Total synthesis of the proposed structure for pyragonicin

Article abstract of DOI:10.1021/ol0508126

(Chemical Equation Presented) The total synthesis of acetogenin 1 reported for pyragonicin and its 10-epimer 32 is described. The common THP ring system was stereoselectively constructed through a Sml₂-induced reductive cyclization of β-alkoxy

Full text of DOI:10.1021/ol0508126

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2783-2786
Total Synthesis of the Proposed
Structure for Pyragonicin
Shunya Takahashi,*,† Narihito Ogawa,† Hiroyuki Koshino,† and Tadashi Nakata*,‡
RIKEN (The Institute of Physical and Chemical Research), Wako, Saitama 351-0198,
Japan, and Department of Chemistry, Faculty of Science, Tokyo UniVersity of Science,
1-3, Kagurazaka, Shinjuku-Ku, Tokyo 162-8601, Japan
shunyat@postman.riken.go.jp; nakata@rs.kagu.uts.ac.jp
Received April 14, 2005
ABSTRACT
The total synthesis of acetogenin 1 reported for pyragonicin and its 10-epimer 32 is described. The common THP ring system was stereoselectively
constructed through a SmI2-induced reductive cyclization of -alkoxy acrylate 5 followed by Mitsunobu inversion, and each chiral center at
â
C-10 was created by Brown’s asymmetric allylation. Compound 1 had spectroscopic data consistent with that of natural pyragonicin, but a
different optical rotation.
The annonaceous acetogenins from the Annonaceae plants
comprise a class of almost 400 natural products that exhibit
a remarkably broad spectrum of biological properties such
as anticancer, antiinfective, immunosuppressive, pesticidal,
and antifeedant activities.1 Structurally, most of these
compounds belong to several classic types with an unsub-
stituted tetrahydrofuran (THF) ring: the mono-THF, the
adjacent bis-THF, and the nonadjacent bis-THF acetogenins.
Recently, several nonclassical acetogenins have been dis-
covered bearing a tetrahydropyran (THP) ring.2 Pyragonicin,
which was isolated from the stem bark of Goniothalamus
giganteus Hook. f. & Thomas (Annonaceae), is a new
member of the family.3 The structure was elucidated by
chemical and spectral means to be 1 possessing an axial
hydroxyl group on the THP ring. The acetogenin was active
in the BST assay4 and showed a selective inhibitory effect
against PACA-2 (pancreatic cancer) cell lines.
Recently, we have been engaged in synthetic studies on
the THP-acetogenins, resulting in the total synthesis of
mucocin, jimenezin, muconin, and pyranicin.5 As part of our
continuing studies in this field, we describe herein the first
total synthesis of 1 and its 10-epimer 32 and the comparison
of their analytical data with those reported for pyragonicin.
† RIKEN.
‡ Tokyo University of Science.
(1) For recent reviews, see: (a) Zafra-Polo, M. C.; Gonzalez, M. C.;
Estornell, E.; Sahpaz, S.; Cortes, D. Phytochemistry 1996, 42, 253-271.
(b) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.;
McLaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275-306. (c) Zafra-Polo, M.
C.; Figadere, B.; Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochemistry
1998, 48, 1087-1117. (d) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J.
Nat. Prod. 1999, 62, 504-540 and references therein.
(2) (a) Shi, G.; Alfonso, D.; Fatope, M. O.; Zeng, L.; Gu, Z.-M.; Zhao,
G.-X.; He, K.; MacDougal, J. M.; McLaughlin, J. L. J. Am. Chem. Soc.
1995, 117, 10409-10410. (b) Shi, G.; Kozlowski, J. F.; Schwedler, J. T.;
Wood, K. V.; MacDougal, J. M.; McLaughlin, J. L. J. Org. Chem. 1996,
61, 7988-7989. (c) Chavez, D.; Acevedo, L. A.; Mata, R. J. Nat. Prod.
1998, 61, 419-421. (d) Fall, D.; Duval, R. A.; Gleye, C.; Laurens, A.;
Hocquemiller, R. J. Nat. Prod. 2004, 67, 1041-1043.
(3) Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L. Tetrahedron
1998, 54, 5833-5844.
(4) Alali, F.; Zeng, L.; Zhang, Y.; Ye, Q.; Hopp, D. C.; Schwedler, J.
T.; McLaughlin J. L. Bioorg. Med. Chem. 1997, 5, 549-555.
(5) (a) Takahashi, S.; Nakata, T. Tetrahedron Lett. 1999, 40, 723-726.
(b) Takahashi, S.; Nakata, T. Tetrahedron Lett. 1999, 40, 727-730. (c)
Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett. 1999, 1, 2025-
2028. (d) Takahashi, S.; Fujisawa, K.; Sakairi, N.; Nakata, T. Heterocycles
2000, 53, 1361-1370. (e) Takahashi, S.; Nakata, T. J. Org. Chem. 2002,
67, 5739-5752. (f) Takahashi, S.; Kubota, A.; Nakata, Angew. Chem., Int.
Ed. 2002, 41, 4751-4754. (g) Takahashi, S.; Kubota, A.; Nakata, T.
Tetrahedron Lett. 2002, 43, 8661-8664. (h) Takahashi, S.; Kubota, A.;
Nakata, T. Tetrahedron 2003, 59, 1627-1638. (i) Takahashi, S.; Kubota,
A.; Nakata, T. Org. Lett. 2003, 5, 1353-1356.
10.1021/ol0508126 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/02/2005

