Enantioselective, chemoenzymatic synthesis, and absolute configuration of the antioxidant (-)-gloeosporiol

Article abstract of DOI:10.1016/j.tet.2010.07.074

The natural antioxidant (-)-gloeosporiol, isolated as a peracetylated derivative from a culture of the fungus Colletotrichum gloeosporioides, has been enantioselectively prepared from 3,4-dihydroxybenzaldehyde by means of a chemoenzymatic synthesis. The k

Full text of DOI:10.1016/j.tet.2010.07.074

Tetrahedron 66 (2010) 8068e8075
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective, chemoenzymatic synthesis, and absolute configuration
of the antioxidant (ꢀ)-gloeosporiol
Gabriela Mancilla a, M. Femenía-Ríos a, Manuel Grande b, R. Hernández-Galán a,
,
a,
*
A.J. Macías-Sánchez a , I.G. Collado
*
a Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Campus Río San Pedro, E-11510 Puerto Real, Cádiz, Spain
b Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, E-37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 May 2010
Received in revised form 24 July 2010
Accepted 26 July 2010
Available online 3 August 2010
The natural antioxidant (ꢀ)-gloeosporiol, isolated as a peracetylated derivative from a culture of the
fungus Colletotrichum gloeosporioides, has been enantioselectively prepared from 3,4-dihydroxy-
benzaldehyde by means of a chemoenzymatic synthesis. The key intermediate was obtained by reso-
lution with a lipase from Pseudomonas cepacia. Its stereochemistry, initially assigned as R, according to
the Kazlaukas empirical rule for secondary alcohols, was independently confirmed by NMR and chi-
rooptic methods. This, in turn, allowed the assignment of compound (ꢀ)-1 as (ꢀ)-(2S,3R,4R)-2-
(30,40dihydroxyphenyl)tetrahydrofuran-3,4-diol.
Keywords:
Colletotrichum gloeosporioides
Chemoenzymatic synthesis
Absolute configuration
Antioxidant
Ó 2010 Published by Elsevier Ltd.
1. Introduction
for an assignment of the absolute stereochemistry of the natural
product (ꢀ)-1.
The filamentous fungi of the Colletotrichum genus are considered
major plant pathogens worldwide.1 The ubiquitous Colletotrichum
gloeosporioides (Penz.) Penz. & Sacc. (teleomorph Glomerella cingu-
lata) has been the subject of a number of studies, including its use in
the production of secondary metabolites.2 As part of our research
program on the rational control of phytopathogenic fungi,3 we are
interested in the relationship between the infective capabilities of
certain phytopathogenic fungi and the role of their secondary me-
tabolites in the infection mechanisms.
Enzymes have become standard catalysts in organic synthesis, in
order to perform regio-, stereoselective, and enantioselective trans-
formations. Lipases in particular have received the most attention
acting with high efficiency in acylation, hydrolysis, and alkoxy-
carbonylation processes.6 Recently, hydrolyzes of 1-arylallyl acetates
catalyzed by Candida antartica lipase were obtained with excellent
enantioselectivities.7 A key feature of enantioselective syntheses is
their ability to determine and control the stereochemistry of the
chiral materials involved. A number of methods are used to de-
termine absolute configuration and, recently, different NMR spec-
troscopy based approaches to this problem have emerged.8,9
Herein we describe the enantioselective preparation of
(ꢀ)-gloeosporiol (1) and consequently its absolute configuration
through the enzymatic resolution of a suitable precursor and the
confirmation of its absolute configuration by NMR and chiroptic
methods.
The 3,4-dihydroxylated, 2-(30,40-dihidroxyphenyl)tetrahydrofu-
ran derivative (ꢀ)-1, was recently isolated from a strain of
C. gloeosporioides and discovered to occur naturally as a single en-
antiomer through racemic synthesis and resolution of the enan-
tiomeric tetrols.4 Determination of the enantiomeric composition
of a material of natural origin, is useful as there are reports of
compounds produced in different enantiomeric proportions, even
when obtained from different parts of the same natural source.5
An enantioselective synthesis of (ꢀ)-1 would not only provide
material for further testing but it would also provide the grounds
2. Results and discussion
The enantioselective synthesis of (ꢀ)-(2S,3R,4R)-gloeosporiol
(1), was achieved as shown in Schemes 1 and 4. The synthetic route
was based on the lipases mediated sequential kinetic resolution of
the aryl-vinyl acetate 3a, to yield the enantiomerically pure key
intermediate 1-arylvinyl alcohol (3). An O-allylation, ring-closing
metathesis, dihydroxylation, and deprotection sequence would led
* Corresponding authors. Tel: þ34 95601 6368; fax: þ34 95601 6193 (I.G.C.); tel:
(þ34) 95601 6405; fax: (þ34) 95601 6193 (A.J.M.-S.); e-mail addresses: antonio-
jose.macias@uca.es (A.J. Macías-Sánchez), isidro.gonzalez@uca.es (I.G. Collado).
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.07.074

G. Mancilla et al. / Tetrahedron 66 (2010) 8068e8075
8069
Table 1
to the desired enantiomerically pure natural product (ꢀ)-1, and, in
Kinetic enzymatic resolution of acetate (ꢁ)-3a by P. cepacia lipase (Scheme 1)
turn, to the elucidation of its absolute stereochemistry.
Entry
t (ꢂC)
t (h)
Ea
(ꢀ)-(S)-3a
(þ)-(R)-3
The treatment of 3,4-dihydroxybenzaldehyde (2) with TBDMSCl
and imidazole in THF,10 rendered a protected aldehyde (2a). Re-
action of compound 2a with vinyl bromide and magnesium turn-
ings, in THF,11 yielded 1-[(30,40-bis-(tert-butyldimethylsilyloxy)
phenyl)]prop-2-en-1-ol ((ꢁ)-3), which can be transformed into the
corresponding acetate (ꢁ)-3a.
(%)b
ee(%)c
(%)b
ee(%)d
a
b
c
48
37
25
25
3
2
7
6
28
32
77
75
50
53
4
2
7
17
31
34
93
94
>99
98
>200
194
96
65
d
a
The asymmetric synthesis of complex molecules has success-
fully employed enantiomerically-enriched allylic alcohols and al-
lylic acetates as chiral intermediates.12 One way of preparing these
intermediates is by enantioselective acylation13 of secondary al-
cohols or the enantioselective hydrolysis14 of the corresponding
esters employing either enzymatic or non-enzymatic methods.
Nevertheless, kinetic resolution of 1-arylallyl alcohols has proven
to be challenging15 and only recently over 99% ee have been
described,7a,b employing an immobilized Candida antarctica lipase.
Lipase mediated kinetic resolution of (ꢁ)-3a was studied using
Pseudomonas cepacia lipase (PS lipase or PSL) (Scheme 1). Pseudo-
monas fluorescens lipase (AK lipase) and Candida rugosa lipase (CRL)
where also considered initially but they failed to react under the
evaluated conditions. Selected results obtained with PSL are sum-
marized in Table 1. Enantiomeric excess (ee) was measured by HPLC
fitted with a chiral column for enantiomerically enriched alcohol
(þ)-(R)-3, while enantiomeric excess for residual acetate (ꢀ)-(S)-3a
was measured by GC or GC/MS fitted with a capillary chiral column.
The effect of temperature and time on the enantiomeric excess
and yield for both alcohol (þ)-(R)-3 and residual acetate (ꢀ)-(S)-3a
were evaluated (Table 1). An increase in the temperature disfavors
both enantiomeric excess and alcohol yield (þ)-(R)-3, while an
Calculated from E¼ln[1 e c(1 þ ee((þ)-(R)-3))]/ln[1 ꢀ c(1 e ee((þ)-(R)-3))],
where c¼ee((ꢀ)-(S)-3a)/(ee((ꢀ)-(S)-3a) þ ee((þ)-(R)-3)).
b
Isolated yields, following alumina column chromatography.
Enantiomeric excess calculated by chiral GC.
Enantiomeric excess calculated by chiral HPLC.
c
d
optimized time was found for enantiomeric excess (>99%) (Table 1,
entry c), which was close to the optimized time for yield (Table 1,
entry d). Optimum reaction conditions for enantiomeric excess were
employed for further preparative uses, rendering (þ)-(R)-3 at a yield
of 31% yield and >99% ee; these conditions gave rise to recovered
acetate (ꢀ)-(S)-3a at a 50% yield and 96% ee (Table 1, entry c).
In accordance with the Kazlaukas empirical rule for secondary
alcohols,16 resolved alcohol should be assigned as (þ)-(R)-3. To
confirm this assignment, we carried out a variable temperature
NMR study of methoxyphenylacetic acid (MPA) derivatives of al-
cohol (þ)-(R)-3. A survey of the literature produced no examples of
assignation of the variable temperature NMR-CDA technique used
for the assignment of the absolute stereochemistry of 1-arylallyl
alcohols.9 We therefore carried out a preliminary model study with
1-phenylallyl alcohols of known absolute configuration.
