Diastereoselective total synthesis of (+)-13-stemarene by fourth generation methods: A formal total synthesis of (+)-18-deoxystemarin

Article abstract of DOI:10.1021/jo200945s

The problem of constructing diastereoselectively the C/D ring system of stemarane diterpenes from a bicyclo[2.2.2]octane intermediate was solved resulting in very simple synthesis of (+)-13-stemarene 1. The obtaining of the latter represents also a formal synthesis of (+)-18-deoxystemarin 2. In the key step, the epimeric mixture 10, dissolved in toluene, was converted by the action of TsOH into (+)-stemar-13-en-15-one 28.

Full text of DOI:10.1021/jo200945s

NOTE
pubs.acs.org/joc
Diastereoselective Total Synthesis of (+)-13-Stemarene by Fourth
Generation Methods: A Formal Total Synthesis of (+)-18-
Deoxystemarin§
Francesca Leonelli, Federico Blesi, Paolo Dirito, Andrea Trombetta, Francesca Ceccacci, Angela La Bella,
Luisa M. Migneco, and Rinaldo Marini Bettolo*
Dipartimento di Chimica, Universitꢀa degli Studi di Roma “La Sapienza”, P.le Aldo Moro, 5, I-00185 Roma, Italy
S Supporting Information
b
ABSTRACT: The problem of constructing diastereoselectively the C/D ring system of
stemarane diterpenes from a bicyclo[2.2.2]octane intermediate was solved resulting in very
simple synthesis of (+)-13-stemarene 1. The obtaining of the latter represents also a formal
synthesis of (+)-18-deoxystemarin 2. In the key step, the epimeric mixture 10, dissolved in
toluene, was converted by the action of TsOH into (+)-stemar-13-en-15-one 28.
temarane diterpenes, characterized by the presence of a
unique bicyclo[3.2.1]octane C/D ring system within the tetra-
Thus, we developed a procedure for the conversion of known
10a,27 the major product of the above-mentioned aldol reaction,
into 12a and applied it to the synthesis of (+)-1 and (+)-2 via 13
(Scheme 2).9 We also described the preparation of key 10b from
the corresponding acetate 12b by methanolysis in the presence of
CH3ONa/La(OTf)3 (Scheme 2).28
More recently, we explored an approach based on the
equilibration with TsOH in benzene at reflux of the ethylene
dithioacetal epimeric mixture 14 (Scheme 3). A 6:4 equilibrium
distribution in favor of the exo epimer 14b, a precursor of key
bicyclo[2.2.2]octan-2-ol 13, was recorded. Epimers 14 were sepa-
rated and the minor endo epimer 14a was re-equilibrated. After
three cycles, 14b was obtained in a 92% diastereoisomeric excess.
Raney-Ni reduction of the latter gave then 13, already converted
into (+)-1 and (+)-2.29
S
cyclic skeleton, were isolated in Central and South America from
plants of the genus of Stemodia1 and Calceolaria,2À5 respectively.
Stemarane diterpenes were also isolated in Japan from Oryza sativa,
the plant of rice, which produces them in response to the invasion of
the fungus Pyricularia oryzae or when exposed to UV radiation or
heavy metals.6,7 Finally, stemarane diterpenes were isolated from the
fungus Phoma betae.8 (+)-13-Stemarene 18À10 and (+)-18-deox-
ystemarin 29 are the simplest compounds in the stemarane family.
Previously, an analogous approach starting from a 8(9)-podo-
carpen-14-one intermediate had been also explored, but the
difficulties arisen in its conversion into the target compound
forced us to abandon it.30À32
We wish now to present a new, general, and much simpler
solution for the construction of stemarane diterpenes C/D ring
system based on the existing endo/exo equilibrium under acidic
conditions between 6-hydroxy-1-methyl-bicyclo[2.2.2]octan-2-
ones (Scheme 1) and the acid catalyzed rearrangement of 6-
exo-hydroxy-1-methyl-bicyclo[2.2.2]octan-2-ones to 4-methyl-
bicyclo[3.2.1]oct-3-en-6-one.
The rearrangement of 6-hydroxy-1-methyl-bicyclo[2.2.2]-
octan-2-one 15 to 4-methyl-bicyclo[3.2.1]oct-3-en-6-one33 16
had been described some years ago by Srikrishna and co-
workers in the frame of a study on the reactivity of isotwistanes
(Scheme 4),34 but it was never applied to the synthesis of
stemarane diterpenes.
The first synthesis of a stemarane diterpene was reported in
1980 by Kelly and co-workers11 who prepared stemarin (()-31
from racemic podocarp-9(11)-en-12-one 4 by the Wiesner photo-
chemical method12 and by rearrangement12À23 (Scheme 1) of
tosylate 8 obtained from 6-exo-hydroxy-1-methyl-bicyclo[2.2.2]
octan-2-one 6b via bicyclo[2.2.2]octan-2-ol 7. Given that 6b was
obtained as minor product of the intramolecular aldol condensa-
tion of 3-(2-oxoethyl)-cyclohexanone 5,24,25 the above-mentioned
synthesis suffered from an inefficient nondiastereoselective step.
