Bioinspired synthesis of pentacyclic onocerane triterpenoids

Article abstract of DOI:10.1039/c7sc03903d

The first chemical synthesis of pentacyclic onocerane triterpenoids has been achieved. A putative biomimetic tricyclization cascade is employed to forge a fused decalin-/oxepane ring system. The synthetic route proceeds to (+)-cupacinoxepin in seven steps and to (+)-onoceranoxide in eight steps in the longest linear sequence, when starting from geranyl chloride and (+)-sclareolide. The bioinspired epoxypolyene cyclization is supported by computational and enzymatic studies.

Full text of DOI:10.1039/c7sc03903d

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Bioinspired Synthesis of Pentacyclic Onocerane Triterpenoids
Florian Bartels,a Young J. Hong,b Daijiro Ueda,c Manuela Weber,a Tsutomu Sato,*c Dean J.
Tantillo,*b and Mathias Christmann*a
Received 00th January 20xx,
Accepted 00th January 20xx
The first chemical synthesis of pentacyclic onocerane triterpenoids has been achieved. A putative biomimetic tricyclization
cascade is employed to forge a fused decalin-/oxepane ring system. The synthetic route proceeds to (+)-cupacinoxepin in
seven steps and to (+)-onoceranoxide in eight steps in the longest linear sequence, when starting from geranyl chloride
and (+)-sclareolide. The bioinspired epoxypolyene cyclization is supported by computational and enzymatic studies.
DOI: 10.1039/x0xx00000x
www.rsc.org/
H
Triterpenoids constitute an important family of diverse natural
products with unique biological activities.1 Their structural
complexity is generated by cyclase enzymes that convert
simple acyclic isoprenoid precursors into polycyclic
molecules.2, 3 For example, onocerane triterpenes were shown
OxidationLevel 0
HO
OH
to be biosynthesized from squalene (1) or its oxidized
) by cyclizations initiated at both termini.4 The
H
CL:4, HL:2
derivatives (
2, 3
BmeTC
BmeTC
5
onocerandiol ( )
6%
intermediates and products can be distinguished by their
oxidation level (OL), (carbo-)cyclization level (CL), and the
hydration level (HL), i.e. the number of incorporated water
molecules. Following core assembly, functional group
modifications (FGMs) or C-H-oxidations5 may occur (Scheme
OH
H
H
HH
O
9
squalene (1)
1). In
compounds, Schuehly and coworkers reported the isolation of
a
bioassay-guided screening for anti-malarial
CL:4,HL:1
H
onoceranoxide (7)
a novel triterpenoid from the bark of Cupania cinerea.6
12%
OxidationLevel 1
O
Cupacinoxepin (
Plasmodium falciparum K1 strain (8.7
4
) showed moderate activity against the
M) and features a novel
FGM C-H ox.
ꢀ
fused pentacyclic onocerane scaffold composed of three six-
membered carbocycles and two oxepanes. Although data from
a single crystal suitable for X-ray crystallography was obtained,
the absolute configuration could not be determined.6 Previous
OH
H
O
OH
thiswork
H
12
synthetic work on the onceranes7-10 was focused on the
H
H
O
H
11-14
OH
10
tetracyclic C2-symmetrical congeners onocerandiol (
-onocerin (
and -onocerin (
5
)
and
23
15-22. The biosynthesis of onoceranoxide (
) via 824, 25 was hypothesized to proceed via
7)
HO
α
6)
H
FGM
CL:4, HL:1
α
6
2
)
epoxysqualene (
cyclization of squalene and diepoxysqualene, respectively
(Scheme 1). This process was elegantly mimicked by Corey’s
double allylsilane epoxypolyene cyclization.16 However, the
O
O
H
H
O
11
)
H
H
myrrhanol C (
highly substituted oxepane in cupacinoxepin
onoceranoxide (
(4) and
26, 27 required a novel synthetic strategy.
CL:4, HL:1
7)
4
cupacinoxepin ( )
OxidationLevel 2
O
H
O
OH
Me
Me
a.Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustraße 3,
14195 Berlin, Germany.
LCC
LCD
Me
b.Department of Chemistry, University of California-Davis, Davis, California 95616,
USA.
