Asymmetric synthesis of (+)-17-: Epi -methoxy-kauran-3-one through tandem oxidative polycyclization-pinacol process

Article abstract of DOI:10.1039/c6ob01142j

A synthesis of (+)-17-epi-methoxy-kauran-3-one, an O-methylated isomer of the natural diterpene 17-hydroxy-kauran-3-one, has been achieved. The strategy is based on a diastereoselective oxidative polycyclization-pinacol tandem process consisting of transforming a functionalized phenol into a compact and complex tetracycle, which represents the main core of kaurane family members. The synthesis also includes an enantioselective Yamamoto's allylation, a diastereoselective Ru-catalyzed hydrocyanation, a ring-closing metathesis and a reductive isomerization process as key steps. The structure of our synthetic substrate was determined through comparison with an O-methylated derivative of the natural compound.

Full text of DOI:10.1039/c6ob01142j

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DOI: 10.1039/C6OB01142J
Organic & Biomolecular Chemistry
PAPER
Asymmetric Synthesis of (+)-17-Epi-methoxy-kauran-3-one
Through Tandem Oxidative Polycyclization-Pinacol Process
Gaëtan Maertens,a Samuel Desjardinsa and Sylvain Canesia
Received 00th January 20xx,
Accepted 00th January 20xx
A synthesis of (+)-17-epi-methoxy-kauran-3-one, an O-methylated isomer of the natural diterpene 17-hydroxy-kauran-3-
one, has been achieved. The strategy is based on a diastereoselective oxidative polycyclization-pinacol tandem process
consisting in transforming a functionalized phenol into a compact and complex tetracycle, which represents the main core
of kaurane family members. The synthesis also includes an enantioselective Yamamoto’s allylation, a diastereoselective
Ru-catalyzed hydrocyanation, a ring-closing metathesis and a reductive isomerization process as key steps. The structure
of our synthetic substrate was determined through comparison with an O-methylated derivative of the natural compound.
DOI: 10.1039/x0xx00000x
www.rsc.org/
groups.2,3,4 However, some other members of the kaurane
family have received much less attention, and to the best of our
Introduction
Kauranes and their enantiomer ent-kauranes represent a wide
family of natural diterpenes. They are isolated from numerous
natural sources and have been shown to possess a variety of
knowledge, total syntheses of 17-hydroxy-kaurane-3-one
4 or
3-oxo-kaur-15-en-17-ol are absent from the literature.
5
Cationic polycyclizations of polyunsaturated compounds
remain relevant transformations in the terpene-derived natural
products synthesis field. Such polycyclizations have been used
in biomimetic syntheses to access complex structures
containing quaternary carbon centers with noteworthy
diastereoselectivity.5 In this case, selective electrophilic
activation of a π-bond generates a cationic species that is
trapped in an intramolecular manner by other nucleophilic -
bonds, which can subsequently react with other unsaturations.
Moreover, the presence of a final electrophilic species resulting
from the cyclization cascade may trigger 1,2-substituent shifts
such as Wagner-Meerwein, pinacol or Prins-pinacol
rearrangements to conclude the cascade. The latter, whose
utility has already been demonstrated in total synthesis,6 allows
redesigning molecular structures and accessing highly
interesting
biological
properties
such
as
antidiabetic/antiobesity, antispasmodic, antiallergic activities or
immunosuppressive and platelet antiaggregating effects.1 The
main tetracyclic carbon-skeleton of kauranes
multiple contiguous asymmetric centers and several quaternary
carbon centers, Figure 1.1a
1 exhibits
Me
Me
Me
O
O
B
A
H
D
Me
O
C
Me
Me
O
O
1, main core
of kauranes
2, maoecrystal V
O
functionalized
compounds,
also
with
very
good
O
O
stereoselectivity. Our conviction that linking these two
powerful synthetic tools may provide an attractive approach to
diterpene main cores combined with our interest in total
synthesis of polycyclic natural compounds through oxidative
dearomatization of phenols7 led us to consider a new synthetic
pathway to kaurane family members. In this paper, we describe
our recent efforts toward the asymmetric synthesis of 17-
HO
Me
HO
Me
Me
Me
HO
O
O
4, 17-hydroxy-kauran-3-one
5, 3-oxo-kaur-15-en-17-ol
3, sculponeatin N
Figure 1. Main core of kauranes and representative family members.
