Synthesis of D- and L-Deoxymannojirimycin via an Asymmetric Aminohydroxylation of Vinylfuran

Article abstract of DOI:10.1021/ol006907j

(Equation Presented) The Sharpless catalytic asymmetric aminohydroxylation has been applied to 2-vinylfuran, producing β-hydroxyfurfurylamine 5a with enantioexcess of >86% and 21% yield from furfural. The Cbz and TBS protected amino alcohol 5a was converted into both the D- and L-isomers of deoxymannojirimycin (DMJ) and deoxygulonojirimycin in five to seven steps and 48% and 66% overall yields. The key steps include the use of an aza-Achmatowicz reaction, a diastereoselective Luche reduction, diastereoselective dihydroxylation, and a tandem Cbz deprotection/reductive amination.

Full text of DOI:10.1021/ol006907j

ORGANIC
LETTERS
2001
Vol. 3, No. 3
401-404
Synthesis of D- and
L-Deoxymannojirimycin via an
Asymmetric Aminohydroxylation of
Vinylfuran
Michael H. Haukaas and George A. O’Doherty*
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
odoherty@chem.umn.edu
Received November 21, 2000
ABSTRACT
The Sharpless catalytic asymmetric aminohydroxylation has been applied to 2-vinylfuran, producing â-hydroxyfurfurylamine 5a with enantioexcess
of >86% and 21% yield from furfural. The Cbz and TBS protected amino alcohol 5a was converted into both the D- and L-isomers of
deoxymannojirimycin (DMJ) and deoxygulonojirimycin in five to seven steps and 48% and 66% overall yields. The key steps include the use
of an aza-Achmatowicz reaction, a diastereoselective Luche reduction, diastereoselective dihydroxylation, and a tandem Cbz deprotection/
reductive amination.
In an effort to find new glycosidation inhibitor-based anti-
fungal agents, we are interested in a short and flexible route
to the 1-deoxy iminosugar natural product deoxymannojir-
mycin (DMJ).1,2 Deoxymannojirimycin has been shown to
be a potent inhibitor of the mammalian Golgi R-mannosi-
dase-1 activity, blocking the conversion of high-mannose
oligosaccharides to complex oligosaccharides3 without in-
hibiting the biosynthesis of lipid-linked oligosaccharides.4
Iminosugars (azasugars) are compounds that result from
the replacement of a sugar ring O-atom with an NH-group
and typically are excellent glycosidase inhibitors.5 Some
examples of these iminosugars are deoxymannojirimycin (1,
DMJ, mannosidase inhibitor),1,2 deoxynojirimycin (2, DNJ,
glucosidase inhibitor),6,7 and deoxygulonojirimycin (3, DGJ,
fucosidase inhibitor)8 (Figure 1). The enzymatic recognition
(1) Isolation from Lonchocarpus sericeus. Fellows, L. E.; Bell, E. A.;
Lynn, D. G.; Pilkiewicz, F.; Miura, I.; Nakanishi, K. J. Chem. Soc., Chem.
Commun. 1979, 977.
Figure 1.
(2) For the first synthesis of DMJ, see: Kinast, G.; Schedel, M. Angew.
Chem., Int. Ed. Engl. 1981, 20, 805.
(3) (a) Humphries, M. J.; Matsumoto, K.; White, S. L.; Molyneux, R.
J.; Olden, K. Cancer Res. 1988, 48, 1410. (b) Dennis, J. W.; Koch, K.;
Beckner, D. J. Natl. Cancer Inst. 1989, 81, 1028.
of differences in charge and shape of these inhibitors
determines the inhibition selectivity.9
(4) (a) Goss, P. E.; Reid, C. L.; Bailey, D.; Dennis, J. W. Clin. Cancer
Res. 1997, 3, 1077-1086. (b) Kornfeld, R.; Kornfeld, S. Annu. ReV.
Biochem. 1985, 54, 631. For a review, see: (c) Schachter, H.; Roseman, S.
In The Biochemistry of Glycoproteins and Proteoglycans; Lennarz, W. J.,
Ed.; Plenum Press: New York, 1980; Chapter 3.
