Stereoselective benzylic α-acylamino radical cyclisation: A model study for the Tacaman indole alkaloid skeleton

Article abstract of DOI:10.1039/a602932i

Radical cyclisation with tributyltin hydride of the α-phenylsulfanyl lactam 6, prepared in nine steps from D-ribose via the corresponding phthalimide, gives the all-cis tetrahydropyrido[2,1-a]isoindolone 7 stereoselectively as the major diastereomer. The

Full text of DOI:10.1039/a602932i

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Stereoselective benzylic á-acylamino radical cyclisation: a model
study for the Tacaman indole alkaloid skeleton
Rainer Clauss and Roger Hunter*
Department of Chemistry, University of Cape Town, Rondebosch 7700, South Africa
Radical cyclisation with tributyltin hydride of the α-phenylsulfanyl lactam 6, prepared in nine steps from
D -ribose via the corresponding phthalimide, gives the all-cis tetrahydropyrido[2,1-a]isoindolone 7
stereoselectively as the major diastereomer. The structure of the product is established by 1H N M R
spectroscopy and corroborated by formation of the cis-lactone 8. The diastereoselectivity is shown to be
controlled by the allylic/homoallylic cis-ketal group, and a transition state is proposed. The sequence
constitutes the first simple model study for C/D ring fusion of the Tacaman indole alkaloid skeleton via
the relatively unexplored C-3–C-14 bond disconnection.
-ribose to its 2,3-O-isopropylidene derivative9 was routinely
Introduction
carried out in around 65% yield by using a stoichiometric
amount of conc. H2SO4 in dry acetone at 0 ЊC for about 2 h. A
non-aqueous isolation procedure similar to that of Hughes and
Speakmann,10 involving quenching with KOH (2 equiv.) in
MeOH together with some anhydrous K2CO3 to help coagu-
lation of the precipitated salts, was then used. Filtration of the
mixture and evaporation of solvent gave a quantitative yield of
products which could be chromatographed or used directly in
the next step.
In the last decade or so, the cyclisation of α-acylamino radicals
has developed into a powerful methodology for nitracycle syn-
thesis, following the pioneering studies by Hart and co-workers
in the 1980s. Synthetic targets involving the methodology include
pyrrolizidine and indolizidine alkaloids,1a–e functionalised
β-lactams,2 cyclic α-amino acids,3 the oxoindole gelsemine4 and
the synthetic vitamin (+)-biotin.5 In all of the cases reported to
date in which the α-acylamino radical has been derived from an
imide, the latter has been based on succinimide. In this paper,
we present the first study of cyclisation of α-acylamino radicals
derived from phthalimide. The purpose of the study was to gain
information on factors controlling the diastereoselectivity of
ring closure onto a chiral -ribose-derived chain. This was car-
ried out as a simple model study of C/D ring fusion of the
Tacaman 6 indole alkaloid skeleton via the C-3–C-147 bond (see
Scheme 1 for Tacaman numbering8).
Oxime derivatives of carbohydrates from hydroxylamine
were first reported in 188711 as a means of characterisation. As
with the thioketalisation of sugars, oximation results in ring
opening to afford chiral, acyclic chains useful in synthesis.
Recently, in this regard, the groups of Bartlett 12 and Marco-
Contelles13 have used this to good effect in the radical cyclis-
ation of carbohydrate-derived oxime ethers to aminocyclitols.
Oximation of 2,3-O-isopropylidene--ribofuranose with O-
benzylhydroxylamine hydrochloride in pyridine gave the organ-
ically soluble crystalline oxime-diol 2 in 85% yield after the
normal work-up and chromatography. Crystallisation of the
crude product from ethyl acetate–hexane afforded a 70% yield
(2 crops). Alternatively, a 50% overall yield of 2 for the two
steps after fractional crystallisation could be achieved using the
crude product from step 1. The product gave satisfactory spec-
tral and analytical data and was isolated initially as a 2:1 E :Z
mixture. Repeated crystallisation furnished the pure (E)-isomer
for characterisation. Oxime to amine reduction could be
accomplished smoothly by LiAlH4–THF at room temperature.
However, not unexpectedly, the amino-diol product was too
water soluble for isolation via two phase organic extraction, and
a derivatisation–isolation procedure was developed. Careful
quenching of the LiAlH4 reaction mixture at 0 ЊC with an NEt3–
H2O (5:1) mixture resulted in the formation of a flocculent
white precipitate after about 30 min which could be filtered off.
Evaporation of solvent using benzene to remove any residual
water furnished the amine-diol which was immediately deriva-
tised to the phthalimide 3 using N-ethoxycarbonylphthal-
imide14 with triethylamine in CH2Cl2. Column chromatography
of the crude mixture (no work-up required) consistently gave a
60% overall yield of the desired imide for the two steps. The
imide 3 gave satisfactory analytical and spectral data with an
ABX spin system for the diastereotopic protons at C-1 (sugar
numbering) and the methine proton at C-2 (Scheme 2).
Scheme 1
Results and discussion
With the crystalline imide-diol in hand, the scene was set for
conversion to the radical precursor. 1,2-Diol cleavage of 3 with
Our retrosynthetic analysis identified -ribose as a suitable
starting material for construction of the chiral enoate chain.
The acid-catalysed ketalisation of the 2,3-hydroxy groups of
NaIO4
in water proceeded uneventfully in high yield, and was
superior to Pb(OAc)4 in terms of practical handling. The alde-
J. Chem. Soc., Perkin Trans. 1, 1997
71

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resolution mass for characterisation. All the other intermedi-
ates were crystalline solids and gave satisfactory combustion
microanalyses. Scheme 3 summarises the conversion of 3 to 6.
