Total synthesis of (-)-deguelin via an iterative pyran-ring formation strategy

Article abstract of DOI:10.1039/c5cc02215k

Enantioselective synthesis of (-)-deguelin was accomplished via an iterative pyran-ring formation approach. The key features involve the anionic addition of a chromene unit to aryloxy alkyl aldehyde for the double cyclization precursor and iterative pyran ring formation by Pd-catalyzed O-arylation and C-arylation, respectively. This journal is

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DOI: 10.1039/C5CC02215K
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Total Synthesis of (-)-Deguelin via an Iterative Pyran-
Ring Formation Strategy
Cite this: DOI: 10.1039/x0xx00000x
a
a
b
a
a
Seungbeom Lee, Hongchan An, Dong-Jo Chang, Jaebong Jang, Kyeojin Kim,
a
a
a
Jaehoon Sim, Jeeyeon Lee and Young-Ger Suh*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Enantioselective synthesis of (-)-deguelin was accomplished enantioselective total synthesis of (-)-deguelin and its enantiomer by
employing a catalytic process. We have also made efforts to
establish a concise and versatile synthetic strategy for (-)-deguelin.
Herein, we describe the asymmetric total synthesis of (-)-deguelin
based on iterative intramolecular Pd-catalyzed arylation of β-
via an iterative pyran-ring formation approach. The key
features involve anionic addition of a chromene unit to
aryloxyalkyl aldehyde for the double cyclization precursor
and iterative pyran ring formations by Pd-catalyzed
arylation and -arylation, respectively.
O-
hydroxy ketone.
C
Deguelin (1) is a natural rotenoid isolated from several botanical
1
sources and has been considered as one of the most active natural
2
pesticides and insecticides. Deguelin has attracted much attention
from biologists and chemists due to its promising anticancer and
chemopreventive properties. It inhibits induction of ornithine
3, 4
decarboxylase, an enzyme associated with tumour progression.
Fluorescently-labelled deguelin conjugates show strong cellular co-
localization with mitochondria, the site of the electron-transport
5
chain in human cells. Recently, we reported that deguelin interfered
with ATP binding to Heat Shock Protein 90 (HSP90), a protein
associated with the stabilization and translocation of hypoxia
6
-9
inducible factor-1α (HIF-1α). In addition, we identified a key
skeleton (2) responsible for HSP90 inhibition and developed a
number of pharmacologically and toxicologically improved deguelin
1
0, 11
analogues.
More recently, we have disclosed the significant
suppressing effects of these compounds in hypoxia-mediated retinal
11
neovascularization and vascular leakage in the diabetic retina.
Scheme 1 Synthetic approach to (-)-deguelin
Our initial synthetic approach to (-)-deguelin (1) is illustrated in
Scheme 1. We envisioned that double Pd-catalyzed arylation of β-
hydroxy ketone 5 would yield the desired cis-fused bisbenzopyran
system of 1 by transferring a chirality of the β-hydroxy moiety to the
α-position of ketone. The final diastereoselective pyran ring
formation was anticipated based on Pd-catalyzed α-arylation of
ketone 4. The first pyran ring formation would be possible via Pd-
catalyzed O-arylation of β-hydroxy ketone 5, which can be prepared
from aldehyde 7 via a convergent procedure. Anionic addition of
chromene 6 to aldehyde 7, which is derived by a carbonylative
epoxide opening of 8, provides 5. Chromene 6, which was discussed
Figure 1 Structures of (-)-deguelin (1), SH1280 (2) and rotenone (3)
Syntheses and synthetic studies of deguelin have been reported by
1
2-18
several research groups.
Although racemic or formal syntheses
of deguelin from rotenone (3) have been reported, the first
asymmetric synthesis of (-)-deguelin was achieved in 2010 by
Winssinger and coworkers. Recently, the Scheidt group reported the
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1
0
in a previous report by us, is conveniently prepared via a sequence via O-arylation with aryl bromide. Cyclization under other reaction
of chemoselective propargylation of 6-nitro-resorcinol and conditions resulted in the decomposition of the starting material or
regioselective Claisen rearrangement of the resulting alkyl aryl ether. the production of side products with a trace amount of 4.
The synthesis was initiated by preparation of the double
cyclization precursor 5 as depicted in Scheme 2. Treatment of 3,4- Table 1 Pd-catalyzed intramolecular O-arylation
dimethoxyphenol
produced epoxide 8 in 98% yield.
with CO in the presence of Co (CO) and MOM protection of the
9
with (S)-glycidyl 3-nitrobenzenesulfonate
19, 20
OMe
Carbonylative ring opening of
MeO
O
O
8
2
8
21
Br
resulting β-hydroxy ester afforded 10 as a single product.