This noteworthy structure has raised the interest of the
scientific community, and during the past decades, some
syntheses of ent-kauranes, including the unusual maoecrystal V
hydroxy-kauran-3-one
4 via an oxidative polycyclization-
pinacol cascade8 as key step to yield the main core of the target
2
and sculponeatin N 3, have been achieved by leading
and the synthesis of (+)-17-epi-methoxy-kauran-3-one 27
.
Laboratoire de Méthodologie et Synthèse de Produits Naturels, Université du
Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, H3C 3P8, Québec,
Canada; E-mail: canesi.sylvain@uqam.ca
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Results and discussion
A
potential retrosynthesis of 4 includes an enantioselective
Yamamoto allylation to generate the first asymmetric center of 7
from aldehyde 6, an ozonolysis followed by a Corey-Fuchs
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alkynylation to introduce the lateral chain of 11, a diastereoselective
hydrocyanation and an olefination to produce diene 15, a metathesis
to close the cyclohexenic ring of 21, a SN2 to introduce the chlorine
atom stereoselectively, followed by a stereoselective oxidative
polycyclization-pinacol tandem process to assemble the key
tetracyclic core 23, a selective reduction of the aldehyde of 23,
followed by a reductive isomerization to deliver enone 25 and
finally, a sequence made of di-alkylation and hydrogenation to
provide 17-hydroxy-kauran-3-one 4, Scheme 1.
At this stage, it is necessary to prepare the molVeicewulAerticfloerOntlhinee
DOI: 10.1039/C6OB01142J
cyclohexene ring construction by a ring-closing metathesis. To
this end, Michael acceptor 11 is submitted to
a
diastereoselective hydrocyanation process involving ruthenium-
based catalyst 12 in the presence of trimethylsilyl cyanide,
lithium phenoxide and methanol, as reported by the group of
Ohkuma,12 Scheme 3. Under these conditions, the second
asymmetric center of 13 is installed in 72% yield and 95% de.
The first attempt to produce the required terminal alkene of 15
through Wittig olefination mainly resulted in the degradation of
the starting material. Further experiments, such as Petasis or
Julia-type reactions, also failed to deliver diene 15 in good
yields. However, preliminary treatment of 13 with
(trimethylsilyl)methyllithium 14 followed by Lewis-acid
mediated activation furnished the desired compound 15 in 75%
(93% brsm). Finally, bromine atoms are introduced at the
ortho-positions of the phenol in 62% yield over three steps.
These electron-withdrawing atoms mainly serve to protect
ortho-positions against
a nucleophile attack during the
“umpolung activation”, thus destabilizing the formation of a
cation near these positions and forcing the lateral chain to react
at the required para position of the phenol during the
polycyclization process described in Scheme 5.
Ru-catalyst 12 (1 mol%)
MOMO
O
TMS-CN (1.5 eq) / MeOH
TBSO
C6H5OLi (1 mol%)
72%, de = 95%
11
MOMO
MOMO
O
Scheme 1. Potential retrosynthesis of 17-hydroxy-kauran-3-one 4.
TMSCH2Li (14)
TBSO
TBSO
then BF3.OEt2
15
13
The synthesis begins with the treatment of known aldehyde
NC
NC
75% (93% brsm)
69 with allyltributyltin in the presence of AgOTf and (S)-
BINAP10 to generate allylic alcohol
7, presenting the required
first asymmetric center in 87% yield and 95% ee, Scheme 2.
OMe
16, R = H
17, R = TBS
TBSCl
Imid.
