A new stereoselective synthesis of (-)-isoavenaciolide and (-)-avenaciolide

Article abstract of DOI:10.1021/jo9611935

The synthesis of isoavenaciolide and avenaciolide in their natural enantiomeric forms are described. In both syntheses, α-(phenylthio)-β-[(methoxycarbonyl)methyl]-γ-lactones obtained by the base-induced cyclization of enantiomerically enriched γ-[(phenylthio)acyl] α,β-unsaturated esters were used as starting materials. In the isoavenaciolide synthesis the key step is the stereoselective hydroxylation of the enolate generated in the (methoxycarbonyl)methyl chain that permits the bis-lactonization by a double transesterification. The configuration in the quaternary center vicinal to the carbonyl group in the ring was critical in order to obtain successfully the α-methylene lactone. In avenaciolide, the stereoselective synthesis of the bis-lactone unit was performed taking advantage of the presence of the phenyl sulfide group which by previous activation was used as leaving group to obtain the fused ring by an intramolecular substitution utilizing the carboxylate of the β-substituent as nucleophile. In this case, the α-methylene lactone was obtained by previously reported methodology.

Full text of DOI:10.1021/jo9611935

8448
J . Org. Chem. 1996, 61, 8448-8452
A New Ster eoselective Syn th esis of (-)-Isoa ven a ciolid e a n d
(-)-Aven a ciolid e
Carmen M. Rodr´ıguez, Toma´s Mart´ın, and Victor S. Mart´ın*
Instituto Universitario de Bio-Orga´nica “Antonio Gonza´lez”, Universidad de La Laguna Carretera de La
Esperanza, 2, 38206 La Laguna, Tenerife, Spain
Received J une 24, 1996X
The synthesis of isoavenaciolide and avenaciolide in their natural enantiomeric forms are described.
In both syntheses, R-(phenylthio)-â-[(methoxycarbonyl)methyl]-γ-lactones obtained by the base-
induced cyclization of enantiomerically enriched γ-[(phenylthio)acyl] R,â-unsaturated esters were
used as starting materials. In the isoavenaciolide synthesis the key step is the stereoselective
hydroxylation of the enolate generated in the (methoxycarbonyl)methyl chain that permits the bis-
lactonization by a double transesterification. The configuration in the quaternary center vicinal
to the carbonyl group in the ring was critical in order to obtain successfully the R-methylene lactone.
In avenaciolide, the stereoselective synthesis of the bis-lactone unit was performed taking advantage
of the presence of the phenyl sulfide group which by previous activation was used as leaving group
to obtain the fused ring by an intramolecular substitution utilizing the carboxylate of the
â-substituent as nucleophile. In this case, the R-methylene lactone was obtained by previously
reported methodology.
In tr od u ction
Avenaciolide (1)1 and isoavenaciolide (2)2 are naturally
occurring secondary metabolites isolated from cultures
of Aspergillus and Penicillium species. The bis-lactonic
structure exhibited by these compounds as well as the
potent biological activity manifested by avenaciolide1a
have attracted a great deal of attention, and numerous
syntheses of such compounds have been reported.3
A particularly interesting approach for us to the
synthesis of these compounds is the one reported by
Burke et al.3 in which both compounds are obtained in a
stereodivergent manner using the common intermediate
3 mainly by use of a series of lactone rearrangements.
Considering our recently reported methodology to the
synthesis of highly substituted γ-butyro lactones in their
enantiomeric forms,4 we decided to explore the synthesis
of both avenaciolide and isoavenaciolide following the
synthetic design outlined in Scheme 1 through the
synthon 6 potentially available from 4.4b
F igu r e 1.
Sch em e 1
As depicted in the retrosynthesis in Scheme 1, a key
step is the stereoselective hydroxylation of 4. Gratify-
ingly, the enolate of the highly substituted γ-butyro-
lactone 4 was stereoselectively hydroxylated with MoOPH5
to the R-hydroxy ester 6 in 85% yield as the only
stereoisomer detected by NMR. The great stereoselec-
tivity observed in this reaction is attributed to the more
stable conformation adopted by the enolate 54b in which
the hydrogen of the sp2 carbon is oriented inside the ring
of the γ-lactone forcing the reactions with electrophiles
to occur using the re face since the si face is sterically
hindered by the substituents of the carbon vicinal to the
carbonyl lactone (Scheme 2). The treatment of 6 with
catalytic CSA in refluxing toluene for 72 h yielded 7 in
83% yield and a remaining amount of the starting
material (≈12%). The stereochemistry of the stereo-
centers in 7 was clearly determined by NOE studies.
Thus, the irradiation of the proton located at C3a showed
NOE enhancements in the C6a and C4 protons. The cis-
relative positions of the protons located at C3a and C6a
were also deduced from the NOE between the protons of
such carbons when the proton at C6a was irradiated. In
order to obtain the desired R-methylene lactone 2, the
sulfide 7 was oxidized almost quantitatively to the
sulfoxide 8 which decomposed to a mixture of uncharac-
terized compounds upon heating. This result was ac-
counted by us as the effect of the preferential elimination
of the proton situated in the bridge carbon which is
situated syn relative to the sulfoxide group.6
X Abstract published in Advance ACS Abstracts, November 1, 1996.
