A short and enantiospecific synthesis of (-)-nupharamine

Article abstract of DOI:10.1055/s-2005-918942

A short and convergent synthesis of the naturally occurring sesquiterpenoid piperidine alkaloid (-)-nupharamine is presented starting from (-)-isopinocampheol via cross metathesis and reductive amination as the key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918942

2826
LETTER
A Short and Enantiospecific Synthesis of (–)-Nupharamine
E
nantiosp
u
ecific Synthe
l
sis of
(
i
–)-Nup
a
haramine n Gebauer, Siegfried Blechert*
Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 135, 10623 Berlin, Germany
Fax +49(30)31423619; E-mail: blechert@chem.tu-berlin.de
Received 31 August 2005
O
Abstract: A short and convergent synthesis of the naturally
occurring sesquiterpenoid piperidine alkaloid (–)-nupharamine is
presented starting from (–)-isopinocampheol via cross metathesis
and reductive amination as the key steps.
reductive
amination
1
O
NH
Cbz
5
OH
Key words: catalysis, reductive amination, terpenes, alkaloids,
cross metathesis
Mes N N Mes
O
Cl
Ru
Cl
O
CM
O
6
Aquatic plants of the genus Nuphar (Nymphaeaceae)
have shown to be the source of a large class of terpenoid
alkaloids some of which exhibit immunosuppressive,
antifungal or insecticidal activity.1 As a unique structural
motif, the Nuphar alkaloids share a 3-furyl group and
almost all display a quinolizidine core (Figure 1).
Hoveyda–Blechert
catalyst
NH
Cbz
HO
OH
8
7
Scheme 1 Retrosynthetic analysis.
N
N
mentation of the cyclobutane ring of several pinanes in-
cluding (+)-isopinocampheol has been reported,5 we
envisaged that thermolysis of 8 would furnish dienol 9a as
an adequate substrate for the preparation of the desired
metathesis precursor 7.
O
H
OH
O
O
(–)-nupharamine (1)
(+)-nupharidine (2)
Although the yield of dienol has been rather modest5a
(25%) the multigram availability of enantiopure 8 and its
one-step conversion into 9a as an appropriately substitut-
ed precursor of the correct absolute configuration should
be a fair compensation.
HO
N
N
O
O
OH
CHO
(–)-nupharolutine (3)
(+)-nuphacristine (4)
In our hands flash pyrolysis at 480 °C and 15 mbar in the
gas phase gave a 20:1 mixture6 of the isomeric dienols 9a
and 9b in 23% yield together with 50% of recovered start-
ing material. Since removal of 9b was difficult by column
chromatography we chose to proceed with the mixture
and attempt separation at a later stage. The selective
hydration of trisubstituted double bonds yielding tertiary
alcohols has been successfully achieved either by epoxi-
dation and subsequent ring-opening7 or addition of tri-
fluoro acetic acid (TFA) and subsequent acetate
cleavage.8 For the latter purpose we considered phthal-
imide 10 to be an ideal intermediate as it would allow the
introduction of nitrogen under the required inversion of
configuration through a Mitsunobu reaction and at the
same time eliminate the possibility of acid-promoted in-
tramolecular N-alkylation. Simultaneous N,O-deprotec-
tion and N-reprotection should in turn afford the desired
CM precursor 7.
Figure 1 Selected Nuphar alkaloids.
Isolated from the rhizome of the yellow water lily Nuphar
japonica,2 a perennial herb used as diuretic and stomach
analgesic, (–)-nupharamine (1) is one of only a few ses-
quiterpenoid piperidines and has served as an attractive
target in several enantioselective syntheses.3 On the basis
of our previous work towards the synthesis of substituted
N-heterocycles4 we herein wish to report a short and con-
vergent synthesis of 1 via an olefin cross metathesis (CM)
– reductive amination sequence starting from furyl vinyl
ketone 6 and enantiopure amino alcohol 7, the latter being
derived in three steps from (–)-isopinocampheol (8) as an
inexpensive chiral building block (Scheme 1).
