Polyhydroxylated indolizidine alkaloids - An efficient synthesis of 1-deoxy-8,8a-di-epi-castanospermine

Article abstract of DOI:10.1016/S0040-4020(03)00918-9

A new and efficient enantioselective total synthesis of the title deoxycastanospermine derivative has been developed, based on amino acid and β-ketophosphonate chemistry, as well as employment of internal asymmetric induction for the creation of the new chiral centers proved successful. With proper choice of reaction conditions, the approach can also be applied in selective preparation of several isomers of deoxycastanospermine. The length (9 steps) and overall yield of the title compound trihydroxyindolidine 1, 7.3%, compares well with the literature syntheses of similar compounds.

Full text of DOI:10.1016/S0040-4020(03)00918-9

Tetrahedron 59 (2003) 6947–6954
Polyhydroxylated indolizidine alkaloids—an efficient synthesis of
1-deoxy-8,8a-di-epi-castanospermine
a,b
Ari M. P. Koskinena,b and Oili A. Kallatsa
,
*
aLaboratory of Organic Chemistry, Department of Chemical Technology, Helsinki University of Technology, Kemistintie 1, P.O. Box 6100,
Espoo 02015 HUT, Finland
bDepartment of Chemistry, University of Oulu, Fin-90570 HUT Espoo, Finland
Received 28 April 2003; revised 27 May 2003; accepted 10 June 2003
Abstract—A new and efficient enantioselective total synthesis of the title deoxycastanospermine derivative has been developed, based on
amino acid and b-ketophosphonate chemistry, as well as employment of internal asymmetric induction for the creation of the new chiral
centers proved successful. With proper choice of reaction conditions, the approach can also be applied in selective preparation of several
isomers of deoxycastanospermine. The length (9 steps) and overall yield of the title compound trihydroxyindolidine 1, 7.3%, compares well
with the literature syntheses of similar compounds.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of indolizine alkaloids. The continuous chiral
carbinol centers of the target compounds can be introduced
through selective reduction of carbonyl groups and selective
oxidation of double bond. Herein we report an efficient
enantioselective synthesis of the title compound, 1-deoxy-
8,8a-di-epi-castanospermine (Fig. 2).
Aminosugar glycosidase inhibitors are structural analogs of
monosaccharides in which the ring oxygen has been
replaced by nitrogen. These alkaloids include polyhydroxy-
lated derivatives of piperidine (A), pyrrolidine (B),
pyrroline (C), indolizine (D) and pyrrolizidine (E) (Fig. 1).1
Two earlier syntheses of the title compound have been
reported.6 The NMR data given in the older one6a has been
reported to be erroneous.6b,c In this work we also found that
none of the products reported by Chan correspond to the title
compound.
Castanospermine2,3 has attracted continued interest by
synthetic and medicinal chemists for its inhibitory action
toward various glucosidase enzymes and promising effects
against autoimmune diseases (e.g. HIV-infection and
diabetes). More than 60 syntheses of castanospermine and
its analogs have been published since the first one by Ganem
and Bernotas in 1984.4,5
The work described in this paper is part of a broader
program aimed at developing new synthetic methods based
on amino acids, which are inexpensive and easily available
chiral compounds in both enantiomeric forms. A specific
goal in this program to develop methods to utilize internal
asymmetric induction in such a way that chirality will be
derived from pre-existing chiral centers in the molecule
without the need to resort to external sources of chirality.
Specifically, this work aims at utilizing the proline-derived
b-ketophosphonates as chiral building blocks in the
Keywords: alkaloid; enantioselection; dihydroxylation; reduction.
*
Corresponding author. Address: Laboratory of Organic Chemistry,
Department of Chemical Technology, Helsinki University of
Technology, Kemistintie 1, P.O. Box 6100, Espoo 02015 HUT,
Finland. Tel.: þ358-9-451-2526; fax: þ358-9-451-2538;
e-mail: ari.koskinen@hut.fi
Figure 1. Alkaloidal glycosidase inhibitors. (A)) Nojirimycin; (B) (2R,5R)-
dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine DMDP; (C) (3R,4R,5R)-
3,4-dihydroxy-5-hydroxymethyl-1-pyrroline FR-900483; (D) castano-
spermine; (E) alexine.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00918-9

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A. M. P. Koskinen, O. A. Kallatsa / Tetrahedron 59 (2003) 6947–6954
2.2. Synthetic analysis (Scheme 2)
The amino acid synthetic sequence, based on proline as
starting material, belongs among the pyrrolidine syntheses.
Thus, the piperidine ring would be annealed after
installment of all the chiral centers in 6 (Scheme 2).
The continuous chiral carbinol centers in 6 were envisioned
to arise from an anti-selective dihydroxylation of the
corresponding allylic alcohol 5a (Kishi selectivity).7
Based on our earlier experiences in the sphinogisine
synthesis, we expected that the chirality in the allylic
alcohol center in 5a could be efficiently derived from the
a0-chiral a,b-unsaturated enone 4.8 The enone would be
efficiently available from L-proline through the b-keto-
phosphonate 3.9
Figure 2.
2. Results and discussion
2.1. Earlier synthetic strategies for castanospermine
analogues
2.3. Synthesis of the allylic alcohol (Scheme 3)
The earlier syntheses of castanospermine analogues can be
divided into three main classes according to how the
indolizidine skeleton is constructed (Scheme 1). The first
two classes are based on the first strategic disconnection in
the indolizidine skeleton. In the pyrrolidine approach the
last synthetic step in building up the carbon framework is
always the formation of the bond between C-5 and nitrogen.
In the piperidine approach the last transformation is the
formation of the bond between C-3 and nitrogen. The third
class, the miscellaneous strategies include all those
strategies that do not fall into the first two classes.
