Synthesis of eight 1-deoxynojirimycin isomers from a single chiral cyanohydrin

Article abstract of DOI:10.1002/ejoc.201200377

Eight configurational 1-deoxynojirimycin isomers have been synthesized starting from a chiral cyanohydrin as the common precursor. The cyanohydrin chiral pool building block is easily accessible in large quantities by using almond hydroxynitrile lyase as the chiral catalyst in condensing hydrogen cyanide and crotonaldehyde. Our work complements the large body of literature on the synthesis of 1-deoxynojirimycin derivatives with the distinguishing feature that eight stereoisomers of this important class of glycosidase inhibitors can be derived from a common precursor in an efficient manner.

Full text of DOI:10.1002/ejoc.201200377

Job/Unit: O20377
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Date: 10-05-12 10:29:10
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FULL PAPER
DOI: 10.1002/ejoc.201200377
Synthesis of Eight 1-Deoxynojirimycin Isomers from a Single Chiral
Cyanohydrin
Adrianus M. C. H. van den Nieuwendijk,[a] Richard J. B. H. N. van den Berg,[a]
Mark Ruben,[a] Martin D. Witte,[a] Johannes Brussee,[b] Rolf G. Boot,[c]
Gijsbert A. van der Marel,[a] Johannes M. F. G. Aerts,[c] and Herman S. Overkleeft*[a]
Keywords: Enzymes / Enzyme catalysis / Inhibitors / Enantioselectivity / Synthesis design
Eight configurational 1-deoxynojirimycin isomers have been
synthesized starting from a chiral cyanohydrin as the com-
mon precursor. The cyanohydrin chiral pool building block
large body of literature on the synthesis of 1-deoxynojirimy-
cin derivatives with the distinguishing feature that eight
stereoisomers of this important class of glycosidase inhibitors
is easily accessible in large quantities by using almond hy- can be derived from a common precursor in an efficient man-
droxynitrile lyase as the chiral catalyst in condensing hydro-
gen cyanide and crotonaldehyde. Our work complements the
ner.
gated. We have reported on a number of conversions involv-
ing cyanohydrins that lead to valuable chiral building
blocks.[5] For example, (2R,3E)-2-hydroxypent-3-enenitrile
(1), derived from crotonaldehyde and HCN can be prepared
in 99% enantiomeric purity by using either purified
paHNL[6] or defatted almond meal containing the enzyme
(Scheme 1).[7] (2R,3E)-2-Hydroxypent-3-enenitrile bears
three individual functionalities that can be addressed inde-
pendently. In the unprotected form it has been used in the
synthesis of α-hydroxy esters,[8] α-hydroxy acids[9] and vici-
nal diols.[10] The protected forms can be used to produce
chiral nitrones,[11] cyclic 1,2-ethanolamines,[12] chiral piper-
idinols,[12] α-hydroxy-β-amino acids,[13] tetronic acids[14] and
1,2-ethanolamines.[15]
Introduction
Hydroxynitrile lyases (HNLs), also known as oxynitril-
ases, have attracted great interest from the synthetic organic
chemistry community for more than a century. The first use
of a HNL derived from almonds (paHNL) was reported by
Rosenthaler in 1908.[1] In 1965 a range of optically active
cyanohydrins, starting from both aromatic and aliphatic al-
dehydes, were synthesized by Becker and Pfeil, who used a
buffered aqueous ethanol mixture as the solvent.[2,3] These
early results demonstrated for the first time the potential of
paHNL in the construction of chiral compounds, although
the highest ee reported was 87%.[2] Further significant pro-
gress was made in 1987 when Effenberger et al. reported
the synthesis of (R)-mandelonitrile, catalysed by paHNL.
By performing the reaction in a two-phase system, they ob-
tained (R)-mandelonitrile in 99.3% ee and 95% yield.[4]
Since then, the role of HNLs in organic synthesis has grad-
ually grown and today they are an important synthetic tool
in the production of a wide range of both (R)- and (S)-
cyanohydrins with high enantioselectivity and high yields.[5]
The versatility of cyanohydrins as optically active build-
ing blocks in synthetic chemistry has been widely investi-
Scheme 1. Preparation of cyanohydrins 1 and 2. Reagents and con-
ditions: a) HCN, EtOAc, 0.1 m aq. citrate buffer, pH 5.4, paHNL;
b) TBDPS-Cl, imidazole, DMF, 0 °CǞroom temp.
Recently we reported on the synthesis of two new orthog-
onally protected building blocks for the stereoselective syn-
thesis of 1-deoxynojirimycin (1-DNJ) isomers.[16] Starting
from cyanohydrin 2, building blocks 6 and 7 were obtained
after a three-step synthesis, as depicted in Scheme 2. Cya-
nohydrin 2 was converted into secondary amines 3 and 4 in
a one-pot DIBAL-H reduction/transimination/NaBH4 re-
duction sequence[17] employing either (R)-benzyloxyvinyl-
glycinol [(R)-5] or (S)-benzyloxyvinylglycinol [(S)-5] in the
transimination step.[16] Subsequent N-Boc protection and
ring-closing metathesis readily afforded 6 and 7 in overall
yields of 72%.
[a] Leiden Institute of Chemistry, Leiden University,
P. O. Box 9502, 2300 RA Leiden, The Netherlands
Fax: +31-71-5274537
E-mail: h.s.overkleeft@chem.leidenuniv.nl
[b] Leiden Amsterdam Centre for Drug Research, Leiden
University,
P. O. Box 9502, 2300 RA Leiden, The Netherlands
[c] Department of Medical Biochemistry, Academic Medical
Center,
Amsterdam, The Netherlands
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200377.
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Scheme 2. Conversion of cyanohydrin 2 into the building blocks 6
and 7. Reagents and conditions: a) diethyl ether, DIBAL-H,
–80 °CǞ0 °C; b) MeOH, –90 °C; c) amine 5 (3 equiv.), room
temp., 20 h; d) NaBH4; e) Boc2O, TEA, THF, 50 °C, 20 h;
f) Grubbs G1 cat., 4 mol-%, DCM, reflux, 48 h.
Scheme 3. Preparation of d-1-deoxynojirimycin isomers from pre-
cursor 6. Reagents and conditions: a) K2OsO4·2H2O, NMO, THF/
H2O (85:15), 24–72 h; b) separation by silica gel column
chromatography; c) TBAF, THF, 18 h; d) Ph3P, DEAD, PhCO2H,
THF, –75 °C for 12 h, then room temp.; e) NaOH, MeOH, H2O;
f) MeOH, 6 m HCl, H2, Pd/C (10%); g) acetone, 2,2-dimethoxy-
propane, pTsOH, 1 h; h) Dess–Martin, DCM; i) NaBH4, EtOH,
–75 °CǞroom temp.; k) K2OsO4·2H2O, NMO, acetone/H2O (1:1),
18 h.
We anticipated that compounds 6 and 7 would be good
starting materials in the synthesis of a number of the 16
possible 1-DNJ isomers by oxidation of the double bond
present in 6 and 7. We demonstrated the validity of this
reasoning through the synthesis of d-allo- and d-galacto-1-
DNJ (12 and 13) from 6 (Scheme 3) and the preparation
of l-altro-1-DNJ (20) from 7 (Scheme 4).[16] As part of an
ongoing program to synthesize new potential inhibitors of
enzymes involved in the glycosylceramide metabolism[18] we
report herein the synthesis of eight configurational isomers
of 1-deoxynojirimycin, more specifically, all the isomers fea-
turing a 3,4-cis-diol moiety.[19]
To prepare d-altro-1-DNJ (18) from compound 6, we
turned to an approach in which the silyl protection in 6
was removed and the resulting alcohol was subjected to a
Mitsunobu reaction at 0 °C. In this way the benzoic ester
of compound 17 was obtained as an inseparable mixture
of two diastereoisomers in a ratio of 85:15. Decreasing the
Results and Discussion
To synthesize the d-1-DNJ isomers, as depicted in starting temperature of the Mitsunobu reaction to –70 °C
Scheme 3, the trans-substituted cyclic compound 6 served and subsequent warming to room temperature improved
as the starting material. By means of an Upjohn dihydrox- the diastereoselectivity to 98:2. Retaining the temperature
ylation reaction, diols 8 and 9 were obtained in a 1:1 ratio, at –75 °C for 12 h, followed by slow warming to room tem-
as determined by LC–MS. The mixture was separated by perature afforded the benzoate of 17 as a single dia-
careful silica gel column chromatography to afford 8 and 9 stereoisomer, as determined by RP-HPLC. Unfortunately,
in equal amounts. Subsequent removal of the TBDPS group we could not separate the benzoate of 17 completely from
followed by catalytic hydrogenation under acidic conditions the side-products of the Mitsunobu reaction. However, sub-
afforded d-allo- and d-galacto-1-DNJ (12 and 13) in high sequent saponification afforded the pure alcohol 17 in 87%
yields.[16] All the spectral and analytical data are in agree- yield. Note that alcohol 17 with a 2S,5S configuration is
ment with those reported in the literature.[20,21]
separable from the 2S,5R diastereoisomer by column
To prepare d-talo-1-DNJ (16), the protected galacto-1- chromatography. Alcohol 17 was subjected to Upjohn dihy-
DNJ (9) served as the starting compound. The 3,4-cis-diol droxylation,[23] which afforded a single stereoisomeric com-
was protected as the acetonide and subsequently the pound in 82% yield.
TBDPS group was removed to give alcohol 14. An at-
Comparison of the NMR and optical rotation data of 17
tempted Mitsunobu reaction on 14 failed and the starting with the earlier prepared l isomer revealed that indeed the
material was recovered. Hence, the free hydroxy in 14 was N-Boc-2-OBn-protected d-altro-1-DNJ had been obtained.
oxidized to the corresponding ketone after which NaBH4 Hydrogenation under acidic conditions gave d-altro-1-DNJ
reduction at –75 °C afforded 15 as the sole product in 69% (18) in 80% yield over two steps and in 70% overall yield
yield over the two steps. Catalytic hydrogenation of 15 un- based on starting compound 6. The analytical and spectro-
der acidic conditions afforded d-talo-1-DNJ (16) in quanti- scopic data are in complete agreement with literature
tative yield (Scheme 3).[22]
data.[24]
2
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1-Deoxynojirimycin Isomers from a Single Chiral Cyanohydrin
The enantiomers of the four 1-DNJ isomers presented Dess–Martin oxidation and after a completely selective
above are accessible from building block 7 in a similar fash- NaBH4 reduction and complete deprotection by catalytic
ion. Direct dihydroxylation of compound 7 afforded diol 19 hydrogenation under acidic conditions we obtained l-talo-
exclusively. Desilylation using TBAF and subsequent cata- 1-DNJ (30)[28] in 62% yield after three steps.
lytic hydrogenation under acidic conditions gave l-altro-1-
DNJ (20)[25] in an overall yield of 75% over the three steps
(Scheme 4).[16]
Conclusions
We have successfully synthesized a pallet of eight 1-de-
oxynojirimycin isomers out of the 16 possible isomers, all
starting from the common precursor cyanohydrin 2. The
process involved transformation of 2 into the cyclic building
blocks 6 and 7 in overall yields of 76%. Compound 6 was
converted into d-1-DNJ isomers 12 and 13 (36% overall,
three steps), 16 (20%, six steps) and 18 (71%, five steps).
Building block 7 provided the l-1-DNJ isomers 20 (75%,
three steps), 27 and 28 (29 and 25%, respectively, seven
steps) and 30 (14%, ten steps). The chemistry described
above renders compounds 6 and 7 valuable extensions to
the already known strategies for the synthesis of 1-DNJ de-
rivatives and its analogues from chiral pool carbo-
hydrates[29] and de novo synthetic strategies,[24a,30] often
from chiral building blocks.[31] We are currently investiga-
ting the potential of using orthogonally protected imino-
sugars 8, 9, 15, 19, 25 and 26 as starting points in the syn-
thesis of the other eight 1-DNJ isomers.
Experimental Section
Compounds 1–13: Detailed experimental procedures for the synthe-
sis of compounds 1,[12] 2[12] and 3–13[16] have been reported pre-
viously.
