Efficient synthesis of structurally diverse diazabicycloalkanes: Scaffolds for modular dipeptide mimetics with tunable backbone conformations

FULL PAPER

Efficient Synthesis of Structurally Diverse Diazabicycloalkanes: Scaffolds for

Modular Dipeptide Mimetics with Tunable Backbone Conformations

Wolfgang Maison,*^[a]Daniel C. Grohs,^[a]and Alexander H. G. P. Prenzel^[a]

Keywords: Peptidomimetics / Cleavage reactions / Cancer targeting / Combinatorial chemistry

A stereoselective synthesis of new dipeptide mimetics based

on a diazabicycloalkane scaffold is reported. The route starts

from enantiomerically pure azabicycloalkenes 1 that are bis-

istry and the ring sizes of the diazabicycloalkane scaffold.

The syntheses of conformationally constrained dipeptide

analogues in four to five steps are presented. With the syn-

(hydroxylated) and coupled N-terminally to a second amino theses of dipeptide mimetics 19a−c, suitable linker moieties

acid. The key step of the reaction sequence is an oxidative for conjugation of diazabicycloalkanes to other functional

cleavage of the resulting dipeptides 5 to give highly func- molecules like markers or solid phases are introduced, mak-

tionalised diazabicycloalkanes 6, which can be easily con-

verted into a number of dipeptide mimetics with defined and

variable stereochemistry and a number of different amino

acid side chains. The backbone dihedral angles within these

ing these compounds modular dipeptide mimetics that might

find applications as modular ligands or as solid-phase-at-

tached scaffolds in combinatorial chemistry.

( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

dipeptide mimetics can be tuned by varying the stereochem- Germany, 2004)

Introduction

enthalpy penalty for the receptor-binding event. In addition

to advantageous binding properties these compounds often

have improved pharmacological profiles. In this context,

fused bicyclic systems play an important role in the field of

drug discovery. Azabicycloalkanes of type II in Figure 1

have been used as tools for rigidifying peptide structures

Peptides and proteins play a crucial role in the trans-

mission of information in biological systems. As a conse-

quence, many peptides serve as lead structures for the devel-

opment of new pharmaceuticals. However, their utility as

therapeutics or diagnostics is limited due to their suscepti-

bility to protease degradation, poor bioavailability, and ra-

pid excretion.^[1]In addition, many small peptides lack selec-

tivity to a certain receptor due to their high conformational

flexibility. A common strategy to overcome these problems

is the synthesis of peptide analogues mimicking the bioac-

tive conformation of native peptides at the receptor level.^[2]

Many different classes of these peptidomimetics have been

reported, including amide surrogates^[3]such as aminome-

thylene, oxymethylene, alkene, sulfoxide and others, as well

as displacement of a peptide segment with a scaffold.^[4]The

purpose of these modifications is to (a) increase the binding

affinity and specificity of peptidomimetics to a given recep-

tor, (b) increase the longevity of the compound by reducing

the likelihood of degradation, and (c) increase the lipophil-

icity for improved absorption of the compound in biologi-

cal systems.

in order to probe conformation-activity relationships.^[5]

A

number of structurally related bicyclic peptide analogues

with different ring sizes and heteroatoms have been pre-

pared and incorporated into peptides as turn mimetics.^[6Ϫ9]

Besides this large body of work on turn mimetics there are

relatively few known conformationally restricted analogues

of extended peptide conformations.^[10]The limited interest

in these structures is surprising because it is known that a

number of biomolecular receptors recognize their peptidic

ligands in extended conformations.^[11]Among these recep-

tors are proteases,^[12]MHC proteins^[13]and transferases,^[14]

all of which are involved in important disease-related bio-

logical processes. Rigid mimetics of extended peptide con-

formations could thus provide valuable ligands for recep-

tors that bind to non-turn peptide conformations such as

cancer-specific proteases.

Structurally rigid peptidomimetics, in particular, have

found numerous applications in medicinal chemistry since

they are conformationally preorganised or fixed into a

shape that is recognised by a receptor, thus reducing the

Results and Discussion

We have recently introduced the highly functionalised di-

azabicycloalkanes I as rigid dipeptide analogues.^[15]Al-

though a number of efficient syntheses to azabicycloalkanes

of type II in Figure 1 are known, less attention has been

paid to diazabicycloalkane derivatives.^[16Ϫ18]Demands for

[a]

Universität Hamburg, Institut für Organische Chemie,

Martin-Luther-King-Platz 6, 20146 Hamburg, Germany

Fax: (internat.) ϩ 49-40-428382495

E-mail: maison@chemie.uni-hamburg.de

Eur. J. Org. Chem. 2004, 1527Ϫ1543

DOI: 10.1002/ejoc.200300700

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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W. Maison, D. C. Grohs, A. H. G. P. Prenzel

FULL PAPER

Figure 1. Proposed (I) and known (II) bicyclic dipeptide mimics

a suitable synthetic route to compounds I are high. Such a

route has to be (a) short and high yielding, (b) compatible

with various side-chain functionalities R¹and R², (c)

stereoselective with respect to five stereocentres, and (d)

variable in stereochemistry and ring sizes. Furthermore, a

suitable synthesis has to provide access to compounds with

linker moieties because we are interested in modular ligands

that can be attached to markers or a solid phase.^[19]

Scheme 1. Retrosynthetic analysis of dipeptide mimics V

Keeping these requirements in mind we selected struc-

tures of type V in Scheme 1 as target compounds. An obvi-

ous starting point for the retrosynthetic analyses of these

bicyclic peptidomimetics V (Scheme 1) is the disconnection

of the bicyclic ring system along the tertiary amide and the

aminal function. A suitably functionalised disubstituted

cyclic amino acid IV would therefore be a key intermediate.

A look at the recent literature reveals that the synthesis of

such 3,5-substituted prolines (n ϭ 0)^[20Ϫ22]and especially

3,6-substituted pipecolic acids (n ϭ 1)^[22,23]is not a trivial

task since there are only a few general routes to enantiomer-

ically pure compounds and all of them are multistep pro-

cedures. Our first efforts were therefore directed to the de-

velopment of a short route to suitably functionalised cyclic

amino acids of type IV. For this purpose we envisioned aza-

bicycloalkenes III, which in turn can be synthesised by a

known cycloaddition,^[24Ϫ26]as precursors which, upon oxi-

dative cleavage of the alkene moiety, should give cyclic am-

ino acids IV. Coupling of an additional amino acid to its

N-terminus and intramolecular cyclisation would then give

the desired bicyclic structures V.

Scheme 2. Synthesis of substituted pipecolic acid derivatives

The two-step protocol to enantiomerically pure cyclic ent proline and pipecolic acid derivatives that might be use-

amino acids 3 is outlined in Scheme 2. Oxidative cleavage ful intermediates for natural product synthesis.^[27]

of the azabicyclooctene 1b^[26]with reductive workup gives

To avoid the difficult peptide coupling to substituted cyc-

diol 2 in good yield. Hydrogenolytic removal of the N- lic amino acids of type IV (Scheme 1) a second route via

benzyl group gives the free amino acid 3, which provides all bis(hydroxylated) azabicycloalkanes VI was tried. Peptide

the necessary functionalities for the synthesis of diaza- couplings to the structurally similar unnatural amino acid

bicycloalkanes V. Unfortunately, peptide couplings to the azabicycloheptanecarboxylic acid are known to proceed un-

N-terminus of the sterically hindered pipecolic acid deriva- der standard conditions in good yield.^[28]It was therefore

tive 3 proved to be extremely difficult. A number of com- assumed that a second amino acid should be easy to couple

mon peptide coupling reagents (among them highly ef- to VI to give the corresponding dipeptide. Oxidative cleav-

ficient reagents like TFFH and HATU) failed to give the age of the diol function within this dipeptide should then

desired dipeptides in reasonable yield.

lead to an intermediate bis(aldehyde) in which the α-ami-

The synthetic route outlined in Scheme 2 is an efficient noaldehyde was supposed to cyclise immediately intramol-

procedure for the preparation of enantiomerically pure, ecularly to the target compound V.

substituted proline and pipecolic acid derivatives, and al-

The first part of this synthesis is outlined in Scheme 3.

though these cyclic amino acids, like 3, did not allow the Enantiomerically pure azabicycloalkenes 1 were synthesised

synthesis of the desired diazabicycloalkanes V (Scheme 1), in one step according to a literature protocol from (R)-

they proved to be valuable precursors for a range of differ- phenylethylamine, cyclopentadiene or cyclohexadiene and

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Efficient Synthesis of Structurally Diverse Diazabicycloalkanes

FULL PAPER

the appropriate glyoxylate by an aza-DielsϪAlder reaction should be noted that the stereochemistry of the azabicy-

on a large scale.^[29]

cloalkane moiety of these dipeptides can be easily varied by

the use of different azabicycloalkenes 1, as shown by the

synthesis of compound 5k, starting from 1d, that is outlined

in Scheme 3. Different ring sizes (n ϭ 0, 1 in Scheme 3) can

also be synthesised starting from azabicycloheptenes, like

1a, or azabicyclooctenes, like 1b.

Table 1. Yields for dipeptides 5 synthesised according to Scheme 3

Starting

compd.

n

R¹

R²

Amine 4 Dipeptide 5,

yield

1a

1b

1c

1d

0

1

0

1

Et

CH₂CO₂Me

CH₂OH

H

CH(CH₃)₂

(CH₂)₄NHBoc

(CH₂)₂SMe

CH₂CO₂Me

4a

4b

4c

5a, 42%

5b, 60%

5c, 71%

5d, 82%

5e, 72%

5f, 73%

5g, 75%

5h, 72%

5i, 70%

5j, 53%

5k, 33%

Scheme 3. Conversion of azabicycloalkenes 1aϪd to dipeptides

5aϪk; reagents and conditions: a) cat. K₂OsO₂(OH)₄, K₃Fe(CN)₆,

K₂CO₃, tBuOH/H₂O, 12 h, room temp.; alternatively for 4c:

KMnO₄, aq NaOH, tBuOH/H₂O, 0 °C, 15 min; b) H₂(1 atm), 5%

Pd/C, EtOH, room temp., 24 h; c) N-protected amino acid, DCC,

HOBt, DMF, 12 h, 0 °C to room temp.

tBu CH₂CO₂tBu

tBu (CH₂)₂CO₂tBu 4c

tBu CH₂OTBDMS 4c

Et

CH₂CO₂Me

4d

Bis(hydroxylation) of azabicycloalkenes 1a, 1b, and 1d

was performed with K₂OsO₂(OH)₄/K₂CO₃and K₃Fe(CN)₆

as cooxidant in good yields. Alternatively, this oxidation

may be performed with KMnO₄in aqueous NaOH. Yields

for this procedure were slightly lower, as shown for com-

pound 1c in Scheme 3. However, the use of KMnO₄is more

convenient and cheaper for large-scale preparations. Both

oxidation methods gave the respective diols as a single dia-

stereoisomer (dr Ͼ 95:5) as depicted in Scheme 3. Sub-

sequent removal of the phenylethyl group with hydrogen

and palladium on activated charcoal gave aminodiols 4aϪd

in good yield. The relative stereochemistry of these azabicy-

As mentioned above, dipeptides 5 should be ideal precur-

sors for oxidative cleavage and subsequent intramolecular

cyclisation to bicyclic peptide mimetics of the general struc-

ture V in Scheme 1. We assumed that treatment of diols 5

with sodium periodate would give an intermediate bis(al-

dehyde) that would immediately cyclise intramolecularly

with a carbamate (Boc or Cbz) NH group of the second

amino acid to form the desired bicyclic ring system V.

This combination of oxidative cleavage and intramolecu-

lar attack of the intermediate bis(aldehyde) by the carba-

mate NH proceeds with good yields and varying stereo-

selectivities with respect to the formation of the aminal in

6 (Scheme 4). However, it should be noted, that N-acylated

aminals like 6 are configurationally not stable under acidic

conditions. In consequence, epimerisation of compounds 6

at the aminal position occurred upon storage in CDCl₃and

on silica gel leading to a stable 1,3-cis configuration of R²

and the aminal OH group as depicted in Scheme 4 for all

aminals 6, except for compound 6c, where R²is hydrogen

(glycine as a second amino acid). Compounds 6 were used

in the next steps without further purification.

4

cloalkanes can be derived from the characteristic J coup-

lings in the bicyclic ring system of 4b and 4d, as outlined in

Figure 2. Additional 2D-NOESY analysis was in agreement

with these structures as indicated in Figure 2 by significant

NOESY cross-peaks for all aminodiols 4. Furthermore, the

structure of 4a was verified by X-ray analysis of its N-phen-

ylethyl-substituted precursor (data not shown).^[30]

Figure 2. Characteristic ⁴J couplings (bold lines) and key NOEs

(arrows) for compounds 4a, 4b, and 4d

As anticipated, peptide couplings of N-protected amino

acids to the aminodiols 4aϪd proceed in good yields under

standard coupling conditions (DCC/HOBt) and can be per-

formed on a large scale. A range of different dipeptides 5

was thus obtained on a gram scale in only three steps start-

ing from azabicycloalkenes 1. Table 1 summarises a collec-

tion of different functionalised dipeptide derivatives 5 in-

Scheme 4. Synthesis of bicyclic dipeptide mimetics 6; for the defi-

nition of residues see Tables 2 and 3; reagents and conditions: a)

corporating some common proteinogenic amino acids. It NaIO₄, acetone/H₂O, 0 °C to room temp., 30Ϫ60 min

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FULL PAPER

All NMR spectra of bicyclic aminals 6, 9, and 11 show occurred regioselectively at the free aldehyde position leav-

substantial line broadening at room temperature and a ing the aminal unaltered. Subsequent hydrogenolytic re-

double set of signals due to rotational isomerism around moval of the Cbz group and in situ reduction of the inter-

the partial CϭN double bond of the carbamate protecting mediate imine gave diazabicycloalkane 8, an H-Gly-HSer-

group. This double set of signals equilibrated in all cases at OEt mimetic, in good yield.

temperatures around 340 K in [D₆]DMSO, a coalescence

Since our interest in diazabicyloalkane dipeptide mi-

temperature that is expected for these tertiary amides.^[31,32]metics was motivated to a large degree by the search for

The existence of two energetically similar rotamers for the ligands for certain cancer-specific carboxypeptidases,^[35]po-

tertiary amide in 6 hints that the substituents next to the lyanionic structures were of special interest to us.^[36,37]In

nitrogen atom (R²and OH in Scheme 4) must be in an axial consequence, we were aiming for Asp(Glu)ϪAsp(Glu) mi-

arrangement, since steric interactions with the carbamate metics. Aldehydes 6a, 6g, 6h, and 6j, derived by periodate

protecting group are minimised in this position. This bis(ax- cleavage from dipeptides 5a, 5g, 5h, and 5j, respectively,

ial) arrangement is a consequence of pseudo-allylic 1,3- were therefore oxidised with NaClO₂to give the carboxylic

strain^[33]that would be apparent in an equatorial arrange- acids 9aϪd (Scheme 6). Treatment of these Cbz-protected

ment between R²and OH and the carbamate protecting diazabicycloalkanes with hydrogen and palladium on acti-

group.

Bicyclic aminals 6 are ideal precursors for a range of dif-

vated charcoal gave amines 10aϪd, which are confor-

ferent dipeptide mimetics since the aldehyde function at-

tached to the proline or pipecolic acid portion of the bicyc-

lic core can be easily converted into a number of different

side-chain functionalities. Since the structure and topology

of the second side-chain R²are only limited by the choice

of α-amino acid coupled to azabicycloalkanes 4, both am-

ino acid side-chains can be varied and a range of different

dipeptide mimetics is accessible. In addition, the aminal

function in 6 should offer a suitable site for attachment of

linker moieties to the bicyclic core, for example by alky-

lation of an N-acyliminium ion generated in situ.^[34]

In a first attempt to check the synthetic potential of di-

peptides 5 for the synthesis of diazabicycloalkanes we tried

a periodate cleavage of 5c and a subsequent reduction of

the resulting aldehyde side chain in 6c with sodium borohy-

dride, as outlined in Scheme 5. This reduction to alcohol 7

Scheme 6. Oxidative side-chain modification of aldehydes 6; re-

agents and conditions: a) NaIO₄, acetone/H₂O, 0 °C to room temp.,

30Ϫ60 min; b) NaClO₂, 2-methyl-2-butene, NaH₂PO₄, tBuOH,

H₂O, room temp., 12 h; c) Pd/C, EtOH, room temp., 24 h

Scheme 7. Wittig transformations to side-chain-modified dipeptide

Scheme 5. Reductive conversion of aldehyde 6c to Gly-HSer mi-

mimetics 12; reagents and conditions: a) NaIO₄, acetone/H₂O, 0

metic 8; reagents and conditions: a) NaIO₄, acetone/H₂O, 0 °C to °C to room temp., 30Ϫ60 min; b) Ph₃PϭCHCO₂R³, THF, room

room temp., 30Ϫ60 min; b) NaBH₄, MeOH, 0 °C, 1 h; c) Pd/C, temp., 12 h; c) Pd/C, EtOH, room temp., 24 h; d) NaIO₄, Ph₃Pϭ

EtOH, room temp., 24 h

CHCO₂R³, Et₂O, room temp., 24 h

Table 2. Yields for aminals 9 and amines 10 synthesised according to Scheme 6

Starting compd.

n

R¹

R²

Aldehyde 6

Aminal 9, yield

Amine 10, yield

5a

5h

5j

0

1

Et

CH₂CO₂Me

CH₂CO₂tBu

CH₂OTBDMS

CH₂CO₂Me

6a

6h

6j

9a, 99%

9b, 25%

9c, 62%^[a]

9d, 21%

10a, 92%

10b, 64%

10c, 58%

10d, 82%

tBu

Et

5g

6g

[a]

Partial loss of the TBDMS protecting group occurred in this reaction (see Exp. Sect.).

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Table 3. Yields for the conversion of dipeptides 5 to X_AA-HGlu mimetics 12 according to Scheme 7

Starting compd.

R¹

R²

R³

Aldehyde 6^[a]

Aminal 11, yield

Amine 12, yield

5a

5h

5i

Et

CH₂CO₂Me

Me

tBu

Ϫ

6h

6i

6j

11a, 69%^[b]

11b, 55%

11c, 21%

11d, 43%

12a, 100%

12b, 77%

12c, 83%

12d, 92%

tBu

CH₂CO₂tBu

(CH₂)₂CO₂tBu

CH₂OTBDMS

5j

[a]

[b]

Aldehydes 6 were isolated as crude products and used without further purification in the next step. Aminal 11a was synthesised in

a one-pot procedure (method d in Scheme 7).

mationally constrained Asp-Asp, Asp-HGlu, and Ser-Asp

mimetics (Table 2).

Variation of the side-chain length in dipeptide mimetics

12 (Scheme 7) to homoglutamate analogues was achieved by

periodate cleavage of dipeptides 5 and subsequent Wittig

reaction of the resulting aldehydes 6h, 6i, and 6j to give the

α,β-unsaturated carboxylic acid esters 11bϪd, respectively,

in good yield almost exclusively as the (E) isomer [(E)/(Z) ϭ

95:5]. Hydrogenation of the Cbz-protected Wittig adducts

11bϪd gave diazabicycloalkanes 12bϪd, respectively, which

are conformationally constrained Asp-HGlu, Glu-HGlu,

Ser-HGlu mimetics (Table 3).

Scheme 8. Side reaction in Wittig conversions of hindered bicyclic

aldehyde 6i

Even more advantageous, the Wittig transformations

outlined in Scheme 7 can be performed as a one-pot pro-

cedure together with a periodate cleavage directly from diols

5 according to a recently introduced protocol from

Taylor,^[38]as shown in Scheme 7 for the synthesis of aminal

11a (method d).

It should be noted that conformationally constrained and

enantiomerically pure dipeptide mimetics like 12a

(Scheme 7) can thus be synthesised in only four steps from

readily available azabicyloalkenes 1 on a gram scale.

