Lewis acid assisted vinylogous Mannich and Mukaiyama aldol reactions: A route to densely hydroxylated indolizidine alkaloid analogues

Article abstract of DOI:10.1002/(SICI)1099-0690(199906)1999:6<1395::AID-EJOC1395>3.0.CO;2-T

The hydroxymethyl-substituted indolizidines 6 and 7, representative members of a ring-B-expanded alexine-australine subclass, are readily accessible by starting with furan-based silyloxydiene 12 and hydroxymethyl hemiaminal 11, through a synthesis sequence involving a scantily exploited vinylogous version of the Mannich reaction. The key iminium electrophilic acceptor 11 is, in turn, available through a vinylogous intermolecular Mukaiyama aldolization process between pyrrole-based silyloxydiene 8 and (S)- glyceraldehyde 9.

Full text of DOI:10.1002/(SICI)1099-0690(199906)1999:6<1395::AID-EJOC1395>3.0.CO;2-T

FULL PAPER
Lewis Acid Assisted Vinylogous Mannich and Mukaiyama Aldol Reactions:
A Route to Densely Hydroxylated Indolizidine Alkaloid Analogues
Gloria Rassu,*[a] Paola Carta,[a] Luigi Pinna,[b] Lucia Battistini,[c] Franca Zanardi,[c]
Domenico Acquotti,[d] and Giovanni Casiraghi*[c]
Keywords: Alkaloids / Vinylogous Mannich reaction / Vinylogous Mukaiyama aldol reaction / Glycosylation inhibitors
The hydroxymethyl-substituted indolizidines
representative members of ring-B-expanded alexine–
australine subclass, are readily accessible by starting with
furan-based silyloxydiene 12 and hydroxymethyl
6
and 7,
scantily exploited vinylogous version of the Mannich
reaction. The key iminium electrophilic acceptor 11 is, in
a
turn, available through
a
vinylogous intermolecular
Mukaiyama aldolization process between pyrrole-based
hemiaminal 11, through a synthesis sequence involving a
silyloxydiene 8 and (S)-glyceraldehyde 9.
Densely hydroxylated indolizidine and pyrrolizidine alka-
loids are a growing progeny of naturally occurring mo-
lecules whose relevance is reflected in an impressive number
of research papers and review articles dealing with iso-
lation,[1] biological evaluation,[2] and total and analogue
syntheses.[3] Representatives of this compound class (Figure
1) are, for example, the indolizidine members castanosper-
mine (1)[4] and swainsonine (2),[5] and the pyrrolizidines
australine (3),[6] alexine (4),[7] and casuarine (5),[8] all of
them exhibiting useful therapeutical potential as glycosyl-
ation inhibitors, as well as antiviral, and anticancer ag-
ents.[2]
We approached the total synthesis of the indolizidine
skeleton A (Scheme 1) exploiting the vinylogous version of
a Lewis acid assisted Mannich reaction[9] of type C ϩ D,
wherein a mechanistically active, chiral N-carbamoylimin-
ium intermediate D would undergo vinylogous addition to
silyloxy-substituted diene C in the indicated regiosense (γ
attack only) and with complete diastereoface guidance. The
threo,trans-configured binuclear adduct B so formed would
be eventually elaborated to an indolizidine A by a short
sequence consisting of double-bond functionalization
(hydrogenation or dihydroxylation), intramolecular lactam-
ization, and carbonyl-to-methylene reduction. The reali-
zation of this plan is described herein in the context of total
syntheses of 3-(hydroxymethyl)indolizidines 6 and 7, rep-
resentative members of a ring-B-expanded alexine-aus-
traline alkaloid subclass.
Figure 1. Relevant hydroxylated indolizidine and pyrrolizidine
alkaloid compounds
11, whose synthesis was accomplished by starting with 2,3-
O-isopropylidene--glyceraldehyde (9, ex commercially
available -gulono-1,4-lactone; Scheme 2). Vinylogous Mu-
kaiyama aldolization[10] of N-(tert-butoxycarbonyl)-2-(tert-
butyldimethylsilyloxy)pyrrole (8) with glyceraldeyde 9 un-
der the conditions indicated, followed by catalytic hydro-
genation afforded the hydroxylated pyrrolidinone 10 in 70%
The specific pyrrolidine precursor used to create the op-
erative Mannich acceptor was the chiral nonracemic aminal
[a]
Istituto per l’Applicazione delle Tecniche Chimiche Avanzate del yield for the two steps. The triol side chain within 10 was
CNR,
then shortened to a protected hydroxymethyl group, as
Via Vienna 2, I-07100 Sassari, Italy
[b]
[c]
shown, and the lactam carbonyl group carefully reduced to
a hydroxy group (Super Hydride ) to provide, after proper
methylation, compound 11 (41% yield from 10).