(1) (a) Brookes, D.; Tidd, B. K.; Turner, W. B. J . Chem. Soc. 1963,
5385. (b) Ellis, J . J .; Stodola, F. H.; Vesonder; R. F.; Glass, C. A. Nature
(London) 1964, 203, 1382. (c) Brookes, D.; Sternhell, S.; Tidd, B. K.;
Turner, W. B. Aust. J . Chem. 1965, 18, 373. (d) Hughes, D. L. Acta
Crystallogr. 1978, B34, 3674.
(2) Aldridge, D. C.; Turner, W. B. J . Chem. Soc. 1971, 2431.
(3) (a) Burke, S. D.; Pacofsky, G. J .; Piscopio, A. D. Tetrahedron Lett.
1986, 27, 3345. (b) Burke, S. D.; Pacofsky, G. J .; Piscopio, A. D. J .
Org. Chem. 1992, 57, 2228, and references cited therein.
(4) (a) Rodr´ıguez, C. M.; Mart´ın, V. S. Tetrahedron Lett. 1991, 32,
2165. (b) Rodr´ıguez, C. M.; Mart´ın, T.; Ram´ırez, M. A.; Mart´ın, V. S.
J . Org. Chem. 1994, 59, 4461.
With this consideration in mind, we expected that the
elimination step would be controlled by changing the
(5) Vedejs, E.; Larsen, S. Org. Synth. 1986, 64, 127.
S0022-3263(96)01193-0 CCC: $12.00 © 1996 American Chemical Society

Synthesis of (-)-Isoavenaciolide and (-)-Avenaciolide
J . Org. Chem., Vol. 61, No. 24, 1996 8449
Sch em e 2
Sch em e 4
Sch em e 5
Sch em e 3
8
the benzyl ester using FeCl3 cleanly yielded the free
R-hydroxy acid 16 in an almost quantitative manner.
Unfortunately, when 16 was submitted to refluxing
toluene in the presence of catalytic CSA, 7 was again
obtained by the double transesterification sequence. The
failure to produce the desired inversion in the oxygenated
secondary carbon in the lactone ring was attributed to
the presence of a quaternary center vicinal to the
carbonyl γ-lactone. Thus, we decided to try to prepare
directly the known R-methylene lactone 3. Consequently,
we protected the hydroxy group in 15 as benzyl ether,
and the sulfide 17 was oxidized under standard condi-
tions using a 1 equiv amount of MCPBA, obtaining the
sulfoxide 18 which when heated yielded the R-methylene
lactone 19 in 75% yield. Disappointingly, all attempts
to obtain the free R-hydroxy acid 3 proved unsuccessful.
At this point of the synthesis, we decided to reconsider
our strategy and focused our attention on the enantiomer
of the sulfide 9 (20),4b in which we pondered the possibil-
ity of performing the synthesis of the desired bis-lactone
skeleton taking advantage of the presence of a sulfide
group as a potential leaving group.9 Thus, 20 was
submitted to basic hydrolysis yielding the free carboxylic
acid 21 in 92% yield. With this compound in our hands
we performed the synthesis of the bis-lactone 23, that
was neatly accomplished by a one-pot procedure with
stereochemistry at the carbon in which the phenyl sulfide
group is located. Thus, we decided to recommence the
synthetic sequence using the diastereoisomer of 4 in such
an epimeric center. The alkylation of the readily avail-
able butyrolactone 94b under newly developed conditions,7
using LiN(TMS)2 as base and with addition of MeI at -90
°C, furnished the diastereoisomeric γ-lactone 10 as the
only detectable stereoisomer by NMR analysis. As
expected, the hydroxylation of 10 proceeded following the
same stereochemical course relative to the vicinal stereo-
center, regardless of the stereochemistry in the quater-
nary carbon adjacent to the carbonyl butyrolactone,
cleanly affording 11, which when heated with a catalytic
amount of CSA in toluene for 72 h yielded the bis-lactone
12 in 76% isolated yield and unreacted 11 (≈15%). The
oxidation of 12 with MCPBA cleanly yielded the sulfoxide
13 in 96% yield, that when heated in refluxing toluene
afforded isoavenaciolide (2) in 85% yield, mp 126-127
°C, [R]25D -154 (c 1.1, EtOH) [lit.3 mp 128-129 °C, [R]25
D
treatment of 21 with Me3O+ BF4 to generate the
-
-155.83 (c 0.5, EtOH)].
sulfonium salt 22 and further basic treatment with
KOBu-t, in 86% overall yield. Finally, the methylenation
of 23 with Stiles’s reagent10 yielded natural avenaciolide
(1) in 68% yield, mp 49-50 °C, [R]25D -41.1 (c 1.1, EtOH)
We decided to explore the synthesis of avenaciolide (1)
by a similar sequence to that used for the synthesis of 2,
essentially performing the bis-lactonization over the free
R-hydroxy acid instead of the methyl ester since, in such
cases, the stereochemical course of the bis-annelation3
would be an inversion of configuration in the carbon
where the oxygen of the γ-lactone is located. In order to
obtain the free acid under very mild conditions, we
decided to prepare the benzyl ester 15 using the same
general sequence outlined in Scheme 4. The cleavage of
[lit.3 mp 51-52 °C, [R]25 -39.7 (c 1.28, EtOH)].
