Total Synthesis of the Schisandraceae Nortriterpenoid Rubriflordilactone A

Article abstract of DOI:10.1002/chem.201703229

Full details of the total synthesis of the Schisandraceae nortriterpenoid natural product rubriflordilactone A are reported. Palladium- and cobalt-catalyzed polycyclizations were employed as key strategies to construct the central pentasubstituted arene from bromoendiyne and triyne precursors. This required the independent assembly of two AB ring aldehydes for combination with a common diyne component. A number of model systems were explored to investigate these two methodologies, and also to establish routes for the installation of the challenging benzopyran and butenolide rings.

Full text of DOI:10.1002/chem.201703229

A Journal of
Accepted Article
Title: Total synthesis of the Schisandraceae nortriterpenoid
rubriflordilactone A
Authors: Edward Alexander Anderson, Guilhem Chaubet, Shermin
Goh, Mujahid Mohammad, Birgit Gockel, Marie-Caroline
Cordonnier, Hannah Baars, and Andrew Phillips
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201703229
Link to VoR: http://dx.doi.org/10.1002/chem.201703229
Supported by

Chemistry - A European Journal
10.1002/chem.201703229
FULL PAPER
Total synthesis of the Schisandraceae nortriterpenoid
rubriflordilactone A
[
a]
[a]
[a]
[a]
Guilhem Chaubet, Shermin S. Goh, Mujahid Mohammad, Birgit Gockel, Marie-Caroline A.
[
a]
[b]
[a]
[a]
Cordonnier, Hannah Baars, Andrew W. Phillips and Edward A. Anderson*
Abstract: Full details of the total synthesis of the Schisandraceae
nortriterpenoid natural product rubriflordilactone A are reported.
O
O
Palladium- and cobalt-catalyzed polycyclizations were employed as
key strategies to construct the central pentasubstituted arene from
bromoendiyne and triyne precursors. This required the independent
assembly of two AB ring aldehydes for combination with a common
diyne component. A number of model systems were explored to
investigate these two methodologies, and also to establish routes for
the installation of the challenging benzopyran and butenolide rings.
O
O
O
O
O
H
H
HO
O
H
O
H
O
O
O
H
H
O
O
H
H
H
O
H
1
: Shindilactone A
Schisandra chinensis
2: Rubriflordilactone A
Schisandra rubriflora
O
O
H
OH
H
H
O
OH
O
O
O
H
O
O
O
H
H
O
O
O
H
H
Introduction
R
H
H
OH
O
3: Schilancitrilactone B (R = (R)-Me)
5: Propindilactone G
The Schisandraceae family of climbing plants are widely
distributed throughout east Asia. Extracts of these plants have
been employed in traditional medicine for thousands of years,
with uses ranging from antihepatitis and anticancer properties, to
4: Schilancitrilactone C (R = (S)-Me)
Schisandra propinqua
Schisandra lancifolia
O
O
O
H
O
H
O
O
O
H
[
1]
O
H
antioxidant and immune regulatory activity. Due in part to this
ethnopharmacological history, much effort has been dedicated
to the characterization of their bioactive constituents, resulting in
the isolation of more than 420 triterpenoids from
H
O
O
O
O
H
H
O
O
OH
HO
H
H
6: Rubriflordilactone B
7: Lancifodilactone G
Schisandra lancifolia
Schisandra rubriflora
[
2]
Schisandraceae species since 1973. Around a third of these
have been termed 'schinortriterpenoids', which specifically refers
to nortriterpenoids isolated from the Schisandra genus; a subset
of representative structures is depicted in Figure 1. The
schinortriterpenoids are thought to derive from the
Figure 1. Schinortriterpenoid natural products prepared by total synthesis, and
common structural features.
[
2]
rearrangement of a cycloartane-type carbon skeleton, and
invariably feature complex polyoxygenated ring systems with
numerous stereocenters. Aside from their inherent skeletal
complexity, they have attracted more recent attention due to
tetrahydrofuran, a neighbouring seven-membered C-ring, and an
α-methylated-γ-lactone, which is unsaturated in most family
members. Among this myriad of synthetically-attractive
[
11]
targets,
our group has been particularly interested in the
[
2]
[12]
their moderate anti-HIV activity, coupled with low cytotoxicity.
Following the first isolation of schinortriterpenoid
micrandilactone A) in 2003, the first total synthesis of a
member of this natural product family was achieved by Yang et
rubriflordilactones,
for which we reported a total synthesis
[
13]
a
rubriflordilactone A in 2015. Here we disclose full details of the
evolution of our strategy towards this natural product, including
the exploration of a number of model systems that provided
valuable information in the synthetic campaign, and insight into
the scalability of the ultimate synthetic route.
[
3]
(
[
4]
al. in 2011 with the synthesis of (±)-schindilactone A (1). Since
then, total syntheses of several other members of this family
[
5]
have been reported, including rubriflordilactone A
(2, Li,
[
6]
[7]
2
014), schilancitrilactones B and C (3, 4, Tang, 2015),
[
8]
propindilactone G (5, Yang, 2015), rubriflordilactone B (6, Li,
Results and Discussion
[
9]
[10]
2
016), and lancifodilactone G (7, Yang, 2017).
Despite
pronounced structural diversity, several features remain
common to most of these natural products, including a fused AB
ring system comprising a γ-lactone and gem-dimethyl substituted
From a retrosynthetic perspective (Scheme 1), we planned that
the butenolide G ring could be introduced by a late-stage
Mukaiyama aldol-type addition of silyloxyfuran
9 onto an
oxocarbenium ion, which could be formed from an acetal
derivative 8. Following functional group manipulations including
F ring formation, hexacycle 10 was further deconstructed via two
[
a]
b]
Dr G. Chaubet, S. S. Goh, M. Mohammad, Dr B. Gockel, M.-C. A.