Scheme 2 Reagents and conditions: i, acetone, H2SO4, 65%; ii, BnO-
NH3+ClϪ, pyridine, 85%; iii, LiAlH4, THF; iv, N-ethoxycarbonyl-
phthalimide, NEt3, CH2Cl2, 60% over 2 steps
hyde gave satisfactory NMR data but eluded microanalytical
characterisation and was therefore converted directly to the
homologated enoate ester 4 in 85% yield for the two steps
(E :Z = 20:80) using the stabilised Wittig ylide (ethoxycarbonyl-
methylene)triphenylphosphorane in CH2Cl2 at 0 ЊC. The high
(Z)-stereoselectivity encountered in this Wittig reaction is well
established 15 for α-alkoxyaldehydes.
Scheme 3 Reagents and conditions: i, NaIO4, EtOH, H2O; ii, Ph3P-
CHCO2Et, CH2Cl2, 85% over 2 steps; iii, Bu3SnH, AIBN, reflux, 70%;
iv, NaBH4, MeOH, Ϫ20 ЊC, 94%; v, PhSH (3 equiv.), BF3ؒEt2O, 80%
α,β-Unsaturated esters frequently have been used as radical
acceptors for regiocontrolled ring cyclisation 20 in six-membered
ring synthesis since for simple heptenyl radicals the 6-exo pro-
cess is only 7 times faster than the 7-endo alternative.21 Of
particular interest to our work was the demonstration, by
the Marco-Contelles group,13 that a glucose-derived precursor
undergoes radical cyclisation to a six-membered carbocycle
using an enoate radical acceptor. Furthermore, the cyclisation
proceeded with good stereoselectivity under the directing influ-
ence of an allylic/homoallylic ketal functionality. Cyclisation of
our precursor 6 was realised under the normal conditions of
slow addition (10 h addition, 48 h reflux) of Bu3SnH (3.5 equiv.)
and AIBN (cat.) to a dry, deoxygenated benzene solution of 6 at
reflux temperature. Chromatography of the product furnished
the tricyclic isoindolone in 60% yield (Scheme 4). It was then
At this point in the synthesis we were aware of the divergence
from our approach because of the Wittig result. Since the stereo-
chemical configuration of double bond acceptors is known to
play an important role in the stereoselectivity of radical cyclisa-
tions,16 we decided to isomerise the (Z)-isomer to the (E)-isomer
in order to bring the route back on track. This decision was
later justified when we established that the (Z)-isomer converts
to its (E)-isomer during radical cyclisation. Various reagents
have been developed for thermodynamic Z to E isomerisation,
with radical based procedures17 involving the benzenethiyl and
tris(trimethylsilyl)silyl radicals as the methods of choice. For
isomerising the mixture of enoate esters (Z :E = 80:20), we
found that overnight refluxing in benzene with Bu3SnH (1
equiv.) and azoisobutyronitrile (AIBN) (cat.) gave a 70%
isolated yield of pure (E)-isomer 4 after column chromato-
graphy. No cyclisation product involving the β-position of
the double bond and the imide carbonyl carbon was identified.
We also discovered that the titanate complex LiTi(OPri)4-
(SPh),18 easily prepared from PhSLi (BuLi–PhSH) and Ti(OPri)4
in THF at 0 ЊC, isomerised 4 at Ϫ25 ЊC over 18 h to a 98:2
E :Z mixture in 66% isolated yield. Details of this new pro-
cedure for low temperature isomerisation will be published
elsewhere.
To complete the synthesis, the imide of the (E)-enoate ester 4
was chemoselectively reduced with NaBH4 to the alcohol-
amide 5 in a MeOH–THF mixture at Ϫ20 ЊC without reduc-
tion of the double bond. We found it unnecessary to use HCl-
saturated EtOH which has been used by other workers19 in
reducing imides. The alcohol-amide 5 was isolated as a crystal-
line solid in very high yield (>90%) and, interestingly, as a single
diastereoisomer. For final conversion to the radical precursor 6,
standard methods developed by other workers in the field, such
as PhSH–p-TsOH 1a,b and PhSSPh–Bu3P,1c did not result in
clean substitution. Ultimately, we found low temperature
(<Ϫ20 ЊC) treatment with PhSH (3 equiv.) and BF3ؒOEt2 (3
equiv.) in CH2Cl2 to serve the purpose, producing the desired
product as a mixture of diastereoisomers (ca. 1:1) as an oil in
75% isolated yield after flash chromatography. The final target
was the only compound in the series which required a high
Scheme 4 Reagents and conditions: i, Bu3SnH, AIBN, reflux, 60%
established that essentially the same result (56% yield after
chromatography) could be realised using less reagent (1.5 equiv.
72
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Bu3SnH) and a shorter reaction time (10 min addition, 4 h
reflux). No product due to hydrogen reduction of the phenylsul-
fanyl group could be isolated in any of the reactions, indicating
that the cyclisation is much faster than reduction and that, con-
sequently, a relatively high concentration of tin hydride may be
tolerated. HPLC analysis of the chromatography fraction
revealed it to be a 8:2 mixture of diastereoisomers. A single
recrystallisation from ethyl acetate–hexane afforded the major
component, which was pure by HPLC. From 1H and 13C NMR
spectra it was evident that 7 was a single, cyclised diastereo-
isomer from the loss of the phenylsulfanyl and enoate ester
double bond protons and the appearance of three new signals
corresponding to protons at C-1, -1a and -10b (see Scheme 4 for
numbering). In order to decide which of the four possible dia-
stereoisomers was actually produced, the protons were config-
urationally assigned using vicinal coupling constants from 2D
COSY and decoupling experiments. Assuming a chair con-
formation for the new piperidine ring, from the doublet for H-
10b (J3 11.2 Hz) it became clear that H-1 and H-10b, both
flanking the new σ-bond from the cyclisation, are in a trans-
diaxial relationship. Furthermore, since H-1 and H-2 are in a
gauche relationship (J 3.2 Hz) by NMR spectral analysis, the
absolute configurations at C-1 and C-10b could be established
as (1R,10bS) as shown in the diagram, with the C-10b hydro-
gen, the ethoxycarbonylmethylene group at C-1 and the two -
ribose-derived oxygens at carbons 2 and 3 in an all cis-
orientation.
