Diastereoselective aldol reactions of furaldehyde using a chiral boronate as auxiliary: Application to the synthesis of enantiomerically pure and highly functionalized 2,3-disubstituted furanyl alcohols

Article abstract of DOI:10.1002/1099-0690(200301)2003:1<82::AID-EJOC82>3.0.CO;2-X

The aldol reactions of various ketene silyl acetals of lithium enolates with furaldehyde 2, which bears a chiral boronate group at the furan C-3 position, as auxiliary have been studied. It was found that (R) diastereoselectivity was more favorable than (S) diastereoselectivity and moderate diastereoselectivity was achieved. Some of the resulting aldol diastereomers were chromatographically separable by simple flash column chromatography on silica gel, leading to optically pure aldol adducts. The absolute stereochemistry of the aldol adducts were determined by X-ray crystallographic analysis. Further transformation of the carbon-boron bond to a carbon-carbon bond was achieved in a Suzuki coupling reaction to furnish highly functionalized and enantiomerically pure 2,3-disubstituted furyl alcohols. One of the furyl alcohols was allowed to rearrange to hydroxypyranone in order to demonstrate the usefulness of this methodology. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/1099-0690(200301)2003:1<82::AID-EJOC82>3.0.CO;2-X

FULL PAPER
Diastereoselective Aldol Reactions of Furaldehyde Using a Chiral Boronate as
Auxiliary: Application to the Synthesis of Enantiomerically Pure and Highly
Functionalized 2,3-Disubstituted Furanyl Alcohols
Kin-Fai Chan[a][‡] and Henry N. C. Wong*[a]
Dedicated to Professor Zhi-Tang Huang on the occasion of his 75th birthday
Keywords: Diastereoselectivity / Aldol reaction / Rearrangement / Cross-coupling
The aldol reactions of various ketene silyl acetals or lithium
enolates with furaldehyde 2, which bears a chiral boronate
group at the furan C-3 position, as auxiliary have been
studied. It was found that (R) diastereoselectivity was more
favorable than (S) diastereoselectivity and moderate dia-
stereoselectivity was achieved. Some of the resulting aldol
diastereomers were chromatographically separable by
simple flash column chromatography on silica gel, leading to
optically pure aldol adducts. The absolute stereochemistry of
the aldol adducts were determined by X-ray crystallographic
analysis. Further transformation of the carbon−boron bond to
a carbon−carbon bond was achieved in a Suzuki coupling
reaction to furnish highly functionalized and enantiomer-
ically pure 2,3-disubstituted furyl alcohols. One of the furyl
alcohols was allowed to rearrange to hydroxypyranone in or-
der to demonstrate the usefulness of this methodology.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
6-Hydroxy-2H-pyran-3(6H)-one (1) is a very useful syn-
thetic intermediate in the quest for biologically active nat-
ural products. Owning to its wide capability of accommod-
ating other functional groups, its derivatives have become
important building blocks for the synthesis of oxygenated
natural products (Figure 1).[1] Many methods have therefore
been developed in order to realize these compounds.[2] To
access these compounds through an oxidative rearrange-
ment of furanyl alcohols, a variety of reagents have been
reported. For example, m-chloroperbenzoic acid
(mCPBA),[3] peracetic acid,[4] pyridinium chlorochromate
(PCC),[5] iodobenzenediacetate (IBDA)[6] and N-bromosuc-
cinimide (NBS)[7] were all employed as oxidants. The use
of bromine in methanol,[8] bromine in water[9] and anodic
oxidation[10] has also been reported.
Figure 1. Mechanism for furyl alcohol rearrangement to hydroxy-
pyranone
resolution of racemic furyl alcohols, asymmetric catalytic
allylation of furaldehyde[15] and asymmetric catalytic
Mukaiyama aldol reaction of furaldehyde.[16] Despite this,
the synthesis of structurally more elaborate chiral 2,3-disub-
stituted furyl alcohols still awaits investigation. Arai[17] re-
ported that chiral 3-sulfinyl-2-furaldehyde reacted with ket-
ene silyl acetals in the presence of a lanthanide triflate as
Lewis acid catalyst to furnish aldol products with high dia-
stereoselectivities and in high yields. In line with this no-
tion, we are interested in synthesizing chiral 2,3-disubsti-
tuted furyl alcohols employing a chiral boronate as auxili-
ary, which could facilitate further functionalization of the
carbonϪboron bond to a carbonϪcarbon bond by a Su-
zuki coupling reaction. In this paper we wish to report the
Conventional routes developed for the synthesis of chiral
furyl alcohols include Sharpless asymmetric dihy-
droxylation of vinylfuran,[11] asymmetric catalytic hydro-
genation of furyl ketone,[12] kinetic[13] and enzymatic[14]
[‡]
Present address: Department of Applied Biology and Chemical
Technology, Hong Kong Polytechnic University,
Hung Hom, Kowloon, Hong Kong SAR, China
[a]
Department of Chemistry and Central Laboratory of the
Institute of Molecular Technology for Drug Discovery and
Synthesis, The Chinese University of Hong Kong,
Shatin, New Territories, Hong Kong SAR, China
Fax: (internat.) ϩ 852/2603-5057
E-mail: hncwong@cuhk.edu.hk
82
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0101Ϫ0082 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 82Ϫ91

Diastereoselective Aldol Reactions of Furaldehyde
FULL PAPER
aldol reactions of various ketene silyl acetals or lithium en- Reactions with Ketene Silyl Acetals
olates with optically active furaldehyde 2 bearing a chiral
We first studied the Mukaiyama aldol reactions of fural-
dehyde 2 with ketene silyl acetal 3a (Table 1). In most cases,
the reactions proceeded smoothly to furnish silyl ethers 4
in good yields with low diastereoselectivities. Both dia-
stereomers were chromatographically separable, leading to
pure diastereomers. The newly created chiral center of 4b
boronate auxiliary at the furan C-3 position.
Results and Discussion
The required chiral furaldehyde 2 is available in three was substantiated by an X-ray crystallographic analysis and
steps from the commercially available 3-bromofuran.[18] confirmed to be of (R) configuration (Figure 2).[19] The best
With this compound in hand we next studied its behavior result for this reaction was then achieved by the use of La-
in the reaction with various ketene silyl acetals.
(OTf)3 as catalyst at room temperature, which led to silyl
Table 1. Mukaiyama aldol reactions of aldehyde 2 with ketene silyl acetal 3a
Entry
Conditions
Solvent
Catalyst
Temp.
Time
Yield
de[a]
Configuration
1
2
3
4
5
6
7
8
9
La(OTf)3
La(OTf)3
La(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
ZnCl2
ZnCl2
CeCl3
Y(OTf)3
DME
DME
DME
DME
Et2O
THF
Et2O
Et2O
DME
DME
room temp.
Ϫ78 °C
0.5 h
4 h
3 h
12 h
12 h
24 h
1 h
10 h
12 h
12 h
92%
89%
70%
52%
81%
79%
72%
35%
84%
45%
50%
0%
7%
26%
15%
0%
(R)
(Ϫ)
(R)
(R)
(R)
(Ϫ)
(Ϫ)
(R)
(R)
(R)
0 °C
room temp.
room temp.
0 °C
room temp.
Ϫ78 °C
0%
39%
19%
27%
room temp.
room temp.
10
[a]
1
Determined by H NMR analysis of the crude reaction mixture. The major diastereomer is indicated in the parentheses. All reactions
were performed once only and the de values are approximate.
Figure 2. X-ray crystal structure of 4b
Eur. J. Org. Chem. 2003, 82Ϫ91
83

K.-F. Chan, H. N. C. Wong
FULL PAPER
Table 2. Mukaiyama aldol reactions of aldehyde 2 with ketene silyl
acetal 3b
Entry
Conditions
Catalyst Solvent Temp.
Yield
de[a]
Time
3 h
Scheme 1. i) 1  HCl, THF, room temp., 15 min, 98%; ii) Ac2O,
1
La(OTf)3 DME
reflux
76% 46% (R)
pyridine, reflux, 2 h, 82%
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
ZnCl2
FeCl3
Yb(OTf)3 DME
ZnCl2
ZnCl2
Zn(OTf)2 DME
ZnCl2 DME
Et2O
DME
room temp. 12 h 89% 57% (R)
reflux
reflux
0 °C
Ϫ40 °C
reflux
0 °C
48 h 47% 13% (R)
48 h 79% 56% (R)
48 h 88% 67% (R)
96 h 32% 60% (R)
to other lanthanide triflates [Yb(OTf)3] and employment of
other solvents also showed no improved diastereoselectivity.
