The total synthesis of (-)-suaveoline

Article abstract of DOI:10.1039/b005695m

A new synthesis of the indole alkaloid (-)-suaveoline from L-tryptophan is reported (overall yield ca. 14%). Key synthetic steps include a high yielding cis-specific Pictet-Spengler reaction, a one-pot Horner-Wadsworth-Emmons and alkylation procedure, a vinylogous Thorpe cyclisation and the direct formation of a 3,4,5-trisubstituted pyridine from a 1,5-dinitrile. The direct conversion of ajmaline to semi-synthetic suaveoline is also described. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b005695m

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The total synthesis of (Ϫ)-suaveoline
Patrick D. Bailey and Keith M. Morgan
Department of Chemistry, Heriot-Watt University, Riccarton, Edinburgh, UK EH14 4AS
1
Received (in Cambridge, UK) 14th July 2000, Accepted 1st September 2000
First published as an Advance Article on the web 19th October 2000
A new synthesis of the indole alkaloid (Ϫ)-suaveoline from -tryptophan is reported (overall yield ca. 14%). Key
synthetic steps include a high yielding cis-specific Pictet–Spengler reaction, a one-pot Horner–Wadsworth–Emmons
and alkylation procedure, a vinylogous Thorpe cyclisation and the direct formation of a 3,4,5-trisubstituted pyridine
from a 1,5-dinitrile. The direct conversion of ajmaline to semi-synthetic suaveoline is also described.
Introduction
Polycyclic indole alkaloids such as suaveoline 1, ajmaline 2 and
alkaloid G have elicited intense synthetic interest over many
years,1 because of their intriguing structures and interesting
biological properties.
Our work in this area has been based on the kinetically
controlled Pictet–Spengler reaction to access the cis-1,3-disub-
Scheme 2 Proposed retro-synthetic analysis of suaveoline 1.
stituted tetrahydro-β-carboline skeleton 3 required for these
a vinylogous Thorpe cyclisation and the eventual formation
bridged structures, and we have achieved formal syntheses of a
of a 3,4,5-trisubstituted pyridine.
range of alkaloids including ajmaline and suaveoline through
We describe herein an extremely efficient total synthesis of
suaveoline based on this approach, along with an efficient
convergence with the tetracyclic aldehyde 4 (Scheme 1).2
method for obtaining semi-synthetic suaveoline (which is not
readily available) from ajmaline.
Results and discussion
Reaction of the readily available homologous nitrile 5, with the
silyl protected aldehyde 6 (itself prepared by silyl protection
and PCC oxidation of propane-1,3-diol), under our conditions
of kinetic control,3 afforded the cis-1,3-disubstituted tetra-
hydro-β-carboline 7 in 80% isolated yield, with none of the
trans isomer apparently generated (Scheme 3). Similarly high
Scheme 1
We wished to complete our own total synthesis, but in
the synthetic routes described in the preceding paper† we
encountered great difficulty in introducing a four carbon
fragment to C15 (ajmaline numbering) of bridged inter-
mediates such as 4, and a more efficient route was clearly
needed. We chose to investigate the possibility of introducing
a suitable four carbon fragment prior to the formation
of a tetracyclic bridge, leading to the new route implied by
the retro-synthetic analysis outlined in Scheme 2. Thus key
objectives included a cis-selective Pictet–Spengler reaction,
Scheme 3 Reagents and conditions: i, DCM, 3 Å molecular sieves,
0 ЊC, 60 h then TFA, Ϫ78 ЊC to room temp., 6 h (82%); ii, BnBr (neat),
† Preceding paper: P. D. Bailey, K. M. Morgan, David I. Smith
and J. M. Vernon, J. Chem. Soc., Perkin Trans. 1, 2000 (DOI: 10.1039/
b005694o).
NaHCO3, 70 ЊC, 24 h (79%); iii, MeI, NaH, DMF, 0 ЊC, 1 h (100%); iv,
TBAF, THF, room temp., 2 h (83%); v, (COCl)2, Me2SO, DCM,
Ϫ60 ЊC, 20 min then NEt3, Ϫ60 ЊC to room temp., 1 h (100%).
3578
J. Chem. Soc., Perkin Trans. 1, 2000, 3578–3583
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b005695m

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cis-selectivity (>10:1) has been observed in only two other
cases,4 also involving aldehydes of the type RCH2CHO (where
R is bulky and contains one or more remote aromatic rings,
perhaps able to π-stack to the indole moiety at a crucial stage of
the cyclisation mechanism). Serendipity played a part at this
point in the synthesis when a small scale benzylation reaction in
DCM boiled dry leaving the carboline 7 in neat benzyl bromide
at 70 ЊC. The carboline 7 turned out to be much more stable
than most previously obtained carbolines (which are suscep-
tible to oxidative degradation) and under these conditions
was benzylated in good yield. N-Methylation of the indole
fragment, removal of the silyl protection and Swern oxidation
to the aldehyde 8 all proceeded in high overall yield.
To test the viability of our new synthetic route we next
attempted the model synthesis of a de-ethyl suaveoline deriv-
ative. The required Horner–Wadsworth–Emmons reaction
with diethyl cyanomethylphosphonate gave the α,β-unsaturated
nitrile 9 as a mixture of cis and trans isomers. An initial attempt
to use potassium methoxide as a base to facilitate the key
vinylogous Thorpe cyclisation failed, with the addition product
10 being the only material isolated. However, a subsequent
attempt with potassium tert-butoxide led to the desired bridged
1,5-dinitrile 11 in good yield. This material effectively repres-
ented the first synthetically useful addition of functionality
at C15 (ajmaline numbering) in our hands. Crucially, the
planned reduction of the dinitrile 11 with DIBAL-H followed
by treatment with hydroxylamine hydrochloride in refluxing
ethanol actually led directly to the formation of a 3,4-
disubstituted pyridine, the de-ethyl suaveoline derivative 13,
presumably via oxidative cyclisation of a species such as the
diimine 12 (Scheme 4).
