Intramolecular direct Aldol reactions of sugar diketones: Syntheses of valiolamine and validoxylamine G

Article abstract of DOI:10.1021/ol801889n

(Chemical Equation Presented) A new and stereoselective intramolecular direct aldol reaction of diketones derived from carbohydrates has been developed to construct carbocycles with D-gluco-, D-galacto, D-manno-, and L-ido-configurations. The stereochemical outcome of the aldol reaction of the diketone is dependent on the base used. Transformation of D-gluco-aldols readily affords valiolamine which also constitutes a formal synthesis of voglibose. Facile conversion of D-gluco-cyclohexanones into validoxylamine G has been achieved in 12 steps with 15.1% overall yield from D-glucose.

Full text of DOI:10.1021/ol801889n

ORGANIC
LETTERS
2008
Vol. 10, No. 18
4137-4139
Intramolecular Direct Aldol Reactions of
Sugar Diketones: Syntheses of
Valiolamine and Validoxylamine G
Tony K. M. Shing* and Hau M. Cheng
Department of Chemistry and Center of NoVel Functional Molecules, The Chinese
UniVersity of Hong Kong, Shatin, Hong Kong, China
tonyshing@cuhk.edu.hk
Received August 13, 2008
ABSTRACT
A new and stereoselective intramolecular direct aldol reaction of diketones derived from carbohydrates has been developed to construct
carbocycles with D-gluco-, D-galacto-, D-manno-, and L-ido-configurations. The stereochemical outcome of the aldol reaction of the diketone is
dependent on the base used. Transformation of D-gluco-aldols readily affords valiolamine which also constitutes a formal synthesis of voglibose.
Facile conversion of D-gluco-cyclohexanones into validoxylamine G has been achieved in 12 steps with 15.1% overall yield from D-glucose.
The direct aldol reaction is one of the most concise and
efficient carbon-carbon bond-forming reactions in the
arsenal of synthetic chemists.1 Direct aldol reactions cata-
lyzed by L-proline and its derivatives have become a rapidly
expanding area in contemporary organic synthesis during the
past years.2 Recently, DBU and DIPEA have been demon-
strated to promote intermolecular direct aldol reactions.3
These results have prompted us to disclose our efforts in
the intramolecular variant of the direct aldol reactions which
were employed to construct hydroxylated carbocycles from
carbohydrates, a long-standing theme of our research pro-
gram.4
pseudo-1,1′-N-linked disaccharides on the basis of transfor-
mation from quinic acid.5 As a continuation of our efforts
targeting pseudoamino oligosaccharides for biological evalu-
ation, an efficient entry for hydroxylated carbocycles is
required to transform them into primary carba-monosaccha-
ride units with D-gluco-, D-galacto-, and D-manno-configura-
tions.
In this paper, we describe facile construction of car-
bocycles via an intramolecular direct aldol reaction of
diketones derived from carbohydrates and the transformation
of the cyclized D-gluco-aldols into R-D-glucosidase inhibitors
valiolamine (5), voglibose (6), and validoxylamine G (7).
Orally active antidiabetic medicine voglibose (6) (code:
AO-128) is a N-substituted glycerol derivative of valiolamine
(5)6 and has attracted considerable interest due to its excellent
inhibitory activity against R-D-glucosidases and its action
Our endeavors in carba-aminodisaccharide synthesis have
produced valienamine and 2-epi-valienamine containing
(1) Modern aldol reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim,
Germany, 2004.
(2) Review: de Figueiredo, R. M.; Christmann, M. Eur. J. Org. Chem.
2007, 16, 2575–2600.
(5) (a) Shing, T. K. M.; Kwong, C. S. K.; Cheung, A. W. C.; Kok,
S. H.-L.; Yu, Z.; Li, J.; Cheng, C. H. K. J. Am. Chem. Soc. 2004, 126,
15990–15992. (b) Kok, S. H.-L.; Lee, C. C.; Shing, T. K. M. J. Org. Chem.
2001, 66, 7184–7190. (c) Shing, T. K. M.; Li, T. Y.; Kok, S. H. L. J. Org.
Chem. 1999, 64, 1941–1946. (d) Shing, T. K. M.; Wan, L. H. J. Org. Chem.
1996, 61, 8468–8479. (e) Shing, T. K. M.; Tai, V. W.-F. J. Org. Chem.
1995, 60, 5332–5334.
(3) Markert, M.; Mulzer, M.; Schetter, B.; Mahrwald, R. J. Am. Chem.
Soc. 2007, 129, 7258–7259.
(4) (a) Shing, T. K. M.; Wong, A. W. F.; Ikeno, T.; Yamada, T. J. Org.
Chem. 2006, 71, 3253–3263. (b) Shing, T. K. M.; Wong, W. F.; Ikeno, T.;
Yamada, T. Org. Lett. 2007, 9, 207–209. (c) Shing, T. K. M.; Wong, W. F.;
Cheng, H. M.; Kwok, W. S.; So, K. H. Org. Lett. 2007, 9, 753–756. (d)
Shing, T. K. M.; Cheng, H. M. J. Org. Chem. 2007, 72, 6610–6613.
(6) Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.; Matsui,
K. J. Med. Chem. 1986, 29, 1038–1046.
10.1021/ol801889n CCC: $40.75
Published on Web 08/26/2008
2008 American Chemical Society