(5) (a) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2301-
2324. (b) Ganem, B. Acc. Chem. Res. 1996, 29, 340-347.
(6) Isolated from mulberries. Yagi, M.; Kouno, T.; Aoyagi, Y.; Murai,
H. Nippon Nogeikaku Kaishi 1976, 50, 571.
(7) For the first synthesis of DNJ, see: (a) Paulsen, H.; Sangster, I.;
Heyns, K. Chem. Ber. 1967, 100, 802. For a recent synthesis, see: (b) Polt,
R.; Sames, D.; Chruma, J. J. Org. Chem. 1999, 64, 6147. For a recent
review, see: (c) Fechter, M. H.; Stutz, A. E.; Tauss, A. Curr. Org. Chem.
1999, 3, 269-285.
10.1021/ol006907j CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/16/2001

There have been several successful approaches to DMJ
(1), most of which obtain their asymmetry from carbohy-
drates, chiral auxiliaries, or resolution methods.2,10 Because
of the flexibility it offered in terms of diastereo- and
enantiocontrol through ligand selection, we were interested
in the synthesis of iminosugars via an asymmetric amino-
hydroxylation/aza-Achmatowicz approach (Scheme 1).11
ates similar to 5a and 5c were unstable and hydrolyzed to
3-hydroxypyridines under aza-Achmatowicz conditions
(Scheme 1).11 In contrast, Zhou13b and Altenbach14 found
that a sulfonamide protecting group was compatible with the
aza-Achmatowicz reaction (mCPBA). Nevertheless, we
choose to carry forward a N-Cbz protecting group because
of the potential for step reduction and ease of purification.
In addition, we found that the preparation of furyl sulfona-
mide 5b via the Sharpless asymmetric aminohydroxylation
(AA)15 reaction of vinylfuran proved problematic.16
Scheme 1
Drawing from our successful experience with the Sharpless
asymmetric dihydroxylation of vinylfuran and subsequent
diastereoselective conversion to D- and L-sugars,17 we
envisioned the synthesis of the manno-iminosugar 1 being
synthesized via an analogous route (Scheme 1). Herein we
report our application of the asymmetric aminohydroxylation
to vinylfuran and the subsequent highly diastereoselective
conversion into two iminosugars, deoxymannojirmycin (DMJ)
1 and deoxygulonojirimycin (DGJ) 3.
Enantiomerically enriched N-Cbz-protected amino alcohols
6 and 9 were obtained by application of the Sharpless
asymmetric aminohydroxylation (AA) chemistry to vinyl-
furan 7 (Scheme 2).18 Key to this approach is a simple in
By employing the aza-Achmatowicz reaction, â-hydroxy-
furfurylamine 512 can be converted into various piperidines,
including iminosugar 1 (DMJ).10o,p,13 In his studies of the
aza-Achmatowicz reaction, Ciufolini observed that carbam-
Scheme 2
(8) For the first synthesis of DGJ, see: (a) Leontein, K.; Lindberg, B.;
Lonngren, J. Acta Chem. Scand. B 1982, 36, 515-518. (b) For more recent
syntheses, see: Le Merrer, Y.; Poitout, L.; Depezay, J.-C.; Dosbaa, I.;
Geoffroy, S. Foglietti, M.-J. Bioorg. Med. Chem. 1997, 5, 519-533. (c)
Liao, L.-X.; Wang, Z.-M.; Zhou, W.-S. Tetrahedron: Asymmetry 1999,
10, 3649-57.
(9) Tyms, A. S.; Berrie, E. M.; Ryder, T. A.; Nash, R. J.; Hegarty, M.
P.; Taylor, T. L.; Mobberly, M. A.; Davis, J. M.; Bell, E. A.; Jeffries, D.
J.; Taylor-Robinson, D.; Fellows, L. E. Lancet 1987, 1025.
(10) For syntheses of DNJ/DMJ before 1994 and a concise approach to
DNJ/DMJ from dicarbonyl sugars, see: (a) Baxter, E. W.; Reitz, A. B. J.