Fig. 1
sible mediating effect of the ketal grouping arises. Analysis of
the two conformers in which the ethoxycarbonylmethylene
group is quasi-equatorial suggests that an H ؒ ؒ ؒ H gauche 1,2-
allylic relationship leading to the observed product is preferred
to an H ؒ ؒ ؒ C–O interaction (Fig. 1).
As an extension of this line of thinking, it was decided to
study the stereoselectivity of cyclisation of 6 as its unprotected
1,2-diol. To this end, the ketal-alcohol-amide 5 was deprotected
in refluxing acidified EtOH to afford the [1,3]oxazino[2,3-a]-
isoindolone derivative 9 via intramolecular cyclisation involving
the liberated allylic hydroxy group. The configuration at C-10b
was not assigned, but is likely to be S (α-H). Treatment with an
excess of PhSH (5 equiv.) and p-TsOH (1 equiv.) furnished a
low yield (44%) of the target 10 as a single diastereoisomer
(Scheme 6). Radical cyclisation with Bu3SnH (1.5 equiv.) and
In order to provide unequivocal support in favour of cis-
stereochemistry between the C-1 and C-2 substituents, a cis-
lactone was prepared. To this end, the cyclisation product 7
underwent successive hydrolytic treatment with acid and base,
for cleavage of the ketal and ester groups respectively, to afford
the acid-diol which was isolated but not characterised. Lactoni-
sation with dicyclohexylcarbodiimide (DCC) in refluxing
CH2Cl2 afforded (3aR,4S,11bS,11cR)-3a,4,5,11c-tetrahydro-4-
Scheme 6 Reagents and conditions: i, H3O+, reflux, 66%; ii, PhSH,
p-TsOH, 44%
hydroxyfuro[3Ј,2Ј:3,4]pyrido[2,1-a]isoindol-2(1H),
7(11bH)-
dione 8 in 34% overall yield for the three steps. Compound
8 gave an anticipated large trans-diaxial coupling constant
(J3 9.6 Hz) between H-11b and H-11c as well as a carbonyl
stretch in the IR spectrum at 1770 cmϪ1 for the lactone ring,
thus confirming the cis-stereochemistry as postulated (Scheme
5).
AIBN (cat.) in refluxing benzene as before gave a cyclised prod-
uct (60%) after column chromatography which proved to be a
1:1:1 mixture of three diastereoisomers by HPLC and 1H
NMR spectral analysis, thus confirming the importance of the
isopropylidene ketal as a stereo-directing auxiliary.
Conclusion
In conclusion, this study reports the first application of benzylic
α-acylamino radicals in nitracycle synthesis for potential appli-
cation in the indole and isoquinoline alkaloid arena. Further-
more, it highlights the potential of an allylic/homoallylic ketal
grouping for controlling the diastereoselectivity of 6-exo-trig
radical cyclisations to nitracycles. Regarding the Tacaman skel-
eton, although this study translates to an undesired trans-
relationship at the D/E ring junction, it has succeeded in dem-
onstrating that the absolute configuration of the benzylic pos-
ition translating to C-3 in the alkaloid may be controlled.
Reduction of the lactam carbonyl group of the cyclised product
7 would provide an efficient entry into stereoselectively func-
tionalised benzo[a]indolizidines.22
Scheme 5 Reagents and conditions: i, H3O+, reflux, HOϪ; ii, DCC
Gratified with the high level of stereoselectivity of cyclis-
ation, albeit to give an unwanted cis-relationship between the
benzylic hydrogen and ethoxycarbonylmethylene group (trans-
lating to an undesired trans D/E ring fusion in the Tacaman
skeleton), we focused our attention on the importance of
the allylic/homoallyic ketal grouping. Marco-Contelles has
recently13 demonstrated high stereoselectivity (93:7) in the
cyclisation of chiral carbohydrate-derived chains to furnish six-
membered carbocycles. Of note regarding our work was the
use of both of the crucial structural elements, the enoate ester
radical acceptor terminus and a trans-1,3-dioxolane ketal
grouping attached to the allylic/homoallylic positions of the
chain. The stereoselectivity was rationalised in terms of a chair-
like transition state with the substituents, including the all-
important radical terminus, occupying quasi-equatorial posi-
tions. Extending these ideas to our own system, the question of
conformational preference in the transition state and the pos-
Future research will focus on applying the methodology to a
more advanced model for the Tacaman skeleton.