(þ)-(R)- and (ꢀ)-(S)-1-Phenylprop-2-en-1-ol (7) obtained from
commercial sources were independently treated with (R)- and (S)-
MPA, to yield all four possible diastereomers ((þ)- and (ꢀ)-8, (þ)-
and (ꢀ)-9) (Scheme 2). The 1H NMR of each of these diastereomeric
esters was recorded at 25 ꢂC and ꢀ60 ꢂC using TMS as the internal
O
O
reference for chemical shifts. Differences in chemical shifts (DdT1T2
)
between the highest temperature (T1¼25 ꢂC) and the lowest one
(T2¼ꢀ60 ꢂC) for the proton signals of the groups attached to the
chiral center of the alcoholic moiety were recorded as shown in
Scheme 2.
H
H
TBDMSCl
RO
RO
THF
87%
RO
RO
2
From the data obtained, it can be deduced that, on one hand H-
2000 and H-4000, protons from the aromatic ring attached to the chiral
center on the alcohol (L1), and on the other hand, H-300cis and H-
300trans, protons from the methylenic portion of the double bond
attached to the chiral center (L2), undergo observable chemical shift
variations consistent with Riguera’s rule.9 H-200, the most deshiel-
ded proton of the ABX spin system and the one from the methynic
portion of the double bond attached to the chiral center, does not
consistently follows the rule. Probably, in the most stable confor-
mation at each temperature, this proton is too far away to be
influenced by shielding of the chiral acidic moiety.
Compound (þ)-3 was independently treated with (R)- and (S)-
MPA, to yield one diastereoisomer in each instance (compounds 10
and 11). The 1H NMR of each of these diastereomeric esters was
recorded at 25 ꢂC and ꢀ60 ꢂC, using a TMS as the internal reference
for chemical shifts. Differences in chemical shifts (DdT1T2) between
the highest temperature (T1¼25 ꢂC) and the lowest one
(T2¼ꢀ60 ꢂC) for proton signals of groups attached to the chiral
center of the alcoholic moiety were recorded as shown in Scheme 3.
Once each proton of the product was identified, through mono-
and bidimensional NMR spectra, comparison of high and low
temperature spectra shows changes in chemical shifts, which are
consistent with those observed for (R)- and (S)-MPA esters of
(þ)-(R)-1-phenylprop-2-en-1-ol. Therefore, the structural assign-
ment for compound 3 can be confirmed as (þ)-(R)-1-(3,4-bis(tert-
butyldimethylsilyloxi)phenyl)prop-2-en-1-ol, as predicted by the
Kazlaukas empirical rule.16
R=H
2a R=TBDMS
OR'
H2C CHBr
Mg, THF
73%
RO
RO
3
( ) R = TBDMS
R' = H
Ac2O
py
3a
( ) R = TBDMS
R' = Ac
PSL, 1,4-dioxane
3a
( )
0.1 M KH2PO4/KOH
(pH 7)
OH
OAc
R
S
+
RO
RO
RO
RO
3a
3
(-)-(S)-
(+)-(R)-
R = TBDMS
R = TBDMS
Scheme 1. Preparation and kinetic enzymatic resolution of acetate (ꢁ)-3a by P. cepacia
lipase (for details see Table 1).

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G. Mancilla et al. / Tetrahedron 66 (2010) 8068e8075
2'
benzyl alcohol corresponds to one in which the proton is nearly
eclipsed with the benzene ring, the positive C.E. of the 1Lb ab-
sorption band suggests an configuration for the carbinol
H OCH3
2
R
R
O
H3"a
according to the benzene sector rules.17 Hydrolysis of (ꢀ)-3a pro-
duced the enantiomeric alcohol (ꢀ)-3, which displays two positive
Cotton effects (D3238þ0.67 and D3275þ0.05) as expected for the S
stereoisomer. This assignment is also supported by the CD spectra
of commercial (þ)-(R)-7 and (ꢀ)-(S)-7, which displayed C.E. at
D3255ꢀ0.02 and D3255þ0.02 (1Lb band), and D3224ꢀ0.50 and
D3224þ0.40 (1La band), respectively, in agreement with the pre-
dictions of the benzene sector rules.
(R)-MPA
EDC
OH
O
DMAP
R
R
H3"b
2''
CH2Cl2
r.t.
4'''
7
(+)-(R)-
8
(-)-(1''R,2R)-
H3CO H
R
Not always the sector rules can be easily applied to the 1Lb
absorption bands to establish the stereochemistry of chiral carbi-
nols because the 1Lb band is altered by vibrational transitions and
the sign of this band can sometimes be reversed by the sub-
stituents on the benzene ring, i.e., (R)-3,4-dialkoxy phenyl carbi-
nols can display positive or negative C.E.18 Fortunately, the 1La
band is less affected by the vibronic coupling and is more reliable
in correlating the sign of the C.E. with the absolute
configuration of molecules with an aromatic ring contiguous to
a chiral center applying the benzene sector rules.19 Consequently,
the negative C.E. of (þ)-3 at 238 nm also supports the proposed R
configuration for this enantiomer.
O-Allylation of compound (þ)-(R)-3 was carried out by treat-
ment with (TMS)2NLi and allyl bromide in THF,20 producing the
allyl ether (þ)-(R)-1-(30,40-bis-(tert-butyldimethylsilanoxy)phe-
nyl)-prop-2-en-1-yl (4) at a yield of 98%. Ring-closing metathesis
on the non-conjugated diene (þ)-(R)-4, using (PCy3)2Cl2RuCHPh
(first-generation Grubbs’ catalyst)21 yielded (þ)-(R)-2-[(30,40-bis-
(tert-butyldimethylsilanoxy)phenyl)]-2,5-dihydrofuran (5) after
2 h reaction time (99%). Dihydroxylation of the compound with the
OsO4/Me3NO22 system produced a 1:7 mixture of syn-diols (ꢀ)-6a
and (ꢀ)-6b; 10% and 70% yields, respectively. The product ratio
observed reflects the preference of the reagent for the least hin-
dered face of the olefin in the precursor compound (þ)-(R)-5. The
stereochemistry of the minor compound (ꢀ)-6a could be de-
termined by NOE experiments as 2S,3S,4S. This, in turn, permitted
the assignment of the stereocomplementary compound (ꢀ)-6b as
2S,3R,4R. Treatment of the major diastereoisomer (ꢀ)-(2S,3R,4R)-
2-[(30,40-bis-(tert-butyldimethylsilanoxy)phenyl)]tetrahydrofuran-
3,4-diol (6b) with I2/MeOH23 yielded led to (ꢀ)-(2S,3R,4R)-gloeo-
sporiol (1), with an enantiomeric excess >99% (optical purity).24 As
shown in Scheme 4, the entire synthesis took place with no loss
of enantiomeric purity. Peracetylation of (ꢀ)-1 with Py/Ac2O
yielded (ꢀ)-(2S,3S,4R)-2-(30,40-diacetoxyphenyl)-3,4-diacetoxyte-
trahydrofuran (1a), which presented physical and spectroscopic
data consistent with those observed for the sample obtained by
chemical resolution from (ꢁ)-6a24 and the isolated tetracetate
from the culture of C. gloeosporioides.4
O
O
(R)-MPA
EDC
OH
+0.18
+0.06
-0.03
DMAP
S
S
+0.04
CH2Cl2
r.t.
-0.05
7
(-)-(S)-
9
(-)-(1''S,2R)-
H3CO H
S
O
O
(S)-MPA
EDC
+0.18
+0.06
-0.03
DMAP
R
7
(+)-(R)-
+0.04
CH2Cl2
r.t.
-0.05
9
(+)-(1''R,2S)-
H OCH3
S
O
-0.02
(S)-MPA
EDC
O
+0.12
DMAP
-0.03
S
7
(-)-(S)-
+0.02
CH2Cl2
r.t.
+0.02
8
(+)-(1''S,2S)-
Scheme 2. Preparation of (R) and (S) methoxyphenylacetic acid (MPA) esters of en-
antiomers of (þ)-(R)- and (ꢀ)-(S) 1-phenylprop-2-en-1-ol. Selected atom numbering is
shown for compound (ꢀ)-(100R,2R)-8. Differences in chemical shifts, DdT1T2 (T1¼25 ꢂC,
T2¼ꢀ60 ꢂC) are shown for selected protons in compounds (ꢀ)-(100S,2R)-9, (þ)-(100R,2S)-
9, and (þ)-(100S,2S)-8.
The proposed absolute configuration for 3 was also confirmed
by circular dichroism. The CD curve of the (þ)-3 enantiomer dis-
played two negative Cotton effects (C.E.) at 238 nm (D3ꢀ0.56) and
275 nm (D3ꢀ0.04) associated with the 1Lb and 1La absorption bands,
respectively. Assuming that the preferred conformation of the
Scheme 3. Preparation of (R)- and (S)-MPA esters of (þ)-(R)-1-(3,4-bis(tert-butyldimethylsilyloxi)phenyl)prop-2-en-1-ol (compounds (ꢀ)-(100R,2R)-10 and (þ)-(100R,2S)-11).
Differences in chemical shifts, DdT1T2 (T1¼25 ꢂC, T2¼ꢀ60 ꢂC) are shown for selected protons in compounds (ꢀ)-(100R,2R)-10 and (þ)-(100R,2S)-11).

G. Mancilla et al. / Tetrahedron 66 (2010) 8068e8075
8071
(7), using NMR techniques and chirooptic methods, the stereo-
chemistry of the key intermediate (þ)-3 was unequivocally de-
termined. This, in turn, permitted the assignment of compound
(ꢀ)-1 as (ꢀ)-(2S,3R,4R)-2-(30,40dihydroxyphenyl)tetrahydrofuran-
3,4-diol.
