An alternative stereoselective synthesis of greensporone C

Article abstract of DOI:10.1016/j.tetlet.2018.10.020

Greensporone C, a new 14-membered resorcylic acid lactone, has been synthesized from inexpensive and commercially available starting materials. This convergent synthesis utilizes Cross metathesis using the Grubbs Hoveyda catalyst, alkylation of 1,3-dithia

Full text of DOI:10.1016/j.tetlet.2018.10.020

Accepted Manuscript
An Alternative Stereoselective Synthesis Of Greensporone C
Venkata Naresh Vema, Y. Bharathi kumari, Sridhar Musulla, RamaKrishnam
Raju Addada, Srinivasa Rao Alapati
PII:
S0040-4039(18)31228-0
https://doi.org/10.1016/j.tetlet.2018.10.020
TETL 50330
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 August 2018
10 October 2018
11 October 2018
Please cite this article as: Vema, V.N., kumari, Y.B., Musulla, S., Addada, R.R., Alapati, S.R., An Alternative
Stereoselective Synthesis Of Greensporone C, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.10.020
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.
An Alternative Stereoselective Synthesis Of
Greensporone C
Leave this area blank for abstract info.
Venkata Naresh Vema,a,b Bharathi kumari, Y.b Sridhar Musulla,a RamaKrishnam Raju Addada,a Srinivasa Rao
Alapatia*
OH
O
OMe O
OH
OMe
Br
5 steps
OMe O
HO
BnO
O
6 steps
HO
TBSO
6steps
O
Greensporone C
5
S
S

1
Tetrahedron Letters
An Alternative Stereoselective Synthesis Of Greensporone C
Venkata Naresh Vema,a,b Bharathi kumari, Y.b Sridhar Musulla,a RamaKrishnam Raju Addada,a Srinivasa
Rao Alapati,a*
a
GVK Biosciences Private Limited, Medicinal Chemistry Divison 28A, IDA ,Nacharam, Hyderabad-500076, Telangana.
bDepartment of Chemistry, Jawaharlal Nehru Technological University, Hyderabad-500 085, Telangana, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Greensporone C, a new 14-membered resorcylic acid lactone, has been synthesized from
inexpensive and commercially available starting materials. This convergent synthesis utilizes
Cross metathesis using the Grubbs Hoveyda catalyst, alkylation of 1,3-dithiane and
Yamaguchi macrolactonization as key steps.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Greensporone C
Resorcylic acid lactones
Cross metathesis
Grubbs Hoveyda catalyst
Yamaguchi macrolactonization.
Resorcylic acid lactones (RALs) have been known for decades,
with the first isolation of radicicol (monorden) in 19531, followed
by zearalenone2, LL-Z1640-23, and hypothemycin4. After that a
series of 14-membered resorcylic acid lactones, such as radicicol
A5, aigialomycins A–E6, and paecilomycins A–F7 were reported
as fungal polyketide metabolites. All of these compounds have
received considerable attention, due to their potent biological
properties, which include antifungal8, cytotoxic9, antimalarial9,
nematicidal activities.10
absolute configuration of the stereogenic center (C-2) of was
determined as 2S. The first total synthesis of greensporone C was
reported by Kwanruthai Tadpetch and Co-Workers in 201712.
Due to the promising biological activity and the impressive
structural features, greensporone C (1) appeared to be an
attractive target for total synthesis. In continuation of our interest
on the total synthesis of biologically active natural products,13,14
we herein, report an alternative strategy to achieve the total
synthesis of Greensporone C (1) utilizing the Cross metathesis
and Yamaguchi macrolactonization as the key steps.
Recently, a series of 14 resorcylic acid lactones were isolated by
Oberlies and co-workers in 201411 from a culture of the
freshwater aquatic fungus Halenospora sp. Among them,
greensporone C (1) (Figure 1) exhibited more potent cytotoxic
activity against the MDA-MB-435 (breast cancer) and HT-29
(colon) cancer cell lines, with IC50 values of 2.9 and 7.5 mM,
respectively.
The retrosynthetic analysis of 1 is shown in Scheme 1.
Retrosynthetically, Greensporone C (1) could be derived by
macrolactonization from the hydroxy acid 2 followed by
deprotection of thioacetal and benzyl groups. Hydroxy acid 2
could be accessible by the coupling reaction of bromide 3 and
dithiane 4. wherein, 3 could be envisaged from the Orsellinic
acid 6, while, dithiane
4 could be achieved from the
commercially available 1,8-nonadiene 5.
OMe O
OMe O
OMe O
OH
(S)
O
O
OH
HO
BnO
(E)
HO
O
S
S
1
2
O
Figure 1: Greensporone C (1)
OH
O
OMe O
TBSO
OH
OMe
Br
+
The structure of greensporone C (1) was elucidated using various
spectroscopic and spectrometric techniques, including
HRESIMS, 1D-NMR (1H and 13C), and 2D-NMR (COSY,
edited-HSQC, and HMBC). According to this, greensporone C
(1) consist of 14-membered macrolide core structure with single
asymmetric center and which is fused to a benzenoid unit. The
S
S
5
HO
BnO
5
6
3
4
Scheme 1: Retrosynthetic strategy of 1