HO
HO
c. Department of Applied Biological Chemistry and Graduate School of Science and
Technology, Niigata University, Ikarashi 2-8050, Nishi-ku, Niigata 950-2181,
Japan.
H
H
O
CL:4, HL:0
α-onocerin (6)
diepoxysqualene (3)
pre-α-onocerin (8)
Scheme 1 Core assembly of onocerane triterpenes with regard to
the oxidation level (OL), cyclization level (CL) and the hydration
level (HL). LCC and LCD = Lycopodium clavitum C and D respectively.
Electronic Supplementary Information (ESI) available: Detailed experimental
procedures, spectral data, DFT calculation, X-ray crystallographic data for
13 (CIF), 10 (CIF), 22 (CIF).
See DOI: 10.1039/x0xx00000x
4 (CIF),
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Chemical synthesis of ditertiary ethers is a daunting task.28-38
Unfortunately, the seemingly obvious approach to form the
oxepane from two tertiary alcohols is outpaced by competing
cationic pathways.13, 14 Inspired by the cyclization of squalene to 7
via 9 catalyzed by Bacillus megaterium tetraprenyl-β-curcumene
cyclase (BmeTC),23 we identified myrrhanol C (11)39 or epoxy dienol
12 as potential precursors for the synthesis of 10. While the actual
biosynthetic pathway is unknown, the realization of an epoxydiene
tricyclization appeared more feasible in a laboratory setting. Finally,
oxidation of the secondary alcohol 10 to cupacinoxepin (4) (via the
intermediacy of a ketone) completes the putative biosynthesis. Only
a few examples of polyene cyclizations40-45 using tertiary alcohols as
nucleophiles are known,46-48 and to the best of our knowledge
polyene tricyclizations using tertiary alcohols to form oxepanes
have only been achieved enzymatically so far.23, 49 In order to probe
this key cyclization (12 → 10) in the laboratory, we selected epoxy
dienol 12 as our retrosynthetic target (Scheme 2).
a) LiAlH4
then KOH
Rochelle's salt
2-Me-C6H4CH2Br
O
O
O
H
b) n-BuLi
OH
OH
(44%)
(quant.)
H
H
H
15
17
13 [X-ray]
Scheme 3 Synthesis of fragment 13. Reagents and conditions: a)
LiAlH4 (0.7 eq.), THF, 0 °C, 40 min then 2-Me-C6H4CH2Br (2.1 eq.),
KOH (4.0 eq.), Rochelle’s salt (1.2 eq.), DMF, 45 °C, 27 h, quant.; b)
n-BuLi (4.0 eq.), THF, −78 °C, 10 min to −13 °C, 90 min, 44% (over 2
steps).
Vinyl iodide 14 was prepared from geranyl chloride via nucleophilic
substitution with lithiated 1861 followed by desilylation with TBAF
(Scheme 4). Negishi’s zirconium-catalyzed carboalumination62, 63 of
19 with AlMe3 and subsequent trapping of the vinylaluminium
intermediate with iodine afforded vinyl iodide 20.64,
65
We envisioned the cyclization precursor 12 to be generated in a
B-alkyl Suzuki-Miyaura coupling between an alkylborane derived
from 13 and vinyl iodide 14.50 The two fragments were traced back
to the readily available starting materials (+)-sclareolide (15) and
geranyl chloride (16), respectively.51-53
Dihydroxylation of the dimethyl-substituted alkene with the
(DHQD)2PHAL ligand66 (33% yield, 97% ee) proceeded with low
position-selectivity which is reflected by the small amount of
recovered starting material (25%). Using the Corey-Noe-Lin (CNL)
ligand67 increased the position-selectivity to give the terminal diol in
36% yield (94% ee) with 49% of recovered alkene.68 Mesylation of
the secondary alcohol and subsequent treatment with K2CO3
afforded epoxide 14 in 81% yield.69 With alkene 13 and vinyl iodide
14 in hand, the crucial coupling was investigated (Scheme 5).
