Communication

pubs.acs.org/JACS

Enantioselective Total Synthesis of (+)-Wortmannin

Yinliang Guo,†,§ Tianfei Quan,‡,§ Yandong Lu,† and Tuoping Luo*,†,‡
†
Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education and Beijing National Laboratory 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
*
S Supporting Information

ABSTRACT: A concise and enantioselective total syn-

thesis 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.

P hosphoinositide 3-kinases (PI3Ks) play essential roles in a

wide range of cellular processes and have consequently
emerged as important 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 Compounds belonging to this structural class of
natural products have a highly reactive [6,6,5]-furanocyclohex-
adienone 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 residue 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 oncology,3,4 wortmannin Figure 1. Representative examples of natural products containing an
electrophilic [6,6,5]-tricyclic furan moiety and our retrosynthetic analysis
has recently found application in regenerative medicine,8 of wortmannin (1).
highlighting the need for further work toward the evaluation of
this molecule and its analogues using the state-of-the-art
technologies. construct the C10 quaternary carbon as part of a de novo synthesis
In contrast to the large number of studies pertaining to the of racemic wortmannin over 35 steps.9b Based on this strategy,
biological significance of wortmannin (1), only two strategies Shibasaki and co-workers further developed a formal synthesis of
have been reported to date for the successful construction of this (+)-wortmannin using asymmetric catalysis.9c It is noteworthy
natural product, both of which were developed by Shibasaki that the research groups of Keay,10 Shibasaki,11 and Trauner have
group.9 One of the most challenging tasks in the synthesis of also used an intramolecular Heck reaction to achieve the
wortmannin (1) involves the construction of the quaternary asymmetric synthesis of several natural products closely related
stereogenic center at C10. Starting from hydrocortisone, the first to wortmannin (2 and 3).12 During the review process of this
reported synthesis circumvented the need to construct the C10
stereogenic center, as well as the B−C−D tricyclic ring system.9a Received: March 13, 2017
The second strategy used an intramolecular Heck reaction to Published: May 5, 2017

© 2017 American Chemical Society 6815 DOI: 10.1021/jacs.7b02515

J. Am. Chem. Soc. 2017, 139, 6815−6818
Journal of the American Chemical Society Communication

Scheme 1. Total Synthesis of (+)-Wortmannin (1)a

a
Reagents 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 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), 4 Å 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%.

manuscript, Guerrero and co-workers reported elegant asym- fully, this strategy would also secure the C1 stereogenic center.
metric syntheses of furanosteroids (−)-viridin and (−)-viridiol, The epoxide in 8 could be reliably introduced by a Sharpless
which featured an intramolecular Heck reaction as well.13 asymmetric epoxidation, leading us back to ketone 9 given the fact
Based on our ongoing interest in chemotypes capable of that 10 is known.18 It was envisaged that ketone 9 could be
reacting with proteinogenic amino acid residues,14 we envisaged prepared by the coupling of enolate 11 with furan 12 or suitable
that the electrophilic [6,6,5]-tricyclic furan moiety found in equivalents.
various natural products could hold great potential for this In the forward direction (Scheme 1), we started from acid 13,
purpose, the chemical synthesis of which started from hibiscone C which was synthesized in three steps from (+)-Hajos−Parrish
(4) by Smith group in 1982.15 We recently reported the first ketone following reported procedures.19 The connection of
enantioselective synthesis of (−)-hibiscone C (4),16 but an Hajos−Parrish ketone and the furan moiety via direct Hajos−
innovative strategy would be needed to access wortmannin (1) in Parrish alkylation20 was deprioritized due to the two-fold
an efficient and modular manner. Careful consideration of the alkylation in the model reaction and the multistep preparation
structural features of wortmannin (1) suggested that intermediate of the halofuran electrophile (see Figure S1 in Supporting
5 could be prepared from the corresponding pentacycle 6 through Information for details). We subsequently designed a cascade
olefin epoxidation and late-stage allylic oxidation. In turn, it was transformation based on the unique properties of π-propargyl-
envisaged 6 could be traced back to furan 7 by opening the lactone palladium to achieve the first connection (Figure S2).21 Under the
ring. We planned to conduct an intramolecular Friedel−Crafts optimized reaction conditions (Table S1), acid 13 reacted with
alkylation between the furan and epoxide moiety in 8 to install the propargyl carbonate 14 to afford the coupling product 15 in 42%
critical C10 stereogenic center in which the SN2 mechanism yield on a multigram scale, while the decarboxylated product 16
framework would allow for specific stereocontrol.17 If success- was isolated in 33% yield and reconverted to acid 13 in one step.19
6816 DOI: 10.1021/jacs.7b02515
J. Am. Chem. Soc. 2017, 139, 6815−6818
Journal of the American Chemical Society Communication

