Synthesis and glycosidase inhibitory study of new polyhydroxylated indolizidines

Article abstract of DOI:10.1002/ejoc.200800684

The synthesis of two polyhydroxylated indolizidines as potenticial glycosidase inhibitors is reported. The piperidine ring was formed by an intramolecular Mannich-type reaction between ethyl trans-4-oxo-2-butenoate and the two β-amino ketones (-)-1-(2-methyl-1,3-dioxan-2-yl)propan-2-amine and (+)-1-(benzyloxymethyl)-2-(2-methyl-1,3-dioxan-2-yl)ethylamine. The synthesis of this amine was performed in eight steps from L-aspartic acid. The key steps of the formation of the framework involved dihydroxylation, nucleophilic substitution, and reduction. The last hydroxy group was introduced by hydrolysis of the acetal moiety followed by reduction of the resulting ketone. The inhibitory properties of the two synthesized indolizidines were evaluated against a variety of commercial glycosidases. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800684

FULL PAPER
DOI: 10.1002/ejoc.200800684
Synthesis and Glycosidase Inhibitory Study of New Polyhydroxylated
Indolizidines
Delphine Baumann,[a] Khalil Bennis,[a] Isabelle Ripoche,*[a] Vincent Théry,[b] and
Yves Troin*[a]
Keywords: Glycosidase inhibitors / Enzymes / Polyhydroxylated indolizidines / Piperidines / Hydroxylation / Intramolecular
Mannich reaction
The synthesis of two polyhydroxylated indolizidines as po-
tenticial glycosidase inhibitors is reported. The piperidine
ring was formed by an intramolecular Mannich-type reaction
between ethyl trans-4-oxo-2-butenoate and the two β-amino
ketones (–)-1-(2-methyl-1,3-dioxan-2-yl)propan-2-amine and
(+)-1-(benzyloxymethyl)-2-(2-methyl-1,3-dioxan-2-yl)ethyl-
amine. The synthesis of this amine was performed in eight
the framework involved dihydroxylation, nucleophilic substi-
tution, and reduction. The last hydroxy group was introduced
by hydrolysis of the acetal moiety followed by reduction of
the resulting ketone. The inhibitory properties of the two
synthesized indolizidines were evaluated against a variety of
commercial glycosidases.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
steps from L-aspartic acid. The key steps of the formation of
droxylated piperidine, pyrrolidine, pyrrolizidine, or nortro-
pane alkaloids. The glycosidase inhibition activity of these
compounds is related to their structural analogy to the nat-
ural sugar. Under physiological pH, these heterocyles are
presumed to be partially protonated in the active site of
the enzyme, mimicking the positively charged oxygen of the
transition state of the glucoside during its enzymatic hydrol-
ysis.[2]
Introduction
During the last decade, glycosidase inhibitors have been
extensively studied for their biological and therapeutic ap-
plications. Glycosidases represent a class of enzymes in-
volved in a wide range of biological events such as intestinal
digestion, post-translational processing of glycoproteins,
and lysosomal catabolism of glycoconjugates. For this
reason, glycosidase inhibitors have been widely investigated
In the past forty years, more than 100 polyhydroxylated
as drug candidates to treat a variety of diseases such as alkaloids have been isolated from plants and microorga-
diabetes, viral infections including HIV, cancer metastasis, nisms.[3] Among these alkaloids, representative examples
hepatitis, and Gaucher’s disease.[1] Most glycosidase inhibi- are deoxynojirimycin, swainsonine, castanospermine, and
tors are sugar mimics characterized by a polyhydroxylated lentiginosine (Figure 1). These alkaloids have been de-
structure containing an endocyclic nitrogen, namely polyhy- scribed as potent inhibitors of various glycosidases.[4]
Figure 1. Examples of glycosidase inhibitors.
Due to the wide range of biological activities of polyhy-
[a] Laboratoire de Chimie des Hétérocycles et des Glucides, Ecole
droxylated alkaloids and their scarcity in natural sources,
many stereoselective syntheses of natural and unnatural an-
alogues have already been described.[5] The synthesis of
stereoisomeric analogues of these natural compounds is of
considerable interest since it could open the way to struc-
ture-activity relationship (SAR) studies. Among them, the
syntheses of swainsonine, castanospermine, and bicyclic an-
Nationale Supérieure de Chimie de Clermont-Ferrand,
B. P. 187, 63174 Aubière Cedex, France
Fax: +33-4-73407008
E-mail: Yves.Troin@univ-bpclermont.fr
[b] Synthèse et Etudes de Systèmes à Intérêt Biologique SEESIB,
Université Blaise Pascal,
63177 Aubière Cedex, France
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Scheme 1. Retrosynthetic strategy.
alogues have been rigorously studied. The majority of these lecular Mannich-type reaction between the β-amino
known syntheses are based on one-directional strategies ketones of type IV and the commercially available aldehyde
with carbohydrates as starting materials,[6] although asym- 1.
metric synthesis through non carbohydrate substrates is be-
As several methods have been developed within our
coming popular.[7] In this context, a new versatile synthetic group to prepare substituted optically pure β-amino
strategy that could lead to polyhydroxylated indolizidines ketones of type IV, we envisage the preparation of a wide
would be highly useful for further SAR studies and drug range of indolizidines of type I by simply changing the na-
discovery.
ture of the R substituent.
We report herein the synthesis of new trihydroxylated in-
dolizidines with the methodology developed within our
group to synthesize polysubstituted piperidines. This
method, based on an intramolecular Mannich-type reaction
between an aldehyde and an enantiopure β-amino ketone,
Results and Discussion
We initially checked the validity of the proposed syn-
allows for the formation of optically pure cis-2,6-disubsti- thetic scheme with chiral amine (–)-2 (R = Me, Scheme 2),
tuted piperidines[8] and has been applied to the synthesis of since its preparation in enantiomerically pure form, by reso-
several natural products.[9]
lution of the racemic mixture with tartaric acid, is well
We focused our attention on the synthesis of polyhy- known.[10] In a second step, in order to increase the affinity
droxylated indolizidines of type I substituted on the piperi- with the receptor, a new hydroxy functionality (R =
dine ring (Scheme 1). These indolizidines could be obtained CH2OH) was introduced. The key intermediate, (–)-3, was
from indolizidines of type II by cleavage of the acetal moi- obtained by the condensation of amine (–)-2 with aldehyde
ety and stereoselective reduction of the resulting carbonyl 1 under conditions developed by our group to prepare pip-
group. Compounds of type II could be isolated from the eridines in good yield (90%) and high diastereoselectivity
diastereoselective dihydroxylation of a key intermediate of (de Ͼ 95%). Herein, only the cis-2,6-piperidine was de-
1
type III, followed by cyclization on the ester moiety and tected in the H NMR spectrum. Further protection of the
subsequent reduction of the amide group. Finally, com- piperidine with a carbamate group under standard condi-
pounds of type III could be prepared through an intramo- tions furnished the expected compound (+)-4 in high yield.
Scheme 2. Synthesis of diols (–)-5a and (+)-5b.
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New Polyhydroxylated Indolizidines
Scheme 3. Synthesis of indolizidinones (Ϯ)-6a and (Ϯ)-6b.
We then tried the asymmetric dihydroxylation[11] with AD-
mix-α or AD-mix-β, since this sequence had been success-
fully applied on a very similar model.[12] However, in this
case, no reaction was observed, probably due either to the
electron-poor double bond or to the high steric hindrance
between the catalyst and the bulky protective group of pip-
eridine (+)-4. Dihydroxylation was eventually achieved
with a catalytic amount of K2OsO4 and N-methylmorph-
oline N-oxide (NMO) as an oxidant[13] and gave a dia-
stereomeric mixture of diols (–)-5a and (+)-5b in a 1:3 ratio,
resulting from the OsO4 approach to each of the two dia-
stereotopic double-bond faces. At this stage of the synthe-
sis, one crucial point was the determination of the configu-
ration of the stereogenic centres created during the dihy-
droxylation step.
We checked this relative configuration with a more rigid
bicyclic skeleton by NOE experiments. The determination
of the relative configuration of the two hydroxy groups was
performed on the more accessible racemic compounds. As
shown in Scheme 3, hydrogenolysis of carbamates (Ϯ)-5a
and (Ϯ)-5b, followed by treatment of the resulting piperi-
dines with DIPEA, cleanly afforded the corresponding in-
dolizidinones, and at this stage, the hydroxy groups were
converted into the corresponding acetates to furnish the in-
dolizidinones (Ϯ)-6a and (Ϯ)-6b, suitable for convenient
NMR measurements.
Figure 2. Selected NOE studies and molecular models of com-
pounds (Ϯ)-6a and (Ϯ)-6b.
1
The NOESY H spectrum of (Ϯ)-6a showed a 6% NOE
enhancement between H-1Ј and H-8aЈ (Figure 2), which
corresponds to a calculated distance of 2.24 Å, whereas the
same analysis conducted with (Ϯ)-6b showed an effect be-
tween H-1Ј and H-8Јax (enhancement: 6%; distance 2.24 Å).
This is in agreement with the calculated distances (2.36 Å
and 2.43 Å, respectively) of the most stable conformations
obtained after geometry optimization (MACRO-
MODEL).[14] These experiments allowed us to assign the
configuration (1ЈSR,2ЈRS) to isomer (Ϯ)-6a and
(1ЈRS,2ЈSR) configuration to isomer (Ϯ)-6b.
The synthesis of polyhydroxylated indolizidine (–)-12
(Scheme 4) was pursued with the major diol (+)-5b. Hydro-
genolysis of carbamate (+)-5b cleanly afforded piperidine
(+)-7, which was treated with DIPEA to give the corre-
sponding indolizidinone.[15] The lactam carbonyl was di-
rectly reduced with LiAlH4, and the alcohols were pro-
tected as benzyl ethers to afford the corresponding indoliz-
idine (–)-9 in 35% yield over three steps. Regeneration of
the keto group of (–)-9 was realized in acidic medium and
cleanly afforded indolizidinone (–)-10 in 69% yield. Stereo-
[16]
selective reduction of the carbonyl group with NaBH4
Scheme 4. Synthesis of the indolizidine (–)-12.
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FULL PAPER
furnished exclusively equatorial piperidinol (–)-11 (de Ͼ 11.5 Hz) and H-7 and H-6ax (3JH,H = 11.5 Hz), which were
95% from NMR spectra). The stereochemistry of com- characteristic of trans diaxial coupling constants. Finally,
pound (–)-11 was confirmed by careful examination of the hydrogenolysis of the benzyl groups over PdCl2[17] gave tar-
coupling constants between H-7 and H-5ax (3JH,H
=
get compound (–)-12 in quantitative yield.
