Stereoselective synthesis of a novel spiroacetal-dihydropyrone related to auripyrone

Article abstract of DOI:10.1016/j.tetlet.2006.01.045

A model spiroacetal-dihydropyrone related to that found in auripyrones A and B has been synthesised by a spiroacetalisation dehydration cascade. The route includes an unusual mutual kinetic diastereoselecting aldol reaction combining the key fragments.

Full text of DOI:10.1016/j.tetlet.2006.01.045

Tetrahedron Letters 47 (2006) 2025–2028
Stereoselective synthesis of a novel spiroacetal-dihydropyrone
related to auripyrone
Michael V. Perkins,* Saba Jahangiri and Max R. Taylor
School of Chemistry, Physics and Earth Sciences, Flinders University, GPO Box 2100, Adelaide, South Australia 5001, Australia
Received 18 November 2005; revised 30 December 2005; accepted 12 January 2006
Available online 3 February 2006
Abstract—A model spiroacetal-dihydropyrone related to that found in auripyrones A and B has been synthesised by a spiroacetali-
sation dehydration cascade. The route includes an unusual mutual kinetic diastereoselecting aldol reaction combining the key
fragments.
Ó 2006 Elsevier Ltd. All rights reserved.
Auripyrones A (1) and B (2) are two recently reported
polypropionate natural products isolated from a Japa-
nese specimen of the sea hare Dolabella auricularia
(Aplysiidae) in 1996 by Suenga et al.1 (Fig. 1). From
the spectroscopic analysis, Suenga et al. concluded that
the auripyrone ring system consists of a highly substi-
tuted spiroacetal-dihydropyrone in which all the alkyl
substituents were positioned equatorially, except for
the C102 methyl which was axial. Both the acetal oxy-
gens were determined to be axially oriented with respect
to the other ring and hence were in the anomerically
favoured (EE) positions. An additional structural
component of the auripyrones was the c-pyrone ring.
Auripyrones A (1) and B (2) were found to exhibit
potent cytotoxic activity against HeLa S3 cells with
IC50 values of 0.26 and 0.48 lg/mL, respectively.1
spiroacetal ring system but lacks the c-pyrone ring and
the stereocentre at C18. Instead the spiroacetal dihydro-
pyrone is flanked by two isopropyl groups at C9 and
C17. The model compound 3 also contains the opposite
stereochemistry at C10. This stereochemistry chosen as
having an equatorially oriented methyl at C10 was antici-
pated to result in an easier construction of the spiro-
acetal-dihydropyrone. Furthermore generation of this
required stereotetrad was anticipated to be straightfor-
ward, based on previous results.3 Thus easy access to
the acyclic precursor would enable investigation of the
conditions required for cyclisation (and dehydration)
to construct the spiroacetal-dihydropyrone model com-
pound 3 (Fig. 2).
Scheme 1 shows the required acyclic precursor 4 for the
nucleophilic cyclisation cascade to give model com-
pound 3. Triketone 4 was proposed to be formed from
an aldol reaction between ketone 5 and aldehyde 6, fol-
lowed by oxidation. Aldehyde 6 contains all the required
stereocentres for compound 3, except for C14 and the
spiro centre C13 that are proposed to form under
thermodynamic control. The stereocentres present in
We set out to synthesise an analogue of the auripyrones
using stereoselective aldol methodology. The model
compound 3 contains the correctly substituted C9–C17
O
7
3
RO
O
5
9
10
12
auripyrone A (1): R =
auripyrone B (2): R =
O
H
H
18
Et
O
O
O
O
14
17
17
O
18
17
O
O
O
H
H
16
O
O
RO
O
HO
O
9
9
H
H
H
10
Figure 1.
10
H
H
H
H
H
H
H
3
model spiroacetal-dihydropyrone
auripyrones A (1) and B (2)
Figure 2.