O
OH
Br
H
H
(TMS)2NLi
RO
RO
THF
RO
RO
42%
(+)-(R)-4
(96% based on
(+)-(R)-3
R=TBDMS
4. Experimental
reacted material)
R=TBDMS
4.1. General experimental procedures
25
[α]D + 1.4
>99 % e.e. (HPLC)
Melting points were measured with a Reichert-Jung Kofler block
and are uncorrected. Optical rotations were determined with
a PerkineElmer 341 polarimeter. IR spectra were recorded on
a PerkineElmer Spectrum BX FT-IR spectrophotometer. UV spectra
were recorded on a UVevis Varian Cary 50. 1H- and 13C NMR mea-
surements were obtained on Varian INOVA 400 NMR spectrometer
with SiMe4 as an internal reference. NMR assignments were made
by a combination of 1D and 2D techniques. Multiplicities are de-
scribed using the following abbreviations: s¼singlet, d¼doublet,
t¼triplet, q¼quartet, m¼multiplet, br¼broad. In 13C NMR the mul-
tiplicities refer to the resonances in the off-resonance spectra and
they were elucidated using the distortionless enhancement by po-
larization transfer (DEPT) spectral editing technique, with second-
ary pulses at 90ꢂ and 135ꢂ. Mass spectra were recorded on
a Finnigan Voyager mass spectrometer at 70 eV. ESI-MS spectra
were recorded on a THERMO- Finnigan LCQ mass spectrometer
(4.6 kV, 25 V, 220 ꢂC, N2). High resolution mass spectra were
recorded on a Finnigan MAT95S spectrometer. Purification by semi-
preparative HPLC was performed with a Hitachi/Merck L-6270 ap-
paratus equipped with a UVevis detector (L 4250) and a differential
refractometer detector (RI-71). Analytical HPLC was performed with
a Elite LaChrom-Hitachi L-2130 apparatus equipped with a UV de-
tector (L-2400). CD spectra were recorded on a Jobin-Ybon MarkIII
Dichrograph in ethanol as solvent. Enantiomeric excess de-
termination was accomplished either by HPLC using a Chiracel OD
column, Daicel Japan, or by GC using a CycloSil-B column, Agilent
J&W, USA; ee were calculated by comparing the area of each peak.
TLC was performed on Merck Kiesegel 60 F254, 0.2 mm thick. Silica
gel (Merck) was used for column chromatography. For column
chromatography, Merck silica gel 60 (0.040e0.063 mm) was used.
Dried solvents were obtained from PureSolvÒ equipment and other
materials were obtained from commercial supplies and used
without further purification. Petroleum ether refers to the fraction
boiling in the range of 60e80 ꢂC. PSL enzyme was obtained from
Amano Enzyme, Inc.; PPL and CRL enzymes were obtained from
SigmaeAldrich Co and all of them were used as received.
O
Grubbs' catalyst
(first-generation)
H
CH2Cl2
98%
RO
RO
(+)-(R)-5
R=TBDMS
O
OsO4
H
OH
Me3NO
+
OH
tBuOH/H2O
RO
pyridine
reflux
RO
(-)-(2S,3S,4S)-6a (8%)
R=TBDMS
O
H
OH
OH
RO
RO
(73%)
OR
(-)-(2S,3R,4R)-6b
R=TBDMS
O
H
I2/MeOH
reflux
(-)-6b
OR
41%
RO
RO
4.1.1. 30,40-Bis-(tert-butyldimethylsilanoxy)benzaldehyde (2a). A so-
lution of TBDMSCl (14.9 g, 72.4 mmol) in dry THF (20 mL), was added
dropwise to a stirred solution of 3,4-dihydroxybenzaldehyde (2)
(5 g, 36.2 mmol) and imidazol (9.9 g, 144.8 mmol) in dry THF
(100 mL), under argon. Stirring is maintained for 48 h and then
water (50 mL) and Et2O (50 mL) were added. The aqueous layer was
separated and extracted with Et2O (2ꢃ50 mL). The combined or-
ganic layers were washed with brine (50 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. Flash chroma-
tography (petroleum ether/ethyl acetate, 95:5) afforded a white
solid 2a (11.5 g, 87%): mp 39e41 ꢂC; 1H NMR (400 MHz, C6D6):
(-)-(2S,3R,4R)-1 R=H
[α]D25 -38 >99% e.e.
(optical purity)
Ac2O
py
93%
(-)-(2S,3S,4R)-1a R=Ac
[α]D25 -34 >99% e.e.
(optical purity)
Scheme 4. Enantioselective preparation of (ꢀ)-(2S,3R,4R)-gloeosporiol (1) from
(þ)-(R)-3.
d
(ppm) 0.13 (s,12H, 2(eSi(CH3)2)), 0.98 (s,18H, 2(eSiC(CH3)3)), 6.77
(d, J¼8.2 Hz, 1H, H-50), 7.11 (dd, J¼1.6, 8.2 Hz, 1H, H-60), 7.56 (d,
3. Conclusion
J¼1.6 Hz, 1H, H-20), 9.66 (s, 1H, H-1); 13C NMR (100 MHz, C6D6):
d
(ppm) ꢀ4.14 (q, 4C, 2(eSi(CH3)2)), 18.6 (s, 2C, 2(eSiC(CH3)3)), 25.9
We have achieved enantioselective chemoenzymatic synthesis
of the antioxidant (ꢀ)-gloeosporiol (1). Based on the study of the
model compounds, (þ)-(R)- and (ꢀ)-(S)-1-phenylprop-2-en-1-ol
(q, 6C, 2(-SiC(CH3)3)), 120.6 (d, C-20), 121.2 (d, C-50), 125.3 (d, C-60),
131.8 (s, C-10), 148.0 (s, C-40), 153.0 (s, C-30), 189.7 (d, C-1); selected
HMBC correlations: C-10/H-50; C-30/H-20, H-50; C-40/H-20, H-50;

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G. Mancilla et al. / Tetrahedron 66 (2010) 8068e8075
IR (neat)
n
(cmꢀ1) 1698, 1592, 1256, 841; EIMS m/z (rel int.): 366
the solvent evaporated under reduced pressure, to yield compound
[M]þ$ (0.58), 309 (59), 253 (12),195 (21),193 (15),179 (15), 73 (100);
HREIMS: m/z calcd for C19H34O3Si2¼366.2046; found 366.1993.
(ꢁ)-3a (129.0 mg, 87%). Colorless oil; 1H NMR (400 MHz, CDCl3):
d
(ppm) 0.18 (s,12H, 2(eSi(CH3)2)), 0.97 (s,18H, 2(eSiC(CH3)3)), 2.08
(s, 3H, OCOCH3), 5.21 (dd, J¼1.4, 10.3 Hz, 1H, H-3b), 5.23 (dd, J¼1.4,
16.9 Hz, 1H, H-3a), 5.96 (ddd, J¼5.8, 10.3, 16.9 Hz, 1H, H-2), 6.15 (d,
J¼5.8 Hz, 1H, H-1), 6.78e6.81 (m, 3H, H-20, H-50, H-60); 13C NMR
4.1.2. (ꢁ)-(1S(R))-1-[(30,40-Bis-(tert-butyldimethylsilanoxy)phenyl)]
prop-2-en-1-ol ((ꢁ)-3). A solution of vinyl bromide (24.3 mL,
24.3 mmol,1 M solution) and compound 2a (2.97 g, 8.10 mmol) was
added dropwise to a magnetically stirred suspension of magnesium
turnings (602.9 mg, 24.3 mmol) in THF (1 mL), under argon. The
magnesium had previously been activated by adding a few crystals
of iodine and then stirring under a protective atmosphere for 12 h.
After 0.5 h, the reaction was quenched by carefully adding a satu-
rated solution of NH4Cl in water (20 mL) followed by Et2O (50 mL).
The aqueous and organic layers were separated and the aqueous
layer then extracted with Et2O (2ꢃ50 mL). The combined organic
layers were washed with brine (50 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. Flash chroma-
tography using a gradient of solvents from petroleum ether to pe-
troleum ether/ethyl acetate (96:4) yielded compound (ꢁ)-3 as
(100 MHz, CDCl3):
d
(ppm) ꢀ4.1 (q, 4C, 2(eSi(CH3)2)), 18.4 (s, 2C, 2
(eSiC(CH3)3)), 21.3 (q, OCOCH3), 25.9 (q, 6C, 2(eSiC(CH3)3)), 75.7 (d,
C-1), 116.4 (t, C-3), 120.2 (d, C-20*), 120.4 (d, C-50*), 120.8 (d, C-60*),
131.8 (s, C-10), 136.5 (d, C-2), 146,8 (s, 2C, C-30, C-40), 170.0 (s,
OCOCH3). *Interchangeable signals; selected HMBC correlations: C-
10/H-50, H-1, H-2; C-30, C-40/H-20, H-50, H-60; IR (neat)
n )
(cmꢀ1
2936, 1768, 1747, 1574, 1508, 1254, 1231, 835, 780; EIMS m/z (rel
int.): 436 [M]þ$ (2), 379 (5), 247 (6), 205 (100), 73 (72).