1. K2CO3, MeOH
Br
O
RO
Br
2. NBS
96%
The hydroxyl group is then protected as a ketal in the presence
65% (2 steps)
NC
of MOMCl, and an ozonolysis produces aldehyde
yield over two steps. Nucleophilic addition involving the anion
resulting from a reaction between 1,1-dibromo-1,5-hexadiene
8 in 93%
O
Ar
P
2 O
9
NH2
NH2
Ru
and BuLi11 affords alcohol 10 as an epimeric mixture that is
used to reduce the alkyne with LiAlH4, thus furnishing the
required trans-alkene moiety. Finally, oxidation of the allylic
alcohols with Dess-Martin periodinane converges to Michael
acceptor 11 in 73% yield over three steps.
P
O
Ar2
O
12 (1% mol.) / Ar = p-Tolyl
Scheme 3. Synthesis of diene 17.
O
OH
SnBu3
TBSO
TBSO
H
(S)-BINAP (5%)
AgOTf (5%)
The cylohexenic ring of 18 is then closed through metathesis
mediated by a 2nd generation Hoyveda-Grubb catalyst and the
cyano group is transformed into an aldehyde using DIBAL-H in
86% yield over two steps, Scheme 4. The reaction between
aldehyde 18 and lithium (trimethylsilyl)acetylide delivers
propargylic alcohol 19 as an epimeric mixture ( 95% yield)
which is then protected with a bulky TIPS group under standard
conditions. Such protection is required to avoid possible side-
reactions resulting from interactions between a free hydroxy
and cationic species generated during the polycyclyzation
process. Subsequent selective deprotection of the benzylic
alcohol under mild acidic conditions generated by treatment of
6
7
87%, ee = 95%
Br
9
1. MOMCl
OMOM
DIPEA
Br
TBSO
O
n-BuLi
2. O3, Et3N
8
93% (2 steps)
MOMO
OH
MOMO
O
1. LiAlH4
TBSO
TBSO
11
2. DMP
10
73% (3 steps)
Scheme 2. Synthesis of Michael acceptor 11.
2 | J. Name., 2012, 00, 1-3
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With the tetracyclic core 23 in hand, further elaborations are needed
DOI: 10.1039/C6OB01142J
to reach the target. Selective reduction of the aldehyde in the
CBr4 in isopropanol and followed by a treatment with K2CO3 in
methanol to furnish phenol 20 in 69% yield over three steps.
Finally, the benzylic chlorine atom of 21 is installed with
inversion of configuration through a SN2 pathway involving
thionyl chloride.
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presence of a hindered hydride generates alcohol 24 in 90% yield,
Scheme 6. Reductive isomerization performed with zinc in acetic
acid subsequently enables the selective reduction of both the allylic
chlorine and allylic bromine generated in situ via double bond
isomerization, thus delivering 25 in 67% yield. At this stage, the
gem-dimethyl segment must be introduced at the α-position of
ketone 25. To this end, 25 is treated with t-BuOK in DMSO in the
presence of methyl iodide, yielding intermediate 26 in 50% yield. It
should be stressed that the unprotected primary alcohol is also
methylated in this transformation, but O-methylation may be
avoided by TBS protection if necessary. Another hydrogenation
process in the presence of Adams’ catalyst17 facilitates the removal
of the last bromine atom and allows for the reduction of remaining
unsaturations. Under these conditions, partial reduction of the ketone
to an epimeric alcohol mixture is noted. Nevertheless, further
treatment with Dess-Martin periodinane produces desired compound
27 in 90% yield.
OMe
O
H
MeO
Br
1. Hoveyda-
Grubbs II
Br
O
O
TBSO
Br
TBSO
Br
2. DIBAL-H
NC
86% (2 steps)
18
17
TMS
1. TIPSOTf, Et3N
HO
MeO
Br
TMS
2. CBr4, i-PrOH
O
n-BuLi
3. K2CO3, MeOH
69% (3 steps)
TBSO
Br
95%
19
TIPSO
OH
TIPSO
Cl
SOCl2
DCM
Br
Br
HO
Br
HO
Br
20
21
Scheme 4. Synthesis of precursor 21.