D
In conclusion, we have described efficient routes to the
natural enantiomers of avenaciolide (1) and isoavenaci-
olide (2), using as starting materials R-(phenylthio)-â-
[(methoxycarbonyl)methyl]-γ-lactones easily obtained with
absolute stereochemical control by the base-induced
(6) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J . Am. Chem. Soc. 1976,
98, 4887.
(7) Rodr´ıguez, C. M.; Mart´ın, T.; Ram´ırez, M. A.; Mart´ın V. S. J .
Org. Chem. 1994, 59, 8081.
(8) Padro´n, J . I.; Va´zquez, J . T. Tetrahedron: Asymmetry 1995, 6,
857.
(9) Bravo, P.; Resnati, G.; Viani, F. Tetrahedron Lett. 1985, 26, 2913.
(10) Parker, W. L.; J ohnson, F. J . Org. Chem. 1973, 38, 2489.

8450 J . Org. Chem., Vol. 61, No. 24, 1996
Rodr´ıguez et al.
A solution of the mixture of sulfoxides 8 (100 mg, 0.25 mmol)
in dry toluene (2.5 mL, 0.1 M) was submitted to reflux for 1 h.
After this period, TLC showed the end of the reaction showing
the formation of an irresolvable mixture of compounds.
P r ep a r a t ion of Met h yl (2S,3S,4R)-[2-oct yl-5-oxo-4-
(p h en ylth io)tetr a h yd r ofu r a n -3-yl]a ceta te (9). 9 was ob-
tained by the general procedure used in ref 4b using the nonyl
aldehyde as the starting material (see supporting information).
P r ep a r a tion of Meth yl (2S,3S,4R)-[4-Meth yl-2-octyl-5-
oxo-4-(p h en ylth io)tetr a h yd r ofu r a n -3-yl]a ceta te (10). To
a solution of hexamethyldisilazane (0.3 mL, 1.45 mmol) in
THF:HMPA (4:1, 2.6 mL:0.7 mL) was added n-butyllithium
(0.8 mL, 1.6 M in n-hexane, 1.32 mmol) at 0 °C and the mixture
stirred for 15 min. The solution was then cooled to -90 °C
and 9 (250 mg, 0.66 mmol) added in THF:HMPA (4:1, 2.6 mL:
0.7 mL) over a period of 5 min. The mixture was additionally
stirred for 15 min and iodomethane (82 µL, 1.32 mmol) added
dropwise. After the addition, the reaction was maintained
with stirring for 4 h at this temperature. Then, the reaction
mixture was poured into HCl aqueous solution (15% w/v, 25
mL), ice, and ether (25 mL) and vigorously stirred. After 5
min, the mixture was extracted with ether (2 × 15 mL), and
the combined organic phases were washed with a saturated
aqueous solution of NaHCO3 (15 mL) and brine (15 mL), dried,
and concentrated. Purification by column chromatography
gave the R-methyl-γ-butyrolactone 10 (238 mg, 92% yield) as
cyclization of enantiomerically enriched γ-[(phenylthio)-
acyl] R,â-unsaturated esters. The methodology could be
easily extended to other related natural products such
as ethisolide2 simply by the proper choice of the length
of the alkyl group of the precursor 9 (R ) C2H5-n).
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Essentially similar to those used
in ref 4b.
P r ep a r a tion of Meth yl (2S,3S,4S)-[4-Meth yl-2-octyl-5-
oxo-4-(p h en ylth io)tetr a h yd r ofu r a n -3-yl]a ceta te (4). The
γ-butyrolactone was obtained for the general procedure used
in ref 4b using the nonyl aldehyde as the starting material.
(See supporting information).
Gen er al P r ocedu r e for th e Hydr oxylation of â-[(Alkoxy-
car bon yl)m eth yl]-γ-lacton es. Preparation of Methyl 2-[(2R)-
Hydroxy]-2-[(2S,3S,4S)-4-methyl-2-octyl-5-oxo-4-(phenylthio)-
tetrahydrofuran-3-yl]acetate (6). To a solution of hexamethyl-
disilazane (0.3 mL, 1.4 mmol) in THF (1.6 mL) was added
n-butyllithium (0.8 mL, 1.6 M in n-hexane, 1.3 mmol) at 0 °C
with stirring. After the mixture was stirred for 15 min, the
solution was then cooled to -78 °C, and the γ-butyrolactone 4
(250 mg, 0.6 mmol) was added in THF (1.6 mL) over a period
of 5 min. The mixture was additionally stirred at this tem-
perature for 30 min and then treated with solid oxodiperoxo-
molybdenum-pyridine-HMPA complex (MoOPH) (554 mg,
1.3 mmol) in a single portion. The temperature was allowed
to warm to -50 °C and stirred for 2 h. The resulting blue-
green solution was poured into ether (10 mL) and freshly
prepared saturated NaHSO3 solution (10 mL). The organic
layer was washed with H2O (2 × 8 mL), dried over MgSO4,
and concentrated to provide a crude mixture. Purification by
silica gel column chromatography afforded the R-hydroxy
an oil: [R]25 -26.3 (c 3.61, CHCl3); 1H-NMR (CDCl3) δ: 0.86
D
(t, J ) 7.0 Hz, 3 H), 1.23 (m, 12 H), 1.37 (s, 3 H), 1.53 (m, 2
H), 2.29 (m, 1 H), 2.60 (m, 2 H), 3.72 (s, 3 H), 4.02 (m, 1 H),
7.36 (m, 3 H), 7.58 (m, 2 H);
13C-NMR (CDCl3) δ: 14.1 (q),
18.2 (q), 22.6 (t), 24.6 (t), 29.1 (t), 29.2 (t), 29.3 (t), 31.8 (t),
32.1 (t), 33.1 (t), 43.8 (d), 52.0 (q), 55.7 (s), 81.4 (d), 129.0 (d),
129.5 (s), 129.9 (d), 137.1 (d), 171.6 (s), 176.5 (s); IR (CHCl3)
(cm-1): 2955, 2857, 1767, 1737, 1439; MS m/z (relative
intensity): 392 (M)+ (48), 283 (100), 251 (78); HRMS calcd for
C22H32O4S (M)+: 392.2021, found 392.2027.
