De novo asymmetric synthesis of 8a-epi-swainsonine

Article abstract of DOI:10.1021/jo702476q

(Chemical Equation Presented) An enantioselective and diastereocontrolled approach to 8a-epi-D-swainsonine has been developed from achiral furfural. The key step to this synthesis was a one-pot procedure for the hydrogenolytic removal of two protecting groups and two intramolecular reductive amination reactions. The absolute stereochemistry was introduced by asymmetric Noyori reduction of furfuryl ketone. This route relies on diastereoselective palladium-catalyzed glycosylation to install the anomeric bond, and Luche reduction, diastereoselective dihydroxylation to set up the manno- stereochemistry of the indolizidine precursor.

Full text of DOI:10.1021/jo702476q

De Novo Asymmetric Synthesis of 8a-epi-Swainsonine
Jason N. Abrams, Ravula Satheesh Babu, Haibing Guo, Dianna Le, Jennifer Le,
Joshua M. Osbourn, and George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
george.odoherty@mail.wVu.edu
ReceiVed NoVember 18, 2007
An enantioselective and diastereocontrolled approach to 8a-epi-D-swainsonine has been developed from
achiral furfural. The key step to this synthesis was a one-pot procedure for the hydrogenolytic removal
of two protecting groups and two intramolecular reductive amination reactions. The absolute stereo-
chemistry was introduced by asymmetric Noyori reduction of furfuryl ketone. This route relies on
diastereoselective palladium-catalyzed glycosylation to install the anomeric bond, and Luche reduction,
diastereoselective dihydroxylation to set up the manno-stereochemistry of the indolizidine precursor.
Introduction
The indolizidine alkaloids widely occur in nature and have
attracted great interests for the synthetic chemists because of
their potent and wide range of biological activities.1 The
iminosugar natural product, (-)-swainsonine (1) (Figure 1), is
one of the most well-known members of the polyhydroxylated
indolizidine family. It was first isolated from the fungus
Rhizoctonia leguminicola2 and subsequently has also been found
in several other plant and fungal sources.3 Swainsonine has been
shown to be a potent inhibitor of both lysosomal R-D-
mannosidase4 and mannosidase II,5 which is also believed to
be its source of anticancer, antimetastatic, antitumor-prolifera-
tive, and immunoregulating activities.6 As part of an effort to
elucidate its interesting biological properties, there has been a
need for the syntheses of swainsonine,7 its enantiomer as well
as modified swainsonine derivatives. In particular, unnatural
FIGURE 1. (-)-Swainsonine (1) and (-)-8a-epi-swainsonine (2).
diastereomers of swainsonine have become attractive synthetic
targets. To date, over ten optically active diastereomers have
been reported.7a Several of these diastereomers demonstrated
comparable R-D-mannosidase inhibitory activity to (-)-swain-
sonine. For instance, 8a-epi-swainsonine (2) has also been shown
to be an effective inhibitor of lysosomal R-D-mannosidase, with
93% the activity of swainsonine (1).8
In contrast to the synthesis of swainsonine (1), there have
been only a few syntheses of 8a-epi-swainsonine (2).9 As part
of our program aimed at the synthesis and study of iminosugars,
we became interested in the synthesis of 8a-epi-swainsonine
(2), as well as its enantiomer. Previously, we reported our de
novo asymmetric approach to either enantiomer of swainsonine
and its epimer, 8-epi-swainsonine.7m,n The route to swainsonine
occurred in only 13 steps from achiral furan and γ-butyrolactone
6 (Scheme 1).7m This strategy relies on a one-pot global
hydrogenolysis/alkylation/reductive amination of azide sugar 3
to establish the indolizidine ring system and a regio-, diaste-
(1) (a) Michael, J. P. Nat. Prod. Rep. 2004, 19, 625-649. (b) Asano,
N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645-1680.
(2) (a) Guengerich, F. P.; DiMari, S. J.; Broquist, H. P. J. Am. Chem.
Soc. 1973, 95, 2055-2056. (b) Schneider, M. J.; Ungemach, F. S.; Broquist,
H. P.; Harris, T. M. Tetrahedron 1983, 39, 29-32.
(3) (a) Hino, M.; Nakayama, O.; Tsurumi, Y.; Adachi, K.; Shibata, T.;
Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1985, 38, 926-
935. (b) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J. Chem.
1979, 32, 2257-2264. (c) Molyneux, R. J.; James, L. F. Science 1982,
216, 190-191.
(4) Liao, Y. F.; Lal, A.; Moremen, K. W. J. Biol. Chem. 1996, 271,
28348-28358.
(5) (a) Elbein, A. D.; Solf, R.; Dorling, P. R.; Vosbeck, K. Proc. Natl.
Acad. Sci. U.S.A. 1981, 78, 7393-7397. (b) Kaushal, G. P.; Szumilo, T.;
Pastuszak, I.; Elbein, A. D. Biochemistry 1990, 29, 2168-2176. (c)
Pastuszak, I.; Kaushal, G. P.; Wall, K. A.; Pan, Y. T.; Sturm, A.; Elbein,
A. D. Glycobiology 1990, 1, 71-82.
(6) (a) White, S. L.; Schweitzer, K.; Humphries, M. J.; Olden, K.
