Total synthesis of the biphenyl alkaloid (-)-lythranidine

Article abstract of DOI:10.1002/anie.201402550

A sequence comprising a ring-closing alkyne metathesis of a propargyl alcohol derivative, followed by a ruthenium-catalyzed redox isomerization of the derived cycloalkyne and a transannular aza-Michael addition allowed the formation of the distinguishing

Full text of DOI:10.1002/anie.201402550

Angewandte
Chemie
DOI: 10.1002/anie.201402550
Natural Products
Total Synthesis of the Biphenyl Alkaloid (ꢀ)-Lythranidine**
Konrad Gebauer and Alois Fꢀrstner*
Abstract: A sequence comprising a ring-closing alkyne meta-
thesis of a propargyl alcohol derivative, followed by a ruthe-
nium-catalyzed redox isomerization of the derived cycloalkyne
and a transannular aza-Michael addition allowed the forma-
tion of the distinguishing piperidine-metacyclophane frame-
work of the Lythraceum alkaloid lythanidine in a few high-
yielding steps. This application attests to the excellent func-
tional-group tolerance of a molybdenum alkylidyne complex
endowed with triphenylsilanolate ligands, which enabled the
macrocyclization even in the presence of protic functionalities,
and thus illustrates the power of contemporary catalytic
acetylene chemistry for target-oriented synthesis.
M
ost alkaloids derived from plants of the Lythraceae family
comprise a substituted quinolizidine core, however, a small
subset features a rather unique piperidine-metacyclophane
structure, as illustrated by lythranidine (1) and its close
relatives lythranine (2) and lythramine (3; Scheme 1).[1]
Isolated from the perennial plant Lythrum anceps Makino,[2]
which serves as herbal remedy as well as for ritual purposes in
Japan (“miso-hagi”, “bon-bana”), the 2,6-piperidine-dietha-
nol subunit of 1–3 bears a certain resemblance to Lobelia
alkaloids such as lobelin (4), a well-known respiratory
stimulant. The 2,6-trans-stereochemistry in 1–3 and the
presence of a macrocyclic frame with an embedded biphenyl
motif are distinguishing structural elements. The diaryl axis of
1–3 is considerably skewed to relieve unfavorable interactions
between the peripheral phenol and phenol ether sites;
however, the barrier remains small enough that the rotamers
can equilibrate and atropisomers do not persist in solution.[3]
Although these unusual structural attributes led to fairly
detailed physico-chemical studies,[3,4] preparative approaches
to this class of alkaloids and biological studies are scarce. The
only known forays to racemic 1 were either completely
unselective or even delivered a C3,C11-bis-epimeric product,
and therefore hardly meet todayꢀs standards.[5,6] Encouraged
by this state of affairs, we now present the first concise and
stereoselective total synthesis of optically pure 1 as the parent
compound of this family.
Scheme 1. Selected Lythraceae alkaloids and retrosynthetic analysis of
lythranidine (1). The inset shows possible decomposition pathways on
attempted metathesis of propargylic alcohol derivatives. X=generic
anionic ligand.
be linked with the macrocyclization event through catalytic
acetylene chemistry (Scheme 1). To this end, a ring-closing
alkyne metathesis (RCAM)[7,8] reaction of a propargylic
alcohol derivative was envisaged as the key strategic maneu-
ver. Such substrates however, although potentially highly
versatile,[9] had basically been beyond reach of alkyne meta-
thesis for two major reasons: on the one hand, they are
endangered upon contact with the standard alkylidyne
catalysts, most of which are fairly Lewis acidic species by
virtue of their high-valent d0 metal center (compare with the
putative adduct of type E).[10] Even if they stay uncompro-
mised and enter into the catalytic cycle in the first place,
propargyl alcohol derivatives may not subsist as they can give
rise to metal alkylidyne intermediates of type F, which carry
a potential leaving group next to the nucleophilic carbon
center. In fact, it was only recently that we were able to show
that such substrates can be successfully engaged with the help
of molybdenum alkylidyne complexes endowed with triar-
ylsilanolate ligands as the most active and selective catalysts
presently available.[11,12] Yet, only a small set of model
compounds has been investigated so far and the methodology
needs further scrutiny by implementation into more demand-
ing settings. The lythranidine case provides an excellent
Our synthesis plan centered on the perception that the
formation of the 2,6-trans-disubstituted piperidine ring might
[*] M. Sc. K. Gebauer, Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
[**] Generous financial support by the Max-Planck-Gesellschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged. We
thank C. Wirtz for excellent NMR support and M. Hebenbrock for
assistance in the preparation of the building blocks.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402550.
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opportunity: supposed that a macrocyclic compound of type
B can be formed in this way, a subsequent ruthenium-
catalyzed redox isomerization[13] should unravel an enone A,
which in turn might intercept a transannular amine donor[14,15]
and hence allow the lythranidine skeleton to be forged in
a few straightforward operations.
amide)[18,19] at low temperature gave the desired Mannich
product 14, and was well suited for material throughput.[20] As
expected, the reduction of 14 using LiAlH(OtBu)3 in Et2O at
low temperature furnished the required 1,3-syn configured
aminoalcohol 15 with decent selectivity (d.r. = 4.5:1).[21] As
the minor anti isomer could be separated by flash chroma-
tography, this route was practical and allowed gram amounts
of compound 16 to be secured after silylation of the secondary
alcohol.
