Synthesis of 1-Deoxy-D-galactohomonojirimycin via Enantiomerically Pure Allenylstannanes

Article abstract of DOI:10.1021/jo0303012

1-Deoxy-D-galactohomonojirimycin was synthesized in seven steps from optically pure allenylstannane 4 and L-lactate-derived aldehyde 5 in 48% overall yield. The key step was the Lewis acid catalyzed reaction of 4 and 5 to give the syn-amino alcohol in exc

Full text of DOI:10.1021/jo0303012

VOLUME 69, NUMBER 7
APRIL 2, 2004
© Copyright 2004 by the American Chemical Society
Syn th esis of 1-Deoxy-D-ga la ctoh om on ojir im ycin via
En a n tiom er ica lly P u r e Allen ylsta n n a n es
Michal Achmatowicz and Louis S. Hegedus*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
hegedus@lamar.colostate.edu
Received September 23, 2003
1-Deoxy-D-galactohomonojirimycin was synthesized in seven steps from optically pure allenylstan-
nane 4 and L-lactate-derived aldehyde 5 in 48% overall yield. The key step was the Lewis acid
catalyzed reaction of 4 and 5 to give the syn-amino alcohol in excellent yield and very high
diastereoselectivity.
In tr od u ction
methodology to the synthesis of 1-deoxy-D-galacto-
homonojirimycin (3)10 is reported below.
Polyhydroxylated piperidine alkaloids (azasugars) have
been the subject of intensive investigation because of
their ability to inhibit carbohydrate-processing en-
zymes.1,2 The wide range of biological activities displayed
by this class of compounds has resulted in extensive
synthetic studies.3 1-Deoxyazasugars are of particular
interest because of their enhanced stability.4 Among
these, 1-deoxynojirimycin5 (1) and its stereoisomers6 have
been the target of a number of recent syntheses, as have
their C-6 homologues 2.7 Recently, an efficient synthesis
of optically active R-aminoallenylstannanes8 as well as
Resu lts a n d Discu ssion
The synthesis of 1-deoxy-D-galactohomonojirimycin (3)
is presented in Scheme 1. Optically active allenylstan-
nane 4 was synthesized as previously described9 from
propargyl bromide and optically active diphenyloxazoli-
dinone in 54% overall yield. The requisite aldehyde 5 was
synthesized by protection of diethyl L-tartrate as the
(5) (a) Somfai, P.; Marchand, P.; Torsell, S.; Lindstro¨m, U. M.
Tetrahedron 2003, 59, 1293. (b) Comins, D. L.; Fulp, A. B. Tetrahedron
Lett. 2001, 42, 6839. (c) Kiguchi, T.; Ninomiya, I.; Naito, T. Tetrahedron
2000, 56, 5819. (d) Matos, C. R. R.; Lopes, R. S. C.; Lopes, C. C.
Synthesis 1999, 571. (e) Kazmaier, U.; Grandel, R. Eur. J . Org. Chem.
1998, 1833. (f) Lindstro¨m, U. M.; Somfai, P. Tetrahedron Lett. 1998,
39, 7173.
(6) (a) Knight, J . G.; Tchabanenko, K. Tetrahedron 2003, 59, 281.
(b) Spreitz, J .; Stutz, A. E.; Wrodnigg, T. M. Carbohydr. Res. 2002,
337, 183. (c) Mehta, G.; Mahal, N. Tetrahedron Lett. 2000, 41, 5741.
(d) Meyers, A. I.; Andres, C. J .; Resek, J . E.; Woodall, C. C.;
McLaughlin, M. A.; Lee, P. H.; Price, D. A. Tetrahedron 1999, 10, 8931.
(e) Xu, Y.-M.; Zhou, W.-S. J . Chem. Soc., Perkin Trans. 1 1997, 741.
(7) (a) Patil, N. T.; Tilekar, J . N.; Dhavale, D. D. J . Org. Chem. 2001,
66, 1065. (b) Saha, N. N.; Desai, V. N.; Dhavale, D. D. Tetrahedron
2001, 57, 39. (c) Szolcsa´nyi, P.; Gracza, T.; Koman, M.; Pro´nayova´, N.;
Liptaj, T. Tetrahedron: Asymmetry 2000, 11, 2579. (d) Szolcsa´nyi, P.;
Gracza, T.; Koman, M.; Pro´nayova´, N.; Liptaj, T. Chem. Commun.
2000, 471. (e) Desai, V. N.; Saha, N. N.; Dhavale, D. D. Chem.
Commun. 1999, 1719. (f) Compernolle, F.; J oly, G.; Peetars, K.; Toppet,
S.; Hoonaert, G. Tetrahedron 1997, 53, 12739. (g) Herders, C.; Schiffer,
T. Tetrahedron 1996, 52, 14745. (h) Lundt, I.; Madsen, R. Synthesis
1995, 787. (i) Kilonda, A.; Compernolle, F.; Toppet, S.; Hoornaert, G.
J . Tetrahedron Lett. 1994, 48, 9047. (j) Rassu, G.; Pinna, L.; Spanu,
P.; Culeddy, N.; Casiraghi, G.; Fava, G. G.; Ferrari, M. B.; Pelosi, G.
Tetrahedron 1992, 48, 727.
their highly syn selective reactions with aldehydes was
reported from these laboratories.9 The application of this
(1) For a review on the mechanism of enzymic glycosyl transfer,
see: Sinot, M. L. Chem. Rev. 1990, 90, 1171.
(2) For reviews on azasugar inhibitors, see: (a) Bols, M. Acc. Chem.
Res. 1998, 31, 1. (b) Ganem, B. Acc. Chem. Res. 1996, 29, 340. (c) Sears,
P.; Wong, C. H. Angew. Chem., Int. Ed. 1999, 38, 2300. (d) Iminosugars
as Glycosidase Inhibitors: Nojirimycin and Beyond; Stutz, A. E., Ed.;
Wiley-VCH: Weinheim, Germany, 1999.
(3) For recent reviews, see: (a) Yoda, H. Curr. Org. Chem. 2002, 6,
223. (b) Asano, N.; Hashimoto, H. Glycosciences 2001, 3, 2541. (c)
Kazmaier, U. Recent Res. Dev. Org. Chem. 1998, 2 (part 2), 351.
