Straightforward synthesis of diverse 1-deoxyazapyranosides via stereocontrolled nucleophilic additions to six-membered cyclic nitrones

Article abstract of DOI:10.1002/ejoc.201001045

A systematic study of diastereoselective nucleophilic addition of Grignard reagents to six-membered chiral tri-O-benzyl cyclic nitrones is described. With all eight chiral cyclic nitrones and asymmetric reaction conditions in hand, a practical methodology is established for the preparation of diverse 1-deoxyazapyranosides bearing various stereogenic centers. We have developed practical methods to prepare all eight six-membered chiral cyclic nitrones. Using these cyclic nitrones and diastereoselective nucleophilic additions, 12 examples of diverse 1-deoxyazapyranosides including enantiomers were synthesized to demonstrate the generality and flexibility of this new approach.

Full text of DOI:10.1002/ejoc.201001045

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001045
Straightforward Synthesis of Diverse 1-Deoxyazapyranosides via
Stereocontrolled Nucleophilic Additions to Six-Membered Cyclic Nitrones
Ting-Hao Chan,[a] Yi-Fan Chang,[a] Jung-Jung Hsu,[a] and Wei-Chieh Cheng*[a]
Keywords: Diastereoselectivity / Natural products / Nucleophilic addition / Alkaloids / Grignard reaction
A systematic study of diastereoselective nucleophilic ad-
dition of Grignard reagents to six-membered chiral tri-O-
benzyl cyclic nitrones is described. With all eight chiral cyclic
nitrones and asymmetric reaction conditions in hand, a prac-
tical methodology is established for the preparation of di-
verse 1-deoxyazapyranosides bearing various stereogenic
centers.
Five-membered cyclic nitrones have been extensively ap-
plied in synthetic chemistry, especially for the preparation
of pyrrolodine-based molecules.[5–7] In our previous re-
ports,[6] we developed a concise method to prepare various
azafuranosides, such as DMDP, ADMDP, and their iso-
mers, by using five-membered cyclic nitrones as key inter-
mediates.[6]
In contrast, the use of six-membered tri-O-benzyl chiral
cyclic nitrones[7–9] as key intermediates to study their dia-
stereoselective nucleophilic additions towards the synthesis
of 1-deoxyazapyranosides has scarcely been investigated[10b]
(Figure 2). Perhaps the systematic preparation of chiral six-
membered cyclic nitrones is not available; thus, their syn-
thetic study and application are limited.
Introduction
Naturally occurring or synthetic 1-deoxyazapyranosides
(piperidine-based alkaloids) bearing multihydroxy groups
with proper configurations possess various biological activi-
ties to modulate carbohydrate-processing enzymes and thus
are utilized for therapeutic studies, especially in the treat-
ment of various diseases such as diabetes, cancer, and viral
infections, and lysosomal storage disorders.[1] For example,
DMJ is a specific inhibitor of Golgi mannosidase I to block
conversion of high mannose to complex oligosaccharides;
Miglitol is for the treatment of type II diabetes; and Amigal
(DGJ) is a chemical chaperone for Fabry disease (Figure 1).
Due to their versatile biological behaviors, many of the syn-
thetic efforts are toward the preparation of these molecules
and their derivatives.[2–4]
Figure 2. General synthetic criteria and the relationship between 1-
deoxyazapyranosides and polyhydroxylated piperidines.
To extend our research interests and create a practical
synthetic method for various polyhydroxylated piperidines,
in this communication we report new synthetic routes to
prepare all eight enantiopure tri-O-benzyl six-membered cy-
clic nitrones (Figure 3) that undergo diastereoselective nu-
cleophilic additions with Grignard reagents. With proper
stereocontrol, highly diverse 1-deoxyazapyranosides will be
prepared to demonstrate the flexibility of this new synthetic
strategy.
Figure 1. Examples of biologically interesting 1-deoxyazapyranos-
ides (polyhydroxylated piperidines).
[a] Genomics Research Center, Academia Sinica,
128, Academia Road, Sec. 2, Taipei 115, Taiwan
Fax: +886-2-2789-8771
E-mail: wcheng@gate.sinica.edu.tw
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001045.
