First stereoselective total synthesis of decytospolides A and B

Article abstract of DOI:10.1016/j.tetlet.2012.05.094

The first stereoselective total synthesis of decytospolides A and B has been accomplished starting from n-hexanal. The key steps involved in this synthesis are Horner-Wittig reaction, Sharpless asymmetric epoxidation, and oxa-Michael reaction.

Full text of DOI:10.1016/j.tetlet.2012.05.094

Tetrahedron Letters 53 (2012) 4054–4055
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First stereoselective total synthesis of decytospolides A and B
⇑
P. Janardhan Reddy, A. Srinivas Reddy, J. S. Yadav, B. V. Subba Reddy
Natural Products Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first stereoselective total synthesis of decytospolides A and B has been accomplished starting from
n-hexanal. The key steps involved in this synthesis are Horner–Wittig reaction, Sharpless asymmetric
epoxidation, and oxa-Michael reaction.
Received 17 April 2012
Revised 19 May 2012
Accepted 20 May 2012
Available online 26 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Natural product synthesis
Horner–Wittig reaction
oxa-Michael reaction
Sharpless asymmetric epoxidation
Decytospolide
The 2,6-disubstituted tetrahydropyran containing natural
products such as phorboxazoles,1 (ꢀ)-centrolobine,2 bryostatins,3
leucascandrolide A,4 and neopeltolide5 are found to exhibit prom-
ising biological properties which make them attractive synthetic
targets to organic chemists.6 In particular, decytospolides A and
B were isolated recently from Cytospora sp., an endophytic fungus
from Ilex canariensis (Fig. 1).7 Decytospolide B shows strong cyto-
toxicity than decytospolide A. However, to date, there have been
no reports on the total synthesis of decytospolides A and B.
Following our interest on the synthesis of biologically active
natural products having tetrahydropyran ring system,8 we, herein
report a stereoselective total synthesis of decytospolides A and B
employing Horner–Wittig reaction and intramolecular oxa-Mi-
chael reaction as key steps.
utive reactions like allyl Grignard and Horner–Wittig reactions
(Scheme 1).
Our synthetic approach for the total synthesis of decytospolides
A and B is outlined in Scheme 2. We began our synthesis from n-
hexanal. Accordingly, n-hexanal was converted into epoxide 7 in
three steps using known procedures. Regioselective ring opening9
of epoxy alcohol 7,10 with p-methoxybenzyl alcohol in the pres-
ence of Ti(OiPr)4 gave the diol 8 in 82% yield. Selective protection
of primary alcohol 8 with p-toluenesulfonyl chloride, triethyl-
amine, and a catalytic amount of dibutyltin oxide gave the tosylate
which then treated with a base to afford the epoxide 4 in 81% yield,
over two steps. Epoxide 4 was then subjected to allylation with
allylmagnesium bromide in the presence of a catalytic amount of
CuI to afford the secondary alcohol 9 in 90% yield.11 Alcohol 9
was protected as its MOM ether 10 using MOM-Cl and DIPEA in
the presence of a catalytic amount of DMAP. Oxidative cleavage
of terminal olefin 10 using OsO4, 2,6-lutidine, and NaIO4 gave the
aldehyde in a single step,12 which was subsequently homologated
by Horner–Wittig reaction with dimethyl 2-oxobutanephospho-
In our retrosynthetic analysis, we assume that decytospolides A
and B could be prepared by oxa-Michael addition of secondary
alcohol onto
a,b-unsaturated ketone 3. The Michael acceptor 3
could in turn be obtained from epoxide 4 by utilizing two consec-
nate in the presence of NaH and 18-crown-6 to afford the
a,b-
unsaturated ketone 3 in 80% yield over two steps.13
O
O
OPMB
O
RO
O
O
OMOM
3
HO
1 R = H
2 R = OAc
OPMB
1 R = H
2 R = OAc
Figure 1. Structure of decytospolides A and B.
n-Hexanal
O
4
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (B.V. Subba Reddy).
Scheme 1. Retrosynthesis of decytospolides A and B.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.094

