Divergent total synthesis of 1,6,8a-tri-epi-castanospermine and 1-deoxy-6,8a-di-epi-castanospermine from substituted azetidin-2-one (β-lactam), involving a cascade sequence of reactions as a key step

Article abstract of DOI:10.1039/c4ob00948g

A divergent, short, and novel total synthesis of 1,6,8a-tri-epi- castanospermine (7) and 1-deoxy-6,8a-di-epi-castanospermine (8) has been developed via a common precursor, 15, obtained from d-mannitol derived β-lactam. The key step involves a one pot cascade sequence of trimethyl sulfoxonium ylide based cyclization of epoxy sulfonamide 14via epoxide ring opening, one carbon homologation followed by intramolecular cyclization. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00948g

Organic &
Biomolecular Chemistry
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PAPER
Divergent total synthesis of 1,6,8a-tri-epi-
castanospermine and 1-deoxy-6,8a-di-epi-
castanospermine from substituted azetidin-2-one
(β-lactam), involving a cascade sequence of
reactions as a key step†‡
Cite this: Org. Biomol. Chem., 2014,
12, 7389
Dipak Kumar Tiwari,a Kishor Chandra Bharadwaj,b Vedavati G. Puranikc and
Dharmendra Kumar Tiwari*a,b
A divergent, short, and novel total synthesis of 1,6,8a-tri-epi-castanospermine (7) and 1-deoxy-6,8a-di-
epi-castanospermine (8) has been developed via a common precursor, 15, obtained from D-mannitol
derived β-lactam. The key step involves a one pot cascade sequence of trimethyl sulfoxonium ylide based
cyclization of epoxy sulfonamide 14 via epoxide ring opening, one carbon homologation followed by
intramolecular cyclization.
Received 8th May 2014,
Accepted 30th July 2014
DOI: 10.1039/c4ob00948g
www.rsc.org/obc
tor activity.5 To the best of our knowledge, at present only one
asymmetric method is available in the literature towards the
Introduction
Polyhydroxylated alkaloids containing cyclic amines are found synthesis of 1-O-ethyl derivative of 1,6,8a-tri-epi-castano-
among various natural resources, including plants and micro- spermine (7),13a whereas 1-deoxy-6,8a-di-epi-castanospermine
organisms.1 They have gained much attention over the past (8) has been synthesised by some racemic14a,b and asymmetric
few decades owing to their glycosidase inhibitor activity.2 approaches (Fig. 1).14c–f
Castanospermine (1)3 and its analogues (2–8)4 which represent
Azetidin-2-ones or β-lactams are an important class of
polyhydroxylated indolizidine alkaloids have received consider- organic compounds having a wide range of biological activi-
able interest over the years, mainly due to their therapeutic ties. In addition to their medicinal value, β-lactams have
potential in the treatment of various diseases such as dia- served as valuable synthons for the synthesis of various
betes,5 obesity,6 cancer,7 viral infections,8,9 and HIV-1.10 The
subtle variation of stereocentres of castanospermine (1), result-
ing in a broad spectrum of biological activities, has led to the
spurt in publications dealing with the synthesis of various
stereoisomers of castanospermine (1).11,12 Amongst all poss-
ible stereoisomers of castanospermine (1), one of the least
explored isomers in terms of their synthesis are 1,6,8a-tri-epi-
castanospermine (7) and 1-deoxy-6,8a-di-epi-castanospermine
(8) although the latter one is known for α-L-fucosidase inhibi-
aDivision of Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Tarnaka, Hyderabad-500007, India. E-mail: dktiwari@iict.res.in,
dkt80.org@gmail.com; Fax: (+91)-40-2716-0921; Tel: (+91)-40-2719-1527
bOrganic Chemistry Division, National Chemical Laboratory, Homi Bhabha Road,
Pune, 411008, India
cCentre for Materials Characterization, National Chemical Laboratory, Homi Bhabha
Road, Pune, 411008, India
†Dedicated to Prof. Ganesh Pandey on the occasion of his 60th birthday.
‡Electronic supplementary information (ESI) available: Copies of 1H NMR and
13C NMR spectra for all compounds, single crystal X-ray data for compound 15.
CCDC 939342. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ob00948g
Fig. 1 Polyhydroxylated indolizidines.
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natural products.15 As a part of our ongoing research program
about the application of azetidin-2-ones as a synthon,16 we
therefore embarked on the development of an entirely new
and versatile strategy for the synthesis of 1,6,8a-tri-epi-castano-
spermine (7) and 1-deoxy-6,8a-di-epi-castanospermine (8),
starting from a suitably substituted β-lactam (11). To the best
of our knowledge so far β-lactam has not been used in the syn-
thesis of these alkaloids.
