Enantioselective total syntheses of (-)-isonitramine, (-)-sibirine, and (+)-nitramine by ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.201101256

Concise enantioselective total syntheses of naturally occurring 2-azaspiro[5,5]undecan-7-ol (Nitraria) alkaloids viz. (-)-isonitramine, (-)-sibirine, and (+)-nitramine are accomplished in 42, 38, and 25 % overall yield, respectively, in six steps starting

Full text of DOI:10.1002/ejoc.201101256

FULL PAPER
DOI: 10.1002/ejoc.201101256
Enantioselective Total Syntheses of (–)-Isonitramine, (–)-Sibirine, and
(+)-Nitramine by Ring-Closing Metathesis
Ganesh Pandey,*[a] Prasanna Kumara C,[a] Shiva Kumar Burugu,[a] and
Vedavati G. Puranik[b]
Keywords: Allylation / Amino alcohols / Alkaloids / Metathesis / Total synthesis
Concise enantioselective total syntheses of naturally occur-
ring 2-azaspiro[5,5]undecan-7-ol (Nitraria) alkaloids viz. (–)-
isonitramine, (–)-sibirine, and (+)-nitramine are ac-
complished in 42, 38, and 25% overall yield, respectively, in
six steps starting from enantiomerically pure (S)-methyl 3-allyl-
2-oxo-1,2,3,6-tetrahydropyridine-3-carboxylate (Ͼ99%ee).
The key feature of the syntheses involves diastereoselective
Hosomi–Sakurai allylation followed by ring-closing meta-
thesis.
Introduction
The spiropiperidine structural subunit found in a variety
of naturally occurring and synthetically derived products
displays interesting biological properties. For instance, the
1-azaspiro[5, 5]undecane-8-ol alkaloid histrionicotoxin (1)
isolated from the skin of the neotropical poisonous frog
Dendrobates histrionicus is a very potent nicotinic receptor
antagonist,[1a] whereas pinnaic acid (2), a novel polyketide
containing a 6-azaspiro[4,5]decane subunit, isolated from
Okinawan bivalve Pinna muricata has shown phospholi-
pase A2 (PLA2) inhibitory activity.[1b] Similarly, synthetic
spiro[piperidine-2,2Ј-adamantane] (3) has proved to be
active against influenza viruses.[1c] The three structurally re-
lated spiropiperidine alkaloids, viz. (–)-isonitramine (4),
(–)-sibirine (5), and (+)-nitramine (6), isolated[2] from Nitra-
ria sibrica and Nitraria Schoberi have received considerable
synthetic and pharmacological interest due to the potent
biological activity in the class of γ-amino alcohols and due
to their resemblance with the basic molecular framework of
the neurotoxin histrionicotoxin (1, Figure 1). Generally,
most of these alkaloids are isolated as racemates[3] despite
the presence of many stereocenters. Although, several race-
mic[4] syntheses of one or more of these alkaloids have ap-
peared since their isolation, only a few enantioselective[5]
syntheses are known. Moreover, only a few general strate-
gies enabling the production of all of these three alkaloids
in the natural configurations have also appeared.[5a,5g]
Figure 1. Representatives of azaspiroalkaloids.
The stereocontrolled construction of the secondary hy-
droxy and the adjacent all-carbon quaternary stereogenic
center is difficult and poses a significant challenge for the
syntheses of these deceptively simple-looking molecules.
Existing synthetic routes[5] have generally relied on the for-
mation of either a C–N or C–C bond of the spiro carbon
atom, that is, C1–C6, C5–C6, or C6–C7. A plausible simpler
strategy with the formation of the C10–C9 bond from a suit-
able precursor has remained unexplored. In this context,
[a] Division of Organic Chemistry, National Chemical Laboratory,
Homi Bhabha Road, Pune-411008, India
Fax: +91-020-2590-2628
E-mail: gp.pandey@ncl.res.in
[b] Centre for Materials Characterization,
National Chemical Laboratory,
Homi Bhabha Road, Pune-411008, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101256.
Figure 2. Existing key disconnections of the spiro skeleton.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7372–7377

Total Syntheses of (–)-Isonitramine, (–)-Sibirine, and (+)-Nitramine
we have evaluated a ring-closing metathesis (RCM) strategy
from 9 (Ͼ99%ee), recently synthesized for the construction
of (+)-vincadifformine from our group,[6] and report herein
a short enantioselective syntheses of all the three (i.e., 4, 5,
and 6) naturally occurring Nitraria alkaloids (Figure 2) in
optically pure form.
Results and Discussion
In continuation of our interest in the syntheses of Aspi-
dosperma alkaloids,[6] we became interested in developing a
new and concise route for the syntheses of Nitraria alk-
aloids from optically pure precursor 9 (Ͼ99%ee) and
viewed their syntheses through the strategy depicted retro-
synthetically in Scheme 1. The syntheses of (–)-isonitramine
Scheme 1. Retrosynthetic analysis of (–)-isonitramine, (–)-sibirine,
and (+)-nitramine.
