Total synthesis of deoxymannojirimycin and D-mannolactam via carbonylation of 5-vinyloxazolidin-2-ones

Article abstract of DOI:10.1016/S0040-4020(02)01534-X

The stereoselective synthesis of piperidine alkaloids deoxymannojirimycin and D-mannolactam from D-serine has been achieved. The key step involves palladium-catalysed decarboxylative carbonylation of a serine-derived 5-vinyloxazolidin-2-one to give 6-(tert-butyldimethylsilyloxymethyl)-3,6-dihydro-1H-pyridin-2-one which was subsequently converted into the title compounds.

Full text of DOI:10.1016/S0040-4020(02)01534-X

Tetrahedron 59 (2003) 281–286
Total synthesis of deoxymannojirimycin and D-mannolactam via
carbonylation of 5-vinyloxazolidin-2-ones
*
Julian G. Knight and Kirill Tchabanenko
School of Natural Sciences, Newcastle University, Bedson Building, Newcastle upon Tyne NE1 7RU, UK
Received 27 September 2002; revised 5 November 2002; accepted 28 November 2002
Abstract—The stereoselective synthesis of piperidine alkaloids deoxymannojirimycin and D-mannolactam from D-serine has been achieved.
The key step involves palladium-catalysed decarboxylative carbonylation of a serine-derived 5-vinyloxazolidin-2-one to give 6-(tert-
butyldimethylsilyloxymethyl)-3,6-dihydro-1H-pyridin-2-one which was subsequently converted into the title compounds. q 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Polyhydroxylated piperidine alkaloids are frequently found
in living systems,1 and display a wide range of biological
activities due to their ability to mimic carbohydrate
substrates in a variety of enzymatic processes.2 Selective
inhibition of a number of enzymes involved in the binding
and processing of glycoproteins has rendered piperidine
alkaloids important tools in the study of biochemical
Scheme 1. Proposed route to piperidines.
pathways.3 Deoxymannojirimycin 14 has been shown to
inhibit a-L-fucosidase, a-D-mannosidase and a-D-glucosi-
2. Results and discussion
dase activity,5 while D-mannolactam 2 inhibits both a-D-
D-Serine was converted in four steps into aldehyde 5 in 79%
overall yield and .98% ee via a route previously reported25
for its enantiomer. Addition of vinyl magnesium bromide,
followed by treatment of the resulting diastereoisomeric
N-Boc amino alcohols with potassium tert-butoxide resulted
in a mixture of anti and syn vinyloxazolidinones 6, in a 2:1
ratio, which were subjected to carbonylation. Heating a
solution of 6 in ethanol at 608C under pressure of CO
(65 atm) in the presence of PdCl2(PPh3)2 (10 mol%) for
32 h gave the d-lactam 7 in 81% yield. We planned to use
the stereocentre at the 6-position of the lactam 7 to control
the sequential introduction of hydroxyl groups around the
ring. Stereoselective epoxidation, by treatment with Oxonew,
proceeded in 95% yield to give a 4.1:1 ratio of the anti (8a)
and syn (8b) epoxides, respectively. Although the stereo-
chemistry of these epoxides could not be unambiguously
assigned at this point, the ultimate conversion of the major
epoxide into D-mannolactam and deoxymannojirimycin
served to confirm our assumption that epoxidation occurs
preferentially on the less hindered face of the double bond,
away from the bulky CH2OTBS group. We anticipated that
base-mediated epoxide opening to the corresponding allylic
alcohols would occur under mild conditions because the
allylic protons in the 3-position are a to the lactam carbonyl
group. In the event, the epoxides were separated by column
mannosidase and a-D-glucosidase.6 Both compounds have
potential therapeutic value and a number of carbohydrate
based7–12 and de novo13–22 total syntheses have been
reported.
Recently we reported23,24 a novel approach to d-lactams 4
via a palladium-catalyzed decarboxylative carbonylation of
5-vinyloxazolidin-2-ones 3 (Scheme 1). Lactams 4 are
ideally functionalized for elaboration into polyhydroxylated
piperidines and we now report the total synthesis of
deoxymannojirimycin 1 and D-mannolactam 2 using this
approach.
Keywords: deoxymannojirimycin; carbonylation; D-mannolactam.
*
Corresponding author. Tel./fax: þ44-191-2227068; e-mail: j.g.knight@
ncl.ac.uk
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01534-X

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J. G. Knight, K. Tchabanenko / Tetrahedron 59 (2003) 281–286
tetraacetate 11a and a triacetate 11b, which were easily
separable by chromatography. Unfortunately, we were
unable to convert 11a into 2 due to problems with isolation
of the D-mannolactam from the deacetylation mixture. In
fact, it proved possible to isolate the major triol 10a from the
dihydroxylation by column chromatography and this was
then deprotected by treatment with TFA/water to give
D-mannolactam 2.7 Recrystallization of 2 proved straight-
forward since, despite our expectations,27 we found it to be
only sparingly soluble in cold water.
