A General Biomimetic Hetero-Diels-Alder Approach to the Core Skeletons of Xenovulene A and the Sterhirsutins A and B

Article abstract of DOI:10.1021/acs.orglett.8b04003

A biomimetic, regio- and stereoselective approach to the 5,6,11-tricyclic core skeleton of xenovulene A, as well as sterhirsutins A and B, is described. The key steps are a biomimetic inverse-electron-demand hetero-Diels-Alder cycloaddition of α-humulene and a ribose-derived vinyl ketone, followed by acid-catalyzed rearrangement of the 1,3-dioxolane that neighbors the resultant cyclic enol ether.

Full text of DOI:10.1021/acs.orglett.8b04003

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
A General Biomimetic Hetero-Diels−Alder Approach to the Core
Skeletons of Xenovulene A and the Sterhirsutins A and B
̈
Pei-Jun Li, Gerald Drager, and Andreas Kirschning*
Institute of Organic Chemistry and Center of Biomolecular Drug Research (BMWZ), Leibniz Universitat
B, 30167 Hannover, Germany
̈
Hannover, Schneiderberg
1
*
S Supporting Information
ABSTRACT: A biomimetic, regio- and stereoselective
approach to the 5,6,11-tricyclic core skeleton of xenovulene
A, as well as sterhirsutins A and B, is described. The key steps
are a biomimetic inverse-electron-demand hetero-Diels−Alder
cycloaddition of α-humulene and a ribose-derived vinyl
ketone, followed by acid-catalyzed rearrangement of the 1,3-
dioxolane that neighbors the resultant cyclic enol ether.
enovulene A (1), an oxygenated humulene-containing
chemical consideration that further suggests a biosynthetic
origin via hetero-DA union.
X
meroterpene, was isolated from Acremonium strictum in
1
1
995 (Figure 1). It was found to be an inhibitor of
In continuation of our recent work on biomimetic Diels−
5
Alder cycloadditions in the synthesis of the elansolids, we now
disclose a regio- and stereoselective approach to the tricyclic
core skeleton of xenovulene A (1) and the sterhirsutins A (2)
and B (3) by means of a hetero-Diels−Alder cycloaddition.
Our retrosynthetic analysis of xenovulene A and sterhirsutins
A and B is depicted in Scheme 1. We envisioned that advanced
diastereomeric hetero-Diels−Alder products 5a and 5b,
6
accessible from vinyl ketone 6 and α-humulene (7), would
serve as key intermediates to access the three natural products
7
1
−3 via enone 4. We planned to prepare ketone 6 by a short
Scheme 1. Retrosynthetic Analysis of Key Intermediates 4
and 5 en Route to Xenovulene A (1) and Sterhirsutins A (2)
and B (3)
Figure 1. Structures of xenovulene A (1), sterhirsutins A (2) and B
3).
(
benzodiazepine binding to the human γ-aminobutyric acid
GABA) receptor with an IC50 value of 40 nM. Additionally,
(
2
antidepressant effects were encountered for 1. Structurally
related to xenovulene are sterhirsutin A and B (2 and 3), which
were isolated by Liu and co-workers from Stereum hirsutum in
2
014. Both diastereoisomers exhibit moderate antiproliferative
activities against human myelogenous leukemia (K562) cells
with IC50 values of 13 and 16 μg/mL, respectively.
3
Although these meroterpenes originate from different fungal
species, they all share a similar 5,6,11-tricyclic core structure.
Biosynthetically, this core structure may be constructed
through an inverse hetero-Diels−Alder cycloaddition (hetero-
DA) between an α,β-unsaturated ketone fragment and the
3
,4
sesquiterpene α-humulene. Notably, the two diastereomeric
forms, sterhirsutins A and B, also appear to be the endo- and
exo-products of a possible Diels−Alder reaction, a stereo-
Received: December 14, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04003
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
6
a,b,12
6c
sequence through 1,4-addition and methenylation of cyclo-
pentenone 8, which itself can be prepared from D-ribose (9).
ditions.
Related to these findings, the groups of Liu
6d
8
and George utilized highly reactive diene precursors, such as
o-quinone methides in the synthesis of (rac) guajadiol B and
hyperjapones A−E, respectively. In the present case, we rely on
an α,β-unsaturated ketone as diene in the transformation with
α-humulene (7), which lacks the reactivity of quinone
methides. To our delight, we found that heating a solvent-
free mixture of 16 with an excess of 7, followed by TBAF-
mediated TBS deprotection, afforded the desired cycloadducts
18a and 18b in 2:1 diastereomeric ratio and 51% combined
yield over two steps (Scheme 3 and Table 1, entry 5). The
A key issue points to the regioselectivity of the cycloaddition
with respect to the dienophile, α-humulene (7), as the
sterically least congested double bond at C-1/C-2 has to react
9
exclusively.
