Diastereoselective addition reactions of furyl aldehydes using chiral boronates as auxiliary: Application to the enantioselective synthesis of 2,3-disubstituted furyl alcohols

Article abstract of DOI:10.1021/ol010196n

matrix presented The addition reactions of various nucleophiles to a furyl aldehyde bearing a chiral boronate at the C-3 position furnished chromatographically separable diastereomers. The R diastereoselection was more favorable when no additive was added

Full text of DOI:10.1021/ol010196n

ORGANIC
LETTERS
2001
Vol. 3, No. 25
3991-3994
Diastereoselective Addition Reactions of
Furyl Aldehydes Using Chiral Boronates
as Auxiliary: Application to the
Enantioselective Synthesis of
2,3-Disubstituted Furyl Alcohols†
Kin-Fai Chan and Henry N. C. Wong*
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
hncwong@cuhk.edu.hk
Received September 4, 2001
ABSTRACT
The addition reactions of various nucleophiles to a furyl aldehyde bearing a chiral boronate at the C-3 position furnished chromatographically
separable diastereomers. The R diastereoselection was more favorable when no additive was added. Surprisingly, when lithium alkoxides
were selected as additives, the S diastereoselection is superior instead. Further transformation of C−B bonds to C−C bonds was achieved by
using standard Suzuki coupling conditions to give optically active 2,3-disubstituted furyl alcohols.
6-Hydroxy-2H-pyran-3(6H)-one (1) contains several func-
tionalities that could allow facile introductions of other
functional groups. In this way, derivatives of 1 have become
important building blocks for the synthesis of biologically
active natural products (Figure 1).1 The easiest way to access
this type of compounds is through the oxidative rearrange-
ment of furyl alcohols by peracid.1b Conventional methods
developed for the synthesis of furyl alcohols include Sharp-
less asymmetric aminohydroxylation of vinylfuran,2a kinetic
resolution,2b enzymatic resolution of racemic 2-furyl alcohols,2c
asymmetric allylation,2d and aldol reaction2e of furyl aldehyde
† Dedicated to Professor Qi-Yi Xing of Peking University on the occasion
of his 90th birthday.
‡ An area of Excellence of the University Grants Committee (Hong
Kong).
(1) (a) Chen X.-T.; Bhattacharya, S. K.; Zhou, B.; Gutteridge, C. E.;
Pettus, T. R. R.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 6563. (b)
Takeuchi, M.; Taniguchi, T.; Ogasaware, K. Synthesis 1999, 341. (c)
Taniguchi, T.; Nakamura, K.; Ogasaware, K. Synthesis 1997, 509. (d)
Harding, M.; Nelson, A. J. Chem. Soc., Chem. Commun. 2001, 695. (e)
Taniguchi, T.; Takeuchi, M.; Kadota, K.; ElAzab, A. S.; Ogasaware, K.
Synthesis 1999, 1325.
Figure 1. Oxidative rearrangement of furfuryl alcohol and
structures of diols 2 and 3.
10.1021/ol010196n CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/17/2001

as well as asymmetric catalytic hydrogenation of furyl
ketone.2f Despite the high yield and high enantioselectivity,
all the synthesized furyl alcohols possess only C-2 substit-
uents. 2,3-Disubstituted furyl alcohols, on the other hand,
have attracted less attention.
PDC in CH2Cl2 furnished furyl aldehydes 7 without destroy-
ing the chiral boronate moiety.
From the X-ray crystallographic analysis of 7a (Figure
2a) and 7b (Figure 2b), it is evident that, compared to the
Boronic esters of (S)-pinanediol (2)3 and (2R,3R)-1,4-
dimethoxy-1,1,4,4-tetraphenyl-2,3-butanediol (3)4 (Figure 1)
have been used as efficient chiral auxiliaries in asymmetric
synthesis. Moreover, the diastereoselective aldol reactions
of chiral 3-(p-tolylsulfinyl)furfural with silyl ketene were also
reported recently.5 In connection with our interest in the
realization of highly functionalized pyranone 1, we wish to
report our employment of boronic esters as chiral auxiliaries
for the synthesis of optically pure 2,3-disubstituted furyl
alcohols.
