Stereoselective synthesis of (-)-malyngolide, (+)-malyngolide and (+)-tanikolide using ring-closing metathesis

Article abstract of DOI:10.1016/S0040-4020(02)01594-6

The stereoselective syntheses of the naturally occurring δ-lactones (+)-tanikolide and (-)-malyngolide as well as of the unnatural (+)-enantiomer of the latter are described. Key steps in each of these syntheses were stereoselective additions of organomet

Full text of DOI:10.1016/S0040-4020(02)01594-6

Tetrahedron 59 (2003) 857–864
Stereoselective synthesis of (2)-malyngolide, (1)-malyngolide and
(1)-tanikolide using ring-closing metathesis
†
a
a
a
Miguel Carda,a Santiago Rodrıguez, Encarnacion Castillo, Alejandro Bellido,
,
,
*
´
Santiago Dıaz-Oltra and J. Alberto Marco
´
a
b
,
*
´
a
´
´
´
´
Depart. de Q. Inorganica y Organica, Univ. Jaume I, Castellon, E-12080 Castellon, Spain
´
Depart. de Q. Organica, Univ. de Valencia, D. Moliner, 50, E-46100 Burjassot, Valencia, Spain
b
Received 25 October 2002; revised 25 November 2002; accepted 4 December 2002
Abstract—The stereoselective syntheses of the naturally occurring d-lactones (þ)-tanikolide and (2)-malyngolide as well as of the
unnatural (þ)-enantiomer of the latter are described. Key steps in each of these syntheses were stereoselective additions of organometallic
reagents to a-oxygenated ketones and olefin ring-closing metatheses. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
dation.6 The chiral starting materials were D-glyceraldehyde
acetonide and L-erythrulose, the latter being currently
developed by our group as an useful C4 chiron.7
Investigations on the chemical components of the marine
cyanobacterium Lyngbya majuscula Gomont have given
rise to a plethora of new biologically active compounds.1
One of these is malyngolide (2)-1 (Scheme 1), a d-lactone
displaying antibiotic activity against pathogenic species of
Staphylococcus, Mycobacterium, Pseudomonas and related
genera.1a A further component isolated from the same
source is tanikolide (þ)-2, a structurally related lactone with
antifungal and molluscicidal properties.1b Total syntheses of
(2)-1, its unnatural antipode (þ)-1 and (þ)-2 have been
published by several groups.2 – 4 Two years ago, we
described a further synthetic approach to (þ)-1 using a
strategy which included an olefin ring-closing metathesis
(RCM).5 In the present report, we disclose in full the total
syntheses of both enantiomers of malyngolide, (þ)-1 and
(2)-1, and of the natural enantioner of tanikolide, (þ)-2. All
three syntheses are based on our recently described
methodology of sequential allylation/RCM/allylic oxi-
2. Results and discussion
The synthetic sequence previously reported5 for (þ)-1
(Scheme 2) relied upon a stereoselective nucleophilic
allylation of protected L-erythrulose derivatives of general
formula 3.8 This was performed under nonchelation control
by means of allyl tributyltin in the presence of a Lewis acid.
This generated the quaternary stereogenic carbon in alcohol
49 with the configuration of the unnatural malyngolide
enantiomer. Tosylation of 4 afforded 5,10 which was
treated with base to yield epoxide 6. Nucleophilic
opening of the oxirane ring in 6 with a n-octylcuprate
reagent11 gave tertiary carbinol 7, which was then
O-alkylated with methallyl chloride to ether 8. The latter
underwent RCM6 in the presence of ruthenium catalyst
Scheme 1.
Keywords: erythrulose; glyceraldehyde; ring-closing metathesis; lactones; malyngolide; tanikolide.
*
Corresponding authors. Tel.: þ34-96-3544337; fax: þ34-96-3544328; e-mail: alberto.marco@uv.es
†
Present address: Dept. Farm. y Tecn. Farm., Fac. C. Exp. y de la Salud, Univ. Cardenal Herrera-CEU, Moncada, Valencia, Spain.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01594-6

858
M. Carda et al. / Tetrahedron 59 (2003) 857–864
Scheme 2. Synthesis of (þ)-malyngolide. Reaction conditions: (a) monotosylation. (b) base treatment (65–67% for the two steps, see details in the Section 3).
(c) Me(CH2)7MgBr, CuI, THF, 2308C (80%). (d) KH, methallyl chloride, THF, K (75%). (e) 3% PhCHvRuCl2(PCy3)2, CH2Cl2, K (92%). (f) CrO3/3,5-DMP,
CH2Cl2, 2208C (77%). (g) H5IO6, Et2O, 6 h, rt, then L-Selectride, THF, 90 min, 2788C (65% overall) (Tr¼trityl; TPS¼t-butyldiphenylsilyl; p-Ts¼p-
toluenesulphonyl).
12
PhCHvRuCl2-(PCy3)2 to furnish dihydropyran 9 in an
excellent 92% yield. Allylic oxidation of 9 with the CrO3/
3,5-DMP complex6,13 yielded the a,b-unsaturated d-lactone
10,14 which was then subjected to oxidative cleavage of the
dioxolane ring with periodic acid in Et2O.15 In our previous
synthesis,5 the intermediate unstable aldehyde 11 was not
isolated but immediately reduced with NaBH4 in iso-
propanol to yield dehydromalyngolide,16 then converted
into (þ)-1 through catalytic hydrogenation.17 This
procedure has now been improved in that crude 11 is
treated with L-selectride at 2788C. This causes not only
reduction of the aldehyde function but also saturation of the
conjugated CvC bond18 to afford (þ)-1 in 65% overall
yield.2c,19
the latter furnished dihydropyrane 14, which was then
subjected to allylic oxidation as above to yield lactone 15.13
The latter proved, however, more sensitive than 10 to the
acidic conditions of oxidative acetal cleavage with periodic
acid, as well as to those of acid hydrolysis.20 Hydrogenation
of the conjugated double bond afforded the saturated lactone
16, the acetal group of which was amenable to acid
hydrolysis to 17. Oxidative cleavage of the diol moiety in 17
with lead tetraacetate, followed by immediate reduction of
the intermediate unstable aldehyde18 yielded (þ)-2, with
physical and spectral properties identical to those reported.4
In the syntheses of (þ)-1 and (þ)-2 described above, a
derivative of the commercially available sugar L-ery-
thrulose was the starting material. As described above, the
synthesis relied on a stereoselective nucleophilic allylation
of its carbonyl group under nonchelation control. The
synthesis of the naturally occurring (2)-1 would therefore
demand either to start with a D-erythrulose derivative or to
perform stereoselective allylations of L-erythrulose deriva-
tives under chelation control. The reluctance of the more
readily available erythrulose acetals to participate in
chelation-controlled allylations of the carbonyl group9 led
us to discard the latter approach. While D-erythrulose
Tanikolide differs from malyngolide solely in lacking the
a-carbonyl methyl group and in having a longer aliphatic
chain (n-undecyl instead of n-nonyl). Furthermore, natural
(þ)-2 has the same absolute configuration as (þ)-1 at the
quaternary carbon center. Consequently, the same strategy
was adapted without relevant changes to its synthesis
(Scheme 3). Epoxide 6 was opened with a n-decylcuprate
reagent11 under the same conditions as above. This provided
alcohol 12, which was then O-allylated to ether 13. RCM of
Scheme 3. Synthesis of (þ)-tanikolide. Reaction conditions: (a) Me(CH2)9MgBr, CuI, THF, 2308 (75%). (b) KH, allyl chloride, THF, K (75%). (c) 3%
PhCHvRuCl2(PCy3)2, CH2Cl2, K (85%). (d) CrO3/3,5-DMP, CH2Cl2, 2208C (70%). (e) H2, Pd/C (90%). (f) aq. AcOH, 408C (87%). (g) Pb(OAc)4, THF, then
L-Selectride, THF, 90 min, 2788C (55% overall).

