Stereoselective Synthesis of Tricyclic Diproline Analogues that Mimic a PPII Helix: Structural Consequences of Ring-Size Variation

Article abstract of DOI:10.1002/ejoc.201402737

Polycyclic proline-derived scaffolds (ProMs) have recently demonstrated their value as conformationally defined dipeptide analogs for the modular construction of secondary structure mimetics, specifically interfering with PPII helix-mediated protein-protein interactions. We disclose the stereoselective synthesis of two new tricyclic amino acid scaffolds (ProM-4 and ProM-8) that differ from the first generation scaffold ProM-1 by the size of ring A. Conformational preferences and subtle structural differences of the three homologous scaffolds were analyzed by X-ray crystallography, computational calculations, and NMR spectroscopy. N-tert-butoxycarbonyl(Boc)-3-(1-propenyl)azetidine-2-carboxylic acid was prepared from L-aspartic acid through β-lactam intermediates. The corresponding piperidine-based building block rac-N-Boc-3-vinylpipecolic acid was synthesized by Cu-catalyzed 1,4-addition of vinyl-MgBr to methyl N-Boc-2,3-dehydropipecolate. Target molecules were prepared through peptide coupling of the respective ring A building blocks with cis-5-vinylproline tert-butyl ester and subsequent ring-closing metathesis. Selective deprotection of a tert-butyl carbamate (N-Boc protecting group) in the presence of a tert-butyl ester was achieved with trifluoroacetic acid at 0 C. Two new tricyclic amino acid scaffolds, which differ from the first generation scaffold by the size of ring A, were stereoselectively synthesized. The conformational analysis of the three homologous scaffolds was revealed by NMR spectroscopy.

Full text of DOI:10.1002/ejoc.201402737

FULL PAPER
DOI: 10.1002/ejoc.201402737
Stereoselective Synthesis of Tricyclic Diproline Analogues that Mimic a PPII
Helix: Structural Consequences of Ring-Size Variation
Arne Soicke,[a] Cédric Reuter,[a] Matthias Winter,[a] Jörg-Martin Neudörfl,[a]
Nils Schlörer,[a] Ronald Kühne,*[b] and Hans-Günther Schmalz*[a]
Keywords: Amino acids / Peptidomimetics / Helical structures / Conformation analysis / Metathesis / Nitrogen heterocycles
Polycyclic proline-derived scaffolds (ProMs) have recently
demonstrated their value as conformationally defined di-
peptide analogs for the modular construction of secondary
structure mimetics, specifically interfering with PPII helix-
mediated protein–protein interactions. We disclose the
stereoselective synthesis of two new tricyclic amino acid
scaffolds (ProM-4 and ProM-8) that differ from the first gen-
eration scaffold ProM-1 by the size of ring A. Conformational
preferences and subtle structural differences of the three
acid was prepared from L-aspartic acid through β-lactam in-
termediates. The corresponding piperidine-based building
block rac-N-Boc-3-vinylpipecolic acid was synthesized by
Cu-catalyzed 1,4-addition of vinyl-MgBr to methyl N-Boc-
2,3-dehydropipecolate. Target molecules were prepared
through peptide coupling of the respective ring A building
blocks with cis-5-vinylproline tert-butyl ester and subse-
quent ring-closing metathesis. Selective deprotection of a
tert-butyl carbamate (N-Boc protecting group) in the pres-
homologous scaffolds were analyzed by X-ray crystallogra- ence of a tert-butyl ester was achieved with trifluoroacetic
phy,computationalcalculations,andNMRspectroscopy.N-tert-
acid at 0 °C.
butoxycarbonyl(Boc)-3-(1-propenyl)azetidine-2-carboxylic
Introduction
The selective modulation of protein-protein interactions
by means of synthetic small molecules represents a chal-
lenging research task at the interface of chemistry, biology
and medicine.[1] In this context, protein domains specialized
in recognition of so-called proline-rich motifs (PRMs) have
recently attracted attention as potential drug targets.[2] To
be recognized by their specific binding domains, PRMs
must adopt a left-handed polyproline type 2 (PPII) helix
secondary structure.[3] Recently, we envisioned that suitable
interface inhibitors could possibly be developed by replac-
ing flexible Pro-Pro units of proline-rich peptide chains by
synthetic diproline analogs (“ProMs”) rigidified in a PPII
helix conformation.[4] After inspecting molecular models we
devised and stereoselectively synthesized tricyclic scaffold
Figure 1. The diproline analog ProM-1 and its lower and higher
homologs ProM-8 and ProM-4, respectively, as tricyclic scaffolds
rigidified in a PPII helix conformation.
During investigations we learned, however, that not all
1a (ProM-1), in which a vinylidene unit bridges two proline diproline units of a PRM can just be replaced by 1a and
rings such that the system is forced to adopt an almost per- that, following our approach, the development of efficient
fect PPII helix conformation (Figure 1). And indeed, we and selective ligands for specific PRM-binding domains will
found that a Pro-Pro unit within a PRM peptide, which require a combination of different ProMs with various con-
specifically binds to the Fyn-SH3 domain, could be substi- formational and steric features.[5] Consequently, we were in-
tuted by 1a without loss of binding affinity.[4a]
terested in the lower and higher homologues of 1a, i.e. azet-
idine- and piperidine-based scaffolds 2a (ProM-8) and 3a
(ProM-4), respectively, which differ from 1a (ProM-1) only
in the size of the “eastern” heterocyclic ring (ring A). We
here report the stereoselective synthesis of fluorenylmethyl-
oxycarbonyl (Fmoc)-protected scaffolds 2b and 3b as well
as the conformational analysis of these tricyclic ring sys-
tems based on data from X-ray crystallography, NMR spec-
troscopy and quantum chemical calculations.
[a] Department of Chemistry, University of Cologne,
Greinstrasse 4, 50939 Köln, Germany
E-mail: schmalz@uni-koeln.de
www.schmalz.uni-koeln.de
[b] Leibniz Institute for Molecular Pharmacology (FMP),
Robert-Roessle-Strasse 10, 13125 Berlin, Germany
www.fmp-berlin.info/research/structuralbiology/
researchgroups/kuehne/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402737.
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Results and Discussion
Synthetic Strategy
with tert-butyldimethylsilyl (TBS) chloride to give 10 on a
15-gram scale. Screening of different Grignard reagents (R-
MgCl; R = tBu, Bu, Et, iPr) revealed that the cyclization
of 10 was most efficiently achieved with tBuMgCl to afford
β-lactam 11 in 68% yield after (a first) chromatographic
purification.[6,7] Hydrogenolytic cleavage of the benzyl ester
(H2, Pd/C) and subsequent trans-diastereoselective allyl-
ation of carboxylic acid 12 (through dianion formation) af-
forded 13 in good overall yield (dr Ͼ 95:5).[6a,8]
Although treatment of 13 with diazomethane in Et2O/
MeOH afforded methyl ester 14 in high yield, various
attempts to convert β-lactams 13 or 14 into the correspond-
ing azetidine derivative through amide reduction (deoxy-
We decided to follow a similar strategy for the synthesis
of 1b[4] by building up the tricyclic scaffolds 2b and 3b,
respectively, through peptide coupling and subsequent ring-
closing metathesis (Scheme 1).[5] Therefore, a crucial chal-
lenge of the present study was the stereoselective synthesis
of the required building blocks of type 4, 6 and 7.
Synthesis of the Azetidine Building Block 4
The synthesis of N-tert-butoxycarbonyl-(Boc-)protected genation)[9] failed. We tried a variety of reagents such as
azetidine building block 4 (Scheme 2) began with conver- LiAlH4,[10] diisobutylaluminium hydride (DIBAL-H),[11]
sion of inexpensive l-aspartic acid (8) into β-lactam 13 by LiEt3BH[12] and AlH2Cl (generated from DIBAL-H and
following the route of Baldwin.[6] For this purpose, 8 was AlCl3)[13] under different conditions, but this resulted either
first converted into its dibenzyl ester, which was isolated as in the opening of the four-membered ring or afforded an
crystalline hydro tosylate 9. After treatment with aqueous inseparable mixture of products. Therefore, we decided to
K2CO3 the (sensitive) free amine was directly N-protected change the N-protecting group. Cleavage of the TBS group
Scheme 1. Strategy for the synthesis of compounds of type 1–3.
Scheme 2. Synthesis of azetidine building block 4. Reagents and conditions: (a) BnOH, pTsOH, benzene, 105 °C, 8 h; (b) K2CO3, CH2Cl2;
(c) TBSCl, DMAP, Et3N, CH2Cl2, room temp., 16 h; (d) tBuMgCl, Et2O, room temp., 16 h; (e) H2, Pd/C, THF, room temp., 24 h; (f) LDA
(2.2 equiv.), allyl bromide, THF, room temp., 3 h, KHSO4 (aq.); (g) CH2N2, MeOH, room temp., 1 h; (h) CsF, MeOH, room temp., 1 h;
(i) Boc2O, DMAP, Et3N, CH2Cl2, room temp., 16 h; (j) LiBEt3H, THF, –78 °C, 1 h; (k) BF3·OEt2, Et3SiH, CH2Cl2, –78 °C, 3 h; (l) LiAlH4,
THF, room temp., 76 h; (m) Boc2O, CH2Cl2, room temp., 6 h; (n) RhCl3·3H2O, EtOH, reflux, 16 h; (o) TEMPO, BAIB, NaHCO3, H2O/
MeCN, room temp., 3 h; (p) Jones reagent, acetone, room temp., 3 h.
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Synthesis of Tricyclic Diproline Analogues that Mimic a PPII Helix
with cesium fluoride gave 15 from which N-Boc derivative 1,4-vinylation (1.5 equiv. of vinyl-MgBr, 0.2 equiv. of
16 was obtained under standard conditions. Attempts to CuBr·SMe2, –35 °C, 6 h) afforded desired trans-product
convert 16 into azetidine 17 by subsequent treatment with rac-23 in 32% isolated yield after separation of the minor
LiEt3BH and Et3SiH only resulted in the formation of an cis-isomer (and side products resulting from 1,2-addition to
acyclic amino alcohol. However, the desired azetidine was the ester group) by column chromatography. Finally, the es-
finally obtained by reduction of unprotected β-lactam 15 ter was hydrolyzed with LiOH in H2O/THF/MeOH at
[10a,10b]
with 4 equiv. of LiAlH4
followed by N-Boc protec- 50 °C to afford carboxylic acid building block rac-6 without
tion. On a small scale, product 17 was obtained in 57% epimerization at C2.
yield (over 2 steps) but lower yields (12–36%) were ob-
served when the reaction sequence was repeated on a multi
mmol scale. Nevertheless, with substantial amounts of 17
in hand, completion of the synthesis could be attempted.
Isomerization of the allyl to a propenyl side chain was
achieved in 91% yield by treatment of 17 with RhCl3 tri-
hydrate (10 mol-%) in EtOH[14] to afford 18 (E/Z = 3.1:1).
The final oxidation of the alcohol functionality with Jones
reagent gave acid 4 in moderate yield (40%) after chromato-
graphic purification. As an alternative, oxidation of 18 was
performed by using the protocol of Epp and Widlandski[15]
that uses catalytic amounts of 2,2,6,6-tetramethyl-1-piperid-
inyloxy (TEMPO) in the presence of 2 equiv. of bis(acetoxy)
iodobenzene (BAIB)[16] in 1:1 MeCN/H2O (62% yield). In
this case, no chromatographic purification was required as,
after basic extraction, carboxylic acid 4 was obtained in
pure form. The trans-configuration was confirmed by 2D
NMR spectroscopy (H,H-COSY, NOESY).
Figure 2. Structure of 22 (top) and rac-6 (bottom) in the crystalline
state; the bond lengths and angles around the N atom of 6 are
shown separately.
Synthesis of Piperidine Building Block rac-6
The required trans-configuration of rac-6 was confirmed
by X-ray crystal structure analysis (Figure 2). Interestingly,
both C-bound substituents at the aza-cyclohexane chair de-
mand an axial position in this case (to minimize repulsive
steric interactions) whereas the carbamate C–N bond
clearly exhibits double bond character, with a C–N bond
length of 1.35 Å. The angular sum (359.2°) indicates almost
perfect planar geometry at the nitrogen center.
In analogy to our synthesis of 3-vinylproline deriva-
tives[4b] we decided to synthesize corresponding piperidine
system 6 through Cu-catalyzed 1,4-addition of vinylmagne-
sium bromide to a N-protected dehydroamino acid interme-
diate.[17] By starting from racemic pipecolic acid (rac-19)
double protected derivative rac-21 was prepared through
methyl ester formation (MeOH, SOCl2) and N-Boc protec-
tion (Boc2O, Et3N) (Scheme 3). Without purification, prod-
uct rac-21 was obtained in nearly quantitative yield and
then converted into dehydro derivative 22 by applying the
bromination/elimination protocol of Kublitskii and
Trukhan.[18] Thus, after α-lithiation of rac-21 with lithium
Synthesis of Pyrolidine Building Block 7
cis-Vinylproline building block 7, required for both
bis(trimethylsilyl)amide (LiHMDS) in tetrahydrofuran ProM-4 and ProM-8, was synthesized according to a strat-
(THF) at –30 °C, bromination at –90 °C and final elimi- egy developed in our laboratory (Scheme 4).[4b] A crucial
nation of the unstable bromo intermediate (by stirring with step of this synthesis is the conversion of nitrile 24, which
aqueous citric acid), α,β-unsaturated ester 22 was obtained is readily prepared in three steps from (S)-proline (23), into
in 71% isolated yield, and its structure was confirmed aldehyde 25. In the original procedure, 24 was stirred with
by X-ray crystallography (Figure 2). The Cu-catalyzed Raney-Ni under an atmosphere of hydrogen in slightly basic
Scheme 3. Synthesis of building block rac-6. Reagents and conditions: (a) SOCl2, MeOH, room temp., 16 h; (b) Boc2O, Et3N, dioxane/
H2O, room temp., 8 h; (c) LiHMDS, THF, –30 °C, 3.5 h; (d) Br2, –90 °C, 1 h to room temp., then citric acid H2O, 30 min; (e) vinyl-MgBr,
CuBr·SMe2, THF, –35 °C, 6 h, then NH4Cl, H2O; (f) column chromatography; (g) LiOH, THF/MeOH/H2O, 50 °C, 5 h.
