A temperature-guided diastereoselectivity switch during the desymmetrization of meso-7-azabicyclo[2.2.1]heptadiene: New strategy towards the synthesis of aminocyclitols

Article abstract of DOI:10.1002/chem.201100418

Strike while the iron is hot: A temperature-guided diastereoselectivity switch has been observed in the desymmetrization of meso-7-azabicyclic alkadiene. Both enantiomeric forms of this bicyclic structural framework are formed by using either of the enant

Full text of DOI:10.1002/chem.201100418

DOI: 10.1002/chem.201100418
A Temperature-Guided Diastereoselectivity Switch During the
Desymmetrization of meso-7-AzabicycloACTHUNRGTNE[NUG 2.2.1]heptadiene: New Strategy
towards the Synthesis of Aminocyclitols
Ganesh Pandey* and Salla Rajender[a]
Dedicated to Prof. S. V. Kessar for his outstanding contribution to organic chemistry
Asymmetric desymmetrization is an attractive and power-
explanation and its application in the synthesis of amino-
ACHTUNGTRENUNcNG yclitols.
Compound meso-7 was readily obtained (72% yield) by
reacting cycloadduct[6] 5 with 1 equivalent of sodium salt of
thiophenol followed by controlled oxidation using 2.1 equiv-
alents of mCPBA as an oxidizing agent (Scheme 2). Desym-
ful strategy for the synthesis of many important chiral build-
ing blocks with multiple stereocenters.[1] Synthetic methods
concerning the construction of the 7-azabicyclo-
ACHTUNGTRENNUNG[2.2.1]heptane skeleton in optically pure form have received
much attention because this structural motif is contained in
several biologically important and structurally complex com-
pounds and is also used in their synthesis.[2] Our research
group has recently reported the desymmetrization of meso-1
to construct enantiopure 7-azabicyclic system 4 and demon-
strated its application in the synthesis of conduramines.[3]
While exploring further the potential of this strategy with
meso-7, to investigate the scope of functionalization of the
Scheme 2. Synthesis of meso-precursor.
ꢀ
C5 C6 olefinic bond, we stumbled upon an unusual observa-
tion of diastereoselectivity switch from ꢀ1008C!358C that
provides the opportunity of obtaining both enantiomers of 4
using either one of the enantiomer of the hydrobenzoin 2 as
an enantiodiscriminating reagent (Scheme 1). Although tem-
metrization of 7 by the usual experimental protocol, estab-
lished earlier by our research group,[3] (stirring 2 h with an
equivalent amount of the sodium salt of (R,R)-2 at 08C),
produced a mixture of all four diastereomers[7] of the corre-
sponding desymmetrized ketals 8 and 9 in 2:2:6:1 ratios
(Scheme 3). This observation was in sharp contrast and sur-
prising to our earlier observations[3] (Scheme 1). Therefore,
it occurred to us to perform the same reaction at lower tem-
perature with the hope that this might improve the diaster-
eoselctivity. Indeed, desymmetrization at ꢀ1008C gave
endo-(+)-8 in high yield (89%) and in excellent diastereose-
lectivity (99:1 d.r.)[7] which was fully characterized by
1H NMR, 13C NMR, mass spectroscopy, and the endo orien-
tation of SO2Ph group was unambiguously confirmed by
NOESY interactions.[8] To provide a conclusive structural
proof for endo-(+)-8, it was dihydroxylated (OsO4, 50%
aqueous NMO, acetone/water (9:1)) to obtain (+)-10 in
91% yield whose X-ray crystal analysis[9a] (Figure 1) estab-
lished its structure. To support this observation, desymmetri-
zation of 7 was also performed with the opposite enantiomer
(S,S)-2 which gave the single diastereomer endo-(ꢀ)-8,
whose structure and absolute configuration was also con-
firmed by X-ray analysis of the corresponding dihydroxylat-
ed derivative (ꢀ)-10 (Figure 1).[9b]
Scheme 1. Desymmetrization of meso-7-azabicycloalkene system. Boc=
tert-butyloxycarbonyl.
perature is known to play a significant role in changing the
stereoselectivity in various reactions,[4,5] this is a novel obser-
vation of temperature-guided reversal of diastereoselectivity
in the desymmetrization reaction. Herein, we wish to report
this unprecedented diastereoselectivity switch, a plausible
[a] Dr. G. Pandey, S. Rajender
Division of Organic Chemistry
National Chemical Laboratory
Pune-411 008 (India)
To probe further the role of the temperature on the dia-
stereoselectivity, desymmetrization of 7 with (R,R)-2 was
screened at different temperatures in the range of
ꢀ1008C!508C and the results are presented in Table 1. Al-
Fax : (+91)202590-2628
E-mail: gp.pandey@ncl.res.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100418.
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Chem. Eur. J. 2011, 17, 6304 – 6308