Employing our own experience on the regiospecific
synthesis of substituted furans,6 pyrroles,7 and thiophenes,8
furyl aldehydes 7 were designed as our initial target
molecules, which in turn were synthesized from com-
mercially available 3-bromofuran (4) via the regiospecific
route as shown in Scheme 1.
Figure 2. (a) X-ray crystal structure of 7a; (b) X-ray crystal
structure of 7b with a predicted more favorable Re-face nucleophilic
attack.
diol 2 as chiral auxiliary, the bulky diol 3 with C2 symmetry
more effectively occupies the space around the carbonyl
group on the furan ring. As the Si-face of the carbonyl group
was blocked by a bulky substituent, the less hindered Re-
face attack of nucleophiles to the carbonyl group was
expected, leading possibly to high diastereoselectivity. An
AM1 calculation also confirms this conformation.11 More-
over, the huge geometric differentiation between the resulting
diastereomers should also allow for a successful separation
of both diastereomers by flash column chromatography.
We first investigated the addition reactions of furyl
aldehyde 7a (entry 1, Table 1). The addition reaction of 7a
with n-BuLi furnished 8a and 9a, which are not separable
on column chromatography, in moderate yield and low
diastereoselectivity. The newly created chiral centers of the
diastereomers were confirmed by their conversions to the
corresponding Mosher ester.12 This unsatisfactory outcome
may be attributed to the less pronounced stereochemical
environment of the chiral auxiliary around the carbonyl
group. We then turned our focus to the addition reactions of
7b. Thus, addition reactions of 7b with various nucleophiles
afforded diastereomers 8b-h and 9b-h in good yields and
moderate diastereoselectivities (entries 2-8, Table 1). As
expected, these diastereomers can be efficiently separated
by flash column chromatography leading to pure diastere-
omers. Further increasing the nucleophile’s bulkiness allows
an easier separation of both diastereomers (entries 5-8, Table
1). The newly created chiral centers were also confirmed by
conversion to the corresponding Mosher ester, by Riguera’s
method,13 and by X-ray crystallographic analysis.14
Scheme 1. Synthesis of Furyl Aldehydes 7
Regiospecific depotonation9 of 4 with LDA at -78 °C in
THF gave R-lithiated furan, which was further quenched by
gaseous formaldehyde to furnish furyl alcohol 5. Transfor-
mation of the C-Br bond of 5 to the C-B bond of 6 was
successful after a series of reactions, including metalation
with 2 equiv of n-BuLi, boronation with triisopropyl borate,
hydrolysis of borate salt, and dehydration of furyl boronic
acid with the corresponding diols. Mild oxidation10 of 6 with
(2) (a) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401. (b)
Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. J. Org. Chem. 1989,
54, 2085. (c) Kita, Y.; Naka, T.; Imanishi, M.; Akai, S.; Takebe, Y.; Matsugi,
M. J. Chem. Soc., Chem. Commun. 1998, 1183. (d) Keck, G. E.; Yu, T.
Org. Lett. 1999, 1, 289. (e) Ohkuma, T.; Koizumi, M.; Yoshida, M.; Noyori,
R. Org. Lett. 2000, 2, 1749. (f) Burk, M. J.; Hems, W.; Herzberg, D.; Malan,
C.; Zanotti-Gerosa, A. Org. Lett. 2000, 2, 4173.
(3) For a review, see: Matteson, D. S. Chem. ReV. 1989, 89, 1535.
(4) (a) Nakayama, K.; Rainier, J. D. Tetrahedron 1990, 46, 4165. (b)
Luithle, J. E. A.; Pietruszka, J. J. Org. Chem. 1999, 64, 8287. (c) Luithle,
J. E. A.; Pietruszka, J. J. Org. Chem. 2000, 65, 9194.
(5) Arai, Y.; Masuda, T.; Masaki, Y. Synlett 1997, 1459.
(6) Wong, M. K.; Leung, C. Y.; Wong, H. N. C. Tetrahedron 1997, 53,
3497.