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Scheme 4. Synthesis of building block 7. Reagents and conditions: (a) tBuOH, Boc2O, Et3N, room temp., 4 h; DMAP, room temp., 16 h;
HCl (1 n), 50 °C, 1 h; (b) –2 e–, 260 mA, MeOH, Bu4NBF4, 0 °C, 2.32 Fmol–1; (c) TMSCN, TMSOTf (1 vol.-%), CH2Cl2, –40 °C, 1.5 h;
(d) H2, Raney-Ni, Py/AcOH/H2O, 50 °C, 5 h; (e) KHMDS, Ph3PCH3Br, THF, room temp. 1 h, then –78 °C to room temp., 2.5 h;
(f) TMSOTf, CH2Cl2, 0 °C, 5 min; (g) separation of diastereomers by column chromatography.
medium (pyridine, water, acetic acid) at 80 °C to afford the Synthesis of Tricyclic Scaffold 3b (Fmoc-ProM-4)
product after 72 h in only moderate yield (51%) as a 1.7:1
(cis/trans) mixture of diastereomers. By bubbling a con-
tinuous flow of hydrogen through the reaction mixture and
by lowering the temperature to 50 °C the reaction pro-
By employing building blocks rac-6 and 7 the synthesis
of 3b (Fmoc-ProM-4) was performed in a similar fashion
as described above for the synthesis of 2b (Scheme 6). Thus,
ceeded faster and product 25 was obtained after only 5 h in
PyBOP coupling of rac-6 with 7 cleanly afforded 28 as an
higher yield (61%) and with significantly improved dia-
expected mixture of diastereomers, which could not be sep-
arated. However, subsequent ring-closing metathesis (by
stereoselectivity (cis/trans = 3:1).
The conversion of the aldehyde into a vinyl side chain
using 20 mol-% of Grubbs II catalyst) proceeded smoothly,
was achieved in 90% yield through Wittig reaction by using
and the two diastereomeric tricyclic products were readily
separable by column chromatography. Thus, both isomers,
i.e. 3c and dia-3c, were isolated in pure form in 42% yield
each.
The relative configuration of 3c and dia-3c, respectively,
was unambiguously assigned by X-ray crystallography (see
Figure 3), which also revealed the preferred conformation
of the tricyclic scaffolds.
oven-dried Ph3PCH3Br and KHMDS to afford 26, still as
a mixture of diastereomers (cis/trans = 4:1). After selective
cleavage of the N-Boc protection group with trimethylsilyl
trifluoromethanesulfonate (TMSOTf), the diastereomers
could be separated by column chromatography and desired
cis-3-vinylproline ester 7 was obtained as a pure dia-
stereomer in 43% isolated yield on a multi-gram scale.
By having successfully constructed the ring system of
ProM-4 with the correct configuration, the final conversion
of 3c into Fmoc-protected derivative 3b was performed (in
Synthesis of Tricyclic Scaffold 2b (Fmoc-ProM-8)
The synthesis of ProM-8 (as its Fmoc derivative 2b) was 81% yield) by following the established procedure
concluded as shown in Scheme 5. Building blocks 4 and 7 (Scheme 6).
were connected through peptide coupling [by using (benzo-
We also converted diastereomeric cyclization product
triazol-1-yloxy)tripyrrolidinophosphonium hexafluoro- dia-3c into corresponding Fmoc derivative dia-3b under
phosphate (PyBOP)] to give dipeptide 27 in 78% yield. Af- standard conditions (Scheme 7). Of note, we found that se-
ter treatment of 27 with 10 mol-% of Grubbs II catalyst in lective cleavage of the N-Boc group is also possible in the
CH2Cl2 at reflux temperatures, the tricyclic product 2c was presence of the tert-butyl ester function. Thus, when dia-3c
obtained in 46% yield. The yield of the ring closing metath- was treated with an excess TFA at 0 °C (instead of at room
esis reaction could not be significantly improved by increas- temp) for 1 h followed by Fmoc-protection of deprotected
ing the amount of catalyst, by prolonging the reaction time, intermediate 29, ester dia-3d was obtained in 76% yield.
or by running the reaction at lower temperature. The final
To probe whether TFA-mediated selective cleavage of a
conversion of 2c into 2b was achieved by following our N-Boc carbamate in the presence of a tert-butyl ester func-
standard procedure[4b] by global deprotection [with tri- tion can also be applied to other substrates, we chose l-N-
fluoroacetic acid (TFA)] and subsequent Fmoc-protection Boc tert-butylproline 30 as a model substrate, which had
of the amino function to afford target compound 2b in 76% served as an intermediate in the synthesis of building block
yield.
7 (see Scheme 4). And indeed, treatment of 30 with an ex-
Scheme 5. Synthesis of 2b (Fmoc-ProM-8). Reagents and conditions: (a) PyBOP, DIPEA, MeCN, room temp., 16 h; (b) Grubbs II catalyst
(10 mol-%), CH2Cl2, reflux, 24 h; (c) TFA, CH2Cl2, room temp., 1 h; NaHCO3, Fmoc-Cl, THF, room temp., 16 h.
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Synthesis of Tricyclic Diproline Analogues that Mimic a PPII Helix
Scheme 6. Synthesis of 3b (Fmoc-ProM-4). Reagents and conditions: (a) PyBOP, DIPEA, MeCN, room temp., 20 h; (b) Grubbs II catalyst
(20 mol-%), CH2Cl2, reflux, 48 h; (c) TFA, CH2Cl2, room temp., 1 h; NaHCO3, Fmoc-Cl, THF, room temp., 16 h.
cess of TFA in CH2Cl2 at 0 °C resulted in a clean transfor-
mation to afford amine 31 in 82% isolated yield (Scheme 8).
Scheme 8. Selective N-Boc deprotection of tert-butyl ester 30.
Conformational Analysis
As mentioned in the introduction, an important aspect
of the present study was to create a homologues series of
rigid scaffolds that mimic a diproline unit in the PPII helix
conformation (i.e. 1, 2 and 3), which differ slightly in their
geometry. By having successfully achieved the syntheses, we
next performed a careful conformational analysis to ident-
ify the structural consequences of ring-size variation. For
this purpose we calculated the energy minima of all possible
rotamers of N-Boc-protected tert-butyl esters 1c, 2c and 3c
by using TURBOMOLE 6.3[19] in combination with geom-
etry optimization (functional: TPSS; basis set: TZVPP) and
successive frequency calculations. As Figure 4 shows, the
calculated geometry of the tricyclic core structure of 1c al-
most perfectly matches the geometry of this compound in
Figure 3. Structure of tricyclic scaffolds 3c (top) and dia-3c (bot-
tom) in the crystalline state.
the crystalline state. Even the conformation of the Boc pro-
Scheme 7. Global deprotection or selective N-Boc cleavage of dia-3c by treatment with excess TFA at either 23 °C or 0 °C, respectively,
and subsequent Fmoc protection.
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tecting groups differs only slightly between the calculated the three structures, as indicated by the different exit vectors
and the X-ray structure of 1c.[20]
defined by the exocyclic N–C bond at ring A. Also, the
steric demand of the lipophilic part of ring A decreases in
the homologous series from 3c to 1c to 2c.
Another interesting aspect is the effect of the ring size on
the structural flexibility of the three systems as reflected by
their different NMR spectroscopic behavior. In contrast to
1c, which shows two major signal sets in the 1H NMR
(CDCl3, 300 MHz, 20 °C) spectrum that represents two dis-
tinct conformations (rotamers; ratio 2:1) along the C–N
bond of the N-Boc unit, the corresponding spectrum of
azetidine derivative 2c exhibits only a single set of signals.
This observation reflects a lower rotational barrier. In the
case of piperidine derivative 3c, the 1H NMR spectrum (300
or 600 MHz) at room temperature did not allow any assign-
ments because of severe signal broadening (coalescence)
and the presence of superimposed rotamer signals. How-
ever, at lower temperatures (below –30 °C) two major rota-
mers are detected (ratio 1:1.5). All in all it could be shown
that modified systems ProM-4 (3c) and ProM-8 (2c) exhibit
a slower conformational dynamic relative to original system
1c (ProM-1) with five-membered ring C.
Figure 4. Structure of 1c in the crystalline state (red) relative to the
calculated minimum conformation (blue).
To structurally compare three homologues compounds
1c, 2c, and 3c we superimposed the central amide units of
the calculated lowest energy conformers as shown in Fig-
ure 5. Obviously, the geometry of rings B and C (including
the tert-butyl ester side chain) is almost identical for all
three compounds, whereas subtle but significant deviations
emerge from the variation of the A-ring size. Most notably,
the twist of the pseudo-dipeptidic core structure differs in
Conclusions
In summary, we have elaborated stereoselective synthetic
routes to homo- and nor-proline derivatives 4 and rac-6,
to complete a homologues series of 3-vinylproline-related
building blocks, which were subsequently employed for the
construction of the new tricyclic scaffolds ProM-4 and
ProM-8 (as their Fmoc-protected derivatives 2b and 3b).
Like the original scaffold ProM-1, these compounds repre-
sent conformationally defined diproline mimetics, rigidified
in a PPII conformation. Subtle structural differences be-
tween the three scaffolds were identified by careful confor-
mational analysis (based on X-ray data and quantum chem-
ical calculations). In addition, differences in the conforma-
tional dynamics were revealed by NMR spectroscopic mea-
surements. The new scaffolds described here will be em-
ployed in future as modules of our ProM-based construc-
tion kit for the modeling-guided development of specific
small molecule interface inhibitors for (so far undruggable)
PPII-mediated protein–protein interactions.
Experimental Section
General: All oxygen- or moisture-sensitive reactions were carried
out under an argon atmosphere. All glassware was flame-dried un-
der vacuum before use and flushed with argon. Solids were added
under a continuous flow of argon. Syringes and cannulas were
flushed with argon before use. If not otherwise indicated, chemicals
were employed without further purification. All solvents were dried
and distilled before use. THF was distilled from sodium/benzo-
phenone under argon. Dichloromethane was distilled from calcium
hydride under argon. Dry acetonitrile was purchased from Acros
(99.5%, extra dry over molecular sieves). The concentration of
Grignard reagents was determined by titration against iodine dis-
solved in a solution of LiCl (0.5 m) in THF. NMR spectra were
Figure 5. Comparison of the (calculated) geometries of 1c, 2c, and
3c. The superimposed structures are shown from two different per-
spectives.
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Synthesis of Tricyclic Diproline Analogues that Mimic a PPII Helix
recorded at room temp with a Bruker DPX 300, Avance II 300,
DRX 500, Avance II+ 600. The spectra are reported by using the
following abbreviations to express the multiplicities: s = singlet, d
= doublet, t = triplet, dd = double doublet, td = triple doublet, tt
= triple triplet, ddd = double double doublet, qd = tetra doublet,
combined organic layers were washed with saturated aqueous
NaHCO3 and brine (1.2 L) and dried with MgSO4. After removal
of the solvent under reduced pressure succinate 10 was obtained as
yellow oil (116.0 g, 0.271 mol, 86%), which was used without fur-
ther purification. [α]2D0 = –18.4 (c = 0.930, CHCl3). Rf = 0.32 (Et2O/
1
m = multiplet, br. s = broad singlet. Most 13C NMR spectra were cyclohexane = 1:1). H NMR: (300 MHz, CDCl3): δ = 0.01; 0.13
recorded with a DeptQ or APT sequence with complete proton
decoupling. The non-trivial assignments are based on H,H-COSY,
HMQC, HMBC, NOESY and single proton NOE spectra. Prepar-
(2ϫs, 6 H, 7-H), 0.86 (s, 9 H, 9-H), 2.67–2.82 (m, 2 H, 3-H), 3.88–
3.96 (m, 1 H, 2-H), 5.06–5.17 (m, 4 H, 5-H), 7.26–7.35 (m, 10 H,
H-Ar) ppm. 13C NMR: (75 MHz, CDCl3): δ = –5.2; –3.7 (C7), 0.8
ative electrolysis was performed with a Voltcraft VLP-1602 Pro (C8), 25.9 (C9), 41.8 (C3), 52.5 (C2), 66.4; 66.7 (C5), 128.2–128.4
power supply and Didac-Tec 48ϫ28 mm graphite plate electrode.
Commercial methanol was used without further purification. IR
spectra were recorded in ATR mode (attenuated total reflection) at
room temp on a Paragon 100 FTIR spectrometer from Perkin–
Elmer. The absorptions are characterized by the abbreviations w
(weak), medium (m) strong (s). HRMS and low-resolution MS
were measured with a Finnigan MAT 900s (ESI). Melting points
were determined with a Büchi B-545 in open capillary tubes or
with a Wagner und Munz Mikro-Heiztisch System PolyTherm A.
