Stereodynamics of nitrogen chiral centers in aza-β3- cyclodipeptides

Article abstract of DOI:10.1002/chir.22160

The present work is devoted to the synthesis, conformational analysis, and stereodynamic study of aza-β³-cyclodipeptides. This pseudopeptidic ring shows E/Z hydrazide bond isomerism, eight-membered ring conformation, and chirotopic nitrogen atoms, all of which are elements that are prone to modulate the ring shape. The (E,E) twist boat conformation observed in the solid state by X-ray diffraction is also the ground conformation in solution, and emerges as the lowest in energy when using quantum chemical calculations. The relative configuration associated with ring chirality and with the two nitrogen chiral centers is governed by steric crowding and adopts the (P)S_NS_N/(M)R_NR_N combination which projects side chains in equatorial position. The nitrogen pyramidal inversion (NPI) at the two chiral centers is correlated with the ring reversal. The process is significantly hindered as was shown by VT-NMR experiments run in C₂D₂Cl₄, which did not make it possible to determine the barrier to inversion. Finally, these findings make it conceivable to resolve enantiomers of aza-β³-cyclodipeptides by modulating the backbone decoration appropriately.

Full text of DOI:10.1002/chir.22160

CHIRALITY 25:341–349 (2013)
Stereodynamics of Nitrogen Chiral Centers in aza-b3-Cyclodipeptides
1
1
1
1
2
3
*
PHILIPPE LE GREL, AIKATERINI ASPROGENIDI, PHILIPPE HUEZ, BARBARA LE GREL, ARNAUD SALAÜN, THIERRY ROISNEL,
MICHEL POTEL,3 ELHAM RASTI,4 AND ALEXANDRE HOCQUET
5
1ICMV UMR CNRS 6226, Université de Rennes I, 263 avenue du Général Leclerc, 35042 Rennes Cedex, France,
2CBMN, UMR 5248, 2 rue Robert Escarpit, 33 607 Pessac, France,
3CSM, UMR CNRS 6226, Université de Rennes I, 263 avenue du Général Leclerc, 35042 Rennes Cedex, France,
4Department of Chemistry, University of Technology, 8415483111 Isfahan, Iran, Republique Islamique
5UMR CNRS-INPL 7568, B.P. 451, 54001 Nancy, France,
ABSTRACT
The present work is devoted to the synthesis, conformational analysis, and
stereodynamic study of aza-b3-cyclodipeptides. This pseudopeptidic ring shows E/Z hydrazide
bond isomerism, eight-membered ring conformation, and chirotopic nitrogen atoms, all of which
are elements that are prone to modulate the ring shape. The (E,E) twist boat conformation
observed in the solid state by X-ray diffraction is also the ground conformation in solution, and
emerges as the lowest in energy when using quantum chemical calculations. The relative config-
uration associated with ring chirality and with the two nitrogen chiral centers is governed by
steric crowding and adopts the (P)SNSN/(M)RNRN combination which projects side chains in
equatorial position. The nitrogen pyramidal inversion (NPI) at the two chiral centers is corre-
lated with the ring reversal. The process is significantly hindered as was shown by VT-NMR
experiments run in C2D2Cl4, which did not make it possible to determine the barrier to inversion.
Finally, these findings make it conceivable to resolve enantiomers of aza-b3-cyclodipeptides by mod-
ulating the backbone decoration appropriately. Chirality 25:341–349, 2013. © 2013 Wiley Periodicals, Inc.
KEY WORDS: aza-b3-pseudopeptides; conformation; chiral nitrogen atom; pyramidal inversion;
inversion barrier; diasteromerization; VT-NMR; X-ray structure; quantum
chemical calculation
INTRODUCTION
closure mechanism for 1,2-dipropyldiaziridines15 and 3,4-
diterbutyle-1,3,4-oxadiazolidines.16 On the whole, slow NPI
remained for 60 years the quasi-exclusive prerogative17 of small
cyclic compounds (Fig. 1).
The control of nitrogen chirality1 is intrinsically challenging2
due to the low energetic barrier associated with nitrogen
pyramidal inversion (NPI).3 Yet, it was anticipated early on that
nitrogen containing three-membered rings should invert
slowly because of the increase of angular strain imposed by
the sp3 to sp2 transition during the inversion.4 This was
confirmed 20 years later when it was demonstrated experimen-
tally, through pioneering VT-NMR experiments, that alkyl
During our work on aza-b3-peptides, we discovered that the
NPI level is significantly hindered in aza-b3-cyclo tetra and
cyclohexapeptides (Fig. 2).18 Although not as strong as for
compounds above, this phenomenon is really remarkable con-
sidering the size of such macrocycles (16- or 24-membered
rings). The backbone of aza-b3-cyclopeptides folds into a strongly
favored secondary structure where chiral nitrogen atoms Ni are
H-bonded to hydrazididic NHi+1 together with the oxygen atom
of the COi–1 (Fig. 3, left).19 Acting as a soft quaternarization of
the chiral center, the Ni...HNi+1 H-bonding certainly contributes
significantly to the slowing down of the NPI. The bulkiness of
side chains on the chiral nitrogen centers reinforces the confor-
mation. Finally, the contribution of the antiparallel alignment of
the adjacent NHCO dipoles possibly further stabilizes the folded
state as suggested by the work of Sam Gellman20 concerning the
role of secondary interaction21 in the context of folding phenom-
ena (Fig. 3, right). In this ground conformation, the absolute
configurations of the nitrogen chiral centers alternate in a
¼
aziridines (Fig. 1) display G values of around 80 kJmol–1.5 It
was then found that a further increase of the inversion barriers
occurs when the nitrogen atom is connected to a neighboring
element bearing one or more electron lone pairs.6 In the case
of strong electron withdrawing substituent, like fluoro7 or
alkoxy8 groups, the energy barriers jump to over 120 kJmol–1,
making it possible to resolve racemates at room temperature.
