Exploratory studies toward a synthesis of flavaglines. A novel access to a highly substituted cyclopentenone intermediate

Article abstract of DOI:10.1016/j.tetlet.2014.12.093

The gold(I)-catalyzed intramolecular siloxycyclization developed by Rhee and collaborators was shown to operate also on alkyl ethers to generate a highly substituted 2-cyclopentenone 8, extending the application of this reaction. Conversion of 8 to known anticancer natural products following a reported strategy was examined.

Full text of DOI:10.1016/j.tetlet.2014.12.093

Tetrahedron Letters 56 (2015) 727–730
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Exploratory studies toward a synthesis of flavaglines. A novel access
to a highly substituted cyclopentenone intermediate
⇑
Christine Basmadjian, Qian Zhao, Laurent Désaubry
Laboratory of Therapeutic Innovation (UMR 7200), University of Strasbourg-CNRS, Faculty of Pharmacy, 67401 Illkirch, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The gold(I)-catalyzed intramolecular siloxycyclization developed by Rhee and collaborators was shown
to operate also on alkyl ethers to generate a highly substituted 2-cyclopentenone 8, extending the appli-
cation of this reaction. Conversion of 8 to known anticancer natural products following a reported strat-
egy was examined.
Received 13 September 2014
Revised 14 December 2014
Accepted 16 December 2014
Available online 23 December 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopentenones
Carbocationic rearrangement
Propargyl alcohols
Flavaglines
Isolated from medicinal plants of the genus Aglaia, flavaglines
have attracted considerable attention due to their remarkable
structural complexity and unique biological activities, which
conversion to an acyl chloride and a Sonogashira coupling conve-
niently afforded ketone 5 as a sole E isomer. Condensation with
lithiated trimethoxybenzene gave adduct 6 in 71% yield.
With carbinol 6 in hand, we tested many esterification proto-
cols.9 However, all our attempts were unsuccessful due to lack of
reactivity or high instability of expected ester 7.
1
–5
include a strong cytotoxicity that is specific to cancer cells.
In
the course of our medicinal program aiming at developing flavag-
lines with enhanced pharmacological properties,5 we considered
to prepare novel flavaglines using a strategy developed by Ragot
,6
This failure led us to explore another strategy based on the
recently described gold(I)-catalyzed synthesis of highly substituted
cyclopentenones by an intramolecular siloxycyclization process
7
and coll. at Bayer (Scheme 1). These authors achieved the synthe-
sis of the flavagline core 3 in three steps from cyclopentenone 1a,
using an intramolecular hydroxy epoxide opening in the key step.
Although the disclosed preparation of unsubstituted cyclo-
pentenone 1a could be achieved in 4 steps with an overall yield
of 14%, the introduction of substituents necessary for the antican-
cer activity (e.g., R = OMe) was not reported. In order to synthesize
pharmacologically active flavaglines, we considered to prepare 1b
by another approach. While symmetrical 3,4-diaryl-cyclopent-2-
1
0
developed by Rhee and coll. (Scheme 3). The utility of this
approach was validated with the total synthesis of herbertene nat-
1
1
ural products. Although this reaction was described exclusively
1
2
3
3
with tertiary silyl ethers (R = SiEt , R and R – H), we considered
that the phenyl and the trimethoxyphenyl groups of substrate 11
should sufficiently stabilize the carbocationic intermediate to
allow the reaction to proceed (Scheme 4). This hypothesis was sup-
ported by Toste’s report of a related Au(I)-catalyzed carboxyalk-
oxylation using benzylic ethers as substrates to synthesize
enones can easily be obtained from
a,b-diketones, the synthesis
of cyclopentenones substituted by different aryl moieties is more
tedious.
1
2
indenyl ethers. Thus, the silyl ether was replaced by an ethoxy
group due to its easier preparation.
At the heart of our approach to prepare 1b is the Rautenstrauch
rearrangement, which is particularly efficient to prepare variously
Indeed, the direct molybdenum(VI)-catalyzed transposition and
etherification of allylic alcohol 6 at 50 °C afforded a 1:1 mixture of
8
substituted cyclopentenones. To test the viability of this strategy,
1
3
we first examined the reactivity of the Rautenstrauch’s substrate 7.
Our attempt of synthesis of ester 7 is depicted in Scheme 2. Per-
kin condensation of acid 4 and benzaldehyde followed by the
ethers 9 and 10 in a 55% yield. Gratifyingly, increasing the tem-
perature to 65 °C improved the ratio to 1:3 in favor of the desired
ether 10 in a 85% yield. Increasing the temperature further pro-
moted the decomposition of this product. Desilylation provided
alkyne 11, which gratifyingly proved to be a good substrate for
the Rhee’s annulation reaction. The attempt to perform this reac-
tion on silylated alkyne 10 also afforded 8 (58%).
⇑
Corresponding author. Tel.: +33 036 885 4141; fax: +33 036 885 4320.
E-mail address: desaubry@unistra.fr (L. Désaubry).
http://dx.doi.org/10.1016/j.tetlet.2014.12.093
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