M. Carda et al. / Tetrahedron 59 (2003) 857–864
859
Scheme 4. Synthesis of (2)-malyngolide. Reaction conditions: (a) Me(CH2)8MgBr, THF, rt. (b) PCC, NaOAc, CH2Cl2, rt (60% for the two steps). (c) allyl
bromide, indium powder, aq. THF, rt (73% of a 4.5:1 stereoisomeric mixture). Steps (d)–(g) as for (þ)-1 (Scheme 2).
derivatives can be prepared from D-isoascorbic acid,8a the
somewhat lengthy synthetic procedure led us to explore an
alternative way through chiral ketone 18, readily prepared in
two steps from D-glyceraldehyde acetonide (Scheme 4).
This ketone proved unreactive towards allyl tributyltin and
magnesium bromide etherate, even at room temperature,
where decomposition started to take place.21 Allyllithium
and allylmagnesium bromide gave, however, an about 3:1
mixture of the enantiomer of alcohol 7 (ent-7, major
compound) and its epimer at the starred carbon. A
somewhat better stereoselectivity was observed under
Barbier conditions.22 Treatment of 18 with indium powder
and allyl bromide in aqueous THF gave a 4.5:1 mixture of
ent-7 and its epimer, which could not be separated under
normal chromatographic conditions. O-Methallylation of
this mixture gave the corresponding epimeric ethers (ent-
8þepimer), which were subjected to RCM under the same
conditions as above. The major compound ent-9 was
separated at this stage from the minor epimer and found to
be identical with compound 9 in all aspects except for
the sign of the optical rotation. Compound ent-9 was
then converted as described above into natural malyngolide,
(2)-1.
from CaH2. Hydrocarbons were freshly distilled from
sodium wire. Tertiary amines were freshly distilled from
KOH. Unless detailed otherwise, ‘work-up’ means pouring
the reaction mixture into satd aqueous NH4Cl, extraction
with the solvent indicated in parenthesis, additional washing
with 5% aq. NaHCO3, (if acids had been utilized in the
reaction) or with 5% aq. HCl (if bases had been utilized),
drying over anhydrous Na2SO4 or MgSO4 and solvent
removal in vacuo. Where solutions were filtered through a
Celite pad, the pad was additionally washed twice with the
same solvent used, and the washings incorporated to the
main organic layer. Column chromatography was per-
formed on silica gel (Su¨d-Chemie AG, 60-200m) with the
eluent indicated in each case.
3.1. (2S,40S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-
hydroxypent-4-enyl p-toluenesulfonate, 5 and (4S,20S)-4-
(2-allyloxiranyl)-2,2-dimethyl-1,3-dioxolane, 6
Two alternative procedures A and B were used to convert
diol 4 into epoxide 6 via tosylate 5. While both gave
comparable overall yields, method B was more comfortable
of use.
In summary, we have completed total, stereoselective
syntheses of the naturally occurring, biologically active
lactones (2)-malyngolide and (þ)-tanikolide, as well as of
the antipodal, unnatural form of the former. Precursors from
the chiral pool were the starting materials. Further work
related to the synthesis of natural lactones using RCM is
underway and will be reported in due course.23
Method A. Diol 49 (2.02 g, 10 mmol) was dissolved under
Ar in dry CH2Cl2 (50 mL) and treated sequentially with
Et3N (2.1 mL, 15 mmol), DMAP (60 mg, 0.5 mmol) and
p-TsCl (2.1 g, ca. 11 mmol). The mixture was stirred for
24 h at reflux (TLC monitoring) and worked up (CH2Cl2).
For analytical purposes, an aliquot of the residue was
chromatographed on silica gel (hexanes–EtOAc, 7:3) to
yield pure 5. For synthetic purposes, the crude tosylate was
used directly in the next step.
3. Experimental
A 35% suspension of KH in mineral oil (1.15 g, equivalent
to ca. 10 mmol of active hydride) was washed three times
under Ar with dry hexane. Dry THF (25 mL) was then
added, followed by a solution of the crude tosylate 5 in dry
THF (40 mL). The solution was then stirred at room
temperature for 30 min. Work-up (EtOAc) and column
chromatography on silica gel (hexane–EtOAc 9:1)
furnished 6 (1.23 g, 67% overall from 4).
NMR spectra (Varian Unity 400 and 500 NMR spec-
trometers) were measured in CDCl3 solution at 258C. 13C
NMR signal multiplicities were determined with the DEPT
pulse sequence. Mass spectra were run by the electron
impact (EIMS, 70 eV) on a VG AutoSpec mass spec-
trometer. IR spectra were recorded as oily films on NaCl
plates (oils) or as KBr pellets (solids). Optical rotations were
measured at 258C. Reactions which required an inert
atmosphere were carried out under argon with flame-dried
glassware. Commercial reagents were used as received.
THF and Et2O were freshly distilled from sodium-
benzophenone ketyl. Dichloromethane was freshly distilled
Method B. Diol 4 (2.02 g, 10 mmol) was dissolved under Ar
in dry CH2Cl2 (25 mL) and treated sequentially with
nBu2SnO (50 mg, 0.2 mmol), Et3N (2 mL, ca. 14 mmol)
and p-TsCl (2.29 g, ca. 12 mmol).24 The mixture was stirred

860
M. Carda et al. / Tetrahedron 59 (2003) 857–864
for 3–4 h at room temperature (TLC monitoring) and
worked up (CH2Cl2). The crude tosylate was used directly in
the next step and cyclized to 6 according to a literature
procedure.25
[a]D¼þ0.6 (c 3.8; CHCl3); IR nmax (cm21): 3480 (br, OH),
3076, 2980, 2928, 2855, 1457, 1371, 1216, 1160, 1069, 915,
1
861; H NMR (500 MHz) d 5.79 (1H, ddt, J¼17.3, 10,
7 Hz), 5.10 (1H, br d, J¼10 Hz), 5.08 (1H, br d,
J¼17.3 Hz), 4.00 (1H, dd, J¼7.7, 6.6 Hz), 3.95 (1H, dd,
J¼8, 6.6 Hz), 3.86 (1H, dd, J¼8, 7.7 Hz), 2.30 (1H, dd,
J¼14, 6.5 Hz), 2.05 (1H, dd, J¼14, 8.2 Hz), 1.90 (1H, br s,
OH), 1.55 (2H, m), 1.41 (3H, s), 1.35 (3H, s), 1.40–1.20
(14H, br m), 0.87 (3H, t, J¼7 Hz); 13C NMR (125 MHz) d
108.9, 73.1 (C), 133.1, 80.1 (CH), 118.4, 64.6, 39.3, 37.3,
32.0, 30.2, 29.7, 29.6, 29.3, 23.2, 22.7 (CH2), 26.4, 25.5,
14.1 (CH3); EIMS, m/z (% rel. int.) 283.2273 [Mþ2Me] (9),
257 (14), 197 (18), 171 (20), 155 (100). Calcd for
C18H34O3–Me, M¼283.2273. Anal. calcd for C18H34O3:
C, 72.44; H, 11.48. Found, C, 72.69; H, 11.40.
