Hexulose derivatives and lipase-mediated diastereomeric resolution in the enantiospecific total synthesis of (-)-talaromycins C and E

Article abstract of DOI:10.1002/1099-0690(20021)2002:2<309::AID-EJOC309>3.0.CO;2-V

Diastereomeric enzymatic (Chirazyme L-2, c.-f., C2) resolution of 3-C-acetoxymethyl-l,2,3,4,5-pentadeoxy-6,7:8,9-diO-isopropylidene-β-D- g7uco- and -D-manno-dec-6-ulo-6,10-pyranose (6), obtained from "diacetone D-fructose aldehyde" (3) and the corresponding phosphorane from (3-benzyloxy-2-ethylpropyl)triphenylphosphonium iodide (2), has enabled us to synthesize spiroketals (3R,4S,5S,6R,9R)- and (3R,4S,5S,6A,9S)-9-ethyl-3,4-isopropylidenedioxy-l,7-dioxaspiro[5.5]undecane (7 and 8). An attempt to transform 8 into (-)-talaromycins G and 9-epi-A was unsuccessful. However, (-)-talaromycins C and E could be enantiospecifically prepared from spiroketal 7 in twelve steps. WILEY-VCH Verlag GmbH 2002.

Full text of DOI:10.1002/1099-0690(20021)2002:2<309::AID-EJOC309>3.0.CO;2-V

FULL PAPER
Hexulose Derivatives and Lipase-Mediated Diastereomeric Resolution in the
Enantiospecific Total Synthesis of (؊)-Talaromycins C and E
[a]
[a]
[a]
[a]
´
´
Isidoro Izquierdo,* Marıa T. Plaza, Miguel Rodrıguez, and Juan A. Tamayo
Keywords: Asymmetric synthesis / Enzyme catalysis / -Fructose / Lipases / Spiroketals / (Ϫ)-Talaromycins C and E
Diastereomeric enzymatic (Chirazyme L-2, c.−f., C2) resolu- us to synthesize spiroketals (3R,4S,5S,6R,9R)- and
tion of 3-C-acetoxymethyl-1,2,3,4,5-pentadeoxy-6,7:8,9-di-
O-isopropylidene-β- -gluco- and - -manno-dec-6-ulo-6,10-
pyranose (6), obtained from ‘‘diacetone -fructose aldehyde’’
(3) and the corresponding phosphorane from (3-benzyloxy-
(3R,4S,5S,6R,9S)-9-ethyl-3,4-isopropylidenedioxy-1,7-dioxa-
spiro[5.5]undecane (7 and 8). An attempt to transform 8 into
(−)-talaromycins G and 9-epi-A was unsuccessful. However,
(−)-talaromycins C and E could be enantiospecifically pre-
D
D
D
2-ethylpropyl)triphenylphosphonium iodide (2), has enabled pared from spiroketal 7 in twelve steps.
Introduction
ose is used as a chiral starting material, among them. To
the best of our knowledge, however, no enantiospecific syn-
theses of the rest of the talaromycins in Scheme 1 (C, D,
E, etc.) have been reported to date. Retrosynthetic analysis
(Scheme 2) indicates that transformation of talaromycins A,
B, and 9-epi-AϪG into the corresponding talaromycins
CϪE and DϪF, would be feasible through inversion of the
configuration at C-4, as has been previously proved to be
the case in less highly elaborated analogues.[7] The four lat-
ter talaromycins would thus be prepared from the common
1,2,3,4,5-pentadeoxy-3-C-hydroxymethyldec-6-ulose inter-
mediate 5, depending on the C-3 configuration (starred car-
bon atom).
Talaromycins (see Scheme 1), spiroketal mycotoxins, are
produced by the fungus Talaromyces stipitatus. Talaromy-
cins A and B were isolated and identified for the first time
by Lynn et al.,[1] but in a reinvestigation, the same group[2]
was also able to observe the presence of additional isomers
such as talaromycins C, D, E, G, and F,[3] differing only in
the configuration of the stereogenic centres in the A (C-3,4)
and B (C-9) rings. Some of these compounds, as well as
others with structures representing estrone-talaromycin hy-
brids, were shown to be active against neuroblastoma[2] and
human lung cancer cells,[4] respectively.
A synthesis of the (3R) intermediate dec-6-ulose derivat-
ive 5, representing the formation of the spiroketal structure
of talaromycins A, B, C, and E in a chiron with the required
structure, functionalization, and stereochemistry, and ob-
tained by enzymatic desymmetrization of 2-ethyl-1,3-pro-
panediol, was recently reported by our group.[8] Unfortu-
nately, a later attempt to obtain the corresponding (3S)-5
was unsuccessful, since the same chirality was obtained
even after the use of different enzymes.[9] In order to gener-
alize this synthetic approach, a similar, but racemic, syn-
thon has now been used for the preparation of (3RS)-5,
which was then submitted to a diastereomeric enzymatic
resolution. In addition, the protected -fructose derivative
used in this paper may be viewed as an excellent chiral start-
ing material for general synthesis of compounds with the
1,7-dioxaspiro[5.5]undecane skeleton, in accordance with
results previously reported,[6,10] in terms not only of the
partial transfer of the inherent chirality in the sugar to the
target molecule, but also even of control over the stereo-
chemistry of the spiroketalization process. In this context,
we now report the first synthesis of enantiomerically pure
talaromycins C and E, which represent a novel and straight-
forward route to mycotoxin talaromycins.
Scheme 1. Talaromycins
Enantiospecific syntheses of talaromycins A and B based
on various synthetic approaches can be found in the literat-
ure,[5] that reported by our own group,[6] in which -fruct-
[a]
Department of Organic Chemistry, Faculty of Pharmacy,
University of Granada,
18071 Granada, Spain
Fax: (internat.) ϩ 34-958/243845
E-mail: isidoro@platon.ugr.es
Eur. J. Org. Chem. 2002, 309Ϫ317
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1434Ϫ193X/02/0102Ϫ0309 $ 17.50ϩ.50/0
309

´
I. Izquierdo, M. T. Plaza, M. Rodrıguez, J. A. Tamayo
FULL PAPER
Scheme 2. Retrosynthesis of talaromycins
hydrogenated to give the related (3RS)-5 (89% yield), the
physical and spectroscopic data of which were as previously
reported[6] (see Scheme 3).
Results and Discussion
Treatment of 1-O-benzyl-2-ethyl-3-iodopropanol[11] (1)
with triphenylphosphane in dry toluene afforded the corres-
Diastereomeric resolution of (3RS)-5 was performed by
ponding phosphonium salt 2. Subsequent treatment of 2 partial esterification with an immobilized enzyme as cata-
with ‘‘diacetone -fructose aldehyde’’[6] (3) in the presence lyst. Thus, treatment of (3RS)-5 in diethyl ether with vinyl
of potassium tert-butoxide gave 3-C-(benzyloxymethyl)- acetate in the presence of Chirazyme L-2, c.Ϫf., C2 gave
1,2,3,4,5-pentadeoxy-6,7:8,9-di-O-isopropylidene-β--
the corresponding acetate derivative (3S)-6 together with
gluco- and --manno-dec-4-ene-6-ulo-6,10-pyranose (4) as a unreacted (3R)-5 (see Scheme 4 and Figure 1). It was not
mixture of (E) and (Z) isomers, which was subsequently possible to determine the diastereomeric excess of either
Scheme 3. Synthesis of (3RS)-5: a: Ph3P/toluene/∆T; b: KϩtBuOϪ/THF; c: 10% Pd-C/H2/MeOH
Scheme 4. Diastereomeric resolution of (3RS)-5): a: Chirazyme L-2, c.Ϫf., C2/vinyl acetate/ether; b: Me2CO/Hϩ; c: NaMeO/MeOH;
d: Ac2O/Cl2CH2/Et3N/DMAP; e: Chirazyme L-2, c.Ϫf., C2/buffer (pH ϭ 7)/room temp.
310
Eur. J. Org. Chem. 2002, 309Ϫ317

Enantiospecific Total Synthesis of (Ϫ)-Talaromycins C and E
FULL PAPER
compound by GLC, even in a capillary β-DEX 325 col-
umn, their transformation into the spiroketals
(3R,4S,5S,6R,9R)- and (3R,4S,5S,6R,9S)-9-ethyl-3,4-iso-
propylidenedioxy-1,7-dioxaspiro[5.5]undecane (7 and 8),[12]
as shown in Scheme 4, being necessary. This was achieved
by treatment with acetone/sulfuric acid, which brought
about concomitant isopropylidenation at the C-3,4 posi-
tions. Since the result was only a small diastereomeric ex-
cess, the partial enzymatic hydrolysis of (3RS)-6 was also
investigated (see Figure 1), and this gave a better diastere-
omeric excess. This may be attributable either to the larger
size or the hydrophobicity of the substituent at the ste-
reocentre.
An attempt to transform 8 into the related talaromycin
G and 9-epi-talaromycin A was carried out as follows.
Compound 8 was deoxygenated by a modified Barton pro-
cedure,[13] through its 5-O-xanthate (9) to afford 10 (in 89%
yield from 8), which was submitted to acid hydrolysis in
order to obtain the required free 3,4-diol (13). Unfortu-
nately, however, a complex mixture was produced, from
which it was possible to isolate and identify the expected
spiroketal 13 (52%) together with 11 (20%) and 12 (23%).
