New asymmetric route to bridged indole alkaloids: Formal enantiospecific syntheses of (-)-suaveoline, (-)-raumacline and (-)-Nb-methylraumacline

Article abstract of DOI:10.1039/a606081a

The homologous nitrile 13 derived from L-tryptophan undergoes a modified Pictet-Spengler reaction with methyl propynoate, under conditions of kinetic control, to afford the cis-tetrahydro-β-carboline 15a (cis:trans = 77:23). After protection, Dieckmann-Thorpe cyclisation to the bridged keto nitrile 20 proceeds in 90% yield. Simple functional group modifications via the alcohol 21a and nitrile 22 (structures confirmed by X-ray crystallography) allow convergence with the tetracyclic α,β-unsaturated aldehyde 10, which is an advanced intermediate for the synthesis of a range of bridged indole alkaloids.

Full text of DOI:10.1039/a606081a

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New asymmetric route to bridged indole alkaloids: formal
enantiospecific syntheses of (؊)-suaveoline, (؊)-raumacline and
(؊)-Nb-methylraumacline
Patrick D. Bailey,*,a Ian D. Collier,a Sean P. Hollinshead,b
Madeleine H. Moore,b Keith M. Morgan,b David I. Smithc and
John M. Vernonb
a
Department of Chemistry, Heriot-Watt University, Riccarton, Edinburgh UK, EH14 4AS
b Department of Chemistry, University of York, Heslington, York UK, YO1 5DD
c Department of Chemical Development, Sterling Winthrop Pharmaceuticals Research Division,
Sterling Winthrop Research Centre, Alnwick, Northumberland UK, NE66 2JH
The homologous nitrile 13 derived from L-tryptophan undergoes a modified Pictet–Spengler reaction with
methyl propynoate, under conditions of kinetic control, to afford the cis-tetrahydro-â-carboline 15a
(cis :trans = 77 :23). After protection, D ieckmann–Thorpe cyclisation to the bridged keto nitrile 20 proceeds
in 90% yield. Simple functional group modifications via the alcohol 21a and nitrile 22 (structures confirmed
by X-ray crystallography) allow convergence with the tetracyclic á,â-unsaturated aldehyde 10, which is an
advanced intermediate for the synthesis of a range of bridged indole alkaloids.
Originally obtained from many species of Rauwolfia, the indole
alkaloids of the ajmaline–sarpagine family (e.g. 1–5) have been
CO2Me
NBn
O
NBn
N
N
Me
Me
H
OH
HO
H
8
9
O
N
NR
CO2Me
N
Me
N
H
Et
OH
Me
H
H
Et
ajmaline 1
R = H raumacline 2
R = Me Nb-methylraumacline 3
OHC
H
H
NBn
H
N
Me
N
OH
O
NH
NMe
N
N
10
Me
Me
H
H
H
Scheme 1
Et
sauveoline 4
macroline 5
Our own development of the cis-selective Pictet–Spengler
reaction has allowed us to achieve asymmetric syntheses of
bridged indole alkaloids using cheaper proteinogenic -trypto-
phan 7, again via the bridged ketone 9.4 However, conversion of
this to the α,β-unsaturated aldehyde 10 is not trivial, and a more
direct route would be a great advantage. We therefore studied
the feasibility of introducing the additional carbon at the first
step in the synthesis, leading to the route implied by the retro-
synthetic analysis outlined in Scheme 2.
CO2H
NH2
3
cf.
Nb
in
N
N
H
1
6
L-trytophan 7
widely studied, both because of their diverse biological proper-
ties, and because of their structural complexity.1 The tetracyclic
subunit 6† occurs in all these alkaloids and recent asymmetric
syntheses have been centred around the construction of related
key intermediates such as 9 and 10 via the methodology outlined
in Scheme 1.
Starting from -tryptophan, Cook has achieved the synthesis
of a range of these alkaloids, for which the α,β-unsaturated
aldehyde 10 is a common advanced intermediate.2 Key steps
involve the stereospecific formation of the trans-tetrahydro-β-
carboline 8, followed by epimerisation of the C(3) chiral centre
during Dieckmann cyclisation to give (after hydrolysis and
decarboxylation) the tetracyclic ketone 9. A similar initial strat-
egy has been employed by Magnus in his elegant synthesis of
the kopsinine alkaloids.3
NC
OHC
NR
OH
NR
N
Me
N
Me
NC
NC
NH2
NR
N
H
N
Me
X
O
O
X
† Numbering and N-notation for tetrahydro-β-carbolines are indicated
on structure 6.
