A concise synthesis of castanospermine by the use of a transannular cyclization

Article abstract of DOI:10.1021/jo9019495

(Chemical Equation Presented) A nine-step synthesis of (+)-castanospermine has been accomplished in 22% overall yield from methyl α-D- glucopyranoside. The key transformations involve a zinc-mediated fragmentation of benzyl-protected methyl 6-iodoglucopyr

Full text of DOI:10.1021/jo9019495

pubs.acs.org/joc
A Concise Synthesis of Castanospermine by the
Use of a Transannular Cyclization
Thomas Jensen, Mette Mikkelsen, Anne Lauritsen,
Thomas L. Andresen, Charlotte H. Gotfredsen, and
Robert Madsen*
Department of Chemistry, Building 201,
Technical University of Denmark,
DK-2800 Lyngby, Denmark
rm@kemi.dtu.dk
FIGURE 1. Retrosynthesis for (þ)-castanospermine.
Received September 11, 2009
boat conformation.3 The alkaloid is also a potent antiviral
agent,4 and the 6-butanoyl analogue is currently undergoing
clinical trials for treatment of hepatitis C.5 As a result,
(þ)-castanospermine has been the target of a number of
total syntheses starting from either a carbohydrate,6 tartaric/
malic acid,7 or an achiral substrate via an enantioselective
approach.8 The shortest synthesis is an eight-step route from
2,5-dihydrofuran where an asymmetric tandem [4 þ 2]/
[3 þ 2] cycloaddition serves as the key step.8d All other
syntheses of the natural product have used more than
10 synthetic steps.
The rings in the indolizidine system are usually formed in
two separate steps. We envisioned using a transannular
cyclization9 from epoxide A to form the azabicycle in one
step (Figure 1). The epoxide would arise from a diastereose-
lective epoxidation of the nine-membered cycloalkene B,
which would be prepared by ring-closing metathesis from
diene C. The latter can originate from reductive amination of
unsaturated aldehyde D which is available by zinc-mediated
fragmentation of methyl 6-deoxy-6-iodo-R-D-glucopyrano-
side. Herein, we describe a nine-step synthesis of (þ)-casta-
nospermine from methyl R-D-glucopyranoside by the use of a
medium-ring metathesis reaction and a transannular cycliza-
tion as the pivotal steps.
A nine-step synthesis of (þ)-castanospermine has been
accomplished in 22% overall yield from methyl R-D-gluco-
pyranoside. The key transformations involve a zinc-mediated
fragmentation of benzyl-protected methyl 6-iodoglucopyra-
noside, ring-closing olefin metathesis, and strain-release
transannular cyclization to afford the indolizidine skeleton
of the natural product.
The indolizidine alkaloid (þ)-castanospermine was first
isolated in 1981 from the seeds of the Australian legume
Castanospermum australe.1 It is structurally related to
D-glucose and is a powerful inhibitor of both mammalian
and plant R- and β-glucosidases.2 The complexation to a
β-glucosidase has been studied by X-ray crystallography,
and the natural product was shown to bind in a distorted
The requisite starting material for the reductive fragmenta-
tion was prepared in two steps from cheap and commercially
available methyl R-D-glucopyranoside. Treatment with iodine
and triphenylphosphine gave 6-iodopyranoside 2 which was
separated from triphenylphosphine oxide by reversed-phase
column chromatography (Scheme 1).10 Initially, we attempted
to perform the fragmentation-amination sequence with the
(1) Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.; Pryce,
R. J.; Arnold, E.; Clardy, J. Phytochemistry 1981, 20, 811.
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Doms, R. W.; Diamond, M. S. J. Virol. 2005, 79, 8698.
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Agents Chemother. 2004, 15, 141.
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(6) (a) Machan, T.; David, A. S.; Liawruangrath, B.; Pyne, S. G.
Tetrahedron 2008, 64, 2725. (b) Karanjule, N. S.; Markad, S. D.; Shinde,
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P. V. Org. Lett. 2005, 7, 2691. (d) Kim, J. H.; Seo, W. D.; Lee, J. H.; Lee,
B. W.; Park, K. H. Synthesis 2003, 2473. (e) Zhao, H.; Hans, S.; Cheng, X.;
Mootoo, D. R. J. Org. Chem. 2001, 66, 1761. (f) Overkleeft, H. S.; Pandit,
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Tetrahedron 2003, 59, 1293. (d) Denmark, S. E.; Martinborough, E. A. J.