against disorders caused by hyperglycemia.7 Validoxylamine
G (7), a pseudoaminodisaccharide possessing valienamine
(4) and valiolamine (5),8 was found to be a very potent R-D-
glucosidase inhibitor among the validamycin complexes.9
Two syntheses of validoxylamine G (7) have been addressed
with inefficient installation of the amine linkage; as a result,
the overall yields were only 0.11 and 1.56% from optically
resolved Diels-Alder endo-adduct10 and D-glucose,11 re-
spectively, which hampered large scale production of 7 for
further biological studies.
clization conditions to give a D-galacto-cyclohexanone 11,
and the results are shown in Table 2. L-Proline-catalyzed
Table 2. Aldol-Cyclization Conditions of Diketone 12
First, the formation of carbocycles (aldols) from D-glucose
is shown in Table 1. It is noteworthy that L-proline-catalyzed
results
entry
conditions
11
13
Table 1. Aldol-Cyclization Conditions of Diketone 8
1
2
3
4
5
6
7
(L)-Proline (0.3 equiv), DMSO
(D)-Proline (0.3 equiv), DMSO
Et3N (1.5 equiv), CH2Cl2
92%
67%
99%
96%
34%
36%
35%
-
-
-
-
42%
40%
37%
DIPEA (1.5 equiv), CH2Cl2
LDA (1 equiv), Toluene, -78 °C
NaHMDS (1 equiv), Toluene, -78 °C
KHMDS (1 equiv), Toluene, -78 °C
results
entry
conditions
9
10
11
direct aldol reaction provided 11 in 92% yield, albeit the
long reaction time of 12 days (entry 1). When D-proline was
employed, the reaction also gave 11, but in a lower 67%
yield (entry 2). Fortunately, Et3N gave 11 exclusively in an
excellent yield within one day (entry 3). Strong bases
afforded a mixture of aldols 11 and 13 in similar amounts
(entries 5-7).
1
2
3
4
5
6
7
L-Proline (0.3 equiv), DMSO
(D)-Proline (0.3 equiv), DMSO
Et3N (1.5 equiv), CH2Cl2
82% 8%
2%
52%
95%
94%
-
-
-
-
-
-
-
-
-
-
42%
62%
75%
DIPEA (1.5 equiv), CH2Cl2
LDA (1 equiv), Toluene, -78 °C
NaHMDS (1 equiv), Toluene, -78 °C
KHMDS (1 equiv), Toluene, -78 °C
-
-
The aldol-cyclization was further extended to prepare a
D-manno-carbocycle as shown in Table 3. L-Proline-catalyzed
the direct aldol reaction of diketone 812 (prepared from
D-glucose in 6 steps with 30.8% overall yield) to give three
cyclohexanones regioselectively, and L-ido-aldol 9 was
isolated as the major carbocycle (entry 1). The structures of
9 and 11 were confirmed by X-ray crystallography, and the
constitution of 10 was confirmed by conversion into known
5. D-Proline only provided epimerized compound 11 in 52%
yield (entry 2). It is surprising that amine bases, Et3N and
DIPEA, effected cyclization to give C-4 epimerized aldol
11 exclusively (entries 3-4). Among the strong bases used
(entries 5-7), KHMDS gave the best yield of a very useful
synthetic intermediate 10 stereospecifically, with the tertiary
alcohol oriented at the R-face. The elaboration of 9 and 10
into valiolamine (5), voglibose (6), and validoxylamine G
(7) will be addressed later in this paper.
Table 3. Aldol-Cyclization Conditions of Diketone 14
entry
conditions
results
60%
decomposed
decomposed
decomposed
decomposed
decomposed
decomposed
1
2
3
4
5
6
7
(L)-Proline (0.3 equiv), DMSO
(D)-Proline (0.3 equiv), DMSO
Et3N (1.5 equiv), CH2Cl2
DIPEA (1.5 equiv), CH2Cl2
LDA (1 equiv), Toluene, -78 °C
NaHMDS (1 equiv), Toluene, -78 °C
KHMDS (1 equiv), Toluene, -78 °C
Diketone 1213 (prepared from D-galactose in 6 steps with
29.8% overall yield) was subjected to different carbocy-
(7) Chen, X.; Zheng, Y.; Shen, Y. Curr. Med. Chem. 2006, 13, 109–
116.
direct aldolization of diketone 1413 (prepared from D-
mannose in 5 steps with 40% overall yield) furnished
cyclohexanone 15 as a single diastereomer in 60% yield
(entry 1). However, the use of D-proline did not afford any
aldol (entry 2). Both amines (entries 3-4) and strong bases
(entries 5-7) only gave fruitless results.
(8) Kameda, Y.; Asano, N.; Yamaguchi, T.; Matsui, K.; Horii, S.;
Fukase, H. J. Antibiot. 1986, 39, 1491–1494.
(9) Chen, X.; Fan, Y.; Zheng, Y.; Shen, Y. Chem. ReV. 2003, 103, 1955–
1977.
(10) Miyamoto, Y.; Ogawa, S. J. Chem. Soc. Chem. Commun. 1990,
14, 999–1000.
(11) (a) Fukase, H.; Horii, S. J. Org. Chem. 1992, 57, 3651–3658. (b)
Fukase, H.; Horii, S. J. Org. Chem. 1992, 57, 3642–3650.
(12) Shing, T. K. M.; Cheng, H. M.; Wong, W. F.; Kwong, C. S. K.;
Li, J.; Lau, C. B. S.; Leung, P. S.; Cheng, C. H. K. Org. Lett. 2008, 10,
3145–3148.
With cyclohexanones 9 and 10 in hand, attention was
directed to synthesize valiolamine (5) and its containing
4138
Org. Lett., Vol. 10, No. 18, 2008

