Enantioselective Total Synthesis of (+)-Wortmannin

Article abstract of DOI:10.1021/jacs.7b02515

A concise and enantioselective total synthesis of the potent PI3K inhibitor (+)-wortmannin is described. A Pd-catalyzed cascade reaction was first developed to connect a synthon derived from Hajos-Parrish ketone to a furan moiety. The subsequent Friedel-Crafts alkylation of the β-position of a furan ring to an epoxide was optimized to establish the C10 quaternary center. (+)-Wortmannin was eventually accomplished by transformations following a late-stage oxidation of the furan allylic position. Kinome profiling and in vitro enzymatic assays were performed on 17-β-hydroxy-wortmannin and an epoxide analogue.

Full text of DOI:10.1021/jacs.7b02515

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Communication
Enantioselective Total Synthesis of (+)-Wortmannin
Yinliang Guo, Tianfei Quan, Yandong Lu, and Tuoping Luo
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Enantioselective Total Synthesis of (+)-Wortmannin
Yinliang Guo,†,§ Tianfei Quan,‡,§ Yandong Lu,† Tuoping Luo*,†,‡
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†Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education and Beijing National Labora-
tory for Molecular Science, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China,
‡Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing
100871, China
Supporting Information Placeholder
catalysis.9c It is noteworthy that the research groups of Keay,10 Shi-
ABSTRACT: A concise and enantioselective total synthesis of
the potent PI3K inhibitor (+)-wortmannin is described. A Pd-cata-
basaki,11 and Trauner have also used an intramolecular Heck reac-
tion to achieve the asymmetric synthesis of several natural products
closely-related to wortmannin (2 and 3).12 During the review pro-
cess of this manuscript, Guerrero and co-workers reported elegant
asymmetric syntheses of furanosteroids (−)-viridin and (−)-viridiol,
which featured an intramolecular Heck reaction as well.13
lyzed cascade reaction was first developed to connect a synthon de-
rived from Hajos-Parrish ketone to a furan moiety. The subsequent
Friedel-Crafts alkylation of the β–position of a furan ring to an
epoxide was optimized to establish the C10 quaternary center. (+)-
Wortmannin was eventually accomplished by transformations fol-
lowing a late-stage oxidation of the furan allylic position. Kinome
profiling and in vitro enzymatic assays were performed on 17-β-
hydroxy-wortmannin and an epoxide analog.
Phosphoinositide 3-kinases (PI3Ks) play essential roles in a wide
range of cellular processes and have consequently emerged as im-
portant targets for drug discovery.1 It is noteworthy, however, that
one of the most potent PI3K inhibitors reported to date is the
furanosteroid—natural product wortmannin (1, Figure 1).2 Com-
pounds belonging to this structural class of natural products have a
highly reactive [6,6,5]-furanocyclohexadienone lactone moiety
with a calculated strain energy of 12.1 kcal/mol.3 Wortmannin can
therefore inhibit the activity of PI3Ks via a unique mechanism-of-
action involving the formation of a covalent bond to a lysine resi-
due in the ATP-binding loop, as well as a hydrogen bond to the
hinge domain (the C-17 carbonyl group).4 Given that this reactive
lysine residue is conserved across all of the active kinases in the
kinome,5 1 also inhibits several other kinases including PLK1 and
DNA-PK.6 However, wortmannin (1) has been shown to exhibit a
reasonable degree of selectivity for specific kinases and has been
widely used as a chemical probe to investigate biological processes
associated with PI3Ks.7 In addition to its potential in the area of
onolcogy,3,4 wortmannin has recently found application in regener-
ative medicine,8 highlighting the need for further work towards the
evaluation of this molecule and its analogs using the state-of-the-
art technologies.
In contrast to the large number of studies pertaining to the bio-
logical significance of wortmannin (1), only two strategies have
been reported to date for the successful construction of this natural
product, both of which were developed by Shibasaki group.9 One
of the most challenging tasks in the synthesis of wortmannin (1)
involves the construction of the quaternary stereogenic center at
C10. Starting from hydrocortisone, the first reported synthesis cir-
cumvented the need to construct the C10 stereogenic center, as well
as the B-C-D tricyclic ring system.9a The second strategy used an
intramolecular Heck reaction to construct the C10 quaternary car-
bon as part of a de novo synthesis of racemic wortmannin over 35
steps.9b Based on this strategy, Shibasaki and co-workers further
developed a formal synthesis of (+)-wortmannin using asymmetric
Figure 1. Representative examples of natural products containing
an electrophilic [6,6,5]-tricyclic furan moiety and our retrosyn-
thetic analysis of wortmannin (1).