Scheme 5. Synthesis of amine 15.
Scheme 6. Synthesis of optically pure amine (+)-15.
Figure 3. Determination of the optically purity of amine (+)-15 by NMR spectroscopy with (+)-mandelic acid as a chiral solvating agent.
a) racemic mixture, b) enantiomer (+)-15.
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New Polyhydroxylated Indolizidines
Since the synthetic route proved to be efficient, we then Weinreb amide[20] (+)-17 in moderate yield. At this stage
concentrated our efforts on the synthesis of the hy- of the synthesis, compulsory protection of the alcohol was
droxymethyl analogue of (–)-12, which required the synthe- required to obtain a subsequent efficient protection of the
sis of the corresponding amine of type IV, in which R is a carbonyl group. While standard conditions (NaH, benzyl
protected hydroxymethyl group. Therefore, we envisaged the bromide) did not furnish benzyl ether (–)-19 in an accept-
preparation of amine 15 (R = CH2OBn, Scheme 5), as this able yield, treatment of (+)-18 with Ag2O and benzyl bro-
benzyl ether should be stable under the conditions used in mide furnished desired compound (–)-19 in 70% yield.[21]
the synthesis. We hoped to obtain the corresponding op- Acetalation of the carbonyl group of (–)-19 was then
tically pure amine 15 by resolution of the racemic mixture, achieved[22] in the presence of trimethyl orthoformate and
as described for amine (–)-2.
1,3-propanediol to give the corresponding acetal (–)-20. Fi-
Michael addition of phthalimide to α,β-unsaturated nally, selective hydrogenolysis of the benzyl carbamate fur-
ketone 13[18] gave the phthalimido ketone 14 in good yield. nished amine (+)-15, which was prepared in 8 steps in 6.3%
Protection of the ketone as a dioxane followed by hydraz- overall yield starting from -aspartic acid.
inolysis of the phthalimide moiety furnished desired amine
15 in excellent yield.
The enantiomeric purity of amine (+)-15 was checked by
1H NMR spectroscopy with (+)-mandelic acid as a chiral
Unfortunately, all attempts at the resolution of the race- solvating agent.[23] Comparison of spectra obtained from
mic mixture of amine 15 by fractional crystallization with racemic 15 (Figure 3a) and its (+) isomer (Figure 3b) dem-
tartaric or dibenzoyl tartaric acid were unsuccessful. Thus, onstrated an excellent stereoisomeric ratio (better than
we decided to develop an asymmetric synthesis of amine 95%, Figure 3), proving that no racemisation had occurred
15, starting from the known chiral amino ester (–)-16[19] during the synthesis.
(Scheme 6), readily obtained in three steps from -aspartic
acid.
With optically pure amine (+)-15 in hand, the asymmet-
ric synthesis of the indolizidine (–)-27 (Scheme 7) was
The transformation of ester (–)-16 to the corresponding achieved with the strategy developed for the synthesis of
methyl ketone (+)-18 was performed by the corresponding the indolizidine (–)-12. Condensation of amine (+)-15 with
Scheme 7. Synthesis of indolizidine (–)-27.
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D. Baumann, K. Bennis, I. Ripoche, V. Théry, Y. Troin
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sium sulfate. The mixture was refluxed for 2 h under an inert atmo-
sphere and then cooled to room temperature and transferred to a
solution of dry p-toluenesulfonic acid (4.80 g, 25.2 mmol) in tolu-
ene (150 mL). The resulting mixture was stirred at 60 °C for 2 h
and then washed with saturated aqueous NaHCO3 (50 mL). The
resulting aqueous layer was extracted with dichloromethane
(3ϫ50 mL), and the combined organic layers were washed with
brine (2ϫ50 mL), dried, and concentrated. The residue was puri-
fied by chromatography on silica gel (ethyl acetate and then ethyl
acetate/MeOH, 9:1) to give piperidine (–)-3 (2.71 g, 80%) as a yel-
aldehyde 1 under the conditions previously described gave
the corresponding piperidine (+)-21. Protection of the pi-
peridine moiety and dihydroxylation furnished diols (+)-
23a and (+)-23b in a 1:3 ratio.
As for the previous synthesis, the final steps were con-
ducted on the major isomer (+)-23b. Cleavage of the carba-
mate by hydrogenolysis in the presence of palladium on
charcoal furnished compound (–)-24 quantitatively.[24]
Treatment of the latter under more basic conditions (DBU
instead of DIPEA) led to the cyclization of the resulting low oil. Rf (ethyl acetate/MeOH, 9:1) = 0.54. [α]2D5 = –16.7 (c = 1.1,
CHCl ). IR (film): ν = 3311, 1720, 1656, 1144, 1011 cm–1. 1H NMR
˜
amine on the ester. Reduction of the amide with LiAlH4
and conversion of the hydroxy groups into benzyl ethers
afforded (–)-25. Regeneration of the keto functionality un-
der the conditions previously described did not furnish the
desired product but a mixture, in which no identifiable com-
pound was obtained. Thus, the cleavage of the acetal moiety
was achieved by a two-step sequence:[25] formation of the
corresponding thioacetal, cleanly obtained by transace-
talation of (–)-25 with propanedithiol, followed by hydroly-
3
3
(400 MHz, CDCl3): δ = 6.91 (dd, JH,H = 15.6 Hz, 1 H, H-3), 5.98
3
3
(d, JH,H = 15 Hz, 1 H, H-2), 4.20 (q, JH,H = 7 Hz, 2 H, CH2
ester), 3.91 (m, 4 H, 2ϫOCH2 dioxane), 3.53 (m, 1 H, H-8Ј), 2.92
(m, 1 H, H-10Ј), 2.31 (m, 1 H, H-7Јeq), 2.21 (m, 1 H, H-11Јeq), 1.78
(m, 2 H, CH2 dioxane), 1.27 (t, 3JH,H = 7 Hz, 3 H, CH3 ester), 1.21
(t, JH,H = 12, JH,H = 12 Hz, 1 H, H-7Јax), 1.13–1.06 (m, 4 H,
CH3, H-11Јax) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.5
(C=O), 149.5 (C-3), 120.5 (C-2), 97.1 (C-6Ј), 60.4 (OCH2 ester),
59.4, 59.2 (2ϫOCH2 dioxane), 53.8 (C-10Ј), 47.8 (C-8Ј), 41.1 (C-
3
2
sis of the thioacetal in the presence of [bis(trifluoroacetoxy)- 11Ј), 38.2 (C-7Ј), 25.5 (CH2 dioxane), 22.3 (CH3), 14.2 (CH3 ester)
ppm. HRMS (ESI): calcd. for C14H24NO4 [M + H]+ 270.1705;
found 270.1709.
iodo]benzene [PhI(TFA)2] and trifluoroacetic acid. The cor-
responding indolizidinone (+)-26 was obtained in 40%
overall yield. Stereoselective reduction[16] of the ketone with
Ethyl (E)-3-[(8R,10R)-9-Benzyloxycarbonyl-10-methyl-1,5-dioxa-9-
NaBH4, followed by hydrogenolysis of the benzyl groups azaspiro[5.5]undec-8-yl]acrylate [(+)-4]: To a solution of piperidine
[17]
(–)-3 (3.38 g, 12.6 mmol) in dichloromethane (400 mL) was added
K2CO3 (0.4  solution, 66 mL, 25.2 mmol). The mixture was co-
oled to 0 °C, and a solution of benzyl chloroformate (2.34 mL,
18.9 mmol) in dichloromethane (50 mL) was added dropwise. The
mixture was stirred at room temperature for 24 h, and the resulting
aqueous layer was extracted with dichloromethane (3ϫ100 mL).
The combined organic layers were dried and concentrated. The res-
idue was purified by chromatography on silica gel (ethyl acetate/
cyclohexane, 1:1) to afford piperidine (+)-4 (4.57 g, 90%) as a yel-
low oil. Rf (ethyl acetate/cyclohexane, 1:1) = 0.56. [α]2D5 = +3.1 (c
over PdCl2
(Scheme 7).
gave indolizidine (–)-27 in excellent yield
Following a standard procedure,[26] indolizidines (–)-12
and (–)-27, together with their racemic analogues (Ϯ)-12
and (Ϯ)-27, were evaluated as inhibitors of six commer-
cially available glycosidases: Baker’s yeast α-glucosidase, al-
mond β-glucosidase, green coffee bean α-galactosidase, β-
galactosidase from Aspergillus oryzae, jack bean α-mannos-
idase and α-fucosidase from bovine kidney, with the corre-
sponding p-nitrophenyl glycopyranoside as a substrate. = 1.0, CHCl ). IR (film): ν = 1714, 1698, 1655, 1149 cm–1. 1H
˜
3
3
NMR (400 MHz, CDCl3): δ = 7.34 (m, 5 H, Ph), 7.05 (dd, JH,H
= 16, 7 Hz, 1 H, H-3), 5.87 (d, JH,H = 16 Hz, 1 H, H-2), 5.14 (s,
While compounds 12 and (–)-12 showed no inhibitory ac-
tivity against the selected glycosidases, indolizidine 27 selec-
tively inhibited Aspergillus oryzae β-galactosidase (Ki =
157 µ), yet (–)-27 had no activity on the same glycosidase.
3
2 H, CH2Ph), 4.94 (m, 1 H, H-8Ј), 4.40 (m, 1 H, H-10Ј), 4.09 (q,
3JH,H = 7 Hz, 2 H, CH2 ester), 3.88 (m, 4 H, 2ϫOCH2 dioxane),
2
3
2
2.26 (dt, JH,H = 14, JH,H = 2.5 Hz, 1 H, H-11Јeq), 2.15 (dt, JH,H
3
2
3
= 14, JH,H = 2.5 Hz, 1 H, H-7Јeq), 1.84 (dd, JH,H = 14, JH,H
=
2
3
7 Hz, 1 H, H-11Јax), 1.82 (dd, JH,H = 14, JH,H = 7 Hz, 1 H, H-
7Јax), 1.65 (m, 2 H, CH2 dioxane), 1.27 (d, 3JH,H = 7 Hz, 3 H, CH3
ester), 1.20 (t, 3JH,H = 7 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.4 (C=O ester), 155.4 (C=O carbamate), 149.2 (C-
3), 136.5 (C ipso), 128.5, 128.0, 127.9 (Car), 121.7 (C-2), 96.1 (C-
6Ј), 67.4 (CH2Ph), 60.3 (CH2 ester), 59.5 (2ϫOCH2 dioxane), 51.4
(C-10Ј), 48.8 (C-8Ј), 35.9 (C-11Ј), 35.7 (C-7Ј), 25.2 (CH2 dioxane),
21.8 (CH3), 14.2 (CH3 ester) ppm. HRMS (ESI): calcd. for
C22H29NO6Na [M + Na]+ 426.1893; found 426.1901.
