A Carbohydrate-based approach for the total synthesis of xyolide

Article abstract of DOI:10.1055/s-0033-1339896

We have achieved a total synthesis of xyolide, a bioactive nonenolide, by following a carbohydrate-based approach starting from d-(-)-ribose. The key reactions involved epoxide opening with a long-chain aliphatic Grignard reagent, Yamaguchi esterification

Full text of DOI:10.1055/s-0033-1339896

LETTER
▌2679
lAetteCr arbohydrate-Based Approach for the Total Synthesis of Xyolide
Total Synthesis of Xyolide
Debendra K. Mohapatra,* D. Prabhakar Reddy, Dnyaneshwar S. Karhale, Jhillu S. Yadav
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: mohapatra@iict.res.in
Received: 16.08.2013; Accepted after revision: 05.09.2013
O
Abstract: We have achieved a total synthesis of xyolide, a bioac-
OH
O
tive nonenolide, by following a carbohydrate-based approach start-
ing from D-(–)-ribose. The key reactions involved epoxide opening
with a long-chain aliphatic Grignard reagent, Yamaguchi esterifica-
tion, and a ring-closing-metathesis reaction. The longest linear se-
quence was nine steps and the overall yield was 30%.
OH
O
O
O
O
O
O
O
O
OH
OH
5
OH
OH
OH
OH
Key words: lactones, total synthesis, Grignard reactions, esterifica-
1
2
3
tion, ring closure, metathesis
OH
O
O
O
O
O
O
Naturally occurring ten-membered lactones, isolated as
fungal metabolites and commonly known as decanolides,
have attracted considerable attention from synthetic or-
ganic chemists and bioorganic chemists because of their
interesting structural features and biological properties,
such as their anticancer, antifungal, antibacterial, and an-
tiviral activities.1 For example stagonolide A (2)2 and her-
barumins I and II (6 and 7, respectively)3 are phytotoxins
that inhibit the growth of certain invasive weeds.2a,4 Pho-
mol (9) exhibits antifungal and antibacterial activity (Fig-
ure 1).5
OH
OH
OH
OH
OH
4
5
6
OH
OH
HO
O
HO
O
O
O
O
O
OH
OH
OH
O
O
OH
OH
7
8
Recently, xyolide (1), a new nonenolide, was isolated
from the Amazonian endophytic fungus Xylaria fejeenis.
Its structure was determined by a combination of one- and
two-dimensional NMR spectroscopy and its absolute con-
figuration was determined by means of exciton-coupled
circular dichroism studies.6 The lowest concentration of 1
with a detectable activity against Pythium ultimum was
425 μM.
9
Figure 1 Structures of xyolide (1), stagonolide A (2), stagonolide B
(3), 4-epi-stagonolide B (4), stagonolide C (5), herbarumin I (6), her-
barumin II (7), pinolide (8), and phomol (9)
give the lactol 16.9 Treatment of lactol 16 with methyl(tri-
phenyl)phosphorane, generated in situ from methyl(tri-
phenyl)phosphonium bromide and potassium tert-
butoxide, gave olefin 17 (Scheme 2).10
As part of our ongoing research program on ring-closing
metathesis (RCM)7 for macrolide synthesis,8 we focused
on a total synthesis of xyolide as a demonstration of the
use of RCM.
Selective tosylation of the primary alcohol followed by
treatment with sodium hydride gave epoxide 18,11 which
was subjected to epoxide ring opening with hexylmagne-
sium bromide to provide the secondary alcohol 1312 in
88% yield.13
In our retrosynthetic analysis (Scheme 1), we envisaged
that the target molecule 1 might be prepared from lactone
10 and succinic anhydride. The lactone 10 could be ob-
tained from ester 11 by RCM; 11, in turn, could be ob-
tained by coupling the two key fragments 13 and 14. The
alcohol fragment 13 could be derived from D-(–)-ribose,
whereas the acid fragment 14 could be easily prepared
from the known epoxide 15.