View this journal online at
wileyonlinelibrary.com
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T.-H. Chan, Y.-F. Chang, J.-J. Hsu, W.-C. Cheng
SHORT COMMUNICATION
Oxidation of alkene 3 followed by oxime formation with
NH2OTBDPS gave 5 (86%). Treatment of 5 with the suc-
cessive transformations (ozonolysis, reduction, mesylation,
and deprotection with concomitant cyclization) generated
1b smoothly in a yield of 57% over the four steps from 5
(Scheme 2). Likewise, cyclic nitrones 1d, 1f, and 1h were
prepared in 30–35% overall yield (see the Supporting Infor-
mation).
Figure 3. Chemical structures of all eight six-membered tri-O-
benzyl chiral cyclic nitrones 1a–h.
Scheme 2. New approach (method B) for the preparation of 1b by
double-bond flipping. Reagents and conditions: (a) DMSO,
(COCl)2, DCM, (iPr)2EtN, –78 °C
Ǟ
room temp.;
(b) H2NOTBDPS, PPTS, MgSO4, toluene, reflux; (c) 1. O3, MeOH,
–78 °C, then Me2S; 2. NaBH4, MeOH, 0 °C Ǟ room temp.;
(d) MsCl, Et3N, DCM; (e) TBAF, THF, reflux.
Results and Discussion
In our model study for the preparation of cyclic nitrone
1a, the Wittig olefination of 2,3,4-tri-O-benzyl--arabino-
pyranoside (2) followed by mesylation gave alkene 4 in an
overall 95% yield over the two steps. After ozonolysis of 4,
hydroxylamine[10,11] was directly added to obtain 1a in 85%
yield, and the overall yield was 79% for the four steps
(Scheme 1).
Notably, cyclic nitrones 1a and 1b are all from the same
starting material 2 and the only difference is that the unsat-
urated double bond is on the right side in 1a and that is on
the left side in 1b (Figure 3). All eight cyclic nitrones 1a–h
were systematically prepared through methods A and B,
and it is the first time that all of them have been prepared
from only four inexpensive chiral pools, including - and -
arabinose, -xylose, and -ribose. With all eight cyclic
nitrones 1a–h in hand, we had the privilege to comprehen-
sively investigate their diastereoselective chemistry in nucle-
ophilic additions and also to investigate their further syn-
thetic applications.
As shown in Table 1, we utilized 1a as our representative
model to investigate the asymmetric addition under various
conditions. Satisfactorily, all reactions proceeded in good
Scheme 1. Preparation of 1a through method A. Reagents and con-
ditions: (a) MePPh3Br, nBuLi, THF, –78 °C Ǟ room temp.;
(b) MsCl, Et3N, DCM; (c) O3, MeOH/DCM, –78 °C, then DMS;
(d) H2NOH·HCl, NaHCO3, MeOH, reflux.
Table 1. Diastereoselective nucleophilic addition of Grignard rea-
gents to cyclic nitrone 1a.
Compared with Tamura’s method[8] or our previous
modified conditions,[12] this new method possesses several
merits should be addressed: (1) a multigram-scale synthesis
of nitrones can be achieved; (2) the procedure is practical
and reagents are inexpensive; (3) the overall yield for four
steps is improved to 79%. Gratifyingly, cyclic nitrones 1c,
1e, and 1g were obtained in 45–71% overall yield by using
this approach from the corresponding 2,3,4-tri-O-benzyl-al-
dopyranoses (Scheme 1, method A). However, if applying
this approach to prepare 1b, 1d, 1f, and 1h, the use of ex-
pensive -lyxose, -xylose, -ribose, and -lyxose, respec-
tively, as the starting material is inevitable (see the Support-
ing Information).