Scheme 2 Retrosynthetic analysis of route to bridged indole alkaloids
J. Chem. Soc., Perkin Trans. 1, 1997
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Modified Pictet–Spengler reactions between activated
alkynes and tryptamine derivatives were first reported by
Massiot et al.5 We later extended this methodology to include a
range of tryptophan derivatives, and demonstrated that sub-
stituents on Nin and/or Nb greatly reduced the cis-selectivity.6
Thus, we planned to protect both nitrogens after the Pictet–
Spengler reaction but prior to the next key step, Dieckmann–
Thorpe cyclisation. Simple functional group interconversions
should then lead to the required α,β-unsaturated aldehyde.7
any electron withdrawing character caused problems later on in
the synthesis, due to opening of the tetrahydro-β-carboline ring
being promoted in preference to the desired C(15)–C(16) ring
closure (Scheme 5).9
NC
N
O
N
Me
16
O
Et
CN
X
NCOPr
Variety of bases
Results and discussion
N
Me
The homologated nitrile 13 has been prepared by Kutney et al.,8
but in order for us easily to process a large quantity of
-tryptophan (1 mol), several modifications were required. For
the initial reduction, commercially available solutions of
LiAlH4 in THF were employed, with increased reaction times
ensuring complete conversion. A modified work-up procedure
then generated granular precipitates of lithium and aluminium
salts, which were easily removed by filtration. Slow addition of
toluene-p-sulfonyl chloride to a solution of crude amino alco-
hol in pyridine at 0 ЊC afforded the bis(toluene-p-sulfonate) 11
which was refluxed with potassium cyanide in methanol to
afford the nitrile 12 as an amorphous solid. By performing a
single recrystallisation at this point we avoided column chrom-
atography in the whole of this sequence, since subsequent
detosylation with sodium in liquid ammonia proceeded very
cleanly. Thus, the homologated nitrile 13 was readily obtained
from -tryptophan in 50% overall yield (Scheme 3).
CO2Me
CN
15
16
NHCOPr
N
Me
CO2Me
17
Scheme 5
We performed a wide range of trial reactions in seeking a
suitable protecting group for the Nb nitrogen. Steric hindrance
proved to be a major problem and TLC indicated that protec-
tion of the cis-tetrahydro-β-carboline 15a was slower than of
the trans-isomer 15b. Eventually we benzylated this nitrogen in
reasonable yield (44% yield of 18a from 15a, Scheme 6) by
NC
NC
3
ii
i
15a/b
NBn
NBn
1
L-Trp
i, ii
N
H
N
Me
CO2Me
CO2Me
18a and C1
epimer 18b
19
iii
iii
OTs
CN
NHTs
NHR
N
H
N
H
NC
11
R = Ts 12
R = H 13
NBn
N
Me
iv
O
20
Scheme 3 Reagents and conditions: i, LAH, THF; ii, TsCl, pyridine; iii,
KCN, MeOH; iv, Na, NH3 (liq.)
Scheme 6 Reagents and conditions: i, BnBr, NaHCO3, CH2Cl2, reflux,
96 h; ii, MeI, NaH, DMF, room temp., 30 min; iii, LiNEt2, THF,
Ϫ78 ЊC, 1 h
The homologated nitrile 13 was treated with methyl pro-
pynoate to afford the enamines 14a and b. Acidification with
excess trifluoroacetic acid (TFA) promoted a rapid, kinetically
controlled ring closure and afforded a 77:23 mixture (insepar-
able at this stage) of cis:trans diastereoisomers 15a and b in
60% overall yield (Scheme 4).
treating 15a and b with benzyl bromide in refluxing dichloro-
methane over NaHCO3 for several days, and recycling un-
reacted starting material 15a. The Nin-methyl moiety is present
in many indole alkaloids, such as ajmaline 1, and methylation
with sodium hydride and methyl iodide in dimethylformamide
(DMF) proceeded smoothly to afford the fully protected
tetrahydro-β-carboline 19 in 92% yield (Scheme 6).
13
i
The critical C(15)–C(16) ring closure to the tetracyclic ketone
20, mediated by the action of lithium diethylamide on 19 in
tetrahydrofuran at Ϫ78 ЊC, proceeded exceptionally cleanly on
a large scale; aqueous work-up and flash chromatography
afforded the ketone 20 in 90% overall yield. All resonances in
the NMR spectra of 20 were unusually broad, presumably since
this material existed as a mixture of C(16)-epimers and the con-
jugated enol (Scheme 7).
ii
CN
CN
NH
NH
N
H
N
H
CO2Me
CO2Me
14a and b
15a and b
The oxygen functionality at C(15) was removed via a two-
step process, the first part of which was hydride reduction of
the ketone 20 to the alcohol 21a. The reduction displayed
remarkably high diastereoselectivity (>90%). The relative
stereochemistry was originally assigned on the basis of NOE
experiments (Fig. 1) and later confirmed by an X-ray structure
of the OTMS derivative 21b10 (Fig. 2).
From molecular models, it would appear that the re face of
the ketone (i.e. away from the indole system) is the less hin-
dered, and we infer that reduction from this side occurred more
Scheme 4 Reagents and conditions: i, methyl propynoate, CHCl3,
reflux, 100 h; ii, cool to 0 ЊC, and add TFA (2 equiv.), 30 min
Protection of both nitrogens was required firstly to facilitate
separation of the cis-tetrahydro-β-carboline 15a from the trans-
isomer 15b, and secondly to prevent unwanted cyclisations in
later steps. However, as our target alkaloids all possessed the
Nin-methyl sub-structure, we chose to ‘protect’ the indole nitro-
gen by methylation, once the Nb-protection was in place. The
choice of applicable Nb-protecting groups was limited, since
1210
J. Chem. Soc., Perkin Trans. 1, 1997

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NC
OHC
ii
i
21a
NBn
NBn
N
Me
N
Me
22
10
O
MeO
F3C
Ph
iii, iv
O
*
NBn
N
Me
23a (R)-ester at *
23b (S)-ester at *
Scheme 8 Reagents and conditions: i, POCl3, pyridine, benzene, reflux,
48 h; ii, DIBAL, CH2Cl2, Ϫ78 ЊC (30 min) to room temp. (5 h); iii,
NaBH4, MeOH, room temp., 2 h; iv, (R)- or (S)-PhC(OMe)(CF3)COCl,
pyridine, CH2Cl2, room temp.
