Intramolecular 5-endo-trig aminopalladation of β-hydroxy-γ- alkenylamine: Efficient route to a pyrrolidine ring and its application for the synthesis of (-)-8,8a-di-epi-swainsonine

Article abstract of DOI:10.1039/c3ra45409f

The intramolecular aminopalladation reaction of l-serine derived β-hydroxy-γ-alkenylamines undergoes 5-endo-trig cyclization to furnish pyrrolidine rings in high yields. The pyrrolidines thus obtained were used in the synthesis of (-)-8,8a-di-epi-swainsonine, a specific and competitive inhibitor (Ki value 2 × 10^-6 M) of lysosomal α-mannosidases.

Full text of DOI:10.1039/c3ra45409f

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Intramolecular 5-endo-trig aminopalladation of
b-hydroxy-g-alkenylamine: efficient route to a
pyrrolidine ring and its application for the synthesis
of (ꢀ)-8,8a-di-epi-swainsonine†
Cite this: RSC Adv., 2014, 4, 2161
*
Priyanka Singh and Gautam Panda
Received 26th September 2013
Accepted 13th November 2013
The intramolecular aminopalladation reaction of L-serine derived b-hydroxy-g-alkenylamines undergoes
5-endo-trig cyclization to furnish pyrrolidine rings in high yields. The pyrrolidines thus obtained were
used in the synthesis of (ꢀ)-8,8a-di-epi-swainsonine, a specific and competitive inhibitor (Ki value 2 ꢁ
10ꢀ6 M) of lysosomal a-mannosidases.
DOI: 10.1039/c3ra45409f
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inhibitor of a-D-mannosidases, including the glycoprotein-
processing enzyme mannosidase II.13 It also exhibits important
Introduction
antimetastatic, antitumor, anticancer and immune regulating
activity.13a Swainsonine was the rst inhibitor to be selected for
testing as an anticancer drug, reaching advanced clinical trials.
(ꢀ)-8,8a-di-epi-swainsonine was specic and competitive
inhibitors (Ki value 2 ꢁ 10ꢀ6 M) of lysosomal a-mannosidases
in vitro and induced storage of mannose-rich oligosaccharides
in human broblasts in culture.13b
Due to its promising biological prole and interesting
structure, number of synthetic approaches towards naturally
occurring (ꢀ)-swainsonine 2 and its analogues have appeared.14
In fact, swainsonine has become a classic target for the
demonstration of new synthetic methods and/or strategies
relevant to synthesis of pyrrolidine.14b However, ring closing
metathesis, mitsunobu cyclization and simple nucleophilic
displacement reactions were mainly used for accessing pyrro-
lidines. All these strategies were neither atom economical nor
ecofriendly. At present, more than 40 syntheses of swainsonine
have been reported that constitute 8 to >20 steps (average
approximately 14 steps). Among them, aminopalladation of
allylic alcohol perhaps is the most efficient as it is atom
economical, with formation of water as byproduct.
The common abundance of the pyrrolidine ring in natural
products as well as its use as a ligand and chiral auxiliary1 in
asymmetric synthesis2 led to the development of a number of
synthetic methods for its construction.3 In particular, intra-
molecular methodologies mainly involve either metal-assisted
C–C bond formation of aminoalkenes4 or C–N bond formation,5
including rhodium/copper carbenoid N–H insertion;6 with
special mention about cyclization of alkenylamines to construct
nitrogen heterocycles.7
Palladium (0)-catalyzed allylic substitution in particular
provides efficient C–N bond formation.8 In such reactions,
esters and carbamates of allylic alcohols have frequently been
used as substrates because of the low reactivity of the parent
alcohol as a leaving group. However, to the best of our
knowledge, only a single report is known about palladium (II)-
mediated 5-endo-trig cyclization of g-alkenylamine leading to
the formation of a pyrrolidine ring.9
Inspired by these reports and as a part of our continuing
interest in the synthesis of alkaloids,10 we investigated
the intramolecular aminopalladation with L-serine derived
b-hydroxy-g-alkenylamines and found that 5-endo-trig cyclized
product is indeed a prominent one. The L-serine derived pyr-
rolidines thus obtained in high yield, are found to be adequate
precursors in the synthesis of alkaloids.
