing in mind

the mixtures of products generated in our other sulfenyla-

tions), since reaction on the more exposed convex face of

the system appeared to be hindered by the prenyl substituent.

We subsequently secured the stereochemical assignment

shown in Scheme 8 by X-ray crystallography, Figure 5.

The structure shows clearly that installation of the new SPh

substituent has occurred anti to the prenyl group and on the

Figure 3. X-ray structure of 38b (N-PMB group has been omitted for clarity).

OH

H

O

Ph

H

N

PMB

N

Ph

R

PMBN

Li

O

N

R

H

O

A

43

Figure 4. Tentative assignment of stereochemistry for 43a and 43b.

(i)

Bn N

N Bn

Li

O

12

O

1.1 equiv.

(i) mCPBA, CH₂Cl₂

THF, -78 °C

PMBN

PhS

then NaHCO₃(aq)

PMBN

Ph

PMBN

N

(ii) PhSSPh

(ii) Δ, toluene

N

Bn

O

H

O

38b

44 (64%)

45 (94%) E:Z = 1:1

Scheme 8. Sulfenylation and sulfoxide elimination sequence, starting from 38b.

3720

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

O

AgOTf, THF

65%

PMBN

N

PhS

Bn

O

H

44

Ph

P

N

O

N

(i)

O

Bn N N Bn

12

O

Li

PMBN

THF, -78 °C

48

N

(ii) FN(SO₂Ph)₂

(iii) TMSOTf

Bn

H

43%

38b

Scheme 10. Stereoselective cyclisations of DKPs 44 and 38b.

Figure 5. X-ray structure of 44 (N-PMB group has been omitted for clarity).

more concave face of the bicyclic system. Subsequent sulfox-

ide elimination proved very efﬁcient, providing 45 as a mixture

of geometrical isomers.

Ylidenepiperazine-2,5-diones, such as 45, have been dem-

onstrated to undergo intermolecular alkene trapping reactions,

analogous to the cyclisation that we planned, under acidic con-

ditions, for example, conversion of starting DKP 46 into prod-

uct 47 on heating with 1,1-diphenylethene and formic acid,

Scheme 9.^27b

compared to the AgOTf method, although the yield of 48

was only moderate. The success of this strategy makes avail-

able bridged DKP 48 in only six steps from the starting com-

mercial phenylalanine 10b.

Finally, we attempted to apply this approach to a brevian-

amide F derivative (i.e., a variant of structure 27) capable of un-

dergoing double cyclisation to form a polycyclic fused indole

represented by 30. Preparation of the suitably protected DKP

49 was straightforward,³³following the procedure outlined be-

fore, and we were pleased to ﬁnd that prenylation was highly

regio- and stereoselective, as before, to give 50, Scheme 11.

O

H

N

H

N

Ph

MeN

Ph

MeN

Ph

HCO₂H

Ph

O

Ph

H

N

PMBN

NBoc

PMBN

47 61%

46

(i) LiHMDS, THF, -78 °C

N

Scheme 9. A known cationic trapping result on a DKP framework.

(ii)

Br

NBoc

Unfortunately, treatment of our related DKP 45 with a num-

ber of acidic reagents, including formic acid, TFA and mineral

acids, led only to destruction of the starting material.

We turned instead to previous reports in which substitution

of thioether groups on a DKP scaffold had been accomplished

using AgOTf.³¹Reaction of 44 under these conditions gave

rise to a single cyclised product to which we assigned structure

48 by comparison of NMR data with those published previ-

ously by Williams and co-workers, Scheme 10.³²

Pleasingly, the relative conﬁguration of this product at C-6

is correct for the synthesis of paraherquamide and stephacidin

natural products; the absolute stereochemistry being opposite

to that of our prime targets, the stephacidins, following the

aforementioned revision.

As shown, we also developed a novel one-pot transforma-

tion of 38b, to give the same tricyclic DKP product 48, by se-

quential treatment with base 12, electrophilic ﬂuorinating

agent FN(SO₂Ph)₂and then trimethylsilyltriﬂate. This proce-

dure was based on another report from the Davies group, in

which halo-diketopiperazines were employed as chiral glycine

cation equivalents.^27aInitial DKP ﬂuorination was used as an

access to the 2-chloro derivatives via transhalogenation. In our

hands, in situ ﬂuorination followed by Lewis acid activation,

using TMSOTf provided a direct and reliable protocol,

49

50 74%

Scheme 11. Synthesis of DKP substrate 50 for attempted double cyclisation.

Unfortunately, we were then unable, under any of the con-

ditions employed before, to further substitute DKP 50 in order

to install the appropriate ‘trigger’ for cationic double cyclisa-

tion. This failure is most likely due to the extremely crowded

nature of this DKP system due to the presence of the Boc-pro-

tected indole. We have not persisted with this approach, since

we have subsequently established an alternative approach that

enables much more concise access to the desired intermediates

27. This new chemistry, which has enabled us to realise the

desired double cyclisation as outlined in Scheme 6 will be

described elsewhere in due course.

3. Experimental part

3.1. Preparation of 3-allyl-1,4-bis-(4-methoxybenzyl)-3-

piperazine-2,5-dione 10

To a solution of HMDS (0.65 mL, 3.10 mmol) in THF

(3 mL), cooled to ꢀ78 ^ꢁC, was added n-BuLi (1.8 mL of

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

3721

a 1.6 M solution in hexanes, 2.8 mmol) and the solution was

warmed to rt for 15 min. The reaction mixture was added,

via cannula, to a suspension of 1,4-bis-(4-methoxybenzyl)-

piperazine-2,5-dione 9 (1.0 g, 2.8 mmol) in THF (10 mL) at

ꢀ10 ^ꢁC. After stirring the reaction mixture for 1 h, it was

cooled to ꢀ78 ^ꢁC and allyl bromide (0.24 mL, 2.80 mmol)

was added. The mixture was allowed to warm to rt over 2 h

and then the reaction mixture was quenched by the cautious

addition of a saturated aqueous solution of ammonium chlo-

ride (10 mL). The mixture was separated and the aqueous

phase was extracted with CHCl₃(2ꢂ10 mL). The combined

organic extracts were washed with water (10 mL), brine

(10 mL), dried (MgSO₄) and the solvent was evaporated under

reduced pressure. The crude product was puriﬁed by ﬂash col-

umn chromatography on silica gel (petrol/EtOAc, 2:1) to yield

allyl DKP 10 as a colourless solid (0.75 g, 67%), mp 80e

82 ^ꢁC. n_max(CHCl₃)/cm^ꢀ12936, 2838, 1663, 1613, 1463,

1321, 1304, 1036; d_H(400 MHz, CDCl₃) 2.57 (1H, ddd,

J 14.5, 7.5, 5.2, CHHCH]CH₂), 2.66 (1H, ddd, J 14.2, 7.5,

4.2, CHHCH]CH₂), 3.76 (1H, d, J 17.5, NCHHCO), 3.80

(3H, s, OCH₃), 3.80 (3H, s, OCH₃), 3.92 (1H, d, J 17.5,

NCHHCO), 3.98 (1H, d, J 14.5, NCHHAr), 3.99 (1H, dd,

J 5.2, 4.2, NCHCO), 4.18 (1H, d, J 14.5, NCHHAr), 4.82

(1H, d, J 14.5, NCHHAr), 5.07 (1H, dd, J 10.1, 1.6,

HHC]CHCH₂), 5.10 (1H, dd, J 17.1, 1.6, HHC]CHCH₂),

5.19 (1H, d, J 14.5, NCHHAr), 5.60 (1H, dddd, J 17.1, 10.1,

7.5, 7.5, CH₂]CHCH₂), 6.86 (4H, d, J 8.6, Ar, CH), 7.18

(4H, d, J 8.6, Ar, CH); d_C(125 MHz, CDCl₃) 36.1 (CH₂), 46.2

(CH₂), 49.0 (CH₂), 49.2 (CH₂), 55.4 (2ꢂOCH₃), 58.9 (CH),

114.3 (Ar, CH), 114.4 (Ar, CH), 120.9 (H₂C]CH), 127.3 (C,

Ar), 127.5 (C, Ar), 129.9 (Ar, CH), 130.0 (Ar, CH), 130.8

(CH]CH₂), 159.5 (2ꢂC, Ar), 164.3 (C]O), 165.9 (C]O);

m/z (EI) C₂₃H₂₆N₂O₄requires: 394.1893, found M^þ: 394.1894.

as a colourless crystalline solid (2.75 g, 75%), mp 168e

170 ^ꢁC. Found: C, 71.85; H, 6.94; N, 6.35. C₂₆H₃₀N₂O₄

requires: C, 71.87; H, 6.96; N, 6.45. n_max(CHCl₃)/cm^ꢀ12937,

2838, 1651, 1613, 1457, 1318, 1304, 1036; d_H(400 MHz,

CDCl₃) 2.71 (2H, ddd, J 14.7, 7.1, 4.5, CHHCH]CH₂),

2.88 (2H, dddd, J 14.7, 7.1, 2.8, 1.4, CHHCH]CH₂), 3.79

(2H, d, J 14.7, NCHHAr), 3.81 (6H, s, OCH₃), 3.99 (2H,

dd, J 4.5, 2.8, COCHN), 5.13 (2H, dd, J 10.2, 1.6,

HHC]CHCH₂), 5.18 (2H, dd, J 17.1, 1.6, HHC]CHCH₂),

5.51 (2H, d, J 14.7, NCHHAr), 5.57 (2H, dddd, J 17.1, 10.2,

7.1, 7.1, CH₂CH]CH₂), 6.86 (4H, d, J 8.5, Ar, CH), 7.20

(4H, d, J 8.5, Ar, CH); d_C(125 MHz, CDCl₃) 35.1 (CH₂),

45.6 (CH₂), 55.4 (OCH₃), 57.0 (CH), 114.3 (Ar, CH), 120.5

(H₂C]CH), 127.1 (Ar, C), 130.0 (Ar, CH), 130.8 (H₂C]

CH), 159.5 (Ar, C), 166.2 (C]O); m/z (EI) C₂₆H₃₀N₂O₄

requires: 434.2206, found M^þ: 434.2192. A sample for

X-ray crystal structure determination was prepared from

DKP 11a (50 mg) via recrystallisation from petrol (2 mL)

and EtOAc (0.2 mL) over a period of 5 days.

3.2.2. (3R*,6S*)-3,6-Dibenzyl-1,4-bis-(4-methoxybenzyl)-

piperazine-2,5-dione 11b

The above procedure was followed using HMDS (1.5 mL,

7.1 mmol), n-BuLi (3.9 mL of a 1.6 M solution in hexanes,

6.2 mmol), 1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione 9

(2.00 g, 5.64 mmol), benzyl bromide (1.7 mL, 14 mmol) and

THF (45 mL). The crude product was puriﬁed by ﬂash column

chromatography on silica gel (CH₂Cl₂/(CH₃)₂CO, 99:1), then

recrystallised (EtOAc) to yield the dibenzyl DKP 11b as a col-

ourless crystalline solid (0.89 g, 60%), mp 204e206 ^ꢁC. n_max

(CHCl₃)/cm^ꢀ12937, 2838, 1645, 1613, 1454, 1303, 1035; d_H

(400 MHz, CDCl₃) 3.18 (4H, d, J 3.8, CHHPh), 3.75 (2H, t,

J 3.8, COCHN), 3.82 (6H, s, OCH₃), 3.88 (2H, d, J 14.8,

NCHHAr), 5.44 (2H, d, J 14.8, NCHHAr), 6.68 (4H, d, J 8.6,

AreOMe, CH), 6.75 (4H, d, J 8.6, AreOMe, CH), 7.04 (2H,

d, J 6.1, Ar, CH), 7.04 (2H, d, J 8.5, Ar, CH), 7.21 (2H, ddd,

J 6.1, 6.1, 1.2, Ar, CH), 7.21 (2H, ddd, J 8.5, 8.5, 1.2, Ar,

CH), 7.28 (2H, dddd, J 8.5, 6.1, 1.4, 1.2, Ar, CH); d_C

(100 MHz, CDCl₃) 35.5 (CH₂), 45.8 (CH₂), 55.4 (OCH₃),

57.6 (CH), 114.2 (Ar, CH), 126.3 (Ar, C), 127.1 (Ar, CH),

128.8 (Ar, CH), 129.9 (Ar, CH), 135.1 (Ar, CH), 159.3 (Ar,

C), 165.6 (C]O); m/z (EI) C₃₄H₃₄N₂O₄requires: 534.2518,

found M^þ: 534.2538.

3.2. Typical procedure for double alkylation of 9 to give

trans-DKPs 11

3.2.1. (3R*,6S*)-3,6-Diallyl-1,4-bis-(4-methoxybenzyl)-

piperazine-2,5-dione 11a

To a solution of HMDS (3.9 mL, 19 mmol) in THF

(15 mL), cooled to ꢀ78 ^ꢁC, was added n-BuLi (11.3 mL of

a 1.6 M solution in hexanes, 18 mmol) and the solution was

warmed to rt for 15 min. The basic solution was added, via

cannula to a suspension of 1,4-bis-(4-methoxybenzyl)pipera-

zine-2,5-dione 9 (3.0 g, 8.5 mmol) in THF (30 mL) at

ꢀ10 ^ꢁC. After stirring the reaction mixture for 1 h, it was

cooled to ꢀ78 ^ꢁC and allyl bromide (1.83 mL, 21.2 mmol)

was added. The mixture was allowed to warm to rt over 2 h

and then the reaction was quenched by the cautious addition

of a saturated aqueous solution of ammonium chloride

(30 mL). The mixture was separated and the aqueous phase

was extracted with CHCl₃(2ꢂ25 mL). The combined organic

extracts were washed with water (25 mL), brine (25 mL),

dried (MgSO₄) and the solvent was evaporated under reduced

pressure. The crude product was puriﬁed by ﬂash column

chromatography on silica gel (CH₂Cl₂/CH₃COCH₃, 99:1),

then recrystallised (EtOAc) to yield the title compound 11a

3.2.3. (3R*,6S*)-3,6-Diethyl-1,4-bis-(4-methoxybenzyl)-

piperazine-2,5-dione 11c

The above procedure was followed using HMDS (0.97 mL,

4.6 mmol), n-BuLi (2.9 mL of a 1.6 M solution in hexanes,

4.7 mmol), 1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione 9

(0.75 g, 2.1 mmol), iodoethane (0.85 mL, 11 mmol) and THF

(12 mL). The crude product was puriﬁed by ﬂash column

chromatography on silica gel (petrol/EtOAc, 2:1), then recrys-

tallised (EtOAc) to yield the diethyl DKP 11c as a colourless

crystalline solid (0.28 g, 32%), mp 168e170 ^ꢁC. Found: C,

69.92; H, 7.31; N, 6.80%. C₂₄H₃₀N₂O₄requires: C, 70.22;

H, 7.37; N, 6.82%. n_max(CHCl₃)/cm^ꢀ12971, 2838, 1650,

1613, 1461, 1319, 1303, 1036; d_H(400 MHz, CDCl₃) 0.77

3722

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

(6H, dd, J 7.4, 7.4, CH₃CH₂), 2.01 (2H, dqd, J 14.6, 7.4, 4.9,

CH₃CHH), 2.19 (2H, dqd, J 14.6, 7.4, 2.5, CH₃CHH), 3.71

(2H, d, J 14.6, NCHHAr), 3.80 (6H, s, OCH₃), 3.98 (2H,

dd, J 4.9, 2.5, COCHN), 5.53 (2H, d, J 14.6, NCHHAr), 6.86

(4H, d, J 8.7, Ar, CH), 7.20 (4H, d, J 8.6, Ar, CH); d_C

(100 MHz, CDCl₃) 7.2 (CH₃), 24.1 (CH₂), 45.4 (CH₂), 55.4

(OCH₃), 57.6 (CH), 114.3 (Ar, CH), 127.5 (Ar, C), 129.9

(Ar, CH), 159.4 (Ar, C), 166.7 (C]O); m/z (EI)

C₂₄H₃₀N₂O₄requires: 410.2206, found M^þ: 410.2207.

(400 MHz, CDCl₃) 2.50 (1H, dddd, J 14.9, 7.0, 5.6, 1.2,

CHHCH]CH₂), 2.66 (1H, dd, J 14.3, 5.8, CHHCH]CH₂),

2.74 (1H, dddd, J 14.9, 7.3, 2.9, 1.4, CHHCH]CH₂), 2.96

(1H, dd, J 14.3, 8.2, CHHCH]CH₂), 3.25 (1H, d, J 14.0,

CHHPh), 3.25 (1H, dd, J 5.6, 2.9, NCHCO), 3.25 (1H, d,

J 14.0, CHHPh), 3.80 (6H, s, OCH₃), 3.99 (1H, d, J 14.6,

NCHHAr), 4.19 (1H, d, J 14.9, NCHHAr), 4.82 (1H, dd,

J 16.9, 2.0, CH₂CH]CHH), 4.87 (1H, d, J 10.2, 2.0,

CH₂CH]CHH), 4.92 (1H, d, J 14.9, NCHHAr), 5.00 (1H,

dd, J 10.0, 1.7, CH₂CH]CHH), 5.03 (1H, dd, J 16.7, 1.7,

CH₂CH]CHH), 5.19 (1H, dddd, J 16.9, 10.2, 8.2, 8.2,

CH₂CH]CH₂), 5.43 (1H, d, J 14.6, NCHHAr), 5.50 (1H,

dddd, J 16.9, 10.2, 7.0, 7.0, CH₂CH]CH₂), 6.74 (2H, d,

J 8.8, AreOMe, CH), 6.82 (4H, d, J 8.8, Ar, CH), 7.00e7.04

(2H, m, Ar, CH), 7.12e7.18 (2H, m, Ar, CH), 7.22 (1H, m,

Ar, CH), 7.39 (2H, d, J 8.8, Ar, CH); d_C(125 MHz, CDCl₃)

36.0 (CH₂), 42.4 (CH₂), 43.7 (CH₂), 46.2 (CH₂), 46.5 (CH₂),

55.3 (2ꢂOCH₃), 56.9 (CH), 77.1 (C-3), 113.7 (Ar, CH),

113.9 (Ar, CH), 119.3 (H₂C]CH), 119.7 (CH₂C]CH),

127.0 (Ar, C), 127.3 (Ar, CH), 128.6 (Ar, CH), 130.1 (Ar,

CH), 130.2 (Ar, C), 130.5 (2ꢂCH]CH₂), 131.9 (Ar, CH),

132.0 (Ar, CH), 135.0 (Ar, C), 159.0 (Ar, C), 159.1 (Ar, C),

166.5 (C]O), 167.4 (C]O); m/z (ESI) C₃₃H₃₆N₂NaO₄re-

quires: 547.2567, found [MNa]^þ: 547.2534.

3.2.4. (3R*,6S*)-3,6-Diisopropyl-1,4-bis-(4-methoxy-

benzyl)piperazine-2,5-dione 11d

The above general procedure was followed using HMDS

(2.62 mL, 12.4 mmol), n-BuLi (8.0 mL of a 1.6 M solution in

hexanes, 12 mmol), 1,4-bis-(4-methoxybenzyl)piperazine-2,5-

dione

9

(2.00 g, 5.64 mmol), 2-iodopropane (1.4 mL,

14 mmol) and THF (60 mL). The crude product was puriﬁed

by recrystallisation (EtOAc) to yield the diisopropyl DKP

11d as a colourless crystalline solid (1.32 g, 53%), mp

192e193 ^ꢁC (lit. mp 180 ^ꢁC).¹⁵Found: C, 68.40; H, 7.10; N,

3.61%. C₂₆H₃₄N₂O₄requires: C, 68.55; H, 7.06; N, 3.61%.

n_max(CHCl₃)/cm^ꢀ12963, 2838, 1650, 1614, 1463, 1303,

1036; d_H(500 MHz, CDCl₃) 0.80 (6H, d, J 6.9, CH(CH₃)₂),

1.12 (6H, d,

J 7.0, CH(CH₃)₂), 2.34e2.37 (2H, m,

CH(CH₃)₂), 3.77 (2H, d, J 2.7, C]OCHN), 3.81 (6H, s,

OCH₃), 3.89 (2H, d, J 14.7, NCHHAr), 5.31 (2H, d, J 14.7,

NCHHAr), 6.86 (4H, d, J 8.6, Ar, CH), 7.18 (4H, d, J 8.6,

Ar, CH); d_C(125 MHz, CDCl₃) 15.9 (CH₃), 20.0 (CH₃), 30.8

(CH), 46.3 (CH₂), 55.3 (OCH₃), 62.6 (CH), 114.0 (Ar, CH),

127.5 (Ar, C), 130.0 (Ar, CH), 159.3 (Ar, C), 165.7 (C]O);

m/z (EI) C₂₆H₃₄N₂O₄requires: 438.2519, found M^þ: 438.2520.

