A facile synthesis of a polyhydroxylated 2-azabicyclo[3.2.1]octane

Article abstract of DOI:10.1021/jo0619231

(Chemical Equation Presented) Synthetic or natural aza-sugars have shown promise as a therapeutic approach to a variety of disease states by acting as transition state mimics to sugar processing enzymes. Although the synthesis of functionalized bicyclo[3.

Full text of DOI:10.1021/jo0619231

azabicycle has been reported,8 the route is low yielding and
does not allow for the introduction of the 4-hydroxyl group.
An alternative synthesis prepared a lactone derivative of 3,
which incorporated the 4-hydroxyl group, but the synthesis is
quite long and low yielding.9 Therefore, we decided to
investigate the selective functionalization of N-tosyl-2-azabicyclo-
[3.2.1]octa-3,6-diene (2) as a starting point for our synthesis of
3. Compound 2 is readily available,10,11 and the two double
bonds can be chemoselectively differentiated to provide the
target compound 3 (Scheme 1).
A Facile Synthesis of a Polyhydroxylated
2-Azabicyclo[3.2.1]octane
Damon D. Reed and Stephen C. Bergmeier*
Department of Chemistry and Biochemistry, Clippinger
Laboratories, Ohio UniVersity, Athens, Ohio 45701
bergmeis@ohiou.edu
The reaction of tosyl azide12 with norbornadiene, 1, yielded
the desired N-tosyl-2-azabicyclo[3.2.1]octa-3,6-diene 2 in good
yield.10,11 With compound 2 in hand, regioselective dihydroxy-
lation of the unfunctionalized olefin was attempted with OsO4/
NMO under a variety of solvent and temperature conditions.
Although the desired product 4 was isolated from OsO4/NMO-
mediated dihydroxylation, low yields, and difficulties with
purification prompted the investigation of other dihydroxylation
methodologies. Surprisingly, AD-mix R or â chemoselectively
dihydroxylates the desired double bond to form the racemic exo-
diol 4 in excellent yield. The kinetic resolution of [2.2.1] bicyclic
systems via AD-mix-mediated dihydroxylation provides little
to no enantioselectivity;13 therefore, it is not surprising that there
was no enantioselectivity in the dihydroxylation of 2 to form
4. Although previous research into the functionalization of
[2.2.1] bicyclic systems has elucidated that the chemoselectivity
between two olefins is typically the result of sterics and not
electronics,14 further research needs to be done on this [3.2.1]
azabicyclic system to determine which dictates the chemose-
lectivity observed in the dihydroxylation of 2 (Scheme 2).
Yields associated with the protection of the exo-diol, as the
acetonide 5, were dependent on the amount of time between
purification of 4 and formation of the acetonide, 5. When diol
4 is stored as a neat liquid at room temperature under an argon
atmosphere, two distinct compounds (mass 408 and 779) were
observed. Both of these compounds subsequently decomposed
to a number of unidentified products. The conversion of 4 to 5
immediately after isolation provided consistently high yields
of 5.
ReceiVed September 18, 2006
Synthetic or natural aza-sugars have shown promise as a
therapeutic approach to a variety of disease states by acting
as transition state mimics to sugar processing enzymes.
Although the synthesis of functionalized bicyclo[3.2.1]-
octanes has been reported, the procedures are relatively long
and low yielding. Herein, we report the facile synthesis of
polyhydroxylated 2-azabicyclo[3.2.1]octane that can be
selectively functionalized.
The first naturally occurring sugar-mimic, i.e., aza-sugar or
polyhydroxylated alkaloid, was isolated in 1966.1 Since then,
numerous aza-sugars have been isolated and can be divided into
five general classes: piperidines, pyrrolidines, indolizidines,
pyrrolizidines, and nortropanes.2 Numerous polyhydroxylated
alkaloids from these structural classes, synthetic and natural,
have shown promise as anti-viral or anti-infective agents as well
as in the treatment of diabetes.2 Aza-sugars inhibit enzymes
involved in sugar processing by acting as transition state
mimics.3 1-Deoxymannojirimycin (DNJ) is an example of a
polyhydroxylated monocyclic alkaloid, aza-sugar, that acts as
a glycosidase inhibitor.4 Currently, a derivative of DNJ, N-
hydroxyethyl-DNJ, is marketed by Glaxo as Miglitol for the
treatment of type II diabetes.5 As part of our program aimed at
preparing analogues of the norditerpenoid alkaloid methylly-
caconitine, we required an efficient synthesis of the amino-
sugar 3.
