Enantioselective approach to functionalized quinolizidines: Synthesis of (+)-julandine and (+)-cryptopleurine

Article abstract of DOI:10.1039/c2ob25689d

An efficient synthesis of functionalized quinolizidines was developed from an enantiomerically enriched γ-nitroketone, which is easily prepared by an organocatalytic ketone-nitroalkene Michael addition. Oxidative ring expansion of the nitroketone followed

Full text of DOI:10.1039/c2ob25689d

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 6776
www.rsc.org/obc
PAPER
Enantioselective approach to functionalized quinolizidines: synthesis of
(+)-julandine and (+)-cryptopleurine†
Sunil V. Pansare* and Rajendar Dyapa
Received 7th April 2012, Accepted 21st June 2012
DOI: 10.1039/c2ob25689d
An efficient synthesis of functionalized quinolizidines was developed from an enantiomerically enriched
γ-nitroketone, which is easily prepared by an organocatalytic ketone–nitroalkene Michael addition.
Oxidative ring expansion of the nitroketone followed by reductive ring-opening leads to a suitably
functionalized nitrodiol which is an intermediate to the title compounds.
Introduction
The quinolizidine motif is a prominent structural unit in numer-
ous alkaloids.1 The structurally related phenanthroquinolizidine
alkaloids2 are also well known and these have attracted consider-
able interest due to their anticancer,3 antiviral,4 amoebicidal5 and
anti-inflammatory6 activities. The synthesis of quinolizidines,7
aryl-fused quinolizidines8 and phenanthroquinolizidines9 has
therefore continued to engage synthetic chemists over the years.
Fig. 1 (+)-Julandine (1) and (+)-cryptopleurine (2).
Herein, we describe a stereoselective synthesis of the secophe-
nanthroquinolizidine alkaloid (+)-julandine (1),10 an antimicro-
bial agent,11 and the corresponding phenanthroquinolizidine
oxidative cyclization of julandine10e and hence a route to julan-
(+)-cryptopleurine (2),12 the enantiomer of which has antiviral,13
dine would also establish access to cryptopleurine.
amoebicidal14 and anticancer3 activity (Fig. 1). The synthesis of
Retrosynthetically, the 2,3-diaryl quinolizidine motif of julan-
1 and 2 is based on a γ-nitroketone precursor which is readily
dine may be accessible by aryl cross-coupling from a 7-aryl
prepared by an organocatalytic ketone–nitroalkene Michael
indolizidinone such as A (Scheme 1) which derives from the
addition.
functionalized piperidine B. This piperidine intermediate can be
made from the reductive cyclization of the nitroketone C which
can be obtained by the reductive opening of the lactone
D. Ultimately, lactone D derives from a Baeyer–Villiger oxi-
Results and discussion
dation of the corresponding γ-nitroketone which leads us to the
organocatalytic, ketone–nitroalkene Michael addition of an
appropriate cyclic ketone and nitroalkene.
Accordingly, the organocatalytic Michael addition of cyclo-
hexane-1,4-dione monoethylene ketal and 4-methoxy-β-nitro-
The interest in quinolizidines is an outcome of our ongoing
studies on the development and application of the organocataly-
tic ketone–nitroalkene Michael addition reaction.15 This reaction
has been extensively studied and although the development of
new catalysts for the process continues at a significant pace,
further application of the nitroketone Michael adducts has pro-
gressed relatively slowly.16 It was therefore decided to examine
the utility of a suitable γ-nitroketone in a general approach to the
quinolizidine motif. The initial target of the investigation was the
naturally occurring (+)-julandine, since only one enantioselective
synthesis of the unnatural (–)-julandine has been reported.10a In
addition, cryptopleurine can be obtained in one step by the
styrene employing
a
chiral pyrrolidine-based triamine
catalyst15a,16j provided the requisite γ-nitroketone 3 in good
yield and stereoselectivity (er = 96 : 4, dr >19 : 1, Scheme 2).
Baeyer–Villiger oxidation of 3 provided the corresponding
lactone 4 which was reduced with sodium borohydride to the
nitrodiol 5 (92%, 2 steps). The primary alcohol in 5 was then
selectively acetylated to provide the corresponding acetate 6
(94%) which was converted to the nitroketone 7 by deketaliza-
tion with iodine in acetone (90%).17
Department of Chemistry, Memorial University, St. John’s,
Newfoundland A1B 3X7, Canada. E-mail: spansare@mun.ca
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob25689d
With the nitroketone 7 in hand, the construction of the quinoli-
zidine framework was initiated. This process involved the prep-
aration of a suitably substituted piperidine from 7 and then
6776 | Org. Biomol. Chem., 2012, 10, 6776–6784
This journal is © The Royal Society of Chemistry 2012

View Article Online
Scheme 1 Retrosynthetic analysis of the diaryl quinolizidine motif.
Scheme 2 Baeyer–Villiger oxidation of 3 and synthesis of nitroketone 7.
construction of the quinolizidine by cyclization. Reduction of
the nitroketone with zinc in aq. ammonium chloride provided the
nitrone 8, presumably from the hydroxylamine derived from 7.
Reduction of the nitrone with tetramethylammonium triacetoxy-
borohydride provided the N-hydroxy piperidine 9 as a single dia-
stereomer. The stereoselectivity of this reduction is presumably
due to an intramolecular, hydroxyl-directed reduction of 8
(Scheme 3). Reduction of the N–O bond in 9 (TiCl3 followed by
aqueous NaOH18) provided the corresponding amino alcohol 10
which was protected to provide 11.19 Conversion of 11 into the
quinolizidine motif required a one carbon homologation. This
was achieved by conversion to the mesylate 12 and subsequent
cyanation to provide 13.
Conversion of 13 to the corresponding quinolizidinone 14
(Scheme 4) could be accomplished by hydrolysis of the nitrile to
the acid, esterification with concommitant removal of the Boc
group and subsequent cyclization of the aminoester (63%
overall). The overall conversion of 13 to 14 could also be
achieved in one step (30%) by treatment of 13 with HCl in
methanol followed by basification of the crude product.
However, the multi-step procedure proceeds with higher overall
yield (63%) and is therefore the method of choice. Oxidation of
14 provided the keto lactam 15 which was then converted to the
enol triflate 16. This is the key intermediate for the
target alkaloids.
The conversion of 16 to (+)-julandine (1) was achieved by a
Suzuki cross-coupling with 3,5-dimethoxyphenyl boronic acid to
generate the lactam 17 followed by reduction with LAH to give
1 (73%, 2 steps). As expected, oxidative cyclization of 1 with
thallium trifluoroacetate10e provided (+)-cryptopleurine (2, 62%,
Scheme 5).
Conclusion
In conclusion, an efficient synthesis of functionalized quinolizi-
dines was developed from a simple γ-nitroketone starting
material which is readily available from the organocatalytic
ketone–nitroalkene Michael addition reaction. The methodology
was applied in the first total synthesis of the natural enantiomer
of the diaryl quinolizidine alkaloid (+)-julandine and the structu-
rally related phenanthroquinolizidine alkaloid (+)-cryptopleurine.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6776–6784 | 6777

View Article Online
Scheme 3 Stereoselective reduction of nitrone 8 and synthesis of piperidine 13.
Scheme 4 Synthesis of the quinolizidine framework from 13.
The synthetic strategy should be particularly amenable to the
preparation of focused libraries of analogs of these alkaloids by
judicious selection of the nitroalkene and the aryl component in
the cross-coupling step. We are currently examining this possi-
bility as well as other synthetic applications of nitroketones and
nitrones related to 3 and 8 respectively.
from CaH2 and sodium/benzophenone respectively. Commercial
precoated silica gel plates were used for TLC. Silica gel for
column chromatography was 230–400 mesh. All melting points
are uncorrected. Optical rotations were measured at the sodium
D line on a digital polarimeter at ambient temperature.