Treatment of alkene 13 (neat) with 9-BBN dimer at 85 °C for 4 h led
to the expected borane, which was directly used in the B-alkyl
Suzuki−Miyaura reacꢀon69-71 to afford epoxy dienol 12 in 77% yield
on gram scale. The stage was then set to examine the putative
biomimetic tricyclization.72 We anticipated the formation of the
oxepane to be unfavorable both for entropic and enthalpic
reasons.73 A variety of Brønsted and Lewis acids46 failed to give the
desired product, but gratifyingly, treatment of 12 with EtAlCl2 at
−78 °C under high dilution (CH2Cl2, 1 mM) afforded a separable
mixture of target compound 10 (20%) along with another
pentacyclic product 21 (12%).74-76 Spirocyclic motifs similar to 21
have been found in several bioactive natural products.77-80 Further
conditions for the tricyclization of 9 were investigated but no
product formation could be observed.46
The synthesis of fragment 1354 started with the conversion of 15
56
into the corresponding benzyl ether 17 using a one-pot55,
reduction/alkylation sequence (Scheme 3). To this end, reduction of
(+)-sclareolide with LiAlH4 in THF at 0 °C57 was followed by
treatment with Rochelle salt, DMF, KOH and 2-Me-C6H4CH2Br to
afford benzyl ether 17 in excellent yield.
A [2,3]-Wittig-type
fragmentation mediated by n-BuLi directly yielded fragment 13 in
an acceptable yield of 44% over two steps.58,59 The subtle deviation
of the ether group from the literature-known benzyl ether to its 2-
Me-benzyl derivative increased the yield from 21% to 44%. A
screening of different ether derivatives showed alkyl substituents
with benzylic hydrogen atoms in the 2-position of the aromatic ring
to give higher yields of 13. Moreover, we observed a temperature
dependence of the fragmentation yield, maximizing at −13 °C.46
The configuration of 13 was confirmed by X-ray crystallography.60
Scheme 2 Retrosynthetic analysis of 10 based on an epoxypolyene
cyclization of precursor 12.
2 | J. Name., 2012, 00, 1-3
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TMS
a) 9-BBN-dimer
then Pd(dppf)Cl2
AsPh3, NaOH
18
O
18
a) n-BuLi,
then TBAF
b) Cp2ZrCl2, AlMe3
then I2
OH
13
14
(77%)
H
12
X
2 steps
(59%)
[1.2 g synthesized in one batch]
I
16
19
OH
OR
: X = Cl
: X = CH2C≡CH
20
CNL-ligand
H
H
I
O
b) EtAlCl2
c) K2OsO2(OH)4
CNL-ligand
(36%, 94% ee)
N
H
O
H
H
O
(20% 10
12% 21)
O
O
N
O
N
d) MsCl
then K2CO3
(81%)
H
H
N
N
N
I
10 [X-ray]
21 R = H
22 R = 4-BrC6H4CO
c)
14
O
[X-ray]
Scheme 4 Synthesis of fragment 14. Reagents and conditions: a)
n-BuLi (1.2 eq.), 18 (1.2 eq.), THF, −78 °C, 2.5 h then TBAF (1.3 eq.),
−78 °C to 23 °C, 24 h, 82%; b) Cp2ZrCl2 (0.25 eq.), AlMe3 (3.0 eq.),
H2O (1.0 eq.), CH2Cl2, −23 °C, 1 h then I2 (1.2 eq.), THF, −23 °C to
23 °C, 16 h, 72%; c) K2OsO2(OH)4 (0.3 Mol-%), CNL-ligand (0.2 Mol-
%), K3Fe(CN)6 (3.0 eq.), MeSO2NH2 (1.0 eq.), K2CO3 (3.0 eq.), t-BuOH,
H2O, 1 °C, 53 h, 36%, 94% ee, and 49% of 20; d) MsCl (1.1 eq.),
pyridine (15 eq.), CH2Cl2, 0 °C to 23 °C, 18 h then K2CO3 (10 eq.),
MeOH, 2.5 h, 81%.
O
O
d) TCDI
e) n-Bu3SnH
AIBN
f) DMP
then
AcOOH
H
H
10
2 steps
(77%)
(66%)
H
HH
H
O
O
H
H
4 [X-ray]
7
The structures of oxepane 10 and p-Br-benzoate derivative 22 were
confirmed by X-ray crystallography. Despite its rather low yield, the
cyclization generated four stereogenic centers and the remaining
Scheme 5 Synthesis of cupacinoxepin 4 and onoceranoxide 7.
