A concise stereoselective total synthesis of decarestrictine J

Article abstract of DOI:10.1016/j.tetlet.2016.07.066

In this communication, a concise and efficient synthetic route for the synthesis of decarestrictine J in enantioselective way has been described. In this synthesis, Yamaguchi esterification and ring closing metathesis (RCM) for macrocyclic ring formation

Full text of DOI:10.1016/j.tetlet.2016.07.066

Accepted Manuscript
A concise stereoselective total synthesis of decarestrictine J
RamaKrishnam Raju Addada, Venkata Reddy Regalla, Mallikarjuna Rao Vajja,
Venkata Naresh Vema, Venkateswara Rao Anna
PII:
S0040-4039(16)30912-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.066
TETL 47928
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 May 2016
18 July 2016
19 July 2016
Please cite this article as: Addada, R.R., Regalla, V.R., Vajja, M.R., Vema, V.N., Anna, V.R., A concise
stereoselective total synthesis of decarestrictine J, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.07.066
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
A concise stereoselective total synthesis of decarestrictine J
Leave this area blank for abstract info.
RamaKrishnam Raju Addada a,b, Venkata Reddy Regalla b, Mallikarjuna Rao Vajja b, Venkata Naresh Vemab, Venkateswara
Rao Anna a, *
OH
OH OPMB
7 steps
O
4 steps
O
HO
O
O
S S
O
3 steps
TBSO
HO

1
Tetrahedron Letters
A concise stereoselective total synthesis of decarestrictine J
RamaKrishnam Raju Addada a,b, Venkata Reddy Regalla b, Mallikarjuna Rao Vajja b, Venkata Naresh
Vemab, Venkateswara Rao Anna a, *
a
Department of Chemistry, K L University, Vaddeswaram, Guntur (Dist), A.P, India.
GVK Biosciences Private Limited, Medicinal Chemistry Divison 28A, IDA ,Nacharam, Hyderabad-500076, Telangana.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this communication, a concise and efficient synthetic route for the synthesis of decarestrictine
J in enantioselective way has been described. In this synthesis, Yamaguchi esterification and
Ring Closing Metathesis (RCM) for macrocyclic ring formation have been applied as key steps.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Decarestrictine J
Regioselective ring opening
tert-Butyldimethylsilyl glycidyl ether
Yamaguchi esterification
Ring-closing metathesis
while, Compound 4 could be achieved from the commercially
available TBS protected glycidol 6.
Decarestrictines, a very important class of secondary metabolites,
isolated from various Penicillium strains. The decarestrictines
show interesting activity in cell line tests with HEP-G2 liver cells
due to an inhibitory effect on cholesterol biosynthesis1-3.
S
S
Decarestrictine J (1), a minor component of the decarestrictine
family, was isolated from a culture broth of Penicillium
simplicissimum (Fig. 1) and it was shown to inhibit the
biosynthesis of cholesterol.2,3 Due to the promising biological
activity and the impressive structural features of decarestrictine J
(1), appeared to be an attractive target for total synthesis.4-6
O
O
O
O
OPMB
HO
O
1
2
O
O
OH
S
S
OH
OPMB
O
+
HO
4
HO
O
5
3
Decarestrictine j (1)
Figure 1: Decarestrictine J (1)
O
TBSO
In continuation of our interest on the total synthesis of
biologically active natural products, we herein report the an
alternate and efficient route to total synthesis of decarestrictine J
(1) employing Regioselective ring opening of epoxy alcohol,
Yamaguchi esterification and ring-closing metathesis (RCM) as
key transformations.
Retrosynthetic analysis of 1 (Scheme 1) revealed that bis-olefin 2
could be the late stage intermediate, which on RCM protocol
would give the macrolide ring structure. Bis-olefin 2, in turn
could be realized by esterfication of alcohol segment 3 with acid
segment 4, wherein, 3 could be envisaged from the alcohol 5,
6
Scheme 1: Retrosynthetic strategy of 1
Based on retrosynthetic analysis, we visualized that alcohol 3 and
carboxylic acid could form the key fragments for
decarestrictine J 1. The synthesis of the alcohol segment 3
commenced with known homoallylic alcohol 5, which was
converted into silylether 7 using TBSCl and imidazole in CH2Cl2
in 81% yield. Ozonolysis of 7 followed by Wittig olefination of
the resulting aldehyde afforded 8 in 79% yield. Reduction of 8
4

