Total synthesis and stereochemical assignment of myriaporones 1, 3, and 4

Article abstract of DOI:10.1002/anie.200353348

Two stereoselective aldol reactions, a nitrile oxide cycloaddition, and a stereoselective late-stage epoxidation were key steps in the total synthesis of myriaporones 1, 3, and 4 (see scheme). The synthesis allowed the unambiguous assignment of stereogeni

Full text of DOI:10.1002/anie.200353348

Communications
Natural Products Synthesis
Therefore, our goal is to provide material to facilitate such
studies and, herein, we report the total synthesis of myriapor-
ones 1, 3, and 4 (2a,c,d) and the unambiguous assignment of
their previously undetermined stereogenic configurations at
C5 and C6.
Total Synthesis and Stereochemical Assignment of
Myriaporones 1, 3, and 4**
Recently, we reported the completion of the carbon
skeleton of myriaporone 1 (2a) through a stereoselective
homoallenylboration and a nitrile oxide cycloaddition.[5a]
Construction of myriaporone 4 (2d) began with known
alcohol 3[3c] (Scheme 1). Oxidation with IBX[6] was followed
Kristen N. Fleming and Richard E. Taylor*
The natural products tedanolide (1a) and 13-deoxytedanolide
(1b), which were isolated by Schmitz et al.[1] and Fusetani
et al.,[2] respectively, exhibit picomolar activity against a range
of cancer cell lines. Their biological activity coupled with their
scarcity has prompted considerable synthetic attention.[3] Our
interest in these compounds stems from the isolation of a
related class of natural products, the myriaporones (2a–d),
reported by Rinehart et al. in 1995.[4,5] The myriaporones are
nearly identical structurally to the C10–C23 portion of
tedanolide (1a); it is therefore possible that these two classes
of compounds share the same biological receptor and have
similar modes of action. As a result of their limited
availability, the biology of both classes remains a mystery.
Scheme 1. Synthesis of C5-epimeric isoxazolines 9a and 9b. Reagents
and conditions: a) IBX, 95%; b) Bu2BOTf, Et3N, 93%; c) TBSOTf,
85%; d) LiBH4; e) TBSCl, 89% (two steps); f) OsO4, NMO, 95%;
g) NaIO4, 84%; h) Bu2BOTf, Et3N, 99%; i) LiBH4; j) TBSCl, 92% (two
=
steps); k) PrNO2, PhNCO, 64%; l) DDQ, 88%; m) IBX; n) Ph3P
CHCH3, 63% (two steps). IBX=o-iodoxybenzoic acid; Tf=trifluorome-
thanesulfonyl; TBS=tert-butyldimethylsilyl; NMO=N-methylmorpho-
line-N-oxide; DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
[*] K. N. Fleming, Prof. R. E. Taylor
Department of Chemistry and Biochemistry
Walther Cancer Research Center, University of Notre Dame
251 Nieuwland Science Hall
by an Evans aldol[7] reaction to set the C8 and C9 stereo-
centers in high yield and excellent diastereoselectivity. During
the course of that work, incorporation of the epoxide at an
early stage limited the scope of reaction conditions that
subsequent intermediates could withstand and ultimately
prevented completion of the total synthesis. Since then, Loh
and Feng[3g] and Smith III et al.[3k] reported highly selective
late-stage epoxidations in their efforts toward tedanolide.
With these results as precedence, our focus switched to the
incorporation of this particularly sensitive functional group in
the penultimate step of the synthesis.
Notre Dame, IN USA 46556-5670
Fax: (+1)574-631-6652
E-mail: taylor.61@nd.edu
[**] Support was provided by the National Cancer Institute/National
Institutes of Health (CA81128). K.N.F. thanks the University of
Notre Dame for support through a J. Peter Grace Prize Fellowship
and Searle Fellowship. Professor Kenneth Rinehart is acknowledged
for providing spectra of authentic material.
Supporting information for this article (experimental and charac-
terization data for synthetic and authentic samples of 2a,c,d) is
available on the WWW under http://www.angewandte.org or from
the author.