Thus, after having achieved by the same tools (i.e., the Wiesner
photochemical method and the bicyclo[2.2.2]octane f bicyclo-
[3.2.1]octane rearrangement) the synthesis of aphidicolin and
stemodane diterpenoids,19À22,26 a diastereoselective route to
the stemarane C/D ring system from a 6-hydroxy-1-methyl-
bicyclo[2.2.2]octan-2-one intermediate represented a synthetic
challenge to us.
Received: May 19, 2011
Published: July 04, 2011
r
2011 American Chemical Society
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|

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NOTE
Scheme 1. R. B. Kelly’s and Co-Workers’ (()-Stemarin (3) Total Synthesis
Scheme 2. Synthesis of (+)-13-Stemarene (1) and (+)-18-Deoxystemarin (2) by Inversion of the HO-C(12) Configuration
Scheme 3. Synthesis of (+)-13-Stemarene (1) and (+)-18-
Deoxystemarin (2): Acid Catalyzed Equilibration of Ethylene
Dithioacetals 14
Scheme 5. Mechanistic Hypothesis for Conversion of 17
into 18
Scheme 4. The 6-Hydroxy-1-methyl-bicyclo[2.2.2]octan-2-
one 15 f 4-Methyl-bicyclo[3.2.1]oct-3-en-6-one 16 Rear-
rangement As Proposed by Srikrishna et al.34
experimental conditions on known 17,28 available in seven steps
from 2-methoxytetralin.
Best results were obtained when the epimeric mixture 17
dissolved in toluene was heated at 85 °C for 2 days in the
presence of TsOH. The rearranged compound 18 was obtained
cleanly as the only product (Scheme 5).
The role of the bridgehead methyl in stabilizing the carboca-
tion resulting from the rearrangement was confirmed by the fact
Since no experimental details were available in the literature,34
before moving to the target compound, we adjusted the
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that when the same experimental conditions were applied to
present; the regiochemistry of the addition follows from the
chemical shift of the HÀC(11) which, being adjacent to both a
double bond and a carbonyl function, is deshielded of about 1
ppm as compared to the H2ÀC(13). Previously the regio- and
stereochemistry of the addition had been established by the
obtaining of the final compound.19,27 Photoadduct (+)-23 was
then exposed to NaHMDS in THF at À78 °C. Upon addition of
CH3I in the presence of HMPA, the methylated photoadduct 24
was obtained. This methodology allowed us to shorten the
previous procedure by two steps.9,27 Compound 24 was con-
verted into the acetal 25 and the exocyclic methylene cleaved
with OsO4/NaIO4 to give the cyclobutanone 26. Compounds
24À26 are mixtures of epimers at C(13). This stereochemical
inhomogeneity is of no consequence since it will disappear when
the bicyclo[2.2.2]octane system will be formed.
NaBH4 reduction of 26 afforded then the cyclobutanol 27
which was used in the next step without purification. Thus treat-
ment of 27 with a 2:1 THF/2 N HCl mixture caused deprotection
of the carbonyl function unveiling an aldol system which under-
wenta retroaldolÀaldol reaction giving 10 asan about 80:20 endo/
exo epimeric mixture.9,27 This equilibrium distribution is due to an
unfavorable 1,3 boat-axial interaction experimented in the exo
epimer by the pseudo-axially oriented hydroxy group.25
known 1935 no reaction occurred.
On the basis of the stereoelectronic requirements of the
bicyclo[2.2.2]octane f bicyclo[3.2.1]octane rearrangement12À23
and on the endo/exo 6-hydroxybicyclo[2.2.2]octan-2-one equilib-
rium, under the reaction conditions adopted, we propose for the
rearrangement the rationale described in Scheme 5, where the
protonated exo hydroxyl acts as the leaving group and the acyl
group migration occurs from the anti side. The endo epimer does
not undergo rearrangement because the carbonyl function at C(2)
prevents the development of a positive charge on the adjacent
bridged carbon.
After completing the model work, we then turned to the
synthesis of (+)-13-stemarene 1 (Scheme 6). Our starting
material was (À)-podocarp-9(11)-en-12-one 22, the only pro-
duct of a vinilogous equilibrium at C(8).36 Compound (À)-22 is
available either from podocarpic acid 2037 or from (S)-5,
8a-dimethyl-3,4,8,8a-tetrahydronaphtalene-1,6(2H,7H)-dione
21.38
Since the intermediate characterizations of the synthesis of 10
from (À)-22 were not fully described in the past,9,19,27 we report
also the experimental related to this section of the synthesis.
Thus, the mixture 10 was dissolved in toluene and heated at
85 °C in the presence of TsOH. Unlike the model compound,
after 24 h, the rearrangement of 10 to (+)-28 was complete.