Conclusions
In conclusion, we have developed a new versatile and ef-
ficient synthetic route to prepare optically pure polyhy-
droxylated indolizidines, in which we could introduce vari-
ous substituents on the piperidine moiety. The synthesis is
based on an intramolecular Mannich-type reaction, fol-
lowed by an asymmetric dihydroxylation and cyclization.
The evaluation of the inhibitory properties revealed that
only racemic indolizidine 27 showed a modest inhibitory
activity on Aspergillus oryzae β-galactosidase.
Benzyl (8R,10R)-8-[(1S,2R)-2-Ethoxycarbonyl-1,2-dihydroxyethyl]-
10-methyl-1,5-dioxa-9-azaspiro[5.5] undecane-9-carboxylate [(–)-5a]
and Benzyl (8R,10R)-8-[(1R,2S)-2-Ethoxycarbonyl-1,2-dihydroxy-
ethyl]-10-methyl-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxylate
[(+)-5b]: To a solution of piperidine (+)-4 (1.0 g, 2.5 mmol) in ace-
tone/water (15:10, 25 mL) were added N-methylmorpholine oxide
(577 mg, 5 mmol) and K2OsO4·2H2O (45 mg, 0.13 mmol). The
mixture was stirred at room temperature for 12 h. Solvents were
evaporated off, and osmium salts were removed by filtration
through a pad of silica gel. The residue was purified by chromatog-
raphy on silica gel (ethyl acetate/cyclohexane, 1:1), to give the two
Experimental Section
Ethyl (E)-3-[(8R,10R)-10-Methyl-1,5-dioxa-9-azaspiro[5.5]undec-8-
yl]acrylate [(–)-3]: To a solution of amine (–)-2 (2.00 g, 12.6 mmol)
in anhydrous dichloromethane (100 mL) were added ethyl trans-4-
oxo-2-butenoate 1 (1.22 mL, 13.8 mmol) and anhydrous magne-
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New Polyhydroxylated Indolizidines
diastereoisomers, (–)-5a (212 mg, 20%) and (+)-5b (638 mg, 60%),
as pale yellow oils.
ppm. 13C NMR (100 MHz, C6D6): δ = 170.4, 166.2 (3ϫC ipso),
96.4 (C-7Ј), 75.0 (C-1Ј), 71.9 (C-2Ј), 59.1, 59.0 (2ϫOCH2 dioxane),
55.1 (C-5Ј), 50.0 (C-8Јa), 40.8 (C-6Ј), 34.1 (C-8Ј), 25.5 (CH2 diox-
ane), 20.1 (OCH3), 19,0 (CH3) ppm. HRMS (ESI): calcd. for
C16H24NO7 [M + H]+ 342.1553; found 342.1557.
(–)-5a: Rf (ethyl acetate) = 0.57. [α]2D5 = –9.5 (c = 1.1, CHCl3). IR
1
(film): ν = 3478, 1714, 1680 cm–1. H NMR (400 MHz, CDCl ): δ
˜
3
= 7.35 (m, 5 H, Ph), 5.15 (s, 2 H, CH2Ph), 4.69 (m, 1 H, H-8), 4.57
(m, 1 H, H-10), 4.39 (m, 1 H, H-1Ј), 4.30–4.23 (m, 3 H, CH2 ester, Following the procedure described for piperidine (Ϯ)-6a, starting
H-2Ј), 4.00–3.84 (m, 4 H, 2ϫOCH2 dioxane), 2.32 (m, 1 H, H-
11eq), 2.19 (m, 1 H, H-7eq), 1.87 (m, 1 H, CH2 dioxane), 1.85 (dd,
2JH,H = 14, 3JH,H = 7.5 Hz, 1 H, H-7ax), 1.77 (dd, 2JH,H = 14, 3JH,H
from piperidine (Ϯ)-5b (27.5 mg, 0.06 mmol), piperidine (Ϯ)-6b
(14.3 mg, 66% over 3 steps) was obtained as a colourless oil. Rf
1
(ethyl acetate/MeOH, 9:1) = 0.72. H NMR (400 MHz, CDCl3): δ
3
3
= 7.5 Hz, 1 H, H-11ax), 1.62 (m, 1 H, CH2 dioxane), 1.37 (d, 3JH,H = 5.37 (d, JH,H = 6.5 Hz, 1 H, H-2Ј), 5.00 (t, JH,H = 6.5 Hz, 1 H,
3
= 7 Hz, 3 H, CH3), 1.29 (t, JH,H = 7 Hz, 3 H, CH3 ester) ppm.
H-1Ј), 3.96–3.85 (m, 4 H, 2ϫOCH2 dioxane), 3.53 (m, 1 H, H-5Ј),
13C NMR (100 MHz, CDCl3): δ = 194.1 (C=O ester), 173.4 (C=O
3.44 (ddd, JH,H = 13, JH,H = 6, JH,H = 3 Hz, 1 H, H-8Јa), 2.68
2
3
3
2
3
carbamate), 136.5 (C ipso), 128.5, 128.1, 127.9 (Car), 96.2 (C-6), (dt, JH,H = 13, JH,H = 3 Hz, 1 H, H-8Јeq), 2.18–2.12 (m, 4 H, H-
71.3, 71.1 (C-1Ј, C-2Ј), 67.6 (CH2Ph), 62.1 (CH2 ester), 59.7
(2ϫOCH2 dioxane), 51.9 (C-10), 46.5 (C-8), 37.1 (C-11), 33.3 (C-
7), 25.2 (CH2 dioxane), 20.7 (CH3), 14.1 (CH3 ester) ppm. HRMS
(ESI): calcd. for C22H31NO8Na [M + Na]+ 460.1947; found
460.1955.
6Јeq, COCH3), 2.10 (s, 3 H, COCH3), 1.81–1.69 (m, 2 H,
CH2 dioxane), 1.66 (d, 3JH,H = 7 Hz, 3 H, CH3), 1.50 (dd, 2JH,H
=
=
3
2
3
14, JH,H = 11.5 Hz, 1 H, H-6Јax), 1.42 (t, JH,H = 13, JH,H
13 Hz, 1 H, H-8Јax) ppm. 13C NMR (100 MHz, C6D6): δ = 170.4,
166.2 (3ϫC ipso), 96.1 (C-7Ј), 76.3 (C-1Ј), 75.4 (C-2Ј), 59.2, 59.1
(2ϫOCH2 dioxane), 56.2 (C-5Ј), 49.1 (C-8Јa), 41.1 (C-6Ј), 37.4 (C-
8Ј), 25.5 (CH2 dioxane), 20.2 (OCH3), 19.6 (CH3) ppm. HRMS
(ESI): calcd. for C16H24NO7 [M + H]+ 342.1553; found 342.1558.
(+)-5b: Rf (ethyl acetate) = 0.52. [α]2D5 = +9.5 (c = 1.1, CHCl3). IR
1
(film): ν = 3442, 1732, 1690 cm–1. H NMR (400 MHz, CDCl ): δ
˜
3
= 7.35 (m, 5 H, Ph), 5.19, 5.14 (2 d, J = 12.5 Hz, 2 H, CH2Ph, AB
system), 4.58 (m, 1 H, H-11), 4.33 (m, 1 H, H-1Ј), 4.24 (m, 3 H, Ethyl (2S,3R)-2,3-dihydroxy-3-[(8R,10R)-10-methyl-1,5-dioxa-9-aza-
H-2Ј, CH2 ester), 3.95 (m, 4 H, 2ϫOCH2 dioxane), 3.03 (m, 1 H,
spiro[5.5]undec-8-yl]propanoate [(+)-7]: A solution of piperidine
(+)-5b (290 mg, 0.66 mmol) in methanol (10 mL) containing 10%
2
2
H-11eq), 2.02 (d, JH,H = 14 Hz, 1 H, H-7eq), 1.81 (dd, JH,H = 14,
3JH,H = 7.5 Hz, 1 H, H-7ax), 1.61 (m, 3 H, H-11ax, CH2 dioxane), Pd/C (66 mg) was stirred under hydrogen for 2 h. The catalyst was
3
3
1.29 (d, JH,H = 7 Hz, 3 H, CH3), 1.27 (t, JH,H = 7 Hz, 3 H, CH3
filtered off, and the filtrate was concentrated to afford piperidine
(+)-7 (190 mg, 95%) as a white solid; m.p. 118 °C. Rf (ethyl acetate/
ester) ppm. 13C NMR (100 MHz, CDCl3): δ = 184.4 (C=O ester),
169.5 (C=O carbamate), 135.9 (C ipso), 128.6, 128.4, 128.0 (Car), MeOH, 9:1) = 0.3 [α]2D5 = +2.9 (c = 1.0, CHCl ). IR (KBr): ν =
˜
3
1
96.2 (C-6), 72.4, 69.9 (C-1Ј, C-2Ј), 68.2 (CH2Ph), 61.3 (CH2 ester),
59.7, 59.6 (2ϫOCH2 dioxane), 52.6 (C-10), 46.7 (C-8), 41.3 (C-11),
37.1 (C-7), 25.2 (CH2 dioxane), 21.3 (CH3), 14.1 (CH3 ester) ppm.
HRMS (ESI): calcd. for C22H31NO8Na [M + Na]+ 460.1947; found
460.1951.
