A Double Allylation Strategy for Gram-Scale Guaianolide Production: Total Synthesis of (+)-Mikanokryptin

Article abstract of DOI:10.1002/anie.201611078

With over 5000 members isolated to date, sesquiterpene lactones represent a prolific source of medicinal agents with several derivatives in human clinical trials. The guaianolides, a major subset of this group, have been intensely investigated from both m

Full text of DOI:10.1002/anie.201611078

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611078
German Edition: DOI: 10.1002/ange.201611078
Natural Products Synthesis
A Double Allylation Strategy for Gram-Scale Guaianolide Production:
Total Synthesis of (+)-Mikanokryptin
Xirui Hu, Silong Xu, and Thomas J. Maimone*
Abstract: With over 5000 members isolated to date, sesquiter-
pene lactones represent a prolific source of medicinal agents
with several derivatives in human clinical trials. The guaiano-
lides, a major subset of this group, have been intensely
investigated from both medicinal and chemical-synthesis
perspectives for decades. To date, the myriad stereochemical
permutations presented by this enormous family have pre-
cluded the synthesis of many unique members. Herein we
report the total synthesis of the trans-fused 8,12-guaianolide
(+)-mikanokryptin in 10 steps from (+)-carvone. Notably, this
synthesis is the first gram-scale total synthesis of a guaianolide
natural product.
S
esquiterpene lactones from the Asteraceae family of plants
represent one of the largest and most biologically significant
[1]
classes of plant secondary metabolites. Their presence in
both traditional herbal medicine regimes as well as modern
[
1,2]
human medicine have been extensively documented.
In
particular, a-methylene-g-lactone-containing members have
[
3]
[4]
strong documented anticancer, anti-inflammatory, anthel-
[
5]
[6]
mintic, and antimigraine activity. Multiple members have
also been shown to inhibit aspects of the NF-kB signaling
[
7]
pathway, a central mediator of the human immune response
whose deregulation is noted in inflammatory and auto-
[
8]
immune diseases as well as various human cancers.
The 5,7-fused bicyclic family of guaianolides is perhaps
the flagship subset of sesquiterpene lactone natural products
and two major, isomeric subtypes, the 6,12-guaianolides and
8
,12-guaianolides, have been isolated (Scheme 1A). Despite
extensive studies on the chemical synthesis of 6,12-guaiano-
[9]
Scheme 1. A) Guaianolide ring systems and various members of the
8,12-guaianolide family. B) A double allylation disconnection to access
lides, 8,12-guaianolides have received relatively limited
[
10]
attention from the synthetic community.
Mikanokryptin
8,12-guaianolides from simple precursors.
(1), isolated in 1975 by Herz and co-workers, belongs to the
continually growing family of trans-fused 8,12-guaianolides,
which are largely unexplored and present stereochemistry
patterns not readily addressed by current strategies (Sche-
me 1A). In developing a synthetic route to this family, we
viewed a double allylation disconnection as potentially
capable of constructing the guaianolide ring system 2 from
two simple, hypothetical fragments 3 and 4 (Scheme 1B). Of
significant concern to us was the paucity of examples of seven-
membered-ring formation by metal-mediated intramolecular
[
11]
[
12,13]
Barbier-type allylation relevant to this synthetic problem.
Herein we disclose the realization of this plan. Our straight-
forward total synthesis of 1 is suitable for the formation of
multigram quantities of advanced intermediates and a gram
of the natural product in a single synthetic pass.
[
*] X. Hu, Prof. Dr. S. Xu, Prof. Dr. T. J. Maimone
Department of Chemistry, University of California, Berkeley
826 Latimer Hall, Berkeley, CA 94720 (USA)
Our studies began with the construction of a precursor to
intermediate 3, for which we turned to the chiral pool of
E-mail: maimone@berkeley.edu
Prof. Dr. S. Xu
[
14]
terpenes. For the past several decades, limonene, isopule-
Current address: Department of Chemistry, School of Science
Xi’an Jiaotong University, Xi’an, 710049 (P.R. China)
[
15]
[16]
gol, and carvone have found broad application in the
synthesis of guaianane sesquiterpenes, among which carvone
is of particular utility for the synthesis of guaianolides with
oxidation at C3. Favorskii-type ring contractions have fea-
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201611078.