The structures of 11 and 12 were determined on the basis
of the following results. A dramatic change in the values
and signs of their optical rotations would indicate that in-
version of the configuration at the spiroketal centre had oc-
curred. On the other hand, the 13C chemical shift values for
the spiro carbon atom Ϫ δ ϭ 96.55 for 11 and 106.87 for
12 Ϫ suggested[14] a 1,7-dioxaspiro[5.5]undecane and a 1,6-
dioxaspiro[4.5]decane, respectively. In addition, 8a-H in 11
and 7a-H in 12 appeared as triplets (J ϭ 10.9 Hz), indicat-
ing equatorial dispositions of the ethyl groups at C-9 and
C-8, respectively. Compounds 11 and 12 could arise
through acid-catalysed isomerization of 13, which would al-
leviate the steric strain produced by the axial ethyl group in
13; this could be demonstrated during the recording of its
NMR spectrum, in which traces of acid in the solvent
(Cl3CD) promoted its isomerization. These findings
prompted the authors to give up this attempt.
Compound 7 was transformed into the known diol 16 by
a previously reported procedure,[6] but including C-5 deoxy-
genation by the modified Barton procedure mentioned
above (Scheme 6). Compound 16 was regioselectively
O-silylated at C-4 by way of its n-dibutylstannylene derivat-
ive 17 to afford 18 (in 72% yield from 16), which was
oxidised with PCC to afford the corresponding ketone 19,
which was coupled with methylenetriphenylphosphorane to
afford 20. Hydroboration/oxidation of 20 gave an un-
resolved mixture (3:7 ratio) of 4-O-silylated talaromycins B
(21) and A (22), which were separated as their benzoyl
derivatives 23 and 24, respectively.
Figure 1. Kinetics of enzymatically catalysed acetylation of (3RS)-
5 and enzymatically catalysed hydrolysis of (3RS)-6; GLC analysis
of compounds 7 and 8 produced by spiroketalization of 5 after
enzymatic acetylation and enzymatic hydrolysis, respectively
of 27 and 30 gave the expected target molecules (Ϫ)-talaro-
Compounds 23 and 24 were O-desilylated to afford 25 mycins E (72%) and C (86%), respectively.
(50%) and 28 (82%), together with minute quantities of
The results described above indicate that the use of the
their corresponding 12-O Ǟ 4-O benzoyl group migration chiral pool (carbohydrates) combined with chiral catalysts
compounds (26, 12.5% and 29, 8%, respectively, Scheme 7). (lipases), both from natural sources, may be an excellent
Both 25 and 28 were submitted to a Mitsunobu reaction[15] methodology by which to overcame many problems in the
with Ph3P/3,5-dinitrobenzoic acid/DEAD to give 27 stereoselective synthesis of complex biologically active nat-
(quantitative) and 30 (45%). Finally, Zemplen deacylation ural products.
Eur. J. Org. Chem. 2002, 309Ϫ317
311

´
I. Izquierdo, M. T. Plaza, M. Rodrıguez, J. A. Tamayo
FULL PAPER
Scheme 5. Deisopropylidenation of 10: a: NaH/THF/imidazole/CS2/MeI; b: H3PO4/dioxane/H2O/Et3N/AIBN; c: AcOH/H2O/40 °C/45
min
Scheme 6. Synthesis of protected (Ϫ)-talaromycins B (23) and A (24): a: NaH/THF/imidazole/CS2/MeI; b: H3PO4/dioxane/H2O/Et3N/
˚
AIBN; c: AcOH/H2O/50 °C/1 h; d: nBu2SnO/MeOH; e: TBDMSCl/dioxane; f: PCC/CH2Cl2/NaAcO/MS (4 A); g: NaCH2SOCH3/
Ph3PCH3Br/DMSO; h: BH3ϪSMe2/THF, then NaOH/H2O2; i: BzCl/Et3N/CH2Cl2
with H2SO4. Column chromatography was performed on silica gel
Experimental Section
(Merck, # 7734). Spectroscopic (1H and 13C NMR, MS) and/or
analytical data were obtained with chromatographically homogen-
eous samples.
General Remarks: Solutions were dried with MgSO4 before concen-
tration under reduced pressure. The 1H and 13C NMR spectra were
recorded with Bruker AM 300, AXM 300, ARX 400, and AMX (3-Benzyloxy-2-ethylpropyl)triphenylphosphonium Iodide (2): A so-
500 spectrometers for solutions in CDCl3 (internal Me4Si). IR spec-
tra were recorded with a PerkinϪElmer 782 instrument and mass
lution of triphenylphosphane (2.67 g, 10.2 mmol) and 1-O-benzyl-
2-ethyl-3-iodopropanol[11] (1; 3.1 g, 10.2 mmol) in dry toluene
spectra with a Micromass Mod. Platform II and Autospec-Q mass (50 mL) was heated under reflux for 3 d. During this time, 2 (8.2 g,
spectrometers. Optical rotations were measured for solutions in 81%) precipitated as a white crystalline solid, which was collected
CHCl3 (1-dm tube) with a Jasco DIP-370 polarimeter. GLC was by filtration, washed with diethyl ether and dried; m.p. 167Ϫ168
Ϫ1
1
˜
performed with a HewlettϪPackard 6890 gas chromatograph °C. IR (KBr): ν ϭ 3051, 3025, 756, and 694 cm (aromatic). H
equipped with a split/splitless injector, a flame-ionisation detector,
and a capillary HP-5 column (30 m ϫ 0.25 mm i.d. ϫ 0.25 µm film
thickness) at 3 min at 180 °C, program to 250 °C, 10 °C/min. The
He flow rate was 1.1 mL/min, the injection port and the zone-de-
tector temperatures were 275 °C. TLC was performed on precoated
NMR: δ ϭ 7.85Ϫ7.21 (3 m, 20 H, 4 Ph), 4.33 and 4.29 (2 d, 2 H,
J ϭ 11.3 Hz, PhCH2), 3.97 (ddd, 1 H, J1a,2 ϭ 5.2, J1a,1b ϭ 13.6,
J1a,P ϭ 16.0 Hz, 1a-H), 3.63 (t, 1 H, J2,3a ϭ J3a,3b ϭ 9 Hz, 3a-H),
3.58Ϫ3.49 (m, 2 H, 1b,3b-H), 2.02 (m, 1 H, 2-H), 1.49 and 1.20 (2
m, 2 H, CH2CH3), 0.78 (t, 3 H, J ϭ 7.43 Hz, CH2CH3). 13C NMR:
60 F254 silica gel aluminium sheets and detection was by charring δ ϭ 137.70, 134.90, 133.81, 133.71, 130.44, 130.32, 128.21, 127.91,
312 Eur. J. Org. Chem. 2002, 309Ϫ317

Enantiospecific Total Synthesis of (Ϫ)-Talaromycins C and E
FULL PAPER
solution of 5 (7.8 g, 23.6 mmol) in diethyl ether (100 mL) and vinyl
acetate (10 mL, 100 mmol) and the mixture was kept at room tem-
perature and monitored by GLC. After 1 h, at least 50% conversion
had occurred. The reaction was quenched by filtering off the en-
zyme and thoroughly washing with diethyl ether. The combined
filtrate and washings were concentrated and the residue was chro-
matographed (diethyl ether/hexane, 1:2 Ǟ diethyl ether), to yield
(3S)-6 (4.32 g, 49%) first. [α]2D7 ϭ Ϫ6.6 (c ϭ 1). IR (film): ν˜ ϭ 1740
1
(OAc), 1382 and 1373 cmϪ1 (CMe2). H NMR: δ ϭ 4.54 (dd, 1 H,
J7,8 ϭ 2.4, J8,9 ϭ 8 Hz, 8-H), 4.20 (dd, 1 H, 9-H), 4.06 (d, 1 H, 7-
H), 3.97 (m, 2 H, CH2OAc), 3.82 (dd, 1 H, J9,10ax ϭ 1.9, J10ax,10eq ϭ
13 Hz, 10ax-H), 3.69 (d, 1 H, 10eq-H), 2.02 (s, 3 H, Ac), 1.89Ϫ1.51
(m, 5 H, 3,4,4Ј,5,5Ј-H), 1.50, 1.45, and 1.32 (3 s, 12 H, 2 CMe2),
1.39Ϫ1.32 (m, 2 H, 2,2-H), 0.88 (t, 3 H, J1,2 7.4 ϭ Hz, 1,1,1-H).
13C NMR: δ ϭ 171.40 (MeCO), 108.94 and 107.44 (2 CMe2),
104.21 (C-6), 73.90 (C-7), 70.89 and 70.67 (C-8,9), 66.71 (C-1Ј),
60.97 (C-10), 38.71 (C-3), 38.07 (C-5), 26.48, 25.85, 25.16, and
24.16 (2 CMe2), 23.98 and 23.58 (C-2,4), 21.07 (MeCO), 10.89 (C-
1). HRMS (LSIMS): found 395.2043 [Mϩ ϩ Na]; calcd. 395.2046.