To circumvent this dilemma and to develop more practi-
cal methodology, our initial attempts to reduce O-TBDPS
oxime to the amine did not work well due to the extremely
sensitive conditions required for oxime reduction (Ͻ10%
yield; see the Supporting Information).[13] After reinvestig-
ation, the problem was finally overcome by switching both
Entry
Nu
Conditions
Product,
Ratio
yield [%][a]
anti/syn[b,c]
1
2
3
4
5
6
7
8
iPr
Bn
THF, 0 °C
THF, 0 °C
THF, 0 °C
THF, 0 °C
THF, –78 °C
7, 79
8, 93
9, 81
10, 86
10, 83
10, 85
10, 83
10, 80
Ն95:5[d]
Ն95:5[d]
77:23
66:33
62:38
19:81
10:90
5:95
allyl
vinyl
vinyl
vinyl
vinyl
THF, Et2AlCl, –78 °C
DCM, Et2AlCl, –78 °C
vinyl DCM, (iBu)2AlCl, –78 °C
[a] Isolated yield. [b] Determined by NMR spectroscopic analysis.
[c] Configuration assigned after hydrogenolysis or reductive cleav-
functional groups before the intramolecular cyclization. age of the N–O bond. [d] Ref.[12]
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Straightforward Synthesis of Diverse 1-Deoxyazapyranosides
yields (79–93%). The assignment of the configurations of Table 2. Stereocontrolled nucleophilic additions to various cyclic
nitrones.
the adducts by NMR spectroscopic analysis was carried out
after the reductive cleavage of the N–O bond (Zn/AcOH)
or after catalytic hydrogenation [Pd(OH)2, H2] because of
the broad signal peaks caused by the N-hydroxy group.[14]
When a bulky nucleophile such as isopropylMgBr or
BnMgBr was adopted, corresponding adduct 7 or 8 (2,3-
anti adduct; J2,3 = 9.0 Hz) was exclusively obtained
(Table 1, Entries 1 and 2). The use of a smaller nucleophile
such as vinylMgBr gave diastereoisomers, and the ratio was
not affected dramatically by the reaction temperature
(Table 1, Entries 4 and 5). The results could be rationalized
by using the proposed model in Scheme 3, where a nucleo-
phile favors approach to 1a from the less sterically hindered
side to afford the 2,3-anti adduct as the exclusive or major
product.
Entry Cyclic
nitrone
Conditions
Product,
Ratio[b,c]
anti/syn
yield [%][a]
1
2
3
4
5
6
7
8
1b
1b
1c
1c
1e
1e
1g
1h
THF, –78 °C
DCM, (iBu)2AlCl, –78 °C
THF, –78 °C
DCM, (iBu)2AlCl, –78 °C
THF, –78 °C
11, 87
11, 85
12, 71
12, 75
13, 73
13, 72
14, 85
15, 83
Ն95:5
33:67
83:17
5:95
Ն95:5
Ն95:5
63:37
Ն95:5
DCM, (iBu)2AlCl, –78 °C
THF, –78 °C
THF, –78 °C
[a] Isolated yield. [b] Determined by NMR spectroscopic analysis.
[c] Configuration assigned after hydrogenolysis or reductive cleav-
age of the N–O bond.
nating solvent (THF), more 2,3-syn isomer was observed
(Table 1, Entries 6 and 7). In addition, when the bulky
Lewis acid (iBu)2AlCl was used (Table 1, Entry 8), adduct
10 was produced as the 2,3-syn isomer with the highest ex-
cess observed for our study (Table 1, Entry 8; Ն95dr). To
explain this observation, we proposed a mechanistic path-
way based on the antiperiplanar lone pair theory (stereo-
electronic effect),[17] in which the Lewis acid chelates to the
oxygen of the nitrone moiety to generate a chair-like transi-
tion state as the favored form, and subsequently, a nucleo-
Scheme 3. Proposed mechanism for a nucleophile attacking 1a with
or without premixing Lewis acid (LA).
Compounds 1a, 1b, 1c, and 1e are the corresponding phile readily attacks the axial position to yield a major 2,3-
enantiomers of 1g, 1h, 1d, and 1f, respectively; thus, we syn adduct (Scheme 3).
could conveniently use the former four cyclic nitrones as
When cyclic nitrones 1b, 1c, and 1e were tested, a similar
representative substrates for an extensive diastereoselectiv- trend of Lewis acid induced reversal of diastereoselectivity
ity study. Vinylmagnesium bromide (vinylMgBr) was cho- was observed (Table 2), except in the case of 1e. Only one
sen as our model nucleophile because of the versatile syn- single adduct 13 possessing a 2,3-anti configuration was ob-
thetic utility of the vinyl moiety[15] (Table 2).
