New strategy for the synthesis of ladybird beetle azaphenalene alkaloids using a combination of allylboration and intramolecular metathesis. Total synthesis of (±)-Hippocasine and (±)-epi-Hippodamine

Article abstract of DOI:10.1007/s11172-014-0464-3

A new strategy for assembly a tricyclic skeleton of ladybirds azaphenalene alkaloids (coccinellides) was developed based on the combination of allylboration reaction and intramolecular metathesis. The first key step is the 1,2-organolithiation of 4-picoline with (4,4-dieth-oxybutyl)lithium with subsequent reductive allylation with triallylborane leading to trans-2-allyl-6-(4,4-diethoxybutyl)-4-methyl-1,2,3,6-tetrahydropyridine. The 4,4-diethoxybutyl substituent was further converted to 4-acetoxy-5-hexenyl in four steps, then, the product obtained was involved in the second key step, the intramolecular allylic amination upon treatment with a [Pd] or an [Ir] catalyst giving diastereomeric bicyclic terminal dienes (μ1: 1), which were separated by chromatography. The stereochemistry of one of the dienes is the same as that in alkaloid Hippocasine. The third key step (the intramolecular metathesis reaction) includes the final assembly of the azaphenalene system. The tricyclic derivative obtained contains two differently substituted C=C bonds, selective hydrogenation of one of which (Pd/C) leads to (±)-Hippocasine, whereas exhaustive hydrogenation gives (±)-epi-Hippodamine.

Full text of DOI:10.1007/s11172-014-0464-3

Russian Chemical Bulletin, International Edition, Vol. 63, No. 2, pp. 529—537, February, 2014
529
New strategy for the synthesis of ladybird beetle azaphenalene alkaloids using
a combination of allylboration and intramolecular metathesis.
Total synthesis of ( )ꢀHippocasine and ( )ꢀepiꢀHippodamine*
N. Yu. Kuznetsov,a,b S. E. Lyubimov,b I. A. Godovikov,b and Yu. N. Bubnova,b
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: bubnov@ineos.ac.ru, nkuznff@ineos.ac.ru
A new strategy for assembly a tricyclic skeleton of ladybirds azaphenalene alkaloids (cocꢀ
cinellides) was developed based on the combination of allylboration reaction and intramolecuꢀ
lar metathesis. The first key step is the 1,2ꢀorganolithiation of 4ꢀpicoline with (4,4ꢀdiethꢀ
oxybutyl)lithium with subsequent reductive allylation with triallylborane leading to transꢀ2ꢀ
allylꢀ6ꢀ(4,4ꢀdiethoxybutyl)ꢀ4ꢀmethylꢀ1,2,3,6ꢀtetrahydropyridine. The 4,4ꢀdiethoxybutyl subꢀ
stituent was further converted to 4ꢀacetoxyꢀ5ꢀhexenyl in four steps, then, the product obtained
was involved in the second key step, the intramolecular allylic amination upon treatment with
a [Pd] or an [Ir] catalyst giving diastereomeric bicyclic terminal dienes (~1 : 1), which were
separated by chromatography. The stereochemistry of one of the dienes is the same as that in
alkaloid Hippocasine. The third key step (the intramolecular metathesis reaction) includes the
final assembly of the azaphenalene system. The tricyclic derivative obtained contains two
differently substituted C=C bonds, selective hydrogenation of one of which (Pd/C) leads to
(
)ꢀHippocasine, whereas exhaustive hydrogenation gives ( )ꢀepiꢀHippodamine.
Key words: Hippocasine, epiꢀHippodamine, allylboranes, allylboration, nitrogen heteroꢀ
cycles, cyclization, metathesis.
Ladybird beetles (Coccinellidae) is a large Coleoptera
family with more than 5000 species worldwide,1—3 about
100 of which live in Russia.1 These beetles and their larvae
are very voracious and play an important environmental
role in the regulation of the population of crop pests, conꢀ
suming a large amounts of aphids, psyllides, mealy and
citrus coccids, scale insects, and mites. Many coccinellid
species have bright coloration (red, yellow, rarely black),
thus noticeably differing from most other insects. Despite
the bright colour pattern, ladybirds have little enemies:
apparently, only parasites,4 ants, quails,2 and amphibiꢀ
ans.5 Other insects and birds do not eat them. This is
explained by a highly developed mechanism of chemical
defence of coccinellids, known as reflex bleeding.1 When
disturbed or molested, these insects "throw away" small
droplets of bitter and very toxic hemolymph
from the tibioꢀfemoral joints of their legs, thus repelling
the potential predators. In 1970th, by alcoholic extraction
of grounded adult coccinellids were isolated and characꢀ
terized eight alkaloids, which were found to be differently
joint isomers of 2ꢀmethylperhydro[9b]azaphenalene or
its monodehydro analogs (hippocasine and hippocasine
Nꢀoxide)1,2,6 (Fig. 1).
Apparently, coccinellids are the only natural source of
these compounds, however, on a milligram scale.1,2 To
date, all the alkaloids7,8 shown in Fig. 1 are synthesized,
including methods using perhydro[9b]boraphenalene as
the starting compounds.7b,c
There are data that some azaphenalene alkaloid derivꢀ
atives, viz., azaphenalene esters and amides of aromatic
acids, are powerful antagonists of serotonin receptors,9
thus attracting attention of researches who are dealing
with the search of agents for treatment of diseases of the
central nervous system, brain, and digestive tract.
In the present work, we describe a total synthesis
of alkaloids ( )ꢀHippocasine and ( )ꢀepiꢀHippodamine
(the isomer of Hippodamine alkaloid) from 4ꢀpicoline.
We for the first time used allylboration reaction, palladiꢀ
umꢀ and iridiumꢀcatalyzed intramolecular allylic aminaꢀ
tion, and metathesis reaction as the key steps of the
synthesis.
* On the occasion of the 80th anniversary of the N. D. Zelinsky
Institute of Organic Chemistry of the Russian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0529—0537, February, 2014.
1066ꢀ5285/14/6302ꢀ0529 © 2014 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Kuznetsov et al.
Fig. 1. Alkaloids of azaphenalene family produced by coccinellides.
Results and Discussion
Earlier, we have developed a general approach to the
preparation of various transꢀ6ꢀRꢀ2ꢀallylꢀ3ꢀpiperideines
(tetrahydropyridines), based on the combination of the
long known 1,2ꢀorganolithiation of pyridines10 and subseꢀ
quent transꢀ2ꢀallylation with triallylborane in the presꢀ
ence of alcohols11 (Scheme 2).
The retroꢀsynthetic analysis (Scheme 1) shows that
hippocasine and some other perhydro[9b]azaphenalene
compounds can be obtained by the reductive transꢀ6ꢀalkylꢀ
2ꢀallylation of 4ꢀpicoline and subsequent closure of secꢀ
ond and third rings.
Scheme 2
Scheme 1
R = Alk, Ar
Reagents and conditions: i. 1) RLi, –70—0 C; 2) All3B, MeOH
(4 equiv.), –15 C; 3) NaOH, H2O.