Our initial attempt at RCM[7] of 7a by using Grubbs first
(4) and (–)-sibirine (5) commenced with the transformation generation catalyst failed to give expected product 11.
of enantiopure 9 (Ͼ99%ee) into 10 by lithium aluminum Therefore, we carried out this reaction with Grubbs second
hydride reduction followed by N-Cbz protection {81% generation catalyst, which pleasingly afforded 11 in 85%
yield, [α]2D6 = +1.16 (c = 1.21, CHCl3)}. The oxidation of yield. Hydrogenation of 11 over Pd/C (5%) in methanol
10 by using 2-iodoxybenzoic acid (IBX) in ethyl acetate un- gave 4 in 90% yield {[α]2D5 = –4.9 (c = 1.1, CHCl3); ref.[5f]
der reflux afforded 8 in 96% yield {[α]2D6 = +166.83 (c = [α]D25 = –4.5 (c = 0.24, CHCl3)}. Similarly, reduction of 11
1.01, CHCl3)}. Allylation of 8 with allylmagnesium brom- in the presence of aqueous formaldehyde[8] gave (–)-sibirine
ide though gave desired 7 albeit in low yield (Ͻ15%). (5) in 82% yield {[α]2D5 = –23.1 (c = 0.76, CHCl3); ref.[5g]
Therefore, we resorted to Hosomi–Sakurai’s protocol in- [α]2D5 = –25.4 (c = 0.4, CHCl3)}. The spectroscopic data of
volving the use of allyltrimethylsilane in the presence of 4 and 5 were in good agreement with the literature da-
BF3·Et2O, which gave desired 7 in 92% yield [78:22dr ta.[5e,5j] Finally, the absolute structure of 4 was also con-
(α/β)]. The formation of the major diastereomer can poss- firmed by X-ray diffraction analyses.[9]
ibly be explained through a Felkin–Anh model (Scheme 2).
Fortunately, both diastereomers of 7 were separable by flash (+)-nitramine (6) also from corresponding 13a, speculated
column chromatography.
to be formed by chelation-controlled allylation[10] of 12. It
Encouraged by these results, we envisaged synthesizing
Scheme 2. Syntheses of (–)-isonitramine and (–)-sibirine. Reagents and conditions: (a) LAH, THF, reflux, 8 h; (b) CbzCl, NaHCO3,
dioxane/water, r.t., 5 h, 81%; (c) IBX, EtOAc, reflux, 8 h, 96%; (d) allyltrimethylsilane, CH2Cl2, BF3·OEt2, –78 °C, 6 h, 92%; (e) Grubbs
2nd generation catalyst, CH2Cl2, reflux, 5 h, 85%; (f) Pd/C, MeOH, H2, 5 h, 90%; (g) Pd/C, MeOH, aq. HCHO, H2, MeOH, 30 h, 82%.
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G. Pandey, C. Prasanna Kumara, S. Kumar Burugu, V. G. Puranik
FULL PAPER
was visualized that reaction of 12 with allyltrimethylsilane CH2Cl2); ref.[5a] [α]D25 = +23.0 (c = 1.58, CH2Cl2)}
in the presence of a Lewis acid (e.g., SnCl4 and/or TiCl4) (Scheme 3). All the spectroscopic data were in good agree-
may involve a hexacoordinate metal chelate complex direct- ment with the literature report.[5h]
ing the approach of the nucleophilic allyltrimethylsilane,
possibly from the least-hindered face of the conformation-
ally locked (Cram-chelate model) carbonyl group (Fig-
ure 3).
Conclusions
In summary, we have developed an efficient enantioselec-
tive synthetic route to (–)-isonitramine, (–)-sibirine, and (+)-
nitramine in 42, 38, and 25% overall yield, respectively. The
key feature of the syntheses involved diastereoselective Ho-
somi–Sakurai allylation followed by ring-closing metathesis.
Experimental Section
Figure 3. Speculative generation of 13a through a Cram–chelate-
General Remarks: All air- and moisture-sensitive reactions were
performed under an atmosphere of argon with oven-dried (125 °C)
glassware. Anhydrous tetrahydrofuran (THF) was distilled from so-
dium/benzophenone. Dichloromethane (DCM) was distilled from
calcium hydride and stored over 4 Å molecular sieves. Solvents
used for chromatography were distilled at their respective boiling
points by using known procedures. All reagents and solvents were
purchased from commercial sources. Reactions were monitored by
type model.
