Titanium(II)-mediated cyclizations of (silyloxy)enynes: A total synthesis of (-)-7-demethylpiericidin A1

Article abstract of DOI:10.1021/ja057434k

A concise total synthesis of 7-demethylpiericidin A1 has been completed. The synthesis features a titanium(II)-mediated cyclization of a (silyloxy)enyne as the key step and proceeds in nine steps from tiglic aldehyde. Copyright

Full text of DOI:10.1021/ja057434k

Published on Web 12/17/2005
Titanium(II)-Mediated Cyclizations of (Silyloxy)enynes: A Total Synthesis of
(-)-7-Demethylpiericidin A1
Katie A. Keaton and Andrew J. Phillips*
Department of Chemistry and Biochemistry, UniVersity of Colorado, Boulder, Colorado 80309-0215
Received October 31, 2005; E-mail: andrew.phillips@colorado.edu
The piericidins1 are a class of pyridine-containing antibiotics that
display a broad range of biological effects, including cytotoxicity,
anti-microbial and insecticidal activity. This activity has been
ascribed to their structural homology to Coenzyme Q10 and
concomitant effectiveness as inhibitors of mitochondrial electron
transport.2 Although the biological effects of the piericidins as
inhibitors of electron transport have been well studied, they have
not yet drawn the same level of synthetic attention as related
compounds that also act via this mode, such as the annonaceous
acetogenins. Apart from the recent paper from Boger and co-
workers describing the total synthesis of piericidins A1 and B1,3
there has been only a handful of reports describing efforts toward
the synthesis of these valuable biological probes.4
Figure 1. 7-Demethylpiericidins and an overview of synthesis strategy.
Scheme 1 a
In 1996, Kimura and co-workers described the isolation and
structure elucidation of two further antibiotics of the piericidin class,
7-demethylpiericidin A1 (SN-198D, 1, Figure 1) and 7-demethyl-
3′-rhamnopiericidin A1 (SN-198B, 2).5 These two compounds
inhibited the KB human nasopharyngeal cancer cell line with IC50
a Reagents and conditions: (1) n-BuLi, THF, then (MeO)3B then aq.
values of 11.0 and 4.5 µg mL-1, respectively. In this Communica-
AcOOH, 70%; (2) SEMCl, Ag2CO3, 97%; (3) t-BuLi, THF, then 1,2-
dibromotetrachloro ethane, 79%; (4) LiTMP, THF, -78 to -40 °C then
MeI, -40 °C, 85%; (5) t-BuLi then Bu3SnCl, 96%.
tion, we present a convergent total synthesis of 7-demethylpiericidin
A1 that is patterned on the strategy outlined in Figure 1 and features
an application of our recently described Ti(II)-mediated cyclization
of (silyloxy)enynes as the key reaction for the assembly of the
polyene domain.6,7
Sonogashira coupling with iodide 1112 provided (silyloxy)enyne
12 in 87% yield and set the stage for the key cyclization.
Gratifyingly, subjecting 12 to the conditions employed in our earlier
studies (ClTi(OPri)3, i-PrMgCl, -40 °C) resulted in cyclization to
produce the desired cyclic siloxane 13 in 52% yield.13
The final steps of the synthesis commenced with removal of the
silyl ether (HF‚pyr, 84%, 13f14) and acylation (MeO2CCl,
pyridine, 97%) to give allylic carbonate 15. Coupling of the polyene
and pyridine-containing domains was achieved by a Stille coupling
between 15 and pyridine 8 with Pd2(dba)3 in DMF to provide 16
in 55% yield.14 Simultaneous removal of the SEM ether and cyclic
siloxane was achieved by treatment with TBAF (75 °C, DMF) to
produce 7-demethylpiericidin A1 in 70% yield. Synthetic 7-
demethylpiericidin A1 was identical in all respects to natural 1.15
In conclusion, we have described a synthesis of 7-demethyl-
piericidin A1 that proceeds in nine steps from tiglic aldehyde via 9
The synthesis of the 2-stannylpyridine-containing component is
shown in Scheme 1. Commercially available 2,3-dimethoxypyridine
3 was converted to pyridinol 4 in 70% yield by ortho-metalation
with n-BuLi, quenching with (MeO)3B, and oxidation with peracetic
acid.8 Subsequent protection as the SEM ether (Ag2CO3, SEMCl)
provided 5 in 97% yield. Directed ortho-metalation and halogenation
(tert-BuLi then BrCl2CCCl2Br, 79%, 5f6), followed by LiTMP-
mediated halogen dance9,10 and alkylation with methyl iodide led
to pyridine 7 in 85% yield. Lithium halogen exchange and
quenching with chlorotributylstannane gave 8 in 96% yield and
completed the synthesis of this fragment.
The polyene domain synthesis commenced with allylic alcohol