With the exception of 11a and 12a, all compounds de-

picted in Scheme 7 were synthesised using a Cbz/tBu pro-

tection strategy. We have used this strategy because of the

better crystallisation properties of the intermediates, which

is particularly advantageous for large-scale preparations.

gave dipeptide mimetics 19aϪc. These compounds are es-

pecially noteworthy because the primary amine provides a

suitable anchor for conjugation with marker moieties such

as fluorescence dyes^[39]or radiopharmaceutical markers.^[40]

Compounds 19aϪc are therefore the first examples of

modular dipeptide mimetics on the basis of a diazabicy-

cloalkane scaffold.

Conclusion

In summary, we have reported a short and efficient syn-

However, the bulky tBu esters in dipeptides 5hϪj lead to thetic sequence for a number of new diazabicycloalkanes

significantly lower yields of the desired alkenes 11 during which are useful mimetics of various dipeptide confor-

Wittig reactions, as can be seen for the conversion of alde- mations. Our synthesis starts with a stereoselective aza-

hyde 6i to olefin 11c (Scheme 8). The reason for this unex- DielsϪAlder reaction providing enantiomerically pure aza-

pected finding is the formation of a ring-opened second bicycloalkenes 1 on a large scale. Compounds 1 are key

Wittig adduct 13. Small portions (13%) of this side product intermediates in our synthetic route to diazabicycloalkanes,

were also detected during conversion of aldehyde 6h to ole- since they provide the synthetically more challenging part

fin 12b.

of our target compounds (such as the dipeptide mimetics

Acylation of diazabicycloalkanes 12 can be performed 15, 17, and 19): a suitably disubstituted cyclic amino acid

under standard conditions with acetic anhydride, benzoyl with defined (and variable) stereochemistry. It is therefore

chloride, or 6-aminocaproic acid without detectable epimer- not surprising that azabicycloalkenes 1 can be used to syn-

isation as outlined in Scheme 9. N-Acetylated diazabicy- thesise a number of different functionalised cyclic amino

cloalkanes 14 and N-benzoylated diazabicycloalkanes 16 acids^[27]which are useful intermediates in natural product

were thus obtained in good yields from the free amines 12. synthesis^[41Ϫ43]and interesting rigid building blocks for

Deprotection of these compounds was done by treatment peptide synthesis.^[44Ϫ46]

with a 50% solution of TFA in dichloromethane for 3 h,

giving deprotected dipeptide mimetics 15 and 17 quantitat- to be valuable precursors of diazabicycloalkanes 15, 17, and

ively upon evaporation of the solvent/acid mixture. 19. The major advantages of our route are: a) synthetic ef-

In this report we have demonstrated azabicycloalkenes 1

Acylation of diazabicycloalkane 12bϪd with N-Boc-pro- ficiency, since diazabicycloalkane target compounds can be

tected 6-aminocaproic acid and subsequent deprotection synthesised in only five steps starting from an appropriate

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W. Maison, D. C. Grohs, A. H. G. P. Prenzel

FULL PAPER

Scheme 9. Acylation of diazabicycloalkanes and subsequent deprotection; reagents and conditions: a) Ac₂O, dichloromethane, diisopropylethyl-

amine; b) BzCl, dichloromethane, diisopropylethylamine; c) BocHN(CH₂)₅CO₂H, DCC, HOBt, DMF; d) 50% TFA in dichloromethane

Spots were visualised with iodine, ninhydrin (5% in EtOH) or an Mo/

Ce staining mixture [50 g of ammonium molybdate() tetrahydrate,

1 g of cerium() sulfate in 100 mL of concentrated H₂SO₄and

900 mL of water]. For preparative chromatography Merck silica gel

60, 230Ϫ400 mesh was used. Melting points were determined in open

capillaries in a Dr. Lindström instrument and are uncorrected. Op-

tical rotations [α]_Dwere determined with a PerkinϪElmer polar-

imeter (241 MC), at 20 °C, c ϭ 1 in methanol unless otherwise indi-

cated. ¹H and ¹³C NMR spectra were recorded with a Bruker

(Karlsruhe) AMX 400 spectrometer (400 MHz/100.6 MHz) or a

glyoxylate, (R)-phenylethylamine, and cyclopentadiene or

cyclohexadiene; b) practicability for large-scale synthesis; c)

a possible fine-tuning of the backbone dihedral angles of

the target dipeptide mimetic since stereochemistry and ring

sizes in diazabicycloalkanes can be varied by altering reac-

tion conditions and input of the aza-DielsϪAlder reaction;

d) structural diversity, since both amino acid side-chains of

the imitated dipeptide can be varied broadly; and e) estab-

lishment of suitable conjugation sites for marker moieties.

Diazabicycloalkanes 19aϪc, for example, are therefore di- Bruker (Karlsruhe) DRX 5001 spectrometer (500 MHz/125.8 MHz).

Chemical shifts, δ, are presented in parts per million (ppm) and coup-

ling constants, J, in Hertz (Hz) from tetramethylsilane (TMS: δ ϭ

0 ppm) as the internal standard for CDCl₃and residual solvent peaks

for [D₄]MeOH and [D₆]DMSO. Mass spectra were obtained with

a VG/70Ϫ250 F (VG Analytical) instrument in FAB mode in a p-

nitrobenzyl alcohol matrix or an MAT 95 Trap XL (Thermo Finni-

gan) instrument in ESI mode (positive mode) using polypropylene

glycol or polyethylene glycol as internal standard. Elemental analyses

were performed with a C,H,N-Analyser EA 1108 from Carlo Erba.

The following starting materials were synthesised according to litera-

peptide mimetics with a modular character since they can

be conjugated to other functional moieties. Conjugation to

markers is one possibility and we are currently probing di-

azabicycloalkanes like 19aϪc for use as modular ligands for

cancer-specific receptors.

Conjugation of diazabicycloalkanes to a solid support is

another interesting possibility that would enable one to use

the highly functionalised diazabicycloalkane scaffold for

combinatorial chemistry. This would, of course, need or-

thogonal protection groups at all four functionalities in ture procedures: methyl (triphenylphosphanylidene)acetate,^[47]tert-

butyl (triphenylphosphanylidene)acetate,^[48]6-(tert-butoxycarbonyla-

compounds like 6. We are currently working on the syn-

thesis of these orthogonal protected scaffolds for combina-

torial chemistry.

mino)hexanoic acid,^[49]ethyl (1S,3S,4R)-2-[(1R)-phenylethyl]-2-azab-

icyclo[2.2.1]-hept-5-ene-3-carboxylate (1a),^[50]ethyl (1S,3S,4R)-2-

[(1R)-phenylethyl]-2-azabicyclo[2.2.2]oct-5-en-3-carboxylate (1b),^[50]

ethyl (1R,3S,4S)-2-[(1R)-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-

carboxylate (1d).^[26]EA ϭ ethyl acetate; PE ϭ petroleum ether; 50/

Experimental Section

70 ϭ boiling range 50Ϫ70 °C.

General Remarks: ‘‘Dry’’ solvents were purified prior to use as fol- tert-Butyl (1S,3S,4R)-2-[(1R)-Phenylethyl]-2-azabicyclo[2.2.1]hept-

lows: methanol was distilled from magnesium, dichloromethane was 5-ene-3-carboxylate (1c): Di-tert-butylfumarate (35.0 g, 0.153 mol)

distilled from CaCl₂, THF and Et₂O were distilled from sodium and was dissolved in dry dichloromethane and cooled to Ϫ80 °C.

benzophenone under nitrogen. Thin layer chromatography (TLC) Ozone was bubbled through the solution at Ϫ80 °C for 7 h until a

analyses were performed on silica gel 60 F₂₅₄plates from Merck.

blue colour persisted. The solution was purged with nitrogen for

1532

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Eur. J. Org. Chem. 2004, 1527Ϫ1543

Efficient Synthesis of Structurally Diverse Diazabicycloalkanes

FULL PAPER

2 min and subsequently treated with dimethyl sulfide (57 mL, 0.77

mol) in 50 mL of dichloromethane and stirred at 0 °C for 30 min.

compound as a colourless oil. R_fϭ 0.33 (ethyl acetate/hexane, 1:1;

iodine). H NMR (500 MHz, CDCl₃): δ ϭ 1.29 (t, J ϭ 7.3 Hz, 3

1

Most of the solvent was evaporated at 0Ϫ5 °C in vacuo and the H), 1.33 (d, J ϭ 7.0 Hz, 3 H), 1.50 (m, 1 H), 1.57 (m, 1 H), 1.76

remaining residue dissolved in 700 mL of dry dichloromethane.

Molecular sieves (4 A, 100 g) and (R)-phenylethylamine (37.1 g,

0.306 mol) were added and the mixture was stirred with a mechan-

(m, 1 H), 1.82 (m, 1 H), 1.92 (m, 1 H), 3.52 (d, J ϭ 2.6 Hz, 1 H),

3.53 (m, 1 H), 3.54 (dd, J ϭ 5.3 Hz, 10.7 Hz, 1 H), 3.76 (dd, J ϭ

3.8 Hz, 10.7 Hz, 1 H), 3.84 (m, 1 H), 3.88 (dd, J ϭ 3.4 Hz, 11.0 Hz,

1 H), 4.17 (m, 2 H), 4.50 (q, J ϭ 7.0 Hz, 1 H), 7.26 (t, J ϭ 7.2 Hz,

˚

ical stirrer under nitrogen at 0 °C for 30 min. The solution was

cooled to Ϫ80 °C and TFA (34.9 g, 0.306 mol), Et₂OϪBF₃(43.4 g, 1 H), 7.36 (m, 2 H), 7.41 (d, J ϭ 7.3 Hz, 2 H). ¹³C NMR (125 MHz,

0.306 mol) and cyclopentadiene (20.2 g, 0.306 mol) were added at

20 min intervals. The resulting mixture was stirred at Ϫ80 °C for

2 h and was allowed to reach room temperature overnight. A satu-

rated aqueous K₂CO₃solution (400 mL) was added slowly and the

mixture was filtered through Celite. The filter cake was rinsed three

times with 200 mL of dichloromethane. The filtrate was collected

and phases were separated. The aqueous phase was extracted twice

with 300 mL of dichloromethane and the combined organic ex-

tracts were washed with 200 mL of water, dried with Na₂SO₄, and

the solvent was removed in vacuo to give 82.5 g of a yellow oil that

slowly crystallised. This crude product was recrystallised from PE

(50/70) to give 44.8 g of colourless crystals. The remaining mother

liquor was concentrated to dryness and the remaining solid purified

by column chromatography (PE/ethyl acetate, 11:1) on silica gel to

give an additional 19.4 g (combined 64.2 g, 70% yield) of the title

CDCl₃): δ ϭ 14.61, 16.17, 22.39, 24.90, 38.73, 55.26, 56.52, 57.13,

60.67, 64.28, 64.47, 127.66, 128.00, 128.92, 144.35 175.89. HRMS

(FAB): calcd. for C₁₈H₂₇NO₄[MH^ϩ] 322.2018, found 322.2014.

C₁₈H₂₇NO₄: calcd. C 67.26, H 8.47, N 4.36; found C 67.31, H 8.49,

N 4.35.

Ethyl

(2S,3S,6S)-3,6-Bis(hydroxymethyl)piperidine-2-carboxylate

(3): Diol 2 (0.29 g) was dissolved in 10 mL of ethanol and 50 mg of

Pd/C (5%) was added. The resulting suspension was stirred under

hydrogen at room temperature for 24 h. The reaction mixture was

filtered through Celite and the Celite washed with 200 mL of di-

chloromethane. Evaporation of the solvent in vacuo gave 0.16 g

(78%) of the title compound as a colourless oil. R_fϭ 0.39 (diethyl

ether/methanol, 95:5; ninhydrin). ¹H NMR (500 MHz, CDCl₃):

δ ϭ 4.22 (m, 2 H), 3.87 (dd, J ϭ 8.2 Hz, 10.7 Hz, 1 H), 3.84 (d,

J ϭ 2.5 Hz, 1 H), 3.70 (dd, J ϭ 5.4 Hz, 10.7 Hz, 1 H), 3.64 (br., 3

H), 3.57 (dd, J ϭ 3.4 Hz, 11.1 Hz, 1 H), 3.42 (dd, J ϭ 7.9 Hz,

11.1 Hz, 1 H), 2.99 (m, 1 H), 2.35 (m, 1 H), 1.62 (m, 2 H), 1.37

(m, 2 H), 1.29 (t, J ϭ 7.3 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃):

δ ϭ 14.63, 23.36, 23.56, 36.40, 53.48, 56.61, 61.50, 64.12, 66.22,

174.24. HRMS (FAB): calcd. for C₁₀H₁₉NO₄[MH^ϩ] 218.1392,

found 218.1391. C₁₀H₁₉NO₄: calcd. C 55.28, H 8.81, N 6.45; found

C 55.30, H 8.79, N 6.44.

compound and 7.25 g (8% yield) of

a second isomer with

(1R,3R,4S) stereochemistry. 1c: R_fϭ 0.47 [ethyl acetate/PE (50/70),

1:9; iodine]. [α]²_D⁰ϭ Ϫ78.4 (c ϭ 1.03, CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ ϭ 1.16 (s, 9 H), 1.36 (d, J ϭ 9.1 Hz, 1 H), 1.38 (d, J ϭ

6.3 Hz, 3 H), 2.10Ϫ2.11 (m, 1 H), 2.11 (d, J ϭ 9.1 Hz, 1 H),

2.84Ϫ2.85 (m, 1 H), 3.00 (q, J ϭ 6.3 Hz, 1 H), 4.26 (d, J ϭ 1.0 Hz,

1 H), 6.35 (dd, J ϭ 5.7 Hz, 1.3 Hz, 1 H), 6.40 (dd, J ϭ 4.7 Hz,

1.5 Hz, 1 H), 7.14Ϫ7.17 (m, 1 H), 7.19Ϫ7.23 (m, 2 H), 7.28Ϫ7.30

(m, 2 H). ¹³C NMR (125 MHz, CDCl_3,): δ ϭ 27.72, 27.85, 45.30,

49.33, 62.76, 64.05, 65.61, 79.82, 126.95, 128.12, 128.27, 133.12,

136.42, 145.42, 173.44. HRMS (FAB): calcd. for C₁₉H₂₅NO₂

[MH^ϩ] 300.1964, found 300.1969. C₁₉H₂₅NO₂: calcd. C 76.22, H

8.42, N 4.68; found C 76.16, H 8.45, N 4.64. (1R,3R,4S) Isomer:

R_fϭ 0.74 (ethyl acetate/PE 50/70, 1:9; iodine). [α]²_D⁰ϭ ϩ96.0 (c ϭ

0.96, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ ϭ 1.11 (d, J ϭ 7.9 Hz,

1 H), 1.15 (d, J ϭ 6.3 Hz, 3 H), 1.44 (s, 9 H), 1.85 (d, J ϭ 7.9 Hz,

1 H), 2.26Ϫ2.27 (m, 1 H), 2.94 (q, J ϭ 6.3 Hz, 1 H), 2.96Ϫ2.98 (m,

1 H), 3.43Ϫ3.45 (m, 1 H), 5.93 (d, J ϭ 5.7 Hz, 1 H), 6.33 (d, J ϭ

5.7 Hz, 1 H), 7.17Ϫ7.19 (m, 1 H), 7.23Ϫ7.25 (m, 2 H), 7.29Ϫ7.31

(m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ ϭ 24.17, 28.23, 45.77,

49.60, 63.45, 63.54, 64.97, 80.36, 127.09, 127.70, 128.42, 133.76,

136.17, 145.48, 174.29. HRMS (FAB): calcd. for C₁₉H₂₅NO₂[MH^ϩ]

300.1964, found 300.1960. C₁₉H₂₅NO₂: calcd. C 76.22, H 8.42, N

4.68; found C 76.20, H 8.37, N 4.67.

General Procedure for the Synthesis of Aminodiols 4 (GP 1): Alkene

1 (31.0 mmol) was dissolved in 90 mL of tBuOH and 90 mL of

water. K₃Fe(CN)₆(30.4 g, 93 mmol), K₂CO₃(12.7 g, 93 mmol),

and a catalytic amount of K₂OsO₂(OH)₄(100 mg) were added. The

resulting yellowish slurry was stirred at room temperature for 12 h.

Addition of 100 mL of water, extraction with ethyl acetate, drying

of the combined organic phases with Na₂SO₄, and removal of the

solvent gave the crude product, which was purified by column chro-

matography on silica gel (hexane/ethyl acetate, 1:1) to give the diol

as a yellow oil. This diol was dissolved in dry EtOH and 500 mg

of 5% Pd on activated charcoal was added. The suspension was

stirred under hydrogen for 24 h and subsequently filtered through

a plug of Celite. The solvent was removed under reduced pressure

to give aminodiols 4.

Ethyl (1S,3S,4S,5S,6R)-5,6-Dihydroxy-2-azabicyclo[2.2.1]heptane-

3-carboxylate (4a): The title compound was synthesised according

to GP 1 from alkene 1a (46.9 g, 173 mmol) and obtained as a yel-

low oil in 31.3 g (90%) yield. R_fϭ 0.32 (CH₂Cl₂/MeOH, 9:1; ninhy-

drin). [α]²_D⁰ϭ ϩ11.7 (c ϭ 1, CHCl₃). ¹H NMR (500 MHz, CDCl₃):

δ ϭ 1.26 (t, J ϭ 7.2 Hz, 3 H), 1.31 (d, J ϭ 11.0 Hz, 1 H), 1.80 (d,

J ϭ 11.0 Hz, 1 H), 2.57 (s, 1 H), 3.27 (s, 1 H), 3.41 (m, 1 H), 3.89

(d, J ϭ 6.6 Hz, 1 H), 3.91 (d, J ϭ 6.6 Hz, 1 H), 4.01Ϫ4.08 (br., 3

H), 4.15Ϫ4.22 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ ϭ 14.21,

29.16, 47.20, 58.98, 60.20, 62.09, 72.04, 72.33, 172.86. HRMS

(FAB): calcd. for C₉H₁₆NO₄[MH^ϩ] 202.1079; found 202.1081.

C₉H₁₅NO₄: calcd. C 53.72, H 7.51, N 6.96; found C 53.80, H 7.49,

N 6.90.

Ethyl (2S,3S,6S)-3,6-Bis(hydroxymethyl)-1-[(1R)-1-phenylethyl]pip-

eridine-2-carboxylate (2): Alkene 1b (1.68 g) was dissolved in 40 mL

of methanol and cooled to Ϫ80 °C. Ozone was bubbled through

the solution at Ϫ80 °C for 20 min until a blue colour persisted.

The solution was purged with nitrogen for 2 min and subsequently

treated with 9 mL of dimethyl sulfide in 9 mL of dichloromethane

and stirred at room temperature for 12 h. The solution was cooled

again to 0 °C and NaBH₄(0.89 g, 23.6 mmol) was added. The re-

sulting solution was stirred at 0 °C for 1 h and then treated with

100 mL of water. After stirring for 30 min at room temperature, the

solution was extracted three times with 150 mL of ethyl acetate.