4.1.4. (þ)-(R)-1-[(30,40-Bis-(tert-butyldimethylsilanoxy)phenyl)]-prop-
2-en-1-ol ((þ)-(R)-3) and (ꢀ)-(S)-1-[(30,40-bis-(tert-butyldimethylsi-
lanoxy)phenyl)]-prop-2-en-1-yl acetate ((ꢀ)-(S)-3a): optimization
procedure6b,c. In a typical procedure, PSL (P. cepacia lipase, 677 mg)
was added to a solution of (ꢁ)-3a (128 mg, 0.29 mmol) in 1,4-dioxane
(1.9 mL) and pH 7 buffer (0.1 M KH2PO4/KOH, 9.4 mL). The suspen-
sion was shaken at 25 ꢂC, and the progress of the reaction was fol-
lowed by TLC (petroleum ether/ethyl acetate 90:10). Then, after
removal of the enzyme by filtration, the reaction crude was extracted
with ethyl acetate (3ꢃ15 mL). The organic layer was washed with
brine (30 mL), dried over anhydrous Na2SO4, and the solvent re-
moved under reduced pressure. Further purification of the residue
by column chromatography over neutral alumina (petroleum ether/
a yellow oil (2337 mg, 73%); 1H NMR (400 MHz, C6D6):
d (ppm) 0.20
(s, 12H, 2(eSi(CH3)2)), 1.04 (s, 18H, 2(eSiC(CH3)3)), 1.46 (br s, 1H,
OH), 4.88 (dd, J¼1.6, 4.4 Hz, 1H, H-1), 4.97 (ddd, J¼1.6, 1.6, 10.4 Hz,
1H, H-3b), 5.21 (ddd, J¼1.6, 1.6, 17.1 Hz, 1H, H-3a), 5.91 (ddd, J¼4.4,
10.4, 17.1 Hz, 1H, H-2), 6.81 (dd, J¼1.7, 8.1 Hz, 1H, H-60), 6.87 (d,
J¼8.1 Hz, 1H, H-50), 7.07 (d, J¼1.7 Hz, 1H, H-20); 13C NMR (100 MHz,
C6D6):
d
(ppm) ꢀ4.00 (q, 2C, (eSi(CH3)2)*), ꢀ3.99 (q, 2C, (eSi(CH3)2)
*), 18.62 (s, (eSiC(CH3)3)y), 18.64 (s, (eSiC(CH3)3)y), 26.12 (q, 3C,
(eSiC(CH3)3)z), 26.14 (q, 3C, (eSiC(CH3)3)z), 74.7 (d, C-1), 114.0 (t, C-
3), 119.9 (d, C-20#), 120.0 (d, C-50#), 121.3 (d, C-60), 137.1 (s, C-10),
141.3 (d, C-2), 146,6 (s, C-30), 147.3 (s, C-40). *yz#Interchangeable
signals; selected HMBC correlations: C-10/H-1; C-30/H-20; IR
ethyl acetate, 95:5) afforded alcohol (þ)-(R)-3 (35 mg, 31% yield,
25
>99% ee); [
a
]
þ1.4 (c 0.4, CHCl3); C.D. (ethanol): D3238ꢀ0.56;
D
D3275ꢀ0.04 and residual acetate (ꢀ)-(S)-3a (63 mg, 50% yield, 96%
(neat)
n
(cmꢀ1) 3350, 1574, 1508, 1254, 835, 780; EIMS m/z (rel int.)
ee); [
a
]
25 ꢀ1.8 (c 0.4, CHCl3). Chiral HPLC for compound 3 (Chiracel
D
394 [M]þ$ (4), 337 (12), 247 (7), 205 (100), 73 (90); HREIMS: m/z
calcd for C21H38O3Si2¼394.2359; found 394.2355.
OD petroleum ether/2-propanol (99.9:0.1), 0.500 mL minꢀ1
)
tR¼52 min ((ꢀ)-(S)-3), tR¼55 min ((þ)-(R)-3). Chiral GC for com-
pound 3a (Agilent J&W CycloSil-B column, oven 160 ꢂC isothermal)
tR¼145 min ((S)-3a), tR¼150 min ((R)-3a).
4.1.3. (ꢁ)-1-[(30,40-Bis-(tert-butyldimethylsilanoxy)phenyl)]-prop-2-
en-1-yl acetate ((ꢁ)-3a). Acetic anhydride (210.3 mg, 2.06 mmol)
was added dropwise to a stirred solution of compound (ꢁ)-3
(135.0 mg, 0.34 mmol) in dry pyridine (1 mL). After 24 h the re-
action mixture was diluted with EtOAc (50 mL) and washed se-
quentially with 2 N HCl (2ꢃ50 mL), a diluted solution of CuSO4
(2ꢃ50 mL) and brine (50 mL), then dried over Na2SO4, filtered, and
Relationships between reaction temperature and reaction times
with yields and enantiomeric excess are shown in Table 1.
4.1.5. (ꢀ)-(S)-1-[(30,40-Bis-(tert-butyldimethylsilanoxy)phenyl)]-
prop-2-en-1-ol ((ꢀ)-(S)-3). A solution of KOH (11.5 mg, 0.2 mmol)
in H2O (3 mL) was added to a stirred solution of compound (ꢀ)-(S)-

G. Mancilla et al. / Tetrahedron 66 (2010) 8068e8075
8073
3a (45 mg, 0.1 mmol) in MeOH (11.5 mL). The solution was shaken
at 25 ꢂC for 5 h. The reaction crude was neutralized with HCl 2 N,
and solvent was removed under reduced pressure. The resulting
crude was suspended in water (15 mL) and then extracted with
ethyl acetate (3ꢃ15 mL). The organic layer was washed with brine
(30 mL), dried over anhydrous Na2SO4, and solvent removed under
reduced pressure. Further purification of the residue by column
chromatography over neutral alumina (petroleum ether/ethyl ac-
HMBC correlations: C-10/H-50, H-20, H-5a or H-5b; C-40/H-50,
H-60; C-30/H-20; IR (neat) (cmꢀ1) 1509, 1255, 840, 781; EIMS m/z
n
(rel int.): 406 [M]þ$ (1), 217 (95), 115 (6), 73 (100); HREIMS: m/z
calcd for C22H38O3Si2¼406.2359; found 406.2372.
4.1.8. (ꢀ)-(2S,3S,4S)-2-[(30,40-Bis-(tert-butyldimethylsilanoxy)phe-
nyl)] tetrahydrofuran-3,4-diol ((ꢀ)-(2S,3S,4S)-6a) and (ꢀ)-(2S,3R,4R)-
2-[(30,40-bis-(tert-butyldimethylsilanoxy)phenyl)]tetrahydro-furan-
3,4-diol ((ꢀ)-(2S,3R,4R)-6b). Trimethylamine N-oxide dihydrate
(8 mg, 0.07 mmol), pyridine (0.01 mL), and water (0.2 mL) were
added to a solution of compound (þ)-(R)-5 (20 mg, 0.05 mmol) in
t-BuOH (2 mL) and stirred at 25 ꢂC. A 2.5% w/w solution of OsO4 in
t-BuOH (0.2 mL, 0.02 mmol) was added dropwise and the reaction
was heated to reflux for 24 h. The reaction mixture was then cooled
to room temperature, sodium bisulfite (20 mL, 20% w/v) was added
and the reaction mixture was stirred for a further 1 h. Most of the
butanol and water were removed under reduced pressure and the
residue was then extracted into Et2O (3ꢃ30 mL). The combined
organic layers were washed with brine (1ꢃ30 mL), dried over an-
hydrous Na2SO4, and solvent evaporated under reduced pressure.
Flash chromatography (CHCl3) afforded a white solid (ꢀ)-(2S,3S,4S)-
6a (2 mg, 8%) and a colorless oil (ꢀ)-(2S,3R,4R)-6b (16 mg, 73%).
etate, 95:5) afforded alcohol (ꢀ)-(S)-3 (12 mg, 29% yield, 96% ee);
25
[
a]
ꢀ1.3 (c 0.8, EtOH); C.D. (ethanol): D3238þ0.67; D3275þ0.05.
D
4.1.6. (þ)-(R)-1-[(30,40-Bis-(tert-butyldimethylsilanoxy)phenyl)]
prop-2-en-1-yl allyl ether ((þ)-(R)-4). A solution of LiHMDS in THF
(0.81 mL, 1 M, 0.81 mmol) was added dropwise to a stirred solution
of compound (þ)-(R)-3 (290 mg, 0.74 mmol) in dry THF (5 mL), kept
under argon and at 0 ꢂC. The resulting solution was stirred for
15 min and then allyl bromide (97 mg, 0.81 mmol) was added
dropwise. The reaction was then heated to reflux for 12 h, cooled
and a saturated solution of NH4Cl in water (20 mL) was carefully
poured onto the reaction mixture and then ethyl acetate (50 mL)
was added. The aqueous and organic layers were separated and the
aqueous layer was then extracted with ethyl acetate (2ꢃ50 mL).
