Total synthesis of catenioblin B

Article abstract of DOI:10.1016/j.tetlet.2014.09.034

Herein we report the first total synthesis of catenioblin B (1) via a titanium(IV) mediated regioselective epoxide ring-opening, Grignard reaction, Luche's reduction and TEMPO/BAIB mediated intramolecular cyclization as the key steps.

Full text of DOI:10.1016/j.tetlet.2014.09.034

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of catenioblin B
a,
Theegala Srinivas a,b, Helmut M. Hügel b, , Palakodety Radha Krishna
⇑
⇑
a D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b RMIT University, School of Applied Science, Melbourne, VIC 300, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report the first total synthesis of catenioblin B (1) via a titanium(IV) mediated regioselective
epoxide ring-opening, Grignard reaction, Luche’s reduction and TEMPO/BAIB mediated intramolecular
cyclization as the key steps.
Received 25 June 2014
Revised 6 September 2014
Accepted 8 September 2014
Available online xxxx
Ó 2014 Published by Elsevier Ltd.
Keywords:
Catenioblins
Pyranone derivative
Sharpless epoxidation
Regioselective epoxide ring-opening
Grignard reaction
In recent years polyol containing chiral d-lactones have
attracted much attention due to their importance as building
blocks in natural product synthesis1 and their various biological
activity profiles. Recently, catenioblin B2 (1) a polyketide derived
pyranone was isolated from the insect pathogenic fungus
Paecilomyces cateniobliquus. The fungal strain P. cateniobliquus.
YMF1.01799 showed good inhibitory activity towards growth of
cotton bollworms and nematodes and regulate growth of insects.
Catenioblin B (1) is structurally related to prelactone C3 but
contains a cis vicinal diol at the C3–C4 positions (Fig. 1).
OH
OH
3
3
HO
2
2
1
4
4
1
O
O
5 O
O
5
Catenioblin B 1
Prelactone C
Figure 1. Structures catenioblin B and prelactone C.
mono silyl ether compound 4 (90%) which on benzoyl group depro-
tection (K2CO3/MeOH/0 °C) resulted in diol 5 (85%). Masking of diol
5 as its acetonide (2,2 DMP/PPTS/CH2Cl2/0 °C) gave compound 6
(80%). Later, deprotection of TBS ether with TBAF furnished
primary alcohol 74b (86%).
Next the primary alcohol 7 was subjected to Swern oxidation
followed by Grignard reaction6 (1-propenyl magnesiumbromide/
THF/0 °C) to afford syn/anti diastereomeric mixture along with its
E,Z-isomers of allyl alcohol 8 (82% over two steps). Further, the
diasteromeric mixture (without separation) was subjected to
The retrosynthetic analysis of catenioblin (Scheme 1) depicts
the regioselective epoxide ring-opening reaction4 of known epoxy
alcohol 25 as the synthetic tool in accessing polyol system en route
the crucial compound 11, while 11 in turn could be conceived from
epoxy alcohol derivative 3 via a sequence of transformations
followed by Grignard reaction, and oxidation. A key step in the syn-
thesis of the crucial fragment 11 was a Luche’s reduction, followed
by the deprotection of the PMB-ether and pyranone ring cycliza-
tion under TEMPO/BIAB conditions and finally deprotection of
the cis-diol would furnish the natural product 1.
Dess–Martin periodinane oxidation to provide the a,b-unsaturated
Accordingly, the known epoxy alcohol 2 (Scheme 2) was
accessed from the readily available starting material, 1,3 propane-
diol by a reported procedure.5 Thus, the epoxy alcohol 2 when sub-
jected to the regioselective ring-opening reaction with benzoic
acid4 (Bz-OH/Ti(OiPr)4/CH2Cl2/0 °C) afforded 1,2 diol 3 (85%). Diol
3 on selective silyl protection (TBSCl/n-Bu2SnO/CH2Cl2/0 °C) gave
ketone as a E/Z mixture 9 (92% in 3:2 ratio). The purified E-isomer 9
was reduced under Luche’s reduction conditions7 (CeCl3Á7H2O/
NaBH4/MeOH/À78 °C) to afford chiral allylic alcohol 10 (90%).