Analytical thin layer chromatography was performed on silica
coated alumina plates that contained a fluorescent indicator, visual-
ized by UV light, by treatment with a cerium reagent [prepared
by dissolving phosphomolybdic acid (2 g) and Ce(SO4)2 (1 g) in a
mixture of concentrated H2SO4 (10 mL) and water (90 mL)] or with
a KMnO4 solution (0.5% solution in 1 m NaOH) followed by heat-
ing. Flash column chromatography was conducted by using either
silica gel DAVISIL®LC60A 40–63 μm from GRACE DIVISION
or Allox N for column chromatography 50–200 μm, Brockmann I
from ACROS. X-ray measurements were carried out with a Nonius
Kappa CCD diffractometer. Optical rotation was measured with a
Perkin–Elmer Polarimeter 343 with a cuvette path length of 10 cm.
Concentrations are given in g/100 mL of solvent.
(C-Ar ), 135.6 (C1, C4), 170.5 (C1), 174.3 (C4) ppm. IR: ν = 3381
˜
t
(w), 3031 (w), 2949 (s), 2852 (m), 1732 (s), 1596 (w), 1496 (m), 1454
(s), 1406 (m), 1378 (m), 1250 (s), 1210 (s), 1152 (s), 1026 (m), 1002
(s), 829 (s), 749 (s), 695 (s) cm–1. GC–MS (EI): m/z (%) = 428 (1),
412 (2), 370 (24), 292 (30), 178 (19), 91 (100), 57 (2).
Benzyl (S)-1-(tert-Butyldimethylsilyl)-4-oxoazetidine-2-carboxylate
(11):[6a] Under argon atmosphere dibenzyl aspartate 10 (44.2 g,
0.103 mol) was dissolved in Et2O (500 mL) and the solution was
cooled to 0 °C before tBuMgCl (56.5 mL, 0.113 mol, 2.0 m in Et2O)
was added dropwise over 45 min. The resulting yellow suspension
was stirred at room temp overnight before the mixture was
quenched at 0 °C with saturated aqueous NH4Cl (100 mL) and ex-
tracted with Et2O (2ϫ 200 mL). The combined organic layers were
washed with H2O (200 mL) and brine (200 mL), dried with MgSO4
and the solvent was removed under reduced pressure. The crude
product was purified by chromatography (SiO2, EtOAc/cyclohex-
ane = 1:3) to give β-lactam 11 (21.7 g, 0.070 mol, 68%) as a yellow
oil. [α]2D0 = –38.4 (c = 0.500, CHCl3) {ref.[6a] [α]2D0 = –61.2 (c = 1.550 ,
CHCl3)}. Rf = 0.61 (EtOAc/cyclohexane = 1:2). 1H NMR:
(300 MHz, CDCl3): δ = 0.06; 0.24 (2ϫs, 6 H, 8-H), 0.93 (s, 9 H,
10-H), 3.04/3.31 (2ϫm, 2 H, 3-H), 4.06 (m, 1 H, 2-H), 5.18 (s, 2
H, 6-H), 7.36 (s, 5 H, H-Ar) ppm. 13C NMR: (75 MHz, CDCl3): δ
= –6.4; –6.0 (C8), 18.4 (C9), 26.1 (C10), 43.9 (C3), 48.7 (C2), 67.2
(C6), 128.5–128.6 (C-Art), 134.9 (C7), 171.0 (C4), 172.0 (C5) ppm.
L
-Aspartic Acid Dibenzyl Ester p-Toluenesulfonate (9):[21] To l-as-
partic acid 8 (90.0 g, 0.676 mol) and benzyl alcohol (422 mL,
4.057 mol) in benzene (650 mL) was added p-toluenesulfonic acid
monohydrate (160.7 g, 0.845 mol) at 80 °C before heating the mix-
ture to reflux for 8 h under removal of water by means of a Dean–
Stark apparatus. After cooling to room temp the solvent was re-
moved under reduced pressure. The remaining white solid was
washed with methyl tert-butyl ether (MTBE; 3ϫ1 L) and dried for
8 h at 80 °C in vacuo to give sulfonate 9 (306.9 g, 0.630 mol, 93%)
IR: ν = 2946 (m), 2927 (m), 2855 (m), 1740 (s), 1496 (w), 1469 (m),
˜
1347 (m), 1275 (s), 1172 (s), 1076 (s), 1012 (s), 936 (m), 823 (s), 748
(s), 696 (s) cm–1. GC–MS (EI): m/z (%) = 320 (1), 262 (2), 91 (100),
57 (10).
(S)-1-(tert-Butyldimethylsilyl)-4-oxoazetidine-2-carboxylic
Acid
(12):[6a] To a solution of β-lactam 11 (25.3 g, 0.079 mol) in THF
(130 mL) was added Pd/C (2.0 g) and the mixture was intensively
stirred under an atmosphere of hydrogen (balloon) at room temp
for 24 h. The suspension was filtered with THF (150 mL) through
a short pad of Celite® and the solvent was removed under reduced
pressure to give carboxylic acid 12 (17.5 g, 0.076 mol, 96%) as a
as a white solid. [α]2D0 = +6.9 (c = 1.100 , CHCl3) {ref.[21] [α]2D0
=
+5.2 (c = 1.000 , CHCl3)}, m.p. 158 °C {ref.[21] 155–156 °C}. Rf =
1
0.54 (EtOAc/cyclohexane = 1:1). H NMR: (300 MHz, CDCl3): δ
= 2.25 (s, 3 H, 7-H), 3.00–3.20 (qd, J = 18.1, 4.7 Hz, 2 H, 3-H),
4.48 (s, 1 H, 4-H), 4.88–5.04 (m, 4 H, 5-H), 6.98 (d, J = 7.8 Hz, 2
H, 9-H), 7.16–7.25 (m, 10 H, H-Ar), 7.71 (d, J = 7.8 Hz, 2 H, 10-
H), 8.39 (br. s, 3 H, -NH3+) ppm. 13C NMR: (75 MHz, CDCl3): δ
= 21.3 (C7), 33.8 (C3), 49.6 (C2), 67.1; 68.2 (C5), 126.1 (C10),
126.2–128.4 (C-Art), 128.8 (C9), 134.5; 135.1 (C6), 140.2 (C11),
white solid, which was used without further purification. [α]2D0
=
–77.1 (c = 0.500, CHCl3) {ref.[6a] [α]2D0 = –71.7 (c = 1.030 , CHCl3)},
m.p. 142 °C {ref.[6a] 147–148 °C}. Rf = 0.38 (EtOAc/cyclohexane =
2:1). 1H NMR: (300 MHz, CDCl3): δ = 0.16; 0.30 (2ϫs, 6 H, 6-
H), 0.96 (s, 9 H, 8-H), 3.11 (dd, J = 15.3, 2.6 Hz, 1 H, 3-Hβ), 3.40
(dd, J = 15.3, 6.0 Hz, 1 H, 3-Hα), 4.07 (dd, J = 5.9, 2.7 Hz, 1 H,
2-H), 9.05 (br. s, 1 H, -COOH) ppm. 13C NMR: (75 MHz, CDCl3):
δ = –6.3; –6.6 (C6), 18.5 (C7), 26.1 (C8), 43.8 (C3), 48.6 (C2), 171.5
141.3 (C8), 167.9 (C1), 169.8 (C4) ppm. IR: ν = 3446 (w), 3026
˜
(m), 2948 (m), 1745 (s), 1731 (s), 1592 (m), 1529 (m), 1183 (m),
1126 (m), 1034 (s), 1010 (s), 695 (s) cm–1. GC–MS (EI): m/z (%) =
314 (1), 178 (32), 91 (100), 65 (16).
(C5), 180.0 (C4) ppm. IR: ν = 2922 (s), 2853 (s), 2706 (m), 2593
˜
Dibenzyl (S)-2-(tert-Butyldimethylsilylamino)succinate (10): Sulfon-
ate 9 (152.3 g, 0.314 mol) was dissolved in aqueous K2CO3 (1 m,
2 L) and the solution was extracted with CH2Cl2 (3ϫ1 L). The
combined organic layers concentrated in vacuo and the crude prod-
uct (yellow oil) was dissolved in CH2Cl2 (1.5 L). After addition
of TBSCl (43.7 g, 0.290 mol), 4-(dimethylamino)pyridine (DMAP;
1.7 g, 0.014 mol) and Et3N (88.5 mL, 0.635 mol) the mixture was
stirred for 16 h under argon before it was quenched with saturated
aqueous NH4Cl (1.2 L). After extraction with CH2Cl2 (1.5 L) the
(m), 2506 (m), 1734 (s), 1684 (s), 1464 (m), 1341 (s), 1315 (s), 1254
(s), 1215 (s), 1186 (s), 1104 (m), 1086 (m), 1022 (m), 1003 (m), 964
(m), 839 (s), 820 (s), 781 (s), 681 (m) cm–1.
(2S,3R)-3-Allyl-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carbox-
ylic Acid (13):[6a] Under an argon atmosphere, a Schlenk tube was
charged with carboxylic acid 12 (16.7 g, 0.073 mol) in THF
(100 mL) and the solution was cooled to 0 °C. A solution of lithium
diisopropylamide (LDA; 0.153 mol) in THF, freshly prepared in a
Eur. J. Org. Chem. 2014, 6467–6480
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6473

H.-G. Schmalz et al.
FULL PAPER
separate flask, was then added dropwise over 10 in through a can-
nula to give a deep red solution. After 15 min, allyl bromide
(13.9 mL, 0.160 mol) was added at 0 °C and the now pale yellow
solution was allowed to stir at room temp for 3 h. After addition
5.86 (tt, J = 13.6, 6.8 Hz, 1 H, 8-H) ppm. 13C NMR (mixture of
rotamers) (75 MHz, CDCl3): δ = 27.9 (C12), 31.8. (C7), 52.7 (C2),
54.2 (C3), 54.9 (C6), 84.0 (C11), 118.8 (C9), 132.2 (C8), 164.8
(C10), 169.6 (C4), 175.2 (C5) ppm. IR: ν = 3073 (w), 2978 (m),
˜
of aqueous KHSO4 (1 m, 700 mL), the mixture was extracted with 2926 (w), 1806 (vs.), 1749 (s), 1724 (vs.), 1640 (w), 1473 (m), 1436
EtOAc (700 mL). The organic phases were washed with aqueous
KHSO4 (1 m, 700 mL) and brine (700 mL), dried with MgSO4 and
concentrated under reduced pressure to give β-lactam 13 (15.5 g,
0.058 mol, 79%) as a white solid. [α]2D0 = –69.1 (c = 1.000, CHCl3)
{ref.[6a] [α]2D0 = –68.6 (c = 1.000 , CHCl3)}, m.p. 136 °C (2ϫEt2O/
hexane) {ref.[6a] 112–114 °C}. Rf = 0.48 (MeOH/CH2Cl2 = 1:30).
1H NMR: (300 MHz, CDCl3): δ = 0.13; 0.30 (2ϫs, 6 H, 9-H), 0.96
(s, 9 H, 11-H), 2.44–2.61 (m, 2 H, 6-H), 3.42 (m, 1 H, 3-H), 3.81
(m, 1 H, 2-H), 5.17 (t, J = 12.7 Hz, 2 H, 8-H), 5.74–5.88 (td, J =
16.9, 6.9 Hz, 1 H, 7-H), 8.77 (br. s, 1 H, -COOH) ppm. 13C NMR:
(75 MHz, CDCl3): δ = –6.4; –5.9 (C9), 18.6 (C10), 26.1 (C11), 32.4
(C6), 53.8 (C2), 56.9 (C3), 118.5 (C8), 133.1 (C7), 173.9 (C5), 178.1
(s), 1366 (vs.), 1318 (vs.), 1253 (s), 1203 (s), 1143 (vs.), 1076 (s),
1016 (s), 990 (m), 920 (m), 853 (m), 806 (w), 770 (s), 736 (w) cm–1.
GC–MS (EI): m/z (%) = 196 (4), 168 (3), 153 (2), 126 (14), 111
(15), 84 (6), 67 (29), 57 (100), 41 (36). HRMS (ESI): calcd. for [M
+ Na]+ 292.11554; found 284.11556.
Methyl (2S,3R)-3-Allyl-4-oxoazetidine-2-carboxylate (15): Methyl
ester 14 (14.0 g, 49.4 mmol) was dissolved in MeOH (500 mL). Af-
ter addition of CsF (11.3 g, 74.1 mmol) the mixture was stirred at
room temp for 1 h. After removal of the solvent under reduced
pressure the crude product was diluted with CH2Cl2 (500 mL) and
washed with aqueous solution of NaHCO3 (500 mL), distilled H2O
(500 mL) and brine (500 mL). The organic layer was dried with
MgSO4 and concentrated under reduced pressure to give amine 15
(7.8 g, 46.1 mmol, 93%) as a light brown oil, which was used with-
out further purification. [α]2D0 = –3.3 (c = 1.000, CHCl3). Rf = 0.33
(C4) ppm. IR: ν = 2927 (s), 2853 (s), 2593 (m), 1742 (s), 1703 (s),
˜
1640 (m), 1469 (m), 1413 (m), 1326 (s), 1253 (s), 1183 (s), 1153 (s),
1096 (s), 1068 (s), 1004 (m), 986 (m), 918 (s), 840 (s), 824 (s), 780
(s), 681 (s) cm–1.
