Short and efficient synthesis of chiral furyl carbinols from carbohydrates

Article abstract of DOI:10.1021/ol070412d

Common sugar derivatives can be transformed in a few steps into chiral-substituted furyl carbinols. The mildness of the reaction conditions and the good yields obtained make this procedure an interesting alternative to the conventional processes.

Full text of DOI:10.1021/ol070412d

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1721-1724
Short and Efficient Synthesis of Chiral
Furyl Carbinols from Carbohydrates
Alicia Boto,* Da´cil Herna´ndez, and Rosendo Herna´ndez*
Instituto de Productos Naturales y Agrobiolog´ıa CSIC, AVda. Astrof´ısico Fco. Sa´nchez
3, 38206-La Laguna, Tenerife, Spain
alicia@ipna.csic.es; rhernandez@ipna.csic.es
Received February 19, 2007
ABSTRACT
Common sugar derivatives can be transformed in a few steps into chiral-substituted furyl carbinols. The mildness of the reaction conditions
and the good yields obtained make this procedure an interesting alternative to the conventional processes.
Furans are versatile building blocks in the synthesis of natural
or bioactive products,1 by reduction or oxidation of the
aromatic ring and by Diels-Alder cycloadditions.
Among them, chiral furyl carbinols have proven particu-
larly useful.2 For instance, the oxidative rearrangement of
carbinol 1 (Scheme 1) affords a spirocyclic precursor of the
To prepare chiral furyl carbinols, several methods have
been developed,5 including asymmetric reduction of furyl
ketones,6 acid- or base-promoted addition of furan to chiral
aldehydes,7 aldol reaction of chiral enolates with furfurals,8
Sharpless dihydroxylation of vinyl furans,9 and resolution
of racemic mixtures.10
We report here a flexible, efficient alternative to the
synthesis of chiral furyl carbinols 3 (Scheme 2), which avoids
harsh conditions (such as strong bases) and allows introduc-
tion of a variety of substituents onto the 2-, 3-, and 5-ring
Scheme 1
Scheme 2
selective antifungal populacandin D.3a Furyl carbinols have
also been used to obtain higher-carbon sugars,4 with com-
pound 2 being a key intermediate in the synthesis of KDO,
an essential component of the Gram-negative bacteria cell
wall.3b
10.1021/ol070412d CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/31/2007

The synthesis of the polyhydroxylated ketones 5 can be
performed from readily available sugar derivatives 6 in one
or two steps (Scheme 3). Thus, the substrates 6 react with
(diacetoxyiodo)benzene (DIB) and iodine, generating ano-
meric alkoxyl radicals. These intermediates undergo â-scis-
sion and oxidation, to give the oxycarbenium ions 7, which
are trapped by acetate ions from the reagent. The resulting
acetates 8, under treatment with a Lewis acid and a silylenol
ether, give the corresponding ketones 5.
Scheme 3
The transformation of representative sugar substrates 9-11
(derived from ribose, mannose, and rhamnose) into their
acetates 12-14 is shown in Scheme 4. The reaction
proceeded in good yield and good stereoselectivity.
The conversion of acetates 12-14 into ketones 15-19
(Scheme 4) also proceeded in good yield. In contrast, the
one-pot generation of phenyl ketones 15, 17, and 19 from
sugar substrates 9-11 gave low yields. It must be noted that
in all cases 1,2-trans stereoselectivity was obtained.
Modification of the polyhydroxylated chains afforded other
derivatives. Thus, the formate groups in 18 and 19 were
hydrolyzed, and the resulting alcohols were oxidized to
diketones 20 and 21, respectively.
positions. The furans 3 would be formed by cyclization of
unsaturated hydroxyketones 4, generated in situ from ketones
5 by elimination of the â-alkoxyl group. The substrates 5
would be formed from readily available carbohydrates 6,
using a fragmentation-alkylation reaction developed by our
group.11
The polyhydroxylated ketones 15-18 and 20-21 were
treated under basic conditions, to obtain the unsaturated
Scheme 4
1722
Org. Lett., Vol. 9, No. 9, 2007