The de of allylic alcohol 10 was calculated as 93.4% by LCMS
{column: XCB C18 column, 30% water (NH4OAc 10 mm) in acetoni-
trile, flow rate: 1 mL/min, 254 nm, tr(major) = 9.555 min, tr(minor)
= 8.843 min} in favor of S-alcohol (major).10 The absolute stereo-
chemistry at C5 was tentatively assigned as ‘S’ based on literature
⇑
Corresponding authors. Tel.: +91 40 27193518; fax: +91 40 27160387.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
http://dx.doi.org/10.1016/j.tetlet.2014.09.034
0040-4039/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Srinivas, T.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.034

2
T. Srinivas et al. / Tetrahedron Letters xxx (2014) xxx–xxx
OH
OH
O
HO
OBz
OH
OH
O
PMBO
OH
PMBO
OH
O
O
2
11
O
3
Catenioblin B 1
Scheme 1. Retrosynthetic analysis of the catenioblin B (1).
OBz
O
ref . 5
a
b
e
HO
OH
OH
PMBO
PMBO
OH
2
3
OH
OPMB
OBz
OH
c
d
PMBO
OTBS
PMBO
OTBS
OTBS
O
OH
OH
5
4
O
6
OPMB
OPMB
O
OPMB
OH
OPMB
OH
f
g
h
i
OH
O
O
O
O
O
O
O
O
7
9
10
8
OH
O
HO
O
O
HO
OH
j
k
O
O
12
O
O
O
11
1
Scheme 2. Reagents and conditions: (a) BzOH, Ti(OiPr)4, CH2Cl2, 0 °C to rt, 3 h, 85%; (b) TBSCl, n-Bu2SnO, imidazole, CH2Cl2, 0 °C to rt, 3 h, 90%; (c) K2CO3, MeOH, 0 °C to rt, 2 h,
85%; (d) 2,2-DMP, PPTS, CH2Cl2, 0 °C to rt, 6 h, 80%; (e) TBAF, THF, 0 °C to rt, 2 h, 86%; (f) (i) (COCl)2, DMSO, Et3N, CH2Cl2, À78 °C, 1 h, (ii) 1-propenyl magnesium bromide, dry
THF, 0 °C, 2 h (82% over two steps); (g) DMP, CH2Cl2, 0 °C to rt, 1 h, 92%; (h) CeCl3, NaBH4, MeOH, À78 °C, 4 h, 90%; (i) DDQ, 0 °C to rt, 2 h, 88%; (j) TEMPO, BAIB, CH2Cl2: H2O
(3:1) 0 °C to rt, 4 h, 88%.; (k) Amberlyst, CH3CN, 0 °C to rt, 5 h, 78%.
OH
3
HO
4
5
2
6
8
O
O
1
7
1
b
b
a
Figure 2. (a) NOESY spectrum (in CDCl3) of 1; (b) energy minimized structure of 1.
evidence7 and confirmed by extensive NMR studies conducted sub-
C5H/C3H suggested that both protons are in trans orientation to
each other and with opposite facial orientation. This was supported
by NOE correlation between C3H/C1H, C3H/Me-B, C5H/Me-A, C5H/
C7H and C6H/C7H confirming its assigned stereochemistry.
Finally the primary alcohol 11 was subjected to TEMPO/BAIB
conditions8 to afford the cyclized product 12 (88%) that upon
sequently. Next, deprotection of the PMB group in allylic alcohol 10
under DDQ conditions led to the crucial primary alcohol 11 (88%).
And the assignment of stereochemistry at C5 stereogenic carbon as
‘S’ in compound 11 was based on the 1H–1H COSY and NOESY
experiments (Fig. 2) that revealed the absence of NOE between
Please cite this article in press as: Srinivas, T.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.034

T. Srinivas et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
OH
1
2
OH
6
4
8
5
3
7
O
O
A
11
B
a
b
Figure 3. (a) NOESY spectrum (in CDCl3) of 11; (b) energy minimized structure of 11.
Science 1995, 268, 1487; (c) Esumi, T.; Fukayama, H.; Oribe, R.; Kawazoe, K.;
Iwabuchi, Y.; Irie, H.; Hatakayama, S. Tetrahedron Lett. 1997, 38, 4823; (d)
Hanefeld, U.; Hooper, A. M.; Stauntons, J. Synthesis 1999, 401; (f) Chakraborty,
T. K.; Subhasish, T. Tetrahedron Lett. 2001, 42, 1375.
deprotection of acetonide group under acidic conditions with
Amberlyst9 led to the final target 1 (78%). The spectral data of
the target compound 1 was in fairly good agreement with that of
the isolated natural product (see SI).10 However, the optical rota-
4. (a) Radha Krishna, P.; Prabhakar, S.; Rama Krishna, K. V. S. RSC Adv. 2013, 3,
23343; (b) Radha Krishna, P.; Rajesh, N.; Rama Krishna, K. V. S. Tetrahedron Lett.
2014, 55, 3381.