Biological importance of swainsonine motivated us to
develop short and exible approach for it. The use of the
intramolecular aminopalladation strategy with L-serine derived
Among azasugar, (ꢀ)-swainsonine 2 (Fig. 1) was rst isolated
from the fungus Rhizoctonia leguminicolain11 in 1973 and later
found in several plants and fungi.12 It is found to be an effective
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, B.S.
10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow-226031, UP, India.
E-mail: gautam.panda@gmail.com; gautam_panda@cdri.res.in; Fax: +91-522-
2623405; Tel: +91-522-2612411-18, extn 4661, 4662
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for all the new compounds. See DOI: 10.1039/c3ra45409f
Fig. 1 Biologically active azasugars
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b-hydroxy-g-alkenylamines for the formation of pyrrolidine ring
and further elaboration to swainsonine, to the best of our
knowledge, is not known. Our efforts are directed toward the
successful implementation of this methodology for the
synthesis of 8,8a-di-epi-swainsonine.
Result and discussion
Reterosynthetic analysis
The retrosynthetic strategy for (ꢀ)-8,8a-diepiswainsonine 1 is
delineated in Scheme 1. We envisaged that 1 could be elabo-
rated from 3 by mesylation of alcohol followed by deprotection
of protecting groups and subsequent cyclization of the resulting
crude product. The precursor 4 could in turn be prepared from
oxidation of intermediate 5 followed by diastereoselective
Grignard reaction, protection of delivered alcohol as silyl ether
and hydroboration. Compound 5 could be easily obtained from
key intermediate 6 by dihydroxylation followed by acetonide
protection. The key intermediate 6 could be achieved by
commercially available S-Garner aldehyde15 by Grignard reac-
tion with vinyl magnesium bromide followed by acetonide
deprotection and subsequent cyclization of resulting interme-
diate by Pd(II) catalysed reaction.The synthesis of (ꢀ)-8,8a-die-
piswainsonine 1 was initiated from the commercially available
S-Garner aldehyde as shown in Scheme 2. Nucleophilic addition
Scheme 2
The stereochemical outcome of the Upjohn dihydroxyl-
ation of 9 could be explained by the fact that in 9 the addition
of bulky osmium reagent from the a-face of the molecule is
preferred over the b-face attack, since the b-face attack is
sterically hindered by NBoc and OTBDMS functionality.
(Fig. 2)
ꢂ
of vinyl magnesium bromide to S-Garner aldehyde at 0 C fur-
nished mixture of diastereomers 7.10 Acetonide deprotection of
7 by treatment with para-toluene sulphonic acid (PTSA) yielded
allylic alcohol 8. We did not observe any deprotection of Boc
group or isomerisation of allylic alcohol. The allyl alcohol 8 was
treated with 15 mol% PdCl2 (CH3CN)2 in THF at room
temperature furnishing the cyclized product 6 in 75% yield.
Alcohol 6 was further protected as silyl ether using TBDMSCl/
imidazole yielded 9 in quantitative yield. Application of Upjohn
dihydroxylation (DH)16 on 9 furnished the diol 10 as the only
isolable diastereomer in 78% yield. Protection of the two
hydroxyl groups of 10 with 2,2-dimethoxypropane (DMP) in
presence of catalytic amount of PTSA afforded the compound 11
in 82% yield accompanied with deprotection of silyl group.
Oxidation of alcohol 11 under Swern condition produced
multiple spots but fortunately under Parikh-doering17 condition
i.e. use of sulphur trioxide, dry DCM, DMSO and triethylamine
as a base yielded aldehyde which was further used in subse-
quent steps without purication. Diastereoselective nucleo-
philic addition of allyl magnesium bromide to aldehyde 12
delivered mixture of diastereomers 13 and 14 in 3 : 1 ratio.
In order to establish the stereochemistry of newly generated
carbinol in 14, it was converted into oxazolidinone 15 and its 2D
NMR studies conrmed the structure of 14 (Scheme 3).
