Total Synthesis of Cryptotrione

Article abstract of DOI:10.1002/anie.202009255

The total synthesis of cryptotrione (1) was enabled by substrate-controlled diastereoselective construction of the bicyclo[3.1.0]hexene framework through platinum-catalyzed enyne cycloisomerization and Lewis acid induced polyene cyclization to construct the abietane-type tricyclic diterpene skeleton. The stereogenic tertiary carbon center in the side chain was installed in a diastereodivergent manner by conjugate addition reactions.

Full text of DOI:10.1002/anie.202009255

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Accepted Article
Title: Total Synthesis of Cryptotrione
Authors: Henry N. C. Wong, Mao-Yun Lyu, Zhuliang Zhong, Vanessa
Kar-Yan Lo, and Xiao-Shui Peng
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Total Synthesis of Cryptotrione
Mao-Yun Lyu, Zhuliang Zhong, Vanessa Kar-Yan Lo, Henry N. C. Wong,* Xiao-Shui Peng *
[
a]
Prof. Dr. H. N. C. Wong, Prof. Dr. X.-S. Peng
School of Science and Engineering, The Chinese University of Hong Kong (Shenzhen), Longgang District, Shenzhen, China
E-mail: hncwong@cuhk.edu.hk; xspeng@cuhk.edu.cn
[
[
b]
c]
Dr. M.-Y. Lyu, Dr. Z. Zhong, Prof. Dr. H. N. C. Wong, Prof. Dr. X.-S. Peng
Department of Chemistry, and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
SAR, China
Dr. Vanessa Kar-Yan Lo
State Key Laboratory of Synthetic Chemistry and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China
Dedicated to Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences on the occasion of its 70th Anniversary
Abstract: The first total synthesis of cryptotrione (1) has been
achieved
through
substrate-controlled
diastereoselective
construction of the bicyclo[3.1.0]hexene framework via platinum-
catalyzed enyne cycloisomerization, Lewis-acid induced polyene
cyclization to construct the abietane type tricyclic diterpene skeleton,
as well as diastereo-divergent conjugate addition to generate the
tertiary carbon center on the side chain.
In 2010, cryptotrione (1) (Figure 1), a novel C35-terpene with an
unprecedented skeleton, was isolated from the bark of
Cryptomeria japonica by the Kuo group.[1] Since the isolation of
the first cryptotrione member from the Cryptomeria japonica
family in 1983 nine cryptotrione family members, including
chamaecydin
(2),
isochamaecydin
(3)
and
cryptoquinonemethides D and E (4, 5), have been isolated.[1-2]
All share this unprecedented skeleton possessing an abietane-
type diterpene quinone methide spiro-annulated with a thujone-
type bicyclo[3.1.0]hexane ring system. Cryptotrione (1), the
structurally most complex member of this family, interestingly
exhibits anticancer activity against human oral epidermoid
carcinoma KB cells with an IC50 value of 6.44 ± 2.23 μM, only
slightly weaker than that of the clinically used anticancer drug,
etoposide (VP-16, IC50~2.0 μM).[1] To the best of our knowledge,
there have been no reports of its total synthesis, although the
Figure 1. Representative Structures of Cryptotrione Family.
Our retrosynthetic analysis of the structure of cryptotrione (1)
has revealed the bicyclo[3.1.0]hexane unit and quinone methide
species as the structural features common to the cryptotrione
family. Based on our preliminary results and reports of gold- or
platinum-catalyzed cycloisomerization of 1,n-enynes into
bicyclo[n.1.0]hexane derivatives[4,5] (Figure 2), we proposed to
Shi
group
demonstrated
the
construction
of
its
bicyclo[3.1.0]hexane core.[3] The promising bioactivity of these
unprecedented molecules, coupled with the synthetic challenges
arising from their bicyclo[3.1.0]hexane unit, attracted our interest.
Here we report the first total synthesis of cryptotrione (1)
employing the efficient platinum-catalyzed assembly of the
bicyclo[3.1.0]hexane structural unit and quinone methide moiety.
