Stereoselective Heck-Matsuda arylations of chiral dihydrofurans with arenediazonium tetrafluoroborates; an efficient enantioselective total synthesis of (-)-isoaltholactone

Article abstract of DOI:10.1055/s-2007-983781

The Heck-Matsuda arylation of chiral 2-(S)-hydroxymethyl dihydrofurans (endocyclic enolethers) and its derivatives, employing arenediazonium tetrafluoroborates, was developed into a highly efficient, practical and diastereoselective synthetic process. This methodology was applied to the total synthesis of the styryllactone (-)-isoaltholactone in seven steps with an overall yield of ～25%, from the readily available chiral 2-hydroxymethyldihydrofuran. The strategy permits the synthesis of several other aromatic analogues of isoaltholactone. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983781

PAPER
2279
Stereoselective Heck–Matsuda Arylations of Chiral Dihydrofurans with
Arenediazonium Tetrafluoroborates; An Efficient Enantioselective Total
Synthesis of (–)-Isoaltholactone
E
nantioselecti
a
u
nthesis of
(
–
l
)-Isoalt
oholactone Roberto Rodrigues Meira, Angélica Venturini Moro, Carlos Roque Duarte Correia*
Instituto de Química, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, CEP 13084-971, Campinas, São Paulo, Brazil
Fax +55(19)35213086; E-mail: roque@iqm.unicamp.br
Received 1 March 2007
Dedicated to Professor Paul A. Wender on the occasion of his 60th birthday for his outstanding contributions to organic chemistry
O
O
Abstract: The Heck–Matsuda arylation of chiral 2-(S)-hydroxy-
methyl dihydrofurans (endocyclic enolethers) and its derivatives,
employing arenediazonium tetrafluoroborates, was developed into
a highly efficient, practical and diastereoselective synthetic process.
This methodology was applied to the total synthesis of the styryllac-
tone (–)-isoaltholactone in seven steps with an overall yield of
~25%, from the readily available chiral 2-hydroxymethyldihydrofu-
ran. The strategy permits the synthesis of several other aromatic an-
alogues of isoaltholactone.
OH
O
O
OH OH
goniothalamin (1)
goniotriol (2)
HO
O
Key words: Heck reaction, palladium, diazonium compounds, ca-
talysis, stereoselectivity
O
O
O
O
HO
HO
O
(+)-isoaltholactone (4)
goniopyrone (3)
The styryllactones are a diverse group of secondary me-
tabolites displaying an outstanding range of biological ac-
tivities. Several of its members have been indicated as
possessing cytotoxic activity against cancer cells, anti-
inflammatory and antibiotic activity, action as immuno-
supressors, trypanocidal and antifertility agents. The sty-
ryllactone family encompasses many basic frameworks
ranging from the simple pyranones (goniothalamins) and
furanones to the more complex bicyclic pyrano-pyra-
H
OH
HO
O
O
O
OH
O
H
HO
goniofurone (5)
O
goniobutenolide A (6)
Figure 1 Examples of styryllactones
nones,
furano-pyranone,
and
furano-furanones
(Figure 1).1
rich olefins using arenediazonium tetrafluoroborates of-
fers several advantages over the traditional Heck method-
ology using aryl halides and aryl triflates; they are usually
milder, easier to carry out, much faster and more econom-
ical.5
In view of such structural diversity associated with the po-
tential therapeutic applications of these compounds, it is
no surprise they have been attracting a lot of attention
from the scientific community. Much work has been done
and the syntheses of the natural and unnatural analogues
for biological screening have been one of the major objec-
tives of these studies.1,2 Synthetic efficiency, allied to
route flexibility are desirable features of a modern syn-
thetic strategy in order to permit the synthesis of ana-
logues.3
An overview of the general strategy for the synthesis of
styryllactones of several types is illustrated in Figure 2.
The designed strategy also has the advantage of adding
synthetic flexibility by simple changes in the nature of the
arenediazonium. Stereocontrol of the Heck process can
also open the possibility of addressing the synthesis of
other styryllactones and closely related compounds.
Attracted by the fact that many of these important com-
pounds bear an aromatic ring next to a heteroatom in a fu-
ran substructure, we felt that the Heck arylation of
dihydrofurans employing arenediazonium salts could be
an excellent alternative to the construction of the natural
compounds and an entry to the synthesis of new ana-
logues.4 The phosphine-free Heck arylation of electron-
Our expectations at the onset of these studies were cen-
tered on the delicate stereocontrol of the Heck arylation
reaction of a chiral dihydrofuran, based on previous re-
sults derived from the Heck arylation of endocyclic ene-
carbamates.5a,6 Excellent trans selectivity can be achieved
in the preparation of substituted 3-pyrrolines 9 as indicat-
ed in Table 1.6 Since the trans Heck adduct was expected
to be the major adduct, we directed the synthetic applica-
tion of these Heck studies to the total synthesis of
isoaltholactone 4. Isoaltholactone 4,7 a furano-pyranone
SYNTHESIS 2007, No. 15, pp 2279–2286
x
x.
x
x
.
