Asymmetric syntheses of (-)-1-deoxymannojirimycin and (+)-1- deoxyallonojirimycin via a ring-expansion approach

Article abstract of DOI:10.1021/ol400735z

The asymmetric syntheses of (-)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin are described herein. The ring-closing iodoamination of two epimeric bishomoallylic amines to give the corresponding 5-iodomethylpyrrolidines was followed by in situ ring-expansion to give two diastereoisomerically pure (>99:1 dr) cyclic carbonates. Subsequent deprotection gave (-)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin as single diastereoisomers in 7.4 and 3.3% overall yield, respectively, from commercially available starting materials.

Full text of DOI:10.1021/ol400735z

ORGANIC
LETTERS
2013
Vol. 15, No. 8
2042–2045
Asymmetric Syntheses
of (ꢀ)-1-Deoxymannojirimycin and
(þ)-1-Deoxyallonojirimycin via
a Ring-Expansion Approach
Stephen G. Davies,* Aude L. A. Figuccia, Ai M. Fletcher, Paul M. Roberts, and
James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
steve.davies@chem.ox.ac.uk
Received March 19, 2013
ABSTRACT
The asymmetric syntheses of (ꢀ)-1-deoxymannojirimycin and (þ)-1-deoxyallonojirimycin are described herein. The ring-closing iodoamination of
two epimeric bishomoallylic amines to give the corresponding 5-iodomethylpyrrolidines was followed by in situ ring-expansion to give two
diastereoisomerically pure (>99:1 dr) cyclic carbonates. Subsequent deprotection gave (ꢀ)-1-deoxymannojirimycin and (þ)-1-deoxyallonojirimycin
as single diastereoisomers in 7.4 and 3.3% overall yield, respectively, from commercially available starting materials.
The potent biological activity displayed by polyhy-
droxylated piperidines (iminosugars) has made them very
attractive targets for total synthesis;1 for example, (ꢀ)-1-
deoxynojirimycin 6 is an effective glycosidase inhibitor and
has potential in the treatment of cancer and HIV.2 As part
of our ongoing research program directed toward the de
novo preparation of imino- and aminosugars,3 we recently
reported an oxidation and ring-contraction approach for
the synthesis of (ꢀ)-1-deoxynojirimycin 6 and its stereo-
isomer (þ)-1-deoxyaltronojirimycin.4 Inour synthesisof 6,
chemoselective oxidation5 of dihydroazepine 1 was fol-
lowed by resolution via preparative chiral HPLC which
gave 2 as a single diastereoisomer (>99:1 dr) in >99% ee.
Treatment of 2 with MsCl produced tetrahydropyridine 4,
presumably via the intermediacy of aziridinium 3. Subse-
quent elaboration of 4 produced (ꢀ)-1-deoxynojirimycin 6
in 10% overall yield (Figure 1).
(1) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645. (b) Davis, B. G. Tetrahedron:
Asymmetry 2009, 20, 652.
(5) For example, see: (a) Aciro, C.; Davies, S. G.; Roberts, P. M.;
Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6,
3762. (b) Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.;
Russell, A. J.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751. (c) Bond,
C. W.; Cresswell, A. J.; Davies, S. G.; Fletcher, A. M.; Kurosawa, W.; Lee,
J. A.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. J. Org.
Chem. 2009, 74, 6735. (d) Brennan, M. B.; Claridge, T. D. W.; Compton,
R. G.; Davies, S. G.; Fletcher, A. M.; Henstridge, M. C.; Hewings, D. S.;
Kurosawa, W.;Lee, J. A.;Roberts, P. M.;Schoonen, A. K.;Thomson, J. E.
J. Org. Chem. 2012, 77, 7241.
(6) (a) Davies, S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.;
Russell, A. J.; Savory, E. D.; Smith, A. D.; Thomson, J. E. Tetrahedron:
Asymmetry 2009, 20, 758. (b) Brock, E. A.; Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 1594. (c) Davies,
S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron
2012, 68, 4302. (d) Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.;
Thomson, J. E. Org. Lett. 2012, 14, 4278.
(2) For example, see: (a) Cross, P. E.; Baker, M. A.; Carver, J. P.;
Dennis, J. W. Clin. Cancer Res. 1995, 1, 935. (b) Qian, X.; Moris-Varas,
F.; Fitzgerald, M. C.; Wong, C.-H. Bioorg. Med. Chem. 1996, 4, 2055.
(c) Nakagawa, K.; Kubota, H.; Tsuzuki, T.; Kariya, J.; Kimura, T.;
Oikawa, S.; Miyazawa, T. Biosci. Biotechnol. Biochem. 2008, 72, 2210.
(d) Winchester, B. G. Tetrahedron: Asymmetry 2009, 20, 645.
(3) For example, see: (a) Bagal, S. K.; Davies, S. G.; Fletcher, A. M.;
Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J. E. Tetrahedron Lett.
ꢀ
2011, 52, 2216. (b) Csatayova, K.; Davies, S. G.; Lee, J. A.; Roberts,
P. M.; Russell, A. J.; Thomson, J. E.; Wilson, D. L. Org. Lett. 2011,
13, 2606.
(4) (a) Bagal, S. K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell,
A. J.; Scott, P. M.; Thomson, J. E. Org. Lett. 2010, 12, 136. (b) Bagal,
S. K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson,
J. E. J. Org. Chem. 2010, 75, 8133.
r
10.1021/ol400735z
Published on Web 04/09/2013
2013 American Chemical Society

