Stereoselective synthesis and cyclisation of the acyclic precursor to auripyrone A and B

Article abstract of DOI:10.1016/j.tetlet.2006.03.096

The acyclic precursor to the auripyrones has been synthesized by a stereoselective aldol strategy. This compound fails to undergo cyclisation to form the spiroacetal dihydropyrone ring system found in auripyrone A and B; instead, it forms a dihydropyrone

Full text of DOI:10.1016/j.tetlet.2006.03.096

Tetrahedron Letters 47 (2006) 3791–3795
Stereoselective synthesis and cyclisation of the acyclic precursor
to auripyrone A and B
Michael V. Perkins,* Rebecca A. Sampson, John Joannou and Max R. Taylor
School of Chemistry, Physics and Earth Sciences, Flinders University, GPO Box 2100, 5001 South Australia, Australia
Received 31 December 2005; revised 8 March 2006; accepted 15 March 2006
Available online 12 April 2006
Abstract—The acyclic precursor to the auripyrones has been synthesized by a stereoselective aldol strategy. This compound fails to
undergo cyclisation to form the spiroacetal dihydropyrone ring system found in auripyrone A and B; instead, it forms a dihydro-
pyrone ring by cyclisation of the C11 hydroxyl onto the C15 carbonyl with subsequent dehydration. In contrast, a model compound
was prepared and shown to cyclise to both the spiroacetal dihydropyrone ring system and the dihydropyrone ring.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Auripyrones A (1) and B (2) are two polypropionate
natural products isolated from Japanese specimens of
the sea hare, Dolabella auricularia (Aplysiidae), in 1996
by Suenaga and co-workers1 (Fig. 1). The structure
was assigned, as shown, from extensive 1H and 13C spec-
troscopic analysis. [The C20 configuration for auripy-
rone B (2) was not assigned.]
oxygens were determined to be axially oriented with
respect to the other ring and hence were in the anomer-
ically favoured positions. Auripyrones A and B were
found to exhibit potent cytotoxic activity against HeLa
S3 cells with IC50 values of 0.26 lg/mL and 0.48 lg/mL,
respectively.1
The putative acyclic precursor to the auripyrones con-
tains a degree of symmetry with a central stereopentad,
a remote stereocentre (C18) and two triones. With the
pseudo symmetry of the system broken by the acyl
group, the free hydroxyl initiates a spiroacetalisation
dehydration with one trione while the other trione cyc-
lises to form the c-pyrone ring.
Notably the auripyrone ring system consisted of a highly
substituted spiroacetal dihydropyrone in which all the
alkyl substituents were positioned equatorially, except
for the C-102 methyl which was axial. Both the acetal
We have previously reported the synthesis of a C10 epi-
meric model spiroacetal dihydropyrone,3 and we now
report the synthesis of the correct C10 model spiroacetal
dihydropyrone and the attempted cyclisation of the acy-
clic precursor to the auripyrones. Scheme 1 shows the
proposed retrosynthesis of the auripyrones. It was antic-
ipated that deprotection of acyclic precursor 3 would
allow the cyclisation dehydration cascade to form the
spiroacetal dihydropyrone and that subsequent acyl-
ation would give auripyrones A (1) or B (2). Triketone
3 was proposed to be formed from an aldol coupling
between ketone 4 and aldehyde 5, followed by oxidation.
Oxidation and cyclisation of compound 6 would form
the pyrone ring and subsequent removal of the Evans
auxiliary was proposed to give aldehyde 5. Aldol reac-
tion between aldehyde 7 and ketone 8 was anticipated
to give compound 6. Compound 7 was to be prepared
by a substrate directed hydroboration followed by
O
O
O
OR OH
O
O
O
O
H
Et
O
Me
O
RO
Me
16
O
O
H
OR
O
O
Me
H
Me
Me
O
O
O
H
O
10
Me
H
H
H
auripyrone A (1): R =
auripyrone B (2): R =
O
2'
Figure 1.
