Total synthesis of motualevic acids A-E

Article abstract of DOI:10.1016/j.tetlet.2009.12.113

The first total synthesis of motualevic acids A-E, isolated from Siliquariaspongia sp., starting from commercially available 1,10-decanediol, is described. The key steps in the synthetic sequence involve stereoselective olefination, Corey-Fuchs reaction, and amide coupling.

Full text of DOI:10.1016/j.tetlet.2009.12.113

Tetrahedron Letters 51 (2010) 1124–1125
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Tetrahedron Letters
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Total synthesis of motualevic acids A–E
*
Gangarajula Sudhakar , Vilas D. Kadam, Vaddu V. N. Reddy
Organic Chemistry Division-II, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of motualevic acids A–E, isolated from Siliquariaspongia sp., starting from com-
mercially available 1,10-decanediol, is described. The key steps in the synthetic sequence involve stere-
oselective olefination, Corey–Fuchs reaction, and amide coupling.
Received 26 November 2009
Revised 17 December 2009
Accepted 21 December 2009
Available online 28 December 2009
Ó 2010 Published by Elsevier Ltd.
Motualevic acids A–F (1–6), a new class of brominated long
chain acids, along with a new enantiomer of (4E)-S-antazirine1,2
7 (Fig. 1) were recently isolated from Siliquariaspongia sp. by Bew-
ley and co-workers.3 The crude extracts from Siliquariaspongia sp.
are found to inhibit the growth of Staphylococcus aureus (SA) and
methicillin-resistant Staphylococcus aureus (MRSA) in a disk diffu-
sion assay. Antimicrobial disk diffusion assays performed with
pure motualevic acids A–F (1–6) and (4E)-R-antazirine 7 traced
the MRSA-inhibitory activity to acids 1 and 6, which inhibited
to get aldehyde 11 in 88% overall yield. The aldehyde 11 was con-
verted to gem-dibromoalkene 12 by Corey–Fuchs reaction8 in 86%
yield. The ester hydrolysis using LiOH in THF/MeOH/H2O system
resulted in the desired motualevic acid E9 (5) with 72% yield
(Scheme 1).
The motualevic acid E (5) was coupled with glycine methyl ester
hydrochloride using EDCI, HOBt as coupling reagents in the pres-
ence of Et3N in CH2Cl2 to give methyl ester of motualevic acid A.
the growth of MRSA at loadings of 10 and 5
The same assay performed with SA showed compounds 1, 2, 5,
and 6 to be active at respective loadings of 10, 10, 50, and 2 g/
lg/disk, respectively.
O
Br
O
H
H
N
l
N
OH
Br
R
disk. Based on their observation,3 antimicrobial activity toward
MRSA is dependent on the presence of a carboxylic acid group. This
is supported by the fact that ester bearing antazirines and azirino-
mycine1,2 lack antimicrobial activity while azirinomycine showed
antimicrobial activity in its naturally occurring acid form. The
new residues of natural products with simple and interesting
structure along with significant biological profile attracted us for
the total synthesis of motualevic acids A–E.
7
Br
O
O
8
Motualevic acid A (1)
Motualevic acid C (3)
R = OH
Br Motualevic acid B (2)
R = NH2
Br
OH
Motualevic acid D (4)
R = N(CH3)2
Br
7
Br
O
N
O
Motualevic acid E (5)
Br
OR
7
Motualevic acid F (6)
R = H
(-)-(E)-Antazirine (7)
R = CH3
The synthetic strategy, we planned, will not only give motual-
evic acids but also their analogs, which may have interesting bio-
logical properties. Our synthesis started from a key intermediate4
8, which in turn can be synthesized from a commercially available
1,10-decanediol. Treatment of 8 with KCN in the presence of cata-
lytic amount of 18-crown-6 in acetonitrile at room temperature
gave cyanide moiety5 that was treated with DIBAL-H at ꢀ78 °C to
provide aldehyde6 9 in 75% yield over two steps. Two carbon Wittig
olefination was carried out in CH2Cl2 at room temperature to get
Figure 1. Structures of motualevic acids A–F and (4E)-R-antazirine.
