Synthesis of two nuphar alkaloids by allenic hydroxylamine cyclisation

Article abstract of DOI:10.1055/s-0029-1219554

A highly diastereoselective silver-catalysed cyclisation of a 2-substituted β-allenic hydroxylamine is reported. The resulting trans-isoxazolidine is converted into two Nuphar alkaloids by a sequence involving cross-metathesis and intramolecular reductive amination. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219554

866
LETTER
Synthesis of Two Nuphar Alkaloids by Allenic Hydroxylamine Cyclisation
Synthesisof
T
w
o
o
N
uphar
A
lk
d
aloids erick W. Bates,* Chia Juan Lim
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, 637371 Singapore, Singapore
Fax +6567911961; E-mail: Roderick@ntu.edu.sg
Received 6 January 2010
acylation (95%). Several catalysts were screened for the
Abstract: A highly diastereoselective silver-catalysed cyclisation
Claesson cyclisation (Table 1). The highest yield and
of a 2-substituted b-allenic hydroxylamine is reported. The result-
highest selectivity for the trans-isoxazolidine 58 was
ing trans-isoxazolidine is converted into two Nuphar alkaloids by a
achieved using silver triflate in anhydrous dichlo-
romethane. Due to the hygroscopic nature of this salt, mo-
lecular sieves were added to the reaction mixture. It was
found that the diastereoselectivity was distinctly lower
when water was present. To eliminate the possibility that
the cyclisation is due to acid generated by hydrolysis of
the salt,9 the allenic hydroxylamine was treated with tet-
rafluoroboric acid. No cyclisation was observed. The two
isomers of the isoxazolidine 5 were inseparable at this
stage, but could be separated by chromatography after
cleavage of the N–O bond using molybdenum hexacarbo-
nyl.10 The major isomer of amino alcohol derivative 6
proved to be crystalline, and its structure could be con-
firmed by X-ray crystallography (Figure 2).11
sequence involving cross-metathesis and intramolecular reductive
amination.
Key words: piperidines, allenes, cyclisation, silver, alkaloids
Most of the Nuphar alkaloids, trisubstituted piperidine al-
kaloids, were isolated from the Japanese water lily,
Nuphar japonica. One member of the family was isolated
from the scent glands of the North American beaver.1 A
number of syntheses of these alkaloids in both racemic
and optically active forms have been reported.2 In this let-
ter, we wish to report racemic syntheses of nupharamine
(1, Figure 1) and the otherwise unnamed bicyclic Nuphar
alkaloid, 5-(3-furyl)-8-methyloctahydroindolizidine (2),
using the Claesson cyclisation3 of an allenic hydroxyl-
amine to control the 2,3-stereochemistry. We have previ-
ously shown in the syntheses of sedamine4 and
porantheridine5 that this cyclisation is a useful and practi-
cal route to stereochemically defined 1,3-amino alcohols.
These cyclisations employed a b-allenic hydroxylamine
derivative with a substituent at the 1-position. In contrast,
the allenic hydroxylamine required for Nuphar synthesis
would have a methyl group at the 2-position.
1. MeCH2C(OEt)3, AcOH, Δ
2. LiAlH4, Et2O
•
OH
OH
65%
Me
3
1. PhthNOH, DIAD, Ph3P
2. H2NNH2
Ag+
(see Table 1)
•
ONHBoc
3. Boc2O, NaOH
Me
4
74%
Me
Mo(CO)6, NaBH4
MeCN, H2O
OH
O
N
83%
NHBoc
Boc
5
6
N
N
H
OH
O
O
Scheme 1 Allene synthesis and cyclisation
Table 1 Cyclisation of Allene 4
1
2
Figure 1
Entry Catalyst (mol%)
Solvent
trans/cis Yield (%)
The desired allenic substrate was easily prepared on a
multigramme scale by a Johnson–Claisen rearrangement6
involving propargyl alcohol and triethyl orthopropionate
catalysed by acetic acid (Scheme 1). This reaction pro-
ceeded in essentially quantitative yield. Reduction of the
resulting ester group with lithium aluminium hydride
gave the primary allenic alcohol 36b,c which was converted
into the Boc-protected hydroxylamine 4 by the usual se-
quence of Mitsunobu reaction with N-hydroxyphthal-
imide (78%),7 dephthaloylation (quantitative), and
1
2
3
4
5
6
AgNO3 (20)
AgBF4 (35)
acetone–H2O
CH2Cl2
1.7:1
10:1
45
46
23
96
91
0
AgNO3/SiO2 (20) CH2Cl2
7:1
1:1
22:1
–
AgOTf (20)
AgOTf (20)
HBF4 (30)
acetone–H2O
CH2Cl2
CH2Cl2
SYNLETT 2010, No. 6, pp 0866–0868
x
x.