(7S)-7-[(1R)-1-(4-Methoxyphenyl)-2-nitroethyl]-1,4-dioxaspiro-
Experimental section
[4.5]decan-8-one (3)
All commercially available reagents were used without purifi-
cation. All reactions requiring anhydrous conditions were per-
formed under an atmosphere of dry nitrogen using oven dried
glassware. Dichloromethane and tetrahydrofuran were distilled
To a solution of 1,4-cyclohexanedione monoethylene ketal
(13.0 g, 83.7 mmol), N1,N1-dimethyl-N2-(((S)-pyrrolidin-2-yl)-
methyl)ethane-1,2-diamine15a (572 mg, 3.34 mmol) and
p-toluene sulfonic acid monohydrate (634 mg, 3.34 mol) in
6778 | Org. Biomol. Chem., 2012, 10, 6776–6784
This journal is © The Royal Society of Chemistry 2012

View Article Online
Scheme 5 Synthesis of (+)-julandine (1) and its conversion to (+)-cryptopleurine (2).
DMF (30 mL) was added 4-methoxy-β-nitrostyrene (3.00 g,
16.7 mmol) and the resulting solution was stirred at ambient
temperature for 48 h. Ethyl acetate (100 mL) was added and the
solution washed with water, aq. HCl (3N), dried (Na2SO4) and
concentrated. The residue obtained was purified by flash chrom-
atography on silica gel to provide 4.6 g of a solid. This was dis-
solved in ethyl acetate (23 mL) and precipitated by addition of
hexanes (70 mL). The procedure was repeated once to provide
3.5 g (62%) of 3 with 96% ee. In repeated runs, 3 was obtained
in 90–96% ee. Spectroscopic data for 3 is in agreement with that
reported in the literature.16j
50 mL) and the combined organic layers were dried (Na2SO4)
and concentrated to provide 2.7 g (94%) of the diol 5 as a
pale yellow gum. This material was pure by 1H NMR and
was used in the next step without purification. An analytical
sample was obtained by flash chromatography on silica gel
(EtOAc).
IR (neat): 3493, 2960, 2837, 1550, 1511, 1378, 1248, 1059
1
1028, 829 cm−1; H NMR (500 MHz, CDCl3): δ 7.10 (d, 2H, J
= 8.6, ArH), 6.85 (d, 2H, J = 8.6, ArH), 5.06–5.02 (dd, 1H, J =
5.2, 12.7, CH2NO2), 4.61–4.57 (dd, 1H, J = 9.7, 12.7,
CH2NO2), 4.05–3.99 (m, 1H, Ar–CH), 3.99–3.93 (m, 5H,
CHOH, OCH2CH2O), 3.78 (s, 3H, OCH3), 3.55 (t, 2H, J = 6.2,
CH2OH), 3.42–3.38 (td, 1H, J = 5.2, 9.5, CHOH), 1.70–1.57
(m, 4H, CH2CHOH, CH2Cketal), 1.50–1.39 (m, 2H,
CH2CH2OH); 13C NMR (75 MHz, CDCl3): δ 159.2 (ArC-
OCH3), 129.3 (ArCipso), 129.1 (2 × ArC), 114.5 (2 × ArC),
111.8 (OCO), 78.5 (CH2NO2), 70.1 (CHOH), 64.9
(OCH2CH2O), 64.6 (OCH2CH2O), 62.6 (CH2OH), 55.3
(ArOCH3), 50.3 (HO–CHCH2), 40.3 (Ar–CHCH2), 33.3
(CH2CCH2), 26.7 (CH2CH2OH); MS (API-ES): m/z 378
(M + Na); MALDI-TOF MS: 378.1611 (378.1529 calc. for
C17H25NO7Na (M + Na)); [α]2D3 = + 40.5 (c 1, CHCl3).
(S)-7-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)-1,4,8-trioxaspiro-
[4.6]undecan-9-one (4)
To a solution of the nitroketone 3 (3.1 g, 9.24 mol) in anhydrous
dichloromethane (60 mL) at ambient temperature, was added
solid sodium phosphate heptahydrate (3.21 g, 12.0 mol) fol-
lowed by m-chloro perbenzoic acid (∼77%, 4.94 g, 28.7 mmol).
The resulting white slurry was stirred vigorously for 16 h.
Dichloromethane (100 mL) was added and the solution was
washed with 5% aq. NaOH (2 × 60 mL). The organic layer was
dried (Na2SO4) and concentrated to provide 3.20 g, (98%) of 4
as a white, solid foam. This material was pure by 1H NMR
(500 MHz) and was used in the next step without purification.
Spectroscopic data for 4 is in agreement with that reported in the
literature.16j [α]D23 = +58.3 (c 1, CHCl3).
3-(2-((2S,3R)-2-Hydroxy-3-(4-methoxyphenyl)-4-nitrobutyl)-1,3-
dioxolan-2-yl)propyl acetate (6)
A solution of the diol 5 (2.1 g, 5.9 mmol) in dry dichloro-
methane (35 mL) was cooled to −78 °C and acetyl chloride
(0.50 mL, 7.09 mmol) and collidine (1.43 mL, 11.8 mmol) were
added. The solution was stirred at −78 °C for 4 h and then
diluted with dichloromethane (50 mL). The resulting solution
was warmed to ambient temperature and washed with aq. HCl
(0.5 M, 2 × 25 mL). The organic layer was dried (Na2SO4) and
concentrated to provide 2.2 g (94%) of the acetate 6 as a pale
(2S,3R)-1-(2-(3-Hydroxypropyl)-1,3-dioxolan-2-yl)-3-(4-methoxy-
phenyl)-4-nitrobutan-2-ol (5)
To a solution of the lactone 4 (2.85 g, 8.11 mmol) in ethanol
(30 mL), was added sodium borohydride (0.46 g, 12.1 mmol).
The mixture was stirred at room temperature for 3 h, then cooled
to 0 °C and the solution was acidified (pH ∼ 5) with aq. HCl
(0.5 M). The acidic solution was extracted with EtOAc (2 ×
1
yellow gum. This material was pure by H NMR and was used
in the next step without purification. An analytical sample was
Org. Biomol. Chem., 2012, 10, 6776–6784 | 6779
This journal is © The Royal Society of Chemistry 2012

View Article Online
obtained by flash chromatography on silica gel (EtOAc–hexanes,
6 : 4).
was diluted with dichloromethane (50 mL) and the solution was
washed with water (10 mL), dried (Na2SO4) and concentrated
under reduced pressure to provide 1.6 g (90%) of 8 as a pale
IR (neat): 3496, 2961, 1731, 1550, 1513, 1375, 1242, 1141,
1
1
1032, 829 cm−1; H NMR (500 MHz, CDCl3): δ 7.10 (d, 2H, J
yellow foam. This material was pure by H NMR and was used
= 8.7, ArH), 6.85 (d, 2H, J = 8.7, ArH), 5.06–5.02 (dd, 1H, J =
5.3, 12.7, CH2NO2), 4.61–4.57 (dd, 1H, J = 9.6, 12.7,
CH2NO2), 3.99–3.92 (m, 8H, Ar–CH, CHOH, OCH2CH2O,
CH2OAc) 3.78 (s, 3H, ArOCH3), 3.42–3.38 (td, 1H, J = 5.3,
9.5, CHOH), 2.03 (s, 3H, COCH3) 1.67–1.64 (m, 3H,
in the next step without purification.
IR (neat): 2948, 1735, 1611, 1509, 1459, 1230, 1140, 1031,
1
826 cm−1; H NMR (500 MHz, CDCl3): δ 7.21 (d, 2H, J = 8.7,
ArH), 6.90 (d, 2H, J = 8.7, ArH), 4.37–4.32 (apparent br t, 1H,
J = 13.4, ArCH), 4.20–4.19 (br s, 1H, CHOH), 4.14–4.11 (t, 2H,
J = 6.5, CH2OAc), 3.94–3.90 (dd, 1H, J = 5.5, 14.9, CH2N),
3.80 (s, 3H, OCH3), 3.25–3.21 (m, 1H, CH2N), 2.89–2.53 (m,
4H, CH2CvN, CvNCH2CH2) 2.01 (s, 3H, COCH3), 1.99–1.92
(m, 2H, CH2CH2OAc); 13C NMR (75 MHz, CDCl3): δ 171.1
(COCH3), 159.0 (ArC–OCH3), 145.0 (CvNO), 129.4 (ArCipso),
128.7 (2 × ArC), 114.3 (2 × ArC), 65.1 (CHOH), 63.8 (OCH2),
57.5 (OCH3), 55.2 (CH2NO), 43.5 (Ar–CH), 37.6 (CH2CvN),
28.1 (CH2CH2O), 23.5 (COCH3) 20.9 (NvCCH2); MS (APCI,
pos.): m/z 322.4 (M + 1); MALDI-TOF MS: 344.1557
(344.1474 calcd for C17H23NO5Na (M + Na)).