This approach was applied for the synthesis of a numꢀ
ber of important piperidine11c,d,12a,b and indolizidꢀ
ine11c,d,12c alkaloids. The same combination of these two
oneꢀpot reactions was the first key step in our synthesis of
azaphenalene compounds. To accomplish the synthesis
according to the retroꢀsynthetic Scheme 1, we started from
the development of a convenient method for the preparaꢀ

Hippocasine and epiꢀHippodamine: total synthesis
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
531
tion of 4,4ꢀdiethoxyꢀ1ꢀbutenes 2 (Scheme 3), consisting
in the monoallylation of triethyl orthoformate with trialꢀ
lylꢀ, trimethallylꢀ, or tricrotylborane in the presence of
zinc trifluoromethanesulfonate as a catalyst (1 mol.%) at
70 C. The preparative yields of acetals 2a—c are 89—94%
(Table 1).
ucts. Moreover, in all the cases, the reaction resulted in
a mixture of acetal and the starting orthoformate, which
cannot be separated by distillation, that makes it impossiꢀ
ble to use it for the synthetic purposes. It should be noted
that the thermal reaction of triallylborane with HC(OEt)3
(135—140 C, without catalyst) follows an alternative
pathway and leads to the formation of a mixture of diallylꢀ
boronic acid ester (All2BOEt) and triallylmethylboronic
acid ester [All3C—B(OEt)2] (35%).13
Scheme 3
Substitution of the EtO group in orthoformate is acꢀ
companied by allylic rearrangement (Scheme 4), apparꢀ
ently, through the transition state with cyclic electron
transfer. This is indicated by the formation from tricrotylꢀ
borane 1c of acetal 2c with a terminal C=C bond and
ꢀmethyl group. The fragment M can be both boron and
zinc derivative.14
Scheme 4
R1 = R2 = H (a); R1 = Me; R2 = H (b); R1 = H; R2 = Me (c)
Reagents and conditions: i. 1) Zn(OTf)2, 1 mol.(%), 70 C, 6 h;
2) NaOH, H2O
It should be noted that these reactions are carried out
without solvent. Their progress and completion were conꢀ
veniently monitored using 1H NMR spectra, that makes it
possible to control consumption of triethyl formate and
amount of the unreacted boronallylic fragments. Despite
all three allylic groups in the starting boron derivative are
involved in the reaction, we used a small excess of borane
(R3B : HC(OEt)3 = 1 : 2.5—2.9) for the more rapid proꢀ
ceeding of the reaction. It appeared that other Lewis acids
(Et2O•BF3, ZnCl2, InCl3) also catalyzed the reaction,
but less efficiently (see Table 1). Thus, on the addition of
triallylborane to a mixture of orthoformate and Et2O•BF3,
a strong warmingꢀup was observed accompanied by the
formation of a considerable amount of polymeric prodꢀ
ucts, while the yield of the target acetal 2a was only 36%.
The allylation of the orthoformate in the presence of ZnCl2
and InCl3 proceeded with higher yields (58 and 67%), but
was also complicated by the formation of polymeric prodꢀ
Acetal 2a obtained according to Scheme 3 was further
transformed to iodide 3 using a modified procedure15
through the hydroboration and subsequent cleavage of the
trialkylborane formed with iodine in the presence of the
equimolar amount of potassium ethylate (obtained by the
dissolution of ButOK in anhydrous ethanol) (Scheme 5).
Note a high synthetic potential of iodoacetal 3, which was
earlier used (as dimethyl acetal) in the synthesis of a taxol
derivative for the expansion of one of the carbocycles by
four carbon atoms at once.16
Table 1. Allylation of triethyl orthoformate with allylic boranes
Scheme 5
R3B (EtO)3CH
(equiv.)
t/
C
Time/
h
Lewis acid
(mol.%)
Yield
(%)
1a
1a
1a
1а
1b
1c
1.5
1.8
2.0
2.9
2.9
2.9
5—12
20—30
25
24
1.5
3
Et2O•BF3 (10%)
ZnCl2 (5%)
InCl3 (5%)
Zn(OTf)2 (1%)
Zn(OTf)2 (1%)
36
58
67
94
89
92
25а, 75b 1а, 6b
25а, 75b 1а, 6b
25а, 85b 1а, 10b Zn(OTf)2 (1%)
a Conditions for the initial exothermic reaction.
b Conditions for the subsequent process.
Reagents and conditions: i. 1) BH3•Me2S; 2) I2/ButOK/EtOH);
ii. 2 ButLi, Et2O, –90  20 C.

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Kuznetsov et al.
Table 2. Yields and ratios of amines 12 and 13*
The reaction of iodoacetal 3 with tertꢀbutyllithium
(2 equiv.) led to the formation of the lithium derivative 4,
which was used for 1,2ꢀorganolithiation of 4ꢀpicoline17
(Scheme 6). Subsequent treatment of the lithium amide 5
with triallylborane 1a and methanol11a,12a—c gave transꢀ2ꢀ
allylꢀ6ꢀ(4,4ꢀdiethoxybutyl)ꢀ4ꢀmethylꢀ1,2,3,6ꢀtetrahydroꢀ
pyridine (6) (isolated by chromatography, 74%), which
was a key compound in the synthesis of the target product.
Entry
Catalyst/ligand
12 : 13
Yield (%)
1
2
3
[AllylPdCl]2/no ligand
[AllylPdCl]2/(S)ꢀPipphos
[Ir(COD)Cl]2/(S)ꢀPipphos/Pyrr 51 : 49
23 : 77
42 : 58
67
87
80
* The ratios of isomers were determined by GLC, 115 C, carrier
gas N2 (1.8 bar); retention times for compounds 12 and 13 are
6.24 and 6.87 min, respectively.
Scheme 6
(S)ꢀPipphos =
; Pyrr =
.
such a diastereoselectivity is observed in the palladiumꢀ
catalyzed (Pd/C, H2) intramolecular reductive amination
of related substrates.18 As it is seen from Tables 2, the
amination reaction with the Pdꢀcatalyst is successful even
without phosphorus ligands, leading to a mixture of dienes
12 and 13 (~1 : 3) in 67% yield (entry 1). Both dienes were
isolated in the individual states using chromatography on
silica gel.
The relative configurations of the chiral centers in
diene 13 were established based on the NMR spectra: iniꢀ
tially we assigned all the signals in the proton spectrum of
the compound (1H—1H COSY experiment), then we deꢀ
termined steric interactions of hydrogen atoms (NOESY)
(Fig. 2). As it is seen from Fig. 2, both substituents gave
nuclear Overhauser effect (NOE) between each other and
hydrogen at position 9a, besides, hydrogen atoms at posiꢀ
tions 4 and 6 also interact.
