A flexible and efficient synthesis of the pyrrolidine α-glycosidase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB-1)

Article abstract of DOI:10.1039/b002707n

The synthesis of the pyrrolidine α-glycosidase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB-1) was discussed. The synthesis used serine-derived α-dibenzylamino aldehyde in a highly diastereoselective glycolate aldol reaction. The glycolate derivative of Evans' oxazolidinone compound was found to be prepared using benzyl-oxyacetyl chloride and 4-benzyloxazolidin-2-one. The analysis showed that the deprotection of the N-benzyl protecting groups was completed within the first 2-3 h of the reaction.

Full text of DOI:10.1039/b002707n

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A flexible and efficient synthesis of the pyrrolidine ꢀ-glycosidase
inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB-1)
Alison N. Hulme,* Charles H. Montgomery and David K. Henderson
1
Department of Chemistry, The University of Edinburgh, Kings Buildings, West Mains Road,
Edinburgh, UK EH9 3JJ
Received (in Cambridge, UK) 5th April 2000, Accepted 12th April 2000
Published on the Web 23rd May 2000
The α-glucosidase inhibitor 1,4-dideoxy-1,4-imino--arabinitol (DAB-1) 8 is synthesised in ten steps
from -serine with an overall yield of 49%; the key step of this synthesis makes use of the readily
prepared serine-derived α-dibenzylamino aldehyde 3 in a highly diastereoselective glycolate aldol
reaction.
Introduction
The use of serine-derived aldehydes in synthesis1 has been
hampered by their reactivity and susceptibility to epimeris-
ation. The development of the Garner aldehyde 1 has helped to
Scheme 1 Reagents, conditions and yields: i) CH3COCl, MeOH, reflux,
3 h, 98%; ii) K2CO3, BnBr, CH3CN, rt, 24 h, 95%; iii) TBDPSCl, imida-
zole, DMF, rt, 18 h, 100%; iv) DIBAL-H, PhCH3, Ϫ78 ЊC, 30 min, 93%;
v) (COCl)2, DMSO, CH2Cl2, Ϫ78 ЊC, 1 h; Et3N, 100%; vi) DIBAL-H,
PhCH3, Ϫ78 ЊC, 5 min, 90%.
Serine-derived aldehydes.
overcome these problems,2 but the diastereoselectivity displayed
in the reactions of N-Boc-protected aldehydes is often poor.3
We, like others, have been attracted to the highly anti diastereo-
selective nucleophilic addition reactions that N,N-dibenzyl-α-
amino aldehydes have been shown to undergo4 and the more
recent reports of syn diastereoselective additions of dialkylzinc
reagents to the same aldehydes.5 These N,N-dibenzyl-α-amino
aldehydes have also been shown to have a greater configur-
ational stability than their benzyloxycarbonyl- or tert-butoxy-
carbonyl-protected counterparts, making them more widely
applicable to synthesis.
3.† Treatment of 5 with the silyl chloride in the presence of
imidazole resulted in a quantitative conversion to protected
α-amino ester 6. A range of reduction/oxidation protocols for
the production of aldehyde 3 was investigated. However, the
most efficient method was found to involve a two-step DIBAL-
H reduction–Swern oxidation procedure.
The optical purity of alcohol 7 was confirmed by chiral
HPLC using a Chiracel OD column (solvent; 5% propan-2-ol
in hexane). Reassuringly, when compared with traces for the
racemic alcohol, this showed that there was no appreciable
racemisation of alcohol 7 even on storage (Ϫ20 ЊC) for up to a
month (material >98% ee). The most probable route for such
racemisation might involve silyl group migration from the C(1)
to C(3) alcohol.11 Samples of the Swern oxidation product alde-
hyde 3 were subjected to the usual work-up procedure and then
treated with DIBAL-H to regenerate alcohol 7 in order to check
the enantiopurity. This was also confirmed by chiral HPLC to
be >98% ee. Thus aldehyde 3 could be produced with high
optical purity in 5 steps and an overall yield of 86% from
-serine.
Early reports of
a tert-butyldimethylsilyl (TBDMS)-
protected aldehyde 2a largely remained unnoticed due to a lack
of experimental detail,6 and the benzyl-protected aldehyde 2b7
lacks the orthogonal nature of protecting groups required to
make it truly useful. The methoxymethyl-protected aldehyde 2c
was used in studies directed towards the addition of dialkylzinc
reagents to N,N-dibenzyl-α-amino aldehydes.5 However, it is the
recent publication of reports making use of 2a in the synthesis
of γ-hydroxy-β-amino alcohols8 and N,N-dibenzylsphingo-
sines9 that has prompted us to report our own success in this
area with the synthesis of the tert-butyldiphenylsilyl (TBDPS)-
protected aldehyde 3.
