Synthesis of phytuberin. 4-endo-tet acid-catalyzed cyclization of α-hydroxy epoxides

Article abstract of DOI:10.1021/jo034129d

The total synthesis of phytuberin, a phytoalexin of the Solanum genus, from (-)-α-santonin is reported. The key steps include (a) reductive cleavage of the C-O bond of the γ-lactone with concomitant protection of the C1 double bond, (b) Sharpless stereocontrolled hydroxy-assisted epoxidation of allylic alcohol 6 and simultaneous deprotection of the C1 double bond, (c) a rare 4-endo-tet acid-catalyzed cyclization of an α-hydroxy epoxide, and (d) an unprecedented 4-exo selenocyclization of a homoallylic alcohol.

Full text of DOI:10.1021/jo034129d

Syn th esis of P h ytu ber in . 4-en d o-tet Acid -Ca ta lyzed Cycliza tion of
r-Hyd r oxy Ep oxid es
Thierry Prange´,† Mar´ıa S. Rodr´ıguez,‡ and Ernesto Sua´rez*,§
Instituto de Productos Naturales y Agrobiologı´a del C.S.I.C., Carretera de La Esperanza 3,
38206 La Laguna, Tenerife, Spain, Departamento de Qu´ımica Orga´nica, Universidad de La Laguna,
Tenerife, Spain, and LURE, Universite´ Paris-Sud, Paris, 91405 Orsay Cedex, France
esuarez@ipna.csic.es
Received J anuary 30, 2003
The total synthesis of phytuberin, a phytoalexin of the Solanum genus, from (-)-R-santonin is
reported. The key steps include (a) reductive cleavage of the C-O bond of the γ-lactone with
concomitant protection of the C1 double bond, (b) Sharpless stereocontrolled hydroxy-assisted
epoxidation of allylic alcohol 6 and simultaneous deprotection of the C1 double bond, (c) a rare
4-endo-tet acid-catalyzed cyclization of an R-hydroxy epoxide, and (d) an unprecedented 4-exo
selenocyclization of a homoallylic alcohol.
SCHEME 1. Retr osyn th etic An a lysis of
P h ytu ber in
The phytoalexin phytuberin (1) is produced by potato
tubers and tobacco leaves in response to bacterial and
fungal elicitors treatment.1 Its structure was determined
by X-ray crystallographic analysis of its dihydro deriva-
tive,2 and biosynthetic studies directly related this stress
metabolite with 2-secoeudesman sesquiterpenes.3 The
antimicrobial activity of phytuberin has been studied in
vitro against potato pathogenic and nonpathogenic fungi
and bacteria, and only modest antifungal activity was
observed.4 The tetrahydrofuro[3,2-b]furan moiety has
attracted considerable attention from synthetic chemists,
and a number of strategies have been published.5 All of
them started with readily accessible terpenoids such as
(-)-carvone,5a,c,e,f (-)-2-carone,5b and elemol.5d
Our own strategy for the synthesis of phytuberin (1)
from (-)-R-santonine (2) is outlined in the retrosynthetic
pathway depicted in Scheme 1. The basic approach
involves reductive cleavage of the C-O of the γ-lactone,
selective reduction of the carbonyl group, and stereo- and
regiocontrolled hydroxyl-assisted epoxidation of the al-
lylic alcohol to give the intermediate A. The intermediate
diol B may be prepared by ozonolysis of the olefin, after
protection of the hydroxyl group at C-3, followed by
reductive workup. Intramolecular acid-catalyzed cycliza-
tion of the 3,4-hydroxy epoxide (C2-O f C5-O) and
subsequent Mitsunobu cyclization of the newly formed
C1, C4 diol would be expected to lead to the required
hydrofuro[3,2-b]furan system. It should be noted that
although the intramolecular cyclization of the epoxide
implies an, a priori, disfavored 5-endo-tet process,6 many
examples of this reaction have been highlighted in the
recent literature.7 No problems are anticipated in the
final steps of the sequence, elimination of the 3-hydroxyl
group and formation of the hydroxyisopropyl side chain.
Intramolecular opening of an epoxide by an appropri-
ately situated hydroxyl group is one of the most conve-
* To whom correspondence should be addressed. Fax: 34-922-
260135.
† Universite´ Paris-Sud.
‡ Universidad de La Laguna.
§ Instituto de Productos Naturales y Agrobiolog´ıa.
(1) (a) Coxon, D. T.; Price, K. R.; Howard, B.; Curtis, R. F. J . Chem.
Soc., Perkin Trans. 1 1977, 53-59. (b) Hughes, D. L.; Coxon, D. T. J .
Chem. Soc., Chem. Commun. 1974, 822-823. (c) Lyon, G. D. Physiol.
Plant Pathol. 1972, 2, 411-416. (d) Varns, J . L.; Kuc´, J .; Williams, E.
B. Phytopathology 1971, 61, 174-177.
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10.1021/jo034129d CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/01/2003
4422
J . Org. Chem. 2003, 68, 4422-4431

Synthesis of Phytuberin
SCHEME 2a
nient methods to build up substituted tetrahydrofuran
rings.8 Nevertheless, this is not an easy process since the
reaction may lead to a number of products, depending
on the substrate structure and reaction conditions. For
example, one of the most studied processes, the opening
of γ-hydroxy epoxides, may occur in either an 6-endo or
5-exo-tet fashion depending on substituents,9 and the use
of an antibody10 or Co(salen) complex catalysts.11 The
rearrangement of â-hydroxy epoxides may also occur
through the two possible 5-endo7 or 4-exo12 cyclization
modes. Some examples of cyclization of R-hydroxy ep-
oxides via 3-exo-tet (Payne rearrangement) have been
described,13 but the alternative 4-endo cyclization mode
remains unknown.
Resu lts a n d Discu ssion
We chose the commercially available (-)-R-santonin (2)
as the starting material on the basis of the above-
mentioned retrosynthetic analysis. The reaction of 2 with
an excess of ethanolic sodium phenoxide afforded, after
acid methylation, the phenylsulfanyl derivative 3, in
which apart from the desired cleavage of the lactone ring
the protection of the C1 double bond was achieved by
a
Reagents and conditions: (a) (i) PhSH, Na, EtOH, reflux, 20
h; (ii) CH2N2, Et2O, 68%; (b) NaBH4, CeCl3, MeOH, rt, 15 min,
91%; (c) Ph3P, HCO2H, DEAD, THF, 96%; (d) K2CO3, MeOH, 0
°C, 15 min, 94%; (e) TBHP, VO(acac)3, PhH, rt, 4 h, 91%; (f)
i-Pr2NH, PhH, 120 °C, sealed tube, 20 h, 86%; (g) Ac2O, Py, rt, 18
h, 94%.
(7) For recent examples of disfavored 5-endo cyclization of â-hydroxy
epoxides, see: (a) Harris, J . M.; O’Doherty, G. A. Tetrahedron 2001,
57, 5161-5171. (b) Emery, F.; Vogel, P. J . Org. Chem. 1995, 60, 5843-
5854. (c) Coxon, J . M.; Morokuma, K.; Thorpe, A. J .; Whalen, D. J .
Org. Chem. 1998, 63, 3875-3883. (d) Mukai, C.; Sugimoto, Y.; Ikeda,
Y.; Hanaoka, M. J . Chem. Soc., Chem. Commun. 1994, 1161-1162.
(e) J isaka, M.; Ohigashi, H.; Takagaki, T.; Nozaki, H.; Tada, T.; Hirota,
M.; Irie, R.; Huffman, M. A.; Nishida, T.; Kaji, M.; Koshimizu, K.
Tetrahedron 1992, 48, 625-632. (f) Garc´ıa-Granados, A.; Mart´ınez, A.;
Mart´ınez, J . P.; Onorato, M. E. J . Chem. Soc., Perkin Trans. 1 1990,
1261-1266. (g) Bilton, J . N.; J ones, P. S.; Ley, S. V.; Robinson, N. G.;
Sheppard, R. N. Tetrahedron Lett. 1988, 29, 1849-1852. (h) Hoppe,
D.; Tarara, G.; Wilckens, M.; J ones, P. G.; Schmidt, D.; Stezowski, J .
J . Angew. Chem., Int. Ed. Engl. 1987, 26, 1034-1035. For a related
5-endo-cyclization of an R,â-dihydroxy epoxide see: Fuchser, J .;
Grabley, S.; Noltemeyer, M.; Philipps, S.; Thiericke, R.; Zeeck, A.
Liebigs Ann. Chem. 1994, 831-835.
Michael addition (Scheme 2).14 Unfortunately, all at-
tempts to reduce the C3 carbonyl group stereoselectively
to the R-alcohol failed, possibly due to the highly steri-
cally hindered â-face of the molecule. Instead, the â-al-
cohol 4 was obtained by NaBH4/CeCl3 reduction15 and
subsequently inverted by using a Mitsunobu reaction16
to give the desired R-alcohol 6 in 82% overall yield.
Sharpless stereocontrolled hydroxyl-assisted epoxida-
tion of allylic alcohol 6 with TBHP in the presence of VO-
(acac)3 as catalyst was achieved concomitantly with
sulfide oxidation to furnish the sulfoxide 7.17 Under these
conditions the yield of overoxidation to the undesired
sulfone 8 could be kept to an acceptable level (9%). The
required allyl alcohol 9 was produced by pyrolytic syn-
elimination of the sulfoxide 7 in benzene at 120 °C.18 It
is worth noting that the necessary protection-deprotec-
tion of the C1 double bond has been performed in a
convenient manner by taking advantage of other reac-
tions of the synthetic protocol.
(8) (a) Koert, U. Synthesis 1995, 115-132. (b) Harmange, J . C.;
Figade`re, B. Tetrahedron: Asymmetry 1993, 4, 1711-1754. (c) Boivin,
T. L. B. Tetrahedron 1987, 43, 3309-3362.
(9) (a) Nicolaou, K. C.; Prasad, C. V.; Somers, P. K.; Hwang, C.-K.
J . Am. Chem. Soc. 1989, 111, 5330-5334. (b) Adiwidjaja, G.; Florke,
H.; Kirschning, A.; Schaumann, E. Tetrahedron Lett. 1995, 36, 8771-
8774. (c) Mori, Y.; Yaegashi, K.; Furukawa, H. J . Am. Chem. Soc. 1996,
118, 8158-8159. (d) Oishi, T.; Maeda, K.; Hirama, M. Chem. Commun.
1997, 1289-1290. (e) Mukai, C.; Sugimoto, Y.; Ikeda, Y.; Hanaoka,
M. Tetrahedron 1998, 54, 823-850. (f) Neogi, P.; Doundoulakis, T.;
Yazbak, A.; Sinha, S. C.; Sinha, S. C.; Keinan, E. J . Am. Chem. Soc.
1998, 120, 11279-11284. (g) Fujiwara, K.; Hayashi, N.; Tokiwano, T.;
Murai, A. Heterocycles 1999, 50, 561-593. (h) Coxon, J . M.; Thorpe,
A. J . J . Org. Chem. 1999, 64, 5530-5541. (i) Fujiwara, K.; Morishita,
H.; Tokiwano, T.; Murai, A. Heterocycles 2001, 54, 109-110.
(10) (a) Sinha, S. C.; Keinan, E.; Reymond, J .-L. J . Am. Chem. Soc.
1993, 115, 4893-4894. (b) Na, J .; Houk, K. N.; Shevlin, C. G.; J anda,
K. D.; Lerner, R. A. J . Am. Chem. Soc. 1993, 115, 8453-8454.
(11) Wu, M. H.; Hansen, K. B.; J acobsen, E. N. Angew. Chem., Int.
