A highly practical RCM approach towards a molecular building kit of spirocyclic reverse turn mimics

Article abstract of DOI:10.1002/chem.200600432

The development of privileged molecular scaffolds efficiently mimicking reverse turn motifs and thus increasing both binding and selectivity and enabling the elucidation of the bio-active conformation of a natural peptide has attracted remarkable interest. The frequent occurrence of proline in various turn patterns initiated the design of proline-based reverse turn mimetics. As a structural hybridization of a highly potent type VI β-turn inducer 1 with saturated spirocyclic lactams 3 efficiently mimicking type II β turns, we developed a versatile synthetic route towards unsaturated spirocyclic lactams of type 2, when Seebach's self-reproduction of chirality methodology was combined with a peptide coupling reaction and Grubbs' ring-closing metathesis. By this means, a variety of model peptides with six- up to nine-membered lactam rings were accessible following a uniform pathway. Introduction of suitably protected templates into solid-phase peptide synthesis gave rise to unsaturated spirocyclic analogues of the naturally occurring neuropeptide neurotensin. Spectroscopic investigations as well as DFT calculations on a high level of theory revealed a remarkable dependence of the reverse-turn inducing potency on the ring size. While the secondary structure of the unsaturated spirocyclic ε-lactam 12 closely agrees with the reference γlactam 3a, the unsaturated δ-lactam 11 serves as an extraordinarily potent β-turn inducer which is even superior to β-lactams of type 3b. The eight-membered unsaturated spirocyclic lactam 13 adopts a conformation almost ideally matching the prerequisites for a canonical type II β turn with the highest stability of the whole series. In contrast, the nine-membered spirolactam 14 represents a scaffold with a high conformational flexibility.

Full text of DOI:10.1002/chem.200600432

FULL PAPER
DOI: 10.1002/chem.200600432
A Highly Practical RCM Approach towards a Molecular Building Kit of
Spirocyclic Reverse Turn Mimics
Holger Bittermann, Frank Bçckler, Jürgen Einsiedel, and Peter Gmeiner*[a]
Abstract: The development of privi-
leged molecular scaffolds efficiently
mimicking reverse turn motifs and thus
increasing both binding and selectivity
and enabling the elucidation of the bio-
active conformation of a natural pep-
tide has attracted remarkable interest.
The frequent occurrence of proline in
various turn patterns initiated the
design of proline-based reverse turn
mimetics. As a structural hybridization
of a highly potent type VI b-turn in-
ducer 1 with saturated spirocyclic lac-
tams 3 efficiently mimicking type II b
turns, we developed a versatile synthet-
ic route towards unsaturated spirocyclic
lactams of type 2, when Seebachꢀs self-
reproduction of chirality methodology
was combined with a peptide coupling
reaction and Grubbsꢀ ring-closing
metathesis. By this means, a variety of
model peptides with six- up to nine-
membered lactam rings were accessible
following a uniform pathway. Introduc-
tion of suitably protected templates
into solid-phase peptide synthesis gave
rise to unsaturated spirocyclic ana-
logues of the naturally occurring neu-
ropeptide neurotensin. Spectroscopic
investigations as well as DFT calcula-
tions on a high level of theory revealed
a remarkable dependence of the re-
verse-turn inducing potency on the ring
size. While the secondary structure of
the unsaturated spirocyclic e-lactam 12
closely agrees with the reference g-
lactam 3a, the unsaturated d-lactam 11
serves as an extraordinarily potent b-
turn inducer which is even superior to
b-lactams of type 3b. The eight-mem-
bered unsaturated spirocyclic lactam 13
adopts a conformation almost ideally
matching the prerequisites for a canon-
ical type II b turn with the highest sta-
bility of the whole series. In contrast,
the nine-membered spirolactam 14 rep-
resents a scaffold with a high confor-
mational flexibility.
Keywords:
metathesis
·
peptidomimetics · reverse turns ·
spiro compounds
Introduction
four amino acids residues i, i+1, i+2 and i+3 in a defined
three-dimensional pattern.[3] Employing unsaturated con-
straint elements, we took advantage of the versatility of
Grubbsꢀ ring-closing metathesis, since the availability of a
set of similar scaffolds giving rise to a spectrum of reverse
turn geometries with individually situated and adaptable
side chains is crucial to the success of a bioisosteric replace-
ment.[4] The frequent occurrence of proline in the positions
i+1and i+2 of b turns of type I/II and VI, respectively,
and their ability to trigger biological signals by cis/trans iso-
merization attracted special interest to proline-based reverse
turn mimetics.[2b,5] Built on (S)-proline in position i+2, we
have recently reported on a rational molecular design of
type VI b turn inducing peptide mimetics 1 when Seebachꢀs
self-reproduction of chirality and Grubbsꢀ ring-closing meta-
thesis allowed the construction of differently sized lactam
bridges and, thus, fine tuning of conformational behavior.[6]
To extend our synthetic approach towards type II b-turn in-
ducing model systems, the proline-derived reverse turn nu-
cleating moiety had to be moved into position i+1enabling
the formation of an olefin-based lactam bridge to the back-
Reverse-turn conformations play a crucial role in biological
recognition and signal transduction processes. As an exam-
ple, over one hundred peptide activated GPCRs bind li-
gands with turn structure.[1] Thus, the development of privi-
leged molecular scaffolds efficiently mimicking reverse turn
motifs is of paramount importance when structural con-
straints are exploited to increase both binding and selectivi-
ty and to elucidate the bioactive conformation of the natural
peptide.[2] Considerable efforts have been invested in the de-
velopment of lactam-bridged b-turn mimics presenting the
[a] Dr. H. Bittermann, Dr. F. Bçckler, Dr. J. Einsiedel,
Prof. Dr. P. Gmeiner
Department of Medicinal Chemistry
Friedrich Alexander University Erlangen-Nürnberg
Schuhstrasse 19, 91052 Erlangen (Germany)
Fax : (+49)9131-852-2585
E-mail: gmeiner@pharmazie.uni-erlangen.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2006, 12, 6315 – 6322
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6315

bone nitrogen of Xaa
our target scaffold 2 rigidizing the backbone dihedral angles
(i+1) and y(i+1) involved cis/trans isomerization and
A
f
A
ACHTREUNG
formal migration of the lead compound 1. The target struc-
ture 2 is also the rational consequence of structural hybridi-
zation of 1 with the saturated templates of type 3, being
characterized as the most potent type II b-turn inducers, yet
(see below).[3,7]
We herein present a practical and high yielding chirospe-
cific synthesis of six- to nine-membered model peptide sur-
rogates, solid-phase supported application towards an artifi-
cial neuropeptide analogue and structural characterization
which was based on spectroscopic investigations and subse-
quent DFT-based refinement.
Results and Discussion
Starting from natural proline, chiral building blocks 4a–
d[7a,8] could be readily synthesized by Seebachꢀs self-repro-
duction of chirality methodology[9] and subsequent introduc-
tion of the nitrogen protection groups Boc and Troc, respec-
tively (Scheme 1). Due to the strong steric demand of the
reactants, peptide-bond formation between the protected a-
alkenyl proline derivatives 4a,b and the glycine, b-alanine
and tyrosine derived N-alkenyl amino acids 5a–e[10] turned
out to be challenging when most of the newly established
coupling methods failed and acid chloride formation had to
be circumvented to avoid formation of Leuchs anhydride.[11]
Fortunately, ligation of the glycine and b-alanine derived
building blocks 5a–d could be accomplished yielding 57–
88% of 6a–e when the highly reactive coupling reagent
HATU was used in NMP at elevated temperatures for up to
three days in a strictly oxygen and moisture free reaction
vessel. Facilitating the activation by SOCl2, Troc protection
proved to be advantageous for coupling of the tyrosine de-
rived secondary amine 5e to give 7a,b in 68–74% yield. To
promote formation of six- to nine-membered ring systems,
the metathesis precursors of type 6 and 7 were subjected to
5 mol% of Grubbsꢀ second generation ruthenium-based cat-
alyst[12] in refluxing dichloromethane. In all cases, we ob-
served smooth RCM resulting in formation of the spirocyclic
lactams 8a–e and 9a,b, respectively, in 65–97% yield. Ex-
change of protecting groups was accomplished almost quan-
titatively when the N-Troc derivatives 9a,b were converted
into the N-Boc protected building blocks 10a,b.