2
Tetrahedron Letters
25 oC, 4 h, 85%. (c) TBS-Cl, Imidazole, CH2Cl2, 0 oC to 25 oC, 2 h, 88%. (d)
Based on retrosynthetic analysis, we visualized that bromide
LAH, THF, 0 oC to 25 oC, 3h, 74%; (e) acrolein, Hoveyda-Grubbs II, CH2Cl2,
25 oC, 83%; (f) 1,3-propanedithiol, CAN, CHCl3, 0 oC to 25 oC, 4 h, 77%;
3 and dithiane 4 are the the key fragments for synthesis of
Greensporone C (1). Accordingly, we first focused on the
synthesis of bromide intermediate 3. As discussed in
With the two key intermediates 3 and 4 in hand, we next focused
on its coupling towards the synthesis of Greensporone C,
Accordingly, dithiane 4 was lithiated by n-BuLi at −20 °C and
then alkylated with bromide 3 to provide the desired product 14
in 89% yield (Scheme 4). Later, the resulting compound 14 was
subjected to base (LiOH) hydrolysis in THF:MeOH:H2O (3:1:1)
to afford the corresponding acid 15, which on desilylation with
TBAF in THF at 0 C to 25 C for 3 h afforded hydroxy acid 2 in
89% yield. After successful synthesis of hydroxy acid fragment
2, which was subjected to macrolactonisation under Yamaguchi
high dilution conditions17 to provide the lactone 16 in 67% yield.
Macrolactonization using the Yamaguchi protocol produced the
desired lactone 16 without effect on stereochemistry at the carbon
bearing the hydroxyl group. Next, removal of 1,3 dithaine group
in compound 16 with CaCO3 and MeI, in CH3CN:H2O for 3 h
afforded the lactone 17 in 66% yield.
retrosynthetic analysis, the synthesis of the bromide
3
commenced from known Orsellinic acid 6 (Scheme 2), which
was protected as the di-isopropylidene ketal using acetone in the
presence of TFAA and TFA to obtain 7 in 92% yield. Later, the
phenolic hydroxy functionality in compound 7 was protected as
its benzyl ether 8 by using BnBr, NaH in 87% yield. Next,
removal of acetonide protecting group from 8 with TFA gave
the hydroxy acid 9, which on O-methylation and esterification of
acid with dimethyl sulphate in the presence of K2CO3 in acetone
at reflux for 4 h afforded methyl ester 10 in 86% yield. Finally,
bromination at the benzylic position of 10 with N-
bromosuccinimide (NBS) and benzoyl peroxide gave bromide 3
in 79% yield.
o
o
OH
O
O
O
O
O
OH
a
O
O
b
c
OMe O
OTBS
OMe O
TBSO
HO
HO
BnO
OMe
OMe
Br
a
7
6
8
+
S
S
BnO
BnO
OH OH
OMe OMe
OMe OMe
O
S
S
3
4
O
14
d
O
e
Br
OMe O
OTBS
BnO
OMe O
OH
BnO
BnO
9
10
3
OH
c
OH
b
BnO
Scheme 2: Synthesis of fragment 3; Reagents and conditions: (a) TFAA,
BnO
o
o
o
S
S
TFA, acetone, 25 C, 24h, 92%; (b) BnBr, NaH, THF, 0 C to 25 C, 6 h,
87%; (c) TFA:H2O (9:1), 24 h, 81%; (d) DMS, K2CO3, acetone, reflux, 4h,
86% (e) NBS, benzoyl peroxide, CCl4, reflux, 6 h, 79%
S
S
15
2
OMe O
OMe O
After successful synthesis of one key intermediate 3, we next
turned our attention to the synthesis of another key fragment 4
(Scheme 3). Accordingly, commercially available 1,8-nonadiene
5 was subjected to Sharpless dihydroxylation15 using AD-mix-α
O
O
e
d
RO
BnO
S
S
O
16
17 R = Bn
1 R = H
o
in t-BuOH/H2O at 0 C to 25 oC for 32 h to give the diol 11 in
f
65% yield with an enantiomer ratio of about 92:8. The primary
hydroxy group in diol 11 was selectively protected as tosylate 12
in 85% yield by treatment with p-TsCl/Bu2SnO in CH2Cl2 at 25
oC for 4 h. Next, subsequent silylation of the secondary alcohol in
tosylate 12 with TBSCl and imidazole in CH2Cl2 gave 13 in 88%
yield. Next, Removal of tosylate from compound 13 with LAH
in dry THF furnished compound 14 in 74% yield. The olefin 14
was subjected to Cross metathesis with acrolein using the
second-generation Grubbs Hoveyda catalyst16 to give (E)-α,β-
unsaturated aldehyde 15 exclusively in 83% yield. Later,
aldehyde 15 was transformed into 1,3-dithiane 4 in 77% with 1,3-
propanedithiol and ceric ammonium nitrate as a catalyst in
chloroform.
Scheme 4: Synthesis of target compound 1 Reagents and conditions: (a)
n-BuLi, dry THF, -20 oC, 3 h, 89%; (b) LiOH, THF:MeOH:H2O (3:1:1),
rt, 4 h, 83%; (c) TBAF, THF, 0 oC to 25 oC, 3 h, 89%; (d) i) 2,4,6-
trichlorobenzoyl chloride, Et3N, dry THF, 25 oC, 2 h; ii) DMAP, toluene,
o
90 °C, 10 h, 67%; (e) CaCO3, MeI, CH3CN:H2O (9:1), 45 C, 3 h, 66%;
(f) TiCl4, CH2Cl2, 0 oC to 25 oC, 2 h, 76%.
In the final step, deprotection of benzyl ether in lactone 17 was
removed successfully using TiCl4 at 0 °C to 25 oC to afford
25
Greensporone C (1) [[]D = +101.6 (c 0.74, MeOH) in 76%
yield. The spectral data of 1 (1H NMR, 13C NMR and HRMS) are
in good agreement with the reported values of natural
Greensporone C.11
OH
OH
a
b
HO
TsO
5
12
11
5
Conclusions
OTBS
OTBS
13
c
Thus, in summary a short and efficient stereoselective total
synthesis of Greensporone C (1) has been achieved in convergent
manner from the known commercially available starting
materials. The key steps includes Grubbs Hoveyda catalyst,
alkylation of 1,3-dithiane and Yamaguchi macrolactonization.
e
d
TsO
14
OTBS
OTBS
S
f
CHO
S
15
4
Scheme 3: Synthesis of fragment 4: Reagents and conditions: (a) AD-mix-α,
t-BuOH/H2O, 0 C to 25 C, 32 h, 65%. (b) Bu2SnO, p-TsCl, Et3N, CH2Cl2,
Acknowledgement
o
o