Scheme 4. Preparation of l-1-deoxynojirimycin isomers from pre-
cursor 7. Reagents and conditions: a) TBAF, THF, 18 h; b) Ph3P,
DEAD, PhCO2H, THF, –75 °C for 12 h, then room temp.;
c) NaOH, MeOH, H2O; d) DMF, TBDPS-Cl, imidazole;
e) K2OsO4·2H2O, NMO, THF/H2O (85:15), 24–72 h; f) separation
by silica gel column chromatography; g) MeOH, 6 m HCl, H2,
Pd/C (10%); h) acetone, 2,2-dimethoxypropane, pTsOH, 1 h;
i) Dess–Martin, DCM; j) NaBH4, EtOH, –75 °CǞroom temp.;
k) K2OsO4·2H2O, NMO, acetone/H2O (1:1), 48 h.
tert-Butyl (2R,3S,4R,5S)-2-(Benzyloxymethyl)-3,4-O-isopropylid-
ene-5-(tert-butyldiphenylsilyloxy)piperidine-1-carboxylate: Diol
9
(800 mg, 1.69 mmol) was dissolved in a mixture of THF (20 mL)
and 2,2-dimethoxypropane (2.00 mL). A few crystals of p-tolu-
enesulfonic acid were added and the mixture was stirred at room
temperature overnight. TLC analysis showed complete conversion
and the mixture was diluted with EtOAc and washed with an aque-
ous solution of NaHCO3 and brine. Drying (Na2SO4), filtration
and evaporation of the solvent gave a crude product that was puri-
fied by silica gel column chromatography (PE/EtOAc, 96:4Ǟ90:10)
to afford the target compound as a colourless oil (764 mg, 72%).
Compound 7 was transformed into trans-substituted
building block 21 by a three-step procedure that involved
removal of the TBDPS group, Mitsunobu substitution with
benzoic acid and subsequent saponification. Dihydrox-
ylation of 21 led to an inseparable mixture of the diols 22
and 23 in a ratio of 4:1. Therefore we deemed it necessary
to re-install a TBDPS group on 21 to obtain compound 24
in almost quantitative yield. Unfortunately, we were unable
to completely remove the impurities resulting from the silyl
protection reaction. Nonetheless, compound 24 was sub-
jected to Upjohn dihydroxylation and in this way protected
l-allo-1-DNJ (25)[26] and l-galacto-1-DNJ (26)[27] were ob-
tained in a ratio of around 1:1. After separation by column
chromatography and two deprotection steps, l-allo-1-DNJ
(27) and l-galacto-1-DNJ (28) were obtained in high yields.
By protecting the diol in 26 as an acetonide and subsequent
removal of the TBDPS group, we obtained alcohol 29. This
[α]2D3 = –30.2 (c = 1.0, CHCl ). IR (film): ν = 2933, 2859, 1696,
˜
3
1393, 1366, 1145, 1104, 1057, 990 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.67 (d, J = 6.9 Hz, 2 H, Ph), 7.63 (d, J = 6.9 Hz, 2
H, Ph), 7,42–7.21 (m, 11 H, Ph), 4.64 (d, J = 4.2 Hz, 1 H, 3-H),
4.56 (s, 2 H, CH2Ph), 4.24–3.80 (m, 4 H, 2-H, 5-H, 6-H, CH2O),
3.77 (s, 1 H, 4-H), 3.71 (app. t, J = 8.9 Hz, 1 H, CH2O), 3.21 (d, J
= 13.4 Hz, 1 H, 6-H), 1.39 (s, 9 H, OtBu), 1.33 (s, 3 H, CH3), 1.22
(s, 3 H, CH3), 1.07 (s, 9 H, SitBu) ppm. 13C NMR (101 MHz,
CDCl3): δ = 156.56 (C=O), 138.54 (Cq, Ph), 135.73 (Ph), 133.54
(Cq, Ph), 133.19 (Cq, Ph), 129.77, 129.70, 128.18, 127.63, 127.58,
127.55, 127.40 (Ph), 107.67 (O-C-O), 79.90 (Cq, OtBu), 75.03 (C-
5), 73.08 (CH2Ph), 70.97 (C-3), 69.55 (C-4), 50.75 (C-2), 28.27
(OtBu), 26.94 (SitBu), 26.63 (CH3), 24.18 (CH3), 19.13 (Cq,
SitBu) ppm. HRMS: calcd. for [C37H49NO6Si + H]+ 632.34019;
found 632.34040.
tert-Butyl (2R,3S,4R,5S)-2-(Benzyloxymethyl)-3,4-O-isopropylid-
alcohol was converted into the corresponding ketone by ene-5-hydroxypiperidine-1-carboxylate (14): A solution of TBAF in
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THF (1 m, 2.60 mL, 2.60 mmol) was added to a solution of the
above TBDPS ether (764 mg, 1.21 mmol) in THF (15 mL). After
2 h, TLC analysis revealed complete conversion. The mixture was
concentrated in vacuo and purified by silica gel column chromatog-
raphy (PE/EtOAc, 95:5Ǟ90:10Ǟ75:25) to afford the product as a
clear colourless oil (445 mg, 93%). [α]2D1 = –26.6 (c = 1.0, CHCl3).
(2R,3S,4R,5R)-2-(Hydroxymethyl)piperidine-3,4,5-triol
Hydro-
chloride ( -talo-1-DNJ Hydrochloride, 16): Alcohol 15 (184 mg,
D
0.468 mmol) was dissolved in a mixture of MeOH (15 mL) and
aqueous 6 m HCl (3 mL). The flask was purged with argon, Pd/C
(10%, 25 mg) was added and a balloon filled with H2 was placed
on top of the reaction mixture, which was stirred vigorously over-
night at room temperature. After filtration and evaporation of the
IR (film): ν = 3434, 2978, 1676, 1454, 1367, 1253, 1212, 1165, 1145,
˜
1
1054, 993, 875 cm–1. H NMR (400 MHz, CDCl3): δ = 7.35–7.23 solvents, the crude product (93 mg) was obtained in quantitative
(m, 5 H, Ph), 4.61 (dd, J = 6.7, 5.3 Hz, 1 H, 3-H), 4.57 (d, J =
12.1 Hz, 1 H, CH2Ph), 4.54 (d, J = 12.1 Hz, 1 H, CH2Ph), 4.20
(br. s, 1 H, 2-H), 4.03 (dd, J = 6.7, 1.6 Hz, 1 H, 4-H), 3.85–3.65
yield. [α]2D1 = +3.6 (c = 1.0, MeOH), [α]2D1 = +2.4 (c = 1.0, H2O)
{ref.[22f] [α]D = –21 (MeOH)}. 1H NMR (400 MHz, D2O): δ = 4.26
(s, 1 H, 5-H), 4.18 (s, 1 H, 3-H), 3.89 (m, 3 H, CH2O, 4-H), 3.54
(m, 4 H, CH2O, 5-H, 6-H), 3.36 (d, J = 12.5 Hz, 1 H, 6-H), 3.00 (d, J = 13.7 Hz, 1 H, 6-H), 3.43 (app. t, J = 6.3 Hz, 1 H, 2-H),
(br. s, 1 H, OH), 1.44 (s, 3 H, CH3), 1.43 [s, 9 H, (CH3)3], 1.34 (s,
3.35–3.25 (m, 1 H, 6-H) ppm. 13C NMR (101 MHz, D2O): δ =
3 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 156.85 (C=O), 67.66 (C-3), 67.16 (C-4), 66.67 (C-5), 60.41 (C-2), 59.21 (CH2O),
138.39 (Cq, Ph), 128.14, 127.41, 127.36 (Ph), 108.18 (O-C-O), 48.42 (C-6) ppm. HRMS: calcd. for [C6H13NO4 + H]+ 164.09173;
80.24 (Cq, OtBu), 76.23 (C-4), 72.84 (CH2Ph), 71.05 (C-3), 68.47 found 164.09144.
(C-5), 68.42 (CH2O), 51.01 (C-2), 42.90 (C-6), 28.21 (OtBu), 26.70
tert-Butyl (2S,5R)-2-(Benzyloxymethyl)-5,6-dihydro-5-hydroxypyr-
idine-1(2H)-carboxylate: Silyl ether 6 (2.20 g, 3.95 mmol) was dis-
solved in THF (25 mL) and cooled to 0 °C after which a 1 m solu-
(CH3), 24.43 (CH3) ppm. HRMS: calcd. for [C21H31NO6 + Na]+
416.20436; found 416.20421.
tion of TBAF (6.00 mL, 6.00 mmol) was added dropwise. The mix-
tert-Butyl (2S,3R,4R)-2-(Benzyloxymethyl)-3,4-O-isopropylidene-5-
ture was warmed to room temperature and stirred overnight. It was
oxopiperidine-1-carboxylate: Dess–Martin reagent (0.903 g,
then diluted with EtOAc (200 mL), washed with water (25 mL) and
2.13 mmol) was added to a solution of alcohol 14 (445 mg,
brine (25 mL), dried (MgSO4), filtered and concentrated to afford
1.13 mmol) in DCM (30 mL). After 5 h, TLC analysis revealed
the crude product, which was purified by silica gel column
complete conversion. The mixture was filtered through a pad of
chromatography (PE/EtOAc, 4:1Ǟ7:3Ǟ3:2) to afford the product
Celite, concentrated in vacuo and purified by silica gel column
as a clear colourless oil (1.19 g, 94%). [α]2D1 = –287 (c = 1.0, CHCl3).
chromatography (PE/EtOAc, 90:10Ǟ75:25) to afford the product
IR (film): ν = 3429, 2976, 2857, 1686, 1420, 1365, 1249, 1171,
˜
as a clear colourless oil (368 mg, 83%). [α]2D1 = +27.8 (c = 0.80,
1128 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.46–7.18 (m, 5 H,
Ph), 6.06 (dd, J = 10.1, 5.6 Hz, 1 H, 4-H), 5.94 (dd, J = 10.1,
3.9 Hz, 1 H, 3-H), 4.78–4.45 (m, 3 H, 2-H, CH2Ph), 4.32–3.98 (m,
2 H, 5-H, 6-H), 3.53 (br. s, 2 H, CH2O), 3.16 (m, 1 H, 6-H), 2.57
(s, 1 H, OH), 1.44 (s, 9 H, OtBu) ppm. 13C NMR (101 MHz,
CDCl3): δ = 155.15 (C=O), 137.91 (Cq, Ph), 130.20 (C-3), 129.47
(C-4), 128.20, 127.38, 127.27 (Ph), 79.89 (Cq, OtBu), 72.93
(CH2Ph), 70.11 (CH2O), 62.36 (C-5), 51.91 and 50.83 (C-2), 46.49
and 45.02 (C-6), 28.23 (OtBu) ppm. HRMS: calcd. for [C18H25NO4
+ H]+ 320.18563; found 320.18588.
CHCl ). IR (film): ν = 2981, 1744, 1698, 1369, 1163, 1099,
˜
3
872 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.35–7.21 (m, 5 H,
Ph), 5.14–4.80 (m, 2 H, 2-H, 3-H), 4.41 (m, 4 H, 4-H, 6-H, CH2Ph),
3.78 (d, J = 18.8 Hz, 1 H, 6-H), 3.62 (br. s, 1 H, CH2O), 3.40 (br.
s, 1 H, CH2O), 1.47 (s, 3 H, CH3), 1.46 (s, 9 H, OtBu), 1.37 (s, 3
H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 203.21 (C=O),
154.71 (NC=O), 137.56 (Cq, Ph), 128.19, 127.54, 127.40 (Ph),
111.01 (O-C-O), 81.09 (Cq, OtBu), 77.37 (C-4), 73.23 (C-3), 72.89
(CH2Ph), 65.75 (CH2O), 28.11 (OtBu), 26.06 (CH3), 24.15
(CH3) ppm. HRMS: calcd. for [C21H29NO6 + H]+ 392.20676;
found 392.20668.
tert-Butyl (2S,5S)-5-(Benzoyloxy)-2-(benzyloxymethyl)-5,6-dihydro-
pyridine-1(2H)-carboxylate: A solution of the previous alcohol
(1.19 g, 3.73 mmol), triphenylphosphane (1.17 g, 4.46 mmol) and
tert-Butyl (2R,3S,4R,5R)-2-(Benzyloxymethyl)-3,4-O-isopropylid-
ene-5-hydroxypiperidine-1-carboxylate (15): NaBH4 (48.0 mg, benzoic acid (0.741 g, 6.07 mmol) in THF (20 mL) was cooled to
1.26 mmol) was added to a solution of the aforementioned ketone
(185 mg, 0.473 mmol) in ethanol (20 mL) at –75 °C. The mixture
was warmed slowly in a cooling bath to –20 °C over around 2 h.