3.3.2. (3S*,6S*)-3,6-Diallyl-3-ethyl-1,4-bis-(4-methoxy-

benzyl)piperazine-2,5 dione rac-13b

The above general procedure was followed using N,N⁰-

dibenzylethylene diamine (59 mL, 0.25 mmol), n-BuLi

(0.32 mL of a 1.6 M solution in hexane, 0.50 mmol),

(3R*,6S*)-3,6-diallyl-1,4-bis-(4-methoxybenzyl)piperazine-

2,5-dione 11a (100 mg, 0.230 mmol) and iodoethane (92 mL,

1.2 mmol). The crude product was puriﬁed by ﬂash column

chromatography on silica gel (petrol/EtOAc, 3:1) to yield

the title DKP 13b as a colourless solid (44 mg, 41%), mp

82e83 ^ꢁC. n_max(CHCl₃)/cm^ꢀ12936, 2838, 1652, 1614,

1457, 1354, 1318, 1304, 1036; d_H(500 MHz, CDCl₃) 0.51

(3H, dd, J 7.3, 7.3, CH₃CH₂), 1.84 (1H, dq, J 14.4, 7.3,

CHHCH₃), 2.18 (1H, dq, J 14.4, 7.3, CHHCH₃), 2.48 (1H,

dd, J 14.4, 7.0, CHHCH]CH₂), 2.73 (1H, ddd, J 14.6, 7.3,

5.8, CHHCH]CH₂), 2.77 (1H, dd, J 14.4, 7.6, CHHCH]

CH₂), 2.88 (1H, ddd, J 14.6, 7.3, 3.5, CHHCH]CH₂), 3.79

(3H, s, OCH₃), 3.81 (3H, s, OCH₃), 3.88 (1H, J 14.6,

NCHHAr), 4.03 (1H, dd, J 5.8, 3.5, NCHCO), 4.32 (1H, d,

J 15.0, NCHHAr), 4.82 (1H, d, J 15.0, NCHHAr), 4.87 (1H,

dd, J 17.1, 1.7, HHC]CH), 4.97 (1H, dd, J 10.2, 1.7,

HHC]CH), 5.13 (1H, dd, J 17.1, 1.5, HHC]CH), 5.18

(1H, dd, J 10.2, 1.5, HHC]CH), 5.43 (1H, dddd, J 17.3,

10.2, 7.3, 7.3, CH₂CH]CH₂), 5.49 (1H, d, J 14.6, NCHHAr),

5.75 (1H, dddd, J 17.3, 10.2, 7.3, 7.3, CH₂CH]CH₂), 6.80

(2H, d, J 6.7, Ar, CH), 6.86 (2H, d, J 6.7, Ar, CH), 7.21

(2H, d, J 8.6, Ar, CH), 7.32 (2H, d, J 8.6, Ar, CH); d_C

(125 MHz, CDCl₃) 8.1 (CH₃), 32.2 (CH₂), 37.0 (CH₂), 42.5

(CH₂), 45.2 (CH₂), 46.1 (CH₂), 55.3 (OCH₃), 55.4 (OCH₃),

57.0 (CH), 70.4 (C-3), 113.7 (Ar, CH), 114.2 (Ar, CH),

119.1 (H₂C]CH), 119.5 (H₂C]CH), 126.7 (Ar, C), 127.5

(Ar, C), 130.2 (CH]CH₂), 130.2 (CH]CH₂), 132.6 (Ar,

3.3. Typical procedure for substitution of trans-DKPs 11 to

give products 13 (Table 1)

3.3.1. (3R*,6S*)-3,6-Diallyl-3-benzyl-1,4-bis-(4-methoxy-

benzyl)piperazine-2,5-dione rac-13a

N,N⁰-Dibenzylethylene diamine (59 mL, 0.25 mmol) was dis-

solved in THF (2 mL), cooled to ꢀ78 ^ꢁC and n-BuLi (0.32 mL

of a 1.6 M solution in hexanes, 0.50 mmol) added. The solution

was warmed to rt for 10 min before being recooled to ꢀ78 ^ꢁC.

The mixture was then added via cannula, over a period of

5 min, to a solution of (3R*,6S*)-3,6-diallyl-1,4-bis-(4-meth-

oxybenzyl)piperazine-2,5-dione 11a (100 mg, 0.230 mmol) in

THF (15 mL) at ꢀ78 ^ꢁC. After stirring the solution for 1 h, ben-

zyl bromide (0.14 mL, 1.2 mmol) was added and the solution

was stirred for a further 2 h. The reaction mixture was quenched

by the careful addition of a saturated aqueous solution of

ammonium chloride (10 mL). After warming to rt the phases

were separated and the organic phase was washed with brine

(10 mL). The aqueous phase was extracted with CH₂Cl₂

(2ꢂ10 mL), then the combined organic extracts were dried

(MgSO₄) and the solvent was evaporated under reduced pres-

sure. The crude product was puriﬁed by ﬂash column chroma-

tography on silica gel (petrol/EtOAc, 3:1) to yield the title DKP

13a as a colourless solid (92 mg, 76%), mp 100e102 ^ꢁC. n_max

(CHCl₃)/cm^ꢀ12937, 2838, 1650, 1613, 1456, 1304, 1036; d_H

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

3723

CH), 132.8 (Ar, CH), 158.9 (Ar, C), 159.4 (Ar, C), 167.2

(C]O), 167.4 (C]O); m/z (EI) C₂₈H₃₄N₂O₅requires:

462.2519, found M^þ: 462.2502.

4.4, NCHCO), 4.54 (1H, d, J 14.6, NCHHAr), 4.86 (1H, dd,

J 10.2, 2.0, HHC]CHCH₂), 4.91 (1H, dd, J 17.2, 2.0,

HHC]CHCH₂), 5.09 (1H, d, J 14.6, NCHHAr), 5.10 (1H,

m, H₂C]CHCH₂), 5.33 (1H, d, J 14.6, NCHHPMB), 6.69

(4H, br s, AreOMe, CH), 6.84 (2H, d, J 8.8, Ar, CH), 6.97

(2H, d, J 6.8, Ar, CH), 7.09 (2H, d, J 6.8, Ar, CH), 7.17e

7.37 (6H, m, Ar, CH), 7.42 (2H, d, J 8.8, Ar, CH); d_C

(100 MHz, CDCl₃) 41.0 (CH₂), 43.0 (CH₂), 43.2 (CH₂), 46.3

(CH₂), 46.5 (CH₂), 55.3 (OCH₃), 55.4 (OCH₃), 59.3 (CH),

71.7 (C-3), 113.8 (Ar, CH), 113.9 (Ar, CH), 120.2

(H₂C]CH), 126.7 (Ar, CH), 127.0 (Ar, C), 127.7 (Ar, CH),

128.6 (Ar, CH), 128.9 (Ar, CH), 129.1 (Ar, CH), 130.2 (Ar,

CH), 130.4 (Ar, C), 130.8 (Ar, CH), 131.0 (Ar, CH), 131.2

(CH₂]CH), 135.8 (Ar, C), 139.1 (Ar, C), 159.1 (2ꢂAr, C),

166.2 (C]O), 168.0 (C]O); m/z (EI) C₃₇H₃₈N₂O₄requires:

574.2831, found M^þ: 574.2841.

3.3.3. (3R*,6S*)-3,6-Diallyl-1,4-bis-(4-methoxybenzyl)-3-

phenylsulfanylpiperazine-2,5-dione rac-13c

The above general procedure was followed using N,N⁰-di-

benzylethylene diamine (59 mL, 0.25 mmol), n-BuLi (0.32 mL

of a 1.6 M solution in hexane, 0.50 mmol), (3R*,6S*)-3,6-

diallyl-1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione

11a

(100 mg, 0.230 mmol) and diphenyl disulﬁde (0.25 g,

1.2 mmol), as a solution in THF (1.5 mL). The crude product

was puriﬁed by ﬂash column chromatography on silica gel (pet-

rol/EtOAc, 3:1) to yield the title DKP 13c as a colourless solid

(61 mg, 49%), mp 206e208 ^ꢁC. n_max(CHCl₃)/cm^ꢀ12998,

1657, 1613, 1403, 1303, 1036; d_H(400 MHz, CDCl₃) 2.55

(1H, m, CHHCH]CH₂), 2.72 (1H, dddd, J 14.8, 7.4, 2.7,

1.4, CHHCH]CH₂), 2.77 (1H, dd, J 14.0, 5.6, CHHCH]

CH₂), 3.15 (1H, dd, J 14.0, 8.0, CHHCH]CH₂), 3.19 (1H,

dd, J 5.6, 2.9, NCHCO), 3.80 (3H, s, OCH₃), 3.82 (3H, s,

OCH₃), 4.14 (1H, d, J 14.7, NCHHAr), 4.64 (1H, d, J 15.1,

NCHHAr), 4.71 (1H, d, J 14.7, NCHHAr), 4.77 (1H, dd,

J 16.9, 1.9, HHC]CHCH₂), 4.84 (1H, dd, J 10.4, 1.9,

HHC]CHCH₂), 4.96 (1H, dd, J 10.4, 1.9, HHC]CHCH₂),

5.00 (1H, dd, J 17.1, 1.9, HHC]CHCH₂), 5.05 (1H, m,

H₂C]CHCH₂), 5.39 (1H, dddd, J 17.1, 10.4, 7.4, 7.4,

H₂C]CHCH₂), 5.48 (1H, d, J 15.1, NCHHAr), 6.81 (2H, d,

J 6.7, AreOMe, CH), 6.82 (2H, d, J 8.7, AreOMe, CH),

7.08 (2H, d, J 8.7, AreOMe, CH), 7.15 (2H, dd, J 8.2, 7.3,

SAr, CH), 7.30 (2H, dd, J 8.2, 1.2, SAr, CH), 7.34 (2H, d,

J 8.7, AreOMe, CH), 7.37 (1H, m, SAr, CH); d_C(100 MHz,

CDCl₃) 36.4 (CH₂), 40.1 (CH₂), 47.0 (CH₂), 47.5 (CH₂), 55.3

(OCH₃), 55.4 (OCH₃), 57.7 (CH), 80.0 (C-3), 113.8 (Ar, CH),

114.0 (Ar, CH), 119.8 (H₂C]CH), 120.8 (H₂C]CH), 127.6

(Ar, C), 129.2 (Ar, CH), 129.5 (Ar, C), 130.0 (Ar, C), 130.2

(Ar, CH), 130.4 (Ar, CH), 130.6 (CH]CH₂), 130.7

(CH]CH₂), 131.1 (Ar, CH), 137.0 (Ar, CH), 159.4 (2ꢂAr,

C), 164.1 (C]O), 167.3 (C]O); m/z (CI) C₃₂H₃₅N₂O₄S

requires: 543.2318 found [MH]^þ: 543.2318.

3.3.5. (3S*,6S*)-3,6-Dibenzyl-3-ethyl-1,4-bis-(4-methoxy-

benzyl)piperazine-2,5-dione rac-13e

The above general procedure was followed using N,N⁰-di-

benzylethylene diamine (48 mL, 0.21 mmol), n-BuLi

(0.26 mL of a 1.6 M solution in hexane, 0.41 mmol),

(3R*,6S*)-3,6-dibenzyl-1,4-bis-(4-methoxybenzyl)piperazine-

2,5-dione 11b (100 mg, 0.187 mmol) and iodoethane (75 mL,

0.94 mmol). The crude product was puriﬁed by ﬂash column

chromatography on silica gel (petrol/EtOAc, 4:1) to yield

the title DKP 13e as a colourless solid (39 mg, 37%), mp

85e87 ^ꢁC. n_max(CHCl₃)/cm^ꢀ12938, 2838, 1644, 1613,

1455, 1035; d_H(400 MHz, CDCl₃) 0.36 (3H, t, J 7.1,

CH₃CH₂), 1.25 (1H, dd, J 14.6, 7.0, CHHPh), 1.94 (1H, dq,

J 14.2, 7.1, CHHCH₃), 2.24 (1H, dd, J 14.6, 4.3, CHHPh),

2.32 (1H, dq, J 14.2, 7.1, CHHCH₃), 3.11 (1H, d, J 13.8,

CHHPh), 3.27 (1H, d, J 13.8, CHHPh), 3.27 (1H, d, J 14.6,

NCHHAr), 3.75 (3H, s, OCH₃), 3.80 (3H, s, OCH₃), 4.02

(1H, dd, J 7.0, 4.3, NCHCO), 4.36 (1H, d, J 14.8, NCHHAr),

5.18 (1H, d, J 14.6, NCHHAr), 5.34 (1H, d, J 14.8, NCHHAr),

6.68 (4H, br s, AreOMe, CH), 6.84 (2H, d, J 8.7, Ar, CH),

6.96 (2H, d, J 7.0, Ar, CH), 7.10 (2H, d, J, 7.0, Ar, CH),

7.17e7.31 (4H, m, Ar, CH), 7.35 (2H, app. t, J 7.5, Ar,

CH), 7.42 (2H, d, J 8.7, Ar, CH); d_C(100 MHz, CDCl₃) 8.1

(CH₃), 32.2 (CH₂), 41.0 (CH₂), 43.5 (CH₂), 46.3 (CH₂), 46.5

(CH₂), 55.3 (CH), 59.6 (2ꢂOCH₃), 72.3 (C-3), 113.8 (Ar,

CH), 114.0 (Ar, CH), 126.7 (Ar, CH), 127.3 (Ar, C), 127.7

(Ar, CH), 12.7 (Ar, CH), 128.9 (Ar, CH), 129.1 (Ar, CH),

130.0 (Ar, CH), 130.6 (Ar, C), 130.7 (Ar, CH), 130.9 (Ar,

CH), 136.1 (Ar, C), 139.3 (Ar, C), 159.0 (Ar, C), 159.2 (Ar,

C), 168.3 (C]O), 166.8 (C]O); m/z (EI) C₃₆H₃₈N₂O₄re-

quires: 562.2831, found M^þ: 562.2820.

3.3.4. (3S*,6S*)-3-Allyl-3,6-dibenzyl-1,4-bis-(4-methoxy-

benzyl)piperazine-2,5-dione rac-13d

The above general procedure was followed using N,N⁰-

dibenzylethylene diamine (48 mL, 0.21 mmol), n-BuLi

(0.32 mL of a 1.6 M solution in hexane, 0.50 mmol),

(3R*,6S*)-3,6-dibenzyl-1,4-bis-(4-methoxybenzyl)piperazine-

2,5-dione 11b (100 mg, 0.187 mmol), allyl bromide (81 mL,

0.94 mmol) and THF (15 mL). The crude product was puriﬁed

by ﬂash column chromatography on silica gel (petrol/EtOAc,

4:1) to yield the title DKP 13d as a colourless solid (74 mg,

69%), mp 58e60 ^ꢁC. n_max(CHCl₃)/cm^ꢀ12938, 2838, 1645,

1613, 1456, 1309, 1036; d_H(400 MHz, CDCl₃) 1.31 (1H,

dd, J, 14.6, 7.0, CHHPh), 2.27 (1H, dd, J 14.6, 4.4, CHHPh),

2.75 (1H, dd, J 14.3, 5.6, CHHCH]CH₂), 3.06 (1H, dd,

J 14.3, 8.2, CHHCH]CH₂), 3.10 (1H, d, J 13.8, CCHHPh),

3.27 (1H, d, J 14.6, NCHHAr), 3.29 (1H, d, J 13.8, CCHHPh),

3.76 (3H, s, OCH₃), 3.82 (3H, s, OCH₃), 3.96 (1H, dd, J 7.0,

3.3.6. (3R*,6S*)-3,6-Dibenzyl-1,4-bis-(4-methoxybenzyl)-3-

phenylsulfanylpiperazine-2,5-dione rac-13f

The above general procedure was followed using N,N⁰-

dibenzylethylene diamine (48 mL, 0.21 mmol), n-BuLi

(0.26 mL of a 1.6 M solution in hexane, 0.41 mmol),

(3R*,6S*)-3,6-dibenzyl-1,4-bis-(4-methoxybenzyl)piperazine-

2,5-dione 11b (100 mg, 0.187 mmol) and diphenyl disulﬁde

(204 mg, 0.94 mmol) as a solution in THF (1.5 mL). The

3724

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

crude product was puriﬁed by ﬂash column chromatography

(petrol/EtOAc, 4:1) to yield the title DKP 13f as a colourless

solid (73 mg, 61%), mp 140e142 ^ꢁC. n_max(CHCl₃)/cm^ꢀ1

2936, 2838, 1657, 1613, 1455, 1402, 1351, 1310, 1036; d_H

(400 MHz, CDCl₃) 1.71 (1H, dd, J 14.6, 6.4, CHHPh), 2.08

(1H, dd, J 14.6, 5.8, CHHPh), 3.36 (1H, d, J 13.7, CHHPh),

3.43 (1H, d, J 14.7, NCHHAr), 3.60 (1H, dd, J 6.4, 5.8,

COCHN), 3.71 (1H, d, J 13.7, CHHPh), 3.77 (3H, s, OCH₃),

3.85 (3H, s, OCH₃), 5.00 (1H, d, J 14.7, NCHHAr), 5.15

(1H, d, J 14.7, NCHHAr), 5.32 (1H, d, J 14.7, NCHHAr),

6.31 (2H, d, J 8.8, AreOMe, CH), 6.62 (2H, d, J 8.8,

AreOMe, CH), 6.70e6.75 (4H, m, Ar, CH), 6.89 (2H, d, J

8.8, AreOMe, CH), 7.13e7.21 (8H, m, Ar, CH), 7.29 (2H,

dd, J 8.7, 1.3, Ar, CH), 7.36 (1H, dddd, J 8.7, 6.2, 1.3, 1.3,

Ar, CH), 7.48 (2H, d, J 8.8, Ar, CH); d_C(100 MHz, CDCl₃)

41.1 (CH₂), 42.7 (CH₂), 47.1 (CH₂), 48.1 (CH₂), 55.3

(OCH₃), 55.4 (OCH₃), 59.0 (CH), 82.5 (C-3), 113.9 (Ar,

CH), 113.9 (Ar, CH), 126.3 (Ar, C), 126.7 (Ar, CH), 127.6

(Ar, CH), 128.4 (Ar, CH), 128.5 (Ar, CH), 129.1 (Ar, CH),

129.3 (Ar, CH), 129.7 (Ar, CH), 130.0 (Ar, C), 130.1 (Ar,

CH), 130.7 (Ar, C), 131.4 (Ar, CH), 131.7 (Ar, CH), 134.5

(Ar, C), 136.0 (Ar, CH), 137.7 (Ar, C), 159.1 (Ar, C), 159.3

(Ar, C), 163.8 (C]O), 167.3 (C]O); m/z (EI)

C₄₀H₃₉N₂O₄S requires: 643.2606, found [MH]^þ: 643.2594.

