Enantioselective synthesis and absolute configurations of aculeatins A and B

Article abstract of DOI:10.1016/j.tetlet.2005.09.146

The two naturally occuring, bioactive spiroacetals aculeatins A and B have been synthesized for the first time in enantiopure form using an asymmetric allylation as the only chirality source. A further key step was a stereoselective aldol reaction with re

Full text of DOI:10.1016/j.tetlet.2005.09.146

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8407–8410
Enantioselective synthesis and absolute configurations of
aculeatins A and B
a
a
a,
b,
*
´
*
Eva Falomir, Paula Alvarez-Bercedo, Miguel Carda and J. Alberto Marco
aDepart. de Q. Inorga´nica y Orga´nica, Univ. Jaume I, Castello´n, E-12080 Castello´n, Spain
bDepart. de Q. Orga´nica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
Received 14August 2005; revised 21 September 2005; accepted 23 September 2005
Available online 10 October 2005
Abstract—The two naturally occuring, bioactive spiroacetals aculeatins A and B have been synthesized for the first time in enan-
tiopure form using an asymmetric allylation as the only chirality source. A further key step was a stereoselective aldol reaction with
remote induction. The absolute configurations of the natural products have been established and the previously assigned relative
configurations have been corrected.
Ó 2005 Elsevier Ltd. All rights reserved.
The aculeatins A and B are two epimeric spiroacetals
isolated five years ago from the terrestrial plant species
Amomum aculeatum Roxb. (fam. Zingiberaceae). They
were assigned structures (relative configurations) 1 and
2, respectively. A more complex variant, aculeatin C 3,
was also isolated from the same plant (Fig. 1). Later,
the same authors reported the isolation of a fourth
member of this compound family, named aculeatin D
and assigned structure and relative configuration 4.1,2
These compounds were found to display antiprotozoal
activity against some Plasmodium and Trypanosoma spe-
cies. In addition, they showed antibacterial activity and
were cytotoxic against the KB cell line.
O
O
O
O
O
O
12
12
OH
OH
1
2
O
O
O
O
O
O
O
O
11
12
The aculeatins A–D represent a novel type of natural
compounds displaying the unusual, previously unre-
ported 1,7-dioxadispiro[5.1.5.2]pentadecane system. The
observed biological activity of the aculeatins may be
related to the presence of a Michael acceptor moiety.3
The spiroacetals themselves are also interesting mole-
cular fragments, which are present in many pharmacologi-
cally relevant substances such as macrolide or polyether
antibiotics.4 In view of this and of the aforementioned
biological activities, it is not surprising that the aculea-
tins have already aroused interest in the synthetic com-
OH
OH
OH
6
3
4
Figure 1. Published structures and relative configurations of aculeatins
A–D.
munity. As a matter of fact, two papers have very
recently appeared, which deal with the synthesis of acule-
atins A, B, and D, in all cases in racemic form.5 Both syn-
theses relied upon the same type of phenolic oxidation to
form the 1,7-dioxadispiro[5.1.5.2]pentadecane system
(see below). In this communication, we present the first
synthesis of 1 and 2 in enantiopure form.
Keywords: Aculeatins; Enantioselective synthesis; Phenol oxidation;
Aldol reaction; Asymmetric allylation.
*
The retrosynthetic concept is depicted in Scheme 1.
Thus, the dispirocyclic system is to be created via pheno-
Corresponding authors. Tel.: +3496 3543437; fax: +3496 354
4328; e-mail: alberto.marco@uv.es
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.146