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Scheme 2. Gram-scale total synthesis of (+)-mikanokryptin (1). Reagents and conditions: a) carvone (1 equiv), Na CO (3 equiv), SO Cl (1.2 equiv, added
2
3
2
2
slowly over 2 h), DCM, 08C, then CeCl ·7H O (1.1 equiv), NaBH (3 equiv), MeOH, 08C, 1 h, 78%; b) TBDPSCl (1.2 equiv), imidazole (3 equiv), DMAP
3
2
4
(
0.05 equiv), DMF, room temperature, 8 h, 90%; c) O , pyridine (0.3 equiv), DCM, À788C, 20–40 min, then DMS (2 equiv), room temperature, 8 h, then
3
piperidine (0.15 equiv), AcOH (0.2 equiv), 408C, 16 h, 42%; d) In (1.5 equiv), 7 (1.2 equiv), 8 (1 equiv), H O (1 equiv), DMF, room temperature, 8 h, 67%,
2
d.r. 2:1; e) TESOTf (4 equiv), 2,4,6-collidine (6 equiv), DCM, 08C, 24 h, 78%; f) SnCl (4.5 equiv), NaI (9 equiv), DMF, 608C, 12 h, 90%; g) NaOMe
2
(
0.1 equiv), MeOH, 16 h, then AcOH (0.1 equiv), PtO (0.1 equiv), H (1 atm), 6 h, 96%; h) [Rh(PPh ) Cl] (0.1 equiv), H (1 atm), PhH, 1 h, 54%; i) TBAF
2
2
3
3
2
(
3 equiv), THF, room temperature, 24 h; DBU (1.1 equiv), toluene, DCM, D, 69%; j) MnO , DCM, room temperature, 16 h, 97%. DBU=1,8-diazabicyclo-
2
[5.4.0]undec-7-ene, DCM=dichloromethane, DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylformamide, DMS=dimethyl sulfide, TBDPSCl=tert-
butyldiphenylsilyl chloride, TESOTf=triethylsilyl trifluoromethanesulfonate, TBAF=tetra-n-butylammonium fluoride. All X-ray crystal structures shown were
obtained during preliminary studies conducted with (À)-carvone.
tured prominently in this regard, and typical result in
cyclopentane-containing building blocks in 5–8 synthetic
related 8,12-guianolides (Scheme 1), a cis arrangement
between the C6 hydroxy group and the neighboring acrylate
group is required on the future cycloheptane ring. Although
guaianolides with a trans arrangement of these groups have
been studied (see geigerin, for example, Scheme 1A),
fewer tactics exist to access this pattern and sometimes rely on
[
13a,c–g,16a–d]
steps.
we developed a robust three-step protocol from carvone
Scheme 2). The isopropenyl group of carvone was first
chlorinated at the allylic position (SO Cl , Na CO ), and then
Considering the desire for D4,5 unsaturation,
[10b–d]
(
2
2
2
3
directly subjected to the Luche reduction conditions. This
one-pot procedure afforded chloro-substituted cis-carveol 5
reliably on a 30 g scale in approximately 80% yield. Silylation
of 5 with tert-butyldiphenylsilyl chloride cleanly provided silyl
ether 6 in excellent yield (> 90%). Inspired by previous work
the inversion or epimerization of a trans-configured precur-
[19]
sor. We were pleased to find that allylic bromide 8, which
can be prepared in two steps from commercially available
materials on a decagram scale, functioned well in this
[20,21]
setting.
Under indium-mediated conditions, 8 could be
[
17]
with limonene, ozonolysis of 6 in the presence of catalytic
quantities of pyridine (0.3 equiv) resulted in chemoselective
cleavage of the trisubstituted olefin under carefully moni-
chemoselectively activated in the presence of allylic chloride
7, and was found to cleanly add to the aldehyde moiety to give
9 (d.r. 2:1 at C6) in 67% yield on a 14 g scale. Allylation
protocols based on activation with Cr, Zn, Pd, Cd, Sn, Pb, and
Bi were found to be inferior with respect to both yield and
[18]
tored cryogenic conditions. The sensitive dicarbonyl inter-
mediate thus formed following reductive quenching with
dimethyl sulfide underwent intramolecular aldol condensa-
tion in the presence of piperidine and acetic acid to afford
enal 7 in a one-pot procedure. Large quantities of 7 (ca. 100 g)
were readily prepared in our laboratory through this three-
step procedure, which is envisioned to serve as the foundation
for syntheses of numerous guaianolides with D4,5 unsatura-
tion.