CHCH2Cketal, CketalCH2), 1.50–1.46 (m, 3H, CHCH2Cketal
,
CH2CH2OAc); 13C NMR (75 MHz, CDCl3): δ 171.6 (C(O)-
CH3), 159.7 (ArC–OCH3), 129.8 (ArCipso), 129.6 (2 × ArC),
115.0 (2
× ArC), 112.0 (OCO), 79.0 (CH2NO2), 70.6
(CH2OAc), 65.5 (CHOH) 65.2 (OCH2CH2O), 64.7
(OCH2CH2O), 55.8 (OCH3), 50.8 (CHCH2Cketal) 40.9 (Ar–CH),
33.8 (CketalCH2CH2), 23.5 (OC(O)CH3) 21.5 (CH2CH2O); MS
(API-ES, pos.): m/z 420.4 (M + Na); MALDI-TOF MS:
420.1704 (420.1634 calc. for C19H27NO8Na (M + Na));
[α]2D3 = +23.6 (c 0.5, CHCl3).
(6S,7R)-6-Hydroxy-7-(4-methoxyphenyl)-8-nitro-4-oxooctyl
3-((2R,4S,5S)-4-Hydroxy-5-(4-methoxyphenyl)-N-hydroxy-
acetate (7)
piperidin-2-yl)propyl acetate (9)
A solution of the ketal 6 (2.2 g, 5.5 mmol) and iodine (0.07 g,
0.55 mmol) in acetone (20 mL) was stirred at ambient tempera-
ture for 1 h. The acetone was removed under reduced pressure
and the residue was diluted with dichloromethane. The resulting
solution was washed successively with aqueous Na2S2O3 (5%
w/v, 2 × 25 mL) and brine (1 × 25 mL). The organic layer was
dried (Na2SO4) and concentrated under reduced pressure to
provide 1.85 g (95%) of the nitroketone 7 as a yellow solid. This
To a solution of tetramethylammonium borohydride (2.62 g,
9.96 mmol) in acetonitrile (14 mL) was added acetic acid
(14 mL). The mixture was stirred at 0 °C for 5 min and a solu-
tion of the nitrone 8 (1.6 g, 4.98 mmol) in acetonitrile (6 mL)
was added. The mixture was stirred at 0 °C for 1 h and then
basified (pH ∼ 8) with aqueous NaOH (5% solution). The
mixture was extracted with dichloromethane (2 × 60 mL) and
the combined extracts were dried (Na2SO4) and concentrated to
give 1.48 g (92%) of 9 as a brown gum. This material was pure
1
material was pure by H NMR and was used in the next step
1
without purification. Mp: 77–80 °C; IR (neat): 3402, 2955,
by H NMR and was used in the next step without purification.
An analytical sample was obtained by flash chromatography on
silica gel (CH2Cl2–MeOH, 98 : 2).
1
1735, 1708, 1548, 1380, 1253, 1227, 1111, 1036, 820 cm−1; H
NMR (500 MHz, CDCl3): δ 7.09 (d, 2H, J = 8.7, ArH), 6.87 (d,
2H, J = 8.7, ArH), 5.09–5.06 (dd, 1H, J = 5.1, 12.8, CH2NO2),
4.62–4.58 (dd, 1H, J = 9.8, 12.8, CH2NO2), 4.21–4.18 (m, 1H,
ArCH), 4.03–4.01 (br t, 2H, J = 6.3, CH2OAc), 3.79 (s, 3H,
OCH3), 3.49–3.44 (m, 2H, CHOH, CHOH), 2.43–2.37 (m, 4H,
CH2COCH2) 2.01 (s, 3H, COCH3), 1.86–1.82 (m, 2H,
CH2CH2O); 13C NMR (75 MHz, CDCl3): δ 210.6 (CO) 171.0
(OC(O)CH3), 159.4 (ArC–OCH3), 129.0 (2 × ArC), 128.6
(ArCipso), 114.7 (2 × ArC), 78.4 (CH2NO2), 69.6 (CHOH), 63.3
(CH2OAc), 55.3 (OCH3), 49.1 (CH2C(O)), 46.8 (ArCH), 39.7
(C(O)CH2), 22.4 (CH2CH2CO), 20.9 (OC(O)CH3); MS
(API-ES, pos.): m/z 376 (M + Na); MALDI-TOF MS: 376.1443
(376.1372 calc. for C17H23NO7Na (M + Na).
IR (neat): 3415, 2923, 1731, 1512, 1238, 1032, 819 cm−1; 1H
NMR (500 MHz, CDCl3): δ 7.14 (d, 2H, J = 8.7, ArH), 6.88 (d,
2H, J = 8.7, ArH), 4.10–4.07 (t, 2H, J = 6.7, OCH2), 3.91 (br s,
1H, CHOH), 3.79 (s, 3H, OCH3), 3.58–3.48 (m, 1H, NCH),
3.31–3.20 (m, 2H, NCH2, CHOH), 3.03 (br d, J = 12.4, 1H,
CH2N), 2.86–2.82 (m, 1H, ArCH), 2.11–2.00 (m, 5H, COCH3,
CHCH2CH), 1.74–1.55 (m, 2H, CH2CH2OAc), 1.50–1.42 (m,
2H, NCHCH2); MS (APCI, pos.): m/z 324.2 (M + 1); HRMS
(CI): m/z 324.1812 (324.1811 calc. for C17H26NO5 (M + H));
[α]2D3 = +39.1 (c 0.7, CHCl3).
(2S,4S,5R)-2-(3-Hydroxypropyl)-5-(4-methoxyphenyl)piperidin-
4-ol (10)
(3R,4S)-4-Hydroxy-6-(3-acetoxypropyl)-3-(4-methoxyphenyl)-
2,3,4,5-tetrahydropyridine-1-oxide (8)
To a stirred solution of the hydroxylamine 9 (0.9 g, 2.78 mmol)
in methanol (20 mL) was added aq. TiCl3 (15%, 3.77 mL,
3.70 mmol) at 0 °C and the mixture was stirred at 0 °C for 4 h.
Aqueous NaOH (20% w/v, 27 mL) was added and the mixture
was filtered to remove inorganic salts. The residue washed with
methanol and the combined filtrates were concentrated under
reduced pressure. The resulting aqueous solution was extracted
with dichloromethane (3 × 40 mL) and the combined organic
extracts were dried (Na2SO4) and concentrated to provide 0.65 g
A solution of NH4Cl (0.297 g, 5.55 mmol) in water (5 mL) was
added to a solution of the nitroketone 7 (1.96 g, 5.55 mmol) in
THF (24 mL). Activated Zn powder (3.51 g, 55.5 mmol) was
added and the mixture was stirred vigorously at room tempera-
ture under nitrogen for 3 h. The mixture was filtered through
Celite, the residue was washed with THF, and the combined
filtrates were concentrated under reduced pressure. The residue
6780 | Org. Biomol. Chem., 2012, 10, 6776–6784
This journal is © The Royal Society of Chemistry 2012

View Article Online
(88%) of the amino alcohol 10 as a yellow solid. This material
was pure by H NMR and was used in the next step without
purification.
(3 × 25 mL), brine (1 × 25 mL) dried (Na2SO4) and concen-
trated. The residue was purified by flash chromatography on
silica gel (hexanes–EtOAc, 2 : 8) to provide 0.85g (64%) of 12
as a white solid.