Cordonnier, A. W. Phillips, Prof E. A. Anderson
[
14]
Chemistry Research Laboratory, University of Oxford
metal-catalyzed polycyclization strategies,
involving either
[
15]
12 Mansfield Road, Oxford, OX1 3TA, U.K.
palladium-catalyzed cyclization of bromoendiyne 11, or cobalt-
E-mail: edward.anderson@chem.ox.ac.uk
H. Baars
[16]
catalyzed cyclotrimerization of triyne 12, both of which offered
[
a powerful means to construct the core CDE ring system and its
central pentasubstituted arene D ring in a single step. These
substrates would be accessed by addition of the diyne 13 to
appropriate AB ring aldehydes 14 or 15. Notably, this strategy
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, D-52074 Aachen, Germany
Supporting information for this article is given via a link at the end of
the document.
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Chemistry - A European Journal
10.1002/chem.201703229
FULL PAPER
Mukaiyama
aldol
O
Oxidative cleavage
Tamao ox.
O
OH
OH
OH
OPMB
a, b
SnBu3
c
Br
d, e
Br
O
O
G
X
H
O
O
H
O
O
O
61%
(2 steps)
41%
68%
(2 steps)
A
O
H
OSiR3
O
H
F
B
D
OH
OTBS
OTBS
OH
18
(4.5 g)
84%,
C
E
H
H
(7.1 g)
16
(23.9 g)
17
(6.5 g)
9
H
H
8
Rubriflordilactone A (2)
PMBO
f, g
OH
93% ee
Br
2
1
catalytic cyclization
O
O
(1.4 g)
SiR3
HO
PMBO
R
O
65%
PMBO Br
OH
H
SiR3
nucleophilic
addition
O
Br
h-j
O
k
O
H
O
H
HO
H
H
83%
(3 steps)
H
PMBO
O
OH
19
(4.1 g)
OH
RO
22
Br
11: R = CBr=CH2
(dr = 1:0.6)
20
(1.9 g)
1
0
1
2: R = CCH
(0.48 g)
O
2
4%
TBSO
OH
O
O
TMS
SiR3
O
H
Br
O
HO
TMS
TBSO
H
OR
H
+
OH
OTBS
2
3
O
O
l, m
n, o
f-k
51%
H
H
p
34%
OH
H
H
98%
2 steps)
89%
(2 steps)
O
O
15
(
TBSO
1
4
13
CO
24
22.0 g)
2
Et
OH
25
(5.0 g)
(
5.2 g)
(
O
TMS
Scheme 1. Retrosynthetic analysis of rubriflordilactone A.
2
6
neatly segregates the AB ring system, which is common to most
schinortriterpenoid natural products, from the rest of the
framework, where most variation is found.
Scheme 2. Reagents and conditions for large scale synthesis of 19 and 23.
Masses indicate the scale reactions were conducted on. a) PdCl
2
(PPh
SnH, THF; b) TBSCl, imid., DMF, 0 °C to rt; c) Pd(dba)
4 mol%), 2,3-dibromopropene, toluene, 70 °C; d) PMBTCA, Sc(OTf)
; f) Ti(Oi-Pr) , D-(–)-diethyl
, –20 °C; g) allylMgBr, THF, 0 °C; h) Dess-
Cl ; i) 2-methyl-2-butene, NaClO , NaH PO
O (2:1); j) BOPCl, py, MeCN; k) MeMgBr, THF –50 °C to rt; l) TBSCl,
imid., DMAP, CH Cl ; m) n-BuLi, THF, –78 °C; EtOCOCl, –78 °C to rt; n)
TMSC≡CCH MgBr, CuBr•SMe , THF, –40 °C; then 24, THF, –78 °C; o)
DIBALH, CH Cl , –78 °C → rt; p) MeMgBr, THF, –5 °C. BOPCl = bis(2-oxo-3-
3
)
2
(
(
3 mol%), Bu
3
2
3
(5
Investigations commenced with the construction of the AB
ring system, which would need to bear either a bromoalkene
mol%), PhMe; e) CSA (10 mol%), MeOH; then NEt
tartrate, t-BuOOH, 4Å MS, CH Cl
Martin periodinane, NaHCO , CH
t-BuOH/H
3
4
2
2
3
2
2
2
2
4
,
(
14) or terminal alkyne (15) moiety. The former route began with
[
17]
2
hydrostannylation of butyne-1,4-diol,
followed by
a
2
2
regioselective monosilylation (16, Scheme 2, yields are given for
the largest scales these reactions were performed on). Stille
coupling with 2,3-dibromopropene, followed by a protecting
group switch, gave allylic alcohol 18 bearing the requisite
2
2
2
2
oxazolidinyl) phosphinic chloride; CSA = (±)-camphorsulfonic acid; dba =
dibenzylidene acetone; DIBALH = diisobutylaluminium hydride; DMAP = 4-
dimethylamino pyridine; PMB
methoxybenzyl trichloroacetimidate.
=
4-methoxybenzyl. PMBTCA
=
4-
[
18]
bromoalkene side chain. A Sharpless asymmetric epoxidation
allowed the smooth installation of the key AB ring stereocentres,
and the resulting epoxide underwent regioselective ring
[
19]
opening with allylmagnesium chloride to give primary alcohol
9. Formation of the β-lactone 20 in three steps enabled the
problem was the capricious Stille coupling of 16 with 2,3-
dibromopropene, which is not only inconvenient on large scale
due to toxicity issues, but was also consistently plagued by the
formation of side-product 27, which resulted from a second Stille
coupling of desired product 17 with stannane 16. Several
conditions were screened in attempts to improve this step, a
selection of which are depicted in Figure 2a. Neither increasing
the equivalents of dibromopropene (Entry 2), nor slow addition
of the stannane to a mixture of catalyst and electrophile (Entry 3),
improved the yield, albeit the latter conditions did suppress the
formation of 27. Switching to other sources of palladium did not
improve matters (Entries 4, 5), including the use of a Pd(II)-
succinimide complex reported by Taylor and Fairlamb to give
superior yields in π-allyl Stille couplings to common Pd(0)
1
introduction of the B ring gem-dimethyl motif by double addition
of methylmagnesium bromide, to generate diol 21. The
formation of significant amounts of byproduct ketone 22 was
also observed (see below).
A similar strategy was followed for the synthesis of the
analogous alkyne derivative 23. The route this time started with
propargyl alcohol, which was efficiently converted to alkyne 24 in
[
20]
two steps, before undergoing a syn-carbocupration
with a
[
21]
propargylic cuprate reagent
generated in situ from the
corresponding Grignard, to give enyne 25. Reduction of the ethyl
ester efficiently delivered allylic alcohol 26, which underwent an
equivalent sequence of transformations as described above to
give diol 23, this time with a TMS-protected alkyne sidechain.