2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-983781; Art ID: C01007SS
© Georg Thieme Verlag Stuttgart · New York

2280
P. R. R. Meira et al.
PAPER
O
O
O
Ph
Ph
NH2
NaNO2
O
HO
OH
HO2C
O
O
OH
O
HCl, H2O
(85%)
OH
O
O
O
(–)-isoaltholactone
ent-altholactone
11
L
-glutamic acid (10)
1. BH3⋅SMe2
O
O
THF (88%)
Ph
Ph
RO
RO
2. TBSCl, imidazole
CH2Cl2 (98%)
O
TBSO
3. DIBAL-H, CH2Cl2
4. MsCl, Et3N, CH2Cl2, ∆
(75%, over 2 steps)
12
O
RO
Scheme 1 Synthesis of the chiral dihydrofuran 12
Figure 2 Synthesis plan
The synthesis of the chiral dihydrofuran occurred un-
eventfully, but one should be careful with the volatility of
the compounds obtained after diborane reduction of the
carboxylic acid 11 (Scheme 1).9
natural product belonging to the styryllactone family, was
isolated from several species of the malaysian tree Gonio-
thalamus (G. malayanus, G. montanus and G. tapis). For
strategic and economical reasons we targeted the synthe-
sis of the enantiomer of the natural product, the (–)-
isoaltholactone (ent-4). As for many other styryllactones,
isoaltholactone also displays important biological activi-
ties, including antitumor, antifungal and antibacterial
properties.1b,7a
With the enantiomerically enriched dihydrofuran 12 in
hand, we then initiated our study of the Heck arylation us-
ing a few representative arenediazonium tetrafluorobo-
rates. The Heck arylation was probed with borates bearing
an electron-rich substituent and with non-substituted ben-
zenediazonium tetrafluoroborate in order to find optimum
conditions for the arylation process (Table 2). As the ben-
zenediazonium tetrafluoroborate is a rather unstable com-
pound when in solution, especially when exposed to light
or warmed above 40 °C (generation of an aryl cation), op-
timizing the arylating conditions for this salt was impor-
tant since it would be needed for the synthesis of most of
the natural styryllactones.
Table 1 Heck–Matsuda Arylation of Endocyclic Enecarbamatesa
N2BF4
OR
OR
+
N
N
CO2t-Bu
CO2t-Bu
MeO
OMe
7
8
9
Employing the same reaction conditions applied previ-
ously for the arylation of endocyclic enecarbamates,6 pro-
vided only moderate to good yields of the desired Heck
adducts (Table 2). As expected, the trans stereoisomer
was observed as the major adduct in almost all cases, ex-
cept for entries 7 and 8. The efficiency of the Heck aryla-
tion seems to parallel the stability of the arenediazonium
salt in solution. Hence, higher yields were obtained with
arenediazonium salts bearing electron-donating substitu-
ents. An intriguing feature of these Heck arylations is the
sharp change in the stereoselectivity observed with the un-
protected dihydrofuran 13 when reacting with p-methoxy-
benzenediazonium tetrafluoroborate (Table 2, entries 7
and 8). The trans:cis ratio of the diastereoisomeric Heck
adduct seems to depend very subtly on the amount of wa-
ter content in the reaction solvent in a relationship that is
still unclear. Also intriguing is the fact that no changes in
the stereoselectivity were observed with the other two di-
azonium salts tested. Changing the reaction solvent from
acetonitrile to other polar solvents, such dimethyl sulfox-
ide (DMSO) and acetone did not improve yields or change
the stereoselectivity of these Heck reactions.
R
Yield
92
trans:cis ratio
92:08
TBDPS
Tr
H
96
90:10
95
48:52
a Reaction conditions: Pd2(dba)3 (1 mol%), NaOAc, MeCN, r.t., 15–
30 min.
These previous studies have demonstrated the critical role
played by steric hindrance in controlling the facial selec-
tivity of the olefin during the Heck arylation. The function
played by the free alcohol, however, is still not clear. We
hypothesize that it could, to some extent, direct the Heck
arylation by interacting with the incoming cationic
arylpalladium complex. The Heck arylation of dihydro-
furans (endocyclic enolethers) offers another opportunity
to evaluate the influence of these structural elements on
the stereochemical outcome of the Heck–Matsuda reac-
tion.
We started our studies by preparing chiral tert-butyldi-
methylsiloxymethyl-4,5-dihydrofuran (12) in multigram
quantities from L-glutamic acid, following the procedure
described by Silverstein and Kocienski in five steps with
an overall yield of 55%.8
With the aim of improving the synthetic potential of the
Heck–Matsuda arylation of the chiral dihydrofuran 12,
some changes in the reaction conditions were evaluated.