21a, αβ-unsaturated nitrile 22 and aldehyde (Ϫ)-10 were pre-
pared. The overall yield for the seven-step synthesis of the α,β-
unsaturated aldehyde (Ϫ)-10 from the homologated nitrile 22
was 15%. The tetracyclic aldehyde (Ϫ)-10 is an intermediate in
Cook’s recent synthesis of suaveoline and the related indole
alkaloids raumacline and Nb-methylraumacline.2 Our work
constitutes a formal synthesis of these natural products, and
represents a particularly efficient approach for accessing alkal-
oids of the ajmaline–sarpagine family.
1
Fig. 1 Selected NMR data for 21a (NOEs and H NMR) indicating
the relative stereochemistry
NC
NC
H
NBn
O
NBn
OH
N
Me
N
Me
20
20a
'H–'
Experimental
Melting points were determined on a Reichert hot-stage micro-
scope apparatus and are uncorrected. IR Spectra were recorded
on a Pye-Unicam SP3-200 or a Perkin-Elmer 1420 spectro-
photometer. NMR Spectra were recorded on a JEOL FX90Q
spectrometer at 90 MHz (1H) or 22.5 MHz (13C), unless other-
wise stated; chemical shifts are quoted in ppm downfield from
Me4Si as internal standard and coupling constants J are given
i
NC
H
H
CN
NBn
H
NBn
O
N
Me
N
Me
RO
1
20b
in Hz. For H NMR spectra, signals showing strong second
21a, R = H
order effects (e.g. AB quartets) have been quoted with the posi-
tions of the outer peaks stated, and the apparent coupling con-
stant(s); for 13C NMR spectra, off-resonance multiplicities are
given in parentheses, although the number of attached hydro-
gens was usually determined using DEPT. Mass spectra were
obtained by electron impact on an AEI MS-3074 or a VG
Autospec spectrometer. The specific rotations of oils/foams of
basic compounds were found to be unreliable (possibly due to
traces of water or acid); consequently only [α]D values (in 10Ϫ1
deg cm2 gϪ1) for crystalline intermediates are quoted. Solvents
were dried by standard methods or obtained anhydrous from
Rathburn Chemicals or Aldrich; ether refers to diethyl ether.
Flash chromatography was performed using silica gel 60 (230–
400 mesh) as the stationary phase.
ii
21b, R = TMS
Scheme 7 Reagents and conditions: i, NaBH4, MeOH, room temp.,
2 h; ii, Me3SiCl, CH2Cl2, imidazole, Ϫ10 ЊC to room temp., 1 h
rapidly when the nitrile was anti (rather than syn). Thus, a single
keto nitrile diastereoisomer was continuously removed from the
enol–keto equilibrium mixture, allowing the single diastereo-
isomer 21a to be obtained in excellent yield (Scheme 7).
Dehydration of 21a with phosphoryl chloride and pyridine in
dry refluxing benzene afforded the α,β-unsaturated nitrile 22, in
87% yield (X-ray structure shown in Fig. 2). Finally, diisobutyl-
aluminium hydride (DIBAL) reduction of the nitrile 22 in
CH2Cl2 at Ϫ78 ЊC afforded the corresponding aldimine, which
was easily hydrolysed by aqueous acid on warming to room
temperature to afford the aldehyde (Ϫ)-10 isolated in 99% yield
(Scheme 8).
The enantiomeric purity of the aldehyde (Ϫ)-10 was deter-
mined by NaBH4 reduction to the alcohol, followed by analysis
of the 19F NMR spectra of the (R)- and (S)-Mosher’s esters 23a
and b (Fig. 3).11 By forming both the (R)- and (S)-esters, we were
able to locate the diastereoisomeric 19F signals definitively, and
show that 23a and 23b [and hence (Ϫ)-10] were optically pure
within our detection limits (ee >97%).
Preparation of (2S)-2-amino-3-(2-indolyl)propan-1-ol
Lithium aluminium hydride (2.4 l of 1  solution in THF, 2.4
mol, 9.6 equiv.) was transferred by cannula into a dry 5 l reac-
tion vessel, stirred with an efficient pneumatic stirrer and cooled
to 0 ЊC. -Tryptophan (160 g, 0.78 mol) was added in small
batches, then the solution was stirred for a further 30 min at
ambient temperature before being gently heated to reflux. After
48 h the reaction mixture was cooled to 0 ЊC and cautiously
treated with water (90 ml), aqueous NaOH (90 ml of 15% solu-
tion) and water (270 ml). Vigorous stirring was maintained for
30 min and the granular inorganic precipitate was removed by
filtration and washed with THF. Evaporation of the combined
filtrates under reduced pressure afforded a colourless oil which
was redissolved in EtOAc, washed three times with saturated
brine, dried over MgSO4, filtered and evaporated to afford the
Conclusions
The modified homologation procedure enabled 1 mol of -
tryptophan to be processed through to the nitrile 13. Using this
material, large quantities of the tetracyclic ketone 20, alcohol
J. Chem. Soc., Perkin Trans. 1, 1997
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Fig. 2 (a) X-Ray crystal structure of the TMS-protected alcohol 21b,‡ with the TMS group removed for clarity. (b) X-Ray crystal structure of the
α,β-unsaturated nitrile 22,§ where the position of the double bond was confirmed by the C(15)–C(16) bond length of 1.332(8) Å.