With a convenient preparation of aldehyde 3 in hand we
wished to demonstrate its applicability in synthesis. The
polyhydroxylated pyrrolidines are exciting targets due to the
range of biological activities they exhibit12 including action as
glycosidase inhibitors,13 and as potential anti-HIV candidates.14
Results and discussion
-Serine may be readily converted to its methyl ester hydro-
chloride salt 4 (98%)10 which is subsequently N,N-dibenzyl-
protected under non-aqueous conditions to give 5 in good yield
(95%, Scheme 1). The TBDPS protecting group was chosen as
a suitable orthogonal protecting group, not least due to the stab-
ility it exhibits in subsequent manipulations to give aldehyde
† We, as others,8,9 have found that the use of aluminium reducing agents
(LiAlH4 or DIBAL-H) gave rise to deleterious silyl deprotection when
the TBDMS protecting group was employed.
DOI: 10.1039/b002707n
J. Chem. Soc., Perkin Trans. 1, 2000, 1837–1841
This journal is © The Royal Society of Chemistry 2000
1837

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Table 1 1H NMR spectral data for 8ؒHCl (D2O; 400 MHz)16a and 8ؒHF (D2O; 600 MHz)
C(5)H2
C(4)H
C(3)H
C(2)H
C(2)CH2OH
8ؒHCl ppm (Hz)
8ؒHF ppm (Hz)
3.37 (12.7, 2.6)
3.38 (12.6, 2.7)
3.58 (12.7, 4.6)
3.61 (12.6, 5.0)
4.34 (4.6, 2.6)
4.36 (5.0, 2.7)
4.10 (4.1, 2.5)
4.12 (3.7)
3.62 (8.4, 4.6, 4.1)
3.65 (8.2, 4.2)
3.84 (12.3, 8.4)
3.86 (12.2, 8.2)
3.96 (12.3, 4.6)
3.98 (12.2, 4.6)
There have been a number of recent approaches towards their
synthesis, utilising both carbohydrate and non-carbohydrate
precursors.12,15 Our approach towards the synthesis of 1,4-
dideoxy-1,4-imino--arabinitol (DAB-1) 8 (Scheme 2),16 iden-
Scheme 2 Retrosynthetic analysis of DAB-1.
Scheme 3 Reagents, conditions and yields: i) Et3N, n-Bu2BOTf,
CH2Cl2, Ϫ78 → 0 ЊC, 3 h; 3, CH2Cl2, Ϫ78 → 0 ЊC, 2.5 h, 82%;
ii) (MeO)NHMeؒHCl, Me3Al, THF, Ϫ30 ЊC; 11, THF, 0 ЊC, 2 h, 100%;
iii) Pd(OH)2, H2 (1 atm), MeOH, 72 h, 71%; iv) BH3ؒTHF, THF, reflux,
18 h, 100%; v) HF (48% aq.), CH3CN, rt, 15 min; MeOSiMe3; Dowex
OHϪ, 100%.
tified the C(3)–C(4) bond of the intermediate pyrrolidin-2-one 9
as a key disconnection, allowing a syn diastereoselective gly-
colate aldol reaction with serine-derived aldehyde 3 to set the
desired stereochemistry. It was anticipated that a diastereoselec-
tive synthesis of 9 would require ‘matched’ stereoselectivity of
the two chiral components; the boron enolate derived from the
glycolate Evans’ oxazolidinone 1017 and the aldehyde 3.
steps to DAB-1 8, the direct reduction of aldol adduct 11 to
give pyrrolidinone 13a was investigated. Although a quanti-
tative recovery of material was achieved, it was found to be
a 1:1 mixture of the desired pyrrolidinone 13a and its benzyl-
protected counterpart 13b. Isolated 13b was found to be
extremely resistant to subsequent deprotection under a range of
conditions. Thus conversion to the pyrrolidinone 13a via the
Weinreb amide 12 became the method of choice.
Reduction of the lactam by heating to reflux a THF solution
of 13a and borane15h gave the protected polyhydroxylated
pyrrolidine 14 in quantitative yield. Finally, silyl deprotection
made use of an aqueous solution of HF in acetonitrile. Excess
of fluoride was removed at the end of the procedure by reaction
with methoxytrimethylsilane and separation of the resultant
fluorosilane by evaporation,19 a protocol that has recently
found considerable use in the synthesis of oligosaccharides.
Purification was then achieved simply by trituration of the
resultant solid with ethyl acetate to give the hydrofluoride salt
of DAB-1 8 as a single diastereomer in 10 steps and 49% overall
yield from -serine. The hydrofluoride salt was found to give 1H
NMR data in good agreement with those reported for the
hydrochloride salt (Table 1), and an optical rotation of similar
The glycolate derivative of Evans’ oxazolidinone, compound
10, was prepared using the literature procedure from benzyl-
oxyacetyl chloride and 4-benzyloxazolidin-2-one.18 Formation
of the Z-boron enolate (Bu2BOTf, Et3N, CH2Cl2) and reaction
with aldehyde 3 gave the desired syn aldol adduct 11 in excellent
yield as a single diastereomer (82%, Scheme 3). This was cleanly
converted to Weinreb amide 12 without protection of the
secondary hydroxy group. Hydrogenation using Pearlman’s
catalyst [Pd(OH)2, H2] was effective in removing the benzyl pro-
tecting groups from both the hydroxy and the amino groups,
and in situ cyclisation gave pyrrolidinone 13a (≡9) in 71% yield.
