Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the synthesis of an elusive conformationally restricted analogue of α-methylhomoserine

Amino Acids

DOI 10.1007/s00726-015-2100-4

ORIGINAL ARTICLE

Highly stable atropisomers by electrophilic amination of a chiral

γ‑lactam within the synthesis of an elusive conformationally

restricted analogue of α‑methylhomoserine

Paolo Amabili¹· Adolfo Amici²· Annafelicia Civitavecchia¹· Beatrice Maggiore¹·

Mario Orena¹· Samuele Rinaldi¹· Alessandra Tolomelli³

Received: 6 August 2015 / Accepted: 11 September 2015

Abstract Starting from chiral-protected 4-hydroxymethyl

pyrrolidin-2-ones, the otherwise elusive 3,4-trans-3,3,4-

trisubstituted isosteres of α-methyl homoserine, tethered

on a γ-lactam ring, were prepared exploiting stereoselective

electrophilic aminations. These reactions led to the isola-

tion and characterization of a novel type of atropisomers,

exceedingly stable at room temperature, that were directly

converted to the desired products by a novel non-reductive

N–N bond cleavage reaction.

chains of biologically active peptides, in order to obtain

novel bioactive conformations (Al-Obeidi et al. 1998;

Hruby and Balse 2000; Toniolo et al. 2001; Ahn et al.

2002; Bursavich and Rich 2002; Eguchi and Kahn 2002;

Hruby 2002; Craik et al. 2002; Vagner et al. 2008; Wu and

Gellman 2008; Grauer and Konig 2009; Zuckermann and

Kodadek 2009; Matej et al. 2009; Hruby and Cai 2013;

Avan et al. 2014). Within this topic, γ-lactams are of main

concern and a lot of conformationally restricted analogues

of amino acids tethered on this heterocyclic ring were intro-

duced in bioactive peptides, often leading to isosteres dis-

playing improved biological potency and selectivity with

respect to the parent structures (Montaner et al. 2001; Frei-

dinger 2003; Perdih and Kikelj 2006; Dolbeare et al. 2003;

Galaud and Lubell 2005; Broadrup et al. 2005; Seufert

et al. 2006; Otvos et al. 2007; Jamieson et al. 2009; Lesma

et al. 2009; Virlouvet and Podlech 2010; St-Cyr et al. 2010;

Boy et al. 2011). The γ-lactam core occurs in a variety of

naturally occurring biologically active molecules (Bryskier

2005; Takao et al. 2007; Nay et al. 2009) such as Lacta-

cystin (Gulder and Moore 2010) and Salinosporamide A

(Shibasaki et al. 2007), potent inhibitors of the 20S protea-

some and anticancer drug candidates. Moreover, γ-lactams

are useful intermediates in the total synthesis of a number

of biologically active non-peptidic compounds (Martelli

et al. 2014a, b). Therefore, novel synthetic methodolo-

gies leading to highly substituted enantiopure analogues of

amino acids tethered on γ-lactams, or to polyfunctionalised

γ-lactams’ backbones suitable for further transformations,

deserve a large practical interest.

Keywords Isosteres · γ-Lactams · Amination ·

Stereoselectivity · Atropisomers

Introduction

A promising approach in developing small useful peptid-

omimetics relies on restriction of either backbone or side

Handling Editor: J. Bode.

Electronic supplementary material The online version of this

article (doi:10.1007/s00726-015-2100-4) contains supplementary

material, which is available to authorized users.

* Samuele Rinaldi

s.rinaldi@univpm.it

1

Department of Life and Environmental Sciences,

Università Politecnica delle Marche, Via Brecce Bianche,

60131 Ancona, Italy

2

Department of Odontostomatologic and Specialized Clinical

In the last years, we have synthesized conformationally

constrained analogues of (S) and (R)-α-amino acids teth-

ered on a pyrrolidin-2-one ring, having both a 3,4-trans-

and a 3,4-cis-disubstitution (Galeazzi et al. 2003; 2005a,

b; 2007), a 3,4,4-trans- and a 3,4,4-cis-trisubstitution,

Sciences, Università Politecnica delle Marche, Via Brecce

Bianche, 60131 Ancona, Italy

3

Department of Chemistry ‘‘G. Ciamician’’, Alma

Mater Studiorum University of Bologna, Via Selmi 2,

40126 Bologna, Italy

1 3

P. Amabili et al.

Fig. 1 Atom numbering for

the generic γ-lactam cycle,

target compounds 1, conforma-

tionally constrained γ-lactam

analogues 2 and 3, (S)-α-

methylhomoserine 4 and (S)-α-

methylaspartic acid 5

Scheme 1 i LiAlH₄, anhydrous THF, −23 °C: 7 87 % yield. ii

NaH, then BnBr, anhydrous DMF, rt: 8a 82 % yield. iii Benzhy-

dryl chloride, DIPEA, reﬂuxing anhydrous DMF: 8b 93 % yield. iv

Trityl chloride, DIPEA, reﬂuxing anhydrous DMF: 8c 91 % yield.

v TMP, n-BuLi, then MeI, anhydrous THF, −23 °C: 9a 75 % yield

(trans:cis = 81:19); 9b 83 % yield (trans:cis = 80:20); 9c 80 % yield

(trans:cis = 70:30)

(Crucianelli et al. 2010) and a 3,3,4-cis-trisubstitution (Civ-

itavecchia et al. 2014). Moreover, either foldamers display-

ing a stable secondary structure (Menegazzo et al. 2006;

Galeazzi et al. 2011; Martelli et al. 2012) or a constrained

analogue of dipeptide DG (Galeazzi et al. 2008) was pre-

pared starting from β-amino acids tethered on γ-lactams,

even in the β-peptoid form.

1990), compound 6 was easily synthesized in a multigram

scale, and subsequent reduction with lithium aluminium

hydride afforded the hydroxymethyl derivative 7 in high

yield (Scheme 1). Since problems arose when the dianion

of 7 reacted with electrophiles (Galeazzi et al. 2003), we

tested a homologous series of hydroxyl-protecting groups,

with the aim of evaluating also the effect of the increasing

steric hindrance at C-4 on the stereoselectivity of the fol-

lowing steps.

Results and discussion

Thus, benzyl, benzhydryl and trityl ethers 8a–c were

prepared in very good yield by reaction with NaH and ben-

zyl bromide in dry DMF for 8a or with DIPEA (N,N-diiso-

propylethylamine) and the appropriate chloride in reﬂuxing

dry DMF for 8b and 8c (Scheme 1). Then, the methylation

at C-3 of compounds 8a–c was carried out by sequential

addition of 0.5 equivalents of 2,2,6,6-tetramethylpiperidine

(TMP) and 1.1 equivalents of n-BuLi and stoichiometric

MeI to a solution of 8a–c in anhydrous THF at −23 °C.

The transient occurrence of a brownish colour during the

n-BuLi dropwise addition, which persisted after one equiv-

alent of added base, conﬁrmed both the preliminary forma-

tion of LiTMP as the actual deprotonating reagent and its

very rapid reaction with all the substrates 8a–c.

The reactions proceeded in moderate to good yields to

give, with low stereoselectivities, inseparable mixtures

of 3,4-trans and 3,4-cis diastereomers 8a–c, and the con-

ﬁguration of the main products was assigned as 3,4-trans

by inspection of NOESY 1D spectra. We were not able to

explain the anomalous small decrease in stereoselectivity

with the increase in bulkiness of the ether-protecting group,

which was in contrast with the previous data we obtained

Within a programme aimed to prepare isosteres of (S)-

α-methylhomoserine, 4, tethered on a γ-lactam ring, we

report here the synthesis of 1, the fully protected form of

the 3,3,4-trans-trisubstituted analogue 2. It is worth men-

tioning that other three diastereomeric analogues of this lat-

ter compound have already been obtained in our laboratory

(Fig. 1). In fact, exploiting an alkylation–acylation–curtius

rearrangement sequence (Civitavecchia et al. 2014), both

the 3,3,4-cis diastereomers were easily prepared. In addi-

tion, an imine alkylation (Crucianelli et al. 2009) allowed

to synthesize the protected compound 3, a conformationally

constrained analogue of (S)-α-methylaspartic acid 5. How-

ever, since both approaches were ineffective for a practical

and stereoselective synthesis of 1 that has remained so far

elusive, a different synthetic strategy was planned.

Firstly, we devised 7 as a practical starting material,

which was obtained in a more straightforward way with

respect to the already-reported procedure (Galeazzi et al.

2003). Thus, by the reaction of itaconic acid and (S)-pheny-

lethylamine according to a literature method (Nielsen et al.

1 3

Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the…

Fig. 2 By-products 9a′–c′

obtained in the methylation

reactions of compounds 8a–c

using silyl ethers having increasing bulkiness (Civitavec-

chia et al. 2014). However, either changes of reaction con-

ditions, directed to attain a better stereoselectivity, or sep-

aration of the diastereomeric mixtures, were not required

because the subsequent metalation step preceding the elec-

trophilic amination leads to the same planar intermediate

lithium enolate for both diastereomers.

always predominating, so that protons on C-3 that must be

abstracted by the base mainly lie on the same side of the

substituent at C-4. This should slow down the enolate for-

mation, thus favouring any other side reaction.

In fact, the amination reaction carried out with di-tert-

butyl azodicarboxylate (DBAD) was unexpectedly chal-

lenging, since attempted deprotonation of 9a with LiH-

MDS, followed by DBAD addition, resulted in no reaction

at −78 °C and only in slow decomposition of starting

material and DBAD when temperature was raised to 0 °C

or room temperature. In addition, when the reported con-

ditions were used (Evans et al. 1986; Trimble and Vederas

1986) and preformed LiTMP was added at −78 °C for

15 min, followed by dropwise addition of DBAD dissolved

in THF, only traces of the desired compound 10a were pre-

sent in the reaction mixture and about 70 % of starting 9a

was recovered after chromatographic puriﬁcation. Interest-

ingly, from the TLC analysis of commercial DBAD and

a comparative trial with LiTMP but without the starting

compound, we ascertained that almost all the by-products

observed in the reactions were already present in di-tert-

butyl azodicarboxylate or were generated by the reaction

with LiTMP and the following workup.

An interesting and unexpected observation concerns the

by-products arising from methylation of compounds 8a–c.

In fact, although only a stoichiometric amount of methyl

iodide was used, dimethylated products were invariably

isolated in low yield by chromatographic puriﬁcation of

the reaction mixtures (Fig. 2). However, while derivatives

9a′ (15 % yield) and 9c′ (11 % yield) were at some extent

expected owing to further deprotonation of 9a (or 9c) by

the unreacted Li-enolate or the excess LiTMP, followed by

reaction with MeI, the formation of compound 9b′ (10 %

yield, trans:cis = 62:38), due to reaction at benzhydrylic

proton, was rather surprising. In addition, methylation of

8a gave small traces of other not well-identiﬁed by-prod-

ucts, very probably having methyl groups added at the

benzylic positions of the ether-protecting group or of the

1

chiral auxiliary, as evidenced by the H NMR spectra of

less polar fractions after chromatographic separation. This

preference, at least partial, for the generation of anions onto

benzyl-type ethers with respect to a more acidic “expected”

deprotonation site is quite rare in literature. In fact, some

examples were reported only for the metalation of dithianes

(Furuta et al. 2005, 2010) and for an attempted preparation

of cyclopropane derivatives (van der Linden 1994). Even-

tually, the yields of by-products 9a′–c′ increased when

the reactions were carried out at 0 °C (25, 18 and 21 %

yields for 9a′, 9b′ and 9c′, respectively) with a concomi-

tant decrease in the yields of the desired products (52, 66

and 61 % yields for 9a, 9b and 9c, respectively). On the

other hand, the addition of methyl iodide at −78 °C did not

lead to any substantial improvement in comparison with the

reaction at −23 °C.