Table 1. Transformation of Polyhydroxylated Ketones into Chiral Furyl Carbinols
conditions
15-21 f 22-27
unsaturated
ketonea
conditions
22-27 f 28-33
furans
(%)a
one-pot process (15-21 f 28-33)
entry
ketone
conditions (furan yield, %)a
1
2
3
4
5
6
15
16
17
18
20
21
NaHCO3, MeOH, 12 h
NaHCO3, MeOH, 12 h
NaHCO3, MeOH, 12 h
NaHCO3, MeOH, 12 h
NaHCO3 or BuNH2, MeOH, 12 h
NaHCO3 or BuNH2, MeOH, 12 h
22 (-)b
23 (90)
24 (95)
25 (70)
26 (-)b
27 (-)b
-
28 (-)
29 (65)
30 (89)
31 (30)
32 (-)
33 (-)
C (74)e
Ac
Bd
Ac
-
C (-)e/D (55)f/E (32)g/F (68)h
C (87)e
C (-)e/D (29)f/E (31)g/F (67)h
E (60)g
C (74)e
-
a The yields are given for products purified by chromatography on silica gel. bNot isolated (labile compound). cMethod A: AcOH, 12 h. dMethod B: 2%
e
f
HCl (aq) in MeOH (pH 4), 12 h. Method C: NaHCO3, MeOH, 12 h; then 2% aq HCl to pH ) 4, 12 h. Method D: NaHCO3, MeOH, 12 h; then AcOH,
12 h. gMethod E: BuNH2/MeOH at 60 °C, 6 h; then AcOH, overnight. hMethod F: Formates 16 or 18 were hydrolyzed with NaHCO3 in MeOH, 0.5 h; the
crude alcohols were treated as described in method E.
derivatives 22-27 (Table 1). These intermediates would then
be transformed into furyl carbinols 28-33.
cyclization procedure was developed (method C or D:
NaHCO3 in MeOH, 12 h, then acidification with HCl (aq)
or AcOH). The direct transformation of phenyl ketones 15,
Although the conjugated ketones 22, 26, and 27 (entries
1, 5, and 6) were unstable and could not be isolated, the
unsaturated ketones 23-25 were formed in good yields
(entries 2-4). These three intermediates underwent cycliza-
tion to the furans 29-31 under acid treatment (method A or
B).
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Org. Lett., Vol. 9, No. 9, 2007
1723

17, and 21 into the furyl carbinols 28, 30, and 33 (entries 1,
3, and 6) proceeded as desired. However, the tetrahydrobenzo
furans 29, 31, and 32 (entries 2, 4, and 5) were formed in
modest or low yields.
In summary, we have shown that common sugar deriva-
tives can be easily transformed in few steps into chiral, highly
substituted furyl carbinols. These compounds are useful
synthetic intermediates, and many have interesting biological
properties. The mildness of the reaction conditions and the
good yields obtained make this procedure an interesting
alternative to the conventional processes.
A modification of the one-pot procedure (method E) still
gave low yields of the tetrahydrobenzofurans 29 and 31
(entries 2 and 4), but in contrast, furan 32 was formed in
good yield (entry 5). Finally, good results were achieved with
a two-step process (method F: hydrolysis of the formate
group in 16 or 18 and cyclization of the crude alcohols).
Acknowledgment. This work was supported by the
Research Program PPQ2003-01379 of the Plan Nacional de
Investigacio´n Cient´ıfica, Desarrollo e Innovacio´n Tecno-
lo´gica, Ministerios de Ciencia y Tecnolog´ıa y de Educacio´n
y Ciencia, Spain. We also acknowledge financial support
from FEDER funds. D.H. thanks the Ministerio de Educacio´n
y Ciencia for a FPU fellowship.
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Supporting Information Available: Procedures for the
synthesis of compounds 12-33 and 1H and 13C NMR spectra
for compounds 12-21, 23-25, and 28-33. This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) Boto, A.; Herna´ndez, R.; Sua´rez, E. Tetrahedron Lett. 2001, 42,
9176-9170 and references cited therein.
OL070412D
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Org. Lett., Vol. 9, No. 9, 2007