A concise and modular synthesis of pyranicin

Article abstract of DOI:10.1021/ol802041c

(Chemical Equation Presented) A modular, 13-step synthesis of the tetrahydropyran-containing annonaceous acetogenin pyranicin is reported. Key features are the use of an Achmatowicz oxidation - Kishi reduction sequence for the assembly of a pyranone from a furan and the application of Fu's alkyl - alkyl Suzuki coupling for subunit union.

Full text of DOI:10.1021/ol802041c

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4955-4957
A Concise and Modular Synthesis of
Pyranicin
Nolan D. Griggs and Andrew J. Phillips*
Department of Chemistry and Biochemistry, UniVersity of Colorado at Boulder,
Boulder, Colorado 80309-0215
andrew.phillips@colorado.edu
Received September 1, 2008
ABSTRACT
A modular, 13-step synthesis of the tetrahydropyran-containing annonaceous acetogenin pyranicin is reported. Key features are the use of an
Achmatowicz oxidation-Kishi reduction sequence for the assembly of a pyranone from a furan and the application of Fu’s alkyl-alkyl Suzuki
coupling for subunit union.
The annonaceous acetogenins, a group of polyketides that are
generally identified by the presence of one or two tetrahydro-
furan rings, now number greater than 400 compounds.1 A small
subset of the acetogenins, including mucocin and jimenezin,
contain both a tetrahydrofuran ring and a tetrahydropyran ring.
As a class, these compounds have attracted substantial scientific
attention due to their rich and varied biological activities which
include anticancer, antiinfective, immunosuppressive, pesticidal,
and antifeedant properties.
Pyranicin (1, Figure 1) was isolated from the stem bark of
Goniothalamus giganteus and is the prototype of acetogenins
that contain a single tetrahydropyran ring.2 Despite what could
be argued to be substantial structural simplification relative to
more complex acetogenins, pyranicin retains impressive bio-
logical activity, with <1 µg/mL ED50 values against a number
of cancer cell lines and particularly noteworthy effects against
the PACA-2 (pancreatic cancer) cell line (ED50 ) 1.3 ng/mL).
As part of our ongoing interest in the synthesis of natural
product inhibitors of electron transport,3 we describe in this
communication a total synthesis of 1.4
Figure 1. Pyranicin and overall synthesis strategy.
amenable to the synthesis of a variety of compounds that could
illuminate SAR for pyranicin. With this in mind, we settled on
a strategy that called for the preparation of three key subunits:
pyran 2, alkynyl olefin 3, and butenolide 4. Pyran 2 would be
preparedbyourrecentlydescribedAchamatowiczoxidation-Kishi
From the outset, an overarching goal of our studies was to
develop a concise and modular synthesis that would be
(3) Keaton, K. A.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 408.
(4) For other total syntheses see: (a) Strand, D.; Norrby, P.-O.; Rein, T.
J. Org. Chem. 2006, 71, 1879. (b) Strand, D.; Rein, T. Org. Lett. 2005, 7,
199. (c) Takahashi, S.; Kubota, A.; Nakata, T. Org. Lett. 2003, 5, 1353.
(d) Hattori, Y.; Furuhata, S.-i.; Okajima, M.; Konno, H.; Abe, M.; Miyoshi,
H.; Goto, T.; Makabe, H. Org. Lett. 2008, 10, 717. (e) Furuhata, S.-i.;
Hattori, Y.; Okajima, M.; Konno, H.; Abe, M.; Miyoshi, H.; Goto, T.;
Makabe, H. Tetrahedron 2008, 64, 7695.
(1) For a review see: Bermejo, A; Figadere, B.; Zafra-Polo, M.-C.;
Barrachina, I; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269, and
references cited therein.
(2) Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L. Tetrahedron
1998, 54, 5833.
10.1021/ol802041c CCC: $40.75
Published on Web 10/10/2008
2008 American Chemical Society

