Cyclombandakamines A1 and A2, Oxygen-Bridged Naphthylisoquinoline Dimers from a Congolese Ancistrocladus Liana

Article abstract of DOI:10.1021/acs.orglett.7b00209

Cyclombandakamines A₁ (1) and A₂ (2), both with an unprecedented pyrane-cyclohexenone-dihydrofuran sequence and six stereocenters and two chiral axes, are the first oxygen-bridged dimeric naphthylisoquinoline alkaloids. They were isolated from the leaves of an as yet unidentified Congolese Ancistrocladus species. Their stereostructures were established by spectroscopic, chemical, and chiroptical methods in combination with DFT and TDDFT calculations. They apparently originate from a cascade of oxidative cyclization reactions of open-chain naphthylisoquinoline dimers and exhibit significant antiprotozoal activities.

Full text of DOI:10.1021/acs.orglett.7b00209

Letter
pubs.acs.org/OrgLett
Cyclombandakamines A and A , Oxygen-Bridged
1
2
Naphthylisoquinoline Dimers from a Congolese Ancistrocladus Liana
Blaise Kimbadi Lombe,† , †T orsten Bruhn, Doris Feineis, Virima Mudogo, Reto Brun,
,‡
†,§
†
‡
∥,⊥
and Gerhard Bringmann*
†
Institute of Organic Chemistry, University of Wu
̈
rzburg, Am Hubland, D-97074 Wu
de Kinshasa, B.P. 202 Kinshasa XI, Democratic Republic of the Congo
Federal Institute for Risk Assessment, Max-Dohrn-Straße 8-10, D-10589 Berlin, Germany
̈
rzburg, Germany
‡
́ ́
Faculte des Sciences, Universite
§
∥Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland
⊥University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland
*
S Supporting Information
ABSTRACT: Cyclombandakamines A (1) and A (2), both
1
2
with an unprecedented pyrane−cyclohexenone−dihydrofuran
sequence and six stereocenters and two chiral axes, are the first
oxygen-bridged dimeric naphthylisoquinoline alkaloids. They
were isolated from the leaves of an as yet unidentified
Congolese Ancistrocladus species. Their stereostructures were
established by spectroscopic, chemical, and chiroptical
methods in combination with DFT and TDDFT calculations.
They apparently originate from a cascade of oxidative
cyclization reactions of “open-chain” naphthylisoquinoline
dimers and exhibit significant antiprotozoal activities.
1
aphthylisoquinoline alkaloids from tropical Ancistrocla-
dimers, thus possessing a constitutionally highly unsymmetric
central biaryl axis, located in the peri position neighboring one of
the outer axes. This close proximity of two bulky aryl substituents
renders 3a and 3b the sterically most crowded naphthylisoquino-
line alkaloids found to date in nature, making the search for
further novel-type metabolites in this phytochemically so
productive Congolese Ancistrocladus species a rewarding task.
In this paper, we report on the isolation and structural
elucidation of two novel dimeric naphthylisoquinoline alkaloids,
cyclombandakamines A (1) and A (2), which feature, for the
first time, oxygen bridges that link the “northwestern”
naphthalene moiety to both the adjacent isoquinoline portion
and the other “southeastern” naphthalene part, resulting in eight
condensed rings. Compared with 3a and 3b, they possess only
two chiral biaryl axes but have two additional stereogenic centers.
Furthermore, we describe their anti-infective activities and
discuss their presumable biosynthetic origin.
N
daceae and Dioncophyllaceae lianas are the first known2
tetrahydroisoquinoline natural products of polyketidic origin.
They consist of a naphthalene and an isoquinoline subunit
connected by a biaryl axis, which isin most casesrotationally
hindered. Their broad structural variety is further enlarged by the
occurrence of dimeric representatives, with up to four stereo-
3
,4
genic centers and three chiral axes. Depending on the
individual structures, some of them possess pronounced
3
−5
1
2
antiprotozoal and antiviral activities.
