Building carbohydrates on the dioxanone scaffold: stereoselective synthesis of d-glycero-d-manno-2-octulose

Article abstract of DOI:10.1016/j.tetlet.2007.10.100

The title compound has been synthesized via two proline-catalyzed aldol addition reactions of 2,2-dialkyl-1,3-dioxan-5-ones: the first addition to 1,3-dithiane-2-carboxaldehyde, followed by reduction to the corresponding diol, protection of the OH groups

Full text of DOI:10.1016/j.tetlet.2007.10.100

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 9195–9198
Building carbohydrates on the dioxanone scaffold:
stereoselective synthesis of D-glycero-D-manno-2-octulose
Nagarjuna Palyam, Izabella Niewczas and Marek Majewski*
Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, SK, Canada S7N 5C9
Received 27 September 2007; revised 16 October 2007; accepted 18 October 2007
Available online 24 October 2007
Abstract—The title compound has been synthesized via two proline-catalyzed aldol addition reactions of 2,2-dialkyl-1,3-dioxan-5-
ones: the first addition to 1,3-dithiane-2-carboxaldehyde, followed by reduction to the corresponding diol, protection of the OH
groups and dithiane hydrolysis afforded a protected D-ribose that was used in the second aldol addition reaction.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Recently, higher monosaccharides (higher-carbon su-
gars), and carbohydrates having the backbone that is
longer than the usual five or six carbon atoms, and their
derivatives, have been receiving increasing attention,
among other reasons, due to their interesting biological
properties.1,2 Monosaccharide derivatives having ten to
twelve carbon atoms in the carbon skeleton include rare
higher aldoses that occur as chiral fragments in some
antibiotics, for example, hikosamine (a hemiaminal of
an eleven carbon aldose), a core component of the
nucleoside antibiotic Hikizimycin.3 Other examples
include lincosamine (the eight carbon carbohydrate
moiety of the commercially available antibiotic Linco-
mycin),4 and sialic acids5 such as KDO (C8) and KDN
(C9). Increasing numbers of higher monosaccharides
that show interesting biological properties are being dis-
covered in nature,6 but overall higher sugars are still
rather esoteric species. A search of the literature
revealed that few higher monosaccharides had been
described, especially larger than nonoses. There is a
growing need for efficient synthetic methodologies to
access these compounds, however, their multiple func-
tional groups and the presence of numerous stereogenic
centres make them rather challenging synthetic targets.
Several synthetic approaches were developed over the
years. Most of the methodologies employed abundant
pentoses or hexoses as starting materials and homologa-
tion or coupling as the strategy.7 The work of Jarosz8a
and Dondoni8b deserves special mention.
During the last decade, a number of studies have
appeared describing the use of 2,2-dialkyl-1,3-dioxan-
5-ones as scaffolds for the synthesis of ketohexoses and
other poly-oxygenated compounds and the topic has
been reviewed.9,10 Dioxanones have proven to be good
substrates for reactions involving organocatalysis and
several studies on the proline-catalyzed stereoselective
transformations of dioxanones were reported, including
the syntheses of ketohexoses and some higher sugars.11
Below, we describe our recent observations pertaining
to stereocontrolled synthesis of higher sugars from
dioxanones via proline-catalyzed aldol reaction as the
key step.
Our synthetic strategy is shown in Scheme 1. We visua-
lized the synthesis of a ketooctose from two dioxanone
building blocks. This, in principle, could be done either
in ‘one pot’ or stepwise, the latter approach would
necessitate using a number of different protecting
groups. The successful strategy should lead to the syn-
thesis of one enantiomer selectively, that is, the control
of absolute and relative stereochemistry would be
required. It should be noted that previous work on
dioxanones involving enantioselective deprotonation,12
as well as organocatalysis,11 solved the former problem
(enantioselectivity control) and we were optimistic that,
in view of the extensive literature concerning diastere-
oselectivity control in aldol chemistry,13 the latter prob-
lem (controlling relative stereochemistry) would also be
solved. Eventually, a versatile strategy should make
Keywords: Higher sugars; Organocatalysis; Proline; Stereoselective
aldol reaction; Dioxanone.
