Angewandte

Communications Chemie

International Edition: DOI: 10.1002/anie.201611078

Natural Products Synthesis German Edition: DOI: 10.1002/ange.201611078

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.

Sesquiterpene lactones from the Asteraceae family of plants

represent one of the largest and most biologically significant
classes of plant secondary metabolites.[1] Their presence in
both traditional herbal medicine regimes as well as modern
human medicine have been extensively documented.[1, 2] In
particular, a-methylene-g-lactone-containing members have
strong documented anticancer,[3] anti-inflammatory,[4] anthel-
mintic,[5] and antimigraine activity.[6] Multiple members have
also been shown to inhibit aspects of the NF-kB signaling
pathway,[7] a central mediator of the human immune response
whose deregulation is noted in inflammatory and auto-
immune diseases as well as various human cancers.[8]
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 1 A). Despite
extensive studies on the chemical synthesis of 6,12-guaiano-
lides,[9] 8,12-guaianolides have received relatively limited Scheme 1. A) Guaianolide ring systems and various members of the
attention from the synthetic community.[10] Mikanokryptin 8,12-guaianolide family. B) A double allylation disconnection to access
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- two simple, hypothetical fragments 3 and 4 (Scheme 1 B). Of
me 1 A).[11] In developing a synthetic route to this family, we significant concern to us was the paucity of examples of seven-
viewed a double allylation disconnection as potentially membered-ring formation by metal-mediated intramolecular
capable of constructing the guaianolide ring system 2 from Barbier-type allylation relevant to this synthetic problem.[12, 13]
Herein we disclose the realization of this plan. Our straight-
forward total synthesis of 1 is suitable for the formation of
[*] X. Hu, Prof. Dr. S. Xu, Prof. Dr. T. J. Maimone multigram quantities of advanced intermediates and a gram
Department of Chemistry, University of California, Berkeley of the natural product in a single synthetic pass.
826 Latimer Hall, Berkeley, CA 94720 (USA)
Our studies began with the construction of a precursor to
E-mail: maimone@berkeley.edu
intermediate 3, for which we turned to the chiral pool of
Prof. Dr. S. Xu
Current address: Department of Chemistry, School of Science terpenes. For the past several decades, limonene,[14] isopule-
Xi’an Jiaotong University, Xi’an, 710049 (P.R. China) gol,[15] and carvone[16] have found broad application in the
Supporting information and the ORCID identification number(s) for synthesis of guaianane sesquiterpenes, among which carvone
the author(s) of this article can be found under http://dx.doi.org/10. is of particular utility for the synthesis of guaianolides with
1002/anie.201611078. oxidation at C3. Favorskii-type ring contractions have fea-

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Scheme 2. Gram-scale total synthesis of (+)-mikanokryptin (1). Reagents and conditions: a) carvone (1 equiv), Na2CO3 (3 equiv), SO2Cl2 (1.2 equiv, added
slowly over 2 h), DCM, 0 8C, then CeCl3·7 H2O (1.1 equiv), NaBH4 (3 equiv), MeOH, 0 8C, 1 h, 78 %; b) TBDPSCl (1.2 equiv), imidazole (3 equiv), DMAP
(0.05 equiv), DMF, room temperature, 8 h, 90 %; c) O3, pyridine (0.3 equiv), DCM, !78 8C, 20–40 min, then DMS (2 equiv), room temperature, 8 h, then
piperidine (0.15 equiv), AcOH (0.2 equiv), 40 8C, 16 h, 42 %; d) In (1.5 equiv), 7 (1.2 equiv), 8 (1 equiv), H2O (1 equiv), DMF, room temperature, 8 h, 67 %,
d.r. 2:1; e) TESOTf (4 equiv), 2,4,6-collidine (6 equiv), DCM, 0 8C, 24 h, 78 %; f) SnCl2 (4.5 equiv), NaI (9 equiv), DMF, 60 8C, 12 h, 90 %; g) NaOMe
(0.1 equiv), MeOH, 16 h, then AcOH (0.1 equiv), PtO2 (0.1 equiv), H2 (1 atm), 6 h, 96 %; h) [Rh(PPh3)3Cl] (0.1 equiv), H2 (1 atm), PhH, 1 h, 54 %; i) TBAF
(3 equiv), THF, room temperature, 24 h; DBU (1.1 equiv), toluene, DCM, D, 69 %; j) MnO2, DCM, room temperature, 16 h, 97 %. DBU = 1,8-diazabicyclo-
[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 (!)-carvone.