The next step was introduction of the hydroxyl at C-4. It has
been noted that exocyclic hydroboration of related [2.2.1]heptene
systems is controlled by the steric bulk of the bridgehead
substituents.15 Our expectation was that 5 would follow this
general trend. Treatment of 5 with 9-BBN followed by an
oxidative workup yielded the desired compound, 6a, albeit in
moderate yields. Clearly 5 appears to follow this general rule
of [2.2.1] systems of preferential hydroboration in the exo
position. In an effort to improve the yield, hydroboration with
Remarkably few examples of this ring system have been
reported.6,7 While the synthesis of the trans-6,7-diol [3.2.1]
* To whom correspondence should be addressed. Tel: 740-517-8462. Fax:
740-593-0148.
(1) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahe-
dron: Asymmetry 2000, 11, 1645-1680.
(8) Johansen, S. K.; Korno, H. T.; Lundt, I. Synthesis 1999, 171-177.
(9) Gonzalez-Alvarez, C. M.; Quintero, L.; Santiesteban, F.; Fourrey,
J. L. Eur. J. Org. Chem. 1999, 3085-3087.
(2) Pearson, M. S. M.; Mathe-Allainmat, M.; Fargeas, V.; Lebreton, J.
Eur. J. Org. Chem. 2005, 2159-2191.
(3) Lillelund, V. H.; Jensen, H. H.; Liang, X. F.; Bols, M. Chem. ReV.
2002, 102, 515-553.
(10) Oehlschlager, A. C.; Zalkow, L. H. J. Org. Chem. 1965, 30, 4205-
4211.
(4) Andersen, S. M.; Lundt, I.; Marcussen, J.; Yu, S. Carbohydr. Res.
2002, 337, 873-890.
(11) Rhee, H.; Yoon, D. O.; Jung, M. E. Nucleosides Nucleotides Nucleic
Acids 2000, 19, 619-628.
(5) Pearson, M. S. M.; Saad, R. O.; Dintinger, T.; Amri, H.; Mathe-
Allainmat, M.; Lebreton, J. Bioorg. Med. Chem. Lett. 2006, 16, 3262-
3267.
(12) Curphey, T. J. Org. Prep. Proc. Int. 1981, 13, 112-115.
(13) Bakkeren, F.; Klunder, A. J. H.; Zwanenburg, B. Tetrahedron 1996,
52, 7901-7912.
(6) Fox, B. L.; Reboulet, J. E. J. Org. Chem. 1968, 33, 3639-3641.
(7) Ong, H. H.; Anderson, V. B.; Wilker, J. C. J. Med. Chem. 1978, 21,
758-763.
(14) Mayo, P.; Tam, W. Tetrahedron 2002, 58, 9527-9540.
(15) Brown, H. C.; Knights, E. F.; Scouten, C. G. J. Am. Chem. Soc
1974, 96, 7765-7770.
10.1021/jo0619231 CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/05/2007
1024
J. Org. Chem. 2007, 72, 1024-1026

SCHEME 1. General Plan for Synthesis of 3
SCHEME 2. Osmylation of Diene 2
FIGURE 1. Dihedral angles and observed coupling constants for
diastereomeric alcohols.
SCHEME 3. Hydroboration/oxidation of Enamine
FIGURE 2. Observed NOESY cross-peaks.
SCHEME 4. Detosylation of Azabicycle
BH3‚THF was tested and subsequently provided a higher yield
of 6a with a small amount of the endo isomer, 6b, which was
easily separated via recrystallization (Scheme 3).
The relative stereochemistry of bicyclo[2.2.1]heptane systems
is often determined by the coupling constant between adjacent
hydrogens as a result of the dihedral angle between the two
hydrogens.14,16 This method appears to be applicable to the
azabicyclo[3.2.1]octane system as well.
In summary, we have elucidated a facile synthesis of a
polyhydroxylated [3.2.1] azabicycle that can be further func-
tionalized. Selective functionalization of the secondary amine
and the differentiable hydroxyl groups will provide access to a
host of derivatives.