NaOH (8 g, 200 mmol) and tetrabutylammonium hydrogen
sulphate (6.8 g, 20 mmol) were dissolved in water (70 mL)
and mixed with a solution of the crude tosylate in CH2Cl2
(40 mL). The biphasic reaction mixture was then vigorously
stirred for 3 h at room temperature. Work-up (CH2Cl2) and
column chromatography on silica gel (hexanes–EtOAc,
9:1) gave epoxide 6 (1.2 g, 65% overall yield from 4).
3.1.1. (2S,4S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-
hydroxypent-4-enyl p-toluenesulfonate, 5. Colorless
needles, mp 59–608C, [a]D¼þ6.8 (c 2.2; CHCl3); IR nmax
(cm21): 3500 (br, OH), 3076, 2987, 2935, 1641, 1599, 1456,
3.3. (4S,10R)-2,2-Dimethyl-4-[1-(2-methylallyloxy)-1-
nonylbut-3-enyl]-1,3-dioxolane, 8
1
1366, 1260, 1214, 1178, 1097, 1068, 983, 842, 815; H
NMR (400 MHz) d 7.78 (2H, d, J¼8 Hz), 7.34 (2H, d,
J¼8 Hz), 5.68 (1H, ddt, J¼17, 11, 7 Hz), 5.10–5.00 (2H,
m), 4.02 (1H, dd, J¼8, 6.5 Hz), 3.93 (2H, br s), 3.92 (1H, dd,
J¼8, 6.5 Hz), 3.86 (1H, t, J¼8 Hz), 2.80 (1H, br s, OH),
2.43 (3H, s), 2.20 (2H, m), 1.33 (3H, s), 1.26 (3H, s); 13C
NMR (100 MHz) d 145.0, 132.5, 109.3, 72.1 (C), 131.1,
129.8, 128.1, 76.9 (CH), 119.8, 70.9, 64.0, 37.6 (CH2), 26.1,
25.1, 21.6 (CH3); EIMS, m/z (% rel. int.) 341.1047
[Mþ2Me] (42), 315 (46), 155 (90), 101 (100), 91 (73).
Calcd for C17H24O6S–Me, M¼341.1059. Anal. calcd
for C17H24O6S: C, 57.28; H, 6.79. Found, C, 57.34; H, 6.90.
A 35% suspension of KH in mineral oil (0.69 g, equivalent
to ca. 6 mmol of active hydride) was washed three times
under Ar with dry hexane. Dry THF (5 mL) was then added,
followed by a solution of 7 (895 mg, 3 mmol) in dry THF
(20 mL). The solution was stirred at room temperature for
30 min. Methallyl chloride (590 mL, 6 mmol) was then
added dropwise, followed by tetrabutylammonium iodide
(37 mg, 0.1 mmol). The reaction mixture was then heated
overnight at reflux. Work-up (EtOAc) and column chroma-
tography on silica gel (hexanes–EtOAc, 19:1!9:1) furn-
ished 8 (793 mg, 75%): oil, [a]D¼23.5 (c 3.2; CHCl3); IR
nmax (cm21): 3077, 2970, 2921, 2853, 1640, 1458, 1379,
3.1.2. (4S,20S)-4-(2-Allyloxiranyl)-2,2-dimethyl-1,3-
dioxolane, 6. Colorless oil, [a]D¼24.8 (c 7.2; CHCl3); IR
nmax (cm21): 3079, 2988, 2936, 1457, 1436, 1381, 1372,
1
1210, 1159, 1068, 915, 861, 740; H NMR (500 MHz) d
5.82 (1H, ddt, J¼17.3, 10, 7 Hz), 5.07 (1H, br d,
J¼17.3 Hz), 5.06 (1H, br d, J¼10 Hz), 4.96 (1H, br s),
4.80 (1H, br s), 4.13 (1H, t, J¼7.4 Hz), 4.06 (1H, br d,
J¼12.5 Hz), 3.95–3.90 (3H, m), 2.35 (1H, dd, J¼14.5,
6.8 Hz), 2.18 (1H, dd, J¼14.5, 7.8 Hz), 1.72 (3H, br s), 1.65
(2H, m), 1.42 (3H, s), 1.32 (3H, s), 1.40–1.20 (14H, br m),
0.88 (3H, t, J¼7 Hz); 13C NMR (125 MHz) d 143.4, 108.6,
77.7 (C), 134.0, 80.4 (CH), 117.6, 110.2, 66.7, 65.1, 39.4,
32.8, 32.0, 30.3, 29.6, 29.5, 29.3, 23.1, 22.7 (CH2), 26.4,
24.9, 19.7, 14.1 (CH3); EIMS, m/z (% rel. int.) 337.2743
[Mþ2Me] (2), 311 (4), 251 (33), 155 (100). Calcd for
C22H40O3–Me, M¼337.2743. Anal. calcd for C22H40O3: C,
74.95; H, 11.44. Found, C, 75.00; H, 11.66.
1
1260, 1219, 1158, 1071, 1000, 963, 920, 848; H NMR
(500 MHz) d 5.72 (1H, ddt, J¼17.3, 10, 7 Hz), 5.11 (1H, br
d, J¼17.3 Hz), 5.08 (1H, br d, J¼10 Hz), 4.17 (1H, t,
J¼6.6 Hz), 4.02 (1H, dd, J¼8.3, 6.6 Hz), 3.80 (1H, dd,
J¼8.3, 6.6 Hz), 2.82 (1H, d, J¼5.2 Hz), 2.62 (1H, d,
J¼5.2 Hz), 2.42 (1H, dd, J¼14.8, 7 Hz), 2.38 (1H, dd,
J¼14.8, 7 Hz), 1.36 (3H, s), 1.31 (3H, s); 13C NMR
(125 MHz) d 109.7, 58.0 (C), 132.2, 76.3 (CH), 118.6, 65.6,
48.8, 36.0 (CH2), 26.1, 25.4 (CH3); EIMS, m/z (% rel. int.)
169.0870 [Mþ2Me] (94), 101 (64), 81 (100). Calcd for
C10H16O3–Me, M¼169.0864. Anal. calcd for C10H16O3: C,
65.19; H, 8.75. Found, C, 65.01; H, 8.94.