Scheme 5 Reagents and conditions: i, NH2OHؒHCl, EtOH, reflux, 24 h
(89%).
We were further surprised to discover that this reaction was
acutely solvent (and temperature) dependent, thus, whilst no
reaction was observed in refluxing toluene, replacing ethanol
with n-butanol led to the direct conversion of ajmaline 2
into suaveoline 1 in 30% overall yield (Scheme 6). This semi-
Scheme 6 Reagents and conditions: i, NH2OHؒHCl, n-BuOH, reflux,
24 h (30%).
synthetic suaveoline was identical to our synthetic material. The
full mechanism to account for this transformation is discussed
in detail elsewhere,6 but we believe that atmospheric oxygen
may be involved in the formation of the nitrate 16, which then
undergoes two ring opening steps to a dialdehyde derivative and
ultimately undergoes condensation with hydroxylamine to form
the pryridine ring of suaveoline.
The total synthesis of suaveoline itself was next attempted,
again from the aldehyde 8. Rather than attempting an alkyl-
ation of the 1,5-dinitrile 11, the introduction of the four
remaining carbons of the suaveoline skeleton was attempted
via a one-pot Horner–Wadsworth–Emmons and alkylation
procedure that could generate the required reagent in situ. This
procedure proved successful, with the α,β-unsaturated nitrile 17
being isolated in 83% overall yield (Scheme 7). The required
bridged skeleton 18 was then constructed by another vinyl-
ogous Thorpe cyclisation, again using potassium tert-butoxide
(67% yield), giving 18 as a mixture of diastereoisomers. Reduc-
tion of the dinitrile 18 with DIBAL-H followed by treatment
with hydroxylamine hydrochloride produced the required 3,4,5-
trisubstituted pyridine directly and so led to the formation of
N-benzyl-(Ϫ)-suaveoline 19 in 53% yield. When attempting to
reduce only one of the nitrile groups, we also discovered that
pyridine formation was not dependent upon treatment with
hydroxylamine hydrochloride, and that an acid work-up from
the DIBAL-H reduction was sufficient to generate the pyridine
ring directly. Indeed it proved impossible to isolate anything
other than N-benzylsuaveoline 19 or starting material 18.
Debenzylation of 19 under standard conditions (H2, Pd–C,
MeOH) failed, as expected from our earlier work involving
similar bridged skeletons and related results from Cook.1b
However, debenzylation of 19ؒHCl (H2, Pd–C, EtOH) yielded
(Ϫ)-suaveoline 1 cleanly. This material was identical in all
Scheme 4 Reagents and conditions: i, P(O)(OEt)2CH2CN, NaH, DMF,
0 ЊC, 10 min (97%); ii, KOMe, MeOH, room temp., 24 h (40%); iii, KO-
t-Bu, THF, 0 ЊC to room temp., 30 min (43%); iv, DIBAL-H, DCM,
Ϫ78 ЊC to room temp., 10 h then NH2OHؒHCl, EtOH, reflux, 24 h
(12%).
Although we were encouraged by this seemingly straight-
forward route to suaveoline derivatives, the isolated yield of
pure pyridine derivative 13 was low, so before embarking on
a synthesis of suaveoline itself we wanted to prepare a semi-
synthetic sample of suaveoline from ajmaline. As part of our
ongoing efforts towards the total synthesis of ajmaline 2 we
were also anxious to obtain the cyano-alcohol 15, because
it can be converted into ajmaline,5 and is very similar to a
synthetic intermediate that we had previously made en route to
(Ϫ)-suaveoline. To our surprise, treatment of ajmaline 2 with
hydroxylamine hydrochloride in refluxing ethanol yielded the
cyano-alcohol 15 directly in 89% yield, presumably via the
oxime 14 (Scheme 5).
J. Chem. Soc., Perkin Trans. 1, 2000, 3578–3583
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Preparation of 3-(tert-butyldiphenylsilyloxy)propan-1-al 6
The aldehyde was prepared in two steps from propane-1,3-diol.
(a) Propane-1,3-diol (50 ml, 47.5 g, 625 mmol) and imidazole
(3.4 g, 50 mmol) were stirred in DCM (200 ml) at room temp.
TBDPS-Cl (10 g, 36 mmol) in DCM (30 ml) was added
dropwise over 9 h then the reaction stirred overnight. The
solution was then washed twice with aqueous citric acid, twice
with brine, dried over MgSO4 and evaporated to 13.6 g of
colourless oil. This material was subjected to flash chrom-
atography on silica eluted with a solvent gradient of DCM to
1:9 Et2O–DCM to yield 5.2 g (46%) of 3-(tert-butyldiphenyl-
silyloxy)propan-1-ol as a colourless oil: Rf 0.25 (DCM); 1H
NMR δ 1.05 (9H, s, C(CH3)3), 1.82 (2H, quintet, J 5.7 Hz,
HOCH2CH2), 2.56 (1H, t, J 5.5 Hz, OH), 3.80–3.91 (4H, m,
HOCH2CH2CH2), 7.35–7.72 (10H, m, ArH); 13C NMR δ 19.0
(s), 26.7 (q), 34.2 (t), 61.9 (t), 63.2 (t), 127.7 (d), 129.7 (d), 133.1
(s), 135.5 (d).
(b) The 1-(tert-butyldiphenylsilyloxy)propan-1-ol (3.77 g,
12 mmol) was added to 1:1 PCC–Florisil (8.6 g, 20 mmol of
PCC) in DCM (25 ml) and stirred at room temp. overnight,
then filtered through Florisil, dried over MgSO4, and evapor-
Scheme 7 Reagents and conditions: i, NaH, DMF, 0 ЊC then EtBr; ii,
NaH, DMF, 0 ЊC, 1 h (83%); iii, KOt-Bu, THF, 0 ЊC to room temp., 10
min (67%); iv, DIBAL-H, DCM, Ϫ78 ЊC to room temp., 24 h then
NH2OHؒHCl, EtOH, reflux, 24 h (53%); v, HCl, EtOH then evaporate,
Pd–C, H2, EtOH (66%).