Reagents and conditions: a) 13 (1.4 eq.), 9-BBN dimer (2.8 eq.),
85 °C, 4 h then 14 (1.0 eq.), Pd(dppf)Cl2 (0.1 eq.), AsPh3 (0.4 eq.),
NaOH (6.0 eq.), 1 °C, 17 h, 77%; b) EtAlCl2 (3.0 eq.), CH2Cl2 (1 mM),
−78 °C, 1.5 h, 20% 10, 12% 21; c) 4-BrC6H4COCl (5.0 eq.), 4-DMAP
(20 eq.), 50 °C, 3 d, 73%; d) TCDI (20 eq.), 4-DMAP (20 eq.), CH2Cl2,
70 °C 13.5 h, 83%; e) n-Bu3SnH (3.0 eq.), AIBN (cat.), toluene,
160 °C, 10 min to 120 °C, 20 min then n-Bu3SnH (3.0 eq.), AIBN
(cat.), 160 °C, 10 min to 120 °C, 20 min, 93%; f) DMP (2.0 eq.),
CH2Cl2, 23 °C, 4 h then AcOOH (10 eq.), NaOAc (20 eq.), 17 h then
AcOOH (10 eq.), NaOAc (20 eq.), 5 h, 66%. DMP = Dess-Martin
carbon skeleton in
a single transformation. Additionally, the
secondary alcohol in 10 might serve as a handle in future SAR
studies and enable the evaluation of this class of pentacyclic
onocerane triterpenoids as potential antimalarial drug leads.81, 82 In
addition, recent work in the field of C-H functionalization has
demonstrated the sclareolide scaffold to be amenable for the
selective introduction of other functional groups.83-90 Next, the
major cyclization product 10 was subjected to a one-pot Dess–
Martin/Baeyer–Villiger oxidation91-94 to afford cupacinoxepin in 66%
yield (1.7% overall yield starting from 16). The spectroscopic data,
including the optical rotation, matched those reported in the
literature, thereby determining the absolute configuration of (+)-
cupacinoxepin.6 In addition, we were able to obtain a crystal
suitable for the direct determination of the absolute configuration
of 4 by X-ray crystallography. Onoceranoxide 7 was formed from 10
via formation of the thiocarbamate and subsequent reduction with
tributyltin hydride in 77% yield (2 steps) (2.0% overall yield starting
from 16).95 The spectroscopic data matched those reported in the
literature.26
periodinane, TCDI
=
1,1’-thiocarbonyldiimidazole, AIBN
=
azobisisobutyronitrile.
For 23, 7-membered ring formation was predicted to be preferred
over other pathways by several kcal/mol. For 24, 1,2-hydride shift
to form 25/6-membered ring formation was predicted to be
preferred over formation of a 7-membered ring by several kcal/mol.
As shown in the transition state structure for formation of 25, the
hydride shift appears to be assisted by the tertiary hydroxyl group
(via a favorable electrostatic interaction between the partially
negatively charged oxygen and the partially positively charged
In order to investigate the mechanism of the epoxypolyene
cyclization in more detail and to get insight into the low selectivity
for the desired trans-anti-trans pathway, well established density
functional theory (DFT) methods were applied (mPW1PW91/6-
31+G(d,p)//B3LYP/6-31+G(d).46 Two epimeric trans-decalin-type
structures (S-epimer 23 and R-epimer 24, Scheme 6) were
predicted, based on inherent reactivity preferences (i.e., in the
absence of solvent or enzyme),96 to result from epoxydiene
migrating hydrogen; related interactions have been described
99
previously).98,
In addition, the biosynthetic relevance of the
epoxypolyene cyclization was probed by incubation of 12 with
BmeTC. GC-MS analysis revealed the formation of 10 along with an
elimination product.46 The absence of 21 indicates the influence of
BmeTC in overriding inherent reactivity and enforcing the chair-
chair conformation leading to 10.
cyclization, consistent with previous work by Corey and Shenvi on
97
related systems.35a,75,
The predicted major intermediate 23 is
derived from a chair-chair conformation, while 24 is derived from a
chair-boat conformation.75, 80
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OH
H
OH
(S)
H
H
10
H
O
OH
O
H
H
H
10+H+
23
OH
H
H
OH
OH
OH
hydroxy
assisted
1,2-hydride
shift
H
(R)
H
(R)
H
H
12
21
OH
OH
O
H
H
H
H
25
21+H+
24
Scheme 6 Carbocation rearrangements leading to 10 and 21, modeled with H+ in place of Lewis acid (LA).