Results and discussion
Our retrosynthetic plan is depicted in Scheme 1. We envi-
sioned that the advanced intermediate 15 could serve as a
common precursor for the synthesis of both 7 and 8. This
could in turn be obtained from a domino sequence of epoxide
ring opening of 14 by trimethyl sulfoxonium ylide, followed by
an intramolecular cyclization reaction. Compound 14 which
would have all the required stereocentres can be synthesised
from the β-lactam 11.
Scheme 2 Synthesis of hydroxyl pyrrolidine (15). (a) Et3N, CH2Cl2, −20
to 25 °C, 65%; (b) (i) LiAlH4, THF, 0 °C, reflux 4–6 h; (ii) H2/Pd–C (10%),
EtOAc, 1 atm, rt, 12 h; (c) TsCl, K2CO3, DCM–H2O (1 : 1), rt, 3 h, 67% over
three steps; (d) (i) TsCl, Bu2SnO (cat.), Et3N, CH2Cl2, 0 °C to rt 4 h; (ii)
K2CO3, CH3CN, rt, 10 h, 88.5%, over two steps. (e) NaH, (CH3)3SOI,
DMSO, 85 °C, 24 h, 77%.
The required β-lactam 11 in turn can be obtained from
D-mannitol derived imine 10.
To this end, the required β-lactam 11 was prepared in high
yield using [2 + 2] cycloaddition reaction of ketene (generated
in situ from benzyloxy acetyl chloride 9) and imine 10 (derived
from D-mannitol)17 (Scheme 2). The β-lactam 11 had all the
required stereocentres and their stereochemistry was con-
firmed by the single crystal structure obtained at a later stage
of synthesis (vide infra). 11 was then treated with lithium alu-
minium hydride in refluxing THF, leading to opening of the
ring, which was then subjected to reductive hydrogenolysis
using 10% Pd/C in the presence of hydrogen at atmospheric
pressure giving diol 12. The diol 12 being very polar and rela-
tively unstable in nature was immediately subjected to selective
tosylation of primary amine giving 13 in 67% yield over three
steps. In order to prepare the proposed epoxy amine 14, the
primary hydroxyl group of 13 was first regioselectively tosylated
under Martinelli’s protocol18 using catalytic Bu2SnO in the
presence of Et3N in dichloromethane at room temperature.
The resulting ditosyl compound upon treatment with K2CO3 in
CH3CN at room temperature produced the required epoxy
amine 14 in 88.5% yield over two steps. With epoxy amine 14
in hand, we proceeded to the key step of pyrrolidine ring con-
struction. This was achieved by heating 14 (85 °C) in DMSO in
the presence of NaH and trimethyl sulfoxonium iodide, which
resulted in the formation of the desired hydroxy pyrrolidine 15
in 77% yield as a white crystalline solid (m.p. 151–153 °C). The
reaction is believed to proceed via a cascade sequence of
epoxide ring opening by in situ generated ylide, followed by
proton abstraction and subsequent ring closure by nitrogen.19
At this stage the single crystal analysis of 15 revealed that
the hydrogen attached to C14, C11, and C8 were on the same
side, thus confirming the required stereochemistry (Fig. 2).
After successfully installing the required stereocentres,
along with construction of the pyrrolidine ring, we turned our
attention to the completion of synthesis of 1,6,8a-tri-epi-castano-
spermine 7 (Scheme 3). The N-detosylation of 15 was suc-
cessfully achieved under Birch reduction conditions (Na–liq.
NH3) giving 16. Other methods for deprotection such as
Na–Hg, Mg/MeOH, or Na/naphthalene for the detosylation of
15 were found to be either unsuccessful or low yielding. The
resulting crude amine was immediately protected as a Cbz
group to give carbamate 16 in 85% yield over two steps. Fur-
thermore, the terminal acetonide group in 16 was first depro-
tected by stirring it in CH3COOH–MeOH–H2O (6 : 3 : 1) to
obtain triol 17. The primary hydroxy group of 17 was tosylated
Scheme 1 Retrosynthetic analysis of 1,6,8a-tri-epi-castanospermine (7)
and 1-deoxy-6,8a-di-epi-castanospermine (8).
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Scheme 4 Synthesis of 1-deoxy-6,8a-di-epi-castanospermine (8): (a)
MsCl, Et3N, cat. DMAP, DCM, 0 °C, 1 h, 91%; (b) LAH, THF, reflux, 5 h; (c)
aq. K2CO3, CbzCl, DCM–H2O (1 : 1), 0 °C to rt, 1 h, 82% over two steps;
(d) CH3COOH–MeOH–H2O (6 : 3 : 1), reflux, 5 h, 77%; (e) Et3N, TsCl,
Bu2SnO (cat.), CH2Cl2, 0 °C, 2 h, 88%; (f) H2, Pd–C (10%), NaOAc,
MeOH, rt, 12 h; (g) Dowex 50W-X8, THF–H2O (3 : 1), reflux 12 h, 86%
over two steps.
