Total synthesis of the Amaryllidaceae alkaloid clivonine

Article abstract of DOI:10.1039/c0ob00895h

Two syntheses of the Amaryllidaceae alkaloid clivonine (1) are described. Both employ previously reported 7-arylhydrindane 6 as an intermediate but differ in the method employed for subsequent introduction of what becomes the ring-B lactone carbonyl carbon (C7). The synthesis featuring a Bischler-Napieralski reaction for this transformation constitutes the first asymmetric synthesis of natural (+)-clivonine. Crystal structures for compounds (±)-13, (±)-16, (-)-20 and (±)-28 are also reported.

Full text of DOI:10.1039/c0ob00895h

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PAPER
Total synthesis of the Amaryllidaceae alkaloid clivonine†
Helmut Haning,a,b Carles Giro´-Man˜as,c Victoria L. Paddock,c Christian G. Bochet,d,b Andrew J. P. White,c
Gerald Bernardinelli,b Inderjit Mann,e Wolfang Oppolzer‡b and Alan C. Spivey*c,b
Received 18th October 2010, Accepted 13th January 2011
DOI: 10.1039/c0ob00895h
Two syntheses of the Amaryllidaceae alkaloid clivonine (1) are described. Both employ previously
reported 7-arylhydrindane 6 as an intermediate but differ in the method employed for subsequent
introduction of what becomes the ring-B lactone carbonyl carbon (C7). The synthesis featuring a
Bischler–Napieralski reaction for this transformation constitutes the first asymmetric synthesis of
natural (+)-clivonine. Crystal structures for compounds ( )-13, ( )-16, (-)-20 and ( )-28 are also
reported.
Introduction
The Amaryllidaceae are herbaceous perennials that produce a
diverse array of alkaloid secondary metabolites. These alkaloids
can mostly be classified as belonging to one of eight skeletally
distinct subclasses all derived biosynthetically from a common
precursor, norbelladine.1–3 Clivonine (1), along with homolycorine
(2), hippeastrine (3) and lycorenine (4) are prominent members of
the lycorenine subclass; these alkaloids feature a tetracyclic 2-
benzopyrano-[3,4-g]indole skeleton and display growth inhibition
of various tumour cells,4–6 DNA binding properties,7 anti-viral
activity,8,9 antifungal activity,10 and insect antifeedant activity11
(Fig. 1).12
Fig. 1 Structures of the lycorenine-class Amaryllidaceae alkaloids
clivonine (1), homolycorine (2), hippeastrine (3) and lycorenine (4).
Also showing atom numbering/ring designations and correct absolute
stereochemistry for natural (+)-clivonine (i.e. 3aR,5S,5aR,11bS,11cR).
in 1971 these assignments and the absolute stereochemistry
were confirmed by Jeffs et al. via chemical correlation with a-
dihydrohippeastrine§.16–19
Irie developed the first total synthesis of ( )-clivonine in 197320–22
(17 steps, 0.43% overall yield from piperonal) and we have recently
described the second23 (12 steps, 6.1% overall yield from enone 5).
Our synthesis featured the use of a thermal retro-Cope elimination
reaction24 to install the B-C and C-D ring-junction stereochemistry
in a 7-arylhydrindane advanced intermediate 6.25 This compound
was then converted into a lycorine-type iminium salt having a
1H-pyrrolo[3,2,1-d,e]phenanthridine/galanthan skeleton, which
by sequential hydration, methylation and oxidation underwent a
biomimetic ‘ring-switch’ to give clivonine (1) (Scheme 1).
(+)-Clivonine (1) was first isolated as white prisms in 0.0007%
yield from an ethanolic extract of freshly collected rhizomes and
leaves of Clivia miniata Regel in 1956 by Wildman, who also
tentatively proposed the correct gross topology of the molecule.13
In 1965 Mehlis suggested relative (and absolute) stereochemistry
for (+)-clivonine but assigned the stereochemistry of the C5/5a
cis-diol centres relative to the others incorrectly.14 In 1967 the
stereochemical assignment of these centres was revised by Do¨pke
et al. from 1H NMR data of the C5 acetate derivative15 and
Herein, we describe two alternative syntheses of clivonine (1),
from 7-arylhydrindane 6, one via a lycorine-type intermediate
but featuring a non-biomimetic sequence of reactions to effect
the ‘ring-switch’ and the other not proceeding via a lycorine-type
intermediate. These syntheses were primarily developed to deliver
authentic samples of clivonine (1) in order to aid development of
the biomimetic ‘ring-switch’ approach and have therefore not been
fully optimised. The first of these syntheses was carried out from
aBayer Schering Pharma AG, Mu¨llerstr. 178, 13353, Berlin, Germany
bDepartment of Organic Chemistry, University of Geneva, 30, Quai Ernest
Ansermet, CH-1211, Geneva 4, Switzerland
cDepartment of Chemistry, Imperial College London, South Kensington cam-
pus, London, UK SW7 2AZ. E-mail: a.c.spivey@imperial.ac.uk; Fax: (+)
44 (0)20 75945841; Tel: (+) 44 (0)20 75945841
dDepartment of Chemistry, University of Fribourg, 9 Ch. du Musee, CH-
1700, Fribourg, Switzerland
eGSK Tonbridge, Old Powder Mills, Leigh, Tonbridge, Kent, UK TN11 9AN
† Electronic supplementary information (ESI) available: crystallographic
analyses for compounds ( )-13, ( )-16, (-)-20 and ( )-28 including CIF files.