Am. Chem. Soc. 1999, 121, 3046. (e) Reymond, J.-L.; Pinkerton, A. A.; Vogel,
P. J. Org. Chem. 1991, 56, 2128. (f) Bhide, R.; Mortezaei, R.; Scilimati, A.;
Sih, C. J. Tetrahedron Lett. 1990, 31, 4827.
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(h) Gerspacher, M.; Rapoport, H. J. Org. Chem. 1991, 56, 3700. (i) Miller,
S. A.; Chamberlin, A. R. J. Am. Chem. Soc. 1990, 112, 8100. (j) Anzeveno,
P. B.; Angell, P. T.; Creemer, L. J.; Whalon, M. R. Tetrahedron Lett. 1990,
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(l) Setoi, H.; Takeno, H.; Hashimoto, M. Tetrahedron Lett. 1985, 26, 4617.
(m) Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1984, 25, 165.
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A.; Madsen, R. Org. Biomol. Chem. 2006, 4, 2898. (c) Sudau, A.; Munch, W.;
Bats, J. W.; Nubbemeyer, U. Chem.;Eur. J. 2001, 7, 611. (d) White, J. D.;
Hrnciar, P. J. Org. Chem. 2000, 65, 9129.
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Madsen, R. Synthesis 2002, 1721.
8886 J. Org. Chem. 2009, 74, 8886–8889
Published on Web 10/26/2009
DOI: 10.1021/jo9019495
r
2009 American Chemical Society

Jensen et al.
JOCNote
SCHEME 1a
Grubbs’ first generation catalyst 9 nor the ruthenium
indylidene catalyst 1012 afforded any of the desired product
(Table, entry 1 and 2). Gratifyingly, the more reactive
ruthenium carbene complexes endowed with an N-hetero-
cyclic carbene ligand provided the desired product in mode-
rate to good yield (entries 3-6).
A byproduct in all these reactions was the 8-membered
N-heterocycle, which likely results from ruthenium-cata-
lyzed isomerization of the electron-rich terminal double
bond in 6 followed by elimination of propene instead of
ethylene during the ring closure.13 Grubbs’ catalyst 12
proved to be the best catalyst, providing the desired product
in 71% yield along with only 9% of the byproduct. When 12
was added in a dropwise manner over 20 h alkene 7 was
obtained in 78% yield (entry 7). Attempts to run the reaction
at a higher concentration, adding Ti(O-i-Pr)4 or BHT let
to a decreased yield of 7 (entries 8-10). In addition, when
10 mol % of 12 was used or when performing the reaction
in refluxing toluene the yield dropped significantly (entry 11
and 12).
aReagents and conditions: (a) I2, PPh3, imidazole, THF, 65 °C; (b) Bn-
OC(NH)CCl3, TfOH, p-dioxane, 22 °C; (c) Zn, THF/H2O, ultrasound,
˚
40 °C; (d) homoallylamine, 4 A molecular sieves, AcOH, NaCNBH3, THF,
0-22 °C; (e) (CF3CO)2O, Et3N, CH2Cl2, 0 °C.
unprotected 6-iodopyranoside 2, but this approach was ham-
pered by difficult isolation procedures for the highly polar
intermediates. Therefore, we settled for a strategy relying on
benzyl protection of 2. The hydroxy groups were protected
smoothly under acidic conditions utilizing an excess of benzyl
trichloroacetimidate. The attained tribenzyl ether 3 was soni-
cated in the presence of activated, powdered zinc to furnish
unsaturated aldehyde 4. The aldehyde could easily be purified
by the use of silica gel chromatography without epimerization
of the R-stereocenter. However, upon standing, this stereocen-
ter epimerized readily even when the compound was stored in
the freezer; hence, in practice the crude aldehyde was used
directly in the subsequent step.
