Use of enantiomerically pure 7-azabicyclo[2.2.1]heptan-2-ol as a chiral template for the synthesis of aminocyclitols

Article abstract of DOI:10.1021/ol801381t

(Chemical Equation Presented) Using enantiopure 7-azabicyclo[2.2.1]heptane- 2-ol, the synthesis of cis- as well as trans-2-aminocyclohexanols, dihydroconduramine E-1, and ent-conduramine F-1 has been described.

Full text of DOI:10.1021/ol801381t

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3611-3614
Use of Enantiomerically Pure
7-Azabicyclo[2.2.1]heptan-2-ol as a
Chiral Template for the Synthesis of
Aminocyclitols
Ganesh Pandey,*,† Keshri Nath Tiwari,† and V. G. Puranik‡
DiVision of Organic Chemistry and Centre for Material Characterization, National
Chemical Laboratory, Pune 411008, India
gp.pandey@ncl.res.in
Received June 19, 2008
ABSTRACT
Using enantiopure 7-azabicyclo[2.2.1]heptane-2-ol, the synthesis of cis- as well as trans-2-aminocyclohexanols, dihydroconduramine E-1, and
ent-conduramine F-1 has been described.
Various aminocyclitols, natural (1) as well as synthetic
(Figure 1), possess the ability to mimic oligosaccharides,1
making them potential candidates as inhibitors of glycosi-
dases. In particular, conduramines 2 and 3, apart from being
used as probes for biological functions of oligosaccharides,2,3
have also served as important synthetic precursors of amino-
and diaminocyclitols4 and for many other biologically active
compounds.5 Therefore, it is not surprising to see the
considerable research interest by synthetic chemists toward
the synthesis of aminocyclitols6 and conduramines.7
† Division of Organic Chemistry.
‡ Centre for Material Characterization.
Owing to our broad interest in the design, synthesis, and
(1) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300–
2324.
evaluation of new azasugars as glycosidase inhibitors,8 it
(2) (a) For biological properties of conduramines, see: Lysek, R.; Favre,
S.; Vogel, P. Tetrahedron 2007, 63, 6558–6572, and references cited therein.
(b) Lysek, R.; Schutz, C.; Vogel, P. Bioorg. Med. Chem. Lett. 2005, 15,
3071–3075.
(3) Paul, B. J.; Willis, J.; Martinot, T. A.; Ghiviriga, I.; Abboud, K. A.;
Hudlicky, T. J. Am. Chem. Soc. 2002, 124, 10416–10426.
(4) (a) Chida, N.; Ohtsuka, M.; Nakazawa, K.; Ogawa, S. J. Org. Chem.
1991, 56, 2976–2983. (b) Schurrle, K.; Beier, B.; Piepersberg, W. J. Chem.
Soc., Perkin Trans. 1 1991, 2407–2412.
(5) (a) Hudlicky, T.; Rouden, J.; Luna, H. J. Org. Chem. 1993, 58, 985–
987. (b) Hudlicky, T.; Rouden, J.; Luna, H.; Allen, S. J. Am. Chem. Soc.
1994, 116, 5099–5107. (c) Hudlicky, T.; Nugent, T.; Griffeth, W. J. Org.
Chem. 1994, 59, 7944–7946. (d) Chida, N.; Ohtsuka, M.; Ogawa, S.
Tetrahedron Lett. 1991, 32, 4525–4528. (e) Hudlicky, T.; Olivo, H. F. J. Am.
Chem. Soc. 1994, 116, 5108–5115.
Figure 1. Some bioactive cyclic polyhydroxylated amines.
10.1021/ol801381t CCC: $40.75
Published on Web 07/23/2008
2008 American Chemical Society