In comparing the efficiency of these two approaches, the first
striking difference appears during the synthesis of Sharpless
epoxidation substrates 18 and 25, where the route to the latter
proved significantly higher yielding (87% to 25 from propargyl
alcohol vs. 17% to 18 from butyne-1,4-diol). The root of this
[
22]
sources.
Surprisingly, use of an allylic carbonate coupling
Me, Entry 6) delivered none of the expected
partner (X = OCO
2
[
23]
π-allyl Stille coupling product, yielding instead a 1:0.86 mixture
of alcohols 28 and 29, again highlighting the unexpected
reactivity of the vinylic C–Br bond over the allylic electrophile.
The reluctance to form a π-allylpalladium intermediate from
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Chemistry - A European Journal
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FULL PAPER
a
PMBO
HO
PMBO
HO
OH
Entry
[Pd]
X (equiv.) Yield 17 (%)
OH
[
Pd] (4 mol%)
Br
OH
OH
Br
Br
Br
Br
a
b, c
OH
1
Pd(dba)2
Pd(dba)2
Br (3)
Br (4)
46
47
SnBu3
X
2
83%
72%
3[a]
4[b]
5
Pd(dba)2
Br (4)
16
O
O
PhMe, 70 °C
6 h
OH
O
Pd(PPh3)2
Pd(PPh ) NBS
Br (3)
dec.
1
21
(418 mg)
33
34
(194 mg)
OTBS
OTBS
Br (3)
25
0[c]
3
2
(352 mg)
1
6
17
6
Pd(dba)2
OCO2Me (3)
d
79%
O
O
O
OH
OTBS
MeO2CO
OH
O
OH
O
Br
Br
Br
g
e, f
H
H
OH
OH
OCO2Me
O
86%
40%
OTBS
Br
OTBS
28
OTBS
(2 steps)
O
O
2
7
29
O
O
35
OH
1
4
36
(64 mg)
Me–
b
(52 mg)
(153 mg)
PMBO
O
TBSO
TMS
OH
H
Br
O
TBSO
HO
PMBO
O
OH
OH
OH
Br
22
TBSO
MeMgBr
a
MgBr
2
1 +
+
TMS
O
O
TMS
O
80%
O
Me–
HO
PMB
O
(
158 mg)
45:25:21:7
ratio of isomers
H
2
0
31
OH
TMS
2
3
37
38
TMS
MeMgBr
c, d
TBSO
(212 mg)
TBSO
O
TBSO
O
7
7%
O
OH
H
25 +
26
O
BrMg
OH
TMS
Me–
O
e, f
H
O
TMS
3
0
32
TMS
38%
(2 steps)
O
O
O
O
OMe
39
O
Figure 2. a: Attempted optimization of π-allyl Stille coupling of stannane 26. All
g
reactions were carried out on a 150 mg scale. [a] Addition of stannane to a
H
51% (2 steps)
solution of bromide. [b] Catalyst formed in situ from Pd(dba)
treatment with H . [c] 32% yield of a mixture of 28 and 29. b: Addition of
MeMgBr to β-lactones 20 and 30.
2
/ 2 PPh
3
on
O
73%
TMS
OMe
2
O
H
O
O
OH
O
H
e, f
4
1
1
5
HO
H
4
7%
(
2 steps)
dibromopropene may be due to the inductive electron-
withdrawing effect of the bromine atom at the 2-position
disfavoring π-complexation of the metal prior to oxidative
addition. In a further attempt to overcome this problem, we
examined bromoalkene installation by alkyne bromoboration
40
2
6% (2 steps)
Scheme 3. Reagents and conditions: a) OsO
,4-dioxane / H O; b) TFA, CH Cl , 0 °C; c) CSA (10 mol%), MeOH, 0 °C; d)
SO •py, i-Pr EtN, DMSO, CH Cl , 0 °C; e) (PhO) P(O)CH CO Et, KHMDS,
Cl / H O, 0 °C; g) K CO , MeOH. TFA =
4 4
(2 mol%), NaIO , 2,6-lutidine,
1
2
2
2
3
2
2
2
2
2
2
(
3
using BBr or B-Br-9-BBN); a number of desilylated alkynes
THF –20 °C → 0 °C; f) TFA, CH
2
2
2
2
3
were screened from the sequence towards alkyne 15, but all led
only to decomposition.
trifluoroacetic acid.
A second major difference between the two routes arose
during the addition of methylmagnesium bromide to β-lactone 20, affords a less constrained intermediate, which is able to access
and its equivalent in the alkyne route (30, Figure 2b). When
using 20, tertiary alcohol 21 was isolated in 66% yield along with
epimerized ketone 22 (24%), which due to being a poorly-
separable epimeric mixture proved impossible to recycle in
satisfactory yield. On performing the same reaction on alkyne-
lactone 30, no epimerization of byproduct ketone 26 was
observed, and its subsequent reaction with methylmagnesium
bromide smoothly delivered an additional 34% of diol 25 (an
overall yield of 75%). A possible explanation for this difference in
reactivity involves formation of complex 31 following addition of
MeMgBr to lactone 20, via chelation of the tertiary alkoxide,
OPMB group, and carbonyl oxygen to the magnesium ion. The
conformations such as 32 in which the methyl nucleophile can
now approach with less steric hindrance, and epimerization is
disfavored due to poor alignment of the σ(C-H) and π*(C=O) orbitals.
Despite these complications, we were nonetheless able to
access appreciable quantities of the AB ring carbon frameworks
for each of the two derivatives, with the synthesis of 22
performed on more than gram scale with good yields. With these
intermediates in hand, we now addressed completion of the AB
rings, and the unveiling of the aldehyde sidechain from the
pendent allyl group.