With compound 13 in hand, we proceeded towards the total
synthesis of (ꢀ)-8-8a-diepi-swainsonine 1. Protection of
secondary alcohol 13 as its TBS ether (TBSOTf, 2,6-lutidine)
provided compound 16 in 76% yield. Nevertheless, hydro-
boration of compound 16 with BH3$THF and 9-BBN in tetra-
hydrofuran were unsuccessful and resulted in recovery of
starting material. Finally treatment with BH3$SMe2 in tetrahy-
drofuran at room temperature followed by oxidation of result-
ing intermediate with H2O2 smoothly furnished primary
alcohol18 17 (Scheme 4) in 78% overall yield. Treatment of 17
with methanesulfonyl chloride in the presence of pyridine gave
crude product which was used in next step without further
purication. Deprotection of protective group by TMSOTf/
2,6-lutidine and following cyclization of the resulting crude
Scheme 1
Fig. 2 Preferred attack from a-face.
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reference CDCl3 appeared at 77.16 ppm. IR spectra were recor-
ded on FT-IR spectrophotometers. Optical rotations were
determined by using a 1 dm cell at 25 ꢂC in chloroform,
methanol and water as the solvents; concentrations mentioned
are in g per 100 mL.
Scheme 3
Synthetic procedures
(S)-tert-Butyl 1,3-dihydroxypent-4-en-2-ylcarbamate 8. To a
solution of 7 (5.0 g, 19.4 mmol) in methanol (75 ml) at 0 ꢂC,
PTSA (1.0 g) was added and allowed to stir for 3 h at room
temperature. Aer completion of reaction it was quenched with
aqueous NaHCO3 solution. Methanol was evaporated and
aqueous layer was extracted with ethyl acetate (50 mL ꢁ 3). The
combined organic layer was washed with water, brine, dried
over anhydrous Na2SO4, and concentrated under vacuo to a
colorless oil which on column chromatographic purication,
gave the pure compound colorless oil, 8 (3.35 g, 79%). Eluent for
column chromatography: EtOAc/hexane (40/10, v/v); Rf 0.3
(EtOAc); 1H NMR (300 MHz, CDCl3) d 5.97–5.83 (m, 1H), 5.52 (d,
1H, J ¼ 7.9 Hz), 5.39–5.30 (m, 1H), 5.21 (t, 1H, J ¼ 10.6 Hz), 4.41–
4.29 (m, 1H), 4.17–4.07 (m, 1H), 3.87 (d, 1H, J ¼ 7.6 Hz), 3.73–
3.64 (m, 2H), 3.13 (bs, 1H), 1.44–1.42 (m, 9H); 13C NMR (75
MHz, CDCl3) d 156.6, 156.3, 137.6, 137.4, 116.4, 116.0, 79.8,
73.9, 71.8, 62.8, 61.9, 55.2, 28.3; IR (neat, cmꢀ1) 3428, 3011,
2979, 1691, 1509, 1393, 1053, 760, 606; mass (ESI-MS) m/z 240
Scheme 4
product gave the protective (ꢀ)-8,8a di-epi-swainsonine in one
pot manner. Finally removal of protective (ꢀ)-8,8a-di-epi-
swainsonine with MeOH/(COCl)2 gave 1 {[a]2D8 ꢀ14 (c 0.50,
MeOH); ref. 19 [a]2D5 ꢀ14 (c 0.51, MeOH)} in 76% overall yield.
The 1H and 13C NMR spectral data were in consonance with that
reported in the literature.19,20
+
[M + Na] ; HRMS (ESI TOF (+)): calcd for C10H19NNaO4 [M +
Na]+: 240.1212, measured 240.1207.