3.2. (4R,40S)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)tridec-1-
en-4-ol, 7
3.4. (2R,40S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-
methyl-2-nonyl-3,6-dihydro-2H-pyran, 9
CuI (1.52 g, 8 mmol) was heated in vacuo in a three-necked
flask until the solid turned light yellow. The flask was then
filled with Ar and cooled to 2308C, followed by addition of
dry Et2O (30 mL). A 2 M solution of n-octylmagnesium
bromide in Et2O (10 mL, 20 mmol) was then added
dropwise to the aforementioned CuI suspension. The
resulting mixture was stirred for 20 min at 2308C. Epoxide
6 (921 mg, 5 mmol) was dissolved in dry Et2O (10 mL) and
added dropwise via syringe to the solution of the
organocopper reagent. The reaction mixture was then
stirred for 6–8 h at 2308C (TLC monitoring). The reaction
was then quenched with satd aq. ammonium chloride and
worked up (EtOAc). Column chromatography on silica gel
(hexanes–EtOAc, 4:1) afforded alcohol 7 (1.19 g, 80%): oil,
Compound 8 (705 mg, 2 mmol) and ruthenium complex
PhCHvRuCl2-(PCy3)2 (49 mg, 0.06 mmol) were dissolved
under Ar in dry, degassed CH2Cl2 (100 mL) and heated at
reflux for 12–18 h (TLC monitoring). After removal of all
volatiles in vacuo, the residue was chromatographed on
silica gel (hexanes–EtOAc, 9:1) to furnish cyclic ether 9
(597 mg, 92%): oil, [a]D¼þ31.9 (c 3.6; CHCl3); IR nmax
(cm21): 2970, 2921, 2856, 1458, 1372, 1263, 1210, 1068,
857, 738; 1H NMR (400 MHz) d 5.42 (1H, m), 4.31 (1H, dd,
J¼8, 6.9 Hz), 3.96 (1H, dd, J¼8, 6.9 Hz), 3.94 (2H, m), 3.69
(1H, t, J¼8 Hz), 2.43 (1H, ddq, J¼17, 2.5, 2.5 Hz), 1.80–
1.70 (3H, br m), 1.58 (3H, br s), 1.42 (3H, s), 1.36 (3H, s),
1.35–1.20 (14H, br m), 0.86 (3H, t, J¼7 Hz); 13C NMR
(100 MHz) d 131.4, 109.5, 73.5 (C), 116.8, 78.6 (CH), 64.8,

M. Carda et al. / Tetrahedron 59 (2003) 857–864
861
64.3, 32.5, 31.9, 30.5, 29.6, 29.5, 29.3, 27.7, 22.8, 22.7
3.7. (4R,40S)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)penta-
dec-1-en-4-ol, 12
(CH2), 26.3, 25.3, 18.6, 14.1 (CH3); EIMS, m/z (% rel. int.)
324.2659 [Mþ] (2), 309 (4), 223 (70), 155 (100), 101 (26).
Calcd for C20H36O3, M¼324.2664. Anal. calcd for
C20H36O3: C, 74.03; H, 11.18. Found, C, 73.91; H, 11.00.
CuI (1.52 g, 8 mmol) was heated in vacuo in a three-necked
flask until the solid turned light yellow. The flask was then
filled with Ar and cooled to 2308C, followed by addition of
dry Et2O (20 mL). A 1 M solution of n-decylmagnesium
bromide in Et2O (20 mL, 20 mmol) was then added
dropwise to the aforementioned CuI suspension. The
resulting mixture was stirred for 20 min at 2308C. Epoxide
6 (921 mg, 5 mmol) was dissolved in dry Et2O (10 mL) and
added dropwise via syringe to the solution of the
organocopper reagent. The reaction mixture was then
stirred for 6–8 h at 2308C (TLC monitoring). The reaction
was then quenched with satd aq. ammonium chloride and
worked up (EtOAc). Column chromatography on silica gel
(hexanes–EtOAc, 4:1) afforded alcohol 12 (1.22 g, 75%):
oil, [a]D¼20.1 (c 3.8; CHCl3); IR nmax (cm21): 3480 (br,
OH), 3077, 2984, 2930, 2854, 1457, 1380, 1371, 1251,
3.5. (6R,40S)-6-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3-
methyl-6-nonyl-5,6-dihydropyran-2-one, 10
Finely powdered chromium trioxide (1.2 g, 12 mmol) was
dried in vacuo in a dessicator containing P2O5. Then it was
suspended under Ar in dry CH2Cl2 (10 mL), cooled to
2208C and treated rapidly at this temperature with 3,5-
dimethylpyrazole (1.16 g, 12 mmol). After stirring the
mixture for 15 min, ether 9 (325 mg, 1 mmol) dissolved in
dry CH2Cl2 (5 mL) was added. The reaction mixture was
then stirred for 1 h at 2208C, treated with 5 M aqueous
NaOH (5 mL) and further stirred at 08C for 1 h. The reaction
mixture was then poured into diluted HCl, and the organic
layer was washed with brine and dried over anhydrous
Na2SO4. Filtration through Celite and solvent removal in
vacuo were followed by column chromatography on silica
gel (hexanes–EtOAc, 4:1) to yield 10 (260 mg, 77%): oil,
[a]D¼29.9 (c 10; CHCl3); IR nmax 2941, 2856, 1720
1
1216, 1161, 1069, 916, 861; H NMR (400 MHz) d 5.79
(1H, ddt, J¼17.3, 10, 7 Hz), 5.10 (1H, br d, J¼10 Hz), 5.08
(1H, br d, J¼17.3 Hz), 3.99 (1H, dd, J¼7.8, 6.4 Hz), 3.95
(1H, dd, J¼7.8, 6.4 Hz), 3.87 (1H, t, J¼7.8 Hz), 2.28 (1H,
dd, J¼14, 6.5 Hz), 2.04 (1H, dd, J¼14, 8.2 Hz), 1.55 (2H,
m), 1.41 (3H, s), 1.35 (3H, s), 1.40–1.20 (18H, br m), 0.87
(3H, t, J¼7 Hz); 13C NMR (100 MHz) d 108.9, 73.1 (C),
133.1, 80.1 (CH), 118.5, 64.6, 39.3, 37.3, 32.0, 30.2, 29.8,
29.7 (£2), 29.6, 29.3, 23.2, 22.7 (CH2), 26.5, 25.5, 14.2
(CH3); EIMS, m/z (% rel. int.) 311.2530 [Mþ2Me] (11),
285 (24), 225 (18), 183 (100). Calcd for C20H38O3–Me,
M¼311.2586. Anal. calcd for C20H38O3: C, 73.57; H, 11.73.
Found, C, 73.69; H, 11.60.
1
(lactone CvO), 1121, 1058 cm21; H NMR (500 MHz) d
6.44 (1H, m), 4.33 (1H, dd, J¼7.1, 6.3 Hz), 4.00 (1H, dd,
J¼9, 7.1 Hz), 3.91 (1H, dd, J¼9, 6.3 Hz), 2.58 (1H, ddq,
J¼18.5, 2.5, 2.5 Hz), 2.45 (1H, ddq, J¼18.5, 2.5, 2.5 Hz),
1.89 (3H, d, J¼1.5 Hz), 1.70–1.60 (2H, m), 1.42 (3H, s),
1.32 (3H, s), 1.40–1.20 (14H, br m), 0.87 (3H, t, J¼7 Hz);
13C NMR (125 MHz) d 164.4, 127.4, 109.9, 83.6 (C), 137.3,
77.9 (CH), 64.7, 34.4, 31.8, 30.0, 29.5 (£2), 29.2, 28.2, 23.5,
22.6 (CH2), 26.1, 24.7, 17.0, 14.1 (CH3); EIMS, m/z (% rel.
int.) 323.2224 [Mþ2Me] (26), 237 (100), 155 (55), 101
(68). Calcd for C20H34O4–Me, M¼323.2222. Anal. calcd
for C20H34O4: C, 70.97; H, 10.12. Found, C, 71.01; H,
10.00.