With access to 7, we started to investigate conditions for
installing the epoxide and mediating the transannular cycli-
zation. Initially cyclononene 7 was treated with excess m-
CPBA in CH2Cl2, and even though the reaction provided
one major product as judged by 1H NMR, the reaction was
sluggish and all efforts to purify the epoxide led to decom-
position. Attempts to buffer the reaction with NaHCO3 or
NaH2PO4 were largely unsuccessful and the addition of KF
to complex m-chlorobenzoic acid decreased the reaction rate
markedly. Luckily, after some experimentation it was found
that the in situ generated dioxirane of 1,1,1-trifluoroacetone
cleanly converted 7 into the desired epoxide (more than 80%
We attempted to perform the reductive amination as
a one-pot sequence where 4 was formed with zinc in
the presence of NaCNBH3 or NaBH(OAc)3, homoallyl
amine,11 and acetic acid. Unfortunately, these experiments
only provided the desired amine 5 in a moderate yield along
with reduced aldehyde and epimerized amine. Thus, we
decided to perform the zinc-mediated fragmentation and
the reductive amination in two separate steps. After some
experimentation, it was found that employing NaCNBH3
as the reducing agent in the presence of an excess of
1
of the desired diastereomer as judged by H NMR of the
crude reaction mixture). The crude product was used directly
in the next step to avoid decomposition of the acid-labile
epoxide during workup. Before identifying optimal reaction
conditions, a range of different bases and solvents such as
Na2CO3, K2CO3, LiOH, NaOH, MeOH, EtOH, and THF
were investigated for the key N-deprotection/transannular
cyclization. In the event, treating the crude epoxide with
2 equiv of water and 20 equiv of KO-t-Bu in Et2O at 0 °C and
allowing the reaction mixture to reach room temperature
furnished indolizidine 15 in 44% yield over the two steps
along with 15% of the strained byproduct 16 (Scheme 2).
The structure of the latter was assigned by 2D NMR
spectroscopy.
Finally indolizidine 15 was deprotected by hydrogenolysis
using H2 over Pd/C to afford (þ)-castanospermine in almost
quantitative yield. Physical and spectral data for the syn-
thetic material were found to be consistent with those for the
natural product.1
In conclusion, we have developed a concise synthesis of
enantiopure (þ)-castanospermine. The synthesis comprises
no more than nine steps from methyl R-D-glucopyranoside
and provides the natural product in 22% overall yield. The
key steps are a zinc-mediated reductive fragmentation of 3,
a challenging ruthenium-catalyzed ring-closing metathesis
reaction of diene 6, and a strain-driven N-deprotection/trans-
annular cyclization cascade. This synthesis further under-
scores the effectiveness of employing a zinc-fragmentation
˚
homoallyl amine and powdered 4 A molecular sieves in
THF furnished the desired amine in 89% yield. Careful
adjustment to pH 7-8 using acetic acid and allowing for
complete formation of the imine before adding NaCNBH3
proved to be crucial in order to avoid epimerization and
direct reduction of the aldehyde. Amine 5 was readily
converted into the corresponding trifluoroacetamide 6 by
treatment with trifluoroacetic anhydride in the presence of
triethylamine.
With diene 6 in hand, we set out to identify reaction
conditions that would furnish the nine-membered (Z)-alkene
7 efficiently. Initial experiments with Grubbs’ second-gen-
eration catalyst revealed that ring-closing metathesis had to
be performed under highly dilute conditions in refluxing
benzene or toluene. When the reaction was performed at
more than 1.0 mM concentration of diene 6 the homodimer
was the predominant product. Furthermore, reactions con-
ducted at ambient temperature or at 40 °C in CH2Cl2 under
highly dilute conditions (0.2 mM) did not afford any reaction
and the starting material could be isolated quantitatively.
Therefore we decided to screen several metathesis catalysts
(Table 1) for this crucial reaction. Surprisingly, neither
(11) Jacobson, M. A.; Williard, P. G. J. Org. Chem. 2002, 67, 3915.
€
€
(12) Furstner, A.; Guth, O.; Duffels, A.; Seidel, G.; Liebl, M.; Gabor, B.;
Mynott, R. Chem.;Eur. J. 2001, 7, 4811.