Experimental
IR spectra were recorded on a Perkin-Elmer Paragon 1000 IR
spectrophotometer in chloroform. High performance liquid
chromatography (HPLC) was carried out on a Waters 510
instrument with a 440 Absorbance Detector. 1H and 13C NMR
spectra were recorded on either a Varian VXR-200 (at 200.06
1
MHz for H and 50.31 MHz for 13C) or a Varian Unity 400 (at
J. Chem. Soc., Perkin Trans. 1, 1997
73

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1
399.95 MHz for H and 100.58 MHz for 13C) spectrometer in
precipitate with Et3N–MeOH–EtOAc (20:70:10, 3 × 50 cm3),
the solvent specified. Chemical shifts (δ) are quoted using
residual chloroform (δ 7.24) or tetramethylsilane as an internal
standard; J values are given in Hz. Mass spectra were recorded
on a VG micromass 16F mass spectrometer at 70 eV or at the
mass spectrometry unit in the Cape Technicon. Thin layer
chromatography (TLC) was performed on aluminium plates
coated with Merck silica gel 60F254. Compounds were visual-
ised with iodine, or by spraying with either ceric ammonium
nitrate in 9  H2SO4 or a 2.5% solution of anisaldehyde in
H2SO4–EtOH (1:10) followed by heating at 100 ЊC. Column
chromatography was carried out on silica gel 60 (Merck 7734)
using ethyl acetate–hexane mixtures. Mps were recorded on a
Reichert Jung hot-stage melting point apparatus and are uncor-
rected. Elemental analyses for C, H and N were carried out
using a Heraeus CHN rapid combustion analyser. Optical rota-
tions were determined in the solvents indicated at 20 ЊC using a
Perkin-Elmer 141 polarimeter. For the radical cyclisation reac-
tions, the benzene solvent was distilled from sodium and
deoxygenated with nitrogen prior to use. O-Benzylhydroxyl-
amine hydrochloride and tributyltin hydride were purchased
from Aldrich Chemical Company.
removal of the solvent under reduced pressure, with azeotropic
removal of H2O with benzene, furnished crude 1-amino-2,3-O-
isopropylidene--ribose (2.05 g). The latter was then dissolved
in dichloromethane (25 cm3), cooled to 0 ЊC and triethylamine
(10 cm3) and N-ethoxycarbonylphthalimide (3.06 g, 14 mmol)
added. After 18 h the volume of solvent was reduced and the
residue chromatographed directly with ethyl acetate–hexane to
give crystalline 3 (2.8 g, 8.2 mmol, 60% for 2 steps), mp 129–
133 ЊC (Found: C, 59.56; H, 5.92; N, 4.20. C16H19NO6 requires
C, 59.81; H, 5.96; N, 4.36%); [α]D Ϫ66 (c 0.5 in MeOH);
νmax(CDCl3)/cmϪ1 3600, 2988, 2938, 1773, 1716; δH (400 MHz,
CDCl3) 1.26 (3 H, s), 1.46 (3 H, s), 3.0 (1 H, br s, OH), 3.60 (1
H, br s, OH), 3.73 (1 H, dd, J 6.3, 11.9, H-5), 3.86–3.95 (2 H, m,
H-4, H-5), 3.92 (1 H, dd, J 3.6, 13.8, H-1), 3.99 (1 H, dd, J 9.8,
13.8, H-1), 4.14 (1 H, dd, J 5.8, 8.9, H-3), 4.62 (1 H, ddd, J 3.6,
5.8, 9.8, H-2), 7.6–7.8 (4 H, aromatic); δC(100 MHz, CDCl3)
25.8, 27.8, 38.8 (C-1), 64.7 (C-5), 69.5 (C-4), 74.3 (C-2), 76.4 (C-
3), 109.5 (ketal), 123.3, 132.1, 133.9 (aromatic), 168.5 (CO);
m/z 306 (M+ Ϫ CH3, 7%), 161 (22), 160 (33), 59 (100), 43 (40).
Ethyl (4R,5S)-6-phthalimido-4,5-(propane-2,2-diyldioxy)hex-2-
enoate 4
2,3-O-Isopropylidene-D-ribofuranose 19,10
To a solution of 3 (2.0 g, 6.23 mmol) in ethanol (100 cm3) was
added sodium periodate (2.0 g, 9.32 mmol) in water (50 cm3) at
0 ЊC. The solution was stirred for 18 h after which time the
volume of solvent was reduced and the crude product extracted
with ethyl acetate. The organic phase was washed with brine,
dried and the solvent evaporated to afford crude (2S,3S)-4-
phthalimido-2,3-(propane-2,2-diyldioxy)butanal (1.71 g, 5.9
mmol, 95%) which was dissolved in dichloromethane (100 cm3),
cooled to 0 ЊC and (ethoxycarbonylmethylene)triphenylphos-
phorane (2.46 g, 7.08 mmol) added. The mixture was stirred
overnight at room temperature, the solvent removed under
reduced pressure and the residue chromatographed with ethyl
acetate–hexane (4:6) to afford 4 (1.9 g, 5.30 mmol, 85% for 2
steps) as a mixture (E :Z = 20:80 by 1H NMR) of isomers.
To a suspension of -ribose (5.0 g, 33.4 mmol) in acetone (150
cm3) at 0 ЊC was added conc. H2SO4 (2 cm3, 37.5 mmol) drop-
wise. The reaction was stirred for a further 2 h before being
quenched with KOH (4.5 g, 80.2 mmol) in MeOH (50 cm3) at
0 ЊC. To the suspension was added K2CO3 (2.5 g, 18.1 mmol),
and the mixture left stirring for 0.5 h. After the solids had been
filtered off and washed with acetone, the solvent was removed
under reduced pressure, leaving a syrup of 1 (6.2 g, 32.6 mmol,
98%) which could be used without further purification. For
characterisation purposes a sample was chromatographed (500
mg) to give pure 1 as a syrup (0.33 g, 66%); δH (200 MHz,
CDCl3) major epimer: 1.23 and 1.48 (6 H, 2 × s), 3.55 (2 H, br
s, OH), 3.68 (2 H, d, J 3.3, H-5), 4.36 (1 H, t, J 3.3, H-4), 4.50 (1
H, d, J 6.0, H-3), 4.79 (1 H, d, J 6.0, H-2), 5.48 (1 H, s, H-1); δC
(50 MHz, CDCl3) major epimer: 24.6, 26.0, 63.0 (C-5), 81.0
(C-4), 86.5 (C-3), 87.4 (C-2), 102.5 (C-1), 112.0 (ketal).