1
ated to yield the aldehyde 6 (2.4 g, 77%): Rf 0.75 (DCM); H
NMR δ 1.04 (9H, s, C(CH3)3), 2.60 (2H, br td, J 5.9, 1.8 Hz,
CH2CHO), 4.02 (2H, t, J 5.9 Hz, CH2OSi), 7.35–7.71 (10H, m,
ArH), 9.81 (1H, br s, CHO); IR νmax/cmϪ1 (thin film) 1728.
respects both to the natural product,1a and to the semi-synthetic
suaveoline 1 we had earlier synthesized from ajmaline.
Preparation of (1S,3S)-3-cyanomethyl-1-[2-(tert-butyldiphenyl-
silyloxy)ethyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 7
Conclusion
The amino nitrile (733 mg, 3.68 mmol) was dissolved in dry
DCM (50 ml) and stirred over 3 Å molecular sieves. The alde-
hyde 6 (1.56 g, 5 mmol) was then added and the reaction stirred
at 0 ЊC for 60 h. After cooling to Ϫ78 ЊC, TFA (855 mg, 578 µl,
7.5 mmol) was added and the reaction stirred at Ϫ78 ЊC for 3 h
before being allowed to warm slowly to 0 ЊC and stirred for a
further 1 h, then finally warmed to room temp. and stirred for
2 h. The solvent was then decanted from the sieves which were
then washed 5 times with chloroform and aqueous NaHCO3.
The combined organic phase was washed with brine, dried over
MgSO4 and evaporated to give a yellow oil (2.7 g). This material
was subjected to flash chromatography on silica eluted with
1:9 Et2O–DCM to yield the tetrahydro-β-carboline 7 (1.49 g,
82%). A second reaction run at double this scale afforded the
carboline 7 in 75% yield.
We have developed a new route to complex cage-like indole
alkaloids which utilises a cis-selective Pictet–Spengler reaction
and avoids the difficult addition to C15 (ajmaline numbering)
of advanced tetracyclic intermediates by virtue of an early con-
struction of the required carbon skeleton prior to a vinylogous
Thorpe cyclisation. We utilised this new methodology in
a total asymmetric synthesis of (Ϫ)-suaveoline 1, starting
from -tryptophan in ca. 14% overall yield. We have also
developed an easy method for the direct conversion of ajmaline
to the pentacyclic intermediate 15 and semi-synthetic (Ϫ)-
suaveoline 1.
Experimental
Rf 0.46 (1:9 Et2O–DCM); 1H NMR δ 1.17 (9H, s, C(CH3)3),
1.76 (1H, br s, NH), 1.88 (1H, dq, J 14.5, 3.8 Hz, one
of CH2CH2OSi), 2.21 (1H, dq, J 14.5, 7.1 Hz, one of CH2-
CH2OSi), 2.59 (1H, ddd, J 15.0, 10.6, 2.5 Hz, one of Ar-
CH2CH), 2.64 (2H, br d, J 6.4 Hz, CH2CN), 2.97 (1H, ddd,
J 15.0, 4.0, 1.8 Hz, one of ArCH2CH), 3.33 (1H, ddt, J 10.6, 6.4,
4.2 Hz, ArCH2CH), 3.98 (2H, dd, J 7.1, 3.7 Hz, CH2CH2OSi),
4.28–4.38 (1H, m, ArCHCH2), 7.08–7.75 (14H, m, ArH), 8.96
(1H, br s, indole NH); 13C NMR δ 19.2 (s), 24.9 (t), 27.0 (q),
28.3 (t), 37.6 (t), 51.1 (d), 53.6 (d), 62.8 (t), 107.2 (s), 111.0 (d),
117.9 (d), 119.3 (d), 121.5 (d), 126.9 (s), 127.9 (d), 130.0 (d),
132.6 (s), 132.7 (s), 135.5 (d), 135.7 (s); IR νmax/cmϪ1 (CHCl3)
3698, 3607, 3476, 3367, 2251 (w), 1605, 1477, 1435; MS m/z 493
(Mϩ, 3%), 393 (23), 210 (9), 199 (44), 195 (10), 77 (7), 28 (100);
found m/z 493.2543, calc. for C31H35N3OSi 493.2549.
NMR spectra were recorded on a Bruker AC200 at 200 MHz
(1H) and 50 MHz (13C) or a Bruker DPX400 at 400 MHz (1H)
and 100 MHz (13C). Chemical shifts were measured in ppm
on the δ scale downfield from tetramethylsilane as internal
standard. The solvent employed was CDCl3, unless otherwise
stated. When pairs of diastereoisomers were not separated the
diastereomeric NMR resonances are bracketed thus {}. All 13
C
1
data are quoted with H multiplicities (off resonance results)
in parentheses thus (), although this multiplicity was inferred
from DEPT experiments. Infrared spectra were recorded on a
Perkin-Elmer 1420 ratio recording spectrophotometer. Optical
rotations were recorded on a Perkin-Elmer 141 polarimeter at
room temp. Mass spectra were obtained by electron impact
on an a VG AUTOSPEC spectrometer. Analytical TLC was
carried out on Merck aluminium sheet silica gel 60 F254 plates
(thickness 0.2 mm). Spots were visualised with a UV hand
lamp. Flash chromatography was performed using silica gel
60 (230–400 mesh) as the stationary phase. THF was dried
by distillation from sodium or obtained anhydrous from
Aldrich. DMF was obtained anhydrous from Aldrich and was
stored under dry argon. Chlorinated solvents were distilled
from phosphorus pentaoxide. Toluene and ethoxyethane were
distilled and stored over sodium. DIBAL-H 1 M solution in
DCM was obtained from Aldrich and stored under dry argon.