Photoaddition of allene to (À)-22 in THF at À78 °C gave
quantitatively the photoadduct 23. The stereochemistry of the
newly formed ring was established by NOESY experiments in
which a cross-peak between the HÀC(11) and CH3ÀC(10) is
Thioacetalization of (+)-28 with ethanedithiol and BF3 Et2O
3
at rt afforded then (+)-29 which was transformed by the action of
Raney-Ni in EtOH at 60 °C into (+)-1. Previous attempts to
Scheme 6. Regio- and Diastereoselective Synthesis of (+)-1 and (+)-2 from (À)-22 by the 6-Hydroxy-1-methyl-bicyclo-
[2.2.2]octan-2-one f 4-Methylbicyclo[3.2.1]oct-3-en-6-one Rearrangement
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NOTE
perform the deoxygenation of (+)-28 via the corresponding
hydrazone or tosylhydrazone were unsuccessful.
Compound (+)-1 was identical to the compound previously
prepared by us through the longer route.9 Having (+)-1 been
previously converted into (+)-2, its obtainment represents also a
formal diastereoselective total synthesis of the latter.
Preparation of (+)-23 from (À)-22. A Pyrex vessel containing a
solution of (À)-9(11)podocarpen-12-one (À)-22 (2.0 g, 8.1 mmol) in
THF (25 mL) was cooled at À78 °C and an excess of allene was
condensed. The solution was irradiated under Ar at À78 °C with a 500
W mercury vapor lamp until the TLC (Et2O/n-hexane = 4/6, Rf 23 > Rf
22) showed the disappearance of the starting material (≈4 h). The solu-
tionwas allowed to warm-upslowly tort and thesolventevaporatedunder
reduced pressure. The residue was purifiedbySiO2 CC(Et2O/n-hexane =
1/9) to give (+)-23 (1.8 g, 6.3 mmol) as a white solid. Yield: 78%. Mp
(EtOH/H2O = 96/4) 84.0À86.3 °C. [R]D = +30.6 (CHCl3, c = 2.3); IR
(CCl4): 1699; 1H NMR (CDCl3): 4.89 (sextet, J = 2.6, 2H), 3.51À3.40
(m, 1H), 2.80 (dt, Jt = 2.6, Jd = 17.5, 1H), 2.65À2.49 (overlapped
multiplets, 2 H), 2.15 (dddd, Jd = 1.0, Jd = 7.5, Jd = 11.4, Jd = 19.0, 1H),
1.98À1.02 (overlapped multiplets, 13H), 0.97À0.86 (m, 1H), 0.84
(s, 3H), 0.83 (s, 3H), 0.79 (s, 3H). 13C NMR (CDCl3): 211.6, 141.1,
109.5, 55.5, 49.6, 46.4, 42.3, 39.1, 38.5, 36.5, 33.19, 33.16, 31.7, 31.4, 28.7,
25.3, 22.0, 21.2, 18.5, 15.9. GC-MS: 286 (M+, 6), 271 (26), 253 (15), 243
(12), 229(12), 215 (13), 211 (11), 201 (9), 189 (43), 173 (36), 161 (30),
145 (37), 133 (40), 119 (50), 105 (67), 91 (82), 83 (55), 69 (57), 55
(100). HPLC: column, Nucleosil; eluent, AcOEt/n-hexane 5/95, tR = 8.0,
purity 99%.
Preparation of 24 from (+)-23. A solution of sodium bis-
(trimethylsilyl)amide (NaHMDS, 5.5 mL, 1 M in THF, 5.5 mmol)
was added at À78 °C to a solution of (+)-23 (1.5 g, 5.2 mmol) in THF
(185 mL). After 1 h at the same temperature, the resulting sodium
enolate was added to a solution of CH3I (0.65 mL, 10 mmol) in
hexamethylphosphoramide (HMPA, 2.8 mL, 16 mmol). The solution
was stirred at À78 °C until the TLC (Et2O/n-hexane = 3/7) showed the
disappearance of the starting material (≈ 3 h). The reaction mixture was
allowed to warm to rt, and after neutralization with 2 N HCl, the solution
was diluted with Et2O, washed with brine, and dried over anhydrous
Na2SO4. The organic phase was then filtered and evaporated to dryness
under reduced pressure. The residue was purified by SiO2 CC (Et2O/
n-hexane = 10/90) to give 24 as a C-(13) diastereoisomeric mixture of
24a and 24b (1.4 g, 4.7 mmol, 24a/24b = 74:26; Rf 24a > Rf 24b). Yield:
90%. The mixture of the two diastereoisomers was purified by semi-
preparative HPLC (column, Nucleodur; eluent, AcOEt/n-hexane 1:99).