The combined organic phases were washed with water (50 mL) and

brine (50 mL) and dried with Na₂SO₄. After filtration, the solvent

was removed in vacuo and 1.86 g of the crude product was ob-

tained as a yellow oil. Purification by column chromatography over

silica gel (ethyl acetate/hexane, 1:1) gave 1.48 g (78%) of the title

Ethyl (1S,3S,4S,5S,6R)-5,6-Dihydroxy-2-azabicyclo[2.2.2]octane-3-

carboxylate (4b): The title compound was synthesised according to

GP 1 from alkene 1b (28.1 g, 98 mmol) and obtained as a yellow

oil in 18.8 g (89%) yield. R_fϭ 0.20 (CH₂Cl₂/MeOH, 9:1; ninhyd-

Eur. J. Org. Chem. 2004, 1527Ϫ1543

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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1533

W. Maison, D. C. Grohs, A. H. G. P. Prenzel

FULL PAPER

rin). ¹H NMR (500 MHz, [D₄]MeOH): δ ϭ 1.24Ϫ1.27 (m, 1 H),

1.31 (t, J ϭ 7.3 Hz, 3 H), 1.51Ϫ1.60 (m, 1 H), 1.82Ϫ1.89 (m, 1

carboxylate (5a): The title compound was synthesised according to

GP 2 from amine 4a (4.0 g, 20 mmol) and Cbz-Asp(OMe)-OH

H), 1.90Ϫ196 (m, 1 H), 2.16Ϫ2.18 (m, 1 H), 2.94Ϫ2.96 (m, 1 H), (6.15 g, 21.9 mmol) and was obtained in 3.9 g (8.3 mmol, 42%)

3.63Ϫ3.66 (m, 1 H), 4.06 (ddd, J ϭ 8.5, 3.8, 1.4 Hz, 1 H), 4.10 yield. R_fϭ 0.30 (EA/PE, 7:3; Mo/Ce). [α]²_D⁰ϭ Ϫ52.2 (c ϭ 1.01,

(ddd, J ϭ 8.5, 2.8, 1.4 Hz, 1 H), 4.21Ϫ4.33 (m, 2 H). ¹³C NMR

(125 MHz, CDCl₃): δ ϭ 14.75, 14.94, 20.93, 36.49, 50.47, 57.91,

62.95, 67.80, 68.24, 175.89. HRMS (FAB): calcd. for C₁₀H₁₈NO₄

CHCl₃). ¹H NMR (500 MHz, [D₄]MeOH, mixture of rotamers):

δ ϭ 7.26Ϫ7.37 (m, 5 H), 5.00Ϫ5.14 (m, 2 H), 4.87 (t, 0.8 H, J ϭ

7.3 Hz), 4.48 (t, 0.2 H, J ϭ 5.3 Hz), 4.30 (s, 0.2 H), 4.28 (s, 0.8 H),

[MH^ϩ] 216.1236, found 216.1239. C₁₀H₁₇NO₄: calcd. C 55.80, H 4.07Ϫ4.19 (m, 2 H), 3.99Ϫ4.06 (m, 1 H), 3.89 (d, J ϭ 5.7 Hz, 0.8

7.96, N 6.51; found C 55.64, H 7.99, N 6.52.

H), 3.82 (s, 1 H), 3.74 (d, J ϭ 5.7 Hz, 0.2 H), 3.69 (s, 2.4 H), 3.64

(s, 0.6 H), 2.91 (dd, J ϭ 6.7, 16.7 Hz, 0.2 H), 2.81 (dd, J ϭ 6.3,

16.1 Hz, 0.8 H), 2.65 (dd, J ϭ 7.9, 16.1 Hz, 1 H), 2.60 (s, 0.2 H),

2.49 (s, 0.8 H), 1.92Ϫ1.98 (m, 0.8 H), 1.85Ϫ1.89 (m, 1 H),

1.68Ϫ1.71 (m, 0.2 H), 1.24 (t, J ϭ 7.2 Hz, 3 H). ¹³C NMR

(125 MHz, [D₄]MeOH, mixture of rotamers): δ ϭ 173.09, 172.10,

171.62, 171.50, 170.91, 158.08, 157.58, 138.10, 138.03, 129.45,

129.00, 128.83, 73.53, 73.50, 73.31, 71.89, 67.86, 67.23, 63.12,

62.98, 62.44, 61.31, 52.51, 52.35, 50.75, 50.20, 48.16, 38.26, 37.27,

29.92, 14.40, 14.29. HRMS (FAB): calcd. for C₂₂H₂₉N₂O₉[MH^ϩ]

465.1873, found 465.1878.

tert-Butyl (1S,3S,4S,5S,6R)-5,6-Dihydroxy-2-azabicyclo[2.2.1]hep-

tane-3-carboxylate (4c): Alkene 1c (12.0 g) was dissolved in a mix-

ture of 180 mL of tBuOH and 130 mL of water. The solution was

cooled to 0 °C and a solution of KMnO₄(4.6 g, 29.1 mmol) and

NaOH (1.0 g) in 160 mL of water was added slowly over 10 min.

NaHSO₃(39% in water; 100 mL) was added and the resulting solu-

tion was filtered through Celite. The filtrate was concentrated in

vacuo to a volume of 350 mL and extracted three times with

100 mL of dichloromethane. The combined organic extracts were

dried with Na₂SO₄, filtered, and the solvent was removed in vacuo.

The crude product was purified by column chromatography on sil-

ica gel [ethyl acetate/PE (50/70), 1:1] to give the diol as a colourless

oil in 4.3 g (65%) yield. This diol was dissolved in 200 mL of dry

MeOH and treated with 300 mg of 5% palladium on activated

charcoal. The suspension was stirred under hydrogen for 24 h and

subsequently filtered through a plug of Celite. The solvent was re-

moved under reduced pressure and the crude product purified by

column chromatography on silica gel (dichloromethane/MeOH,

98:2) to give the title compound as a colourless oil in 2.95 g (70%)

yield. R_fϭ 0.33 (dichloromethane/MeOH, 9:1). [α]²_D⁰ϭ ϩ12.3 (c ϭ

1, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ ϭ 3.87 (d, J ϭ 6.0 Hz,

1 H), 3.87 (d, J ϭ 6.0 Hz, 1 H), 3.20Ϫ3.49 (br., 2 H), 3.34 (s, 1 H),

3.07 (s, 1 H), 2.55 (s, 1 H), 1.77 (d, J ϭ 11.0 Hz, 1 H), 1.48 (s, 9

H), 1.27 (d, J ϭ 11.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ ϭ

172.84, 82.18, 72.95, 72.81, 60.08, 59.88, 47.58, 29.04, 28.14.

HRMS (ESI): calcd. for C₁₁H₁₉NO₄[MH^ϩ] 230.1392, found

230.1396.

Ethyl

(1S,3S,4S,5S,6R)-2-[(2S)-2-Benzyloxycarbonylamino-3-

hydroxypropionyl]-5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-3-carb-

oxylate (5b): The title compound was synthesised according to GP

2 from amine 4a (4.01 g, 19.3 mmol) and Cbz-Ser-OH (5.3 g,

22 mmol) and was obtained in 5.0 g (60%) yield. R_fϭ 0.20 (EA/

PE, 7:3, Mo/Ce). [α]²_D⁰ϭ Ϫ32.7 (c ϭ 1.00, CHCl₃). ¹H NMR

(500 MHz, [D₄]MeOH): δ ϭ 7.25Ϫ7.38 (m, 5 H), 5.13 (d, J ϭ

12.0 Hz, 1 H), 5.08 (d, J ϭ 12.0 Hz, 1 H), 4.55 (dd, J ϭ 6.9 Hz, 1

H), 4.37 (d, J ϭ 7.6 Hz, 1 H), 4.28 (s, 1 H), 4.15 (q, J ϭ 7.3 Hz, 2

H), 4.08 (dd, J ϭ 5.5, 7.6 Hz, 1 H), 3.89 (t, J ϭ 5.5 Hz, 1 H), 3.80

(dd, J ϭ 5.7, 11.4 Hz, 1 H), 3.68 (dd, J ϭ 6.9, 11.4 Hz, 1 H), 2.50

(s, 1 H), 1.97Ϫ2.05 (m, 1 H), 1.62Ϫ1.92 (m, 1 H), 1.24 (t, J ϭ

7.3 Hz, 3 H). ¹³C NMR (125 MHz, [D₄]MeOH): δ ϭ 171.70,

171.37, 158.96, 138.52, 129.89, 129.45, 129.28, 127.25, 126.71,

68.00, 63.67, 63.66, 63.20, 61.97, 61.60, 61.47, 55.48, 48.61, 31.74,

14.91. HRMS (FAB): calcd. for C₂₂H₃₁N₂O₈[MH^ϩ] 423.1767,

found 423.1780.

Ethyl (1S,3S,4S,5S,6R)-2-(2-Benzyloxycarbonylaminoacetyl)-5,6-di-

hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate (5c): The title

compound was synthesised according to GP 2 from amine 4a

(1.00 g, 4.65 mmol) and Cbz-Gly-OH (1.94 g, 9.3 mmol) and was

obtained in 1.34 g (71%) yield. R_fϭ 0.21 (dichloromethane/MeOH,

Ethyl (1R,3S,4R,5R,6S)-5,6-Dihydroxy-2-azabicyclo[2.2.2]octane-3-

carboxylate (4d): The title compound was synthesised according to

GP 1 from alkene 1d (3.40 g, 11.9 mmol) and obtained as a yellow

oil in 2.20 g (86%) yield. R_fϭ 0.27 (CH₂Cl₂/MeOH, 9:1; ninhyd-

1

rin). [α]²_D⁰ϭ Ϫ7.0. H NMR (500 MHz, [D₄]MeOH): δ ϭ 1.31 (t,

1

95:5; Mo/Ce). H NMR (500 MHz, CDCl₃): δ ϭ 7.37Ϫ7.33 (m, 5

J ϭ 7.1 Hz, 3 H), 1.45Ϫ1.55 (m, 1 H), 1.62Ϫ1.71 (m, 1 H),

2.00Ϫ2.10 (m, 1 H), 2.11Ϫ2.19 (m, 1 H), 2.31 (m, 1 H), 3.14 (ddd,

J ϭ 5.4, 3.6, 2.8 Hz, 1 H), 3.77 (ddd, J ϭ 8.4, 3.6, 1.3 Hz, 1 H),

3.95 (ddd, J ϭ 8.4, 3.6, 1.8 Hz, 1 H), 4.03 (d, J ϭ 2.5 Hz, 1 H),

4.20Ϫ4.40 (m, 2 H). ¹³C NMR (125 MHz, [D₄]MeOH): δ ϭ 14.41,

17.36, 17.54, 35.28, 51.15, 57.95, 63.64, 64.25, 65.75, 172.68.

HRMS (FAB): calcd. for C₁₀H₁₈NO₄[MH^ϩ] 216.1236, found

216.1230. C₁₀H₁₇NO₄: calcd. C 55.80, H 7.96, N 6.51; found C

55.86, H 7.90, N 6.55.

H), 5.83 (br., 1 H), 4.33 (s, 1 H), 4.26 (q, J ϭ 7.1 Hz, 2 H), 4.13

(dd, J ϭ 17.0 Hz, 5.0 Hz, 1 H), 4.06 (dd, J ϭ 17.0 Hz, 3.5 Hz, 1

H), 3.98Ϫ3.93 (m, 2 H), 3.81 (m, 1 H), 3.73Ϫ3.71 (br., 1 H),

3.62Ϫ3.60 (br., 1 H), 2.36 (m, 1 H), 2.12Ϫ2.10 (m, 1 H), 1.93Ϫ1.89

(m, 1 H), 1.77Ϫ1.72 (m, 1 H), 1.37Ϫ1.33 (m, 1 H), 1.30 (t, J ϭ

7.1 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ ϭ 171.57, 170.15,

157.12, 136.67, 128.94, 128.58, 128.34, 67.50, 66.59, 65.70, 61.88,

58.09, 50.14, 43.20, 36.02, 18.86, 14.61, 13.24. HRMS (FAB): calcd.

for C₂₀H₂₇N₂O₇[MH^ϩ] 407.1818, found 407.1840. C₂₀H₂₆N₂O₇:

calcd. C 59.10, H 6.45, N 6.89; found C 59.00, H 6.51, N 6.90.

General Procedure for the Synthesis of Dipeptides 5 (GP 2): Amine

4 (4.65 mmol) and the appropriate amino acid (9.30 mmol) were

dissolved in 20 mL of dry DMF. A solution of HOBt (0.63 g,

4.65 mmol) in 20 mL of dry DMF and a solution of DCC (1.15 g,

5.58 mmol) in 10 mL of dry DMF were added. The resulting sus-

pension was stirred at room temp. under nitrogen for 12 h. DCU

was filtered off and DMF was removed in vacuo. The crude prod-

uct was purified by column chromatography on silica gel to give

dipeptides 5 as colourless sticky solids.

Ethyl (1S,3S,4S,5S,6R)-2-[(2S)-2-Benzyloxycarbonylamino-3-meth-

ylbutyryl]-5,6-dihydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate

(5d): The title compound was synthesised according to GP 2 from

amine 4a (1.00 g, 4.65 mmol) and Cbz-Val-OH (2.33 g, 9.3 mmol)

and was obtained in 1.86 g (82%) yield. R_fϭ 0.24 (dichlorometh-

ane/MeOH, 95:5; Mo/Ce). ¹H NMR (500 MHz, CDCl₃): δ ϭ

7.37Ϫ7.29 (m, 5 H), 5.73 (d, J ϭ 9.1 Hz, 1 H), 5.10 (d, J ϭ 12.3 Hz,

1 H), 5.04 (d, J ϭ 12.3 Hz, 1 H), 4.57Ϫ4.49 (m, 1 H), 4.34 (m, 1

H), 4.22 (q, J ϭ 7.1 Hz, 2 H), 4.05Ϫ4.04 (m, 1 H), 3.98Ϫ3.95 (m,

1 H), 3.93Ϫ3.92 (m, 1 H), 2.35 (m, 1 H), 2.19Ϫ2.13 (m, 1 H),

Ethyl (1S,3S,4S,5S,6R)-2-[(2S)-2-Benzyloxycarbonylamino-3-meth-

oxycarbonylpropionyl]-5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-3-

1534

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Eur. J. Org. Chem. 2004, 1527Ϫ1543

Efficient Synthesis of Structurally Diverse Diazabicycloalkanes

FULL PAPER

2.05Ϫ1.98 (m, 1 H), 1.95Ϫ1.91 (m, 1 H), 1.88Ϫ1.85 (m, 1 H),

Asp(OtBu)-OH (7.11 g, 22.0 mmol) and was obtained in 7.40 g

1.35Ϫ1.33 (m, 1 H), 1.28 (t, J ϭ 7.1 Hz, 3 H), 1.06 (d, J ϭ 6.6 Hz, (72%) yield. R_fϭ 0.38 (EA/PE, 1:1; Ce/Mo). ¹H NMR (500 MHz,

3 H), 0.96 (d, J ϭ 6.6 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ ϭ

171.75, 170.32, 157.17, 136.57, 128.94, 128.60, 128.31, 67.49, 66.43,

65.83, 61.71, 58.11, 56.35, 51.16, 36.25, 32.08, 19.77, 18.80, 17.69,

[D₄]MeOH, mixture of rotamers): δ ϭ 7.25Ϫ7.39 (m, 5 H),

5.02Ϫ5.16 (m, 2 H), 4.81Ϫ4.85 (m, 1 H), 4.29 (s, 0.3 H), 4.22 (s,

0.7 H), 4.00 (d, J ϭ 5.7 Hz, 1 H), 3.87 (d, J ϭ 5.7 Hz, 1 H), 3.71

14.60, 13.22. HRMS (FAB): calcd. for C₂₃H₃₂N₂O₇[MH^ϩ] (s, 1 H), 2.71 (dd, J ϭ 6.0, 16.1 Hz, 1 H), 2.53 (dd, J ϭ 8.2, 16.1 Hz,

449.2288, found 449.2309. C₂₃H₃₂N₂O₇: calcd. C 61.59, H 7.19, N

6.25; found C 61.28, H 7.13, N 6.29.

1 H), 2.46 (s, 1 H), 1.95 (d, J ϭ 11.0 Hz, 1 H), 1.87 (d, J ϭ 11.0 Hz,

1 H), 1.45 (s, 9 H), 1.44 (s, 9 H). ¹³C NMR (125 MHz, [D₄]MeOH):

δ ϭ 129.44, 129.00, 128.87, 73.65, 73.55, 67.85, 62.85, 61.99, 51.05,

48.22, 38.85, 29.77, 28.26, 28.21. HRMS (FAB): calcd. for

C₂₇H₃₉N₂O₉[MH^ϩ] 535.2656, found 535.2651.

Ethyl (1S,3S,4S,5S,6R)-2-[(2S)-2-Benzyloxycarbonylamino-6-(tert-

butoxycarbonylamino)hexanoyl]-5,6-dihydroxy-2-azabicyclo[2.2.2]-

octane-3-carboxylate (5e): The title compound was synthesised ac-

cording to GP 2 from amine 4a (0.50 g, 2.32 mmol) and ε-Boc-α-

Cbz-Lys-OH (1.76 g, 4.64 mmol) and was obtained in 0.97 g (72%)

tert-Butyl (1S,3S,4S,5S,6R)-2-[(2S)-2-Benzyloxycarbonylamino-4-

tert-butoxycarbonylbutyryl]-5,6-dihydroxy-2-azabicyclo[2.2.1]-

heptane-3-carboxylate (5i): The title compound was synthesised ac-

cording to GP 2 from amine 4c (4.42 g, 19.3 mmol) and Cbz-

Glu(OtBu)-OH (7.42 g, 22.0 mmol) and was obtained in 7.41 g

(70%) yield. R_fϭ 0.30 (EA/PE, 1:1; Mo/Ce). [α]²_D⁰ϭ Ϫ36.9 (c ϭ

1

yield. R_fϭ 0.42 (dichloromethane/MeOH, 9:1; Mo/Ce). H NMR

(500 MHz, [D₄]MeOH): δ ϭ 7.40Ϫ7.35 (m, 5 H), 5.50 (s, 2 H),

4.46Ϫ4.45 (m, 1 H), 4.32 (s, 1 H), 4.25Ϫ4.15 (m, 2 H), 4.05Ϫ4.01

(m, 2 H), 3.98Ϫ3.95 (m, 1 H), 3.05Ϫ3.01 (m, 2 H), 2.27Ϫ2.20 (m,

1 H), 2.18Ϫ2.11 (m, 1 H), 1.99Ϫ1.95 (m, 1 H), 1.88Ϫ1.86 (m, 1

H), 1.81Ϫ1.61 (m, 2 H), 1.51Ϫ1.49 (m, 1 H), 1.45 (s, 9 H),

1.35Ϫ1.27 (m, 2 H). ¹³C NMR (125 MHz, [D₄]MeOH): δ ϭ 174.15,

172.06, 158.86, 138.58, 129.87, 129.69, 129.41, 129.22, 67.75, 66.85,

62.72, 59.70, 55.21, 52.95, 52.57, 48.79, 37.84, 31.09, 31.03, 29.23,

24.03, 20.02, 14.96, 14.26. HRMS (FAB): calcd. for C₂₉H₄₄N₃O₉

[MH^ϩ] 578.3078, found 578.3076. C₂₉H₄₃N₃O₉: calcd. C 60.30, H

7.50, N 7.27; found C 60.52, H 7.61, N 7.29.

1

0.57, CHCl₃). H NMR (400 MHz, CDCl₃, mixture of rotamers):

δ ϭ 7.27Ϫ7.37 (m, 5 H), 5.60 (d, J ϭ 8.8 Hz, 0.9 H), 5.57 (d, J ϭ

8.5 Hz, 0.1 H), 5.09 (d, J ϭ 12.3 Hz, 1 H), 5.02 (d, J ϭ 12.3 Hz, 1

H), 4.60 (ddd, J ϭ 4.1, 8.8 Hz, 0.9 H, 4.7), 4.48 (br., 0.1 H), 4.26

(s, 1 H), 3.94 (d, J ϭ 4.8 Hz, 0.9 H), 3.89 (d, J ϭ 4.8 Hz, 1 H),

3.82 (d, J ϭ 4.7 Hz, 0.1 H), 3.77 (s, 1 H), 2.76 (s, 0.1 H), 2.59 (s,

0.9 H), 2.33Ϫ2.42 (m, 1.8 H), 2.26Ϫ2.32 (m, 0.2 H), 2.00Ϫ2.10 (m,

1 H), 1.94 (d, J ϭ 10.7 Hz, 1 H), 1.89 (d, J ϭ 10.8 Hz, 1 H), 1.81

(ddd, J ϭ 6.3, 8.5, 8.8 Hz, 1 H), 1.44 (s, 9 H), 1.43 (s, 9 H). ¹³C

NMR (100 MHz, CDCl₃, major rotamer): δ ϭ 172.53, 168.38,

128.66, 128.31, 128.06, 82.00, 81.00, 72.62, 72.46, 67.24, 61.17,

60.41, 51.65, 47.06, 30.79, 29.21, 28.39, 28.24, 28.11. HRMS

(FAB): calcd. for C₂₃H₃₁N₂O₉[MH^ϩ] 549.2812, found 549.2818.