1
Mp: 138–140 °C; IR (neat): 3554, 2910, 2843, 1511, 1461,
1240, 1182, 1056, 1026, 817 cm−1
;
1H NMR (500 MHz,
Mp: 140–144 °C; IR (neat): 3441, 2937, 1676, 1511, 1418,
1353, 1247, 1167, 915, 830 cm−1; 1H NMR (500 MHz, CDCl3):
δ 7.23 (d, 2H, J = 8.7, ArH), 6.85 (d, 2H, J = 8.7, ArH), 4.46
(br m, 1H, NCH), 4.29–4.18 (m, 3H, NCH2, OCH2), 4.16–4.14
(m, 1H, CHOH), 3.79 (s, 3H, OCH3), 3.36–3.30 (dd, 1H, J =
4.1, 14.2, NCH2), 3.07–3.05 (m, 1H, ArCH), 3.02 (s, 3H,
SO2CH3), 1.92–1.61 (m, 6H, CHCH2CH, NCHCH2,
CH2CH2O), 1.45 (s, 9H, C(CH3)3); 13C NMR (75 MHz,
CDCl3): δ 7.13 (d, 2H, J = 8.7, ArH), 6.89 (d, 2H, J = 8.7,
ArH), 4.10 (d, 1H, J = 2.32, CHOH), 3.79 (s, 3H, OCH3),
3.64–3.54 (m, 2H, CH2OH), 3.38–3.35 (t, 1H, J = 12.5, NCH2),
3.08–3.03 (m, 1H, NCH) 3.03–2.97 (dd, 1H, J = 4, 12.5,
NCH2), 2.79–2.74 (m, 1H, ArCH), 1.96–1.92 (dt, 1H, J = 13.8,
3.0, CHCH2CH), 1.79–1.75 (m, 1H, CHCH2CH), 1.65–1.57 (m,
3H, NCHCH2, CH2CH2OH), 1.42–1.39 (m, 1H, NCHCH2); 13C
NMR (75 MHz, CDCl3): δ 158.6 (ArC–OCH3), 132.8 (ArCipso),
128.8 (2 × ArC), 114.2 (2 × ArC), 69.3 (CHOH), 62.8
(CH2OH), 55.3 (OCH3), 49.8 (CHNH), 46.7 (CH2NH), 44.1
(Ar–CH), 39.4 (CHCH2CH), 35.6 (NHCHCH2) 30.4
(CH2CH2OH); MS (APCI, pos.): m/z 266.2 (M + 1); MALDI-
TOF MS: 266.1796 (266.1756 calc. for C15H24NO3 (M + H)).
t
CDCl3): δ 158.8 (ArC–OCH3), 155.0 (CO2 Bu), 130.8 (2 ×
ArC), 130.1 (ArCipso), 113.9 (2 × ArC) 80.2 (C(CH3)3), 69.7
(CH2O), 66.4 (CHOH), 55.3 (OCH3), 50.4 (NCH), 44.4
(CH2N), 42.8 (ArCH), 37.4 (SO2CH3), 33.0 (CHCH2CH), 28.5
(C(CH3)3), 27.2 (NCHCH2), 26.3 (CH2CH2OMs); MS (APCI,
pos.): m/z 344.1 (M-Boc + 2); HRMS (CI): m/z 344.1538
(344.1532 calc. for C16H26NO5S (M-Boc + 2H).
(2S,4S,5R)-tert-Butyl 4-hydroxy-2-(3-hydroxypropyl)-5-(4-methoxy-
phenyl)piperidine-1-carboxylate (11)
(2S,4S,5R)-tert-Butyl-2-(3-cyanopropyl)-4-hydroxy-5-(4-methoxy-
phenyl)piperidine-1-carboxylate (13)
To a solution of the aminol 10 (0.85 g, 3.21 mmol) and triethyl-
amine (0.54 mL, 3.84 mmol) in dry dichloromethane (10 mL) at
0 °C was slowly added a solution of the (Boc)2O (0.706 g,
3.24 mmol) in dichloromethane (5 mL). The mixture was stirred
at ambient temperature for 16 h, saturated NaHCO3 was added
and the aqueous phase was extracted with CH2Cl2 (2 × 50 mL).
The combined organic layers were washed with aqueous HCl
(0.5 M, 2 × 25 mL). The organic layer was dried (Na2SO4) and
concentrated to provide 1.1 g (94%) of 11 as a pale yellow gum.
To a solution of the mesylate 12 (0.82 g, 1.85 mmol) in an-
hydrous DMSO (15 mL), at ambient temperature, was added
NaCN (18 g, 3.69 mmol). The mixture was stirred at 70 °C for
2 h and cooled to ambient temperature. Ethyl acetate (40 mL)
was added and the mixture was washed with water (3 × 30 mL)
and brine (30 mL). The organic layer was dried (Na2SO4) and
concentrated to provide 0.65 g (95%) of 13 as a yellow solid.
1
This material was pure by H NMR and was used in the next
1
This material was pure by H NMR and was used in the next
step without purification.
step without purification. An analytical sample was obtained by
purification by flash chromatography on silica gel (EtOAc).
IR (neat): 3403, 2936, 1658, 1511, 1420, 1246, 1164, 1067,
IR (neat): 3447, 2934, 2248, 1678, 1511, 1416, 1246, 1162,
1
1113, 831 cm−1; H NMR (500 MHz, CDCl3): δ 7.22 (d, 2H, J
= 8.7, ArH), 6.85 (d, 2H, J = 8.7, ArH), 4.46 (br s, 1H, NCH),
4.33–4.30 (br dd, 1H, J = 2.2, 14.2, NCH2), 4.19–4.13 (m, 1H,
CHOH), 3.79 (s, 3H, OCH3), 3.35–3.31 (dd, 1H, J = 4.0, 14.2,
NCH2), 3.07–3.05 (m, 1H, ArCH), 2.44 (t, 2H, J = 6.8,
CH2CN), 2.04–1.96 (m, 1H, CHCH2CH), 1.80–1.77 (m, 1H,
CHCH2CH), 1.70–1.62 (m, 4H, NCHCH2, CH2CH2CN), 1.46
(s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3): δ 158.8 (ArC–
1
823 cm−1; H NMR (500 MHz, CDCl3): δ 7.25 (d, 2H, J = 8.7,
ArH), 6.85 (d, 2H, J = 8.7, ArH), 4.48–4.46 (br m, 1H, NCH),
4.33–4.30 (br dd, 1H, J = 3.4, 14.1 NCH2), 4.21–4.14 (m, 1H,
CHOH), 3.80 (s, 3H, OCH3), 3.72–3.70 (m, 2H, CH2OH),
3.37–3.33 (dd, 1H, J = 4.2, 14.1, NCH2), 3.06 (br m, 1H,
ArCH), 1.89–1.53 (m, 6H, CHCH2CH, NCHCH2, CH2CH2OH),
1.46 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3): δ 158.8
OCH3), 155.0 (CO2 Bu), 130.7 (2 × ArC), 130.0 (ArCipso),
t
t
(ArC–OCH3), 155.3 (CO2 Bu), 130.8 (2
×
ArC), 130.2
119.5 (CN), 113.8 (2 × ArC), 80.2 (C(CH3)3), 66.3 (CHOH),
55.3 (OCH3), 50.0 (NCH), 44.4 (CH2N), 42.8 (Ar–CH), 33.1
(CHCH2CH), 30.2 (NCHCH2), 28.4 (C(CH3)3), 22.5
(CH2CH2CN), 17.0 (CH2CN); MS (APCI, pos.): m/z 275.3
(M-Boc + 2); HRMS (CI): m/z 375.2292 (375.2284 calc. for
C21H31N2O4 (M + H); [α]2D3 = +27.0 (c 0.6, CHCl3).
