The 5-endo-trig cyclization of D-glucose derived γ-alkenylamines with mercury (II) salts: Synthesis of 1-deoxy-castanospermine and its 8a-epi-analogue

Article abstract of DOI:10.3390/10080893

The intramolecular aminomercuration of γ-alkenylamines 1a, 1b and 4 was shown to afford the 5-endo-trig cyclized product exclusively in good yield. The utility of pyrrolidine derivatives thus obtained from D-glucose derived γ-alkenylamines 1a and 1b was d

Full text of DOI:10.3390/10080893

Molecules 2005, 10, 893-900
molecules
ISSN 1420-3049
http://www.mdpi.org
The 5-Endo-trig Cyclization of D-Glucose Derived
γ-Alkenylamines with Mercury (II) Salts: Synthesis of 1-Deoxy-
castanospermine and its 8a-epi-Analogue†
Dilip D. Dhavale* and Santosh M. Jachak
Department of Chemistry, Garware Research Centre, University of Pune, Pune- 411 007, India. Fax
(+91) 20-25691728.
* Author to whom correspondence should be addressed; e-mail ddd@chem.unipune.ernet.in.
† Dedicated to Prof. K.K. Balasubramanian on the occasion of his 65th birthday.
Received: 15 October 2004; in revised form: 4 January 2005 / Accepted: 10 January 2005 /
Published: 31 August 2005
Abstract: The intramolecular aminomercuration of γ-alkenylamines 1a, 1b and 4 was
shown to afford the 5-endo-trig cyclized product exclusively in good yield. The utility of
pyrrolidine derivatives thus obtained from D-glucose derived γ-alkenylamines 1a and 1b
was demonstrated in the synthesis of 1-deoxycastanospermine (3a) and 1-deoxy-8a-epi-
castanospermine (3b).
Keywords: Aminosugars, aminomercuration, alkaloids, enzyme inhibitors, nitrones.
Introduction
The pyrrolidine ring skeleton constitutes an important molecular backbone for a number of
heterocyclic compounds. Among the strategies available for the synthesis of pyrrolidine ring skeletons
one of the most attractive is the stereoselective intramolecular amido- and/or amino-mercuration
reaction of δ−alkenylamines [1]. The reaction affords 2-substituted pyrrolidine rings through preferred
5-exo-trig cyclization, in addition to the 6-endo-trig cyclized piperidine ring skeleton in minor amounts
[2]. In case of γ-alkenylamines, however, only a single report is known on the mercury (II) mediated
5-endo-trig cyclization, leading to the formation of pyrrolidine ring, while the 4-exo-trig product is not
obtained due to the ring strain involved in the four membered ring system [1d, 3]. Recently, we have

Molecules 2005, 10
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reported the utility of D-glucose derived γ-alkenylamine 1 for the synthesis of the polyhydroxylated
quinolizidine homocastanospermine alkaloids [4].
Figure 1
2
3
1
N 4
N
HO
N
5
6
8a
H 8
H
H
7
HO
OH
HO
OH
HO
OH
OH
OH
OH
3a
2
3b
This class of compounds, in particular the polyhydroxylated indolizidine alkaloid castanospermine
(2), has attracted considerable attention because of their promising glycosidase inhibitory activity. In
the pursuit of structure-activity relationships a number of natural and unnatural derivatives of
castanospermine [5] have been synthesized and evaluated for glycosidase inhibition in the treatment of
various diseases such as diabetes [6], cancer [7], and viral infections, including AIDS [8]. As a part of
our continuing interest in the synthesis of azasugars [9], we thought of utilizing the intramolecular
aminomercuration strategy, in a 5-endo-trig fashion, with the D-glucose derived γ-alkenylamine 1 for
the construction of a pyrrolidine ring skeleton that could be elaborated to 1-deoxy castanospermine
(3a) and its 8a-epi analogue 3b (Figure 1) [10]. Our results with the successful mercury (II) mediated
5-endo-trig cyclization of γ-alkenylamines towards the pyrrolidine ring skeleton are discussed.
