Asymmetric synthesis of the pyran antibiotic (-)-centrolobine

Article abstract of DOI:10.1016/j.tetlet.2005.07.162

An expedient total synthesis of (-)-centrolobine is achieved involving asymmetric Keck allylation and stereoselective intramolecular oxy-Michael reactions as key steps in 8% overall yield.

Full text of DOI:10.1016/j.tetlet.2005.07.162

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6651–6653
Asymmetric synthesis of the pyran antibiotic (ꢀ)-centrolobineI
S. Chandrasekhar,* S. Jaya Prakash and T. Shyamsunder
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 23 May 2005; revised 21 July 2005; accepted 29 July 2005
Available online 15 August 2005
Abstract—An expedient total synthesis of (ꢀ)-centrolobine is achieved involving asymmetric Keck allylation and stereoselective
intramolecular oxy-Michael reactions as key steps in 8% overall yield.
Ó 2005 Published by Elsevier Ltd.
2,6-Disubstituted tetrahydropyran scaffolds have gained
prominence recently owing to their excellent biological
properties.1 This unit is also present in several natural
products with cis stereoconnectivity at the 2,6-positions.
Some recent examples, which fall into this class, include
leucascandrolides,2 phorboxazoles,3 (+)-SCH 351448,4
(ꢀ)-centrolobine and others. Owing to the challenges
posed by the substitution pattern and also due to the
interesting biological properties, the synthesis of these
compounds has attracted attention. Various approaches
leading to (ꢀ)-centrolobine have been reported (Fig. 1).5
ether followed by detosylation and methylation fur-
nished 5 in 53% overall yield (Scheme 1).
Hydroxyl protecting group manipulation was necessary
as allylation of 4-methoxybenzaldehyde under Keck
conditions was not successful in our hands, whilst Ipc2B-
(allyl)8 gave a high yield of the allylated product (89%),
but with poor enantioselectivity. One-pot ozonolysis-
Wittig olefination9 was quite effective to give the a,b-
unsaturated ester 6 in 84% yield. One-pot reduction of
the olefin and ester groups with excess LiAlH4 furnished
8 in synthetically unacceptable yields but this could be
circumvented by stepwise olefin reduction with Mg/
MeOH10 to furnish 7 in 81% yield followed by ester
Our own interest in the synthesis of enantiopure bio-
actives6 prompted us to explore the possibility of syn-
thesizing (ꢀ)-centrolobine, the results of which are
presented herein. Retrosynthetic analysis of (ꢀ)-centrol-
obine revealed two fragments 2 and 3. 4-Tosyloxybenz-
aldehyde was subjected to Keck allylation7 with
allyltributyltin in the presence of (S)-BINOL and
Ti(OiPr)4 to produce homoallylic alcohol 4 in 73% yield.
The optical purity of 4 was found to be 97% ee by chiral
HPLC. Protection of the 2° hydroxyl group as the TBS
(-)-centrolobine
O
OTBS
OBn
MeO
9
CHO
O
O
O
P
EtO
EtO
(1)
OH
MeO
+
OTBS
(-)-centrolobine
OBn
MeO
3
2
Figure 1.
Keywords: Keck allylation; Intramolecular oxy-Michael reaction;
(ꢀ)-Centrolobine; 2,6-Disubstituted tetrahydropyran.
q IICT Communication No. 050615.
CHO
TsO
Scheme 1. Retrosynthetic analysis.