At that moment TLC analysis revealed complete conversion. The
reaction mixture was diluted with EtOAc (100 mL), washed with
water (10 mL) and brine (10 mL), dried (MgSO4), filtered and con-
centrated. Purification by silica gel column chromatography (PE/
EtOAc, 90:10Ǟ75:25Ǟ50:50) afforded alcohol 15 as a clear
colourless oil (155 mg, 83%). [α]2D1 = –19.8 (c = 1.0, CHCl3). IR
–75 °C at which temperature a solution of diethyl azodicarboxylate
(0.784 g, 4.51 mmol) in THF (7 mL) was dropwise over 1 h. Stirring
was continued at –75 °C for 12 h after which the temperature was
slowly raised to room temperature over 5 h. TLC analysis con-
firmed complete conversion of the starting alcohol and the reaction
mixture was diluted with EtOAc (100 mL) and washed with 1 m
HCl (10 mL), an aqueous saturated solution of NaHCO3 (25 mL)
and brine (25 mL). The organic layer was dried (MgSO4), filtered
and concentrated to afford the crude product, which was purified
by silica gel column chromatography (PE/EtOAc, 95:5Ǟ90:10) to
(film): ν = 3475, 2980, 2934, 1694, 1455, 1367, 1252, 1161, 1088,
˜
1
1030, 873 cm–1. H NMR (400 MHz, CDCl3): δ = 7.35–7.22 (m, 5
afford the product as a clear colourless oil (1.57 g, 100%). [α]2D1
=
H, Ph), 4.77–4.66 (m, 1 H, 3-H), 4.55 (s, 2 H, CH2Ph), 4.35 (app. –27.2 (c = 1.0, CHCl ). IR (film): ν = 2979, 2863, 2359, 1721, 1694,
˜
3
t, J = 5.9 Hz, 1 H, 4-H), 4.13 (d, J = 3.3 Hz, 1 H, 2-H), 3.87 (m,
2 H, 6-H, CH2O), 3.70 (app. t, J = 8.8 Hz, 1 H, CH2O), 3.63–3.52 (400 MHz, CDCl3): δ = 8.04 (d, J = 7.5 Hz, 2 H, Ph), 7.54 (app. t,
1417, 1364, 1316, 1260, 1156, 1108, 1069 cm–1. 1H NMR
(m, 1 H, 5-H), 3.02–2.92 (app. t, J = 12.0 Hz, 1 H, 6-H), 2.87 (br.
s, 1 H, OH), 1.49 (s, 3 H, CH3), 1.43 (s, 9 H, OtBu), 1.39 (s, 3 H,
CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 155.15 (C=O),
138.34 (Cq, Ph), 128.11, 127.41, 127.36 (Ph), 108.47 (O-C-O), 80.22
J = 7.4 Hz, 1 H, Ph), 7.43 (m, 2 H, Ph), 7.36–7.23 (m, 5 H, Ph),
5.99 (m, 2 H, 3-H, 4-H), 5.52 (br. s, 1 H, 5-H), 4.80–4.40 (m, 4 H,
2-H, 6-H, CH2Ph), 3.62 (m, 2 H, CH2O), 3.17–2.94 (m, 1 H, 6-H),
1.47 (ds, 9 H, OtBu) ppm. 13C NMR (101 MHz, CDCl3): δ =
(Cq, OtBu), 72.86 (CH2Ph), 72.61 (C-3), 72.16 (C-4), 67.67 (CH2O), 170.51 and 165.64 (C=O), 154.11 (NC=O), 138.02 (Cq, Ph), 133.28,
66.24 (C-5), 50.70 (C-2), 42.18 (C-6), 28.18 (OtBu), 26.18 (CH3), 132.99 (Cq, Ph), 129.93, 129.74, 129.52, 129.13, 128.20, 127.94,
24.51 (CH3) ppm. HRMS: calcd. for [C21H31NO6 + H]+ 394.22241;
found 394.22209.
127.64, 127.43, 127.28 (C-3, C-4, Ph), 80.28 (Cq, OtBu), 72.94
(CH2Ph), 70.38 (CH2O), 66.06 (C-5), 51.88 and 50.93 (C-2), 42.16
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20377
/KAP1
Date: 10-05-12 10:29:10
Pages: 11
1-Deoxynojirimycin Isomers from a Single Chiral Cyanohydrin
1
and 40.58 (C-6), 28.20 (OtBu) ppm. H NMR (400 MHz, CDCl3,
and 6 m HCl (6 mL). The solution was purged with nitrogen after
which Pd/C (10%, 60 mg) was added and the reaction mixture was
stirred under a balloon of H2 overnight. The mixture was filtered
333 K): δ = 8.02 (d, J = 7.9 Hz, 2 H, Ph), 7.51 (dd, J = 10.9, 4.0 Hz,
1 H, Ph), 7.43–7.36 (m, 2 H, Ph), 7.34–7.21 (m, 5 H, Ph), 6.01–
5.91 (m, 2 H, 3-H, 4-H), 5.51 (dd, J = 9.1, 6.5 Hz, 1 H, 5-H), 4.64 through a Whatman® glass-fibre filter and concentrated to afford
(br. s, 1 H, 2-H), 4.57 (d, J = 12.2 Hz, 1 H, CH2Ph), 4.53 (d, J =
the title compound as a white solid (310 mg, quant.). [α]2D1 = +39.2
12.2 Hz, 1 H, CH2Ph), 4.51 (br. s, 1 H, 6-H) 3.70–3.57 (m, 2 H, (c = 0.5 MeOH) {ref.[24a] [α]2D5 = +31.1 (c = 0.5 MeOH), ref.[24d] [α]
CH2O), 3.04 (app. t, J = 11.0 Hz, 1 H, 6-H), 1.47 (s, 9 H,
OtBu) ppm. 13C NMR (101 MHz, CDCl3, 333 K): δ = 165.63
(C=O), 154.24 (NC=O), 138.19 (Cq, Ph), 133.19, 132.90 (Ph),
130.14 (Cq, Ph), 130.00, 129.58, 129.05, 128.23, 127.85, 127.45,
127.36 (C-3, C-4, Ph) 80.31 (Cq, OtBu), 73.18 (CH2Ph), 70.73
(CH2O), 66.25 (C-5), 51.67 (C-2), 28.31 (Cq, OtBu) ppm. HRMS:
calcd. for [C25H29NO5 + Na]+ 446.19357; found 446.19379.
D = +33.2 (c = 0.5 MeOH)}. 1H NMR (400 MHz, D2O): δ = 4.14–
4.08 (m, 1 H, 5-H), 4.02–3.96 (m, 2 H, 3-H, 4-H), 3.93 (dd, J =
12.6, 3.3 Hz, 1 H, CH2O), 3.79 (dd, J = 12.6, 6.8 Hz, 1 H, CH2O),
3.38–3.27 (m, 2 H, 2-H, 6-H), 3.18 (dd, J = 13.5, 2.7 Hz, 1 H, 6-
H) ppm. 13C NMR (101 MHz, D2O): δ = 68.15 (C-3), 65.89 (C-5),
63.28 (C-4), 57.86 (CH2O), 55.53 (C-2), 43.60 (C-6) ppm. HRMS:
calcd. for [C6H13NO4 + H]+ 164.09173; found 164.09169.
tert-Butyl (2S,3S,4R,5S)-2-(Benzyloxymethyl)-5-(tert-butyldiphenyl-
silyloxy)-3,4-dihydroxypiperidine-1-carboxylate (19): Compound 7
(651 mg, 1.17 mmol) was dissolved in a mixture of THF (6.0 mL)
and water (0.60 mL) and cooled to 0 °C. N-Methylmorpholine N-
oxide monohydrate (665 mg, 4.93 mmol) and K2OsO4·2H2O
(20.0 mg, 0.054 mmol, 4.6 mol-%) were then added. After 24–48 h,
TLC analysis showed complete conversion of the starting material.
The reaction mixture was quenched with a saturated aqueous solu-
tion of NaHSO3 (10 mL) and stirred for 30 min. Then the mixture
was diluted with water (50 mL) and extracted with EtOAc
(3ϫ30 mL). The combined organic layers were washed with 0.6 m
HCl, saturated NaHCO3 and brine. Drying (Na2SO4), filtration
and evaporation of the solvent afforded a crude product that was
purified by silica gel column chromatography (PE/EtOAc,
tert-Butyl (2S,5S)-2-(Benzyloxymethyl)-5,6-dihydro-5-hydroxypyr-
idine-1(2H)-carboxylate (17): The above benzoate (155 mg,
0.366 mmol) was dissolved in a mixture of MeOH (4.0 mL) and
H2O (1.0 mL). The mixture was cooled on ice and 4 m NaOH
(0.40 mL) was added. The mixture was stirred at room temp. over-
night. TLC showed complete conversion of the ester and the mix-
ture was diluted with EtOAc (30 mL), washed with water (5 mL)
and brine (5 mL), dried (MgSO4), filtered and concentrated. After
purification by silica gel column chromatography (PE/EtOAc,
90:10Ǟ80:20Ǟ70:30), the title alcohol was obtained as a colour-
less oil (109 mg, 93%). [α]2D1 = –146 (c = 1.0, CHCl ). IR (film): ν
˜
3
= 3426, 2928, 1695, 1456, 1418, 1366, 1257, 1155, 1071, 1020 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.19 (m, 5 H, Ph), 5.94 (d,
J = 10.3 Hz, 1 H, 4-H), 5.80 (dd, J = 10.3, 3.0 Hz, 1 H, 3-H), 4.56
(d, J = 12.1 Hz, 1 H, CH2Ph), 4.51 (d, J = 12.1 Hz, 1 H, CH2Ph),
4.48 (s, 1 H, 2-H), 4.42–4.06 (m, 2 H, 5-H, 6-H), 3.59–3.48 (m, 2
H, CH2O), 2.76 (m, 2 H, 6-H, OH), 1.43 (s, 9 H, OtBu) ppm. 13C
NMR (101 MHz, CDCl3): δ = 154.47 (C=O), 137.90 (Cq, Ph),
133.14 (C-4), 131.70, 129.96, 128.34, 127.60 (Ph), 127.48 (C-3),
80.16 (Cq, OtBu), 73.10 (CH2Ph), 70.48 (CH2O), 63.49 (C-5), 28.33
(OtBu) ppm. HRMS: calcd. for [C18H25NO4 + Na]+ 342.16758;
found 342.16762.
7:3Ǟ1:1) to afford 19 (635 mg, 92%) as a colourless oil. [α]2D2
=
+52.0 (c = 1.0, CHCl ). IR (film): ν = 3396, 2976, 2358, 1664,
˜
3
1420, 1365, 1251, 1167, 1073, 750, 698 cm–1. H NMR (400 MHz,
1
CDCl3): δ = 7.72–7.64 (m, 4 H, Ph), 7.45–7.25 (m, 11 H, Ph), 4.53
(d, J = 12.0 Hz, 1 H, CH2Ph), 4.48 (d, J = 12.0 Hz, 1 H, CH2Ph),
4.45 (br. s, 1 H, 2-H), 4.03 (s, 1 H, 3-H), 3.98–3.88 (m, 1 H, 4-H),
3.79 (s, 1 H, 5-H), 3.56 (d, J = 5.3 Hz, 2 H, CH2O), 2.85 (t, J =
11.8 Hz, 1 H, 6-H), 2.49 (br. s, 1 H, OH), 2.25 (br. s, 1 H, OH),
1.34 (s, 9 H, OtBu), 1.08 (s, 9 H, SitBu) ppm. 13C NMR (101 MHz,
CDCl3): δ = 155.13 (C=O), 137.82 (Cq, Ph), 135.70, 135.61 (Ph),
133.59 (Cq, Ph), 129.89, 128.34, 127.80, 127.74, 127.60, 127.36 (Ph),
80.01 (Cq, OtBu), 73.88 (C-5), 73.04 (CH2Ph), 69.77 (C-4), 69.51
(C-3), 68.62 (CH2O), 28.20 (OtBu), 26.94 (SitBu), 19.26 (Cq,
SitBu) ppm. 1H NMR (400 MHz, DMSO, 353 K): δ = 7.74 (d, J =
6.5 Hz, 2 H, Ph), 7.66 (d, J = 6.5 Hz, 2 H, Ph), 7.47–7.36 (m, 6 H,
Ph), 7.36–7.25 (m, 5 H, Ph), 4.53 (d, J = 12.1 Hz, 1 H, CH2Ph),
4.49 (d, J = 12.2 Hz, 1 H, CH2Ph), 4.43 (d, J = 3.5 Hz, 1 H, OH),
4.25 (m, 1 H, 2-H), 4.09 (d, J = 6.5 Hz, 1 H, OH), 3.99–3.87 (m,
3 H, 3-H, 4-H, 6-H), 3.71–3.64 (m, 1 H, 5-H), 3.64–3.53 (m, 2 H,
CH2O), 2.74 (td, J = 12.0, 2.6 Hz, 1 H, 6-H), 1.29 (s, 9 H, OtBu),
1.06 (s, 9 H, SitBu) ppm. 13C NMR (101 MHz, DMSO, 353 K): δ
= 153.92 (C=O), 138.01 (Cq, Ph), 135.08, 134.90 (Ph), 133.91 (Cq,
Ph), 133.47 (Cq, Ph), 129.12, 129.06, 127.68, 127.06, 127.01, 126.87,
126.79 (Ph), 78.24 (Cq, OtBu), 72.43 (C-5), 71.86 (Cq, Ph), 69.48
(C-4), 68.63 (C-3), 67.65 (CH2O), 56.23 (C-2), 45.09 (C-6), 27.60
(OtBu), 26.51 (SitBu), 18.58 (Cq, SitBu) ppm. HRMS: calcd. for
[C34H45NO6Si + Na]+ 614.29084; found 614.29086.