The key Mannich reaction between aminal 11 and 2-(tert-
butyldimethylsilyloxy)furan (12) (Scheme 3) was conducted
under catalysis by tert-butyldimethylsilyl trifluoromethanes-
ulfonate (TBSOTf, 0.6 mol-equiv., CH2Cl2). Unsaturated
`
Dipartimento di Chimica dellЈUniversita,
Via Vienna 2, I-07100 Sassari, Italy
`
Dipartimento Farmaceutico dellЈUniversita,
Viale delle Scienze, I-43100 Parma, Italy
Fax: (internat.) ϩ39-0521/905006
E-mail: casirag@ipruniv.cce.unipr.it
[d]
Centro Interdipartimentale Misure “G. Casnati” dell’Univer-
`
sita,
Viale delle Scienze, I-43100 Parma, Italy
Eur. J. Org. Chem. 1999, 1395Ϫ1400
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0606Ϫ1395 $ 17.50ϩ.50/0
1395

G. Casiraghi et al.
FULL PAPER
Scheme 2. Synthesis of the key Mannich acceptor 11
(66% yield after protection of the secondary alcohol as TBS
ether). Subsequent carbonyl reduction (BH3 · DMS) and
acidic treatment (6  aq. HCl, THF) eventually produced
(3S,8S,8aS)-8-hydroxy-3-(hydroxymethyl)indolizidine (6),
which was isolated as a free base upon ammonia treatment
(50% yield; 20% overall yield from 11).
Scheme 1. Synthetic strategy for indolizidines A
The basic chemistry exploited to transform aminal 11
into 6 was then adopted to arrive at densely hydroxylated
adduct 13 was then isolated as the single reaction compo- indolizidine 7. Thus, the double bond within intermediate
nent in 78% isolated yield. From 13, the synthesis of model 13 was subjected to cis-dihydroxylation by using the well-
indolizidine 6 was first carried out by double-bond hydro- documented KMnO4/dicyclohexano-18-crown-6 ether
genation followed by selective removal of the N-Boc pro- phase transfer oxidative protocol,[12] stereoselectively af-
tecting group (TMSOTf, thiophenol), giving rise to the bi- fording diol 16 in 72% yield. Removal of the Boc protecting
nuclear lactone 14 in 79% yield over the two steps.[11] Fol- group under the above selective conditions effected con-
lowing basic treatment (NaOMe, MeOH), the γ-lactone comitant γ-lactone-to-δ-lactam expansion, straightfor-
ring in 14 was cleanly rearranged to a δ-lactam, thereby wardly furnishing hydroxylated indolizidinone 17 (84%
furnishing the requisite fused bicyclic indolizidinone 15 yield). After persilylation (TMSCl, pyridine), the lactam
Scheme 3. Synthesis of hydroxylated indolizidines 6 and 7
1396
Eur. J. Org. Chem. 1999, 1395Ϫ1400

Lewis Acid Assisted Vinylogous Mannich and Mukaiyama Aldol Reactions
FULL PAPER
obtained with a Bruker AC-300 or Varian XL-300 and are reported
in parts per million (δ) relative to tetramethylsilane (0.0 ppm) as
an internal reference, with coupling constants in Hz. Ϫ Rotations
were measured with a PerkinϪElmer 241 Polarimeter and are given
in units of 10Ϫ1 deg·cm2·gϪ1. Elemental analyses were performed
by the Microanalytical Laboratory of University of Sassari. Ϫ
Melting points were determined with an Electrothermal apparatus
and are recorded uncorrected. Ϫ All the solvents were distilled be-
fore use: THF from Na/benzophenone, Et2O from LiAlH4, CH2Cl2
from CaH2.
carbonyl group was reduced to
a methylene group
(BH3 · DMS) and all the silyl ether functions were cleaved
(6  HCl) to provide (3S,6S,7S,8R,8aS)-6,7,8-trihydroxy-3-
(hydroxymethyl)indolizidine (7) in 49% yield (23% overall
yield from 11).
The stereostructure of indolizidine 7 could not be simply
1
established on the basis of its H-NMR spectrum owing to
extensive signal overlap. However, the proton spectrum of
the corresponding tetra-O-acetyl derivative 18 proved
quickly readable, allowing precise assignment of the relative
(and hence absolute) stereodisposition of the molecule.