Biochem. Biophys. Res. Commun. 1988, 150, 615-625. (b) Yagita, M.;
Saksela, E. Scand. J. Immunol. 1990, 31, 275-282. (c) Kino, T.; Inamura,
N.; Nakahara, K.; Kiyoto, S.; Goto, T.; Terano, H.; Kohsaka, M.; Aoki,
H.; Imanaka, H. J. Antibiot. 1985, 38, 936-940.
10.1021/jo702476q CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/01/2008
J. Org. Chem. 2008, 73, 1935-1940
1935

Abrams et al.
SCHEME 1. Retrosynthetic Analysis of (-)-Swainsonine (1)
SCHEME 2. Retrosynthetic Analysis of
(-)-8a-epi-Swainsonine (2)
reoselective palladium-catalyzed allylation to introduce the C-4
azide functional group.10 Herein we report the expansion of this
de novo approach to the synthesis of 8a-epi-swainsonine (2)
from achiral commercially available starting material furfural
12. The key to the synthesis is a stereoselective one-pot reductive
cyclization transformation to install the indolizidine system of
8a-epi-swainsonine (2).
Our related de novo approach to the synthesis of 8a-epi-
swainsonine (2) is outlined in Scheme 2. We envisioned that
the 8a-epi-swainsonine (2) could be derived from the protected
8a-epi-swainsonine 7. The indolizidine ring of 7 in turn could
be established from a one-pot reductive cyclization of acetonide
ketone 9 via an intermediate hemiacetal 8. The acetonide 9
would arise from diastereoselective palladium-catalyzed gly-
cosylation, dihydroxylation, and Luche reduction of Boc-
protected pyranone 10. Finally it was envisioned that pyranone
10 could be prepared from acylfuran 11, which in turn could
be prepared from commercially available furfural (12).
SCHEME 3. Synthesis of Furfuryl Alcohols
Results and Discussion
The synthesis of 8a-epi-swainsonine began with commercially
available furfural 12 (Scheme 3), which underwent Grignard
addition with allyl magnesium chloride to afford a racemic
homoallylic alcohol (()-13 in excellent yield (88%). The
(7) For a review of swainsonine syntheses, see: (a) Nemr, A. E.
Tetrahedron 2000, 56, 8579-8629. For more recent syntheses, see: (b)
Martin, R.; Murruzzu, C.; Pericas, M. A.; Riera, A. J. Org. Chem. 2005,
70, 2325-2328. (c) Heimgaertner, G.; Raatz, D.; Reiser, O. Tetrahedron
2005, 61, 643-655. (d) Song, L.; Duesler, E. N.; Mariano, P. S. J. Org.
Chem. 2004, 69, 7284-7293. (e) Lindsay, K. B.; Pyne, S. G. Aust. J. Chem.
2004, 57, 669-672. (f) Pearson, W. H.; Ren, Y.; Powers, J. D. Heterocycles
2002, 58, 421-430. (g) Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002,
67, 7774-7780. (h) Buschmann, N.; Rueckert, A.; Blechert, S. J. Org.
Chem. 2002, 67, 4325-4329. (i) Zhao, H.; Hans, S.; Cheng, X.; Mootoo,
D. R. J. Org. Chem. 2001, 66, 1761-1767. (j) Ceccon, J.; Greene, A. E.;
Poisson, J. F. Org. Lett. 2006, 8, 4739-4712. (k) Au, C. W. G.; Pyne, S.
G. J. Org. Chem. 2006, 71, 7097-7099. (l) Dechamps, I.; Pardo, D.; Cossy,
J. ARKIVOC 2007, 5, 38-45. (m) Guo, H.; O’Doherty, G. A. Org. Lett.
2006, 8, 1609-1612. (n) Guo, H.; O’Doherty, G. A. Tetrahedron 2008,
64, 304-313. (o) Dechamps, I.; Pardo, D. G.; Cossy, J. Tetrahedron 2007,
63, 9082-9091. For the first syntheses, see: (p) Mezher, H. A.; Hough,
L.; Richardson, A. C. J. Chem. Soc., Chem. Commun. 1984, 447-448. (q)
Fleet, G. W. J.; Gough, M. J.; Smith, P. W. Tetrahedron Lett. 1984, 25,
1853-1856.
secondary alcohol in (()-13 was protected as a TBS-ether
(TBSCl/Et3N) in good yield (74%), followed by a hydrobora-
tion-oxidation to give primary alcohol (()-14 (BH3 then
NaOOH) (70%). The primary alcohol in (()-14 was converted
into tosylate (()-15 (TsCl/pyridine/DMAP), which was subse-
quently displaced with sodium azide to yield azide (()-16 in
good yield for the two steps (53%). The two different N-
protected amino furan alcohols (()-19 and (()-20 were prepared
from azide (()-16 by a three-step approach involving azide
reduction/N-protection/TBS-deprotection. Azide (()-16 was
reduced with triphenylphosphine to generate a primary amine,
which was protected (Boc2O and CbzCl) in situ to provide both
the Boc-amide (()-17 (86%) and the Cbz-amide (()-18 (85%).