Thus, atom C(4) has R*ꢀconfiguration in the major
isomer 13 and, correspondingly, S* in isomer 12. From
this it follows that the configuration of stereocenters in
minor isomer 12 correspond to the configurations of the
chiral centers in alkaloid hippocasine (see Fig. 1). To inꢀ
crease the amount of the required isomer 12, the cyclization
of diene 11 was carried out in the presence of the phosꢀ
phite ligand (S)ꢀPipphos (see Table 2, entry 2); In this
case, the ratio of isomers 12 : 13 became 1 : 1.4. When an
Reagents and conditions: i. 0  20 C, Et2O, 1 h; ii. 1)
–15 C; 2) MeOH, NaOH.
,
Further, amine 6 was converted to the NꢀBocꢀderivaꢀ
tive 7, which was hydrolyzed in aqueous acetic acid to
aldehyde 8 (Scheme 7). The reaction of the latter with
vinylmagnesium bromide at –90 C furnished the allylicꢀ
type alcohol 9. Here two moments should be noted: 1)
vinylation of aldehyde 8 at temperatures above –70 C is
accompanied by the side processes, and the yield of
carbinol 9 decreases; 2) the vinylation reaction proceeds
diastereoselectively: only one diastereomer of alcohol 9
was obtained (confirmed by the NMR spectroscopic data),
that can be explained by the formation of a cyclic strucꢀ
ture in the coordination of the vinylmagnesium bromide
with the C=O groups of the side chain and the Bocꢀproꢀ
tection, with the bulky tertꢀbutyl group blocking one of the
sides of the aldehyde group in the course of the vinylation.
The subsequent acylation of carbinol 9 and removal of the
Boc protecting group in compound 10 by treatment with
trifluoroacetic acid resulted in the synthesis of amine 11.
Its intramolecular catalytic cyclization (allylic amination
upon treatment with allylpalladium dichloride or an iridiꢀ
um catalyst) led to a mixture of diastereomeric bicyclic
amines 12 and 13 in the ratio from ~1 : 3 to ~1 : 1 in 67—87%
total yield (see Scheme 7, Table 2). It should be noted that
Fig. 2. NOE in determination of configurations of centers in
compound 13.

Hippocasine and epiꢀHippodamine: total synthesis
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
533
Scheme 7
iridium catalyst [Ir(COD)Cl]2 was used with (S)ꢀPipphos
and pyrrolidine additive to accelerate the reaction,19
dienes 12 and 13 were obtained in the ratio 1 : 1 (see Table 2,
entry 3). Treatment of diene 12 with the second generaꢀ
tion Grubb´s catalyst (Scheme 8) gives the intramolecular
metathesis reaction with the formation of hydroazaphenꢀ
alene derivative 14 containing two different C=C bond,
the structure of which was confirmed by mass spectromeꢀ
try and NMR spectroscopy.
The presence of the differently substituted C=C bonds
in diene 14 allowed us to selectively hydrogenate the diꢀ
substituted double bond and obtain alkaloid hippocasine
(see Scheme 8), which was completely characterized
by spectroscopy for the first time in the present work.
Exhaustive hydrogenation of hippocasine gave epiꢀhipꢀ
podamine,8f the level of the minor epimer at the methꢀ
yl group (hippodamine alkaloid) was 6% (1H NMR
spectrum).
In conclusion, we developed a new strategy for the
assembly of tricyclic skeleton of the azaphenalene alkaꢀ
loids of coccinellids, which is based on the combination of
allylboration reaction and intramolecular metathesis. This
strategy was used for the synthesis of alkaloid hippocasine
and an epimer of hippodamine alkaloid, epiꢀhippodamine.
To accomplish this synthesis, we developed a new atomꢀ
saving method for the preparation of 4,4ꢀdiethoxyꢀ1ꢀ
butenes through the Znꢀcatalyzed allylation of triethyl
orthoformate with allylic boranes. The second and third rings
of the azaphenalene system were builtꢀup by the catalytic
reactions: allylic amination and intramolecular metatheꢀ
sis. We believe that the approach suggested can be used in
the synthesis of other compounds of azaphenalene family.
Scheme 8

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Kuznetsov et al.
J = 6.6 Hz) (cf. Ref. 14). 13C NMR (CDCl3, 100 MHz), : 139.64,
Experimental
114.47, 105.94, 62.07, 61.90, 41.11, 15.15 (2 C), 14.67.
n18 1.4122.
Reactions were carried out under dry argon. All the solvents
D
1,1ꢀDiethoxyꢀ4ꢀiodobutane (3). The compound BH3•Me2S
(BMS) (3.87 g, 4.83 mL, 51 mmol) was added to a solution of
4,4ꢀdiethoxyꢀ1ꢀbutene (2a) (21 g, 0.146 mol) in THF (60 mL)
over 10 min at 0 C with stirring. After the addition was completꢀ
ed, the cooling was removed, and the reaction mixture was stirred
for 1 h at 20 C. Anhydrous EtOH (1 mL) was added to neutralꢀ
ize excessive borohydride, then I2 (38.1 g, 0.15 mol) was added
in portions with stirring, maintaining temperature below 15 C.
A solution of ButOK (18.8 g, 0.168 mol) in anhydrous EtOH
(70 mL) was added dropwise to the mixture obtained, maintainꢀ
ing temperature within 15—25 C, then, the suspension formed
was stirred for 24 h. Excessive iodine was neutralized by addition of
aqueous Na2S2O3 and K2CO3 to adjust pH ~8 (to prevent hydrolysis
of the acetal). The mixture was poured into brine (500 mL), the
product was extracted with hexane (3 × 100 mL). The combined
extracts were washed with brine, dried with K2CO3, concentratꢀ
ed, and distilled in vacuo to isolate iodoacetal 3 (26.6 g, 67%),
b.p. 97—98 C (0.5 Torr). 1H NMR (CDCl3, 300 MHz), : 4.48
(t, 1 H, CH(OEt)2, J = 5.6 Hz); 3.62 (dq, 2 H, OCHaHb, J = 9.3 Hz,
J = 7.1 Hz); 3.46 (dq, 2 H, OCHaHb, J = 9.3 Hz, J = 7.1 Hz);
3.25 (t, 2 H, CH2I, J = 6.9 Hz); 1.94—1.82 (m, 2 H, CHCH2);
1.74—1.64 (m, 2 H, CH2CH2I); 1.18 (t, 6 H, 2 OCH2CH3,
J = 7.1 Hz). 13C NMR (CDCl3, 75 MHz), : 101.87, 61.19 (2 C),
34.46, 28.82, 15.32 (2 C), 6.74. Found (%): C, 35.36; H, 6.31;
I, 46.59. C8H17IO2. Calculated (%): C, 35.31; H, 6.30; I, 46.63.
