Synthesis of the A,B,C-ring system of hexacyclinic acid

Article abstract of DOI:10.1021/ol048720o

(Chemical Equation Presented) The synthesis of the A,B,C-ring system (2) of hexacyclinic acid (1) is achieved starting from a selective Diels-Alder reaction followed by vinyl cuprate addition. The diastereoselective reduction of the ketone carbonyl at C16

Full text of DOI:10.1021/ol048720o

ORGANIC
LETTERS
2004
Vol. 6, No. 22
3889-3892
Synthesis of the A,B,C-Ring System of
Hexacyclinic Acid†
Timo Stellfeld,‡ Ulhas Bhatt,§ and Markus Kalesse*
Institut fu¨r Organische Chemie, UniVersita¨t HannoVer, Schneiderberg 1 B,
30167 HannoVer, Germany
markus.kalesse@oci.uni-hannoVer.de
Received July 6, 2004
ABSTRACT
The synthesis of the A,B,C-ring system (2) of hexacyclinic acid (1) is achieved starting from a selective Diels−Alder reaction followed by vinyl
cuprate addition. The diastereoselective reduction of the ketone carbonyl at C16 could be achieved with LiAlH4. An intramolecular Michael
addition established the ring system stereoselectively, providing access to the selective generation of 9 out of the 14 stereocenters of hexacyclinic
acid.
Hexacyclinic acid (1) was isolated through chemical screen-
ing by Zeeck, Ho¨fs, and Walker from Streptomyces cellu-
losae subsp. (stem S 1013) with the aid of their OSMAC
approach (OSMAC ) one strain many compounds).1 It
reveals a unique hexacyclic carbon skeleton that is paralleled
by (-)-FR182877 (3), isolated from Streptomyces sp.
No9885 by Fujisawa Pharmaceutical Company in 1998.2 The
two compounds exhibit striking similarities in their archi-
tecture but have major structural and stereochemical differ-
ences. The differences in AB and BC ring fusion sites
especially demand different synthetic strategies (Figure 1).
The C13-C17 cis fusion in hexacyclinic acid is contrasted
by a trans substitution pattern in (-)-FR182877.3 Similarly,
the C10-C18 trans fusion in hexacyclinic acid is contrasted
by a cis substitution pattern in (-)-FR182877.
Other significant differences are the acetylation at C14
and the carboxylic acid moiety at C25 in hexacyclinic acid;
(-)-FR182877 features a free hydroxyl group instead of an
acetate at C14 and a C25 methyl group instead of a
carboxylic acid moiety, respectively. Probably the most
important difference is located at C5 and C20: hexacyclinic
acid exhibits a hydroxyl group at C5, whereas (-)-FR182877
has a C5-C20 double bond at this position. It has been
proposed that the Michael acceptor serves as the pharma-
† Dedicated to Prof. A. Zeeck on the occasion of his 65th birthday.
‡ Current address: Freie Universita¨t Berlin, Takustr. 3, 14195 Berlin,
Germany.
§ Current address: Albany Molecular Research, Inc., 21 Corporate Circle,
P.O. Box 15098, Albany, NY 12212-5098.
(1) Ho¨fs, R.; Walker, M.; Zeeck, A. Angew. Chem., Int. Ed. 2000, 39,
3258.
(2) (a) Sato, B.; Muramatsu, H.; Miyauchi, M.; Hori, Y.; Takase, S.;
Hino, M.; Hashimoto, S.; Terano, H. J. Antibiot. 2000, 53, 123. (b) Sato,
B.; Nakaijama, H.; Hori, Y.; Takase, S.; Hino, M.; Hashimoto, S.; Terano,
H. J. Antibiot. 2000, 53, 204. (c) Yoshimura, S.; Sato, B.; Kinoshita, B.;
Takase, S.; Terano, H. J. Antibiot. 2000, 53, 615. Revised structure: (d)
Yoshimura, S.; Sato, B.; Kinoshita, B.; Takase, S.; Terano, H. J. Antibiot.
2002, 55, C1.
Figure 1. Comparison of the retrosynthetic analyses of hexacyclinic
acid (1) and FR182877 (3).
(3) Hexacyclinic acid numbering is used for both compounds.
10.1021/ol048720o CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/01/2004