1
(MeOH/CH2Cl2 = 1:30). H NMR: (300 MHz, CDCl3): δ = 2.41–
Methyl (2S,3R)-3-Allyl-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-
carboxylate (14): A solution of carboxylic acid 13 (15.5 g,
0.058 mol) in MeOH (150 mL) was cooled to 0 °C and a freshly
prepared solution of CH2N2 (450 mL, 0.250 mol–0.280 mol in
Et2O) was added carefully. The mixture was stirred at room temp
for 1 h. After careful removal of the solvent and all volatile com-
pounds the crude product was purified through a pad of silica
(EtOAc/cyclohexane = 1:2) to give β-lactam 14 (14.0 g, 0.049 mol,
86%) as a yellow oil. [α]2D0 = –49.3 (c = 1.000, CHCl3). Rf = 0.61
(EtOAc/cyclohexane = 1:4). 1H NMR: (300 MHz, CDCl3): δ =
0.09; 0.28 (2ϫs, 6 H, 10-H), 0.95 (s, 9 H, 12-H), 2.46–2.53 (m, 2
H, 7-H), 3.33–3.37 (dd, J = 9.0, 3.8 Hz, 1 H, 3-H), 3.75 (s, 3 H, 6-
H), 3.77 (d, J = 2.0 Hz, 1 H, 2-H), 5.11–5.19 (m, 2 H, 9-H), 5.74–
5.85 (m, 1 H, 8-H) ppm. 13C NMR: (75 MHz, CDCl3): δ = –6.4;
–5.9 (C10), 18.5 (C11), 32.4 (C7), 52.3 (C6), 54.0 (C2), 56.7 (C3),
2.59 (m, 2 H, 7-H), 3.32 (t, J = 6.7 Hz, 1 H, 3-H), 3.73 (s, 3 H, 6-
H), 3.87 (d, J = 1.7 Hz, 1 H, 2-H), 5.08–5.18 (t, J = 14.4 Hz, 2 H,
9-H), 5.72–5.85 (m, 1 H, 8-H), 6.76 (br. s, 1 H, -NH) ppm. 13C
NMR: (75 MHz, CDCl3): δ = 32.0 (C7), 52.4 (C6), 52.5 (C2), 56.4
(C3), 118.0 (C9), 133.0 (C8), 169.1 (C5), 171.5 (C4) ppm. IR: ν =
˜
3273 (m), 3073 (m), 2946 (m), 2846 (w), 1733 (s), 1653 (m), 1640
(m), 1540 (m), 1436 (m), 1363 (m), 1280 (m), 1263 (m), 1206 (s),
1106 (m), 1053 (m), 993 (m), 920 (m), 760 (m) cm–1. GC–MS (EI):
m/z (%) = 169 (1), 111 (48), 84 (20), 67 (100), 39 (34). HRMS (ESI):
calcd. for [M + Na]+ 192.06311; found 192.06253.
tert-Butyl (2S,3S)-3-Allyl-2-(hydroxymethyl)azetidine-1-carboxylate
(17): Under argon atmosphere β-lactam 15 (0.200 g, 1.182 mmol)
was dissolved in THF (3 mL) and cooled to 0 °C. After dropwise
addition of a LiAlH4 solution (5.9 mL, 5.91 mmol, 1 m in THF)
the mixture was stirred under an argon atmosphere at room temp
for 76 h and quenched at 0 °C with H2O (0.3 mL). After stirring
for 15 min aqueous NaOH (15 wt.-%, 0.3 mL) was added. Stirring
was continued for 15 min before addition of H2O (0.6 mL). After
stirring for further 30 min, the slurry was filtered with CH2Cl2
(10 mL) through a plug of Celite®. Removal of the solvent gave
a pale yellow oil (0.220 g), which was dissolved under an argon
atmosphere in CH2Cl2 (3 mL) and stirred with Boc2O (0.515 g,
2.360 mmol) at room temp for 6 h. After removal of the solvent
under reduced pressure the crude product was purified by
chromatography (SiO2, EtOAc/cyclohexane = 1:2) to give alcohol
17 (0.152 g, 0.669 mmol, 57%) as a light yellow oil. For reproduced
reactions on scales above 2 mmol up to 8 mmol the yield decreased
to 12–36%. [α]2D0 = –2.7 (c = 1.000, CHCl3). Rf = 0.41 (EtOAc/
118.2 (C9), 133.3 (C8), 172.6 (C5), 173.4 (C4) ppm. IR: ν = 2928
˜
(s), 2856 (s), 1749 (s), 1640 (m), 1470 (s), 1435 (s), 1390 (m), 1363
(s), 1280 (s), 1256 (s), 1200 (s), 1176 (s), 1153 (s), 1068 (s), 1026 (s),
1003 (m), 918 (s), 824 (s), 773 (s), 679 (s) cm–1. GC–MS (EI): m/z
(%) = 284 (2), 268 (1), 242 (1), 226 (92), 198 (6), 116 (100), 100
(95), 41 (19). HRMS (ESI): calcd. for [M + H]+ 284.16692; found
284.16764.
1-tert-Butyl 2-Methyl (2S,3R)-3-Allyl-4-oxoazetidine-1,2-dicarb-
oxylate (16): Methyl ester 14 (0.600 g, 2.112 mmol) was dissolved
in MeOH (21 mL) and CsF (0.481 g, 3.168 mmol) was added. The
mixture was stirred at room temp for 1 h before the solvent was
removed under reduced pressure. The crude product was dissolved
in CH2Cl2 (20 mL) and washed with aqueous NaHCO3 (10 mL),
H2O (10 mL) and brine (10 mL). The organic layer was dried with
MgSO4 and concentrated under reduced pressure to give a yellow
1
cyclohexane = 1:2). H NMR (mixture of rotamers) (300 MHz,
oil (0.340 g), which was dissolved in CH2Cl2 (4 mL) in an argon- CDCl3): δ = 1.45 (s, 9 H, 11-H), 2.30–2.31 (m, 3 H, 3-H, 6-H),
flushed Schlenk tube. Then, Boc2O (0.877 g, 4.022 mmol), Et3N
(0.28 mL, 2.011 mmol) and DMAP (0.246 g, 2.013 mmol) were
carefully added to give an orange solution (CAUTION: gas evol-
3.48–3.51 (m, 1 H, 4-Hβ), 3.72 (m, 2 H, 5-H), 3.84–3.89 (m, 1 H,
4-Hα), 3.98–4.10 (m, 1 H, 2-H), 4.10–4.20 (br. s, 1 H, -OH), 4.99–
5.05 (m, 2 H, H7), 5.59–5.73 (m, 1 H, H6) ppm. 13C NMR (mixture
ution!), which was stirred at room temp for 16 h before the solvent of rotamers) (75 MHz, CDCl3): δ = 27.7; 28.3 (C11), 30.8 (C3),
was removed under reduced pressure. The residue was purified by
chromatography (SiO2, EtOAc/cyclohexane = 1:2) to give β-lactam
16 (0.363 g, 1.348 mmol, 64%) as a yellow oil. [α]2D0 = –45.5 (c =
37.2 (C6), 52.0 (C4), 66.2 (C5), 68.8 (C2), 80.3 (C9), 116.8 (C8),
134.3 (C7), 152.4 (C9) ppm. IR: ν = 3410 (b), 3071 (w), 2973 (s),
˜
2928 (m), 2880 (m), 1738 (m), 1694 (s), 1667 (s), 1476 (s), 1408 (s),
1.000, CHCl3). Rf = 0.68 (EtOAc/cyclohexane = 1:2). 1H NMR 1364 (s), 1279 (s), 1252 (s), 1139 (s), 1085 (s), 1034 (s), 990 (s), 913
(mixture of rotamers) (300 MHz, CDCl3): δ = 1.50 (s, 9 H, 12-H),
2.43–2.67 (m, 2 H, 7-H), 3.25–3.31 (m, 1 H, 3-H), 3.80 (s, 3 H, 6- 196 (18), 171 (9), 57 (100). HRMS (ESI): calcd. for [M + Na]+
H), 4.11 (d, J = 2.9 Hz, 1 H, 2-H), 5.16–5.22 (m, 2 H, 9-H), 5.72– 250.14136; found 250.14020.
(s), 857 (s), 771 (s) cm–1. GC–MS (EI): m/z (%) = 227 (1), 211 (1),
6474
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6467–6480

Synthesis of Tricyclic Diproline Analogues that Mimic a PPII Helix
tert-Butyl (2S,3S)-2-(Hydroxymethyl)-3-(prop-1-en-1-yl)azetidine-1- MeOH (78 mL) was carefully added SOCl2 (7.3 mL, 0.101 mol) at
carboxylate (18): Under an argon atmosphere RhCl3·3H2O
0 °C over 1 h (CAUTION: gas evolution!). After stirring at room
(0.008 g, 0.030 mmol) was stirred in EtOH (2 mL) at 70 °C for temp for 16 h the solvent was removed under reduced pressure. The
30 min. Alcohol 17 (0.140 g, 0.616 mmol) in EtOH (1 mL) was
added to the reaction vessel. The mixture was heated to reflux for
16 h (reaction progress detected by GC–MS), cooled to room temp
white solid was washed with Et2O (5ϫ 70 mL) and dried overnight
under vacuo to give hydrochloride rac-20 (13.7 g, 0.076 mol, 99%)
1
as a white solid, m.p. 208–209 °C {ref.[22] 206–207 °C}. H NMR
and filtered with EtOAc (20 mL) through a plug of silica. The (300 MHz, [D6]DMSO): δ = 1.68–2.04 (m, 6 H, 3-H, 4-H, 5-H),
crude product was purified by chromatography (SiO2, EtOAc/cy- 2.88–3.19 (m, 2 H, 6-H), 3.74 (s, 3 H, 8-H), 4.05 (m, 1 H, 2-H),
clohexane = 1:2) to give propenyl alcohol 18 (0.128 g, 0.563 mmol, 9.65 (br. s, 2 H, -NH2+) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
91%) as a light yellow oil. [α]2D0 = –6.6 (c = 0.300, CDCl3). Rf =
= 21.5 (C4), 21.6 (C5), 26.0 (C3), 43.7 (C6), 53.2; 55.9 (C2, C8),
0.48 (EtOAc/cyclohexane = 1:2). 1H NMR (mixture of rotamers) 169.6 (C7) ppm. IR: ν = 3372 (m), 2946 (w), 2900 (w), 2700 (m),
˜
(300 MHz, CDCl3): δ = 1.46 (s, 9 H, 11-H), 1.60; 1.68 (2ϫd, J =
5.3 Hz, & 4.8 Hz, 3 H, 8-H, E/Z-ratio = 3.1:1), 2.84 (br. s, 1 H, 3-
H), 3.59–3.66 (m, 1 H, 4-Hβ), 3.71–3.74 (m, 2 H, 5-H), 3.87–3.99
2526 (m), 2413 (w), 1742 (s), 1630 (m), 1583 (w), 1433 (m), 1360
(w), 1330 (w), 1273 (m), 1225 (m), 1206 (m), 1080 (w), 1030 (m),
886 (m) cm–1. GC–MS (EI): m/z (%) = 143 (2), 128 (1), 100 (1), 84
(m, 1 H, 4-Hα), 4.13 (br. s, 1 H, -OH), 5.47–5.59 (m, 2 H, 6-H, 7- (100), 56 (34), 41 (7).
H) ppm. 13C NMR (mixture of rotamers) (75 MHz, CDCl3): δ =
13.2; 17.8 (C8), 28.3 (C11), 34.3 (C3), 52.6 (C4), 65.8 (C5), 69.5;
70.0 (C2), 80.4 (10), 126.8; 127.7 (C7), 129.7; 129.9 (C6), 157.4
1-tert-Butyl 2-Methyl (rac)-Piperidine-1,2-dicarboxylate (rac-21):[23]
To a solution of hydrochloride rac-20 (10.0 g, 0.056 mol) in diox-
ane/water (240 mL, 1:1) was added Boc2O (14.6 g, 0.067 mol) and
Et3N (18 mL, 0.128 mol). After stirring at room temp for 8 h and
acidification (HCl, 2 n) to pH 4 the mixture was extracted with
EtOAc (500 mL). The organic layer was washed with brine
(500 mL), dried with MgSO4 and concentrated under reduced pres-
sure to give pipecolic carboxylate rac-21 (13.5 g, 0.056 mol, 100%)
as a light yellow oil. Rf = 0.66 (EtOAc/cyclohexane = 1:4). 1H
NMR (300 MHz, CDCl3): δ = 1.16–1.65 (m, 14 H, 3-H, 4-H, 5-
Hβ, 11-H), 2.13–2.18 (m, 1 H, 5-Hα), 2.88; 3.92 (2ϫm, 2 H, 6-H),
3.69 (s, 3 H, 8-H), 4.69–4.85 (m, 1 H, 2-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 20.7 (C4), 24.7 (C5), 26.8 (C3), 28.2 (C11),
41.0; 42.0 (C6), 51.9 (C8), 53.7; 54.8 (C2), 79.8 (C10), 155.9 (C9),
(C9) ppm. IR: ν = 3421 (b), 2969 (m), 2928 (m), 2880 (m), 1740
˜
(m), 1697 (s), 1672 (s), 1477 (m), 1453 (m), 1391 (s), 1365 (s), 1275
(s), 1252 (s), 1140 (vs.), 1088 (m), 1038 (m), 965 (m), 931 (w), 856
(w), 772 (w) cm–1. GC–MS (EI): m/z (%) = 196 (3), 171 (2), 154
(8), 96 (34), 80 (9), 68 (30), 57 (100), 41 (65). HRMS (ESI): calcd.
for [M + Na]+ 250.14136; found 250.14128.