x
x.
2
0
1
0
Advanced online publication: 26.02.2010
DOI: 10.1055/s-0029-1219554; Art ID: D00510ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Two Nuphar Alkaloids
867
Piperidine 12 was converted into nupharamine (1) using a
slight modification of the literature method: N-protection
as a benzyl carbamate, formation of the tertiary alcohol
using excess methylmagnesium bromide, and deprotec-
tion by palladium-catalysed reduction with ammonium
formate.2i Alternatively, heating ester 12 in toluene at
reflux2i,19 yielded the known lactam 13 which was con-
verted into 5-(3-furyl)-8-methyloctahydroindolizidine (2)
by reduction with lithium aluminium hydride in 50% yield
(two steps).2i
Me
OH
Figure 2 X-ray crystal structure of amino alcohol derivative 6
6
NHBoc
Attempts to convert the alcohol group of 6 into a bromide
or iodide were unsuccessful as the halo compounds
proved to be unstable during handling. Therefore, to
achieve the required chain elongation, alcohol 6 was oxi-
dized to aldehyde 7 (Scheme 2). The Swern oxidation
proved to be the best method for this transformation. This
compound, which would undergo epimerization at C2 on
prolonged standing, was immediately coupled with the
furyl phosphonate 812 in a Horner–Wadsworth–Emmons
reaction to give diene 9 in 87% yield from alcohol 6. Use
of barium hydroxide13 proved to be superior to the
Masamune–Roush modification.14 In the latter case, the
reaction failed to go to completion.
Me2SO, (COCl)2,
Et3N, CH2Cl2
O
O
Me
Ba(OH)2
(EtO)2P
O
THF, H2O
+
87% (from 6)
7
8
NHBoc
Me
O
O
CO2Me
HG-II, toluene
9
75%
NHBoc
O
H2 (100 psi)
(Ph3P)3RhCl
toluene
O
Me
MeO2C
94%
10
NHBoc
Me
O
O
The synthesis of nupharamine (1) then required cross-
metathesis15 with commercially available 2-methylbut-3-
en-2-ol. Our attempts to achieve this transformation were
uniformly disappointing due to the steric hindrance en-
cumbering both partners. Cross-metathesis with methyl
acrylate, on the other hand, worked satisfactorily to give
ester 10, although it was necessary to employ the second-
generation Hoveyda–Grubbs catalyst (HG-II, 5 mol%) by
gradual addition to a toluene solution of the substrates at
70 °C16 with continuous bubbling of nitrogen17 to obtain
optimum yield (75%) and conversion. No metathesis was
observed at the internal alkene of 9.
O
1. TFA, CH2Cl2
2. NaBH4, MeOH, 0 °C
MeO2C
85%
11
NHBoc
Δ or MeMgBr
N
MeO2C
N
H
O
O
12
13
O
1. CbzCl, K2CO3
2. MeMgBr
3. HCO2NH4, Pd/C
LiAlH4
50% from 12
49%
Reduction of the two alkenes of ester 10 proved trouble-
some. Both are somewhat hindered and, with palladium
on carbon as the catalyst, hydrogenation even at atmo-
spheric pressure, resulted in reduction of the furan in ad-
dition to the alkenes. Use of Wilkinson’s catalyst with
hydrogen at ambient pressure (balloon) resulted in partial
reduction of the double bond conjugated to the ester.