Reactions were routinely run under an argon atmosphere unless
otherwise stated.
Preparation of (1S,3S)-2-benzyl-3-cyanomethyl-1-[2-(tert-butyl-
diphenylsilyloxyethyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
The carboline 7 (2.6 g, 5.27 mmol) was dissolved in DCM (10
ml) and stirred over excess NaHCO3 (4.2 g) and benzyl bromide
added (4.3 g, 3 ml, 25 mmol). The reaction was heated to 70 ЊC
under a stream of argon and the DCM allowed to evaporate,
then the reaction was kept at 70 ЊC overnight. After cooling to
room temp., water and chloroform were added, and the organic
layer then washed with brine, dried over MgSO4 and evaporated
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to an oil, then subjected to flash chromatography on silica
eluted with a solvent gradient of DCM to 1:19 Et2O–DCM to
yield the N-benzylcarboline (2.38 g, 77%).
30.4 (q), 36.9 (t), 52.6 (d), 53.8 (d), 60.7 (t), 61.3 (t), 103.3 (s),
109.0 (d), 118.1 (d), 118.7 (s), 119.4 (d), 121.8 (d), 126.7 (s),
127.5 (d), 128.5 (2 × d), 129.4 (2 × d), 133.5 (s), 137.8 (s), 138.4
(s); IR νmax/cmϪ1 (CHCl3) 3420, 2247, 1400; MS m/z 359 (Mϩ,
6%), 341 (3), 314 (61), 273 (4), 183 (11), 170 (8), 91 (65), 36
(100); found m/z 359.1967, calc. for C23H25N3O 359.1998.
Rf 0.81 (1:9 Et2O–DCM); 1H NMR δ 1.14 (9H, s, C(CH3)3),
1.78–2.24 (2H, m, CH2CH2OSi), 2.44 (1H, dd, J 16.7, 7.3 Hz,
one of CH2CN), 2.60 (1H, dd, J 16.7, 8.4 Hz, one of CH2CN),
2.74 (1H, br d, J 16.0 Hz, one of ArCH2CH), 3.18 (1H, br dd,
J 16.0, 5.7 Hz, one of ArCH2CH), 3.65–3.77 (1H, m, ArCH2-
CH), 3.84–3.97 (4H, m, CH2CH2OSi and NCH2Ph), 4.12–4.18
(1H, m, ArCHCH2), 7.01–7.70 (19H, m, ArH), 8.94 (1H, br s,
indole NH); 13C NMR δ 19.2 (s), 22.0 (t), 23.3 (t), 27.1 (q), 39.1
(t), 54.1 (d), 54.7 (d), 58.8 (t), 63.6 (t), 103.7 (s), 110.7 (d), 117.9
(d), 119.0 (s), 119.2 (d), 121.6 (d), 126.8 (d), 126.9 (d), 127.2 (d),
127.3 (d), 127.7 (d), 127.9 (d), 128.5 (d), 129.9 (d), 130.0 (d),
132.6 (s), 133.0 (s), 133.8 (s), 135.4 (2 × d), 135.9 (s), 139.3 (s);
IR νmax/cmϪ1 (CHCl3) 3440, 2251, 1589, 1466, 1431; MS m/z 583
(Mϩ, 2%), 492 (3), 300 (47), 199 (100), 91 (21), 28 (39); found
m/z 583.3020, calc. for C38H41N3OSi 583.3019; [α]D20 Ϫ11 (c 1,
CHCl3).
Preparation of (1S,3S)-2-benzyl-3-cyanomethyl-1-formylmethyl-
2,3,4,9-tetrahydro-9-methyl-1H-pyrido[3,4-b]indole 8
Oxalyl chloride (125 mg, 86 ml, 1 mmol) was stirred in dry
DCM (3 ml) at Ϫ60 ЊC (using a chloroform–dry ice bath).
DMSO (156 mg, 140 ml, 2 mmol) in dry DCM (1 ml) was added
slowly and the mixture stirred at Ϫ60 ЊC for 2 min. The alcohol
(270 mg, 0.75 mmol) in dry DCM (2 ml) was then added drop-
wise and the reaction stirred at Ϫ60 ЊC for 20 min. Triethyl-
amine (477 mg, 659 ml, 4.7 mmol) was added and the reaction
allowed to warm to room temp., then water (20 ml) was added
and then the aqueous layer washed with DCM. The combined
organic layers were washed with brine, 1% HCl (aq), saturated
NaHCO3 (aq) and brine, then dried over MgSO4 and evapor-
ated to afford the aldehyde 8 in quantitative yield (269 mg) as a
pale yellow foam. This material was only partially characterised
before being used directly in Horner–Wadsworth–Emmons
reactions.
Preparation of (1S,3S)-2-benzyl-3-cyanomethyl-1-[2-(tert-butyl-
diphenylsilyloxy)ethyl]-2,3,4,9-tetrahydro-9-methyl-1H-pyrido-
[3,4-b]indole
The N-benzylcarboline (2.38 g, 4.08 mmol) and MeI (607 mg,
266 ml, 4.28 mmol) were stirred together in dry DMF (25 ml)
at 0 ЊC. NaH (180 mg of 60% dispersion in mineral oil, 4.28
mmol) was then added and the reaction stirred for 30 min at
0 ЊC, then 1 h at room temp. The DMF was then removed
by evaporation and the residue partitioned between EtOAc
and brine. The organic layer then twice washed with brine,
dried over MgSO4 and evaporated to yield the fully protected
carboline as a white foam (2.44 g, 100%).
1
Rf 0.50 (1:9 Et2O–DCM); H NMR δ 2.55 (1H, dd, J 16.7,
8.3 Hz, one of CH2CHO), 2.66–2.82 (3H, m, one of ArCH2CH
and CHCH2CN), 2.93 (1H, ddd, J 16.7, 9.8, 3.0 Hz, one of
CH2CHO), 3.19 (1H, ddd, J 16.2, 6.3, 1.5 Hz, one of ArCH2-
CH), 3.57–3.65 (4H, m, indole NCH3 and ArCH2CH), 3.89
(2H, s, NCH2Ph), 4.62 (1H, ddd, J 9.8, 4.6, 1.5 Hz, ArCHCH2),
7.11–7.55 (9H, m, ArH), 9.72 (1H, dd, J 2.8, 1.0 Hz, CHO).