Proline derived phosphonate 3 has been synthesized
previously by Heathcock and von Geldern9 from Boc-
proline methyl ester and dimethyllithiomethylphoshonate
(DMMP).
The most common application of the phosphonates is
Horner–Wadsworth–Emmons olefination.10 Preparation of
non-racemic phosphonates has recently been reviewed by
Wiemer.11
Scheme 1.
Scheme 2.

A. M. P. Koskinen, O. A. Kallatsa / Tetrahedron 59 (2003) 6947–6954
6949
Scheme 3.
The phosphonate anion was generated at 2788C in THF by
addition of n-BuLi, and to confirm the anion formation the
mixture was allowed to warm to 2408C. The white
suspension was then cooled back to 2788C and proline
ester 2 was added. After the addition the mixture was
allowed to warm to room temperature. Clarification of the
reaction mixture indicated that the actual reaction took place
already at 2308C.
racemization of base labile substrates. Yields and optical
purities of this modification are comparable and in some
cases even better than with LiCl/DBU or LiCl/DIPEA.15 In
terms of practical advantages, K2CO3 is not only inexpen-
sive but makes the purification procedure simple, consisting
simply of filtration of the reaction mixture.
Thus, treatment of b-ketophosphonate 3 with powdered
K2CO3 in MeCN, followed by addition of benzyloxy-
acetaldehyde16 led to the desired reaction. As the reaction
proceeded the mixture began to change color from white to
yellow. The reaction mixture remains heterogeneous
throughout the reaction, therefore scaling the reaction
affects the reaction times: smaller scale reactions from 6
to 16 mmol were complete in 20 h, but when the reaction
was scaled up to 38 mmol the reaction time doubled to 43 h.
Enone 4 was much less prone to racemization on silica than
the corresponding serine derived enones, and purification on
silica gel chromatography could be performed (94%ee).12
The yields varied from 55 to 68%.
The product was isolated from the reaction mixture by first
adding 10 wt% citric acid with vigorous stirring until the pH
was slightly acidic (5–6). Lowering the pH below 5 resulted
in decomposition of the product phosphonate. Isolation was
completed by extraction with EtOAc.
Purification of the phosphonate was performed by filtering
through silica with two eluent systems. In larger scale
reactions (.10 mmol scale), up to 25% of the starting
material remained unreacted. The less polar unreacted
proline ester 1 was eluted with 20% EtOAc/hexanes and
then the phosphonate with 100% EtOAc. No racemization
of the unreacted proline ester was detected. Optical purity of
the product was determined by chiral HPLC (98%ee).
Reduction of unsaturated carbonyl compounds has been a
challenge for synthetic chemists because reduction of the
carbonyl function often is accompanied by saturation of the
olefinic functionality. The literature reports some methods
to show regioselectivity, e.g. 9-BBN,17 NABH4 in the
presence of lanthanoid salts,18 diisopropylaluminumhydride
(DIBAL-H),19 and hindered alkylborohydrides.20
The yield reported by Heathcock and von Geldern was 96%
but they did not disclose the actual reaction conditions or the
scale. In our work the yield varied from 75 to 85%,
depending on the scale. The lower yields were obtained in
repeated 100 mmol scale. The pure b-ketophoshonate is a
clear liquid and can be stored in a freezer without
racemization.
Utilization of internal asymmetric induction in the reduction
step in such a way that chirality at the a position would
determine the stereochemistry of the formed alcohol
without the need to resort to chiral reducing agents has
proved useful for serine-derived enones.8 Similar approach
was chosen in this work. The general synthetic sequence
relies on anti selective reduction of the enone 4.
Conventional methods for the HWE reaction, although
milder than standard Wittig procedure, are still too vigorous
for base-sensitive substrates, e.g. NaH in THF. Masamune
and Roush discovered that LiCl enhances the acidity of
phosphonate by complexation with phosphonate carbanion
and thus allows the use of weaker bases like DBU and
DIPEA.12 However, these conditions usually require
chromatographic purification of the product, which often
is not stereochemically stable during purification.
Reduction experiments were performed under several
different conditions to achieve selective reduction and the
desired anti isomer 5a. For purposes of comparison, both
chelation controlled and non-chelation controlled reaction
conditions were tested. The diastereoselectivity of each
reaction was determined by HPLC (Table 1).
An alternative mild base system method has been described
by us for the preparation of base sensitive a-diazocarbonyl
compounds.13 This method was later optimized for the
HWE reaction for serine derivatives.14 In the modification,
K2CO3/MeCN forms a base/solvent system that is strong
enough to accomplish the reaction yet mild enough to avoid
Selectivities can be understood by looking at the two sets of
energy minimum conformations for enone 4 found by
standard Monte Carlo conformation search (Fig. 3).21 On
steric grounds, conformation A can be considered more

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A. M. P. Koskinen, O. A. Kallatsa / Tetrahedron 59 (2003) 6947–6954
Table 1. Reduction experiments
barrier of rotation of the enone side chain. This is further
attested by the fact that we were not able to see meaningful
nOe’s in the spectra of 4.24
Entry
Conditions
Selectivity anti/syna
1
2
3
4
5
DIBAL-H, toluene, 2788C
NaBH4, CeCl3·9H2O, MeOH
NaBH4, CeCl3·9H2O, i-PrOH
9-BBN, THF, 08C
1.3:1
2.4:1
1.1:1
–
The reduction under the Luche conditions in methanol was
scaled up to 19 mmol. The combined yield of the isomeric
alcohols 5a and 5b was quantitative regardless of the scale
and the selectivity remained the same. The anti-alcohol, 5a,
was enriched with MPLC to a 20:1 mixture which was used
in further reaction steps.