*
Corresponding author. Tel.: +61 8 8201 2496; fax: +61 8 8201
2905; e-mail: mike.perkins@flinders.edu.au
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.045

2026
M. V. Perkins et al. / Tetrahedron Letters 47 (2006) 2025–2028
HO
17
O
9
13
9
14
10
13
10
O
O
+
O
4
OP OP
O
14
O
H
3
12
OH
O
O
OP OP
5
6
H
11
9
10
+
O
O
8
OP OP
7
9
Scheme 1. Retrosynthesis of compound 3.
Scheme 3. Synthesis and X-ray structure (displacement ellipsoids at
50% level) of acetal 20. Reagents and conditions: (a) (i) TiCl4
i
(1.1 equiv), CH2Cl2, ꢀ78 °C, 30 min; (ii) Pr2EtN (1.2 equiv), 1 h; (iii)
the ketone 5 are either lost on oxidation or become read-
ily enolisable (between two carbonyl groups). Carbon 12
in aldehyde 6 was proposed to be formed by a substrate
directed hydroboration of alkene 7. The stereotriad C9–
C11 in alkene 7 was to be formed by a stereoselective
anti aldol, syn reduction sequence using 2-methyl-
pentan-3-one (8) and methacrolein (9).
isobutyraldehyde (2 equiv), 45 min, ꢀ78 °C ! ꢀ20 °C (b) pyridine
(2 equiv), TMSCl (2 equiv), 0 °C, 30 min, 0 °C ! rt, 2 h; (c) (i) TiCl4
i
(1.2 equiv), CH2Cl2, ꢀ90 °C, 15 min; (ii) Pr2EtN (1.1 equiv), 30 min;
(iii) aldehyde 15 (1 equiv), 1.5 h, ꢀ90 °C ! ꢀ78 °C, 30 min; (iv) pH 7
buffer (d) HFÆpyr/pyr, rt, 4 h.
formed methyl stereocentre was tentatively assigned at
this stage as anti from literature precedent. Oxidation
of alcohol 14 with PCC gave aldehyde 15 in good yield.7
The stereoselective synthesis of aldehyde 6 is shown in
Scheme 2. The one-pot, boron mediated aldol condensa-
tion3 of ketone 8 and methacrolein (9) with in situ reduc-
tion of the intermediate boron aldolate 10 using LiBH4
produced the syn-diol 11 in 85% yield and >95% ds.4
The syn stereochemistry of reduction was confirmed by
protection of the diol as acetonide 12 and subsequent
The Ti(IV) mediated aldol reaction8 of diethylketone 16
with isobutyraldehyde gave ketone 17 with a high level
of syn selectivity (90% ds) and the major isomer could
be purified (Scheme 3). Protection as the trimethylsilyl
ether gave the ketone 18 ready for aldol coupling with
1
13
analysis of the H and C NMR.5
Protection of the diol as the di-tert butylsilylene6 gave
intermediate 13 which was stereoselectively hydro-
borated with BH3ÆSMe2 to give alcohol 14 as a single
detectable isomer. The configuration of the newly
a
b
(85%, >95% ds)
O
O
chex
OH OH
8
10
chex
11
12
O
B
d
c
(69%)
(85%)
O
O
O
O
13
Si
tBu tBu
(61%
>95% ds)
e
HO
f
H
(94%)
14 O
O
O 15 O
O
Si
tBu tBu
Si
tBu tBu
Scheme 2. Reagents and conditions: (a) (i) (cC6H11)2BCl (1.5 equiv),
Et3N (1.5 equiv), Et2O, ꢀ15 °C, 2 h; (ii) methacrolein (9) (1.7 equiv),
ꢀ15 °C, 2 h; (b) (i) in situ LiBH4 (2 equiv), ꢀ78 °C, 2 h; (ii) MeOH,
10% NaOH, H2O2, 0 °C, 2 h; (c) (CH3)2C(OCH3)2, PPTS, rt, 3 h; (d)
tBu2Si(OTf)2 (1.5 equiv), 2,6-lutidine (3.5 equiv), CH2Cl2, rt, 4 h; (e) (i)
BH3ÆSMe2 (10 equiv), THF, rt, 16 h; (ii) H2O2, 10% NaOH, THF,
0 °C ! rt, 2 h; (f) PCC (4 equiv), CH2Cl2.