[
22]
diastereoselectivity. Notably, the incorporation of 1 equiv-
alent of H O proved important; without it, slightly lower
2
diastereoselectivity was observed as well as extensive in situ
formation of the 6,12-lactone framework. With larger quanti-
ties, increased decomposition of 8 was observed. The sensitive
homoallylic alcohol 9 and the minor diastereomer were then
subjected to the mild deacetalization protocol reported by
[23]
With the western fragment completed, we turned toward
the first of two allylation reactions. For mikanokryptin (1) and
Fujioka, Kita, and co-workers (TESOTf, 2,4,6-collidine),
2
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[
24]
which also silylated the C6 alcohol, thus leading to 10. At
this stage, the minor diastereomer could also be separated.
With substrate 10 accessible on large scales, we were well-
positioned to evaluate the second, seven-membered-ring-
forming allylation reaction (Table 1). We commenced our
cyclized product was obtained. When all reagents (SnCl , NaI,
2
and 10) were simply mixed together and heated in a single
step (entry 8), a remarkably clean reaction ensued at 608C to
afford 11 in 90% yield as a single diastereomer. Notably, this
reaction was performed on a 7 g scale without a depression in
yield.
With a six-step, multigram-scale synthesis of the full
guaianolide skeleton complete, only redox manipulations
were required to complete the target. Chemoselective reduc-
tion of the D10,14 alkene in 11 proved challenging in the
presence of the more reactive a-methylenelactone. In the
presence of the Wilkinson catalyst, only the latter was
reduced to give 13 (Scheme 2). With PtO /H , both olefins
Table 1: Investigation of metal-mediated allylation conditions for the
synthesis of the 5,7,5-fused guaianolide lactone system.
2
2
could be readily hydrogenated. Taking advantage of the high
reactivity of the a-methylenelactone toward conjugate addi-
tion, we first treated 11 with a catalytic quantity of sodium
methoxide (10 mol%) in MeOH, and then reduced the
methanol addition product with the Adam catalyst (PtO2,
[
a]
[b]
Entry
Conditions
Yield [%]
14
[
c]
1
1
15
rsm
[
d]
1
2
CrCl , cat. NiCl , DMF, 608C
In , NaI, DMF, 608C
10
13
27
0
0
0
17
–
–
–
–
–
–
34
–
–
2
2
0
[e]
[d]
AcOH, H ) in near quantitative yield (96%) in the same flask.
2
[
[
[
[
[
[
f]
f]
f]
f]
f]
g]
3
4
5
6
7
8
NaI; SmI , HMPA–THF, À788C
17
51
–
–
–
–
2
When attempting the global desilylation of 12 (TBAF, THF),
we noticed that a base-mediated retro-conjugate addition of
MeOH occurred, thus resulting in a 5:2 mixture of the
deprotected conjugated ester and the methanol adduct in
83% yield. When DBU was added to the crude mixture, the
reaction could be pushed to completion in favor of the
conjugated ester product; thus, the ester was isolated in 69%
yield on a gram scale. Finally, the addition of freshly activated
0
NaI; Zn , aq. NH Cl, THF, rt
4
0
NaI; Mg , cat. (CH Br) , THF, rt
NaI; iPrMgCl, THF, 08C
NaI; SnCl , DMF, rt
SnCl , NaI, DMF, 608C
2
2
–
–
[e]
53
90
–
–
20
–
9
–
2
[e]
2
[
[
[
a] Reactions were performed on a 30 mg scale unless otherwise stated.
b] Yield of the isolated product. [c] Recovered starting material.
d] Diastereomeric ratio: 11/8-epi-11 2:1. [e] A single diastereomer was
obtained. [f] The starting material was first treated with NaI in acetone
for 8 h. [g] The reaction was performed on a 7 g scale.