The combined organic layers were dried over anhydrous Na2SO4
and the solvent evaporated under reduced pressure. Flash chro-
matography (petroleum ether/ethyl acetate, 97:3) allowed the re-
covery of 164 mg of starting material (þ)-(R)-3 and afforded
compound (þ)-(R)-4 as a yellow oil (134 mg, 42%, 96% based on
4.1.9. (ꢀ)-(2S,3S,4S)-2-[(30,40-Bis-(tert-butyldimethylsilanoxy)phe-
nyl)]tetrahydro-furan-3,4-diol ((ꢀ)-(2S,3S,4S)-6a). Mp 105e113 ꢂC;
[
a
]
25 ꢀ6 (c 0.2, MeOH); 1H NMR (400 MHz, CD3OD):
d (ppm) 0.18 (s,
D
6H, (eSi(CH3)2)*), 0.20 (s, 6H, (eSi(CH3)2)*), 0.98 (s, 9H, (eSiC
(CH3)3)y), 0.99 (s, 9H, (eSiC(CH3)3)y), 3.82 (m,1H, H-5az), 3.85 (m,1H,
H-3), 4.21 (m, 1H, H-4), 4.25 (m, 1H, H-5bz), 4.54 (d, J¼7.6 Hz, 1H, H-
2), 6.82 (d, J¼8.4 Hz,1H, H-50), 6.86 (dd, J¼2.0, 8.4 Hz,1H, H-60), 6.89
(d, J¼2.0 Hz, 1H, H-20). *yzInterchangeable signals; selected NOESY
correlations: H-2/H-3; H-3/H-2, H-4; H-4/H-3, H-5a, H-5b; 13C
reacted material): [
a
]
25 þ20 (c 1, MeOH); 1H NMR (400 MHz, C6D6):
D
d
(ppm) 0.17 (s, 6H, (eSi(CH3)2)*), 0.22 (s, 6H, (eSi(CH3)2)*), 1.03 (s,
9H, (eSiC(CH3)3)y), 1.04 (s, 9H, (eSiC(CH3)3)y), 3.88 (m, 2H, H-4a, H-
4b), 4.64 (m, 1H, H-1), 5.03 (ddd, J¼1.6, 1.6, 9.6 Hz, 1H, H-3b), 5.05
(tdd, J¼1.6,1.6, 9.4 Hz,1H, H-6b), 5.25 (ddd, J¼1.6,1.6,17.3 Hz,1H, H-
3a), 5.30 (tdd, J¼1.6, 1.6, 17.2 Hz, 1H, H-6a), 5.88 (m, 1H, H-5), 5.93
(m, 1H, H-2), 6.86 (dd, J¼1.6, 8.2 Hz, 1H, H-60), 6.89 (d, J¼8.2 Hz, 1H,
H-50), 7.15 (d, J¼1.6 Hz, 1H, H-20). *yInterchangeable signals; 13C
NMR (100 MHz, CD3OD):
d
(ppm) ꢀ3.89 (q, 2C, (eSi(CH3)2)*), ꢀ3.83
(q, (eSi(CH3)(CH3))*), ꢀ3.79 (q, (eSi(CH3)(CH3))*), 19.3 (s, (eSiC
(CH3)3)y), 19.4 (s, (eSiC(CH3)3)y), 26.47 (q, 3C, (eSiC(CH3)3)z), 26.51
(q, 3C, (eSiC(CH3)3)z), 72.4 (d, C-4), 74.4 (t, C-5), 79.9 (d, C-3), 83.9 (d,
C-2), 120.2 (d, C-20), 120.4 (d, C-60), 122.1 (d, C-50), 135.5 (s, C-10),
147.6 (s, C-30#),148.0 (s, C-40#). *yz#Interchangeable signals; IR (neat)
NMR (100 MHz, C6D6):
d
(ppm) ꢀ4.0 (q, 4C, 2(eSi(CH3)2)), 18.6 (s,
(eSiC(CH3)3)*), 18.7 (s, (eSiC(CH3)3)*), 26.09 (q, 3C, (eSiC(CH3)3)y),
26.14 (q, 3C, (eSiC(CH3)3)y), 69.1 (t, C-4), 81.9 (d, C-1), 115.3 (t, C-3),
115.8 (t, C-6), 120.2 (d, C-20), 120.7 (d, C-60), 121.3z(d, C-50), 135.1 (s,
n
(cmꢀ1) 3400, 1509, 1254, 840, 781; EIMS m/z (rel int.) 440 [M]þ
z
C-10), 135.5 (d, C-5), 139.9 (d, C-2), 146.7 (s, C-30 ), 147.4 (s, C-40 ).
(53), 405 (4), 385 (25), 367 (30), 323 (50), 293 (30), 237 (68), 209
(100), 175 (95), 167 (37), 115 (40);$HREIMS m/z calcd for
C22H40O5Si2¼440.2414; found 440.2433.
*yzInterchangeable signals; selected HMBC correlations: C-10/H-
60, H-2, H-1; IR (neat) (cmꢀ1) 1509, 1255, 840, 781; EIMS m/z (rel
n
int.): 434 [M]þ$ (5), 377 (20), 247 (9), 205 (92), 73 (100); HREIMS
m/z calcd for C24H42O3Si2 434.2673; found 434.2675.
4.1.10. (ꢀ)-(2S,3R,4R)-2-[(30,40-Bis-(tert-butyldimethylsilanoxy)phe-
25
nyl)]tetrahydro-furan-3,4-diol ((ꢀ)-(2S,3R,4R)-6b). [
a
]
ꢀ19 (c 1.6,
D
4.1.7. (þ)-(R)-2-[(30,40-Bis-(tert-butyldimethylsilanoxy)phenyl)]-2,5-
dihydrofuran ((þ)-(R)-5). (PCy3)2Cl2RuCHPh (30 mg, 0.04 mmol)
was added to a degassed and stirred solution of compound (þ)-(R)-
4 (79 mg, 0.2 mmol) in dry CH2Cl2 (5 mL) under argon and at 25 ꢂC.
The reaction mixture was heated to reflux for 2 h and then the
solvent was evaporated under reduced pressure and the crude re-
action mixture was immediately purified by flash chromatography
MeOH); >99% ee(optical purity); 1H NMR (400 MHz, CD3OD):
(ppm) 0.18 (s, 3H, (eSi(CH3)(CH3))*), 0.19 (s, 3H, (eSi(CH3)(CH3))*),
d
0.20 (s, 6H, (eSi(CH3)2)*), 0.98 (s, 9H, (eSiC(CH3)3)y), 0.99 (s, 9H,
(eSiC(CH3)3)y), 1.28 (br s, 2H, 2OH), 3.82 (dd, J¼7.0, 8.4 Hz, 1H, H-
5az), 3.99 (dd, J¼7.0, 8.4 Hz, 1H, H-5bz), 4.09 (m, 1H, H-3), 4.46 (ddd,
J¼4.8, 7.0, 7.0 Hz,1H, H-4), 4.78 (d, J¼3.6 Hz, 1H, H-2), 6.81 (2H, H-50,
H-60), 6.97 (d, J¼1.6 Hz, 1H, H-20). *yInterchangeable signals; 13C
(petroleum ether/EtOAc, 98:2) to afford compound (þ)-(R)-5 as
NMR (100 MHz, CD3OD):
d
(ppm) ꢀ3.86 (q, 2C, (eSi(CH3)2)*), ꢀ3.82
25
a yellow oil (27 mg, 98%): [
(400 MHz, C6D6):
a]
þ41 (c 1.4, MeOH); 1H NMR
(q, (eSi(CH3)(CH3))*), ꢀ3.80 (q, (eSi(CH3)(CH3))*),19.3 (s, 2C, 2(eSiC
(CH3)3)y), 26.5 (q, 3C, (eSiC(CH3)3)z), 26.6 (q, 3C, (eSiC(CH3)3)z), 72.5
(d, C-5), 73.5 (t, C-4), 74.1 (d, C-3), 84.6 (d, C-2), 121.5 (d, C-50#), 121.8
(d, C-60#), 122.1 (d, C-20), 132.5 (s, C-10), 147.4 (s, C-30), 147.6 (s, C-40).
D
d (ppm) 0.17 (s, 6H, (eSiC(CH3)2)*), 0.20 (s, 6H,
(eSiC(CH3)2)*), 1.03 (s, 9H, (eSiCC(CH3)3)y), 1.04 (s, 9H, (eSiCC
(CH3)3)y), 4.53 (dddd, J¼1.6, 2.4, 4.0, 12.8 Hz, 1H, H-5a), 4.64 (dddd,
J¼1.6, 2.4, 6.0, 12.8 Hz, 1H, H-5b), 5.50 (m, 1H, H-3), 5.58 (m, 1H, H-
4), 5.71 (m, 1H, H-2), 6.79 (dd, J¼2.2, 8.2 Hz, 1H, H-60), 6.87 (d,
J¼8.2 Hz, 1H, H-50), 7.04 (d, J¼2.2 Hz, 1H, H-20). *yInterchangeable
*
yz#Interchangeable signals; IR (neat) (cmꢀ1) 3390, 1513,1255, 840,
n
781; EIMS m/z (rel int.) 440 [Mþ] (25), 383 (15), 323 (26), 233 (68),
209 (25) (72); 179 (100); 175 (36); 115 (56); 103 (24); HREIMS m/z
calcd for C22H40O5Si2¼440.2414; found 440.2391.
signals; 13C NMR (100 MHz, C6D6):
d
(ppm) ꢀ4.02 (q, 2C, (eSiC
(CH3)2)*), ꢀ3.95 (q, 2C, (eSiC(CH3)2)*), 18.61 (s, (eSiC(CH3)3)y),
18.64 (s, (eSiC(CH3)3)y), 26.12 (q, 3C, (eSiC(CH3)3)z), 26.16 (q, 3C,
(eSiC(CH3)3)z), 75.6 (t, C-5), 87.7 (d, C-2), 119.95 (d, C-20), 120.03 (d,
C-60), 121.4 (d, C-50), 126.6 (d, C-3), 130.6 (d, C-4), 136.6 (s, C-10),
146.7 (s, C-40), 147.3 (s, C-30). *yzInterchangeable signals; selected
4.2. General procedure for MPA derivatives
A solution of starting material (0.37 mmol) in dry CH2Cl2
(1.5 mL) was treated with DMAP (4 mg, 0.03 mmol) and (þ)-(2S

8074
G. Mancilla et al. / Tetrahedron 66 (2010) 8068e8075
(R))-2-methoxy-2-phenylacetic acid (68 mg, 0.41 mmol). After
15 min stirring at room temperature, EDC (N-(3-dimethylamino-
propyl)-N0-ethylcarbodiimide) (79 mg, 0.41 mmol) was added.
