Asymmetric Total Synthesis of Lancifodilactone G Acetate

Article abstract of DOI:10.1021/jacs.7b02561

Asymmetric total synthesis of structurally intriguing and highly oxygenated lancifodilactone G acetate (7) has been achieved for the first time in 28 steps from a cheap commodity chemical, 2-(triisopropylsiloxy)-1,3-butadiene.

Full text of DOI:10.1021/jacs.7b02561

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Communication
Asymmetric Total Synthesis of Lancifodilactone G Acetate
Dong-Dong Liu, Tianwen Sun, Kuang-Yu Wang, Yong Lu, Su-Lei
Zhang, Yuanhe Li, Yan-Long Jiang, Jia-Hua Chen, and Zhen Yang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 09 Apr 2017
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Asymmetric Total Synthesis of Lancifodilactone G Acetate
Dong-Dong Liu,a,§ Tian-Wen Sun,a,§ Kuang-Yu Wang,a Yong Lu,a Su-Lei Zhang,a Yuan-He Li,a Yan-Long Jiang,a
Jia-Hua Chena,* and Zhen Yang*,a,b
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aKey Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National
Laboratory for Molecular Science (BNLMS), College of Chemistry and Molecular Engineering, and Peking-Tsinghua Center
for Life Sciences, Peking University, Beijing 100871, China.
bLaboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate
School, Shenzhen, 518055, China
Email: jhchen@pku.edu.cn, zyang@pku.edu.cn
Supporting Information Placeholder
As one of the most important member of the schinortriterpenoids
ABSTRACT: Asymmetric total synthesis of structurally
family, 1 represents the most challenging target for total synthesis
intriguing and highly oxygenated lancifodilactone G acetate (7)
owing to the difficulties associated with the construction of its
has been achieved for the first time in 28 steps from cheap
commodity chemical 2-(triisopropylsiloxy)-1,3-butadiene.
highly congested FGH tricyclic ring and its unusual 7–5–7 tricyclic
ring (CDE) system. The ring system has not yet been assembled in
the laboratory and represents a noteworthy target for both
synthetic7 and computational8 chemists. Herein a 28-step route to
Lancifodilactone G (1, Figure 1) was isolated from the medicinal
lancifodilactone G acetate 7 (Scheme 1) is documented, in which the
plant Schisandra lancifolia by Sun and co-workers in 2005, and its
central poly-fused ring system is constructed through a sequence of
structure has been determined by X-ray crystallographic analysis.1
key reactions featuring a ring-closing metathesis reaction and
Unlike the other members of the schinortriterpenoids family (such
Pauson-Khand reaction.
as 2-6, Figure 1), 1 contains a CD ring that bears a rare
non-resonance-stabilized aliphatic enol (C-8/C-16),2
a highly
congested FGH tricyclic ring system containing six contiguous
stereogenic centers, and an unusual two-fold anomerically stabilized
bis-spiro system.3
Figure 1: Naturally occurring schinortriterpenoids.
O
F
O
A
O
Me
H
3
O
Me
Me
Me
2
O
E
O
H
H
H
H
O
O
HO
O
D
O
G
O
8
B
O
C
H
5
O
H
16
O
O
7
O
OH
6
H
Me
Me
O
H
Me
H
Me
HO
Me
O
1: lancifodilactone G
2: schindilactone A
O
O
O
Me
HO
H
O
H
Me
O
Me
O
O
H
O
O
O
Me
O
Me
Me
Me
Me
H
H
H
H
Me
O
H
Me
H
4: schilancitrilactone B
3: rubriflordilactone A
O
H
O
O
O
O
Me
O
H
O
X
O
H
Me
O
Me
HO
H
Me
19
O
Me
H
H
Me
O
Me
O
OH
O
H
H
Me
O
H
Me
6: arisandilactone A (X = OH)
6a: 19-dehydroxyl arisandilactone A (X = H)
5: propindilactone G
Scheme 1: Strategic bond disconnections of 7.