The amino furan alcohols (()-19 and (()-20 were eventually
obtained after TBS-deprotection with TBAF in excellent yields
((()-19: 86%; (()-20: 93%). This route was amenable to the
large-scale synthesis (>30 g) of the furan amino alcohols (()-
19 and (()-20.
(8) Cenci di Bello, I.; Fleet, G. W. J.; Namgoong, S. K.; Tadano, K.;
Winchester, B. Biochem. J. 1989, 259, 855-861.
(9) (a) Dudot, B.; Micouin, L.; Baussanne, I.; Royer, J. Synthesis 1999,
688-694. (b) Keck, G. E.; Romer, D. R. J. Org. Chem. 1993, 58, 6083-
6089. (c) Bi, J.; Aggarwal, V. K. Chem. Commun. 2008, 120-122. (d)
Kim, Y. G.; Cha, J. K. Tetrahedron Lett. 1989, 30, 5721-5724. (e) Tadano,
K.; Hotta, Y.; Morita, M.; Suami, T.; Winchester, B.; Cenci di Bello, I.
Bull. Chem. Soc. Jpn. 1987, 60, 3667-3671. (f) Tadano, K.; Hotta, Y.;
Morita, M.; Suami, T.; Winchester, B.; Cenci di Bello, I. Chem. Lett. 1986,
2105-2108.
(10) Kartika, R.; Taylor, R. E. Chemtracts: Org. Chem. 2007, 19, 385-
390.
1936 J. Org. Chem., Vol. 73, No. 5, 2008

Synthesis of 8a-epi-Swainsonine
SCHEME 4. Preliminary Studies toward the Synthesis of
SCHEME 5. Enantioselective Synthesis of Pyranone
Bicyclic C-4 Amino Sugar
SCHEME 6. Synthesis of Acetonide Ketone 9
We next turned our attention to the installation of the C-4
amino-functionality via an intramolecular allylation strategy
(Scheme 4). The racemic furfural alcohol (()-19 underwent
oxidative ring expansion to afford the hemiacetal (()-21 under
typical Achmatowicz conditions (NBS/NaOAc/H2O)11 in excel-
lent yield (93%). The anomeric alcohol in (()-21 was converted
to a mixture of benzyl protected pyranones (()-22â and (()-
22R in 1:1 ratio (BnBr/Ag2O, 65%). The diastereomers (()-
22â and (()-22R were easily separated by silica gel column
chromatography. Diastereoselective Luche reduction (NaBH4/
CeCl3)12 of R-pyranone (()-22R gave allylic alcohol (()-23,
followed by treatment with ethyl chloroformate to form carbon-
ate (()-24 in 39% yield for the two steps. Next we attempted
to cyclize the carbamate of (()-24 to form the bicyclic adduct
(()-25 via a palladium-catalyzed cyclization π-allyl intermedi-
ate. Unfortunately despite our survey of various conditions, we
were unable to find any sign of the desired product (()-25.13
Similar efforts to cyclize the allylic alcohol (()-23 into the C-4
diastereomer of (()-25 via an SN2 type displacement were
unsuccessful. Thus, we decided to investigate alternative
mechanistic approaches for the installation of the C-4 amino
group (vide infra).
excellent yield (91%) of furfuryl alcohol 20 in high enantiomeric
excess (>96% ee).15 Once again Achmatowicz reaction provided
the ring-expanded pyranone product 26 in good yield (92%).
The hemiacetal in 26 could be acylated with Boc2O to generate
the Boc-protected pyranones 10R and 10â with a diastereose-
lectivity of 7:1 (R/â) and good yield (80%).16
With pyranone 10R in hand, we next investigated the
synthesis of acetonide 9 via a sequence of reduction/protection/
oxidation reaction steps (Scheme 6). Diastereoselective pal-
ladium-catalyzed glycosylation of Boc-pyranone 10R with
Our revised approach to 8a-epi-swainsonine (2) began with
our efforts to install asymmetry into the pyranone 10R, via an
oxidation/asymmetric reduction sequence. Because of our previ-
ous success in our swainsonine (1) synthesis,7m we turned to
the Noyori reduction of 11 (Scheme 5). Thus, racemic furfuryl
alcohol (()-20 was oxidized to give furfuryl ketone 11 with
MnO2 oxidation in excellent yield (90%). Exposure of the
furfuryl ketone 11 to the Noyori conditions14 afforded an
(11) (a) Achmatowicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165-
176. For its recent use in carbohydrate synthesis, see: (b) Guo, H.;
O’Doherty, G. A. Org. Lett. 2005, 7, 3921-3924.
(12) (a) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226-2227. (b)
Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401-404.
(13) Although these efforts to install the C-4 amino-group functionality
via intramolecular cyclization were unsuccessful, the intramolecular azide
displacement was very successful and led to the synthesis of swainsonine,
see ref 7m.
(15) The absolute stereochemistry and the level of enantioexcess of 20
were determined by the method of Mosher, see: (a) Sullivan, G. R.; Dale,
J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143-2147. (b) Yamaguchi,
S.; Yasuhara, F.; Kabuto, K. T. Tetrahedron 1976, 32, 1363-1367.