The following characteristic features of this reaction
could be noted: (1) only a catalytic amount of Lewis acid
catalyst (20 mol%) was added in each case; (2) in most
cases, the reactions proceeded smoothly under extremely
mild conditions to give products in high yield. However,
there was still no improvement in the diastereoselectivity.
We then carried out the Mukaiyama aldol reactions of
furaldehyde 2 with another ketene silyl acetal 3b (Table 2).
All reactions proceeded smoothly to furnish silyl ethers 5
in good yields and improved diastereoselectivities. However,
the use of ZnCl2 as a catalyst in Et2O as a solvent at room
temperature furnished silyl ethers 5 in 89% yield and over
57% de. Decreasing the reaction temperature to 0 °C gave
slightly better diastereoselectivity (67% de). By comparing
Entries 5, 8, 11 and 12 of Table 2, it was found that DME
Et2O
Et2O
4 h
86% 43% (R)
48 h 59% 72% (R)
48 h 59% 48% (R)
Ti(OiPr)4 CH2Cl2 reflux
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
THF
iPr2O
PhMe
reflux
0 °C
0 °C
4 h
12 h 80% 69% (R)
3 h 91% 67% (R)
32% 54% (R)
CH2Cl2 room temp. 48 h 46% 58% (R)
dioxane room temp. 12 h 95% 63% (R)
DME
THF
room temp. 2 h
87% 65% (R)
Ϫ78 °C to 16 h 98% 58% (R)
room temp.
17
18
ZnCl2
ZnCl2
hexane room temp. 14 h 75% 61% (R)
benzene room temp. 14 h 99% 63% (R)
[a]
Determined by 1H NMR analysis of the crude reaction mixture.
The major diastereomer is indicated in the parentheses. All reac-
tions were performed once only and the de values are approximate.
ethers 4 in 92% yield with 50% de. However, when the reac- was the best solvent for this reaction in affording silyl ethers
tion was conducted at Ϫ78 °C, the diastereoselectivity de- 5 in 72% de. In all cases in which the reaction was con-
creased dramatically to 0% de. Change of the Lewis acid ducted at room temperature using ZnCl2 as a catalyst in a
Figure 3. X-ray crystal structure of 7
84
Eur. J. Org. Chem. 2003, 82Ϫ91

Diastereoselective Aldol Reactions of Furaldehyde
FULL PAPER
variety of solvents, silyl ethers 5 were furnished in good protection of the hydroxy group of 6b with an acetate group
yield and over 50% diastereoselectivity.
furnished compound 7 as a crystalline material. Subsequent
X-ray crystallographic analysis of 7 showed the chiral
center resulting from the aldol reaction to be of (R) config-
uration (Figure 3).[19]
It is worthwhile to note that diastereomers 5aϪb were
chromatographically not separable. However, upon depro-
tection of the trimethylsilyl groups of both diastereomers
with 1  HCl (Scheme 1), furyl alcohols 6aϪb were chro-
matographically separable, allowing isolation of the diaster-
eomerically pure diastereomers. Our attempts to crystallize
both diastereomers 6a and 6b were unsuccessful and thus
X-ray crystallographic analysis could not be used to deter-
mine the absolute stereochemistry of 6a nor 6b. Fortunately,
Comparing ketene silyl acetals 3a and 3b, ketene silyl ace-
tal 3b is structurally more hindered. For this reason, its re-
action with furaldehyde 2 should in principle give better
diastereoselectivities than those of ketene silyl acetal 3a. We
then postulated that increasing the bulkiness of the ketene
silyl acetal would possibly lead to higher diastereoselectiv-
ity. Aldol reactions of aldehyde 2 with ketene silyl acetal
3c were then carried out (Table 3). However, there was no
improvement in the observed diastereoselectivity. Aldol re-
actions between aldehyde 2 and ketene silyl acetal 3c af-
forded furyl alcohols 8 in good yield with only moderate
diastereoselectivities. X-ray crystallographic analysis of the
less-polar diastereomer 8a confirmed that the newly created
chiral center was of (S) configuration (Figure 4).[19]
Table 3. Mukaiyama aldol reactions of aldehyde 2 with ketene silyl
acetal 3c
The mechanism proposed for Mukaiyama aldol reaction
has been discussed in detail.[20] It was believed that a three-
component reaction intermediate, i.e., Lewis acid, ketene
silyl acetal and carbonyl group was involved.[21] In this reac-
tion, a Lewis acid coordinates with and activates the car-
bonyl functional group. Due to the steric effect exerted by
the bulky group, the ketene silyl acetal may then attack on
the less hindered Re-face of the furaldehyde 2 to give rise to
the (R) diastereomer because the nearest diphenylcarbinol
group in the boronate moiety shields the carbonyl Si-face
(Figure 5). Thus, (R) diastereoselectivity was more favor-
Entry
Conditions
Catalyst Solvent Temp.
Yield
de[a]
Time
1
2
3
4
ZnCl2
ZnCl2
ZnCl2
DME
iPr2O
THF
0 °C
12 h 80% 46% (R)
room temp. 12 h 65% 33% (R)
0 °C
12 h 90% 43% (R)
24 h 72% 24% (R)
Yb(OTf)3 PhMe reflux
[a]
Determined by 1H NMR analysis of the crude reaction mixture.
The major diastereomer is indicated in the parentheses. All reac-
tions were performed once only and the de values are approximate. able over (S) diastereoselectivity.
Figure 4. X-ray crystal structure of 8a
Eur. J. Org. Chem. 2003, 82Ϫ91
85

K.-F. Chan, H. N. C. Wong
FULL PAPER
could be determined directly from a crude diastereomeric
mixture through 1H NMR analysis. For compounds 10aϪb,
their conversion into the known silyl ethers 4 proceeded
smoothly and the chiral center could be confirmed
(Scheme 2). For compounds 11aϪb, their conversion into
silyl ethers 12 proceeded smoothly to furnish 12a and 12b,
which were chromatographically still not separable. Fortu-
nately, the major diastereomer 12b could be selectively crys-
tallized from a diastereomeric mixture. The newly created
chiral center of the major diastereomer 12b was then
studied by X-ray crystallographic analysis and confirmed
to be of (R) configuration (Figure 6).[19] In this way, the
diastereoselectivities were indirectly determined by 1H
NMR spectroscopy. Moreover, the reaction of the cyclic li-
thium enolate 9c, which was generated from cyclohep-
tanone and LDA in anhydrous Et2O at low temperature,
furnished pure compound 13 in 55% yield and other un-
identified diastereomers in 23% yield. The two newly cre-
ated chiral centers of 13 were confirmed by X-ray crystallo-
graphic analysis (Figure 7).[19] It is noteworthy that the (R)
Figure 5. The arrow indicats the more favorable Re-face attack of
aldehyde 2
Reactions with Lithium Enolates
We also investigated the aldol reactions of furaldehyde 2
with a simple lithium enolate 9a (Table 4). Furyl alcohols
10aϪb were isolated in 68% yield with over 50% de. How-
ever, increasing the bulkiness of the nucleophile by the em-
ployment of another lithium enolate 9b resulted in lower
diastereoselectivity. The use of THF as solvent, the addition
of tetramethylethylenediamine (TMEDA) or the inverse ad-
dition all did not improve the observed diastereoselectivity.
Diastereomers 10aϪb and 11aϪb were chromatographic-
Scheme 2. i) Me3SiCl, imidazole, THF, room temp., 3 h; ii) Et2O,
ally also not separable. However, their diastereomeric ratio Ϫ78 °C to room temp., 14 h
Table 4. Aldol reactions of aldehyde 2 with lithium enolates 9
Entry
9
Conditions
Temp.
Products
Yield
de[a]
Additive
Solvent
Time
1
9a
9b
9b
9b
9b
None
None
None
TMEDA
None
THF
DME
THF
THF
THF
Ϫ78 °C to room temp.
12 h
12 h
12 h
12 h
12 h
10aϪb
11aϪb
11aϪb
11aϪb
11aϪb
68%
72%
85%
94%
78%
56% (R)
23% (R)
20% (R)
16% (R)
22% (R)
2
Ϫ60 °C to room temp.