Scheme 1. a) 1) Cl3CCHO, MeCN (87%); 2) 4a,c: i) LDA, then
HCOOCH3, THF, ꢀ78 ! ꢀ408C (65%), ii) MePPh3Br, KOtBu, PhMe,
808C (58–74%); 4b,d: LDA, then allyl bromide, THF, ꢀ78 ! ꢀ408C
(69%); b) 1) MeOH, AcCl, 2.5–7 d; 2) 4a,b: i) Na2CO3, ii) Boc2O,
CH2Cl2, 60–67 h; 4c,d: Cl3CCH2OCOOSu, DIPEA, CH2Cl2, 1.5–2.5 h; 3)
NaOH, MeOH, H2O, 50–608C, 1–2.5 h (33–57%); c) 6a–e: HATU,
DIPEA, NMP, 858C, 1–3 d (57–88%); 7a,b: 1) SOCl2, DMF, CHCl3, tol-
uene, 50–608C, 1.25–2 h; 2) 5e, DIPEA, NMP, 60–658C, 1–2.5 h (68–
74%); d) [Ru], CH2Cl2, reflux, 0.5–6 h (65–97%); e) 1) Zn, HOAc, 3.5–
4.5 h, 2) Na2CO3, 3) Boc2O, CH2Cl2, 6–13 h (94–95%).
sentative structural investigations on the seven-membered
system, the Boc group was replaced by an acetyl and ethyl
functionality resulting in formation of the peptide surrogates
16 and 17, respectively. To demonstrate the suitability of our
molecular scaffolds for solid phase supported peptide syn-
thesis, the conformationally constrained neurotensin 8–13
analogues[13] of type 18 should be prepared starting from a
PAM resin that was preloaded with Boc-Leu. In fact, the
Boc protected amino acids isoleucine, Nw-tosylarginine and
Pro-Tyr surrogates that were obtained by saponification of
10a,b could be efficiently attached following HATU cou-
pling and TFA deprotection. After cleavage and removal of
the side chains using neat HF and HPLC purification, the
neurotensin mimics of type 18 were isolated in pure form.
To investigate the conformational properties of our re-
verse-turn model system in comparison to the [4.3]- and
[4.4]-spirocyclic lead compounds 3b and 3a, respectively, IR
and NMR spectroscopic studies including variable tempera-
ture (VT) and NOESY experiments were performed in
To provide comparable reverse-turn model systems for
conformational studies, the molecular scaffolds of type 8
were transformed into the corresponding N-methylamides
11–15 by reaction with methylamine (Scheme 2). For repre-
6316
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Chem. Eur. J. 2006, 12, 6315 – 6322

Reverse Turn Mimics
FULL PAPER
1
changes of H NMR signals as a measure for the stability of
secondary structures indicate that the unsaturated spirocy-
clic e-lactam 12 might form an even more stable intramolec-
ular H-bond than the reference g-lactam 3a when Dd/DT
values of ꢀ4.8 and ꢀ5.6 ppbKꢀ1 were observed, respectively.
The spectroscopic properties of the homologous b-alanine
derivative 15 illustrate that a ring enlargement of the back-
bone substantially reduces reverse-turn stability (Dd/DT=
9.9 ppbKꢀ1). HMQC, H,H-COSY and NOESY investiga-
tions on the ring geometry of 12 were carried out, revealing
a chair-like folding of the ring with the double bond orient-
ed away from the hydrogen bond. DFT calculations re-
Scheme 2. a) 11–15: CH3NH2, EtOH, 08C to RT, 1.75–26 h (73–98%);
vealed a y
from a canonical type II b turn and a low pseudo-dihedral
angle b (i+2),N(i+3)) of 21.28, the latter
(C=O(i),Ca(i+1),Ca
A
16, 17: 1 ) TFA, CHCl2, 08C (to RT), 30 min; 2) 16: AcCl, DIPEA,
2
CH2Cl2, RT, 1 8 h;17: EtBr, Na2CO3, DMF, 608C, 14 h; 3) CH3NH2,
EtOH, RT, 2–2.75 h (24–79%); b) 1) NaOH, H2O, THF, MeOH, 08C,
1.5–2 h (96–99%); 2) SPPS: resin = Boc-Leu-O-PAM, amino acids =
A
G
A
ACHTREUNG
being expected minimal in the case of a b turn. Overall, the
secondary structure of the unsaturated spirocyclic e-lactam
12 closely agrees with the reference g-lactam 3a.
Boc-Ile-OH, Boc-Arg(Tos)-OH, coupling: HATU, DIPEA, NMP/TFA;
A
3) HF, anisole; 4) HPLC.
Table 1. Analytical data of the model peptides.
2 mm solution thus excluding in-
termolecular interactions. With
the aim to further refine the ex-
perimentally derived structures,
density functional calculations
Structure[a]
NMR
Dd/DT [ppbKꢀ1
IR
DFT
d(NH) [ppm][b]
]
n(NH) [cmꢀ1
]
y
(i+1 ) [8]
d [Š][e]
b [8][f]
[c]
[d]
7.64
ꢀ4.0
ꢀ4.8
3337
3340
128.5
131.2
2.03
2.06
18.1
on
a
high level of theory
(d,p)) were per-
(B3LYP/6-311G
ACHTREUNG
formed. This approach facilitat-
ed the extraction of diagnostic
structural indicators and, in
turn, the confirmation of struc-
tural properties by comparing
DFT-based calculated NMR
data with the experimentally
obtained signals. Our initial
studies were directed to the
azepinone 12. For a type-II b
turn, a stable hydrogen bond
between the Boc C=O group
and the NH will be expected
which was clearly indicated by
the extensive absorption bands
at 3340 cmꢀ1 (Table 1). On the
7.63
7.29
21.2
4.4
ꢀ4.0
3352
120.8
179.7
2.15
3.48
28.5
2.05[g]
3368
3455
6.61n.d.
113.3
2.16
ꢀ8.6
ꢀ
other hand, N H stretching ab-
sorptions in the range of
3450 cmꢀ1 being diagnostic for
non-hydrogen bonded states
could not be detected. NMR
derived d(NH) values unambig-
uously demonstrated the exis-
tence of a 10-membered intra-
molecular hydrogen bond when
NH of the N-Boc and N-acetyl
derivatives 12 and 16 resonated
significantly more downfield
(7.63 ppm) than that N-ethyl-
amine 17 (6.38 ppm). Tempera-
3359
3459
3337
3450
3375
15
16
17
7.38
7.63
6.38
ꢀ9.9
ꢀ4.6
n.d.
7.81
8.23
ꢀ5.6
ꢀ4.6
3337
3338
132.8
124.3
2.10
2.08
21.2
11.8
[a] The least energy conformers obtained by DFT calculations are depicted. [b] 2 mm CDCl3 solution, 300 K.
[c] 2 mm CDCl3 solution. [d] 2 mm CHCl3 solution. [e] d(C=O(i)···HN(i+3)). [f] b (i+2),
(C=O(i),Ca(i+1),Ca
(C=O(i+1)···HN(i+3)).
G
G
A
A
ACHTREUNG
ture dependent chemical shift N(i+3)) pseudo-dihedral angle. [g] d
U
A
ACHTREUNG
Chem. Eur. J. 2006, 12, 6315 – 6322
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www.chemeurj.org
6317

P. Gmeiner et al.
rected. aD values were measured on a Perkin Elmer 241polarimeter.
NMR data were acquired on a Bruker AM-360, Avance 360 MHz or
Avance 600 MHz spectrometer. Chemical shifts are noted in ppm relative
to TMS. IR spectroscopy was carried out on a Jasco FT/IR 410 spectrom-
eter. EI-MS, ESI-MS and HRMS were performed on Finnigan MAT
TSQ 70, Bruker esquire 2000 and JEOL GCmate II spectrometers, re-
spectively. Peptide synthesis was carried out using an ACT 90 peptide
synthesizer from Advanced Chemtech. Preparative HPLC was performed
on an Agilent 1100 Series preparative HPLC system with a VWL detec-
tor.
Formal contraction of the unsaturated constraint element
leads to the novel six-membered unsaturated spirolactam 11
showing vicinal coupling constants of the allylic CH2 posi-
tion that indicate a fairly planar ring geometry. According
to diagnostic IR and NMR data including a low temperature
coefficient of ꢀ4.0 ppbKꢀ1 and the calculated C=O(i)···HN-
A
an extraordinarily potent b-turn inducer which is even supe-
rior to b-lactams of type 3b.
(R)-N-(2-Allyl-N-tert-butoxycarbonylprolin-1-yl)-N-but-3-enylglycine
methyl ester (6c): In a thoroughly dried apparatus (R)-N-Boc-a-allylpro-
line (4b; 100 mg, 0.392 mmol) and HATU (164 mg, 0.431 mmol) were
dissolved in NMP (4 mL). After addition of DIPEA (134 mL,
0.783 mmol), the mixture was stirred at room temperature for 15 min,
whereupon a solution of N-but-3-enylglycine methyl ester (5b; 112 mg,
0.782 mmol) in NMP (1mL) was added. The mixture was heated to
858C. After 28 h, another portion of 5b (56.0 mg, 0.391mg) in NMP
(0.5 mL) was added and stirring was continued for 23 h, until no remain-
ing active ester was detectable by IR spectroscopy of a small sample.