Ed. 1999, 38, 2012-2014.
Acetylation of alcohol 9 followed by ozonolysis under
reductive workup afforded diol 11 (Scheme 3). After
considerable experimentation, we found that the acid-
catalyzed cyclization of the hydroxy epoxide 11 was best
performed by treatment with methanesulfonic acid at 0
(12) For recent examples of oxetane formation by acid-catalyzed
cyclization of â-hydroxy epoxides under an 4-exo-tet process see: (a)
Mosimann, H.; Vogel, P. Heterocycles 2000, 52, 171-183. (b) Wu, M.
H.; Hansen, K. B.; J acobsen, E. N. Angew. Chem., Int. Ed. 1999, 38,
2012-2014. (c) Wittenberg, J .; Beil, W.; Hoffmann, H. M. R. Tetrahe-
dron Lett. 1998, 39, 8259-8262. (d) Reineckee, J .; Hoffmann, H. M.
R. Chem. Eur. J . 1995, 1, 368-373. (e) Martin, O. R.; Rafka, R. J .;
Szarek, W. A. Carbohydr. Res. 1989, 185, 77-90. (f) Hatakeyama, S.;
Sakurai, K.; Numata, H.; Ochi, N.; Tanako, S. J . Am. Chem. Soc. 1988,
110, 5201-5203. (g) Waddel, T. G.; Tetrahedron Lett. 1985, 26, 6277-
6280.
(13) (a) Trost, B. M.; Greenspan, P. D.; Geissler, H.; Kim, J . H.;
Greeves, N. Angew. Chem., Int. Ed. Engl. 1994, 106, 2296-2298. (b)
Paquette, L. A.; Balogh, D. W. J . Am. Chem. Soc. 1982, 104, 774-783.
(c) Paulsen, H.; Sumfleth, E.; Sinnwell, V.; Meyer, N.; Seebach, D.
Chem. Ber. 1980, 113, 2055-2062.
(14) Francisco, C. G.; Freire, R.; Rodr´ıguez, M. S.; Sua´rez, E.
Tetrahedron Lett. 1991, 28, 3413-3416.
(15) (a) Luche, J . L. J . Am. Chem. Soc. 1978, 100, 2226-2227. (b)
Gemal, A. L.; Luche, J . L. J . Am. Chem. Soc. 1981, 103, 5454-5459.
(16) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughes, D. L.
Organic Reactions; J ohn Wiley & Sons: New York, 1972; Vol. 42,
Chapter 2, pp 335-656. (c) Hughes, D. L. Org. Prep. Proc. Int. 1996,
28, 127-164.
(17) (a) Sharpless, K. B.; Verhoeven, T. R. Aldrichim. Acta 1979,
12, 63-74. (b) Pfenninger, A. Synthesis 1986, 89-116. (c) Sharpless,
K. B.; Michaelson, R. C. J . Am. Chem. Soc. 1973, 95, 6136-6137. (d)
Hill, J . G.; Rossiter, B. E.; Sharpless, K. B. J . Org. Chem. 1983, 48,
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7965-7967.
J . Org. Chem, Vol. 68, No. 11, 2003 4423

Prange´ et al.
SCHEME 3a
SCHEME 4a
a
Reagents and conditions: (a) (i) O3, Me2S, CH2Cl2-MeOH (1:
1), -78 °C, 20 min; (ii) NaBH4, -78 °C to rt, 1.5 h, 81%; (b) MsOH,
CH2Cl2, 0 °C, 1 h, 53%; (c) Ph3P, DEAD, CHCl3, 1 h, 95%; (d)
K2CO3, MeOH, rt, 15 min, 87%.
°C. After a preliminary 1H NMR study, it became evident
that the obtained diol 12 did not have the required
tetrahydofuran structure; instead, a rather unexpected
spirooxetane had been formed. Since all our attempts at
obtaining crystalline material suitable for X-ray analysis
were to no avail, we decided to continue with our
synthetic plan. Intramolecular cyclization of the diol 12
under Mitsunobu conditions afforded the tetrahydrofuran
derivative 13 in excellent yield. Mild hydrolysis with K2-
CO3 in methanol afforded the crystalline alcohol 14. The
structure and stereochemistry of alcohol 14 was deter-
mined unambiguously by single-crystal X-ray crystal-
lographic analysis. The reaction seems to proceed through
4-endo-tet type ring closure, a hitherto unknown process.
On the other hand, the stereochemistry is inverted at the
reactive center, while that of C3 and C4 remains un-
changed. Evidently, an intramolecular transesterification
of the C3 acetate moiety to the primary adjacent alcohol
must take place prior to the cyclization stage. When the
C3 protective group was changed (e.g. benzyl), to avoid
the transesterification reaction and to favor the 5-exo
rearrangement, the reaction gave unchanged starting
material or led to rather complex mixtures if run under
more forcing conditions.
a
Reagents and conditions: (a) TBHP, VO(acac)3, PhH, rt, 3 h,
85%; (b) PhH, reflux, 5 h, 93%; (c) Ac2O, Py, rt, 18 h, 94%; (d) (i)
O3, Me2S, CH2Cl2-MeOH (1:1), -78 °C, 15 min; (ii) NaBH4, -78
°C to rt, 1.5 h, 82%; (e) MsOH, CH2Cl2, 0 °C, 30 min, 46%; (f) Ph3P,
DEAD, CHCl3, rt, 15 min, 91%; (g) K2CO3, MeOH, rt, 15 min, 85%.
tural confirmation of alcohol 22 was accomplished by a
combination of the double resonance and NOESY spectra.
Notable features of the NOESY spectra are the cross-
peaks between the C-3 proton and the C-4 methyl protons
and C-1R proton, and between the C-4 methyl protons
and the C-10 methyl protons (1,3-pseudodiaxial disposi-
tion). An important diagnostic feature emerged when a
4
small yet significant J (W)-coupling of 0.8 Hz between
H-1R and the methyl group at C-10 (established by
decoupling and COSY correlation) was observed in the
1H NMR spectrum of 22. A quasiperfect coplanarity
among the implicated atoms is observed in a minimized
structure of 22. This long-range coupling was not found
in the spectrum of the diastereoisomeric alcohol 14. These
facts strongly support the stereo- and regiochemical
arrangement of structure 21, and since no appreciable
amount of other stereoisomers was detected, the rear-
rangement can be regarded as essentially stereospecific.
Although we have been unsuccessful in obtaining the
hydrofuro[3,2-b]furan system of phytuberin by the meth-
odology outlined in the introductory section, we believed
that oxetane 14 can be transformed into the required
system by the three-step ring-expansion reaction de-
scribed in Scheme 5. This methodology was first tested
on the model 14 being aware that the 2,3-dihydrofuran
moiety is too reactive to be compatible with the modifica-
tion of the side chain. For the reductive opening of the
hydroxy-oxetane 14 we have used our previously reported
methodology for the rearrangement of 2,3-epoxy alco-
hols.20 Thus, treatment with imidazole, triphenylphos-
phine, and iodine afforded the homoallyl alcohol 24 in
good yield. As expected, the iodine derivative 23 could
be isolated as an intermediate formed in the early stage
of the reaction,21 that it is transformed into compound
To gain insight into the mechanism of the reaction, the
3â-acetoxy â-epoxide 18 was prepared starting from the
3â-hydroxy derivative 4 by following an identical reaction
sequence as described for 10 (Scheme 4). Molecular
mechanics calculations showed that the steric energy of
compound 20 is approximately 2 kcal mol-1 more stable
than that of the corresponding diastereomer 12, and no
special steric interactions were expected to hinder the
reaction.19 Indeed, under the same acidity conditions, diol
19 rearranged to the isomeric spirooxetane 20. No other
isomers due to different modes of competing cyclization
1
reactions were detected by careful H NMR analysis of
the reaction mixture. The moderate yield obtained may
be due to adventitious intermolecular hydrolysis of the
epoxide or other undetermined reactions. Analogously,
the diol 20 under intramolecular Mitsunobu cyclization
conditions afforded the dioxa-bicyclo[3.2.0]heptane de-
rivative 21, which was hydrolyzed to alcohol 22. Struc-
(19) Molecular mechanics calculation was carried out with CS
Chem3D Ultra, version 6.0.
(20) Dorta, R. L.; Rodr´ıguez, M. S.; Salazar, J . A.; Sua´rez, E.
Tetrahedron Lett. 1997, 38, 4675-4678.
4424 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of Phytuberin
SCHEME 5a
SCHEME 6a
a
Reagents and conditions: (a) Ph3P, imidazole, I2, PhCH3,
reflux, 2 h, 97%; (b) Ph3P, imidazole, I2, PhCH3, reflux, 4 h, 70%;
(c) N-(phenylseleno)phthalimide, p-TsOH, CH2Cl2, rt, 7 h, 75%;
(d) (i) O3, CH2Cl2, -78 °C; (ii) Et3N, cyclohexane, reflux, 30 min,
60%.
24 after a prolonged reaction time. The acid-catalyzed
reaction of compound 24 with N-(phenylseleno)phthal-
imide gave the 5-endo cyclized compound 25.22 Finally,
by using organoselenium methodology the aryl selenide
afforded the desired olefin 26 by an oxidation-selenoxide
elimination sequence. The structure of 26 was confirmed
by spectroscopic data, the chemical shift and shape of the
signals of the protons at C1, C2, and C3 being identical
with those found in the downfield portion of the 1H NMR
spectrum of phytuberin.1a
Taking into account the impossibility of modifying the
side chain when the 2,3-dihydrofuran is present, it was
decided to return to oxetane 13. Hydrolysis to the
hydroxy acid and protection of the primary alcohol with
TBDPSCl as described in Scheme 6 afforded acid 28,
which was submitted to Barton’s oxidative radical de-
carboxylation.23 The isomeric mixture of alcohols obtained
was oxidized with PCC to give ketone 29, and subsequent
treatment with methylmagnesium bromide afforded al-
cohol 30. Desilylation, and reductive opening of the
R-hydroxyoxetane as described for compound 14, gave
homoallylic alcohol 33. As in the case of compound 14,
the iodine 32 is an isolable intermediate of the reaction.
The following phenylselenylation reaction deserves a
brief comment: when the reaction was stopped im-
mediately after the starting material was consumed
(monitored by TLC), the oxetane 34 (51%) was the
principal product obtained apart from the expected
tetrahydrofuran derivative 35 (22%). Upon prolonged
reaction time all oxetane was transformed into the
tetrahydrofuran (75%). This also happened when pure
oxetane was submitted to the standard reaction condi-
tions. Furthermore, when oxetane 34 was submitted to
a
Reagents and conditions: (a) (i) KOH, MeOH, 40 °C, 23 h; (ii)
t-BuPh2SiCl, TEA, DMAP, CH2Cl2, rt, 2 h 45 min, 95%; (b) KOH,
MeOH, rt, 1 h, 82%; (c) (i) (COCl)2, DMF, PhH, rt, 1 h; (ii)
N-hydroxypyridine-2-thione sodium salt, CH2Cl2, rt, 2 h; (iii)
(PhS)3Sb, Et2O, rt, 1.5 h, 72%; (iv) PCC, NaOAc; CH2Cl2, rt, 2 h,
79%; (d) MeMgBr, Et2O, -78 °C, 45 min, 96%; (e) tetrabutyl-
ammonium fluoride, THF, rt, 2.5 h, 100%; (f) I2, Ph3P, imidazole,
2,6-lutidine, H2O, PhH, 1,2-dichloroethane, 80 °C, 15 min, 98%;
(g) N-(phenylseleno)phthalimide, p-TsOH, CH2Cl2, rt, 6.5 h, 75%;
(h) Ac2O, Py, DMAP, 40 °C, 24 h, 60%; (i) O3, CH2Cl2, -78 °C,
then Py, CCl4, reflux, 1.5 h, 62%.
acidic conditions an equilibrium was reached after 6.5 h
and a mixture was obtained containing 34 and 35 in a
3:7 ratio, as established by 1H NMR. The structures and
stereochemistries of 34 and 35 were elucidated by
extensive NMR studies including COSY, DEPT, HMQC,
HMBC, and NOESY experiments. For example, NOESY
correlations between H-1â and H-3 and the C-10 methyl
group, and between 2H-2 and the C-4 methyl group for
compound 34, and between H-1â and H-2â and the C-10
methyl group for compound 35 were clearly observable.