9,11 which was silylated with ethynyl(diisopropyl) bromosilane to
give alkynylsilane 10 in 78% yield (Scheme 2). Subsequent
9
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J. AM. CHEM. SOC. 2006, 128, 408-409
10.1021/ja057434k CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
a Reagents and conditions: (1) ethynyl(diisopropyl)bromosilane, Et3N, DMAP, CH2Cl2, 78%; (2) PdCl2(PPh3)2, CuI, Et3N, 87%; (3) ClTi(OPri)3, i-PrMgCl,
52%; (4) HF‚pyr, 84%; (5) MeO2CCl, pyr, CH2Cl2, 97%; (6) 8, Pd2(dba)3, LiCl, DMF, 55%; (7) TBAF, DMF, 75 °C, 70%.
(5) Kimura, K.; Takahashi, H.; Miyata, N.; Yoshihama, M.; Uramoto, M. J.
and highlights the utility of the titanium(II)-mediated cyclization
of (silyloxy)enynes in the context of complex natural products
Antibiot. 1996, 49, 697.
(6) O’Neil, G. W.; Phillips, A. J. Tetrahedron Lett. 2004, 45, 4253.
synthesis.
Acknowledgment. We thank Professor Tarek Sammakia for
helpful discussions with regard to halogen dance chemistry. This
research was supported by the National Cancer Institute (NCI
5R01CA110246). This work was facilitated by NMR facilities
purchased partly with funds from an NSF Shared Instrumentation
Grant (CHE-0131003).
(7) For other recent applications of group IV metal chemistry to polyketides,
see: (a) Bahadoor, A. B.; Flyer, A.; Micalizio, G. C. J. Am. Chem. Soc.
2005, 127, 3694. (b) Shimp, H. L.; Micalizio, G. C. Org. Lett. 2005, 7,
5111.
(8) Tre´court, F.; Mallet, M.; Mongin, O.; Que´guiner, G. J. Org. Chem. 1994,
59, 6173.
(9) For reviews of the halogen dance reaction, see: (a) Bunnett, J. F. Acc.
Chem. Res. 1972, 5, 139. (b) Froehlich, J. In Progress in Heterocyclic
Chemistry; Suschitzky, H., Scriven, E. F. V., Eds.; Oxford: New York,
1994; Vol. 6, pp 1-35.
(10) For recent applications, see: (a) Sammakia, T.; Stangeland, E. L.;
Whitcomb, M. C. Org. Lett. 2002, 4, 2385. (b) Comins, D. L.; Saha, J.
Tetrahedron Lett. 1995, 36, 7995. (c) Guillier, F.; Nivoliers, F.; Godard,
A.; Marsais, F.; Que´guiner, G. Tetrahedron Lett. 1994, 35, 6489. (d)
Marsais, F.; Pineau, P.; Nivolliers, F.; Mallet, M.; Turck, A.; Godard, A.;
Que´guiner, G. J. Org. Chem. 1992, 57, 565.
Supporting Information Available: Characterization data and
spectra for new compounds (6-8, 10-16). This material is available
free of charge via the Internet at http://pubs.acs.org.
(11) Alcohol 9 was synthesized by addition of vinylmagnesium bromide to
tiglic aldehyde and then kinetic resolution employing Sharpless asymmetric
epoxidation. See: Honda, T.; Mizutani, H.; Kanai, K. J. Chem. Soc., Perkin
Trans. 1 1996, 1729.
(12) Synthesized from 4-iodo-3-methyl-3-buten-1-ol (Marshall, J. A.; Eidam,
P. Org. Lett. 2004, 6, 445) by a sequence consisting of (a) silylation
(TBSCl, imidazole, 86%); (b) conversion to the allylic alcohol (t-BuLi,
paraformaldehyde, 82%), (c) protection of the allylic alcohol and removal
of the TBS ether (TBDPSCl, imidazole then AcOH, 79%), (d) oxidation-
olefination (Dess-Martin periodinane, CH2Cl2, then CHI3, CrCl2, THF-
dioxane, 75% over two steps).
References
(1) (a) Piericidin A: Tamura, S.; Takahashi, N.; Miyamoto, S.; Mori, R.;
Suzuki, S.; Nagatsu, J. Agric. Biol. Chem. 1963, 27, 576. (b) Structure
revision: Yoshida, S.; Shiraishi, S.; Fujita, K.; Takahashi, N. Tetrahedron
Lett. 1975, 16, 1863. (c) Piericidin B and piericidin stereochemistry
determination: Takahashi, N.; Suzuki, A.; Kimura, Y.; Miyamoto, S.;
Tamura, S. Tetrahedron Lett. 1967, 8, 1961. (d) Stereochemical revision:
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(3) Schnermann, M. J.; Boger, D. L. J. Am. Chem. Soc. 2005, 127, 15704.
(4) Previous synthetic studies and analogue synthesis: (a) Ono, M.; Yoshida,
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(13) To the limits of detection by 1H NMR analysis of the crude reaction
mixture, this reaction produces a single diastereoisomer (dr >95:5). In
this instance, the major side reaction is simple reduction of the enyne.
(14) Under the conditions employed, this coupling provided a ∼2.5:1 ratio of
E:Z diastereoisomers at the ∆2,3 olefin, from which the desired compound
could be isolated by chromatography on AgNO3-impregnated silica.
(15) See the Supporting Information for details.
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