Total synthesis of (S)-(-)-curvularin: A ring-closing-metathesis-based construction of the macrocyclic framework

Article abstract of DOI:10.1055/s-2008-1078504

A convergent, flexible, and efficient approach to the synthesis of curvularin is described. Key step is the high-yielding macrocyclic ring formation by ring-closing metathesis (RCM) using the Grubbs second-generation catalyst. Georg Thieme Verlag Stuttgar

Full text of DOI:10.1055/s-2008-1078504

LETTER
1801
Total Synthesis of (S)-(–)-Curvularin: A Ring-Closing-Metathesis-Based
Construction of the Macrocyclic Framework
Total
S
ynthesis of
e
(
S
)-(–)-Cur
b
vularin endra K. Mohapatra,* Hasibur Rahaman, Rita Pal, Mukund K. Gurjar
Organic Chemistry Division, National Chemical Laboratory, Pune 411008, India
Fax +91(20)25902629; E-mail: dk.mohapatra@ncl.res.in
Received 25 April 2008
OH
O
OBn OTBS
Abstract: A convergent, flexible, and efficient approach to the syn-
thesis of curvularin is described. Key step is the high-yielding mac-
rocyclic ring formation by ring-closing metathesis (RCM) using the
Grubbs second-generation catalyst.
HO
BnO
Key words: curvularin, cytotoxic, ring-closing metathesis, Pinnick
O
O
O
O
oxidation, Wittig reaction
curvularin (1)
3
Curvularin belongs to a unique class of 12-membered
fused resorcinylic macrolides. Curvularin (1)1,2 and relat-
ed compounds have been reported as metabolites pro-
duced by members of the Curvularia,3,4 Alternaria,5,6 and
Penicillium7–9 genera. 11,12-Dehydrocurvularin (2) co-
occurs with curvularin in Drechslera australiensis.10
These macrolides possess interesting biological proper-
ties, including phytotoxicity,5 cytotoxicity toward sea ur-
chin embryogenesis,8 inhibition of cell division,8
inhibition of expression of human inducible nitric oxide
synthase,11 and growth-promoting activity in farm ani-
mals.12 The interesting 12-membered fused lactone family
and their potent biological activities attracted our atten-
tion for the total synthesis.
TBSO
BnO
BnO
OH
O
OBn
O
7
4
OBn
TBSO
OH
BnO
O
+
OH
5
6
OBn
Despite the great number of reports13 regarding the syn-
thesis of curvularin, no effort was made for the construc-
tion of macrocyclic framework using ring-closing
metathesis. During the final step of our synthesis, Kunz et
al.13j for the first time reported the ring-closing metathesis
approach for the synthesis of curvularin and its homo-
logues. The retrosynthetic strategy was envisaged utiliz-
ing a highly convergent coupling sequence for two
intermediates 5 and 6. The first coupling would entail es-
terification of an appropriately substituted aromatic acid 6
with an optically pure secondary alcohol 5 containing the
Scheme 1 Retrosynthetic analysis of curvularin (1)
single stereogenic center present in curvularin. In the con-
cluding coupling, ring-closing metathesis of a diene 4
would lead to the desired 12-membered macrolide 3. The
substituted aromatic acid could be achieved from readily
available alcohol 714 through a tactical combination of
functional group manipulation, that is, one-carbon Wittig
homologation, sequential hydroboration–oxidation, allyl-
ation by Grignard reaction and Pinnick oxidation
(Scheme 1).
Synthesis of densely functionalized, substituted aromatic
acid began with commercially available 3,5-benzyloxy-
benzyl alcohol 7,15 which was oxidized to aldehyde using
PDC, followed by one-carbon Wittig olefination with in-
cipient methylenetriphenyl phosphorane generated in situ
from MeP+Ph3I– and n-BuLi in THF to provide olefin 8.
The styrene derivative 8 was subjected to the sequential
hydroboration–oxidation,16 protection of the hydroxy
group as its PMB ether to provide 9 (Scheme 2).
