First enantioselective total synthesis of penicimarin B, aspergillumarins A and B

Article abstract of DOI:10.1016/j.tetlet.2014.03.067

A convergent enantioselective synthesis of penicimarin B, aspergillumarin A and B has been reported using Brown's allylation, DeBrabander-Bhattacharjee lactonization and Grubbs cross coupling metathesis. During this synthesis we have standardized the conditions for DeBrabande-Bhattacharjee lactonization to obtain excellent yield (>90%).

Full text of DOI:10.1016/j.tetlet.2014.03.067

Tetrahedron Letters 55 (2014) 2921–2923
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First enantioselective total synthesis of penicimarin B,
aspergillumarins A and B
⇑
Jhillu Singh Yadav , Anand Kumar Mishra, Soma Shekar Dachavaram, S. Ganesh Kumar, Saibal Das
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convergent enantioselective synthesis of penicimarin B, aspergillumarin A and B has been reported
using Brown’s allylation, DeBrabander–Bhattacharjee lactonization and Grubbs cross coupling metathe-
sis. During this synthesis we have standardized the conditions for DeBrabande–Bhattacharjee lactoniza-
tion to obtain excellent yield (>90%).
Received 29 January 2014
Revised 12 March 2014
Accepted 13 March 2014
Available online 20 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Penicimarin
Aspergillumarin
Brown’s allylation
Grubbs catalyst
Natural products
In 2012, Li et al. reported two new dihydroisocoumarin
derivatives, aspergillumarin A and aspergillumarin B (Fig. 1). Those
were isolated from the culture broth of a marine derived fungus
Aspergilus sp., which was isolated from the fresh leaves of man-
grove tree Bruguiera gymnorrhiza collected from the South China
sea.1 Li et al. elucidated the structure of those isolated compounds
and the absolute configuration at C3 as R was assigned, unfortu-
nately they could not assign the configuration of the hydroxyl
group at C40 of aspergillumarin B. Later on in 2013, Wang and
co-workers extracted a sponge-derived fungus, Penicillium sp.
MWZ14-4, to lead the isolation of the aspergillumarins A and B
along with 12 other new compounds.2 Spectral data suggested that
one compound (compound 2, Fig. 1) was closely similar to asperg-
illumarin B (1), with the main differences being the additional
methoxy signal (dH 3.93, s) and the absence of a chelated hydroxyl
signal (dH 11.01, s) in 1H NMR spectra. With the help of HMBC cor-
relation and modified Mosher’s ester studies, Wang and co-work-
ers suggested the absolute configuration of 2 as 3R, 40S. They also
assign the absolute configuration for aspergillumarin B as 3R, 40S.
Aspergillumarins A and B show moderate antibacterial activi-
ties against seven terrestrial pathogenic bacteria namely Esche-
richia coli, Staphylococcus aureus, Staphylococcus albus, Bacillus
subtilis, Bacillus cereus, Micrococcus tetragenus, Kocuria rhizophila
and two other marine pathogenic bacteria, Vibrio parahemolyticus
and Vibrio anguillarum.2
OH
O
OH
O
O
OH
O
O
1
3
OR
O
1
OH
9
O
1
9
O
3
OH
7
O
O
O
3
O
7
OH
O
1`
3`
5`
1`
3`
5`
O
OH
10
O
10
(1) R= H, Aspergillumarin B
(2) R= Me, Penicimarin B
(3) R= H, Aspergillumarin A
2
4
OH
O
Figure 1. Structure of penicimarin B and aspergillumarins.
OH
OH
5
⇑
Corresponding author. Tel.: +91 40 2719 3737; fax: +91 40 2716 0512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
Scheme 1. Retrosynthetic analysis.
http://dx.doi.org/10.1016/j.tetlet.2014.03.067
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2922
J. S. Yadav et al. / Tetrahedron Letters 55 (2014) 2921–2923
O
O
O
O
O
OH
O
O
c
O
b
a
OH
OTf
OH
OH
6
9
7
5
Scheme 4. Reagents and conditions: (a) 13 (2 equiv), Grubbs-II, CH2Cl2, reflux, 3 h,
87%; (b) Pd/C, H2, EtOAC, rt, 12 h, 90%; (c) Dess–Martin periodinane, CH2Cl2, 2 h,
0 °C to rt, quant.