These facts seem to indicate that the kinetic oxetane,
formed by a 4-exo pathway, rearranges to the thermo-
dynamic 5-endo tetrahydrofurane ring through regiose-
lective nucleophilic anti-opening of the same selenirani-
um cation intermediate originated by attack at the Si
face of the double bond. As far as we know, no examples
of 4-exo processes in the selenocyclization reaction of
homoallylic alcohols have been reported until now. An
analogous equilibrium between 5-exo and 6-endo-tet
cyclizations in 3-hydroxy seleniranium ions shifted to-
ward the formations of tetrahydropyrans has been ob-
served.24
(21) Garegg, P. J .; Samuelsson, B. J . Chem. Soc., Perkin Trans. 1
1980, 2866-2869.
(22) For reviews see: (a)Organoselenium Chemistry; Liotta, D., Ed.;
Wiley: NewYork, 1987. (b) Paulmier, C. Selenium Reagents and
Intermediates in Organic Synthesis; Pergamon: Oxford, UK, 1986. (c)
Nicolaou, K. C.; Petasis, N. A. Selenium in Natural Products Synthesis;
CIS: Philadelphia, PA, 1984. For 5-endo cyclization of homoallylic
alcohols with organoselenium reagents see: (d) Lipshutz, B. H.; Barton,
J . C. J . Am. Chem. Soc. 1992, 114, 1084-1086. (e) Fragale, G.; Wirth,
T. Eur. J . Org. Chem. 1998, 1361-1369.
At this stage, acetylation of the tertiary hydroxyl group
to give 36 and oxidation to the selenoxide followed by
thermal syn-elimination afforded phytuberin (1), identical
with an authentic sample obtained by infection of potato
tubers with Erwinia carotovora var. carotovora.
(23) (a) Barton, D. H. R.; Bridon, D.; Zard, S. Z. Tetrahedron 1989,
45, 2615-2626. (b) Barton, D. H. R.; Bridon, D.; Zard, S. Z. J . Chem.
Soc., Chem. Commun. 1985, 1066-1068. For the preparation of
(PhS)3Sb see: (c) Bielig, H.-J .; Lu¨tzel, G.; Reidies, A. Chem. Ber. 1956,
89, 775-790.
J . Org. Chem, Vol. 68, No. 11, 2003 4425

Prange´ et al.
SCHEME 7a
interaction between the C-1â and the methyl protons of
the O-Me can be detected in the NOESY spectrum of 37.
Although the relatively low yields obtained (approxi-
mately 40-50%) preclude a stereochemical analysis of
the hydrolysis reactions, both compounds 37 and 38 could
be formed from the same â-epoxide, through a stabilized
oxycarbenium ion intermediate in the first case and by
an SN2 mechanism in the latter.29
In conclusion, during the transformation of (-)-R-
santonin into phytuberin, following in essence a biomi-
metic methodology, we have discovered examples of a
number of apparently unprecedented processes: The
4-endo-tet acid-catalyzed cyclization of R-hydroxy ep-
oxides, the 4-exo selenocyclization of a homoallylic alco-
hol, and the equilibrium between 4-exo and 5-endo
cyclizations that, through a 3-hydroxyseleniranium ion,
is observed in the aforementioned seleniocyclization of
homoallylic alcohols.
a
Reagents and conditions: (a) dimethyldioxirane, CH2Cl2, -17
°C, 30 min, then MeOH, 1 h, 46%; (b) dimethyldioxirane, CH2Cl2,
-17 °C, 30 min, then BnNH2, 23 h, 53%.
Due to its low antifungal activity it seems unlikely that
phytuberin itself has any relevance to the resistance of
solanum plants to fungal infection.4 We considered the
possibility that the hitherto unknown 2,3-epoxy-phytu-
berin could be the active principle in a manner similar
to that described in the aflatoxin family.25
Exp er im en ta l Section
Meth yl (11S)-1â-P h en ylth io-3-oxo-eu d esm -4-en -13-oa te
(3). To a solution of sodium thiophenoxide (200 mL, 15.9 mmol)
prepared from sodium (366 mg, 15.9 mmol) and benzenethiol
(15.7 gr, 143.1 mmol) in ethanol (185 mL) was added (-)-R-
santonin (2) (1 g, 4.07 mmol) and the mixture was stirred
under argon at reflux temperature for 20 h. The reaction
mixture was then poured into 5% aqueous HCl and extracted
with CH2Cl2. The organic layer was washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The
residue was dissolved in ether (20 mL) and treated at 0 °C
with an ethereal solution of diazomethane. After 1 h the
solution was evaporated and the residue purified by silica gel
column chromatography (hexanes-EtOAc, 9:1) to give com-
pound 3 (1.03 g, 2.77 mmol, 68%) and methyl (11S)-3-oxo-
eudesma-1,4-dien-13-oate (140 mg, 0.53 mmol, 13%). Com-
pound 3: Rf 0.28 (hexanes-EtOAc, 8:2); mp 114.5-115.5 °C
(from n-pentane-acetone); [R]D -70 (c 0.222); IR 1650, 1740
cm-1; UV (EtOH) 249 nm (ꢀ 17 224); 1H NMR (200 MHz) δ
1.19 (3H, d, J ) 7.0 Hz), 1.26 (3H, s), 1.74 (3H, s), 3.32 (1H, br
t, J ) 9.6 Hz), 3.70 (3H, s), 7.26 (3H, m), 7.42 (2H, m); 13C
NMR (50.3 MHz) δ 11.0 (CH3), 14.2 (CH3), 18.0 (CH3), 24.7
(CH2), 32.4 (CH2), 39.4 (CH2), 40.9 (CH), 40.9 (C), 41.8 (CH2),
45.0 (CH), 51.7 (CH3), 56.7 (CH), 127.6 (CH), 129.3 (2 × CH),
129.6 (C), 132.9 (2 × CH), 134.8 (C), 161.8 (C), 176.1 (C), 197.0
(C); MS m/z (rel intensity) 372 (M+, 23), 344 (2), 263 (93), 236
(12), 231 (13), 203 (34), 175 (100); HRMS calcd for C22H28O3S
372.1759, found 372.1730. Anal. Calcd for C22H28O3S: C, 70.93;
H, 7.58; S, 8.61. Found: C, 70.84; H, 7.38; S, 8.49. Methyl
(11S)-3-oxo-eudesma-1,4-dien-13-oate: oil; IR (CCl4) 1738,
With the small amount of phytuberin available we
decided to study the formation of this epoxide and its
reactivity under mild hydrolysis conditions. The reactions
are outlined in Scheme 7; phytuberin was epoxidized with
dimethyldioxirane26 in acetone and in situ hydrolyzed
with an excess of anhydrous methanol or benzylamine
to afford compound 37 or 38, respectively. The apparent
lability of the epoxide discouraged us from attempting
its isolation.27 The stereochemistry of compounds 37 and
38 was tentatively assigned exclusively on the basis of
NOESY experiments;28 strong NOEs between the C-3R
proton and the C-4 methyl protons are observed in both
compounds, while cross-peaks between the C-2â proton
and C-1â and the C-10 methyl protons are only observ-
able in the spectrum of 38. On the other hand, a strong
(24) For the formation of tetrahydrofurans and tetrahydropyrans
by acid-catalyzed cyclization of 3-hydroxy selenides see: (a) Grut-
tadauria, M.; Noto, R. Tetrahedron Lett. 1999, 40, 8477-8482. (b) Clive,
D. L. J .; Russel, C. G.; Chittattu, G.; Singh, A. Tetrahedron 1980, 36,
1399-1408. (c) Rouessac, A.; Rouessac, F. Tetrahedron 1981, 37, 4165-
4170. (d) Murata, S.; Suzuki, T. Tetrahedron Lett. 1987, 28, 4415-
4416. (e) Toshimitsu, A.; Aoai, T.; Uemura, S.; Okano, M. J . Org. Chem.
1981, 46, 3021-3026.
(25) (a) Baertschi, S. W.; Raney, K. D.; Stone, M. P.; Harris, T. M.
J . Am. Chem. Soc. 1988, 110, 7929-7931. (b) For a review on epoxides
as DNA-alkylating agents see: Rajski, S. R.; Williams, R. M. Chem.
Rev. 1998, 98, 2723-2795.
(26) (a) Murray, R. W.; J eyaramen, R. J . Org. Chem. 1985, 50, 2847-
2853. (b) Adam, W.; Chen, Y.-Y.; Cremer, D.; Gauss, J .; Scheutzow,
D.; Schindler, M. J . Org. Chem. 1987, 52, 2800-2830. (c) Adam, W.;
Bialas, J .; Hadjiarapoglou, L. Chem. Ber. 1991, 124, 2377.
(27) When the crude epoxidation residue, obtained by careful
elimination of the excess of dimethyldioxirane (DMD) and solvent with
dry nitrogen following the standard protocol (ref 25a), was treated with
dry methanol, a complex mixture resulted in which we were unable to
detect any compound 37. For previous reports on the intrinsic lability
of the 2,6-dioxabicyclo[3.1.0]hexane system prepared by DMD oxidation
of 2,3-dihydrofurans see: (a) Timmers, C. M.; Verheijen, J . C.; Marel,
A.; Boom, J . H. Synlett 1997, 851-853. (b) J ohnson, W. W.; Harris, T.
M.; Guengerich, F. P. J . Am. Chem. Soc. 1996, 118, 8213-8220.
(28) Although the NOESY experimental results support the pro-
posed structures we are aware of their inherent limitations in this type
of system when only one stereoisomer is available. Both hydrolysis
compounds 37 and 38 should be formed from the theoretically more
hindered, but also probably more stable, endo-epoxide. A similar
situation is observed for the exo- and endo-epoxides of aflatoxin B1 (ref
29).
1
1664 cm-1; H NMR (400 MHz) δ 1.21 (3H, s), 1.22 (3H, d, J
) 6.8 Hz), 1.89 (3H, d, J ) 0.8 Hz), 2.47 (1H, dddd, J ) 7.2,
7.2, 7.2, 7.2 Hz), 2.74 (1H, ddd, J ) 13.2, 3.2, 2.0 Hz), 3.72
(3H, s), 6.23 (1H d, J ) 9.8 Hz), 6.74 (1H, d, J ) 9.6 Hz); 13C
NMR (50.3 MHz) δ 10.4 (CH3), 14.3 (CH3), 23.4 (CH3), 24.2
(CH2), 31.9 (CH2), 37.8 (CH2), 40.3 (C), 42.2 (CH), 44.9 (CH),
51.6 (CH3), 126.3 (CH), 129.3 (C), 156.4 (CH), 159.0 (C), 175.9
(C), 186.2 (C); MS m/z (rel intensity) 262 (M+, 45), 247 (5),
230 (19), 215 (6), 175 (100); HRMS calcd for C16H22O3 262.1569,
found 262.1590. Anal. Calcd for C16H22O3: C, 73.25; H, 8.45.