The second fraction was (3R)-5 (3.8 g, 48.7%). [α]2D4 ϭ Ϫ12.7 (c ϭ
1). The physical and spectroscopic data of which matched those
previously reported.[8] Zemplen deacetylation of (3S)-6 with 0.5 
NaOMe in methanol afforded, after workup and column chroma-
tography (diethyl ether), (3S)-5 (quantitative); tR ϭ 9.16 min;
[α]2D7 ϭ Ϫ6.9 (c ϭ 1).
Scheme 7. Synthesis of (Ϫ)-talaromycins
E
and C: a:
nBu4NF·3H2O/THF; b: Ph3P/3,5-dinitrobenzoic acid/DEAD/48 h/
room temp.; c: NaMeO/MeOH
Spiroketalization of (3R)- and (3S)-5: A solution of (3R)-5 (3.8 g,
11.5 mmol) in a 20:1 acetone/conc. H2SO4 mixture (80 mL) was
kept at room temperature for 8 h. GLC then revealed that (3R)-5
had disappeared and that two new compounds were present in a
4:1 ratio. The reaction mixture was neutralised (NH3), filtered, and
concentrated. Column chromatography (diethyl ether/hexane, 1:3)
first gave crystalline (3R,4S,5S,6R,9R)-9-ethyl-5-hydroxy-3,4-iso-
propylidenedioxy-1,7-dioxaspiro[5.5]undecane[6,8] (7; 820 mg), tR ϭ
7.61 min. Eluted second was a mixture of 7 and its 9-epimer 8
(1.25 g). Treatment of (3S)-5 (3.77 g, 11.4 mmol) as above gave 7
and 8 in a 2:3 ratio (GLC). Workup of the reaction mixture as
above allowed the isolation of 7 (700 mg), a mixture of 7 and 8
(500 mg) and finally pure, crystalline 8[6] (865 mg), tR ϭ 7.51 min.
119.54 and 118.69 (Ph), 73.20 and 72.12 (C-3,PhCH2), 36.47 (C-
2), 25.72 and 25.35 (C-1, CH2CH3), 11.62 (CH2CH3). C30H32IOP
(566.44): calcd. C 63.61, H 5.69; found C 63.19, H 5.55.
3-C-(Benzyloxymethyl)-1,2,3,4,5-pentadeoxy-6,7:8,9-di-O-isopro-
pylidene-β-D-gluco- and -D-manno-dec-4-ene-6-ulo-6,10-pyranose (4):
A solution of tBuOK (2.23 g, 19 mmol) in dry THF (15 mL) was
added dropwise under argon to a stirred solution of 2,3:4,5-di-O-
isopropylidene-β--arabino-hexos-2-ulopyranose[6]
(3;
4.8 g,
18.6 mmol) and compound 2 (9.8 g, 17.3 mmol) in the same solvent
(70 mL). After 10 min, the resulting orange solution became brown
and the reaction mixture was left at room temperature for 1 h. GLC
then revealed the absence of 3 and the presence of two new com-
pounds (tR ϭ 15.36 and 15.60 min). The solvent was evaporated
and the residue was partitioned between diethyl ether and water.
The organic phase was separated and the aqueous phase was ex-
tracted with diethyl ether (2 ϫ 20 mL). The combined organic ex-
tracts were washed with brine and concentrated. Column chroma-
tography (diethyl ether/hexane, 1:3) of the residue gave 4 (5.36 g,
74%), as a mixture of (E) and (Z) isomers. An aliquot was cau-
Acetylation of (3RS)-5: DMAP (135 mg), Et3N (8.6 mL, 61 mmol),
and Ac2O (5.9 mL, 61 mmol) were added to a solution of (3RS)-5
(13.2 g, 40 mmol) in dry Cl2CH2 (50 mL), and the mixture was kept
at room temperature for 6 h. TLC (diethyl ether/hexane, 1:2) then
revealed the presence of a faster-running compound. Workup of
the reaction mixture as usual, followed by column chromatography
(diethyl ether/hexane, 1:3), afforded (3RS)-6 (14.3 g, 96%).
1
tiously rechromatographed to afford first (Z)-4 and then (E)-4. H
NMR (inter alia): (Z)-4: δ ϭ 5.61 and 5.60 (2 d, J4,5 ϭ 11.7 Hz, 5-
H), 5.42 and 5.38 (2 dd, J3,4 ϭ 9.8 Hz, 4-H); (E)-4: δ ϭ 5.90 and
5.89 (2 dd, J4,5 ϭ 15.4, J3,4 ϭ 8.7 Hz, 4-H), 5.66 and 5.63 (2 d, 5-
H). HRMS (LSIMS): found 419.2435 [Mϩ ϩ 1]; calcd. 419.2434.
Partial Enzymatic (Chirazyme L-2, c.؊f., C2) Hydrolysis of (3RS)-
6: The title enzyme (3 g) was added to a gently stirred suspension
of (3RS)-6 (4 g, 10.7 mmol) in 50 mL of a buffered (pH ϭ 7) aque-
ous 0.5  phosphate solution (KH2PO4). Stirring was maintained
for 3.5 h. GLC analysis of the mixture then showed 50% conver-
sion. The enzyme was filtered off, and the filtrate was saturated
with NaCl and repeatedly extracted with diethyl ether. Concentra-
tion of the extract and column chromatography (diethyl ether/hex-
ane, 1:2) of the residue afforded (3R)-6 (1.77 g, 44%) and (3S)-5
(1.35 g, 38%). Zemplen deacetylation of (3R)-6 (1.77 g, 4.5 mmol)
as above gave (3R)-5 (1.57 g, quantitative).
1,2,3,4,5-Pentadeoxy-3-C-hydroxymethyl-6,7:8,9-di-O-isopro-
pylidene-β-D-gluco- and -D-manno-dec-6-ulo-6,10-pyranose (5): A so-
lution of (E)-,(Z)-4 (5.36 g, 12.4 mmol) in methanol (60 mL) was
hydrogenated [75 psi (5.2 bar) H2] over 10% Pd-C (125 mg) for
48 h. GLC then showed the absence of (E)-,(Z)-4 and the presence
of a new compound (tR ϭ 9.16 min). The catalyst was filtered off
and washed with methanol, and the combined filtrate and washings
were concentrated. Column chromatography (diethyl ether/hexane,
1:1) of the residue gave pure 5 (3.76 g, 89%) as a colourless syrup
that showed the same spectroscopic data as previously reported.[6]
Spiroketalization of (3S)- and (3R)-5 Produced from the Enzymatic
Hydrolysis: Treatment of (3S)-5 (1.35 g, 4.1 mmol) with acetone/
conc. sulfuric acid under the conditions described above afforded
7 and 8 in a 1:9 ratio (GLC). Workup of the reaction mixture as
Partial Enzymatic (ChirazymeԹ L-2, c.؊f., C2) Acetylation of 5:
Chirazyme L-2, c.Ϫf., C2 (300 mg) was added to a gently stirred above first gave 7 (50 mg), then a mixture of 7 and 8 (125 mg), and
Eur. J. Org. Chem. 2002, 309Ϫ317 313

´
I. Izquierdo, M. T. Plaza, M. Rodrıguez, J. A. Tamayo
FULL PAPER
finally 8 (704 mg). In the same manner, (3R)-5 (1.57 g, 4.76 mmol) pounds of lower mobility. The mixture was concentrated and codis-
was transformed into a mixture of 7 and 8 in a 6:1 ratio (GLC).
This was partially resolved, after workup and column chromato-
tilled with toluene to remove the acetic acid, and the residue was
submitted to chromatography (diethyl ether/hexane, 1:4) to yield
graphy, into 7 (675 mg), a mixture of 7 and 8 (145 mg) and, finally, (3R,4S,6S,9S)-9-ethyl-3,4-dihydroxy-1,7-dioxaspiro[5.5]undecane
(11; 324 mg, 20%) first. [α]2D4 ϭ ϩ118 (c ϭ 1). IR (film): ν ϭ 3471
cmϪ1 (OH). 1H NMR: δ ϭ 3.92 (m, 1 H, 4-H), 3.66Ϫ3.57 (m, 3
H, 2eq,3,8eq-H), 3.46 (t, 1 H, J2ax,3eq ϭ J2ax,2eq ϭ 13.5 Hz, 2ax-
H), 3.27 (t, 1 H, J8ax,8eq ϭ J8ax,9 ϭ 10.9 Hz, 8ax-H), 3.10 (br. s, 2
H, O3,4-H), 2.04 (dd, 1 H, J5,5Ј ϭ 14.6, J4,5 ϭ 3.3 Hz, 5-H), 1.71
(dd, 1 H, J4,5Ј ϭ 3.2 Hz, 5-H), 1.64Ϫ1.35 (m, 5 H, 9,10,10Ј,11,11Ј-
H), 1.14 (m, 2 H, CH2CH3), 0.87 (t, J ϭ 7.4 Hz, 3 H, CH2CH3).
13C NMR: δ ϭ 96.55 (C-6), 67.82 (C-3), 66.32 (C-4), 65.74 (C-8),
59.35 (C-2), 36.69 (C-5), 36.41 (C-9), 34.43 (C-11), 25.15 and 24.49
(C-10,CH2CH3), 11.13 (CH2CH3). HRMS (LSIMS): found
˜
8 (135 mg).