In order to evaluate our proposed hypothesis, 12 ob-
tained in 66% yield from 9 by simple functional group
transformations was treated with allyltrimethylsilane in
CH2Cl2 in the presence of SnCl4 at –78 °C to give corre-
sponding allylated product 13 in 87% yield [96:4dr (β/α);
HPLC, Chiralcel OD-H (250ϫ4.6 mm) column, isopro-
thin-layer chromatography (TLC, 0.25 mm silica gel plates, 60F254
)
panol/n-hexane
= λ =
15:85, 0.5 mLmin–1 (25 Kgf),
and visualized by UV light, ethanolic solution of phosphomolybdic
acid, and iodine. Column chromatography was performed on silica
gel 60–120/100–200/230–400 mesh obtained from commercial
sources. Typical syringe and cannula techniques were used to trans-
fer air- and moisture-sensitive reagents. Melting points were
225 nm, 25 °C)].
To improve the yield as well as the diastereomeric ratio,
the same reaction was also carried out by using TiCl4; how-
ever, there was no significant improvement in the dia-
stereomeric ratio [83% yield, 97.4:2.6dr (β/α)].[11] RCM of
13a under reaction conditions identical to those described
above for 7a afforded 14 (81%), which upon usual hydro-
genation furnished 15 in 94% yield. X-ray diffraction analy-
sis[9] of recrystallized 15 confirmed its absolute configura-
tion. Lithium aluminum hydride reduction of 15 produced
(+)-nitramine (6) in 60% yield {[α]2D5 = +21.4 (c = 0.3,
measured with a Thermonik melting point apparatus. H and 13C
1
NMR spectra were recorded with Bruker AC-200, AV-400, and
DRX 500 instruments in deuteriated solvents. 13C NMR chemical
shifts are reported in ppm relative to the central line of CDCl3 (δ =
77.0 ppm). Electrospray ionization (ESI) mass spectrometry (MS)
experiments were recorded with a Finnigan Mat-1020 spectrometer
and were performed to obtain molecular mass of the compound.
High-resolution mass spectrometric data were obtained by using
an MSI Concept through direct insertion probe. Optical rotations
were measured with a JASC P-1030 Polarimeter.
(S)-Benzyl
5-Allyl-5-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-
carboxylate (10): To an ice-cooled stirred slurry of lithium alumi-
num hydride (0.47 g, 12.41 mmol) in anhydrous THF (12 mL) was
added a solution of 9 (0.2 g, 1.03 mmol) in anhydrous THF (4 mL).
The reaction mixture was warmed to room temperature and heated
at reflux for 8 h. The reaction was cooled to room temperature,
quenched carefully with moist Na2SO4, and filtered, and the resi-
due was washed with DCM and concentrated. To a solution of the
resulting crude amino alcohol dissolved in dioxane/water (1:1,
6 mL) was added sodium hydrogen carbonate (0.17 g, 2.06 mmol)
followed by the slow addition of benzyl chloroformate (0.16 mL,
1.13 mmol) in dioxane (1 mL) under vigorous stirring at 0 °C. The
reaction mixture was stirred for another 5 h at ambient tempera-
ture, and dioxane was evaporated. Water (20 mL) was poured into
the residue, which was extracted with ethyl acetate (3ϫ20 mL). The
combined organic layers were dried with Na2SO4, filtered, concen-
trated under reduced pressure, and purified by column chromatog-
raphy (SiO2; EtOAc/petroleum ether, 2:8) to afford 10 as a colorless
Scheme 3. Synthesis of (+)-nitramine and ORTEP diagram of 15.
Reagents and conditions: (a) NaBH4, CeCl3·7H2O, r.t., 48 h, 78%;
(b) IBX, EtOAc, reflux, 8 h, 85%; (c) allyltrimethylsilane, SnCl4/
TiCl4, CH2Cl2, –78 °C, 87%; (d) Grubbs 2nd generation catalyst,
CH2Cl2, r.t., 3 h, 81%; (e) Pd/C, H2, MeOH, r.t., overnight, 94%;
(f) LAH, THF, r.t., 80 h, 60%.
oil (0.24 g, 81%). Rf = 0.28 (EtOAc/petroleum ether, 3:7). [α]2D6
=
+1.16 (c = 1.21, CHCl ). IR (film, CHCl ): ν = 3434, 2925, 1683,
˜
3
3
1434, 1237 cm–1. H NMR (400 MHz, CDCl3): δ = 7.35–7.30 (m,
5 H), 5.81–5.59 (m, 3 H), 5.15–5.06 (m, 4 H), 4.20–4.09 (m, 1 H),
3.93–3.68 (m, 2 H), 3.33 (app. s, 2 H), 3.12, 2.87 (2 d, J = 13.0 Hz, 1
1
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Total Syntheses of (–)-Isonitramine, (–)-Sibirine, and (+)-Nitramine
H), 2.26–2.11 (m, 2 H), 1.87 (br. s, 1 H) ppm. 13C NMR (100 MHz,
was added Grubbs 2nd generation catalyst (21 mg, 7 mol-%). The
CDCl3) (rotamers): δ = 156.51 (155.57), 136.6, 133.7, 130.6 (129.8), solution was heated to reflux for 5 h, at which point TLC analysis
128.6, 128.2, 128.0, 125.1 (125.7), 118.3, 67.5, 65.7 (65.8), 46.1 indicated the reaction was complete. The reaction mixture was then
(46.4), 43.9 (43.7), 41.3, 36.9 ppm. HRMS (EI): calcd. for concentrated. Purification by flash column chromatography
C17H21NO3: 287.15214; found 287.14669.