(16) The relative stereochemistry and the level of diastereoselective
induction were determined by analysis of the allylic coupling constants in
1
the H NMR, see: (a) Babu, R. S.; Guppi, S. R.; O’Doherty, G. A. Org.
(14) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521-2522.
Lett. 2006, 8, 1605-1608. (b) Guppi, S. R.; O’Doherty, G. A. J. Org. Chem.
2007, 72, 4966-4969.
J. Org. Chem, Vol. 73, No. 5, 2008 1937

Abrams et al.
SCHEME 7. Synthesis of 8a-epi-Swainsonine (2) via a
One-Pot Reductive Cyclization Reaction
diastereocontrolled route illustrates the utilities of Noyori
reduction, palladium-catalyzed glycosylation, diastereoselective
dihydroxylation, and one-pot reductive cyclization. This 8a-epi-
swainsonine was achieved in 19 steps and 5.1% overall yield
from achiral furfural 12. Further application of this approach
to the synthesis of various analogues and biological activity
testing is ongoing.
Experimental Section19
Benzyl 4-(Furan-2-yl)-4-oxobutylcarbamate (11). To a solution
of alcohol (()-20 (2.89 g, 10 mmol) in THF (50 mL) was added
activated MnO2 (13 g) then the solution was left to stir for 12 h
and the reaction mixture was filtered through a Celite pad and
concentrated under reduced pressure to yield furfuryl ketone 11
(2.58 g, 9.0 mol, 90%): colorless oil, Rf 0.48 (60% EtOAc/hexane);
IR (thin film, cm-1) 3343, 2943, 1672, 1529, 1468, 1250, 1018,
1
758; H NMR (600 MHz, CDCl3) δ 7.56 (d, J ) 1.8 Hz, 1H),
7.29-7.35 (m, 5H), 7.17 (d, J ) 3.6 Hz, 1H), 6.52 (dd, J ) 3.6,
1.8 Hz, 1H), 5.08 (s, 2H), 4.94 (br, 1H), 3.74 (q, J ) 6.6 Hz, 2H),
2.88 (t, J ) 6.6 Hz, 2H), 1.94 (p, J ) 6.6 Hz, 2H); 13C NMR (150
MHz, CDCl3) δ 188.9, 156.5, 152.7, 146.4, 136.7, 128.6, 128.2 (2
C), 117.2, 112.3, 66.7, 40.7, 35.6, 24.3; ClHRMS calcd for [C16H17-
NO4H+] 288.1236, found 288.1235.
Benzyl (R)-4-(Furan-2-yl)-4-hydroxybutylcarbamate (20). To
a 5 mL flask was added furfuryl ketone 11 (5.74 g, 20 mmol),
CH2Cl2 (20 mL), formic acid/triethylamine 26 mL (5:7, molar ratio),
and Noyori asymmetric transfer hydrogenation catalyst (S)-Ru(η6-
mesitylene)-(R,R)-TsDPEN (241 mg, 2.0 mol %). The resulting
solution was stirred at room temperature for 24 h. Water (80 mL)
was added to dilute and the reaction was extracted with EtOAc (3
× 100 mL). The combined organic layers were washed with
saturated NaHCO3, dried over Na2SO4, and concentrated under
reduced pressure to afford crude oil. The crude product was purified
by silica gel flash chromatography eluting with 6% EtOAc/hexane
to give furyl alcohol 20 (28.7 g, 106.4 mmol, 91%): white solid;
Rf 0.35 (60% EtOAc/hexane); mp 143-144 °C; [R]25D +11 (c 1.2,
CH2Cl2); IR (thin film, cm-1) 3417, 3338, 2943, 1699, 1529, 1258,
1010, 739; 1H NMR (600 MHz CDCl3) δ 7.29-7.36 (m, 6H), 6.32
(dd, J ) 3.6, 1.8 Hz, 1H), 6.22 (d, J ) 1.8 Hz, 1H), 5.08 (s, 2H),
4.88 (br, 1H), 4.70 (q, J ) 6.6 Hz, 1H), 3.23 (m, 2H), 2.26 (d, J
) 4.8 Hz, 1H, OH), 1.87 (m, 2H), 1.66 (s, J ) 6.6 Hz, 1H), 1.57
(s, J ) 6.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 156.6 (2 C),
142.0, 136.7, 128.6 (2 C), 128.2, 110.2, 106.0, 67.5, 66.7, 40.8,
32.6, 26.2; ClHRMS calcd for [C16H19NO4Na+] 312.1212, found
312.1211.