After cooling down, brine and water (5 mL each) were added and the
mixture was extracted with Et2O (5ꢂ5 mL). The combined organic layers
were washed with saturated NaHCO3, 5% aqueous citric acid, brine, and
water (5 mL each), dried with MgSO4, concentrated and the residue was
purified by column chromatography (hexanes/ethyl acetate 6:1 ! 5:1)
furnishing 6c as a colorless oil (128 mg, 86% based on 4b). Rf = 0.39
On the other hand, both a significant attenuation of the
intramolecular hydrogen bond and an increase of stability of
the type II b turn were observed for the eight-membered
template 13. To better understand this, careful NMR work
was done when diagnostic NOESY data were indicative for
a boat-like conformer with the double-bond directed away
from the hydrogen bond. After DFT-based geometry opti-
mization, the extraordinary low temperature coefficient of
ꢀ4.0 ppbKꢀ1 could be explained very well when the charac-
teristic torsion angle y(i+1) of 120.88 and the pseudo-dihe-
A
dral angle b=4.48 almost perfectly agreed to the ideal
angles of 120 and 08, respectively. The upfield shift for
d(NH) and higher IR wavenumbers are obviously due to
(hexanes/ethyl acetate 1:1); [a]D25
=
24.0 (c = 0.5, CHCl3); 1H NMR
the higher C=O(i)···HN(i+3) distance of 2.15 Š. Significant
G
(360 MHz, CDCl3; rotamers and broadened signals were observed): d =
1.43, 1.45 (2ꢂs, 9H, Boc), 1.89–2.06 (m, 2H, CH2), 2.14–2.42 (m, 4H,
CH2), 2.74 (dd, 1H, J=14.0, 7.8 Hz, CH2), 2.91(dd, 1H, J=14.0, 6.0 Hz,
CH2), 3.13–3.33 (m, 1H, CH2), 3.41–3.53 (m, 2H, CH2), 3.59–3.67 (m,
2H, CH2), 3.73 (s, 3H, OCH3), 4.33 (d, 0.68H, J=16.7 Hz, CaH2), 4.45
(d, 0.32H, J=18.1 Hz, CaH2), 5.03–5.18 (m, 4H, C=CH2), 5.67–5.84, 5.82
(m and dddd, 2H, J=17.2, 12.4, 4.9, 4.9 Hz, C=dsCH); 13C NMR
(90 MHz, CDCl3; rotamers were observed): d = 21.7, 22.5 (2CH2), 28.5,
28.6 (2Boc CH3), 32.6, 32.7, 35.0, 36.0, 40.9, 42.5, 47.8, 48.2, 48.4, 48.7,
49.0, 52.2 (CH2, OCH3), 68.2, 68.4 (2Ca), 80.0, 80.7 (2Boc Cq), 117.5,
117.9, 118.7, 118.9, 134.3, 134.4, 134.5, 134.7 (C=C), 153.4, 153.5 (2Boc
C=O), 170.2, 170.5, 173.8, 173.9 (ester and amide C=O); IR (neat): n˜ =
2977, 1751, 1695, 1645 cmꢀ1; EIMS: m/z: 380 [M +]; elemental analysis
calcd (%) for C20H32N2O5: C 63.14, H 8.48, N 7.36; found: C 62.88, H
8.41, N 7.44.
NMR line-broadening which could be reduced at low tem-
perature indicated a certain conformational flexibility of the
eight-membered ring. It is also worthy of note that the DFT-
based predictions of chemical shift values were very close to
measured d values clearly corroborating the NOESY de-
rived boat conformation of the azocinone moiety.
Quite differently, the nine-membered spirolactam 14 rep-
resents a scaffold with a high conformational flexibility
when the spectroscopic data indicated an equilibrium of H-
bonded and -nonbonded structures. Theoretical investiga-
tions involving molecular dynamic and subsequent DFT cal-
culations led to the assumption that formation of a g turn is
also energetically favored for 14.
(R)-(1-tert-Butoxycarbonyl-6-oxo-1,7-diazaspiro
A
acetic acid methyl ester (8c): In thoroughly dried apparatus 6c
a
In conclusion, we were able to establish a uniform syn-
thetic procedure towards a set of type II b-turn mimics dis-
playing complementary properties. In accordance to our
studies on type VI b-turn inducers, the eight-membered
lactam inducer afforded the most stable reverse turn. Based
on an X-ray or NMR derived 3D-structure of a biological
target, deviating back-bone geometries and flexibilities of
scaffolds of type 2 resulting in alternative displacements and
adaptabilities of recognition elements, especially a side
chain in position i+2, can be exploited for a structure based
design of highly specific inhibitors.
(61.7 mg, 0.162 mmol) was dissolved in CH2Cl2 (79 mL). A solution of
Grubbs’ 2nd generation catalyst (6.7 mg, 4.9 mol%) in CH2Cl2 (2 mL)
was added while stirring. The solution was heated to reflux for 4 h, then
it was allowed to cool down to room temperature. After addition of silica
gel the solvent was removed in vacuo and the crude product adsorbed to
the silica gel was purified by column chromatography (hexanes/ethyl ace-
tate 2:1 ! 1:1), furnishing 8c as a yellow oil (51.5 mg, 90%). Rf = 0.27
(hexanes/ethyl acetate 1:2); [a]2D2 = ꢀ61.4 (c = 0.5, CHCl3); 1H NMR
(360 MHz, CDCl3; rotamers and broadened signals were observed): d =
1.46 (s, 9H, Boc), 1.75–1.84 (m, 1H, CH2), 1.86–1.94 (m, 1H, CH2), 2.00
(ddd, 1H, J=14.7, 7.2, 4.8 Hz, CH2), 2.35–2.42 (m, 2H, CH2), 2.54 (ddd,
1H, J=11.4, 6.7, 4.5 Hz, CH2), 2.66–2.96 (m, 2H, CH2), 3.39–3.51(m,
2H, CH2), 3.56–3.68 (m, 2H, CH2), 3.69 (s, 3H, OCH3), 3.96–4.07 (m,
1H, CH2), 4.30 (d, 0.3H, J=17.0 Hz, CaH2), 4.57 (d, 0.7H, J=17.0 Hz,
CaH2), 5.38–5.51(m, 1H, C =CH), 5.79–5.89 (m, 0.3H, C=CH), 5.94–6.04
(m, 0.7H, C=CH); 13C NMR (90 MHz, CDCl3; rotamers were observed):
d = 22.5, 22.6, 27.7 (CH2), 28.7 (Boc CH3), 28.8, 40.9, 47.4, 48.7, 49.2,
49.6, 49.9, 52.1( CH2 and OCH3), 70.7 (spiro C), 79.2 (Boc Cq), 125.5,
128.6 (C=C), 154.7, 155.0 (Boc C=O), 170.3, 173.5 (ester, lactam C=O);
IR (neat): n˜ = 2974, 1750, 1704, 1687, 1649 cmꢀ1; EIMS: m/z: 352 [M +];
elemental analysis calcd (%) for C18H28N2O5 ꢂ0.25H2O: C 60.57, H 8.05,
N 7.85; found: C 60.79, H 8.16, N 7.66.
Experimental Section
Methods and materials: Reagents and solvents were obtained from com-
mercial sources unless stated otherwise, and were used as received. Reac-
tions were carried out under nitrogen atmosphere except aminolysis,
Troc cleavage and ester hydrolysis. Column chromatography was per-
formed using 60 mm silica gel from Merck. For TLC silica gel 60 F254
plates from Merck were used (UV, I2 or ninhydrin detection). Melting
temperatures were determined on a Buechi 510 apparatus and are uncor-
(R)-(1-tert-Butoxycarbonyl-6-oxo-1,7-diazaspiro
A
acetic acid N-methylamide (13): A methylamine solution (8m in ethanol,
6318
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Chem. Eur. J. 2006, 12, 6315 – 6322

Reverse Turn Mimics
FULL PAPER
2 mL) was added while stirring to 8c (19.3 mg, 0.0545 mmol) on an ice
bath. After 45 min at 08C and 1.75 h at room temperature the solvent
was removed in vacuo and the residue was purified by flash chromatogra-
phy (hexanes/ethyl acetate 1:2 ! 0:1), furnishing 13 as a colorless solid
(18.4 mg, 96%). M.p. 69–728C; Rf = 0.32 (CH2Cl2/methanol 95:5); [a]D25
= 63.8 (c = 1.0, CHCl3); 1H NMR (600 MHz, CDCl3, 220 K): d = 1.46
155.6 (Boc C=O), 170.4, 175.3 (amide and lactam C=O); IR (neat): n˜ =
3336, 2971, 2932, 1686, 1637 cmꢀ1; IR (2 mm, CHCl3): n˜ = 3455 (w), 3368
(s) cmꢀ1 EIMS: m/z: 365 [M +]; elemental analysis calcd (%) for
;
C19H31N3O4: C 62.44, H 8.55, N 11.50; found: C 62.39, H 8.63, N 11.48.