assemble the bicyclo[3.1.0]hexane moiety in compound 9 from
1
,5-enyne species 10. Moreover, in consideration of the steric
effect of the isopropyl group on the benzene ring, we reasoned
that the enyne cycloisomerization of substrate with an
a
isopropyl group could lead to the undesired stereochemistry of
the bicyclo[3.1.0]hexane moiety. This could also facilitate
efficient synthesis of other cryptotrione family members through
functional group modification of the 1,5-enyne substrate.[5f,5i,5m]
The 1,5-enyne precursor 10 could be readily prepared from
commercially available homoveratric acid (11) through a known
procedure.[6] Once alcohol 9, with a bicyclo[3.1.0]hexane unit,
was achieved, alkylation of relevant ketone derivative of alcohol
9
could lead to polyene 8. Compound 8, with an a-alkyl group,
would then undergo Lewis acid-mediated stereoselective
cyclization followed by isopropylation to provide the
corresponding trans-polycyclic species 7, in which the
stereocyclization could be controlled by the stereochemistry of
the relevant a-alkyl group in ketone 8. Subsequent installation of
the side chain on 7 could afford alkene 6. The generation of the
1
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relevant quinone methide species followed by Wacker oxidation
To our pleasure, the PtCl
2
-catalyzed enyne isomerization[5k,5l,5m]
would eventually afford synthetic cryptotrione (1).
2
of 12a occurred smoothly with 20 mol% PtCl at 100 °C in
toluene for 18 hours, affording 13a in 44% isolated yield with a
dr > 30:1 (Table 1, entry 2). While 12b containing smaller
3
protection group (TBS vs iPr Si) gave slightly lower yield under
the same conditions (Table 1, entry 3). Enyne 12c with a β-
benzyloxy group also gave the desired 13c in 30% yield with a
similar dr > 30:1(Table 1, entry 3).[4] In contrast, enyne 12d with
a methoxyl group (Table 1, entry 6) gave poor yield (20%) and
dr (12:1), presumably due to insufficient steric hindrance.
2
Replacing the acetyl protection group on R to pivaloyl improved
the yield only slightly (Table 1, entries 4 vs 5), implying that the
β-triisopropylsiyl group at C15' dominated stereoselectivity. We
then further optimized cycloisomerization for catalyst and solvent
using enyne 12e (Supporting Information). After varying the
4
platinum(II) or platinum(IV) halides, 10 mol% of PtCl gave the
best result of 75% isolated yield (entries 7-8). Screening of
solvents showed that 1,4-dioxane gave even better yields than
those know cases usually using toluene as the solvent.[5f,5k-n]
Moreover, this isomerization was easily scaled up to 15g using
1
0 mol% PtCl
4
catalyst at 115 °C, affording 13e in 71% yield
(
entry 8).
Figure 2. Retrosynthetic Analysis of Cryptotrione (1).
Thus, we commenced our synthesis by developing an
assembly protocol for the bicyclo[3.1.0]hexane structural unit.
Starting from the commercially available homoveratric acid (11),
various enynes 12a-e were prepared, via a known carbene-
Scheme 1. Synthesis of Bicyclo[3.1.0]hexene Species
Table 1. Optimization of 1,5-Enyne Cycloisomerization[a]
insertion procedure,[3] followed by
a
series of classic
transformations (Scheme 1 and Supporting Information). Next,
we focused on the conversion of enynes 12a-e into the desired
bicyclo[3.1.0]hexene species 13a-e, as opposed to the
undesired 13´a-e. In order to understand the stereoeffects of the
protective hydroxyl groups in enynes 12a-e, we prepared both
C15'-α-silyloxy-1,5-enyne species and C15'-β-silyloxy-1,5-enyne
species via diastereoselective reduction. Treatment of the α-
silyloxy-1,5-enyne under Toste’s Au-catalyzed conditions5i
generated the undesired bicyclo[3.1.0]hexene compound whose
relative configuration of the cyclopropane ring differed from that
of cryptotrione (1) (Supporting Information). We therefore turned
our attention to cycloisomerization of C15'-β-silyloxy-1,5-enynes
.
Entry Enyne
Catalyst
mol%)
PAuSbF
Solvent Ratio[b] t(h) Yield[c]
(
(13:13')
(%)
1
2
12a Ph
3
6
CH
2
Cl
2
-
0.5
0
12a PtCl
2
(20)
Toluene >30:1 18
44
3
4
5
12b PtCl
2
2
(20)
(20)
Toluene >30:1 18
Toluene >30:1 18
32
30
12c PtCl
1
2d PtCl
2
2
4
(20)
(20)
(10)
Toluene 12:1
6
20
47
75
71
1
2a-e as a way to generate the bicyclo[3.1.0]hexane unit for
total synthesis of cryptotrione (1), expecting that the C15'-β-
silyloxy group would cause substantial steric hindrance to impact
relevant cycloisomerization, leading to key precursors 13a-e with
the desired stereochemistry. Unfortunately, in the presence of
6
7
12e PtCl
12e PtCl
Toluene >30:1 18
Dioxane >30:1
Dioxane >86:1
4
7
8[d]
4
12e PtCl (10)
1
0% Ph
3
PAuCl/AgSbF6,[5i] enyne 12a decomposed completely
(
Entry 1), and enyne 12c with a β-benzyloxy group even initiate
[
a] Standard conditions: 12 (0.05 mmol) and platinum catalyst in solvent (5
novel gold-catalyzed tandem cycloisomerization.[4] We
mL) at 100 °C under argon. [b] dr ratio determined by 1H NMR spectra after
a
therefore turned to platinum-catalyzed enyne isomerization.[5h-n]
global deprotection of 13 and 13'. [c] Isolated yield. [d] 15g scale at 115 °C.