The main tetracyclic core of kaurane family members 23 is
produced through diastereoselective oxidative
a
polycyclization-pinacol cascade8 from precursor 20 in 25%
yield over two steps, Scheme 5. This process first implies
oxidative dearomatization13,14 or “Umpolung activation”15 of
phenol 21 mediated by phenyliodine bis(trifluoroacetate). As
reported by Kita and coworker,16 in the presence of HFIP, a
highly electrophilic species 22, known as “phenoxenium”, is
produced under these conditions. The latter is trapped by the 
bond of the cyclohexenic ring moiety, which in turn reacts with
the alkyne, and the process is ended by a pinacol transposition
according to chair-like transition state 22. It should be stressed
that the diastereoselectivity of this cascade is governed by the
benzylic chlorine atom, which is located equatorially in a chair-
like transition state to minimize both steric and stereoelectronic
interactions, and forces the lateral chain to attack on the desired
top face of the phenoxenium species to control the first
Scheme 6. Synthesis of (+)-17-epi-methoxy-kauran-3-one 27.
To verify the stereoselectivity of the hydrogenation process, a small
amount of commercially available natural 17-hydroxy-kauran-17-
one has been O-alkylated under mild conditions in the presence of
Ag2O and methyl iodide, yielding the O-methyl analog 28, Scheme
1
7. The H NMR spectra of 27 and 28 are very similar except for a
small difference in the shift of methyl groups, which were slightly
more shielded in the natural derivative.18 Our synthetic diterpene
adduct 27 is also slightly less polar by TLC. These small differences
are indicative of a cis decalin junction,19 meaning that during the
hydrogenation process leading to 27, the reduction is not controlled
by the presence of the angular methyl group as is sometimes
observed,20 but rather by the bowl shape of the main core.
stereocenter of the cascade.
9
H
7 H 3
8
7
(R)
Cl
(R)
2
5
PhI(OCOCF3)2
HFIP, 0°C
1 Me
TIPSO
TIPSO
1
3
Cl
8
Br
OH
H
O
O
Br
4
6
25% (2 steps
from 20)
6
Ag2O, MeI
95%
22
HO
MeO
21
Br
O
Br
Me
Me
4
Br
Cl
Br
28, 17-methoxy-kauran-3-one
O
Cl
O
(R)
(R)
1
9
9
1
=
6
6
Br
Scheme 7. O-methylation of natural 17-hydroxy-kauran-3-one.
8
7
Br
2
4
2
8
Me
Me
7
23
O
5
23
3
3
O
Scheme 5. Oxidative polycyclization-pinacol tandem process.
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further qualified as app (apparent), br (broad), c (complex).
To address the diastereoselectivity issue encountered during the
hydrogenation process, other experimental conditions were
tested, Table 1. Changing the pressure (Table 1, entry b) also
furnished epimer 27 in 90% yield. Substitution of methanol by
a more polar solvent (Table 1, entry c) once again delivered
undesired isomer 27 but with a significant decrease in
efficiency. Finally, using Pd/C as a catalyst in dioxane21 (Table
1, entry d) also failed to produce the required trans-decalin
moiety, generating 27 in 75% yield.
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Coupling constants, J, are reported in Hz. Mass spectra (m/e)
DOI: 10.1039/C6OB01142J
were measured in the electrospray (ESI) mode.