L-Selectride, THF, 2788C
1:5.3
a
Ratios determined by HPLC from crude reaction mixture. The mass
balance in each experiment was satisfactory (.95%).
2.4. Determination of the stereochemistry of the
reduction
For determination of its stereochemistry, the alcohol 5a was
converted to (S)- and (R)-MTPA esters according to the
procedure of Kobayashi et al.25,26
The NMR spectra were measured at 500 MHz and the
signals were assigned with reference to two-dimensional
correlation spectra (HSQC). Chemical shift differences (Dd)
between the (R) and (S) isomers were calculated and the
results were compared against the Mosher configuration
model (Fig. 4). The stereochemistry of the alcohol 5a was
assigned to be R.
Figure 3. Minimum energy conformations for enone 4.
favorable because steric repulsion between the ‘side chain’
and the N-Boc group is minimized.22 Thus, a non-
coordinating large hydride reagent would attack from0 the
less hindered side of the molecule along the axis a in
conformation A to give the syn-alcohol as the major
product. The experimental results are in accordance with
this, as L-selectride, bulky, non-coordinating alkylboro-
hydride, in coordinating solvent cleanly gave syn-alcohol
5b.
2.5. Synthesis of (2S,10S,2R/S,3R/S)-N-tert-butoxy-
carbonyl)-2-[(40-benzyloxy-10,20,30-trihydroxy)butyl]-
pyrrolidine (Scheme 4)
Osmium tetroxide catalyzed cis hydroxylation of the
alcohol 5a produced two isomers in approximate ratio 5:1.
On the basis of the mechanistic rationalization,27 the major
Chelation controlled conditions should favor hydride attack
from the opposite face of the alkene. However, in this case
steric requirements for selective reaction are not fulfilled. In
condition 1, aluminum coordinates to carbonyl group prior
to reduction. The bulky aluminum complex only slightly
favors conformation B leading to anti-alcohol. Both faces
are thus accessible to hydride attack and practically no
selection was detected. Low selectivity was accompanied by
a considerable amount of 1,4-reduction.
Figure 4. Determination of the configuration by Mosher method.
Another anti selective reduction protocol is hydride
reduction under Luche conditions.23 It has been suggested
that cerium metal forms an adduct with the alcoholic
solvent, which then coordinates to the carbonyl oxygen.
Reduction with an alkoxyborohydride occurs from the less
hindered side of the complex. The selectivity was not
marked in this case either, but no 1,4-reduction was detected
and the yield of the two alcohols was almost quantitative. In
i-propyl alcohol the reaction rate was much slower and the
selectivity was lost completely. This might be because the
actual reducing species in this solvent is NaBH4.
On steric grounds 9-borabicyclononane should give the anti
isomer, but no reaction was detected. It has been reported
that this reagent has reduced reactivity with sterically
hindered ketones.23
The low selectivities are obviously due to relatively low
Scheme 4.

A. M. P. Koskinen, O. A. Kallatsa / Tetrahedron 59 (2003) 6947–6954
6951
isomer was assumed to be the anti isomer. The assignment
was also later confirmed by NMR (see below).
asymmetric induction for the creation of the new chiral
centers proved successful. With proper choice of reaction
conditions, the approach can also be applied in selective
preparation of several isomers of deoxycastanospermine.
The length (9 steps) and overall yield of the trihydroxy-
indolidine 1, 7.3%, compares well with the literature
syntheses.
The reaction was performed under standard conditions
(OsO4 and N-methylmorpholine-N-oxide in acetone/water),
and was complete in 16 h. The main isomer 6a crystallized
almost completely from the reaction mixture when 25%
EtOAc/hexane was added. The residue was chromato-
graphed to give pure all syn triol 6b. The reaction yielded
57% of 6a and 17% of 6b. The major isomer was used in the
synthesis of trihydroxyindolizidine 1.
4. Experimental
4.1. General
2.6. Concluding the synthesis of (6S,7R,8S,8aS)-6,7,8-
trihydroxyindolizidine 1 (Scheme 4)
THF was distilled prior to use from sodium/benzophenone,
MeCN from phosphorus pentoxide, MeOH from mag-
nesium methoxide, CH2Cl2 from CaH2 and toluene was
distilled from Na. Diethyl ether was distilled from LiAlH4
and stored over sodium. Triethylamine and pyridine were
distilled and stored over molecular sieves. Other solvents
and reagents were used as obtained from the supplier
without further purification.
In order to convert triol 6a to the bicyclic indolizidine the
benzyloxy group should be replaced by a good leaving
group to facilitate cyclization. Literature examples show
that removal of the nitrogen protective group would then
lead to instant cyclization.28 Mesylate was chosen as the
leaving group.
To differentiate the hydroxyl groups in the mesylation step,
triol 6a was first converted to acetyl protected 7. Acetylation
in standard conditions (Ac2O, pyr, CH2Cl2, DMAP) gave 7
almost quantitatively (96%). Debenzylation by catalytic
hydrogenation gave the primary alcohol 8 (96%).
All air and moisture sensitive reactions were carried out
under positive argon atmosphere with magnetic stirring.
Evaporation of the solvents was performed with a Bu¨chi
rotavapor followed by static evaporation with an oil pump.
Analytical TLC was performed using precoated aluminium
plates (Merck Kieselgehl 60 F254). The chromatograms
were visualized with UV and/or polyphosphomolybdic acid
in 90% EtOH (10 g/100 mL), anisaldehyde/glacial acetic
acid/H2SO4/EtOH (5:1:5:90), 10% H2SO4/H2O or
ninhydrin in i-PrOH (1 g/100 mL, 3–5 drops of glacial
acetic acid). Flash chromatography was performed using
Silica gel 60 (E. Merck) as the stationary phase. HPLC was
performed using the following columns: Shandon Hypersil
Silica Column with Waters Guard-PakTM precolumn fitted
with ResolveTM silica inserts for normal phase chroma-
tography and Daicel chiralcel OD 25 cm£0.46 cm with
Daicel chiralcel OD 5 cm£0.46 cm precolumn for chiral
chromatography.