(S)-tert-Butyl
2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-
Conclusion
carboxylate: 6. To the stirred solution of 8 (1.90 g, 8.70 mmol) in
dry THF (173 mL) under N2 atmosphere, PdCl2(CH3CN)2 (0.45 g,
1.70 mmol) was added. Solution was allowed to stir for 3 h. Aer
completion of reaction it was quenched with aqueous NH4Cl
and extracted with ethyl acetate (10 mK ꢁ 3). The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4 and concentrated under vacuo to a light yellow oil which
on column chromatographic purication, gave the pure
compound light yellow oil, 6 (1.30 g, 75%). Eluent for column
chromatography: EtOAc/hexane (10/40, v/v), [a]2D8 ¼ ꢀ1.53 (c 0.4,
CH3OH); Rf 0.50 (1.5/3.5 EtOAc/hexane); 1H NMR (300 MHz,
CDCl3) d 5.83–5.56 (m, 2H), 4.64 (s, 1H), 4.13–4.03 (m, 2H), 3.68
(s, 1H), 3.51 (s, 1H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3) d
In summary, we have described straightforward and short
syntheses of (ꢀ)-8,8a-di-epi-swainsonine from S-Garner aldehyde.
Although more than 40 syntheses of swainsonine constituting 8
to over 20 steps (average length of 14 steps) have been reported,
our distinctive approach provides access to this potentially
important indolizidine in 10 steps from S-Garner aldehyde with
7.1% overall yield. The key step in the sequence is the palladiu-
m(II)-catalyzed cyclization of the allylic intermediate 8.
Experimental section
General
Organic solvents were dried by standard methods. All the 156.4, 126.6, 80.4, 67.4, 66.8, 54.1, 28.3; IR (neat, cmꢀ1) 3424,
products were characterized by 1H, 13C, two-dimensional 2086, 1640, 1340, 659; mass (ESI-MS) m/z 222 [M + Na]+; HRMS
homonuclear COSY (correlation spectroscopy), heteronuclear (ESI TOF (+)): calcd for C10H17NaO3 [M + Na]+: 222.1106,
single quantum coherence (HSQC), Nuclear Overhauser effect measured 222.1111.
spectroscopy (NOESY), IR, ESI-MS, HRMS (direct analysis in real
(S)-tert-Butyl 2-((tert-butyldimethylsilyloxy)methyl)-2,5-dihy-
time, DART) and HRMS (quadrupole time of ight, Q-TOF). dro-1H-pyrrole-1-carboxylate: 9. To an ice cooled solution of
Analytical TLC was performed using 2.5 ꢁ 5 cm plates coated alcohol 6 (1.0 g, 5.0 mmol) in dry DCM (20 mL), imidazole
with a 0.25 mm thickness of silica gel (60F-254) using UV light (0.68 g, 6.0 mmol) was added followed by tert-butyldimethyl-
as visualizing agent and an acidic solution of ninhydrin, and chlorosilane (0.91 g, 10.0 mmol). The reaction mixture was
heat as developing agents. Column chromatography was per- stirred at the same temperature for 30 min. Aer completion of
formed using silica gel (60–120 and 100–200 mesh). NMR the reaction, it was diluted with dichloromethane and washed
spectra were recorded on 300 MHz (1H) and 50, 75 MHz (13C). with water followed by brine. The organic layers were dried over
ꢂ
Experiments were recorded in CDCl3 and D2O at 25 C. Chem- Na2SO4. The solvent was evaporated and the residue was chro-
ical shis are given on the d scale and are referenced to the TMS matographed over silica gel to furnish 9 (1.52 g, 97%) as
at 0.00 ppm for proton and 0.00 ppm for carbon. For 13C NMR colorless oil, eluent for column chromatography. eluent for
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column chromatography: EtOAc/hexane (3/47, v/v), [a]2D8 ¼ +68 CH2Cl2 (2.65 mL) and DMSO (3.34 mL) at 0 ꢂC was added SO3$Py
(c 0.7, CHCl3); Rf 0.50 (0.5/4.5 EtOAc/hexane) 1H NMR (300 MHz, complex (1.33 g, 8.35 mmol) and triethylamine (1.16 mL,
CDCl3) d 5.77–5.70 (m, 2H), 4.48–4.38 (m, 1H), 4.20–4.05 (m, 8.35 mmol) respectively. The reaction mixture was allowed to
1H), 3.98–3.89 (m, 1H), 3.85–3.77 (m, 1H), 3.74–3.46 (m, 1H), stir at same temperature for 2 h. Then, the reaction was
1.43–1.41 (d, 9H, J ¼ 4.6 Hz), 0.82–0.81 (d, 9H, J ¼ 3.9 Hz), quenched with water, the organic layer was separated, and the
ꢀ0.02-(ꢀ)0.03 (d, 6H, J ¼ 4.2 Hz); 13C NMR (75 MHz, CDCl3) d aqueous layer was extracted with CH2Cl2. The combined organic
154.0, 153.9, 128.8, 127.8, 125.8, 125.6, 79.3, 78.9, 65.5, 65.3, layers were washed with brine (10 mL), dried over Na2SO4, and
64.5, 63.1, 54.0, 53.7, 25.7, ꢀ5.5, ꢀ5.6; IR (neat, cmꢀ1) 3398, concentrated under vacuo to obtain the aldehyde 12, which was
3081, 2861, 1627, 1459, 1252, 762; mass (ESI-MS) m/z 214 [M-Boc used as such for the next step without purication. To a stirred
+ H]+.; HRMS (ESI TOF (+)): calcd for C11H24NOSi [M-Boc + H]+: solution of 12 (0.36 g, 1.33 mmol) in dry THF under N2 atmo-
214.1627, measured 214.1631.