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Scheme 1. Total Synthesis of (+)-Wortmannin (1) a
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aReagents and conditions: (a) 14 (1.05 equiv), Pd2(dba)3 (0.02 equiv), dppf (0.08 equiv), DIPEA (2.4 equiv), PhCl, 130 °C, 1.5 h; 15, 42%;
16, 33%; (b) TBSCl (1.1 equiv), imidazole (1.3 equiv), DMF, 1.5 h, 0 °C to RT, 85%; (c) NiCl2·6H2O (5.0 equiv), NaBH4 (15.0 equiv),
MeOH, −90 °C to −60 °C , 69%; (d) LHMDS (2.0 equiv), PhNTf2 (1.8 equiv), THF, −78 °C to 0 °C , 98%; (e) 10 (1.3 equiv), Pd2(dba)3 (0.04
equiv), AsPh3 (0.24 equiv), NMP, 70 °C , 6 h, 69%; (f) TBHP (2.0 equiv), (−)-DIPT (0.5 equiv), Ti(OiPr)4 (0.4 equiv), 4Å MS, DCM, −40 °C ,
5 h, 68% ; (g) NaH (2.5 equiv), MeI (2.0 equiv), DMF, −10 °C to rt, 91%; (h) Ph4PBF4 (3 equiv), DCM:HFIP (4:1), −15 °C, 65 h; (i)
TBAF·3H2O, rt, 1 h; 20, 47% (2 steps); (j) TEMPO (0.3 equiv), PhI(OAc)2 (1.5 equiv), DCM, rt, 20 h, 93%; (k) NaClO2 (5.0 equiv),
NaH2PO4·2H2O (5.0 equiv), 2-methyl-2-butene (30.0 equiv), tBuOH:THF:H2O (3:2:1), rt, 1.5 h; (l) CMPI (6.0 equiv), Et3N (8.0 equiv),
DCM, rt, 12 h, 75% (2 steps); (m) Urea hydrogen peroxide (4.0 equiv), TFAA (1.5 equiv), Na2CO3 (6.0 equiv), DCM, 0 °C, 1.5 h, 69%
(brsm: 85%); (n) NBS (1.5 equiv), AIBN (0.3 equiv), CCl4, reflux, 1.5 h; then AgBF4 (1.2 equiv), Et3N (2.0 equiv), DMSO, rt, 65%; (o)
Et2NH (2.0 equiv), DCM, rt, 20 min; then DBN (4.0 equiv), DCM, 35°C, 6 h; then HCl, THF, 35°C, 15 h, 25% (brsm: 40%); (p) Ac2O (15
equiv), pyridine, rt, 12 h; then 3HF·Et3N, THF, 45 °C, 76%; (q) DMP (1.5 equiv), DCM, 0 °C to rt, 2.5 h, 85%.
Based on our ongoing interest in chemotypes capable of reacting
with proteinogenic amino acid residues,14 we envisaged that the
electrophilic [6,6,5]-tricyclic furan moiety found in various natural
products could hold great potential for this purpose, the chemical
synthesis of which started from hibiscone C (4) by Smith group in
1982.15 We recently reported the first enantioselective synthesis of
(−)-hibiscone C (4),16 but an innovative strategy would be needed
to access wortmannin (1) in an efficient and modular manner. Care-
ful consideration of the structural features of wortmannin (1) sug-
gested that intermediate 5 could be prepared from the correspond-
ing pentacycle 6 through olefin epoxidation and late-stage allylic
oxidation. In turn, it was envisaged 6 could be traced back to furan
7 by opening the lactone ring. We planned to conduct an intramo-
lecular Friedel-Crafts alkylation between the furan and epoxide
moiety in 8 to install the critical C10 stereogenic center, in which
the SN2 mechanism framework would allow for specific stereocon-
trol.17 If successfully, this strategy would also secure the C1 stere-
ogenic center. The epoxide in 8 could be reliably introduced by a
Sharpless asymmetric epoxidation, leading us back to ketone 9
given the fact that 10 is known.18 It was envisaged that ketone 9
could be prepared by the coupling of enolate 11 with furan 12 or
suitable equivalents.