Changes in the catalyst, the catalyst loading, influence of
Synthesis 2007, No. 15, 2279–2286 © Thieme Stuttgart · New York

PAPER
Enantioselective Total Synthesis of (–)-Isoaltholactone
2281
Table 2 Heck Arylation of Dihydrofuran 12 and 13 with Arenediazonium Tetrafluoroboratesa
N2BF4
O
O
RO
O
RO
RO
G
G
G
+
Pd2(dba)3
NaOAc
solvent, r.t.
b cis
a trans
12: R = TBS
13: R = H
Entry
1
Product
14
R
G
Solvent
MeCN
Ratio trans/cisb
92:08
Yield (%)c
TBS
TBS
TBS
TBS
H
4-OMe
4-OMe
H
65
66
55
70
63
66
64
63
50
60
53
55
55
70
72
2
14
MeCN–H2O (10:1)
MeCN
92:08
3
15
92:08
4d
5
15
H
MeCN
92:08
16
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
H
MeCN
93:07
6
16
H
MeCN–H2O (1:1)
MeCN–H2O (10:1)
MeCN–H2O (10:0.5)
DMSO
91:09
7
16
H
50:50
8
16
H
60:40
9
16
H
92:08
10
11
12
13
14
15
16
H
MeCN–DMSO (1:1)
MeCN
93:07
17
H
92:08
17
H
H
MeCN–H2O (10:1)
acetone
93:07
17
H
H
93:07
18
H
NHCO2Me
NHCO2Me
MeCN
92:08
18
H
MeCN–H2O (10:1)
93:07
a Reactions carried out using 2 mol% of the catalyst.
b Determined by GC.
c Yields for isolated compounds as diastereomeric mixtures.
d Reaction carried out using 4 mol% of the catalyst.
additives to improve the performance of the catalyst, tem- 14 was obtained in 85% yield as a 94:6 diastereomeric
perature of the reaction, and the ratio of olefin to arenedi- mixture favoring the trans adduct (Table 3, entry 6).
azonium salts were evaluated. These studies were initially
carried out with the most stable p-methoxybenzenediazo-
nium tetrafluoroborate. It is worth noting that, on a few
occasions, we found it advantageous to generate the active
palladium(0) catalyst just before the Heck arylation by in
situ reduction of palladium(II) acetate using equimolecu-
A further effort was carried out to improve yields of the
Heck–Matsuda arylation when using benzenediazonium
tetrafluoroborate, since the trans adduct 15a from this
arylation reaction should constitute the starting material
for the synthesis of the (–)-isoaltholactone 4 (Table 4).
As shown in Table 4, the desired 2-phenyl-3,4-dihydro-
furans 15 could be prepared in good to excellent yields as
a mixture of diastereomers, favoring the trans adduct, by
using an excess of the starting olefin 12. Best conditions
were achieved with 4 mol% of Pd2(dba)3, employing 1.2
equivalents of the chiral endocyclic enolether 12 (Table 4,
entry 9), affording the phenyldihydrofurans 15a and 15b
in 90% yield as a 94:06 diasteromeric mixture. Though
the two diastereomers formed a mixture that was insepa-
rable by column chromatography, luckily, the desilylated
Heck adducts (use of TBAF, in THF as indicated in
lar amounts of dihydrofuran in acetonitrile.10 This proce-
dure generates a finely suspended palladium(0) that is
made somewhat more stable by the addition of anisole as
an additive. Anisole seems to considerably slow down the
formation of the inactive palladium black, which precipi-
tates with time. When the olefin was added just after for-
mation of the pre-catalysts, followed by the addition of the
arenediazonium salt, a considerable increase in yields for
the Heck arylation was observed (Table 3). Using only 2
mol% of palladium(II) acetate at 50 °C, the Heck adduct
Synthesis 2007, No. 15, 2279–2286 © Thieme Stuttgart · New York

2282
P. R. R. Meira et al.
PAPER
Table 3 Optimization of the Heck Arylation of 12 with p-Methoxybenzenediazonium Tetrafluoroborate
N2BF4
O
O
TBSO
O
TBSO
TBSO
OMe
OMe
OMe
+
Pd catalyst
NaOAc
MeCN, r.t.
12
14a
14b
Entry
Catalysta
Catalyst loading (mol%)
Additiveb
–
Ratio trans/cisc
90:10
Yield (%)d
1
2
3
4
5
6e
7
8
Pd(PhCN)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
2
2
60
77
66
84
86
85
–
anisole (15:1)
anisole (4:1)
anisole (4:1)
anisole (4:1)
anisole (4:1)
phenanthrolinef
–
95:05
2
95:05
8
94:06
4
95:05
2
94:06
10
2
–
92:08
65
a Pd(OAc)2 and Pd(PhCN)2Cl2 were reduced in situ with an equimolar amount of dihydrofuran prior to the addition of the substrate and the
arenediazonium salt.
b Additive added to the reaction mixture to help stabilize the Pd species. The parenthesis indicate the ratio of additive to Pd.
c Determined by GC.
d Yields for isolated compounds as diastereomeric mixtures (homogeneous material by TLC).
e Reaction carried out at 50 °C.
f No reaction observed when using phenanthroline as additive.
Table 4 Optimization of the Heck Arylation of 12 with Benzenediazonium Tetrafluoroborate
N2BF4
O
O
TBSO
O
TBSO
TBSO
+
Pd2(dba)3
NaOAc
MeCN, r.t.
12
15a
15b
Entry
Catalyst loading (mol%)
Olefin (equiv)
Ratio trans/cisa
92:08
Yield (%)b
1
2
2
2
2
2
4
5
4
4
1.0
1.2
1.3
1.5
1.7
1.0
1.0
1.1
1.2
55
60
63
85
66
70
69
85
90
2
93:07
3
92:08
4
94:06
5
93:07
6
92:08
7
91:09
8
93:07
9
94:06
a Determined by GC
b Yields for isolated compounds as diastereomeric mixtures (homogeneous material by TLC).
