Convergent synthesis of pyragonicin

Article abstract of DOI:10.1021/jo060970q

This paper describes a second-generation synthesis of an antitumor tetrahydropyran (THP) acetogenin, pyragonicin. The key step involved an olefin cross-metathesis between the THP segment and the terminal γ-lactone residue. The coupling reaction in the pre

Full text of DOI:10.1021/jo060970q

Convergent Synthesis of Pyragonicin
Shunya Takahashi,*,† Yayoi Hongo,† Narihito Ogawa,†
Hiroyuki Koshino,† and Tadashi Nakata‡
RIKEN (The Institute of Physical and Chemical Research),
Wako-shi, Saitama, 351-0198, Japan, and Department of
Chemistry, Faculty of Science, Tokyo UniVersity of Science,
1-3 Kagurazaka, Shinjuku-Ku, Tokyo 162-8601, Japan
FIGURE 1. Structure of pyragonicin.
attention of synthetic organic chemists, and this has consequently
stimulated efforts to synthesize these natural products.2
shunyat@riken.go.jp
ReceiVed May 10, 2006
Recently, we have been engaged in synthetic studies on
acetogenins, resulting in the total synthesis of nonclassical THP
acetogenins.3-7 In the synthetic study of such acetogenins,
construction of the cyclic-ether moiety and its coupling with
the γ-lactone residue are major problems throughout the
synthetic course. In particular, mild reaction conditions are
needed for such coupling because the γ-lactone part is unstable
under basic conditions.8 Several methods including Sonogashira
coupling,9 Wittig reaction,10 and alkylation of γ-lactone11 have
been reported. However, a more efficient method for the
coupling is still required for total synthesis of these natural
products and detailed examination of their biological activity.
In a previous paper, we demonstrated that an intermolecular
cross-metathesis is a powerful tool for total syntheses of
acetogenins.12 To extend the methodology, we planned to
synthesize acetogenins of greater complexity. Here, we describe
the second-generation synthesis of pyragonicin (1) based on the
method (Figure 1). Pyragonicin (1), which was isolated from
the stem bark of Goniothalamus giganteus Hook. f. & Thomas
(Annonaceae),13 is a new member of the family possessing an
This paper describes a second-generation synthesis of an
antitumor tetrahydropyran (THP) acetogenin, pyragonicin.
The key step involved an olefin cross-metathesis between
the THP segment and the terminal γ-lactone residue. The
coupling reaction in the presence of Grubbs’ second-
generation catalyst resulted in an unseparable mixture of a
desired coupling product and its one-carbon eliminated
product while the use of Grubbs’ first-generation catalyst
afforded the former exclusively. A novel MOM-migrating
reaction found in a cyclization reaction is also discussed.
(2) For recent examples, see: (a) Nattrass, G. L.; Diez, E.; McLachlan,
M. M.; Dixon, D. J.; Ley, S. V. Angew. Chem., Int. Ed. 2005, 44, 580-
584. (b) Wilkox, C. S.; Gudipati, V.; Lu, H.; Turkyilma, S.; Curran, D. P.
Angew. Chem., Int. Ed. 2005, 44, 6938-6940. (c) Tinsley, J. M.; Roush,
W. R. J. Am. Chem. Soc. 2005, 127, 10818-10819. (d) Hwang, C. H.;
Keum, G.; Sohn, K. II.; Lee, D. H.; Lee, E. Tetrahedron Lett. 2005, 46,
6621-6623. (e) Narayan, R. S.; Borhan, B. J. Org. Chem. 2006, 71, 1416-
1429. (f) Criso´stomo, F. R. P.; Carrillo, R.; Leo´n, L. G.; Mart´ın, T.; Padro´n,
J. M.; Mart´ın, V. S. J. Org. Chem. 2006, 71, 2339-2345 and references
therein.