sphere at ꢀ78 ꢂC, allyle magnesium bromide (2.67 mmol, 1 M)
(2S,3S,4R)-tert-Butyl 2-((tert-butyldimethylsilyloxy)methyl)- was added and allowed to stir for two hour at same temperature.
3,4-dihydroxypyrrolidine-1-carboxylate: 10. To a solution of 9 Aer completion of reaction, it was quenched with saturated
(1.04 g, 2.72 mmol) in a 10 : 1 mixture of acetone–H2O (50.4 mL) solution of NH4Cl, and extracted with ethyl acetate (20 mL ꢁ 3).
was added N-methylmorpholine N-oxide (0.72 g, 6.24 mmol) The combined organic layers were washed with brine, dried
and 2.5% OsO4 in t-butanol (8.0 mL). The reaction mixture was over anhydrous Na2SO4, and concentrated under vacuo to a
stirred at room temperature for 3 h. Aer addition of aqueous colorless oil. Purication by ash chromatography afforded
NaHSO3 solution (8 mL), the mixture was stirred for an addi- compound 13 as major (0.23 g, 56%) and 14 (0.08 g, 19%) as
tional 1 h at room temperature, and extracted with EtOAc (3 ꢁ minor product.
25 ml). The combined organic layers were washed with brine,
For 13, eluent for column chromatography: EtOAc/hexane
dried over anhydrous Na2SO4 and concentrated under vacuo to (7.5/42.5, v/v), [a]2D8 ¼ 10.67 (c 0.1, CH3OH); Rf 0.5 (1/4 EtOAc/
1
a colorless oil, which on column chromatographic purication hexane) H NMR (300 MHz, CDCl3) d 5.81–5.70 (m, 1H), 5.10–
gave the pure compound 10 (Colorless oil, 0.88 g, 78%). eluent 5.05 (m, 2H), 4.65–4.58 (m, 3H), 3.89 (d, 1H, J ¼ 12.1 Hz), 3.78–
for column chromatography: eluent for column chromatog- 3.75 (m, 1H), 3.71–3.67 (m, 1H), 3.41–3.38 (m, 1H), 2.33–2.21
28
raphy: EtOAc/hexane (20/30, v/v), [a]D ¼ +12.9 (c 0.2, CH3OH); (m, 2H), 1.39 (12H, bs), 1.35 (s, 3H); IR (neat, cmꢀ1) 3398, 3020,
Rf 0.50 (2/1 EtOAc/hexane) 1H NMR (300 MHz, CDCl3) d 4.29 (d, 2401, 1684, 1409, 1163, 1056, 926, 669; mass (ESI-MS) m/z 214
1H, J ¼ 3.9 Hz), 4.2 (m, 1H), 3.89–3.86 (m, 1H), 3.71–3.62 (m, [M-Boc + H]+; HRMS (ESI TOF (+)): calcd for C16H28NO5 [M-Boc +
4H), 3.48–3.42 (m, 2H), 1.42 (s, 9H), 0.86 (d, 9H, J ¼ 13 Hz), 0.03 H]+: 214.1443, measured 214.1446.