As shown in Table S2, this Pd-catalyzed cascade reaction was Scheme 2. Alternative Approach to (+)-Wortmannin (1) from
discovered to be an efficient method for the preparation of 5a
substituted furans. Following the protection of the primary
alcohol in 15 as the corresponding TBS ether, we performed the
stereoselective 1,4-reduction of the enone moiety to furnish
ketone 9 in 69% yield.22 This reaction also afforded 1,2-reduction
product as a major side product (17% yield), which could be
subjected to PCC oxidation to recycle the enone starting material
17 (see Supporting Information for details). Installation of the
triflate under the kinetic-controlled 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 primary alcohol delivered the
cyclization precursor 8 in 62% overall yield as a single
diastereomer.
A series of condition screening were conducted using substrate
8 to determine the optimal conditions for the cyclization (see a
Reagents and conditions: (a) 3HF·Et3N, THF, 45 °C, 17 h, 95%; (b)
Table S3 in Supporting Information for details). To the best of DMP (2.0 equiv), DCM, 0 °C to rt, 1.5 h, 89%; (c) Et2NH (2.0
our knowledge, there have been very few reports describing the equiv), DCM, rt, 20 min; then DBN (4.0 equiv), DCM, 35 °C, 4 h;
functionalization of furan β-position in the Friedel−Crafts then HCl, THF, 35 °C, 12 h, 54% (brsm: 62%); (d) Ac2O (12 equiv),
alkylation involving an epoxide.23 While various Lewis acids pyridine, rt, 12 h, 84%.
only led to decomposition 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 reconstruction of the furan ring, to give 27 in 54% yield (62%
although the cyclization product 7 was contaminated with based on recovered starting material), which was converted to
unidentified side products even after purification by flash (+)-wortmannin (1) upon acetylation. All of the analytic data for
chromatography. Therefore, the partially purified 7 was the synthesized samples of 1, 24, and 27 were consistent with
subsequently treated with TBAF at room temperature to afford those reported in the literature (Tables S4−S6).2,9,27
diol 20 as a single diastereomer in 47% yield over two steps on a We next subjected wortamnnin and its analogues to character-
gram-scale.24 ization by biochemical assays. In order to determine the selectivity
The stage was then set to investigate the elaboration of 20 to profiles using the KinomeScan approach (DiscoverX),28 the
give wortmannin (1). The selective oxidation of the primary binding constants (Kds) of 1, 24, and 25 against several PI3Ks
alcohol in 20 followed by lactonization of the resulting carboxylic were first determined using the same platform, which also
acid with Mukaiyama’s reagent afforded 6, completing the revealed that (−)-hibiscone C (4) was unable to bind the ATP
pentacyclic skeleton of wortmannin. The epoxidation of 6 was binding site of p110α (Table S7). Consistent with previous
found to be sluggish even in the presence of excess in situ- reports,4b,29 17-β-hydroxy-wortmannin (24) was found to be
generated trifluoroacetyl peroxide,25 but the reaction cleanly more potent than 1, whereas the activities of 25 were at least an
produced the desired product as a single stereoisomer in 69% order of magnitude weaker than those of 1 except for its activities
yield (85% based on recovered starting material), leaving only one against VPS34 and p110β. The profiling of compounds 24 (1 μM)
allylic methylene in 21. The subsequent exposure of 21 to N- and 25 (5 μM) against a panel of 468 kinases showed they only
bromosuccinimide (NBS) in the presence of the radical initiator interacted with class I PI3Ks, VPS34, and PI3K-C2β, while clinical
AIBN resulted in successful formation of the corresponding p110α mutations did not have an adverse impact on the binding of
bromo intermediate, which underwent an immediate Kornblum these inhibitors (Figure S3 and Table S9).30 Compounds 24 and
oxidation to afford 5 in 65% isolated yield.26 It is noteworthy that a 25 were also evaluated using a series of enzymatic assays
similar intermediate bearing a benzoyl protecting group on the (Invitrogen), which confirmed that the introduction of an
C17 hydroxyl group instead of a TBS ether was reported in the epoxide moiety to the C-ring led to a pronounced drop (>280-
semisynthesis of wortmannin.9a With this in mind, we applied the fold) in the inhibitory activity, although this effect was less
same sequence of operations as those developed by Shibasaki and prominent for PI3Kβ (p110β/p85α) and VPS34 (Table S8).
co-workers to obtain 23 (via 22), albeit in low yield (25%, 40% Given that several other changes to the C-ring substitution
based on recovered starting material).9a Nonetheless, subsequent patterns in wortmannin were reasonably tolerated,4b,29 further
acetylation and TBS deprotection of 23 delivered the previously investigation is needed to provide a rationale of our observation
reported 17-β-hydroxy-wortmannin (24),4b,c which was oxidized that the inclusion of an epoxide moiety resulted in significant
with DMP to give (+)-wortmannin (1) in 85% yield. The low decrease of activity.
yield of 23 was attributed in part to the lability of TBS protecting In summary, starting from the known acid 13 and triol 14, we
group under the acidic reaction conditions (see Supporting have achieved the total synthesis of (+)-wortmannin (1) in 18
Information for details), which prompted us to develop an steps (21 steps from Hajos−Parrish ketone) (Scheme S1).31 The
alternative and high yielding approach to 1 (Scheme 2). To this key features of our synthesis include the systematic optimization
end, the removal of TBS protecting group in 5 afforded 25 in of a Pd-catalyzed cascade reaction and an intramolecular Friedel−
excellent yield, which was oxidized to give ketone 26. The Crafts alkylation, as well as the application of a late-stage allylic
structure of 26 was unambiguously confirmed by X-ray oxidation. Most notably, our approach allows for the synthesis of
diffraction. Compound 26 was subjected to the same one-pot new wortmannin analogues to expand research territory of such
procedure involving the opening of the electrophilic furan ring an important irreversible kinase inhibitor, which is currently
with diethylamine, eliminative opening of the epoxide, and underway in our group and will be reported in due course.
6817 DOI: 10.1021/jacs.7b02515
J. Am. Chem. Soc. 2017, 139, 6815−6818
Journal of the American Chemical Society Communication

