Synthesis of l-altro-1-deoxynojirimycin, d-allo-1-deoxynojirimycin, and d-galacto-1-deoxynojirimycin from a single chiral cyanohydrin

Article abstract of DOI:10.1021/ol101556k

The chemoenzymatic synthesis of three 1-deoxynojirimycin-type iminosugars is reported. Key steps in the synthetic scheme include a Dibal reduction-transimination-sodium borohydride reduction cascade of reactions on an enantiomerically pure cyanohydrin, itself prepared employing almond hydroxynitrile lyase (paHNL) as the common precursor. Ensuing ring-closing metathesis and Upjohn dihydroxylation afford the target compounds.

Full text of DOI:10.1021/ol101556k

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3957-3959
Synthesis of L-altro-1-Deoxynojirimycin,
D-allo-1-Deoxynojirimycin, and
D-galacto-1-Deoxynojirimycin from a
Single Chiral Cyanohydrin
Adrianus M. C. H. van den Nieuwendijk,† Mark Ruben,† Sander E. Engelsma,†
Martijn D. P. Risseeuw,† Richard J. B. H. N. van den Berg,† Rolf G. Boot,§
Johannes M. Aerts,§ Johannes Brussee,‡ Gijs A. van der Marel,† and
Herman S. Overkleeft*,†
Leiden Institute of Chemistry and Leiden Amsterdam Centre for Drug Research,
Leiden UniVersity, P.O. Box 9502, 2300 RA Leiden, The Netherlands, and Department
of Medical Biochemistry, Acadamic Medical Center, Amsterdam, The Netherlands
h.s.oVerkleeft@chem.leidenuniV.nl
Received July 7, 2010
ABSTRACT
The chemoenzymatic synthesis of three 1-deoxynojirimycin-type iminosugars is reported. Key steps in the synthetic scheme include a Dibal
reduction-transimination-sodium borohydride reduction cascade of reactions on an enantiomerically pure cyanohydrin, itself prepared employing
almond hydroxynitrile lyase (paHNL) as the common precursor. Ensuing ring-closing metathesis and Upjohn dihydroxylation afford the target compounds.
Hydroxynitrile lyases have proven their value over the last
25 years in the enantioselective synthesis of cyanohydrins.
The resulting chiral cyanohydrins are valuable and highly
versatile starting materials in the stereoselective synthesis
of a variety of compounds with important biological or
medicinal properties, including natural products.1 Examples
include, among others, R-hydroxy acids,2 R-hydroxy esters,3
1,2-ethanol amines,2,4 carbohydrates,5 aziridines,6 piperidi-
nols,7 sphingosines,8 R-hydroxy-ꢀ-amino acids,9 and ꢀ-hy-
droxy-R-amino acids.10
Recently we reported7b on the almond (R)-hydroxynitrile
lyase-mediated conversion of O-TBDPS-protected cyano-
hydrin 111 into chiral and functionalized piperidine derivative
3. The strategy applied involved conversion of cyanohydrin
(4) (a) Brussee, J.; Dofferhof, F.; Kruse, C. G.; van der Gen, A.
Tetrahedron 1990, 46, 1653–1658. (b) Zandbergen, P.; van den Nieu-
wendijk, A. M. C. H.; Brussee, J.; van der Gen, A.; Kruse, C. G. Tetrahedron
1992, 48, 3977–3982.
(5) Avi, M; Gaiberger, R.; Feichtenhofer, S.; Griengl, H. Tetrahedron
2009, 65, 5418–5426.
† Leiden Institute of Chemistry.
‡ Leiden Amsterdam Centre for Drug Research.
(6) (a) Effenberger, F.; Stelzer, U. Tetrahedron: Asymmetry 1995, 6,
283–286. (b) Ritzen, M.; van Oers, M. C. M.; van Delft, F.; Rutjes, F. P. J. T.
J. Org. Chem. 2009, 74, 7548–7551.
§ Acadamic Medical Center.
(1) For selected reviews, see: (a) Holt, J.; Hanefeld, U. Curr. Org. Synth.
2009, 6, 15–37. (b) Brunel, J. -M.; Holmes, I. P. Angew. Chem., Int. Ed.
