Total synthesis of aculeatins A and B via a tethered oxa-Michael approach

Article abstract of DOI:10.1016/j.tetlet.2007.05.026

A stereocontrolled total synthesis of aculeatins A and B has been achieved in eight steps and in 15% overall yield. The key feature of this synthetic approach is the application of a Marouka allylation and tethered intramolecular oxa-Michael reaction to i

Full text of DOI:10.1016/j.tetlet.2007.05.026

Tetrahedron Letters 48 (2007) 4683–4685
Total synthesis of aculeatins A and B via a tethered
oxa-Michael approachI
S. Chandrasekhar,* Ch. Rambabu and T. Shyamsunder
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 16 March 2007; revised 27 April 2007; accepted 3 May 2007
Available online 10 May 2007
Abstract—A stereocontrolled total synthesis of aculeatins A and B has been achieved in eight steps and in 15% overall yield. The key
feature of this synthetic approach is the application of a Marouka allylation and tethered intramolecular oxa-Michael reaction to
install the required stereocentres on the tetrahydropyran ring.
Ó 2007 Elsevier Ltd. All rights reserved.
Spirocyclic natural products continue to fascinate syn-
thetic organic chemists due to their challenging architec-
ture, which has to be installed in a stereo- and
enantioselective manner. Several spirocyclic natural
products have been discovered which possess biological
properties.1 The isolation of aculeatins A 1 and B 2
(Fig. 1) as epimeric spiroacetals2 followed by their race-
mic total synthesis3 happened in quick succession. How-
ever, the only total synthesis of this rare natural product
in optically pure form was reported very recently by
Marco et al. involving asymmetric allylation using chiral
diisocampheyl borane, Wacker oxidation and a boron
aldol as key reactions.4
(overall yield of about 15%). Retrosynthesis revealed
tetradecanal 6 and the known 4-benzyloxyphenyl acetyl-
ene 5 as starting materials (Scheme 1).
The aldehyde 6 was subjected to an enantioselective
Maruoka allylation6 using titanium complex (S,S)-I
and allyltri-n-butyltin to furnish the homoallylic alcohol
7 in 86% yield with excellent an enantioselectivity of
98% ee (determined by chiral HPLC).7 A one-pot ozono-
lysis, followed by two-carbon homologation8 using eth-
oxycarbonylmethylene triphenylphosphorane produced
the d-hydroxy-a,b-unsaturated ester 8, which is set up
for the tethered intramoleclar oxa-Michael reaction to
install the second stereocentre. As anticipated, treatment
of 8 with benzaldehyde and potassium tert-butoxide at
0 °C in anhydrous THF furnished benzylidene acetal 9
in good yield.9 The diastereoselectivity was greater than
95% favouring the more stable syn-isomer. The conver-
sion of the ester functionality in 9 to Weinreb amide 4
via acid 10 was uneventful. The addition of lithiated 4-
benzyloxyphenyl acetylene10 5 furnished alkynone11 3.
Catalytic hydrogenolysis of the benzylidene, benzyloxy
and acetylene groups gave 11 (not isolated) and further
treatment with phenyliodonium(III) bis(trifluoroace-
tate) (PIFA)12 in acetone–H2O (9:1) yielded a mixture
of aculeatins A and B in a ratio of 5:2, which were sep-
arated by column chromatography. All the compounds
were fully characterized by NMR, mass and IR
spectroscopy13 and the spectral data of 1 and 2 were
in full agreement with those reported in the literature4
(Scheme 2).
Our interest is designing strategies towards pyran-con-
taining natural products5 has culminated in a practical
synthesis of both aculeatins A and B in good yields
O
O
O
O
O
O
11
11
OH
OH
1
2
Figure 1.
Keywords: Aculeatin; Marouka allylation; Oxa-Michael reaction;
Spirocyclic natural products.
q IICT Communication No. 070315.
*
In conclusion, a stereodivergent, short, high yielding
synthesis of aculeatins A and B, which should be
Corresponding author. Tel.: +91 40 27193210; fax: +91 40
27160512; e-mail: srivaric@iict.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.026