From the leaves of a botanically as yet unidentified
Ancistrocladus species growing in the northwestern part of the6
Democratic Republic of the Congo near the town of Mbandaka,
we have recently isolated two structurally remarkable anti-
plasmodial dimers, mbandakamines A (3a) and B (3b) (Figure
). They are the first 6′,1″-coupled naphthylisoquinoline
4
1
LC−MS investigations on further fractions obtained during
the isolation of 3a and 3b hinted at the presence of another,
minor dimeric alkaloid with a mass 12 mass units greater than
that of 3a and 3b and a slightly different UV curve, especially in
the range from 280 to 400 nm (Figure S1). Preparative HPLC on
a reversed-phase column provided a beige amorphous powder.
+
According to HR-ESI-MS (m/z 797.3783, [M + 1] ), it had a
molecular formula of C H N O , suggesting that it might be a
49
52
2
8
Received: January 20, 2017
Figure 1. Structures of mbandakamines A (3a) and B (3b).
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00209
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Organic Letters
Letter
dehydro derivative of 3a or 3b with an additional N- or O-methyl
2″, C-4″, and C-10″. From the HMBC correlations from H-7″,
H-7‴, and H-4 ‴ [δ 3.06 (1H, dd, J = 17.1, 4.51 Hz)] to C-5‴,
group.
eq
H
1
Its H NMR spectrum displayed a full set of signals indicative
the northwestern half 1-B was found to be 5‴,8″-coupled, like
of an unsymmetric dimer, with four methoxy groups, as in 3a/b,
the additional methyl being attached to one of the nitrogen
atoms (Table S1). In the aromatic region, only seven protons
the southeastern part 1-A (Figure 2). Joint HMBC correlations
from H-7′, CH -2″, and both protons at C-3″ to a quaternary
3
carbon (δ 85.3) proved this C atom to be C-1″ (Figure 2),
C
3
,4
were observed, instead of eight or 10 as usual, hinting at a
novel-type structure. Likewise unprecedented was the presence
of three (instead of two) methylene groups with diastereotopic
hence indicating that the two molecular portions 1-A and 1-B are
4
coupled through C-6′ and C-1″, respectively, as in 3a/b.
In contrast to 3a and 3b and all other known naphthylisoqui-
noline alkaloids, ROE interactions between H-7″ and both
protons and the observation of a quaternary carbon at δ 196.0 in
C
the 13C7 NMR spectrum, indicative of a tetralone carbonyl
diastereotopic protons, H-4 ‴ (for the NMR data, see Table S1)
eq
carbon.
and H-4 ‴ [δ 3.84 (1H, dd, J = 17.1, 5.4 Hz)], were observed
ax
H
Similar to 3a/b, the southeastern part of 1, denoted as 1-A
Figure 2, right) showed NMR signals typical of a 5,8′-coupled
(Figure 2, 1-B), suggesting that the two moieties in that
northwestern half are not orthogonal but much closer to one
another than usual, firmly pressed against each other, apparently
by being part of a tight ring. This is due to an ether bond between
O-6‴ and C-1″, which furthermore explains the observed
(
downfield shift of this carbon (δ 85.3). In a similar way, the
C
chemical shift of C-2″ (δ 92.3) indicated that this atom is
C
involved in an ether bond with the spatially close oxygen, O-5′,
like the above-mentioned linkage between C-1″ and O-6‴, thus
establishing the northern part of 1-B to be a tetralone subunit.
Hence, the isolated dimer was found to be the first cyclized (since
twofold-oxygen-bridged) N-methyl analogue of 3a and 3b. It was
therefore named cyclombandakamine A1.
This novel-type naphthylisoquinoline dimer is also stereo-
chemically thrilling: it possesses not only the usual two
stereocenters in each of the isoquinoline moieties and one
stereogenic axis in the southeastern half but also, for the first
time, two additional stereocenters in the tetralone moiety.
Furthermore, the C,C axis linking the two northwestern bicyclic
aryls (C-5‴ to C-8″) remains a further potential stereogenic
element.