Results and Discussion
In order to know whether the differentially substituted γ-alkenylamines obey the usual Baldwin’s
ring closure rule or not [10], we have investigated the model reaction with α-phenyl-substituted-γ-
alkenylamine 4. The required compound 4 was obtained by 1,3-addition of allylmagnesium bromide to
the benzaldehyde-derived nitrone 5 [11], followed by reductive cleavage of the N−O bond with zinc-
acetic acid (Scheme 1) [4]. The reaction of γ-alkenylamine 4 with mercury (II) acetate in (1:1) THF-
water at 25 °C for 18 h, followed by reductive demercuration with sodium borohydride afforded the 5-
endo-trig product 6 exclusively in 81% yield.
Scheme 1
H
Bn
O
Bn
H
N
N
i, ii
iii
N
Bn
5
6
4
Reagents and conditions: (i) Allylmagnesium bromide (2.5 equiv),
dry THF, 0 °C, 2h, 93%; (ii) Zn (2.0 equiv), Cu(OAc)2, AcOH, 70 °C,
1h, 80%; (iii) Mercury acetate (2.5 equiv),THF-water (1:1), NaBH4
(4.0 equiv), rt, 18h, 81%

Molecules 2005, 10
895
With the success in 5-endo-trig aminomercuration of γ-alkenylamine 4 in hand, we have exploited
the same strategy with the D-glucose derived γ-alkenylamine 1. As reported earlier, the reaction of D-
glucose nitrone 7 with allylmagnesium bromide in the presence of TMSOTf (1 equiv) at –78 °C in dry
THF, afforded a diastereomeric mixture of D-gluco- and L-ido- configurated N-benzylhydroxylamines
8a and 8b in the ratio of 86:14 (Scheme 2). The treatment of 8a and 8b, individually, with zinc-acetic
acid afforded the D-gluco-γ-alkenylamine 1a and L-ido-γ-alkenylamine 1b in good yield [4]. In the
next step, the aminomercuration of 1a with mercury (II) acetate in THF-water (1:1) at room
temperature for 18 h, followed by reductive demercuration with sodium borohydride afforded
exclusively the 5-endo-trig cyclized product 9a in 78% yield. Similarly, the aminomercuration of 1b
afforded the pyrrolidine derivative 9b in 76% yield. The spectroscopic and analytical data obtained for
9a and 9b were in agreement with the assigned structures.
Scheme 2
Bn
R1
R1
R
N
R
O
i
ii
O
O
O
O
O
O
BnO
BnO
BnO
O
O
O
7
1a R = NHBn, R1 = H
1b R = H, R1 = NHBn
8a R = N(OH)Bn, R1 = H
8b R = H, R1 = N(OH)Bn
iii
Bn
N
Cbz
N
N
H
H
iv
v
O
O
H
HO
OH
O
O
HO
BnO
O
O
OH
10a α−H
10b β−H
9a α−H
9b β−H
3a α−H
3b β−H
Reagents and conditions: (i) Allylmagnesium bromide (2.5 equiv),
TMSOTf (1.0 equiv), dry THF, -78°C, 2h, 92%; (ii) Zn (2.0 equiv),
Cu(OAc)2, AcOH, 70 °C, 1h, 78%; (iii) Mercury acetate (2.5
equiv),THF-water (1:1), NaBH4 (4.0 equiv), rt, 18h, 77%; (iv) a) H2,
10% Pd-C,MeOH, rt, 12h, b) Cbz-Cl (1.5 equiv), NaHCO3, EtOH, rt, 2h;
(v) a) TFA/H2O, rt, 2.5h, b) H2, 10% Pd-C, MeOH, 25 °C, 12h.
In the subsequent step, removal of N− and O−benzyl groups in 9a by hydrogenation using 10% Pd-
C, followed by selective N−protection with benzyl chloroformate afforded 10a in 74% yield [12].
Deprotection of the 1,2-acetonide group in 10a with TFA-water, followed by hydrogenation afforded
1-deoxy-castanospermine (3a). The reaction sequence was repeated for L-ido-configurated-pyrrolidine
derivative 9b and the corresponding C5-epimeric compound 10b was obtained in good yield.
Deprotection of the 1,2-acetonide group of 10b with TFA-water, followed by hydrogenation afforded
1-deoxy-8a-epi-castanospermine (3b). The physical and the analytical data as well as the optical
rotation for 3a and 3b were found to be consistent with those reported in the literature [9f].