(DCM/acetone, 10:0Ǟ9.8:0.2) afforded 11 (0.09 g, 85%). Rf = 0.3
(acetone/DCM, 0.3:9.7). [α]2D5 = +57.61 (c = 1.07, CHCl3). IR (film,
(S)-Benzyl 5-Allyl-5-formyl-5,6-dihydropyridine-1(2H)-carboxylate
(8): To a solution of 10 (0.1 g, 0.34 mmol) dissolved in ethyl acetate
(7 mL) was added IBX (0.19 g, 0.68 mmol). The resulting suspen-
sion was heated at reflux for 8 h, cooled to room temperature, and
filtered through a pad of Celite. The filtrate cake was washed with
ethyl acetate (2ϫ4 mL), and the combined filtrates were concen-
trated to give aldehyde 8 as a colorless sticky liquid (0.095 g, 96%).
Rf = 0.38 (EtOAc/petroleum ether, 2:8). [α]2D6 = +166.83 (c = 1.01,
CHCl ): ν = 3450, 3029, 2898, 1686, 1432, 1238 cm–1. 1H NMR
˜
3
(500 MHz, CDCl3): δ = 7.34–7.28 (m, 5 H), 5.87 (app. dt, J = 2.46,
10.24 Hz, 1 H), 5.76 (d, J = 8.53 Hz, 1 H), 5.59 (br. s, 2 H), 5.13
(br. s, 2 H), 3.95 (m, 2 H), 3.71 (br. s, 1 H), 3.56–3.25 (m, 2 H),
2.39–2.28 (m, 1 H), 2.08–1.93 (m, 4 H) ppm. 13C NMR (125 MHz,
CDCl3, rotamers): δ = 155.8, 136.5 130.0, 128.3, 127.9, 127.7,
124.6, 123.5 (122.9), 71.7 (71.0), 67.1, 48.6, 43.5, 38.8, 32.6,
31.4 ppm. HRMS (EI): calcd. for C18H21NO3 299.15214; found
299.15306.
CHCl ). IR (film, CHCl ): ν = 3017, 2849, 1722, 1702, 1431,
˜
3
3
1238 cm–1. 1H NMR (400 MHz, CDCl3, rotamers): δ = 9.53 (9.50)
(2 s, 1 H), 7.35–7.29 (m, 5 H), 5.99, 5.91 (2 app. d, J = 9.5 Hz, 1
H), 5.74–5.65 (m, 2 H), 5.15–5.09 (m, 4 H), 4.18–3.99 (m, 2 H),
(–)-Isonitramine (4): To a solution of 11 (0.108 g, 0.36 mmol) in
anhydrous MeOH (10 mL) was added Pd/C (0.075 g). The suspen-
3.85–3.78 (m, 1 H), 3.28,3.17 (2d, J = 13.3 Hz, 1 H), 2.37–2.33 (m, sion was allowed to stir for 5 h at room temperature under an at-
2 H) ppm. 13C NMR (100 MHz, CDCl3, rotamers): δ = 200.8,
mosphere of hydrogen. The suspension was filtered through Celite
155.7 (155.4), 141.8, 136.4, 133.8 (133.3), 131.7 (131.9), 128.6 and concentrated under reduced pressure. Purification by flash col-
(128.2), 128.1 (127.3), 125.5 (124.9), 119.6, 67.6, 51.5, 44.9, 43.2, umn chromatography (CHCl3/MeOH/NH3(aq.), 46:50:4; Rf = 0.3)
37.8 ppm. HRMS (EI): calcd. for C17H19NO3 285.13649; found
285.13631.