(13) Schmidt, B. Eur. J. Org. Chem. 2004, 1865.
J. Org. Chem. Vol. 74, No. 22, 2009 8887

Jensen et al.
JOCNote
SCHEME 2a
TABLE 1. Optimization of the Key Ring-Closing Metathesis Reaction
catalyst
[6]
% yield % yield
(7)a
entry (20 mol %) solvent T (°C) (mM)
(8)a
aReagents and conditions: (a) CF3COCH3, Oxone, NaHCO3, Na2ED-
TA, CH3CN/H2O, -10 to 0 °C; (b) KO-t-Bu, H2O, Et2O, 0-22 °C; (c)
H2, Pd/C, HCl, MeOH, 22 °C.
1
2
3
4
5
6
7
8
9
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhMe
80
80
80
80
80
80
80
80
80
80
80
110
0.2
0.2
0.2
0.2
0.2
0.2
0.5
1.0
0.5
0.5
0.5
0.5
10
11
12
13
14
12b
12
12
12
12e
12
52
71
63
59
78
51
73
69
52
41
16
9
11
10
7
12
8
13
5
ring-closing metathesis sequence in the development of highly
efficient synthetic routes from carbohydrates.
9c
10d
11
12
Experimental Section
N-But-3-enyl-((2S,3S,4R)-2,3,4-tris(benzyloxy)hex-5-enyl)-
amine (5). The iodide 310 (2.0 g, 3.75 mmol) was dissolved in
a mixture of THF (16.9 mL) and H2O (1.88 mL), Zn (2.46 g,
37.6 mmol) was added, and the flask was immersed into a
sonication apparatus preheated to 40 °C. The solution was
sonicated for 60 min upon which TLC revealed full conversion
of the starting material. The suspension was filtered through
a plug of Celite using Et2O (50 mL). Saturated aqueous
NaHCO3 (25 mL) was added to the filtrate, the phases were
separated, and the aqueous phase was extracted with Et2O
(3 ꢀ 25 mL). The combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo
to afford a pale yellow viscous oil which was purified by flash
chromatography (heptane/EtOAc = 9:1 f 4:1) to afford
aldehyde 4 as a colorless oil (1.55 g, 99%). The oil was used
directly in the next step since the aldehyde epimerizes when
stored in the freezer. To a solution of the aldehyde (1.55 g,
3.71 mmol) and homoallyl amine11 (2.64 g, 37.1 mmol) in THF
18
aYield of isolated product. bCatalyst added over 20 h. cWith 30 mol %
of (Ti(O-i-Pr)4 as additive. dWith 30 mol % of BHT as additive. e10 mol
% catalyst added over 20 h.
˚
(65.6 mL) were added activated 4 A powdered molecular
sieves (7.43 g) followed by AcOH (2.75 mL) in a dropwise
manner until pH = 7-8. The suspension was cooled to 0 °C,
and after stirring for 30 min, NaCNBH3 (1.17 g, 18.6 mmol)
was added in one portion and the mixture was allowed to
warm to 21 °C. The reaction was stirred for 14 h and then
quenched by addition of saturated aqueous NaHCO3 (25 mL).
