A new method of synthesising (±)-thalictroidine and (±)-hygrine

Article abstract of DOI:10.1016/j.tetlet.2011.01.132

A new route to synthesise (±)-thalictroidine and (±)-hygrine by tandem S_N2-Micheal reaction is described.

Full text of DOI:10.1016/j.tetlet.2011.01.132

Tetrahedron Letters 52 (2011) 1520–1522
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A new method of synthesising ( )-thalictroidine and ( )-hygrine
⇑
T. Ponpandian, S. Muthusubramanian
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new route to synthesise ( )-thalictroidine and ( )-hygrine by tandem SN2-Micheal reaction is
Received 3 January 2011
Revised 20 January 2011
Accepted 27 January 2011
Available online 1 February 2011
described.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
( )-Thalictroidine
( )-Hygrine
Tandem SN2-Micheal reaction
Wittig reagent
Piperidine alkaloids
Pyrrolidine alkaloids
Nitrogen containing heterocycles are well known for their bio-
logical activity.1 This has led to a great number of studies concern-
ing the development of new methodology towards these molecules
over the years.2 Thalictroidine (1), a piperidine alkaloid, was orig-
inally isolated in 1999 by Kennelly et al.3 from a North American
‘Blue Cohosh’ (Caulophyllum thalictroides). This alkaloid is used in
certain dietary preparations. Hygrine (2) is a pyrrolidine alkaloid
found in a variety of plants including coca leaves. Hygrine has been
the subject of several biological and pharmacological studies,4 as it
is the precursor of tropane skeleton.5 The synthesis of thalictroi-
dine (1) has been reported6 and a number of routes available to-
wards the synthesis of hygrine (2).7 These methods have some
disadvantages—either they involve multiple steps or result in low
yield. In this Letter, we wish to report a method of synthesising
( )-thalictroidine (1) and ( )-hygrine (2) (Fig. 1) by a simple route
in high yield.
CH3
O
O
CH3
N
N
CH3
OH
(+)-Thalictroidine (1)
(+)-Hygrine (2)
Figure 1.
ictroidine (1) and ( )-hygrine (2) and the results are presented
here.
A retrosynthetic analysis of the alkaloids 1 and 2 (Scheme 1)
identifies the respective precursors for the synthesis of 1 and 2.
Accordingly, Wittig reaction between 5-bromo-1-pentanal (3)12
and 4-methoxyphenacylphosphonium bromide (4)13 in the pres-
ence of aqueous sodium hydroxide yielded 84% of 5 (Scheme
2).14 Tandem SN2 substitution and aza-Michael addition of 5 and
methylamine hydrochloride in the presence of potassium carbon-
ate gave quantitative yield of 6 even at room temperature.15
Initially, the demethylation of 6 was effected with 3 equiv of
BBr3 and the yield of 1 was only 50%. When four equivalents of
BBr3 were employed, it resulted in 60% of 1. Further increase in
the quantity of BBr3 failed to improve the yield. It must be men-
tioned that when the demethylation was conducted under neutral
condition, using lithium chloride (5 equiv) in refluxing DMF, only
5% of 1 was obtained. As acidic and neutral conditions did not
Bunce et al.8 developed a methodology for the preparation
of five-membered and six-membered nitrogen and sulphur hetero-
cycles through tandem SN2-Micheal reaction. Recently, Duen-
ren Hou et al. have applied the tandem SN2 substitution and
intramolecular aza-Micheal addition sequence to prepare ethyl
2-piperidineacetate as an intermediate towards the syntheses of
(À)-allosedridine and (À)-2-epi-ethylnorlobelol.9 Asymmetric syn-
thesis of natural (À)-sparteine has also been achieved by a similar
route10 and this tandem procedure is extensively used.11 This strat-
egy is now extended for the synthesis of natural products ( )-thal-
⇑
Corresponding author. Tel.: +91 452 2458246; fax: +91 452 2459845.
E-mail address: muthumanian2001@yahoo.com (S. Muthusubramanian).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.132