afforded solid 4, which upon crystallization with ethyl acetate/pe-
troleum ether gave colorless crystals. M.p. 94.7–95.5 °C. [α]2D5 = –4.9
(c = 1.1, CHCl3) {ref.[5f] [α]2D5 = –4.5 (c = 0.24, CHCl3)}. IR (film,
(S)-Benzyl 5-Allyl-5-[(S)-1-hydroxybut-3-enyl]-5,6-dihydropyridine-
1(2H)-carboxylate (7): A solution of aldehyde 8 (0.287 g, 1 mmol)
in anhydrous DCM (34 mL) at –78 °C under an argon atmosphere
was treated with BF3·OEt2 (0.31 mL, 2.51 mmol). After 15 min, al-
lyltrimethylsilane (0.31 mL, 2 mmol) was added, and the resulting
solution was stirred for 6 h at –78 °C. The reaction was poured into
saturated aqueous NaHCO3 solution (10 mL) and extracted with
DCM (3ϫ30 mL). The extracts were combined, washed with brine
(25 mL), dried with Na2SO4, filtered, and concentrated under re-
duced pressure. The crude residue upon flash column chromato-
graphic separation afforded major isomer 7a (0.23 g) and minor
isomer 7b (0.067 g) as a colorless oil. Total yield: 0.3 g (92%). Rf
= 0.5 (minor), 0.42 (major; acetone/DCM, 0.2:9.8; p-anisaldehyde
staining solution). Data for major isomer 7a: [α]2D6 = +20.49 (c =
1
CHCl ): ν = 3407, 2933, 1215 cm–1. H NMR (400 MHz, CDCl ):
˜
3
3
δ = 3.78–3.44 (br. s, 2 H), 3.62 (dd, J = 3.51, 11.29 Hz, 1 H), 3.01
(br. d, J = 10.8 Hz, 1 H), 2.91 (d, J = 11.29 Hz, 1 H), 2.57 (td, J
= 3.26, 11.55 Hz, 1 H), 2.49 (d, J = 11.3 Hz, 1 H), 2.22 (d, J =
14 Hz, 1 H), 2.08–1.97 (m, 1 H), 1.72–1.66 (m, 2 H), 1.56–1.43 (m,
2 H), 1.39–1.32 (m, 2 H), 1.27–1.15 (m, 2 H), 1.08–1.03 (m, 1 H),
0.97–0.90 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 80.4,
60.6, 47.1, 36.6, 36.1, 29.6, 28.6, 24.2, 23.0, 20.2 ppm. HRMS (EI):
calcd. for C10H19NO 169.14666; found 169.14445.
(–)-Sibirine (5): Aqueous formaldehyde (37% solution, 0.1 mL,
1.1 mmol) was added to a stirred solution of carbamate 11 (0.033 g,
0.11 mmol) in distilled methanol (5 mL). The reaction mixture was
stirred at room temperature under an atmosphere of hydrogen in
the presence of a catalytic amount of Pd/C (0.02 g) for 30 h. After
1.18, CHCl ). IR (film, CHCl ): ν = 3454, 2912, 1698, 1435,
˜
3
1
3
1240 cm–1. H NMR (500 MHz, CDCl3): δ = 7.35–7.28 (m, 5 H), completion of the reaction, the reaction mixture was filtered
5.78–5.65 (m, 4 H), 5.13–5.03 (m, 6 H), 4.01–3.86 (m, 2 H), 3.75– through a pad of Celite, concentrated, and subjected to column to
3.65 (m, 1 H), 3.52 (d, J = 10.45 Hz, 1 H), 3.35–3.26 (m, 1 H), 2.34 chromatography afford 5 as a colorless oil (0.016 g, 82%). [α]2D5
(dd, J = 6.6, 13.75 Hz, 2 H), 2.11–2.03 (m, 2 H), 1.73 (br. s, 1
–23.1 (c = 0.76, CHCl3) {ref.[5g] [α]2D5 = –25.4 (c = 0.4, CHCl3)}.
H) ppm. 13C NMR (125 MHz, CDCl3, rotamers): δ = 155.6 1H NMR (400 MHz, CDCl3): δ = 0.84–1.0 (m, 2 H), 1.16–1.27 (m,
=
(155.5), 136.6, 135.8 (135.7), 134.0, 130.2 (129.9), 128.4, 127.9,
124.8 (124.3), 118.0, 74.4 (73.8), 67.1, 45.3, 43.3, 42.4, 39.4,
36.6 ppm. HRMS (EI): calcd. for C20H25NO3 327.18344; found
327.18377. Data for minor isomer 7b: [α]2D6 = +19.56 (c = 0.77,
2 H), 1.33–1.40 (m, 2 H), 1.44–1.54 (m, 2 H), 1.68–1.74 (m, 2 H),
1.85–1.95 (m, 2 H), 2.07–2.17 (m, 2 H), 2.21 (s, 3 H), 2.60 (d, J =
11.3 Hz, 1 H), 2.79 (br. d, J = 7 Hz, 1 H), 3.58 (dd, J = 11.2,
3.2 Hz, 1 H), 3.21–3.86 (v. br., 1 H, OH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 20.32, 23.0, 24.0, 27.5, 29.4, 37.0, 37.1,
CHCl ). IR (film, CHCl ): ν = 3454, 2912, 1698, 1435, 1240 cm–1.