occurred to us that designing a chiral template to obtain
aminocyclitols (natural and synthetic) would be an important
contribution to this area. In this context, we envisioned the
potential of substrate 8 for the synthesis of various ami-
nocyclohexanols. Compound 8 could easily be obtained from
optically pure 7-azabicyclo[2.2.1]hept-2-one 6, synthesized
by us a few years ago9 via asymmetric desymmetrization of
meso-4 (Scheme 1). We had developed this strategy to
synthesize (-)-epibatidine,10 a powerful non-opiod analgesic.
Scheme 2
.
Imaginative Pathway for the Synthesis of
Aminocyclitols
Scheme 1. Synthesis of Chiral Template 8
AcOH, 60 psi) provided 6 in 70% yield as a diastereomeri-
cally pure compound12 along with the recovery of starting
material 5 (30%) (Scheme 1).
We hoped that reduction of 6 with lithium borohydride
would furnish only 8, owing to endo-attack of the hydride
on carbonyl group. However, it unexpectedly gave a dia-
stereomeric mixture of alcohols 7 and 8 (1:9) (Scheme 3).
The idea of utilizing 8 as a chiral template for the synthesis
of aminocyclitols in general emerged from its rigid bicyclic
structure11 and suitably juxtaposed functionalities for its easy
transformation to aminocyclohexenol derivative 9 useful for
the synthesis of scores of aminocyclitols as described in
Scheme 2. In this paper, we disclose our preliminary results
on the successful demonstration of the synthesis and use of
8 as a chiral template for the synthesis of aminocyclitols.
Desymmetrized compound 5 was obtained in 80% yield
(99% de) by asymmetric desymmetrization of meso-4 by
employing our previously described protocol.9 Removal of
the ketal moiety from 5 by hydrogenation (Pd/C, 10 mol%,
Scheme 3. Reduction of Ketone
(6) Alegret, C.; Benet-Buchholz, J.; Riera, A. Org. Lett. 2006, 8, 3069–
3072, and references cited therein.
(7) (a) Kelebekli, L.; Celik, M.; Sahin, E.; Kara, Y.; Balci, M.
Tetrahedron Lett. 2006, 47, 7031–7035. (b) Spielvogel, D.; Kammerer, J.;
Prinzbach, H. Tetrahedron Lett. 2000, 41, 7863–7867. (c) Akgun, H.;
Hudlicky, T. Tetrahedron Lett. 1999, 40, 3081–3084. (d) Jotterand, N.;
Vogel, P. Synlett 1998, 1237–1239. (e) Trost, B. M.; Pulley, S. R.
Tetrahedron Lett. 1995, 36, 8737–8740. (f) Leung-Toung, R.; Liu, Y.;
Muchowski, J. M.; Wu, Y.-L. J. Org. Chem. 1998, 63, 3235–3250.
(8) (a) Pandey, G.; Kapur, M. Tetrahedron Lett. 2000, 41, 8821–8824.
(b) Pandey, G.; Kapur, M. Synthesis 2001, 1263–1267. (c) Pandey, G.;
Kapur, M. Org. Lett. 2002, 4, 3883–3886. (d) Pandey, G.; Kapur, M.; Khan,
M. I.; Gaikwad, S. M. Org. Biomol. Chem. 2003, 1, 3321–3326. (e) Pandey,
G.; Dumbre, S. G.; Khan, M. I.; Shabab, M.; Puranik, V. G. Tetrahedron
Lett. 2006, 47, 7923–7926. (f) Pandey, G.; Dumbre, S. G.; Khan, M. I.;
Shabab, M. J. Org. Chem. 2006, 71, 8481–8488. (g) Pandey, G.; Dumbre,
S. G.; Pal, S.; Khan, M. I.; Shabab, M. Tetrahedron 2007, 63, 4756–4761.
(9) Pandey, G.; Tiwari, S. K.; Singh, R. S.; Mali, R. S. Tetrahedron
Lett. 2001, 42, 3947–3949.
Fortunately, both diastereomers could be easily separated by
silica gel column chromatography.
The relative configurations of both alcohols were unam-
biguously deduced from their 1H NMR spectrum in CDCl3.
For illustration, the H-2 in 7 appeared as dd (J ) 9.3, 4.4
Hz) coupling with bridgehead H-1 and H-3 whereas H-3
appeared as ddd (J ) 9.6, 9.3, 4.6 Hz) coupling with H-2,
bridgehead H-4 and -OH. The coupling with -OH (J ) 9.6
Hz) was confirmed by D2O exchange which simplified the
coupling to dd (J ) 9.3, 4.6 Hz). Similarly, in the case of 8,
the H-2 showed doublet (J ) 6.5 Hz) coupling only with
H-3, whereas H-3 appeared as dd (J ) 9.7, 6.5 Hz) coupling
with H-2 as well as O-H indicating the endo-orientation
for H-3. This observation is in complete agreement with the
(10) Spand, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J. C.;
Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475–3478.
(11) (a) For 7-azanorbornane systems, see: Hernandez, A.; Marcos, M.;
Rapoport, H. J. Org. Chem. 1995, 60, 2683–2691. (b) Moreno-Vargas, A. J.;
Robina, I.; Petricci, E.; Vogel, P. J. Org. Chem. 2004, 69, 4487–4491, and
references cited therein. (c) Wei, Z.-L.; George, C.; Kozikowski, A. P.
Tetrahedron Lett. 2003, 44, 3847–3850.
(12) The observed NMR splitting pattern in 6 is because of restricted
rotation about the NCO bond (rotamers). For similar observations, see: Pavri,
N. P.; Trudell, M. L. Tetrahedron Lett. 1997, 38, 7993–7996.
3612
Org. Lett., Vol. 10, No. 16, 2008