Similarly, the synthesis of the acid fragment 14 began
from known chiral epoxide 15,14 which upon treatment
with butyllithium and trimethylsulfonium iodide in tetra-
hydrofuran at −78 °C gave the allylic alcohol 19 in 85%
yield.15 The hydroxy group of allylic alcohol 19 was pro-
tected as a silyl ether by treatment with tert-butyl(dimeth-
yl)silyl chloride and imidazole in anhydrous
dichloromethane to give the protected enediol 20 in 95%
yield. Removal of the 4-methoxybenzyl group by treat-
ment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in
dichloromethane–water (9:1) gave the corresponding pri-
mary alcohol 21 in 93% yield.16 This was converted into
We began our synthesis of alcohol fragment 13 by pro-
tecting D-(–)-ribose by treatment with acetone in the pres-
ence of a catalytic amount of concentrated sulfuric acid to
SYNLETT 2013, 24, 2679–2682
Advanced online publication: 28.10.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339896; Art ID: ST-2013-D0788-L
© Georg Thieme Verlag Stuttgart · New York

2680
D. K. Mohapatra et al.
LETTER
O
OH
a
c
b
O
O
O
OH
PMBO
PMBO
PMBO
HO
OH
15
20
19
21
O
O
O
O
OTBS
OTBS
d
O
OH
O
OH
xyolide (1)
OTBS
10
HO
O
OR
14
O
O
Scheme 3 Reagents and conditions: (a) BuLi, TMSI, THF, 0 °C, 2 h
(85%); (b) TBSCl, imidazole, CH2Cl2, 0 °C to r.t. (95%); (c) DDQ,
CH2Cl2–H2O (9:1), 0 °C, 2 h (93%); (d) DMP, CH2Cl2, 0 °C (91%)
then NaClO2, NaH2PO4, t-BuOH–H2O–2-methylbut-2-ene, 0 °C, 2 h
(92%).
O
O
11. R = H
12. R = TBS
required lactone 22. To overcome this problem, we sur-
mised that it might be advantageous to remove the tert-bu-
tyl(dimethyl)silyl group before attempting the RCM
macrocyclization. Accordingly, we removed the silyl
group from 12 by treatment with hydrogen fluoride–pyri-
dine in tetrahydrofuran to give the alcohol 11.22 RCM of
11 with second-generation Grubbs catalyst in refluxing
dichloromethane gave the ten-membered lactone 1023 ex-
clusively as the E-isomer. The identity of compound 10
was ascertained by inspection of its spectroscopic data.
OH
OTBS
D-(–)-ribose
+
HO
O
O
O
14
15
13
O
PMBO
Scheme 1 Retrosynthetic analysis of xyolide (1)
O
OH
a
acid 14 by a two-step sequence; oxidation of 14 with
Dess–Martin periodinane in dichloromethane gave the
corresponding aldehyde,17 and oxidation of the aldehyde
under Pinnick conditions18 (NaClO2, NaH2PO4, t-BuOH–
H2O–2-methylbut-2-ene) gave acid 1419 in 84% yield over
the two steps (Scheme 3).
+
HO
O
OTBS
O
O
13
14
OTBS
O
Having prepared alcohol fragment 13 and acid fragment
14, our next task was to couple the two fragments and con-
duct the RCM reaction. Accordingly, the two fragments
13 and 14 were coupled under Yamaguchi conditions20
(2,4,6-trichlorobenzoyl chloride, Et3N, THF then DMAP,
toluene) to give the diene 1221 in 92% yield (Scheme 4).