Details of the DFT modelling for compound 11 and its C3a epimer and
NMR spectra for compounds 1, 8, 9, 11–13, 16 and 25–31. CCDC reference
numbers 792816–792819. For ESI and crystallographic data in CIF or
other electronic format see DOI: http://dx.doi.org/10.1039/c0ob00895h/
§ The absolute stereochemistry of (+)-a-dihydrohippeastrine was secured
from chemical correlation to dihydrolycorine hydrobromide, which had
been subject to anomalous dispersion single crystal X-ray structure
determination (see ref.16. T. Kitagawa, S. Uyeo and N. Yokoyama, J. Chem.
Soc., 1959, 3741–3751. and 17. M. Shiro, T. Sato and H. Koyama, Chem.
Ind., 1966, 1229.).
‡ Deceased March 15, 1996.
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Scheme 1 Our previous synthesis of ( )-clivonine (1) from enone
( )-5 (see ref.23). Also showing atom numbering for 7-arylhydrindane
(octahydroindole) 6 and ring designations for the subsequent lycorine-type
(galanthan) salt.
enantiomerically pure enone (+)-5 and therefore constitutes the
first asymmetric synthesis of natural (+)-clivonine (1).
Results and discussion
For the synthesis of enone ( )-5 two routes were used both
26–29
starting from meso-cyclohexa-3,5-dienyl-1,2-diol acetonide.¶
The first was via a telescoped variant23 of the method de-
scribed by Hudlicky30 and by Borchardt31 involving epoxida-
tion then Pd(0)/acid-mediated rearrangement, and the second
was via singlet oxygen addition27 then Kornblum–DeLaMare
rearrangement.32,33 Both afforded similar overall yields of enone
( )-5 but the former was preferred on step-count and reaction
duration grounds. Synthesis of enone (+)-(5S,6S)-5 was from
commercially available Pseudomonas putida derived (+)-(2S,3S)-1-
chloro-4,6-cyclohexadiene-2,3-diol acetonide via a modification34
of the method described by Oppolzer35 involving singlet oxygen
addition, polystyrene-supported thiourea mediated hydrogenoly-
sis/acetate protection then Pd(0)/TMDS mediated reduction.
These enones were converted through to 7-arylhydrindanes ( )-
6 and (+)-6 according to our published procedure;23 the following
summary draws attention to some synthetic details that were not
previously highlighted for this sequence of steps (Scheme 2).
1,2-Aryl lithium addition and acetate trapping (5 → 7, 92%
yield) requires 2 h at -78 ◦C in THF, followed by warming
to RT, and then addition of freshly distilled acetic anhydride.
Development of the Ireland–Claisen rearrangement (7 → 10)
required some optimisation as it was found that use of n-BuLi
as a base led to exclusive formation of diene 8 (95% yield) and
use of too dilute solutions of LDA led simply to rearrangement
to the 1,3-transposed allylic acetate 9 (43% yield). However, the
optimised Ireland–Claisen conditions could even be performed
on the crude acetate 7 and the resulting acid reacted directly
with diazomethane following work-up to give the methyl ester
10 on a large scale (~20 g) in yields of 65–85% over the 3 steps.
Conversion of this ester to the aldehyde 12 was carried out either
directly using DIBAL-H at low temperature or by reduction to
alcohol 11 using LiBH4 then re-oxidation using the Dess–Martin
periodinane; yields were comparable (80–85%). Interestingly,
attempted conversion of aldehyde 12 into the corresponding oxime
14 using hydroxylamine hydrochloride and magnesium sulfate in
Scheme 2 Synthesis of 7-arylhydrindane 6 and the molecular structures
of acetal ( )-13 and nitrone ( )-16 (X-ray).