(2S,3S)-1-(tert-Butoxycarbonyl)-3-(prop-1-en-1-yl)azetidine-2-carb-
oxylic Acid (4). Method A: Propenyl alcohol 18 (0.200 g,
0.880 mmol), BAIB (0.624 g, 1.936 mmol), NaHCO3 (0.148 g,
1.760 mmol) and TEMPO (0.028 g, 0.176 mmol) were dissolved in
a mixture of H2O/MeCN (1:1, 8 mL) and stirred at room temp for
3 h. Aqueous NaOH (7 mL, 1 m) was added until pH 10. The mix-
ture was diluted with MTBE (60 mL) and the separated aqueous
layer was washed with MTBE (2ϫ 50 mL). The combined wash
phases were extracted with H2O (50 mL). The aqueous layers were
acidified with HCl (20 mL, 1 m) until pH Ͻ 1 and extracted with
MTBE (3ϫ 60 mL). The combined organic layers were dried with
MgSO4 and evaporated under reduced pressure to give azetidine-
carboxylic acid 4 (0.132 g, 0.547 mmol, 62%) as a colorless oil in
excellent purity.
172.3 (C7) ppm. IR: ν = 2972 (m), 2938 (m), 2859 (w), 1807 (w),
˜
1741 (s), 1692 (s), 1446 (m), 1391 (s), 1338 (s), 1246 (s), 1204 (s),
1154 (s), 1073 (m), 1043 (m), 1007 (m), 929 (m), 874 (m), 771
(w) cm–1. GC–MS (EI): m/z (%) = 243 (1), 184 (27), 142 (35), 128
(100), 110 (2), 84 (100), 57 (100).
1-tert-Butyl 2-Methyl 5,6-Dihydropyridine-1,2(4H)-dicarboxylate
(22):[18] Under an argon atmosphere pipecolic carboxylate rac-21
(7.1 g, 29.2 mmol) was dissolved in THF (30 mL) and cooled to
–30 °C. A solution of LiHMDS (32.3 mL, 1 m in THF) was added
over 2 h and stirring of the resulting mixture was continued at
–30 °C for 1.5 h. Then the yellow solution was cooled –90 °C (N2,
Heϫ) and bromine (1.65 mL, 32.3 mmol) was added dropwise
(CAUTION: efficient cooling and stirring required!) over 1 h. Af-
terwards the cooling bath was removed allowing the mixture to
warm to room temp, aqueous citric acid (40 mL, 1 m) was added.
The mixture was stirred at room temp for 30 min and the phases
were diluted with EtOAc (200 mL). The organic layer was washed
with H2O (2ϫ 200 mL), dried with MgSO4 and concentrated under
reduced pressure. The crude product was purified by chromatog-
raphy (SiO2, EtOAc/cyclohexane = 1:2) to give a light yellow oil.
Colorless crystals of carboxylate 22 (5.0 g, 20.6 mmol, 71%) were
obtained after recrystallization (Et2O/Hex = 1:2), m.p. 68 °C
{ref.[18] 73–75 °C}. Rf = 0.54 (EtOAc/cyclohexane = 1:2), 0.44
(EtOAc/cyclohexane = 1:4). 1H NMR (300 MHz, CDCl3): δ = 1.41
(s, 9 H, 11-H), 1.76–1.80 (m, 2 H, 5-H), 2.14–2.26 (m, 2 H, 4-H),
3.54–3.57 (m, 2 H, 6-H), 3.75 (s, 1 H, 8-H), 5.57 (t, J = 2.8 Hz, 1
H, 3-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.6 (C5), 22.9
(C4), 27.9 (C11), 41.3; 43.0 (C6), 51.8; 53.6 (C8), 81.2 (C10), 121.8
Method B: To freshly prepared chromic acid (1.16 mL, 2.6 m) prop-
enyl alcohol 18 (68.2 mg, 0.030 mmol) in acetone (3.0 mL) was
added dropwise at 0 °C and stirred after warming to room temp
for 3 h. After quenching with iPrOH (5 mL) and H2O (5 mL) the
mixture was extracted with EtOAc (3ϫ 10 mL) and the organic
layer was dried with MgSO4. After removal of the solvent the resi-
due was purified by chromatography (SiO2, EtOAc/cyclohexane =
1:2 + 1 vol.-% AcOH) to give azetidinecarboxylic acid 4 (29.6 mg,
0.012 mmol, 40%) with slight impurities. [α]2D0 = –70.2 (c = 0.350,
1
CHCl3). Rf = 0.22 (MeOH/CH2Cl2 = 1:50 + 1 vol.-% AcOH). H
NMR (mixture of rotamers) (300 MHz, CDCl3): δ = 1.45 (s, 9 H,
11-H), 1.65; 1.70 (2ϫd, J = 5.3, 4.8 Hz, 8-H, E/Z-ratio = 3.1:1),
3.25 (m, 1 H, 3-H), 3.64–3.73 (m, 1 H, 4-Hβ), 4.01–4.14 (m, 1 H,
4-Hα), 4.44 (m, 1 H, 2-H), 5.53–5.72 (s, 2 H, 6-H, 7-H), 10.95 (br.
s, 1 H, -COOH) ppm. 13C NMR (mixture of rotamers) (75 MHz,
CDCl3): δ = 13.2; 17.7 (C8), 28.1 (C11), 36.4 (C3), 52.9; 53.6 (C4),
66.1; 66.6 (C2), 81.6 (C10), 128.4; 128.9; 129.0 (C6, C7), 156.7 (C9),
173.5 (C5) ppm. IR: ν = 2974 (w), 2926 (w), 2886 (w), 1737 (w),
˜
1703 (s), 1659 (s), 1477 (w), 1413 (s), 1392 (s), 1366 (s), 1281 (w),
1246 (w), 1140 (s), 965 (m), 895 (w), 855 (m), 770 (m), 730 (w),
683 (w) cm–1. HRMS (ESI): calcd. for [M – H]– 240.12303; found
240.12379.
(C3), 132.7 (C2), 153.0 (C9), 165.5 (C7) ppm. IR: ν = 2975 (m),
˜
2948 (m), 2880 (w), 1730 (s), 1696 (s), 1643 (m), 1453 (m), 1361 (s),
1336 (s), 1250 (s), 1152 (s), 1066 (s), 962 (m), 873 (m), 771 (s), 730
(w) cm–1. GC–MS (EI): m/z (%) = 241 (4), 168 (19), 141 (92), 126
(46), 109 (10), 82 (44), 57 (100), 41 (53).
(rac)-2-(Methoxycarbonyl)piperidin-1-ium Chloride (rac-20):[22] To a
suspension of d/l-pipecolic acid rac-19 (10.0 g, 0.077 mol) in
Eur. J. Org. Chem. 2014, 6467–6480
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6475

H.-G. Schmalz et al.
FULL PAPER
1-tert-Butyl 2-Methyl (rac/trans)-3-Vinylpiperidine-1,2-dicarboxyl-
ate (rac-23): Under argon atmosphere vinyl-MgBr (118.0 mL,
47.2 mmol, 0.4 m in THF) was cooled to –35 °C and CuBr·SMe2
(1.3 g, 6.3 mmol) was added. The suspension was stirred at –35 °C
for 1 h and carboxylate 22 (7.6 g, 31.5 mmol) was added. After stir-
(300 MHz, CDCl3): δ = 1.42–1.48 (m, 18 H, 8-H, 12-H), 2.00–2.12
(m, 4 H, 3-H, 4-H), 4.02–4.46 (m, 2 H, 2-H, 5-H), 9.55–9.67 (m, 1
H, 9-H) ppm. 13C NMR (mixture of diastereomers and rotamers)
(75 MHz, CDCl3): δ = 24.6; 25.3; 26.3; 26.4; 28.2; 29.1; 29.3; 30.0
(C3, C4), 26.9; 28.0 (C8, C12), 60.4; 60.5; 60.6 (C5), 65.4 (C2),
ring at –35 °C for 6 h the mixture was quenched with aqueous 80.8; 81.1; 81.3; 81.5; 81.6; 81.7 (C7, C11), 153.3; 154.0; 154.3
NH4Cl (saturated) and NH3 (300 mL, 1:1). After extraction with
MTBE (2ϫ 500 mL) the organic layer was washed with aqueous
NH4Cl (1 L) and brine (1 L), dried with MgSO4 and evaporated
under reduced pressure. The crude product was purified by
chromatography (SiO2, EtOAc/cyclohexane = 1:4) (cis-isomer
eluted first, then 1,2-product, then trans-isomer) to give desired
trans-vinylpiperidine rac-23 (2.7 g, 10.0 mmol, 32%) as a yellow oil.
(C10), 171.4; 171.5; 171.6 (C10), 200.2; 201.1 (C9) ppm. IR: ν =
˜
2975 (m), 2926 (w), 1733 (s), 1698 (s), 1696 (s), 1476 (m), 1453 (m),
1386 (s), 1365 (s), 1290 (m), 1253 (m), 1223 (m), 1150 (s), 1123 (s),
1090 (m), 1063 (m), 980 (m), 843 (m), 771 (m) cm–1. GC–MS (EI):
m/z (%) = 299 (1), 270 (9), 207 (3), 198 (2), 170 (16), 140 (6), 114
(51), 98 (17), 80 (14), 70 (38), 57 (52), 41 (100), 39 (61).
Di-tert-butyl (2S)-5-Vinylpyrrolidine-1,2-dicarboxylate (26):[4b] Un-
der an argon atmosphere was added at room temp. KHMDS
(77.8 mL, 0.051 mol, 15 % in toluene) to a suspension of
Ph3PCH3Br (18.1 g, 0.051 mol) in THF (150 mL). After stirring at
room temp for 1 h the reaction mixture was cooled to –78 °C and
aldehyde 25 (6.1 g, 0.020 mol) in THF (50 mL) was added. The
mixture was warmed to room temp and was stirred for 2.5 h. The
reaction was quenched aqueous saturated Na/K tartrate (120 mL),
diluted with H2O (80 mL) and extracted with MTBE (3ϫ 250 mL).
The organic layer was washed with brine (500 mL), dried with
MgSO4 and evaporated under reduced pressure. The crude product
was purified by chromatography (SiO2, EtOAc/cyclohexane = 1:9)
to give vinylproline 26 (5.4 g, 0.018 mol, 90%) as mixture of its
diastereomers (cis/trans = 4:1, GC–MS) as a light yellow oil. Rf =
0.26 (EtOAc/cyclohexane = 1:9). 1H NMR (mixture of dia-
stereomers and rotamers) (300 MHz, CDCl3): δ = 1.64–1.77 (m, 18
H, 8-H, 13-H), 1.84–2.17 (m, 4 H, 3-H, 4-H), 4.12–4.54 (m, 2 H,
2-H, 5-H), 5.05–5.39 (m, 2 H, 10-H), 5.71–5.93 (m, 1 H, 9-H) ppm.
13C NMR (mixture of diastereomers and rotamers) (75 MHz,
CDCl3): δ = 28.0; 28.3 (C8, C13), 26.9; 27.3; 29.0; 30.0; 30.9; 31.5
(C3, C4), 59.4; 59.7; 60.2; 60.4; 60.6; 61.0 (C2, C5), 79.5; 79.6; 79.7;
79.9; 80.9 (C7, C12), 113.7; 113.8; 114.6; 114.9 (C10), 138.1; 138.5;
1
Rf = 0.56 (EtOAc/cyclohexane = 1:4). H NMR (mixture of rota-
mers) (300 MHz, CDCl3): δ = 1.45 (s, 9 H, 13-H), 1.53–1.76 (m, 4
H, 4-H, 5-H), 2.78–3.00 (m, 2 H, 3-H, 6-Hβ), 3.75 (s, 1 H, 8-H),
3.90–4.10 (m, 1 H, 6-Hα), 4.82 (m, 1 H, 2-H), 5.11–5.19 (m, 2 H,
10-H), 5.84–5.95 (ddd, J = 17.1, 10.5, 6.3 Hz, 1 H, 9-H) ppm. 13C
NMR (mixture of rotamers) (75 MHz, CDCl3): δ = 19.6 (C5), 25.9
(C4), 27.9 (C11), 37.9 (C3), 41.2–41.7 (C6), 52.1 (C8), 57.2–57.9
(C2), 80.0 (C12), 115.5 (C10), 138.7 (C9), 155.7 (C11), 172.0
(C7) ppm. IR: ν = 2975 (m), 2948 (m), 2880 (w), 1730 (s), 1696 (s),
˜
1643 (m), 1453 (m), 1361 (s), 1336 (s), 1250 (s), 1152 (s), 1066 (s),
962 (m), 873 (m), 771 (s), 730 (w) cm–1. GC–MS (EI): m/z (%) =
241 (4), 168 (19), 141 (92), 126 (46), 109 (10), 82 (44), 57 (100), 41
(53). HRMS (ESI): calcd. for [M + Na]+ 292.15193; found
292.15048.