N-(tert-Butoxycarbonyl)-2-(tert-butyldimethylsiloxy)pyrrole (8) was
prepared from pyrrole (Aldrich) according to a described proto-
col.[13] 2-(tert-Butyldimethylsilyloxy)furan (12) was obtained from
2-furaldehyde (Aldrich) according to a reported method.[13] 2,3-O-
Isopropylidene--glyceraldehyde (9) was prepared from 5,6-O-iso-
propylidene--gulonic acid 1,4-lactone (Fluka) according a con-
venient described procedure.[14]
N-(tert-Butoxycarbonyl)-6,7-O-isopropylidene-2,3-dideoxy-L-arabino-
heptono-1,4-lactam (10): To a solution of 2,3-O-isopropylidene--
glyceraldehyde (9) (6.0 g, 46 mmol) in anhydrous Et2O (300 mL)
were added silyloxypyrrole 8 (13.6 g, 46 mmol) and SnCl4 (8.1 mL,
69 mmol) under argon at Ϫ80°C. The mixture was stirred at this
temperature for 3 h, then a saturated aqueous NaHCO3 solution
was added at Ϫ80°C and, after ambient temperature was reached,
the resulting mixture was extracted with Et2O (3 ϫ 60 mL). After
drying (MgSO4), the solution was concentrated under reduced
pressure and the crude product was crystallized from CH2Cl2/hex-
ane to give 11.3 g (78%) of an α,β-unsaturated lactam intermediate
that was subjected to the hydrogenation procedure. Palladium (10%
on carbon, 1.1 g) was added to a solution of this α,β-unsaturated
lactam (11.2 g, 35.7 mmol) in anhydrous THF (180 mL) in the pres-
ence of a small amount of NaOAc (0.46 g) at room temperature.
The reaction vessel was evacuated by aspirator and thoroughly
purged with hydrogen (three times), and the resulting hetero-
geneous mixture was stirred under hydrogen from a balloon. After
24 h, the hydrogen was evacuated, the catalyst filtered off, and the
filtrate was concentrated under vacuum to give a crude residue
which was subjected to flash-chromatographic purification (3:2,
EtOAc/hexanes). There was obtained 10.2 g (90%) of saturated lac-
tam 10 as a white solid, m.p. 102Ϫ105°C. Ϫ [α]D20 ϭ Ϫ60.14 (c ϭ
Figure 2. Stereostructure of tetra-O-acetyl indolizidine 18 as dedu-
1
ced from H-NMR parameters
The spectral parameters are fully consistent with the
structure shown in Figure 2, where the piperidine moiety
adopts a 4C1 () conformation (8aC6 in the figure) with a 1-
deoxy--ribo configuration. In particular, the coupling con-
stant between 8-H and 8a-H (J8,8a ϭ 2.4 Hz) confirms the
cis relationship for these protons (and hence, the 4,5-threo
disposition within the precursor adduct 13), while a strong
NOE contact between 8a-H and 9-H2 (not with 3-H) con-
firms the cis relationship between the 8a-H proton and the
hydroxymethyl appendage, thus corroborating the 5,8-trans
arrangement for 13. The J7,8 ϭ J6,7 ϭ 3.6 Hz are consistent
with an all-cis disposition of the piperidine substituents,
and confirm the highly diastereoselective cis-anti character
of the dihydroxylation stage (13 Ǟ 16). These results also
firmly establish the configuration of the model indolizidine
6, as shown.
To conclude, the chemistry herein disclosed delineates a
new, viable entry to the indolizidine nucleus amenable to
further adaptations and substituent variations. The success-
ful exploitation of scantily investigated vinylogous versions
of the Lewis acid assisted Mannich and Mukaiyama aldol-
ization protocols[9][10] to assemble the key precursors of this
synthesis (13 and 11) is remarkable and project the silyloxy
diene methodology among the reliable tools in the contem-
porary organic synthesis.
1
1.0, CHCl3). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 4.31 (ddd, J ϭ
7.7, 5.9, 1.9 Hz, 1 H), 4.09 (m, 2 H), 3.98 (m, 1 H), 3.75 (t, J ϭ
6.0 Hz, 1 H), 2.70 (ddd, J ϭ 17.7, 12.1, 9.1 Hz, 1 H), 2.39 (ddd,
J ϭ 17.7, 8.7, 2.2 Hz, 1 H), 2.16 (m, 2 H), 1.75 (br. s,1 H), 1.54 (s,
9 H), 1.40 (s, 3 H), 1.34 (s, 3 H). Ϫ 13C NMR (75 MHz, CDCl3):
δ 175.0, 151.2, 109.3, 83.2, 76.7, 74.0, 67.2, 60.9, 31.9, 27.9 (3 C),
26.5, 25.1, 21.6. Ϫ C15H25NO6 (315.37): calcd. C 57.13, H 7.99, N
4.44; found C 57.16, H 8.10, N 4.50.