Also, oxaziridines9 and 1,2-dialkyldiaziridines,10 in which the
nitrogen chiral center is connected to an endocyclic hetero-
atom, display high barriers to inversion. In the case of cyclic
1,2-dialkyl-hydrazines, the steric compression between adjacent
bulky substituents on nitrogen atoms during the inversion
makes it possible to induce slow NPI in larger rings like
1,2-di-tert-butyl-diazetidine,11 and 1,3,4-oxadiazolidines,12 even
though intrinsic ring strain becomes negligible in the latter
¼
Additional Supporting Information may be found in the online version of
this article.
Contract grant sponsor: ARED Grant from Region Bretagne Financial Support.
*Correspondence to: Philippe Le Grel, Université Rennes 1, UMR CNRS 6226,
263 avenue du Général Leclerc 35042 Rennes Cedex, France. E-mail:
philippe.legrel@univ-rennes1.fr
Received for publication 06 April 2012; Revised 05 June 2012; Accepted
12 July 2012
DOI: 10.1002/chir.22160
Published online 9 May 2013 in Wiley Online Library
(wileyonlinelibrary.com).
case. High G values are also observe in 2-methoxy-1,2-
oxazolidines13 where the nitrogen chiral center is connected
to both endocyclic and exocyclic electronegative elements. It is
worth noting that although the mechanism of enantiomerization
of nitrogen in small heterocycles is most often considered as
arising from hindered NPI, some studies suggest alternative
pathways like ion pair formation14 in the case of N-chloro-
diaziridine or N-chloro-oxaziridine, or a ring opening–ring
© 2013 Wiley Periodicals, Inc.

342
LE GREL ET AL.
Fig. 1. Synoptic presentation of typical heterocyclic structures where the
slowdown of NPI takes place.
Fig. 4. The two mirror-image invertomers of an aza-b3-cyclohexapeptide.
chromatography was performed with silica gel 60 (particle size 40–63mm).
1H and 13C NMR were measured on a 500 MHz (500 MHz for 1H, and
125 MHz for 13C), a 300MHz (300MHz for 1H; 75MHz for 13C), or a
200 MHz (200 MHz for 1H; 50MHz for 13C) NMR spectrometer. Chemical
shifts (d) are reported in parts per million (ppm) for 1H and for 13C NMR
spectra. Coupling constants (J) are reported in hertz (Hz). High-resolution
mass spectrometric analyses were performed with an ESI source and were
carried out at the CRMPO (Centre Régional de Mesures Physiques de
l’Ouest) in Rennes, France.
The conformation of the new compounds described here was studied
combining both 1D and 2D NMR analysis using a Brüker AV 500 spec-
trometer, X-ray diffraction on a Nonius Kappa CCD, and quantum
chemical calculations at the HF/STO3-G22 and B3LYP/6-31G+(d,p)23
levels. For every calculation, the Gaussian 03 software24 has been used
for geometry optimizations and frequency calculations that made it
possible to check for the absence of imaginary frequencies for every
encountered minimum.
Fig. 2. General chemical structures of aza-b3-cyclotetramers and
cyclohexamers.
General Synthesis and Characterization of
Compounds C1–C3 (scheme 1-3)
General procedure for conversion of Boc-protected aza-b3-amino
acid to the corresponding deprotected aza-b3-amino ester
(step i). To compound Boc-aza-b3 Phe-OH, 1, 4 g (14 mmol), or
Boc-NMe-aza-b3 Phe-OH, 2, 2.65 g (9 mmol), or Boc-NMe-aza-b3 (a-Methyl-
Phe)-OH, 3, 6.35g (20mmol) dissolved in respectively 40ml, 15ml, and
50 ml of MeOH cooled to ꢀ10 ꢁC, was added dropwise a solution of of
thionyl chloride (28, 18, and 40 mmol, respectively) in 20 ml of DCM.
The solution was then allowed to warm to room temperature (25 ꢁC)
and stirred for a further 5h. Solvents were then co-evaporated twice with
DCM and twice with Et2O, and the crude resulting oil was dissolved in
30 ml of DCM. The organic layer was washed twice with 30 ml of 1 M
NaHCO3, dried over Na2SO4, and evaporated to give the corresponding
methyl ester 3.12 g (94%) of H-aza-b3 Phe-OMe 1a, 1.73g (92%) of H-
NMe-aza-b3 Phe-OMe 2a, and 4 g (87%) of H-NMe-aza-b3 (a-Methyl-Phe)
-OMe 3a.