Found: C, 73.32; H, 8.29.
Meth yl (11S)-3â-Hyd r oxy-1â-p h en ylth io-eu d esm -4-en -
13-oa te (4). To a solution of ester 3 (100 mg, 0.27 mmol) in
methanol (6 mL) were added cerium trichloride (100.7 mg, 0.27
mmol) and sodium borohydride (10.3 mg, 0.27 mmol). The
mixture was stirred at room temperature for 10 min, diluted
with water, and extracted with CH2Cl2. The combined organic
(29) Iyer, R. S.; Coles, B. F.; Raney, K. D.; Thier, R.; Guengerich, F.
P.; Harris, T. M. J . Am. Chem. Soc. 1994, 116, 1603-1609.
4426 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of Phytuberin
1
extracts were washed with brine, dried, and evaporated. The
residue was purified by Chromatotron chromatography (hex-
anes-EtOAc, 8:2) to give ester 4 (92 mg, 0.24 mmol, 91%): Rf
0.20 (hexanes-EtOAc, 8:2); mp 83.5-85 °C (from n-pentane);
[R]D -28 (c 0.222); IR 3580, 3500-3340, 1720 cm-1; UV (EtOH)
EtOAc, 4:6); H NMR (200 MHz) δ 1.18 (3H, d, J ) 7.1 Hz),
1.32 (3H, s), 1.38 (3H, s), 3.68 (3H, s), 3.89 (1H, m), 7.48 (5H,
m); MS m/z (rel intensity) 280 (M+ - PhSOH, 15), 263 (6),
247 (8), 234 (14), 186 (26), 147 (38). Anal. Calcd for C22H30
-
O5S: C, 65.00; H, 7.44; S, 7.89. Found: C, 64.93; H, 7.49; S,
1
257 nm (ꢀ 10 846); H NMR (200 MHz) δ 1.16 (3H, d, J ) 6.7
7.91. Compound 8: Rf 0.22 (hexanes-EtOAc, 4:6); IR (CCl4)
Hz), 1.17 (3H, s), 1.66 (3H, s), 2.98 (1H, dd, J ) 13.4, 2.7 Hz),
3.70 (3H, s), 4.03 (1H, m), 7.26 (3H, m), 7.41 (2H, m); 13C NMR
(50.3 MHz) δ 14.3 (CH3), 14.4 (CH3), 19.4 (CH3), 25.3 (CH2),
30.9 (CH2), 36.8 (CH2), 39.9 (C), 40.2 (CH2), 41.6 (CH), 45.3
(CH), 51.6 (CH3), 56.7 (CH), 71.5 (CH), 126.9 (CH), 128.0 (C),
129.1 (2 × CH), 132.1 (2 × CH), 136.2 (C), 138.2 (C), 176.7
(C); MS m/z (rel intensity) 374 (M+, 17), 357 (0.3), 264 (13),
247 (48), 233 (16), 215 (20), 187 (32), 159 (100); HRMS calcd
for C22H30O3S 374.1949, found 374.1932. Anal. Calcd for
1736 cm-1 1H NMR (500 MHz) δ 1.16 (3H, d, J ) 7.1 Hz),
;
1.33 (3H, s), 1.35 (3H, s), 2.38 (1H, dddd, J ) 7.0, 7.0, 7.0, 7.0
Hz), 2.69 (1H, ddd, J ) 13.5, 2.5, 2.5 Hz), 2.92 (1H, dd, J )
13.7, 3.3 Hz), 3.67 (3H, s), 3.71 (1H, br d, J ) 4.9 Hz), 7.47
(3H, m), 7.65 (2H, m); 13C NMR (125.7 MHz) δ 13.9 (CH3), 16.4
(CH3), 17.6 (CH3), 24.3 (CH2), 24.3 (CH2), 29.0 (CH2), 34.9
(CH2), 37.6 (CH), 38.0 (C), 44.5 (CH), 51.4 (CH3), 65.5 (C), 65.8
(CH), 67.5 (CH), 72.9 (C), 126.1 (2 × CH), 129.1 (2 × CH), 131.7
(CH), 142.5 (C), 175.8 (C); MS m/z (rel intensity) 407 (M+
-
C
22H30O3S: C, 70.55; H, 8.07; S, 8.56. Found: C, 70.64; H, 8.04;
S, 8.47.
Meth yl (11S)-3r-F or m yloxy-1â-p h en ylth io-eu d esm -4-
Me, <1), 375 (4), 347 (5), 281 (69), 263 (28), 237 (46); HRMS
calcd for C21H27O6S 407.1428, found 407.11613. Anal. Calcd
for C22H30O6S: C, 62.54; H, 7.16; S, 7.59. Found: C, 62.67; H,
7.32; S, 7.58.
en -13-oa te (5). To a solution of ester 4 (2 g, 5.35 mmol),
triphenylphosphine (2.803 g, 10.7 mmol), and formic acid (0.4
mL, 10.7 mmol) in THF (50 mL) was added dropwise a solution
of DEAD (1.68 mL, 10.7 mmol) in dry THF (8 mL) at room
temperature under argon. After 1 h the reaction mixture was
poured into water and extracted with CH2Cl2. The organic
layer was dried (Na2SO4) and the solvent evaporated in vacuo
to give a crude product that was purified by silica gel column
chromatography (hexanes-EtOAc, 9:1) to yield ester 5 (2.07
g, 5.15 mmol, 96%): oil; Rf 0.45 (hexanes-EtOAc, 8:2); IR 1715
Meth yl (11S)-4r,5r-Ep oxy-3r-h yd r oxy-eu d esm -1-en -13-
oa te (9). To a solution of ester 7 (4 g, 9.85 mmol) in benzene
(100 mL) was added diisopropylamine (1.7 mL, 12.3 mmol) in
a heavy wall hydrolysis tube with a high vacuum Teflon valve.
The tube was immersed in a preheated silicon oil bath at 120
°C for 20 h. After this time the reaction mixture was poured
into water and the organic layer was successively washed with
10% aqueous HCl solution, a saturated aqueous NaHCO3
solution, and brine. The organic layer was dried (Na2SO4), and
the solvent was evaporated in vacuo to give a crude product
that was purified by column chromatography (hexanes-
EtOAc, 6:4) to give ester 9 (2.37 g, 8.46 mmol, 86%): oil; Rf
1
cm-1; H NMR (200 MHz) δ 1.11 (3H, s), 1.17 (3H, d, J ) 7.1
Hz), 1.62 (3H, s), 3.27 (1H, dd, J ) 11.1, 5.5 Hz), 3.70 (3H, s),
5.28 (1H, m), 7.31 (5H, m), 8.05 (1H, s); 13C NMR (50.3 MHz)
δ 14.1 (CH3), 16.6 (CH3), 18.0 (CH3), 25.1 (CH2), 30.4 (CH2),
32.8 (CH2), 39.5 (C), 39.6 (CH2), 41.3 (CH), 45.1 (CH), 51.3
(CH3), 53.9 (CH), 72.2 (CH), 126.5 (CH), 128.9 (2 × CH), 131.0
(2 × CH), 131.8 (C), 136.0 (C), 143.3 (C), 160.5 (C), 176.1 (C);
MS m/z (rel intensity) 402 (M+, 12), 356 (5), 325 (1), 309 (1),
247 (68), 215 (28), 159 (100); HRMS calcd for C23H30O4S
402.1927, found 402.1896. Anal. Calcd for C23H30O4S: C, 68.63;
H, 7.51; S, 7.96. Found: C, 68.50; H, 7.32; S, 8.09.
0.40 (hexanes-EtOAc, 1:1); IR 3560, 3520-3200, 1720 cm-1
;
1H NMR (500 MHz) δ 1.00 (3H, s), 1.15 (3H, d, J ) 7.1 Hz),
1.50 (3H, s), 2.42 (1H, dddd, J ) 6.4, 6.4, 6.4, 6.4 Hz), 3.67
(3H, s), 4.13 (1H, br s), 5.26 (1H, dd, J ) 10.3, 1.7 Hz), 5.35
(1H, dd, J ) 10.3, 1.6 Hz); 13C NMR (100.6 MHz) δ 13.8 (CH3),
14.7 (CH3), 23.1 (CH3), 24.0 (CH2), 28.7 (CH2), 34.0 (CH2), 36.0
(C), 38.2 (CH), 44.5 (CH), 51.4 (CH3), 66.4 (C), 68.8 (C), 69.5
(CH), 123.8 (CH), 135.9 (CH), 176.0 (C); MS m/z (rel intensity)
280 (M+, 2), 265 (13), 237 (13), 219 (11), 205 (41); HRMS calcd
Meth yl (11S)-3r-Hyd r oxy-1â-p h en ylth io-eu d esm -4-en -
13-oa te (6). To a solution of potassium carbonate (1 g, 7.23
mmol) in methanol (50 mL) was added ester 5 (2 g, 4.98 mmol)
and the solution was stirred at 0 °C for 15 min. The reaction
mixture was then poured into 10% aqueous HCl and extracted
with CH2Cl2. The organic layer was dried (Na2SO4), and the
solvent was evaporated in vacuo to give a crude product that
was purified by silica gel column chromatography (hexanes-
EtOAc, 8:2), to give ester 6 (1.751 g, 4.68 mmol, 94%): oil; Rf
for
C
C16H24O4 280.1674, found 280.1650. Anal. Calcd for
16H24O4: C, 68.55; H, 8.65. Found: C, 68.34; H, 8.48.
Meth yl (11S)-3r-Acetoxy-4r,5r-ep oxy-eu d esm -1-en -13-
oa te (10). To a solution of ester 9 (200 mg, 0.714 mmol) in
pyridine (3 mL) was added acetic anhydride (1 mL, 10.61
mmol) and the reaction mixture was stirred at room temper-
ature overnight. The solution was then poured into 10%
aqueous HCl solution and extracted with EtOAc. The organic
extracts were washed with NaCO3H and brine, dried over Na2-
SO4, and evaporated in vacuo. The reaction crude was purified
by Chromatotron chromatography (hexanes-EtOAc, 8:2) to
give ester 10 (216 mg, 0.67 mmol, 94%): Rf 0.33 (hexanes-
EtOAc, 8:2); mp 76.5-77.8 °C (from n-pentane); [R]D +8 (c
0.238); IR 1725 cm-1; 1H NMR (200 MHz) δ 1.02 (3H, s), 1.14
(3H, d, J ) 7.0 Hz), 1.34 (3H, s), 2.13 (3H, s), 3.66 (3H, s),
5.20 (1H, dd, J ) 10.2, 1.8 Hz), 5.35 (1H, dd, J ) 10.2, 2.2
Hz), 5.52 (1H, dd, J ) 2.0, 2.0 Hz); 13C NMR (50.3 MHz) δ
13.8 (CH3), 14.6 (CH3), 20.9 (CH3), 22.6 (CH3), 24.1 (CH2), 28.5
(CH2), 34.1 (CH2), 36.4 (C), 38.2 (CH), 44.5 (CH), 51.2 (CH3),
63.7 (C), 67.0 (C), 71.7 (CH), 120.3 (CH), 137.1 (CH), 170.6
(C), 175.7 (C); MS m/z (rel intensity) 322 (M+, 1), 307 (3), 291
(10), 280 (100), 263 (48), 205 (59); HRMS calcd for C18H26O5
322.1802, found 322.1791. Anal. Calcd for C18H26O5: C, 67.06;
H, 8.13. Found: C, 66.93; H, 8.22.