The second part of the optimized route towards the AB ring
aldehyde 14 commenced with an oxidative cleavage of the
alkene in 21, which resulted in the regioselective formation of
lactol 33 (Scheme 3). This ring was destined to act as a
protecting group for the neighbouring tertiary alcohol, in order to
stereoelectronically-favored attack of
a
second methyl
nucleophile necessitates pseudo-axial approach from the
hindered concave face of this chelate, which instead undergoes
epimerization due to alignment of the σ(C-H) and π*(C=O) orbitals in
this conformation. On the other hand, when performing this
reaction on 30, the presence of a non-coordinating OTBS group
[
12a]
avoid unreactive substrates later in the sequence.
Oxidative
PMB ether cleavage was found to proceed optimally by a short
exposure to trifluoroacetic acid; subsequent methyl acetal
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Chemistry - A European Journal
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FULL PAPER
formation delivered diol 34. This was oxidized under Parikh-
Doering conditions, and converted to lactol 36 via a (Z)-selective
O
OH
O
O
HO
O
OH
a
b
[
24]
Ando olefination / lactonization, followed by hydrolysis of the
methyl acetal. Finally, cyclization of the B-ring was readily
achieved by a high-yielding oxa-Michael reaction under mildly
basic conditions, delivering the AB ring aldehyde 14.
81%
96%
dr > 20:1
H
OPMB
OPMB
OPMB
4
3
4
2
44
(8.0 g)
45
(14.0 g)
(3.6 g)
98%
2 steps)
c, d
HO
(
When the same sequence was performed on the alkyne
derivative 23, we now observed the formation of a mixture of
four isomers after the initial oxidative cleavage step,
corresponding to two regioisomeric lactols, each as an epimeric
mixture. The difference between this and the bromoalkene route
can presumably be explained by the increased steric bulk of the
bromoalkene sidechain disfavouring lactols equivalent to 38.
These isomers could not be separated, and were carried
through the next two steps as a mixture, after which we were
able to separate the isomeric aldehyde acetals 39 and 40 in
good overall yield (77% over two steps). Pleasingly, these
successfully converged to lactol 41 after olefination and acetal
hydrolysis, presumably due to acid-catalyzed isomerization
during methyl acetal deprotection. AB ring aldehyde 15 was
isolated as a single compound after oxa-Michael cyclization.
We now had in hand the aldehydes required for the different
cyclization strategies, which were both due to be coupled with
the CDE ring diyne 13. The synthesis of this crucial component
started from carboxylic acid 42 (Scheme 4, obtained in two steps
O
H
f
e
8
8%
97%
H
H
H
OPMB
g
OPMB
OPMB
4
8
47
46
(4.1 g)
(4.2 g)
88%
SiMe2Bn
SiMe2Bn
SiMe2Bn
h, i
j, k
H
8
3%
2 steps)
90%
(2 steps)
H
H
H
(
OPMB
O
4
9
50
13
Scheme 4. Reagents and conditions: a) EDC•HCl, NEt
NEt
MeOH / PhMe, 0 °C → rt; d) DIBALH, CH
CH Cl ; f) NaHMDS, [Ph PCH
LiHMDS, THF, –78 °C; BnMe
NaHCO , CH Cl ; j) CBr , PPh
k) n-BuLi, THF, –78 °C
benzoquinone; DMP Dess-Martin periodinane; EDC
dimethylaminopropyl) carbodiimide.
3
, DMAP; b) LiHMDS,
3
, PhMe, –78 °C → rt; then 5% NaOH; then conc. HCl; c) TMSCHN
Cl , –78 °C → rt; e) DMP, NaHCO
2
,
,
2
2
3
2
2
3
2
I]I, THF, –78 °C → rt; NaHMDS, –78 °C → rt; g)
SiCl, –78 °C to rt, 88%; h) DDQ, CH Cl ; i) DMP,
, CH Cl , 0 °C; then 50, NEt , –30 °C → 0 °C;
rt. DDQ 2,3-Dichloro-5,6-dicyano-1,4-
1-ethyl-3-(3-
2
2
2
3
2
2
4
3
2
2
3
→
=
[
25]
from 1,5-pentane diol),
enantiopure alcohol 43 (prepared by enzymatic kinetic resolution,
which underwent esterification with
=
=
[
26]
absolute configuration confirmed by Mosher ester analysis).
The resulting ester 44 underwent a diastereoselective Ireland-
Claisen rearrangement, setting up the two vicinal stereogenic
centres of carboxylic acid 45. The stereoselectivity of this
rearrangement arises from the high (Z)-selectivity of the
enolization in the presence of excess triethylamine, as observed
different molecules, including natural product-like polycyclic
[
30]
[31]
systems
and axially chiral biaryls,
no applications of this
chemistry in natural product total synthesis had been reported at
the outset of our work. A particular challenge in the present
synthetic context is the need for the palladium catalyst to
mediate a 7-membered ring formation, a feat not reported in the
bromoenediyne methodological context, albeit precedented in
[
27]
by Collum et al.
It is worth noting that the use of other
[
25]
conditions, such as LiHMDS
/
TMSCl,
led to inferior
diastereoselectivity (9:1) compared to the direct rearrangement
[
32]
other
carbopalladative
cyclizations.
Importantly,
the
of the lithium enolate. 45 was converted to its methyl ester
bromoenediyne cyclization benefits from the presence of a
silane substituent at the terminus of the diyne component, which
avoids side reactions based on further carbopalladation
processes. This is particularly convenient for our synthesis,
where we envisaged that this alkynylsilane, which is converted
to an arylsilane in the cyclization, would serve as a masked
(
2
TMSCHN ) to improve the subsequent reduction to primary
alcohol 46, which was oxidized to aldehyde 47 (95% yield over 3
steps); direct reduction of acid 45 to alcohol 46, or of the
intermediate methyl ester to aldehyde 47, delivered poor yields /
[
28]
decomposition. Stork-Zhao olefination
of 47 and in situ
elimination of the intermediate (Z)-vinyl iodide yielded alkyne 48,
which was converted to its benzyldimethylsilane derivative 49 in
good yield. Installation of the second alkyne was achieved by
PMB ether deprotection, oxidation, Ramirez olefination, and
Fritsch-Buttenberg-Wiechell rearrangement to give diyne 13 in
excellent yield. Overall, 13 could readily be prepared on
multigram scale (~3.5 g) in a total of 12 steps from alcohol 43
[
33]
phenol through eventual aromatic Tamao oxidation.
membered ring formation is similarly challenging for the
7-
[
16a-c]
cyclotrimerization approach,
but for both strategies we had
already demonstrated that simple bromoendiynes and triynes
could access the abridged CDE cores. Before embarking upon
the synthesis of the full rubriflordilactone A framework, we now
decided to explore advanced model systems to assess the
feasibility of each route with diyne 13, and also to establish
(
43% overall yield). With diyne 13 in hand, we turned our
attention to exploration of its conversion to the full CDEFG ring
system via metal-catalyzed cyclization and FG ring construction,
as a prelude to an assault on the natural product itself.
conditions for F and
G ring installation, and thereby the
synthesis of a truncated CDEFG rubriflordilactone A analogue.