3
18. Spectral data of 3: IR (neat): 2966, 1722, 1595, 1463, 1439, 1380,
VNV thanks JNT University for constant encouragement
during this research program. VNV is also grateful to GVK
Biosciences for providing basic research facility.
1161, 1112, 1063 cm–1; H NMR (400 MHz, CDCl3) δ: 7.46-7.23 (m,
5H), 6.51 (d, 1H, J = 2.1 Hz), 6.39 (d, 1H, J = 2.1 Hz), 5.23 (s, 2H), 4.88
(s, 2H), 3.87 (s, 3H), 3.79 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 169.1,
163.4, 161.2, 142.6, 136.2, 128.6, 128.1, 127.7, 116.7, 110.2, 70.1, 55.7,
52.2, 34.1; ESIMS: 365 (M+H)+. Spectral data of 4: IR (neat): 3066,
1
References and notes
2983, 2931, 1611, 1521, 1236, 1052 cm–1; []D +66.3 (c 1.1, CHCl3);
25
1.
2.
Delmotte, P.; Delmotte, J. Nature 1953, 171, 344.
Stob, M.; Baldwin, R. S.; Tuite, J.; Andrews, F. N. Nature, 1962, 196,
1318.
1H NMR (300 MHz, CDCl3) δ 5.76 (m, 1H), 5.51 (m, 1H), 4.67 (d, 1H, J
= 7.9 Hz), 3.56 (m, 1H), 2.81-2.69 (m, 4H), 2.19-2.09 (m, 2H), 1.91-1.77
(m, 2H), 1.41-1.21 (m, 8H), 1.13 (d, 3H, J = 6.2 Hz), 0.89 (s, 9H), 0.14
(s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 138.7, 124.9, 68.3,
47.1, 40.2, 33.3, 29.9, 28.2, 26.5, 26.3, 26.1, 25.8, 24.2, 18.3, -4.1, -4.6;
ESIMS: 397 (M+Na)+. Spectral data of 2: IR (neat): 3447, 2941, 2857,
3.
Ellestad, G. A.; Lovell, F. M.; Perkinson, N. A.; Hargreaves, R. T. J.
Org. Chem., 1978, 43, 2339.
4.
5.
6.
Nair, M. S. R.; Carey, S. T. Tetrahedron Lett., 1980, 21, 2011.
Winssinger, N.; Barluenga, S. Chem. Commun. 2007, 22.
Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.;
Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
Xu, L. X.; He, Z. X.; Xue, J. H.; Chen, X. P.; Wei, X. Y. J. Nat. Prod.
2010, 73, 885.
Shier, W. T.; Shier, A. C.; Xie, W.; Mirocha, C. J. Toxicon 2001, 39,
1435.
Isaka, M.; Yangchum, A.; Intamas, S.; Kocharin, K.; Jones, E. B. G.;
Kongsaeree, P.; Prabpai, S. Tetrahedron 2009, 65, 4396.
1741, 1622, 1441, 1363, 1263, 1033, 924, 703 cm-1 []D +21.6 (c 0.8,
25
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.39-7.21 (m, 5H), 6.47 (d, 1H, J
= 2.0 Hz), 6.33 (d, 1H, J = 2.0 Hz), 5.66 (d, 1H, J = 15.8 Hz), 5.44 (m,
1H), 5.11 (s, 2H), 3.85 (s, 3H), 3.73 (m, 1H), 3.48 (s, 2H), 2.88-2.73 (m,
