Short and straightforward synthesis of (-)- 1- deoxygalactonojirimycin

Article abstract of DOI:10.1021/ol100037c

"Chemical Equation Presented" The mildness and low basicity of vinylzinc species functioning as a nucleophile in addition to α-chiral aldehydes is characterized by lack of epimerization of the vulnerable stereogenic center. This is demonstrated by a highl

Full text of DOI:10.1021/ol100037c

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1145-1147
Short and Straightforward Synthesis of
(-)-1-Deoxygalactonojirimycin
Oskari K. Karjalainen, Mikko Passiniemi, and Ari M. P. Koskinen*
Aalto UniVersity School of Science and Technology, Faculty of Chemistry and
Materials Sciences, Department of Chemistry, P.O. Box 16100, FI-00076 Aalto,
Finland
ari.koskinen@tkk.fi
Received January 6, 2010
ABSTRACT
The mildness and low basicity of vinylzinc species functioning as a nucleophile in addition to r-chiral aldehydes is characterized by lack of
epimerization of the vulnerable stereogenic center. This is demonstrated by a highly diastereoselective synthesis of 1-deoxygalactonojirimycin
in eight steps from commercial starting materials with overall yield of 35%.
Nojirimycins are a family of polyhydroxylated piperidine
alkaloids. The first congener of these sugar mimics, nojirimycin
(1, Figure 1), was isolated in 1966 from the fermentation broths
of several Streptomyces strains.1 Originally, nojirimycin was
found to possess antibiotic activity; it was later reported to be
a potent R-glycosidase inhibitor.2 Today, more than 20 natural
piperidine aza-sugars are known, as well as a plethora of
synthetic derivatives. Already, their glycosidase inhibitory
potential has been realized in the treatment of type II diabetes
mellitus3 and lysosomal storage disorders.4 1-Deoxygalac-
tonojirimycin (DGJ, 2) is not a naturally occurring iminosugar
but is nevertheless a potent galactosidase inhibitor.5 A simple
and concise route to enantiopure 2 and derivatives thereof should
prove invaluable.
Figure 1. Structures of nojirimycin (1) and DGJ (2).
atoms C-2, C-3, C-4, and C-5. For DGJ, the configuration
is (2R,3S,4R,5S). The first synthesis of deoxynojirimycin was
reported in 1967 by Paulsen et al.,6 and since then all of the
possible eight diastereomers have been synthesized by
different groups.7
We reasoned (Scheme 1) that ent-2 can be obtained by
direct SN2-type displacement of a leaving group by the amino
group in 3. The required mesylate 3 can in turn be
synthesized from the partly protected tetraol 4, the product
The deoxynojirimycin family of iminosugars comprises a
six-carbon skeleton with different configurations at carbon
(1) Inouye, S.; Tsuruoka, T.; Niida, T. J. Antibiot. 1966, 19, 288–292.
(2) Niwa, T.; Inouye, S.; Tsuruoka, T.; Niida, T.; Koaze, Y. Agric. Biol.
Chem. 1970, 34, 966–967.
(3) Fattorusso, E.; Scafati, O. T. Modern Alkaloids; Wiley-VCH: New
York, 2008; pp 111-133.
(5) Kato, A.; Kato, N.; Kano, E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto,
T.; Banba, Y.; Ouchi, H.; Takahata, H.; Asano, N. J. Med. Chem. 2005,
48, 2036–2044.
(4) Cox, T.; Lachmann, R.; Hollak, C.; Aerts, J.; van Weely, S.; Hribicek,
M.; Platt, F.; Butters, T.; Dwek, R.; Moyses, C.; Gow, I.; Elstein, D.; Zimran,
A. Lancet 2000, 355, 1481–1485.
(6) Paulsen, H.; Sangster, I.; Heyens, K. Chem. Ber. 1967, 100, 802–815.
10.1021/ol100037c  2010 American Chemical Society
Published on Web 02/19/2010