Scheme 1. Synthesis of the Diels-Alder Precursor
Figure 2. Proposed transition states for the Diels-Alder reaction.
cophoric group in (-)-FR182877. The absence of such an
electrophilic fragment in hexacyclinic acid may be respon-
sible for the 2 orders of magnitude weaker antitumor
activity.4e Furthermore, acetylation at C14 cannot be ruled
out as the reason for the observed diminished activity of
hexacyclinic acid. Taking these observations into consider-
ation, it becomes obvious that there is a vital interest to
provide synthetic access to these compounds not only to
deconvolute the biological activity but also to provide
compounds with an altered and eventually optimized biologi-
cal profile.
As in the syntheses of (-)-FR182877,4 we envisioned that
a Diels-Alder reaction probably acts in the biosynthesis to
build up the AB-carbon skeleton of hexacyclinic acid. As a
consequence of these retrosynthetic considerations, the
functionality at C16 has to be incorporated as a ketone
carbonyl group if one considers the transition state shown
in Figure 2 as the pivotal control element during the Diels-
Alder reaction. As a consequence, selective reduction at a
later stage in synthesis is a synthetic detour that is not
necessary in the synthesis of (-)-FR182877.
be extended with phosphonocrotonate 6 using LDA as a base.
DIBAl-H reduction followed by oxidation with manganese
dioxide established the double-unsaturated aldehyde 7 in 64%
yield over five steps (Scheme 1). An Evans aldol reaction is
followed by transformation into the Weinreb amide 8. From
here, TBS protection, DIBAl-H reduction, and addition of
acetylene Grignard followed by reoxidation with the Dess-
Martin periodinane provided the Diels-Alder precursor 9.
In contrast to the C18-substituted triene 10, which did not
cyclize under various conditions, acetylenic compound 9
underwent clean cyclization to hexadiene 11 in toluene at
75 °C (Scheme 2).
A second, even more severe obstacle was the fact that
precursors having substitution at C18 (10, Scheme 1) would
not undergo intramolecular Diels-Alder reaction. This
problem could be solved by using the acetylenic precursor
9 and introducing the required side chain through a sequence
of cuprate addition and cross metathesis.
Scheme 2. Diels-Alder Reaction and Subsequent
Functionalization
To close the third ring we considered an intramolecular
Michael addition as the method of choice, in contrast to (-)-
FR182877, where a hetero-Diels-Alder reaction was ap-
plied.5
The synthesis began with racemic alcohol 4 that was TBS-
protected and cleaved through ozonolysis.6 Aldehyde 5 could
(4) (a) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. J.
Org. Chem. 1936, 1, 645. (b) Vanderwal, C. D.; Vosburg, D. A.; Sorensen,
E. J. Org. Lett. 2001, 3, 407. (c) Vosburg, D. A.; Vanderwal, C. D.;
Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393. (d) Evans, D. A., Starr,
J. T. Angew. Chem., Int. Ed. 2002, 41, 1787. (e) Evans, D. A., Starr, J. T.
J. Am. Chem. Soc. 2003, 125, 13531.
(5) Another strategy was reported by Clarke et al. in the synthesis of a
model DEF-ring core of hexacyclinic acid: (a) Clarke, P. A.; Grist, M.;
Ebden, M. Wilson, C. Chem. Commun. 2003, 1560. Roush et al. reported
on a Morita-Baylis-Hillman approach for the formation of the C-ring of
FR182877, which is closely related to the Michael aldol reaction: (b)
Methot, J. L.; Roush, W. R Org. Lett. 2003, 5, 4223.
The subsequent addition of vinyl cuprate at -78 °C
established the desired configuration at C18 through an attack
(6) Sugai, T.; Katho, O.; Ohta, H. Tetrahedron 1995, 51, 11987.
Org. Lett., Vol. 6, No. 22, 2004
3890