O
O
O
O
O
d, e
O
f
O
O
OH
O
O
O
10
8
O
O
b
a
O
O
OBn
4
OH
O
g
O
15
16
c
2
4
Scheme 5. Reagents and conditions: (a) K2CO3, MeI, DMF, 0 °C to rt, 5 h, 90%; (b) 13
(2 equiv), Grubbs-II, CH2Cl2, reflux, 3 h, 94%; (c) Pd/C, H2, EtOAC, rt, 12 h, 90%.
Scheme 2. Reagents and conditions: (a) Acetone, DMAP, SOCl2, DME, 0 °C to rt,
23 h, 96%; (b) Pyridine, Tf2O, CH2Cl2, 1 h, 0 °C, 98%; (c) Pd(PPh3)4, LiCl, allyltribu-
tyltin, THF, reflux, 48 h, 99%; (d) NMO, OsO4, Acetone:H2O (3:1), rt, 4 h, 98%; (e)
NaIO4, NaHCO3, THF:H2O (2:1), 0 °C to rt, 92%; (f) (+)Ipc2B-allyl, ether, 2 h, ꢀ100 °C,
68%; (g) NaH, THF, DMF, 2 h, ꢀ20 °C, 92%.
The next significant step in the synthesis of the aspergilluma-
rins B and A, was the coupling of two olefins 4 and 13. Cross
coupling of these olefins (1 equiv of 4 and 2 equiv of 13) with the
use of 10 mol % of Grubbs 2nd generation catalyst yielded 85% of
compound 14.7 Finally, hydrogenation of olefin with 10% Pd/C gave
natural product aspergillumarin B (1) in 90% yield8 and further
oxidation of 1 with Dess–Martin periodinane produced another
natural product 3 in quantitative yield2 (Scheme 4). Spectral data
(1H NMR and 13C NMR) of synthesized compounds 19 and 310 were
found to be in good agreement with the reported data of the
natural products.1,2 The optical rotation values of synthesized com-
A retrosynthetic analysis of 1, 2 and 3 is shown in (Scheme 1),
we envisioned construction of the target molecules from a com-
mon key intermediate 4, which could be achieved from 2,6-dihy-
droxybenzoic acid by employing a simple reaction sequence
engaging Stille coupling and Brown’s Ipc2Blallylation.
Our synthesis commenced with the construction of the benzo-
lactone moiety 6 (Scheme 2). Next, the phenolic compound 6
was treated with TfO2 in pyridine to produce the corresponding
the triflate compound 7, which allowed to react in a Stille3 fashion
with allyl stannane in the presence of catalytic [Pd(PPh3)4] and LiCl
under reflux in THF to afford terminal olefin 8 in 99% yield. Dihydr-
oxylation of 8 with N-methylmorpholine (NMO) and OsO4 followed
by oxidative cleavage with NaIO4 gave aldehyde 9 in 90% yield in
32
32
pound 1 are ([
a]
ꢀ24.5 (c 1, CHCl3), [
a
]
ꢀ26 (c 0.21, CHCl3)
D
D
32
20
[lit. [
a]
ꢀ18.6 (c 0.20, CHCl3)])1 and 3 ([
a]
ꢀ32 (c 1, CHCl3),
D
D
32
20
[a]
ꢀ30 (c 0.27, CHCl3) [lit. [
a]
ꢀ10.3 (c 0.27, CHCl3)]).1
D
D
After the success in the syntheses of 1 and 3, we turned our
attention towards the synthesis of penicimarin B (2). The key inter-
mediate compound 4 was methylated with MeI and NaH to have
compound 15 in 90% yield (Scheme 5). Cross coupling between
compound 15 (1 equiv) and the olefin 13 (2 equiv) by using
10 mol % of Grubbs 2nd generation catalyst furnished exclusively
the E-olefin 16 in 94% yield which is quite remarkable.7 Trans ole-
fin was confirmed by 1H NMR where a common coupling constant
J = 15.56 Hz for both olefinic protons at dH 5.53–5.60, m, 1H and dH
5.70–5.79, m, 1H was observed. It is worthwhile to mention that
compound 16 can also be achieved from 14 by simple methylation
of the aromatic hydroxyl group in good yield (see Ref. 11). Now
two steps.4 Chiral allylation of aldehyde 9 with Brown’s Ipc2Bl-allyl
32
at ꢀ100 °C furnished compound 10 in 68% yield3 [
a
]
D ꢀ41 (c 0.8,
acetone) [lit. [
a]
ꢀ40 (c 0.79, acetone)].3 With homoallyl 10 in
D
hand our next task was to make the common key intermediate
dihydroisocoumarine derivative lactone 4. Expected lactonization
is reported to be achieved using NaH by Bhattacharjee and Braban-
der in their synthesis of Apicularen A5 and was used later by oth-
ers.3,6 Unfortunately, in our moiety the yield was limited to <30%
under such condition. Then by altering a few of its parameters,
better results were obtained where it was found that 1.5 equiv of
NaH in THF and DMF (1:1 ratio) at ꢀ20 °C resulted in the desired
lactone 4 in 92% yield.