Fig. 2 ORTEP diagram of 15 (ellipsoids are drawn at 40% probability).
affording 21, which was immediately subjected to Cbz protec-
tion, delivering 22 in 85% yield over two steps. Compound 22
was easily converted into target molecule 8 (Scheme 4) follow-
ing a similar sequence of steps as those described above for
the synthesis of 7 (Scheme 3, from 16 to 7). The spectral data
and specific rotation of 8 [α]2D7 = +23.6 (c = 0.90, MeOH) were
in excellent agreement with the reported values {[α]2D7 +23.5
(c = 0.90, MeOH)}.14f
Scheme 3 Synthesis of 1,6,8a-tri-epi-castanospermine (7). Reagents
and conditions: (a) (i) Na/liq. NH3, −78 °C, 1 h; (ii) aq. K2CO3, CbzCl,
CH2Cl2, 0 °C to rt, 30 min, 85% over two steps; (b) CH3COOH–MeOH–
H2O (3 : 2 : 1), reflux, 5 h, 75%; (c) Et3N, TsCl, Bu2SnO (cat.), CH2Cl2, 0 °C,
2 h, 90%; (d) H2, Pd–C (10%), NaOAc, rt, 12 h, (e) Dowex 50W-X8, THF–
H2O (3 : 1) reflux 12 h, 90% over two steps.
Conclusions
In conclusion, we have demonstrated a new and flexible
approach for the syntheses of 1,6,8a-tri-epi-castanospermine 7
and 1-deoxy-6,8a-di-epi-castanospermine 8 from D-mannitol
triacetonide derived β-lactam. The key features of this
regioselectively to afford 18 in 90% yield. The –NCbz deprotec- approach include the construction of hydroxyl pyrrolidine 15
tion and cyclization was performed via catalytic hydrogenation from epoxy amine using trimethyl sulfoxonium ylide.
(Pd/C, 10%) in the presence of sodium acetate in MeOH giving
the desired product 19. The reaction mixture was then filtered
through a pad of celite and concentrated. To the residue was
then added THF–H2O (3 : 1) and acidic Dowex 50W-X8, and the
Experimental
mixture was heated for 12 hours, giving the target molecule 7
in 90% yield over two steps.
All reactions requiring anhydrous conditions were performed
under a positive pressure of argon using oven-dried glassware
(110 °C), which were cooled under argon. Solvents for anhy-
drous reactions were dried according to Perrin and co-workers’
method.20 CH3CN, CH2Cl2, and triethylamine were distilled
over CaH2 and stored over molecular sieves and KOH, respecti-
vely. THF was distilled from sodium benzophenone ketyl.
Solvents used for chromatography were distilled at their
After successfully completing the total synthesis of 1,6,8a-
tri-epi-castanospermine 7, we focused our efforts towards 8
from the common intermediate 15. Mesylation of the free
hydroxyl moiety of 15 produced 20, which upon LAH reduction
led to the deoxygenation at C14 position. To our delight, LAH
reduction also led to the N-detosylation in the same pot,
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respective boiling points according to known procedures. Pet- J = 11.4 Hz), 4.92 (1H, d, J = 14.9 Hz), 4.70 (1H, d, J = 11.4 Hz),
roleum ether used in the column had a boiling range of 4.65 (1H, d, J = 4.99 Hz), 4.16–4.01 (3H, m), 3.85–3.79 (3H, m),
60–80 °C. All commercial reagents were obtained from Sigma– 3.70 (1H, dd, J = 6.8, 5.1 Hz), 1.37 (3H, s), 1.29 (3H, s), 1.21
Aldrich and Lancaster Chemical Co. (U.K.). MsCl was distilled (6H, s). 13C NMR (CDCl3, 50 MHz) δ: 167.44, 136.79, 135.52,
before use. The progress of the reactions was monitored by 128.87, 128.64, 128.44, 128.18, 128.08, 127.66, 110.07, 109.29,
TLC, performed on aluminium sheets precoated with silica gel 80.85, 79.13, 78.28, 75.60, 73.07, 65.53, 57.70, 45.02, 27.42,
60 (Merck, 230–400 mesh). Compounds were visualized by 26.99, 26.11, 25.22. MS: m/z = 468 (M + 1).
heating after dipping in an alkaline solution of KMnO4 and
(NH4)6Mo7O24 (6.25 g) in aqueous H2SO4 (250 mL). Column
Compound 13
chromatography was performed on silica gel (100–200 for all
A solution of benzyloxy β-lactam 11 (23.25 g, 50 mmol) in THF
compounds and 230–400 mesh for 7 and 8). Typical syringe
(60 mL) was added dropwise to a suspension of LiAlH4 (4.75 g,
and cannula techniques were used to transfer air and moist-
125 mmol) in THF (100 mL) at 0 °C over a period of 15 min.