The palladium-catalyzed cyclization of bromoenediyne 51
The palladium-catalyzed polycyclization of bromoendiynes
has been known for more than 25 years, since the pioneering
(
generated in two steps from 13 and aldehyde 52, 73%) was first
[
15c, 29]
[15a, b]
studied (Scheme 5). We were pleased to find that the additional
pendent alkene functionality in this diyne was tolerated, although
a small optimization was necessary to reach a satisfying 69%
work from the groups of de Meijere
and Negishi.
Although this field has expanded to the synthesis of many
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201703229
FULL PAPER
O
O
SiMe2Bn
OTIPS
O
5
2
67
OH
H
Br
OH
OTES
O
a, b
1%
c
H
OTES
Br
a-d
e
O
9
69%
H
35%
4 steps)
99%
O
SiMe2Bn (2 steps)
(
OTBS
51
SiMe2Bn
H
6
6
65
68
g
f, g
6%
7
SiMe2Bn
H
OR
53: R = TBS
80%
(2 steps)
OH
OH
a
d
1
3
OH
OH
OH
5
6: R = H
O
O
O
7
7%
O
80% (56)
73% (53)
b
k
H
O
O
O
5
5
OR
89%
H
54 R = H
b
99%
e
7
4
71
69
5
7 R = TBS
k
50% (2 steps)
i
89%
OH
h
OH
H
OH
H
O
O
O
O
g, h
f
OTf
6
0%
O
O
j
O
(2 steps)
61
OR
O
from 58: 66%
from 59: 56% (unopt.)
58: 69% (R = TBS)
59: 80% (R = H)
7
3
72
70
OH
O
H
RO
H
6
2
R'
R'
Scheme 6. Reagents and conditions: a) Ph
, Pd/C, MeOH; c) TESCl, imid., DMAP, CH
e) BF •OEt , Et O, –78 °C → 0 °C; f) MsCl, NEt
THF; h) Conditions (see text); i) Tf
mol%), dppf or (S)-tolBINAP (12 mol%), K
CH Cl °C. DIAD
bis(diphenylphosphino)ferrocene; Ms = SO
3
PCHCO
Cl ; d) DIBALH, CH
, CH Cl , 0 °C → rt; g) TBAF,
EtN, CH Cl , 0 °C; j) Pd(OAc) (10
3
CO , PhMe, 90 °C; k) DIAD, PPh ,
2
Me, PhMe, 110 °C; b)
H
2
2
2
2
2
Cl , –78 °C;
H
6
6
3
4
HO
Si
3
2
2
3
2
2
6
6
3:64
3:13
OH
O
2
O, i-Pr
2
2
2
2
2
60
Si
3
O
OH
R'
H
2
2
,
0
=
diisopropyl azodicarboxylate; dppf
Me; TES = SiEt ; Tf = SO
=
1,1'-
3
CF .
R'
2
3
2
R' =
OR
H
H
[
36]
Ayres and Gopalan.
Suspecting that formation of the
Scheme 5. Reagents and conditions: a) 13, LiHMDS, THF, –78 °C; then add
aldehyde; b) TBSCl, imid., DMAP, CH Cl ; c) Pd(PPh (5 mol%), NEt
MeCN, 80 °C; d) CpCo(CO) (20 mol%), PPh (40 mol%), PhCl, MW (300 W),
50 °C; e) TBAF, THF; then MeOH, H , KHCO
(4 mol%), NMO, acetone / H
intermediate diol was the problematic step in the one-pot
Johnson-Lemieux reaction, we tested a stepwise procedure; in
the event, Upjohn dihydroxylation yielded 61% of intermediate
diols, which pleasingly underwent smooth oxidative cleavage in
under 10 minutes using the Shing protocol of silica-supported
2
2
3
)
4
3
,
2
3
1
2
O
2
3
; f) Et
3
SiH, ZnCl
2
, CH
2
Cl
2
2
;
,
TBAF, THF; g) OsO
4
2
O (3:1); h) NaIO
4
/ SiO
2 2
CH Cl . Cp = cyclopentadienyl; NMO = N-methylmorpholine-N-oxide.
[
37]
sodium periodate.
This delivered a 63:13 mixture of open-
chain aldehyde 63 and lactol 64 (98%).
yield of tricycle 53. When employing triyne 54 (obtained from 13
and aldehyde 55, 77%), we were delighted to obtain an 80%
yield of 56 for the cobalt-catalyzed cyclotrimerization under
microwave heating conditions, which were essential for success
The introduction of the G-ring could conceivably proceed
through either of these intermediates. To explore these
alternatives, we first studied two simpler model systems lacking
the 7-membered C ring and the F ring methyl group. The first of
[
12b, 34]
in 7-membered ring formation.
The cyclization also proved
these was aldehyde 65, an analogue of aldehyde 63, which was
efficient with the TBS-protected triyne variant 57, albeit in slightly
lower yield (73%), which allowed the two parallel approaches to
converge at a common intermediate 53 in readiness for Tamao
oxidation and cationic reduction of the benzylic alcohol / ether. In
this oxidation, the conditions optimized previously required slight
[38]
prepared from known indanone 66
by Wittig olefination,
alkene and ester reduction, and protection of the phenol as a
TES ether (to prevent issues with equilibrium of the intermediate
phenol-aldehyde and the corresponding lactol). Promoted by
3 2
BF •OEt , 65 was reacted with silyloxyfuran 67 (prepared in four
[
35]
adjustment
to achieve good yields of phenol 58, due to the
[39]
steps from citraconic anhydride)
to afford the DEG ring
1
problematic formation of disiloxane 60 as observed in crude H
NMR spectra. Cationic benzylic reduction of 59 proceeded
smoothly, delivering 61 in 77% yield. This two-step sequence
could similarly be performed on the free alcohol 56.
alcohol 68 in quantitative yield.