Protection of the free hydroxyl of the lactam 9a was
expected to lead to a higher selectivity in the dihydroxyl-
ation and, hence, both epimers 9a and 9b were subjected to
benzylation. Whereas 9a gave the expected N,O-dibenzyl-
ated product 12 in 64% yield, we were surprised to find that
the diastereoisomeric lactam 9b did not behave in the same
way. Attempted N,O-dibenzylation of 9b gave rise to a C,N-
dibenzylated product as a single diastereoisomer, as judged
by 1H NMR, which we have tentatively assigned as bicyclic
lactam 13. Compound 13 may be formed via migration of
the silicon from the primary to the secondary hydroxyl
group, intramolecular conjugate addition of the resulting
primary alkoxide to the enamide, followed by benzylation
of the intermediate enolate 14. The stereochemistry of 13 is
proposed on the assumption that benzylation will preferen-
tially occur on the less-hindered face of the enolate 14 to
form bicyclic 13 as a single diastereoisomer (Scheme 4). A
related cyclization of a 5,6-syn 6-hydroxymethyl-5-
benzoyloxypyridinone to an oxazabicyclo[3.2.1]octane
under mild basic conditions has been reported.28
Dihydroxylation of the fully protected lactam 12 gave the
4,5-anti diol 15 in high diastereoselectivity with only traces
Scheme 2. Reagents and conditions: (a) Ref. 25 four steps, 79%;
(b) H2CvCHMgBr (2.5 equiv.), THF, 2788C to rt, 3 h; (c) KOtBu, THF,
rt, 3 h, 75% from 5; (d) PdCl2(PPh3)2 (10 mol%), CO (65 atm), EtOH,
608C, 32 h, 81%; (e) Oxone (5 equiv.), NaHCO3 (15 equiv.), acetone/H2O,
rt, 3 h, 95% (8a/8b, 4.1:1); (f) DBU (2 equiv.) CH2Cl2, reflux, 3 h, 95%.
chromatography and each was converted in excellent yield
into the corresponding a,b-unsaturated lactam (9a and 9b,
respectively) on treatment with DBU (Scheme 2).
Our initial strategy centered on dihydroxylation of the
lactam 9a bearing an unprotected hydroxyl group. Dihydro-
xylation of 9a gave a 3.2:1 mixture of diastereoisomeric
triols 10a and 10b. The major isomer was expected26 to
arise from dihydroxylation anti to the allylic hydroxyl group
10a (Scheme 3). In order to aid isolation of the triol lactams,
they were treated with acetic anhydride. Surprisingly,
peracetylation of the mixture of 10a and 10b resulted in
Scheme 4. Reagents and conditions: (a) NaH (2 equiv.), DMF, BnBr, 08C
to rt, 3 h (13, 50%; 12 64%); (b) OsO4 (7 mol%), NMO (3 equiv.), tBuOH,
rt, 3 h, 89%; (c) LiAlH4 (5 equiv.), Et2O, rt, 3 h, 89%; (d) Bu4NF
(1.5 equiv.), THF, rt, 1 h; (e) H2, Pd/C, EtOH, HCl, rt, 2 h, 68% from 15.
Scheme 3. Reagents and conditions: (a) OsO4 (9 mol%), NMO (3 equiv.),
tBuOH, rt, 3 h, 56% (10a/10b, 3.2:1); (b) Ac2O, reflux, 4 h, 56% from 9a;
(c) TFA/H2O (1:1), rt, 10 h, 70%.

J. G. Knight, K. Tchabanenko / Tetrahedron 59 (2003) 281–286
283
of the 4,5-syn isomer detectable by NMR. Reduction of the
lactam with LiAlH4 in diethyl ether produced the piperidine
16 which was converted to the hydrochloride salt of
deoxymannojirimycin 1 via TBAF promoted TBS deprotec-
tion and catalytic hydrogenolytic benzyl deprotection.13
The hydrochloride salt of 1 showed identical data to that
previously reported.29
separated. The aqueous phase was extracted with additional
ethyl acetate (2£20 ml). The combined organic extracts
were washed with brine (2£50 ml), dried (MgSO4) and the
solvent was removed under reduced pressure to give the
crude allylic alcohols as a pale yellow oil (12.37 g), to
which was added THF (150 ml) and potassium tert-butoxide
(8.35 g, 74.5 mmol) while stirring at room temperature. The
resulting dark red suspension was stirred for 3 h and
saturated aqueous ammonium chloride (20 ml) was added.
The resulting mixture was stirred for 10 min and concen-
trated on a rotary evaporator. Ethyl acetate (100 ml) and
water (50 ml) were added and phases were separated. The
aqueous phase was extracted with additional ethyl acetate
(2£20 ml). The combined organic extracts were washed
with brine (2£50 ml), dried (MgSO4) and the solvent was
removed under reduced pressure to give the crude
oxazolidinones as a dark red oil. Flash column chromato-
graphy on silica gel using petrol/ethyl acetate (2:1) as eluent
afforded oxazolidinones 6 as a colorless oil (7.23 g, 75%) in
a 2:1 (4R,5S)/(4R,5R) ratio. nmax/cm21 (film) 3293 (NH),
2954, 1760 (CvO); dH (500 MHz, CDCl3) 6.85 (1H, br s,
NH, major), 6.65 (1H, br s, NH minor), 6.00–5.75 (1H, m,
CHvCH2, major and minor), 5.37 (1H, d, J¼18.3 Hz,
CHvCHaH b, minor), 5.32 (1H, d, J¼17.4 Hz, CHvCHaH b,
major), 5.27 (1H, d, J¼12.1 Hz, CHvCH aHb, minor), 5.20
(1H, d, J¼10.5 Hz, CHvCH aHb, major), 5.05 (1H, dd,
J¼7.2, 7.0 Hz; H-5, minor), 4.72 (1H, dd, J¼5.2, 5.1 Hz; H-5,
major), 3.80 (1H, m, H-4, minor), 3.60–3.47 (3H, m,
CH2OTBS major and minor, H-4 major), 0.80 (9H, s,
(CH3)3C major and minor), 0.00 (6H, s, (CH3)2Si major and
minor), dC (125 MHz, CDCl3) 160.30, 159.71, 135.46,
130.97, 120.66, 118.45, 80.97, 80.85, 64.07, 62.59, 57.62,
55.87, 21.03, 20.08, 15.06, 14.72, 25.05, 25.10; m/z (EIþ)
257 (Mþ, 10%), 141 (60), 117 (80), 91 (100). Found (Mþ)