(+)-24a: Mp (EtOH/H2O = 96/4) 86.1À87.6 °C. [R]D = +37.0
(n-hexane c = 2.4); IR (CCl4): 1697; 1H NMR (C6D6): 4.90 (dt, Jd =
2.6, Jt = 2.7, 1H), 4.80 (dt, Jd = 2.6, Jt = 2.5, 1H), 3.65À3.52 (m, 1 H),
2.67À2.47 (m, 2H), 2.42À2.26 (m, 1H), 1.99 (td, Jt= 8.4, Jd = 13.5, 1H),
1.61 (tt, J = 3.3, J = 12.7, 1H), 1.52À0.84 (overlapped multiplets, 14 H),
0.79 (s, 3H), 0.71 (s, 3H), 0.68 (s, 3H), 0.67À0.65 (m, 1H). 13C NMR
(CDCl3): 212.5, 142.4, 109.2, 55.9, 51.1, 46.5, 42.4, 39.4, 39.2, 34.3, 33.2,
33.1, 32.6, 31.7, 30.9, 28.9, 22.0, 21.3, 18.7, 17.6, 15.5. GC-MS: 300 (M+,
6), 285 (15), 267 (10), 257 (16), 243 (11), 229 (10), 215 (15), 201 (11),
189 (96), 176 (28), 161 (47), 147 (35), 133 (53), 119 (58), 105 (73), 91
(97), 81 (63), 69 (75), 55 (100). HPLC: analytical column, Nucleodur;
eluent, AcOEt/n-hexane 1/99, tR = 9.8, purity 100%. (À)-24b: Mp
(EtOH/H2O = 96/4) 82.4À83.4 °C. [R]D = À10.5 (n-hexane, c = 3.0);
IR (CCl4): 1697; 1H NMR (C6D6): 5.06 (q, J = 2.8, 1H), 4.81 (dt, Jd =
In conclusion, a simple and efficient synthesis of (+)-1 from 10
was achieved. This approach is remarkable in that, owing to the
stereospecificity of the rearrangement and to the 6-hydroxy-1-
methyl-bicyclo[2.2.2]octan-2-ones endo/exo equilibrium, the
whole 6-hydroxy-1-methyl-bicyclo[2.2.2]octan-2-ones endo/exo
mixture is converted into the rearrangement product in which is
also present the C(13)ÀC(14) double bond, a typical feature of
some stemarane diterpenoids and a necessary tool for the
introduction of the R configurated HO-C(13) when needed.
The approach to stemarane diterpenes via a 9(11)-podocar-
pen-12-one meets now all selectivity criteria. Besides, the corre-
lation between the individual synthetic operations was brought
to a maximum, ensuring high efficiency to the whole process.
Experiments are now in progress in our laboratory to extend
this approach to the synthesis of more complex stemarin 3,1
2-deoxyoryzalexin S 302 and oryzalexin S 31.6,7
’ EXPERIMENTAL SECTION
General. All solvents were analytical grade. TLC: silica gel 60 F254
.
Column Chromatography (CC): silica gel 60, 70À230 mesh ASTM. Mp
uncorrected. IR Spectra: in cmÀ1. 1H and 13C NMR (compounds 18,
23À29): at 300.13 and 75.48 MHz, respectively; δ in ppm relative to the
residual solvent peak of C6D6 at 7.15 and 128.02 ppm and CDCl3 at 7.26
and 77.0 ppm for 1H and 13C, respectively; 1H and 13C NMR
(compound 1): at 400.13 and 100.61 MHz, respectively; J in Hz. HPLC
analysis: RID detector; analytical columns: EC 250/4 Nucleosil 100-5;
EC 250/4 Nucleodur 100-5; EC 250/4 Nucleosil 100-5 C18; flow rate of
0.8 mL/min; semipreparative column: VP 250/10 Nucleodur 100-5;
flow rate of 6 mL/min; tR in min. TsOH was monohydrate.
Preparation of 18 from 17. A solution of 17 (68 mg; 0.33 mmol)
and TsOH (62 mg, 0.33 mmol) in toluene (17 mL) was heated at 85 °C
until TLC (Et2O/n-hexane = 4/6, Rf 17 < Rf 18) showed the
disappearance of the starting material (≈ 48 h). After cooling to rt,
the whole was diluted with Et2O, washed with a saturated NaHCO3
aqueous solution and finally with brine. After drying over anhydrous
Na2SO4, the organic phase was filtered and evaporated to dryness under
reduced pressure. The residuewas purified bySiO2 CC (Et2O/n-hexane =
1/99) to give 18 (37 mg, 0.56 mmol) as an oil. Yield: 60%. IR (CHCl3):
2.9, Jt = 2.4, 1H), 3.60À3.47 (m, 1 H), 2.50 (A of ABX2, JAB = 17.4, JAX
=
2.6, 1H), 2.30 (B of ABMX2, JAB = 17.4, JBX = 2.7, JBM = 3.1, 1H)
1.99À1.80 (m, 1H), 1.59À0.85 (overlapped multiplets, 16H), 0.81
(s, 3H), 0.77À0.70 (overlapped multiplets, 4H), 0.64 (s, 3H). 13C NMR
(C6D6): 210.1, 141.6, 109.2, 55.1, 49.4, 46.5, 45.5, 42.4, 39.0, 36.7, 34.1,
33.2, 33.1, 31.7, 31.6, 28.7, 22.2, 21.3, 19.2, 18.7, 15.9. GC-MS: 300 (M+,
2), 285 (16), 267 (5), 257 (10), 244 (8), 229 (9), 215 (14), 201 (8), 189
(100), 173 (24), 161 (33), 145 (29), 133 (41), 119 (45), 105 (53), 91
(78), 81 (43), 69 (61), 55 (76). HPLC: analytical column, Nucleodur;
eluent, AcOEt/n-hexane 1/99, tR = 13.0, purity 100%.