MeOH led to formation of the dimethylacetal 13 (39% yield)
on which a single crystal X-ray structure determination was
performed to confirm the relative stereochemistry in the racemic
series. Omission of the dehydrating agent and use of thermally
milder conditions however gave the oxime 14 as a ~1.2 : 1 mixture
of (E)- and (Z)-isomers in 82% yield. The Borch reduction
of this mixture using NaCNBH3/HCl required precise control
of the dilution and pH (using methyl orange) of the reaction
medium and the duration of the reaction. A range of unidentified
products formed when HCl addition was too slow (i.e. pH >4) and
nitrone 16, the structure of which was secured by a single crystal
X-ray structure determination, was the unexpected major product
when HCl addition was too fast (i.e. pH <3). This product
presumably arises from partial deprotection of the acetonide under
the acidic conditions and condensation of the released acetone
with hydroxylamine 15 (the yield never exceeded 48%). However,
under optimised conditions the labile hydroxylamine 15 could
be obtained in 83% yield. Direct thermolysis of this compound
in degassed toluene effected the retro-Cope elimination reaction
to give the N-hydroxy-7-arylhydrindane 17 almost quantitatively
(98% yield). Relatively high dilution is important in this reaction
to preclude competing disproportionation to the corresponding
amine and nitro derivatives and degassing is required to prevent
R
radical coupling to an azoxydimer. Raneyꢀ-Ni hydrogenolysis
of N-hydroxy-7-arylhydrindane 6 in wet ethanol gave the 7-
arylhydrindane 6 in 94% yield.
A particular aspect of the above synthesis that intrigued us was
the fact that the retro-Cope elimination reaction of hydroxylamine
15 proceeded significantly more rapidly than that of its C3a epimer,
which we had previously studied en route to lycorine-type alkaloid
(+)-trianthine, when compared under identical conditions (i.e.
15 → 17, 91% yield after 14 h vs. 93% after 70 h for its C3a
epimer, both in degassed benzene at 0.01 M).35 Inspection of the
1H NMR spectra of pre-cyclisation intermediates in both series
(i.e. compounds 10, 11, 12, 14 and 1523 cf . their C3a epimers35)
reveals that the protons in their respective cyclohexene C-rings
display systematic differences indicating that the two series adopt
¶ This compound is commercially available or can be prepared from 1,4-
cyclohexadiene (4 steps, 87% yield, see ref. 26. C. R. Johnson, P. A. Ple
and J. P. Adams, J. Chem. Soc., Chem. Commun., 1991, 1006–1007, 27.
Y. Sutbeyaz, H. Secen and M. Balci, J. Chem. Soc., Chem. Commun., 1988,
1330–1331, 28. N. C. Yang, M.-J. Chen and P. Chen, J. Am. Chem. Soc.,
1984, 106, 7310–7315.) or from myo-inositol (3 steps, 36% yield, see ref. 29
F. Fabris, E. Rosso, A. Paulon and O. De Lucchi, Tetrahedron Lett., 2006,
47, 4835–4837.).
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conformationally distinct half-chair structures in solution.ꢀ How-
ever, the relative positions of H3a suggest that in the clivonine
series this proton is pseudo-axial (and hence the C3a side chain
pseudo-equatorial) and in the trianthine series it is pseudo-
equatorial (and the C3a side-chain pseudo-axial) indicating that
both their fused-bicyclic (dioxolane/cyclohexene) cores adopt
conformations in which the allylic C6a–O bond is pseudo-axial (e.g.
for alcohol 11 H3a is at d 2.45 ppm cf . its epimer at d 2.63 ppm)36
These conformational preferences were corroborated by DFT
molecular modelling at the 6-31G(d,p) level in the gas phase.
The crystal structures of compounds 13 and 16 (Scheme 2) reveal
that, at least in the clivonine series, this conformation persists also
in the solid phase. Since retro-Cope elimination is geometrically
precluded unless the C3a side chain adopts a pseudo-axial confor-
mation this means that the faster cyclising epimer 15, leading to
clivonine, must ring-flip in order to react. This places the aforemen-
tioned allylic C–O bond pseudo-equatorial and the corresponding
allylic C–H bond pseudo-axial. Strain-release, or a favourable H-
bonding interaction between the hydroxylamine hydroxyl and one
of the syn dioxolane oxygens in the transition state24 might explain
the higher rate of cyclisation but it likely reflects more facile
cyclisation on the alkene face anti to the pseudo-axial allylic sC–H
bond (i.e. the best donor, cf. a Cieplak effect, Scheme 3)37–39**.
form ring-B based on our successful use of this approach in the
synthesis (+)-trianthine from a diastereomeric 7-arylhydrindane35
(Scheme 4).
Scheme 4 Synthesis of clivonine (+)-1 using a von Braun-type reaction
as a key step and the molecular structure of amine (-)-20 (X-ray).