The strategies for the preparation of both CM partners are
outlined in Scheme 2. Since regioselective thermal frag-
Unfortunately, Mitsunobu reaction of 9a,b with 1.1 equiv-
alents of phthalimide, DEAD and PPh3 in THF led to ex-
tensive elimination (ca. 60%) probably due to the high
steric demand of the intermediate phosphonium species.
SYNLETT 2005, No. 18, pp 2826–2828
Advanced online publication: 12.10.2005
DOI: 10.1055/s-2005-918942; Art ID: G28205ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.1
1
.2
0
0
5

LETTER
Enantiospecific Synthesis of (–)-Nupharamine
2827
7
10
a
8
+
OH
9b
OH
9a
a
73%
23%
81%
b
20:1
O
NH
O
b or c
d
NH
OH
Boc
7
NPhth
OH
Cbz
50 or 60%
79%
13
10
5
a
74%
O
H2
2–5%
Pd/C
various
solvents
O
H
OH
e
f
6
94%
65%
O
O
c
O
1
NH
11
12
75%
OH
Boc
Scheme 2 Reagents and conditions: a) 480 °C, 15 mbar, gas phase;
b) phthalimide, MePPh2, DEAD (1.1 equiv each), THF, 0 °C, 1 h; c)
(i) MsCl (1.2 equiv), pyridine, r.t., 2 h; (ii) NaN3 (5 equiv), DMF,
50 °C, 60 h; (iii) LAH (4 equiv), Et2O, 0 °C, 1 h; (iv) phthalic anhy-
dride (1 equiv), THF, 60 °C, 2 h; (v) CDI (2 equiv), THF, r.t., 1 h; d)
(i) 30% TFA (10 equiv) in CHCl3, r.t., 16 h; (ii) MeNH2 (50 equiv),
EtOH, 55 °C, 24 h; (iii) Cbz-Cl (1.1 equiv), aq NaHCO3, CHCl3, r.t.,
16 h; e) vinyl magnesium bromide (1.1 equiv), Et2O, 0 °C, 1 h; f)
MnO2 (10 equiv), CH2Cl2, 40 °C, 24 h.
14
Scheme 3 Reagents and conditions: a) 6 (1.2 equiv), 10 mol% (2-
isopropoxyphenylmethylene)–[1,3-bis(2,4,6-trimethylphenyl)-2-imi-
dazolidinylidene]ruthenium dichloride, CH2Cl2, 40 °C, 72 h; b) (i)
30% TFA (10 equiv) in CHCl3, r.t., 16 h; (ii) MeNH2 (50 equiv),
EtOH, 55 °C, 24 h; (iii) Boc2O (1.1 equiv), aq NaHCO3, CHCl3, r.t.,
16 h; c) (i) H2 (1 atm), 5 mol% Pd/C, acetone, r.t., 15 min; (ii) 10%
TFA in CH2Cl2, r.t., 1 h; (iii) NaBH4 (1 equiv), EtOH, 0 °C, 1 h.
Thus, slightly better results were obtained by using
MePPh2 as the phosphine component, whereas Me2PPh
gave no further improvement.
or the use of other commercial catalysts gave no improve-
ment in this case.
In course of the finishing piperidine formation we were
surprised to find that various attempts to achieve the
intended reductive amination by means of hydrogenolysis
failed due to concomitant reduction of the 3-acyl furan
moiety. As reduction of the conjugated double bond in 5
was fortunately the most rapid process, we reasoned that
its selective hydrogenation followed by N-deprotection
and final diastereoselective hydride reduction of the re-
sulting imine should constitute a simple alternative for
construction of the piperidine ring.12 In consequence, Boc
protection of the crude amino alcohol derived from 1013
followed by CM reaction under the approved conditions
provided the suitable cyclization precursor 14 in good
overall yield.14 Finally, careful hydrogenation of 14 in
aprotic media, Boc cleavage with 10% TFA in CH2Cl2
and treatment of the imine intermediate with NaBH4 in
EtOH produced 1 as a single stereoisomer3c in 75%
yield,15 whose spectroscopic data3d,16 and optical rotation2
In order to overcome this drawback, an alternative two-
step SN2-process was investigated. While mesylation of
9a,b and reaction with phthalimide potassium salt (2
equiv, DMF, 50 °C, 72 h) failed completely, substitution
using sodium azide under the same conditions occurred
smoothly, showing only small amounts of elimination
product. The LAH reduction of the crude azide, treatment
with phthalic anhydride and cyclization of the resulting
phthalamic acid using carbonyldiimidazole (CDI)9 was
therefore found to be an alternative route affording 10 in
60% yield over five steps.