Scheme 4. Synthesis and X-ray structure (displacement ellipsoids at
50% level) of spiroacetal-dihydropyrone 3. Reagents and conditions:
(a) Dess–Martin periodinane, CH2Cl2, rt, 2 h; (b) (i) HFÆpyr/pyr, rt,
4 h; (ii) p-TsOH, rt, 3 h.

M. V. Perkins et al. / Tetrahedron Letters 47 (2006) 2025–2028
2027
Table 1. 1H and 13C NMR data for the spiroacetal-dihydropyrone 3
and dehydrated product 22
syn preference of the ketone 18. Thus each enantiomer
of the enolate of ketone 18 selectively reacts with the
correct enantiomer of aldehyde 15.
H
H
16
The remainder of the synthesis is shown in Scheme 4.
Dess–Martin oxidation of the aldol adduct 19 gave the
triketone 21 (enol forms were present from spectro-
scopic analysis) which was deprotected with HF–pyri-
dine buffered with excess pyridine to give a complex
mixture of diols and hemiacetals. After trialing a variety
of acidic conditions it was found that treatment with
p-TsOH resulted in the formation of two cyclised prod-
ucts in equal quantity. The first compound was identi-
O
H
O
H
O
HO
O
O
H
H
H
H
O
10
H
H
H
H
21
21
20
20
8
9
9
HO
H
10
8
10
11
12
11
7
7
12
O
O
22
22
23
14
23
1
fied by H and 13C NMR analysis as the cyclised and
13
13
O
O
14
19
19
15
16
24
15
16
24
dehydrated product, spiroacetal-dihydropyrone 3. Com-
pound 3 gave crystals suitable for single crystal X-ray
analysis10 and the structure was thus confirmed as
shown in Scheme 4. The second product showed similar
1H and 13C NMR (see Table 1) except for an apparent
dehydration of the C11 hydroxyl, giving a C11–C12
double bond and was thus assigned as compound 22.
The configuration at the C14 methyl could not be
assigned. The formation of the latter product can be
rationalized to form from initial dehydration of the
acyclic precursor.
18
18
17
17
O
O
25
25
3
22
C
Model spiroacetal 3a,b,c,e
Dehydrated Spiroacetal
22a,b,c
d13
C
d1H, m, 3J (Hz)
d13
C
d1H, m, 3J (Hz)
7
8
19.99 0.81, d, 7.2
27.91 1.79, qqd,
20.21 0.86, d, 7.2
28.22 1.84, qqd,
7.2, 6.6, 1.8
78.13 3.21, dd, 10.2, 1.8
30.88 2.22–2.17, m
134.16 5.59, m
130.64
7.2, 7.2, 2.4
9
73.79 3.47, dd, 10.8, 2.4
37.43 1.65, dqd, 10.8, 6.6, 3
74.53 3.66, ddd, 10.2, 3, 3
38.55 1.98, qd, 7.2, 3
10
11
12
In conclusion, we have shown the successful cyclisation–
dehydration of a suitable trione precursor to give a C10
epimeric model spiroacetal-dihydropyrone 3 analogous
to that found in the marine natural product auripyrone.
While this product was accompanied by the dehydrated
compound 22, extension of this approach to the synthe-
sis of auripyrone seems viable and is being investigated.
13 108.2d
103.64
14
44.66 2.85, q, 6.6
44.45 2.86, q, 7.2
194.91
15 194.04
16 108.4d
17 166.84
106.84
170.05
18
19
20
21
22
23
24
25
30.03 2.97, qq, 7.2, 7.2
30.37 2.91, qq, 7.2, 7.2
20.56 1.17, d, 7.2
13.73 0.78, d, 7.2
13.48 0.94, d, 6.6
12.88 1.20, d, 7.2
7.75 1.125, d, 6.6
8.82 1.73, s
19.2
1.12, d, 6.6
14.52 0.78, d, 6.6
16.55 0.90, d, 7.2
18.25 1.76, m
0.99, d, 7.2
1.74, s
19.76 1.11, d, 6.6
Acknowledgements
8
We thank the Australian Research Council (Large ARC
Grant #A00000585 to M.V.P.), for support. We also
thank Professor W. T. Robinson of the University of
Canterbury, Christchurch, New Zealand, who collected
the diffraction data for compounds 20 and 3.