2004, 43, 2752–2778. (c) North, M. Tetrahedron: Asymmetry 2003, 14,
147–176. (d) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649–3682.
(2) Ziegler, T.; Ho¨rsch, B.; Effenberger, F. Synthesis 1990, 575–578.
(3) Brussee, J.; Loos, W. T.; van der Gen, A. Tetrahedron 1990, 46,
979–986.
(7) (a) Monterde, M. I.; Nazabadioko, S.; Rebolledo, F.; Brieva, R.;
Gotor, V. Tetrahedron: Asymmetry 1999, 10, 3449–3455. (b) van den
Nieuwendijk, A. M. C. H.; Ghisaidoobe, A. B. T.; Overkleeft, H. S.; Brussee,
J.; van der Gen, A. Tetrahedron 2004, 60, 10385–10396.
(8) Johnson, D. V.; Felfer, U.; Griengl, H. Tetrahedron 2000, 56, 781–
790.
10.1021/ol101556k  2010 American Chemical Society
Published on Web 08/06/2010

(e.g., (S)-9), as described by Barrow13 and Ellman.14,15
Barrow and co-workers reported a diastereomeric ratio of 5.9:
1 for the addition of vinylmagnesium bromide to the O-
TBDMS-protected derivative of imine 9. Ellman improved the
diastereoselectivity of this type of reaction by changing the
solvent from DCM to toluene and the addition of AlMe3 as a
Lewis acid. This afforded diastereoselectivities up to 97:3.
Scheme 1. Synthetic Outline
Scheme 2. Preparation of (S)-O-Benzylvinylglycinol ((S)-4)
1 into allylamine 2, followed by N-protection and ring-
closing metathesis to afford 3 in high yield (Scheme 1). We
anticipated that use of a more functionalized allyl amine,
for instance (S)-4 or (R)-4, could lead to a set of highly
functionalized and orthogonally protected cyclic intermedi-
ates 6 (Scheme 1) that in turn should be readily transformed
into 1-deoxynojirimycin-type iminosugars 7. In this paper,
we report on our results in the stereoselective synthesis of
two new cyclic precursors 6 starting from O-TBDPS-
protected cyanohydrin 1, and their use in the synthesis of
L-altro-1-deoxynojirimicin (L-altro-1-DNJ), D-allo-1-deox-
ynojirimicin (D-allo-1-DNJ), and D-galacto-1-deoxynojir-
imicin (D-galacto-1-DNJ).
We applied the Ellman reaction conditions14 to the addition
of vinylmagnesium bromide to imine (S)-9. The reaction
afforded adduct 10 in a diastereomeric ratio of 96:4 as
1
determined by H NMR. After silica gel column chromatog-
raphy, enantiomerically pure 10 was obtained in 80% yield.
Removal of the chiral auxiliary under acidic conditions gave
(S)-4 in high yield and >99% ee as established by chiral HPLC
on the N-tosylated derivative of (S)-4. Amine (R)-4 was obtained
in similar yields and >99% ee from (R)-9 (Scheme 2).
In the first instance, we investigated the synthesis of
amines (R)- and (S)-4. To this end, we adapted a strategy
reported by Taylor et al.12 for the synthesis of vinyl glycinol
starting from D-serine. Selective removal of the acetonide
from oxazolidine 8 with 70% acetic acid gave an intermediate
alcohol that was benzylated under standard conditions
(Scheme 2). Subsequent acidic removal of the Boc group
afforded amine (S)-4, which was analyzed by chiral HPLC
as its N-tosyl derivative. These analyses revealed that in
multiple separate syntheses the ee’s of the amines (R)- and
(S)-4 varied from 94 to 98%, and we were unable to achieve
complete stereochemical control via this route. Arguably,
racemization under the basic conditions in the Wittig reaction
that converts Garner’s aldehyde into oxazolidine 8 is at the
basis of the observed loss in ee.
