Stereoselective synthesis of bioactive natural spiroacetals aculeatins A and B

Article abstract of DOI:10.1016/j.bmcl.2010.01.162

The stereoselective synthesis of two naturally occurring bioactive spiroacetals, aculeatins A and B has been accomplished using 1-tetradecanal as the starting material. The sequence introduces diastereoselective iodine-induced electrophilic cyclization an

Full text of DOI:10.1016/j.bmcl.2010.01.162

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2303–2305
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Stereoselective synthesis of bioactive natural spiroacetals aculeatins A and B q
*
Biswanath Das , Martha Krishnaiah, Chithaluri Sudhakar
Organic Chemistry Division–I, Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of two naturally occurring bioactive spiroacetals, aculeatins A and B has
been accomplished using 1-tetradecanal as the starting material. The sequence introduces diastereoselec-
tive iodine-induced electrophilic cyclization and ring opening of epoxide with 1,3-dithiane as the key
steps.
Received 24 November 2009
Revised 25 January 2010
Accepted 30 January 2010
Available online 10 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The paper is dedicated to Oishika (daughter
of the senior author) on the occasion of her
15th birthday
Keywords:
Aculeatins A and B
Bioactive compound
Stereoselective synthesis
Diastereo iodo cyclization
Epoxide opening
Aculeatins A and B, two epimeric spiroacetals, were isolated
from the plant Amomum aculeatum (Zringiberaceae).1 The com-
pounds were found to be antiprotozoal against Plasmodium and
Trypanozoma species. They also showed high cytotoxic activity
against the KB cell line and several human cancer cell lines includ-
ing Lu1 (human lung cancer) and MCF-7 (human breast cancer) cell
lines.1,2 Due to interesting structural pattern and impressive bioac-
tivity the synthesis of aculeatins A and B is an important target to
the organic chemists.3 Here we would like to mention an alterna-
tive efficient approach for the synthesis of these two compounds.
from 1-tetradecanal (8)]. The cyclization product 6 can be con-
verted into the epoxide 5 which can undergo ring opening with
1,3-dithiane and subsequently required alkylation.
The synthesis of aculeatins A and B (Scheme 2) was initiated
from commercially available 1-tetradecanal (8) which on enantio-
selective Maruoka allylation4 using titanium complex (S,S)-I and
allyl tri-n-butyltin produced the homoallylic alcohol 9 in 82% yield
with an enantioselectivity of 97% (determined by chiral HPLC).3d
Compound 9 was treated with di-tert-butyl dicarbonate in the
presence of DMAP in MeCN5 to furnish the homoallylic tert-butyl
carbonate 7 (88%) which was suitable for diastereoselective io-
dine-induced electrophilic cyclization to introduce the required
stereogenic centre. The treatment of 7 with iodine in MeCN at
À20 °C afforded the iodocarbonate 6 (73%) with high diastereose-
lectivity (de 95%) favouring syn-isomer.6 The pure syn-isomer
was separated by column chromatography. The compound was
then treated with K2CO3 in MeOH to form the desired syn-epoxy
alcohol 10 in 84% yield.6a The secondary hydroxyl group of the
epoxide 10 was protected with tBuMe2SiCl (TBS-Cl) to produce
the TBS-protected epoxide 5 (89%). The epoxide ring of 5 was sub-
sequently opened7 with 1,3-dithiane using n-BuLi in THF at À78 °C
to yield the product 11 (86%) which was again treated with TBS-Cl
to form 4 in 89% yield. Compound 4 was then reacted with TBS-
protected 4-hydroxyphenylethyl iodide (A) using n-BuLi at
À78 °C to afford the required intermediate 3 (84%). The iodide A
was prepared from TBS-protected 4-hydroxystilbene (12) by treat-
ment with DMSBH3 at room temperature and subsequently with
O
O
O
O
O
O
11
11
HO
HO
1
2
The retrosynthetic analysis of 1 and 2 (depicted in Scheme 1)
indicates that the key intermediate 3 can be prepared by diastereo-
selective iodine-induced electrophilic cyclization of 7 [derived
q
Part 73 in the series ‘Synthetic studies on natural products’.
* Corresponding author. Tel./fax: +91 40 7160512.
E-mail address: biswanathdas@yahoo.com (B. Das).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.162