lactone 6 (222 mg, 85% yield) as an oil: [R]25 -54.1 (c 1.6,
D
CHCl3); 1H-NMR (CDCl3) δ: 0.88 (t, J ) 6.8 Hz, 3 H), 1.30
(m, 12 H), 1.42 (s, 3 H), 1.54 (m, 2 H), 2.61 (dd, J ) 10.1, 2.8
Hz, 1 H), 3.05 (d, J ) 4.2 Hz, 1 H), 3.88 (s, 3 H), 4.65 (dd, J )
4.2, 2.8 Hz, 1 H), 4.80 (m, 1 H), 7.40 (m, 3 H), 7.55 (m, 2 H);
13C-NMR (CDCl3) δ: 14.1 (q), 22.2 (q), 22.6 (t), 25.5 (t), 29.1
(t), 29.2 (t), 29.3 (t), 31.8 (t), 33.9 (t), 53.3 (q), 54.0 (s), 55.7 (d),
67.0 (d), 76.7 (d), 128.4 (s), 128.8 (d), 130.0 (d), 137.7 (d), 174.1
(s), 174.4 (s); IR (CHCl3) (cm-1): 3525, 3025, 2956, 1763; MS
m/z (relative intensity): 408 (M)+ (2), 251 (78), 182 (22), 109
(93); HRMS calcd for C22H32O5S (M)+: 408.1971, found 408.1981.
Gen er a l P r oced u r e for th e Th er m a l Bis-Cycliza tion
of â-[Hydr oxy(alkoxycar bon yl)m eth yl]-γ-lacton es. Prepa-
ration of (3S,3aR,4S,6aR)-3-Methyl-4-octyl-3-(phenylthio)di-
hydrofuro[3,4-b]furan-2,6-dione (7). To a solution of 6 (160 mg,
0.4 mmol) in dry toluene (3.9 mL, 0.1 M) was added a catalytic
amount of camphorsulfonic acid. The reaction mixture was
submitted to reflux for 72 h. Then, the solvent was evapo-
rated, and the obtained residue was purified by silica gel
column chromatography yielding the bis-lactone 7 (123 mg,
83% yield) as an oil and remaining starting material 6 (19 mg,
P r ep a r a tion of Meth yl 2-[(2R)-Hyd r oxy]-[(2S,3S,4R)-
4-m eth yl-2-octyl-5-oxo-4-(p h en ylth io)tetr a h yd r ofu r a n -3-
yl]a ceta te (11). The general hydroxylation procedure (used
above to obtain 6) was applied to 10 on a 200 mg (0.51 mmol)
scale to -50 °C for 2 h, affording 11 (162 mg, 78% yield) as an
1
oil: [R]25 -29.4 (c 1.97, CHCl3); H-NMR (CDCl3) δ: 0.88 (t,
D
J ) 6.9 Hz, 3 H), 1.22 (m, 12 H), 1.39 (m, 2 H), 1.55 (s, 3 H),
2.59 (d, J ) 10.1 Hz, 1 H), 2.99 (br s, 1 H), 3.83 (s, 3 H), 4.4
(m, 1 H), 4.48 (bs, 1 H), 7.39 (m, 3 H), 7.55 (m, 2 H); 13C-NMR
(CDCl3) δ: 14.1 (q), 19.4 (q), 22.6 (t), 24.6 (t), 29.1 (t), 29.2 (t),
29.3 (t), 31.8 (t), 34.1 (t), 50.1 (d), 53.1 (q), 54.5 (s), 67.6 (d),
76.7 (d), 128.9 (d), 130.0 (d), 136.9 (s), 137.1 (d), 174.4 (s), 176.1
(s); IR (CHCl3) (cm-1): 3525, 3025, 2956, 1763; MS m/z
(relative intensity): 408 (M)+ (2), 251 (78), 109 (93); HRMS
calcd for C22H32O5S (M)+: 408.1971, found 408.1981.