3.3.8. Ring-closing metathesis to give (Z)-1-benzyl-7,9-bis-

(4-methoxybenzyl)-7,9-diazabicyclo[4.2.2]dec-3-ene-8,10-

dione 18

To a solution of (3R*,6S*)-3,6-diallyl-3-benzyl-1,4-bis-

(4-methoxybenzyl)piperazine-2,5-dione (rac-13a) (38 mg,

0.072 mmol) in toluene (5 mL) was added Grubb’s 2nd gener-

ation catalyst (6.0 mg 0.01 mmol) and the mixture was heated

at 70 ^ꢁC for 16 h. The solvent was evaporated under reduced

pressure and the residue was puriﬁed by ﬂash column chroma-

tography on silica gel (petrol/EtOAc, 7:3) to yield the bicyclic

DKP 18 as a colourless solid (33 mg, 92%), mp 176e179 ^ꢁC.

n_max(CHCl₃)/cm^ꢀ12975, 2935, 2838, 1660, 1613, 1455, 1353,

1319, 1304, 1036; d_H(400 MHz, CDCl₃) 2.18 (1H, app. dq,

J 18.8, 2.1, CHHCH]CH), 2.64 (1H, m, CHHCH]CH), 2.92e

2.96 (2H, m, CHHCH]CH), 3.20 (1H, d, J 16.8, CHHPh), 3.73

(1H, d, J 15.4, NCHHAr), 3.80 (3H, s, OCH₃), 3.83 (3H, s,

OCH₃), 3.90 (1H, d, J 14.6, NCHHAr), 3.95 (1H, d, J 16.8,

CHHPh), 4.18 (1H, app t, J 3.8, NCHCO), 4.95 (1H, m,

CH]CH), 5.24 (1H, m, CH]CH), 5.28 (1H, d, J 14.6,

NCHHAr), 5.46 (1H, d, J 15.4, NCHHAr), 6.70 (2H, d, J 8.7,

AreOMe, CH), 6.88 (2H, d, J 8.7, AreOMe, CH), 7.14e7.28

(9H, m, Ar, CH); d_C(100 MHz, CDCl₃) 35.9 (CH₂), 40.9

(CH₂), 45.3 (CH₂), 46.2 (CH₂), 47.2 (CH₂), 55.3 (OCH₃), 55.4

(OCH₃), 57.2 (NCHCO), 65.6 (NCCO), 113.8 (Ar, CH), 114.3

(Ar, CH), 122.1 (HC]CH), 124.0 (HC]CH), 126.5 (CH),

127.8 (Ar, C), 128.1 (Ar, CH), 128.7 (Ar, CH), 129.4 (Ar,

CH), 130.0 (Ar, CH), 130.1 (Ar, C), 136.6 (Ar, C), 159.1 (Ar,

C), 159.5 (Ar, C), 168.8 (C]O), 169.3 (C]O); m/z (ESI)

C₃₁H₃₂N₂NaO₄requires: 519.2254, found [MNa]^þ: 519.2252.

3.3.7. (3R*,6S*)-3-Benzyl-3,6-diethyl-1,4-bis-(4-methoxy-

benzyl)piperazine-2,5-dione 13g

The above general procedure was followed using N,N⁰-

dibenzylethylene diamine (32 mL, 0.14 mmol), n-BuLi

(0.17 mL of a 1.6 M solution in hexane, 0.27 mmol),

(3R*,6S*)-3,6-diethyl-1,4-bis-(4-methoxybenzyl)piperazine-

2,5-dione 11c (50 mg, 0.12 mmol) and benzyl bromide (80 mL,

0.60 mmol). The crude product was puriﬁed by ﬂash column

chromatography (petrol/EtOAc, 4:1) to yield the title DKP

13g as a colourless solid (44 mg, 72%), mp 138e141 ^ꢁC.

n_max(CHCl₃)/cm^ꢀ12938, 2838, 1648, 1612, 1456, 1353,

1304, 1035; d_H(400 MHz, CDCl₃) 0.46 (3H, dd, J 7.3, 7.3,

CCH₂CH₃), 0.61 (3H, dd, J 7.3, 7.3, CHCH₂CH₃), 1.76 (1H,

dqd, J 14.7, 7.3, 2.6, CHCHHCH₃), 1.92 (1H, dq, J 14.0,

7.3, CCHHCH₃), 2.10 (1H, dqd, J 14.7, 7.3, 2.6, CHCHHCH₃),

2.35 (1H, dq, J 14.7, 7.3, CCHHCH₃), 3.09 (1H, dd, J 2.6, 2.6,

COCHN), 3.19 (1H, d, J 13.7, CHHPh), 3.27 (1H, d, J 13.7,

CHHPh), 3.80 (3H, s, OCH₃), 3.80 (3H, s, OCH₃), 4.05 (1H,

d, J 14.6, NCHHAr), 4.07 (1H, d, J 14.6, NCHHAr), 4.76

(1H, d, J 14.6, NCHHAr), 5.48 (1H, d, J 14.6, NCHHAr),

6.77 (2H, d, J 8.7, AreOMe, CH), 6.83 (2H, d, J 8.7,

AreOMe, CH), 6.95 (2H, d, J 8.7, AreOMe, CH), 6.98 (2H,

d, J 6.6, Ar, CH), 7.12 (2H, dd, J 8.6, 6.6, Ar, CH), 7.21

(1H, dddd, J 8.2, 6.6, 1.2, 1.2, Ar, CH), 7.43 (2H, d, J 8.7, C

AreOMe, CH); d_C(100 MHz, CDCl₃) 7.5 (CH₃), 8.8 (CH₃),

24.2 (CH₂), 31.5 (CH₂), 44.2 (CH₂), 45.9 (CH₂), 46.7 (CH₂),

55.3 (OCH₃), 55.3 (OCH₃), 58.0 (CH), 71.9 (C-3), 113.8 (Ar,

CH), 113.9 (Ar, CH), 127.7 (Ar, C), 128.5 (Ar, CH), 291.1

(Ar, C), 130.1 (Ar, CH), 130.2 (Ar, CH), 130.4 (Ar, CH),

130.7 (Ar, CH), 135.2 (Ar, C), 158.9 (Ar, C), 159.0 (Ar, C),

167.8 (C]O), 168.2 (C]O); m/z (EI) C₃₁H₃₆N₂O₄requires:

500.2675, found M^þ: 500.2661.

3.4. Typical procedure for substitution of cis-DKP 22a to give

products 13 (Table 2)

In the case of DKP 22a the same procedure was followed as

for the centrosymmetric trans-DKPs 11 (see typical procedure

for product 13a).

3.4.1. (3S,6S)-3-Allyl-3,6-dibenzyl-1,4-bis-(4-methoxy-

benzyl)piperazine-2,5-dione 13d

The general procedure was followed, using N,N⁰-dibenzyl-

ethylene diamine (48 mL, 0.21 mmol), n-BuLi (0.26 mL of

a 1.6 M solution in hexanes, 0.41 mmol), (3S,6S)-3,6-di-

benzyl-1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione

22a

(100 mg, 0.187 mmol), THF (13 mL) and allyl bromide

(80 mL, 0.94 mmol).

The crude product was puriﬁed by ﬂash column chromatog-

raphy on silica gel (petrol/EtOAc, 3:1) to yield DKP (ꢀ)-13d

as a colourless solid (98 mg, 91%), mp 59e61 ^ꢁC. [a]_D¹⁸ꢀ98.7

(c 0.51, CHCl₃); spectroscopic data were identical to those for

the racemic material.

3.4.2. (3S,6S)-3,6-Dibenzyl-3-ethyl-1,4-bis-(4-methoxy-

benzyl)piperazine-2,5-dione 13e

The general procedure was followed using N,N⁰-dibenzyl-

ethylene diamine (48 mL, 0.21 mmol), n-BuLi (0.26 mL of

a 1.6 M solution in hexanes, 0.41 mmol), (3S,6S)-3,6-di-

benzyl-1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione

22a

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

3725

(100 mg, 0.187 mmol), THF (15 mL) and iodoethane (70 mL,

0.94 mmol). The crude product was puriﬁed by ﬂash column

chromatography on silica gel (petrol/EtOAc, 3:1) to yield

DKP (ꢀ)-13e as a colourless solid (98 mg, 91%), mp 91e

93 ^ꢁC. [a]_D¹⁸ꢀ94.4 (c 0.62, CHCl₃); spectroscopic data were

identical to those for the racemic material.

Second isomer d_H(400 MHz, CDCl₃) 1.66 (1H, dd, J 14.7,

6.4, CHCHHPh), 2.35 (1H, dd, J 14.7, 4.7, CHCHHPh), 3.41

(1H, d, J 14.0, CCHHAr), 3.44 (1H, d, J 14.9, NCHHAr),

3.45 (1H, br s, OH), 3.77 (1H, d, J 14.0, CCHHPh), 3.78

(3H, s, OCH₃), 3.80 (3H, s, OCH₃), 3.86 (1H, dd, J 6.4, 4.7,

CHCH₂Ph), 4.86 (1H, d, J 14.9, NCHHAr), 5.19 (1H, d,

J 14.9, NCHHAr), 5.35 (1H, d, J 14.9, NCHHAr), 5.51 (1H,

br s, CHOH), 6.71 (4H, br s, Ar, CH), 6.84 (2H, d, J 8.8, Ar,

CH), 6.88 (4H, m, Ar, CH), 7.19e7.29 (11H, m, Ar, CH),

7.39 (2H, d, J 8.8, Ar, CH).

3.4.3. (3R,6S)-3,6-Dibenzyl-1,4-bis-(4-methoxybenzyl)-3-

phenylsulfanylpiperazine-2,5-dione 13f

The general procedure was followed using N,N⁰-dibenzyl-

ethylene diamine (48 mL, 0.21 mmol), n-BuLi (0.26 mL of

a 1.6 M solution in hexanes, 0.41 mmol), (3S,6S)-3,6-di-

3.4.5. (3S,6S)-3-Carboethoxy-3,6-dibenzyl-1,4-bis-(4-

methoxybenzyl)piperazine-2,5-dione 13i

benzyl-1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione

22a

The general procedure was followed using N,N⁰-dibenzyl-

ethylene diamine (48 mL, 0.21 mmol), n-BuLi (0.26 mL of

a 1.6 M solution in hexanes, 0.41 mmol) (3S,6S)-3,6-di-

benzyl-1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione 22a

(100 mg, 0.187 mmol), THF (15 mL) and ethyl cyanoformate

(90 mL, 0.94 mmol). The crude product was puriﬁed by ﬂash

column chromatography on silica gel (petrol/EtOAc, 3:1) to

yield the title DKP (ꢀ)-13i as a colourless oil (111 mg, 98%),

[a]¹_D⁸ꢀ14.8 (c 0.97, CHCl₃); n_max(CHCl₃)/cm^ꢀ12958, 2838,

1746, 1657, 1613, 1455, 1356, 1304, 1039; d_H(400 MHz,

CDCl₃) 0.98 (3H, dd, J 7.2, 7.2, CH₃CH₂), 1.00 (1H, dd, J

14.5, 6.4, CHHPh), 2.32 (1H, dd, J 14.5, 4.0, CHHPh), 3.06

(1H, d, J 14.8, NCHHAr), 3.24 (1H, dq, J 10.7, 7.2, CHHCH₃),

3.60 (1H, d, J 14.3, CHHPh), 3.74 (1H, d, J 14.3, CHHPh), 3.76

(3H, s, OCH₃), 3.80 (3H, s, OCH₃), 3.96 (1H, dq, J 10.7, 7.2,

CHHCH₃), 3.97 (1H, dd, J 6.4, 4.0, NCHCO), 4.32 (1H, d, J

14.9, NCHHAr), 5.13 (1H, d, J 14.9, NCHHAr), 5.33 (1H, d, J

14.8, NCHHAr), 6.68 (4H, br s, AreOMe, CH), 6.84 (2H, d,

J 8.6, AreOMe, CH), 6.93 (2H, d, J 6.8, Ar, CH), 7.14 (2H, d,

J 7.2, Ar, CH), 7.21e7.35 (6H, m, Ar, CH), 7.41 (2H, app t, J

7.5, Ar, CH); d_C(125 MHz, CDCl₃) 13.5 (CH₃), 38.2 (CH₂),

41.1 (CH₂), 46.3 (CH₂), 46.8 (CH₂), 55.3 (OCH₃), 55.4

(OCH₃), 59.2 (CH), 62.4 (CH₂), 72.7 (C-3), 113.6 (Ar, CH),

113.9 (Ar, CH), 126.8 (Ar, C), 126.9 (Ar, CH), 128.0 (Ar,

CH), 128.5 (Ar, C), 128.7 (Ar, CH), 129.0 (Ar, CH), 129.2

(Ar, CH), 129.6 (Ar, CH), 130.6 (Ar, CH), 131.2 (Ar, CH),

134.7 (Ar, C), 138.9 (Ar, C), 159.2 (Ar, C), 159.2 (Ar, C),

163.4 (C]O), 167.0 (C]O), 167.8 (C]O); m/z (EI)

C₃₇H₃₈N₂O₆requires: 606.2730, found M^þ: 606.2738.

(100 mg, 0.187 mmol), THF (15 mL) and diphenyl disulﬁde

(200 mg, 0.94 mmol) as a solution in THF (1 mL). The crude

product was puriﬁed by ﬂash column chromatography on sil-

ica gel (petrol/EtOAc, 3:1) to yield the title DKP (þ)-13f as

a colourless solid (120 mg, 99%), mp 146e149 ^ꢁC. [a]_D¹⁸

þ22.3 (c 0.67, CHCl₃); spectroscopic data were identical to

those for the racemic material.

3.4.4. (3S,6S)-1,4-Bis-(4-methoxybenzyl)-3,6-dibenzyl-3-

(hydroxyl(phenyl)methyl)piperazine-2,5-dione 13h

The general procedure was followed using N,N⁰-dibenzyl-

ethylene diamine (48 mL, 0.21 mmol), n-BuLi (0.26 mL of

a

1.6 M solution in hexanes, 0.41 mmol), (3S,6S)-3,6-

dibenzyl-1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione 22a

(100 mg, 0.187 mmol), THF (15 mL) and benzaldehyde

(0.10 mL, 0.94 mmol). The crude product was puriﬁed by

ﬂash column chromatography on silica gel (petrol/EtOAc,

3:1) to yield the title DKP 13h, as a 1:1 mixture of diastereo-

isomers, as a colourless solid (109 mg, 96%). An analytical

sample was prepared by preparative TLC (petrol/EtOAc,

4:1), mp 70e72 ^ꢁC. n_max(CHCl₃)/cm^ꢀ13603, 2936, 2838,

1650, 1612, 1444, 1357, 1304, 1036; d_H(400 MHz, CDCl₃)

1.52 (1H, dd, J 14.6, 6.1, CHCHHPh), 2.14 (1H, dd, J 14.6,

5.0, CHCHHPh), 3.41 (1H, d, J 14.6, NCHHAr), 3.44 (1H,

d, J 14.3, CCHHPh), 3.60 (1H, dd, J 6.1, 5.0, CHCH₂Ph),

3.75 (3H, s, OCH₃), 3.81 (3H, s, OCH₃), 4.13 (1H, d, J

14.3, CCHHPh), 4.84 (1H, d, J 14.6, NCHHAr), 5.00 (1H,

d, J 14.6, NCHHAr), 5.06 (1H, d, J 14.6, NCHHAr), 5.31

(1H, d, J 11.1, CHOH), 5.88 (1H, d, J 11.1, CHOH), 6.10

(2H, d, J 8.8, Ar, CH), 6.54 (2H, d, J 8.5, Ar, CH), 6.77

(2H, dd, J 7.3, 3.5, Ar, CH), 6.82 (2H, d, J 8.8, Ar, CH),

6.88e6.92 (2H, m, Ar, CH), 7.04 (2H, d, J 7.3, Ar, CH),

7.10 (2H, dd, J 7.3, 7.3, Ar, CH), 7.16e7.22 (7H, m, Ar,

CH), 7.43 (2H, d, J 8.8, Ar, CH); d_C(100 MHz, CDCl₃)

39.6 (CH₂), 40.6 (CH₂), 46.1 (CH₂), 47.2 (CH₂), 55.3

(OCH₃), 55.4 (OCH₃), 58.6 (CH), 72.8 (C-3), 75.8 (CH),

113.9 (Ar, CH), 114.1 (Ar, CH), 125.4 (Ar, C), 126.7 (Ar,

CH), 127.0 (Ar, CH), 127.5 (Ar, CH), 127.7 (Ar, CH), 128.3

(Ar, CH), 128.5 (Ar, CH), 128.7 (Ar, CH), 129.0 (Ar, CH),

129.9 (Ar, C), 130.0 (Ar, CH), 131.3 (Ar, CH), 131.7 (Ar,

CH), 135.5 (Ar, C), 138.4 (Ar, C), 139.5 (Ar, C), 159.1 (Ar,

C), 159.4 (Ar, C), 167.3 (C]O), 167.7 (C]O); m/z (ESI)

C₄₁H₄₀N₂NaO₅requires: 663.2829, found [MNa]^þ: 663.2803.

3.5. Typical procedure for substitution of cis-DKP 22c to give

products 13jeo (Table 2)

3.5.1. (3R,6S)-3-Allyl-1,4-bis-(4-methoxybenzyl)-3,6-

dimethylpiperazine-2,5-dione 13j

To a solution of N,N⁰-dibenzylethylene diamine (67 mL,

0.29 mmol) in THF (3 mL) at ꢀ78 ^ꢁC was added n-BuLi

(0.36 mL of a 1.6 M solution in hexane, 0.57 mmol). The solu-

tion was warmed to rt for 10 min, before being recooled to

ꢀ78 ^ꢁC. The basic solution was added via cannula to a solution

of (3S,6S)-3,6-dimethyl-1,4-bis-(4-methoxybenzyl)piperazine-

2,5-dione 22c (100 mg, 0.261 mmol) in THF (30 mL) at

ꢀ78 ^ꢁC. After 60 min, allyl bromide (0.23 mL, 2.6 mmol) was

added and the solution was stirred for a further 75 min. The

3726

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

reaction mixture was quenched by the careful addition of a satu-

rated solution of ammonium chloride (10 mL). After warming to

rt the mixture was separated and the organic phase was washed

with brine (10 mL). The aqueous phase was extracted with

CH₂Cl₂(25 mL), the combined organic extracts dried (MgSO₄)

and the solvent evaporated under reduced pressure. The crude

product was puriﬁed by ﬂash column chromatography on silica

gel (petrol/EtOAc, 2:1) to yield the DKP (þ)-13j as a colourless

oil (92 mg, 84%), mp 93e94 ^ꢁC. [a]_D²⁴þ4.2 (c 1.4, CHCl₃); n_max

(CHCl₃)/cm^ꢀ12958, 2838, 1657, 1650, 1614, 1461, 1304, 1038;

d_H(400 MHz, CDCl₃) 1.41 (3H, s, CCH₃), 1.56 (3H, d, J 6.9,

CHCH₃), 2.62 (1H, dd, J 14.7, 7.0, CHHCH]CH₂), 3.00 (1H,

dd, J 14.7, 7.1, CHHCH]CH₂), 3.78 (3H, s, OCH₃), 3.80 (3H,

s, OCH₃), 3.89 (1H, d, J 14.7, NCHHAr), 3.96 (1H, q, J 6.9,

NCHCO), 4.17 (1H, d, J 15.4, NCHHAr), 5.05 (1H, dd, J 10.3,

1.5, HHC]CH), 5.11 (1H, d, J 15.4, NCHHAr), 5.11 (1H, dd,

J 17.2, 1.5, HHC]CH), 5.37 (1H, d, J 14.7, NCHHAr), 5.45

(1H, dddd, J 17.2, 10.3, 7.1, 7.0, CH₂CH]CH₂), 6.83 (2H, d, J

6.8, Ar, CH), 6.86 (2H, d, J 6.8, Ar, CH), 7.20 (4H, app. t, J

9.0, Ar, CH); d_C(100 MHz, CDCl₃) 19.8 (CH₃), 27.0 (CH₃),

42.5 (CH₂), 44.9 (CH₂), 46.4 (CH₂), 53.7 (CH), 55.3 (OCH₃),

55.3 (OCH₃), 65.6 (C-3), 114.0 (Ar, CH), 114.2 (Ar, CH),

120.2 (CH₂]CH), 127.6 (Ar, C), 128.8 (Ar, CH), 129.9 (Ar,

CH), 130.4 (Ar, C), 131.6 (CH]CH₂), 158.8 (Ar, C), 159.4

(Ar, C), 167.9 (C]O), 168.3 (C]O); m/z (EI) C₂₅H₃₀N₂O₄re-

quires: 442.2206, found M^þ: 442.2200.

a 1.6 M solution in hexane, 0.57 mmol), (3S,6S)-3,6-di-

methyl-1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione 22c

(100 mg, 0.261 mmol), THF (30 mL) and diphenyl disulﬁde

(1.1 g, 5.2 mmol) as a solution in THF (10 mL). The crude

product was puriﬁed by ﬂash column chromatography on sil-

ica gel (petrol/EtOAc, 3:1) to yield the DKP (ꢀ)-13l as a col-

ourless solid (104 mg, 81%), mp 124e126 ^ꢁC. [a]_D²⁴ꢀ6.2 (c

1.1, CHCl₃); n_max(CHCl₃)/cm^ꢀ12936, 2838, 1658, 1613,

1455, 1304, 1036; d_H(400 MHz, CDCl₃) 1.41 (3H, d, J 6.9,

CHCH₃), 1.72 (3H, s, CCH₃), 3.05 (1H, q, J 6.9, NCHCO),

3.79 (3H, s, OCH₃), 3.81 (3H, s, OCH₃), 4.23 (1H, d,

J 14.8, NCHHAr), 4.58 (1H, d, J 15.7, NCHHAr), 4.69 (1H,

d, J 14.9, NCHHAr), 5.44 (1H, d, J 15.7, NCHHAr), 6.82e

6.88 (4H, m, Ar, CH), 7.05 (2H, d, J 9.0, Ar, CH), 7.16e

7.21 (4H, m, Ar, CH), 7.34 (1H, dd, J 8.3, 1.4, Ar, CH),

7.40 (1H, m, Ar, CH), 7.51 (1H, d, J 8.1, 1.4, Ar, CH); d_C

(125 MHz, CDCl₃) 20.5 (CH₃), 26.2 (CH₃), 46.1 (CH₂), 47.6

(CH₂), 54.2 (CH), 55.3 (OCH₃), 55.4 (OCH₃), 75.5 (C-3),

114.0 (Ar, CH), 114.1 (Ar, CH), 127.8 (Ar, C), 128.3 (Ar,

CH), 129.2 (Ar, CH), 129.8 (Ar, C), 130.0 (Ar, CH), 130.0

(Ar, C), 130.4 (Ar, CH), 137.1 (Ar, CH), 158.7 (Ar, C),

159.2 (Ar, C), 165.2 (C]O), 168.2 (C]O); m/z (CI)

C₂₈H₃₁N₂O₄S requires: 491.2005, found [MH]^þ: 491.2003.