4684
S. Chandrasekhar et al. / Tetrahedron Letters 48 (2007) 4683–4685
OBn
Ph
5
O
O
O
+
1 or 2
Ph
11
3
O
O
O
OMe
OBn
N
11
Me
4
CHO
6
11
Scheme 1.
Ph
OH
OH
c
d
a
O
O
b
COOEt
CHO
COOEt
11
11
6
11
11
Ph
8
7
9
Ph
Ph
O
O
O
O
O
O
O
O
e
f
OMe
COOH
N
11
11
11
4
3
10
Me
OBn
O
OH OH
g
h
1 + 2
11
O
O
OiPr
O
OH
11
Ti
O
Ti
O
PriO
(S,S)-I
Scheme 2. Reagents and conditions: (a) (S,S)-I (10 mol %), Bu3SnCH2CH@CH2, CH2Cl2, ꢀ15 °C to 0 °C, 24 h, 86%; (b) (i) O3, CH2Cl2, ꢀ78 °C,
45 min, then PPh3; (ii) Ph3P@CHCO2Et, CH2Cl2, rt, 2 h, 80% (for two steps); (c) PhCHO, t-BuOK, THF, 0 °C, 45 min, 69%; (d) LiOH, THF–H2O
(3:1) 0 °C to rt, 4 h, 91%; (e) NH(Me)(OMe)ÆHCl, DCC, Et3N, DMAP, CH2Cl2, 0 °C to rt, 90%; (f) n-BuLi, 5, THF, ꢀ78 °C to ꢀ22 °C, 75%; (g) Pd–
C, H2, EtOAc, rt; (h) PhI(OOCCF3)2, Me2CO–H2O (9:1), rt, 10 min, 52 (two steps), 2.5:1 mixture of aculeatins A and B.
Kobayashi, J. I.; Sakurada, E.; Ishikawa, T. J. Chem. Soc.,
Perkin Trans. 1 1992, 1681–1684; In addition an alkaloid
of undefined structure with name aculeatin was isolated
from the Papaver aculeatum: Maturova, M.; Pavlaskova,
D.; Santavy, F. Planta Med. 1966, 14, 22–41.
amenable to scale up, has been achieved in an overall
yield of 15%.
Acknowledgement
3. Wong, Y. S. Chem. Commun. 2002, 686–687.
4. (a) Falomir, E.; Alvarez-Bercedo, P.; Carda, M.; Marco, J.
A. Tetrahedron Lett. 2005, 46, 8407–8410; (b) Alvarez-
Bercedo, P.; Falomir, E.; Carda, M.; Marco, J. A.
Tetrahedron 2006, 62, 9641–9649.
C.R. and T.S. thank the CSIR, New Delhi, for research
fellowships.
5. (a) Chandrasekhar, S.; Prakash, S. J.; Shyamsunder, T.
Tetrahedron Lett. 2005, 46, 6651–6653; (b) Chandrase-
khar, S.; Shyamsunder, T.; Prakash, S. J.; Prabhakar, A.;
Jagadeesh, B. Tetrahedron Lett. 2006, 47, 47–49; (c)
Chandrasekhar, S.; Rambabu, Ch.; Prakash, S. J. Tetra-
hedron Lett. 2006, 47, 1213–1215.
References and notes
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7706.
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tin, isolated from Toddalia asiatica (T. aculeate): Ishii, H.;
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7. Homoallylic alcohol 7 was converted to its 4-nitrobenzo-
ate for determination of the ee by chiral HPLC [chiral cel

S. Chandrasekhar et al. / Tetrahedron Letters 48 (2007) 4683–4685
4685
OB-H, iPrOH/hexanes (1:99), flow rate 0.4 mL/min,
RT = 8.12 (0.89%), 9.15 (99.1%)].
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13. Representative analytical data: Compound 7: Waxy white
25
solid; ½aꢁD +5.00 (c 1, CHCl3); IR (KBr): m 3346 (br,OH),
2924, 2852 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.86–
;
5.72 (m, 1H), 5.13–5.07 (m, 2H), 3.63–3.55 (m, 1H), 2.31–
2.23 (m, 1H), 2.15–2.05 (m, 1H), 1.43–1.37 (m, 2H), 1.35–
1.25 (m, 22H), 0.88 (t, 3H, J = 6.7 Hz). 13C NMR
(75 MHz, CDCl3): d 134.9, 118.0, 70.6, 41.9, 36.8, 31.9,
29.6–29.3 (br, several overlapped signals), 25.6, 22.6, 14.1.
(ESI-MS): m/z 277 [M+Na]. Compound 9: Waxy white
25
solid; ½aꢁD +1.50 (c 1, CHCl3); IR (KBr): m 2924, 2852,
1
1727 (ketone C@O), 1106, 1025, 751, 728, 696; H NMR
12. For a review on hypervalent iodine compounds, see: (a)
Zhadankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102,
2523–2584; For more recent developments, see: (b) Mori-
aty, R. M. J. Org. Chem. 2005, 70, 2893–2903; (c) Wirth,
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oxidations of phenolic compounds with hypervalent
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Org. React. 2001, 57, 327–415; For reagents for oxidative
spiroacetalizations of arenes, including hypervalent iodine
(200 MHz, CDCl3): d 7.39–7.34 (m, 2H), 7.27–7.18 (m,
3H), 5.43 (s, 1H), 4.23–4.12 (m, 1H), 4.05 (q, 2H,
J = 6.9 Hz), 3.75–3.67 (m, 1H), 2.61 (dd, 1H, J = 15.6,
6.0 Hz), 2.37 (dd, 1H, J = 15.6, 6.0 Hz), 1.65–1.35 (m,
4H), 1.28–1.159 (m, 25H), 0.81 (t, 3H, J = 6.9 Hz) 13C
NMR (50 MHz, CDCl3): d 170.4, 138.6, 127.9, 126.1,
100.5, 96.2, 76.6, 73.2, 60.3, 40.9, 36.6, 35.9, 32.0, 29.7 (br,
several overlapped signals), 29.4, 25.4, 25.1, 22.7, 14.3,
14.2. (ESI-MS): m/z 455.3 [M+Na].