In the event, direct Pictet–Spengler ring closure to give amine
20 using Eschenmoser’s salt (N,N-dimethyliminium iodide)46,47
proved to be less high yielding than in the trianthine series
(53% cf . 92%35). Since this yield could not be improved by
the use of the corresponding N,N-dimethyliminium triflate,48 we
employed a three-step approach via methyl carbamate formation
(→18, 98% yield), a Bischler–Napieralski reaction using Banwell’s
conditions49,50 (4-DMAP/Tf2O, → 19, 82% yield) and then lactam
reduction (LiAlH4, → 20, 95% yield).†† A single crystal X-ray
structure determination on amine 20 confirmed the introduction of
the desired trans B-C and cis C-D ring-junction stereochemistry by
the retro-Cope elimination reaction and the successful completion
of the required galanthan skeleton (Scheme 4). The stage was
now set for the von Braun-type cleavage of the benzylic C-
N bond in ring-B. The optimum reagent for this key step was
found to be phenylchloroformate,51 which proved superior to both
ethylchloroformate52 and a-chloroethylchloroformate53 and gave
the ring-opened benzyl chloride 21 in 89% yield when used in
conjunction with NaHCO3 in refluxing CH2Cl2. Conversion of this
chloride to an oxygen-based function turned out to be challenging:
attempted silver-salt assisted nucleophilic substitution resulted
in reclosure of ring-B to give amine 20 and treatment with
KOAc/TMEDA,54 polymer-supported carbonate,55 and CrO3,56
Scheme 3 Conformational analysis of the retro-Cope elimination sub-
strate 15 (clivonine series) and its C3a epimer (trianthine series)35 showing
the relative orientations of the CH and CO bonds at their respective
allylic C6 stereocentres. A favourable sCH→p*CC Cieplak stereoelectronic
interaction (cf. sCH→p*CC) may account for the more facile cyclisation in
the clivonine series.
Based on precedent from the work of Mizukami,42 Kotera
et al.,43 and Harken et al.44 who have reported multi-step con-
versions of isolated natural lycorine-type alkaloids to lycorenine-
type congeners exploiting the classical von Braun reaction45 (using
cyanogen bromide), we envisaged that a related strategy could be
deployed to access clivonine (1) from lycorine-type progenitor 20.
The synthesis of 1H-pyrrolo[3,2,1-d,e]phenanthridine 20 from 7-
arylhydrindane 6 was envisaged via a Pictet–Spengler reaction to
ꢀ Specifically, in the clivonine series H5 appears at d 4.2–4.3 ppm as a ddd
or q (J ~5 Hz) and H6 at d ~4.8 ppm as a d (J ~5 Hz), whereas in the
trianthine series the corresponding protons are downfield shifted: H5 at d
4.5–4.6 ppm and H6 at d 4.9 ppm.
** Knight and Salter have proposed that allylic oxygenation favours
retro-Cope elimination reactions but a strong conformational dependence
for this has not been noted previously (see ref. 40, D. W. Knight,
R. Salter, Tetrahedron Lett., 1999, 40, 5915–5918). That the retro-Cope
elimination proceeds via a dissymmetric concerted pathway in which the
hydroxylamine nitrogen has some nucleophilic character and the alkene
some electrophilic character is supported by computational studies by
Tronchet (see ref. 41. I. Komaromi and J. M. J. Tronchet, J. Phys. Chem. A,
1997, 101, 3554–3560) and by our own observations that these reactions
are facilitated by electron withdrawing substituents on the alkene.
†† Lactam 19 and amine 20 were explored as precursors to the cor-
responding lactamol (hemiaminal) via ‘half-reduction’ (using LiEt3BH)
and oxidation (using Polonovski–Poitier chemistry) respectively in our
development of the biomimetic approach to clivonine (see ref. 23. C. Giro-
Manas, V. L. Paddock, C. G. Bochet, A. C. Spivey, A. J. P. White, I. Mann
and W. Oppolzer, J. Am. Chem. Soc, 2010, 132, 5176–5178.).