Isomerisation of (E)/(Z)-4 to (E)-4
To a solution of (E)/(Z)-4 (1.0 g, 2.8 mmol) in benzene (25 cm3)
was added tributyltin hydride (0.8 cm3, 2.97 mmol) and azo-
isobutyronitrile (AIBN) (25 mg, 0.15 mmol) and the mixture
refluxed for 18 h. After removal of solvent under reduced pres-
sure the residue was chromatographed to give pure (E)-4 (0.7 g,
70%), mp 123–124 ЊC (Found: C, 63.28; H, 5.86; N, 3.73.
C19H21NO6 requires C, 63.50; H, 5.89; N, 3.90%); [α]D Ϫ110.4 (c
0.5 in CHCl3); νmax(CHCl3)/cmϪ1 3022, 1774, 1717, 1662, 1615;
δH (400 MHz, CDCl3) 1.28 (3 H, t), 1.31 (3 H, s), 1.55 (3 H, s),
3.40 (1 H, dd, J 3.3, 13.8, H-6), 3.79 (1 H, dd, J 10.4, 13.8, H-6),
4.19 (2 H, q), 4.68 (1 H, ddd, J 3.3, 6.6, 10.4, H-5), 4.86 (1 H,
ddd, J 1.6, 5.1, 6.6, H-4), 6.24 (1 H, dd, J 1.6, 15.6, H-2), 6.93
(1 H, dd, J 5.1, 15.6, H-3), 7.66–7.84 (4 H, m); δC(100 MHz,
CDCl3) 14.2, 25.7, 27.7, 39.6 (C-6), 60.7 (CH2 of Et), 74.5 and
75.9 (C-4 and C-5), 110.0 (ketal), 123.3, 123.8 (C-2), 132.0,
134.0, 140.3 (C-3), 165.6 and 168.1 (2 × CO); m/z 359 (M+,
1.2%), 344 (M+ Ϫ 15, 22), 199 (51), 160 (100), 141 (19).
1-Benzyloxyimino-2,3-O-isopropylidene-D-ribose 2
To a solution of crude 1 (4.61 g, 24.3 mmol) in CH2Cl2 (25 cm3)
and pyridine (10 cm3) was added O-benzylhydroxylamine
hydrochloride (3.95 g, 24.7 mmol) at 0 ЊC. The mixture was
stirred for 15 h after which time an ice-cold solution of dilute
aqueous HCl was added until the mixture became acidic. The
product was extracted into ethyl acetate and the organic phases
washed with saturated aqueous NaHCO3 and brine. Drying
and evaporation of solvent afforded crude 2 which was
recrystallised from ethyl acetate–hexane to give pure 2 (3.5 g,
11.9 mmol, 50% for 2 steps), mp 95–96 ЊC [(E)-isomer] (Found:
C, 61.30; H, 7.27; N, 4.77. C15H21NO5 requires C, 61.0; H, 7.17;
N, 4.74%); [α]D Ϫ32.2 (c 4.9 in EtOH); νmax(CHCl3)/cmϪ1 3585,
3015, 1600; δH (200 MHz, CDCl3) (E)-isomer: 1.32 (3 H, s,), 1.43
(3 H, s), 2.6–3.4 (2 H, br s, OH), 3.5–3.8 (3 H, m, H-4 and H-5),
4.12 (1 H, dd, J 6.2, 8.4, H-3), 4.74 (1 H, dd, J 6.2, 7.2, H-2),
5.07 (2 H, s, PhCH2), 7.2–7.4 (5 H, m), 7.50 (1 H, d, J 7.2, H-1);
δC(50 MHz, CDCl3) (E)-isomer: 25.9, 28.2, 64.6 (C-5), 70.2
(C-4), 75.6 (C-2), 76.7 (PhCH2), 78.3 (C-3), 110.7 (ketal), 128.8,
128.9, 129.0, 137.7 (aromatic), 149.5 (C-1); m/z 295 (M+, 1%),
280 (M+ Ϫ 15, 2.6), 91 (100), 43 (39).
Ethyl (2E,4R,5S)-6-(1,3-dihydro-3-hydroxy-1-oxoisoindol-2-yl)-
4,5-(propane-2,2-diyldioxy)hex-2-enoate 5
To a solution of 4 (0.78 g, 2.19 mmol) in THF (12 cm3) and
MeOH (30 cm3) cooled to Ϫ40 ЊC was added sodium boranuide
(0.5 g, 14 mmol). The reaction temperature was kept below
Ϫ20 ЊC for 1.5 h, after which time the reaction was quenched
with aqueous NH4Cl and the product extracted into ethyl acet-
ate following removal of the methanol under reduced pressure.