Fig. 3. Left; the secondary structure adopted by backbone of an aza-b3-
cyclohexapeptide (H-bonds in dotted lines). Right; antiparallel alignment of
the NHCO dipoles (dipole orientation in yellow dotted arrows).
syndiotactic arrangement, and the two invertomers of the
macrocycle interconvert by the reversal of the ring-backbone
together with the NPI of the full set of chiral centers in a
correlated way (Fig. 4).
It is noticeable that aza-b3-peptidic macrocycles contain hy-
drazide bonds as amide surrogates, confirming the appeal of
the N,N link with the aim of designing new scaffolds that
are prone to slowing down NPI. This led us to engage in
the synthesis and conformational analysis of new cycles in-
cluding aza-b3-aminoacid residues. It is of particular interest
to study the stereodynamics of nitrogen chiral centers in
aza-b3-cyclodipeptides. Actually, although the size of aza-b3-
cyclodipeptides does not allow internal H-bonding, we
anticipated that the presence of the two planar hydrazidic
fragments inside the cycle should act as a serious conforma-
tional constraint that could control the relative configuration
of the chiral centers and possibly reduce the NPI level. The
present article describes our preliminary findings.
General coupling procedure (step ii). All coupling steps leading to
aza-b3-peptidic dimers were performed using the EDC (1.2 eq relative to
the acid) activation in DCM. The mixture was stirred for 12 h. The
organic layer was washed successively twice with 15 ml of 1 N HCl, twice
with 15 ml of water, and twice with 15 ml of 1 N NaHCO3, dried on
Na2SO4, and evaporated. This material was carried on without
further purification.
General procedure for saponification (step iii). To a solution of ester
(10 mmol) in 20 ml acetonitrile was added NaOH 2 N (12 mmol). The mix-
ture was stirred for 3 h at room temperature. After evaporation of acetoni-
trile, the residue was diluted with 30 ml of water, washed twice with ether
(2 ꢂ 30 ml), acidified by addition of HCl 2 N, and extracted with DCM
(2 ꢂ 50 ml). The combined DCM extracts were dried over Na2SO4. Filtra-
tion and evaporation of the solvent afforded the corresponding acid.
MATERIALS AND METHODS
Materials and Instrumentation
All chemicals and solvents were of laboratory grade from commercial
suppliers and were used without further purification. Silica gel
Chirality DOI 10.1002/chir

AZA-b3-CYCLODIPEPTIDES
343
General cyclization procedure (step iv). Typically, a linear precursor
(1 mmol) Boc-aza-b3 Phe-aza-b3 Phe-OH 1c, or Boc-aza-b3 Phe-NMe-aza-
b3 Phe-OH 2c, or Boc-aza-b3 Phe-NMe-aza-b3 (a-Methyl-Phe)-OH 3c
was treated with a mixture of DCM/TFA (6 ml/4 ml) for 12 h. The excess
of TFA was then co-evaporated under reduced pressure with toluene
(3 ꢂ 20 ml) then ether (3 ꢂ 20 ml) until a white foam appeared. The crude
residue was dissolved in 20 ml of DCM and 10 mmol of triethylamine was
added. This solution was poured drop by drop into a solution of EDCI
(6 mmol) and HOBT (6 mmol) in 1.5 liters of DCM. The reaction was
stirred vigorously for 24 h. The volume was then reduced to around
100 ml. The addition of 20 ml of 1 N HCl under stirring gave rise to the ap-
pearance of a white solid (HOBT, HCl) which was filtrated by suction.
The solution was then washed successively with 20 ml of 1 N HCl, twice
with 20 ml of water, twice with 20 ml of 1 N NaHCO3, dried on Na2SO4,
and evaporated. For compound C1–C3 the crude reaction product was
obtained as a foam. Compounds C1–C3 were precipitated by addition of
diethyl ether to give a white solid which was filtered. Yield C1: (42%),
C2: (34%), C3: (28%). Monocrystals of C1 were obtained from a toluene/
ethanol mixture. Monocrystals of C2 and C3 were grown in toluene.
then 4.14 g of glyoxylic acid (45 mmol). After 0.5 h of stirring, the mixture
was acidified with a solution of 2 N HCl until pH ꢃ 1–2. The mixture was
stirred for 1 h at room temperature. The pH was adjusted to 9 using solid
NaHCO3. EtOH was removed in vacuo and the aqueous phase was
washed twice with 30 ml of DCM. The aqueous phase was acidified with
a solution of 1 N HCl, extracted twice with 30 ml of DCM. The organic
layers were dried over Na2SO4. Filtration and evaporation of the solvent
gave monomer Boc-NMe-aza-b3 Phe-OH 2 (6.4 g, 73%) as a colorless oil.
1H NMR (200 MHz, CDCl3) d (ppm): 1.39 (s, 9H, 3xCH3), 2.98 (s, 3H,
CH3), 3.60 (s, 2H, CH2), 4.10 (s, 2H, CH2), 7.31–7.39 (m, 5H, C6H5).