2304
B. Das et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2303–2305
OTBS OTBS
OTBS OTBS
OTBS
S
O
1 or 2
S
S
S
12
12
12
3
4
5
OTBS
O
OBOC
O
O
CHO
I
12
12
12
6
7
8
Scheme 1. Retrosynthetic analysis.
O
OH
12
OBOC
O
O
a
c
b
CHO
12
I
Complex (S,S)-I
12
12
6
d
7
8
9
OTBS OH
S
OTBS
e
f
O
OH
O
S
12
12
g
12
11
5
10
OTBS OTBS
OTBS OTBS
h
S
i
S
S
1 & 2
S
12
12
(5:1)
4
3
OTBS
i
Scheme 2. Reagents and conditions: yields: (a) TiCl4 (5 mol %), Ti(OiPr)4 (15 mol %), rt, 1 h, Ag2O (10 mol %), rt, 5 h, (S,S)-I (20 mol %), rt, 2 h, allyl tri-n-butyltin, 0 °C, 12 h, 82%;
(b) BOC2O, DMAP, CH3CN, 0 °C to rt, 10 h, 89%; (c) I2, CH3CN, À20 °C, 6 h, 72%; (d) K2CO3, MeOH, rt, 30 min, 81%; (e) TBS-Cl, Imidazole, DCM, 0 °C to rt, 5 h, 89%; (f) 1,3-dithiane,
n-BuLi, THF–HMPA (9:1), À78 °C, 1 h, 86%; (g) TBS-Cl, imidazole, DCM, 0 °C to rt, 5 h, 89%; (h) compound A, n-BuLi, THF–HMPA (9:1), À78 °C, 84%; (i) p-TSA-MeOH, 0 °C and
PIFA, MeCN/H2O (6:1), 0 °C, 5 min.
NaBH4 and H2O2 at 0 °C8 followed by iodination9 (Scheme 3). The
intermediate 3 was then treated with p-TSA at 0 °C to room tem-
perature and finally with phenyliodonium (III) bis (trifloroacetate)
(PIFA) at 0 °C3a to afford aculeatins A (1) and B (2) (5:1) (Scheme 2).
Which were separated by column chromatography. The physical
and spectral properties of 1 and 2 were found to be identical to
those of the naturally occurring compounds.1
In the present synthesis two key steps involving diastereoselec-
tive iodine-induced electrophilic cyclization and ring opening of
epoxide with 1,3-dithiane have been introduced for the synthesis
i
O
O
OPr
Ti
O
O
O
Ti
iPrO
Complex (S,S)-I
OH
I
j
k
TBSO
TBSO
TBSO
12
A
13
Scheme 3. Reagents and conditions: yields: (j) BH3ÁDMS, THF, 0 °C to rt, H2O2, NaOAc, 85%; (k) I2, Ph3P, imidazole, ether/acetonitrile (3:1), 0 °C to rt, 1 h, 90%.