0.18 (hexanes-EtOAc, 8:2); IR 3590, 3520-3340, 1725 cm-1
;
1H NMR (200 MHz) δ 1.05 (3H, s), 1.12 (3H, d, J ) 6.9 Hz),
1.69 (3H, s), 3.35 (1H, dd, J ) 9.7, 6.8 Hz), 3.64 (3H, s), 3.85
(1H, m), 7.27 (5H, m); 13C NMR (50.3 MHz) δ 14.1 (CH3), 17.2
(CH3), 18.0 (CH3), 25.2 (CH2), 30.3 (CH2), 36.0 (CH2), 39.6 (C),
39.6 (CH2), 41.4 (CH), 45.2 (CH), 51.4 (CH3), 53.3 (CH), 69.9
(CH), 126.1 (CH), 128.9 (2 × CH), 130.5 (2 × CH), 131.9 (C),
136.6 (C), 139.6 (C), 176.5 (C); MS m/z (rel intensity) 374 (M+,
28), 357 (1), 264 (94), 249 (34), 177 (100), 159 (75); HRMS calcd
for C22H30O3S 374.1939, found 374.1927. Anal. Calcd for
C
22H30O3S: C, 70.55; H, 8.07; S, 8.56. Found: C, 70.44; H, 8.08;
S, 8.37.
Met h yl (11S)-4r,5r-E p oxy-3r-h yd r oxy-1â-p h en ylsu l-
fin yl-eu d esm a n -13-oa te (7). To a solution of ester 6 (3.1 g,
8.3 mmol) and vanadyl acetylacetonate (44 mg, 0.166 mmol)
in benzene (64 mL) was added dropwise over 30 min tert-butyl
hydroperoxide (2.55 M in toluene, 19.5 mL, 49.7 mmol). The
mixture was stirred at room temperature for 2 h, poured into
a 2% aqueous solution of sodium bisulfite, and extracted with
CH2Cl2. The organic layer was dried (Na2SO4), and the solvent
was evaporated in vacuo to give a crude product that was
purified by column chromatography (hexanes-EtOAc, 1:1 f
3:7) to give sulfoxide 7 (3.07 g, 7.56 mmol, 91%) and sulfone 8
(306 mg, 0.72 mmol, 9%). Compound 7: Rf 0.10 (hexanes-
Met h yl (3R,4R,5S,11S)-3-Acet oxy-1,2-d ih yd r oxy-4,5-
ep oxy-1,2-secoeu d esm a n -13-oa te (11). A solution of com-
pound 10 (221 mg, 0.69 mmol) in CH2Cl2/MeOH (46 mL, 1:1)
was cooled to -78 °C, and a slow stream of ozone was
introduced into the solution until it became blue. Excess ozone
was removed by flushing the solution with argon. Me2S (0.61
mL, 8.28 mmol) was then added and the resulting mixture
was stirred for 20 min at this temperature before being treated
J . Org. Chem, Vol. 68, No. 11, 2003 4427

Prange´ et al.
with sodium borohydride (79 mg, 2.07 mmol). The reaction
mixture was allowed to rise to room temperature and stirring
was continued for 1.5 h. The reaction was quenched by the
addition of 5% aqueous HCl solution and extracted with CH2-
Cl2. The organic extracts were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue
was purified by Chromatotron chromatography (hexanes-
EtOAc, 6:4) to give ester 11 (199 mg, 0.556 mmol, 81%): oil;
Rf 0.16 (hexanes-EtOAc, 1:1); 1H NMR (500 MHz) δ 1.04 (3H,
s), 1.14 (3H, d, J ) 7.1 Hz), 1.34 (3H, s), 2.12 (3H, s), 3.67
(3H, s), 3.22 (1H, br d, J ) 8.2 Hz), 3.81 (1H, br d, J ) 9.3
Hz), 4.24 (1H, dd, J ) 11.2, 2.7 Hz), 4.28 (1H, m), 4.38 (1H,
dd, J ) 11.2, 7.7 Hz); 13C NMR (50.3 MHz) δ 13.5 (CH3), 14.4
(CH3), 20.0 (CH3), 20.8 (CH3), 24.0 (CH2), 33.7 (CH2), 36.3
(CH2), 37.8 (CH), 38.3 (C), 44.5 (CH), 51.4 (CH3), 66.8 (C), 67.0
(CH2), 71.3 (CH), 71.8 (C), 72.0 (CH2), 171.7 (C), 176.0 (C); MS
m/z (rel intensity) 340 (M+ - H2O, 1), 322 (1), 279 (11), 223
(48), 149 (100); HRMS calcd for C18H28O7 340.1886, found
340.1914. Anal. Calcd for C18H30O7: C, 60.32; H, 8.44. Found:
C, 60.43; H, 8.47.
layer was washed twice with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by Chromatotron chromatography (hexanes-EtOAc, 1:1) to
give alcohol 14 (26.1 mg, 0.087 mmol, 87%): Rf 0.14 (hexanes-
EtOAc, 6:4); mp 95-95.7 °C (n-hexane); IR 3528, 1731 cm-1
;
1H NMR (500 MHz) δ 0.96 (3H, s), 1.14 (3H, d, J ) 7.1 Hz),
1.41 (3H, s), 2.05 (1H, ddd, J ) 13.4, 3.2, 2.2 Hz), 2.29 (1H,
dddd, J ) 7.1, 7.1, 7.1, 7.1 Hz), 3.64 (1H, d, J ) 8.7 Hz), 3.69
(3H, s), [3.74 (2H, m) after D2O: 3.68 (1H, dd, J ) 12.4, 4.3
Hz) and 3.73 (1H, dd, J ) 12.4, 4.3 Hz)], 3.95 (1H, d, J ) 8.7
Hz), 4.27 (1H, dd, J ) 4.7, 4.7 Hz); 13C NMR (50.3 MHz) δ
13.3 (CH3), 14.2 (CH3), 15.2 (CH3), 23.8 (CH2), 33.1 (CH2), 34.1
(CH2), 38.5 (CH), 43.6 (C), 45.0 (CH), 51.5 (CH3), 62.3 (CH2),
76.7 (CH2), 84.6 (CH), 86.2 (C), 95.8 (C), 176.1 (C); MS (CI)
m/z (rel intensity) 299 (M+ + H, 50), 280 (2), 267 (4), 238 (99),
223 (100), 211 (13); HRMS calcd for C16H24O4 280.1675, found
280.1656. Anal. Calcd for C16H26O5: C, 64.41; H, 8.78. Found:
C, 64.63; H, 8.90. Crystal data for 14: a crystal of 0.1 × 0.3 ×
0.5 mm3 was grown from methanol, C16H26O5, orthorhombic,
space group P212121, Z ) 4, a ) 25.656(4) Å, b ) 6.288(2) Å, c
) 9.913(3) Å. The data were measured on a Philips PW-1100
four-circle automatic diffractometer operating with Cu KR
radiation (λ ) 1.5418 Å) monochromated by graphite, at room
temperature, up to 2θ ) 126°. Two equivalent portions of the
reciprocal space were recorded (2528 intensities). The structure
was solved by direct methods and refined with anisotropic
thermal factors for non-hydrogen atoms to R ) 6.5% (unitary
weights) and Rw ) 5.8% [weights ) 5.3/σ(F)2]. All the hydro-
gens were located on Fourier-difference syntheses. Data merg-
ing and processing led to a unique set of 1285 structure factors
(Rsymm ) 2.8%) of which 1025 were observed [I g 2σ(I)]. No
decomposition corrections were applied but empirical absorp-
tion corrections were made at the end of the isotropic refine-
ments, using the unmerged data set.
Meth yl (3R,4R,5R,11S)-2-Acetoxy-3,5-ep oxy-1,4-d ih y-
d r oxy-1,2-secoeu d esm a n -13-oa te (12). To a solution of ester
11 (75 mg, 0.209 mmol) in CH2Cl2 (5 mL) was added meth-
anesulfonic acid (7 µL, 0.104 mmol) and the solution was
stirred at 0 °C for 20 min. The reaction mixture was then
poured into aqueous saturated NaCO3H and extracted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue
was purified by Chromatotron chromatography (benzene-
EtOAc, 6:4) to give ester 12 (40 mg, 0.11 mmol, 53%): oil; Rf
0.21 (hexanes-EtOAc, 6:4); IR (CCl4) 3230, 1739 cm-1 1H
;
NMR (200 MHz) δ 0.91 (3H, s), 1.14 (3H, d, J ) 7.1 Hz), 1.45
(3H, s), 2.08 (3H, s), 3.68 (3H, s), 3.50 (1H, d, J ) 11.7 Hz),
4.09 (1H, dd, J ) 12.1, 7.7 Hz), 4.19 (1H, d, J ) 11.7 Hz), 4.29
(1H, dd, J ) 12.1, 3.5 Hz), 4.64 (1H, dd, J ) 7.7, 3.5 Hz); 13C
NMR (100.6 MHz) δ 14.5 (CH3), 19.1 (CH3), 19.3 (CH3), 20.9
(CH3), 23.4 (CH2), 30.7 (CH2), 36.2 (CH2), 37.9 (CH), 43.8 (C),
44.8 (CH), 51.5 (CH3), 64.8 (CH2), 68.0 (CH2), 77.1 (C), 86.1
(CH), 94.9 (C), 171.0 (C), 176.3 (C); MS m/z (rel intensity) 327
(M+ - OMe, 1), 309 (1), 297 (2), 281 (4), 265 (4), 255 (7), 237
(12), 225 (24); HRMS calcd for C17H25O5 309.1702, found
309.1680. Anal. Calcd for C18H30O7: C, 60.32; H, 8.44. Found:
C, 60.54; H, 8.39.
ter t-Bu tyl(d ip h en yl)silyl (3R,4R,5R,11S)-2-ter t-Bu tyl-
(d ip h en yl)silyloxy-1,4:3,5-d iep oxy-1,2-secoeu d esm -13-
oa te (27). To a solution of ester 13 (82 mg, 0.24 mmol) in
methanol (0.5 mL) was added 5.7 N aqueous KOH (0.2 mL)
under stirring. The mixture was kept at 40 °C for 23 h then
cooled to room temperature and acid resin Dowex 50× (195
mg) was added and stirring continued at room temperature
until pH 5. The reaction was diluted with CH2Cl2, filtered, and
concentrated under reduced pressure and the residue was
directly used for the next step without further purification.