3.8. (4S,10R)-4-(1-Allyloxy-1-undecylbut-3-enyl)-2,2-
dimethyl-1,3-dioxolane, 13
A 35% suspension of KH in mineral oil (0.69 g, equivalent
to ca. 6 mmol of active hydride) was washed three times
under Ar with dry hexane. Dry THF (5 mL) was then added,
followed by a solution of 12 (980 mg, 3 mmol) in dry THF
(20 mL). The solution was stirred at room temperature for
30 min. Methallyl chloride (590 mL, 6 mmol) was then
added dropwise, followed by tetrabutylammonium iodide
(37 mg, 0.1 mmol). The reaction mixture was then heated
overnight at reflux. Work-up (EtOAc) and column chroma-
tography on silica gel (hexanes–EtOAc, 19:1!9:1)
furnished 13 (825 mg, 75%): oil, [a]D¼28.7 (c 2;
CHCl3); IR nmax (cm21): 3077, 2983, 2931, 2855, 1640,
3.6. (1)-Malyngolide, (1)-1
Lactone 10 (169 mg, 0.5 mmol) was dissolved under Ar in
dry Et2O (2 mL) and treated with periodic acid hydrate
(171 mg, 0.75 mmol). The reaction mixture was then stirred
for 6 h at room temperature, then diluted with Et2O (10 mL)
and filtered through Celite. The ethereal layer was then
stirred for 15 min with solid K2CO3 (ca. 50 mg) to remove
traces of acid and filtered again. Solvent removal in vacuo
afforded crude 11, which was dissolved under Ar in dry THF
(5 mL) and cooled to 2788C. A 1 M solution of L-selectride
in THF (1.25 mL, 1.25 mmol) was added via syringe. The
reaction mixture was then stirred at 2788C for 90 min.
Work-up (CH2Cl2) and column chromatography on silica
gel (hexanes–EtOAc, 4:1!1:1) provided (þ)-1 (88 mg,
65% overall yield from 10): oil, [a]D¼þ12.3 (c 1; CHCl3),
for synthetic (þ)-malyngolide, lit.2c [a]D¼þ12.4 (c 2;
CHCl3). 1H NMR (500 MHz) d 3.66 (1H, d, J¼12 Hz), 3.47
(1H, dd, J¼12 Hz), 2.42 (1H, ddq, J¼11, 7, 7 Hz), 2.00–
1.60 (7H, br m), 1.35–1.20 (14H, br m), 1.24 (3H, d,
J¼7 Hz), 0.86 (3H, t, J¼6.5 Hz); 13C NMR (125 MHz) d
175.0, 86.8 (C), 35.6 (CH), 67.8, 36.5, 31.9, 30.0, 29.5, 29.4,
29.3, 26.4, 23.7, 22.6, 17.1 (CH2), 25.2, 14.1 (CH3). EIMS,
m/z (% rel. int.) 239.1999 [Mþ2CH2OH] (28), 237 (100),
155 (85). Calcd for C16H30O3–CH2OH, M¼239.2011.
1
1458, 1379, 1370, 1261, 1211, 1159, 1067, 916, 862; H
NMR (400 MHz) d 5.95–5.75 (2H, m), 5.25 (1H, dq, J¼17,
1.5 Hz), 5.10–5.05 (3H, m), 4.20 (1H, ddt, J¼12.7, 5.2,
1.6 Hz), 4.12 (1H, dd, J¼8, 6.6 Hz), 4.06 (1H, ddt, J¼12.7,
5.2, 1.6 Hz), 3.95–3.90 (2H, m), 2.36 (1H, dd, J¼14.5,
6.8 Hz), 2.15 (1H, dd, J¼14.5, 7.7 Hz), 1.70–1.60 (2H,
m), 1.43 (3H, s), 1.31 (3H, s), 1.35–1.20 (18H, br m),
0.88 (3H, t, J¼7 Hz); 13C NMR (100 MHz) d 108.7, 77.8
(C), 136.1, 133.9, 80.4 (CH), 117.7, 115.2, 65.0, 64.3, 39.4,
32.6, 32.0, 30.3, 29.7, 29.6 (£2), 29.5, 29.4, 23.1, 22.7
(CH2), 26.4, 24.8, 14.2 (CH3). EIMS, m/z (% rel. int.)
351.2890 [Mþ2Me] (2), 325 (22), 265 (31), 183 (100), 101
(40). Calcd for C23H42O3–Me, M¼351.2899. Anal. calcd
for C23H42O3: C, 75.36; H, 11.55. Found, C, 75.20; H,
11.56.

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M. Carda et al. / Tetrahedron 59 (2003) 857–864
3.9. (2R,40S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-
undecyl-3,6-dihydro-2H-pyran, 14
(5 mL) was then added via syringe. The solution was stirred
for 24 h at ambient pressure and temperature, then filtered
through Celite. Solvent removal in vacuo and column
chromatography on silica gel (hexanes–EtOAc, 4:1)
furnished 16 (223 mg, 90%): oil, [a]D¼þ6.9 (c 4.3;
CHCl3); IR nmax (cm21): 2965, 2925, 2855, 1737 (lactone
CvO), 1459, 1371, 1329, 1259, 1158, 1068, 927, 856, 800;
1H NMR (400 MHz) d 4.23 (1H, dd, J¼7.1, 6.5 Hz), 4.00
(1H, dd, J¼8.8, 7.1 Hz), 3.79 (1H, dd, J¼8.8, 6.5 Hz), 2.42
(2H, m), 2.00–1.70 (4H, m), 1.60–1.50 (2H, m), 1.43 (3H,
s), 1.32 (3H, s), 1.35–1.20 (18H, br m), 0.86 (3H, t,
J¼7 Hz); 13C NMR (100 MHz) d 171.6, 109.7, 85.3 (C),
79.3 (CH), 64.8, 36.5, 31.9, 30.1, 30.0, 29.7, 29.6 (£2), 29.5,
29.3, 25.8, 22.9, 22.7, 17.0 (CH2), 26.1, 24.6, 14.1 (CH3);
EIMS, m/z (% rel. int.) 354.2764 [Mþ] (3), 339 [Mþ2Me]
(36), 253 (100), 225 (40), 101 (58). Calcd for C21H38O4,
M¼354.2770. Anal. calcd for C21H38O4: C, 71.14; H, 10.80.
Found, C, 71.22; H, 10.66.