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*
ASSOCIATED CONTENT
S Supporting Information
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KinomeScan profile of 24 and 25 (XLSX) (10) Maddaford, S. P.; Andersen, N. G.; Cristofoli, W. A.; Keay, B. A. J.
Crystallographic data for 26 (CIF) Am. Chem. Soc. 1996, 118, 10766.

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(11) Miyazaki, F.; Uotsu, K.; Shibasaki, M. Tetrahedron 1998, 54, 13073.
AUTHOR INFORMATION (12) Kienzler, M. A.; Suseno, S.; Trauner, D. J. Am. Chem. Soc. 2008,
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Corresponding Author (13) Del Bel, M.; Abela, A. R.; Ng, J. D.; Guerrero, C. A. J. Am. Chem. Soc.
*[email protected] 2017, DOI: 10.1021/jacs.7b02829.
ORCID (14) Zhao, S.; Dai, J.; Hu, M.; Liu, C.; Meng, R.; Liu, X.; Wang, C.; Luo,
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Tuoping Luo: 0000-0003-2156-3198 (15) Koft, E. R.; Smith, A. B. J. Am. Chem. Soc. 1982, 104, 5568.
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The authors declare no competing financial interest.

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the X-ray crystallography data. (24) The major side product in this key transformation was determined

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to be diene 19, resulting from the ring opening of epoxide (see Table S3
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6818 DOI: 10.1021/jacs.7b02515

J. Am. Chem. Soc. 2017, 139, 6815−6818