(7) Liu, J.-H.; Yang, Q.-C.; Mak, T. C. W.; Wong, H. N. C. J. Org.
Chem. 2000, 65, 3587.
(11) Courtesy of Prof. Yundong Wu, The Hong Kong University of
Science and Technology.
(12) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M. J. Org. Chem. 1986, 51, 2370.
(13) (a) Latypov, Sh. K.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Am.
Chem. Soc. 1998, 120, 877. (b) Latypov, Sh. K.; Seco, J. M.; Quin˜oa´, E.;
Riguera, R. J. Org. Chem. 1996, 61, 8569. (c) Latypov, Sh. K.; Seco, J.
M.; Quin˜oa´, E.; Riguera, R. J. Org. Chem. 1995, 60, 1538.
(8) Ye, X.-S.; Wong, H. N. C. J. Org. Chem. 1997, 62, 1940.
(9) Ly, N. D.; Schlosser, M. HelV. Chim. Acta 1977, 60, 2085.
(10) Matteson, D. S. In Stereodirected Synthesis with Organo-boranes;
Hafner, K., Rees, C. W., Trost, B. M., Lehn, J.-M., von Rague´ Schleyer,
P., Eds.; Springer-Verlag: Heidelberg, 1995; p 107.
3992
Org. Lett., Vol. 3, No. 25, 2001

nucleophile and a subsequent intramolecular delivery of the
alkyl group to the aldehyde could not be ruled out.15
However, this intramolecular alkyl transfer process does not
seem to lead to a good diastereomeric control. Moreover,
initial treatment of 7b with 1 equiv of t-BuLi followed by
subsequent addition of 1 to 3 equiv of PhCtCLi gave better
diastereoselectivity.16 This indicates that the first equivalent
of nucleophile is likely to attack the trigonal planar boronate
before the alkylation of the carbonyl group.
Table 1. Addition Reactions of 7a and 7ba
Tetrahedral borate species have been known for decades.17
The idea of forming tetrahedral borate species from trigonal
planar boronates, in which the chiral director is closer to
the aldehyde, led us to select alkoxides as additives. By
simply using 11B NMR spectroscopy,18 an upfield shift to
about δ 7 ppm was observed when 7b (δ 30.8 ppm) was
mixed with lithium alkoxides, indicating the formation of
yield,
de,
1
b
c
tetrahedral borate species (Table 2). H NMR analysis of a
entry
nucleophile
n-BuLi
n-PrMgBr
n-BuLi
t-BuLi
PhCdCLi
n-C5H11CdCLi
conditions
products
%
%
1
2
3
4
5
Et2O, -78 °C 8a 9a
THF, -78 °C 8b 9b
Et2O, -78 °C 8c 9c
THF, -78 °C
THF, 0 °C
THF, 0 °C
47
45
64
29
79
75
81
85
84
81
86
94
92
23 (R)
23 (R)
33 (R)
33 (R)
38 (R)
23 (R)
20 (R)
71 (R)
72 (R)
56 (R)
6 (R)
Table 2. Addition Reaction of 7b with Nucleophiles Using
8d 9d
8e 9e
Lithium Alkoxides as Additivea
6
8f
9f
7
8
9
10
11
12
13
CH2dC(SiMe3)MgBr THF, -78 °C
8g 9g
Me3SiCH2MgCl
Me3SiCH2MgCl
Me3SiCH2MgCl
Me3SiCH2MgCl
Me3SiCH2MgCl
Me3SiCH2MgCl
Et2O, -78 °C 8h 9h
DME, -60 °C 8h 9h
PhMe, -78 °C 8h 9h
DCM, -78 °C 8h 9h
Hex, -78 °C
THF, -78 °C
yield,
de,
c
d
8h 9h
8h 9h
3 (R)
0 (-)
entry
nucleophile
t-BuLi
additive 11B δ b products
%
%
1
2
3
4
5
6
7
8
9
MeOLi
EtOLi
7.6
7.0
7.0
7.6
7.6
7.5
7.5
7.5
7.5
8d 9d
8d 9d
8h 9h
8d 9d
8h 9h
8d 9d
8h 9h
8d 9d
8d 9d
54
64
57
49
51
37
40
46
70
50 (S)
67 (S)
71 (S)
99 (S)
73 (S)
95 (S)
82 (S)
99 (S)
58 (S)
t-BuLi
a All reactions were carried out by adding nucleophiles (4 equiv) to furyl
aldehydes 7. b Total isolated yield of 8 and 9. c Determined by 1H NMR
analysis of crude mixture. The major diastereomer is indicated in the
parentheses.