Figure 2. Key ROESY (double arrows) and HMBC (single arrows)
interactions of 1 indicative of the constitutions of the southeastern
moiety (1-A) and the northwestern part (1-B), including the key
HMBC correlation between them (in green) that evidences their site of
connection.
monomeric naphthylisoquinoline, with the other (northwestern)
4
part, 1-B, linked via C-6′. The pattern included a meta coupling
The relative configurations at the stereocenters in the two
isoquinoline moieties were determined to be trans from ROESY
of the two aromatic protons, H-1′ [δ 6.51 (1H, pt, J = 1.1 Hz)]
H
and H-3′ [δ 6.80 (1H, d, J = 1.2 Hz)], sequential ROESY
H
interactions between CH -1 and H-3, between CH -1‴ and H-
interactions {H-7′ [δ 6.38 (1H, s)]−H-4 [δ 2.33 (1H, dd, J =
3
3
H
eq
H
3
‴ (Figure 3), and between CH -3‴ and H-1‴. The latter, quite
1
1
4
7.9, 4.9 Hz)]−H-4 [δ 1.94 (1H, dd, J = 17.9, 11.4 Hz)]−H-
3
ax
H
′−CH -2′ [δ 2.29 (3H, pd, J = 0.3 Hz)]−H-3′−OCH -4′ [δ
3
H
3
H
.00 (3H, s)]}, and HMBC correlations from H-7 [δ 6.41 (1H,
H
s)], H-4 , and H-7′ to C-5 (δ 119.7). An HMBC interaction of
eq
C
H-7′ (colored in green in Figure 2) to a quaternary carbon (δ
C
8
5.3) belonging to 1-B established C-6′ (δ 121.0) as the
C
connection site of 1-A to 1-B.
The northwestern part 1-B (Figure 2, left) is spectroscopically
more complex. It possesses an N-methylated isoquinoline
portion with a methoxy group [δ 3.72 (3H, s)] at C-8‴ (δ
H
C
1
58.0). This was evidenced by a series of ROESY correlations
{
CH -3‴ [δ 0.93 (3H, d, J = 6.7 Hz)]−CH -N [δ 2.92 (3H,
Figure 3. Key ROESY interactions indicating the relative and (given the
results of oxidative degradation for C-3 and C-3‴) absolute
configurations of 1. The blue arrows concern the correlations within
the molecular halves and the black and green ones the interactions
between them.
3
H
3
H
s)]−CH -1‴ [δ 1.73 (3H, d, J = 6.6 Hz)]−OCH -8‴−H-7‴
3
H
3
[δ 6.47 (1H, s)]} together with HMBC correlations from CH -
H
3
N to C-1‴ (δ 57.9) and C-3‴ (δ 55.1) and from H-1‴, H-7‴,
C
C
and OCH -8‴ jointly to C-8‴.
3
An AB spin system {H-7″ [δ 8.04 (1H, d, J = 9.0 Hz)], H-6″
H
[
δ 7.35 (1H, d, J = 9.0 Hz)]}, ROESY interactions of H-6″ with
unusual interaction hinted at the presence of a second, less
common conformation in the western isoquinoline part,
presumably as a consequence of the repulsive van der Waals
interactions of the tightly pressed H-4‴ and H-7″. Ruthenium-
H
OCH -5″ [δ 3.97 (3H, s)], and HMBC correlations from H-7″
3
H
to C-5″ (δ 160.6) and C-9″ (δ 138.3), from OCH -5″ to C-5″,
C
C
3
and from H-6″ to C-10″ (δ 119.4) proved the position of
C
8
OCH -5″ and thus evidenced the aforementioned carbonyl
mediated oxidative degradation established the absolute
3
group to be at C-4″ (Figure 2, 1-B). This assignment was
configuration at both C-3 and C-3‴ to be R, which, with respect
to the above-assigned relative trans configuration, evidenced R
configurations at C-1 and C-1‴ too. From the ROESY
interactions of H-4 with H-1′ and of H-4 with H-7′ (Figure
corroborated by the low-field shifts of the diastereotopic protons
[
δ 3.12 (1H, dd, J = 0.7, 14.6 Hz) and δ 3.03 (1H, d, J = 14.6
H
H
Hz)] at C-3″, by their ROESY interactions with CH -2″ [δ 1.85
3
H
ax
eq
(
3H, pd, J = 0.3 Hz)], and by their HMBC correlations with CH -
3) and on the basis of the above-established absolute R
3
B
DOI: 10.1021/acs.orglett.7b00209
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
configurations at C-3 and C-1, the axis in the southeastern
naphthylisoquinoline half, 1-A, was determined to be P-
configured, as in 3a/b.
the presence of seven aromatic protons and a carbonyl function,
but with one additional CH group (δ 2.96 and δ 41.5). The
3
H
H
1D and 2D NMR data (Figure 5a and Table S2) proved that this
methyl group is linked to the nitrogen of the southeastern
naphthylisoquinoline half. This is the only constitutional
difference compared with 1.