Interception of the hydrogenation reaction before its comple-
tion revealed that deprotection of the N-benzyl protecting
groups was complete within the first 2–3 h of reaction. How-
ever, removal of the O-benzyl group was more sluggish and
usually required 24–72 h to reach completion. Examination of
1
the coupling constants displayed in the 600 MHz H NMR
spectrum of pyrrolidinone 13a confirmed the predicted stereo-
chemistry; C(3)–C(4) J 7.3 Hz from the syn aldol, with C(4)–
C(5) J 7.3 Hz due to Felkin–Anh selectivity exhibited by
aldehyde 3. In an attempt to reduce the number of synthetic
1838
J. Chem. Soc., Perkin Trans. 1, 2000, 1837–1841

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magnitude: 8ؒHF [α]D ϩ26.3 (c 0.30, H2O), cf. 8ؒHCl [α]D ϩ37.9
(c 0.53, H2O).20 ‡
Methyl (2R)-2-dibenzylamino-3-hydroxypropanoate 5
To a solution of -serine methyl ester hydrochloride 4 (15.0 g,
96.5 mmol) in acetonitrile (240 cm3) was added potassium
carbonate (66.6 g, 0.483 mol) followed by benzyl bromide
(41.1 g, 28.6 cm3, 0.240 mol). The mixture was stirred for 24 h.
Water (300 cm3) was added and the aqueous phase was extracted
with EtOAc (3 × 300 cm3). The combined organic extracts were
dried, and concentrated under reduced pressure. The residue
was chromatographed on silica gel [hexane–EtOAc (4:1)] to
give methyl ester 5 (27.5 g, 95%) as an oil; [α]D ϩ146.5 (c 0.96,
CHCl3); νmax (neat)/cmϪ1 3455, 1731, 1601, 1585, 1494; δH (200
MHz; CDCl3) 7.39–7.21 (10H, m), 3.92 (2H, d, J 13.4)
3.80 (3H, s), 3.80–3.69 (2H, m), 3.69 (2H, d, J 13.4), 3.59
(1H, dd, J 15.0, 7.5), 2.58 (1H, br s); δC (50.3 MHz; CDCl3)
171.1, 138.6, 128.9, 128.4, 127.3, 61.6, 59.2, 54.6, 51.2; m/z
(FAB) 299 (Mϩ, 59%), 268 (100), 240 (96), 181 (41), 92 (41);
HRMS (FAB) (Found: Mϩ, 299.1576. C18H21NO3 requires m/z,
299.1521).
A small quantity of the hydrofluoride salt was converted to
the free base 8 (Dowex OHϪ) to allow spectral comparison.
Again the 1H and 13C NMR data were in good agreement with
those reported in the literature.16b It was noted that chemical
shifts in the 1H NMR spectrum of the natural product showed
significant concentration and pH dependence. Synthetic DAB-1
8 prepared by this route was found to have a specific optical
rotation of [α]D ϩ8.2 (c 0.25, H2O), cf. [α]D ϩ7.8 (c 0.46, H2O).20
Conclusions
The synthesis of DAB-1 8 has served to illustrate the utility of
the tert-butyldiphenylsilyl-protected aldehyde 3 in aldol-type
reactions. The synthesis has great potential for the development
of analogues of the natural product through the judicious
choice of aldol coupling partners and further studies are
underway in this area.
Experimental
General
Methyl (2R)-3-(tert-butyldiphenylsiloxy)-2-(dibenzylamino)-
propanoate 6
To a solution of ester 5 (11.4 g, 37.8 mmol) and tert-
butyldiphenylsilyl chloride (TBDPSCl) (20.8 g, 19.7 cm3, 75.6
mmol) in DMF (60 cm3) was added imidazole (10.5 g, 151
mmol). The mixture was stirred for 18 h. Brine (150 cm3) was
added and the aqueous phase was extracted with CH2Cl2
(3 × 150 cm3). The combined organics were dried, and concen-
trated under reduced pressure. The residue was chromato-
graphed on silica gel [hexane–EtOAc (15:1)] to give the benzyl-
protected methyl ester 6 (20.4 g, 100%) as an oil; [α]D ϩ30.9
(c 2.2 CHCl3); νmax (neat)/cmϪ1 1734, 1592; δH (200 MHz;
CDCl3) 7.67–7.22 (20H, m), 4.06 (1H, dd, J 10.2, 6.2), 4.03 (2H,
d, J 14.3), 4.00 (1H, dd, J 10.2, 6.2), 3.77 (2H, d, J 14.3), 3.76
(3H, s), 3.70 (1H, t, J 6.2), 1.05 (9H, s); δC (62.8 MHz; CDCl3)
171.8, 139.6, 135.4, 133.0, 129.5, 128.5, 128.1, 127.5, 126.8,
63.2, 62.8, 55.3, 51.0, 26.5, 19.0; m/z (FAB) 537 (Mϩ, 100%), 478
(40), 268 (35), 135 (25); HRMS (FAB) (Found: Mϩ, 537.2721.