1652, 1436, 1385, 1288, 1246 cm–1. H NMR (400 MHz, CDCl3):
3
δ = 4.95 (br. s, 3 H, 2ϫOH, NH), 4.40 (d, JH,H = 2.5 Hz, 1 H,
H-3), 4.25 (qd, 3JH,H = 7, 4JH,H = 2 Hz, 2 H, CH2 ester), 4.00–3.85
2
3
(m, 5 H, H-2, 2ϫOCH2 dioxane), 3.27 (ddd, JH,H = 12.5, JH,H
3
= 4.5, JH,H = 2.5 Hz, 1 H, H-8Ј), 3.01 (m, 1 H, H-10Ј), 2.54 (td,
2JH,H = 13.5, JH,H = 2.5, JH,H = 2.5 Hz, 1 H, H-7Јeq), 2.22 (td,
3
4
(1ЈSR,2ЈRS,5ЈRS,8aЈRS)-5Ј-Methyl-3Ј-oxohexahydro-1ЈH-spiro-
[1,3-dioxane-2,7Ј-indolizine]-1Ј,2Ј-diyl Diacetate [(؎)-6a] and
(1ЈRS,2ЈSR,5ЈSR,8aЈSR)-5Ј-Methyl-3Ј-oxohexahydro-1ЈH-spiro-
[1,3-dioxane-2,7Ј-indolizine]-1Ј,2Ј-diyl Diacetate [(؎)-6b]: A solu-
tion of piperidine (Ϯ)-5a (290 mg, 0.66 mmol) in methanol (10 mL)
containing 10% Pd/C (66 mg) was stirred under hydrogen for 2 h.
The catalyst was filtered off, and the filtrate was concentrated to
afford the diol (190 mg, 95%) as a pale yellow oil. Rf (ethyl acetate/
MeOH, 5:1) = 0.2. To a solution of the diol (80 mg, 0.27 mmol) in
anhydrous toluene (10 mL) was added DIPEA (128 µL,
0.66 mmol). The mixture was refluxed for 12 h. Evaporation of the
solvents gave the indolizidinone as a pale yellow oil. The crude
product was directly engaged in the next step. Rf (ethyl acetate/
MeOH, 9:1) = 0.36. To a solution of the previously prepared piperi-
dine (15.0 mg, 0.06 mmol) in anhydrous pyridine (85 µL,
1.05 mmol) were added acetic anhydride (100 µL, 1.05 mmol, 18
equiv.) and a crystal of DMAP. The mixture was stirred at room
temperature under an inert atmosphere for 12 h. Solvents were re-
moved under reduced pressure, and the majority of the pyridine
was eliminated by the addition and evaporation of toluene. The
residue was purified by chromatography on silica gel (ethyl acetate/
2JH,H = 13.5, 3JH,H = 3, 4JH,H = 3 Hz, 1 H, H-11Јeq), 1.82–1.64 (m,
2
3
2 H, CH2 dioxane), 1.43 (dd, JH,H = 13.5, JH,H = 12.5 Hz, 1 H,
H-7Јax), 1.37–1.27 (m, 4 H, H-11Јax, CH3 ester), 1.18 (d, JH,H
3
=
6.5 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.7
(C=O ester), 96.2 (C-6Ј), 72.1, 71.9 (C-3, C-2), 62.1 (CH2 ester),
59.5, 59.4 (2ϫOCH2 dioxane), 56.9 (C-10Ј), 49.4 (C-8Ј), 40.4 (C-
11Ј), 32.7 (C-7Ј), 25.4 (CH2 dioxane), 20.6 (CH3), 14.2 (CH3 ester)
ppm. HRMS (ESI): calcd. for C14H26NO6 [M + H]+ 304.1760;
found 304.1774.
(1ЈR,2ЈR,5ЈR,8aЈR)-1Ј,2Ј-bis(benzyloxy)-5Ј-methylhexahydro-1ЈH-
spiro[1,3-dioxane-2,7Ј-indolizine] [(–)-9]: To a solution of piperidine
(+)-7 (80 mg, 0.27 mmol) in anhydrous THF (10 mL) was added
DIPEA (128 µL, 0.66 mmol). The mixture was refluxed for 12 h.
Evaporation of the solvents gave the indolizidinone 8 as a pale
yellow oil. The crude product 8 was directly engaged in the next
step. Rf (ethyl acetate/MeOH, 9:1) = 0.35. To a stirred solution
of crude indolizidinone 8 (46.3 mg, 0.18 mmol) in anhydrous THF
(10 mL) was added LiAlH4 (28 mg, 0.72 mmol). The mixture was
refluxed for 2 h. After cooling to 0 °C, water was added (2 mL)
followed by NaOH (1 , 1 mL). The residue was filtered trough
cyclohexane, 1:1) to give (Ϯ)-6a (14.3 mg, 70%) as a colourless oil. Celite® and Na2SO4, washed with ethyl acetate, and then the sol-
1
Rf (ethyl acetate/MeOH, 9:1) = 0.75. H NMR (400 MHz, C6D6):
δ = 5.57 (d, 3JH,H = 5.5 Hz, 1 H, H-2Ј), 5.36 (dd, 3JH,H = 7.5, 3JH,H
= 5.5 Hz, 1 H, H-1Ј), 3.78 (m, 1 H, H-8Јa), 3.36 (m, 4 H, 2ϫOCH2
vents were removed to afford a pale yellow oil. The product was
directly engaged in the next step. Rf (ethyl acetate/MeOH, 9:1) =
0.17. To a solution of the last product (35 mg, 0.144 mmol) in anhy-
2
3
dioxane), 3.12 (m, 1 H, H-5Ј), 2.13 (dt, JH,H = 13, JH,H = 3 Hz, drous THF (4 mL), cooled to 0 °C, was added NaH (14 mg,
2
3
1 H, H-8Јeq), 1.96 (dt, JH,H = 13.5, JH,H = 3 Hz, 1 H, H-6Јeq), 0.58 mmol). The mixture was stirred at 0 °C under Ar for 45 min.
3
1.71 (s, 3 H, COCH3), 1.66 (d, JH,H = 6.5 Hz, 3 H, CH3), 1.49 (s, To this mixture was added dropwise a solution of benzyl bromide
3 H, COCH3), 1.34–1.11 (m, 4 H, CH2 dioxane, H-6Јeq, H-8Јax) (35 µL, 0.3 mmol) in DMF (4 mL), and the mixture was stirred for
Eur. J. Org. Chem. 2008, 5289–5300
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5295

D. Baumann, K. Bennis, I. Ripoche, V. Théry, Y. Troin
FULL PAPER
48 h under an inert atmosphere and then quenched by the addition
of water. The resulting solution was extracted with diethyl ether
(3ϫ10 mL), and the combined organic layers were washed with
brine, dried, and concentrated. The residue was purified by
chromatography on silica gel (ethyl acetate/cyclohexane, 2:8) to give
indolizidine (–)-9 (40 mg, 35% over 3 steps) as a pale oil. Rf (ethyl
acetate/cyclohexane, 1:1) = 0.63. [α]2D5 = –21.9 (c = 1.0, CHCl3). IR
1.87 (m, 1 H, H-8eq), 2.21–1.42 (m, 3 H, H-8ax, H-6ax, OH), 1.09
3
(d, JH,H = 6 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 138.1 (2ϫC ipso), 128.4, 128.3, 127.9, 127.8, 127.7 (Car), 88.7
(C-1), 82.4 (C-2), 73.1, 72.2 (2ϫCH2Ph), 69.6 (C-7), 66.4 (C-5),
55.8 (C-8a), 55.5 (C-3), 42.8 (C-6), 38.4 (C-8), 20.1 (CH3) ppm.
HRMS (ESI): calcd. for C23H30NO3 [M + H]+ 368.2226; found
368.2209.
(film): ν = 2964, 2930, 2868, 1454, 1378, 1325, 1300, 1142, 1092
˜
(1R,2R,5R,7S,8aR)-5-Methyloctahydroindolizin-1,2,7-triol [(–)-12]:
To a solution of indolizidinol (–)-11 (80 mg, 0.22 mmol) in meth-
anol (10 mL) was added PdCl2 (76 mg, 0.43 mmol). The mixture
was stirred under hydrogen for 3 d, filtered through Celite®, and
washed with dichloromethane. The solvents were removed, and the
crude product was eluted on DOWEX® 50WX8 (200–400 mesh,
H+) with water and then aqueous NH4OH (1 ) to give polyhy-
droxylated indolizidine (–)-12 (41 mg, quantitative) as a pale yellow
oil. Rf (ethyl acetate/MeOH, 5:1) = 0.10. [α]2D5 = –28.8 (c = 0.77,
cm–1 1H NMR (400 MHz, CDCl3): δ = 7.35–7.20 (m, 10 H,
.
2ϫPh), 4.54, 4.39 (2 d, J = 12 Hz, 2 H, CH2Ph, AB system), 4.52,
4.48 (2 d, J = 12 Hz, 2 H, CH2Ph, AB system), 3.93–3.74 (m, 5 H,
2ϫOCH2 dioxane, H-2Ј), 3.61 (m, 1 H, H-1Ј), 3.45 (m, 1 H, H-
3
3Јa), 3.14 (d, JH,H = 10.5 Hz, 1 H, H-3Јb), 2.55 (m, 1 H, H-5Ј),
2.29 (m, 1 H, H-8Јa), 2.19 (m, 1 H, H-8Јeq), 1.98 (m, 1 H, H-6Јeq),
1.65 (m, 2 H, CH2 dioxane), 1.31 (m, 2 H, H-6Јax, H-8Јax), 0.98 (d,
3JH,H = 6 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
138.4, 138.1 (2ϫC ipso), 128.7, 128.3, 127.9, 127.7, 127.6 (Car),
97.4 (C-7Ј), 88.9 (C-1Ј), 82.5 (C-2Ј), 72.1, 71.4 (2ϫCH2Ph), 64.1
(C-5Ј), 59.5, 59.1 (2ϫOCH2 dioxane), 55.5 (C-3Ј), 53.7 (C-8Јa),
41.7 (C-6Ј), 34.9 (C-8Ј), 25.6 (CH2 dioxane), 19.9 (CH3) ppm.
HRMS (ESI): calcd. for C26H34NO4 [M + H]+ 424.2488; found
424.2481.
1
3
MeOH). H NMR (400 MHz, CD3OD): δ = 3.93 (ddd, JH,H = 6,
3
3
3
3JH,H = 4, JH,H = 2 Hz, 1 H, H-2), 3.59 (dd, JH,H = 9, JH,H
=
=
2
3
4 Hz, 1 H, H-1), 3.54 (m, 1 H, H-7), 2.97 (dd, JH,H = 11, JH,H
1.5 Hz, 1 H, H-3a), 2.58 (dd, JH,H = 11, JH,H = 7.5 Hz, 1 H, H-
2
3
3b), 2.26 (m, 1 H, H-5), 2.16–2.06 (m, 2 H, H-8a, H-6eq), 1.83 (m,
3
1 H, H-8eq), 1.21 (m, 5 H, H-8ax, H-6ax, 3ϫOH), 1.03 (d, JH,H
=
6.5 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CD3OD): δ = 83.9
(C-1), 77.7 (C-2), 69.2 (C-8a, C-7), 59.4 (C-3), 57.8 (C-5), 43.2 (C-
8), 37.9 (C-6), 19.8 (CH3) ppm. HRMS (ESI): calcd. for C9H18NO3
[M + H]+ 188.1287; found 188.1290.