Clean and complete reduction of both alkenes, without de-
tectable furan reduction was finally achieved using
Wilkinson’s catalyst under hydrogen at 100 psi, cleanly
giving ester 11 in 94% yield.
N
N
H
1
O
OH
2
O
Scheme 2 Nuphar alkaloid synthesis
Racemic, but highly diastereoselective, syntheses of two
Nuphar alkaloids have been completed with a common
isoxazolidine intermediate, generated by a highly stereo-
selective silver-catalysed allenic hydroxylamine cyclisa-
tion, have been completed. Studies on the asymmetric
synthesis are in hand.
Removal of the Boc group in the usual way, followed by
a mildly basic workup yielded a crude tetrahydropyridine
which was directly reduced with sodium borohydride to Acknowledgment
give the desired piperidine 1218 as a single diastereomer,
We thank Nanyang Technological University and the Singapore
Ministry of Education Academic Research Fund Tier 2 (grant
T206B1220RS) for support of this work.
following the procedure of Blechert.2j
Synlett 2010, No. 6, 866–868 © Thieme Stuttgart · New York

868
R. W. Bates, C. J. Lim
LETTER
monoclinic; space group: P2 (1)/n; unit cell dimensions:
References and Notes
a = 11.1651 (4) Å, a = 90°, b = 11.2768 (4) Å, b = 115.343
(2)°, c = 11.1785 (5) Å, g = 90°; volume: 1272.00(9) Å3; Z:
4; density(calcd): 1.124 Mg/m3; absorption coefficient:
0.081 mm–1; F(000): 472; crystal size: 0.30 × 0.30 × 0.14
mm3; q range for data collection: 2.16–27.67°; index ranges:
–14 £ h £ 14, –12 £ k £ 14, –14 £ l £ 14; reflections
collected: 12787; independent reflections: 2983
(1) (a) Arata, Y.; Ohahshi, T. Yakagaku Zasshi 1957, 77, 792.
(b) Maurer, B.; Ohloff, G. Helv. Chim. Acta 1976, 59, 1169.
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E. R. J. Org. Chem. 1980, 45, 3664. (b) Ohnuma, T.; Tabe,
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García, I. Chem. Rev. 2008, 108, 3174.
(4) Bates, R. W.; Nemeth, J.; Snell, R. H. Synthesis 2008, 1033.
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Commun. 1970, 1412. (b) Konegawa, T.; Ohtsuka, Y.;
Ikeda, H.; Sugai, T.; Ohta, H. Synlett 1997, 1297. (c) Ma,
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[R(int) = 0.0586]; completeness to q = 27.67°: 99.9%;
absorption correction; semi-empirical from equivalents;
max. and min. transmission: 0.9888 and 0.9762; refinement
method: full-matrix least-squares on F2; data/restraints/
parameters: 2983/0/144; goodness-of-fit on F2; 1.067; final
R indices [I > 2s(I)]R1 = 0.0652, wR2 = 0.1952; R indices
(all data); R1 = 0.1041, wR2 = 0.2283; largest diff. peak and
hole; 0.425 and –0.298 e Å–3. Details have been deposited
with the Cambridge Crystallographic Data Centre, CCDC
764203, and may be obtained at http://www.ccdc.cam.ac.uk.
(12) Diethyl methylphosphonate (8.71 g, 57.3 mmole) in THF
(30 mL) and added via cannula to a solution of n-BuLi (48
mL of a 1.6 M solution in hexane, 71.6 mmol) in THF (50
mL) at –78 °C. A solution of the Weinreb amide of 3-furoic
acid (6.64 g, 47.7 mmol) in THF (20 mL) and added via
cannula to the mixture. The mixture was stirred for 2 h. 2 M
HCl was added to the mixture, and it was extracted twice
with Et2O. The combined organic layers were dried
(MgSO4), and concentrated to give phosphonate 8 as a
brown oil (15 g, 1.29 mmol, 72%), which was used without
purification. 1H NMR (300 MHz, CDCl3): d = 1.30 (t,
J = 7.05 Hz, 6 H, CH3), 3.39 (d, J = 22.7 Hz, 2 H, PCH2),
4.14 (m, 4 H, CH2), 6.80 (t, J = 1.2 Hz, 1 H, CH), 7.43 (s, 1
H, CH), 8.16 (s, 1 H, CH). 13C NMR (100 MHz, CDCl3):
d = 16.2 (d, J = 5.7 Hz), 40.6 (d, J = 127.8 Hz), 62.7, 108.8,
127.7, 144.2, 149.1, 185.6 (d, J = 6.7 Hz).