In the forward direction (Scheme 1), we started from acid 13,
which was synthesized in 3 steps from (+)-Hajos−Parrish ketone
following reported procedures.19 The connection of Hajos-Parrish
ketone and the furan moiety via direct Hajos-Parrish alkylation20
was deprioritized due to the twofold alkylation in the model reac-
tion and the multistep preparation of the halofuran electrophile (see
Figure S1 in Supporting Information for details). We subsequently
designed a cascade transformation based on the unique properties
of π-propargylpalladium to achieve the first connection (Figure
S2).21 Under the optimized reaction conditions (Table S1), acid 13
reacted with propargyl carbonate 14 to afford the coupling product
15 in 42% yield on a multi-gram scale, while the decarboxylated
product 16 was isolated in 33% yield and reconverted to acid 13 in
one step.19 As shown in Table S2, this Pd-catalyzed cascade reac-
tion was discovered to be an efficient method for the preparation of
substituted furans. Following the protection of the primary alcohol
in 15 as the corresponding TBS ether, we performed the stereose-
lective 1,4-reduction of the enone moiety to furnish ketone 9 in 69%
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yield.22 This reaction also afforded 1,2-reduction product as a major
wortmannin (24) was found to be more potent than 1, whereas the
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side product (17% yield), which could be subjected to PCC oxida-
tion to recycle the enone starting material 17 (see Supporting Infor-
mation for details). Installation of the triflate under the kinetic-con-
trolled enolization conditions, followed by a Stille coupling with
10 provided allylic alcohol 18 in 68% yield over two steps. The
Sharpless epoxidation of 18, followed by methylation of the pri-
mary alcohol delivered the cyclization precursor 8 in 62% overall
yield as a single diastereomer.
activities of 25 were at least an order of magnitude weaker than
those of 1 except for its activities against VPS34 and p110β. The
profiling of compounds 24 (1 μM) and 25 (5 μM) against a panel
of 468 kinases showed they only interacted with class I PI3Ks,
VPS34 and PI3K-C2β, while clinical p110α mutations did not have
an adverse impact on the binding of these inhibitors (Figure S3 and
Table S9).30 Compounds 24 and 25 were also evaluated using a se-
ries of enzymatic assays (Invitrogen), which confirmed that the in-
troduction of an epoxide moiety to the C-ring led to a pronounced
drop (>280 fold) in the inhibitory activity, although this effect was
less prominent for PI3Kβ (p110β/p85α) and VPS34 (Table S8).
Given that several other changes to the C-ring substitution patterns
in wortmannin were reasonably tolerated,4b,29 further investigation
is needed to provide a rationale of our observation that the inclusion
of an epoxide moiety resulted in significant decrease of activity.
A series of condition screening were conducted using substrate
8 to determine the optimal conditions for the cyclization (see Table
S3 in Supporting Information for details). To the best of our
knowledge, there have been very few reports describing the func-
tionalization of furan β–position in the Friedel-Crafts alkylation in-
volving an epoxide.23 While various Lewis acids only led to de-
composition of the starting material 8, we were delighted to find
1,1,1,3,3,3-hexofluoroisopropol (HFIP) and Ph4PBF4 additive
greatly facilitated the desired transformation,17 although the cy-
clization product 7 was contaminated with unidentified side prod-
ucts even after purification by flash chromatography. Therefore,
the partially purified 7 was subsequently treated with TBAF at
room temperature to afford diol 20 as a single diastereomer in 47%
yield over two steps on a gram scale.24
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Scheme 2. The Alternative Approach to (+)-Wortmannin (1)
from 5 a
The stage was then set to investigate the elaboration of 20 to give
wortmannin (1). The selective oxidation of the primary alcohol in
20 followed by lactonization of the resulting carboxylic acid with
Mukaiyama’s reagent afforded 6, completing the pentacyclic skel-
eton of wortmannin. The epoxidation of 6 was found to be sluggish
even in the presence of excess in situ-generated trifluoroacetyl per-
oxide,25 but the reaction cleanly produced the desired product as a