Synthesis and characterization of H-NMe-aza-b3 Phe-OMe
2a. Thionyl chloride (2.50 g, 21mmol) was added dropwise to a solution
of monomer Boc-NMe-aza-b3 Phe-OH 2 (3.08g, 10.48mmol) in MeOH
(20 ml). The mixture was stirred for 12h at room temperature. MeOH was
evaporated; triturating the residue in diethyl ether, followed by filtration,
gave the chlorhydrate HCl, HNMe-aza-b3 Phe-OMe quantitatively. 1H
NMR (200MHz, CDCl3) d (ppm): 3.01 (s, 3H, CH3), 3.81 (s, 3H, CH3),
3.94 (s, 2H, CH2), 4.47 (s, 2H, CH2), 7.39 (s, 5H, C6H5). The chlorhydrate
was dissolved in 10ml of water, 20ml of DCM were added, and the
pH of the aqueous phase was then adjusted to 8–9 using 1 N NaHCO3.
The organic layer was dried over Na2SO4 and DCM was evaporated to
give H-NMe-aza-b3 Phe-OMe 2a (2.3 g, 90%) as a clear oil which was
engaged immediately in the next step without further purification. 1H
NMR (200MHz, CDCl3) d (ppm): 2.99 (s, 3H, CH3), 3.79 (s, 3H, CH3),
3.93 (s, 2H, CH2), 4.45 (s, 2H, CH2), 7.38 (s, 5H, C6H5) 11.25 (broad,
2H, NH, HCl).
Synthesis and characterization of compound C1. Compound Boc-
aza-b3 Phe-OH 1 was obtained as described in our previous work.25 Pre-
cursors H-aza-b3 Phe-aza-b3 Phe-OMe 1a, Boc-(aza-b3 Phe)2-OMe 1b,
and Boc-(aza-b3 Phe)2-OH 1c were obtained following general procedure,
respectively: Inversion/protection (step i), coupling procedure (step ii), and
saponification (step iii). They were roughly purified and used as such.
Compound C1 was obtained following general cyclization procedure (step
iv). Yield: 42%. Mp = 236 ꢁC. Crystals of C1 were grown from a toluene/
ethanol mixture. 1H NMR (500 MHz, CDCl3 10–2 M, 298 K) d (ppm):
3.45 (broad, 2H, NCH2CO), 3.92 (broad, 6H, NCH2CO and 2CH2Ph),
7.29 (broad, 2H, NH), 7.37–7.34 (m, 10H, aromatics). 13C NMR
(75 MHz, CDCl3) d (ppm): 62.3 (CH2), 62.5 (CH2), 128 (CH), 128.6
(CH), 129 (CH), 135.7 (C), 171.6 (CO). HRMS (ESI) Calcd for
C18H20N4O2Na 347.1484; Found, 347.1487.
Synthesis and characterization of Boc-aza-b3 Phe-NMe-aza-b3
Phe-OH 2c. Monomer H-NMe-aza-b3 Phe-OMe 2a (1.14g, 5.5 mmol)
was coupled with monomer Boc-aza-b3 Phe-OH 1 following general
coupling procedure ii to give dimer Boc-aza-b3 Phe-NMe-aza-b3 Phe-OMe
2b quantitatively as a yellow oil. Compound 2b was saponified into
Boc-aza-b3 Phe-NMe-aza-b3 Phe-OH 2c (white foam, 96% for the two steps)
following general procedure iii. 1H NMR (200 MHz, CDCl3) d (ppm): 1.32
(s, 9H, 3xCH3), 3.03 (s, 3H, CH3), 3.53–4.16 (m, 8H, 4xCH2), 6.44 (broad,
1H, OH), 7.01 (s, 1H, NH), 7.28–7.37 (m, 10H, 2xC6H5).
Synthesis and characterization of compound C2. All precursors of
C2 were roughly purified and used as such.
Synthesis and characterization of Boc-NMe-NH2. To a cooled solu-
tion (0 ꢁC) of methylhydrazine (3.45 g, 75 mmol) in DCM (80 ml) was
added dropwise a solution of di-tert-butyldicarbonate (16.35 g, 75 mmol)
in 80 ml of DCM. The mixture was stirred at room temperature for 3 h.
The solvent was evaporated to afford quantitatively compound Boc-
NMe-NH2 as an oil. 1H NMR (200 MHz, CDCl3) d (ppm): 1.48 (s, 9H,
3xCH3), 3.07 (s, 3H, CH3), 4.13 (broad, 2H, NH2).