using TBAF gave 13 in 77% yield (Scheme 1). The relative
configuration within 13 was unambiguously established by
single crystal X-ray diffraction analysis (Figure 2),12 with
the absolute (R,R,R,R)-configuration within 13 following
from the known configuration of the N-R-methylbenzyl
fragment. This analysis therefore also secured the assigned
configurations within 8ꢀ12.
Scheme 1. Preparation of Cyclization Precursors 11 and 12
Figure 1. Synthesis of (ꢀ)-1-deoxynojirimycin 6 via a ring-
contraction approach.
Herein we report an alternative ring-expansion proce-
dure for the preparation of1-deoxyiminosugars employing
our ring-closing iodoamination6 protocol to effect cycliza-
tion of bishomoallylic amines (which can be readily pre-
pared from the corresponding R,β-unsaturated ester using
our diastereoselective aminohydroxylation procedure7 fol-
lowed by reduction and reaction with vinylmagnesium
bromide), followed by ring-expansion of the resultant
iodomethylpyrrolidines and deprotection.
Conjugate addition of lithium (R)-N-benzyl-N-(R-
methylbenzyl)amide to 7 (prepared in 61% yield and
>99:1 dr over three steps from cis-but-2-ene-1,4-diol),8
followed by oxidation of the resultant enolate with
(ꢀ)-camphorsulfonyloxaziridine [(ꢀ)-CSO], gave β-amino
ester 8 in 80% yield and >99:1 dr.8a The stereochemical
outcome of this reaction was initially assigned by reference
to our transition state mnemonic9 and by analogy to the
well established outcome of this aminohydroxylation
protocol,7,10 and was later confirmed unambiguously by
single crystal X-ray diffraction analysis of a derivative.
Subsequent O-benzyl protection of 8 and reduction of the
ester moiety within 9 gave alcohol 10 in 80% overall yield
(from 8). Oxidation of the primary hydroxyl functionality
within 10, followed by reaction of the resultant aldehyde
with vinylmagnesium bromide, gave a 65:35 mixture of 11
and 12.11 After chromatographic purification of the crude
reaction mixture, 11 was isolated in 55% yield and >99:1 dr,
and 12 was isolated in 26% yield and >99:1 dr. Deprotec-
tion of the O-silyl group within the major diastereoisomer 11
Figure 2. X-ray crystal structure of (R,R,R,R)-13 (selected
H-atoms are omitted for clarity).
Ring-closing iodoamination of 11 under our previously
optimized conditions6 produced a mixture of iodomethyl-
pyrrolidine 14 (>99:1 dr) and N-(R-methylbenzyl)-
acetamide; after purification of the crude reaction mixture
14 was isolated in 20% yield and >99:1 dr. The relative
(7) For reviews of this methodology, see: (a) Davies, S. G.; Smith,
A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833. (b) Davies,
S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron:
Asymmetry 2012, 23, 1111.
(8) (a) Abraham, E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.;
Roberts, P. M.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655.
(b) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davies, S. G.;
Georgiou, M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell,
1
configuration within 14 was tentatively assigned by H
NMR NOE analysis, and from its 13C NMR spectrum,
which displayed a diagnostic peak for the CH2I carbon atom
(δC = 3.4 ppm which is indicative of a 4,5-cis-relationship);6a,13
ꢀ
ꢀ
A. J.; Sanchez-Fernandez, E. M.; Scott, P. M.; Smith, A. D.; Thomson,
J. E. Org. Biomol. Chem. 2008, 6, 1665.
(9) Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asym-
metry 1994, 5, 1999.
(10) Bunnage, M. E.; Chernega, A. N.; Davies, S. G.; Goodwin, C. J.
J. Chem. Soc., Perkin Trans. 1 1994, 2373.
(11) Attempts to improve the diastereoselectivity of this process
(solvent, temperature, counterion redox, etc.) were not successful.
(12) Crystallographic data (excluding structure factors) for the struc-
tures of 13, 19 CHCl3, and 25 have been deposited with the Cambridge
3
Crystallographic Data Centre as supplementary publication numbers
CCDC 926152ꢀ926154, respectively.
Org. Lett., Vol. 15, No. 8, 2013
2043