Attempts at RCM of diene 12 under various conditions us-
ing first- or second-generation Grubbs catalyst or second-
generation Hoveyda–Grubbs catalyst failed to provide the
O
OTBS
O
O
b
c
22
O
O
OH
O
O
O
12
O
O
11
OH
OH
OH
O
O
d
O
a
b
O
O
O
HO
O
OH
OH
HO
HO
OH
O
O
e
OH
O
O
D-(–)-ribose
16
17
OH
O
O
O
OH
O
c
d
OH
O
O
O
1
O
O
10
18
13
Scheme 4 Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chlo-
ride, Et3N, DMAP, THF, toluene, 0 °C to r.t., 8 h (92%), (b) Grubbs
I, II, or Hoveyda–Grubbs II (cat.), CH2Cl2, reflux, 24 h; (c) HF·py,
THF, 0 °C to r.t., 4 h (93%); (d) Grubbs II (cat.), CH2Cl2, reflux, 12 h
(78%); (e) succinic anhydride, DMAP, py, CH2Cl2, 0 °C to r.t., 12 h
(91%) then HCl, 0 °C to r.t. 12 h (89%).
Scheme 2 Reagents and conditions: (a) H2SO4 (cat.), acetone, r.t., 3
h (93%); (b) (Ph)3P+Me Br–, t-BuOK, THF, 0 °C to r.t., 13 h (87%);
(c) Et3N, Bu2SnO, TsCl, 0 °C to r.t., 5 h, then NaH, THF, 0 °C to r.t.,
4 h (79%, two steps); (d) Me(CH2)5MgBr, THF, 1 h, −15 °C (88%).
Synlett 2013, 24, 2679–2682
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Xyolide
2681
J. Chem. Soc., Perkin Trans. 1 1998, 371. (k) Gerlach, K.;
Quitschalle, M.; Kalesse, M. Tetrahedron Lett. 1999, 40,
3553. (l) Nevalainen, M.; Koskinen, A. M. P. Angew. Chem.
Int. Ed. 2001, 40, 4060.
The geometry of the olefin in 10 was established from
coupling constants. The signal for one olefinic proton ap-
peared at δ = 5.49 ppm as a doublet of doublets of doublets
(J = 1.5, 9.6, 15.8 Hz), whereas that of the other proton ap-
peared at δ = 5.87 ppm as a doublet of doublets (J = 1.7,
15.8 Hz).
(8) (a) Mohapatra, D. K.; Reddy, D. P.; Dash, U.; Yadav, J. S.
Tetrahedron Lett. 2011, 52, 151. (b) Mohapatra, D. K.;
Somaiah, R.; Rao, M. M.; Caijo, F.; Mauduit, M.; Yadav, J.
S. Synlett 2010, 1223. (c) Mohapatra, D. K.; Dash, U.;
Naidu, P. R.; Yadav, J. S. Synlett 2009, 2129. (d) Mohapatra,
D. K.; Sahoo, G.; Ramesh, D. K.; Sastry, G. N. Tetrahedron
Lett. 2009, 50, 5636. (e) Mohapatra, D. K.; Rahman, H.; Pal,
R.; Gurjar, M. K. Synlett 2008, 1801. (f) Mohapatra, D. K.;
Ramesh, D. K.; Giardello, M. A.; Chorghade, M. S.; Gurjar,
M. K.; Grubbs, R. H. Tetrahedron Lett. 2007, 48, 2621.
(g) Gurjar, M. K.; Karmakar, S.; Mohapatra, D. K.
Tetrahedron Lett. 2004, 45, 4525. (h) Gurjar, M. K.;
Nagaprasad, R.; Ramana, C. V.; Karmakar, S.; Mohapatra,
D. K. ARKIVOC 2005, (iii), 237. (i) Mohapatra, D. K.;
Yellol, G. S. ARKIVOC 2005, (iii), 144. (j) Mohapatra, D.
K.; Durugkar, K. A. ARKIVOC 2004, 146. (k) Mohapatra, D.
K.; Yellol, G. S. ARKIVOC 2003, (ix), 21.