reduction sequence,5 and our plans for subunit coupling involved
the use of Carreira’s asymmetric alkynylation6 and Fu’s recently
described alkyl-alkyl Suzuki coupling.7
diastereoisomer (>20:1 by H NMR analysis). This three-
1
step sequence conveniently provided the desired pyran in
33% overall yield. Hydrogenation of the enone, followed
by reduction of the ketone with L-Selectride gave axial
alcohol 9 in 86% yield (two steps). Protection of the
secondary alcohol as the TBS ether, removal of the benzyl
ether (88% yield, two steps), and oxidation with Dess-Martin
periodinane led to aldehyde 2 (99% yield). Reaction with
known alkyne 311 under Carreira’s asymmetric alkynylation
conditions (Et3N, Zn(OTf)2, (-)-NME, PhMe) and subse-
quent protection of the secondary alcohol as the TBS ether
gave 10 (82% yield over two steps).
The synthesis of the tetahydropyran-containing domain
commenced with commercially available furan 58 (Scheme 1).
Scheme 1. Synthesis of the C7-C32 Pyran-Containing Domain
The synthesis of butenolide 4 began with the alkylation of
alkyne 1112 with epoxide 1213 in the presence of BF3·OEt2,
followed by immediate protection of the homopropargyl alcohol
with TBDSPCl to give 13 in 88% yield (Scheme 2). Careful
removal of the TBS ether with ethanolic PPTS (95% yield)
and hydroalumination-iodination of the alkyne following
Denmark’s procedure14 produced vinyl iodide 14 in 90% yield.
In accord with Stille’s original report15 and Hoye’s application
in the context of acetogenin synthesis,16 when 14 was subjected
to Pd(0) under 50 psi CO, carbonylative lactonization occurred
to yield the desired butenolide 15 in 90% yield. Oxidative
removal of the PMB ether with DDQ in wet CH2Cl2 (82%
yield) unveiled primary alcohol 16. Conversion of the alcohol
to the bromide 4 was readily achieved by Hannesian’s NBS-
Ph3P protocol17 in 87% yield.
With routes to 10 and 4 secured we were positioned to
examine the proposed Fu-type Suzuki coupling for subunit
union (Scheme 2).18 To this end, when 10 was treated with 1.1
equiv of freshly prepared 9-BBN in THF at room temperature,
hydroboration was selective for the terminal alkene over the
internal alkyne19 to yield intermediate borane 17. When this
borane was exposed to bromide 4, Pd(PCy3)2 and K3PO4·H2O
smooth cross-coupling ensued to yield the desired compound
18 in 60% yield. In our hands, this coupling was robust with
20 mol % Pd(PCy3)2 catalyst loading and 1.2 equiv of bromide
4. In the current example, deviation from these conditions
resulted in decreased and variable yields of the desired
compound. The synthesis was then completed in a straightfor-
ward fashion by removal of the silyl protecting groups with
aqueous HF in acetonitrile (92% yield), and reduction of the
alkyne to the hydrocarbon using Wilkinson’s catalyst in
benzene-ethanol to produce pyranicin 1 in 89% yield. The
(9) Kobayashi, Y.; Kusakabe, M.; Kitano, Y.; Sato, F. J. Org. Chem.
1988, 53, 1586.
Addition of dodecylmagnesium bromide produced furfuryl
alcohol 6, which was subjected to the Sharpless asymmetric
kinetic resolution reported by Sato9,10 to yield the intermediate
pyranone hemiacetal 7. Immediate reduction with i-Pr3SiH
in the presence of BF3·OEt2 gave pyran 8 as a single
(10) For the CaH2/SiO2 modified conditions employed here see: (a)
Yang, Z. C.; Zhou, W. S. Tetrahedron Lett. 1995, 36, 5617. (b) Zhou, W. S.;
Lu, Z.; Wang, Z. Tetrahedron Lett. 1991, 32, 1467. (c) Wang, Z.; Zhou,
W.; Lin, G. Tetrahedron Lett. 1985, 26, 6221.
(11) Garcia-Fandino, R.; Aldegunde, M. J.; Codesido, E. M.; Castedo,
L.; Granja, J. R. J. Org. Chem. 2005, 70, 8281.
(12) Brimble, M. A.; Bryant, C. J. Org. Biomol. Chem. 2007, 5, 2858.
(13) Marshall, J. A.; Schaaf, G.; Nolting, A. Org. Lett. 2005, 7, 5331.
(14) (a) Chan, K.; Cohen, N.; DeNoble, J. P.; Specian, A. C.; Saucy,
G. J. Org. Chem. 1976, 41, 3497. (b) Denmark, S. E.; Jones, T. K. J. Org.
Chem. 1982, 47, 4595.
(5) (a) Henderson, J. A.; Jackson, K. L.; Phillips, A. J. Org. Lett. 2007,
9, 5299. (b) Um, J. M.; Houk, K. N.; Phillips, A. J. Org. Lett. 2008, 10,
3769. (c) See also: Nicolaou, K. C.; Frederick, M. O.; Burtoloso, A. C. B.;
Denton, R. M.; Rivas, F.; Cole, K. P.; Aversa, R. J.; Gibe, R.; Umezawa,
T.; Suzuki, T. J. Am. Chem. Soc. 2008, 130, 7466.
(15) Cowell, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193.
(16) Hoye, T. R.; Humpal, P. E.; Jimenez, J. I.; Mayer, M. J.; Tan, L.;
Ye, Z. Tetrahedron Lett. 1994, 35, 7517.
(6) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
(7) Netherton, M. R.; Dai, C.; Neuschu¨tz, K.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 10099.
(17) Ponpipom, M. M.; Hanessian, S. Carbohydr. Res. 1971, 18, 342.
(18) For other examples of the use of this reaction in total synthesis
see: (a) Das, S.; Abraham, S.; Sinha, S. C. Org. Lett. 2007, 9, 2273. (b)
Keaton, K. A.; Phillips, A. J. Org. Lett. 2007, 9, 2717.
(8) This furan is also readily prepared by benzylation of (hydroxymethyl)
furfural. See: Cottier, L.; Descotes, G.; Eymard, L.; Rapp, K. Synthesis
1995, 303.
(19) Brown, C. A.; Coleman, R. A. J. Org. Chem. 1979, 44, 2328.
4956
Org. Lett., Vol. 10, No. 21, 2008