Compound 13 (733 mg, 2 mmol) and ruthenium complex
PhCHvRuCl2-(PCy3)2 (49 mg, 0.06 mmol) were dissolved
under Ar in dry, degassed CH2Cl2 (100 mL) and heated at
reflux for 12–18 h (TLC monitoring). After removal of all
volatiles in vacuo, the residue was chromatographed on
silica gel (hexanes–EtOAc, 19:1) to furnish cyclic ether 14
(575 mg, 85%): oil, [a]D¼þ24.4 (c 2.1; CHCl3); IR nmax
(cm21): 3035, 2970, 2926, 2854, 1459, 1374, 1370, 1261,
1
1211, 1161, 1100, 1069, 859, 800; H NMR (400 MHz) d
5.77 (1H, dtt, J¼10, 4.5, 2 Hz), 5.70 (1H, br d, J¼10 Hz),
4.32 (1H, t, J¼7.4 Hz), 4.16 (1H, br d, J¼17 Hz), 4.10 (1H,
br d, J¼17 Hz), 3.97 (1H, dd, J¼8, 7.4 Hz), 3.70 (1H, dd,
J¼8, 7.4 Hz), 2.48 (1H, dddt, J¼17, 2.5, 2.5, 2.5 Hz), 1.90–
1.70 (3H, br m), 1.44 (3H, s), 1.37 (3H, s), 1.35–1.20 (18H,
br m), 0.87 (3H, t, J¼7 Hz); 13C NMR (100 MHz) d 109.5,
73.7 (C), 125.0, 122.5, 78.7 (CH), 64.7, 61.1, 32.5, 31.9,
30.4, 29.7, 29.6 (£2), 29.5, 29.3, 27.7, 22.9, 22.7 (CH2),
26.2, 25.2, 14.1 (CH3). EIMS, m/z (% rel. int.) 338.2834
[M]þ (1), 323 (5), 237 (58), 183 (100), 101 (22). Calcd for
C21H38O3, M¼338.2821. Anal. calcd for C21H38O3: C,
74.51; H, 11.31. Found, C, 74.72; H, 11.44.
3.12. (6R,10S)-6-(1,2-Dihydroxyethyl)-6-undecyltetra-
hydropyran-2-one, 17
Lactone 16 (177 mg, 0.5 mmol) was dissolved in 75%
aqueous AcOH (2 mL) and stirred at 408C for 48 h. The
solvent was then azeotropically removed in vacuo (aided by
addition of EtOAc), the residue dissolved in Et2O (10 mL)
and stirred in the presence of solid K2CO3 (ca. 100 mg) to
remove traces of AcOH. Column chromatography of the
oily residue on silica gel (hexanes–EtOAc, 1:1) afforded 17
(137 mg, 87%): oil, [a]D¼þ13.5 (c 1; CHCl3); IR nmax
(cm21): 3430 (br, OH), 2950, 2921, 2854, 1722, 1459, 1337,
1254, 1036, 925; 1H NMR (400 MHz) d 3.86 (1H, dd,
J¼8.4, 3.2 Hz), 3.72 (1H, dd, J¼11.2, 3.2 Hz), 3.55 (1H, dd,
J¼11.2, 8.4 Hz), 2.46 (2H, m), 2.05–1.90 (2H, br m), 1.85–
1.60 (6H, br m), 1.35–1.20 (18H, br m), 0.88 (3H, t,
J¼6.8 Hz); 13C NMR (100 MHz) d 172.2, 87.2 (C), 75.5
(CH), 62.1, 37.1, 31.9, 30.1, 29.9, 29.7, 29.6 (x 2), 29.5,
29.4, 26.0, 23.1, 22.7, 16.9 (CH2), 14.2 (CH3); EIMS, m/z
(% rel. int.) 253.2190 [Mþ2CHOHCH2OH] (100), 225
(455). Calcd for C18H34O4–CHOHCH2OH, M¼253.2167.
Anal. calcd for C18H34O4: C, 68.75; H, 10.90. Found, C,
68.92; H, 10.77.
3.10. (6R,40S)-6-(2,2-Dimethyl-1,3-dioxolan-4-yl)-6-
undecyl-5,6-dihydropyran-2-one, 15
Finely powdered chromium trioxide (1.2 g, 12 mmol) was
dried in vacuo in a dessicator containing P2O5. Then it was
suspended under Ar in dry CH2Cl2 (10 mL), cooled to
2208C and treated rapidly at this temperature with 3,5-
dimethylpyrazole (1.16 g, 12 mmol). After stirring the
mixture for 15 min, ether 14 (338 mg, 1 mmol) dissolved
in dry CH2Cl2 (5 mL) was added. The reaction mixture was
then stirred for 1 h at 2208C, treated with 5 M aqueous
NaOH (5 mL) and further stirred at 08C for 1 h. The reaction
mixture was then poured into diluted HCl, and the organic
layer was washed with brine, dried over anhydrous Na2SO4.
Filtration and solvent removal in vacuo was followed by
column chromatography on silica gel (hexanes–EtOAc,
9:1!4:1) to yield 15 (246 mg, 70%): oil, [a]D¼26.7 (c 1.9;
CHCl3); IR nmax (cm21): 2985, 2932, 2854, 1721 (lactone
1
CvO), 1459, 1382, 1263, 1215, 1159, 1072, 853, 811; H
3.13. (1)-Tanikolide, (1)-2
NMR (400 MHz) d 6.77 (1H, dt, J¼10, 4.5 Hz), 6.00 (1H,
dt, J¼10, 2 Hz), 4.35 (1H, dd, J¼7.1, 6.2 Hz), 4.02 (1H, dd,
J¼8.8, 7.1 Hz), 3.84 (1H, dd, J¼8.8, 6.2 Hz), 2.64 (1H, ddd,
J¼19, 4.4, 2 Hz), 2.47 (1H, ddd, J¼19, 4.1, 2 Hz), 1.70–
1.60 (2H, m), 1.43 (3H, s), 1.33 (3H, s), 1.35–1.20 (18H, br
m), 0.87 (3H, t, J¼7 Hz); 13C NMR (100 MHz) d 163.0,
110.1, 83.8 (C), 143.6, 120.6, 78.0 (CH), 64.7, 34.5, 31.9,
30.0, 29.7, 29.6 (£2), 29.5, 29.4, 27.9, 23.5, 22.7 (CH2),
26.1, 24.6, 14.2 (CH3). EIMS, m/z (% rel. int.) 352.2605
[M]þ (4), 337 (42), 251 (84), 183 (62), 101 (100). Calcd for
C21H36O4, M¼352.2613. Anal. calcd for C21H36O4: C,
71.55; H, 10.29. Found, C, 71.51; H, 10.30.