*
Corresponding author. Tel.: +61 8 8201 2496; fax: +61 8 8201
2905; e-mail: mike.perkins@flinders.edu.au
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.096

3792
M. V. Perkins et al. / Tetrahedron Letters 47 (2006) 3791–3795
a (97%,
c
O
O
90% ds)
auripyrone
A (1) and B (2)
(69%)
b (96%,
>97% ds)
O
O
O
OP1
OP1
OP1 OP1
O
O
OH OH
O
14
15
16
3
d-f
(78%,
81% ds)
H
g
O
+
H
(87%)
O
OP2
O
OP1
O 18
RO
R= H
R= TES 20
O
O 17 O
O
5
4
Si
Bn
h
O
19
tBu tBu
i
(35%)
(82%)
O
N
17
13
9
O
OP1
OH
O
O
O
OH
14
10
6
Bn
O
TESO
O
OH
O
Si
only isomer
tBu tBu
observed
13
O
N
H
+
OP2
O
OP1
OP1
Scheme 2. Reagents and Conditions: (a) (i) TiCl4 (1.0 equiv), CH2Cl2,
ꢀ78 ꢁC, 30 min; (ii) iPr2EtN (1.1 equiv); (iii) methacrolein (11)
(2 equiv), ꢀ78 ꢁC, 2 h; (b) DIBAL-H (3 equiv), ꢀ78 ꢁC, 4 h,
!ꢀ25 ꢁC; (c) (CH3)2C(OCH3)2, PPTS, rt, 3 h; (d) tBu2Si(OTf)2
(2 equiv), 2,6-lutidine (3.5 equiv), CH2Cl2, 40 ꢁC, 24 h; (e) (i) [Thex-
BH2]2ÆTMEDA (3 equiv), THF, rt, 48 h; (ii) H2O2, 10% NaOH, THF,
rt, 20 h; (f) PCC (4 equiv), CH2Cl2, (g) (i) TiCl4 (1.0 equiv), CH2Cl2,
O
O
7
8
Bn
Bn
O
N
N
O
H
+
O
10
O
O
OH
9
O
OH
O
O
11
i
ꢀ78 ꢁC, 30 min; (ii) Pr2EtN (1.1 equiv), 1.5 h; (iii) isobutyraldehyde
Scheme 1. Retrosynthesis of auripyrones A (1) and B (2).
(2 equiv), 1.5 h, ꢀ78 ꢁC ! ꢀ50 ꢁC; (h) pyridine (2 equiv), TES-triflate
(1 equiv), ꢀ78 ꢁC, 30 min, ꢀ78 ꢁC!rt, 2 h; (i) (i) TiCl4 (1.0 equiv),
i
CH2Cl2, ꢀ78 ꢁC, 30 min; (ii) Pr2EtN (1.1 equiv), 1 h; (iii) aldehyde 17
oxidation of compound 9. A stereoselective aldol, in a
reduction sequence using the Evans dipropionate 104
and methacrolein (11), generates the required stereo-
tetrad present in 9.
(0.5 equiv), 1.5 h, ꢀ78 ꢁC!ꢀ50 ꢁC, 30 min; (iv) pH 7 buffer.
with [ThexBH2]2ÆTMEDA10 (88%, 81% ds) and oxida-
tion with PCC gave aldehyde 17 (98%).
The Ti(IV)-mediated aldol reaction6 of pentan-3-one
(18) with isobutyraldehyde gave ketone 19 with a high
level of syn selectivity (90% ds, the major isomer could
be separated) (Scheme 2). Protection of the triethylsilyl
ether gave ketone 20, ready for aldol coupling with alde-
hyde 17. Precomplexation of 20 with TiCl4 at ꢀ78 ꢁC for
30 min, followed by the addition of diisopropylethyl-
amine and aldehyde 17 remarkably gave a racemic mix-
ture of a single diastereomer assigned as compound 13
in rather poor yield (35%). Formation of the single race-
mic product 13 from the coupling of two racemic frag-
ments is an unusual example of mutual kinetic
diastereoselection. In this case, a large Felkin prefer-
ence11 of aldehyde 17 is matched in a fast reaction with
the syn–syn preference of ketone 20. Thus, each enantio-
mer of the enolate of ketone 20 selectively reacts with
the correct enantiomer of aldehyde 17.