(R)-3-(1-tert-Butoxycarbonyl-6-oxo-1,7-diazaspiro[4.6]undec-9-en-7-yl)-
propionic acid N-methylamide (15): Colorless gum; Rf = 0.18 (CH2Cl2/
methanol 95:5); [a]2D4 0.5, CHCl3); 1H NMR (360 MHz,
32.0 (c
AHCTREUNG
(s, 9H, Boc), 1.90–1.97 (m, 1H, C3’Ha), 2.01(ddd, 1H,
J=12.2, 6.8,
=
=
3.5 Hz, C4’Ha), 2.06–2.12, 2.08 (m and dd, 2H, J=14.6, 8.2 Hz, C3’Hb,
C12’Hb), 2.41–2.46 (m, 2H, C9’H2), 2.60–2.65 (m, 1H, C4’Hb), 2.81(d, 3H,
J=4.6 Hz, NCH3), 3.10 (ddd, 1H, J=16.1, 3.1, 3.1 Hz, C8’Hb), 3.42, 3.45
(d and dd, 2H, J=16.8, 14.6, 7.4 Hz, C2H2 and C12’Ha), 3.50 (ddd, 1H, J=
10.7, 7.6, 3.5 Hz, C2’H2), 3.56 (ddd, 1H, J=10.7, 8.9, 7.2 Hz, C2’H2), 4.65
(brd, 1H, J=16.8 Hz, C2H2), 5.16 (bddd, 1H, J=16.1, 10.7, 5.9 Hz,
C8’Ha), 5.57–5.65 (m, 2H, HC10’=C11’H), 7.56 (q, 1H, J=4.6 Hz, NH);
13C NMR (90 MHz, CDCl3): d = 23.5 (C3’H2), 26.2 (NCH3), 28.5 (Boc
CH3), 28.6 (C9’H2), 34.3 (C12’H2), 39.0 (C4’H2), 46.8 (C8’H2), 48.1( C2’H2),
53.2 (C2H2), 70.1(spiro C), 80.1(Boc Cq), 124.2 (C11’H), 128.7 (C10’H),
154.9 (Boc C=O), 169.5 (amide C=O), 174.0 (lactam C=O); IR (neat): n˜
CDCl3): d = 1.46 (s, 9H, Boc), 1.78–1.90 (m, 2H, CH2), 1.95–2.09 (m,
2H, CH2), 2.18–2.24 (m, 2H, CH2), 2.65 (ddd, 1H, J=13.2, 11.3, 4.2 Hz,
CH2), 2.81(d, 3H, J=4.6 Hz, NCH3), 3.17 (ddd, 1H, J=13.5, 11.3,
2.7 Hz, CH2), 3.36–3.59 (m, 4H, CH2), 4.25 (ddd, 1H, J=13.5, 4.2,
4.2 Hz, CH2), 4.38 (ddd, 1H, J=15.0, 6.1, 1.7 Hz, CH2), 6.05 (dddd, 1H,
J=9.4, 7.7, 5.5, 1.7 Hz, C=CH), 6.12–6.20 (m, 1H, C=CH), 7.37 (brs, 1H,
NH); 13C NMR (90 MHz, CDCl3): d
= 23.5, 26.6 (CH2, NCH3), 28.7
(Boc CH3), 32.8, 36.0, 37.6, 47.5, 48.6, 51.4 (CH2), 69.8 (spiro C), 80.0
(Boc Cq), 131.0, 132.1 (C=C), 155.0 (Boc C=O), 173.6, 174.8 (amide,
lactam C=O); IR (neat): n˜ = 3338, 2976, 1691, 1671, 1655, 1633 cmꢀ1; IR
(2 mm, CHCl3): n˜ = 3459 (w), 3358 (s) cmꢀ1; EIMS: m/z: 351[ M +].
= 3357, 2974, 2930, 1670, 1633 cmꢀ1; IR (2 mm, CHCl3): n˜ = 3352 cmꢀ1
;
(R)-(1-Acetyl-6-oxo-1,7-diazaspiro[4.6]undec-9-en-7-yl)acetic acid methyl
G
EIMS: m/z: 351[ M +]; elemental analysis calcd (%) for C18H29N3O4 ꢂ
ester: Compound 8b (39.6 mg, 0.117 mmol) was dissolved in CH2Cl2
(1mL) and treated with TFA/CH 2Cl2 (1:1, 1 mL) while cooling with an
ice bath. After 30 min the solvent was removed, the residue was re-dis-
solved in CH2Cl2 and evaporated to dryness. After addition of CH2Cl2
(1mL) and DIPEA (60.0 mL, 0.350 mmol), the mixture was cooled with
an ice bath and treated with acetyl chloride in CH2Cl2 (10%, 100 mL,
0.141 mmol). The mixture was stirred at room temperature for 3.5 h,
whereupon another portion of acetyl chloride solution (10%, 50 mL,
0.0703 mmol) was added and stirring was continued for 14.5 h. Subse-
quently, the mixture was diluted with CH2Cl2 (3 mL), washed with aque-
ous HCl (1n, 2 mL), and the aqueous phase was re-extracted with
CH2Cl2 (3ꢂ2 mL). The combined organic layers were dried with MgSO4,
evaporated to dryness and the residue was purified by column chroma-
tography (CH2Cl2/methanol 98:2 ! 95:5), furnishing the title compound
as an almost colorless viscous oil (30.0 mg, 91%). Rf = 0.20 (CH2Cl2/
methanol 95:5); [a]2D4 = ꢀ59.6 (c = 0.25, CHCl3); 1H NMR (360 MHz,
CDCl3): d = 1.87–2.10, 2.05 (m and s, 7H, CH2 and acetyl CH3), 2.23–
2.35 (m, 1H, CH2), 3.51–3.83, 3.61, 3.72 (m, d, s, 8H, J=17.4 Hz, CH2,
NCH2, C2H2, OCH3), 4.30 (dd, 1H, J=15.4, 5.1 Hz, NCH2), 4.78 (d, 1H,
J=17.4 Hz, C2H2), 5.98–6.08 (m, 2H, HC=CH); 13C NMR (90 MHz,
CDCl3): d = 23.69, 23.73 (CH2, acetyl CH3), 33.1, 36.7, 48.1, 49.7 (CH2),
52.1, 52.6 (OCH3, CH2), 70.4 (spiro C), 128.5, 130.8 (C=C), 169.6, 170.4
0.25H2O: C 60.74, H 8.35, N 11.81; found: C 60.77, H 8.24, N 11.37.
Starting from 4a,b and from 5a,c,d, respectively, compounds 11, 12, 14,
and 15 were prepared analogously:
(R)-(1-tert-Butoxycarbonyl-6-oxo-1,7-diazaspiro
acid N-methylamide (11): Colorless oil; Rf
ACHTREUNG
=
95:5); [a]2D2 = 47.8 (c = 0.5, CHCl3); 1H NMR (600 MHz, CDCl3): d =
1.44 (s, 9H, Boc), 1.85–1.95 (m, 2H, CH2), 2.09–2.15 (m, 1H, CH2), 2.43–
2.48 (m, 1H, CH2), 3.52 (d, 3H, J=4.7 Hz, NCH3), 3.27 (d, 1H, J=
16.8 Hz, C2H2), 3.52 (ddd, 1H, J=10.5, 7.1, 4.7 Hz, C2’H2), 3.60 (ddd, 1H,
J=10.5, 7.3, 7.3 Hz, C2’H2), 3.87 (ddd, 1H, J=18.1, 3.0, 2.1 Hz, C8’H2),
4.09 (ddd, 1H, J=18.1, 3.0, 2.1 Hz, C8’H2), 5.02 (d, 1H, J=16.8 Hz,
C2H2), 5.64 (ddd, 1H, J=10.2, 2.1, 2.1 Hz, C=CH), 5.80 (ddd, 1H, J=
10.2, 3.0, 3.0 Hz, C=CH), 7.67 (brs, 1H, NH); 13C NMR (90 MHz,
CDCl3): d = 23.9, 26.3 (CH2, NCH3), 28.7 (Boc CH3), 39.4, 48.3, 49.8
(CH2), 62.2 (spiro C), 80.6 (Boc Cq), 120.7, 128.7 (C=C), 155.1 (Boc C=
O), 168.6, 170.6 (amide, lactam C=O); IR (neat): n˜ = 3338, 2975, 1753,
1670 (b), 1657 cmꢀ1 (shoulder); IR (2 mm, CHCl3): n˜
= ;
3337 cmꢀ1
EIMS: m/z: 223 [M +ꢀBoc], [M +] not observed, elemental analysis calcd
(%) for C16H25N3O4: C 59.43, H 7.79, N 12.99; found: C 59.49, H 7.76, N
12.98.
(R)-(1-tert-Butoxycarbonyl-6-oxo-1,7-diazaspiro[4.6]undec-9-en-7-yl)ace-
N
(ester and amide C=O), 174.6 (lactam C=O); IR (neat): n˜
1634 cmꢀ1; EIMS: m/z: 280 [M +].