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gave multiple unidentified products. Finally, introduction of
oxygen at the benzylic position could be achieved by oxidation with
trimethylamine-N-oxide57 giving aldehyde 22 in 81% yield. Treat-
ment of this compound with LiAlH4 effected conversion of the
carbamate to the desired N-methyl function albeit with concomi-
tant aldehyde to alcohol reduction giving aminoalcohol 23 in 89%
yield. A reversed order of events was also explored but all attempts
at carbamate reduction directly on benzyl chloride 21 using a vari-
ety of hydride reagents (e.g. LiAlH4) effected reclosure of ring-B to
give amine 20 exclusively. Reoxidation of alcohol 23 could not be
realized via various Swern-type protocols58 but conversion to alde-
hyde 24 was achieved, albeit in a disappointing yield of 37% using
the Dess–Martin periodinane.59‡‡ Finally, treatment with NaClO2
in t-BuOH/H2O60 gave the carboxylic acid which upon immediate
treatment with HCl in MeOH (to remove the acetonide and induce
lactone formation) gave (+)-clivonine (1), with spectroscopic data
identical to that reported for the natural product, in 21% yield. The
overall yield from 7-arylindoline (+)-6 was therefore 3.8% over the
8 steps [i.e. 1.9% over the 15 steps from enone (+)-5)] although
there is clearly room for optimisation of the final oxidation steps.
We also explored routes towards clivonine (1) from arylindoline
( )-6 that did not involve the introduction of C7 (ultimately the lac-
tone carbonyl carbon) concomitant with closure to a lycorine-type
galanthan ring system [cf. the aforementioned Pictet–Spengler
(6 → 20) and Bischler–Napieralski reactions (18 → 19)] but
rather by initial N-functionalisation and then formylation or
sequential bromination/carbonylation. Our initial plan was to
start by introducing the methyl group onto the nitrogen then
perform SEAr functionalisaton of the aryl ring-A but when this
proved problematic, due to the nucleophilicity of the tertiary
amine function, we opted to protect the nitrogen as an amide
during the SEAr functionalisaton. This allowed bromination and
subsequent carbonylation and provided efficient access to an N-
benzyl analogue of clivonine 31 but left a difficult final FGI to
replace this group with the N-methyl group found in ( )-clivonine
itself (Scheme 5).
Protection of 7-arylindoline ( )-6 with phenylchloroformate
gave the corresponding carbamate 25 in 72% yield. This compound
could be reduced cleanly to the N-methyl derivative 26 using
LiAlH4 (99% yield). However, all attempts to effect electrophilic
formylation (e.g. using DMF/POCl3 or TiCl4/Cl2CHOMe) or
bromination of this compound (e.g. using Br2 or NBS) gave
intractable mixtures of multiple products apparently arising from
reaction of these reagents at nitrogen. To circumvent this, we opted
to perform bromination on the carbamate prior to reduction
to the N-methyl derivative. Our initial attempts at bromination
utilised methyl carbamate 18 and also resulted in very unpromising
mixtures of multiple products. By contrast, the bromination
of phenyl carbamate 25 using Br2 was somewhat cleaner but
the desired brominated N-methyl derivative 27 was obtained in
just 21% yield following LiAlH4 reduction due to partial C–Br
bond hydrogenolysis concomitant with the carbamate reduction.
Scheme 5 Synthesis of clivonine ( )-1 directly from 7-arylhydrindane
( )-6 and the molecular structure of 4-chlorobenzamide ( )-28 (X-ray).
Intrigued by the difference in reactivity towards electrophilic
bromination between the alkyl and aryl carbamate derivatives 18
and 25, and cognisant that the latter (and also the structurally
related phenyl carbamate derivatives 21 and 22, Scheme 4) showed
distinct peak-broadning in their 1H NMR spectra at RT, which we
attributed to restricted mutual rotation of the carbamate and 7-
indoline aryl groups,§§ we hypothesised that intramolecular p–
p interactions could be positively influencing the outcome of
our attempted bromination reactions. To test this notion, N-(4-
chlorobenzoyl) derivative 28 was prepared from 7-arylindoline 6
in 61% yield. A single crystal X-ray structure determination on
this compound revealed that in the solid state the amide and 7-
indoline aryl groups are orientated for face-to-face p–p stacking
(Scheme 5). Pleasingly, amide 28 underwent relatively clean
bromination to give the corresponding bromo-N-(4-chlorobenzyl)
derivative in 80% yield following amide reduction with LiAlH4.
Subsequent bromine-lithium exchange using t-BuLi at -78 ◦C
followed by reaction with DMF afforded a separable mixture
of aldehyde 29 (64% yield) and the debrominated product 30
(32% yield). Upon acetonide deprotection using aqueous HCl, a
crude lactol/aldehyde containing mixture was obtained which on
treatment with Fetizon’s reagent (i.e. Ag2CO3–CeliteꢀR )61 furnished
lactone 31 in 82% yield. Finally, N-debenzylation/methylation of
lactone 31 was accomplished using Overman’s one-pot procedure62
1
to afford ( )-clivonine (1) in an unoptimised ~20% yield (by H
NMR). The overall yield from 7-arylindoline ( )-6 via this route
was therefore ~5.1% over the 6 steps [i.e. ~2.5% over the 13
steps from enone ( )-5)] although again there is clearly room for
optimisation of the final N-debenzylation/methylation procedure.