C34H39NO3Si requires m/z, 537.2699).
All reactions involving air- or water-sensitive reagents were
carried out under an atmosphere of argon using flame- or
oven-dried glassware. Unless otherwise noted, starting
materials and reagents were obtained from commercial sup-
pliers and were used without further purification. THF was
distilled from Na–benzophenone ketyl immediately prior to use.
Toluene, CH2Cl2, Et3N, and DMF were distilled from calcium
hydride. Anhydrous methanol and acetonitrile were used as
supplied by Aldrich. Unless otherwise indicated, organic
extracts were dried over anhydrous magnesium sulfate and con-
centrated under reduced pressure using a rotary evaporator.
Purification by flash column chromatography was carried out
using Merck Kieselgel 60 silica gel as the stationary phase.
Chiral HPLC was performed using a Waters instrument
equipped with a UV detector and a Chiracel OD column
(internal diameter 4.6 mm). All solvents for use in HPLC analy-
sis were vacuum filtered and degassed prior to use, and a stand-
ard flow rate of 0.5 cm3 minϪ1 was used. IR spectra were meas-
ured on a Biorad FTS-7 or Perkin-Elmer Paragon 1000 FT-IR
(2S)-3-(tert-Butyldiphenylsiloxy)-2-(dibenzylamino)propan-1-ol
7
1
spectrometer as thin films unless otherwise stated. H and 13C
NMR spectra were measured on a Varian Gemini 200, Bruker
AC250, Bruker AM250 or Varian Inova 600 spectrometer;
J-values are in Hz. Mps were determined on a Gallenkamp
Electrothermal Melting Point apparatus and are uncorrected.
Optical rotations were measured on an AA-1000 polarimeter
with a path length of 1.0 dm, at the sodium -line, at room
temperature. Elemental analysis was carried on a Perkin-Elmer
2400 CHN Elemental Analyser. Fast atom bombardment
(FAB) mass spectra were obtained using a Kratos MS50TC
mass spectrometer at The University of Edinburgh.
To a solution of ester 6 (3.0 g, 5.6 mmol) in anhydrous toluene
(20 cm3) at Ϫ78 ЊC was added diisobutylaluminium hydride
(DIBAL-H) [14.0 cm3 (1.0 M in toluene), 14.0 mmol]. The mix-
ture was stirred at Ϫ78 ЊC for 30 min then quenched by drop-
wise addition of methanol (≈10 cm3). The resulting mixture was
allowed to warm to room temperature and diluted with CH2Cl2
(100 cm3). Saturated aq. sodium potassium tartrate (75 cm3)
was added and the biphasic mixture was stirred vigorously for
3 h by which time two clear phases were apparent. The organic
phase was separated and the aqueous phase was extracted with
CH2Cl2 (3 × 100 cm3). The combined organics were dried, and
concentrated under reduced pressure. The residue was chrom-
atographed on silica gel [hexane–EtOAc (5:1)] to give alcohol 7
(2.64 g, 93%) as an oil; [α]D Ϫ58.4 (c 1.15, CHCl3); νmax (neat)/
cmϪ1 3451, 1593; δH (200 MHz; CDCl3) 7.74–7.19 (20H, m),
3.90 (1H, dd, J 10.7, 6.0), 3.88 (2H, d, J 13.4), 3.75 (1H,
dd, J 10.7, 6.0), 3.61 (2H, d, J 13.4), 3.58 (2H, d, J 7.5), 3.10
(1H, dt, J 7.4, 6.0), 2.92 (1H, br s), 1.10 (9H, s); δC (62.8
MHz; CDCl3) 139.4, 135.5, 132.9, 129.8, 129.7, 128.8, 128.3,
127.7, 61.3, 59.9, 59.4, 53.9, 26.7, 19.0; m/z (FAB) 510
([M ϩ H]ϩ, 91%), 480 (92), 240 (99), 197 (100), 77 (50); HRMS
(FAB) (Found: [M ϩ H]ϩ, 510.2829. C33H40NO2Si requires m/z,
510.2828).
Methyl (2R)-2-amino-3-hydroxypropanoate hydrochloride 4
Acetyl chloride (56.1 g, 50.8 cm3, 0.715 mol) was added drop-
wise to methanol (300 cm3) at 0 ЊC. The mixture was stirred
for ca. 15 min and -serine (25.0 g, 0.238 mol) was then
added portionwise to the solution. The resulting mixture
was heated to reflux and held at reflux for 3 h. Concentration
under reduced pressure provided hydrochloride salt 4 (36.2 g,
98%) as a solid. Recrystallisation from methanol provided an
analytical sample; mp 164–166 ЊC (Aldrich 163–166 ЊC); [α]D
–4.0 (c 4.0, EtOH); δH (200 MHz; D2O) 4.13 (1H, t, J 3.8), 3.95
(1H, dd, J 12.7, 4.1), 3.83 (1H, dd, J 12.7, 3.5), 3.70 (3H, s);
δC (50.3 MHz; D2O) 168.6, 58.8, 54.3, 53.3 (Found: C, 30.57; H,
6.33; N, 8.79. Calc. for C4H9NO3ؒHCl: C, 30.87; H, 6.43; N,
9.00%).