(1R,2R,5R,8aR)-1,2-Bis(benzyloxy)-5-methylhexahydroindolizin-7-
one [(–)-10]: To a solution of indolizidine (–)-9 (39 mg, 0.09 mmol)
in dichloromethane (5 mL) was added dropwise TFA (50% aque-
ous, 160 µL, 1.1 mmol). The mixture was stirred at room tempera-
ture for 3 h and quenched with a saturated solution of NaHCO3.
The resulting aqueous layer was extracted with dichloromethane
(3 ϫ 10 mL), and the combined organic layers were dried with
Na2SO4 and concentrated. The residue was purified by chromatog-
raphy on silica gel (ethyl acetate/cyclohexane, 1:2) to give indolizid-
ine (–)-10 (23.3 mg, 69%) as a pale yellow oil. Rf (ethyl acetate/
2-(1-Benzyloxymethyl-3-oxobutyl)isoindol-1,3-dione [(؎)-14]: To a
solution of (E)-5-(benzyloxy)pent-3-en-2-one [(Ϯ)-13, 10.1 g,
53.3 mmol)] in ethyl acetate (250 mL) was added phthalimide
(7.9 g, 53.7 mmol). The reaction mixture was stirred for 5 min, and
a solution of benzyltrimethylammonium hydroxide (Triton B®,
200 µL) was added. The mixture was refluxed for 3 h, and the solu-
tion was neutralized by the addition of NaOH (1 ). The aqueous
layer was extracted with ethyl acetate (3ϫ50 mL), and the com-
bined organic layers were dried on Na2SO4, filtered, and concen-
trated. Recrystallization of the residue from ethanol gave 5-ben-
zyloxy-4-phthalimido-2-pentanone [(Ϯ)-14, 16.2 g, 89 %)] as a
cyclohexane, 1:1) = 0.66. [α]2D5 = –4.8 (c = 0.88, CHCl3). H NMR
1
(400 MHz, CDCl3): δ = 7.47–7.27 (m, 10 H, 2ϫPh), 4.53, 4.49 (2
d, J = 11.5 Hz, 2 H, CH2Ph, AB system), 4.55, 4.42 (2 d, J = 12 Hz,
3
3
2 H, CH2Ph, AB system), 3.99 (dd, JH,H = 6, JH,H = 2.5 Hz, 1
3
3
H, H-2), 3.79 (dd, JH,H = 7, JH,H = 2.5 Hz, 1 H, H-1), 3.32 (d,
3JH,H = 10.5 Hz, 1 H, H-3a), 2.65 (m, 1 H, H-8eq), 2.50–2.35 (m,
4 H, H-8a, H-8ax, H-5, H-3b), 2.28 (m, 2 H, H-6ax, H-6eq), 1.17 (d,
3JH,H = 6 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
208.0 (C-7), 137.8, 137.7 (2ϫC ipso), 128.4, 128.1, 127.9, 127.7
(Car), 89.5 (C-1), 82.1 (C-2), 72.1, 71.5 (2ϫCH2Ph), 67.5 (C-5),
56.7 (C-8a), 55.3 (C-3), 48.3 (C-6), 45.5 (C-8), 20.6 (CH3) ppm.
HRMS (ESI): calcd. for C23H28NO3 [M + H]+ 366.2069; found
366.2057.
white solid; m.p. 138 °C; Rf (ethyl acetate/cyclohexane, 1:1) = 0.60.
1
IR (film): ν = 1774, 1706, 1608, 1496, 1172, 1090, 1030 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 7.81 (m, 2 H, Ph), 7.68 (m, 2 H,
2
Ph), 7.27 (m, 5 H, Ph), 5.05 (m, 1 H, H-4), 4.54 (d, JH,H = 12 Hz,
2
1 H, CH2Ph), 4.53 (d, JH,H = 12 Hz, 1 H, CH2Ph), 3.75 (m, 2 H,
H-5), 3.15 (m, 2 H, H-3), 2.15 (s, 3 H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 205.1 (C-2), 168.3 (2ϫC=O imide), 137.7
(C ipso), 134.3, 133.9 (Car), 131.8 (2ϫC ipso), 128.3, 127.7, 123.5,
123.2 (Car), 72.8 (CH2Ph), 69.1 (C-5), 46.1 (C-3), 42.3 (C-4), 30.1
(C-1) ppm. HRMS (ESI): calcd. for C20H20NO4 [M + H]+
360.1210; found 360.0921.
(1R,2R,5R,7S,8aR)-1,2-Bis(benzyloxy)-5-methyloctahydroindolizin-
7-ol [(–)-11]: NaBH4 (6.3 mg, 0.17 mmol) was added to a solution
of indolizidine (–)-10 (60 mg, 0.17 mmol, 1 equiv.) in methanol
(5 mL), under an inert atmosphere, and the mixture was cooled to
–10 °C. The mixture was stirred at –10 °C for 15 min, and the sol-
1-Benzyloxymethyl-2-(2-methyl-1,3-dioxan-2-yl)ethylamine [(؎)-15]:
vent was removed. The residue was dissolved in water (0.1 mL) To a solution of phthalimide (Ϯ)-14 (8 g, 23.8 mmol) in toluene
and extracted with ethyl acetate (4ϫ3 mL). The combined organic
layers were dried with Na2SO4 and concentrated. The residue was
purified by chromatography on silica gel (ethyl acetate/cyclohexane,
1:1) to give indolizidinol (–)-11 (56 mg, 90%) as a pale yellow oil.
Rf (ethyl acetate/cyclohexane, 1:1) = 0.23. [α]2D5 = –12.5 (c = 0.82,
(70 mL) were added 1,3-propanediol (3.5 mL, 47.5 mmol) and p-
toluenesulfonic acid (5 mg). The mixture was refluxed with a
Dean–Stark apparatus for 6 h. After being cooled to room tem-
perature, saturated aqueous NaHCO3 was added. The aqueous
layer was extracted with dichloromethane (3 ϫ 30 mL), and the
combined organic layers were washed with brine (2ϫ20 mL), dried
on Na2SO4, filtered, and concentrated. To a solution of this crude
phthalimide (8.40 g, 21.3 mmol) in methanol (100 mL) was added
hydrazine monohydrate (1.27 g, 25.3 mmol). The mixture was re-
fluxed for 5 h, and the methanol was evaporated. The white precipi-
CHCl ). IR (film): ν = 3390, 2854, 1496, 1453, 1198, 1094 cm–1.
˜
3
1H NMR (400 MHz, CDCl3): δ = 7.40–7.27 (m, 10 H, 2ϫPh),
4.60, 4.45 (2 d, J = 12 Hz, 2 H, CH2Ph, AB system), 4.57, 4.54 (2
d, J = 12 Hz, 2 H, CH2Ph, AB system), 3.94 (m, 1 H, H-2), 3.75
3
3
3
(dd, JH,H = 8.5, JH,H = 2.5 Hz, 1 H, H-1), 3.65 (tt, JH,H = 11.5,
3JH,H = 4.5 Hz, 1 H, H-7), 3.23 (d, JH,H = 10.5 Hz, 1 H, H-3a), tate thus formed was treated with aqueous KOH (2.6 , 14 mL)
3
2.36–2.24 (m, 2 H, H-3b, H-6eq), 2.12–2.02 (m, 2 H, H-8a, H-5), and extracted with dichloromethane (5ϫ30 mL). The combined
5296
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5289–5300

New Polyhydroxylated Indolizidines
organic layers were dried with Na2SO4, filtered, and concentrated
to furnish amine (Ϯ)-15 (5.6 g, 90% over two steps) as a white
solid; m.p. 146 °C; Rf (ethyl acetate/MeOH, 9:1) = 0.10. IR (KBr):
2.33 mmol) and silver oxide (216 mg, 0.93 mmol) were added. The
mixture was stirred for 4 h, and benzyl bromide (280 µL,
2.33 mmol) and silver oxide (216 mg, 0.93 mmol) were added again.
The precipitate was filtered trough Celite® and washed with dichlo-
ν = 3422, 1605, 1579, 1246, 1073 cm–1 1H NMR (400 MHz,
.
˜
CDCl3): δ = 8.19 (br. s, 2 H, NH2), 7.40–7.25 (m, 5 H, Ph), 4.60, romethane (3ϫ10 mL). The filtrate was concentrated, and the resi-
4.57 (2 d, J = 12 Hz, 2 H, CH2Ph, AB system), 3.92–3.05 (m, 4 H, due was purified by chromatography on silica gel (ethyl acetate/
3 ϫ OCH dioxane, CH), 3.88–3.79 (m, 2 H, OCH dioxane, cyclohexane, 1:9) to give (–)-19 (370 mg, 70%) as a white solid;
CH2OBn), 3.78–3.72 (m, 1 H, CH2OBn), 2.17 (m, 1 H, CH2), 2.10–
1.96 (m, 1 H, CH2 dioxane), 1.79 (dd, 1 H, CH2), 1.46 (s, 3 H,
CH3), 1,36 (d, 1 H, CH2 dioxane) ppm. 13C NMR (100 MHz,
CDCl3): δ = 137.4 (C ipso), 128.5, 127.9, 127.8 (Car), 98.9 (C),
73.3 (CH2Ph), 69.5 (CH2OBn), 60.1, 60.0 (2ϫOCH2 dioxane), 48.1
(CH), 40.6 (CH2), 25.2 (CH2 dioxane), 18.9 (CH3) ppm. HRMS
(ESI): calcd. for C15H24NO3 [M + H]+ 266.1756; found 266.1750.
m.p. 52 °C; Rf (ethyl acetate/cyclohexane, 1:4) = 0.19. [α]2D5 = –8.5
(c = 1.1, CHCl ). IR (KBr): ν = 1711, 1686, 1543, 1410, 1268, 1062
˜
3
cm–1 1H NMR (400 MHz, CDCl3): δ = 7.40–7.27 (m, 10 H,
.