Ethyl (1S,3S,4S,5S,6R)-2-[(2S)-2-Benzyloxycarbonylamino-4-meth-

ylsulfanylbutyryl]-5,6-dihydroxy-2-azabicyclo[2.2.2]octane-3-

carboxylate (5f): The title compound was synthesised according to

GP 2 from amine 4a (1.00 g, 4.65 mmol) and Cbz-Met-OH (2.63 g,

9.30 mmol) and was obtained in 1.63 g (73%) yield. R_fϭ 0.53 (hex-

ane/EtOAc, 1:1; iodine). ¹H NMR (500 MHz, CDCl₃): δ ϭ

7.39Ϫ7.29 (m, 5 H), 5.74 (d, J ϭ 8.5 Hz, 1 H), 5.07 (d, J ϭ 8.5 Hz,

2 H), 4.83 (dd, J ϭ 5.7, 7.6 Hz, 1 H), 4.35 (s, 1 H), 4.22 (m, 2 H),

4.15 (s, 1 H), 3.99Ϫ3.91 (m, 2 H), 3.58 (s, 2 H), 2.64Ϫ2.55 (m, 2

H), 2.35 (s, 1 H), 2.19Ϫ1.80 (m, 8 H) 2.10 (s, 3 H), 1.35Ϫ1.24 (m,

4 H), 1.38 (t, J ϭ 7.2 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ ϭ

171.32, 170.13, 156.74, 136.50, 128.92, 128.61, 128.42, 67.51, 66.54,

65.82, 61.74, 58.01, 50.91, 50.19, 33.21, 30.00, 18.93, 15.78, 14.62,

13.20. HRMS (FAB): calcd. for C₂₃H₃₃N₂O₇S [MH^ϩ] 481.2008,

found 481.2003. C₂₃H₃₂N₂O₇S: calcd. C 57.48, H 6.71, N 5.83;

found C 57.65, H 6.62, N 5.69.

tert-Butyl

(1S,3S,4S,5S,6R)-2-[(2S)-Benzyloxycarbonylamino-3-

(tert-butyldimethylsilanyloxy)propionyl]-5,6-dihydroxy-2-azabicyclo-

[2.2.1]heptane-3-carboxylate (5j): The title compound was syn-

thesised according to GP 2 from amine 4c (3.60 g, 15.7 mmol) and

Cbz-Ser(OTBDMS)-OH (5.15 g, 14.6 mmol) and was obtained in

4.38 g (53%) yield. R_fϭ 0.58 (EA/PE, 2:1; Mo/Ce). [α]²_D⁰ϭ Ϫ35.8

(c ϭ 1, CHCl₃). ¹H NMR (400 MHz, CDCl₃, mixture of rotamers):

δ ϭ 7.27Ϫ7.33 (m, 5 H), 5.62 (d, J ϭ 8.8 Hz, 0.7 H), 5.48 (d, J ϭ

7.9 Hz, 0.3 H), 5.01Ϫ5.10 (m, 2 H), 4.61 (m, 0.7 H), 4.48 (s, 0.3

H), 4.25 (s, 0.7 H), 4.17Ϫ4.21 (m, 0.3 H), 4.14 (s, 0.3 H), 3.94 (d,

J ϭ 5.5 Hz, 1 H), 3.89 (d, J ϭ 5.5 Hz, 1 H), 3.80Ϫ3.84 (m, 0.8 H),

3.72Ϫ3.79 (m, 1.9 H), 3.61 (t, J ϭ 9.3 Hz, 0.3 H), 2.71 (s, 0.3 H),

2.57 (s, 0.7 H), 1.86Ϫ1.94 (m, 2 H), 1.43 (s, 9 H), 0.88 (s, 9 H),

0.07 (s, 3 H), 0.06 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃, mixture

of rotamers): δ ϭ 168.93, 168.52, 136.28, 128.67, 128.60, 128.33,

128.14, 128.06, 81.75, 72.65, 72.52, 72.24, 70.85, 67.24, 65.53,

64.23, 61.31, 60.83, 60.63, 59.93, 54.60, 54.04, 48.60, 46.99, 29.28,

28.09, 27.98, 27.28, 26.19, 25.97, 18.41, 5.33, 5.51. HRMS (FAB):

calcd. for C₂₃H₃₁N₂O₉[MH^ϩ] 565.2945, found 565.2914.

Ethyl (1S,3S,4S,5S,6R)-2-[(2S)-2-Benzyloxycarbonylamino-3-meth-

oxycarbonylpropionyl]-5,6-dihydroxy-2-azabicyclo[2.2.2]octane-3-

carboxylate (5g): The title compound was synthesised according to

GP 2 from amine 4b (3.2 g, 15 mmol) and Cbz-Asp(OMe)-OH

(5.8 g, 21 mmol) and was obtained in 5.3 g (73%) yield. R_fϭ 0.29

(EA/PE, 7:3; Mo/Ce). [α]²_D⁰ϭ Ϫ21.7 (c ϭ 0.945, MeOH). ¹H NMR

(500 MHz, CDCl₃): δ ϭ 7.28Ϫ7.38 (m, 5 H), 5.96 (d, J ϭ 9.1 Hz,

1 H), 5.05Ϫ5.14 (m, 3 H), 4.30 (br., 1 H), 4.10Ϫ4.23 (m, 3 H),

3.98Ϫ4.04 (m, 1 H), 3.88Ϫ3.94 (m, 1 H), 3.66 (s, 3 H), 2.75 (dd,

J ϭ 4.7, 15.8 Hz, 1 H), 2.63 (dd, J ϭ 7.8, 16.0 Hz, 1 H), 2.34 (br.,

1 H), 2.10Ϫ2.19 (m, 1 H), 1.85Ϫ1.96 (m, 1 H), 1.76Ϫ1.85 (m, 1 H),

1.23Ϫ1.31 (m, 1 H), 1.26 (t, J ϭ 7.1 Hz, 3 H). ¹³C NMR (100 MHz,

CDCl₃): δ ϭ 170.83, 169.82, 169.67, 136.08, 128.71, 128.48, 128.13,

67.51, 66.24, 65.00, 61.45, 57.96, 52.34, 50.78, 48.29, 38.02, 35.77,

18.62, 14.30, 13.01. HRMS (FAB): calcd. for C₂₃H₃₁N₂O₉[MH^ϩ]

479.2030, found 479.2029.

Ethyl (1R,3S,4R,5R,6S)-1-[(2S)-Benzyloxycarbonylamino-3-meth-

oxycarbonylpropionyl]-5,6-dihydroxy-2-azabicyclo[2.2.2]octane-3-

carboxylate (5k): The title compound was synthesised according to

GP 2 from amine 4d (0.75 g, 3.72 mmol) and Cbz-Asp(OMe)-OH

(1.91 g, 6.79 mmol) and was obtained in 0.59 g (33%) yield. R_fϭ

1

0.42 (PE/EA, 7:3; Mo/Ce). H NMR (400 MHz, [D₄]MeOH, mix-

ture of rotamers): δ ϭ 7.10Ϫ7.50 (m, 5 H), 4.80 (dd, J ϭ 5.4,

8.8 Hz, 1 H), 4.30 (d, J ϭ 3.2 Hz, 1 H), 4.06Ϫ4.20 (m, 4 H), 3.87

(dd, J ϭ 3.5, 3.9 Hz, 1 H), 3.67 (s, 3 H), 2.94 (dd, J ϭ 9.1, 16.7 Hz,

1 H), 2.62 (dd, J ϭ 5.7, 16.7 Hz, 1 H), 2.34Ϫ2.38 (m, 1 H),

2.05Ϫ2.25 (m, 2 H), 1.75Ϫ1.85 (m, 2 H), 1.30Ϫ1.39 (m, 3 H). ¹³C

NMR (100 MHz, [D₄]MeOH): δ ϭ 171.64, 170.67, 170.59, 156.76,

128.42, 127.93, 127.73, 67.20, 65.18, 63.44, 60.46, 59.75, 52.46,

tert-Butyl (1S,3S,4S,5S,6R)-2-[(2S)-2-Benzyloxycarbonylamino-3-

tert-butoxycarbonylpropionyl]-5,6-dihydroxy-2-azabicyclo[2.2.1]-

heptane-3-carboxylate (5h): The title compound was synthesised ac-

cording to GP 2 from amine 4c (4.42 g, 19.3 mmol) and Cbz-

Eur. J. Org. Chem. 2004, 1527Ϫ1543

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1535

W. Maison, D. C. Grohs, A. H. G. P. Prenzel

FULL PAPER

59.75, 52.46, 50.70, 50.45, 36.02, 35.38, 18.57, 17.10, 14.54. HRMS General Procedure for the Oxidation of Aldehydes to Carboxylic

(FAB): calcd. for C₂₃H₃₀N₂O₉[MH^ϩ] 478.1951, found 478.1959.

Acids 9 (GP 4): An aqueous solution (5 mL of water per mmol of

6) of NaClO₂(1.3 equiv.) and NaH₂PO₄(1.2 equiv.) was added to

a solution of aldehyde 6 (1 equiv.) and 2-methylbut-2-ene (2 equiv.)

in tBuOH (60 mL per mmol of 6). The mixture was stirred at room

temp. for 12 h before the solvent was removed in vacuo. The crude

product was purified by column chromatography (CH₂Cl₂/MeOH,

gradient) on silica gel to give products 9 as colourless sticky solids.

Ethyl (6S,7S,10S)-7-Hydroxymethyl-4-oxooctahydropyrido[1,2-a]py-

razine-6-carboxylate (8): Diol 5c (450 mg, 1.11 mmol) was dissolved

in 20 mL of acetone/8 mL of water and cooled to Ϫ25 °C. NaIO₄

(400 mg, 1.87 mmol) was added and the solution was stirred at Ϫ25

°C for 30 min. Brine (50 mL) was added and the resulting aqueous

solution was extracted with ethyl acetate. The organic phases were

dried with Na₂SO₄, filtered, and the solvent was removed in vacuo

to give 290 mg (65%) of 6c as a colourless oil. The product con-

tained some minor impurities but was used without further purifi-

cation in the next step. Aminal 6c (290 mg, 0.72 mmol) was dis-

solved in 25 mL of dry MeOH and NaBH₄(65 mg, 1.43 mmol) was

added at 0 °C. The solution was stirred at 0 °C for 1 h. After ad-

dition of 25 mL of water, the solution was stirred at room tempera-

ture for an additional 15 min. The solution was subsequently satu-

rated with NaCl and extracted with ethyl acetate. Drying of the

combined organic phases with Na₂SO₄and removal of the solvent

in vacuo gave the crude product as a 7:3 mixture of diastereoiso-

mers, which was purified by column chromatography on silica gel

to give 119 mg (41%) of (1S)-7 and 51 mg (17%) of (1R)-7 as a

second fraction as colourless oils. (1S)-7: R_fϭ 0.28 (EtOAc/hexane,

9:1; Mo/Ce). ¹H NMR (CDCl₃, 500 MHz): δ ϭ 7.41Ϫ7.34 (m, 5

H), 5.59 (m, 1 H), 5.50 (m, 1 H), 5.19 (s, 2 H), 4.45 (d, J ϭ 17.7 Hz,

1 H), 4.30Ϫ4.21 (m, 2 H), 4.05 (d, J ϭ 17.7 Hz, 1 H), 3.82Ϫ3.79

(m, 2 H), 3.55Ϫ3.50 (m, 2 H), 2.54Ϫ2.53 (m, 1 H), 1.85Ϫ1.61 (m,

3 H), 1.50Ϫ1.42 (m, 1 H), 1.30 (t, J ϭ 7.1 Hz, 3 H). ¹³C NMR

(100 MHz, CDCl₃): δ ϭ 171.62, 136.01, 129.01, 128.79, 128.50,

74.75, 68.32, 62.30, 60.80, 55.99, 53.22, 44.62, 36.98, 21.74, 21.43,

14.55. HRMS (FAB): calcd. for C₂₀H₂₆N₂O₇[MH^ϩ] 407.1818,

found 407.1799. (1R)-7: R_fϭ 0.35 (EtOAc/hexane, 9:1; Mo/Ce). ¹H

NMR (CDCl₃, 500 MHz): δ ϭ 7.41Ϫ7.34 (m, 5 H), 5.59 (s, 1 H),

5.50 (s, 1 H), 5.19 (s, 2 H), 4.45 (d, J ϭ 17.7 Hz, 1 H), 4.30Ϫ4.21

(m, 2 H), 4.05 (d, J ϭ 17.7 Hz, 1 H), 3.82Ϫ3.79 (m, 2 H),

3.55Ϫ3.50 (m, 2 H), 2.54Ϫ2.53 (m, 1 H), 1.85Ϫ1.61 (m, 3 H),

1.50Ϫ1.42 (m, 1 H), 1.30 (t, J ϭ 7.1 Hz, 3 H). ¹³C NMR (100 MHz,

CDCl₃): δ ϭ 171.62, 171.04, 166.40, 135.91, 129.04, 128.86, 128.47,

76.72, 68.47, 62.19, 60.80, 58.60, 53.50, 43.68, 37.61, 25.41, 22.58,

14.55. HRMS (FAB): calcd. for C₂₀H₂₆N₂O₇[MH^ϩ] 407.1818,

found 407.1814. 8: The combined diastereoisomers (1S)-7 and

(1R)-7 (170 mg, 0.42 mmol) were dissolved in dry EtOH and

100 mg of 5% Pd on activated charcoal was added. The suspension

was stirred under hydrogen for 24 h and subsequently filtered

through a plug of Celite. The solvent was removed under reduced

pressure to give amine 8 as a colourless oil in 107 mg (100%) yield.

R_fϭ 0.54 (dichloromethane/methanol, 8:2). ¹H NMR (CDCl₃,

500 MHz): δ ϭ 5.45 (s, 1 H), 4.15 (q, J ϭ 7.1 Hz, 1 H), 3.62Ϫ3.57

(m, 3 H), 3.53Ϫ3.48 (m, 2 H), 3.18Ϫ3.17 (m, 1 H), 2.69Ϫ2.65 (m,

1 H), 2.52Ϫ2.50 (m,1 H), 1.68Ϫ1.65 (m, 1 H), 1.60Ϫ1.52 (m, 1 H),

1.42Ϫ1.31 (m, 2 H), 1.31 (t, J ϭ 7.1 Hz, 3 H). ¹³C NMR (100 MHz,

CDCl₃): δ ϭ 171.24, 171.01, 62.26, 61.93, 53.98, 52.34, 50.55,

49.54, 25.54, 22.11, 14.63. HRMS (FAB): calcd. for C₁₂H₂₁N₂O₄

[MH^ϩ] 257.1501, found 257.1532.

General Procedure for the Hydrogenation to Amines 10 and 12 (GP

5): Aminals 9 or 11 were dissolved in dry EtOH and a catalytic

amount of 5% Pd on activated charcoal (50 mg/mmol aminal) was

added. The suspension was stirred under hydrogen for 24 h and

subsequently filtered through a plug of Celite. The solvent was re-

moved under reduced pressure to give products 10 or 12.

Ethyl (3S,6S,7S,9S)-7-Carboxy-3-methoxycarbonylmethyl-4-oxooc-

tahydropyrrolo[1,2-a]pyrazine-6-carboxylate (10a): Dipeptide 5a

(2.00 g, 4.34 mmol) was treated with NaIO₄as described in GP 3

to give of the crude aldehyde 6a (1.95 g, 4.22 mmol), which was

used without further purification in the next step. This aldehyde

was oxidised according to GP 4 to give 1.91 g of the carboxylic

acid 9a (92%). R_fϭ 0.62 (dichloromethane/MeOH, 8:2; Mo/Ce).

[α]²_D⁰ϭ ϩ40.2 (c ϭ 0.955, CHCl₃). ¹H NMR (500 MHz, CDCl₃,

mixture of rotamers): δ ϭ 7.35 (m, 5 H), 5.95 (br., 1 H), 5.92 (s,

0.5 H), 5.79 (s, 0.5 H), 5.17 (m, 2 H), 4.89 (d, J ϭ 6.8 Hz, 1 H),

4.82 (br. m, 0.5 H), 4.73 (br. m, 0.5 H), 4.18 (q, J ϭ 7.1 Hz, 2 H),

3.97 (br. m, 1 H), 3.64 (s, 1.5 H), 3.56 (s, 1.5 H), 3.10 (br. m, 2 H),

2.93 (br. m, 1 H), 2.40 (m, 2 H), 1.23 (t, J ϭ 7.1 Hz, 3 H). ¹³C

NMR (100 MHz, [D₄]MeOH, mixture of rotamers): δ ϭ 173.43,

173.06, 172.83, 168.18, 155.25, 154.98, 137.44, 129.58, 129.32,

129.21, 129.11, 74.28, 73.80, 68.95, 68.87, 63.89, 63.83, 63.74,

62.78, 53.65, 53.37, 52.38, 52.30, 41.13, 40.02, 33.41, 14.39. HRMS

(FAB): calcd. for C₂₂H₂₆N₂O₁₀[M ϩ Na]^ϩ501.1485, found

501.1501. 10a: Aminal 9a (0.35 g. 0.73 mmol) was hydrogenated

according to GP 5 to give 0.22 g (92%) of the title compound 10a.

R_fϭ 0.19 (dichloromethane/MeOH, 8:2; ninhydrin). [α]²_D⁰ϭ Ϫ33.9

(c ϭ 0.34, MeOH). ¹H NMR (500 MHz, [D₄]MeOH): δ ϭ 4.81 (d,

J ϭ 7.9 Hz, 1 H), 4.24Ϫ4.18 (m, 2 H), 3.99 (dd, J ϭ 8.5 Hz, 1 H),

3.97Ϫ3.90 (m, 1 H), 3.71 (s, 3 H), 3.27Ϫ3.22 (m, 1 H), 3.14Ϫ3.07

(m, 1 H), 2.88Ϫ2.76 (m, 3 H), 2.48Ϫ2.42 (ddd, J ϭ 5.4, 6.9,

12.3 Hz, 1 H), 1.80 (dd, 1 H, J ϭ 12.0 Hz), 1.27 (t, J ϭ 6.9 Hz, 3

H). ¹³C NMR (100 MHz, [D₄]MeOH): δ ϭ 175.59, 173.46, 172.28,

170.15, 62.98, 62.74, 60.58, 54.29, 52.42, 47.91, 44.79, 37.49, 35.89,

14.41. HRMS (FAB): calcd. for C₁₄H₂₀N₂O₇[MH^ϩ] 329.1349,

found 329.1366.

tert-Butyl (3S,6S,7S,9S)-3-tert-Butoxycarbonylmethyl-7-carboxy-4-

oxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylate (10b): Dipeptide

5h (1.71 g, 3.20 mmol) was treated with NaIO₄as described in GP

3 to give 1.80 g of the crude aldehyde 6h, which was used without

further purification in the next step. This aldehyde was oxidised

according to GP 4 to give 0.44 g of the carboxylic acid 9b (25%).