257.1451 C12H23NO3Si requires 257.1447.
3. Conclusion
In summary, we have succeeded in applying our palladium
catalyzed decarboxylative carbonylation of the serine-
derived 5-vinyloxazolidinone 6 to the stereoselective total
synthesis of polyhydroxylated piperidine alkaloids deoxy-
mannojirimycin 1 and D-mannolactam 2. We are currently
applying this methodology to the synthesis of more complex
piperidines and this work will be reported in due course.
4. Experimental
4.1. General
Melting points were determined on a Linkham TC92 hot
stage and are uncorrected. Optical rotations were measured
on a polAAr 2001 digital polarimeter at ambient tempera-
ture and are reported as follows [a]TD (c g/100 ml, solvent).
Infrared spectra were recorded on a Nicolet 20 PCIR
instrument. Mass spectra were recorded on Micromass
autospec M and Kratos MS80 RF spectrometers in electron
impact (EI) mode. 1H NMR spectra were recorded on
Bruker AC 200 (200 MHz), Bruker WM 300 (300 MHz),
JEOL LA 500 (500 MHz) and Bruker AMX 500 (500 MHz)
spectrometers at ambient temperature. 13C NMR were
recorded on Bruker AC 200 (50 MHz) and JEOL LA 500
(125 MHz) spectrometers at ambient temperature. Thin
layer chromatography was performed on EM reagent
0.25 mm silica gel 60-F plates. Flash column chromatog-
raphy was performed on Fluorochem LC3025 silica gel
(40–63 mm). All reactions were carried out under an
atmosphere of nitrogen in pre-dried glassware unless
otherwise stated. Where necessary, solvents were dried
prior to use. Dichloromethane (CH2Cl2) was distilled from
calcium hydride under nitrogen immediately prior to use.
Ethanol was distilled from magnesium under nitrogen and
4.1.2. 6S-6-(tert-Butyldimethylsilanyloxymethyl)-3,6-
dihydro-1H-pyridin-2-one 7. The mixture of vinyl oxa-
zolidinones 6 (3.380 g, 13.1 mmol) and PdCl2(PPh3)2
(911 mg, 1.3 mmol) in EtOH (50 ml) was transferred to a
300 ml autoclave. The autoclave was pressurized with CO
(60 atm) and heated to 608C (the pressure increased to
65 atm) with stirring for 32 h. After cooling and depressur-
ization the crude reaction mixture was filtered through a
short pad of Celite and the solvent was evaporated under
reduced pressure. Purification of the crude material by
column chromatography (eluted with EtOAc/petrol, 1:2)
afforded the d-lactam 7 as a pale yellow oil (2.57 g, 81%);
[a]2D0¼210.4 (c¼1.5, CHCl3); nmax/cm21 (film) 3226 (br),
1656 (s), 1089 (br), 1022 (br), 800 (s); dH (500 MHz,
CDCl3) 6.51 (1H, br s, NH), 5.76 (1H, m, CHvCH), 5.56
(1H, m, CHvCH), 4.02 (1H, m, H-6), 3.63 (1H, dd, J¼9.4,
4.0 Hz, one of CH2OTBS), 3.37 (1H, dd, J¼9.4, 8.6 Hz, one
˚
stored over 4 A molecular sieves. Ether and tetrahydrofuran
(THF) were distilled from sodium/benzophenone ketyl
immediately prior to use. All chemicals were purchased
from the Aldrich, Fluka, Sigma or Lancaster chemical
companies and were used as supplied except where indicated.
4.1.1. (4R,5RS)-4-(tert-Butyldimethylsilanyloxymethyl)-
5-vinyloxazolidin-2-one 6. To a stirred solution of
aldehyde 525 (14.19 g, 46.7 mmol) in THF (150 ml) was
added vinylmagnesium bromide (117 ml, 1.0 M solution in
THF, 117 mmol) at 2788C dropwise over 30 min and the
resulting solution was stirred for 1 h, allowed to warm to
room temperature and stirred for an additional 3 h, cooled to
08C and saturated aqueous ammonium chloride (20 ml) was
added. The resulting mixture was stirred for 10 min and
concentrated on a rotary evaporator. Ethyl acetate (100 ml)
and water (50 ml) were added and the phases were
t
of CH2OTBS), 2.86 (2H, m, 2H-3), 0.83 (9H, s, Bu), 0.00
(6H, s, Si(CH3)2); dC (125 MHz, CDCl3) 25.45, 18.44,
25.79, 31.53, 56.0, 66.91, 121.52, 128.00, 169.03; m/z (EIþ)
241 (Mþ, 20%), 132 (80), 116 (40), 91 (100). Found (Mþ)
241.1501, C12H23NO2Si requires 241.1498.