Diol 17 (125 mg, 0.4 mmol) was dissolved under Ar in dry
CH2Cl2 (3 mL) and treated with lead tetraacetate (163 mg,
0.44 mmol). The reaction mixture was then stirred for 1–2 h
at room temperature (TLC monitoring), then diluted with
CH2Cl2 (10 mL) and filtered through Celite. After solvent
removal in vacuo, the residue was dissolved in Et2O
(10 mL) and treated with solid K2CO3 (ca. 100 mg) to
remove traces of AcOH, followed by stirring at room
temperature for 15 min. Filtration and solvent removal in
vacuo afforded a crude aldehyde which was dissolved under
Ar in dry THF (5 mL) and cooled to 2788C. A 1M solution
of L-selectride in THF (0.6 mL, 0.6 mmol) was added via
syringe. The reaction mixture was then stirred at 2788C for
90 min. Work-up (CH2Cl2) and column chromatography on
silica gel (hexanes–EtOAc, 1:1) provided (þ)-2 (62 mg,
55% overall from 17): oil, [a]D¼þ2.9 (c 0.8; CHCl3); for
natural (þ)-tanikolide, lit.1b [a]D¼þ2.3 (c 0.65; CHCl3);
for synthetic (þ)-tanikolide, lit.4a [a]D¼þ2.9 (c 0.65;
3.11. (6R,40S)-6-(2,2-Dimethyl-1,3-dioxolan-4-yl)-6-
undecyltetrahydropyran-2-one, 16
Paladium catalyst (5% Pd/C, 50 mg) was suspended in
EtOH (5 mL) and stirred under an H2 atmosphere for 5 min.
A solution of lactone 15 (246 mmol, 0.7 mmol) in solvent

M. Carda et al. / Tetrahedron 59 (2003) 857–864
863
CHCl3) and lit.4c [a]D¼þ3.0 (c 0.8; CHCl3). IR nmax
(cm21): 3440 (br, OH), 2950, 2924, 2846, 1724, 1460, 1336,
1250, 1051, 927, 722; 1H NMR (400 MHz) d 3.65 (1H, br d,
J¼12 Hz), 3.55 (1H, br d, J¼12 Hz), 2.48 (2H, m), 2.10
(1H, br s, OH), 2.00–1.60 (6H, br m), 1.35–1.20 (18H, br
m), 0.87 (3H, t, J¼6.8 Hz); 13C NMR (100 MHz) d 171.6,
86.5 (C), 67.6, 36.7, 31.9, 30.0, 29.8, 29.7, 29.6, 29.5, 29.4,
29.3, 26.7, 23.5, 22.7, 16.7 (CH2), 14.1 (CH3); EIMS, m/z
(% rel. int.) 285.2424 [MþH]þ (1), 253 (100), 225 (45), 129
(20). Calcd for C17H33O3, M¼285.2429.
mixture under the same reaction conditions describe
above for compound 8. The NMR signals of the major
component of the mixture were coincident with those of
compound 8.
3.17. (2S,40R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-
methyl-2-nonyl-3,6-dihydro-2H-pyran, ent-9
Obtained through ring-closing metathesis (RCM) of com-
pound ent-8 (þepimer) under the same reaction conditions
describe above for 9. Separation of stereoisomers was
feasible by means of column chromatography on silica gel
(hexanes–EtOAc, 19:1, then 9:1). This afforded ent-9 as an
oil, [a]D¼230.6 (c 4.1; CHCl3), with spectral data identical
to those of 9.
3.14. (R)-1-(2,2-Dimethyl-1,3-dioxolan-4-yl)decan-1-one,
18
Freshly prepared isopropylidene D-glyceraldehyde26
(650 mg, 5 mmol) was dissolved at 08C under Ar in dry
Et2O (10 mL) and treated dropwise with a 1 M solution of
n-nonylmagnesium bromide in Et2O (10 mL, 10 mmol).
The cooling bath was then removed and the mixture was
stirred for 1 h at room temperature. Work-up (Et2O) and
column chromatography on silica gel (hexanes–EtOAc,
9:1) provided a mixture of two diastereoisomeric
n-nonylcarbinols, which was used directly in the next step.
3.18. (6S,40R)-6-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3-
methyl-6-nonyl-5,6-dihydropyran-2-one, ent-10
Obtained through allylic oxidation of ent-9 under the same
reaction conditions describe above for 10: oil, [a]D¼þ10 (c
10; CHCl3), with spectral data identical to those of 10.
3.19. (2)-Malyngolide, (2)-1
Pyridinium chlorochromate (1.3 g, ca. 6 mmol) and NaOAc
(246 mg, 3 mmol) were added under Ar to a solution of the
alcohol mixture in dry CH2Cl2 (4 mL). The mixture was
stirred overnight at room temperature, then diluted with
Et2O (10 mL) and filtered through Celite. Solvent removal
in vacuo and column chromatography of the residue on
silica gel (hexanes–EtOAc, 19:1!9:1) furnished ketone 18
(769 mg, 60% overall yield for the two steps): oil, [a]D¼þ4
(c 2.2; CHCl3), IR nmax (cm21): 2980, 2942, 2860, 1721
(ketone CvO), 1460, 1374, 1259, 1211, 1150, 1075, 818;
1H NMR (400 MHz) d 4.40 (1H, dd, J¼7.7, 5.7 Hz), 4.17
(1H, dd, J¼8.5, 8 Hz), 3.94 (1H, dd, J¼8.5, 5.7 Hz), 2.56
(2H, td, J¼7.5, 1.5 Hz), 1.55 (2H, m), 1.45 (3H, s), 1.36
(3H, s), 1.30–1.20 (12H, br m), 0.85 (3H, t, J¼7 Hz); 13C
NMR (100 MHz) d 211.0, 110.8 (C), 80.3 (CH), 66.5, 38.6,
31.8, 29.4, 29.3, 29.2, 29.1, 22.9, 22.6 (CH2), 26.0, 25.0,
14.1 (CH3); EIMS, m/z (% rel. int.) 241.1804 [Mþ2Me]
(11), 173 (34), 155 (32), 129 (40), 101 (100), 73 (56). Calcd
for C15H28O3 –Me, M¼241.1803. Anal. calcd for
C15H28O3: C, 70.27; H, 11.01. Found, C, 70.30; H, 11.20.
Obtained through sequential periodic acid oxidation and
L-selectride reduction of ent-10 under the same reaction
conditions describe above for (þ)-1: oil, [a]D¼212.2 (c 1;
CHCl3), for natural (2)-malyngolide, lit.1a [a]D¼213 (c 2;
CHCl3); for synthetic (2)-malyngolide, lit.2b [a]D¼212.5
(c 0.8; CHCl3) and lit.3b [a]D¼212.4 (c 2.5; CHCl3).
Spectral data identical to those of (þ)-1 (see above).
Acknowledgements
The authors acknowledge financial support by the Ministry
of Science and Technology through DGI and FEDER funds
´
`
(Project BQU2002-00468), by Fundacio Caixa Castello-
Univ. Jaume I (project PI-1B2002-06) and by the
Conselleria de Cultura de la Generalitat Valenciana (project
GV-99-77-1-02). E. C. and S. D.-O. thank the latter
institution for predoctoral fellowships. The authors further
thank the S.C.S.I.E. at the University of Valencia for mass
spectral measurements.
3.15. (4S,40R)-4-(2,2-Dimethyl-1,3-dioxolan-yl)tridec-1-
en-4-ol, ent-7 (1R,R-epimer)
Ketone 18 (769 mg, 3 mmol) was dissolved in 1:1 THF/H2O
(30 mL) and treated sequentially with allyl bromide
(780 mL, 9 mmol), tetrabutylammonium bromide (2.3 g,
3 mmol) and indium powder (690 mg, 6 mmol). The
mixture was stirred for 18 h at room temperature. Work-
up (EtOAc) and column chromatography on silica gel
(hexanes–EtOAc, 9:1) afforded ent-7 as a 4.5:1 mixture
with its epimer (653 mg, 73%). The NMR signals of the
major component of the mixture were coincident with those
of compound 7.