= 2952,
tic acid N-methylamide (12): Colorless gum; Rf = 0.18 (CH2Cl3/methanol
95:5); [a]2D4 = 27.5 (c = 0.2, CHCl3); 1H NMR (600 MHz, CDCl3): d =
1.46 (s, 9H, Boc), 1.84 (ddd, 1H, J=11.9, 7.4, 3.4 Hz, C4’Ha), 1.87–1.94
(m, 1H, C3’H2), 2.00–2.05 (m, 1H, C3’H2), 2.12 (dd, 1H, J=14.2, 7.7 Hz,
(R)-(1-Acetyl-6-oxo-1,7-diazaspiro
methylamide (16): Starting from (R)-(1-acetyl-6-oxo-1,7-diazaspiro-
[4.6]undec-9-en-7-yl)acetic acid methyl ester, the compound was pre-
A
C
11’Hb), 2.24–2.29 (m, 1H, C4’Hb), 2.82 (d, 3H, J=4.5 Hz, NCH3), 3.36,
ACHTREUNG
3.37, 3.36–3.40 (dd, d, m, 3H, J=14.7, 7.6, 16.8 Hz, C8’Hb, C2H2, C11Ha),
3.50–3.57 (m, 2H, C2’H2), 4.56 (ddd, 1H, J=14.7, 6.4, 1.5 Hz, C8’Ha), 5.09
(d, 1H, J=16.8 Hz, C2H2), 6.11–6.15 (m, 1H, C10’H), 6.24–6.28 (m, 1H,
pared analogously to 13 to yield a colorless oil that partially solidifies
upon standing. Rf = 0.37 (CH2Cl2/methanol 9:1); [a]2D3 = 43.6 (c = 0.5,
CHCl3); 1H NMR (600 MHz, CDCl3): d = 1.91 (ddd, 1H, J=12.5, 7.0,
3.4 Hz, C4’Ha), 2.01–2.08 (m, 1H, C3’Ha), 2.09 (dd, s, 4H, J=14.1, 7.6 Hz,
C9’H), 7.69 (brss, 1H, NH); 13C NMR (90 MHz, CDCl3): d
= 23.4
(C3’H2), 26.2 (NCH3), 28.5 (Boc CH3), 32.5 (C11’H2), 37.4 (C4’H2), 45.7
(C8’H2), 48.4 (C2’H2), 55.2 (C2H2), 69.5 (spiro C), 80.3 (Boc Cq), 131.0
(C9’H), 132.5 (C10’H), 155.2 (Boc C=O), 169.3 (amide C=O), 175.2
(lactam C=O); IR (neat): n˜ = 3344, 2978, 2881, 1668, 1635 cmꢀ1; IR
(2 mm, CHCl3): n˜ = 3340 cmꢀ1; ESI-MS: m/z: 337.1[ M +]; elemental
analysis calcd (%) for C17H27N3O4 ꢂH2O: C 57.45, H 8.2, N 11.82; found:
C 57.48, H 7.87, N 11.84.
C
11’Hb, acetyl CH3), 2.17 (m, 1H, C3’Hb), 2.33 (dddd, 1H, J=12.5, 10.6,
7.4, 1.7 Hz, C4’Hb), 2.83 (d, 3H, J=4.9 Hz, NCH3), 3.38, 3.39 (dd, d, J=
14.7, 7.6, 16.8 Hz, C8’Hb, C2H2), 3.46 (dddd, 1H, J=14.1, 5.8, 1.7, 1.7 Hz,
C
11’Ha), 3.65 (ddd, 1H, J=9.9, 7.6, 2.8 Hz, C2’Ha), 3.70 (ddd, 1H, J=9.9,
9.6, 6.8 Hz, C2’Hb), 4.61(ddd, 1H, J=14.7, 6.4, 1.9 Hz, C8’Ha), 5.04 (d,
1H, J=16.8 Hz, C2H2), 6.13–6.17 (m, 1H, C=C10’H), 6.28–6.33 (m, 1H,
C=C9’H), 7.69 (brs, 1H, NH); 13C NMR (90 MHz, CDCl3): d
= 23.3
(acetyl CH3), 24.1( C3’H2), 26.4 (NCH3), 31.7 (C11’H2), 37.1( C4’H2), 45.8
(C8’H2), 49.6 (C2’H2), 55.4 (C2H2), 70.3 (spiro C), 131.6 (C=C9’), 132.3 (C=
C10’), 169.2, 170.0 (2ꢂamide C=O), 174.7 (lactam C=O); IR (neat): n˜ =
3324, 2951, 1671, 1624 cmꢀ1; IR (2 mm, CHCl3): n˜ = 3337 cmꢀ1; EIMS:
m/z: 279 [M +]; elemental analysis calcd (%) for C14H21N3O3 ꢂ0.25H2O:
C 58.32, H 7.69, N 14.57; found: C 58.45, H 7.39, N 14.67.
(R)-(1-tert-Butoxycarbonyl-6-oxo-1,7-diazaspiro
acetic acid N-methylamide (14): Colorless crystals; M.p. 1768C; Rf
A
=
0.17 (CH2Cl2/methanol 95:5); [a]2D5 = ꢀ70.2 (c = 0.5, CHCl3); 1H NMR
(360 MHz, CDCl3; strongly broadened signals were observed): d = 1.47
(s, 9H, Boc), 1.67–1.92 (m, 3H, CH2), 2.04–2.64 (m, 6H, CH2), 2.77 (d,
3H, J=4.6 Hz, NCH3), 2.94–3.12 (m, 1H, CH2), 3.23–3.94 (m, 5H, CH2),
4.05–4.25 (m, 1H, CH2), 5.68 (ddd, 1H, J=9.8, 9.8, 7.2 Hz, C=CH), 5.87–
6.15 (m, 1H, C=CH), 6.63 (brs, 1H, NH); 13C NMR (90 MHz, CDCl3; ro-
tamers were observed): d = 22.6, 22.7, 23.2, 26.3, 26.4 (CH2, NCH3),
28.6, 28.7 (Boc CH3), 35.9, 37.3, 45.8, 48.3, 52.1, 52.3 (CH2), 71.3, 71.7
(spiro C), 79.6, 79.7 (Boc Cq), 128.7, 129.0, 131.1, 132.0 (C=C), 155.4,
(R)-(1-Ethyl-6-oxo-1,7-diazaspiro[4.6]undec-9-en-7-yl)acetic acid methyl
A
ester: Compound 8b (42.0 mg, 0.124 mmol) was dissolved in CH2Cl2
(1mL) and treated with TFA (0.5 mL) while cooling with an ice bath.
After stirring for 5 min at this temperature and 30 min at room tempera-
ture, the solvent was removed and the residue was dried thoroughly.
Chem. Eur. J. 2006, 12, 6315 – 6322
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6319

P. Gmeiner et al.
After dissolving the crude product in DMF (2 mL) and transferring the
solution to a sealed tube, Na2CO3 (39.0 mg, 0.368 mmol) and ethyl bro-
mide (28.0 mL, 0.375 mmol) were added and the mixture was heated to
808C for 2.25 h and 608C for 14 h under nitrogen. After cooling down,
water and saturated aqueous Na2CO3 were added and the mixture was
extracted with Et2O (4ꢂ). The combined organic layers were dried with
MgSO4, concentrated and the residue was purified by column chromatog-
raphy (CH2Cl2/methanol/dimethylethylamine 95:4:1), furnishing the title
compound as a colorless oil (11.1 mg, 34%). Rf = 0.26 (CH2Cl2/methanol
2:1); [a]2D4 = ꢀ16.5 (c = 0.2, CHCl3); 1H NMR (360 MHz, CDCl3; broad-
ened signals were observed): d = 1.12 (dd, 3H, J=7.1, 7.1 Hz, CH2CH3),
1.74–1.93 (m, 3H, CH2), 2.22 (brd, 1H, J=17.7 Hz, CH2CH3), 2.31–2.38
67.7, 68.4 (C2), 74.6, 75.3 (Cl3CCH2), 95.0, 95.8 (Cl3C), 119.5, 119.6 (C=
CH2), 132.6, 132.7 (C=CH2), 152.4 (carbamate C=O), 174.0, 174.7 (ester
C=O); IR (neat): n˜ = 3079, 2954, 2883, 1744, 1720, 1639 cmꢀ1; EIMS:
m/z: 345, 343, 347 [M +]; elemental analysis calcd (%) for C12H16Cl3NO4 ꢂ
0.25H2O: C 41.28, H 4.76, N 4.01; found: C 41.22, H 4.94, N 3.90.