4.1.3. (1R,2R,6S) 2-(tert-Butyldimethylsilanyloxy-
methyl)-7-oxa-3-aza-bicyclo[4.1.0]heptan-4-one 8a and
(1S,2R,6R) 2-(tert-butyldimethylsilanyloxymethyl)-7-
oxa-3-aza-bicyclo[4.1.0]heptan-4-one 8b. To a stirred

284
J. G. Knight, K. Tchabanenko / Tetrahedron 59 (2003) 281–286
suspension of the d-lactam 7 (562 mg, 2.33 mmol) and
sodium hydrogen carbonate (3 g, 35 mmol) in acetone
(50 ml) and water (25 ml) was added Oxone (7.2 g,
11.66 mmol) over 5 min and the suspension was stirred
for 3 h at room temperature when TLC indicated complete
consumption of the stating material. The organic phase was
extracted into ethyl acetate (3£50 ml), and the combined
organic extracts were washed with 10% aqueous sodium
bisulfite (50 ml) and water (2£50 ml), dried (MgSO4) and
the solvent was removed under reduced pressure to give the
mixture of epoxides 8a and 8b as a yellow oil. Purification
by column chromatography (eluted with EtOAc/petrol, 1:1)
gave 8a (457 mg, 76%) as a colorless oil; [a]2D0¼þ32.5
(c¼1.0, CHCl3); nmax/cm21 (film) 3140 (NH), 1645
(CvO), 1030; dH (500 MHz, CDCl3) 7.30 (1H, br s, NH),
3.80 (1H, m, H-2), 3.73 (1H, dd, J¼10.4, 3.3 Hz, one of
CH2OTBS), 3.68 (1H, dd, J¼10.4, 4.6 Hz, one of CH2-
OTBS), 3.31 (1H, dd, J¼4.1, 2.1 Hz; H-1), 3.25 (1H, br d,
J¼4.1 Hz, H-6), 2.77 (1H, br d, J¼18.3 Hz, one of H-5),
4.1.5. (5R,6R)-6-(tert-Butyldimethylsilanyloxymethyl)-5-
hydroxy-5,6-dihydro-1H-pyridin-2-one 9b. Following the
procedure for the synthesis of 9a, epoxide 8b (35 mg,
0.14 mmol) afforded the dihydropyridinone 9b (33 mg,
95%) as a pale yellow oil: [a]2D0¼219.2 (c¼0.4, CHCl3);
n
max/cm21 (film) 3210 (br NH, OH), 1608 (CvO), 1022; dH
(500 MHz, CDCl3) 6.62 (1H, dd, J¼10.5, 4.9 Hz, H-4), 5.85
(1H, d, J¼10.5 Hz, H-3), 5.82 (1H, br s, NH), 4.17 (1H, m,
H-5), 3.79 (1H, m, H-6), 3.45 (1H, dd, J¼10.8, 2.5 Hz, one
of CH2OTBS), 3.39 (1H, dd, J¼10.8, 3.4 Hz, one of
CH2OTBS), 2.85 (1H, br s, OH), 0.8 (9H, s, tBu), 0.00 (6H,
s, Si(CH3)2); dC (125 MHz, CDCl3) 165.5, 143.8, 122.0,
70.9, 65.8, 55.8, 20.8, 14.5, 26.0; m/z (EIþ) 257 (Mþ, 10%),
125 (60), 132 (50), 91 (100). Found (Mþ) 257.1455,
C12H23NO3Si requires 257.1447.
4.1.6. (3S,4S,5R,6R)-6-(tert-Butyldimethylsilanyloxy-
methyl)-3,4,5-trihydroxy-piperidin-2-one 10a. To a stir-
red solution of the dihydropyridinone 9a (204 mg,
0.79 mmol) and NMO (321 mg, 2.4 mmol) in tBuOH
(10 ml) was added a drop of water and osmium tetroxide
t
2.67 (1H, br d, J¼18.3 Hz, one of H-5) 0.81 (9H, s, Bu),
0.00 (3H, s, one of (CH3)2Si), 20.02 (3H, s, one of
(CH3)2Si); dC (125 MHz, CDCl3) 175.6, 68.2, 61.7, 52.8,
50.4, 40.1, 21.3, 14.5, 25.5; m/z (EIþ) 257 (Mþ, 20%), 141
(80), 116 (40), 91 (100). Found (Mþ) 257.1460,
C12H23NO3Si requires 257.1447; and 8b as a colorless oil
(109 mg, 19%); [a]2D0¼29.6 (c¼0.2, CHCl3); nmax/cm21
(film) 3140 (NH), 1645 (CvO), 1030; dH (500 MHz,
CDCl3) 5.93 (1H, br s, NH), 3.78 (1H, d, J¼10.6 Hz, one of
CH2OTBS), 3.76 (1H, d, J¼10.6 Hz, one of CH2OTBS),
3.58 (1H, t, J¼10.6 Hz, H-2), 3.33 (1H, ddd, J¼4.3, 2.1,
1.8 Hz; H-6), 3.19 (1H, d, J¼4.3 Hz, H-1), 2.84 (1H, dd,
J¼18.6, 1.8 Hz, one of H-5), 2.64 (1H, dd, J¼18.6, 2.1 Hz,
t
(1.5 ml, 0.05 M solution in BuOH, 75 mmol) and the
resulting solution was stirred at room temperature for 3 h.