into saturated brine (1 l). The inorganic precipitate formed was
removed by filtration and washed with CH2Cl2. The combined
filtrates were shaken together, the organic layer separated and
the aqueous layer extracted twice with CH2Cl2. The combined
organic extracts were washed four times with 2  hydrochloric
acid and twice with saturated brine, dried over MgSO4, filtered
and evaporated to afford the bis(toluene-p-sulfonate) 11 as a
yellow oil (330 g, 89%). All data were identical to those reported
previously.8
Preparation of (3S)-3-(tosylamino)-4-(2-indolyl)butanenitrile 12
Potassium cyanide (25 g, 380 mmol, 2 equiv.) and the bis-
(toluene-p-sulfonate) 11 (100 g, 200 mmol) were refluxed
together in anhydrous MeOH (1500 ml) for 2 h. After cooling,
the solvent was removed under reduced pressure and the solid
residue partitioned between EtOAc and saturated brine. The
organic layer was washed six times with saturated brine, dried
over MgSO4, filtered and evaporated to afford the nitrile 12 as
an amorphous brown solid (64 g, 98%). This material was redis-
solved in hot MeOH, treated with decolorising charcoal, fil-
tered and allowed to cool, to afford pale yellow cubic crystals
of 12 (43 g, 70%). All data were identical to those reported
previously.8
Fig. 3 (a) 19F NMR of (R)-Mosher’s ester 23a (crude product). (b) 19
NMR of (R)- plus (S)-Mosher’s esters 23a and 23b, for assignment of
peaks. Spiking experiments allowed quantification of the diastereo-
isomeric peaks and confirmed the ee of (Ϫ)-10 to be >97%.
F
amino alcohol as a colourless oil (143 g, 97%). All data were
identical to those reported previously.8
Preparation of (3S)-3-amino-4-(2-indolyl)butanenitrile 13
Sodium (36 g, 1.56 mol, 5 equiv.) was added in small portions to
a stirred solution of the tosylamino nitrile 12 (110 g, 311 mmol)
in liquid ammonia (2 l) at Ϫ78 ЊC. The reaction was stirred for
2 h then quenched with excess NH4Cl. The solvent was allowed
to evaporate at atmospheric pressure overnight and the white
residue was partitioned between 2  aqueous hydrochloric acid
and EtOAc. The aqueous layer was washed with EtOAc, basified
with conc. aqueous ammonia and extracted three times with
EtOAc. The combined extracts were dried over MgSO4, filtered
and evaporated to afford the amino nitrile 13 as an amorphous
solid (47 g, 75%). All data were identical to those reported
previously.8
Preparation of (2S)-3-(2-indolyl)-2-(tosylamino)propyl toluene-
p-sulfonate 11
The amino alcohol (142 g, 0.75 mol) was stirred in anhydrous
pyridine (800 ml) at 0 ЊC, and toluene-p-sulfonyl chloride (500
g, 2.6 mol, 3.5 equiv.) was added in small portions over 5 h. The
reaction mixture was maintained at 0 ЊC for 20 h then poured
‡ Crystal data for compound 21b: C26H31N3OSi, Mr = 429.64, crystal
dimensions 0.30 × 0.50 × 0.50 mm. Orthorhombic space group P212121,
a = 9.987(2), b = 30.88(6), c = 8.095(2) Å, V = 2496(4) Å3, Z = 4,
Dc = 1.143 g cmϪ3, Mo-Kα radiation (graphite monochromator),
λ = 0.710 69 Å, µ = 1.15 cmϪ1, F(000) = 720. Total of 2574 reflections
collected at 296 K in an ω scan. An empirical absorption correction was
applied. The structure was solved by direct methods (SHELXS86) and
refinement converged with Rw = 0.052. All hydrogen atoms were placed
at calculated positions.
Preparation of (1S,3S)- and (1R,3S)-3-(cyanomethyl)-1-
[(methoxycarbonyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido[3,4-
b]indoles 15a and b
§ Crystal data for compound 22: C23H21N3, Mr = 339.44, crystal dimen-
sions 0.30 × 0.40 × 0.60 mm. Orthorhombic, space group P212121,
a = 10.777(4), b = 18.682(3), c = 8.927(6) Å, V = 1997(1) Å3, Z = 4,
Dc = 1.254 g cmϪ3, Mo-Kα radiation (graphite monochromator),
λ = 0.710 69 Å, µ = 0.75 cmϪ1, F(000) = 720. Total of 4616 reflec-
tions collected at 296 K in an ω scan of which 1854 were unique. A
polynomial absorption correction was applied. The structure was
solved by direct methods (SHELXS86) and refinement converged with
Rw = 0.048. All hydrogen atoms were placed at calculated positions. For
both compounds 21b and 22, atomic coordinates, bond lengths and
angles and thermal parameters have been deposited at the Cambridge
Crystallographic Data Centre. See refs. 10 and 7.