Formylation17 was effected with POCl3, DMF to give al-
dehyde 10,18 which on Grignard reaction with allylmagne-
sium bromide gave the hydroxyl compound 11.19 The
alcohol was protected as its TBS ether using TBSCl20 to
OH
O
OH
O
11
11
6
6
13
2
HO
HO
4
4
1
1
O
O
O
O
curvularin (1)
11,12-dehydrocurvularin (2)
Figure 1
SYNLETT 2008, No. 12, pp 1801–1804
Advanced online publication: 19.06.2008
DOI: 10.1055/s-2008-1078504; Art ID: G15008ST
x
x
.x
x
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

1802
D. K. Mohapatra et al.
LETTER
BnO
BnO
TBSO
BnO
OH
a
b
OH
O
a
+
OBn
OBn
OH
7
8
OBn
6
5
O
OBn OTBS
BnO
OPMB
BnO
OPMB
d
TBSO
BnO
c
b
c
O
BnO
OBn
OBn
10
9
O
O
O
HO
TBSO
BnO
OBn
4
3
BnO
f
e
OBn OH
OBn
O
OPMB
OPMB
d
OBn
11
OBn
BnO
BnO
12
O
O
O
O
TBSO
BnO
TBSO
15
16
BnO
O
g
OH
O
OH
OH
e
OBn
OBn
HO
13
6
O
O
Scheme 2 Reagents and conditions: a) (i) PDC, MS 4 Å, CH2Cl2,
0 °C to r.t., 1.5 h; (ii) P+Ph3MeI–, n-BuLi, THF, 0 °C, overnight, 91%
(in two steps); b) (i) BH3⋅DMS, THF, 0 °C, 3 h, 89%, (ii) PMB-Cl,
NaH, DMF, 0 °C, 3 h, 81%; c) DMF, POCl3, 0–75 °C, 2 h, 82%; d)
allyl bromide, Mg, Et2O, r.t., 3 h, 88%; e) TBSCl, imidazole, DMF,
0 °C, 4 h, 98%; f) DDQ, CH2Cl2, buffer (pH = 7), r.t., 1.5 h, 93%; g)
(i) IBX, DMSO, THF, r.t., 1 h, 97%, (ii) NaClO2, NaH2PO4, t-BuOH,
THF, H2O, 2-methyl-2-butene, 2 h, 94%.
1
Scheme 4: Reagents and conditions: a) DCC, DMAP, CH2Cl2, 0 °C
to r.t., 2 h, 91%; b) Grubbs’ second-generation catalyst, toluene,
70 °C, overnight, 83%; c) TBAF, THF, r.t., 48 h, 97%; d) IBX,
DMSO, THF, r.t., 1.5 h, 98%; e) 10% Pd/C, H2, EtOAc, r.t., 1.5 h,
ingly, the esterification was accomplished using DCC,26
DMAP in CH2Cl2 to furnish 4.27 After having synthesized
the diene derivative 4, the stage was finally set for the con-
struction of macrocyclic framework. Accordingly, on ex-
posure of 4 to the Grubbs second-generation catalyst28 in
toluene at 70 °C led to the formation of an E/Z mixture of
unsaturated macrocycle 3 in 83% yield. The newly gener-
ated double bond of 3 was of no consequence, as it would
finally be hydrogenated in the later stage of synthetic se-
quence. All the spectral and elemental analysis secured
the assigned structure. Macrolactone 3 was converted into
hydroxyl lactone 15 by treating with TBAF (1 M) in THF
at ambient temperature.
OH
Mg, CuCN, THF
O
+
Cl
0 °C to r.t., overnight
5
14
Scheme 3 Synthesis of fragment 5
obtain 12. Cleavage of PMB ether by treating with DDQ21
followed by IBX oxidation of alcohol 13 afforded the cor-
responding aldehyde which on Pinnick22 oxidation gave
the required acid 6.23
With the aromatic segment readily in hand, our next atten-
tion was to obtain the desired alcohol 5 with commercially
available (S)-(–)-methyloxirane (14) as delineated in
Scheme 3.