With both (S)-4 and (R)-4 in hand, we proceeded with
the conversion of 1 into secondary amine 11 via the Dibal
reduction-transimination-NaBH4 reduction sequence of
reactions.4b,7b Initial experiments afforded amine 11 in
60-65% yields. These results correlate well with a recent
report16 in which the same sequence of events is featured as
the key step en route to functionalized morpholines. With
the exception of the amounts of Dibal-H applied (we apply
1.5 equiv of Dibal-H as opposed to 5 equiv applied by Rutjes
and co-workers), parameters such as reaction time and
concentrations were comparable. We anticipated that yields
could be improved by increasing the concentration of the
reaction partners of the transimination process (see Support-
ing Information for experimental details). Indeed, in this
fashion, we were able to improve the yields to 78-80%
(Scheme 3). In addition, the excess of amine (S)-4 could be
readily recovered by silica gel column chromatography.
With amine 11 in hand, we set out to synthesize key
intermediates 12 and 14. Boc-protection of 11, which had to
As an alternative, we turned our focus to a methodology
for the synthesis of protected 1,2-amino alcohols starting
from enantiomerically pure tert-butanesulfinyl aldimines
(9) Tromp, R. A.; van der Hoeven, M.; Amore, A.; Brussee, J.;
Overhand, M.; van der Marel, G. A.; van der Gen, A. Tetrahedron:
Asymmetry 2001, 12, 1109–1112.
(13) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.;
Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051–2054.
(14) Tang, P. T.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001,
66, 8772–8778.
(10) Zandbergen, P.; Brussee, J.; van der Gen, A.; Kruse, C. G.
Tetrahedron: Asymmetry 1992, 3, 769–774.
(15) For an excellent review on the chemistry of chiral sulfinimides,
see: Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. ReV. 2010, 110,
3600–3740.
(11) Zandbergen, P.; van der Linden, J.; Brussee, J.; van der Gen, A.
Synth. Commun. 1991, 21, 1387–1391.
(12) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis 1998,
1707–1709.
(16) Ritzen, B.; Hoekman, S.; Dura´n Verdasco, E.; van Delft, F. J.;
Rutjes, F. P. J. T. J. Org. Chem. 2010, 75, 3461–3464.
3958
Org. Lett., Vol. 12, No. 17, 2010

Scheme 3
.
Conversion of 1 into Key Intermediates 12 and 14
Scheme 5. Synthesis of L-altro-1-DNJ (20)
cyanohydrin 1. As there are also (S)-hydroxynitrile lyases
available (for instance HbHNL from HeVea Brasiliensis),1
enantiomeric 17, 18, and 20 should be accessible with equal
ease. Alternatively, desilylation of 12 and 14, followed by a
Mitsunobu reaction should, formally, lead to the enantiomers
of both 12 and 14. The chemistry described above makes
compounds 12 and 14 valuable extensions to the already
known synthetic strategies toward 1-deoxynojirimycin de-
rivatives and analogues from chiral pool carbohydrates18 and
de noVo synthetic strategies,19 often from chiral building
blocks.19b-e We are currently investigating the application
of orthogonally protected iminosugars 15, 16, and 19 in the
synthesis of potential inhibitors of enzymes involved in the
glucosylceramide metabolism.20
be executed in THF at 50 °C in the presence of 2 equiv of
triethylamine, followed by RCM with first-generation Grubbs
catalyst afforded the cyclic iminosugar precursor 12 in 91%
yield over two steps. In the same fashion, via amine 13,
precursor 14 was obtained in comparable yields (Scheme 3).
Next, we turned our efforts to the conversion of 12 and 14
into the target 1-deoxynojirimycin-type hydroxylated pip-
eridines. Application of the Upjohn dihydroxylation procedure
to alkene 12 gave a 1:1 mixture of compounds 15 and 16. The
diastereomeric mixture could be readily separated by column
chromatography affording enantiomerically pure 15 and 16 in
45% and 44% yield, respectively. A two-step deprotection
sequence comprising desilylation using TBAF followed by
catalytic hydrogenation under acidic conditions to remove the
Boc and benzyl protective groups afforded D-allo-1-DNJ (17)
and D-galacto-1-DNJ (18) in good yields (Scheme 4).
Acknowledgment. This work is supported by The Neth-
erlands Organization for Scientific Research (NWO).