Synthesis 2007, No. 15, 2279–2286 © Thieme Stuttgart · New York

PAPER
Enantioselective Total Synthesis of (–)-Isoaltholactone
2283
Scheme 2) could be easily separated by flash chromatog-
raphy.
O
HO
O
HO
OsO4, NMO
Ph
Ph
HO
With the optimal conditions for the synthesis of aryl dihy-
drofuran 15a attained, we proceeded with the synthesis of
(–)-isoaltholactone (ent-4), as indicated in Scheme 2. Re-
moval of the silyl protecting group, followed by treatment
with potassium osmate and N-methylmorpholine N-oxide
(NMO) afforded the triol 19 which, without further puri-
fication, was treated with 2,2-dimethoxypropane and p-
toluenesulfonic acid to provide acetonide 20 in good over-
all yields over the three steps (Scheme 2).
OH
17a
19
H
O
O
O
O
Os
O
O
O
O
O
Os
O
O
O
or
OTBS
Equation 1 Rationale for the substrate-directable dihydroxylation
of dihydrofuran 17a
1. TBAF, THF
O
HO
O
(95%)
Ph
Ph
2. K2OsO4, NMO
(90%)
HO
cis stereochemistry seems to be characteristic of a-alkoxy
aldehydes. In an attempt to improve yields at this stage, an
alternative olefination procedure was also pursued in or-
der to generate the cis-enoate 21 starting from the ace-
tonide 20. Thus, after Swern oxidation of 20, the aldehyde
intermediate was reacted with ethyl [bis(3-methylphen-
oxy)phosphoryl]acetate [(o-cresol)2P(O)CH2COOEt] to
generate the cis-enoate 21 in a moderate 64% yield (over
2 steps). Although specific for the construction of cis-a,b-
unsaturated esters, the protocol developed by Ando was
not advantageous in the present case.13
OH
15a
19
O
O
2,2-DMP, PTSA
acetone (60–80%)
HO
Ph
or 2,2-DMP, PTSA
CH2Cl2, 24 h (54%)
O
Me
20
Me
Scheme 2 Synthesis of the intermediate acetonide 20
The dihydroxylation was carried out in high yield (90%),
with excellent stereocontrol, to furnish only one detect-
able diastereomeric triol, which was converted into the
corresponding 2,3;3,4-cis acetonide 20 using two differ-
ent protocols. Surprisingly, acetonide formation was a
rather capricious transformation. Treatment of triol 19
with 2,2-dimethoxypropane in acetone led to the corre-
sponding acetonide in an inconsistent 60–80% yield, to-
gether with the generation of several side products.
Changing the reaction solvent to dichloromethane led to
the acetonide 20 in a much cleaner reaction but only in a
moderate yield (54%). In spite of the lower yield for the
latter protocol, this more reproducible transformation was
adopted.
As previously reported, treatment of cis-enoate 21 with
catalytic p-toluenesulfonic acid in methanol, followed by
sonication, provided (–)-isoaltholactone (ent-4) in 70%
yield (2 steps).7b A slightly better protocol for acetonide
deprotection and the final closure of the intermediate hy-
droxy ester to the desired lactone was the use of 50%
aqueous trifluoroacetic acid (Equation 2). Thus, treatment
of cis-enoate 21 with an aqueous solution of trifluoroace-
tic acid for 48 hours at room temperature furnished (–)-
isoaltholactone {[a]D23 –24.5 0.5 (c 0.20, EtOH)} in 80%
yield. The spectroscopic and spectrometric data obtained
for the (–)-isoaltholactone obtained in this work was in
excellent agreement with those reported in the literature.7a
We believe that dihydroxylation is controlled by steric
hindrance of the larger phenyl group, combined with a di-
recting effect from the primary alcohol, as an example of
a substrate-directable reaction (Equation 1).11 A similar
transformation was performed by us during the total syn-
thesis of codonopsinine.6
O
O
HO
1. Swern
Ph
Ph
EtO2C
2.
Ph3P
O
O
O
O
O
OEt
Me
Me
21
Me
20
Me
MeOH
75% (2 steps)
From this point on, the synthesis of isoaltholactone was
rather straightforward and followed, in part, the approach
proposed by Yadav and co-workers (Scheme 3).7a,b Thus,
oxidation of the primary alcohol functionality present in
20, using Swern conditions, gave an unstable aldehyde
which was immediately subjected to a Wittig olefination
with ethoxycarbonylmethylene phosphorane in methanol
to furnish the cis-enoate 21 in 75% yield (over 2 steps).
According to the work of Valverde and co-workers,12 this
H
O
1. PTSA, MeOH
2. ))), benzene
Ph
O
O
H
OH
(–)-isoaltholactone (4)
70% (2 steps)
Scheme 3 Completing the synthesis of (–)-isoaltholactone 4 using
Yadav’s strategy
Synthesis 2007, No. 15, 2279–2286 © Thieme Stuttgart · New York

2284
P. R. R. Meira et al.
PAPER
H
H
tert-Butyl{[(2S,5S)-5-(4-methoxyphenyl)-2,5-dihydrofuran-2-
yl]methoxy}dimethylsilane (14a)
O
O
50% CF3CO2H (aq),
Ph
IR (film): 2953, 2929, 2856, 1512, 1248, 1077, 834, 777 cm–1.