ure-sensitive reagents. All melting points were recorded with
The ice bath was removed and the reaction mixture was
allowed to stir for 4–6 h under reflux conditions and then
Thermonik and Büchi melting-point instruments. IR spectra
were recorded with Perkin-Elmer 599-B IR and 1620 FT-IR
cooled to 0 °C again and subsequently quenched by saturated
spectrometers. 1H NMR spectra were recorded with Bruker ACF
aqueous solution of sodium sulfate. The white precipitate
200, AV 400 and DRX 500 instruments operating at 200, 400
was filtered through a sintered funnel, and the filtrate was
and 500 MHz, respectively, by using deuterated solvents.
washed with ethyl acetate. Solvent was removed under reduced
pressure to obtain a colourless oil (20.1 g), which was sub-
sequently dissolved in freshly distilled EtOAc (100 mL). 10%
Chemical shifts are reported in ppm, proton coupling con-
stants (J) are reported as absolute values in Hz, and multi-
plicity is given as follows: br., broad; s, singlet; d, doublet; t,
Pd/C (2.0 g) was added to it and the mixture was allowed to stir
triplet; dt, doublet of triplets; ddd, doublet of doublet of
under a hydrogen balloon for 12 h. The mixture was filtered
doublet; m, multiplet. 13C NMR spectra were recorded with
over celite and the primary amine 12 was obtained as a color-
less oil (11.3 g). Compound 12 was found to be highly polar
Bruker ACF 200, AV 400 and DRX 500 instruments operating at
50, 100 and 125 MHz, respectively. Optical rotations were
and relatively unstable at room temperature. Thus the result-
recorded at 27 °C in a 1 dm cell. Mass spectra were recorded
ing amine was dissolved in DCM (40 mL) and an aqueous solu-
with a PE SCIEX API QSTAR pulsar spectrometer (LC-MS), an
tion of K2CO3 (5.89 g, 42 mmol) in H2O (40 mL) was added
dropwise over a period of 10 min at room temperature. To the
resulting solution, tosyl chloride (7.98 g, 42 mmol) was added
portionwise under stirring. The reaction mixture was allowed
automated GC-MS with a solid-probe facility mass spectro-
meter. X-ray data were collected at T = 296 K with a SMART
APEX CCD single crystal X-ray diffractometer by using Mo-Kα
radiation (λ = 0.7107 Å) to a maximum θ range of 25.00°. The
to stir for an additional 3 h, then washed successively with
structures were solved by direct methods using SHELXTL.21 All
water (20 mL) and brine (20 mL), dried over sodium sulphate
the data were corrected for Lorentzian, polarisation and
and was concentrated to dryness. The crude product was
absorption effects. SHELX-97 (SHELXTL) was used for struc-
chromatographed (50% ethyl acetate–petroleum ether) to give
ture solution and full matrix least-squares refinement on F2.
the desired product 13 (15.0 g, 67% yield over three steps) as a
Hydrogen atoms were included in the refinement as per the
riding model. The refinements were carried out using
SHELXL-97. Microanalysis data were obtained using a Carlo-
Erba CHNS-O EA 1108 elemental analyser.
white sticky solid. [α]2D7 −13.5 (c 1.5 in CHCl3): Anal. Calcd for
C20H31NO6: C, 53.92; H, 7.01; N, 3.14. Found: C, 53.85, H, 7.14;
N, 3.24. IR (νmax, CHCl3) 3450, 3293, 1599, 1066, 1160 cm−1
;
1H NMR (CDCl3, 500 MHz): δ: 7.78 (2H, d, J = 8.5 Hz), 7.30
(2H, d, J = 8.5 Hz), 4.12–4.01 (1H, m), 3.98–3.62 (8H, m), 2.42
(3H, s), 1.46 (3H, s), 1.36 (3H, s), 1.28 (3H, s), 1.23 (3H, s).
13C NMR (CDCl3, 125 MHz) δ: 143.77, 137.79, 129.71, 129.61,
127.30, 127.04, 110.13, 109.81, 80.49, 77.73, 76.81, 71.11,
68.07, 62.90, 54.01, 26.78, 26.68, 26.08, 25.01, 21.52. MS: m/z =
446 (M + 1).
Compound 11
A solution consisting of benzyloxy acetyl chloride 9 (5.6 mL,
38 mmol) in dichloromethane (100 mL) was added dropwise
to a stirred solution containing imine 10 (9.6 g, 30 mmol),
triethyl amine (10.58 mL, 76 mmol) in dichloromethane
(200 mL) at −20 °C. The reaction mixture was stirred overnight
at room temperature, washed with saturated sodium bicarbon-
Compound 14
ate solution (100 mL), brine (100 mL), dried and evaporated to To a solution of 13 (8.0 g, 17.9 mmol) in DCM (100 mL) were
give the crude product, which was purified by column added n-Bu2SnO (180 mg, 0.72 mmol), p-toluenesulfonyl chlor-
chromatography in 20% ethyl acetate–petroleum ether to give ide (3.7 g, 1.96 mmol) and triethyl amine (3.5 mL, 19.6 mmol)
11 (9.13 g, 65%) as a white solid. m.p.: 114–116 °C (from at 0 °C. The reaction mixture was allowed to reach room temp-
MeOH), [α]2D7 +12.5 (c 1.2 in CHCl3); Anal. Calcd for erature and was stirred for an additional 2 h. It was then fil-
C27H33NO6: C, 69.36; H, 7.11; N, 2.99. Found: C, 69.32, H, 7.15; tered through a small pad of celite and the filtrate was
N, 3.12. IR: (νmax, CHCl3): 3054, 2950, 1741, 1598, 1480 cm−1
1H NMR (CDCl3, 200 MHz) δ: 7.37–7.27 (10H, m), 4.94 (1H, d, product (10 g), which was further dissolved in CH3CN
.