this stereochemical outcome is also consistent with our
previous observations concerning this class of ring-closing
iodoamination reaction.6a Subsequent treatment of 14 with
AgBF4 in CH2Cl2 promoted the formation of aziridinium
ion 15, and the relative configuration within 15 was estab-
lished by 1H NMR NOESY analysis. Treatment of 15 with
NaHCO3 in dioxane/H2O (3:1) gave ring-expanded, cyclic
carbonate 16 in quantitative yield.14,15 We then developed a
procedure for the preparation of carbonate 16 directly from
11 upon treatment with I2 and NaHCO3 in a mixture of
dioxane/H2O (3:1),16 followed by treatment with Ac2O to
facilitate the separation of 16 from the 1-phenylethanol
by-product. Methanolysis of the carbonate functionality
within 16 and acetate protection of the C(4) and C(5)
hydroxyl groups within 17 gave 18 in quantitative yield.
The relative configurations within 16ꢀ18 were assigned
based on 1H NMR NOE and 3J coupling constant analyses.
Deprotection of the O-silyl group within 18, which was
Scheme 2. Ring-Closing Iodoamination of 11
achieved upon treatment with HF pyridine, followed
3
by methanolysis produced 19 in 70% yield and >99:1 dr
(Scheme 2). The relative configuration within 19 was
unambiguously established by single crystal X-ray diffrac-
tion analysis (Figure 3);12 furthermore, the determination
of a Flack x parameter17 of ꢀ0.09(12) for this crystal
structure allowed the assigned absolute (R,R,R,R)-config-
uration within 19, and hence also the assigned configura-
tions within 14ꢀ18, to be confirmed.
Under the optimized conditions, the reaction of 11 with
I2 and NaHCO3 in a mixture of dioxane/H2O (3:1) followed
by immediate O-desilylation of 16, upon treatment with
HF pyridine, and methanolysis of the carbonate function-
3
ality within 20 gave triol 19 in 40% isolated yield (from 11)
and >99:1 dr. Subsequent global hydrogenolytic deprotec-
tion of 19 was achieved in the presence of Pearlman’s
catalyst [Pd(OH)2/C] which gave (ꢀ)-1-deoxymannojirimy-
cin 2118,19 in 87% yield and >99:1 dr (Scheme 3). The spec-
troscopic data for this sample of 21, including its specific
Figure 3. X-ray crystal structure of (R,R,R,R)-19 CHCl3
3
(CHCl3 and selected H-atoms are omitted for clarity).
20
rotation {[R]D ꢀ38.6 (c 1.0 in H2O)}, were in excellent
agreement with literature data {lit.20 for sample isolated
from a natural source [R]D ꢀ41.4 (c0.74 in H2O); lit.18 [R]D
20
Scheme 3. Synthesis of (ꢀ)-1-Deoxymannojirimycin 21
ꢀ40 (c 1.35 in H2O); lit.19 [R]D ꢀ36.1 (c 0.33 in H2O)}.
22
The reaction of the epimeric substrate 12 produced a
73:27 mixture of diol 22 and carbonate 23;21 methanolysis
(13) (a) Tamaru, Y.; Kawamura, S.; Tanaka, K.; Yoshida, Z. Tetra-
€
hedron Lett. 1984, 25, 1063. (b) Palmer, A. M.; Jager, V. Synlett 2000,
1405.
(14) Cyclic carbonates have previously been prepared upon treat-
ment of vic-halohydrins with (Me4N)HCO3; see: Venturello, C.;
D’Aloisio, R. Synthesis 1985, 33.
(15) Direct treatment of 14 with NaHCO3 in dioxane/H2O (3:1) also
gave cyclic carbonate 16 in quantitative yield.
(16) Verhelst, S. H. L.; Paez Martinez, B.; Timmer, M. S. M.; Lodder,
G.; van der Marel, G. A.; Overkleeft, H. S.; van Boom, J. H. J. Org.
Chem. 2003, 68, 9598.
(17) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876.
(18) Broxterman, H. J. G.; Neefjes, J. J.; van der Marel, G. A.;
Ploegh, H. L.; van Boom, J. H. J. Carbohydr. Chem. 1988, 7, 593.
(19) Concia, A. L.; Lozano, C.; Castillo, J. A.; Parella, T.; Joglar, J.;
of the crude reaction mixture then gave diol 22 exclusively
(confirming the homochirality of 22 and 23), and then
acetate protection facilitated the isolation of 24 as a single
diastereoisomer in 43% yield (from 12). The relative
ꢀ
Clapes, P. Chem.;Eur. J. 2009, 15, 3808.
(20) Asano, N.; Oseki, K.; Kizu, H.; Matsui, K. J. Med. Chem. 1994,
37, 3701.
(21) An authentic sample of diol 22 was prepared in quantitative yield
upon transesterification of 24 with K2CO3 and MeOH.
2044
Org. Lett., Vol. 15, No. 8, 2013