The IBX oxidation of the secondary hydroxyl functional-
ity in 15 led to the ketolactone 16.29 Finally, global depro-
tection and concomitant reduction of the olefin with
catalytic hydrogenation13b using 10% Pd/C afforded cur-
vularin (1) in 90% yield. The spectroscopic (1H NMR, 13C
NMR)30 and analytical data were in all respects identical
to those reported in the literature.8,13j
The epoxide 14 was subjected to CuCN coordinated re-
gioselective nucleophilic opening24 with allylmagnesium
chloride to provide the alcohol 5 in 87% yield, the struc-
ture of which was adequately substantiated by spectral
studies.25
In conclusion, a convergent synthesis of (S)-curvularin
has been achieved via ring-closing metathesis reaction as
With two subunits in hand, we proceeded to couple both
intermediates 5 and 6 as described in Scheme 4. Accord-
Synlett 2008, No. 12, 1801–1804 © Thieme Stuttgart · New York

LETTER
Total Synthesis of (S)-(–)-Curvularin
1803
CDCl3): d = 34.9, 55.2, 70.1, 70.2, 70.6, 72.3, 98.4, 110.1,
113.6, 117.4, 127.3, 127.6, 128.2, 128.3, 128.7, 129.2,
130.7, 135.9, 135.9, 145.3, 159.0, 163.4, 164.4, 190.3 ppm.
Anal. Calcd for C31H30O5: C, 77.16; H, 6.27. Found: C,
77.46; H, 6.21.
the key step starting from readily available starting mate-
rials. This protocol is promising for gram-quantity synthe-
sis of the above molecule and its analogues.
(19) Analytical and Spectral Data of 11
Acknowledgment
IR (neat): 3400, 2930, 1600, 1512, 1454, 1383, 1302, 1247,
1151, 1084, 1030, 822, 738, 698 cm–1. 1H NMR (200 MHz,
CDCl3): d = 2.42–2.55 (m, 1 H), 2.64–2.79 (m, 1 H), 2.84–
3.03 (m, 2 H), 3.51–3.67 (m, 2 H), 3.77 (s, 3 H), 4.39 (d,
J = 11.5 Hz, 1 H), 4.45 (d, J = 11.6 Hz, 1 H), 4.85–4.95 (m,
2 H), 4.97 (s, 2 H), 5.01–5.02 (m, 1 H), 5.05 (s, 2 H), 5.66–
5.87 (m, 1 H), 6.42 (d, J = 2.4 Hz, 1 H), 6.51 (d, J = 2.4 Hz,
1 H), 6.83 (d, J = 8.5 Hz, 2 H), 7.20 (d, J = 8.5 Hz, 2 H),
7.33–7.41 (m, 10 H) ppm. 13C NMR (50 MHz, CDCl3): d
34.6, 55.2, 70.0, 70.1, 70.4, 72.6, 99.2, 108.2, 113.7, 114.3,
116.0, 118.7, 126.3, 126.9, 127.2, 127.6, 127.8, 128.0,
128.5, 128.6, 129.3, 130.4, 132.0, 134.0, 136.7, 136.8,
138.9, 139.3, 158.1, 158.3, 159.1. Anal. Calcd for C34H36O5:
C, 77.84; H, 6.92. Found: C, 77.69; H, 6.82.
H.R. and R.P. thank CSIR, New Delhi for financial assistance in the
form of a Senior Research Fellowship. We also thank Dr. Ganesh
Pandey, HOD, Organic Chemistry Division, for his valuable
suggestions and support. Help from Dr. P. R. Rajmohanan for NMR
data is also well recorded.
References and Notes
(1) Musgrave, O. C. J. Chem. Soc. 1956, 4301.
(2) Birch, A. J.; Musgrave, O. C.; Rickards, W. R.; Smith, H.
J. Chem. Soc. 1959, 3146.
(3) Munro, H. D.; Musgrave, O. C.; Templeton, R. J. Chem. Soc.
C 1967, 947.
(4) Coombe, R. G.; Jacobs, J. J.; Watson, T. R. Aust. J. Chem.
1968, 21, 783.
(5) Robeson, J. D.; Strobel, G. A. Z. Naturforsch., C: Biosci.
(20) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
6190.
