Formal total synthesis of stigmatellin A

Article abstract of DOI:10.1016/j.tetlet.2017.08.048

An efficient and stereoselective approach for the formal total synthesis of Stigmatellin A has been described. The key steps involved in this synthesis are desymmetrization of the bicyclic olefin to introduce two methyl and two hydroxyl chiral centers, Fr

Full text of DOI:10.1016/j.tetlet.2017.08.048

Accepted Manuscript
Formal total synthesis of stigmatellin A
J.S. Yadav, G.Revathi, B.V. Subba Reddy
PII:
S0040-4039(17)31055-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.048
TETL 49238
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 July 2017
16 August 2017
19 August 2017
Please cite this article as: Yadav, J.S., G.Revathi, Reddy, B.V.S., Formal total synthesis of stigmatellin A,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.08.048
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Formal total synthesis of stigmatellin A
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J. S. Yadav,* G.Revathi, B. V. Subba Reddy

1
Tetrahedron Letters
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Formal total synthesis of stigmatellin A
J. S. Yadav,* G.Revathi, B. V. Subba Reddy
Centre for Semiochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, Email: yadavpub@gmail.com; Fax: 91-40-27160512
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient and stereoselective approach for the formal total synthesis of Stigmatellin A has
been described. The key steps involved in this synthesis are desymmetrization of the bicyclic
olefin to introduce two methyl and two hydroxyl chiral centers, Friedel Crafts acylation,
regioselective demethylation, Baker-Venkataraman rearrangement and Grubbs cross metathesis.
Received in revised form
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Desymmetrization
Friedel Crafts acylation
Regioselective demethylation
Baker-Venkataraman rearrangement
Cross-metathesis
Stigmatellin A and B are two novel antibiotics, which were1
isolated from the gliding bacterium Stigmatella aurantiaca .
They are powerful inhibitors of electron transport in chloroplasts
Chromone system 3 was proposed to be synthesized via the
esterfication of aromatic hydroxyl group 5 with acid fragment 6
followed by Baker-Venkataraman rearrangement. The fragment 4
could be obtained from a commercially available tiglic aldehyde
2
and mitochondria. The absolute configuration of Stigmatellin A
was confirmed as (S,S,S,S) by chemical correlation. The salient
3
7 via the Barbier allylation. Stigmatellin A(1) could be
synthesized by the coupling of fragments 3 and 4 through a
cross-metathesis followed by elimination reaction.
features of this stigmatellin A include the presence of chromone
system, four stereogenic centers and conjugated triene. Due to its
fascinating structural features and inherent antibiotic behavior,
4
,5,6
there reports are on its total synthesis.
Following our interest on the total synthesis of biologically active
polyketide natural products by adopting desymmetrization
7
,8
strategy. We herein describe the formal total synthesis of
stigmatellin A .
Retrosynthetically, stigmatellin A (Scheme 1) can be cleaved into
three fragments, i.e aromatic fragment 5, acid fragment 6 (chiral)
and dienyl acetate 4. Aromatic part 5 was proposed to be
synthesized from tetramethoxy benzene via Friedel Crafts
acylation and regioselective demethylation. The carboxylic acid
moiety 6 could be obtained from a known bicyclic lactone 9.

