Chemoenzymatic total synthesis of paecilocin A and 3-butyl-7- hydroxyphthalide

Article abstract of DOI:10.1016/j.tetlet.2013.12.089

A highly enantioselective total synthesis of paecilocin A and 3-butyl-7-hydroxyphthalide is described. The key steps involved in this synthesis are enzymatic kinetic resolution and Alder-Rickert reaction.

Full text of DOI:10.1016/j.tetlet.2013.12.089

Tetrahedron Letters 55 (2014) 1303–1305
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chemoenzymatic total synthesis of paecilocin
A and 3-butyl-7-hydroxyphthalide
b
c
c,
Ch. Sreelakshmi a,b, A. Bhaskar Rao a, , M. Lakshmi Narasu , P. Janardhan Reddy , B. V. Subba Reddy
⇑
⇑
a Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Institute of Science & Technology, Jawaharlal Nehru Technological University, Hyderabad 500 085, India
c Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, 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:
A highly enantioselective total synthesis of paecilocin A and 3-butyl-7-hydroxyphthalide is described.
The key steps involved in this synthesis are enzymatic kinetic resolution and Alder–Rickert reaction.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 21 October 2013
Revised 23 December 2013
Accepted 25 December 2013
Available online 3 January 2014
Keywords:
Paecilocin A
3-Butyl-7-hydroxyphthalide
Enzymatic kinetic resolution
Alder–Rickert reaction
The new polyketide, paecilocin A (1) was isolated along with
the other three new polyketides 3,4,5 (Fig. 1) from the fungus Pae-
cilomyces variotii, which was derived from the jellyfish Nemopilema
nomurai.1 Compounds 1, 3 and 4 are found to exhibit a promising
inhibitory activity against pathogenic bacteria including methicil-
lin-resistant Staphylococcus aureus 3089 (MRSA) and multi-drug-
resistant (MDR) Vibrio parahaemolyticus 7001. The structure of 1
is almost identical to 3-butyl-7-hydroxyphthalide 2 (Fig. 1), which
was isolated previously from a culture broth of Penicillium vulpi-
num.2 The relative configuration of 3-butyl-7-hydroxyphthalide 2
was determined in 2003 by Ohzeki and Mori.3 To the best of our
knowledge, there are no reports on the synthesis of paecilocin A
(1). Furthermore, the lactones are known to show diverse biologi-
cal activities such as hormones, pheromones and antibiotics, there-
fore we were interested to take up the synthesis of these natural
products 1 and 2 in an elegant way using lipase mediated kinetic
resolution of the propargyl alcohol (to create the stereocenter of
the target molecule) and Alder–Rickert reaction (to construct the
functionalized aromatic precursor) as the key steps.
The key alkyne esters 7a and 7b were proposed to be obtained
from readily accessible aldehydes 9a and 9b via the formation of
chiral propargyl alcohols using a known literature procedure.4a
The synthesis of target molecules 1 and 2 began from the com-
mercially available aldehydes 9a and 9b respectively. Accordingly,
the propargyl alcohols 10a and 10b were easily prepared in 87% &
83% yield by the addition of monolithiumacetylide4b to aldehydes
9a and 9b respectively.
The enzymatic kinetic resolution of racemic propargylic alco-
hols 10a and 10b using Novozym-4355,6 in the presence of vinyl
OH
OH
OMe
O
O
O
( )5
( )n
MeO
n = 5, Paecilocin A (1)
n = 1, (-)-Butyl-7-hydroxy-
phthalide (2)
1S = Paecilocin B (3)
1R = Paecilocin C (4)
The retrosynthetic analysis of target molecules 1 and 2 is de-
picted in Scheme 1. The synthesis of target molecules was pro-
posed to be accomplished from the aromatic moieties 6a and 6b
which in turn could be prepared via the Alder–Rickert reaction be-
OH
OH
O
tween 1,4-cyclohexadiene
respectively.
8 and alkyne esters 7a and 7b
Paecilocin D (5)
⇑
Corresponding authors.
E-mail address: basireddy@iict.res.in (B.V.S. Reddy).