In the tetralone subunit, the linkage of O-6‴ with C-1″
sterically fixes the western axis, making its absolute configuration
and that of C-1″ mutually dependent: a P configuration at the
western biaryl axis and R at C-1″ entailing each other, like M
implying S. This phenomenon reduced the number of remaining
possible stereoisomers from eight (as expected for three
independent stereogenic elements) to only four, two of them
with a cis array of the dihydrofuran−cyclohexenone system and
two with a trans junction, which, however, would be severely
strained (Figure S2a). Indeed, the ROE interaction between
CH -2″ and H-7‴ (Figures 3 and S2) indicated the dihydrofuran
3
and cyclohexenone rings to be cis-fused, thus further reducing the
number of possible diastereomers to only two, with 1″R,2″S,8″P
and 1″S,2″R,8″M configurations (Figure S2b).
These two remaining isomers were distinguished by the
ROESY interactions observed between CH -3‴ and H-7′ and
3
between CH -3‴ and H-7 (Figure 3, green arrows), which
3
Figure 5. (a) ROESY (double arrows) and HMBC (single arrows)
showed that C-1″, C-2″, and the C-8″−C-5‴axis are R-, S-, and P-
interactions of cyclombandakamine A (2) relevant for its constitution.
2
configured, respectively. In the other possible diastereomer, with
Colored correlations (in red and blue) highlight differences in the
eastern part of 2 compared with that of 1. (b) Comparison of the ECD
spectra of 1 and 2.
the 1″S,2″R,8″M configuration, CH -3‴ would point in the
3
opposite direction (Figure S3) and thus would be far away from
H-7′ and H-7, so that no spatial interactions between these nuclei
would be expected. Consequently, cyclombandakamine A (1) is
1
Stereochemical differences between the two alkaloids were
found in the southeastern half of the second dimer, too (Figure
1
R,3R,5P,1″R,2″S,8″P,1‴R,3‴R-configured, i.e., with the full
absolute stereostructure presented in the abstract graphic.
To further verify our experimental assignment, both
5
a). In this part, the proton at C-3, which is axial, as is obvious
from the coupling constants of H-4 [δ 2.31, (1H, dd, J = 17.5,
ax
H
1″R,2″S,8″P- and 1″S,2″R,8″M-configured diastereomers were
1
1.9 Hz)] and H-4 [δ 1.97 (1H, dd, J = 17.5, 2.9 Hz)], showed
eq H
subjected to a B97-D3/def2-TZVP-based conformational
analysis. From the resulting lowest-energy conformers, one for
each diastereomer was chosen. The experimentally observed
ROE interactions matched well only with the ones predicted for
the optimized structure of the 1″R,2″S,8″P isomer. Moreover,
the electronic CD (ECD) spectrum calculated for the
a ROESY interaction with H-1, thus indicating a cis configuration
at C-1 versus C-3 instead of trans as in the respective part of 1. In
addition, this alkaloid displayed ROESY interactions between H-
4ax and H-7′ and between H-4 and H-1′ (Figure 5a), opposite
eq
to the ones observed for 1-A (Figure 2). In the northwestern half,
the relative configurations of all stereogenic elements were
identical to those in 1-B, i.e., trans configuration for both C-3‴
versus C-1‴ and C-1″ relative to C-2″. The oxidative degradation
provided a ca. 1:1 ratio of R- and S-configured N-methyl-3-
aminobutyric acid as a consequence of the opposite config-
urations at C-3 and C-3‴, leaving open the question of whether
the molecule is 3R,3‴S- or 3S,3‴R-configured. Considering the
aforementioned relative configurations of all stereogenic
elements and the ROESY interactions observed between its
two halves, among them H-7 with CH -3‴ and H-7′ with CH -
1″R,2″S,8″P diastereomer at the TDCAM-B3LYP/def2-SVP
level showed good agreement with the experimental spectrum of
the isolated product (Figure 4, left), while that of the
3
3
3
‴ (Table S2 and Figure 5a), a 3R,3‴S configuration would lead
to the overall 1S,3R,5M,1″S,2″R,8″M,1‴S,3‴S configuration,
while 3S,3‴R would give a total 1R,3S,5P,1″R,2″S,8″P,1‴R,3‴R
configuration, i.e., the enantiomer. The close similarity of the
ECD curves of the second compound with that of 1 (Figure 5b)
established that the new alkaloid possesses the absolute
stereostructure 2, as shown in the abstract graphic, i.e., with
the 1R,3S,5P,1″R,2″S,8″P,1‴R,3‴R configuration. It was hence-
Figure 4. Comparison of the experimental ECD spectrum of 1 with the
ones calculated for (left) 1″R,2″S,8″P- and (right) 1″S,2″R,8″M-
configured isomers.