Synthesis of compound C2. Compound C2 was obtained following
general cyclization procedure (step iv). Yield: 34%. Mp = 162 ꢁC. Crystals
of C2 were obtained in toluene. 1H NMR (500 MHz, CDCl3/10–2 M/
298 K) d (ppm): 3.02 (s, 3H, CH3), 3.42 (d, J = 13.5Hz, 1H, CHB1), 3.53
(d, J = 13.8Hz, 1H, CHB2), 3.90 (d, J = 13.8Hz, 1H, CHA2), 3.92
(d, J = 12.9Hz, 1H, CHB3), 3.93 (s, 2H, CH2), 4.04 (d, J = 13.5Hz, 1H,
CHA1), 4.07 (d, J= 12.9Hz, 1H, CHA3), 6.54 (s, 1H, NH), 7.31–7.38 (m, 10H,
CHar). 13C NMR (75MHz, CDCl3/10–2 M/298 K) d (ppm): 25.64 (CH3),
58.36 (CH2), 58.64 (CH2), 62.11 (CH2), 64.02 (CH2), 128.04 (CHp), 128.08
(CHp), 128.62 (CH), 128.65 (CH), 128.92 (CH), 129.20 (CH), 135.62 (C),
135.80 (C), 170.75 (CO), 170.77 (CO). HRMS (ESI) Calcd for
Synthesis and characterization of Boc-NMe-N=CHPh. Benzalde-
hyde (7.95 g, 75 mmol) was added slowly to a solution of Boc-NMe-NH2
(10.95 g, 75 mmol) in diethyl ether (100 ml) The mixture was stirred for
12 h at room temperature. The solution was dried with Na2SO4, then fil-
tered. Evaporation of the solvent afforded quantitatively hydrazone Boc-
NMe-N=CHPh as an oil. 1H NMR (200 MHz, CDCl3) d (ppm): 1.56 (s,
9H, 3xCH3), 3.10 (s, 3H, CH3), 7.35–7.43 (m, 3H, 3xCH), 7.70–7.77 (m,
2H, 2xCH), 7.85 (s, 1H, CH).
C19H22N4O2Na 361.16405; Found, 361.1640.
Synthesis and characterization of compound C3. All precursors of
C3 were roughly purified and used as such.
Synthesis and characterization of hydrazone Boc-NMe-N=C(Me)
Synthesis and characterization of hydrazine Boc-NMe-NHBn. To
a stirred solution of hydrazone Boc-NMe-N=CHPh (17.55g, 75mmol) in
120ml EtOH were added 5.20 g (82.75 mmol) of sodium cyanoborohydrure.
After 30 min of stirring, the mixture was acidified with a solution of
2 N HCl to pH ꢃ 1–2. Then, the pH was adjusted to 9 using solid
NaHCO3. EtOH was removed in vacuo and the aqueous phase was
extracted twice with DCM. The combined organic layers were
dried over Na2SO4. Filtration and evaporation of the solvent give
Boc-NMe-NHBn as an oil (15.5 g, 88%). 1H NMR (200 MHz, CDCl3)
d (ppm): 1.48 (s, 9H, 3xCH3), 3.02 (s, 3H, CH3), 4.10 (s, 2H, CH2),
7.31–7.40 (m, 5H, C6H5).
Ph. To
a
solution of Boc-NMe-NH2 (15.87 g, 0.11 mol) and
acetophenone (13 g, 0.11 mol) in 150 ml of diethyl ether were added two
drops of acetic acid. After stirring for 12 h, the mixture was dried over
Na2SO4, filtrated, and evaporated to give hydrazone BocNMe-N=C(Me)
Ph (26.96 g) quantitatively as an oil. NMR 1H (300 MHz, CDCl3/298 K)
d (ppm): 1.48 (s, 9H, 3xCH3), 2.29 (s, 3H, CH3), 3.23 (s, 3H, CH3),
7.17–7.85 (m, 5H, CHar).
Synthesis and characterization of hydrazine Boc-NMe-NH(CH(Me)
Phe). To a solution of hydrazone Boc-NMe-N=C(Me)Ph (26.96 g,
0.11 mol) in 100 ml of EtOH were added 7.51 g (0.12 mol) of sodium
cyanoborohydrure. The mixture was stirred for 2 h after having adjusted
the solution to pH 5–6 using 2 N HCl. The mixture was acidified to pH 1
using 2 N HCl and stirred for 15 min. Then, NaHCO3 (powder) was added
to adjust the solution to pH 9. EtOH was removed in vacuo and the
Synthesis and characterization of Boc-NMe-aza-b3 Phe-OH 2. To a
solution of hydrazine Boc-NMe-NHBn (7.08 g, 30 mmol) in EtOH (50 ml)
were added successively 2.83 g of sodium cyanoborohydride (45 mmol),
Chirality DOI 10.1002/chir

344
LE GREL ET AL.
aqueous phase was extracted twice with DCM (20 ml). The organic layer
was dried over Na2SO4. Filtration and evaporation of the solvent gave
Boc-NMe-NH(CH(Me)Phe) as a clear oil (27.15 g, 98%). 1H NMR
(300 MHz, CDCl3/298 K) d (ppm): 1.26 (d, J = 6.5 Hz, 3H, CH3), 1.40 (s,
9H, 3xCH3), 2.73 (s, 3H, CH3), 4.11 (q, J = 6.5 Hz, 1H, CH), 7.18–7.30
(m, 5H, CHar).
modest but reaction conditions were not optimized for this
preliminary study.
Conformational Analysis
In contrast to the chemical shift of H-bonded NH (9–10 ppm)
present in large aza-b3-macrocycles,18a–c NH signals for aza-b3-
cyclodipeptides appear at much higher field (around 6.5 ppm).