The reaction was quenched by addition of aqueous saturated
sodium metabisulfite (5 ml) and concentrated on a rotary
evaporator. To the resulting mixture was added ethyl acetate
(30 ml) and water (10 ml), the layers were separated, and
the organic layer was washed with 1 M HCl (5 ml) and
water (10 ml), dried (MgSO4) and the solvent was removed
under reduced pressure to give the crude product mixture.
NMR analysis indicated the presence of two diastereomeric
dihydroxylation products in a 3.2:1 ratio. Column chroma-
tography (elution with 20:1 DCM/MeOH) afforded the
major diastereoisomer, triol 10a, a white prisms (98 mg,
t
one of H-5), 0.81 (9H, s, Bu), 0.00 (6H, Si(CH3)2); dC
(125 MHz, CDCl3) 179.0, 67.5, 62.8, 51.9, 50.6, 38.1, 25.1,
13.8, 24.8; m/z (EIþ) 257 (Mþ, 20%), 141 (80), 116 (40), 91
(100). Found (Mþ) 257.1460, C12H23NO3Si requires
257.1447.
43%): mp 125–1278C; [a]2D0¼4.5 (c¼0.8, CHCl3); nmax
/
cm21 (KBr) 3324 (br, OH), 1741 (CvO), 1116, 838; dH
(500 MHz, d6-DMSO) 7.04 (1H, br s, NH), 5.05 (1H, d,
J¼3.7 Hz, H-3), 4.87 (1H, d, J¼7.4 Hz, H-5), 4.63 (1H, d,
J¼4.2 Hz, H-6), 3.88 (1H, m, H-4), 3.71–3.58 (2H, m,
CH2OTBS), 3.30 (3H, br s, OH), 0.82 (9H, s, tBu), 0.01 (3H,
s, one of Si(CH3)2), 20.01 (3H, s, one of Si(CH3)2); dC
(125 MHz, d6-DMSO) 172.1, 71.6, 68.7, 65.4, 62.0, 56.3,
25.8, 17.9, 25.3. m/z (CIþ) 292 (MHþ, 37%), 234 (100),
216 (15), 116 (15), 75 (30). Found (MHþ) 292.1593,
C12H26NO5Si requires 292.1580. The minor diastereo-
isomer 10b was not isolated.
4.1.4. (5S,6R)-6-(tert-Butyldimethylsilanyloxymethyl)-5-
hydroxy-5,6-dihydro-1H-pyridin-2-one 9a. A solution of
epoxide 8a (157 mg, 0.61 mmol) and DBU (185 mg,
1.22 mmol) in CH2Cl2 (10 ml) was heated at reflux for 3 h
at which time tlc indicated complete consumption of the
starting material. Saturated aqueous ammonium chloride
(10 ml) was added and the phases were separated. The
aqueous phase was extracted with CH2Cl2 (2£10 ml),
the combined organic extracts were dried (MgSO4), and
the solvent was removed under reduced pressure to give a
yellow oil. Purification by column chromatography (eluted
with EtOAc/petrol, 1:1) gave the dihydropyridinone 9a as a
pale yellow oil (149 mg, 95%); [a]2D0¼223.5 (c¼1.1,
CHCl3); nmax/cm21 (film) 3210 (br NH, OH), 1608
(CvO), 1022; dH (500 MHz, CDCl3) 6.50 (1H, dd,
J¼210.1, 3.1 Hz; H-4), 6.31 (1H, br s, NH), 5.77 (1H,
dd, J¼10.1, 1.8 Hz; H-3), 4.23 (1H, m, H-5), 3.75–3.66
(2H, m, H-6 and OH), 3.58 (1H, dd, J¼15.2, 1.2 Hz, one
of CH2OTBS), 3.55 (1H, dd, J¼15.2, 1.0 Hz, one of
CH2OTBS), 0.81 (9H, s, tBu), 0.00 (3H, s, one of
Si(CH3)2), 20.02 (3H, s, one of Si(CH3)2); dC (125 MHz,
CDCl3) 165.2, 143.6, 123.9, 65.3, 64.5, 58.8, 25.8, 18.2,
25.5; m/z (EIþ) 257 (Mþ, 10%), 125 (60), 132 (50), 91
(100). Found (Mþ) 257.1455, C12H23NO3Si requires
257.1447.
4.1.7. (3S,4S,5R,6R)-3,4,5-Triacetoxy-1-acetyl-2-(tert-
butyldimethylsilanyloxymethyl)-6-oxo-piperidine 11a
and (3R,4R,5R,6R)-3,4,5-triacetoxy-2-(tert-butyl-
dimethylsilanyloxymethyl)-6-oxo-piperidine 11b. To the
crude dihydroxylation product of dihydropyridinone 9a
(210 mg, 0.81 mmol) was added acetic anhydride (20 ml)
and the resulting mixture was refluxed for 4 h, cooled to
room temperature and concentrated on a rotary evaporator.