The mixture was filtered and the filter cake washed with
EtOAc (3 ꢀ 50 mL). The phases were separated, and the
aqueous phase was extracted with EtOAc (3 ꢀ 25 mL). The
combined organic layers were washed with brine (25 mL),
dried over Na2SO4, filtered, and concentrated under reduced
pressure to afford a pale yellow oil. The crude product was
purified by flash chromatography (CH2Cl2/MeOH = 9:1) to
afford 5 (1.56 g, 89% over two steps) as a colorless oil: Rf =
0.23 (CH2Cl2/MeOH = 9:1); [R]21D -39.4 (c 1.6, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.30-7.22 (m, 15H), 5.86 (ddd,
J = 14.0, 9.9, 7.6 Hz, 1H), 5.62 (ddt, J = 13.8, 10.3, 7.0 Hz,
1H), 5.31-5.19 (m, 2H), 4.98 (ddd, J = 13.8, 3.0, 1.3 Hz, 1H),
4.95-4.91 (m, 1H), 4.72 (d, J = 11.4 Hz, 1H), 4.67 (d, J =
11.4 Hz, 1H), 4.61 (d, J = 11.5 Hz, 1H), 4.59 (d, J = 11.7 Hz,
1H), 4.54 (d, J = 11.5 Hz, 1H), 4.31 (d, J = 11.7 Hz, 1H), 4.00
(dd, J = 7.5, 4.7 Hz, 1H), 3.79 (dd, J = 11.4, 5.7 Hz, 1H), 3.55
(t, J = 5.0 Hz, 1H), 2.69 (dd, J = 12.4, 5.0 Hz, 1H), 2.59 (dd,
J = 12.4, 6.8 Hz, 1H), 2.43 (t, J = 6.9 Hz, 2H), 2.06 (q, J =
6.9 Hz, 2H); 13C NMR (50 MHz, CDCl3) δ 138.4, 138.1, 136.0,
135.5, 128.2, 128.1, 127.8, 127.5, 118.5, 116.2, 82.0, 80.3, 78.6,
74.7, 73.1, 70.4, 49.4, 48.7, 33.8; IR (neat) 3088, 3065, 3029,
2976, 2863, 1496, 1454, 1392, 1351, 1330, 1306, 1207, 1088,
1067, 996, 917, 734, 697 cm-1; HRMS (ESIþ) calcd for
C
31H37NO3Na ([M þ Na]þ) 494.2666, found 494.2647.
N,N-But-3-enyl-((2S,3S,4R)-2,3,4-tris(benzyloxy)hex-5-enyl)-
trifluoroacetamide (6). Amine 5 (1.13 g, 2.30 mmol) was dis-
solved in CH2Cl2 (24.0 mL), Et3N (1.0 mL, 727 mg, 7.2 mmol)
was added, and the solution was cooled to 0 °C. Trifluoroacetic
anhydride (680 μL, 1.0 g, 4.8 mmol) was added in a dropwise
manner, and the reaction was stirred for 30 min at 0 °C. The
mixture was diluted with CH2Cl2 (50 mL) and quenched with
saturated aqueous NaHCO3 (25 mL) at 0 °C. The phases were
separated, and the aqueous phase was extracted with CH2Cl2
(2 ꢀ 25 mL). The combined organic phases were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude oil was purified by flash chromatography (heptane/
EtOAc = 98:2 f 95:5) to afford 6 (1.26 g, 93%) as a viscous
colorless oil: Rf = 0.41 (heptane/EtOAc = 7:3); [R]21 -52.8
D
1
(c 2.0, CHCl3); H NMR (300 MHz, CDCl3) major rotamer
δ 7.34-7.14 (m, 15H), 5.90 (ddd, J = 17.3, 10.4, 7.9 Hz, 1H),
5.72-5.46 (m, 1H), 5.32 (dd, J = 10.2, 1.2 Hz, 1H), 5.29-5.21
(m, 1H), 5.06-4.91 (m, 2H), 4.76 (d, J = 11.8 Hz, 1H), 4.70 (d,
J = 11.8 Hz, 1H), 4.64 (d, J = 11.8 Hz, 1H), 4.55 (d, J = 11.4
Hz, 1H), 4.47 (d, J = 11.4 Hz, 1H), 4.38 (d, J = 11.8 Hz, 1H),
4.15 (dd, J = 7.8, 5.0 Hz, 1H), 4.06 (ddd, J = 8.6, 5.0, 3.4 Hz,
1H), 3.77 (dd, J = 13.9, 3.4 Hz, 1H), 3.52-3.29 (m, 4H), 2.19 (q,
J = 7.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ major rotamer
157.1 (q, JCF = 35.6 Hz), 138.1, 138.1, 138.0, 135.1, 133.3, 128.4,
8888 J. Org. Chem. Vol. 74, No. 22, 2009

Jensen et al.