Conclusions
In summary, we have reported the total synthesis of the lycorine-
type Amaryllidaceae alkaloid clivonine (1) via two routes. Both
‡‡ This oxidation appears to be difficult, Irie et al. obtained just a 10% yield
of clivonine by oxidation of the same substance but lacking the acetonide
protecting group using MnO2 (see ref. 20. H. Irie, Y. Nagai, K. Tamoto and
H. Tanaka, J. Chem. Soc., Chem. Commun., 1973, 302–303, 21. H. Tanaka,
H. Irie, S. Babu, S. Uyeo, A. Kuno and Y. Ishiguro, J. Chem. Soc., Perkin
Trans. I, 1979, 535–538, 22. H. Tanaka, Y. Nagai, H. Irie, S. Uyeo and
A. Kuno, J. Chem. Soc., Perkin Trans. 1, 1979, 874–878.).
§§ The broad peaks in the 1H NMR spectra of carbamates 21, 22 and 25
at RT became sharp when recorded at ~330 K. By contrast, the broad
peaks in the 1H NMR spectrum of amide 27 remained unchanged at
328 K suggesting higher barriers to aryl/aryl mutual rotation in this latter
derivative.
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routes employ previously reported 7-arylhydrindane 6, which is
prepared using a retro-Cope elimination as the key step, as an
intermediate. They differ in the method employed for subsequent
introduction of what becomes the ring-B lactone carbonyl carbon
(C7). The first route described (Scheme 4) features a Bischler–
Napieralski reaction for this transformation and constitutes the
first asymmetric synthesis of natural clivonine [(+)-1] as it was
prepared from enantiomerically pure enone (+)-5 (15 steps, 1.9%
overall yield). The second route described (Scheme 5), which
employs bromination/carbonylation for C7 introduction, however
provides more efficient access to racemic clivonine (1) from enone
( )-5 on both a step-count and yield basis (13 steps, ~2.5% overall
yield). Moreover, this second approach potentially provides access
to a range of clivonine analogues having alternative N-substituents
following N-debenzylation. The fact that neither synthesis exceeds
the efficiency of our previously described route to ( )-clivonine (1)
utilising a biomimetic ring-switch approach (Scheme 1; 12 steps,
6.1% overall yield) underscores the efficiency of that approach but
also reflects to some extent the fact that the final steps of these
latest approaches remain to be fully optimised.
identical fashion to the above racemates, in the same yields and had
identical spectroscopic characteristics but the following physical
properties and optical rotations: (+)-(1S,5S,6S)-735 white solid:
Mp 115–116 ◦C (Et2O), [a]D +6.5 (c. 1.00, MeOH, 20 ◦C); (+)-
(3R,5S,6R)-10 colourless oil: [a]D +19.5 (c. 1.00, CHCl3, 20 ◦C);
(+)-(3R,5S,6R)-12 white solid: Mp 79 ◦C (Et2O/pentane), [a]D
+26.4 (c.◦0.95, CHCl3, 20 ◦C); (+)-(E,3R,5S,6R)-14 white solid:
◦
Mp 139 C (Et2O/pentane), [a]D +11.4 (c. 0.98, CHCl3, 20 C);
(-)-(Z,3R,5S,6R)-14 white solid: Mp 141 ◦C (Et2O/pentane), [a]D
◦
-9.8 (c. 0.84, CHCl3, 20 C); (+)-(3R,5S,6R)-15 white solid: Mp
99–102 ◦C (MeOH/Et2O), [a]D +14.6 (c. 1.16, CHCl3, 20 ◦C);
(+)-(3aR,5S,6R,7S,7aR)-17 white solid: Mp 61–65 ◦C (Et2O),
[a]D +65.0 (c. 0.50, CHCl3, 20 ◦C); (+)-(3aR,5S,6R,7S,7aR)-6
colourless oil, [a]D +13.3 (c. 0.25, CHCl3, 20 ◦C).