These signals are sensitive to dilution effects and to the
Synthesis and characterization of Boc-NMe-aza-b3 (a-Methyl-Phe)-
OH 3. To a solution of Boc-NMe-NH(CH(Me)Phe) (27.15 g, 0.11 mol)
in EtOH (100 ml), at 0 ꢁC, were added successively 13.66 g of sodium
cyanoborohydride (0.22 mol), then 20 g of glyoxylic acid (0.22 mol). After
3 h of stirring, a solid appeared and was filtered. The mixture was acidi-
fied with 2 N HCl until pH ꢃ 1–2. The mixture was stirred for 1 h at room
temperature. NaHCO3 (powder) was added until pH ꢃ 9. EtOH was re-
moved in vacuo and the aqueous phase was washed with 30 ml of
DCM. The aqueous phase was acidified with 1 N HCl, and extracted twice
with DCM. The organic layer was dried over Na2SO4. Filtration and evap-
oration of the solvent gave monomer Boc-NMe-aza-b3 (a-Methyl-Phe)-OH
3 (27.47 g, 66%) as a colorless oil. Due to the presence of several rotamers
1H and 13C NMR spectra of 3 cannot be detailed and are given as such in
the Supporting Information (SI, pp. 7–8).
Fig. 5. Chemical structures of aza-b3-cyclodipeptides C1, C2, and C3.
Synthesis and characterization of H-NMe-aza-b3 (a-Methyl-Phe)-
OH 3a. Thionyl chloride (2.28 g, 19.4 mmol) was added dropwise to a
solution of Boc-NMe-aza-b3 (a-Methyl-Phe)-OH 3 (3 g, 9.7 mmol) in
MeOH (10 ml). The mixture was stirred for 12 h at room temperature
then evaporated to dryness. The crude product was dissolved in 10 ml
of water, 20 ml of DCM were added, then the pH of the aqueous phase
was adjusted to 8–9 using 1 N NaHCO3. The organic layer was dried
(Na2SO4) and DCM was evaporated to give H-NMe-aza-b3 (a-Methyl-
Phe)-OH 3a (2.15 g, 86%) as a clear oil. 1H NMR (300 MHz, CDCl3/
298 K) d (ppm): 1.43 (d, 3H, CH3), 2.53 (s, 3H, CH3), 3.33 (d, 1H, CHB),
3.55 (d, J = 6 Hz, 1H, CHA), 3.69 (s, 3H, CH3), 4.09 (q, 1H, CH), 7.32–7.34
(m, 5H, CHar).
Synthesis and characterization of Boc-aza-b3 Phe-NMe-aza-b3 (a-
Methyl-Phe)-OH 3c. Monomer H-NMe-aza-b3 (a-Methyl-Phe)-OH 3a
(4 g, 18 mmol) was coupled with monomer Boc-aza-b3 Phe-OH 1 (5.04 g,
18 mmol) following general coupling procedure ii to give dimer Boc-aza-
b3 Phe-NMe-aza-b3 (a-Methyl-Phe)-OMe 3b as a yellow oil (8.24 g,
94%). Compound 3b was saponified into Boc-aza-b3 Phe-NMe-aza-b3
(a-Methyl-Phe)-OH 3c as a white foam (7.57 g, 95%) following general
procedure for saponification (step iii).
Fig. 6. Calculated (E,E) eq-eq twist boat conformation as the lowest in energy.
1H NMR (300 MHz, CDCl3) d (ppm): 1.16 (d, 3H, J = 6.5 Hz, CH3),
1.34 (s, 9H, 3xCH3), 2.97 (s, 3H, NCH3), 3.00–4.23 (m, 7H, 3xCH2, CH),
7.24–7.46 (m, 11H, 2xC6H5, NH).
Synthesis of compound C3. Compound C3 was obtained following
general cyclization procedure (step iv). Yield: 28%. Mp C3M = 156 ꢁC. Mp
C
3m = 154 ꢁC. Crystals of C3M were obtained in toluene. 1H NMR of
C3M (500 MHz, CDCl3/10–2 M/298 K) d (ppm): 1. 34 (d, J = 6.4 Hz, 3H,
CH3), 3.03 (s, 3H, CH3), 3.21 (dd, J = 1.2 Hz, J = 14 Hz, 1H, CHB1), 3.56
(d, J = 13 Hz, 1H, CHB2), 3.65 (d, J = 14 Hz, 1H, CHA1), 3.86 (q, J = 6.4 Hz,
1H, CH), 3.88 (d, J = 13 Hz, 1H, CHB3), 4.01 (d, J = 13 Hz, 1H, CHA3),
4.33 (d, J = 13 Hz, 1H, CHA2), 6.37 (s, 1H, NH), 7.21–7.47 (m, 10H,
10xCHar). 13C NMR of C3M (75 MHz, CDCl3/10–2 M/298 K) d (ppm):
21.98 (CH3), 25.34 (CH3), 57.87 (CH2), 62.13 (CH2), 62.33 (3xCH),
64.45 (CH2), 127.60 (CH), 128.05 (CHp), 128.16 (CHp), 128.54 (CH),
128.85 (CH), 129.34 (CH), 135.47 (C), 141.86 (C), 170.89 (CO), 171.43
(CO). HRMS (ESI) Calcd for C20H24N4O2Na 375.1797; Found, 375.1797.