(5R,6aR,9R,11aR,11bR)-2,4-dibromo-5-chloro-11b-methyl-3-
oxo-3,5,6,9,10,11,11a,11b-octahydro-6a,9-
methanocyclohepta[a]naphthalene-8-carbaldehyde (23). To
a
solution of compound 20 (105 mg, 1.00 eq, 0.175 mmol) in
anhydrous DCM (3 mL) under argon atmosphere was added SOCl2
(38µL, 3.00 eq, 0.525 mmol). The solution was refluxed for 8 hours
and then a solution of sat. aq. NaHCO3 (5 mL) was added. The
aqueous phase was extracted with DCM (3 * 10 mL) and the
combined organic layers were washed with sat. aq. NaCl, dried over
Na2SO4 and concentrated under reduced pressure. The crude product
was filtrated on a plug of silica gel (hexanes/EtOAc, 9:1) and was
used without further purification. To a vigorously stirred solution of
the above crude phenol in a mixture of HFIP/DCM (5:3 ; 1 mL) at
room temperature was added over 5 seconds a solution of
PhI(CO2CF3)2 (83 mg, 1.10 eq, 0.192 mmol) in a mixture of
HFIP/DCM (5:3, 0.6 mL). After addition of PIFA, the solution was
stirred for 2 min, quenched with 1 mL of acetone and filtered over
silica gel (EtOAc). The filtrate was concentrated under reduced
pressure and the residue was purified by flash chromatography
(hexanes/EtOAc, 3:1) to afford 20.3 mg of tetracyclic core 23 in 25
% yield over 2 steps. 1H NMR (300 MHz, CDCl3) δ = 9.67 (s, 1H),
7.31 (s, 1H), 6.13 (s, 1H), 5.42 (t, J=9.5, 1H), 3.05 – 3.00 (m, 1H),
2.46 (d, J=9.6, 2H), 2.18 (dd, J=12.9, 5.0, 1H), 2.05 – 1.98 (m, 1H),
1.90 – 1.82 (m, 1H), 1.72 (s, 3H), 1.46 – 1.40 (m, 2H), 0.96 – 0.85
(m, 2H); 13C NMR (151 MHz, CDCl3) δ = 188.9, 172.4, 158.6,
155.2, 149.9, 147.5, 127.6, 119.3, 56.4, 52.5, 51.1, 40.0, 36.9, 31.1,
29.8, 25.2, 23.0; HRMS (ESI) Calc. For C18H17Br2ClO2 (M+Na)+:
482.9155, found : 482.9159; [α]D (25°C, c = (11.6 mg/ 2mL),
AcOEt) = -4.3°.
Table 1. Hydrogenation of 26.
O
O
1. Conditions
2. DMP
MeO
MeO
Br
Me
Me
26
27 (cis decalin) /
29 (trans decalin)
Yield (%)
(2 steps)
entry
Product
Conditions
a
b
c
d
PtO2, H2 (1 atm), MeOH
PtO2, H2 (4 atm), MeOH
PtO2, H2 (1 atm), AcOH
Pd/C, H2 (1 atm), Dioxane
27
27
27
27
90
90
53
75
We also considered using a less bulky diimide to invert the
stereoselectivity. To this end, 26 has been treated with 2-
nitrobenzenesulfonylhydrazide in the presence of triethylamine.
However, under these conditions, a complex mixture of compounds
was recovered.
Conclusions
(5R,6aR,9R,11aR,11bR)-2,4-dibromo-5-chloro-8-
(hydroxymethyl)-11b-methyl-5,6,9,10,11,11a-hexahydro-6a,9-
methanocyclohepta[a]naphthalen-3(11bH)-one (24). To a solution
of aldehyde 23 (57 mg, 1.00 eq, 0.124 mmol) in dry THF (1.2 mL) at
-78°C under argon atmosphere was added dropwise LiAlH(Ot-Bu)3
(0.137 mL at 1.0 M, 1.10 eq, 0.137 mmol). The resulting solution
was stirred at -78°C for 15 min and sat. aq. NH4Cl (5 mL) was
added. The aqueous phase was extracted with EtOAc (3 * 5 mL).
The combined organic layers were washed with sat. aq. NaCl, dried
over Na2SO4 and concentrated under vacuum. The crude mixture
was purified by flash chromatography (hexanes/EtOAc, 7:3) to
afford pure alcohol 24 as a white solid (51 mg, 90%). 1H NMR (300
MHz, CDCl3) δ 7.32 (s, 1H), 5.34 (t, J = 9.5 Hz, 1H), 5.04 (s, 1H),
4.12 (d, J = 1.3 Hz, 2H), 2.57 (m, 1H), 2.39-2.32 (d, J = 10 Hz, 2H),
2.12 – 2.03 (dd, J = 12.6, 4.8 Hz, 1H), 1.96 (dd, J = 10.0, 5.1 Hz,
1H), 1.83 – 1.71 (m, 2H), 1.67 (s, 3H), 1.64 – 1.49 (m, 4H). 13C
NMR (75 MHz, CDCl3) δ 172.7, 159.7, 156.0, 149.2, 126.9, 123.0,
119.0, 60.7, 57.0, 52.5, 52.0, 49.9, 49.0, 41.1, 39.9, 31.0, 25.4, 23.4.