tert-Butyl (2R,3R,4S,5R)-2-(Benzyloxymethyl)-3,4,5-trihydroxypip-
eridine-1-carboxylate: Alcohol 17 (350 mg, 1.10 mmol) and N-
methylmorpholine N-oxide monohydrate (NMO) (205 mg,
1.52 mmol) were dissolved in a mixture of acetone (10 mL) and
water (10 mL). Subsequently, K2OsO4·2H2O (20 mg, 0.054 mmol)
was added and the reaction stirred at ambient temperature over-
night, after which TLC analysis showed complete conversion of
alcohol 17. The reaction mixture was quenched with a saturated
aqueous solution of NaHSO3 (30 mL) and stirred for 1 h. The mix-
ture was extracted with EtOAc (3ϫ50 mL) and the combined or-
ganic fractions were washed with brine (20 mL), dried (MgSO4),
filtered and concentrated to afford the crude product. After purifi-
cation by silica gel column chromatography (PE/EtOAc, 1:1Ǟ0:1),
the title triol was obtained as a colourless oil (320 mg, 82%). [α]2D2
= –52.2 (c = 1.0, CHCl ). IR (film): ν = 3404, 2977, 2906, 1654,
˜
3
1420, 1366, 1166, 1078 cm–1. 1H NMR (400 MHz, MeOD): δ =
7.33–7.25 (m, 5 H), 4.55 (d, J = 12.0 Hz, 1 H), 4.50 (d, J = 12.0 Hz,
1 H), 4.47 (s, 1 H), 4.25–4.08 (m, 1 H), 4.01 (s, 1 H), 3.83–3.68 (m,
1 H), 3.56 (dd, J = 16.5, 4.8 Hz, 3 H), 2.68 (d, J = 11.3 Hz, 1 H),
1.43 (s, 9 H) ppm. 13C NMR (101 MHz, MeOD): δ = 139.40,
129.38, 128.68, 81.36, 74.02, 73.93, 70.62, 68.64, 67.75, 59.25,
45.56, 28.61 ppm. HRMS: calcd. for [C18H27NO6 + H]+ 354.19111;
found 354.19120; calcd. for [C18H27NO6 + Na]+ 376.17306; found
376.17311.
tert-Butyl (2S,3S,4R,5S)-2-(Benzyloxymethyl)-3,4,5-trihydroxypip-
eridine-1-carboxylate: TBDPS ether 19 (688 mg, 1.16 mmol) was
dissolved in THF (20 mL). A 1 m solution of TBAF in THF
(2.0 mL, 2.0 mmol) was added at room temperature and the reac-
tion mixture was stirred at ambient temperature overnight. TLC
indicated complete conversion and the mixture was concentrated.
(2R,3R,4S,5R)-2-(Hydroxymethyl)piperidine-3,4,5-triol
Hydro- The crude compound was purified by silica gel column chromatog-
chloride (D-altro-1-DNJ Hydrochloride, 18): The triol from above
(550 mg, 1.56 mmol) was dissolved in a mixture of MeOH (20 mL)
raphy (PE/EtOAc, 3:1Ǟ1:1Ǟ0:1) to afford the title compound as
a colourless oil (337 mg, 82%). [α]2D0 = +48.8 (c = 1.0, CHCl3). IR
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20377
/KAP1
Date: 10-05-12 10:29:10
Pages: 11
H. S. Overkleeft et al.
FULL PAPER
(film): ν = 3396, 2976, 2358, 1664, 1420, 1365, 1251, 1167, 1073,
and benzoic acid (0.736 g, 6.03 mmol) was dissolved in THF
750 cm–1. 1H NMR (400 MHz, MeOD): δ = 7.40–7.22 (m, 5 H, (20 mL). At –75 °C a solution of DEAD (0.690 mL, 4.44 mmol) in
Ph), 4.56 (d, J = 12.1 Hz, 1 H, CH2Ph), 4.51 (d, J = 12.1 Hz, 1 H, THF (7 mL) was added dropwise over 10 min. After stirring at
CH2Ph), 4.46 (br. s, 1 H, 2-H), 4.19–4.07 (m, 1 H, 6-H), 4.00 (br. –75 °C for 12 h, the mixture was slowly warmed to room tempera-
˜
s, 1 H, 3-H), 3.80–3.69 (m, 1 H, 5-H), 3.59 (d, J = 6.6 Hz, 2 H,
CH2O), 3.54 (dd, J = 9.4, 3.1 Hz, 1 H, 4-H), 2.68 (br. s, 1 H, 6-H),
1.44 (s, 9 H, OtBu) ppm. 13C NMR (101 MHz, CDCl3): δ = 155.84
ture. TLC analysis revealed complete conversion and the reaction
mixture was diluted with EtOAc (100 mL) and then washed with
aqueous 0.5 m HCl (20 mL), saturated aqueous NaHCO3 (20 mL)
(C=O), 137.69 (Cq, Ph), 128.34, 127.64, 127.48 (Ph), 80.51 (Cq, and brine (20 mL). After drying (MgSO4), filtration and concentra-
OtBu), 73.14 (C-2), 72.88 (CH2Ph), 69.33 (C-3), 67.55 (CH2O),
66.80 (C-4), 28.27 (OtBu) ppm. HRMS: calcd. for [C18H27NO6 +
H]+ 354.19111; found 354.19122.
tion in vacuo, the crude product was obtained. At this stage RP-
HPLC analysis indicated Ͻ1% of the 2S,5R isomer in the crude
product. Purification by silica gel column chromatography (PE/
EtOAc, 95:5Ǟ90:10) afforded the product as a clear colourless oil
(2S,3S,4R,5S)-2-(Hydroxymethyl)piperidine-3,4,5-triol
Hydro-
(1.32 g, 94%). [α]2D1 = +299 (c = 1.0, CHCl ). IR (film): ν = 2972,
˜
3
chloride ( -altro-1-DNJ Hydrochloride, 20): The protected l-altro-
L
2861, 1717, 1690, 1419, 1363, 1335, 1266, 1169, 1107, 1069,
1025 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.06 (m, 2 H, Ph),
7.65–7.12 (m, 8 H, Ph), 6.16 (m, 2 H, 3-H, 4-H), 5.30 (m, 1 H, 5-
H), 4.90–4.70 (m, 1 H, 2-H), 4.64–4.40 (m, 3 H, CH2Ph, 6-H), 3.61
(m, 2 H, CH2O), 3.31–3.21 (m, 1 H, 6-H), 1.38 (m, 9 H,
OtBu) ppm. 13C NMR (101 MHz, CDCl3): δ = 169.82 and 165.95
(C=O), 154.62 (NC=O), 137.92 (Cq, Ph), 133.47 (C-3), 133.15,
132.90, 132.47, 129.96, 129.89 (Ph), 129.56 (Cq, Ph), 128.20, 128.10,
127.45, 127.31 (Ph), 123.91, 123.54 (C-4), 79.73 (Cq, OtBu), 72.92
(CH2Ph), 70.29 (CH2O), 65.31 (C-5), 52.05 and 51.02 (C-2), 43.25
and 42.09 (C-6), 28.02 (OtBu) ppm. 1H NMR (400 MHz, 333 K,
CDCl3): δ = 8.10–7.96 (d, J = 7.8 Hz, 2 H, Ph), 7.50 (dd, J = 15.2,
7.8 Hz, 1 H, Ph), 7.43–7.19 (m, 7 H, Ph), 6.13 (s, 2 H, 3-H, 4-H),
5.28 (s, 1 H, 5-H), 4.81 (br. s, 1 H, 2-H), 4.62–4.39 (m, 3 H, CH2Ph,
6-H), 3.61 (d, J = 5.0 Hz, 2 H, CH2O), 3.31 (d, J = 13.8 Hz, 1 H,
6-H), 1.36 (s, 9 H, OtBu) ppm. 13C NMR (101 MHz, 333 K,
CDCl3): δ = 165.99 (C=O), 154.70 (NC=O), 138.16 (Cq, Ph),
133.07 (C-3), 132.74, 130.40 (Ph), 129.97 (Cq, Ph), 129.67, 128.25,
128.11, 127.49, 127.37 (Ph), 123.78 (C-4), 79.83 (Cq, OtBu), 73.19
(CH2Ph), 70.60 (CH2O), 65.53 (C-5), 51.67 (C-2), 43.15 (C-6),
1-deoxynojirimicin (335 mg, 0.949 mmol) from above was dissolved
in a mixture of MeOH (20 mL) and aqueous 6 m HCl (4 mL). The
flask was purged with argon, Pd/C (10%, 30 mg) was added and a
balloon filled with hydrogen gas was placed on top of the reaction.
The mixture was stirred overnight at room temperature. Pd/C was
removed by filtration and the filtrate evaporated to yield the crude
product (187 mg, 99%) as a white foam that needed no further
purification. [α]2D1 = –31.4 (c = 0.5, MeOH) {ref.[25] [α]2D0 = –31.4 (c
1
= 1.0, MeOH)}. H NMR (400 MHz, MeOD): δ = 4.11 (app. t, J
= 1.2 Hz, 1 H, 5-H), 4.01–3.97 (m, 2 H, 3-H, 4-H), 3.93 (dd, J =
12.8, 3.2 Hz, 1 H, CH2O), 3.79 (dd, J = 12.8, 6.8 Hz, 1 H, CH2O),
3.36–3.28 (m, 2 H, 2-H, 6-H), 3.18 (dd, J = 13.6, 2.6 Hz, 1 H, 6-
H) ppm. 13C NMR (101 MHz, D2O): δ = 68.41 (C-3), 66.15 (C-5),
63.55 (C-4), 58.12 (CH2O), 55.79 (C-2), 43.86 (C-6) ppm. HRMS:
calcd. for [C6H13NO4 + H]+ 164.09173; found 164.09157.
tert-Butyl (2R,5R)-2-(Benzyloxymethyl)-5,6-dihydro-5-hydroxypyr-
idine-1(2H)-carboxylate: TBDPS ether 7 (3.40 g, 6.10 mmol) was
dissolved in THF (50 mL), cooled on an ice bath and a 1 m solution
of TBAF in THF (12 mL, 12 mmol) was added. After stirring on
the ice bath for 1 h and then for 4 h at room temperature, TLC
analysis revealed complete conversion of the starting material. The
solution was concentrated to 25% of its volume, diluted with
EtOAc (100 mL) and washed with water (15 mL) and brine
(15 mL). Drying (MgSO4), filtration, evaporation of the solvents
and purification by silica gel column chromatography (PE/EtOAc,
90:10Ǟ80:20Ǟ60:40) afforded the product as a clear colourless
28.20 (OtBu) ppm. HRMS: calcd. for [C25H29NO5
446.19379; found 446.19348; calcd. for [C25H29NO5
424.21185; found 424.21196.
+
+
Na]+
H]+
tert-Butyl (2R,5S)-2-(Benzyloxymethyl)-5,6-dihydro-5-hydroxypyr-
idine-1(2H)-carboxylate (21): The benzoate from above (1.67 g,
3.94 mmol) was dissolved in a mixture of MeOH (100 mL) and
water (20 mL). Subsequently aqueous 4 m NaOH (10 mL) was
added at 0 °C. The reaction mixture was warmed up to room tem-
perature and after 3 h TLC analysis revealed complete conversion
of the starting material. The reaction mixture was concentrated to
a quarter of its volume and diluted with EtOAc (200 mL), washed
with brine (2ϫ50 mL), dried (MgSO4), filtered and concentrated.