(4) For recent synthetic efforts, see the following and the references
therein: (a) Han, H. Tetrahedron Lett. 2003, 44, 157. (b) Sawada, D.;
Takahashi, H.; Ikegami, S. Tetrahedron Lett. 2003, 44, 3085. For
reviews, see: (c) Pandit, U. K.; Overkleeft, H. S.; Borer, B. C.;
Biera¨ugel, H. Eur. J . Org. Chem. 1999, 959. (d) Zhow, W.-S.; Lu, Z.-
H.; Xu, Y.-M.; Liao, L.-X.; Wang, Z.-M. Tetrahedron 1999, 55, 11959.
(8) For a review on the use of chiral allenylstannanes in synthesis,
see: Marshall, J . A. Chem. Rev. 1996, 96, 31.
(9) Ranslow, P. B. D.; Hegedus, L. S.; de los Rios, C. J . Org. Chem.
2003, in press.
(10) To the best of our knowledge, this particular diastereoisomer
has not previously been synthesized.
10.1021/jo0303012 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/12/2003
J . Org. Chem. 2004, 69, 2229-2234
2229

Achmatowicz and Hegedus
SCHEME 1 a
a
Reagents and conditions: (i) cyclohexanone, PhH, TsOH, rfx; (ii) LiAlH4, THF, rfx; (iii) NaH, TBSCl, THF, 25 °C; (iv) Dess-Martin
periodanane, CH2Cl2, 25 °C; (v) BF3‚OEt2, CH2Cl2, -70 °C; (vi) Cy2BH, THF, 0 f 25 °C, and then H2O2, aq NaHCO3, 0 f 25 °C; (vii)
Mukaiyama reagent, Et3N, CH2Cl2, 25 °C; (viii) DEAD, Ph3P, THF, -20 f +25 °C; (ix) 80 psi H2, catalyst Pd(OH)2, Boc2O, THF, 25 °C;
(x) HF‚Py, MeCN, 25 °C; (xi) DEAD, Ph3P, THF, -20 f +25 °C; (xii) LiAlH4, THF, -20 °C; (xiii) HCl/MeOH, 25 °C.
cyclohexanone ketal followed by lithium aluminum hy-
dride reduction to the C2-symmetric diol. Monosilylation11
followed by Dess-Martin oxidation produced the desired
aldehyde in 62% overall yield from diethyl L-tartrate.
Condensation of the aldehyde with optically active alle-
nylstannane 4 in the presence of BF3‚OEt2 produced
protected aminotetraol 6 in 86% yield with greater than
95% syn selectivity (as expected from previous studies).9
The absolute configuration was confirmed by X-ray
crystallography. Hydroboration/oxidation of the silyl-
alkyne12 produced hydroxy acid 7 in excellent yield.
Although 4-hydroxybutyric acids often lactonize spon-
taneously, hydroxy acid 7 proved resistant to cyclization,
requiring activation of either the carboxylic acid (Mu-
kaiyama)13 or the hydroxyl group (Mitsunobu)14 to effect
lactonization. Remarkably, both procedures gave the
same lactone diastereoisomer 8, in excellent yield. This
is likely to be a case of the unusual but precedented15
Mitsunobu reaction with sterically hindered alcohols with
retention.16 Cleavage of the oxazolidinone by hydro-
genolysis using Pearlman’s catalyst in the presence of
Boc anhydride proceeded under mild conditions and in
excellent yield. Removal of the silyl protecting group was
problematic. The most effective agent was HF‚Py, but the
process had to be closely monitored to prevent over-
reaction. Best yields were obtained by running the
reaction to a 92% conversion. Pushing to 100% conversion
decreased the yield, and the product was easily separated
from the starting material. Mitsunobu cyclization of the
primary alcohol 10 produced bicyclic amino lactone 11,
the stereochemistry of which was confirmed by hydrolysis
of a portion of the cyclohexanone ketal (dil HCl/MeOH)
and acquisition of an X-ray crystal structure of the
resulting diol. Reduction of the lactone with lithium
aluminum hydride followed by hydrolysis of the ketal and
recrystallization from methanol/ether gave the hydro-
chloride salt of 3 in 48% overall yield.
A more direct route was originally planned (Scheme
2) which, although ultimately unsuccessful, revealed
some interesting chemistry. Benzyl-protected aminotet-
raol 13 was synthesized in comparable yield following
procedures developed in Scheme 1. Direct conversion of
this alkyne to lactone 14 was achieved using a palladium-
catalyzed process developed by Gore et al.17 Although
the transformation was successful, yields exceeding
50% could never be achieved, even when stoichiometric
(11) (a) Chattopadhyay, A.; Dhotare, B. Tetrahedron: Asymmetry
1998, 9, 2715. (b) Vriesma, B. K.; Buter, J .; Kellogg, R. M. J . Org.
Chem. 1984, 49, 110.
(12) Alemany, C.; Bach, J .; Farras, J .; Garcia, J . Org. Lett. 1999, 1,
1831.
(13) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1979, 18, 707.
(14) (a) Mistunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem.
Soc. J pn. 1967, 40, 935. (b) Hughes, D. L. Org. React. 1992, 42, 335.
(15) (a) Liao, X.; Wu, Y.; DeBrabander, J . K. Angew. Chem., Int.
Ed. 2003, 42, 1648. (b) Smith, A. B., III; Safonov, I. G.; Corbett, R. M.
J . Am. Chem. Soc. 2002, 124, 11102. (c) Ahn, C.; DeShong, P. J . Org.
Chem. 2002, 67, 1754.
(16) Silyl migration from the terminal to the internal OH group in
6, followed by cyclization to give an eight-membered lactone, which
rearranged to the butyrolactone on subsequent desilylation, was
deemed less likely.
(17) Compain, P.; Gore, J .; Vatele, J .-M. Tetrahedron 1996, 52,
10405.