Scheme 3. Cross-Metathesis and Michael Addition
Figure 3. Catalysts for the cross-metathesis reaction.
from the convex face and furnished the final syn addition
product 12. The selective reduction at C16 thus became the
pivotal transformation. Here, the hydride source had to
approach the carbonyl carbon from the most hindered side,
the interior of the concave face. A variety of reagents were
tested for diastereoselective reduction, but most reducing
reagents, and in particular bulky regents such as L-selectride,
gave the undesired isomer with good selectivity, inversion
of which under Mitsunobu conditions could not be achieved.
Only reduction with LiAlH4 provided the required config-
uration at C16 with >20:1 selectivity.
Next, a cross metathesis is required to install the conju-
gated ester functionality for an intramolecular Michael
addition. Several metathesis catalysts have been used in order
to induce this transformation, and it turned out that the
Hoveyda-Grubbs second-generation catalyst 187 and Grela’s
p-nitro-substituted analogue 198 (Figure 3) could facilitate
this transformation in equal yields (80%, Scheme 3).
product 2 was obtained as an inseparable mixture (4:1) of
two diastereomers. NOESY experiments and coupling con-
stants give strong evidence that the major isomer exhibits
the desired stereochemistry, matching the title compound 2
(Figure 4). The NOESY cross-peak between H20 and H16
TBDPS-protection and hydrolysis of one TBS group was
followed by TPAP oxidation in 79% yield over three steps
to yield ketoester 15. With compound 15 in our hands, we
were in a position to perform the crucial step to close the
C-ring via a Michael reaction.
Several reagents and conditions were tried for this
transformation without success.9 Eventually, thermodynamic
TMS-enol ether formation was achieved with TMSI and
(TMS)2NH in 1,2-dichloroethane as the solvent10 and in-
stantly provided the cyclobutane adduct 16 through a
subsequent aldol reaction in 68% yield.11
Figure 4. Assignment of the stereochemistry confirms the forma-
tion of the desired diastereomer 2 (the numbering corresponds to
the natural product).
Finally, cyclobutane 16 was opened with TBAF in THF
to establish the A,B,C-ring system (2) of hexacyclinic acid
with nine contiguous chiral centers in 20 steps. Cyclization
supports the correct stereochemistry at C19. Assuming that
the configuration between the four- and five-membered rings
in 16 is cis since the trans configuration would produce high
ring strain, the new stereocenters in 2 must be cis-configured.
For C8, we have no direct evidence, but the coupling
constants of H9b also indicate H9b-H8 trans configuration.
(7) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A.
H. J. Am. Chem. Soc. 1999, 121, 791.
(8) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem., Int. Ed.
2002, 41, 4038.
(9) For example, treatment of ketone 15 with secondary amines like
proline, pyrrolidine, or diethylamine did not give any reaction.
(10) Ihara, M.; Taniguchi, T.; Makita, K.; Takano, M.; Ohnishi, M.;
Taniguchu, N.; Fukumoto, K.; Kabuto, C. J. Am. Chem. Soc. 1993, 115,
8107.
Interestingly, the intramolecular Michael addition parallels
recent results on the biosynthesis of hexacyclinic acid from
the Zeeck group. Through feeding experiments, it could be
shown that the tetrahydropyran oxygen O6 is not derived
from acetate or propionate but from external water (Figure
(11) 1H NMR indicates the formation of four stereoisomers of the
cyclobutane intermediate 16. The geometry of the intermediate enol ether
is suspected to be a mixture, with the (E)-isomer as the major isomer. For
the formation of a thermodynamic enol ether with TMSI/(TMS)2NH, see
also: Sedrani, R.; Krallen, J.; Cabrejas, L. M. M.; Papageorgiou, C. D.;
Senia, F.; Rohrbach, S.; Wagner, D.; Thai, B.; Eme, A.-M. J.; France, J.;
Oberer, L.; Rihs, G.; Zenke, G.; Wagner, J. J. Am. Chem. Soc. 2003, 125,
3849.
(12) Meyer, S. W. Dissertation, Georg-August-Universita¨t zu Go¨ttingen,
Go¨ttingen, Germany, 2003.
Org. Lett., Vol. 6, No. 22, 2004
3891

Further work toward the completion of the total synthesis
of hexacyclinic acid continues and will be reported in due
course.
Acknowledgment. This work was supported by the DFG
and the Fonds der Chemischen Industrie. We thank Prof.
Zeeck for insight into the biosynthesis and A. Stelmakh for
helpful discussion. A sample of the ruthenium catalyst 19,
provided by Dr. Karol Grela, is gratefully acknowledged.
Figure 5. Formation of the C-ring seems to take place through a
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for 11-13, 15, 16, 2, and
intermediates, as well as a copy of the NOESY spectrum of
2. This material is available free of charge via the Internet
at http://pubs.acs.org.
Prins-like reaction in the biosynthesis.
5).12 A vinylogous Prins reaction is therefore proposed as
the biosynthetic route, in contrast to the hetero Diels-Alder
reaction in (-)-FR182877.
OL048720O
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Org. Lett., Vol. 6, No. 22, 2004