Clivonine (1)
Method 1 [(+)-1 via oxidation then hydrolysis of aldehyde (+)-
24]: To a solution of aldehyde (+)-24 (11 mg, 0.031 mmol) in
t-BuOH (1.3 mL) was added 2-methyl-2-butene (167 mL, 111 mg,
1.578 mmol) dropwise followed by a solution of 85% w/w NaClO2
(33 mg, 0.31 mmol) and NaH2PO4·2H2O (27 mg, 0.173 mmol)
in H2O (500 mL). The reaction mixture was stirred for 14 h at
RT, partitioned between CH2Cl2 (10 mL) and brine (10 mL), the
phases separated, the aqueous phase re-extracted with CH2Cl2
(4 ¥ 10 mL), the combined organic phases dried over Na2SO4
and concentrated in vacuo. The solid yellow residue (crude acid,
~10 mg) was then dissolved in MeOH (2 mL) and cooled to 0 ◦C. To
this solution was added dropwise a solution of acetyl chloride
(200 mL) in MeOH (2 mL) also at 0 ◦C. The resulting solution was
stirred for 10 min at 0 ◦C and then 4 h at RT before concentrating in
vacuo. The residue was dissolved in CH2Cl2 (10 mL), washed with
sat. aq. NaHCO3, (15 mL), the phases separated, the aqueous
phase re-extracted with CH2Cl2 (5 ¥ 5 mL) and the combined
organic phases dried over Na2SO4 and concentrated in vacuo. The
residue was purified by FC (SiO2; pentane/Et2O/MeOH (NH3
sat.), 50 : 45 : 5] to give clivonine [(+)-1] 13,15,18,19,64,65 as a colourless
Experimental section
General Directions. All reactions were performed under an-
hydrous conditions and an inert atmosphere of N2 in the oven
or flame dried glassware. Yields refer to chromatographically
and spectroscopically (1H NMR) homogenous materials, unless
otherwise indicated. Reagents were used as obtained from com-
mercial sources or purified according to known procedures.63 Flash
chromatography (FC) was carried out using Merck Kiesegel 60
F254 (230–400 mesh) silica gel. Only distilled solvents were used
as eluents. Thin layer chromatography (TLC) was performed on
Merck DC-Alufolien or glass plates pre-coated with silica gel
60 F254 which were visualised either by quenching of ultraviolet
fluorescence (lmax = 254 nm) or by charring with 5% w/v
phosphomolybdic acid in 95% EtOH, 10% w/v ammonium
molybdate in 1 M H2SO4, or 10% KMnO4 in 1 M H2SO4.
Observed retention factors (Rf ) are quoted to the nearest 0.05. All
reaction solvents were distilled before use and stored over activated
◦
◦
solid (2 mg, 21%).23 Mp 198–200 C (Lit. 199–200 C);13 Rf 0.7
(CHCl3/MeOH, 9 : 1); vmax/cm-1 (neat): 1036, 1274, 1477, 1710,
2924, 3420; dH (400 MHz, CDCl3): 1.80 (1H, ddd, J 15.3, 6.3, 3.9,
C4HH), 2.05–2.15 (1H, m, C4HH), 2.22–2.31 (2H, m, C2HH &
C3HH), 2.48–2.58 (5H, m, NCH3, C3aH, C3HH), 2.89 (1H, dd, J
10.0, 6.7, C11cH), 3.22 (1H, dd, J 12.3, 10.0, C11bH), 3.25–3.32 (1H,
m, C2HH), 4.09 (1H, dd, J 12.3, 2.7, C5aH), 4.24 (1H, dd, J 6.3,
2.7, C5H), 6.02 (2H, AB, J 5.0, OCH2O), 7.46 (1H, s, C8H), 7.74
(1H, s, C11H), OH absent;); dC (125 MHz, CDCl3) 28.73 (t), 30.82
(t), 33.12 (d), 33.43 (d), 45.22 (q), 52.95 (t), 67.41 (d), 69.50 (d),
81.81 (d), 101.82 (t), 107.15 (d), 109.34 (d), 118.69 (s), 140.77 (s),
146.68 (s), 152.67 (s), 164.68 (s); m/z (ESI+) 318 (MH+, 28%), 282
(70); Found m/z MH+, 318.1345, C17H20NO5, requires 318.1341
(D = 1.3 ppm). Unfortunately, we were unable to obtain an optical
rotation on our synthetic sample; the natural material is reported
to have [a]D +41.2 (c. 1.11, CHCl3, 23 ◦C)13
˚
4 A molecular sieves, unless otherwise indicated. Anhydrous
CH2Cl2 was obtained by refluxing over CaH2. Anhydrous THF
and Et2O were obtained by distillation, immediately before use,
from sodium/benzophenone ketyl under an inert atmosphere of
N2. Anhydrous DMF was obtained by distillation from CaH2
under reduced pressure. Ethylene glycol was distilled immediately
prior to use. Petrol refers to the fraction of light petroleum
◦
boiling between 40–60 C. NMR J values are given in Hz. High
Resolution Mass Spectrometry (HRMS) measurements are valid
to 5 ppm. Microanalyses were performed by Mr Stephen Boyer
(Microanalysis Service, London Metropolitan University).