2230 J . Org. Chem., Vol. 69, No. 7, 2004

Synthesis of 1-Deoxy-D-galactohomonojirimycin
SCHEME 2 a
recently reported from these laboratories. An unusual
Mitsunobu lactonization with retention prevented the use
of the route for the synthesis of the D-gulodiastereoisomer
of 1-deoxyhomonojirimycin.
Exp er im en ta l Section
Mon osilyla tion of th e C2-Sym m etr ic Diol To P r od u ce
th e Tr is-O-P r otected Tetr ol. A 60% NaH dispersion in
mineral oil (1.09 g, 27 mmol) was placed in an argon-flushed
0.20 L flask and washed with dry hexanes. The oil-free hydride
was suspended in dry THF (10 mL), and the reaction vessel
was placed in a dry ice/acetone bath. A solution of the bis-O-
protected tetrol (5.2 g, 25.5 mmol) in THF (40 mL) was added
under argon with stirring. A moderate gas evolution was
observed, and the reaction mixture turned into a thick slurry.
The cooling bath was removed, and the reaction mixture was
allowed to reach room temperature with vigorous stirring. For
a brief period of time, the reaction mixture became much less
viscous and then almost completely solidified. This was diluted
with dry THF (60 mL), and the resulting slurry was stirred
at room temperature for 1 h. A solution of tert-butyldimeth-
ylchlorosilane (3.84 g, 25.5 mmol) in dry THF (20 mL) was
slowly added. A moderately exothermic reaction took place,
and within 5 min the reaction mixture became homogeneous.
The resulting cloudy mixture was stirred further at room
temperature for 2.5 h, then poured onto Et2O (350 mL), washed
with 10% w/w aq K2CO3 (20 mL) and brine, and dried over
anhyd MgSO4. The solvent removal produced a cloudy yellow-
ish liquid (9 g), which was purified by distillation under
reduced pressure to afford the title compound as a colorless
oil (7.50 g). Yield: 93%. [R]22D: +8.7 (c 3.9, CHCl3) [lit.11 [R]22
:
D
+3.54 (c 3.9, CHCl3)]. 1H NMR (CDCl3, 300 MHz) δ: 4.02-
3.60 (m, 6H), 2.30 (bs, 1H), 1.60 (bs, 8H), 1.44-1.32 (m, 2H),
0.89 (s, 9H), 0.08 (s, 6H). 13C NMR (CDCl3, 75 MHz) δ: 109.6,
79.8, 77.8, 63.9, 62.9, 36.7, 36.5, 25.9, 25.2, 24.0, 23.9, 18.2,
-5.3. FT-IR (film): 3462, 2934, 2858, 1472, 1463, 1449, 1364,
1254, 1097, 837, 778 cm-1. HRMS (FAB+, m/z): calcd for
a
Reagents and conditions: (i) KF, MeOH, rfx; (ii) Cr(CO)5-
C
C
16H32O4Si (M+), 316.2070; found, 316.2073. Anal. Calcd for
16H32O4Si: C, 60.76; H, 10.13. Found: C, 60.56; H, 9.89.
Dess-Ma r t in Oxid a t ion of t h e L-Ta r t r a t e-Der ived
(THF) or Mo(CO)5(THF), THF, 25 °C; (iii) catalyst Pd(OAc)2,
catalyst CuCl2, wet DMF, air, 25 °C; (iv) Scheme 1; (v) Dess-
Martin periodanane, CH2Cl2, 25 °C; (vi) H2, catalyst Pd/C, catalyst
CSA.
Alcoh ol To P r od u ce th e Ald eh yd e 5. To a stirred solution
of the alcohol (4.74 g, 15.0 mmol) in dry CH2Cl2 (120 mL) was
added Dess-Martin periodanane (8.27 g, 19.5 mmol) in one
portion at room temperature. The reaction progress was
monitored by TLC [hexanes/EtOAc (9:1); alcohol, Rf 0.2;
aldehyde 5, Rf 0.3]. The reaction mixture was poured into a
vigorously stirred mixture of saturated aq NaHCO3 (120 mL),
saturated aq Na2S2O3 (120 mL), and CH2Cl2 (120 mL). Once
an organic layer became clear, it was separated and set aside.
The aqueous layer was extracted with CH2Cl2 (500 mL).
Combined organic solutions were dried over anhyd MgSO4 and
stripped in vacuo. Flash chromatography [140 g of silica, eluted
with hexanes/Et2O (8:2 f 1:1)] afforded pure 5 as a clear
viscous liquid (3.9 g). Yield: 83%. [R]22D: +5.7 (c 2.5, CHCl3).
1H NMR (CDCl3, 300 MHz) δ: 9.75 (s, 1H), 4.30 (dd, J 1 ) 1
Hz, J 2 ) 6.9 Hz, 1H), 4.11 (dt, J 1 ) 4.5 Hz, J 2 ) 6.9 Hz, 1H),
3.98-3.80 (m, 1H), 3.78 (d, J ) 4.5 Hz, 1H), 1.80-1.30 (m,
10H), 0.88 (s, 9H), 0.06 (s, 3H), 0.05 (bs, 3H). 13C NMR (CDCl3,
75 MHz) δ: 200.9, 112.0, 81.7, 77.1, 63.1, 36.5, 35.8, 26.0, 25.9,
25.0, 23.9, 23.8, 18.4, -5.2, -5.3. FT-IR (film): 3443, 2934,
2857, 1736, 1472, 1463, 1449, 1364, 1254, 1144, 1098, 837
cm-1. HRMS (FAB+, m/z): calcd for C16H31O4Si (M + H+),
315.1992; found, 315.1979.
amounts of palladium(II) were used. The chromium and
molybdenum carbonyl catalyzed cyclization of homopro-
pargyl alcohols of McDonald was also attempted.18 In this
case, no reaction was observed under a variety of condi-
tions. Thus, the hydroboration/oxidation sequence in
Scheme 1 provided the most efficient route from 13 to
14.
Dess-Martin oxidation of the primary alcohol to the
aldehyde went well, providing 15 in excellent yield. The
protecting groups in 15 were chosen to be removed under
conditions suitable for the reductive amination of alde-
hydes, with the hope that the free amino aldehyde 16
(Scheme 2) would spontaneously cyclize to the imine and
reduce to the desired bicyclic lactone. This would shorten
the synthesis by three steps. However, the hydrogenation
was very sluggish and resulted in a mixture of products,
none of which contained the piperidine ring. Thus, this
route was abandoned.