1
1732; H NMR (CDCl3): 5.26À5.41 (m, 1H), 2.62 (pd, J = 4.0, 1H),
1.92À2.22 (overlapped multiplets, 3H), 1.48À1.89 (overlapped multi-
plets, 9H), 1.04À1.45 (overlapped multiplets, 4H); 13C NMR (CDCl3):
210.5, 131.6, 128.3, 55.1, 51.6, 45.4, 39.4, 38.0, 32.1, 31.3, 26.4, 22.7, 22.0;
MS: m/z = 190 (M+, 21), 148 (45), 131(24), 119 (20), 105 (100%), 91
(68), 77 (30), 65 (19); HRMS: calcd. for C13H18O [M + Na]+: 213.1255;
found 213.1261.
Preparation of 25 from 24. A solution of 24 (1.4 g, 4.7 mmol),
ethane-1,2-diol (15 mL, 0.27 mol), and TsOH (45 mg, 0.24 mmol) in
benzene (0.20 L) was placed into a two-neck flask fitted with a
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DeanÀStark apparatus, a condenser, and a CaCl2 tube. The mixture was
then heated to reflux until the TLC (Et2O/n-hexane = 1/9) showed the
disappearance of the starting material (≈24 h). After cooling to rt, the
mixture was poured into a separatory funnel, diluted with Et2O and
washed with a saturated NaHCO3 solution, and dried over anhydrous
Na2SO4. The organic phase was then filtered and evaporated to dryness
under reduced pressure. The residue was purified by SiO2 CC (Et2O/
n-hexane = 4/96) to give 25 (1.5 g, 4.3 mmol) as a C-(13) diaster-
eoisomeric mixture of 25a and 25b (25a/25b = 32:68; Rf 25a > Rf 25b).
Yield: 91%. The mixture of the two diastereoisomers was purified by
semipreparative HPLC (column, Nucleodur; eluent, AcOEt/n-hexane
0.5:99.5). (À)-25a: Mp (EtOH/H2O = 96/4) 140.4À141.5 °C. [R]D =
86 (66), 79 (11), 69 (25), 55 (22). HPLC: analytical column, Nucleodur;
eluent, AcOEt/n-hexane 10/90, tR = 9.4, purity 100%.
Preparation of 10 from 26. A solution of 26 (1.13 g, 3.3
mmol) in Et2O/MeOH 1:1 (65 mL) was treated with NaBH4 (0.65 g,
17 mmol) at 0 °C. The resulting mixture was stirred until the TLC
(Et2O/n-hexane = 3/7) showed the disappearance of the starting
material (≈15 min). H2O was then added slowly at 0 °C to quench
the excess of NaBH4. After neutralization with 2 N HCl, the solution
was diluted with Et2O, washed with brine, and dried over anhydrous
Na2SO4. The organic phase was then filtered and evaporated to
dryness under reduced pressure to give 27 (1.1 g) which was used as
such in the next step.
1
A solution of the crude 27 (1.1 g) in THF/2 N HCl 4:1 (140 mL) was
refluxed until the TLC (Et2O/n-hexane = 6/4) showed the disappear-
ance of the starting material (≈ 12 h). After cooling to rt, the whole was
diluted with Et2O, washed with a saturated NaHCO3 aqueous solution
and finally with brine. After drying over anhydrous Na2SO4, the organic
phase was filtered and evaporated to dryness under reduced pressure.