The annonaceous acetogenins from the Annonaceae plant are
a relatively new class of natural products that have a wide range
of biological activities such as antitumor, cytotoxic, antimicro-
bial, antimalarial, pesticidal, and immunosuppressive effects.1
They are characterized by the presence of one to three
tetrahydrofuran (THF) rings in the center of a long alkyl chain
with a butenolide moiety at the end and classified into three
types according to the number of THF rings and their connection
patterns. Besides such classical types, acetogenins have also been
discovered that bear a double bond, a tetrahydropyran (THP)
ring, and an oxirane ring (s) in the long chain. Their structural
diversity and remarkable biological activities have attracted the
(3) (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.; Fujisawa, K.; Sakairi, N.; Nakata, T. Heterocycles 2000,
53, 1361-1370. (d) Takahashi, S.; Nakata, T. J. Org. Chem. 2002, 67,
5739-5752. (e) Takahashi, S.; Kubota, A.; Nakata, T. Angew. Chem., Int.
Ed. 2002, 41, 4751-4754.
(4) Takahashi, S.; Maeda, K.; Hirota, S.; Nakata, T. Org. Lett. 1999, 1,
2025-2028.
(5) (a) Takahashi, S.; Kubota, A.; Nakata, T. Tetrahedron Lett. 2002,
43, 8661-8664. (b) Takahashi, S.; Kubota, A.; Nakata, T. Tetrahedron
2003, 59, 1627-1638.
* Corresponding author. Phone: +81-48-467-9223. Fax: +81-48-462-4627.
† RIKEN.
‡ Tokyo University of Science.
(1) For reviews, see: (a) Rupprecht, J. K.; Hui, Y.-H.; McLaughlin, J.
L. J. Nat. Prod. 1990, 53, 237-278. (b) Fang, X.-P.; Rieser, M. J.; Gu,
Z.-M.; Zhao, G.-X.; McLaughlin, J. L. Phytochem. Anal. 1993, 4, 27-67.
(c) Gu, Z.-M.; Zhao, G.-X.; Oberlies, N. H.; Zeng, L.; McLaughlin, J. L.
Recent AdVances in Phytochemistry; Plenum Press: New York, 1995; Vol.
29, pp 249-310. (d) Koert, U. Synthesis 1995, 115-132. (e) Hoppe, R.;
Scharf, H.-D. Synthesis 1995, 1447-1464. (f) Figade`re, B. Acc. Chem. Res.
1995, 28, 359-365. (g) Zafra-Polo, M. C.; Gonza´lez, M. C.; Estornell, E.;
Sahpaz, S.; Cortes, D. Phytochemistry 1996, 42, 253-271. (h) Zeng, L.;
Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He, K.; McLaughlin, J. L. Nat.
Prod. Rep. 1996, 13, 275-306. (i) Zafra-Polo, M. C.; Figade`re, B.; Gallardo,
T.; Tormo, J. R.; Cortes, D. Phytochemistry 1998, 48, 1087-1117. (j) Alali,
F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504-540. (k)
Berrnejo, A.; Figade`re, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.;
Cortes, D. Nat. Prod. Rep. 2005, 22, 269-303 and references therein.
(6) Takahashi, S.; Kubota, A.; Nakata, T. Org. Lett.2003, 5, 1353-1356.
(7) Takahashi, S.; Ogawa, N.; Koshino, H.; Nakata, T. Org. Lett. 2005,
7, 2783-2786.
(8) Duret, P.; Figade`re, B.; Hocquemiller, R.; Cave´, A. Tetrahedron Lett.
1997, 38, 8849-8852, and references therein.
(9) For example, see: Neogi, P.; Doundoulakis, T.; Yazbak, A.; Sinha,
S. C.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1998, 120, 11279-11284.
See also: Sonogashira, K.; Thoda, Y. Migihara, N. Tetrahedron Lett. 1975,
13, 4467-4470.
(10) For example, see: Hoppen, S.; Ba¨urle, S.; Koert, U. Chem. Eur. J.
2000, 6, 2382-2396.
(11) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2004, 69,
1993-1998.