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40
27160512; e-mail addresses: srivaric@iict.res.in; srivaric@gmail.com
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.07.162

6652
S. Chandrasekhar et al. / Tetrahedron Letters 46 (2005) 6651–6653
CO2Et
CHO
a
b, c, d
e
OH
OTBS
OTBS
TsO
TsO
MeO
MeO
4
5
6
CO2Me
OH
CHO
g
f
i
OTBS
h
OTBS
OTBS
O
O
P
MeO
MeO
EtO
EtO
MeO
7
8
2
3
OBn
O
O
k
j
O
(-)-centrolobine
1
OTBS
OBn
MeO
OBn
10
MeO
9
i
˚
Scheme 2. Reagents and conditions: (a) (S)-BINOL, Ti( OPr)4, allyltributyltin, 4 A MS, CH2Cl2, ꢀ20 °C, 70 h, 73%, 97% ee; (b) TBDMSCl,
imidazole, CH2Cl2, 0 °C, 4 h, 87%; (c) Mg/MeOH, rt, 3 h, 85%; (d) K2CO3, Mel, acetone, 0 °C to reflux, 4 h, 73%; (e) (i) O3, CH2Cl2, ꢀ78 °C, 1 h,
then TPP; (ii) Ph3P@CHCO2Et, CH2Cl2, rt, 2 h, 84% (for two steps); (f) Mg/MeOH, rt, 3 h, 81%; (g) LAH, THF, 0 °C to rt, 3 h, 76%; (h) IBX,
DMSO, rt, 4 h, 80%; (i) 3, Ba(OH)2Æ8H2O, THF/H2O (4:1), rt, 5 h, 81%; (j) HF–Py, THF, 0 °C to reflux, 4 h, 80%; (k) Pd/C, H2 atm, HCl, EtOH/
EtOAc/H2O (5:1:1), 10 h, 70%.
Galeffi, C.; Casinovi, C. G.; Marini-Bettolo, G. B. Gazz.
reduction at 0 °C with LAH yielding 8 in 76% yield. To
Chim. Ital. 1965, 95–100; (c) Aragao Craveiro, A.; da
Costa Prado, A.; Gottlieb, O. R.; Welerson de Albuquer-
que, P. C. Phytochemistry 1970, 9, 1869–1875; (d)
install the requisite enone for intramolecular oxy-
Michael reaction, the 1° alcohol group in 8 was oxidized11
with IBX to 5-aryl pentanaldehyde derivative 2 in 80%
Alcantara, A. F. de C.; Souza, M. R.; Pilo-Veloso, D.
yield, which on further homologation with Hornerꢀs
Fitoterapia 2000, 71, 613–615.
phosphonate12 3 under mild basic conditions provided
2. (a) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L.
the key synthon 9 in 81% yield. The olefin geometry
J. Am. Chem. Soc. 2000, 122, 12894–12895; (b) Fettes, A.;
1
could not be assigned from the H NMR spectrum as
the resonances corresponding to the olefin overlapped
with the aromatic protons. However, the 13C spectrum
was homogeneous (d 130.7 and 114.8). Exposure of silyl
ether-enone 9 to HF-pyridine triggered in situ silyl cleav-
age followed by intramolecular oxy-anion Michael addi-
tion13 to provide substituted pyran 10 in 4 h and in 80%
yield. The ꢁsynꢀ selectivity of the 2,6-disubstituted pyran
was confirmed by cleavage of the benzyl ether with Pd/
C/HCl14 to furnish (ꢀ)-centrolobine. In the absence of
HCl the pyran ring was destroyed.15 The optical purity
and other spectral data16 were in full accordance with
those reported for the natural product (Scheme 2).
Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 4098–
4101.
3. (a) Forsyth, C. J.; Ahmed, F.; Clink, R. D.; Lee, C. S.
J. Am. Chem. Soc. 1998, 120, 5597–5598; (b) Smith, A. B.,
III; Minbiole, K. P.; Verhoest, P. R.; Schelhass, M. J. Am.
Chem. Soc. 2001, 123, 10942–10953.
4. (a) Soltani, O.; Brabander, J. K. D. Org. Lett. 2005, 13,
2791–2793; (b) Kang, E. J.; Cho, E. J.; Lee, Y. E.; Ji,
M. K.; Shin, D. M.; Chung, Y. K.; Lee, E. J. Am. Chem.
Soc. 2004, 126, 2680–2681.