Schinortriterpenoids are reported to exhibit anti-hepatitis,
A retrosynthetic overview of the main strategic operations is
depicted in Scheme 1. Our strategy involved the following steps: (1)
oxidation of the alcohol at C-16 to give a ketone, followed by
acetylation to afford 7; (2) a sequence of reactions, featuring a
Grignard reaction, cross-metathesis reaction, and lactonization to
form the two-fold anomerically stabilized bis-spiro system in 8; (3) a
antitumor, and anti-HIV agents.4 As a result, much effort has been
paid to their total syntheses,5 with the aim of accelerating the
evaluation of their pharmacological potential. This has recently
culminated in the total syntheses of 2-55 and 6a.6
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tetramethyl thiourea (TMTU)/Co2(CO)8-catalyzed Pauson–Khand
The ester side chain in 18 was extended through two discrete
reaction9 of enyne 10 for the stereoselective construction of highly
congested bicyclo[6.3.0]undecan-2-one10 9, which bears an
all-carbon quaternary chiral center at C-13; (4) a ring-closing
metathesis (RCM) reaction to form the tri-substituted olefin based
on an oxa-bridged eight-membered ring in 10; and (5) an
oxazaborolidine-catalyzed11 asymmetric intermolecular Diels–Alder
reaction12 of diene 14 with dienophile 15 for the enantioselective
synthesis of ketoester 13 with 87% ee.
operations that involved a Pd-catalyzed cross-coupling reaction of
12 with vinyloxy silane B in the presence of CuF2, followed by
1
2
3
4
5
6
7
8
18
Pd-catalyzed hydrogenation. As a result, ketoester 18 was formed in
75% overall yield. Grignard reaction of 18 with Grignard reagent C
afforded a tertiary alcohol, which then underwent an intramolecular
lactonization to give 19. Lastly, treatment of 19 with LiHMDS and
oxidation of the resulting enolate with MoOPH,19 followed by
treatment with Ag2O/BnBr20 for the benzylation to give the desired
product 20 in 80% yield. Notably, both the Grignard reaction and the
oxidative hydroxylation used for the formation of 19 and 20 were
diastereoselective owing to the steric effect of the OTES group at
C-10 (the conformation analysis is provided in SI). The structure of
19 was confirmed by X-ray crystallographic analysis.
Scheme 2. Synthesis of compound 20.
9
TIPSO
O
10
11
12
13
14
15
16
17
18
19
20
21
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23
24
25
26
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a) A, DCM, -78 o
C
10
OTIPS
EtO
TBSO
(95%, 87% ee)
O
14
+
5
F3
C
OEt
CF3
13
CF3
Scheme 3. Synthesis of compound 22.
O
H
TBSO
b) MeMgCl (85%)
c) O2, KHMDS
P(OMe)3, then
TESCl (42%)
A =
+
N
O
O
CF3
B
15
- H
Me
NTf2
O
O
OTES
OTES
H
OTIPS
Br
d) tBuOK, CHBr3
petroleum ether
OTIPS
O
O
4
4
Br
H
Me
Me
TBSO
TBSO
16
17
e) AgClO4 H2O
(49%, 2 steps)
.
f) B, PdCl2[P(o-tol)3)]2
CuF2 (77%)
g) Pd/C, H2 (97%)
O
O
OTES
O
OTES
O
COOtBu
10
5
O
O
Br
8
8
4
OTBS
B =
7
7
H
OtBu
18
H
Me
MgBr
TBSO
Me
TBSO
12
h)
(84%)
C =
Me
Me
O
O
O
OTES
OTES
O
O
i) LiHMDS, LiCl, MoOPH
(85%)
O
9
9
16
O
O
(j) BnBr, Ag2O
(94%)
OBn
H
H
H
H
Me
20
Me
19
TBSO
TBSO
14
15
A
(1.0 equiv.), (20 mol %),
Reagents and conditions: (a)
(1.5 equiv.),
CH2Cl2, -78 oC, 12 h, 95% (87% ee); (b) MeMgCl (2.0 equiv.), THF, -78 oC to -20
oC, 0.5 h, 85% (dr = 1.7 : 1); (c) KHMDS (2.0 equiv.), THF, -78 oC to 0 oC
followed by addition of P(OMe)3 (2.0 equiv.), O2, 0 oC, 1 h; then, TESCl (1.5
equiv.), 42% and 38% C-4 isomer; (d) KOtBu (6.0 equiv.), CHBr3 (6.0 equiv.),
petroleum ether, -20 oC, 2 h; (e) AgClO4.H2O (2.0 equiv.), acetone, rt, 12 h, 49%
for two steps; (f) (1-tert-butoxyvinyloxy)-(tert-butyl)di-methylsilane (3.0 equiv.),
PdCl2/[P(o-tol)3]2 (0.1 equiv.), CuF2 (3.0 equiv.), THF, reflux, 12 h, 77%; (g) Pd/C
(10 wt%), H2, EtOAc, 50 oC, 1 h, 97%; (h) Grignard reagent (5.0 equiv.), THF, -
78 oC to 0 oC, 84%; (i) LiHMDS (3.5 equiv.), LiCl (5.0 equiv.), THF, -78 oC,
MoOPH (3.5 equiv.), 2h; 85%; (j) Ag2O (2.0 equiv.), BnBr (2.0 equiv.), 35 oC, 12
h, 94%.