Ϫ78 °C to room temp.
Ϫ78 °C to room temp.
Ϫ78 °C to room temp.
3[b]
4
5[c]
[a]
1
Determined by H NMR analysis of the crude reaction mixture. The major diastereomer is indicated in the parentheses. All reactions
[b]
[c]
were performed once only and the de values are approximate.
enolate 9b.
Enolate 9b was added to aldehyde 2.
Aldehyde 2 was added to
86
Eur. J. Org. Chem. 2003, 82Ϫ91

Diastereoselective Aldol Reactions of Furaldehyde
FULL PAPER
iodoalkyne afforded furyl diol 15e in low yield due to the
side reaction leading to diol 15d.
Figure 6. X-ray crystal structure of 12b
Scheme 3. i) DIBAL-H, THF, 0 °C, 2 h, 94%; ii) iodotoluene, 84%;
iii) 4-iodoacetophenone, 95%; iv) iodobenzene, 89%; v) 1-iodo-3-
phenylacetylene, 15d, 42%, 15e, 38%; vi) vinyl bromide, 75%; vii)
2-bromopropene, 70%; A: Pd(PPh3)4, Ba(OH)2, DME/H2O (4:1),
reflux, 1 h
Chiral 2,3-disubstituted furyl alcohols are able to serve
as important precursors for hydroxypyranones. Thus, for
furyl diol 15c, a selective protection of the primary alcohol
in the presence of a secondary alcohol with pivaloyl chlor-
ide (PivCl) was achieved to afford furyl alcohol 16 in high
yield. Subsequent treatment of furyl alcohol 16 with NBS
in refluxing ethyl acetate afforded hydroxypyranone 17 in
82% yield (Scheme 4).
Figure 7. X-ray crystal structure of 13
Scheme 4. i) PivCl, pyridine, room temp., 1 h, 89%; ii) NBS, EtOAc,
reflux, 4 h, 82%
diastereoselectivity was more favorable than the (S) dia-
stereoselectivity.
Conclusion
Functionalization of the C؊B bond and Rearrangement of
Furyl Alcohols
In conclusion, diastereoselective aldol reactions of vari-
For fural alcohol 6b, a direct cross coupling with an aryl ous ketene silyl acetals or lithium enolates with furaldehyde
iodide under the standard Suzuki coupling condition was 2, which has a chiral boronate group at the furan C-3 posi-
not successful to give the optically pure 2,3-disubstituted tion as auxiliary, were discussed. In all cases, (R) diastereo-
furyl alcohol. The employment of stronger bases such as selectivity was more favorable than (S) diastereoselectivity,
Ba(OH)2 also did not give the desired product. However, which can be rationalized by the steric effect on the chiral
when the ester group of compound 6b was reduced by diiso- auxiliary. Some of the resulting aldol adducts were found
butylaluminum hydride (DIBAL-H) to afford diol 14 to be chromatographically separable leading to pure dia-
(Scheme 3), a direct cross coupling with halides under stereomers. The transformation of a carbonϪboron bond of
standard Suzuki coupling conditions was now successful to chiral furyl alcohols into a carbonϪcarbon bond was
furnish optically pure 2,3-disubstituted furyl alcohols with achieved by employing palladium-catalyzed Suzuki coup-
various functionalities.[22] Suzuki coupling with aryl iodides ling with various halides to afford optically active 2,3-dis-
generally afforded furyl diols 15aϪc in high yields. Cross ubstituted furyl alcohols. Further investigations on conver-
coupling with vinyl bromides afforded furyl diols 15fϪg in sion of furyl aldehyde 2 to imine derivatives and their reac-
reasonable yields. However, Suzuki coupling with an tions are currently underway.
Eur. J. Org. Chem. 2003, 82Ϫ91
87

K.-F. Chan, H. N. C. Wong
FULL PAPER
128.4, 129.7, 141.1, 141.4, 141.6, 162.6, 169.9 ppm. MS: m/z (%) ϭ
741 (100) [M ϩ Na]ϩ. Compound 4b was isolated as a white
foam.4b: Softening range: 140Ϫ146 °C. [α]2D0 ϭ Ϫ71 (c ϭ 0.89,
acetone). 1H NMR (CDCl3): δ ϭ Ϫ0.24 (s, 9 H), 1.33 (t, J ϭ
7.2 Hz, 3 H), 2.52 (dd, J ϭ 10.5, 10.5 Hz, 1 H), 3.02 (s, 6 H), 4.19
(m, 2 H), 5.12 (dd, J ϭ 2.7, 10.5 Hz, 1 H), 5.45 (s, 2 H), 6.12 (d,
J ϭ 1.8 Hz, 1 H), 7.16Ϫ7.21 (m, 8 H), 7.27Ϫ7.40 (m, 14 H) ppm.
13C NMR (CDCl3): δ ϭ Ϫ0.7, 14.4, 43.2, 51.8, 60.1, 64.7, 77.8,
83.3, 113.7, 127.2, 127.5, 127.9, 128.4, 129.7, 141.2, 163.4,
170.3 ppm. MS: m/z (%) ϭ 741 (100) [M ϩ Na]ϩ. Crystallization
of 4b from 3% EtOAc in hexane at room temperature gave colorless
crystals, which were suitable for X-ray crystallographic analysis.
Elemental analysis was carried out on a mixture of both diastereo-
mers. C42H47BO8Si (718.71): calcd. C 70.19, H 6.59; found C 70.06,
H 6.73.
Experimental Section
General Remarks: NMR spectra were recorded with a Bruker MHz
DPX spectrometer at 300.13 MHz for H and 75.47 MHz for 13C.
1
All NMR measurements were carried out at room temperature and
the chemical shifts are reported as ppm on the delta scale downfield
from tetramethylsilane (TMS: δ ϭ 0.00 ppm) or relative to the res-
1
onance of CDCl3 (δ ϭ 7.26 ppm in the H, δ ϭ 77.0 ppm for the
central line of the triplet in the 13C modes, respectively). Coupling
constants (J) are reported in Hz. Low-resolution mass spectra were
obtained with an HP 5989B mass spectrometer by electron ioniza-
tion mode at an ionizing voltage of 70 eV or API 2000 LC/MS/MS
system and the relevant data were tabulated as m/z. Optical rotation
measurements were recorded with a PerkinϪElmer 341 Polari-
meter. Melting points were measured using an Electrothermal
IA9100 digital melting point apparatus and are uncorrected. Ele-
mental analyses were performed at the Shanghai Institute of Or-
ganic Chemistry, The Chinese Academy of Sciences, China or at
MEDAC Ltd, Department of Chemistry, Brunel University, Ux-
bridge, U.K. X-ray crystallographic analyses were obtained by
SHELXTL PLUS (PC version) with a P4 X-ray four-circle dif-
fractometer or a Bruker CCD Area Detector. The plates used for
thin-layer chromatography (TLC) were E. Merck silica gel 60F254
(0.25-mm thickness) precoated on an aluminum plate and they
were visualized under both long (365-nm) and short (254-nm) UV
light. Compounds on TLC plates were visualized with a spray of
5% (w/v) dodecamolybdophosphoric acid in ethanol, or with acidi-
fied potassium permanganate solution, and with subsequent heat-
ing. Chromatography purifications were carried out using E. Merck
silica gel 60 (230Ϫ400 mesh) or Qingdao Haiyang silica gel
(300Ϫ400 mesh). All reactions involving moisture-sensitive com-
pounds were performed in flame-dried apparatus under nitrogen
introduced by alternately evacuating and filling the reaction vessel
3 times with dried nitrogen.