5. (a) Colobert, F.; DesMazery, R.; Solladie, G.; Carreno,
M. C. Org. Lett. 2002, 4, 1723–1725; (b) Marumoto, S.;
Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett.
2002, 4, 3919–3922; (c) Evans, P. A.; Cui, J.; Gharpure,
S. J. Org. Lett. 2003, 21, 3883–3885; (d) Boulard, L.;
BouzBouz, S.; Cossy, J.; Franck, X.; Fifadere, B. Tetra-
hedron Lett. 2004, 45, 6603–6605; (e) Clarke, P. A.;
Martin, W. H. C. Tetrahedron Lett. 2004, 45, 9061–9063;
(f) Jennings, M. P.; Clemens, R. T. Tetrahedron Lett. 2005,
46, 2021–2024.
In summary, we have achieved the stereoselective total
synthesis of (ꢀ)-centrolobine. This general strategy for
synthesizing the cis-pyran skeleton should allow the
preparation of structurally related compounds.
6. (a) Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S. S.;
Reddy, M. S. Tetrahedron Lett. 2004, 45, 9299–9301; (b)
Chandrasekhar, S.; Babu, B. N.; Reddy, N. R.; Chandra-
iah, L. Arkivoc 2005, ix, 40–47; (c) Chandrasekhar, S.;
Jagadeshwar, V.; Prakash, S. J. Tetrahedron Lett. 2005,
46, 3127–3129.
Acknowledgements
Two of us (S.J.P. and T.S.) thank CSIR, New Delhi for
research fellowships.
7. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem.
Soc. 1993, 115, 8467–8468.
8. (a) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org.
Chem. 1987, 52, 319–320; (b) Crosby, S. R.; Harding,
J. R.; King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett.
2002, 4, 577–580.
References and notes
1. (a) De Albuquerque, I. L.; Galeffi, C.; Casinovi, C. G.;
Marini-Bettolo, G. B. Gazz. Chim. Ital. 1964, 287; (b)

S. Chandrasekhar et al. / Tetrahedron Letters 46 (2005) 6651–6653
6653
9. Hon, Y. S.; Lu, L.; Li, S. Y. J. Chem. Soc., Chem.
Commun. 1990, 1627–1628.
10. Hudlicky, T.; Natchus, M. G.; Sinai-Zingde, G. J. Org.
Chem. 1987, 52, 4641–4644.
11. Hartman, C.; Meyer, V. Chem. Ber. 1893, 26, 1727.
12. Solladie, G.; Wilb, N.; Bauder, C. J. Org. Chem. 1999, 64,
5447–5452. The Horner phosphonate was synthesized
from commercially available ethyl para-hydroxybenzoate.
(i) Protection of the phenol as the benzyl ether. (ii) The
ester was treated with methyl diethylphosphonate.
6.88 (m, 3H), 5.27 (s, 2H), 4.75 (t, J = 6.7 Hz, 1H), 3.93 (s,
3H), 2.60–2.27 (m, 2H), 1.98–1.57 (m, 4H), 1.01 (s, 9H),
0.15 (s, 3H), 0.00 (s, 3H); 13C NMR (75 MHz, CDCl3): d
202.4, 189.4, 162.6, 158.8, 148.8, 137.2, 130.7, 128.6, 128.2,
127.4, 126.9, 125.5, 114.5, 113.4, 74.7, 70.2, 55.15, 44.0,
40.2, 32.8, 25.8, 24.4, 18.2, ꢀ4.6, ꢀ4.9; MS (LC): m/z 531
(M++H); IR (neat) cmꢀ1 2942, 1726, 1609, 1510, 1461,
1248, 1172, 1087, 835.