(3R,4R,5S,6R,9S)-9-Ethyl-3,4-isopropylidenedioxy-5-[(methylthio)-
thiocarbonyloxy]-1,7-dioxaspiro[5.5]undecane (9): A solution of 8
(2.18 g, 8. mmol) in anhydrous THF (10 mL) was added under ar-
gon at room temperature to a stirred suspension of NaH (480 mg,
16 mmol, 80% oil dispersion) in the same solvent (20 mL) and im-
idazole (50 mg). After 30 min, carbon disulfide (1.13 mL,
18.8 mmol) was added, followed after an additional 30 min by
methyl iodide (1.2 mL, 19 mmol). The mixture was stirred for 1 h.
TLC (diethyl ether/hexane, 3:2) then showed the presence of a fas-
ter-running compound. The excess hydride was destroyed by cau-
tious addition of diethyl ether saturated with water (5 mL), and
then water (5 mL). The organic phase was separated and the aque-
ous phase was extracted with diethyl ether (3 ϫ 10 mL). The com-
bined extracts were washed with brine and water and concentrated,
and the residue was chromatographed (diethyl ether/hexane, 1:3) to
yield syrupy 9 (2.8 g, 97%); tR ϭ 12.8 min. [α]2D5 ϭ Ϫ159 (c ϭ 1).
239.1259 [Mϩ
ϩ Na]; calcd. 239.1259. Eluted second was
(2R,3S,5S,8S)-8-ethyl-3-hydroxy-2-hydroxymethyl-1,6-dioxaspiro-
[4.5]decane (12; 370 mg, 23%). [α]2D2 ϭ ϩ98 (c ϭ 1). IR (film): ν ϭ
˜
1
3467 cmϪ1 (OH). H NMR: δ ϭ 4.08 (m, 2 H, 2,3-H), 3.69 (dd, 1
H, J2Јa-2Јb ϭ 11.7, J2Јa,2 ϭ 3.7 Hz, 2Јa-H), 3.59 (dd, 1 H, J2Јb,2
3.6 Hz, 2Јb-H), 3.59 (m, 1 H, 7eq-H), 3.49 (t, 1 H, J7ax,8
ϭ
ϭ
J7ax,7eq ϭ 10.9 Hz, 7ax-H), 2.45 (m, 2 H, 2Ј,3-OH), 1.97 (dd, 1 H,
J3,4 ϭ 1.2, J4,4Ј ϭ 13.6 Hz, 4-H), 1.89 (dd, 1 H, J3,4Ј ϭ 5.9 Hz, 4Ј-
H), 1.79Ϫ1.37 (m, 5 H, 8,9,9Ј,10,10Ј-H), 1.16 (m, 1 H, CH2CH3),
0.86 (t, J ϭ 7.4 Hz, 3 H, CH2CH3). 13C NMR: δ ϭ 106.87 (C-5),
88.06 (C-2), 73.81 (C-3), 66.30 (C-7), 63.30 (C-2Ј), 46.37 (C-4),
36.68 (C-8), 32.66 (C-10), 25.91 and 25.13 (C-9,CH2CH3), 11.22
(CH2CH3). HRMS (LSIMS): found 239.1258 [Mϩ ϩ Na]; calcd.
239.1259. Finally, the third fraction was (3R,4S,6R,9S)-9-ethyl-3,4-
IR (film): ν˜ ϭ 1383 and 1373 (CMe2), and 1207 cmϪ1 (CϭS). H
NMR: δ ϭ 5.83 (d, 1 H, J4,5 ϭ 8 Hz, 5-H), 4.41 (dd, 1 H, J3,4
5.4 Hz, 4-H), 4.25 (dd, 1 H, 3-H), 4.03 (d, 1 H, J2ax,2eq ϭ 13.4 Hz,
2ax-H), 3.86 (dd, 1 H, J2eq,3 ϭ 2.8 Hz, 2eq-H), 3.71 (dd, 1 H,
J8ax,8eq ϭ 11.1, J8ax,9 ϭ 2.8 Hz, 8ax-H), 3.53 (br. d, 1 H, 8eq-H),
2.56 (s, 3 H, SMe), 1.92 (tt, 1 H, J10ax,10eq ϭ J10ax,11ax ϭ 13.3,
1
ϭ
J9,10ax ϭ J10ax,11eq ϭ 4.4 Hz, 10ax-H), 1.65 (dt, 1 H, J11ax,11eq
ϭ
dihydroxy-1,7-dioxaspiro[5.5]undecane (13; 850 mg, 52%). [α]2D6
ϭ
13.7, J11ax,10eq ϭ 4.6 Hz, 11ax-H), 1.51 and 1.31 (2 s, 6 H, CMe2),
1.60Ϫ1.31 (m, 5 H, 9,10eq,11eq-H, CH2CH3), 0.88 (t, J ϭ 7.4 Hz,
3 H, CH2CH3). 13C NMR: δ ϭ 217.22 (CϭS), 109.62 (CMe2),
97.77 (C-6), 82.93 (C-5), 74.35 and 74.32 (C-3,4), 64.01 (C-8), 59.22
(C-2), 34.03 (C-9), 27.81 and 26.54 (CMe2), 25.15 (C-11), 22.14
and 21.59 (C-10, CH2CH3), 19.32 (MeS), 12.36 (CH2CH3). HRMS
(LSIMS): found 363.1294 [Mϩ ϩ 1]; calcd. 363.1300.
Ϫ1
Ϫ104 (c ϭ 1). IR (film): ν ϭ 3438 cm (OH). 13C NMR: δ ϭ
96.58 (C-6), 67.84 (C-3), 66.34 (C-4), 65.77 (C-8), 59.35 (C-2), 39.72
(C-5), 36.44 (C-9), 34.45 (C-11), 25.16 and 24.51 (C-10,CH2CH3),
11.13 (CH2CH3). HRMS (LSIMS): found 239.1260 [Mϩ ϩ Na];
calcd. 239.1259.
˜
(3R,4S,6R,9R)-9-Ethyl-3,4-isopropylidenedioxy-1,7-dioxaspiro-
[5.5]undecane (15): Et3N (6 mL, 42 mmol) and aqueous 50% H3PO2
(4.5 mL) were added to a solution of (3R,4R,5S,6R,9R)-9-ethyl-3,4-
isopropylidenedioxy-5-[(methylthio)thiocarbonyloxy]-1,7-dioxa-
spiro[5.5]undecane[6] (14; 2.8 g, 7.73 mmol) in dioxane (50 mL),
and the mixture was refluxed for 2 h. During this time, AIBN
(200 mg) was added portionwise (25 mg each). The reaction was
monitored by GLC, showing the presence of 15 (tR ϭ 5.31 min).
The solvent was evaporated, water (30 mL) was added, and the
resulting suspension was extracted with diethyl ether (3 ϫ 10 mL).
The combined extracts were concentrated and the residue was sub-
mitted to column chromatography (diethyl ether/hexane, 1:3) to
yield pure 15 (1.74 g, 95%) as a syrup, which showed the same
physical and spectroscopic data as previously reported.[6]
(3R,4S,6R,9S)-9-Ethyl-3,4-isopropylidenedioxy-1,7-dioxaspiro-
[5.5]undecane (10): Et3N (6.7 mL, 47 mmol) and aqueous H3PO2
(50%, 5 mL) were added to a solution of 9 (2.95 g, 8.15 mmol) in
dioxane (50 mL), and the mixture was refluxed for 90 min. During
this time, AIBN (200 mg) was added portionwise (25 mg each). The
reaction was monitored by GLC, showing the presence of 10 (tR ϭ
5.38 min). The solvent was evaporated, water (30 mL) was added,
and the resulting suspension was extracted with diethyl ether (3
ϫ10 mL). The combined extracts were concentrated and the res-
idue was submitted to column chromatography (diethyl ether/hex-
ane, 1:3) to yield pure 10 (1.92 g, 92%) as a syrup. [α]2D5 ϭ Ϫ149
Ϫ1
(c ϭ 1). IR (film): ν ϭ 1382 and 1371 cm (CMe2). 1H NMR:
˜
δ ϭ 4.38 (dt, 1 H, J4,5ax ϭ 8.2, J3,4 ϭ J4,5eq ϭ 6.1 Hz, 4-H), 4.06
(br. dd, 1 H, 3-H), 3.94 (br. d, 1 H, J2ax,2eq ϭ 13.2 Hz, 2ax-H), 3.83
(dd, 1 H, J2eq,3 ϭ 2.5 Hz, 2eq-H), 3.76 (dd, 1 H, J8ax,8eq ϭ 11.2,
(3R,4S,6R,9R)-4-(tert-Butyldimethylsilyloxy)-9-ethyl-3-hydroxy-
1,7-dioxaspiro[5.5]undecane (18): A solution of 15 (2.1 g, 8.2 mmol)
in aqueous acetic acid (60%, 15 mL) was heated at 50 °C for 1 h.