In conclusion, we have provided an access to a new class of 3.
pentacyclic onocerane triterpenoids. Additionally, we have
completed the first asymmetric synthesis of antiprotozoal agent 4.
(+)-cupacinoxepin and (+)-onoceranoxide and determined their
absolute configuration. By using an epoxypolyene cascade 5.
tricyclization as the key step, we were able to rapidly assemble the
fused pentacyclic structure in a single synthetic operation. The 6.
putative biosynthetic precursor was assembled from two terpene
derived fragments using a B-alkyl Suzuki−Miyaura reacꢀon. Our
synthetic route to cupacinoxepin consists of seven steps from 7.
geranyl chloride, four of which are C-C bond formations.
R. Thimmappa, K. Geisler, T. Louveau, P. O'Maille and A.
Osbourn, Annu. Rev. Plant Biol., 2014, 65, 225-257.
V. Domingo, J. F. Arteaga, J. F. Quilez del Moral and A. F.
Barrero, Nat. Prod. Rep., 2009, 26, 115-134.
B. Meunier, S. P. de Visser and S. Shaik, Chem. Rev., 2004,
104, 3947-3980.
M. S. Gachet, O. Kunert, M. Kaiser, R. Brun, M. Zehl, W.
Keller, R. A. Muñoz, R. Bauer and W. Schuehly, J. Nat.
Prod., 2011, 74, 559-566.
A. F. Barrero, M. M. Herrador, J. F. Quílez del Moral, P.
Arteaga, J. F. Arteaga, M. Piedra and E. M. Sánchez, Org.
Lett., 2005, 7, 2301-2304.
8.
M. Nishizawa, H. Nishide and Y. Hayashi, Tetrahedron
Lett., 1984, 25, 5071-5074.
Conflicts of interest
9.
R. Carman and H. Deeth, Aust. J. Chem., 1971, 24, 1099-
1102.
There are no conflicts to declare.
10.
E. E. van Tamelen, M. A. Schwartz, E. J. Hessler and A.
Storni, Chem. Commun. (London), 1966, 409-411.
P. F. Vlad, K. I. Kuchkova, A. N. Aryku and K. Deleanu,
Russ. Chem. Bull., 2005, 54, 2656-2658.
E. Romann, A. J. Frey, P. A. Stadler and A. Eschenmoser,
Helv. Chim. Acta, 1957, 40, 1900-1917.
E. J. Corey and R. R. Sauers, J. Am. Chem. Soc., 1957, 79,
3925-3926.
E. J. Corey and R. R. Sauers, J. Am. Chem. Soc., 1959, 81,
1739-1743.
D. H. R. Barton and K. H. Overton, J. Chem. Soc.
(Resumed), 1955, 2639-2652.
Y. Mi, J. V. Schreiber and E. J. Corey, J. Am. Chem. Soc.,
2002, 124, 11290-11291.
Y. Tsuda, N. Kashiwaba, M. Kajitani and J. Yasui, Chem.
Pharm. Bull., 1981, 29, 3424-3426.
G. Stork, A. Meisels and J. E. Davies, J. Am. Chem. Soc.,
1963, 85, 3419-3425.
Acknowledgements
11.
12.
13.
14.
15.
16.
17.
18.
19.
We thank the Studienstiftung des deutschen Volkes for a doctoral
fellowship (F.B.), Buchler GmbH (Braunschweig) for a generous
donation of dihydrochinidin-hydrochloride, Joanna Najdek, Anna
Timofeeva, Luciné V. Gabriel, Ryan Allen for experimental
assistance with the [2,3]-Wittig-type fragmentation, Tobias Olbrisch
for the isolation of α-onocerin and Dr. Jens Schmidt and Prof. Dr.