T. Ponpandian, S. Muthusubramanian / Tetrahedron Letters 52 (2011) 1520–1522
1521
CH3
O
N
n(H2C)
NHCH3
R
R
(CH2)n
O
1/2
O
O
(CH2)n
Br
Br
+
R
(CH2)n
RCOCH2PPh3Br
1: R = 4-Hydroxyphenyl, n = 2
2: R = Methyl, n = 1
Scheme 1.
O
Br
Ph3P
(a)
Br
+
Br
CH3
O
O
O
3
4
H3C
O
5
(b)
O
O
(c)
N
N
CH3
CH3
OH
OCH3
1
6
Scheme 2. Reagents and conditions: (a) aq NaOH, dichloromethane, 84%; (b) CH3NH2ÁHCl, K2CO3, acetonitrile, rt, 7 h, 99%; (c) EtSNa, DMF, 90 °C, 3 h, 92%.
Table 1
Demethylation of 6 under different conditions
No.
Reagent
Temperature (°C)
Reaction time (h)
Yield (%) of 1
1
2
3
4
5
3 equiv BBr3, MDC
4 equiv BBr3, MDC
5 equiv BBr3, MDC
5 equiv LiCl, DMF
5 equiv EtSNa, DMF
rta
rta
rta
130
90
36
36
36
24
3
50
60
60
5
92
a
Addition of the reagent at À78 °C.
result in satisfactory yield of 1, the demethylation was tried under
basic condition employing sodium ethanethiolate (5 equiv) in DMF
at 90 °C. Excellent yield (92%) was obtained under this condition16
and the product obtained did not require further tedious purifica-
tion (Scheme 2, Table 1).
A similar approach has led to the formation of ( )-hygrine (2)
from 4-bromo-1-butanal (7)17 and dimethyl (2-oxopropyl)phos-
phonate (8). The enone formed (9)18 undergoes tandem SN2 substi-
tution and intramoleculer aza-Micheal addition with methylamine
hydrochloride to give 2 (Scheme 3). The tandem process requires