˜
3
3
1H NMR (500 MHz, CDCl3): δ = 7.35–7.31 (m, 5 H), 5.89–5.59 46.4, 56.3, 69.8, 80.4 ppm. HRMS (EI): calcd. for
(m, 4 H), 5.15–5.02 (m, 6 H), 4.19–4.10 (m, 1 H), 4.0 (3.85) (2 d,
J = 13.48 Hz, 1 H), 3.77–3.70 (m, 1 H), 3.46–3.40 (m, 1 H), 3.10
(2.93) (2 d, J = 13.48 Hz, 1 H), 2.34–2.16 (m, 4 H), 1.82 (1.76)
(app. br. s, 1 H) ppm. 13C NMR (125 MHz, CDCl3, rotamers): δ =
156.4 (155.41), 136.5 (135.8), 134.15 (134.09), 131.7 (130.4), 128.58
(128.50), 128.17 (128.07), 127.8, 125.3 (124.8), 117.8 (117.7), 116.7,
73.8 (73.2), 67.3 (67.1), 45.8 (45.7), 43.7 (43.4), 43.15 (43.07), 36.9
(36.4), 35.7 (35.4) ppm. MS (ESI): m/z = 328.13 [M + H]+, 350.11
[M + Na]+, 366.11 [M + K]+. C20H25NO3 (327.42): calcd. C 73.37,
H 7.70, N 4.28; found C 73.24, H 7.61, N 4.21.
C11H21NO183.16231; found 183.16196.
(R)-3-Allyl-3-(hydroxymethyl)-1,6-dihydropyridin-2(3H)-one (9a):
To a suspension of NaBH4 (390 mg, 10.03 mmol) and cerium chlor-
ide heptahydrate (529 mg, 1.42 mmol) in ethanol (6 mL) was added
dropwise a solution of 9 (190 mg, 0.97 mmol) in ethanol (2 mL)
over 1 h. The reaction mixture was stirred for 2 d at room tempera-
ture, then poured into a saturated aqueous NH4Cl solution, and
extracted with DCM (3ϫ15 mL). The combined organic layers
were dried with Na2SO4, filtered, and evaporated under reduced
pressure. This residue was purified by column chromatography
(acetone/petroleum ether, 1:1) to afford 9a (126 mg, 78%) as a col-
(6S,11S)-Benzyl
11-Hydroxy-2-azaspiro[5,5]undeca-4,8-diene-2-
carboxylate (11): To a degassed solution of 7a (0.119 g, 0.36 mmol)
orless liquid. Rf = 0.33 (acetone/petroleum ether, 6:4). [α]2D5
=
in anhydrous DCM (10 mL) under an argon atmosphere at 20 °C
–26.8050 (CHCl c = 0.4). IR (film, CHCl ): ν = 3400, 3020, 1697,
˜
3
3
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G. Pandey, C. Prasanna Kumara, S. Kumar Burugu, V. G. Puranik
FULL PAPER
1215, 759 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.66 (br. s, 1 H),
5.96–5.90 (m, 1 H), 5.74–5.64 (m, 1 H), 5.46 (d, J = 10.29 Hz, 1
H), 5.12–5.05 (m, 2 H), 3.94 (br. s, 2 H), 3.71 (d, J = 10.79 Hz, 1
(dd, J = 7.33, 13.43 Hz, 1 H), 2.05–1.99 (m, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 174.6, 135.7, 132.9, 127.7, 121.6, 118.7,
116.6, 76.2, 49.5, 43.0, 40.8, 38.3 ppm. MS (ESI): m/z = 208.27 [M
H), 3.57 (d, J = 10.79 Hz, 1 H), 2.76–2.68 (m, 2 H), 2.16 (dd, J = + H]+. C12H17NO2 (207.27): calcd. C 69.54, H 8.27, N 6.76; found
7.03, 13.55 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 174.5,
132.7, 127.5, 122.7, 118.4, 68.0, 47.7, 43.2, 39.2 ppm. MS (ESI):
m/z = 168.31 [M + H]+, 190.25 [M + Na]+. C9H13NO2 (167.21):
calcd. C 64.65, H 7.84, N 8.38; found C 64.51, H 7.78, N 8.26.
C 69.51, H 8.30, N 6.70.