TLC (ethyl acetate) then revealed the presence of a slower-running
compound. The reaction mixture was concentrated and repeatedly
codistilled in order to remove acetic acid. Column chromatography
(diethyl ether Ǟ diethyl ether/methanol, 10:1) then afforded the
diol 16 (1.57 g, 88.6%) as a syrup. Di-n-butyltin oxide (1.56 g,
6.3 mmol) was added to a solution of 16 (1.36 g, 6.3 mmol) in an-
hydrous methanol (40 mL). The suspension was heated for 2 h un-
der reflux, and then concentrated to afford the 3,4-dibutylstanny-
lene derivative 17 as a syrup that was dried under vacuum over
J8ax,9 ϭ 3 Hz, 8ax-H), 3.37 (dt, 1 H, J8eq,9 ϭ J8eq,10eq ϭ 2 Hz, 8eq-
H), 1.98 (m, 1 H, 10ax-H), 1.89 (dd, 1 H, J5ax,5eq ϭ 13.7 Hz, 5eq-
H), 1.64 (dd, 1 H, 5ax-H), 1.49 and 1.33 (2 s, 6 H, CMe2),
1.61Ϫ1.33 (m, 6 H, 9,10eq,11ax,11eq-H, CH2CH3), 0.90 (t, J ϭ
7.3 Hz, 3 H, CH2CH3). 13C NMR: δ ϭ 108.49 (CMe2), 96.78 (C-
6), 71.77 (C-3), 70.06 (C-4), 63.86 (C-8), 60.21 (C-2), 37.98 (C-5),
34.48 (C-9), 31.08 (C-11), 28.05 and 26.18 (CMe2), 22.73 and 22.45
(C-10,CH2CH3), 12.24 (CH2CH3). HRMS (LSIMS): found
279.1579 (Mϩ ϩ Na); calcd. 279.1572.
Deisopropylidenation of 10: A solution of 10 (1.92 g, 7.5 mmol) in
aqueous acetic acid (60%, 15 mL), was heated at 40 °C for 45 min. P2O5 overnight. A solution of 17 in dry dioxane (40 mL) was
TLC (ethyl acetate) then showed the presence of three new com-
314
treated with tert-butyldimethylchlorosilane (1.04 g, 6.93 mmol),
Eur. J. Org. Chem. 2002, 309Ϫ317

Enantiospecific Total Synthesis of (Ϫ)-Talaromycins C and E
FULL PAPER
and heated at 40 °C for 3 d. TLC (diethyl ether/hexane, 1:2) then were added dropwise and the mixture was stirred for 30 min at
revealed a faster-running compound. Methanol (1 mL) was added
room temperature. The reaction mixture was extracted with diethyl
and the reaction mixture was stirred for 15 min and then concen- ether (3 ϫ 10 mL) and the combined extracts were concentrated.
trated. Column chromatography (diethyl ether/hexane, 1:6) of the
Column chromatography (diethyl ether/hexane, 1:5) of the residue
gave an irresolvable mixture (510 mg) of (3R,4S,6R,9R)-4-(tert-bu-
tyldimethylsilyloxy)-9-ethyl-3-hydroxymethyl-1,7-dioxaspiro-
residue gave 18 (1.74 g, 72%); tR ϭ 8.9 min. [α]2D4 ϭ Ϫ97 (c ϭ 1).
Ϫ1
IR (film): ν ϭ 3578 cm (OH). 1H NMR: δ ϭ 4.11 (ddd, 1 H,
˜
J3,4 ϭ 5.5, J4.5ax ϭ 11.1, J4,5eq ϭ 3.4 Hz, 4-H), 3.80 (dd, 1 H, [5.5]undecane (21) and its (3S,4S,6R,9R)-epimer 22 in a 3:7 ratio,
J2ax,2eq ϭ 12.7, J2ax,3 ϭ 2 Hz, 2ax-H), 3.65 (d, 1 H, 2eq-H), 3.64 as a colourless syrup. GLC analysis: 22 (tR ϭ 9.99) and 21
(dd, 1 H, 3-H), 3.52 (br. d, 1 H, 8eq-H), 3.20 (t, 1 H, J8ax,8eq
ϭ
(10.16 min).
J8ax,9 ϭ 10.8 Hz, 8ax-H), 2.53 (d, 1 H, J3,OH ϭ 1.8 Hz, OH), 1.75
(t, 1 H, J5ax,5eq ϭ 11.1 Hz, 5ax-H), 1.81Ϫ1.41 (3 m, 6 H,
5eq,9,10ax,10eq,11ax,11eq-H), 1.14 (m, 2 H, CH2CH3), 0.88 (s, 9
H, CMe3), 0.87 (t, J ϭ 7.5 Hz, 3 H, CH2CH3), 0.08 (s, 6 H, SiMe2).
13C NMR: δ ϭ 97.08 (C-6), 68.17 (C-3), 66.53 (C-4), 65.63 (C-8),
62.11 (C-2), 38.84 (C-5), 36.81 (C-9), 35.15 (C-11), 25.84 (CMe3),
25.32 and 24.86 (C-10, CH2CH3), 18.06 (CMe3), 11.27 (CH2CH3),
Ϫ4.42 and Ϫ4.68 (SiMe2). HRMS (LSIMS): found 331.2307 [Mϩ
ϩ 1]; calcd. 331.2305.
(3R,4S,6R,9R)- and (3S,4S,6R,9R)-3-Benzoyloxymethyl-4-(tert-bu-
tyldimethylsilyloxy)-9-ethyl-1,7-dioxaspiro[5.5]undecane (23 and 24):
Et3N (0.4 mL, 2.9 mmol) and
a solution of BzCl (0.2 mL,
1.66 mmol) in dry CH2Cl2 (5 mL) were added to a stirred and co-
oled (ice/water) solution of 21 and 22 (510 mg, 1.48 mmol) in the
same solvent (15 mL). The reaction mixture was kept at room tem-
perature for 24 h. TLC (diethyl ether/hexane, 1:1) then revealed the
presence of two new products of higher mobility. Conventional
workup and column chromatography (hexane Ǟ diethyl ether/hex-
ane, 1:25) first gave 23 (190 mg, 29%) as a colourless syrup. [α]2D7
ϭ
(4S,6R,9R)-4-(tert-Butyldimethylsilyloxy)-9-ethyl-3-oxo-1,7-dioxa-
spiro[5.5]undecane (19): Sodium acetate (180 mg, 2.2 mmol), mo-
˜
Ϫ10 (c ϭ 1). IR (film): ν ϭ 3071 (aromatic), 1728 (CϭO), 775 and
711 cmϪ1 (aromatic). 1H NMR: δ ϭ 8.06Ϫ7.43 (3 m, 5 H, Ph),
4.51 (dd, 1 H, J3,12 ϭ 3.1, J12,12Ј ϭ 11.2 Hz, 12-H), 4.25 (dd, 1 H,
J3,12Ј ϭ 7.5 Hz, 12Ј-H), 4.06 (dt, 1 H, J3,4 ϭ J4,5ax ϭ 10.5, J4,5eq ϭ
5.0 Hz, 4-H), 3.82 (dd, 1 H, J2eq,3 ϭ 4.6 Hz, 2eq-H), 3.58 (t, 1 H,
J2ax,2eq ϭ J2ax,3 ϭ 11.6 Hz, 2ax-H), 3.60Ϫ3.52 (m, 1 H, 8eq-H),
3.23 (t, 1 H, J8ax,8eq ϭ J8ax,9 ϭ 10.9 Hz, 8ax-H), 2.04 (m, 1 H, 3-
H), 1.97 (dd, 1 H, J5ax,5eq ϭ 12.8 Hz, 5eq-H), 1.50 (dd, 1 H, 5ax-
H), 1.76Ϫ1.09 (m, 7 H, 9,10ax,10eq,11ax,11eq-H, CH2CH3), 0.90
(s, 9 H, CMe3), 0.89 (t, J ϭ 7.3 Hz, 3 H, CH2CH3), 0.09 and 0.07
(2 s, 6 H, SiMe2). 13C NMR: δ ϭ 166.53 (CO), 133.01, 130.30,
129.62, and 128.47 (Ph), 97.36 (C-6), 65.89 (C-4), 65.27 (C-8), 63.23
and 61.26 (C-2,12), 45.19 (C-5), 44.22 (C-3), 36.78 (C-9), 35.40 (C-
11), 25.87 (CMe3), 25.36 and 25.01 (C-10,CH2CH3), 18.02 (CMe3),
11.27 (CH2CH3), Ϫ4.82 and Ϫ3.93 (SiMe2). HRMS (LSIMS):
found 471.2549 [Mϩ ϩ Na]; calcd. 471.2543. Eluted second was 24
˚
lecular sieves (4 A, powder; 2.5 g), and pyridinium chlorochromate
(2.4 g, 11 mmol) were added to a stirred and cooled (ice/water) so-
lution of 18 (1.9 g, 5.75 mmol) in anhydrous CH2Cl2 (25 mL). Stir-
ring was maintained at room temperature for 30 min. TLC (diethyl
ether/hexane, 1:2) then revealed a new compound of higher mobil-
ity. The mixture was diluted with diethyl ether (50 mL) and stirred
for 1 h, filtered through silica gel G and concentrated to a residue
that was percolated (diethyl ether) through silica gel to give 19
˜
(1.55 g, 82%) as a colourless syrup, tR ϭ 8.6 min. IR (film): ν ϭ
1744 cmϪ1 (CϭO). This was used in the next step.