The organic phase was washed with brine, dried and the solvent
evaporated to give crystalline 5 (0.74 g, 2.05 mmol, 94%) pure
enough by TLC for the next step. For characterisation purposes
a sample was recrystallised from CCl4–hexane, mp 121–126 ЊC
(Found: C, 62.81; H, 6.42; N, 3.76. C19H23NO6 requires C,
1-Phthalimido-2,3-O-isopropylidene-D-ribose 3
To a solution of 2 (4.0 g, 13.6 mmol) in dry THF was added
LiAlH4 (2.1 g, 54.3 mmol) in small portions at 0 ЊC. The reac-
tion was left stirring for 24 h after which time water (8 cm3) was
added slowly at 0 ЊC followed by triethylamine (45 cm3). The
slurry was stirred for an additional 0.5 h and the white precipi-
tate then filtered off using Celite. After copious washing of the
74
J. Chem. Soc., Perkin Trans. 1, 1997

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63.15; H, 6.42; N, 3.87%); [α]D Ϫ33.6 (c 0.5 in CHCl3);
νmax(CHCl3)/cmϪ1 3557, 3368, 1703; δH (200 MHz, CDCl3) 1.27
(3 H, t), 1.34 (3 H, s), 1.60 (3 H, s), 3.31 (1 H, dd, J 10.2, 14.3,
H-6), 3.70 (1 H, br s, OH), 3.77 (1 H, dd, J 2.5, 14.3, H-6), 4.16
(2 H, q), 4.59 (1 H, ddd, J 2.5, 7.1, 10.2, H-5), 4.82 (1 H, ddd, J
1.6, 5.6, 7.1, H-4), 6.07 (1 H, d, J 9.9, benzylic H), 6.15 (1 H, dd,
J 1.6, 15.6, H-2), 6.90 (1 H, dd, J 5.6, 15.6, H-3), 7.4–7.8 (4 H,
m); δC(50 MHz, CDCl3) 14.2, 25.4, 27.8, 40.3 (C-6), 60.7 (Et),
76.2, 77.0 (C-4 and C-5), 82.7 (benzylic), 109.8 (ketal), 123.4
(2 C), 123.6 (C-2), 129.8, 131.5, 132.3, 141.7 (C-3), 144.0, 165.8
and 167.3 (2 × CO); m/z 361 (M+, 0.9%), 346 (M+ Ϫ 15, 7), 133
(100).
temperature. The pH was adjusted to 8 with conc. HCl and the
volume of solvent reduced in vacuo to produce a residue which
was filtered and washed copiously with acetone and acetic acid.
The solvent of the filtrate was then removed under reduced
pressure with the acetic acid azeotroped off with toluene. A
portion of the crude product (52 mg, 0.19 mmol) was dissolved
in THF–CH2Cl2 (6 cm3, 1:1) and dicyclohexylcarbodiimide
(415 mg, 2.01 mmol) added. The solution was refluxed for 7 h
and stirred for a further 12 h at room temperature. The solids
were then filtered off and washed with hot ethyl acetate.
Removal of solvent followed by chromatography gave 8 (25 mg,
0.096 mmol, 51% based on portion taken), mp 223–230 ЊC
(ethyl acetate–acetone) (Found: C, 64.89; H, 5.14; N, 5.42.
C14H13NO4 requires: C, 64.86; H, 5.05; N, 5.40%); [α]D +37.1 (c
0.64 in EtOH); νmax(CHCl3)/cmϪ1 1770, 1700; δH (400 MHz,
CD3COCD3) 2.75 (1 H, m, J 5.1, 7.2, 8.8, 9.6, H-11c), 2.93 (1 H,
dd, J 5.1, 17.4, H-1), 3.04 (1 H, dd, J 8.8, 17.4, H-1), 3.42 (1 H,
dd, J 6.0, 13.3, H-5), 4.10 (1 H, dd, J 4.4, 13.3, H-5), 4.25 (1 H,
m, H-4), 4.69 (1 H, d, J 9.6, H-11b), 4.73 (1 H, dd, J 3.0, 7.2,
H-3a), 4.98 (1 H, d, J 5.4, OH), 7.50–7.74 (4 H, m, aromatic);
δC(100 MHz, CD3COCD3) 34.7 (C-1), 40.2 (C-5), 42.8 (C-11c),
59.3 (C-11b), 66.6 (C-4), 80.0 (C-3a), 123.1, 123.9, 129.2, 132.4,
133.0 and 146.7 (aromatic), 167.1 and 176.3 (2 × CO); m/z 259
(M+, 100%), 217 (68), 132 (97).
Ethyl (2E,4R,5S)-6-(1,3-dihydro-3-phenylsulfanyl-1-oxoisoindol-
2-yl)-4,5-(propane-2,2-diyldioxy)hex-2-enoate 6
Thiophenol (0.47 cm3, 4.6 mmol) was added to a solution of 5
(553 mg, 1.53 mmol) in CH2Cl2 (12 cm3) followed by boron
trifluoride–diethyl ether complex (0.56 cm3, 4.60 mmol) which
was added dropwise at Ϫ78 ЊC. The reaction was stirred for
4 h at a temperature below Ϫ20 ЊC, after which time it was
quenched by adding aqueous sodium carbonate. The crude
product was extracted into ethyl acetate, dried and the solvent
evaporated to give 6 (490 mg, 1.08 mmol, 2 epimers, 80% based
on 70 mg recovered starting material) as an oil after chrom-
atography; δH (400 MHz, CDCl3) major epimer: 1.2–1.4 (6 H,
m, Me), 1.50 (3 H, s, Me), 3.41 (1 H, dd, J 4.0, 14.2, H-6), 3.52
(1 H, dd, J 10.6, 14.2, H-6), 4.16 (2 H, q), 4.51 (1 H, m, H-5),
4.79 (1 H, ddd, J 1.6, 5.2, 6.4, H-4), 5.82 (1 H, s, benzylic), 6.18
(1 H, dd, J 1.6, 15.6, H-2), 6.8–7.7 (10 H, m, H-3 and aromatic);