(21) Solsona, J. G.; Romea, P.; Urpi, F. Org. Lett. 2003, 5, 4681.
(22) Pinnick, H. W.; Balkrishna, S. B.; Childers, W. E. Jr.
Tetrahedron 1981, 37, 2091.
1981, 36, 1081.
(6) Arai, K.; Rawlings, B. J.; Yoshizawa, Y.; Vederas, J. C.
J. Am. Chem. Soc. 1989, 111, 3391.
(23) Analytical and Spectral Data of 6
IR (neat): 3065, 3031, 2927, 2855, 1730, 1602, 1454, 1385,
1254, 1105, 836, 756, 616 cm–1. 1H NMR (200 MHz,
CDCl3): d = –0.11 (s, 3 H), 0.05 (s, 3 H), 0.88 (s, 9 H), 2.40–
2.54 (m, 1 H), 2.61–2.75 (m, 1 H), 3.96 (d, J = 16.7 Hz, 1 H),
4.45 (d, J = 16.7 Hz, 1 H), 4.97–5.08 (m, 6 H), 5.55–5.58 (m,
1 H), 5.68–5.89 (m, 1 H), 6.52–6.60 (m, 2 H), 7.30–7.48 (m,
10 H) ppm. 13C NMR (50 MHz, CDCl3): d = –3.7, 17.9, 25.6,
34.8, 40.2, 70.0, 70.2, 77.5, 99.1, 104.2, 114.3, 114.7, 119.3,
126.9, 127.1, 127.5, 127.7, 127.8, 127.9, 128.0, 128.1,
128.2, 128.4, 128.5, 128.6, 131.8, 132.4, 136.2, 136.3,
136.6, 136.9, 141.7, 154.9, 159.8, 170.4 ppm. Anal. Calcd
for C32H40O5Si: C, 72.14; H, 7.57. Found: C, 72.31; H, 7.39.
(24) Poppe, L.; Recseg, K.; Novak, L. Synth. Commun. 1995, 25,
3993.
(7) Raistrick, H.; Rice, F. A. H. J. Chem. Soc. C 1971, 3069.
(8) Kobayashi, A.; Hino, T.; Yata, S.; Itoh, T. J.; Sato, H.;
Kawazu, K. Agric. Biol. Chem. 1988, 52, 3119.
(9) Hi, S.; Shizuri, Y.; Yamamura, S.; Kawai, K.; Terada, Y.;
Furukawa, H. Tetrahedron Lett. 1989, 30, 2241.
(10) Turner, W. B.; Aldridge, D. C. Fungal Metabolites 11;
Academic Press: London, 1983.
(11) Yao, Y.; Hausding, M.; Erkel, G.; Anke, T.; Förstermann,
U.; Kleinert, H. Mol. Pharmacol. 2003, 63, 383.
(12) Commercial Solvent Corp. Br. Patent GB 1114 954, 1968.
(13) Previous syntheses: (a) Baker, P. M.; Bycroft, B. W.;
Roberts, J. C. J. Chem. Soc. C 1967, 913. (b) Gerlach, H.
Helv. Chim. Acta 1977, 60, 3039. (c) Takahashi, T.; Ikeda,
H.; Tsuji, J. Tetrahedron Lett. 1980, 3885. (d) Wasserman,
H. H.; Gambale, R. J.; Pulwer, M. J. Tetrahedron Lett. 1981,
1737. (e) Birch, A. J.; Mani, N. S.; Rao, G. S. R. S. J. Chem.
Soc., Perkin Trans. 1 1990, 1423. (f) Kasar, R. A.; Khan, R.
A.; Desphande, V. H.; Ayyangar, N. R. Tetrahedron Lett.
1991, 32, 1599. (g) Bracher, F.; Schulte, B. Liebigs Ann./
Recl. 1997, 1979. (h) Liang, Q.; Sun, Y.; Yu, B.; She, X.;
Pan, X. J. Org. Chem. 2007, 72, 9846. (i) Miyagi, T.;
Kuwahara, S. Biosci. Biotechnol. Biochem. 2007, 71, 1592.
