Synthesis of (+)-Lentiginosine and Its Pyrrolizidine Analogue Based on Intramolecular Cyclization of α-Sulfinyl Carbanions

Article abstract of DOI:10.1002/ejoc.201301671

A synthesis of (+)-lentiginosine and its pyrrolizidine analogue was accomplished in six steps, starting from L-(+)-tartaric acid. The key step of these syntheses involves the intramolecular cyclization of α-sulfinyl carbanions for the construction of the indolizidine or pyrrolizidine ring.

Full text of DOI:10.1002/ejoc.201301671

FULL PAPER
DOI: 10.1002/ejoc.201301671
Synthesis of (+)-Lentiginosine and Its Pyrrolizidine Analogue Based on
Intramolecular Cyclization of α-Sulfinyl Carbanions
Sakkarin Du-a-man,[a] Darunee Soorukram,[a] Chutima Kuhakarn,[a]
Patoomratana Tuchinda,[a] Vichai Reutrakul,[a] and Manat Pohmakotr*[a]
Keywords: Natural products / Chiral pool / Diastereoselectivity / Carbanions / Cyclization
A synthesis of (+)-lentiginosine and its pyrrolizidine ana- molecular cyclization of α-sulfinyl carbanions for the con-
logue was accomplished in six steps, starting from L-(+)-tar- struction of the indolizidine or pyrrolizidine ring.
taric acid. The key step of these syntheses involves the intra-
ties have attracted a number of synthetic efforts toward
their total syntheses in both racemic and enantiopure
forms. We successfully developed a general strategy for the
preparation of 1-azabicyclic[m.n.0] compounds based on
the intramolecular cyclization of α-sulfinyl carbanions.[6]
The method was applied as convenient strategies for synthe-
ses of (Ϯ)-tashiromine, (Ϯ)-indolizidine 167B and 209D,[7]
(Ϯ)-lupinine,[8] and (+)-swainsonine.[9] To further exploit
the synthetic utility of the intramolecular cyclization of α-
sulfinyl carbanions as a convenient, general synthetic route
to polyhydroxylated 1-azabicyclic compounds, we describe
herein a synthesis of (+)-lentiginosine (1)[10] and its known
pyrrolizidine analogue (2)[11] starting from l-(+)-tartaric
acid.
Introduction
Polyhydroxylated indolizidines and pyrrolizidines are im-
portant classes of naturally derived compounds. They have
received considerable attention due to their interesting
structural scaffolds and biological activities such as glycos-
idase inhibitory activity.[1] A series of these types of com-
pounds, including (–)-swainsonine,[2] (+)-castanosperm-
ine,[3] (+)-hyacinthacine A2,[1b,4] and (+)-lentiginosine (1)[5]
are widely found in plants and microorganisms (Figure 1).
Their intriguing structures and important biological activi-
Results and Discussion
The synthetic sequence is shown in Scheme 1. Sulf-
inylimides 6a and 6b were envisioned as key intermediates
for accessing the 1-azabicyclic core structures of (+)-lentig-
inosine (1) and its analogue 2, respectively.[12] Thus, our in-
vestigation began with the synthesis of 6a and 6b starting
from l-(+)-tartaric acid. Treatment of aminosulfides 3a and
3b with l-(+)-tartaric acid in xylene heated to reflux for
15 h afforded the corresponding chiral hydroxyimides 4a
and 4b in 68 and 72% yields, respectively. Protection of the
hydroxyl groups of 4a and 4b by employing tert-butyldi-
methylsilyl chloride (TBSCl)/imidazole in N,N-dimethyl-
formamide (DMF) at 0 °C to room temperature for 1 h pro-
vided the corresponding chiral sulfides 5a and 5b in 98 and
91% yields, respectively. Oxidation of chiral sulfides 5a and
5b by employing NaIO4 in aqueous methanol at 0 °C to
room temperature for 17 h furnished the required sulf-
inylimides 6a (88% yield) and 6b (82% yield), each as two
diastereomeric mixtures (undetermined diastereomeric
ratios).
Figure 1. Some biologically active pyrrolizidines and indolizidines.
[a] Department of Chemistry and Center of Excellence for
Innovation in Chemistry, Faculty of Science, Mahidol
University,
Rama VI Road, Bangkok 10400, Thailand
E-mail: manat.poh@mahidol.ac.th
http://chemistry.sc.mahidol.ac.th
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301671.
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Synthesis of (+)-Lentiginosine and Its Pyrrolizidine Analogue
after reductive cleavage of the phenylsulfinyl group of 7b.
Therefore, the stereochemistry (hydroxyl group cis to the
OTBS group) of compounds 7a and 8a was assigned on the
basis of that of 8b.
At this stage, the construction of the core indolizidine
and pyrrolizidine scaffolds was achieved. Next, the conver-
sions of 7a and 7b into (+)-lentiginosine (1) and its ana-
logue 2 were performed. Upon reductive cleavage of the
phenylsulfinyl group followed by reduction of the resulting
imide, (+)-lentiginosine (1) was expected to be obtained.
Reductive cleavage of the phenylsulfinyl group of 7a was
accomplished by using a combination of NiCl2·6H2O/
[13]
NaBH4
in aqueous methanol at 0 °C to room tempera-
ture for 30 h. The corresponding indolizidinone 8a was iso-
lated in 74% yield as a single isomer. Subsequently, re-
[14]
duction of 8a with LiAlH4 in THF heated to reflux fur-
nished (+)-lentiginosine (1) in 61% yield. The spectroscopic
data and specific optical rotation of the synthesized (+)-
lentiginosine (1) are consistent with reported values {mp
108–109 °C (MeOH); [α]2D3 = +3.3 (c = 0.7, MeOH) [ref.[15]
m.p. 106 °C; [α]2D0 = +3.0 (c = 0.7, MeOH)]}. By following
a
similar synthetic sequence, 7b was treated with
NiCl2·6H2O/NaBH4 in aqueous methanol, leading to 8b
(72% yield as a single isomer), which was subjected to Li-
AlH4-mediated reduction to give the known pyrrolizidine
analogue 2 in 72% yield {mp 163–164 °C; [α]2D3 = +11.3 (c
= 0.5, MeOH) [ref.[11] m.p. 164–165 °C; [α]2D3 = +11 (c =
0.5, MeOH)]}.
The observed stereochemical outcomes of the reduction
reactions mediated by LiAlH4 can be explained by attack
of the hydride on the iminium ion derived from 8a or 8b
taking place from the pseudoaxial direction as governed by
stereoelectronic principles (Scheme 2).
Scheme 1. Synthesis of (+)-lentiginosine (1) and its analogue 2.
With the key sulfinylimides 6a and 6b in hand, the intra-
molecular cyclization of their α-sulfinyl carbanions to the
expected dihydroxylated 1-azabicyclic compounds 7a and
7b was carried out. Treatment of 6a with lithium hexa-
methyldisilazide (LiHMDS; 2.2 equiv.) in tetrahydrofuran
(THF) at –78 °C followed by slow warming to room temp.
for 4 h afforded the expected cyclized product 7a in 81%
yield as an inseparable mixture of diastereomers. Under
similar reaction conditions, 6b provided 7b in 79% yield as
an inseparable mixture of diastereomers. The formation of
Scheme 2. Proposed transition-state for reduction of 8a and 8b by
LiAlH4.