(2RS,5S)-N-(tert-Butoxycarbonyl)-5[(tert-butyldiphenylsilyl)-
oxymethyl]-2-methoxypyrrolidine (11): Lactam 10 (10 g, 31.7 mmol)
was dissolved with 50 mL of 80% aqueous acetic acid, and the
resulting solution was allowed to react at 50°C. The reaction was
monitored by TLC and was judged complete after 8 h. The solution
was concentrated to give a crude triol intermediate which was used
as such in the subsequent step. The crude triol was then dissolved
in CH2Cl2 (200 mL) and treated with a 0.65  aq. NaIO4 solution
Experimental Section
General: Flash chromatography was performed on ICN Biomed-
icals silica gel 32Ϫ63 µm, using the indicated solvent mixtures. (108 mL) and chromatography-grade SiO2 (21 g). The resulting
Analytical thin-layer chromatography was performed on Merck sil- slurry was vigorously stirred for 15 min at which time TLC showed
ica gel 60 F254 plates (0.25 mm). The compounds were visualized by complete consumption of the starting material. The slurry was fil-
dipping the plates in an aqueous H2SO4 solution of cerium sulfate/
ammonium molybdate or in an ethanolic solution of ninhydrin,
followed by charring with a heat gun. Ϫ 1H-NMR spectra were
tered under suction and the silica gel thoroughly washed with
CH2Cl2 and ethyl acetate. The filtrates were concentrated to leave
the crude aldehyde which was directly subjected to reductive
Eur. J. Org. Chem. 1999, 1395Ϫ1400
1397

G. Casiraghi et al.
FULL PAPER
workup. Thus, crude aldehyde (6.1 g, 28.6 mmol) was dissolved in
methanol (140 mL) and the solution treated with NaBH4 (2.13 g,
56.3 mmol) at Ϫ30°C. After 30 min, the temperature was allowed
(s, 9 H), 1.04 (s, 9 H). Ϫ 13C NMR (75 MHz, CDCl3, 25°C, major
rotamer): δ 173.2, 154.8, 153.3, 135.5 (4 C), 133.2 (2 C), 129.7 (2
C), 127.7 (4 C), 120.4, 84.4, 80.1, 64.0, 59.4, 58.3, 28.3, 28.1 (3 C),
to rise to Ϫ15°C, while stirring was continued until the starting 27.5, 26.7 (3 C), 19.1. Ϫ C30H39NO5Si (521.73): calcd. C 69.06, H
aldehyde was consumed (1 h). The slurry was quenched by adding
acetone and a saturated aqueous citric acid solution. The mixture
was concentrated to leave an oily residue, which was subjected to
flash chromatographic purification on silica gel (ethyl acetate as an
eluant) to furnish a pure alcohol (5.2 g, 85%) as a colorless oil,
which was used as such in the subsequent step. Thus, the intermedi-
ate alcohol was dissolved in DMF (32 mL), and TBDPSCl (7.3 g,
26.6 mmol) and imidazole (1.8 g, 26.6 mmol) were sequentially ad-
ded at room temperature. After being stirred for 18 h, the mixture
was quenched by addition of an aqueous saturated Na2SO4 solu-
tion and extracted with ethyl acetate. The extracts were dried and
concentrated under vacuum to give an oily residue, from which a
pure protected lactam (9.1 g, 83%) was isolated as an oil by silica
gel flash chromatography (70:30, hexanes/ethyl acetate). To a solu-
tion of the obtained pyrrolidinone (9.0 g, 19.8 mmol) in THF (160
mL) was added a 1.0  THF solution of LiEt3BH (21.8 mL,
21.3 mmol) at Ϫ78°C, under argon. After 3 h, the reaction was
quenched with methanol and water, and, after ambient temperature
was reached, the resulting slurry was extracted with CH2Cl2. The
extracts were dried (MgSO4) and the solvent removed under vac-
uum to give a crude aminol, which was used in the subsequent step.
Thus, the crude product was dissolved in anhydrous diethyl ether
(150 mL), and trimethyl orthoformate (5.3 mL, 48.4 mmol),
7.53, N 2.68; found C 69.10, H 7.35, N 2.65.
(5S,2ЈS,5ЈS)-5-[5Ј-(tert-Butyldiphenylsilyloxymethyl)pyrrolidin-2Ј-yl]-
tetrahydrofuran-2-one (14): A solution of butenolide 13 (4.8 g,
9.2 mmol) in anhydrous THF (60 mL) in the presence of AcONa
(130 mg) was subjected to catalytic hydrogenation with 10% Pd on
carbon (486 mg) at room temperature for 24 h. The catalyst was
then filtered off and the filtrate concentrated to give, after flash-
chromatographic purification (60:40, hexanes/EtOAc), a protected
bicyclic compound (4.3 g, 90%) that was then subjected to depro-
tection at the amino function. To a solution of saturated bicyclic
compound (4.2 g, 8.0 mmol) in anhydrous CH2Cl2 (200 mL) were
added thiophenol (1.2 mL, 12 mmol) and TMSOTf (2.2 mL,
12 mmol) under argon at 0 °C with stirring. After 1 h, the reaction
was quenched with a saturated aqueous NaHCO3 solution, ex-
tracted with EtOAc (3 ϫ 100 mL), dried (MgSO4), and concen-
trated in vacuo. The residue was flash-chromatographed on silica
gel (90:10, EtOAc/MeOH) to furnish 3.0 g (88%) of pure N-depro-
tected derivative 14 as an oil. Ϫ [α]20 ϭ Ϫ11.0 (c ϭ 1.4, CHCl3).