7
28
C. Basmadjian et al. / Tetrahedron Letters 56 (2015) 727–730
Scheme 3. Proposed mechanism for the gold(I)-catalyzed cyclopentanone forma-
tion developed by Rhee and coll.1
0
Scheme 1. Bayer synthesis of the flavagline core (the synthesis of pharmacolog-
ically active compounds (R = OMe) was not reported with this approach).7
1
2
) PhCHO, Ac O, Et N
2 3
SiMe3
1
10°C, 5 h
O
) (COCl) , cat. DMF,
2
CH2Cl2, 1 h
OH
O
Ph
3
)
SiMe3
MeO
MeO
MeO
PdCl (PPh ) ,
1
4
2
3 2
5
,4-dioxane, rt, 12h
1
,3,5-(MeO) Ph,
3
6
2 % for 3 steps
sec-BuLi,
-
78°C to rt, 4 h
7
1 %
OMe
OAc
MeO
OMe
OH
SiMe3
SiMe3
Scheme 4. Synthesis of cyclopentenone 8.
MeO
MeO
Ph
Ph
1) ArB(OH)2, PdCl2(PPh3)2,
MeO
MeO
O
Cl
K PO H O, PhMe,
3
4
2
R
7
6
80°C, 4h
2)
TBDMS
Rautenschrauch
rearrangement
n-BuLi, THF, -78°C
Ph
OEt
MeO
MeO
OMe
O
12
3) MoO2(acac)2, EtOH,
NH PF , CH CN, 65°C MeO
Ph
R = H: 13
4
6
3
4
) TBAF, MeOH, THF, rt
R = Cl: 14
MeO
Au[(C H ) P]Cl
Ph
6 5 3
AgSbF , i-PrOH,
6
MeO
CH Cl , rt
2
2
8
R
Scheme 2. Attempt synthesis of an advanced precursor of flavaglines.
O
The synthesis of two other cyclopentenones was next examined
Scheme 5). The substrates of the Au-catalyzed cyclization were
(
Ph
prepared from acyl chloride 12 through Suzuki coupling, ethynyla-
tion, rearrangement and desilylation of the alkyne. Enyne 13
harboring an unsubstituted phenyl afforded the desired cyclo-
pentenone 15 in a satisfactory yield of 50%. Interestingly, introduc-
tion of a chlorine atom in the para position increased the yield to
MeO
R = H: 15 (50 %)
R = Cl: 16 (75 %)
Scheme 5. Synthesis of cyclopentenones 15 and 16.
7
5%, probably due to a higher stabilization of the carbocationic
intermediate.
Reduction of ketone 17 was not diastereoselective under various
conditions ( -selectride; Red-Al; NaBH ; NaBH , CeCl O). In
ꢀ7H
addition, the mixture of 18 and 19 significantly degraded during
Thanks to the assistance of ketone, 8 was selectively mono-
demethylated upon treatment with BBr in a 75% yield (Scheme 6).
3
L
4
4
3
2

C. Basmadjian et al. / Tetrahedron Letters 56 (2015) 727–730
729
Scheme 6. Synthesis of the allylic alcohols 18/19 and attempts to generate the flavagline scaffold.
At this point, attempts at following Ragot’s strategy using a pro-
tected phenol were examined (Scheme 7). 2-Naphthylmethyl
(NAP) group was selected as the protecting group due to extremely
mild conditions involved in its removal by catalytic hydrogenoly-
OMe
ONAP
O
NAP-Br,
K CO
O
MeO
MeO
+
2
3
DMF, rt
17
NAPO
MeO
OMe
24
73 %
sis. The adduct was obtained as a pair of atropoisomers 21 and
Ph
Ph
9
5 % brsm
0
2
1 . As far as we know atropoisomerism for 1,2-diaryl cyclopent-
enes has not been reported hitherto.
2
1
21'
MeO
Diastereoselective reduction with
L
-selectride afforded alcohols
0
2
2 and 22 with 71% of conversion. Epoxidation of cyclopentenols
L-selectride
0
THF, -78°C to rt, 5 h
21/22 under various conditions (m-CPBA, NaHCO
; VO(acac)
2
,
3
5
0 %, 71 % brsm
t-BuO H; H , NaOH; 4-nitroperbenzoic acid, NaHCO
2
2
O
2
3
) provided
none of the desired product probably due to the low reactivity of
the sterically hindered alkene and instability of the product.
Under Sharpless type conditions (t-BuO H, Ti(Oi-Pr) , 4 Å MS),
2 4
formation of the ketone was predominant, probably due to ring
strain release.
The inability to obtain substrate 23 suggests that the method
reported by Bayer scientist is restricted to the synthesis of flavag-
lines that are not substituted by the functional groups necessary
for the pharmacological activity. Indeed, none of the required dec-
orations proposed in this Letter were described in Bayer patents.
OMe
OH
ONAP
OH
MeO
MeO
+
NAPO
OMe
Ph
Ph
22
22'
MeO
MeO
MeO
OMe
OMe HO
HO
OH
Acknowledgments
O
MeO
Ph
NAPO
MeO
O
L.D. was supported by the ‘Association pour la Recherche sur le
Cancer’ (ARC). We are also grateful to AAREC Filia Research and
ANRT for fellowships to C.B. and Q.Z. and also Julie Schmitt for
technical help.
Ph
23
24
OMe
0
Scheme 7. Synthesis of the atropoisomeric allylic alcohols 22/22 and epoxidation
attempts to synthesize flavagline 24.
Supplementary data
Supplementary data (experimental procedures for the synthesis
of compounds 5, 6, 8, 10–16) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2014.12.093.
purification steps. After extensive work, we eventually were able to
quantitatively prepare a mixture of 18/19 in a 1/1 ratio using 4
equivalents of LiAlH .
4
With 18 and 19 in hand, we tried to convert these reactive
allylic alcohols into the flavagline precursor 20 using many meth-
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