Alternatively, treatment of 7a with 10 mol-% pTsOH in
7a and 7b resulted from intramolecular cyclization of the CH2Cl2 at reflux for 2.5 h furnished the corresponding sulf-
initially formed α-sulfinyl carbanion derived from the corre- inylindolizidinone 9 in 61% yield as a separable 2:1 dia-
sponding sulfinylimides 6 onto the carbonyl group of the stereomeric mixture. A better yield of 9 (78%) was obtained
imide moiety from the opposite face to the α-substituted when 7a was treated with BF3·OEt2 at –78 °C to room tem-
OTBS group to provide the cyclized products 7, in which perature for 6 h. Our attempted reductive dehydroxylation
the hydroxyl group is oriented cis to the OTBS group, as employing Et3SiH and BF3·OEt2 in CH2Cl2 at reflux also
shown in Scheme 1. It is worth mentioning that the stereo- gave the same result, providing phenylsulfinylindolizidinone
chemistry of 7b was subsequently assigned by NOE experi- 9 in 85% yield (Scheme 3). Reductive cleavage of the phen-
ments of compound 8b (see the Supporting Information) ylsulfinyl group of sulfinylindolizidinone
9
by using
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M. Pohmakotr et al.
FULL PAPER
lation over magnesium turnings. Column chromatography was per-
formed with Merk silica gel 60H (Art. 7734) or 60H (Art. 7736).
Reverse-phase chromatography was performed on solid phase ex-
traction (VertiPak, C18-LP Tube). Other common solvents (hex-
anes, CH2Cl2 and ethyl acetate) were distilled before use.
NiCl2·6H2O/NaBH4 in THF/MeOH at 0 °C to room temp.
for 24 h furnished enantiopure chiral indolizidinone 10 in
74% yield. As reported by Ha and co-workers,[15] indolzid-
inone 10 was used as a precursor for the synthesis of (+)-
lentiginosine by sequential treatment with Et3SiH/
CF3COOH, desilylation by using CH3OH/HCl and 4-(Phenylsulfanyl)butan-1-amine (3a):[16] To a suspension of NaH
[65% in mineral oil, 835 mg, 22 mmol; washed with anhydrous hex-
ane (3ϫ 15 mL)] in anhydrous DMF (6 mL) was slowly added a
solution of phthalimide (2.94 g, 20 mmol) in anhydrous DMF
(10 mL) at 0 °C under an argon atmosphere. The reaction mixture
was stirred for 1 h until the generation of hydrogen gas ceased, then
a solution of 1-bromo-4-phenylsulfanylbutane (5.40 g, 22 mmol) in
anhydrous DMF (5 mL) was added dropwise. The reaction mixture
was warmed to room temperature and stirred for 2 h, then poured
onto ice-water and extracted with EtOAc (3ϫ 50 mL). The com-
bined organic layers were washed with brine and dried with an-
hydrous Na2SO4. Filtration and evaporation gave a viscous yellow
oil of a crude product, which was purified by column chromatog-
raphy [SiO2 (Art. 7736); EtOAc/hexanes (1:1)] to give 2-[4-(phen-
ylsulfanyl)butyl]isoindoline-1,3-dione (4.03 g, 65%) as a colorless
LiAlH4-mediated reduction.
1
viscous oil. H NMR (300 MHz, CDCl3): δ = 7.89–7.79 (m, 2 H,
ArH), 7.77–7.68 (m, 2 H, ArH), 7.36–7.20 (m, 4 H, PhH), 7.19–
7.11 (m, 1 H, PhH), 3.70 (t, J = 7.0 Hz, 2 H, NCH2), 2.96 (t, J =
7.1 Hz, 2 H, CH2SPh), 1.97–1.79 (m, 2 H, CH2), 1.79–1.62 (m, 2
H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.3 (2ϫCO),
136.2 (C), 133.8 (2ϫCH), 132.0 (2ϫC), 129.3 (2ϫCH), 128.8
(2ϫCH), 125.9 (CH), 123.1 (2ϫCH), 37.3 (CH2), 33.1 (CH2), 27.5
Scheme 3. An alternative synthesis of (+)-lentiginosine (1).
(CH ), 26.2 (CH ) ppm. IR (Nujol): ν = 1719 (s), 1438 (s), 743 (s),
˜
2
2
718 (s), 691 (s) cm–1. MS: m/z (%) = 311 (37) [M+], 202 (80), 160
Conclusions
(100), 133 (15), 77 (15).
We have demonstrated the synthetic utility of intramolec-
ular cyclization of α-sulfinyl carbanions as a convenient
strategy for the synthesis of (+)-lentiginosine (1) and its
pyrrolizidine analogue (2), starting from readily available l-
(+)-tartaric acid. Asymmetric syntheses of other poly-
hydroxylated indolizidines and pyrrolizidines by employing
this strategy are under investigation.
A
solution of 2-[4-(phenylsulfanyl)butyl]isoindoline-1,3-dione
(3.94 g, 12.6 mmol) in aqueous NaOH (50% w/v, 38 mL) was
stirred and heated to reflux for 18 h. After cooling, the reaction
mixture was diluted with water (15 mL) and extracted with EtOAc
(3ϫ20 mL). The combined organic layers were washed with brine
and dried with anhydrous Na2SO4 followed by filtration and evapo-
ration to give analytically pure 3a (2.06 g, 90%) as a viscous liquid.
1H NMR (300 MHz, CDCl3): δ = 7.33–7.23 (m, 4 H, PhH), 7.17–
7.12 (m, 1 H, PhH), 2.91 (t, J = 7.1 Hz, 2 H, CH2NH2), 2.67 (t, J
= 6.9 Hz, 2 H, CH2SPh), 1.77 (br. s, 2 H, NH2), 1.71–1.53 (m, 4 H,
2ϫCH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 136.6 (C), 128.9
(2ϫCH), 128.7 (2ϫCH), 125.6 (CH), 41.3 (CH2), 33.3 (CH2), 32.4
Experimental Section
General Methods: 1H NMR spectra were recorded with a Bruker
Advance-300, a Bruker Ascend-400, or a Bruker Advance-500 spec-
trometer. 13C NMR were recorded with an Advance-300 (75 MHz),
Ascend-400 (100 MHz), or Advance-500 (125 MHz) spectrometer
in CDCl3 by using tetramethylsilane as an internal standard.
Chemical shifts (δ) reported are given in part per million (ppm)
downfield from tetramethylsilane. IR spectra were recorded with
either a Jasco A-302 or a Perkin–Elmer 683 Infrared spectrometer.
Mass spectra were recorded with a Thermo Finnigan Polaris Q
mass spectrometer. High-resolution mass spectra were recorded
with either a HR-TOF-MS Micromass model VQ-TOF2 or a Fin-
nigan MAT 95 mass spectrometer. Specific rotations were recorded
with a Jasco P1020 polarimeter. Melting points were recorded with
a Buchi 501 melting-point apparatus.
(CH ), 26.3 (CH ) ppm. IR (neat): ν = 3283 (br), 2932 (s), 1651 (s),
˜
2
2
1480 (s), 1439 (s), 1088 (s) cm–1. MS: m/z (%) = 182 (31) [M+ + 1],
181 (15) [M+], 165 (34), 135 (20), 123 (9), 109 (16), 91 (8), 72 (100),
65 (18). HRMS (ESI-TOF): calcd. for C10H16NS [M+ + H]
182.0998; found 182.1020.