Via reduction of aldehyde 3. To a solution of aldehyde 3 (see
below), (78.0 mg, 0.15 mmol) in toluene (1.0 cm3) at Ϫ78 ЊC was
added DIBAL-H [0.21 cm3 (1.0 M in toluene), 0.21 mmol]. The
‡ Specific optical rotations [α]D are given in units of 10Ϫ1 deg cm2 gϪ1
.
J. Chem. Soc., Perkin Trans. 1, 2000, 1837–1841
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mixture was stirred at Ϫ78 ЊC for 5 min, then quenched by
sequential addition of water (50 mm3), aq. sodium hydroxide
(50 mm3; 1 M), and water (1 cm3). The resulting mixture was
allowed to warm to room temperature and was extracted with
CH2Cl2 (3 × 2 cm3). The combined extracts were dried, and
concentrated under reduced pressure. The residue was chrom-
atographed on silica gel [hexane–EtOAc (5:1)] to give alcohol 7
(70 mg, 90%) as a colourless oil, HPLC (S enantiomer) tR = 5.2
min, (R enantiomer) tR = 6.2 min [hexane–propan-2-ol (19:1)],
>98% ee.
127.6, 127.2, 126.7, 78.3, 72.5, 72.1, 66.6, 61.3, 59.6, 55.8, 54.6,
37.2, 26.7, 18.9; m/z (FAB) 833 ([M ϩ H]ϩ, 100%), 478 (15);
HRMS (FAB) (Found: [M ϩ H]ϩ, 833.3954. C52H57N2O6Si
requires m/z, 833.3985).
(2S,3R,4R)-2-Benzyloxy-5-(tert-butyldiphenylsiloxy)-4-dibenzyl-
amino-3-hydroxy-N-methoxy-N-methylpentanamide 12
To a suspension of dry N,O-dimethylhydroxylamine hydro-
chloride (4.20 g, 43.0 mmol) in THF (7.5 cm3) at Ϫ30 ЊC was
added trimethylaluminium [21.5 cm3 (2 M in toluene), 43.0
mmol]. The solution was allowed to warm to room temperature
over ca. 15 min, after which time a clear solution remained. The
solution was recooled to Ϫ30 ЊC and a Ϫ30 ЊC solution of the
aldol adduct 11 (1.43 g, 1.72 mmol) in THF (5 cm3) was added
dropwise via cannula. The mixture was warmed to 0 ЊC and
stirred at 0 ЊC for 2 h. The reaction mixture was then cannu-
lated into a rapidly stirred biphasic mixture of CH2Cl2 (50 cm3)
and saturated aq. sodium potassium tartrate (50 cm3) and
stirred for 5 h whereupon two clear phases were observed. The
organic phase was separated and the aqueous phase was
extracted with CH2Cl2 (3 × 50 cm3). The combined organics
were dried, and concentrated under reduced pressure. The resi-
due was chromatographed on silica gel [hexane–EtOAc (4:1)]
to give amide 12 (1.23 g, 100%) as a solid, mp 42–43 ЊC; [α]D
Ϫ30.4 (c 1.1, CHCl3); νmax (neat)/cmϪ1 3458, 1664, 1597; δH (600
MHz; CDCl3) 7.74–7.16 (25H, m), 4.62 (1H, br s), 4.36 (1H, d,
J 10.7), 4.20 (1H, td, J 7.8, 2.1), 4.10 (1H, dd, J 11.0, 4.5), 4.07
(1H, dd, J 11.0, 5.6), 3.93 (1H, d, J 10.7), 3.89 (2H, d, J 14.0),
3.72 (2H, d, J 14.0), 3.40 (3H, s), 3.20 (1H, ddd, J 7.8, 5.6, 4.5),
3.15 (3H, s), 2.75 (1H, br d, J 6.8), 1.08 (9H, s); δC (62.8 MHz;
CDCl3) 171.4, 140.0, 137.5, 135.7, 135.6, 133.3, 133.0, 129.6,
128.7, 128.1, 127.9, 127.9, 127.6, 127.5, 127.4, 126.7, 75.2, 71.4,
70.9, 60.9, 60.8, 59.3, 54.8, 32.1, 26.7, 18.9; m/z (FAB) 717
([M ϩ H]ϩ, 30%), 639 (11), 478 (100), 278 (37), 135 (77), 91
(92); HRMS (FAB) (Found: [M ϩ H]ϩ, 717.3728. C44H53N2-
O5Si requires m/z, 717.3724).