(7) (a) Grochowski, E.; Jurczak, J. Synthesis 1976, 682.
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Honda, Y.; Ohnuki, T.; Yukawa, T. Bull. Chem. Soc. Jpn.
1991, 64, 175.
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Synthesis 1985, 1097.
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Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183.
(8) NMR spectroscopic data for the trans isomer: 1H NMR (300
MHz, CDCl3): d = 1.08 (3 H, d, J = 6.8 Hz, CH3), 1.45 (9 H,
s, t-Bu), 2.39 (1 H, m, CH), 3.41 (1 H, t, J = 8.3 Hz, CH2),
3.93 (1 H, t, J = 6.9 Hz, CH), 4.10 (1 H, t, J = 7.2 Hz,CH2),
5.13 (1 H, J = 10.1 Hz, =CH), 5.22 (1 H, J = 17.0 Hz, =CH),
5.76 (1 H, ddd, J = 7.2, 10.2, 16.8 Hz, =CH). 13C NMR (75
MHz, CDCl3): d = 14.5, 28.2, 43.8, 69.1, 75.0, 81.8, 115.8,
136.7, 157.0.
(15) Connon, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003, 42,
1900.
(16) Bieniek, M.; Michrowska, A.; Usanov, D. L.; Grela, K.
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(9) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem. Eur. J. 2004,
10, 484.
Zhao, H. J. Am. Chem. Soc. 2004, 126, 10210.
(18) NMR data for piperidine 12: 1H NMR (400 MHz, CDCl3):
d = 0.89 (d, J = 6.4 Hz, 3 H), 1.10–1.30 (m, 3 H), 1.35–1.50
(1 H, m), 1.55–1.70 (1 H, m), 1.75–1.85 (2 H, m), 1.95–2.05
(1 H, m), 2.25–2.32 (1 H, m), 2.40–2.45 (2 H, m), 3.57 (m,
1 H), 3.65 (s, 3 H), 6.37 (s, 1 H), 7.33 (m, 2 H). 13C NMR
(100 MHz, CDCl3): d = 18.4, 28.6, 30.2, 33.9, 34.1, 35.5,
51.5, 53.2, 62.3, 109.1, 129.5, 138.3, 142.7, 174.5.
(19) Lactam 13 is also obtained if ester 12 is treated directly with
methylmagnesium bromide.
(10) (a) Cicchi, S.; Got, A.; Brandi, A.; Guarna, A.; Sarlos, F. D.
Tetrahedron Lett. 1990, 31, 3351. (b) Zhang, D.; Süling, C.;
Miller, M. J. J. Org. Chem. 1998, 63, 885. (c) Mulvihill, M.
J.; Gage, J. L.; Miller, M. J. J. Org. Chem. 1998, 63, 3357.
(d) Li, F.; Brogan, J. B.; Gage, J. L.; Zhang, D.; Miller, M. J.
J. Org. Chem. 2004, 69, 4538. (e) Yang, Y.-K.; Choi, J.-H.;
Tae, J. J. Org. Chem. 2005, 70, 6995. (f) Calvet, G.;
Blanchard, N.; Kouklovsky, C. Synthesis 2005, 3346.
(11) A suitable crystal was obtained from EtOAc–hexane.
Empirical formula: C11H21NO3; formula weight: 215.29;
temp: 173 (2) K; wavelength: 0.71073 Å; crystal system:
Synlett 2010, No. 6, 866–868 © Thieme Stuttgart · New York