tained from 1e, no matter whether the Lewis acid was pre-
As expected, all the addition reactions in Table 2 pro- mixed or not (Table 2, Entries 5 and 6). Presumably, the
ceeded in good yield (71–87%). For the results of 2,3-syn steric hindrance effect of three tri-O-benzyl substituents (all
and 2,3-anti selectivity, the reaction of 1b with vinylMgBr syn configurations) imposes 1e into a stable conformation,
exhibited excellent anti selectivity (Table 2, Entry 1; which cannot be twisted in the presence of a Lewis acid.
Ն95:5dr). Using the same reaction conditions, compound
The valuable information encouraged us to challenge the
1e was completely converted into single anti adduct 13 new strategy for the preparation of various biologically
(Table 2, Entry 5). In contrast, when 1c was converted into interesting piperidines, also called 1-deoxyazapyranosides.
adduct 12, the minor 2,3-syn isomer was observed (Table 2, In our first case study, piperidine 17 (DMJ) was efficiently
Entry 3; 83:17dr). Analysis of the results in Tables 1 and 2 prepared in 75% yield from intermediate 16 (Scheme 4).
showed that the facial selectivity is significantly affected by Following a similar approach, other DMJ-based analogues,
the steric hindrance effect of the O-benzyl groups at C3 and such as 18 (5-epi-DMJ), 19 (6-homo-5-epi-DMJ), 20 (6-
C4 and less influenced by the O-benzyl substituent at C5.
homo-DMJ), and more complicated derivatives 21–24, were
Interestingly, when 1a was pretreated with a Lewis also prepared (Figure 4), and the synthesis of their interme-
acid[16] followed by the addition of vinylMgBr (Table 1, En- diates is described in the Supporting Information. Piper-
tries 6–8), the diastereoselectivity was significantly changed, idines 19, 20, and 22–24 are new azasugar-based molecules
and the ratio of isomers was dependent on the reaction con- and have not been reported yet. Next, we turned to synthe-
ditions such as the Lewis acid and solvent. When a nonco- size various enantiopure 1-deoxyazapyranosides with diver-
ordinating solvent (DCM) was utilized instead of a coordi- gent stereocenters to demonstrate the generality of this new
Eur. J. Org. Chem. 2010, 5555–5559
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5557

T.-H. Chan, Y.-F. Chang, J.-J. Hsu, W.-C. Cheng
SHORT COMMUNICATION
approach. As illustrated in Figure 5, -DMJ (25), DNJ (26), be systematically studied. Using these cyclic nitrones and
DGJ (27), and 5-epi-DGJ (28) were prepared in 35–54% stereocontrolled synthesis, 12 examples of diverse 1-deoxy-
overall yield from 1g, 1d, and 1h, respectively, through a azapyranosides including enantiomers were synthesized to
similar synthetic route. Obviously, as long as an appropriate demonstrate the generality and flexibility of this new ap-
tri-O-benzyl cyclic nitrone is chosen from our nitrone li- proach. We are applying this method to prepare biologically
brary (1a–h), the most desired 1-deoxyazapyranoside interesting molecules to systematically modulate sugar-pro-
should be generated after concise transformations with cessing enzymes, and the results will be published in due
stereocontrolled nucleophilic addition as the key step.
course.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, compound characterization data, and
copies of the NMR spectra.
Acknowledgments
Scheme 4. Reagents and conditions: (a) 1. VinylMgBr, THF, 0 °C;
2. excess Zn, AcOH, room temp.; (b) 1. (Boc)2O, Et3N, DCM;
2. O3, MeOH/DCM, –78 °C, then DMS; 3. NaBH4, MeOH;
4. 10% HCl(aq.), MeOH, 70 °C; (c) H2 (g), Pd(OH)2/C, 10%
HCl(aq.)/MeOH, room temp.
We thank the National Science Council and the Academia Sinica
for financial support.
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Conclusions
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nitrones 1a–h were prepared as key intermediates so that
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Received: July 23, 2010
Published Online: September 13, 2010
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