The residue was purified by SiO2 CC (AcOEt/n-hexane = 35/65) to give
10 (0.93 g, 3.0 mmol) as a C-(13) diastereoisomeric mixture of 10a and
10b (10a/10b = 80:20; Rf 10a < Rf 10b). Yield: 91%. (+)-10a: Mp
(n-hexane) 145.9À147.0 °C. [R]D = +22.3 (CHCl3, c = 2.0); IR
À47.6 (n-hexane, c = 2.1); H NMR (C6D6): 5.54À5.44 (m, 1H),
5.04À4.95 (m, 1H), 3.59À3.41 (m, 4H), 2.97 (bs, 1H), 2.62À2.38
(m, 2H), 2.20À2.01 (m, 2H), 1.76À1.21 (overlapped multiplets, 13H),
1.12 (s, 3H), 1.10À0.89 (overlapped multiplets, 3H), 0.86 (s, 3H), 0.85
(s, 3H). 13C NMR (C6D6): 144.6, 111.3, 109.5, 64.3, 63.5, 49.0, 47.2,
46.9, 42.6, 39.3, 39.0, 35.7, 33.5, 33.2, 32.4, 32.1, 31.0, 29.2, 22.3, 21.5,
20.4, 19.0, 15.7. GCÀMS: 344 (M+, 9), 329 (4), 205 (9), 113 (100), 105
(7), 100 (11), 91 (11), 73 (15), 69 (16), 55 (14). HPLC: analytical
column, Nucleodur; eluent, AcOEt/n-hexane 1/99, tR = 6.6, purity
100%. (+)-25b: Mp (EtOH/H2O = 96/4) 138.6À140.1 °C. [R]D
=
1
(CHCl3): 1713; H NMR (C6D6): 3.54 (dt, Jt = 3.6, Jd = 9.2, 1H),
+54.3 (n-hexane, c = 2.3); 1H NMR (C6D6): 5.37À5.29 (m, 1H),
5.03À4.95 (m, 1H), 3.65À3.44 (m, 4H), 2.87À2.76 (m, 1H),
2.55À2.32 (m, 3H), 2.24À2.05 (m, 1H), 1.71À1.06 (overlapped
multiplets, 11H), 1.03 (d, J = 6.8, 3H), 0.99 (s, 3H), 0.96À0.87
(m, 1H), 0.86 (s, 3H), 0.83 (s, 3H), 0.83À0.70 (m, 1H). 13C NMR
(C6D6): 146.2, 113.5, 108.8, 65.3, 64.6, 49.5, 48.2, 47.0, 42.6, 39.2, 35.9,
33.5, 33.2, 31.8, 31.3, 30.8, 30.6, 30.2, 22.3, 21.6, 18.9, 15.9, 15.2. GC-
MS: 344 (M+, 12), 329 (6), 205 (10), 113 (100), 105 (6), 100 (12), 91
(11), 79 (6), 73 (15), 69 (17), 55 (13). HPLC: analytical column,
Nucleodur; eluent, AcOEt/n-hexane 1/99, tR = 8.1, purity 100%.
Preparation of 26 from 25. AsolutionofOsO4 (30 mg, 0.12 mmol),
pyridine (0.6 mL), and H2O (12 mL) was treated with a solution of 25
(1.4 g, 4.1 mmol) in THF (60 mL). After stirring in the dark for 10 min, the
solution was treated with a suspension of NaIO4 (7.2 g, 33 mmol) in H2O
(24 mL) and the resulting mixture was stirred in the dark until the TLC
(Et2O/n-hexane = 3/7) showed the disappearance of the starting material
(≈120 h). The suspension was filtered through a Celite pad, and the filtrate
was diluted with Et2O, while the organic phase was washed with H2O, brine
and dried over anhydrous Na2SO4. The organic phase was then filtered and
evaporated to dryness under reduced pressure. The residue was purified by
SiO2 CC (Et2O/n-hexane = 3/7) to give 26 (1.2 g, 3.5 mmol) as a C-(13)
diastereoisomeric mixture of 26a and 26b (26a/26b = 23:77; Rf 26a > Rf
26b). Yield: 85%. (+)-26a: Mp (n-hexane) 166.4À167.8 °C. [R]D = +23.0
(CCl4, c = 2.1); IR (CCl4): 1780; 1H NMR (C6D6): 4.10À3.91 (m, 1H),
3.76 (td, Jd = 4.0, Jt = 6.7, 1H), 3.60 (ddd, J = 4.0, J = 6.7, J = 7.7, 1H),
3.48À3.27 (m, 1H), 3.11À2.95 (m, 2H), 2.53 (dd, J = 7.3, J = 16.9, 1H),
1.74À1.53 (m, 2H), 1.52À0.83 (overlapped multiplets, 15H), 0.78 (s, 3H),
0.76 (s, 3H), 0.73 (s, 3H), 0.72À0.62 (m, 1H). 13C NMR (C6D6): 203.0,
110.1, 67.1, 65.9, 65.0, 47.2, 47.0, 46.4, 42.3, 40.6, 40.2, 36.4, 34.3, 33.4, 33.2,
32.4, 30.1, 22.7, 21.1, 18.8, 16.5, 14.5. GC-MS: 346 (M+, 1), 134 (55), 120
(10), 113 (45), 100 (8), 91 (11), 87 (100), 79 (9), 69 (17), 55 (18).