As shown in Figure 1, the dihedral angle between 3Hexo and
4Hendo protons of 6a is calculated to be 77°.17 The observed
coupling constant as expected is <1.0 Hz. The dihedral angle
between 3Hendo and 4Hendo of 6a is calculated to be 41.8° and
a 3.0 Hz coupling constant is observed. The calculated dihedral
angle in the minor isomer, 6b, between 3Hexo and 4Hexo protons
is 33.9° and shows a coupling constant of 6.6 Hz. The coupling
constant between 3Hendo and 4Hexo is not observable. NOESY
experiments provided additional confirmation (Figure 2). 4Hendo
of 6a showed strong cross-peaks with both H6 and H7 but not
to H8. 4Hexo of 6b showed a strong cross-peak to H8 but not to
H6 or H7.
The final step in this synthesis is the removal of the N-tosyl
protecting group. The removal of a tosyl group from a nitrogen
is often a non-straightforward transformation. The rather drastic
reaction conditions used for these deprotections are not always
amenable to the presence other functionality. We initially
examined sodium napthalenide mediated N-detosylation of 6a
which yielded a complex mixture of products.18 We next
examined the relatively mild photolytic N-detosylation.19 After
optimizing irradiation time, compound 3 was isolated in
consistently good yields (Scheme 4).
Experimental Section
N-Tosyl-2-azabicyclo[3.2.1]octa-3,6-diene (2).10,11 Tosyl azide12
(13.4 g, 146.0 mmol) was dissolved in anhydrous benzene (100
mL) under an argon atmosphere at rt. Freshly distilled norborna-
diene (10.56 mL, 49.0 mmol) was added in one aliquot, while the
tosyl azide solution was being stirred vigorously. After 5 min, the
rate of stirring was decreased and the reaction was stirred for 3
days at rt. The reaction was then concentrated and chromatographed
(gradient elution; 0-50% EtOAc in hexane) to yield 9.59 g (66%)
of 2 as white crystals: Rf ) 0.70 (1:1, EtOAc/hexane); mp ) 81-
1
84 °C (lit. uncorrected mp 76-79 °C); H NMR (CDCl3) δ 7.72
(d, 2H, J ) 9.0 Hz), 7.32 (d, 2H, J ) 9.0 Hz), 6.30 (dd, 1H, J )
9.0, 3.0 Hz), 6.15 (dd, 1H, J ) 2.73 Hz), 5.26 (m, 2H), 4.75 (s,
1H), 2.66 (m, 1H), 2.44 (s, 3H), 1.74 (m, 1H), 1.31 (d, 1H, J )
9.0 Hz); 13C NMR (CDCl3) δ 143.6, 139.2, 137.1, 129.7, 126.7,
121.9, 121.2, 110.6, 59.6, 36.0, 34.6, 21.6.
N-Tosyl-2-azabicyclo[3.2.1]oct-3-ene-6,7-diol (4). Methane-
sulfonamide (1.76 g, 18.5 mmol), AD-mix R (25.9 g, 2.8 g/mmol),
acetone (92.5 mL), and H2O (92.5 mL, HPLC grade) were added
to a 2 L double-neck round-bottom flask. The reaction was flushed
with argon for 10 min while being stirred vigorously with a
mechanical stirrer at rt. Compound 2 (2.42 g, 9.25 mmol) was
dissolved in acetone (15.2 mL) and transferred to the reaction flask
in one aliquot, with an additional acetone (15.2 mL) wash of the
addition vessel. The reaction was stirred vigorously for 3 h at rt
then quenched with Na2SO3 (30.5 g) followed by the addition of
EtOAc (305 mL). After 5 min of vigorous stirring, the reaction
was partitioned between EtOAc and H2O (120 mL). The aqueous
layer was then extracted again with EtOAc. The organic layers were
combined and washed with NaOH (2 × 120 mL, 2 M), dried over
MgSO4, filtered, concentrated, and chromatographed (gradient
elution; 0-100% EtOAc in hexane) to yield 2.54 g (93%) of 4 as
(16) Silverstein, R. M.; Webster, F. X. Spectrometric identification of
organic compounds, 6th ed.; Wiley: New York, 1998.
(17) Molecular modeling was performed with Spartan ’04 for Macintosh,
Wavefunction Inc., Irvine, CA. The lowest energy conformer for each
compound was obtained using molecular mechanics MMFF basis set.
(18) Bergmeier, S. C.; Seth, P. P. Tetrahedron Lett. 1999, 40, 6181-
6184.