(4S,6R,9R)-4-(tert-Butyldimethylsilyloxy)-9-ethyl-3-methylene-1,7-
dioxaspiro[5.5]undecane (20): Methyltriphenylphosphonium brom-
ide (4.3 g, 12 mmol) was added under argon to a stirred solution
of NaCH2SOMe, produced from a dispersion of sodium hydride in
oil (80%, 370 mg, 12.4 mmol) and imidazole (62 mg) in anhydrous
methyl sulfoxide (20 mL). The mixture was stirred for 15 min and
a solution of 19 (1.55 g, 4.73 mmol) in anhydrous diethyl ether
(10 mL) was added dropwise. After 30 min, TLC (diethyl ether/hex-
ane, 1:1) then revealed a new compound of higher mobility. The
reaction mixture was diluted with water (20 mL) and extracted with
diethyl ether (3 ϫ15 mL). The combined extracts were concentrated
and the residue was chromatographed (diethyl ether/hexane, 1:10)
to yield 20 (1 g, 64% from 18) as a colourless syrup; tR ϭ 7.8 min.
(390 mg, 59%). [α]2D5 ϭ Ϫ110 (c ϭ 1). IR (film): ν ϭ 3066 (Ph),
˜
1
1726 (CϭO), 776 and 711 cmϪ1 (Ph). H NMR: δ ϭ 8.05Ϫ7.42 (3
m, 5 H, Ph), 4.49 (t, 2 H, 12,12Ј-H), 4.33 (dt, 1 H, J3,4 ϭ J4,5eq
5.4, J4,5ax ϭ 11.6 Hz, 4-H), 3.84 (dd, 1 H, J2ax,2eq ϭ 11.2, J2eq,3
ϭ
ϭ
1.2 Hz, 2eq-H), 3.71 (br. d, 1 H, 2ax-H), 3.54 (m, 1 H, 8eq-H), 3.23
(t, 1 H, J8ax,9 ϭ J8ax,8eq ϭ 10.9 Hz, 8ax-H), 2.16 (m, 1 H, 3-H),
1.82Ϫ1.08 (m, 9 H, 5ax,5eq,9,10ax,10eq,11ax,11eq-H, CH2CH3),
0.90 (s, 9 H, CMe3), 0.89 (t, J ϭ 7.3 Hz, 3 H, CH2CH3), 0.09 and
0.07 (2 s, 6 H, SiMe2). 13C NMR: δ ϭ 166.78 (CO), 132.85, 130.63,
129.63 and 128.35 (Ph), 97.17 (C-6), 65.67 (C-4), 65.38 (C-8), 61.06
and 59.05 (C-2,12), 41.31 (C-5), 40.63 (C-3), 36.74 (C-9), 35.29 (C-
11), 25.87 (CMe3), 25.36 and 25.02 (C-10,CH2CH3), 18.08 (CMe3),
11.26 (CH2CH3), Ϫ4.60 and Ϫ4.69 (SiMe2). HRMS (LSIMS):
found 471.2544 [Mϩ ϩ Na]; calcd. 471.2543.
Ϫ1
1
[α]2D3 ϭ Ϫ98 (c ϭ 1). IR (film): ν ϭ 1665 cm (CϭC). H NMR:
δ ϭ 5.13 (t, 1 H, J12,12Ј ϭ J4,12 ϭ 2.1 Hz, 12-H), 4.93 (br. s, 1 H,
12Ј-H), 4.57 (m, 1 H, 4-H), 4.15 (d, 1 H, J2ax,2eq ϭ 12.1 Hz, 2ax-
H), 3.96 (d, 1 H, 2eq-H), 3.59 (br. dd, 1 H, J8eq,9 ϭ 3.9 Hz, 8eq-
H), 3.28 (t, 1 H, J8ax,8eq ϭ J8ax,9 ϭ 10.9 Hz, 8ax-H), 2.00 (dd, 1
H, J4,5eq ϭ 5.7, J5ax,5eq ϭ 12.4 Hz, 5eq-H), 1.71Ϫ1.36 (m, 5 H,
9,10ax,10eq,11ax,11eq-H), 1.51 (t, 1 H, J4,5ax ϭ 12.3 Hz, 5ax-H),
1.17 (m, 2 H, CH2CH3), 0.93 (s, 9 H, CMe3), 0.90 (t, J ϭ 7.3 Hz,
3 H, CH2CH3), and 0.10 (s, 6 H, SiMe2). 13C NMR: δ ϭ 146.93
(C-3), 107.17 (C-12), 97.72 (C-6), 67.10 (C-4), 65.55 and 64.34 (C-
2,8), 47.32 (C-5), 36.82 (C-9), 35.11 (C-11), 25.94 (CMe3), 25.37
and 25.05 (C-10, CH2CH3), 18.33 (CMe3), 11.27 (CH2CH3), Ϫ4.69
and Ϫ4.84 (SiMe2). HRMS (LSIMS): found 327.2350 [Mϩ ϩ 1];
calcd. 327.2356.
˜
(3R,4S,6R,9R)-3-Benzoyloxymethyl-9-ethyl-4-hydroxy-1,7-dioxa-
spiro[5.5]undecane (25): A solution of Bu4NF·3H2O (135 mg,
0.43 mmol) in THF (5 mL) was added under argon to a solution
of 23 (160 mg, 0.35 mmol) in the same solvent (5 mL). After 1 h,
TLC (diethyl ether/hexane, 1:1) then revealed two new, slower-run-
ning compounds. The solvent was removed, water (5 mL) was ad-
ded and extraction was performed with diethyl ether (2 ϫ 15 mL).
The combined extracts were concentrated and the residue was chro-
matographed (diethyl ether/hexane, 1:1), to afford first 25 (60 mg,
50%). [α]2D1 ϭ Ϫ49 (c ϭ 1). IR (film): ν ϭ 3448 (OH), 3076 (Ph),
˜
Hydroboration/Oxidation of 20: BH3SMe2 (10 , 0.4 mL, 4 mmol)
was added, dropwise under argon, to an ice-cooled and stirred solu-
1
1723 (CϭO), 758 and 711 cmϪ1 (Ph). H NMR: δ ϭ 8.03Ϫ7.41 (3
tion of 20 (660 mg, 2.02 mmol) in anhydrous THF (10 mL). After m, 5 H, Ph), 4.56 (dd, 1 H, J12,12Ј ϭ 11.5, J3,12 ϭ 6.2 Hz, 12-H),
2 h, aqueous NaOH (3 , 5 mL), and aqueous H2O2 (30%, 5 mL) 4.42 (dd, 1 H, J3,12Ј ϭ 3.4 Hz, 12Ј-H), 3.95 (dt, 1 H, J3,4 ϭ J4,5ax ϭ
Eur. J. Org. Chem. 2002, 309Ϫ317
315

´
I. Izquierdo, M. T. Plaza, M. Rodrıguez, J. A. Tamayo
FULL PAPER
10.8, J4,5eq 5.0 Hz, 4-H), 3.84 (dd, 1 H, J2eq,3 ϭ 4.7, J2ax,2eq
ϭ
3.8 Hz, 12-H), 3.71 (dd, 1 H, J3,12Ј ϭ 3.7 Hz, 12Ј-H), 3.64 (dd, 1
11.5 Hz, 2eq-H), 3.56 (t, 1 H, J2ax,3 ϭ 11.5 Hz, 2ax-H), 3.51 (m, 1 H, J2eq,3 ϭ 4.5 Hz, 2eq-H), 3.61 (m, 1 H, 8eq-H), 3.33 (t, 1 H,
H, 8eq-H), 3.21 (t, 1 H, J8ax,8eq ϭ J8eq,9 ϭ 10.9 Hz, 8ax-H), 2.05 8ax,8eq ϭ J8ax,9 ϭ 10.9 Hz, 8ax-H), 2.82 (br. s, 1 H, OH), 1.90 (dd,
J
(dd, 1 H, J5ax,5eq ϭ 12.7 Hz, 5eq-H), 1.97 (m, 1 H, 3-H), 1.48 (dd, 1 H, J5ax,5eq ϭ 14.3, J4,5eq ϭ 3 Hz, 5eq-H), 1.80 (m, 1 H, 3-H),
1 H, 5ax-H), 1.75Ϫ1.06 (2 m, 7 H, 9,10ax,10eq,11ax,11eq-H, 1.69Ϫ1.10 (m, 8 H, 5ax,9,10ax,10eq,11ax,11eq-H, CH2CH3), 0.88
CH2CH3), and 0.87 (t, J ϭ 7.4 Hz, 3 H, CH2CH3). 13C NMR: δ ϭ
(t, J ϭ 7.5 Hz, 3 H, CH2CH3). 13C NMR: δ ϭ 96.98 (C-6), 68.16
167.02 (CO), 133.25, 129.73, and 128.52 (Ph), 97.34 (C-6), 65.37 (C-4), 65.67 (C-8), 63.30 (C-12), 57.57 (C-2), 40.80 (C-5), 40.73 (C-
(C-8), 65.10 (C-4), 63.14 and 61.13 (C-2,12), 44.37 (C-3), 44.16
(C-5), 36.75 (C-9), 35.25 (C-11), 25.26 and 24.89 (C-10,CH2CH3),
3), 36.56 (C-9), 35.08 (C-11), 25.20 (CH2CH3), 24.44 (C-10), 11.18
(CH2CH3). HRMS (LSIMS): found 253.1415 [Mϩ ϩ Na]; calcd.
and 11.20 (CH2CH3). HRMS (LSIMS): found 357.1673 253.1416.
