Asymmetric total synthesis of pyranicin

Article abstract of DOI:10.1021/ol900814w

The asymmetric total synthesis of pyranicin (1) is reported. The butenolide ring was constructed via an asymmetric alkylation/ring-closing metathesis strategy. The three stereocenters in the left-hand tetrahydropyran ring were installed by sequential chir

Full text of DOI:10.1021/ol900814w

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2695-2698
Asymmetric Total Synthesis of Pyranicin
Michael T. Crimmins* and Danielle L. Jacobs
Kenan & Caudill Laboratories of Chemistry, UniVersity of North Carolina at Chapel
Hill, Chapel Hill, North Carolina 27599
crimmins@email.unc.edu
Received April 14, 2009
ABSTRACT
The asymmetric total synthesis of pyranicin (1) is reported. The butenolide ring was constructed via an asymmetric alkylation/ring-closing
metathesis strategy. The three stereocenters in the left-hand tetrahydropyran ring were installed by sequential chiral auxiliary-mediated aldol
reactions. Closure of the tetrahydropyran and fusion of the alkyl backbone were affected via a sequential ring-closing metathesis-cross-
metathesis strategy.
Pyranicin (1), a novel member of the annonaceous acetogenin
family of natural products, was isolated in 1997 by McLaugh-
lin and co-workers from the stem bark of the Goniothalamus
giganteus tree native to Thailand.1 Since 1982, over 400
molecules in the annonaceous acetogenin family have been
identified, but pyranicin is one of only two known acetoge-
nins to bear a tetrahydropyran (THP) ring.2 These polyether
natural products typically possess a terminal γ-methyl-
butenolide and are capped with a long hydrophobic alkyl
chain. Annonaceous acetogenins are the most powerful
inhibitors of mitochondrial complex I (NADH-ubiquinone
oxidoreductase) in both mammalian and insect electron
transport systems. It is believed that their ability to interrupt
the final electron transfer from NADH to ubiquinone
decreases cellular ATP production, leading to cell death by
apoptosis. This unique mode of biological activity has
characterized the acetogenins as promising antifeedant and
pesticide treatments, as well as antimalarial, antiparasitic,
and antitumor drugs, and they have recently exhibited
promising results against Parkinsonism.3 Pyranicin, in par-
ticular, demonstrates selective in vitro cytotoxicity (ED50 10-2
µg/mL) against human pancreatic adenocarcinomal cell lines
(PACA-2).1 Recent studies have further revealed in vivo
cytotoxicity (ID50 9.4 µM) of pyrancin against the growth
of promyelocytic leukemia cells (HL-60), alternatively
attributed to its ability to inhibit DNA polymerase in the
cancerous cells.4 The interesting structures and potent
biological activity have made the annonaceous acetogenins
the subject of a significant amount of synthetic work.5 The
first total synthesis of pyranicin was accomplished by Nakata
and Takahashi6 with subsequent reports by Rein,7 Makabe,8
and Phillips.9
Herein, we describe an enantioselective total synthesis of
pyranicin, taking advantage of chlorotitanium enolates of
N-glycolyloxazolidinones to establish the syn 1,2-oxygen
relationship at C15-C16 and C19-C20.10 The pyranicin
(4) (a) Takahashi, S.; Yonezawa, Y.; Kubota, A.; Ogawa, N.; Maeda,
K.; Koshino, H; Nakata, T.; Yoshida, H.; Mizushina, Y. Int. J. Oncol. 2008,
32, 451–458. (b) Ishimaru, C.; Takeuchi, T.; Yonezawa, Y.; Kuriyama, I.;
Takemura, M.; Kato, I; Sugawara, F.; Yoshida, H.; Mizushina, Y. Lett.
Drug Design Disc. 2007, 4, 239–245.
(5) For a recent review, see: Li, N.; Shi, Z. H.; Tang, Y.; Chen, J.; Li,
X. Beilstein J. Org. Chem. 2008, 4, 48 DOI:, 10.3762/bjoc.4.48.
(6) Takahashi, S.; Kubota, A.; Nakata, T. Org. Lett. 2003, 5, 1353–
1356.
(7) Strand, D.; Rein, T. Org. Lett. 2005, 7, 199–202. Strand, D.; Norrby,
P. O.; Rein, T. J. Org. Chem. 2006, 71, 1879–1891.
(1) Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L. Tetrahedron
1998, 54, 5833–5844.
(8) (a) Hattori, Y.; Furuhata, S.; Okajima, M.; Konno, H.; Abe, M.;
Miyoshi, H.; Goto, T.; Makabe, H. Org. Lett. 2008, 10, 717–720. (b)
Furuhata, S.; Hattori, Y.; Okajima, M.; Konno, H.; Abe, M.; Miyoshi, H.;
Goto, T; Makabe, H. Tetrahedron 2008, 64, 7695–7703.
(2) Bermejo, A.; Figade´re, B.; Zafra-Polo, M.-C.; Barrachina, I.;
Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269–303.
(3) For a recent reviewm see: McLaughlin, J. L. J. Nat. Prod. 2008,
71, 1311–1321.
(9) Griggs, N. D.; Phillips, A. J. Org. Lett. 2008, 10, 4955–4957.
(10) Crimmins, M. T.; She, J. Synlett 2004, 1371–1374.
10.1021/ol900814w CCC: $40.75
Published on Web 05/13/2009
 2009 American Chemical Society

