Tandem intramolecular Michael-Aldol reaction as a tool for the construction of the C-ring of hexacyclinic acid

Article abstract of DOI:10.1021/ol061096q

The tandem intramolecular Michael-aldol reaction was studied as a tool for the construction of the C-ring of hexacyclinic acid. By changing the reaction conditions it was possible to selectively obtain either the kinetic or the thermodynamic product. Retr

Full text of DOI:10.1021/ol061096q

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3485-3488
Tandem Intramolecular Michael-Aldol
Reaction as a Tool for the Construction
of the C-Ring of Hexacyclinic Acid
Andriy Stelmakh, Timo Stellfeld,‡ and Markus Kalesse*
Institute of Organic Chemistry, UniVersity of HannoVer, Schneiderberg 1B,
30167 HannoVer, Germany
markus.kalesse@oci.uni-hannoVer.de
Received May 4, 2006
ABSTRACT
The tandem intramolecular Michael-aldol reaction was studied as a tool for the construction of the C-ring of hexacyclinic acid. By changing
the reaction conditions it was possible to selectively obtain either the kinetic or the thermodynamic product. Retro-aldol reaction and subsequent
epimerization provides four individual cyclopentane derivatives that can be incorporated as building blocks in natural product syntheses.
Hexacyclinic acid (1), a polyketide produced by Streptomyces
cellulosae subsp. griserubiginosus (strain S1013), was iso-
lated in 2000 by Zeeck and co-workers.1 It exhibits similar
Even though no total synthesis of hexacyclinic acid has
been put forward, the complex structure combined with its
biological activity has initiated several partial syntheses.5,6
We have published the synthesis of the ABC fragment of
hexacyclinic acid6 employing an intramolecular Diels-Alder
reaction followed by a tandem intramolecular Michael-aldol
reaction7 as the pivotal steps to furnish 4 (Scheme 1). It was
obtained as an inseparable mixture of diastereomers, making
(3) Edler, M. C.; Buey, R. M.; Gussio, R.; Marcus, A. I.; Vanderwal, C.
D.; Sorensen, E. J.; Diaz, J. F.; Giannakakou, P.; Hamel, E. Biochemistry
2005, 44, 11525-11538.
(4) (a) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am. Chem.
Soc. 2002, 124, 4552-4553. (b) Vanderwal, C. D.; Vosburg, D. A.; Weiler,
S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393-5407. (c) Evans,
D. A.; Starr, J. T. Angew. Chem., Int. Ed. 2002, 41, 1787-1790. (d) Evans,
D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531-13540.
(5) (a) Clarke, P. A.; Grist, M.; Ebden, M.; Wilson, C. Chem. Commun.
2003, 1560-1561. (b) Clarke, P. A.; Grist, M.; Ebden, M. Tetrahedron
Lett. 2004, 45, 927-929. (c) Clarke, P. A.; Cridland, A. P. Org. Lett. 2005,
7, 4221-4224. (d) Clarke, P. A.; Davie, R. L.; Peace, S. Tetrahedron 2005,
61, 2335-2351. (e) James, P.; Felpin, F.-X.; Landais, Y.; Schenk, K. J.
Org. Chem. 2005, 70, 7985-7995. (f) Funel, J.; Prunet, J. J. Org. Chem.
2004, 69, 4555-4558. (g) Methot, J. L.; Roush, W. R. Org. Lett. 2003, 5,
4223-4226.
(6) Stellfeld, T.; Bhatt, U.; Kalesse, M. Org. Lett. 2004, 6, 3889-3892.
(7) (a) Ihara, M.; Ohnishi, M.; Takano, M.; Makita, K.; Taniguchi, N.;
Fukumoto, K. J. Am. Chem. Soc. 1992, 114, 4408-4410. (b) Ihara, M.;
Taniguchi, T.; Makita, K.; Takano, M.; Ohnishi, M.; Taniguchi, N.;
Fukumoto, K.; Kabuto, C. J. Am. Chem. Soc. 1993, 115, 8107-8115. (c)
Ihara, M.; Taniguchi, T.; Tokunaga, Y.; Fukumoto, K. J. Org. Chem. 1994,
59, 8092-8100. (d) Ihara, M.; Taniguchi, T.; Yamada, M.; Tokunaga, Y.;
Fukumoto, K. Tetrahedron Lett. 1995, 36, 8071-8074. (e) Takasu, K.;
Ueno, M.; Ihara, M. Tetrahedron Lett. 2000, 41, 2145-2148.
Figure 1. Hexacyclinic acid (1) and (-)-FR 182877 (2).
structural features compared to (-)-FR182877 (2) isolated
in 1998 from Streptomyces sp. No. 9885 by Fujisawa
Pharmaceutical Company.2 (-)-FR182877 (WS 9885B,
Cyclostreptin) has attracted broad scientific interest due to
its potent cytotoxic activity.3 Consequently, biomimetic total
syntheses of (-)-FR1828774b-d and its enantiomer4a have
been described by the groups of Evans and Sorensen.
‡ Current address: Schering AG, Mu¨llerstrasse 178, 13342 Berlin,
Germany.
(1) Ho¨fs, R.; Walker, M.; Zeeck, A. Angew. Chem., Int. Ed. 2000, 39,
3258-3261.
(2) Sato, B.; Muramatsu, H.; Miyauchi, M.; Hori, Y.; Takase, S.; Hino,
M.; Hashimoto, S.; Terano, H. J. Antibiot. 2000, 53, 123-130.
10.1021/ol061096q CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/01/2006