(1ЈS,4R,5R)-5a and (1ЈR,4R,5R)-5b: Table 2, Entry 1. These com-
pounds were prepared from aldehyde 2 (78 mg, 0.14 mmol), ketene
silyl acetal 3b (105 mg, 0.56 mmol), La(OTf)3 (16 mg) and DME
(15 mL) at refluxing temperature according to the General Proced-
ure 1 described above. Purification by column chromatography on
silica gel (30 g, 5% EtOAc in hexane) afforded the diastereomeric
mixture of 5a and 5b (79 mg) in 76% yield with 46% de as a white
1
foam. H NMR (CDCl3): δ ϭ Ϫ0.33 (s, 9 H), 0.47 (s, 3 H), 0.97
(s, 3 H), 1.26 (t, J ϭ 7.2 Hz, 3 H), 2.99 (s, 6 H), 4.05Ϫ4.21 (m, 2
H), 5.02 (s, 1 H), 5.43 (s, 2 H), 6.26 (d, J ϭ 1.8 Hz, 1 H), 7.18Ϫ7.20
(m, 6 H), 7.25Ϫ7.39 (m, 15 H) ppm. 13C NMR (CDCl3): δ ϭ Ϫ0.9,
14.4, 18.5, 23.7, 48.9, 51.9, 60.2, 72.5, 78.1, 83.4, 114.1, 127.3,
127.4, 127.8, 128.5, 129.7, 141.3, 141.4, 141.6, 161.1, 176.3 ppm.
MS: m/z (%) ϭ 769 (100) [M ϩ Na]ϩ. C44H51BO8Si (746.77): calcd.
C 70.77, H 6.88; found C 70.56, H 7.01.
(1ЈS,4R,5R)-6a and (1ЈR,4R,5R)-6b: 1  HCl (10 mL) was added
dropwise to a well-stirred solution of a diastereomeric mixture of
5a and 5b (150 mg, 0.20 mmol) in THF (20 mL) at room temp. The
resulting mixture was stirred for 15 min at that temperature and
was quenched by addition of saturated NaHCO3 (30 mL). Extrac-
tion with CH2Cl2 (15 mL ϫ 3), drying with MgSO4, filtration and
evaporation of the solvent under reduced pressure gave the crude
reaction mixture. Purification by flash column chromatography on
silica gel (60 g, 10% EtOAc in hexane) afforded the diastereomeric
mixture of 6a and 6b (93 mg, 98%). Further purification by flash
column chromatography on silica gel (60 g, 5% EtOAc in hexane)
afforded diastereomerically pure 6a first and then 6b. Compound
6a was isolated as a white foam. 6a: Softening range: 62Ϫ68 °C.
General Procedure 1 for the Lewis Acid Catalyzed Mukaiyama Aldol
Reaction of Furaldehyde 2 with Various Ketene Silyl Acetals: A
Lewis acid catalyst was added to a well-stirred solution of aldehyde
2 and ketene silyl acetal in a specified solvent at a specified temper-
ature. The mixture was then stirred until all the starting material
was consumed. If ZnCl2 was employed as the Lewis acid, saturated
NaHCO3 was then added to quench the reaction. If another Lewis
acid was employed, H2O was added. The mixture was then ex-
tracted with CH2Cl2 (15 mL ϫ 3). The combined extracts were
dried with MgSO4. Filtration and evaporation of the solvent gave
the crude residue, which was then purified by column chromato-
graphy on silica gel to afford the desired compound.
1
[α]2D0 ϭ Ϫ67 (c ϭ 1.15, acetone). H NMR (CDCl3): δ ϭ 0.82 (s, 3
H), 0.85 (s, 3 H), 1.24 (t, J ϭ 7.2 Hz, 3 H), 3.00 (s, 6 H), 3.58 (d,
J ϭ 10.2 Hz, 1 H), 4.11Ϫ4.16 (m, 2 H), 4.67 (d, J ϭ 9.9 Hz, 1 H),
(1ЈS,4R,5R)-4a and (1ЈR,4R,5R)-4b: Table 1, Entry 1. This reaction
was performed from aldehyde 2 (100 mg, 0.18 mmol), ketene silyl 5.45 (s, 2 H), 6.17 (d, J ϭ 1.5 Hz, 1 H), 7.16Ϫ7.35 (m, 21 H) ppm.
acetal 3a (115 mg, 0.72 mmol), La(OTf)3 (21 mg) and DME 13C NMR (CDCl3): δ ϭ 14.1, 19.8, 22.2, 47.4, 51.9, 60.6, 73.3,
(15 mL) at room temp. according to the General Procedure 1 de-
scribed above. Purification by column chromatography on silica gel
78.2, 83.4, 114.0, 127.4, 127.7, 127.9, 128.4, 129.6, 140.8, 140.9,
141.0, 162.5, 176.5 ppm. MS: m/z (%) ϭ 697 (100) [M ϩ Na]ϩ.
(40 g, 5% EtOAc in hexane) afforded compounds 4 (118 mg) in Compound 6b was also isolated as a white foam. 6b: Softening
92% yield with 50% de (R). Further purification by flash column
chromatography on silica gel (40 g, 3% EtOAc in hexane) afforded
diastereomerically pure 4a first and then 4b. Compound 4a was
range: 53Ϫ58 °C. [α]2D0 ϭ Ϫ64 (c ϭ 3.67, acetone). 1H NMR
(CDCl3): δ ϭ 0.79 (s, 3 H), 1.00 (s, 3 H), 1.27 (t, J ϭ 7.2 Hz, 3 H),
3.03 (s, 6 H), 3.68 (d, J ϭ 9.0 Hz, 1 H), 4.18 (q, J ϭ 7.2 Hz, 2 H),
4.66 (d, J ϭ 9.0 Hz, 1 H), 5.46 (s, 2 H), 6.19 (d, J ϭ 1.8 Hz, 1 H),
isolated as a white foam. 4a: Softening range: 70Ϫ76 °C. [α]2D0
ϭ
1
Ϫ51 (c ϭ 1.23, acetone). H NMR (CDCl3): δ ϭ Ϫ0.18 (s, 9 H), 7.18Ϫ7.38 (m, 21 H) ppm. 13C NMR (CDCl3): δ ϭ 14.0, 20.7, 23.8,
1.02 (t, J ϭ 7.2 Hz, 3 H), 2.78 (dd, J ϭ 10.5, 10.8 Hz, 1 H), 3.04
(s, 6 H), 3.90 (q, J ϭ 7.2 Hz, 2 H), 5.16 (dd, J ϭ 3.0, 10.6 Hz, 1
46.3, 51.8, 60.8, 72.5, 77.7, 83.3, 113.5, 127.3, 127.6, 127.8, 128.4,
129.6, 141.1, 141.3, 161.8, 177.1 ppm. MS: m/z (%) ϭ 697 (100) [M
H), 5.49 (s, 2 H), 6.17 (d, J ϭ 1.8 Hz, 1 H), 7.16Ϫ7.22 (m, 8 H), ϩ Na]ϩ. Elemental analysis was carried out on a mixture of both
7.28Ϫ7.41 (m, 14 H) ppm. 13C NMR (CDCl3): δ ϭ Ϫ0.4, 14.2,
diastereomers. C41H43BO8 (674.59): calcd. C 73.00, H 6.42; found
42.8, 51.9, 60.0, 64.2, 77.6, 83.4, 114.0, 127.2, 127.4, 127.5, 127.8, C 72.90, H 6.50.
88
Eur. J. Org. Chem. 2003, 82Ϫ91

Diastereoselective Aldol Reactions of Furaldehyde
FULL PAPER
(1ЈR,4R,5R)-7: Acetic anhydride (0.1 mL, 1.1 mmol) was added to
a well-stirred solution of 6b (95 mg, 0.14 mmol) in pyridine (5 mL).
