Formal Total Synthesis of (+)-Cortistatins A and J

Article abstract of DOI:10.1002/chem.201502890

An efficient formal total synthesis of (+) cortistatins A and J has been accomplished, by exploiting a highly diastereoselective intramolecular [4+3] cycloaddition of epoxy enolsilanes as the key reaction to construct rings B and C of the cortistatins in

Full text of DOI:10.1002/chem.201502890

DOI: 10.1002/chem.201502890
Communication
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Natural Products |Hot Paper|
Formal Total Synthesis of (+)-Cortistatins A and J
Liping Kuang, Lok Lok Liu, and Pauline Chiu*[a]
Due to their promising bioactivities and therapeutic poten-
tial, unique architectures but low availability from natural sour-
ces, the cortistatins have attracted much attention from the or-
ganic chemistry community.[3] To date, six research groups
have accomplished the synthesis of the cortistatins.[4] In addi-
tion, four formal syntheses, as well as many synthetic studies,
have also been reported.[5,6] The oxygen-bridged ring B, the
nucleus of all cortistatins, has been assembled by a range of
methods,[4–6] including cycloisomerizations, ring-closing meta-
theses, ring expansions, cyclizations by radical, alkylation,
cross-coupling, Michael and aldol reactions, as well as cycload-
ditions, many of which involve the furan nucleus.[4h,5d,6f–h] Fol-
lowing our first work on a partial structure,[6k] herein we report
the asymmetric formal total synthesis of cortistatins A (1) and J
(2), intercepting advanced intermediates in the Nicolaou–Chen
total synthesis[4c–d] and the Yamashita–Hirama total synthesis.[4g]
This approach featured a highly diastereoselective intramolecu-
lar [4+3] cycloaddition of epoxy enolsilanes with furan, a reac-
tion developed in our group, to construct the key oxygen-
bridged ring B concomitantly with ring C.[7,8]
Abstract: An efficient formal total synthesis of (+) cortista-
tins A and has been accomplished, by exploiting
J
a highly diastereoselective intramolecular [4+3] cycloaddi-
tion of epoxy enolsilanes as the key reaction to construct
rings B and C of the cortistatins in one step.
In 2006 and 2007, Kobayashi and co-workers reported the iso-
lation of a family of novel steroidal alkaloids named the cortis-
tatins: unique, rearranged steroidal alkaloids possessing nitro-
gen heterocyclic substituents in their eastern quadrants, from
the Indonesian marine sponge, Corticium simplex.[1] Studies re-
vealed that cortistatin A (1, Figure 1) showed a powerful and
Our synthesis of key cycloaddition precursor 11 commenced
from the commercially available cyclopentanedione 4, which is
destined to be ring D of cortistatins A and J, and to serve as
the chiral linker to unite the diene and the dienophile for the
key intramolecular [4+3] cycloaddition. A number of reactions
were examined to achieve the desymmetrizing reduction of cy-
clopentanedione 4, including a CBS-reduction,[6k] but asymmet-
ric transfer hydrogenation was ultimately found to be the
most robust transformation for scale-up. Reduction using cata-
lyst (R,R)-Ts-DENEB (5)[9] produced 6a with consistently excel-
lent ee and up to 95% yield of the two diastereomers (Table 1).
Optimization of the reaction conditions by decreasing the reac-
tion temperature eventually afforded 6a in >99% ee and 77%
reduction yield (Table 1, entry 3). In this manner, alcohol 6a
was prepared on a 15 to 42 g scale, with excellent ee and ac-
ceptable diastereoselectivity.
Figure 1. The most bioactive cortistatin congeners.
selective antiangiogenic activity (IC50 =1.8 nm) against human
umbilical vein endothelial cells (HUVECs).[1a] Cortistatin J (2,
Figure 1) exhibited the next most potent antiproliferative activ-
ity against HUVECs at 8 nm.[1c] Recently, Valente and Baran pa-
tented 3 (Figure 1), the didehydro derivative of 1, as an effec-
tive antiviral agent against human immunodeficiency virus
(HIV) in infected cells (1 pm <EC50 <2 nm).[2] All of these bio-
logical activities make these natural products significant leads
for further study.