Model reactions leading to the formation of de-ethyl suaveoline
derivative 13
Rf 0.83 (1:9 Et2O–DCM); 1H NMR δ 1.05 (9H, s, C(CH3)3),
1.68–2.11 (2H, m, CH2CH2OSi), 2.43 (2H, dd, J 8.0, 4.4 Hz,
CH2CN), 2.59 (1H, br d, J 16.2 Hz, one of ArCH2CH), 3.12
(1H, br dd, J 16.2, 6.2 Hz, one of ArCH2CH), 3.43–3.50 (1H,
m, ArCH2CH), 3.60 (3H, s, indole NCH3), 3.72–3.88 (2H, AB
system, J 13.4 Hz, NCH2Ph), 3.88–4.00 (1H, m, one of
CH2CH2OSi), 4.10 (1H, dd, J 9.2, 4.6 Hz, one of CH2CH2OSi),
4.16–4.25 (1H, m, ArCHCH2), 7.06–7.69 (19H, m, ArH); 13C
NMR δ 19.1 (s), 20.5 (t), 24.6 (t), 27.0 (q), 30.4 (q), 38.7 (t), 51.4
(d), 52.5 (d), 61.2 (t), 61.6 (t), 103.5 (s), 108.9 (d), 118.0 (d),
118.7 (s), 119.3 (d), 121.6 (d), 126.8 (s), 127.5 (d), 127.8 (d),
128.5 (d), 128.8 (d), 129.7 (d), 129.8 (d), 133.5 (s), 133.7 (s),
134.8 (s), 135.6 (d), 137.8 (s), 139.0 (s); IR νmax/cmϪ1 (CHCl3)
2252, 1593, 1476, 1467, 1400; MS m/z (15 eV) 597 (Mϩ, 13%),
582 (4), 557 (4), 541 (6), 506 (8), 409 (15), 407 (32), 315 (100),
213 (100), 199 (100), 91 (100); [α]D20 Ϫ26 (c 1, CHCl3).
(a) Horner–Wadsworth–Emmons reaction. Diethyl cyano-
methylphosphonate (177 mg, 162 µl, 1 mmol) was added to
NaH (30 mg of 80% dispersion in mineral oil, 1 mmol) in DMF
(2 ml) at 0 ЊC and stirred for 10 min. This mixture was then
added to a solution of the aldehyde 8 (200 mg, 0.55 mmol) in
DMF (4 ml), stirred at Ϫ20 ЊC. The reaction was stirred for 1 h,
then the DMF removed by evaporation and the residue treated
with PhMe and evaporated again to remove the last traces of
DMF. The residue was then partitioned between chloroform
and brine, the organic layer twice washed with brine, dried over
MgSO4 and evaporated. The residue was then subjected to flash
chromatography on silica eluted chloroform to yield the trans
alkene (108 mg), cis alkene (70 mg) and some mixed cis–trans
compounds (25 mg, total yield 203 mg, 97%).
1H NMR (cis) δ 2.46–2.92 (5H, m, one of ArCH2CH,
ArCHCH2, and CH2CN), 3.14 (1H, ddd, J 16.1, 6.2, 1.5 Hz,
one of ArCH2CH), 3.53–3.63 (1H, m, ArCH2CH), 3.66 (3H, s,
indole NCH3), 3.63–3.89 (2H, AB system, J 13.4 Hz, NCH2Ph),
3.96 (1H, dd, J 11.0, 2.5 Hz, ArCHCH2), 5.17 (1H, d, J 10.9 Hz,
CHCHCN), 6.78 (1H, ddd, J 10.9, 8.5, 6.3 Hz, CHCHCN),
7.04–7.47 (9H, m, ArH).
Preparation of (1S,3S)-2-benzyl-3-cyanomethyl-1-(2-hydroxy-
ethyl)-2,3,4,9-tetrahydro-9-methyl-1H-pyrido[3,4-b]indole
The fully protected carboline (2.5 g, 4.08 mmol) was dissolved
in THF (12 ml) and stirred at room temp. TBAF (8.2 ml of 1 M
solution in THF, 8.2 mmol) was added dropwise and the reac-
tion stirred for 2 h. The THF was then removed by evaporation
and the residue partitioned between chloroform and brine. The
organic layer was twice washed with brine, dried over MgSO4
and evaporated to a red oil, then subjected to flash chrom-
atography on silica eluted with a solvent gradient of DCM
to 1:9 Et2O–DCM to yield the deprotected alcohol as a white
foam (1.22 g, 83%).
1H NMR (trans) δ 2.48 (2H, td, J 7.2, 1.4 Hz, ArCHCH2),
2.63–2.75 (3H, m, one of ArCH2CH and CH2CN), 3.14 (1H,
ddd, J 16.1, 6.1, 1.5 Hz, one of ArCH2CH), 3.44–3.65 (1H, m,
ArCH2CH), 3.54 (3H, s, indole NCH3), 3.60–3.87 (2H, AB
system, J 13.4 Hz, NCH2Ph), 3.87–3.91 (1H, m, ArCHCH2),
5.29 (1H, dt, J 16.4, 1.4 Hz, CHCHCN), 6.51 (1H, dt, J 16.4,
7.2 Hz, CHCHCN), 7.05–7.48 (9H, m, ArH).
Rf 0.2 (1:9 Et2O–DCM); 1H NMR δ 1.67–1.98 (2H, m,
CH2CH2OH), 2.62 (1H, br s, OH), 2.63 (1H, dd, J 16.5, 8.8 Hz,
one of ArCH2CH), 2.74–2.93 (2H, m, CH2CN), 3.21 (1H, dd,
J 16.5, 6.4 Hz, one of ArCH2CH), 3.61 (3H, s, indole NCH3),
3.58–3.85 (3H, m, ArCH2CH and CH2CH2OH), 3.69–3.90 (2H,
AB system, J 12.9 Hz, NCH2Ph), 4.02–4.13 (1H, m, ArCH-
CH2), 7.09–7.60 (9H, m, ArH); 13C NMR δ 20.8 (t), 24.8 (t),
(b) Small-scale cyclisation attempt with potassium methoxide.