Thus, we puriﬁed the electrophile by ﬂash chromatogra-

phy on oven-dried silica gel and subsequent azeotropically

drying with anhydrous THF (see "Experimental" section).

Treatment at 0 °C for 15 min with either in situ generated

or preformed LiTMP, followed by cooling at −78 °C and

dropwise addition of pure DBAD dissolved in THF, led

always to an almost complete conversion of 9a. However,

product 10a was invariably obtained in only 23–25 % yield,

together with a lot of unidentiﬁed by-products. We have

already noted (Civitavecchia et al. 2014) this tendency to

give an unsatisfying yield when a similar lithium enolate

bearing a methyl group at C-3 was treated with another

reactive and planar electrophile, methyl chloroformate, in

striking contrast with the high yield obtained in the same

reaction starting from the corresponding C-3 unmethylated

analogue. All these observations are in agreement with the

aforementioned tendency to the generation of by-products

when the pyrrolidinonic C-3 already bears a methyl sub-

stituent. However, when the electrophilic amination was

carried out metalating at −23 °C with in situ generated

LiTMP, followed by slow addition at −78 °C of puriﬁed

Whereas the above-reported behaviour is not impor-

tant per se, since practical amounts of the pure desired

compounds could be anyway easily obtained, problems

could arise in the subsequent electrophilic amination reac-

tions carried out on the corresponding lithium enolates.

In effect, in 9a–c the 3,4-trans relative conﬁguration is

1 3

P. Amabili et al.

of a highly predominating (10a, ratio of areas A_trans-10a:A_cis-

= 92:8), or a sole (10b and 10c), 3,3,4-trans-trisubsti-

10a

tuted product. Although from a theoretical point of view a

single HPLC peak could be ascribed either to a single dias-

tereomer or to a completely unresolved mixture, this can

hardly apply to the present case. Indeed, especially using

the chiral OD-H column, the two peaks for 10a were very

well separated (see "Experimental" section). Thus, a perfect

superimposition in the case of a diastereomeric mixture for

both 10b and 10c, which differ from 10a only in the dimen-

sion of protecting groups, seemed to be extremely unlikely.

Moreover, the fact that two structurally different columns

(achiral RP-C18 and chiral OD-H) gave the same results

strongly strengthened our conclusions.

Scheme 2 i TMP, n-BuLi, anhydrous THF, −23 °C, then DBAD in

anhydrous THF, −78 °C: 10a 36 % yield; 10b 41 % yield; 10c 45 %

yield

DBAD dissolved in THF, product 10a was obtained in

36 % yield (Scheme 2). Unfortunately, when the metala-

tion was performed at −78 °C, the yield was not further

improved. Exploiting the preceding methodology, but start-

ing from compounds 9b and 9c, the corresponding ami-

nated products 10b and 10c were obtained in 41 and 45 %

yields, respectively.

The subsequent cleavage of the N–N bond was chosen

both to remove traces of the undesired 3,3,4-cis diastere-

omer from 10a and to prepare fully protected compounds

1a–c. In fact, from our previous experiences with trans/cis

diastereomeric mixtures of a lot of 3,4-disubstituted and

3,3,4-trisubstituted compounds tethered on a γ-lactam ring

reported above, we noted that in the presence of hydro-

gen bond donating functionalities the diastereomers were

almost always chromatographically inseparable. This

observation, together with the need for a chemoselective

methodology not affecting protecting groups, led us to

exclude traditional reductive methods (Feuer and Brown

1970; Mellor and Smith 1984; Jacobi et al. 1984; Brimble

and Heathcock 1993; Alonso et al. 2000; Chandrasekhar

et al. 2001; Ding and Friestad 2004; Sinha et al. 2006) and

to use instead a modiﬁcation of an already-reported elimi-

native N–N cleavage (Magnus et al. 2009).

Thus, at ﬁrst compounds 10a–c were treated with NaH

in dry THF followed by N-alkylation with methyl bro-

moacetate, to give a smooth and clean reaction and a fur-

ther unexpected result (Scheme 3). In fact, starting from

10b and 10c, we obtained two products with very different

relative mobility (Rf) on silica gel TLC, whereas 10a gave

two highly predominating compounds accompanied by

very small traces of two other species, again with notably

different Rf. At ﬁrst, these results seemed to be in whole

contrast with the supposed diastereomeric purity of starting

compounds 10b–c and the high diastereomeric enrichment

of 10a, mainly because under the reaction conditions the

We wish to emphasize here that conﬁgurations of

products 10a–c, reported in Scheme 2, were deﬁnitively

assigned after the derivatisation reported below. In fact, the

1

presence in H and ¹³C NMR spectra of at least three sets

of broad signals for most of the protons and carbons of pure

products prevented to assign with certainty both stereo-

chemistry and diastereomeric ratios. As an example, for 10a

the NH resonances at 6.66, 6.61, 6.31 and 6.15 ppm were

about in a 1.18:4.45:1.55:1 ratio and were compatible both

with four rotamers for a single diastereomer and with two

or three rotamers for a diastereomer plus one or two rotam-

ers for the other diastereomer. Due to the extremely broad

signals, the uncertainty about diastereoselectivity remained

also after the NOESY 1D and ROESY experiments, even

if the major set of resonances seemed to be likely assigned

to the expected 3,3,4-trans isomer. However, this behaviour

was not unexpected, owing to the probably slow rotation

around N–N, N–C-3 and N–C(=O) bonds due to either the

high steric congestion and the partial double-bond char-

acter of N–C(=O) bonds in carbamate moieties. Eventu-

ally, HPLC elution on both an achiral reverse phase C18

column and a chiral OD-H column suggested the presence

Scheme 3 i NaH, then BrCH-

₂CO₂Me, anhydrous THF, rt:

(M)‑11a 63 % yield, (P)‑11a

26 % yield; (M)‑11b 51 %

yield, (P)‑11b 40 % yield; (M)‑

11c 53 % yield, (P)‑11c 44 %

yield

1 3

Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the…

1

Fig. 3 Details of ROESY experiments for (M)‑11c (left) and (P)‑11c (right). Circles on H spectra indicate peaks of interest that are superim-

posed with other peaks, and rectangles on the right ROESY spectrum indicate decisive cross-peaks. The assignment as H¹and H²is arbitrary

epimerization should be impossible. However, this behav-

iour could be ascribed to the presence of stable atropiso-

mers, as depicted in Scheme 3, where congestion due to

changing from NH to N-alkyl group leads to a completely

hindered rotation around the chirality axis (the N–N single

bond), in (M)- and (P)-11a–c.

but with about a 1.5:1 ratio, for all the second eluted (P)-

11a–c atropisomers. However, only the atropisomers of 11c

furnished reliable ROESY spectra suitable for our goal,

because in these cases the signals of methyl groups on the

pyrrolidinonic C-3 atoms, critical to obtain the desired

cross-peaks, were sufﬁciently deshielded and thus not

completely covered by the methyl protons of Boc groups

(Fig. 3). In fact, only for the minor rotamer of (P)-11c the

methyl signal at about 1.21 ppm appeared as a shoulder, but

its corresponding cross-peaks remained well distinguish-

able from the ones of the superimposed signal of the major

rotamer of a Boc group.

As reported in Fig. 3, both the methyl signals at

1.14 ppm (major rotamer) and 1.21 ppm (minor rotamer)

gave evident cross-peaks with the corresponding doublets

at 3.99 ppm (major rotamer) and 4.18 ppm (minor rotamer)

of one of the two protons of CH₂CO₂Me moiety, arbitrarily

indicated as H². Conversely, neither H¹nor H²of (M)-11c

highlighted no cross-peaks, conﬁrming the different posi-

tioning of this methylene group in the two atropisomers

and thus the possibility to make the desired comparison

between the experimental and computational results.

Our computational approach was chosen based on some

simple observations. Firstly, the most obvious alternative,

that is molecular dynamics, was not suitable since an ad

hoc parametrization for the whole di-tert-butyl hydrazine-

dicarboxylate fragment is lacking in every force ﬁeld.

On the other hand, a complete conformational analysis

The axial chirality indicated in Scheme 3 and used

throughout the article (M for all the ﬁrst eluted and P for all

the second eluted compounds) has been ascertained by the

coupled NMR–computational approach described below,

due to the fact that no crystalline compound suitable for

crystallographic analysis has been obtained. From a syn-

thetic point of view, the assignment of conﬁguration around

the chirality axis could be considered unimportant, because

it will be lost after the eliminative cleavage. On the other

hand, it deserves remarkable interest owing to both the

novelty of this type of extremely stable atropisomers, hav-

ing a hindered N–N bond between two non-heteroaromatic

and in general non-heterocyclic moieties, and the possible

future applications as chiral catalysts, after appropriate

derivatisation.

Thus, after chromatographic separation, we have under-

taken exhaustive mono- and bidimensional NMR analysis

of all compounds 11a–c, coupled with a computational

1

approach. Inspection of H and ¹³C spectra highlighted

very similar signals patterns among all the ﬁrst eluted atro-

pisomers ((M)-11a–c) that evidenced also the presence of

two rotamers in about a 3:1 ratio, and the same occurred,

1 3

P. Amabili et al.

Fig. 4 Most stable conform-

ers, computed at M06-2X/6-

311G(d,p) level, for model

(M)-m11 (left) and (P)-m11

(right) atropisomers (unneces-

sary hydrogens omitted for clar-

ity), with details of distances

relevant for comparisons with

ROESY experiments

with ab initio and DFT techniques would have been tre-

mendously time consuming, albeit energetically accu-

rate, owing to both molecular size and number of rotat-

able bonds. Thus, in order to compare the experimentally

obtained ROESYs with the ones expected from calcula-

tions, we decided to use PM3 semiempirical method (Stew-

art 1989a, b) for preliminary calculations on model (M) and

(P)-m11 atropisomers, where the alkoxymethyl substitu-

ent at C-4 was changed for a methyl group. All the minima

were then submitted at B3LYP/6-31G(d) level calcula-

tions (Becke 1993; Lee et al. 1988), and the search for the

most stable conformers was completed by the appropriate

rotations of substituents (see the Supporting Material for

a detailed methodological description and for optimized

geometries and energies). Eventually, only the limited sub-

sets of structures within 2 kcal/mol above the two global

minima for both atropisomers were reﬁned at M06-2X/6-

311G(d,p) (Zhao and Truhlar 2006) level. All calculations

were performed with Gaussian 09 (Gaussian 09, Revision

E.01, Frisch et al. 2009).

The results obtained by DFT calculations clearly high-

lighted that, for both atropisomers, the substituents onto

hydrazidic nitrogens have the expected approximate

orthogonal arrangement in all conformers. However, there

are two strikingly different dispositions of the hydrazidic

moiety bonded to the pyrrolidinonic C-3 atom for the most

stable conformers of M and P atropisomers (Fig. 4). In

fact, in the global minimum for (M)-m11 the N–N bond

is roughly synperiplanar with the C(=O)–C-3 bond of

γ-lactam ring, the dihedral angle being 35°, while in (P)-

m11 the N–N bond is almost perfectly synperiplanar with

the C-3-Me bond and the relative dihedral is only 6°. The

different distances between the nearest hydrogen atoms of

CH₂CO₂Me and C-3-CH₃groups, that are 3.41 Å and 2.69

Å for M and P isomers (Fig. 4), respectively, furnished an

easy tool to discern the atropisomers on the basis of experi-

mental ROESYs (Fig. 3).

In particular, for the computed most stable conformer

of P atropisomer an evident cross-peak is expected even in

1

the case of the quite broad signals in the experimental H

spectra, in perfect agreement with the observed ROESYs.

On the contrary, the greater interproton distance in the case

of M atropisomer should result in a complete lack of signal

or, at the most, in a very low one, thus allowing the safe

assignment of the M and P conﬁgurations to all the ﬁrst and

second eluted atropisomers, respectively (Fig. 3). It is note-

worthy that the certainty of the reported assignment further

increases considering the other conformers that follow the

two global minima in the order of stability for both the

M06-2X/6-311G(d,p) and B3LYP/6-31G(d) computations

(see discussion and Cartesian coordinates in Supplemen-

tary Material).