(19) Hamada, T.; Nishida, A.; Yonemitsu, O. J. Am. Chem. Soc. 1986,
108, 140-145.
J. Org. Chem, Vol. 72, No. 3, 2007 1025

1
a white foam: Rf ) 0.17 (1:1, EtOAc/hexane); H NMR (CDCl3)
110.6, 80.9, 80.2, 65.4, 59.0, 48.2, 45.6, 25.8, 25.6, 23.6, 21.6. Anal.
Calcd for C17H23NO5S: C, 57.77; H, 6.56; N, 3.96. Found: C,
57.62; H, 6.60; N, 3.80. HPLC (Discovery-C8 column): 6a had a
retention time of 10.4 min and a purity of 95%. 6b: 1H NMR
(CDCl3) δ 7.71 (d, 2H, J ) 8.3 Hz), 7.34 (d, 2H, J ) 8.0 Hz),
4.55 (d, 1H, J ) 5.37 Hz), 4.19 (d, 1H, J ) 3.87 Hz), 3.87 (m,
2H), 3.80 (d, 1H, J ) 5.40 Hz), 2.52 (s, 1H), 2.45 (s, 3H), 2.35
(bs, 1H), 2.19 (m, 1H), 2.00 (m, 1H), 1.40 (s, 3H), 1.31 (d, 1H,
J ) 12.69 Hz); 1.18 (s, 3H); 13C NMR (CDCl3) δ 143.8, 135.9,
130.0, 127.2, 110.2, 80.7, 78.4, 65.8, 58.0, 47.0, 46.6, 30.7, 25.6,
23.5, 21.6. HPLC (Discovery-C8 column): 6b had a retention time
of 10.7 min and a purity of 98%.
δ 7.57 (d, 2H, J ) 8.25 Hz), 7.24 (d, 2H, J ) 8.19 Hz), 6.36 (d,
1H, J ) 7.74 Hz), 5.02 (t, 1H, J ) 7.68 Hz), 4.00 (m, 3H), 3.85
(bs, 2H), 2.34 (s, 3H), 2.25 (m, 1H), 1.72 (m, 1H), 0.76 (d, 1H,
J ) 11.97 Hz); 13C NMR (CDCl3) δ 144.0, 135.7, 130.0, 126.9,
124.5, 110.2, 78.6, 76.5, 62.0, 40.0, 24.1, 21.6.
6,7-exo-Isopropylidenedioxy-N-tosyl-2-azabicyclo[3.2.1]oct-3-
ene (5). Compound 4 (4.92 g, 16.6 mmol) was immediately
transferred to a round-bottom flask and dissolved in acetone (120
mL, ACS grade). Anhydrous magnesium sulfate (21.4 g), pTSA
(50 mg, 0.26 mmol), and 2,2-dimethoxypropane (31 mL, 250 mmol)
were added, and the reaction was stirred overnight at rt. The reaction
was filtered, concentrated and chromatographed (gradient elution;
0-100% EtOAc in hexane) to yield 5.17 g (93%) of 5 as a clear
viscous liquid: Rf ) 0.63 (1:1, EtOAc/hexane); 1H NMR (CDCl3)
δ 7.69 (d, 2H, J ) 8.0 Hz), 7.32 (d, 2H, J ) 8.0 Hz), 6.51 (dd, 1H,
J ) 7.5, 0.5 Hz), 5.09 (t, 1H, J ) 7.0 Hz), 4.45 (d, 1H, J ) 5.0
Hz), 4.38 (d, 1H, J ) 5.5 Hz), 4.21 (d, 1H, J ) 3.5 Hz), 2.44 (s,
3H), 2.38 (m, 1H), 1.89 (m, 1H), 1.40 (s, 3H), 1.23 (s, 3H), 0.89
(d, 1H, J ) 12.5 Hz); 13C NMR (CDCl3) δ 143.9, 135.9, 129.9,
126.8, 124.8, 109.4, 109.0, 85.1, 84.4, 59.0, 36.9, 25.7, 23.86, 23.57,
21.46. Anal. Calcd for C17H21NO4S: C, 60.87; H, 6.31; N, 4.18.
Found: C, 61.04; H, 6.51; N, 4.10.
