Angewandte
Chemie
pure cis isomer after chromatography.[16] Finally, the re-
oxidation of the side chain was achieved under mild
conditions by TEMPO-mediated oxidation with bis-
(acetoxy)iodobenzene (BAIB) in MeCN/water.[17] This way,
the building block 12 was obtained (in 12% overall yield from
5). Its relative configuration was secured by X-ray analysis
(Figure 3).
Figure 2. Model of an Ac-bHAsp-[ProM-5]-capped a-helical peptide.
The four carbonyl oxygen atoms of the bHAsp-[ProM-5] take part in
hydrogen bonds stabilizing the a-helical secondary structure of the
peptide.
Figure 3. Structure of the cis-4-vinylproline 12 in the crystalline state.
C gray, H white, O red, N blue.[38]
As protecting groups, the combination of a N-Boc and
a tert-butyl ester appeared to be most promising according to
our previous experience.[12] The required building block of
type 3, that is, the (so far unknown) N-Boc-protected cis-4-
vinylproline derivative 12, was synthesized in a seven-step
sequence (Scheme 2).
The second building block, that is, the trans-5-vinyl-
proline derivative 16, was synthesized as shown in Scheme 3.
Exploiting our one-pot double-protection procedure,[18] (S)-
proline (13) was first converted into the N-Boc-tert-butyles-
Scheme 3. Synthesis of the type 3 building block 16: a) Boc2O, NEt3,
then DMAP, RT, 15 h, quant.; b) Bu4NBF4, À2 eÀ, MeOH, 08C,
260 mA, 5 cm, 47% (3 steps); c) BF3·Et2O, CuBr·SMe2, vinyl-MgBr,
THF, À788C, 47%; d) TMSOTf, CH2Cl2, 08C, 5 min, 87%. DMAP=4-
(N,N-dimethylamino)pyridine, TMS=trimethylsilyl, OTf=trifluorome-
thanesulfonate.
Scheme 2. Synthesis of the type 3 building block 12: a) SOCl2, MeOH,
RT, 15 h, quant.; b) Boc2O, NEt3, MeCN, RT, 15 h, 98%; c) TsCl, NEt3,
CH2Cl2, RT, 15 h, 88%; d) NaCN, DMSO, 808C, 5 h, 94%; e) DIBALH,
CH2Cl2/nHex, À788C to RT, 7.5 h, 62%; f) Ph3PMeBr, BuLi, THF/nHex,
RT, 2 h, 32%; g) TEMPO, BAIB, MeCN/H2O, RT, 3 h, 76%. Boc=tert-
butoxycarbonyl, DIBALH=diisobutylaluminum hydride,
ter, which was electrochemically oxidized[12b,19] to the
methoxylated derivative 14. The crude product (14) was
then reacted with an excess of a vinyl MgBr-derived cuprate
in the presence of BF3·Et2O, exactly following the procedure
of Nagaike et al.[20] to afford the pure trans isomer 15 (after
chromatography) in 47% overall yield from 13 (3 steps).
Selective cleavage of the N-Boc protecting group was
smoothly achieved with TMSOTf (CH2Cl2, 08C, 5 min) to
give the pure amine 16 after aqueous work-up. It should be
mentioned that the configuration of 16 (obtained by a differ-
ent route as a minor diastereomer) had been secured by X-ray
crystal structure analysis in the course of our previous
work.[12]
The connection of the two vinylproline building blocks 12
and 16 was then carried out using COMU[21] as a coupling
reagent in the presence of Hꢀnigꢁs base to give 17 in 61%
yield (Scheme 4). The comparable low yield of 17 reflects the
steric bulkiness of the coupling partners.
An X-ray crystal structure analysis of the coupling
product 17 (Figure 4) confirmed its expected configuration
but also indicated an unfavorable pre-organization of the
vinyl moieties with respect to cyclization. Nevertheless, the
TEMPO=(2,2,6,6-tetramethylpiperidin-1-yl)oxyl, BAIB=bis-
(acetoxy)iodobenzene, Ts=para-tolylsulfonyl.
Starting from commercially available (S)-trans-4-hydrox-
yproline (5), the double protected derivative 7 was prepared
in high yield through methyl ester formation and Boc
protection.[13] Activation of the OH group by tosylation[14]
and treatment of the resulting intermediate 8 with NaCN in
DMSO at 808C then afforded the SN2 substitution product 9
with good diastereoselectivity (14:1).[15] Attempts to convert
the nitrile to an aldehyde function through Raney-Ni-
mediated hydrogenation[12] was associated with an epimeri-
zation at the 4-position, affording a 1:2 (cis/trans) mixture of
diastereomeric aldehydes. In contrast, the reduction of 9 with
DIBALH (3 equiv) proceeded without epimerization. The
crude product (isolated in 62% yield and identified by NMR
as the hemiacetal 10) was directly converted by Wittig
reaction to afford the vinyl prolinol derivative 11 as the
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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