Scheme 2. Synthesis of the Butenolide Domain and Completion of the Synthesis
physical characteristics of synthetic material (1H and 13C NMR,
HRMS) matched those reported by McLaughlin.2 Optical
rotation data was in accord with that reported by Rein and
Takahashi.20,21
In conclusion, we have described a concise (13 steps
longest linear sequence) and efficient (10% overall yield)
synthesis of pyranicin. Beyond these metrics, the synthesis
is modular and will prove amenable to the synthesis of a
variety of analogues. This work also highlights the utility of
the Achmatowicz oxidation-Kishi reduction sequence for
the assembly of pyrans and the strategic potential of
alkyl-alkyl Suzuki couplings in a complex setting.
(20) As described and discussed by Rein and Takahashi in references
4a, 4b, and 4c, there is a discrepancy between the optical rotations for
synthetic and natural pyranicin: natural pyranicin [R]D -9.7 (c 0.008,
CHCl3); synthetic pyranicin (Takahashi): [R]D +19.5 (c 0.55, CHCl3);
synthetic pyranicin (Rein): [R]D +21.1 (c 0.24, CHCl3). Our material had
optical rotation of [R]D +24.8 (c 0.20, CHCl3).
(21) The possibility of the discrepancy in optical rotations being due to
aggregation effects seemed unlikely as the rotation in chloroform for our
synthetic material does not vary significantly with changing concentration:
Acknowledgment. We thank Eli Lilly and Company (via
the Lilly Grantee Program), the AP Sloan Foundation, and
the National Cancer Institute (CA 110246) for support of
this research.
concentration (c)
R
[R]D
Supporting Information Available: Procedures for the
synthesis of new compounds, along with characterization
data, and spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
0.200
0.125
0.063
0.031
0.015
+0.049
+0.022
+0.016
+0.007
+0.003
+24.8
+17.8
+26.3
+22.7
+21.3
OL802041C
Org. Lett., Vol. 10, No. 21, 2008
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