4-exo-Hydroxy-6,7-exo-isopropylidenedioxy-2-azabicyclo[3.2.1]-
octane (3). Compound 6a (0.531 g, 1.5 mmol) and 1,4-dimethoxy-
benzene (0.62 g, 4.5 mmol) were placed in a 250 mL Pyrex round-
bottom flask and dissolved in absolute EtOH (90 mL). A solution
of NaBH4 (0.567 g, 15 mmol) in H2O (10 mL, HPLC grade) was
added to the 250 mL round-bottom flask. The 250 mL round-bottom
flask was flushed with argon for 30 min before being placed
adjacent to a high-pressure Xe-Hg lamp (455 W). The reaction
was then vigorously stirred during 3 h of irradiation. The reaction
was then flushed with argon for 30 min before being concentrated
to dryness. The residue was triturated with EtOAc, dried over Na2-
SO4, filtered, concentrated, and chromatographed (gradient elution;
0-100% EtOAc in hexane) to yield 0.26 g (86%) of 3 as an off
4-exo-Hydroxy-6,7-exo-isopropylidenedioxy-N-tosyl-2-
azabicyclo[3.2.1]octane (6). Compound 5 (0.77 g, 2.31 mmol) was
dissolved in anhydrous THF (4.36 mL), flushed with argon, and
cooled to -78 °C. BH3‚THF (4.36 mL, 4.20 mmol) was added
slowly over 5 min, and the reaction was kept at -78 °C for 30
min before being warmed to rt. After hydroboration was complete
(3 h, determined by TLC), EtOH (12.9 mL), NaOH (4.3 mL, 6.0
M), and H2O2 (10.4 mL, 30%) were slowly added, and the reaction
was heated to 60 °C for 1 h. The reaction was cooled to room
temperature, and excess K2CO3 was added followed by vigorous
stirring for 5 min. The reaction was extracted with EtOAc, dried
over MgSO4, filtered, and concentrated. Compound 6a was purified
via recrystallization in boiling EtOAc to yield 0.53 g (65%) of 6a
as white crystals. The mother liquor was concentrated and chro-
matographed (gradient elution; 0-100% EtOAc in hexane) to yield
92 mg (11%) of 6b as a viscous colorless liquid: 6a, Rf ) 0.20;
1
white powder: mp ) 110-113 °C; H NMR (CDCl3) δ 4.53 (d,
1H, J ) 5.2 Hz), 4.37 (d, 1H, J ) 5.2 Hz), 4.18 (s, 2H), 3.69 (bs,
1H), 3.26 (d, 1H, J ) 3.0 Hz), 2.75 (d, 1H, J ) 14.3 Hz), 2.62
(dd, 1H, J ) 14.3, 3.4 Hz), 2.35 (m, 1H), 1.96 (d, 1H, J ) 12.2
Hz), 1.68 (m, 1H), 1.38 (s, 3H), 1.27 (s, 3H); 13C NMR (CDCl3)
δ 110.1, 82.6, 80.6, 66.6, 57.9, 47.4, 46.0, 26.8, 25.8, 23.7. Anal.
Calcd for C10H17NO3: C, 60.26; H, 8.60; N, 7.03. Found: C, 60.09;
H, 8.85; N, 6.75.
Acknowledgment. We thank Dr. Kumar Pichumani for
NMR assistance. This work was supported by Ohio University
through a NanoBioTechnology Initiative fellowship (DDR) and
by NIH Grant No. DA013939.
1
6b, Rf ) 0.30 (1:1, EtOAc/hexane). 6a: mp ) 168-170 °C; H
Supporting Information Available: 1H, 13C NMR and 2D
spectra for all prepared compounds as well as HPLC traces for
compounds 6a and 6b. This material is available free of charge
via the Internet at http://pubs.acs.org.
NMR (CDCl3) δ 7.74 (d, 2H, J ) 8.2 Hz), 7.34 (d, 2H, J ) 8.1
Hz), 4.25 (m, 2H), 4.04 (d, 1H, J ) 5.3 Hz), 3.85 (s, 1H), 3.65 (d,
1H, J ) 14.0 Hz), 2.70 (dd, 1H, J ) 14.0, 3.1 Hz), 2.45 (s, 4H),
2.28 (s, 1H), 1.96 (d, 1H, J ) 12.7 Hz), 1.83 (m, 1H), 1.42 (s,
3H), 1.21 (s, 3H); 13C NMR (CDCl3) δ 143.7, 136.0, 129.8, 127.4,
JO0619231
1026 J. Org. Chem., Vol. 72, No. 3, 2007