δC(100 MHz, CDCl3) major epimer: 14.2 (Me of Et), 25.6, 27.8,
40.4 (C-6), 60.6 (CH2 of Et), 66.6, 76.1 and 77.4 (C-4, C-5 and
benzylic), 109.8 (ketal), 123.1–135.3 (C-2 and aromatics), 140.9
(C-3), 142.7 (aromatic), 165.7 and 167.7 (2 × CO) (Found: M+,
453.1591. C25H27NO5S requires M, 453.1610).
(2R,3S)-3,4-Dihydro-2-[(E)-2-ethoxycarbonylethenyl]-3-
hydroxy-2H-[1,3]oxazino[2,3-a]isoindol-6(10bH)-one 9
Water (1 cm3) and conc. H2SO4 (0.10 cm3, 1.88 mmol) were
added to a solution of 5 (606 mg, 1.68 mmol) in EtOH (7 cm3).
The solution was refluxed for 12 h, after which time it was
neutralised by adding aqueous sodium carbonate. After
removal of EtOH under reduced pressure, the mixture was
extracted with ethyl acetate and the organic extracts dried and
the solvent evaporated. Chromatography of the residue yielded
9 (335 mg, 1.10 mmol, 66%), mp 170–173 ЊC (ethyl acetate–
hexane) (Found: C, 63.46; H, 5.69; N, 4.62. C16H17NO5
requires C, 63.34; H, 5.65; N, 4.62%); [α]D Ϫ80 (c 0.7 in CHCl3);
νmax(CHCl3)/cmϪ1 3410, 1710, 1660, 1618; δH (400 MHz,
CD3SOCD3) 1.20 (3 H, t), 3.09 (1 H, dd, J 10.1, 12.5, H-4), 3.22
(1 H, ddd, J 5.4, 9.4, 10.1, H-3), 4.12 (2 H, q), 4.32 (1 H, dd, J
5.4, 12.5, H-4), 4.38 (1 H, ddd, J 1.7, 4.4, 9.4, H-2), 5.79 (1 H, d,
J 5.6, OH), 5.94 (1 H, s, H-10b), 6.00 (1 H, dd, J 1.7, 15.8, H-2b),
7.01 (1 H, dd, J 4.4, 15.8, H-2a), 7.58–7.74 (4 H, m); δC(100
MHz, CD3SOCD3) 14.1, 44.3 (C-4), 60.7, 66.0 (C-3), 79.5 (C-2),
84.5 (C-10b), 122.9, 123.6, 123.8, 130.3, 132.3 (2 × C), 140.3
and 142.9 (C-2a, C-2b and aromatic), 166.3 (2 × CO); m/z 258
(M+ Ϫ 45, 9%), 175 (100), 146 (26), 132 (94).
(1R,2R,3S,10bS)-1,2,3,10b-Tetrahydro-1-ethoxycarbonyl-
methyl-2,3-(propane-2,2-diyldioxy)pyrido[1,2-a]isoindol-
6(4H)-one 7
To a refluxing solution of 6 (490 mg, 1.08 mmol) in benzene (30
cm3) was added a solution of tributyltin hydride (0.44 cm3, 1.64
mmol) and AIBN (10 mg, 0.06 mmol) in benzene (20 cm3)
dropwise over 10 min. The solution was refluxed until no more
starting material remained by TLC (4 h), the solvent was
removed under reduced pressure and the residue chromato-
graphed with ethyl acetate–hexane. The product fraction (225
mg, 0.65 mmol, 60%) was recrystallised from ethyl acetate–
hexane to furnish HPLC pure (1R,2R,3S,10bS)-1,2,3,10b-
tetrahydro-1-ethoxycarbonylmethyl-2,3-(propane-2,2-diyl-
dioxy)pyrido[2,1-a]isoindol-6(4H)-one 7 (130 mg, 0.38 mmol,
35%), mp 149–152 ЊC (Found: C, 65.98; H, 6.95; N, 4.02.
C19H23NO5 requires C, 66.07; H, 6.70; N, 4.05%); [α]D 26.2 (c 1.0
in EtOH); νmax(CHCl3)/cmϪ1 3053, 2986, 1730, 1690, 1617;
δH (400 MHz, CDCl3) 1.23 (3 H, t), 1.37 (3 H, s), 1.54 (3 H, s),
2.02 (1 H, m, J 3.2, 3.2, 6.8, 11.2, H-1), 2.88 (1 H, dd, J 3.2,
15.9, H-1a), 2.93 (1 H, dd, J 6.9, 15.9, H-1a), 3.32 (1 H, dd,
J 6.6, 13.8, H-4), 4.12 (2 H, q), 4.28 (1 H, dd, J 6.4, 13.8, H-4),
4.38 (1 H, q, J 3 × 6.4, H-3), 4.45 (1 H, d, J 11.2, H-10b), 4.47
(1 H, dd, J 3.2, 6.4, H-2), 7.49 (3 H, m), 7.85 (1 H, m); δC(100
MHz, CDCl3) 14.2, 25.5, 27.8, 33.1 (C-1a), 39.8 (C-1), 40.4
(C-4), 56.3 (C-10b), 60.8 (CH2 of Et), 71.1 (C-3), 74.2 (C-2),
109.2 (ketal), 123.3, 124.2, 128.6, 131.2, 132.6 and 144.1 (aro-
matics), 166.9 and 171.2 (2 × CO); m/z 345 (M+, 73), 330
(M+ Ϫ 15, 5), 287 (45), 200 (100), 145 (43), 43 (99).