HPLC: analytical column, Nucleodur; eluent, AcOEt/n-hexane 10/90, tR =
4.8, purity 100%. (+)-26b: Mp (n-hexane) 152.1À153.8 °C. [R]D = +52.1
(CCl4, c = 2.2); IR (CCl4): 1776; 1H NMR (C6D6): 3.67À3.35 (m, 4H),
3.02 (dd, J = 1.8, J = 4.2, 1H), 2.67 (A of ABX, JAB = 18.4, JAX = 4.2, 1H),
2.59 (B of ABX, JAB = 18.4, JBX = 1.8, 1H), 2.28À2.10 (m, 1H), 1.76À1.59
(m, 1H), 1.59À0.97 (overlapped multiplets, 11H), 0.94 (d, J = 6.7, 3H),
0.90 (s, 3H), 0.86À0.53 (overlapped multiplets, 8H). 13C NMR (C6D6):
205.0, 111.1, 65.02, 65.00, 64.0, 47.7, 46.9, 46.2, 42.2, 39.2, 35.1, 33.8, 33.3,
33.1, 31.5, 31.0, 30.0, 22.2, 21.4, 18.6, 15.7, 15.5. GCÀMS: 346 (M+, 1), 262
(6), 134 (81), 126 (5), 120 (17), 113 (100), 105 (14), 100 (16), 91 (16),
2.58 (d, J = 4.1, 1H), 2.29 (ddd, J = 3.5, J = 9.2, J = 14.3, 1H), 2.19 (A of
AB, JAB = 18.4, 1H), 1.99 (B of ABX, JAB = 18.4, JBX = 3.5, 1H),
1.55À0.90 (overlapped multiplets, 17H), 0.86 (s, 3H), 0.79 (s, 3H), 0.70
(s, 3H), 0.62 (q, J = 10.8, 1H). 13C NMR (C6D6): 214.3, 74.0, 48.9, 46.3,
44.3, 43.3, 42.3, 38.6, 38.2, 34.4, 33.7, 33.33, 33.29, 33.0, 32.7, 22.5, 22.4,
19.0, 16.7, 16.1. GCÀMS: 304 (M+, 6), 260 (24), 244 (41), 176 (11),
165 (12), 159 (8), 150 (13), 145 (7), 135 (24), 120 (100), 105 (53), 91
(38), 81 (41), 69 (59), 55 (59). HPLC: analytical column, Nucleodur;
eluent, AcOEt/n-hexane 30/70, tR = 7.0, purity 99%. (+)-10b: Mp
(n-hexane/Et2O) 211.6À212.7 °C. [R]D = +50.7 (CHCl3, c = 2.2); IR
1
(CHCl3): 1709; H NMR (C6D6): 3.32À3.17 (m, 1H), 1.93À1.69
(overlapped multiplets, 3H), 1.67À0.86 (overlapped multiplets, 19H),
0.83 (s, 3H), 0.79 (s, 3H), 0.68 (s, 3H). 13C NMR (C6D6): 214.4, 70.2,
49.0, 46.2, 44.2, 42.4, 42.1, 38.7, 34.3, 33.3, 33.25, 33.23, 33.0, 31.9, 31.5,
22.5, 22.4, 19.0, 16.4, 15.8. GCÀMS: 304 (M+, 12), 286 (11), 260
(59), 244 (38), 176 (21), 165 (25), 147 (30), 135 (32), 123 (73), 105
(60), 91 (57), 81 (68), 69 (100), 55 (87). HPLC: analytical column,
Nucleodur; eluent: AcOEt/n-hexane 30/70, tR = 5.2, purity 99%.
Preparation of (+)-28 from 10. A solution of 10 (0.23 g;
0.74 mmol) and TsOH (0.13 g, 0.69 mmol) in toluene (37 mL) was
heated at 85 °C until TLC (Et2O/n-hexane = 1/1, Rf 10 < Rf (+)-28)
showed the disappearance of the starting material (≈24 h). After cooling
to rt, the whole was diluted with Et2O, washed with a saturated NaHCO3
aqueous solution and finally with brine. After drying over anhydrous
Na2SO4, the organic phase was filtered and evaporated to dryness under
reduced pressure. The residue was purified by SiO2 CC (Et2O/n-hexane =
5/95) to give (+)-28 (0.16 g, 0.56 mmol) as a white solid. Yield: 76%.
Mp (n-hexane) 67.3À68.2 °C. [R]D = 546.8 (CHCl3, c = 1.96); UV
(CH3CN): λmax291 nm (ε = 432 MÀ1 cmÀ1), λmax 218 nm (ε = 3451
1
MÀ1 cmÀ1); IR (CCl4): 1738; H NMR (C6D6): 0.72 (s, 3H), 0.77
(s, 3H), 0.81 (s, 3H), 0.87À1.54 (overlapped multiplets, 12H),
1.56À1.63 (m, 1H), 1.65 (ps, 3H), 1.82 (B of ABX, JAB = 18.4, JBX
=
1.7, 1H), 1.85À1.95 (m, 1H), 2.08 (A of AB, JAB = 18.4, 1H), 2.52
(ps, 1H), 5.05À5.20 (m, 1H); 13C NMR (C6D6): 17.0, 18.8, 21.7, 22.48,
22.52, 26.3, 32.0, 32.6, 33.4, 34.0, 38.8, 42.31, 42.33, 43.9, 47.6, 47.9,
55.4, 128.6, 131.5, 207.7; MS: m/z = 286 (M+, 34), 271 (10), 244 (8),
229 (6), 215 (6), 159 (8), 147 (18), 131 (12), 118 (28), 106 (100%), 91
(40), 81 (21), 69 (30). HRMS: calcd. for C20H30O [M + Na]+:
309.2194; found 309.2206; HPLC: eluent, AcOEt/n-hexane 4/96; tR:
8.0 min, purity 99%.