Molecules 2005, 10
896
Conclusions
We have demonstrated that the intramolecular aminomercuration of γ-alkenylamines, derived from
aromatic as well as from sugar substrates, results in exclusive 5-endo-trig cyclisation leading to
pyrrolidine ring skeletons. The utility of 5-endo-trig cyclized pyrrolidine derivatives 9a and 9b was
demonstrated in the synthesis of 1-deoxy-castanospermine analogues 3a and 3b, respectively.
Acknowledgements
We are thankful to CSIR, New Delhi for the SRF to SMJ. We are grateful to UGC, New Delhi for
the financial support to procure the high field NMR (300 MHz) facility.
Experimental
General
Melting points were recorded with a Thomas-Hoover melting point apparatus and are uncorrected.
IR spectra were recorded with a FTIR-8400, Shimadzu spectrophotometer as a thin film or in nujol
1
mulls and are expressed in cm−1. H-NMR (300 MHz) and 13C-NMR (75 MHz) Mercury YH 300,
Varian, spectra were recorded in CDCl3 as a solvent unless otherwise noted. NMR Chemical shifts are
reported in δ ppm) downfield from TMS. Elemental analyses were carried out with Hosli elemental
analyzer. Optical rotations were measured with JASCO DIP 181 polarimeter using sodium light (D
line 589.3 nm) at 25 °C. TLC was performed on pre-coated plates (0.25 mm, silica gel 60 F254).
Column chromatography was carried out with 100-200-mesh silica gel. The reactions were carried out
in oven-dried glassware under dry N2. Allylmagnesium bromide was prepared prior to use from Mg
and allyl bromide in dry ether. N-Benzylhydroxylamine hydrochloride, Cbz-Cl, and mercury acetate
was purchased from Aldrich and/or Fluka. Methanol (MeOH), diethyl ether (Et2O), dichloromethane
(CH2Cl2) and THF were purified and dried before use. Petroleum ether (PE) refers to a distillation
fraction collected between 40-60 °C. After work up, organic layers were washed with water and brine,
dried over anhydrous sodium sulfate and evaporated under reduced pressure.
Preparation of N-benzyl-N-(1-phenylbut-3-enyl)amine (4).
Allylmagnesium bromide (1M in Et2O, 1.4 mL, 6.52 mmol) was added dropwise to a stirred
solution of nitrone 5 (0.725 g, 3.43 mmol) in THF at 0 °C. The mixture was stirred at 0 °C for 2h, then
quenched with a saturated solution of NH4Cl (5 mL) and filtered. The filtrate was concentrated and the
residue was dissolved in Et2O (30 mL). The ethereal layer was washed with brine, dried with sodium
sulphate and evaporated to give oil, which was used directly in the next step. Zinc dust (0.257 g, 4.50
mmol) was added to a solution of copper (II) acetate (0.015 g) in glacial acetic acid (1 mL) under
nitrogen and the mixture was stirred at room temperature for 15 min until the color disappeared. The
crude oil (0.30 g, 0.75 mmol) in glacial acetic acid (0.7 mL) and water (0.3 mL) was added, the
reaction mixture was heated at 70 °C for 1h and then cooled to room temperature. The sodium salt of
EDTA (0.1 g) was added and the mixture was stirred for 10 min and then made alkaline to pH 10 by
addition of 3N NaOH. The resulting solution was extracted with CHCl3 (10 mL x 3) the combined

Molecules 2005, 10
897
organic layer was washed with brine dried over Na2SO4 and evaporated to give oil. Purification by
column chromatography gave 4 (0.21 g, 70%) as a thick liquid; Rf = 0.51 (EtOAc/hexane = 3:7); IR
ν
max (neat) = 3475, 1634 cm−1; 1H-NMR: δ 1.66-1.82 (1H, bs, exchanges with D2O), 2.32-2.51 (2H, m,
H-8), 3.53 (1H, d, J = 13.2 Hz, N-CH2Ph), 3.62-3.76 (2H, m, H-7, N-CH2Ph), 4.98-5.12 (2H, m, H-9),
5.62-5.79 (1H, m, H-10), 7.18-7.42 (10H, m, Ar-H); 13C-NMR: δ 42.6, 51.1,61.5, 117.7, 126.9, 127.2,
127.3, 128.3, 128.4, 134.9; Anal. Calcd. for C17H19N: C, 86.03; H, 8.07; Found C, 86.23; H, 8.19.