[Mϩ
ϩ
Na]; calcd. 357.1678. The second fraction was
(3S,4S,6R,9R)-3-Benzoyloxymethyl-9-ethyl-4-hydroxy-1,7-dioxa-
spiro[5.5]undecane (28): Compound 24 (360 mg, 1.04 mmol) was de-
silylated in THF (10 mL) as above, with Bu4NF·3H2O (395 mg,
1.25 mmol). Workup of the reaction mixture and chromatography
first gave syrupy 28 (220 mg, 82%). [α]2D4 ϭ Ϫ89 (c ϭ 1.61). IR
(film): ν˜ ϭ 3434 (OH), 3040 (aromatic), 1724 (CϭO), 758 and 711
cmϪ1 (aromatic). 1H NMR: δ ϭ 8.08Ϫ7.42 (3 m, 5 H, Ph), 4.74
(dd, 1 H, J12,12Ј ϭ 10.9, J3,12 ϭ 4.2 Hz, 12-H), 4.49 (dd, 1 H,
(3S,4S,6R,9R)-4-benzoyloxy-9-ethyl-3-hydroxymethyl-1,7-dioxa-
spiro[5.5]undecane (26, 20 mg, 12.5%). 1H NMR: δ ϭ 8.05Ϫ7.45
(3 m, 5 H, Ph), 5.51 (dt, 1 H, J3,4 ϭ J4,5ax ϭ 11.2, J4,5eq ϭ 5.1 Hz,
4-H), 3.85 (t, 1 H, J2ax,2eq ϭ J2ax,3 ϭ 11.5 Hz, 2ax-H), 3.75 (dd, 1
H, J2eq,3 ϭ 5 Hz, 2eq-H), 3.62 (dd, 1 H, J12,12Ј ϭ 12.3, J3,12 ϭ 4 Hz,
12-H), 3.61Ϫ3.51 (m, 1 H, 8eq-H), 3.54 (dd, 1 H, J3,12Ј ϭ 2.3 Hz,
12Ј-H), 3.27 (t, 1 H, J8ax,9 ϭ J8ax,8eq ϭ 10.9 Hz, 8ax-H), 2.14 (dd,
1 H, J5ax,5eq ϭ 12.3 Hz, 5eq-H), 1.76 (t, 1 H, 5ax-H), 1.92Ϫ1.07
(m, 8 H, 3,9,10ax,10eq,11ax,11eq-H, CH2CH3), 0.89 (t, J ϭ 7.5 Hz,
3 H, CH2CH3). 13C NMR: δ ϭ 167.31 (CO), 133.38, 129.85,
129.69, 128.51 (Ph), 97.16 (C-6), 68.66 (C-4), 65.36 (C-8), 61.47,
59.78 (C-2,12), 44.53 (C-3), 41.11 (C-5), 36.73 (C-9), 35.20 (C-11),
25.28 and 24.93 (C-10,CH2CH3), 11.23 (CH2CH3).
J3,12Ј ϭ 9.5 Hz, 12Ј-H), 4.40 (m, 1 H, 4-H), 3.85 (dd, 1 H, J2,3
ϭ
1.7, J2,2Ј ϭ 11.7 Hz, 2-H), 3.75 (dd, 1 H, J2Ј,3 ϭ 1.6 Hz, 2Ј-H), 3.55
(m, 1 H, 8eq-H), 3.25 (t, 1 H, J8ax,8eq ϭ J8eq,9 ϭ 10.9 Hz, 8ax-H),
2.30 (m, 1 H, 3-H), 2.10 (d, 1 H, J4,OH ϭ 3.2 Hz, OH), 1.89 (dd, 1
H, J5ax,5eq ϭ 13, J4,5eq ϭ 4.7 Hz, 5eq-H), 1.57 (t, 1 H, J4,5ax
12.8 Hz, 5ax-H), 1.78Ϫ1.08 (3 m, 7 H, 9,10ax,10eq,11ax,11eq-H,
(3R,4R,6R,9R)-3-Benzoyloxymethyl-4-(3,5-dinitrobenzoyloxy)-9- CH2CH3), 0.89 (t, J ϭ 7.4 Hz, 3 H, CH2CH3). 13C NMR: δ ϭ
ϭ
ethyl-1,7-dioxaspiro[5.5]undecane (27): Ph3P (140 mg, 0.54 mmol),
3,5-dinitrobenzoic acid (114 mg, 0.54 mmol) and DEAD (0.1 mL,
166.87 (CO), 133.02, 130.37, 129.64, and 128.42 (Ph), 97.09 (C-6),
65.52 (C-8), 65.33 (C-4), 61.20 and 59.61 (C-2,12), 40.48 (C-5),
0.54 mmol) were added to a solution of 25 (60 mg, 0.18 mmol) in 40.10 (C-3), 36.73 (C-9), 35.29 (C-11), 25.29 and 24.95 (C-
anhydrous THF (5 mL), and the mixture was kept at room temper-
ature for 48 h. TLC (diethyl ether/hexane, 1:1) then showed a new
compound of higher mobility. Diethyl ether (5 mL) was added and
10,CH2CH3), 11.20 (CH2CH3). HRMS (LSIMS): found 357.1680
[Mϩ
Na]; calcd. 357.1680. The second fraction was
(3R,4S,6R,9R)-4-benzoyloxy-9-ethyl-3-hydroxymethyl-1,7-dioxa-
ϩ
the resulting solution was washed with saturated aqueous Na2CO3 spiro[5.5]undecane (29; 30 mg, 8%) as a colourless syrup. 1H NMR:
solution and water. Concentration of the solvent gave a residue that
δ ϭ 8.03Ϫ7.39 (3 m, 5 H, Ph), 5.64 (dt, 1 H, J3,4 ϭ J4,5eq ϭ 5.4,
was submitted to column chromatography (diethyl ether/hexane, J4,5ax ϭ 11.9 Hz, 4-H), 3.96 (d, 2 H, J12,3 ϭ 6.5 Hz, 12,12-H), 3.88
1:4) to afford 27 (95 mg, quantitative) as a pale yellow syrup.
(s, 2 H, 2,2-H), 3.58 (m, 1 H, 8eq-H), 3.24 (t, 1 H, J8ax,8eq ϭ J8ax,9 ϭ
10.9 Hz, 8ax-H), 2.23 (m, 1 H, 3-H), 1.98 (dd, 1 H, J5ax,5eq
12.8 Hz, 5eq-H), 1.78 (t, 1 H, 5ax-H), 1.76Ϫ1.04 (m, 7 H, 9,10ax,
[α]2D8 ϭ Ϫ75 (c ϭ 1). IR (film): ν ϭ 3074 (aromatic), 1730 and 1727
ϭ
˜
(CϭO, benzoate and 3,5-dinitrobenzoate), 731 and 713 cmϪ1 (aro-
matic). 1H NMR: δ ϭ 9.16 (m, 3 H, 3,5-dinitrobenzoyl), 7.95Ϫ7.37 10eq,11ax,11eq-H, CH2CH3), 0.87 (t, J ϭ 7.5 Hz, 3 H, CH2CH3).
(3 m, 5 H, Ph), 5.62 (br. s, 1 H, 4-H), 4.32 (dd, 1 H, J12,12Ј ϭ 11.3, 13C NMR: δ ϭ 165.59 (CO), 133.09, 130.36, 129.62, and 128.46
J3,12 ϭ 7 Hz, 12-H), 4.24 (dd, 1 H, J3,12Ј ϭ 7.1 Hz, 12Ј-H), 4.10 (t, (Ph), 97.40 (C-6), 69.39 (C-4), 65.48 (C-8), 59.63 and 59.31 (C-
1 H, J2ax,3 ϭ J2ax,2eq ϭ 11.5 Hz, 2ax-H), 3.83 (dd, 1 H, J2eq,3
4.5 Hz, 2eq-H), 3.75 (m, 1 H, 8eq-H), 3.46 (t, 1 H, J8ax,8eq
ϭ
2,12), 39.98 (C-3), 37.52 (C-5), 36.63 (C-9), 35.23 (C-11), 25.28 and
24.93 (C-10,CH2CH3), 11.20 (CH2CH3).
ϭ
J8ax,9 ϭ 10.9 Hz, 8ax-H), 2.53 (m, 1 H, 3-H), 2.12 (dd, 1 H,
J5ax,5eq ϭ 15.1, J4,5eq ϭ 2.7 Hz, 5eq-H), 1.83 (dd, 1 H, J4,5ax
(3S,4R,6R,9R)-3-Benzoyloxymethyl-4-(3,5-dinitrobenzoyloxy)-9-
ethyl-1,7-dioxaspiro[5.5]undecane (30): Compound 28 (200 mg,
0.58 mmol) was treated with Ph3P (456 mg, 1.74 mmol), 3,5-di-
nitrobenzoic acid (368 mg, 1.74 mmol), and DEAD (0.27 mL,
1.74 mmol) in dry THF (5 mL) as above to afford syrupy 30
ϭ
1.8 Hz, 5ax-H), 1.72Ϫ1.11 (m, 7 H, 9,10ax,10eq,11ax,11eq-H,
CH2CH3), 0.89 (t, J ϭ 7.4 Hz, 3 H, CH2CH3). 13C NMR: δ ϭ
166.26 and 162.16 (2 CO), 148.64, 134.76, 133.31, 129.75, 129.68,
129.58, 128.50, 122.26 (Ph, DNBz), 95.14 (C-6), 69.51 (C-4), 65.69
(C-8), 62.31 (C-12), 57.40 (C-2), 38.70 (C-5), 38.09 (C-3), 36.49 (C-
9), 35.39 (C-11), 25.36 and 24.86 (C-10,CH2CH3), 11.21 (CH2CH3).