The mixture was heated to reflux for 2 h. When TLC showed con-
sumption of all starting material, the reaction was quenched by
adding 3  HCl (20 mL). Extraction with CH2Cl2 (10 mL ϫ 3),
extracted with CH2Cl2 (10 mL ϫ 3), dried with MgSO4, and fil-
tered to give a crude mixture. Purification by flash column chroma-
tography on silica gel (50 g, 15% EtOAc in hexane) afforded the
inseparable diastereomeric mixture of 10a and 10b (80 mg, 68%) as
1
a white foam with 56% de (R). H NMR (CDCl3, major diastere-
washing with saturated NaHCO3, drying with MgSO4, filtration omer 10b): δ ϭ 1.28 (t, J ϭ 6.9 Hz, 3 H), 2.37Ϫ2.44 (m, 1 H),
and evaporation of the solvent under reduced pressure gave the
crude reaction mixture. Purification by flash column chromato-
graphy on silica gel (50 g, 5% EtOAc in hexane) afforded the de-
sired compound 7 (83 mg, 82%) as a white solid. M.p. 164Ϫ165
2.55Ϫ2.67 (m, 1 H), 3.00 (s, 6 H), 3.08 (d, J ϭ 5.7 Hz, 1 H),
4.09Ϫ4.21 (m, 2 H), 4.90Ϫ4.97 (m, 1 H), 5.45 (s, 2 H), 6.17 (d, J ϭ
1.5 Hz, 1 H), 7.16Ϫ7.38 (m, 21 H) ppm; (minor diastereomer 10a):
δ ϭ 1.21 (t, J ϭ 7.2 Hz, 3 H), 2.37Ϫ2.44 (m, 1 H), 2.55Ϫ2.67 (m,
1 H), 2.95 (d, J ϭ 7.2 Hz, 1 H), 3.01 (s, 6 H), 4.09Ϫ4.21 (m, 2 H),
1
°C. [α]2D0 ϭ Ϫ49 (c ϭ 1.40, CHCl3). H NMR (CDCl3): δ ϭ 0.56
(s, 3 H), 1.02 (s, 3 H), 1.08 (t, J ϭ 7.2 Hz, 3 H), 1.91 (s, 3 H), 3.04 4.90Ϫ4.97 (m, 1 H), 5.48 (s, 2 H), 6.17 (d, J ϭ 1.5 Hz, 1 H),
(s, 6 H), 3.92Ϫ4.00 (m, 1 H), 4.14Ϫ4.25 (m, 1 H), 5.46 (s, 2 H),
7.16Ϫ7.38 (m, 21 H) ppm. 13C NMR (CDCl3): δ ϭ 14.1, 14.2, 40.2,
5.90 (s, 1 H), 6.23 (d, J ϭ 1.8 Hz, 1 H), 7.17Ϫ7.22 (m, 7 H), 41.0, 44.9, 51.9, 60.5, 64.1, 64.6, 78.1, 83.4, 114.0, 127.4, 127.6,
7.26Ϫ7.43 (m, 14 H) ppm. 13C NMR (CDCl3): δ ϭ 14.1, 19.5, 20.6, 127.9, 128.4, 129.5, 140.9, 141.0, 141.0, 163.3, 171.4 ppm. MS:
23.3, 29.7, 46.8, 51.8, 60.4, 72.9, 77.8, 83.3, 114.2, 127.2, 127.3,
m/z (%) ϭ 669 (100) [M ϩ Na]ϩ. C39H39BO8 (646.53): calcd. C
127.4, 127.8, 128.5, 129.7, 141.0, 141.5, 141.7, 157.0, 168.6, 72.45, H 6.08; found C 72.46, H 5.94.
175.3 ppm. MS: m/z (%) ϭ 686 (34) [MH Ϫ Et]ϩ, 740 (6) [MH ϩ
(1ЈS,4R,5R)-11a and (1ЈR,4R,5R)-11b: Table 4, Entry 2. This reac-
Na]ϩ. C43H45BO9 (716.62): calcd. C 72.07, H 6.33; found C 72.14,
H 6.57. Crystallization of 7 from 5% EtOAc in hexane at room
temperature gave colorless crystals, which were sufficient for X-ray
crystallographic analysis.
tion was carried out with 2 (200 mg, 0.36 mmol), enolate 9b (0.5 m
in DME, 2.9 mL, 1.45 mmol) and anhydrous DME (20 mL) ac-
cording to the procedure described above for the preparation of
compounds 10. Purification by flash column chromatography on
silica gel (80 g, 15% EtOAc in hexane) afforded the diastereomeric
mixture of 11a and 11b (175 mg, 72%) with 23% de (R). The dias-
tereomeric mixture of 11a and 11b was isolated as a white foam. 1H
NMR (CDCl3, major diastereomer 11b): δ ϭ 1.45 (d, J ϭ 3.3 Hz, 1
H), 1.48 (s, 9 H), 2.28Ϫ2.34 (m, 1 H), 2.47Ϫ2.55 (m, 1 H), 3.01 (s,
6 H), 4.86Ϫ4.93 (m, 1 H), 5.45 (s, 2 H), 6.17 (d, J ϭ 1.5 Hz, 1 H),
7.16Ϫ7.38 (m, 21 H) ppm; (minor diastereomer 11a): δ ϭ 1.41 (s,
9 H), 1.45 (d, J ϭ 3.3 Hz, 1 H), 2.28Ϫ2.34 (m, 1 H), 2.47Ϫ2.55
(m, 1 H), 3.02 (s, 6 H), 4.86Ϫ4.93 (m, 1 H), 5.49 (s, 2 H), 6.17 (d,
J ϭ 1.5 Hz, 1 H), 7.16Ϫ7.38 (m, 21 H) ppm. 13C NMR (CDCl3):
δ ϭ 28.0, 28.1, 41.2, 42.3, 51.9, 64.2, 64.8, 78.1, 80.6, 80.8, 83.4,
113.9, 114.1, 127.4, 127.4, 127.6, 127.7, 127.8, 127.9, 127.9, 128.2,
128.4, 129.5, 140.7, 140.8, 140.9, 141.1, 163.5, 164.6, 170.1,
170.8 ppm. MS: m/z (%) ϭ 197 (34) [Ph2COMeϩ], 697 (59) [M ϩ
Na]ϩ. C41H43BO8 (674.59): calcd. C 73.00, H 6.42; found C 72.91,
H 6.50.
(1ЈS,4R,5R)-8a and (1ЈR,4R,5R)-8b: Table 3, Entry 1. These com-
pounds were prepared from aldehyde 2 (91 mg, 0.16 mmol), ketene
silyl acetal 3c (149 mg, 0.65 mmol), ZnCl2 (5 mg) and DME
(15 mL) at 0 °C according to the General Procedure 1 described
above. Purification by column chromatography on silica gel (30 g,
10% EtOAc in hexane) afforded compounds 8a and 8b (93 mg) in
80% yield with 46% de (R). Further purification by column chro-
matography on silica gel (30 g, 5% EtOAc in hexane) afforded dia-
stereomerically pure 8a first and then 8b. Compound 8a was isol-
ated as a white solid. 8a: M.p. 172Ϫ173 °C. [α]2D0 ϭ Ϫ71 (c ϭ 1.40,
acetone). 1H NMR (CDCl3): δ ϭ 0.75Ϫ1.08 (m, 3 H), 1.23 (t, J ϭ
7.2 Hz, 3 H), 1.27Ϫ1.32 (m, 3 H), 1.49Ϫ1.52 (m, 2 H), 1.61Ϫ1.66
(m, 1 H), 1.87Ϫ1.91 (m, 1 H), 3.00 (s, 6 H), 3.56 (d, J ϭ 11.1 Hz,
1 H), 4.07Ϫ4.17 (m, 2 H), 4.39 (d, J ϭ 11.1 Hz, 1 H), 5.44 (s, 2
H), 6.17 (d, J ϭ 1.8 Hz, 1 H), 7.14 (d, J ϭ 1.5 Hz, 1 H), 7.18Ϫ7.25
(m, 6 H), 7.28Ϫ7.36 (m, 14 H) ppm. 13C NMR (CDCl3): δ ϭ 14.1,
22.8, 23.2, 25.6, 26.9, 29.1, 30.8, 51.9, 52.4, 60.5, 74.6, 78.3, 83.4,
114.1, 127.4, 127.6, 127.9, 128.4, 129.6, 140.8, 141.1, 162.2,
174.8 ppm. MS: m/z (%) ϭ 197 (100) [Ph2COMeϩ], 697 (Ͻ 1) [M
Ϫ OH]ϩ. Crystallization of 8a from 5% EtOAc in hexane at room
temperature gave colorless crystals, which were sufficient for X-ray
crystallographic analysis. Compound 8b was isolated as a white
foam. 8b: Softening range: 72Ϫ81 °C. [α]2D0 ϭ Ϫ27 (c ϭ 1.20, acet-
(1ЈS,4R,5R)-4a and (1ЈR,4R,5R)-4b: Me3SiCl (0.1 mL, 0.80 mmol)
was added to a well-stirred solution of 10 (70 mg, 0.11 mmol), im-
idazole (29 mg, 0.43 mmol) in THF (10 mL) at room temp. The
reaction mixture turned milky immediately. The mixture was stirred
for a further 3 h. Saturated NaHCO3 solution (20 mL) was added
to quench the reaction. Extraction with CH2Cl2 (10 mL ϫ 3), dry-
ing with MgSO4, and filtration gave crude colorless oil. Purification
by flash column chromatography on silica gel (50 g, 5% EtOAc in
hexane) afforded a diastereomeric mixture of 4a and 4b (73 mg,
94%), whose physical and spectrometric data are identical with
those reported previously.