12
The synthesis of vinyl ketones 16 and 17 commenced with
protection of the C2 and C3 positions of D-ribose (9) as an
acetonide, followed by treatment with vinylmagnesium bro-
8
mide to give triol 10 in 80% yield (Scheme 2). Oxidative
a
Scheme 2. Synthesis of Vinyl Ketone 5
Scheme 3. Hetero-Diels−Alder Cycloaddition, Synthesis
and X-ray Analysis (Graphical Representation) of Silyl
Ether 19a, and Acid-Catalyzed Rearrangement of Acetonide
a
1
8a−b ( )
a
TBAF = tetra-n-butylammonium fluoride.
Table 1. Studies on the Hetero-Diels−Alder Cycloaddition
a
Cy = cyclohexyl, TBS = tert-butylsilyl, DMAP = 4-dimethylamino-
pyridine, LDA = lithium diisopropyl.
a
a
cleavage of the remaining 1,2-diol with sodium metaperiodate
entry
conditions
time/h
yield (%)
dr
b
followed by Wittig olefination with triphenylphosphonium
1
2
3
4
5
6
7
16/7 (1:10), solvent
16/7 (1:10), additive
16/7 (1:20), 150 °C
16/7 (1:20), 150 °C
16/7 (1:20), 150 °C
48
24
48
120
240
120
120
10
c
methylidene provided diene 12 in good yield and selectivity.
d
d
d
Ring-closing metathesis of diene 12 using the Grubbs catalyst
type I gave the corresponding cyclopentenol, which was
20
50
51
50
1:1
2:1
2:1
2:1
directly oxidized with MnO to afford cyclopentenone 8 in
2
d
6
0% yield over two steps. Photochemical activation of
16/7 (1:5), 150 °C
17/7 (1:5), 150 °C
d
methanol and 1,4-addition to cyclopentenone 8 then furnished
alcohol 13 in 65% yield. After protection as TBS-ether (90%
yield), the resulting ketone 14 was treated with lithium
8a
a
Yields and dr refer to the isolated and purified products after two
b
c
steps. Toluene, xylene, nitrobenzene; refluxing. AlCl , SnCl ,
3
4
d
diisopropylamide (LDA) and Eschenmoser’s salt (Me N =
Sc(OTf) ; refluxing in toluene. Sealed tube.
2
3
CH I) followed by iodomethane to afford enone 16 in 70%
2
11c
yield after Hofmann elimination.
Alternatively, enone 17
isomers were separable by column chromatography (18a: R =
f
was prepared from 8 by 1,4-addition with (t-BuOCH ) CuLi
2
2
0
.6; 18b: R = 0.55; ethyl acetate/petroleum ether 1:1);
f
and subsequent Eschenmoser methenylation in 65% yield over
1
1
however, NMR analysis, including NOE experiments, was not
sufficient to unequivocally prove the configuration of the newly
formed stereogenic centers. Final confirmation only came after
TBS protection of diastereoisomer 18a, which provided
compound 19a as a crystalline solid and permitted X-ray
diffraction analysis.
two steps.
With methyl vinyl ketone 16 in hand, we turned our
attention to the hetero-Diels−Alder cycloaddition using α-
humulene (7), the biomimetic key reaction. A seminal study by
Baldwin et al. on the Diels−Alder cycloaddition with
humulene utilized a quinone methide benzotropolone as the
diene, which was generated in situ under thermal con-
B
DOI: 10.1021/acs.orglett.8b04003
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
This hetero-Diels−Alder cycloaddition of 16 with α-
humulene (7), however, required some optimization, which
is summarized in Table 1. Initially, the reaction was carried out
in several high-boiling-point solvents (toluene, xylene, and
nitrobenzene) with heating at reflux temperature for 48 h.
Under these conditions, an inseparable mixture of homodimers
derived from 16 was detected by high-resolution mass
spectrometry (entry 1). Addition of Lewis acids such as
AlCl , SnCl , and Sc(OTf) only led to the decomposition of
state B is less favored due to an interaction of the acetonide
group (concave hemisphere) with the other methyl group in 7.
Finally, acid-catalyzed rearrangement of acetonides 18a and
18b provided enones 20a and 20b, respectively (Scheme 3).
This transformation was not initially expected, but to our
delight, it provided a desirable advanced intermediate in one
step, which is poised for late-stage modification to the full
structure of xenovulene A (1) and sterhirsutene A (2). A
plausible mechanism for this unique transformation is
summarized in Scheme 5. Supported by the oxygen atom
3
4
3
1
3
16 (entry 2).