R_fϭ 0.45 (dichloromethane/MeOH, 9:1; Mo/Ce). [α]²_D⁰ϭ ϩ50.3

(c ϭ 1, CHCl₃). ¹H NMR (500 MHz, CDCl₃, mixture of conform-

ers): δ ϭ 7.31Ϫ7.40 (m, 5 H), 5.88 (s, 0.5 H), 5.73 (s, 0.5 H),

General Procedure for the Periodate Cleavage of Dipeptides to Alde-

hydes 6 (GP 3): Dipeptide 5 (1.0 equiv.) was dissolved in a 2.5:1 5.12Ϫ5.26 (m, 2 H), 4.79 (d, J ϭ 6.6 Hz, 1 H), 4.66 (br., 0.4 H),

mixture of acetone/water (15 mL per 5 mmol) and cooled to 0 °C.

NaIO₄(2.0 equiv.) was added and the resulting mixture was stirred

at 0 °C for 2 h and then left to reach room temp. After stirring at

room temp. for 20 min, brine was added (15 mL per mmol of 5)

4.60 (br., 0.6 H), 3.90Ϫ4.01 (m, 1 H), 3.19 (t, J ϭ 17.7 Hz, 0.6 H),

3.05Ϫ3.14 (m, 2 H), 2.86 (d, J ϭ 19.2 Hz, 0.4 H), 2.43Ϫ2.54 (m, 1

H), 2.32Ϫ2.43 (m, 1 H), 1.45 (s, 9 H), 1.42 (s, 5.4 H), 1.41 (s, 3.6

H). ¹³C NMR (100 MHz, [D₄]MeOH, mixture of conformers): δ ϭ

and the resulting aqueous solution was extracted with ethyl acetate. 172.18, 171.56, 170.73, 169.73, 83.37, 83.27, 82.42, 82.09, 63.99,

The organic phases were dried with Na₂SO₄, filtered, and the sol- 63.69, 60.17, 60.11, 55.58, 54.04, 49.94, 44.86, 38.57, 38.39, 36.09,

vent was removed in vacuo to give colourless aldehydes 6 that were 35.99, 28.37, 28.20. HRMS (ESI): calcd. for C₂₇H₃₆N₂NaO₁₀[M

used without further purification in the next step.

ϩ Na]^ϩ571.2267, found 571.2301. 10b: Aminal 9b (0.32 g,

1536

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Eur. J. Org. Chem. 2004, 1527Ϫ1543

Efficient Synthesis of Structurally Diverse Diazabicycloalkanes

FULL PAPER

0.58 mmol) was hydrogenated according to GP 5 to give 0.15 g

(100 MHz, CDCl₃, mixture of rotamers): δ ϭ 175.14, 169.70,

(64%) of the title compound 10b. R_fϭ 0.36 (dichloromethane/

163.43, 163.25, 158.03, 135.90, 128.80, 128.73, 128.63, 128.48,

MeOH, 9:1; ninhydrin). [α]²_D⁰ϭ Ϫ37.9 (c ϭ 0.605, MeOH). ¹H 128.32, 128.20, 82.64, 71.66, 71.29, 68.35, 68.15, 63.35, 62.40,

NMR (500 MHz, [D₄]MeOH, mixture of conformers):

4.62Ϫ4.75 (m, 1 H), 4.03Ϫ4.17 (m, 0.2 H), 3.95Ϫ3.99 (m, 0.8 H), 18.33, Ϫ5.55, Ϫ5.66. HRMS (ESI): calcd. for C₂₈H₄₂N₂NaO₉Si [M

3.86Ϫ3.96 (m, 0.8 H), 3.59Ϫ3.79 (m, 0.2 H), 3.36Ϫ3.50 (m, 0.2 H),

ϩ Na]^ϩ601.2557, found 601.2359. 10c: Aminal 9c (150 mg,

δ

ϭ

62.29, 62.24, 61.95, 61.87, 58.21, 58.11, 45.63, 33.87, 28.02, 25.80,

3.21Ϫ3.32 (m, 0.8 H), 2.94Ϫ3.07 (m, 1 H), 2.77Ϫ2.89 (m, 1 H), 0.43 mmol) was hydrogenated according to GP 5 and purified by

2.54Ϫ2.77 (m, 2 H), 2.34Ϫ2.45 (m, 1 H), 1.62Ϫ1.83 (m, 1 H), 1.47 column chromatography with dichloromethane/methanol as the

(s, 14.4 H), 1.46 (s, 3.6 H). ¹³C NMR (100 MHz, [D₄]MeOH, mix-

eluent to give 63 mg (58%) of the title compound 10c. R_fϭ 0.37

ture of conformers): δ ϭ 172.18, 171.56, 170.73, 169.73, 83.37, (dichloromethane/methanol, 9:1; Mo/Ce). [α]²_D⁰ϭ Ϫ16.9 (c ϭ

1

83.27, 82.42, 82.09, 63.99, 63.69, 60.17, 60.11, 55.58, 54.04, 49.94,

1.685, MeOH). H NMR (500 MHz, CDCl₃): δ ϭ 6.39 (br., 2 H),

44.86, 38.57, 38.39, 36.09, 35.99, 28.37, 28.20. HRMS (ESI): calcd. 4.71 (d, J ϭ 7.6 Hz, 1 H), 3.92Ϫ3.96 (m, 3 H), 3.67 (dd, 1 H, J ϭ

for C₁₉H₃₀N₂NaO₇[M ϩ Na]^ϩ421.1951, found 421.1948.

5.4 Hz), 3.29 (dd, J ϭ 3.5, 12.0 Hz, 1 H), 2.98Ϫ3.05 (m, 1 H),

2.90Ϫ2.96 (m, 1 H), 2.32Ϫ2.38 (m, 1 H), 1.77 (dd, J ϭ 11.4,

22.7 Hz, 1 H), 1.45 (s, 9 H), 0.89 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3

H). ¹³C NMR (100 MHz, CDCl₃): δ ϭ 175.05, 169.89, 165.99,

82.40, 63.03, 61.98, 58.33, 57.62, 46.48, 44.41, 34.58, 28.05, 25.99,

18.32, Ϫ5.30, Ϫ5.33. HRMS (ESI): calcd. for C₂₀H₃₆N₂NaO₆Si [M

ϩ Na]^ϩ451.2240, found 451.2236.

Ethyl (3S,6S,7S,10S)-7-Carboxy-3-methoxycarbonylmethyl-4-oxo-

octahydropyrido[1,2-a]pyrazine-6-carboxylate (10d): Dipeptide 5g

(5.0 g, 10.5 mmol) was treated with NaIO₄as described in GP 3 to

give 4.71 g (94%) of the crude aldehyde 6g, which was used without

further purification in the next step. This aldehyde was oxidised

according to GP 4 to give 1.04 g of the carboxylic acid 9d (21%).

R_fϭ 0.38 (dichloromethane/MeOH, 9:1; Mo/Ce). [α]²_D⁰ϭ ϩ37.8

General Procedure for the Olefination of Aldehydes 6 to Alkenes 11

(c ϭ 1.1, CHCl₃). ¹H NMR (500 MHz, CDCl₃, mixture of rota- (GP 6): The appropriate phosphorane (2 equiv.) was added to a

mers): δ ϭ 7.30Ϫ7.39 (m, 5 H), 5.80 (br. s, 1 H), 5.69 (br., 0.5 H), solution of aldehyde 6 (1 equiv.) in dry THF (30 mL per mmol

5.53 (br., 0.5 H), 5.10Ϫ5.23 (m, 2 H), 4.90 (t, J ϭ 5.4 Hz, 0.5 H),

4.80 (t, J ϭ 4.7 Hz, 0.5 H), 4.15Ϫ4.22 (m, 2 H), 3.74 (br., 0.5 H),

3.72 (br., 0.5 H), 3.66 (s, 1.5 H), 3.55 (s, 1.5 H), 3.35 (br., 1 H),

aldehyde) and the resulting mixture was stirred at room temp. for

12 h. The solvent was removed in vacuo and the resulting crude

product was purified by column chromatography (EtOAc/PE,

3.10Ϫ3.24 (m, 1 H), 2.94Ϫ3.08 (m, 1 H), 2.28 (d, J ϭ 12.9 Hz, 1 gradient) to give alkenes 11 as white solids.

H), 1.93 (dd, J ϭ 16.2, 13.2 Hz, 1 H), 1.58Ϫ1.67 (m, 1 H), 1.52

(ddt, J ϭ 3.1, 3.8, 12.9 Hz, 1 H), 1.22Ϫ1.37 (m, 3 H). ¹³C NMR

(100 MHz, CDCl₃, mixture of rotamers): δ ϭ 175.29, 128.74,

128.54, 128.35, 128.24, 74.88, 74.39, 68.64, 68.47, 62.22, 56.25,

56.15, 53.46, 52.67, 52.61, 52.50, 52.36, 40.21, 39.13, 37.12, 23.20,

21.08, 20.95, 14.27. HRMS (FAB): calcd. for C₂₃H₂₈N₂NaO₁₀[M

ϩ Na]^ϩ515.1642, found 515.1657. (10d): Aminal 9d (0.39 mmol,

0.19 g) was hydrogenated according to GP 5 to give 0.11 g (82%)

of the title compound 10d. R_fϭ 0.13 (dichloromethane/MeOH,

9:1; Mo/Ce). [α]²_D⁰ϭ Ϫ15.8 (c ϭ 0.525, MeOH). ¹H NMR

(500 MHz, [D₄]MeOH): δ ϭ 5.81 (s., 1 H), 4.43Ϫ4.48 (m, 1 H),

3.91Ϫ3.98 (m, 1 H), 3.77 (s, 3 H), 3.58Ϫ3.71 (m, 1 H), 3.41 (dd,

J ϭ 6.9, 12.9 Hz, 1 H), 3.35 (br., 1 H), 3.21 (dd, J ϭ 7.6, 18.0 Hz,

1 H), 3.08 (dd, J ϭ 2.8, 18.0 Hz, 1 H), 2.28Ϫ2.34 (m, 1 H),

1.64Ϫ1.80 (m, 3 H), 1.31 (t, J ϭ 7.3 Hz, 3 H). ¹³C NMR (100 MHz,

[D₄]MeOH): δ ϭ 174.46, 171.93, 170.69, 166.03, 63.45, 54.98,

54.32, 53.14, 51.20, 44.41, 41.37, 34.56, 26.78, 22.86, 14.45. HRMS

(ESI): calcd. for C₁₅H₂₂N₂NaO₇[M ϩ Na^ϩ] 365.1325, found

365.1345.

Ethyl

(3S,6S,7S,9S)-7-(2-Methoxycarbonylethyl)-3-(methoxycar-

bonylmethyl)-4-oxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylate

(12a): NaIO₄(1.1 g, 5.1 mmol) was dissolved in 7.85 mL of water.

This aqueous 0.65  solution was added dropwise to a vigorously

stirred suspension of 12 g of silica in 40 mL of Et₂O. A solution of

5a (2.0 g, 4.3 mmol) and methyl (triphenylphosphanylidene)acetate

(2.6 g, 7.8 mmol) in 20 mL of Et₂O was added to this mixture. The

reaction mixture was stirred at room temp. for 12 h and a further

portion of methyl (triphenylphosphanylidene)acetate (2.6 g,

7.8 mmol) was added. The mixture was stirred at room temp. for a

further 12 h, filtered and the solvent was removed under reduced

pressure. The crude product was purified by column chromatogra-

phy (ethyl acetate/petroleum ether, gradient) to obtain 11a in 1.4 g

(2.7 mmol, 69%) yield. R_fϭ 0.73 (EtOAc/PE, 7:3; Mo/Ce). [α]²_D⁰

ϭ

1

ϩ37.8 (c ϭ 1.21, CHCl₃). H NMR [500 MHz, CDCl₃, mixture of

rotamers and (E)/(Z) isomers]: δ ϭ 7.31Ϫ7.40 (m, 5 H), 6.93 (dd,

J ϭ 7.9, 15.8 Hz, 0.8 H), 6.19 (t, J ϭ 10.4 Hz, 0.2 H), 5.96 (d, J ϭ

15.8 Hz, 1 H), 5.89Ϫ5.94 (m, 0.4 H), 5.73Ϫ5.79 (m, 0.6 H),

5.58Ϫ5.64 (br., 0.5 H), 5.10Ϫ5.27 (m, 2 H), 5.00Ϫ5.08 (br., 0.5 H),

4.68Ϫ4.74 (m, 0.4 H), 4.61Ϫ4.67 (m, 0.6 H), 4.24 (d, J ϭ 9.1 Hz,

1 H), 4.18Ϫ4.24 (m, 1 H), 4.13Ϫ4.18 (q, J ϭ 7.9 Hz, 1 H),

3.97Ϫ4.07 (m, 1 H), 3.75 (s, 1.8 H), 3.69 (s, 1.2 H), 3.68 (s, 1.8 H)

3.62 (s, 1.2 H), 3.07Ϫ3.30 (m, 2 H), 2.94Ϫ3.03 (m, 1 H), 2.31 (dt,

tert-Butyl

(3S,6S,7S,9S)-(tert-Butyldimethylsilanyloxymethyl)-7-

carboxy-4-oxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylate (10c):

Dipeptide 5j (2.01 g, 3.56 mmol) was treated with NaIO₄as de-

scribed in GP 3 to give 2.0 g of the crude aldehyde 6j, which was

used without further purification in the next step. This aldehyde J ϭ 5.7, 6.6 Hz, 0.2 H), 2.15Ϫ2.26 (m, 1.6 H), 2.02Ϫ2.09 (m, 0.2

was oxidised according to GP 4 and purified by column chromatog-

raphy with EtOAc/PE as eluent to give 0.4 g (19%) of the car-

boxylic acid 9c and 0.8 g (43%) of the corresponding deprotected

alcohol. R_f(9c) ϭ 0.38 (dichloromethane/MeOH, 9:1; Mo/Ce).

[α]_D²⁰ϭ ϩ14.4 (c ϭ 1.95, CHCl₃). ¹H NMR (500 MHz, CDCl₃, mix-

ture of rotamers): δ ϭ 7.31Ϫ7.39 (m, 5 H), 5.85 (dd, J ϭ 2.5,

H), 1.25 (t, J ϭ 6.9 Hz, 3 H). ¹³C NMR [100 MHz, [D₄]MeOH,

mixture of rotamers and (E)/(Z) isomers]: δ ϭ 166.23, 164.85,

144.99, 128.79, 128.63, 128.33, 123.50, 122.43, 73.70, 73.31, 68.51,

68.36, 64.45, 63.55, 62.16, 62.00, 61.88, 61.66, 52.68, 52.17, 51.88,

51.48, 44.22, 35.09, 35.57, 34.11, 14.33. HRMS (FAB): calcd. for

C₂₅H₃₁N₂O₁₀[MH^ϩ] 519.1979, found 519.2003. 12a: Aminal 11a

9.5 Hz, 0.5 H), 5.72 (dd, J ϭ 2.5, 9.8 Hz, 0.5 H), 5.37 (d, J ϭ (1.27 g, 2.45 mmol) was hydrogenated according to GP 5 to give

9.3 Hz, 0.5 H), 5.16Ϫ5.26 (m, 2.5 H), 4.70Ϫ4.74 (m, 1.5 H), 0.91 g (100%) of the title compound 12a. R_fϭ 0.50 (dichlorometh-

4.66Ϫ4.68 (m, 0.5 H), 4.26Ϫ4.32 (m, 1 H), 3.84Ϫ3.94 (m, 1.5 H), ane/MeOH, 95:5; Mo/Ce). [α]²_D⁰ϭ Ϫ81.5 (c ϭ 0.455, CHCl₃). H

3.69 (dd, J ϭ 1.6, 10.1 Hz, 0.5 H), 3.00Ϫ3.08 (m, 1 H), 2.30Ϫ2.41 NMR (500 MHz, CDCl₃): δ ϭ 4.15 (q, J ϭ 7.6 Hz, 2 H), 4.06 (d,

1

(m, 2 H), 1.46 (s, 9 H), 0.87 (s, 4.5 H), 0.85 (s, 4.5 H), 0.09 (s, 1.5 J ϭ 7.9 Hz, 1 H), 3.90 (dd, J ϭ 3.5, 10.1 Hz, 1 H), 3.74Ϫ3.81 (m,

H), 0.08 (s, 1.5 H), 0.07 (s, 1.5 H), 0.06 (s, 1.5 H). ¹³C NMR 1 H), 3.63 (s, 3 H), 3.61 (s, 3 H), 3.13 (dd, J ϭ 13.2, 4.1 Hz, 1 H),

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W. Maison, D. C. Grohs, A. H. G. P. Prenzel

FULL PAPER

2.83 (dd, J ϭ 16.3, 3.7 Hz, 1 H), 2.60 (dd, J ϭ 16.3, 9.7 Hz, 1 H),

calcd. for C₃₄H₄₉N₂O₁₀[MH^ϩ] 645.3387, found 645.3440. 12c:

2.57 (dd, J ϭ 13.2, 9.5 Hz, 1 H), 2.36 (t, J ϭ 7.6 Hz, 2 H), 2.31 Aminal 11c (0.71 g, 1.10 mmol) was hydrogenated according to GP

(br. s, 1 H), 2.10Ϫ2.20 (m, 2 H), 2.00 (ddd, J ϭ 13.9, 6.3, 7.3 Hz, 5 to give 0.45 g (83%) of the title compound 12c. R_fϭ 0.23 (di-

1 H), 1.73 (ddd, J ϭ 13.9, 6.0, 7.9 Hz, 1 H), 1.22 (t, J ϭ 7.3 Hz, 3

chloromethane/MeOH, 98:2; Mo/Ce). [α]²_D⁰ϭ Ϫ40.2 (c ϭ 0.99,

1

H), 1.25 (dd, J ϭ 11.4, 10.8 Hz, 1 H). ¹³C NMR (100 MHz, CHCl₃). H NMR (500 MHz, CDCl₃): δ ϭ 3.97 (d, J ϭ 7.6 Hz, 1

CDCl₃): δ ϭ 173.13, 172.32, 171.55.168.55, 63.76, 61.37, 60.18,

H), 3.74 (ddt, J ϭ 4.1, 6.3, 10.7 Hz), 3.33 (dd, J ϭ 4.4, 10.4 Hz, 1

53.44, 51.79, 51.68, 44.76, 41.50, 37.16, 37.94, 32.14, 28.87, 14.13. H), 3.05 (dd, J ϭ 4.1, 13.6 Hz, 1 H), 2.56 (dd, J ϭ 10.1, 13.6 Hz,

HRMS (FAB): calcd. for C₁₇H₂₇N₂O₇[MH^ϩ] 371.1818, found 1 H), 2.36 (d, J ϭ 6.9 Hz, 1 H), 2.34 (d, J ϭ 6.9 Hz, 1 H), 2.28 (t,

371.1834.