Mesylation of the primary alcohol (MsCl, Et3N) furnished
9, which was cyclized in two steps. The N-Boc protecting
group was removed with trifluoroacetic acid in CH2Cl2. The
reaction was over in 2 h, after which the mixture was
evaporated to dryness to remove excess of TFA. The residue
was dissolved in acetonitrile and 300 mol% triethylamine
was added to liberate TFA salt. Cyclization took place
smoothly when the mixture was stirred at room temperature
to give (6S,7R,8S,8aS)-6,7,8-triacetoxyindolizidine 10 in
50% yield over two steps.
Hydrolysis of 10 gave (6S,7R,8S,8aS)-6,7,8-trihydroxyin-
dolizidine 1 in 77% yield. The title compound was thus
synthesized in 9 steps and 7.3% overall yield. The
stereochemistry of the product was assigned by NMR
(coupling constants shown in Fig. 5). The NMR data was
identical with those reported by Martin.6b
Melting points were determined with Gallenkamp melting
point apparatus MFB-595 and are uncorrected. Optical
rotations were determined on a Perkin–Elmer digital
polarimeter in a 1 dm/1 mL cell (c¼g/100 mL).
The mass spectra were measured by the Mass Spectrometry
Laboratory in the University of Oulu on a Kratos MS 80.
Elemental analyses were performed by the Trace Element
Laboratory in the University of Oulu. NMR spectra were
recorded on Bruker AM200 (1H 200.13 MHz, 13C
50.32 MHz), or Bruker DX400 (1H 400.13 MHz, 13C
100.62 MHz) or Bruker DPX 500 (1H NMR 500.13 MHz,
13C 125.77 MHz). Chemical shifts are reported in ppm (d)
and referenced to internal tetramethylsilane (TMS) or
solvent residual signal.
Figure 5.
3. Conclusions
4.1.1. (2S)-N-(tert-Butoxycarbonyl)-2-[(dimethoxy-phos-
phinyl)-acetyl] pyrrolidine 3. Dimethylmethyl-phos-
phonate (0.866 mL, 8 mmol, 200 mol%) in THF (10 mL)
was cooled to 2788C. n-BuLi (8 mmol, 200 mol%) was
added dropwise keeping internal temperature below 2658C.
A new and efficient enantioselective total synthesis of
the title deoxycastanospermine derivative has been
developed, based on amino acid and b-ketophosphonate
chemistry, as well as employment of internal

6952
A. M. P. Koskinen, O. A. Kallatsa / Tetrahedron 59 (2003) 6947–6954
After addition the mixture was allowed to warm to 2208C
bath and then cooled back to 2788C. L-Boc-proline methyl
ester 2 (0.916 g, 4 mmol, 100 mol%) dissolved in THF
(5 mL) was added into the mixture keeping temperature
below 2658C. The resulting white suspension was allowed
to warm slowly to room temperature and stirred for an
additional 4 h. The reaction was quenched with 10 wt%
citric acid and the pH was adjusted to 3. EtOAc (20 mL) was
added and the layers were separated. The aqueous phase was
extracted with EtOAc (2£10 mL). The combined organic
phases were washed with brine and dried over Na2SO4.
After filtration, the solvent was evaporated. The crude
product was purified by flash chromatography (silica, 100%
EtOAc) to give 3 as a clear oil (1.1 g, 3.4 mmol, 85.2%). Rf
(EtOAc)¼0.13. [a]2D0¼þ18.7 (c¼4.6, CH2Cl2). dH
(200 MHz, CDCl3) 1.34, 1.35 (2s, 9 H, rotamers), 1.74–
2.13 (m, 4H), 3.14, (m, 2H, rotamers), 3.4 (m, 2H), 3.69 (d,
5a: Rf (25% EtOAc/hex)¼0.08. [a]2D0¼261.0 (c¼1.0,
CH2Cl2). dH (200 MHz, CDCl3) 1.45 (s, 9H), 1.70–2.04
(m, 4H), 3.14–3.52 (m, 2H), 4.04 (d, 2H, J¼5.5 Hz), 4.15–
4.26 (m, 1H), 4.5 (s, 2H), 5.68 (dd, 1H, J¼15.7, 6.1 Hz),
5.84 (dt, 1H, J¼15.7, 5.5 Hz), 7.22–7.38 (m, 5H). dC
(50 MHz, CDCl3) 24.0, 28.4 (4C), 48.1, 62.8, 70.2, 71.9,
75.1, 80.3, 127.6, 128.4, 129.0, 131.2, 138.4, 156.9. HRMS
m/z calcd for C20H29NO4 (Mþ1) 348.2175, found 348.2168.
5b: Rf (25% EtOAc/hex)¼0.08. [a]2D0¼262.4 (c¼1.0,
CH2Cl2). dH (200 MHz, CDCl3) 1.47 (s, 9H), 1.75–1.91
(m, 4H), 3.28–3.43 (m, 2H), 3.83–3.87 (m, 2H), 4.05 (d,
2H, J¼5.6 Hz), 4.52 (s, 2H), 5.31 (bs, 1H), 5.7 (dd, 1H,
J¼15.4 Hz, 6.4 Hz), 5.88 (dt, 1H, J¼15.6 Hz, 5.2 Hz),
7.30–7.34 (m, 5H). dC (50 MHz, C6D6) 22.9, 27.4, 46.5,
62.3, 69.3, 71.2, 75.5, 79.0, 126.8, 127.3, 127.9, 132.3,
138.3, 156.7. HRMS m/z calcd for C20H29NO4 (Mþ1)
348.2175, found 348.2167.