concentrated under reduced pressure to obtain the crude
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(150 mL), and K2CO3 (3.45 g, 25.04 mmol) was added to it in allowed to stir until all ammonia had evaporated. The remain-
four portions at room temperature. The reaction mixture was ing solid was filtered through a sintered funnel and washed
allowed to stir at the same temperature for 6 h. After com- with ethyl acetate three times. Evaporation of solvent under
pletion of the starting material (as monitored by TLC), the reduced pressure gave 0.18 g of product. This crude product
mixture was passed through a pad of celite and the filtrate was was immediately dissolved in CH2Cl2 (10 mL). To the solution
concentrated to give the crude product which was purified by was added aq. K2CO3 (1.24 g, 9 mmol) in 2 mL water and the
column chromatography (25% ethyl acetate–pet. ether) to mixture was cooled in an ice bath. To this stirred biphasic
obtain 14 (6.0 g, 88.5% over two steps) as a colorless oil. [α]2D7 solution was added dropwise a solution of benzylchloro-
−5.65 (c 0.5 in CHCl3): Anal. Calcd for C20H29NO7S: C, 56.19; formate (0.85 mL, 6 mmol) in CH2Cl2 (5 mL), and the reaction
H, 6.84; N, 3.28. Found: C, 56.24; H, 6.79; N, 3.31. IR (νmax
,
mixture was allowed to stir at room temperature for
CHCl3): 3449, 2987, 1629, 1372 cm−1 1H NMR (CDCl3, 30 minutes. The organic phase was washed with brine, and
;
200 MHz) δ: 7.77 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), evaporated. The residue was chromatographed on silica gel
5.75 (1H, d, J = 9.8 Hz), 4.11 (1H, dd, J = 8.7, 5.8 Hz), 3.90–3.77 (40% ethyl acetate–pet. ether) to give 16 (0.24 g, 85%) over two
(4H, m), 3.61 (1H, dd, J = 7.75, 2.98 Hz), 3.19–3.18 (1H, m), steps as a colourless oil. [α]2D7 +3.88 (c 0.5 in CHCl3); Anal.
2.76 (1H, dd, J = 4.93, 2.63 Hz), 2.65 (1H, dd, J = 5.11, 4.17 Hz), Calcd for C22H31NO7: C, 62.69; H, 7.41; N, 3.32. Found: C,
2.41 (3H, s), 1.48 (3H, s), 1.39 (3H, s), 1.34 (3H, s), 1.24 (3H, s). 62.72; H, 7.53; N, 3.41; IR (νmax, CHCl3); 3453, 2986, 1699,
13C NMR (CDCl3, 50 MHz) δ: 143.51, 138.19, 129.69, 126.95, 1412 cm−1
;
1H NMR (CDCl3, 400 MHz) δ: 7.35–7.30 (5H, m),
110.42, 109.55, 79.94, 77.72, 76.46, 68.18, 51.55, 50.11, 43.02, 5.13 (2H, s), 4.41–4.24 (1H, m), 4.16–4.14 (5H, m), 3.48–3.45
26.79, 26.63, 26.08, 25.26, 21.01. MS: m/z = 428 (M + 1).
(2H, m), 2.39 (1H, d, J = 8.51 Hz), 2.20–2.16 (1H, m), 2.03–1.99
(1H, m), 1.37 (3H, s), 1.35 (3H, s), 1.33 (3H, s), 1.30 (3H, s). 13
NMR (CDCl3, 125 MHz) δ: 155.94, 136.58, 128.44, 128.04,
C
Compound 15
NaH (60% mineral oil, 0.7 g, 17.55 mmol) was placed in a 109.54, 109.28, 77.46, 71.54, 67.26, 67.09, 66.38, 58.89, 44.31,
flame dried flask and then DMSO (30 mL) was added. To this 32.25, 27.22, 26.53, 26.01, 25.14. MS: m/z = 422 (M + 1).