With the aim of quantitatively determining the thermal

stability of atropisomers, which is a crucial feature in view

of a synthesis of chiral catalysts, we have undertaken sim-

ple kinetics experiments aimed to evaluate the possibility

of interconversion between M and P isomers. It should be

noted ﬁrstly that atropisomers generated by hindered rota-

tion around an N–N single bond are relatively rare in lit-

erature, and mostly limited to nitrogen atoms tethered on

heteroaromatics, or in general on heterocyclic compounds

(Alkorta et al. 2012). In the few cases reported of struc-

tures similar to 11a–c, they were metastable if compounds

were not in the solid state, as already observed for various

acyclic tetraacyl hydrazines (Platts and Coogan 2000; Coo-

gan and Passey 2000; Arthur et al. 2009), and some stereo-

stability occurred only when one or both nitrogen atoms

were tethered on a planar cyclic fragment. For example, the

most stable atropisomers were found among diacyl or acyl-

phenyl derivatives of N-aminocamphorimides, for which

1 3

Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the…

free energy barriers for N–N rotation of 96–100 kJ mol⁻¹

were estimated (Verma and Prasad 1973), and in

3,3′-biquinazoline-4,4′-diones with an additional bridging

(t_1/2≈ 24 h at 110 °C). Nevertheless, they were again com-

pletely labile at room temperature, with a barrier of about

85 kJ mol⁻¹, when the bridging was missing (Coogan et al.

1999; Coogan and Passey 2000). Even in the case of the

sterically encumbered lactic acid derivative of tetraacyl

hydrazine (Arthur et al. 2009), an experimental free energy

barrier of merely 83 kJ mol⁻¹conﬁrmed the theoretical

ﬁndings about the simple tetraformylhydrazine (Platts and

Coogan 2000). The computational analysis demonstrated

that for unbridged compounds there is the possibility to cir-

cumvent the excessively high barrier for the direct rotation

around the N–N bond in the most stable conformer. Indeed,

starting from a value of more than 140 kJ mol⁻¹, found for

the direct rotation of tetraformylhydrazine N–N bond, the

barrier was calculated to be only 77 kJ mol⁻¹after prelimi-

nary rotations about two N–C amide bonds.

k₁and k₁′ for the forward and backward reactions, respec-

tively (Eq. 1). Species A and B are (M)-11a and (P)-11a in

the kinetic experiment carried out starting from pure (M)-

11a, with k_M-P= k₁and k_P-M= k₁′ while the contrary apply

starting from the pure P atropisomer.

k₁

→

A

B

(1)

←

′

k₁

When the initial concentration of B at time t = 0 is null

([B]₀= 0), the concentration at every time t is given by

Eq. 2, where [A]₀is the initial concentration of A, that is to

say that [B] rises with exponential growth until its equilib-

rium value and the reaction behaves like a ﬁrst order with

(k₁+ k₁^′) as the rate constant (Upadhyay 2006).

ꢀ

ꢁ

k₁[A]₀

k₁+ k₁^′

′

1

t

)

(

1

[B] =

1 − e^{− k +k}

(2)

In striking contrast, since our compounds do not have

nitrogen atoms tethered on heterocycles, at a ﬁrst glance

they appear unable to properly direct the carbonyl groups

and the other substituents to give an extremely high rota-

tional barrier. However, simple TLC controls evidenced that

they were stable for more than 3 months at room tempera-

ture in their standard state (viscous oil or waxy solid) or in

solution of dichloromethane or ethyl acetate. Thus, we per-

formed preliminary experiments submitting (M)-11a to 24-h

reﬂux in cyclohexane (81 °C) and toluene (111 °C) solu-

tions, but no equilibration occurred in the former case, while

only traces of epimerization were evidenced by TLC in the

latter case. Then, we decided to use xylenes’ mixture (boil-

ing point 138–140 °C) as the solvent for kinetics on pure

(M) and (P)-11a and to analyse by HPLC the samples, taken

at the appropriate intervals, after previous determination of

the response factor F on mixtures of known composition

(see details in the "Experimental" section) (Scheme 4).

The most likely kinetic scheme for the interconversion

of atropisomers is a reversible process where the reaction

is simple ﬁrst order in both directions, with rate constants

An alternative way of writing Eq. 2, useful to directly

obtain the equilibrium value [B]_eqand k₁from the inter-

polation of experimental data by nonlinear regression, is

given in Eq. 3.

ꢁ

ꢂ

ꢀ

ꢃ

[A]

[B]

0

_eqk₁

t

[B] = [B]_eq1 − e⁻

(3)

In the same way, the concentrations of [A] at vari-

ous times follow an exponential decay to the equilibrium

concentration [A]_eq, with the same overall rate constant

(k₁+ k₁^′) (Szabo 1969).

[A]₀

ꢀ

ꢁ

[A] =

′

(4)

(k₁+ k₁) k₁e^{−(k +k )t}+ k₁

1

Eventually, the equilibrium constant K_eqcan be easily

computed exploiting Eq. 5, where either the extrapolated

equilibrium concentrations or the rate constants can be

used.

Scheme 4 Equilibration of (M)

and (P)-11a in reﬂuxing xylene

1 3

P. Amabili et al.

100

90

80

70

60

50

40

30

20

10

0

k₁

k₁^′

[B]_eq

[A]_eq

K_eq

=

(5)

The ﬁtting of experimental data reported in Fig. 5

by nonlinear regression always gave correlation coefﬁ-

cients R²> 0.99, and the computed values for k_M-P, k_P-M

% of (P)-11a from equilibration of (M)-11a

% of (M)-11a from equilibration of (M)-11a

% of (P)-11a from equilibration of (P)-11a

% of (M)-11a from equilibration of (P)-11a

and K_eqwere, respectively, k_M-P= 0.116

0.002 min⁻¹

,

k_P-M= 0.021

0.001 min⁻¹and K_eq= 5.56 from

the equilibration of (M)-11a atropisomer and k_M-

_P= 0.121 0.003 min⁻¹, k_P-M= 0.022 0.001 min⁻¹and

K_eq= 5.59 from the equilibration of (P)-11a atropisomer.

The rate constants for the interconversion of one atropi-

somer into the other, k_M-Pand k_P-M, and the overall constant

for the equilibration process (k_M-P+ k_P-M), allowed us to

estimate the corresponding free energy barriers (ΔG^#) by

means of the Eyring equation (Eyring 1935) (Eq. 6), where

R is the gas constant, T is the reaction’s temperature, k is

the opportune rate constant, h is the Planck’s constant, k_Bis

the Boltzmann’s constant and a transmission coefﬁcient of

unity in the transition state theory was assumed.

0

50

100

150

200

t/min

Fig. 5 Results of kinetic experiments on pure (M)-11a and (P)-11a

of the occurrence of a partial decomposition in preliminary

trials on atropisomers of 11b, which became extensive on

the trityl-protected compounds 11c.

ꢀ

ꢁ

Then, by simple treatment with LiHMDS in anhydrous

THF, diastereomerically pure compounds 1a‑c, the fully

protected mimetics of (S)-β-methylhomoserine, were

obtained in satisfying yield without a thorough optimiza-

tion of reaction conditions (Scheme 5), and conﬁguration

at γ-lactam C-3 was deﬁnitely conﬁrmed by means of

NOESY 1D experiments.

kh

ꢀG^#= −RT ln

(6)

k_BT

Using a temperature of 412.15 K (139 °C) and the

mean values for k_M-P= 0.1185 min⁻¹(1.975 × 10⁻³

s

⁻¹),

k_P-M= 0.0215 min⁻¹(3.583 × 10⁻⁴

s

⁻¹) and (k_M-P+ k_P-

_M) = 0.140 min⁻¹(2.333 × 10⁻³

s

⁻¹), the estimated bar-

riers were 123.4 kJ/mol for the conversion from M to P

atropisomer, 129.2 kJ/mol for the conversion from P to M

atropisomer and 122.8 kJ/mol for the overall equilibration

process. These values are quite impressive if compared to

the ones reported above for other hydrazine derivatives

with unbridged N atoms. In fact, they are more than 20 kJ/

mol higher with respect to the largest values measured in

literature, but in perfect agreement with the experimen-

tal stability of atropisomers 11a–c for months, both as

pure compounds and in solution. Assuming an approxi-

mate constancy of ΔG^#with temperature and rearranging

Eq. 6 to obtain the rate constants at room temperature, we

found k_M-P298= 4.717 10⁻²year⁻¹(1.496 × 10⁻⁹s⁻¹), k_P-

Conclusions

We reported here the stereoselective synthesis of the otherwise

elusive fully protected conformationally constrained isosteres

of α-methyl homoserine, 1a–c, tethered on a γ-lactam ring,

exploiting the electrophilic amination reaction of a lithium

enolate followed by eliminative N–N bond cleavage. Even-

tually, we observed the formation of atropisomers displaying

an unprecedented stability around the N–N single bond, with

completely hindered rotation due to the N-alkylation step pre-

ceding the eliminative cleavage. This last behaviour can be of

great interest and will be the subject of future studies, directed

towards the synthesis of other atropisomeric compounds based

on a γ-lactam structure and, after a suitable derivatisation, of

chiral catalysts exploiting this kind of axial chirality.

= 4.439 × 10⁻³year⁻¹(1.408 × 10⁻¹⁰

s

⁻¹) and (k_M-

M298

+ k_{P-M 298}

)

= 5.161 × 10⁻²year⁻¹(1.637 × 10⁻⁹

s

⁻¹).

P

The corresponding estimated half-lives were then

14.69 years [from (M) to (P)-11a], 156.1 years [from (P)

to (M)-11a] and 13.43 years for the overall equilibration

process.

Having demonstrated that isomers of 11a–c are undoubt-

edly two atropisomers with an unexpected, extreme stabil-

ity at room temperature, we proceeded to the ﬁnal N–N

bond cleavage exploiting a variant of the Cs₂CO₃/reﬂuxing

MeCN methodology (Magnus et al. 2009). We preferred to

avoid cesium carbonate because of its hygroscopicity and

Experimental

Melting points were obtained on an Electrothermal appa-

ratus IA 9000 and are uncorrected. H and ¹³C NMR

1

spectra were determined on a Varian MR400 spectrom-

eter, at 400 and 100 MHz for H and ¹³C, respectively,

1

1 3

Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the…

Scheme 5 (i) LiHMDS, anhydrous THF, 0 °C, then rt: 1a 75 % yield from (M)-11a, 70 % yield from (P)-11a; 1b 69 % yield from (M)-11b,

76 % yield from (P)-11b; 1c 81 % yield from (M)-11c, 74 % yield from (P)‑11c

in CDCl₃unless otherwise reported. Chemical shifts

are reported in ppm relative to residual solvent signals

were submitted for three times to the dissolution in a

few millilitres of anhydrous dichloromethane, followed

by in vacuo evaporation. Diastereomerically pure com-

pound 6 was obtained according to Nielsen et al. (1990).

The kinetics were performed by rapidly adding 0.5 mL

of a stock 0.1 M solution of pure compounds [(M)-11a

or (P)-11a] in xylenes to a reﬂuxing 4.5 mL xylenes’

mixture. At suitable times, 100 μL was rapidly taken,

evaporated under vacuum at room temperature and dis-

solved in 1 mL of n-hexane:2-propanol 95:5 solution.