To a solution of the above acid in CH2Cl2 (1 mL) were added
sequentially triethylamine (69.6 mg, 0.69 mmol), 4-(dimethy-
lamino)pyridine (9.8 mg, 0.08 mmol), and tert-butyldiphenyl-
silyl chloride (132 mg, 0.48 mmol) at room temperature. The
reaction mixture was stirred under argon for 2 h and 45 min,
then poured into a saturated aqueous solution of NaHSO4 and
extracted with EtOAc. The organic layer was washed with a
saturated aqueous solution of NaHCO3, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by Chromatotron chromatography (hexanes-EtOAc, 95:5) to
give compound 27 (173 mg, 0.227 mmol, 95%) as a syrup: Rf
Met h yl (3R,4R,5R,11S)-2-Acet oxy-1,4:3,5-d iep oxy-1,2-
secoeu d esm a n -13-oa te (13). To a solution of ester 12 (42 mg,
0.117 mmol) and triphenylphosphine (77 mg, 0.29 mmol) in
dry CHCl3 was added dropwise a solution of DEAD (46 µL,
0.29 mmol) at room temperature under argon. After 30 min
the reaction mixture was poured into a 1% aqueous solution
of sodium hydroxide and extracted with CH2Cl2. The organic
layer was washed with 5% aqueous HCl solution and dried
(Na2SO4), and the solvent was evaporated in vacuo to give a
crude product that was purified by Chromatotron chromatog-
raphy (benzene-EtOAc, 8:2) to yield ester 13 (38 mg, 0.112
mmol, 95%): oil; Rf 0.42 (hexanes-EtOAc, 8:2); 1H NMR (200
MHz) δ 0.95 (3H, s), 1.14 (3H, d, J ) 7.1 Hz), 1.39 (3H, s),
2.10 (3H, s), 3.68 (3H, s), 3.66 (1H, d, J ) 8.8 Hz), 3.95 (1H, d,
J ) 8.8 Hz), 4.10 (1H, dd, J ) 6.7, 12.1 Hz), 4.25 (1H, dd, J )
4.0, 12.3 Hz), 4.40 (1H, dd, J ) 4.0, 6.6 Hz); 13C NMR (50.3
MHz) δ 13.3 (CH3), 14.7 (CH3), 15.5 (CH3), 21.0 (CH3), 24.0
(CH2), 33.7 (CH2), 34.1 (CH2), 38.5 (CH), 43.6 (C), 45.2 (CH),
51.6 (CH3), 64.7 (CH2), 77.0 (CH2), 82.1 (CH), 86.2 (C), 96.1
(C), 176.3 (C), 177.7 (C); MS m/z (rel intensity) 322 (M+ - H2O,
1), 309 (5), 297 (2), 280 (2), 267 (1), 256 (1), 249 (4), 238 (59),
223 (100); HRMS calcd for C18H28O6 340.1886, found 340.1874.
Anal. Calcd for C18H28O6: C, 63.51; H, 8.29. Found: C, 63.72;
H, 8.13.
0.27 (hexanes-EtOAc, 9:1); IR 2933, 1717, 1472, 1114 cm-1
;
1H NMR (500 MHz) δ 0.93 (3H, s), 1.07 (9H, s), 1.11 (9H, s),
1.15 (3H, d, J ) 7.0 Hz), 1.42 (3H, s), 1.85 (1H, m), 2.05 (1H,
br d, J ) 13.6 Hz), 2.43 (1H, dddd, J ) 6.9, 6.9, 6.9, 6.9 Hz),
3.64 (1H, d, J ) 8.7 Hz), 3.73 (2H, d, J ) 5.9 Hz), 3.96 (1H, d,
J ) 8.7 Hz), 4.26 (1H, dd, J ) 5.9, 5.9 Hz), 7.36 (10H, m), 7.66
(10H, m); 13C NMR (50.3 MHz) δ 12.8 (CH3), 13.2 (CH3), 15.5
(CH3), 19.2 (2 × C), 22.9 (CH2), 26.8 (3 × CH3), 27.0 (3 × CH2),
33.8 (CH2), 33.9 (CH2), 37.9 (CH), 43.4 (C), 46.1 (CH), 64.4
(CH2), 76.7 (CH2), 84.3 (CH), 86.5 (C), 95.2 (C), 127.7 (8 × CH),
129.7 (CH), 129.7 (CH), 130.1 (2 × CH), 131.8 (2 × C), 133.5
(2 × C), 135.3 (4 × CH), 135.6 (2 × CH), 135.7 (2 × CH), 174.6
(C); MS-FAB m/z (rel intensity) 783 (M+ + Na, 3), 761(3), 703
(4), 684 (2), 527 (1), 463(18), 405 (9), 385(48), 241 (62), 199
(67), 135 (100); HRMS-FAB calcd for C47H60NaO5Si2 783.3877,
found 783.3888. Anal. Calcd for C47H60O5Si2: C, 74.17; H, 7.95.
Found: C, 74.03; H, 7.91.
Meth yl (3R,4R,5R,11S)-1,4:3,5-Diep oxy-2-h yd r oxy-1,2-
secoeu d esm a n -13-oa te (14). Acetate 13 (34.4 mg, 0.1 mmol)
in 2% of K2CO3 in MeOH (3.3 mL) was stirred at room
temperature for 15 min, poured into a saturated aqueous
solution of NaHSO4, and extracted with CHCl3. The organic
4428 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of Phytuberin
(3R,4R,5R,11S)-2-ter t-Bu t yl(d ip h en yl)silyloxy-1,4:3,5-
d iep oxy-1,2-secoeu d esm -13-oic Acid (28). To a solution of
compound 27 (105 mg, 0.138 mmol) in methanol (0.28 mL) was
added 2.9 N aqueous KOH (0.14 mL) under stirring. The
mixture was kept at room temperature for 1 h. Acid resin
Dowex 50× (82 mg) was added and the mixture was stirred
until it reached pH 6. The reaction was diluted with CH2Cl2,
filtered, and concentrated under reduced pressure. The residue
was purified by Chromatotron chromatography (hexanes-
EtOAc, 7:3 f 2:8 then CHCl3-MeOH, 5:5) to give compound
28 (59 mg, 0.113 mmol, 82%) and a small amount of the
hydroxy acid (4 mg, 0.014 mmol, 10%). Compound 28: Rf 0.53
NaO4Si 515.2593, found 515.2563. Anal. Calcd for C30H40O4-
Si: C, 73.13; H, 8.18. Found: C, 73.19; H, 8.25.
(3R,4R,5R)-2-ter t-Bu tyl(d ip h en yl)silyloxy-1,4:3,5-d iep -
oxy-1,2-secoeu d esm a n -11-ol (30). To a solution of ketone
29 (21.8 mg, 0.044 mmol) in ether (0.9 mL) at -78 °C was
added dropwise methylmagnesium bromide (0.32 mL, 0.95
mmol) under a nitrogen atmosphere. The reaction mixture was
stirred for 45 min, then quenched at this temperature with
cold saturated aqueous sodium bisulfate solution and allowed
to warm to room temperature for 30 min. Then it was poured
into a saturated aqueous sodium bisulfate solution and
extracted with EtOAc. The organic layer was washed with a
saturated aqueous sodium bicarbonate solution and twice with
brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by Chromatotron chroma-
tography (hexanes-EtOAc, 8:2) to give alcohol 30 (23.3 mg,
0.046 mmol, 96%): Rf 0.31 (hexanes-EtOAc, 7:3); IR 3609,
2934, 1472, 1383, 1242, 1113 cm-1; 1H NMR (200 MHz) δ 0.97
(3H, s), 1.07 (9H, s), 1.16 (6H, s), 1.46 (3H, s), 3.65 (1H, d, J )
8.6 Hz), 3.76 (1H, d, J ) 5.2 Hz), 3.77 (1H, d, J ) 6.6 Hz),
3.97 (1H, d, J ) 8.7 Hz), 4.29 (1H, dd, J ) 5.6, 5.6 Hz), 7.40
(6H, m), 7.69 (4H, m); 13C NMR (50.3 MHz) δ 13.4 (CH3), 15.6
(CH3), 19.2 (C), 21.6 (CH2), 26.7 (CH3), 26.8 (3 × CH3), 27.2
(CH3), 30.2 (CH2), 34.2 (CH2), 43.4 (C), 46.7 (CH), 64.3 (CH2),
72.2 (C), 76.7 (CH2), 84.2 (CH), 86.5 (C), 95.6 (C), 127.7 (4 ×
CH), 129.7 (2 × CH), 133.1 (2 × C), 135.7 (4 × CH); MS m/z
(rel intensity) 451 (M+ - C4H9, 12), 433 (13), 403 (3), 373 (5),
355 (3), 307 (7), 241 (100). Anal. Calcd for C31H44O4Si: C, 73.18;
H, 8.72. Found: C, 73.09; H, 8.90.
(hexanes-EtOAc, 1:1); IR 3514, 2931, 1706, 1464, 1112 cm-1
;
1H NMR (200 MHz) δ 0.95 (3H, s), 1.07 (9H, s), 1.14 (3H, d, J
) 7.2 Hz), 1.47 (3H, s,), 3.65 (1H, d, J ) 8.6 Hz), 3.75 (2H, d,
J ) 5.5 Hz), 3.96 (1H, d, J ) 8.7 Hz), 4.27 (1H, dd, J ) 5.7,
5.7 Hz), 7.39 (5H, m), 7.68 (5H, m); 13C NMR (50.3 MHz) δ
13.2 (CH3), 13.3 (CH3), 15.5 (CH3), 19.1 (C), 23.2 (CH2), 26.8
(3 × CH3), 33.2 (CH2), 33.9 (CH2), 37.8 (CH), 43.4 (CH), 44.3
(C), 64.3 (CH2), 76.6 (CH2), 84.3 (CH), 86.5 (C), 95.2 (C), 127.7
(4 × CH), 129.7 (2 × CH), 133.1 (C), 133.2 (C), 135.61 (2 ×
CH), 135.63 (2 × CH), 181.1 (C); MS-FAB m/z (rel intensity)
545 (M+ + Na, 13), 241 (24), 221 (17), 199 (14), 135 (24);
HRMS-FAB calcd for C31H42NaO5Si 545.2699, found 545.2675.
Anal. Calcd for C31H42O5Si: C, 71.23; H, 8.10. Found: C, 71.09;
H, 7.91.