tert-Butylcarbonate 3-((2R,6S)-6-(Benzyloxy)-3,6-dihydro-3-
oxo-2H-pyran-2-yl)propylcarbamate (10R). Furyl alcohol 20 (2.0
g, 6.92 mmol), 21 mL of THF, and 7 mL of H2O were added to a
round-bottom flask then the mixture was cooled to 0 °C. Solid
NaHCO3 (1.16 g, 13.8 mmol), NaOAc‚3H2O (1.41 g, 10.3 mmol),
and NBS (1.2 g, 6.92 mmol) were added to the solution and the
mixture was stirred for 0.5 h at 0 °C. The reaction was quenched
with saturated NaHCO3 (50 mL), extracted (3 × 50 mL) with Et2O,
dried (Na2SO4), concentrated under reduced pressure, and purified
by silica gel chromatography eluting with 60% EtOAc/hexane to
give hemiacetal 26 (1.94 g, 6.37 mmol, 92%): Rf 0.35 (60% EtOAc/
hexane). Hemiacetal 26 (1.94 g, 6.37 mmol) was dissolved in CH2-
Cl2 (4.4 mL) and the solution was cooled to -78 °C. A CH2Cl2
(2.0 mL) solution of (Boc)2O (1.65 g, 7.6 mmol) and a catalytic
amount of DMAP (150 mg, 1.23 µmol) were added to the reaction
benzyl alcohol in the presence of palladium(0) and triphen-
ylphosphine provided an O-benzyl ether 27 in excellent yield
(88%).17 Luche reduction of the C-4 ketone in 27 produced the
equatorial allylic alcohol 28 in excellent yield (87%). The
manno-stereochemistry in triol 29 was installed by dihydroxy-
lation of allylic alcohol 28 under Upjohn conditions18 (OsO4/
NMO) in excellent yield (89%). Selective acetonide protection
of C-2/C-3 cis-hydroxyl groups of 29 with 2,2-dimethoxypro-
pane and a catalytic amount p-TsOH afforded acetonide 30
(87%), which in turn was oxidized to provide acetonide ketone
9 under Swern conditions ((COCl)2/DMSO/Et3N, -78 °C).
To complete the synthesis of 8a-epi-swainsonine, a one-pot
reductive cyclization was used to install the indolizidine ring
(Scheme 7). This transformation involved hydrogenolytic depro-
tection and double reductive amination with a catalytic amount
of palladium hydroxide and 1 atm of hydrogen gas. Hydro-
genolysis of the Cbz-protecting group in 9 should provide
primary amine 31, which could be converted into Schiff base
32. Amino sugar 33 would be formed by hydrogenation of imine
32. Hydrogenolytic deprotection of the Bn-protecting group in
33 should give hemiacetal 8, which can equilibrate to intermedi-
ate hydroxy aldehyde 34. An intramolecular reductive amination
of 34 should afford the protected 8a-epi-swainsonine 7 via a
bicyclic iminium ion intermediate 35. Finally, 8a-epi-swainso-
nine (2) was obtained by acidic hydrolysis of the acetonide 7
in excellent yield (70%, two steps) after ion-exchange chroma-
tography (Basic HO- form).
Conclusions
In conclusion, a de novo asymmetric approach to 8a-epi-
swainsonine (2) has been developed. This highly enantio- and
(18) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973-1976. (b) Shan, M.; O’Doherty, G. A. Org. Lett. 2006, 8,
5149-5152.
(19) Presented in this Experimental Section are the experimental
procedures and spectral data for the new compounds required for the
synthesis of 8a-epi-swainsonine. Complete experimental procedures and
spectral data for all compounds are presented in the Supporting Information.
(17) (a) Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125,
12406-12407. For its application in the de novo syntheses see: (b) Babu,
R. S.; Zhou, M.; O’Doherty, G. A. J. Am. Chem. Soc. 2004, 126, 3428-
3429. (c) Guo, H.; O’Doherty, G. A. Angew. Chem., Int. Ed. 2007, 46,
5206-5208.
1938 J. Org. Chem., Vol. 73, No. 5, 2008

Synthesis of 8a-epi-Swainsonine
mixture. The reaction was stirred for 14 h at -78 °C and quenched
with 100 mL of saturated NaHCO3, extracted with Et2O (3 × 100
mL), dried (Na2SO4), and concentrated under reduced pressure. The
crude product was purified with silica gel flash chromatography
eluting with 10% EtOAc/hexane to give 2.06 g (5.1 mmol, 80%)
of two diastereomers of Boc-protected pyranone 10R and 10â in
(4% MeOH/Et2O) to give triol 29 (199 mg, 0.48 mmol, 89%); Rf
0.06 (60% EtOAc/hexane); mp 48-52 °C; [R]25 -56 (c 1.0,
D
MeOH); IR (thin film, cm-1) 3387, 2927, 1691, 1455, 1429, 1361,
1
1061; H NMR (600 MHz, CD3OD) δ 7.33-7.42 (m, 10H), 5.14
(s, 2H), 4.86 (s, 1H), 4.78 (d, J ) 12.0 Hz, 1H), 4.57 (d, J ) 12.0
Hz, 1H), 3.91 (dd, J ) 3.6, 1.8 Hz, 1H), 3.78 (dd, J ) 9.0, 3.6 Hz,
1H), 3.59 (m, 1H), 3.54 (dd, J ) 9.0, 9.0 Hz, 1H), 3.24 (t, J ) 7.2
Hz, 2H), 1.96-2.01 (m, 1H), 1.82-1.89 (m, 1H), 1.62-1.69 (m,
1H), 1.54-1.62 (m, 1H); 13C NMR (150 MHz, CD3OD) δ 159.0,
139.1, 138.6, 129.6, 129.2, 129.0, 128.9 (2 C), 128.8, 100.7, 73.6,
72.8, 72.5, 72.3, 70.1, 67.4, 42.1, 29.9, 27.4; CIHRMS calcd for
[C23H29O7NNa+] 454.1842, found 454.1841.