D
Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 7.65 (m, 4 H), 7.40 (m, 6 H),
4.36 (q, J ϭ 7.2 Hz, 1 H), 3.63 (dd, J ϭ 10.2, 4.5 Hz, 1 H), 3.53
(dd, J ϭ 10.2, 6.0 Hz, 1 H), 3.44 (m, 1 H), 3.28 (q, J ϭ 7.2 Hz, 1
H), 2.56 (m, 3 H), 2.25 (m, 1 H), 1.9 (m, 3 H), 1.52 (m, 2 H), 1.04
(s, 9 H). Ϫ 13C NMR (75 MHz, CDCl3): δ 177.3, 135.5 (4 C), 133.3
(2 C), 129.7 (2 C), 127.7 (4 C), 83.6, 65.7, 61.2, 59.6, 28.7, 27.0,
26.8 (4 C), 25.1, 19.2. Ϫ C25H33NO3Si (423.63): calcd. C 70.88, H
7.85, N 3.30; found C 70.65, H 7.96, N 3.50.
˚
BF3 ؋ OEt2 (700 µL) and powdered 4-A molecular sieves (500 mg)
were sequentially added at room temperature. After 30 min, the
reaction was quenched with brine and few drops of Et3N. The mix-
ture was extracted with diethyl ether and, after drying, the solvent
evaporated to give crude O-methyl derivative 11, which was purified
by silica gel flash chromatography (9:1, hexanes/ethyl acetate). The
yield was 6.1 g (65% for the last two steps, 41% from 10) of 11 as
(3S,8S,8aS)-3-(tert-Butyldiphenylsilyloxymethyl)-8-(tert-butyldi-
methylsilyloxy)indolizidin-5-one (15): To a solution of N-depro-
tected compound 14 (2.9 g, 6.8 mmol) in anhydrous methanol (28
mL) was added a catalytic amount of sodium methoxide in meth-
anol under argon at 0°C with stirring. After 1 h, the reaction was
quenched with brine, extracted with ethyl acetate, dried (MgSO4)
and concentrated under vacuum. Purification by flash chromatog-
raphy (90:10, EtOAc/MeOH) gave 2.0 g (69%) of a protected indol-
a colorless oil. Ϫ [α]20 ϭ Ϫ31.2 (c ϭ 1.3, CHCl3). Ϫ 1H NMR
D
(300 MHz, CDCl3) (major anomer): δ ϭ 7.65 (m, 4 H), 7.38 (m, 6
H), 5.17 (m, 1 H), 3.8Ϫ4.1 (m, 2 H), 3.6 (m, 1 H), 3.20 (s, 3 H),
2.0Ϫ2.2 (m, 2 H), 1.85 (m, 1 H), 1.75 (m, 1 H), 1.41 (s, 9 H), 1.05
(s, 9 H). Ϫ 13C NMR (75 MHz, CDCl3) (major anomer): δ ϭ
154.9, 135.8 (4 C), 133.7 (2 C), 129.5 (2 C), 127.5 (4 C), 89.6, 79.5,
66.3, 59.1, 55.0, 31.4, 28.2 (3 C), 26.7 (3 C), 22.5, 19.6. Ϫ
C27H39NO4Si (469.70): calcd. C 69.04, H 8.37, N 2.98; found C
69.10, H 8.35, N 3.04.
izidinone as a white solid, m.p. 58Ϫ60°C. Ϫ [α]20 ϭ Ϫ83.0 (c ϭ
D
1.2, CHCl3). This compound was subjected to O-TBS protection.
Thus, TBSCl (2.0 g, 13.5 mmol) and imidazole (0.9 g, 13.5 mmol)
were sequentially added to a solution of the bicyclic compound
(1.9 g, 4.5 mmol) in anhydrous DMF (20 mL) under stirring at
room temperature. After 24 h, further portions of TBSCl (2.0 g,
13.5 mmol) and imidazole (0.9 g, 13.5 mmol) were added, and the
resulting solution was stirred for additional 12 h. The reaction was
then quenched with 5% aqueous citric acid and the resulting mix-
ture extracted with ethyl acetate (3 ϫ 30 mL). The combined or-
ganic layers were dried (MgSO4) and concentrated under vacuum
to afford a crude residue that was purified by flash chromatography
(8:2, hexanes/EtOAc). Protected bicyclic compound 15 (2.3 g, 96%)
was obtained as a colorless oil. Ϫ [α]20D ϭ Ϫ44.6 (c ϭ 2.4, CHCl3).