The cyano amine 13 (35 g, 176 mmol) and methyl propynoate
(30 g, 357 mmol) were stirred together in CHCl3 (1 l), under
reflux for 100 h. The solution was then cooled to 0 ЊC, TFA
(37.3 g, 25 ml, 352 mmol, 2 equiv.) added and stirring main-
tained for 30 min. Water (500 ml) was added, followed by aque-
ous 2  NaOH dropwise to basify the aqueous layer (to pH 8).
The organic layer was separated from the basic aqueous layer
which was extracted a further five times with CH2Cl2. The com-
bined organic extracts were dried over MgSO4, filtered and
evaporated to afford the amines 15a and b as an amorphous
1212
J. Chem. Soc., Perkin Trans. 1, 1997

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yellow solid (55 g). Flash chromatography on silica eluted with
a solvent gradient (1:9 ether–CH2Cl2 to 2:10:88 MeOH–
Et2O–CH2Cl2) afforded the carbolines 15a and b as a pale yel-
low foam (30 g, 60%), mp 186–188 ЊC; δH 1.82 (1 H, br s, NbH),
2.40–3.21 (6 H, m, ArCH2CHCH2CN and CH2CO2Me), 3.50 (1
H, m), 3.70 (3 H, s, CO2CH3), 4.38 (1 H, m), 6.95–7.48 (4 H, m,
ArH), 8.50–8.71 (1 H, br s, NinH); δC 24.1 (t), 24.8 (t), 27.8 (t),
28.3 (t), 40.3 (t), 40.8 (t), 47.0 (d), 47.4 (d), 50.0 (d), 50.9 (d),
52.2 (q), 107.2 (s), 108.2 (s), 111.2 (d), 117.8 (s), 118.1 (d), 119.6
(d), 122.1 (d), 126.8 (s), 134.3 (s), 136.1 (s), 173.2 (s), 173.4 (s);
νmax/cmϪ1 3455, 2240, 1734; m/z 283 (Mϩ), 210 (Found: Mϩ,
283.1327. C16H17N3O2 requires M, 283.1321).
CHCH2CO2Me), 7.02–7.56 (9 H, m, ArH); δC 20.6 (t), 24.2 (t),
30.5 (q), 41.5 (t), 51.3 (d), 51.9 (q), 53.3 (d), 61.1 (t), 104.4 (s),
109.0 (d), 118.3 (d), 118.7 (s), 119.5 (d), 122.1 (d), 127.5 (d),
128.5 (d), 128.6 (d), 133.0 (s), 137.8 (s), 138.6 (s), 171.4 (s); νmax
/
cmϪ1 2240, 1742; m/z 387 (Mϩ), 347, 314, 91 (Found: Mϩ,
318.1943. C24H25N3O2 requires M, 318.1947).
Ring closure of the cis cyano ester 19
A solution of the cyano ester 19 (11.24 g, 29.0 mmol) in 20 ml
of THF was added dropwise to a stirred solution of lithium
diethylamide (7.5 equiv.) at Ϫ78 ЊC. This base was prepared by
the slow addition of BuLi (21.7 ml of 10  solution in hexanes,
217 mmol) to a stirred solution of freshly distilled diethylamine
(16 g, 22.3 ml, 217 mmol) in 200 ml of THF at 0 ЊC. The reac-
tion mixture was stirred at Ϫ78 ЊC for 1 h, quenched with brine
and then allowed to warm to ambient temperature and
extracted with EtOAc. The combined extracts were dried over
MgSO4, filtered and evaporated. Flash chromatography of the
residue on silica eluted with 1:19 MeOH–CH2Cl2 afforded the
tetracyclic ketone 20 as a pale yellow foam (9.25 g, 90%). This
gave broad NMR spectra that indicated a mixture of com-
pounds, and this crude material was used in the next step.
Preparation of (1S,3S)- and (1R,3S)-2-benzyl-3-(cyanomethyl)-
1-[(methoxycarbonyl)methyl]-1,2,3,4-tetrahydro-9H-pyrido-
[3,4-b]indoles 18a and b
The amines 15a and b (40 g, 141 mmol) and benzyl bromide
(26.6 g, 155 mmol, 18.4 ml, 1.1 equiv.) were stirred over
NaHCO3 (110 g, ca. 10 equiv.) in refluxing CH2Cl2 (450 ml) for
96 h, then the mixture was cooled, filtered and evaporated.
Flash chromatography of the residue on silica eluted with a
gradual solvent gradient (1:9 ether–CH2Cl2 to 5:10:85 MeOH–
ether–CH2Cl2) afforded three main components: the (1S,3S) cis
isomer 18a (9.5 g, 24%); the (1R,3S) trans isomer 18b (8.8 g,
72%) and starting material 15a and b (13.8 g, 40%). Recycling
the 13.8 g of starting material under identical conditions
afforded two main components: the (1S,3S) cis isomer 18a (3.3
g, 18%) and starting material 15a and b (10.0 g, 72%). Sub-
sequent recycling afforded the (1S,3S) cis isomer 18a (total of
17.5 g, 44%).