The residue was purified by silica gel column chromatography (PE/
EtOAc, 90:10Ǟ80:20Ǟ60:40) to afford the product as a clear
colourless oil (1.00 g, 80%). [α]2D0 = +270 (c = 1.0, CHCl3). IR
oil (1.75 g, 90%). [α]2D1 = +140 (c = 1.0, CHCl ). IR (film): ν =
˜
3
3422, 2978, 2868, 1694, 1418, 1366, 1155, 1112, 1072 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 7.38–7.22 (m, 5 H, Ph), 5.93 (d, J
= 10.4 Hz, 1 H, 4-H), 5.79 (dd, J = 10.4, 2.7 Hz, 1 H, 3-H), 4.66–
4.02 (m, 5 H, CH2Ph, 2-H. 5-H, 6-H), 3.73–3.42 (m, 2 H, CH2O),
3.40–2.60 (m, 2 H, 6-H, OH), 1.43 (s, 9 H, OtBu) ppm. 13C NMR
(101 MHz, CDCl3): δ = 154.33 (C=O), 137.80 (Cq, Ph), 131.92,
128.17, 127.42, 127.32 (C-3, C-4, Ph), 80.01 (Cq, OtBu), 72.89
(CH2Ph), 70.32 (CH2O), 64.32 (C-5), 63.20 (C-2), 51.69 (C-2),
44.07 (C-6), 28.19 (OtBu) ppm. 1H NMR (400 MHz, 333 K,
CDCl3): δ = 7.35–7.18 (m, 5 H, Ph), 5.89 (dd, J = 10.4, 1.5 Hz, 1
H, 4-H), 5.78 (ddd, J = 10.4, 3.7, 1.5 Hz, 1 H, 3-H), 4.60–4.44 (m,
3 H, 2-H, CH2Ph), 4.28–4.11 (m, 2 H, 5-H, 6-H), 3.57 (d, J =
5.7 Hz, 2 H, CH2O), 2.77 (dd, J = 11.9, 8.7 Hz, 1 H, 6-H), 2.23 (s,
1 H, OH), 1.44 (s, 9 H, OtBu) ppm. 13C NMR (101 MHz, 333 K,
CDCl3): δ = 154.54 (C=O), 138.31 (Cq, Ph), 131.89, 128.31, 127.53,
127.51, 127.35 (C-3, C-4, Ph), 80.06 (Cq, OtBu), 73.35 (CH2Ph),
70.96 (CH2O), 63.69 (C-5), 51.91 (C-2), 45.48 (C-6), 28.43
(OtBu) ppm. HRMS: calcd. for [C18H25NO4 + Na]+ 342.16758;
found 342.16753.
(film): ν = 3422, 2976, 2830, 1686, 1420, 1364, 1248, 1170, 1126,
˜
1
1069, 735 cm–1. H NMR (400 MHz, CDCl3): δ = 7.37–7.24 (m, 5
H, Ph), 6.07 (dd, J = 10.0, 5.5 Hz, 1 H, 3-H), 5.95 (dd, J = 10.1,
3.8 Hz, 1 H, 4-H), 4.72 (br. s, 1 H, 2-H), 4.54 (d, J = 12.1 Hz, 1
H. CH2Ph), 4.50 (d, J = 12.1 Hz, 1 H, CH2Ph), 4.34–3.99 (m, 2 H,
2-H, 6-H), 3.54 (br. s, 2 H, CH2O), 3.17 (d, J = 34.6 Hz, 1 H, 6-
H), 2.35 (br. s, 1 H, OH), 1.45 (s, 9 H, OtBu) ppm. 13C NMR
(101 MHz, CDCl3): δ = 155.21 (C=O), 137.96 (Cq, Ph), 129.64,
128.25, 127.45, 127.33 (C-3, C-4, Ph), 79.98 (Cq, OtBu), 73.00
(CH2Ph), 70.16 (CH2O), 62.56 (C-2), 28.29 (OtBu) ppm. 1H NMR
(400 MHz, CDCl3, 333 K): δ = 7.35–7.20 (m, 5 H, Ph), 6.04 (dd, J
= 10.1, 5.5 Hz, 1 H, 4-H), 5.94 (dd, J = 10.1, 4.0 Hz, 1 H, 3-H),
4.64 (s, 1 H, 2-H), 4.53 (d, J = 12.1 Hz, 1 H, CH2Ph), 4.49 (d, J =
12.1 Hz, 1 H, CH2Ph), 4.21 (d, J = 13.8 Hz, 1 H, 6-H), 4.07–4.00
(m, 1 H, 2-H), 3.55 (d, J = 5.4 Hz, 2 H, CH2O), 3.16 (d, J =
tert-Butyl
(2R,5S)-5-(Benzoyloxy)-2-(benzyloxymethyl)-5,6-dihy-
dropyridine-1(2H)-carboxylate: A mixture of the alcohol from
above (1.05 g, 3.29 mmol), triphenylphosphane (1.11 g, 4.24 mmol)
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20377
/KAP1
Date: 10-05-12 10:29:10
Pages: 11
1-Deoxynojirimycin Isomers from a Single Chiral Cyanohydrin
13.8 Hz, 1 H, 6-H), 2.01 (br. s, 1 H, OH), 1.45 (s, 9 H, OtBu) ppm.
13C NMR (101 MHz, CDCl3, 333 K): δ = 155.29 (C=O), 138.23
brine. Drying (Na2SO4), filtration and evaporation of the solvent
afforded a crude 1:1 mixture of two diastereoisomers (determined
(Cq, Ph), 130.12, 128.27, 127.63, 127.49, 127.39 (C-3, C-4, Ph), by LC–MS and TLC). Silica gel column chromatography (PE/
79.98 (Cq, OtBu), 73.20 (CH2Ph), 70.44 (CH2Ph), 62.81 (C-5),
51.68 (C-2), 46.00 (C-6), 28.37 (OtBu) ppm. HRMS: calcd. for
EtOAc, 4:1) afforded the faster running isomer (830 mg, 45%) as
a clear colourless oil.
[C18H25NO4
+
Na]+ 342.16758; found 342.16764; calcd. for
[C18H25NO4 + H]+ 320.18563; found 320.18579.
tert-Butyl (2S,3S,4R,5R)-2-(Benzyloxymethyl)-5-(tert-butyldiphen-
ylsilyloxy)-3,4-dihydroxypiperidine-1-carboxylate (25): [α]2D1 = –10.4
tert-Butyl (2R,5S)-2-(Benzyloxymethyl)-5,6-dihydro-5-(tert-butyldi-
phenylsilyloxy)pyridine-1(2H)-carboxylate (24): Alcohol 21 (1.02 g,
3.19 mmol) was dissolved in DMF (20 mL) and subsequently imid-
azole (340 mg, 5.00 mmol) and TBDPS-Cl (1.30 g, 4.72 mmol) were
added. The reaction mixture was stirred at ambient temperature
overnight after which TLC indicated complete conversion of 21.
Water (60 mL) was added and the mixture extracted with diethyl
ether (3ϫ30 mL). The combined organic fractions were washed
with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and
concentrated. The crude product was purified by silica gel column
chromatography (PE/EtOAc, 97:3Ǟ95:5) to afford the product as
a mixture of compound 24 and TBDPS-OH [clear colourless oil,
2.49 g, 140%; contained 1.74 g (98%) of compound 24, determined
from 1H NMR data]. [α]2D1 = +167 (c = 1.0, CHCl3). From a second
column chromatography an analytical sample of 24 was obtained.
(c = 1.0, CHCl ). IR (film): ν = 3496, 2932, 2858, 1694, 1455, 1428,
˜
3
1393, 1365, 1250, 1170, 1104, 935 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.70 (m, 4 H, Ph), 7.47–7.36 (m, 6 H, Ph), 7.32–7.20
(m, 5 H, Ph), 4.68 (s, 1 H, 2-H), 4.44 (s, 2 H, CH2Ph), 4.04 (s, 2
H, 5-H, 6-H), 3.97–3.63 (m, 3 H, 3-H, 4-H, OH), 3.52 (d, J =
5.1 Hz, 2 H, CH2O), 2.87 (d, J = 11.2 Hz, 1 H, 6-H), 2.77 (d, J =
10.6 Hz, 1 H, OH), 1.44 (s, 9 H, OtBu), 1.11 (s, 9 H, SitBu) ppm.
13C NMR (101 MHz, CDCl3): δ = 155.75 (C=O), 137.63 (Cq, Ph),
136.10, 135.82, 135.61 (Ph), 132.65 (Cq, Ph), 132.07 (Cq, Ph),
130.15, 130.03, 128.37, 127.83, 127.80, 127.67, 127.41 (Ph), 80.14
(Cq, OtBu), 73.16 (CH2Ph), 72.04 (C-5), 71.31 (C-3), 69.12 (CH2O),
67.62 (C-4), 28.26 (OtBu), 27.02 (SitBu), 19.22 (Cq, SitBu) ppm.
1H NMR (400 MHz, CDCl3 333 K): δ = 7.71 (m, 4 H, Ph), 7.45–
7.34 (m, 6 H, Ph), 7.30–7.20 (m, 5 H, Ph), 4.66 (app. t, J = 5.3 Hz,
1 H, 2-H), 4.44 (s, 2 H, CH2Ph), 4.07 (d, J = 13.3 Hz, 1 H, 6-H),
4.05 (s, 1 H, 5-H), 3.90 (d, J = 11.1 Hz, 1 H, 3-H), 3.66 (d, J =
11.1 Hz, 2 H, 4-H, OH), 3.57–3.48 (m, 2 H, CH2O), 2.87 (d, J =
13.3 Hz, 1 H, 6-H), 2.69 (d, J = 10.2 Hz, 1 H, OH), 1.43 (s, 9 H,
OtBu), 1.11 (s, 9 H, SitBu) ppm. 13C NMR (101 MHz, CDCl3): δ
= 155.84 (C=O), 137.87 (Cq, Ph), 136.18, 135.96, 135.72 (Ph),
132.96 (Cq, Ph), 132.48 (Cq, Ph), 130.13, 130.04, 128.41, 127.87,
127.82, 127.70, 127.50 (Ph), 80.15 (Cq, OtBu), 73.36 (CH2Ph),
72.20 (C-5), 71.38 (C-3), 69.26 (CH2O), 67.87 (C-4), 58.41 (C-2),
45.98 (C-6), 28.38 (OtBu), 27.16 (SitBu), 19.31 (Cq, SitBu) ppm.
[α]2D1 = +185 (c = 1.0, CHCl ). IR (film): ν = 2932, 2858, 1694,
˜
3
1428, 1366, 1249, 1172, 1106, 1028, 822 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.71 (d, J = 7.4 Hz, 2 H, Ph), 7.66 (d, J = 7.4 Hz, 2
H, Ph), 7.46–7.33 (m, 6 H, Ph), 7.32–7.22 (m, 5 H, Ph), 5.86–5.78
(dd, J = 10.1, 3.9 Hz, 1 H, 4-H), 5.67 (br. s, 1 H, 3-H), 4.81–4.56
(m, 1 H, 2-H), 4.51 (d, J = 12.4 Hz, 1 H, CH2Ph), 4.47 (d, J =
12.4 Hz, 1 H, CH2Ph), 4.41–4.12 (m, 1 H, 5-H), 4.07 (br. s, 1 H,
6-H), 3.51 (m, 2 H, CH2O), 3.35–2.86 (m, 1 H, 6-H), 1.49 (s, 9 H,
OtBu), 1.05 (s, 9 H, SitBu) ppm. 13C NMR (101 MHz, CDCl3): δ
= 154.85 (C=O), 138.15 (Cq, Ph), 135.70 (Ph), 135.44 (Cq, Ph),
134.75 (Ph), 133.85 (Cq, Ph), 129.61, 129.47, 129.39, 128.21, 127.58,
127.53, 127.39, 127.28 (Ph), 79.49 (Cq, OtBu), 72.91 (CH2Ph),
70.47 (CH2O), 63.82 (C-5), 28.38 (OtBu), 26.83 (SitBu), 19.13 (Cq,
SitBu) ppm. 1H NMR (400 MHz, CDCl3 333 K): δ = 7.73–7.68 (m,
2 H, Ph), 7.68–7.63 (m, 2 H, Ph), 7.41–7.30 (m, 6 H, Ph), 7.29–
7.18 (m, 5 H, Ph), 5.80 (dd, J = 10.2, 3.9 Hz, 1 H, 4-H), 5.70–5.61
(m, 1 H, 3-H), 4.68 (br. s, 1 H, 2-H), 4.50 (d, J = 12.2 Hz, 1 H,
CH2Ph), 4.46 (d, J = 12.2 Hz, 1 H, CH2Ph), 4.25 (d, J = 13.4 Hz,
1 H, 6-H), 4.12–4.06 (m, 1 H, 5-H), 3.51 (d, J = 5.4 Hz, 2 H,
CH2O), 3.01 (d, J = 13.4 Hz, 1 H, 6-H), 1.48 (s, 9 H, OtBu), 1.05
(s, 9 H, SitBu) ppm. 13C NMR (101 MHz, CDCl3 333 K): δ =
154.97 (C=O), 138.46 (Cq, Ph), 135.85, 135.84, 134.85 (Ph), 134.66
(Cq, Ph), 134.27 (Cq, Ph), 129.64, 129.57, 129.52, 128.29, 127.64,
127.56, 127.47, 127.41 (Ph), 79.55 (Cq, OtBu), 73.20 (CH2Ph),
70.82 (CH2O), 64.16 (C-5), 51.52 (C-2), 46.30 (C-6), 28.52 (OtBu),
27.00 (SitBu), 19.25 (Cq, SitBu) ppm. HRMS: calcd. for
[C34H43NO4Si + H]+ 558.30341; found 558.30334.