*
Corresponding author. Tel.: +1 306 966 4671; fax: +1 306 966
4730; e-mail: majewski@usask.ca
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.100

9196
N. Palyam et al. / Tetrahedron Letters 48 (2007) 9195–9198
R1 R2
R1 R2
O
O
OH
O
O
O
OH OH OH
O
O
HO
+
+
OH
O
O
O
O
OH O
O
OH OH
O
O
3
R1 R2
R1 R2
1
2
4
3
Scheme 1. Retrosynthetic plan for higher monosaccharides starting from dioxanones.
selective synthesis of several ketooctose stereoisomers
possible (ideally all 32 of them). In this preliminary
study, we have focused on D-glycero-D-manno-2-octu-
lose, which is one of the natural products found in
opium poppy.14
protocols (HgCl2/HgO, I2/NaHCO3, Dess–Martin peri-
odinane) but the reaction gave a mixture of products in
each case. Fortunately, Corey’s protocol16 (NBS/
AgNO3 in aqueous acetonitrile) cleanly gave aldehyde
9—a protected form of D-ribose.
A brief experimental examination of the ‘one pot’ stra-
tegy yielded unpromising results. We then directed our
attention to the stepwise approach.
To eliminate any uncertainties in stereochemical assign-
ments at this stage we needed a crystalline derivative.
Thus, we prepared compound 7b from tert-butylmethyl
dioxanone (3b) by an analogous approach (Scheme 2).
Only one diastereoisomer of the aldol was detected by
NMR in this case. Fortunately, the corresponding
reduction product 7b was crystalline and provided us
with a crystal structure confirming the cis–anti stereo-
chemistry of the aldol and the syn arrangement of the
OH groups in the reduced aldol (Fig. 1).
Scheme 2 illustrates our synthesis of the chiral aldehyde
reagent:
a
protected form of D- ribose. The
precedented11e (S)-proline-catalysed aldol reaction of
2,2-dimethyl-1,3-dioxan-5-one (3a, dioxanone) with
1,3-dithiane-2-carbaldehyde 5 gave, in the presence of
lithium chloride (a weak Lewis acid), the corresponding
anti aldol product 6a. The reaction proceeded in high
yield (98%) and with high diastereo- and enantioselecti-
vity (de 96%, ee 92%). As we have emphasized in our
preceding communications,15 the presence of LiCl was
beneficial to higher selectivity. Stereoselective reduction
of the aldol adduct 6a with NaBH(OAc)3 resulted in the
syn-1,3-diol product 7a. This interesting (note syn selec-
tivity and not anti that might have been expected) result
was in agreement with reports by both Barbas11l and
Enders.11e–g The hydroxyl groups in the reduced prod-
uct were protected as benzyl ethers using standard con-
ditions giving the protected form of D-ribose, where the
thioacetal group masked the aldehyde functionality. To
unmask this group, compound 8 was first subjected to
oxidative hydrolysis conditions using several different
With the aldehyde reagent 9 in hand, the stage was set
for the key aldol reaction. We have used organocatalytic
conditions and two different dioxanones as nucleophiles.
The results are summarized in Table 1 (see Scheme 3).