8.7
19.29 1.15, d, 7.2
a Varian Unity Inova 600 MHz NMR spectrometer.
b Assignments assisted by 1H–13C HMBC, HSQC, 1H–1H COSY.
c Chemical shifts in ppm referenced to CHCl3 at 7.26 ppm and to
CDCl3 at 77.0 ppm.
d Indicates tentative assignment and may be interchanged.
e –OH observed at d 2.60 ppm.
Supplementary data
Copies of the H and 13C NMR spectra for compounds
3 and 22 are available. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.01.045.
1
aldehyde 15. Precomplexation of 18 with TiCl4 at
ꢀ90 °C for 15 min followed by addition of diisopropyl-
ethylamine and aldehyde 15 remarkably gave compound
19 as a racemic mixture of a single diastereomer (the
TMS group was removed under the reaction or product
isolation conditions).9 The stereochemistry of the prod-
uct 19 was proven by deprotection of a small sample
using HF–pyridine buffered with excess pyridine. Fortu-
nately, the product of this reaction formed crystals suit-
able for single crystal X-ray analysis.10 This revealed the
hemiacetal structure 20 and thus the structure of com-
pound 19 as shown. Formation of the single racemic
product 19 from the coupling of two racemic fragments
is an unusual example of mutual kinetic diastereoselec-
tion. In this case a large anti-Felkin preference11 of the
aldehyde 15 is matched in a fast reaction with the syn–
References and notes
1. Suenaga, K.; Kigoshi, H.; Yamada, K. Tetrahedron Lett.
1996, 37, 5151.
2. The numbering system used for the natural product
auripyrone will for consistency be used for the model
compound throughout.
3. Paterson, I.; Perkins, M. V. Tetrahedron Lett. 1992, 33,
801; Paterson, I.; Perkins, M. V. Tetrahedron 1996, 52,
1811; Sampson, R. A.; Perkins, M. V. Org. Lett. 2002, 4,
1655.

2028
M. V. Perkins et al. / Tetrahedron Letters 47 (2006) 2025–2028
4. All new compounds gave spectroscopic data in agreement
with the assigned structures. Compound 13 had 1H NMR
(CDCl3, 300 MHz): 4.86 (2H, m), 4.13 (1H, d,
(20), 108 (67), 137 (23), 180 (100), 235 (12), 263 (6), 306
+
(19); HRMS (EI) calcd for C19H30O3 (M+) 306.2189,
d
found 306.2194.
J = 10 Hz), 3.66 (1H, dd, J = 2.1, 9.6 Hz), 1.87 (1H,
qqd, J = 6.8, 6.8, 2 Hz), 1.75 (3H, dd, J = 1, 1 Hz), 1.66–
1.81 (1H, m), 1.04 (9H, s), 1.02 (9H, s), 1.02 (3H, d,
J = 6.6 Hz), 0.86 (3H, d, J = 6.9 Hz), 0.63 (3H, d,
J = 6.6 Hz). 13C NMR (CDCl3, 75.5 MHz): d 145.8,
113.8, 85.6, 82.7, 37.8, 30.2, 27.8, 27.3, 23.1, 20.3, 20.2,
16.5, 13.7, 12.6. MS (EI) m/z 57 (7), 75 (22), 113 (10), 155
(28), 213 (6), 255 (100); HRMS (EI) calcd for C18H36O2Si
312.2479, found 312.2484. Compound 15 had 1H NMR
(CDCl3, 300 MHz): d 9.83 (1H, d, J = 3.4 Hz), 3.91 (1H,
dd, J = 10, 2 Hz), 3.62 (1H, dd, J = 9.6, 2.2 Hz), 2.61 (1H,
qdd, J = 6.8, 3.0, 3.0 Hz), 1.97–1.76 (2H, m), 1.28 (3H, d,
J = 7 Hz), 1.02 (9H, s), 1.00 (3H, d, J = 6.6 Hz), 0.96 (9H,
s), 0.83 (3H, d, J = 7.8 Hz), 0.79 (3H, d, J = 8 Hz); 13C
NMR (CDCl3, 75.5 MHz): d 205.6, 82.9, 82.3, 49.2, 39.1,
30.0, 27.8, 27.1, 23.2, 20.2, 20.2, 13.7, 12.1, 11.8. Com-
5. In agreement with Rychnovsky, S. D.; Rogers, B.; Yang,
G. J. Org. Chem. 1993, 58, 3511. Compound 12 was found
to have acetonide methyl 13C NMR signals at d = 19.6
and 30.1 ppm.