We first envisaged completion of the DEFG rings by
intramolecular 1,6-oxa-Michael addition from diene 69. Whilst
formation of this diene from 68 was unproblematic, all attempts
to effect the conjugate addition failed, including a wide range of
With phenol 61 in hand, we next investigated oxidative
cleavage of the (E)-alkene sidechain.
process was first tested, but this proved rather capricious under
classical conditions (5 mol% aq. OsO , 4.0 equiv. NaIO , 2.0
equiv. 2,6-lutidine, 35-64% yield). Attempted ozonolysis in
CH Cl at –78 °C gave rise to a complex mixture of products,
whilst the use of RuCl triggered the formation of biphenyl 62,
presumably via an oxidative radical coupling as observed by
A Johnson-Lemieux
basic (e.g. t-BuOK, NaH, KHMDS, Cs CO
2
3 3
) or acidic (e.g. InCl ,
Sc(OTf) , FeCl , TiCl , La(NO •5H O, p-TsOH) conditions.
3
3
4
3
)
3
2
4
4
These reactions mostly resulted in no conversion (which we
attributed to the poor nucleophilicity of the phenoxide ion and /
or the reversibility of addition) or decomposition.
2
2
3
Other pathways were then explored using phenol 71, which
[40]
was accessed by acidic deprotection of the TES group in 68.
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Chemistry - A European Journal
10.1002/chem.201703229
FULL PAPER
O
OH
O
O
O
Cl
of siloxyfuran 67. Optimal results were found using 1.5
a
∗
2 2
equivalents of 67 with 40 mol% of zinc chloride in CH Cl ,
7
6
93% (crude)
H
2
allowing the reaction mixture to slowly warm up from –40 °C to
room temperature overnight. This led to the isolation of 47% of
the DEFG-ring system 78, as a 1:1 mixture of diastereomers.
Pleasingly, facial selectivity for addition to the oxocarbenium ion
was high, presumably directed by the proximal stereocentre and
stereoelectronic effects; the low stereoselectivity at the newly-
formed butenolide stereocentre presumably reflects poor facial
selectivity in an open transition state. In an effort to improve this
ratio, we examined epimerization of this stereocentre, reasoning
that the conversion of the newly appended G ring back to a
silyloxyfuran could improve the dr upon reformation of the
butenolide by hydrolysis. Siloxyfuran 79 was generated by
treatment of 78 with TIPSOTf and triethylamine at 0 °C, and a
variety of conditions were then screened to reform the G ring
7
5
77
b
47%, 1:1 dr
O
O
1
00
H
O
H
7
5
2
5
0
5
0
7
7
7
5
7
6
H
78
c
OTIPS
O
H
H
O
0
20
40
60
80
7
9
Time (min)
Scheme 7. Reagents and conditions: a) SOCl
2
2
, ZnCl , PhMe, 0 °C→rt; b)
(
TBAF, THF; CSA, MeOH; citric acid aq. / CH
2 2
Cl ; AcOH / THF /
ZnCl , CH Cl , –40 °C→rt; c) TIPSOTf, Et N, CH Cl , 0 °C.
2
2
2
3
2 2
H
2
O). Unfortunately, these all yielded almost exclusively the
elimination product 69, likely again due to the good leaving
group ability of the phenol, with only trace amounts of 78
observed as a mixture of diastereomers.
However, attempted intramolecular palladium-catalyzed C–O
[
41]
bond formation
after regioselective conversion of the phenol
Despite the poor dr observed with this model system, the
group to triflate 72 proved unsuccessful. A final attempt to
successful incorporation of the
G ring was nonetheless
construct the F-ring was made via an intramolecular Mitsunobu
encouraging. We were delighted to observe similar reactivity
[
42]
reaction, which resulted only in the elimination of the alcohol
to diene 69 even at temperatures as low as –78 °C. We
surmised that the stability deriving from conjugation of the diene
in 69 was an insurmountable barrier to cyclization, a hypothesis
that was confirmed by the successful isolation of dihydroDEFG
ring product 73 when the equivalent Mitsunobu cyclization was
carried out on the saturated derivative 74.
when switching to the more elaborate CDEF ring system 64
(
Scheme 8), with formation of the chloropyran derivative 80 from
the corresponding dimer 81 (4 equiv. SOCl , 5 equiv. ZnCl ).
Monitoring of the reaction by H NMR spectroscopy (Scheme
a-c) showed almost complete conversion of lactol 64 to a
2
2
1
8
mixture of dimer 81 and chloropyran 80 over 45 minutes,
although almost two hours reaction time was necessary to reach
complete conversion (Scheme 8a). The reaction pathway was
confirmed by subjecting dimer 81 to similar reaction conditions(8
With these unfruitful results in hands, we decided to adjust
the order of FG ring formation, and examine the addition of a
butenolide nucleophile to an oxocarbenium ion derived from an
F ring acetal (or similar derivative). Based on some preliminary
experiments using pyranyl acetals or acetates, it soon became
apparent that a good leaving group would be required in the
generation of the oxocarbenium ion, and we were attracted to
the report of Vercellotti et al. on the use of thionyl chloride and
equiv. SOCl
2 2
, 10 equiv. ZnCl , Scheme 8b). The obtained
chloropyran was used without further purification in the ZnCl
2
-
promoted butenolide addition step. Pleasingly, this delivered the
CDEFG ring system as a single diastereomer at the F ring
stereocentre, and a 1:1 diastereomeric mixture at the butenolide
[45]
stereocentre (82 and 83)
in 45% yield over two steps. The
[
43]
zinc chloride to effect the formation of pyranosyl chlorides.
truncated natural product 82 is of interest itself in the study of
structure-activity relationships in the rubriflordilactones.