8408
E. Falomir et al. / Tetrahedron Letters 46 (2005) 8407–8410
OR
O
O
11
CHO
10
9
12
13
a
8
1
BnO
BnO
OH
OH
O
6
7
R = H
R = Bn
7O
5
2
b
14
O
12
12
6
15
OBn O
4
5
3
c
d
OH
OH
phenolic
oxidation
Aculeatins A-B
8
BnO
OR1 OR2
R1, R2 = H
OBn
OP OH OH
aldol
f,g
12
I
12
9
BnO
e
10 R1, R2 = CMe2
PO
O
O
O
OP
O
O
Aculeatin A
+
Aculeatin B
h
+
12
II
11
12
HO
PO
asymmetric allylation
Scheme 2. Reagents and conditions: (a) allylBIpc2 from (ꢀ)-DIP-Cl
and allylmagnesium bromide, Et2O, 3 h, ꢀ90 °C; (b) NaH; THF, then
BnBr, rt, overnight, 85% overall from 5; (c) PdCl2, CuCl2, aq DMF,
O2, 2 d, 75%; (d) Bu2BOTf, EtNiPr2, CH2Cl2, ꢀ78 °C, 1 h, then
addition of n-tetradecanal, 3 h, ꢀ78 °C, then LiBH4, 2 h, ꢀ78 °C, 65%
overall; (e) 2,2-dimethoxypropane, camphorsulfonic acid (cat.),
Me2CO, rt, 1 d, 72%; (f) H2 (1 atm), 10% Pd/C, EtOAc, rt, 6 h, 70%;
(g) (COCl)2, DMSO, CH2Cl2, ꢀ78 °C, then Et3N, ꢀ78 ! 0 °C, 87%;
(h) PhI(OOCCF3)2, Me2CO/H2O (9:1), rt, 24h, 65% overall, 5.5:1
mixture of aculeatins A and B.
CHO
III
(P = protecting group)
PO
Scheme 1.
lic oxidation of an appropriately substituted intermedi-
ate ketone, related in turn to the protected triol I. The
latter is derived from the aldol reaction of ketone II with
n-tetradecanal. Intermediate II should be obtained from
a suitably protected dihydro-p-coumaraldehyde III
by means of asymmetric allylation and functional
manipulation.
and spectral properties associated with aculeatin A.1 It
was stable and showed no noticeable tendency to isom-
erize to the minor stereoisomer. NOE measurements evi-
denced the absence of dipolar correlations between the
methine proton H-2 and one methylene proton at C-15
(for numbering, see Scheme 1). This strongly suggests
that its configuration has to be represented as 2 (see
Fig. 2), not 1 as proposed.1 In addition, structure 2 ben-
Scheme 2 shows the details of the synthesis. Thus, the
known 3-(p-benzyloxyphenyl)propanal 56 was subjected
to asymmetric allylation using the chiral allylborane
prepared as reported from allylmagnesium bromide
and (ꢀ)-DIP-Cl [(ꢀ)-diisopinocampheylchloroborane].7
Homoallyl alcohol 6 was obtained in over 96% ee as
judged by NMR examination of the Mosher ester.8 Benz-
ylation of the hydroxyl group followed by Wacker oxi-
dation9 provided methyl ketone 8. Boron aldol
reaction10 of this ketone with n-tetradecanal followed
by in situ reduction with LiBH4 afforded the monobenz-
ylated anti,syn-1,3,5-triol 9 as a single diastereomer.11
Protection of the two free hydroxyl groups as an aceto-
nide followed by debenzylation and Swern oxidation
afforded 11. Hydrolytic cleavage of the acetonide moiety
furnished the expected b,d-dihydroxy ketone albeit in
low yield (<35%). Fortunately, treatment of acetonide
11 with phenyliodonium bis(trifluoroacetate) not only
caused the desired phenolic oxidation5,12 but also aceto-
nide hydrolysis and subsequent spiroacetalization. This
yielded a 5.5:1 mixture of two optically active products
with spectral properties identical to those reported for
aculeatin A and aculeatin B.1
Aculeatin A, (-)-2
Aculeatin B, (+)-1
O
O
O
O
O
O
12
12
OH
OH
H
H
H
H
O
H
O
H
15
2
H
2
H
O
6
H
H
6
H
H
O
OH
O
15
OH
NOE
H
H
O
A more close examination of the respective NMR spec-
tral properties revealed, however, an important issue.
The major product exhibited in fact the optical rotation
Figure 2. Corrected structures and absolute configurations of acule-
atins A and B.

