14 research outputs found
2‑Naphthylmethoxymethyl as a Mildly Introducible and Oxidatively Removable Benzyloxymethyl-Type Protecting Group
2-Naphthylmethoxymethyl
(NAPOM) was developed for the protection
of various hydroxy (including phenolic hydroxy and carboxy) and mercapto
groups. The NAPOM group can be introduced in extremely mild conditions
(naphthylÂmethoxyÂmethyl chloride, 2,6-lutidine, room temperature)
without concomitant acyl migration in a 1,2-diol system. Furthermore,
selective removal of NAPOM in the presence of naphthylmethyl (NAP)
and <i>p</i>-methoxybenzyl (PMB) groups and, conversely,
that of PMB in the presence of NAPOM were realized. These results,
as well as its easy handling and compatibility with various solvents,
show that NAPOM is a novel and useful choice as a protecting group
Stereoselective Synthesis of the C1–C29 Part of Amphidinol 3
Stereoselective synthesis of the
C1–C29 part of amphidinol
3 (AM3) was achieved. The C1–C20 part was assembled from three
building blocks via regioselective cross metathesis to form the C4–C5
double bond and addition of an alkenyllithium and a lithium acetylide
to two Weinreb amides followed by asymmetric reduction to form the
C9–C10 and C14–C15 bonds, respectively. The C21–C29
part was synthesized via successive cross metathesis and oxa-Michael
addition sequence to construct the 1,3-diol system at C25 and C27
and Brown asymmetric crotylation to introduce the stereogenic centers
at C23 and C24. Coupling of the C1–C20 and C21–C29 parts
was achieved by Julia–Kocienski olefination and regio- and
stereoselective dihydroxylation of the C20–C21 double bond
in the presence of the C4–C5 and C8–C9 double bonds
to afford the C1–C29 part of AM3
Confirmation of the Absolute Configuration at C45 of Amphidinol 3
Amphidinol 3 (AM3), a membrane-active agent isolated
from the dinoflagellate <i>Amphidinium klebsii</i>, consists
of a long carbon chain containing
25 stereogenic centers. Although the absolute configuration of AM3
was determined by extensive NMR analysis and degradation of the natural
product, the partial structure corresponding to the tetrahydropyran
ring system was found to be antipodal to that of karlotoxin 2, a structurally
related compound recently isolated from the dinoflagellate <i>Karlodinium veneficum</i>. By extensive degradation of the natural
product and conversion of the resulting alcohol to an MTPA ester,
the absolute configuration at C45 of AM3 was confirmed to be <i>R</i>, supporting the originally proposed structure
Synthesis of the MN Ring of Caribbean Ciguatoxin C‑CTX‑1 via Desymmetrization by Acetal Formation
The MN ring of Caribbean ciguatoxin C-CTX-1 was synthesized
from
a meso-syn-2,7-dimethyloxepane derivative
corresponding to the M ring via desymmetrization by acetal formation
with a camphor derivative, followed by construction of the N ring
via the Horner–Wadsworth–Emmons reaction and acetal
formation. The meso-syn-2,7-dimethyloxepane
derivative was synthesized via photoinduced electrocyclization of
a conjugated exo-diene under flow conditions, giving
a cyclobutene derivative, followed by ring expansion via oxidative
cleavage and diastereoselective reduction of a β-hydroxy ketone
Head-to-Tail Interaction between Amphotericin B and Ergosterol Occurs in Hydrated Phospholipid Membrane
Amphotericin B (AmB) is thought to exert its antifungal
activity by forming an ion-channel assembly in the presence of ergosterol.
In the present study we aimed to elucidate the mode of molecular interactions
between AmB and ergosterol in hydrated phospholipid bilayers using
the rotational echo double resonance (REDOR) spectra. We first performed <sup>13</sup>CÂ{<sup>19</sup>F}ÂREDOR experiments with C14-<sup>19</sup>F-labeled AmB and biosynthetically <sup>13</sup>C-labeled ergosterol
and implied that both “head-to-head” and “head-to-tail”
orientations occur for AmB–ergosterol interaction in the bilayers.