(12) Takahashi, S.; Ogawa, N.; Sakairi, N.; Nakata, T. Tetrahedron 2005,
61, 6540-6545.
10.1021/jo060970q CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/13/2006
J. Org. Chem. 2006, 71, 6305-6308
6305

SCHEME 1. Synthetic Plan of Pyragonicin (1)
SCHEME 2. Synthesis of the Segment 2a
a Reagents and conditions: (a) CH(OEt)3, propionic acid, 135-140 °C, 77%; (b) AD-mix â, MeSO2NH2, t-BuOH-H2O, 0 °C; (c) 3 N KOH, methanol,
60 °C, and then p-TsOH, CH2Cl2, rt, 74% (two steps); (d) TBDPSOTf, 2,6-lutidine, CH2Cl2, rt, 88%; (e) DIBAL, CH2Cl2, -78 °C; (f) Ph3PdCHCO2Me,
toluene, 70 °C, 91% (two steps); (g) MOMBr, i-Pr2NEt, CH2Cl2, rt, 90%; (h) DIBAL, toluene, -78 °C, 96%; (i) L-DET, Ti(O-i-Pr)4, t-BuO2H, MS4A,
CH2Cl2, -23 °C, 21% for 15, 64% for 16; (j) CSA, CH2Cl2, rt, 50% for 15, 26% for 17, and 16% for 18; (k) TBAF, THF, rt, 73%; (l) CSA, CH2Cl2, rt,
73%; (m) BzCl, pyridine, CH2Cl2, -20 °C to rt, and then MsCl, -20 °C to rt; (n) aq NaOH, MeOH-THF, 0 °C; 67% (two steps); (o) ref 7.
axial hydroxyl group on the THP ring.14 The acetogenin was
active in the BST assay and showed a selective inhibitory effect
against PACA-2 (pancreatic cancer) cell lines.
to lactonization under acidic conditions to afford hydroxy lactone
1019 as a white solid (74% yield after recrystallization). The
free hydroxy group was protected as the corresponding tert-
butyldiphenylsilyl ether to give 11. The use of other O-protecting
groups such as tetrahydropyranyl ether and tert-butyldimeth-
ylsilyl ether was found to be unreliable at a later stage.
Compound 11 was treated with diisobutylaluminum hydride
(DIBAL) and then methyl triphenylphosphoranylideneacetate
to give unsaturated ester 12 in 91% yield from 11. Methoxy-
methylation of 12 led to MOM ether 13, which was reduced
with DIBAL to afford allyl alcohol 14 in good yield. The alcohol
14 was epoxidized with Ti(O-i-Pr)4 and t-BuO2H in the presence
of L-diethyl tartrate to give epoxide 16 along with tetrahydro-
furan 15. The stereochemistry of the latter was confirmed by
chemical transformation of 16 (vide infra). The silyl group in
16 was removed with tetrabutylammonium fluoride to provide
alcohol 5. Exposure of this to acidic conditions [D-10-camphor-
sulfonic acid (CSA), dichloromethane] led to a cyclic-ether
formation to give THP ether 19 in 73% yield. In this case, a
trace amount of THF derivative was also observed. As
anticipated, attempts20 for direct 6-exo cyclization from 16 into
19 gave unsatisfactory results; treatment of 16 with CSA in
dichloromethane provided 15 (50%), 1-O-MOM derivative 17
(26%), and 2-O-MOM ether 18 (16%). A facile rearrangement
of the MOM group seems to be due to the neighboring group
participation of a 1- or 2-hydroxyl group to the intermediary
cation (i) (Figure 2). Although formyl acetals21 are sometimes
In our first-generation synthesis of 1,7 the carbon backbone
was constructed by Wittig reaction of formyl γ-lactone with
phosphonium ylide derived from tetrahydropyran (THP) seg-
ment 2 in which the THP ring was synthesized by a SmI2-
induced reductive cyclization of â-alkoxyacrylate derivative. Our
new synthetic process directed toward 1 includes an intermo-
lecular cross-metathesis15 of 2 and lactone 3 as illustrated in
Scheme 1. According to the previous results,7 disconnection of
the pentenyl unit in 2 leads to THP derivative 4. This would be
synthesized from epoxy alcohol 5 through a 6-exo cyclization.