[
44]
Initial attempts to form an F ring chloropyran from lactol 75
(
Scheme 7) unexpectedly resulted in the formation of mixtures of
These collected model systems had provided valuable
information on suitable method been developed to optimize
the desired chloropyran 76, and dimer 77; however, we found
that by extending the reaction time, 76 could be isolated in
excellent yield (~93%, crude) and as a single diastereomer,
which was assigned as the α-anomer on the basis of coupling
incorporation of the
F
and
G
rings. Despite poor
diastereoselectivity at the butenolide stereocentre, the furan
addition reaction exhibited high stereoselectivity at the F ring,
and excellent regioselectivity on the butenolide itself, which gave
us much confidence for our assault on the total synthesis of
rubriflordilactone A. This commenced with the separate addition
of the CDE diyne 13 to AB-ring aldehydes 14 and 15 (Scheme
1
[44]
constants in the H NMR spectrum. Monitoring of the reaction
1
by H NMR spectroscopy revealed a rapid initial formation of the
dimer (<10 min), followed by slower conversion to 76. We
hypothesize that activation of lactol 75 by thionyl chloride / zinc
chloride indeed leads to the formation of the corresponding
oxocarbenium ion, which is rapidly trapped by unreacted lactol
to give dimer 77, a process that is favoured at the beginning of
the reaction when lactol concentration is high. However, dimer
formation appears to be a reversible process, where the action
of zinc chloride reforms an oxocarbenium that is trapped by
chloride as the reaction progresses.
9
). To our delight, the TBS-protected secondary alcohol 84
(
deriving from aldehyde 14) underwent palladium-catalyzed
cascade cyclization to give 85 in an excellent 91% yield. As
observed previously, the triynes arising from addition of 13 to
aldehyde 15 could be cyclotrimerized to the ABCDE ring system
without (triyne 86) or with (triyne 87) protection of the secondary
alcohol as a TBS ether. However, a decrease in yield was noted
With chloropyran 76 in hand, we next addressed the addition
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Chemistry - A European Journal
10.1002/chem.201703229
FULL PAPER
OH
O
OTIPS
O
O
O
6
7
O
H
O
H
6
3
H
H
H
H
H
H
H
H
O
O
O
O
Cl
O
+
a
b
H
4
7%, 1:1 dr
H
H
H
O
OH
2
8
1
80
82
83
6
4
a 100
c
80
7
5
2
5
0
5
0
6
4
8
0
81
81
8
1
8
0
t = 47 min
t = 30 min
t = 21 min
t = 11 min
t = 0 min
0
30
60
90
120
Time (min)
b 1
00
7
5
2
5
0
5
0
8
8
1
0
6
3 64
6
3
64
0
200
400
600
800
Time (min)
1
Scheme 8. Reagents and conditions: a) SOCl
2
, ZnCl
2
, PhMe, 0 °C → rt; b) ZnCl
2
, CH
2
Cl
2
, –40 °C → rt. Graph a: Reaction profile (monitored by H NMR for
1
conversion of lactol 64 to chloropyran 80 via dimer 81; Graph b: Reaction profile for conversion of 81 to 80; Graph c: Example H NMR timecourse experiment.
when using the protected triyne 87 (54%), due to an unexpected
isomerization of the alkene sidechain to terminal alkene 88
the stereochemistry of the AB rings in other schinortriterpenoid
compounds (including those calculated and measured using CD
[
47]
(
22%). As this behaviour was not observed in the model
spectroscopy, and prepared by synthesis) indicates otherwise.
An explanation for this discrepancy remains unclear.
systems, or indeed for triyne 86 (67% of ABCDE alcohol 89), we
assume that the presence of this bulky silyl ether substituent
adjacent to the site of cyclotrimerization must retard the initial
[
46]
oxidative coupling, which allows isomerization to compete.
Conclusions
Tamao oxidation and benzylic reduction were performed on
both the free alcohol 89 and its silyl ether analogue 85,
delivering phenol 90 in 65% yield (2 steps) and 51% yield (3
steps) respectively; a stepwise alkene dihydroxylation / diol
cleavage then cleanly installed the F ring (91, 85% yield). As
observed before, treatment of lactol 91 with thionyl chloride and
zinc chloride generated chloropyran 92 via dimer 93, with a
reaction time of 3 h required for complete chloropyran formation.
Introduction of the G ring was carried out under the same
conditions as used for the model systems, which led to the
isolation of rubriflordilactone A 3 in 38% yield, along with 33% of
its C23-epimer 94 (over 2 steps).
A series of model studies provided a firm synthetic footing for
the formation of the CDE rings of (+)-rubriflordilactone A using
either a palladium-catalyzed cascade cyclization or a cobalt-
catalyzed cyclotrimerization, and for the installation of the F and
G rings though the intermediacy of a chloropyran. NMR studies
revealed that this latter compound is formed via a pyran dimer,
which over time is converted to the chloropyran. The two
transition metal-catalyzed routes were applied to the total
synthesis, with late-stage convergency between the approaches.
Comparison of spectroscopic data revealed an inconsistency in
the specific rotation between synthetic and isolation samples,
which remains unresolved. The modular nature of the synthesis
renders it suitable for application to other members of the
Schisandraceae family; efforts towards the total synthesis of
such compounds are currently underway in our laboratory.
Although all spectroscopic data for synthetic (+)-3 were in
agreement with that of the natural product, and the Li group's
synthetic sample, the specific rotation was found to be equal in
2
5
D
value but of opposite sign to the isolation sample ([α] +58.3 (c
2
D
5
[5],[26]
=
0.114, MeOH); lit. [α]
–58.1 (c = 0.114, MeOH)).