25
Compound 10: ½aꢁD ꢀ54.40 (c 0.5, CHCl3); solid, mp 132–
135 °C; 1H NMR (300 MHz, CDCl3):
d 7.91 (d,
J = 8.8 Hz, 2H), 7.46–7.29 (m, 5H), 7.16 (d, J = 8.6 Hz,
2H), 6.95 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H),
5.11 (s, 2H), 4.35 (d, J = 8.6 Hz, 1H), 4.20–3.99 (m, 1H),
3.77 (s, 3H), 3.32 (dd, J = 6.7, 15.7 Hz, 1H), 2.97 (dd,
J = 6.7, 15.7 Hz, 1H), 2.04–1.57 (m, 6H); 13C NMR
(75 MHz, CDCl3): d 196.9, 162.5, 158.7, 136.2, 135.4,
130.7, 130.5, 128.6, 128.1, 127.3, 127.0, 114.4, 113.5, 79.4,
75.1, 70.0, 55.2, 45.2, 33.0, 31.6, 23.8; MS (LC): m/z 417
(M++H), 211; IR (neat) cmꢀ1 3443, 2930, 1608, 1359,
1248, 1096, 794.
O
P
O
O
P
K2CO3, BnBr,
acetone
CO2Et
OEt
OEt
OEt
OEt
CO2Et
0
0C to reflux
3 h, 82%
HO
n-BuLi,
-78 0C, 2 h, 79%
BnO
BnO
13. (a) OꢀBrien, M.; Taylor, N. H.; Thomas, E. J. Tetrahedron.
Lett. 2002, 43, 5491–5494; (b) Yadav, J. S.; Bandyopadhy,
A.; Kunwar, A. C. Tetrahedron. Lett. 2001, 42, 4907–4911.
14. Rao, A. V. R.; Chanda, B.; Borate, H. B. Tetrahedron
1982, 38, 3555–3561.
15. Compound 10 was subjected to standard catalytic hydro-
genation (Pd/C, 1 atm of H2, EtOH) to yield the ring
cleaved compound 11 as the sole product (Ref. 5f).
1
Compound 11: H NMR (300 MHz, CDCl3): d 7.03–6.89
(m, 4H), 6.75–6.61 (m, 4H), 3.76 (s, 3H), 3.60–3.47 (m,
1H), 2.65–2.47 (m, 4H), 1.72–1.18 (m, 8H); MS (LC); m/z
315 (M++H).
25
Compound 1: solid, mp 82–85 °C; ½aꢁD ꢀ91.7 (c 0.5,
25
CHCl3), lit.1c,5b; mp 84–86 °C, ½aꢁD ꢀ93.1 (c 0.16, CHCl3);
1H NMR (300 MHz, acetone-d6): d 8.06 (s, OH), 7.31 (d,
J = 8.6 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.88 (d,
J = 8.6 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 4.30 (dd, J =
1.9, 11.2 Hz, 1H), 3.78 (s, 3H), 3.46–3.41 (m, 1H), 2.71–
2.57 (m, 2H), 1.91–1.62 (m, 6H), 1.46–1.37 (m, 1H), 1.33–
1.24 (m, 1H); 13C NMR (50 MHz, acetone-d6) d 160.4,
157.0, 137.9, 134.7, 130.9, 128.5, 116.7, 115.0, 80.6, 78.4,
56.2, 40.3, 35.4, 32.9, 32.2, 25.5; MS (LC): m/z 313.1
(M++H), 107; IR (neat) cmꢀ1 3401, 2934, 1613, 1513,
1247, 1034.
O
HO
11
Pd/C, 1 atm H2
MeO
EtOH
OBn
O
OH
MeO
10
16. Spectral data for selected compounds:
25
Compound 9: ½aꢁD ꢀ41.7 (c 0.5, CHCl3); 1H NMR
(300 MHz, CDCl3): d 8.04 (d, J = 8.8 Hz, 2H), 7.59–7.45
(m, 5H), 7.32 (d, J = 8.5 Hz, 2H), 7.21–7.05 (m, 3H), 7.03–