(3R,4R,5R)-2-ter t-Bu tyl(d ip h en yl)silyloxy-1,4:3,5-d iep -
oxy-1,2-seco-12-n or -eu d esm a n -11-on e (29). The acid chlo-
ride was prepared immediately prior to use by treatment of
the acid 28 (167 mg, 0.32 mmol) in benzene (1.6 mL) with
oxalyl chloride (229 mg, 1.8 mmol) and DMF (0.09 mL) at room
temperature under argon and stirring for 1 h. The reaction
mixture was evaporated to dryness, redissolved in benzene (1.6
mL), and evaporated to dryness again yielding the crude acid
chloride that was used in the following reaction without
purification. To a solution of the acid chloride (0.32 mmol) in
dry degassed CH2Cl2 (1.6 mL) was added the sodium salt of
N-hydroxypyridine-2-thione (50 mg, 0.33 mmol). After being
stirred for 2 h at room temperature under an inert atmosphere,
the reaction mixture was rapidly filtered through a short pad
of Celite, and the solvent was evaporated under vacuum
without heating. The light-sensitive yellow residue was used
as such in the next reaction. The crude thiohydroxamate ester
(0.32 mmol) and antimony trisphenylsulfide (359 mg, 0.8
mmol) in ether (16 mL) were stirred for 1.5 h at room
temperature under aerial oxidation. The white solid was
filtered through a short pad of Celite, and the solution was
evaporated to dryness. Purification of the residue by column
chromatography (hexanes f hexanes-EtOAc, 9:1) afforded the
mixture of nor-alcohols (115 mg, 0.23 mmol, 72%). To a
solution of the alcohols (115 mg, 0.23 mmol) in anhydrous CH2-
Cl2 (0.33 mL) were added pyridinium chlorochromate (109 mg,
0.506 mmol) and sodium acetate (8.2 mg, 0.1 mmol) and the
mixture was stirred at room temperature for 2 h. Then dry
ether (1 mL) was added and the supernatant solution was
decanted from the black gum. The insoluble residue was
washed thoroughly with anhydrous ether whereupon it became
a black granular solid. The combined organic extracts were
passed through a short pad of Celite and concentrated under
reduced pressure. The residue was purified by Chromatotron
chromatography (hexanes-EtOAc, 9:1) to afford ketone 29
(89.3 mg, 0.18 mmol, 79%): Rf 0.53 (hexanes-EtOAc, 7:3); IR
2932, 1708, 1464, 1113 cm-1; 1H NMR (500 MHz) δ 0.98 (3H,
s), 1.06 (9H, s), 1.48 (3H, s), 2.11 (3H, s), 3.65 (1H, d, J ) 8.7
Hz), 3.74 (1H, dd, J ) 11.6, 4.5 Hz), 3.78 (1H, dd, J ) 11.6,
6.1 Hz), 3.97 (1H, d, J ) 8.7 Hz), 4.27 (1H, dd, J ) 5.8, 4.9
Hz), 7.40 (6H, m), 7.68 (4H, m); 13C NMR (50.3 MHz) δ 13.2
(CH3), 15.7 (CH3), 19.2 (C), 23.1 (CH2), 26.7 (3 × CH3), 28.0
(CH3), 29.7 (CH2), 33.7 (CH2), 43.5 (C), 49.2 (CH), 64.1 (CH2),
76.7 (CH2), 84.5 (CH), 86.5 (C), 94.7 (C), 127.7 (4 × CH), 129.8
(2 × CH), 133.0 (C), 135.1 (C), 135.7 (4 × CH), 210.9 (C); MS-
FAB m/z (rel intensity) 515 (M+ + Na, 1), 401 (2), 355 (2), 341
(3R,4R,5R)-1,4:3,5-Diep oxy-1,2-secoeu d esm a n e-2,11-
d iol (31). To a solution of silyl ether 30 (12.1 mg, 0.024 mmol)
in THF (0.9 mL) was added a solution of tetrabutylammonium
fluoride (15.7 mg, 0.06 mmol) in THF (0.2 mL). The reaction
mixture was stirred at room temperature for 2.5 h, poured into
a saturated aqueous solution of NaHCO3, and extracted with
chloroform. The organic extract was dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified
by Chromatotron chromatography (hexanes-EtOAc, 1:9) to
afford the diol 31 (6.5 mg, 0.024 mmol, 100%): Rf 0.15
(hexanes-EtOAc, 4:6); 1H NMR (200 MHz) δ 0.99 (3H, s), 1.22
(6H, s), 1.43 (3H, s), 3.66 (1H, d, J ) 8.7 Hz), 3.74 (2H, m),
3.67 (1H, d, J ) 8.7 Hz), 4.31 (1H, dd, J ) 4.6, 4.6 Hz); 13C
NMR (50.3 MHz) δ 13.4 (CH3), 15.3 (CH3), 21.6 (CH2), 27.0 (2
× CH3), 29.6 (CH2), 34.3 (CH2), 43.5 (C), 46.8 (CH), 62.3 (CH2),
72.2 (C), 76.7 (CH2), 84.6 (CH), 86.2 (C), 96.4 (C); MS m/z (rel
intensity) 270 (M+, <1), 269 (1), 210 (100); HRMS calcd for
C
15H24O3 252.1725, found 252.1746. Anal. Calcd for C15H26O4:
C, 66.64; H, 9.69. Found: C, 66.72; H, 9.91.
(3S,4R,5R)-1,4:3,5-Diep oxy-2-iod o-1,2-secoeu d esm a n -
11-ol (32) a n d (4R,5R)-1,4-Ep oxy-1,2-secoeu d esm -2-en e-
5,11-d iol (33). To a solution of the diol 31 (2.4 mg, 0.0089
mmol) in benzene (0.29 mmol) were added sequentially 1,2-
dichloroethane (0.09 mL), water (1.6 µL), imidazole (0.5 mg,
0.0074 mmol), 2,6-lutidine (2.0 mg, 0.019 mmol), triphenylphos-
phine (9.3 mg, 0.0356 mmol), and iodine (6.8 mg, 0.0267 mmol).
More benzene (0.19 mL) was added to the reaction mixture
and it was stirred at room temperature until the reagents were
completely dissolved. Then the reaction mixture was stirred
at 80 °C for 15 min, poured into an ice-cooled aqueous solution
of sodium thiosulfate, and extracted with ether. The combined
extracts were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by Chromatotron chromatography (benzene-EtOAc, 7:3) to
give the olefin 33 (1.2 mg, 0.0047 mmol, 54%) and iodine 32
(1.6 mg, 0.0042 mmol, 44%). Olefin 33: crystalline solid, Rf
0.18 (hexanes-EtOAc, 7:3); mp 84.3-86.2 °C (from n-pentane);
[R]D +47 (c 0.94); IR (film) 3418, 3086, 2970, 1639, 1470, 1368,
1274, 1041, 919 cm-1; 1H NMR (500 MHz) δ 0.97 (3H, s), 1.18
(3H, s), 1.20 (3H, s), 1.35 (3H, s), 3.57 (1H, d, J ) 8.6 Hz),
3.68 (1H, d, J ) 8.6 Hz), 5.09 (1H, ddd, J ) 10.8, 1.7, 1.2 Hz),
5.30 (1H, ddd, J ) 17.4, 1.6, 1.3 Hz), 5.99 (1H, dd, J ) 17.4,
10.8 Hz); 13C NMR (50.3 MHz) δ 19.2 (CH3), 20.4 (CH2), 25.3
(1), 327 (2), 281 (8), 241 (13); HRMS-FAB calcd for C30H40
-
J . Org. Chem, Vol. 68, No. 11, 2003 4429

Prange´ et al.
(CH3), 27.6 (CH3), 27.7 (CH3), 31.6 (CH2), 35.1 (CH2), 44.2 (C),
44.3 (CH), 72.4 (C), 77.6 (CH2), 81.1 (C), 88.4 (C), 112.3 (CH2),
140.8 (CH); MS m/z (rel intensity) 254 (M+, 8), 236 (3), 218
(11), 203 (15), 165 (30), 151 (26), 137 (15), 123 (100); HRMS
calcd for C15H26O3 254.1882, found 254.1971. Anal. Calcd for
C15H26O3: C, 70.83; H, 10.30. Found: C, 70.95; H, 10.23. Iodine
32: Rf 0.30 (hexanes-EtOAc, 7:3); IR (film) 3443, 2929, 1470,
(benzene-EtOAc, 8:2) to afford compound 35 (1.5 mg, 0.0037
mmol, 75%).
Acid -Ca ta lyzed Isom er iza tion of (3R,4R,5R)-1,4:3,5-
Diep oxy-2-p h en ylsela n yl-1,2-secoeu d esm a n -11-ol (34). To
a solution of pure 34 (1.6 mg, 0.004 mmol) in CH2Cl2 (0.15
mL) was added p-TsOH (2 mg, 0.01 mmol). The reaction
mixture was stirred at room temperature for 7.5 h, poured into
a saturated aqueous solution of NaHCO3, and extracted with
CH2Cl2. After this time the equilibrium ratio of 35/34 in the
crude reaction mixture was determined to be 70/30 by 1H
NMR.
1
1026, 956 cm-1; H NMR (500 MHz) δ 0.98 (3H, s), 1.20 (6H,
s), 1.43 (3H, s), 2.06 (1H, ddd, J ) 13.4, 3.4, 1.9 Hz), 3.23 (1H,
dd, J ) 10.0, 8.6 Hz), 3.27 (1H, dd, J ) 10.3, 6.4 Hz), 3.66
(1H, d, J ) 8.6 Hz), 3.94 (1H, d, J ) 9.0 Hz), 4.46 (1H, dd, J
) 8.6, 6.2 Hz); 13C NMR (100.6 MHz) δ 5.4 (CH2), 13.4 (CH3),
15.2 (CH3), 21.6 (CH2), 26.8 (CH3), 27.1 (CH3), 31.2 (CH2), 34.3
(CH2), 43.3 (C), 46.9 (CH), 72.3 (C), 76.9 (CH2), 84.4 (CH), 86.3
(C), 95.0 (C); MS-FAB m/z (rel intensity) 382 (M+ + 2, 8), 369
(3), 313 (11), 154 (15), 136 (30), 109 (26); HRMS-FAB calcd
(3S ,4S ,5R )-1,4:2,5-Die p oxy-3-p h e n ylse la n yl-1,2-se c-
oeu d esm a n -11-yl Aceta te (36). To a solution of compound
35 (6.6 mg, 0.016 mmol) in pyridine (0.07 mL) were added
4-(dimethylamino)pyridine (1 mg, 0.008 mmol) and acetic
anhydride (24.5 mg, 0.24 mmol). The reaction mixture was
stirred at 40 °C for 24 h, poured into a saturated aqueous
solution of NaHSO4, and extracted with EtOAc. The organic
extract was washed with a saturated aqueous solution of
NaHCO3 and brine and concentrated under reduced pressure.
The residue was purified by Chromatotron chromatography
(hexanes-EtOAc, 8:2) to give compound 36 (4.3 mg, 0.0095
mmol, 60%): Rf 0.70 (hexanes-EtOAc, 7:3); [R]D +40 (c 0.77);
for C15H27IO3 382.1005, found 382.0993. Anal. Calcd for C15H25
IO3: C, 47.38; H, 6.63. Found: C, 47.51; H. 6.47.
-
(3R,4R,5R)-1,4:3,5-Die p oxy-2-p h e n ylse la n yl-1,2-se c-
oeu d esm a n -11-ol (34) a n d (3S,4S,5R)-1,4:2,5-Diep oxy-3-
p h en ylsela n yl-1,2-secoeu d esm a n -11-ol (35). Met h od A:
To a solution of compound 33 (10 mg, 0.04 mmol) and p-TsOH
(3.8 mg, 0.02 mmol) in CH2Cl2 (0.74 mL) was added dropwise
a solution of N-(phenylseleno)phthalimide (18.1 mg, 0.06
mmol) in CH2Cl2 (0.36 mL) for 15 min. The reaction mixture
was stirred at room temperature for 2 h and 20 min under
inert atmosphere, poured into a saturated aqueous solution
of NaHCO3, and extracted with CH2Cl2. The organic extracts
were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by a short
chromatography column (hexanes) for elimination of the
(PhSe)2 and then by Chromatotron chromatography (benzene-
EtOAc, 85:15) to give compound 34 (8.3 mg, 0.02 mmol, 51%)
and compound 35 (3.6 mg, 0.0088 mmol, 22%). Compound 34:
Rf 0.20 (benzene-EtOAc, 8:2); [R]D +78 (c 1.5); IR (film) 3444,
3057, 2929, 1732, 1580, 1479, 1384, 1260, 1022, 957 cm-1; 1H
NMR (500 MHz) δ 0.94 (3H, s), 1.17 (3H, s), 1.18 (3H, s), 1.38
(3H, s), 3.06 (1H, d, J ) 7.3 Hz), 3.60 (1H, d, J ) 8.6 Hz), 3.89
(1H, d, J ) 8.6 Hz), 4.31 (1H, dd, J ) 7.3, 7.3 Hz), 7.23 (3H,
m), 7.51 (2H, m); 13C NMR (50.3 MHz) δ 13.3 (CH3), 15.4 (CH3),
21.6 (CH2), 26.9 (2 × CH3), 30.8 (CH2), 31.2 (CH2), 34.2 (CH2),
43.3 (C), 46.8 (CH), 72.2 (C), 76.7 (CH2), 82.9 (CH), 86.8 (C),
95.0 (C), 127.2 (CH), 129.1 (2 × CH), 132.4 (C), 133.2 (2 ×
CH); MS m/z (rel intensity) 410 (M+, 1), 392 (2), 235 (4), 210
1
IR (film) 2927, 1728, 1580, 1470, 1368, 1258, 1130 cm-1; H
NMR (500 MHz) δ 1.02 (3H, s), 1.39 (3H, s), 1.42 (3H, s), 1.63
(3H, s), 1.94 (3H, s), 3.41 (1H, dd, J ) 11.4, 8.1 Hz), 3.56 (1H,
d, J ) 8.5 Hz), 3.59 (1H, d, J ) 8.5 Hz), 3.80 (1H, dd, J )
11.4, 9.0 Hz), 4.18 (1H, dd, J ) 8.6, 8.5 Hz), 7.24 (3H, m), 7.53
(2H, m); 13C NMR (50.3 MHz) δ 16.4 (CH3), 21.1 (CH2), 22.4
(CH3), 22.7 (CH3), 23.1 (CH3), 23.4 (C), 31.1 (CH2), 35.0 (CH2),
42.5 (CH), 46.6 (C), 56.1 (CH), 73.6 (CH2), 80.3 (CH2), 84.1 (C),
91.8 (C), 92.4 (C), 127.3 (CH), 129.8 (C), 129.1 (2 × CH), 133.8
(2 × CH), 170.4 (C); MS m/z (rel intensity) 452 (M+, 57), 392
(7), 295 (5), 235 (14), 184 (100); HRMS calcd for C23H32O480Se
452.1466, found 452.1458. Anal. Calcd for C23H32O4Se: C,
61.19; H, 7.14. Found: C, 61.01; H, 7.52.