Finally, esterification of lactone 10 with succinic anhy-
dride in the presence of pyridine and 4-(N,N-dimethylami-
no)pyridine24 followed by removal of the isopropylidene
group with hydrochloric acid gave xyolide (1)25 as an
amorphous solid in 81% yield over the two steps. The an-
alytical and spectroscopic data for 1 agreed well with
those reported in the literature.6
In summary, we have accomplished a total synthesis of
xyolide by following a carbohydrate-based approach,
starting from a cheap and commercially available D-(–)-ri-
bose; the longest linear sequence consisted of nine steps,
and the overall yield was 30%.
(9) Moon, H. Y.; Choi, W. J.; Kim, H. O.; Jeong, L. S.
Tetrahedron: Asymmetry 2002, 13, 1189.
(10) Choi, W. J.; Moon, H. R.; Kim, H. L.; Yoo, B. N.; Lee, J. A.;
Shink, D. H.; Jeong, L. S. J. Org. Chem. 2004, 69, 2634.
(11) Srihari, P.; Kumaraswamy, B.; Yadav, J. S. Tetrahedron
2009, 65, 6304.
Acknowledgment
The authors thank the Council of Scientific and Industrial Research
(CSIR), New Delhi for financial support as part of XII Five Year
Plan program under the title ORIGIN (CSC-0108). D.P.R. thanks
the Council of Scientific and Industrial Research (CSIR), New
Delhi, India, for financial assistance in the form of research fellow-
ships.
(12) Analytical Data for 13
[α]D27 +11.3 (c 1.0, CHCl3). IR (neat): 3458, 2957, 2896,
1470, 1256, 1086, 924, 837 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 6.04 (m, 1 H), 5.45–5.29 (m, 2 H), 4.64 (m, 1
H), 3.97 (dd, J = 1.7, 6.4 Hz, 1 H) 3.66 (m, 1 H), 1.75–1.67
(m, 2 H), 1.48 (s, 3 H), 1.37 (s, 3 H), 1.36–1.23 (m, 10 H),
0.88 (t, J = 7.0 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ =
134.6, 118.2, 108.5, 80.6, 78.3, 69.8, 33.6, 31.7, 29.5, 29.1,
27.7, 25.2, 25.0, 22.5, 14.0. MS (ESI): m/z = 279 [M + Na]+.
(13) Lipshutz, B. H.; Sengupta, S. Org. React. (N. Y.) 1992, 41,
135.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
(14) Kumar, P. C.; Sai, N. S.; Ravinder, M.; Singam, N. K.; Rao,
V. J. Synthesis 2011, 451.
(1) For a review on synthetic, biosynthetic, and
pharmacological aspects of decanolides, see: (a) Dräger, G.;
Kirschning, A.; Thiericke, R.; Zerlin, M. Nat. Prod. Rep.
1996, 13, 365. (b) Ferraz, H. M. C.; Bombonato, F. I.;
Longo, L. S. Jr. Synthesis 2007, 3261. (c) Riatto, V. B.; Pilli,
R. A.; Victor, M. M. Tetrahedron 2008, 64, 2279.
(2) (a) Yuzikhin, O.; Mitina, G.; Berestetskiy, A. J. Agric. Food
Chem. 2007, 55, 7707. (b) Evidente, A.; Cimmino, A.;
Berestetskiy, A.; Mitina, G.; Andolfi, A.; Motta, A. J. Nat.
Prod. 2008, 71, 31.
(15) (a) Trygstad, T. M.; Pang, Y.; Forsyth, C. J. J. Org. Chem.
2009, 74, 910. (b) Yu, P.; Li, C.; Guozhu, Z.; Liming, Z.
J. Am. Chem. Soc. 2009, 131, 5062. (c) Pradhan, T. R.;
Mohapatra, D. K. Tetrahedron: Asymmetry 2012, 23, 709.
(16) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron
Lett. 1982, 23, 885. (b) Mohapatra, D. K.; Bhimireddy, E.;
Krishnarao, P. S.; Das, P. P.; Yadav, J. S. Org. Lett. 2011,
13, 744.
(17) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 415.
(18) (a) Balkrishna, S. B.; Childers, W. E. Jr.; Pinnick, H. W.