Prior to the synthesis of the complex acyclic precursor to
the auripyrones, a model compound was prepared and
cyclised. The model compound 12 (Fig. 2) contains the
correct C9–C17 spiroacetal ring system but lacks
the c-pyrone ring and the stereocentre at C18. Instead,
the spiroacetal dihydropyrone is flanked by two isopro-
pyl groups at C9 and C17. Generation of the required
stereotetrad was anticipated to be straightforward,
based on the previous results.5
The stereoselective synthesis of racemic compound 13 is
shown in Scheme 2. The Ti(IV)-mediated aldol reaction6
of 2-methylpentan-3-one (14) with methacrolein (11)
(90% ds), followed by syn reduction7 (>97% ds) with DI-
BAL-H, gave diol 15. The syn stereochemistry of reduc-
tion was confirmed by protection of the diol 15 as
1
acetonide 16 and by subsequent analysis of the H and
13C NMR.8 Protection of the diol as the di-tert butylsil-
ylene9 (91%), followed by stereoselective hydroboration
Direct proof of the stereochemistry of compound 13 was
not possible, but the Felkin preference of aldehyde 17
was determined by reaction with the Ti(IV) enolate of
pentan-3-one (18) (Scheme 3). In this case, reaction with
the achiral enolate again gave a single detectable prod-
uct 21 in 55% yield. Deprotection of product 21 using
HF–pyridine buffered with excess pyridine (HFÆpyr/
pyr) gave hemiacetal 22, which formed crystals suitable
for single crystal X-ray analysis.12 This proved the struc-
ture of hemiacetal 22 and thus the structure of com-
pound 21 as shown. The high Felkin preference for
aldehyde 17 is in stark contrast to the previously
reported3 anti-Felkin preference of the c-epimeric alde-
hyde 23. The underlying cause of this switch in facial
O
O
O
O
OP1 OP1
auripyrone A (1) and B (2) linear precursor
O
O
O
O
OP1 OP1
model linear precursor 12
Figure 2.

M. V. Perkins et al. / Tetrahedron Letters 47 (2006) 3791–3795
3793
assigned as compound 26. (The configuration at the
C14 methyl could not be assigned.) These first two
products were analogous to those obtained previ-
ously.3 A third product (55%), assigned as dihydro-
pyrone 27, was formed by the alternative cyclisation
of the C11 hydroxyl onto the C15 carbonyl and subse-
quent dehydration. In contrast to our previous model
system, the presence of the axial methyl in this sprio-
acetal system partly tips the balance towards this
alternative undesired cyclisation.
HO
b
a
(94%)
O OH
22
18
21
O
O
O
OH
O
Si
tBu tBu
(55%, >95% ds)
HO
HO
O
OH
HO
22
X-ray structure of 22
Despite the modest yield obtained in the model cyclisa-
tion, the enantiomerically pure linear precursor to
auripyrone was prepared (Schemes 5 and 6). Reaction
of the Sn(II) enolate6a of the Evans dipropionate equiv-
alent4 ketone 10 with methacrolein (11) proceeded with
high selectivity giving the syn–anti product 28 in good
yield as the only detectable isomer. Reduction with DI-
BAL-H again gave good syn selectivity.7
tBu
Si
O
Me
H
tBu
Si
O
OHC
H
H
H
iPr
Me
iPr
tBu
tBu
O
O
H
Me
Me
H
H
CHO
syn-pentane
interactions
avoided
syn-pentane
interactions
avoided
H
23
17
Scheme 3. Synthesis and X-ray structure (displacement ellipsoids at
50% level) of hemiacetal 22. Reagents and Conditions: (a) (i) TiCl4
i
The poor yields in the aldol reactions of aldehyde 17
(1.1 equiv), CH2Cl2, ꢀ78 ꢁC, 30 min; (ii) Pr2EtN (1.2 equiv), 1 h; (iii)
aldehyde 17 (0.5 equiv), 45 min, ꢀ78 ꢁC!ꢀ30 ꢁC; (b) HFÆpyr/pyr, rt,
were attributed to the steric bulk of the protecting
t
2 h.