2
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Scheme 2. Synthesis of Diol 21.
With crucial precursor 13e in hand, we turned to the
synthesis of diol 21. Desilylation of 13e followed by
hydrogenation yielded alcohol 14 in 75% yield (Scheme 2) and
X-ray crystallographic analysis showed the bicyclo[3.1.0]hexane
skeleton to have the same relative configuration as in natural
cryptotrione (1).[24] Oxidation of 14 with Dess-Martin periodinane
furnished the corresponding ketone, which then underwent
monoalkylation with geranyl bromide using one equivalent of
To construct the abietane-type skeleton, we explored Lewis
acid-induced polyene cyclization of the acetate of alcohol 17 to
yield the trans-decalin product 18.[8] Based on Stork–
Eschenmoser’s rule,[9] we anticipated that cyclization of the C7-
β-trans-polyene acetate of compound 17 would favorably
proceed via a double-chair transition state to afford the trans-
decalin product 18, containing a C10-β-angular methyl. After
careful optimization (see Table S4 in Supporting Information),
LDA in
diastereomeric mixture of monoalkylated polyene ketones 15 in
2% yield (84% brsm) together with 15% yield of the dialkylated
a
mixed solvent (THF:DMPU 10:1) to afford
a
Bi(OTf)
3
-induced polycyclization[10] was indeed able to convert
the acetate of 17 into the abietane-type product 18 in 67% yield
as a single diastereomer, after further cyclization of partially
cyclized intermediates.
7
by-product. The mixture of ketones 15 was inseparable by
column chromatography and, since it also proved unstable and
prone to decomposition. We then sought to stabilize ketones 15
by reducing the carbonyl groups to hydroxyl groups, because we
reasoned that the hydroxyl group would decrease the acidity of
the a-proton, preventing the cyclization precursor from potential
epimerization. Screening of various reducing reagents showed
ketone 15 was reduced diastereoselectively by L-selectride at
low temperature (see Table S3 in Supporting Information for
details), affording syn-C7,15'-β,β-polyene alcohol 17 as a major
diastereomer (dr = 13:1) in 33% yield (48% brsm), as well as
syn-C7,15'-α,α-polyene alcohol 16 as a single isomer in 35%
yield. Alcohol 16 was able to undergo oxidation followed by
epimerization to regenerate ketones 15 (dr = 1:1) in 88% yield.
To stabilize the polyene alcohol 17 and prevent it from
undergoing cation-olefin cyclization under acidic conditions,[7] we
converted its hydroxyl group into the acetate in high yield,
containing the polyene and hydroxyl groups on the β-side
After constructing the trans-decalin skeleton, we began to
install the isopropyl group onto the benzene ring. Neither N-
bromosuccinimide (NBS) with various promoters (Ph
AgNTf
,[12] AuCl ,[13] or zwitterionic-salt[14]) nor NBS with a strong
Brønsted acid in DMF, such as H SO , were able to deliver a
3
P=S,[11]
2
3
2
4
successful bromination, but bromide 19 was produced in 30%
yield (50% brsm) using NBS and AcOH. Employing two
equivalents of NBS in the co-solvents hexafluoroisopropanol
(HFIP) and DMF, the yield of bromide 19 was increased to 53%
yield (69% brsm). Our efforts to direct isopropylation of bromide
19, using newly developed direct isopropylation conditions,[15]
yielded only reductive product 18 and n-propyl-substituted
product (Supporting Information). We then tried to introduce the
isopropyl group stepwise under Stoltz’s conditions.[16] As
expected, bromide 19 smoothly underwent sterically hindered
Suzuki-Miyaura
coupling
with
potassium
isopropenyltrifluoroborate to produce the alkene 20 in 80% yield
as an inseparable atropisomeric mixture (ca. 3:1). Attempts at
direct hydrogenation of alkene 20 using a variety of classic
(
Supporting Information).