tured prominently in this regard, and typical result in related 8,12-guianolides (Scheme 1), a cis arrangement
cyclopentane-containing building blocks in 5–8 synthetic between the C6 hydroxy group and the neighboring acrylate
steps.[13a,c–g, 16a–d] Considering the desire for D4,5 unsaturation, group is required on the future cycloheptane ring. Although
we developed a robust three-step protocol from carvone guaianolides with a trans arrangement of these groups have
(Scheme 2). The isopropenyl group of carvone was first been studied (see geigerin, for example, Scheme 1 A),[10b–d]
chlorinated at the allylic position (SO2Cl2, Na2CO3), and then fewer tactics exist to access this pattern and sometimes rely on
directly subjected to the Luche reduction conditions. This the inversion or epimerization of a trans-configured precur-
one-pot procedure afforded chloro-substituted cis-carveol 5 sor.[19] We were pleased to find that allylic bromide 8, which
reliably on a 30 g scale in approximately 80 % yield. Silylation can be prepared in two steps from commercially available
of 5 with tert-butyldiphenylsilyl chloride cleanly provided silyl materials on a decagram scale, functioned well in this
ether 6 in excellent yield (> 90 %). Inspired by previous work setting.[20, 21] Under indium-mediated conditions, 8 could be
with limonene,[17] ozonolysis of 6 in the presence of catalytic chemoselectively activated in the presence of allylic chloride
quantities of pyridine (0.3 equiv) resulted in chemoselective 7, and was found to cleanly add to the aldehyde moiety to give
cleavage of the trisubstituted olefin under carefully moni- 9 (d.r. 2:1 at C6) in 67 % yield on a 14 g scale. Allylation
tored cryogenic conditions.[18] The sensitive dicarbonyl inter- protocols based on activation with Cr, Zn, Pd, Cd, Sn, Pb, and
mediate thus formed following reductive quenching with Bi were found to be inferior with respect to both yield and
dimethyl sulfide underwent intramolecular aldol condensa- diastereoselectivity.[22] Notably, the incorporation of 1 equiv-
tion in the presence of piperidine and acetic acid to afford alent of H2O proved important; without it, slightly lower
enal 7 in a one-pot procedure. Large quantities of 7 (ca. 100 g) diastereoselectivity was observed as well as extensive in situ
were readily prepared in our laboratory through this three- formation of the 6,12-lactone framework. With larger quanti-
step procedure, which is envisioned to serve as the foundation ties, increased decomposition of 8 was observed. The sensitive
for syntheses of numerous guaianolides with D4,5 unsatura- homoallylic alcohol 9 and the minor diastereomer were then
tion. subjected to the mild deacetalization protocol reported by
With the western fragment completed, we turned toward Fujioka, Kita, and co-workers (TESOTf, 2,4,6-collidine),[23]
the first of two allylation reactions. For mikanokryptin (1) and