group, and in an attempt to reduce this the Bu groups
were replaced with iPr groups on the silyene. Thus, pro-
tection of the diol was carried out using iPr2Si(OTf)2and
2,6-lutidine, giving compound 29. Hydroboration ([Thex-
BH2]2ÆTMEDA10) and oxidation (PCC) gave aldehyde
30. Aldol reaction of aldehyde 30 with the Ti(IV) enol-
ate6 of ketone 31 (as a racemic 4:1 syn:anti mixture)
gave a mixture of isomers of 32. (The TES group was
removed under the reaction or product isolation condi-
tions.) The major isomer was assigned as the product
of aldehyde 30 coupling with the matched enantio-
mer6c,d of the major syn isomer of ketone 31. Oxidation
to the trione (Dess–Martin Periodinane15), followed by
selectivity of the aldehyde is the change in conformation
of the C11–C12 bond in the rigidly held cyclic silylene,
such that syn pentane interactions are avoided with the
C10 methyl (Scheme 3).13
Removal of the TES protecting group from 13 was
achieved with p-TSOH, and Dess–Martin oxidation
gave triketone 24 (enol forms were present from spectro-
scopic analysis). Deprotection with HFÆpyr/pyr gave a
complex mixture of diols and hemiacetals but treatment
with p-TsOH resulted in the formation of three cyclised
products, as shown in Scheme 4.
16
treatment with Ph3P/CCl4 gave pyrone 33. Reductive
removal of the Evans auxiliary with LiBH4, followed
by oxidation (Dess–Martin Periodinane15) gave alde-
hyde 34.
1
The first compound (26%) which was identified by H
and 13C NMR analysis as the desired cyclised product
was spiroacetal dihydropyrone 25.14 The second prod-
uct (22%) showed similar 1H and 13C NMR spectra
except for an apparent dehydration of the C11 hydr-
oxyl, giving a C11–C12 double bond and was thus
Reaction of 2-(S)-2-methylbutanal (prepared by oxida-
tion of the commercially available alcohol 35) with the
Ti(IV) enolate6 of pentan-3-one (18) gave the separable
enantiomerically pure ketones 36 (55%) and 37 (22%)
(Scheme 6). The minor (Felkin11b) product 37 was used
as it was assumed to be matched6c,d with the facial pref-
erence of aldehyde 34. Protection of 37 as the TMS ether
38, followed by formation of the Ti(IV) enolate and
reaction with aldehyde 34, gave as expected a single iso-
mer of product 39. Oxidation of 39 (Dess–Martin Peri-
odinane15) gave trione 40. Unfortunately, deprotection
(HFÆpyr/pyr) and treatment with p-TsOH resulted
only in the formation of the unwanted cyclised product
41, with none of the desired spiroacetal dihydropyrones
42.
17
O
13
O
9
a, b
14
10
Si
13
O
O
O
(92%, 2 steps)
tBu tBu
24
c
HO
H
O
O
O
O
OH
+
+
O
O
In conclusion, we have shown the successful cyclisation–
dehydration of a suitable trione precursor to give a mod-
el spiroacetal dihydropyrone 25, analogous to that
found in the marine natural products auripyrone A (1)
and B (2). But extension of this approach to the synthe-
sis of auripyrones failed to yield the desired cyclisa-
tion. Successful cyclisation to form the spiroacetal
O
O
(26%)
O
(22%)
(51%)
25
26
27
Scheme 4. Synthesis of spiroacetal dihydropyrone 25. Reagents and
conditions: (a) p-TSOH, CH2Cl2/MeOH; (b) Dess–Martin period-
inane, CH2Cl2, rt, 3 h; (c) (i) HFÆpyr/pyr, rt, 2 h; (ii) p-TsOH, rt, 3 h.