3-Phenylsulfanylpropan-1-amine (3b):[17] To a suspension of NaH
[65% in mineral oil, 4.51 g, 120 mmol, washed with anhydrous hex-
ane (3ϫ25 mL)] in anhydrous DMF (30 mL) was slowly added a
solution of phthalimide (14.71 g, 100 mmol) in anhydrous DMF
(95 mL) at 0 °C under an argon atmosphere. The reaction mixture
was stirred for 1 h until the generation of hydrogen gas ceased, then
a
solution of 1-bromo-3-phenylsulfanylpropane (27.74 g,
120 mmol) in anhydrous DMF (125 mL) was slowly added. After
stirring at 0 °C for 1 h, the reaction mixture was slowly warmed to
room temperature and stirred for 2 h, then it was poured onto ice-
water and vigorously stirred. The precipitates were filtered and
recrystallized from ethanol to give 2-(3-phenylsulfanylpropyl)iso-
indoline-1,3-dione (22.46 g, 76%) as white crystals (m.p. 81–82 °C).
1H NMR (300 MHz, CDCl3): δ = 7.89–7.81 (m, 2 H, ArH), 7.77–
7.68 (m, 2 H, ArH), 7.39–7.33 (m, 2 H, PhH), 7.33–7.24 (m, 2 H,
THF was distilled from sodium-benzophenone ketyl. The molarity
of nBuLi (in hexane) was determined by titration with diphenylace-
tic acid in THF at 0 °C. Reactions involving anions were run under
an argon atmosphere. All glassware and syringes were oven-dried
and kept in
a desiccator before use. Hexamethyldisilazane
(HMDS), DMF, dichloromethane (CH2Cl2) and hexane were dried
by distillation over calcium hydride. Methanol was dried by distil-
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Synthesis of (+)-Lentiginosine and Its Pyrrolizidine Analogue
PhH), 7.24–7.15 (m, 1 H, PhH), 3.83 (t, J = 7.0 Hz, 2 H, NCH2),
2.96 (t, J = 7.3 Hz, 2 H, CH2SPh), 2.02 (quint., J = 7.1 Hz,
CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.2 (2ϫCO), 135.7
(C), 133.9 (2ϫCH), 132.0 (2ϫC), 129.8 (2ϫCH), 128.9 (2ϫCH),
with EtOAc (3ϫ10 mL). The combined organic layers were washed
with water, brine, and dried with anhydrous Na2SO4. Filtration fol-
lowed by evaporation gave a crude product, which was purified by
column chromatography [SiO2 (Art. 7736); EtOAc/hexanes, 1:4] to
126.2 (CH), 123.2 (2ϫCH), 36.9 (CH2), 31.4 (CH2), 28.1 give 5a (340 mg, 99%) as a colorless viscous oil. [α]2D6 = +73.9 (c =
(CH ) ppm. IR (Nujol): ν = 1731 (s), 1411 (s), 865 (s), 840 (m), 687 0.5, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.35–7.28 (m, 4 H,
˜
2
(m) cm–1. MS: m/z (%) = 297 (62) [M+], 188 (100), 160 (46).
PhH), 7.22–7.18 (m, 1 H, PhH), 4.46 (s, 2 H, 2ϫCHO), 3.54–3.45
(m, 2 H, NCH2), 2.93 (t, J = 7.2 Hz, 2 H, CH2SPh), 1.75 (quint.,
J = 7.7 Hz, 2 H, CH2), 1.66–1.61 (m, 2 H, CH2), 0.97 [s, 18 H,
2ϫSiC(CH3)3], 0.24 [s, 6 H, Si(CH3)2], 0.19 [s, 6 H, Si(CH3)2] ppm.
13C NMR (125 MHz, CDCl3): δ = 173.4 (2ϫCO), 136.1 (C), 129.4
(2ϫCH), 128.9 (2ϫCH), 126.0 (CH), 76.8 (2ϫCH), 38.1 (CH2),
33.1 (CH2), 26.7 (CH2), 26.3 (CH2), 25.6 (6ϫCH3), 18.2 (2ϫC),
A
solution of 2-(3-phenylsulfanylpropyl)isoindoline-1,3-dione
(2.98 g, 10 mmol) in aqueous NaOH (50 w/v, 30 mL) was heated to
reflux for 20 h. After cooling, the reaction mixture was diluted with
water (20 mL), extracted with EtOAc (3ϫ40 mL), and the com-
bined organic layers were washed with brine, dried with anhydrous
Na2SO4, and concentrated under reduced pressure to give 3b
(1.63 g, 97%). 1H NMR (300 MHz, CDCl3): δ = 7.39–7.25 (m, 4
H, PhH), 7.23–7.15 (m, 1 H, PhH), 3.00 (t, J = 7.2 Hz, 2 H,
CH2NH2), 2.84 (t, J = 6.8 Hz, 2 H, CH2SPh), 1.80 (quint., J =
6.9 Hz, 2 H, CH2), 1.47–1.31 (br. s, 2 H, NH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 136.5 (C), 129.0 (2ϫCH), 128.8 (2ϫCH),
125.8 (CH), 40.9 (CH2), 32.7 (CH2), 31.0 (CH2) ppm. IR (Nujol):
–4.5 (2ϫCH ), –5.1 (2ϫCH ) ppm. IR (neat): ν = 1727 (s), 1473
˜
3
3
(m), 1361 (s), 1253 (s), 1124 (s) cm–1. MS: m/z (%) = 524 (1) [M+],
466 (41), 438 (12), 165 (100), 73 (14). HRMS (ESI-TOF): calcd.
for C26H45NO4SSi2Na [M+ + Na] 546.2506; found 546.2500.
(3R,4R)-3,4-Bis(tert-butyldimethylsilyloxy)-1-(3-phenylsulfanylprop-
yl)pyrrolidine-2,5-dione (5b): By following the procedure described
for 5a, the reaction of 4b (4.22 g, 15 mmol), imidazole (3.06 g,
45 mmol) and tert-butyldimethylsilyl chloride (4.97 g, 33 mmol) in
anhydrous DMF (40 mL) gave 5b (6.85 g, 90%) as a colorless vis-
cous oil after column chromatography [SiO2 (Art. 7736); EtOAc/
ν = 3317 (br), 3276 (br), 2854 (s), 1633 (s), 1557 (s), 1463 (s) cm–1.
˜
MS: m/z (%) = 167 (7) [M+], 165 (28), 151 (16), 147 (15), 123 (22),
121 (23), 109 (36), 95 (52), 81 (74), 77 (50), 67 (100), 55 (93).