(rac/trans)-1-(tert-Butoxycarbonyl)-3-vinylpiperidine-2-carboxylic
Acid (rac-6): Carboxylate rac-23 (1.100 g, 4.084 mmol) was dis-
solved in MeOH (4.1 mL) and THF (12.3 mL). After addition of
aqueous LiOH (4.1 mL, 2 n, 8.168 mmol) the mixture was stirred
at 50 °C for 5 h (pH 10). After cooling to room temp the aqueous
phase was washed with MTBE (5 mL) and acidified at 0 °C with
HCl (10 mL, 1 n) until pH 1. After extraction with CH2Cl2 (5ϫ
10 mL) the organic layer was dried with MgSO4 and was concen-
trated under reduced pressure to give carboxylic acid rac-6 (0.922 g,
3.611 mmol, 88%) as a white solid, m.p. 112 °C. Rf = 0.22 (MeOH/
CH2Cl2 = 1:60 + 1 vol.-% AcOH). 1H NMR (mixture of rotamers)
(300 MHz, CDCl3): δ = 1.46 (m, 10 H, 5-Hβ, 12-H), 1.54–1.70 (m,
3 H, 4-H, 5-Hα), 3.04–3.13 (m, 2 H, 3-H, 6-Hβ), 3.97–4.02 (m, 1
H, 6-Hα), 4.79–4.94 (m, 1 H, 2-H), 5.07–5.20 (m, 2 H, 9-H), 5.84–
5.96 (ddd, J = 17.1, 10.5, 6.2 Hz, 1 H, 9-H) ppm. 13C NMR (mix-
ture of rotamers) (75 MHz, CDCl3): δ = 19.5 (C5), 25.8 (C4), 28.3
(C12), 37.8 (C3), 40.0–42.2 (C6), 56.7–57.8 (C2), 80.4; 80.6 (C11),
138.6; 139.2 (C9), 153.6; 153.7 (C11), 172.0; 172.1 (C6) ppm. IR: ν
˜
= 2974 (m), 2930 (m), 2873 (w), 1738 (s), 1693 (s), 1643 (w), 1477
(m), 1454 (m), 1384 (s), 1363 (s), 1325 (m), 1292 (m), 1254 (s), 1218
(s), 1148 (s), 1066 (m), 1024 (w), 987 (m), 957 (m), 912 (s), 874 (m),
856 (m), 843 (m), 771 (m), 686 (w) cm–1. GC–MS (EI): m/z (%) =
297 (1), 196 (25), 168 (10), 140 (100), 114 (3), 96 (100), 70 (9), 79
(8), 57 (100), 41 (38), 39 (14).
tert-Butyl (2S,5R)-5-Vinylpyrrolidine-2-carboxylate (7):[4b] Under
an argon atmosphere vinylproline 26 (6.1 g, 0.021 mol) was dis-
solved in CH2Cl2 (75 mL). After cooling to 0 °C TMSOTf
(3.74 mL, 0.021 mol) was added dropwise. Stirring was continued
for 5 min and the reaction was stopped by addition of aqueous
NaHCO3 (20 mL) until no further gas evolution was visible. The
aqueous layer was extracted with CH2Cl2 (5ϫ 20 mL). The organic
layer was dried with MgSO4 and evaporated under reduced pres-
sure. The crude product was purified by chromatography (SiO2,
MeOH/CH2Cl2 = 1:25) and separated to its diastereomers to give
amine 7 (1.7 g, 0.009 mol, 43%) as colorless crystals. [α]2D0 = –35.0
(c = 1.500 , CHCl3) {ref.[4b] [α]2D0 = –35.1 (c = 1.475 , CHCl3)}. Rf
115.5 (C9), 138.5 (C8), 156.1 (C10), 177.0 (C7) ppm. IR: ν = 3071
˜
(w), 2969 (w), 2936 (w), 2860 (w), 1734 (m), 1692 (s), 1650 (s), 1473
(w), 1415 (m), 1391 (m), 1365 (s), 1310 (w), 1250 (m), 1140 (s),
1017 (w), 989 (w), 918 (m), 877 (m), 770 (w) cm–1. HRMS (ESI):
calcd. for [M + Na]+ 278.13628; found 278.13529.
Di-tert-butyl (2S)-5-Formylpyrrolidine-1,2-dicarboxylate (25):[4b] To
a mixture of cyanopyrrolidine 24 (for synthesis of 24 see ref.[4b]
)
(15.0 g, 0.051 mol) in pyridine/AcOH/H2O (2:1:1, 210 mL) was
added Raney-Ni (34.8 g, 50% in H2O). Under vigorous stirring at
50 °C the mixture was saturated with H2 under a continuous stream
of gas. After 5 h at 50 °C (progress controlled by GC–MS) the reac-
1
= 0.27 (MeOH/CH2Cl2 = 1:25). H NMR (300 MHz, CDCl3): δ =
tion was diluted with H2O (300 mL) and extracted with EtOAc 1.49 (m, 10 H, 8-H, 4Ј-H), 1.88–1.97; 2.07–2.11 (2ϫm, 3 H, 3-H,
(3ϫ 300 mL). The organic layer was intensely washed with H2O
(3ϫ 700 mL) to remove all Ni-impurities and dried with MgSO4.
After evaporation under reduced pressure the residue was purified
by chromatography (SiO2, EtOAc/cyclohexane = 1:6) to provide
aldehyde 25 (9.2 g, 0.031 mol, 61%) as mixture of its diastereomers
(cis/trans = 3:1, GC–MS) as yellow oil. Rf = 0.23 (EtOAc/cyclohex-
4-H), 2.28 (br. s, 1 H, -NH), 3.57–3.71 (m, 2 H, 2-H, 5-H), 5.03–
5.23 (ddd, J = 13.7, 10.9, 0.8 Hz, 2 H, 10-H), 5.83–5.94 (ddd, J =
10.2, 9.7, 7.2 Hz, 1 H, 9-H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 27.9 (C8), 30.4; 31.9 (C3, C4), 60.7 (C2), 62.2 (C5), 81.0 (C7),
115.0 (C10), 140.1 (C9), 174.4 (C6) ppm. IR: ν = 3346 (w), 3286
˜
(w), 3073 (w), 2973 (m), 2933 (m), 2866 (w), 1723 (s), 1649 (w),
ane = 1:4). 1H NMR (mixture of diastereomers and rotamers) 1476 (w), 1453 (m), 1426 (w), 1390 (m), 1363 (s), 1280 (m), 1223
6476
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6467–6480

Synthesis of Tricyclic Diproline Analogues that Mimic a PPII Helix
(s), 1150 (s), 1100 (s), 1033 (w), 990 (m), 913 (s), 846 (s), 756 (m), 1151 (s), 1075 (w), 1027 (w), 967 (w), 919 (w), 848 (w), 787
(w) cm–1. GC–MS (EI): m/z (%) = 197 (1), 114 (3), 96 (100), 79
(11), 68 (11), 57 (13), 41 (29).
(w), 731 (m), 645 (w) cm–1. HRMS (ESI): calcd. for [M + H]+
379.22275; found 379.22274: calcd. for [M + Na]+ 401.20469; found
401.20461.
tert-Butyl (2S,5R)-1-[(2S,3S)-1-(tert-Butoxycarbonyl)-3-(prop-1-en-
1-yl)azetidine-2-carbonyl]-5-vinylpyrrolidine-2-carboxylate (27): Un-
der an argon atmosphere azetidinecarboxylic acid 4 (0.060 g,
0.249 mmol) and amine 7 (0.059 g, 0.298 mmol) were dissolved in
MeCN (2 mL) and N,N-diisopropylethylamine (DIPEA; 0.13 mL,
(2aS,4aR,7S,9aS)-1-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-9-oxo-
2,2a,4a,5,6,7,9,9a-octahydro-1H-azeto[3,2-e]pyrrolo[1,2-a]azepine-
7-carboxylic Acid (2b): A solution of tricyclic 2c (0.045 g,
0.119 mmol) in CH2Cl2 (2 mL) was cooled to 0 °C and TFA (2 mL)
0.746 mmol) was added. After the solution was cooled to 0 °C was added dropwise. After warming to room temp stirring was con-
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophos-
phate (PyBOP; 0.143 g, 0.274 mmol) in MeCN (2 mL) was added
dropwise. The mixture was stirred at room temp for 16 h and the
solvent was removed under reduced pressure. The residue was dis-
tinued for 1 h and the solvent was removed under reduced pressure.
Aqueous, half-saturated NaHCO3 (3 mL) was added (pH 8). After
addition of Fmoc-Cl (0.044 g, 0.170 mmol) in THF (1.5 mL) the
solution was stirred at room temp for 16 h and then diluted with
solved in MTBE (20 mL) and washed with H2O (10 mL). The CH2Cl2 (5 mL). The solution was acidified at 0 °C with HCl (3 mL,
aqueous layer was extracted with MTBE (2ϫ 10 mL). The com-
bined organic phases were dried with MgSO4 and concentrated un-
der reduced pressure. The crude product was purified by
chromatography (SiO2, EtOAc/cyclohexane = 1:3) to give dipeptide
27 (0.081 g, 0.193 mmol, 78%) as a yellow oil. [α]2D0 = –40.3 (c =
1 n) to pH 1. After separation the aqueous layer was extracted with
CH2Cl2 (2ϫ 5 mL). The combined organic layers were dried with
MgSO4 and concentrated under reduced pressure. The crude prod-
uct was purified by chromatography (SiO2, MeOH/CH2Cl2 = 1:15
+ 1 vol.-% AcOH) to give 2b (0.040 g, 0.090 mmol, 76 %) with
0.490, CHCl3). Rf = 0.19 (EtOAc/cyclohexane = 1:3). 1H NMR slight impurities of AcOH as a white solid. [α]2D0 = –65.2 (c = 0.320,
(mixture of rotamers) (300 MHz, 288 K, CDCl3): δ = 1.40–1.49 (m, CHCl3), m.p. 141 °C. Rf = 0.32 (MeOH/CH2Cl2 = 1:15 + 1 vol.-%
18 H, 8-H, 20-H), 1.56–1.72 (m, 3 H, 17-H), 1.81–1.93 (m, 2 H, 4-
AcOH). 1H NMR (mixture of rotamers) (300 MHz, CDCl3): δ =
H), 2.05–2.22 (m, 2 H, 3-H), 3.19 (m, 1 H, 13-H), 3.58–3.63 (m, 1 1.86–2.01 (m, 2 H, 3Ј-H, 4Ј-H), 2.26–2.30 (m, 2 H, 3-H, 4-H), 3.53
H, 14Ј-H), 4.20–4.31 (m, 1 H, 14-H), 4.36–4.44 (m, 1 H, 5-H), 4.51 (m, 1 H, 9-H), 3.75 (m, 1 H, 12Ј-H), 3.98 (m, 1 H, 12-H), 4.23 (t,
(dd, J = 19.0, 4.3 Hz, 1 H, 12-H), 4.53; 4.80 (2ϫm, 1 H, 2-H), J = 6.8 Hz, 1 H, 15-H), 4.40 (m, 2 H, 14-H), 4.55 (m, 1 H, 5-H),
5.14; 5.40 (2ϫm, 2 H, 10-H), 5.49–5.57 (m, 2 H, 15-H, 16-H),
4.77 (m, 2 H, 2-H, 10-H), 5.49 (d, J = 11.0 Hz, 1 H, 8-H), 5.89 (d,
5.84–5.91 (m, 1 H, 9-H) ppm. 13C NMR (mixture of rotamers) J = 10.8 Hz, 1 H, 7-H), 7.30 (m, 2 H, 18-H), 7.36 (m, 2 H, 19-H),
(75 MHz, 288 K, CDCl3): δ = 17.8 (C17), 26.7; 27.0; 31.7; 31.8 (C3, 7.63 (m, 2 H, 17-H), 7.76 (m, 2 H, 20-H), 9.72 (br. s, 1 H,
C4), 27.9; 28.3; 31.0; 31.3 (C8, C20), 36.2; 36.6 (C13), 52.8; 54.1
(C14), 60.3 (C2), 60.8; 60.9; 61.0 (C12), 64.0; 64.2; 65.0 (C5), 79.6;
81.0; 81.2 (C7, C19), 116.6; 117.0 (C10), 127.7; 127.9; 130.0; 130.1
-COOH) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.1 (C3), 33.1
(C4), 33.5 (C9), 47.0 (C15), 53.6 (C12), 60.0 (C2, C5), 66.2 (C11),
67.6 (C14), 119.8 (C20), 125.3 (C17), 127.1 (C18), 127.3 (C8), 127.7
(C15, C16), 138.1; 138.7 (C9), 155.0; 155.8 (C18), 169.7; 169.8 (C6), (C19), 129.0 (C7), 141.2 (C21), 143.7 (C16), 158.8 (C13), 171.0
170.5; 170.9 (C11) ppm. IR: ν = 2973 (m), 2926 (w), 2880 (w), 1736 (C6), 174.8 (C11) ppm. IR: ν = 3354 (w), 3058 (w), 2950 (w), 1711
˜
˜
(m), 1700 (s), 1650 (s), 1476 (w), 1453 (m), 1423 (m), 1390 (s), 1363 (s), 1449 (m), 1415 (m), 1319 (m), 1300 (w), 1272 (w), 1189 (m),
(s), 1300 (m), 1253 (w), 1206 (w), 1146 (s), 1090 (w), 1033 (w), 986 1130 (w), 1102 (w), 1032 (w), 969 (w), 909 (w), 759 (s), 739 (s),
(w), 963 (w), 926 (w), 863 (w), 843 (w), 770 (w) cm–1. GC–MS (EI): 620 (w) cm–1. HRMS (ESI): calcd. for [M + H]+ 445.17580; found
m/z (%) = 405 (3), 364 (7), 347 (10), 308 (10), 290 (11), 263 (27), 445.17582: calcd. for [M + Na]+ 467.15774; found 467.15768.
