Synthesis of (3R,5S)-5-hydroxy-de-O-methyllasiodiplodin: A facile and stereoselective approach

Article abstract of DOI:10.1016/j.tetlet.2015.04.005

A concise and facile synthesis of (3R,5S)-5-hydroxy-de-O-methyllasiodiplodin has been demonstrated in 12 steps starting from methylacetoacetate and (±)propylene oxide. The key reactions involved are Jacobsen's hydrolytic kinetic resolution, Sharpless asymmetric epoxidation, Mitsunobu, and ring closing metathesis reaction for the construction of macrolactone with two chiral substitutions on it.

Full text of DOI:10.1016/j.tetlet.2015.04.005

Accepted Manuscript
Synthesis of (3R,5S)-5-hydroxy-de-O-methyllasiodiplodin: a facile and stereo-
selective approach
Sheshurao Bujaranipalli, Saibal Das
PII:
S0040-4039(15)00619-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.04.005
TETL 46142
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
12 February 2015
31 March 2015
1 April 2015
Please cite this article as: Bujaranipalli, S., Das, S., Synthesis of (3R,5S)-5-hydroxy-de-O-methyllasiodiplodin: a
facile and stereoselective approach, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.04.005
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Synthesis of (3R,5S)-5-Hydroxy-de-O-
methyllasiodiplodin: A facile and stereoselective
approach
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Sheshurao Bujaranipalli, Saibal Das*

1
Tetrahedron Letters
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Synthesis of (3R,5S)-5-hydroxy-de-O-methyllasiodiplodin: A facile and
stereoselective approach
Sheshurao Bujaranipalli and Saibal Das*
Natural Products Chemistry Division, CSIR- Indian Institute of Chemical Technology, Tarnaka, Hyderabad – 500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A concise and facile synthesis of (3R,5S)-5-hydroxy-de-O-methyllasiodiplodin has been
demonstrated in 12 steps starting from methylacetoacetate and ( )propylene oxide. The key
reactions involved are Jacobsen’s hydrolytic kinetic resolution, Sharpless asymmetric
epoxidation, Mitsunobu and ring closing metathesis reaction for the construction of
macrolactone with two chiral substitutions on it.
Received in revised form
Accepted
Available online
Keywords:
Methyllasiodiplodin
Natural Product
Kinetic resolution
Asymmetric epoxidation
Mitsunobu reaction
Ring closing metathesis.
2015 Elsevier Ltd. All rights reserved.
Introduction
Numerous naturally occurring orsellinic acid type macrolides
such as radicicol,1 zearalenone,2 lasiodiplodin,3 resorcylide,4 etc.,
are well documented to possess a variety of interesting biological
properties.5 Among these lasiodiplodins are 12-membered
resorcyclic acid lactones that act in the inhibition of
prostaglandin biosynthesis,6 potent anti-leukemic activity,7
OH
O
O
HO
OH
cytotoxic,8
potent
nonsteroidal
antagonist
of
the
mineralocorticoid receptor (MR),9 anti-microbial activity,10
potato micro-tuber inducing activities, plant-gowth inhibitor3 and
also act as a Hill reaction inhibitor.11 Recently, this family of
compounds has been reported to exhibited significant
proliferation function, in vitro, of primary osteoblasts (OBs)12 as
well. In addition, (3R,5S)-5-hydroxy-de-O-methyllasipdiplodin8 1
(Figure 1) isolated from the fungus Syncephalastrum racemosum
(Syncephalastraceae) from the soil in tropical and subtropical
regions showed to have prominent cytotoxicity against
cholangiocarcinoma, KKU-M139, KKU-M156 and KKU-M213,
a panel of three human cancer cell lines with IC50 values in the
range of 14-19 µg/ml.
Figure 1. (3R,5S)-5-hydroxy-de-O-methyllasiodiplodin 1
Results and Discussion
The retro synthetic analysis reveals two key fragments: an
aliphatic side chain with free secondary hydroxyl motiety 4, and
aromatic acid 3 which can be coupled via Mitsunobu
esterification to give the intermediate 2 (Scheme 1).
In pursuit, towards the interest for lasiodiplodins synthesis
having wide range of biological profiles and our ongoing interest
in the total synthesis of biologically active natural products,13
herein, we report the stereoselective synthesis of 1 employing
hydrolytic kinetic resolution (HKR), Shapeless asymmetric
epoxidation, Mitsunobu reaction and a ring- closing metathesis
(RCM) as the key steps starting from a very common and
inexpensive starting materials, methyl acetoacetate and ( )
propylene oxide.
*Corresponding author. Phone : +91-40-2719-1887; Fax: +91-40-2716-
0512. E-mail: saibal@iict.res.in
Scheme 1. Retrosynthetic plan of compound 1