(5S,2ЈS,5ЈS)-5-[1Ј-(tert-Butoxycarbonyl)-5Ј-(tert-butyldiphenylsilyl-
oxymethyl)pyrrolidin-2Ј-yl]-2(5H)-furanone (13): To a solution of
azafuranose 11 (5.8 g, 12.3 mmol) in anhydrous CH2Cl2 (100 mL)
cooled to Ϫ80°C under N2 was added TBSOTf (1.7 mL, 7.4 mmol)
dropwise. The resulting mixture was stirred at Ϫ80°C for 15 min,
after which time it was treated with 3.2 g (16.1 mmol) of silylenol
ether 12. After being stirred for an additional hour at the same
temperature, the reaction mixture was quenched by the addition
of saturated aqueous NaHCO3 and, after room temperature was
reached, the mixture was extracted with CH2Cl2 (3 ϫ 50 mL). The
combined organic layers were dried with MgSO4, filtered, and con-
centrated under vacuum to provide an oily residue that was purified
by flash chromatography (hexanes/EtOAc, 80:20). Pure 2,3-unsatu-
rated butenolide 13 (5.0 g, 78%) was obtained as a 70:30 mixture
1
Ϫ H NMR (300 MHz, CDCl3): δ ϭ 7.65 (m, 4 H), 7.40 (m, 6 H),
4.24 (m, 1 H), 4.05 (m, 2 H), 3.78 (dd, J ϭ 10.2, 2.4 Hz, 1 H), 3.58
(td, J ϭ 8.7, 2.7 Hz, 1 H), 2.47 (ddd, J ϭ 17.7, 12.6, 6.6 Hz, 1 H),
2.24 (dd, J ϭ 17.7, 6.0 Hz, 1 H), 1.7Ϫ2.1 (m, 6 H), 1.05 (s, 9 H),
0.87 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H). Ϫ 13C NMR (75 MHz,
CDCl3, 25°C): δ ϭ 168.6, 135.5 (4 C), 133.6 (2 C), 129.5 (2 C),
127.6 (4 C), 64.5, 64.3, 63.9, 57.9, 28.6, 27.1, 26.8 (3 C), 26.3, 25.7
(3 C), 24.5, 19.3, 18.0, Ϫ4.6, Ϫ5.0. Ϫ C31H47NO3Si2 (537.89):
calcd. C 69.22, H 8.80, N 2.60; found C 69.70, H 8.85, N 2.69.
of rotamers, an oil. Ϫ [α]20 ϭ Ϫ117.0 (c ϭ 5.0, CHCl3). Ϫ 1H
D
NMR (300 MHz, CDCl3, 25°C, major rotamer): δ ϭ 7.62 (m, 4
H), 7.57 (dd, J ϭ 5.8, 1.5 Hz, 1 H), 7.41 (m, 6 H), 6.03 (dd, J ϭ
5.7, 2.0 Hz, 1 H), 5.42 (dt, J ϭ 3.2, 1.7 Hz, 1 H), 4.38 (dd, J ϭ 7.9,
3.4 Hz, 1 H), 3.85 (m, 1 H), 3.65 (dd, J ϭ 9.7, 2.9 Hz, 1 H), 3.57
(3S,8S,8aS)-8-Hydroxy-3-(hydroxymethyl)indolizidine (6): To
a
(dd, J ϭ 9.7, 6.5 Hz, 1 H), 2.0Ϫ2.3 (m, 3 H), 1.72 (m, 1 H), 1.24 solution of protected derivative 15 (2.1 g, 3.9 mmol) in dry THF
1398 Eur. J. Org. Chem. 1999, 1395Ϫ1400

Lewis Acid Assisted Vinylogous Mannich and Mukaiyama Aldol Reactions
(15 mL) was added dropwise at room temperature a solution of were washed with water, dried with MgSO4, and concentrated in
FULL PAPER
BH3·DMS (1.2 mL, 12.0 mmol) under argon. The reaction was
stirred for 4 h and was quenched by careful addition of MeOH (8
mL). The residue was concentrated under reduced pressure and
purified by flash chromatography on silica gel (90:10, hexanes/
vacuo furnishing a crude residue that was flash-chromatographed
on silica gel (90:10, hexanes/EtOAc) to afford 2.6 g (94%) of a
TMS-protected derivative as an oil. To a solution of this TMS-
protected intermediate (2.5 g, 3.7 mmol) in THF (15 mL),
EtOAc) to give 1.5 g of a pure reduced derivative (2.8 mmol, 71%) BH3 · DMS (1.1 mL, 11.1 mmol) was added dropwise at room tem-
as a glass. To a solution of this compound (1.4 g, 2.8 mmol) in perature. The reaction was stirred for 1 h, quenched by careful ad-
THF (80 mL), a 6  aqueous HCl solution (2 mL) was added dition of methanol (10 mL), and the solvent was evaporated to
dropwise. The mixture was stirred overnight at room temperature,