1
one). H NMR (CDCl3): δ ϭ 0.70Ϫ0.77 (m, 1 H), 1.12Ϫ1.43 (m,
6 H), 1.25 (t, J ϭ 7.2 Hz, 3 H), 1.52Ϫ1.54 (m, 2 H), 2.01Ϫ2.04 (m,
1 H), 3.03 (s, 6 H), 3.52 (d, J ϭ 10.5 Hz, 1 H), 4.12Ϫ4.23 (m, 2
H), 4.55 (d, J ϭ 10.5 Hz, 1 H), 5.45 (s, 2 H), 6.17 (d, J ϭ 1.8 Hz,
1 H), 7.13 (d, J ϭ 1.8 Hz, 1 H), 7.18Ϫ7.20 (m, 5 H), 7.29Ϫ7.40
(m, 15 H) ppm. 13C NMR (CDCl3): δ ϭ 14.0, 22.1, 22.8, 25.9, 26.9,
29.3, 32.7, 50.5, 51.8, 60.7, 72.1, 77.6, 83.3, 113.6, 127.3, 127.6,
127.8, 128.4, 129.6, 140.9, 141.2, 141.3, 161.7, 175.8 ppm. MS:
m/z (%) ϭ 197 (100) [Ph2COMeϩ], 697 (Ͻ 1) [M Ϫ OH]ϩ. Ele-
mental analysis was carried out on a mixture of both diastereomers.
C44H47BO6 (714.65): calcd. C 73.95, H 6.63; found C 73.83, H 6.89.
(1ЈR,4R,5R)-12b: This compound was prepared from a diastereom-
eric mixture of 11 (150 mg, 0.22 mmol), imidazole (60 mg,
0.88 mmol), Me3SiCl (0.2 mL, 1.59 mmol) and THF (20 mL) ac-
cording to the procedure described above for the synthesis of 4.
Purification by flash column chromatography on silica gel (70 g,
5% EtOAc in hexane) afforded the diastereomeric mixture of 12a
and 12b (159 mg, 96%). The major diastereomer 12b (28 mg) was
crystallized from 3% EtOAc in hexane and was isolated as colorless
(1ЈS,4R,5R)-10a and (1ЈR,4R,5R)-10b: Table 4, Entry 1. Freshly
prepared enolate 9a (0.5 m in THF, 1.5 mL, 0.75 mmol) was added crystals. 12b: M.p. 207Ϫ208 °C. [α]2D0 ϭ Ϫ69 (c ϭ 0.55, CHCl3).
to a well-stirred solution of 2 (102 mg, 0.18 mmol) in anhydrous
THF (10 mL) at Ϫ78 °C under N2. The mixture was then stirred 2.7, 14.9 Hz, 1 H), 2.44 (dd, J ϭ 10.5, 14.9 Hz, 1 H), 3.02 (s, 6 H),
for 12 h from Ϫ78 °C to room temp. and the reaction was quenched 5.05 (dd, J ϭ 2.7, 10.6 Hz, 1 H), 5.45 (s, 2 H), 6.09 (d, J ϭ 1.8 Hz,
by addition of saturated NH4Cl (30 mL). The resulting mixture was 1 H), 7.16Ϫ7.21 (m, 7 H), 7.25Ϫ7.40 (m, 14 H) ppm. 13C NMR
1H NMR (CDCl3): δ ϭ Ϫ0.25 (s, 9 H), 1.52 (s, 9 H), 1.82 (dd, J ϭ
Eur. J. Org. Chem. 2003, 82Ϫ91
89

K.-F. Chan, H. N. C. Wong
FULL PAPER
(CDCl3): δ ϭ Ϫ0.6, 28.2, 44.3, 51.8, 64.9, 79.8, 83.3, 113.7, 127.2, Ba(OH)2 (0.5 g) and 20% H2O in DME as solvent (10 mL) accord-
127.5, 127.9, 128.4, 129.7, 141.2, 163.5, 169.5 ppm. MS: m/z (%) ϭ ing to the General Procedure 2 described above. Purification by
197 (25) [Ph2COMeϩ], 769 (64) [M ϩ Na]ϩ. C44H51BO8Si (746.77): flash column chromatography on silica gel (30 g, 20% EtOAc in
calcd. C 70.77, H 6.88; found C 71.07, H 7.12.
hexane) afforded 15a (14 mg, 84%) as a white solid: M.p. 121Ϫ123
1
°C. [α]2D0 ϭ Ϫ23 (c ϭ 0.50, CHCl3). H NMR (CDCl3): δ ϭ 0.80
(1ЈR,1ЈЈR,4R,5R)-13: This compound was prepared from
2
(s, 3 H), 0.90 (s, 3 H), 2.31 (s, 3 H), 3.37 (d, J ϭ 10.8 Hz, 1 H),
3.63 (d, J ϭ 10.8 Hz, 1 H), 4.74 (s, 1 H), 6.39 (d, J ϭ 1.8 Hz, 1 H),
7.13 (d, J ϭ 8.1 Hz, 2 H), 7.22 (d, J ϭ 8.1 Hz, 2 H), 7.36 (d, J ϭ
1.8 Hz, 1 H) (signals of two OH groups were not observed) ppm.
13C NMR (CDCl3): δ ϭ 19.2, 20.1, 21.4, 39.3, 71.2, 72.2, 110.9,
123.8, 127.3, 128.4, 129.5, 135.8, 140.5, 148.5 ppm. HRMS: calcd.
for C16H20O3 260.1412; found 260.1401.
(100 mg, 0.18 mmol), enolate 9c (0.38
m in Et2O, 1.9 mL,
0.72 mmol) and anhydrous Et2O (20 mL) according to the proced-
ure described above for synthesis of compounds 10. Purification by
flash column chromatography on silica gel (60 g, 15% EtOAc in
hexane) afforded diastereomerically pure 13 (66 mg, 55%) and
other diastereomers (28 mg, 23%). Compound 13 was isolated as a
white foam. M.p. 151Ϫ152 °C. [α]2D0 ϭ Ϫ67 (c ϭ 0.75, acetone). 1H
NMR (CDCl3): δ ϭ 0.78Ϫ0.90 (m, 1 H), 0.98Ϫ1.05 (m, 1 H),
1.14Ϫ1.32 (m, 2 H), 1.47Ϫ1.68 (m, 2 H), 1.76Ϫ1.84 (m, 2 H),
2.38Ϫ2.42 (m, 2 H), 2.86 (dt, J ϭ 3.9, 9.6 Hz, 1 H), 3.03 (s, 6 H),
4.86 (dd, J ϭ 6.0, 9.0 Hz, 1 H), 5.46 (s, 2 H), 6.20 (d, J ϭ 1.8 Hz,
1 H), 7.17Ϫ7.20 (m, 6 H), 7.23 (d, J ϭ 1.8 Hz, 1 H), 7.31Ϫ7.40
(m, 14 H) ppm. 13C NMR (CDCl3): δ ϭ 24.0, 27.3, 28.0, 28.9,
43.2, 51.8, 56.5, 68.0, 77.8, 83.3, 107.6, 113.6, 127.2, 127.3, 127.6,
127.9, 128.4, 129.6, 141.0, 141.2, 141.6, 162.3, 215.7 ppm. MS:
m/z (%) ϭ 197 (19) [Ph2COMeϩ], 693 (100) [M ϩ Na]ϩ.
C42H43BO7 (670.60): calcd. C 75.22, H 6.46; found C 75.20, H 6.53.
Crystallization of 13 from 5% EtOAc in hexane at room
temperature gave colorless crystals, which were sufficient for X-ray
crystallographic analysis.
(R)-1-[3-(4-Methoxyphenyl)-2-furyl]-2,2-dimethylpropane-1,3-diol
(15b): This compound was prepared from 14 (32 mg, 0.05 mmol),
Pd(PPh3)4 (12 mg, 0.01 mmol), p-iodoacetophenone (50 mg,
0.20 mmol), Ba(OH)2 (0.5 g) and 20% H2O in DME as solvent
(10 mL) according to the General Procedure 2 described above.