JOCNote
128.4, 128.4, 128.3, 128.0, 127.9, 127.9, 127.8, 127.6, 119.3,
117.8, 116.4 (q, JCF = 288 Hz), 80.7, 80.2, 76.0, 73.9. 73.8,
70.6, 48.8, 48.6, 32.9; 19F NMR (282 MHz, CDCl3) δ major
rotamer -69.43 (s, 3F); minor rotamer -68.34 (s, 3F); IR (Neat)
3089, 3067, 3032, 2910, 2871, 1687, 1454, 1252, 1206, 1144, 1122,
1089, 1072, 735, 698 cm-1; HRMS (ESIþ) calcd for C33H36F3-
NO4Na ([M þ Na]þ) 590.2489, found 590.2472.
(1.2 μL, 0.064 mmol) and KO-t-Bu (71 mg, 0.634 mmol) were
added. After 30 min of stirring, the mixture was allowed to
warm to room temperature and stirred for an additional 10 h.
H2O (2.5 mL) was added, the phases were separated, and the
aqueous phase was extracted with CH2Cl2 (3 ꢀ 2.5 mL). The
combined organic layers were dried over K2CO3, filtered, and
concentrated under reduced pressure. The crude oil was purified
by preparative TLC (heptane/CH2Cl2/MeOH = 7:7:2) to afford
15 (7.6 mg, 44% over two steps) as a pale yellow oil: Rf = 0.4
(3S,4S,5R)-3,4,5-Tris(benzyloxy)-1-trifluoroacetyl-1-azacy-
clonon-6-ene (7). Diene 6 (100 mg, 0.185 mmol) was dissolved
in benzene (370 mL, 0.5 mM). The solution was degassed by
sonication (5 min under a positive flow of Ar) and heated to
80 °C. Catalyst 12 (21 mg, 0.037 mmol) was dissolved in
benzene (20 mL) and added to the mixture in a dropwise
manner over 20 h by the use of a syringe pump. After being
stirred for an additional 4 h, the reaction mixture was allowed
to cool to room temperature and concentrated under reduced
pressure to afford a dark green oil. The crude oil was purified
by flash chromatography (heptane/EtOAc = 98:2 f 95:5) to
afford 7 (78 mg, 78%) as a colorless oil which crystallized upon
(heptane/CH2Cl2/MeOH
=
7:7:2); [R]21 þ35.5 (c 0.96,
D
CH2Cl2) (lit.6i [R]26 þ36.4 (c 1.2, CH2Cl2)); 1H NMR (300
D
MHz, CDCl3) δ 7.72-7.22 (m, 15H), 4.99 (d, J = 10.9 Hz, 1H),
4.87 (d, J = 11.6 Hz, 2H), 4.80 (d, J = 11.5 Hz, 1H), 4.71 (d, J =
11.6 Hz, 1H), 4.66 (d, J = 11.6 Hz, 1H), 4.31-4.14 (m, 1H),
3.74-3.62 (m, 2H), 3.61-3.51 (m, 1H), 3.26 (dd, J = 10.6, 4.9 Hz,
1H), 3.16-3.00 (m, 1H), 2.26-2.06 (m, 1H), 2.00 (t, J = 10.4,
1H), 1.94 (dd, J = 9.4, 3.6 Hz, 1H), 1.79-1.71 (m, 1H), 1.40 (d,
J = 8.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 138.8 (2C),
138.4, 128.5 (3C), 128.3, 128.1, 127.9, 127.8, 127.6, 127.5, 87.3,
79.2, 76.9, 75.6, 74.3, 72.9, 71.8, 70.7, 54.3, 51.6, 33.6; IR (Neat)
3450, 3088, 3063, 3030, 2925, 2855, 2812, 1713, 1678, 1606, 1497,
1454, 1400, 1167, 1135, 1097, 1068, 1028, 734, 697 cm-1; HRMS
(ESIþ) calcd for C29H33NO4Na ([M þ Na]þ) 482.2303, found
482.2293.