However, communications with the Li group revealed that both
synthetic samples were in agreement. Although this at first
suggests that both we (and Li et al.) had synthesized the
unnatural enantiomer of the natural product, the stereoselective
nature of our synthetic routes, combined with the conservation of
Experimental Section
Experimental details are given in the Supporting Information.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201703229
FULL PAPER
O
O
Br
H
H
SiMe2Bn
O
1
4
Br
H
O
O
c
O
O
a, b
50%
2 steps)
O
O
SiMe2Bn
H
H
(
H
OTBS
O
f, g
(from 89)
O
84
O
SiMe2Bn
H
O
OH
H
(
71% brsm)
SiMe2Bn
f-h
from 85)
H
H
(
H
RO
85 (R = TBS):
a
85%
O
e
91% from 84
4% from 87
90
1
3
O
O
5
65% (2 steps from 89)
51% (3 steps from 85)
O
O
8
9 (R = H): 67% from 86
H
H
OR
O
H
H
8
8
6 R = H
7 R = TBS
d
98%
O
O
O
SiMe Bn
2
1
5
88: 22% from 87
4% from 86
i, j 85% (2 steps)
H
O
H
H
TBSO
O
O
H
O
O
OTIPS
O
H
H
O
O
O
O
2
3
O
O
6
7
H
H
O
H
H
O
O
k
O
H
l
O
O
Cl
O
O
O
OH
3
: (+)-rubriflordilactone A
H
H
H
(38%, 2 steps)
H
H
H
2
+
9
2
93
91
9
4: (+)-C23-epi-rubriflordilactone
33%, 2 steps)
(
Scheme 9. Reagents and conditions: a) 13, n-BuLi, THF, –78 °C; then add aldehyde 14 or 15, –78 °C → –10 °C; b) TBSOTf, 2,6-lutidine, CH
Pd(PPh (10 mol%), NEt , MeCN, 80 °C; d) TBSCl, imid., DMAP, CH Cl ; e) CpCo(CO) (20 mol%), PPh (40 mol%), PhCl, MW (300 W), 150 °C; f) TBAF, THF;
then MeOH, H , KHCO ; g) Et SiH, ZnCl , CH Cl ; h) TBAF, THF; i) OsO (2 mol%), NMO, acetone / H O (3:1); j) NaIO / SiO , CH Cl ; k) SOCl , ZnCl , PhMe,
°C→rt; l) 67, ZnCl , CH Cl , –40 °C→rt.
2 2
Cl , 0 °C → rt; c)
3
)
4
3
2
2
2
3
2
O
2
3
3
2
2
2
4
2
4
2
2
2
2
2
0
2
2
2
These include details of the synthetic procedures, spectroscopic
Nat. Prod. Rep. 2008, 25, 871; e) Y. Zhang, Z. Chen, J. Zhao, Q. Tian,
X. Wang, Studies in Natural Products Chemistry, Vol. 53 (Ed.: A. u.
Rahman), Elsevier, 2017, pp. 109-141.
1
13
data, and copies of the H and C NMR spectra for novel
compounds.
[
[
3]
4]
R. T. Li, Q. S. Zhao, S. H. Li, Q. B. Han, H. D. Sun, Y. Lu, L. L. Zhang,
Q. T. Zheng, Org. Lett. 2003, 5, 1023.
a) Q. Xiao, W. W. Ren, Z. X. Chen, T. W. Sun, Y. Li, Q. D. Ye, J. X.
Gong, F. K. Meng, L. You, Y. F. Liu, M. Z. Zhao, L. M. Xu, Z. H. Shan,
Y. Shi, Y. F. Tang, J. H. Chen, Z. Yang, Angew. Chem. Int. Ed. 2011,
Acknowledgements
5
0, 7373; b) T.-W. Sun, W.-W. Ren, Q. Xiao, Y.-F. Tang, Y.-D. Zhang,
We thank the EPSRC for an Advanced Research Fellowship
Y. Li, F.-K. Meng, Y.-F. Liu, M.-Z. Zhao, L.-M. Xu, J.-H. Chen, Z. Yang,
Chem. Asian J. 2012, 7, 2321; c) Y. Li, Z.-X. Chen, Q. Xiao, Q.-D. Ye,
T.-W. Sun, F.-K. Meng, W.-W. Ren, L. You, L.-M. Xu, Y.-F. Wang, J.-H.
Chen, Z. Yang, Chem. Asian J. 2012, 7, 2334; d) W.-W. Ren, Z.-X.
Chen, Q. Xiao, Y. Li, T.-W. Sun, Z.-Y. Zhang, Q.-D. Ye, F.-K. Meng, L.
You, M.-Z. Zhao, L.-M. Xu, Y.-F. Tang, J.-H. Chen, Z. Yang, Chem.
Asian J. 2012, 7, 2341.
(
EAA) (EP/E055273/1) and additional funding (EP/K005391/1),
Marie Skłodowska-Curie actions for an Individual Fellowship
GC, GA N° 656012), A*STAR for National Science
Scholarship (SSG), and postdoctoral support through
(
a
a
fellowship from the German Academic Exchange Service (BG).
Scott Zona is acknowledged for the image of Schisandra
rubriflora.
[
5]
W. L. Xiao, L. M. Yang, N. B. Gong, L. Wu, R. R. Wang, J. X. Pu, X. L.
Li, S. X. Huang, Y. T. Zheng, R. T. Li, Y. Lu, Q. T. Zheng, H. D. Sun,
Org. Lett. 2006, 8, 991.
Keywords: cyclotrimerization • natural products • total synthesis
[
[
[
6]
7]
8]
J. Li, P. Yang, M. Yao, J. Deng, A. Li, J. Am. Chem. Soc. 2014, 136,
16477.
•
transition metal catalysis • cascade cyclization
L. Wang, H. Wang, Y. Li, P. Tang, Angew. Chem. Int. Ed. 2015, 54,
5
732.
[
[
1]
2]
J. L. Hancke, R. A. Burgos, F. Ahumada, Fitoterapia 1999, 70, 451.
a) L. You, X.-T. Liang, L.-M. Xu, Y.-F. Wang, J.-J. Zhang, Q. Su, Y.-H.
a) For reviews on Schisandraceae natural products, see: X. Li, P. H.-Y.
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Entry for the Table of Contents
FULL PAPER
The total synthesis of the
Guilhem Chaubet, Shermin S. Goh,
Schisandraceae nortriterpene
rubriflordilactone A is reported.
Palladium- and cobalt-catalyzed
polycyclizations were employed as
key strategies to construct the central
arene D ring from bromoendiyne and
triyne precursors. A number of model
systems were explored to investigate
these two methodologies, and also to
establish routes for the installation of
the challenging benzopyran and
butenolide rings.
Mujahid Mohammad, Birgit Gockel,
Marie-Caroline A. Cordonnier, Hannah
Baars, Andrew W. Phillips and Edward
A. Anderson*
Page No. – Page No.
Total synthesis of the
Schisandraceae nortriterpenoid
rubriflordilactone A
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