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101556K
(17) Examples of analytical data: compound 17 (i) Ikota, N.; Hirano,
J.-I.; Gamage, R.; Nakagawa, H.; Hama-Inaba, H. Heterocycles 1997, 46,
637–644. (ii) Gupta, P.; Vankar, Y. D. Eur. J. Org. Chem. 2009, 1925–
1933 Compound 18: (i) Ruiz, M.; Ruanova, T. M.; Blanco, O.; Nu´n˜ez, F.;
Pato, C.; Ojea, V. J. Org. Chem. 2008, 73, 2240–2255. (ii) Paulsen, H.;
Hayauchi, Y.; Sinnwell, V. Chem. Ber. 1980, 113, 2601–2608. (iii) McDon-
nell, C.; Cronin, L.; O’Brien, J. L.; Murphy, P. V. J. Org. Chem. 2004, 69,
3565–3568. Compound 20: (i) Dhavale, D. D.; Markad, S. D.; Karanjule,
N. S.; PrakashaReddy, J. J. Org. Chem. 2004, 69, 4760–4766. (ii) Barili,
P. R.; Berti, G.; D’Andrea, F.; Rensis, D. E.; Puccioni, L. Tetrahedron
1997, 53, 3407–3416.
Scheme 4. Synthesis of D-allo-1-DNJ (17) and D-galacto-1-DNJ (18)
(18) For reviews see: (a) Compain, P.; Chagnault, V.; Martin, O. R.
Tetrahedron: Asymmetry 2009, 20, 672–711. (b) Compain, P.; Martin, O. R.,
Eds. Iminosugars: From Synthesis to Therapeutic Applications; Wiley-VCH:
Weinheim, 2007. (c) Cipolla, L.; La Ferla, B.; Nicotra, F. Curr. Top. Med.
Chem. 2003, 3, 485–511.
(19) For recent examples, see: (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, 136–139. (b) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H. Org.
Lett. 2003, 5, 2527–2529. (c) Takahata, H.; Banba, Y.; Sasatani, M.;
Nemoto, H.; Kato, A.; Adachi, I. Tetrahedron 2004, 60, 8199–8205. (d)
Ruiz, M.; Ruanova, T. M.; Blanco, O.; Nu´n˜ez, F.; Pato, C.; Ojea, V. J.
Org. Chem. 2008, 73, 2240–2255. (e) Best, D.; Wang, C.; Weymouth-
Wilson, A. C.; Clarkson, R. A.; Wilson, F. X.; Nash, R. J.; Miyauchi, S.;
Kato, A.; Fleet, G. W. J. Tetrahedron: Asymmetry 2010, 21, 311–319.
(20) (a) Wennekes, T.; van den Berg, R. J. B. H. N.; Boltje, T. J.; Donker-
Koopman, W. E.; Kuijper, B.; van der Marel, G. A.; Strijland, A.; Verhagen,
C. P.; Aerts, J. M. F. G.; Overkleeft, H. S. Eur. J. Org. Chem. 2010, 1258–
1283. (b) Wennekes, T.; van den Berg, R. J. B. H. N.; Boot, R. G.; van der
Marel, G. A.; Overkleeft, H. S.; Aerts, J. M. F. G. Angew. Chem., Int. Ed.
2009, 48, 8848–8869. (c) Wennekes, T.; van den Berg, R. J. B. H. N.;
Donker, W.; van der Marel, G. A.; Strijland, A.; Aerts, J. M. F. G.;
Overkleeft, H. S. J. Org. Chem. 2007, 72, 1088–1097. (d) Wennekes, T.;
Meijer, A. J.; Groen, A. K.; Boot, R. G.; Groener, J. E.; van Eijk, M.;
Ottenhoff, R.; Bijl, N.; Ghauharali, K.; Song, H.; O’Shea, T. J.; Liu, H. L.;
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Application of the Upjohn dihydroxylation to compound
14 afforded diol 19 as the single enantiomer in 92% yield.
Deprotection via the protocol described above gave L-altro-
1-DNJ (20) in a good 75% overall yield from 14 (Scheme
5). The spectral and analytical data of the compounds 17,
18, and 20 were in complete agreement with literature data.17
In conclusion, we have described the syntheses of three
out of sixteen possible 1-deoxynojirimicin isomers from
Org. Lett., Vol. 12, No. 17, 2010
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