The alkene (10 mg of mixed cis–trans, 0.03 mmol) was dissolved
in dry MeOH and successive equivalents of KOt-Bu were added
until a reaction was observed by TLC, then the reaction was
stirred overnight. Water and CHCl3 were added and the organic
phase washed with brine, dried over MgSO4 and evaporated.
J. Chem. Soc., Perkin Trans. 1, 2000, 3578–3583
3581

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The residue was then subjected to flash chromatography on
silica, eluted with chloroform to yield a small sample (4 mg) of
the addition product 10.
chromatography on silica eluted with a solvent gradient of
CHCl3 to 1:19 MeOH–CHCl3 afforded the cyano alcohol as a
white foam (29 mg, 89%). The aliphatic region of the 1H NMR
of this material contained many overlapping multiplets and
could not be fully assigned. The structure was confirmed by
X-ray crystallography, as previously reported.6
1H NMR (400 MHz) δ 1.74 (1H, ddd, J 14.7, 11.5, 1.5 Hz,
one ArCHCH2), 2.02 (1H, ddd, J 14.7, 10.5, 2.2 Hz, one
ArCHCH2), 2.43–2.79 (5H, m, one of ArCH2CH, CH2CN and
CH(OCH3)CH2CN), 2.99 (3H, s, OCH3), 3.12 (1H, ddd, J 16.2,
6.5, 1.7 Hz, one of ArCH2CH), 3.44–3.68 (1H, m, CH(OCH3)-
CH2CN), 3.61 (3H, s, indole NCH3), 3.70–3.84 (2H, AB system,
J 13.5 Hz, NCH2Ph), 3.89–3.95 (1H, m, ArCH2CH), 4.12 (1H,
d, J 11.5 Hz, ArCHCH2), 7.14–7.53 (9H, m, ArH); MS m/z 412
(Mϩ, 29%), 380 (8), 314 (100), 273 (21), 183 (37), 170 (26), 91
(100); found m/z 412.2257, calc. for C26H28N4O 412.2263.
1H NMR δ 1.15 (3H, t, J 7.3 Hz, CH2CH3), 1.48–1.70 (3H,
m), 1.81–2.29 (4H, m), 2.33 (1H, s), 2.65 (1H, br d, J 7.5 Hz),
2.70 (3H, s, indole NCH3), 3.12 (1H, td, J 9.5, 3.9 Hz), 3.35–
3.53 (4H, m), 4.04 (1H, br d, J 1.1 Hz), 6.70 (1H, br d, J 7.8 Hz,
ArH), 6.82 (1H, td, J 7.4, 1.0 Hz, ArH), 7.16 (1H, td, J 7.8, 1.4
Hz, ArH), 7.50 (1H, br dd, J 7.4, 1.4 Hz, ArH); 13C NMR
δ 11.3 (q), 23.2 (t), 29.8 (t), 34.6 (d), 34.9 (q), 39.1 (d), 39.8 (t),
45.0 (d), 48.2 (d), 50.9 (d), 54.3 (s), 76.9 (d), 81.3 (d), 109.7 (d),
119.8 (d), 122.1 (s), 123.3 (d), 127.3 (d), 133.1 (s), 154.1 (s); MS
m/z 323 (Mϩ, 9%), 179 (14), 157 (5), 28 (100); found m/z
323.2003, calc. for C20H25N3O 323.1998.
(c) Successful cyclisation to tetracycle 11. The alkene 9
(100 mg of trans isomer, 0.26 mmol) was dissolved in dry THF
(10 ml) and stirred at 0 ЊC. KOt-Bu (30 mg, 0.27 mmol)
was added and the reaction allowed to warm to room temp.
and stirred 30 min. Saturated citric acid (aq) was added, then
the THF was removed by evaporation, the aqueous mixture
extracted with CHCl3 and then the organic layer dried over
MgSO4 and evaporated. The residue was subjected to flash
chromatography on silica, eluted with a solvent gradient of
DCM to 1:9 Et2O–DCM to yield the tetracycle dinitrile 11 as
Conversion of ajmaline to suaveoline 1
Ajmaline (163 mg, 0.5 mmol) was suspended in PhMe (10 ml)
and stirred with excess NH2OHؒHCl (350 mg) and refluxed for
24 h. When no reaction was observed by TLC the PhMe was
removed by evaporation and replaced with a 1:1 mixture of
EtOH–CHCl3 and the mixture heated for another 24 h. TLC
indicated that the cyano alcohol 15 was the only product, so the
solvent was evaporated and replaced with n-BuOH and the
mixture refluxed for another 24 h (in air, not in an inert atmos-
phere). TLC indicated that a single major product had been
formed, so saturated NaHCO3 (aq) and CHCl3 were added,
then the organic layer washed with brine, dried over MgSO4
and evaporated. Flash chromatography on silica, eluted with
1
a white foam (43 mg, 43%). The H NMR of this material
showed a complex mixture of stereoisomers which were not
fully resolved, however, mass spectral data at least confirmed
the molecular formula prior to the attempted final pyridine
formation.