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which also silylated the C6 alcohol, thus leading to 10.[24] At cyclized product was obtained. When all reagents (SnCl2, NaI,
this stage, the minor diastereomer could also be separated. and 10) were simply mixed together and heated in a single
With substrate 10 accessible on large scales, we were well- step (entry 8), a remarkably clean reaction ensued at 60 8C to
positioned to evaluate the second, seven-membered-ring- afford 11 in 90 % yield as a single diastereomer. Notably, this
forming allylation reaction (Table 1). We commenced our reaction was performed on a 7 g scale without a depression in
yield.
With a six-step, multigram-scale synthesis of the full
Table 1: Investigation of metal-mediated allylation conditions for the
synthesis of the 5,7,5-fused guaianolide lactone system. 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 PtO2/H2, both olefins
could be readily hydrogenated. Taking advantage of the high
reactivity of the a-methylenelactone toward conjugate addi-
Entry Conditions[a] Yield [%][b] tion, we first treated 11 with a catalytic quantity of sodium
11 14 15 rsm[c]
methoxide (10 mol %) in MeOH, and then reduced the
1 CrCl2, cat. NiCl2, DMF, 60 8C 10[d] 17 – – methanol addition product with the Adam catalyst (PtO2,
2 In0, NaI, DMF, 60 8C 13[e] – – – AcOH, H2) in near quantitative yield (96 %) in the same flask.
3[f ] NaI; SmI2, HMPA–THF, !78 8C 27[d] 17 – –
When attempting the global desilylation of 12 (TBAF, THF),
4[f ] NaI; Zn0, aq. NH4Cl, THF, rt 0 51 – 34
5[f ] NaI; Mg0, cat. (CH2Br)2, THF, rt 0 – – –
we noticed that a base-mediated retro-conjugate addition of
6[f ] NaI; iPrMgCl, THF, 0 8C 0 – – – MeOH occurred, thus resulting in a 5:2 mixture of the
7[f ] NaI; SnCl2, DMF, rt 53[e] – 20 9 deprotected conjugated ester and the methanol adduct in
8[g] SnCl2, NaI, DMF, 60 8C 90[e] – – – 83 % yield. When DBU was added to the crude mixture, the
[a] Reactions were performed on a 30 mg scale unless otherwise stated. reaction could be pushed to completion in favor of the
[b] Yield of the isolated product. [c] Recovered starting material. conjugated ester product; thus, the ester was isolated in 69 %
[d] Diastereomeric ratio: 11/8-epi-11 2:1. [e] A single diastereomer was yield on a gram scale. Finally, the addition of freshly activated
obtained. [f] The starting material was first treated with NaI in acetone MnO2 provided mikanokryptin (1) in near-quantitative yield
for 8 h. [g] The reaction was performed on a 7 g scale. through highly chemoselective allylic oxidation. Notably, one
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]D =+ 235.08,
natural: [a]D =+ 2648 (c = 0.098, MeOH)). Moreover, it is
envisioned that intermediate 11, readily accessible in multi-
gram quantities, could serve as a versatile intermediate for the
synthesis of guaianolides containing both D4,5 and D10,14
functionalization.[27]
investigation by exploring the venerable Nozaki–Hiyama– In summary, we have completed a short, enantiospecific,
Kishi (NHK) reaction (entry 1), which has proven efficient in gram-scale total synthesis of mikanokryptin, a complex 8,12-
many syntheses of medium-sized rings.[22a] The desired trans- guaianolide. Although guaianolides have been the subject of
formation proceeded in low yield (10 %) and with moderate numerous synthetic campaigns, most total synthetic routes to
diastereoselectivity (d.r. 2:1). Surprisingly, the major products date have produced low-milligram quantities of material.[28]
formed in this reaction were a mixture of two diastereomeric To the best of our knowledge, this approach represents the
cyclooctanes 14. This competition (eight- versus seven- first gram-scale, fully synthetic entry into this coveted
membered-ring formation) was also observed under sama- sesquiterpene family. Two highly robust and scalable allyla-
rium iodide mediated cyclization conditions with an allylic tion processes were critical in processing large quantities of
iodide substrate, although in this case the formation of the material. Through variations on this strategy, the synthesis of
seven-membered ring to give 11 prevailed slightly (entry 3).[25] other mikanokryptin-type 8,12-guaianolides should be possi-
In contrast, indium- and zinc-mediated conditions were more ble. Such endeavors, in addition to the exploration of
selective for a single product (entries 2 and 4). In the former alternative reagent-controlled allylation methods to enable
case, 11 was afforded as a single diastereomer (13 %), whereas the synthesis of all guaianolide stereochemical patterns, are
the latter produced 14 (51 %), and recovered 10 (34 %). currently under way and will be reported in due course.
Magnesium-based conditions were ineffective for this trans-
formation (entries 5 and 6). Gratifyingly, tin(II) chloride
proved to be a superior reductant.[22h, 26] Finkelstein conver- Acknowledgements
sion of 10 into an allylic iodide, followed by SnCl2-mediated
cyclization, afforded synthetically useful quantities of 11 This research was supported by the NIH (GM116952). T.J.M.
(53 %), along with the recovery of 10, and cycloheptanol 15 is an Alfred P. Sloan Fellow and Cottrel Scholar. Bristol-
(Table 1, entry 7). Notably, only one diastereomer of each Myers Squibb, Amgen, and the UC Berkeley Graduate

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Division are acknowledged for providing predoctoral fellow- 1975, 14, 1664; c) W. F. Reynolds, R. G. Enriquez, M. A. Chavez,
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[26] a) G. P. Boldrini, L. Lodi, E. Tagliavini, C. Tarasco, C. Trombini, [28] For notable exceptions, see Ref. [16d] and a) C. Li, X. Yu, X. Lei,
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[27] The treatment of 1 with Zn0 in acetic acid at reflux gave 11b,13-
dihydroxerantholide in 60 % yield. This transformation allows Manuscript received: November 15, 2016
access to mikanokryptin-type guaianolides without C6 hydrox- Final Article published: && &&, &&&&

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 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 (+)-mikanokryptin (see scheme) in
myriad stereochemical permutations of 10 steps from (+)-carvone has been
the guaianolide sesquiterpene lactones developed on the basis of two highly
have precluded the synthesis of many robust and scalable allylation processes,
unique members. Now a total synthesis which were critical for processing large
of the trans-fused 8,12-guaianolide quantities of material.

6 www.angewandte.org ! 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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These are not the final page numbers!