HRMS (ESI) Calc. For C18H19Br2ClO2 (M+H)+: 462.9492, found :
462.9463; Calc. For. C18H19Br2ClO2 (2M+Na)+: 942.8773, found :
942.8781; [α]D (25°C, c = (18.4 mg/ 1 mL), AcOEt) = +27.8°.
In summary, we have developed a synthesis of (+)-17-epi-methoxy-
kauran-3-one, an O-methylated epimer of natural 17-hydroxy-
kauran-3-one. The most innovative step of our strategy is a
diastereoselective oxidative polycyclization-pinacol tandem process
consisting in transforming an elaborated phenol into the main
tetracyclic core of kaurane family members with complete control of
the stereoselectivity. The synthesis also includes an enantioselective
Yamamoto allylation, a Corey-Fuchs alkynylation, a Ru-mediated
diastereoselective hydrocyanation and a ring-closing metathesis as
key steps. Comparing our synthetic substrate and an O-methylated
derivative of extracted 17-hydroxy-kauran-3-one led us to conclude
that we actually synthesized an undesired epimer derivative of the
natural product. This work illustrates the potential of oxidative
dearomatizations for the rapid and efficient construction of complex
polycyclic structures serving as key intermediates in total synthesis
of natural compounds.
Experimental
(6aS,9R,11aR,11bR)-2-bromo-8-(hydroxymethyl)-11b-methyl-
6,9,10,11,11a,11b-hexahydro-6a,9-
methanocyclohepta[a]naphthalen-3(4H)-one (25). To a solution of
alcohol 24 (20 mg, 1 eq, 0.043 mmol) in i-PrOH (4.7 mL) were
added AcOH (0.04 mL, 15. eq, 0.65 mmol) and Zn (28 mg, 10.00 eq,
0.43 mmol). The resulting mixture was refluxed for 10 min and
filtrated over silica gel (EtOAc). The residue was dissolved in CHCl3
(5 mL) and washed with water (3 mL) and sat. aq. NaCl, dried over
Na2SO4 and concentrated under vacuum. The crude mixture was
purified by flash chromatography (hexanes/EtOAc, 85:15) to afford
General experimental details
Unless otherwise indicated, 1H and 13C NMR spectra were
recorded at 300 and 75 MHz, respectively, in CDCl3 solutions.
Chemical shifts are reported in ppm on the
δ scale.
Multiplicities are described as s (singlet), d (doublet), dd, ddd,
etc. (doublet of doublets, doublet of doublets of doublets, etc.),
t (triplet), td (triplet of doublets), q (quartet), m (multiplet) and
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1
pure enone 25 as a white solid (10 mg, 67%). H NMR (300 MHz,
CDCl3) δ 7.60 (s, 1H), 5.56 (dt, J = 6.5, 2.0 Hz, 1H), 5.39 (s, 1H),
4.21 (d, J = 1.2 Hz, 2H), 3.52 (d, J = 17.2 Hz, 1H), 3.19 (d, J = 17.3
Hz, 1H), 2.67 – 2.45 (m, 1H), 2.41 – 2.24 (m, 1H), 2.14 – 2.04 (m,
1H), 2.03 – 1.97 (m, 1H), 1.95 (d, J = 5.9 Hz, 1H), 1.92 – 1.76 (m,
3H), 1.34 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 190.5, 157.3,
146.9, 135.7, 127.1, 123.3, 121.9, 61.2, 52.5, 46.4, 46.3, 45.7, 44.1,
39.4, 34.0, 29.8, 25.5, 21.4; LRMS (ESI) : Calc. For C18H21BrO2 :
349-351, found : 349-361; [α]D (25°C, c = (6.8 mg/ 1 mL), CHCl3) =
- 27.7°.
government of Quebec (FQRNT and CCVC) for their
View Article Online
DOI: 10.1039/C6OB01142J
precious financial support in this research
.