In both cases 10 was obtained as a single diastereomer
after column chromatography.10 Finally, treatment with
TFA in CHCl3, aminolysis with excess methylamine in
EtOH and introduction of the benzyl carbamate furnished
7 in high overall yield.
Addition of vinyl magnesium bromide to 3-furfural (11)
and mild oxidation of the crude carbinol 12 gave rise to
enone 6, which decomposed even at low temperature and
was preferably prepared freshly before use.
20
{[a]D –38.7 (c 0.75, CHCl3)} were in accordance with
the ones reported.
In conclusion, we have described an exceptionally short
and efficient (27% overall yield from 9a,b) approach to
(–)-nupharamine, utilizing commercially available (–)-
isopinocampheol as the only source of chirality. Further-
more, our convergent strategy should enable easy access
to derivatives bearing substituents other than the 3-furyl
group, as well as their enantiomers when starting from
(+)-isopinocampheol.
With both coupling partners in hands, CM reaction of 7
using 10 mol% of the Hoveyda–Blechert catalyst11 and a
slight excess (1.2 equiv) of 6 proceeded slowly, giving the
desired amino enone 5 in 73% yield (Scheme 3). It should
be noted that the application of higher temperatures (60–
80 °C in dichloroethane), larger amounts (2–5 equiv) of 6
Synlett 2005, No. 18, 2826–2828 © Thieme Stuttgart · New York

2828
J. Gebauer, S. Blechert
LETTER
which was dissolved in CHCl3 (4 mL) and treated with sat.
NaHCO3 solution (0.5 mL) followed by Boc2O (120 mg,
0.54 mmol) in 1 mL CHCl3. After 16 h at r.t. H2O (5 mL) was
added and the aqueous phase was extracted with CH2Cl2
(3 × 5 mL). The combined organic phases were dried,
concentrated, diluted with Et2O and filtered. Flash
chromatography (SiO2) of the concentrate gave 97 mg (81%)
of 13 as a clear viscous oil. [a]D20 –7.0 (c 1.0, CHCl3). 1H
NMR (500 MHz, CDCl3): d = 5.76 (m, 1 H), 5.08 (m, 2 H),
4.29 (br d, J = 8.4 Hz, 1 H), 3.57 (m, 1 H), 2.34 (m, 1 H),
1.60–1.30 (m, 5 H), 1.44 (s, 9 H), 1.21 (s, 6 H), 1.03 (d,
J = 6.8 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): d =
156.2, 139.5, 115.9, 79.1, 70.7, 54.8, 41.6, 39.9, 29.6, 29.4,
28.5, 27.9, 16.3 ppm. IR (ATR): n = 3345, 2969, 2932, 1690,
1504, 1365, 1250, 1173, 913 cm–1. HRMS (EI): m/z calcd for
C14H26NO3 [M+ – CH3]: 256.1913; found: 256.1929. Anal.
Calcd for C15H29NO3: C, 66.38; H, 10.77; N, 5.16. Found: C,
66.67; H, 10.58; N, 5.45.
References
(1) See, for example: (a) Cybulski, J.; Wróbel, J. T. In The
Alkaloids, Vol. 35; Brossi, A., Ed.; Academic Press: New
York, 1989, 215–257. (b) Miyazawa, M.; Yoshio, K.;
Ishikawa, Y.; Kameoka, H. J. Agric. Food Chem. 1998, 46,
1059. (c) Michael, J. P. Nat. Prod. Rep. 1999, 16, 675.
(d) Matsuda, M.; Shimoda, H.; Yoshikawa, M. Bioorg. Med.
Chem. 2001, 9, 1031.
(2) Arata, Y.; Ohashi, T. Yakugaku Zasshi 1957, 77, 792.