Lew is Acid Ca ta lyzed Ad d ition of th e Allen ylsta n n a n e
4 to th e Ald eh yd e 5 To P r od u ce th e Hom op r op a r gylic
Alcoh ol 6. The allenylstannane 4 (6.38 g, 10.0 mmol) and
freshly prepared aldehyde 5 (3.50 g, 11.1 mmol) were combined
in a 100 mL Schlenk flask under argon. Dry CH2Cl2 (50 mL)
was added, and the resulting orange solution was cooled to
-78 °C under argon. Neat BF3‚Et2O (5.6 mL, 44 mmol) was
added dropwise over a period of 25 min (the first few drops
In conclusion, an efficient synthesis of 1-deoxy-D-galac-
tohomonojirimycin has been achieved in 48% overall yield
from the literature starting materials. The synthesis is
based on newly developed allenylstannane chemistry
(18) McDonald, F. E. Chem. Eur. J . 1999, 5, 3103 and references
therein.
J . Org. Chem, Vol. 69, No. 7, 2004 2231

Achmatowicz and Hegedus
caused the solution to turn dark greenish and then dark
orange). The reaction mixture was stirred between -75 and
-70 °C for 48 h and then quickly poured into a vigorously
stirred ice-cold mixture of CH2Cl2 (400 mL), saturated aq
NaHCO3 (200 mL), and water (200 mL). An additional portion
of CH2Cl2 (100 mL) was used to rinse the Schlenk flask. The
resulting heterogeneous mixture was stirred for an additional
15 min while slowly reaching room temperature. The layers
were separated, and the aqueous layer was extracted with
CH2Cl2. The combined organic solutions were washed with
saturated aq NaHCO3 and brine and dried over anhyd MgSO4.
Solvent removal under reduced pressure afforded a clear
orange oil (10 g). Flash chromatography [300 g of silica, eluted
with hexanes/Et2O (8:2 f 65:35)] afforded 6 as a cream-colored
crystalline solid (5.0 g). Mixed fractions were chromatographed
again to give an additional portion of pure 6 (0.7 g). X-ray
quality crystals (long thin plates) were obtained by recrystal-
lization from Et2O/hexanes (slow evaporation). Yield: 86%.
0.15 (s, 6H). 13C NMR (CDCl3, 100 MHz) δ: 175.5, 159.2, 134.7,
134.3, 128.4, 128.3, 128.1, 127.8, 125.9, 110.2, 80.8, 80.4, 78.3,
74.3, 65.4, 64.3, 53.0, 36.5, 36.2, 34.0, 25.9, 25.0, 23.7, 23.6,
18.4, -5.4. FT-IR (film): 2933, 2857, 1733, 1718, 1457, 1418,
1362, 1252, 1116, 837 cm-1. HRMS (FAB+, m/z): calcd for
C
34H48NO8Si (M + H+), 626.3149; found, 626.3148. Anal. Calcd
for C34H47NO8Si: C, 65.28; H, 7.52; N, 2.24. Found: C, 65.32;
H, 7.46; N, 2.36.
La cton iza tion of th e γ-Hyd r oxyca r boxylic Acid 7 To
P r od u ce th e La cton e 8. A mixture of the γ-hydroxycarboxy-
lic acid 7 (0.85 g, 1.36 mmol) and the Mukaiyama reagent (2-
chloro-1-methylpyridinium iodide) (0.70 g, 2.7 mmol) was
dissolved in dry CH2Cl2 (34 mL). The resulting yellow suspen-
sion was stirred and treated with Et3N (0.76 mL, 5.4 mmol)
at room temperature. Within 10 min after the addition, no
starting material could be detected by TLC. The reaction
mixture was poured into a mixture of Et2O (150 mL) and
CH2Cl2 (50 mL). The resulting yellowish opaque mixture was
washed with saturated aq NaHCO3 (resulting in almost
complete decolorization of both layers) and brine. The layers
were separated, and the aqueous layer was extracted with
CH2Cl2 (50 mL). Combined organic solutions were dried over
anhyd MgSO4 and concentrated to produce an orange oil.
Flash chromatography (45 g of silica, eluted with Et2O)
afforded 8 as an off-white foam, which was further recrystal-
lized from CH2Cl2/hexanes (0.82 g). Yield: 99%. Mp: 187 °C
(Et2O). [R]22D:+10.9 (c 1.95, CHCl3). 1H NMR (CDCl3, 400 MHz)
δ: 7.16-7.06 (m, 6H), 6.99-6.80 (m, 4H), 5.89 (d, J ) 7.6 Hz,
1H), 5.07 (d, J ) 7.6 Hz, 1H), 5.07-4.99 (m, 1H), 4.63 (dd, J 1
) 6.0 Hz, J 2 ) 9.2 Hz, 1H), 4.39 (dd, J 1 ) 7.6 Hz, J 2 ) 8.8 Hz,
1H), 4.18-4.13 (m, 1H), 3.97 (dd, J 1 ) 2.4 Hz, J 2 ) 11.6 Hz,
1H), 3.85 (dd, J 1 ) 2.8 Hz, J 2 ) 11.6 Hz, 1H), 2.40-2.26 (ABX,
7 lines, 2H), 1.82-1.60 (m, 8H), 1.54-1.32 (m, 2H), 0.96 (s,
9H), 0.13 (s, 3H), 0.12 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ:
172.3, 157.7, 135.0, 133.5, 128.7, 128.5, 128.0, 127.8, 125.9,
111.1, 82.0, 81.1, 80.4, 72.2, 64.7, 62.1, 51.4, 36.8, 36.6, 31.2,
26.0, 25.1, 23.9, 23.8, 18.4, -5.1, -5.3. FT-IR (film): 2932,
1
Mp: 113-114 °C (pentane). [R]22D: -46.0 (c 1.70, CHCl3). H
NMR (CDCl3, 400 MHz) δ: 7.11-7.03 (m, 6H), 6.92-6.88 (m,
4H), 5.80 (d, J ) 8.0 Hz, 1H), 5.37 (d, J ) 8.0 Hz, 1H), 4.81 (d,
J ) 4.0 Hz, 1H), 4.22 (d, J ) 5.6 Hz, 1H), 4.11-4.06 (m, 4
lines, 2H), 3.97-3.89 (m, 6 lines, 2H), 3.77 (dd, J 1 ) 5.2 Hz,
J 2 ) 10.8 Hz, 1H), 1.67-1.56 (m, 8H), 1.45-1.37 (m, 2H), 0.95
(s, 9H), 0.14 (s, 3H), 0.13 (s, 3H), -0.08 (s, 9H). 13C NMR
(CDCl3, 100 MHz) δ: 158.6, 134.6, 134.2, 128.0, 127.9, 127.8,
126.2, 110.1, 98.5, 92.7, 81.1, 79.8, 77.7, 74.3, 65.1, 64.2, 49.7,
36.7, 36.3, 25.9, 25.1, 23.9, 23.8, 18.4, -0.44, -5.4. FT-IR
(film): 3396, 2933, 2857, 2180, 1739, 1455, 1407, 1250, 843
cm-1. Anal. Calcd for C37H53NO6Si2: C, 66.97; H, 7.99; N, 2.11.