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DOI: 10.1002/anie.200353348
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Angewandte
Chemie
The aldol product 4 was converted efficiently into bis(TBS
ether) 5 by protection, reductive cleavage of the chiral
auxiliary, and a second protection step. Oxidative cleavage of
the terminal olefin was followed by a second Evans aldol
reaction to form the C6–C7 bond and to provide 6 in nearly
quantitative yield. The appropriate oxazolidinone was chosen
to generate the R configuration at C6, an assumption based on
the corresponding stereogenic center C14 in tedanolide (1a).
Once again, the chiral auxiliary was removed reductively and
the primary hydroxy was protected with TBSCl to provide
compound 7 in excellent yield for the 10-step conversion from
3. Regioselective nitrile oxide cycloaddition led to the
formation of isoxazoline 8 as an inseparable mixture of
diastereomers at C5.[8] The lack of selectivity of this reaction
was desired because of the uncertain relative stereochemical
configuration of the target molecule. Removal of the PMB
protecting group was followed by oxidation to the aldehyde
and olefination to give 9a and 9b. Upon installation of the
C13–C14 cis double bond, the two diastereomers were easily
separated by column chromatography and each taken on
independently. The configuration of the C5 stereogenic center
of each diastereomer was assigned upon completion of the
synthesis (see below).
The less-polar diastereomer 9a was converted into
myriaporones 3 and 4 (2c,d) by the sequence outlined in
Scheme 2. Dess–Martin periodinane[9] was used to oxidize the
secondary hydroxy group to the corresponding ketone.
Subsequent global silyl deprotection and reprotection pro-
vided 10a. Reduction of the isoxazoline group with Mo(CO)6
successfully unmasked the b-hydroxyketone[10] and set the
stage for the key epoxidation reaction. It was necessary to use
slightly less than one equivalent of MCPBA and to maintain
the reaction temperature at À 508C to prevent overoxidation.
Under the optimized conditions, only the desired epoxide (as
a single diastereomer) and unreacted starting material were
obtained. The final step, deprotection of the primary hydroxy
groups with TAS-F,[11] resulted in the formation of the desired
product, myriaporone 4 (2d) as an equilibrium mixture with
myriaporone 3 (2c). The 1H NMR spectrum of the final
deprotected product from diastereomer 9a was identical to
that of an authentic sample of the natural product (see
Supporting Information) and showed the presence of an
equilibrating mixture of myriaporones 3 and 4. Diastereomer
9b was converted into 5-epi-myriaporone 4 (2d) by an
identical sequence (full details included in the Supporting
Information).
The stereochemical configuration at C5 was determined
by 1H NMR spectroscopic analysis of myriaporone 3 (2c).
Vicinal coupling constants account for the fact that C5-OH
and 6-H are both axial (Figure 1). Thus we have unambigu-
Figure 1. 1H NMR spectroscopic analysis of myriaporone 3 (C1–C7) for
the assignment of the relative stereochemistry of C5 and C6.
ously determined the stereochemistry of the myriaporone
class of polyketides to correspond identically to the stereo-
chemical pattern of the macrolide tedanolide (1a).
The use of acetate protecting groups instead of TBS ethers
led to an unexpected reaction (Scheme 3). An attempted mild
deprotection of 12a, prepared from diasteromer 9a, induced
selective elimination to form myriaporone 1 (2a). In fact, this
Scheme 3. Selective elimination for the synthesis of myriaporone 1.
Reagents and conditions: a) KCN, 66%.
elimination is quite facile and 12a proved difficult to
handle upon preparation. The propensity for this group
to eliminate suggests that the compound designated
myriaporone 1 (2a) may actually be a product of
isolation rather than a direct product of polyketide
biosynthesis. Not surprisingly, the C5 stereogenic
center of 2a was determined to have the identical
configuration to that of the corresponding center in
myriaporones 3 and 4 (2c,d).
An important phase of this research has been
completed. The efficiency of the synthetic route
presented herein has enabled the preparation of
significant quantities of these interesting marine natu-
ral products as well as analogues.[12] Studies currently
underway will seek to identify the biological receptor
and mode of action of the myriaporones. Furthermore,
modified routes may provide access to compounds
more closely related to tedanolide.