Org. Chem. 1994, 59, 3175. For syntheses of DMJ after 1994, see: (b)
Asano, K.; Hakogi, T.; Iwama, S.; Katsumura, S. Chem. Commun.1999,
41-42. (c) Campbell, J. A.; Lee, W. K.; Rapoport, H. J. Org. Chem. 1995,
60, 4602-4616. (d) Cook, G. R.; Beholz, L. G.; Stille, J. R. J. Org. Chem.
1994, 59, 3575-3584. (e) Dondoni A.; Perrone, D. J. Org. Chem. 1995,
60, 47-49. (f) Hudlicky, T.; Rouden, J.; Luna, H.; Allen, S. J. Am. Chem.
Soc. 1994, 116, 5099-5107. (g) Johnson, C. R.; Golebiowski, A.; Schoffers,
E.; Sundram, H.; Braun, M. P. Synlett 1995, 313-314. (h) Lee, S. G.; Yoon,
Y. J.; Shin, S. C.; Lee, B. Y.; Cho, S. D.; Kim, S. K.; Lee, J. H. Heterocycles
1997, 45, 701-706. (i) Lemerrer, Y.; Poitout, L.; Depezay, J. C.; Dosbaa,
I.; Geoffroy, S.; Foglietti, M. J. Bioorg. Med. Chem. 1997, 5, 519-533. (j)
Liao, L.-X.; Wang, Z.-M.; Zhang, H.-X.; Zhou, W.-S. Tetrahedron:
Asymmetry 1999, 10, 3649-3657. (k) Meyers, A. I.; Price, D. A.; Andres,
C. J. Synlett 1997, 533. (l) Meyers, A. I.; Andres, C. J.; Resek, J. E.;
Woodall, C. C.; McLaughlin, M. A.; Lee, P. H.; Price, D. A. Tetrahedron
1999, 55, 8931-8952. (m) Park, K. H.; Yoon, Y. J.; Lee, S. G. J. Chem.
Soc., Perkin Trans. 1 1994, 2621-2623. (n) Wu, X.-D.; Khim, S.-K.; Zhang,
X.; Cederstrom, E. M.; Mariano, P. S. J. Org. Chem. 1998, 63, 841-859.
(o) Xu, Y.-M.; Zhou, W.-S. Tetrahedron Lett. 1996, 37, 1461-1462. (p)
Xu, Y.-M.; Zhou, W.-S. J. Chem. Soc., Perkin Trans. 1 1997, 741-746.
(q) Asano, K.; Hakogi, T.; Iwama, S. Katsumura, S. Chem Commun. 1999,
41-42.
situ preparation of vinylfuran. Treatment of an ether solution
of vinylfuran with the sodium salt of N-chlorobenzylcar-
bamate and a 4% OsO4/5% (DHQ)2PHAL admixture leads
to a good yield of regioisomers (84%). The regioisomers 6
and 9 (1:2 ratio) were easily purified by selective TBS
protection of the primary alcohol followed by silica gel
chromatography. The highest enantiomeric excess of 6 was
obtained with the (DHQ)2PHAL ligand system, which gives
5a in a ∼21% yield from furfural 8 (>86% ee). The
enantiomer of 5a was also prepared by this sequence (24%,
>86% ee) with the use of (DHQD)2PHAL ligand.19 This
(14) Altenbach, H.-J.; Wischnat, R. Tetrahedron Lett. 1995, 36, 4983.
(15) Li, G. G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2813-2817.
(16) Bushey, M. L.; Haukaas, M. H.; O’Doherty, G. A. J. Org. Chem.
1999, 64, 2984.
(11) For an excellent review of the subject, see: Ciufolini, M. A.;
Hermann, C. Y. W.; Dong, Q.; Shimizu, T.; Swaminathan, S.; Xi, N. Synlett
1998, 105.
(12) Previously, Ciufolini/Wong and Zhou have shown that furans similar
to 5 can be produced via resolution strategies: (a) Drueckhammer, D. G.;
Barbas, C. F., III; Nozaki, K.; Wong, C.-H.; Wood, C. Y.; Ciufolini, M. A.
J. Org. Chem. 1988, 53, 1607. (b) Xu, Y.-M.; Zhou, W.-S. Tetrahedron
Lett. 1996, 37, 1461.