P r ep a r a t ion of (3R,3a R,4S,6a R)-3-Met h yl-4-oct yl-3-
(p h en ylth io)d ih yd r ofu r o[3,4-b]fu r a n -2,6-d ion e (12). The
general thermal bis-cyclization procedure (used above to obtain
7) was applied to 11 on a 150 mg (0.37 mmol) scale for 72 h,
yielding 12 (105 mg, 76% yield) as an oil and remaining
starting material 11 (30 mg, 15%). Compound 12: [R]25D +21.1
(c 1.75, CHCl3); 1H-NMR (CDCl3) δ: 0.89 (t, J ) 7.2 Hz, 3 H),
1.30 (m, 12 H), 1.60 (s, 3 H), 2.06 (m, 1 H), 2.55 (m, 1 H), 3.33
(dd, J ) 8.0, 4.9 Hz, 1 H), 4.69 (ddd, J ) 8.0, 8.0, 4.9 Hz, 1 H),
5.04 (d, J ) 8.0 Hz, 1 H), 7.36 (m, 3 H), 7.47 (m, 2 H); 13C-
NMR (CDCl3) δ: 14.0 (q), 22.6 (t), 23.5 (q), 26.6 (t), 29.1 (t),
29.3 (t), 29.6 (t), 29.8 (t), 31.8 (t), 51.8 (s), 53.1 (d), 73.6 (d),
78.9 (d), 127.6 (s), 129.0 (d), 130.7 (d), 137.9 (d), 170.5 (s), 172.4
(s); IR (CHCl3) (cm-1): 2928, 2856, 1792, 1281; MS m/z
(relative intensity): 376 (M)+ (3), 182 (3), 55 (100); HRMS calcd
for C21H28O4S (M)+: 376.1708, found 376.1700.
12%). Compound 7: [R]25 -27.3 (c 1.3, CHCl3); 1H-NMR
D
(CDCl3) δ: 0.89 (t, J ) 6.8 Hz, 3 H), 1.29 (m, 12 H), 1.55 (m,
1 H), 1.65 (s, 3 H), 1.92 (m, 1 H), 3.31 (dd, J ) 8.0, 5.9 Hz, 1
H), 4.61 (m, 1 H), 4.88 (d, J ) 8.0 Hz, 1 H), 7.44 (m, 3 H), 7.55
(m, 2 H); 13C-NMR (CDCl3) δ: 14.1 (q), 20.9 (q), 22.6 (t), 26.8
(t), 29.1 (t), 29.2 (t), 29.3 (t), 30.3 (t), 31.8 (t), 47.6 (d), 52.6 (s),
73.9 (d), 80.3 (d), 129.0 (s), 129.5 (d), 130.5 (d), 136.9 (d), 170.2
(s), 175.4 (s); IR (CHCl3) (cm-1): 2928, 2856, 1792, 1281; MS
m/z (relative intensity): 376 (M)+ (3), 109 (82), 55 (100); HRMS
calcd for C21H28O4S (M)+: 376.1708, found 376.1700.
Gen er a l P r oced u r e for th e Th er m a l Elim in a tion of
th e P h en ylth io Gr ou p . Oxid a tion a n d P yr olysis of 7. To
a stirred solution of 7 (100 mg, 0.27 mmol) in dry CH2Cl2 (2.7
mL) was added MCPBA (66 mg, 0.27 mmol) at -20 °C. The
reaction was stirred for 1 h at this temperature and then
quenched with potassium fluoride (62 mg, 1.06 mmol) and
vigorously stirred for 0.5 h. The mixture was filtered through
a pad of Celite and washed with ether (3 × 10 mL). The
resulting solution was concentrated, and the crude isomeric
mixture of sulfoxides 8 (100 mg) was used without purification.
P r ep a r a tion of (-)-Isoa ven a ciolid e (2). The general
thermal elimination used above for 7 was applied to 12 on a
100 mg (0.27 mmol) scale, yielding isoavenaciolide (2) (59 mg,
82% yield), as a solid: mp 126-127 °C, [R]25 -154° (c 1.1,
D
EtOH) [lit.3b mp 128-129 °C, [R]25 -155.8° (c 0.5, EtOH)];
D
1H-NMR (CDCl3) δ: 0.88 (t, J ) 6.6 Hz, 3 H), 1.27 (m, 12 H),
1.61 (m, 2 H), 3.98 (m, 1 H), 4.75 (m, 1 H), 5.10 (d, J ) 8.8 Hz,
1 H), 5.87 (d, J ) 2.1 Hz, 1 H), 6.61 (d, J ) 2.4 Hz, 1 H); 13C-
NMR (CDCl3) δ: 14.0 (q), 22.6 (t), 26.0 (t), 29.1 (t), 29.2 (t),

Synthesis of (-)-Isoavenaciolide and (-)-Avenaciolide
J . Org. Chem., Vol. 61, No. 24, 1996 8451
29.3 (t), 31.7 (t), 32.4 (t), 41.7 (d), 74.6 (d), 80.3 (d), 128.8 (t),
130.8 (s), 167.7 (s), 169.8 (s); IR (CHCl3) (cm-1): 2956, 2929,
2857, 1788; MS m/z (relative intensity): 267 (M + 1)+ (5), 124
(21), 96 (100).
P r ep a r a tion of Ben zyl (2S,3S,4S)-[4-Meth yl-2-octyl-5-
oxo-4-(p h en ylth io)tetr a h yd r ofu r a n -3-yl]a ceta te (14). The
γ-butyrolactone 14 was obtained for the general procedure
used in ref 4b using the nonyl aldehyde as the starting
material. (See supporting information).