With 20 in hand, we then proceeded to the synthesis of the most
challenging intermediate, 22. Aside from the obvious difficulties
posed by the high steric demand of the F ring in 22, a unique issue
associated with the formation of the oxabicyclo[4.2.1]nonene core21
bearing a sterically hindered tri-substituted olefin in 21 also made
this synthesis challenging. Initial attempts to construct 21 from 11
through RCM reactions22 using the Grubbs I and Grubbs II catalysts
failed to afford any of the desired product. However, when the
Hoveyda–Grubbs II23 catalyst (8 mol%) was used, the expected
annulation proceeded smoothly. Exposure of lactone 20 to vinyl
magnesium bromide at 0 °C resulted in the formation of dienes 11 as
a pair of diastereoisomers in a ratio of 5:1. These diastereoisomers
were treated without separation with the Hoveyda–Grubbs II
catalyst (8 mol%) at 85 °C in toluene for 8 h to give 21, which was
obtained in 76% overall yield as a single isomer. This in situ
epimerization24 was remarkable and in line with our early
observation,6 and might be of general utility in similarly challenging
synthetic contexts.
Scheme 2 shows our synthesis of bis-lactone 20. Knowing that the
enantioselective synthesis of ketoester 13 using a Diels–Alder
reaction with an acyclic ketone as the dienophile is challenging,13 we
conducted a systematic investigation. Pleasingly, enantioselective
synthesis was achieved when the Diels–Alder reaction was carried
out in the presence of oxazaborolidine A14 as the catalyst, and 12
was obtained in 95% yield with 87% ee. This reaction worked well on
a 100-g scale, and provided a good foundation from which to pursue
the total synthesis of 1. To construct lactone 16, 13 was reacted with
MeMgCl, and the resultant lactone was treated with KHMDS
followed by reaction with O2 in the presence of P(OMe)3,15 and
quenching with TESCl to give gave silyl ether 16 in 36% overall yield,
together with its diastereoisomer in 33%, respectively.
We then turned our attention to the later steps in the synthesis of
20. Reaction of 16 with dibromomethylene (derived from CHBr3 and
KOtBu in petroleum ether16) was followed by ring-expansion of
To make 22, 21 was treated with KHMDS in THF at 0 oC for 15 min,
and the resultant alkoxide was reacted with but-2-ynoic pivalic
anhydride25 to afford enyne 10 in 86% yield. Thus, under the
optimized PKR conditions, 10 was treated with the complex of
tetramethyl thiourea (TMTU) and Co2(CO)8 in dry toluene under a
17
resulting dibromocyclopropane 17 with AgClO4 to afford vinyl
bromide 12 in 49% yield over two steps, and the ee value of 12 is
99% after recrystallization from a mixed solvent of CH2Cl2 and
hexane.
o
balloon pressure of CO26 at 95 C for 8 hours, enone 9 was obtained
in 73% yield as
a
sole isomer. This stereoselectively
TMTU/Co-catalyzed PKR that yielded enone 927 in such a high yield
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is truly remarkable. The structure of 9 was confirmed by X-ray
oxygen atom in the G ring, which could facilitate enolization from
1
2
3
4
5
6
7
8
crystallographic analysis of the crystals derived from its racemic
sample (see SI for details). The next mission was to stereoselectively
introduce the contiguous stereogenic centers at C-20 and C-22 in 22
involving Pd/C catalyzed hydrogenation. Thus, approach of the
catalyst to the double bond from the more accessible top face within
9 set up the stereogenic centers at C-20 and C-22, and the opposite
stereochemistry at C-20 in the resultant product was inverted by the
treatment with DBU28 to afford 22 in 78% yield.