transꢀ2ꢀAllylꢀ6ꢀ(4,4ꢀdiethoxybutyl)ꢀ4ꢀmethylꢀ1,2,3,6ꢀtetraꢀ
hydropyridine (6). A 1.5 M solution of ButLi (102.7 mL, 0.154 mol)
in pentane was added rapidly to a stirred solution of iodoacetal 3
(20.0 g, 73.5 mmol) in Et2O (200 mL) at –90 C, the mixture was
stirred for another 20 min, then the cooling was removed. The
mixture was allowed to warmꢀup to ~20 C, which was accomꢀ
panied by the formation of a white precipitate of organolithium
compound 4. The suspension obtained was cooled in a waterꢀice
bath to 0—5 C, followed by addition of 4ꢀpicoline (6.79 g, 7.11 mL,
73 mmol) and stirring for 1 h at 20 C. Then, the mixture was
cooled to –15 C, followed by addition of triallylborane (9.78 g,
12.6 mL, 73 mmol). The yellow twoꢀphase mixture was heated
to 10 C and MeOH (20 mL) was added, followed by a dropꢀ
wise addition of a 20% aqueous NaOH (20 mL). The reaction
mixture was deboronated by reflux for 30 min, the aqueous layer
was saturated with K2CO3. The organic layer was separatꢀ
ed, washed with brine, dried with K2CO3, concentrated, and
used were purified according to the standard procedures. NMR
spectra were recorded on Bruker Avance (300, 400 and 600 MHz)
spectrometers. Column chromatography was carried out using
Merck silica gel (60—230 mesh). Mass spectra were recorded on
a Finnigan Polaris Q Ion Trap instrument. Grubb´s ruthenium
catalyst, benzylidene[1,3ꢀbis(2,4,6ꢀtrimethylphenyl)ꢀ2ꢀimidꢀ
azolidinylidene]dichloro(tricyclohexylphosphine)ruthenium is
a commercial reagent available from Aldrich. Complexes
20
21
[Ir(COD)Cl]2 and [AllylPdCl]2 were obtained according to
the described procedures.
4,4ꢀDiethoxyꢀ1ꢀbutene (2a). Triallylborane (11.6 g, 14.9 mL,
86 mmol) was added to a mixture of triethyl orthoformate (37 g,
41.6 mL, 0.25 mol) and Zn(OTf)2 (0.91 g, 1 mol.%, 2.5 mmol)
with cooling in a bath with a tap water (25 C). After the exoꢀ
thermic reaction was completed (1 h), the reaction mixture was
stirred for another 6 h at 75 C. The reaction progress was monꢀ
itored by 1H NMR spectroscopy, following the disappearance of
the signals for the allylic (CH2=) and formate (CH) protons.
Then, the cooled reaction mixture was poured into 20% aqueous
NaOH (200 g) with vigorous stirring. The emulsion obtained was
extracted with diethyl ether (3×100 mL), the combined extracts
were dried with potassium carbonate, concentrated using a rotaꢀ
ry evaporator. The residue was distilled in vacuo using a waterꢀ
jet pump to isolate a fraction with b.p. 46—48 C (10 Torr). The
1
yield was 33.85 g (94%). H NMR (CDCl3, 300 MHz), : 5.86
(ddt, 1 H, CH=, J = 17.2 Hz, J = 10.2 Hz, J = 7.0 Hz); 5.21—5.10
(m, 2 H, CH2=); 4.57 (t, 1 H, OCH, J = 5.8 Hz); 3.73 (m, 2 H,
OCH2); 3.55 (m, 2 H, OCH2); 2.45 (tt, 2 H, CH2allyl, J = 1.0 Hz,
J = 5.8 Hz); 1.26 (t, 6 H, 2 Me, J = 7.1 Hz) (cf. Ref. 22a). 13C NMR
(DMSOꢀd6, 75 MHz), : 133.76 (CH=), 116.94 (CH2=), 101.55
(CHO2); 60.44 (2 CH2O); 38.07 (Me), 15.12 (Me). n18 1.4075
D
(cf. Ref. 22b).
4,4ꢀDiethoxyꢀ3ꢀmethylꢀ1ꢀbutene (2b). The reaction and
workꢀup were carried out similarly to those in the preparation of
compound 2a. Trimethallylborane (7.7 g, 44 mmol) was added
to a mixture of triethyl orthoformate (18.8 g, 0.127 mol) and
Zn(OTf)2 (0.47 g, 1.3 mmol), the reaction mixture was allowed
to stand for 1 h at 25 C, then heated for 6 h at 70 C. Distillation
gave a fraction with b.p. 62—65 C (10 Torr). The yield was:
18.46 g (92%). 1H NMR (CDCl3, 300 MHz), : 4.80—4.78 (m, 1 H,
CHAHB=); 4.76—4.74 (m, 1 H, CHAHB=); 4.61 (t, 1 H, OCH,
J = 5.8 Hz); 3.64 (dq, 1 H, OCH2, J = 9.3 Hz, J = 7.1 Hz); 3.49
(dq, 1 H, OCH2, J = 9.3 Hz, J = 7.1 Hz); 2.33 (d, 1 H,
CH2methallyl, J = 5.8 Hz); 1.76 (s, 2 H, Me), 1.18 (t, 3 H, 2 Me,
J = 7.1 Hz) (cf. Ref. 22c). 13C NMR (CDCl3, 100 MHz), : 141.50,
112.73, 101.79, 60.93 (2 C), 41.88, 23.08, 15.25 (2 C). n18D 1.4113.
4,4ꢀDiethoxyꢀ2ꢀmethylꢀ1ꢀbutene (2c). The reaction and
workꢀup were carried out similarly to those in the preparation of
compound 2a. Tricrotylborane (4.0 g, 22.7 mmol) was added to
a mixture of triethyl orthoformate (9.74 g, 65.8 mmol) and
Zn(OTf)2 (0.24 g, 0.65 mmol), the solution was allowed to stand
for 1 h at 25 C, then heated for 10 h at 85 C. Distillation led to
the isolation of a fraction with b.p. 60—62 C (10 Torr). The
yield was 9.25 g (89%). 1H NMR (CDCl3, 400 MHz), : 5.83
(ddd, 1 H, CH=, J = 7.3 Hz, 10.5 Hz, 17.1 Hz); 5.06—5.00 (m, 2 H,
CH2=); 4.19 (d, 1 H, CH(OEt)2, J = 6.7 Hz); 3.69—3.60 (m, 2 H,
OCHaHb); 3.52—3.44 (m, 2 H, OCHaHb); 2.49—2.41 (m, 1 H,
CHCH3); 1.20—1.15 (m, 6 H, 2 OCH2CH3); 1.01 (d, 3 H, Me,
purified by chromatography (eluent EtOAc—MeOH—NH3aq
,
50 : 1 : 0.1) to obtain compound 6 (15.2 g, 74%) as a yellow oil.