fragment 3 (Figure 1). Dihydropyran precursor 2 would be
accessed via an asymmetric glycolate aldol addition of
glycolyloxazolidinone 4 and aldehyde 5. The butenolide ring
would be constructed via esterification of acrylic acid 7 with
(S)-3-buten-2-ol (6), followed by RCM.
Aldehyde 5 was prepared from (S)-benzylglycidyl ether
as illustrated in Scheme 1. Lewis acid promoted addition11
of lithiated homopropargyl alcohol 8 to (S)-benzyl glycidyl
ether provided alkyne 9. The alkyne was reduced, and
removal of the benzyl group was accomplished employing
Raney nickel to deliver diol 10. Selective sulfonylation of
the primary alcohol was best affected employing 2,4,6-
triisopropylsulfonyl chloride (TrisCl) under standard condi-
tions whereupon treatment with base afforded epoxide 11.
Subsequently, the (S)-epoxide underwent copper(I)-promoted
reaction with butenylmagnesium bromide to provide alcohol
12. Ensuing alcohol protection, selective removal of the PMB
ether,12 and Swern oxidation13 of the primary alcohol
provided the target aldehyde 5 in good yield over three steps.
Figure 1. Original retrosynthesis of pyranicin.
Preparation of triene 2 began with a glycolate aldol
reaction between benzylglycolyloxazolidinone 13 and tride-
canal, providing aldol adduct 14 in good yield and excellent
diastereoselectivity (Scheme 1).10 This reaction established
the stereocenters at C19 and C20 at an early stage. The
secondary alcohol was then protected as its triethylsilyl (TES)
carbon backbone was envisioned to arise from a tandem ring-
closing metathesis (RCM)-cross-metathesis (CM) reaction
that would close the tetrahydropyran ring from triene 2 while
concurrently joining the tetrahydropyran unit and butenolide
Scheme 1. Preparation of Triene 2
2696
Org. Lett., Vol. 11, No. 12, 2009

Scheme 2. Preparation of Butenolide 3
ether, and the chiral auxiliary was reductively removed with
lithium borohydride.
isolation. In an attempt to ease the problems with isolation
of alcohol 6, while still maintaining the necessary terminal
olefin functionality for the ensuing RCM reaction, we
investigated the use of alcohol 22 in an alternative relay ring-
closing metathesis (RRCM) strategy, recently demonstrated
by Hoye17 (Scheme 2). We anticipated that while the
increased molecular weight of the ether fragment of alcohol
22 would effectively improve the isolation of the chiral
alcohol, the additional atoms would be removed as dihy-
drofuran during the ensuing relay metathesis, providing
butenolide 3. The synthesis of bis-allylic ether 22 was thus
pursued. L-Ethyl lactate was protected as its tert-butyldiphe-
nylsilyl (TBDPS) ether 20, which was subsequently reduced
to the corresponding aldehyde (Scheme 2). Olefination of
the intermediate aldehyde employing carboethoxymethylene
triphenylphsophorane yielded R,ꢀ-unsaturated ester 21, which
was then reduced to the allylic alcohol. Alkylation of the
alcohol with allyl bromide gave the allyl ether, which was
exposed to n-Bu4NF to provide the desired alcohol 22 in
80% over two steps.
Oxidation13 of primary alcohol 15 followed by Wittig
methylenation provided the protected diol, which was
selectively deprotected under fluoride conditions to give
secondary alcohol 16. Subsequent alkylation of the free
alcohol with bromoacetic acid gave the glycolic acid, and
further transformation into glycolylimide 4 was accomplished
via nucleophilic addition of lithiated oxazolidinone 17 to the
intermediate mixed pivaloyl anhydride.14
A second titanium-mediated glycolate aldol reaction10 with
aldehyde 5 established the stereocenters at C15 and C16
providing the aldol adduct 18 in 74% yield (>95:5 dr). The
RCM precursor 2 was prepared from aldol adduct 18 by a
four-step sequence. Protection of the C15 hydroxyl as its
TES ether followed by reductive removal of the auxiliary
gave the primary alcohol 19. Dess-Martin oxidation15 of
the alcohol to the aldehyde and final methylenation com-
pleted the synthesis of triene 2.
Our efforts were directed next toward the preparation of
γ-methylbutenolide 3. The C34 stereocenter was to be
installed via esterifcation using (S)-3-buten-2-ol (6). Although
the enantiomer of the alcohol had previously been prepared
in our total synthesis of giganticin,16 the volatility of the
alcohol (bp ) 92 °C) created difficulty with its successful
The synthesis of acrylate 7 began with installation of the
C4 stereocenter via asymmetric alkylation18 of p-methoxy-
benzylglycolyloxazolidinone 23 with allylic iodide 24,19
giving protected allyl alcohol 25 with high (>95:5) diaste-
reoselectivity (Scheme 2). Reductive removal of the chiral
auxiliary unmasked a primary alcohol 26, which allowed for
(11) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–394.
(12) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021–3028.
(16) Crimmins, M. T.; She, J. J. Am. Chem. Soc. 2004, 126, 12790–
12791.
(13) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480–2482.
(17) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J. Z.; Zhao,
H. Y. J. Am. Chem. Soc. 2004, 126, 10210–10211.
(18) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D Org. Lett. 2000, 2,
2165–2167.
(14) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77–82.
(15) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. Dess, D. M.; Martin,
J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
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Villieras, J.; Rambaud, M. Org. Synth. 1988, 66, 220–224.
Org. Lett., Vol. 11, No. 12, 2009
2697