(2R)-3-(tert-Butyldiphenylsiloxy)-2-(dibenzylamino)propanal 3
To a solution of oxalyl chloride (0.45 g, 0.31 cm3, 3.6 mmol)
in CH2Cl2 (15 cm3) at Ϫ78 ЊC was added dropwise a solution
of DMSO (0.57 g, 0.43 cm3, 4.5 mmol) in CH2Cl2 (0.5 cm3).
The mixture was stirred for ca. 5 min whereupon it became
cloudy. A solution of alcohol 7 (1.57 g, 3.08 mmol) in
CH2Cl2 (5.0 cm3) at Ϫ78 ЊC was introduced via cannula. The
resulting clear solution was stirred at Ϫ78 ЊC for 1 h. Tri-
ethylamine (1.20 g, 1.63 cm3, 11.7 mmol) was added and the
resulting cloudy solution was allowed to warm to room tem-
perature. Water (10 cm3) was added, producing two clear
phases. The organic phase was separated and the aqueous
phase was extracted with CH2Cl2 (3 × 10 cm3). The combined
organics were washed sequentially with 1% HCl (20 cm3),
water (20 cm3), saturated aq. sodium bicarbonate (20 cm3) and
brine (20 cm3), then dried, and concentrated under reduced
pressure to give aldehyde 3 (1.56 g, 100%) as an oil which was
used in the aldol reaction without further purification, νmax
(neat)/cmϪ1 3068, 2711, 1731, 1601, 1588, 1494; δH (200 MHz;
CDCl3) 9.80 (1H, s), 7.76–7.26 (20H, m), 4.16 (1H, dd,
J 11.0, 5.7), 4.09 (1H, dd, J 11.0, 5.7), 3.98 (2H, d, J 13.9), 3.90
(1H, d, J 13.9), 3.52 (1H, t, J 5.7); δC (50.3 MHz; CDCl3)
202.8, 139.3, 135.6, 135.5, 132.8, 132.7, 129.8, 128.6, 128.3,
127.7, 127.1, 67.8, 60.5, 55.6, 26.7, 19.9.
(2ЈS,3ЈR,4S,4ЈR)-4-Benzyl-3-[2Ј-Benzyloxy-5Ј-(tert-butyl-
diphenylsiloxy)-4Ј-dibenzylamino-3Ј-hydroxypentanoyl]-
oxazolidin-2-one 11
(3S,4R,5R)-5-(tert-Butyldiphenylsiloxymethyl)-3,4-dihydroxy-
pyrrolidin-2-one 13a
A solution of the Weinreb amide 12 (1.00 g, 1.40 mmol) and
Pearlman’s catalyst [1.00 g; 20% Pd(OH)2/C] in methanol (10
cm3) was exposed to a hydrogen atmosphere (1 atm) and stirred
vigorously for 72 h. The mixture was then filtered through a pad
of Celite and concentrated under reduced pressure. The residue
was chromatographed on silica gel [hexane–EtOAc (2:3)] to
give pyrrolidinone 13a (0.383 g, 71%) as a foam; [α]D ϩ11.5
(c 1.1, CHCl3); νmax (neat)/cmϪ1 3424, 1720; δH (600 MHz;
CDCl3) 7.61–7.25 (10H, m), 6.15 (1H, br s), 4.67 (1H, br s), 4.28
(1H, d, J 7.7), 3.98 (1H, br t, J 7.3), 3.88 (1H, dd, J 10.7, 3.5),
3.79 (1H, br s), 3.61 (1H, dd, J 10.7, 7.3), 3.51 (1H, td, J 7.3,
3.5), 1.03 (9H, s); δC (50.2 MHz; CDCl3) 174.2, 135.5, 132.6,
130.0, 127.9, 75.7, 64.4, 58.0, 26.6, 19.0; m/z (FAB) 386
([M ϩ H]ϩ, 15%), 307 (40), 154 (100), 107 (75), 77 (61); HRMS
(FAB) (Found: [M ϩ H]ϩ, 386.1776. C21H28NO4Si requires m/z,
386.1787).
To a solution of the glycolate equivalent 1018 (3.42 g, 10.5
mmol) in CH2Cl2 (57 cm3) at Ϫ78 ЊC was added triethylamine
(1.39 g, 1.91 cm3, 13.7 mmol) followed by dropwise addition of
dibutylboron triflate (1.0 M in CH2Cl2; 12.8 cm3, 12.8 mmol).