EtO2C
Ph
THF
O
O
O
1H NMR (300 MHz, CDCl3): d = 0.07 (s, 3 H), 0.08 (s, 3 H), 0.91
(s, 9 H), 3.65 (dd, J = 10.2, 6.8 Hz, 1 H), 3.77 (dd, J = 10.2, 4.6 Hz,
1 H), 3.79 (s, 3 H), 5.01 (m, 1 H), 5.77 (dt, J = 5.8, 1.8 Hz, 1 H),
5.91 (dt, J = 4.4, 1.8 Hz, 1 H), 6.00 (dt, J = 5.5, 1.8 Hz, 1 H), 6.87
(d, J = 8.4 Hz, 2 H), 7.22 (d, J = 8.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = –5.4, –5.3, 18.4, 25.9, 55.3, 66.0,
86.9, 87.7, 113.8, 127.9, 128.2, 131.3, 133.9, 159.3.
r.t., 48 h
(80%)
O
OH
Me
(21)
Me
(–)-isoaltholactone (4)
Equation 2 Alternative protocol for the synthesis of (–)-isoaltho-
lactone 4
In conclusion, the total synthesis of (–)-isoaltholactone
was achieved in seven steps with an overall yield of ~25%
from the readily available chiral dihydrofuran 12. The key
steps in the synthetic route featured a highly stereoselec-
tive and efficient Heck–Matsuda arylation of a chiral
endocyclic enolether (an electron-rich olefin) using arene-
HRMS (ESI): m/z [M + 1]+ calcd for C18H28O3Si: 321.1886; found:
321.1915.
Methyl 4-[(2S,5S)-5-(Hydroxymethyl)-2,5-dihydrofuran-2-
yl]phenylcarbamate (18a)
[a]D22 –182 (c 0.38, CHCl3).
diazonium tetrafluoroborates, a substrate-directed dihy- IR (film): 3331, 2955, 2871, 1709, 1601, 1537, 1314, 1227, 1067
cm–1.
droxylation to set the correct configuration of four
1H NMR (300 MHz, CDCl3): d = 3.64 (dd, J = 11.7, 5.1 Hz, 1 H),
3.76–3.90 (m, 4 H), 5.11–5.18 (m, 1 H), 5.82 (d, J = 5.5 Hz, 1 H),
5.97 (t, J = 5.8 Hz, 1 H), 6.81 (d, J = 16.5 Hz, 1 H), 7.22 (d, J = 8.0
Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 52.4, 65.1, 87.2, 87.6, 118.8, 126.7,
127.3, 132.2, 136.3, 137.7, 154.1.
adjacent stereocenters, and a straightforward acetonide
deprotection-lactonization promoted by trifluoroacetic
acid. The strategy contains enough flexibility to permit
the synthesis of the natural product (+)-isoaltholactone
(use of D-glutamic acid) and several other aromatic ana-
logues of these styryllactones for pharmacological assays.
Results along these lines will be reported in due course.
HRMS (ESI): m/z [M + 1]+ calcd for C13H15NO4: 250.1079; found:
250.0987.
All reagents were of the highest available purity from commercial
sources and were used as supplied, unless stated otherwise in the ex-
perimental procedures. Solvents were purified by standard meth-
ods.14 1H NMR and 13C NMR data were recorded on a Varian
Gemini 2000 (7.0 T) or Varian Inova (11.7 T) spectrometer with
TMS as internal standard. The ESI-MS spectra were acquired using
a Q-Tof Ultima API (Micromass, UK), by direct infusion of the
compound solution in H2O–MeCN (1:1). Infrared spectra (IR) were
obtained on a Thermo-Nicolet IR-200 spectrometer and absorptions
are reported in reciprocal centimeters. HPLC analyses were per-
formed with a Hewlett–Packard HP-1100/HP-3395. Optical rota-
tions were measured with a Perkin–Elmer 341 polarimeter or on a
Jasco F720 Spectro polarimeter.
[(2S,5S)-5-Phenyl-2,5-dihydrofuran-2-yl]methanol (17a)
To a stirred solution of Heck adduct 15 (0.29 g, 1 mmol) in THF (1
mL), was added TBAF (1.0 M, 1.2 mL, 1.2 mmol). The reaction
was stirred for 1 h then quenched by addition of H2O (2 mL) and ex-
tracted into EtOAc (3 × 5 mL). The combined organic layers were
dried over Na2SO4, filtered and the solvent was evaporated in
vacuo. The oily residue was purified by flash chromatography
(hexane–EtOAc, 7:3) to provide the corresponding trans primary
alcohol 17a (homogeneous material on TLC).
Yield: 0.158 g (90%); yellowish oil; [a]D22 –385 (c 0.4, CHCl3).
IR (film): 3403, 2916, 2870, 1453, 1063, 1034 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.64 (dd, J = 11.5, 5.3 Hz, 1 H),
3.80 (dd, J = 11.5, 3.1 Hz, 1 H), 5.12–5.18 (m, 1 H), 5.85 (dt,
J = 5.5, 1.8 Hz, 1 H), 5.89 (dt, J = 6.2, 1.8 Hz, 1 H), 6.00 (dt,
J = 6.2, 1.8 Hz, 1 H), 7.25–7.37 (m, 5 H).