HRMS (LSIMS): found 551.1644 [Mϩ ϩ Na]; calcd. 551.1642.
(143 mg, 45%). [α]2D8 ϭ Ϫ89 (c ϭ 1). IR (film): ν ϭ 3035 (aromatic),
˜
1739 and 1725 (CϭO, benzoate and 3,5-dinitrobenzoate), 730 and
714 cmϪ1 (aromatic). 1H NMR: δ ϭ 9.21 (s, 3 H, 3,5-dinitro-
benzoyl), 8.05Ϫ7.45 (3 m, 5 H, Ph), 5.48 (br. d, 1 H, 4-H), 4.54 (d,
(3S,4R,6R,9R)-9-Ethyl-4-hydroxy-3-hydroxymethyl-1,7-dioxaspiro- J ϭ 7.7 Hz, 2 H, 12,12-H), 4.30 (dd, 1 H, J2,2Ј ϭ 12, J2,3 ϭ 3 Hz,
[5.5]undecane [(؊)-Talaromycin E]: NaOMe (0.5 , 0.5 mL) was ad- 2-H), 3.77 (m, 1 H, 8eq-H), 3.71 (br. d, 1 H, 2Ј-H), 3.42 (t, 1 H,
ded to a solution of 27 (90 mg, 0.17 mmol) in anhydrous methanol
(10 mL), and the reaction mixture was maintained at room temper-
ature for 5 h. TLC (diethyl ether/hexane, 1:1) showed the presence
J8ax,8eq ϭ J8ax,9 ϭ 10.9 Hz, 8ax-H), 2.31 (m, 1 H, 3-H), 2.01 (dd, 1
H, J5,5Ј ϭ 15.1, J4,5 ϭ 2.8 Hz, 5-H), 1.95 (dd, 1 H, J4,5Ј ϭ 3.7 Hz,
5Ј-H), 1.78Ϫ1.10 (m, 7 H, 9,10ax,10eq,11ax,11eq-H, CH2CH3),
of a slower-running compound. The reaction mixture was neutral- 0.90 (t, J ϭ 7.5 Hz, 3 H, CH2CH3). 13C NMR: δ ϭ 166.48 and
ized and concentrated. Column chromatography (methanol/ether,
1:5) of the residue gave (Ϫ)-talaromycin E (28 mg, 72%) as a vis-
161.82 (2 CO), 148.73, 134.70, 133.36, 129.77, 129.72, 128.58 and
122.37 (Ph), 95.20 (C-6), 69.85 (C-4), 65.86 (C-8), 63.34 (C-12),
56.71 (C-2), 37.29 (C-3), 36.47 (C-9), 35.34 (C-5,11), 25.28 and
Ϫ1
cous, colourless oil. [α]2D7 ϭ Ϫ94 (c ϭ 1). IR (film): ν ϭ 3462 cm
˜
(OH). 1H NMR: δ ϭ 4.14 (br. d, 1 H, 4-H), 3.91 (t, 1 H, J2ax,2eq ϭ 24.82 (C-10,CH2CH3), 11.22 (CH2CH3). HRMS (LSIMS): found
J2ax,3 ϭ 11.9 Hz, 2ax-H), 3.79 (dd, 1 H, J12,12Ј ϭ 11.3, J3,12
ϭ
551.1647 [Mϩ ϩ Na]; calcd. 551.1642.
316
Eur. J. Org. Chem. 2002, 309Ϫ317

Enantiospecific Total Synthesis of (Ϫ)-Talaromycins C and E
FULL PAPER
[2]
[3]
N. J. Phillips, R. J. Cole, D. G. Lynn, Tetrahedron Lett. 1987,
28, 1619Ϫ1622.
(3R,4R,6R,9R)-9-Ethyl-4-hydroxy-3-hydroxymethyl-1,7-dioxaspiro-
[5.5]undecane [(؊)-Talaromycin C]: Zemplen deacylation of 30
(120 mg, 0.23 mmol) with 0.5  NaOMe in anhydrous methanol
(10 mL), followed by the same workup as above, gave (Ϫ)-talaro-
In Scheme 1 we have represented the enantiomers of the struc-
tures of talaromycins D, F, and G reported in ref.[2] since those
authors could not establish their absolute configurations.
L. F. Tietze, G. Schneider, J. Wölfling, A. Fecher, T. Nöbel, S.
Petersen, I. Schuberth, C. Wulff, Chem. Eur. J. 2000, 6,
3755Ϫ3760.
C. Iwata, N. Maezaki, K. Hattori, M. Fujita, Y. Moritani, Y.
Takemoto, T. Tanaka, T. Imanishi, Chem. Pharm. Bull. 1993,
41, 946Ϫ950 and references therein.
mycin C (45 mg, 86%) as a viscous, colourless oil. [α]2D7 ϭ Ϫ122
[4]
[5]
1
(c ϭ 1). H NMR (500 MHz; C6D6): δ ϭ 4.08 (br. dd, 1 H, J2,3
ϭ
3.2, J2,2Ј 11.8 Hz, 2-H), 4.08 (br. s, 1 H, 4-H), 3.64 (d, 1 H, 2Ј-H),
3.56 (dd, 1 H, J12,12Ј ϭ 10.6, J3,12 ϭ 7.8 Hz, 12-H), 3.46 (dd, 1 H,
J3,12Ј ϭ 6.9 Hz, 12Ј-H), 3.33 (ddd, 1 H, J8eq,9 ϭ 4.5, J8eq,10eq
ϭ
1.8 Hz, 8eq-H), 3.21 (t, 1 H, J8ax,8eq ϭ J8ax,9 ϭ 11 Hz, 8ax-H), 1.88
(m, 1 H, 3-H), 1.78 (br. dd, 1 H, J5,5Ј ϭ 14.4, J4,5 ϭ 2.4 Hz, 5-H),
1.56 (dd, 1 H, J4,5Ј ϭ 3.5 Hz, 5Ј-H), 1.55Ϫ0.90 (m, 7 H, 9,10ax,10-
[6]
[7]
I. Izquierdo, M.-T. Plaza, Carbohydr. Res. 1990, 205, 293Ϫ304.
´
I. Izquierdo, M.-T. Plaza, M. Rodrıguez, J. A. Tamayo, L. Ma-
cias, J. Carbohydr Chem. 2001, 20, 447Ϫ457.
eq,11ax,11eq-H, CH2CH3), 0.77 (t, J ϭ 7.5 Hz, 3 H, CH2CH3). 13
C
[8]
[9]
´
I. Izquierdo, M.-T. Plaza, M. Rodrıguez, J. A. Tamayo, Tetra-
NMR: δ ϭ 97.01 (C-6), 65.88 (C-4), 65.47 (C-8), 62.45 (C-12),
56.54 (C-2), 43.93 (C-3), 37.80 (C-5), 36.71 (C-9), 35.46 (C-11),
25.38 (CH2CH3), 24.79 (C-10), 11.16 (CH2CH3). HRMS (LSIMS):
found 253.1416 [Mϩ ϩ Na]; calcd. 253.1416.
hedron: Asymmetry 1999, 10, 449Ϫ455.
J. A. Tamayo, PhD Dissertation, University of Granada, Gran-
ada, Spain, 2001.
[10] [10a]
˜
I. Izquierdo, M.-T. Plaza, R. Acuna, J. Chem. Ecol. 1991,
[10b]
˜
I. Izquierdo, M.-T. Plaza, R. Acuna, J.
17, 1529Ϫ1541.
Chem. Ecol. 1992, 18, 115Ϫ125.
[11]
[12]
[13]
[14]
[15]
M. Sefkow, A. Neidlein, T. Sommerfeld, F. Sternfeld, M. A.
Maestro, D. Seebach, Liebigs Ann. Chem. 1994, 719Ϫ729.
Corrigendum: The (4R) configuration for compound 7 and 8
that appeared in refs.[6,8], should read (4S).
D. H. R. Barton, D. O. Jang, J. C. Jaszberenyi, Tetrahedron
Lett. 1992, 33, 5709Ϫ5712.
Acknowledgments
´
The authors are deeply grateful to the Ministerio de Educacion y
Cultura (Spain) for financial support (Project PB98-1357) as well as
for a grant (J. A. T.), and to Roche Co. for the gift of several lipases.
W. Francke, W. Reith, W. Sinnvell, Chem. Ber. 1980, 113,
2686Ϫ2693.
O. Mitsunobu, Synthesis 1981, 1Ϫ28.
[1] [1a]
D. G. Lynn, N. J. Phillips, W. C. Hutton, J. Shabanowitz,
D. I. Fennell, R. J. Cole, J. Am. Chem. Soc. 1982, 104,
[1b]
7319Ϫ7322.
W. C. Hutton, N J. Phillips, D. W. Graden, D.
Received July 3, 2001
G. Lynn, J. Chem. Soc., Chem. Commun. 1983, 864Ϫ866.
[O01341]
Eur. J. Org. Chem. 2002, 309Ϫ317
317