was added trimethyl sulfoxinium iodide (3.86 g, 17.55 mmol)
Compound 17
at room temperature. The reaction mixture was then stirred for
an additional 30 min until the bubbling of the milky white A solution of 16 (1.28 g, 3 mmol) containing acetic acid
suspension ceased. A solution of epoxy amine 14 (5.0 g, (6 mL), methanol (3 mL), and water (1 mL) was heated at
11.7 mmol) in DMSO (10 mL) was added dropwise to the reac- reflux temperature for 4 h. The reaction mixture was cooled
tion mixture and then the reaction mixture was heated at to 0 °C and then solid sodium bicarbonate was added until
80 °C for 20 h. The mixture was then cooled and diluted with all acetic acid was neutralized. The reaction mixture was
100 mL of water and extracted with ethyl acetate (5 × 150 mL). extracted with ethyl acetate (100 mL), washed with water
The organic layer was washed with aqueous sodium thiosulfate (50 mL), and the organic layer was dried over sodium sulphate
(50 mL), brine (50 mL) and dried over sodium sulfate. The and evaporated. Purification of the residue by column
solvent was evaporated under reduced pressure and the chromatography (40% acetone–petroleum ether) gave 17
product was purified by column chromatography (40% ethyl (0.85 g, 75%) as a colourless oil. [α]2D7 −13.56 (c 1.5 in CHCl3);
acetate–pet. ether) to obtain 15 (4.0 g, 77%) as a white crystal- Anal. Calcd for C19H27NO7: C, 59.83; H, 7.14; N, 3.67. Found:
line solid. m.p.: 151–153 °C (from CHCl3); [α]2D7 +9.8 (c 0.6 in C, 59.75; H, 7.22; N, 3.59; IR (νmax, CHCl3) 3417, 2985, 1682,
CHCl3): Anal. Calcd for C21H31NO7S: C, 57.12; H, 7.08; N, 3.17. 1417 cm−1 1H NMR (CDCl3, 200 MHz) δ: 7.35 (5H, bs), 5.13
;
Found: C, 57.18; H, 6.99; N, 3.33. IR (νmax, CHCl3): 3393, 1598, (2H, s), 4.43–4.31 (m, 2H), 4.30–4.21 (2H, m), 3.84–3.79 (2H,
1372, 1091 cm−1; 1H NMR (CDCl3, 200 MHz) δ: 7.74 (2H, d, J = m), 3.50–3.43 (2H, m), 2.44 (1H, d, J = 10.36 Hz), 2.29–2.05
8.19 Hz), 7.30 (2H, d, J = 8.19 Hz), 4.69–4.64 (1H, m), 4.20–4.13 (2H, m), 1.38 (3H, s), 1.30 (3H, s). 13C NMR (CDCl3, 50 MHz) δ:
(3H, m), 4.01–3.95 (2H, m), 3.81 (1H, dd, J = 5.83, 3.80 Hz), 156.68, 136.01, 128.51, 128.22, 127.82, 108.80, 79.34, 75.75,
3.64–3.54 (1H, m), 3.38 (1H, ddd, J = 11.68, 7.28, 4.27 Hz), 2.43 73.36, 71.58, 67.64, 65.09, 58.94, 44.12, 32.58, 27.09, 26.45. MS:
(3H, s), 1.86–1.72 (2H, m), 1.46 (3H, s), 1.39 (3H, s), 1.41 (3H, m/z = 382 (M + 1).
s), 1.33 (3H, s). 13C NMR (CDCl3, 50 MHz) δ: 143.91, 133.71,
129.72, 127.87, 109.96, 109.74, 81.63, 78.55, 76.89, 73.21,
Compound 18
67.49, 60.98, 47.07, 33.62, 27.35, 26.76, 26.57, 26.5, 25.47, To a solution of 17 (0.8 g, 2.09 mmol) in DCM (15 mL) were
21.58. MS: m/z = 464 (M + Na).
added catalytic n-Bu2SnO (50 mg), p-toluenesulfonyl chloride
(0.48 g, 2.5 mmol) and triethyl amine (1.0 mL, 7.31 mmol) at
0 °C. The reaction mixture was allowed to attain room tempera-
Compound 16
To a round bottom flask, fitted with a cold finger condenser ture and was stirred for an additional 2 h. The reaction
(acetone/solid CO2), containing 15 (0.3 g, 0.68 mmol) was mixture was filtered through a small pad of celite and the fil-
introduced ammonia ca. 100 mL at −78 °C. Small pieces of trate was concentrated under reduced pressure to give the
sodium were added to the stirring solution until the solution crude product, which was purified by column chromatography
became persistently dark blue. After 30 min, the reaction using 30% ethyl acetate–pet. ether to obtain 18 (0.95 g, 84%)
mixture was quenched by the addition of solid NH4Cl, and as a colourless oil. [α]2D7 +7.67 (c 1.1 in CHCl3); Anal. Calcd for
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C26H33NO9S: C, 58.30; H, 6.21; N, 2.62. Found: C, 58.27; H, Compound 22
6.26; N, 2.57; IR (νmax, CHCl3) 3402, 2985, 1674, 1115 cm−1
.