+58.6 (c 0.7, CHCl3); 1H-NMR (CDCl3) δ: 0.88 (t, J ) 6.9 Hz,
3 H), 1.29 (m, 12 H), 1.42 (m, 2 H), 3.05 (d, J ) 1.9 Hz, 1 H),
4.0 (d, J ) 5.1 Hz, 1 H), 4.38 (d, J ) 11.8 Hz, 1 H), 4.57 (m, 1
H), 4.71 (d, J ) 11.8 Hz, 1 H), 5.17 (d, J ) 12.0 Hz, 1 H), 5.21
(d, J ) 12.0 Hz, 1 H), 5.41 (d, J ) 1.9 Hz, 1 H), 6.22 (d, J )
2.2 Hz, 1 H), 7.23 (m, 3 H), 7.32 (m, 2 H), 7.38 (m, 5 H); 13C-
NMR (CDCl3) δ: 14.1 (q), 22.6 (t), 24.7 (t), 29.1 (t), 29.2 (t),
29.3 (t), 31.8 (t), 36.1 (t), 47.0 (d), 67.2 (t), 72.8 (t), 78.7 (d),
78.8 (d), 124.1 (t), 128.2 (d), 128.3 (d), 128.4 (d), 128.7 (d), 128.8
(d), 128.9 (d), 134.9 (s), 135.1 (s), 136.3 (s), 169.5 (s), 170.1 (s);
IR (CHCl3) (cm-1): 3031, 2929, 2857, 1756; MS m/z (relative
intensity): 300 (M - 164)+ (2), 107 (3), 91 (100); HRMS calcd
for C20H28O2 (M - 164)+: 300.2089, found 300.2080.
P r ep a r a tion of Ben zyl 2-[(2R)-Hyd r oxy]-2-[(2S,3S,4S)-
4-m eth yl-2-octyl-5-oxo-4-(p h en ylth io)tetr a h yd r ofu r a n -3-
yl]a ceta te (15). The general hydroxylation procedure (used
above to obtain 6) was applied to 14 on a 825 mg (1.76 mmol)
scale to -50 °C for 2 h, affording the R-hydroxy lactone 15
P r ep a r a t ion of Met h yl (2R,3R,4S)-[2-Oct yl-5-oxo-4-
(p h en ylt h io)t et r a h yd r ofu r a n -3-yl]a cet a t e (20). The γ-
butyrolactone 20 was obtained for the general procedure used
in ref 4b using the nonyl aldehyde as the starting material.
(See supporting information).
(648 mg, 76% yield) as an oil: [R]25 -42.1 (c 1.9, CHCl3); 1H-
D
NMR (CDCl3) δ: 0.89 (t, J ) 6.9 Hz, 3 H), 1.32 (m, 12 H), 1.41
(s, 3 H), 1.48 (m, 2 H), 2.57 (dd, J ) 10.04, 2.8 Hz, 1 H), 3.19
(d, J ) 4.3 Hz, 1 H), 4.66 (dd, J ) 4.3, 2.8 Hz, 1 H), 4.77 (m,
1 H), 5.19 (d, J ) 11.9 Hz, 1 H), 5.34 (d, J ) 11.9 Hz, 1 H),
7.32 (m, 3 H), 7.40 (m, 5 H), 7.52 (m, 2 H); 13C-NMR (CDCl3)
δ: 14.1 (q), 22.2 (q), 22.7 (t), 25.6 (t), 29.1 (t), 29.2 (t), 29.4 (t),
31.8 (t), 33.9 (t), 53.9 (s), 55.8 (d), 67.1 (d), 68.3 (t), 76.7 (d),
127.5 (s), 128.5 (d), 128.7 (d), 128.8 (d), 129.0 (d), 130.0 (d),
134.4 (s), 137.7 (d), 173.6 (s), 174.3 (s); IR (CHCl3) (cm-1): 3524,
3018, 2927, 1762; MS m/z (relative intensity): 485 (M + 1)+
(2), 393 (2), 91 (100); HRMS calcd for C28H37O5S (M + 1)+:
485.2362, found 485.2367.
P r ep a r a tion of (2R,3R,4S)-2-[2-Octyl-5-oxo-4-(p h en yl-
th io)tetr a h yd r ofu r a n -3-yl]a cetic Acid (21). To a stirred
solution of 20 (200 mg, 0.53 mmol) in THF:H2O (4:1, 4.2 mL:
1.1 mL) was added NaOH (85 mg, 2.12 mmol) at 0 °C. The
reaction was stirred for 1 h, until starting material was not
detected by TLC. Then concentrated HCl was added at 0 °C
until pH ≈ 1 was reached and the reaction mixture extracted
with AcOEt (2 × 20 mL). The combined organic phases were
washed with 50 mL of a saturated solution of brine, dried over
MgSO4, evaporated in vacuo, and purified by column chroma-
tography to give the acid 21 (177 mg, 92% yield) as an oil:
[R]25D +3.3 (c 3.3, CHCl3); 1H-NMR (CDCl3) δ: 0.87 (t, J ) 6.9
Hz, 3 H), 1.22 (m, 12 H), 1.59 (m, 2 H), 2.38 (ddd, J ) 10.2,
7.0, 3.5 Hz, 1 H), 2.65 (d, J ) 7.0 Hz, 2 H), 3.76 (d, J ) 10.2
Hz, 1 H), 4.18 (ddd, J ) 8.1, 8.1, 3.5 Hz, 1 H), 7.32 (m, 3 H),
7.55 (m, 2 H); 13C-NMR (CDCl3) δ: 14.0 (q), 22.6 (t), 25.0 (t),
29.1 (t), 29.2 (t), 29.3 (t), 31.8 (t), 33.9 (t), 42.5 (d), 51.2 (d),
82.5 (d), 129.2 (d), 131.0 (s), 133.2 (d), 134.4 (d), 173.9 (s), 176.5
(s); IR (CHCl3) (cm-1): 3027, 2857, 1768, 1715; MS m/z
(relative intensity): 364 (M)+ (52), 238 (7), 109 (99). Anal.