7:1: Rf 0.21 (30% Et2O/hexane); [R]25 -46 (c 1.0, CH2Cl2); IR
D
(thin film, cm-1) 3347, 2979, 2932, 1749, 1698, 1525, 1274, 1252,
1154, 941, 843; 1H NMR (600 MHz, CDCl3) δ 7.28-7.35 (m, 5H),
6.86 (dd, J ) 10.2, 3.6 Hz, 1H), 6.32 (d, J ) 3.6 Hz, 1H), 6.20 (d,
J ) 10.2 Hz, 1H), 5.08 (s, 2H), 4.84 (m, 1H), 4.52 (dd, J ) 7.2,
3.6 Hz, 1H), 3.62 (m, 2H), 1.97-2.03 (m, 1H), 1.73-1.80 (m, 1H),
157-1.68 (m, 2H), 1.51 (s, 9H); 13C NMR (150.8 MHz, CDCl3) δ
195.1, 156.4, 151.9, 141.1, 136.7, 128.8, 128.6, 128.2, 128.1, 89.2,
83.8, 75.3, 66.7, 40.6, 27.7, 26.6, 25.2; ClHRMS calcd for [C21H27-
NO7H+] 406.1866, found 406.1862.
Benzyl 3-((3aS,4S,6R,7R,7aS)-4-(Benzyloxy)tetrahydro-7-hy-
droxy-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)propyl-
carbamate (30). p-Toluenesulfonic acid monohydrate (43.3 mg, 5
mol %) was added to a stirred solution of triol 29 (2.0 g, 4.64 mmol)
and 2,2-dimethoxypropane (13.0 mL) in acetone (46 mL) for 0.5 h
at 0 °C. The reaction mixture was quenched with sodium bicarbon-
ate solution (20 mL), acetone was removed in vacuo, then the
reaction mixture was extracted with Et2O (3 × 25 mL), dried (Na2-
SO4), and concentrated under reduced pressure. The crude product
was purified with silica gel flash chromatography eluting with 50%
EtOAc/hexane to give 1.90 g (4.04 mmol, 87%) of acetonide 30
as a colorless oil: Rf 0.59 (60% EtOAc/hexane); mp 118-120 °C;
[R]25D +32 (c 0.8, CH2Cl2); IR (thin film, cm-1) 3355, 2985, 2934,
Benzyl 3-((2R,6S)-6-(Benzyloxy)-3,6-dihydro-3-oxo-2H-pyran-
2-yl)propylcarbamate (27). To a solution of Boc-protected pyra-
none 10R (773 mg, 1.91 mmol) and benzyl alcohol (0.41 g, 3.82
mmol) in dry CH2Cl2 (1.9 mL) was added a CH2Cl2 (1.9 mL)
solution of Pd2(DBA)3‚CHCl3 (24.6 mg, 2.5 mol % Pd) and PPh3
(25.5 mg, 10 mol %) at 0 °C under an argon atmosphere. After
being stirred for 2 h from 0 °C to room temperature, the reaction
mixture was quenched with 50 mL of saturated NaHCO3, extracted
with Et2O (3 × 50 mL), dried (Na2SO4), and concentrated under
reduced pressure. The crude product was purified with silica gel
flash chromatography eluting with 10% EtOAc/hexane to give
benzyl ether 27 (664 g, 1.68 mmol, 88%) as a colorless oil: Rf
1
1698, 1525, 1455, 1243, 1219, 1066, 1023, 911; H NMR (270
MHz, CDCl3) δ 7.27-7.38 (m, 10H), 5.13(br, 1H, NH), 5.10 (s,
2H), 5.07 (s, 1H), 4.73 (d, J ) 12.0 Hz, 1H), 4.51 (d, J ) 12.0 Hz,
1H), 4.18 (d, J ) 6.0 Hz, 1H), 4.11 (dd, J ) 6.0, 7.2 Hz, 1H), 3.61
(ddd, J ) 9.0, 9.0 Hz, 1H), 3.44 (m, 2H), 3.23 (m, 2H), 1.74-1.99
(m, 2H), 1.39-1.66 (m, 2H), 1.51 (s, 3H), 1.34 (s, 3H); 13C NMR
(67.5 MHz, CDCl3) δ 156.5, 136.8, 136.5, 128.5, 128.4, 128.1 (2
C), 128.0, 127.9, 109.3, 96.0, 78.6, 75.7, 72.8, 69.3, 69.0, 66.6,
40.9, 28.3, 28.0, 26.2, 25.9; CIHRMS calcd for [C26H33NO7Na+]
494.2149, found 494.2154.