235 (9), 219 (8), 196 (7), 180 (12), 140 (30), 96 (53), 57 (50), 41
(100). HRMS (ESI): calcd. for [M + H]+ 443.2516; found 443.2514:
calcd. for [M + Na]+ 421.2697; found 421.2698.
tert-Butyl 2-[(2S,5R)-2-(tert-Butoxycarbonyl)-5-trans-vinylpyrrol-
idine-1-carbonyl]-3-vinylpiperidine-1-carboxylate (28): Under an ar-
gon atmosphere piperidinecarboxylic acid rac-6 (0.470 g,
Di-tert-butyl (2aS,4aR,7S,9aS)-9-Oxo-2,2a,4a,5,6,7,9,9a-octahydro- 1.84 mmol) and amine 7 (0.331 g, 1.68 mmol) were dissolved in
1H-azeto[3,2-e]pyrrolo[1,2-a]azepine-1,7-dicarboxylate (2c): Under
an argon atmosphere dipetide 27 (0.120 g, 0.285 mmol) and
Grubbs II catalyst (0.025 g, 0.029 mmol) were heated to reflux in
CH2Cl2 (7 mL) for 24 h. Then dimethyl sulfoxide (DMSO; 0.5 mL)
MeCN (10 mL) and DIPEA (0.86 mL, 5.04 mmol) was added. Af-
ter the solution was cooled to 0 °C PyBOP (1.134 g, 2.18 mmol) in
MeCN (10 mL) was added dropwise. The mixture was stirred at
room temp for 20 h and the solvent was removed under reduced
was added at room temp and the mixture was stirred overnight. pressure. The residue was dissolved in MTBE (50 mL) and washed
After removal of CH2Cl2 under reduced pressure the crude product
was purified by chromatography (SiO2, EtOAc/cyclohexane = 1:3)
to give tricyclic 2c (0.050 g, 0.119 mmol, 46%) as a yellow oil and
with H2O (20 mL). The aqueous layer was extracted with MTBE
(3ϫ 20 mL). The combined organic phases were dried with MgSO4
and concentrated under reduced pressure. The crude product was
purified by chromatography (SiO2, EtOAc/cyclohexane = 1:3) to
unreacted starting material 27 (0.046 g, 0.104 mmol, 36%). [α]2D0
=
–105.2 (c = 0.285 , CHCl3). Rf = 0.26 (EtOAc/cyclohexane = 1:1).
give dipeptide 28 (0.601 g, 1.38 mmol, 82%) as a yellow oil. Rf =
1
1H NMR (mixture of rotamers) (300 MHz, CDCl3): δ = 1.44 (m, 0.44/0.47 (diastereomers) (EtOAc/cyclohexane = 1:3). H NMR
18 H, 8-H, 17-H), 1.82–1.97 (m, 1 H, 4Ј-H), 2.01–2.06 (m, 2 H, 3- (mixture of diastereomers and rotamers) (600 MHz, CDCl3): δ =
H), 2.18–2.34 (m, 2 H, 4-H), 3.50 (m, 1 H, 11-H), 3.70 (m, 1 H,
1.35–1.48 (m, 20 H, 15-H, 8-H, 21-H), 1.48–2.22 (m, 7 H, 3-H, 4-
14Ј-H), 3.87 (m, 1 H, 14-H), 4.59–4.65 (m, 2 H, 2-H, 5-H), 4.72 (d, H, 14-H, 16Ј-H), 2.42–3.26 (m, 1 H, 13-H), 3.36–3.98 (m, 1 H, 16-
J = 10.0 Hz, 1 H, 12-H), 5.51 (d, J = 10.8 Hz, 1 H, 10-H), 5.89 (dd, H), 4.12–4.93 (m, 3 H, 2-H, 5-H, 12-H), 4.93–5.09 (m, 2 H, 10Ј-H,
J = 10.8, 2.0 Hz, 1 H, 9-H) ppm. 13C NMR (mixture of rotamers) 18-H), 5.15–5.43 (m, 1 H, 10-H), 5.65–5.97 (m, 2 H, 9-H, 17-
(75 MHz, CDCl3): δ = 27.1 (C4), 27.9; 28.2 (C8, C17), 33.0 (C3),
33.1 (C11), 53.3 (C14), 58.9 (C5), 59.7 (C2), 66.3 (C12), 80.5; 81.4
(C7, C16), 127.3 (C10), 129.6 (C9), 158.3 (C15), 169.3 (C13), 171.0
H) ppm. 13C NMR (mixture of diastereomers and rotamers)
(150 MHz, CDCl3): δ = 19.5; 23.6; 23.7; 25.1; 26.3; 26.7; 26.8; 29.1;
27.7; 30.2; 32.6 (C3, C4, C14, C15), 27.7; 27.8; 28.1; 28.2 (C8, C21),
37.3; 37.4; 37.8 (C13), 41.5 (C16), 52.5; 53.5; 55.8; 59.9; 60.5; 60.8;
61.4; 61.8 (C2, C5, C12), 79.4; 80.8; 81.6 (C7, C20), 114.6; 114.9;
(C6) ppm. IR: ν = 2974 (m), 2929 (w), 1711 (s), 1681 (s), 1650 (s),
˜
1477 (w), 1454 (m), 1390 (s), 1365 (s), 1318 (m), 1256 (m), 1218
Eur. J. Org. Chem. 2014, 6467–6480
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6477

H.-G. Schmalz et al.
FULL PAPER
A116.0 (C10, C18), 137.9; 138.2; 139.1; 139.4; 139.5 (C9, C17),
1152 (s), 1074 (w), 1039 (w), 944 (w), 903 (w), 855 (w), 829 (w),
773 (w), 755 (w), 730 (w) cm–1. HRMS (ESI): calcd. for [M + H]+
407.25405; found 407.25430: calcd. for [M + Na]+ 429.23600; found
429.23606.
155.2 (C19), 171.1 (C6), 172.1 (C11) ppm. IR: ν = 3071 (w), 2962
˜
(m), 2928 (m), 2866 (w), 1734 (s), 1680 (s), 1646 (s), 1418 (w), 1361
(s), 1340 (s), 1310 (m), 1249 (s), 1204 (m), 1147 (s), 1065 (w), 1014
(w), 990 (m), 919 (s), 871 (m), 847 (w), 766 (w), 645 (m) cm–1. GC–
MS (EI): m/z (%) = 434 (1), 361 (3), 305 (7), 277 (4), 210 (15), 182
(7), 154 (100), 110 (57), 57 (39), 41 (66). HRMS (ESI): calcd. for [M
+ H]+ 435.28535; found 435.28465: calcd. for [M + Na]+ 457.26729;
found 457.26594.
(4aR,6aR,9S,11aS)-1-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-11-
oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo-
[1,2-a]azepine-9-carboxylic Acid (3b): A solution of tricyclic 3c
(0.190 g, 0.475 mmol) in CH2Cl2 (2 mL) was cooled to 0 °C and
TFA (2 mL) was added dropwise. After stirring at room temp for
1 h the solvent was removed and under reduced pressure and aque-
ous, half-saturated NaHCO3 (5 mL) was added (pH 8). After ad-
dition of Fmoc-Cl (0.184 g, 0.713 mmol) in THF (6 mL) the solu-
tion was stirred at room temp for 16 h and then diluted with
CH2Cl2 (25 mL). The solution was acidified at 0 °C with HCl
(10 mL, 1 n) to pH 1. After separation the aqueous layer was ex-
tracted with CH2Cl2 (2 ϫ 20 mL). The combined organic layers
were dried with MgSO4 and concentrated under reduced pressure.
The crude product was purified by a Reveleris® flash chromatog-
raphy system (SiO2, MeOH/CH2Cl2 gradient: 0–20%) to give 3b
(0.181 g, 0.383 mmol, 81%) as a colorless solid. [α]2D0 = –64.7 (c =
Di-tert-butyl (4aR,6aR,9S,11aS)-11-Oxo-2,3,4,4a,6a,7,8,9,11,11a-
decahydro-1H-pyrido[3,2-e]pyrrolo[1,2-a]azepine-1,9-dicarboxylate
(3c) and Di-tert-butyl (4aS,6aR,9S,11aR)-11-Oxo-2,3,4,4a,
6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo[1,2-a]azepine-
1,9-dicarboxylate (dia-3c): Under an argon atmosphere dipetide 28
(0.495 g, 1.14 mmol) and Grubbs II catalyst (0.194 g, 0.23 mmol)
were heated to reflux in CH2Cl2 (25 mL) for 48 h. Then DMSO
(0.5 mL) was added at room temp and the mixture was stirred over-
night. After removal of CH2Cl2 under reduced pressure the crude
product was purified by chromatography (SiO2, EtOAc/cyclohex-
ane = 1:3Ǟ1:1) to give desired tricyclic 3c (0.193 g, 0.48 mmol,
42%) and its diastereomer dia-3c (0.195 g, 0.48 mmol, 42%). Data
for 3c: colorless crystals. [α]2D0 = –91.6 (c = 0.425, CHCl3), m.p. 72–
73 °C. Rf = 0.49 (EtOAc/cyclohexane = 1:1). 1H NMR (mixture of
rotamers, 1:1.5) (600 MHz, 248 K, CDCl3): δ = 1.42–1.97 (m, 18
H, 8-H, 19-H), 1.59–1.71 (m, 1 H, 15Ј-H), 1.71–1.87 (m, 2 H, 14-
H), 1.87–2.01 (m, 2 H, 4Ј-H, 15-H), 1.87–2.01 (m, 2 H, 3-H), 2.27–
2.38 (m, 1 H, 4-H), 2.60 (t, J = 10.4 Hz, 1 H, 13-H), 3.18–3.27 (m,
1 H, 16Ј-H), 3.90 (dd, J = 13.9, 8.6 Hz, 0.6 H, 16-Hrot1), 3.99 (dd,
J = 13.9, 8.1 Hz, 0.4 H, 16-Hrot2), 4.45 (d, J = 11.7 Hz, 0.4 H, 12-
Hrot2), 4.55–4.58 (m, 0.6 H, 12-Hrot1), 4.58–4.59 (m, 0.4 H, 2-Hrot2),
4.61–4.62 (m, 1 H, 5-H), 4.67–4.70 (m, 0.6 H, 2-Hrot1), 5.54–5.62
(m, 2 H, 9-H, 10-H) ppm. 13C NMR (mixture of rotamers, 1:1.5)
(150 MHz, 248 K, CDCl3): δ = 21.1; 21.5 (C15), 26.3; 26.5; 26.7
(C14), 27.2; 27.6 (C3), 27.7; 27.8; 28.1; 28.3 (C8, C19); 32.8; 32.9
(C4), 33.3; 33.5 (C13), 36.7; 38.0 (C16), 55.9; 56.3 (C2), 58.4; 59.0
(C12), 59.8; 60.0 (C5), 79.4; 79.7; 81.2; 81.4 (C7, C18), 128.2; 128.4;
132.3; 132.7 (C9, C10), 155.2; 155.8 (C17), 170.1; 170.4 (C11),
1
0.295, CHCl3), m.p. 157 °C. Rf = 0.13 (MeOH/CH2Cl2 = 1:15). H
NMR (mixture of rotamers, 1.5:1) (600 MHz, 258 K, CDCl3): δ =
0.78–0.89 (m, 0.6 H, 13Ј-H-Hrot1), 1.36–1.41 (m, 0.4 H, 13Ј-Hrot2),
1.51–1.59; 1.69–2.16; 2.18–2.32 (3ϫm, 7 H, 3-H, 4-H, 12-H, 13-
H), 2.34–2.37 (m, 0.6 H, 11-Hrot1), 2.61–2.67 (m, 0.4 H, 11-Hrot2),
2.97–3.07 (m, 0.4 H, 14Ј-Hrot2), 2.37–3.45 (m, 0.6 H, 14Ј-Hrot1),
3.55–3.61 (m, 0.4 H, 5-Hrot2), 3.81–3.85 (m, 0.4 H, 10-Hrot2), 3.92–
3.96 (m, 0.4 H, 14-Hrot2), 4.02–4.06 (m, 0.6 H, 14-Hrot1), 4.15 (m,
0.4 H, 17-Hrot2), 4.28–4.33 (m, 1.2 H, 16Ј-Hrot1, 17-Hrot1), 4.41–
4.46 (m, 1 H, 2-Hrot2, 16-Hrot1), 4.56–4.58 (m, 0.4 H, 16Ј-Hrot2),
4.65 (d, J = 11.6 Hz, 0.6 H, 10-Hrot1), 4.68–4.74 (m, 0.6 H, 5-Hrot1),
4.76 (d, J = 8.6 Hz, 0.6 H, 2-Hrot1), 5.00–5.05 (m, 0.4 H, 16-Hrot2),
5.36 (m, 0.8 H, 7-Hrot2, 8-Hrot2), 5.36 (m, 1.2 H, 7-Hrot1, 8-Hrot1),
7.32–7.35 (m, 2 H, 20-H), 7.39–7.44 (m, 2 H, 20-H), 7.56–7.63 (m,
2 H, 21-H), 7.72–8.80 (m, 2 H, 19-H), 7.32–7.35 (m, 2 H, 22-H),
8.81 (br. s, 1 H, -COOH) ppm. 13C NMR (mixture of rotamers,
1.5:1) (150 MHz, 258 K, CDCl3): δ = 20.7, 21.5 (C13), 25.7; 25.8;
25.9; 26.2 (C3, C12), 32.8; 33.1 (C4), 32.9; 33.2 (C11), 37.1; 38.1
(C14), 46.8; 47.9 (C17), 56.2; 57.0 (C5), 58.4; 59.0 (C10), 59.9; 60.0
(C2), 62.2; 67.6 (C16), 119.6; 119.7; 119.9 (C22), 124.5; 124.8;
124.9; 125.1 (C19), 126.8; 126.9; 127.0; 127.1; 127.2; 127.5; 127.6
(C8, C20, C21), 132.2; 132.3 (C7), 141.0; 141.1; 141.2 (C23), 143.1;
143.4; 143.9; 144.4 (C18), 155.3; 156.2 (C15), 172.4; 172.8 (C9),
170.9; 171.2 (C6) ppm. IR: ν = 2970 (w), 2928 (w), 2867 (w), 1736
˜
(m), 1697 (s), 1666 (s), 1477 (w), 1433 (m), 1409 (s), 1390 (s), 1363
(s), 1329 (w), 1283 (w), 1257 (w), 1222 (m), 1151 (s), 1129 (s), 1075
(w), 1006 (w), 947 (w), 904 (w), 851 (w), 833 (w), 770 (w) cm–1.