The samples were injected in a Hewlett-Packard 1100

chromatograph equipped with a Daicel Chiralcel OD-H

column and a diode-array UV detector (λ = 210 nm),

eluting with n-hexane:2-propanol 99:1 with a ﬂow rate

of 0.5 mL/min [t_R= 37.1 [(P)-11a], 43.0 [(M)-11a]

min]. The percentages of atropisomers at various times

were obtained correcting the experimentally observed

1

(δ = 7.26 and 77.16 ppm for H and ¹³C NMR, respec-

tively), and coupling constants (J) are given in Hz. Opti-

cal rotations, [α]_D, were recorded at room temperature

on a Perkin-Elmer Model 241 polarimeter at the sodium

D line (concentration in g/100 mL). LC electrospray

ionization mass spectra were obtained with a Finnigan

Navigator LC/MS single-quadrupole mass spectrometer,

cone voltage 25 V and capillary voltage 3.5 kV, injecting

samples dissolved in methanol. Elemental analyses were

performed with a Carlo Erba CHN Elemental Analyser.

Column chromatography was performed using Kiesel-

gel 60 Merck (230–400 mesh ASTM). The pure com-

pounds for kinetic experiments ((M)-11a and (P)-11a)

were obtained from a further chromatographic puriﬁca-

tion with cyclohexane and ethyl acetate distilled under

vacuum. Tetrahydrofuran and DMF were distilled from

sodium-benzophenone and P₄O₁₀, respectively, under an

argon atmosphere. DBAD was puriﬁed by ﬂash chroma-

tography on oven-dried silica gel, using a 98:2 mixture

of cyclohexane and ethyl acetate dried on anhydrous

Na₂SO₄as the eluent. After evaporation at reduced pres-

sure and room temperature of eluents, pure DBAD was

azeotropically dried for three times by dissolution in

anhydrous THF followed by in vacuo evaporation, then

the ﬂask was ﬁlled with argon and stored at −18 °C.

Xylenes’ mixture was distilled from sodium under an

argon atmosphere, and only the central fraction (boil-

ing point 138–140 °C) was used for kinetics. Column

chromatography was performed with Merck Kieselgel

60 (230–400 mesh ASTM) unless otherwise speciﬁed.

The TLC analysis was performed with sheets of silica

gel Fluka TLC-PET, using exposure to UV light and

immersion in aqueous KMnO₄, followed by heating and

by possible immersion in H₂SO₄9 M. The cooling baths

at −23 °C were obtained using both ice and acetone pre-

cooled at −18 °C in a freezer. To eliminate traces of

eluents from the pure chromatographed products, these

percent areas with the response factor F = (A_(M)-11a

_(M)-11a)/(A_(P)-11a/M_(P)-11a), where A and M are percent

areas and molarities, respectively. The response fac-

tor F = 1.47 0.03 was formerly determined from the

injection of 5 samples with known concentration ratios

_(M)-11a/M_(P)-11a(0.1, 0.5, 1, 5, 10) for a total concen-

/

M

tration M_(M)-11a+ M_(P)-11a= 1 mM. The known sam-

ples were obtained by appropriate dilutions of the stock

0.1 M solutions of pure compounds [(M)-11a and (P)-

11a) with an n-hexane:2-propanol 95:5 solution. Com-

pounds 7, 8a–c, 9a′, 9c′, (M)-11a–c, (P)-11a–c and

1a‑c were characterized as diastereomerically pure by

1

careful examination of their H and ¹³C NMR spectra,

because no peaks ascribable to diastereomers were vis-

ible within the limits of detection. Compounds 10b and

10c were characterized as diastereomerically pure by

careful examination of their HPLC traces relative to

two different columns (chiral OD-H column and achiral

RP-C18 column), where no peaks ascribable to diastere-

omers were visible within the limits of detection, and by

subsequent derivatisation (see "Results and discussion"

section).

1 3

P. Amabili et al.

(S)‑4‑(Hydroxymethyl)‑1‑((S)‑1‑phenylethyl)

pyrrolidin‑2‑one, 7

CDCl₃): δ 1.48 (d, J = 7.0 Hz, 3H), 2.20–2.28 (m, 1H),

2.47–2.58 (m, 2H), 3.08 (dd, J = 7.4 Hz, J = 9.8 Hz, 1H),

3.15 (dd, J = 5.1 Hz, J = 9.8 Hz, 1H), 3.37 (dd, J = 7.4 Hz,

J = 9.0 Hz, 1H), 3.44 (dd, J = 5.1 Hz, J = 9.0 Hz, 1H),

4.48 (d, J = 12.1 Hz, 1H), 4.52 (d, J = 12.1 Hz, 1H), 5.48

(q, J = 7.0 Hz, 1H), 7.24–7.37 (m, 10ArH).

To a solution of compound 6 (16.1 g, 65 mmol) in anhy-

drous THF (300 mL) under inert atmosphere at -23 °C,

LiAlH₄(2 M in THF, 19.5 mL, 39 mmol) was slowly

added under vigorous stirring. After 1 h, the reaction

was quenched by sequential slow addition of methanol

(10 mL) and HCl 6 M (25 mL), then all the volatiles were

removed under vacuum. The residue was dissolved in

ethyl acetate (500 mL) and HCl 0.5 M (300 mL) and then,

after separation, the organic phase was washed with HCl

1 M (3 × 50 mL) and water (50 mL). The uniﬁed aque-

ous phases were newly extracted with ethyl acetate AcOEt

(500 mL) and, after separation, the organic phase was

washed with HCl 1 M (3 × 50 mL) and water (50 mL).

The combined organic phases were dried over anhydrous

Na₂SO₄, the solvent was evaporated under reduced pressure

and the residue was puriﬁed by silica gel chromatography

(ethyl acetate) to give diastereomerically pure compound 7

in 87 % yield (12.5 g, 56.55 mmol) as a low melting white

solid. The identity of compound 7 was conﬁrmed by com-

parison of the ¹H NMR data with the ones of its enantiomer

(S)‑4‑((Benzhydryloxy)methyl)‑1‑((S)‑1‑phenylethyl)

pyrrolidin‑2‑one, 8b

To a solution of compound 7 (3.3 g, 15 mmol) in dry DMF

(15 mL) at room temperature, DIPEA (5.65 mL, 33 mmol)

and benzhydryl chloride (6.08 g, 30 mmol) were sequen-

tially added. The reaction mixture was stirred at reﬂux for

1 h, cooled at room temperature and diluted with an Na₂CO₃

saturated solution (20 mL), a cyclohexane:ethyl acetate 1:1

solution (400 mL) and water (200 mL). After separation, the

organic phase was washed with water (3 × 100 mL). The uni-

ﬁed aqueous phases were extracted with additional 400 mL of

cyclohexane:ethyl acetate 1:1 solution and, after separation,

the organic phase was washed with water (3 × 50 mL). The

combined organic phases were dried over anhydrous Na₂SO₄,

concentrated under vacuum and dissolved in 150 mL of

cyclohexane:dichloromethane 9:1 solution. After addition of

3 g of activated charcoal, the mixture was gently stirred over-

night, ﬁltered through Celite and washed thoroughly with a

cyclohexane:dichloromethane 9:1 solution (20 mL) and then

with cyclohexane (3 × 20 mL). The solvents were eliminated

under vacuum, and the crude product was puriﬁed by silica gel

chromatography (cyclohexane:ethyl acetate 75:25) to afford

diastereomerically pure compound 8b in 93 % yield (5.38 g,

13.97 mmol) as a colourless viscous oil. NOTE: occasion-

ally, the chromatographed product resulted brownish and sus-

ceptible to a very slow decomposition if stored at room tem-

perature. In these cases, the product was submitted to another

1

synthesized in Fava et al. (1999). H NMR (400 MHz,

CDCl₃): δ 1.50 (d, J = 7.0 Hz, 3H), 2.21–2.28 (m, 1H),

2.33–2.56 (m, 3H), 3.05 (dd, J = 7.6 Hz, J = 9.8 Hz, 1H),

3.17 (dd, J = 5.4 Hz, J = 9.8 Hz, 1H), 3.55 (dd, J = 6.6 Hz,

J = 10.8 Hz, 1H), 3.62 (dd, J = 5.6 Hz, J = 10.8 Hz, 1H),

5.47 (q, J = 7.0 Hz, 1H), 7.18–7.43 (m, 5ArH).

(S)‑4‑((Benzyloxy)methyl)‑1‑((S)‑1‑phenylethyl)

pyrrolidin‑2‑one, 8a

To a solution of compound 7 (4.98 g, 22.6 mmol) in anhy-

drous DMF (68 mL) under inert atmosphere at room tem-

perature, NaH (60 % dispersion in mineral oil, 1.36 g,

34 mmol) was added under vigorous stirring. After 10 min,

benzyl bromide (4.14 mL, 34 mmol) was added and the

mixture was stirred for 3 h, then the reaction was diluted

with a 1:1 cyclohexane:ethyl acetate solution (400 mL) and

water (400 mL). After separation, the organic phase was

washed with water (3 × 50 mL), then the combined aqueous

phases were newly extracted with a 1:1 cyclohexane:ethyl

acetate solution (400 mL). After separation, the organic

phase was washed with water (3 × 50 mL). The combined

organic layers were dried over anhydrous Na₂SO₄and

evaporated under reduced pressure, then the residue was

puriﬁed by silica gel chromatography (cyclohexane:ethyl

acetate 70:30) to obtain diastereomerically pure compound

8a in 82 % yield (5.76 g, 18.54 mmol) as a colourless oil.

The identity of compound 8a was conﬁrmed by compari-

1

puriﬁcation with activated charcoal. H NMR (400 MHz,

CDCl₃): δ 1.46 (d, J = 7.0 Hz, 3H), 2.23–2.31 (m, 1H),

2.51–2.59 (m, 2H), 3.10 (dd, J = 7.8 Hz, J = 9.8 Hz, 1H),

3.18 (dd, J = 5.1 Hz, J = 9.8 Hz, 1H), 3.38 (dd, J = 7.0 Hz,

J = 9.0 Hz, 1H), 3.43 (dd, J = 5.1 Hz, J = 9.0 Hz, 1H), 5.31

(s, 1H), 5.48 (q, J = 7.0 Hz, 1H), 7.22–7.36 (m, 15ArH). ¹³

C

NMR (100 MHz, CDCl₃): δ 16.2, 31.6, 34.9, 45.5, 49.0, 71.2,

84.1, 127.0, 127.1, 127.2, 127.6, 127.7, 127.8, 128.55, 128.61,

128.67, 140.3, 142.0, 142.1, 173.5. [α]_D−72.9 (c 0.84,

CHCl₃). ESI–MS: m/z calcd. for C₂₆H₂₇NNaO₂[M + Na]⁺

408.2; found 408.1. Anal. calcd. for C₂₆H₂₇NO₂: C, 81.01; H,

7.06; N, 3.63. Found: C, 80.81; H, 6.89; N, 3.77.