a
b
THPO
CHO
THPO
Br
HO
OH
8
8
8
8
9
c
d
OEt
OEt
THPO
Br
OHC
Br
8
7
O
O
10
11
a
,b-unsaturated ester7 10 exclusively as the (E)-isomer in 80%
f
e
OEt
OH
Br
yield. Deprotection of the THP ether moiety in 10 with catalytic
amount of PTSA in MeOH resulted in a primary hydroxyl functional
group that was oxidized using Swern oxidation reaction conditions
Br
7
7
O
O
12
Motualevic acid E (5)
Scheme 1. Reagents and conditions: (a) (i) HBr, toluene, reflux, 16 h; (ii) DHP, PPTS,
CH2Cl2, 16 h, 73% over two steps; (b) (i) KCN, 18-crown-6, CH3CN, 50 h; (ii) DIBAL-
H, CH2Cl2, ꢀ78 °C, 2 h, 75% over two steps; (c) Ph3P@CHCO2Et, CH2Cl2, overnight,
80%; (d) (i) PTSA, MeOH, 0 °C to rt, 4 h; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C,
0.5 h, 88% over two steps; (e) CBr4, Ph3P, CH2Cl2, 1 h, 86%; (f) LiOH, THF/MeOH/H2O
(3:1:1), overnight, 72%.
* Corresponding author. Tel.: +91 40 27191435; fax: +91 40 27193382.
E-mail addresses: gsudhakar@iict.res.in, gangarajulasudhakar@gmail.com
(G. Sudhakar).
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.12.113

G. Sudhakar et al. / Tetrahedron Letters 51 (2010) 1124–1125
1125
Br
O
group of 15 using a catalytic amount of PTSA in MeOH resulted
in a primary hydroxyl group that was oxidized to aldehyde with
Swern oxidation reaction conditions to give compound 16 in 85%
yield over two steps. The aldehyde 16 was converted to terminal
dibromide 17 in 70% yield under Corey–Fuchs6 reaction conditions.
Subsequent hydrolysis using LiOH in a mixture of THF/H2O/MeOH
system gave the desired motualevic acid B14 (2) in 72% yield
(Scheme 4). The spectral data of the newly synthesized compounds
1–59–12,14 coincided with those of the natural material.3
In conclusion, we have achieved the first total synthesis of
motualevic acids A–E in a practically applicable way starting from
commercially available 1,10-decanediol employing well estab-
lished methods, stereoselective olefination, Corey–Fuchs reactions,
amide coupling as the key steps. Application of this strategy to ob-
tain analogs of the motualevic acids A–F as well as antazirine and
its analogs for evaluation of their biological activity is under pro-
gress and will be reported in due course.
H
a
N
5
Br
Motualevic acid A (1)
OH
7
O
Scheme 2. Reagents and conditions: (a) (i) EDCI, HOBt, CH3O2CCH2NH2ꢁHCl, Et3N,
CH2Cl2, 0 °C to rt, 3 h; (ii) LiOH, THF/MeOH/H2O (3:1:1), 2 h, 76% over two steps.
Br
O
H
N
a
Br
NH2
7
O
Motualevic acid C (3)
1
b
Br
O
H
N
Br
NMe2
7
O
(4)
Motualevic acid D
Scheme 3. Reagents and conditions: (a) ClCO2C2H5, NH4OH, Et3N, THF, ꢀ20 °C,
1.5 h, 83%; (b) EDCI, HOBt, (CH3)2NHꢁHCl, Et3N, CH2Cl2 0 °C to rt, 2 h, 65%.
Acknowledgments
a
O
b
The authors wish to thank CSIR, New Delhi, India, for a research
fellowship (V.D.K). G.S. is thankful to Dr. J. S. Yadav, Director, IICT
and Dr. T. K. Chakraborty, Director, CDRI for their support and
encouragement.