(3R,4R)-3,4-Dihydroxy-1-(4-phenylsulfanylbutyl)pyrrolidine-2,5-di-
one (4a): A mixture of (+)-l-tartaric acid (659 mg, 4.4 mmol) and
3a (789 mg, 4.4 mmol) in xylene (10 mL) was heated to reflux over-
night (18 h). The precipitates were filtered and recrystallized from
CH2Cl2 to give 4a (679 mg, 53 %) as a white solid (m.p. 121–
hexanes, 1:4]. [α]2D4 = +89.3 (c = 1, CHCl3). H NMR (300 MHz,
1
CDCl3): δ = 7.39–7.26 (m, 4 H, PhH), 7.25–7.17 (m, 1 H, PhH),
4.48 (s, 2 H, 2ϫCHO), 3.72–3.55 (m, 2 H, NCH2), 2.90 (t, J =
7.2 Hz, 2 H, CH2SPh), 1.92 (quint., J = 7.1 Hz, 2 H, CH2), 0.97
[s, 18 H, 2 ϫ SiC(CH3)3], 0.25 [s, 6 H, Si(CH3)2], 0.20 [s, 6 H,
Si(CH3)2] ppm. 13C NMR (75 MHz, CDCl3): δ = 173.3 (2ϫCO),
135.6 (C), 129.9 (2 ϫ CH), 128.9 (2 ϫ CH), 126.3 (CH), 76.8
(2ϫCH), 37.7 (CH2), 31.5 (CH2), 27.1 (CH2), 25.6 (6 ϫCH3), 18.2
122 °C). [α]2D5 = +88.3 (c = 1, MeOH). H NMR (300 MHz, [D6]-
1
acetone): δ = 7.39–7.28 (m, 4 H, PhH), 7.24–7.16 (m, 1 H, PhH),
5.45–5.38 (m, 2 H, 2ϫOH), 4.49 (br. d, J = 3.6 Hz, 2 H, 2ϫCH),
3.60–3.40 (m, 2 H, NCH2), 3.00 (t, J = 7.1 Hz, 2 H, CH2SPh),
1.80–1.70 (m, 2 H, CH2), 1.70–1.57 (m, 2 H, CH2) ppm. 13C NMR
(75 MHz, [D6]acetone): δ = 175.0 (2 ϫ CO), 137.5 (C), 129.7
(2ϫCH), 129.5 (2ϫCH), 126.5 (CH), 75.8 (2ϫCH), 38.3 (CH2),
(2ϫC), –4.5 (2ϫCH ), –5.1 (2ϫCH ) ppm. IR (CHCl ): ν = 1719
˜
3
3
3
(s), 1362 (m), 1109 (s) cm–1. MS: m/z (%) = 510 (16) [M+ + H], 494
(21), 452 (100), 424 (59), 151 (54), 73 (36). HRMS (ESI-TOF):
calcd. for C25H43NO4SSi2Na [M+ + Na] 532.2349; found 532.2344.
33.0 (CH ), 27.3 (CH ), 26.9 (CH ) ppm. IR (Nujol): ν = 3359 (br),
˜
2
2
2
1702 (s), 1462 (s), 1376 (s) cm–1. MS: m/z (%) = 295 (100) [M+],
277 (68), 186 (29), 168 (40), 158 (20), 139 (21), 132 (15), 123 (19),
110 (78). HRMS (ESI-TOF): calcd. for C14H17NO4SNa [M+ + Na]
318.0776; found 318.0770.
(3R,4R)-3,4-Bis(tert-butyldimethylsilyloxy)-1-(4-phenylsulfinylbut-
yl)pyrrolidine-2,5-dione (6a): To a solution of 5a (1.05 g, 2 mmol) in
methanol (12 mL) at 0 °C was added a solution of NaIO4 (511 mg,
2.4 mmol) in water (3 mL). The mixture was stirred vigorously and
slowly warmed to room temperature overnight (18 h). After fil-
tration of the precipitates of NaIO3, the filtrate was extracted with
EtOAc (3ϫ15 mL) and the combined organic layers were washed
with brine and dried with anhydrous Na2SO4. Filtration followed
by evaporation afforded a crude product, which was purified by
column chromatography [SiO2 (Art. 7734); EtOAc/hexanes, 2:3] to
give 6a (944 mg, 88%) as a mixture of diastereomers as a colorless
viscous oil. 1H NMR (400 MHz, CDCl3): δ (isomers A and B) =
7.61–7.55 (m, 4 H, PhH A and B), 7.54–7.44 (m, 6 H, PhH A and
B), 4.43 (s, 4 H, 4ϫCHO A and B), 3.53–3.35 (m, 4 H, 2ϫNCH2
A and B), 2.86–2.71 (m, 4 H, 2ϫCH2SOPh A and B), 1.80–1.48
(m, 8 H, 2ϫCH2CH2 A and B), 0.92 [s, 36 H, 2ϫSiC(CH3)3 A and
B], 0.20 [s, 12 H, 2ϫSi(CH3)2 A and B], 0.15 [s, 12 H, 2ϫSi(CH3)2
A and B] ppm. 13C NMR (100 MHz, CDCl3): δ (isomer A
marked*) = 173.3 (4ϫCO A and B), 143.6 (C*), 143.5 (C), 131.0
(2ϫCH A and B), 129.2 (4ϫCH A and B), 123.9 (4ϫCH A and
B), 76.8 (4ϫCH A and B), 56.1 (CH2*), 56.0 (CH2), 37.8 (2ϫCH2
(3R,4R)-3,4-Dihydroxy-1-(3-phenylsulfanylpropyl)pyrrolidine-2,5-di-
one (4b): By following the procedure described for 4a, the reaction
of (+)-l-tartaric acid (1.46 g, 9.7 mmol) and 3b (1.63 g, 9.7 mmol)
in xylene (20 mL) gave 4b (1.97 g, 72%) as a white solid (m.p. 147–
1
148 °C). [α]2D5 = +84.4 (c = 1, MeOH). H NMR (300 MHz, [D6]-
acetone): δ = 7.42–7.28 (m, 4 H, PhH), 7.26–7.17 (m, 1 H, PhH),
5.53–5.25 (br., 1 H, OH), 4.52 (s, 2 H, 2ϫCH), 3.69–3.53 (m, 2 H,
NCH2), 2.98 (t, J = 7.3 Hz, 2 H, CH2SPh), 2.86 (br., 1 H, OH),
1.88 (quint., J = 7.1 Hz, 2 H, CH2) ppm. 13C NMR (75 MHz, [D6]-
acetone): δ = 175.1 (2 ϫ CO), 137.1 (C), 129.8 (4 ϫ CH), 126.8
(CH), 75.8 (2ϫCH), 38.0 (CH2), 31.2 (CH2), 28.0 (CH2) ppm. IR
(Nujol): ν = 3272 (br), 1713 (s), 1687 (s), 1463 (s) cm–1. MS: m/z
˜
(%) = 281 (100) [M+], 263 (54), 259 (51), 197 (34), 188 (32), 172
(71), 169 (56), 154 (78), 144 (71), 110 (58), 91 (38), HRMS (ESI-
TOF): calcd. for C13H15NO4SNa [M+ + Na] 304.0619; found
304.0612.
(3R,4R)-3,4-Bis(tert-butyldimethylsilyloxy)-1-(4-phenylsulfanylbut- A and B), 26.6 (CH2*), 26.5 (CH2), 25.6 (12ϫCH3 A and B), 19.4
yl)pyrrolidine-2,5-dione (5a): To a mixture of 4a (194 mg, 0.7 mmol)
and imidazole (148 mg, 2 mmol) in anhydrous DMF (1 mL) at 0 °C
under an argon atmosphere was slowly added a solution of tert-
(CH2*), 19.3 (CH2), 18.2 (4ϫC A and B), –4.5 (4ϫCH3 A and B),
–5.1 (4ϫCH A and B) ppm. IR (neat): ν = 1728 (s), 1716 (s), 1473
˜
3
(m), 1444 (m), 1361 (s), 1252 (s), 1121 (s), 1048 (m) cm–1. MS: m/z
butyldimethylsilyl chloride (236 mg, 1.5 mmol) in anhydrous DMF (%) = 540 (41) [M+ + 1], 483 (76), 398 (43), 356 (29), 328 (31), 165
(1 mL). After stirring at room temperature for 1 h, the reaction was
quenched with cold water (2 mL) and the mixture was extracted
(28), 74 (57). HRMS (ESI-TOF): calcd. for C26H45NO5SSi2Na [M+
+ Na] 562.2455; found 562.2454.