(d, 6H, J ¼ 20.3 Hz); 13C NMR (75 MHz, CDCl3) d 154.7, 79.9,
(3aS,4S,6aR)-tert-Butyl 4-((R)-1-hydroxybut-3-enyl)-2,2-dime-
79.6, 74.8, 74.1, 70.1, 69.4, 64.2, 62.6, 61.8, 51.7, 51.2, 28.4, 25.8, thyldihydro-3aH-[1,3]dioxolo[4,5-c]pyrrole-5(4H)-carboxylate: 14.
25.6, 18.1, -3.6, -3.5; IR (neat, cmꢀ1) 3437, 3021, 1733, 1374, Eluent for column chromatography: EtOAc/hexane (8/42, v/v),
1247, 769, 668; mass (ESI-MS) m/z 248 [M-Boc + H]+.; HRMS (ESI [a]2D8 ¼ +45 (c 0.6, CHCl3); Rf 0.4 (1/4 EtOAc/hexane) H NMR
1
TOF (+)): calcd for C11H26NO3Si [M Boc + H].+: 248.1682, (300 MHz, CDCl3) d 5.75 (m, 1H), 5.13–5.07 (m, 2H), 4.65 (m,
measured 248.1691.
3H), 3.97–3.61 (m, 3H), 3.45–3.41 (m, 1H), 2.3–2.18 (m, 2H),
(3aS,4S,6 aR)-tert-butyl 4-(hydroxymethyl)-2,2-dimethyldihy- 1.39–1.34 (m, 15H); IR (neat, cmꢀ1) 3398, 3020, 2401, 1684,
dro-3aH-[1,3]dioxolo[4,5-c]pyrrole-5(4H)-carboxylate: 11. To a 1409, 1163, 1056, 926, 669; mass (ESI-MS) m/z 314 [M + H]+;
solution of compound 10 (0.81 g, 2.31 mmol) and DMP (0.57 ml, HRMS (ESI TOF (+)): calcd for C16H28NO5 [M + H]+: 314.3972,
4.65 mmol) in dry acetone (60 ml), catalytic amount of p-TsOH measured 314.3975.
was added and allowed to stir for 3 h at room temperature. The
(3aS,3bS,4R,8aR)-4-Allyl-2,2-dimethyltetrahydro-[1,3]dioxolo-
mixture was quenched with saturated NaHCO3 aqueous solu- [40,50:3,4]pyrrolo[1,2-c]oxazol-6(3aH)-one: 15. To a cooled (0 C)
tion and extracted with EtOAc for three times. The combined solution of alcohol 14 (0.05 g, 0.15 mmol) in dry THF (2.25 mL)
organic layers were washed with brine and dried over anhydrous was added sodium hydride (0.008 g, 0.32 mmol), in one portion,
Na2SO4. Filtered and concentrated, the residue was puried by under nitrogen atmosphere and allowed to stir for 1 hour at
chromatography on silica gel to give 11 as white semi solid (0.51 same temperature. Aer completion of reaction, it was
g, 82%). Eluent for column chromatography: EtOAc/hexane (20/ quenched by addition of satd aq. NH4Cl, and extracted with
30, v/v), [a]2D8 ¼ +29 (c 10, CHCl3); Rf 0.40 (1.5/3.5 EtOAc/hexane) ethyl acetate (3 ꢁ 5 mL). The combined organic layers were
1H NMR (300 MHz, CDCl3) d 4.64–4.52 (m, 2H), 4.03–3.92 (m, dried (Na2SO4) and concentrated under reduced pressure. The
1H), 3.75–3.58 (m, 3H), 3.42 (dd, 1H, J ¼ 12.6, 4.8 Hz), 2.95 (bs, residue was puried by silica gel ash column chromatography
1H), 1.28 (bs, 12H), 1.24 (s, 3H); 13C NMR (75 MHz, CDCl3) d to afford 15 (0.04 g, 95%) as a white semi solid. eluent for
155.3, 154.4, 111.7, 11.5, 81.9, 80.3, 80.1, 79.1, 78.8, 77.3, 65.2, column chromatography: EtOAc/hexane (8/42, v/v), Rf 0.50 (1/4
ꢂ
65.0, 63.0, 62.8, 52.7, 28.3, 27.0, 24.9; IR (neat, cmꢀ1) 3426, 2978, EtOAc/hexane) H NMR (300 MHz, CDCl3) d 5.94–5.75 (m, 2H),
1
1679, 1413, 1218, 1129, 977, 859, 765, 668; mass (ESI-MS) m/z 5.27–5.18 (m, 2H), 4.80–4.70 (m, 2H), 4.57 (t, 1H, J ¼ 6.6 Hz),
296 [M + Na]+; HRMS (ESI TOF (+)): calcd for C13H23NNaO5 [M + 4.15–4.09 (m, 1H), 3.84 (t, 1H, J ¼ 6.6 Hz), 3.31–3.26 (m, 1H),
Na].+: 296.1473, measured 296.1470.