Preparation of N-benzyl-2-phenyl pyrrolidine (6).
Compound 4 (0.200 g, 0.84 mmol) in THF (5 mL) was added to a stirred solution of mercury
acetate (0.538 g, 1.68 mmol) in THF-water (1:1, 15 mL). The reaction mixture was stirred at rt for 18
h, quenched by sodium borohydride (0.124 g, 3.36 mmol) and then extracted into CHCl3 (10 mL x 3).
The CHCl3 layer was dried and evaporated to afford a thick liquid that was purified by column
chromatography to afford 6 (0.164 g, 81%) as a thick liquid; Rf = 0.55 (EtOAc/Hexane = 3:7);
1H-NMR: δ 1.70-1.98 (3H, m, H-8, H-9), 2.16-2.30 (2H, m, H-9, H-10), 3.06 (1H, d, J = 12.9 Hz, N-
CH2Ph), 3.08-3.18 (1H, m, H-10), 3.97 (1H, t, J = 8.1 Hz, H-7), 3.88 (1H, d, J = 12.9 Hz, N-CH2Ph),
7.19-7.59 (10H, m, Ar-H); 13C-NMR: δ 22.4, 35.3, 53.3, 58.1, 69.6, 126.6, 126.7, 126.8, 127.1, 127.4,
127.6, 127.9, 128.1, 128.3, 128.5, 139.5, 143.6; Anal. Calcd. for C17H19N: C, 86.03; H, 8.07; Found C,
86.31; H, 8.29.
Preparation of 5,6,7,8-tetradeoxy-5,8-(N-benzylimino)-1,2-O-isopropylidene-α-D–gluco-oct-1,4-
furanose (9a).
To a stirred solution of mercury acetate (0.827 g, 2.59 mmol) in THF-water (1:1, 10 mL) was added
compound 1a (0.530 g, 1.29 mmol) in THF (5 mL). The reaction mixture was stirred at rt for 18 h,
quenched by sodium borohydride (0.196 g, 5.18 mmol) and then extracted into CHCl3 (10mL x 3). The
CHCl3 layer was dried and evaporated to afford a thick liquid that was purified by column
chromatography to afford 9a (0.278 g, 78%) as a thick liquid; Rf = 0.43 (EtOAc/hexane = 3:7); [α]D =
−72.8 (1.0 c, CHCl3); IR νmax (neat) = 2927, 1604 cm−1; 1H-NMR: δ 1.32 (3H, s, −CH3), 1.51 (3H, s, -
CH3), 1.68-1.79 (2H, m), 1.90-2.01 (2H, m), 2.20-2.319 (1H, m), 2.85-2.89 (1H, m), 3.24 (1H, dt, J =
8.1, 4.2 Hz), 3.44 (1H, d, J = 13.2 Hz), 3.99-4.10 (3H, m), 4.40 (1H, d, J = 12.0 Hz), 4.62 (1H, d, J =
13
12.0 Hz), 4.63 (1H, d, J = 3.9 Hz), 5.89 (1H, d, J = 3.9 Hz), 7.18-7.38 (10H, m); C-NMR: δ 24.1,
26.3, 26.5, 28.6, 54.5, 60.1, 61.1, 71.2, 81.6, 82.1, 83.1, 104.5, 111.2, 126.5, 127.3, 127.6, 128.0,
128.2, 128.3, 137.2; Anal. Calcd. for C25H31NO4: C, 73.32; H, 7.63 Found C, 73.11; H, 7.45.
Preparation of 5,6,7,8-tetradeoxy-5,8-(N-benzylimino)-1,2-O-isopropylidene-β-L-ido-oct-1,4 furanose
(9b).