References
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3.16. (4R,10S)-2,2-Dimethyl-4-[1-(2-methylallyloxy)-1-
nonylbut-3-enyl]-1,3-dioxolane, ent-8 (1R,R-epimer)
2. For two recent syntheses of (2)-1 with a comprehensive
account of previous work: (a) Winter, E.; Hoppe, D.
Tetrahedron 1998, 54, 10329–10338. (b) Maezaki, N.;
It was obtained from ent-7 as a 4.5:1 diastereoisomeric

864
M. Carda et al. / Tetrahedron 59 (2003) 857–864
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14. Attempts at preparing lactone 10 in a more direct way by RCM
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1984, 49, 576–579.
3. For more recent syntheses of (2)-1, see: (a) Kanada, R. M.;
Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2000, 41,
3631–3635. (b) Wan, Z. H.; Nelson, S. G. J. Am. Chem. Soc.
2000, 122, 10470–10471. (c) Trost, B. M.; Tang, W. P.;
Schulte, J. L. Org. Lett. 2000, 4013–4015. (d) Date, M.;
Tamai, Y.; Hattori, T.; Takayama, H.; Kamikubo, Y.; Miyano,
S. J. Chem. Soc., Perkin Trans. 1 2001, 645–653. (e) Suzuki,
T.; Ohmori, K.; Suzuki, K. Org. Lett. 2001, 1741–1744.
(f) Ghosh, A. K.; Shirai, M. Tetrahedron Lett. 2001, 42,
6231–6233.
´
(b) Rodrıguez, S.; Castillo, E.; Carda, M.; Marco, J. A.
Tetrahedron 2002, 58, 1185–1192.
15. (a) Wu, W.-L.; Wu, Y.-L. J. Org. Chem. 1993, 58,
3586–3588. (b) Xie, M.; Berges, D. A.; Robins, M. J.
J. Org. Chem. 1996, 61, 5178–5179.
4. For syntheses of (þ)-2, see: (a) Kanada, R. M.; Taniguchi, T.;
Ogasawara, K. Synlett 2000, 1019–1021. (b) Tanaka, H.;
Kozuki, Y.; Ogasawara, K. Tetrahedron Lett. 2002, 43,
4175–4178. For syntheses of (^)-2, see: (c) Zhang, R. Z.;
Wang, Z. Q.; Wei, F. P.; Huang, Y. R. Synth. Commun. 2002,
32, 2187–2194. (d) Krauss, J. Nat. Prod. Lett. 2001, 15,
393–399. A synthesis of the unnatural enantiomer of
tanikolide, (2)-2, is described in the supplementary
information of Ref. 3b.
16. When the reduction of aldehyde 11 with NaBH4 was
conducted for 18 h at room temperature, (þ)-malyngolide
was formed in 15% yield, together with 60% of dehydro-
malyngolide. Attempts at achieving a complete saturation of
the conjugated CvC bond by increasing the reaction time and/
or the amount of NaBH4 were unsuccessful, however, and led
only to reduction of the lactone carbonyl group.
17. Hagiwara, H.; Uda, H. J. Chem. Soc., Perkin Trans. 1 1985,
1157–1159.
´
5. Carda, M.; Castillo, E.; Rodrıguez, S.; Marco, J. A.
Tetrahedron Lett. 2000, 41, 5511–5513.
´
6. Carda, M.; Castillo, E.; Rodrıguez, S.; Uriel, S.; Marco, J. A.
18. The reduction of the aldehyde function in the intermediate
products resulting from oxidative cleavage of 10, ent-10 and
17 has to be performed at low temperature, otherwise
reductive opening of the lactone ring becomes competitive.
19. Part of the data presented here have been taken from the PhD
Synlett 1999, 1639–1641.
7. Marco, J. A.; Carda, M.; Gonzalez, F.; Rodrıguez, S.; Castillo,
E.; Murga, J. J. Org. Chem. 1998, 63, 698–707.
´
´
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Thesis of E. Castillo (Univ. Jaume I, Castellon, Spain, 2000).
´ ´
8. (a) Marco, J. A.; Carda, M.; Gonzalez, F.; Rodrıguez, S.;
Murga, J. Liebigs Ann. Chem. 1996, 1801–1810. (b) Carda,
20. Products of Michael addition to the conjugated double bond
were detected during attempts at hydrolytic cleavage of the
acetonide moiety in 15. In view of this, acetal hydrolysis was
performed in saturated lactone 16 under carefully controlled
conditions, as this compound was prone to translactonization
and/or hydrolytic ring opening in acidic media.
´
¨
M.; Rodrıguez, S.; Murga, J.; Falomir, E.; Marco, J. A.; Roper,
H. Synth. Commun. 1999, 29, 2601–2610.
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9. Carda, M.; Castillo, E.; Rodrıguez, S.; Gonzalez, F.; Marco,
J. A. Tetrahedron: Asymmetry 2001, 12, 1417–1429, and
references cited therein.
21. Stronger Lewis acids caused destruction of the acetonide
moiety (see Refs. 7 and 9).
10. The stereostructure of tosylate 5 has been further secured with
the aid of an X-ray diffraction analysis. Crystallographic data
(excluding structure factors) have been deposited at the
Cambridge Crystallographic Data Center as supplementary
material with reference CCDC-195658. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK (fax: þ44(0)-1223-336033
or e-mail: deposit@ccdc.cam.ac.uk).
22. Li, C.-J.; Chan, T. H. Organic Reactions in Aqueous Media;
Wiley: New York, 1997; Chapter 4.
23. For recent contributions of our group, see: (a) Carda, M.;
´ ´
Gonzalez, F.; Castillo, E.; Rodrıguez, S.; Marco, J. A.; Eur,
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J. Org. Chem. 2002, 2649–2655. (b) Carda, M.; Rodrıguez, S.;
Segovia, B.; Marco, J. A. J. Org. Chem. 2002, 67, 6560–6563.
´
(c) Murga, J.; Falomir, E.; Garcıa-Fortanet, J.; Carda, M.;
11. (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41,
135–631. (b) In Modern Organocopper Chemistry; Krause,
N., Ed.; Wiley/VCH: Weinheim, 2002.
Marco, J. A. Org. Lett. 2002, 3447–3449. (d) Falomir, E.;
Murga, J.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2003, 44,
539–541.
12. (a) Fu¨rstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012–3043.
(b) Trnka, T.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29.
13. This oxidation also produced small amounts (10–15%) of the
oxygenation product (a cyclic ketone) at the alternative allylic
position.
24. Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447–450.
25. Banfi, L.; Bernardi, A.; Colombo, C.; Gennari, C.; Scolastico,
C. J. Org. Chem. 1984, 49, 3784–3790.
26. Dumont, A.; Pfander, H. Helv. Chim. Acta 1983, 66, 814–823.