E. Falomir et al. / Tetrahedron Letters 46 (2005) 8407–8410
8409
efits from a favorable anomeric effect,13 in agreement
with the higher stability of aculeatin A. In support of
this reasoning, the minor isomer, which was unstable
and isomerized slowly to the major one, showed a
marked NOE between the methine proton H-2 and
one methylene proton at C-15. These properties, which
are associated to aculeatin B, are only compatible with
stereostructure 1 (Fig. 2), which does not exhibit a
favorable anomeric effect. A further support is given
by the markedly higher d value of H-2 in aculeatin A
(d 4.10 vs d 3.86 ppm in aculeatin B), which points to
its 1,3-diaxial relation with the anomeric oxygen atom.
In summary, the Swiss workers1 erroneously inter-
changed the relative stereostructures of the aculeatins
A and B, which are in consequence 2 and 1, respectively.14
6. Ronald, R. C.; Wheeler, C. J. J. Org. Chem. 1984, 49,
1658–1660.
7. Ramachandran, P. V.; Chen, G.-M.; Brown, H. C.
Tetrahedron Lett. 1997, 38, 2417–2420; For a recent
review on asymmetric allylborations, see: Ramachandran,
P. V. Aldrichim. Acta 2002, 35, 23–35.
8. Uray, G. In Houben-Weyl’s Methods of Organic Chemis-
try, Stereoselective Synthesis; Helmchen, G., Hoffmann,
R. W., Mulzer, J., Schaumann, E., Eds.; Georg Thieme:
Stuttgart, 1996; Vol. 1, pp 253–292.
9. Tsuji, J. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Winterfeldt, E., Eds.; Pergamon Press:
Oxford, 1993; Vol. 7, pp 449–468.
10. Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1–
200.
11. The aldol addition step of the enolborane of b-alkoxy
methyl ketone 8 to n-tetradecanal takes place with
essentially complete stereoselectivity, which reflects a high
anti-1,5-induction. This remote induction has previously
been observed by Evans and co-workers in related cases:
The optical rotation values of the synthetic compounds
were very similar to those of the natural compounds and
the signs are the same. Our synthesis therefore has led to
the natural enantiomers of both aculeatins and permit-
ted the establishment of their absolute configurations
(Fig. 2).15
´
Evans, D. A.; Coˆte, B.; Coleman, P. J.; Connell, B. T. J.
Am. Chem. Soc. 2003, 125, 10893–10898; The in situ
reduction of the intermediate aldol with LiBH4 gives only
a syn-1,3-diol fragment, as expected: Paterson, I.; Chan-
non, J. A. Tetrahedron Lett. 1992, 33, 797–800.
12. For a review on hypervalent iodine compounds, see:
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–
2584; For more recent developments, see: Moriarty, R. M.
J. Org. Chem. 2005, 70, 2893–2903; Wirth, T. Angew.
Chem., Int. Ed. 2005, 44, 3656–3665; For oxidations of
phenolic compounds with hypervalent iodine reagents,
see: Moriarty, R. M.; Prakash, O. Org. React. 2001, 57,
327–415; For reagents of oxidative spiroacetalizations of
arenes, including hypervalent iodine compounds, see:
Acknowledgments
Financial support has been granted by the Spanish Min-
istry of Education and Science (project BQU2002-
00468), and by the AVCyT (projects GRUPOS03/180
and GV05/52). P.A.-B. thanks the Spanish Ministry of
Education and Science for a predoctoral fellowship
(FPI program).
´
Rodrıguez, S.; Wipf, P. Synthesis 2004, 2767–2783.
13. Graczyk, P. P.; Mikołajczyk, M. Top. Stereochem. 1994,
21, 159–349.
14. The way of drawing the aculeatins in Ref. 1 is confusing,
as two spiroconnected rings are simultaneously used as
reference rings for stereochemical representation.