To a suspension of LAH (0.18 g, 4.8 mmol) in THF (5 mL) was
added a solution of 20 (0.5 g, 0.96 mmol) in THF (2 mL) at
0 °C and refluxed while stirring for 5 h. The reaction mixture
was quenched with aq. sodium sulfate, extracted with ethyl
acetate (5 × 15 mL) and solvent was removed under reduced
pressure to give 21 (0.26 g). The crude 21 (0.26 g, 0.96 mmol)
was dissolved in DCM (3 mL) containing aq. solution of K2CO3
(0.4 g, 2.89 mmol). CbzCl (0.2 mL, 1.4 mmol) was added to it
at 0 °C. The reaction mixture was stirred at the same tempera-
ture for another 30 minutes. The organic layer was then
washed with water (1 × 5 mL) and brine (1 × 5 mL). Solvent
was removed under reduced pressure and residue was purified
by column chromatography (15% ethyl acetate–pet. ether) to
yield 22 (0.32 g, 82% over two steps) as a colourless oil. [α]D27
−12.96 (c 1.3 in CHCl3); Anal. Calcd for C22H31NO6: C, 65.17;
1H NMR (CDCl3, 200 MHz) δ: 7.86 (2H, d, J = 8.5 Hz), 7.39–7.29
(7H, m), 5.21–5.06 (2H, m), 4.20–4.15 (1H, m), 3.85–3.66 (4H,
m), 3.48–3.46 (1H, m), 3.43 (1H, dt, J = 6.30, 3.27 Hz),
3.42–3.41 (2H, m), 2.41 (3H, s), 2.22–2.01 (2H, m), 1.34 (3H, s),
1.27 (3H, s). 13C NMR (CDCl3, 50 MHz) δ: 156.86 144.56,
136.12, 132.82, 129.66, 128.53, 128.05, 108.93, 80.19, 77.19,
74.02, 71.93, 71.36, 67.37, 58.42, 43.71, 33.13, 27.02, 26.47,
21.58. MS: m/z = 536 (M + 1).
1,6,8a-Tri-epi-castanospermine (7)
A mixture of 18 (0.1 g, 0.18 mmol), sodium acetate (0.073 g,
0.9 mmol) and 10% Pd/C (20 mg) in methanol (1.5 mL) was
hydrogenated at atmospheric pressure for 10 h. The catalyst
was filtered, methanol was evaporated and the residue was dis-
solved in DCM. The organic layer was washed with water and
brine, and dried over sodium sulfate. Solvent was removed and
the crude product 19 obtained was dissolved in THF–H2O
(3 : 1) and refluxed overnight with Dowex 50W-X8 (50 mg). The
reaction mixture was filtered and washed with MeOH. The
remaining residue was eluted with 2 N NH3 solution. The NH3
solution was evaporated to give the crude product, which was
purified by column chromatography (MeOH–EtOAc 10%) to
obtain 1,6,8a-tri-epi-castanospermine 7 (19 mg, 90%) as a
colorless oil. [α]2D7 −60.34 (c 0.7 in CHCl3); Anal. Calcd for
C8H15NO4: C, 50.78; H, 7.99; N, 7.40. Found: C, 50.81; H, 7.95;
H, 7.71; N, 3.45. Found: C, 65.22; H, 7.61; N, 3.54; IR (νmax
,
CHCl3) 1597, 1353 cm−1 1H NMR (CDCl3, 200 MHz) δ:
;
7.38–7.34 (5H, m), 5.20–5.12 (2H, m), 4.27–3.98 (5H, m),
3.62–3.42 (2H, m), 2.04–2.01 (2H, m), 2.0–1.85 (2H, m), 1.35
(12H, bs). 13C NMR (CDCl3, 100 MHz shows a mixture of rota-
mers, values for major peaks are written) δ: 155.95, 136.90,
128.46, 127.89, 127.79, 127.67, 109.52, 109.45, 81.99, 77.99,
77.24, 76.83, 66.45, 57.69, 47.42, 27.29, 26.87, 26.86, 26.24,
25.27. MS: m/z = 406 (M + 1).
Compound 23
1
N, 7.43; IR (νmax, neat) 3434, 1403, 1265 cm−1; H NMR (D2O,
A solution of 22 (0.81 g, 2 mmol) in acetic acid (4 mL), metha-
nol (2 mL) and water (0.75 mL) was heated at reflux tempera-
ture for 4–6 h. The reaction mixture was cooled to 0 °C and
then solid sodium bicarbonate was added until all of the
acetic acid was neutralized. The reaction mixture was extracted
with ethyl acetate (50 mL), washed with water (20 mL), and the
organic layer was dried over sodium sulphate and evaporated.
Purification of the residue by column chromatography (30%,
acetone–petroleum ether) gave 23 (0.53 g, 72%) as a colourless
oil. [α]2D7 −31.52 (c 1.25 in CHCl3); Anal. Calcd for C19H27NO6:
C, 62.45; H, 7.45; N, 3.83. Found: C, 62.42; H, 7.53; N, 3.79.