Column chromatography (eluting with ethyl acetate/petrol
1:2) afforded the tetraacetate 11a as a pale yellow oil
(171 mg, 44% from 9a) [a]2D0¼þ24.5 (c¼1.2, CHCl3);
n
max/cm21 (film) 1760, 1748, 1680, 1656, 1646, 1115, 920;
dH (500 MHz, CDCl3) 5.71 (1H, d, J¼2.4 Hz, H-3), 5.66
(1H, dd, J¼4.3, 2.4 Hz, H-4), 5.43 (1H, dd, J¼4.3, 3.9 Hz,
H-5), 4.55 (1H, m, H-6), 3.78 (1H, dd, J¼10.7, 1.8 Hz, one
of CH2OTBS), 3.70 (1H, dd, J¼10.7, 2.8 Hz, one of

J. G. Knight, K. Tchabanenko / Tetrahedron 59 (2003) 281–286
285
CH2OTBS), 2.46 (3H, s, Ac), 2.47 (3H, s, Ac), 2.10 (3H, s,
t
Ac), 1.95 (3H, s, Ac), 0.81 (9H, s, Bu), dC (125 MHz,
(100). Found (Mþ) 437.2390 C26H35NO3Si requires
437.2386.
CDCl3) 172.3, 169.7, 169.2, 168.8, 167.8, 68.5, 67.9, 67.3,
64.1, 57.6, 27.6, 25.8, 25.7, 25.5, 20.6, 18.4, 25.6; m/z (EIþ)
459 (Mþ, 5%), 417 (10), 375 (30), 333 (37), 44 (100). Found
(Mþ) 459.1937, C20H33NO9Si requires 459.1925 and the
triacetate 11b (41 mg, 12% from 9a) as a colorless oil
[a]2D0¼29.7 (c¼0.6, CHCl3); nmax/cm21 (film) 3120 (NH),
1751 (CvO), 1675 (CvO), 1655 (CvO), 1640 (CvO),
1115, 881; dH (500 MHz, CDCl3) 5.98 (1H, br s, NH), 5.75
(1H, d, J¼5.9 Hz, H-3), 5.39 (1H, d, J¼5.9 Hz, H-4), 4.37
(1H, d, J¼9.4 Hz, H-5), 4.00 (1H, m, H-6), 3.78 (1H, dd,
J¼10.7, 2.1 Hz, one of CH2OTBS), 3.57 (1H, dd, J¼10.7,
3.4 Hz, one of CH2OTBS), 2.05 (3H, s, Ac), 2.04 (3H, s,
Ac), 1.96 (3H, s, Ac), 0.82 (9H, s, tBu), 0.00 (6H, s, SiMe2);
dC (125 MHz, CDCl3) 170.9, 170.3, 169.7, 168.7, 80.8,
69.6, 66.1, 61.0, 50.1, 25.8, 23.2, 20.5, 20.2, 18.3, 25.5; m/z
(EIþ) 417 (Mþ, 13%), 375 (25), 333 (50), 291 (17), 44
(100). Found (Mþ) 417.1823, C18H31NO8Si requires
417.1819.
4.1.10. (1R,4R,5R,8S)-2,4-Dibenzyl-8-(tert-butyl-
dimethylsilanyloxy)-6-oxa-2-aza-bicyclo[3.2.1]octan-3-
one 13. In a similar benzylation procedure, dihydro-
pyridinone 9b (132 mg, 0.75 mmol) gave bicycle 13
(66 mg, 50%) as a colorless oil: [a]2D0¼212.9 (c¼0.5,
CHCl3); nmax/cm21 (film) 1675 (CvO), 1455, 1092; dH
(500 MHz, CDCl3) 7.34–7.20 (10H, m, Ar), 6.36 (1H, d,
J¼15.3 Hz, one of PhCH2N), 4.82 (1H, dd, J¼5.5, 2.5 Hz;
H-8), 4.11 (1H, d, J¼15.3 Hz, one of PhCH2N), 3.80 (1H,
dd, J¼11.6, 2.5 Hz, H-5), 3.73 (2H, m, H-1 and H-4), 3.16
(1H, dd, J¼20.4, 2.4 Hz, one of H-7), 3.01 (1H, dd, J¼20.4,
5.1 Hz, one of H-7), 2.73 (1H, br d, J¼11.6 Hz, one of
PhCH2), 2.67 (1H, br d, J¼11.6 Hz, one of PhCH2), 0.86
t
(9H, s, Bu), 0.00 (6H, s, Si(CH3)2); dC (125 MHz, CDCl3)
169.7, 137.1, 136.3, 128.6, 128.5, 128.1, 127.8, 127.5,
127.3, 91.8, 69.5, 61.9, 60.3, 56.7, 47.4, 31.2, 25.8, 18.2,
25.5; m/z (EIþ) 437 (Mþ, 20%), 345 (20), 228 (40), 117
(50), 92 (100). Found (Mþ) 437.2390 C26H35NO3Si requires
437.2386.
4.1.8. D-Mannolactam (2). A solution of piperidinone 10a
(65 mg, 0.22 mmol) in TFA/water (1:1, 5 ml) was stirred for
10 h and the solvents were removed under reduced pressure
to give the crude product, which was recrystallized from
water to give 2 as white solid (27.3 mg, 70%) dH (300 MHz,
D2O) 3.20 (1H, m), 3.54 (2H, m), 3.76 (1H, dd, J¼12.0,
5.2 Hz), 4.02 (2H, m); dC (75 MHz, D2O) 57.3, 61.1, 67.1,
68.2, 71.8, 174.0; mp 164–1678C, [a]2D0¼þ1.2 (c¼0.2,
water) (lit.27 mp 168–1708C, [a]2D0¼þ1.6 (c¼1.0,
water)).