Our synthetic strategy directed toward 1 was based on a
convergent process involving the Wittig reaction of aldehyde
26,5f with phosphonium salt 3 as illustrated in Scheme 1.7
Scheme 2
Scheme 1
The chiral center at the C-10 position of 3 was to be
introduced by asymmetric allylation8 to the THP aldehyde
4. Construction of the 14,18-syn-17,18-cis-THP ring system
would be achieved by SmI2-induced reductive cycliza-
tion9 of the â-alkoxy acrylate 5 having a formyl group
followed by stereoinversion at the C-17 position. The acrylate
5 would be prepared through a chain extension of 2,3-O-
isopropylidene-D-threitol (6) reported by Kotsuki et al.10 In
addition, this strategy would enable us to make the C-10
epimer 32 through a change in the chiral ligand.
The synthesis of 3 began with the triflation of threitol
derivative 7 (Scheme 2).11 The resulting triflate reacted with
allylmagnesium bromide in the presence of copper bromide
to give olefin 8 in 83% yield. Lemieux-Johnson oxidation
of 8 afforded an aldehyde, which was transformed into
methyl acetal 9. After benzylation of 9, the benzyl ether 10
(6) Sinha, S. C.; Sinha, A.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc.
1997, 119, 12014-12015.
was subjected to transacetalization12 to give the thioacetal
11 in 98% yield. Oxy-Michael addition of 11 to ethyl
propiolate followed by dethioacetalization of 12 afforded the
key intermediate 5 in 82% yield. SmI2-induced reductive
cyclization of 5 was effected by treatment with 2.5 equiv of
SmI2 in the presence of methanol (3.0 equiv) in THF at 0
°C to give THP ester 13 in 86% yield. The stereochemistry
around the THP ring system was established by NMR
analysis of the corresponding acetate 13a, including NOE
(7) The numbering system in ref 3 was adopted.
(8) (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092-
2093. (b) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1987,
52, 319-320.
(9) (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron
Lett. 1999, 40, 2811-2814. (b) Matsuo, G.; Hori, N.; Nakata, T. Tetrahedron
Lett. 1999, 40, 8859-8863. (c) Hori, N.; Matsukura, H.; Nakata, T. Org.
Lett. 1999, 1, 1099-1101. (d) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata,
T. Tetrahedron 2002, 58, 1853-1864. (e) Matsuo, G.; Kadohama, H.;
Nakata, T. Chem. Lett. 2002, 148-149.
(10) (a) Kotsuki, H.; Kadota, I.; Ochi, M. J. Org. Chem. 1990, 55, 4417-
4422. (b) Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahedron Lett. 1990, 31,
4609-4612.
(11) Schnurrenberger, P.; Hungerbu¨hler, E.; Seebach, D. Tetrahedron
Lett. 1984, 25, 2209-2212.
(12) Corey, E. J.; Shimoji, K. Tetrahedron Lett. 1983, 24, 1289-1292.
Org. Lett., Vol. 7, No. 13, 2005
2784