hydrogenation of 16 with 10% Pd/C gave penicimarin B12 (2) in
30
90% yield. Spectral data (1H and 13C) and specific rotation [
a]
D
After the construction of lactone 4, we gave our attention
towards the creation of the side chain which contained one chiral
32
ꢀ66.0 (c 0.45, CHCl3) [lit. [
a
]
ꢀ69 (c 0.5, CHCl3)]2 values were
D
found in agreement with the literature values.2
hydroxyl centre.
L
-ethyl lactate was selected as a starting material
-lactate
In conclusion, we believe that this reaction sequence is short to
complete an enantioselective total synthesis of the natural prod-
ucts such as Penicimarin B (overall yield 41%, in 10 steps), asperg-
illumarin B (overall yield 42%, in 9 steps) and aspergillumarin A
(overall yield 42%, in 10 steps). Side chain 13 was constructed in
3 steps with 62% overall yield. The synthesis involves direct and
straight forward reaction conditions such as Brown’s allylation,
Stille coupling and Grubbs cross coupling metathesis, which makes
this synthetic route simple and convenient.
to obtain the side chain, first hydroxyl group of (ꢀ)-ethyl-
L
11 was protected with benzyl ether protection using NaH and
benzyl bromide to obtain compound 12 in 95% yield, which was
then treated with DIBAL-H at ꢀ78 °C followed by one carbon
Wittig reaction to furnish compound 13 in 65% yield7 (for 2 steps,
Scheme 3).
OH
OBn
OBn
a
b, c
O
O
Acknowledgments
O
O
11
12
13
A.K.M. and D.S.S. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi for fellowships. G.K.S. thanks UGC for
fellowship. The authors also thank the Council of Scientific and
Industrial Research (CSIR)-New Delhi for financial support under
Scheme 3. Reagents and conditions: (a) NaH, BnBr, cat., TBAI, THF, 0 °C to rt, 3 h,
95%; (b) DIBAL-H, CH2Cl2, ꢀ78 °C, 0.5 h; (c) CH3IPPh3, t-KBuO, THF, 0 °C to rt, 3 h,
65% for two steps.

J. S. Yadav et al. / Tetrahedron Letters 55 (2014) 2921–2923
2923
(m, 1H), 2.88–2.99 (m, 2H), 1.83–1.98 (m, 2H, 1 proton from OH group) 1.68–
1.79 (m, 1H), 1.56–1.65 (m, 2H), 1.45–1.55 (m, 2H), 1.19–1.23 (m, 3H); 13C
NMR (125 MHz, CDCl3): d 169.9, 162.0, 139.4, 136.1, 117.9, 116.1, 108.4, 79.6,
67.8, 38.7, 34.7, 32.8, 23.6, 21.1; MS (ESI) (m/z): 251 [M+H]+, 273 [M+Na]+;
HRMS-ESI: Calcd for C14H18NaO4: 273.1097, found 273.1119 [M+Na]+.
ORIGIN programme (12th five year plan), J.C. Bose and CSIR
Bhatnagar Fellowship.
Supplementary data
32
32
20
10. Aspergillumarin A: [
a
]
D ꢀ32 (c 1, CHCl3), [
a
]
D ꢀ30 (c 0.27, CHCl3, [lit. [a]
D
ꢀ10.3 (c 0.27, CHCl3)].1; IR (KBr): 3447, 2922, 2853, 1713, 1673, 1618, 1462,
1232, 1163, 1115, 807, 747, 698 cmꢀ1 1H NMR (500 MHz, CDCl3): d 10.98 (s,
;
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
03.067.