The construction of the bis-spiro system was another strategic
transformation, and involved three discrete operations: chemo- and
stereo-selective vinylation, intermolecular cross-metathesis29 using
the Hoveyda–Grubbs II catalyst, and Pd-catalyzed hydrogenation–
lactonization. This sequence delivered desired siproketal 8 in 37%
overall yield. Removal of the silyl protecting groups with anhydrous
TBAF, followed by selective silylation with TBSCl, resulted in a
tertiary alcohol, which was then protected with Ac2O/TEA/DMAP to
give acetate 24 in 56% yield over two steps.
the ketone to the enol form. With this chemistry in mind, we
oxidized 27 with DMP, and unstable intermediate 28 immediately
underwent a Pd-catalyzed stereoselective hydrogenation that
removed both double bonds at C-1/C-2 and C-25/C-27, as well as the
TBS group,34 to give ketone 29. However, attempts to convert
ketone 29 to its enol under various conditions did not result in the
expected enolization, and in most cases 29 simply decomposed.
To promote the enolization, ketone 28 was treated with
Ac2O/Et3N and, to our delight, the expected enol acetate was
9
obtained. This compound then underwent
a Pd/C-catalyzed
hydrogenation reaction to give lancifodilactone G acetate (7). The
structure of 7 was confirmed by X-ray single crystallography.
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Scheme 5. Total synthesis of lancifodilactone G acetate 7.
Scheme 4. Synthesis of compound 26.
In summary, the asymmetric total synthesis of lancifodilactone G
acetate 7 has been completed in 28 steps. Salient features of this
work include: (1) development of
a highly enantioselective
oxazaborolidine-catalyzed Diels–Alder reaction using substituted
(E)-4-oxopent-2-enoates 15 as the dienophile to synthesize key
intermediate 13; (2) demonstration of the efficiency of the RCM
approach for accessing a oxabicyclo[4.2.1]nonene core bearing a
sterically hindered tri-substituted olefin; and (3) application of our
Co/TMTU-catalyzed Pauson-Khand reaction to the stereoselective
synthesis of the highly congested F ring of 7, which bears an
all-carbon quaternary chiral center at C-13. We currently work on the
conversions of compounds 29 and 7 to lancifodilactone G (1), and
the results will be reported in due course.
To apply the Dieckmann-type condensation30 for the formation of
the A ring, the benzyl group in 24 was removed by hydrogenation
and the resultant product was treated with LiHMDS in THF at −78 °C
to give lactone 25 in 78% yield. It is imperative that the benzyl group
in 24 is removed to allow the carbonyl group at C-1 and the acetate
at C-10 to come closer together and thus facilitate the subsequent
ring closing reaction. Thereafter, further treatment of 25 with
Martin’s sulfurane31 resulted in the formation of α,β-unsaturated
lactone 26 in good yield.
ASSOCIATED CONTENT
With key intermediate 26 in hand, we proceeded with the
methylation at C-25, as illustrated in Scheme 5. This process
involved α-methylenation of lactone as the key step. Briefly, 26 was
Supporting Information
Experimental procedures and compound characterization (cif,
pdf). This material is available free of charge via the Internet at
http://pubs.acs.org.
treated with LiHMDS in THF at −78 °C, and then reacted with
N,N-dimethyl- methyleneammonium iodide32 (Eschenmoser’s
reagent).
This
was
followed
by
treatment
with
2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT)33 in the presence of
TEA to afford methylene-containing 27 in 58% yield.
AUTHOR INFORMATION
The final challenge in the total synthesis of lancifodilactone G (1)
called for the introduction of an enol moiety. We speculated that, in
the presence of water, the enol of lancifodilactone G (1) might form
a hydrogen-bonded network involving the enol proton and the
§These authors contribute equally to this work.
Corresponding Authors
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Am. Chem. Soc. 1987, 109, 2182. (b) Scholl, M.; Grubbs, R. H. Tetrahedron Lett.
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step-wise, featuring a RCM reaction for the formation of cyclopetenone core,
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cyclopetenone followed by reaction with MeI.
jhchen@pku.edu.cn, zyang@pku.edu.cn
1
2
3
4
5
6
7
ACKNOWLEDGMENT
We thank Prof. Wen-Xiong Zhang and Dr. Neng-Dong Wang for the
X-ray crystallographic analysis, and Mr. Zi-Ang Nan at IChEM for the
refine of the results of X-ray crystallographic analysis. This work is
supported by Natural Science Foundation of China (Grant Nos.
21372016, 21572009 and 21472006) for financial support.
8
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(28) Fonquerna, S.; Moyano, A.; Perics, M. A.; Riera, A. Tetrahedron:
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