6. (a) Trost, B. M.; Caldwell, C. G. Tetrahedron Lett. 1981,
22, 4999; (b) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett.
1982, 23, 4871; (c) Trost, B. M.; Caldwell, C. G.;
Murayama, E.; Heissler, D. J. Org. Chem. 1983, 48,
3252.
7. Aldehyde 15 was rather unstable and partly decomposed
upon chromatography and storage. The best results were
obtained when freshly prepared aldehyde was used in the
subsequent reaction.
8. (a) Evans, D. A.; Clark, J. S.; Metternich, R.; Novak, V.
J.; Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866; (b)
´
Evans, D. A.; Urpı, F.; Somers, T. C.; Clark, J. S.;
1
pound 19 had H NMR (CDCl3, 200 MHz): d 4.21 (1H,
Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215; (c)
Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J.
Am. Chem. Soc. 1991, 113, 1047.
dd, J = 2, 9 Hz), 3.73 (1H, dd, J = 2.8, 9.8 Hz), 3.52 (1H,
dd, J = 2.3, 10.1 Hz), 3.47 (1H, dd, J = 2.8, 8.4 Hz), 2.95
(1H, dq, J = 2.9, 7.2 Hz), 2.82 (1H, qd, J = 6.9, 2 Hz),
2.71–3.01 (2H, br s), 2.16 (1H, m), 1.56–2.03 (2H, m), 1.11
(3H, d, J = 7.2 Hz), 1.10 (3H, d, J = 6.8 Hz), 1.00 (9H, s),
0.97 (9H, s), 0.94–1.016 (9H, m), 0.84 (3H, d, J = 7.2 Hz),
0.81 (3H, d, J = 7 Hz), 0.76 (3H, d, J = 6.6 Hz); 13C NMR
(CDCl3, 50 MHz): d 220.7, 85.3, 84.2, 76.3, 70.5, 47.2,
45.9, 40.3, 37.6, 30.6, 30.0, 27.9, 27.3, 23.2, 20.3, 20.3, 19.0,
18.97, 16.7, 13.8, 12.5, 9.7, 8.2. Compound 3 had 1H NMR
(CDCl3, 600 MHz): see Table 1. 13C NMR (CDCl3,
150 MHz): see Table 1. MS (EI) m/z 43 (100), 69 (39),
108 (47), 137 (17), 180 (72), 183 (67), 235 (9), 263 (7), 281
9. The aldol condensation between the aldehyde 15 and the
Ti(IV) enolate of the unprotected b-hydroxy ketone 17 by
the methodology reported by Luke, G. P.; Morris, J. J.
Org. Chem. 1995, 60, 3013, produced varied results. Thus
the preferred procedure used the protected ketone 18 as
described.
10. Crystallographic data (excluding structure factors) for the
structures 3 and 20 in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 289593 and CCDC
289592, respectively. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(0) 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
+
(9), 306 (11); HRMS (ESI) calcd for C19H32NaO4
(M+Na+) 347.2193, found 347.2211. Compound 22 had
1H NMR (CDCl3, 600 MHz): see Table 1. 13C NMR
(CDCl3, 150 MHz): see Table 1. MS (EI) m/z 43 (29), 93
11. Roush, W. R. J. Org. Chem. 1991, 56, 4151.