Stirring was maintained for 3e24 h. Then, the solvent was removed
under reduced pressure. The crude reaction mixture, dissolved in
ethyl acetate, was sequentially washed with water, twice with
saturated NaHCO3 solution, and twice with water, dried with an-
hydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification was achieved by flash column chromatography on
silica gel 230e400 mesh (elution with 90:10 petroleum ether/ethyl
acetate) to obtain compounds (þ)-(100S,2S)-8, (ꢀ)-(100R,2R)-8,
(þ)-(100R,2S)-9, (þ)-(100S,2R)-9, (100R,2R)-10 and (þ)-(100R,2S)-11.
3031, 1749, 1494, 1455, 1246, 1170, 1113, 930, 698; EIMS m/z (rel
int.): 282 [M]þ$ (0.1), 121 (100), 118 (4), 117 (20), 91 (21), 77 (23);
HREIMS calcd for C18H18O3 (Mþ): 282.1256; found: 282.1251.
4.2.4. (ꢀ)-(100S,2R)-(1-Phenylprop-2-en-1-yl) 2-methoxy-2-phenyl-
25
acetate ((ꢀ)-(100S,2R)-9). Yellow oil (98 mg, 93% yield); [
(c 6.5, CHCl3).
a
]
ꢀ79
D
4.2.5. (ꢀ)-(100R,2R)-(1-(3,4-Bis(tert-butyldimethylsilyloxy)phenyl)-
allyl) 2-methoxy-2-phenylacetate ((ꢀ)-(100R,2R)-10). Yellow oil
25
(12 mg, 45% yield); [
a]
ꢀ3 (c 0.6, CHCl3); 1H NMR (400 MHz,
D
CDCl3) d (ppm): 0.12 (s, 6H, eSi(CH3)2), 0.15 (s, 6H, eSi(CH3)2), 0.94
(s, 9H, eSiC(CH3)3), 0.95 (s, 9H, eSiC(CH3)3), 3.39 (s, 3H, eOCH3),
4.79 (s, 1H, H-2), 5.18 (d, J¼1.3 Hz, 1H, H-3a00), 5.22 (ddd, J¼1.3,
8.3 Hz, 1H, H-3b00), 5.94 (ddd, J¼5.7, 10.5, 17.0 Hz, 1H, H-200), 6.16 (d,
J¼5.7 Hz, 1H, H-100), 6.54 (dd, J¼2.2, 8.2 Hz, 1H, H-6000), 6.64 (d,
J¼8.2 Hz, 1H, H-5000), 6.68 (d, J¼2.2 Hz, 1H, H-2000), 7.27e7.32 (3H, H-
30, H-40, H-50), 7.34e7.38 (m, 2H, H-20, H-60); 1H NMR (400 MHz,
4.2.1. (þ)-((100S,2S)-1-Phenylprop-2-en-1-yl) 2-methoxy-2-phenyl-
acetate ((þ)-(100S,2S)-8). Yellow oil (89 mg, 84% yield). [
a
]
25 þ29 (c
D
5.9, CHCl3); 1H NMR (400 MHz, CDCl3, 25 ꢂC)
d (ppm): 3.42 (s, 3H,
eOCH3), 4.84 (s, 1H, H-2), 5.23 (ddd, J¼1.2, 10.5 Hz, 1H, H-3b00), 5.27
(ddd, J¼1.2,17.0 Hz,1H, H-3a00), 5.98 (ddd, J¼6.2,10.5,17.0 Hz,1H, H-
200), 6.28 (d, J¼6.2 Hz, 1H, H-100), 7.04e7.08 (2H, H-2000, H-6000),
7.18e7.22 (3H, H-3000, H-4000, H-5000), 7.30e7.35 (3H, H-30, H-40, H-50),
7.38e7.42 (2H, H-20, H-60); 1H NMR (400 MHz, CD2Cl2/CS2 (1:4),
CD2Cl2/CS2 (1:4), 25 ꢂC)
d (ppm): 0.10 (s, 6H, eSi(CH3)2), 0.14 (s, 6H,
eSi(CH3)2), 0.93 (s, 9H, eSiC(CH3)3), 0.94 (s, 9H, eSiC(CH3)3), 3.30
(s, 3H, eOCH3), 4.64 (s, 1H, H-2), 5.11 (dd, J¼1.4, 2.3 Hz, 1H, H-3a00),
5.14 (dd, J¼1.4, 2.1 Hz, 1H, H-3b00), 5.85 (ddd, J¼5.7, 10.2, 17.3 Hz, 1H,
H-200), 6.01 (d, J¼5.9 Hz,1H, H-100), 6.49 (dd, J¼2.2, 8.2 Hz,1H, H-6000),
6.57 (d, J¼8.2 Hz, 1H, H-5000), 6.60 (d, J¼1.9 Hz, 1H, H-2000), 7.10e7.23
(3H, H-30, H-40, H-50), 7.23e7.28 (m, 2H, H-20, H-60); 1H NMR
25 ꢂC)
d (ppm): 3.31 (s, 3H, eOCH3), 4.68 (s, 1H, H-2), 5.14 (ddd,
J¼1.3, 2.2 Hz, 1H, H-3b00), 5.17 (ddd, J¼1.3, 8.6 Hz, 1H, H-3a00), 5.88
(ddd, J¼6.2, 10.3, 16.8 Hz, 1H, H-200), 6.11 (d, J¼5.9 Hz, 1H, H-100),
6.97e7.01 (m, 2H, H-2000, H-6000), 7.11e7.16 (3H, H-3000, H-4000, H-5000),
7.20e7.24 (3H, H-30, H-40, H-50), 7.24e7.28 (m, 2H, H-20, H-60); 1H
(400 MHz, CD2Cl2/CS2 (1:4), ꢀ60 ꢂC)
d (ppm): 0.08 (s, 6H, eSi
NMR (400 MHz, CD2Cl2/CS2 (1:4), ꢀ60 ꢂC)
d
(ppm): 3.32 (s, 3H,
(CH3)2), 0.12 (s, 6H, eSi(CH3)2), 0.92 (s, 9H, eSiC(CH3)3), 0.93 (s, 9H,
eSiC(CH3)3), 3.30 (s, 3H, eOCH3), 4.67 (s, 1H, H-2), 5.13 (d, J¼8.8 Hz,
1H, H-3a00), 5.22 (dd, J¼1.2 Hz, 1H, H-3b00), 5.84 (ddd, J¼5.8, 10.6,
16.7 Hz, 1H, H-200), 5.96 (d, J¼5.7 Hz, 1H, H-100), 6.43 (dd, J¼2.2,
8.2 Hz, 1H, H-6000), 6.54 (d, J¼9.4 Hz, 1H, H-5000), 6.54 (br s, 1H, H-2000),
7.25 (5H, H-20, H-30, H-40, H-50, H-60); 13C NMR (100 MHz, CDCl3)
eOCH3), 4.73 (s, 1H, H-2), 5.16 (ddd, J¼1.3, 2.4 Hz, 1H, H-3b00), 5.20
(ddd, J¼1.2,1.9, 9.2 Hz,1H, H-3a00), 5.86 (ddd, J¼5.9,10.4,17.0 Hz,1H,
H-200), 6.05 (d, J¼6.3 Hz, 1H, H-100), 6.83e6.91 (m, 2H, H-2000, H-6000),
7.08e7.16 (3H, H-3000, H-4000, H-5000), 7.28 (5H, H-20, H-30, H-40, H-50,
13
H-60); C NMR (100 MHz, CDCl3, 25 ꢂC)
d (ppm): 57.3 (c, eOCH3),
76.7 (d, C-100), 82.6 (d, C-2), 117.4 (t, C-300), 126.5 (d, C-2000, C-6000),
127.2 (d, C-20, C-60), 127.8 (d, C-3000, C-5000), 128.2 (d, C-4000), 128.4 (d,
C-40), 128.6 (d, C-30, C-50), 135.7 (d, C-200), 135.9 (s, C-10), 138.2 (s, C-
d
(ppm): ꢀ4.2 (c, 4C, eSi(CH3)2), 18.4 (s, 2C, eSiC(CH3)3), 25.9 (c, 6C,
eSiC(CH3)3), 57.4 (c, eOCH3), 76.5 (d, C-100), 82.8 (d, C-2), 117.0 (t, C-
3000), 120.1 (d, C-6000), 120.2 (d, C-2000), 120.7 (d, C-5000), 127.2 (d, C-20, C-
6 ), 128.5 (d, C-30, C-50), 128.6 (d, C-40), 131.1 (s, C-1000), 135.9 (d, C-
200), 136.0 (s, C-10), 146.6 (s, C-3000), 146.8 (s, C-4000), 169.7 (s, C-1); IR
1000), 169.4 (s, C-1); IR (neat)
n
(cmꢀ1) 2931, 1749, 1455, 1245, 1197,
1112, 993, 929, 697; EIMS m/z (rel int.): 282 [M]þ$ (0.1), 121 (100),
118 (4), 117 (20), 91 (21), 77 (23); HREIMS calcd for C18H18O3 (Mþ):
282.1256; found: 282.1248.