(ArCipso), 113.8 (2 × ArC) 80.1 (C(CH3)3), 66.4 (CHOH), 62.6
(CH2OH), 55.3 (OCH3), 50.8 (NCH), 44.4 (CH2N), 42.8
(ArCH), 33.0 (CHCH2CH), 29.3 (NCHCH2), 28.5 (C(CH3)3),
27.6 (CH2CH2OH); MS (APCI, pos.): m/z 266.2 (M-Boc + 2);
HRMS (CI): m/z 266.1751 (266.1756 calc. for C15H24NO3
(M-Boc + 2H); [α]2D3 = +68.2 (c 1, CHCl3).
(7R,8S,9aS)-Hexahydro-8-hydroxy-7-(4-methoxyphenyl)-1H-
quinolizin-4(6H)-one (14)
3-((2S,4S,5R)-1-(tert-Butoxycarbonyl)-4-hydroxy-5-(4-methoxy-
phenyl)piperidin-2-yl)propyl methanesulfonate (12)
A solution of the nitrile 13 (0.61 g, 1.63 mmol) in aqueous
NaOH (2 M, 6 mL) and ethanol (6 mL) was heated at 85 °C for
16 h. The ethanol was removed under reduced pressure and
resulting solution was acidified (pH ∼ 4) with aqueous HCl
(0.5 M). The acidic solution was extracted with dichloromethane
(2 × 50 mL) and the combined extracts were dried (Na2SO4) and
To a stirred solution of 11 (1.1 g, 3.01 mmol) in dichloromethane
(15 mL) was added DIPEA (0.53 mL) followed by methanesul-
fonyl chloride in dichloromethane (10 mL) over 15 min. at 0 °C.
The mixture was stirred at 0 °C for 3 h. Cold water (10 mL) was
added and the organic layer was separated, washed with water
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6776–6784 | 6781

View Article Online
concentrated to provide 0.61 g (95%) of 4-((2S,4S,5R)-1-(tert-
butoxycarbonyl)-4-hydroxy-5-(4-methoxyphenyl)piperidin-2-
yl)-butanoic acid (13a) as a brown solid. This material was pure
by 1H NMR and was used in the next step without purification.
Mp: 88–90 °C; IR (neat): 3423, 2933, 1666, 1511, 1418,
1245, 1160, 1033, 829, 730 cm−1; 1H NMR (500 MHz, CDCl3):
δ 7.22 (d, 2H, J = 7.9, ArH), 6.84 (d, 2H, J = 7.9, ArH), 4.42
(br s, 1H, NCH), 4.31 (br d, 1H, J = 13.9, NCH2), 4.14–4.12 (br
m, 1H, CHOH), 3.79 (s, 3H, OCH3), 3.33–3.30 (br dd, 1H, J =
2.7, 13.9, NCH2), 3.03 (br s, 1H, ArCH), 3.0–2.5 (br, CO2H),
2.39 (br s, 2H, CH2COOH), 1.79–1.61 (m, 6H, CHCH2CH,
NCHCH2, CH2CH2COOH), 1.45 (s, 9H, C(CH3)3); 13C NMR
(75 MHz, CDCl3): δ 178.4 (CO2H), 158.7 (ArC–OCH3 or
CO2 Bu), 155.1 (ArC–OCH3 or CO2 Bu), 130.8 (2 × ArC),
130.3 (ArCipso), 113.7 (2 × ArC), 80.1 (C(CH3)3), 66.3
(CHOH), 55.2 (ArOCH3), 50.7 (NCH), 44.2 (CH2N), 42.8 (Ar–
CH), 34.1 (CH2CO2H), 32.3 (CHCH2CH), 30.2 (NCHCH2),
28.4 (C(CH3)3), 21.8 (CH2CH2CO2H); MS (APCI, pos.): m/z
294.2 (M-Boc + 2); HRMS (CI pos.): m/z 294.1711 (294.1705
calc. for C16H24NO4 (M-Boc + 2H).
IR (neat): 3349, 2945, 1606, 1514, 1478, 1442, 1245, 1171,
1
1035, 831 cm−1; H NMR (500 MHz, CDCl3): δ 7.14 (d, 2H, J
= 8.7, ArH), 6.89 (d, 2H, J = 8.7, ArH), 4.77–4.74 (dd, 1H, J =
4.2, 12.8, NCH2), 4.1 (br m, 1H, CHOH), 3.8 (s, 3H, OCH3),
3.78–3.74 (m, 1H, NCH), 3.20–3.15 (t, 1H, J = 12.8, NCH2),
2.85–2.81 (br m, 1H, ArCH), 2.48–2.40 (m, 1H, NCOCH2),
2.38–2.31 (m, 1H, NCOCH2), 2.02–1.97 (m, 2H, CHCH2CH,
CHOH), 1.86–1.82 (m, 1H, NCHCH2CH2), 1.74–1.68 (m, 3H,
CHCH2CH, COCH2CH2) 1.55–1.48 (m, 1H, CHCH2CH2); 13C
NMR (75 MHz, CDCl3): δ 169.6 (NCO), 158.7 (ArC–OCH3),
131.9 (ArCipso), 128.6 (2 × ArC), 114.2 (2 × ArC), 68.7
(CHOH), 55.3 (OCH3), 50.0 (NCH), 45.3 (CH2N), 40.3 (Ar–
CH), 39.6 (CHCH2CH), 33.0 (COCH2), 29.7 (NCHCH2), 19.1
(CH2CH2CO); MS (APCI, pos.): m/z 276.5 (M + 1); HRMS
(CI): m/z 275.1526 (275.1521 calc. for C16H21NO3 (M+)).
t
t
(3R,9aS)-Hexahydro-3-(4-methoxyphenyl)-1H-quinolizine-2,6-
dione (15)
To a solution of the above acid (0.60 g, 1.53 mmol) in metha-
nol (12 mL) at 0 °C was added SOCl2 (0.51 mL, 7.02 mmol)
and the mixture was stirred at ambient temperature for 16 h. The
methanol was removed under reduced pressure, the residue was
diluted with dichloromethane (25 mL) and the resulting solution
was washed with water (10 mL). The organic layer was dried
(Na2SO4) and concentrated under reduced pressure to provide
0.43 g, (91%) of methyl 4-((2S,4S,5R)-4-hydroxy-5-(4-methoxy-
phenyl)piperidin-2-yl)butanoate (13b) as an off white solid. This
To a stirred solution of the alcohol 14 (0.45 g, 1.63 mmol) in
dichloromethane (15 mL) was added DMSO (8 mL) followed by
DIPEA (2.4 mL) at 0 °C. Solid SO3·pyridine (781 mg,
4.90 mmol) was added in small portions and the mixture was
stirred at 0 °C for 1 h. Water (10 mL) was added and the mixture
was diluted with dichloromethane (20 mL). The mixture was
washed with water (2 × 30 mL) and the organic layer was dried
(Na2SO4) and concentrated to provide 420 mg (94%) of 15 as a
brown solid.
1
material was pure by H NMR and was used in the next step
without purification.
Mp: 88–90 °C; IR (neat): 2921, 1719, 1624, 1514, 1447,
1338, 1242, 1171, 1022, 826 cm−1 1H NMR (500 MHz,
;
IR (neat): 3123, 2940, 1727, 1610, 1510, 1433, 1240, 1168,
CDCl3): δ 7.06 (d, 2H, J = 8.7, ArH), 6.89 (d, 2H, J = 8.7,
ArH), 5.15–5.08 (dd, 1H, J = 12.7, 6.2, NCH2), 3.85–3.82 (m,
1H, NCH) 3.79 (s, 3H, OCH3), 3.67–3.61 (dd, 1H, J = 12.7, 6.2,
NCH2), 3.00–2.91 (t, 1H, J = 12.4, ArCH), 2.58–2.55 (m, 2H,
COCH2), 2.50–2.46 (m, 2H, NCOCH2), 2.18–2.09 (m, 1H,
NCHCH2), 1.97–1.78 (m, 2H, COCH2CH2), 1.72–1.63 (m, 1H,
NCHCH2); 13C NMR (75 MHz, CDCl3): δ 206.2 (CO), 169.4
(NCO), 159.0 (ArCOCH3),129.9 (2 × ArC), 126.8 (ArC), 114.1
(2 × ArC), 56.0 (NCH), 55.4 (OCH3), 55.3 (ArCCH), 48.3
(NCH2), 47.7 (COCH2), 32.8 (NCOCH2), 29.6 (COCH2CH2),
18.9 (NCHCH2); MS (APCI pos.): m/z 274.1 (M + 1); HRMS
(CI+): m/z 273.1371 (273.1365 calc. for C16H19NO3, M+).