4.1.11. (3S,4R,5R,6R)-1-Benzyl-5-benzyloxy-6-(tert-
butyldimethylsilanyloxymethyl)-3,4-dihydroxy-piperi-
din-2-one 15. To a stirred solution of dihydropyridinone 12
(303 mg, 0.7 mmol) and NMO (284 mg, 2.1 mmol) in
tBuOH was added a drop of water and osmium tetroxide
t
(1 ml, 0.05 M solution in BuOH, 0.05 mmol), the reaction
mixture was stirred for further 3 h at room temperature,
quenched by addition of aqueous saturated sodium meta-
bisulfite (5 ml) and concentrated on a rotary evaporator. To
the resulting mixture was added ethyl acetate (50 ml) and
water (20 ml). The layers were separated and the organic
layer was washed with 1 M HCl (10 ml) and water
(2£10 ml), dried (MgSO4) and the solvent was removed
under reduced pressure. Purification of the crude product by
column chromatography (eluted with ethyl acetate) gave the
piperidinone 15 (293 mg, 89%) as white solid: mp 87–
898C; [a]2D0¼23.6 (c¼1.1, CHCl3); nmax/cm21 (KBr) 3409
(OH), 1645 (CvO), 1250, 1074; dH (300 MHz, CDCl3)
7.39–7.11 (10H, m, Ar), 5.27 (1H, d, J¼15.6 Hz, one of
PhCH2), 4.50 (1H, d, J¼12.0 Hz, one of PhCH2), 4.44 (1H,
d, J¼12.0 Hz, one of PhCH2), 4.42 (1H, m, H-3), 4.37 (1H,
td, J¼3.6, 2.1 Hz, H-6), 4.32 (1H, d, J¼15.6 Hz, one of
PhCH2), 3.97 (1H, dd, J¼2.1, 1.8 Hz, H-4), 3.61–3.78 (3H,
m, CH2OTBS and H-5), 3.39 (1H, br s, OH), 3.21 (1H, br s,
4.1.9. (5S,6R)-1-Benzyl-5-benzyloxy-6-(tert-butyl-
dimethylsilanyloxymethyl)-5,6-dihydro-1H-pyridin-2-
one 12. To a stirred solution of dihydropyridinone 9a
(233 mg, 0.91 mmol) in dry DMF (20 ml) was added
sodium hydride (73 mg, 60% dispersion in mineral oil,
1.8 mmol) at 08C, the resulting mixture was stirred for
30 min and benzyl bromide (311 mg, 1.82 mmol) was
added. The suspension was allowed to warm to room
temperature and stirred for an additional 3 h. Saturated
aqueous ammonium chloride (5 ml) was added followed by
water (20 ml) and ethyl acetate (50 ml). The layers were
separated and the aqueous layer was extracted with ethyl
acetate (2£20 ml). the combined organic extracts were
washed with brine (2£30 ml), dried (MgSO4) and concen-
trated to give a crude oil which was purified by column
chromatography (eluted with EtOAc/petrol, 1:3) to give the
lactam 12 as a colorless oil (245.8 mg, 64%) [a]2D0¼97.0
(c¼1.5, CHCl3); nmax/cm21 (film) 1668 (CvO), 1455,
1092; dH (500 MHz, CDCl3) 7.36–7.14 (10H, m, Ar), 6.50
(1H, dd, J¼9.7, 5.0 Hz; H-4), 6.17 (1H, d, J¼9.7 Hz, H-3),
5.34 (1H, d, J¼14.9 Hz, one of PhCH2N), 4.38 (1H, d,
J¼11.6 Hz, one of PhCH2O), 4.31 (1H, d, J¼11.6 Hz, one
of PhCH2O), 4.11 (1H, dd, J¼5.0, 1.5 Hz, H-5), 4.10 (1H, d,
J¼14.9 Hz, one of PhCH2N), 3.72 (1H, ddd, J¼9.2, 4.9,
1.5 Hz; H-6), 3.62 (1H, dd, J¼10.1, 4.9 Hz, one of
CH2OTBS), 3.41 (1H, dd, J¼10.1, 9.2 Hz, one of CH2-
OTBS), 0.86 (9H, s, tBu), 0.02 (3H, s, one of Si(CH3)2), 0.00
(3H, s, one of Si(CH3)2); dC (125 MHz, CDCl3) 162.2,
137.0, 134.4, 128.5, 128.2, 127.9, 127.8, 127.6, 127.4,
127.3, 126.8, 69.9, 68.2, 61.1, 59.5, 48.2, 25.6, 18.0, 25.6;
m/z (EIþ) 437 (Mþ, 20%), 345 (20), 228 (40), 117 (50), 92
t
OH), 0.80 (9H, s, Bu), 0.01 (3H, s, one of SiMe2), 20.01
(3H, s, one of SiMe2); dC (75 MHz, CDCl3) 171.2, 137.4,
128.5, 128.4, 128.2, 127.8, 127.7, 127.5, 127.4, 75.2, 71.4,
69.6, 68.9, 68.1, 58.9, 47.6, 20.8, 15.6, 25.6. Found (Mþ)
471.2462 C26H37NO5Si requires 471.2441.
4.1.12. (3R,4R,5R,6R)-1-Benzyl-5-benzyloxy-6-(tert-
butyldimethylsilanyloxymethyl)piperidin-3,4-diol
16.