3
9H, J(P, H), 11.3 Hz), 4.2 (m, 1H). dC (50 MHz, CDCl3)
23.5, 24.3, 28.1, 29.3, 35.9, 38.5, 46.6, 52.6, 65.5, 65.9,
79.8, 80.2, 153.5, 154.5, 201.3. HRMS m/z calcd for
C13H24NO6P (Mþ1) 322.1420, found 322.1459.
4.1.4. R-MTPA ester of 5a. Alcohol 5a (20 mg, 0.06 mmol,
100 mol%) was dissolved in CH2Cl2 (1 mL), and R-MTPA
(54 mg, 0.23 mmol, 400 mol%), dicyclohexylcarbodiimide
(36.6 mL, 0.23 mmol, 400 mol%) and 4-(N,N-dimethyl)-
aminopyridine (10 mg, 0.08 mmol, 120 mol%) were added.
The resulting mixture was stirred at room temperature for
15 min after which it was diluted with CH2Cl2 and filtered.
The filtrate was washed successively with 10 wt% citric
acid, dilute NaHCO3 solution, water and brine and dried
over anhydrous Na2SO4. After evaporation of solvents the
residue was dissolved in hexane and filtered to remove
residual DCC. The product was purified by filtering through
a short silica pad to give the product as a yellowish oil
(20 mg, 0.035 mmol, 59%). Rf (25% EtOAc/hex)¼0.46.
[a]2D0¼22.8 (c¼1.0, CHCl3). dH (500 MHz, CDCl3) 1.5 (s,
9H), 1.73, 1.63 (m, 2 H), 1.9 (m, 2H), 3.08 (m, 1H), 3.4, 3.36
(m, rotamers, tot. 1H), 3.49 (s, 3H), 3.96, 3.82 (m, rotamers,
tot 1H), 4.03 (d, 2H, J¼4.6 Hz), 4.50 (d, 2H, J¼4.3 Hz),
5.64 (m, 1H), 5.88 (ddt, 1H), 6.12 (m, 1H), 7.35–7.29 (m,
10H). dC (125 MHz, CDCl3) 23.2, 23.9, 25.3, 26.3, 26.9,
28.38, 28.45, 47.0, 47.2, 55.2, 59.7, 69.4, 72.0, 72.3, 76.1,
76.4, 79.6, 80.2, 84.9, 122.3, 124.6, 126.5, 126.6, 126.8,
127.4, 127.7, 128.6, 129.6, 131.6, 132.1, 138.0, 154.1,
154.6, 165.6, 166.0. HRMS m/z calcd for C30H36F3NO5
(Mþ17) 564.2572, found 564.2541.
4.1.2. (2S)-N-(tert-Butoxycarbonyl)-2-[(40-benzyloxy-10-
oxo)-E-but-20-en]pyrrolidine 4. To a solution of b-keto-
phosponate 3 (12.14 g, 37.8 mmol, 100 mol%) in MeCN
(200 mL) was added powdered K2CO3 (15.7 g, 113.4 mmol,
300 mol%). The resulting mixture was stirred for 15 min
after which benzyloxyacetaldehyde (5.68 g, 37.8 mmol,
100 mol%) in MeCN (60 mL) was added. The mixture
was stirred at room temperature for 48 h after which 10 wt%
citric acid was added until pH was 5. The mixture was
extracted with CH2Cl2 (3£50 mL) and the organic layers
were combined and successively washed with water and
brine, and dried over anhydrous Na2SO4. Filtration and
evaporation gave crude product which was purified by flash
chromatography (silica, 20% EtOAc/hex) to give enone 4 as
a yellowish oil (8.86 g, 25.7 mmol, 68%). Rf (25% EtOAc/
hex)¼0.1. [a]2D0¼228.2 (c¼1.0, CH2Cl2). dH (200 MHz,
CDCl3) 1.36, 1.45 (2s, 9H), 1.82–2.22 (m, 4H), 3.41–3.58
(m, 2H), 4.20 (dd, 2H, J¼1.9, 4.1 Hz), 4.38 (dd, 1H, J¼5.3,
8.3 Hz), 4.57 (s, 2H), 6.53 (dt, 1H, J¼15.6, 1.9 Hz), 6.98 (dt,
1H, J¼15.6, 4.1 Hz), 7.29–7.36 (m, 5H). dC (50 MHz,
CDCl3) 23.7, 28.3 (29.0), 30.2, 46.7, 64.4 (63.7), 68.9, 72.9,
79.9, 124.8, 125.5, 127.6, 127.8, 128.4, 137.7, 143.3, 153.9,
198.4. HRMS m/z calcd for C20H27NO4 (Mþ1) 346.2018,
found 346.2055.
4.1.5. S-MTPA ester of 5a. Prepared as above. Yield 79%
of a yellowish oil. Rf (75% EtOAc/hex)¼0.72. [a]2D0¼226.9
(c¼1.18, CHCl3). dH (500 MHz, CDCl3) 1.46 (s, rotamers,
9H), 1.51, 1.55 (m, 2H), 1.87 (m, 2H), 2.6 (m, 1H), 3.26,
3.16 (m, rotamers, 1H), 3.55 (s, 3H), 3.91, 3.77 (m,
rotamers, tot. 1H), 4.04 (s, 2H), 4.51 (d, 2H, J¼10.1 Hz),
5.73 (m, 1H), 5.99 (ddt, 1H), 6.11 (m, 1H), 7.50–7.32 (m,
10 H). dC (125 MHz, CDCl3) 23.2, 23.9, 25.3, 26.3, 28.4,
28.5, 46.6, 46.8, 55.5, 59.8, 59.8, 69.4, 72.1, 72.4, 76.1,
76.3, 79.4, 80.0, 84.5, 122.2, 124.5, 126.6, 126.7, 127.0,
127.1, 127.3, 127.65, 127.74, 128.3, 129.4, 132.38, 132.43,
137.9, 138.0, 153.9, 154.5, 165.5. HRMS m/z calcd for
C30H36F3NO5 (Mþ17) 564.2572, found 564.2548.