The reaction of 1b (0.255 g, 0.62 mmol) with mercury acetate (0.397 g, 1.24 mmol) and sodium
borohydride (0.092 g, 2.49 mmol) under the same reaction conditions reported for 9a, gave 9b (0.168
g, 72%) as a thick liquid; Rf = 0.40 (EtOAc/hexane = 3:7); [α]D = −61.3 (c 0.7, CHCl3); IR νmax (neat)
= 2927, 1604 cm−1; 1H-NMR: δ 1.36 (3H, s), 1.54 (3H, s), 1.59-1.79 (3H, m), 1.80-1.93 (1H, m), 2.18-
2.27 (1H, m), 2.88-3.02 (2H, m), 3.32 (1H, d, J = 13 Hz), 3.88 (1H, d, J = 2.5 Hz), 4.23 (1H, bd, J =

Molecules 2005, 10
898
7.0 Hz), 4.46 (1H, d, J = 11.5 Hz), 4.54 (2H, m), 4.68 (1H, d, J = 11.5 Hz), 6.01 (1H, d, J = 4.0 Hz),
7.20-7.39 (10H, m).
Preparation of 5,6,7,8-tetradeoxy-5,8-(N-benzoxycarbonylimino)-1,2-O-isopropylidene-α-D-gluco-
oct-1,4-furanose (10a).
10% Pd-C (0.100 g) was added to a solution of compound 9a (0.278 g, 0.67 mmol) in MeOH (5
mL) and the solution was hydrogenated at 80 psi for 16 h. The catalyst was filtered and washed with
methanol and the filtrate concentrated to give a sticky solid that was dissolved in EtOH/H2O (2 mL,
1:1) and sodium bicarbonate (0.17 g, 1.97 mmol) and then benzyloxycarbonyl chloride (0.10 g, 0.59
mmol) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. Usual workup followed by
extraction with CHCl3 (5 mL x 3) afford a thick liquid that was purified by column chromatography
(PE/EtOAc = 92:8) to give 10a (0.13 g, 74%) as a thick liquid; Rf = 5.5 (hexane/EtOAc = 6:4); [α]D =
+29.00 (c 0.56, CHCl3) [reported +28.30 (c, 1.1, CHCl3)]; IR νmax (neat) = 3366, 1675 cm−1; 1H-NMR:
δ 1.31 (3H, s, CH3), 1.49 (3H, s, CH3), 1.84-2.05 (3H, m), 2.09-2.15 (1H, m), 3.38-3.45 (2H, m), 3.80
(1H, dd, J = 10.2, 1.8 Hz), 4.02 (1H, d, J = 1.8 Hz), 4.14 (1H, dd, J = 10.2, 6.2 Hz), 5.26 (1H, bs,
exchanges with D2O), 4.59 (1H, d, J = 3.7 Hz), 5.14 (2H, ABq, J = 12.5 Hz), 5.90 (1H, d, J = 3.7Hz),
7.26-7.38 (5H, m); 13C-NMR: δ 23.0, 26.1, 27.1, 28.2, 48.8, 59.9, 68.1, 73.9, 81.0, 85.0, 105.2, 112.3,
128.0, 128.4, 129.1, 136.0, 157.1; Anal. Calcd. for C19H25NO6: C, 62.79; H, 6.93. Found: C, 62.68; H,
6.81.
Preparation of 5,6,7,8-Tetradeoxy-5,8-(N-benzoxycarbonylimino)-1,2-O-isopropylidene-β-L-ido-oct-
1,4-furanose (10b).
The reaction of 9b (0.20 g, 0.82 mmol) with 10% Pd-C (0.06 g, 4.1 mmol) in methanol followed by
reaction with benzyloxycarbonyl chloride (0.16 g, 0.94 mmol) under the same reaction conditions
reported for 10a gave 10b (0.22 g, 74%) as a thick liquid; Rf = 0.42 (hexane/EtOAc = 6:4); [α]D =
−72.27 (c 0.44, CHCl3); IR νmax (neat) = 3390, 1693 cm−1; 1H-NMR: δ 1.30 (3H, s), 1.48 (3H, s), 1.82-
1.94 (2H, m), 1.96-2.20 (2H, m), 3.42-3.58 (2H, m), 4.0 (1H, t, J = 3.0 Hz), 4.13 (1H, d, J = 2.9 Hz),
4.26-4.34 (1H, m), 4.48 (1H, d, J = 3.6 Hz), 5.13 (2H, ABq, J = 12.3 Hz), 5.87 (1H, d, J = 3.6 Hz),
7.24-7.42 (5H, m); 13C-NMR: δ 23.6, 26.1, 26.7, 29.7, 47.2, 55.5, 67.5, 75.7, 84.0, 85.0, 104.5, 111.2,
127.8, 128.0, 128.4, 136.3, 158.7; Anal. Calcd. for C19H25NO6: C, 62.79; H, 6.93. Found: C, 62.80; H,
6.79.