2
Tetrahedron Letters
which was then protected as its acetonide using 2,2-DMP, p-TSA
1
1
2 2
in CH Cl to afford the compound 13 in 80% yield. Swern
1
oxidation of the primary alcohol 13 followed by a two carbon
2
Wittig reaction resulted in the formation of α,β-unsaturated ester
1
1
4 in 86% yield. Reduction of the double bond from compound
13
4 using NaBH
4
and NiCl
2
in MeOH afforded the saturated
ester, which was further reduced with LiAlH
4
in THF to give the
alcohol 15 in 87% yield. The free hydroxyl group of 15 was
protected as its benzyl ether using benzyl bromide and NaH in
presence of a phase transfer catalyst (TBAI) in THF to afford the
compound 16 in 92% yield. Deprotection of the acetonide group
1
6 using C.S.A in MeOH afforded the diol. The selective
protection of primary hydroxyl group with TBDMSCl using
imidazole in CH Cl the TBS ether 17 in 90% yields.
2
2
Methylation of the free hydroxyl group with MeI using NaH in
THF afforded the methyl ether. A subsequent desilylation using
TBAF in THF gave the alcohol 18 in 90% yields. The primary
alcohol 18 was then converted into iodo derivative by a standard
Accordingly, the synthesis of aromatic fragment 5 began from a
readily available tetramethoxy benzene 8. The Friedel-Crafts
acylation of tetramethoxy benzene 8 with propanoyl chloride in
1
4
2
protocol involvingI , TPP and imidazole, which up on treatment
with t-BuOK in dry THF at 0 °C gave the terminal olefin 19 in
79% yield. Debenzylation of compound 19 under radical
conditions using Li-naphthalenide in anhydrous THF at 30 °C
9
the presence AlCl
deprotection of methyl groups from compound 10 using BCl
3
afforded the ketone 10. Regioselective
3
1
0
15
afforded the dihydroxy compound.
The chemoselective
gave the alcohol 20 in 95% yield. A subsequent oxidation of
the hydroxyl group of 20 using TEMPO/BAIB in a mixture of
protection of one of the hydroxyl groups using MOM chloride,
DIPEA in CH Cl afforded the aromatic fragment 5 in 80% yield
over two steps (Scheme 2). The analytical data of 5 was found to
1
6
2
2
3
CH CN and water gave the acid 6 in 92% yield (Scheme 3).
4
The coupling of acid 6 with aromatic hydroxyl group 5 using
DCC, DMAP in CH Cl afforded the ester 21 along with the
be identical with the data reported in literature.
2
2
1
7
The synthesis of acid fragment 6 began with the reductive
cleavage of bicyclic lactone 9. The key intermediate 9 was
synthesized by desymmetrization of bicyclic olefin 11. Thus the
water insoluble dicyclohexyl urea. In order to facilitate the ease
of isolation of the product, the combination of EDC and DMAP
was used to afford the pure ester 21 in 70% yield. The ester 21
was then converted into chromone 3 in 67% yield by means
Baker-Venkataraman rearrangement using Na in dry methanol
under reflux for 2h (Scheme 4).
8
treatment of 9 with LiAlH
8
4
in dry THF afforded the triol 12 in
7e
4
5% yield,
O
O
O
OMe OH OH
ref.8
O
2
,2-DMP, p-TSA (cat)
OMe O
O
LiAlH4, THF
HO
0 oC-r.t, 5h, 85%
Acetone,1h, 80%,
HO
OMe
1
1
9
OMe
12
1
3
OMe O
O
1
) (COCl)2, DMSO, Et3N
CH2Cl2, -78 o
) Ph3PCHCO2Et
Benzene, rt, 86%
1) NiCl2, NaBH4, MeOH
0 oC-r.t, 95%
OMe O
O
NaH / BnBr, THF, TBAI
0 oC-r.t, 4h 92%
OMe O
O
BnO
C
EtOOC
HO
2
2) LiAlH4, THF
16
0 oC-r.t, 2h, 93%
15
14
(
1) I2, TPP, Imidazole
THF:ether(3:1), 0 o
1
) MeI, NaH, THF
OMe OMe OH
1
) CSA, MeOH
C
OMe OH OTBS
0 oC-r.t, 12h, 90%
0 oC-r.t, 3h, 95%
(2) BuOK, THF, 0 oC, 3h
t
BnO
BnO
2) TBAF, THF
0 oC-r.t, 3h, 95%
79% over two steps
2) TBS Chloride,Imidazole
18
CH2Cl2, 0 oC-r.t, 1h, 95%
17
OMe OMe
OMe OMe
OMe OMe
TEMPO, BAIB
CH3CN, H2O, r.t, 6h, 92%
Li-naphthalene, THF
20 oC, 30min, 95%
HO
HOOC
BnO
-
2
0
6
1
9
Scheme 3. Synthesis of acid fragment 6