Data for cis isomer 18a: Rf 0.42 (CHCl3); δH 2.25–3.28 (6 H,
m, ArCH2CHCH2CN and CH2CO2Me), 3.58–3.68 (1 H, m,
ArCH2CH), 3.73 (3 H, s, CO2CH3), 3.95 (2 H, s, CH2Ph), 4.24–
4.45 (1 H, m, CHCH2CO2Me), 7.03–7.55 (9 H, m, ArH), 8.75 (1
H, br s, NinH); δC 21.8 (t), 23.5 (t), 41.3 (t), 52.0 (q), 52.1 (d),
53.1 (d), 59.6 (t), 104.3 (s), 111.1 (d), 118.1 (d), 118.5 (s), 119.5
(d), 122.2 (d), 126.9 (s), 127.5 (d), 128.3 (d), 128.6 (d), 132.2 (s),
136.0 (s), 138.7 (s), 174.0 (s); νmax/cmϪ1 3435, 2245, 1728, 1654;
m/z 373 (Mϩ), 333, 300, 282, 91 (Found: Mϩ, 373.1789.
C23H23N3O2 requires M, 373.1790).
Data for trans isomer 18b: Rf 0.33 (CHCl3); mp 143.5–145 ЊC
[ether–light petroleum (bp 40–60 ЊC)]; [α]D ϩ97.4 (c = 1,
MeOH); δH 2.59–2.88 (6 H, m, ArCH2CHCH2CN and
CH2CO2Me), 3.24–3.83 (2 H, ABq, J 14.1, CH2Ph), 3.45–3.60
(1 H, m, ArCH2CH), 3.62 (3 H, s, CO2CH3), 4.15 (1 H, dd,
J 8.3, 6.1, CHCH2CO2Me), 7.02–7.55 (9 H, m, ArH), 8.53 (1 H,
br s, NinH); δC 21.7 (t), 23.1 (t), 40.2 (t), 49.8 (t), 51.5 (d), 51.9
(q), 52.8 (d), 107.1 (s), 111.2 (d), 118.0 (s), 118.1 (d), 119.6 (d),
122.l (d), 126.6 (s), 127.3 (d), 128.5 (d), 133.3 (s), 136.1 (s), 138.6
(s), 173.2 (s); νmax/cmϪ1 3470, 2250, 1740; m/z 373 (Mϩ), 333,
300, 282, 91 (Found: Mϩ, 373.1789. C23H23N3O2 requires M,
373.1790).
Preparation of (6S,8S,9S,10S)-12-benzyl-9-cyano-8-hydroxy-5-
methyl-6,7,8,9,10,11-hexahydro-6,10-epimino-5H-cyclooct[b]-
indole 21a
Sodium borohydride (8.8 g, 233 mmol, 40 equiv.) was added in
portions to a stirred solution of the tetracyclic ketone 20 (8.27
g, 23.3 mmol) in anhydrous MeOH (250 ml). After 2 h the
solvent was evaporated and the residue partitioned between
CH2Cl2 and water. The organic layer was washed sequentially
with water and brine, dried over MgSO4, filtered and evapor-
ated to afford a pale yellow foam. Flash chromatography of this
material on silica eluted with a solvent gradient (1:9 ether–
CH2Cl2 to 2:10:88 MeOH–ether–CH2Cl2) afforded the tetra-
cyclic alcohol 21a as a white foam (4.0 g, 47%) and starting
material as a pale yellow foam (4.1 g, 50%). Recycling starting
material afforded a total of 7.5 g of the alcohol 21a (90%), [α]D
Ϫ46.5after recrystallisation (MeOH);mp 159–160.5 ЊC (MeOH)
(Found: C, 77.0; H, 6.4; N, 11.7. Calc. for C23H23N3O: C,
77.3; H, 6.5; N, 11.8%); δH (360 MHz) (see Fig. 1) 2.03 (1 H, d,
J 12.0, OH), 2.12 (1 H, dt, J 14.2, 2.4, HB), 2.22 (1 H, dt, J 14.2,
4.3, HC), 3.21 (1 H, dd, J 17.3, 1.2, 11-H), 3.29 (1 H, dd, J 17.3,
6.5, 11-H), 3.43 (1 H, dd, J 5.2, 4.2, HE), 3.58–3.71 (2 H, ABq,
J 13.2, CH2Ph), 3.61 (3 H, s, Nin CH3), 3.67 (1 H, br t, J 5.6, HF ),
3.93 (1 H, dd, J 4.3, 2.7, HA), 4.20 (1 H, dtd, J 12.0, 4.2, 2.2,
HD ), 7.15–7.58 (9 H, m, ArH); δC 17.8 (t), 28.2 (q), 35.2 (t), 39.2
(d), 45.9 (d), 50.4 (d), 56.5 (t), 63.8 (d), 102.2 (s), 108.2 (d),
117.7 (d), 118.1 (s), 118.8 (d), 121.1 (d), 125.3 (s), 126.5 (d),
2 × 127.5 (d), 134.7 (s), 136.5 (s), 136.8 (s); νmax/cmϪ1 3505,
2225; m/z 357 (Mϩ), 91 (Found: Mϩ, 357.1841. C23H23N3O
requires M, 357.1841).