P. Janardhan Reddy et al. / Tetrahedron Letters 53 (2012) 4054–4055
4055
O
Acknowledgement
a
b
OH
H
P.J.R and A.S.R thank CSIR, New Delhi, for the award of
fellowships.
5
6
OPMB
O
References and notes
c
d
OH
OH
OH
1. (a) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J. Am. Chem. Soc.
1996, 118, 9422; (b) Forsyth, C. J.; Ahmed, F.; Clink, R. D.; Lee, C. S. J. Am. Chem.
Soc. 1998, 120, 5597; (c) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.;
Schelhass, M. J. Am. Chem. Soc. 2001, 123, 10942.
2. Chan, P. K.; Loh, P. T. Org. Lett. 2005, 7, 4491.
3. Szallasi, Z.; Du, L.; Levine, R.; Lewin, N. E.; Nguyen, P. N.; Williams, M. D.; Pettit,
G. R.; Blumberg, P. M. Cancer Res. 1996, 56, 2105.
4. (a) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122,
12894; (b) Fettes, A.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 4098.
5. Crane, E. A.; Scheidt, K. A. Angew. Chem., Int. Ed. 2010, 49, 8316.
6. (a) Michelet, W.; Genet, J. P. Curr. Org. Chem. 2005, 9, 405; (b) Nicolaou, K. C.;
Kim, D. W.; Baati, R.; O’Brate, A.; Giannakakou, P. Chem. Eur. J. 2003, 9, 6177; (c)
Wender, P. A.; Verma, V. A. Org. Lett. 1893, 2006, 8.
8
7
OPMB
OH
OPMB
f
e
O
9
4
OPMB
OMOM
O
OPMB
g
OMOM
10
7. Lu, S.; Sun, P.; Li, T.; Kurtan, T.; Mandi, A.; Antus, S.; Krohn, K.; Draeger, S.;
Schulz, B.; Yi, Y.; Li, L.; Zhang, W. J. Org. Chem. 2011, 76, 9699.
3
8. Yadav, J. S.; Reddy, N. R.; Harikrishna, V.; Reddy, B. V. S. Tetrahedron Lett. 2009,
50, 1318.
9. Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557.
10. (a) Liu, J.; Yang, J.-H.; Ko, C.; Hsung, R. P. Tetrahedron Lett. 2006, 47, 6121; (b)
Donald, C. D.; Robert, P. D.; Yanzhi, Z.; Christopher, K. M.; Archana, K.; Aurora,
S. P.; Yuesheng, W. J. Org. Chem. 2003, 58, 718.
OH
O
h
i
O
O
MOMO
OMOM
12
11
11. Ebine, M.; Fuwa, H.; Sasak, M. Org. Lett. 2008, 10, 2275.
12. Chandrasekhar, S.; Mahipal, M.; Kavitha, M. J. Org. Chem. 2009, 74, 9531.
13. Trapani, G.; Reho, A.; Latrofa, A.; Liso, G. Synthesis 1988, 81.
14. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885.
15. Paterson, I.; Anderson, E. A.; Dalby, S. M.; Genovino, J.; Lim, J.; Moessner, C.
Chem. Commun. 1852, 2007, 43.
k
j
O
O
O
O
AcO
HO
16. (a) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J. Org. Chem. 1995,
60, 4419; (b) Fuji, K.; Kawabata, T.; Fujita, E. Chem. Pharm. Bull. 1980, 28, 3662.
17. Spectral data for decytospolide A (1): ½a2D0ꢁ +8.3 (c 0.8, CHCl3); 1H NMR (CDCl3,
300 MHz): d 3.80–3.69 (1H, m), 3.32–3.21 (1H, m), 3.03 (1H, dt, J = 9.0, 2.2 Hz),
2.66 (1H, dd, J = 15.0, 8.1 Hz), 2.55–2.44 (2H, m), 2.39 (1H, dd, J = 15.0, 4.9 Hz),
2.13–2.03 (1H, m), 1.88–1.16 (12H, m), 1.04 (3H, t, J = 7.3 Hz), 0.88 (3H, t,
J = 6.4 Hz); 13C NMR (CDCl3, 75 MHz): d 210.0, 82.1, 74.0, 70.5, 48.3, 37.0, 32.9,
31.9, 31.8, 31.2, 24.9, 22.6, 14.0, 7.5; IR (neat): mmax 3422, 2933, 2862, 1711,
1
2
Scheme 2. Synthesis of decytospolides A and B. Reagents and conditions: (a) (i)
PPh3 = CHCO2Et, CH2Cl2, 25 °C, 6 h; (ii) DIBAL-H, CH2Cl2, 25 °C, 2 h; (b) Ti(OiPr)4, (+)-
DIPT, t-BuOOH, CH2Cl2, ꢀ20 °C, 6 h; (c) Ti(OiPr)4, PMB-OH, toluene, reflux, 2 h; (d) (i)
TsCl, Et3N, CH2Cl2, 25 °C, 3 h; (ii) NaH, THF, 28 °C, 4 h; (e) allylMgBr, CuI, THF,
ꢀ30 °C, 2 h; (f) MOM-Cl, DIPEA, CH2Cl2, 23 °C, 6 h; (g) (i) OsO4, 2,6-lutidine, NaIO4,