COMMUNICATION
Table 1. Temperature- and solvent-dependent desymmetrization of meso-
7.
Solvent
T
[8C]
t
Yield
[%]
8/9 (d.r.)[a]
[h]
THF
THF
THF
THF
ꢀ100
ꢀ78
0
35
50
3.5
3.5
2.0
2.0
2.0
3.5
2.0
2.0
89
91
85
76
28
67
48
62
99:1
92:8
diastereomeric mixture
8:92
1:99
75:25
20:80
15:85
THF
toluene
toluene
dioxane
ꢀ78
35
35
[a] Diastereomeric ratios were confirmed by HPLC analysis (XBridge
RP-18 column, 250ꢁ4.6 mm, CH3CN/H2O=60:40).
enantiomeric pairs of 7-azabicyclic ketones 4 upon hydroge-
nation[3b] and should show opposite sign of optical rotation
if, indeed, they are diastereomers. To confirm this, both exo-
8 and exo-9 were hydrogenated (Pd/C, 10 mol%, AcOH, 60
psi) to produce (+)-4 ([a]2D7 =+57.1 (c 0.60, CHCl3), lit.
[3b]= +57.9) and (ꢀ)-4 ([a]2D7 =ꢀ55.6 (c 0.75, CHCl3)), re-
spectively (Scheme 4). The optical rotation values were in
Scheme 3. Temperature-dependent desymmetrization. NMO=4-methyl-
morpholine-N-oxide.
though diastereoselectivity of exo-9 was found very high
(99:1 d.r.) at 508C, poor yield (28%) led us to standardize it
at 358C (92:8 d.r., 79% yield). Furthermore, to confirm the
structure and absolute configuration of exo-9, it was also di-
hydroxylated to corresponding 11 in the similar manner as
described for 8 for X-ray analysis[9c] (Figure 1). It was sur-
prising to note that its diastereoselectivity was opposite
except the exo-orientation of the phenylsulfonyl group com-
pared to endo-(+)-8 formed at ꢀ1008C.
Scheme 4. Synthesis of (+/ꢀ)-4.
Intrigued by this unusual result of inversion of diastereo-
selectivity from ꢀ1008C!358C, we also investigated the de-
symmetrization in different solvents as solvent is also known
to play significant role in diastereoselective and enantiose-
lective reactions.[5b,10] However, from the results (Table 1) it
is apparent that the solvent has no significant role in altering
the diastereoselectivity, particularly in this case.
complete agreement with those reported previously by our
research group.[3b] To provide further support to the fact
that both exo-8 and exo-9 are, indeed, chiral acetal deriva-
tives of enantiomeric bicyclic scaffolds, they were converted
into their corresponding known dihydroxylated derivatives
(+)-12 [a]2D7 +48.1 (c 0.65, CHCl3) and (ꢀ)-12 ([a]2D7 ꢀ50.8
At this stage, we also visualized that exo-8, easily obtain-
ACHTUNGTRENNUNGable by endo-(+)-8 epimerization, and exo-9 would afford
Figure 1. ORTEP diagrams of (+)-10, (ꢀ)-10 and 11. Ellipsoids set at the 50% probability level, hydrogen atoms omitted for clarity.
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G. Pandey and S. Rajender
Figure 2. Proposed transition state.
the synthesis of aminocyclitols possesing either 1, 2-trans-,
or cis-vicinal amino alcohol moiety, respectively, by follow-
ing the protocol recently developed by our research
group.[3b] Aminocyclitols or aminoglycosides represent an
important class of antibiotics having significant relevance in
the medicinal chemistry.[14] Owing to their prominent biolog-
ical roles and structural importance, there has been consid-
erable interest in designing as well as developing new strat-
egies for the syntheses of aminocyclitols.[15] An overview of
the methodologies reported[16] on the synthesis of aminocy-
clitols indicates that the main challenge[15h] in this area lies
in the stereoselective installation of 1,2-vicinal amino alco-
hol moiety, most importantly[14c–f] trans, in a functionalized
cyclohexane moiety (Scheme 6). To synthesize aminocycli-
tols with a vicinal trans-aminocyclohexenol moiety (e.g., 1-
neo-inosamine), we got encouraged to attempt its synthesis
from (+)-10. Hydrogenation of (+)-10 provided 14, which
upon reduction with LiBH4 at ꢀ1008C furnished exclusively
15 (77% yield), characterized by 1H NMR and NOESY
analysis. Because the base-induced opening of this azabicy-
clic skeleton 15 to aminocyclitol structural framework re-
quired antiperiplanarity[3b] between phenylsulphone and C-5
Scheme 5. Synthesis of (+/ꢀ)-12 and 13. DMP=2,5-dimethylpyrrole,