(R)-N-(2,2,2-Trichloroethoxycarbonyl)-2-allylproline (4d): (R)-N-(2,2,2-
Trichloroethoxycarbonyl)-2-allylproline methyl ester (2.20 g, 6.38 mmol)
was dissolved in methanol (30 mL), and aqueous NaOH (2n, 30 mL) was
added while stirring thoroughly. After heating the mixture to 508C for
2.5 h, water (5 mL) was added and methanol was evaporated under re-
duced pressure (408C, 95 mbar). The remaining solution was washed with
diethyl ether (2ꢂ20 mL), adjusted to pH<1by addition of hydrochloric
acid (5n) and extracted with diethyl ether (2ꢂ10 mL). The combined or-
ganic layers were dried with MgSO4, concentrated and purified by
column chromatography (CH2Cl2/HCOOH 95:5), furnishing 4d as a pale
yellow viscous oil (1.72 g, 81%). Rf = 0.24 (CH2Cl2/HCOOH 95:5); [a]D22
(m, 1H, CH2), 2.44–2.53 (m, 1H, CH2), 2.61(brd, 1H,
J=17.7 Hz,
CH2CH3), 2.76–2.86 (m, 2H, CH2), 3.00–3.07 (m, 1H, CH2), 3.94–4.04,
4.00 (m, d, 2H, J=17.4 Hz, CH2, C2H2), 4.07–4.15 (m, 1H, CH2), 4.29 (d,
1H, J=17.4 Hz, C2H2), 5.72–5.79 (m, 1H, C=CH), 5.82–5.88 (m, 1H, C=
CH); 13C NMR (90 MHz, CDCl3): d = 14.3 (CH2CH3), 21.3, 32.1, 33.5
(CH2), 44.4, 50.0, 50.5 (NCH2), 52.3, 52.8 (OCH3, CH2), 78.0 (spiro C),
1
= 21.8 (c = 1.0, CHCl3); H NMR (360 MHz, CDCl3; rotamers were ob-
served): d = 1.84–2.03 (m, 2H, C4H2), 2.11–2.32 (m, 2H, C3H2), 2.64–
2.72 (m, 1H, allyl CH2), 3.07–3.16 (m, 1H, allyl CH2), 3.48, 3.53 (2ddd,
1H, J=10.6, 7.4, 7.4 Hz; 10.6, 7.5, 7.5 Hz, NCH2), 3.78, 3.80 (2ddd, 1H,
J=10.6, 7.2, 4.9 Hz; 10.6, 7.4, 4.9 Hz, NCH2), 4.73, 4.77, 4.80, 4.80 (4d,
2H, J=11.9, 11.0, 11.9, 11.0 Hz, Cl3CCH2), 5.14–5.20 (m, 2H, C=CH2),
5.65–5.81(m, 1H, C H=C), 10.50 (brs, 1H, COOH); 13C NMR (90 MHz,
CDCl3; rotamers were observed): d = 22.5, 22.9, 35.5, 37.3, 37.5, 38.8,
48.8, 49.6 (CH2), 67.4, 68.6 (C2), 74.9, 75.3 (Cl3CCH2), 95.0, 95.5 (Cl3C),
119.9, 120.0 (C=CH2), 132.0, 132.3 (C=CH2), 152.3, 153.1 (carbamate C=
125.2, 128.7 (C=C), 170.0, 175.4 (C=O); IR (neat): n˜
=
2962, 1749,
1645 cmꢀ1; EIMS: m/z: 266 [M +].
(R)-(1-Ethyl-6-oxo-1,7-diazaspiro
methylamide (17): Starting from (R)-(1-ethyl-6-oxo-1,7-diazaspiro-
[4.6]undec-9-en-7-yl)acetic acid methyl ester, the compound was pre-
pared analogously to 13 to yield a pale yellow oil. Rf = 0.12 (CH2Cl2/
methanol 1:1); [a]D24 0.1, CHCl3); 1H NMR (360 MHz,
G
ACHTREUNG
=
ꢀ151 (c
=
CDCl3, 2 mm; broadened signals were observed): d = 1.08–1.23 (m, 3H,
CH2CH3), 1.80–2.06 (m, 3H, CH2), 2.26 (brd, 1H, J=16.8 Hz, CH2CH3),
2.32–2.51(m, 2H, C H2), 2.58 (brd, 1H, J=16.8 Hz, CH2CH3), 2.68–3.23,
2.78 (m, d, 6H, J=4.3 Hz, CH2, NCH3), 3.79 (d, 1H, J=15.3 Hz, C2H2),
3.93–4.32, 4.28 (m, brd, 3H, J=15.3 Hz, CH2, C2H2), 5.77–5.90 (m, 2H,
HC=CH), 6.38 (brs, 1H, NH); IR (neat): n˜ = 3411, 3321, 2925, 1668
O), 178.0, 179.8 (COOH); IR (neat):n˜ = 3077, 2980, 2883, 1718 cmꢀ1
;
EIMS: m/z: 331, 329, 333 [M +]; elemental analysis calcd (%) for
C11H14Cl3NO4 ꢂ0.5H2O: C 38.90, H 4.45, N 4.12; found: C 39.08, H 4.27,
N 4.01.
(S)-N-Allyl-O-(2,6-dichlorobenzyl)tyrosine methyl ester: To a solution of
(S)-O-(2,6-dichlorobenzyl)tyrosine methyl ester[10d] (2.00 g, 5.12 mmol) in
DMF (20 mL) was added DIPEA (1.75 mL, 10.2 mmol), followed by allyl
bromide (1.08 mL, 12.8 mmol) while stirring at room temperature. After
2 h, water (20 mL) was added and the mixture was extracted with Et2O
(3ꢂ20 mL).[10e] The combined organic layers were washed with brine
(20 mL), dried with MgSO4, concentrated, and the residue was purified
by flash chromatography (hexanes/ethyl acetate 9:1 ! 3:1), yielding the
title compound as a pale yellow oil (1.62 g, 80%). Rf = 0.18 (hexanes/
ethyl acetate 2:1); [a]D24 = 16.1 (c = 2.0, CHCl3); 1H NMR (360 MHz,
CDCl3): d = 1.58 (brs, 1H, NH), 2.92 (d, 2H, J=6.7 Hz, C3H2), 3.12
(dddd, 1H, J=13.9, 6.0, 1.3, 1.3 Hz, allyl CH2), 3.27 (dddd, 1H, J=13.9,
6.0, 1.3, 1.3 Hz, allyl CH2), 3.53 (t, 1H, J=6.7 Hz, C2H), 3.66 (s, 3H,
OCH3), 5.07 (dddd, 1H, J=10.2, 1.9, 1.3, 1.3 Hz, CH=CH2), 5.13 (dddd,
1H, J=17.2, 1.9, 1.3, 1.3 Hz, CH=CH2), 5.25 (s, 2H, OCH2), 5.82 (dddd,
1H, J=17.2, 10.2, 6.0, 6.0 Hz, CH=CH2), 6.93–6.97 (m, 2H, CHaryl), 7.10–
7.14 (m, 2H, CHaryl), 7.22–7.26 (m, 1H, CHaryl), 7.35–7.37 (m, 2H,
CHaryl); 13C NMR (90 MHz, CDCl3): d = 38.9 (CH2), 50.6 (OCH3), 51.6
(CH2), 62.1( CaH), 65.3 (OCH2), 115.0, 116.4, 128.5, 129.9, 130.2, 130.4,
132.2, 136.1, 137.0, 157.8 (Caryl, C=C), 175.0 (C=O); IR (neat): n˜ = 3332,
3076, 2948, 2840, 1736, 1643 cmꢀ1; EIMS: m/z: 393, 395 [M +]; elemental
analysis calcd (%) for C20H21Cl2NO3: C 60.92, H 5.37, N 3.55; found: C
60.79, H 5.33, N 3.51.
(shoulder), 1647 cmꢀ1; IR (2 mm, CHCl3): n˜ = 3450 (s), 3375 (w) cmꢀ1
;
EIMS: m/z: 265 [M +]; HRMS: m/z: calcd for C14H23N3O2: 265.1790;
found: 265.1790.
(R)-N-(2,2,2-Trichloroethoxycarbonyl)-2-allylproline methyl ester: Acetyl
chloride (8.60 mL, 121 mmol) was added slowly to methanol (50 mL)
while thoroughly stirring on an ice bath. After 5 min a solution of
(2R,5R)-5-(2-propenyl)-2-trichloromethyl-1-aza-3-oxabicyclo-
A
and the ice bath was removed. After stirring at room temperature for
4.5 d, the solvent was removed in vacuo, the residue was re-dissolved in
methanol and evaporated to dryness. Hydrochloric acid (1n, 20 mL) was
added and the mixture was washed with diethyl ether (2ꢂ10 mL). The
pH of the mixture was gradually adjusted to 12 by addition of aqueous
NaOH (2n) and extracted with diethyl ether (4ꢂ10 mL). The combined
organic layers were dried with MgSO4, evaporated at 700 mbar and
added to an ice-cold methanolic HCl solution, freshly prepared from
acetyl chloride (2 mL, 28.1mmol) and methanol (10 mL). The solution
was evaporated almost to dryness and the hydrochloride of (S)-2-allyl-
proline methyl ester was precipitated by addition of diethyl ether and
dried thoroughly (2.30 g, ꢁ92%, crude).