(S)‑1‑((S)‑1‑Phenylethyl)‑4‑((trityloxy)methyl)pyrroli‑

din‑2‑one, 8c

1

son of the H NMR data with the ones of its enantiomer

To a solution of compound 7 (4.17 g, 19 mmol) in dry

DMF (19 mL) at room temperature, DIPEA (4.88 mL,

1

synthesized in Galeazzi et al. (2003). H NMR (400 MHz,

1 3

Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the…

28.5 mmol) and trityl chloride (10.60 g, 38 mmol) were

sequentially added. The reaction mixture was stirred at reﬂux

for 0.5 h, cooled at room temperature and diluted with an

Na₂CO₃saturated solution (30 mL), a cyclohexane:ethyl

acetate 1:1 solution (500 mL) and water (250 mL). After

separation, the organic phase was washed with water

(3 × 100 mL). The uniﬁed aqueous phases were extracted

with cyclohexane:ethyl acetate 1:1 solution (500 mL) and,

after separation, the organic phase was washed with water

(3 × 100 mL). The combined organic phases were dried

over anhydrous Na₂SO₄, concentrated under vacuum and

dissolved in 190 mL of cyclohexane:dichloromethane 95:5

solution. After addition of 4 g of activated charcoal, the mix-

ture was gently stirred overnight, ﬁltered through Celite and

washed thoroughly with a cyclohexane:dichloromethane

95:5 solution (30 mL) and then with cyclohexane

(3 × 30 mL). The solvents were eliminated under vacuum,

and the crude product was puriﬁed by silica gel chromatogra-

phy (cyclohexane:ethyl acetate 80:20) to give diastereomeri-

cally pure compound 8c in 91 % yield (7.97 g, 17.27 mmol)

as a pale yellow spongy solid. NOTE: occasionally, the chro-

matographed product resulted brownish and susceptible to a

very slow decomposition if stored at room temperature. In

these cases, the product was submitted to another puriﬁcation

with activated charcoal. ¹H NMR (400 MHz, CDCl₃): δ 1.43

(d, J = 7.2 Hz, 3H), 2.18-2.26 (m, 1H), 2.48–2.58 (m, 2H),

3.04 (dd, J = 7.0 Hz, J = 9.0 Hz, 1H), 3.05–3.16 (m, 2H),

3.15 (dd, J = 5.1 Hz, J = 9.0 Hz, 1H), 5.47 (q, J = 7.2 Hz,

1H), 7.22–7.37 (m, 14ArH), 7.40–7.43 (m, 6ArH). ¹³C NMR

(100 MHz, CDCl₃): δ 16.2, 31.8, 35.1, 45.4, 48.9, 65.4, 86.6,

127.18, 127.22, 127.6, 128.0, 128.64, 128.71, 140.3, 143.9,

173.5. [α]_D−62.5 (c 1, CHCl₃). ESI–MS: m/z calcd. for

C₃₂H₃₁NNaO₂[M+Na]⁺484.2; found 484.1. Anal. calcd.

for C₃₂H₃₁NO₂: C, 83.26; H, 6.77; N, 3.03. Found: C, 83.06;

H, 6.61; N, 3.17.

anhydrous Na₂SO₄, and the solvent was eliminated under

reduced pressure. The residue was puriﬁed by silica gel

chromatography (cyclohexane:ethyl acetate) to give the

inseparable diastereomeric mixture of products trans and

cis-9a–c and the dimethylated by-products 9a–c′.

(3S,4S)‑4‑((Benzyloxy)methyl)‑3‑me‑

thyl‑1‑((S)‑1‑phenylethyl)pyrrolidin‑2‑one,

trans‑9a and (3R,4S)‑4‑((benzyloxy)methyl)‑3‑me‑

thyl‑1‑((S)‑1‑phenylethyl)pyrrolidin‑2‑one, cis‑9a

Starting from 8a and following the general procedure, the

title compounds were obtained in 75 % global yield (2.43 g,

7.52 mmol, trans-9a:cis-9a = 81:19) as a colourless oil.

¹H NMR (400 MHz, CDCl₃, mixture of diastereomers): δ

1.13 (d, J = 7.4 Hz, 3H, 19 %), 1.22 (d, J = 7.0 Hz, 3H,

81 %), 1.46 (d, J = 7.0 Hz, 3H, 19 %), 1.50 (d, J = 7.2 Hz,

3H, 81 %), 2.05–2.14 (m, 1H), 2.32 (dq, J = 7.0 Hz,

J = 8.2 Hz, 1H, 81 %), 2.61–2.68 (m, 1H, 19 %), 3.00 (dd,

J = 7.0 Hz, J = 9.8 Hz, 1H, 19 %), 3.06 (dd, J = 9.8 Hz,

J = 11.7 Hz, 1H, 81 %), 3.08 (dd, J = 9.7 Hz, J = 11.7 Hz,

1H, 81 %), 3.16 (dd, J = 4.7 Hz, J = 9.8 Hz, 1H, 19 %),

3.33–3.37 (m, 1H, 19 %), 3.43 (dd, J = 7.4 Hz, J = 9.0 Hz,

1H, 81 %), 3.52 (dd, J = 5.5 Hz, J = 9.0 Hz, 1H, 19 %),

3.55 (dd, J = 4.7 Hz, J = 9.0 Hz, 1H, 81 %), 4.47 (d,

J = 12.1 Hz, 1H, 19 %), 4.49 (d, J = 12.1 Hz, 1H, 81 %),

4.52 (d, J = 12.1 Hz, 1H, 19 %), 4.53 (d, J = 12.1 Hz, 1H,

81 %), 5.47 (q, J = 7.0 Hz, 1H, 19 %), 5.48 (q, J = 7.2 Hz,

1H, 81 %), 7.24–7.37 (m, 10ArH). ¹³C NMR (100 MHz,

CDCl₃, mixture of diastereomers): δ 10.5 (19 %), 15.4

(81 %), 15.9 (19 %), 16.0 (81 %), 35.6 (19 %), 39.1 (19 %),

40.0 (81 %), 40.8 (81 %), 43.7 (19 %), 43.9 (81 %), 48.9

(81 %), 48.9 (19 %), 68.8 (19 %), 71.1 (81 %), 73.2 (81 %),

73.3 (19 %), 126.9 (81 %), 127.0 (19 %), 127.3 (81 %),

127.4 (19 %), 127.56 (81 %), 127.69 (19 %), 127.70,

128.4, 128.5, 137.91 (19 %), 137.94 (81 %), 140.25

(19 %), 140.27 (81 %), 176.0 (81 %), 176.2 (19 %). [α]_D

-86.6 (c 0.98, CHCl₃). ESI–MS: m/z calcd. for C₂₁H₂₅N-

NaO₂[M + Na]⁺346.2; found 346.1. Anal. calcd. for

C₂₁H₂₅NO₂: C, 77.98; H, 7.79; N, 4.33. Found: C, 78.05;

H, 7.90; N, 4.24.

General procedure for the methylation reactions

To a solution of compound 8a–c (10 mmol) dissolved in

anhydrous THF (30 mL) under inert atmosphere at −23 °C,

tetramethylpiperidine (0.843 mL, 5 mmol) and n-BuLi

(2.5 M in hexanes, 4.4 mL, 11 mmol) were sequentially

added; the mixture was stirred for 15 min and then methyl

iodide (0.660 mL, 10.5 mmol) was added. After 30 min,

the reaction mixture was quenched with water (20 mL) and

the most part of THF was evaporated at reduced pressure

and room temperature. After the addition of ethyl acetate

(150 mL) and water (50 mL), the phases were separated

and the organic one was washed with water (20 mL) and

brine (5 mL). The combined aqueous phases were extracted

with ethyl acetate (100 mL) and, after separation, the

organic phase was washed with water (20 mL) and brine

(5 mL). The combined organic layers were dried over

(S)‑4‑((Benzyloxy)methyl)‑3,3‑dimethyl‑1‑((S)‑1‑pheny‑

lethyl)pyrrolidin‑2‑one, 9a′

Starting from 8a and following the general procedure, the

diastereomerically pure title compound was obtained in

15 % yield (503 mg, 1.49 mmol) as a pale yellow solid. Col-

ourless crystals were obtained after recrystallization from

1

cyclohexane. Mp 75–76 °C. H NMR (400 MHz, CDCl₃):

δ 1.02 (s, 3H), 1.21 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H), 2.16-

2.24 (m, 1H), 2.97 (dd, J = 7.8 Hz, J = 9.8 Hz, 1H), 3.02

(dd, J = 7.8 Hz, J = 9.8 Hz, 1H), 3.39 (dd, J = 7.8 Hz,

1 3

P. Amabili et al.

J = 9.0 Hz, 1H), 3.55 (dd, J = 5.8 Hz, J = 9.0 Hz, 1H),

4.46 (d, J = 12.1 Hz, 1H), 4.49 (d, J = 12.1 Hz, 1H), 5.45

(q, J = 7.0 Hz, 1H), 7.21–7.36 (m, 10ArH). ¹³C NMR

(100 MHz, CDCl₃): δ 16.0, 18.7, 24.8, 42.8, 42.9, 43.2,

48.8, 69.4, 73.4, 127.0, 127.4, 127.7, 127.8, 128.5, 128.6,

138.0, 140.4, 178.8. [α]_D−87.7 (c 1.83, CHCl₃). ESI–MS:

m/z calcd. for C₂₂H₂₇NNaO₂[M + Na]⁺360.2; found

360.1. Anal. calcd. for C₂₂H₂₇NO₂: C, 78.30; H, 8.06; N,

4.15. Found: C, 78.42; H, 8.19; N, 4.08.

yellow waxy solid. ¹H NMR (400 MHz, CDCl₃, mixture of

diastereomers): δ 1.13 (d, J = 7.4 Hz, 3H, 38 %), 1.22 (d,

J = 7.4 Hz, 3H, 62 %), 1.46 (d, J = 7.4 Hz, 3H, 38 %),

1.51 (d, J = 7.4 Hz, 3H, 62 %), 1.86 (s, 3H), 2.03–2.12 (m,

1H, 62 %), 2.25–2.33 (m, 1H, 38 %), 2.39 (dq, J = 7.4 Hz,

J = 8.6 Hz, 1H, 62 %), 2.66 (dq, J = 7.4 Hz, J = 8.2 Hz,

1H, 38 %), 3.01 (dd, J = 7.2 Hz, J = 10.0 Hz, 1H, 38 %),

3.05-3.18 (m, 2H), 3.21 (dd, J = 6.8 Hz, J = 9.2 Hz, 1H,

62 %), 3.29 (dd, J = 5.1 Hz, J = 8.6 Hz, 1H, 38 %), 3.32

(dd, J = 5.1 Hz, J = 9.0 Hz, 1H, 62 %), 5.50 (q, J = 7.4 Hz,

1H), 7.21–7.38 (m, 15ArH). ¹³C NMR (100 MHz, CDCl₃,

mixture of diastereomers): δ 10.7 (38 %), 15.7 (62 %),

16.18 (62 %), 16.23 (38 %), 25.56 (38 %), 25.63 (62 %),

36.0 (38 %), 39.3 (38 %), 40.3 (62 %), 41.1 (38 %), 43.9,

49.0, 61.0 (38 %), 63.3 (62 %), 80.52 (62 %), 80.58 (38 %),

126.65 (62 %), 126.74 (38 %), 126.83 (62 %), 126.99

(38 %), 127.04 (62 %), 127.2 (38 %), 128.08, 128.09,

128.6, 140.4 (38 %), 140.5 (62 %), 146.4 (38 %), 146.5

(62 %), 146.6 (62 %), 146.7 (38 %), 176.3 (62 %), 176.4

(38 %). [α]_D−68.6 (c 1.42, CHCl₃). ESI–MS: m/z calcd.

for C₂₈H₃₁NNaO₂[M + Na]⁺436.2; found 436.0. Anal.

calcd. for C₂₈H₃₁NO₂: C, 81.32; H, 7.56; N, 3.39. Found:

C, 81.49; H, 7.72; N, 3.27.