Calcd for C20H28O4S: C, 65.90; H, 7.75; S, 8.78. Found: C,
65.58; H, 8.00; S, 8.43.
Alter n a tive P r ep a r a tion of 7. To a stirred solution of
15 (300 mg, 0.62 mmol) in dry CH2Cl2 (12.4 mL) under argon
was added anhydrous FeCl3 (200 mg, 1.24 mmol) at 0 °C. The
reaction was stirred for 1 h, until starting material was not
detected by TLC. Then, the reaction was quenched by addition
of water (15 mL) and diluted with CH2Cl2 (10 mL). The
mixture was stirred for 10 min and then extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were dried over
MgSO4 and concentrated to provide the R-hydroxy acid lactone
16, which was used without purification.
To a solution of crude 16 in dry toluene (6.2 mL) was added
a catalytic amount of CSA. The reaction mixture was submit-
ted to reflux for 72 h. Then, the solvent was evaporated and
the obtained residue was purified by silica gel column chro-
matography yielding 7 (140 mg, 60% yield) and remaining
starting material 15 (105 mg, 35%).
P r ep a r a tion of (3a S,4R,6a R)-4-Octyld ih yd r ofu r o[3,4-
b]fu r a n -2,6-d ion e (23). To a stirred solution of lactone 21
(150 mg, 0.41 mmol) in a mixture of CH2Cl2:CH3NO2 (1:1, 2.1
mL:2.1 mL) was added trimethyloxonium tetrafluoroborate (61
mg, 0.41 mmol) at -5 °C. The temperature was allowed to
warm to rt and stirred for 1 h. Then the solvent was removed
in vacuum at 0 °C, and the crude sulfonium salt 22 was
dissolved in dimethylformamide (8.2 mL, 0.05 M). The solu-
tion was then cooled to -45 °C, and solid potassium tert-
butoxide (50 mg, 0.41 mmol) was added. The temperature was
allowed to warm to 0 °C and stirred for 1 h. The resulting
solution was poured into ether (20 mL) and washed with
saturated solution of NH4Cl (25 mL), dried over MgSO4,
concentrated, and purified by column chromatography to give
P r epar ation of Ben zyl 2-[(2R)-Ben zyloxy]-2-[(2S,3S,4S)-
4-m eth yl-2-octyl-5-oxo-4-(p h en ylth io)tetr a h yd r ofu r a n -3-
yl]a ceta te (17). To a suspension of NaH (22 mg, 0.74 mmol,
80% in mineral oil) in dry DMF (3.1 mL) under argon was
added dropwise 15 (300 mg, 0.62 mmol) in dry DMF (3.1 mL)
at 0 °C. The reaction mixture was stirred for 15 min, after
which time was added benzyl bromide (110 µL, 0.93 mmol).
The reaction was allowed to warm to rt and stirred for 1 h.
After this period, TLC showed complete conversion. Then, to
the reaction mixture were added AcOH (200 µL) and H2O (10
mL), and it was extracted with ether (3 × 10 mL). The
combined organic phases were washed with
a saturated
23 (90 mg, 86% yield), as an oil: [R]25 -2.45 (c 1.96, CHCl3);
D
aqueous solution of NaHCO3 (25 mL) and brine (25 mL), dried
over MgSO4, concentrated, and purified by column chroma-
1H-NMR (CDCl3) δ: 0.88 (t, J ) 6.7 Hz, 3 H), 1.27 (m, 12 H),
1.69 (m, 2 H), 2.54 (dd, J ) 18.1, 3.8 Hz, 1 H), 2.93 (dd, J )
18.1, 9.4 Hz, 1 H), 3.05 (m, 1 H), 4.34 (m, 1 H), 5.0 (d, J ) 7.7
Hz, 1H); 13C-NMR (CDCl3) δ: 13.9 (q), 22.5 (t), 24.8 (t), 29.0
(t), 29.1 (t), 29.2 (t), 31.6 (t), 32.6 (t), 35.1 (t), 39.9 (d), 77.2 (d),
85.1 (d), 170.4 (s), 174.2 (s); IR (CHCl3) (cm-1): 2956, 2929,
1795, 1782; MS m/z (relative intensity): 355 (M + 1)+ (18),
212 (3), 55 (100).