3
OMe
O
OMe
O
O
O
OMe OMe
OMe OMe
EDC, DMAP
HO
OH
MeO
MeO
CH2Cl2, 3h, 70%
O
OMOM
OMOM
O
2
1
6
5
OMe
O
O
OMe
OMe OMe
OMe OMe
Na/MeOH
2h, 67%
MeO
MeO
O
O
OMOM
OMOM
3
21
Scheme 4. Synthesis of chromone fragment 3
Synthesis of dienyl acetate fragment 4 began from a readily
available tiglic aldehyde 7. Allylation of the tiglic aldehyde 7
To the total synthesis of stigmatellin A, we attempted the
deprotection of MOM ether of compound 26 using various
reagents under different conditions as shown in Table 1.
Unfortunately, none of them gave the desired product
with allyl bromide in the presence of zinc and aq. NH
afforded the racemic alcohol 22 in 94% yields. Protection free
hydroxyl group as its acetyl ester using Ac O, Et N in the
presence DMAP gave the compound 4 in 90% yield (Scheme 5).
4
Cl in THF
2
3
Table 1: Deprotection of MOM ether in compound 26 under
different conditions
Sl.No
1
Reaction condition
5N HCl in CH Cl , 30min
Results
2
2
Complex of mixture of
compounds
2
3
4
5
6
2 N HCl in THF, 3h
TiCl in CH Cl , 0 °C , 15min
Cl :CH CN
Complex of mixture of
compounds
4
2
2
Complex of mixture of
compounds
TMSCl, NaI in CH
1:1)
Montmorillonite K 10 Clay in
CH Cl , r.t, 1h
Montmorillonite K 10 Clay in
CH Cl , 50 °C, 1h
, 7H O, reflux, 1h
.7H O, reflux, 3h
2
2
3
Complex of mixture of
compounds
(
No reaction
2
2
Complex of mixture of
compounds
In order to couple compound 4 and 3, we adopted the olefin
2
2
1
cross-metathesis strategy using Grubbs catalyst . Initially, we
8
7
8
CeCl
CeCl
3
3
2
No reaction
Complex of mixture of
compounds
attempted the reaction in the presence of free hydroxyl group in
nd
fragment 4 and fragment 3 using Grubbs 2 generation catalyst
2
in the formation 24 in 40% yield. Next we performed the
reaction with protected hydroxyl group as acetate in fragment 4
Conclusion
nd
and fragment 3 using Grubbs 2 generation catalyst leading to
In conclusion, the stereoselective formal total synthesis of
stigmatellin has been accomplished through a
exclusive formation of trans product 25 in high 92% yield.
Hydrolysis of the acetate in compound 25 using K CO in MeOH
A
2
3
desymmetrization strategy. The required chiral centers were
established through Brown’s asymmetric hydroboration. Baker-
Venkataraman rearrangement has been successfully adopted to
construct the chromone ring system. Grubbs cross metathesis has
been utilized to generate internal olefin in the target molecule.
Our approach is simple and very useful to prepare key fragments
of stigmatellin A.
resulted secondary alcohol 24 in 80% yield. Mesylation of the
secondary hydroxyl group in compound 24 using MsCl, TEA in
2 2
CH Cl followed by elimination using NaI, DBU in DME gave
the triene 26 in 57% yield (Scheme 6).
OMe O
OMe O
OMe OMe
RO
23 (10 mol%)
OMe OMe
OR
CH2Cl2, reflux, 3h, 92%
MeO
O
MeO
O
OMOM
3
OMOM
4
OMe O
24, R = H, 40%
25, R = Ac, 92%
OMe OMe
OAc
OMe O
K2CO3, MeOH
0 oC, 3h, 80%
MeO
O
OMe OMe
OH
OMOM
2
5
MeO
O
OMOM
24
OMe O
N
N
Mes
Mes
Cl
TEA, MsCl, DCM, 3h
NaI, DBU, DME, reflux, 3h, 57%
OMe OMe
H
Ru
MeO
O
Cl
Ph
OMOM
26
23
PCy3
Grubbs second generation
catalyst (G-II)
Scheme 6. Synthesis of MOM protected stigmatellin A

4
Tetrahedron Letters
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Supplementary Material
Supplementary data associated with this article can be found,
in the online version at

5
Highlights
It describes the formal total synthesis of
•
stigmatellin A
•
•
•
•
Friedel-Crafts acylation was achieved using
Lewis acid.
Chromone system was constructed by
Baker-Venkataraman rearrangement.
Desymmetrization has been adapted to
establish chiral centers.
Side chain was extended by Grubbs-cross
metathesis.