conversion to the terminal alkene via Swern13 oxidation and
subsequent olefination with methylenetriphenylphsophorane.
Removal of the primary TBS ether followed by a two-stage
oxidation yielded the corresponding acrylic acid 7. Esteri-
fication of acid 7 with alcohol 22 was best affected via the
intermediate mixed pivaloyl anhydride. Initial attempts at
closure of the butenolide under standard RRCM conditions
only gave the corresponding ring-opened diene 29, presum-
ably formed after the initial expulsion of dihydrofuran,
followed by intermolecular carbene transfer. However, by
sparging the reaction with argon, we were able to increase
the yield of butenolide 3 from 23% to 70%, without any
trace of straight-chain byproduct 29.20
C6 alkene of the tetrahydropyran unit, it was hoped that the
two processes could be accomplished concurrently in a single
exposure to a ruthenium carbene.21
Despite the differences in the reactivities of the two
coupling fragments, however, the ensuing tandem RCM/CM
reaction proved to be quite difficult to control, and suitable
conditions for the tandem sequence could not be identified.
The best results were found when the cross-metathesis was
performed between the ring-closed monomer 30 and buteno-
lide 3. Therefore, it was necessary to isolate the ring-closed
monomer before subjecting it to cross-metathesis with
butenolide 3. In the event, triene 2 was exposed to the Grubbs
second-generation catalyst22 to close the tetrahydropyran ring.
After the ring-closing metathesis product 30 was isolated in
quantitative yield, the cross-metathesis between alkene 30
and butenolide 3 was achieved with the Hoveyda-Grubbs
catalyst23 in 58% yield based on recovered starting material.
Finally, exposure of triene 31 to excess tosylhydrazine and
sodium acetate in aqueous dimethoxyethane at reflux,24
resulted in selective hydrogenation of the C17-C18 and
C5-C6 alkenes and removal of the triethylsilyl protecting
group, while leaving the butenolide olefin in tact. Subjection
of the resultant butenolide to BF3·OEt2 in dimethyl sulfide
provided pyranicin (1) in 68% yield. The synthetic sample
was identical in all aspects (1H, 13C, [R]D) to the natural
product.1
The completion of the synthesis required the closure of
the tetrahydropyran ring via a ring-closing metathesis and
assembly of the THP and butenolide fragments through a
cross-metathesis reaction (Scheme 3). Given the expected
Scheme 3. Completion of the Synthesis
In summary, a highly convergent total synthesis of
pyranicin (1) has been completed. The key fragments were
constructed employing asymmetric glycolate aldol and alky-
lation reactions followed by ring-closing metatheses; a cross-
metathesis was utilized to convergently construct the back-
bone of the natural product.
Acknowledgment. Financial support from the National
Institute of General Medical Sciences (GM60567)) is grate-
fully acknowledged. We gratefully acknowledge a generous
gift of (S)-benzylglycidyl ether from Daiso, Inc.
Supporting Information Available: Experimental pro-
cedures and copies of 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL900814W
(21) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
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(22) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360–11370.
rapid closure of the tetrahydropyran and the difference in
reactivity between the C5 alkene of the butenolide and the
(23) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168–8179.
(24) For examples, see: (a) Marshall, J. A.; Chen, M. J. Org. Chem.
1997, 62, 5996–6000. (b) Crimmins, M. T.; Zhang, Y.; Diaz, F. A. Org.
Lett. 2006, 8, 2369–2372. (c) See ref 8.
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2005, 347, 1869–1874.
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