Isofagomine 3 was found to be a very potent and competitive inhibitor for β-glucosidase 7, and 1-deoxyfuconojirimycin 4 is the most
powerful inhibitor of α-fucosidases known to date 8.
However, various comparative studies on simple glycolipid analogues have demonstrated a marked dependence of the selectivity
and/or potency of the inhibitors/ligands upon the position of the alkyl chain (1-C-or N-alkyl derivatives) 9. Meanwhile, Butters, T. D.
and co-workers also found that the presence of a hydrophobic N-alkyl chain of iminosugars provided an increase in inhibitory potency
to glucosidases 10. Actually, two N-alkyliminosugars have been approved as drugs: N-hydroxyethyl-1-deoxynojirimycin 5 (Glyset
TM) to treat complications associated with type II diabetes since 1996 and N-butyl-1-deoxynojirimycin 6 (ZavescaTM) for the
treatment of Gaucher’s disease since 2003 11. N-Alkylated iminosugars also show potent antiviral activities 12. Those promising
results of N-alkyliminosugars for drug discovery, have warranted further exploration of more original structural N-alkyliminosugars.
Henrein, as a part of our continuing interest in their synthesis 13, we report an efficient strategy for the synthesis of new six-member
and five-member N-alkyliminosugars from D-ribose.
Synthetic strategies for N-alkyliminosugars reported in the literature may be divided into two general categories 14: (a)
Constructing the nitrogen heterocycle via intramolecular cyclization, or (b) using a nucleophilic amine as a donor to achieve
intermolecular cyclization. However, the later intermolecular protocols often prove to be less effective with many intramolecular
byproducts and have to date been less exploited than the intramolecular approaches, which were well-documented strategies. Herein,
we employed iodine-induced intramolecular cyclization of acyclic alkenylamines as the key step to form the nitrogen heterocycle.
Synthesis of those novel N-alkyliminosugars commenced with the formation of 2,3-O-isopropylidene-D-ribofuranoside 7 from D-
ribose (Scheme 1). Given the propensity of ribose to form the thermodynamically more stable pyranose ring, short reaction times were
required to favour formation of the desired furanoside 15. Thus, in accordance with a procedure by Levene and Stiller 16, D-ribose
was subjected to 70% aqueous HClO
4
and 2,2-dimethoxypropane in MeOH for 2 h, resulting in D-ribofuranoside 7 in 87% yield with
trace amounts of the pyranose structural isomer. Installation of an iodide at the primary position was then carried out by heating a
o
2
solution of 7, triphenylphosphine, I and imidazole in methylbenzene at 80 C for 5 h to generated 8 in 79% yield. Ring-opening of 8 to
the unsaturated aldehyde 9 by Boord elimination was achieved with n-butyllithium 17. Since the aldehyde 9 is volatile, the aldehyde
was used without further purification in subsequential reductive amination with alkylamines and generated linear alkenylamines 10a-i
in moderate to good yield (Table 1).
With the key precursors 10a-i in hand, we used the iodine-induced cyclilization of the acyclic alkenylamines with I
dioxane-H O to construct the iodopyrrolidines 11a-i 18. Interestingly, we found that the absence of NaHCO could also lead to the
same results and with relative higher yield. We reasoned that the alkenylamines functioned as a weak base could replace NaHCO . The
2 3
/NaHCO in
2
3
3
employ of the documented method for hydrolyzing iodine to hydroxyl under room temperature with 4 mol/L NaOH proved to be
o
invalid in our experiment 19, whereas we elevated temperature to 60 C and monitored two products by TLC for each substrate
(
Table 1), and the ratio of these two products are about 1:1.
The structures of the two products were elucidated by NMR, which were determined as hydroxylpyrrolidine 12 and
hydroxylpiperidine 13. Then, 12a and 13a were chosen as representatives to determine the stereochemistry. Generally, the vicinal
coupling constants are commonly used to determine the relative stereochemistry of sugar analogues. H-C (2) was an upturned proton
(J2,3 < 9.0 Hz) for compound 12a. This result was later assigned by NOESY experiments (Fig. 2), which gave a middle correlation
between H-C (2) and H-C (3) suggesting 2,3-cis protons. The C (3) stereochemistry of compound 13a was determined by the coupling
constants between H-C (3) and H-C (2), H-C (4) (J2,3, J3,4 < 9.0 Hz) due to their axial-equatorial relationships, which supported that the
H-C (3) was an equatorial proton. The assignation was further confirmed by NOEs, which gave a moderate correlation between H-C
(3) and α-H-C (2), weak correlation between H-C (3) and α-H-C (6), and weak correlation between the vicinal equatorial protons H-C
(3) and H-C (4).
The general procedures for preparing the final products 12a–i and 13a-i are described as following: To dissolve compound 11a-i
+
-
(
6
1.5 mmol) to 10 mL THF, 10 mL of 4 mol/L aq. NaOH, to which 0.15 g [CH
3
(CH
2 3 4
) ] N I were added. The mixture was refluxed at
o
0 C for 24 h. Then, A yellow oil was obtained after usual workup, which was separated by a silica gel (300–400 mesh) column using
petroleum ether/ethyl acetate (5:1→3:1) to obtain pure compound 12a-i and 13a-i. The detailed synthetic procedures and the related
data of other compounds are provided in the Supporting information.
The formation of two products in the hydrolyzation can be explained via a carbocation rearrangement mechanism. In this two-phase
hydrolyzation reaction, iodine, as a leaving group, is transported to water phase by phase transfer catalyst Bn NI. The newly created
4
primary carbocation is attacked by hydroxyl ion and obtained pyrrolidine. Meanwhile, the primary carbocation tends to rearrange to
more stable secondary carbocation, which is attacked by hydroxyl ion to form a piperidine product (Scheme 2).
Wang, Haibo