Scheme 2. Completion of the synthesis of myriaporones 3 and 4. Reagents
and conditions: a) DMP, 98%; b) HF·Et3N, 83%; c) TBSCl, 81%; d) Mo(CO)6,
65%; e) MCPBA, 62%; f) TAS-F, 70%. DMP=Dess–Martin periodinane;
MCPBA=m-chloroperoxybenzoic acid; TAS-F=tris(dimethylamino)sulfur (tri-
methylsilyl)difluoride.
Received: November 18, 2003 [Z53348]
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
[4] a) K. L. Rinehart, K. Tachibana, J. Nat. Prod. 1995, 58, 344;
b) K. L. Rinehart, J.-F. Cheng, J.-S. Lee, US Patent 5,514,708,
1996 [Chem. Abstr. 1996, 125, 5896].
[5] For studies specifically targeting the myriaporones, see refer-
ence [3c] and a) R. E. Taylor, B. R. Hearn, J. P. Ciavarri, Org.
Lett. 2002, 4, 2953 b) B.-Z. Zheng, M. Yamauchi, H. Dei, O.
Yonemitsu, Chem. Pharm. Bull. 2000, 48, 1761.
Keywords: aldol reaction · diastereoselectivity · epoxidation ·
natural products · total synthesis
.
[1] F. J. Schmitz, S. P. Gunasekera, G. Yalamanchili, M. B. Hossain,
D. van der Helm, J. Am. Chem. Soc. 1984, 106, 7251.
[2] N. Fusetani, T. Sugawara, S. Matsunaga, H. Hirota, J. Org. Chem.
1991, 56, 4971.
[6] M. Frigerio, M. Santagostino, Tetrahedron Lett. 1994, 35, 8019.
[7] D. A. Evans, E. B. Sjogren, J. Bartroli, R. L. Dow, Tetrahedron
Lett. 1986, 27, 4957.
[8] K. V. Gothelf, K. A. Jørgensen, Chem. Rev. 1998, 98, 863.
[9] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
[10] P. B. Baraldi, A. Barco, S. Benetti, S. Manfredini, D. Simoni,
Synthesis 1987, 276.
[3] a) T. Matsushima, K. Horita, N. Nakajima, O. Yonemitsu,
Tetrahedron Lett. 1996, 37, 385; b) J.-F. Liu, A. Abiko, Z. Pei,
D. C. Buske, S. Masamune, Tetrahedron Lett. 1998, 39, 1873;
c) R. E. Taylor, J. P. Ciavarri, B. R. Hearn, Tetrahedron Lett.
1998, 39, 9361; d) W. R. Roush, G. C. Lane, Org. Lett. 1999, 1, 95;
e) M. E. Jung, R. Marquez, Org. Lett. 2000, 2, 1669; f) T.
Matsushima, N. Nakajima, B.-Z. Zheng, O. Yonemitsu, Chem.
Pharm. Bull. 2000, 48, 855; g) T.-P. Loh, L.-C. Feng, Tetrahedron
Lett. 2001, 42, 3223; h) K. Matsui, B. Z. Zheng, S. Kusaka, M.
Kuroda, K. Yoshimoto, H. Yamada, O. Yonemitsu, Eur. J. Org.
Chem. 2001, 3615; i) J. Hassfeld, M. Kalesse, Synlett 2002, 2007;
j) W. R. Roush, J. S. Newcom, Org. Lett. 2002, 4, 4739; k) A. B.
Smith III, C. M. Adams, S. A. Lodise Barbosa, A. P. Degnan, J.
Am. Chem. Soc. 2003, 125, 350.
[11] K. A. Scheidt, H. Chen, B. C. Follows, S. R. Chemler, D. S.
Coffey, W. R. Roush, J. Org. Chem. 1998, 63, 6436.
[12] During the review of this manuscript, we learnt of a successful
total synthesis of myriaporones 1, 3, and 4 through a sequence
that involves an early-stage incorporation of the epoxide. See
preceding Communication in this issue: M. Pꢀrez, C. del Pozo, F.
Reyes, A. Rodrꢁguez, A. Francesch, A. M. Echavarren, C.
Cuevas, Angew. Chem. 2004, 116, 1756; Angew. Chem. Int. Ed.
2004, 43, 1724.
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