(neat)
n
(cmꢀ1) 2858, 1750, 1510, 1295, 1254, 1168, 1117, 904, 840,
731, 697; EIMS m/z (rel int.): 542 [M]þ$ (4), 377 (20), 205 (100), 121
(27), 77 (7), 73 (71); HREIMS calcd for C28H44O5Si2 (Mꢀ26):
516.2727; found: 516.9697.
4.2.2. (ꢀ)-(100R,2R)-(1-Phenylprop-2-en-1-yl) 2-methoxy-2-phenyl-
acetate ((ꢀ)-(100R,2R)-8). Yellow oil (89 mg, 84% yield); [
a
]
25 ꢀ29 (c
D
5.2, CHCl3).
4.2.6. (þ)-(100R,2S)-(1-(3,4-Bis(tert-butyldimethylsilyloxy)phenyl)-
allyl) 2-methoxy-2-phenylacetate ((þ)-(100R,2S)-11). Yellow oil
25
4.2.3. (þ)-(100R,2S)-(1-Phenylprop-2-en-1-yl) 2-methoxy-2-phenyl-
(15 mg, 56% yield); [
a
]
þ39 (c 0.4, EtOH); 1H NMR (400 MHz,
D
acetate ((þ)-(100R,2S)-9). Yellow oil (82 mg, 78% yield); [
a
]
25 þ79 (c
CDCl3) d (ppm): 0.17 (s, 6H, eSi(CH3)2), 0.18 (s, 6H, eSi(CH3)2), 0.97
D
5.5, CHCl3); 1H NMR (400 MHz, CDCl3)
d
(ppm): 3.40 (s, 3H, eOCH3),
(s, 18H, eSiC(CH3)3), 3.38 (s, 3H, eOCH3), 4.77 (s, 1H, H-2), 4.87
(ddd, J¼1.4, 17.1 Hz,1H, H-3a00), 5.02 (ddd, J¼1.4,10.6 Hz,1H, H-3b00),
5.78 (ddd, J¼5.2, 10.6, 17.1 Hz, 1H, H-200), 6.18 (ddd, J¼1.4, 5.2 Hz, 1H,
H-100), 6.75 (br s, 2H, H-2000, H-6000), 6.80 (br s, 1H, H-5000), 7.31e7.38
(3H, H-30, H-40, H-50), 7.41e7.45 (m, 2H, H-20, H-60); 1H NMR
4.82 (s, 1H, H-2), 4.97 (ddd, J¼1.4, 17.2 Hz, 1H, H-3b00), 5.07 (ddd,
J¼1.4, 10.5 Hz, 1H, H-3a00), 5.84 (ddd, J¼5.5, 10.5, 17.2 Hz, 1H, H-200),
6.32 (d, J¼5.5 Hz, 1H, H-100), 7.31 (m, 2H, H-2000, H-6000), 7.33e7.40
(6H, H-30, H-40, H-50, H-3000, H-4000, H-5000), 7.45e7.48 (m, 2H, H-20, H-
60); 1H NMR (400 MHz, CD2Cl2/CS2 (1:4), 25 ꢂC)
d
(ppm): 3.31 (s, 3H,
(400 MHz, CD2Cl2/CS2 (1:4), 25 ꢂC)
d (ppm): 0.14 (s, 6H, eSi(CH3)2),
eOCH3), 4.66 (s, 1H, H-2), 4.96 (ddd, J¼1.3, 17.0 Hz, 1H, H-3a00), 5.04
(ddd, J¼1.4, 10.5 Hz, 1H, H-3b00), 5.78 (ddd, J¼5.5, 10.5, 17.0 Hz, 1H,
H-200), 6.14 (td, J¼1.4, 5.5 Hz, 1H, H-100), 7.16e7.20 (m, 2H, H-2000, H-
6000), 7.20e7.28 (6H, H-30, H-40, H-50, H-3000, H-4000, H-5000), 7.30e7.34
(m, 2H, H-20, H-60); 1H NMR (400 MHz, CD2Cl2/CS2 (1:4), ꢀ60 ꢂC)
0.15 (s, 6H, eSi(CH3)2), 0.95 (s, 18H, eSiC(CH3)3), 3.30 (s, 3H,
eOCH3), 4.61 (s, 1H, H-2), 4.89 (ddd, J¼1.4, 17.1 Hz, 1H, H-3a00), 5.00
(ddd, J¼2.3, 10.5 Hz, 1H, H-3b00), 5.73 (ddd, J¼5.3, 10.5, 17.1 Hz, 1H,
H-200), 6.02 (d, J¼5.3 Hz, 1H, H-100), 6.65 (br s, 2H, H-2000, H-6000), 6.67
(br s, 1H, H-5000), 7.22e7.27 (3H, H-30, H-40, H-50), 7.28e7.31 (m, 2H,
d
(ppm): 3.29 (s, 3H, eOCH3), 4.68 (s, 1H, H-2), 4.78 (ddd, J¼1.2,
H-20, H-60); 1H NMR (400 MHz, CD2Cl2/CS2 (1:4), ꢀ60 ꢂC)
d (ppm):
17.0 Hz, 1H, H-3b00), 4.98 (ddd, J¼1.4, 10.6 Hz, 1H, H-3a00), 5.74 (ddd,
J¼5.6, 10.6, 17.0 Hz, 1H, H-200), 6.10 (ddd, J¼1.4, 5.0 Hz, 1H, H-100),
7.19e7.23 (m, 2H, H-2000, H-6000), 7.25e7.29 (6H, H-30, H-40, H-50, H-
3000, H-4000, H-5000), 7.30e7.36 (m, 2H, H-20, H-60); 13C NMR (100 MHz,
0.13 (s, 6H, eSi(CH3)2), 0.15 (s, 6H, eSi(CH3)2), 0.95 (s, 18H, eSiC
(CH3)3), 3.29 (s, 3H, eOCH3), 4.58 (d, J¼16.9 Hz, 1H, H-3a00), 4.66 (s,
1H, H-2), 4.90 (d, J¼10.8 Hz, 1H, H-3b00), 5.68 (ddd, J¼4.5, 10.8,
16.7 Hz, 1H, H-200), 5.98 (d, J¼4.5 Hz, 1H, H-100), 6.64 (sa, 2H, H-2000,
H-6000), 6.67 (sa, 1H, H-5000), 7.32 (5H, H-20, H-30, H-40, H-50, H-60); 13C
CDCl3) d
(ppm): 57.3 (c, eOCH3), 76.4 (d, C-100), 82.5 (d, C-2), 116.7 (t,
C-300), 127.1 (d, C-2000, C-6000), 127.2 (d, C-20, C-60), 128.2 (d, C-3000, C-
5000), 128.5 (d, C-4000), 128.5 (d, C-40), 128.7 (d, C-30, C-50), 135.3 (d, C-
NMR (100 MHz, CDCl3)
d
(ppm): ꢀ4.1 (c, 4C, eSi(CH3)2), 18.4 (s, 2C,
eSiC(CH3)3), 25.9 (c, 6C, eSiC(CH3)3), 57.3 (c, eOCH3), 76.2 (d, C-100),
200), 136.1 (s, C-10),, 138.3 (s, C-1000), 169.5 (s, C-1); IR (neat)
n
(cmꢀ1
)
82.6 (d, C-2),116.2 (t, C-300), 120.4 (d, C-5000),120.6 (d, C-6000),120.8 (d,

G. Mancilla et al. / Tetrahedron 66 (2010) 8068e8075
8075
C-2000), 127.3 (d, C-20, C-60), 128.6 (d, C-40), 128.7 (d, C-30, C-50), 131.2
(s, C-1000), 135.5 (d, C-200), 136.3 (s, C-10), 146.8 (s, C-3000), 147.0 (s, C-
spectra for compounds.(ꢀ)-1,(ꢀ)-1a (synthetic), (ꢀ)-1a (isolated
from C. gloeosporioides), 2a, (ꢁ)-3, (þ)-4, (þ)-5, (ꢀ)-6a, (ꢀ)-6b,
(þ)-8, (þ)-9, (ꢀ)-10, (þ)-11, (ꢀ)-12, (þ)-13. C.D. spectra for com-
pounds (ꢀ)-(S)-3, (þ)-(R)-3, (ꢀ)-(S)-7, (þ)-(R)-7. Supplementary
data associated with this article can be found in online version at
doi:10.1016/j.tet.2010.07.074. These data include MOL files and
InChIKeys of the most important compounds described in this
article.