2ϫPh), 5.39 (m, 1 H, NH), 5.08 (s, 2 H, CH2Ph), 4.48 (s, 2 H,
CH2Ph), 4.20 (m, 1 H, H-2), 3.56 (m, 2 H, H-1), 2.78 (m, 2 H, H-
3), 2.12 (s, 3 H, H-5) ppm. 13C NMR (100 MHz, CDCl3): δ = 207.3
(C-3), 155.7 (C=O carbamate), 137.8, 136.5 (2ϫC ipso), 128.5,
128.4, 128.1, 128.0, 127.8, 127.7, 126.9 (Car), 73.2 (C-1), 70.8
(OCH2Ph), 66.7 (COOCH2Ph), 47.4 (C-2), 44.4 (C-3), 30.5 (C-5)
ppm. HRMS (ESI): calcd. for C20H23NO4Na [M + Na]+ 364.1525;
found 364.1526.
Benzyl {(2S)-1-Hydroxy-4-[methoxy(methyl)amino]-4-oxobutan-2-
yl}carbamate [(+)-17]: To a solution of N,O-dimethylhydroxylamine
hydrochloride (1.82 g, 18.7 mmol) in anhydrous dichloromethane
(90 mL), cooled to 0 °C, was added a solution of trimethylalumin-
ium (2  in hexane, 9.35 mL, 18.7 mmol). The mixture was stirred
at room temperature for 2 h, and then a solution of β-amino ester
Benzyl [(2S)-1-(Benzyloxy)-3-(2-methyl-1,3-dioxan-2-yl)propan-2-
yl]carbamate [(–)-20]: To a solution of (–)-19 (172 mg, 0.504 mmol)
(–)-16 (9.36 mmol, 2.5 g) in anhydrous dichloromethane (20 mL) in trimethylorthoformate (552 µL, 5.04 mmol) were added 1,3-pro-
was added dropwise. The mixture was stirred for 12 h, cooled to
0 °C, and neutralised with saturated aqueous NH4Cl. The aqueous
layer was extracted with dichloromethane (3ϫ50 mL). The com-
bined organic layers were dried on Na2SO4, filtered, and concen-
trated. The residue was purified by chromatography on silica gel
(ethyl acetate) to give amide (+)-17 (1.9 g, 70%) as a colourless oil.
panediol (373 µL, 5.04 mmol) and p-toluenesulfonic acid (3.8 mg,
0.02 mmol). The mixture was stirred at room temperature for 12 h,
diluted with dichloromethane (10 mL), and washed with saturated
aqueous NaHCO3. The aqueous layer was extracted with dichloro-
methane (3ϫ10 mL), and the combined organic layers were dried
with Na2SO4, filtered, and concentrated. The residue was purified
by chromatography on silica gel (ethyl acetate/cyclohexane, 1:9) to
give (–)-20 (140 mg, 70%) as a colourless oil. Rf (ethyl acetate/cy-
clohexane, 1:4) = 0.20. [α]2D5 = –18.8 (c = 1.02, CHCl3). IR (film):
Rf (ethyl acetate) = 0.59. [α]2D5 = +4.2 (c = 1.03, CHCl3). IR (film):
1
ν = 1715, 1650, 1531, 1455, 1255, 1056 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 7.40–7.28 (m, 5 H, Ph), 5.79 (m, 1 H, NH), 5.08 (s, 2
H, CH2Ph), 4.05 (m, 1 H, H-2), 3.75 (m, 2 H, H-1), 3.70 (s, 3 H,
ν = 1715, 1513, 1430, 1249, 1094 cm–1 1H NMR (400 MHz,
.
˜
OCH3), 3.30 (br. s, 1 H, OH), 3.16 (s, 3 H, NCH3), 2.82 (m, 2 H, CDCl3): δ = 7.40–7.25 (m, 10 H, 2ϫPh), 5.39 (m, 1 H, NH), 5.10
H-3) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.3 (C=O amide), (s, 2 H, CH2Ph), 4.52 (s, 2 H, CH2Ph), 4.12 (m, 1 H, H-2), 3.97–
156.3 (C=O carbamate), 136.4 (C ipso), 128.5, 128.2, 128.1 (Car), 3.89 (m, 2 H, OCH2 dioxane), 3.85–3.75 (m, 2 H, OCH2 dioxane),
66.7 (CH2Ph), 64.4 (C-1), 61.3 (CH3), 49.7 (C-2), 33.4 (C-3), 32.0 3.66–3.51 (m, 2 H, H-1), 2.05 (m, 2 H, H-3), 1.92–1.76 (m, 2 H,
(NCH3) ppm. HRMS (ESI): calcd. for C14H20N2O5Na [M + Na]+
319.1270; found 319.1283.
CH2 dioxane), 1.43 (s, 3 H, CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 156.0 (C=O carbamate), 138.4, 136.9 (2 ϫC ipso),
128.8, 128.5, 128.3, 127.9, 127.7, 127.5 (Car), 98.7 (C-4), 73.1 (C-
1), 72.5 (OCH2Ph), 66.4 (COOCH2Ph), 59.7 (2ϫOCH2 dioxane),
47.6 (C-2), 41.3 (C-3), 25.4 (CH2 dioxane), 19.9 (C-5) ppm. HRMS
(ESI): calcd. for C23H29NO5Na [M + Na]+ 422.1943; found
422.1927.
Benzyl [(2S)-1-Hydroxy-4-oxopentan-2-yl]carbamate [(+)-18]: A
solution of amide (+)-17 (1.4 g, 4.7 mmol) in anhydrous THF
(100 mL) under Ar was cooled to 0 °C, and methylmagnesium bro-
mide (3  in THF, 16 mL, 47.3 mmol) was added slowly. The mix-
ture was stirred at room temperature for 15 min, cooled to 0 °C,
and neutralised with saturated aqueous NH4Cl (30 mL). The aque-
ous layer was extracted with dichloromethane (3ϫ50 mL), and the
combined organic layers were dried on Na2SO4, filtered, and con-
centrated. The residue was purified by chromatography on silica
gel (ethyl acetate/cyclohexane, 9:1) to furnish ketone (+)-18 (0.6 g,
50%) as a white solid; m.p. 81–81.5 °C; Rf (ethyl acetate) = 0.58.
(S)-1-Benzyloxymethyl-2-(2-methyl-1,3-dioxan-2-yl)ethylamine [(+)-
15]: To a solution of carbamate (–)-20 (80 mg, 0.2 mmol) in meth-
anol (15 mL), 10 % Pd/C (20 mg) was added. The mixture was
stirred for 1 h at room temperature, and the catalyst was filtered
through Celite® and washed with methanol. The solvents were re-
moved to give amine (+)-15 (45 mg, quantitative) as a white solid;
m.p. 146 °C. Rf (ethyl acetate) = 0.4. [α]2D5 = +6.5 (c = 1.03, CHCl3).
HRMS (ESI): calcd. for C15H24NO3 [M + H]+ 266.1756; found
266.1750.
[α]2D5 = +4.8 (c = 1.01, CHCl ). IR (KBr): ν = 1712, 1690, 1539,
˜
3
1316, 1166, 1070 cm–1. 1H NMR (400 MHz, CDCl3, 50 °C): δ =
7.34 (m, 5 H, Ph), 5.38 (br. s, 1 H, NH), 5.09 (s, 2 H, CH2Ph), 4.03
(m, 1 H, H-2), 3.71 (m, 2 H, H-1), 2.78 (m, 2 H, H-3), 3.35 (br. s,
1 H, OH), 2.15 (s, 3 H, H-5) ppm. 13C NMR (100 MHz, CDCl3):
δ = 208.1 (C-4), 156.4 (C=O carbamate), 136.3 (C ipso), 128.5,
128.2, 128.1 (Car), 66.8 (CH2Ph), 63.9 (C-1), 49.4 (C-2), 44.3 (C-
3), 30.5 (C-5) ppm. HRMS (ESI): calcd. for C13H17NO4Na [M +
Na]+ 274.1055; found 274.1055.
Ethyl (E)-3-[(8R,10S)-10-Benzyloxymethyl-1,5-dioxa-9-azaspiro-
[5.5]undec-8-yl]acrylate [(+)-21]: Following the procedure described
for piperidine (–)-3, starting from amine (+)-15 (2.00 g, 7.5 mmol),
piperidine (+)-21 (1.69 g, 60%) was obtained as a pale yellow oil.
Rf (ethyl acetate/cyclohexane, 1:1) = 0.25. [α]2D5 = +3.3 (c = 1.01,
CHCl ). IR (film): ν = 3311, 1719, 1655, 1145, 1094 cm–1. 1H NMR
˜
3
3
Benzyl [(2S)-1-(Benzyloxy)-4-oxopentan-2-yl]carbamate [(–)-19]: To
a solution of ketone (+)-18 (390 mg, 1.55 mmol) in anhydrous
dichloromethane (5 mL) were added benzyl bromide (280 µL,
2.33 mmol) and silver oxide (216 mg, 0.93 mmol, 0.6 equiv.). The
mixture was stirred for 4 h, and then benzyl bromide (280 µL,
(400 MHz, CDCl3): δ = 7.34–7.20 (m, 5 H, Ph), 6.83 (dd, JH,H
=
3
3
16, JH,H = 6 Hz, 1 H, H-3), 5.89 (d, JH,H = 16 Hz, 1 H, H-2),
4.46, 4.43 (2 d, J = 12 Hz, 2 H, CH2Ph, AB system), 4.11 (q, 3JH,H
= 7 Hz, 2 H, CH2 ester), 3.83 (m, 4 H, 2ϫOCH2 dioxane), 3.43
(m, 2 H, H-8Ј, H-1ЈЈa), 3.29 (m, 1 H, H-1ЈЈb), 3.03 (m, 1 H, H-
Eur. J. Org. Chem. 2008, 5289–5300
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5297

D. Baumann, K. Bennis, I. Ripoche, V. Théry, Y. Troin
FULL PAPER
10Ј), 2.25 (m, 1 H, H-7Јeq), 2.07 (m, 1 H, H-11Јeq), 2.02 (br. s, 1 H, 128.6, 128.4, 128.0 (Car), 96.2 (C-6), 72.6 (CH2Ph), 72.0 (C-1ЈЈ),
NH), 1.65 (m, 2 H, CH2 dioxane), 1.25–1.17 (m, 4 H, H-7Јax, CH3 70.0 (C-1Ј, C-2Ј), 68.3 (CH2Ph), 61.3 (CH2 ester), 59.7, 59.6
2
3
ester), 1.12 (t, JH,H = 12.5, JH,H = 12.5 Hz, 1 H, H-11Јax) ppm.