1522
T. Ponpandian, S. Muthusubramanian / Tetrahedron Letters 52 (2011) 1520–1522
CH3
O
O
H3C
N
O
CH3
CH3
CH3
(b)
(a)
P
Br
H
Br
+
O
O
O
O
CH3
2
7
9
8
Scheme 3. Reagents and conditions: (a) NaH, À10 °C, 1 h, 83%; (b) CH3NH2ÁHCl, K2CO3, acetonitrile, 70 °C, 24 h, 85%.
13. Triphenylphosphine (3.4 g, 13.1 mmol) was added to
a solution of 4-
three days for completion, when the reaction was carried out at
room temperature. However, the reaction gets completed within
24 h at 70 °C,19 though the yields were almost same in both the
conditions.
Thus ( )-thalictroidine and ( )-hygrine have been synthesised
through a common strategy involving the tandem SN2 substitu-
tion—aza-Micheal addition as a key step with relatively good
yield and minimum number of steps compared to the reported
methods.
methoxyphenacyl bromide (3 g, 13.1 mmol) in acetonitrile (20 mL) under
nitrogen atmosphere at 20 °C. The reaction mixture was heated in an oil bath
(85 °C) for 2 h, cooled and then poured slowly into diethyl ether (200 mL). The
white solid obtained was filtered and dried to give 4 (92%). mp 228–229 °C; 1
H
dH (400 MHz, CDCl3) d 3.87 (3H, s), 6.22 (2H, d), 6.98 (2H, d), 7.62–7.67 (m, 6H),
7.73–7.75 (m, 3H), 7.91–7.96 (m, 6H), 8.43 (2H, d).
14. To a solution of 4 (5.5 g, 11.2 mmol) in dichloromethane (25 mL) was added
2 M aqueous sodium hydroxide (12 mL). The mixture was stirred at room
temperature for 14 h. The aqueous layer was extracted with dichloromethane
(8 mL). 5-Bromo-1-pentanal 312 (1.85 g, 11.2 mmol) was added to the
dichloromethane extract over a period of 45 min at room temperature. The
reaction mixture was stirred for 1 h. The solvent was removed under vacuum,
and the product was purified by column chromatography (SiO2, ethyl acetate/
hexane, 1:10; Rf 0.25) to yield 5 (84%) as a light-yellow oil. dH (300 MHz, CDCl3)
1.69 (2H, quintet), 1.92 (2H, quintet), 2.35 (2H, quartet), 3.44 (2H, t), 3.87 (3H,
s), 6.89–7.07 (4H, m), 7.95 (2H, d); dC (75 MHz, CDCl3) 26.6, 31.7, 32.1, 33.2,
55.4, 113.7, 125.9, 130.6, 130.7, 147.5, 163.3, 188.8; m/z 297.0.
Acknowledgements
The authors thank DST, New Delhi for assistance under the IRH-
PA program for the NMR facility and Orchid Research Laboratory
Ltd for providing the laboratory facilities.
15.
A suspension of 5 (1 g, 3.4 mmol), methylamine hydrochloride (0.30 g,
4.4 mmol) and potassium carbonate (1.4 g, 10.1 mmol) in acetonitrile
(25 mL) was stirred at room temperature for 7 h. The suspension was filtered
and concentrated to give 6 (99%) as a light-yellow oil. dH (300 MHz, CDCl3)
1.34–1.36 (2H, m), 1.63–1.69, (4H, m), 2.27 (3H, s), 2.58 (1H, br s), 2.80–2.88
(3H, m), 3.32 (1H, dd), 3.87 (3H, s), 6.94 (2H, d), 7.95 (2H, d); dC (75 MHz,
CDCl3) 23.6, 25.7, 32.2, 41.8, 43.5, 55.4, 56.3, 59.6, 113.7, 130.3, 130.4, 163.5,
197.8; m/z 248.1.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.132.
16. To
a slurry of sodium hydride [58 mg, (2.4 mmol) of a 57% mineral oil
dispersion washed twice with n-hexane (8 mL)] in dry DMF (1 mL) cooled to
5 °C was added ethanethiol (126 mg, 2 mmol) in dry DMF (1 mL) dropwise
slowly preventing foaming under nitrogen atmosphere. The mixture was
stirred for 15 min after the addition and then 6 (100 mg, 0.4 mmol) in dry DMF
(1 mL) was added. The resultant mixture was heated at 90 °C for 3 h, cooled to
room temperature, poured into water (20 mL) and extracted with
dichloromethane. The aqueous layer was neutralized with dilute acetic acid,
saturated with sodium chloride and extracted with dichloromethane. The
combined organic solution was dried over anhydrous sodium sulfate, filtered,
and concentrated to give 1 (92%) as a colourless gum. dH (300 MHz, CDCl3)
1.41–1.78 (6H, m), 2.38 (3H, s), 2.40–2.44 (1H, m), 2.85–3.06 (3H, m), 3.40 (1H,
dd), 6.84 (2H, d), 7.82 (2H, d); dC (75 MHz, CDCl3) 196.5, 163.8, 131.0, 128.0,
116.4, 60.0, 56.4, 42.7, 41.2, 31.2, 24.5, 23.3; mmax cmÀ1 (Neat) 3435, 2928,
1660, 1601, 1582, 1166, 847 cmÀ1; m/z 234.1.
References and notes
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18. To a solution of 4-bromo-1-butanal (7)17 (1 g, 6.6 mmol) and dimethyl (2-
oxopropyl)phosphonate 8 (1.1 g, 6.6 mmol) in THF (15 mL) was added sodium
hydride (6 Â 0.03 g, 7.9 mmol, 57% dispersion in mineral oil, in intervals of
10 min) at À10 °C. The reaction mixture was stirred for 1 h at À10 °C. It was
then quenched with water (15 mL) and extracted with ethyl acetate. The
combined organic solution was dried over anhydrous sodium sulfate, filtered
and concentrated. Purification by column chromatography (SiO2, ethyl acetate/
hexane, 1:10; Rf 0.2) gave 9 (83%) as a light yellow oil. dH (300 MHz, CDCl3)
2.00–2.09 (2H, m), 2.26 (3H, s), 2.33–2.45 (2H, m), 3.43 (2H, t), 6.14 (1H, dd),
6.77 (1H, dt); dC (75 MHz, CDCl3) 27.0, 30.6, 30.8, 32.4, 132.0, 145.6, 198.2.
19. A suspension of 9 (100 mg, 0.52 mmol), methylamine hydrochloride (42 mg,
0.63 mmol) and potassium carbonate (220 mg, 1.6 mmol) in acetonitrile (5 mL)
was heated at 70 °C for 24 h. The suspension was filtered and concentrated to
give 2 (63 mg, 0.46 mmol, 85%) as light yellow oil. 1H NMR (400 MHz, CDCl3) d
1.69–1.80 (m, 4H), 2.05–2.13 (m, 1H), 2.16 (s, 3H), 2.31 (s, 3H), 2.40–2.46 (dd,
1H), 2.53–2.56 (m, 1H), 2.78–2.83 (dd, 1H), 3.03–3.07 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 22.2, 31.1, 31.4, 40.6, 48.5, 56.9, 61.9, 208.2; IR mmax cmÀ1
(Neat) 1713; m/z 142.1.