Ethyl (2E,4R,5S)-6-(1,3-dihydro-3-phenylsulfanyl-1-oxoisoindol-
2-yl)-4,5-dihydroxyhex-2-enoate 10
Thiophenol (0.37 cm3, 3.57 mmol), toluene-p-sulfonic acid (130
mg, 0.75 mmol) and magnesium sulfate (1 g) were added to a
solution of 9 (214 mg, 0.71 mmol) in CH2Cl2 (6 cm3) at room
temperature. After stirring the solution for 24 h, aqueous
sodium carbonate was added and the product extracted into
CH2Cl2. Drying of the organic extracts, removal of solvent and
chromatography furnished 10 (128 mg, 0.31 mmol, 44%) as an
oil and a single diastereomer; δH (200 MHz, CDCl3) 1.25 (3 H,
t), 3.53 (1 H, br s, OH), 3.97 (1 H, dd, J 3.1, 14.8, H-6), 4.05 (2
H, m, H-4 and H-5), 4.14 (2 H, q), 4.27 (1 H, dd, J 3.6, 14.8, H-
6), 4.83 (1 H, br d, J 4.1, OH), 6.04 (1 H, s), 6.18 (1 H, dd, J 1.8,
15.7, H-2), 6.95–7.67 (10 H, m, H-3 and aromatic); δC(50 MHz,
CDCl3), 14.2, 42.0 (C-6), 60.5 (CH2 of Et), 69.4 (benzylic), 71.6
and 74.3 (C-4 and C-5), 122.6, 123.9, 124.6, 128.3, 129.4 (3 C),
130.0, 131.3, 132.9, 136.1 (2 C), 144.5 and 147.4 (C-2, C-3 and
aromatic), 167.8 and 170.9 (2 × CO) (HRMS: Found M+,
413.1290. C22H23NSO5 requires for M, 413.1297).
(3aR,4S,11bS,11cR)-3a,4,5,11c-Tetrahydro-4-hydroxyfuro-
[3Ј,2Ј:3,4]pyrido[2,1-a]isoindol-2(1H),7(11bH)-dione 8
To a solution of 7 (98 mg, 0.28 mmol) in EtOH (10 cm3) and
water (1 cm3) was added conc. H2SO4 (0.04 cm3, 0.72 mmol)
and the solution refluxed for 3 h. Potassium hydroxide (121 mg,
2.16 mmol) was added and the solution stirred for 12 h at room
Radical cyclisation of 10
To a refluxing solution of 10 (92 mg, 0.22 mmol) in benzene (20
J. Chem. Soc., Perkin Trans. 1, 1997
75

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cm3) was added a solution of tributyltin hydride (0.10 cm3, 0.37
mmol) and AIBN (10 mg, 0.06 mmol) in benzene (10 cm3) over
a period of 3 h. Refluxing was continued for a further 12 h.
After removal of solvent under reduced pressure, the residue
was chromatographed to afford the cyclised product as an oil
K. Karinen, D. Din Belle and A. Tolvanen, Tetrahedron Lett., 1996,
37, 1513.
7 Syntheses of the pentacyclic Hunteria indole alkaloid skeleton have
generally used Pictet–Spengler or Bischler–Napieralski cyclisation
via the C2–C3 bond as a key step. For articles with extensive liter-
ature coverage see: M. Node, H. Nagasawa and K. Fuji, J. Am.
Chem. Soc., 1987, 109, 7901; M. D. Kaufman and P. A. Grieco,
J. Org. Chem., 1994, 59, 7197.
8 Biogenetic numbering used by Chemical Abstracts for Hunteria
indole alkaloids and originally introduced by J. Trojánek, O. Strouf,
J. Holubek and Z. Cekan, Tetrahedron Lett., 1961, 702. Also, see
J. Le Men and W. I. Taylor, Experientia, 1965, 21, 508.
9 P. A. Levene and E. T. Stiller, J. Biol. Chem., 1933, 102, 187.
10 N. A. Hughes and P. R. H. Speakmann, Carbohydr. Res., 1965, 1,
171.
1
(40 mg, 0.13 mmol, 60%). H NMR spectral analysis indicated
that cyclisation had occurred to give more than one isomer.
HPLC analysis indicated a total of three isomers in equal
proportions.
Acknowledgements
We thank the Foundation for Research and Development
(FRD) Pretoria for financial support.
11 P. Richsbieth, Ber., 1887, 20, 2673.
12 P. A. Bartlett, K. L. McLaren and P. C. Ting, J. Am. Chem. Soc.,
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13 J. Marco-Contelles, C. Pozuelo, M. L. Jimeno, L. Martinez and
A. Martinez-Grau, J. Org. Chem., 1992, 57, 2625.
14 G. H. L. Nefkens, Nature (London), 1960, 185, 309.
15 S. Valverde, M. Martin-Lomas, B. Herradon and S. Garcia-Ochoa,
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16 C. S. Wilcox and L. M. Thomasco, J. Org. Chem., 1985, 50, 546.
17 O. Miyata, T. Shinada, I. Ninomiya and T. Naito, Synthesis, 1990,
1123; C. Ferreri, M. Ballestri and C. Chatgilialoglu, Tetrahedron
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18 A. G. M. Barrett and K. Kasdorf, Chem. Commun., 1996, 325.
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20 C. P. Jasperse, D. P. Curran and T. L. Fevig, Chem. Rev., 1991, 91,
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Paper 6/02932I
Received 26th April 1996
Accepted 21st August 1996
76
J. Chem. Soc., Perkin Trans. 1, 1997