MS m/z 380 (Mϩ, 69%), 340 (11), 289 (13), 273 (88), 222
(33), 182 (49), 91 (72), 28 (100); found m/z 380.2005, calc. for
C25H24N4 380.2001.
a
1:19 saturated methanolic ammonia–CHCl3 afforded
semi-synthetic suaveoline (59 mg, 30% overall). All data for this
material were identical to those reported previously.1a
(d) Formation of de-ethyl suaveoline derivative 13. The
dinitrile 11 (43 mg, 0.11 mmol) was dissolved in dry DCM
(5 ml) and then cooled to Ϫ78 ЊC. DIBAL-H (440 µl of 1 M
solution in DCM, 0.44 mmol) was then added slowly and the
reaction stirred at Ϫ78 ЊC for 30 min, then allowed to warm to
room temp. and stirred for 10 h. The reaction was then cooled
again to Ϫ78 ЊC and quenched with excess saturated NH4Cl
(aq) and 0.1 M H2SO4 and stirred at room temp. for 1 h. The
aqueous mixture extracted with CHCl3 and then the organic
layer dried over MgSO4 and evaporated. The residue was
immediately dissolved in EtOH with excess NH2OHؒHCl
(40 mg), and the mixture refluxed overnight. The EtOH was
then removed by evaporation and the residue partitioned
between EtOAc and saturated NaHCO3 (aq) and the organic
layer washed with brine, dried over MgSO4 and evaporated.
Flash chromatography on silica, eluted with a solvent gradient
of DCM to 1:19 Et2O–DCM afforded the de-ethyl suaveoline
derivative 13 (5 mg, 12%) along with a larger quantity of a
complex mixture containing more 13 by TLC (34 mg).
One-pot Horner–Wadsworth–Emmons–alkylation to the
alkene 17
Diethyl cyanomethylphosphonate (266 mg, 243 µl, 1.5 mmol)
was added to NaH (66 mg of 60% dispersion in mineral oil,
1.65 mmol) in DMF (10 ml) at 0 ЊC and stirred for 10 min. EtBr
(180 mg, 123 µl, 1.65 mmol) was added and the reaction
allowed to warm to room temp. and stirred for 1 h. This mixture
was then added to another portion of NaH (64 mg of 60%
dispersion in mineral oil, 1.60 mmol) in DMF (5 ml) at 0 ЊC and
stirred for 15 min. This mixture was then added dropwise to a
stirred solution of the crude aldehyde 8 (270 mg) in DMF (10
ml) at room temp. The reaction was stirred for 1 h, then the
DMF removed by evaporation and the residue treated with
PhMe and evaporated again to remove the last traces of DMF.
The residue was then partitioned between chloroform and
brine, the organic layer twice washed with brine, dried over
MgSO4 and evaporated. The residue was then subjected to flash
chromatography on silica eluted chloroform to yield the trans
alkene (76 mg), cis alkene (53 mg) and some mixed cis–trans
(126 mg, total yield 255 mg, 83%).
1H NMR (400 MHz) δ 2.74 (1H, br d, J 15.7 Hz, one of
ArCHCH2), 2.77 (1H, d, J 16.5 Hz, one of ArCH2CH), 3.41–
3.59 (2H, m, one of ArCH2CH and one of ArCHCH2), 3.62
(3H, s, indole NCH3), 3.76–3.44 (2H, AB system, J 13.5 Hz,
NCH2Ph), 4.24 (1H, d, J 5.2 Hz, ArCH2CH), 4.40 (1H, d, J 5.4
Hz, ArCHCH2), 6.91 (1H, d, J 5.1 Hz, pyr-H), 7.04–7.45 (9H,
m, ArH), 8.24 (1H, d, J 5.1 Hz, pyr-H), 8.43 (1H, s, pyr-H); MS
m/z (15 eV) 365 (Mϩ, 18%), 273 (42), 258 (18), 233, (12), 91
(74), 66 (92), 36 (100); found m/z 365.1915, calc. for C25H23N3
365.1892.
1
Data for cis alkene 17: Rf 0.60 (1:9 Et2O–DCM); H NMR
δ 1.08 (3H, t, J 7.5 Hz, CH2CH3), 2.15 (2H, q, J 7.5 Hz,
CH2CH3), 2.54–2.91 (5H, m, one of ArCH2CH, ArCHCH2,
and CH2CN), 3.21 (1H, dd, J 16.1, 6.3 Hz, one of ArCH2CH),
3.63–3.69 (1H, m, ArCH2CH), 3.73 (3H, s, indole NCH3),
3.64–3.95 (2H, AB system, J 13.4 Hz, NCH2Ph), 3.92–4.01 (1H,
m, ArCHCH2), 6.32 (1H, t, J 7.1 Hz, CHC(Et)CN), 7.14–7.57
(9H, m, ArH); 13C NMR δ 12.5 (q), 21.7 (t), 24.9 (t), 27.4 (t),
30.6 (q), 37.3 (t), 54.0 (d), 54.9 (d), 61.3 (t), 104.2 (s), 109.1 (d),
117.3 (s), 117.8 (s), 118.1 (s), 118.7 (s), 119.4 (d), 122.0 (d), 126.4
(s), 127.7 (d), 128.5 (2 × d), 129.1 (2 × d), 132.8 (s), 137.9 (s),
138.4 (s), 144.1 (d); MS m/z 408 (Mϩ, 1%), 391 (2), 330 (4), 314
(100), 289 (4), 273 (9), 183 (27), 168 (15), 91 (100); found m/z
408.2281, calc. for C27H28N4 408.2314.