The chiral oxygen functions in 5 will be installed by the
Sharpless protocol.16 Therefore, unsaturated ester 6 with the
requisite carbon skeleton was selected as the starting material.
On the other hand, the lactone 3 should be prepared by an
alkylation of γ-lactone 817 with iodide 7.
Synthesis of 2 began from asymmetric dihydroxylation (AD-
mix â, methanesulfonamide, t-BuOH-water) of 6 which was
obtained by ortho ester Claisen rearrangement of 918 (Scheme
2). The resulting dihydroxy ester was, upon hydrolysis, subjected
(13) Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L. Tetrahedron
1998, 54, 5833-5844.
(14) For recent total synthesis of pyragonicin, see: (a) Strand, D.; Rein,
T. Org. Lett. 2005, 7, 2779-2781. (b) Strand, D.; Norrby, P.-O.; Rein, T.
J. Org. Chem. 2006, 71, 1879-1891.
(15) Grubbs, R. H. In Handbook of Metathesis; Wiley-VCH: New York,
2003; Vols. 1-3.
(18) Davis, C. J.; Hurst, T. E.; Jacob, A. M.; Moody, C. J. J. Org. Chem.
2005, 70, 4414-4422.
(16) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780. Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483-
2547.
(19) For antipode; Cave´, A.; Chaboche, C.; Figade`re, B.; Harmange, J.
C.; Laurens, A.; Peyrat, J. F.; Pichon, M.; Szlosek, M.; Cotte-Lafitte, J.;
Que´ro, A. M. Eur. J. Med. Chem. 1997, 32, 617-623.
(17) White, J. D.; Somers, T. C.; Reddy, G. N. J. Org. Chem. 1992, 57,
4991-4998.
(20) Cyclization of the corresponding 6-O-THP analogue with CSA in
2-methyl-2-propanol-dichloromethane resulted in a complex mixture.
6306 J. Org. Chem., Vol. 71, No. 16, 2006

a minor component other than 21. Being an unseparable mixture,
these compounds were, without separation, employed for further
spectroscopic analyses.27 By the detailed analyses of 2D-NMR
including HSQC-TOCSY, one of the allylic positions of the
double bond in the minor product was revealed to be MOMoxy
methine (J ) 7.5 Hz), and the other was assigned to the
â-position of TBDMSoxy methine, suggesting that there is an
elimination of one methylene carbon (C-9)28 and no migration
of the double bond in 21. Furthermore, the coupling products
showed an ion peak at m/z 959.6028 along with the pseudo
parent ion peak at m/z 973.6253 corresponding to [M + Na]+
of 21 in the HRFAB-MS spectra. These results indicate that
the minor product was 22 eliminated one-carbon from 21.29 The
compound 22 seemed to result from the initital isomerization
of the double bond in 2 followed by metathesis with 3 via
elimination of propene. To suppress the side reaction,30 addition
of 1,4-benzoquinone31 was attempted. The contamination,
however, was not prevented, although the chemical yield was
improved (64%). On the other hand, the use of Grubbs’ first-
generation catalyst 2532 gave a promising result. Thus, 2 and 3
(3.0 molar equiv) was treated with the catalyst (30 mol %) in
dichloromethane at 40 °C to provide 2133 in 43% yield (78%
yield based on the starting material 2 consumed).34 No
FIGURE 2. Intramolecular MOM migration.
