First stereoselective total synthesis of Neocosmosin A: A facile approach

Article abstract of DOI:10.1016/j.tetlet.2014.08.065

First stereoselective concise synthesis of Neocosmosin A, with in vitro binding affinity for human opioid and cannabinoid receptors, has been reported using readily available starting materials such as methylacetoacetate, cyclohexanone, and homoallyl alco

Full text of DOI:10.1016/j.tetlet.2014.08.065

Tetrahedron Letters 55 (2014) 5629–5631
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First stereoselective total synthesis of Neocosmosin A:
a facile approach
⇑
Soma Shekar Dachavaram, Kondbarao Balasaheb Kalyankar, Saibal Das
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
First stereoselective concise synthesis of Neocosmosin A, with in vitro binding affinity for human opioid
and cannabinoid receptors, has been reported using readily available starting materials such as methy-
lacetoacetate, cyclohexanone, and homoallyl alcohol involved in the key transformations. There are three
fragments involved in the synthesis of target molecule, bearing acid functionality, (R)-pent-4-en-2-ol, and
Weinreb amide which are synthesized in four, eight, and three steps, respectively. Then the fragments
were coupled in four steps to yield the target molecule in an overall yield of 28.6%.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 24 May 2014
Revised 11 August 2014
Accepted 16 August 2014
Available online 23 August 2014
Keywords:
Neocosmosin A
Resorcylic acid lactones
Total synthesis
In 2012, Cutler’s bioassay-guided fractionation of a fungus
Neocosmospora sp. (UM-031509) resulted in the isolation of three
new resorcylic acid lactones,1 Neocosmosin A (1), Neocosmosin B
(2), and Neocosmosin C (4) (Fig. 1). Structures of these compounds
were established on the basis of extensive 1D and 2D NMR spectro-
scopic analysis, mass spectrometric (ESI-MS) data, and X-ray
crystallography. Neocosmosin A (1) has in vitro binding affinity
for human opioid receptors and is reported to inhibit selectively
5
8
18
O
O
O
O
O
2
12
HO
10
O
HO
15
O
OR
OR
R= Me, Neocosmosin A (1)
R= H, Monocillin IV (3)
R= H, Neocosmosin B (2)
R= Me, Neocosmosin C (4)
d-44.7%, r-11.4%, and
l-22.4% with reference to naloxone and for
Figure 1. Structures of Neocosmosin A–C and monocillin IV.
cannabinoid receptor CB2-44.5% with reference to CP 55,940.2
According to Cutler compound 1 is a white amorphous solid,
and it is structurally similar to monocillin IV (3), as shown by its
NMR data, optical rotation, and X-ray diffraction. The asymmetric
carbon atom C-2 in monocillin IV was determined as R-configura-
tion from single-crystal X-ray diffraction. Therefore, the absolute
configuration of the asymmetric carbon atom C-2 in compound 1
was proposed to be analogous to that of monocillin IV (3).
Furthermore, the geometry of the double bond in compound 1
(C4–C5) was difficult to determine by coupling constants because
of the overlap of H-4 and H-5. The geometry of the double bond
(C4–C5) in monocillin IV was found to be E configuration from
single-crystal X-ray diffraction.3 Therefore, they propose the
geometry of the double bond (C4–C5) in compound 1 to be the E
configuration. Due to its strong affinities for human opioid recep-
tors, we became interested in developing a general synthesis of
Neocosmosin A by employing simple reaction sequence.
In the retrosynthetic analysis of compound 1 (Scheme 1), we
envisioned the construction of the target compound 1 by using
Grubb’s RCM on 5, which could be easily achieved by lithiation
of compound 8 with compound 6 and Mitsunobu esterification of
compound 7, respectively. On the other hand compounds 6, 7,
and 8 could easily be obtained from commercially available
starting material cyclohexanone 9, homoallyl alcohol 10, and
methylacetoacetate 11, respectively.