TSA=toluenesulfonic acid.
(c 0.65, CHCl3)[11] and also to (+)-13 ([a]2D5 +38.7 (c 1.0,
CHCl3) and (ꢀ)-13 ([a]2D6 ꢀ41.4 (c 1.0, CHCl3), respectively
(Scheme 5), which were found to be enantiomeric pairs.
With these results, it became apparent that there is a tem-
perature-guided diastereoselectivity switch in the desymmet-
rization of 7 and both enantiomers of the desymmetrized
product could be obtained only by changing the reaction
ꢀ
temperature. To confirm the role of the C5 C6 olefinic
double bond for this unusual observation, desymmetriza-
tyion of 1 using (R,R)-2 was also screened from ꢀ1008C!
358C, which was always found to give 3 as a single dia-
ACHTUNGTRENNUNG
stereomer[12] irrespective of the temperature used. Although
at this stage we have no definite explanation for the role of
ꢀ
the C5 C6 double bond in effecting the diastereoselectivity
switch with temperature, we tentatively suggested the in-
volvement of two plausible transition states A and B at dif-
ferent temperatures. Transition state A appears to be fa-
ꢀ
vored at ꢀ1008C owing to the p p stacking interactions be-
tween the aromatic ring of the chiral diolate and the elec-
ꢀ
tron rich C5 C6 double bond, whereas the decrease of the
entropy is compensated by enthalpic stabilization by rise in
intermolecular interactions producing 8. On the other hand,
with the rise of the temperature, the value of the TDS term
(Eyring plot)[4,5b,13] increases towards the free energy change
because of weaker intermolecular interactions, thereby fa-
voring the transition state B in which the nucleophile ap-
proaches from the above face of the meso bicyclic skeleton
owing to steric crowding and producing 9 as a predominant
diastereomer (Figure 2).[3] To rule out the possible role of
N-Boc rotamers in this observed diaACTHUNRGTNNEUGstereoACHTUNGTERNsNUGN electivity switch,
desymmetrization of corresponding N-Me derivative of 7
was also studied at different temperatures and did not show
any significant difference.
Having established temperature-guided diastereoselectiv-
ity switch in the desymmetrization of 7 and a strategy to
obtain both enantiomers of 4, 12, and 13 using (R,R)-2 as an
enantiodiscriminating partner, we turned our attention to-
wards utilizing either (+)-10 or 11 as a chiral template for
Scheme 6. Synthesis of 1-neo-inosamine.
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Temperature-Guided Diastereoselectivity Switch
COMMUNICATION
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Experimental Section
[9] CCDC-797430, 797431, and 797432 contain the supplementary crys-
tallographic data for this paper. These data can be obtained free of
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www.ccdc.cam.ac.uk/data_request/cif.
A solution of (R,R)-hydrobenzoin (0.451 g, 2.11 mmol) dissolved in anhy-
drous THF (6 mL) was added dropwise to an ice-cooled anhydrous THF
(3 mL) solution containing suspension of NaH (0.172 g, 4.33 mmol, 60%
suspension in mineral oil). After complete addition, the reaction mixture
was allowed to stir at room temperature for 0.5 h and then cooled to
ꢀ1008C. A solution of 7 (1 g, 2.11 mmol) dissolved in anhydrous THF
(8 mL) was added dropwise into the flask while stirring at ꢀ1008C. The
reaction mixture was further allowed to stir at the same temperature for
an additional 3.5 h. After complete disappearance of 7, the reaction was
quenched at the same temperature with dropwise addition of methanol
(2 mL). Standard work-up followed by silica gel flash column chromatog-
raphy with ethyl acetate/petroleum ether (1:5!2:5) gave endo-(+)-8 as a
white solid (1.02 g, 89%). The diastereomeric purity was confirmed by
HPLC analysis.
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Keywords: azabicycloheptane
·
aminocyclitols
·
desymmetrization · diastereoselectivity · synthetic methods
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Received: February 8, 2011
Published online: April 26, 2011
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