1
″S,2″R,8″M diastereomer was virtually opposite (Figure 4,
right). This confirmed the above-established full absolute
stereostructure of 1 and indicated that its CD curve is largely
dominated by the tetralone chromophore (see the Supporting
Information).
forth named cyclombandakamine A .
2
Cyclombandakamines A (1) and A (2) are the first examples
1
2
of (twofold) O-bridged naphthylisoquinoline dimers. As out-
lined in Scheme 1, the direct biogenetic precursor of 1 might be
an N-methylated derivative of 3a/b, like compound 8. This
dimer should arise from three oxidative coupling steps, viz., those
linking 4 and 5 to give the two monomers 6 and 7 (blue axes),
differing only in their O- and N-methylation patterns, and one
oxidative cross-coupling of 6 and 7 to yield the mbandakamine
analogue 8 (red axis). Compound 8 could then be further
Investigations of fresh, genetically identical plant material
collected at the same site resulted in the isolation of a second,
similar compound. It had a molecular formula of C H N O , as
5
0
55
2
8
+
evidenced by HR-ESI-MS (m/z 811.3952, [M + 1] ), thus
showing a molecular weight 14 units greater than that of 1. Its H
and C spectra revealed close similarities to those of 1, including
1
13
C
DOI: 10.1021/acs.orglett.7b00209
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Organic Letters
Letter
Scheme 1. Proposed Biosynthetic Pathway of 1
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00209.
Experimental details and additional data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: bringman@chemie.uni-wuerzburg.de.
ORCID
Gerhard Bringmann: 0000-0002-3583-5935
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Deutsche Forschungsgemein-
schaft (Br 699/14-2; SFB 630 “Agents against Infectious
Diseases”). B.K.L. thanks the Deutscher Akademischer Aus-
tauchdienst, the Excellence Scholarship Program BEBUC, the
Else-Kro
Stiftung for generous support. We acknowledge experimental
assistance from Dr. M. Grune, Mrs. P. Altenberger, and Mrs. E.
Ruckdeschel (NMR), Dr. M. Buchner and Mrs. J. Adelmann
MS), Mrs. M. Michel (oxidative degradation), and Dr. C.
Steinert (work on the crude extract), from the University of
Wurzburg. We also thank Prof. G. Heubl and Dr. F. Turini from
̈
ner-Fresenius-Stiftung, and the Holger-Poehlmann-
̈
̈
(
oxidized to give enone 10 through another phenol-oxidative
activation via phenoxy radical 9, now leading to an intramolecular
C−O coupling (green C−O bond). In this step, a P configuration
at the northwestern axis would create the observed R
configuration at C-1″. Subsequent intramolecular Michael
addition of the phenolic oxygen function at C-5′ (inducing the
observed cis array and hence the S configuration at C-2″) would
̈
̈
the University of Munchen for phylogenetic analyses.
DEDICATION
■
Dedicated to Professor Dr. Dr. h.c. Lutz F. Tietze, University of
Go
̈
ttingen, on the occasion of his 75th birthday.
REFERENCES
■
then give 1. Thus, cyclombandakamine A (1) would arise from
1
(
1) (a) Bringmann, G.; Pokorny, F. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: New York, 1995; Vol. 46, pp 127−271.
b) Bringmann, G.; Francois, G.; Ake Assi, L.; Schlauer, J. Chimia
1998, 52, 18.