2 h; (ii) CH3CH2COCH2PO(OMe)2, NaH, 18-Crown-6, 28 °C, 6 h; (h) DDQ, CH2Cl2:H2O
(10:1), 3 h; (i) KOtBu, THF, ꢀ20 °C, 0.5 h; (j) BF3.OEt2, (CH3)2S, ꢀ10 °C, 1 h; (k)
pyridine, Ac2O, 28 °C, 18 h.
1459 cmꢀ1 ESI-MS: m/z 265 [M+Na]+; HRMS (ESI) Calcd for C14H26O3Na
;
265.17742. Found: 265.17718; decytospolide B (2): ½a2D0ꢁ +22.6 (c 1.2, CHCl3); 1H
NMR (CDCl3, 300 MHz): d 4.51–4.39 (1H, m), 3.83–3.72 (1H, m), 3.25 (1H, dt,
J = 9.3, 2.4 Hz), 2.68 (1H, dd, J = 15.1, 7.9 Hz), 2.48 (2H, m), 2.38 (1H, dd, J = 15.2,
4.9 Hz), 2.20–2.10 (1H, m), 2.04 (3H, s), 1.81–1.19 (11H, m), 1.04 (3H, t,
J = 7.3 Hz), 0.87 (3H, t, J = 6.1 Hz); 13C NMR (CDCl3, 75 MHz): d 209.8, 170.2,
79.3, 74.2, 72.0, 48.2, 37.2, 31.9, 31.7, 30.8, 29.3, 24.8, 22.6, 21.1, 14.0, 7.4;
IR(neat): mmax 2928, 2856, 1739, 1460, 1372 cmꢀ1; ESIMS: m/z 307 [M+Na]+;
HRMS (ESI) Calcd for C16H28O4Na 307.18798. Found: 307.18799.
1-((2R,5S,6R)-5-(Methoxymethoxy)-6-pentyl-tetrahydro-2H-pyran-2-yl)butan-2-
one (12): ½a2D0ꢁ +7 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz): d 4.72 (1H, d,
J = 6.8 Hz), 4.60 (1H, d, J = 6.8 Hz), 3.80–3.69 (1H, m), 3.37 (3H, s), 3.24–3.08
(2H, m), 2.65 (1H, dd, J = 15.1, 8.1 Hz), 2.55–2.33 (3H, m), 2.23–2.13 (1H, m),
1.86–1.69 (1H, m), 1.55–1.18 (10H, m), 1.04 (3H, t, J = 7.1 Hz), 0.87 (3H, t,
J = 6.4 Hz); 13C NMR (CDCl3, 75 MHz): d 209.9, 95.2, 80.5, 75.6, 74.0 55.5, 48.3,
37.0, 32.0, 31.8, 31.0, 30.0, 24.9, 22.6, 14.0, 7.4; IR (neat): mmax 2933, 1714,
1459, 1377 cmꢀ1; ESIMS: m/z 309 [M+Na]+; HRMS (ESI) Calcd for C16H30O4Na
309.20363. Found: 309.20336.
Oxidative deprotection of p-methoxybenzyl ether 3 with DDQ14
followed by base induced intramolecular oxa-Michael reaction of
the resulting alcohol (KOtBu, THF, ꢀ20 °C) gave the tetrahydropy-
ran ring 12 as a sole product in 70% yield over two steps.15 Finally,
the removal of MOM group from compound 12 using BF3.OEt2 and
DMS16 afforded the title compound 1, decytospolide A in 85% yield,
which was then acetylated under standard conditions to furnish
the decytosploide B in 90% yield (Scheme 2). The optical rotation
and spectral data of synthetic compounds 1 and 217 are identical
with those of natural products.7
In summary, we have demonstrated a highly stereoselective to-
tal synthesis of decytospolides A and B using a readily accessible
starting material, n-hexanal involving Horner–Wittig reaction,
Sharpless asymmetric epoxidation and intramolecular oxa-Michael
reaction as the key steps. Our approach provides an easy access for
decytospolides A and B.
(8S,9R,E)-9-(4-Methoxybenzyloxy)-8-(methoxymethoxy) tetradec-4-en-3-one (3):
½
a2D0ꢁ +12.5 (c 0.2, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.29–7.23 (2H, m),
6.90–6.80 (3H, m), 6.16–6.08 (1H, m), 4.78 (1H, d, J = 6.7 Hz), 4.64–4.59 (2H,
m), 4.45 (1H, d, J = 10.5 Hz), 3.80 (3H, s), 3.70–3.63 (1H, m), 3.48–3.38 (4H, m),
2.56 (2H, q, J = 14.3 Hz), 2.49–2.35 (1H, m), 2.33–2.16 (1H, m), 1.87–1.21 (10H,
m) 1.10 (3H, t, J = 7.5 Hz), 0.88 (3H, t, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): d
201.0, 159.1, 146.5, 130.8, 130.1, 129.4, 113.7, 96.3, 80.3, 78.4, 71.9, 55.8, 55.2,
33.2, 31.9, 30.7, 29.0, 28.8, 25.6, 22.6, 14.0, 8.1; IR (neat): mmax 3423, 2957,
2927, 1709, 1605 cmꢀ1; ESI-MS: m/z 407 [M+Na]+.