Heck Arylation; General Procedure
To a stirred solution of the endocyclic enolether 12 (0.079 g, 0.36
mmol) in MeCN (2 mL), was added NaOAc (0.097 g, 1.08 mmol),
Pd2(dba)3 (0.014 g, 4 mol%) and benzenediazonium tetrafluorobo-
rate (0.058 g, 0.3 mmol). The reaction mixture was stirred for ~15
min, until nitrogen evolution was no longer noticeable. The crude
reaction mixture was then filtered through SiO2 and the solvent was
evaporated in vacuo. The crude residue was purified by flash chro-
matography (hexane–EtOAc, 9:1) to give the Heck adduct 15
(0.079 g, 90%) as a diastereomeric mixture (94:6), which appeared
as homogeneous material on TLC.
13C NMR (75 MHz, CDCl3): d = 65.0, 87.4, 88.0, 126.3, 126.5,
128.0, 128.5, 132.3, 141.3.
HRMS (ESI): m/z [M + 1]+ calcd for C11H12O2: 177.0916; found:
177.0878.
[(2S,5R)-5-(4-Methoxyphenyl)-2,5-dihydrofuran-2-yl]meth-
anol (16a)
[a]D22 –301 (c 0.32, CHCl3).
IR (film): 3430, 2930, 2871, 1610, 1511, 1243, 1033 cm–1.
tert-Butyldimethyl{[(2S,5S)-5-phenyl-2,5-dihydrofuran-2-
yl]methoxy}silane (15a)
1H NMR (300 MHz, CDCl3): d = 2.20 (br s, 1 H), 3.63 (dd, J = 10.2,
6.8 Hz, 1 H), 3.79 (dd, J = 10.2, 4.6 Hz, 1 H), 3.80 (s, 3 H), 5.11–
5.14 (m, 1 H), 5.82 (d, J = 5.5 Hz, 1 H), 5.91 (d, J = 5.5 Hz, 1 H),
5.99 (d, J = 5.5 Hz, 1 H), 6.88 (d, J = 9.0, 2 H), 7.22 (d, J = 9.0,
2 H).
13C NMR (75 MHz, CDCl3): d = 55.3, 65.1, 87.0, 87.7, 13.9, 126.6,
127.8, 132.4, 133.4, 159.5.
IR (film): 2954, 2928, 2856, 1255, 1084, 834 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.09 (s, 6 H), 0.92 (s, 9 H), 3.66
(dd, J = 11.5, 5.3 Hz, 1 H), 3.81 (dd, J = 11.5, 3.1 Hz, 1 H), 5.03–
5.10 (m, 1 H), 5.81 (d, J = 5.9 Hz, 1 H), 5.93 (d, J = 6.2 Hz, 1 H),
5.99 (d, J = 6.2 Hz, 1 H), 7.25–7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = –5.4, –5.3, 18.3, 25.8, 65.0, 84.0,
85.0, 123.0, 124.2, 124.5, 124.8, 125.8, 141.2.
HRMS (ESI): m/z [M + 1]+ calcd for C12H14O3: 207.1021; found:
207.1063.
HRMS (ESI): m/z [M + 1]+ calcd for C17H26O2Si: 291.1780; found:
291.1697.
Synthesis 2007, No. 15, 2279–2286 © Thieme Stuttgart · New York

PAPER
Enantioselective Total Synthesis of (–)-Isoaltholactone
2285
(2S,4S,5S,3R)-2-Hydroxymethyl-5-phenyltetrahydro-3,4-
furandiol (19)
mote the precipitation of the remaining triphosphine oxide. After a
second filtration, the solvent was evaporated in vacuo and the resi-
due was purified by flash chromatography (hexane–EtOAc, 9:1) to
furnish the corresponding cis-enoate 21 (0.029 g, 75% yield over
two steps).
To a stirred solution of the homoallylic alcohol 17a (0.106 g, 0.6
mmol) in H2O–acetone–t-BuOH (0.42 mL, 0.17 mL, 0.07 mL, re-
spectively), was added NMO (0.21 g, 1.8 mmol) and K2OsO4 (0.011
g, 5 mol%). The reaction mixture was stirred at r.t. for 72 h then
quenched by the addition of sat. NaHSO3 (3 mL) and stirred for 30
min. The reaction mixture was extracted into EtOAc (2 × 5 mL) and
the organic layers were combined, dried over anhyd Na2SO4, fil-
tered, and the solvent evaporated in vacuo. The corresponding triol
19 appeared as a single spot on TLC and was used in the next step
without further purification.
Wittig Olefination; General Procedure 2
To a stirred suspension of NaH (0.006 g, 0.70 mmol, 60% disper-
sion in mineral oil) in anhyd THF (0.5 mL), under argon, at 0 °C,
was added (o-cresol)2P(O)CH2COOEt (0.052 g, 0.70 mmol) dis-
solved in anhyd THF (0.3 mL). The reaction mixture was stirred at
0 °C for 10 min then cooled to –78 °C. To this mixture was then
added the crude aldehyde prepared above (0.035 g, 0.14 mmol) dis-
solved in anhyd THF (0.3 mL) and the reaction mixture was stirred
at –78 °C for 1 h. The reaction was quenched by the addition of sat.