Eur. J. Org. Chem. 2014, 1708–1715
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1711

M. Pohmakotr et al.
FULL PAPER
(3R,4R)-3,4-Bis(tert-butyldimethylsilyloxy)-1-(3-phenylsulfinylprop-
yl)pyrrolidine-2,5-dione (6b): By following the procedure described
for 6a, a solution of 5b (6.69 g, 13 mmol) in methanol (80 mL) was
treated with a solution of NaIO4 (3.10 g, 14 mmol) in water
(20 mL) to give a colorless oil of 6b (5.43 g, 79%) after column
chromatography [SiO2 (Art. 7734); EtOAc/hexanes, 1:1] as a mix-
HRMS (ESI-TOF): calcd. for C26H45NO5SSi2Na [M+ + Na]
562.2455; found 562.2457.
(1R,2R)-1,2-Bis(tert-butyldimethylsilyloxy)-7a-hydroxy-7-(phenyl-
sulfinyl)tetrahydro-1H-pyrrolizin-3(2H)-one (7b): By following the
procedure described for 7a, a solution of 6b (7.33 g, 14 mmol) in
anhydrous THF (70 mL) was treated with a solution of LiHMDS
[prepared by reacting hexamethyldisilazane (7 mL, 33 mmol) in
THF (70 mL) with nBuLi (1.31 m in hexane, 23.4 mL, 31 mmol)]
at –78 °C to room temperature for 3 h. Purification by column
chromatography [SiO2 (Art. 7734); EtOAc/hexanes, 2:3] afforded
7b (5.79 g, 79%) as a mixture of diastereomers as a white semi-
solid. The following spectroscopic data are of a mixture of two
major diastereomers A and B. 1H NMR (400 MHz, CDCl3): δ (iso-
mer A marked*) = 7.47–7.41 (m, 4 H, PhH A and B), 7.41–7.32
(m, 6 H, PhH A and B), 4.53–4.43 (br., 2 H, OH A and B), 4.38
(d, J = 6.6 Hz, 2 H, CHO A and B), 3.91 (d, J = 6.6 Hz, 2 H, CHO
A and B), 3.53 (ddd, J = 10.9, 8.3, 5.3 Hz, 2 H, NCHH A and B),
3.26–3.15 (m, 2 H, NCHH A and B), 2.86–2.72 (m, 4 H, 2 ϫ
CHSOPh and 2ϫ CHH A and B), 1.69–1.56 (m, 2 H, CHH A and
B), 0.88 [s, 18 H, 2ϫSiC(CH3)3*], 0.79 [s, 18 H, 2ϫSiC(CH3)3],
0.15 (s, 6 H, 2ϫSiCH3*), 0.11 (s, 6 H, 2ϫSiCH3*), 0.06 (s, 6 H,
2ϫSiCH3), 0.00 (s, 6 H, 2ϫSiCH3) ppm. 13C NMR (100 MHz,
CDCl3): δ (isomer A marked*) = 171.1 (CO*), 168.8 (CO), 142.6
(C*), 141.3 (C), 131.0 (2ϫCH A and B), 129.4 (2ϫ CH), 129.2
(2ϫ CH*), 124.2 (2ϫ CH), 124.0 (2ϫ CH*), 99.4 (C*), 92.1 (C),
80.7 (CH*), 79.0 (CH), 77.9 (CH*), 76.4 (CH), 69.7 (CH), 62.8
(CH*), 40.8 (CH2), 39.8 (CH2*), 26.0 (3ϫCH3*), 25.9 (3ϫCH3),
25.6 (3ϫCH3*), 25.5 (3 ϫ CH3), 22.8 (CH2*), 21.7 (CH2), 18.3
(C*), 18.0 (C), 17.9 (C*), 17.8 (C), –3.7 (CH3), –3.9 (CH3*), –4.3
(CH3), –4.4 (CH3*), –4.5 (CH3), –4.6 (CH3*), –4.7 (CH3), –5.2
1
ture of diastereomers. H NMR (300 MHz, CDCl3): δ (isomers A
and B) = 7.64–7.55 (m, 4 H, PhH A and B), 7.55–7.43 (m, 6 H,
PhH A and B), 4.45 (s, 2 H, CHO A), 4.44 (s, 2 H, CHO B), 3.73–
3.44 (m, 4 H, 2 ϫ NCH2 A and B), 2. 89–2. 64 (m, 4 H,
2ϫCH2SOPh A and B), 2.18–1.97 (m, 2 H, 2ϫCHH A and B),
1.97–1.76 (m, 2 H, 2ϫCHH A and B), 0.92 [s, 36 H, 4ϫSiC-
(CH3)3 A and B], 0.20 [s, 12 H, 2ϫSi(CH3)2 A and B], 0.15 [s, 12
H, 2ϫSi(CH3)2 A and B] ppm. 13C NMR (75 MHz, CDCl3): δ
(isomer A marked*) = 173.4 (4ϫCO A and B), 143.3 (C), 143.2
(C*), 131.1 (CH*), 131.0 (CH), 129.2 (4ϫCH A and B), 124.0
(2ϫCH*), 123.9 (2ϫ CH), 76.8 (4ϫCH A and B), 54.5 (2ϫCH2
A and B), 37.3 (CH2*), 37.2 (CH2), 25.6 (12ϫCH3 A and B), 20.9
(CH2), 20.8 (CH2*), 18.1 (4ϫC A and B), –4.5 (4ϫCH3 A and B),
–5.1 (4ϫCH A and B) ppm. IR (CHCl ): ν = 1720 (s), 1445 (m),
˜
3
3
1403 (m), 1362 (m), 1111 (m), 1043 (m) cm–1. MS: m/z (%) = 526
(3) [M+ + H], 468 (100), 314 (49), 210 (26), 167, (76), 149 (35), 73
(34). HRMS (ESI-TOF): calcd. for C25H43NO5SSi2Na [M+ + Na]
548.2298; found 548.2293.
(1R,2R)-1,2-Bis(tert-butyldimethylsilyloxy)-8a-hydroxy-8-(phenyl-
sulfinyl)hexahydroindolizin-3(2H)-one (7a): To a cooled solution of
hexamethyldisilazane (0.88 mL, 4.2 mmol) in anhydrous THF
(10 mL) at –78 °C under an argon atmosphere was added dropwise
n-BuLi (1.48 m in hexane, 2.6 mL, 3.8 mmol). The resulting solu-
tion was stirred at –78 °C for 1 h and slowly transferred by using
a Teflon tube to a cooled solution of 6a (927 mg, 1.7 mmol) in
THF (10 mL) at –78 °C. The mixture was stirred and slowly
warmed to room temperature for 4 h, then the reaction was
quenched with water (10 mL), and extracted with EtOAc
(3ϫ20 mL). The combined organic layers were washed with brine
and dried with anhydrous Na2SO4. Filtration followed by evapora-
tion gave a yellow oil of a crude product, which was purified by
column chromatography [SiO2 (Art. 7734); EtOAc/hexanes, 2:3] to
afford 7a (749 mg, 81%) as a mixture of diastereomers as a white
semi-solid. The following spectroscopic data are of a mixture of
(CH *) ppm. IR (CHCl ): ν = 3421 (br), 1718 (s), 1445 (m), 1424
˜
3
3
(m), 1336 (m), 1256 (m), 1121 (m), 1086 (m), 840 (s) cm–1. MS: m/z
(%) = 526 (2) [M+], 507 (14) [M+ – H2O], 467 (36), 450 (30), 382
(24), 342 (100), 286 (23), 250 (20), 210 (26), 149 (51), 73 (47).
HRMS (ESI-TOF): calcd. for C25H43NO5SSi2Na [M+ + Na]
548.2298; found 548.2293.