0.21 (30% EtOAc/hexane); [R]25 -24 (c 1.1, CH2Cl2); IR (thin
D
film, cm-1) 3357, 3033, 2937, 1695, 1525, 1246, 1097, 1024, 737;
1H NMR (600 MHz, CDCl3) δ 7.29-7.38 (m, 10H), 6.83 (dd, J )
10.2, 3.0 Hz, 1H), 6.10 (d, J ) 10.2 Hz, 1H), 5.28 (d, J ) 3.0 Hz,
1H), 5.10 (s, 2H), 4.90 (br, 1H), 4.81 (d, J ) 12.0 Hz, 1H), 4.68
(d, J ) 12.0 Hz, 1H), 4.44 (dd, J ) 7.2, 3.6 Hz, 1H), 3.23 (m,
2H), 1.94-1.99 (m, 1H), 1.68-1.75 (m, 1H), 1.55-1.67 (m, 2H);
13C NMR (150.8 MHz, CDCl3) δ 196.3, 156.4, 143.5, 137.1, 136.7,
128.6 (2 C), 128.5, 128.2, 128.1 (2 C), 127.8, 92.3, 73.8, 70.9,
66.6, 40.9, 26.7, 25.6; CIHRMS calcd for [C23H25O5NNa+]
418.1630, found 418.1631.
Benzyl 3-((3aS,4S,6R,7aR)-4-(Benzyloxy)tetrahydro-2,2-dim-
ethyl-7-oxo-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)propylcarbam-
ate (9). To a solution of (COCl)2 (0.17 mL, 2 mmol) in CH2Cl2 (4
mL) was added DMSO (0.58 mL, 4.0 mmol) at -78 °C, and the
mixture was stirred for 10 min. A solution of alcohol 30 (471 mg,
1 mmol) in 2 mL of CH2Cl2 was added to the resulting mixture,
with stirring for 0.5 h at -78 °C. Then triethylamine (0.57 mL,
4.0 mmol) was added at -78 °C and the reaction mixture was
warmed to 0 °C for 1 h. Water (50 mL) was added to quench the
mixture, and the aqueous mixture was extracted with Et2O (3 ×
80 mL), dried (Na2SO4), and concentrated under reduced pressure.
The crude product was purified with silica gel flash chromatography
eluting with 50% Et2O/hexane to give ketone 9 (431 mg, 1.84 mmol,
92%) as a colorless oil: Rf 0.53 (40% EtOAc/hexane); [R]25D +83
(c 1.0, CH2Cl2); IR (thin film, cm-1) 3376, 2934, 1709, 1521, 1455,
1229, 1073, 1018, 910, 857; 1H NMR (270 MHz, CDCl3) δ 7.27-
7.39 (m, 10H), 5.09 (s, 2H), 5.04 (s, 1H), 5.0 (br, 1H), 4.72 (d, J
) 11.8 Hz, 1H), 4.57 (d, J ) 11.8 Hz, 1H), 4.47 (dd, J ) 6.6, 1H),
4.43 (d, J ) 6.6, 1H), 4.18 (dd, J ) 4.8, 8.4 Hz, 1H), 3.2 (m, 2H),
1.22-1.92 (m, 4H), 1.46 (s, 3H), 1.35 (s, 3H); 13C NMR (67.5
MHz, CDCl3) δ 204.0, 156.4, 136.6, 136.3, 128.6, 128.5, 128.2,
128.1, 128.0 (2 C), 111.4, 95.9, 78.6, 75.8, 73.4, 70.0, 66.6, 40.7,
27.6, 26.7, 25.9, 25.4; CIHRMS calcd for [C26H31O7NNa+]
492.1998, found 492.1999.
(3aR,9R,9aS,9bS)-Octahydro-2,2-dimethyl-[1,3]dioxolo[4,5-a]-
indolizin-9-ol (7). To a solution of acetonide ketone 9 (300 mg,
0.68 mmol) in dry EtOH/THF (3 mL, v/v ) 1:1) was added Pd-
(OH)2/C (100 mg). The reaction mixture was stirred under an
atmosphere of H2 at room temperature for 3 days, filtered off
through a short pad of Celite, and concentrated under reduced
pressure. The resulting crude product was purified with silica gel
flash chromatography eluting with 10% MeOH/EtOAc to give
protected (-)-8a-epi-D-swainsonine 7 (111 mg, 0.52 mmol, 76%);
Rf 0.68 (50% MeOH/EtOAc); [R]25D -25 (c 1.35, CH2Cl2); IR (neat,
Benzyl 3-((2R,3R,6S)-6-(Benzyloxy)-3,6-dihydro-3-hydroxy-
2H-pyran-2-yl)propylcarbamate (28). A CH2Cl2 (0.57 mL) solu-
tion of pyranone 27 (450 mg, 1.14 mmol) and MeOH/CeCl3 (0.57
mL, 1 M) was cooled to -78 °C. NaBH4 (45 mg, 1.17 mmol) was
added and the reaction mixture was stirred at - 78 °C for 0.5 h.