Christian B. W. Stark (Universität Hamburg) for experimental data
and a generous donation of the Corey-Noe-Lin catalyst. The
computational work was supported by the US National Science
Foundation.
Notes and references
1.
2.
J. Gershenzon and N. Dudareva, Nat. Chem. Biol., 2007, 3,
408-414.
R. Xu, G. C. Fazio and S. P. T. Matsuda, Phytochemistry,
2004, 65, 261-291.
N. Danieli, Y. Mazur and F. Sondheimer, Tetrahedron,
1967, 23, 509-514.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 4
Please do not adjust margins

Please do not adjust margins
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Page 5 of 6
View Article Online
DOI: 10.1039/C7SC03903D
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ARTICLE
20.
21.
22.
J. Kokosi and C. Schmidt, Synth. Commun., 1985, 15, 341- 45.
354.
R. F. Church, R. E. Ireland and J. A. Marshall, Tetrahedron 46.
T. N. Barrett and A. G. M. Barrett, J. Am. Chem. Soc., 2014,
136, 17013-17015.
See Supporting Information for details.
S. Nakamura, K. Ishihara and H. Yamamoto, J. Am. Chem.
Soc., 2000, 122, 8131-8140.
Lett., 1961, 2, 34-38.
47.
S. Berger and D. Sicker, Classics in Spectroscopy: Isolation
and Structure Elucidation of Natural Products, Wiley-VCH, 48.
Weinheim, 2009.
M. Uyanik, H. Ishibashi, K. Ishihara and H. Yamamoto, Org.
Lett., 2005, 7, 1601-1604.
23.
24.
25.
D. Ueda, T. Hoshino and T. Sato, J. Am. Chem. Soc., 2013, 49.
135, 18335-18338.
M. G. Rowan, P. D. G. Dean and T. W. Goodwin, FEBS 50.
Lett., 1971, 12, 229-232.
T. Araki, Y. Saga, M. Marugami, J. Otaka, H. Araya, K. 51.
Saito, M. Yamazaki, H. Suzuki and T. Kushiro, 52.
ChemBioChem, 2016, 17, 288-290.
H. Ageta, K. Shiojima and K. Masuda, Chem. Pharm. Bull., 53.
1982, 30, 2272-2274.
T. Abe and T. Hoshino, Org. Biomol. Chem., 2005, 3, 3127-
3139.
D. Urabe, T. Asaba and M. Inoue, Chem. Rev., 2015, 115,
9207-9231.
J. Mulzer, Nat. Prod. Rep., 2014, 31, 595-603.
Z. G. Brill, M. L. Condakes, C. P. Ting and T. J. Maimone,
Chem. Rev., 2017, DOI: 10.1021/acs.chemrev.6b00834.
T. Newhouse, P. S. Baran and R. W. Hoffmann, Chem. Soc.
Rev., 2009, 38, 3010-3021.
For an attempted synthesis, see: J. H. George, M.
McArdle, J. E. Baldwin and R. M. Adlington, Tetrahedron,
2010, 66, 6321-6330.
26.
27.
28.
29.
Y. Arai, M. Yamaide, S. Yamazaki and H. Ageta, 54.
Phytochemistry, 1991, 30, 3369-3377.
A. S. Kleinke, D. Webb and T. F. Jamison, Tetrahedron,
2012, 68, 6999-7018.
55.
C. Vaxelaire, P. Winter and M. Christmann, Angew. Chem.
Int. Ed., 2011, 50, 3605-3607.
H. Bouanou, J. A. Gil, R. Alvarez-Manzaneda, R. Chahboun
and E. Alvarez-Manzaneda, J. Org. Chem., 2016, 81, 56.
Y. Hayashi, Chem. Sci., 2016, 7, 866-880.
K. K. W. Kuan, H. P. Pepper, W. M. Bloch and J. H. George,
Org. Lett., 2012, 14, 4710-4713.
10002-10008.
57.
30.
31.
M. T. Corbett and J. S. Johnson, Chem. Sci., 2013, 4, 2828-
2832.
58.
M. Matsushita, Y. Nagaoka, H. Hioki, Y. Fukuyama and M.
Kodama, Chem. Lett., 1996, 25, 1039-1040.