literature reports13,14 where no coupling is seen between
bridgeheadandtheendo-protoninthe7-azabicyclo[2.2.1]heptane
system. Since reduction of 6 at room temperature produced
diastereomeric mixtures of the corresponding alcohols (7 and
8), it became obvious to us that there was an epimerization
of H-2 during reduction. Therefore, it occurred to us to
investigate the reduction at lower temperature with the hope
that it might offer diastereoselectivity. However, to our
surprise, the results showed complete reversal in the dias-
tereoselectivity and the ratio of 7 and 8 with respect to
temperature is shown in Table 1.
Scheme 4. Anionic Fragmentation of 8
Table 1. Yields and Ratio of 7 and 8 during Reduction of
Ketone
entry
T (°C)
ratio (7/8)
time
yield (%) (combined)
1
2
3
-78
-90
25
7:3
7.5:2.5
1:9
30 min
45 min
12 h
75
70
78
it failed to give any product. A close look at the structure of
7 indicated that in this molecule, the orientation of sulfone
moiety is endo which may not allow the fragmentation due
to the lack of antiperiplanarity between the bonds to be
cleaved. Therefore, in order to support our observation, we
epimerized the endo-sulfone moiety to exo using KHMDS
as a base, which gave 13 in 70% yield. The epimerization
of 7 was not successful using LiHMDS, possibly due to the
chelation of the lithium between hydroxyl and sulfonyl
oxygen. The structure of 13 was confirmed on the basis of
1H NMR analysis in CDCl3 as H-2 appeared as a doublet (J
) 3.6 Hz) which is possible only when sulfone is exo-
oriented. Subjecting 13 to the usual anionic rearrangement
The formation of both 7 and 8, possibly, could be
rationalized by considering the base mediated (BH4 )
-
epimerization of H-2 and the orientation of phenylsulfonyl
group directing the face of hydride attack on the carbonyl
group. While at room temperature, the thermodynamically
more stable exo-phenylsulfonyl moiety directs the endo-
attack of the hydride ion resulting 8 as the major product, 7
is formed in larger proportions at lower temperature due to
kinetically more favored endo-phenylsulfone.
Initially, we tried the anionic rearrangement of 8 using
bases such as LiHMDS and n-BuLi; however, they failed to
give any product. Finally, ring opening of 8 succeeded by
the addition of excess of methyl magnesium bromide7f in a
THF solution at room temperature producing 9a in 80% yield
yielded 9b in 70% yield [crystalline solid; mp 125 °C; [R]25
D
as a crystalline solid [mp 131 °C; [R]25 -69.0 (c 1.00,
+14.6 (c 0.40, CHCl3)] (Scheme 5). The stereochemistry of
9b was confirmed by carrying out COSY experiments.
Since both 9a as well as 9b can be obtained from
desymmetrized compound 6, simple experimental manipula-
tions such as sulfonyl group removal, reduction of the olefinic
D
CHCl3)] (Scheme 4). Owing to undefined couplings between
the two stereochemical protons (H-1 and H-6) in the 1H NMR
of 9a in CDCl3, it proved difficult to assign relative
configuration satisfactorily. Although 9a was a good crystal-
line compound, it did not diffract properly for X-ray analysis.
Therefore, we removed the phenylsulfonyl group from 9a
using 6% sodium amalgam in a buffered methanol and
derivatized the free hydroxyl to corresponding O-acetate 11.
Luckily, this compound turned out to be a good crystalline
solid (mp 66 °C) and produced the X-ray structure15 (Figure
2) confirming the cis-1,6-amino alcohol configuration for 9a
(Scheme 4). Highly encouraged with the success of the ring-
opening reaction of 8, we considered that 7 could also be
equally susceptible for rearrangement. However, reaction of
7 with methyl magnesium bromide under similar reaction
conditions as described for 8 was not equally rewarding as
(13) Pandey, G.; Bagul, T. D.; Sahoo, A. K. J. Org. Chem. 1998, 63,
760–768
.
(14) Ramey, K. C.; Lini, D. C.; Moriarty, R. M.; Gopal, H.; Welsh,
H. G. J. Am. Chem. Soc. 1967, 89, 2401–2408
.
(15) Crystallographic data for the structure reported in this paper have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-691970.
Figure 2. ORTEP diagram of 11.
Org. Lett., Vol. 10, No. 16, 2008
3613