J ϭ 7.7 Hz, 2 H), 2.07Ϫ2.15 (m, 3 H), 1.95Ϫ1.99 (m, 1 H),

1.80Ϫ1.87 (m, 1 H), 1.69 (m, 1 H), 1.45 (s, 9 H), 1.41 (s, 9 H), 1.40

(s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ ϭ 173.14, 171.26, 169.74,

164.70, 81.99, 80.65, 80.25, 64.54, 60.45, 56.27, 44.29, 41.68, 37.30,

33.82, 33.46, 29.51, 28.26, 28.14, 28.13, 27.60. HRMS (ESI): calcd.

for C₂₆H₄₄N₂NaO₇[M ϩ Na]^ϩ519.3046, found 519.3073.

tert-Butyl (3S,6S,7S,9S)-7-(2-tert-Butoxycarbonylethyl)-3-tert-but-

oxycarbonylmethyl-4-oxooctahydropyrrolo[1,2-a]pyrazine-6-

carboxylate (12b): Dipeptide 5h (1.56 g, 2.92 mmol) was treated

with NaIO₄as described in GP 3 to give 1.50 g of the crude alde-

hyde 6h, which was used without further purification in the next

step. This aldehyde was treated with tert-butyl (triphenylphos-

tert-Butyl (3S,6S,7S,9S)-7-(2-tert-Butoxycarbonylethyl)-3-(tert-

phanylidene)acetate according to GP 6 to give 1.02 g of the olefin butyldimethylsilanyloxymethyl)-4-oxooctahydropyrrolo[1,2-

11b (55%). R_fϭ 0.33 (EtOAc/PE, 1:2; Mo/Ce). [α]²_D⁰ϭ ϩ24.6 (c ϭ

0.365, MeOH). H NMR (500 MHz, [D₄]MeOH, mixture of rota-

a]pyrazine-6-carboxylate (12d): Dipeptide 5j (2.01 g, 3.56 mmol)

was treated with NaIO₄as described in GP 3 to give 2.01 g of the

1

mers): δ ϭ 7.29Ϫ7.44 (m, 5 H), 6.83 (dd, J ϭ 7.9, 15.5 Hz, 1 H), crude aldehyde 6j, which was used without further purification in

5.91 (d, J ϭ 15.3 Hz, 1 H), 5.90 (br., 0.5 H), 5.87 (br., 0.5 H), 5.25 the next step. This aldehyde was treated with tert-butyl (triphenyl-

(d, J ϭ 12.6 Hz, 1 H), 5.18 (d, J ϭ 12.6 Hz, 1 H), 4.96Ϫ5.01 (m,

phosphanylidene)acetate according to GP 6 to give 1.00 g of the

0.5 H), 4.90Ϫ4.96 (m, 0.5 H), 4.07 (d, J ϭ 9.2 Hz, 1 H), 3.99 (dd, olefin 11d (43%). R_fϭ 0.21 (EtOAc/PE, 1:4; Mo/Ce). [α]²_D⁰ϭ ϩ31.0

J ϭ 5.0, 5.4 Hz, 0.5 H), 3.97 (dd, J ϭ 5.0, 5.4 Hz, 0.5 H), 2.91Ϫ3.00 (c ϭ 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃, mixture of rota-

(m, 1 H), 2.70Ϫ2.83 (m, 1 H), 2.61Ϫ2.69 (m, 0.5 H), 2.53Ϫ2.59 (d,

J ϭ 15.5 Hz, 0.5 H), 2.14Ϫ2.22 (m, 1 H), 1.92Ϫ2.01 (m, 1 H), 1.49

mers): δ ϭ 7.37Ϫ7.32 (m, 5 H), 6.80 (dd, J ϭ 2.8, 15.5 Hz, 0.5 H),

6.77 (dd, J ϭ 2.8, 15.5 Hz, 0.5 H), 5.86 (d, J ϭ 15.5 Hz, 1 H), 5.85

(s, 9 H), 1.46 (s, 4.5 H), 1.45 (s, 9 H), 1.41 (s, 4.5 H). ¹³C NMR (m, 0.4 H), 5.72 (dd, J ϭ 2.5, 8.2 Hz, 0.6 H), 5.29 (d, J ϭ 8.2 Hz,

(100 MHz, [D₄]MeOH, mixture of rotamers): δ ϭ 171.06, 168.49, 0.6 H), 5.24 (d, J ϭ 12.0 Hz, 0.6 H), 5.18 (d, J ϭ 12.0 Hz, 1.4 H),

166.71, 146.33, 137.44, 129.55, 129.22, 128.96, 126.33, 83.45, 81.83,

74.19, 73.65, 68.74, 65.39, 63.70, 53.59, 52.19, 45.50, 42.57, 41.35,

5.11 (d, J ϭ 8.2 Hz, 0.4 H), 4.70 (s, 0.6 H), 4.65 (s, 0.4 H),

4.31Ϫ4.27 (m, 1 H), 4.10 (d, J ϭ 4.7 Hz, 0.5 H), 4.08 (d, J ϭ

35.27, 28.36, 28.32, 28.26. HRMS (FAB): calcd. for C₃₉H₅₇N₂O₁₁4.7 Hz, 0.5 H), 3.91 (m, 1 H), 3.86 (dd, J ϭ 1.9, 9.8 Hz, 0.6 H),

[MH^ϩ] 631.3231, found 631.3246. 12b: Aminal 11b (0.58 g, 3.69 (dd, J ϭ 1.9, 9.8 Hz, 0.4 H), 2.88 (m, 1 H), 2.19Ϫ2.10 (m, 1

0.92 mmol) was hydrogenated according to GP 5 to give 0.34 g

H), 2.08Ϫ2.00 (m, 1 H), 1.49 (s, 9 H), 1.46 (s, 9 H), 0.87 (s, 5.4 H),

(77%) of the title compound 12b. R_fϭ 0.22 (dichloromethane/

0.86 (s, 3.6 H), 0.10 (s, 5.4 H), 0.09 (s, 3.6 H), 0.07 (s, 5.4 H), 0.60

MeOH, 91:1; ninhydrin). [α]²_D⁰ϭ Ϫ53.6 (c ϭ 1.0, CHCl₃). ¹H NMR (s, 3.6 H). ¹³C NMR (100 MHz, CDCl₃, mixture of rotamers): δ ϭ

(500 MHz, CDCl₃): δ ϭ 4.57 (br., 1 H), 4.03 (d, J ϭ 7.1 Hz, 1 H), 165.55, 163.74, 144.73, 129.11, 129.04, 128.93, 128.78, 128.62,

3.99 (d, J ϭ 7.6 Hz, 1 H), 3.95 (m, 1 H), 3.37 (d, J ϭ 11.0 Hz, 1

128.50, 125.58, 82.77, 81.18, 72.00, 71.65, 68.61, 68.42, 64.15,

H), 2.96 (d, J ϭ 16.5 Hz, 1 H), 2.82 (d, J ϭ 11.0 Hz, 1 H), 2.74 64.10, 63.40, 62.65, 62.44, 58.46, 58.34, 44.31, 34.50, 28.51, 28.42,

(dd, J ϭ 8.8, 16.5 Hz, 1 H), 2.30 (t, J ϭ 7.6 Hz, 2 H), 2.13Ϫ2.26 26.08, 5.20, 5.23, 5.32. HRMS (FAB): calcd. for C₃₄H₅₃N₂O₉Si

(m, 2 H), 1.98 (dt, J ϭ 6.7, 14.3 Hz, 1 H), 1.71 (ddd, J ϭ 6.7, 7.4, [MH^ϩ] 661.3520, found 661.3545. 12d: Aminal 11d (0.95 g,

14.3 Hz, 1 H), 1.46 (s, 9 H), 1.43 (s, 9 H), 1.42 (s, 9 H), 1.23Ϫ1.28 1.44 mmol) was hydrogenated according to GP 5 to give 0.74 g

(m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ ϭ 172.14, 170.77,

(100%) of the title compound 12d. R_fϭ 0.11 (EtOAc/PE, 1:1;

1

170.42, 82.13, 81.54, 80.67, 65.82, 58.26, 52.86, 44.83, 41.60, 37.33, ninhydrin). [α]²_D⁰ϭ Ϫ54.0 (c ϭ 1.0, CHCl₃). H NMR (400 MHz,

36.97, 33.76, 29.14, 28.26, 28.22, 28.09. HRMS (FAB): calcd. for CDCl₃, mixture of conformers): δ ϭ 4.16 (d, 0.3 H J ϭ 3.8,

C₂₅H₄₃N₂O₇[MH^ϩ] 483.3070, found 483.3074.

10.1 Hz), 4.06 (m, 0.3 H), 4.04 (d, J ϭ 7.6 Hz, 0.3 H), 3.98 (d, J ϭ

7.6 Hz, 0.7 H), 3.81Ϫ3.94 (m, 2 H), 3.77 (dd, J ϭ 2.5, 10.1 Hz, 0.3

H), 3.58 (dd, J ϭ 7.6, 3.8 Hz, 0.7 H), 3.55 (t, J ϭ 2.5 Hz, 0.3 H),

3.17Ϫ3.25 (m, 0.6 H), 3.14 (dd, J ϭ 3.8, 12.0 Hz, 0.7 H), 2.85 (dd,

J ϭ 10.1, 12.0 Hz, 0.7 H), 2.29Ϫ2.35 (m, 2 H), 2.06Ϫ2.23 (m, 2

H), 1.94Ϫ2.03 (m, 1 H), 1.71 (ddd, J ϭ 7.9, 14.5, 21.8 Hz, 1 H),

1.48 (s, 9 H), 1.44 (s, 9 H), 1.06Ϫ1.20 (m, 1 H), 0.88 (s, 6.3 H),

0.86 (s, 2.7 H), 0.06 (s, 2.1 H), 0.05 (s, 2.1), 0.03 (s, 0.9 H), 0.01

(0.9 H). ¹³C NMR (100 MHz, CDCl₃, mixture of conformers): δ ϭ

65.80, 64.46, 64.25, 64.10, 59.73, 58.50, 49.45, 45.34, 41.65, 37.28,

37.03, 33.94, 33.88, 29.49, 28.24, 28.23, 26.06, 26.03. HRMS (ESI):

calcd. for C₂₆H₄₈N₂NaO₆Si [M ϩ Na]^ϩ535.3179, found 535.3180.

tert-Butyl

(3S,6S,7S,9S)-3,7-Bis(2-tert-butoxycarbonylethyl)-4-

oxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylate (12c): Dipeptide

5i (2.00 g, 3.65 mmol) was treated with NaIO₄as described in GP

3 to give 2.40 g of the crude aldehyde 6i, which was used without

further purification in the next step. This aldehyde was treated with

tert-butyl (triphenylphosphanylidene)acetate according to GP 6 to

give 0.61 g of the olefin 11c (21%). R_fϭ 0.45 (EtOAc/PE, 1:2; Mo/

Ce). [α]²_D⁰ϭ ϩ26.4 (c ϭ 1.0, CHCl₃). ¹H NMR (500 MHz,

[D₄]MeOH, mixture of rotamers): δ ϭ 7.31Ϫ7.42 (m, 5 H), 6.82

(dd, J ϭ 8.2, 15.5 Hz, 1 H), 5.88Ϫ5.97 (m, 2 H), 5.15Ϫ5.25 (m, 2

H), 4.51Ϫ4.58 (m, 0.5 H), 4.43Ϫ4.50 (m, 0.5 H), 4.07 (d, J ϭ

9.5 Hz, 1 H), 3.92Ϫ3.97 (m, 1 H), 2.90Ϫ3.00 (m, 1 H), 2.46Ϫ2.54

(m, 1 H), 2.24Ϫ2.39 (m, 2 H), 2.14Ϫ2.23 (m, 1 H), 2.01Ϫ2.12 (m,

One-Pot Oxidation/Wittig Reaction and Subsequent Reduction to

Dipeptide Mimetic 12a: NaIO₄(1.1 g, 5.1 mmol) was dissolved in

1 H), 1.94Ϫ2.00 (m, 1 H), 1.49 (s, 9 H), 1.48 (s, 9 H), 1.46 (s, 4.5 7.85 mL of water. This aqueous 0.65  solution was added drop-

H), 1.44 (s, 4.5 H). ¹³C NMR (100 MHz, [D₄]MeOH, mixture of wise to a vigorously stirred suspension of 12 g of silica in 40 mL

rotamers): δ ϭ 168.83, 146.14, 129.63, 129.37, 126.40, 124.12, of Et₂O. A solution of 5a (1.8 g, 3.9 mmol) and methyl (triphenyl-

83.55, 81.92, 81.46, 74.35, 74.04, 68.91, 65.46, 63.73, 63.49, 55.89,

phosphanylidene)acetate (2.6 g, 7.8 mmol) in 20 mL of Et₂O was

55.79 45.55, 34.82, 32.08, 29.39, 28.38, 28.35, 28.26. HRMS (FAB): added to this mixture. The reaction mixture was stirred at room

1538

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Eur. J. Org. Chem. 2004, 1527Ϫ1543

Efficient Synthesis of Structurally Diverse Diazabicycloalkanes

temp. for 12 h and another portion of methyl (triphenylphosphany-

FULL PAPER

(3S,6S,7S,9S)-2-Acetyl-3,7-bis(2-carboxyethyl)-4-oxooctahydro-

lidene)acetate (2.6 g, 7.8 mmol) was added. The mixture was stirred pyrrolo[1,2-a]pyrazine-6-carboxylic Acid (15b): Amine 12c (65 mg,

at room temp. for a further 12 h, filtered, and the solvent was re-

moved under reduced pressure. The crude product was purified by

0.13 mmol) was converted according to GP 7 and purified by col-

umn chromatography with ethyl acetate/PE as the eluent to give

column chromatography (ethyl acetate/petroleum ether, gradient) 14b as a colourless oil in 58 mg (80%) yield. R_fϭ 0.49 (ethyl acet-

1

to obtain 11a in 1.4 g (2.7 mmol, 69%) yield. Subsequent hydrogen-

ation according to GP 5 led to title compound 12a in 100% yield.

ate/PE, 4:1; Mo/Ce). [α]²_D⁰ϭ ϩ17.6 (c ϭ 1.35, CHCl₃). H NMR

(500 MHz, CDCl₃, mixture of rotamers): δ ϭ 5.06 (dd, J ϭ 4.5,

9.1 Hz, 0.4 H), 4.88 (dd, J ϭ 3.2, 13.2 Hz, 0.6 H), 4.35 (t, J ϭ

7.1 Hz, 0.6 H), 4.00 (d, J ϭ 7.6 Hz, 0.4 H), 3.98 (d, J ϭ 7.9 Hz,

0.6 H) 3.94 (dd, J ϭ 3.2, 13.9 Hz, 0.4 H), 3.82 (dt, J ϭ 4.1, 11.0 Hz,

0.4 H), 3.76 (dt, J ϭ 4.1, 13.1 Hz, 0.6 H), 3.11 (dd, J ϭ 10.7,

13.9 Hz, 0.4 H), 2.52 (dd, J ϭ 10.7, 13.6 Hz, 0.6 H), 2.41 (dd, J ϭ

7.3 Hz, 1.2 H), 2.23Ϫ2.36 (m, 3.6 H), 2.17Ϫ2.23 (m, 2 H), 2.13 (s,

1.8 H), 2.11 (s, 1.2 H), 1.92Ϫ2.09 (m, 2.2 H), 1.68Ϫ1.78 (m, 1 H),

1.47 (s, 5.4 H), 1.46 (s, 3.6 H), 1.43 (s, 3.6 H), 1.43 (s, 5.4 H), 1.41

(s, 5.4 H), 1.40 (s, 3.6 H). ¹³C NMR (100 MHz, CDCl₃, mixture of

rotamers): δ ϭ 172.65, 172.11, 171.89, 170.59, 170.47, 169.55,

168.74, 166.96, 166.17, 82.29, 82.25, 81.01, 80.75, 80.74, 80.34,

64.50, 64.48, 58.30, 57.81, 57.69, 53.97, 46.48, 41.71, 41.59, 41.02,

36.61, 36.49, 33.73, 32.50, 31.97, 29.36, 29.29, 28.22, 28.19, 28.18,

28.09, 27.92, 27.92, 26.69, 21.70, 21.39. HRMS (ESI): calcd. for

C₂₈H₄₆N₂NaO₈[M ϩ Na]^ϩ561.3152, found 561.3136. 15b: The

title compound was synthesised according to GP 7 from 14b

(48.4 mg, 0.09 mmol) and obtained as a colourless solid in 33 mg

(100%) yield. [α]²_D⁰ϭ ϩ22.5 (c ϭ 0.307, H₂O). ¹H NMR (500 MHz,

D₂O, mixture of rotamers): δ ϭ 5.01 (dd, J ϭ 4.1, 10.1 Hz, 0.8 H),

4.73 (dd, J ϭ 3.2, 13.5 Hz, 0.2 H), 4.60 (dd, J ϭ 5.7, 9.9 Hz, 0.2

H), 4.25 (dd, J ϭ 3.2, 14.2 Hz, 0.8 H), 4.15 (d, J ϭ 8.5 Hz, 1 H),

3.97 (dt, J ϭ 4.1, 11.0 Hz, 0.8 H), 3.82 (dt, J ϭ 4.1, 11.0 Hz, 0.2

H), 3.24 (dd, J ϭ 10.7, 14.2 Hz, 0.8 H), 2.83 (dd, J ϭ 11.0, 13.6 Hz,

0.2 H), 2.49Ϫ2.60 (m, 2.4 H), 2.46 (dd, J ϭ 6.6, 13.2 Hz, 1.6 H),

2.32Ϫ2.43 (m, 2 H), 2.23Ϫ2.32 (m, 1 H), 2.20 (s, 2.4 H), 2.19 (s,

0.6 H), 2.09Ϫ2.17 (m, 1 H), 2.01Ϫ2.09 (m, 1 H), 1.76Ϫ1.85 (m, 1

H), 1.43 (dd, J ϭ 11.3, 12.7 Hz, 0.8 H), 1.42 (dd, J ϭ 7.6, 18.9 Hz,

0.2 H). ¹³C NMR (100 MHz, D₂O, mixture of rotamers): δ ϭ

178.20, 177.55, 175.25, 173.24, 169.24, 64.25, 58.94, 58.34, 58.07,

53.93, 45.74, 41.68, 40.69, 35.47, 35.28, 32.18, 30.49, 30.44, 28.05,

26.97, 26.00, 20.93, 20.85. HRMS (ESI): calcd. for C₁₆H₂₃N₂O₈

[MH^ϩ] 371.1454, found 371.1458.

General Procedure for the Synthesis of Diazabicycloalkanes 15 (GP

7): A solution of 0.21 mmol of the appropriate amine in dry di-

chloromethane was cooled to 0 °C under nitrogen and DIPEA

(23.4 µL, 0.24 mmol) and acetic acid anhydride (22.2 µL,

0.24 mmol) were added. The reaction mixture was stirred for 3 h at

this temperature before it was acidified by adding 5 mL of saturated

NH₄Cl solution. The resulting mixture was extracted with dichloro-

methane and the organic phase was dried with Na₂SO₄. The sol-

vent was removed under reduced pressure to give the crude product

which was purified by column chromatography to give pure 14.

Compound 14 was dissolved in 50% TFA in dichloromethane and

stirred at room temp. for 3 h before the TFA and dichloromethane

were removed at reduced pressure to give target structure 15.

(3S,6S,7S,9S)-2-Acetyl-7-(2-carboxyethyl)-3-carboxymethyl-4-oxo-

octahydropyrrolo[1,2-a]pyrazine-6-carboxylic Acid (15a): Amine 12b

(100 mg, 0.21 mmol) was converted according to GP 7 and purified

by column chromatography with CH₂Cl₂/MeOH as the eluent to

give 14a as a colourless oil in 97 mg (92%) yield. R_fϭ 0.33

(CH₂Cl₂/MeOH, 98:2; Mo/Ce). [α]²_D⁰ϭ ϩ22.6 (c ϭ 1.0, CHCl₃).