(j) Elzner, S.; Schmidt, D.; Schollmeyer, D.; Erkel, G.;
Anke, T.; Kleinert, H.; Förstermann, U.; Kunz, H.
ChemMedChem 2008, 3, 924.
(25) Analytical and Spectral Data of 5
[a]D25 +9.89 (c 1.1, CHCl3). IR (neat): 3435, 3019, 1598,
1403, 1215, 1118, 758, 669 cm–1. 1H NMR (200 MHz,
CDCl3): d = 1.17 (d, J = 6.2 Hz, 3 H), 1.46–1.58 (m, 2 H),
1.99 (br s, 1 H), 2.06–2.20 (m, 2 H), 3.79 (quin, J = 6.2 Hz,
1 H), 4.90–5.07 (m, 2 H), 5.71–5.91 (m, 1 H) ppm. 13C NMR
(50 MHz, CDCl3): d = 23.4, 30.1, 38.2, 67.4, 114.7, 138.4
ppm. Anal. Calcd for C6H12O: C, 71.95; H, 12.08. Found: C,
71.89; H, 12.11.
(26) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394.
(27) Analytical and Spectral Data of 4
[a]D25 +7.86 (c 1.5, CHCl3). IR (neat): 2929, 2371, 2361,
2341, 1730, 1604, 1383, 1257, 1146, 1068, 773, 696, 667
cm–1. 1H NMR (200 MHz, CDCl3): d = –0.16 (s, 3 H), 0.01
(s, 3 H), 0.86 (s, 9 H), 1.22 (d, J = 5.7 Hz, 1.5 H), 1.25 (d,
J = 5.7 Hz, 1.5 H), 1.47–1.79 (m, 2 H), 1.99–2.16 (m, 2 H),
2.37–2.50 (m, 1 H), 2.61–2.75 (m, 1 H), 3.70–3.88 (m, 1 H),
4.37–4.50 (m, 1 H), 4.92–5.07 (m, 9 H), 5.50–5.56 (m, 1 H),
5.67–5.91 (m, 2 H), 6.48 (d, J = 2.3 Hz, 1 H), 6.53 (br s, 1
H), 7.31–7.42 (m, 10 H) ppm. 13C NMR (50 MHz, CDCl3):
d = –5.2, –4.9, 18.2, 19.9, 20.0, 25.9, 29.6, 29.7, 35.1, 69.9,
70.2, 70.5, 70.6, 98.9, 108.5, 108.6, 115.0, 116.4, 124.2,
126.9, 127.2, 127.5, 127.7, 128.0, 128.4, 128.5, 128.6,
135.9, 136.8, 137.0, 137.7, 158.2, 158.3, 170.9, 171.9 ppm.
Anal. Calcd for C38H50O5Si: C, 74.23; H, 8.20. Found: C,
74.01; H, 8.22.
(14) Venkatachalam, T. K.; Huang, H.; Yu, G.; Uckun, F. M.
Synth. Commun. 2004, 34, 1489.
(15) (a) Díez-Barra, E.; González-Verdú, P.; Tolosa, J.
Tetrahedron 2004, 60, 1563. (b) Hawker, C. J.; Fréchet, J.
M. J. J. Am. Chem. Soc. 1990, 112, 7638.
(16) Rosenthal, A.; Sprinzl, M. Can. J. Chem. 1969, 47, 4477.
(17) Makara, G. M.; Klubek, K.; Anderson, W. K. Synth.
Commun. 1996, 26, 1935.
(18) Analytical and Spectral Data of 10
IR (neat): 3032, 2933, 1673, 1598, 1572, 1513, 1436, 1384,
1320, 1247, 1152, 1090, 1031, 820, 754, 698 cm–1. 1H NMR
(200 MHz, CDCl3): d = 3.21 (t, J = 6.6 Hz, 2 H), 3.59 (t,
J = 6.6 Hz, 2 H), 3.67 (s, 3 H), 4.35 (s, 2 H), 4.95 (s, 2 H),
4.99 (s, 2 H), 6.40 (d, J = 2.2 Hz, 1 H), 6.42 (d, J = 2.2 Hz,
1 H), 6.73 (d, J = 8.6 Hz, 2 H), 7.12 (d, J = 8.7 Hz, 2 H),
7.22–7.32 (m, 10 H), 10.45 (s, 1 H) ppm. 13C NMR (50 MHz,
Synlett 2008, No. 12, 1801–1804 © Thieme Stuttgart · New York

1804
D. K. Mohapatra et al.
LETTER
(28) For general reviews on RCM, see: (a) Grubbs, R. H. Angew.