Conversion of ajmaline to the cyano alcohol 15
Ajmaline (32.6 mg, 0.1 mmol) was dissolved in EtOH (2 ml)
and stirred with excess NH2OHؒHCl (35 mg) and stirred at
room temp. overnight then refluxed for 24 h. Saturated
NaHCO3 (aq) and CHCl3 were added, then the organic layer
washed with brine, dried over MgSO4 and evaporated. Flash
3582
J. Chem. Soc., Perkin Trans. 1, 2000, 3578–3583

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Data for trans alkene 17: Rf 0.52 (1:9 Et2O–DCM); 1H NMR
δ 1.04 (3H, t, J 7.5 Hz, CH2CH3), 2.07 (2H, br q, J 7.5 Hz,
CH2CH3), 2.37–3.71 (4H, m, ArCHCH2, and CH2CN), 2.80
(1H, dd, J 16.1, 3.1 Hz, one of ArCH2CH), 3.23 (1H, dd, J 16.1,
6.3 Hz, one of ArCH2CH), 3.55–3.59 (1H, m, Ar CH2CH), 3.61
(3H, s, indole NCH3), 3.67–3.97 (2H, AB system, J 13.3 Hz,
NCH2Ph), 3.88–3.95 (1H, m, ArCHCH2), 6.32 (1H, br t, J 7.1
Hz, CHC(Et)CN), 7.18–7.53 (9H, m, ArH); 13C NMR δ 12.4
(q), 22.1 (2 × t), 24.7 (t), 30.4 (q), 35.0 (t), 53.9 (d), 54.5 (d), 61.2
(t), 104.8 (s), 109.1 (d), 117.5 (s), 118.2 (s), 118.3 (s), 119.3 (s),
119.6 (d), 126.4 (s), 127.9 (d), 128.7 (2 × d), 129.1 (2 × d), 133.4
(s), 137.8 (s), 138.1 (s), 143.9 (d).
In a second reaction, the dinitrile 18 (20 mg, 0.05 mmol) was
dissolved in dry DCM (3 ml) and then cooled to Ϫ78 ЊC.
DIBAL-H (50 µl of 1 M solution in DCM, 0.05 mmol) was
then added slowly and the reaction stirred at Ϫ78 ЊC for 1 h,
then allowed to warm to room temp. and stirred for 100 h. The
reaction was then cooled to 0 ЊC and quenched with excess
saturated NH4Cl (aq) and 0.1 M H2SO4 and stirred at room
temp. for 1 h. The aqueous mixture was extracted with CHCl3
and the organic layer dried over MgSO4 and evaporated to yield
only starting material (by TLC and crude 1H NMR). Recycling
this material under the same reaction conditions, but with
increasing quantities of DIBAL-H led solely to the formation
of N-benzylsuaveoline 19 identical to that we had produced
previously.
Vinylogous Thorpe cyclisation to the tetracycle 18
Each fraction from the one-pot Horner–Wadsworth–Emmons–
alkylation reaction was reacted separately using the following
general method. The alkene 17 was dissolved in dry THF evap-
orated to dryness, then redissolved and cooled to 0 ЊC. KOt-Bu
(1 eq.) was added in portions and the reaction monitored by
TLC. After 10 min, the solvent was removed by evaporation
and the residue partitioned between CHCl3 and brine. The
organic layer was then dried over MgSO4 and evaporated. The
Formation of suaveoline 1
N-Benzylsuaveoline 19 (9 mg, 0.02 mmol) was dissolved in
dry EtOH (1 ml) and methanolic HCl (100 µl of 1 M solution,
0.1 mmol) was added. The solution was evaporated to dry-
ness and redissolved in EtOH (5 ml) and catalytic Pd–C (50%
water, Degussa type) added and the mixture stirred under
a hydrogen atmosphere for 2 h, then a further quantity of
catalyst was added prior to stirring under H2 for another
1 h. The solution was then filtered through a pad of silica
which was washed with methanolic ammonia to give 8 mg of
crude product, homogeneous by TLC. Flash chromatography
on silica eluted with a slight solvent gradient 1:99 to 3:97
saturated methanolic ammonia–CHCl3 afforded suaveoline
as a white foam (4 mg, 66%). This material was identical in
all respects to our semi-synthetic material and to the natural
product.1a
1
crude H NMR spectra for each reaction were very similar, so
the residues were combined to yield 300 mg of crude product
which was subjected to flash chromatography on silica eluted
with a solvent gradient of CHCl3 to 1:49 Et2O–DCM to yield
the tetracycle dinitrile 18 as a pale yellow foam (170 mg, 67%).
1
The H NMR of this material showed a complex mixture of
stereoisomers which were not fully resolved, however, mass
spectral data again confirmed the molecular formula prior to
the attempted final pyridine formation. Rf 0.60 (ninhydrin Ϫve,
whereas 17 is ϩve) (1:9 Et2O–DCM); MS m/z 408 (Mϩ, 4%),
347 (2), 273 (6), 177 (7), 91 (29), 49 (50), 28 (100); found m/z
408.2307, calc. for C27H28N4 408.2314.
Acknowledgements
We thank Dr A. S. F. Boyd and Dr R. Fergusson for NMR and
mass spectra, and EPSRC for funding.
Formation of N-benzylsuaveoline 19
The dinitrile 18 (41 mg, 0.10 mmol) was dissolved in dry DCM
(6 ml) and then cooled to Ϫ78 ЊC. DIBAL (400 µl of 1 M
solution in DCM, 0.4 mmol) was then added slowly and the
reaction stirred at Ϫ78 ЊC for 1 h, then allowed to warm to
room temp. and stirred for 24 h. The reaction was then cooled
again to 0 ЊC and quenched EtOH (1 ml) then evaporated to
dryness. The residue was then dissolved in EtOH with excess
NH2OHؒHCl (70 mg), and the mixture refluxed overnight. The
EtOH was then removed by evaporation and the residue
partitioned between CHCl3 and saturated NaHCO3 (aq). The
aqueous layer was washed five times with CHCl3 and the com-
bined organic extracts washed with brine, dried over MgSO4
and evaporated to give a crude yield of 69 mg. Flash chrom-
atography on silica eluted with a solvent gradient of DCM to
1:19 Et2O–DCM afforded N-benzylsuaveoline 19 (21 mg,
53%). All data for this material were identical to those reported
previously,1b except that our optical rotation was found to be
slightly higher, following rigorous purification to a white foam
{[α]D17 Ϫ149 (c 0.33, CHCl3); lit.1b (from oil) [α]D24 Ϫ127 (c 0.33,
CHCl3)}.
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