NH4Cl (3 mL) and extracted into Et2O (3 × 5 mL). The combined
organic layers were dried over Na2SO4, filtered and the solvent
evaporated in vacuo. The residue was purified by flash chromatog-
raphy (hexane–EtOAc, 9:1) to provide the corresponding cis-enoate
21.
(4S,6S,6aS,3aR)-2,2-Dimethyl-6-phenylperhydrofuro[3,4-
d][1,3]dioxol-4-ylmethanol (20)
To a stirred solution of the triol 19 (0.126 g, 0.6 mmol) in anhyd
CH2Cl2 (9 mL), under argon at r.t., was added anhyd PTSA (0.011
g, 0.06 mmol) and 2,2-dimethoxypropane (2.5 mL, 28 mmol). The
reaction mixture was stirred for 2 h at r.t. then quenched by the ad-
dition of sat. NaHCO3 (5 mL). The reaction was extracted into
EtOAc (2 × 5 mL) and the organic layers were combined, dried over
anhyd Na2SO4, filtered, and the solvent evaporated in vacuo. The
crude residue was purified by flash chromatography (hexane–
EtOAc, 1:1) to give the corresponding acetonide 20.
20
Yield: 0.025 g (64% yield over two steps); [a]D –82.0 (c 1.43,
CHCl3) {Lit.7e [a]D20 –97.3 (c 1.50, CHCl3)}.
1H NMR (300 MHz, CDCl3): d = 1.29 (t, J = 7.4 Hz, 3 H), 1.34 (s,
3 H), 1.55 (s, 3 H), 4.15 (q, J = 7.4 Hz, 2 H), 4.93–5.03 (m, 2 H),
5.21 (s, 1 H), 5.34–5.42 (m, 1 H), 5.95 (dd, J = 11.8, 1.4 Hz, 1 H),
6.42 (dd, J = 11.8, 6.7 Hz, 1 H), 7.21–7.36 (m, 5 H).
Yield: 0.1 g (54% over two steps).
IR (film): 3452, 2985, 2936, 1373, 1209, 1069, 1047 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.36 (s, 3 H), 1.58 (s, 3 H), 2.55
(br s, 1 H), 3.93–4.03 (m, 2 H), 4.05–4.12 (m, 1 H), 4.78 (dd,
J = 5.9, 4.0 Hz, 1 H), 4.95 (dd, J = 6.2, 1.5 Hz, 1 H), 5.22 (s, 1 H),
7.21–7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 24.7, 26.2, 61.4, 80.4, 81.6, 84.5,
87.5, 113.1, 125.5, 127.5, 128.6, 138.5.
13C NMR (75 MHz, CDCl3): d = 14.1, 24.9, 26.3, 60.3, 78.2, 83.0,
85.0, 87.3, 112.7, 120.9, 125.5, 127.4, 128.6, 138.5, 145.5, 165.6,
171.1.
MS (ESI): m/z = 319 [M + 1]+, 273, 215, 197.
(3aS,2R,3R,7aR)-3-Hydroxy-2-phenyl-3,3a,5,7a-tetrahydro-
2H-furo[3,2-b]pyran-5-one [(–)-Isoaltholactone, ent-4)
HRMS (ESI): m/z [M + 1]+ calcd for C14H18O4: 251.1283; found:
To a stirred solution of the cis-enoate 21 (0.016 g, 0.05 mmol) in an-
hyd MeOH (0.25 mL) was added PTSA (0.94 mg, 0.005 mmol) to
give a slightly cloudy solution. The reaction mixture was stirred at
r.t. for 4 h then the solvent was evaporated in vacuo to furnish a
white solid. This crude solid was dissolved in benzene (1 mL) and
placed in an ordinary laboratory ultrasonic bath at r.t. for 6 h. The
solvent was then evaporated in vacuo and the residue was purified
by flash chromatography (hexane–EtOAc, 2:8) to give a colorless
oil (0.008 g, 70% yield over two steps) corresponding to (–)-
isoaltholactone (ent-4) (homogeneous material on TLC).
251.1273.
Ethyl (Z)-3-{(4S,6S,6aS,3aR)-2,2-Dimethyl-6-phenylperhydro-
furo[3,4-d][1,3]dioxol-4-yl}-2-propenoate (21)
To a stirred solution of anhyd DMSO (0.02 mL, 0.28 mmol) in an-
hyd CH2Cl2 (0.05 mL), at –78 °C, under argon, was added drop-
wise, oxalyl chloride (0.02 mL, 0.20 mmol) and the reaction was
stirred for 15 min. A solution of acetonide 20 (0.034 g, 0.14 mmol)
in anhyd CH2Cl2 (0.14 mL) was added dropwise and the reaction
was stirred at –78 °C for 2 h. Freshly distilled Et3N (0.1 mL, 0.69
mmol) was added and the reaction was stirred at –78 °C for a further
15 min then the cooling bath was then removed and the temperature
was allowed to come to r.t. After stirring for 20 min, the reaction
medium was then diluted with Et2O (0.7 mL) and quenched with
H2O (5 mL). After extraction into Et2O (3 × 5 mL), the combined
organic layers were washed with sat. NaCl (3 mL), dried over anhyd
MgSO4, and concentrated in vacuo. The crude material, correspond-
ing to the intermediate aldehyde, was used in the next step without
further purification.