tography, yielding 17 (327 mg, 92% yield) as an oil: [R]25
D
-11.1 (c 3.1, CHCl3); 1H-NMR (CDCl3) δ: 0.89 (t, J ) 7.0 Hz,
3 H), 1.23 (m, 12 H), 1.34 (s, 3 H), 1.42 (m, 2 H), 2.61 (dd, J )
9.8, 4.4 Hz, 1 H), 4.44 (d, J ) 4.4 Hz, 1 H), 4.62 (d, J ) 10.5
Hz, 1 H), 4.65 (m, 1 H), 4.71 (d, J ) 10.5 Hz, 1 H), 5.21 (d, J
) 12.0 Hz, 1 H), 5.32 (d, J ) 12.0 Hz, 1 H), 7.39 (m, 15 H);
13C-NMR (CDCl3) δ: 14.1 (q), 22.3 (q), 22.7 (t), 25.6 (t), 29.1
(t), 29.2 (t), 29.3 (t), 31.8 (t), 34.3 (t), 53.7 (s), 55.0 (d), 67.3 (t),
72.7 (t), 75.2 (d), 78.5 (d), 128.1 (d), 128.2 (d), 128.3 (d), 128.5
(d), 128.6 (d), 128.7 (d), 128.8 (d), 130.1 (d), 135.0 (s), 136.8
(s), 137.2 (s), 137.6 (d), 171.1 (s), 174.5 (s); IR (CHCl3) (cm-1):
3015, 2975, 1750, 1457; MS m/z (relative intensity): 483 (M
- 91)+ (1), 135 (12), 91 (100); HRMS calcd for C28H35O5S (M -
91)+: 483.2205, found 483.2223.
P r ep a r a tion of (-)-Aven a ciolid e (1). 23 (75 mg, 0.3
mmol) in dry DMF (1.5 mL) was added to a 2 M solution of
methyl methoxymagnesium carbonate (0.8 mL, 1.53 mmol) in
DMF and the mixture heated under a slow stream of dry argon
at 120 °C for 5 h, until TLC showed the end of the reaction.
The resulting solution was poured into a mixture of ice cold 6
N HCl (10 mL) and ether (10 mL) and shaken until all of the
precipitated solid had dissolved. The ether phase was washed
with water (10 mL) and brine (10 mL) and then dried over
magnesium sulfate. Removal of the ether under reduced
pressure afforded the bis-lactonic acid, which was used without
purification.
P r ep a r a tion of Ben zyl 2-[(2R)-Ben zyloxy]-2-[(2S,3S)-
4-m et h ylen e-2-oct yl-5-oxot et r a h yd r ofu r a n -3-yl]a cet a t e
(19). The general thermal elimination used above for 7 was
applied to 17 on a 300 mg (0.52 mmol) scale, yielding the
methylene lactone 19 (181 mg, 75% yield) as an oil: [R]25
D

8452 J . Org. Chem., Vol. 61, No. 24, 1996
Rodr´ıguez et al.
The crude diacid was treated with 5 mL/mmol of compound
of a stock solution (prepared from 4 mL of acetic acid, 2.9 mL
of 37% formaldehyde in water, 1 mL of diethylamine, and 105
mg of NaOAc) and stirred vigorously under argon at rt for 2
h, until evolution of carbon dioxide ceased. The resulting
solution was poured into water (10 mL) and ether (10 mL).
Ack n ow led gm en t. This research was supported by
the DGICYT (PB92-0489), the Human Capital and
Mobility Program (ERBCHRXCT93-0288) of the Euro-
pean Community and the Consejer´ıa de Educacio´n,
Cultura y Deportes del Gobierno de Canarias. C.M.R.
thanks the M.E.C., and T.M. the Gobierno Auto´nomo
de Canarias, for a fellowship.
The ether phase was washed with
a saturated aqueous
solution of NaHCO3 (10 mL) and brine (10 mL), dried, and
concentrated. Purification by column chromatography gave
(-)-avenaciolide (1) (53 mg, 68% yield), as a solid: mp 49-50
°C, [R]25 -41.1° (c 1.1, EtOH) [lit.3b mp 51-52 °C, [R]25
D
D
Su p p or tin g In for m a tion Ava ila ble: Copies of 13C-NMR
spectra for the new and final compounds, and experimental
details for the synthesis of 4, 9, 14, and 20 (24 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
1
-39.7° (c 1.28, EtOH)]; H-NMR (CDCl3) δ: 0.89 (t, J ) 6.7
Hz, 3 H), 1.28 (m, 12 H), 1.80 (m, 2 H), 3.55 (m, 1 H), 4.43
(ddd, J ) 6.5, 6.5, 4.0 Hz, 1 H), 5.04 (d, J ) 8.5 Hz, 1 H), 5.87
(d, J ) 2.1 Hz, 1 H), 6.48 (d, J ) 2.4 Hz, 1 H); 13C-NMR (CDCl3)
δ: 14.0 (q), 22.6 (t), 24.8 (t), 29.1 (t), 29.3 (t), 29.6 (t), 31.8 (t),
36.0 (t), 44.2 (d), 74.2 (d), 85.1 (d), 126.2 (t), 134.6 (s), 167.4
(s), 169.6 (s); IR (CHCl3) (cm-1): 2956, 2929, 2857, 1788; MS
m/z (relative intensity): 267 (M + 1)+(3), 191 (6), 124 (23), 96
(100).
J O9611935