H
THPO
THPO
8
8
8
N
OH
OMe
14
13
O
O
O
O
H
H
N
N
OMe
OMe
d
c
O
O
16
OHC
References and notes
15
7
THPO
Br
8
O
O
H
N
H
1. Saloman, C. E.; Williams, D. H.; Faulkner, D. J. J. Nat. Prod. 1995, 58, 1463–1466.
2. Skepper, C. K.; Molinski, T. F. J. Org. Chem. 2008, 73, 2592–2597.
3. Keffer, J. L.; Plaza, A.; Bewley, C. A. Org. Lett. 2009, 11, 1087–1090.
4. Grube, A.; Timm, C.; Köck, M. Eur. J. Org. Chem. 2006, 1285–1295.
5. Pollard, M. M.; ter Wiel, M. K. J.; van Delden, R. A.; Vicario, J.; Koumura, N.; van
den Brom, C. R.; Meetsma, A.; Feringa, B. L. Chem. Eur. J. 2008, 14, 11610–11622.
6. Ishigami, K.; Katsuta, R.; Watanabe, H. Tetrahedron 2006, 62, 2224–2230.
7. Vig, O. P.; Sharma, M. L.; Verma, N. K.; Malik, N. Indian J. Chem. 1980, 19B, 581–582.
8. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769–3772.
N
OH
OMe
f
e
Br
O
O
8
8
17
Br
Br
Motualevic acid B (2)
Scheme 4. Reagents and conditions: (a) LDA (4 equiv), HC„CCO2H (2 equiv), THF–
HMPA (3:1), 16 h, 50%; (b) EDCI, HOBt, glycine methyl ester hydrochloride, Et3N,
CH2Cl2, 2 h, 69%; (c) Pd/CaCO3/Pb, MeOH, 0.25 h, 72%; (d) (i) PTSA, MeOH, 0 °C to rt,
5 h; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C, 0.5 h 85%; (e) CBr4, Ph3P, CH2Cl2, 0 °C,
1 h, 70%; (f) LiOH, THF/MeOH/H2O (3:1:1), 1 h, 82%.
9. Spectral data of motualevic acid E (5): 1H NMR (500 MHz, CDCl3): d 7.04 (dt,
J = 15.9, 6.7 Hz, 1H), 6.36 (t, J = 7.5 Hz, 1H), 5.87 (d, J = 15.9 Hz, 1H), 2.24 (q,
J = 6.7 Hz, 2H), 2.10 (dt, J = 7.5, 6.7 Hz, 2H), 1.53–1.40 (m, 4H), 1.37–1.20 (m,
10H); 13C NMR (75 MHz, CDCl3): d 172.1, 152.1, 138.6, 120.5, 88.4, 32.8, 32.1,
29.2, 29.1, 29.0, 28.9, 28.8, 27.7, 27.6; IR (film): mmax 2927, 2854, 1696, 1649,
1222 cmꢀ1; ESI-MS: m/z 403 [M+Na]+.
Subsequent hydrolysis with LiOH in THF/MeOH/H2O system affor-
ded motualevic acid A10 (1) in 76% yield over two steps (Scheme 2).
Motualevic acids C (3) and D (4) can be derived from motualevic
acid A (1) as shown in Scheme 3. To motualevic acid A (1) and ethyl
chloroformate in the presence of Et3N in THF at ꢀ20 °C, was added
NH4OH to give motualevic acid C11 (3) in 83% yield. Motualevic
acid A (1) was reacted with N,N0-dimethylamine hydrochloride
using EDCI, HOBt in the presence of Et3N in CH2Cl2 to give motual-
evic acid D12 (4) in 65% yield.
For the synthesis of motualevic acid B (2), the Z isomer of motu-
alevic acid A (1), we adopted a different synthetic strategy. Treat-
ment of 8 at ꢀ15 °C at room temperature for 16 h with dianion
of propiolic acid,13 prepared in situ by reacting propiolic acid in
HMPA with LDA in THF at ꢀ40 °C and at ꢀ15 °C for 2 h, gave the
acetylenic acid 13 in moderate yield. The acid 13 was reacted with
glycine methyl ester hydrochloride using EDCI, HOBt in the pres-
ence of Et3N in CH2Cl2 to give the expected product 14 in 69% yield.