Purification by flash column chromatography on silica gel (30 g,
20% EtOAc in hexane) afforded 15b (14 mg, 95%) as a white solid:
M.p. 132Ϫ135 °C. [α]2D0 ϭ Ϫ28 (c ϭ 0.45, CHCl3). 1H NMR
(CDCl3): δ ϭ 0.84 (s, 3 H), 0.95 (s, 3 H), 2.51 (br, 1 H), 2.61 (s, 3
H), 3.44 (d, J ϭ 10.5 Hz, 1 H), 3.55 (d, J ϭ 5.4 Hz, 1 H), 3.72 (d,
J ϭ 10.8 Hz, 1 H), 4.82 (d, J ϭ 5.4 Hz, 1 H), 6.51 (d, J ϭ 1.8 Hz,
1 H), 7.47 (d, J ϭ 1.8 Hz, 1 H), 7.51 (d, J ϭ 8.4 Hz, 2 H), 7.98 (d,
J ϭ 8.4 Hz, 2 H) ppm. 13C NMR (CDCl3): δ ϭ 20.0, 22.4, 26.6,
40.3, 72.1, 73.2, 111.4, 123.9, 128.5, 128.8, 135.6, 138.6, 141.9,
150.7, 197.8 ppm. HRMS: calcd. for C17H20O4288.1362; found
288.1357.
(1ЈR,4R,5R)-14: Diisobutylaluminum hydride (DIBAL-H, 1  in
PhMe, 1.2 mL, 1.20 mmol) was added dropwise to a well-stirred
solution of 6b (190 mg, 0.28 mmol) in anhydrous THF (20 mL) at
0 °C under N2. The mixture was then stirred for 2 h at 0 °C; Et2O
(60 mL) was then added to the reaction mixture. Saturated aq.
NH4Cl (2 mL) and H2O (1 mL) were added until a heavy white
precipitate was formed. The precipitate was removed by filtration
and the filtrate was dried with MgSO4. The crude reaction mixture
was then subjected to column chromatography on silica gel (60 g,
25% EtOAc in hexane) to give diol 14 (167 mg, 94%) as a white
foam. Softening range: 75Ϫ88 °C. [α]2D0 ϭ Ϫ53 (c ϭ 1.17, acetone).
1H NMR (CDCl3): δ ϭ 0.64 (s, 3 H), 0.73 (s, 3 H), 2.28 (br, 1 H),
2.67 (d, J ϭ 6.9 Hz, 1 H), 3.02 (s, 6 H), 3.11 (dd, J ϭ 4.5, 11.4 Hz,
1 H), 3.31 (dd, J ϭ 6.9, 11.1 Hz, 1 H), 4.58 (d, J ϭ 6.6 Hz, 1 H),
5.46 (s, 2 H), 6.22 (d, J ϭ 1.8 Hz, 1 H), 7.17Ϫ7.20 (m, 6 H), 7.24
(d, J ϭ 1.8 Hz, 1 H), 7.31Ϫ7.39 (m, 14 H) ppm. 13C NMR
(CDCl3): δ ϭ 20.3, 21.2, 40.1, 51.9, 71.4, 73.8, 77.8, 83.3, 113.6,
127.3, 127.7, 127.9, 128.3, 129.6, 140.9, 141.2, 141.5, 162.6 ppm.
MS: m/z (%) ϭ 197 (100) [Ph2COMeϩ], 655 (34) [M ϩ Na]ϩ.
C39H41BO7 (632.55): calcd. C 74.05, H 6.53; found C 74.03, H 6.77.
(R)-1-[3-(1,1Ј-Biphenyl-4-yl)-2-furyl]-2,2-dimethylpropane-1,3-diol
(15c): This compound was prepared from 14 (52 mg, 0.08 mmol),
Pd(PPh3)4 (12 mg, 0.01 mmol), iodobenzene (67 mg, 0.33 mmol),
Ba(OH)2 (0.5 g) and 20% H2O in DME as solvent (15 mL) accord-
ing to the General Procedure 2 described above. Purification by
flash column chromatography on silica gel (30 g, 20% EtOAc in
hexane) afforded 15c (18 mg, 89%) as a white solid: mp: 111Ϫ113
1
°C. [α]2D0 ϭ Ϫ16 (c ϭ 2.10, CHCl3). H NMR (CDCl3): δ ϭ 0.87
(s, 3 H), 0.97 (s, 3 H), 2.37 (dd, J ϭ 4.8, 5.1 Hz, 1 H), 3.17 (d, J ϭ
5.7 Hz, 1 H), 3.45 (dd, J ϭ 3.6, 10.8 Hz, 1 H), 3.71 (dd, J ϭ 5.1,
10.5 Hz, 1 H), 4.81 (d, J ϭ 5.4 Hz, 1 H), 6.48 (d, J ϭ 1.8 Hz, 1 H),
7.29Ϫ7.41 (m, 5 H), 7.44 (d, J ϭ 1.8 Hz, 1 H) ppm. 13C NMR
(CDCl3): δ ϭ 20.1, 22.4, 40.3, 72.2, 73.2, 111.8, 124.9, 127.1, 128.5,
128.7, 133.5, 141.6, 149.8 ppm. HRMS: calcd. for C15H18O3
246.1256; found 246.1227.
(R)-1-(2-Furyl)-2,2-dimethylpropane-1,3-diol (15d) and (R)-2,2-Di-
methyl-1-{3-[4-(phenylethynyl)phenyl]-2-furyl}propane-1,3-diol
(15e): This compound was prepared from 14 (62 mg, 0.10 mmol),
Pd(PPh3)4 (12 mg, 0.01 mmol), 1-iodo-3-phenylacetylene (89 mg,
0.41 mmol), Ba(OH)2 (0.5 g) and 20% H2O in DME as solvent
(10 mL) according to the General Procedure 2 described above.
Purification by flash column chromatography on silica gel (30 g,
20% EtOAc in hexane) afforded 15e (10 mg, 38%) first and then
15d (7 mg, 42%). Compound 15e was isolated as a colorless oil.
General Procedure 2 for the Palladium-Catalyzed Suzuki Coupling
Reaction of Chiral Furylboronate with Various Halides: A base was
added at once to a well-stirred solution containing chiral furyl-
boronate, Pd(PPh3)4 and halide in the solvent mentioned, under
nitrogen at room temp. The resulting mixture was heated to reflux
for 2 h and was poured into cold water. The mixture was then ex-
tracted with Et2O (10 mL ϫ 3). The combined extracts were dried
with MgSO4. Filtration and evaporation of the solvent gave the
crude residue, which was then purified by column chromatography
on silica gel to afford the desired compound. As chiral furyl alco-
hols are very sensitive to acidic conditions, Et3N (1% v/v) must be
added to the eluent used for chromatography in order to minim-
ize racemization.
1
15e: [α]2D0 ϭ Ϫ25 (c ϭ 0.15, CHCl3). H NMR (CDCl3): δ ϭ 1.00
(s, 3 H), 1.02 (s, 3 H), 2.45 (br, 1 H), 3.24 (d, J ϭ 5.4 Hz, 1 H),
3.52 (d, J ϭ 11.1 Hz, 1 H), 3.69 (d, J ϭ 10.8 Hz, 1 H), 4.92 (d, J ϭ
4.8 Hz, 1 H), 6.48 (d, J ϭ 2.1 Hz, 1 H), 7.32Ϫ7.35 (m, 3 H), 7.37
(d, J ϭ 1.8 Hz, 1 H), 7.46Ϫ7.49 (m, 2 H) ppm. 13C NMR (CDCl3):
δ ϭ 20.0, 22.0, 40.6, 71.6, 74.5, 80.6, 93.1, 105.6, 112.7, 123.0,
128.3, 128.4, 131.3, 141.7, 157.5 ppm. HRMS: calcd. for C17H18O3
270.1256; found 270.1238. Compound 15d was also isolated as a
colorless oil. 15d: [α]2D0 ϭ ϩ20 (c ϭ 0.80, CHCl3). 1H NMR
(R)-2,2-Dimethyl-1-[3-(4-methylphenyl)-2-furyl]propane-1,3-diol
(15a): This compound was prepared from 14 (40 mg, 0.06 mmol),
Pd(PPh3)4 (12 mg, 0.01 mmol), p-iodotoluene (55 mg, 0.25 mmol), (CDCl3): δ ϭ 0.93 (s, 6 H), 2.44 (br, 1 H), 3.02 (d, J ϭ 4.2 Hz, 1
90 Eur. J. Org. Chem. 2003, 82Ϫ91

Diastereoselective Aldol Reactions of Furaldehyde
H), 3.49 (d, J ϭ 10.8 Hz, 1 H), 3.63 (d, J ϭ 10.8 Hz, 1 H), 4.65 (d, with MgSO4 and filtration furnished a crude reaction mixture,
FULL PAPER
J ϭ 3.3 Hz, 1 H), 6.27 (d, J ϭ 3.0 Hz, 1 H), 6.36 (dd, J ϭ 1.8,
which was subjected to column chromatography on silica gel (30 g,
3.3 Hz, 1 H), 7.38 (dd, J ϭ 0.9, 1.8 Hz, 1 H) ppm. 13C NMR 15% EtOAc in hexane) to give compound 17 (19 mg, 82%) as a
1
(CDCl3): δ ϭ 19.5, 22.1, 39.5, 71.7, 75.8, 107.5, 110.1, 141.7, colorless oil. H NMR (CDCl3): δ ϭ 0.85 (s, 3 H), 1.08 (s, 3 H),
155.1 ppm. HRMS: calcd. for C9H14O3 170.0943; found 170.0925.