1
1030, 828 cm−1; H NMR (500 MHz, CDCl3): δ 7.14 (d, 2H,
J = 8.6, ArH), 6.87 (d, 2H, J = 8.6, ArH), 4.08–4.07 (br m, 1H,
CHOH), 3.79 (s, 3H, ArOCH3), 3.67 (s, 3H, CO2CH3),
3.39–3.31 (t, 1H, J = 12.0, NCH2), 3.00–2.91 (m, 2H, NCH,
ArCH), 2.84–2.79 (m, 1H, NCH2), 2.37–2.32 (t, 2H, J = 7.4,
CH2CO2CH3), 1.99–1.92 (dt, 1H, J = 2.9, 13.6, CHCH2CH),
1.73–1.63 (m, 4H, CHCH2CH, CH2CH2CO, CHNH), 1.49–1.35
(m, 2H, NCHCH2); 13C NMR (75 MHz, CDCl3): δ 174.0
(CO2CH3), 158.5 (ArC–OCH3), 133.3 (ArCipso), 128.8 (2 ×
ArC), 114.1 (2 × ArC), 69.3 (CHOH), 55.3 (ArOCH3), 51.6
(CO2CH3), 49.4 (NHCH), 47.0 (CH2N), 44.8 (ArCH), 39.5
(CHCH2CH), 36.4 (NHCHCH2), 34.1 (CH2CO2CH3), 21.4
(CH2CH2CO2CH3); MS (APCI, pos.): m/z 308.3 (M + 1);
HRMS (CI): m/z 308.1861 (308.1862 calc. for C17H26NO4
(M + H)).
(S)-4,6,7,8,9,9a-Hexahydro-3-(4-methoxyphenyl)-6-oxo-1H-
quinolizin-2-yl trifluoromethanesulfonate (16)
To a solution of the above amino ester (0.38 g, 1.23 mmol) in
THF (6 mL) was added diisopropylethylamine (752 μL,
4.31 mmol) and the solution was heated to reflux for 16 h.
Additional diisopropylethylamine (0.25 mL, 1.43 mmol) was
added and the mixture was refluxed for 2 h. The THF was
removed under reduced pressure, the residue was dissolved
in dichloromethane (30 mL) and the resulting solution was
washed with aqueous HCl (0.5 M, 2 × 10 mL). The organic
layer was dried (Na2SO4) and concentrated to provide 246 mg
(73%) of the lactam 14 as a pale yellow foam. This material was
pure by 1H NMR and was used in the next step without
purification.
To a suspension of KH (66 mg, 0.50 mmol) in THF (2 mL) was
added the ketone 15 (136 mg, 0.50 mmol) at 0 °C. The mixture
was stirred at room temperature for 2 h and a solution of N-phe-
nylbistrifluoromethanesulfonimide (195 mg, 0.55 mmol) in THF
(2 mL) was added dropwise at 0 °C. The mixture was then
stirred for 0.5 h at room temperature. Water (7 mL) was added
and the mixture was extracted with EtOAc (2 × 20 mL). The
combined organic layers were dried (Na2SO4) and concentrated
to give a brown gum which was purified by flash chromato-
graphy on silica gel (EtOAc) to provide 150 mg (74%) of 16 as
a yellow gum.
6782 | Org. Biomol. Chem., 2012, 10, 6776–6784
This journal is © The Royal Society of Chemistry 2012

View Article Online
IR (neat): 2942, 1642, 1512, 1412, 1206, 1138, 1036,
(1 mL) and water (48 μL), were added sequentially with vigor-
ous stirring. The precipitated inorganic salts were filtered and
washed with dichloromethane. The combined filtrates were dried
(Na2SO4) and concentrated to give a yellow gum. This was
purified by flash chromatography on silica gel (CHCl3–MeOH,
99 : 1) to provide 63 mg (89%) of 1 as a pale yellow gum.
IR (neat): 2928, 1604, 1509, 1458 1242, 1172, 1029,
1
833 cm−1; H NMR (500 MHz, CDCl3): δ 7.26 (d, 2H, J = 8.8,
ArH), 6.91 (d, 2H, J = 8.8, ArH), 5.28 (d, 1H, J = 18.4, NCH2),
3.82 (s, 3H, OCH3), 3.82–3.77 (m, 1H, NCH), 3.64 (d, 1H, J =
18.4, NCH2), 2.79–2.72 (m, 1H, COCH2), 2.52–2.49 (m, 1H,
COCH2), 2.49–2.43 (m, 2H, CvCCH2) 2.20–2.11 (m, 1H,
COCH2CH2), 1.99–1.89 (m, 1H, COCH2CH2), 1.81–1.61 (m,
2H, NCHCH2); 13C NMR (75 MHz, CDCl3): δ 169.6 (CvO),
160.0 (TfOCvC), 139.3 (ArCOCH3), 129.7 (2 × ArC), 128.0
(ArC), 124.8 (TfOCvC), 122.5 (q, J = 346.4, CF3), 114.0
(2 × ArC), 55.3 (OCH3), 52.7 (NCH), 45.5 (NCH2), 35.6
(CvCCH2CH), 32.8 (COCH2), 28.3 (NCHCH2), 18.2
(COCH2CH2); MS (APCI pos.): m/z 406.1 (M + 1); HRMS
(CI+): m/z 405.0865 (405.0858 calc. for C17H18NO5SF3, M+).
1
830 cm−1; H NMR (500 MHz, CDCl3): δ 6.98 (d, 2H, J = 8.6,
ArH), 6.69–6.67 (m, 4H, ArH), 6.46 (br s, 1H, ArH), 3.81 (s,
3H, OCH3), 3.73 (s, 3H, OCH3), 3.62–3.59 (br d, 1H, J = 16.5),
3.53 (s, 3H, OCH3) 3.10–3.03 (m, 2H), 2.55–2.51 (br d, 1H, J =
18.1), 2.41–2.30 (m, 2H), 2.11–2.10 (m, 1H), 1.86–1.80 (m,
2H), 1.75–1.70 (br m, 2H), 1.36–1.35 (br m, 2H); 13C NMR
(75 MHz, CDCl3): δ 158.0, 147.9, 147.2, 134.5, 133.2, 131.5,
131.3, 130.2, 120.5, 113.4, 113.0, 110.5, 62.8, 60.4, 57.9, 55.7,
55.6, 55.5, 55.2, 39.6, 33.3, 30.0, 25.9, 24.4; MS (APCI pos.):
m/z 380.5 (M + 1); HRMS (CI+): m/z 379.2151 (379.2147 calc.
for C24H29NO3, M+). [α]D23 = +88.8° (c 0.5, CHCl3, Lit.10a [α]2D6
= −71.6° (c 0.33, CHCl3 for the R-enantiomer).
(S)-2,3,9,9a-Tetrahydro-8-(3,4-dimethoxyphenyl)-7-(4-methoxy-
phenyl)-1H-quinolizin-4(6H)-one (17)
To a stirred solution of the enol triflate 16 (150 mg, 0.37 mmol)
and 3,4-dimethoxyphenyl boronic acid (74 mg, 0.41 mmol) in
dioxane (6 mL) was added a degassed, aqueous solution of
Na2CO3 (118 mg, 1.11 mmol, in 0.50 mL water) and the mixture
was degassed with a stream of nitrogen for 15 min. Pd(PPh3)4
(21 mg, 0.019 mmol) was added and the mixture was heated
with stirring at 85 °C for 90 min. The mixture was then cooled
to ambient temperature, diluted with EtOAc (15 mL) and the
resulting mixture was washed with water (2 × 10 mL). The
organic layer was dried (Na2SO4) and concentrated to give a
brown gum. This was purified by flash chromatography on silica
gel (CH2Cl2–methanol, 98.5 : 1.5) to provide 120 mg (82%) of
17 as a white solid.