5. (a) Jack Li-Yang Chen, J. L.; Brimble, M. A. J. Org. Chem. 2011, 76, 9417; (b) Gao,
Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, B. J. Am.
Chem. Soc. 1987, 109, 5765.
6. Hähn, S.; Kazmaier, U. Eur. J. Org. Chem. 2011, 25, 4931.
7. (a) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226; (b) Prasad, K. R.; Gholap, S. L. J.
Org. Chem. 2008, 73, 2.
8. Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.; Abrams, J. N.; Forsyth, C. J.
Tetrahedron Lett. 2003, 44, 57.
25
tion of the synthetic 1 was found to be [
a
]
D
À6.83 (c 1.5, MeOH);
25
while that of Natural 1 was reported as: [
a
]
À2.72, (c 0.16,
D
MeOH).11Additionally, the purity of synthetic 1 was determined
by HPLC analysis {XCB C18 column; 4.6 Â 150 mm; 40% water
(NH4OAc 10 mm) in acetonitrile; 1 mL/min; 254 nm, tr(major) =
6.958, tr(minor) = 3.019} and found to be 97.2%.10 Similarly, com-
pound 1 (Fig. 3), on 1H–1H COSY and NOESY experiments, showed
the correlation between C3H/C5H, C5H/C7H and C6H/C7H,
confirming that the centre C5 assigned as ‘S’ was indeed correct
and the energy diagrams are also incorporated in the Supporting
information.
9. Mahesh, P. P.; Nigam, P. R.; Christopher, D. S. Org. Lett. 2010, 12, 2954.
10. Spectral
data
of
selected
compounds:
(E)-1-((4S,5S)-5-(2-(4-
Methoxybenzyloxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-one (9).
25
[a
]
D
À14.23 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.24 (d, J = 8.6 Hz, 2H),
6.93–7.05 (m, 1H), d 6.87 (d, J = 8.6 Hz, 2H), 6.5 (dd, J = 1.7, 15.6 Hz, 1H), 4.52–
4.62 (m, 2H), 4.42 (s, 2H), 3.80 (s, 3H), 3.55 (q, J = 5.2, 7.3 Hz, 2H), 1.91 (dd,
J = 1.7, 6.9 Hz, 3H), 1.66–1.77 (m, 2H), 1.61 (s, 3H), 1.39 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 197.2, 159.1, 144.5, 130.4, 127.5, 113.6, 113.7, 109.9, 81.7,
74.9, 72.6, 66.6, 55.2, 30.9, 27.1, 25.0,18.5; MS-ESI: m/z C19H26O5 [M+NH4]+:
352.
In summary, we have accomplished the first total synthesis of
catenioblin B (1) in 12 steps featuring a Sharpless epoxidation,
Ti(IV) promoted nucleophilic regioselective epoxide ring-opening
and intramolecular cyclization as the key reaction steps.
(S,E)-1-((4R,5S)-5-(2-(4-Methoxybenzyloxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)but-2-en-1-ol (10). [
a
]
D
À8.3 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3): d
25
Acknowledgments
7.26 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.71–5.84 (m, 1H), 5.45 (dddd,
J = 1.5, 7.1, 15.48 Hz, 1H), 4.4 (s, 2H), 4.30 (q, J = 6.0, 13.5 Hz, 1H), 4.09 (br s,
1H), 3.96 (t, J = 6.0 Hz, 1H), 3.81 (s, 3H), 3.55–3.61 (m, 2H), 2.35 (br s, 1H),
1.85–1.90 (m, 2H), d 1.71 (d, J = 6.4 Hz, 3H), 1.49 (s, 3H), 1.37 (s, 3H); 13C NMR
(125 MHz, CDCl3): d 159.1, 129.8, 129.2, 113.7, 107.9, 80.2, 74.2, 72.7, 70.7,
67.1, 55.2, 30.2, 25.3, 27.7, 17.9; MS-ESI: m/z C19H28O5 [M+NH4]+: 335.
One of the authors (T.S.) is thankful to the IICT-RMIT Research
Programme (CLP-0092) for the financial support in the form of
research fellowship. The authors are thankful to the respective
Program Directors Dr. M. Lakshmi Kantam (IICT) and Prof. Suresh
Bhargava (RMIT) for the generous support and encouragement.