After having secured the optically pure alcohol 6a, which
was protected as a silyl ether 7 in quantitative yield, enol trifla-
tion afforded 8 on a scale as large as 30 g (Scheme 1). Both
Suzuki–Miyaura and Neigishi coupling reactions of 8 with 9a
or 9b provided low yields of 10. One problem encountered
was the detrimental decomposition of 9a under the reaction
conditions. Finally, a Stille cross-coupling reaction with 9c[10] af-
forded alkenylfuran 10 cleanly in 93% overall yield over two
steps, which was reproducible on a >12 g scale. A cross-meta-
thesis reaction with methyl vinyl ketone, mediated by the Hov-
eyda–Grubbs second-generation catalyst, yielded enone 11,
without concomitant ring-opening of the cyclopentene moiety
(Scheme 1).[11]
[a] L. Kuang,+ L. L. Liu,+ Prof. Dr. P. Chiu
Department of Chemistry and State Key Laboratory of Synthetic Chemistry
The University of Hong Kong
Pokfulam Road, Hong Kong (P. R. China)
E-mail: pchiu@hku.hk
[+] Both authors contributed equally to this work.
Supporting information and ORCID from the author for this article are
available on the WWW under http://dx.doi.org/10.1002/chem.201502890.
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Table 1. Desymmetrizing reduction of 4.[a]
Entry Conditions Yield [%][b] (6a+6b) d.r.[c] (6a/6b) ee [%][d] (6a)
1
2
3
158C, 10 h 93
08C, 24 h 95
À58C, 72 h 94
3.8:1
4.2:1
4.6:1
98
>99
>99
[a] Reactions on a 0.5 mmol scale. [b] Isolated yield of reduction. [c] d.r.
determined by 1H NMR spectroscopy of the crude products. [d] ee deter-
mined by chiral GC analysis.
Using epoxy enolsilanes as oxyallyl cation precursors in the
intermolecular [4+3] cycloaddition with furan was first con-
ceived by Ohno et al., although only a 12% yield for this reac-
tion was reported at the time.[7a] However, because of the mild
conditions to assemble the epoxy enolsilane precursors as well
as to induce cycloaddition, we were interested in further devel-
oping the intramolecular version of this silyl triflate-catalyzed
cycloaddition as a synthetic methodology.
Our studies of this cycloaddition showed that it was both
high-yielding and diastereoselective for the synthesis of carbo-
bicyclic [5.4.0] systems (Scheme 2).[8a] Substituents at various
positions are compatible, and the absolute stereochemistry of
the epoxide determined the facial selectivity of the cycloaddi-
tion. We eventually discovered through computational studies
that the high diastereoselectivity was because the cycloaddi-
tion did not in fact proceed from the putative oxyallyl cation
as an intermediate, but rather, with the activated epoxide itself
as the “dienophile”.[12] Through a backside attack of the epox-
ide by the diene, the stereochemical information of the oxirane
was almost perfectly translated to chirality in the cycloadduct
(Scheme 3). The cycloadducts are amply functionalized, rigid
polycyclic frameworks, which could potentially be further
transformed and used in the synthesis of natural products.[6k]
For the synthesis of the cortistatins, establishing the correct
epoxide stereochemistry was paramount to the success of the
key cycloaddition step. The asymmetric epoxidation of the
enone in the presence of the cyclopentene in 11 was accom-
plished employing Deng’s cinchona-derived catalyst 12, to
generate epoxy ketone 13 as a single diastereomer in 96%
yield.[13] Conversion of ketone 13 to its silyl enol ether yielded
the requisite cycloaddition precursor 14.