4.1.3. (2S,10R/S)-N-(tert-Butoxycarbonyl)-2-[(40-benzyl-
oxy-10-hydroxy)-E-but-20-en]pyrrolidine 5a/b. To a sol-
ution of enone 4 (6.57 g, 19.04 mmol, 100 mol%) and
CeCl3·7H2O (8.87 g, 23.8 mmol, 125 mol%) in MeOH
(150 mL) was added NaBH4 (0.90 g, 23.8 mmol,
125 mol%) in portions. The reaction mixture was then
allowed to stir at room temperature for 10 min. The reaction
was quenched with 10% HCl until pH was 6. The mixture
was diluted with diethyl ether (50 mL) and the layers were
separated. The aqueous layer was extracted with diethyl
ether (3£20 mL). The combined organic layers were
washed with brine and dried over Na2SO4. Filtration and
evaporation gave the crude mixture (2.4:1 anti/syn) which
was purified by MPLC (silica, CHCl3/Et2O 95:5) to give
anti-alcohol 5a (4.21 g, 12.1 mmol, 63.6%) and syn-alcohol
5b (0.6 g, 1.7 mmol, 9.1%).
4.1.6. (2S,10S,20S/R,30S/R)-N-(tert-Butoxycarbonyl)-2-
[(40-benzyloxy-10,20,30-trihydroxy)butyl]pyrrolidine. To
a solution of alcohol 5a (500 mg, 1.44 mmol, 100 mol%)
in acetone/H2O (8:1, 37 mL), NMO (0.399 mg, 2.88 mmol,

A. M. P. Koskinen, O. A. Kallatsa / Tetrahedron 59 (2003) 6947–6954
6953
200 mol%) and OsO4 (0.91 mL, 0.03 mmol, 2 mol%) were
added. The resulting mixture was stirred at room tempera-
ture for 22 h after which saturated NaHSO4 solution
(20 mL) was added. After stirring for 30 min, the solids
were filtered off and the filtrate was washed successively
with water and brine and dried over Na2SO4. Filtration and
evaporation gave crude products 6a and 6b as thick oil in
ratio 5:1. The main product crystallized from ethyl acetate/
hexanes to give pure 6a as a white powder (309 mg,
0.82 mmol, 57%), mp 1138C. Minor isomer 6b was isolated
as a white foam (92 mg, 0.24 mmol, 17%).
calcd for C19H31NO9 (Mþ1) calcd 418.2077, found
418.2031.
4.1.9. (2S,10S,20S,30(R)-N-(tert-Butoxycarbonyl)-2-
[(10,20,30-triacetoxy-40-methanesulfonyl)-butyl]pyrroli-
dine 9. Triethylamine (177 mL, 1.27 mmol, 200 mol%) and
mesyl chloride (74 mL, 0.90 mmol, 150 mol%) were added
to a solution of 8 (266 mg, 0.64 mmol, 100 mol%) in
CH2Cl2 (10 mL) and the mixture was stirred at rt for 2 h.
Water (20 mL) was added and the layers were separated.
The aqueous phase was extracted with 3£15 mL CH2Cl2
and the organic layers were combined and dried over
Na2SO4. Filtration and evaporation gave quantitatively 9 as
clear oil which was used in the next step without further
purification. Rf (75% EtOAc/hex)¼0.70. dH (200 MHz,
CDCl3) (mixture of rotamers) 5.65, 5.50, 5.23 (multiplets,
tot 3H), 4.34, 4.15, 3.95, 3.69, 3.40, 2.90–3.2 (multiplets,
tot 8H), 2.13, 2.13, 2.09, 2.06, 1.99, 1.96 (singlets, tot 9H),
1.6–2.1 (m, 4H), 1.49, 1.41 (singlets, tot 9H). dC (100 MHz,
CDCl3) 170.1, 169.9, 169.3, 169.1, 154.6, 153.6, 79.7, 69.8,
69.7, 69.0, 68.2, 67.9, 67.4, 67.2, 65.6, 56.6, 56.4, 46.7,
46.5, 37.5, 37.2, 28.3, 25.8, 25.7, 24.3, 23.9, 20.7. HRMS
m/z calcd for C20H33NO11S (Mþ1) calcd 496.1853, found
496.1854.
6a: Rf (75% EtOAc/hex)¼0.52. [a]2D0¼244.7 (c¼0.3,
CH2Cl2). dH (200 MHz, CDCl3) 1.45 (s, 9H), 2.13–1.6
(m, 4H), 3.6–3.15 (m, 4H), 3.69 (d, 2H, J¼4.9 Hz), 3.8–
4.25 (m, 4H), 4.56 (s 2H), 7.32 (broad s, 5H). dC (50 MHz,
CDCl3) 24.7, 26.3, 29.0, 48.4, 60.3, 70.1, 71.3, 72.9, 73.3,
73.9, 80.4, 128.2, 128.4, 128.8, 156.2. HRMS m/z calcd for
C20H31NO6 (Mþ1) calcd 382.2230, found 382.2250.