Found: C, 67.12; H, 7.91; N, 2.11.
Hyd r obor a tion /Oxid a tion of th e Hom op r op a r gylic
Alcoh ol 6 To P r od u ce th e γ-Hyd r oxyca r boxylic Acid 7.
To a stirred solution of cyclohexene (5.0 mL, 50 mmol) in dry
THF (24 mL) was slowly added 1.0 M BH3‚THF (25 mL, 25
mmol) at 0 °C. The reaction mixture was allowed to reach room
temperature, while dicyclohexylborane started to precipitate
from the solution. The stirring was continued for 1 h at room
temperature. The resulting dicyclohexylborane suspension was
cooled to -15 °C under argon, and a solution of 6 (3.10 g, 4.65
mmol) in dry THF (48 mL) was added dropwise with a
concominant gas evolution. The resulting mixture was allowed
to reach room temperature, and the stirring was continued
until the reaction mixture became clear (ca. 1 day). This was
placed in an ice bath, and a solution of NaHCO3 (8.4 g, 0.10
mol) and 30% aq H2O2 (19 mL) in water (50 mL) was carefully
added with efficient stirring so that the internal temperature
was kept below 15 °C. Once the exothermic reaction was over,
the cooling bath was removed, and the reaction mixture was
stirred for an additional 3 h at room temperature. Most of the
THF was removed under reduced pressure. The resulting
aqueous slurry was taken-up in CH2Cl2, and the aqueous layer
was adjusted to pH 6-7 by adding small portions of saturated
aq NH4Cl, with occasional stirring between additions. The
organic layer was separated and set aside. The aqueous layer
was extracted with CH2Cl2 (100 mL). The organic portions
(cloudy) were combined and concentrated under vacuum to
approximately half the original volume and then stirred
vigorously for several minutes with a saturated aqueous
solution of NaHCO3 (0.6 g). The resulting cloudy mixture was
treated with silica, and the solvent was removed under reduced
pressure. The silica, loaded with a crude mixture, was trans-
ferred onto a column (100 mg of silica, Et2O) and eluted with
Et2O until all of the cyclohexanol came off. The γ-hydroxycar-
boxylic acid was eluted using a mixture of Et2O/MeOH/AcOH
(90:10:1), affording pure 7 as a colorless foam (2.57 g). Yield:
88%. Mp: 108-110 °C (AcOH). [R]22D: -3.8 (c 1.7, CHCl3). 1H
NMR (CDCl3, 400 MHz) δ: 7.13-6.92 (m, 10H), 5.84 (d, J )
8.0 Hz, 1H), 5.37 (d, J ) 8.0 Hz, 1H), 4.73 (bs, 1H), 4.38 (d, J
) 4.0 Hz, 1H), 4.02 (dd, J 1 ) 6.0 Hz, J 2 ) 10.4 Hz, 1H), 3.95-
3.82 (m, 7 lines, 2H), 2.82-3.68 (m, 2H), 2.74-2.56 (ABX, 8
lines, 2H), 1.58-1.45 (m, 8H), 1.40-1.25 (m, 2H), 0.97 (s, 9H),
2856, 1792, 1762 cm-1. HRMS (FAB+, m/z): calcd for C34H46
NO7Si (M + H+), 608.3044; found, 608.3057. Anal. Calcd for
34H45NO7Si: C, 67.22; H, 7.41; N, 2.31. Found: C, 67.10; H,
-
C
7.28; N, 2.23.
Hyd r ogen a tion of th e Dip h en yloxa zolid in on e Moiety
in 8 To P r od u ce th e NHBoc La cton e (9). The lactone 8
(169 mg, 0.278 mmol), Boc2O (0.12 g, 0.55 mmol), Pearlman’s
catalyst (wet 20% Pd(OH)2, 0.10 g, 0.14 mmol), and EtOAc (6
mL) were combined under argon in a thick-walled glass tube.
The tube was fitted with a pressure head, flushed several times
with hydrogen, and then pressurized to 80 psi H2. The reaction
mixture was stirred vigorously at room temperature with
occasional flushing/repressurizing with H2. Reaction progress
was monitored by TLC [hexanes/Et2O (1:1); 8, Rf 0.1; 9, Rf 0.3].
The catalyst was removed by passing the reaction mixture
through a Celite pad followed by thorough rinsing with THF.