¹H NMR (500 MHz, CDCl₃, mixture of rotamers): δ ϭ 4.93 (t,

J ϭ 4.4 Hz, 0.5 H), 4.90 (dd, J ϭ 4.1, 13.3 Hz, 0.5 H), 4.74 (dd,

J ϭ 5.0, 7.2 Hz, 0.5 H), 4.07 (d, J ϭ 7.8 Hz, 0.5 H), 4.02 (d, J ϭ

7.9 Hz, 0.5 H), 3.91 (dd, J ϭ 3.5, 12.9 Hz, 0.5 H), 3.86 (dddd, J ϭ

3.8, 4.1, 4.6, 10.5 Hz, 0.5 H), 3.78 (ddt, J ϭ 4.1, 10.7, 10.9 Hz, 0.5

H), 3.58 (dd, J ϭ 10.4, 12.9 Hz, 0.5 H), 3.10 (dd, J ϭ 4.8, 16.7 Hz,

0.5 H), 2.88 (dd, J ϭ 4.4, 16.7 Hz, 0.5 H), 2.85 (dd, J ϭ 4.7,

15.8 Hz, 0.5 H), 2.77 (dd, J ϭ 7.6, 15.8 Hz, 0.5 H), 2.63 (dd, J ϭ

10.7, 13.2 Hz, 0.5 H), 2.33 (t, J ϭ 7.6 Hz, 1 H), 2.32 (t, J ϭ 7.6 Hz,

1 H), 2.17Ϫ2.26 (m, 2 H), 2.20 (s, 1.5 H), 2.13 (s, 1.5 H), 2.05 (ddd,

J ϭ 6.3, 7.4, 14.2 Hz, 1 H), 1.75 (ddd, J ϭ 7.0, 7.3, 14.2 Hz, 1 H),

1.48 (s, 4.5 H), 1.47 (s, 4.5 H), 1.44 (s, 4.5 H), 1.43 (s, 4.5 H), 1.42

(3S,6S,7S,9S)-2-Acetyl-7-(2-carboxyethyl)-3-hydroxymethyl-4-oxo-

(s, 4.5 H), 1.39 (s, 4.5 H), 1.29Ϫ1.37 (m, 0.5 H), 1.17Ϫ1.27 (m, 0.5 octahydropyrrolo[1,2-a]pyrazine-6-carboxylic Acid (15c): Amine 12d

H). ¹³C NMR (100 MHz, CDCl₃, mixture of rotamers): δ ϭ (127 mg, 0.25 mmol) was converted according to GP 7 and purified

168.83, 82.31, 82.12, 81.87, 80.92, 80.74, 80.72, 64.74, 64.62, 58.27,

by column chromatography with ethyl acetate/PE as the eluent to

58.01, 55.45, 51.99, 47.91, 41.75, 41.66, 41.38, 39.24, 36.80, 36.55, give 14c as a colourless oil in 78 mg (56%) yield. R_fϭ 0.40 (ethyl

1

36.29, 33.82, 33.76, 29.24, 28.96, 28.24, 28.22, 28.15, 28.12, 22.09,

21.39. HRMS (FAB): calcd. for C₃₂H₄₆N₂O₈[MH^ϩ] 525.3176; NMR (500 MHz, CDCl₃, mixture of rotamers): δ ϭ 4.97 (dd, J ϭ

acetate/hexane, 1:4; Mo/Ce). [α]²_D⁰ϭ ϩ6.8 (c ϭ 0.785, CHCl₃). H

found 525.3265. 15a: The title compound was synthesised accord-

ing to GP 7 from 14a (83.0 mg, 0.16 mmol) as a colourless solid in

3.5, 13.2 Hz, 0.6 H), 4.88 (br., 0.4 H), 4.42 (dd, J ϭ 2.8, 6.0 Hz,

0.6 H), 4.31 (dd, J ϭ 1.9, 20.1 Hz, 0.4 H), 4.04Ϫ4.08 (m, 1 H),

56 mg (100%) yield. [α]²_D⁰ϭ ϩ11.2 (c ϭ 0.37, H₂O). ¹H NMR 3.97Ϫ4.01 (m, 1.4 H), 3.92Ϫ3.97 (m, 0.6 H), 3.85 (dt, J ϭ 3.8,

(500 MHz, D₂O, mixture of rotamers): δ ϭ 4.86 (t, J ϭ 5.7 Hz, 0.6 11.0 Hz, 0.4 H), 3.76 (dt, J ϭ 4.1, 11.0 Hz, 0.6 H), 3.61 (dd, J ϭ

H), 4.69 (t, J ϭ 6.1 Hz, 0.3 H), 4.62 (dd, J ϭ 3.5, 12.9 Hz, 0.3 H),

4.17Ϫ4.23 (m, 0.1 H), 4.08 (dd, J ϭ 3.2, 13.6 Hz, 0.7 H), 3.98Ϫ4.06 2.29Ϫ2.34 (m, 2 H), 2.17Ϫ2.25 (m, 2 H), 2.15 (s, 1.2 H), 2.14 (s,

(m, 0.1 H), 3.85 (d, J ϭ 8.5 Hz, 1 H), 3.77Ϫ3.84 (m, 0.6 H), 1.8 H), 1.94Ϫ2.05 (m, 1 H), 1.71 (dt, J ϭ 6.9, 13.9 Hz, 1 H), 1.48

3.54Ϫ3.61 (m, 0.3 H), 3.24 (dd, J ϭ 10.7, 13.5 Hz, 0.7 H), (s, 5.4 H), 1.47 (s, 3.6 H), 1.44 (s, 3.6 H), 1.43 (s, 5.4 H), 0.85 (s,

11.0, 12.9 Hz, 0.4 H), 2.77 (dd, J ϭ 11.0, 12.9 Hz, 0.6 H),

2.89Ϫ3.02 (m, 0.5 H), 2.75Ϫ2.78 (m, 0.5 H), 2.66Ϫ2.74 (m, 0.3 H),

2.64 (dd, J ϭ 3.5, 15.4 Hz, 1 H), 2.26Ϫ2.33 (m, 2 H), 2.11Ϫ2.20

5.4 H), 0.84 (s, 3.6 H), 0.03 (s, 1.5 H), 0.02 (s, 1.5 H), 0.00 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃, mixture of rotamers): δ ϭ 172.17,

(m, 2 H), 2.10 (s, 1 H), 2.07 (s, 2 H), 1.90Ϫ2.00 (m, 1 H), 1.54Ϫ1.66 172.13, 170.69, 169.78, 168.49, 165.44, 164.33, 82.33, 82.20, 80.74,

(m, 1 H), 1.33Ϫ1.41 (m, 0.3 H), 1.18Ϫ1.29 (m, 0.7 H). ¹³C NMR 64.72, 64.57, 64.49, 64.45, 60.42, 58.15, 57.99, 56.62, 49.12, 41.86,

(100 MHz, D₂O, mixture of rotamers): δ ϭ 174.05, 174.00, 172.59, 41.72, 41.61, 36.73, 36.71, 33.79, 33.75, 29.56, 29.38, 28.23, 28.12,

171.93, 171.79, 171.30, 168.59, 165.74, 165.38, 65.06, 63.76, 63.66, 25.98, 25.92, 21.86, 21.64, 18.28, 18.22, Ϫ5.39, Ϫ5.46. HRMS

58.35, 57.79, 54.79, 54.35, 51.07, 50.69, 46.30, 41.14, 40.39, 37.74,

36.10, 35.54, 35.30, 35.16, 31.84, 28.08, 21.60, 21.08. HRMS (ESI):

calcd. for C₁₅H₂₀N₂NaO₈[M ϩ Na]^ϩ379.1117, found 379.1138.

(ESI): calcd. for C₂₈H₅₀N₂NaO₇Si [M ϩ Na]^ϩ577.3285, found

577.3297. 15c: The title compound was synthesised according to

GP 7 in the presence of 5% H₂O from 14c (57 mg, 0.1 mmol) and

Eur. J. Org. Chem. 2004, 1527Ϫ1543

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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1539

W. Maison, D. C. Grohs, A. H. G. P. Prenzel

FULL PAPER

obtained as a colourless solid in 33 mg (100%) yield. [α]²_D⁰ϭ ϩ18

(c ϭ 0.1, DMSO). H NMR (500 MHz, D₂O, mixture of rotamers pyrrolo[1,2-a]pyrazine-6-carboxylic Acid (17b): Amine 12c (100 mg,

(3S,6S,7S,9S)-2-Benzoyl-3,7-bis(2-carboxyethyl)-4-oxooctahydro-

1

and conformers): δ ϭ 4.89 (t, J ϭ 3.5 Hz, 0.2 H), 4.84 (dd, J ϭ

0.20 mmol) was converted according to GP 8 and purified by col-

4.7, 13.6 Hz, 0.2 H), 4.72 (dd, J ϭ 4.7, 12.3 Hz, 0.4 H), 4.66 (dd, umn chromatography with ethyl acetate/PE as the eluent to give

J ϭ 3.8, 6.3 Hz, 0.2 H), 4.54Ϫ4.61 (m, 0.7 H), 4.36 (dd, J ϭ 3.8, 16b as a colourless oil containing minor impurities in 84 mg (70%)

14.2 Hz, 0.2 H), 4.16Ϫ4.27 (m, 1.6 H), 3.95Ϫ4.15 (m, 1.2 H),

3.80Ϫ3.94 (m, 1 H), 3.41 (dd, J ϭ 10.7, 13.9 Hz, 0.4 H), 3.37 (dd,

J ϭ 11.3, 12.6 Hz, 0.2 H), 3.29 (dd, J ϭ 11.0, 12.6 Hz, 0.4 H), 2.93

yield. R_fϭ 0.56 (ethyl acetate/hexane, 1:1; Mo/Ce). ¹H NMR

(500 MHz, CDCl₃, mixture of rotamers): δ ϭ 7.34Ϫ7.45 (m, 5 H),

5.22 (dd, J ϭ 5.1, 8.2 Hz, 0.7 H), 4.94Ϫ4.96 (m, 0.3 H), 4.29 (br.,

(dd, J ϭ 11.0, 13.6 Hz, 0.2 H), 2.46Ϫ2.61 (m, 3 H), 2.33Ϫ2.46 (m, 0.3 H), 4.01 (d, J ϭ 7.9 Hz, 1 H), 3.98Ϫ4.03 (m, 0.3 H), 3.95 (dd,

1 H), 2.24 (s, 1 H), 2.20 (s, 0.6 H), 2.15 (s, 1 H), 2.10Ϫ2.18 (m, 1

H), 2.10 (s, 0.5 H), 1.83 (ddd, J ϭ 8.5, 15.4, 23.9 Hz, 1 H),

J ϭ 3.2, 13.2 Hz, 0.7 H), 3.77 (dt, J ϭ 4.1, 14.8 Hz, 0.7 H), 3.07

(dd, J ϭ 11.0, 13.2 Hz, 0.7 H), 2.82 (t, J ϭ 12.0 Hz, 0.3 H),

1.50Ϫ1.59 (m, 0.5 H), 1.38Ϫ1.47 (m, 0.5 H). ¹³C NMR (100 MHz, 2.53Ϫ2.62 (m, 0.7 H), 2.31Ϫ2.47 (m, 2.3 H), 2.28 (t, J ϭ 7.3 Hz, 2

D₂O, mixture of rotamers and conformers): δ ϭ 178.21, 174.51, H), 2.10Ϫ2.18 (m, 1 H), 2.01Ϫ2.10 (m, 2 H), 1.93Ϫ2.01 (m, 1 H),

167.62, 162.67, 64.61, 64.26, 62.78, 62.26, 62.16, 60.62, 58.76,

1.64Ϫ1.75 (m, 1 H), 1.48 (s, 9 H), 1.41 (br., 18 H), 1.04Ϫ1.14 (m,

58.37, 56.90, 55.43, 53.94, 48.42, 42.07, 41.07, 41.60, 41.53, 39.98, 1 H). ¹³C NMR (100 MHz, CDCl₃, mixture of rotamers): δ ϭ

35.44, 35.30, 32.05, 32.12, 27.94, 27.86, 27.74, 21.16, 20.97, 20.35. 173.27, 172.60, 172.08, 170.24, 166.65, 135.42, 130.14, 128.99,

HRMS (ESI): calcd. for C₁₄H₂₀N₂NaO₇[M ϩ Na]^ϩ351.1168,

found 351.1183.

128.85, 126.87, 82.29, 80.73, 80.52, 64.53, 64.36, 58.70, 58.45,

58.02, 53.90, 47.47, 41.75, 41.54, 36.66, 36.45, 33.70, 32.53, 33.26,

29.52, 29.28, 28.22, 28.20, 28.09, 27.17. HRMS (ESI): calcd. for

C₃₃H₄₈N₂NaO₈[M ϩ Na]^ϩ623.3328, found 623.3333. 17a: The

title compound was synthesised according to GP 8 from 16b

(77.3 mg, 0.16 mmol) and obtained as a colourless solid containing

minor impurities in 56 mg (100%) yield. ¹H NMR (500 MHz, D₂O,

mixture of rotmers): δ ϭ 7.46Ϫ7.60 (m, 5 H), 5.21 (dd, J ϭ 4.1,

10.1 Hz, 0.9 H), 4.90 (dd, J ϭ 3.5, 13.2 Hz, 0.1 H), 4.55 (dd, J ϭ

5.4, 18.5 Hz, 0.1 H, 6-H), 4.17 (d, J ϭ 9.9 Hz, 1 H), 4.06 (dd, J ϭ

3.5, 14.2 Hz, 0.9 H), 3.88Ϫ3.95 (m, 1 H), 3.29 (dd, J ϭ 10.8,

14.2 Hz, 0.9 H), 3.11 (dd, J ϭ 11.0, 13.2 Hz, 0.1 H), 2.59Ϫ2.67 (m,

2 H), 2.32Ϫ2.58 (m, 4 H), 2.18Ϫ2.27 (m, 1 H), 2.07Ϫ2.17 (m, 2

H), 1.74Ϫ1.82 (m, 1 H), 1.33 (dd, J ϭ 11.7, 23.3 Hz, 1 H). ¹³C

NMR (100 MHz, D₂O): δ ϭ 178.16, 177.16, 175.24, 173.32, 168.80,

131.03, 129.47, 129.47, 126.65, 64.29, 59.00, 54.28, 46.80, 41.60,

35.19, 32.11, 30.61, 27.97, 26.16. HRMS (ESI): calcd. for

C₂₁H₂₄N₂NaO₈[M ϩ Na]^ϩ455.1430, found 455.1426.

General Procedure for the Synthesis of Diazabicycloalkanes 17 (GP

8): A solution of 0.21 mmol of the appropriate amine in dry di-

chloromethane was cooled to 0 °C under nitrogen and DIPEA

(23.4 µL, 0.24 mmol) and benzoyl chloride (28.5 µL, 0.24 mmol)

were added. The reaction mixture was stirred for 3 h at this tem-

perature before it was acidified by adding 5 mL of saturated NH₄Cl

solution. The resulting mixture was extracted with dichlorometh-

ane and the organic phase was dried with Na₂SO₄. The solvent was

removed under reduced pressure to give the crude product which

was purified by column chromatography to give pure 14. Com-

pound 14 was dissolved in 50% TFA in dichloromethane and

stirred at room temp. for 3 h before the TFA and dichloromethane

were removed at reduced pressure to give target structure 17.

(3S,6S,7S,9S)-2-Benzoyl-7-(2-carboxyethyl)-3-carboxymethyl-4-

oxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylic Acid (17a): Amine

12b (100 mg, 0.21 mmol) was converted according to GP 8 and (3S,6S,7S,9S)-2-Benzoyl-7-(2-carboxyethyl)-3-hydroxymethyl-4-

purified by column chromatography with CH₂Cl₂/MeOH as the

eluent to give 16a as a colourless oil in 115 mg (82%) yield. R_fϭ

0.41 (CH₂Cl₂/MeOH, 98:2; Mo/Ce). [α]²_D⁰ϭ ϩ48.5 (c ϭ 1.0,

oxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylic Acid (17c): Amine

12d (489 mg, 0.95 mmol) was converted according to GP 8 and

purified by column chromatography with ethyl acetate/PE as the

CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ ϭ 7.35Ϫ7.47 (m, 5 H), eluent to give 16c as a colourless oil in 450 mg (77%) yield. R_fϭ

5.15 (t, J ϭ 4.1 Hz, 1 H), 4.08 (d, J ϭ 8.5 Hz, 1 H), 3.92 (dd, J ϭ

0.50 (ethyl acetate/hexane, 1:1; Mo/Ce). [α]²_D⁰ϭ ϩ87.7 (c ϭ 0.93,

2.8, 12.6 Hz, 1 H), 3.75Ϫ3.84 (m, 1 H), 3.54 (t, J ϭ 12.0 Hz, 1 H), CHCl₃). ¹H NMR (500 MHz, CDCl₃; mixture of rotamers): δ ϭ

3.21 (dd, J ϭ 4.1, 16.7 Hz, 1 H), 3.05 (dd, J ϭ 4.1, 16.7 Hz, 1 H), 7.47Ϫ7.37 (m, 5 H), 5.05 (s, 0.7 H), 4.99 (dd, J ϭ 3.7, 12.8 Hz, 0.3

2.29 (t, J ϭ 7.3 Hz, 2 H), 2.14Ϫ2.24 (m, 1 H), 2.08 (ddd, J ϭ 5.6, H), 4.41 (dd, J ϭ 1.9, 10.1 Hz, 0.7 H), 4.34 (br. s, 0.3 H), 4.13 (dd,

6.0, 11.6 Hz, 1 H), 2.03 (ddd, J ϭ 6.6, 7.3, 13.9 Hz, 1 H), 1.72 (ddd,

J ϭ 7.3, 7.9, 13.9 Hz, 1 H), 1.48 (s, 9 H), 1.43 (s, 9 H), 1.42 (s, 9

J ϭ 2.5, 10.1 Hz, 0.7 H), 4.12Ϫ4.09 (m, 0.3 H), 4.08 (d, J ϭ 7.7 Hz,

0.7 H), 4.02 (d, J ϭ 7.7 Hz, 0.3 H), 3.96 (dd, J ϭ 3.7, 12.8 Hz, 0.7

H), 1.23 (dd, J ϭ 11.0, 11.6 Hz, 1 H). ¹³C NMR (100 MHz, H), 3.95Ϫ3.92 (m, 0.3 H), 3.87Ϫ3.80 (m, 0.7 H), 3.76 (dd, J ϭ 2.4,

CDCl₃): δ ϭ 172.15, 130.30, 128.83, 127.24, 82.19, 81.06, 80.71, 10.4 Hz, 0.3 H), 3.56 (dd, J ϭ 11.0, 12.9 Hz, 0.7 H), 3.28 (t, J ϭ

64.81, 58.29, 52.04, 49.53, 41.62, 36.52, 36.27, 33.77, 28.93, 28.22,

11.7 Hz, 0.3 H), 2.34 (t, J ϭ 7.6 Hz, 0.6 H), 2.29 (t, J ϭ 7.3 Hz,

28.13. HRMS (FAB): calcd. for C₃₂H₄₆N₂O₈[MH^ϩ] 587.3332; 1.4 H), 2.26Ϫ2.16 (m, 1 H), 2.12Ϫ2.05 (m, 0.7 H), 2.04Ϫ1.93 (m,

found 587.3324. 17a: The title compound was synthesised accord-

ing to GP 8 from 16a (95.0 mg, 0.16 mmol) and obtained as a

colourless solid in 67 mg (100%) yield. [α]²_D⁰ϭ ϩ47.8 (c ϭ 0.625,

1 H), 1.75Ϫ1.62 (m, 1 H), 1.50 (s, 6.3 H), 1.48 (s, 2.7 H), 1.45 (s,

2.7 H), 1.43 (s, 6.3 H), 1.30Ϫ1.19 (m, 1 H), 1.06 (t, J ϭ 11.4 Hz, 1

H), 0.87 (s, 9 H), 0.07 (s, 0.9 H), 0.06 (s, 2.1 H), 0.05 (s, 2.1 H),

0.01 (s, 0.9 H). ¹³C NMR (100 MHz, CDCl₃, mixture of rotamers):

1

H₂O). H NMR (400 MHz, [D₄]MeOH, mixture of rotamers): δ ϭ

7.42Ϫ7.52 (m, 5 H), 5.23 (t, J ϭ 4.3 Hz, 0.1 H), 5.16 (t, J ϭ 4.3 Hz, δ ϭ 172.14, 170.76, 165.25, 162.07, 135.82, 130.03, 128.86, 127.08,

0.9 H), 4.12 (d, J ϭ 8.7 Hz, 1 H), 3.97 (dd, J ϭ 3.3, 13.2 Hz, 1 H), 126.90, 82.27, 80.72, 64.69, 64.50, 58.30, 56.93, 50.20, 43.48, 41.78,

3.85Ϫ3.94 (m, 1 H), 3.55 (dd, J ϭ 10.7, 12.5 Hz, 1 H), 3.15 (dd, 41.59, 36.69, 33.77, 29.62, 29.53, 28.23, 28.14, 26.01, 18.25, Ϫ5.35,

J ϭ 5.1, 16.5 Hz, 1 H), 3.03 (dd, J ϭ 4.3, 16.5 Hz, 1 H), 2.36Ϫ3.48

(m, 2 H), 2.25Ϫ2.36 (m, 1 H), 2.07Ϫ2.21 (m, 2 H), 1.68Ϫ1.80 (m,

Ϫ5.40. HRMS (ESI): calcd. for C₃₃H₅₂N₂NaO₇Si [M ϩ Na]^ϩ

639.3441, found 639.3454. 17c: The title compound was synthesised

1 H), 1.22Ϫ1.33 (m, 1 H). ¹³C NMR (100 MHz, [D₄]MeOH): δ ϭ according to GP 8 from 16c (67 mg, 0.1 mmol) in the presence of

174.63, 174.38, 173.85, 172.69, 168.06, 136.47, 131.52, 129.92,

128.02, 65.43, 65.36, 59.71, 53.15, 49.85, 42.94, 36.78, 36.25, 32.89,

5% H₂O and obtained as a colourless solid in 42 mg (100%) yield.