Scheme 1. Construction of the C-Ring
Scheme 2. The Synthesis of Model Compound 11
tion8,9 of 810 to aldehyde 7. Silyl ether 9 was treated with
TBAF to give aldehyde 10, which was subjected to equili-
bration by using SiO2 in hexane-AcOEt (6:1 v/v) at room
temperature to establish the desired trans-substituted cyclo-
hexane derivative with 8:1 selectivity. Subsequently, the R,â
unsaturated ester was introduced according to the Horner-
Emmons protocol. The 1,3-dioxolane protecting group was
removed in refluxing aqueous acetone with 0.3 equiv of
PPTS to provide methyl ketone 11 as a mixture of cis and
trans diastereomers (1:7) which were separated by HPLC.11
Having 11 in hand, the diastereoselectivity of the tandem
Michael-aldol reaction was studied as summarized in Table
1 (Scheme 3).
it difficult to determine the configuration of the major isomer.
The retro-aldol reaction proceeded when 4 was treated with
TBAF to give the methyl ketone 5 as a 4:1 diastereomeric
mixture. It was stated that the NOESY cross-peak between
H20 and H16 supports the configuration at C19, on the other
hand configurational assignment at C8 was just based on
coupling constants between H8 and H9.6
When 5 was subjected to the action of TBAF (THF, rt, 3
h), total deprotection took place. The diol 6 was obtained as
a 6:1 mixture of diastereomers. Fortunately, diol 6 was
crystalline and we were able to obtain an X-ray structure.
According to the X-ray analysis (Figure 2), eight out of nine
Table 1. TMSI-HMDS Mediated Tandem Michael-Aldol
Reaction
diastereomeric
yield
(%)d
entry
conditionsb
ratio 12a:12bc
1
2
rt, 6 h
1.0:17.5
1.0:14.3
1.0:4.4
1.8:1.0
1.0:1.7
1.5:1.0
5.4:1.0
8.2:1.0
8.2:1.0
12.4:1.0
16.2:1.0
16.2:1.0
17.6:1.0
78
rt, 3 h
79
3
rt, 60 min
82
4
rt, 10 min
87a
77a
82a
81a
83a
70a
81a
49a
79a
71a
5
0 °C, 6 h
6
0 °C, 3 h
7
0 °C, 60 min
0 °C, 10 min
-20 °C, 6 h
-20 °C, 60 min
-20 °C, 10 min
-30 °C, 3 h
-30 °C, 60 min
8
9
10
11
12
13
Figure 2. X-ray structure of 6.
a Incomplete reaction. b For all entries in Table 1 the concentration of
11 was 0.1 M. c Diastereomeric ratio was determined by GC. Other products
were also detected (up to 6), but not listed in Table 1. Analysis was done
on crude products. The composition of crude products (12) was also
controlled by the intensity of the signals corresponding to the OSi(CH3)3
group (δ 0.26-0.15 ppm) in 1H NMR spectra (in C6D6). d For the mixture
of diastereomers after chromatographic purification (hexanes-EtOAc (50:1
v/v), Rf 0.10-0.15).
stereocenters were constructed correctly, leaving only the
configuration at C8 to be opposite that of the natural product.
Formation of a trans-fused cyclobutane derivative as the
product of the tandem Michael-aldol reaction could be an
explanation for the configuration at C8, but also epimeriza-
tion under basic deprotection conditions (4 equiv of TBAF,
THF, rt) could serve as a rational.
When the reaction was carried out at 0, -20, or -30 °C
compound 12a was obtained as the major product. On the
To understand the stereochemical outcome of the tandem
Michael-aldol reaction and to establish the conditions of the
retro-aldol reaction that avoid epimerization, we studied these
transformations on a readily available substrate (11) (Scheme
2).
(8) Takakis, I. M.; Tsantali G. G. J. Org. Chem. 2003, 68, 6455-6458.
(9) (a) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I.
Tetrahedron Lett. 1986, 27, 4025-4028. (b) Nakamura, E.; Matsuzawa,
S.; Horiguchi, Y.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 4029-4032.
(10) Bu¨chi, G.; Wuest, H. J. Org. Chem. 1969, 34, 1122-1123.
(11) See the Supporting Information for details on the HPLC separation
of 11.
Methyl ketone 11 was synthesized in 5 steps starting from
cyclohexene-1-carbaldehyde (7) through a conjugate addi-
3486
Org. Lett., Vol. 8, No. 16, 2006