Our synthesis commenced with the construction of fragment 8
by using methyl acetoacetate 11 (Scheme 2) which was treated
with NaH, n-BuLi mediated intramolecular condensation4 in THF
under reflux to produce the corresponding aromatic dihydroxy
methyl ester 12 in 72% yield. This was allowed to react with TPP,
DIAD, and MeOH in THF at room temperature to obtain exclusively
mono methylated compound 13 in 84% yield. In compound 13, the
phenolic proton signal at d 11.78 in 1H NMR is attributed for the
selective methylation at para to methyl ester of 12. Then it was
treated with MOM chloride, DIPEA, in CH2Cl2 at 0 °C to room tem-
perature to furnish compound 14 in 98% yield. Compound 14 on
⇑
Corresponding author. Tel.: +91 40 2719 1887; fax: +91 40 2716 0512.
E-mail address: saibal@iict.res.in (S. Das).
http://dx.doi.org/10.1016/j.tetlet.2014.08.065
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5630
S.S. Dachavaram et al. / Tetrahedron Letters 55 (2014) 5629–5631
OH
HO
O
O
O
a
O
b
c
OH
OBn
e
OBn
O
HO
10
15
16
O
O
OTBS
OTBS
OTBS
OH
d
O
5
O
1
f
OH
OBn
MOMO
O
O
7
19
18
17
OH
OH
N
O
Scheme 3. Reagents and conditions: (a) (i) BnBr, NaH, TBAI THF, 0 °C to rt, 12 h,
96%; (ii) m-CPBA, CH2Cl2, 0 °C to rt, 12 h, 97%; (iii) (S,S)-(salen)-CoIIIꢁOAc (0.5 mol %),
H2O (0.55 equiv), 0 °C to rt, 18 h, 47%; (b) LiAlH4, THF, 0 °C to rt, 0.5 h, 96%; (c)
TBSCl, imidazole, CH2Cl2, 0 °C to rt, 3 h, 97%; (d) Li–naphthalene, THF, rt to ꢀ20 °C,
1.5 h, 86%; (e) (i) DMSO, oxalyl chloride, Et3N, CH2Cl2, ꢀ78 °C, 2 h; (ii) t-
KOBu,CH3PPh3I, THF, 0 °C to rt, 1 h, 67%; (f) TBAF, THF, 0 °C to rt, 4 h, 85%.
O
6
8
7
O
O
O
OH
O
10
11
9
Scheme 1. Retrosynthetic analysis of compound 1.
O
b
a
further saponification5 with KOH in MeOH/H2O (1:1) gave the
desired aromatic intermediate 8 in 91% yield, which was then used
later for Mitsunobu lactonization with compound 7 as per plan.
The synthesis of fragment 7 began using commercially available
homoallyl alcohol 10 (Scheme 3), which was protected as benzyl
ether using BnBr, NaH, and a catalytic amount of TBAI in THF to
afford benzyl protected alcohol in 96% yield. Then it was subjected
to m-CPBA epoxidation to give racemic epoxide in 97% yield, which
was then subjected to hydrolytic kinetic resolution6 using the
(S,S)-Jacobsen catalyst to obtain optically pure (S)-2-allyloxirane
15 in 47% yield. The regioselective ring opening of epoxide 15 with
LiAlH4 in THF afforded compound 16 in 96% yield. Compound 16
was subsequently protected with TBSCl in imidazole and CH2Cl2
to obtain 17 in 97% yield. Deprotection of the benzyl group with
Li/naphthalene in THF afforded 18 in 86% yield followed by oxida-
tion with DMSO, oxalyl chloride, Et3N in CH2Cl2 to give the corre-
sponding aldehyde. It was then used directly for the one carbon
Wittig reaction to furnish compound 19 in 67% yield (for 2 steps).
Removal of the TBS group from 19 with TBAF furnished the
required alcohol (R)-pent-4-en-2-ol 7 in 85% yield.
HO
CO2Et
CO2Et
20
21
9
OMe
c
N
6
O
Scheme 4. Reagents and conditions: (a) (i) K2S2O8, H2SO4, EtOH rt, 15 h, 80%; (b) (i)
DMSO, oxalyl chloride, Et3N, CH2Cl2, ꢀ78 °C; (ii) t-KOBu,CH3PPh3I, THF, 0 °C to rt,
1 h. (78% over 2 steps) (c) LiHMDS, Weinreb salt, 21, THF, ꢀ78 °C, 0.5 h, 90%.