IR (νmax, CHCl3) 3418, 2934, 1674, 1417 cm−1. 1H NMR (CDCl3,
400 MHz) δ: 7.34 (5H, bs), 5.12 (2H, s), 4.24 (1H, d, J =
6.90 Hz), 4.01 (1H, d, J = 7.2 Hz), 3.98 (1H, dd, J = 8.7, 1.7 Hz),
3.75–3.72 (m, 2H), 3.63–3.55 (m, 3H), 3.53 (1H, dt, J = 11.21,
3.20 Hz), 2.02 (1H, bs), 2.01–1.98 (1H, m), 1.83–1.82 (2H, m),
1.81–1.79 (1H, m), 1.34 (3H, s), 1.28 (s, 3H). 13C NMR (CDCl3,
100 MHz) δ: 156.99, 136.35, 128.50, 128.13, 127.78, 108.21,
83.92, 76.06, 73.22, 67.51, 65.51, 57.93, 47.70, 29.01, 26.92,
26.52, 24.10. MS: m/z = 366 (M + 1).
400 MHz) δ: 4.59–4.56 (m, 1H), 4.26 (1H, dd, J = 3.92, 1.64 Hz),
4.13–4.10 (1H, m), 3.89 (1H, t, J = 7.21, 3.42 Hz), 3.14 (1H, t, J =
17.24, 8.9 Hz), 3.06 (1H, dd, J = 10.6, 4.91 Hz), 2.44–2.36 (1H,
m), 2.28–2.25 (3H, m), 1.75–1.69 (1H, m). 13C NMR (D2O,
100 MHz) δ: 71.95, 69.38, 69.25, 65.01, 63.25, 51.89, 51.25,
32.91. MS m/z = 190 (M + 1).
Compound 20
To a solution of 15 (0.5 g, 1.13 mmol) in DCM (4 mL) were
added Et3N (0.39 mL, 2.8 mmol) and methanesulfonyl chlor-
ide (0.13 mL, 1.7 mmol) at 0 °C. The reaction mixture was
stirred for 30 min at room temperature and was subsequently
quenched with saturated NaHCO3 (5 mL). The reaction
mixture was extracted with EtOAc (3 × 10 mL). The organic
layer was concentrated and the residue was chromatographed
on silica gel (30% EtOAc–petroleum ether) to give 20 (0.54 g,
91%) as a colorless oil. [α]2D7 −13.13 (c 0.6 in CHCl3); Anal.
Calcd for C22H33NO9S2: C, 50.85; H, 6.40; N, 2.70. Found: C,
1
50.81; H, 6.55; N, 2.64; IR (νmax, CHCl3) 1597, 1353 cm−1. H
NMR (CDCl3, 400 MHz) δ: 7.67 (2H, d, J = 8.19 Hz), 7.34 (2H, d,
J = 8.2 Hz), 4.47–4.43 (1H, m), 4.27–4.14 (4H, m), 4.12–4.07
(1H, m), 3.95 (1H, dd, J = 7.54, 5.83 Hz), 3.51 (1H, ddd, J =
Compound 24
12.80, 9.91, 2.89 Hz), 3.31 (1H, dt, J = 11.04, 8.46 Hz), 2.99 (3H, To a solution of 23 (0.5 g, 1.36 mmol) in DCM (8 mL) were
s), 2.44 (3H, s), 2.33–2.31 (1H, m), 2.07–2.03 (1H, m), 1.54 (3H, added catalytic n-Bu2SnO (25 mg), p-toluenesulfonyl chloride
s), 1.42 (3H, s), 1.37 (6H, s). 13C NMR (CDCl3, 100 MHz) δ: (0.28 g, 1.49 mmol) and triethyl amine (0.66 mL, 4.76 mmol)
144.33, 134.52, 130.12, 127.25, 110.18, 109.76, 77.37, 77.24, at 0 °C. The reaction mixture was allowed to reach room temp-
76.94, 76.00, 67.76, 59.72, 45.70, 38.38, 29.20, 27.34, 26.38, erature and was stirred for an additional 2 h. The reaction
26.12, 25.41, 21.56. MS: m/z = 520 (M + 1).
mixture was filtered through a small pad of celite and the
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filtrate was concentrated under reduced pressure to give the
crude product, which was purified by column chromatography
using (30% ethyl acetate–pet. ether) to obtain 24 (0.62 g, 88%)
as a colorless oil. [α]2D7 −11.44 (c 0.7 in CHCl3); Anal. Calcd for
C26H33NO8S: C, 60.10; H, 6.40; N, 2.70. Found: C, 60.25; H,
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Acknowledgements
The authors thank the Department of Science and Technology,
New Delhi, for financial support. The authors are grateful to
the Director, CSIR-NCL and CSIR-IICT for providing the
necessary infrastructure. D. K. T. is grateful to Prof. Ganesh
Pandey for his valuable suggestions.
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7396 | Org. Biomol. Chem., 2014, 12, 7389–7396
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