To stirred solution of piperidinone 15 (183 mg,
a
0.39 mmol) in diethyl ether (20 ml) was added LiAlH4
(76 mg, 2.0 mmol), the resulting suspension was stirred for
3 h at room temperature and quenched at 08C via slow
addition of 10% aqueous NaOH until all visible LiAlH4 had
been consumed. The reaction mixture was filtered, dried and
concentrated to give a crude oil, which was purified by
column chromatography (eluted with EtOAc) to give

286
J. G. Knight, K. Tchabanenko / Tetrahedron 59 (2003) 281–286
3. Elbein, A. D. Ann. Rev. Biochem. 1987, 56, 497–534.
4. For isolation see: Fellows, L. E.; Bell, E. A.; Lynn, D. G.;
Pilkiewicz, F.; Miura, I.; Nakanishi, K. J. Chem. Soc., Chem.
Commun. 1979, 977–978.
piperidine 16 (160 mg, 89%) as a pale yellow oil:
[a]2D0¼218.6 (c¼1.0, CHCl3); nmax/cm21 (film) 3070
(OH), 1495, 1098; dH (300 MHz, CDCl3) 7.40–7.20 (10H,
m, Ar), 4.90 (1H, d, J¼11.1 Hz, one of PhCH2), 4.56 (1H, d,
J¼11.1 Hz, one of PhCH2), 4.16 (1H, d, J¼13.2 Hz, one of
PhCH2), 3.83 (1H, dd, J¼10.4, 2.6 Hz, H-5), 3.76 (1H, dd,
J¼10.4, 2.6 Hz, H-5), 3.73 (1H, m, H-3), 3.64 (1H, m, H-6),
3.55 (1H, dd, J¼8.4, 3.3 Hz, one of CH2OTBS), 3.27 (1H, d,
J¼12.9 Hz, one of PhCH2), 2.91 (1H, dd, J¼12.2, 4.4 Hz,
one of H-2), 2.82 (2H, br s, OH), 2.38 (1H, dd, J¼8.4,
2.6 Hz, one of CH2OTBS), 2.21 (1H, dd, J¼12.2, 1.5 Hz,
one of H-2), 0.09 (9H, tBu), 0.08 (6H, SiMe2); dC (75 MHz,
CDCl3) 138.6, 138.5, 128.9, 128.4, 127.9, 127.7, 127.6,
127.2, 78.4, 74.6, 73.3, 68.1, 66.9, 64.7, 56.7, 54.7, 21.0,
15.4, 25.5; m/z (EIþ) 457 (Mþ, 37%), 367 (60), 253 (18),
117 (50), 91 (100). Found (Mþ) 457.2450 C26H39NO4Si
requires 457.2648.
5. Fuhrmann, U.; Bause, E.; Legler, G.; Ploegh, H. Nature 1984,
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4.1.13. Deoxymannojirimycin hydrochloride salt 1. To a
stirred solution of piperidine 16 (158 mg, 0.34 mmol) in
THF (10 ml) was added TBAF (0.5 ml, 1 M solution in
THF, 0.5 mmol) and the resulting solution was stirred for
1 h and then concentrated. The resulting mixture was taken
up in ethyl acetate (30 ml) and washed with water
(2£10 ml), dried (MgSO4) and the solvent was removed
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1
under reduced pressure to give a crude solid, H NMR of
which showed complete TBS deprotection. To the crude
solid was added EtOH (5 ml), 10% Pd on carbon (0.36 g)
and conc. HCl (3 ml), and the mixture was placed under an
atmosphere of H2 and stirred at rt for 2 h. The reaction
mixture was then filtered and the solvent removed under
reduced pressure to give the crude product which was
recrystallized (MeOH) to give pure deoxymannojirimycin
hydrochloride 1 (45 mg, 68%) as a white solid: mp 192–
1958C; dH (500 MHz, D2O) 3.00 (1H, ddd, J¼10.0, 6.5,
3.0 Hz), 3.10 (1H, d, J¼14.0 Hz), 3.28 (1H, dd, J¼14.0,
3.0 Hz), 3.56 (1H, dd, J¼9.6, 3.0 Hz), 3.70 (1H, dd, J¼12.5,
6.0 Hz), 3.75 (1H, t, J¼6.8 Hz), 6.85 (1H, dd, J¼12.5,
3.5 Hz), 4.10 (1H, m); dC (125 MHz, D2O) 48.25, 58.80,
61.10, 66.40, 66.60, 73.14; [a]2D0¼213.2 (c¼0.8, water)
(lit.29 [a]2D0¼213.8 (c¼1.1, water)).
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3926–3932.
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Acknowledgements
23. Knight, J. G.; Ainge, S. W.; Harm, A. M.; Harwood, S. J.;
Maughan, H. I.; Armour, D. R.; Hollinshead, D. M.; Jaxa-
Chamiec, A. A. J. Am. Chem. Soc. 2000, 122, 2944–2945.
24. Knight, J. G.; Tchabanenko, K. Tetrahedron 2002, 58,
6659–6664.
We thank the EPSRC for funding.
References
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sugars as a Class of Glycosidase Inhibitors. Bioactive
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