(6R,11R)-11-Hydroxy-2-azaspiro[5,5]undeca-4,8-dien-1-one (14): To
a degassed solution of 13a (30 mg, 0.144 mmol) in anhydrous
DCM (5 mL) under an argon atmosphere at room temperature was
added Grubbs 2nd generation catalyst (8.6 mg, 7 mol-%). The solu-
tion was stirred at room temperature for 3 h, at which point TLC
analysis indicated the reaction was complete. The reaction mixture
was adsorbed over silica gel and purified by flash column
chromatography (ethyl acetate/petroleum ether, 1:1) to afford 14 as
(R)-3-Allyl-2-oxo-1,2,3,6-tetrahydropyridine-3-carbaldehyde (12): To
a solution of alcohol 9a (100 mg, 0.598 mmol) in ethyl acetate
(15 mL) was added IBX (217 mg, 0.778 mmol), and the resultant
suspension was heated at reflux for 8 h. After cooling to room tem-
perature, the reaction mixture was filtered through a pad of Celite
and washed with ethyl acetate. The filtrate was concentrated and
purified by column chromatography (ethyl acetate/petroleum ether,
4:6) to give 12 as a colorless liquid (84 mg, 85%). Rf = 0.5 (acetone/
petroleum ether, 1:1). [α]2D5 = +12.92 (CHCl3 c = 0.25). IR (film,
a viscous liquid (21 mg, 81%). Rf = 0.36 (ethyl acetate). [α]2D5
–86.0473 (c = 0.465, CHCl ). IR (film, CHCl ): ν = 3310, 1645,
=
˜
3
3
1
1495, 1216, 757 cm–1. H NMR (500 MHz, CDCl3): δ = 6.7 (br. s,
1 H), 5.82–5.63 (m, 4 H), 4.94 (s, 1 H), 4.0–3.90 (m, 3 H), 2.96–
2.93 (m, 1 H), 2.33–2.19 (m, 2 H), 1.91–1.87 (m, 1 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 176.1, 127.8, 123.4, 122.9, 121.0,
68.8, 43.2, 43.0, 30.0, 29.1 ppm. MS (ESI): m/z = 202.06 [M + Na]
+. C10H13NO2 (179.22): calcd. C 67.02, H 7.31, N 7.82; found C
67.12, H 7.26, N 7.90.
CHCl ): ν = 3288, 1726, 1681, 1654, 1494, 757 cm–1. 1H NMR
˜
3
(400 MHz, CDCl3): δ = 9.66 (s, 1 H), 7.62 (br. s, 1 H), 6.0 (d, J =
10.29 Hz, 1 H), 5.67–5.57 (m, 2 H), 5.12–5.06 (m, 2 H), 3.92 (m, 2
H), 2.82 (dd, J = 7.2, 13.5 Hz, 1 H), 2.40 (dd, J = 7.2, 13.5 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.9, 169.1, 131.2,
124.1, 122.9, 119.6, 58.4, 43.3, 38.5 ppm. MS (ESI): m/z = 166.13
[M + H]+. C9H11NO2 (165.19): calcd. C 65.44, H 6.71, N 8.48;
found C 65.52, H 6.65, N 8.46.
(6R,7R)-7-Hydroxy-2-azaspiro[5,5]undecan-1-one (15): To a solu-
tion of 14 (20 mg, 0.111 mmol) in anhydrous MeOH (5 mL) was
added Pd/C (20 mg), and the mixture was stirred overnight at room
temperature under an atmosphere of hydrogen. The suspension was
filtered through Celite and concentrated under reduced pressure.
Purification by flash column chromatography (ethyl acetate/petro-
leum ether, 1:1) afforded solid 15 (19 mg, 94%), which upon
crystallization with ethyl acetate/petroleum ether gave colorless
Diastereoselective Allylation of Aldehyde 12: To a solution of alde-
hyde 12 (140 mg, 0.848 mmol) in anhydrous DCM (8 mL) at –78 °C
under an argon atmosphere was added the Lewis acid (SnCl4 or
TiCl4, 1 mmol). After 20 min, allyltrimethylsilane (3.392 mmol)
was added dropwise and stirring was continued at –78 °C for 7 h.
Upon complete consumption of the aldehyde, the reaction mixture
was quenched with saturated aqueous sodium hydrogen carbonate
solution and the temperature was allowed to attain room tempera-
ture. The aqueous phase was separated and extracted with DCM.
The organic phase was washed with brine, dried with sodium sul-
fate, filtered, and concentrated to afford the homoallylic alcohol
(152 mg). The diastereomeric ratio was determined by HPLC
analysis {[Chiralcel OD-H (250ϫ4.6 mm), isopropanol/n-hexane =
15:85, 0.5 mLmin–1 (25 Kgf), λ = 225 nm, 25 °C]: tR = 10.708 (for
13a), 11.508 (for 13b) min}. The diastereomeric mixture of homoal-
lylic alcohols 13a/13b was separated by flash column chromatog-
raphy (acetone/petroleum ether, 3:7) to give 148 mg of 13a and
4 mg of 13b.
crystals. M.p. 108–109 °C; Rf = 0.36 (ethyl acetate). [α]2D5
+43.7706 (c = 0.625, CHCl ). IR (film, CHCl ): ν = 3219, 2932,
=
˜
3
3
1
1638, 1446, 1046 cm–1. H NMR (500 MHz, CDCl3): δ = 6.47 (br.
s, 1 H), 5.75 (br. s, 1 H), 3.72 (br. s, 1 H), 3.27–3.26 (m, 2 H), 2.18–
2.12 (m, 1 H), 2.02–1.98 (m, 1 H), 1.84–1.68 (m, 4 H), 1.59–1.35
(m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 179.3, 71.5, 43.4,
42.1, 27.9, 27.9, 27.2, 19.6, 18.8, 18.5 ppm. MS (ESI): m/z = 184.44
[M + H]+. C10H17NO2 (183.25): calcd. C 65.54, H 9.35, N 7.64;
found C 65.46, H 9.31, N 7.58.