Me3SiCH2MgCl EtOLi
t-BuLi n-PrOLi
Me3SiCH2MgCl n-PrOLi
t-BuLi n-BuOLi
Me3SiCH2MgCl n-BuOLi
t-BuLi
t-BuLi
n-AmOLi
n-AmOLi
12-C-4e
It was found that the R diastereomers 8b-d and 8h were
more polar than the S diastereomers 9b-d and 9h. For the
nucleophiles with â-hydrogens (entries 1-4, Table 1),
reduction of 7 to give furyl alcohol 6 was the main reason
for the low reaction yields. To overcome the yield limitation,
nucleophiles without â-hydrogens were employed. Encour-
aging results were obtained by employing Me3SiCH2MgCl
as nucleophile, giving 8h and 9h in 85% isolated yield with
71% de. This satisfactory result prompted us to further
investigate its scope and limitation. It is important to note
that solvents greatly influence the diastereoselectivity of the
addition reactions of 7b with Me3SiCH2MgCl. When cyclic
ether THF was used, no diastereoselectivity was observed
(entry 13, Table 1). Surprisingly, however, when the less
Lewis basic DME or Et2O was employed as solvent, the
diastereoselectivity was tremendously increased to over 70%
(entries 8 and 9, Table 1). Such phenomena can be briefly
explained in term of the Grignard reagent’s reactivity. A
more strongly Lewis basic solvents such as THF would
increase the number of monomeric, solvated species of the
Grignard reagent, leading to enhanced nucleophilicity of the
C-Mg bond, thereby increases its reactivity but decreases
its diastereoselectivity toward the aldehyde group. The
possibility of the formation of a tetrahedral borate intermedi-
ate between the chiral boronate and the organometallic
10
t-BuLi
n-AmOLi
7.5
8d 9d
85
33 (S)
12-C-4f
a All reactions were carried out by mixing lithium alkoxides (1.3 equiv)
with furyl aldehyde 7b in suitable solvents at -78 °C; then nucleophiles
(10 equiv) were added. THF and Et2O were used for nucleophiles t-BuLi
and Me3SiCH2MgCl, respectively. b BF3 as reference. c Total isolated yield
of 8 and 9. d Determined by 1H NMR analysis of crude mixture. The major
diastereomer is indicated in parentheses. e 12-Crown-4 (1.3 equiv). f 12-
Crown-4 (15 equiv).
mixture, which was obtained by mixing lithium d-methoxide
with 7b in d-methanol, also gave strong evidence that the
aldehyde group remained intact. t-BuLi and Me3SiCH2MgCl
were selected to react with the tetrahedral borate species.
Surprising, the diastereoselectivity changed from R diaster-
eomeric selection to S diastereomeric selection. Further
increasing the alkyl chains of the alkoxides resulted in much
higher diastereoselectivity. This observed diastereoselectivity
(15) A 11B signal at δ 9 ppm was detected upon addition of an
organometallic reagent to the chiral furanylboronate.
(16) Employing 1 to 3 equiv of PhCdCLi gave 8e and 9e in 53%, 50%,
and 42% yields in 47% (R), 22% (R) and 71% (R) de, respectively.
(17) (a) Curtis, A. D. M.; Whiting, A. Tetrahedron Lett. 1991, 32, 1507.
(b) Curtis, A. D. M.; Mears, R. J.; Whiting, A. Tetrahedron Lett. 1993, 49,
187.