Notes and references
1
For a review on biological properties, see: (a) P. A. Garcia, A.
B. de Oliveira and R. Batista, Molecules 2007, 12, 455. For
other publications, see: (b) P. R. Jeffries and R. W. Retallack,
Aust. J. Chem. 1968, 21, 1311; (c) G. Drager, X. A. Dominguez,
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Chim. Acta 2006, 89, 64; (e) K. Mori and S. Aki, Liebigs Ann.
(6aS,9R,11aR,11bR)-2-bromo-8-(methoxymethyl)-4,4,11b-
trimethyl-6,9,10,11,11a,11b-hexahydro-6a,9-
methanocyclohepta[a]naphthalen-3(4H)-one (26). To a cooled
solution of enone 25 (4 mg, 1.00 eq, 0.0114 mmol) in anhydrous
DMSO (0.2 mL) under argon atmosphere was added dropwise t-
BuOK (0.046 mL at 1.0 M, 4.00 eq, 0.046 mmol). The resulting
brown solution was stirred for 1 min and CH3I (0.01 mL, 14.00 eq,
0.16 mmol) was added. The mixture was stirred for further 10 min
and sat. aq. NH4Cl (2 mL) was added. The aqueous phase was
extracted with CHCl3 (3 * 2 mL) and the combined organic layers
were washed with sat. aq. NaCl, dried over Na2SO4 and concentrated
under vacuum. The crude mixture was purified by flash
chromatography (hexanes/EtOAc, 95:5) to afford methylated
Chem. 1993, 1, 97; (f) K. Mori and M. Matsui, Tetrahedron
1968, 24, 3095; (g) R. A. Britton, E. Piers and B. O. Patrick, J.
Org. Chem. 2004, 69, 3068; (h) S. P. Yang and J. M. Yue, Nat.
Prod. Res. 2008, 22, 1163; (i) Y. Li, J. Liu, S. Yu, P. Proksch, J.
Gu and W. Lin, Phytochemistry 2010, 71, 2124.
For syntheses of maoecrystal V, see: (a) J. Gong, G. Lin, W.
Sun, C. C. Li and Z. Yang, J. Am. Chem. Soc. 2010, 132, 16745;
(b) F. Peng and S. J. Danishefsky, J. Am. Chem. Soc. 2012,
134, 18860; (c) P. Lu, Z. Gu and A. Zakarian, J. Am. Chem. Soc.
2013, 135, 14552; (d) P. Lu, A. Mailyan, Z. Gu, D. M. Guptill,
H. Wang, H. M. Davies and A. Zakarian, J. Am. Chem. Soc.
2014, 136, 17738; (e) C. Zheng, I. Dubovyk, K. E. Lazarski and
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Zhang, F. Z. Li, J. X. Gong and Z. Yang, Chem. – An Asian J.
2015, 10, 1874.
2
1
compound 26 as a colorless oil (2.4 mg, 55%). H NMR (300 MHz,
CDCl3) δ 7.36 (s, 1H), 5.88 (dd, J = 7.3, 2.9 Hz, 1H), 5.36 (s, 1H),
3.97 (dd, J = 12.9, 1.5 Hz, 1H), 3.87 (dd, J = 12.8, 0.8 Hz, 1H), 3.35
(t, J = 4.7 Hz, 1H), 3.32 (s, J = 6.3 Hz, 3H), 2.58 – 2.50 (m, 1H),
2.09 (dd, J = 16.6, 2.9 Hz, 1H), 1.99 (dd, J = 16.5, 7.3 Hz, 1H), 1.89
(ddd, J = 9.9, 5.1, 2.2 Hz, 1H), 1.85 – 1.67 (m, 2H), 1.49 – 1.44 (m,
3H), 1.41 (s, 3H), 1.36 (s, 3H), 1.35 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 196.7, 154.4, 144.1, 143.9, 128.5, 123.2, 119.3, 70.5, 58.4,
52.2, 50.0, 49.8, 48.2, 43.6, 39.8, 34.1, 32.7, 30.0, 27.1, 24.8, 23.3.