(S)-2,3,6-Trimethoxy-11,12,13,14,14a,15-hexahydro-9H-dibenzo-
[f,h]pyrido[1,2-b]isoquinoline ((+)-cryptopleurine, 2)
A modification of the literature procedure was employed.10e To a
stirred solution of 1 (65 mg, 0.17 mmol) in dichloromethane
(10 mL) at ambient temperature was added thallium(III) trifluoro-
acetate (94 mg, 0.17 mmol) and the mixture was stirred for
30 min. The volatiles were removed under reduced pressure,
water (5 mL) was added to the residue and the mixture was
basified with saturated aqueous sodium carbonate. The mixture
was then extracted with chloroform (2 × 15 mL). The combined
extracts were dried and concentrated. The residue obtained was
purified by flash chromatography on silica gel (CH2Cl2–MeOH,
98 : 2) to give a yellow solid which was recrystallized from
chloroform–acetone to give 40 mg (62%) of 2 as a white crystal-
line solid.
Mp: 94–101 °C; IR (neat): 2944, 1635, 1510, 1454, 1245,
1
1173, 1028, 824 cm−1; H NMR (500 MHz, CDCl3): δ 7.00 (d,
2H, J = 8.7, ArH), 6.71–6.68 (m, 3H, ArH), 6.62 (dd, 1H, J =
8.3, 2, ArH), 6.43 (s, 1H, ArH), 5.20 (d, 1H, J = 18.7 NCH2),
3.81 (s, 3H, OCH3), 3.81–3.79 (m, 1H, NCH), 3.73 (s, 3H,
OCH3), 3.72–3.68 (d, 1H, J = 18.7, NCH2), 3.55 (s, 3H, OCH3),
2.60–2.57 (m, 2H, CvCCH2), 2.48–2.46 (t, 2H, J = 12.7,
COCH2), 2.16–2.11 (m, 1H, NCHCH2) 1.91–1.88 (m, 1H,
COCH2CH2), 1.81–1.72 (m, 2H, COCH2CH2, NCHCH2); 13C
NMR (75 MHz, CDCl3): δ 169.4 (CvO), 158.4 (ArC–OCH3),
148.1 (ArC–OCH3), 147.5 (ArC–OCH3), 133.9 (ArCCvC),
131.9 (CvCCH2CH), 131.2 (CvCCH2N), 131.1 (ArC), 130.4
(2 × ArC), 120.6 (ArCH), 113.5 (2 × ArC), 113.0 (ArC), 110.6
(ArC), 55.7 (NCH), 55.6 (OCH3), 55.2 (OCH3), 52.8 (OCH3),
46.8 (NCH2), 38.9 (CvCCH2CH), 33.0 (COCH2), 28.7
(NCHCH2), 18.5 (COCH2CH2); MS (APCI pos.): m/z 394.2
(M + 1); HRMS (CI+): m/z 394.2016 (394.2018 calc. for
C24H28NO4, M + H).
Mp: 190–194 °C (Lit.20 mp. 197–198 °C (benzene); IR (neat):
2926, 1610, 1509, 1467, 1253, 1141, 1040, 846, 748, 632 cm−1
;
1H NMR (500 MHz, CDCl3): δ 7.91 (s, 1H), 7.9 (d, 1H J = 2.6),
7.26 (s, 1H), 7.20 (dd, 1H, J = 2.6, 9), 4.44 (d, 1H, J = 15.5),
4.10 (s, 3H), 4.06 (s, 3H), 4.01(s, 3H), 3.64 (d, 1H, J = 15.3),
3.28 (d, 1H, J = 10.8), 3.13–3.09 (dd, 1H, J = 4, 16.3),
2.92–2.86 (m, 1H), 2.43–2.39 (t, 1H, J = 10.3), 2.34–2.28 (td,
1H, J = 3.8, 11.5), 2.04 (d, 1H, J = 13.9), 1.89 (d, 1H, J = 12.3),
1.81–1.77 (m, 2H), 1.56–1.44 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ 157.4, 149.4, 148.3, 130.1, 126.5, 125.7, 124.5,
124.1, 123.7, 123.4, 114.8, 104.7, 103.9 (2 × ArC), 57.6, 56.3,
56.2, 56.0, 55.9, 55.5, 34.8, 33.9, 26.0, 24.4; MS (APCI pos.):
m/z 378.1 (M + 1); HRMS (CI+): m/z 377.1990 (377.1991 calc.
for C24H29NO3, M+); [α]D23 = +104.6° (c 0.55, CHCl3); Lit.12d
[α]2D3 = +106 ° (c 1, CHCl3)).
(S)-4,6,7,8,9,9a-Hexahydro-2-(3,4-dimethoxyphenyl)-3-(4-methoxy-
phenyl)-1H-quinolizine ((+)-julandine, 1)
To a suspension of LiAlH4 (38 mg, 1 mmol) in dry THF
(1.5 mL) at 0 °C was slowly added a solution of the lactam 17
(0.10 g, 0.25 mmol) in THF (2 mL). The mixture was stirred for
an hour at 0 °C and then at ambient temperature for 24 h. It was
then cooled to 0 °C and water (18 μL, 1 mmol), 1 N NaOH
Acknowledgements
We gratefully acknowledge financial support from the Natural
Sciences and Engineering Research Council of Canada and the
Canada Foundation for Innovation.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6776–6784 | 6783

View Article Online
Q. Wang, Tetrahedron Lett., 2010, 51, 1377; (c) S. Kim, T. Lee, E. Lee,
J. Lee, G.-J. Fan, S. K. Lee and D. Kim, J. Org. Chem., 2004, 69, 3144;
also see ref. 10a. Synthesis of (S)-(+)-cryptopleurine: (d) T. F. Buckley
and H. Rapoport, J. Org. Chem., 1983, 48, 4222. Selected syntheses of
racemic cryptopleurine: (e) M. Cui and Q. Wang, Eur. J. Org. Chem.,
2009, 5445; (f) S. Kim, Y. Lee, J. Lee, T. Lee, Y. Fu, Y. Song, J. Cho and
D. Kim, J. Org. Chem., 2007, 72, 4886; (g) A. Fuerstner and
J. W. Kennedy, Chem.–Eur. J., 2006, 12, 7398; (h) S. Lebrun,
A. Couture, E. Deniau and P. Grandelaudon, Tetrahedron, 1999, 55,
2659; (i) M. L. Bremmer, N. A. Khatri and S. M. Weinreb, J. Org.
Chem., 1983, 48, 3661; ( j) M. Iwao, K. K. Mahalanabis, M. Watanabe,
S. O. De Silva and V. Snieckus, Tetrahedron, 1983, 39, 1955;
(k) G. G. Trigo, E. Galvez and M. M. Sollhuber, J. Heterocycl. Chem.,
1980, 17, 69. Formal synthesis of racemic cryptopleurine:
(l) S. Yamashita, N. Kurono, H. Senboku, M. Tokuda and K. Orita,
Eur. J. Org. Chem., 2009, 1173; also see ref. 10c–f.
Notes and references
1 (a) M. P. Joseph, Nat. Prod. Rep., 2008, 25, 139; (b) J. W. Daly,
T. F. Spande and H. M. Garraffo, J. Nat. Prod., 2005, 68, 1556.
2 (a) S. R. Chemler, Curr. Bioact. Compd., 2009, 5, 2; (b) Z. Li, Z. Jin and
R. Huang, Synthesis, 2001, 2365.
3 (a) G. R. Donaldson, M. R. Atkinson and A. W. Murray, Biochem.