The necessary building blocks of type C and D were
readily prepared and assembled, as shown in Scheme 2. A
The ortho-directing effect exerted by the MOM group
served the selective metalation of 9 with tBuLi well,[22] thus
setting the basis for an efficient Negishi cross-coupling
reaction with iodide 16 to craft the central biaryl axis.[23]
Because our original plan to maintain the N-sulfinyl group
throughout the synthesis was thwarted by the inability to
perform the projected redox isomerization in the presence of
this group, the sulfinamide was selectively cleaved with the
help of Dess–Martin periodinane[24] and replaced by a benzyl-
oxycarbonyl moiety to give diyne 17 as an adequate cycliza-
tion precursor.
The macrocyclization of diyne 17 through RCAM worked
exceedingly well, even at ambient temperature in the
presence of the now commercially available complex 25,[25]
furnishing the desired product 18 in 91% yield on a 1.4 gram
scale (Scheme 3). Concomitant cleavage of the TBS ether and
the phenolic MOM acetal with dilute HCl in EtOH readily
gave the free propargyl alcohol 20 for the envisaged redox
isomerization.[26] From a chemical viewpoint it is noteworthy
that the order of events could also be reversed: thus, RCAM
was similarly successful with compound 19, which contains
three different protic sites. If one keeps in mind that free
alcohols had precluded alkyne metathesis from occurring as
long as standard Schrock alkylidyne complexes had to be used
as catalysts,[7] this outcome is deemed quite remarkable. It
illustrates a new facet of the excellent functional-group
tolerance of molybdenum alkylidynes endowed with silano-
lates as ancillary ligands,[8,12,25] and augurs well for future
applications of this methodology to even more highly
decorated substrates.
With the supply of 20 secured, we turned our attention to
the formation of the yet missing piperidine ring by a sequence
of redox isomerization of the propargylic alcohol followed by
transannular aza-Michael addition.[13,14] To this end, 20 was
exposed to catalytic amounts of [IndRu(PPh3)2Cl], In(OTf)3
and camphorsulfonic acid in THF at 808C. While the desired
enone 21 was formed cleanly, a spontaneous heterocycle
formation would not proceed under these conditions, as we
had originally hoped. Actually, this step turned out to be
rather challenging, most likely because of an unfavorable
transannular positioning of the reacting sites on the macro-
cyclic frame of 21; to complicate matters further, the incipient
product 22 is somewhat unstable under harsher conditions.
After some optimization, however, the use of pTsOH in 1,2-
dichloroethane at slightly elevated temperature gave well
reproducible results, furnishing the desired piperidine as
a mixture of readily separable isomers in favor of the trans-
disubstituted ring 22 (d.r. = 2.4:1).[27] Attempts at improving
the diastereomeric ratio with the help of chiral Brønsted acids
met with no success.
Scheme 2. a) NaH, MOMCl, THF, 08C!RT, 99%; b) allyl alcohol,
Pd(OAc)2 (1 mol%), Bu4NCl, NaHCO3, DMF, 508C, 80%; c) propynyl-
magnesium bromide, THF, 08C!RT, 71%; d) TBSCl, imidazole,
DMAP, CH2Cl2, 08C!RT, 98%; e) I2, Ag2SO4, MeOH, 89%; f) (COCl)2,
DMSO, Et3N, CH2Cl2, ꢀ788C!RT, 90%; g) (R)-pTol-S(O)NH2, Ti-
(OEt)4, CH2Cl2, reflux, 92%; h) KHMDS, Et2O, ꢀ788C, then 13, 64%
(+ 6% of diastereomer); i) LiAlH(OtBu)3, LiCl, Et2O, ꢀ788C, 79% (+
16% of the 1,3-anti isomer); j) TBDPSCl, imidazole, DMAP, CH2Cl2,
08C!RT, 90%; k) (1) 9, tBuLi, Et2O, 08C; (2) ZnCl2, THF; (3) 16,
Pd(PPh3)4 (2.5 mol%), THF, 608C, 75%; l) Dess–Martin periodinane,
MeCN/CH2Cl2/H2O (8:8:1), 76%; m) CbzCl, Et3N, EtOAc, 08C!RT,
79%; Cbz=benzyloxycarbonyl; DMAP=4-dimethylaminopyridine;
KHMDS=potassium hexamethyldisilazide; MOM=methyloxymethyl;
TBDPS=tert-butyldiphenylsilyl; TBS=tert-butyldimethylsilyl, pTol =p-
tolyl.