Flash chromatography of the concentrated filtrates [9 g of
silica, eluted with hexanes/Et2O (6:4)] afforded pure 9 as a
colorless crystalline solid (135 mg). Yield: 99%. Mp: 99-100
°C (Et2O/hexanes). [R]22D: -4.6 (c 2.8, CHCl3). 1H NMR (CDCl3,
400 MHz) δ: 5.87 (bs, 1H), 4.68-4.55 (m, 1H), 4.58 (q, J )
5.6 Hz, 1H), 4.25 (dd, J 1 ) 5.6 Hz, J 2 ) 8.0 Hz, 1H), 4.00 (qt,
J ) 4.4 Hz, 1H), 3.83-3.73 (ABX, 8 lines, 2H), 2.86 (dd, J 1
)
7.4 Hz, J 2 ) 17.6 Hz, 1H), 2.60 (dd, J 1 ) 6.0 Hz, J 2 ) 17.6 Hz,
1H), 1.69-1.54 (m, 8H), 1.44 (s, 9H), 1.44-1.32 (m, 2H), 0.88
(s, 9H), 0.07 (s, 6H). 13C NMR (CDCl3, 100 MHz) δ: 173.9,
155.1, 111.0, 80.1, 79.5, 78.7, 75.7, 63.3, 49.3, 36.6, 36.0, 28.3,
25.9, 24.9, 23.9, 23.7, 18.3, -5.4, -5.5. FT-IR (film): 3360,
2934, 2857, 1792, 1716, 1519, 1366, 1252, 1166, 837 cm-1
.
HRMS (FAB+, m/z): calcd for C24H44NO7Si (M + H+), 486.2887;
found, 486.2876. Anal. Calcd for C24H43NO7Si: C, 59.38; H,
8.87; N, 2.89. Found: C, 59.46; H, 8.68; N, 2.87.
Desilyla tion of 9 To P r od u ce th e P r im a r y Alcoh ol 10.
To a solution of the silyl ether 9 (1.30 g, 2.68 mmol) in MeCN
(80 mL) was added HF‚Py (1.3 mL) dropwise at room temper-
2232 J . Org. Chem., Vol. 69, No. 7, 2004

Synthesis of 1-Deoxy-D-galactohomonojirimycin
ature. The resulting mixture was stirred at room temperature
until TLC showed only a minor spot corresponding to the
starting material [hexanes/EtOAc (6:4); silyl ether 9, Rf 0.6;
alcohol 10, Rf 0.2]. The reaction mixture was diluted with
CH2Cl2 (500 mL) and washed with saturated aq NaHCO3 (100
mL), followed by brine. The aqueous layer was extracted with
CH2Cl2 (100 mL). Organic layers were combined, dried over
anhyd MgSO4, and concentrated under reduced pressure. Most
of the pyridine was removed under high vacuum at room
temperature. Flash chromatography [70 g of silica, eluted with
hexanes/EtOAc (65:35 f 1:1)] afforded pure 10 as a colorless
foam (916 mg). Yield: 99% (on the basis of the recovered
THF. The filtrates were concentrated under reduced pressure
and chromatographed [30 g of silica, eluted with CH2Cl2/EtOAc
(7:3 f 4:6)] to afford pure 12 as a colorless crystalline solid
(414 mg) along with the intermediate lactol (47 mg). The
recovered lactol was reduced under the same conditions
providing an additional amount of 12 (34 mg). Yield: 89%.
Mp: 168-169 °C (CH2Cl2/hexanes). [R]22D: +41 (c 0.85, MeOH).
1H NMR (CDCl3, 400 MHz) δ: 4.53-4.44 (m, 2H), 4.14-4.05
(m, 9 lines, 1H), 3.78 (dd, J 1 ) 6.4 Hz, J 2 ) 12.0 Hz, 1H), 3.74-
3.66 (m, 1H), 3.60 (dd, J 1 ) 3.6 Hz, J 2 ) 9.6 Hz, 1H), 3.53-
3.44 (m, 2H), 2.97 (bs, 1H), 2.50 (bs, 1H), 2.19-2.09 (m, 8 lines,
1H), 1.85-1.77 (m, 10 lines, 1H), 1.74-1.58 (m, 8H), 1.46 (s,
9H), 1.46-1.38 (m, 2H). 13C NMR (CDCl3, 100 MHz) δ: 156.7,
113.3, 81.0, 78.7, 68.3, 64.6, 59.1, 53.0, 47.4, 36.8, 36.2, 32.3,
28.3, 24.9, 23.8, 23.7. FT-IR (film): 3446, 2935, 2865, 1683,
1669, 1418, 1366, 1163, 1144, 1117 cm-1. HRMS (FAB+, m/z):
calcd for C18H32NO6 (M + H+), 358.2230; found, 358.2221. Anal.
Calcd for C18H31NO6: C, 60.50; H, 8.68; N, 3.92. Found: C,
60.70; H, 8.53; N, 4.16.
starting material). [R]22
:
-13.1 (c 3.1, CHCl3). 1H NMR
D
(CDCl3, 400 MHz) δ: 5.49 (bs, 1H), 4.66-4.56 (m, 1H), 4.48
(t, J ) 6.8 Hz, 1H), 4.15-4.09 (m, 2H), 3.94-3.88 (m, 1H),
3.74-3.67 (m, 1H), 2.92 (dd, J 1 ) 8.0 Hz, J 2 ) 18.0 Hz, 1H),
2.58 (dd, J 1 ) 6.0 Hz, J 2 ) 18.0 Hz, 1H), 1.90 (dd, J 1 ) 4.4 Hz,
J 2 ) 8.4 Hz, 1H), 1.69-1.54 (m, 8H), 1.45 (s, 9H), 1.44-1.33
(m, 2H). 13C NMR (CDCl3, 75 MHz) δ: 174.0, 155.0, 110.8,
81.0, 79.8, 73.2, 61.8, 49.1, 36.4, 36.3, 35.5, 28.3, 24.9, 23.8.
FT-IR (film): 3376, 2936, 2864, 1787, 1699, 1525, 1367, 1166,
1116, 1027 cm-1. HRMS (FAB+, m/z): calcd for C18H30NO7 (M
+ H+), 372.2022; found, 372.2030. Anal. Calcd for C18H29NO7:
C, 58.22; H, 7.82; N, 3.77. Found: C, 58.32; H, 7.58; N, 3.66.
Rem ova l of th e N-Boc/O,O-Dicycloh exylk eta l P r otect-
in g Gr ou p s in 12 To P r od u ce 1-Deoxy-5-h om oga la c-
ton ojir im ycin Hyd r och lor id e (3). A solution of the N-Boc
ketal 12 (114 mg, 0.319 mmol) in MeOH (15 mL) was treated
with 1.4 M HCl in MeOH (6.5 mL, 9.0 mmol) and allowed to
stand at room temperature overnight. Volatiles were removed
under reduced pressure, and the oily residue recrystallized
from MeOH/Et2O to afford pure 3 as thin plates (64 mg).