(1S,2R)-1,2-Bis(tert-butyldimethylsilyloxy)-8-(phenylsulfinyl)-
1,2,6,7-tetrahydroindolizin-3(5H)-one (9); Preparation with Et3SiH
and BF3·OEt2: To a cooled solution of 7a (196 mg, 0.36 mmol) in
anhydrous CH2Cl2 (5 mL) at –78 °C was added Et3SiH (0.6 mL,
3.5 mmol) followed by BF3·OEt2 (0.12 mL, 1.1 mmol). The mixture
was vigorously stirred and slowly warmed to room temperature for
14 h, then the reaction was quenched with saturated NaHCO3 solu-
tion, diluted with water, and extracted with CH2Cl2 (3ϫ15 mL).
The combined organic layers were washed with water and brine,
then dried with anhydrous Na2SO4. After removal of solvent, the
crude product was purified by column chromatography [SiO2 (Art.
7734); EtOAc/hexanes, 2:3] to give 9 (133 mg, 85%; 2:1 mixture of
diastereomers as determined by 1H NMR spectroscopy) as a white
semi-solid. Partial separation of both diastereomers could be
achieved by radial chromatography (hexanes to EtOAc/hexanes,
1:1) to give two pure fractions of F1 and F2.
1
two major diastereomers A and B. H NMR (300 MHz, CDCl3): δ
(isomer A marked*) = 7.63–7.42 (m, 10 H, PhH A and B), 4.46 (s,
1 H, OH*), 4.37 (d, J = 2.1 Hz, 1 H, CHO*), 4.28 (s, 1 H, CHO),
4.18 (d, J = 1.6 Hz, 1 H, OH), 4.12 (s, 1 H, CHO), 4.03 (d, J =
2.1 Hz, 1 H, CHO*), 3.93–3.81 (m, 2 H, NCHH A and B), 3.18–
2.89 (m, 3 H, CHSOPh*, NCHH A and B), 2.75–2.64 (m, 1 H,
CHSOPh), 2.39 (ddd, J = 14.0, 13.7, 3.5 Hz, 1 H, CHH), 2.18 (ddd,
J = 13.5, 13.4, 3.8 Hz, 1 H, CHH*), 1.97–1.74 (m, 2 H, 2ϫ CHH
A and B), 1.64–1.47 (m, 1 H, CHH), 1.47–1.23 (m, 3 H, CHH*,
CHH*, CHH), 0.98–0.89 [m, 36 H, 2ϫSiC(CH3)3 A and B], 0.30–
0.21 [m, 24 H, 2ϫSi(CH3)2 A and B] ppm. 13C NMR (75 MHz,
CDCl3): δ (isomer A marked*) = 170.1 (CO*), 168.6 (CO), 142.7
(C), 140.8 (C*), 130.8 (CH*), 130.7 (CH), 129.2 (2ϫCH), 129.1
(2ϫCH*), 124.5 (2ϫCH*), 124.0 (2ϫCH), 90.3 (C*), 87.7 (C),
Fraction F1 was obtained as a viscous oil (less polar, 46 mg): [α]2D6
79.4 (CH*), 77.2 (CH), 76.6 (CH*), 76.4 (CH), 67.9 (CH), 59.9 = +180.8 (c = 0.5, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ =
(CH*), 36.2 (CH2), 35.9 (CH2*), 26.0 (3ϫCH3*), 25.8 (3ϫCH3),
7.67–7.64 (m, 2 H, PhH), 7.50–7.47 (m, 3 H, PhH), 5.07 (s, 1 H,
25.7 (3ϫCH3*), 25.6 (3ϫCH3), 24.2 (CH2), 23.3 (CH2*), 18.1 (2ϫ CHO), 4.21 (s, 1 H, CHO), 3.75 (dt, J = 13.2, 5.2 Hz, 1 H, NCHH),
C*), 17.9 (2 ϫ C), 15.3 (CH2), 15.2 (CH2*), –3.8 (CH3), –4.0
(CH3*), –4.3 (CH3), –4.4 (2ϫCH3 A and B), –4.9 (2ϫCH3 A and
3.35 (dt, J = 13.2, 6.6 Hz, 1 H, NCHH), 2.52 (dt, J = 16.5, 5.1 Hz,
1 H, CHH), 1.88–1.74 (m, 2 H, CH2), 1.65–1.56 (m, 1 H, CHH),
0.93 [s, 9 H, SiC(CH3)3], 0.91 [s, 9 H, SiC(CH3)3], 0.26 [s, 6 H,
B), –5.0 (CH *) ppm. IR (CHCl ): ν = 3489 (br), 1710 (s), 1464
˜
3
3
(m), 1445 (m), 1428 (m), 1259 (m), 1103 (s), 1085 (s), 1048 (m), Si(CH3)2], 0.17 [s, 6 H, Si(CH3)2] ppm. 13C NMR (75 MHz,
873, 1085 (s), 840 (s) cm–1. MS: m/z (%) = 540 (1) [M+], 442 (51),
CDCl3): δ = 171.6 (CO), 146.8 (C), 142.2 (C), 130.0 (CH), 128.8
(2ϫCH), 125.2 (2ϫCH), 116.3 (C), 77.3 (CH), 73.8 (CH), 39.0
424 (43), 328 (73), 310 (100), 170 (37), 168 (33), 139 (22), 122 (28).
1712
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1708–1715

Synthesis of (+)-Lentiginosine and Its Pyrrolizidine Analogue
(CH2), 25.8 (6ϫCH3), 19.9 (CH2), 18.2 (C), 17.9 (C), 16.5 (CH2), –4.4 (CH ), –4.5 (CH ) ppm. IR (Nujol): ν = 1716 (s), 1463 (s),
˜
3
3
–4.0 (CH ), –4.1 (CH ), –4.2 (CH ), –5.0 (CH ) ppm. IR (neat): ν 1255 (s), 1099 (s) cm–1. MS: m/z (%) = 397 (2) [M+], 352 (32), 334
˜
3
3
3
3
= 1736 (s), 1657 (s), 1216 (s), 835 (s) cm–1. MS: m/z (%) = 522 (1)
(48), 302 (9), 277 (59), 260 (100), 242 (43), 226 (51), 196 (30), 165
[M+ + H], 464 (100), 298 (33), 149 (18), 122 (11), 75 (11), 73 (14). (25), 75 (78).
HRMS (ESI-TOF): calcd. for C26H43NO4SSi2Na [M+ + Na]
(1R,2R)-1,2-Bis(tert-butyldimethylsilyloxy)-8a-hydroxyhexahydro-
544.2349; found 544.2340.
indolizin-3(2H)-one (8a): To a solution of 7a (203 mg, 0.38 mmol)
and NiCl2·6H2O (905 mg, 3.8 mmol) in anhydrous MeOH (3.5 mL)
and anhydrous THF (1.2 mL) at 0 °C was added portionwise
NaBH4 (431 mg, 11.4 mmol). The mixture was stirred and slowly
warmed to room temperature for 30 h. Ni2B was then removed by
filtration and the filtrate was evaporated to dryness. The residue
was diluted with water, extracted with EtOAc (3ϫ10 mL), and the
combined extracts were washed with brine and dried with anhy-
drous Na2SO4. Filtration followed by evaporation afforded a crude
product, which was purified by column chromatography [SiO2 (Art.