compounds. The cyclohexanone 10 was used to synthesize
valiolamine (5) as they have four chiralities in common
(Scheme 1). The remaining stereocenter was installed by a
lamine G (7) in 88% yield. The specific rotation, 1H and 13
C
NMR spectral data are in good agreement with the reported
values.8,11
Scheme 1
Figure 1. Structures of hexoses and R-D-glucosidase inhibitors 4,
5, 6, and 7.
reductive amination of 10 to give protected valiolamine 16.
After acid hydrolysis, the valiolamine (5) was obtained in
In summary, we have developed the first intramolecular
direct aldol reactions of diketones derived from carbohy-
drates, affording cyclohexanones with L-ido-, D-gluco-,
D-galacto-, and D-manno-configurations. The diketone 8,
derived from D-glucose, gave either L-ido-, D-gluco-, or
D-galacto-aldol stereoselectively, depending on the base used.
Efficient transformation of the aldols has presented new
syntheses of valiolamine (5) in 10 steps with 17.2% overall
yield, validoxylamine G (7) in 12 steps with 15.1% overall
yield, and a formal synthesis of voglibose (6). Since
carbohydrates are abundant in nature, transformation of
carbohydrates into carbocycles is a very important conversion
because it provides valuable starting materials for making
pharmaceuticals without shortage of supply. These cabasug-
ars from carbohydrates should have broad application in
chemical biology and could be exploited for a wide range
of functionalized cyclohexenoid or cyclohexanoid targets and
intermediates of pharmaceutical importance.
1
88% yield with specific rotation, H and 13C NMR spectral
data in accord with the literature values.14 Since voglibose
(6) can be accessed by reacting valiolamine (5) with 1,3-
dihydroxyacetone in the presence of Na(CN)BH3,6 the
present synthesis of valiolamine (5) constitutes a formal
synthesis of voglibose (6).
The amine 16 did not couple with allylic chloride 18.12
Hydrogen bonding with the tertiary alcohol might decrease
the nucleophilicity of the amine in the coupling reaction
(Scheme 2). Hence, the tertiary alcohol in 16 was protected
Scheme 2
Acknowledgment. This work was supported by a Strategic
Investments Scheme administered by the Center of Novel
Functional Molecules of The Chinese University of Hong
Kong. The provision of direct grants and graduate student-
ships from The Chinese University of Hong Kong is also
acknowledged.
Supporting Information Available: Experimental pro-
cedures and product characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
as TMS-ether 17. Palladium-catalyzed coupling15 of 17 with
chloride 18 smoothly gave blocked validoxylamine G 19 in
an excellent yield. Acid hydrolysis then afforded validoxy-
OL801889N
(14) Kameda, Y.; Asano, N.; Yoshikawa, M.; Takeuchi, M.; Yamaguchi,
T.; Matsui, K.; Horii, S.; Fukase, H. J. Antibiot. 1984, 37, 1301–1307.
(15) (a) Trost, B. M.; Cossy, J. J. Am. Chem. Soc. 1982, 104, 6881–
6882. (b) Tsuji, J. Palladium Reagents and Catalysts-InnoVations in Organic
Synthesis, 2nd ed.; John Wiley: Chicester, U.K., 1995; p 9.
(13) Preparation of new compounds is described in Supporting Informa-
tion.
Org. Lett., Vol. 10, No. 18, 2008
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