Scheme 5
.
Ring Opening of Epimerized Alcohol
Scheme 6
.
Synthesis of Dihydroconduramine E1 16 and Epoxy
Ketone 19
double bond, and N-Boc deprotection produced cis- as well
as trans-2-aminocyclohexanols (12 and 14), respectively. It
may be important to mention that these compounds have been
fascinating targets for synthesis due to their wide applicability
as ligands in asymmetric syntheses16 and as small molecular
probes for quorum-sensing modulation.17 Optically pure
trans-1,2-aminocyclohexanol (14) is obtained by either the
aminolysis of cyclohexene epoxides using enantiopure me-
thylbenzylamine in the presence of trimethylaluminum18 or
enantioselective opening of the meso-epoxide by an ap-
propriate nucleophile using chiral catalyst.19,20 In contrast,
optical resolution has been the only method available for
the synthesis of enantiomerically pure cis-1,2-aminocyclo-
hexanol (12).21
the synthesis of 3, the free hydroxy moiety of 10 was
protected as the -OTBS ether (17, 86% yield). The allylic
oxidation of 17 by stirring with Pd/C (10 mol %) and
t-BuOOH in DCM at 0 °C furnished enone 18 in 75%
yield.24 The nucleophilic epoxidation of enone 18 using
TBHP and Triton-B in THF at 0 °C yielded single product
As we had obtained 10 in larger quantity initially, we
proceeded to explore its synthetic utility in the synthesis of
ent-conduramine F-1 (3) as well as dihydroconduramine E-1
(16). While conduramine 3, also called norvalienamine, is
as active as valienamine in inhibiting R-glucosidase from
yeast,22 compound 16 is unknown in all respects. Toward
transforming 10 into 16, we carried out OsO4-catalyzed
dihydroxylation of the olefinic bond which gave expected
15 in 75% yield as a single isomer and was characterized
by detailed COSY, NOESY, and 13CMR data. The observed
dihydroxylation stereochemistry of 15 was in accordance
with Donohae’s23 report. The carbamate deprotection using
dilute HCl yielded 16 in 90% yield (Scheme 6) [mp 95 °C
19 in 85% yield as a crystalline solid [mp 110 °C [R]25
D
-45.0 (c 0.50, CHCl3)]. The epoxy ketone 19 was fully
characterized by 1H NMR, 13C NMR, and mass spectra. The
stereochemistry of the epoxide was confirmed by detailed
COSEY and NOESY studies. Compound 19 was transformed
into the corresponding enol triflate by reaction with KHMDS/
Comins reagent25 which upon treatment with Pd(PPh3)4 and
Et3SiH produces the corresponding olefin derivative. One-
pot epoxide ring opening and global deprotection by refluxing
with 0.2 N H2SO4 and 10 N HCl in dioxane produced ent-
conduramine F-1 (3) (Scheme 6). Optimization of the
reactions conditions and the synthesis of corresponding
analogues starting from 9b are in progress and will be
detailed appropriately in a full paper.
[R]25 +55 (c 0.5, H2O)]. To explore its synthetic utility in
D
(16) (a) Schiffers, I.; Rantanen, T.; Schmidt, F.; Bergmans, W.; Zani,
L.; Bolm, C. J. Org. Chem. 2006, 71, 2320–2331. (b) Parrodi, C. A.; Juaristi,
E. Synlett 2006, 2699–2715.
Acknowledgment. K.N.T. is thankful to UGC, New Delhi.
for the award of research fellowship.
(17) Jog, G. J.; Igarashi, J.; Suga, H. Chem. Biol. 2006, 13, 123–128.
(18) Overmann, L. E.; Sugai, S. J. Org. Chem. 1985, 50, 4154–4155.
(19) Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N.
Supporting Information Available: Experimental details
and NMR spectroscopic and mass spectroscopic data for the
new compounds are given in the Supporting Information.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Am. Chem. Soc. 1995, 117, 5897–5898
(20) Schneider, C.; Sreekanth, A. R.; Mai, E. Angew. Chem., Int. Ed.
2004, 43, 5691–5694
.
.
(21) (a) Miyano, S.; Lu, L. D.-L.; Viti, S. M.; Sharpless, K. B. J. Org.
Chem. 1985, 50, 4350–4360. (b) Kawabata, T.; Yamamoto, K.; Momose,
Y.; Yoshida, H.; Nagaoka, Y.; Fuji, K. Chem. Commun. 2001, 2700–2701.
(22) Lysek, R.; Schutz, C.; Favre, S.; O’Sullivan, A. C.; Pillonel, C.;
Krulle, T.; Jung, P. M. J.; Clotet-Codina, I.; Este, J. A.; Vogel, P. Bioorg.
Med. Chem. 2006, 14, 6255–6282.
OL801381T
(24) Yu, J-Q.; Corey, E. J. Org. Lett. 2002, 4, 2727–2730.
(25) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299–
6302.
(23) Donohoe, T. J.; Moore, P. R.; Beddoes, R. L. J. Chem. Soc., Perkin
Trans. 1 1997, 43–52.
3614
Org. Lett., Vol. 10, No. 16, 2008