(+)-Nitramine (6): To an ice-cooled stirred slurry of lithium alumi-
num hydride (0.034 g, 0.9 mmol) in anhydrous THF (3 mL) was
added a solution of 15 (0.011 g, 0.06 mmol) in anhydrous THF
(2 mL). The suspension was stirred at room temperature for 80 h,
after which it was cooled to 0 °C and quenched with the slow alter-
native dropwise addition of saturated aqueous ammonium chloride
solution and a 50% aqueous sodium hydroxide solution (each time
a portion of 3 to 4 drops). The suspension was filtered, the precipi-
tate was thoroughly washed with DCM, and the filtrate was dried
with potassium carbonate, filtered, and concentrated to afford a
yellow viscous liquid. Purification by column chromatography
(CHCl3/MeOH/25% NH4OH, 46:50:4) gave pure 6 (0.006 g, 60%).
(R)-3-Allyl-3-[(R)-1-hydroxybut-3-enyl]-1,6-dihydropyridin-2(3H)-
one (13a): Rf = 0.42 (acetone/petroleum ether, 4:6). [α]2D3 = +38.14
(CHCl , c = 1.1). IR (film, CHCl ): ν = 3395, 1651, 1494, 1217,
˜
3
3
758 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.33 (br. s, 1 H), 5.93–
5.78 (m, 2 H), 5.72–5.63 (m, 2 H), 5.14–5.01 (m, 4 H), 3.95–3.89
(m, 3 H), 2.74 (dd, J = 7.53, 13.55 Hz, 1 H), 2.60 (br. s, 1 H), 2.39
(dd, J = 7.28, 13.56 Hz, 1 H), 2.31–2.26 (m, 1 H), 2.14–2.05 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.2, 135.3, 133.8,
126.4, 122.0, 118.1, 117.9, 74.7, 50.6, 43.4, 39.5, 37.2 ppm. MS
(ESI): m/z = 208.28 [M + H]+, 230.27 [M + Na]. C12H17NO2
(207.27): calcd. C 69.54, H 8.27, N 6.76; found C 69.66, H 8.15, N
6.67.
Rf = 0.25 (CHCl3/MeOH/25% NH4OH), 46:50:4). [α]2D5 = +21.4 (c
= 0.3, CH Cl ). IR (film, CHCl ): ν = 3350, 2940, 1175 cm–1. H
1
˜
2
2
3
NMR (500 MHz, CDCl3): δ = 3.62 (dd, J = 3.96, 9.15 Hz, 1 H),
3.50 (d, J = 12.2 Hz, 1 H), 3.65–3.45 (br. s, 2 H), 3.10–3.07 (m, 1
H), 2.68 (td, J = 3.35, 11.59 Hz, 1 H), 2.43 (d, J = 11.9 Hz, 1 H),
2.16–2.05 (m, 1 H), 1.84–1.78 (m, 2 H), 1.68–1.52 (m, 3 H), 1.43–
1.24 (m, 5 H) 1.09–1.04 (m, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 77.7, 51.8, 46.5, 37.3, 36.7, 35.3, 32.2, 24.0, 22.8,
(R)-3-Allyl-3-[(S)-1-hydroxybut-3-enyl]-1,6-dihydropyridin-2(3H)-
one (13b): Rf = 0.48 (acetone/petroleum ether, 4:6). [α]2D3 = –25.1876
(CHCl , c = 1.45). IR (film, CHCl ): ν = 3401, 3019, 1642, 1215,
˜
3
3
758 cm–1. 1H NMR (500 MHz, CDCl3): δ = 6.91 (br. s, 1 H), 5.94–
5.86 (m, 2 H), 5.72–5.61 (m, 1 H), 5.40–5.38 (m, 1 H), 5.10–5.02
(m, 4 H), 4.15 (d, J = 10 Hz, 1 H), 3.89–3.86 (m, 2 H), 3.51–3.47 21.3 ppm. MS (ESI): m/z = 170.25 [M + H]+. C10H19NO (169.27):
(m, 1 H), 2.91 (dd, J = 7.9, 13.7 Hz, 1 H), 2.34–2.30 (m, 1 H), 2.24
calcd. C 70.96, H 11.34, N 8.28; found C 70.90, H 11.43, N 8.42.
7376
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Eur. J. Org. Chem. 2011, 7372–7377

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Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra, HPLC chromato-
grams, and X-ray crystallographic data.
Acknowledgments
Financial support for our research from the Department of Sci-
ence & Technology, New Delhi, is gratefully acknowledged.
P. K. C. and S. K. B. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, for research fellowships.
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Received: August 29, 2011
Published Online: October 31, 2011
Eur. J. Org. Chem. 2011, 7372–7377
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7377