isolated in cleaving MOM derivatives of 1,2- and 1,3-diols, this
MOM migration is of interest. The application of this interesting
reaction is now underway. Successive treatment of 19 with
benzoyl chloride and methanesulfonyl chloride in pyridine
provided mesyl benzoate, which, upon treatment with base,
furnished epoxide 4 in 67% yield. This new route was quite
simple and required only 13 steps for the preparation of 4 from
9 (cf. 18 steps from 2,3-O-isopropylidene-D-threitol in the
previous route). The epoxide 4 was transformed into the terminal
olefin 2 according to the literature.7
SCHEME 3. Preparation of γ-Lactone Segment 3a
1
contamination of 22 was confirmed by the H NMR and MS
a Reagents and conditions: (a) LiI, AcOH, aq THF, 0 °C; (b) TBSCl,
imidazole, DMF, rt, 75% (two steps); (c) SHMDS, 8, THF, -20 °C, then
HMPA, -20 to +5 °C, 61%.
analyses. Recovered olefin 2 was again submitted to the
metathesis under the same conditions, and a total 57% yield of
21 was attained. In both cases, the production of homodimers
derived from 2 was traced judging by TLC analysis. The olefin
21 underwent hydrogenation35 with diimide to give γ-lactone
23 in 94% yield. Oxidation of 23 followed by syn-elimination
provided butenolide, in which all protecting groups were
subsequently cleaved by hydrogen chloride in methanol-
dichloromethane to give pyragonicin (1). The spectroscopic and
physical properties of 1 were consistent with those of an
authentic sample previously synthesized by us.7
Compound 3 was prepared from known compounds (8 and
2022) in three steps. The epoxide 20 reacted with lithium iodide23
in the presence of acetic acid to give iodohydrin, which was
silylated to provide silyl ether 7 in 75% yield from 20 (Scheme
3). Alkylation of the lactone 8 was achieved by treatment with
sodium hexamethyldisilazide in THF at -20 °C followed by
addition of 7 in the presence of hexamethylphosphoric triamide
(HMPA), giving segment 3 in 61% yield.
Having completed construction of both segments, we next
turned to the final C-C bond formation (Scheme 4). Intermo-
lecular cross-metathesis24 between 2 and 3 was initially tried
using Grubbs’ second-generation catalyst 24.25 Treatment of 2
and 3.0 molar equiv of 3 with the catalyst (30 mol %) in
dichloromethane at 40 °C gave coupling products in 51% yield.26
In the 1H NMR spectrum, olefinic proton signals were severely
overlapped and observed at δ 5.29-5.44 (m), except for a couple
of minor olefinic signals at δ 5.24 (dd, J ) 15.1, 7.5 Hz) and
5.55 (dt, J ) 15.1, 6.6 Hz). The major olefinic signals were
expected to be due to a desired coupling product 21 while the
minor pair was estimated to be derived from olefin signals of
In summary, we have succeeded in convergent synthesis of
1 via an olefin cross-metathesis between THP segment 2 and
lactone 3. The strategy described herein should be applicable
to the preparation of other types of acetogenins.
Experimental Section
(2′R,3RS,5S,8′S,11′R,12′R,15′R,16′R)-3-[2′-(tert-Butyldimeth-
ylsilanyloxy)-8′,11′,15′-(trimethoxymethoxy)-12′,16′-oxidotria-
cont-5′-enyl]-5-methyl-3-phenylsulfanyldihydrofuran-2-one (21).
To a stirred mixture of 2 (14.0 mg, 25.0 µmol) and 3 (31.6 mg,
75.0 µmol) in dichloromethane (0.8 mL) was added Grubbs’ first-
generation catalyst 25 (3.7 mg, 4.1 µmol), and the mixture was
(27) Upon hydrogenation (p-NHNH2, NaOAc), the coupling products
gave the corresponding saturated compounds, which showed two ion peaks
at m/z 961.6218 and 975.6458 in the HR-FABMS spectra, showing that
the minor component was not a positioning isomer of 21 concerning the
double bond.
(21) Barot, B. C.; Pinnick, H. W. J. Org. Chem. 1981, 46, 2981-2983.
(22) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307-1315.