(3S,4S)‑4‑((Benzhydryloxy)methyl)‑3‑me‑

thyl‑1‑((S)‑1‑phenylethyl)pyrrolidin‑2‑one, trans‑9b

and (3R,4S)‑4‑((benzhydryloxy)methyl)‑3‑me‑

thyl‑1‑((S)‑1‑phenylethyl)pyrrolidin‑2‑one, cis‑9b

Starting from 8b and following the general procedure,

the title compounds were obtained in 83 % global yield

(3.321 g, 8.31 mmol, trans-9b:cis-9b = 80:20) as a col-

1

ourless oil. H NMR (400 MHz, CDCl₃, mixture of dias-

tereomers): δ 1.11 (d, J = 7.0 Hz, 3H, 20 %), 1.22 (d,

J = 7.0 Hz, 3H, 80 %), 1.43 (d, J = 7.0 Hz, 3H, 20 %),

1.48 (d, J = 7.0 Hz, 3H, 80 %), 2.08–2.17 (m, 1H, 80 %),

2.37 (dq, J = 7.0 Hz, J = 8.4 Hz, 1H, 80 %), 2.54–2.68 (m,

2H, 20 %), 3.00 (dd, J = 7.0 Hz, J = 9.8 Hz, 1H, 20 %),

3.03–3.11 (m, 2H, 80 %), 3.18 (dd, J = 4.3 Hz, J = 9.8 Hz,

1H, 20 %), 3.33 (dd, J = 8.0 Hz, J = 9.2 Hz, 1H, 20 %),

3.42 (dd, J = 7.0 Hz, J = 9.3 Hz, 1H, 80 %), 3.49 (dd,

J = 4.7 Hz, J = 9.2 Hz, 1H, 20 %), 3.51 (dd, J = 5.1 Hz,

J = 9.3 Hz, 1H, 80 %), 5.30 (s, 1H, 20 %), 5.31 (s, 1H,

80 %), 5.44–5.50 (m, 1H), 7.22–7.36 (m, 15ArH). ¹³C

NMR (100 MHz, CDCl₃, mixture of diastereomers): δ

10.7 (20 %), 15.7 (80 %), 16.2, 35.9 (20 %), 39.3 (20 %),

40.3 (80 %), 41.0 (80 %), 43.9 (80 %), 44.0 (80 %), 49.0,

68.0 (20 %), 70.2 (80 %), 84.2 (80 %), 84.3 (20 %), 126.9

(80 %), 127.00 (20 %), 127.02 (80 %), 127.08 (80 %),

127.16 (20 %), 127.23 (20 %), 127.50 (80 %), 127.53

(20 %), 127.6, 127.7, 128.52 (20 %), 128.55 (80 %),

128.59, 128.7, 140.4 (20 %), 140.5 (80 %), 142.01 (20 %),

142.09 (80 %), 142.16, 176.2 (80 %), 176.3 (20 %). [α]_D

−82.0 (c 1.34, CHCl₃). ESI–MS: m/z calcd. for C₂₁H₂₅N-

NaO₂[M + Na]⁺422.2; found 422.0. Anal. calcd. for

C₂₁H₂₅NO₂: C, 81.17; H, 7.32; N, 3.51. Found: C, 81.30;

H, 7.49; N, 3.38.

(3S,4S)‑3‑Methyl‑1‑((S)‑1‑phenylethyl)‑4‑((trityloxy)

methyl)pyrrolidin‑2‑one, trans‑9c and (3R,4S)‑3‑me‑

thyl‑1‑((S)‑1‑phenylethyl)‑4‑((trityloxy)methyl)pyrroli‑

din‑2‑one, cis‑9c

Starting from 8c and following the general procedure,

the title compounds were obtained in 80 % global yield

(3.82 g, 8.03 mmol, trans-9c:cis-9c = 70:30) as a col-

1

ourless oil. H NMR (400 MHz, CDCl₃, mixture of dias-

tereomers): δ 1.19 (d, J = 7.0 Hz, 3H, 70 %), 1.24 (d,

J = 7.0 Hz, 3H, 30 %), 1.46 (d, J = 7.0 Hz, 3H, 70 %),

1.52 (d, J = 7.0 Hz, 3H, 30 %), 1.95–2.08 (m, 1H), 2.27–

2.35 (m, 1H), 2.96–3.18 (m, 3H, 70 % + 2H, 30 %),

3.21 (dd, J = 5.5 Hz, J = 9.4 Hz, 1H, 70 %), 3.63 (dd,

J = 7.0 Hz, J = 10.5 Hz, 1H, 30 %), 3.76 (dd, J = 5.1 Hz,

J = 10.5 Hz, 1H, 30 %), 5.45 (q, J = 7.0 Hz, 1H, 70 %),

5.49 (q, J = 7.0 Hz, 1H, 30 %), 7.21–7.41 (m, 20ArH).

¹³C NMR (100 MHz, CDCl₃, mixture of diastereomers): δ

10.5 (30 %), 15.7 (70 %), 16.10 (30 %), 16.14 (70 %), 36.1

(30 %), 39.3 (30 %), 40.4 (70 %), 41.0 (70 %), 43.6 (30 %),

43.8 (70 %), 48.8 (30 %), 48.9 (70 %), 61.9 (30 %), 64.5

(70 %), 86.68 (30 %), 86.70 (70 %), 126.99 (70 %), 127.02

(30 %), 127.14 (30 %), 127.16 (70 %), 127.42 (70 %),

127.46 (30 %), 127.9, 128.6 (30 %), 128.7 (70 %), 140.5

(30 %), 143.9 (70 %), 176.2. [α]_D−26.3 (c 0.36, CHCl₃).

ESI–MS: m/z calcd. for C₃₃H₃₃NNaO₂[M + Na]⁺498.2;

found 498.1. Anal. calcd. for C₃₃H₃₃NO₂: C, 83.33; H,

6.99; N, 2.94. Found: C, 83.55; H, 7.17; N, 2.86.

(3S,4S)‑4‑((1,1‑Diphenylethoxy)methyl)‑3‑me‑

thyl‑1‑((S)‑1‑phenylethyl)pyrrolidin‑2‑one, trans‑9b′

and (3R,4S)‑4‑((1,1‑diphenylethoxy)methyl)‑3‑me‑

thyl‑1‑((S)‑1‑phenylethyl)pyrrolidin‑2‑one, cis‑9b′

Starting from 8b and following the general procedure,

the title compounds were obtained in 10 % global yield

(409 mg, 0.99 mmol, trans-9b′:cis-9b′ = 62:38) as a pale

1 3

Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the…

(S)‑3,3‑Dimethyl‑1‑((S)‑1‑phenylethyl)‑4‑((trityloxy)

methyl)pyrrolidin‑2‑one, 9c′

could not be determined by HPLC due to the lack of the rela-

tive response factor, while the ratio of areas was determined

to be A_trans-10a:A_cis-10a= 92:8 by elution with a Chiralcel

OD-H column (n-hexane:2-propanol 9:1, ﬂow rate 1.0 mL/

min, λ = 210 nm, t_trans-10a= 12.8 min, t_cis-10a= 16.1 min).

¹H NMR (400 MHz, CDCl₃, complex mixture of diastere-

omers and rotamers): δ 1.23–1.26 (m, 3H, 86 %), 1.34 (s,

3H, 14 %), 1.42–1.51 (m, 21H), 2.83–3.88 (m, 5H), 4.39–

4.53 (m, 2H), 5.41–5.52 (m, 1H), 6.15 (bs, 1H, 12 %), 6.31

(bs, 1H, 19 %), 6.61 (bs, 1H, 55 %), 6.66 (bs, 1H, 14 %),

7.24–7.46 (m, 10ArH). ¹³C NMR (100 MHz, CDCl₃, only

major rotamer of major diastereomer): δ 16.2, 17.2, 28.3,

39.2, 43.5, 49.6, 67.4, 69.6, 73.3, 81.0, 81.7, 127.4, 127.5,

127.6, 127.7, 127.9, 128.39, 128.45, 128.6, 138.5, 139.7,

156.0, 174.2. [α]_D−68.2 (c 3.93, CHCl₃). ESI–MS: m/z

calcd. for C₃₁H₄₃N₃NaO₆[M + Na]⁺576.3; found 576.2.

Anal. calcd. for C₃₁H₄₃N₃O₆: C, 67.25; H, 7.83; N, 7.59.

Found: C, 67.30; H, 7.87; N, 7.53.

Starting from 8c and following the general procedure,

the diastereomerically pure title compound was obtained

in 11 % yield (524 mg, 1.07 mmol) as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 0.81 (s, 3H), 1.22 (s,

3H), 1.40 (d, J = 7.0 Hz, 3H), 2.19–2.26 (m, 1H), 2.82

(dd, J = 8.2 Hz, J = 9.8 Hz, 1H), 2.97 (dd, J = 7.4 Hz,

J = 9.8 Hz, 1H), 3.06 (dd, J = 7.6 Hz, J = 9.4 Hz, 1H),

3.15 (dd, J = 6.6 Hz, J = 9.4 Hz, 1H), 5.41 (q, J = 7.0 Hz,

1H), 7.21–7.41 (m, 20ArH). ¹³C NMR (100 MHz, CDCl₃):

δ 15.6, 16.2, 28.4, 39.8, 43.0, 43.7, 49.2, 64.0, 86.4, 127.13,

127.17, 127.27, 127.29, 127.4, 127.6, 127.87, 127.91,

128.00, 128.03, 128.08, 128.12, 128.7, 128.8, 129.9, 140.4,

143.8, 147.1, 176.3. [α]_D−18.6 (c 0.39, CHCl₃). ESI–MS:

m/z calcd. for C₃₄H₃₅NNaO₂[M + Na]⁺512.3; found

512.2. Anal. calcd. for C₃₄H₃₅NO₂: C, 83.40; H, 7.20; N,

2.86. Found: C, 83.56; H, 7.37; N, 2.80.

Di‑t‑butyl 1‑((3S,4R)‑4‑((benzhydryloxy)methyl)‑3‑me‑

thyl‑2‑oxo‑1‑((S)‑1‑phenylethyl)pyrrolidin‑3‑yl)hydra‑

zine‑1,2‑dicarboxylate, 10b

General procedure for the electrophilic amination reac‑

tions

To a solution of diastereomeric mixtures of compounds

trans-9a–c and cis-9a–c (6 mmol) in anhydrous THF

(18 mL) at -23 °C under inert atmosphere, tetramethyl-

piperidine (1.62 mL, 9.6 mmol) and n-BuLi (2.5 M in

hexanes, 3.84 mL, 9.6 mmol) were sequentially added.

After 30 min at −23 °C, the reaction was thermostated at

−78 °C, then DBAD (2.21 g, 9.6 mmol) dissolved in 4 mL

of anhydrous THF was slowly added under vigorous stir-

ring. After 30 min, the reaction mixture was quenched with

1 M HCl (15 mL) and diluted with ethyl acetate (300 mL)

and water (300 mL); then the phases were separated and

the organic one was washed with water (100 mL) and brine

(10 mL). The combined aqueous phases were extracted

with 200 mL of ethyl acetate and, after separation, the

organic phase was washed with water (50 mL) and brine

(10 mL). The combined organic layers were dried over

anhydrous Na₂SO₄, and the solvent was eliminated under

reduced pressure. Eventual puriﬁcation of crude products

by silica gel chromatography (cyclohexane:ethyl acetate

70:30) gave products 10a–c.

According to the general procedure and starting from the

diastereomeric mixture of compounds trans and cis-9b,

diastereomerically pure compound 10b was obtained in

41 % yield (1.56 g, 2.48 mmol) as a white spongy solid.

The diastereomeric purity of 10b was determined by HPLC

(Chiralcel OD-H column, n-hexane:2-propanol 9:1, ﬂow

1

rate 1.0 mL/min, λ = 210 nm, t_10b= 10.9 min). H NMR

(400 MHz, CDCl₃, complex mixture of rotamers): δ 1.22–

1.53 (m, 24H), 2.43–2.99 (m, 1H), 3.02-3.15 (m, 1H),

3.17–3.35 (m, 1H), 3.38–3.56 (m, 1H), 3.59–3.84 (m, 1H),

5.26–5.37 (m, 1H), 5.44–5.54 (m, 1H), 6.00 (bs, 1H, 11 %),

6.35–6.38 (m, 1H, 18 %), 6.59–6.61 (m, 1H, 71 %), 7.18–

7.49 (m, 15ArH). ¹³C NMR (100 MHz, CDCl₃, only major

rotamer): δ 16.3, 17.5, 28.26, 28.31, 39.3, 43.2, 49.4, 67.4,

68.2, 80.9, 81.6, 84.2, 126.8, 127.02, 127.17, 127.27, 127.45,

127.47, 127.7, 128.29, 128.38, 128.42, 128.53, 139.8,

142.38, 142.41, 153.6, 155.9, 174.2. [α]_D−62.84 (c 1.09,

CHCl₃). ESI–MS: m/z calcd. for C₃₇H₄₇N₃NaO₆[M + Na]⁺

652.3; found 652.2. Anal. calcd. for C₃₇H₄₇N₃O₆: C, 70.56;

H, 7.52; N, 6.67. Found: C, 70.72; H, 7.77; N, 6.49.