1H NMR (CDCl3, 300 MHz), : 5.87—5.73 (m, 1 H, CH=allyl);
5.40 (s, 1 H, CH=cycle); 5.15—5.08 (m, 2 H, CH2=); 4.49 (t, 1 H,
CH(OEt)2, J = 5.5 Hz); 3.70—3.60 (m, 2 H, OCHaHb); 3.54—3.44
(m, 2 H, OCHaHb); 3.32 (br.s, 1 H, CHN); 3.01—2.93 (m, 1 H,
CHN); 2.75 (br.s, 1 H, NH); 2.21—2.17 (m, 2 H, CH2allyl); 1.96
(dd, 1 H, CHAHBcycle, J = 3.5 Hz, J = 17.3 Hz); 1.78 (dd, 1 H,
CHAHBcycle, J = 8.1 Hz, J = 17.4 Hz); 1.68 (s, 3 H, Me); 1.67—1.62
(m, 2 H, CHCH2); 1.45 (br.s, 4 H, 2 CH2); 1.21 (t, 6 H,
2 OCH2CH3, J = 7.0 Hz). 13C NMR (CDCl3, 75 MHz), : 135.31,
131.79, 123.44, 117.21, 102.58, 60.78, 60.75, 51.89, 46.94, 39.91,
35.99, 35.09, 33.43, 28.29, 23.30, 21.51, 15.18. MS (EI, 70 eV),
m/z (Irel (%)): 282 [MH]+ (6), 252 (3), 236 (9), 206 (8), 194 (24),
192 (10), 190 (34), 164 (11), 150 (65), 148 (51), 146 (12), 136
(22), 107 (10), 95 (12), 94 (100), 93 (8), 79 (7). Found (%):

Hippocasine and epiꢀHippodamine: total synthesis
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
535
C, 72.46; H, 11.18; N, 4.79. C17H31NO2. Calculated (%):
C, 72.55; H, 11.10; N, 4.98.
J = 6.2 Hz, J = 10.4 Hz, J = 16.7 Hz); 5.80—5.70 (m, 1 H,
CH=allyl); 5.55 (s, 1 H, CH=cycle); 5.24 (ddd, 1 H, CHAHB=vinyl
,
,
tertꢀButyl transꢀ2ꢀallylꢀ6ꢀ(4,4ꢀdiethoxybutyl)ꢀ4ꢀmethylꢀ3,6ꢀ
dihydroꢀ1(2H)ꢀpyridinecarboxylate (7). To a solution of comꢀ
pound 6 (3.48 g, 12.36 mmol) in THF (10 mL), Boc2O (3.67 g,
16.8 mmol) was added. The mixture was heated to reflux. The
reaction progress was monitored by TLC (ethyl acetate—hexꢀ
ane, 1 : 15). Then, the solution was concentrated, the product
was isolated by chromatography to obtain ester 7 (4.65 g, 99%)
as a colorless oil. 1H NMR (CDCl3, 300 MHz), : 5.84—5.70
(m, 1 H, CH=allyl); 5.56 (br.s, 1 H, CH=cycle); 5.04—5.00 (m, 2 H,
CH2=); 4.48 (t, 1 H, CH(OEt)2, J = 5.6 Hz); 4.05—4.01 (m, 2 H,
OCHaHb); 3.70—3.60 (m, 2 H, OCHaHb); 3.55—3.45 (m, 2 H,
2 CHN); 2.37—2.23 (m, 2 H, CHAHBcycle, CHAHBallyl); 2.16 (dd,
1 H, CHAHBallyl, J = 9.0 Hz, J = 13.3 Hz); 1.98 (d, 1 H,
CHAHBcycle, J = 15.1 Hz); 1.76 (s, 3 H, Me); 1.74—1.60 (m, 4 H,
2 CH2); 1.49 (s, 9 H, But); 1.39—1.28 (m, 2 H, CHCH2); 1.22
(t, 6 H, 2 OCH2CH3, J = 7.0 Hz). 13C NMR (CDCl3, 75 MHz),
: 155.17, 136.29, 131.71, 122.94, 116.71, 102.87, 79.22, 60.91,
60.84, 52.32, 51.47, 38.23 (br.), 35.64 (br.), 33.67, 31.34, 29.68,
28.49 (3 C), 23.67, 20.66, 15.32. MS (EI, 70 eV), m/z (Irel(%)):
337/336 [M—EtO]+ (3/11), 237 (5), 236 (32), 194 (50), 190
(15), 180 (36), 151 (14), 150 (100), 148 (48), 138 (16), 136 (6),
122 (6), 107 (9), 94 (46), 93 (23), 88 (12), 80 (7), 57 (8), 41 (10).
Found (%): C, 70.06; H, 10.38; N, 3.57. C22H39NO4. Calculatꢀ
ed (%): C, 69.25; H, 10.30; N, 3.67.
J = 1.5 Hz, J = 3.1 Hz, J = 17.2 Hz); 5.10 (dt, 1 H, CHAHB=vinyl
J = 1.4 Hz, J = 1.9 Hz, J = 10.4 Hz); 5.02—4.98 (m, 2 H,
CH2=allyl); 4.16—4.06 (m, 2 H, CHOH, CHN); 4.02—3.95
(m, 1 H, CHN); 2.33 (dm, 1 H, CHAHBallyl, J = 13.3 Hz); 2.26
allyl
(dm, 1 H, CHAHBcycle, J = 15.9 Hz); 2.16 (dt, 1 H, CHAHB
,
J = 8.9 Hz, J = 13.3 Hz); 1.97 (dd, 1 H CHAHBcycle, J = 2.3 Hz,
J = 15.9 Hz); 1.74 (s, 3 H, Me); 1.73 (m, 1 H, CHOHCHAHB);
1.69 (br.s, 1 H, CHOHCHAHB); 1.56—1.50 (m, 2 H, CH2); 1.48
(s, 9 H, But); 1.39—1.30 (m, 2 H, CH2). 13C NMR (CDCl3, 100
MHz), : 155.27, 141.28, 141.20, 136.31, 131.18, 122.96, 116.76,
114.49, 79.35, 73.21, 73.05, 52.26, 51.53, 38.26, 37.02, 36.95,
35.64, 31.41, 31.38, 28.53 (3 C), 23.71, 21.09. MS (EI, 70 eV),
m/z (Irel(%)): 336/335 [M]+ (0.5/2.2), 243 (4), 236 (4), 195 (8),
194 (76), 192 (12), 180 (51), 177 (9), 176 (66), 174 (47), 138 (29),
136 (11), 134 (16), 120 (18), 107 (12), 96 (20), 95 (17), 94 (100),
93 (40), 88 (16), 80 (17), 78 (6), 77 (10), 41 (10). Found (%):
C, 71.65; H, 9.85; N, 4.16. C20H33NO3. Calculated (%): C, 71.60;
H, 9.91; N, 4.18.
tertꢀButyl transꢀ6ꢀ[4ꢀ(acetyloxy)ꢀ5ꢀhexenyl]ꢀ2ꢀallylꢀ4ꢀmethꢀ
ylꢀ3,6ꢀdihydroꢀ1(2H)ꢀpyridinecarboxylate (10). Allylic alcohol 9
(0.42 g, 1.26 mmol) was mixed with pyridine (0.64 mL) and
Ac2O (0.39 g, 0.37 mL, 3.84 mmol) and heated on a water bath.
The reaction progress was monitored by TLC (ethyl acetate—nꢀhexꢀ
ane, 1 : 2). The product was extracted with nꢀhexane, the exꢀ
tracts were washed with water and aqueous sodium bicarbonate,
dried with K2CO3, and concentrated using a rotary evaporator.