13C NMR (100 MHz, CDCl3): δ = 166.5 (C=O ester), 149.4 (C-3),
138.1 (C ipso), 128.9, 128.5, 127.7 (Car), 120.7 (C-2), 96.8 (C-6Ј),
74.6 (C-1ЈЈ), 73.4 (CH2Ph), 60.6 (OCH2 ester), 59.3, 59.2
(2ϫOCH2 dioxane), 53.3 (C-8Ј), 52.0 (C-10Ј), 38.5 (C-7Ј), 35.5 (C-
11Ј), 25.5 (CH2 dioxane), 14.2 (CH3 ester) ppm. HRMS (ESI):
calcd. for C21H30NO5 [M + H]+ 376.2124; found 376.2106.
(2ϫOCH2 dioxane), 50.2 (C-8, C-10), 34.5 (C-11), 27.9 (C-7), 25.0
(CH2 dioxane), 14.1 (CH3 ester) ppm. HRMS (ESI): calcd. for
C29H37NO9Na [M + Na]+ 566.2366; found 566.2387.
Ethyl (2S,3R)-3-[(8R,10S)-10-benzyloxymethyl-1,5-dioxa-9-azaspiro-
[5,5]undec-8-yl]-2,3-dihydroxy-propionate [(–)-24]: Following the
procedure described for (+)-5b, starting from (+)-23b (270 mg,
0.5 mmol), piperidine (–)-24 (204 mg. quantitative) was obtained as
a colourless oil. Rf (ethyl acetate/MeOH, 9:1) = 0.35. [α]2D5 = –6.8
Ethyl (E)-3-[(8R,10S)-9-Benzyloxycarbonyl-10-benzyloxymethyl-
1,5-dioxa-9-azaspiro[5.5]undec-8-yl]acrylate [(–)-22]: Following the
procedure described for piperidine (+)-4, starting from piperidine
(+)-21 (2.10 g, 5.6 mmol), protected piperidine (–)-22 (2.5 g, 90%)
was isolated as a yellow oil. Rf (ethyl acetate/cyclohexane, 1:1) =
0.62. [α]2D5 = –4.1 (c = 1.03, CHCl ). IR (film): ν = 1713, 1768,
1
(c = 0.55, CHCl ). IR (KBr): ν = 3436, 1737, 1250, 1218 cm–1. H
˜
3
NMR (400 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H, Ph), 4.56–4.44
3
4
(m, 2 H, CH2Ph), 4.28 (qd, JH,H = 7, JH,H = 2.5 Hz, 2 H, CH2
ester), 4.00–3.78 (m, 6 H, 2ϫOCH2 dioxane, H-3, H-2), 3.46 (m,
1 H, H-1ЈЈa), 3.35 (m, 1 H, H-1ЈЈb), 3.10 (m, 1 H, H-8Ј), 3.00 (m,
1 H, H-10Ј), 2.50 (m, 1 H, H-7Јeq), 2.17 (m, 1 H, H-11Јeq), 1.78–
1.63 (m, 2 H, CH2 dioxane), 1.35–1.20 (m, 5 H, H-7Јax, H-11Јax,
CH3 ester) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.1 (C=O
ester), 138.1 (C ipso), 128.4, 128.3, 127.8, 127.7, 127.5 (Car), 97.2
(C-6Ј), 74.0 (CH2Ph), 73.4 (C-3 or C-2), 73.3 (C-1ЈЈ), 72.2 (C-3 or
C-2), 61.8 (CH2 ester), 59.3 (2ϫOCH2 dioxane), 55.4 (C-10Ј), 52.2
(C-8Ј), 36.3 (C-11Ј), 35.1 (C-7Ј), 25.5 (CH2 dioxane), 14.2 (CH3
ester) ppm. HRMS (ESI): calcd. for C21H32NO7 [M + H]+
410.2179; found 410.2169.
˜
3
1656, 1290, 1113 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.34–7.17
(m, 10 H, 2ϫPh), 6.95 (dd, JH,H = 16, JH,H = 6.5 Hz, 1 H, H-
3), 5.84 (d, JH,H = 16 Hz, 1 H, H-2), 5.14, 5.11 (2 d, J = 12.5 Hz,
3
3
3
2 H, CH2Ph, AB system), 4.97 (m, 1 H, H-8Ј), 4.56 (m, 1 H, H-
10Ј), 4.52, 4.47 (2 d, J = 12 Hz, 2 H, CH2Ph, AB system), 4.11 (q,
3JH,H = 7 Hz, 2 H, CH2 ester), 3.92–3.71 (m, 4 H, 2ϫOCH2 diox-
ane), 3.61 (m, 1 H, H-1ЈЈa), 3.48 (m, 1 H, H-1ЈЈb), 2.54 (m, 1 H,
H-11Јeq), 2.20 (m, 1 H, H-7Јeq), 1.85 (dd, 2JH,H = 14, 3JH,H = 7 Hz,
1 H, H-7Јax), 1.72 (m, 1 H, CH2a dioxane), 1.64 (dd, 2JH,H = 14.5,
3JH,H = 7 Hz, 1 H, H-11Јax), 1.59 (m, 1 H, CH2b dioxane), 1.19 (m,
3 H, CH3 ester) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.5
(C=O ester), 155.7 (C=O carbamate), 148.9 (C-3), 138.3, 136.4
(2ϫC ipso), 128.5, 128.3, 128.1, 128.0, 127.7, 127.6, 126.9 (Car),
121.6 (C-2), 95.8 (C-6Ј), 72.9 (C-1ЈЈ), 71.1, 67.7 (2ϫCH2Ph), 60.3
(CH2 ester), 59.5 (2ϫOCH2 dioxane), 51.2 (C-8Ј), 50.3 (C-10Ј),
36.6 (C-7Ј), 29.7 (C-11Ј), 25.1 (CH2 dioxane), 14.2 (CH3 ester)
ppm. HRMS (ESI): calcd. for C29H35NO7Na [M + Na]+ 532.2329;
found 532.2285.
(1ЈR,2ЈR,5ЈS,8aЈR)-1Ј,2Ј-Bis(benzyloxy)-5Ј-[(benzyloxy)methyl]hexa-
hydro-1ЈH-spiro[1,3-dioxane-2,7Ј-indolizine] [(–)-25]: Following the
procedure described for piperidine (–)-9, starting from piperidine
(–)-24 (80 mg, 0.2 mmol), indolizidine (–)-25 (38 mg. 35%) was iso-
lated as a pale yellow oil. Rf (ethyl acetate/cyclohexane, 1:1) = 0.63.
[α]2D5 = –15.3 (c = 0.99, CHCl ). IR (film): ν = 1496, 1454, 1246,
˜
3
1092 cm–1. H NMR (400 MHz, CDCl3): δ = 7.37–7.27 (m, 15 H,
1
Ph), 4.61–4.50 (m, 4 H, 2ϫCH2Ph), 4.50, 4.36 (2 d, J = 12 Hz, 2
H, CH2Ph, AB system), 3.87 (m, 5 H, 2ϫOCH2 dioxane, H-2Ј),
Benzyl (8S,10R)-8-Benzyloxymethyl-10-[(1S,2R)-2-ethoxycarbonyl-
1,2-dihydroxyethyl]-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxyl-
ate [(+)-23a] and Benzyl (8S,10R)-8-Benzyloxymethyl-10-[(1R,2S)-
2-ethoxycarbonyl-1,2-dihydroxyethyl]-1,5-dioxa-9-azaspiro[5.5]unde-
cane-9-carboxylate [(+)-23b]: Following the procedure described for
piperidines (–)-5a and (+)-5b, starting from piperidine (–)-22
(710 mg, 1.4 mmol), diastereomeres (+)-23a (106 mg, 14 %) and
(+)-23b (327 mg, 43%) were obtained as pale yellow oils.
3
3
3.71 (dd, JH,H = 8.5, JH,H = 3 Hz, 1 H, H-1Ј), 3.45, 3.30 (m,
JH1Јa,H5Ј = 5, J = 4.5, JH1Јa,H1Јb = 10 Hz, 2 H, H-1Јa, H-
H1Јb,H5Ј
2
1Јb, AB part of ABX system), 3.23 (d, JH,H = 10.5 Hz, 1 H, H-
2
3
4
3Јa), 2.57 (dt, JH,H = 12.5, JH,H = 3, JH,H = 3 Hz, 1 H, H-8Јeq),
2.53–2.43 (m, 2 H, H-3Јb, H-5Ј), 2.33 (m, 1 H, H-8Јa), 2.23 (dt,
3
4
2JH,H = 13, JH,H = 3, JH,H = 3 Hz, 1 H, H-6Јeq), 1.80–1.63 (m, 2
H, CH2 dioxane), 1.45 (m, 1 H, H-6Јax), 1.37 (m, 1 H, H-8Јax) ppm.
13C NMR (100 MHz, CDCl3): δ = 138.3 (C ipso), 128.4, 128.3,
127.9, 127.7, 127.6 (Car), 97.3 (C-7Ј), 88.4 (C-1Ј), 82.8 (C-2Ј), 73.1,
73.0, 72.1, 71.4 (3ϫCH2Ph, CH2OBn), 64.3 (C-8Јa), 59.5, 59.1
(2ϫOCH2 dioxane), 57.9 (C-5Ј), 56.0 (C-3Ј), 36.5 (C-6Ј), 35.4 (C-
8Ј), 25.5 (CH2 dioxane) ppm. HRMS (ESI): calcd. for C33H40NO5
[M + H]+ 530.3866; found 530.3892.
(+)-23a: Rf (ethyl acetate/cyclohexane, 1:1) = 0.28. [α]2D5 = +1.3 (c
= 0.95, CHCl3). The H NMR (400 MHz, CDCl3) was a complex
1
spectrum due to the coexistence of carbamate rotamers. 13C NMR
(100 MHz, CDCl3): δ = 171.7 (C=O ester), 158.2 (C=O carbamate),
138.2, 135.8 (2ϫC ipso), 128.5, 128.3, 128.2, 128.0, 127.6, 127.3
(Car), 95.9 (C-6), 72.7 (CH2Ph), 72.6 (C-1Ј), 72.1 (C-1ЈЈ), 70.1 (C-
2Ј), 68.4 (CH2Ph), 61.3 (CH2 ester), 59.7, 59.6 (2ϫOCH2 dioxane),
52.9 (C-10), 50.3 (C-8), 34.5 (C-11), 27.9 (C-7), 25.1 (CH2 dioxane),
14.3 (CH3 ester) ppm. HRMS (ESI): calcd. for C29H37NO9Na [M
+ Na]+ 566.2366; found 566.2387.