O
OMe
O
Regioselective bromination of ester 10 with NBS at -78 °C followed
by ester reduction with DIBAL produced aldehyde 7. Addition of
aryl anion, prepared from 6 by n-BuLi treatment at -78 °C, to
aldehyde 7 and Dess-Martin oxidation of the resulting alcohol
afforded ketone 11 in 68% yield via 2 steps. Finally, selective MOM
deprotection and demethylation of the benzopyran moiety were
MeO
O
Pd(OAc)2
toluene
4
Br
OMe
MeO
O
TfO
OH
O
O
O
5
O
TfO
O
achieved by BCl treatment of 11 at -78 °C to afford diol 12. To
3
1
3
prepare the double cyclization precursor 5, phenol selective triflation
of 12 was examined under a variety of reaction conditions.
Treatment of 12 with PhNTf in DMF in the presence of potassium
carbonate provided the best result in terms of chemoselectivity and
2
a
Temperature
°C)
Product
(%)
Entry
Ligand
Base
(
conversion yield to afford the desired mono-triflation product 5 in
1
2
3
DPPF
SPhos
JohnPhos
K
3
PO
2
4
reflux
70
70
13 (46)
4 (60)
4 (<10)
6
1 % yield. The minor product was observed to be an ent-4, which
Cs CO3
Cs
was produced via initial triflation of the secondary alcohol of 12,
followed by intramolecular O-alkylation.
2
CO
3
a
DPPF: 1,1′-Bis(diphenylphosphino)ferrocene, JohnPhos: 2-(Di-tert-
butylphosphino)biphenyl, SPhos: 2-Dicyclohexylphosphino-2′,6′-
dimethoxybiphenyl
To complete the synthesis, attempts to achieve the direct α-
arylation of aryl ketone 4 were not successful under various reaction
conditions, including conditions in which Pd(OAc) , Pd (dba) or
2
2
3
PdCl was used as a catalyst and DPPF, BINAP, DtBPF, P(t-Bu) , or
2
3
N-heterocyclic carbene was used as a ligand. In particular, the basic
reaction conditions appeared to consistently induce facile
elimination to yield an α,β-unsaturated carbonyl moiety. Indeed, 4-
chromanone has been reported to undergo ring opening to yield
22, 23
phenolate anions under basic conditions.
Thus, we turned our
attention to an Pd-catalyzed α-arylation of silyl enol ether possessing
an aryl bromide moiety, as shown in Scheme 3, because the base-
induced elimination would not occur in the absence of a carbonyl
24, 25
moiety.
Subsequently, stable TES-enol ether 14 was prepared by
reaction of 4 with TES-triflate in the presence of Et N. Enol ether 14
3
was treated with Pd(OAc) , P(t-Bu) , Bu SnF, and CsF in toluene at
2
3
3
7
0 °C and produced the desired (-)-deguelin (1) as an enantiomeric
26
mixture (84 : 16) in 27% yield, although this result was not
satisfactory.
OMe
OMe
MeO
MeO
O
O
OTES
a
Br
Br
O
O
O
O
O
4
14
OMe
Scheme 2 (a) (S)-(+)-glycidyl-3-nitrobenzenesulfonate, Cs
b) Co (CO) , CO, MeOH, 78%; (c) MOMCl, i-Pr NEt, CH
NBS, THF, -78 °C, 100%; (e) DIBAL-H, THF, -78 °C, 90%; (f) 6, n-BuLi,
THF, -78 °C, 80%; (g) Dess-Martin periodinane, NaHCO , CH Cl , 85%; (h)
BCl , CH Cl , -78 °C, 67%; (i) PhNTf , K CO , DMF, 61%
2
CO
2
3
, DMF, 98%;
Cl , 96%; (d)
2
MeO
O
H
H
(
2
8
2
b
3
2
2
O
O
O
3
2
2
2
2
3
1
Given two pathways for the first Pd-catalyzed O-arylation as
shown in Table 1, we explored intramolecular Pd-catalyzed O-
arylation under various conditions. Treatment of 5 with Pd(OAc)2 Scheme 3 (a) TESOTf, Et
3 2 2 2 3 3
N, CH Cl , 95%; (b) Pd(OAc) , P(t-Bu) , Bu SnF,
and Cs CO in the presence of Sphos or JohnPhos as a ligand in CsF, toluene, 70 °C, 27% (e.r. = 84 : 16)
2
3
toluene at 70 °C produced the desired pyranone 4 as the only product.
However, reaction of 5 with Pd(OAc) and K PO in the presence of
After further attempts to successfully cyclize 4, we decided to
DPPF under reflux provided the cyclization product 13 instead of 4 replace aryl bromide 4 with aryl iodide 15, which was anticipated to
2
3
4
2
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5CC022 K
undergo more facile oxidative addition with the Pd-catalyst. We
ultimately expected that the more reactive oxidative addition would
result in a higher conversion yield and lower racemization during the
C-arylation. As shown in Scheme 4, late-stage iodide substitution
was performed because we were concerned that the labile aryl iodide
moiety would not be tolerable during the O-arylation and preparation
of the second arylation precursor 16.