(18) Noth, H.; Wrackmeyer, B. In N M.R. Spectroscopy of Boron
Compounds; Diehl, P., Fluck, E., Kosfield, R., Eds.; Springer-Verlag: Berlin,
1978.
(14) See Supporting Information.
Org. Lett., Vol. 3, No. 25, 2001
3993

our stable furyl boronic ester of diol 3 with aryl iodide was
successful, giving optically pure 2,3-disubstituted furyl
alcohols 11 and 12 (Table 3).20 Also, as mentioned in the
introduction, these compounds can serve as important
precursors for 6-hydroxy-2H-pyran-3(6H)-one 1. Thus treat-
ment of 12b with m-chloroperbenzoic acid in CH2Cl2
afforded 1a in 91% yield (Figure 4).
Figure 3. Proposed transition state for the addition reactions of
7b with lithium alkoxides as additives.
is explained by assuming the following reaction mechanism
(Figure 3).19 The alkoxides first added to the trigonal planar
boronate center to form a tetrahedral borate, which is a
transition stage, 10, with a seven-membered ring linked by
the lithium ion. Due to the conformational congestion, the
alkyl chain of the alkoxides must point downward, which
blocks the Re-face of carbonyl group. Thus, nucleophiles
must attack the carbonyl group from the less hindered Si-
face. Addition of 12-crown-4, which traps the Li+ ions and
destroys the seven-membered ring transition stage, confirms
our assumption (entries 9-10, Table 2).
Figure 4. Oxidative rearrangement of 12b.
In conclusion, we have described efficient procedures for
the realization of furyl aldehydes 7 and their addition
reactions with different nucleophiles such as Grignard
reagents and alkyllithiums. Conversion of furyl aldehydes 7
to imine derivatives and their addition reactions are currently
underway in our group.
Acknowledgment. The work described in this Letter was
supported by an Earmark Grant from the Research Grants
Council of the Hong Kong Special Administrative Region,
China (Project CUHK 4178/97P) and a Direct Grant (A/C
No. 2060186) administered by the Chinese University of
Hong Kong. H.N.C.W. wishes to thank the Croucher
Foundation (Hong Kong) for a Croucher Senior Research
Fellowship (1999-2000). We also thank Prof. T. C. W. Mak
and Miss H.-W. Li for X-ray crystallographic analysis, Mr.
L. Hou for 11B NMR experiments, and Prof. Y. -X. Cui of
Peking University for variable temperature 1H NMR experi-
ments.
The Suzuki coupling reaction is regarded as one of the
most important transformations of the C-B to C-C bond.
We were not surprised to find that the direct coupling of
Table 3. Suzuki Coupling Reactions of 8 and 9 with Aryl
Iodide
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
starting
conditiona
R
R′
yield, %
8b
8d
8h
9b
9d
9h
A
B
A
A
B
A
n-Pr 11a
t-Bu 11b
Me3SiCH2 11c
n-Pr 12a
t-Bu 12b
Me
H
H
Me
H
H
65b
63
75
65b
57
82
OL010196N
(19) (a) Nozaki, K.; Yoshida, M.; Takaya, H. Bull. Chem. Soc. Jpn. 1996,
69, 2043. (b) Nozaki, K.; Yoshida, M.; Takaya, H. Angew. Chem., Int. Ed.
Engl. 1994, 33, 2452. (c) Shriver, D. F.; Biallas, M. J. J. Am. Chem. Soc.
1967, 89, 1078.
(20) Diol 3 cannot be recovered after the Suzuki coupling reaction.
However, prior reduction of 8d by LiAlH4 gave diol 3 in a nearly
quantitative yield without lose of optical purity, as well as the corresponding
furanboronic acid, which was then subjected to Suzuki coupling conditions
to give furyl alcohol 11b.
Me3SiCH2 12c
a A ) 2 M Na2CO3, PhMe/MeOH (1:1), reflux, 2 h; B ) Ba(OH)2, DME/
H2O (4:1), reflux, 2 h. b Total yield of coupling and protection.
3994
Org. Lett., Vol. 3, No. 25, 2001