HRMS: calcd. for [C34H45NO6Si
592.30908.
+
H]+ 592.30889; found
tert-Butyl (2S,3R,4S,5R)-2-(Benzyloxymethyl)-5-(tert-butyldiphen-
ylsilyloxy)-3,4-dihydroxypiperidine-1-carboxylate (26): Further elu-
tion until the faster running isomer had disappeared (TLC moni-
toring) afforded 82 mg of a mixture of two diastereoisomers. Elu-
tion with PE/EtOAc (7:3) then afforded the slower running isomer
(737 mg, 40%) as a colourless oil. [α]2D0 = +9.4 (c = 1.0, CHCl3).
IR (film): ν = 3405, 2933, 1664, 1428, 1365, 1157, 1106, 882 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.3 Hz, 2 H, Ph),
7.63 (d, J = 8.3 Hz, 2 H, Ph), 7.41–7.23 (m, 11 H, Ph), 4.61 (br. s,
1 H, 2-H), 4.51 (d, J = 12.3 Hz, 1 H, CH2Ph), 4.47 (d, J = 12.3 Hz,
1 H, CH2Ph), 4.38 (m, 1 H, 3-H), 4.17–3.72 (m, 5 H, 6-H, 5-H,
CH2O, OH), 3.67 (s, 1 H, 4-H), 3.16 (d, J = 12.8 Hz, 1 H, 6-H),
2.83 (br. s, 1 H), 1.45 (s, 9 H, OtBu), 1.06 (s, 9 H, SitBu) ppm. 13C
NMR (101 MHz, CDCl3): δ = 136.45 (Cq, Ph), 135.75 (Ph), 135.56
(Ph), 133.48 (Cq, Ph), 133.11 (Cq, Ph), 129.77, 128.54, 128.12,
127.83, 127.65, 127.63 (Ph), 79.97 (Cq, OtBu), 73.61 (CH2Ph),
70.54 (C-5), 70.19 (C-4), 68.31 (CH2O), 66.19 (C-3), 28.31 (OtBu),
26.87 (SitBu), 19.12 (Cq, SitBu) ppm. 1H NMR (400 MHz, CDCl3,
333 K): δ = 7.72–7.59 (m, 4 H, Ph), 7.47–7.18 (m, 11 H, Ph), 4.61–
tert-Butyl (2S,3S,4R,5R)-2-(Benzyloxymethyl)-5-(tert-butyldiphen-
ylsilyloxy)-3,4-dihydroxypiperidine-1-carboxylate (25) and tert-
Butyl (2S,3R,4S,5R)-2-(Benzyloxymethyl)-5-(tert-butyldiphenylsil-
yloxy)-3,4-dihydroxypiperidine-1-carboxylate (26): The silyl ether
24 [2.49 g, 70% purity, 3.12 mmol] from above was dissolved in a 4.54 (m, 1 H, 2-H), 4.50 (s, 2 H, CH2Ph), 4.35 (d, J = 6.9 Hz, 1 H,
mixture of THF (10.0 mL) and water (1.50 mL) and cooled to
–10 °C. N-Methylmorpholine N-oxide monohydrate (1.35 g,
10.0 mmol) and K2OsO4·2H2O (53.0 mg, 0.144 mmol, 4.4 mol-%)
were added subsequently. After 48 h, LC–MS analysis showed com-
plete conversion of the starting material. The reaction mixture was
quenched with a saturated aqueous solution of Na2SO3 (10 mL)
and stirred for 30 min. Then the mixture was diluted with water
(50 mL) and extracted with EtOAc (3ϫ30 mL). The combined or-
ganic layers were washed with 0.6 m HCl, saturated NaHCO3 and
3-H), 3.92 (d, J = 13.3 Hz, 1 H, 6-H), 3.89 (s, 1 H, 5-H), 3.82 (d,
J = 4.3 Hz, 2 H, CH2O), 3.67 (s, 2 H, 4-H, OH), 3.16 (d, J =
13.3 Hz, 1 H, 6-H), 2.69 (s, 1 H, OH), 1.44 (s, 9 H, OtBu), 1.07 (s,
9 H, SitBu) ppm. 13C NMR (101 MHz, CDCl3, 333 K): δ = 155.27
(C=O), 136.85 (Cq, Ph), 135.88 (Ph), 135.71 (Ph), 133.85 (Cq, Ph),
133.51 (Cq, Ph), 129.84, 129.82, 128.62, 128.16, 127.90, 127.74,
127.71 (Ph), 80.00 (Cq, OtBu), 73.83 (CH2Ph), 71.00 (C-5), 70.78
(C-4), 68.70 (CH2O), 66.64 (C-3), 52.79 (C-2), 42.42 (C-6), 28.45
(OtBu), 27.06 (SitBu), 19.26 (Cq, SitBu) ppm. HRMS: calcd. for
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20377
/KAP1
Date: 10-05-12 10:29:10
Pages: 11
H. S. Overkleeft et al.
FULL PAPER
[C34H45NO6Si + H]+ 592.30889; found 592.30913; calcd. for
(CH2O), 67.05 (C-5), 28.68 (OtBu) ppm. HRMS: calcd. for
[C34H45NO6Si + Na]+ 614.29084; found 614.29042.
[C18H27NO6 + H]+ 354.19111; found 354.19138.
tert-Butyl (2S,3S,4R,5R)-2-(Benzyloxymethyl)-3,4,5-trihydroxypip-
eridine-1-carboxylate (22): Silyl ether 25 (715 mg, 1.21 mmol) was
dissolved in THF (20 mL) and cooled on an ice bath. A 1 m solu-
tion of TBAF in THF (3.00 mL, 3.00 mmol) was added dropwise.
Stirring was continued on the ice bath and after 2 h TLC indicated
complete conversion of 25. The mixture was diluted with EtOAc
(150 mL) and washed with water (10 mL) and brine (10 mL). After
drying (MgSO4), filtration and evaporation of the solvents, the
crude product was purified by silica gel column chromatography
(PE/EtOAc, 3:1Ǟ1:1Ǟ0:1). The title triol was obtained as a
colourless oil (408 mg, 96%). [α]2D1 = +35.0 (c = 1.0, CHCl3). IR
(2S,3R,4S,5R)-2-(Hydroxymethyl)piperidine-3,4,5-triol Hydrochlor-
ide (L-galacto-1-DNJ Hydrochloride, 28): The N-Boc-2-OBn-pro-
tected l-galacto-1-DNJ (305 mg, 0.864 mmol) from above was dis-
solved in a mixture of MeOH (20 mL) and 6 m HCl (5 mL) and
transferred into a 250 mL Parr flask. The flask was purged with
argon, Pd/C (10%, 60 mg) was added and the mixture was shaken
vigorously under 4 bar H2 pressure overnight at room temperature.
After filtering through a Whatman® glass-fibre filter and evapora-
tion of the solvents, the crude product (172 mg) was obtained in
quantitative yield. [α]2D2 = –57.8 (c = 1.0, H2O) {ref.[27a] [α]D = –51.4
(c = 1.0, D2O), ref.[27b] [α]D = –51.4 (c = 1.0, H2O)}. 1H NMR
(400 MHz, D2O): δ = 4.15 (dd, J = 2.9, 1.3 Hz, 1 H, 3-H), 4.06
(film): ν = 3396, 2976, 2881, 1686, 1420, 1366, 1249, 1170, 1136,
˜
1
1088 cm–1. H NMR (400 MHz, MeOD): δ = 7.37–7.23 (m, 5 H, (ddd, J = 11.4, 9.6, 5.4 Hz, 1 H, 5-H), 3.87 (dd, J = 12.1, 8.9 Hz,
Ph), 4.62 (br. s, 1 H, 2-H), 4.53 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.48
(d, J = 11.9 Hz, 1 H, CH2Ph), 4.20 (d, J = 14.1 Hz, 1 H, 6-H), 3.97
(br. s, 1 H, 3-H), 3.84 (br. s, 1 H, 5-H), 3.70 (app. t, J = 3.0 Hz, 1
H, 4-H), 3.56 (d, J = 6.5 Hz, 2 H, CH2O), 3.08 (d, J = 14.1 Hz, 1
H, 6-H), 1.44 (s, 9 H, OtBu) ppm. 13C NMR (101 MHz, MeOD):
1 H, CH2O), 3.79 (dd, J = 12.1, 8.9 Hz, 1 H, CH2O), 3.63 (dd, J
= 9.6, 2.8 Hz, 1 H, 4-H), 3.50 (dd, J = 12.5, 5.3 Hz, 1 H, 6-H),
3.41 (dd, J = 8.6, 4.8 Hz, 1 H, 2-H), 2.87 (app. t, J = 12.0 Hz, 1
H, 6-H) ppm. 13C NMR (101 MHz, D2O): δ = 72.86 (C-4), 66.83
(C-3), 64.58 (C-5), 60.03 (C-2), 59.05 (CH2O), 46.04 (C-6) ppm.
δ = 158.01 (C=O), 139.42 (Cq, Ph), 130.72, 129.38, 128.70 (Ph), HRMS: calcd. for [C6H13NO4 + H]+ 164.09173; found 164.09195.
81.35 (Cq, OtBu), 73.97 (CH2Ph), 71.78 (C-3), 70.81 (C-5), 68.93
tert-Butyl (2S,3R,4S,5R)-2-(Benzyloxymethyl)-3,4-O-isopropylid-
(CH2O), 67.89 (C-4), 28.61 (OtBu) ppm. HRMS: calcd. for
ene-5-(tert-butyldiphenylsilyloxy)piperidine-1-carboxylate: Diol 26
(670 mg, 1.13 mmol) was dissolved in a mixture of acetone (20 mL)
[C18H27NO6 + H]+ 354.19111; found 354.19138.
(2S,3S,4R,5R)-2-(Hydroxymethyl)piperidine-3,4,5-triol Hydrochlor-
ide ( -allo-1-DNJ Hydrochloride, 27): The N-Boc-2-OBn-protected
and 2,2-dimethoxypropane (5.00 mL). At 5 °C, BF3·Et2O (50 μL)
was added and the mixture was stirred for 30 min on an ice bath
and then for 30 min at room temperature. After that time, TLC
analysis showed complete conversion and TEA (2 mL) was added.
The mixture was diluted with EtOAc, washed with brine, dried
(Na2SO4), filtered and concentrated to afford a crude product that
was purified by silica gel column chromatography (PE/EtOAc,
98:2Ǟ96:4Ǟ90:10) to afford the target compound as a colourless
L
l-allo-1-DNJ from above (408 mg, 1.16 mmol) was dissolved in a
mixture of MeOH (25 mL) and 6 m HCl (5 mL). The flask was
purged with argon, Pd/C (10%, 89 mg) was added and a balloon
filled with H2 was placed on top of the reaction mixture, which was
stirred vigorously overnight at room temperature. After filtering
through a Whatman® glass-fibre filter and evaporation of the sol-
vents, the crude product (233 mg) was obtained in quantitative
oil (628 mg, 88%). [α]2D2 = +31.2 (c = 1.0, CHCl ). IR (film): ν =
˜
3
yield. [α]2D3 = –27.8 (c = 1.0, H2O) {ref.[26a] [α]2D5 = –37.5 (c = 1.0,
2933, 1697, 1454, 1428, 1393, 1366, 1252, 1145, 1105, 1057, 989,
1
MeOH)}. H NMR (400 MHz, D2O): δ = 4.17 (s, 1 H, 3-H), 4.01 878 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.67 (dd, J = 7.9,
(ddd, J = 11.9, 4.8, 2.5 Hz, 1 H, 5-H), 3.94 (dd, J = 12.7, 3.0 Hz,
1 H, CH2O), 3.89–3.81 (m, 2 H, CH2O, 4-H), 3.33 (ddd, J = 10.4,
4.8, 3.0 Hz, 1 H, 2-H), 3.27 (dd, J = 11.9, 4.8 Hz, 1 H, 6-H), 3.11
(dd, J = 11.9 Hz, 1 H, 6-H) ppm. 13C NMR (101 MHz, D2O): δ =
1.5 Hz, 2 H, Ph), 7.62 (dd, J = 7.9, 1.5 Hz, 2 H, Ph), 7.45–7.23 (m,
11 H, Ph), 4.68–4.61 (m, 1 H, 3-H), 4.56 (s, 2 H, CH2Ph), 4.24–
3.80 (m, 4 H, 2-H, 5-H, 6-H, CH2O), 3.76 (d, J = 1.4 Hz, 1 H, 4-
H), 3.70 (app. t, J = 8.9 Hz, 1 H, CH2O), 3.20 (d, J = 13.7 Hz, 1
69.85 (C-3), 65.27 (C-4), 64.46 (C-5), 57.61 (CH2O), 54.65 (C-2), H, 6-H), 1.39 (s, 9 H, OtBu), 1.33 (s, 3 H, CH3), 1.22 (s, 3 H, CH3),
41.52 (C-6) ppm. HRMS: calcd. for [C6H13NO4 + H]+ 164.09173;
found 164.09173.