Scheme 3
experiments. Thus, irradiation of H14 resulted in enhance-
ment of the H18 peak. In the H NMR (CDCl3) spectra of
istry and the optical purity (93% de) were determined by
the modified Mosher’s method of the corresponding MTPA
esters. After methoxymethylation of 21, the resulting com-
pound 23 was subjected to ozonolysis and subsequent
reductive workup with NaBH4 in one pot to provide alcohol
24 in 91% yield. Iodination of 24 afforded 25, which was
treated with Ph3P in acetonitrile at 60 °C, giving the
phosphonium salt 3 in high yield. Construction of the
complete carbon skeleton of 1 relied on the Wittig reaction
as follows. Generation of the Wittig reagent derived from
1.0 equiv of 3 and 0.95 equiv of sodium bis(trimethylsilyl)-
amide in THF at 0 °C followed by addition of 2 at -78 °C
provided coupling product 27 in 44% yield. Finally, hydro-
genation of 27 using the Wilkinson catalyst afforded lactone
29, in which all of the hydroxy protecting groups were
removed by HCl to produce 1 in high yield. 1H and 13C NMR
spectral data of synthetic 1 were in good agreement with
the reported data of the natural product. Their specific optical
rotations, however, showed sharp contrast. Whereas synthetic
1 showed [R]24D +13.8 (c 0.11, CHCl3), the [R]23D value of
natural 1 was reported to be -25.6 (c 0.008, CHCl3). The
discrepancy suggested synthetic 1 was possibly an enanti-
omer of natural product. The assignment of the relative and
absolute configuration of the seven stereocenters of natural
pyragonicin was based on NMR measurements including
Mosher ester methodology.16 Therefore, we prepared the
corresponding MTPA esters (30 and 31) from 1 and carried
out extensive NMR analyses. Table 1 lists the comparisons
of 1H NMR data.17 In (R)-MTPA derivatives, NMR spectral
1
13a, the signal corresponding to the proton of C-18 was
observed at 3.82 ppm as a triplet of doublets (J17,18 ) 9.6
Hz). These data were consistent with the proposed structure
for 13. The high stereoselectivity is attributable to chelation
control.5f To accomplish stereoinversion at the C-17 position,
the ester 13 was hydrolyzed under basic conditions, giving
the corresponding carboxylic acid. Treatment of this with
diethyl azodicarboxylate13 in the presence of Ph3P led to
formation of a γ-lactone ring, affording bicyclic compound
14 in 96% yield from 13. After DIBAL reduction of 14, the
resulting hemiacetal underwent Wittig reaction to give olefin
15 in 98% yield. Methoxymethylation of 15 followed by
hydrogenation gave diol 16 in 95% yield. Selective tosylation
of 16 was achieved by the action of p-TsCl and triethylamine
in the presence of Bu2SnO14 to afford monotosylate 17. Upon
treatment with potassium carbonate, 17 gave epoxide 18 in
79% yield from 16.
Nucleophilic addition of allylmagnesium chloride to 18
in the presence of copper iodide gave alcohol 19 in 77%
yield (Scheme 3). This compound was converted into
aldehyde 4 via 20 in 85% yield (2 steps). Brown’s asym-
metric allylation of 4 proceeded nicely to give the desired
R-alcohol 21 in 91% yield.15 The newly created stereochem-
(13) Mitsunobu, O. Synthesis 1981, 1-28.
(14) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447-450.
(15) Reaction without a chiral ligand gave a 1:1 mixture of epimers.
Org. Lett., Vol. 7, No. 13, 2005
2785