1H), 7.38–7.42 (m, 1H), 6.88 (d, J = 8.39 Hz, 1H), 6.68 (d, J = 7.32 Hz, 1H), 4.53–
4.60 (m, 1H), 2.88–2.98 (m, 2H), 2.53 (t, J = 6.71 Hz, 2H), 2.16 (s, 3H), 1.72–1.89
(m, 4H); 13C NMR (125 MHz, CDCl3): d 208.2, 169.7, 162.1, 139.2, 136.1, 117.9,
116.2, 108.3, 79.4, 42.8, 33.9, 32.7, 29.9, 18.9; MS (ESI) (m/z): 249 [M+H]+, 271
[M+Na]+; HRMS-ESI: Calcd for C14H16O4: 249.1121, found 249.1132 [M+H]+.
References and notes
11.
OH
O
K2CO3, MeI,
DMF, 00C
O
O
1. Li, S.; Wei, M.; Chen, G.; Lin, Y. Chem. Nat. Compd. 2012, 48, 371–373.
2. Qi, J.; Shao, C. L.; Li, Z. Y.; Gan, L. S.; Fu, X. M.; Bian, W. T.; Zhao, H. Y.; Wang, C. Y.
J. Nat. Prod. 2013, 76, 571–579.
O
OBn
to r.t, 5h, 90%.
O
OBn
3. Nicolaou, K. C.; Kim, D. W.; Baati, R.; O‘Brate, A.; Giannakakou, P. Chem. Eur. J.
2003, 9, 6177–6191.
4. Chakraborty, T. K.; Chattopadhyay, A. M. J. Org. Chem. 2008, 73, 3578–3581.
5. Brabander, K. D.; Bhattacharjee, A. Tetrahedron Lett. 2000, 41, 8069–8073.
6. Trotter, T. N.; Albury, M. M. A.; Jennings, M. P. J. Org. Chem. 2012, 77, 7688.
7. Reddy, G. V.; Kumar, R. S. C.; Sreedhar, E.; Babu, K. S.; Rao, J. M. Tetrahedron Lett.
2010, 51, 1723–1726.
32
32
12. Penicimarin B: [
a
]
ꢀ66 (c 0.45, CHCl3, [lit. [
a
]
ꢀ69 (c 0.5, CHCl3)]2); IR
D
D
(KBr): 3443, 2924, 2853, 1715, 1593, 1472, 1275, 1243, 1087, 802 cmꢀ1 1H
;
NMR (500 MHz, CDCl3): d 7.44 (dd, J = 8.39, 7.62 Hz, 1H), 6.91 (d, J = 8.54 Hz,
1H), 6.80 (d, J = 7.47 Hz, 1H), 4.36–4.42 (m, 1H), 3.94 (s, 3H), 3.79–3.86 (m, 1H),
2.92 (dd, J = 15.86, 11.14 Hz, 1H), 2.82–2.87 (m, 1H), 1.82–1.92 (m, 1H), 1.54–
1.74 (m, 3H), 1.44–1.53 (m, 2H), 1.21 (d, J = 6.10, 3H); 13C NMR (125 MHz,
CDCl3): d 162.7, 161.1, 141.9, 134.4, 119.2, 113.9, 110.9, 77.7, 67.9, 56.2, 38.9,
34.7, 34.4, 23.6, 21.3; MS (ESI) (m/z): 247 [M+H–H2O]+, 287 [M+Na]+; HRMS-
ESI: Calcd for C15H21O4: 265.1434, found 265.1453 [M+H]+.
8. Das, S.; Mishra, A. K.; Kumar, A.; Ghamdi, A. A. K. A.; Yadav, J. S. Carbohydr. Res.
2012, 358, 7–11.
32
32
20
9. Aspergillumarin B: [
a
]
D ꢀ24.5 (c 1, CHCl3), [
a
]
D ꢀ26 (c 0.21, CHCl3 [lit. [a]
D
ꢀ18.6 (c 0.20, CHCl3)].1; IR (KBr): 3402, 2925, 2857, 1671, 1618, 1462, 1233,
1112, 808, 739 cmꢀ1 1H NMR (500 MHz, CDCl3): d 11.0 (s, 1H), 7.37–7.42 (m,
;
1H), 6.87 (d, J = 8.39 Hz, 1H), 6.67–6.70 (m, 1H), 4.54–4.60 (m, 1H), 3.80–3.87