RESULTS AND DISCUSSION
For this preliminary work, we focused on the three model
compounds C1, C2, and C3 (Fig. 5) that were prepared using
routine peptide synthesis (EDCI/HOBt activation) and a final
cyclization step at 1 mM in 42, 34, and 28% yield respectively,
starting from Boc-aza-b3 Phe-OH, Boc-NMe-aza-b3 Phe-OH,
and Boc-NMe-aza-b3 (a-Methyl-Phe)-OH. Yields are very
Chirality DOI 10.1002/chir
Fig. 7. Views of compounds C1–C3 in the solid state (for clarity, side
chains are represented by a single carbon atom, H-bonds in dotted lines);
Top: H-bonding between molecules of compound C1. Bottom right: H-bonding
between enantiomers of compounds C2–C3. Bottom left: the twist boat
conformation shared by all sets of macrocycles C1–C3.

AZA-b3-CYCLODIPEPTIDES
345
presence of small amounts of DMSO, showing that the
hydrazide NH protons are solvent exposed. The chemical
shift of the carbonyle groups, ranging between 172
and 174 ppm, can be unambiguously associated with the E
geometry of the hydrazide group as we showed recently.26
Quantum chemical calculations have been performed at the
HF/STO-3G level for molecule C1 and the HF/STO3-G level
and B3LYP/6-31G+(d,p) level for a model compound where
the two benzyl moieties in C1 have been replaced by two
methyl groups to allow for more accurate calculations.
Thereafter, this model compound will be referred to as C0.
Starting geometries were built upon the crystal structure of
C1 for the twist boat (E,E) conformation, and built from
optimized geometries of cycloocta-1,5-diene for the chair
and the skew (E,E) conformations, and the chair (E,Z) and
(Z,Z) conformations.27
Calculation at the B3LYP/6-31G+(d,p) level led to eight
minima for C0 (see SI, p. 19). The (E,E) combination is highly
favored, the most stable non-(E,E) conformer being from 5 to
9 kcal mol–1 above the (E,E) ones. For molecule C0, the differ-
ence in energy between chair and twist boat conformers at
the highest level of theory is low, less than 1 kcal mol–1 (see
SI, p. 18; table 1). But comparing molecules C0 and C1 at
the HF/STO3-G level reveals that this difference increases
(in favor of the more stable twist boat) with the bulkier benzyl
substituent. Also, the dipolar moment of every chair confor-
mation is nearly zero while it ranges from 4 to 5 D for twist
boat conformations, leading us to surmise that the difference
in energy would be even more in favor of the twist boat con-
formation in a not strictly apolar medium, as the “in vacuo”
theoretical calculations are. According to calculations, the
(E,E) eq-eq twist boat conformation is the lowest in energy
(Fig. 6).
We succeeded in growing crystals for all sets of the com-
pounds. Crystals of compounds C2 and C3 were grown from
toluene; the less soluble C1 cycle was crystallized from a mix-
ture of ethanol and toluene. Thanks to the presence of the two
NHCO fragments, compound C1 built an infinite wavy ribbon
where each molecule makes H-bonding contact with the two
neighboring rings through eight-membered pseudocycles
(Fig. 7, top). Both enantiomers alternate all along the ribbon.
For compounds C2 and C3, the enantiomers H-bond each
other through a 12-membered pseudoring (Fig. 7, bottom
right). Whatever the substitution pattern, and the packing of
molecules inside the crystals, the ring backbone invariably
appears in an (E,E) eq-eq twist boat conformation very close
to the more stable conformer that emerged from calculations
(Fig. 7, bottom left). The lone pairs of electrons of the two
Fig. 10. 1H NMR spectrum of compound C2 (C2D2Cl4, 500 MHz, 10–2 M).
Fig. 8. The ground conformation of (E,E)-aza-b3-cyclodipeptides (top) and
alternative unfavorable combination of chirality elements (bottom).
Fig. 9. 1H NMR region of the methylenic region for compound C1 (CDCl3,
Fig. 11. VT-NMR experiment for compound C2 (C2D2Cl4, 500 MHz, 10–2 M).
Chirality DOI 10.1002/chir
500 MHz, 10–2 M).

346
LE GREL ET AL.
pyramidal nitrogen atoms are both turned inward toward the
backbone. Trigonal nitrogen atoms are slightly pyramidalized
with the lone pair orthogonally oriented relative to the lone
pair of the neighboring chiral nitrogen atom, minimizing elec-
tronic repulsion in the N,N fragment.
The (P)SNSN/(M)RNRN absolute configuration of enantio-
mers observed in the solid state and predicted by calculation
is the optimal combination of both chirality of the two
stereogenic nitrogen centers and intrinsic chirality of the
ring. [The (P)/(M) notation adopted to specify the intrinsic
ring chirality is assigned by looking up the backbone, the
CO vectors being oriented downward. The (P) notation corre-
sponds to the NH-to-CO clockwise reading in accordance
with the rules adopted to specify the sign of helicity.] This
combination of chiral elements best minimizes steric
crowding by projecting the side chains in the eq-eq conforma-
tion (Fig. 8, top).