(23) Bonini, C.; Giuliano, C.; Righi, G.; Rossi, L. Synth. Commun. 1992,
22, 1863-1870.
(28) The numbering system in ref 13 was adopted.
(29) A trace amount of another isomers eliminated C-6 of 21 was also
detected by 2D-NMR, but the full assignment was impossible because of
the complicated signals.
(30) For review: Schmidt, B. Eur. J. Org. Chem. 2004, 1865-1880.
(31) Hong, S. H.; Sanders, D. P. Lee, C. W. Grubbs, R. H. J. Am. Chem.
Soc. 2005, 127, 17160-17161.
(24) Very recently, a quite similar approach to anonaceous acetogenins
has been disclosed: Das, S.; Li, L.-S.; Abraham, S.; Chen, Z.; Sinha, S. C.
J. Org, Chem. 2005, 70, 5922-5931. Keum, G.; Hwang, C. H.; Kang, S.
B.; Kim, Y.; Lee, E. J. Am, Chem. Soc. 2005, 127, 10396-10399. See
also: Fu¨rstner, A.; Dierkes, T. Org. Lett. 2000, 2, 2463-2465. Evans, P.
A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H.-R. J. Am, Chem.
Soc. 2003, 125, 14702-14703. Zhu, L.; Mootoo, D. R. J. Org. Chem. 2004,
69, 3154-3157. Zhu, L.; Mootoo, D. R. Org. Biomol. Chem. 2005, 3, 2750-
2754. Hanessian, S.; Giroux, S.; Buffat, M. Org. Lett. 2005, 7, 3989-3992.
(25) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(32) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. (b) Schwab, P.; Grubbs, R.
H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110.
(33) The ratio (E/Z ) ca. 1/1) was judged by the intensities of Me-Si
1
signals in the H NMR spectra.
(34) The lactone 3 was also recovered easily by silica gel chromatography
(∼30% yield).
(26) The geometrical isomer ratio (E/Z ) ca. 4/1) was judged by the
intensities of separated signals in the 13C NMR spectrum.
(35) Marshall, J. A.; Chen, M. J. Org. Chem. 1997, 62, 5996-6000.
J. Org. Chem, Vol. 71, No. 16, 2006 6307

SCHEME 4. Olefin Cross-Metathesis and Total Synthesis of 1a
a Reagents and conditions: (a) 24, 1,4-benzoquinone, CH2Cl2, 40 °C, 64% for 21 + 22; (b) 25, CH2Cl2, 40 °C, 57% for 21 (after one recycling of
recovered 2); (c) p-TsNHNH2, NaOAc, aq DME, 85 °C, 94%; (d) m-CPBA, CH2Cl2, 0 °C, and then toluene, 105 °C; (e) 10% HCl-MeOH, CH2Cl2, rt, 73%
(two steps).
stirred at 40 °C for 4 h. More catalyst 25 (3.5 mg, 3.9 µmol) was
added, and the mixture was stirred at 40 °C for 3 h and rt for 17
h. Florisil was added with stirring, and the resulting mixture was
filtered through a pad of Celite. The filtrate was concentrated to
give a syrup, which was purified by preparative TLC (n-hexane-
ethyl acetate ) 4:1, 5 developments) to give 21 (10.2 mg) as a
colorless syrup. Recovered starting material 2 (6.3 mg) again reacted
with 3 (14.2 mg) in the presence of 25 (3.2 mg) in dichloromethane
(0.6 mL) at 40 °C for 10 h and was treated as described above to
give 21 (3.4 mg). A total of 13.6 mg (57%) of 21 was obtained.
21 (E/Z ) ca. 1/1): IR (neat) 2924, 2853, 1769, 1471, 1182,
(2′R,5S,8′S,11′R,12′R,15′R,16′R)-3-(2′,8′,11′,15′-Tetrahydroxy-
12′,16′-oxidotriacontanyl)-5-methyl-5H-furan-2-one (Pyragoni-
cin, 1). To a stirred solution of 23 (17.4 mg, 18.2 mmol) in
dichloromethane (0.5 mL) was added m-CPBA (70-75% assay;
4.5 mg) at 0 °C. After 1 h, aqueous saturated NaHCO3/Na2S2O3
(1:1) was added, and the resulting mixture was extracted with ether.