LRMS (ESI): Calc. For C21H27BrO2 (M+H)+: 391-393, found : 391-
393; [α]D (25°C, c = (2.2 mg/ 1 mL), CHCl3) = - 30.0°.
3
4
For syntheses of sculponeatin N, see: (a) B. J. Moritz, D. J.
Mack, L. Tong and R. J. Thomson, Angew. Chem., Int. Ed.
2014, 53, 2988; (b) Z. Pan, C. Zheng, H. Wang, Y. Chen, Y. Li,
B. Cheng and H. Zhai, Org. Lett. 2014, 16, 216.
For syntheses of other kaurane-derived members, see: (a) M.
J. Kenny, L. N. Mander and S. P. Sethi, Tetrahedron Lett.
1986, 27, 3923; (b) M. J. Kenny, L. N. Mander and S. P. Sethi,
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and M. Matsui, Tetrahedron Lett. 1970, 11, 2411; (d) K. Mori;
Y. Nakahara and M. Matsui, Tetrahedron 1972, 28, 3217; (e)
F. E. Ziegler and J. A. Kloek, Tetrahedron 1977, 33, 373; (f) B.
B. Snider, J. Y. Kiselgof and B. M. Foxman, J. Org. Chem.
1998, 63, 7945; (g) J. Y. Cha, J. T. S. Yeoman and S. E.
Reisman, J. Am. Chem. Soc. 2011, 133, 14964; (h) E. C.
Cherney, J. C. Green and P. S. Baran, Angew. Chem., Int. Ed.
2013, 52, 9019; (i) E. C. Cherney, J. M. Lopchuk, J. C. Green
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Lazarski, B. J. Moritz and R. J. Thompson, Angew. Chem., Int.
Ed. 2014, 53, 10588; (k) J. T. S. Yeoman, J. Y. Cha, V. W. Mak
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(+)-17-epi-methoxy-kauran-3-one (27). To a solution of compound
26 (2.4 mg, 1.00 eq, 0.0062 mmol) in methanol (0.3 mL) was added
PtO2 (1.4 mg, 1.00 eq, 0.0062 mmol). The resulting suspension was
stirred for 12h under a 4 atm H2 atmosphere. The mixture was then
then filtrated over celite (EtOAc) and solvents were removed under
vacuum. The crude mixture was dissolved in anhydrous DCM (0.1
mL) under argon atmosphere and Dess-Mastin periodinane (3.2 mg,
1.20 eq, 0.0074 mmol) was added. The resulting solution was stirred
for 10 min at room temperature and sat. aq. NaHCO3 (1 mL) was
added. The aqueous phase was extracted with CHCl3 (3 * 1 mL),
dried over Na2SO4 and concentrated under vacuum. The crude
mixture was purified by flash chromatography (hexanes/EtOAc, 9:1)
to afford (+)-17-epi-methoxy-kauran-3-one 27 as a white solid (1.8
1
mg, 90%). H NMR (300 MHz, CDCl3) δ 3.56 – 3.43 (m, 2H), 3.42
(s, 3H), 2.42 (m, J = 12.1, 8.5, 6.3 Hz, 2H), 2.31 – 2.01 (m, 3H),
1.81 – 1.26 (complex, 15H), 1.24 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 219.6, 73.8, 59.0, 55.3, 54.3, 51.0,
47.4, 43.4, 42.9, 39.7, 38.0, 36.5, 35.6, 34.6, 29.8, 29.5, 27.4, 25.5,
25.3, 23.7, 21.6. HRMS (ESI) Calc. For C21H35O2 (M+H)+:
319.2632, found : 319.2622; [α]D (25°C, c = (2.4 mg/ 1 mL), CHCl3)
= +10.8°.
5
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We are very grateful to the Natural Sciences and
Engineering Research Council of Canada (NSERC), the
Canada Foundation for Innovation (CFI), the provincial
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