3.5.4. (3S,6S)-3-Carboethoxy-1,4-bis-(4-methoxybenzyl)-

3,6-dimethylpiperazine-2,5-dione 13m

The general procedure was followed using N,N⁰-dibenzyl-

ethylene diamine (67 mL, 0.29 mmol), n-BuLi (0.36 mL of

a 1.6 M solution in hexane, 0.57 mmol), (3S,6S)-3,6-di-

methyl-1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione 22c

(100 mg, 0.261 mmol), THF (30 mL) and ethyl cyanoformate

(0.52 mL, 5.2 mmol). The crude product was puriﬁed by ﬂash

column chromatography on silica gel (petrol/EtOAc, 3:1) to

yield the DKP (ꢀ)-13m as a colourless oil (108 mg, 91%).

[a]²_D⁶ꢀ86.9 (c 1.0, CHCl₃); n_max(CHCl₃)/cm^ꢀ12939, 1749,

1660, 1456, 1303, 1114, 1036; d_H(400 MHz, CDCl₃) 1.11

(3H, dd, J 7.2, 7.2, CH₂CH₃), 1.57 (3H, d, J 7.0, CHCH₃),

1.71 (3H, s, CCH₃), 3.73 (1H, dq, J 10.7, 7.2, OCHHCH₃),

3.78 (3H, s, OCH₃), 3.81 (3H, s, OCH₃), 3.86 (1H, d,

J 14.9, NCHHAr), 4.00 (1H, q, J 7.0, NCHCO), 4.11 (1H,

dq, J 10.7, 7.2, OCHHCH₃), 4.33 (1H, d, J 15.3, NCHHAr),

4.59 (1H, d, J 15.3, NCHHAr), 5.40 (1H, d, J 14.9, NCHHAr),

6.81 (2H, d, J 8.7, Ar, CH), 6.85 (2H, d, J 8.7, Ar, CH), 7.17

(4H, app. t, J 10.4, Ar, CH); d_C(100 MHz, CDCl₃) 13.7 (CH₃),

19.4 (CH₃), 22.3 (CH₃), 46.3 (CH₂), 46.8 (CH₂), 53.8 (CH),

55.3 (OCH₃), 55.3 (OCH₃), 62.5 (CH₂), 68.4 (C-3), 113.8

(Ar, CH), 114.3 (Ar, CH), 127.3 (Ar, C), 129.0 (Ar, C),

129.4 (Ar, CH), 129.6 (Ar, CH), 159.0 (Ar, C), 159.4 (Ar,

C), 164.9 (C]O), 167.4 (C]O), 168.0 (C]O); m/z (EI)

C₂₅H₃₀N₂O₆requires: 454.2104, found M^þ: 454.2112.

3.5.2. (3R,6S)-3-Ethyl-1,4-bis-(4-methoxybenzyl)-3,6-

dimethylpiperazine-2,5-dione 13k

The general procedure was followed using N,N⁰-dibenzyl-

ethylene diamine (67 mL, 0.29 mmol), n-BuLi (0.36 mL of

a 1.6 M solution in hexane, 0.57 mmol), (3S,6S)-3,6-dimethyl-

1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione 22c (100 mg,

0.261 mmol) and iodoethane (0.21 mL, 2.6 mmol). The crude

product was puriﬁed by ﬂash column chromatography on silica

gel (petrol/EtOAc, 3:1) to yield the DKP (þ)-13k as a colourless

solid (50 mg, 47%), 100e102 ^ꢁC. [a]_D²⁴þ12.0 (c 0.97, CHCl₃);

n_max(CHCl₃)/cm^ꢀ12936, 2838, 1650, 1613, 1462, 1354.8, 1304,

1037; d_H(500 MHz, CDCl₃) 0.65 (3H, dd, J 7.3, 7.3, CH₂CH₃),

1.38 (3H, s, CH₃), 1.57 (3H, d, J 6.9, CHCH₃), 1.87 (1H, dq, J

14.5, 7.3, CHHCH₃), 2.29 (1H, dq, J 14.5, 7.3, CHHCH₃),

3.79 (3H, s, OCH₃), 3.81 (3H, s, OCH₃), 3.87 (1H, d, J 14.7,

NCHHAr), 4.00 (1H, q, J 6.9, NCHCO), 4.21 (1H, d, J 15.3,

NCHHAr), 4.99 (1H, d, J 15.3, NCHHAr), 5.41 (1H, d, J 14.7,

NCHHAr), 6.83 (2H, d, J 8.8, CH₃OCCH), 6.86 (2H, d, J 8.7,

Ar, CH), 7.19 (2H, d, J 8.7, Ar, CH), 7.23 (2H, d, J 8.8,

CH₃OCCHCH); d_C(125 MHz, CDCl₃) 8.6 (CH₃), 19.8 (CH₃),

27.4 (CH₃), 31.5 (CH₂), 44.7 (CH₂), 46.5 (CH₂), 53.8 (CH),

55.4 (2ꢂOCH₃), 66.2 (C-3), 114.0 (Ar, CH), 114.3 (Ar, CH),

127.7 (Ar, C), 129.0 (Ar, CH), 129.8 (Ar, CH), 130.6 (Ar, C),

158.8 (Ar, C), 159.4 (Ar, C), 168.4 (C]O), 168.6 (C]O); m/z

(EI) C₂₄H₃₀N₂O₄requires: 410.2206, found M^þ: 410.2198.

3.5.5. (S)-1,4-Bis-(4-methoxybenzyl)-3,3,6-trimethyl-

piperazine-2,5-dione 13n

3.5.3. (3R,6S)-1,4-Bis-(4-methoxybenzyl)-3,6-dimethyl-3-

phenylsulfanylpiperazine-2,5-dione 13l

The general procedure was followed using N,N⁰-dibenzyl-

ethylene diamine (67 mL, 0.29 mmol), n-BuLi (0.36 mL of

The general procedure was followed using N,N⁰-dibenzyl-

ethylene diamine (67 mL, 0.29 mmol), n-BuLi (0.36 mL of

a 1.6 M solution in hexane, 0.57 mmol), (3S,6S)-3,6-di-

methyl-1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione 22c

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

3727

(100 mg, 0.261 mmol), THF (30 mL) and methyl iodide

(0.80 mL, 1.3 mmol). The crude product was puriﬁed by ﬂash

column chromatography on silica gel (petrol/EtOAc, 2:1) to

yield DKP (ꢀ)-13n as a colourless oil (79 mg, 76%). [a]_D²⁵

ꢀ51.2 (c 1.15, CHCl₃); n_max(CHCl₃)/cm^ꢀ12935, 2838,

1650, 1454, 1355, 1304, 1036; d_H(500 MHz, CDCl₃) 1.45

(3H, s, CH₃), 1.54 (3H, d, J 7.0, CHCH₃), 1.58 (3H, s,

CH₃), 3.78 (3H, s, OCH₃), 3.80 (3H, s, OCH₃), 3.99 (1H, d,

J 14.7, NCHHAr), 4.03 (1H, q, J 7.0, NCHCO), 4.58 (1H,

d, J 15.4, NCHHAr), 4.70 (1H, d, J 15.4, NCHHAr), 5.23

(1H, d, J 14.7, NCHHAr), 6.83 (2H, d, J 8.6, Ar, CH), 6.87

(2H, d, J 8.6, Ar, CH), 7.17 (4H, d, J 8.6, Ar, CH); d_C

(125 MHz, CDCl₃) 19.0 (CH₃), 26.3 (CH₃), 27.7 (CH₃), 45.3

(CH₂), 46.8 (CH₂), 54.3 (CH), 55.3 (OCH₃), 55.4 (OCH₃),

61.8 (C-3), 114.0 (Ar, CH), 114.3 (Ar, CH), 127.9 (Ar, C),

127.9 (Ar, C), 128.5 (Ar, CH), 129.5 (Ar, CH), 158.7 (Ar,

C), 159.4 (Ar, C), 168.2 (C]O), 169.3 (C]O); m/z (ESI)

C₂₃H₃₀N₂O₄requires: 397.2122, found [MH]^þ: 397.2127.

was extracted with CH₂Cl₂(2ꢂ10 mL). The combined organic

phases were dried (MgSO₄) and the solvent evaporated under

reduced pressure. Toluene (15 mL) was added to the resultant

red oil and the solution heated at reﬂux for 2 h. The solvent

was evaporated under reduced pressure and the crude product

was puriﬁed by ﬂash column chromatography on silica gel

(petrol/EtOAc, 4:1) to yield the title DKP (ꢀ)-23a as a colour-

less solid (27 mg, 70%), mp 70e72 ^ꢁC. [a]_D²⁴ꢀ95.2 (c 0.60,

CHCl₃); n_max(CHCl₃)/cm^ꢀ12936, 2838, 1682, 1614, 1352,

1305, 1037; d_H(500 MHz, CDCl₃) 1.51 (3H, d, J 7.0,

CHCH₃), 3.79 (3H, s, OCH₃), 3.81 (3H, s, OCH₃), 4.08 (1H,

d, J 14.6, NCHHAr), 4.09 (1H, q, J 7.0, NCHCO), 4.57

(1H, d, J 15.5, NCHHAr), 4.99 (1H, d, J 1.2, C]CHH),

5.18 (1H, d, J 15.5, NCHHAr), 5.23 (1H, d, J 14.6, NCHHAr),

5.83 (1H, d, J 1.2, C]CHH), 6.87 (4H, app. t, J 8.4, Ar, CH),

7.11 (2H, d, J 8.6, Ar, CH), 7.22 (2H, d, J 8.6, Ar, CH); d_C

(125 MHz, CDCl₃) 19.6 (CH₃), 46.6 (CH₂), 47.1 (CH₂), 55.2

(OCH₃), 55.3 (OCH₃), 55.4 (CH), 104.9 (C]CH₂), 114.3

(Ar, CH), 114.4 (Ar, CH), 127.6 (Ar, C), 128.0 (Ar, CH),

129.9 (Ar, CH), 129.9 (Ar, C), 136.4 (CH₂]C), 158.8 (Ar,

C), 159.0 (Ar, C), 159.5 (C]O), 166.6 (C]O); m/z (ESI)

C₂₂H₂₄N₂NaO₄requires: 403.1628, found [MNa]^þ: 403.1618.

3.5.6. (3R,6S)-3-Benzyl-1,4-bis-(4-methoxybenzyl)-3,6-

dimethylpiperazine-2,5-dione 13o

The general procedure was followed using N,N⁰-dibenzyl-

ethylene diamine (67 mL, 0.29 mmol), n-BuLi (0.36 mL of

a 1.6 M solution in hexane, 0.57 mmol), (3S,6S)-3,6-di-

methyl-1,4-bis-(4-methoxybenzyl)piperazine-2,5-dione 22c

(100 mg, 0.261 mmol), THF (30 mL) and benzyl bromide

(0.31 mL, 2.6 mmol). The crude product was puriﬁed by ﬂash

column chromatography on silica gel (petrol/EtOAc, 3:1) to

yield the DKP (þ)-13o as a colourless solid (112 mg, 91%),

mp 191e193 ^ꢁC. [a]_D²⁶þ2.3 (c 0.32, CHCl₃); n_max(CHCl₃)/

cm^ꢀ12939, 2838, 1643, 1614, 1461, 1405, 1304, 1038; d_H

(400 MHz, CDCl₃) 1.44 (3H, d, J 6.8, CHCH₃), 1.62 (3H, s,

CCH₃), 3.19 (1H, d, J 14.0, CHHPh), 3.22 (1H, q, J 6.8,

COCHN), 3.38 (1H, d, J 14.0, CHHPh), 3.80 (3H, s, OCH₃),

3.81 (3H, s, OCH₃), 4.08 (1H, d, J 14.8, NCHHAr), 4.18

(1H, d, J 15.4, NCHHAr), 4.92 (1H, d, J 14.8, NCHHAr),

5.43 (1H, d, J 15.4, NCHHAr), 6.78 (2H, d, J 8.7, AreOMe,

CH), 6.87 (4H, d, J 8.8, Ar, CH), 7.06 (2H, dd, J 8.5, 1.5, Ar,

CH), 7.19e7.30 (5H, m, Ar, CH); d_C(100 MHz, CDCl₃) 20.0

(CH₃), 27.2 (CH₃), 44.0 (CH₂), 45.4 (CH₂), 46.7 (CH₂), 53.6

(OCH₃), 53.7 (OCH₃), 55.3 (CH), 66.7 (C-3), 114.0 (Ar,

CH), 114.1 (Ar, CH), 127.2 (CH Ar), 127.4 (Ar, C), 128.3

(Ar, CH), 128.6 (Ar, CH), 129.6 (Ar, CH), 129.9 (Ar, CH),

130.0 (Ar, C), 135.4 (Ar, C), 158.6 (Ar, C), 159.0 (Ar, C),

167.8 (C]O), 168.1 (C]O); m/z (EI) C₂₉H₃₂N₂O₄requires:

472.2362, found M^þ: 472.2355.

3.5.8. Sulfoxide syn-elimination to give (S)-1,4-bis-

(4-methoxybenzyl)-3-benzyl-6-benzylidenepiperazine-

2,5-dione (23b) as an E/Z mixture

To a solution of (3R,6S)-3,6-dibenzyl-1,4-bis-(4-methoxy-

benzyl)-3-phenylsulfanylpiperazine-2,5-dione 13f (100 mg,

0.192 mmol) in CH₂Cl₂(20 mL) was added m-CPBA

(57 mg, 0.19 mmol) and the reaction mixture was stirred at

rt for 4 h. A saturated solution of NaHCO₃(15 mL) was added

and the mixture stirred for a further 30 min. The phases were

separated and the aqueous phase was extracted with CH₂Cl₂

(2ꢂ20 mL). The combined organic extracts were dried

(MgSO₄) and the solvent was evaporated under reduced pres-

sure. Toluene (15 mL) was added to the resultant red oil and

the solution heated at reﬂux for 2 h. The solvent was then

evaporated under reduced pressure and the crude product pu-

riﬁed by ﬂash column chromatography on silica gel (petrol/

EtOAc, 4:1) to yield 23b as a colourless solid, and as

a 1.4:1 mixture of stereoisomers (80 mg, 97%).

Data for mixture of Z-23b and E-23b*: mp 75e78 ^ꢁC; n_max

(CHCl₃)/cm^ꢀ12935, 2838, 1681, 1626, 1456, 1386, 1353,

1304, 1036; d_H(500 MHz, CDCl₃) 3.10 (1H, dd, J 13.6, 8.1,

CHHPh), 3.20 (1H, dd, J 13.6, 6.6, CHHPh*), 3.24 (1H, d,

J 14.9, NCHHAr), 3.25 (1H, dd, J 13.6, 5.1, CHHPh), 3.28

(1H, dd, J 13.6, 4.7, CHHPh*), 3.48 (1H, d, J 14.9,

NCHHAr*), 3.76 (3H, s, OCH₃), 3.79 (3H, s, OCH₃), 3.80

(3H, s, OCH₃*), 3.81 (3H, s, OCH₃*), 3.87 (1H, d, J 14.9,

NCHHAr), 4.16 (1H, dd, J 8.1, 5.1, CHCH₂Ph), 4.31 (1H,

dd, J 6.6, 4.7, CHCH₂Ph*), 4.90 (2H, br s, NCH₂Ar*), 5.17

(1H, d, J 14.9, NCHHAr), 5.23 (1H, d, J 14.9, NCHHAr),

5.29 (1H, J 14.9, NCHHAr*), 6.35 (1H, s, C]CHPh*), 6.72

(2H, d, J 8.9, AreOMe, CH), 6.77 (2H, d, J 8.5, AreOMe,

CH*), 6.80 (2H, d, J 9.0, AreOMe, CH*), 7.10 (2H, d,

J 8.5, AreOMe, CH*), 7.11 (1H, s, C]CHPh), 7.14 (2H, d,

J 9.0, AreOMe, CH*), 7.18 (2H, d, J 8.7, AreOMe, CH),

3.5.7. Sulfoxide syn-elimination to give (S)-1,4-bis-(4-

methoxybenzyl)-3-methyl-6-methylenepiperazine-

2,5-dione 23a

To a solution of (3R,6S)-1,4-bis-(4-methoxybenzyl)-3,6-di-

methyl-3-phenylsulfanylpiperazine-2,5-dione 13l (50 mg,

0.10 mmol) in CH₂Cl₂(10 mL) was added m-CPBA (68 mg,

0.22 mmol) and the reaction mixture was stirred at rt for

16 h. A saturated solution of sodium hydrogencarbonate

(10 mL) was added and the mixture was stirred for a further

30 min. The phases were separated and the aqueous phase

3728

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

7.18e7.28 (15H, m, Ar, CH), 7.30 (2H, d, J 7.3, Ar, CH), 7.31

(2H, d, J 7.3, Ar, CH), 7.38 (1H, d, J 7.3, Ar, CH*), 7.42 (1H,

dd, J 7.3, 7.3, Ar, CH), 7.44 (1H, d, J 7.3, Ar, CH*); d_C

(125 MHz, CDCl₃) 38.4 (CH₂*), 38.7 (CH₂), 47.2 (CH₂*),

47.4 (2ꢂCH₂), 47.7 (CH₂*), 55.2 (OCH₃), 55.3 (OCH₃), 60.8

(CH*), 61.8 (CH), 113.8 (Ar, CH), 114.2 (Ar, CH), 114.2 (Ar,

CH), 114.3 (Ar, CH), 122.9 (C]CH), 123.9 (C]CH*), 127.6

(Ar, CH), 127.7 (Ar, CH), 127.7 (Ar, CH), 127.7 (Ar, CH),

127.8 (Ar, CH), 128.5, 128.6 (Ar, C), 128.6 (Ar, CH), 128.9

(Ar, CH), 129.1 (Ar, CH), 129.1 (Ar, CH), 129.2 (Ar, C),

129.3 (Ar, CH), 129.4 (Ar, CH), 129.5 (Ar, CH), 129.7 (Ar,

CH), 129.8 (Ar, CH), 129.9 (Ar, CH), 133.5 (Ar, C), 134.3

(Ar, C), 135.2 (C]CH), 135.5 (C]CH), 159.0 (Ar, C), 159.1

(Ar, C), 159.2 (Ar, C), 159.4 (Ar, C), 159.8 (C]O), 163.0

(C]O), 166.3 (C]O), 167.6 (C]O); m/z (ESI)

C₃₄H₃₂N₂NaO₄requires: 555.2254, found [MNa]^þ: 555.2257.

that more base was employedd2 equiv for 36b and 3 equiv

for 36c.