1.07 (s, 9 H, SitBu) ppm. 13C NMR (101 MHz, CDCl3): δ = 156.62
(C=O), 138.56 (Cq, Ph), 135.76 (Ph), 133.55 (Cq, Ph), 133.20 (Cq,
Ph), 129.80, 129.72, 128.22, 127.65, 127.60, 127.43 (Ph), 107.70 (O-
C-O), 79.96 (Cq, OtBu), 75.01 (C-5), 73.11 (CH2Ph), 70.97 (C-3),
69.53 (C-4), 50.73 (C-2), 28.29 (OtBu), 26.95 (SitBu), 26.65 (CH3),
24.20 (CH3), 19.15 (Cq, SitBu) ppm. HRMS: calcd. for
[C37H49NO6Si + H]+ 632.34019; found 632.34081.
tert-Butyl (2S,3R,4S,5R)-2-(Benzyloxymethyl)-3,4,5-trihydroxypip-
eridine-1-carboxylate (23): Silyl ether 26 (710 mg, 1.20 mmol) was
dissolved in THF (20 mL) and cooled on an ice bath. A 1.0 m solu-
tion of TBAF (3.00 mL, 3.00 mmol) was added dropwise. Stirring
was continued on the ice bath and after 2 h TLC indicated no con-
version of 26. An extra portion of the 1 m solution of TBAF
(4.00 mL, 4.00 mmol) was added and the reaction stirred overnight.
TLC indicated complete conversion of 26 and the mixture was di-
luted with EtOAc (150 mL) and washed with water (10 mL) and
brine (10 mL). After drying (MgSO4), filtration and evaporation of
the solvents the crude product was purified by silica gel column
tert-Butyl (2S,3R,4S,5R)-2-(Benzyloxymethyl)-3,4-O-isopropylid-
ene-5-hydroxypiperidine-1-carboxylate (29): A solution of TBAF in
THF (1 m, 1.50 mL, 1.50 mmol) was added to a solution of the
above TBDPS ether (628 mg, 0.995 mmol) in THF (15 mL). After
stirring overnight, TLC analysis revealed complete conversion. The
mixture was concentrated in vacuo and purified by silica gel col-
chromatography (PE/EtOAc, 3:1Ǟ1:1Ǟ0:1). The title triol was umn chromatography (PE/EtOAc, 95:5Ǟ90:10Ǟ75:25) to afford
obtained as a colourless oil (390 mg, 92%). [α]2D1 = +39.4 (c = 1.0,
CHCl3). 1H NMR (400 MHz, MeOD): δ = 7.35–7.22 (m, 5 H, Ph),
the product as a clear colourless oil (370 mg, 95%). [α]2D1 = +25.4
(c = 1.0, CHCl ). IR (film): ν = 3414, 2983, 2936, 1695, 1455, 1368,
˜
3
4.63–4.54 (m, 2 H, 2-H, Ch2Ph), 4.45 (d, J = 11.9 Hz, 1 H, Ch2Ph), 1254, 1212, 1166, 1146, 1056, 875 cm–1. 1H NMR (400 MHz,
4.07–3.98 (m, 2 H, CH2O), 3.84 (d, J = 14.3 Hz, 1 H, 6-H), 3.81–
3.71 (m, 3 H, 3-H, 4-H, 5-H), 3.20 (dd, J = 14.3, 1.1 Hz, 1 H, 6-
H), 1.44 (s, 9 H, OtBu) ppm. 13C NMR (101 MHz, MeOD): δ =
CDCl3): δ = 7.36–7.25 (m, 5 H, Ph), 4.62 (dd, J = 6.8, 5.3 Hz, 1
H, 3-H), 4.58 (d, J = 12.1 Hz, 1 H, CH2Ph), 4.54 (d, J = 12.1 Hz,
1 H, CH2Ph), 4.21 (br. s, 1 H, 4-H), 4.03 (dd, J = 6.8, 1.2 Hz, 1 H,
157.81 (C=O), 139.80 (Cq, Ph), 130.71, 129.27, 128.72, 128.54 (Ph), 2-H), 3.82 (m, 2 H, 6-H, CH2O), 3.73 (app. t, J = 8.8 Hz, 2 H, 5-
81.07 (Cq, OtBu), 73.61 (CH2Ph), 72.45 (C-4), 70.71 (C-3), 67.18 H, CH2O), 3.36 (d, J = 13.2 Hz, 1 H, 6-H), 2.46 (br. s, 1 H, OH),
8
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1-Deoxynojirimycin Isomers from a Single Chiral Cyanohydrin
1.44 (s, 3 H, CH3), 1.43 (s, 9 H, OtBu), 1.35 (s, 3 H, CH3) ppm.
13C NMR (101 MHz, CDCl3): δ = 138.43 (Cq, Ph), 128.22, 127.49,
127.45 (Ph), 108.28 (O-C-O), 80.37 (Cq, OtBu), 76.20 (C-4), 72.92
(CH2Ph), 71.05 (C-3), 68.71 (C-5), 68.42 (CH2O), 51.03 (C-2),
28.27 (OtBu), 26.78 (CH3), 24.51 (CH3) ppm. HRMS: calcd. for
[C16H24NO4 + H]+ [M – Boc]+ 294.16998; found 294.16937.
3.40 (app. t, J = 6.4 Hz, 1 H, 2-H), 3.26 (d, J = 13.7 Hz, 1 H, 6-
H) ppm. 13C NMR (101 MHz, D2O): δ = 67.55 (C-3), 67.05 (C-4),
66.58 (C-5), 60.35 (C-2), 59.16 (CH2O), 48.34 (C-6) ppm. HRMS:
calcd. for [C6H13NO4 + H]+ 164.09173; found 164.09168.
Supporting Information (see footnote on the first page of this arti-
cle): General remarks and the 1H and 13C NMR spectra of all
intermediates and final products.
tert-Butyl (2R,3S,4S)-2-(Benzyloxymethyl)-3,4-O-isopropylidene-5-
oxopiperidine-1-carboxylate:
Dess–Martin
reagent
(1.28 g,
3.02 mmol) was added to a solution of alcohol 29 (360 mg,
0.916 mmol) in DCM (20 mL). After 3 h, TLC analysis revealed
complete conversion. The mixture was filtered through a pad of
Celite, concentrated in vacuo and purified by silica gel column
chromatography (PE/EtOAc, 95:5Ǟ90:10Ǟ75:25) to afford the
product as a clear colourless oil (338 mg, 79%). [α]2D3 = –27.4 (c =
Acknowledgments
We thank the Netherlands Organization for Scientific Research
(NWO) for financial support.
[1] L. Rosenthaler, Biochem. Z. 1908, 14, 238–253.
[2] W. Becker, H. Freund, E. Pfeil, Angew. Chem. 1965, 77, 1139;
Angew. Chem. Int. Ed. Engl. 1965, 4, 1079.
1.0, CHCl ). IR (film): ν = 2981, 2915, 1743, 1696, 1455, 1368,
˜
3
1344, 1238, 1212, 1162, 1096, 982, 872 cm–1. H NMR (400 MHz,
1
CDCl3): δ = 7.36–7.23 (m, 5 H, Ph), 5.06 (s, 1 H, 2-H), 4.97–4.82
(m, 1 H, 3-H), 4.58–4.36 (m, 4 H, 4-H, 6-H, CH2Ph), 4.27 (d, J =
18.0 Hz, 1 H, 6-H), 3.79 (d, J = 18.0 Hz, 1 H, 6-H), 3.62 (br. s, 1
H, CH2O), 3.40 (d, J = 7.9 Hz, 1 H, CH2O), 1.47 (s, 3 H, CH3),
1.46 (s, 9 H, OtBu), 1.37 (s, 3 H, CH3) ppm. 13C NMR (101 MHz,
CDCl3): δ = 203.29 (C=O), 154.74 (NC=O), 137.57 (Cq, Ph),
128.22, 127.57, 127.43 (Ph), 111.04 (O-C-O), 81.13 (Cq, OtBu),
77.39 (C-4), 73.21 (C-3), 72.91 (CH2Ph), 65.80 (CH2O), 50.71 (C-
6), 49.76 (C-2), 28.13 (OtBu), 26.09 (CH3), 24.16 (CH3) ppm.
HRMS: calcd. for [C21H29NO6 + H]+ 392.20676; found 392.20654.
[3] W. Becker, E. Pfeil, J. Am. Chem. Soc. 1966, 88, 4299–4300.
[4] F. Effenberger, T. Ziegler, S. Förster, Angew. Chem. 1987, 99,
491; Angew. Chem. Int. Ed. Engl. 1987, 26, 458–460.
[5] For selected reviews, see: a) M. Brovetto, D. Gamenara, P. Sa-
enz Mendez, G. A. Seoane, Chem. Rev. 2011, 111, 4346–4403;
b) J. Holt, U. Hanefeld, Curr. Org. Synth. 2009, 6, 15–37; c) J.-
M. Brunel, I. P. Holmes, Angew. Chem. 2004, 116, 2810; Angew.
Chem. Int. Ed. 2004, 43, 2752–2778; d) M. North, Tetrahedron:
Asymmetry 2003, 14, 147–176; e) R. J. H. Gregory, Chem. Rev.
1999, 99, 3649–3682.
[6] For the purification of paHNL, see: a) W. Becker, E. Pfeil, Bio-
chem. Z. 1963, 337, 156; b) W. Becker, U. Benthin, E. Eschen-
hof, E. Pfeil, Angew. Chem. 1963, 75, 93.
[7] P. Zandbergen, J. van der Linden, J. Brussee, A. van der Gen,
Synth. Commun. 1991, 21, 1387–1391.
tert-Butyl
ene-5-hydroxypiperidine-1-carboxylate:
(2S,3R,4S,5S)-2-(Benzyloxymethyl)-3,4-O-isopropylid-
NaBH4 (60.0 mg,
1.58 mmol) was added to a solution of the previous ketone
(270 mg, 0.690 mmol) in ethanol (25 mL) at –75 °C. The mixture
was warmed slowly on the cooling bath to –20 °C in around 3 h.
After that time, TLC analysis revealed complete conversion. The
reaction mixture was diluted with EtOAc (100 mL), washed with
water (10 mL) and brine (10 mL), dried (MgSO4), filtered and con-
centrated. Purification by silica gel column chromatography (PE/
EtOAc, 90:10Ǟ75:25) afforded the title alcohol as a clear colour-
[8] a) D. R. Deardorff, C. M. Taniguchi, A. C. Nelson, A. P. Pace,
A. J. Kim, A. K. Pace, R. A. Jones, S. A. Tafti, C. Nguyen, C.
O’Connor, J. Tang, J. Chen, Tetrahedron: Asymmetry 2005, 16,
1655–1662;
b)
E. G. J. C.
Warmerdam,
A. M. C. H.
van den Nieuwendijk, C. G. Kruse, J. Brussee, A. van der Gen,
Recl. Trav. Chim. Pays-Bas 1996, 115, 20–24.
[9] U. Felfer, M. Goriup, M. F. Koegl, U. Wagner, B. Larissegger-
Schnell, K. Faber, W. Kroutil, Adv. Synth. Catal. 2005, 347,
951–961.
[10] a) T. Reiss, B. Breit, Chem. Eur. J. 2009, 15, 6345–6348; b) Y.
Schmidt, K. Lehr, U. Breuninger, G. Brand, T. Reiss, B. Breit,
J. Org. Chem. 2010, 75, 4424–4433.
[11] E. Hulsbos, J. Marcus, J. Brussee, A. van der Gen, Tetrahedron:
Asymmetry 1997, 8, 1061–1068.