Scheme 1. Scalable synthesis of 20: a) TBSCl, imidazole, DMF, 258C, 100%;
b) NaHMDS, À788C, THF, PhNTf2; c) 3 mol% [Pd(PPh3)4], LiCl, 9c, THF, reflux,
93% over 2 steps; d) 5% Hoveyda–Grubbs 2nd-generation catalyst, methyl
vinyl ketone, PhMe, 708C, 83%; e) 10% 12, 20% TFA, PhMe, cumene hydro-
peroxide, 258C, 96%; f) LiHMDS, À788C, THF, then TESCl, 85%; g) 20%
TESOTf, CH2Cl2, À788C, 87%; h) Florisil, PhMe, 808C, 90%; i) CSA, MeOH,
258C, 80%; j) 10% Crabtree’s catalyst, CH2Cl2, H2, 258C, 96%; k) Dess–Martin
periodinane, CH2Cl2, 258C, 84%; l) Me4N(OAc)3BH, MeCN/AcOH, À408C, 96%;
m) TESCl, imidazole, DMAP, DMF, 258C, 97%. CSA=camphorsulfonic acid;
DMAP=4-dimethylaminopyridine; NaHMDS=sodium hexamethyl disilazide;
TBSCl=tert-butyldimethylsilyl chloride; TESOTf=triethylsilyl trifluorometha-
nesulfonate; TFA =trifluoroacetic acid.
In our studies of the scope of the intramolecular [4+3] cy-
cloaddition with epoxy enolsilanes as dienophiles, additional
substituents about the furan, as well as at various positions of
the epoxy enolsilane have been examined. However, epoxy
enolsilane 14 was the most complex [4+3] cycloaddition pre-
cursor assembled to date, presenting the reaction within a con-
text of a stereochemically defined tether that introduced addi-
Scheme 2. Intramolecular [4+3] cycloadditions of epoxy enolsilanes.
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Scheme 3. Mechanism of cycloaddition of 14.
tional diastereoselectivity issues, as well as the nucleophilic re-
activity of a proximate cyclopentene functional group. Gratify-
ingly, the key intramolecular [4+3] cycloaddition catalyzed by
TESOTf proved to be versatile enough and compatible with all
of the pre-existing functionalities, and afforded the desired cy-
cloadduct 15 in 87% yield as a single diastereomer, a reaction
which was carried out on as large as a 10 g scale. In this
manner, we successfully completed the assembly of rings B, C,
and D of the target molecule.
Scheme 5. Formal total synthesis of 1 and 2 intercepting 24 in the Nico-
laou–Chen total synthesis: a) NaBH4, MeOH, À788C, 100%; b) TBSCl, imida-
zole, DMAP, DMF, 258C, 86%; c) Et3N·3HF, THF, 258C, 96%; d) Dess–Martin
periodinane, NaHCO3, CH2Cl2, 258C, 100%; e) TFA, CH2Cl2, reflux, 85%.
Catalytic hydrogenation of cycloadduct 15 led to the forma-
tion of a fully saturated product, but with the undesired cis-
fused junction at the CD rings. To establish the trans-fused ste-
reochemistry at C13ÀC14, the siloxy group at C17 must be de-
protected. Therefore, dehydration of cycloadduct 15, followed
by desilylation with camphorsulphonic acid, provided 16 in
72% yield over two steps (Scheme 1). Catalytic hydrogenation
of triene 16 was not chemoselective, and competitive reduc-
tion at the electron-deficient double bond was also observed.
On the other hand, in the presence of Crabtree’s catalyst, only
the reduction of ring D and the dihydrofuran occurred to
afford diol 17 in 96% yield. Bis-oxidation of 17 with Dess–
Martin periodinane afforded the expected ketoaldehyde, which
spontaneously underwent intramolecular aldol cyclization
during chromatographic purification on silica gel, to afford 18
containing the full tetracyclic framework of the cortistatins in
84% overall yield. The stereoselectivity of the aldol cyclization
could be rationalized as shown in Scheme 4.