The solution was stirred at Ϫ78 ЊC for 45 min, then allowed to
warm to 0 ЊC over 30 min and stirred at 0 ЊC for 1.25 h. The
solution was then recooled to Ϫ78 ЊC and a Ϫ78 ЊC solution of
aldehyde 3 (1.47 g, 2.89 mmol) in CH2Cl2 (7.5 cm3) was added
dropwise via cannula. The reaction mixture was stirred at
Ϫ78 ЊC for 1 h, allowed to warm to 0 ЊC over a period of 30 min
and stirred for a further 1 h at 0 ЊC. The reaction was quenched
by the addition of methanol (40 cm3) followed by pH 7 phos-
phate buffer (25 cm3). Hydrogen peroxide (30% aq. solution; 10
cm3) in methanol (10 cm3) was added dropwise to the solution
and the mixture was stirred and warmed to room temperature
over ca. 1 h. The organic phase was separated and the aqueous
phase was extracted with CH2Cl2 (3 × 75 cm3); the combined
organic phase was dried, and concentrated under reduced pres-
sure. The residue was chromatographed on silica gel [hexane–
EtOAc (3.5:1)] to give aldol adduct 11 (1.98 g, 82%) as a solid,
mp 62–63 ЊC; [α]D ϩ14.5 (c 0.87, CHCl3); νmax (neat)/cmϪ1 3559,
1781, 1706; δH (600 MHz; CDCl3) 7.74–7.13 (30H, m), 5.41
(1H, d, J 2.6), 4.47 (1H, dddd, J 10.1, 7.1, 3.2, 2.1), 4.26 (1H, d,
J 11.0), 4.26–4.24 (1H, m), 4.11 (1H, dd, J 9.1, 2.1), 4.08–4.05
(3H, m), 4.06 (1H, d, J 11.0), 3.86 (2H, d, J 13.8), 3.61 (2H, d,
J 13.8), 3.29 (1H, q, J 5.4), 3.22 (1H, dd, J 13.4, 3.2), 3.05 (1H,
br d, J 8.1), 2.58 (1H, dd, J 13.4, 10.1), 1.04 (9H, s); δC (62.8
MHz; CDCl3) 171.1, 152.9, 139.9, 137.2, 135.7, 135.6, 135.2,
133.0, 132.8, 129.6, 129.3, 129.0, 128.8, 128.3, 128.0, 127.6,
(2R,3R,4R)-2-(tert-Butyldiphenylsiloxymethyl)-3,4-dihydroxy-
pyrrolidine 14
To a solution of the pyrrolidinone 13a (160 mg, 0.415 mmol)
in THF (2.0 cm3) at 0 ЊC was added BH3ؒTHF [6.23 cm3 (1 M
solution), 6.23 mmol]. After ca. 10 min the mixture was heated
to reflux and held at reflux for 18 h. The solution was cooled to
0 ЊC and methanol (≈8 cm3) was cautiously added to destroy
any remaining borane. The solution was then concentrated
under reduced pressure. The residue was chromatographed on
silica gel [hexane–EtOAc (1:1)] to give the pyrrolidine 14 (154
mg, 100%) as a solid, mp 150 ЊC; [α]D Ϫ8.1 (c 0.99, MeOH); νmax
(neat)/cmϪ1 3542, 3489, 3350, 3180; δH (600 MHz; CD3OD)
1840
J. Chem. Soc., Perkin Trans. 1, 2000, 1837–1841

View Article Online
7.73–7.70 (4H, m), 7.45–7.39 (6H, m), 5.22 (1H, br s), 4.20 (1H,
br dt, J 4.9, 1.6), 4.08 (1H, dd, J 10.6, 4.9), 4.03 (1H, dt, J 4.4,
1.8), 3.85 (1H, dd, J 10.6, 2.7), 3.17–3.12 (1H, m), 3.07–3.02
(1H, m), 2.79–2.75 (1H, m), 1.07 (9H, s); δC (50.3 MHz;
CD3OD) 134.9, 132.2, 129.2, 127.1, 78.5, 75.1, 73.1, 59.8, 59.0,
25.4, 18.3; m/z (FAB) 372 ([M ϩ H]ϩ, 100%), 198 (4), 49 (6);
HRMS (FAB) (Found: [M ϩ H]ϩ, 372.1995. C21H30NO3Si
requires m/z, 372.1995).
D. K. H.) and Pfizer for support. We also thank Dr C. M.
Hewage for running 600 MHz spectra.
References and notes
1 A. Golebiowski and J. Jurzak, Synlett, 1993, 241.
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2361; (c) P. Garner and J. M. Park, Org. Synth., 1991, 70, 18.
3 J. Jurzak and A. Golebiowski, Chem. Rev., 1989, 89, 149.
4 (a) M. T. Reetz, Angew. Chem., Int. Ed. Engl., 1991, 30, 1531;
(b) M. T. Reetz, Chem. Rev., 1999, 99, 1121.
(2R,3R,4R)-3,4-Dihydroxy-2-(hydroxymethyl)pyrrolidine
hydrofluoride 8ؒHF
5 J. M. Andrés, R. Barrio, M. A. Martínez, R. Pedrosa and A. Pérez-
Encabo, J. Org. Chem., 1996, 61, 4210.