(13) (a) Xi, N.; Ciufolini, M. A. Tetrahedron Lett. 1995, 36, 6595. (b)
Yang, C.-F.; Xu, Y.-M.; Liao, L.-X.; Zhou, W.-S. Tetrahedron Lett. 1998,
39, 9227.
(17) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A., J. Org. Chem.
1999, 64, 2982.
(18) This constitutes an improved procedure as to our previously
published procedure (ref 16).
(19) At a smaller scale, the level of enantioinduction has been as high
as 94%, as determined by Mosher ester analysis. (a) Sullivan, G. R.; Dale,
J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143. (b) Yamaguchi, S.;
Yasuhara, F.; Kabuto, K. T. Tetrahedron 1976, 32, 1363.
402
Org. Lett., Vol. 3, No. 3, 2001

route compares well with the resolution procedures of Zhou
and Wong/Ciufolini.12
Scheme 4
With access to either enantiomer of furan 5a, we decided
to investigate the aza-Achmatowicz rearrangement of 5a
(Scheme 3). Treatment of a buffered aqueous THF solution
Scheme 3
ing 14 to hydrogenolysis conditions yields the tri-1,2,3-deoxy
iminosugar 15 in a near quantitative yield (96%), which was
isolated as a TsOH salt without chromatography.The gulo-
stereochemistry of deoxygulonojirimycin was diastereo-
selectively introduced in 3 via OsO4-catalyzed dihydroxy-
lation (CH2Cl2/H2O, 0 °C) of 14 to form 16 in a 96% yield
(Scheme 5). Neither epimer at C-1 adversely effected the
Scheme 5
of furan 5a with 1 equiv of NBS afforded moderate yields
of 4a as a mixture of hemiaminal diastereomers (55%) along
with 12 and more polar products (such as 10a, 10b, and 11).
Consistent with Ciufolini’s observation, we found small
amounts of 3-hydroxypyridine 11 under these NBS bromo-
nium ion conditions. Initially we were concerned about the
instability of the hemiaminal 4a; however, 4a was stable to
chromatographic purification (SiO2) and benchtop storage
(white solid, mp 72-74 °C). In addition, 4a was compatible
with the strongly acidic conditions of the Jones oxidation,
forming ketolactam 12 in good yields (80%).
We speculated that the aqueous NBS conditions lead to a
greater amount of the ring-opened form of 4a, which in turn
leads to double bond isomerization to form aldehyde 10a
and overoxidation to form carboxylic acid 10b. This was
evident in that use of anhydrous peracid conditions (mCPBA
in CH2Cl2, 0 °C) reproducibly provided improved yields of
4a (81%, along with 7% recovered starting material), whereas
exposure of 4a to excess mCPBA and 1.5 equiv of H2O at
room temperature led to variable yields of 10b (31-53%).
Additionally, this reaction was sensitive to the amount of
peracid; for instance, use of 2.2 equiv of mCPBA led to a
30% yield of 4a and 50% yield of 12.
Hemiaminal 4a was also stable to the acid-catalyzed
conditions required for conversion to the ethylaminal 13 (HC-
(OEt)3, 5% TsOH, 93%). The ethylaminal 13 can be reduced
under Luche20 conditions to provide 14 in an 86% yield (CH3-
OH/CH2Cl2, -78 °C). The allylic alcohol functionality was
introduced in 14 with complete stereocontrol with respect
to the C-6 substituent. This stereoselection was proven by
conversion of both diastereomers of 14 into a single
diastereomer 15. The stereoselectivity of this reduction was
consistent with the results of Zhou13b and others.10m,n Subject-
diastereoinduction during the dihydroxylation of 14. A single
diastereomer of the iminosugar deoxygulonojirimycin was
produced by hydrogenolysis of 16 in 99% yield. The
azasugar was easily purified by isolation as the TsOH salt
and washing with chloroform. In an attempt to find any
diastereomeric impurities, the crude reaction mixture of 17
was peracylated, affording 18 as a mixture of amide rotamers
with no indication of diastereomeric impurities (74%). The
spectral data for 17 and 18 were consistent with those from
previously prepared deoxygulonojirimycin.8
An attempt to isomerize the mixture of epimers at C-1
into a single diastereomer resulted in cyclization of 16 into
a bicycle 19 (5% TsOH/C6H6, 73%) as a single diastereomer
(Scheme 6). Proton NMR analysis (C6D6) showed the
Scheme 6
(20) Luche, J.-L. J. Am. Chem. Soc. 1978, 110, 2226.