Yield: 94%. Mp: 167.5-168.5 °C (MeOH/Et2O). [R]22D: +24.8
Mitsu n obu Cycliza tion of th e N-Boc-P r otected Am in o
Alcoh ol 10 To P r od u ce th e P ip er id in e 11a . A stirred
solution of triphenylphosphine (98 mg, 0.37 mmol) in dry THF
(1.5 mL) was treated with neat DEAD (46 µL, 0.29 mmol) at
-20 °C under argon, and the resulting solution was kept at
-15 °C for 20 min. The resulting pale yellow zwitterion
solution was transferred using an additional portion of the dry
THF (0.5 mL) into a solution of the amino alcohol 10 (73 mg,
0.195 mmol) in dry THF (6.0 mL) at -20 °C. The reaction
mixture was allowed to reach room temperature, and its
progress was monitored by TLC [hexanes/Et2O (2:8); amino
alcohol 10, Rf 0.2; piperidine 11a , Rf 0.6]. Once no further
progress could be observed (3-5 h), a drop of water was added,
and the reaction mixture was concentrated under reduced
pressure. The residue was dissolved in a minimal amount of
CH2Cl2 followed by a dilution with hexanes to effect the
precipitation of a 1,2-dicarbethoxyhydrazine, which was sub-
sequently removed by filtration. The crude mixture was loaded
onto silica by concentrating it together with a dichloromethane/
silica slurry under reduced pressure. Flash chromatography
[5 g of silica, eluted with hexanes/EtOAc (7:3)] afforded pure
11a as a colorless crystalline solid (57 mg). Yield: 82%. Mp:
173-174 °C (Et2O/hexanes). [R]22D: +42 (c 1.2, CHCl3). 1H
NMR (CDCl3, 400 MHz) δ: 5.08 (dd, J 1 ) 3.2 Hz, J 2 ) 7.6 Hz,
1H), 4.83-4.78 (m, 6 lines, 1H), 4.83-4.77 (m, 6 lines, 2H),
3.69 (dd, J 1 ) 3.6 Hz, J 2 ) 10.0 Hz, 1H), 3.38-3.31 (m, 7 lines,
1
(c 1.00, MeOH). H NMR (D2O, 400 MHz) δ: 4.15 (d, J ) 2.0
Hz, 1H), 4.12-4.04 (m, 1H), 3.84-3.72 (m, 1H), 3.67 (dd, J 1
)
3.2 Hz, J 2 ) 9.6 Hz, 1H), 3.50 (AB, J AB ) 5.6 Hz, ∆δAB ) 9.0
Hz, 2H), 3.37 (s, 1H), 2.91 (t, J ) 12 Hz, 1H), 2.04-1.92 (m,
2H). 13C NMR (D2O, 100 MHz) δ: 73.2, 68.4, 64.5, 57.8, 57.3,
46.5, 30.7. FT-IR (film): 3357, 2958, 2825, 2525, 1077, 1024
cm-1. Anal. Calcd for C7H16NO4Cl: C, 39.34; H, 7.49; N, 6.56;
Cl, 16.63. Found: C, 39.70; H, 7.09; N, 6.25; Cl, 16.98.
N-Boc La cton e Diol 11b. 11b was recrystallized from
EtOAc/hexanes. The molecular structure was confirmed by
X-ray analysis. Mp: 175 °C (dec). 1H NMR (CD3CN, 400 MHz)
δ: 4.98 (q, J ) 9.2 Hz, 1H), 4.65 (dd, J 1 ) 4.0 Hz, J 2 ) 8.0 Hz,
1H), 3.98 (q, J ) 4.4 Hz, 1H), 3.86-3.78 (m, 5 lines, 2H), 3.65
(d, J ) 5.2 Hz, 1H), 2.63 (d, J ) 13.6 Hz, 1H), 3.20 (d, J ) 4.4
Hz, 1H), 2.64-2.41 (ABX, 8 lines, 2H), 1.44 (s, 9H). FT-IR
(film): 3420, 2977, 2931, 1772, 1670, 1418, 1367, 1161 cm-1
.
LRMS (FAB+, m/z): 274 (M + H+).
Lew is Acid Ca ta lyzed Con d en sa tion To P r od u ce th e
Hom op r op a gylic Alcoh ol 13. To a solution of freshly pre-
pared aldehyde (2.96 g, 7.15 mmol) in dry CH2Cl2 (7 mL) was
added a solution of the allenylstannane 4 (3.42 g, 5.36 mmol)
in dry CH2Cl2 (20 mL) at -70 °C under argon. To the resulting
orange solution was added dropwise BF3‚Et2O (3.6 mL, 28
mmol) with good stirring over a period of 20 min. The stirring
was continued at -70 °C for 25 h, and then the reaction
mixture was quenched by a quick addition of saturated aq
NaHCO3 (25 mL), followed by an addition of CH2Cl2 (150 mL).
The resulting slurry was stirred vigorously while it was
allowed to warm slowly. The organic layer changed color from
orange to light yellow upon reaching room temperature. The
layers were separated, and the aqueous layer was extracted
once with CH2Cl2 (100 mL). Combined organic solutions were
washed with brine and dried over anhyd MgSO4, and the
solvent was removed under reduced pressure to afford 6.8 g
of a yellowish semisolid. The crude material was loaded onto
silica by concentrating a CH2Cl2 soln/silica slurry and chro-
matographed [100 g of silica, eluted with hexanes/Et2O (8:2
f 1:1)] to afford pure 13 as a colorless oil (3.58 g). Yield: 90%.