Tetrahedron 1981, 37, 2091. (b) Dalcanale, E.; Montanari,
F. J. Org. Chem. 1986, 51, 567.
(3) Rivero-Cruz, J. S.; Macías, M.; Cerda-García-Rojas, C. M.;
Mata, R. J. Nat. Prod. 2003, 66, 511.
(4) Rivero-Cruz, J. F.; García-Aguirre, G.; Cerda-García-Rojas,
C. M.; Mata, R. Tetrahedron 2000, 56, 5337.
(19) Analytical Data for 14: [α]D27 +11.6 (c 1.8, CHCl3). IR
(neat): 3462, 3083, 2927, 2857, 1460, 1379, 1216, 1168,
1055, 925, 874 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.77
(m, 1 H), 5.22–5.06 (m, 2 H), 4.21 (q, J = 5.8 Hz, 1 H), 2.47–
2.36 (m, 2 H), 1.90–1.76 (m, 2 H), 0.89 (s, 9 H), 0.52 (s, 3
H), 0.3 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 180.2,
140.5, 114.5, 72.3, 32.2, 29.4, 25.7, 18.1, −5.0, −4.5. MS
(ESI): m/z = 267 [M + Na]+.
(5) Weber, D.; Sterner, O.; Anke, T.; Gorzalczancy, S.; Martino,
V.; Acevedo, C. J. Antibiot. (Tokyo) 2004, 57, 559.
(6) Baraban, E. G.; Morin, J. B.; Phillips, G. M.; Phillips, A. J.;
Strobel, S. A.; Handelsman, J. Tetrahedron Lett. 2013, 54,
4058.
(7) (a) Gradillas, A.; Pérez-Castells, J. Angew. Chem. Int. Ed.
2006, 45, 6086. (b) Deiters, A.; Martin, S. F. Chem. Rev.
2004, 104, 2199. (c) Grubbs, R. H. Tetrahedron 2004, 60,
7117. (d) Prunet, J. Angew. Chem. Int. Ed. 2003, 42, 2826.
(e) Love, J. A. In Handbook of Metathesis; Grubbs, R. H.,
Ed.; Wiley-VCH: Weinheim, 2003. (f) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (g) Fürstner, A.
Angew. Chem. Int. Ed. 2000, 39, 3012. (h) Maier, M. E.
Angew. Chem. Int. Ed. 2000, 39, 2073. (i) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413. (j) Armstrong, S. K.
(20) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(21) Analytical Data for 12: [α]D27 +22.6 (c 1.5, CHCl3). IR
(neat): 3081, 2929, 2858, 1740, 1464, 1377, 1253, 1215,
1167, 1122, 1074, 925, 838, 725 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 5.86–5.70 (m, 2 H), 5.37–5.03 (m, 4 H), 4.91
(dt, J = 3.4, 7.4 Hz, 1 H), 4.6 (t, J = 7.2 Hz, 1 H), 4.22–4.13
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2679–2682

2682
D. K. Mohapatra et al.
LETTER
(m, 2 H), 2.34–2.25 (m, 2 H), 1.83–1.37 (m, 2 H), 1.48 (s, 3
H), 1.37 (s, 3 H), 1.34–1.22 (m, 12 H), 0.91 (s, 9 H), 0.88 (t,
J = 7.0 Hz, 3 H), 0.51 (s, 3 H), 0.32 (s, 3 H). 13C NMR (75
MHz, CDCl3): δ = 172.6, 140.6, 133.2, 118.3, 114.3, 108.6,
78.8, 78.3, 72.3, 71.7, 32.5, 31.7, 31.1, 29.6, 29.4, 29.1, 27.4,
25.7, 25.1, 24.4, 22.5, 18.1, 14.0, −4.5, −4.9. MS (ESI):
m/z = 505 [M + Na]+.
