Total synthesis of two γ-butyrolactone containing compounds (Z,11S)-3,4-trans-11-hydroxy-3-methyldodec-cis-6-en-4-olide and (Z)-3,4-trans-11-oxo-3-methyldodec-cis-6-en-4-olide

Article abstract of DOI:10.1016/j.tetlet.2014.09.021

The first total synthesis of (Z,11S)-3,4-trans-11-hydroxy-3-methyldodec-cis-6-en-4-olide and (Z)-3,4-trans-11-oxo-3-methyldodec-cis-6-en-4-olide was accomplished using Jacobsen hydrolytic kinetic resolution, Ohira-Bestmann reaction, regioselective alkyne

Full text of DOI:10.1016/j.tetlet.2014.09.021

Tetrahedron Letters 55 (2014) 5976–5978
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of two c-butyrolactone containing compounds
(Z,11S)-3,4-trans-11-hydroxy-3-methyldodec-cis-6-en-4-olide
and (Z)-3,4-trans-11-oxo-3-methyldodec-cis-6-en-4-olide
⇑
Rajesh Nomula, Galla Raju, Palakodety Radha Krishna
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division, 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:
Received 8 July 2014
Revised 3 September 2014
Accepted 5 September 2014
Available online 16 September 2014
The first total synthesis of (Z,11S)-3,4-trans-11-hydroxy-3-methyldodec-cis-6-en-4-olide and
(Z)-3,4-trans-11-oxo-3-methyldodec-cis-6-en-4-olide was accomplished using Jacobsen hydrolytic
kinetic resolution, Ohira–Bestmann reaction, regioselective alkyne addition to terminal carbon atom of
epoxide, intramolecular TEMPO/BAIB mediated oxidative lactonization and partial hydrogenation as
the key steps.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
c
-Butyrolactones
Jacobsen’s kinetic resolution
Regioselective epoxide ring-opening
Lindlar’s catalyst
Total synthesis
The synthesis of substituted
siderable interest in the past few decades since
c
-butyrolactones generated con-
Scheme 2 depicts the synthesis of acetylenic fragment 10 and it
was accessed from the commercially available hex-5-en-1-ol.
Accordingly, when hex-5-en-1-ol was treated with p-anisyl alcohol
and Amberlyst-15 using reported procedure4 it gave the PMB-ether
c-butyrolactones
constitute an important structural motif in a number of bio-active
natural products.1 Very recently, Liu and co-workers isolated four
new 13-carbon
c
-lactone containing natural products from the cul-
5 (85%). Subsequently, m-CPBA epoxidation of compound 5
tures of the basidiomycetes family, Trichaptum pargamenum.2 The
mushroom T. pargamenum fungus is active against fungal, bacterial
and cancer diseases. The chemical structures of the four new buty-
rolactone target molecules (Fig. 1) are endowed with the same
followed by Jacobsen’s hydrolytic kinetic resolution5 using (R,R)-
(salen)CoIII-OAc catalyst A afforded chiral epoxide 66 (38% over
two steps). The spectral data and optical rotation of compound 6
3-methyl c-lactone moiety albeit connected by different Z-alkenyl
substituents at C4 of the ring. Inspired by these interesting struc-
tural features and attractive bio-activity profile herein we describe
the first total synthesis of c-lactones 1 and 2.
6Z
6Z
O
O
O
O
4S
3R
4S
3R
1
2
OH
1
2
O
Retrosynthetic analysis (Scheme 1) suggests that compounds 1
and 2 could be obtained from the coupling of two fragments 10 and
13 to furnish the advanced intermediate 14 which on deprotection
followed by intramolecular oxidation/cyclization leads to the lac-
tone intermediate 16. Conventional transformations of 16 would
result in the target molecules, first to compound 1 and then to
compound 2. In turn, the acetylenic fragment 10 was synthesized
from commercially available hex-5-en-1-ol, while the epoxy frag-
ment 13 was synthesized from the known epoxy alcohol 113 by
employing a few chemical transformations.
11S
11
1
2
(6Z,11S)-3,4-trans-11-hydroxy-3-methyl
(6Z,11S)-3,4-trans-11-oxo-3-methyl
dodec-cis-6-en-4-olide (lit.)2
dodec-cis-6-en-4-olide (lit.)2
(Z)-3,4-trans-11-oxo-3-methyl
(Z,11S)-3,4-trans-11-hydroxy-3-methyl
dodec-cis-6-en-4-olide (revised)14
dodec-cis-6-en-4-olide (revised)14
O
O
O
O
OH
O
(Z,11S)-3,4-Trans -9-hydroxy-3-methyl
dodec-cis-6-en-4-olide (
(Z)-3,4-Trans-9-oxo-3-methyl
dodec-cis-6-en-4-olide (4)
3
)
⇑
Corresponding author. Tel.: +91 40 27193518; fax: +91 40 27160387.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
Figure 1. Structures of c-butyrolactones.
http://dx.doi.org/10.1016/j.tetlet.2014.09.021
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