Figure 1. Naturally occurring paecilocins (A–D) and (ꢀ)-butyl-7-hydroxyphthalide
(2).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.089

1304
Ch. Sreelakshmi et al. / Tetrahedron Letters 55 (2014) 1303–1305
OMe O
OTBS
, n = 5
OH
OMe
O
OMe O
( )n
OMe
( )n
OTBS
MeO
OMe
( )n
a
O
+
O
( )n
7a
OTBS
6a, n = 5
8
7b, n = 1
n = 5, Paecilocin A (1)
n = 1, (-)-Butyl-7-hydroxy-
phthalide (2)
6b,
n = 1
6a
, n = 5; 60%
6b,
n = 1; 62%
OMe
OTBS
, n = 5
OMe
O
O
OH
O
( )n
MeO
+
b
( )n
c
H
O
O
9a
, n = 5
9b, n = 1
O
7a
8
( )n
7b, n = 1
( )n
14a, n = 5; 78%
14b, n = 1; 74%
Scheme 1. Retrosynthetic analysis of paecilocin A (1) and (ꢀ)-butyl-7-hydroxyph-
thalide (2).
n = 5, Paecilocin A (1); 80%
n = 1, Butyl-7-hydroxy-
phthalide (2); 78%
acetate in tert-butyl methyl ether afforded the (S)-acetates 12a and
12b (97% & 95 ee) in 46% and 43% yields, respectively. Deacetyla-
tion of 12a and 12b was achieved by treatment with NaOMe to
furnish 11a and 11b in 93% and 90% yields, respectively. Protection
of secondary alcohols 11a and 11b with TBSCl in the presence of
imidazole and a cat. DMAP in CH2Cl2 gave the TBS ethers 13a
and 13b in 89% and 87% yields respectively. Treatment of alkynes
13a and 13b with n-BuLi followed by addition of methyl chlorofor-
mate gave the acetylenic esters 7a and 7b in 79% and 76% yields
respectively (Scheme 2).7
With acetylenic esters 7a and 7b and 1-methoxycyclohexa-1,4-
diene8 8 in hand, we attempted the critical Alder–Rickert reaction
to construct the functionalized aromatic moiety of the target mol-
ecules. Accordingly, the Alder–Rickert reaction was performed in a
sealed tube at 180 °C with a catalytic amount of N,N-dimethylani-
line to produce the aromatic cores 6a and 6b in 60% & 62% yields
respectively.9 Deprotection of TBS groups from compounds 6a
Scheme 3. Reagents and conditions: (a) N,N-dimethylaniline (cat.), sealed tube,
180 °C, 48 h; (b) TBAF, THF, 0 °C to rt, 3 h; (c) BCl3, CH2Cl2, ꢀ78 °C to rt.
and 6b with TBAF in anhydrous THF gave the phthalates 14a and
14b in 78% and 74% yields respectively.10 Demethylation of meth-
oxyl groups from 14a and 14b using boron trichloride in dichloro-
methane at ꢀ78 °C afforded the target molecule 1 in 80% yield. The
optical rotation and spectral data of the synthetic compound 111
are in agreement with the data reported for the natural product
(Scheme 3).1
Similarly, (ꢀ)-butyl-7-hydroxyphthalide (2) was synthesized
from the commercially available pentanal 9b following the above
sequence of reactions. The analytical data of the (ꢀ)-butyl-
7-hydroxyphthalide 211 were indistinguishable with the data
reported in the literature.2,3
In summary, we have successfully demonstrated the enantiose-
lective total synthesis of paecilocin A and (ꢀ)-butyl-7-hydroxyph-
thalide using lipase mediated kinetic resolution of propargyl
alcohol and Alder–Rickert reaction.
OH
O
a
( )n
( )n
H
Acknowledgments
10a
, n = 5; 87%
9a
9b, n = 1
, n = 5
10b, n = 1; 83%
Ch.S.L. thanks CSIR, New Delhi, India for financial support in the
form of a fellowship. B.V.S. and A.B.R. thanks CSIR, New Delhi for
financial support as a part of XII five year plan program under title
ORIGIN (CSC-0108).
OH
OAc
b
( )n
+
( )n
References and notes
11a
12a
, n = 5; 46%
(R)-
, n = 5; 42%
(R)-11b, n = 1; 40%
12b, n = 1; 43%
1. Liu, J.; Li, F.; Kim, E. L.; Li, J. L.; Hong, J.; Bae, K. Y.; Chung, H. Y.; Kim, H. K.; Jung,
J. H. J. Nat. Prod. 1826, 2011, 74.
2. Makino, M.; Endoh, T.; Ogawa, Y.; Watanabe, K.; Fujimoto, Y. Heterocycles 1998,
48, 1931.
3. Ohzeki, T.; Mori, K. Biosci. Biotechnol. Biochem. 2007, 10, 2240.
4. (a) Duffault, J. M.; Einhorn, J.; Alexakis, A. Tetrahedron Lett. 1995, 36, 2765; (b)
Midland, M. M. J. Org. Chem. 1975, 40, 2250.