2
The intermediate 2 upon ring-closing metathesis followed by
one pot double bond reduction would provide the target molecule
1. The aromatic acid 3 and the chiral aliphatic fragment 4 could
be obtained easily from methylacetoacetate 5 and ( )-propylene
oxide 6 respectively by classical transformations.
epoxide ring of the iodo derivative with activated Zn in
refluxing MeOH18 afforded the desired secondary allylic alcohol
13 in 72% over two steps. Protection of the free secondary
hydroxyl group present in 13 was done with MOMCl (50% in
methyl acetate)19 and Hunig’s base furnished the protected
olefinic diol 14 in 89% yield, subsequent removal of the silyl
ether with TBAF afforded the awaited secondary alcohol 4 in
90% yield.
Having compound 4 in hand, the synthesis towards its
coupling to aromatic partner 3 was focused upon (Scheme 3).
Methyl acetoacetate 5 was transformed into desired Methyl
orsellinate 15 using modified Barrett’s protocol in 50% yield.20
Free phenolic groups present in 15 were protected as their methyl
ethers with dimethyl sulphate and K2CO3 to obtain 16 in 92%
yield. Lithiation of compound 16 at the benzylic position with
LDA at -78oC followed by reaction with homoallylbromide
afforded the desired compound 17 in 62% yield which was then,
saponified to furnish the desired acid 3 in 86% isolated yield.21
Scheme 2. Reagents and conditions: a) (S,S)–Salen Co(OAc)(X) (0.5
mol%), dist. H2O (0.55 equiv), 0oC, 14 h, 45% for 7, 43% for 7a; b)
vinyl magnesium bromide, CuI, THF, -20oC, 12 h, 87%; c)
TBDPSCl, Imidazole, CH2Cl2, 0oC- r.t., 12 h, 90%; d) (1) OsO4,
NMO, acetone: H2O (8:2), r.t., 3 h; (2) NaIO4, CH3CN:H2O (6:4), 30
min; (3) Ph3P=CHO2Et ,benzene, reflux, 3 h, 86% from three steps;
e) DIBAL-H, CH2Cl2, -20oC- r.t., 2 h, 91%; f) (-) DIPT, Ti(OiPr)4,
TBHP, -20oC, 12 h, 80%; g) (1)TPP, Imidazole, I2, THF, 0oC- r.t., 30
min; (2) Zn, MeOH, reflux, 3 h, 72% from two steps; h) MOMCl,
DIPEA, CH2Cl2, 0oC- r.t., 10 h, 89%; i) TBAF, THF, 0oC- r.t., 6 h,
90%.
The synthesis of aliphatic fragment 4 was started from
commercially available propylene oxide (Scheme 2) and racemic
propylene oxide 6 was resolved by using (S,S)–Salen-CoIIIOAc
catalyst (X, Figure 2) to give (S)-propylene oxide 714 which was
subjected to CuI mediated regioselective ring opening with vinyl
magnesium bromide to provide homoallyl alcohol 815 in 87%
yield. The hydroxyl group present in 8 was protected as its
TBDPS ether to obtain 9 in 90% yield. Then, 9 was subjected to
Upjohn dihydroxylation16 followed by oxidative cleavage using
NaIO4 to give the corresponding aldehyde, which was further
treated with (ethoxycarbonyl-methylene)triphenylphosphorane
for two carbon homologation in benzene under reflux conditions
to provide (E)-allyl ester 10. The E-geometry of the double bond
was confirmed by the coupling constant between the respective
olefin protons with (J = 15.7 Hz). Compound 10 was then treated
with DIBAL-H in DCM to furnish the allylic alcohol 11 in 91%
yield which was subjected to Sharpless asymmetric epoxidation
conditions [(-)-DIPT, Ti(OiPr)4, TBHP, -20oC)] to obtain an
epoxy alcohol 12 in 80% yield (99% de, HPLC)17.
Scheme 3. Reagents and conditions: a) NaH, n-BuLi, THF, 0oC to -
78oC to r.t., 12 h, reflux, 24 h, 50%; b) (CH3)2SO4, K2CO3, acetone,
reflux, 10 h, 92%; c) LDA, THF, homo allyl bromide, -78oC, 30 min,
62%; d) KOH, (MeOH:H2O, 1:1), reflux, 10 h, then 1N HCl, 86%.
Having both the key fragments 3 and 4 ready (Scheme 4), the
coupling was achieved using classical Mitsunobu conditions to
obtain the corresponding ester 2 in 61% yield.22 The low yield
may be attributed to the fact that ortho-phenol is protected. The
free hydroxyl group at ortho-position may form hydrogen
bonding with the acid there by increasing the acidity of the acid
which is known to accelerate the reaction.23
Scheme 4: Reagents and conditions: a) TPP, DIAD, THF, 0oC- r.t., 3
h, 61%; b) Grubb’s II generation catalyst (Y), CH2Cl2, reflux, 4 h,
88%; c) Pd/C, H2, 4 N HCl, MeOH, 6 h, 81%; d) AlI3, TBAI,
benzene, 10oC, 45 min, 70%.
Figure 2. (S,S) –Salen Co(III)(OAc) complex, X and Grubb’s II
catalyst, Y
Treatment of the ester with Grubbs II generation catalyst (10
mol %) under the dilution conditions in degassed
dichloromethane at reflux condition furnished an E/Z-mixture of
desired lactone 18 in 88% yield. The newly generated double
The primary hydroxyl group present in 12 was converted to
its corresponding iodo derivative and reductive opening of the