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The Journal of Organic Chemistry
NOTE
Preparation of (+)-29 from (+)-28. To a solution of (+)-28 (60
mg, 0.21 mmol) in 1,2-ethanedithiol (0.40 mL, 4.8 mmol), cooled
(3) Garbarino, J. A.; Molinari, A. Phytochemistry 1990, 29, 3037–3039.
(4) Garbarino, J. A.; Molinari, A. Phytochemistry 1990, 29, 3040–3041.
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Phytochemistry 1991, 30, 3365–3368.
to 0 °C, BF3 Et2O (0.2 mL, 1.3 mmol) was added while stirring. When
3
TLC analysis (n-hexane/Et2O = 9/1, Rf (+)-28 < Rf (+)-29) showed the
disappearance of the starting material (≈10 min), the mixture was
poured into a separatory funnel, diluted with CH2Cl2 (10 mL) and
washed with 2 N NaOH (3 Â 2 mL). The organic phase was washed with
H2O until neutral and finally with brine. It was dried over anhydrous Na2SO4
and evaporated to dryness. The crude mixture was purified by SiO2 CC
(n-hexane/AcOEt = 99/1) to give (+)-29 (65 mg, 0.18 mmol) as a white
solid. Yield: 85%. Mp (MeOH/Et2O) 163.5À164.5 °C. [R]D = 111.9
(CHCl3, c = 1.46); 1H NMR (CDCl3): 0.81 (s, 3H), 0.84 (s, 3H), 0.91
(s, 3H), 0.96À1.77 (overlapped multiplets, 12H), 1.81 (ps, 3H), 1.94 (B of AB,
JAB = 14.8, 1H), 2.00 (dd, J=3.9,J= 11.7, 1H), 2.06À2.20 (m, 1H), 2.32 (d, J=
3.5, 1H), 2.48 (A of AB, JAB = 14.8, 1H), 3.13À3.43 (m, 4H), 5.07À5.18 (m,
1H); 13C NMR (CDCl3): 137.2, 127.0, 76.6, 56.2, 50.4, 50.3, 48.4, 44.6, 42.4,
40.0, 39.2, 38.7, 33.9, 33.4, 32.8, 31.1, 30.2, 24.6, 22.4, 22.2, 18.6, 16.7. MS: m/z=
362 (26), 334 (11), 286 (9), 244 (29), 229 (6), 209 (6), 182 (14), 177 (6),
157 (12), 144 (21), 131 (23), 118 (35), 105 (100%), 91 (46), 81 (24), 69
(39); HRMS: calcd. for C22H34S2 [M + Na]+: 385.2000; found 385.2018.
HPLC: eluent, AcOEt/n-hexane 0.5/99.5; tR: 6.3 min, purity 99%.
Preparation of (+)-1 from (+)-29. A solution of (+)-29 (54 mg,
0.15 mmol) in EtOHabs (20 mL) was stirred at 60 °C with Raney-Ni until
the TLC analysis (n-heptane, Rf (+)-29 < Rf (+)-1) showed the
disappearance of the starting material (≈30 min). The catalyst was
removed by filtration through a Celite pad and the solvent evaporated to
dryness under reduced pressure. The crude mixture was purified by SiO2
CC (n-heptane) to give (+)-1 (31 mg, 0.11 mmol) as an oil. Yield: 76%.
[R]D = +66.9 (CHCl3, c = 2.27). 1H NMR (CDCl3): 4.96 (dd, J = 0.9, J =
4.3, 1H), 2.18 (t, J = 4.5, 1H), 1.95À1.77 (m, 1H), 1.76À1.28 (overlapped
multiplets, 16H), 1.27À1.05 (overlapped multiplets, 4H), 0.95 (s, 3H), 0.85
(s, 3H), 0.82 (s, 3H); 13C NMR (CDCl3): 138.8, 124.2, 51.0, 49.2, 44.5,
43.3, 42.6, 38.9, 33.9, 33.5, 33.4, 32.6, 31.9, 31.7, 29.9, 22.4, 22.3, 22.2, 18.8,
16.8. GCÀMS: 272 (38), 257 (87), 229 (27), 213 (17), 201 (14), 187 (26),
175 (22), 161 (40), 147 (30), 131 (31), 125 (35), 119 (47), 105 (100), 91
(74), 81 (58), 77 (34), 69 (55), 65 (14), 55 (70). HPLC: analytical column,
Nucleosil C18; eluent, (CH3)2CO/H2O 95/5; tR: 6.1 min, purity 99%.
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’ ASSOCIATED CONTENT
Supporting Information. 1H-and 13C NMR spectra of all
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S
b
synthesized compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: rinaldo.marinibettolo@uniroma1.it.
’ ACKNOWLEDGMENT
Support by Universitꢀa degli Studi di Roma “La Sapienza”
(Ateneo 60%) is gratefully acknowledged.
’ DEDICATION
§Dedicated to Professor Goffredo Rosini on the occasion of his
70th birthday.
’ REFERENCES
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