2.68–2.49 (m, 2H), 1.53 (s, 3H), 1.35 (s, 3H); 13C NMR (75 MHz,
(3aS,4S,6aR)-tert-Butyl 4-((S)-1-hydroxybut-3-enyl)-2,2-dime- CDCl3) d 160.1, 131.6, 119.1, 115.0, 79.9, 78.0, 75.3, 67.3, 50.8,
thyldihydro-3aH-[1,3]dioxolo[4,5-c]pyrrole-5(4H)-carboxylate: 13. 34.8, 27.5; IR (neat, cmꢀ1) 3426, 2978, 1679, 1413, 1218, 1129,
To a solution of alcohol 11 (0.45 g, 1.67 mmol) in anhydrous 977, 859, 765, 668; mass (ESI-MS) m/z 262 [M + Na]+; HRMS (ESI
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TOF (+)): calcd for C12H17NNaO4 [M + Na]+: 262.1055, measured quenched with water and extracted with DCM for three times.
262.1059. The combined organic layers were dried and concentrated to
(3aS,4R,6aR)-tert-Butyl 4-((S)-1-(tert-butyldimethylsilyloxy)- give crude product. The solution of above crude product in
4-hydroxybutyl)-2,2-dimethyldihydro-3aH-[1,3]dioxolo[4,5-c]- absolute MeOH (2 mL) was stirred at ꢀ10 ꢂC, then (COCl)2 (0.13
pyrrole-5(4H)-carboxylate: 16. To a solution of compound 13 mL) was slowly dropped. Aer stirring for 12 h at ꢀ10 ꢂC to
(0.1 g, 0.32 mmol) and 2,6-lutꢂidine (0.09 mL, 0.78 mmol) in dry room temperature, the mixture was concentrated in vacuo to
DCM (3 mL) was stirred at 0 C under argon atmosphere. Aer dryness. The resulting crude product was applied to ion-
stirring for 15 min, the reaction mixture was slowly treated with exchange chromatography (Dowex 50X8, H+ form) eluting with
TMSOTf (0.15 mL, 0.38 mmol) and stirred for 4 h at room aqueous ammonium hydroxide solution to give (ꢀ)-8,8a-diepi-
temperature. The resulting mixture was quenched with saturated swainsonine 1 (0.01 g, 76%) as a white powder. Mp 129–130 ꢂC
NaHCO3 aqueous solution and extracted with EtOAc (5 mL ꢁ 3). ref. 19 130–131 ꢂC; {[a]D28 ꢀ14 (c 0.50, MeOH); ref .19 [a]D25 ꢀ14 (c
1
The combined organic layers were washed with brine, dried, and 0.51, MeOH); H NMR (300 MHz, D2O) d 4.22 (q, J ¼ 13.0 Hz,
concentrated. The residue was puried by chromatography on 1H), 3.97 (t, J ¼ 7.4 Hz, 1H), 3.61–3.53 (m, 1H), 3.43 (dd, J ¼ 7.4,
silica gel to give 16 (0.1 g, 76%). eluent for column chromatog- 2.8 Hz, 1H), 2.96 (d, J ¼ 9.32 Hz, 1H), 2.33 ꢀ27 (m, 1H), 2.19–
raphy: EtOAc/hexane (2/48 v/v); [a]2D8 ¼ 5.49 (c 0.1, CH3OH); Rf 0.8 1.99 (m, 3H), 1.80 (d, J ¼ 12.6 Hz, 1H), 1.63 (m, 1H), 1.43–1.31
1