Chem. Int. Ed. 2006, 45, 3760. (b) Chauvin, Y. Angew.
Chem. Int. Ed. 2006, 45, 3741. (c) Schrock, R. R. Angew.
Chem. Int. Ed. 2006, 45, 3748. (d) Fürstner, A.; Müller, C.
Chem. Commun. 2005, 5583. (e) Deiters, A.; Martin, S. F.
Chem. Rev. 2004, 104, 2199. (f) Fürstner, A. Angew. Chem.
Int. Ed. 2000, 39, 3012. (g) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413. (h) Fürstner, A.; Langemann,
K. Synthesis 1997, 792.
136.2, 136.5, 137.2, 156.6, 160.2, 170.8, 204.6 ppm. Anal.
Calcd for C30H30O5: C, 76.57; H, 6.43. Found: C, 76.42; H,
6.49.
(30) Analytical and Spectral Data of 1
[a]D25 –31.89 (c 2.0, EtOH); lit14 [a]D25 –33.0 (c 2.0, EtOH).
IR (Nujol): 3419, 3176, 2933, 2869, 2254, 1719, 1661, 1607,
1589, 1463, 1316, 1264, 1105, 1006, 823, 616. cm–1. 1H
NMR (500 MHz, acetone-d6,): d = 1.13 (d, J = 6.3 Hz, 3 H),
1.24–1.28 (m, 2 H), 1.40–1.50 (m, 3 H), 1.52–1.57 (m, 1 H),
1.59–1.64 (m, 1 H), 1.73–1.80 (m, 1 H), 2.78 (ddd, J = 2.9,
9.8, 15.5 Hz, 1 H), 3.12 (ddd, J = 2.9, 8.7, 15.5 Hz, 1 H), 3.71
(d, J = 15.7 Hz, 1 H), 3.79 (d, J = 15.6 Hz, 1 H), 4.90–4.96
(m, 1 H), 6.36 (d, J = 2.2 Hz, 1 H), 6.41 (d, J = 2.2 Hz, 1 H),
8.82 (br s, 1 H), 9.19 (br s, 1 H) ppm. 13C NMR (50 MHz,
acetone-d6): d = 20.5, 23.4, 24.5, 27.4, 32.8, 39.6, 44.0, 72.6,
102.4, 112.2, 121.3, 136.9, 158.2, 160.1, 171.0, 206.7 ppm.
Anal. Calcd for C16H20O5: C, 65.74; H, 6.90. Found: C,
65.68; H, 6.91.
(29) Analytical and Spectral Data of 16
[a]D25 +45.05 (c 1.0, CHCl3). IR (neat): 3208, 2928, 1728,
1687, 1655, 1601, 1429, 1311, 1154, 1105, 754 cm–1. 1H
NMR (200 MHz, CDCl3): d = 1.09 (d, J = 6.3 Hz, 3 H),
1.47–1.62 (m, 2 H), 1.91–1.99 (m, 1 H), 2.14–2.26 (m, 1 H),
3.05–3.55 (m, 4 H), 4.94–5.02 (m, 5 H), 5.15–5.25 (m, 1 H),
5.38–5.51 (m, 1 H), 6.46 (d, J = 2.1 Hz, 1 H), 6.52 (s, 1 H),
7.22–7.36 (m, 10 H) ppm. 13C NMR (50 MHz, CDCl3): d =
20.9, 30.4, 33.7, 38.0, 49.0, 70.2, 70.6, 72.4, 99.6, 109.5,
120.1, 124.3, 127.2, 127.6, 128.0, 128.1, 128.6, 134.1,
Synlett 2008, No. 12, 1801–1804 © Thieme Stuttgart · New York

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