2
Tetrahedron Letters
with DIBAL-H in dry CH2Cl2 at -78 °C for 2 h furnished the
on oxidative cleavage with NaIO4 followed by oxidation with
NaClO2 and NaH2PO4, 2-methyl-2-butene in aq. t-butanol
afforded carboxylic acid 4 in 71% yield.
corresponding allylic alcohol 9 (84%), which on Sharpless
epoxidation7 with (–)-DIPT, Ti(OiPr)4 and cumene hydroperoxide
in dry CH2Cl2 afforded epoxy alcohol 10 in 75% yield.
Regioselective ring opening8 of epoxy alcohol 10 with p-
methoxybenzyl alcohol in the presence of Ti(OiPr)4 gave the diol
11 in 79% yield. The resulting diol 11, on treatment with Ph3P,
imidazole and I29 at room temperature for four hours gave olefin
12 in 74% yield. In next step, silyl protecting group (TBS) has
been removed from compound 12 using TBAF to afford desired
segment 3 in 88% yield.
With the two fragments 3 and 4 in our hand, we aimed for the
synthesis of final molecule which was shown in Scheme 4. The
connection between the fragments 3 and 4 was performed using
the Yamaguchi esterification11 (2,4,6-trichlorobenzoyl chloride,
Et3N, THF, DMAP, toluene), which yielded key olefin 2 in 69%
yield. Having completed the key intermediate 2, we next planned
for ring-closing metathesis (RCM) reaction of 2 with the Grubbs
second generation catalyst (G-II, 10 mol%).
Accordingly, Bisolefin 2 was then subjected to the RCM reaction
using G-II12 (10 mol %) in dry DCM at reflux temperature
yielded macrolide 15 in 66% yield. In next step, reduction of
double bond followed by the deprotection of p-methoxy benzyl
(PMB) group in compound 15 was achieved in single step using
Pd/C, H2 in EtOAc to afford 16 in 79% yield. Finally,
deprotection of 1,3 dithaine group in compound 16 with CaCO3
and I2, in THF:H2O for 5 h afforded the the Decarestrictine J 1 in
66% yield. The analytical data of our synthetic compound are in
well agreement with the reported data.5 Thus we accomplished
the total synthesis of decarestrictine J in an enantioselective way.
OTBS
O
OTBS
OH
b
a
OMe
8
5
7
OTBS
OTBS
O
e
c
d
OH
OH
9
10
OH
OPMB
OTBS OPMB
OTBS OPMB
g
f
S
S
OH
O
3
11 OH
12
O
OPMB
O
OH
OPMB
S
S
a
+
HO
Scheme 2: Synthesis of segment 3; Reagents and conditions: (a)
TBSCl, Imidazole, CH2Cl2 , RT, 4 h, 81%; (b) i) O3, CH2Cl2, -78
oC, 30 min; ii) Ph3P=CHCOOMe, CH2Cl2, rt, 4 h, 79%; c)
DIBAL-H, CH2Cl2, -78 oC, 2 h, 84%; d) (-)-DIPT, 4Å, cumene
hydroperoxide, Ti(OiPr)4, CH2Cl2, -20 oC, 3 h, 75%; (e)
Ti(OiPr)4, PMB-OH, toluene, reflux, 2 h, 79%; (f) Ph3P, I2,
imidazole, CH2Cl2, 0 °C to rt, 4 h, 74%; (g) TBAF, THF, 0 oC to
rt, 3 h, 88%;
4
2
3
O
O
O
O
c
b
S
S
S
HO
PMBO
S
16
15
O
After completion of the synthesis of alcohol segment 3, we
then start the synthesis of acid segment 4 from commercially
available tert-butyldimethylsilyl glycidyl ether, which was
depicted in scheme 3.
O
d
HO
O
1
OH
S
S
Scheme 4: Synthesis of 1; Reagents and conditions: (a) 2,4,6-
trichlorobenzoyl chloride, Et3N, THF, 2 h, DMAP, toluene, 0 °C to
r.t., 5 h, 69%; (b) Grubb's second generation catalyst, CH2Cl2,
reflux, 12 h, 66%; (c) Pd/C, H2, EtOAc, rt., 2 h, 79%; (d) CaCO3, I2,
THF:H2O (4:1), 0 oC, 66%;
O
b
TBSO
a
TBSO
13
6
O
S
S
OH
S
S
Conclusions
c
HO
HO
In conclusion, total synthesis of Decarestrictine J has been
accomplished in a divergent way starting from commercially
available materials. In this approach, alcohol and acid segments
were synthesized in an efficient manner. Yamaguchi
esterification and ring-closing metathesis reactions (RCM) used
as a key reactions.
4
14
Scheme 3: Synthesis of segment 4; Reagents and conditions: (a) 2-
allyl-1,3-dithiane, n-BuLi, dry THF,–78 °C to –20 °C, 2 h, 83%; (b)
TBAF, THF, 0 C to rt, 3 h, 77%; (c) i) NaIO4, sat. NaHCO3 soln.,
o
CH2Cl2, rt, 6 h; ii) NaClO2, NaH2PO4, 2-methyl-2-butene, t-
BuOH:water (2:1), 0 oC to rt, 3 h, 71%;
Acknowledgement
RKR thanks K L University for constant encouragement
during this research program. RKR is also grateful to GVK
Biosciences for providing basic research facility.
The synthesis of acid segment 4 initiated with commercially
available tert-butyldimethylsilyl glycidyl ether 6, Ring opening
of epoxide 6 with 2-allyl-1,3-dithiane10 yielded compound 13 in
83% yield. Next, subsequent removal of TBS group in compound
13 with TBAF furnished the required diol 14 in 77% yield, which
References and notes
1. Grabley, S.; Granzer, E.; Hütter,K.; Ludwig, D.; Mayer, M.; Thiericke,
R.; Till, G.; Wink, J.;Philipps, S.; Zeeck, A. J. Antibiot.1992, 45, 56-65.