Preparation of (6S,8S,9S,10S)-12-benzyl-9-cyano-8-trimethyl-
silyloxy-5-methyl-6,7,8,9,10,11-hexahydro-6,10-epimino-5H-
cyclooct[b]indole 21b
Preparation of (1S,3S)-2-benzyl-3-(cyanomethyl)-1-[(methoxy-
carbonyl)methyl]-9-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]-
indole 19
The alcohol 21a (50 mg, 0.14 mmol) and imidazole (10.5 mg,
0.15 mmol) were stirred in dry CH2Cl2 (10 ml) at Ϫ10 ЊC. Tri-
methylsilyl chloride (TMSCl) (18.2 mg, 21 ml, 0.17 mmol) was
added slowly and then the reaction was allowed to warm to
room temp. and stirred for 1 h. The organic solution was then
washed with brine, dried over MgSO4, filtered and evaporated
to afford a pale yellow foam (71 mg). Flash chromatography on
silica gel eluted with CH2Cl2 afforded the silyl protected alcohol
(57 mg, 95%). Slow crystallisation of this material from MeOH
afforded large colourless needles suitable for X-ray diffraction
studies.‡,10
Sodium hydride (684 mg of 80% dispersion in oil, 22.8 mmol,
1.05 equiv.) was added to a stirred solution of the N-benzyl
amine 18a (8.1 g, 21.7 mmol) and methyl iodide (3.24 g, 1.42 ml,
22.8 mmol, 1.05 equiv.) in DMF (150 ml) at 0 ЊC. After 1 h the
reaction mixture was allowed to warm to ambient temperature
and stirred for a further 30 min. The DMF was removed under
reduced pressure, and the residue dissolved in EtOAc, washed
sequentially with water and brine, dried over MgSO4, filtered
and evaporated to afford a brown amorphous solid. Flash
chromatography through a short silica column eluted with
CH2Cl2 afforded the cyano ester 19 as a pale yellow foam (7.7 g,
92%); δH 2.45–3.05 (6 H, m, ArCH2CHCH2CN and
CH2CO2Me), 3.38–3.55 (1 H, m, ArCH2CH), 3.63 (3 H, s), 3.71
(3 H, s), 3.86 (2 H, s, CH2Ph), 4.52 (1 H, dd, J 8.4, 6.2,
Mp 186–188 ЊC; Rf 0.84 (1:9 ether–CHCl3); δH (80 MHz)
Ϫ0.43 [9 H, s, SiC(CH3)3], 1.85–2.10 (2 H, m, 7-H2), 3.03–3.39 (4
H, m, 6-H, 7-H2 and CHCN), 3.54 (3 H, s, NinCH3), 3.68–3.91
(3 H, m, CH2Ph and ArCH), 4.05–4.26 (1 H, m, CHOTMS),
J. Chem. Soc., Perkin Trans. 1, 1997
1213

View Article Online
6.92–7.61 (9 H, m, ArH); m/z 429 (Mϩ), 414, 273, 91 (Found:
Mϩ, 429.2235. C26H31N3OSi requires M, 429.2236).
273, 251, 91 (Found: Mϩ, 342.1720. C23H22N2O requires M,
342.1732).
Preparation of (6S,10S,8E)-12-benzyl-9-cyano-5-methyl-
Determination of the optical purity of the á,â-unsaturated
aldehyde (Ϫ)-10
6,7,10,11-tetrahydro-6,10-epimino-5H-cyclooct[b]indole 22
The cyano alcohol 21a (2.31 g, 6.5 mmol), phosphoryl chloride
(4 g, 2.4 ml, 26 mmol, 4 equiv.) and anhydrous pyridine (10.3 g,
10.5 ml, 130 mmol, 20 equiv.) were refluxed in dry benzene (100
ml) for 48 h. The solution was then cooled, treated with water
and stirred for 30 min. The organic layer was separated, twice
washed with saturated aqueous NaHCO3, dried over MgSO4,
filtered and evaporated. Flash chromatography of the residue
on silica eluted with CH2Cl2 afforded the α,β-unsaturated nitrile
22 as a white foam (1.89 g, 87%). A small sample (ca. 10 mg) of
the nitrile 22 was placed in a small vial and dissolved in CHCl3
(ca. 1 ml). The open vial was then placed within a larger vial
containing hexane (10 ml). After 2 weeks, vapour diffusion
produced large, pale yellow crystals of the nitrile 22 in the
smaller vial. These crystals were amenable to X-ray diffraction
Sodium borohydride (13.2 mg, 0.34 mmol) was added to the
aldehyde (Ϫ)-10 stirred in dry MeOH (5 ml) at room tem-
perature. After 2 h the solvent was evaporated and the residue
partitioned between CH2Cl2 and 0.1  aqueous HCl. The
organic layer was washed with saturated aqueous NaHCO3,
dried over MgSO4, filtered and evaporated to afford the alcohol
as a colourless oil (58 mg, 95%) which was used directly for the
formation of both (R)- and (S)-Mosher’s esters 23a and b
according to established procedures.11
Acknowledgements
We thank Dr G. K. Barlow, Mrs B. Chamberlain, Dr T. A.
Dransfield, Mr B. R. Glennie and Dr N. R. McLay for NMR
and mass spectra at York University, and Sterling Research and
SERC for a CASE studentship (to K. M. M.).
,7
studies.§
Mp 190–191 ЊC (MeOH); [α]D Ϫ102 (c 1.0, CH2Cl2) (Found:
C, 81.1; H, 6.1; N, 12.3. Calc. for C23H21N3: C, 81.4; H, 6.2; N,
12.4%); δH 1.98–3.20 (4 H, m), 3.45 (3 H, s, NinCH3), 3.57 (2 H,
References
s, CH Ph), 3.72–4.14 (2 H, m), 6.50–6.62 (1 H, m, CH᎐CCN),
᎐
2
1 Milestone syntheses of ajmaline include the first total synthesis
(S. Masamune, S. K. Ang, C. Egli, N. Nakatsuka, S. Sarkar and
Y. Yasunari, J. Am. Chem. Soc., 1967, 89, 2506) and a biomimetic
approach (E. E. van Tamelen and L. K. Oliver, J. Am. Chem. Soc.,
1970, 92, 2136).