B. Das et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2303–2305
2305
of aculeatins A and B.10 This protocol has not been used earlier for
the synthesis of aculeatins to install a new chiral centre with syn-
selectivity.3 All the steps involved in the present synthesis are
high-yielding and the applied reagents are readily available. The
overall process is simple and straightforward. The ease of synthesis
that this strategy offers is impressive. In some of the earlier meth-
ods (i) the reactions steps were comparatively larger,3f (ii) the
intermediates were obtained in unsatisfactory yields3e and (iii) lar-
ger reaction times were required.3b,c Thus the present method is a
new and efficient advantageous route to the stereoselective syn-
thesis of aculeatins A and B.
Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron 2006, 62, 9641; (d)
Chandrasekhar, S.; Rambabu, Ch.; Shyamsunder, T. Tetrahedron Lett. 2007, 48,
4683; (e) Peuchmaur, M.; Wong, Y.-S. J. Org. Chem. 2007, 72, 5374; (f) Suresh,
V.; Selvam, J. J. P.; Rajesh, K.; Venkateswarlu, Y. Tetrahedron: Asymmetry 2008,
19, 2008.
4. (a) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708;
(b) Gupta, P.; Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2004, 45, 849.
5. Felpin, F.-X.; Lebreton, J. J. Org. Chem. 2002, 67, 9192.
6. (a) Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.; Jernstedt, K. K. J.
Org. Chem. 1982, 47, 4013; (b) Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.;
Sandri, S. J. Org. Chem. 1982, 47, 4626.
7. De Brabander, J.; Vanhessche, K.; Vandewalle, M. Tetrahedron Lett. 1991, 32,
2821.
8. Ashenhurst, J. A.; Gleason, J. L. Tetrahedron Lett. 2008, 49, 504.
9. Sabitha, G.; Padmaja, P.; Sudhakar, K.; Yadav, J. S. Tetrahedron: Asymmetry 2009,
20, 1330.
Acknowledgements
10. The spectral data of two new important intermediates 6 and 10 are given
below.
Compound 6: IR 1722, 1402, 1261 cmÀ1 1H NMR (200 MHz, CDCl3): d 4.52–
;
The authors thank CSIR and UGC, New Delhi for financial
assistance.
4.41 (2H, m), 3.42 (1H, dd, J = 9.0, 4.0 Hz), 3.30 (1H, dd, J = 9.0, 7.0 Hz), 2.42–
2.32 (2H, m), 1.81–1.62 (2H, m), 1.44–1.21 (22H, m), 0.89 (3H, t, J = 7.0 Hz); 13C
NMR (50 MHz, CDCl3): d 148.7, 78.5 75.4, 34.5, 31.8, 31.2, 29.9, 29.6, 29.2,
22.5,14.2, 4.8; MS (ESI): m/z 447 [M+Na]+, 425[M+H]+; HRMS (ESI): m/z
447.1380 [M+Na]+. Calcd for C18H33I O3Na; m/z 447.1372.
References and notes
Compound 10: IR 3419, 1462, 1269 cmÀ1 1H NMR (200 MHz, CDCl3): d 3.84
;
1. Heilimann, J.; Mayr, S.; Brun, R.; Rali, T.; Sticher, O. Helv. Chem. Acta 2000, 83,
2939.
2. Salim, A. A.; Su, B.-N.; Chai, H.-B.; Riswan, S.; Kardono, L. B. S.; Ruskandi, A.;
Farnsworth, N. R.; Swanson, S. M.; Kinghorn, A. D. Tetrahedron Lett. 2007, 48,
1849.
(1H, m), 3.04 (1H, m), 2.72 (1H, t, J = 5.0 Hz), 2.45 (1H, dd, J = 5.0, 4.0 Hz), 2.02
(1H, br s), 1.82 (1H, m), 1.49–1.40 (5H, m), 1.36–1.20 (20H, m), 0.88 (3H, t,
J = 7.0 Hz) 13C NMR (50 MHz, CDCl3): d 70.0, 50.6, 46.2, 39.9, 37.8, 32.0, 29.8,
29.7, 29.0, 25.6, 22.4, 20.8, 14.1; MS (ESI): m/z 293 [M+Na]+; HRMS (ESI): m/z
293.1356 [M+Na]+. Calcd for C18H33I O3Na; m/z 293.1347.
3. (a) Wang, Y.-S. Chem. Commun. 2002, 686; (b) Falomir, E.; Alvarez-Bercedo, P.;
Carda, M.; Marco, J. A. Tetrahedron Lett. 2005, 46, 8407; (c) Alverz-Bercedo, P.;