The extracts were washed with aqueous saturated Na2S2O3, water,
and brine, dried, and concentrated. The residue was dissolved in
toluene (1.0 mL). The solution was heated at 100-105 °C for 1 h
with stirring and concentrated. The residue was passed through a
short column of silica gel {n-hexane-ethyl acetate (10:1 f 2:1)}
to give butenolide (14.1 mg, 90%). To a stirred solution of the
butenolide (10.8 mg, 0.01 µmol) in dichloromethane (0.5 mL) was
added a 10% HCl solution in methanol (0.3 mL) at 0 °C, and the
mixture was stirred at rt for 13 h. After addition of NaHCO3, the
resulting mixture was concentrated, diluted with water, and then
extracted with ethyl acetate. The extracts were washed with water
and brine, dried, and then concentrated. The residue was chro-
matographed on silica gel (n-hexane/ethyl acetate ) 2:1 f 0:1 f
CHCl3/methanol ) 10:1) to give a syrup (7.3 mg), which was
treated with n-hexane-ether to afford 1 (6.2 mg, 81%) as a white
powder; [R]21D ) +12.6 (c 0.11, CHCl3) {lit.13 [R]23D ) -25.6 (c
1
1147, 1097, 1032, 916, 853 cm-1; H NMR (400 MHz, CDCl3,
mixture of diastereomers at C(3)) δ 0.02, 0.03, 0.04 (1.36H, each
s), 0.11, 0.12, 0.15, 0.16 (4.64H, each s), 0.86-0.90 (12H, m),
1.21-2.44 (50.23H, m), 3.02 (0.77H, m), 3.29-3.59 (5H, m), 3.36,
3.37, 3.38 (9H, each s), 3.87 (0.23H, m), 4.29 (0.77H, m), 4.52
(0.77H, m), 4.59-4.82 (6.23H, m), 5.37-5.44 (2H, m), 7.29-7.41
(3H, m), 7.54-7.56 (2H, m); 13C NMR (100 MHz, CDCl3, mixture
of diastereomers at C(3)) δ -4.2, -3.9, -3.8, 14.1, 18.0, 20.4,
21.3, 22.0, 22.4, 22.7, 25.7, 25.9, 26.4, 26.6, 27.5, 27.8, 29.3, 26.6,
29.7, 29.8, 30.0, 31.9, 32.3, 37.6, 38.1, 39.5, 41.2, 41.6, 42.5, 54.9,
55.3, 55.5, 55.7, 69.0, 69.1, 69.8, 71.0, 73.3, 73.6, 79.9, 80.0, 80.8,
95.1, 95.3, 97.1, 125.9, 126.3, 126.5, 128.9, 129.0, 129.5, 129.7,
130.0, 130.3, 130.8, 132.1, 132.4, 136.7, 137.0, 175.0, 177.4; HRMS
calcd for C53H94O10SSiNa [M + Na]+ 973.6235, found 973.6217.