2 (a) M. L. Trudell, D. Soerens, R. W. Weber, L. Hutchins,
D. Grubisha, D. Bennett and J. M. Cook, Tetrahedron, 1992, 10,
1805; (b) X. Fu and J. M. Cook, J. Am. Chem. Soc., 1992, 114, 6910;
(c) L. Zhang, Y. Bi, F. Yu, G. Menzia and J. M. Cook, Heterocycles,
1992, 34, 517; (d) X. Fu and J. M. Cook, J. Org. Chem., 1993, 58,
661.
3 For example, P. Magnus, B. Mugrage, M. R. DeLuca and
G. A. Cain, J. Am. Chem. Soc., 1990, 112, 5520.
4 P. D. Bailey and N. R. McLay, J. Chem. Soc., Perkin Trans. 1, 1993,
441.
5 J. Vercauteren, C. Lavaud, J. Levy and G. Massiot, J. Org. Chem.,
1984, 49, 2278.
7.02–7.58 (9 H, m, ArH); δC 22.6 (t), 29.3 (q), 30.1 (t), 47.5 (d),
53.4 (d), 56.4 (t), 104.2 (s), 109.0 (d), 115.8 (s), 118.2 (s), 118.3
(d), 119.4 (d), 121.6 (d), 126.6 (s), 127.5 (d), 128.6 (d), 128.7 (d),
134.0 (s), 137.1 (s), 137.6 (s), 141.5 (d); νmax/cmϪ1 2200, 1635;
m/z 339 (Mϩ), 248, 91 (Found: Mϩ, 339.1738. C23H21N3 requires
M, 339.1735).
Preparation of (6S,10S,8E)-12-benzyl-5-methyl-6,7,10,11-
tetrahydro-6,10-epimino-5H-cyclooct[b]indole-9-carbaldehyde
10
DIBAL (1.2 ml of 1  solution in CH2Cl2, 1.2 mmol) was added
dropwise to a stirred solution of the nitrile 22 (340 mg, 1 mmol)
in anhydrous CH2Cl2 (20 ml) at Ϫ78 ЊC. After 30 min the reac-
tion mixture was allowed to warm to ambient temperature and
stirring maintained for a further 5 h. The solution was then
cooled to Ϫ78 ЊC and treated sequentially with MeOH, satur-
ated aqueous NH4Cl and 0.1  aqueous H2SO4. Upon warming
to ambient temperature the reaction mixture was extracted with
CH2Cl2. The combined extracts were dried over MgSO4, filtered
and evaporated. Flash chromatography of the residue on silica
eluted with CH2Cl2 afforded the α,β-unsaturated aldehyde (Ϫ)-
10 as a colourless foam (339 mg, 99%), [α]D20 Ϫ220 (c 2.0, CHCl3)
{lit.,2 [α]D24 Ϫ310.5 (c 0.55, CHCl3)} (see Results and discussion).
Importantly, 19F NMR analysis of Mosher’s esters 23a and b
confirmed the high optical purity of our compounds (ee >97%).
δH 2.19–3.30 (5 H, m), 3.58 (3 H, s, NinCH3), 3.59–3.93 (2 H,
ABq, J 13.0, CH2Ph), 4.14 (1 H, dd, J 9.5, 6.6), 6.71 (1 H, br s,
6 P. D. Bailey and S. P. Hollinshead, J. Chem. Soc., Perkin Trans. 1,
1988, 739.
7 Preliminary communication—P. D. Bailey, I. D. Collier, S. P.
Hollinshead, M. H. Moore, K. M. Morgan, D. I. Smith and
J. M. Vernon, J. Chem. Soc., Chem. Commun., 1994, 1559.
8 J. P. Kutney, G. K. Eigendorf, H. Matsue, A. Murai, K. Tanaka,
W. L. Sung, K. Wada and B. R. Worth, J. Am. Chem. Soc., 1978,
100, 938.
9 P. D. Bailey and S. P. Hollinshead, Tetrahedron Lett., 1987, 28,
2879.
10 P. D. Bailey, S. P. Hollinshead, M. H. Moore, K. M. Morgan,
D. I. Smith and J. M. Vernon, Tetrahedron Lett., 1994, 35, 3585.
11 J. A. Dale, D. L. Dull and H. F. Mosher, J. Org. Chem., 1969, 34,
2543.
CH᎐CCHO), 7.05–7.52 (9 H, m, ArH), 9.33 (1 H, s, CHO); δ
᎐
C
21.9 (t), 29.3 (q), 32.4 (t), 48.1 (d), 50.1 (d), 56.3 (t), 105.3 (s),
108.8 (d), 118.3 (d), 119.2 (s), 121.4 (d), 126.9 (s), 127.2 (d),
128.4 (d), 128.7 (d), 134.1 (s), 137.0 (s), 138.5 (s), 143.8 (d),
147.6 (d), 192.5 (d); νmax/cmϪ1 1680, 1642; m/z 342 (Mϩ), 313,
Paper 6/06081A
Received 4th September 1996
Accepted 15th November 1996
1214
J. Chem. Soc., Perkin Trans. 1, 1997