To further confirm the “head-to-tail” pairing, <sup>13</sup>C-labeled ergosterol at the dimethyl terminus (C26/C27) was
synthesized and subjected to the REDOR measurements. The spectra unambiguously
demonstrated the presence of a “head-to-tail” orientation
for AmB–ergosterol pairing. In order to obtain information
on the position of the dimethyl terminus of ergosterol in membrane, <sup>13</sup>CÂ{<sup>31</sup>P}ÂREDOR were carried out using the labeled
ergosterol and the phosphorus atom of a POPC headgroup. Significant
REDOR dephasing was observed at the C26/C27 signal of ergosterol in
the presence of AmB, but not in the absence of AmB, clearly indicating
that the side-chain terminus of ergosterol in the AmB complex comes
close to the bilayer surface
Synthesis and Biological Activity of the C′D′E′F′ Ring System of Maitotoxin
Stereoselective synthesis of the
C′D′E′F′
ring system of maitotoxin was achieved starting from the E′
ring through successive formation of the D′ and C′ rings
based on SmI<sub>2</sub>-mediated reductive cyclization. Construction
of the F′ ring was accomplished via Suzuki–Miyaura cross-coupling
with a side chain fragment and PdÂ(II)-catalyzed cyclization of an
allylic alcohol. The C′D′E′F′ ring system
inhibited maitotoxin-induced Ca<sup>2+</sup> influx in rat glioma
C6 cells with an IC<sub>50</sub> value of 59 ÎĽM
Synthesis and Structure Revision of the C43–C67 Part of Amphidinol 3
Stereoselective synthesis of the C43–C67 part of amphidinol 3 (AM3) and its C51-epimer was achieved starting from a common intermediate corresponding to the tetrahydropyran moiety of AM3, via asymmetric oxidations and Julia–Kocienski olefination. By comparing NMR data of the synthetic specimens with those of AM3, the absolute configuration at C51 of AM3 was revised from <i>R</i> to <i>S</i>
Syntheses and Biological Activities of the LMNO, <i>ent</i>-LMNO, and NOPQR(S) Ring Systems of Maitotoxin
Structure–activity
relationship studies of maitotoxin (MTX),
a marine natural product produced by an epiphytic dinoflagellate,
were conducted using chemically synthesized model compounds corresponding
to the partial structures of MTX. Both enantiomers of the LMNO ring
system were synthesized via aldol reaction of the LM ring aldehyde
and the NO ring ketone. These fragments were derived from a common
cis-fused pyranopyran intermediate prepared through a sequence involving
Nozaki–Hiyama–Kishi reaction, intramolecular oxa-Michael
addition, and Pummerer rearrangement. The NOPQRÂ(S) ring system, in
which the original seven-membered S ring was substituted with a six-membered
ring, was also synthesized through the coupling of the QRÂ(S) ring
alkyne and the NO ring aldehyde and the construction of the P ring
via 1,4-reduction, dehydration, and hydroboration. The inhibitory
activities of the synthetic specimens against MTX-induced Ca<sup>2+</sup> influx were evaluated. The LMNO ring system and its enantiomer induced
36 and 18% inhibition, respectively, at 300 ÎĽM, whereas the
NOPQRÂ(S) ring system elicited no inhibitory activity
The Structure of the Bimolecular Complex between Amphotericin B and Ergosterol in Membranes Is Stabilized by Face-to-Face van der Waals Interaction with Their Rigid Cyclic Cores
Amphotericin B (AmB) is a polyene
macrolide antibiotic isolated
from <i>Streptomyces nodosus</i>. The antifungal activity
of AmB can be attributed to the formation of an ion-channel assembly
in the presence of ergosterol (Erg), in which there are two different
AmB–Erg orientations, parallel and antiparallel, as reported
previously. In this study, to elucidate the structures of those AmB–Erg
complexes based on solid-state nuclear magnetic resonance, a <sup>19</sup>F-labeled AmB derivative was newly prepared by a hybrid synthesis
that utilized degradation products from the drug. Using the 2-(trimethylsilyl)Âethoxymethyl
(SEM) group as the protecting group for the carboxylic acid moiety
of AmB, the fully deprotected labeled AmB compounds were obtained
successfully. Then, these labeled AmBs were subjected to <sup>13</sup>CÂ{<sup>19</sup>F} rotational-echo double-resonance (REDOR) experiments
in hydrated lipid bilayers. The results indicated the coexistence
of parallel and antiparallel orientations for AmB and Erg pairing,
at a ratio of 7:3. A total of six distances between AmB and Erg were
successfully obtained. Geometry analysis using the distance constraints
derived from the REDOR experiments provided the plausible AmB–Erg
complex structure for both the parallel and antiparallel interactions.
The flat macrolide of AmB and the tetracyclic core of Erg closely
contacted in a face-to-face manner, thus maximizing the van der Waals
interaction between the two molecules. This interaction can be attributed
to the coexistence of both the parallel and antiparallel orientations
Comprehensive Molecular Motion Capture for Sphingomyelin by Site-Specific Deuterium Labeling
Lipid rafts have attracted much attention because of
their significant
functional roles in membrane-associated processes. It is thought that
sphingomyelin and cholesterol are essential for forming lipid rafts;
however, their motion characteristics are not fully understood despite
numerous studies. Here we show accurate local motions encompassing
an entire sphingomyelin molecule, which were captured by measuring
quadrupole splittings for 19 kinds of site-specifically deuterated
sphingomyelins (that is, <i>molecular motion capture</i> of sphingomyelin). The quadrupole splitting profiles, which are
distinct from those reported from perdeuterated sphingomyelins or
simulation studies, reveal that cholesterol enhances the order in
the middle parts of the alkyl chains more efficaciously than at the
shallow positions. Comparison with dimyristoylphosphocholine bilayers
suggests that cholesterol is deeper in sphingomyelin bilayers, which
likely explains the so-called umbrella effect. The experiments also
demonstrate that (i) the C2′–C3′ bond predominantly
takes the gauche conformation, (ii) the net ordering effect of cholesterol
in sphingomyelin bilayers is not larger than that in phosphatidylcholine
bilayers, (iii) cholesterol has no specific preference for the acyl
or sphingosine chain, (iv) the acyl and sphingosine chains seem mismatched
by about two methylene lengths, and (v) the motion of the upper regions
of sphingomyelin chains is less temperature dependent than that of
lower regions probably due to intermolecular hydrogen bond formation
among SM molecules. These insights into the atomic-level dynamics
of sphingomyelin provide critical clues to understanding the mechanism
of raft formation