Compound 10 (0.47 g, 99%) was isolated by chromatography as
a dense colorless oil. 1H NMR (CDCl3, 400 MHz), : 5.84—5.70
(m, 2 H, 2CH=vinyl, allyl); 5.55 (br.s, 1 H, CH=cycle); 5.34—5.16
tertꢀButyl transꢀ2ꢀallylꢀ4ꢀmethylꢀ6ꢀ(4ꢀoxobutyl)ꢀ3,6ꢀdiꢀ
hydroꢀ1(2H)ꢀpyridinecarboxylate (8). A solution of ester 7 (3.10 g,
8.12 mmol) in a mixture of THF (4 mL), water (3 mL), and
AcOH (5 mL) was heated for 14 h at 50 C. The reaction progress
was monitored by TLC (ethyl acetate—hexane, 1 : 4). The prodꢀ
uct was extracted with nꢀhexane, dried with K2CO3, concentratꢀ
ed on a rotary evaporator. Compound 8 (1.79 g, 72%) was isolated
by chromatography as a colorless oil. 1H NMR (CDCl3, 400 MHz),
(m, 3 H, CHOAc and CH2=vinyl); 5.04—4.99 (m, 2 H, CH2=allyl);
allyl
4.06—4.00 (m, 2 H, 2 CHN); 2.37—2.12 (m, 3 H, CH2
,
,
cycle
CHAHBcycle); 2.08 (s, 3 H, Ac); 1.98 (dd, 1 H, CHAHB
: 9.74 (t, 1 H, CH=O, J = 1.6 Hz); 5.73 (dddd, 1 H, CH=allyl
,
J = 1.4 Hz, J = 15.9 Hz); 1.67 (s, 3 H, Me); 1.65—1.60 (m, 4 H,
2 CH2); 1.50 (s, 9 H, But); 1.36—1.24 (m, 2 H, CH2). 13C NMR
(CDCl3, 100 MHz), : 170.33, 155.16, 136.52, 136.47, 136.25,
131.92, 122.84, 116.76, 116.61, 116.50, 79.29, 74.83, 74.75,
52.18, 51.47, 38.22, 35.45; 34.20, 34.16, 31.37, 28.49 (3 C), 23.67,
21.20, 20.97. MS (EI, 70 eV), m/z (Irel(%)): 379/378 [MH]+
(0.2/1.5), 266 (5), 237 (10), 236 (63), 180 (38), 177 (14), 176
(100), 174 (47), 147 (5), 146 (5), 138 (20), 134 (11), 120 (12), 108
(8), 96 (17), 95 (12), 94 (75), 93 (31), 91 (11), 88 (13), 80 (12),
44 (6). Found (%): C, 70.15; H, 9.45; N, 3.66. C22H35NO4.
Calculated (%): C, 69.99; H, 9.34; N, 3.71.
J = 6.1 Hz, J = 8.6 Hz, J = 11.4 Hz, J = 17.7 Hz); 5.52 (m, 1 H,
CH=cycle); 5.00—4.97 (m, 2 H, CH2=); 4.06 (m, 1 H, CHN);
3.99 (m, 1 H, CHN); 2.42 (tt, 2 H, CH2CH=O, J = 1.6 Hz,
cycle
J = 7.5 Hz); 2.29—2.20 (m, 2 H, CHAHB
and CHAHBallyl);
2.15 (dt, 2 H, CHAHBallyl, J = 8.8 Hz, J = 13.3 Hz); 1.96 (dd, 1 H,
CHAHBcycle, J = 1.6 Hz, J = 15.9 Hz); 1.73 (s, 3 H, Me);
1.72—1.68 (m, 2 H, CH2); 1.64—1.53 (m, 2 H, CH2); 1.46
(s, 9 H, But). 13C NMR (CDCl3, 100 MHz), : 202.61, 155.22,
136.17, 132.19, 122.52, 116.83, 79.45, 52.02, 51.49, 43.90, 38.21
(br.), 35.00 (br.), 31.44, 28.48 (3 C), 23.67, 17.86. MS (EI, 70 eV),
m/z (Irel(%)): 308 [MH]+ (5,8), 252 (5), 190 (8), 180 (25),
166 (100), 148 (38), 138 (17), 131 (15), 122 (22), 94 (54), 93 (32),
91 (17), 79 (10), 41 (9). Found (%): C, 70.26; H, 9.48; N, 4.60.
C18H29NO3. Calculated (%): C, 70.32; H, 9.51; N, 4.56.
1ꢀ{3ꢀ[(2S*,6S*)ꢀ6ꢀAllylꢀ4ꢀmethylꢀ1,2,5,6ꢀtetrahydropyriꢀ
dinꢀ2ꢀyl]propyl}propꢀ2ꢀenꢀ1ꢀyl acetate (11). Trifluoroacetic acid
(2 mL) was added to compound 10 (0.47 g, 1.24 mmol), and the
mixture was stirred until the starting Bocꢀsubstituted compound
disappeared. The reaction progress was monitored by TLC (ethyl
acetate—nꢀhexane, 1 : 2). The acid was evaporated using a rotaꢀ
ry evaporator, the residue was diluted with CH2Cl2, washed with
aqueous K2CO3, dried with K2CO3, and concentrated using
a rotary evaporator. Amine 11 (0.24 g, 70%) was isolated by chroꢀ
matography (ethyl acetate—methanol, 100 : 1) as a yellow oil
and used further without additional purification. 1H NMR
(CDCl3, 400 MHz), : 5.86—5.74 (m, 2 H, 2 CH=vinyl, allyl);
5.45 (s, 1 H, CH=cycle); 5.32—5.19 (m, 5 H, CHOAc and
tertꢀButyl transꢀ2ꢀallylꢀ6ꢀ(5ꢀhexenylꢀ4ꢀhydroxy)ꢀ4ꢀmethylꢀ
3,6ꢀdihydroꢀ1(2H)ꢀpyridinecarboxylate (9). A 1.21 M solution of
vinylmagnesium bromide (7.3 mL, 8.83 mmol) in THF was addꢀ
ed dropwise to a solution of aldehyde 8 (2.71 g, 8.82 mmol) in
THF (80 mL) at –90 C under argon. The mixture was stirred for
1 h at –90 C, then was allowed to warmꢀup to –40 C. The
reaction progress was monitored by TLC (ethyl acetate—hexꢀ
ane, 1 : 2). Then, the mixture was treated with aqueous NH4Cl,
extracted with nꢀhexane (3 × 50 mL), dried with K2CO3,
and concentrated using a rotary evaporator. Compound 9 (2.57 g,
87%) was isolated by chromatography as a colorless oil. 1H NMR
(CDCl3, 400 MHz), : 5.87 (dddd, 1 H, CH=vinyl, J = 2.3 Hz,
2 CH2=vinyl,allyl); 3.36 (br.s, 1 H, CHN); 3.04—3.01 (m, 1 H,
allyl
CHN); 2.63—2.59 (m, 1 H, CHAHBallyl); 2.38 (dt, 1 H, CHAHB
,
J = 7.9 Hz, J = 13.7 Hz); 2.26 (dd, 1 H, CHAHBcycle, J = 3.3 Hz,

536
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Kuznetsov et al.