3794
M. V. Perkins et al. / Tetrahedron Letters 47 (2006) 3791–3795
Bn
Bn
Bn
a
b, c
N
O
N
O
O
O
N
O
O
O
O
O
O
O
O
O
O
OH
O
O
10
28
29
Si
iPr iPr
d, e
(70%, >95% ds)
f, g
Bn
Bn
O
N
H
h
N
(52%)
O
30
O
O
O
OTES
O
O
O
O
OH
O
OH
O
Si
iPr iPr
(53%, 2 steps)
32
31
Si
syn : anti
4 : 1
iPr iPr
• 3 isomers ratio ~3:1:1
• major isomer shown
i, j
Bn
O
N
H
O
O
k, l
O
O
O
O
O
O
O
33
34
Si
iPr iPr
(59%, 2 steps)
Si
iPr iPr
(48%, 2 steps)
O
O
Scheme 5. Synthesis of pyrone 34. Reagents and conditions: (a) (i) tin(II) triflate 1.3 equiv, CH2Cl2, ꢀ20 ꢁC, Et3N, 10 min, amide 10, 1 h,
ꢀ78 ꢁC!ꢀ50 ꢁC; (ii) methacrolein (11), 1.5 equiv, 30 min, ꢀ78 ꢁC!ꢀ15 ꢁC; (b) DIBAL-H, 4 equiv, ꢀ78 ꢁC; (c) iPr2Si(OTf)2 (2 equiv), 2,6-lutidine
(3.5 equiv), CH2Cl2, 25 ꢁC, 18 h; (d) (i) [ThexBH2]2ÆTMEDA (2 equiv), THF, rt, 72 h, 40 ꢁC, 24 h; (ii) H2O2, MeOH, THF, rt, 2 h; (e) PCC (4 equiv),
i
CH2Cl2; (f) (i) TiCl4 (1.0 equiv), CH2Cl2, ꢀ78 ꢁC, 30 min; (ii) Pr2EtN (1.5 equiv), 1.5 h; (iii) propanal (2 equiv), 1.5 h, ꢀ78 ꢁC ! 0 ꢁC; (g) pyridine
(2 equiv), TES-triflate (1 equiv), 0 ꢁC, 15 h; (h) (i) ketone 31, TiCl4 (2.0 equiv), CH2Cl2, ꢀ78 ꢁC, 30 min; (ii) iPr2EtN (2.5 equiv), 1 h; (iii)
ꢀ78 ꢁC ! ꢀ85 ꢁC, aldehyde 30 (0.5 equiv), ꢀ85 ꢁC ! ꢀ5 ꢁC; (iv) pH 7 buff. (i) Dess–Martin periodinane, CH2Cl2, rt, 4 h; (j) Ph3P (12 equiv), CCl4
(12 equiv), THF, 3 d; (k) LiBH4 (20 equiv), Et2O, ꢀ10 ꢁC (l) Dess–Martin periodinane, CH2Cl2, rt, 3 h.
Acknowledgements
a, b
OH
We thank the Australian Research Council (Large ARC
Grant #A00000585 to MVP) for its support. We extend
our thanks to Professor W. T. Robinson of the Univer-
sity of Canterbury, Christchurch, New Zealand, who
collected the diffraction data for compound 22.
36
(55%)
35
OH
O
O
+
O
d
(43%)
OH
O
O
O
OH
O
O
RO
(22%)
R = H
Si
iPr iPr
39
37
O
O
c
e
(84%)
R = TMS 38
Supplementary data
A short discussion of the facial selectivities of aldehydes
23 and 17 in aldol reactions is available. Supplementary
data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2006.03.096.