Biophys. Res. Commun., 1968, 31, 104; (b) D. Staerk, A. K. Lykkeberg,
J. Christensen, B. A. Budnik, F. Abe and J. W. Jaroszewski, J. Nat. Prod.,
2002, 65, 1299; (c) W. Gao, S. Busson, S. P. Grill, E. A. Gullen,
Y.-C. Hu, X. Huang, S. Zhong, C. Kaczmarek, J. Gutierrez, S. Francis,
D. C. Baker, S. Yu and Y.-C. Cheng, Bioorg. Med. Chem. Lett., 2007, 17,
4338; (d) Y. Fu, S. K. Lee, H.-Y. Min, T. Lee, J. Lee, M. Cheng and
S. Kim, Bioorg. Med. Chem. Lett., 2007, 17, 97.
4 C.-W. Yang, Y.-Z. Lee, I.-J. Kang, D. J. Barnard, J.-T. Jan, D. Lin,
C.-W. Huang, T.-K. Yeh, Y.-S. Chao and S.-J. Le, Antiviral Res., 2010,
51, 1377.
5 K. K. Bhutani, G. L. Sharma and M. Ali, Planta Med., 1987, 53,
532.
13 E. Krmpotic, N. R. Farnsworth and W. M. Messmer, J. Pharm. Sci.,
1972, 61, 1508.
14 N. Entner and A. P. Grollman, J. Protozool., 1973, 20, 160.
15 (a) S. V. Pansare and K. Pandya, J. Am. Chem. Soc., 2006, 128, 9624;
(b) S. V. Pansare and R. L. Kirby, Tetrahedron, 2009, 65, 4557.
6 (a) C. Gopalakrishnan, D. Shankaranarayan, L. Kameswaran and
S. Natarajan, Ind. J. Med. Res., 1979, 69, 513; (b) C. Gopalakrishnan,
D. Shankaranarayanan, S. K. Nazimudeen and L. Kameswaran,
Ind. J. Med. Res., 1980, 71, 940.
7 Selected recent reports: (a) M. Rueping and L. Hubener, Synlett, 2011,
1243; (b) G. Belanger, G. O’Brien and R. Larouche-Gothier, Org. Lett.,
2011, 13, 4268; (c) X.-Y. Dai, X.-Y. Wu, H.-H. Fang, L.-L. Nie, J. Chen,
H.-M. Deng, W.-G. Cao and G. Zhao, Tetrahedron, 2011, 67, 3034;
(d) A. Pepe, M. Pamment, G. Georg and S. V. Malhotra, J. Org. Chem.,
2011, 76, 3527; (e) A. C. Bissembler and M. G. Banwell, Tetrahedron,
2009, 65, 8222; (f) S. M. Amorde, I. T. Jewett and S. F. Martin, Tetra-
hedron, 2009, 65, 3222.
8 (a) J. Jiang, J. Qing and L.-Z. Gong, Chem.–Eur. J., 2009, 15, 7031;
(b) I. Vazzana, E. Terranova, B. Tasso, M. Tonelli, A. Piana, S. Gastaldi
and F. Sparatore, Chem. Biodiversity, 2008, 5, 714; (c) A. Diez, S. Mavel,
J. C. Teulade, O. Chavignon, M. E. Sinibaldi, Y. Troin and M. Rubiralta,
Heterocycles, 1993, 36, 2451; (d) M. Rubiralta, A. Diez, C. Vila,
J. L. Bettiol, Y. Troin and M. E. Sinibaldi, Tetrahedron Lett., 1992, 33,
1233; (e) M. Rubiralta, A. Diez, C. Vila, Y. Troin and M. Feliz, J. Org.
Chem., 1991, 56, 6292; (f) R. Imhof, E. Kyburz and J. J. Daly, J. Med.
Chem., 1984, 27, 165.
9 Selected recent reports: (a) Z. Wang and Q. Wang, Tetrahedron Lett.,
2010, 51, 1377; (b) T.-H. Chuang, S.-J. Lee, C.-W. Yang and P.-L. Wu,
Org. Biomol. Chem., 2006, 4, 860; (c) M. G. Banwell and M. O. Sydnes,
Aust. J. Chem., 2004, 57, 537.
16 Reports on the application of organocatalytic Michael addition products
in total synthesis: (a) S. Zhu, S. Yu, Y. Wang and D. Ma, Angew. Chem.,
Int. Ed., 2010, 49, 4656; (b) H. Ishikawa, T. Suzuki and Y. Hayashi,
Angew. Chem., Int. Ed., 2009, 48, 1304; (c) J. Pavol, D. M. Cockfield
and D. J. Dixon, J. Am. Chem. Soc., 2009, 131, 16632; (d) P. Elsner,
H. Jiang, J. B. Nielsen, F. Pasi and K. A. Jorgensen, Chem. Commun.,
2008, 5827; (e) O. Andrey, A. Vidonne and A. Alexakis, Tetrahedron
Lett., 2003, 44, 7901; (f) P. S. Hynes, P. A. Stupple and D. J. Dixon,
Org. Lett., 2008, 10, 1389; (g) B.-C. Hong, P. Kotame, C.-W. Tsai and
J.-H. Liao, Org. Lett., 2010, 12, 776; (h) S. V. Pansare, R. Lingampally
and R. L. Kirby, Org. Lett., 2010, 12, 556; (i) B.-C. Hong, R. Y. Nimje,
M.-F. Wu and A. Sadani, Eur. J. Org. Chem., 2008, 1149;
( j) S. V. Pansare, R. Lingampally and R. Dyapa, Eur. J. Org. Chem.,
2011, 2235.
17 J. Sun, Y. Dong, L. Cao, X. Wang, S. Wang and Y. Hu, J. Org. Chem.,
2004, 69, 8932.
18 S.-I. Murahashi and Y. Kodera, Tetrahedron Lett., 1985, 26, 4633.
19 The structure of 11 and the 1H NMR assignments are supported by 2D
1H NMR spectroscopy (see the ESI†). The stereochemical assignments
for 11 are based on NOE experiments and correlation to known com-
pounds. (+)-Cryptopleurine has been synthesized earlier by Rapoport
(ref. 12d) from S-α-aminoadipic acid. This synthesis established
the absolute configuration of (+)-cryptopleurine as S. The formation of
(+)-cryptopleurine in our synthesis therefore confirms the absolute
configuration at C-2 in 11 as ‘S’. The configuration at C-5 in 11 derives
from the Michael adduct 3, whose stereochemistry is assigned by corre-
lation of 1H NMR data to that of analogues of 3 whose structures have
10 Synthesis of (R)-(–)-julandine:
(a) H. Suzuki, S. Aoyagi and
C. Kibayashi, J. Org. Chem., 1995, 60, 6114; Synthesis of racemic julan-
dine: (b) M. A. Ciufolini and F. Roschangar, J. Am. Chem. Soc., 1996,
118, 12082; (c) P. A. Grieco and D. T. Parker, J. Org. Chem., 1988, 53,
3325; (d) H. Iida, Y. Watanabe, M. Tanaka and C. Kibayashi, J. Org.
Chem., 1984, 49, 2412; (e) J. E. Cragg and R. B. Herbert, J. Chem. Soc.,
Perkin Trans. 1, 1982, 2487; (f) R. B. Herbert, Chem. Commun., 1978,
794.
been established by X-ray crystallographic analysis (Ar
= Ph,
(A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold and
S. V. Ley, Org. Biomol. Chem., 2005, 3, 84); Ar = 4-BrPh (D. Seebach,
I. M. Lyapkalo and R. Dahinden, Helv. Chim. Acta, 1999, 82, 1829)).
The configuration at C-4 in 11 is established by the cis relationship
between the methine protons at C-4 and C-5 which was confirmed by
NOE experiments.
11 A. Al-Shamma, S. D. Drake, L. E. Guagliardi, L. A. Mitscher and
J. K. Swayze, Phytochemistry, 1982, 21, 485.
12 Synthesis of (R)-(–)-cryptopleurine: (a) M. Cui, H. Song, A. Feng,
Z. Wang and Q. Wang, J. Org. Chem., 2010, 75, 7018; (b) Z. Wang and
20 E. Gellert and N. V. Riggs, Aust. J. Chem., 1954, 7, 113.
6784 | Org. Biomol. Chem., 2012, 10, 6776–6784
This journal is © The Royal Society of Chemistry 2012