4000), 169.6 (s, C-1); IR (neat)
n
(cmꢀ1) 2931, 1751, 1510, 1468, 1295,
1254,1116, 997, 732; EIMS m/z (rel int.): 542 [M]þ$ (4), 377 (20), 205
(100), 121 (27), 77 (7), 73 (71); HREIMS calcd for C28H44O5Si2
(Mꢀ26): 516.2727; found: 516.8416.
4.2.7. (ꢀ)-(2S,3R,4R)-2-(30,40Dihydroxyphenyl)tetrahydrofuran-3,4-
diol ((ꢀ)-(2S,3R,4R)-1). A solution of iodine in methanol (3 mL, 1%
w/v) and compound (ꢀ)-(2S,3R,4R)-6b (15 mg, 0.03 mmol) was
heated to reflux for 3 h. The reaction was then cooled and Na2S2O3
(80 mg) was added to reduce the remaining iodine. The solvent was
removed under reduced pressure and the residue extracted into
ethyl acetate (3ꢃ50 mL), and the solution then washed with brine
(50 mL), dried with Na2SO4, and the solvent was evaporated under
References and notes
1. Freeman, S. Genetic Diversity and Host Specifity of Colletotrichum Species on
Various Fruits In Colletotrichum: Host Specifity, Pathology, and HostePathogen
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Minnesota, 2000; pp 131e144.
2. García-Pajón, C. M.; Collado, I. G. Nat. Prod. Rep. 2003, 20, 426e431.
3. (a) Collado, I. G.; Aleu, J.; Macías-Sánchez, A. J.; Hernández-Galán, R. J. Nat. Prod.
1994, 57, 738e746; (b) Collado, I. G.; Hernández-Galán, R.; Prieto, V.; Hanson, J.
R.; Rebordinos, L. G. Phytochemistry 1996, 41, 513e517; (c) Rebordinos, L.;
Cantoral, J. M.; Prieto, M. V.; Hanson, J. R.; Collado, I. G. Phytochemistry 1996, 42,
383e387; (d) Collado, I. G.; Hanson, J. R.; Macías-Sánchez, A. J.; Mobbs, D. J. Nat.
Prod. 1998, 61, 1348e1351; (e) Durán-Patrón, R.; Hernández-Galán, R.; Re-
bordinos, L. G.; Cantoral, J. M.; Collado, I. G. Tetrahedron 1999, 55, 2389e2400;
(f) Deligeorgopoulou, A.; Macías-Sánchez, A. J.; Mobbs, D. J.; Hitchcock, P. B.;
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Asymmetry 2003, 14, 3917e3924; (c) Oves, D.; Gotor-Fernández, V.; Fernández,
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reduced pressure. Flash chromatography (petroleum ether/acetone
25
80:20) afforded compound (ꢁ)-1 (3 mg, 41%) as a colorless oil: [
a]
D
ꢀ38 (c 0.3, MeOH); >99% ee (optical purity);24 1H NMR (400 MHz,
CD3OD):
d
(ppm) 3.80 (dd, J¼2.4, 8.8 Hz, 1H, H-5b), 3.87 (dd, J¼4.2,
7.6 Hz, 1H, H-3), 4.22 (ddd, J¼2.4, 4.2, 4.6 Hz, 1H, H-4), 4.25 (dd,
J¼4.6, 8.8 Hz, 1H, H-5a), 4.51 (d, J¼7.6 Hz, 1H, H-2), 6.70 (2H, H-50,
H-60), 6.80 (d, J¼2.0 Hz, H-20); 13C NMR (100 MHz, CD3OD):
d (ppm)
72.4 (d, C-4), 74.2 (t, C-5), 79.6 (d, C-3), 84.5 (d, C-2), 114.4 (d, C-20),
116.1 (d, C-50*), 119.0 (d, C-60*), 133.3 (s, C-10), 142.1 (s, C-30#), 146.1
(s, C-40#). *#Interchangeable signals; IR (neat) (cmꢀ1) 3334, 1520;
n
EIMS m/z (rel int.) 212 [M]þ (73), 194 (8), 152 (10), 139 (100);
HREIMS m/z calcd for C10H12O5¼212.0685; found 212.0679.
4.2.8. (ꢀ)-(2S,3S,4R)-2-(30,40-Diacetoxyphenyl)-3,4-diacetoxyte-
trahydrofuran ((ꢀ)-(2S,3S,4R)-1a). Acetic anhydride (189 mg,
1.8 mmol) was added dropwise to a stirred solution of compound
(ꢀ)-(2S,3R,4R)-1 (3 mg, 0.014 mmol) in dry pyridine (1 mL). After
24 h the reaction mixture was diluted with ethyl acetate (50 mL)
and washed sequentially with 2 N HCl (2ꢃ50 mL), a diluted solution
of CuSO4 (2ꢃ50 mL) and brine (50 mL) and was then dried over
Na2SO4, filtered, and the solvent evaporated under reduced pres-
sure. Flash chromatography (petroleum ether/ethyl acetate 80:20)
9. Latypov, S. K.; Seco, J. M.; Quiñoá, E.; Riguera, R. J. Am. Chem. Soc. 1998, 120,
877e882.
10. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190e6191.
11. Hwa, J. C. H.; Sims, H. Org. Synth. 1961, 41, 49e58.
12. (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307e1370; (b)
Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103,
977e1050; (c) Kamal, A.; Azhar, M. A.; Krishnaji, T.; Malik, M. S.; Azeeza, S.
Coord. Chem. Rev. 2008, 252, 569e592.
13. (a) Bellemin-Laponnaz, S.; Tweddell, J.; Ruble, J. C.; Breitling, F. M.; Fu, G. C.
Chem. Commun. 2000, 1009e1010; (b) Rotticci, D.; Norin, T.; Hult, K. Org. Lett.
2000, 2, 1373e1376; (c) Birman, V. B.; Jiang, H. Org. Lett. 2005, 7, 3445e3447;
(d) Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 1999, 121, 5813e5814.
14. Onaran, M. B.; Seto, C. T. J. Org. Chem. 2003, 68, 8136e8141.
15. (a) 81% ee, DKR with lipase: Choi, J. H.; Choi, Y. K.; Kim, Y. H.; Park, E. S.; Kim, E.
J.; Kim, M. J.; Park, J. J. Org. Chem. 2004, 69, 1972e1977; (b) 45% ee, KR via
oxidation Allan, G. R.; Carnell, A. J. J. Org. Chem. 2001, 66, 6495e6497; (c) 95%
ee, KR via epoxidation: Wei, Z.; Arindrajit, B.; Yuji, K.; Yujiro, H.; Hisashi, Y.
Angew. Chem., Int. Ed. 2005, 44, 4389e4391.
afforded compound (ꢀ)-(2S,3S,4R)-1a as a colorless oil (5 mg, 93%).
25
[
a]
ꢀ34 (c 0.5, CHCl3); >99% ee (optical purity).24 The synthetic
D
material exhibits the same spectral data and optical activity as the
natural product (ꢀ)-1a, (see Supplementary data) isolated form the
fungus C. gloeosporioides 20122.4
Acknowledgements
16. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem.
1991, 56, 2656e2665.
This research was supported by grants from MEC, AGL2009-
13359-C02-01, and the Junta de Andalucía, P07-FQM-02689
(Spain). G.M. thanks CONACYT (Mexico) and the Fundación Caro-
lina (Spain) for a studentship.
17. (a) Snatzke, G.; Ho, P. C. Tetrahedron; 1971; 27 3645e3653; (b) Pickard, S. T.;
Smith, H. E. J. Am. Chem. Soc. 1990, 112, 5741e5747; (c) Smith, H. E.; Fontana, L. P.
J. Org. Chem. 1991, 56, 432e435; (d) Smith, H. E. Chem. Rev. 1998, 98, 1709e1740.
18. Nelson, D. G.; Zakir, U.; Scrimgeour, C. M. J. Chem. Soc. C 1971, 898e904.
19. Pescitelli, G.; Di Bari, L.; Caporusso, A. M.; Salvadori, P. Chirality 2008, 20,
393e399.
Supplementary data
20. Ghosh, A. K.; Liu, W. J. Org. Chem. 1996, 61, 6175e6182.
21. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413e4450.
22. Ray, R.; Matteson, D. S. Tetrahedron Lett. 1980, 21, 449e450.
23. Vaino, R.; Szarek, W. A. Chem. Commun. 1996, 2351e2352.
24. Material for comparison of optical purity was obtained by chemical
resolution of racemic (ꢁ)-6b, prepared from unresolved racemic alcohol
(ꢁ)-(3) (see Supplementary data).
Isolation procedure for compound (ꢀ)-1a from C. gloeosporioides
20122. Experimental details for the preparation of compounds
(ꢀ)-12, (þ)-13 (chemical resolution), (þ)-1, (ꢀ)-1 (chemical reso-
lution), (þ)-1a, (ꢀ)-1a (chemical resolution). 1H NMR and 13C NMR