We prefer the way depicted in Figures 1 and 2, where
only the tetrahydropyrane moiety is used as the reference
ring.
References and notes
1. (a) Heilmann, J.; Mayr, S.; Brun, R.; Rali, T.; Sticher, O.
Helv. Chim. Acta 2000, 83, 2939–2945; (b) Heilmann, J.;
Brun, R.; Mayr, S.; Rali, T.; Sticher, O. Phytochemistry
2001, 57, 1281–1285.
2. Confusion has to be avoided between these two com-
pounds and the coumarin aculeatin, isolated from Todda-
lia asiatica (T. aculeata): Ishii, H.; Kobayashi, J.-I.;
Sakurada, E.; Ishikawa, T. J. Chem. Soc., Perkin Trans.
1 1992, 1681–1684; In addition, an alkaloid of undefined
15. Physical and spectral data of the synthetic aculeatins.
Aculeatin A: oil; [a]D ꢀ5.2 (c 0.9; CHCl3), lit.1 [a]D ꢀ5.3 (c
0.2; CHCl3); IR mmax 3550 (br, OH), 1673 (ketone C@O)
cmꢀ1 1H NMR (500 MHz, CDCl3) d 6.85 (1H, dd,
;
J = 10.0, 3.0 Hz), 6.76 (1H, dd, J = 10.0, 3.0 Hz), 6.14
(1H, dd, J = 10.0, 1.7 Hz), 6.10 (1H, dd, J = 10.0, 1.7 Hz),
4.15–4.10 (2H, m), 3.35 (1H, br d, J = 10.0 Hz, OH), 2.38
(1H, m), 2.24(1H, m), 2.05–2.00 (3H, m), 1.93 (1H, br d,
J = 14.0 Hz), 1.79 (1H, br dd, J = 13.7, 2.0 Hz), 1.60–1.40
(5H, br m), 1.40–1.20 (20H, br m), 0.88 (3H, t,
structure with name aculeatin was isolated from Papaver
ˇ
´
´
´
´
aculeatum: Maturova, M.; Pavlaskova, D.; Santavy, F.
Planta Med. 1966, 14, 22–41.
3. For the relevance of Michael acceptor moieties to cyto-
toxicity, see, for example: Buck, S. B.; Hardouin, C.;
Ichikawa, S.; Soenen, D. R.; Gauss, C.-M.; Hwang, I.;
Swingle, M. R.; Bonness, K. M.; Honkanen, R. E.; Boger,
D. L. J. Am. Chem. Soc. 2003, 125, 15694–15695.
4. (a) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617–
1661; (b) Norcross, R. D.; Paterson, I. Chem. Rev. 1995,
J = 6.8 Hz); 13C NMR (125 MHz, CDCl3)
d 185.3,
109.2, 79.8 (C), 150.9, 148.7, 127.4, 127.2, 65.4, 64.9
(CH), 39.2, 38.0, 36.0, 34.2, 32.0, 29.7 (several overlapped
signals), 29.4, 25.7, 22.7 (CH2), 14.1 (CH3); HR EIMS m/z
(rel int.) 418.3117 (M+, 2), 400 (M+ꢀH2O, 6), 310 (6), 236
(25), 165 (100), 107 (73). Calcd for C26H42O4,
M = 418.3083. Aculeatin B: oil; [a]D +53.2 (c 0.4; CHCl3),
lit.1 [a]D +50 (c 0.8; CHCl3); IR mmax 3460 (br, OH), 1670
`
95, 2041–2114; (c) Brimble, M. A.; Fares, F. A. Tetra-
hedron 1999, 55, 7661–7706; (d) Thirsk, C.; Whiting, A. J.
Chem. Soc., Perkin Trans. 1 2002, 999–1023; (e) Yeung,
K.-S.; Paterson, I. Angew. Chem., Int. Ed. 2002, 41, 4632–
4653; (f) Suenaga, K. Bull. Chem. Soc. Jpn. 2004, 77, 443–
451.
1
(ketone C@O) cmꢀ1; H NMR (500 MHz, CDCl3) d 6.99
(1H, dd, J = 10.0, 2.9 Hz), 6.77 (1H, dd, J = 10.0, 2.9 Hz),
6.13 (1H, dd, J = 10.0, 1.8 Hz), 6.10 (1H, dd, J = 10.0,
1.8 Hz), 4.36 (1H, apparent quintuplet, J = 3.2 Hz), 3.86
(1H, m), 2.68 (1H, br dd, J = 12.8, 7.2 Hz), 2.30 (1H, td,
J = 12.3, 7.2), 2.10–2.00 (2H, m), 1.95–1.85 (2H, m), 1.60–
1.40 (8H, br m), 1.40–1.20 (19H, br m), 0.88 (3H, t,
J = 6.9 Hz); 13C NMR (125 MHz, CDCl3) d 185.7, 108.6,
5. (a) Wong, Y.-S. Chem. Commun. 2002, 686–687; (b)
Baldwin, J. E.; Adlington, R. M.; Sham, V. W.-W.;
´
Marquez, R.; Bulger, P. G. Tetrahedron 2005, 61, 2353–
2363.

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E. Falomir et al. / Tetrahedron Letters 46 (2005) 8407–8410
77.6 (C), 152.2, 149.2, 127.2, 127.1, 69.5, 65.2 (CH), 40.7,
38.0, 35.8, 35.4, 35.3, 31.9, 29.7 (several overlapped
signals), 29.4, 29.3, 25.9, 22.7 (CH2), 14.1 (CH3); HR
EIMS m/z (rel int.) 418.3108 (M+, 9), 400 (M+ꢀH2O, 24),
310 (16), 235 (85), 165 (100), 107 (23). Calcd for C26H42O4,
M = 418.3083.