To a solution of the silyl-protected pyrrolidine 14 (19 mg, 0.051
mmol) in acetonitrile (0.75 cm3) was added hydrofluoric acid
[0.141 cm3 (48% solution in water), ~5 equiv.]. The mixture was
stirred for 15 min before being concentrated under reduced
pressure. The residue was treated with methoxytrimethylsilane
(2.0 cm3) and re-concentrated. This process was repeated
twice. The residue obtained was triturated with EtOAc (3 × 1.0
cm3) to give the hydrofluoride salt of DAB-1 8ؒHF (8 mg,
100%) as a tacky solid; [α]D ϩ26.3 (c 0.30, H2O); δH (600 MHz;
D2O) 4.36 (1H, dt, J 5.0, 2.7), 4.12 (1H, br t, J 3.7), 3.98
(1H, dd, J 12.2, 4.6), 3.86 (1H, dd, J 12.2, 8.2), 3.65 (1H,
dt, J 8.2, 4.2), 3.61 (1H, dd, J 12.6, 5.0), 3.38 (1H, dd, J 12.6,
2.7); δC (62.9 MHz; D2O), 75.5, 74.2, 66.6, 58.9, 49.9; m/z
(FAB) 134 ([M ϩ H]ϩ, 30%), 116 (26), 102 (47), 91 (21); HRMS
(FAB) (Found: [M ϩ H]ϩ, 134.0817. C5H12NO3 requires m/z,
134.0817).
6 M. T. Reetz, W. Reif and X. Holdgrün, Heterocycles, 1989, 28, 707.
7 D. Dix and P. Imming, Arch. Pharm. (Weinheim, Ger.), 1995, 328,
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8 T. Laïb, J. Chastanet and J. Zhu, J. Org. Chem., 1998, 63, 1709.
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(b) J. M. Andrés and R. Pedrosa, Tetrahedron: Asymmetry, 1998, 9,
2493.
10 A. McKillop, R. J. K. Taylor, R. J. Watson and N. Lewis, Synthesis,
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11 K. A. Novachek and A. I. Meyers, Tetrahedron Lett., 1996, 37, 1743.
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P. Farid and G. W. J. Fleet, Tetrahedron, 1993, 49, 3359.
13 G. Legler, in Iminosugars as Glycosidase Inhibitors: Nojirimycin and
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14 G. W. J. Fleet, A. Karpas, R. A. Dwek, L. E. Fellows, A. S. Tyms,
S. Petursson, S. K. Namgoong, N. G. Ramsden, P. W. Smith, J. C.
Son, F. X. Wilson, D. R. Witty, G. S. Jacob and T. W. Rademacher,
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D. G. Marquess, J. D. Lloyd, A. L. Winters, N. Asano and G. W. J.
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T. Sifferlen and J. Streith, Synlett, 1997, 1294.
1,4-Dideoxy-1,4-imino-D-arabinitol (DAB-1) 8
A small amount of the HF salt was subjected to ion-exchange
chromatography [Dowex OHϪ; prepared by treatment of
Dowex 1-X2 with 1 M aq. NaOH, followed by flushing with
water until the eluent returned to pH 7] eluting with water to
give the free base 8 as a viscous oil in quantitative yield;
[α]D ϩ8.2 (c 0.25, H2O) {lit.,20 [α]D ϩ7.8 (c 0.46, H2O)};
δH (600 MHz; D2O) 4.16 (1H, dt, J 5.8, 3.9), 3.85 (1H, dd,
J 5.5, 3.9), 3.75 (1H, dd, J 11.5, 4.8), 3.67 (1H, dd, J 11.5,
6.4), 3.12 (1H, dd, J 12.2, 5.8), 2.99 (1H, br q, J 5.5), 2.84
(1H, dd, J 12.2, 3.9); δC (62.9 MHz; D2O), 79.0, 77.4, 65.0,
16 (a) J. Furukawa, S. Okuda, K. Saito and S. I. Hatanaka,
Phytochemistry, 1985, 24, 593; (b) R. J. Nash, E. A. Bell and
J. M. Williams, Phytochemistry, 1985, 24, 1620.
17 D. Haigh, H. C. Birrell, B. C. C. Cantello, D. S. Eggleston, R. C.
Haltiwangerm, R. M. Hindley, A. Ramaswamy and N. C. Stevens,
Tetrahedron: Asymmetry, 1999, 10, 1353.
1
62.0, 50.4. H and 13C NMR data are in good agreement with
the literature.16b,20
18 M. A. M. Fuhry, A. B. Holmes and D. R. Marshall, J. Chem. Soc.,
Perkin Trans. 1, 1993, 2743.
19 R. J. Parry, M. R. Burns, P. N. Skae, J. C. Hoyt and B. Pal, Bioorg.
Med. Chem., 1996, 4, 1077 and references cited therein.
20 G. W. J. Fleet and P. W. Smith, Tetrahedron, 1986, 42, 5685.
Acknowledgements
We thank the EPSRC (GR/96309957 to C. H. M.), The
University of Edinburgh (summer project studentship to
J. Chem. Soc., Perkin Trans. 1, 2000, 1837–1841
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