1H NMR (CDCl3) δ: 7.42-7.24 (m, 10H), 7.10-7.00 (m, 6H),
6.94-6.86 (m, 4H), 5.77 (d, J ) 7.5 Hz, 1H), 5.26 (d, J ) 7.5
Hz, 1H), 5.10 (d, J ) 6 Hz, 1H), 4.80-4.64 (m, 3H), 4.53 (d, J
) 11.4 Hz, 1H), 4.2-4.1 (m, 2H), 3.98-3.86 (m, 2H), 3.86-
3.76 (m, 2H), 0.91 (s, 9H), 0.07 (s, 6H), -0.19 (s, 9H). 13C NMR
(CDCl3) δ: 158.3, 137.7, 137.5, 135.4, 134.1, 128.4, 128.3, 128.1,
1H), 3.01 (dd, J 1 ) 8.8 Hz, J 2 ) 19.2 Hz, 1H), 2.67 (dd, J 1
)
2.8 Hz, J 2 ) 19.2 Hz, 1H), 1.77-1.56 (m, 8H), 1.46 (s, 9H),
1.44-1.38 (m, 2H). 13C NMR (CDCl3, 100 MHz) δ: 174.8, 155.3,
113.8, 94.4, 81.5, 74.5, 67.5, 51.8, 47.7, 36.8, 36.4, 35.9, 28.2,
24.8, 23.7, 23.6. FT-IR (film): 2974, 2936, 2864, 1788, 1695,
1365, 1160, 1122 cm-1. HRMS (FAB+, m/z): calcd for C18H28
-
NO6 (M + H+), 354.1917; found, 354.1939. Anal. Calcd for
18H27NO6: C, 61.19; H, 7.65; N, 3.97. Found: C, 61.32; H,
C
7.50; N, 3.84.
Red u ctive Op en in g of th e La cton e Rin g in 11a To
P r od u ce th e P ip er id in ed iol 12. To a solution of the lactone
11a (500 mg, 1.42 mmol) in dry THF (20 mL) cooled to -20
°C was added portionwise (0.50 mL each) ca. 1 M LiAlH4 in
THF (2.5 mL, 2.5 mmol). Once no further reaction progress
could be observed [TLC; hexanes/EtOAc (1:1)] and most of the
starting material (Rf 0.7) converted into the lactone 12 (Rf 0.2),
leaving just a small amount of the intermediate lactol (Rf 0.4),
the reaction mixture was quenched with EtOAc (0.3 mL)
followed by a careful addition of Na2SO4‚10H2O at -20 °C.
When the vigorous bubbling ceased, the reaction mixture was
allowed to reach room temperature. The resulting slurry was
passed through a Celite pad followed by thorough rinsing with
J . Org. Chem, Vol. 69, No. 7, 2004 2233

Achmatowicz and Hegedus
127.9, 127.8, 127.6, 127.5, 126.1, 99.6, 92.1, 80.1, 79.8, 76.1,
73.7, 73.3, 72.5, 63.6, 62.1, 48.5, 26.0, -0.5, -5.3.
reduced pressure. Flash chromatography [hexanes/EtOAc (7:3
f 1:1)] afforded pure 15 as a cloudy oil (19 mg). Yield: 80%.
1H NMR (CDCl3) Complex: see the Supporting Information.
13C NMR (CDCl3) δ: 201.6, 172.7, 158.2, 136.8, 136.5, 135.2,
133.1, 128.9, 128.7, 128.6, 128.5, 128.4, 127.6, 127.5, 125.7,
99.8, 83.0, 81.4, 80.5, 78.3, 76.1, 74.5, 64.0, 60.4, 51.7, 32.9,
29.5, 21.1, 14.3.
La cton iza tion of th e Hom op r op a r gylic Alcoh ol 13 To
P r od u ce th e Hyd r oxy La cton e 14. A solution of the alcohol
13 (38 mg, 50 µmol), CuCl2‚2H2O (2.1 mg, 25 mol %), and
Pd(OAc)2 (1.2 mg, 10 mol %) in wet DMF (1% water, 0.50 mL)
was stirred at room temperature under air atmosphere for 2
days. The solvent was removed under reduced pressure with
gentle warming. The orange residue was taken-up in CH2Cl2/
Et2O (10:1) and washed with water. The organic layer was
dried over anhyd MgSO4 and concentrated in vacuo. Flash
chromatography [hexanes/EtOAc (1:1)] afforded 14 as an off-
white solid (14 mg). Yield: 47%. 1H NMR (CDCl3) Complex:
see the Supporting Information. 13C NMR (CDCl3) δ: 173.4,
158.5, 137.7, 136.7, 133.1, 129.4, 128.8, 128.6, 128.4, 128.4,
128.2, 128.1, 127.5, 127.4, 125.6, 82.5, 81.4, 80.7, 79.7, 76.5,
72.6, 63.6, 60.1, 51.6, 32.8, 29.5.
Ack n ow led gm en t. Support for this research under
Grant GM26178 from the National Institutes of Health
is gratefully acknowledged. Mass spectra were obtained
on instruments supported by the National Institutes of
Health under the shared instrumentation Grant GM
49631. The cover photograph was provided by Dr. J armo
Holopainen, Department of Ecology and Environmental
Science, University of Kuopio, Finland.
Dess-Ma r tin Oxid a tion of th e Alcoh ol 14 To P r od u ce
th e Ald eh yd e 15. To a stirred solution of the alcohol 14 (24
mg, 40 µmol) in dry CH2Cl2 (0.5 mL) was added Dess-Martin
periodanane (25 mg, 59 µmol) in one portion at room tem-
perature. The reagent went quickly into the solution. The
resulting mixture turned milky-white within 40 min. The
reaction progress was monitored by TLC [hexanes/EtOAc
(1:1); alcohol, Rf 0.2; aldehyde 3, Rf 0.4]. After 1.5 h, the
reaction mixture was diluted with Et2O and vigorously stirred
with a mixture of saturated aq NaHCO3 (1.25 mL) and
saturated aq Na2S2O3 (1.25 mL) until both layers became clear
(ca. 10 min). The organic layer was separated, washed with
brine, dried over anhyd MgSO4, and concentrated under
Note Ad d ed a fter ASAP P ostin g. The aldehyde
structure in the TOC graphic contained an error in the
version posted ASAP December 12, 2003; the corrected
version was posted February 11, 2004.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 5 and 13-15; X-ray structural data for 11b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0303012
2234 J . Org. Chem., Vol. 69, No. 7, 2004