As expected, the reaction gave two different diastereo-
isomeric aldols and, less expectedly, the corresponding
dehydration product.17 Interestingly, there seems to be
an appreciable steric effect in the proline-mediated cata-
lytic cycle: the reactions involving 2-tert-butyl-2-methyl
dioxanone proceeded with higher diastereoselectivity
(cf. entry 1 vs 3 and entry 2 vs 4) than the reactions with
the 2,2-dimethyldioxanone. Thus, switching from C2 to
CS-symmetrical dioxanone has substantially improved
O
OH OH
O
OH
S
CHO
S
S
(i)
(ii)
+
O
O
S
O
O
S
O
O
S
R1 R2
5
R1 R2
R1 R2
7a: y 96%; dr 98:02
7b: y 92%; dr 98:02
6a: y 98%; dr 99:01; er 96:04
6b: y 84%; dr 99:01; er 96:04
3a: R1, R2 = Me
3b: R1 = t-Bu; R2 = Me
(iii)
OBn OBn
OBn OBn
H
S
(iv)
O
O
O
O
O
S
Me Me
Me Me
8
y 87%
9
y 69%
Scheme 2. Synthesis of protected D-ribose. Reagents and conditions: (i) (S)-Proline, (30 mol%) LiCl, DMSO, 5 ꢁC, 48 h; (ii) NaBH(OAc)3, AcOH/
DCM (1:5), ꢀ20 ꢁC, 24 h; (iii) NaH, BnBr, TBAI, THF, 0 ꢁC to rt, 6 h; (iv) NBS, AgNO3, CH3CN/H2O (4:1), 0 ꢁC, 15 min.

N. Palyam et al. / Tetrahedron Letters 48 (2007) 9195–9198
9197
the diastereoselectivity (de up to 92% from 34%). As
reported before,15 the addition of LiCl also improved
the diastereoselectivity (cf. entries 1 and 2, and 3 with 4).
Deprotection of the aldol product 10d was carried under
acidic conditions (2 N HCl solution in THF) to provide
the eight carbon monosaccharide 13, that was isolated
and characterized as the acetate derivative,18 that is,
the protected form of (+)-D-glycero-D-manno-a-oct-2-
ulose 14 (25% overall yield in seven steps) as illustrated
in Scheme 4.
In summary, a derivative of a naturally occurring higher
sugar (+)-D-glycero-D-manno-a-oct-2-ulose 14 was syn-
thesized in seven steps starting from commercially avail-
able dioxanone 3, with the key stereoselective steps
comprising two stereoselective aldol reactions catalyzed
by proline and diastereoselective reduction of dioxanone
aldol, illustrating the potential of this synthetic strategy.
Figure 1. ORTEP diagram for compound 7b.
Table 1. Proline-catalyzed aldol addition of 1,3-dioxan-5-ones to protected D-ribose (9)
Entry
Dioxanone
Additive
Conversiona (%)
Yieldb (%)
dra 10:11
R1
R2
10
12
1
2
3
4
Me
Me
t-Bu
t-Bu
Me
Me
Me
Me
—
LiCl
—
92
88
>98
94
42
51
56
69
22
16
14
8
2:1
7:1
9:1
16:1
LiCl
a Determined by 1H NMR of the crude product.
b After column chromatography (SiO2).
O
O
O
O
OH
O
O
O
O
OH
O
O
OBn OBn
H
H
(S)-Proline (0.30 eq)
Additive (1 eq)
H
+
+
+
O
O
OBn OBn
O
O
OBn OBn
O
O
O
O
OBn OBn
O
O
O
DMSO; 5 °C
R2
R1
R2
R1
R2
R1
R1 R2
48 Hr
12
11
10
3
9
Scheme 3. Synthesis of acetonide-protected octulose (10).
OH
Me Me
OBn
HO
O
2
OH OH OH
O
OH
O
O
5
7
3
O
1
(i)
8
BnO
HO
4
6
OH OH OBn OBn
OH
O
O
OBn OBn
10d
OH
t-Bu
13
(ii)
OAc
O
OH OH OH
OBn
AcO
O
BnO
AcO
OH OH OH OH
(+)-D-glycero-D-manno-2-octulose
OAc
OAc
14
Scheme 4. Synthesis of protected (+)-D-glycero-D-manno-2-octulose (14). Reagents and conditions: (i) 2 N HCl, THF, rt, 2 h; (ii) NaOAc, Ac2O,
reflux, 2 h, yield: 65%.