(1R,2R,5S,8aR)-1,2-Bis(benzyloxy)-5-[(benzyloxy)methyl]hexahydro-
indolizin-7(1H)-one [(+)-26]: To a solution of piperidine (–)-25
(250 mg, 0.47 mmol, 1 equiv.) in anhydrous dichloromethane
(50 mL) were added dropwise 1,3-propanedithiol (237 µL,
2.36 mmol) and BF3·OEt2 (302 µL, 2.36 mmol). The mixture was
stirred at room temperature under an inert atmosphere over 24 h,
diluted with dichloromethane, and washed with saturated aqueous
NaOH (1 ). The two phases were separated, and the aqueous layer
was extracted with dichloromethane (3 ϫ20 mL). The combined
(+)-23b: Rf (ethyl acetate/cyclohexane, 1:1) = 0.27. [α]2D5 = +16.9 (c
= 0.95, CHCl ). IR (film): ν = 3442, 1732, 1692 cm–1. 1H NMR
˜
3
(400 MHz, CDCl3): δ = 7.37–7.20 (m. 10 H, 2ϫPh), 5.10 (s, 2 H,
CH2Ph), 4.75 (m, 1 H, H-10), 4.55 (m, 1 H, CH2Ph), 4.42 (m, 1 H,
CH2Ph), 4.35–4.19 (m, 4 H, CH2 ester, H-1Ј, H-2Ј), 4.12–3.99 (m, organic layers were washed with brine (20 mL), dried on Na2SO4,
2 H, OCH2 dioxane), 3.90–3.80 (m, 2 H, OCH2 dioxane), 3.68 (m,
1 H, H-1ЈЈa), 3.50 (m, 1 H, H-1ЈЈb), 3.14 (m, 1 H, H-8), 2.08 (m,
filtered, and concentrated. The residue was purified by chromatog-
raphy on silica gel (ethyl acetate/cyclohexane, 2:8) to give the dithi-
ane-indolizine (175 mg, 80%) as a colourless oil. Rf (ethyl acetate/
2
3
1 H, H-11eq), 1.86 (m, 1 H, H-7eq), 1.77 (dd, JH,H = 14, JH,H
7.5 Hz, 1 H, H-11ax), 1.58 (m, 1 H, H-7ax), 1.29 (t, JH,H = 7 Hz,
=
3
cyclohexane, 3:7) = 0.62. [α]2D5 = –18.6 (c = 0.88, CHCl3). IR (film):
3 H, CH3 ester) ppm. 13C NMR (100 MHz, CDCl3): δ = 184.4 ν = 1496, 1453, 1112, 1075 cm–1. H NMR (400 MHz, CDCl ): δ
1
˜
3
(C=O ester), 169.5 (C=O carbamate), 138.3, 135.9 (2 ϫC ipso), = 7.39–7.28 (m, 15 H, 3ϫPh), 4.50, 4.45 (2 d, J = 11.5 Hz, 2 H,
5298
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5289–5300

New Polyhydroxylated Indolizidines
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CH2Ph, AB system), 4.44 (s, 2 H, CH2Ph), 4.49, 4.36 (2 d, J =
12 Hz, 2 H, CH2Ph, AB system), 3.86 (dd, 3JH,H = 6, 3JH,H = 3 Hz,
3
3
1 H, H-2Ј), 3.63 (dd, JH,H = 8, JH,H = 3 Hz, 1 H, H-1Ј), 3.45,
3.29 (m, JH1Јa,H5Ј = 5, JH1Ј,H5Ј = 4.5, JH1Јa,H1Јb = 9.5 Hz, 2 H, H-
2
1Јa, H-1Јb, AB part of ABX system), 3.15 (d, JH,H = 10.5 Hz, 1
H, H-3Јa), 2.82–2.52 (m, 7 H, H-8Јeq, 2ϫOCH2 thioacetal, H-8Јa,
2
3
H-5Ј), 2.48 (m, 1 H, H-3Јb), 2.27 (td, JH,H = 14, JH,H = 2.5 Hz,
2
1 H, H-6Јeq), 1.93 (m, 2 H, CH2 thioacetal), 1.68 (dd, JH,H = 14,
[2]
[3]
3JH,H = 11.5 Hz, 1 H, H-6Јax), 1.64 (dd, JH,H = 13, JH,H
=
2
3
11.5 Hz, 1 H, H-8Јax) ppm. 13C NMR (100 MHz, CDCl3): δ =
138.3, 138.2, 138.1 (3ϫC ipso), 130.5, 128.9, 128.5, 128.4, 127.9,
127.8, 127.7, 126.9, 125.9 (Car), 88.5 (C-1Ј), 82.4 (C-2Ј), 73.3, 72.8,
72.2, 71.4 (3ϫCH2-Ph, C-1ЈЈ), 63.1 (C-5Ј), 57.5 (C-8Јa), 56.1 (C-
3Ј), 48.6 (C-7Ј), 40.5 (C-6Ј), 37.3 (C-8Ј), 26.3, 25.9, 25.6 (2ϫSCH2,
CH2) ppm. HRMS (ESI): calcd. for C33H39NO3S2 [M + H]+
562.2408; found 562.2429. To a solution of the dithiane-indolizine
(175 mg, 0.31 mmol) in acetonitrile/water (9:1, 11 mL) was added
[bis(trifluoroacetoxy)iodo]benzene (342 mg, 0.78 mmol) and tri-
fluoroacetic acid (235 µL, 3.1 mmol). The mixture was stirred un-
der Ar at room temperature for 12 h, and that diluted with cyclo-
hexane (15 mL). The aqueous layer was extracted with cyclohexane
(3ϫ8 mL) and neutralized with saturated aqueous K2CO3. 1,2-
Ethanedithiol (1.4 mL) was added, and the mixture was stirred for
5 min. The aqueous layer was extracted with dichloromethane
(3 ϫ 8 mL), and the combined organic layers were dried with
Na2SO4, filtered, and concentrated. The residue was purified by
chromatography on silica gel (ethyl acetate/cyclohexane, 3:7) to give
indolizidinone (+)-26 (87 mg, 50%) as a pale yellow oil. Rf (ethyl
acetate/cyclohexane, 1:1) = 0.75. [α]2D5 = +1.25 (c = 0.64, CHCl3).
[4]
[5]
[6]
IR (film): ν = 1719, 1496, 1454, 1241, 1103 cm–1 1H NMR
.
˜
[7]
(400 MHz, CDCl3): δ = 7.30–7.17 (m, 15 H, Ph), 4.52, 4.40 (2 d, J
= 12 Hz, 2 H, CH2Ph, AB system), 4.44 (m, 4 H, 2ϫCH2Ph), 3.92
(m, 1 H, H-2Ј), 3.73 (m, 1 H, H-1Ј), 3.46, 3.36 (m, JH1Јa,H5Ј = 5,
JH1Јb,H5Ј = 4.5, JH1Јa,H1Јb = 10 Hz, 2 H, H-1Јa, H-1Јb, AB part of
[8]
[9]
2
2
ABX system), 3.25 (d, JH,H = 11 Hz, 1 H, H-3Јa), 2.58 (d, JH,H
= 11 Hz, 1 H, H-8Јeq), 2.49 (m, 2 H, H-5Ј, H-3Јb), 2.36 (m, 4 H,
H-2, H-6Јax, H-6Јeq, H-8Јax) ppm. 13C NMR (100 MHz, CDCl3): δ
= 207.8 (C-7Ј), 137.9, 137.8, 137.7 (3ϫC ipso), 128.9, 128.5, 128.0,
127.9, 127.8 (Car), 89.1 (C-1Ј), 82.4 (C-2Ј), 73.3, 72.5, 72.1, 71.5
(3ϫCH2Ph, C-1ЈЈ), 67.5 (C-8Јa), 60.6 (C-5Ј), 55.8 (C-3Ј), 45.4 (C-
8Ј), 43.5 (C-6Ј) ppm. HRMS (ESI): calcd. for C30H34NO4 [M +
H]+ 472.2504; found 472.2488.
[10]
[11]
[12]
T. Katsuki, V. S. Martin, Org. React. 1996, 48, 1–299.
M. K. Gurjar, L. Ghosh, M. Syamala, V. Jayasree, Tetrahedron
Lett. 1994, 35, 8871–8872.
R. Martin, C. Murruzzu, M. A. Pericas, A. J. Riera, Org.
Chem. 2005, 70, 2325–2328.
(1R,2R,5S,7S,8aR)-5-(Hydroxymethyl)octahydroindolizine-1,2,7-
triol [(–)-27]: Following the procedure for indolizidinone (–)-12,
starting from (+)-26 (80 mg, 0.17 mmol), piperidinol (–)-27 (22 mg,
64% over two steps) was isolated as a pale yellow oil. Rf (ethyl
acetate/MeOH, 5:1) = 0.10. [α]2D5 = –12.0 (c = 0.30, MeOH). 1H
NMR (400 MHz, CD3OD): δ = 4.02 (m, 1 H, H-2Ј), 3.82–3.47 (m,
3 H, H-1Ј, H-7Ј, H-1ЈЈa), 3.32–3.25 (m, 1 H, H-1ЈЈb), 3.27 (m, 1
H, H-3Јa), 3.09 (m, 1 H, H-3Јb), 2.84–2.56 (m, 2 H, H-8Јa, H-5Ј),
2.19 (m, 1 H, H-8Јeq), 1.92 (m, 1 H, H-6Јeq), 1.62–1.35 (m, 2 H, H-
6Јax, H-8Јax) ppm. 13C NMR (100 MHz, CD3OD): δ = 84.1 (C-1Ј),
78.3 (C-2Ј), 69.5 (C-8Јa, C-7Ј), 64.9 (C-1ЈЈ), 64.3 (C-5Ј), 59.9 (C-
3Ј), 38.2 (C-6Ј, C-8Ј) ppm. HRMS (ESI): calcd. for C9H18NO4 [M
+ H]+ 205.2479; found 205.2458.
[13]
[14]
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Supporting Information (see also the footnote on the first page of
this article): General experimental methods, conformational analy-
1
sis of (Ϯ)-6a and (Ϯ)-6b, and copies of H and 13C NMR spectra
of all new compounds.
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D. Baumann, K. Bennis, I. Ripoche, V. Théry, Y. Troin
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Received: July 10, 2008
Published Online: September 30, 2008
5300
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5289–5300