6b: Rf (75% EtOAc/hex)¼0.45. [a]2D0¼231.9 (c¼1.0,
CHCl3). dH (200 MHz, CDCl3) 1.40 (s, 9H), 1.6–1.9 (m,
4H), 3.16–3.30 (m, 4H), 3.60 (d, 2H, J¼5.8 Hz), 3.8 (m,
1H), 4.0 (m, 1H), 4.1 (m, 1H), 5.1 (m, 1H), 7.2 (m, 5H). dC
(50 MHz, CDCl3) 24.4, 28.4, 29.1, 48.1, 70.5, 71.7, 71.9, 73.5,
76.5, 80.6, 127.7, 128.4, 138.0, 157.6. HRMS m/z calcd for
C20H31NO6 (Mþ1) calcd 382.2230, found 382.2257.
4.1.7. (2S,10S,20S,30R)-N-(tert-Butoxycarbonyl)-2-
[(10,20,30-triacetoxy-40-benxyloxy)butyl]-pyrrolidine 7.
Acetic anhydride (2.18 mL, 2500 mol%) and dimethyl-
aminopyridine (18 mg, cat) were added to a solution of 6a
(350 mg, 0.92 mmol, 100 mol%) in CH2Cl2 (20 mL). The
resulting mixture was stirred at rt for 8 h after which the
solvent was evaporated. The crude product was directly
chromatographed (silica, 30% EtOAC/C6) to give 7 as thick
oil (450 mg, 0.89 mmol, 96%). Rf (50% EtOAc/hex)¼0.67.
[a]2D0¼244.3 (c¼1.02, CH2Cl2). dH (200 MHz, CDCl3) d
1.43, 1.51, (2s, 9H, rotamers), 1.6–2.15 (m, tot. 6H), 1.97 (s,
3H), 2.04 (s, 6H), 3.0–3.2 (m, 1H), 3.25–3.6 (m, 3H),
3.65–3.95 (m, 1H, rotamers), 5.15–5.7 (m, 3H), 7.22–7.32
(m, 5H). dC (50 MHz, CDCl3) 20.57, 20.72, 23.98, 25.77,
28.40, 46.68, 56.96, 67.64, 68.71, 69.75, 73.42, 79.60,
127.68, 127.82, 128.31, 137.64, 169.09, 169.70, 170.16.
HRMS m/z calcd for C26H37NO9 (Mþ1) 508.2522, found
508.2547.
4.1.10. (6S,7R,8S,8aS)-6,7,8-Triacetoxyindolizidine 10.
Trifluoroacetic acid (360 mL, 4.85 mmol, 800 mol%) was
added to a solution of 9 (300 mg, 0.606 mmol, 100 mol%) in
CH2Cl2 (8 mL). The resulting mixture was stirred at rt for
2 h after which TLC indicated that all starting material was
consumed. The mixture was evaporated to dryness and the
residue was dissolved in MeCN (5 mL). To this solution
triethylamine (600 mL, 1.8 mmol, 300 mol%) was added
and the mixture was stirred at room temperature for 16 h.
The mixture was evaporated to dryness and chromato-
graphed (silica, 50% EtOAc/hex) to give 10 as a clear oil
(90 mg, 300 mmol, 50%). Rf (75% EtOAc/hex)¼0.44.
[a]2D0¼þ16.0 (c¼1.66, CHCl3). dH (400 MHz, C6D6,
608C) 1.45–1.91 (m, 4H), 1.72 (s, 3H), 1.82 (s, 3H), 2.1
(q, 1H, J¼8.3 Hz), 1.86 (s, 3H), 2.50–2.59 (m, 3H), 2.94
(dt, 1H, J¼2.4, 8.3 Hz), 3.18 (dd, 1H, J¼1.9, 12.6 Hz), 5.14
(dd, 1H, J¼2.2, 5.4 Hz), 5.42 (dd, 1H, J¼3.2, 10.1 Hz), 5.75
(t, 1H, J¼3.2 Hz). dC (100 MHz, C6D6, 608C) 20.2, 20.4,
21.4, 28.5, 51.1, 53.7, 68.7, 70.6, 73.3, 168.7, 169.3. HRMS
m/z calcd for C14H21NO6 299.1369, found 299.1357.
4.1.11. (6S,7R,8S,8aS)-6,7,8-Trihydroxyindolizidine 1.
To a solution of 10 (45 mg, 0.15 mmol, 100 mol%) in
MeOH (5 mL) was added a catalytic amount of NaOMe.
The resulting mixture was stirred at rt for 1 h after which
TLC indicated that all starting material was consumed. The
solvent was evaporated and the residue was chromato-
graphed (silica, 50% EtOH/CHCl3) to give 1 as a white
waxy solid (20 mg, 0.12 mmol, 77%) mp 157–1598C. Rf
(50% CDCl3/MeOH)¼0.24. [a]2D0¼þ15.6 (c¼1.66,
CHCl3). dH (400 MHz, CD3OD) 1.44–1.54 (m, 1H), 1.72
(m, 2H), 1.98 (m, 1H), 2.21 (q, 1H, J¼9.0 Hz), 2.29 (ddd,
1H, J¼6.5, 10.0, 10.0 Hz), 2.48 (dd, 1H, J¼1.1, 11.0 Hz),
2.84 (dd, 1H, J¼1.7, 11.0 Hz), 2.99 (dt, 1H, J¼2.4, 8.8 Hz),
3.58 (dd, 1H, J¼2.8, 10.0 Hz), 3.74–3.78 (m, 2H). dC
(100 MHz, CD3OD) 21.6, 29.0, 54.0, 54.9, 63.8, 71.5, 72.6,
72.8. HRMS m/z calcd for C8H15NO3 173.1052, found
173.1057.
4.1.8. (2S,10S,20S,30R)-N-(tert-Butoxycarbonyl)-2-
[(10,20,30-triacetoxy-40-hydroxy)butyl]pyrrolidine
8.
Compound 7 (400 mg, 0.79 mmol, 100 mol%) was dis-
solved in MeOH (15 mL). Air was evacuated from the
reaction vessel and replaced with argon after which Pd/C
10% (40 mg, 10 wt%) was added. Argon replaced with H2.