With an efficient and scalable route to tetracyclic 20 avail-
able, we proceeded to the synthesis of the Nicolaou–Chen in-
termediate 24 (Scheme 5). Reduction of ketone 20 with
sodium borohydride afforded b-alcohol 21a in quantitative
yield and as a single diastereomer. Quantitative protection
with TBSCl, followed by selective deprotection of the less hin-
dered of the triethylsiloxy groups, yielded alcohol 22 in 96%
yield. Oxidation of 22 with Dess–Martin periodinane under buf-
fered conditions afforded ketone 23, which was subjected to
treatment with trifluoroacetic acid to effect b-elimination to
afford 24 in 16.0% overall yield and in 19 steps by the longest
linear route. This synthetic sample of 24 exhibited identical
spectroscopic data (1H NMR, 13C NMR, IR, MS and optical activi-
ty) compared with those reported. According to the Nicolaou–
Chen synthesis, intermediate 24 can be converted to cortista-
tins A (1) and J (2) by a 12- and 14-step sequence, respective-
ly.[4c,d]
Although the cortistatins could be obtained via 24, evidently
this was a rather early intermediate, as more than 10 steps are
still required to complete the total synthesis of the natural
products. Therefore, we pursued a more efficient approach to
an advanced, isoquinoline-substituted synthetic intermediate,
the Yamashita–Hirama intermediate 31, which would consti-
Scheme 4. Aldol cyclization yielding 18. DMP=Dess–Martin periodinane.
tute
a more rapid access to both cortistatins A and J
(Scheme 6).
Ketone 20 was converted to vinyl triflate 25 in 95% yield by
using NaHMDS and PhNTf2. Suzuki–Miyaura coupling between
30 and pinacolboronate 26 afforded isoquinoline 27 in 85%
yield.
Whereas under the Luche conditions,[14] both the C17 and
C19 carbonyl groups of 18 were reduced, a chemoselective re-
duction was achieved by a hydroxyl-directed triacetoxyborohy-
dride reduction, affording 1,3-diol 19 in excellent yield, and as
a single diastereomer, distinguishing the C17 carbonyl group
for subsequent elaborations.[15] The stereochemistry of 19 was
deduced through computer modelling of both the cis- and
trans-diol diastereomers, which confirmed that the NOE be-
tween H1 and H19 as observed would only be found in cis-19
(see the Supporting Information). Bis-protection of cis-19 with
chlorotriethylsilane provided the key common intermediate 20
in 97% yield.
The conversion of 27 to 28 required a chemoselective reduc-
tion of the cyclopentene over the cyclohexene moiety. Notably,
the corresponding transformation in several previous literature
syntheses was the penultimate step of the total synthesis, that
is, reduction of 3!1 (Figure 1), which suffered either from low
conversion/yield and/or chemoselectivity.[4a,c–e] However, the
desired chemo- and stereoselective reduction was accom-
plished by catalytic hydrogenation of 27 to give 28 as a single
diastereomer in 84% yield, with no over-reduction. The stereo-
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Acknowledgements
We thank the Research Grants
Council of Hong Kong SAR (GRF
Project No. 7011/08P; 7016/12P),
the State Key Laboratory of Syn-
thetic Chemistry, and the Univer-
sity of Hong Kong for funding.
L.K. thanks the University of
Hong Kong for
grant.
a conference
Keywords: alkaloids
·
[4+3]
Scheme 6. Asymmetric formal synthesis of 1 and 2 based on the Yamashita–Hirama total synthesis: a) NaHMDS,
À788C, THF, PhNTf2, 95%; b) 10 mol% [Pd(PPh3)4], K2CO3, 26, THF, reflux, 85%; c) 10% Pd/C, MeOH, H2, 258C, 40 h,
84%; d) Et3N·3HF, THF, 258C, 93%; e) Dess–Martin periodinane, NaHCO3, CH2Cl2, 258C, 85%; f) LDA, THF, N-tert-bu-
tylphenylsulfinimidoyl chloride, À788C, 80%; g) TFA, DCE, 708C, 79%. DCE=1,2-dichloroethane; LDA=lithium dii-
sopropylamide.
cycloaddition cortistatins
·
·
natural products · total synthesis
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enantioselective synthetic route is efficient, and provides both
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work of ring D of the cortistatins on a multigram scale; 2) the
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strates its synthetic utility in the preparation of stereochemical-
ly defined polycyclic compounds, and compatibility with
a range of functional groups. Its further application to the syn-
thetic design of routes to other natural and bioactive com-
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Received: July 23, 2015
Published online on August 27, 2015
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