4H), 2.16-2.04 (m, 2H), 1.88-1.79 (m, 2H), 1.44-1.26 (m, 7H), 1.21-1.17
(m, 1H), 1.11 (d, 3H, J = 6.3 Hz): 13C NMR (75 MHz, CDCl3): δ 171.9,
164.1, 160.9, 141.8, 137.6, 136.1, 128.3, 128.0, 127.7, 125.4, 116.4,
115.0, 98.3, 70.1, 68.3, 62.3, 55.7, 52.6, 40.1, 33.6, 29.8, 28.4, 26.9, 25.7,
7.
8.
9.
10. Dong, J.; Zhu, Y.; Song, H.; Li, R.; He, H.; Liu, H.; Huang, R.; Zhou,
Y.; Wang, L.; Cao, Y.; Zhang, K. J. Chem. Ecol. 2007, 33, 1115.
11. El-Eliman T, Raja HA, Day CS, Chen W-L, Swanson SM, Oberlies NH.
J Nat Prod.2014,77, 2088–2098.
12. Tadpetch, K.; Jeanmard, L.; Rukachaisirikul, V. Tetrahedron Lett.
2017, 58, 3453.
13. Raju, A. R. K.; Reddy, R. V.; Rao, V. M.; Naresh, V. V.; Rao, A. V.
Tetrahedron Lett. 2016, 57, 3933.
14. Sridhar, M.; Kumari, Y.B., Mahesh, M., Rao, A.S.; Naresh, V. V.
Synthetic Communications, 2018, 48, 1657.
24.6, 23.1; ESIMS: 531 (M+H)+. Spectral data of 1: []D +101.6 (c
25
0.74, MeOH); m.p.: 148-151 °C; IR (neat): 3431, 3056, 2929, 2859,
1704, 1629, 1449, 1163, 1071 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.87
(dt, 1H, J = 15.9, 7.5 Hz), 6.47 (d, 1H, J = 2.1 Hz), 6.31 (d, 1H, J = 2.1
Hz), 6.11 (d, 1H, J = 15.9 Hz), 5.23–5.10 (m, 1H), 4.35 (d, 1H, J = 14.9
Hz), 3.75 (s, 3H), 3.44 (d, 1H, J = 14.9 Hz), 2.32–2.19 (m, 2H), 1.71–
1.49 (m, 4H), 1.43-1.35 (m, 2H), 1.33 (d, 3H, J = 6.1 Hz), 1.30-1.19 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 199.1, 168.2, 159.6, 158.9, 150.2,
135.1, 129.9, 116.0, 109.5, 98.7, 71.1, 56.0, 44.1, 34.9, 30.9, 25.8, 25.7,
23.3, 20.5; HRMS (ESI): m/z calcd for C19H24NaO5 (M+Na)+ 355.1516,
found 355.1511.
15. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
16. (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168–8179; (b) Dinh, M. T.; Bouzbouz, S.;
Peglion, J. L.; Cossy, J. Tetrahedron 2008, 64, 5703–5710.
17. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
Click here to remove instruction text...

4
Tetrahedron Letters
Highlights
 An alternative and efficient approach for
synthesis of Greensporone C is reported.
 The synthesis was accomplished from the
known and Cost-effective starting materials.
 Cross metathesis, alkylation of 1,3-dithiane and
Yamaguchi macrolactonization applied as key
steps.