Scheme 3. Tandem Michael-Aldol Reaction
Scheme 4. Reaction of 12a with TBAF
With 12a in hand we performed the retro-aldol reaction
putting our particular focus on the potential epimerization
at C8.
other hand, when the reaction was performed at room
temperature for more than 1 h, product (12b) was formed
selectively. In general, longer reaction times favor the
thermodynamic product with better yields, whereas shorter
reaction times favor the kinetic product (Table 1).
Both 12a and 12b were isolated and analyzed with nOe
experiments to assign their relative stereochemistry.
NOESY spectra of 12a support the structure shown in
Figure 3 with cis-fusion between the cyclopentane and the
When 12a was treated with TBAF (1.0 equiv, -30 °C,
30 min), the corresponding methyl ketone 13a was obtained
in 80% yield (Scheme 4) as indicated by NOESY experi-
ments (Figure 5).
Figure 5. Configurational assignment of 13a by NOESY.
Figure 3. Assignment of the relative stereochemistry of the kinetic
product (12a) with the help of NOESY NMR experiment.
When methyl ketone 13a was additionally treated with
TBAF at room temperature (Scheme 4), epimerized com-
pound 14a was isolated as the sole product and analyzed by
nOe experiments (Figure 6).
cyclobutane rings and trans-orientation between H5 and H6
as in hexacyclinic acid.
In the case of the 12b, a nOe between H4 and H11 is a
strong argument to support the proposed structure (Figure
4).
Figure 6. Assignment of the relative configuration of 14a with
nOe experiments.
When 12b was treated with TBAF over 30 min at -30
°C, a 2.8:1 diastereomeric mixture of two methyl ketones
13b and 14b was isolated. After treatment of this diastereo-
meric mixture with TBAF at room temperature (3 equiv, 3
h), only isomer 14b could be isolated (Scheme 5).
Figure 4. Assignment of the relative stereochemistry of the
thermodynamic product (12b) with nOe experiments.
The structure of 14b was studied with the help of ROESY
(Figure 7).
Org. Lett., Vol. 8, No. 16, 2006
3487

Scheme 5. Reaction of 12b with TBAF
Figure 7. Assignment of the configuration of 14b by ROESY
experiment.
With the results obtained, we can now explain the
unexpected epimerization at the C8 center of 5 under
conditions of silyl deprotection with TBAF and provide a
reliable path for the further elaboration of the total synthesis
of hexacyclinic acid. Additionally, we provided a method
that allows the synthesis of diastereomeric derivatives of
hexacyclinic acid as well as the diastereoselective synthesis
of other 1,2-disubstituted octahydroindene derivatives, with
four diastereomers accessible through either the kinetic or
thermodynamic product and subsequent epimerization.
Acknowledgment. This work was financially supported
by the DFG.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 9, 10, 11, 12a,
12b, 13a, 14a, and 14b. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL061096Q
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Org. Lett., Vol. 8, No. 16, 2006