Table 1. 1H NMR Data (δ) for Compounds 30, 31, 33, and 34
(R)-MTPA ester
(S)-MTPA ester
position
natural
30
33
natural
31
34
3
4
2.57, 2.67
5.34
2.58, 2.66
5.34
2.59, 2.67
5.35
2.54, 2.60
5.30
2.54, 2.59
5.30
2.54, 2.58
5.28
5
1.56
5.02
4.99
3.48
1.26, 1.32
1.70, 2.07
5.02
3.40
1.35, 1.42
6.95
1.53, 1.62
4.90
5.00
3.48
1.26
1.70, 2.07
5.02
3.40
1.36, 1.43
6.95
4.90
1.50, 1.63
4.90
4.95
1.61
4.99
5.02
3.38
1.32, 1.40
1.58, 2.05
4.99
3.32
1.14, 1.25
6.73
1.60, 1.67
5.01
4.99
1.54, 1.63
5.05
5.09
10
13
14
15
16
17
18
19
33
34
35
3.41
3.41
3.46
1.14, 1.21
1.69, 2.04
5.02
3.38
1.36, 1.41
6.95
1.19, 1.34
1.68, 2.06
4.98
3.32
1.15, 1.20
6.73
1.21, 1.40
1.71, 2.07
4.99
3.34
1.15, 1.21
6.72
4.91
1.30
4.90
1.30
4.86
1.27
4.85
1.28
4.85
1.28
1.30
data of synthetic 30 were quite similar to those of the natural
derivative except for the chemical shift of H-10. In contrast,
the four signals for H-10, -13, -14, and -15 of 31 deviated
by 0.02-0.13 ppm compared with the respective signals of
the (S)-MTPA ester derived from natural pyragonicin in the
1H NMR spectrum. These results suggested a difference in
the stereochemistry around the C-10 position and prompted
us to prepare the corresponding 10-epimer 32. Asymmetric
allylation of the intermediate 4 using (-)-B-methoxy-
diisopinocamphenylborane afforded the epimer 22 in 95%
yield (92% de). According to the procedure for the prepara-
tion of 3, the alcohol 22 was transformed into phosphonium
salt 26 in 77% overall yield (4 steps). Wittig reaction of 26
with 2 afforded 28 in 43% yield. Hydrogenation of 28
followed by deprotection reaction provided the C-10 epimer
product and compound 1.18 These results prevent us from
unequivocally stating that natural pyragonicin and compound
1 are identical. To clarify this, a direct comparison of our
synthetic sample with the authentic natural product is
necessary. We provide complete 13C NMR assignments17
including methylene carbons around oxygenic functional
groups for synthetic compounds 1 and 32, which would also
be useful to discuss the structure of natural pyragonicin.
In summary, we have succeeded in a convergent synthesis
of 1 and its 10-epimer 32, employing the SmI2-induced
radical cyclization reaction of 5 and coupling reaction
between 2 and 3 or 26 as the key steps.
Acknowledgment. This work was supported by the
Chemical Biology Project (RIKEN). We are grateful to Ms.
K. Harata for mass spectral measurements and Dr. T. Chihara
and his staff in RIKEN for the elemental analyses.
32 {[R]21 +16.8 (c 0.30, CHCl3)} in 79% yield from 28.
D
1H and 13C NMR spectral data of 32 were not matched with
those of the natural product. Similarly, 1H NMR data of the
corresponding MTPA esters (33 and 34) were different from
those of naturally derived esters (Table 1). On the basis of
the present data, it should be mentioned that reported spectral
data of pyragonicin are quite similar to those of structure 1
rather than 32. However, there is a discrepancy in the
magnitude and sign of the optical rotation for the natural
Supporting Information Available: Experimental pro-
cedures and NMR spectra of 1, 3-5, 8-34, and 13a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0508126
(18) Discrepancies between the optical rotations of synthesized samples
and extracted samples of otherwise apparently identical compounds have
occurred previously: (a) Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Org. Chem.
1999, 64, 7067-7073. (b) Maezaki, N.; Kojima, N.; Sakamoto, A.; Iwata,
C.; Tanaka, T. Org. Lett. 2001, 3, 429-432. (c) Reference 5i. (d) Makabe,
H.; Miyawaki, A.; Takahashi, R.; Hattori, Y.; Konno, H.; Abe, M.; Miyoshi,
H. Tetrahedron Lett. 2004, 45, 973-977. (e) Strand, D.; Rein, T. Org. Lett.
2005, 7, 199-202.
(16) In annonaceous acetogenins bearing a hydroxyl group at C-4, it is
reported that this method could give the information in relation to the
stereochemistry of the methine proton at C-34 as well as the hydroxyl
groups. See: Hoye, T. R.; Hanson, P. R.; Hasenwinkel, L. E.; Ramirez, E.
A.; Zhuang, Z. Tetrahedron Lett. 1994, 35, 8529-8532.
(17) 2D-NMR experiments were used. See Supporting Information.
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