J = 17.9 Hz); 2.15 (s, 3 H, Ac); 2.09—2.05 (m, 1 H, CHAHBcycle);
1.87—1.75 (m, 2 H, CH2); 1.78 (s, 3 H, Me); 1.73—1.60 (m, 2 H,
CH2); 1.53—1.45 (m, 2 H, CH2). MS (EI, 70 eV), m/z (Irel(%)):
278 [MH]+ (0.71), 266 (2); 236 (26), 214 (14), 176 (47), 174 (35),
149 (10), 147 (10), 136 (20), 134 (10), 132 (9), 131 (9), 120 (15),
107 (14), 105 (10), 96 (15), 95 (14), 94 (100), 91 (11), 77 (12),
43 (12), 41 (12). Found: m/z 278.2111 [MH]+. C17H28NO2. Calcuꢀ
lated: (M + H) = 278.2115.
was monitored by TLC (nꢀC6H14—EtOAc, 3 : 1). After the reacꢀ
tion reached completion, the solution was passed through a colꢀ
umn with silica gel, the product was eluted by the mixture of
EtOAc—Et3N, 60 : 1 to obtain azaphenalene derivative 14
1
(29 mg (84%) as a colorless oil. H NMR (CDCl3, 300 MHz),
: 5.78—5.67 (m, 2 H, CH=CH); 5.47—5.45 (m, 1 H, CH=);
3.52—3.43 (br.m, 2 H, 2 CHNCH=); 3.43—3.33 (m, 1 H,
CHN(CH2)2); 2.39 (dt, 1 H, CHAHBCH=, J = 17.7 Hz,
J = 5.0 Hz); 2.25 (dd, 1 H, CHAHBCCH3, J = 5.0 Hz, J = 17.5 Hz);
2.08 (td, 1 H, CHAHBCH=, J = 1.8 Hz, J = 9.4 Hz); 2.00 (dd, 1 H,
CHAHBCCH3, J = 9.4 Hz, J = 17.7 Hz); 1.86—1.75 (m, 1 H,
CH2CHAHBCH2); 1.71 (s, 3 H, CH3); 1.56—1.36 (m, 5 H,
CH2CHAHBCH2, 2 CH2). 13C NMR (CDCl3, 100 MHz),
: 129.80 (CH=CH), 129.40 (br., C=), 123.63 (br., CH=C), 122.38
(CH=CH), 57.12 (CHNCH=), 56.82 (CHNCH=), 41.83
(CHN(CH2)2), 38.89 (CH2CCH3),, 34.27 (CH2CH=), 27.75
(CH2), 27.69 (CH2), 24.48 (CH2CH2CH2), 22.76 (Me). MS
(EI, 70 eV), m/z (Irel(%)): 189 [M]+ (30), 188 (100), 186 (14),
184 (7), 174 (31), 160 (15), 149 (12), 146 (21), 144 (16), 132 (12),
131 (15), 120 (10), 94 (25), 81 (10), 67 (10), 57 (9), 41 (12).
Found (%): C, 82.53; H, 10.15; N, 7.44. C13H19N. Calculatꢀ
ed (%): C, 82.48; H, 10.12; N, 7.40.
(4R*,6S*,9aS*)ꢀ and (4S*,6S*,9aS*)ꢀ6ꢀAllylꢀ8ꢀmethylꢀ4ꢀ
vinylꢀ1,3,4,6,7,9aꢀhexahydroꢀ2Hꢀquinolizines (12) and (13). The
catalyst [AllPdCl]2 (3.6 mg, 1 mol.%, 0,0097 mmol) was added
to a solution of (S)ꢀPipphos (7.7 mg (2 mol.%, 0,019 mmol) in
CH2Cl2 (0.5 mL) with stirring under argon. This solution of the
catalyst and powdered K2CO3 (for the binding of forming AcOH)
was added to a solution of compound 11 (0.27 g, 0.97 mmol) in
CH2Cl2 (2 mL). The reaction progress was monitored by TLC
(EtOAc—MeOH, 100 : 1). The mixture was diluted with CH2Cl2
(10 mL), washed with water, dried with K2CO3, and concentrated
using a rotary evaporator. Two isomers were isolated by column
chromatography in 0.183 g (87%) total yield as a yellow oil. Isomer
(4S*,6S*,9aS*)ꢀ12. Rf max 0.52 (EtOAc—nꢀhexane, 1 : 4), a colꢀ
orless oil. 1H NMR (CDCl3, 600 MHz), : 5.80—5.75 (br.m, 1 H,
CH=vinyl); 5.68 (dddd, 1 H, CH=allyl, J = 5.8 Hz, J = 8.5 Hz,
J = 10.7 Hz, J = 16.2 Hz); 5.23—5.17 (m, 2 H, CH2=vinyl); 5.09
(br.d, 1 H, CH=, J = 9.5 Hz); 5.00—4.97 (m, 2 H, CH2=allyl);
3.24 (br.s, 1 H, CHNCH=); 3.04 (br.s, 1 H, CHNAll); 2.83
(br.s, 1 H, CHNvinyl); 2.35 (dd, 1 H, CHAHBallyl, J = 5.4 Hz,
J = 13.0 Hz); 2.31 (br.s, 1 H, CHAHBallyl); 1.95 (dd, 1 H,
CHAHBCCH3, J = 10.6 Hz, J = 17.9 Hz); 1.87 (d, 1 H,
CHAHBCCH3, J = 17.4 Hz); 1.79—1.72 (m, 2 H, CH2CHNCH=);
1.68 (s, 3 H, Me); 1.66—1.58 (m, 3 H, CH2CHNvinyl, CHAHB);
1.46—1.38 (m, 1 H, CHAHB). 13C NMR (CDCl3, 100 MHz),
: 141.08 (br.), 136.81 (br.), 130.74, 123.68 (br.), 116.50, 115.77
(br.), 63.82, 54.65, 53.16, 33.55 (br.), 32.90 (br.), 32.43 (br.),
27.37, 24.26, 23.18. MS (EI, 70 eV), m/z (Irel(%)): 217 [M]+ (4),
216 (5), 199 (5), 183 (16), 177 (13), 176 (96), 175 (16), 174 (100),
172 (7), 163 (5), 152 (6), 149 (24), 146 (14), 134 (17), 132 (18),
120 (17), 107 (18), 94 (27), 83 (31), 67 (11), 57 (8), 41 (10).
Found: m/z 218.1902 [MH]+. C15H24N. Calculated: (M + H) =
= 218.1903.