9198
N. Palyam et al. / Tetrahedron Letters 48 (2007) 9195–9198
11. Selected papers: (a) Tanaka, F.; Barbas, C. F., III. In
Enantioselective Organocatalysis; Dalko, I. P., Ed.; Wiley-
VCH: Weinheim, 2007, Chapter 2; (b) Enders, D.;
Vrettou, M. Synthesis 2006, 2155; (c) Enders, D.; Chow,
S. Eur. J. Org. Chem. 2006, 4578; (d) Grondal, C.; Enders,
D. Synlett 2006, 3507; (e) Enders, D.; Grondal, C. Angew.
Chem., Int. Ed. 2005, 44, 1210; (f) Grondal, C.; Enders, D.
Tetrahedron 2006, 62, 329; (g) Enders, D.; Gasperi, T.
Chem. Commun. 2007, 88; (h) Grondal, C.; Enders, D.
Adv. Synth. Catal. 2007, 349, 694; (i) Casas, J.; Engqvist,
M.; Ibrahem, I.; Kaynak, B.; Cordova, A. Angew. Chem.,
Int. Ed. 2005, 117, 1367; (j) Ibrahem, I.; Zou, W.; Xu, Y.;
Cordova, A. Adv. Synth. Catal. 2006, 348, 211; (k)
Ibrahem, I.; Cordova, A. Tetrahedron Lett. 2005, 46,
3363; (l) Suri, J. T.; Mitsumori, S.; Alberthofer, K.;
Tanaka, F.; Barbas, C. F., III. J. Org. Chem. 2006, 71,
3822.
Further investigations to expand the scope of this meth-
odology to the synthesis of sialic acids and other higher
sugar derivatives are ongoing and will be reported in due
course.
Acknowledgements
The authors thank NSERC Canada and the University
of Saskatchewan for financial support and Saskatche-
wan Structural Sciences Centre for help in analytical
measurements. We thank Dr. J. Wilson Quail for solv-
ing the crystal structure of compound 7b.
References and notes
12. Majewski, M.; Nowak, P. J. Org. Chem. 2000, 65, 5152.
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14. Haustveit, G.; Wold, K. J. Acta Chem. Scand. 1970, 24,
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1. (a) Levy, D. E.; Fugedi, P. The Organic Chemistry of
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Carbohydrate Chemistry; Horton, D.; McGarvey, G. J.,
Eds.; ACS Symp. Ser.; American Chemical Society—ACS:
Washington, 1989; Vol. 386, Chapter 5.
2. For reviews on higher monosaccharides see: (a) Danishef-
sky, S. J.; DeNinno, M. P. Angew. Chem., Int. Ed. Engl.
1987, 26, 15; (b) Jarosz, S. J. Carbohydr. Chem. 2001, 20,
93; (c) Brimacombe, J. S. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
1989; Vol. 4, pp 157–193; (d) Zamojski, A.; Jarosz, S.
Polym. J. Chem. 1992, 66, 525; (e) Casiraghi, G.; Rassu,
G.. In Studies in Natural Products Chemistry; Atta-ur-
Rahman, Ed.; Elsevier: Amsterdam, 1992; Vol. 11, pp
429–480.
3. (a) Vuilhorgne, M.; Ennifar, S.; Das, B. C.; Paschal, J. W.;
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1974, 27, 783; (c) Fuerstner, A.; Wuchrer, M. Chem. Eur.
J. 2006, 12, 76.
4. Structure Activity Relationships Among the Semisynthetic
Antibiotics; Magerlein, B. J., Pearlman, D., Eds.; Aca-
demic Press: New York, 1977; p 601.
5. (a) Hemeon, I.; Bennet, A. J. Synthesis 2007, 13, 1899; (b)
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Kiefel, M. J.; Itzstein, V. M. Chem. Rev. 2002, 102, 471.
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8. (a) Jarosz, S.; Skora, S.; Kosciolowska, I. Carbohydr. Res.
2003, 7, 13; (b) Dondoni, A.; Merino, P. Org. Synth. 1993,
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15. Majewski, M.; Niewczas, I.; Palyam, N. Synlett 2006,
2387.
16. Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36, 3553.
17. At this stage, we could only assign stereochemistry by
analogy to previously synthesized compounds and by
analysis of NMR coupling constants. The absolute
stereochemistry of compounds 10 and 11 is believed to
be as drawn based on the following: (i) aldol addition of
dioxanones to aldehydes under organocatalytic conditions
is well known to give anti aldols with high selectivity;11,15
(ii) aldol addition of dioxanone enolates proceeds via
equatorial attack,12 and (iii) addition of dioxanone nucleo-
philes to chiral aldehydes having a stereocentre at the a-
carbon does not follow the Felkin-Anh model and results
in the OH group at the new carbinol stereocentre being
syn to the a-alkoxy group derived from the aldehyde.12
Further details will be reported in the full paper.
18. Compound 14: Sodium acetate (0.058 g, 0.70 mmol) and
acetic anhydride (3 mL) were added to the crude com-
pound 13 (25 mg, 0.06 mmol). The resulting mixture was
heated to 90 ꢁC for 2 h and the reaction was quenched
with ice and with saturated NaHCO3 solution. The
mixture was then extracted with AcOEt (3 · 20 mL)
and the combined organic layers were washed with brine.
The organic phase was dried over anhydrous Na2SO4
and concentrated. The crude product was purified by
flash column chromatography (SiO2; 30% AcOEt in
hexane), which afforded the cyclized product 14 (24 mg,
25
65%). ½aꢁD +44.6 (c 1, CHCl3) 1H NMR (CDCl3,
500 MHz): d 7.35–7.19 (m, 10H), 5.43 (d, 1H, J 3.2 Hz),
5.35 (dd, 1H, J1 3.2 Hz, J1 9.9 Hz), 4.77 (dd, 2H, J1
12.1 Hz, J2 12.0 Hz), 4.65 (dd, 3H, J1 10.1 Hz, J2 11.0 Hz),
4.42 (d, 1H, J 12.1 Hz), 4.26 (dd, 1H, J1 8.2 Hz, J2 8.1 Hz),
4.18 (dd, 1H, J1 4.1 Hz, J2 4.0 Hz), 4.1 (t, 1H, J 9.9 Hz),
3.95 (dd, 1H, J1 0.92 Hz, J2 4.0 Hz), 3.82 (dd, 1H, J1
0.92 Hz, J2 9.9 Hz), 2.12 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H),
1.99 (s, 3H), 1.92 (s, 3H). 13C NMR (CDCl3, 125 MHz): d
170.9, 170.2, 170.0, 169.6, 168.0, 138.5, 137.7, 128.7–127.9
(8 CH), 103.99, 77.96, 75.2, 74.8, 73.4, 72.5, 72.3, 67.5,
64.8, 60.6, 22.0, 21.1, 20.95, 20.87, 20.79. HRMS (CI,
9. Enders, D.; Matthias, V.; Lenzen, A. Angew. Chem., Int.
Ed. 2005, 44, 1304.
10. Selected papers: (a) Majewski, M.; Nowak, P. Synlett
1999, 1447; (b) Job, A.; Janec, C. F.; Bettray, W.; Peters,
R.; Enders, D. Tetrahedron 2002, 58, 2253; (c) Enders, D.;
Ince, S. J. Synthesis 2002, 619; (d) Enders, D.; Peiffer, E.;
Raabe, G. Synthesis 2007, 1021; (e) Ortiz, J. C.; Ozores,
L.; Cagide-Fagin, F.; Alonso, R. Chem. Commun. 2006,
4239.
NH3) exact mass calcd for ½Mꢁþ ðC32H38O13 þ NHþÞ
4
required: 648.2656, found: m/z 648.2641. MS (CI, NH3):
m/z (%) = 648 (100) [M+NHþ4 ], 588 (12), 571 (71), 359 (9),
240 (6), 108 (32), 91 (22), 77 (24). IR (Kubelka-Munk):
1751 (s), 1493 (w), 1451 (m) cmꢀ1
.