standing: Rf = 0.18 (heptane/EtOAc = 9:1); [R]21 þ33.8
D
(c 1.6, CHCl3); mp 76-77 °C (heptane/EtOAc); 1H NMR
(300 MHz, CDCl3) δ major rotamer 7.46-7.13 (m, 15H),
5.93-5.84 (m, 1H), 5.72 (t, J = 10.0 Hz, 1H), 4.87 (d, J =
11.1 Hz, 1H), 4.83 (d, J = 10.7 Hz, 1H), 4.70 (t, J = 11.3 Hz,
2H), 4.62 (d, J = 11.7 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H),
4.38-4.27 (m, 1H), 4.05 (ddd, J = 9.3, 6.7, 2.9 Hz, 1H), 3.93
(dd, J = 14.0, 2.7 Hz, 1H), 3.90-3.81 (m, 1H), 3.66 (dd, J =
8.4, 6.7 Hz, 1H), 3.41 (dd, J = 13.9, 9.1 Hz, 1H), 3.07-2.76 (m,
1H), 2.55-2.11 (m, 2H); 13C NMR (125 MHz, CDCl3) δ major
rotamer 158.7 (q, JCF = 35.4 Hz), 138.6, 138.5, 138.1, 133.7,
129.0, 128.3, 128.3, 128.2, 128.1, 127.9, 127.8, 127.5, 127.4,
118.1, 116.2 (q, JCF = 288 Hz), 114.3, 84.5, 78.1, 75.0, 74.6,
73.3, 70.6, 51.9, 48.5, 27.8; 19F NMR (282 MHz, CDCl3)
δ major rotamer -69.6 (s, 3F); minor rotamer -67.9 (s, 3F);
IR (Neat) 3090, 3062, 3031, 2929, 2900, 2871, 1692, 1454, 1205,
1144, 1093, 1068, 736, 698 cm-1; HRMS (ESIþ) calcd for
(3S,4R,5R,6S,7R)-3,4,5-Tris(benzyloxy)-1-azabicyclo[5.2.0]-
nonan-6-ol (16):. Rf = 0.23 (heptane/CH2Cl2/MeOH = 7:7:2);
1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 15H), 4.82 (d, J =
10.9 Hz, 1H), 4.74 (d, J = 11.6 Hz, 1H), 4.73 (d, J = 11.3 Hz,
1H), 4.71 (d, J = 10.9 Hz, 1H), 4.65 (d, J = 11.3 Hz, 1H), 4.55
(d, J = 11.6 Hz, 1H), 3.77 (dd, J = 7.0, 2.7 Hz, 1H), 3.70-3.57
(m, 3H), 3.45 (t, J = 7.6, Hz, 1H), 3.30-3.19 (m, 1H), 3.10 (dd,
J = 11.1, 3.9 Hz, 1H), 3.04-2.93 (m, 1H), 2.46 (dd, J = 10.7,
8.9 Hz, 1H), 2.33-2.18 (m, 1H), 1.90-1.81 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 138.8, 138.5, 138.4, 128.4, 128.3 (2C), 127.9,
127.8, 127.7, 127.6, 127.5, 86.7, 86.4, 78.7, 75.8, 73.9, 73.6, 70.5,
66.2, 59.5, 50.8, 19.7; IR (neat) 3420, 3030, 2923, 2852, 1497,
1363, 1261, 1211, 1139, 1095, 734, 697 cm-1; HRMS (ESIþ)
calcd for C29H33NO4Na ([M þ Na]þ) 482.2303, found
482.2281.
C
31H32F3NO4Na ([M þ Na]þ) 562.2176, found 562.2152.