When enone 16 was heated in α-humuleme (7) as solvent in
a sealed tube at 150 °C for 48 h, and following treatment of the
Scheme 5. Proposed Mechanism for the Acid-Catalyzed
Rearrangement of Acetonide 18 to Enone 20
crude material with TBAF, the desired cycloaddition products
18a,b were isolated in 20% yield over the two steps (entry 3).
Subsequently, the yield could be raised to 50% (dr = 2:1) by
extending the reaction time to 5 days. Longer reaction times
did not lead to a significant improvement (entry 5); however,
the excess of 7 could be decreased to five equivalents under
these conditions without loss of yield (entry 6). In all cases,
vinyl enone 16 was consumed by a [4 + 2]-hetero Diels−Alder
13a,14
dimerization as detected by LCMS.
However, efforts to
purify and isolate the mixture of dimers led to complete
decomposition. Finally, the reaction of enone 17 with α-
humulene (7) yielded a complex and inseparable product
mixture (entry 7).
The diastereoselectivity of the hetero-Diels−Alder cyclo-
addition of 16 with α-humulene (7) is moderate. Two
transition states A and B can be proposed, that explain the
observed facial selectivity (Scheme 4). These are based on two
that neighbors the acetonide ring, proton-mediated migration
of the tetrasubstituted olefin of 18 gives rise to enol ether 21.
Further protonation and opening of the 1,3-dioxolan ring leads
to diene 22, which collapses with loss of acetone to yield enone
Scheme 4. Proposed Transition States of the Hetero-Diels−
Alder Cycloaddition of 16 with α-Humulene (7)
2
0.
In summary, we have developed a concise synthetic
approach to the 5,6,11-tricyclic core skeleton of xenovulene
A (1) and the sterhirsutins A (2) and B (3). A novel
biomimetic hetero-Diels−Alder cycloaddition, involving α-
humulene and a ribose-derived vinyl ketone, was used to
construct the central dihydropyran motif, and acid-catalyzed
rearrangement of the remaining 1,3-dioxolane provided a
useful late-stage intermediate en route to compounds 1−3.
Our study paves the way to rapidly access the full structure of
xenovulene A and the sterhirsutins. Further studies on the total
synthesis of xenovulene A as well as sterhirsutins A and B are
currently underway.
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04003.
principal considerations. The vinyl ketone 16 is characterized
by a convex and a concave face. As a result, the siloxymethyl
substituent is oriented into a pseudoaxial position partly filling
the space of the convex face. Second, Shirahama and co-
workers carried out a molecular mechanics calculation
analysis on the preferred conformations of α-humlenene (7).
They suggested two conformations which differ in a ring flip of
the macrocycle with the methyl groups of the trisubstituted
alkenes being oriented anti to each other and pseudoaxially.
Therefore, one face of the π-bond at C-1/C-2 is shielded by
the macrocycle. As a result a re- and si-face approach with
respect to enone 16 can be postulated, leading to the two
diastereomeric cycloaddition products 19a and 19b. Transition
Detailed experimental procedures, spectral data, and X-
ray crystallography (PDF)
1
5
Accession Codes
CCDC 1884756 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
C
DOI: 10.1021/acs.orglett.8b04003
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
14) (a) Heravi, M. M.; Ahmadi, T.; Ghavidel, M.; Heidari, B.;
AUTHOR INFORMATION
■
Hamidi, H. RSC Adv. 2015, 5, 101999−102075. (b) Palasz, A. Top.
Curr. Chem. (Z) 2016, 374, 24.
Corresponding Author
(
15) (a) Shirahama, H.; Arora, S. H.; Osawa, E.; Matsumoto, T.
*
E-mail: andreas.kirschning@oci.uni-hannover.de.
Tetrahedron Lett. 1983, 24, 2869−2872. (b) Neuenschwander, U.;
Czarniecki, B.; Hermans, I. J. Org. Chem. 2012, 77, 2865−2869.
ORCID
Andreas Kirschning: 0000-0001-5431-6930
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
P.-J.L. is thankful to the Hannover School of Biomolecular
Drug Research (HSBDR) doctoral training center for financial
support. Helpful discussions from Dr. Michael Wolling
(
Boehringer Ingelheim AG & Co. KG, Germany) and Dr.
Matthew D. Norris (Leibniz Universitat Hannover) are kindly
acknowledged.
̈
REFERENCES
■
(
1) Ainsworth, A. M.; Chicarelli-Robinson, M. I.; Copp, B. R.; Fauth,
U.; Hylands, R. J.; Holloway, J. A.; Latif, M.; O’Beirne, G. B.; Porter,
N.; Renno, D. V.; Richards, M.; Robinson, N. J. Antibiot. 1995, 48,
5
(
68−573.