Heck reaction of the MOM-protected 4-iodophenol 6 with
allyl alcohol[16] readily afforded large amounts of the required
propanal derivative 7. Because the projected redox isomer-
ization would planarize the propargylic alcohol center
anyway, there was no need to conduct the addition of the
alkynyl donor in an asymmetric fashion. Thus, 7 was simply
reacted with commercially available propynylmagnesium
bromide and the resulting alcohol 8 was protected as the
corresponding TBS-ether 9 prior to cross-coupling with the
second arene building block 16. This compound was prepared
by a silver-assisted iodination of commercially available 10 in
MeOH, furnishing product 11 with excellent selectivity and in
high yield.[17] The formation of the kinetic potassium enolate
followed by the addition of sulfinimine 13 (readily formed
from 12 and commercially available (R)-p-toluenesulfin-
2
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spectral fingerprint also became much clearer and allowed the
assignments to be confirmed; for details, see the Supporting
Information.
The final cleavage[28] of the TBDPS-ether with TBAF
required buffered conditions and proceeded only slowly but
gave lythranidine (1) in excellent yield and purity. As
expected, two equilibrating diastereomers were detected at
ambient temperature that relate to the known dynamic of the
biaryl motif;[3,4] reasonably sharp spectra were recorded at
+ 458C, which allowed all signals to be resolved and assigned,
and hence the constitution and stereostructure of the
synthetic samples of 1 to be verified. The diasteromeric
product 11-epi-1 was prepared analogously, the spectra of
which are distinctly different from those of the natural
product.
The route presented herein (15 steps, longest linear
sequence, approximately 5% overall yield) is the first
stereoselective entry into a rather intriguing class of alkaloids,
which had been known for a long time but went largely
untapped by the synthetic community. It attests to the
maturity that alkyne metathesis has reached since the
advent of new catalysts of largely improved functional-
group tolerance.[8,25] The straightforward and selective for-
mation of a heterocyclic amino-alcohol motif from an acyclic
diyne precursor exemplifies that the virtues of this method-
ology go far beyond the stereoselective formation of olefins
by semireduction of the acetylenic products initially formed,
which was the most common application in the past.[29,30]
Finally, we would like to emphasize that the present inves-
tigation also provides new impetus for the study of trans-
annular reactivity, which had been recognized as inherently
powerful early on, but was often difficult to harness in
practice.[15] As the access to macrocyclic rings with well-
defined stereochemical patterns becomes increasingly facile,
a more systematic survey of this promising reactivity mode
seems possible. Ongoing work in this laboratory intends to
further illustrate this notion.
Scheme 3. a) 25 (5 mol%), MS 5 ꢁ, toluene, 91% (18) or 78% (20);
b) HCl in EtOH (1% w/w), 89% (20) or 77% (19); c) [IndRu(PPh3)2Cl]
(6 mol%), In(OTf)3 (6 mol%), camphorsulfonic acid (10 mol%), THF,
808C, 74%; d) pTsOH (10 mol%), 1,2-dichloroethane, 458C, 22 (67%
brsm)+9-epi-22 (27% brsm); e) LiAlH(OtBu)3, LiCl, Et2O, 08C, 92%
(23); f) NaBH4, MeOH, 08C, 23 (49%)+11-epi-23 (40%); g) H2
(1 atm), Pd black (10 mol%), aq. HCl, EtOH, 93% (65%, 11-epi
series); h) TBAF, HOAc, THF, 458C, 82% (1); 76% (11-epi-1);
i) HCHO, MeOH, 76% (24), 61% (11-epi-24); brsm=based on
recovered starting material; Ind=indenyl; MS=molecular sieves;
TBAF=tetra-n-butylammonium fluoride; pTs =p-toluenesulfonyl.
Received: February 18, 2014
Published online: && &&, &&&&
Keywords: 1,4 additions · alkynes · metathesis · molybdenum ·
.
ruthenium
Gratifyingly though, the reduction of 22 with LiAlH-
(OtBu)3 in the presence of excess LiCl was highly selective,
although the analysis of the NMR spectra was complicated by
the fact that coalescence of the two conformers could not be
reached, and the rotamers of the Cbz group further compli-
cate matters. To ensure a definite assignment of the newly
formed center, 22 was deliberately subjected to an unselective
reduction with NaBH4. The resulting diastereomers were then
transformed into the corresponding N,O-acetals 24 and 11-
epi-24, which allowed the configuration of the alcoholic
center set through hydride reduction to be assigned by
analysis of the NOE contacts and the coupling pattern.
However, to this end, the spectra had to be recorded at
+ 908C in [D8]toluene, in which they are not obscured any
longer by massive line broadening. After hydrogenolytic
cleavage of the Cbz group in 23 in slightly acidic medium, the
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Natural Products
Triple: The distinguishing piperidine-
metacyclophane framework of the
K. Gebauer, A. Fꢁrstner*
&&&& — &&&&
Lythraceum alkaloid lythanidine was
formed by ring-closing alkyne metathesis
(RCAM) of a propargylic alcohol deriva-
tive followed by redox isomerization and
a proton-catalyzed transannular aza-
Michael addition as the key steps. This
straightforward approach illustrates the
enabling power of catalytic alkyne
Total Synthesis of the Biphenyl Alkaloid
(ꢀ)-Lythranidine
chemistry for target-oriented synthesis.
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