HRMS (ESI): calcd. for [M + H]+ 407.25405; found 407.25432:
calcd. for [M + Na]+ 429.23600; found 429.23601.
Data for dia-3c: Colorless crystals. [α]2D0 = –93.8 (c = 0.500, CHCl3),
m.p. 73–74 °C. Rf = 0.30 (EtOAc/cyclohexane = 1:1). 1H NMR
(mixture of rotamers, 1:1) (600 MHz, 248 K, CDCl3): δ = 1.42–1.45
(m, 19 H, 15Ј-H, 8-H, 19-H), 1.53–1.63 (m, 1 H, 15-H), 1.91–2.13
(m, 4 H, 3Ј-H, 4Ј-H, 14-H), 2.20–2.29 (m, 1 H, 3-H), 2.29–2.35 (m,
1 H, 4-H), 2.75–2.83 (m, 2ϫ0.5 H, 13Ј-Hrot1, 16Ј-Hrot1), 2.83–2.89
(m, 0.5 H, 16Ј-Hrot2), 2.89–2.99 (m, 0.5 H, 13Ј-Hrot2), 3.25 (d, J =
11.6 Hz, 0.5 H, 12-Hrot2), 3.43 (d, J = 11.8 Hz, 0.5 H, 12-Hrot1),
173.5; 173.6 (C6) ppm. IR: ν = 3013 (w), 2940 (w), 2866 (w), 2246
˜
(w), 1696 (s), 1646 (s), 1446 (m), 1423 (m), 1350 (w), 1323 (w), 1280
(w), 1263 (w), 1216 (m), 1170 (m), 1126 (m), 1100 (w), 1080 (w),
1003 (w), 976 (w), 903 (s), 720 (s) cm–1. HRMS (ESI): calcd. for
[M – H]– 471.19145; found 471.19216.
Selective Carbamate Deprotection of the N-Boc-tBu-carboxylate
(dia-3c) Followed by Fmoc Protection
4.03–4.06 (m, 0.5 H, 16-Hrot1), 4.22–4.24 (m, 0.5 H, 16-Hrot2), 4.49– 1-[(9H-Fluoren-9-yl)methyl] 9-tert-Butyl (4aS,6aR,9S,11aR)-11-
4.54 (m, 0.5 H, 2-Hrot1), 4.54–4.58 (m, 0.5 H, 2-Hrot2), 4.59–4.66 Oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo-
(m, 0.5 H, 5-Hrot1), 4.73–4.80 (m, 0.5 H, 5-Hrot2), 5.59–5.63 (m, 1 [1,2-a]azepine-1,9-dicarboxylate (dia-3d): A solution of tricyclic dia-
H, 10-H), 5.99–6.02 (m, 1 H, 9-H) ppm. 13C NMR (mixture of 3c (0.080 g, 0.197 mmol) in CH2Cl2 (1 mL) was cooled to 0 °C and
rotamers, 1:1) (150 MHz, 248 K, CDCl3): δ = 24.4, 25.3 (C15), TFA (1 mL) was added dropwise. After stirring at 0 °C for 1 h the
26.7; 27.1; 27.2 (C3), 27.7; 27.8; 28.2; 28.3 (C8, C19), 31.8 (C4), solvent was removed and under reduced pressure and aqueous,
32.4; 32.9 (C14), 35.6; 36.4 (C13), 49.3; 49.4 (C16), 53.2; 53.4 (C5),
61.1; 61.3 (C2), 64.8; 64.9 (C12), 79.5; 80.8; 81.0; 81.4 (C7, C18), of Fmoc-Cl (0.076 g, 0.295 mmol) in THF (3 mL) the solution was
136.1; 136.3 (C10), 136.5; 136.6 (C9), 154.7; 155.4 (C17), 167.1; stirred at room temp for 16 h and then diluted with CH2Cl2
167.4 (C11), 171.4; 172.0 (C6) ppm. IR: ν = 2973 (w), 2930 (w), (25 mL). The solution was acidified at 0 °C with HCl (5 mL, 1 n)
half-saturated NaHCO3 (2 mL) was added (pH 8). After addition
˜
2874 (w), 1737 (m), 1692 (s), 1638 (s), 1477 (w), 1449 (m), 1408 (s),
to pH 1. After separation the aqueous layer was extracted with
1390 (s), 1364 (s), 1337 (w), 1286 (w), 1245 (m), 1219 (w), 1151 (s), CH2Cl2 (2ϫ 20 mL). The combined organic layers were dried with
6478
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6467–6480

Synthesis of Tricyclic Diproline Analogues that Mimic a PPII Helix
MgSO4 and concentrated under reduced pressure. The crude prod-
uct was purified by a Reveleris® flash chromatography system
(SiO2, MeOH/CH2Cl2 gradient: 0–20%) to give N-Fmoc-potected
tBu carboxylate dia-3d (0.079 g, 0.149 mmol, 76 %) as colorless
crystals. [α]2D0 = –83.0 (c = 0.285, CHCl3), m.p. 85–87 °C. Rf = 0.20
(MeOH/CH2Cl2 = 1:15). 1H NMR (mixture of rotamers)
(500 MHz, CDCl3): δ = 1.07–1.38 (m, 2 H, 15-H), 1.38–1.57 (m,
10 H, 8-H, 14Ј-H), 1.88–2.06 (m, 3 H, 3-H, 4-H, 14-H), 2.09–2.20
(m, 1 H, 3-H), 2.21–2.33 (m, 1 H, 4-H), 2.72–2.96 (m, 2 H, 13-H,
16Ј-H), 3.28–3.47 (m, 1 H, 16-H), 3.89–4.05 (m, 1 H, 12-H), 4.18–
4.23 (m, 1 H, 19-H), 4.34–4.44 (m, 1 H, 15Ј-H), 4.45–4.53 (m, 1 H,
15-H), 4.53–4.60 (m, 1 H, 2-H), 4.63–4.79 (m, 1 H, 5-H), 5.57 (m,
1 H, 10-H), 5.88–5.99 (m, 1 H, 9-H), 7.27–7.33 (m, 2 H, 22-H),
7.36–7.41 (m, 2 H, 23-H), 7.56–7.58 (m, 2 H, 21-H), 7.73–7.75 (m,
2 H, 24-H) ppm. 13C NMR (mixture of rotamers) (125 MHz,
CDCl3): δ = 24.7; 24.9; 25.2; 25.6 (C14, C15), 27.4 (C4), 27.9 (C8),
31.9; 32.1; 32.3 (C3), 36.2 (C13), 47.2 (C19), 48.9 (C16), 53.6; 55.0
(C5), 61.5; 62.2 (C2), 66.3 (C12), 67.2; 67.3 (C18), 81.1 (C7), 119.8;
119.9 (C24), 124.8; 124.9 (C21), 127.0; 127.1 (C22), 127.6; 127.7
(C23), 135.4; 135.8 (C10), 136.6; 136.8 (C9), 141.3; 141.4 (C25),
143.4; 143.6; 143.9; 144.2 (C20); 155.9; 156.1 (C17), 167.3 (C11),
Selective Carbamate Deprotection of (S)-N-Boc-Proline-OtBu (29)
tert-Butyl (S)-Pyrrolidine-2-carboxylate (30): A solution of N-Boc
carboxylate 29 (for synthesis of 29 see ref.[4b]) (0.054 g, 0.200 mmol)
in CH2Cl2 (1 mL) was cooled to 0 °C and TFA (1 mL) was added
dropwise. After stirring at 0 °C for 1 h the solvent was removed
and under reduced pressure and aqueous, half-saturated NaHCO3
(2 mL) was added (pH 8). After separation the aqueous layer was
extracted with CH2Cl2 (2ϫ 20 mL). The combined organic layers
were dried with MgSO4 and concentrated under reduced pressure.
The crude product was purified by chromatography (SiO2, MeOH/
CH2Cl2 = 1:30) to give free amine 30 (0.028 g, 0.164 mmol, 82%)
as a colorless oil. [α]2D0 = –31.7 (c = 1.200, EtOH) {ref.[24] [α]2D0
=
–32.0 (c = 1.200 , EtOH)}. Rf = 0.63 (MeOH/DCM = 1:10). 1H
NMR (300 MHz, CDCl3): δ = 1.39 (s, 9 H, 8-H), 1.60–1.78 (m, 3
H, 3Ј-H, 4-H), 1.95–2.08 (m, 1 H, 3-H), 2.30 (br. s, 1 H, -NH),
2.81–2.85 (dt, J = 10.2, 6.4 Hz, 1 H, 5Ј-H), 2.97–3.05 (dt, J = 10.4,
6.6 Hz, 1 H, 5-H), 3.55–3.60 (dd, J = 8.6, 5.2 Hz, 1 H, 2-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 25.5 (C4), 28.0 (C8), 30.4 (C3),
47.0 (C5), 60.4 (C2), 80.9 (C7), 174.7 (C6) ppm. IR: ν = 3346 (w),
˜
2972 (w), 2926 (w), 2866 (w), 1725 (s), 1476 (w), 1453 (w), 1389
(w), 1366 (m), 1226 (m), 1153 (s), 1116 (m), 846 (w), 800 (w), 743
(w) cm–1.
171.4; 171.5 (C6) ppm. IR: ν = 2969 (w), 2930 (w), 2866 (w), 1736
˜
(m), 1697 (s), 1632 (m), 1449 (m), 1416 (s), 1364 (m), 1301 (w),
1237 (m), 1151 (s), 1122 (m), 1102 (w), 1075 (w), 944 (w), 895 (w),
759 (m), 740 (s), 620 (w) cm–1. HRMS (ESI): calcd. for [M + H]–
529.26970; found 529.26963: calcd. for [M + Na]+ 551.25164; found
551.25113.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, detailed correlation of NMR spec-
1
troscopic data, H and 13C NMR spectra for all new compounds.
Acknowledgments
(4aS,6aR,9S,11aR)-1-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-11-
oxo-2,3,4,4a,6a,7,8,9,11,11a-decahydro-1H-pyrido[3,2-e]pyrrolo-
[1,2-a]azepine-9-carboxylic Acid (dia-3b): A solution of tricyclic dia-
3c (0.190 g, 0.475 mmol) in CH2Cl2 (2 mL) was cooled to 0 °C and
TFA (2 mL) was added dropwise. After stirring at room temp for
1 h the solvent was removed and under reduced pressure and aque-
ous, half-saturated NaHCO3 (5 mL) was added (pH 8). After ad-
dition of Fmoc-Cl (0.184 g, 0.713 mmol) in THF (6 mL) the solu-
tion was stirred at room temp for 16 h and then diluted with
CH2Cl2 (25 mL). The solution was acidified at 0 °C with HCl
(10 mL, 1 n) to pH 1. After separation the aqueous layer was ex-
tracted with CH2Cl2 (2ϫ 20 mL). The combined organic layers
were dried with MgSO4 and concentrated under reduced pressure.
The crude product was purified by a Reveleris® flash chromatog-
raphy system (SiO2, MeOH/CH2Cl2 gradient: 0–20%) to give dia-
3b (0.180 g, 0.380 mmol, 80%) as a colorless solid. [α]2D0 = –29.1 (c
= 0.375, CHCl3), m.p. 131 °C. Rf = 0.14 (MeOH/CH2Cl2 = 1:15).
1H NMR (600 MHz, 248 K, CDCl3): δ = 1.12–1.30 (m, 1 H, 13Ј-
H), 1.30–1.36 (m, 1 H, 12Ј-H), 1.47–1.53 (m, 1 H, 13-H), 1.94–
1.99; 2.04–2.10 (2ϫm, 3 H, 3Ј-H, 4Ј-H, 12-H), 2.25–2.31 (m, 1 H,
3-H), 2.34–2.40 (m, 1 H, 4-H), 2.68–2.80 (m, 1 H, 11-H), 2.80–2.92
(m, 1 H, 14Ј-H), 3.26–3.37 (m, 1 H, 10-H), 3.91–4.01 (m, 1 H, 14-
H), 4.20–4.24 (m, 1 H, 17-H), 4.35–4.40; 4.46–4.58 (2ϫm, 2 H, 16-
H), 4.58–4.61 (m, 1 H, 5-H), 4.70–4.83 (m, 1 H, 2-H), 5.45–5.61
(m, 1 H, 8-H), 5.79–6.02 (m, 1 H, 7-H), 7.30–7.34 (m, 2 H, 20-H),
7.39–7.44 (m, 2 H, 21-H), 7.56–7.58 (m, 2 H, 19-H), 7.77–7.79 (m,
2 H, 22-H) ppm. 13C NMR (150 MHz, 248 K, CDCl3): δ = 24.7
(C13), 25.8 (C4), 31.6 (C12), 31.9 (C3), 35.9 (C11), 46.7; 46.8 (C17),
48.7 (C14), 54.7 (C5), 61.8 (C2), 64.8 (C10), 67.3 (C16), 119.9
(C22), 124.8 (C19), 127.0 (C21), 127.6 (C20), 135.3 (C7), 136.3
(C8), 141.1; 141.2 (C23), 143.1; 143.9 (C18), 156.1 (C15), 170.1
The authors thank the Deutsche Forschungsgemeinschaft (DFG)
and the Schering Stiftung (fellowship to A. S.) for financial sup-
port. Donations of chemicals by BASF, Rockwood-Lithium,
Evonik and Bayer Health Care are gratefully acknowledged. The
authors also would like to thank Kathrin König for NMR support
and Sonisilpa Mohapatra and Johanna Nothacker for their assist-
ance.
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Received: June 11, 2014
Published Online: August 29, 2014
6480
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6467–6480