[12] A. M. C. H. van den Nieuwendijk, A. B. T. Ghisaidoobe, H. S.
Overkleeft, J. Brussee, A. van der Gen, Tetrahedron 2004, 60,
10385–10396.
less oil (213 mg, 78%). [α]2D1 = +19.2 (c = 1.0, CHCl ). IR (film): ν
˜
3
= 3462, 2982, 2934, 1690, 1455, 1393, 1367, 1251, 1212, 1161, 1089,
1
1030, 874 cm–1. H NMR (400 MHz, CDCl3): δ = 7.35–7.24 (m, 5
H, Ph), 4.73 (app. t, J = 5.8 Hz, 1 H, 3-H), 4.56 (s, 2 H, CH2Ph),
4.36 (app. t, J = 5.8 Hz, 1 H, 4-H), 4.14 (br. s, 1 H, 2-H), 3.88 (br.
s, 2 H, 6-H, CH2O), 3.70 (app. t, J = 8.8 Hz, 1 H, CH2O), 3.62–
3.55 (m, 1 H, 5-H), 3.23–2.67 (m, 2 H, 6-H, OH), 1.49 (s, 3 H,
CH3), 1.43 (s, 9 H, OtBu), 1.40 (s, 3 H, CH3) ppm. 13C NMR
(101 MHz, CDCl3): δ = 155.16 (C=O), 138.32 (Cq, Ph), 128.13,
127.73, 127.43, 127.38 (Ph), 108.48 (O-C-O), 80.25 (Cq, OtBu),
72.86 (CH2Ph), 72.61 (C-3), 72.11 (C-4), 67.64 (CH2O), 66.25 (C-
5), 50.66 (C-2), 42.17 (C-6), 28.19 (OtBu), 26.21 (CH3), 24.53
(CH3) ppm. HRMS: calcd. for [C21H31NO6 + H]+ 394.22241;
found 394.22186.
[13] E. G. J. C. Warmerdam, R. D. van Rijn, J. Brussee, C. G.
Kruse, A. van der Gen, Tetrahedron: Asymmetry 1996, 7, 1723–
1732.
[14] J. J. Duffield, A. C. Regan, Tetrahedron: Asymmetry 1996, 7,
663–666.
[15] E. G. J. C. Warmerdam, J. Brussee, A. van der Gen, C. G.
Kruse, Helv. Chim. Acta 1994, 77, 252–256.
[16] A. M. C. H. van den Nieuwendijk, M. Ruben, S. E. Engelsma,
M. D. P. Risseeuw, R. J. B. H. N. van den Berg, R. G. Boot,
J. M. Aerts, J. Brussee, G. A. van der Marel, H. S. Overkleeft,
Org. Lett. 2010, 12, 3957–3959.
[17] P. Zandbergen, A. M. C. H. van den Nieuwendijk, J. Brussee,
A. van der Gen, Tetrahedron 1992, 48, 3977–3982.
[18] a) R. J. B. H. N. van den Berg, T. Wennekes, A. Ghisaidoobe,
W. E. Donker-Koopman, A. Strijland, R. G. Boot, J. M. F. G.
Aerts, H. S. Overkleeft, ACS Med. Chem. Lett. 2011, 2, 519–
522; b) T. Wennekes, R. J. B. H. N. van den Berg, T. J. Boltje,
W. E. Donker-Koopman, B. Kuijper, G. A. van der Marel, A.
Strijland, C. P. Verhagen, J. M. F. G. Aerts, H. S. Overkleeft,
Eur. J. Org. Chem. 2010, 1258–1283; c) T. Wennekes,
(2S,3R,4S,5S)-2-(Hydroxymethyl)piperidine-3,4,5-triol Hydrochlor-
ide
(L-talo-1-DNJ Hydrochloride, 30): The previous alcohol
(213 mg, 0.542 mmol) was dissolved in a mixture of MeOH
(15 mL) and aqueous 6 m HCl (3 mL) and transferred into a
250 mL Parr flask. The flask was purged with argon, Pd/C (10%,
50 mg) was added and the mixture was shaken vigorously under
4 bar H2 pressure overnight at room temperature. After filtering
through a Whatman® glass-fibre filter and evaporation of the sol-
vents, the title product (109 mg) was obtained in quantitative yield.
[α]2D2 = –3.3 (c = 0.90, H2O). {ref.[28a] [α]D = +22 (c = 0.5, MeOH)}.
1H NMR (400 MHz, D2O): δ = 4.23 (s, 1 H, 5-H), 4.15 (s, 1 H, 3-
H), 3.86 (m, 3 H, CH2O, 4-H), 3.50 (d, J = 13.7 Hz, 1 H, 6-H),
Eur. J. Org. Chem. 0000, 0–0
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9

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/KAP1
Date: 10-05-12 10:29:10
Pages: 11
H. S. Overkleeft et al.
FULL PAPER
R. J. B. H. N. van den Berg, R. G. Boot, G. A. van der Marel, [24]
H. S. Overkleeft, J. M. F. G. Aerts, Angew. Chem. 2009, 121,
9006; Angew. Chem. Int. Ed. 2009, 48, 8848–8869; d) T. Wen-
nekes, R. J. B. H. N. van den Berg, W. Donker, G. A.
van der Marel, A. Strijland, J. M. F. G. Aerts, H. S. Overkleeft,
J. Org. Chem. 2007, 72, 1088–1097; e) T. Wennekes, A. J. Me-
ijer, A. K. Groen, R. G. Boot, J. E. Groener, M. van Eijk, R.
For examples of d-altro-1-DNJ, see: a) S. K. Bagal, S. G. Dav-
ies, J. A. Lee, P. M. Roberts, P. M. Scott, J. E. Thomson, J. Org.
Chem. 2010, 75, 8133–8146; b) D. D. Dhavale, S. D. Markad,
N. S. Karanjule, J. PrakashaReddy, J. Org. Chem. 2004, 75,
4760–4766; c) H. Takahata, Y. Banba, M. Sasatani, H. Nem-
oto, A. Kato, I. Adachi, Tetrahedron 2004, 60, 8199–8205; d)
O. V. Singh, H. Han, Tetrahedron Lett. 2003, 44, 2387–2391.
Ottenhoff, N. Bijl, K. Ghauharali, H. Song, T. J. O’Shea, H. L.
Liu, N. Yew, D. Copeland, R. J. B. H. N. van den Berg, G. A.
van der Marel, H. S. Overkleeft, J. M. Aerts, J. Med. Chem.
2010, 53, 689–698.
[25]
For examples of l-altro-1-DNJ, see: a) O. K. Karjalainen,
A. M. P. Koskinen, Org. Biomol. Chem. 2011, 9, 1231–1236;
b) A. Guaragna, S. D’Errico, D. D’Alonzo, S. Pedatella, G.
Palumbo, Org. Lett. 2007, 9, 3473–3476.
[19] For a recent report detailing the preparation of 14 configura-
tional 1-DNJ isomers, see: A. Kato, N. Kato, E. Kano, I. Ad-
achi, K. Ikeda, L. Yu, T. Okamoto, Y. Banba, H. Ouchi, H.
Takahata, N. Asano, J. Med. Chem. 2005, 48, 2036–2044.
[20] For examples of d-allo-1-DNJ, see: a) R. Sridhar, B. Srinivas,
K. Rama Rao, Tetrahedron 2009, 65, 10701–10708; b) B.-C.
Hong, Z.-Y. Chen, A. Nagarajan, R. Kottani, W.-H. Chen, Y.-
F. Jiang, S.-C. Zhang, J.-H. Liao, S. Sarshar, Carbohydr. Res.
2005, 340, 2457–2468; c) I. S. Kim, H. Y. Lee, Y. H. Jung, Het-
erocycles 2007, 71, 1787–1800.
[21] For examples of d-galacto-1-DNJ, see: a) M. Ruiz, T. M. Ru-
anova, O. Blanco, F. Núñez, C. Pato, V. Ojea, J. Org. Chem.
2008, 73, 2240–2255; b) C. R. Johnson, A. Golebiowski, H.
Sundram, M. W. Miller, R. L. Dwaihy, Tetrahedron Lett. 1995,
36, 653–654; c) R. H. Furneaux, P. C. Tyler, L. A. Whitehouse,
Tetrahedron Lett. 1993, 34, 3609–3612; d) H. Paulsen, Y.
Hayauchi, V. Sinnwell, Chem. Ber. 1980, 113, 2601–2608.
[22] For examples of d-talo-1-DNJ, see: a) K. K.-C. Liu, T. Kajim-
oto, L. Chen, Z. Zhong, Y. Ichikawa, C.-H. Wong, J. Org.
Chem. 1991, 56, 6280–6289; b) W. J. Lees, G. M. Whitesides,
Bioorg. Chem. 1992, 20, 173–179; c) C. R. Johnson, A. Gole-
biowski, E. Schoffers, H. Sundram, M. P. Braun, Synlett 1995,
313–314; d) L.-X. Liao, Z.-M. Wang, H.-X. Zhang, W.-S.
Zhou, Tetrahedron: Asymmetry 1999, 10, 3649–3657; e) M.
Ruiz, V. J. Ojea, J. M. Quintela, Synlett 1999, 204–206; f) C. C.
Joseph, H. Regeling, B. Zwanenburg, G. J. F. Chittenden, Car-
bohydr. Res. 2002, 337, 1083–1087.
[26]
[27]
For examples of l-allo-1-DNJ, see: a) P. Gupta, Y. D. Vankar,
Eur. J. Org. Chem. 2009, 12, 1925–1933; b) see ref.[25b]
.
For examples of l-galacto-1-DNJ, see: a) O. K. Karjalainen,
M. Passiniemi, A. M. P. Koskinen, Org. Lett. 2010, 12, 1145–
1147; b) H. Paulsen, M. Matzke, B. Orthen, R. Nuck, W. Reut-
ter, Liebigs Ann. Chem. 1990, 953–963.
[28] For examples of l-talo-1-DNJ, see: a) A. Guaranga, D.
D’Alonzo, C. Paolella, G. Palumbo, Tetrahedron Lett. 2009,
50, 2045–2047; b) M. Ruiz, V. Ojea, T. M. Ruanova, J. M.
Quintela, Tetrahedron: Asymmetry 2002, 13, 795–799; c) H.
Hashimoto, M. Hayakawa, Chem. Lett. 1989, 1881–1884.
[29] For reviews, see: a) P. Compain, V. Chagnault, O. R. Martin,
Tetrahedron: Asymmetry 2009, 20, 672–711; b) B. G. Davis, Tet-
rahedron: Asymmetry 2009, 20, 652–671; c) P. Compain, O. R.
Martin (Eds.), Iminosugars: From Synthesis to Therapeutic Ap-
plications, Wiley-VCH, Weinheim, Germany, 2007; d) L. Ci-
polla, B. La Ferla, F. Nicotra, Curr. Top. Med. Chem. 2003, 3,
485–511; e) N. Asano, R. J. Nash, R. J. Molyneux, G. W. J.
Fleet, Tetrahedron: Asymmetry 2000, 11, 1645–1680.
[30] S. K. Bagal, S. G. Davies, J. A. Lee, P. M. Roberts, A. J. Russell,
P. M. Scott, J. E. Thomson, Org. Lett. 2010, 12, 136–139.
[31] For
examples
of
de
novo
syntheses,
see:
a)
Ref.[19a,19b,20a,20b,21a,21b,23c,23d,24a,24b,25b,26a,27a,27b] in this paper;
b) see also: H. Takahata, Y. Banba, H. Ouchi, H. Nemoto,
Org. Lett. 2003, 5, 2527–2529.
Received: March 26, 2012
Published Online: ᭿
[23] V. VanRheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett. 1976,
17, 1973–1976.
10
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Job/Unit: O20377
/KAP1
Date: 10-05-12 10:29:10
Pages: 11
1-Deoxynojirimycin Isomers from a Single Chiral Cyanohydrin
Bioorganic Chemistry
A. M. C. H. van den Nieuwendijk,
R. J. B. H. N. van den Berg, M. Ruben,
M. D. Witte, J. Brussee, R. G. Boot,
G. A. van der Marel, J. M. F. G. Aerts,
H. S. Overkleeft* ............................ 1–11
The orthogonally protected heterocyclic
building blocks 6 and 7 have been prepared
from cyanohydrin 2 in overall yields of
76%. Compounds 6 and 7 were converted
into eight different stereoisomers of 1-de-
oxynojirimycin in overall yields of 14–75%
in three to ten steps.
Synthesis of Eight 1-Deoxynojirimycin Iso-
mers from a Single Chiral Cyanohydrin
Keywords: Enzymes / Enzyme catalysis /
Inhibitors / Enantioselectivity / Synthesis
design
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