5. For lipase-catalyzed resolution of racemic propargylic alcohols, see: (a) Ohtani,
T.; Kikuchi, K.; Kamezawa, M.; Hamatani, H.; Tachibana, H.; Totani, T.;
OH
OAc
c
d
( )n
( )n
(S)-11a, n = 5; 93%
11b
12a, n = 5
(S)-
, n = 1; 90%
12b
, n = 1
Naoshima, Y. J. Chem. Soc., Perkin Trans.
1 1996, 961; (b) Ohtani, T.;
OTBS
Nakatsukasa, H.; Kamezawa, M.; Tachibana, H.; Naoshima, Y. J. Mol. Catal. B.:
Enzym. 1998, 4, 53; (c) Morishita, K.; Kamezawa, M.; Ohtani, T.; Tachibana, H.;
Kawase, M.; Kishimoto, M.; Naoshima, Y. J. Chem. Soc., Perkin Trans. 1 1999, 513.
6. Raminelli, C.; Comasseto, J. V.; Andrade, L. H.; Porto, A. L. M. Tetrahedron:
Asymmetry 2004, 15, 3117.
OTBS
e
( )n
( )n
MeO
O
13a
13b
, n = 5; 89%
, n = 1; 87%
7a
, n = 5; 79%
7b, n = 1; 76%
7. Yadav, J. S.; Sreenivas, M.; Reddy, A. S.; Reddy, B. V. S. J. Org. Chem. 2010, 75,
8307.
8. The compound was prepared from anisole as given in Vogel’s Text Book of
Practical Organic Chemistry, 5th ed.; 1989; p 1117.
9. (a) Birch, A. J.; Dastur, K. P. Tetrahedron Lett. 1972, 13, 4195; (b) Birch, A. J.;
Dastur, K. P. J. Chem. Soc., Perkin Trans. 1 1973, 1650; (c) Kanakam, C. C.; Mani,
N. S.; Subba Rao, G. S. R. J. Chem. Soc., Perkin Trans. 1 1990, 2233.
Scheme 2. Reagents and conditions: (a) Lithium acetylide–ethylenediamine com-
plex, DMSO, rt; (b) Novozym-435, vinyl acetate, MTBE, rt; (c) NaOMe, MeOH, 0 °C,
1 h; (d) TBSCl, DMAP, imidazole, CH2Cl2, 0 °C to rt, 3 h; (e) ClCO2Me, n-BuLi, THF,
ꢀ78 °C, 1 h.

Ch. Sreelakshmi et al. / Tetrahedron Letters 55 (2014) 1303–1305
1305
10. Dean, F. M.; Goodchild, J.; Houghton, L. E.; Martin, J. A.; Morton, R. B.; Parton,
B.; Price, A. W.; Somvichien, N. Tetrahedron Lett. 1966, 35, 4153.
11. Spectral data for selected compounds:
155.5, 144.9, 132.4, 130.2, 118.6, 109.0, 71.9, 55.8, 52.0, 40.5, 31.8, 29.4, 29.3,
29.2, 25.8, 22.6, 18.1, 14.0, ꢀ4.8, ꢀ5.2; IR (KBr): mmax 2929, 2856, 1735, 1586,
1468, 1435, 1265, 1108, 1069, 835, 776 cmꢀ1; ESI-MS: m/z 445 [M+Na].
(S)-Methyl 2-(1-((tert-butyldimethylsilyl) oxy)pentyl)-6-methoxybenzoate
(6b):
Paecilocin A (1): ½a D25
ꢁ
ꢀ9.4 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d 8.01–
7.67 (br s, 1H), 7.54 (t, 1H, J = 7.9 Hz), 6.92 (d, 1H, J = 7.9 Hz), 6.90 (d, 1H,
J = 7.9 Hz), 5.49 (dd, 1H, J = 7.7, 4.1 Hz), 2.09–1.94 (m, 1H), 1.86–1.70 (m, 1H),
1.58–1.41 (m, 1H), 1.40–1.16 (m, 11H), 0.88 (t, 3H, J = 6.7 Hz); 13C NMR (CDCl3,
75 MHz): d 172.1, 156.4, 150.3, 136.7, 115.2, 113.0, 111.1, 82.9, 34.5, 31.7, 29.6,
29.2, 29.1, 24.7, 22.5, 14.0; IR (KBr): mmax 3430, 2923, 2853, 1742, 1462, 1191,
1079, 967 cmꢀ1; ESI-MS: m/z 263 [M+H].