Partial hydrogenation of the acetylenic moiety in 14 using Lindlar’s
catalyst in MeOH furnished the Z geometry olefin 15 in 72% yield.
The Z geometry of the double bond was apparent from the small 3J
coupling of 11.3 Hz between 2H and 3H. Deprotection of the THP
10. Spectral data of motualevic acid A (1): 1H NMR (300 MHz, CD3OD): d 6.82 (dt,
J = 15.8, 6.8 Hz, 1H), 6.50 (t, J = 7.5 Hz, 1H), 6.02 (d, J = 15.8 Hz, 1H), 3.92 (s, 2H),
2.24 (q, J = 6.8 Hz, 2H), 2.14 (dt, J = 7.5, 6.7 Hz, 2H), 1.56–1.30 (m, 14H); 13C
NMR (75 MHz, CD3OD): d 174.7, 168.6, 145.9, 140.3, 124.5, 89.1, 43.2, 33.9,
33.0, 30.7, 30.5, 30.4, 30.2, 30.0, 29.4, 28.8; IR (film): mmax 2919, 2849, 1733,
1661, 1557, 1262 cmꢀ1; ESI-MS: m/z 438 [M+H]+.
11. Spectral data of motualevic acid C (3): 1H NMR (400 MHz, CDCl3): d 6.87 (dt,
J = 15.1, 6.8 Hz, 1H), 6.42–6.32 (m, 3H), 5.84 (d, J = 15.1 Hz, 1H), 5.57 (bs, 1H),
4.05 (d, J = 5.2 Hz, 2H), 2.18 (dt, J = 7.5, 6.8 Hz, 2H), 2.08 (dt, J = 7.5, 6.8 Hz, 2H),
1.50–1.37 (m, 4H), 1.35–1.24 (m, 10H); 13C NMR (75 MHz, CDCl3): d 173.2,
168.0, 146.6, 139.2, 123.0, 88.2, 42.9, 32.9, 32.0, 29.6, 29.3, 29.2, 29.1, 28.9,
28.1, 27.7; IR (film): mmax 2917, 2848, 1660, 1625, 1551, 1461, 1274,
1132 cmꢀ1; ESI-MS: m/z 437 [M+H]+.
12. Spectral data of motualevic acid D (4): 1H NMR (300 MHz, CD3OD): d 6.81 (dt,
J = 15.3, 6.8 Hz, 1H), 6.47 (t, J = 7.1 Hz, 1H), 6.0 (d, J = 15.3 Hz, 1H), 4.11 (s, 2H),
3.05 (s, 3H), 2.95 (s, 3H), 2.21 (q, J = 6.8 Hz, 2H), 2.11 (q, J = 7.1 Hz, 2H), 1.53–
1.38 (m, 4H), 1.35–1.25 (m, 10H); 13C NMR (75 MHz, CD3OD): d 172.0, 168.0,
146.6, 140.6, 124.6, 89.4, 41.9, 36.6, 35.2, 34.0, 33.0, 30.6, 30.5, 30.4, 30.2, 30.1,
29.4, 28.8; IR (film): mmax 2919, 2850, 1672, 1617, 1507, 1461, 1407, 1216; ESI-
MS: m/z 467 [M+H], 489 [M+Na]+.
13. Bronk, B. S.; Lippard, S. J.; Danheiser, R. L. Organometallics 1993, 12, 3340–3349.
14. Spectral data of motualevic acid B (2): 1H NMR (300 MHz, CD3OD): d 6.49 (t,
J = 7.5 Hz, 1H), 6.07 (dt, J = 11.3, 7.5 Hz, 1H), 5.87 (d, J = 11.3 Hz, 1H), 3.82 (s,
2H), 2.63 (q, J = 7.5 Hz, 2H), 2.12 (q, J = 7.5 Hz, 2H), 1.54–1.26 (m, 14H); IR
(film): mmax 2925, 2855, 1705, 1670, 1607, 1460, 1218 cmꢀ1; ESI-MS: m/z 438
[M+H]+.