3.6.2. (3S,8aR)-8a-Allyl-3-benzyl-2-(4-methoxybenzyl-

octahydropyrrolo[1,2a]pyrazine-1,4-dione 37b

The general procedure was followed using (3S,8aS)-3-benz-

yl-2-(4-methoxybenzyl)octahydropyrrolo[1,2a]pyrazine-1,4-

dione 36b (100 mg, 0.274 mmol), THF (5 mL), LiHMDS

(0.54 mL of a 1.06 M solution in THF, 0.58 mmol) and allyl

bromide (0.11 mL, 1.4 mmol). The crude product was puriﬁed

by ﬂash column chromatography on silica gel (petrol/EtOAc,

3:1) to yield the title DKP 37b as a colourless wax (79 mg,

71%). [a]²_D¹ꢀ37.7 (c 0.70, CHCl₃); n_max(CHCl₃)/cm^ꢀ12957,

2838, 1651, 1614, 1454, 1304, 1036; d_H(500 MHz, CDCl₃)

0.51 (1H, m, CCHHCH₂), 1.41 (1H, m, CH₂CHHCH₂),

1.66e1.69 (2H, m, CCHHCH₂, CH₂CHHCH₂), 2.16 (1H, dd,

J 13.8, 7.2, CHHCH]CH₂), 2.49 (1H, dd, J 13.8, 7.8,

CHHCH]CH₂), 3.13e3.18 (1H, m, NCHHCH₂), 3.22 (1H,

dd, J 13.9, 4.2, CHHPh), 3.29 (1H, dd, J 13.9, 3.0, CHHPh),

3.75 (1H, m, NCHHCH₂), 3.82 (3H, s, OCH₃), 3.97 (1H, d,

J 14.6, NCHHAr), 4.17 (1H, app. t, J 3.6, CHCH₂Ph), 4.98e

5.02 (2H, m, CH₂]CH), 5.40 (1H, m, CH]CH₂), 5.63 (1H,

d, J 14.6, NCHHAr), 6.88 (2H, d, J 7.7, AreOMe, CH), 7.08

(2H, d, J 7.7, AreOMe, CH), 7.21e7.29 (5H, m, Ar, CH); d_C

(125 MHz, CDCl₃) 19.2 (CH₂), 34.0 (CH₂), 36.1 (CH₂), 41.8

(CH₂), 43.2 (CH₂), 45.8 (CH₂), 53.4 (CH₃), 59.5 (CH), 67.2

(C-8a), 114.2 (Ar, CH), 120.3 (HC]CH₂), 127.0 (Ar, C),

127.3 (Ar, CH), 128.5 (H₂C]CH), 130.0 (Ar, CH), 130.5

(Ar, CH), 131.3 (Ar, CH), 134.9 (Ar, C), 159.5 (Ar, C), 163.9

(C]O), 167.9 (C]O); m/z (ESI) C₂₅H₂₈N₂O₃requires:

427.1992, found [MNa]^þ: 427.1997.

3.6. Typical procedure for substitution of proline derived

DKPs 36 to give products 37e43 (Table 3)

3.6.1. (3S,8aR)-8a-Allyl-2-(4-methoxybenzyl)-3-methyl-

octahydropyrrolo[1,2a]pyrazine-1,4-dione 37a

To a solution of (3S,8aS)-2-(4-methoxybenzyl)-3-methyl-

octahydropyrrolo[1,2a]pyrazine-1,4-dione

36a

(100 mg,

0.347 mmol) in THF (30 mL), cooled to ꢀ78 ^ꢁC was added

LiHMDS (0.49 mL of

a

1.06 M solution in THF,

0.52 mmol). After stirring the solution for 1 h, allyl bromide

(0.15 mL, 1.7 mmol) was added. The solution was stirred for

a further 3 h, after which time, the reaction mixture was

quenched by the careful addition of a saturated solution of am-

monium chloride (15 mL). The phases were separated and the

aqueous phase was extracted with diethyl ether (2ꢂ10 mL).

The organic extracts were combined, washed with brine

(15 mL), dried (MgSO₄) and the solvent was evaporated under

reduced pressure. The crude product was puriﬁed by ﬂash col-

umn chromatography on silica gel (petrol/EtOAc, 2:1) to yield

the title compound 37a as a colourless foam (58 mg, 51%).

[a]¹_D⁸ꢀ42.9 (c 0.34, CHCl₃); n_max(CHCl₃)/cm^ꢀ12957, 1652,

1456, 1404, 1304, 1036; d_H(400 MHz, CDCl₃) 1.54 (3H, d,

J 7.0, CHCH₃), 1.94e2.20 (2H, m, CH₂CHHCH₂), 2.17e2.32

(2H, m, CCHHCH₂), 2.44 (1H, dd, J 13.7, 7.6, CHHCH]CH₂),

2.61 (1H, dd, J 13.7, 7.8, CHHCH]CH₂), 3.50 (1H, m,

NCHHCH₂), 3.81 (3H, s, OCH₃), 3.87 (1H, ddd, J 12.3, 8.3,

8.2, NCHHCH₂), 4.04 (1H, q, J 7.0, NCHCO), 4.08 (1H, d,

J 15.2, NCHHAr), 5.10 (1H, dd, J 11.1. 0.9, HC]CHH),

5.14 (1H, dd, J 17.2, 0.9, HC]CHH), 5.34 (1H, d, J 15.2,

NCHHAr), 5.68 (1H, dddd, J 17.2, 11.1, 7.8, 7.6, H₂C]CH),

6.86 (2H, d, J 8.5, Ar, CH), 7.21 (2H, d, J 8.5, Ar, CH); d_C

(100 MHz, CDCl₃) 16.4 (CH₃), 20.0 (CH₂), 35.1 (CH₂), 41.8

(CH₂), 45.2 (CH₂), 45.4 (CH₂), 54.3 (CH), 55.3 (OCH₃), 67.3

(C-8a), 114.1 (Ar, CH), 120.6 (CH]CH₂), 128.4 (Ar, C),

129.2 (Ar, CH), 131.3 (H₂C]CH), 159.1 (Ar, C), 165.7

(C]O), 170.2 (C]O); m/z (ESI) C₁₉H₂₄N₂O₃requires:

328.1787, found [MH]^þ: 328.1789.

3.6.3. (3S,8aR)-8a-Allyl-3-isopropyl-2-(4-methoxybenzyl)-

octahydropyrrolo[1,2a]pyrazine-1,4-dione 37c

The general procedure was followed using (3S,8aS)-2-(4-

methoxybenzyl)-3-isopropylpyrrolooctahydro[1,2a]pyrazine-

1,4-dione 36c (50 mg, 0.16 mmol), THF (10 mL), LiHMDS

(0.45 mL of a 1.06 M solution in THF, 0.47 mmol) and allyl

bromide (68 mL, 0.79 mmol). The crude product was puriﬁed

by ﬂash column chromatography on silica gel (petrol/EtOAc,

3:1) to yield the title DKP 37c as a colourless foam (41 mg,

73%). [a]¹_D⁵ꢀ80 (c 0.19, CHCl₃); n_max(CHCl₃)/cm^ꢀ12963,

1647, 1454, 1342, 1303, 1036; d_H(500 MHz, CDCl₃) 0.77

(3H, d, J 6.9, CH₃), 1.13 (3H, d, J 7.0, CH₃), 1.96e2.10

(3H, m, CCHHCH₂, CH₂CH₂CH₂), 2.22 (1H, ddd, J 9.4,

6.8, 3.3, CCHHCH₂), 2.32 (1H, app. qd, J 6.9, 2.4,

CH(CH₃)₂), 2.37 (1H, dd, J 13.7, 7.4, CHHCH]CH₂), 2.61

(1H, dd, J 13.7, 7.4, CHHCH]CH₂), 3.38 (1H, ddd, J 12.5,

8.7, 5.8, NCHHCH₂), 3.75 (1H, d, J 2.4, NCHCO), 3.81

(3H, s, OCH₃), 3.90 (1H, ddd, J 12.5, 5.5, 3.6, NCHHCH₂),

3.92 (1H, d, J 14.5, NCHHAr), 5.02 (1H, dd, J 10.3, 1.5,

CH₂CH]CHH), 5.08 (1H, dd, J 17.2, 1.5, CH₂CH]CHH),

5.34 (1H, d, J 14.5, NCHHAr), 5.50 (1H, dddd, J 17.2, 10.3,

7.4, 7.4, CH₂CH]CH₂), 6.86 (2H, d, J 8.6, Ar, CH), 7.20

(2H, d, J 8.6, Ar, CH); d_C(125 MHz, CDCl₃) 15.4 (CH₃),

19.7 (CH₂), 20.0 (CH₃), 30.2 (CH), 35.2 (CH₂), 42.2 (CH₂),

43.3 (CH₂), 46.4 (CH₂), 55.4 (OCH₃), 63.7 (CH), 67.1

All reactions of 36a were carried out in a similar way,

using 1.5 equiv of LHMDS with respect to the starting DKP.

For DKPs 36b and 36c, the procedure was the same, except

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

3729

(C-8a), 114.1 (Ar, CH), 120.6 (HC]CH₂), 127.3 (Ar, C),

130.4 (Ar, CH), 131.3 (HC]CH₂), 159.3 (Ar, C), 163.9

(C]O), 168.5 (C]O); m/z (ESI) C₂₁H₂₈N₂NaO₃requires:

379.1992, found [MNa]^þ: 379.1981.

J 8.7, AreOMe, CH), 7.21e7.28 (5H, m, Ar, CH); d_C

(125 MHz, CDCl₃) 18.0 (CH₃), 19.4 (CH₂), 25.9 (CH₃), 34.3

(CH₂), 36.0 (CH₂), 36.5 (CH₂), 43.6 (CH₂), 45.5 (CH₂), 55.4

(OCH₃), 59.2 (CH), 67.5 (C-8a), 114.3 (Ar, CH), 117.2

(C]CH), 127.2 (Ar, CH), 127.3 (Ar, C), 128.4 (Ar, CH),

129.9 (Ar, CH), 130.4 (Ar, CH), 135.0 (Ar, C), 137.1

(CH]C), 159.5 (Ar, C), 163.8 (C]O), 168.4 (C]O); m/z

(ESI) C₂₇H₃₃N₂O₃requires: 433.2491, found [MH]^þ: 433.2486.

A sample for X-ray crystal structure determination was pre-

pared from DKP 38b (25 mg) via vapour diffusion from EtOAc

(0.5 mL) and petrol (5 mL) over a period of 3 days.

3.6.4. (3S,8aR)-2-(4-Methoxybenzyl)-3-methyl-8a-

(3-methylbut-2-enyl)octahydropyrrolo[1,2a]-pyrazine-

1,4-dione 38a

The general procedure was followed using (3S,8aS)-2-(4-

methoxybenzyl)-3-methyloctahydropyrrolo[1,2a]pyrazine-

1,4-dione 36a (100 mg, 0.347 mmol), THF (30 mL), LiHMDS

(0.49 mL of a 1.06 M solution in THF, 0.52 mmol) and

1-bromo-3-methylbut-2-ene (20 mL, 1.7 mmol). The crude

product was puriﬁed by ﬂash column chromatography on silica

gel (petrol/EtOAc, 2:1) to yield the title DKP 38a as a colourless

foam (76 mg, 60%). [a]¹_D⁴ꢀ52 (c 0.58, CHCl₃); n_max(CHCl₃)/

cm^ꢀ12935, 2838, 1650, 1614, 1455, 1304, 1036; d_H(500 MHz,

CDCl₃) 1.54 (3H, d, J 7.0, CHCH₃), 1.56 (6H, br s, C(CH₃)₂),

1.92e2.04 (2H, m, CH₂CHHCH₂), 2.16e2.28 (2H, m,

CCHHCH₂), 2.41 (1H, dd, J 14.0, 8.0, CHHCH]C(CH₃)₂),

2.56 (1H, dd, J 14.0, 7.7, CHHCH]C(CH₃)₂), 3.48 (1H, ddd, J

12.6, 9.1, 4.4, NCHHCH₂), 3.79 (3H, s, OCH₃), 3.84 (1H, ddd,

J 12.6, 8.4, 8.4, NCHHCH₂), 3.94 (1H, q, J 7.0, NCHCO), 4.04

(1H, d, J 15.0, NCHHAr), 4.96 (1H, app. tt, J 7.7, 1.2,

CH]C(CH₃)₂), 5.35 (1H, d, J 15.0, NCHHAr), 6.86 (2H, d, J

8.6, Ar, CH), 7.20 (2H, d, J 8.6, Ar, CH); d_C(125 MHz,

CDCl₃) 16.9 (CH₃), 17.9 (CH₃), 20.2 (CH₂), 25.9 (CH₃), 35.6

(CH₂), 36.5 (CH₂), 45.2 (CH₂), 45.4 (CH₂), 54.5 (CH), 55.3

(OCH₃), 67.8 (C-8a), 113.9 (Ar, CH), 117.3 (C]CH), 128.4

(Ar, C), 129.4 (Ar, CH), 137.4 (C]CH), 159.1 (Ar, C), 165.6

(C]O), 170.5 (C]O); m/z (ESI) C₂₁H₂₈N₂NaO₃requires:

379.1992, found [MNa]^þ: 379.1971.

3.6.6. (3S,8aR)-8a-Benzyl-2-(4-methoxybenzyl)-3-methyl-

octahydropyrrolo[1,2a]pyrazine-1,4-dione 39a

The general procedure was followed using (3S,8aS)-2-

(4-methoxybenzyl)-3-methyloctahydropyrrolo[1,2a]pyrazine-

1,4-dione 36a (100 mg, 0.347 mmol), THF (30 mL), LiHMDS

(0.49 mL of a 1.06 M solution in THF, 0.52 mmol) and benzyl

bromide (0.21 mL, 1.7 mmol). The crude product was puriﬁed

by ﬂash column chromatography on silica gel (petrol/EtOAc,

2:1) to yield the title DKP 39a as a colourless foam (82 mg,

62%). [a]²_D⁸þ10 (c 0.18, CHCl₃); n_max(CHCl₃)/cm^ꢀ12957,

1650, 1454, 1374, 1303, 1039; d_H(500 MHz, CDCl₃) 1.26

(3H, d, J 7.0, CH₃), 1.96e2.04 (2H, m, CH₂CHHCH₂), 2.27

(1H, ddd, J 12.8, 11.1, 9.2, CCHHCH₂), 2.39 (1H, ddd,

J 12.8, 7.2, 2.4, CCHHCH₂), 2.63 (1H, q, J 7.0, CHCH₃),

2.93 (1H, d, J 13.4, CHHPh), 3.20 (1H, d, J 13.4, CHHPh),

3.68 (1H, ddd, J 12.6, 9.3, 4.6, NCHHCH₂), 3.80 (3H, s,

OCH₃), 3.95 (1H, ddd, J 12.6, 8.5, 8.5, NCHHCH₂), 4.40

(1H, d, J 15.1, NCHHAr), 4.47 (1H, d, J 15.1, NCHHAr),

6.82 (2H, d, J 8.6, Ar, CH), 7.03 (2H, d, J 8.6, Ar, CH),

7.06 (2H, d, J 7.3, Ar, CH), 7.18 (2H, d, J 8.2, Ar, CH),

7.25 (1H, m, Ar, CH); d_C(125 MHz, CDCl₃) 17.1 (CH₃),

19.8 (CH₂), 36.6 (CH₂), 43.2 (CH₂), 45.0 (CH₂), 46.7 (CH₂),

55.2 (CH), 55.3 (OCH₃), 68.7 (C-7a), 113.9 (Ar, CH), 127.5

(Ar, CH), 128.6 (Ar, CH), 129.0 (Ar, C), 129.2 (Ar, CH),

130.2 (Ar, CH), 135.2 (Ar, C), 158.9 (Ar, C), 165.8 (C]O),

170.3 (C]O); m/z (ESI) C₂₃H₂₇N₂O₃requires: 379.2016,

found [MH]^þ: 379.2026.

3.6.5. (3S,8aR)-3-Benzyl-2-(4-methoxybenzyl)-8a-

(3-methylbut-2-enyl)octahydropyrrolo[1,2a]pyrazine-

1,4-dione 38b

The general procedure was followed using (3S,8aS)-3-benz-

yl-2-(4-methoxybenzyl)octahydropyrrolo[1,2a]pyrazine-1,4-

dione (500 mg, 1.37 mmol), THF (25 mL), LiHMDS

(2.65 mL of a 1.06 M solution in THF, 2.81 mmol) and 1-

bromo-3-methylbut-2-ene (0.80 mL, 6.9 mmol). The crude

product was puriﬁed by ﬂash column chromatography on silica

gel (light petroleum/EtOAc, 3:1), to yield the title DKP 38b as

a colourless solid (467 mg, 82%), mp 90e91 ^ꢁC. [a]_D²⁵ꢀ60.0

(c 0.97, CHCl₃); n_max(CHCl₃)/cm^ꢀ12934, 2839, 1732, 1651,

1614, 1454, 1303, 1109, 1036; d_H(500 MHz, CDCl₃) 0.63

(1H, m, CCHHCH₂), 1.40 (1H, ddd, J 20.0, 9.9, 4.7,

CH₂CHHCH₂), 1.49 (3H, d, J 0.6, CH₃), 1.52 (3H, d, J 0.6,

CH₃), 1.66e1.74 (2H, m, CCHHCH₂, CH₂CHHCH₂), 2.17

(1H, dd, J 14.2, 7.7, CHHCH]C(CH₃)₂), 2.43 (1H, dd, J

14.2, 7.5, CHHCH]C(CH₃)₂), 3.17 (1H, ddd, J 12.3, 9.1,

4.7, NCHHCH₂), 3.23 (1H, dd, J 14.0, 4.2, CHHPh), 3.29

(1H, dd, J 14.0, 3.0, CHHPh), 3.65 (1H, ddd, J 12.3, 9.9,

5.8, NCHHCH₂), 3.81 (3H, s, OCH₃), 3.94 (1H, d, J 14.5,

NCHHAr), 4.13 (1H, app. t, J 3.6, CHCH₂Ph), 4.75 (1H,

app. tt, J 7.6, 1.2, CH]C(CH₃)₂), 5.68 (1H, d, J 14.5,

NCHHAr), 6.88 (2H, d, J 8.7, AreOMe, CH), 7.08 (2H, d,

3.6.7. (3S,8aR)-3-Benzyl-8a-benzyl-2-(4-methoxybenzyl)-

octahydropyrrolo[1,2a]pyrazine-1,4-dione 39b

The general procedure was followed using (3S,8aS)-3-benz-

yl-2-(4-methoxybenzyl)octahydropyrrolo[1,2a]pyrazine-1,4-

dione 36b (100 mg, 0.274 mmol) THF (5 mL), LiHMDS

(0.54 mL of a 1.06 M solution in THF, 0.58 mmol) and benzyl

bromide (0.16 mL, 1.4 mmol). The crude product was puriﬁed

by ﬂash column chromatography on silica gel (petrol/EtOAc,

3:1) to yield the title DKP 39b as a colourless solid (71 mg,

58%), mp 127e129 ^ꢁC. [a]_D²¹ꢀ17.5 (c 0.99, CHCl₃); n_max

(CHCl₃)/cm^ꢀ12937, 2838, 1650, 1614, 1454, 1304, 1036;

d_H(400 MHz, CDCl₃) 0.55e0.64 (1H, ddd, J 19.8, 9.3, 6.5,

CCHHCH₂), 1.49 (1H, m, CH₂CHHCH₂), 1.74e1.86 (2H,

m, CCHHCH₂, CH₂CHHCH₂), 2.79 (1H, d, J 13.4, CCHHPh),

2.98 (1H, dd, J 14.0, 4.2, CHCHHPh), 3.01 (1H, d, J 13.4,

CCHHPh), 3.07 (1H, dd, J 14.0, 3.1, CHCHHPh), 3.39 (1H,

ddd, J 12.1, 9.5, 4.6, NCHHCH₂), 3.56 (1H, app. t, J 3.6,

3730

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

CHCH₂Ph), 3.80 (3H, s, OCH₃), 3.90 (1H, ddd, J 12.1, 9.5,

5.6, NCHHCH₂), 3.91 (1H, d, J 14.8, NCHHAr), 5.32 (1H,

d, J 14.8, NCHHAr), 6.57 (2H, d, J 8.6, AreOMe, CH),

6.71 (2H, d, J 8.6, AreOMe, CH), 6.99e7.05 (4H, m, Ar,

CH), 7.20e7.31 (6H, m, Ar, CH); d_C(100 MHz, CDCl₃)

19.4 (CH₂), 35.2 (CH₂), 35.8 (CH₂), 42.6 (CH₂), 43.5 (CH₂),

45.9 (CH₂), 55.3 (CH₃), 58.8 (CH), 68.6 (C-8a), 114.1 (Ar,

CH), 126.2 (Ar, C), 127.0 (Ar, CH), 127.2 (Ar, CH), 128.5

(Ar, CH), 128.7 (Ar, CH), 129.9 (Ar, CH), 130.1 (Ar, CH),

130.1 (Ar, CH), 135.0 (Ar, C), 135.6 (Ar, C), 159.2 (Ar, C),

164.3 (C]O), 167.5 (C]O); m/z (ESI) C₂₉H₃₁N₂O₃requires:

455.2329, found [MH]^þ: 455.2320.