Di‑t‑butyl 1‑((3S,4R)‑4‑((benzyloxy)methyl)‑3‑me‑

thyl‑2‑oxo‑1‑((S)‑1‑phenylethyl)pyrrolidin‑3‑yl)hydra‑

zine‑1,2‑dicarboxylate, 10a

Di‑tert‑butyl 1‑((3S,4R)‑3‑methyl‑2‑oxo‑1‑((S)‑1‑phe

nylethyl)‑4‑((trityloxy)methyl)pyrrolidin‑3‑yl)hydra‑

zine‑1,2‑dicarboxylate, 10c

According to the general procedure and starting from the

diastereomeric mixture of compounds trans and cis-9a, prod-

uct 10a was obtained as an inseparable diastereomerically

enriched mixture in 36 % yield (1.19 g, 2.15 mmol) as a col-

ourless oil. The exact diastereomeric ratio trans-10a:cis-10a

According to the general procedure and starting from the

diastereomeric mixture of compounds trans and cis-9c, dias-

tereomerically pure compound 10c was obtained in 45 %

yield (1.90 g, 2.69 mmol) as a pale yellow spongy solid.

The diastereomeric purity of 10c was determined by HPLC

1 3

P. Amabili et al.

(Chiralcel OD-H column, n-hexane:2-propanol 93:7, ﬂow

rate 1.0 mL/min, λ = 210 nm, t_10c= 15.1 min). H NMR

in 63 % (690 mg, 1.10 mmol) and in 26 % (285 mg,

0.46 mmol) yields, respectively, as colourless oils. (M)-

11a: ¹H NMR (400 MHz, CDCl₃, mixture of rotam-

ers): δ 1.43–1.47 (m, 15H), 1.53 (s, 9H), 2.64–2.69 (m,

1H, 75 %), 2.75–2.80 (m, 1H, 25 %), 2.86–2.96 (m, 1H,

75 %), 3.00–3.09 (m, 1H, 75 % + 1H, 25 %), 3.12–3.20

(m, 1H, 25 %), 3.30 (dd, J = 6.6 Hz, J = 9.4 Hz, 1H,

75 %), 3.44–3.48 (m, 1H, 25 %), 3.52 (dd, J = 7.4 Hz,

J = 9.4 Hz, 1H, 75 %), 3.62 (s, 3H, 25 %), 3.65 (s, 3H,

75 %), 3.70–3.75 (m, 1H, 75 % + 1H, 25 %), 3.99–4.04

(m, 1H, 25 %), 4.22–4.29 (m, 1H, 25 %), 4.35–4.47 (m,

2H + 1H, 75 %), 5.36–5.41 (m, 1H, 25 %), 5.45–5.53 (m,

1H, 75 %), 7.22–7.34 (m, 8ArH), 7.40–7.48 (m, 2ArH).

¹³C NMR (100 MHz, CDCl₃, only major rotamer): δ 15.9,

28.1, 28.4, 28.5, 40.4, 41.8, 48.8, 51.8, 55.4, 69.0, 73.3,

82.3, 127.7, 127.9, 128.39, 128.40, 128.5, 137.7, 139.9,

156.6, 169.6, 172.7. [α]_D−41.1 (c 0.96, CHCl₃). ESI–MS:

m/z calcd. for C₃₄H₄₇N₃NaO₈[M + Na]⁺648.3; found

648.2. Anal. calcd. for C₃₄H₄₇N₃O₈: C, 65.26; H, 7.57; N,

6.72. Found: C, 65.47; H, 7.71; N, 6.59. (P)-11a: ¹H NMR

(400 MHz, CDCl₃, mixture of rotamers): δ 1.33 (s, 3H,

40 %), 1.35 (s, 3H, 60 %), 1.41–1.46 (m, 18H), 1.51 (d,

J = 7.0 Hz, 6H), 2.97–3.06 (m, 1H), 3.19–3.30 (m, 1H),

3.42–3.63 (m, 2H), 3.67–3.75 (m, 1H), 3.72 (s, 3H, 40 %),

3.73 (s, 3H, 60 %), 3.87–3.96 (m, 1H), 4.37–4.54 (m, 3H),

5.38–5.45 (m, 1H), 7.24–7.35 (m, 8ArH), 7.42–7.45 (m,

2ArH). ¹³C NMR (100 MHz, CDCl₃, mixture of rotamers):

δ 16.2, 16.8 (60 %), 17.0 (40 %), 28.1 (60 %), 28.3 (40 %),

28.4, 38.5 (40 %), 38.8 (60 %), 43.9 (40 %), 44.4 (60 %),

49.4, 51.8 (40 %), 51.9 (60 %), 55.4 (60 %), 56.0 (40 %),

68.4 (60 %), 68.6 (40 %), 69.9 (40 %), 70.4 (60 %), 73.3

(40 %), 73.8 (60 %), 81.7 (40 %), 82.0 (60 %), 82.2, 127.2,

127.4, 127.5, 127.7, 127.8, 127.9, 128.36, 128.43, 128.6,

138.1 (60 %), 138.7 (40 %), 139.8 (60 %), 139.9 (40 %),

156.5, 168.8 (40 %), 169.3 (60 %), 174.0 (60 %), 174.2

(40 %). [α]_D−44.3 (c 1.09, CHCl₃). ESI–MS: m/z calcd.

for C₃₄H₄₇N₃NaO₈[M + Na]⁺648.3; found 648.2. Anal.

calcd. for C₃₄H₄₇N₃O₈: C, 65.26; H, 7.57; N, 6.72. Found:

C, 65.46; H, 7.66; N, 6.63.

1

(400 MHz, CDCl₃, complex mixture of rotamers): δ 1.05 (s,

3H, 75 %), 1.26–1.57 (m, 21H + 3H, 25 %), 2.39–2.62 (m,

1H, 60 %), 2.70–2.75 (m, 1H, 40 %), 2.79–3.32 (m, 3H + 1H,

60 %), 3.72–3.75 (m, 1H, 40 %), 5.38–5.44 (m, 1H), 6.08 (bs,

1H, 17 %), 6.15 (bs, 1H, 12 %), 6.35–6.38 (m, 1H, 42 %),

6.69–6.73 (m, 1H, 29 %), 7.16–7.47 (m, 20ArH). ¹³C NMR

(100 MHz, CDCl₃, complex mixture of rotamers): δ 15.7,

16.2, 17.4, 28.17, 28.24, 28.34, 39.2, 43.1, 49.3, 62.4, 67.2,

80.7, 81.4, 86.9, 87.4, 126.9, 127.25, 127.31, 127.41, 127.7,

128.07, 128.15, 128.3, 128.4, 128.8, 139.8, 143.4, 144.1,

153.6, 155.6, 174.0. [α]_D−58.8 (c 1.14, CHCl₃). ESI–MS:

m/z calcd. for C₄₃H₅₁N₃NaO₆[M + Na]⁺728.4; found 728.2.

Anal. calcd. for C₄₃H₅₁N₃O₆: C, 73.17; H, 7.28; N, 5.95.

Found: C, 73.32; H, 7.40; N, 5.86.

General procedure for the preparation of atropisomers

The thorough elimination of residual traces of eluents and

moisture from the pure starting compounds 10a–c has been

proven to be essential for obtaining high yields, and thus

these were submitted for three times to additional disso-

lutions in a few millilitres of anhydrous dichloromethane,

followed by in vacuo evaporation.

To a solution of compounds 10a–c (1.75 mmol) in

anhydrous THF (5.25 mL) under inert atmosphere at room

temperature, sodium hydride (60 % dispersion in mineral

oil, 105 mg, 2.63 mmol) was added slowly under vigor-

ous stirring. After 15 min, methyl bromoacetate (0.25 mL,

2.63 mmol) was added and the reaction mixture was stirred

for 3 h, then ethyl acetate (5 mL) and water (5 mL) were

sequentially added. After evaporation under vacuum at

room temperature of volatiles, the mixture was diluted

with ethyl acetate (50 mL) and water (10 mL), the phases

were separated and the organic one was washed with

water (3 × 5 mL) and brine (5 mL). The combined aque-

ous phases were extracted with 50 mL of ethyl acetate

and, after separation, the organic phase was washed with

water (3 × 5 mL) and brine (5 mL). The combined organic

phases were dried (Na₂SO₄), and the solvent was elimi-

nated under reduced pressure. The residue was puriﬁed by

silica gel chromatography (cyclohexane:ethyl acetate) to

give the pure M and P atropisomers of compounds 11a–c.

Di‑t‑butyl 1‑((3S,4R)‑4‑((benzhydryloxy)

methyl)‑3‑methyl‑2‑oxo‑1‑((S)‑1‑phenylethyl)pyrroli‑

din‑3‑yl)‑2‑(2‑methoxy‑2‑oxoethyl)hydrazine‑1,2‑dicar‑

boxylate, (M) and (P)‑11b

Di‑t‑butyl 1‑((3S,4R)‑4‑((benzyloxy)methyl)‑3‑me‑

thyl‑2‑oxo‑1‑((S)‑1‑phenylethyl)pyrroli‑

din‑3‑yl)‑2‑(2‑methoxy‑2‑oxoethyl)hydrazine‑1,2‑dicar‑

boxylate, (M) and (P)‑11a

Starting from compound 10b and following the general

procedure, the diastereomerically and atropisomerically

pure atropisomers (M)-11b and (P)-11b were obtained

in 51 % (623 mg, 0.89 mmol) and in 40 % (494 mg,

0.70 mmol) yields, respectively, as white waxy solids. (M)-

1

Starting from compound 10a and following the general

procedure, the diastereomerically and atropisomerically

pure atropisomers (M)-11a and (P)-11a were obtained

11b: H NMR (400 MHz, CDCl₃, mixture of rotamers):

δ 1.42–1.50 (m, 24H), 2.79–2.87 (m, 1H), 2.93–3.02 (m,

1H, 75 %), 3.10–3.24 (m, 1H + 1H, 25 %), 3.32–3.41 (m,

1 3

Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the…

2H, 75 %), 3.45–3.49 (m, 1H, 25 %), 3.56–3.62 (m, 4H),

3.82–3.87 (m, 1H, 25 %), 4.14–4.30 (m, 1H), 5.27 (s, 1H,

75 %), 5.32 (s, 1H, 25 %), 5.36–5.42 (m, 1H, 25 %), 5.46–

5.53 (m, 1H, 75 %), 7.21–7.38 (m, 13ArH), 7.43–7.49 (m,

2ArH). ¹³C NMR (100 MHz, CDCl₃, mixture of rotamers):

δ 16.0 (75 %), 16.1 (25 %), 28.3 (75 %), 28.4 (25 %), 28.50

(25 %), 28.54 (75 %), 38.7 (75 %), 40.6 (25 %), 42.9, 50.4,

51.88 (75 %), 51.94 (25 %), 55.2 (75 %), 55.7 (25 %),

67.2, 68.4, 69.1, 82.4 (75 %), 83.8 (25 %), 84.5 (25 %),

85.1 (75 %), 126.8 (25 %), 126.9 (75 %), 127.0 (25 %),

127.1 (75 %), 127.4 (75 %), 127.6 (25 %), 127.8 (25 %),

128.0 (75 %), 128.49 (25 %), 128.54 (75 %), 128.58

(25 %), 128.63 (75 %), 128.69 (75 %), 128.74 (25 %),

138.5 (75 %), 140.0 (25 %), 141.3 (75 %), 141.4 (75 %),

141.8 (25 %), 141.9 (25 %), 153.3 (75 %), 153.4 (25 %),

156.5 (25 %), 156.8 (75 %), 169.0 (75 %), 169.3 (25 %),

172.5. [α]_D−44.0 (c 2.76, CHCl₃). ESI–MS: m/z calcd.