O
O
O
Si
iPr iPr
40
O
f
O
O
HO
O
O
O
O
OH
O
References and notes
42
41
(55%)
O
O
O
1. Suenaga, K.; Kigoshi, H.; Yamada, K. Tetrahedron Lett.
1996, 37, 5151–5154.
not formed
2. The numbering system used for the natural product
auripyrone will for consistency be used for both the model
compound and the natural product throughout. The
absolute configuration of the auripyrones arbitrarily
drawn by Suenaga et al. is the enantiomer of that targeted
in this synthesis.
3. Perkins, M. V.; Jahangiri, S.; Taylor, M. R. Tetrahedron
Lett. 2006, 47, 2025.
4. (a) Evans, D. A.; Gage, J. R. Org. Synth. 1989, 68, 77–91;
(b) Evans, D. A.; Ennis, M. D.; Le, T. J. Am. Chem. Soc.
1984, 160, 1154; (c) Evans, D. A.; Ng, H. P.; Clark, J. S.;
Rieger, D. L. Tetrahedron 1992, 48, 2127.
Scheme 6. Attempted synthesis of spiroacetal dihydropyrone 42.
Reagents and conditions: (a) (i) COCl2, DMSO, ꢀ78 ꢁC, alcohol 35,
Et3N, 15 min, ꢀ78 ꢁC!ꢀ5 ꢁC; (b) (i) pentan-3-one (18), TiCl4
i
(1.0 equiv), CH2Cl2, ꢀ78 ꢁC, 30 min; (ii) Pr2EtN (1.5 equiv), 1.5 h;
(iii) aldehyde (0.8 equiv), 1 h, ꢀ78 ꢁC!ꢀ5 ꢁC; (c) pyridine (2 equiv),
TMS-Cl (1.2 equiv), ꢀ78 ꢁC!0 ꢁC, 1 h; (d) (i) TiCl4 (1.2 equiv),
CH2Cl2, ꢀ78 ꢁC, 30 min; (ii) iPr2EtN (1.3 equiv), 1 h; (iii)
ꢀ78 ꢁC!ꢀ90 ꢁC, aldehyde 34 (0.2 equiv), 2 h, ꢀ78 ꢁC!ꢀ10 ꢁC; (iv)
pH 7 buffer; (e) Dess–Martin periodinane, CH2Cl2, rt, 3 h; (f) (i)
HFpyr/pyr, rt, 2 h; (ii) p-TsOH, rt, 1 h.
5. (a) Sampson, R. A.; Perkins, M. V. Org. Lett. 2001, 3, 123;
(b) Sampson, R. A.; Perkins, M. V. Org. Lett. 2002, 4,
1655.
dihydropyrone in the auripyrones appears to require
differential protection of the C9 and C11 hydroxyls.

M. V. Perkins et al. / Tetrahedron Letters 47 (2006) 3791–3795
3795
6. (a) Evans, D. A.; Clark, J. S.; Metternich, R.; Novak, V.