R. Nomula et al. / Tetrahedron Letters 55 (2014) 5976–5978
5977
OTBDPS
PMBO
OTBDPS
1 and 2
O
OH
16
O
14
OTBDPS
O
PMBO
PMBO
OH
OH
O
11
13
10
Scheme 1. Retrosynthesis of
c
-lactones 1 and 2.
OH
O
a
b
c
d
Hex-5-en-1-ol
OPMB
OPMB
OPMB
5
6
7
OTBDPS
OTBDPS
OTBDPS
e
f
OPMB
OH
8
10
9
O
O
P
OMe
OMe
N
N
Co
N
N
t-Bu
O
O
t-Bu
OAc
B
t-Bu
t-Bu
(R,R)-)-(salen)CoIII (OAc)
A
Scheme 2. Reagents and conditions: (a) p-anisyl alcohol, Amberlyst-15, CH2Cl2, reflux, 5 h, 85%; (b) (i) m-CPBA, CHCl3, 0 °C, 3 h, (ii) (R,R)-salen-CoIII(OAc)-A (0.5 mol %),
0.55 equiv H2O, 0 °C, 24 h, 38% (over two steps); (c) LAH, THF, 0 °C to rt, 3 h, 89%; (d) TBDPSCl, imidazole, CH2Cl2, 0 °C to rt, 2 h, 94%; (e) DDQ, CH2Cl2/H2O (19:1), 0 °C to rt, 1 h,
90%; (f) (i) (COCl)2, DMSO, Et3N, CH2Cl2, À78 °C, 1 h, (ii) B, K2CO3, MeOH, rt, 4 h, 80% (over two steps).
were in good agreement with reported values. (Optical rotation of
Next, regioselective addition of alkyne 10 (Scheme 4) to epoxide
13 under Yamaguchi conditions10 led to the advanced intermediate
14 (74%). Oxidative deprotection of p-methoxybenzyl ether 14
with DDQ resulted in 1,4 diol 15 (86%). Subsequently, the diol 15
was subjected to oxidative lactonization in the presence of
[bis(acetoxy)iodo]benzene/2,2,6,6-tetramethylpiperdin-1-oxyl11
to obtain 16 (81%). Partial hydrogenation of the alkyne functional-
25
25
synthetic 6 [
a
]
D
+3.8 (c 1.0, CHCl3) reported lit.6
[a]
+4.1 (c 1.0,
D
CHCl3).) Next, reductive epoxide ring-opening reaction with
hydride (LiAlH4/THF/0 °C to rt) furnished the secondary alcohol 7
(89%). Compound 7 on silylation (TBDPSCl/imidazole/CH2Cl2) gave
fully protected compound 8 (94%). Oxidative deprotection of
p-methoxybenzyl ether 8 with DDQ afforded primary alcohol 9
(90%). Finally oxidation of alcohol 9 under Swern conditions
followed by one carbon homologation reaction using Ohira–Best-
mann reagent B7 furnished the required acetylenic fragment 108
(80% over two steps).
Synthesis of the other coupling partner 13 was commenced
from known epoxy alcohol 113 (Scheme 3). Accordingly, epoxide
11 on treatment with Me3Al9 resulted in the corresponding 1,2-
diol (12) along with its regioisomer 1,3-diol (12a) in a 9:1 ratio
as an inseparable mixture (90% combined yield). Hence, the mix-
ture of isomeric diols was subjected to mono tosylation (TsCl/nBu2-
SnO/Et3N/CH2Cl2) followed by methanolysis (K2CO3/MeOH) to
afford the desired chiral epoxide 13 (73% over two steps after puri-
fication by chromatography).
ity in the
c
-lactone 16 using Lindlar’s catalyst12 (Pd/BaSO4-
-lactone 17 (88%). Finally, cleavage of the
quinoline) resulted in
c
silyl ether under TBAF conditions led to the natural product 1
(90%) which was subjected to Dess–Martin periodinane oxidation
to afford the natural product 2 (92%).
The structures of synthetic compounds 1 and 2 were confirmed
by comparing their spectral data2,13 (1H and 13C NMR) with the
reported values and found in good agreement (see SI). However,
25
the specific rotation of synthetic 1 observed as [
a
]
À28.0 (c 0.5,
D
25
MeOH) varied from the reported value of [
a
]
D
+36.5 (c 2.08,
MeOH).2 On the other hand, when the optical rotation of synthetic
25
2 was checked it was found to be: [
a]
+16.2 (c 0.25, MeOH)
+19.9 (c 0.23, MeOH). The
D
25
against the reported value of [
a]
D
PMBO
OH
OH
O
OH
OH
12
a
(major)
b
c
HO
OH
PMBO
OH
PMBO
O
11
13
PMBO
12a
(minor)
12:12a 9:1
Scheme 3. Reagents and conditions: (a) Ref. 3; (b) Me3Al, CH2Cl2, 0 °C, 3 h, 90% (combined yield); (c) (i) TsCl, nBu2SnO, Et3N, CH2Cl2, 0 °C to rt, 3 h, (ii) K2CO3, MeOH, 0 °C to rt,
5 h, 73% (over two steps).