for C₄₀H₅₁N₃NaO₈[M + Na]⁺724.4; found 724.2. Anal.

calcd. for C₄₀H₅₁N₃O₈: C, 68.45; H, 7.32; N, 5.99. Found:

(s, 3H), 1.40–1.50 (m, 21H), 2.68–2.77 (m, 1H), 2.85-2.95

(m, 1H), 3.00–3.11 (m, 2H), 3.25–3.29 (m, 1H), 3.39 (dd,

J = 3.9 Hz, J = 9.4 Hz, 1H), 3.52 (s, 3H, 80 %), 3.56 (s, 3H,

20 %), 4.16–4.29 (m, 1H), 5.33–5.42 (m, 1H, 20 %), 5.45–

5.54 (m, 1H, 80 %), 7.20–7.41 (m, 18ArH), 7.44–7.52 (m,

2ArH). ¹³C NMR (100 MHz, CDCl₃, only major rotamer):

δ 16.1, 28.0, 28.3, 28.5, 40.8, 43.4, 48.6, 51.8, 55.8, 63.9,

67.2, 81.6, 82.3, 87.2, 127.0, 127.2, 127.8, 127.9, 128.4,

128.6, 128.7, 140.1, 143.7, 152.1, 156.3, 169.0, 172.4. [α]_D

−30.1 (c 1.12, CHCl₃). ESI–MS: m/z calcd. for C₄₆H₅₅N-

₃NaO₈[M + Na]⁺800.4; found 800.2. Anal. calcd. for

C₄₆H₅₅N₃O₈: C, 71.02; H, 7.13; N, 5.40. Found: C, 71.26;

1

H, 7.30; N, 5.29. (P)-11c: H NMR (400 MHz, CDCl₃,

mixture of rotamers): δ 1.15 (s, 3H, 55 %), 1.21–1.25 (m,

9H, 45 % + 3H, 45 %), 1.36 (s, 9H, 55 %), 1.44–1.50 (m,

12H), 2.74 (t, J = 9.0 Hz, 1H, 45 %), 2.82 (t, J = 8.6 Hz,

1H, 55 %), 3.03 (t, J = 8.6 Hz, 1H, 45 %), 3.17–3.25 (m,

1H + 1H, 55 %), 3.29–3.39 (m, 1H), 3.61–3.64 (m, 1H,

55 %), 3.69 (s, 3H, 45 %), 3.70 (s, 3H, 55 %), 3.83–3.86

(m, 1H, 45 %), 3.99 (d, J = 17.2 Hz, 1H, 55 %), 4.18 (d,

J = 16.4 Hz, 1H, 45 %), 4.34–4.43 (m, 1H), 5.36–5.41

(m, 1H), 7.18–7.32 (m, 10ArH), 7.36–7.47 (m, 10ArH).

¹³C NMR (100 MHz, CDCl₃, mixture of rotamers): δ

16.2 (55 %), 17.1 (45 %), 27.9 (55 %), 28.1 (45 %), 28.4,

38.5 (55 %), 38.7 (45 %), 43.7 (45 %), 43.9 (55 %), 49.3

(55 %), 49.4 (45 %), 51.7 (45 %), 51.8 (55 %), 54.9 (55 %),

56.0 (45 %), 62.7 (45 %), 62.9 (55 %), 68.4 (45 %), 68.6

(55 %), 81.5 (45 %), 81.69, 81.72 (55 %), 86.85 (45 %),

86.90 (55 %), 126.8 (45 %), 127.1, 127.2, 127.3 (55 %),

127.7 (45 %), 127.8 (55 %), 128.3 (45 %), 128.4 (55 %),

128.8 (45 %), 128.9 (55 %), 139.7 (55 %), 139.9 (45 %),

143.9 (45 %), 144.2 (55 %), 152.97 (55 %), 153.05 (45 %),

154.9 (55 %), 156.1 (45 %), 168.8 (45 %), 169.1 (55 %),

174.0 (45 %),174.2 (55 %). [α]_D−59.8 (c 1.13, CHCl₃).

ESI–MS: m/z calcd. for C₄₆H₅₅N₃NaO₈[M + Na]⁺800.4;

found 800.2. Anal. calcd. for C₄₆H₅₅N₃O₈: C, 71.02; H,

7.13; N, 5.40. Found: C, 71.22; H, 7.27; N, 5.31.

1

C, 68.60; H, 7.49; N, 5.89. (P)-11b: H NMR (400 MHz,

CDCl₃, mixture of rotamers): δ 1.26 (s, 3H, 40 %), 1.29 (s,

3H, 60 %), 1.31–1.52 (m, 21H), 2.99–3.12 (m, 1H), 3.22–

3.41 (m, 2H), 3.42–3.52 (m, 1H), 3.70 (s, 3H, 60 %), 3.71

(s, 3H, 40 %), 3.80-3.90 (m, 1H), 4.06–4.11 (m, 1H), 4.35–

4.46 (m, 1H), 5.25 (s, 1H, 60 %), 5.31 (s, 1H, 40 %), 5.38–

5.46 (m, 1H), 7.16–7.46 (m, 15ArH). ¹³C NMR (100 MHz,

CDCl₃, only major rotamer): δ 16.2 (60 %), 16.3 (40 %),

17.1 (40 %), 17.2 (60 %), 28.0 (60 %), 28.2 (40 %), 28.4,

38.7 (60 %), 38.9 (40 %), 43.8 (40 %), 44.2 (60 %), 49.4,

51.8 (40 %), 52.0 (60 %), 55.3 (60 %), 56.1 (40 %), 68.4

(40 %), 68.5 (60 %), 69.1, 81.7 (45 %), 82.0 (60 %), 82.1

(40 %), 84.1, 84.7 (60 %), 126.9 (40 %), 127.0 (60 %),

127.1 (60 %), 127.3 (40 %), 127.4 (60 %), 127.5 (40 %),

127.6 (60 %), 127.7 (40 %), 128.3 (40 %), 128.4 (60 %),

128.5, 128.6 (40 %), 139.8 (60 %), 140.0 (40 %), 142.2,

142.5 (40 %), 142.6 (60 %), 152.8 (60 %), 153.0 (40 %),

155.3 (60 %), 156.2 (40 %), 168.8 (60 %), 169.2 (40 %),

174.1 (60 %),174.3 (40 %). [α]_D−51.0 (c 0.60, CHCl₃).

ESI–MS: m/z calcd. for C₄₀H₅₁N₃NaO₈[M + Na]⁺724.4;

found 724.2. Anal. calcd. for C₄₀H₅₁N₃O₈: C, 68.45; H,

7.32; N, 5.99. Found: C, 68.64; H, 7.51; N, 5.87.

General procedure for the cleavage of N–N bond

To a solution containing compounds (M) or (P)-11a–c

(350 μmol) in anhydrous THF (1.75 mL) under inert atmos-

phere at 0 °C, LiHMDS (1.06 M in THF, 695 μL, 735 μmol)

was added. The reaction mixture was kept at room tem-

perature and stirred for 3 h, then was quenched with water

(5 mL). After evaporation under vacuum of THF, the mix-

ture was diluted with ethyl acetate (20 mL). After separa-

tion, the organic phase was washed with a saturated sodium

carbonate aqueous solution (2 × 3 mL) and brine (3 mL).

The combined aqueous phases were extracted with ethyl

acetate (20 mL) and, after separation, the organic phase was

washed with a saturated sodium carbonate aqueous solu-

tion (2 × 3 mL) and brine (3 mL). The combined organic

Di‑t‑butyl 1‑(2‑methoxy‑2‑oxoethyl)‑2‑((3S,4R)‑3‑me‑

thyl‑2‑oxo‑1‑((S)‑1‑phenylethyl)‑4‑((trityloxy)methyl)

pyrrolidin‑3‑yl)hydrazine‑1,2‑dicarboxylate, (M)

and (P)‑11c

Starting from compound 10c and following the general pro-

cedure, the diastereomerically and atropisomerically pure

atropisomers (M)-11c and (P)-11c were obtained in 53 %

(725 mg, 0.93 mmol) and in 44 % (597 mg, 0.77 mmol)

yields, respectively, as colourless waxy solids. (M)-11c:

¹H NMR (400 MHz, CDCl₃, mixture of rotamers): δ 1.31

1 3

P. Amabili et al.

layers were dried over anhydrous Na₂SO₄and the sol-

vent evaporated under reduced pressure, then the obtained

crude product was puriﬁed by silica gel chromatography

(cyclohexane:ethyl acetate) to give pure products 1a‑c.

(156 mg, 260 μmol), respectively, as a colourless waxy

solid. ¹H NMR (400 MHz, CDCl₃): δ 0.99 (s, 3H), 1.44 (d,

J = 7.0 Hz, 3H), 1.49 (s, 9H), 2.62 (t, J = 9.4 Hz, 1H),

3.05 (t, J = 9.0 Hz, 1H), 3.14–3.23 (m, 2H), 3.29–3.38 (m,

1H), 4.85 (bs, 1H), 5.45 (q, J = 7.0 Hz, 1H), 7.20–7.30

(m, 10ArH), 7.36–7.42 (m, 10ArH). ¹³C NMR (100 MHz,

CDCl₃): δ 16.1, 17.4, 28.6, 39.3, 41.7, 49.3, 59.9, 62.2,

79.6, 86.9, 127.1, 127.2, 127.4, 127.9, 128.58, 128.61,

139.7, 143.9, 154.3, 174.3. [α]_D−54.8 (c 1.30, CHCl₃).

ESI–MS: m/z calcd. for C₃₈H₄₂N₂NaO₄[M + Na]⁺613.3;

found 613.1. Anal. calcd. for C₃₈H₄₂N₂O₄: C, 77.26; H,

7.17; N, 4.74. Found: C, 77.40; H, 7.29; N, 4.67.

t‑Butyl ((3S,4R)‑4‑((benzyloxy)methyl)‑3‑me‑

thyl‑2‑oxo‑1‑((S)‑1‑phenylethyl)pyrrolidin‑3‑yl) carba‑

mate, 1a

Starting from (M) or (P)-11a and following the general

procedure, diastereomerically pure compound 1a was

obtained in 75 % yield (115 mg, 262 μmol) or 70 % yield

(108 mg, 246 μmol), respectively, as a colourless waxy

solid. ¹H NMR (400 MHz, CDCl₃): δ 1.26 (s, 3H), 1.43 (s,

9H), 1.51 (d, J = 7.0 Hz, 3H), 2.94 (t, J = 9.0 Hz, 1H),

2.98-3.06 (m, 1H), 3.13-3.17 (m, 1H), 3.52 (t, J = 8.6 Hz,

1H), 3.88–3.95 (m, 1H), 4.45 (d, J = 11.9 Hz, 1H), 4.49

(d, J = 11.9 Hz, 1H), 4.99 (bs, 1H), 5.46 (q, J = 7.0 Hz,

1H), 7.24–7.38 (m, 10ArH). ¹³C NMR (100 MHz, CDCl₃):

δ 16.2, 17.6, 28.5, 40.7, 42.8, 49.4, 59.8, 69.2, 73.3, 79.7,

127.1, 127.5, 127.6, 127.7, 128.5, 128.6, 138.2, 139.7,

154.6, 174.3. [α]_D−66.4 (c 1.22, CHCl₃). ESI–MS: m/z

calcd. for C₂₆H₃₄N₂NaO₄[M + Na]⁺461.2; found 461.1.

Anal. calcd. for C₂₆H₃₄N₂O₄: C, 71.21; H, 7.81; N, 6.39.

Found: C, 71.33; H, 7.90; N, 6.30.

Compliance with ethical standards

Conﬂict of interest The authors declare that they have no conﬂict

of interest.

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Article Doi

Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the synthesis of an elusive conformationally restricted analogue of α-methylhomoserine

DOI: 10.1007/s00726-015-2100-4

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Article abstract of DOI:10.1007/s00726-015-2100-4

Full text of DOI:10.1007/s00726-015-2100-4

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