2) Thomas, P.; Sundaram, H.; Krishek, S. J.; Chazot, P.; Xie, X.;
Bevan, P.; Brocchini, S. J.; Latham, C. J.; Charlton, P.; Moore, M.;
Lewis, S. J.; Thornton, D. M.; Stephenson, F. A.; Smart, T. G. J.
Pharmacol. Exp. Ther. 1997, 282, 513−520.
(3) Qi, Q.-Y.; Bao, L.; Ren, J.-W.; Han, J.-J.; Zhang, Z.-Y.; Li, Y.;
Yao, Y.-J.; Cao, R.; Liu, H.-W. Org. Lett. 2014, 16, 5092−5095.
(4) Raggatt, M. E.; Simpson, T. J.; Chicarelli-Robinson, M. I. Chem.
Commun. 1997, 2245−2247. (b) Schor, R.; Schotte, C.; Wibberg, D.;
Kalinowski, J.; Cox, R. J. Nat. Commun. 2018, 9, 1963.
(
5) (a) Weber, A.; Dehn, R.; Schlag
Org. Lett. 2014, 16, 568−571. (b) Wang, L.-L.; Candito, D.; Drag
G.; Kirschning, A. Eur. J. Org. Chem. 2017, 2017, 5582−5591.
6) (a) Baldwin, J. E.; Mayweg, A. V. W.; Neumann, K.; Pritchard,
̈
er, N.; Dieter, B.; Kirschning, A.
̈
er,
(
G. Org. Lett. 1999, 1, 1933−1935. (b) Adlington, R. M.; Baldwin, J.
E.; Mayweg, A. V. W.; Pritchard, G. J. Org. Lett. 2002, 4, 3009−3011.
(
c) Gao, Y.; Wang, G.-Q.; Wei, K.; Hai, P.; Wang, F.; Liu, J.-K. Org.
Lett. 2012, 14, 5936−5939. (d) Lam, H. C.; Spence, J. T. J.; George, J.
H. Angew. Chem., Int. Ed. 2016, 55, 10368−10371.
(7) (a) Heusler, K.; Kalvoda, J. Angew. Chem., Int. Ed. Engl. 1964, 3,
5
25−596. (b) Condakes, M.-L.; Hung, K.; Harwood, S.-J.; Maimone,
T.-J. J. Am. Chem. Soc. 2017, 139, 17783−17786.
8) (a) Parry, R. J.; Burns, M. R.; Skae, P. N.; Hoyt, J. C.; Pal, B.
(
Bioorg. Med. Chem. 1996, 4, 1077−1088. (b) Moon, H. R.; Choi, W.
J.; Kim, H. O.; Jeong, L. S. Tetrahedron: Asymmetry 2002, 13, 1189−
1
(
193.
9) (a) Shirahama, H.; Osawa, E.; Matsumoto, T. J. Am. Chem. Soc.
1
980, 102, 3208−3213. (b) Neuenschwander, U.; Czarniecki, B.;
Hermans, I. J. Org. Chem. 2012, 77, 2865−2869. (c) Zigon, N.;
Hoshino, M.; Yoshioka, S.; Inokuma, Y.; Fujita, M. Angew. Chem., Int.
Ed. 2015, 54, 9033−9037.
(
10) Choi, W. J.; Park, J. G.; Yoo, S. J.; Kim, H. O.; Moon, H. R.;
Chun, M. W.; Jung, Y. H.; Jeong, L. S. J. Org. Chem. 2001, 66, 6490−
494.
11) (a) Wang, P.; Agrofoglio, L. A.; Newton, M. G.; Chu, C. K. J.
6
(
Org. Chem. 1999, 64, 4173−4178. (b) Jin, Y. H.; Liu, P.; Wang, J.;
Baker, R.; Huggins, J.; Chu, C. K. J. Org. Chem. 2003, 68, 9012−9018.
(
c) Gadthula, S.; Rawal, R. K.; Sharon, A.; Wu, D.; Korba, B.; Chu, C.
K. Bioorg. Med. Chem. Lett. 2011, 21, 3982−3985.
12) Takao, K.; Noguchi, S.; Sakamoto, S.; Kimura, M.; Yoshida, K.;
Tadano, K. J. Am. Chem. Soc. 2015, 137, 15971−15977.
13) (a) Li, C.; Yu, X.; Lei, X. Org. Lett. 2010, 12, 4284−4287.
b) Li, C.; Dian, L.; Zhang, W.; Lei, X. J. Am. Chem. Soc. 2012, 134,
2414−12417.
(
(
(
1
D
DOI: 10.1021/acs.orglett.8b04003
Org. Lett. XXXX, XXX, XXX−XXX