Scheme 1. Retrosynthetic Analysis of ent-2
Table 1. Screening of Conditions for the Reductive Coupling of
6 and 7a
entry
solvent
zinc source
yieldb (%)
dr (syn/anti)c
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
toluened
THF
Et2Zn
Me2Zn
ZnBr2
Et2Zn
Et2Zn
ZnBr2
Et2Zn
78
78
55
62
20
n.r.
n.d
>20:1
>20:1
1:1
>20:1
>1:20
THF
Et2Oc
>1:20
a To a suspension of Cp2Zr(H)Cl (2 mmol) in the appropriate solvent
at 0 °C under Ar was added 7 (2 mmol). After the suspension had dissolved,
the reaction was cooled to -40 °C and R2Zn (2 mmol) or ZnBr2 (1 mmol)
was added followed by 6 (1 mmol). The reaction was allowed to warm to
0 °C and stirred until completion. b Isolated yields after chromatography.
of a diastereoselective dihydroxylation of 5. We envisioned
that the highly functionalized key intermediate 5 could be
obtained by reductive coupling of Garner’s aldehyde 6 and
protected propargyl alcohol 7, both of which are com-
mercially available. Compounds 6 and 7 can also be
synthesized from readily available starting materials L-serine
and propargyl alcohol, respectively.
c
Determined by H NMR analysis. d The zirconium species was pregen-
1
erated in CH2Cl2; the solvent was evaporated and replaced by the listed
one.
tions as summarized in Table 1. The best results were
obtained using methylene chloride as solvent and either
Me2Zn or Et2Zn as the zinc source (entries 1 and 2). The
alkyne failed to react with zirconocene hydrochloride in
toluene. Instead, the vinylzirconium species had to be
pregenerated in CH2Cl2, followed by solvent evaporation and
redissolution in toluene (entry 4). THF (entry 5) impressively
reversed the stereochemical outcome, although yields were
low and numerous side products were evident. The vinylzir-
conium species was not soluble in Et2O (entry 7), which
accounted for the poor (less than 10%) conversion. Interest-
ingly, changing the zinc source to ZnBr2 produced a 1:1
mixture of diastereomers in dichloromethane (entry 3), while
in THF no reaction took place (entry 6).
With the optimal conditions in hand, the synthesis was
set into motion as outlined in Scheme 2. Treating 7 with
zirconocene hydrochloride in methylene chloride furnished
the vinylzirconium intermediate which was then transmeta-
lated to the corresponding zinc species by treating it with
diethylzinc. Addition of Garner’s aldehyde 6 to the solution
delivered the desired allylic alcohol 5 in good yield
(73-78%) with virtually complete diastereocontrol.11a We
were not able to isolate or detect the anti-congener. The
stereochemistry was assigned by mechanistic considerations
and later confirmed through analysis of ent-2. Similar results
regarding the diastereoselectivity have been published by
Murakami et al.11b Higher yields (78%) were obtained when
the Schwartz reagent was generated in situ using the
Negishi’s protocol.12 Benzyl protection (with in situ genera-
tion of BnI)13 of the free alcohol followed by dihydroxylation
under Upjohn conditions14 delivered diol 4 in an acceptable
61% yield over two steps. Diastereoselectivity was excellent
Several methodologies for synthesis of allylic amino
alcohols such as 5 have been previously investigated in our
group. Horner-Wadsworth-Emmons-type olefination8 fol-
lowed by Lu¨che reduction of the resulting R,ꢀ-unsaturated
ketone delivers amino alcohols in up to 3:1 syn/anti ratio.9
Unfortunately, the enantiomeric purity is eroded in the
process, which is unacceptable. Direct addition of lithium
nucleophiles to Garner’s aldehyde (6) produces the anti
diastereomers in high dr (17:1) as exemplified in our
synthesis of pachastrissamine.10 In the search for a comple-
mentary method for producing the syn diastereomers we
turned to vinylzinc nucleophiles. Vinylzinc species have been
reported to add to R-chiral aldehydes with high syn
selectivity.11b The nucleophile is generated conveniently from
an alkyne such as 7 by a hydrozirconation-transmetalation
sequence pioneered by Peter Wipf.11 Herein we further show
the utility of this reaction and prove for the first time that
these conditions are nonepimerizing.
We first tackled the reductive coupling of 6 and 7. Several
solvents and zinc sources were screened for optimal condi-
(7) For reviews of synthetic methods, see: (a) Pearson, M. S. M.; Mathe-
Allainmat, M.; Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159–
2191. (b) Afarinkia, K.; Bahar, A. Tetrahedron: Asymmetry 2005, 16, 1239–
1287. (c) Stu¨tz, A. Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond; Wiley-VCH: New York, 1999. For more recent syntheses of
members of the deoxynojirimycin family, see: (d) Palyam, N.; Majewski,
M. J. Org. Chem. 2009, 74, 4390–4392. (e) Bagal, S. K.; Davies, S. G.;
Lee, J. A.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Thomson, J. E. Org.
Lett. 2009, 12, 136–139. (f) Remgasamy, R.; Curtis-Long, M. J.; Ryu, H. W.;
Oh, K. Y.; Park, K. H. Bull. Korean Chem. Soc. 2009, 30, 1531–1534.
(8) Koskinen, A. M. P.; Koskinen, P. M. Synlett 1993, 501–502.
(9) Koskinen, A. M. P.; Koskinen, P. M. Tetrahedron Lett. 1993, 34,
6765–6768.
(10) Passiniemi, M.; Koskinen, A. M. P. Tetrahedron Lett. 2008, 49,
980–983.
(11) (a) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197–5200. (b)
For an application in total synthesis, see: Murakami, T.; Furusawa, K.
Tetrahedron 2002, 58, 9257–9263.
(12) Huang, Z.; Negishi, E. Org. Lett. 2006, 8, 3675–3678.
(13) Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron Lett.
1976, 3535–3536.
1146
Org. Lett., Vol. 12, No. 6, 2010