Direct conversion of the primary alcohol into a leaving
group and subsequent elimination was outcompeted by
intramolecular substitution forming ambroxide.
CCDC 1529115 (13), 1529116 (4), 1529117 (22), 1529118
(10) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre.
E. J. Corey and H. A. Kirst, Tetrahedron Lett., 1968, 9,
5041-5043.
T. Yoshida and E. Negishi, J. Am. Chem. Soc., 1981, 103,
4985-4987.
P. Wipf and S. Lim, Angew. Chem. Int. Ed. Engl., 1993, 32,
1068-1071.
D. J. Clausen, S. Wan and P. E. Floreancig, Angew. Chem.
Int. Ed., 2011, 50, 5178-5181.
V. Domingo, L. Lorenzo, J. F. Quilez del Moral and A. F.
Barrero, Org. Biomol. Chem., 2013, 11, 559-562.
H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless,
Chem. Rev., 1994, 94, 2483-2547.
E. J. Alvarez-Manzaneda, R. Chaboun, E. Alvarez, E.
Cabrera, R. Alvarez-Manzaneda, A. Haidour and J. M. 59.
Ramos, Synlett, 2006, 2006, 1829-1834.
32.
33.
M. Maemoto, A. Kimishima and T. Nakata, Org. Lett.,
2009, 11, 4814-4817.
60.
H. Shigehisa, M. Hayashi, H. Ohkawa, T. Suzuki, H.
Okayasu, M. Mukai, A. Yamazaki, R. Kawai, H. Kikuchi, Y.
Satoh, A. Fukuyama and K. Hiroya, J. Am. Chem. Soc.,
2016, 138, 10597-10604.
S. Pan, J. Xuan, B. Gao, A. Zhu and H. Ding, Angew. Chem.
Int. Ed., 2015, 54, 6905-6908.
L. Catti and K. Tiefenbacher, Chem. Commun., 2015, 51,
892-894.
G. A. Olah, A. P. Fung and R. Malhotra, Synthesis, 1981,
1981, 474-476.
61.
62.
63.
64.
65.
34.
35.
36.
37.
38.
L. Fang, Y. Chen, J. Huang, L. Liu, J. Quan, C.-c. Li and Z.
Yang, J. Org. Chem., 2011, 76, 2479-2487.
O. Piva, in Synthesis of Saturated Oxygenated
Heterocycles II: 7- to 16-Membered Rings, ed. J. Cossy, 66.
Springer Berlin Heidelberg, Berlin, Heidelberg, 2014, DOI:
10.1007/978-3-642-41470-1_1, pp. 283-320.
R. B. Boar, L. A. Couchman, A. J. Jaques and M. J. Perkins,
J. Am. Chem. Soc., 1984, 106, 2476-2477.
R. A. Yoder and J. N. Johnston, Chem. Rev., 2005, 105,
4730-4756.
67.
68.
69.
E. J. Corey, M. C. Noe and S. Lin, Tetrahedron Lett., 1995,
36, 8741-8744.
Determination of the absolute configuration by Mosher
ester analysis.
K. Surendra and E. J. Corey, J. Am. Chem. Soc., 2008, 130,
8865-8869.
39.
40.
41.
L. F. Tietze, G. Brasche and K. M. Gericke, Domino
Reactions in Organic Synthesis, Wiley-VCH, Weinheim, 70.
2006.
S. A. Snyder and A. M. Levinson, in Comprehensive
Organic Synthesis II (Second Edition), ed. M. G., Elsevier, 71.
Amsterdam, 2014, DOI: http://dx.doi.org/10.1016/B978-
0-08-097742-3.00309-8, p. 268.
V. Domingo, L. Silva, H. R. Diéguez, J. F. Arteaga, J. F.
Quílez del Moral and A. F. Barrero, J. Org. Chem., 2009,
74, 6151-6156.
D. T. Hog, F. M. E. Huber, G. Jiménez-Osés, P. Mayer, K. N.
Houk and D. Trauner, Chem. Eur. J., 2015, 21, 13646-
13665.
42.
43.
44.
M. Baunach, J. Franke and C. Hertweck, Angew. Chem. Int. 72.
Ed., 2015, 54, 2604-2626.