Isomer (4R*,6S*,9aS*)ꢀ13. Rf min 0.24 (EtOAc—nꢀhexane,
1 : 4), colorless oil. 1H NMR (CDCl3, 600 MHz), : 5.90—5.84
(m, 1 H, CH=vinyl); 5.80 (dddd, 1 H, CH=allyl, J = 6.0 Hz,
J = 7.9 Hz, J = 10.2 Hz, J = 16.9 Hz); 5.20—5.16 (m, 2 H,
CH2=vinyl); 5.05 (d, 1 H, CH=, J = 11.1 Hz); 5.04—5.00 (m, 2 H,
CH2=allyl); 3.63 (br.s, 1 H, CHNCH=); 3.18—3.15 (m, 1H,
CHNAll); 3.05 (td, 1 H, CHNvinyl, J = 1.9 Hz, J = 9.2 Hz); 2.39
(br.s, 1 H, CHAHBallyl); 2.17 (dt, 1 H, CHAHBallyl, J = 9.0 Hz,
J = 13.5 Hz); 2.07 (dm, 1 H, CHAHBCCH3, J = 19.0 Hz);
1.80—1.74 (m, 1 H, CHAHBCHNCH=); 1.70 (s, 3 H, CH3);
1.65—1.62 (m, 1 H, CHAHBCHNCH=); 1.58—1.48 (m, 4 H,
CHAHBCCH3, CH2CHNvinyl, CHAHB); 1.42—1.34 (m, 1 H,
CHAHB). 13C NMR (CDCl3, 150 MHz), : 142.21, 136.64,
132.48, 122.52, 116.20, 115.25, 59.62, 53.81, 48.49, 37.49, 33.16,
30.64, 26.43, 23.53, 19.84. Found: m/z 218.1902 [MH]+. C15H24N.
Calculated: (M + H) = 218.1903.
(3aS*,6aS*,9aS*)ꢀ8ꢀMethylꢀ1,2,3,3a,4,5,6,6a,7,9aꢀdecaꢀ
hydropyrido[2,1,6ꢀde]quinolizine (( )ꢀhippocasine). A solution
of tricycle 14 (0.1 g, 0.53 mmol) in MeOH (3 mL) was added to
a suspension of 10% Pd/C (17 mg) in MeOH (7 mL). The mixture
obtained was hydrogenated using a Parr apparatus for 1 h at
20 C, hydrogen pressure 2 bar. A progress of the reaction was moniꢀ
tored by TLC (EtOAc—Et3N, 60 : 1). After the starting comꢀ
pound disappeared, the reaction mixture was passed through the
Super Cel layer on a filter funnel and concentrated in vacuo
using a rotary evaporator. The residue was purified by chromaꢀ
tography on silica gel to obtain (+)ꢀhippocasine (76 mg, 76%) as
1
a colorless oil. H NMR (CDCl3, 600 MHz), : 5.38 (sharp m,
1 H, CH=(9)); 3.24 (dm, 1 H, CHNallyl(9a), J = 11.0 Hz);
3.10—3.07 (dm, 1 H, CHN(3a), J = 11.0 Hz); 3.04—2.99 (tt, 1 H,
CHN(6a), J = 4.0 Hz, J = 10.3 Hz); 1.94 (dd, 1 H, CHAHB(7),
J = 4.6 Hz, J = 17.4 Hz), 1.89—1.80 (m, 3 H, CHAHB(7),
CHAHB(2), CHAHB(5)); 1.83—1.78 (m, 2 H, CHAHB(3),
CHAHB(6)); 1.64 (s, 3 H, Me); 1.57 (dm, 1 H, CHAHB(4),
J = 13.3 Hz), 1.55—1.49 (m, 3 H, CHAHB(2), CHAHB(5),
CHAHB(4)), 1.38 (dtd, 1 H, CHAHB(1), J = 3.7 Hz, J = 11.9 Hz,
J = 13.7 Hz); 1.32 (dm, 1 H, CHAHB(1), J = 13.7 Hz); 1.21
(ddd, 1 H, CHAHB(6), J = 5.0 Hz, J = 12.8 Hz, J = 24.2 Hz),
1.09 (dm, 1 H, CHAHB(3), J = 12.4 Hz) (see Ref. 7c). 13C NMR
(CDCl3, 100 MHz), : 130.61 (C(8)), 124.04 (C(9)H=), 58.31
(C(9a)HN), 57.15 (C(3a)), 44.99 (C(6a)), 39.08 (C(7)H2), 34.42
(C(5)H2), 31.83 (C(6)H2), 26.47 (C(1)H2), 25.58 (C(2)H2),
23.46 (C(3)H2), 22.82 (Me), 19.21 (C(4)H2). Found: m/z
192.1756 [MH]+. C13H22N. Calculated: (M + H) = 192.1747.
The longer reaction time (6 h) gave the product of exhausꢀ
tive hydrogenation ( )ꢀepiꢀhippodamine. 1H NMR (CDCl3,
600 MHz), : 2.99—2.92 (m, 3 H, 3 CHN); 2.12 (dt, 1 H,
J = 6.4 Hz, J = 13.7 Hz); 2.00—1.94 (m, 1 H, CHMe); 1.93—1.81
(m, 4 H); 1.59—1.44 (m, 6 H); 1.39 (ddd, 1 H, J = 2.3 Hz,
J = 4.5 Hz, J = 13.3 Hz); 1.36 (ddd, 1 H, J = 2.3 Hz, J = 4.1 Hz,
J = 13.7 Hz); 1.24—1.18 (m, 2 H); 1.11 (d, 3 H, Me, J = 7.7 Hz);
1.04 (dm, 1 H, J = 12.8 Hz). 13C NMR (CDCl3, 100 MHz),
: 58.46, 58.33, 43.20, 40.37, 36.53, 34.64, 31.44, 27.04, 26.64,
25.63, 23.43, 22.03, 19.73 (see Ref. 8f). Found: m/z 194.1898
[MH]+. C13H24N. Calculated: (M + H) = 194.1903.
(3aS*,6aS*,9aR*)ꢀ5ꢀMethylꢀ2,3,3a,6,6a,7,9a,9bꢀoctahyꢀ
droꢀ9bꢀazaphenalene (14). The second generation Grubb´s catalyst
(8 mg, 5 mol.%, 0.009 mmol) was added to a degassed solution of
diene 12 (40 mg, 0.18 mmol) in toluene (5 mL), and the solution
obtained was heated for 20 min at 60 C. A progress of the reaction

Hippocasine and epiꢀHippodamine: total synthesis
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
537
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The authors are grateful to N. S. Ikonnikov for carꢀ
rying out GLC analysis.
This work was financially supported by the Ministry of
Education and Science of the Russian Federation (Proꢀ
gram "Scientific and ScientificꢀPedagogical Specialists
of the Innovative Russia" in 2009—2013 (Agreement
Nos 8435 and 8531), the Council on Grants at the Presiꢀ
dent of the Russian Federation (Program of State Support
for Leading Scientific Schools of the Russian Federation,
Grant NShꢀ5943.2012.3), and the Presidium of the Rusꢀ
sian Academy of Sciences (Program Pꢀ8).
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Received November 20, 2013;
in revised form December 26, 2013