7736); EtOAc/hexanes, 3:7] to give 8a (115 mg, 74%) as a single
isomer as a white semi-solid. [α]2D4 = +6.2 (c = 1, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 3.90 (dd, J = 13.2, 4.9 Hz, 1 H, NCHH),
3.85 (d, J = 1.9 Hz, 1 H, CHO), 3.79 (d, J = 1.9 Hz, 1 H, CHO),
2.97 (dt, J = 13.2, 3.4 Hz, 1 H, NCHH), 2.93 (d, J = 1.7 Hz, 1 H,
OH), 1.89–1.65 (m, 5 H, CHH, CHH, CHH), 1.44–1.28 (m, 1 H,
CHH), 0.19 [s, 9 H, SiC(CH3)3], 0.18 [s, 9 H, SiC(CH3)3], 0.11 [s,
6 H, Si(CH3)2], 0.10 [s, 6 H, Si(CH3)2] ppm. 13C NMR (100 MHz,
CDCl3):δ = 170.6 (CO), 89.8 (C), 79.0 (CH), 76.8 (CH), 36.9 (CH2),
29.6 (CH2), 25.7 (3ϫCH3), 25.6 (3ϫCH3), 24.1 (CH2), 18.9 (CH2),
18.0 (2ϫC), –4.5 (CH3), –4.6 (CH3), –4.8 (CH3), –5.1 (CH3) ppm.
Fraction F2 was obtained as viscous oil (more polar, 34 mg): [α]2D6
= –120.7 (c = 1.7, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 7.60–
7.40 (m, 5 H, PhH), 5.00 (s, 1 H, CHO), 4.20 (s, 1 H, CHO), 3.75–
3.61 (m, 1 H, NCHH), 3.43–3.29 (m, 1 H, NCHH), 2.56 (dt, J =
16.3, 5.1 Hz, 1 H, CHH), 1.95–1.73 (m, 2 H, CHH), 1.73–1.55 (m,
1 H, CHH), 0.97 [s, 9 H, SiC(CH3)3], 0.95 [s, 9 H, SiC(CH3)3], 0.31
(s, 3 H, SiCH3), 0.26 (s, 3 H, SiCH3), 0.25 (s, 3 H, SiCH3), 0.20 (s,
3 H, SiCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.9 (CO),
146.4 (C), 143.0 (C), 130.2 (CH), 129.0 (2ϫCH), 124.4 (2ϫCH),
116.7 (C), 76.8 (CH), 73.1 (CH), 39.0 (CH2), 25.8 (3ϫCH3), 25.7
(3ϫCH3), 19.9 (CH2), 18.2 (C), 18.0 (C), 16.6 (CH2), –4.1 (CH3),
–4.2 (CH ), –4.6 (CH ), –5.0 (CH ) ppm. IR (neat): ν = 1727 (s),
˜
3
3
3
1658 (s), 1216 (s), 834 (s) cm–1. MS: m/z (%) = 522 (1) [M+ + H],
464 (100), 298 (27), 149 (8), 122 (7), 73 (10). HRMS (ESI-TOF):
calcd. for C26H43NO4SSi2Na [M+ + Na] 544.2349; found 544.2349.
Preparation of 9 with p-TsOH: A solution of 7a (135 mg,
0.25 mmol) in anhydrous CH2Cl2 (5 mL) was treated with a cata-
lytic amount of p-toluenesulfonic acid (pTsOH) in the presence of
4 Å molecular sieves. The reaction mixture was vigorously stirred
and heated to reflux for 2.5 h. After cooling, the reaction mixture
was filtered and washed with CH2Cl2. The filtrate was evaporated
to dryness to give a crude product, which was purified by column
chromatography [SiO2 (Art. 7734); EtOAc/hexanes, 2:3] to give 9
(80 mg, 61%) as a white semi-solid.
IR (CHCl ): ν = 3404 (br), 1698 (s), 1447 (m), 1259 (m), 1172
˜
3
(m) cm–1. MS: m/z (%) = 416 (1) [M+ + H], 374 (19), 358 (100),
340 (33), 208 (20), 198 (21), 170 (17), 149 (36), 73 (24). HRMS
(ESI-TOF): calcd. for C20H41NO4SSi2Na [M+ + Na] 438.2472;
found 438.2466.
Preparation of 9 with BF3·OEt2: To a cooled solution of 7a (113 mg,
0.2 mmol) in anhydrous CH2Cl2 (2.5 mL) at –78 °C was added
BF3·OEt2 (0.07 mL, 0.6 mmol). The mixture was stirred and slowly
warmed to room temperature for 6 h, then the reaction was
quenched with saturated NaHCO3 solution, diluted with water, and
extracted with CH2Cl2 (3ϫ5 mL). The combined organic layers
were washed with water and brine, then dried with anhydrous
Na2SO4. Purification by column chromatography [SiO2 (Art. 7734);
EtOAc/hexanes, 2:3] gave 9 (89 mg, 78%) as a white semi-solid.
(+)-Lentiginosine (1): To a suspension of LiAlH4 (25 mg,
0.65 mmol) in anhydrous THF (0.35 mL) was added dropwise a
solution of 8a (53 mg, 0.13 mmol) in anhydrous THF (0.5 mL) at
room temperature. The resulting mixture was heated to reflux for
18 h. After cooling at 0 °C, water (0.5 mL) was carefully added fol-
lowed by 1 n NaOH (0.5 mL) and the resulting mixture was filtered
through a Celite pad and the filtrate was concentrated under re-
duced pressure to give a crude viscous oil, which was purified by
solid phase extraction on reverse phase [C18-LP, MeOH/CH3CN,
2:3] to give 1 (12 mg, 61 %) as a white solid [m.p. 108–109 °C
(MeOH)]; [α]2D3 = +3.3 (c = 0.7, MeOH) [ref.[15] m.p. 106 °C; [α]2D0
= +3.0 (c = 0.7, MeOH)]. 1H NMR (400 MHz, D2O): δ = 4.20–
4.11 (m, 1 H, CH), 3.74 (dd, J = 8.7, 3.3 Hz, 1 H, CH), 3.17–3.05
(m, 1 H, NCHH), 3.04–2.94 (m, 1 H, NCH), 2.93–2.81 (m, 1 H,
NCHH), 2.41–2.19 (m, 2 H, NCHH, NCHH), 2.06–1.92 (m, 1 H,
CHH), 1.92–1.78 (br. d, 2 H, 2ϫOH), 1.78–1.65 (m, 1 H, CHH),
1.61–1.43 (m, 1 H, CHH), 1.43–1.20 (m, 3 H, CHH, CHH,
CHH) ppm. 13C NMR (100 MHz, D2O): δ = 81.9 (CH), 74.9 (CH),
68.4 (CH), 59.6 (CH2), 52.3 (CH2), 26.7 (CH2), 23.3 (CH2), 22.3
(1S,2R)-1,2-Bis(tert-butyldimethylsilyloxy)-1,2,6,7-tetrahydroind-
olizin-(5H)-one (10):[15] To a solution of the diastereomeric mixture
of 9 (89 mg, 0.17 mmol) and NiCl2·6H2O (405 mg, 1.7 mmol) in
anhydrous MeOH (1.5 mL) and anhydrous THF (0.5 mL) at 0 °C
was added portionwise NaBH4 (202 mg, 5.3 mmol). The mixture
was vigorously stirred and slowly warmed to room temperature for
1 h. Upon completion of the reaction, the precipitate of Ni2B was
removed by filtration and the filtrate was concentrated by evapora-
tion. The resulting mixture was diluted with water and extracted
with EtOAc (3ϫ10 mL). The combined extracts were washed with
brine and dried with anhydrous Na2SO4. After solvent removal, the
crude product was purified by column chromatography [SiO2 (Art.