H-7), 0.7 (3H, d, J = 7.2 Hz, H-20). 13C NMR (CDCl3,
151 MHz): d 194.6 (C-15), 166.8 (C-17), 108.4 (C-13),
108.3 (C-16), 75.7 (C-11), 73.1 (C-9), 44.6 (C-14), 36.5 (C-
10), 32.1 (C-12), 30.1 (C-18), 28.9 (C-8), 20.5 (C-19), 19.9
(C-7), 19.4 (C-25), 17.9 (C-20), 12.5 (C-21), 10.3 (C-22),
8.2 (C-24), 7.6 (C-23). Compound 26 had 1H NMR
(CDCl3, 600 MHz): d 5.85 (1H, dd, J = 5.4, 1.8 Hz, H-11),
3.33 (1H, dd, J = 10.2, 2.7 Hz, H-9), 2.9 (1H, qn,
J = 6.9 Hz, H-18), 2.85 (1H, q, J = 6.9 Hz, H-14), 2.10–
2.04 (1H, m, H-10), 1.73 (3H, s, H-22), 1.72 (3H, s, H-24),
1.62–1.54 (1H, m, H-8), 1.119 (3H, d, J = 6.9 Hz, H-19),
1.116 (3H, d, J = 6.9 Hz, H-25), 1.02 (3H, d, J = 6.9 Hz,
H-23), 0.85 (3H, d, J = 7.2 Hz, H-21), 0.82 (3H, d,
J = 7.2 Hz, H-7), 0.8 (3H, d, J = 7.2 Hz, H-20). 13C
NMR (CDCl3, 151 MHz): d 194.6 (C-15), 170.0 (C-17),
133.6 (C-11), 130.5 (C-12), 106.9 (C-16), 104.0 (C-13), 76.9
(C-9), 44.2 (C-14), 30.5 (C-10), 30.4 (C-18), 28.8 (C-8),
19.8 (C-25), 19.7 (C-7), 19.3 (C-19), 18.2 (C-22), 18.2 (C-
20), 12.0 (C-21), 8.7 (C-24), 8.5 (C-23). Compound 27 had
1H NMR (CDCl3, 600 MHz): d 3.91 (1H, dd, J = 13.8,
3 Hz, H-11), 3.81 (1H, q, J = 6.6 Hz, H-16), 3.34 (1H, dd,
J = 6.6, 4.8 Hz, H-9), 2.63 (1H, sept, J = 6.9 Hz, H-18),
2.43 (1H, dq, J = 13.8, 7.2 Hz, H-12), 1.88–1.82 (1H, m,
H-10), 1.77 (3H, s, H-23), 1.74–1.64 (2H, m, H-8 and OH),
1.19 (3H, d, J = 6.6 Hz, H-24), 1.03 (3H, d, J = 6.9 Hz, H-
25), 1.01 (3H, d, J = 6.9 Hz, H-19), 1.0 (3H, d, J = 7.2 Hz,
H-22), 0.9 (3H, d, J = 6.9 Hz, H-20), 0.89 (3H, d,
J = 6.9 Hz, H-21), 0.85 (3H, d, J = 6.9 Hz, H-7). 13C
NMR (CDCl3, 151 MHz): d 211.0 (C-17), 194.9 (C-13),
168.1 (C-15), 110.2 (C-14), 87.3 (C-11), 79.4 (C-9), 47.0 (C-
16), 40.9 (C-12), 39.9 (C-18), 36.0 (C-10), 30.6 (C-8), 19.7
(C-7), 19.1 (C-25), 18.0 (C-19), 17.5 (C-20), 13.5 (C-24),
J.; Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866; (b)
´
Evans, D. A.; Urpı, F.; Somers, T. C.; Clark, J. S.;
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; (d) Evans, D. A.; Dart,
M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem. Soc. 1995,
117, 9073.
7. Kiyooka, S.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett.
1986, 27, 3009.
8. In agreement with Rychnovsky, S. D.; Rogers, B.; Yang,
G. J. Org. Chem. 1993, 58, 3511, Compound 16 was found
to have acetonide methyl 13C NMR signals at d = 19.4
and 30.0 ppm.
9. (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.
10. (a) Paterson, I.; Schaplbach, A. Synlett 1995, 498; (b)
Brown, H. C.; Schwier, J. R.; Singaram, B. J. Org. Chem.
1979, 44, 465.
11. (a) This facial selectivity is opposite to the more usually
observed anti-Felkin facial preference of a-chiral alde-
hydes in aldol reactions of Z enolates; For a discussion of
the facial preference of a-chiral aldehydes see: (b) Roush,
W. R. J. Org. Chem. 1991, 56, 4151.
12. Crystal data for compound 22: C15H30O4, MW
=
˚
273.39, space group I41cd with a = 28.109(9) A, b =
3
˚
˚
˚
V = 7187(6) A ,
28.109(9) A,
T = 168(2) K, Z = 16, density (calc) = 1.014 g cmꢀ3
F(000) = 2432, l(MoKa) = 0.072 mmꢀ1
total of
44,205 intensity data were measured on Bruker
P4 CCD area detector diffractometer using
c = 9.096(5) A,
,
.