15.8 Hz, 1 H), 4.92 (m, 1 H), 4.68 (m, 1 H), 4.16 (m, 1 H),
3.96 (q, J = 4.7, 10.0 Hz, 1 H), 2.34 (m, 1 H), 2.11–2.01 (m,
2 H), 1.78 (m, 1 H), 1.64 (m, 1 H), 1.46 (m, 1 H), 1.54 (s, 3
H), 1.37 (s, 3 H), 1.32–1.20 (m, 10 H), 0.86 (t, J = 6.7 Hz, 3
H). 13C NMR (75 MHz, CDCl3): δ = 175.0, 128.1, 126.2,
109.2, 78.4, 75.5, 75.5, 70.8, 33.5, 31.8, 31.6, 31.1, 29.2,
29.0, 28.3, 26.1, 24.3, 22.5, 13.9. MS (ESI): m/z = 363 [M +
Na]+.
(22) Analytical Data for 11: [α]D27 +28.8 (c 2.1, CHCl3). IR
(neat): 3474, 3083, 2957, 2928, 2858, 1739, 1459, 1427,
1380, 1250, 1216, 1067, 993, 927, 874 cm–1. 1H NMR (300
MHz, CDCl3): δ = 5.90–5.76 (m, 2 H), 5.37–5.12 (m, 4 H),
4.92 (dt, J = 3.4, 7.6 Hz, 1 H), 4.61 (m, 1 H), 4.21–4.15 (m,
2 H), 2.47–2.32 (m, 2 H), 1.92–1.84 (m, 2 H), 1.81 (m, 1 H),
1.69 (m, 1 H), 1.48 (s, 3 H), 1.37 (s, 3 H), 1.31–1.23 (m, 10
H), 0.87 (t, J = 6.7 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ
= 172.8, 140.3, 133.0, 118.4, 115.0, 108.7, 78.7, 78.2, 72.0,
71.9, 31.7, 31.4, 31.0, 30.2, 29.4, 29.0, 27.4, 25.1, 24.5, 22.5,
14.0. MS (ESI): m/z = 391 [M + Na]+.
(24) Kobayashi, Y.; Okui, H. J. Org. Chem. 2000, 65, 612.
(25) Analytical Data for Xyolide (1): [α]D27 +2.6 (c 1.2, CHCl3).
IR (neat): 3613, 3497, 3044, 1744, 1694, 1377, 1059, 968,
772 cm–1. 1H NMR (500 MHz, CDCl3): δ = 5.86 (dd, J = 1.4,
15.8 Hz, 1 H), 5.49 (ddd, J = 1.7, 9.3, 15.8 Hz, 1 H), 5.14 (m,
1 H), 4.99 (td, J = 2.2, 9.6 Hz, 1 H), 4.50 (br s, J = 1.3, 1.9
Hz, 1 H), 3.56 (dd, J = 1.9, 9.6 Hz, 1 H), 2.67–2.62 (m, 2 H),
2.61–2.51 (m, 2 H), 2.37–2.31 (m, 1 H), 2.09–1.96 (m, 3 H),
1.92–1.83 (m, 1 H), 1.59–1.49 (m, 1 H), 1.33–1.20 (m, 10
H), 0.87 (t, J = 6.7 Hz, 3 H). 13C NMR (125 MHz, CDCl3):
δ = 176.1, 174.5, 171.60, 132.7, 123.4, 76.4, 73.1, 72.4, 70.8,
31.7, 31.4, 31.2, 29.5, 29.4, 29.3, 29.1, 28.8, 24.5, 22.6, 14.0.
MS (ESI): m/z = 423 [M + Na]+, 399 [M − H]+.
(23) Analytical Data for 10: [α]D27 +47.2 (c 0.7, CHCl3). IR
(neat): 3484, 3082, 2956, 2928, 2858, 1737, 1459, 1378,
1166, 1065, 927, 874 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 5.81 (dd, J = 3.3, 15.8 Hz, 1 H), 5.65 (ddd, J = 1.8, 8.7,
Synlett 2013, 24, 2679–2682
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