Alternative procedure: To a stirred solution of the cis-enoate 21
(0.032 g, 0.1 mmol) in THF (0.2 mL), was added aq TFA (50%, 2.0
mL). The reaction mixture was stirred for 48 h at r.t. then concen-
trated in vacuo to furnish a white solid. The crude solid was purified
by flash chromatography (hexane–EtOAc, 6:4) to provide the (–)-
isoaltholactone (ent-4) (0.019 g, 80% yield) as homogeneous mate-
rial on TLC.
[a]D23 –24.5 (c 0.2, EtOH) {Lit.7a [a]D20 –32.2 (c 0.3, EtOH).
IR (film): 3500, 3030, 1730, 1645 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.31 (br s, 1 H), 4.28 (m, 1 H),
4.78 (d, J = 7.5 Hz, 1 H), 4.86 (t, J = 5.5, 4.4 Hz, 1 H), 5.05 (t,
J = 5.7 Hz, 1 H), 6.20 (d, J = 10.0 Hz, 1 H), 6.85 (dd, J = 9.9, 4.5
Hz, 1 H), 7.25–7.40 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 67.7, 78.4, 78.6, 83.1, 122.4, 125.6,
128.1, 128.5, 138.6, 141.7, 161.9.
Wittig Olefination; General Procedure 1
To a stirred solution of the crude intermediate aldehyde 21 (0.035 g,
0.14 mmol) in anhyd CH2Cl2 (0.25 mL), under argon, was added the
ylide ethoxycarbonylmethylene phosphorane (0.059 g, 0.17 mmol)
and the reaction mixture stirred at 25 °C for 14 h. The reaction mix-
ture was concentrated in vacuo and n-pentane (5 mL) was added to
the resulting residue to cause the precipitation of triphosphine oxide
that was removed by filtration. Further n-pentane (5 mL) was added
to the filtrate and the mixture was place in an ice bath at 0 °C to pro-
HRMS (ESI): m/z [M + 1]+ calcd for C13H12O4: 233.0814; found:
233.0808.
Synthesis 2007, No. 15, 2279–2286 © Thieme Stuttgart · New York

2286
P. R. R. Meira et al.
PAPER
(6) Severino, E. A.; Costenaro, E. R.; García, A. L. L.; Correia,
C. R. D. Org. Lett. 2003, 5, 305.
(7) (a) Yadav, J. S.; Krishnam, R.; Purushothama, R.; Rajaiah,
G. Tetrahedron: Asymmetry 2005, 16, 3283. (b) Yadav, J.
S.; Rajaiah, G.; Raju, K. Tetrahedron Lett. 2003, 44, 5831.
(c) Peng, X.; Li, A.; Lu, J.; Wang, Q.; Pan, X.; Chan, A. S.
C. Tetrahedron 2002, 58, 6799. (d) Harris, J. M.;
Acknowledgment
This work was supported by a grant from the Research Supporting
Foundation of the State of São Paulo (FAPESP, 05/00721-3). We
also thank CNPq and FAPESP for fellowships and Professor Fábio
Gozzo (Chemistry Institute, Unicamp) for the ESI-MS analyses.
O´Doherty, G. A. Org. Lett. 2000, 2, 2983. (e) Harris, J. M.;
O’Doherty, G. A. Tetrahedron 2001, 57, 5161. (f) Tsubuki,
M.; Kanai, K.; Nagase, H.; Honda, T. Tetrahedron 1999, 55,
2493. (g) Shing, T. K. M.; Tsui, H. C.; Zhou, Z. H. J. Org.
Chem. 1995, 60, 3121. (h) Tsubuki, M.; Kanai, K.; Honda,
T. Synlett 1993, 653. (i) Colegate, S. M.; Din, L. B.; Latiff,
A.; Salleh, K. M.; Samsudin, M. W.; Skelton, B. W.;
Tadano, K.-I.; White, A. H.; Zakaria, Z. Phytochemistry
1990, 29, 1701. (j) Gesson, J. P.; Jacquesy, J. C.; Mondon,
M. Tetrahedron 1989, 45, 2627. (k) Gesson, J. P.; Jacquesy,
J. C.; Mondon, M. Tetrahedron Lett. 1987, 28, 3945.
(8) (a) Ravid, U.; Silverstein, R. M.; Smith, L. R. Tetrahedron
1978, 34, 1449. (b) Takle, A.; Kocienski, P. Tetrahedron
1990, 46, 4503.
(9) The endocyclic enolether 12 is a rather volatile compound.
Use of reduced pressure should be avoided during its
isolation and purification.
(10) An interesting alternative to the use of dihydrofuran is the
use of a balloon of carbon monoxide. A dark blue solution
forms after a few minutes of exposure which stays stable for
a long time, without any signs of Pd precipitation. However,
upon addition of the remaining reagents, formation of Pd
black begins to occur in the reaction medium.
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Synthesis 2007, No. 15, 2279–2286 © Thieme Stuttgart · New York