(3) See, for example: (a) Shimizu, I.; Yamazaki, H. Chem. Lett.
1990, 5, 777. (b) Aoyagi, S.; Shishido, Y.; Kibayashi, C.
Tetrahedron Lett. 1991, 32, 4325. (c) Honda, T.; Ishikawa,
F.; Yamane, S. J. Chem. Soc., Chem. Commun. 1994, 499.
(d) Barluenga, J.; Aznar, F.; Ribas, C.; Valdés, C. J. Org.
Chem. 1999, 64, 3736.
(4) Gebauer, J.; Dewi, P.; Blechert, S. Tetrahedron Lett. 2005,
46, 43.
(5) (a) Schulte-Elte, K. H.; Gadola, M.; Ohloff, G. Helv. Chim.
Acta 1971, 54, 1813. (b) Coxon, J. M.; Garland, R. P.;
Hartshorn, M. P. Aust. J. Chem. 1972, 25, 947.
(6) The ratio of 9a:9b was determined by GCMS.
(7) Kutner, A.; Zhao, H.; Fitak, H.; Wilson, S. R. Bioorg. Chem.
1995, 23, 22.
(8) Cabbalero, E.; Avendaño, C.; Menéndez, J. C. J. Org. Chem.
2003, 68, 6944.
(14) Preparation and Spectral Data of 14.
A solution of amine 13 (27 mg, 0.10 mmol), enone 6 (15 mg,
0.12 mmol) and the Hoveyda–Blechert catalyst (6.3 mg,
0.01 mmol) in dry CH2Cl2 (2 mL) under nitrogen was stirred
for 72 h at 40 °C. The solvent was evaporated and the residue
was purified by flash chromatography (SiO2) to give 27 mg
(74%) of 14 as a brownish solid. Mp 92–94 °C. [a]D20 –24.4
(c 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): d = 8.07 (s, 1
H), 7.45 (s, 1 H), 6.95 (dd, J = 15.5, 8.0 Hz, 1 H), 6.83 (s, 1
H), 6.56 (d, J = 8.0 Hz, 1 H), 4.44 (br d, J = 9.4 Hz, 1 H) 3.69
(m, 1 H), 2.58 (m, 1 H), 1.60–1.30 (m, 5 H), 1.42 (s, 9 H),
1.20 (s, 6 H), 1.13 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (125
MHz, CDCl3): d = 184.4, 156.1, 148.9, 147.6, 144.3, 128.0
127.7, 109.2, 79.4, 70.6, 54.8, 41.6, 39.8, 29.6, 29.4, 28.4,
27.7, 16.3 ppm. IR (ATR): n = 3345, 2970, 2932, 1692,
1668, 1619, 1512, 1365, 1250, 1158, 1055, 873 cm–1. HRMS
(EI): m/z calcd for C16H23NO5 [MH+ – C(CH3)3]: 309.1576;
found: 309.1580. Anal. Calcd for C20H31NO5: C, 65.73; H,
8.55; N, 3.83. Found: C, 65.28; H, 8.07; N, 3.63.
(9) Miller, D. J.; Hammond, S. M.; Anderluzzi, D.; Bugg, T. D.
H. J. Chem. Soc., Perkin Trans. 1 1998, 131.
(10) Preparation and Spectral Data of 10.
To a stirred solution of alcohol 9a,b (154 mg, 1.0 mmol),
phthalimide (162 mg, 1.1 mmol) and MePPh2 (220 mg, 1.1
mmol) in dry THF (5 mL) under nitrogen was added DEAD
(191 mg, 1.1 mmol) dropwise at 0 °C. The mixture was
allowed to warm to r.t. over a period of 1 h before it was
diluted with Et2O, filtered and concentrated. Flash
chromatography (SiO2) of the resulting residue gave 140 mg
(50%) of 10 as a colorless oil. [a]D20 –18.8 (c 0.85, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.78 (m, 2 H), 7.67 (m, 2
H), 5.58 (m, 1 H), 4.97 (t, J = 7.0 Hz, 1 H), 4.91 (dd,
J = 16.9, 1.0 Hz, 1 H), 4.76 (dd, J = 10.1, 1.0 Hz, 1 H), 3.99
(dt, J = 11.0, 4.1 Hz, 1 H), 3.00 (m, 1 H), 2.85 (m, 1 H), 2.45
(m, 1 H), 1.53 (s, 3 H), 1.52 (s, 3 H), 1.14 (d, J = 6.7 Hz, 3
H) ppm. 13C NMR (125 MHz, CDCl3): d = 168.8, 141.2,
134.6, 133.7, 131.8, 123.0, 120.3, 115.1, 56.8, 41.1, 28.4,
25.7, 18.4, 17.8 ppm. IR (ATR): n = 2973, 2928, 1772, 1710,
1390, 1361, 1088, 919, 874, 721 cm–1. HRMS (EI): m/z calcd
for C18H21NO2 [M+]: 283.1572; found: 283.1577. Anal.