(2) Bringmann, G.; Wohlfarth, M.; Rischer, H.; Gru
Angew. Chem., Int. Ed. 2000, 39, 1464.
3) (a) Boyd, M. R.; Hallock, Y. F.; Cardellina, J. H., II; Manfredi, K. P.;
Blunt, J. W.; McMahon, J. B.; Buckheit, R. W., Jr.; Bringmann, G.;
Schaffer, M.; Cragg, G. M.; Thomas, D. W.; Jato, J. G. J. Med. Chem.
994, 37, 1740. (b) Xu, M. J.; Bruhn, T.; Hertlein, B.; Brun, R.; Stich, A.;
Wu, J.; Bringmann, G. Chem. - Eur. J. 2010, 16, 4206. (c) Bringmann, G.;
Zhang, G.; Buttner, T.; Bauckmann, G.; Kupfer, T.; Braunschweig, H.;
Brun, R.; Mudogo, V. Chem. - Eur. J. 2013, 19, 916.
4) Bringmann, G.; Lombe, B. K.; Steinert, C.; Ndjoko Ioset, K.; Brun,
R.; Turini, F.; Heubl, G.; Mudogo, V. Org. Lett. 2013, 15, 2590.
5) Ibrahim, S. R. M.; Mohamed, G. A. Fitoterapia 2015, 106, 194.
four consecutive oxidative coupling steps (forming the bonds
highlighted in blue, red, and green)the highest total number
for a naphthylisoquinoline alkaloid to date. In a similar manner, 2
might originate from a doubly N-methylated 3-epi-derivative of
(
̧
́
̈
ne, M.; Schlauer, J.
3
a.
This thrilling cyclization behavior, which has never been
(
9
,10
observed before in naphthylisoquinoline alkaloids, is certainly
a consequence of the highly condensed structure of the
mbandakamines, in which the phenolic parts are tightly pressed
against each other, thus facilitating the domino-type reaction
sequence depicted in Scheme 1.
̈
1
̈
(
Cyclombandakamines A (1) and A (2) displayed significant
1
2
inhibitory activities in vitro against Plasmodium falciparum NF54,
with IC values of 0.043 and 0.055 μM, respectively. In addition,
(
(6) Turini, F.; Steinert, C.; Heubl, G.; Bringmann, G.; Lombe, B. K.;
Mudogo, V.; Meimberg, H. Taxon 2014, 63, 329.
50
2
was very active against Trypanosoma brucei rhodesiense, with an
(
7) Hemberger, Y.; Zhang, G.; Brun, R.; Kaiser, M.; Bringmann, G.
Chem. - Eur. J. 2015, 21, 14507.
8) Bringmann, G.; God, R.; Schaeffer, M. Phytochemistry 1996, 43,
IC of 0.01 μM (selectivity index >1000), making it a promising
5
0
candidate for further investigations. Compound 1, by contrast,
was much less active (IC = 1.09 μM; Table S3).
(
5
0
1393.
In summary, cyclombandakamines A (1) and A (2) are the
(9) For oxygen-bridged products resulting from similar oxidative
follow-up reactions of other natural biaryls, see, for example:
1
2
first oxygen-bridged naphthylisoquinoline dimers, and the first
such compounds to possess eight stereogenic elements (six
centers and two axes, one of them being thermodynamically
dictated). Their unprecedented structures will trigger more-in-
depth biosynthetic, synthetic, and pharmaceutical investigations.
This work is in progress.
(a) Buchanan, M. S.; Gill, M.; Millar, P.; Phonh-Axa, S.; Raudies, E.;
Yu, J. J. Chem. Soc., Perkin Trans. 1 1999, 795. (b) Fisher, P. J.; Anson, A.
E.; Webster, J.; Adriaenssens, P.; Whitehurst, J. S. Trans. Br. Mycol. Soc.
1
988, 90, 499.
(10) For (non-natural) overoxidized products of monomeric
naphthylisoquinoline alkaloids, see ref 7.
D
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Org. Lett. XXXX, XXX, XXX−XXX