then the solvent was evaporated to dryness under vacuum. The
crude product was flash-chromatographed on silica gel (7:2.5:0.5,
dryness under reduced pressure. The crude product so obtained
(1.7 g, 70%) was dissolved in MeOH (50 mL) and was stirred in
the presence of 6  HCl aqueous solution (2 mL) added overnight
EtOAc/MeOH/30% aq. NH4OH) to afford 6 (325 mg, 68%) as a at room temperature. The solvent was evaporated to dryness under
glassy solid. Ϫ [α]20 ϭ Ϫ11.43 (c ϭ 0.35, CHCl3). Ϫ 1H NMR
vacuum to leave a solid residue which was flash chromatographed
(300 MHz, D2O): δ ϭ 4.14 (m, 1 H), 3.7Ϫ3.9 (m, 3 H), 3.3Ϫ3.6 on silica gel (1:1:1, EtOAc/MeOH/30% aq. NH4OH) to afford in-
D
(m, 2 H), 3.16 (m, 1 H), 1.6Ϫ2.3 (m, 8 H). Ϫ 13C NMR (75 MHz,
dolizidine 7 (0.4 g, 75%) as a glassy solid. Ϫ [α]20 ϭ Ϫ29.5 (c ϭ
D
CD3OD): δ ϭ 68.1, 67.1, 65.0, 60.1, 49.0, 28.5, 24.1 (2 C), 18.2. Ϫ 0.21, CHCl3). Ϫ 1H NMR (300 MHz, CD3OD): δ ϭ 4.08 (m, 1
C9H17NO2 (171.24): calcd. C 63.13, H 10.01, N 8.18; found C H), 4.03 (m, 1 H), 3.7Ϫ3.9 (m, 4 H), 3.53 (dd, J ϭ 12.9, 3.9 Hz, 1
63.20, H 9.93, N 8.21.
H), 3.49 (m, 1 H), 3.27 (dd, J ϭ 12.6, 2.1 Hz, 1 H), 2.1Ϫ2.3 (m, 3
H), 2.0Ϫ2.1 (m, 1 H). Ϫ 13C NMR (75 MHz, CD3OD): δ ϭ 70.4,
70.2, 68.9, 66.4, 66.0, 61.2, 51.9, 25.5, 24.9. Ϫ C9H17NO4 (203.24):
calcd. C 53.19, H 8.43, N 6.89; found C 53.24, H 8.38, N 6.84.
(3R,4R,5R,2ЈS,5ЈS)-5-[1Ј-(tert-Butoxycarbonyl)-5Ј-(tert-butyldi-
phenylsilyloxymethyl)pyrrolidin-2Ј-yl]-3,4-dihydroxytetrahydro-
furan-2-one (16): To a solution of 13 (4.0 g, 7.6 mmol), dissolved
in anhydrous CH2Cl2 (50 mL), were added cis-dicyclohexano-18-
crown-6 ether (335 mg, 0.9 mmol) and powdered KMnO4 (1.3 g,
8.4 mmol). The reaction mixture was stirred for 4 h, and then a
saturated Na2SO3 aqueous solution was added. After neutraliz-
ation with saturated aqueous citric acid, the mixture was extracted
with CH2Cl2 (3 ϫ 40 mL) and EtOAc (3 ϫ 40 mL), dried with
MgSO4, and then concentrated in vacuo. The residue was purified
by flash chromatography (80:20, ethyl acetate/hexanes) to afford
(3S,6S,7S,8R,8aS)-6,7,8-Triacetoxy-3-(acetoxymethyl)indoli-
zidine (18): Acetic anhydride (1.8 mL, 19 mmol) and a catalytic
amount of DMAP (5 mg) were added under argon to a solution of
indolizidine 7 (386 mg, 1.9 mmol) in dry pyridine (2 mL). The mix-
ture was stirred for 12 h at room temperature, quenched with water,
extracted with CH2Cl2 (3 ϫ 15 mL), and dried with MgSO4. Con-
centration of the solution gave a residue that was flash chromato-
graphed on silica gel eluting with EtOAc to afford 635 mg (90%)
of pure protected derivative 18 as a glass. Ϫ [α]20 ϭ Ϫ27.8 (c ϭ
3.0 g (72%) of pure derivative 16 as a pale yellow glass. Ϫ [α]20
ϭ
D
D
1
Ϫ32.04 (c ϭ 4.5, CHCl3). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
7.62 (m, 4 H), 7.39 (m, 6 H), 4.60 (br. s,1 H), 4.42 (br. s,1 H), 4.29
(m, 1 H), 4.12 (m, 3 H), 3.90 (m, 1 H), 3.73 (m, 1 H), 3.56 (m, 1
H), 2.20 (m, 3 H), 1.75 (m, 1 H), 1.24 (s, 9 H), 1.04 (s, 9 H). Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 175.6, 154.4, 135.5 (4 C), 133.2 (2
C), 129.7 (2 C), 127.7 (4 C), 87.4, 80.5, 77.1, 68.5, 63.7, 59.1, 56.7,
28.4, 28.1 (3 C), 26.8 (3 C), 25.8, 19.2. Ϫ C30H41NO7Si (555.75):
calcd. C 64.84, H 7.44, N 2.52; found C 64.91, H 7.39, N 2.50.