3
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COMMUNICATION
Scheme 3. Total Synthesis of Cryptotrione (1)
protocols were completely unsuccessful, probably retarded by
the steric hindrance from acetyl and pivaloyl groups. Reduction
of 20 with DIBAL-H to relieve this steric hindrance, followed by
subsequent hydrogenation, however, successfully led to diol 21
in 91% yield over the two steps.
cryptotrione (1) and its C7'-epimer (25). Upon treatment of 23
4
with LiAlH , subsequent selective tosylation and hydride
replacement[21] of the resulting tosylate, alkene 6 was formed in
30% yield over the 3 steps. Demethylation of 6 under alkaline
conditions[22] then afforded the dihydroxyl intermediate, which
unfortunately could not be auto-oxidized in air to its
corresponding ortho-quinone. Instead, this dihydroxyl phenol
After establishment of the structural framework of
cryptotrione (1), we then focused on the installation of the side
chain. As shown in Scheme 3, selective oxidation of the primary
hydroxyl group of 21 using PIDA-TEMPO[17] led to its aldehyde in
2
intermediate was treated with MnO , generating the para-
quinone methide 6a, which was directly subjected to Wacker
oxidation[23] without further purification, eventually affording
synthetic cryptotrione (1) in 40% yield. Moreover, subjection of
alkene 24 to the similar aforementioned procedures from alkene
23 to cryptotrione (1), 7'-epi-cryptotrione (25) was successfully
achieved in 18% yield over 5 steps. The structure of 7'-epi-
cryptotrione (25) was unambiguously confirmed using X-ray
crystallographic analysis.[24]
9
2% yield, which subsequently underwent Knoevenagel
condensation with dimethyl malonate to afford α,β-unsaturated
malonate 22,[18] the precursor for conjugate addition, in 80%
yield. In our initial studies, conjugate addition of 22 and
homoallylmagnesium bromide (22a) in the presence of CuI
formed 23 and its isomer with poor diastereoselectivity.[19] When
two equivalents Li
presence of 20 equivalents of homoallylmagnesium bromide
22a) at –78 °C,[20] the desired conjugate addition product 23
2 4
CuCl were used as the copper source in the
In summary, we achieved the first total synthesis of
cryptotrione (1) from commercially available homoveratric acid
(11) in a diastereoselective and diastereo-divergent manner.
(
was smoothly achieved in 80% yield with dr > 20:1. Interestingly,
further optimizations (see Supporting Information) showed that
the stereoselectivity of the conjugate addition was totally
This synthetic protocol features with
a novel platinum(IV)
chloride-catalyzed diastereoselective cycloisomerization of 1,5-
enynes to construct the bicyclo[3.1.0]hexane core, a Lewis acid-
induced diastereoselective polyene cyclization, and a stereo-
divergent conjugate addition to construct the tertiary carbon
center of the side chain with full stereocontrol. This synthetic
route would be practical for synthesizing other members of the
structurally unprecedented cryptotrione family and its analogs for
further biological evaluation.
reversed
in
the
presence
of
10
equivalents
CuCl
of
(2
homoallylmagnesium bromide (22a) and Li
2
4
equivalents) at –78 °C with different reagent addition mode (see
Supporting Information), forming 24 (C7'-epimer of 23) with
excellent dr (> 20:1 at C7'). Thus, the stereochemistry at C7'
could be fully controlled using different amounts of
homoallylmagnesium bromide and addition mode, presumably
due to the formation of different copper magnesium complexes.
Thus, alkenes 23 and 24 are ready for the syntheses of
cryptotrione (1) and 7’-epi-cryptotrione (25), respectively. In Acknowledgements
Scheme 3, the Michael acceptor 22 hence served as
a
This work was supported by grants from National Science
diastereo-divergent intermediate for the syntheses of both
Foundation of China (NSFC) (21971219, 21672181), Research
4
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COMMUNICATION
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Angewandte Chemie International Edition
10.1002/anie.202009255
COMMUNICATION
Natural Product Synthesis
Total Synthesis of Cryptotrione
*
*
M.-Y. Lyu, Z. Zhong, V. K. Y. Lo, H. N. C. Wong, X.-S. Peng
The first total synthesis of cryptotrione has been acheived via platinum-catalyzed enyne cycloisomerization from commercially available
homoveratric acid in a diastereoselective and diastereo-divergent manner. This synthetic strategy would be practical for synthesizing other
members of the structurally unprecedented cryptotrione family.
6
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