OMOM
MOMO
O
CO2H
O
a,7
b,6
MeO
MeO
8
22
O
O
O
O
c
MOMO
HO
d
1
O
O
OMe
OMe
Fragment 6 was synthesized from readily available cyclohexa-
none 9 (Scheme 4). Compound 9 on treatment with K2S2O8,
H2SO4 in EtOH produced7 20 in 80% yield which was oxidized with
DMSO, oxalyl chloride, Et3N in CH2Cl2 to furnish the desired alde-
hyde, which was converted to compound 21 using the Wittig
reaction8 in 78% yield (for 2 steps). Then treatment of the Weinreb
salt with LiHMDS followed by ester 21 in THF at ꢀ78 °C gave the
corresponding compound 6 in 90% yield.9
23
5
Scheme 5. Reagents and conditions: (a) DIAD, Ph3P, 7, THF, rt, 0.5 h, 92%; (b) LDA,
ꢀ78 °C to 0 °C, THF then 6, 0 °C, 0.5 h, 82%; (c) 4 N HCl, 48 h, rt, 80%; (d) CH2Cl2,
reflux, Grubbs 2nd catalyst (10 mol %), 3 h, 89%.
After the successful synthesis of 23, we employed RCM protocol
followed by MOM deprotection using 10 mol % of Grubbs 2nd
generation catalyst and 4 N HCl, respectively to achieve 1. But
unexpectedly even at high dilution conditions formation of
compound 1 with desired E configuration was unsuccessful. Nearly
(1:1) mixture of inseparable E and Z isomers was observed
(confirmed by 1H NMR). In order to overcome this challenge,
deprotection of the MOM group was employed in 4 N HCl, at room
temperature for 48 h to furnish the desired compound 5 in 80%
yield. RCM on 5 using 10 mol % of Grubbs 2nd generation catalyst
in high dilution conditions11 gave E olefin 1 as a white amorphous
solid in 89% yield as the major isomer (confirmed by 1H NMR and
The coupling between 7 and 8 was performed using the Mitsun-
obu protocol (Scheme 5) to furnish the key intermediate 22 in 92%
yield. With both the ester 22 and the Weinreb amide 6 in hand,
lithiation10 of 22 at the 10-position using in situ formation of LDA
at ꢀ78 °C followed by reaction with the Weinreb amide 6 provided
the desired ketone 23 in 82% yield.
OH
OH
CO2Me
CO2Me
O
O
a
b
O
HO
MeO
11
12
13
HPLC). Selectivity may be due to the chelation of Ru-complex with
26
the free phenolic group. The specific rotation is [
a
]
D
ꢀ43.6 (c 0.6,
OMOM
CO2Me
OMOM
CO2H
32
CHCl3) [lit. [a]
ꢀ43 (c 0.6, CHCl3)].1 Spectral and physical data12
D
c
d
were found to be in agreement with reported values.1
MeO
MeO
In conclusion, we believe that this reaction sequence is a short
route to the stereoselective total synthesis of the natural product,
Neocosmosin A. The synthesis involves direct and straightforward
reaction conditions such as Mitsunobu lactonization, lithiation
using LDA, and Grubbs ring closing metathesis.
14
8
Scheme 2. Reagents and conditions: (a) NaH, BuLi, THF, ꢀ78 °C to 0 °C to rt, reflux,
26 h, 72%; (b) TPP, DIAD, MeOH, THF, rt, 1.5 h, 84%; (c) MOMCl, DIPEA, CH2Cl2, 10 h,
98%; (d) KOH, MeOH/H2O (1:1), reflux 12 h then AcOH, pH 6, 91%.

S.S. Dachavaram et al. / Tetrahedron Letters 55 (2014) 5629–5631
5631
4. (a) Barrett, A. G. N.; Morris, T. N.; Barton, D. H. R. J. Chem. Soc., Perkin Trans. 1
1980, 2272–2277; (b) Chiarello, J.; Joullie, M. M. Tetrahedron 1988, 44, 41–48.