P h ytu ber in [(4R,5R)-1,4:2,5-Diep oxy-1,2-secoeu d esm -
2-en -11-yl Aceta te] (1). A solution of compound 36 (4 mg,
0.009 mmol) in CH2Cl2 (1.3 mL) was cooled to -78 °C, and
ozone was bubbled through it until the solution turned light
blue. Then nitrogen was bubbled through the solution to expel
excess ozone, the mixture was allowed to warm to room
temperature, and pyridine (7.1 mg, 0.09 mmol) was added.
This mixture was then added dropwise to preheated (60 °C)
carbon tetrachloride, and the solution was refluxed for 1.5 h.
The solution was washed consecutively with saturated aqueous
solutions of NaHSO4, NaHCO3, and brine. The organic extracts
were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by a short chromatography
column (benzene-EtOAc, 95:5) to afford phytuberin (1) (1.6
mg, 0.0054 mmol, 62%): Rf 0.35 (benzene-EtOAc, 9:1); [R]D
-38.8 (EtOH, c 0.92) {lit.1a [R]D -35.9 (EtOH)}; IR 3080, 2918,
2841, 1731, 1622, 1470, 1369, 1257, 1150, 1037 cm-1; 1H NMR
(500 MHz) δ 1.01 (3H, s), 1.43 (3H, s), 1.46 (3H, s), 1.55 (3H,
s), 1.98 (3H, s), 3.27 (1H, d, J ) 8.5 Hz), 3.38 (1H, d, J ) 8.5
Hz), 4.67 (1H, d, J ) 2.7 Hz), 6.43 (1H, d, J ) 2.7 Hz); 13C
NMR (50.3 MHz) δ 16.6 (CH3), 21.5 (CH2), 21.6 (CH3), 22.4
(CH3), 23.1 (CH3), 23.5 (CH3), 28.9 (CH2), 34.5 (CH2), 43.8 (CH),
45.1 (C), 73.7 (CH2), 84.1 (C), 93.3 (C), 94.8 (C), 104.7 (CH),
146.7 (CH), 170.3 (C); MS m/z (rel intensity) 294 (M+, 25), 249
(6), 235 (16), 219 (7), 205 (100); HRMS calcd for C17H26O4
294.1831, found 294.1785. Anal. Calcd for C17H26O4: C, 69.36;
H, 8.90. Found: C, 69.42; H, 9.03.
(83), 192 (89), 177 (100); HRMS calcd for
C
21H30O380Se
410.1360, found 410.1335. Anal. Calcd for C21H30O3Se: C,
61.61; H, 7.39. Found: C, 61.79; H, 7.54. Compound 35: Rf
0.25 (benzene-EtOAc, 8:2); [R]D +33.4 (c 0.38); IR (film) 3452,
3060, 2928, 1732, 1580, 1470, 1379, 1263, 1047 cm-1; 1H NMR
(500 MHz) δ 1.02 (3H, s), 1.15 (3H, s), 1.16 (3H, s), 1.63 (3H,
s), 3.41 (1H, dd, J ) 11.4, 8.0 Hz), 3.56 (1H, d, J ) 8.5 Hz),
3.59 (1H, d, J ) 8.4 Hz), 3.78 (1H, dd, J ) 11.4, 8.9 Hz), 4.18
(1H, dd, J ) 8.7, 8.4 Hz), 7.23 (3H, m), 7.51 (2H, m); 13C NMR
(50.3 MHz) δ 16.5 (CH3), 21.2 (CH2), 22.9 (CH3), 26.8 (CH3),
27.1 (CH3), 31.6 (CH2), 35.2 (CH2), 44.9 (CH), 46.5 (C), 56.1
(CH), 72.4 (C), 73.5 (CH2), 80.4 (CH2), 91.9 (C), 92.4 (C), 127.2
(CH), 129.1 (2 × CH), 129.9 (C), 133.7 (2 × CH); MS m/z (rel
intensity) 410 (M+, 9), 392 (18), 235 (9), 184 (100); HRMS calcd
for C21H30O380Se 410.1360, found 410.1354. Anal. Calcd for
C
21H30O3Se: C, 61.61; H, 7.39. Found: C, 61.75; H, 7.13.
Meth od B: To a solution of compound 34 (2 mg, 0.005 mmol)
and p-TsOH (1 mg, 0.005 mmol) in CH2Cl2 (0.16 mL) was
added dropwise a solution of N-(phenylseleno)phthalimide (4.5
mg, 0.015 mmol) in CH2Cl2 (0.09 mL) for 5 min. The reaction
mixture was stirred at room temperature for 6.5 h under inert
atmosphere, poured into a saturated aqueous solution of
NaHCO3, and extracted with CH2Cl2. The organic extracts
were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by a short
chromatography column (hexanes) for elimination of (PhSe)2
and this was followed by Chromatotron chromatography
(2R,3S,4R,5R)-1,4:2,5-Diep oxy-3-h yd r oxy-2-m et h oxy-
1,2-secoeu d esm a n -11-yl Aceta te (37). To a solution of
phytuberin (1) (10 mg, 0.034 mmol) in CH2Cl2 (0.34 mL) cooled
to -17 °C was added, under a nitrogen atmosphere, a solution
of dimethyldioxirane (0.5 mL, 0.04 mmol, 0.08 M) in acetone
and the mixture was stirred for 30 min. Then an excess of
anhydrous MeOH (0.34 mL) was added and stirring was
continued for 1 h at this temperature. The concentration under
reduced pressure gave a residue that was purified by Chro-
4430 J . Org. Chem., Vol. 68, No. 11, 2003

Synthesis of Phytuberin
matotron chromatography (hexanes-EtOAc, 6:4) to give meth-
oxy alcohol 37 (5.3 mg, 0.015 mmol, 46%): Rf 0.30 (hexanes-
2.28 (1H, dddd, J ) 12.9, 12.9, 3.8, 3.8 Hz), 3.41 (1H, d, J )
8.3 Hz), 3.56 (1H, d, J ) 8.3 Hz), 3.62 (1H, d, J ) 3.0 Hz),
3.86 (1H, d, J ) 13.0 Hz), 4.06 (1H, d, J ) 13.0 Hz), 4.52 (1H,
d, J ) 3.0 Hz), 7.3 (5H, m); major product 13C NMR (125.7
MHz) δ 16.6 (CH3), 21.1 (CH2), 21.2 (CH3), 22.5 (CH3), 23.3
(CH3), 23.4 (CH3), 30.9 (CH2), 34.8 (CH2), 42.6 (CH), 46.0 (C),
50.4 (CH2), 79.1 (CH2), 81.1 (CH), 84.4 (C), 89.6 (CH), 90.8 (C),
92.4 (C), 127.2 (CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 128.5
(CH), 139.4 (C), 170.5 (C); MS m/z (rel intensity) 417 (M+, 3),
EtOAc, 1:1); IR (film) 3443, 2848, 1732, 1471, 1372, 1258 cm-1
;
1H NMR (500 MHz) δ 1.06 (3H, s), 1.41 (3H, s), 1.45 (3H, s),
1.51 (3H, s), 1.97 (3H, s), 2.28 (1H, dddd, J ) 3.8, 3.8, 13.1,
13.1 Hz), 3.41 (3H, s), 3.50 (1H, d, J ) 7.7 Hz), 3.86 (1H, d, J
) 7.7 Hz), 3.94 (1H, s), 4.83 (1H, s); 13C NMR (125.7 MHz) δ
14.1 (CH3), 16.9 (CH3), 20.8 (CH3), 22.7 (CH3), 23.5 (CH3), 24.7
(CH2), 31.2 (CH2), 34.5 (CH2), 42.5 (CH), 44.7 (C), 55.8 (CH3),
78.2 (CH2), 84.4 (C), 85.6 (CH), 91.9 (C), 95.6 (C), 109.0 (CH),
170.3 (C); MS m/z (rel intensity) 311 (M+ - OMe, 6), 284 (16),
269 (11), 252 (18), 221 (32), 192 (39); HRMS calcd for C17H27O5
311.1858, found 311.1906. Anal. Calcd for C18H30O6: C, 63.14;
H, 8.83. Found: C, 63.27; H, 8.93.
(2S,3S,4R,5R)-1,4:2,5-Diepoxy-3-h ydr oxy-2-ben zylam in o-
1,2-secoeu d esm a n -11-yl Aceta te (38). A solution of phytu-
berin (1) (11 mg, 0.038 mmol) in CH2Cl2 (0.38 mL) cooled to
-17 °C was treated with dimethyldioxirane (0.5 mL, 0.04
mmol, 0.08 M) analogously to the case of 37. Then anhydrous
benzylamine (0.4 mL) was added and the mixture was allowed
to warm to room temperature over the course of 6 h and
stirring was continued at this temperature for a further 17 h.
The reaction mixture was then poured into a saturated
aqueous solution of NaHSO4 and extracted with CH2Cl2. The
organic layer was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by Chromatotron chromatography (hexanes-EtOAc, 4:6) to
give amine alcohol 38 (8.4 mg, 0.02 mmol, 53%) as an
inseparable mixture (86:14) of two stereoisomers: Rf 0.28
(hexanes-EtOAc, 1:1); IR (film) 3418, 2930, 1732, 1471, 1456,
1372, 1258 cm-1; major product 1H NMR (500 MHz) δ 1.03
(3H, s), 1.42 (3H, s), 1.45 (3H, s), 1.54 (3H, s), 1.98 (3H, s),
400 (23), 252 (15), 222 (22), 205 (100); HRMS calcd for C24H35
-
NO5 417.2515, found 417.2570. Anal. Calcd for C24H35NO5: C,
69.04; H, 8.45; N, 3.35. Found: C, 69.23; H, 8.37; N, 3.41.
Ack n ow led gm en t. This work was supported by the
Investigation Programmes no. BQU2000-0650 and
BQU2001-1665 of the Direccio´n General de Investiga-
cio´n Cient´ıfica y Te´cnica, Spain. The inocolum of Er-
winia carotovora var. carotorova (CECT 225T) was
provided by the Coleccio´n Espan˜ola de Cultivos Tipo.
The authors thank Dr. Laila Moujir, Departamento de
Microbiolog´ıa y Biolog´ıa Celular, University of La La-
guna for help in the infection of the potato tubers.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures and spectral and analytical data for com-
pounds 15-26; isolation of phytuberin from potato tubers
inoculated with E. carotovora var. carotovora; tables of X-ray
crystallographic data for compound 14. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O034129D
J . Org. Chem, Vol. 68, No. 11, 2003 4431