5978
R. Nomula et al. / Tetrahedron Letters 55 (2014) 5976–5978
OTBDPS
OTBDPS
PMBO
a
b
PMBO
HO
OH
O
14
13
10
OTBDPS
OTBDPS
c
d
O
OH
16
O
15
O
O
O
O
O
O
e
OTBDPS
f
OH
O
17
1
2
Scheme 4. Reagents and conditions: (a) nBuLi, BF3ÁOEt2, THF, À78 °C, 3 h, 74%; (b) DDQ, CH2Cl2/H2O (19:1), 0 °C to rt, 1 h, 86%; (c) TEMPO, BAIB, CH2Cl2/H2O (1:1), 0 °C to rt,
5 h, 81%; (d) H2/Pd-BaSO4, quinoline, EtOAc, 8 h, 88%; (e) TBAF, THF, 0 °C to rt, 8 h, 90%; (f) DMP, CH2Cl2, 0 °C to rt, 1 h, 92%.
discrepancy in the sign of optical rotation for compound 1 may be
due to an error while assigning the absolute stereochemistry at
C11 of natural product, since all the asymmetric carbon atoms
(C3, C4 and C11) in synthetic compounds 1 and 2 were derived
from the known chiral precursors, whose chiral integrity and opti-
cal purity were unambiguously established in the literature earlier.
Consequently, synthetic 1 cannot be the enantiomer of the natural
product 1. Moreover oxidation of synthetic compound 1 led to
compound 2 whose spectral data (1H, 13C) and optical rotation
were in good agreement with the reported data.
In summary, we have accomplished the first total synthesis of
compounds 1 and 2 in 7.9% and 7.3% overall yields, respectively,
starting from hex-5-en-1-ol using Jacobsen’s kinetic resolution,
regioselective alkyne addition to terminal carbon atom of epoxide,
intramolecular TEMPO/BAIB mediated oxidative lactonization and
Lindlar’s hydrogenation as the key steps. Accordingly, compounds
1 and 2 are renamed as (Z,11S)-3,4-trans-11-hydroxy-3-methyldo-
dec-cis-6-en-4-olide and (Z)-3,4-trans-11-oxo-3-methyldodec-cis-
6-en-4-olide, respectively.14
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The authors (R.N. and G.R.) thank the CSIR, New Delhi for the
financial support in the form of fellowships. All the authors thank
CSIR, New Delhi for financial support as part of XII Five Year plan
program under title ORIGIN (CSC-0108).
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.
021.
13. For spectral and experimental data of selected compounds see Supporting
information.
14. The renaming of compounds 1 and 2 were made as suggested by reviewers.