1.80 (1H, dq, J 14.6, 7.4, CHHCH₃), 3.07 (1H, ddd, J 12.1,

10.1, 5.3, NCHHCH₂), 3.24 (1H, dd, J 13.9, 4.2, CHHPh),

3.31 (1H, dd, J 13.9, 3.0, CHHPh), 3.72 (1H, ddd, J 10.1,

7.3, 5.1, NCHHCH₂), 3.80 (3H, s, OCH₃), 3.97 (1H, d,

J 14.4, NCHHAr), 4.22 (1H, app. t, J 3.6, CHCH₂Ph), 5.67

(1H, d, J 14.4, NCHHAr), 6.88 (2H, d, J 8.7, AreOMe, CH),

7.08 (2H, d, J 8.7, AreOMe, CH), 7.21e7.29 (5H, m, Ar, CH);

d_C(100 MHz, CDCl₃) 8.1 (CH₃), 19.3 (CH₂), 30.7 (CH₂), 34.1

(CH₂), 36.1 (CH₂), 43.1 (CH₂), 45.8 (CH₂), 55.3 (CH₃), 59.4

(CH), 67.7 (C-8a), 114.3 (Ar, CH), 127.2 (Ar, C), 127.3 (Ar,

CH), 129.1 (Ar, CH), 130.6 (Ar, CH), 130.7 (Ar, CH), 134.9

(Ar, C), 159.5 (Ar, C), 164.1 (C]O), 168.3 (C]O); m/z (ESI)

C₂₄H₂₉N₂O₃requires: 393.2173, found [MH]^þ: 393.2184.

3.6.8. (3S,8aR)-8a-Benzyl-3-isopropyl-2-(4-methoxybenzyl)-

octahydropyrrolo[1,2a]pyrazine-1,4-dione 39c

3.6.10. (3S,8aR)-8a-Ethyl-3-isopropyl-2-(4-methoxybenzyl)-

octahydropyrrolo[1,2a]pyrazine-1,4-dione 40c

The general procedure was followed using (3S,8aS)-2-(4-

methoxybenzyl)-3-isopropylpyrrolooctahydro[1,2a]pyrazine-

1,4-dione 36c (50 mg, 0.16 mmol), THF (10 mL), LiHMDS

(0.45 mL of a 1.06 M solution in THF, 0.47 mmol) and benzyl

bromide (94 mL, 0.79 mmol). The crude product was puriﬁed

by ﬂash column chromatography on silica gel (petrol/EtOAc,

3:1) to yield the title DKP 39c as a colourless foam (53 mg,

83%). [a]¹_D⁵ꢀ23.9 (c 1.74, CHCl₃); n_max(CHCl₃)/cm^ꢀ12933,

2895, 1651, 1456, 1345, 1303, 1037; d_H(500 MHz, CDCl₃)

0.62 (3H, d, J 7.0, CH₃), 0.91 (3H, d, J 7.0, CH₃), 2.00 (1H,

qd, J 7.0, 2.2, CH(CH₃)₂), 2.02e2.14 (2H, m, CH₂CH₂CH₂),

2.17 (1H, ddd, J 12.2, 9.5, 9.5, CCHHCH₂), 2.38 (1H, ddd,

J 12.2, 9.8, 8.0, CCHHCH₂), 2.89 (1H, d, J 2.2, NCHCO),

2.97 (1H, d, J 13.3, CHHPh), 3.14 (1H, d, J 13.3, CHHPh),

3.58 (1H, ddd, J 12.6, 9.8, 4.7, NCHHCH₂), 3.77 (3H, s,

OCH₃), 4.03 (1H, ddd, J 12.6, 9.5, 6.2, NCHHCH₂), 4.04

(1H, d, J 15.0, NCHHAr), 4.66 (1H, d, J 15.0, NCHHAr),

6.62 (2H, d, J 8.4, AreOMe, CH), 6.70 (2H, d, J 8.8, Ar,

CH), 7.07 (2H, d, J 8.4, AreOMe, CH), 7.28 (2H, dd, J 8.8,

7.3, Ar, CH), 7.32 (1H, d, J 7.3, Ar, CH); d_C(125 MHz,

CDCl₃) 15.1 (CH₃), 19.9 (CH₃), 19.9 (CH₂), 29.9 (CH), 36.5

(CH₂), 43.2 (CH₂), 43.6 (CH₂), 47.2 (CH₂), 55.3 (OCH₃),

63.7 (CH), 68.5 (C-8a), 113.8 (Ar, CH), 127.1 (Ar, C), 127.2

(Ar, CH), 128.7 (Ar, CH), 129.8 (Ar, CH), 130.2 (Ar, CH),

135.5 (Ar, C), 158.9 (Ar, C), 164.2 (C]O), 168.4 (C]O);

m/z (ESI) C₂₅H₃₀N₂NaO₃requires: 429.2149, found [MNa]^þ:

429.2141.

The general procedure was followed using (3S,8aS)-2-(4-

methoxybenzyl)-3-isopropylpyrrolooctahydro[1,2a]pyrazine-

1,4-dione 36c (50 mg, 0.16 mmol), THF (10 mL), LiHMDS

(0.45 mL of a 1.06 M solution in THF, 0.47 mmol) and iodo-

ethane (64 mL, 0.79 mmol). The crude product was puriﬁed by

ﬂash column chromatography on silica gel (petrol/EtOAc, 3:1)

to yield the title DKP 40c as a colourless foam (33 mg, 61%).

[a]¹_D⁵ꢀ70 (c 0.06, CHCl₃); n_max(CHCl₃)/cm^ꢀ12959, 1731,

1644, 1462, 1374, 1046; d_H(500 MHz, CDCl₃) 0.72 (3H, t,

J 7.5, CH₂CH₃), 0.79 (3H, d, J 6.6, CH₃), 1.16 (3H, d, J 7.0,

CH₃), 1.65 (1H, m, CH₂CHHCH₂), 1.94 (2H, q, J 7.5,

CH₂CH₃), 1.94 (1H, m, CH₂CHHCH₂), 2.06 (1H, ddd, J 12.4,

11.0, 9.5, CCHHCH₂), 2.19 (1H, ddd, J 12.4, 7.0, 3.3,

CCHHCH₂), 2.38 (1H, qd, J 7.0, 2.2, CH(CH₃)₂), 3.31 (1H,

ddd, J 12.4, 8.8, 5.9, NCHHCH₂), 3.80 (1H, d, J 2.2, NCHCO),

3.81 (3H, s, OCH₃), 3.91 (1H, m, NCHHCH₂), 3.93 (1H, d,

J 14.4, NCHHAr), 5.40 (1H, d, J 14.4, NCHHAr), 6.87 (2H, d,

J 8.8, Ar, CH), 7.21 (2H, d, J 8.8, Ar, CH); d_C(125 MHz,

CDCl₃) 8.2 (CH₃), 15.5 (CH₃), 19.9 (CH₂), 20.1 (CH₃), 30.3

(CH), 31.2 (CH₂), 35.3 (CH₂), 43.3 (CH₂), 46.4 (CH₂), 55.3

(OCH₃), 63.6 (CH), 67.6 (C-8a), 114.2 (Ar, CH), 127.5 (Ar,

C), 130.3 (Ar, CH), 159.4 (Ar, C), 164.0 (C]O), 168.7

(C]O); m/z (ESI) C₂₀H₂₈N₂NaO₃requires: 367.1992, found

[MNa]^þ: 367.1961.

3.6.11. (3S,8aS)-8a-Carboethoxy-2-(4-methoxybenzyl)-

3-methyloctahydropyrrolo[1,2a]pyrazine-1,4-dione 41a

3.6.9. (3S,8aS)-3-Benzyl-8a-ethyl-2-(4-methoxybenzyl)-

octahydropyrrolo[1,2a]pyrazine-1,4-dione 40b

The general procedure was followed using (3S,8aS)-2-

(4-methoxybenzyl)-3-methyloctahydropyrrolo[1,2a]pyrazine-

1,4-dione 36a (100 mg, 0.347 mmol), THF (30 mL), LiHMDS

(0.49 mL of a 1.06 M solution in THF, 0.52 mmol) and ethyl

cyanoformate (0.17 mL, 1.7 mmol). The crude product was

puriﬁed by ﬂash column chromatography on silica gel (pet-

rol/EtOAc, 2:1) to yield the title DKP 41a as a colourless

foam (103 mg, 83%). [a]²_D⁴ꢀ99 (c 0.41, CHCl₃); n_max

(CHCl₃)/cm^ꢀ12958, 2838, 1738, 1668, 1614, 1458, 1402,

1304, 1037; d_H(500 MHz, CDCl₃) 1.26 (3H, t, J 7.1,

CH₂CH₃), 1.52 (3H, d, J 7.0, CHCH₃), 1.96e2.03 (2H, m,

CH₂CHHCH₂), 2.46 (1H, ddd, J 13.2, 10.2, 8.4, CCHHCH₂),

2.73 (1H, ddd, J 13.2, 6.2, 4.0, CCHHCH₂), 3.62 (1H, ddd,

J 12.1, 7.7, 5.1, NCHHCH₂), 3.73 (1H, ddd, J 12.1, 8.0, 7.3,

The general procedure was followed using (3S,8aS)-3-benz-

yl-2-(4-methoxybenzyl)octahydropyrrolo[1,2a]pyrazine-1,4-

dione 36b (100 mg, 0.274 mmol), THF (5 mL), LiHMDS

(0.54 mL of a 1.06 M solution in THF, 0.58 mmol) and iodo-

ethane (0.11 mL, 1.4 mmol). The crude product was puriﬁed

by ﬂash column chromatography on silica gel (petrol/EtOAc,

3:1) to yield the title DKP 40b as a colourless wax (60 mg,

56%). [a]²_D¹ꢀ72.2 (c 0.68, CHCl₃); n_max(CHCl₃)/cm^ꢀ12971,

2838, 1645, 1614, 1456, 1304, 1035; d_H(400 MHz, CDCl₃)

0.45 (1H, ddd, J 14.8, 4.5, 1.4, CCHHCH₂), 0.61 (3H, t, J 7.4,

CH₂CH₃), 1.34 (1H, m, CH₂CHHCH₂), 1.44 (1H, dq, J 14.6,

7.4, CHHCH₃), 1.58e1.67 (2H, m, CCHHCH₂, CH₂CHHCH₂),

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

3731

NCHHCH₂), 3.79 (3H, s, OCH₃), 4.01 (1H, d, J 15.4,

NCHHAr), 4.06 (1H, q, J 7.0, NCHCO), 4.24 (2H, app. qd,

J 7.1, 1.0, CH₂CH₃), 5.42 (1H, d, J 15.4, NCHHAr), 6.84

(2H, d, J 8.6, Ar, CH), 7.14 (2H, d, J 8.6, Ar, CH); d_C

(125 MHz, CDCl₃) 14.2 (CH₃), 14.8 (CH₃), 21.3 (CH₂), 34.0

(CH₂), 45.3 (CH₂), 46.0 (CH₂), 54.4 (CH), 55.3 (OCH₃),

63.0 (CH₂), 71.2 (C-8a), 114.1 (Ar, CH), 128.4 (Ar, C),

128.7 (Ar, CH), 159.1 (Ar, C), 166.1 (C]O), 166.4 (C]O),

168.7 (C]O); m/z (ESI) C₁₉H₂₅N₂O₅requires: 361.1763,

found [MH]^þ: 361.1728.

6.6, 3.7, CCHHCH₂), 3.38 (1H, ddd, J 12.2, 8.7, 6.0,

NCHHCH₂), 3.78 (1H, ddd, J 12.2, 8.7, 7.7, NCHHCH₂),

3.80 (3H, s, OCH₃), 3.84 (1H, d, J 2.3, NCHCO), 3.91 (1H,

d, J 15.0, NCHHAr), 4.19 (1H, q, J 7.1, OCHHCH₃), 4.20

(1H, q, J 7.1, OCHHCH₃) 5.52 (1H, d, J 15.0, NCHHAr),

6.85 (2H, d, J 8.6, Ar, CH), 7.14 (2H, d, J 8.6, Ar, CH); d_C

(125 MHz, CDCl₃) 14.0 (CH₃), 15.6 (CH₃), 20.1 (CH₂), 20.4

(CH₃), 29.6 (CH), 33.1 (CH₂), 44.4 (CH₂), 46.0 (CH₂), 55.3

(OCH₃), 63.0 (CH₂), 63.4 (CH), 71.0 (C-8a), 114.1 (Ar, CH),

127.5 (Ar, C), 129.5 (Ar, CH), 159.3 (Ar, C), 164.6 (C]O),

164.8 (C]O), 168.5 (C]O); m/z (ESI) C₂₁H₂₈N₂NaO₅

requires: 411.1890, found [MNa]^þ: 411.1870.

3.6.12. (3S,8aR)-3-Benzyl-8a-carboethoxy-2-(4-methoxy-

benzyl)octahydropyrrolo[1,2a]pyrazine-1,4-dione 41b

The general procedure was followed using (3S,8aS)-3-ben-

zyl-2-(4-methoxybenzyl)octahydropyrrolo[1,2a]pyrazine-1,4-

dione 36b (100 mg, 0.274 mmol), THF (5 mL), LiHMDS

(0.54 mL of a 1.06 M solution in THF, 0.58 mmol) and ethyl

cyanoformate (0.14 mL, 1.4 mmol). The crude product was

puriﬁed by ﬂash column chromatography on silica gel (pet-

rol/EtOAc, 3:1) to yield the title DKP 41b as a colourless solid

(83 mg, 69%), mp 118e120 ^ꢁC. [a]_D²¹ꢀ83.3 (c 0.76, CHCl₃);

n_max(CHCl₃)/cm^ꢀ12958, 2838, 1738, 1667, 1613, 1454,

1303, 1111, 1036; d_H(500 MHz, CDCl₃) 1.40 (3H, t, J 7.1,

OCH₂CH₃), 1.98e2.02 (2H, m, CH₂CH₂CH₂), 2.44 (1H,

ddd, J 13.3, 11.0, 9.5, CCHHCH₂), 2.66 (1H, ddd, J 13.3,

5.5, 3.7, CCHHCH₂), 2.85 (1H, dd, J 13.9, 9.9, CHHPh),

3.02 (1H, d, J 15.0, NCHHAr), 3.20 (1H, dd, J 13.9, 5.5,

CHHPh), 3.65 (1H, ddd, J 12.1, 7.0, 5.5, NCHHCH₂), 3.76

(3H, s, OCH₃), 3.80 (1H, ddd, J 12.1, 8.8, 5.9, NCHHCH₂),

4.05 (1H, dd, J 9.9, 5.5, CHCH₂Ph), 4.38 (2H, q, J 7.1,

OCH₂CH₃), 5.04 (1H, d, J 15.0, NCHHAr), 6.76 (2H, d,

J 8.6, AreOMe, CH), 6.86 (2H, d, J 8.6, AreOMe, CH), 7.20

(2H, d, J 7.0, Ar, CH), 7.30 (1H, app. t, J 7.7, Ar, CH), 7.35

(2H, dd, J 7.5, 7.0, Ar, CH); d_C(125 MHz, CDCl₃) 14.3

(CH₃), 20.7 (CH₂), 35.8 (CH₂), 45.9 (CH₂), 46.4 (CH₂), 48.1

(CH₂), 55.3 (OCH₃), 62.9 (CH), 63.1 (CH₂), 70.6 (C-8a),

114.3 (Ar, CH), 127.3 (Ar, CH), 127.6 (Ar, C), 128.8 (Ar,

CH), 129.2 (Ar, CH), 129.7 (Ar, CH), 136.8 (Ar, C), 159.3

(Ar, C), 164.3 (C]O), 165.3 (C]O), 169.8 (C]O); m/z (EI)

C₂₅H₂₉N₂O₅requires: 437.2071, found [MH]^þ: 437.2079.

3.6.14. Preparation of (3S)-2-(4-methoxybenzyl)-3-methyl-

8a-(phenylthio)octahydropyrrolo[1,2a]-pyrazine-

1,4-dione 42a

The general procedure was followed using (3S,8aS)-2-

(4-methoxybenzyl)-3-methyloctahydropyrrolo[1,2a]pyrazine-

1,4-dione 36a (100 mg, 0.347 mmol), THF (30 mL), LiHMDS

(0.49 mL of a 1.06 M solution in THF, 0.52 mmol) and di-

phenyl disulﬁde (20 mg, 1.7 mmol) as a solution in THF

(1 mL). The crude product was puriﬁed by ﬂash column chro-

matography on silica gel (petrol/EtOAc, 2:1) to yield the title

DKP 42a as a 1:1 mixture of diastereoisomers, and in the form

of a colourless foam (71 mg, 52%). Data for diastereomeric

mixture: n_max(CHCl₃)/cm^ꢀ12935, 2838, 1660, 1614, 1456,

1349, 1304, 1110, 1037; d_H(500 MHz, CDCl₃) 1.34 (6H, br

d, J 7.3, CH₃), 1.94e2.08 (2H, m, CH₂), 2.14e2.34 (3H, m,

CH₂), 2.36e2.50 (3H, m, CH₂), 3.09 (1H, q, J 7.0, NCHCO),

3.67e3.84 (4H, m, NCH₂CH₂), 3.79 (3H, s, OCH₃), 3.82

(3H, s, OCH₃), 3.88 (1H, q, J 7.3, NCHCO), 3.98 (1H, d,

J 14.5, NCHHAr), 4.29 (1H, d, J 15.1, NCHHAr), 4.81 (1H,

d, J 15.1, NCHHAr), 5.14 (1H, d, J 14.5, NCHHAr), 6.84

(2H, d, J 8.8, Ar, CH), 6.88 (2H, d, J 8.8, Ar, CH), 7.19e

7.24 (2H, m, SAr, CH), 7.20 (2H, d, J 8.8, Ar, CH), 7.24

(2H, d, J 8.8, Ar, CH), 7.33e7.39 (5H, m, SAr, CH), 7.42

(1H, app. tt, J 7.3, 1.3, SAr, CH), 7.55 (2H, dd, J 8.0, 1.3,

SAr, CH); d_C(125 MHz, CDCl₃) 16.8 (CH₃), 17.8 (CH₃),

19.7 (CH₂), 20.0 (CH₂), 36.0 (CH₂), 36.8 (CH₂), 45.6 (CH₂),

45.8 (CH₂), 46.3 (CH₂), 46.6 (CH₂), 55.1 (CH), 55.3 (OCH₃),

55.4 (OCH₃), 56.6 (CH), 74.2 (C-8a), 75.1 (C-8a), 114.1 (Ar,

CH), 114.2 (Ar, CH), 128.0 (Ar, C), 128.4 (Ar, CH), 129.1

(Ar, CH), 129.2 (Ar, CH), 129.3 (Ar, CH), 129.8 (C, Ar),

130.0 (Ar, CH), 130.2 (Ar, CH), 130.3 (Ar, C), 130.7 (Ar, C),

136.9 (Ar, CH), 137.4 (Ar, CH), 159.1 (Ar, C), 159.4 (Ar, C),

165.3 (C]O), 166.3 (C]O), 166.8 (C]O), 166.9 (C]O);

m/z (CI) C₂₂H₂₅N₂O₃S requires: 397.1586, found [MH]^þ:

397.1574.