1.10 (s, 9 H), 2.61 (d, J ϭ 6.9 Hz, 1 H), 3.71 (d, J ϭ 11.1 Hz, 1 H),
4.18 (d, J ϭ 11.1 Hz, 1 H), 4.65 (d, J ϭ 6.9 Hz, 1 H), 6.40 (s, 1 H),
7.30Ϫ7.38 (m, 5 H) (signals of OH groups were not observed) ppm.
13C NMR (CDCl3): δ ϭ 19.8, 21.7, 27.1, 38.8, 40.0, 69.2, 70.2,
113.1, 121.6, 127.6, 127.7, 128.3, 128.7, 132.3, 151.5, 178.6 ppm.
HRMS: calcd. for C20H26O5 346.1780; found 346.1765.
(R)-2,2-Dimethyl-1-(3-vinyl-2-furyl)propane-1,3-diol (15f): This
compound was prepared from 14 (39 mg, 0.06 mmol), Pd(PPh3)4
(12 mg, 0.01 mmol), vinyl bromide (42 mg, 0.39 mmol), Ba(OH)2
(0.5 g) and 20% H2O in DME as solvent (10 mL) according to the
General Procedure 2 described above. Purification by flash column
chromatography on silica gel (30 g, 20% EtOAc in hexane) afforded
15f (9 mg, 75%) as a colorless oil: [α]2D0 ϭ Ϫ24 (c ϭ 0.35, CHCl3).
1H NMR (CDCl3): δ ϭ 0.92 (s, 3 H), 0.95 (s, 3 H), 2.36 (br, 1 H),
3.01 (d, J ϭ 4.8 Hz, 1 H), 3.49 (d, J ϭ 12.0 Hz, 1 H), 3.67 (d, J ϭ
10.8 Hz, 1 H), 4.77 (d, J ϭ 4.5 Hz, 1 H), 5.16 (dd, J ϭ 1.5, 10.8 Hz,
1 H), 5.45 (dd, J ϭ 1.5, 17.4 Hz, 1 H), 6.54 (d, J ϭ 2.1 Hz, 1 H),
6.65 (dd, J ϭ 10.8, 17.4 Hz, 1 H), 7.33 (d, J ϭ 1.8 Hz, 1 H) ppm.
13C NMR (CDCl3): δ ϭ 19.9, 22.1, 40.4, 71.8, 73.7, 107.6, 111.8,
113.8, 126.4, 141.9, 150.6 ppm. HRMS: calcd. for C11H16O3
196.1099; found 196.1087.
Acknowledgments
The work described in this paper was fully supported by an Ear-
marked Grant from the Research Grants Council of the Hong
Kong SAR, China (Project CUHK 4178/97P) and a Direct Grant
(A/C No. 2060186) administered by the Chinese University of
Hong Kong. We also thank Prof. T. C. W. Mak, Miss H.-W. Li and
Mr. Z.-Y. Zhou for carrying out all X-ray crystallographic analyses.
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1
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H), 0.98 (s, 3 H), 2.02 (dd, J ϭ 0.9, 1.2 Hz, 3 H), 2.45 (br, 1 H),
2.98 (d, J ϭ 5.7 Hz, 1 H), 3.48 (d, J ϭ 10.5 Hz, 1 H), 3.72 (d, J ϭ
10.8 Hz, 1 H), 4.86 (d, J ϭ 5.1 Hz, 1 H), 5.06 (dd, J ϭ 0.9, 2.4 Hz,
1 H), 5.08 (dd, J ϭ 1.5, 3.3 Hz, 1 H), 6.34 (d, J ϭ 1.8 Hz, 1 H),
7.34 (d, J ϭ 2.1 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 20.1, 22.5,
23.7, 40.2, 72.1, 73.0, 110.5, 114.6, 125.7, 136.6, 141.2, 149.3 ppm.
HRMS: calcd. for C12H18O3 210.1256; found 210.1227.
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[9]
[10]
(R)-3-Hydroxy-2,2-dimethyl-3-(3-phenyl-2-furyl)propyl
Pivalate
(16): Pivaloyl chloride (0.05 mL, 0.41 mmol) was added to a well-
stirred solution of diol 15c (20 mg, 0.08 mmol) in anhydrous pyrid-
ine (3 mL) at room temp. under N2. The mixture was then stirred
for 1 h. The reaction was then quenched by adding 1  HCl
(20 mL). Extraction with CH2Cl2 (5 mL ϫ 3), washing with
NaHCO3, drying with MgSO4 and filtration furnished a crude re-
action mixture, which was subjected to column chromatography on
silica gel (20 g, 20% EtOAc in hexane) to give compound 16 (24 mg,
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[12]
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Chem. Commun. 1998, 183Ϫ184.
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837Ϫ838.
[15]
89%) as a colorless oil. [α]2D0 ϭ Ϫ13 (c ϭ 0.20, CHCl3). H NMR
1
[16]
(CDCl3): δ ϭ 0.83 (s, 3 H), 1.08 (s, 3 H), 1.09 (s, 9 H), 2.64 (br, 1
H), 3.74 (d, J ϭ 10.8 Hz, 1 H), 4.19 (d, J ϭ 11.1 Hz, 1 H), 4.75 (s,
1 H), 6.48 (d, J ϭ 1.8 Hz, 1 H), 7.26Ϫ7.39 (m, 5 H), 7.42 (d, J ϭ
1.8 Hz, 1 H) ppm. 13C NMR (CDCl3): δ ϭ 19.9, 21.7, 27.1, 38.8,
40.1, 69.3, 70.2, 111.6, 125.0, 127.0, 128.4, 128.6, 133.5, 141.6,
149.4, 178.6 ppm. HRMS: calcd. for C20H26O4 330.1831; found
330.1821.
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Y. Arai, T. Masuda, Y. Masaki, Synlett 1997, 1459Ϫ1462.
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K.-F. Chan, H. N. C. Wong, Org. Lett. 2001, 3, 3991Ϫ3994.
[19]
CCDC-188529 to -188533 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033;
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T. K. Hollis, B. Bosnich, J. Am. Chem. Soc. 1995, 117,
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3-[6-Hydroxy-3-oxo-4-phenyl-3,6-dihydro-2H-pyran-2-yl]-3-methyl-
butyl Pivalate (17): N-Bromosuccinimide (NBS, 35 mg, 0.20 mmol)
was added at once to a well-stirred solution of 16 (22 mg,
0.07 mmol) in EtOAc (10 mL) at room temp. The mixture was
heated to reflux for 4 h until complete consumption of the starting
material. After cooling the reaction mixture to room temp., 20%
aq. KI solution (20 mL) was added. Washing with saturated aq.
Na2S2O3 solution, extraction with CH2Cl2 (10 mL ϫ 3), drying
[20]
[21]
R. Mahrwald, Chem. Rev. 1999, 99, 1095Ϫ1120.
The chiral auxiliary cannot be recycled after the Suzuki coup-
[22]
ling reactions. For the chiral auxiliary recovery, please see
ref.[18]
Received July 12, 2002
[O02380]
Eur. J. Org. Chem. 2003, 82Ϫ91
91