A fraction of the crude product (2.00 g, ꢁ9.72 mmol) was dispersed in
CH2Cl2 (20 mL) and treated cautiously with DIPEA (5.00 mL,
29.2 mmol), followed by a solution of succinimidyl-(2,2,2-trichloroethyl)-
carbonate (Troc-OSu; 3.67 g, 12.6 mmol) in CH2Cl2 (10 mL). The mixture
was stirred at room temperature for 1.5 h, whereupon the solvent was re-
moved and the residue was purified by twofold column chromatography
(hexanes/ethyl acetate 4:1), furnishing the title compound as a pale
(2S,2’R)-N-Allyl-O-(2,6-dichlorobenzyl)-N-(1-[2,2,2-trichloroethoxycar-
bonyl]-2-allylpyrrolidin-2-ylcarbonyl)tyrosine methyl ester (7b): Com-
pound 4d (510 mg, 1.54 mmol) was dissolved in CHCl3 (5 mL) and tol-
uene (10 mL). After addition of DMF (10 mL), thionyl chloride (550 mL,
7.56 mmol) was added dropwise while stirring. After heating the mixture
to 608C for 1.25 h, the solvents were evaporated and the residue was
dried thoroughly. Subsequently, the crude material was dissolved in NMP
(10 mL). After addition of a solution of N-allyl-O-(2,6-dichlorobenzyl)-
tyrosine methyl ester (608 mg, 1.54 mmol) in NMP (5 mL) and DIPEA
(790 mL, 4.61mmol), the mixture was heated to 65 8C for 2.5 h. After
cooling down, saturated aqueous Na2CO3 (5 mL) and water (10 mL)
were added and the mixture was extracted with diethyl ether (1ꢂ10, 4ꢂ
5 mL). The combined organic layers were washed with aqueous citric
acid (5%, 10 mL), dried with MgSO4, evaporated and the residue was
purified by twofold column chromatography (1. hexanes/ethyl acetate/
yellow oil (2.40 g, 66%). Rf = 0.22 (hexanes/ethyl acetate 4:1); [a]D20
=
25.1( c = 1.0, CHCl3); 1H NMR (360 MHz, CDCl3; rotamers were ob-
served): d = 1.77–1.99 (m, 2H, C4H2), 2.04–2.26 (m, 2H, C3H2), 2.67,
2.69 (2dddd, 1H, J=14.3, 8.4, 0.9, 0.9 Hz; 14.3, 8.5, 0.9, 0.9 Hz, allyl
CH2), 3.12 (dddd, 1H, J=14.3, 6.4, 1.4, 1.4 Hz, allyl CH2), 3.48, 3.53
(2ddd, 1H, J=10.8, 7.4, 7.4 Hz; 10.6, 7.3, 7.3 Hz, NCH2), 3.72, 3.73 (2s,
3H, OCH3), 3.76–3.83 (m, 1H, NCH2), 4.69, 4.73, 4.75, 4.77 (4d, 2H, J=
11.9, 12.0, 11.9, 12.0 Hz, Cl3CCH2), 5.12–5.19 (m, 2H, C=CH2), 5.67–5.81
(m, 1H, CH=C); 13C NMR (90 MHz, CDCl3; rotamers were observed): d
= 22.5, 23.0, 35.6, 37.3, 37.8, 39.1, 48.5, 49.6, 52.5, 52.7 (CH2, OCH3),
6320
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Chem. Eur. J. 2006, 12, 6315 – 6322

Reverse Turn Mimics
FULL PAPER
HCOOH 78:20:2, 2. hexanes/ethyl acetate 3:1), furnishing 7b as a color-
(m, 1H, CHaryl), 7.33–7.36 (m, 2H, CHaryl); 13C NMR (90 MHz, CDCl3;
rotamers and broadened signals were observed): d = 22.3, 23.1( CH2),
28.6 (Boc CH3), 33.7, 34.7, 37.6, 44.9, 48.7, 52.2 (CH2, OCH3), 62.7, 63.4,
65.4, 69.6 (OCH2, C2H, spiro C), 79.5 (Boc Cq), 115.2, 125.8, 128.6, 129.5,
130.5, 130.8, 131.3, 132.4, 137.1 (Caryl, C=C), 154.6, 157.8 (Boc C=O, Caryl),
less gum (744 mg, 68%). Rf = 0.43 (hexanes/ethyl acetate1:1); [a]D19
=
ꢀ57.8 (c = 1.0, CHCl3); 1H NMR (600 MHz, CDCl3; broadened signals
were observed): d = 1.88–2.08 (m, 2H, CH2), 2.10–2.29 (m, 2H, CH2),
2.74 (dd, 1H, J=13.6, 7.7 Hz, C3H2), 2.97–3.22, 3.19 (m, dd, 2H, J=13.6,
6.5 Hz, CH2, C3H2), 3.33–3.72, 3.49, 3.60, 3.70 (m, dd, dd, s, 7H, J=13.9,
4.4; 11.2, 7.8 Hz, CH2, OCH3), 3.74–4.00 (m, 2H, CH2), 4.58 (d, 1H, J=
12.0 Hz, Cl3CCH2), 4.91(d, 1H, J=12.0 Hz, Cl3CCH2), 5.08–5.17 (m, 4H,
C=CH2), 5.25 (s, 2H, OCH2), 5.49–5.73 (m, 1H, CH=C), 5.81(dddd, 1H,
J=17.1, 11.1, 6.1, 6.1 Hz, CH=C), 6.91–6.97 (m, 2H, CHaryl), 7.16–7.24
(m, 3H, CHaryl), 7.35–7.38 (m, 2H, CHaryl); 13C NMR (90 MHz, CDCl3;
broadened signals were observed): d = 22.6, 34.6, 36.0, 40.4, 48.0, 49.3,
52.3 (CH2, OCH3), 65.6, 69.6, 69.9 (OCH2, C2H, C2’), 74.9 (Cl3CCH2),
95.9 (Cl3C), 115.1, 115.3, 119.3, 128.7, 130.5, 130.9, 132.4, 132.5, 133.4,
134.0, 137.2 (Caryl, C=C), 151.9, 157.8 (Caryl, carbamate C=O), 171.3, 171.8
171.7, 175.1 (ester, lactam C=O); IR (neat): n˜
= 2976, 1739, 1688,
1633 cmꢀ1; EIMS: m/z: 602 [M +]; elemental analysis calcd (%) for
C31H36Cl2N2O6: C 61.69, H 6.01, N 4.64; found: C 61.68, H 6.03, N 4.51.
AHCTREUNG
AHCTREUNG
(150 mg, 0.249 mmol) was dissolved in methanol (5 mL) and THF (1 mL)
and cooled with an ice bath. After addition of aqueous NaOH (2n,
5 mL), a precipitate formed which was re-dissolved by addition of THF
(2 mL). After stirring for 1.5 h at this temperature, methanol and THF
were evaporated (408C, 90 mbar), the remaining solution was diluted
with water, acidified to pH 4 with aqueous citric acid (5%) and extracted
with diethyl ether (3ꢂ5 mL). The combined organic layers were washed
with water (5 mL), dried with MgSO4, concentrated and the product was
dried thoroughly in vacuo, furnishing the title compound as a colorless
(ester, amide C=O); IR (neat): n˜
= 2951, 1739 (shoulder), 1719,
1644 cmꢀ1; EIMS: m/z: 704, 706, 708 [M +]; elemental analysis calcd (%)
for C31H33Cl5N2O6: C 52.67, H 4.71, N 3.96; found: C 52.51, H 4.74, N
3.89.
ACHTREUNG
solid (145 mg, 99%). M.p. 94–1018C; Rf
= 0.15 (CH2Cl2/methanol/
HCOOH 95:3:2); [a]2D2 = ꢀ150 (c = 1.0, CHCl3); 1H NMR (600 MHz,
[D5]pyridine, 380 K; broadened signals were observed): d = 1.50 (s, 9H,
Boc CH3), 1.61–1.69 (m, 1H, CH2), 1.77–1.83 (m, 1H, CH2), 1.98 (ddd,
1H, J=12.9, 6.4, 6.4 Hz, CH2), 2.12 (dd, 1H, J=16.1, 5.5 Hz, CH2), 2.35
(ddd, 1H, J=12.9, 7.4, 7.4 Hz, CH2), 3.24 (dd, 1H, J=13.8, 7.7 Hz, CH2),
3.58–3.63, 3.55, 3.65 (m, ddd, dd, 3H, J=10.2, 7.3, 5.0 Hz; 10.2, 7.7 Hz,
CH2), 3.72 (brd, 1H, J=16.1 Hz, CH2), 4.00–4.17 (m, 2H, CH2), 5.32 (s,
2H, OCH2), 5.68–5.86 (m, 3H, C2H, HC=CH), 7.05–7.13 (m, 3H, CHaryl),
7.28–7.31(m, 2H, C Haryl), 7.38–7.42 (m, 2H, CHaryl); 13C NMR (90 MHz,
CDCl3; broadened signals were observed): d = 23.3 (CH2), 28.6 (Boc
CH3), 32.2, 34.2, 37.1, 48.2, 48.6 (CH2), 65.45, 65.55, 69.5 (OCH2, C2H,
spiro C), 81.1 (Boc Cq), 115.3, 128.5, 130.2, 130.4, 130.5, 130.9, 131.2,
132.3, 137.0 (Caryl and C=C), 155.7, 157.7 (Boc C=O, Caryl), 171.3, 175.5
AHCTREUNG
ester (9b): Prepared from 7b (500 mg, 0.707 mmol) in CH2Cl2 (135 mL)
and Grubbsꢀ 2nd generation catalyst (30.0 mg, 5 mol%) in CH2Cl2
(5 mL) as described for 8c (reaction time: 30 min). Column chromatogra-
phy (hexanes/ethyl acetate 2:1) furnished 9b as a colorless solid (464 mg,
97%). M.p. 54–578C; Rf
= =
0.37 (hexanes/ethyl acetate 1:1); [a]D20
ꢀ62.8 (c
=
0.5, CHCl3); 1H NMR (360 MHz, CDCl3; rotamers and
broadened signals were observed): d = 1.83–2.20 (m, 4H, CH2), 2.28
(dddd, 1H, J=13.2, 7.9, 7.9 Hz, CH2), 2.97–3.09 (m, 1H, CH2), 3.28 (dd,
1H, J=14.3, 6.6 Hz, C3H2), 3.55–3.74, 3.70 (m, s, 7H, CH2, OCH3), 4.04
(ddd, 1H, J=16.6, 7.2, 1.1 Hz, CH2), 4.18 (d, 0.35H, J=11.8 Hz,
Cl3CCH2), 4.57 (d, 0.65H, J=11.9 Hz, Cl3CCH2), 4.88 (d, 0.65H, J=
11.9 Hz, Cl3CCH2), 5.08–5.18 (m, 1.35H, C2H, Cl3CCH2), 5.25 (s, 2H,
OCH2), 5.62–5.72 (m, 1H, C=CH), 5.82–5.90 (m, 1H, C=CH), 6.93–6.96
(m, 2H, CHaryl), 7.11–7.17 (m, 2H, CHaryl), 7.21–7.25 (m, 1H, CHaryl),
7.34–7.37 (m, 2H, CHaryl); 13C NMR (90 MHz, CDCl3; rotamers were ob-
served): d = 22.4, 23.1, 33.6, 34.5, 34.7, 35.0, 36.7, 37.7, 44.8, 48.4, 49.6,
52.2, 52.3 (CH2, OCH3), 62.4, 62.6, 65.5, 65.6, 70.1, 70.4 (C2H, OCH2,
spiro C), 74.8, 74.9 (Cl3CCH2), 96.0 (CCl3), 115.3, 126.6, 127.7, 128.6,
130.27, 130.33, 130.4, 130.5, 132.5, 137.2 (Caryl, C=C), 152.9, 153.4, 157.9
(Caryl, carbamate C=O), 171.5, 171.7, 174.0, 174.4 (ester and lactam C=
O); IR (neat): n˜ = 2952, 1737, 1719, 1633 cmꢀ1; EIMS: m/z: 676 [M +];
elemental analysis calcd (%) for C29H29Cl5N2O6: C 51.31, H 4.31, N 4.13;
found: C 51.50, H 4.32, N 3.95.