5. Quang Vu, N.; Chai, C. L. L.; Lim, K. P.; Chia, S. C.; Chen, A. Tetrahedron 2007, 63,
7053–7058.
6. (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould,
A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307–1315; (b)
Cochrane, J. R.; McErlean, C.; Jolliffe, K. A. Org. Lett. 2010, 12, 3394–3397.
7. (a) Zarrabi, S.; Mahmoodi, N. O.; Marvi, O. Monatsh. Chem. 2010, 141, 889–891;
(b) Rosillo, M.; Casarrubios, L.; Domínguez, G.; Perez Castells, Javier Org. Biomol.
Chem. 2003, 1, 1450–1451.
Acknowledgments
D.S.S. and K.B.K. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi for fellowship. S.D. is grateful to the
Council of Scientific and Industrial Research (CSIR)-New Delhi for
research funding under the ORIGIN (CSC-0108) programme of the
12th five year plan.
8. Todd, M.; Baugh, H.; Liu, B.; Padwa, A. Tetrahedron Lett. 1998, 39, 4757–4760.
9. Sridhar, Y.; Srihari, P. Org. Biomol. Chem. 2013, 11, 4640–4645.
10. (a) Barluenga, S.; Moulin, E.; Lopez, P.; Winssinger, N. Chem. Eur. J. 2005, 11,
4935–4952; (b) Karthikeyan, G.; Zambaldo, C.; Barluenga, S.; Zoete, V.; Karplus,
M.; Winssinger, N. Chem. Eur. J. 2012, 18, 8978–8986.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.08.
065.
11. (a) Sheshurao, B.; Gyan Chander, E.; Das, S. Synlett 2013, 1117–1120; (b) Yadav,
J. S.; Reddy, J. S.; Thrimurtulu, M.; Prasad, A. R. Tetrahedron Lett. 2010, 51, 4050–
4052.
32
12. Neocosmosin A: IR (KBr): 3413, 2922, 1713, 1612, 1256, 1044 cmꢀ1; [
a]
D
ꢀ43 (c 0.6, CHCl3)];1H NMR (300 MHz, CDCl3): d
20
References and notes
ꢀ43.5 (c 0.7, CHCl3 [lit. [
a
]
D
12.0 (s, 1H), 6.42 (d, J = 2.5 Hz, 1H), 6.22 (d, J = 2.5 Hz, 1H), 5.42–5.50 (m, 2H),
5.28–5.38 (m, 1H), 4.40 (d, J = 16.8 Hz, 1H), 3.80 (s, 3H), 3.49 (d, J = 16.8 Hz,
1H), 2.45–2.65 (m, 2H), 2.20–2.43 (m, 2H), 1.87–2.17 (m, 4H), 1.38 (d,
J = 6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 208.1, 170.7, 166.0, 163.8, 139.0,
135.0, 124.5, 105.6, 100.1, 72.8, 55.3, 50.2, 40.7, 37.6, 32.6, 25.2, 22.1, 18.9; MS
(ESI) (m/z): 333 [M+H]+, 355 [M+Na]+; HRMS-ESI: calcd for C19H25O5:
333.16977, found 333.16965 [M+H]+.
1. Gao, J.; Radwan, M. M.; Leon, F.; Dale, O. R.; Husni, A. S.; Wu, Y.; Lupien, S.;
Wang, X.; Manly, S. P.; Hill, R. A.; Dugan, F. M.; Cutler, H. G.; Cutler, J. S. J. Nat.
Prod. 2013, 76, 824–828.
2. Ahmad, S.; Dray, A. Curr. Opin. Investig. Drugs 2004, 5, 67–70.
3. Hellwig, V.; Mayer-Bartschmid, A.; Muller, H.; Greif, G.; Kleymann, G.;
Zitzmann, W.; Tichy, H. V.; Stadler, M. J. Nat. Prod. 2003, 66, 829–837.