3.6.13. (3S,8aS)-8a-Carboethoxy-3-isopropyl-2-

(4-methoxybenzyl)octahydropyrrolo[1,2a]pyrazine-

1,4-dione 41c

The general procedure was followed using (3S,8aS)-2-(4-me-

thoxybenzyl)-3-isopropylpyrrolooctahydro[1,2a]pyrazine-1,4-

dione 36c (50 mg, 0.16 mmol), THF (10 mL), LiHMDS

(0.45 mL of a 1.06 M solution in THF, 0.47 mmol) and ethyl

cyanoformate (78 mL, 0.79 mmol). The crude product was pu-

riﬁed by ﬂash column chromatography on silica gel (petrol/

EtOAc, 3:1) to yield the title DKP 41c as a colourless foam

(34 mg, 55%). [a]_D¹⁵ꢀ71.8 (c 0.51, CHCl₃); n_max(CHCl₃)/

cm^ꢀ12965, 2934, 1744, 1658, 1456, 1303, 1037; d_H

(500 MHz, CDCl₃) 0.89 (3H, d, J 6.9, CH₃), 1.18 (3H, d,

J 7.3, CH₃), 1.22 (3H, t, J 7.1, OCH₂CH₃), 1.92e2.00 (2H,

m, CH₂CH₂CH₂), 2.16 (1H, ddd, J 13.0, 10.8, 9.3, CCHHCH₂),

2.40 (1H, app. dp, J 7.0, 2.3, CH(CH₃)₂), 2.90 (1H, ddd, J 13.0,

3.6.15. (3S)-3-Benzyl-2-(4-methoxybenzyl)-8a-(phenyl-

sulfanyl)octahydropyrrolo[1,2a]pyrazine-1,4-dione 42b

The general procedure was followed using (3S,8aS)-3-benz-

yl-2-(4-methoxybenzyl)octahydropyrrolo[1,2a]pyrazine-1,4-

dione 36b (100 mg, 0.274 mmol), THF (5 mL), LiHMDS

(0.54 mL of a 1.06 M solution in THF, 0.58 mmol) and di-

phenyl disulﬁde (0.30 g, 1.4 mmol). The crude product was

puriﬁed by ﬂash column chromatography on silica gel

3732

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

(petrol/EtOAc, 3:1) to yield the title compound 42b as a 2:1

mixture of diastereoisomers, and in the form of a colourless

solid (78 mg, 60%). Data for a diastereomeric mixture

(*¼minor isomer): n_max(CHCl₃)/cm^ꢀ12957, 2934, 2838,

1660, 1613, 1454, 1305, 1036; d_H(400 MHz, CDCl₃) 1.13

(1H, m, CH₂CHHCH₂*), 1.55 (1H, m, CH₂CHHCH₂*), 1.98

(1H, m, CH₂CHHCH₂), 2.04e2.11 (2H, m, CCHHCH₂*),

2.12 (1H, m, CCHHCH₂), 2.23 (1H, m, CH₂CHHCH₂), 2.40

(1H, ddd, J 13.1, 7.0, 6.4, CH₂CHHCH₂), 3.04 (1H, d, J 14.6,

NCHHAr), 3.09 (1H, dd, J 14.1, 3.2, CHHPh*), 3.16 (1H, dd,

J 14.1, 4.1, CHHPh*), 3.31 (1H, dd, J 14.0, 5.5, CHHPh),

3.36 (1H, dd, J 14.0, 9.0, CHHPh), 3.51e3.62 (2H, m,

NCHHCH₂*), 3.64 (1H, app. t, J 3.6, CHCH₂Ph*), 3.70 (1H,

ddd, J 12.2, 9.6, 2.6, NCHHCH₂), 3.77 (3H, s, OCH₃), 3.78

(1H, ddd, J 12.2, 8.5, 3.2, NCHHCH₂), 3.85 (3H, s, OCH₃*),

4.04 (1H, d, J 14.6, NCHHAr*), 4.12 (1H, dd, J 9.0, 5.5,

CHCH₂Ph), 5.15 (1H, d, J 14.6, NCHHAr), 5.32 (1H, d,

J 14.6, NCHHAr*), 6.76 (2H, d, J 8.8, Ar, CH), 6.86 (2H,

d, J 8.8, Ar, CH), 6.88 (2H, d, J 8.8, Ar, CH*), 6.99 (2H, dd,

J 7.9, 1.5, Ar, CH*), 7.11 (2H, d, J 8.5, Ar, CH*), 7.16 (1H,

d, J 7.0, Ar, CH), 7.21 (2H, dd, J 8.2, 1.5, Ar, CH*), 7.23e

7.27 (2H, m, Ar, CH), 7.32e7.53 (5Hþ6H*, m, Ar, CH),

7.67 (2H, dd, J 7.6, 1.5, Ar, CH); d_C(100 MHz, CDCl₃) 19.3

(CH₂), 19.7 (CH₂), 35.7 (CH₂), 35.9 (CH₂), 36.4 (CH₂), 40.3

(CH₂), 44.5 (CH₂), 45.8 (CH₂), 46.7 (CH₂), 47.3 (CH₂), 55.3

(OCH₃), 55.4 (OCH₃), 59.9 (CH), 62.5 (CH), 73.8 (C-8a),

75.8 (C-8a), 114.1 (Ar, CH), 114.2 (Ar, CH), 127.1 (Ar, C),

127.2 (Ar, C), 127.3 (Ar, CH), 127.5 (Ar, CH), 127.9 (Ar, C),

128.4 (Ar, CH), 129.0 (Ar, CH), 129.1 (Ar, CH), 129.2 (Ar,

CH), 129.4 (Ar, CH), 129.7 (Ar, CH), 129.8 (Ar, CH), 129.9

(Ar, CH), 130.1 (Ar, C), 130.2 (Ar, CH), 130.8 (Ar, CH),

130.9 (Ar, C), 134.6 (Ar, C), 136.8 (Ar, CH), 136.9 (Ar, CH),

159.3 (Ar, C), 159.5 (Ar, C), 163.8 (C]O), 165.6 (C]O),

166.1 (2ꢂC]O); m/z (CI) C₂₈H₂₉N₂O₃S requires: 473.1899,

found [MH]^þ: 473.1890.

(1H, m, NCHHCH₂), 3.76 (1H, d, J 2.6, NCHCO), 3.78 (3H,

s, OCH₃), 3.81 (3H, s, OCH₃*), 3.86 (1H, m, NCHHCH₂*),

3.89 (1H, d, J 14.6, NCHHAr), 4.22 (1H, d, J 15.0, NCHHAr*),

4.65 (1H, d, J 15.0, NCHHAr*), 5.44 (1H, J 14.6, NCHHAr),

6.82 (2H, J 8.5, AreOMe, CH), 6.83 (2H, d, J 8.5, AreOMe,

CH*), 7.04 (2H, d, J 8.5, AreOMe, CH*), 7.13 (2H, d, J 8.5,

AreOMe, CH), 7.35 (2H, dd, J 8.1, 1.4, SAr, CH), 7.38 (2H,

dd, J 7.3, 1.5, SAr, CH), 7.40e7.45 (2H, m, 2ꢂSAr, CH),

7.62 (1H, d, J 8.0, SAr, CH*), 7.63 (1H, d, J 8.0, SAr, CH);

d_C(125 MHz, CDCl₃) 15.0 (CH₂), 19.7 (CH₂), 19.8 (CH₂),

19.9 (CH₂), 20.1 (CH₃), 21.1 (CH₃), 30.1 (CH), 33.0 (CH),

36.0 (CH₂), 36.9 (CH₂), 44.6 (CH₂), 45.9 (CH₂), 47.9 (CH₂),

49.5 (CH₂), 55.3 (OCH₃), 55.4 (OCH₃), 64.8 (CH), 67.3

(CH), 73.4 (C-8a), 76.1 (C-8a), 113.9 (Ar, CH), 114.3 (Ar,

CH), 127.9 (Ar, C), 128.2 (Ar, C), 129.0 (Ar, CH), 129.1 (Ar,

CH), 129.5 (Ar, CH), 129.9 (Ar, CH), 130.0 (Ar, CH), 130.2

(Ar, CH), 130.3 (Ar, C), 131.2 (Ar, C), 136.6 (Ar, CH), 137.3

(Ar, CH), 159.1 (Ar, C), 159.3 (Ar, C), 166.2 (C]O), 166.3

(C]O), 166.8 (C]O), 167.2 (C]O); m/z (ESI)

C₂₄H₂₉N₂O₃S requires: 425.1899, found [MH]^þ: 425.1890.

3.6.17. (3S,8aR)-8a-(S)-Hydroxy(phenyl)methyl-2-

(4-methoxybenzyl)-3-methyloctahydropyrrolo-

[1,2a]pyrazine-1,4-dione 43a

The general procedure was followed using (3S,8aS)-2-

(4-methoxybenzyl)-3-methyloctahydropyrrolo[1,2a]pyrazine-

1,4-dione 36a (100 mg, 0.347 mmol), THF (30 mL), LiHMDS

(0.49 mL of a 1.06 M solution in THF, 0.52 mmol) and benz-

aldehyde (0.18 mL, 1.7 mmol). The crude product was puriﬁed

by ﬂash column chromatography on silica gel (petrol/EtOAc,

2:1) to yield the title DKP 43a as a colourless foam (82 mg,

63%). [a]²_D⁸ꢀ11 (c 0.11, CHCl₃); n_max(CHCl₃)/cm^ꢀ12934,

1650, 1455, 1305, 1037; d_H(500 MHz, CDCl₃) 1.40 (3H, d,

J 7.0, CH₃), 1.67 (1H, m, CH₂CHHCH₂), 1.77 (1H, m,

CH₂CHHCH₂), 2.28 (1H, ddd, J 13.5, 10.2, 10.2, CCHHCH₂),

2.65 (1H, ddd, J 13.5, 8.8, 2.9, CCHHCH₂), 3.27 (1H, ddd,

J 11.5, 9.9, 4.8, NCHHCH₂), 3.31 (1H, q, J 7.0, CHCH₃),

3.80 (3H, s, OCH₃), 3.82 (1H, ddd, J 11.5, 9.5, 6.2,

NCHHCH₂), 4.29 (1H, d, J 15.2, NCHHAr), 4.83 (1H, d, J

15.2, NCHHAr), 5.02 (1H, br s, CHOH), 6.85 (2H, d, J 8.8,

Ar, CH), 7.15 (2H, d, J 8.8, Ar, CH), 7.28 (2H, d, J 8.8, Ar,

CH), 7.29 (2H, d, J 8.8, Ar, CH), 7.33 (1H, m, Ar, CH); d_C

(125 MHz, CDCl₃) 16.5 (CH₃), 20.8 (CH₂), 32.5 (CH₂), 46.5

(CH₂), 47.3 (CH₂), 54.9 (CH), 55.3 (OCH₃), 71.4 (C-8a),

78.1 (CH), 114.2 (Ar, CH), 127.3 (Ar, CH), 128.4 (Ar, CH),

128.5 (Ar, C), 128.8 (Ar, CH), 129.0 (Ar, CH), 138.5 (Ar,

C), 159.0 (Ar, C), 166.0 (C]O), 170.3 (C]O); m/z (ESI)

C₂₃H₂₆N₂NaO₄requires: 417.1785, found [MNa]^þ: 417.1786.

3.6.16. (3S)-3-Isopropyl-2-(4-methoxybenzyl)-8a-(phenyl-

sulfanyl)octahydropyrrolo[1,2a]pyrazine-1,4-dione 42c

The general procedure was followed using (3S,8aS)-2-(4-

methoxybenzyl)-3-isopropylpyrrolooctahydro[1,2a]pyrazine-

1,4-dione 36c (50 mg, 0.16 mmol), THF (10 mL), LiHMDS

(0.45 mL of a 1.06 M solution in THF, 0.47 mmol) and di-

phenyl disulﬁde (0.17 g, 0.79 mmol) as a solution in THF

(1 mL). The crude product was puriﬁed by ﬂash column chro-

matography on silica gel (petrol/EtOAc, 3:1) to yield the title

compound 42c as a 1.6:1 mixture of diastereomers, and in the

form of a colourless foam (43 mg, 64%). Data for a diastereo-

meric mixture (*¼minor isomer): n_max(CHCl₃)/cm^ꢀ12932,

1658, 1461, 1304, 1038; d_H(500 MHz, CDCl₃) 0.60 (3H, d,

J 7.0, CH₃*), 0.96 (3H, d, J 7.0, CH₃*), 1.16 (3H, d, J 7.0,

CH₃), 1.27 (3H, d, J 7.0, CH₃), 1.90 (1H, m, CH₂CHHCH₂),

1.99 (1H, ddd, J 13.2, 11.7, 7.7, CCHHCH₂), 2.06 (1H, m,

CH₂CHHCH₂*), 2.09 (1H, ddd, J 13.1, 11.7. 7.7, CCHHCH₂*),

2.19e2.21 (2H, m, 2ꢂCH₂CHHCH₂), 2.28e2.32 (2H, m,

2ꢂCH(CH₃)₂), 2.34e2.41 (2H, m, 2ꢂCCHHCH₂), 2.50 (1H,

ddd, J 13.6, 9.9, 8.0, NCHHCH₂*), 2.74 (1H, ddd, J 13.5,

8.5, 6.5, NCHHCH₂), 2.92 (1H, d, J 2.6, NCHCO*), 3.75

3.6.18. (3S,8aR)-3-Benzyl-8a-(S)-hydroxy(phenyl)methyl)-

2-(4-methoxybenzyl)octahydropyrrolo[1,2a]pyrazine-

1,4-dione 43b

The general procedure was followed using (3S,8aS)-3-benz-

yl-2-(4-methoxybenzyl)octahydropyrrolo[1,2a]pyrazine-1,4-

dione 36b (100 mg, 0.274 mmol), THF (5 mL), LiHMDS

(0.54 mL of a 1.06 M solution in THF, 0.58 mmol) and benz-

aldehyde (0.14 mL, 1.4 mmol). The crude product was

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

3733

puriﬁed by ﬂash column chromatography on silica gel (pet-

rol/EtOAc, 3:1) to yield the title DKP 43b as a colourless

oil (74 mg, 57%). [a]²_D⁸ꢀ0.50 (c 1.2, CHCl₃); n_max

(CHCl₃)/cm^ꢀ13401, 2930, 1652, 1624, 1455, 1305, 1088,

1063; d_H(400 MHz, CDCl₃) 0.41 (1H, ddd, J 12.4, 10.5,

10.2, CCHHCH₂), 1.51 (1H, m, CH₂CHHCH₂), 1.82 (1H,

m, CH₂CHHCH₂), 2.51 (1H, ddd, J 12.4, 8.5, 1.2,

CCHHCH₂), 2.98 (1H, dd, J 14.0, 4.1, CHHPh), 3.12 (1H,

dd, J 14.0, 3.2, CHHPh), 3.39 (1H, ddd, J 12.3, 10.5, 4.5,

NCHHCH₂), 3.60 (1H, app. t, J 3.5, CHCH₂Ph), 3.83 (3H,

s, OCH₃), 3.89 (1H, ddd, J 12.3, 9.9, 6.1, NCHHCH₂),

3.95 (1H, d, J 14.6, NCHHAr), 4.54 (1H, d, J 9.9, CHOH),

4.98 (1H, d, J 9.9, OH), 5.28 (1H, d, J 14.6, NCHHAr),

6.64 (2H, d, J 8.5, Ar, CH), 6.76 (2H, J 8.8, Ar, CH), 7.03

(2H, dd, J 7.6, 1.8, Ar, CH), 7.17 (2H, dd, J 8.5, 1.7, Ar,

CH), 7.26e7.34 (6H, m, Ar, CH); d_C(100 MHz, CDCl₃)

19.4 (CH₂), 31.7 (CH₂), 35.9 (CH₂), 44.3 (CH₂), 46.0

(CH₂), 55.4 (OCH₃), 58.8 (CH), 69.8 (C-8a), 73.4 (CH),

114.2 (Ar, CH), 125.4 (Ar, C), 126.6 (Ar, CH), 127.6 (Ar,

CH), 127.8 (Ar, CH), 128.5 (Ar, CH), 128.7 (Ar, CH),

129.9 (Ar, CH), 130.3 (Ar, CH), 134.8 (Ar, C), 139.1 (Ar,

C), 159.5 (Ar, C), 164.6 (C]O), 168.0 (C]O); m/z (ESI)

C₂₉H₃₀N₂NaO₄requires: 493.2098, found [MNa]^þ:

493.2083.

OCH₃), 4.88 (1H, app. t, J 7.2, CH]C(CH₃)₂), 4.98 (1H, d,

J 15.2, NCHHAr), 5.54 (1H, d, J 15.2, NCHHAr), 6.63 (2H,

d, J 7.3, Ar, CH), 6.85 (2H, d, J 8.6, AreOMe, CH), 6.98

(2H, app. t, J 7.6, Ar, CH), 7.06 (1H, app. t, J 7.3, Ar, CH),

7.30 (2H, d, J 8.6, AreOMe, CH), 7.34 (2H, d, J 7.7, Ar,

CH), 7.36e7.41 (1H, m, Ar, CH), 7.46 (2H, d, J 6.9, Ar,

CH); d_C(125 MHz, CDCl₃) 18.0 (CH₃), 18.8 (CH₂), 25.9

(CH₃), 31.9 (CH₂), 38.2 (CH₂), 41.6 (CH₂), 44.8 (CH₂), 47.6

(CH₂), 55.4 (OCH₃), 66.5 (C-8a), 85.1 (C-3), 114.0 (Ar, CH),

118.0 (C]CH), 127.2 (Ar, CH), 128.0 (Ar, CH), 129.1 (Ar,

CH), 129.7 (Ar, C), 130.2 (Ar, CH), 130.5 (Ar, CH), 130.7

(Ar, C), 131.1 (Ar, CH), 134.5 (Ar, C), 134.7 (C]CH),

137.3 (Ar, CH), 159.1 (Ar, C), 162.0 (C]O), 170.1 (C]O);

m/z (CI) 541 (M^þ, 9%), 448 (M^þꢀBn, 3%), 433 (M^þꢀSPh,

69%), 121 (CH₃OC₆H₄CH₂^þ, 100%), 110 (PhS^þ, 10%). A sam-

ple for X-ray crystal structure determination was prepared from

DKP 44 (25 mg) via vapour diffusion from EtOAc (0.5 mL)

and petrol (5 mL) over a period of 7 days.