7734); EtOAc/hexanes, 1:4] to give 10 (51 mg, 74%) as a colorless
viscous oil. [α]2D2 = +115.8 (c = 6.0, CHCl3) [ref.[15] [α]2D4 = +111.1
(c = 6.02, CHCl3)]. 1H NMR (300 MHz, CDCl3): δ = 4.95–4.87
(m, 1 H, CHO), 4.62–4.54 (m, 1 H, CHO), 4.17 (dd, J = 5.3, 1.2 Hz,
1 H, CH), 3.87–3.71 (m, 1 H, NCHH), 2.94 (ddd, J = 16.5, 9.9,
(CH ) ppm. IR (Nujol): ν = 3270 (br), 1136 (s), 1106 (s), 677
˜
2
(s) cm–1. MS: m/z (%) = 157 (6) [M+], 149 (19), 129 (16), 121 (19),
117 (16), 111 (23), 109 (16), 105 (16), 97 (37), 95 (42), 83 (30), 67
(100).
(1R,2R)-1,2-Bis(tert-butyldimethylsilyloxy)-7a-hydroxytetrahydro-
1H-pyrrolizin-3(2H)-one (8b):[15] By following the procedure de-
3.3 Hz, 1 H, NCHH), 1.96–1.87 (m, 2 H, CHCHH), 1.49–1.34 (m, scried for 8a, a solution of 7b (203 mg, 0.38 mmol) and NiCl2·6H2O
2 H, CHH), 0.93 [s, 18 H, 2ϫSiC(CH3)3], 0.21 (s, 3 H, SiCH3), (905 mg, 3.8 mmol) in anhydrous MeOH (3.5 mL) and anhydrous
0.20 (s, 3 H, SiCH3), 0.18 (s, 3 H, SiCH3), 0.15 (s, 3 H, SiCH3) ppm. THF (2 mL) was treated with NaBH4 (431 mg, 11.4 mmol) at 0 °C
13C NMR (75 MHz, CDCl3): δ = 169.7 (CO), 137.8 (C), 98.9 (CH), to room temperature for 30 h to give a crude product, which was
78.1 (CH), 76.0 (CH), 38.3 (CH2), 25.8 (3ϫCH3), 25.7 (3ϫCH3),
purified by column chromatography [SiO2 (Art. 7736); EtOAc/hex-
21.4 (CH2), 20.5 (CH2), 18.2 (C), 17.9 (C), –4.0 (CH3), –4.2 (CH3), anes, 3:7] to give 8b (51 mg, 74%) as a single isomer as a white
Eur. J. Org. Chem. 2014, 1708–1715
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M. Pohmakotr et al.
FULL PAPER
1
solid (m.p. 104–105 °C); [α]2D5 = +43.3 (c = 1, CHCl3)]. H NMR
(300 MHz, CDCl3): δ = 4.55–4.45 (m, 1 H, CH), 3.98 (d, J =
7.7 Hz, 1 H, CH), 3.75 (s, 1 H, OH), 3.51–3.42 (m, 1 H, NCHH),
3.38–3.26 (m, 1 H, NCHH), 2.40–2.20 (m, 1 H, CHH), 2.14–1.97
(m, 2 H, 2 ϫCHH), 1.68–1.50 (m, 1 H, CHH), 0.94 [s, 18 H,
2ϫSiC(CH3)3], 0.20 (s, 3 H, SiCH3), 0.18 (s, 3 H, SiCH3), 0.14 (s,
3 H, SiCH3), 0.12 (s, 3 H, SiCH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.3 (CO), 91.5 (C), 80.7 (CH), 78.9 (CH), 41.4
(CH2), 38.8 (CH2), 25.8 (3ϫCH3), 25.7 (3ϫCH3), 24.1 (CH2), 18.3
(C), 17.8 (C), –4.3 (2ϫCH3), –4.6 (CH3), –4.8 (CH3) ppm. IR
of (+)- and (–)-swainsonine, see: e) Q. R. Li, G. R. Dong, S. J.
Park, Y. R. Hong, I. S. Kim, Y. H. Jung, Eur. J. Org. Chem.
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[3]
(CHCl ): ν = 3523 (br), 1717 (s), 1259 (s), 1123 (s) cm–1. MS: m/z
˜
3
(%) = 403 (6) [M+ + H], 385 (100), 345 (43), 212 (16),185 (33), 157
(29). HRMS (ESI-TOF): calcd. for C19H39NO4SSi2Na [M+ + Na]
424.2315; found 424.2315.
(1S,2S,7aS)-1,2-Dihydroxypyrrolizidine (2):
A solution of 8b
(600 mg, 1.5 mmol) in anhydrous THF (5 mL) was added to a sus-
pension of LiAlH4 (286 mg, 7.5 mmol) in anhydrous THF (4 mL)
at room temperature. The mixture was heated to reflux for 18 h,
then, after cooling at 0 °C, water (4 mL) was carefully added to the
reaction mixture followed by addition of 1 n NaOH (4 mL). The
resulting mixture was filtered through a Celite pad and the filtrate
was concentrated under reduced pressure to give a crude viscous
oil, which was purified by solid-phase extraction on reverse phase
[C18-LP, CH3CN/MeOH (2:3)] to give lentiginosine analogue 2
(154 mg, 72%) as a white solid (m.p. 163–164 °C); [α]2D3 = +11.3 (c
= 0.5, MeOH) [ref.[11] m.p. 164–165 °C; [α]2D3 = +11 (c = 0.5,
MeOH)]. 1H NMR (400 MHz, CD3OD): δ = 4.04 (ddd, J = 7.1,
5.8, 5.8 Hz, 1 H, CH), 3.64 (dd, J = 5.8, 5.8 Hz, 1 H, CH), 3.26–
3.17 (m, 2 H, NCHH, NCH), 2.92 (ddd, J = 10.4, 6.0, 6.0 Hz, 1
H, NCHH), 2.72 (ddd, J = 10.4, 6.4, 6.4 Hz, 1 H, NCHH), 2.54
(dd, J = 10.6, 7.2 Hz, 1 H, NCHH), 2.03–1.84 (m, 2 H, CHH,
[4]
[5]
CHH), 1.84–1.65 (m,
(100 MHz, CD3OD): δ = 83.0 (CH), 78.7 (CH), 70.7 (CH), 59.6
(CH ), 56.6 (CH ), 31.4 (CH ), 26.2 (CH ) ppm. IR (Nujol): ν =
2
H, CHH, CHH) ppm. 13C NMR
˜
2
2
2
2
3271 (br), 1136 (s), 1105 (m), 1095 (s), 677 (s) cm–1. MS: m/z (%)
= 143 (6) [M+], 83 (72), 82 (64), 78 (21), 70 (42), 67 (18), 55 (100),
54 (60). HRMS (ESI-TOF): calcd. for C7H14NO2 [M+ + H]
144.1025; found 144.1023.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of compounds 1–10.
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Acknowledgments
The authors acknowledge financial support from the Thailand Re-
search Fund (BRG 5380019), the Office of Higher Education Com-
mission and Mahidol University under the National Universities
Initiative, and the Center of Excellence for Innovation in Chemistry
(PERCH-CIC).
S. Chooprayoon, C. Kuhakarn, P. Tuchinda, V. Reutrakul, M.
Pohmakotr, Org. Biomol. Chem. 2011, 9, 531–537.
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Eur. J. Org. Chem. 2014, 1708–1715

Synthesis of (+)-Lentiginosine and Its Pyrrolizidine Analogue
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Received: November 7, 2013
Published Online: Janary 14, 2014
see: a) E. F. J. de Vries, J. Brussee, A. van der Gen, J. Org.
Eur. J. Org. Chem. 2014, 1708–1715
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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