The reaction mixture was diluted with ether (20 mL) and quenched
with 25 mL of saturated NaHCO3, extracted with Et2O (3 × 50
mL), dried (Na2SO4), and concentrated under reduced pressure. The
crude product was purified by silica gel flash chromatography (60%
EtOAc/hexane) to give 393 mg (0.99 mmol, 87%) of allylic alcohol
28 as a colorless oil: Rf 0.18 (50% EtOAc/hexane); [R]25D +24 (c
0.9, CH2Cl2); IR (thin film, cm-1) 3346, 2937, 2878, 1698, 1530,
1
1254, 1021, 734; H NMR (270 MHz, CDCl3) δ 7.24-7.37 (m,
10H), 5.95 (dd, J ) 10.2, 1.2 Hz, 1H), 5.77 (ddd, J ) 10.2, 2.7,
2.3 Hz, 1H), 5.09 (s, 2H), 5.03 (d, J ) 1.2 Hz, 1H), 4.93(br, 1H),
4.79 (d, J ) 11.6 Hz, 1H), 4.58 (d, J ) 11.6 Hz, 1H), 3.88 (dd, J
) 8.1, 7.4 Hz, 1H), 3.65 (dd, J ) 9.2, 7.2 Hz, 1H), 3.26 (m, 2H),
2.15 (d, J ) 7.6, 1H, OH), 1.85-2.01 (m, 1H), 1.71-1.83 (m,
1H), 1.41-1.63 (m, 2H); 13C NMR (67.5 MHz, CDCl3) δ 156.7,
137.8, 136.6, 133.8, 128.6 (2 C), 128.5, 128.2, 128.0, 127.8, 126.5,
93.5, 71.5, 71.2, 67.9, 66.7, 40.9, 28.9, 26.1; CIHRMS calcd for
[C23H27O5NNa+] 420.1787, found 420.1790.
Benzyl 3-((2R,3S,4S,5S,6S)-6-(Benzyloxy)tetrahydro-3,4,5-tri-
hydroxy-2H-pyran-2-yl)propylcarbamate (29). To a tert-butyl
alcohol/acetone (1.52 mL, 1:1, 1 M) solution of allylic alcohol 28
(300 mg, 0.76 mmol) at 0 °C was added a solution of (50% w/v)
of N-methylmorpholine N-oxide/water (0.76 mL). Crystalline OsO4
(2.0 mg, 1 mol %) was added. The reaction mixture was stirred
for 24 h, concentrated onto a small amount of silica gel under
reduced pressure, then purified by silica gel flash chromatography
J. Org. Chem, Vol. 73, No. 5, 2008 1939

Abrams et al.
1
cm-1) 3396, 2985, 2935, 2803, 1373, 1207, 1159, 1071, 866; H
1H), 4.10 (m, 1H), 3.91 (dd, J ) 9.0, 6.6 Hz, 1H), 3.39 (dd, J )
10.2, 6.6 Hz, 1H), 2.95 (dd, J ) 10.2, 1.8 Hz, 1H), 2.14 (dd, J )
10.2, 6.6 Hz, 1H), 2.10 (m, 2H), 1.87-1.90 (m, 1H), 1.69-1.77
(m, 1H), 1.50-1.58 (m, 2H); 13C NMR (150 MHz, D2O, ref CD3-
OD) δ 70.7, 70.5, 67.7, 64.4, 61.4, 53.4, 30.9, 20.1 [lit.9c (D2O, ref
CH3OH, 100 MHz) δ 60.65, 69.41, 66.69, 63.39, 60.37, 52.33,
29.85, 19.10]; CIHRMS calcd for [C8H15NO3H+] 174.1130, found
174.1125.
NMR (600 MHz, CDCl3) δ 4.66 (dd, J ) 6.6, 6.0 Hz, 1H), 4.56
(q, J ) 6.0 Hz, 1H), 4.05 (m, 1H), 3.39 (dd, J ) 9.0, 6.0 Hz, 1H),
2.96 (dt, J ) 10.8, 3.0 Hz, 1H), 2.49 (br. s, 1H), 2.37 (m, 1H),
2.24 (m, 2H), 1.90 (m, 1H), 1.77 (m, 1H), 1.38-1.53 (m, 2H),
1.51 (s, 3H), 1.32 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 113.9,
79.9, 77.3, 72.4, 64.7, 60.4, 52.4, 30.8, 27.2, 25.1, 19.1; CIHRMS
calcd for [C11H19NO3H+] 214.1443, found 214.1438.
(1S,2R,8R,8aS)-Octahydroindolizine-1,2,8-triol (2).9c To a
solution of protected (-)-8a-epi-D-swainsonine 7 (40 mg, 0.14
mmol) in THF (0.4 mL) was added 6 N HCl (0.20 mL) at room
temperature and the reaction was stirred over night. The resulting
mixture was concentrated under reduced pressure and then eluted
with water through an ion exchange column (Dowex 1 × 8 200
OH-, 200 mg). Removal of water in vacuo gave a white powder,
(-)-8a-epi-D-swainsonine 2 (30 mg, 0.13 mmol, 92%): Rf 0.22
(50% MeOH/EtOAc); mp 117-119 °C [lit.9c mp 116-118 °C];
[R]25D -63 (c 1.0, MeOH) [lit.9c [R]21D -64 (c 0.95, MeOH)]; IR
(thin film, cm-1) 3350, 2934, 2801, 1644, 1329, 1157, 1057, 1003;
1H NMR (600 MHz, D2O, ref CD3OD) δ 4.32 (q, J ) 6.6 Hz,
Acknowledgment. We are grateful to the PRF (47094-AC1)
and the NSF (CHE-0415469) for their support of our research
program and NSF-EPSCoR (0314742) for a 600 MHz NMR at
WVU.
Supporting Information Available: Complete experimental
procedures and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO702476Q
1940 J. Org. Chem., Vol. 73, No. 5, 2008