3.6.20. (1R,7R,10R)-1-Benzyl-2,8-diketo-9-(4-methoxy-

benzyl)-10-(1-methylethenyl)-3,9-diazatricyclo-

[4.4.3.0]undecane 45

To a solution of (3S,8aR)-3-benzyl-2-(4-methoxybenzyl)-

8a-(3-methylbut-2-enyl)-3-(phenylthio)octahydropyrrolo[1,2a]-

pyrazine-1,4-dione 44 (50 mg, 0.095 mmol) in CH₂Cl₂

(10 mL), cooled to 0 ^ꢁC, was added m-CPBA as a solution in

CH₂Cl₂(1 mL). After stirring the solution for 16 h, a saturated

solution of sodium hydrogencarbonate (10 mL) was added and

the mixture was stirred for a further 45 min. The phases were

separated and the aqueous phase was extracted with CH₂Cl₂

(15 mL). The combined organic extracts were washed with

brine (10 mL), dried (MgSO₄) and the solvent was evaporated

under reduced pressure. Toluene (10 mL) was added to the res-

idue and the mixture was heated at reﬂux for 45 min. The reac-

tion mixture was allowed to cool to rt and the solvent was

evaporated under reduced pressure. The crude product was pu-

riﬁed by ﬂash column chromatography on silica gel (petrol/

EtOAc, 4:1), to yield the title DKP as a 1:1 mixture of E/Z iso-

mers, and in the form of a colourless oil (37 mg, 94%). n_max

(CHCl₃)/cm^ꢀ12936, 1675, 1625, 1454, 1383, 1304, 1037; d_H

(400 MHz, CDCl₃) 0.80 (1H, m, CH₂), 1.15 (3H, s, CH₃),

1.19 (3H, s, CH₃), 1.53 (3H, s, CH₃), 1.59 (3H, s, CH₃),

1.83e1.95 (4H, m, CH₂), 2.08e2.21 (4H, m, CH₂), 2.29 (1H,

ddd, J 13.1, 10.2, 8.7, CCHHCH₂), 2.48 (1H, ddd, J 12.3,

7.6, 5.3, CCHHCH₂), 2.52 (1H, m, CH₂), 2.95 (1H, m, CH₂),

3.12 (1H, m, CH₂), 3.49 (1H, ddd, J 12.6, 8.2, 4.0, NCHHCH₂),

3.65 (3H, s, OCH₃), 3.67 (1H, m, NCHHCH₂), 3.72 (3H, s,

OCH₃), 3.97 (1H, d, J 14.6, NCHHAr), 4.52 (1H, m,

HC]C(CH₃)₂), 4.66 (1H, d, J 15.5, NCHHAr), 5.05 (1H, m,

HC]C(CH₃)₂), 5.10 (1H, d, J 15.5, NCHHAr), 5.11 (1H, d,

J 14.6, NCHHAr), 6.45 (1H, s, C]CHPh), 6.61 (2H,

d, J 8.8, Ar, CH), 6.72 (2H, d, J 8.8, Ar, CH), 6.78 (2H, d,

J 8.8, Ar, CH), 7.00 (1H, s, C]CHPh), 7.12e7.15 (4H, m,

Ar, CH), 7.17e7.20 (4H, m, Ar, CH), 7.26e7.29 (3H, m, Ar,

CH), 7.32 (1H, d, J 6.1, Ar, CH); d_C(100 MHz, CDCl₃) 8.4

(CH₃), 18.0 (CH₃), 21.0 (CH₂), 26.2 (CH₃), 28.4 (CH₃), 34.0

(CH₂), 34.5 (CH₂), 36.5 (CH₂), 37.3 (CH₂), 38.1 (CH₂), 45.2

3.6.19. (3S,8aR)-3-Benzyl-2-(4-methoxybenzyl)-8a-

(3-methylbut-2-enyl)-3-(phenylthio)octahydropyrrolo-

[1,2a]pyrazine-1,4-dione 44

To a solution of N,N⁰-dibenzylethylene diamine (62 mL,

2.6 mmol) in THF (2 mL) cooled to ꢀ78 ^ꢁC, was added n-

BuLi (0.31 mL of a 1.6 M solution in hexanes, 4.9 mmol).

The solution was allowed to warm to rt for 10 min, then re-

cooled to ꢀ78 ^ꢁC. The basic solution was added via cannula

to a solution of (3S,8aR)-3-benzyl-2-(4-methoxybenzyl)-

8a-(3-methylbut-2-enyl)octahydropyrrolo[1,2a]pyrazine-1,4-

dione 38b (100 mg, 0.231 mmol), in THF (12 mL), cooled to

ꢀ78 ^ꢁC. The solution was stirred for 60 min, after which

time, a solution of diphenyl disulﬁde (0.26 g, 1.2 mmol) in

THF (2 mL) was added. After stirring for a further 70 min,

the reaction mixture was quenched by the careful addition

of a saturated solution of ammonium chloride (10 mL). The

phases were separated and the aqueous phase was extracted

with CH₂Cl₂(2ꢂ10 mL). The combined organic extracts

were washed with brine (10 mL), dried (MgSO₄) and the sol-

vent was evaporated under reduced pressure. The crude prod-

uct was puriﬁed by ﬂash column chromatography on silica

gel (petrol/EtOAc, 3:1), to yield the title DKP 44 as a colour-

less crystalline solid (80 mg, 64%), mp 61e63 ^ꢁC. [a]_D²⁰ꢀ22.8

(c 0.56, CHCl₃); n_max(CHCl₃)/cm^ꢀ12934, 1710, 1656, 1612,

1454, 1392, 1108, 1036; d_H(500 MHz, CDCl₃) 0.62 (1H,

app. dd, J 23.0, 10.4, CCHHCH₂), 1.26e1.36 (2H, m,

CCHHCH₂, CH₂CHHCH₂), 1.32 (3H, s, CH₃), 1.50 (1H, m,

CH₂CHHCH₂), 1.58 (3H, s, CH₃), 1.63 (1H, dd, J 15.1, 7.4,

CHHCH]C(CH₃)₂), 1.73 (1H, dd, J 15.1, 7.0, CHHCH]

C(CH₃)₂), 3.21 (1H, ddd, J 12.5, 10.5, 4.2, NCHHCH₂), 3.23

(1H, d, J 14.0, CHHPh), 3.55 (1H, ddd, J 12.5, 9.6, 7.0,

NCHHCH₂), 3.78 (1H, d, J 14.0, CHHPh), 3.83 (3H, s,

3734

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

(CH₂), 46.0 (CH₂), 47.3 (CH₂), 48.0 (CH₂), 55.2 (OCH₃), 55.3

(OCH₃), 68.2 (C-8a), 68.5 (C-8a), 113.8 (Ar, CH), 114.3 (Ar,

CH), 117.0 (C]CH), 117.2 (C]CH), 120.5 (C]CH), 122.6

(C]CH), 126.7 (Ar, CH), 127.8 (Ar, CH), 128.2 (Ar, CH),

128.3 (Ar, CH), 128.6 (Ar, CH), 128.7 (Ar, C), 128.8 (Ar,

CH), 128.9 (Ar, C), 129.4 (Ar, CH), 129.6 (Ar, CH), 132.1

(Ar, C), 133.9 (Ar, C), 136.8 (C]CH), 137.2 (C]CH),

155.3 (2ꢂC]CH), 158.8 (Ar, CH), 158.9 (Ar, CH), 159.2

(C]O), 161.5 (C]O), 169.6 (C]O), 170.7 (C]O); m/z

(ESI) C₂₇H₃₁N₂O₃requires: 431.2329, found [MH]^þ: 431.2325.

ꢀ78 ^ꢁC. After stirring the solution for 60 min, a solution of

N-ﬂuoro-benzenesulfonimide (33 mg, 1.1 mmol) in THF

(1 mL) cooled to ꢀ78 ^ꢁC was added via cannula. After a fur-

ther 70 min, trimethylsilyl triﬂate (95 mL, 0.53 mol) was added

and the solution allowed to warm to rt over 60 min. The reac-

tion mixture was quenched by the careful addition of a satu-

rated solution of ammonium chloride (10 mL). The phases

were separated and the aqueous phase extracted with

CH₂Cl₂(2ꢂ10 mL). The combined organic extracts were

washed with brine (10 mL), dried (MgSO₄) and the solvent

was evaporated under reduced pressure. The crude product

was puriﬁed by ﬂash column chromatography on silica gel

(petrol/EtOAc, 3:1), to yield DKP 48 as a colourless solid

3.6.21. (1R,7R,10R)-1-Benzyl-2,8-diketo-9-(4-methoxy-

benzyl)-10-(1-methylethenyl)-3,9-diazatricyclo[4.4.3.0]-

undecane 48

1

(10 mg, 43%). H, ¹³C NMR spectra, mp and optical rotation

were identical to the sample prepared via above method.

3.6.21.1. Using the AgOTf method. To a solution of (3S,8aR)-

3-benzyl-2-(4-methoxybenzyl)-8a-(3-methylbut-2-enyl)-3-(phe-

nylthio)octahydropyrrolo[1,2a]pyrazine-1,4-dione 44 (50 mg,

0.095 mmol) in THF (2 mL) at ꢀ10 ^ꢁC, was added silver tri-

ﬂate (37 mg, 0.14 mmol). After stirring the solution for 1 h,

a 1 M solution of sodium hydroxide (5 mL) was added. The

phases were separated and the aqueous phase was extracted

with CH₂Cl₂(10 mL). The combined organic extracts were

washed with brine (5 mL), dried (MgSO₄) and the solvent

was evaporated under reduced pressure. The crude product

was puriﬁed by ﬂash column chromatography on silica gel

(petrol/EtOAc, 3:1), to yield the title bridged DKP 48 as a col-

ourless solid (27 mg, 65%), mp 165e167 ^ꢁC. [a]_D²¹ꢀ4.0 (c

0.65, CHCl₃); n_max(CHCl₃)/cm^ꢀ12965, 1682, 1454, 1393,

1304, 1036; d_H(500 MHz, CDCl₃) 1.53 (3H, s, CH₃), 1.79

(1H, dd, J 13.5, 5.5, CCHHCHC), 1.94 (1H, ddd, J 13.3,

7.0, 7.0, CCHHCH₂), 2.04e2.12 (2H, m, CH₂CHHCH₂),

2.16 (1H, dd, J 13.5, 10.2, CCHHCHC), 2.74 (1H, dd,

J 10.2, 5.5, CCHCH₂C), 2.92 (1H, ddd, J 13.3, 7.3, 7.3,

CCH₂CH₂), 3.17 (1H, d, J 18.0, CHHPh), 3.60 (1H, d,

J 18.0, CHHPh), 3.57e3.65 (2H, m, NCHHCH₂), 3.79 (3H,

s, OCH₃), 4.16 (1H, d, J 15.5, NCHHAr), 4.42 (1H, br s,

HHC]C), 4.72 (1H, app. t, J 1.5, HHC]C), 4.89 (1H, d,

J 15.5, NCHHAr), 6.79 (2H, d, J 8.7, AreOMe, CH), 7.05

(2H, d, J 8.7, AreOMe, CH), 7.19e7.30 (5H, m, Ar, CH);

d_C(125 MHz, CDCl₃) 19.0 (CH₃), 24.2 (CH₂), 29.9 (CH₂),

34.4 (CH₂), 36.2 (CH₂), 44.5 (CH₂), 45.7 (CH₂), 52.4 (CH),

55.3 (OCH₃), 66.1 (C), 68.6 (C), 114.0 (Ar, CH), 116.3

(C]CH₂), 126.1 (Ar, CH), 128.4 (Ar, CH), 128.9 (Ar, CH),

129.2 (Ar, CH), 130.5 (Ar, C), 136.7 (Ar, C), 142.8

(H₂C]C), 159.0 (Ar, C), 167.2 (C]O), 173.7 (C]O); m/z

(EI) C₂₇H₃₁N₂O₃requires: 431.2335, found [MH]^þ: 431.2302.

Acknowledgements

We thank the Engineering and Physical Sciences Research

Council (EPSRC) and the University of Nottingham for ﬁnan-

cial support.

Supplementary data

General experimental conditions and detailed procedures

and compound data for compounds 9, 22aec and 36aec. Tab-

ulated crystal data for compounds 11a, 38b and 44. Supple-

mentary data associated with this article can be found in the

online version, at doi:10.1016/j.tet.2008.02.020.

References and notes

1. Reviews: (a) Martins, M. B.; Carvalho, I. Tetrahedron 2007, 63, 9923; (b)

Dinsmore, C. J.; Beshore, D. C. Tetrahedron 2002, 58, 3297.

2. (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127;

(b) Williams, R. M. Chem. Pharm. Bull. 2002, 50, 711.

3. Recent synthesis: (a) Trost, B. M.; Stiles, D. T. Org. Lett. 2007, 9, 2763;

Overview: (b) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.

4. (a) Qian-Cutrone, J.; Huang, S.; Shu, Y.-Z.; Vyas, D.; Fairchild, C.;

Menendez, A.; Krampitz, K.; Dalterio, R.; Klohr, S. E.; Gao, Q. J. Am.

Chem. Soc. 2002, 124, 14556; (b) Escolano, C. Angew. Chem., Int. Ed.

2005, 44, 7670; (c) von Nussbaum, F. Angew. Chem., Int. Ed. 2003, 42, 3068.

5. (a) Tullberg, M.; Grøtli, M.; Luthman, K. J. Org. Chem. 2007, 72, 195; (b)

Jam, F.; Tullberg, M.; Luthman, K.; Grøtli, M. Tetrahedron 2007, 63,

9881; (c) Tullberg, M.; Luthman, K.; Grøtli, M. J. Comb. Chem. 2006,

8, 915; (d) Wang, H.; Usui, T.; Osada, H.; Ganesan, A. J. Med. Chem.

2000, 43, 1577; (e) Wang, H.; Ganesan, A. Org. Lett. 1999, 1, 1647; (f)

del Fresno, M.; Alsina, J.; Royo, M.; Barany, G.; Albericio, F. Tetra-

hedron Lett. 1998, 39, 2639; (g) Kennedy, A. L.; Fryer, A. M.; Josey,

J. A. Org. Lett. 2002, 4, 1167.

6. (a) Borthwick, A. D.; Davies, D. E.; Exall, A. M.; Hatley, R. J. D.;

Hughes, J. A.; Irving, W. R.; Livermore, D. G.; Sollis, S. L.; Nerozzi,

F.; Valko, K. L.; Allen, M. J.; Perren, M.; Shabbir, S. S.; Woollard,

P. M.; Price, M. A. J. Med. Chem. 2006, 49, 4159; (b) Dandapani, S.;

Lan, P.; Beeler, A. B.; Beischel, S.; Abbas, A.; Roth, B. L.; Porco,

J. A., Jr.; Panek, J. S. J. Org. Chem. 2006, 71, 8934; (c) Besada, P.;

Mamedova, L.; Thomas, C. J.; Costanzi, S.; Jacobsen, K. A. Org. Biomol.

3.6.21.2. Using the in situ ﬂuorinationeTMSOTf method. To

a

solution of N,N⁰-dibenzylethylene diamine (19 mL,

0.079 mmol) in THF (1 mL) at ꢀ78 ^ꢁC was added n-BuLi

(0.98 mL of a 1.6 M solution in hexanes, 0.16 mmol). The so-

lution was allowed to warm to rt for 10 min and then recooled

to ꢀ78 ^ꢁC. The basic solution was added via cannula to

a solution of (3S,8aR)-3-benzyl-2-(4-methoxybenzyl)-8a-

(3-methylbut-2-enyl)-3-(phenylthio)octahydropyrrolo[1,2a]-

pyrazine-1,4-dione 38b (22 mg, 0.053 mmol), cooled to

´

Chem. 2005, 3, 2016; (d) Zeng, Y.; Li, Q.; Hanzlik, R. P.; Aube, J. Bioorg.

Med. Chem. Lett. 2005, 15, 3034.

7. (a) Degrassi, G.; Aguilar, C.; Bosco, M.; Zahariev, S.; Pongor, S.; Venturi,

V. Curr. Microbiol. 2002, 45, 250; (b) Holden, M. T. G.; Chhabra, S. R.;

M. Pichowicz et al. / Tetrahedron 64 (2008) 3713e3735

3735

de Nys, R.; Bainton, N. J.; Hill, P. J.; Maneﬁeld, M.; Kumar, N.; Labatte,

M.; England, D.; Rice, S.; Givskov, M.; Salmond, G. P. C.; Stewart,

G. S. A. B.; Bycroft, B. W.; Kjelleberg, S.; Williams, P. Mol. Microbiol.

1999, 33, 1254.

Hafensteiner, B. D.; Ambhaikar, N. B. Angew. Chem., Int. Ed. 2005, 44,

3892; (c) Baran, P. S.; Hafensteiner, B. D.; Ambhaiker, N. B.; Guerrero,

C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678.

20. (a) Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342; See

also; (b) Myers, A. G.; Herzon. J. Am. Chem. Soc. 2003, 125, 12080; (c)

Wulff, J. E.; Herzon, S. B.; Siegrist, R.; Myers, A. G. J. Am. Chem. Soc.

2007, 129, 4898.

8. (a) Weatherhead-Kloster, R.; Selby, H. D.; Miller, W. B., III; Mash, E. A.

J. Org. Chem. 2005, 70, 8693; (b) Du, Y.; Creighton, C. J.; Tounge, B. A.;

Reitz, A. B. Org. Lett. 2004, 6, 309.

9. As far as we are aware there are no examples of desymmetrisation of cen-

trosymmetric substrates by deprotonation. (a) For a review of chiral lith-

ium amide base reactions, see: O’Brien, P. J. Chem. Soc., Perkin Trans. 1

1998, 1439; For our most recent papers, see: (b) Rodeschini, V.; Simpkins,

N. S.; Wilson, C. J. Org. Chem. 2007, 72, 4265; (c) Rodeschini, V.;

Simpkins, N. S.; Zhang, F. Org. Synth. 2007, 84, 306; (d) Butler, B.;

Schultz, T.; Simpkins, N. S. Chem. Commun. 2006, 3634.

21. (a) Artman, G. D., III; Grubbs, A. W.; Williams, R. M. J. Am. Chem. Soc.

2007, 129, 6336; (b) Greshock, T. J.; Grubbs, A. W.; Tsukamoto, S.;

Williams, R. M. Angew. Chem., Int. Ed. 2007, 46, 2262; See also Ref. 18d.

22. Several other groups have started their studies with the less expensive

L-proline derived series of compounds, but both D- and L-proline are

commercially available.

23. (a) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff,

C. A. Chem. Rev. 2004, 104, 1431; (b) Huang, P.-Q. Synlett 2006, 1133;

(c) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817; (d)

Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.

24. Closure of an indole onto the methylvinyl appendage of a preformed

bridged DKP features in many of the syntheses cited above. Our synthesis

design was inspired by a very early paper from the Williams group, see:

Williams, R. M.; Glinka, T. Tetrahedron Lett. 1986, 27, 3581.

25. For leading references, see: (a) Bull, S. D.; Davies, S. G.; Epstein, S. W.;

Garner, A. C.; Mujtaba, N.; Roberts, P. M.; Savory, E. D.; Smith, A. D.;

Tamayo, J. A.; Watkin, D. J. Tetrahedron 2006, 62, 7911; (b) Davies,

S. G.; Rodriguez-Solla, H.; Tamayo, J. A.; Garner, C. A.; Smith, A. D.

Chem. Commun. 2004, 2502; (c) Bull, S. D.; Davies, S. G.; Epstein,

S. W.; Leech, M. A.; Ouzman, J. V. A. J. Chem. Soc., Perkin Trans. 1

1998, 2321. See also Ref. 10.

10. See: (a) Bull, S. D.; Davies, S. G.; Garner, A. C.; Parkes, A. L.; Roberts,

P. M.; Sellers, T. G. R.; Smith, A. D.; Tamayo, J. A.; Thomson, J. E.; Vick-

ers, R. J. New J. Chem. 2007, 31, 486; (b) Davies, S. G.; Garner, A. C.;

Ouzman, J. V. A.; Roberts, P. M.; Smith, A. D.; Snow, E. J.; Thomson,

J. E.; Tamayo, J. A.; Vickers, R. J. Org. Biomol. Chem. 2007, 5, 2138

and references therein. See also Ref. 25.

11. In some previous chiral base work we established that LiCl was crucial for

high levels of asymmetric induction, see: (a) Bunn, B. J.; Simpkins, N. S.

J. Org. Chem. 1993, 58, 533; (b) Bunn, B. J.; Simpkins, N. S.; Spavold, Z.;

Crimmin, M. J. J. Chem. Soc., Perkin Trans. 1 1993, 3113.

12. For a stereocontrolled access to related bridged DKPs, see: Piccinelli, F.;

Porzi, G.; Sandri, M.; Sandri, S. Tetrahedron: Asymmetry 2003, 14, 393;

For related metathesis chemistry with DKP systems, see Refs. 6c and 8b.

13. Our DKP synthesis follows along known lines, see for example:

(a) Nitecki, D. E.; Halpern, B.; Wesley, J. W. J. Org. Chem. 1968, 33,

864; (b) Danthi, S. N.; Hill, R. A. J. Heterocycl. Chem. 1997, 34, 835.

Article Doi

Studies towards complex bridged alkaloids: regio- and stereocontrolled enolate chemistry of 2,5-diketopiperazines

DOI: 10.1016/j.tet.2008.02.020

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