Calcd for C18H21NO2: C, 76.30; H, 7.47; N, 4.94. Found: C,
75.92; H, 7.55; N, 4.64.
(15) Preparation and Spectral Data of (–)-Nupharamine (1).
To a solution of aminoenone 14 (35 mg, 0.096 mmol) in
acetone (2 mL) was added 10% Pd/C (6 mg, 0.005 mmol) at
r.t. and the heterogeneous mixture was stirred under 1 atm of
hydrogen for 15 min. Filtration and evaporation of the
solvent gave a residue which was dissolved in CH2Cl2 (1
mL), treated with TFA (0.1 mL) and stirred for 1 h. The
solution was then diluted with CH2Cl2 (20 mL), washed with
sat. NaHCO3 solution (5 mL), dried and concentrated. To the
crude imine were added EtOH (1 mL) and at 0 °C NaBH4 (4
mg, 0.1 mmol). After 1 h the solvent was evaporated and the
residue was purified by flash chromatography (Al2O3) to
give 18 mg (75%) of a yellow oil. [a]D20 –38.7 (c 0.75,
CHCl3), {lit.2 [a]D22 –35.4 (CHCl3)}. 1H NMR (500 MHz,
CDCl3): d = 7.34 (m, 2 H), 6.41 (s, 1 H), 3.61 (dd, J = 11.5,
2.0 Hz, 1 H), 2.38 (m, 1 H), 1.85 (m, 2 H), 1.75 (m, 2 H), 1.57
(m, 2 H), 1.45 (m, 2 H), 1.23 (m, 1 H), 1.21 (s, 3 H), 1.19 (s,
3 H), 0.90 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): d = 143.1, 138.5, 129.0, 109.3, 68.9, 63.0, 53.1,
39.7, 34.3, 34.0, 33.7, 30.3, 29.3, 28.5, 18.6 ppm. IR (ATR):
n = 3385, 2966, 2926, 2871, 2850, 1458, 1377, 1161, 1025,
912, 874, 794, 765 cm–1. HRMS (EI): m/z calcd for
(11) For a short review on its unique activity, see: (a) Connon,
S. J.; Blechert, S. Angew. Chem. 2003, 115, 1944.
(b) Hoveyda, H. A.; Gillingham, D. G.; Van Veldhuizen,
J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.; Harrity,
J. P. A. Org. Biol. Chem. 2004, 2, 8.
(12) Boivin, J.; Pothier, J.; Zard, S. Z. Tetrahedron Lett. 1999, 40,
3701.
(13) Preparation and Spectral Data of 13.
To a stirred solution of 10 (140 mg, 0.5 mmol) in CHCl3 (1.2
mL) was added TFA (0.4 mL, 5.0 mmol) dropwise at 0 °C.
After 16 h at r.t. the volatiles were removed in vacuo. To the
residue was added a 8 M solution of MeNH2 in EtOH (3 mL,
24 mmol) and the mixture was stirred at 55 °C for 24 h.
Evaporation of the volatiles gave the crude amino alcohol
C15H25NO2 [M+]: 251.1885; found: 251.1890..
(16) Itatani, Y.; Yasuda, S.; Hanaoka, M.; Arata, Y. Chem.
Pharm. Bull. 1976, 24, 2521.
Synlett 2005, No. 18, 2826–2828 © Thieme Stuttgart · New York