1

[α]²_D⁰ϭ Ϫ5.8 (c ϭ 0.5, H₂O). H NMR (500 MHz, D₂O, mixture

32.79, 29.64, 29.53. HRMS (FAB): calcd. for C₂₀H₂₃N₂O₈[MH^ϩ]: of rotamers and conformers): δ ϭ 7.97Ϫ8.00 (m, 0.5 H), 7.71Ϫ7.75

419.1454; found 419.1454.

(m, 0.5 H), 7.47Ϫ7.60 (m, 4 H), 5.10 (dd, J ϭ 5.0, 12.9 Hz, 0.4 H),

1540

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Eur. J. Org. Chem. 2004, 1527Ϫ1543

Efficient Synthesis of Structurally Diverse Diazabicycloalkanes

FULL PAPER

5.06 (t, J ϭ 3.2 Hz, 0.4 H), 4.94 (dd, J ϭ 3.5, 13.2 Hz, 0.2 H), 13.2 Hz, 0.7 H), 3.86 (d, J ϭ 8.5 Hz, 1 H), 3.72Ϫ3.78 (m, 0.7 H),

4.81Ϫ4.83 (m, 0.4 H), 4.69 (dd, J ϭ 2.2, 4.7 Hz, 0.4 H), 4.44Ϫ4.48 3.50Ϫ3.59 (m, 0.3 H), 3.22 (dd, J ϭ 10.7, 13.6 Hz, 0.7 H),

(m, 0.2 H), 4.17Ϫ4.27 (m, 2 H), 4.14 (dd, J ϭ 3.4, 13.5 Hz, 0.4 H),

2.70Ϫ2.82 (m, 3 H), 2.59Ϫ2.68 (m, 1.3 H), 2.50Ϫ2.55 (m, 0.6 H),

4.09 (dd, J ϭ 3.2, 12.0 Hz, 0.4 H), 3.92Ϫ3.99 (m, 1 H), 3.78 (dd, 2.35Ϫ2.42 (m, 1.4 H), 2.27Ϫ2.34 (m, 2 H), 2.10Ϫ2.23 (m, 2 H),

J ϭ 3.5, 12.3 Hz, 0.2 H), 3.42 (dd, J ϭ 10.7, 13.6 Hz, 0.4 H), 3.36 1.91Ϫ2.01 (m, 1 H), 1.57Ϫ1.65 (m, 1 H), 1.47Ϫ1.57 (m, 4 H),

(dd, J ϭ 11.5, 12.6 Hz, 0.4 H), 3.19 (dd, J ϭ 10.7, 13.2 Hz, 0.2 H),

2.33Ϫ2.57 (m, 4 H), 2.13Ϫ2.20 (m, 0.5 H), 2.00Ϫ2.13 (m, 1 H), 174.04, 172.60, 171.79, 170.67, 165.74, 63.63, 58.44, 51.19, 45.37,

1.68Ϫ1.81 (m, 1 H), 1.44 (dd, J ϭ 10.7, 21.7 Hz, 0.5 H), 1.35 (dd, 41.17, 38.74, 36.10, 35.18, 32.18, 31.81, 28.04, 26.86, 25.42, 25.96.

J ϭ 11.6, 23.3 Hz, 0.5 H). ¹³C NMR (100 MHz, D₂O, mixture of HRMS (ESI): calcd. for C₁₉H₃₀N₃O₈[MH^ϩ] 428.2033, found

1.20Ϫ1.35 (m, 3 H). ¹³C NMR (100 MHz, DMSO [D₆]): δ ϭ

rotamers and conformers): δ ϭ 167.32, 162.61, 134.43, 134.82,

131.06, 129.83, 129.37, 129.31, 128.61, 126.84, 64.51, 64.32, 64.30,

63.46, 63.34, 58.84, 57.25, 55.37, 54.35, 49.61, 44.49, 41.58, 41.30,

36.27, 35.26, 32.09, 31.97, 28.10, 27.85. HRMS (ESI): calcd. for

C₁₉H₂₂N₂NaO₇[M ϩ Na]^ϩ413.1325 found 413.1325.

428.2014.

{6-[(3S,6S,7S,9S)-6-Carboxy-3,7-bis(2-carboxyethyl)-4-oxohexa-

hydropyrrolo[1,2-a]pyrazin-2-yl]-6-oxohexyl}ammonium Trifluoro-

acetate (19b): Amine 12c (64.6 mg 0.13 mmol) was converted ac-

cording to GP 9 and purified by column chromatography with ethyl

acetate/PE as the eluent to give 18b as a colourless oil in 69 mg

(75%) yield. R_fϭ 0.26 (ethyl acetate/hexane, 1:1; cerium sulfate).

[α]²_D⁰ϭ ϩ15.2 (c ϭ 0.94, CHCl₃). ¹H NMR (500 MHz, CDCl₃,

mixture of rotamers): δ ϭ 5.07 (dd, J ϭ 4.4, 9.1 Hz, 0.5 H), 4.88

General Procedure for the Synthesis of Diazabicycloalkanes 19 (GP

9): A solution of 0.21 mmol of the appropriate amine 12 in 2.5 mL

of dry DMF was cooled to 0 °C under nitrogen and a solution of

HOBt (28.4 mg, 0.21 mmol) and 6-(tert-butoxycarbonylamino)hex-

anoic acid (57.8 mg, 0.25 mol) in 2.5 mL of dry DMF was added. (t, J ϭ 13.3 Hz, 0.5 H), 4.68 (br., 0.5 H), 4.60 (br., 0.5 H), 4.39 (t,

A solution of DCC (51.4 mg, 0.25 mmol) in 2.5 mL of dry DMF

was added to this mixture. The reaction mixture was stirred at 0

°C for 3 h and then left to reach room temp. After 15 h, the solvent

was removed under reduced pressure. The resulting solid was dis-

solved in 10 mL of ethyl acetate and this solution was washed with

saturated solutions of KHSO₄, NaHCO₃, and NaCl. The organic

phase was dried with Na₂SO₄and the solvent was removed under

reduced pressure to give the crude product which was purified by

column chromatography to give pure 18. Compound 18 was dis-

solved in 50% TFA in dichloromethane and stirred at room temp.

for 3 h before the TFA and dichloromethane were removed at re-

duced pressure to give target structure 19.

J ϭ 6.9 Hz, 0.5 H), 3.97Ϫ4.02 (m, 1.5 H), 3.78Ϫ3.84 (m, 0.5 H),

3.71Ϫ3.77 (m, 0.5 H), 3.03Ϫ3.15 (m, 2.5 H), 2.54 (dd, J ϭ 10.7,

13.2 Hz, 0.5 H), 2.35Ϫ2.46 (m, 2 H), 2.14Ϫ2.34 (m, 6 H),

1.90Ϫ2.09 (m, 3 H), 1.70Ϫ1.78 (m, 1 H), 1.62Ϫ1.69 (m, 2 H),

1.28Ϫ1.53 (m, 40 H), 1.15Ϫ1.24 (m, 1 H). ¹³C NMR (100 MHz,

CDCl₃, mixture of rotamers): δ ϭ 172.67, 172.13, 171.95, 170.66,

167.10, 166.24, 82.27, 81.00, 80.76, 80.74, 64.51, 64.41, 58.44,

57.91, 56.89, 53.97, 45.58, 41.73, 41.64, 41.15, 40.47, 36.64, 36.53,

33.75, 33.36, 32.58, 32.00, 30.01, 29.43, 29.33, 28.58, 28.24, 28.21,

28.12, 27.97, 26.89, 26.63, 25.05, 24.63. HRMS (FAB): calcd. for

C₃₇H₆₃N₃NaO₁₀[M ϩ Na]^ϩ732.4411, found 732.4437. 19b: The

title compound was synthesised according to GP 9 from 18b

(50 mg, 0.07 mmol) as a colourless solid in 39 mg (100%) yield.

[α]_D²⁰ϭ ϩ28.3 (c ϭ 0.555, H₂O). ¹H NMR (500 MHz, D₂O, mixture

of rotamers): δ ϭ 5.06 (dd, 0.7 H, J ϭ 10.1, 4.1 Hz), 4.73Ϫ4.77

(m, 0.3 H), 4.65 (dd, 0.3 H, J ϭ 5.4, 9.1 Hz), 4.30 (dd, 0.7 H, J ϭ

3.2, 14.5 Hz), 4.16 (d, J ϭ 8.8 Hz, 1 H), 3.91Ϫ3.98 (m, 0.7 H),

3.76Ϫ3.84 (m, 0.3 H), 3.24 (dd, 0.7 H, J ϭ 11.1, 14.5 Hz),

2.98Ϫ3.04 (m, 2 H), 2.86 (dd, 0.3 H, J ϭ 10.7, 13.6 Hz), 2.20Ϫ2.64

(m, 9 H), 2.02Ϫ2.18 (m, 2 H), 1.77Ϫ1.87 (m, 1 H), 1.68Ϫ1.74 (m,

2 H), 1.61Ϫ1.68 (m, 2 H), 1.39Ϫ1.47 (m, 3 H). ¹³C NMR

(100 MHz, D₂O, mixture of rotamers): δ ϭ 178.22, 169.34, 64.24,

59.13, 58.54 (C-5), 57.31 (C-8), 53.97 (C-8), 45.02 (C-6), 41.69 (C-

3), 41.00 (C-6), 39.67 (C-22), 35.50 (C-4), 35.30 (C-4), 32.85 (C-

11), 32.18 (C-15), 30.47 (C-18), 28.05 (C-14), 26.87 (C-21), 25.97

(C-10), 25.65 (C-20), 24.38 (C-19). HRMS (ESI): calcd. for

C₂₀H₃₂N₃O₈[MH^ϩ] 442.2189, found 442.2204.

{6-[(3S,6S,7S,9S)-6-Carboxy-7-(2-carboxyethyl)-3-carboxymethyl-

4-oxohexahydropyrrolo[1,2-a]pyrazin-2-yl]-6-oxohexyl}ammonium

Trifluoroacetate (19a): Amine 12b (100 mg, 0.21 mmol) was con-

verted according to GP 9 and purified by column chromatography

with ethyl acetate/PE as the eluent to give 18a as a colourless oil

in 69 mg (47%) yield. R_fϭ 0.47 (ethyl acetate/hexane, 1:1; Mo/Ce).

[α]²_D⁰ϭ ϩ30.8 (c ϭ 1.21, CHCl₃). ¹H NMR (500 MHz, CDCl₃,

mixture of rotamers): 4.94 (t, J ϭ 4.7 Hz, 0.5 H), 4.89 (dd, J ϭ

3.5, 13.2 Hz, 0.5 H), 4.77 (dd, J ϭ 5.1, 6.9 Hz, 0.5 H), 4.77 (br.,

0.5 H), 4.60 (br., 0.5 H), 4.06 (d, J ϭ 8.2 Hz, 0.5 H), 4.01 (d, J ϭ

7.9 Hz, 0.5 H), 3.96 (dd, J ϭ 3.2, 13.3 Hz, 0.5 H), 3.83 (dt, J ϭ

3.8, 14.8 Hz, 0.5 H), 3.75 (dt, J ϭ 3.9, 15.1 Hz, 0.5 H), 3.51 (dd,

J ϭ 9.0, 13.3 Hz, 0.5 H), 3.04Ϫ3.14 (m, 2.5 H), 2.86 (dd, J ϭ 4.4,

11.7 Hz, 0.5 H), 2.83 (dd, J ϭ 4.7, 16.4 Hz, 0.5 H), 2.73 (dd, J ϭ

6.6, 15.4 Hz, 0.5 H), 2.61 (dd, J ϭ 10.7, 13.2 Hz, 0.5 H), 2.38Ϫ2.51

(m, 1 H), 2.28Ϫ2.37 (m, 3 H), 2.13Ϫ2.26 (m, 2 H), 1.98Ϫ2.09 (m,

1 H), 1.69Ϫ1.78 (m, 1 H), 1.58Ϫ1.69 (m, 2 H), 1.46 (s, 9 H), 1.43

6-[(3S,6S,7S,9S)-6-Carboxy-7-(2-carboxyethyl)-3-hydroxymethyl-4-

oxohexahydropyrrolo[1,2-a]pyrazin-2-yl]-6-oxohexylammonium Tri-

(s, 4.5 H), 1.42 (s, 9 H), 1.41 (s, 4.5 H), 1.38 (s, 9 H), 1.30Ϫ1.38 fluoroacetate (19c): Amine 12d (107 mg, 0.21 mmol) was converted

(m, 3 H). ¹³C NMR (100 MHz, CDCl₃, mixture of rotamers): δ ϭ

according to GP 9 and purified by column chromatography with

172.50, 172.17, 172.12, 171.14, 170.80, 170.65, 170.35, 169.47, ethyl acetate/PE as the eluent to give 18c as a colourless oil in

166.32, 165.65, 82.29, 82.12, 81.81, 80.88, 80.70, 64.72, 64.50, 72 mg (48%) yield. R_fϭ 0.29 (ethyl acetate/hexane, 1:1; cerium sul-

58.36, 58.06, 54.65, 52.04, 46.97, 41.73, 41.64, 41.48, 40.47, 40.40,

fate). [α]²_D⁰ϭ ϩ21.8 (c ϭ 1.2, CHCl₃). ¹H NMR (400 MHz, CDCl₃,

39.29, 36.79, 36.53, 36.28, 33.79, 33.73, 32.69, 29.97, 29.26, 28.94, mixture of rotamers): δ ϭ 4.97 (dd, J ϭ 3.8, 12.7 Hz, 0.5 H), 4.90

28.55, 28.21, 28.20, 28.14, 28.09, 26.53, 25.73, 25.06, 24.67. HRMS (br., 0.5 H), 4.46 (dd, J ϭ 2.8, 5.9 Hz, 0.5 H), 4.31 (dd, J ϭ 2.0,

(ESI): calcd. for C₃₆H₆₁N₃NaO₁₀[M ϩ Na]^ϩ718.4254, found

10.2 Hz, 0.5 H), 3.90Ϫ4.12 (m, 3 H), 3.79Ϫ3.88 (m, 0.5 H),

718.4269. 19a: The title compound was synthesised according to 3.70Ϫ3.78 (m, 0.5 H), 3.58 (dd, J ϭ 10.9, 13.2 Hz, 0.5 H),

GP 9 from 18a (52 mg, 0.07 mmol) as a colourless solid in 39 mg

3.05Ϫ3.16 (m, 2 H), 2.80 (dd, J ϭ 10.5, 13.0 Hz, 0.5 H), 2.29Ϫ2.40

(m, 4 H), 2.15Ϫ2.26 (m, 2 H), 1.97Ϫ2.06 (m, 1 H), 1.62Ϫ1.75 (m,

(100%) yield. [α]²_D⁰ϭ ϩ20.2 (c ϭ 0.4675, H₂O). ¹H NMR

(500 MHz, [D₆]DMSO, mixture of rotamers): δ ϭ 12.25 (br., 3 H), 3 H), 1.46Ϫ1.56 (m, 2 H), 1.48 (s, 4.5 H), 1.48 (s, 1.5 H), 1.44 (s,

7.66 (br., 3 H), 4.89 (dd, J ϭ 5.7 Hz, 0.7 H), 4.71 (dd, J ϭ 6.0 Hz,

0.3 H), 4.63 (dd, J ϭ 3.4, 12.9 Hz, 0.3 H), 4.14 (dd, J ϭ 3.4,

4.5 H), 1.44 (s, 9 H), 1.44 (s, 4.5 H), 1.30Ϫ1.40 (m, 2 H), 1.10Ϫ1.22

(m, 1 H), 0.85 (s, 4.5 H), 0.64 (s, 4.5 H), 0.03 (s, 1.5 H), 0.02 (s, 1.5

Eur. J. Org. Chem. 2004, 1527Ϫ1543

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1541

W. Maison, D. C. Grohs, A. H. G. P. Prenzel

FULL PAPER

[16]

H), 0.00 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃, mixture of rota-

mers): δ ϭ 172.13, 170.71, 170.47, 165.56, 164.38, 82.30, 82.20,

80.72, 64.71, 64.64, 64.48, 64.42, 59.57, 58.24, 58.04, 56.66, 48.22,

42.01, 41.68, 41.59, 40.50, 36.72, 36.68, 33.73, 33.52, 33.06, 30.05,

29.98, 29.53, 29.39, 28.54, 28.21, 28.08, 26.66, 26.60, 25.96, 25.89,

25.72, 25.04, Ϫ5.57. HRMS (ESI): calcd. for C₃₇H₆₇N₃NaO₉Si [M

ϩ Na]^ϩ748.4544, found 748.4504. 19c: The title compound was

synthesised according to GP 9 from 18c (36 mg, 0.05 mmol) as a

colourless solid in 25 mg (100%) yield. [α]²_D⁰ϭ ϩ4.8 (c ϭ 1.26,

H₂O). ¹H NMR (500 MHz, D₂O, mixture of rotamers/conformers):

δ ϭ 4.91 (dd, J ϭ 3.0 Hz, 0.3 H), 4.86 (dd, J ϭ 3.5, 13.6 Hz, 0.2

H), 4.76Ϫ4.81 (m, 0.5 H), 4.70 (dd, J ϭ 3.5, 6.3 Hz, 0.2 H),

4.53Ϫ4.58 (m, 0.7 H), 4.40 (dd, J ϭ 3.5, 13.9 Hz, 0.3 H), 4.31Ϫ4.36

(m, 0.3 H), 4.16Ϫ4.25 (m, 1.3 H), 4.13 (dd, J ϭ 3.5, 13.0 Hz, 0.3

H), 3.87Ϫ4.07 (m, 1.7 H), 3.76Ϫ3.87 (m, 0.3 H), 3.40 (dd, J ϭ 10.7,

13.9 Hz, 0.3 H), 3.28 (dd, J ϭ 12.0, 13.9 Hz, 0.5 H), 2.97Ϫ3.03 (m,

2 H), 2.93 (dd, J ϭ 12.9 Hz, 11.4 Hz, 0.2 H), 2.45Ϫ2.63 (m, 4.3

H), 2.32Ϫ2.45 (m, 1 H), 2.13 (dt, J ϭ 6.5, 13.2 Hz, 1 H), 1.76Ϫ2.06

(m, 2 H), 1.60Ϫ1.75 (m, 4 H), 1.29Ϫ1.54 (m, 3 H). ¹³C NMR

(100 MHz, D₂O, mixture of rotamers/conformers): δ ϭ 162.71,

64.66, 64.24, 63.05, 62.31, 62.25, 59.91, 58.95, 58.53, 56.93, 55.43,

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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Efficient Synthesis of Structurally Diverse Diazabicycloalkanes

FULL PAPER

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1543

Article Doi

Efficient synthesis of structurally diverse diazabicycloalkanes: Scaffolds for modular dipeptide mimetics with tunable backbone conformations

DOI: 10.1002/ejoc.200300700

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