Org. Lett., Vol. 3, No. 3, 2001
403

disappearance of one of the two amomeric protons (5.99 and
5.67 ppm) to a single signal at 5.43 ppm (3.0 Hz). Detailed
analysis of the vicinal H-H coupling constants of this rigid
bicyclic structure was also consistent with the gulose
stereochemistry.
mannose stereochemistry.22 After TBS deprotection of 22
(TBAF, 74%), a single diastereomer of the iminosugar 1
(DMJ) was produced by hydrogenolysis (95%). The azasugar
was easily isolated as the TsOH salt 23 (99%). In fact,
improved overall yields of 23 were achieved by skipping
the TBS deprotection step. The TsOH salt 23 was produced
in a near quantitative yield upon exposure of 22 to the same
hydrogenation/TsOH conditions (95%). In these improved
routes, the N-Cbz group along with the C-1 ethoxy substitu-
tion provided improved selectivity in the dihydroxylation of
14 and 20 over both Zhou’s analogue (N-Ts)10o,p and
Mariano’s C-1 deoxy analogue (N-Bz).10n Because of incon-
sistencies due to concentration effects on the 1H NMR shifts
the mannose isomer 23 was converted into the penta-acetate
24 (73%), which had spectral data identical to the literature
values.23
Finally, the manno-stereochemistry of DMJ was introduced
by conversion of 14 into its C-4 epimer 20 by Mitsunobu
inversion (Scheme 7). Treatment of a CH2Cl2 solution of
Scheme 7
In conclusion, we have demonstrated the completely
diastereoselective conversion of amino alcohol 5a into the
iminosugar deoxymannojirmycin (1) in seven steps and 48%
overall yield and deoxygulonojirimycin (3) in five steps and
66% overall yield. These synthetic studies have allowed us
to further define the scope of the aza-Achmatowicz reaction
and to optimize the diastereoselective introduction of the C-2/
C-3 hydroxyl groups of DMJ. We feel these improvements
have led to a significantly improved enantioselective syn-
thesis of deoxymannojirmycin (DMJ) 1 and deoxygulonojiri-
mycin (DGJ) 3.
Acknowledgment. We thank the University of Minnesota
(grant in aid program), the American Cancer Society for an
Institutional Research Grant (IRG-58-001-40-IRG-19), the
American Chemical Society Petroleum Research Fund (ACS-
PRF 33953-G1), and the Arnold and Mabel Beckman
Foundation for their generous support of our program.
the allylic alcohol 14 with p-nitrobenzoic acid, PPh3, and
DEAD afforded a 84% yield of an ester, which was easily
hydrolyzed with Et3N in MeOH to give 20 (94%). As with
allylic alcohol 14, its C-4 epimer 20 was easily converted
into the 1,2,3-trideoxy iminosugar 2121 by treatment of 20
with a TBAF solution (for TBS removal, 86%), and then
exposure to hydrogenolysis conditions (H2, 5% Pd/C, 61%)
afforded the aminodiol 21 in 52% overall yield. Similarly,
exposure of the allylic alcohol 20 to OsO4-catalyzed dihy-
droxylation conditions (CH2Cl2/H2O, 0 °C) stereoselectively
converts 20 into the mannose stereoisomer 22 in a 92% yield.
As with 14, both epimers of 20 react under the dihydroxy-
lation conditions from the less hindered face to install the
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
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OL006907J
(22) The mannose stereochemistry of 22 was assigned from the observa-
tion that the anomeric proton in both epimers appear in the 1H NMR as
doublets with coupling constant of <2 Hz.
(23) Hardick, D. J.; Hutchinson, D. W.; Trew, S. J.; Wellington, E. M.
H. Tetrahedron 1992, 48, 6285.
(21) Mocerino, M.; Stick, R. V. Aust. J. Chem. 1990, 43, 1183-1193.
404
Org. Lett., Vol. 3, No. 3, 2001