(S,E)-1-((4R,5S)-5-(2-Hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-
À12.9 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3): 5.77–5.90 (m,
25
ol (11). [
a
]
D
1H), 5.46 (ddd, J = 1.5, 6.7, 15.1 Hz, 1H), 4.29–4.36 (m, 1H), 4.11 (t, J = 6.7 Hz,
1H), 4.01 (t, J = 6.0 Hz, 1H), 3.80–3.85 (m, 2H), 2.37 (br s, 1H), 1.86–1.99 (m,
2H), d 1.73 (d, J = 6.0 Hz, 3H), 1.52 (s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 130.3, 129.5, 108.4, 80.4, 76.1, 70.7, 61.1, 32.1, 27.8, 25.4, 17.9; MS-
ESI: m/z C11H20O4 [M+Na]+: 239.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.
034.
(3aS,4S,7aS)-2,2-Dimethyl-4-((E)-prop-1-enyl)dihydro-3aH-[1,3]dioxolo[4,5-
25
c]pyran-6(4H)-one (12). [
a
]
D
À12.43 (c 1.8, CHCl3); 1H NMR (300 MHz, CDCl3):
5.87–5.93 (m, 1H), 5.72 (ddd, J = 1.6, 7.7, 15.5 Hz, 1H), 4.70–4.73 (m, 1H), 4.48
(d, J = 7.7 Hz, 1H), 4.38 (dd, J = 1.8, 7.6 Hz, 1H), 2.88 (dd, J = 2.3, 15.8 Hz, 1H),
2.52 (dd, J = 3.6, 15.8 Hz, 1H), 1.78 (dd, J = 1.5, 6.4 Hz, 3H), 1.47 (s, 3H), 1.34 (s,
3H); 13C NMR (75 MHz, CDCl3): d 171.7, 132.1, 124.2, 109.4, 78.9, 74.7, 71.4,
34.5, 25.9, 24.1, 17.8; MS-ESI: m/z C11H16O4 [M+Na]+: 230.
References and notes
(4S,5S,6S)-4,5-dihydroxy-6-((E)-prop-1-enyl)tetrahydro-2H-pyran-2-one
(1).
1. (a) Hanessian, S. Total Synthesis of Natural Products: The Chiron Approach;
Pergamon Press: Oxford, 1983; (b) Scott, J. W. In Asymmetric Synthesis;
Morrison, J. D., Scott, J. W., Eds.; Academic Press: New York, 1984; Vol. 4, pp
1–226; (c) Mori, K. Tetrahedron 1989, 45, 3233; (d) Kotsuki, H.; Miyazaki, A.;
Ochi, M. Tetrahedron Lett. 1991, 32, 4503; (e) Koch, S. S. C.; Chamberli, A. R. J.
Org. Chem. 1993, 58, 2725; (f) Buisson, D.; Azerad, R. Tetrahedron: Asymmetry
1996, 7, 9; (g) Pearson, W. H.; Hemre, E. J. J. Org. Chem. 1996, 61, 7217; (h)
Warmerdam, E.; Tranoy, I.; Renoux, B.; Gesson, J. P. Tetrahedron Lett. 1998, 39,
8077.
2. Niu, X.-M.; Wang, Y.-L.; Xue, H.-X.; Li, N.; Wei, L.-X.; Mo, M.-H.; Zhang, K.-Q. J.
Agric. Food Chem. 2012, 60, 5604.
3. (a) Boddien, C.; Gerber Nolte, J.; Zeeck, A. Liebigs Ann. 1996, 9, 1381; (b) Cortes,
J.; Wiesmann, K. E. H.; Roberts, G. A.; Brown, M. J. B.; Staunton, J.; Leadlan, P. F.
25
[a
]
D
À6.83 (c 1.5, MeOH); 1H NMR (500 MHz, CDCl3): 5.83–5.87 (m, 1H),
5.60 (ddd, J = 1.5, 6.7, 15.1 Hz, 1H), 4.55–4.59 (m, 1H), 4.33 (t, J = 3.0 Hz, 1H),
4.25 (dd, J = 3.7, 6.7 Hz, 1H), 2.93 (dd, J = 6.7, 18.1 Hz, 1H), 2.51 (dd, J = 3.0,
18.1 Hz, 1H), 1.75 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 175.3, 131.1,
128.1, 89.2, 72.6, 69.0, 38.1, 17.8; MS-ESI: m/z C8H12O4 [M+NH4]+:190.
11. In order to rationalize the differences in optical rotation values between the
synthetic 1 and Natural product 1, it was decided to record the same at
different concentrations for the synthetic 1. While, no specific rotation was
25
detected at c 0.16, only at c 0.7 it was detected as [
a
]
D
À6.95 (c 0.7, MeOH).
Since the reported value is very low, the difference in optical rotation values
between the two might be explained due to error in concentration and
temperature.
Please cite this article in press as: Srinivas, T.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.034