Scheme 4. Synthesis of (þ)-1-Deoxyallonojirimycin 26
Figure 4. X-ray crystal structure of (2R,3R,4S,5S)-25 (selected
H-atoms are omitted for clarity).
was isolated in 39% overall yield (from 12) avoiding the
formation of 24 and purification of all intermediates.
Finally, hydrogenolysis of 25 gave (þ)-1-deoxyallonojir-
imycin 2622,23 as a single diastereoisomer which was iso-
lated in 83% yield (Scheme 4). The spectroscopic data for
20
this sample of 26, including its specific rotation {[R]D
þ28.3 (c 1.0 in H2O)}, were in excellent agreement with
literature data {lit.20 for sample isolated from a natural
25
source [R]D þ25.7(c 0.65in H2O); lit.22 [R]D þ30.5(c 0.15
20
in H2O); lit.23 [R]D þ28.1 (c 0.8 in H2O)}.
In conclusion, the ring-closing iodoamination and ring-
expansion of two epimeric bishomoallylic amines were
achieved in one pot, generating the corresponding cyclic
carbonates as single diastereoisomers. Subsequent depro-
tection gave (ꢀ)-1-deoxymannojirimycin and (þ)-1-deoxy-
allonojirimycin in 7.4 and 3.3% overall yield, respectively,
from commercially available starting materials.
configurations within 22ꢀ24 were initially assigned based
1
3
on a combination of H NMR NOE and J coupling
constant analyses. However, following O-silyl deprotec-
tion, the relative configuration with25was unambiguously
established by single crystal X-ray diffraction analysis
(Figure 4);12 furthermore, the determination of a Flack x
parameter17 of ꢀ0.05(16) for the crystal structure of 25
allowed the assigned absolute (2R,3R,4S,5S)-configura-
tion within 25, and also the assigned configurations within
22ꢀ24, to be confirmed. Under optimized conditions, 25
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of 1H and 13C
NMR spectra, and crystallographic data (for structures
CCDC 926152ꢀ926154). This material is available free of
charge via the Internet at http://pubs.acs.org.
(22) Hong, B.-C.; Chen, Z.-Y.; Nagarajan, A.; Kottani, R.; Chavan,
V.; Chen, W.-H.; Jiang, Y.-F.; Zhang, S.-C.; Liaoa, J.-H.; Sarsharb, S.
Carbohydr. Res. 2005, 340, 2457.
(23) Ikota, N.; Hirano, J.-I.; Gamage, R.; Nakagawa, H.;Hama-Inaba,
H. Heterocycles 1997, 46, 637.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
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