The mixture was allowed to stir at room temperature for
18 h. Filtration through a short celite pad and evaporated to
dryness gave 8 as a white waxy solid (310 mg, 0.74 mmol,
94%). Mp 158–1608C. Rf (50% EtOAc/hex)¼0.31.
[a]2D0¼281.0 (c¼0.57, CHCl3). dH (200 MHz, CDCl3)
main rotamer 1.50 (s, 9H), 1.80–2.1 (m, 4H), 1.98 (s,
1H), 2.05 (s, 3H), 2.15 (s, 6H), 3.14 (m, 1H), 3.43–4.0
(m, 4H), 5.56 (m, 2H), 5.71, (bd, 1H, J¼10.3 Hz). dC
(50 MHz, CDCl3) 20.7, 24.0, 25.7, 28.3, 46.6, 56.8, 60.1,
68.4, 69.8, 70.4, 70.8, 79.8, 153.7, 169.2, 170.5. HRMS m/z

6954
A. M. P. Koskinen, O. A. Kallatsa / Tetrahedron 59 (2003) 6947–6954
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
Acknowledgements
1984, 25, 2183–2186.
13. Koskinen, A. M. P.; Munoz, L. J. Chem. Soc., Chem. Commun.
1990, 652–653.
We thank the Finnish Academy for financial support.
14. Koskinen, A. M. P.; Koskinen, P. M. Synlett 1993, 501–502.
15. Gosselin, F.; Lubell, W. D. J. Org. Chem. 1998, 63,
7463–7471.
References
16. Arndt, H. C.; Carrol, S. A. Synthesis 1979, 202–204.
17. Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1975, 40,
1864–1865.
1. Fellows, L. E.; Kite, G. C.; Nash, R. J.; Simmonds, S. J.;
Scofield, A. M. Plant Nitrogen Metabol. 1989, 395–427.
2. Hohenschultz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.;
Pryce, R. J.; Arnold, E.; Clardy, J. Phytochemistry 1981, 20,
811–814.
18. (a) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103,
5454–5459. (b) Luche, J.-L.; Rodriquez-Hahn, L.; Crabbe, P.
J. Chem. Soc., Chem. Commun. 1978, 601–602.
19. Wilson, K. E.; Seidner, R. T.; Masamune, S. J. Chem. Soc.,
Chem. Commun. 1970, 213–214.
3. Nash, R. J.; Fellows, L. E.; Dring, J. V.; Stirton, C. H.; Carter,
D.; Hegarty, M. P.; Bell, E. A. Phytochemistry 1988, 27,
1403–1404.
20. Corey, E. J.; Becker, K. B.; Varma, R. K. J. Am. Chem. Soc.
1972, 94, 8616–8618.
4. Ganem, B.; Bernotas, R. C. Tetrahedron Lett. 1984, 25,
165–168.
21. Modeling was performed with MacroModel 6.0 with
MMFF94 force field.
22. The corresponding Cbz-protected enones give poorer dia-
5. (a) Burgess, K.; Henderson, I. Tetrahedron 1992, 48,
4045–4066. (b) Herczegh, P.; Kovacs, I.; Sztaricskai, F.
Recent Prog. Chem. Synth. Antibiot. Relat. Microb. Prod.
1993, 2, 751–828.
¨
stereoselectivities in the reduction. Pihko, A. J. and Kylmanen,
M., unpublished results from these laboratories.
23. (a) Brown, H. C.; Krishanmurthy, S.; Yoon, N. M. J. Org.
Chem. 1976, 41, 1778–1791. (b) Krishnamurthy, S.; Brown,
H. C. J. Org. Chem. 1977, 42, 1197–1201.
6. Previous syntheses: (a) St-Denis, Y.; Chan, T.-H. J. Org.
Chem. 1992, 57, 3078–3085. (b) Martin, S. F.; Chen, H.-J.;
Lynch, V. M. J. Org. Chem. 1995, 60, 276–278. (c) Majewski,
M.; Shao, J.; Nelson, K.; Nowak, P.; Irvine, N. M. Tetrahedron
Lett. 1998, 39, 6787–6790, see also (c).
24. Koskinen, A. M. P. Pure Appl. Chem. 1993, 65, 1465–1470.
25. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512–519.
7. (a) Cha, J. K.; Christ, W.; Kishi, Y. Tetrahedron 1984, 40,
2247. (b) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett.
1983, 24, 3943.
26. Kobayashi, M.; Chavacula, R.; Murata, O.; Sarma, N. S.
J. Chem. Res. (S) 1992, 366–367.
8. Koskinen, A. M. P.; Koskinen, P. M. Tetrahedron Lett. 1993,
34, 6765–6768.
27. (a) Cha, J. K.; Kim, N.-S. Chem. Rev. 1995, 95, 1761–1795.
(b) Kallatsa, O. A.; Koskinen, A. M. P. Tetrahedron Lett.
1997, 38, 8895–8898.
9. Heathcock, C. H.; von Geldern, T. W. Heterocycles 1987, 25,
75–78.
28. (a) Zhou, P.; Salleh, H. M.; Honek, J. F. J. Org. Chem. 1993,
58, 264. (b) Jadhav, P. K.; Woerner, F. J. Tetrahedron Lett.
1994, 35, 8973–8976. (c) Koskinen, A. M. P.; Paul, J. M.
Tetrahedron Lett. 1992, 33, 6853–6856. (d) Sibi, M. P.;
Christensen, J. W. Tetrahedron Lett. 1990, 31, 5689–5692.
10. Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961,
83, 1733–1738.
11. Wiemer, D. F. Tetrahedron 1997, 53, 16609–16644.
12. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;