Preparation of (6S,7R,8R,8aR)-6,7,8-Trihydroxy-indolizidine (3a).
A solution of 10a (0.10 g, 0.28 mmol) in 3:2 TFA/H2O (2 mL) was stirred at 25 °C for 2 h. The
TFA was co-evaporated with benzene to furnish a thick liquid, which was directly used in the next
reaction. To a solution of the product in MeOH (5 mL) was added 10% Pd/C (0.01 g), and the solution
was hydrogenated at 80 psi for 16 h. The catalyst was filtered and washed with methanol and the
filtrate concentrated to give a sticky solid which was purified by column chromatography
(CHCl3/MeOH = 9:1) to give 3a (0.04 g, 90%) as a white solid; mp 176-178 °C (reported [3f] 178-181
°C); Rf = 0.45 (CHCl3/MeOH = 9/1); [α]D = +50.10 (c 0.7, MeOH) [reported +50.6 (c 0.2, MeOH)]; IR

Molecules 2005, 10
899
(KBr pellet) = 3380, 3270 cm−1 (broad band); 1H-NMR (pyridine-d5 + D2O) δ 1.39-1.58 (1H, m), 1.64-
1.82 (2H, m), 1.93-2.06 (1H, m), 2.10-2.24 (2H, m), 2.30 (1H, t, J = 10.5 Hz), 2.94 (1H, dt, J = 8.6, 2.0
Hz), 3.43 (1H, dd, J = 5.2, 10.5 Hz), 3.86 (1H, t, J = 8.6 Hz), 3.91 (1H, t, J = 8.6 Hz), 4.33 (1H, ddd, J
= 10.5, 8.6, 5.2 Hz); 13C-NMR (pyridine-d5) δ 21.9, 28.6, 53.2, 56.9, 68.3, 71.5, 75.9, 80.9; Anal.
Calcd. for C8H15NO3: C, 55.47; H, 8.73. Found: C, 55.77; H, 8.98.
Preparation of (6S,7R,8R,8aS)-6,7,8-Trihydroxy-indolizidine (3b).
The reaction of 10b (0.16 g, 0.44 mmol) with TFA/H2O (2 mL, 3:2) under the same conditions
reported for 3a gave the corresponding hemiacetal as a thick liquid, which on hydrogenation with 10%
Pd/C (0.02 g) in methanol gave 3b as a semisolid. Column chromatography using 8:2 CHCl3/MeOH as
an eluent gave (0.065 g, 87%) as a semisolid; Rf = 0.2 (CHCl3/MeOH = 1/1); [α]D = +23.0 (c 0.72,
1
MeOH) [reported [3f] +22.5 (c 1.13, MeOH)]; IR (KBr pellet) = 3360-3250 (broad band) cm−1; H-
NMR (pyridine-d5 + D2O) δ 1.72-2.00 (3H, m), 2.22-2.40 (1H, m), 2.84-3.00 (1H, m), 3.44 (1H, bd, J
13
= 12.3 Hz), 3.49-3.67 (2H, m), 3.69 (1H, bd, J = 12.3 Hz), 4.42 (2H, bs), 4.55 (1H, bs); C-NMR
(pyridine-d5) δ 21.1, 24.5, 54.7, 55.5, 64.6, 70.5, 70.7, 70.9; Anal. Calcd for C8H15NO3: C, 55.47; H,
8.73. Found: C, 55.80; H, 9.02.
References and Notes
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Chem. 1990, 55, 5801-5802.
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ring skeletons. See: (a) Chatgilialoglu, C.; Ferreri, C.; Guerra, M.; Timokhin, V.; Froudakis, G.;
Gimisis, T. J. Am. Chem. Soc. 2002, 124, 10765. (b) Knight, D. W.; Redfern, A. L.; Gilmore, J. J.
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Jachak, S. M.; Dhavale, D. D.; Karche, N. P.; Trombini, C. Synlett 2004, 1549.
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