(3S,4S,5R)-3,4,5-Tris(benzyloxy)-1-trifluoroacetyl-1-azacy-
clooct-6-ene (8):. Rf = 0.20 (heptane/EtOAc = 9:1); [R]22
D
1
þ23.9 (c 0.85, CHCl3); H NMR (300 MHz, CDCl3) δ major
rotamer 7.39-7.19 (m, 15H), 5.89-5.58 (m, 2H), 4.77 (d, J =
11.2 Hz, 1H), 4.70 (d, J = 11.5 Hz, 1H), 4.62 (d, J = 11.3 Hz,
2H), 4.59 (d, J = 11.5 Hz, 1H), 4.50 (d, J = 11.6 Hz, 1H), 4.37
(dd, J = 8.8, 5.4 Hz, 1H), 4.13 (dd, J = 8.5, 5.6 Hz, 1H), 4.02 (d,
J = 13.8 Hz, 1H), 3.82-3.65 (m, 4H); 13C NMR (50 MHz,
CDCl3) δ major rotamer 157.0 (q, JCF = 37.0 Hz), 138.3, 138.2,
137.8, 134.2, 128.3, 127.9, 127.7, 126.0, 116.4 (q, JCF = 287
Hz), 83.5, 78.5, 77.3, 74.6, 72.8, 71.8, 47.2, 46.4; 19F NMR (282
MHz, CDCl3) δ major rotamer -69.5 (s, 3F); minor rotamer
-68.2 (s, 3F); IR (neat) 3088, 3063, 3031, 2924, 2870, 1692,
(þ)-Castanospermine. Tribenzyl ether 15 (23.7 mg, 0.0516
mmol) was dissolved in MeOH (7.1 mL). Pd/C (23 mg, 10% Pd)
and concentrated HCl (78 μL) were added. The mixture was
stirred under an H2 atmosphere at room temperature for 48 h
upon which TLC revealed full conversion of 15. Amberlite IRA-
400 (OH) (1.0 g) was added. After 2 h of stirring, the solution
was filtered through a plug of Celite utilizing MeOH. The filtrate
was concentrated under reduced pressure to provide (þ)-casta-
nospermine (9.2 mg, 94%) as a colorless oil that crystallized
slowly. An analytical sample was prepared by recrystalliza-
tion from EtOH: [R]21D þ72.4 (c 0.22, H2O) (lit.1 [R]25D þ79.7
(c 0.93, H2O)); mp 209-213 °C dec (lit.1 mp 212-215 °C dec);
1H NMR (300 MHz, D2O) δ 4.43-4.25 (m, 1H), 3.65-3.59 (m,
1H), 3.59 (t, J = 9.3 Hz, 1H), 3.32 (t, J = 9.1 Hz, 1H), 3.17 (dd,
J = 10.8, 5.15 Hz, 1H), 3.08 (dt, J = 9.2, 2.1 Hz, 1H), 2.39-2.29
(m, 1H), 2.21 (q, J = 9.2 Hz, 1H), 2.04 (t, J = 10.7 Hz, 1H), 2.02
(dd, J = 9.8, 4.5 Hz, 1H), 1.71 (dddd, J = 13.8, 8.7, 8.5, 1.3 Hz,
1H); 13C NMR (50 MHz, D2O) δ 78.0, 70.4, 69.1, 68.6,
68.0, 54.4, 50.6, 31.7; HRMS (ESIþ) calcd. for C8H15NO4Na
([M þ Na]þ) 212.0894, found 212.0888.
1497, 1454, 1206, 1184, 1143, 1100, 1028, 736, 697 cm-1
;
HRMS (ESIþ) calcd for C30H30F3NO4Na ([M þ Na]þ)
548.2020, found 548.2036.
(1S,6S,7R,8R,8aR)-1-Hydroxy-6,7,8-tris(benzyloxy)indolizi-
dine (15). Oxone (114 mg, 0.185 mmol) and NaHCO3 (24 mg,
0.286 mmol) were added to a solution of Na2EDTA (186 μL,
0.4 mM in H2O) and 1,1,1-trifluoroacetone (100 μL) in CH3CN
(500 μL) at -10 °C (MeOH/ice bath). Within 5 min of stirring,
the suspension became pale yellow. Azacyclononene 7 (20 mg,
0.037 mmol) was dissolved in CH3CN (500 μL) and added in a
dropwise manner. The mixture was allowed to warm to 0 °C and
stirred for 4 h upon which TLC revealed full consumption of 7.
The reaction mixture was diluted with CH2Cl2 (5 mL) and
washed with saturated aqueous NaHCO3. The aqueous phase
was extracted with CH2Cl2 (3 ꢀ 2.5 mL), and the combined
organic layers were dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The crude oil was dissolved
in Et2O (7.4 mL), and the solution was cooled to 0 °C. H2O
Acknowledgment. We thank the Danish National Research
Foundation for financial support.
Supporting Information Available: General methods, copies
of NMR spectra, and NMR assignment of 16 and castanosper-
mine. This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 22, 2009 8889