(0.5/4.5 EtOAc/hexane); H NMR (300 MHz, CDCl3) d 5.82–5.71 (m, 1H); 13C NMR (75 MHz, D2O) d 73.7, 72.0, 71.2, 67.1, 59.4,
(m, 1H), 5.07–5.02 (m, 2H), 4.51–4.50 (m, 2H), 3.87–3.80 (m, 1H), 51.0, 32.7, 23.1; IR (neat, cmꢀ1) 3600–3200; (ESI-MS) m/z 173;
3.74–3.71 (m, 1H), 3.61–3.59 (m, 1H), 3.36–3.30 (m, 1H), 2.23–1.98 found 174 [M + H]+; HRMS (ESI TOF (+)): calcd for C8H16NO3 [M
(m, 2H), 1.49–1.28 (m, 12H), 1.03–0.82 (m, 12H), 0.25–0,07 (m, + H]+: 174.1130, measured 174.1124.
6H); 13C NMR (75 MHz, CDCl3) d 154.9, 135.1, 120.7, 115.7, 80.5,
79.8, 75.5, 69.8, 69.7, 51.7, 38.8, 30.9, 28.4, 26.5, 17.9, ꢀ4.4, ꢀ4.6;
Acknowledgements
IR (neat, cmꢀ1) 3383, 3018, 2930, 1600, 1408, 1215, 926; mass
(ESI-MS) m/z 450 [M + Na]+; HRMS (ESI TOF (+)): calcd for The authors thank BSC 0120 for funding this project. P.S.
C10H19NNaO4 [M + Na]+: 450.2652, measured 240.2699.
cordially thank CSIR for providing fellowships (NET-SRFs).
(3aS,4S,6 aR)-tert-Butyl 4-((S)-1,4-dihydroxybutyl)-2,2-dime- NIPER Trainee Prerna Ganwir is thanked for the preparation of
thyldihydro-3aH-[1,3]dioxolo[4,5-c]pyrrole-5(4H)-carboxylate: 17. useful starting materials. This has CDRI communication no.
To a solution of compound 16 (0.05 g, 0.12 mmol) in dry THF 240/2013/GP/8569.
(3.3 mL) was treated with a solution of BH3$SMe2 0.04 mL at 0 ꢂC
under argon atmosphere. Aer stirring for 8 h at room temper-
ature, the reaction mixture was cooled to 0 ꢂC again, and an
Notes and references
aqueous solution of NaOH (0.48 mL, 3 M) was slowly dropped.
Then, a solution of H2O2 (0.48 ml, 30% in water) was carefully
dropped. The reaction mixture was stirred for 1 h and quenched
with water. The resulting mixture was extracted with ethyl acetate
(10 ꢁ 3). The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated under vacuo to colorless oil
(0.04 g, 78%). eluent for column chromatography: EtOAc/hexane
(20/30, v/v), [a]2D8 ¼ 12.4 (c 0.1, CH3OH); Rf 0.50 (1/1 EtOAc/
hexane); 1H NMR (300 MHz, CDCl3) d 4.60–4.53 (m, 2H), 4.17 (d,
1H, J ¼ 1.6 Hz), 3.83–3.74 (m, 2H), 3.71–3.64 (m, 1H), 3.62–3.55
(m, 2H), 3.45–3.39 (2H, m), 1.69–1.64 (2H, m), 1.49 (9H, s), 1.39
(3H, s), 1.21 (s, 3H), 0.79 (9H, d, J ¼ 4.16), 0.08 (6H, s); IR (neat,
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m/z 468 [M + Na]+; HRMS (ESI TOF (+)): calcd for C22H43NNaO6Si
[M + Na]+: 468.2757, measured 468.2760.
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