MnO provided mikanokryptin (1) in near-quantitative yield
through highly chemoselective allylic oxidation. Notably, one
2
gram of 1 was synthesized in a single pass from (+)-carvone in
6
% overall yield. The absolute configuration of 1 was
confirmed as previously reported (synthetic: [a] =+ 235.08,
D
natural: [a] =+ 2648 (c = 0.098, MeOH)). Moreover, it is
D
envisioned that intermediate 11, readily accessible in multi-
gram quantities, could serve as a versatile intermediate for the
synthesis of guaianolides containing both D and D10,14
4
,5
[27]
functionalization.
investigation by exploring the venerable Nozaki–Hiyama–
Kishi (NHK) reaction (entry 1), which has proven efficient in
In summary, we have completed a short, enantiospecific,
gram-scale total synthesis of mikanokryptin, a complex 8,12-
guaianolide. Although guaianolides have been the subject of
numerous synthetic campaigns, most total synthetic routes to
[22a]
many syntheses of medium-sized rings.
The desired trans-
formation proceeded in low yield (10%) and with moderate
diastereoselectivity (d.r. 2:1). Surprisingly, the major products
formed in this reaction were a mixture of two diastereomeric
cyclooctanes 14. This competition (eight- versus seven-
membered-ring formation) was also observed under sama-
rium iodide mediated cyclization conditions with an allylic
iodide substrate, although in this case the formation of the
[28]
date have produced low-milligram quantities of material.
To the best of our knowledge, this approach represents the
first gram-scale, fully synthetic entry into this coveted
sesquiterpene family. Two highly robust and scalable allyla-
tion processes were critical in processing large quantities of
material. Through variations on this strategy, the synthesis of
other mikanokryptin-type 8,12-guaianolides should be possi-
ble. Such endeavors, in addition to the exploration of
alternative reagent-controlled allylation methods to enable
the synthesis of all guaianolide stereochemical patterns, are
currently under way and will be reported in due course.
[25]
seven-membered ring to give 11 prevailed slightly (entry 3).
In contrast, indium- and zinc-mediated conditions were more
selective for a single product (entries 2 and 4). In the former
case, 11 was afforded as a single diastereomer (13%), whereas
the latter produced 14 (51%), and recovered 10 (34%).
Magnesium-based conditions were ineffective for this trans-
formation (entries 5 and 6). Gratifyingly, tin(II) chloride
[
22h,26]
proved to be a superior reductant.
Finkelstein conver- Acknowledgements
sion of 10 into an allylic iodide, followed by SnCl -mediated
2
cyclization, afforded synthetically useful quantities of 11
This research was supported by the NIH (GM116952). T.J.M.
is an Alfred P. Sloan Fellow and Cottrel Scholar. Bristol-
Myers Squibb, Amgen, and the UC Berkeley Graduate
(
53%), along with the recovery of 10, and cycloheptanol 15
(
Table 1, entry 7). Notably, only one diastereomer of each
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Angewandte
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Division are acknowledged for providing predoctoral fellow-
ships to X.H. S.X. thanks the National Natural Science
Foundation of China (No. 21402149) and the Chinese
Scholarship Council (CSC) fellowship program. We thank
Dr. Hasan Celik and Yujia Tao for NMR spectroscopic
assistance and technical assistance, respectively. Dr. Antonio
DiPasquale is thanked for X-ray crystallographic analysis, for
which support from NIH Shared Instrument Grant S10-
RR027172 is acknowledged.
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Keywords: allylation · guaianolides · natural products ·
terpenes · total synthesis
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Angewandte
Communications
Chemie
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0
[
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dihydroxerantholide in 60% yield. This transformation allows
access to mikanokryptin-type guaianolides without C6 hydrox-
Manuscript received: November 15, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Natural Products Synthesis
X. Hu, S. Xu,
T. J. Maimone*
&&& — &&&
A Double Allylation Strategy for Gram-
Scale Guaianolide Production: Total
Synthesis of (+)-Mikanokryptin
Can’t have too much of a good thing: The
myriad stereochemical permutations of
the guaianolide sesquiterpene lactones
have precluded the synthesis of many
unique members. Now a total synthesis
of the trans-fused 8,12-guaianolide
(+)-mikanokryptin (see scheme) in
10 steps from (+)-carvone has been
developed on the basis of two highly
robust and scalable allylation processes,
which were critical for processing large
quantities of material.
6
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!