0.18, CHCl3). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 5.29 (ddd, J ϭ
3.6, 2.4, 0.9 Hz, 1 H, 8-H), 5.20 (dddd, J ϭ 3.6, 2.7, 2.4, 0.9 Hz, 1
H, 6-H), 4.98 (t, J ϭ 3.6 Hz, 1 H, 7-H), 4.05 (dd, J ϭ 11.4, 4.2 Hz,
1 H, 9a-H), 4.00 (dd, J ϭ 11.4, 5.4 Hz, 1 H, 9b-H), 3.68 (m, 1 H,
3-H), 3.41 (dd, J ϭ 14.1, 2.7 Hz, 1 H, 5-Heq), 3.16 (td, J ϭ 6.9,
2.1 Hz, 1 H, 8a-H), 2.98 (dd, J ϭ 14.1, 2.4 Hz, 1 H, 5-Hax), 2.16
(s, 3 H, CH3), 2.13 (s, 3 H, CH3), 2.10 (m, 1 H, 2α-H), 2.08 (s, 3
H, CH3), 2.00 (s, 3 H, CH3), 1.90 (m, 1 H, 1β-H), 1.4Ϫ1.7 (m, 2
H, 1α-H and 2β-H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 170.9,
170.7, 170.6, 169.2, 69.7, 68.9, 67.3, 65.9, 60.8, 58.9, 48.3, 26.5,
25.1, 21.3, 21.1 (2 C), 20.7. Ϫ C17H25NO8 (371.39): calcd. C 54.98,
H 6.79, N 3.77; found C 54.90, H 6.75, N 3.73.
(3S,6R,7R,8R,8aS)-3-(tert-Butyldiphenylsilyloxymethyl)-
6,7,8-trihydroxyindolizidin-5-one (17): To
a solution of dihy-
droxylated compound 16 (2.9 g, 5.2 mmol) in anhydrous CH2Cl2
(150 mL) were added thiophenol (0.8 mL, 7.8 mmol) and TMSOTf
(1.4 mL, 7.8 mmol) under argon at 0°C with stirring. After 1 h, the
reaction was quenched with a saturated aqueous NaHCO3 solu-
tion, extracted with EtOAc (3 ϫ 100 mL), dried (MgSO4), and
concentrated under vacuum. The residue was flash chromato-
graphed on silica gel (90:10, EtOAc/MeOH) to furnish 2.0 g (84%)
Acknowledgments
`
We thank the Ministero dellЈUniversita e della Ricerca Scientifica
e Tecnologica (MURST), and the Consiglio Nazionale delle Ricer-
che (CNR) for financial support. The Centro Interdipartimentale
of pure indolizidinone 17 as an oil. Ϫ [α]20 ϭ Ϫ44.47 (c ϭ 1.5,
D
1
CHCl3). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 7.58 (m, 4 H), 7.38
`
Misure “G. Casnati” dellЈUniversita di Parma is gratefully
(m, 6 H), 5.20 (br. s,1 H), 4.93 (br. s,1 H), 4.70 (br. s,1 H), 4.20 (m,
1 H), 4.02 (m, 2 H), 3.93 (m, 2 H), 3.69 (bd, J ϭ 10.2 Hz, 1 H),
3.49 (br. s,1 H), 1.7Ϫ2.1 (m, 4 H), 1.05 (s, 9 H). Ϫ 13C NMR
(75 MHz, CDCl3): δ ϭ 168.8, 135.5 (4 C), 133.3 (2 C), 129.7 (2 C),
127.7 (4 C), 67.7, 67.5, 67.3, 63.7, 59.8, 59.1, 29.7, 26.8 (3 C), 25.4,
19.2. Ϫ C25H33NO5Si (455.63): calcd. C 65.90, H 7.30, N 3.07;
found C 65.95, H 7.27, N 3.11.
acknowledged for instrumental facilities.
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