3
25
2. Göhrt, A.; Zeeck, A.; Hütter, K.; Kirsch, R.; Kluge, H.; Thiericke, R. J.
Antibiot. 1992, 45, 66-73.
3. Grabley, S.; Hammann, P.; Hütter, K.; Kirsch, R.; Kluge, H.; Thiericke,
R.; Mayer, M.; Zeeck, A. J. Antibiot.1992, 45, 1176-1181.
4. Yamada, S.; Tanaka, A.; Oritani, T. Biosci. Biotechnol. Biochem. 1995,
59, 1657-1660
13. Spectral data of 3: []D -39.7 (c 0.5, CHCl3); IR (KBr): 3423, 2927,
2831, 1529, 1028 cm–1 1H NMR (CDCl3, 300 MHz): δ 7.19 (d, 2H, J =
8.6 Hz), 6.79 (d, 2H, J = 8.6 Hz), 5.81-5.69 (m, 1H), 5.19-5.04 (m, 2H),
4.49 (m, 1H), 4.44 (d, 1H, J = 11.1 Hz), 4.24 (d, 1H, J = 11.1 Hz), 3.97
(m, 1H), 3.71 (s, 3H), 1.74-1.60 (m, 2H), 1.11 (d, 3H, J = 6.6 Hz); 13C
NMR (CDCl3, 75 MHz):  159.1, 138.3, 129.6, 128.4, 116.6, 114.3, 79.3,
70.1, 65.3, 55.3, 43.6, 23.2; ESIMS: 259 (M+Na)+; Spectral data of 12:
5. Chowdhury, P. S.; Gupta, P.; Kumar, P. Tetrahedron Letters 2009, 50,
7188–7190
[]D -11.7 (c 1.1, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 7.29 (d, 2H, J
25
6. Yadav, J. S.; Lakshmi, K. A.; Reddy, N. M.; Prasad, A. R.; Subba Reddy,
B. V. Tetrahedron 2010, 66, 334–338
= 8.3 Hz), 6.84 (d, 2H, J = 8.3 Hz), 5.53-5.47 (m, 1H), 5.34-5.27 (m,
1H), 5.03 (m, 1H), 4.44 (s, 2H), 4.01-3.94 (m, 1H), 3.73 (s, 3H), 2.91-
2.84 (m, 1H), 2.81-2.70 (m, 4H), 2.60-2.54 (m, 1H), 2.51 (s, 2H), 2.29-
2.21 (m, 2H), 1.91-1.77 (m, 2H), 1.23 (d, 3H, J = 6.0 Hz); 13C NMR
(CDCl3, 75 MHz):  173.6, 159.3, 138.3, 129.8, 128.6, 126.1, 114.3,
83.6, 72.6, 70.1, 67.3, 55.5, 51.2, 47.3, 43.3, 28.3, 24.5, 22.3; ESIMS:
7.
J. Am. Chem. Soc.
Org. React.
b
8. Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557.
9. Garegg, J.; Samuelson, B. Synthesis 1979, 813.
25
10. a) Coulter, M.M.; Kou, K.G.M.; Galligan, B.; Dong, V.M. J. Am. Chem.
Soc. 2010, 132, 16330-16333; (b)Karlson, S.; Högberg, H.-K. Synthesis
2000, 13, 1863-1867; (c) Yus, M.; Najera, C.; Foubelo, F.; Tetrahedron
2003, 59, 6147-6212; (d) Wullschleger, C.W.; Gertsch, J.; Altmann, K.H.
Org. Lett. 2010, 12, 1120-1123.
431 (M+Na)+; Spectral data of 1: M.P. 52–54 oC; (lit.:5 53–55 oC); []D
-144.7 (c 0.39, MeOH); (lit.:5 -154 (c 0.1, MeOH); 1H NMR (CDCl3, 300
MHz): δ 5.21–5.13 (m, 1H), 3.71–3.67 (m, 1H), 3.37 (d, 2H, J = 2.9 Hz),
2.79–2.68 (m, 1H), 2.38–2.29 (m, 1H), 2.11–2.01 (m, 1H), 1.91–1.82 (m,
2H), 1.74–1.49 (m, 3H), 1.31 (d, 3H, J = 6.0 Hz), 13C NMR (CDCl3,
75MHz): 202.8, 166.6, 71.5, 69.4, 51.6, 44.2, 39.3, 37.1, 21.4, 20.9;
ESIMS: 201 (M+H)+.
11. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
12. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(b) Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2003, 125, 10103. (c) Hassan, H. M. A. Chem. Commun. 2010, 46,
9100.

4
Tetrahedron Letters
Highlights
 Decarestrictine J was isolated from a culture broth of Penicillium simplicissimum
 it was shown to inhibit the biosynthesis of cholesterol.
 An alternate and efficient route to total synthesis of decarestrictine J
 Yamaguchi esterification and ring-closing metathesis (RCM) used as key transformations