(2′R,3RS,5S,8′S,11′R,12′R,15′R,16′R)-3-[2′-(tert-Butyldimeth-
ylsilanyloxy)-8′,11′,15′-(trimethoxymethoxy)-12′,16′-oxidotria-
contanyl]-5-methyl-3-phenylsulfanyldihydrofuran-2-one (23). To
a stirred mixture of 21 (18.5 mg, 19.4 µmol) and tosylhydrazine
(241 mg, 1.29 mmol) in 1,2-dimethoxyethane (2.9 mL) was added
dropwise a solution of sodium acetate (131 mg, 1.59 mmol) in water
(2.4 mL) at 85 °C over 2 h. After 1 h, the reaction mixture was
cooled to rt and then extracted with ethyl acetate. The extracts were
washed with water and brine, dried, and concentrated. Chroma-
tography on silica gel with n-hexane-ethyl acetate (1:0 f 10:1
f 4:1) as the eluent gave 23 (17.4 mg, 94%) as a colorless syrup:
IR (neat) 2924, 2853, 1768, 1471, 1183, 1147, 1098, 1032, 916,
853 cm-1; 1H NMR (400 MHz, CD2Cl2, mixture of diastereomers
at C(3)) δ 0.03, 0.05 (1.2H, each s), 0.12, 0.16 (4.8 H, each s),
0.87-0.90 (12H, m), 1.21-2.09 (46.8H, m), 2.31-2.42 (0.4H, m),
3.02 (0.8H, dd, J ) 14.2, 7.8 Hz), 3.26-3.53 (5H, m), 3.34, 3.35,
3.36 (9H, each s), 3.87 (0.2 H, m), 4.26 (0.8H, m), 4.52 (0.8H, m),
0.008, CHCl3), lit.7 [R]24D ) +13.8 (c 0.11, CHCl3), lit.14 [R]23
)
D
+10.3 (c 0.13, CHCl3)}; IR (neat) 3500, 2917, 2851, 1736, 1462,
1082, 1047, 1026, 991 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.88
(3H, t, J ) 6.8 Hz), 1.21-1.76 (43H, m), 1.43 (3H, d, J ) 6.8
Hz), 2.00 (1H, brd, J ) 11 Hz), 2.40 (1H, brdd, J ) 15.1, 7.3 Hz),
2.52 (1H, brd, J ) 15.1 Hz), 3.24 (1H, ddd, J ) 10.2, 7.8, 2.4 Hz),
3.35 (1H, brdd, J ) 7.8, 6.3 Hz), 3.50 (1H, m), 3.59-3.66 (2H,
brs), 3.85 (1H, m), 5.05 (1H, qd, J ) 6.8, 1.0 Hz), 7.18 (1H, m);
13C NMR (100 MHz, CDCl3) δ 14.1, 19.1, 21.5, 22.7, 25.5, 25.6,
28.4, 29.3, 29.4, 29.6, 29.7, 30.5, 31.6, 31.9, 33.3, 37.2, 66.0, 69.9,
71.5, 74.3, 78.0, 80.1, 81.0, 131.1, 151.9, 174.7; HRMS calcd for
C35H65O7 [M + H]+ 597.4730, found 597.4752.
Acknowledgment. We are grateful to Dr. T. Nakamura at
RIKEN for helpful discussions of mass spectral analyses. We
also thank Dr. T. Chihara and his collaborators (RIKEN) for
the elemental analyses. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education,
Science, Sports, and Culture of Japan and by the Special Project
Funding for Basic Science from RIKEN (Directors’ Fund and
the Chemical Biology Project).
4.59-4.73 (6.2H, m), 7.35-7.43 (3H, m), 7.53-7.56 (2H, m); 13
C
NMR (100 MHz, CD2Cl2, mixture of diastereomers at C(3)) δ -4.7,
-3.8, -3.7, 14.2, 18.2, 20.5, 21.5, 22.2, 23.1, 24.8, 25.7, 26.1,
26.6, 28.1, 29.7, 30.0, 30.1, 30.3, 30.4, 32.3, 34.6, 38.3, 38.8, 39.9,
41.6, 42.1, 42.7, 55.6, 55.7, 55.8, 69.8, 70.5, 71.6, 73.7, 74.1, 77.8,
80.2, 80.3, 95.6, 95.7, 97.2, 129.3, 129.9, 130.2, 131.0, 137.0, 137.4,
175.1, 177.5; HRMS calcd for C53H96O10SSiNa [M + Na]+
975.6391, found 975.6403.
Supporting Information Available: Experimental procedures
and NMR spectra of 1, 3, 7, 11-19, and 21-23. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO060970Q
6308 J. Org. Chem., Vol. 71, No. 16, 2006