V. K. Aggarwal, P. A. Bethel and R. Giles, J. Chem. Soc., 73.
Perkin Trans. 1, 1999, 3315-3321.
M. Razzak and J. K. De Brabander, Nat. Chem. Biol., 2011,
7, 865-875.
C. Galli and L. Mandolini, Eur. J. Org. Chem., 2000, 3117-
3125.
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ARTICLE
74.
Journal Name
S. V. Pronin and R. A. Shenvi, Nat. Chem., 2012, 4, 915-
920.
75.
R. A. Shenvi and E. J. Corey, Org. Lett., 2010, 12, 3548-
3551.
76.
E. J. Corey and M. Sodeoka, Tetrahedron Lett., 1991, 32,
7005-7008.
77.
W. H. Gerwick and W. Fenical, J. Org. Chem., 1981, 46, 22-
27.
78.
A. Abad, C. Agulló, M. Arnó, A. C. Cuñat, B. Meseguer and
R. J. Zaragozá, J. Org. Chem., 1998, 63, 5100-5106.
A. Grube, M. Assmann, E. Lichte, F. Sasse, J. R. Pawlik and
M. Köck, J. Nat. Prod., 2007, 70, 504-509.
A. W. Markwell-Heys and J. H. George, Org. Biomol.
Chem., 2016, 14, 5546-5549.
79.
80.
81.
B. T. Grimberg and R. K. Mehlotra, Pharmaceuticals, 2011,
4, 681.
82.
E. L. Flannery, A. K. Chatterjee and E. A. Winzeler, Nat.
Rev. Microbiol., 2013, 11, 849-862.
83.
C. R. Shugrue and S. J. Miller, Chem. Rev., 2017, 117,
11894-11951.
84.
R. K. Quinn, Z. A. Könst, S. E. Michalak, Y. Schmidt, A. R.
Szklarski, A. R. Flores, S. Nam, D. A. Horne, C. D.
Vanderwal and E. J. Alexanian, J. Am. Chem. Soc., 2016,
138, 696-702.
85.
86.
M. S. Chen and M. C. White, Science, 2010, 327, 566-571.
Y. Kawamata, M. Yan, Z. Liu, D.-H. Bao, J. Chen, J. T. Starr
and P. S. Baran, J. Am. Chem. Soc., 2017, 139, 7448-7451.
W. Liu, X. Huang, M.-J. Cheng, R. J. Nielsen, W. A. Goddard
and J. T. Groves, Science, 2012, 337, 1322-1325.
K. Chen, A. Eschenmoser and P. S. Baran, Angew. Chem.
Int. Ed., 2009, 48, 9705-9708.
V. A. Schmidt, R. K. Quinn, A. T. Brusoe and E. J. Alexanian,
J. Am. Chem. Soc., 2014, 136, 14389-14392.
O. F. Jeker, A. G. Kravina and E. M. Carreira, Angew.
Chem. Int. Ed., 2013, 52, 12166-12169.
D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155-
4156.
87.
88.
89.
90.
91.
92.
A. Baeyer and V. Villiger, Ber. Dtsch. Chem. Ges., 1899, 32,
3625-3633.
93.
94.
R. R. Sauers, J. Am. Chem. Soc., 1959, 81, 925-927.
J. Meinwald and E. Frauenglass, J. Am. Chem. Soc., 1960,
82, 5235-5239.
Graphical Abstract
95.
96.
97.
98.
99.
M. Göhl and K. Seifert, Eur. J. Org. Chem., 2014, 6975-
6982.
D. J. Tantillo, Angew. Chem. Int. Ed., 2017, 56, 10040-
10045.
E. J. Corey and B. E. Roberts, Tetrahedron Lett., 1997, 38,
8921-8924.
M. W. Lodewyk, D. Willenbring and D. J. Tantillo, Org.
Biomol. Chem., 2014, 12, 887-894.
S. R. Hare, R. P. Pemberton and D. J. Tantillo, J. Am. Chem.
Soc., 2017, 139, 7485-7493.
The first chemical synthesis of pentacyclic onocerane
triterpenoids (+)-cupacinoxepin and (+)-onoceranoxide is
described.
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