the stereochemistry was proven by analyzing ent-2. Removal
of the TBS protection prior to dihydroxylation only made
the isolation of the desired triol more problematic and caused
the diastereomers to be inseparable. With all the stereocenters
in place, we set out to prepare for the cyclization. Removal
of the silyl protection from the primary alcohol delivered
triol 9. Selective mesylation of the primary alcohol with
mesyl chloride and 2,4,6-collidine as the base proved
straightforward giving 10 with an 89% yield.16 Removal of
the N,O-acetonide and Boc proceeded smoothly in moist
HCl(g)/MeOH delivering 3 in essentially quantitative yield.
Moist HCl/MeOH was found to be most suitable reagent
combination for this deprotection step. TFA worked almost
as efficiently, but gave a colored crude product. The
cyclization in the presence of Hu¨nig’s base in methanol
provided the cyclized product contaminated with DIPEA
salts. Deprotection with palladium on charcoal under hy-
drogen atmosphere in acidic methanol delivered ent-2 as its
hydrochloride salt. Simple washing with chloroform, fol-
lowed by recrystallization from H2O/EtOH gave pure ent-2
HCl in 78% yield over three steps. The physical and spectral
properties matched fully those reported in the literature.17
The enantiopurity was confirmed by NMR analysis of both
C-2 Mosher’s esters of tetraacetylated ent-2 and was
determined to be >99% by NMR.18
Scheme 2. Synthesis of (-)-DGJ (ent-2)
In summary, we have synthesized enantiopure (-)-2 in a
highly diastereoselective manner from readily available
starting materials in 8eight steps. We are currently exploring
the use of 5 and anti-5 as building blocks for other
stereoisomers of the 1-deoxynojirimycin family.
(>12:1),15 and the unwanted all-syn diastereomer could be
separated by column chromatography at this point. Again,
Acknowledgment. Helsinki University of Technology is
gratefully acknowledged for the funding of this project.
(14) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973–1976.
(15) Generally, dihydroxylations of acyclic allylic alcohols are expected
to proceed with 4-7:1 anti/syn diastereoselectivity. Cha, J. K.; Christ, W. G.;
Kishi, Y. Tetrahedron Lett. 1983, 37, 3943–3946.
(16) Burke, S. D.; O’Donnell, C. J. J. Org. Chem. 1998, 63, 8614–
8616.
Supporting Information Available: Experimental pro-
cedures and full characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Asano, N.; Oseki, K.; Kizu, H.; Matsui, K. J. Med. Chem. 1994,
37, 3701–3706. (b) Paulsen, H.; Matzke, M.; Orthen, B.; Nuck, R.; Reutter,
W. Liebigs Ann. Chem. 1990, 953–963.
(18) See the Supporting Information for details.
OL100037C
Org. Lett., Vol. 12, No. 6, 2010
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