Fig. 14. Evolution profile of diastereomerization starting from C3M
.
Actually, partly changing these elements of chirality invari-
ably leads to unfavorable situations by collapsing the side
chain with the ring backbone (inversion of one N*; (P)RNSN/
(M)SNRN) or by collapsing the side chains (inversion of both
N* or ring reversal, (P)RNRN/ (M)SNSN) (Fig. 8, bottom).
Calculations on C1 show that when comparing diastereoiso-
mers as eq-eq, eq-ax, or ax-ax structures, the eq-eq is the
most stable in the twist boat conformation and in the chair
conformation (see SI, p. 18; table 1), with the ax-eq leveling
around 3 kcal mol–1 above, and the ax-ax being highly
disfavored (when it actually leads to a minimum). None of
the less favorable diastereoisomeric conformations (Fig. 8,
bottom) is observed in the NMR spectra of compounds C1,
C2, or C3. Thus, the equilibrium between the (P)SNSN/(M)
RNRN enantiomeric forms of the molecule is a fast process
that requires the inversion of the three elements of chirality
in a correlated manner.
The present structural analysis strongly supports that the
(E,E) eq-eq twist boat shape which corresponds to the (P)
Fig. 12. Equilibrium between the two C3M and C3m diastereoisomers.
Fig. 13. Top: 1H NMR spectrum of the two C3M and C3m diastereoisomers of compound C3 at the thermodynamic equilibrium (CDCl3, 300 MHz, 10–2 M, 298 K).
Bottom: 1H NMR spectrum of pure major C3M compound (CDCl3, 300 MHz, 10–2 M, 298 K).
Chirality DOI 10.1002/chir

AZA-b3-CYCLODIPEPTIDES
347
Scheme 1. Synopsis of the synthetic route leading to compound C1.
Scheme 2. Synopsis of the synthetic route leading to compound C2.
Scheme 3. Synopsis of the synthetic route leading to compound C3.
SNSN/(M)RNRN combination of chiral elements is the ground
conformation of the aza-b3-cyclodipeptides C1–C3.
a better resolution that makes it possible to observe the dou-
blet of the B part of one methylenic group. The A part over-
laps with the other methylenic signal which starts itself to
decoalesce (Fig. 9). Due to its poor solubility in CDCl3,
cooling the sample further leads to aggregation and precipita-
tion of compound C1 in the NMR tube. In any case, this
Chirality DOI 10.1002/chir
VT-NMR Experiments to Assess the NPI Level
The methylenic signals of compound C1 are broad at room
temperature, but simply cooling the sample to 273 K leads to

348
LE GREL ET AL.
3. (a) Weston Jr, RE. Vibrational energy level splitting and optical isomerism
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images of the twist boat conformation is slow enough to
discriminate the environment of the two protons in the
methylenic groups at this temperature.
In compound C2, the presence of the additional methyl
group introduces an element of steric crowding resulting
from N,N’-disubstitution on one hydrazide bond. In response
to this modification, all the methylenic protons of C2 now
appear as sharp AB systems (Fig. 10). Increasing the temper-
ature up to 403 K (C2D2Cl4) leads to no significant changes in
the general shape of the signals, although the slight thicken-
ing of the signal observed at 403 K suggests a possible transi-
tion of the spin systems toward coalescence (Fig. 11).
¼
However, the G values of compound C2 cannot be calcu-
lated from the VT-NMR experiment.
Compound C3 was thus synthesized in order to check the
ability of the backbone to reverse. Due to the presence of
the exocyclic asymmetric carbon atom, the reversal of com-
pound C3 gives rise to an equilibrium between the two C3M
(P)RSNSN/(M)SRNRN and C3m (P)SSNSN/(M)RRNRN,
respectively the major and minor diastereoisomers
(Fig. 12). At 298 K, the thermodynamic ratio is 82% and
18% of C3M and C3m, respectively (Fig. 13). Double
crystallization gives the pure major C3M compound that
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,
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CONCLUSIONS
The present work allowed us to solve the conformation of
aza-b3-cyclodipeptides, which is shared both by the solution
and the solid state. In the (E,E) eq-eq twist boat ground
shape, the presence of the two nearly planar (E)-hydrazide
moieties acts as a strong conformational constraint. Increas-
ing the steric crowding of the hydrazide bond raises signifi-
cantly the energetic barrier associated with the molecule
reversal. Thus, the NPI slowing-down steric effect already
observed for the hydrazino link in cyclic hydrazines can
be reproduced using the hydrazide link (CO–N–N). This
leads us to add a new scaffold to the small family of com-
pounds with restricted NPI. Certainly, the expected level
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¼
of G probably might not be raised as high as for smaller
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enantiomers of appropriately designed aza-b3-cyclodipeptides
is conceivable. Further investigations are currently being
¼
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Chirality DOI 10.1002/chir