A
1
a
9.5 (C-23), 9.4 (C-22), 7.0 (C-21). Compound 39 had H
a
NMR (CDCl3, 300 MHz): 4.18 (1H, dd, J = 7.2, 2.7 Hz,
CHO), 4.16 (1H, dd, J = 8.1, 1.8 Hz, CHO), 3.99 (1H, dd,
J = 8.7, 1.8 Hz, CHO), 3.59 (1H, dd, J = 7.5, 3.3 Hz,
CHO), 3.20–3.10 (1H, m, CHC@O), 3.02 (1H, dq, J = 7.2,
6.9 Hz, vinyl CHCH3), 2.91 (1H, dq, J = 7.2, 3.6 Hz,
CHC@O), 2.61 (2H, q, J = 7.5 Hz, vinyl CH2CH3), 1.96
(3H, s, vinyl CH3), 1.95 (3H, s, vinyl CH3), 1.86–1.80 (1H,
m, CHCH3), 1.76–1.65 (1H, m, CHCH3), 1.50–1.37 (2H,
br s, 2 · OH), 1.24 (3H, d, J = 6.9 Hz, CHCH3), 1.21
(3H, t, J = 7.5 Hz, CH2CH3), 1.14 (3H, d, J = 7.2 Hz,
CHCH3), 1.08 (3H, d, J = 6.9 Hz, CHCH3), 1.01–0.86
(29H, m, 8 · CHCH3, 2 · SiCHCH3, CH2CHCH3,
CH2CHCH3). 13C NMR d (75.5 MHz, CDCl3) 219.7,
179.9, 164.5, 163.8, 119.7, 117.7, 79.9, 79.4, 74.3, 71.9,
49.7, 47.1, 40.0, 39.3, 36.8, 34.5, 25.6, 24.7, 17.5, 17.3,
16.9, 16.88, 14.7, 13.5, 13.3, 12.6, 11.9, 11.4, 11.0, 10.6,
10.2, 9.7, 9.6, 3.8; ESMS Calculated for C34H60O7Si
0.10 · 0.11 · 0.60 mm3 crystal giving 1911 unique reflec-
tions. One thousand five hundred and eighty eight
reflections with F2 >0 (reflns/paras = 9.2) were used in
the refinement; R(F2 > 2rF2) = 0.039, Rw = 0.068. Crys-
tallographic data (excluding structure factors) for the
structure 22 in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 293472. 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].
13. (a) See Supplementary data for a more detailed discussion;
(b) Joannou, J. PhD Thesis, Flinders University, 2003.
14. All new compounds gave spectroscopic data in agreement
with the assigned structures. Compound 25 had 1H NMR
(CDCl3, 600 MHz): d 3.58 (1H, dd, J = 3.6, 3.0 Hz, H-11),
3.42 (1H, dd, J = 10.2, 2.4 Hz, H-9), 2.97 (1H, sept,
J = 6.9 Hz, H-18), 2.84 (1H, q, J = 7.2 Hz, H-14), 2.05
(1H, dq, J = 7.2, 3.3 Hz, H-12), 1.92 (1H, m, H-10), 1.66
(3H, s, H-24), 1.62 (1H, m, H-8), 1.55 (1H, br s, OH), 1.12
(3H, d, J = 6.9 Hz, H-19), 1.1 (3H, d, J = 6.9 Hz, H-25),
1.09 (3H, d, J = 7.2 Hz, H-22), 1.08 (3H, d, J = 7.2 Hz, H-
23), 0.8 (3H, d, J = 7.2 Hz, H-21), 0.72 (3H, d, J = 7.2 Hz,
20
[M+Na]+Å: 631.4001; found 631.4006; ½aꢁD ꢀ2.65 (c 0.753,
CHCl3).
15. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155;
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277.
16. Arimoto, H.; Yokoyama, R.; Nakamura, K.; Okumura,
Y.; Uemura, D. Tetrahedron 1996, 52, 13901.