single stereoisomer in 69% yield (85% based on recovered starting
material), leaving only one allylic methylene in 21. The subsequent
exposure of 21 to N-bromosuccinimide (NBS) in the presence of
the radical initiator AIBN resulted in successful formation of the
corresponding bromo intermediate, which underwent an immediate
Kornblum oxidation to afford 5 in 65% isolated yield.26 It is note-
worthy that a similar intermediate bearing a benzoyl protecting
group on the C17 hydroxyl group instead of a TBS ether was re-
ported in the semisynthesis of wortmannin.9a With this in mind, we
applied the same sequence of operations as those developed by Shi-
basaki and co-workers to obtain 23 (via 22), albeit in low yield
(25%, 40% based on recovered starting material).9a Nonetheless,
subsequent acetylation and TBS deprotection of 23 delivered the
previously reported 17-β-hydroxy-wortmannin (24),4b,4c which was
oxidized with DMP to give (+)-wortmannin (1) in 85% yield. The
low yield of 23 was attributed in part to the lability of TBS protect-
ing group under the acidic reaction conditions (see Supporting In-
formation for details), which prompted us to develop an alternative
and high yielding approach to 1 (Scheme 2). To this end, the re-
moval of TBS protecting group in 5 afforded 25 in excellent yield,
which was oxidized to give ketone 26. The structure of 26 was un-
ambiguously confirmed by X-ray diffraction. Compound 26 was
subjected to the same one-pot procedure involving the opening of
the electrophilic furan ring with diethylamine, eliminative opening
of the epoxide, and re-construction of the furan ring, to give 27 in
54% yield (62% based on recovered starting material), which was
converted to (+)-wortmannin (1) upon acetylation. All of the ana-
lytic data for the synthesized samples of 1, 24 and 27 were con-
sistent with those reported in the literature (Tables S4-6).2,8,27
aReagents and conditions: (a) 3HF·Et3N, THF, 45 °C, 17 h, 95%;
(b) DMP (2.0 equiv), DCM, 0 °C to rt, 1.5 h, 89%; (c) Et2NH (2.0
equiv), DCM, rt, 20 min; then DBN (4.0 equiv), DCM, 35°C, 4 h;
then HCl, THF, 35°C, 12 h, 54% (brsm: 62%); (d) Ac2O (12 equiv),
pyridine, rt, 12 h, 84%.
In summary, starting from the known acid 13 and triol 14, we
have achieved the total synthesis of (+)-wortmannin (1) in 18 steps
(21 steps from Hajos-Parrish ketone) (Scheme S1).31 The key fea-
tures of our synthesis include the systematic optimization of a Pd-
catalyzed cascade reaction and an intramolecular Friedel-Crafts al-
kylation, as well as the application of a late-stage allylic oxidation.
Most notably, our approach allows for the synthesis of new wort-
mannin analogs to expand research territory of such an important
irreversible kinase inhibitor, which is currently underway in our
group and will be reported in due course.
ASSOCIATED CONTENT
Supporting Information
Detailed experimental procedures, compound characterization data,
data of in vitro kinase assays, the CIF for 26 and complete ref 28.
This material is available free of charge via the Internet at
http://pubs.acs.org.
We next subjected wortamnnin and its analogs to characteriza-
tion by biochemical assays. In order to determine the selectivity
profiles using the KinomeScan approach (DiscoverX),28 the bind-
ing constants (Kds) of 1, 24 and 25 against several PI3Ks were first
determined using the same platform, which also revealed that (−)-
hibiscone C (4) was unable to bind the ATP binding site of p110α
(Table S7). Consistent with previous reports,4b,29 17-β-hydroxy-
AUTHOR INFORMATION
Corresponding Author
tuopingluo@pku.edu.cn
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Author Contributions
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4
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8
§ These authors contributed equally.
ACKNOWLEDGMENT
This work was supported by generous start-up funds from the Na-
tional “Young 1000 Talents Plan” Program, College of Chemistry
and Molecular Engineering, Peking University and Peking-Tsing-
hua Center for Life Sciences, and the National Science Foundation
of China (Grant Nos. 21472003, 31521004 and 21672011). We
thank Dr. Nengdong Wang and Prof. Wenxiong Zhang (Peking
University) for their help in analyzing the X-ray crystallography
data.
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