(lactam C=O, COOH); IR (neat): n˜
= ;
2975, 1733, 1685, 1653 cmꢀ1
APCI-MS: m/z: 589 [M ++H]; elemental analysis calcd (%) for
C30H34Cl2N2O6: C 61.12, H 5.81, N 4.75; found: C 61.08, H 6.00, N 4.61.
AHCTREUNG
AHCTREUNG
AHCTREUNG
=
(CH2Cl2/methanol/HCOOH 93:2:5); [a]2D2 = ꢀ90.3 (c = 1.0, CHCl3);
1H NMR (360 MHz, [D5]pyridine, 380 K): d = 1.43 (s, 9H, Boc CH3),
1.63–1.73 (m, 1H, CH2), 1.75–1.83 (m, 1H, CH2), 2.04–2.16 (m, 1H,
CH2), 2.41(ddd, 1H, J=12.4, 7.0. 5.2 Hz, CH2), 3.30 (dd, 1H, J=14.6,
8.5 Hz, CH2), 3.53 (ddd, 1H, J=10.2, 7.2, 7.2 Hz, CH2), 3.65 (dd, 1H, J=
14.6, 6.6 Hz, CH2), 3.78–3.86 (m, 1H, CH2), 4.04–4.08 (m, 2H, CH2), 5.31
(s, 2H, OCH2), 5.56–5.60 (m, 1H, C2H), 5.63 (ddd, 1H, J=10.0, 3.2,
3.2 Hz, C=CH), 5.72 (ddd, 1H, J=10.0, 1.3, 1.3 Hz, C=CH), 7.04–7.08
(m, 2H, CHaryl), 7.11–7.13 (m, 1H, CHaryl), 7.27–7.30 (m, 2H, CHaryl),
7.40–7.44 (m, 2H, CHaryl); 13C NMR (90 MHz, CDCl3; rotamers and
strongly broadened signals were observed): d = 22.8, 23.6 (CH2), 28.0,
28.5 (Boc CH3), 28.2, 29.7, 33.6, 38.6, 48.1( CH2), 62.5, 63.3, 65.4, 65.5,
66.1(O CH2, C2H, spiro C), 80.0, 81.2 (Boc Cq), 115.0, 115.4, 121.0, 127.5,
128.5, 129.6, 129.9, 130.0, 130.4, 130.9, 131.0, 132.3, 137.0 (Caryl, C=C),
153.7, 154.9, 157.6, 157.8 (Boc C=O, Caryl), 170.6, 171.0 (lactam C=O,
COOH); IR (neat): n˜ = 3361, 2925, 1736, 1693, 1656 cmꢀ1; EIMS: m/z:
575, 574 [M +]; elemental analysis calcd (%) for C29H32Cl2N2O6: C 60.53,
H 5.60, N 4.87; found: C 60.40, H 5.78, N 4.86.
ACHTREUNG
ACHTREUNG
Compound 9b (300 mg, 0.442 mmol) was dissolved in acetic acid
(10 mL). Zinc dust (600 mg in 6 portions) was added during 2.5 h while
stirring vigorously. After complete addition, stirring was continued for
1h, whereupon the mixture was filtered through Celite and the residue
was rinsed thoroughly with acetic acid. The filtrate was concentrated in
vacuo, dispersed in water (5 mL) and treated with saturated aqueous
Na2CO3 (5 mL). The mixture was extracted with diethyl ether (1ꢂ5, 4ꢂ
3 mL), the combined organic layers were dried with MgSO4, evaporated
to dryness and dried thoroughly. Subsequently, the residue was dissolved
in a solution of Boc2O (156 mg, 0.715 mmol) in CH2Cl2 (5 mL). After stir-
ring for 6 h, another portion of Boc2O (312 mg, 1.43 mmol) in CH2Cl2
(2 mL) was added and stirring was continued for 13 h, whereupon the
solvent was removed and the residue was purified by column chromatog-
raphy (hexanes/ethyl acetate 2:1), furnishing 10b as a colorless solid
(251mg, 94%). M.p. 58–60 8C; Rf = 0.31(hexanes/ethyl acetate 1:)1;
[a]2D4 = ꢀ80.4 (c = 0.5, CHCl3); 1H NMR (600 MHz, CDCl3, 330 K; ro-
tamers and broadened signals were observed): d = 1.41 (s, 9H, Boc
CH3), 1.74–2.10, 2.06 (m, dd, 4H, J=15.3, 7.0 Hz, CH2), 2.21(ddd, 1H,
J=12.7, 7.6, 7.6 Hz, CH2), 3.04 (dd, 1H, J=13.4, 8.1 Hz, CH2), 3.25 (dd,
1H, J=14.4, 6.4 Hz, CH2), 3.37–3.73, 3.58, 3.68 (m, ddd, s, 7H, J=10.4,
7.4, 7.4 Hz, CH2, OCH3), 3.88–4.47 (m, 1H, CH2), 5.04–5.13 (m, 1H,
C2H), 5.24 (s, 2H, OCH2), 5.68–5.75 (m, 1H, C=CH), 5.84–5.91(m, 1H,
C=CH), 6.91–6.94 (m, 2H, CHaryl), 7.15–7.18 (m, 2H, CHaryl), 7.20–7.23
Peptide synthesis: Commercially available PAM (4-hydroxymethyl)phe-
nylacetamide) resin preloaded with Boc-Leu was deprotected using TFA/
CH2Cl2/indole (50:50:0.1; 20 min), followed by neutralization with 10%
DIPEA in CH2Cl2 followed by several washes with CH2Cl2. Boc-Ile-OH,
the carboxylic acids derived from 10a,b, and Boc-Arg(Tos)-OH were
R
coupled according to the following procedure: HATU (3–5 equiv) and
the carboxylic acid (3–5 equiv) were dissolved in NMP (least volume pos-
sible). After addition of DIPEA (6–10 equiv) the mixture was added to
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6321

P. Gmeiner et al.
the resin and agitated for 8–16 h, followed by several CH2Cl2 washes. If
possible, complete acylation was monitored with the Kaiser Test. When
c) T. Hoffmann, R. Waibel, P. Gmeiner, J. Org. Chem. 2003, 68, 62–
69.
the test indicated incomplete coupling or when Boc-Arg
A
[5] A. Wittelsberger, M. Keller, L. Scarpellino, L. Partiny, H. Acha-
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coupled to the secondary amino group of the spirocyclic templates, re-
spectively, the procedure was repeated. After deprotection with TFA
(20 min), the next coupling cycle was started. Upon completion, the N-
termini were deblocked (TFA) and the HF cleavage from the resin using
anisole as the scavenger (HF/anisole 9:1, 2 h, 08C;) was performed. HF
was evaporated and the resin was washed with tert-butyl methyl ether.
The pure peptides were obtained by extraction of the resin with acetic
acid, followed by lyophilization and purification via preparative HPLC
(gradient elution: 5–35% CH3CN + 0.1% TFA/H2O + 0.1% TFA) on
a ZORBAX 300SB-C18 PrepHT (21.2ꢂ250 mm, 7 mm) column.
[6] T. Hoffmann, H. Lanig, R. Waibel, P. Gmeiner, Angew. Chem. 2001,
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This work was supported by the Deutsche Forschungsgemeinschaft, and
the Fonds der Chemischen Industrie. L. Lomlim and I. Torres-Berger are
acknowledged for helpful discussions and technical assistance.
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Received: March 29, 2006
Published online: May 26, 2006
6322
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ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6315 – 6322