½ ꢁ
a 3D1 +10.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d 7.32 (t, 1H, J = 7.9 Hz),
7.13 (d, 1H, J = 7.6 Hz), 6.78 (d, 1H, J = 8.2 Hz), 4.60 (t, 1H, J = 6.1 Hz), 3.89 (s,
3H), 3.82 (s, 3H), 1.65–1.54 (m, 2H), 1.32–1.17 (m, 4H), 0.93–0.81 (m, 12H),
0.01 (s, 3H), ꢀ0.16 (s, 3H); 13C NMR (CDCl3, 75 MHz): d 168.4, 155.5, 144.9,
132.4, 130.2, 118.6, 109.0, 71.9, 55.8, 52.0, 40.5, 31.8, 29.4, 29.3, 29.2, 25.8,
(ꢀ)-Butyl-7-hydroxyphthalide (2): ½a D25
ꢁ
ꢀ49.7 (c 1.2, CHCl3); 1H NMR (CDCl3,
22.6, 18.1, 14.0, ꢀ4.8, ꢀ5.2; IR (KBr):
1435, 1376, 1265, 1110, 1066, 938, 837, 776 cmꢀ1; ESI-MS: m/z 367 [M+H].
(S)-Undec-1-yn-3-ol (11a):
+12.6 (c 1.0, CHCl3); 1H NMR (CDCl3,
mmax 2954, 2931, 2857, 1734, 1586, 1468,
600 MHz): d 8.01–7.67 (br s, 1H), 7.54 (t, 1H, J = 7.9 Hz), 6.92 (d, 1H, J = 7.9 Hz),
6.90 (d, 1H, J = 7.9 Hz), 5.49 (dd, 1H, J = 7.7, 4.1 Hz), 2.09–1.94 (m, 1H), 1.86–
½ ꢁ
a 3D1
1.70 (m, 1H), 1.58–1.41 (m, 1H), 1.40–1.16 (m, 11H), 0.88 (t, 3H, J = 6.7 Hz); 13
C
300 MHz): d 4.40–4.34 (m, 1H), 2.46 (d, 1H, J = 2.1 Hz), 1.93–1.86 (br s, 1H),
1.76–1.67 (m, 2H), 1.52–1.41 (m, 2H), 1.39–1.21(m, 10H), 0.88 (t, 3H,
J = 7.0 Hz); 13C NMR (CDCl3, 75 MHz): d 85.0, 72.7, 62.2, 37.6, 31.8, 29.4, 24.9,
NMR (CDCl3, 75 MHz): d 172.1, 156.4, 150.3, 136.7, 115.2, 113.0, 111.1, 82.9,
34.2, 26.7, 22.3, 13.8; IR (KBr): mmax 3427, 2924, 2854, 1742, 1627, 1462, 1375,
1193, 1078, 769 cmꢀ1; ESI-MS: m/z 215 [M+H].
22.6, 14.0; IR (KBr): m
max 3311, 2925, 2855, 1462, 1028, 653, 627 cmꢀ1; EI-MS:
(S)-Methyl 2-(1-((tert-butyldimethylsilyl) oxy)nonyl)-6-methoxybenzoate
(6a):
m/z 191 [M+Na].
(S)-Hept-1-yn-3-ol (11b):
½
a 3D1
ꢁ
ꢀ20.0 (c 0.5, CHCl3); 1H NMR (CDCl3,
½
a 2D0
ꢁ
+12.3 (c 0.7, CHCl3); 1H NMR (CDCl3, 300 MHz): d 7.32 (dd, 1H, J = 8.1,
300 MHz): d 4.07 (dd, 1H, J = 11.2, 4.7 Hz), 2.32 (d, 1H, J = 1.6 Hz), 1.67–1.63
7.9 Hz), 7.13 (d, 1H, J = 7.9 Hz), 6.78 (d, 1H, J = 8.1 Hz), 4.60 (dd, 1H, J = 6.2,
6.0 Hz), 3.90 (s, 3H), 3.82 (s, 3H), 1.65–1.54 (m, 2H), 1.32–1.17 (m, 12H), 0.93–
0.81 (m, 12H), 0.01 (s, 3H), ꢀ0.16 (s, 3H); 13C NMR (CDCl3, 75 MHz): d 168.4,
(br s, 1H), 1.53–1.19 (m, 6H), 0.92 (t, 3H, J = 7.0 Hz); 13C NMR (CDCl3, 75 MHz):
d 73.7, 72.0, 64.9, 42.7, 27.0, 22.6, 14.0; IR (KBr):
mmax 3448, 2957, 2928, 2865,
1713, 1650, 1461, 1377, 1122, 767 cmꢀ1; EI-MS: m/z 113 [M+H].