Scheme 5 (a) DIBAL-H, THF, -78 °C; (b) 6, n-BuLi, THF, -78 °C; (c)
TPAP, NMO, 4 Å MS, CH Cl , 84% for 3 steps; (d) BCl , CH Cl , -78 °C
, DMF, 72% (f) Sphos, Pd(OAc) , Cs CO , toluene,
°C, 100%; (g) NIS, TFA, MeCN, rt, 64%; (h) TESOTf, Et N, CH Cl , rt,
00%
2
2
3
2
2
,
6
7
1
4%; (e) PhNTf
0
2
, K
2
CO
3
2
2
3
3
2
2
With the desired silyl enol ether 20, we investigated Pd-catalyzed
C-arylation to obtain the enantiomerically enriched (-)-deguelin (1).
Generally, AsPh was superior to other ligands, including P(t-Bu) in
terms of conversion yield and stereoselectivity. Presumably AsPh3
3
3
Scheme 4 Revised synthetic approach to (-)-deguelin
stabilizes the Pd-substrate-stannane complex ultimately leading to
As outlined in Scheme 5, the revised synthesis commenced with
the preparation of the advance intermediate 16, which would later be
iodinated after the first arylation to afford the second Pd-catalyzed
arylation precursor 15. DIBAL reduction of ester 10 and coupling of
the resulting aldehyde with the chromene unit 6 followed by Ley
oxidation afforded ketone 18. Global deprotection of 18 and
chemoselective triflation of the resulting diol produced mono-triflate
30, 31
increase of the yield and stereoselectivity.
As shown in Table 2,
CsF (1.4 equiv.) was essential as a fluoride source to produce the
cyclization product. Interestingly, reaction in a solvent containing
toluene and THF (10 : 1) while gradually raising the temperature
resulted in effective arylation although partial racemization was
observed in the polar solvent, presumably via initial elimination of
18
the phenoxy group. Noticeably, the use of benzene considerably
1
6 as a first arylation precursor. Chemoselective triflation was again
enhanced both the enantioselectivity and conversion yield. In this
particular case, the reaction was completed with minimal
racemization. Consequently, the final cyclization was completed in
extensively examined under a variety of reaction conditions. Finally,
PhNTf2 treatment of diol in DMF in the presence of potassium
carbonate provided the desired mono-triflate 16 in 72% yield, which
was higher than the yield obtained for 5.
7
2% conversion yield with an 80 : 20 enantiomeric ratio. A decrease
in reaction time for C-arylation increased the enantiomeric ratio up
to 90 : 10 although the conversion yield was reduced to 30%. Clearly,
the significantly improved result was likely due to the facile
arylation of the iodinated precursor as well as the optimized reaction
conditions, including the solvent and ligand type.
In summary, the complete synthesis of (-)-deguelin was achieved
through 12 steps with 10.5% overall yield. The key features of our
synthesis include the efficient preparation of the double cyclization
precursor via highly convergent assembly of two aromatic systems
and facile construction of the cis-fused bisbenzopyran skeleton via
Pd-catalyzed O and C-arylation. In addition, the key architecture of
the intermediate involves carbonylative epoxide ring opening
catalyzed by cobalt. Our iterative intramolecular arylation strategy
appears to widely applicable in rotenoid synthesis.
The Pd-catalyzed O-arylation of 16 toward tetrahydropyanone 19
was greatly improved, as shown in Scheme 5, under the reaction
conditions described for aryl bromide 4. At this stage, preparation of
intermediate 19 by a different strategy and its direct cyclization to (-
18
)-deguelin was independently reported by Scheidt’s group,
although the conversion yield was still not satisfactory. Thus, we
executed our own strategy to complete the synthesis of deguelin in
expecting improved results in terms of enantioselectivity and
conversion yield. We attempted the regioselective iodination of 19
without affecting another aromatic system, which was coupled
before iodination relative to the halogenation substrate 10 shown in
Scheme 2. We optimized the iodination conditions to obtain the
2
7-29
desired iodination product 15 in a moderate yield.
The ketone 15
was quantitatively converted to silyl enol ether 20, which could be
purified by chromatography.
This work was supported by the National Research Foundation of
Korea (NRF) grant for the Global Core Research Center (GCRC)
funded by the Korea government (MSIP) (No. 2011-0030001) and
by the National Research Foundation of Korea grant funded by the
Korean government (2009-0083533).
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Table 2 Pd-catalyzed intramolecular C-arylation
Entry Ligand
Bu
3
SnF (equiv.)
CsF (equiv.)
Solvent
Reaction time (h)
a
Temperature (℃ )
Results
<10% of 1
Degradation
1 (20~40%)
Degradation
No reaction
15
er
1
2
3
4
5
6
7
8
9
P(t-Bu)
3
1.4
3
1.4
3
1.4
1.4
1.4
3
1.4
3
0
1.4
toluene
O/N
70
AsPh
3
68 : 32
4
O/N
THF, DMF, MeCN or Et
2
O
60
Toluene : THF (10 : 1)
m-xylene
benzene
1 (60%)
1 (23%)
45 : 55
65 : 35
90 : 10
80 : 20
1
1 (30%)
1 (72%)
19
1
0
benzene
3.5
O/N
1
1
DCE
a
O/N: over night
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Y.-G. Suh and J. H. Kim, J. Mol. Med., 2014, 1-10.
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