3
13. (a) Bujaranipalli, S.; Eppa, G. C.; Das, S. Synlett 2013, 24,
bond was of no consequence, as it would finally be hydrogenated
in the later stage of the synthetic sequence. One pot reduction of
the double bond and the MOM ether was achieved using (Pd/C,
H2, 4N HCl) condition to obtain 19 in 81% yield. Demethylation
of 19 with freshly prepared AlI3 at 10oC furnished the target
molecule 1 in 70% yield.24 The spectral data of the thus
synthesized target compound was in agreement with the natural
product. The optical rotation of 1 showed +20.5 (c=0.4, MeOH)
compared to reported value +22.2 (c=0.1, MeOH).8,25
1117-1120. (b) Dachavaram, S. S.; Kalyankar, K. B.; Das, S.
Tetrahedron Lett. 2014, 55, 5629-5631. (c) Yadav, J. S.; Das, S.;
Reddy, J. S.; Thrimurtulu, N.; Prasad, A. R. Tetrahedron Lett.
2010, 51, 4050-4052.
14. Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Furrow, M. E.;
Jacobsen, E. N. J. Am. Chem. Soc 2002, 124, 1307-1315.
15. (a) Kumar, P.; Gupta, P.; Naidu, S. V. Chem. Eur. J. 2006, 12,
1397-1402. (b) Thirupathi, B.; Gundapaneni, R, R.; Mohapatra, D,
K. Synlett 2011, 18, 2667-2670.
16. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973-1976.
In conclusion, we have demonstrated the synthesis of (3R,5S)-
5-hydroxy-de-O-methyllasipdiplodin (1) starting from propylene
oxide and methylacetoacetate in 12 steps. The two chiral centers
were generated by using Jacobsen’s hydrolytic kinetic resolution
and Sharpless asymmetric epoxidation followed by Mitsunobu
reaction conditions. The strategy described, gives an opening for
the synthesis of various methyl-hydroxyl (MH) lasiodiplodins of
interest, for several usages to chemists and biologists.
17. Gao. Y.; Klunder, J. M.; Hanson, R. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc 1987, 109, 5765-5780.
18. Rao, A. V. R.; Reddy. E. R.; Joshi, B. V.; Yadav, J. S.
Tetrahedron Lett. 1987, 28, 6497-6500.
19. Berliner, M. A.; Belecki, K. J. Org. Chem. 2005, 70, 9618-9621.
20. (a) Barrett, A. G. M.; Morris, T. M; Barton, D. H. R. J. Chem.
Soc., Perkin. Trans. 1. 1980, 2272-2277. (b) Chiarello, J.; Joullie,
M. M. Tetrahedron 1988, 44, 41-48.
21. Vu, N. Q.; Chai, C. L. L.; Lim, K. P.; Chia, S. C.; Chen, A.
Tetrahedron 2007, 63, 7053-7058.
22. Mitsunobu, O.; Yamada, Y. Bull. Chem. Soc. Jpn. 1967, 10, 2380–
2382.
Acknowledgments
23. (a) Lampilas, M.; Lett, R. Tetrahedron Lett. 1992, 33, 773–776;
(b) Lampilas, M.; Lett, R. Tetrahedron Lett. 1992, 33, 777–780.
24. Kreipl, A. T.; Reid, C.; Steglich, W. Org. Lett. 2002, 4, 3287-
3288.
B.S.R thanks UGC, New Delhi, India for fellowship. Authors
also thank CSIR, New Delhi for financial supports through
Project ORIGIN/CSC-0108 under 12th Five Year Plan.
25. (3R,5S)-5-hydroxy-de-O-methyllasipdiplodin (1): Mp: 160-
162oC. IR
(neat): 3435, 3189, 2928, 2860, 1640, 1615, 1588,
-1
Supporting Information
1498, 1459, 1358, 1316, 1257, 1204, 1173, 1088, 1021, 830 cm ;
1H NMR (500 MHz, CD3OD): δ = 11.56 (s, 1H), 6.19 (J = 2.4 Hz,
1H), 6.15 (d, J = 2.4 Hz, 1H), 5.49-5.43 (m, 1H), 3.91-3.85 (m,
1H), 3.45-3.38 (m, 1H), 2.32-2.23 (m, 2H), 1.88 (dd, J = 15.8, 5.3
Hz, 1H), 1.74-1.66 (m, 1H), 1.65-1.41 (m, 7H), 1.34 (d, J = 6.3
Hz, 3H) ppm.; 13C NMR (75 MHz, CD3OD): 173.1, 166.0, 163.5,
149.6, 111.8, 105.9, 101.8, 70.7, 69.5, 39.6, 34.0, 32.3, 31.5, 27.1,
21.4 ppm.; MS (ESI): m/z = 317 (M+Na)+. HRMS (ESI): calcd.
for C16H23O5 (M+H)+ 295.1540, found 295.1534.
Supplementary data associated with this article can be found,
in the online version.
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