Detailed procedures for the syntheses of ( )-5, ( )-6, ( )-7, ( )-
10, ( )-12, ( )-14, ( )-15 and ( )-17 can be found in the Supple-
mentary Material for ref.23 ◦Enantiomerically pure (+)-(5S,6S)-535
{white needles: Mp 82–83 C (EtOAc/pentane), [a]D +107.0 (c.
1.00, MeOH, 20 ◦C)} was prepared from enantiopure chloro-
diene derivative (+)-(2S,3S)-1-chloro-4,6-cyclohexadiene-2,3-diol
(CSS-Almac, Craigavon, Northern Ireland) via a modification34 of
the method described by Oppolzer.35 The subsequent enantiopure
intermediates 7, 10, 12, 14, 15, 17 and 6 were prepared in an
Method 2 [( )-1 via hydrogenolysis/reductive amination of 4-
chlorobenzylamine ( )-31]: Under an atmosphere of H2, Pearlman’s
catalyst [Pd(OH)2/C] (5 mg, 10 mol%) and formaldehyde (37%
aq., 2 mL) were added to a solution of 4-chlorobenzylamine ( )-
31 (10 mg, 0.02 mmol) in EtOAc/MeOH (1 : 10, 2 mL) at RT. After
stirring for 5 h, the suspension was filtered and concentrated
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Org. Biomol. Chem., 2011, 9, 2809–2820 | 2813
©

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in vacuo to give a mixture of compounds including clivonine [( )-1,
~20% by 1H NMR] which was not isolated.
for C18H20O6, C, 65.05%; H, 6.07%; O, 28.88%, found C, 64.97%;
H, 6.09%; O, 28.94%.
(3R*,5S*,6R*)-5,6-Di-O-isopropylidene-3-(2-oxoethyl)-1-[3,4-
(methylenedioxy)phenyl]cyclohex-1-ene 12.23. To a stirred solu-
tion of methyl ester ( )-10 (6.73 g, 19.43 mmol) in THF (150 mL)
at 0 ◦C was added LiBH4 (68.02 mL, 2 M in THF, 136.04 mmol)
and the mixture warmed to RT. After stirring for 40 h the reaction
was quenched with H2O (100 mL) and the organic phase extracted
with EtOAc (4 ¥ 100 ml). The combined organic phases were
washed with brine (200 mL), dried over Na2SO4 and concentrated
in vacuo to give alcohol ( )-11 as a yellow foam (5.34 g, 86%): Rf
0.39 (Et2O/petrol, 3 : 1); vmax/cm-1 (neat) 3427, 2924, 1720, 1504,
1488, 1371, 1244, 1215, 1038, 935, 749; dH (CDCl3, 400 MHz) 1.44
(1H, m, C4HH), 1.47 (3H, s, CH3), 1.52 (3H, s, CH3), 1.61 (1H, br s,
OH), 1.73 (1H, td, J 13.9, 6.5, C3HH), 1.86 (1H, td, J 13.5, 6.5,
C3HH), 2.01 (1H, app dt, J 12.1, 4.7, C4HH), 2.45 (1H, m, C3aH),
3.84 (2H, m, C3bH2), 4.32 (1H, app dt, J 10.5, 5.0, C5H), 4.83 (1H,
d, J 5.0, C6H), 5.98 (2H, s, OCH2O), 6.17 (1H, d, J 2.3, C2H), 6.82
(1H, d, J 8.3, CArH), 7.07–7.10 (2H, 2 ¥ CArH); dC (CDCl3, 100
MHz) 26.26 (q), 28.64 (q), 31.54 (d), 32.48 (t), 38.09 (t), 60.03 (t),
72.38 (d), 74.41 (d), 101.65 (t), 106.38 (d), 108.24 (d), 108.79 (d),
119.50 (d), 132.91 (d), 133.33 (s), 133.36 (s), 147.00 (s), 147.82 (s);
m/z (EI+) 318 (M+, 32), 260 (46), 215 (52), 91 (100); Found: m/z
(5S*,6R*)-5,6-Di-O-isopropyldiene-1-[3,4-(methylenedioxy)ph-
enyl]cyclohex-1,3-diene 8. In a flame-dried 2-neck flask equipped
with a condenser, n-BuLi (0.19 mL, 2.26 M in hexanes, 0.43 mmol)
was added dropwise to a solution of acetate ( )-7 (120 mg,
0.36 mmol) in THF (12 mL) at -78 ◦C. After stirring for 10 min,
freshly distilled TMSCl (55 ml, 0.433 mmol) was added dropwise.
After stirring for further 10 min, the dry ice bath was removed and
the solution was allowed to reach RT over 3 h. The solution was
then refluxed for 7 h, cooled to RT and partitioned between Et2O
(50 mL) and brine (50 mL). The organic phase was extracted with
Et2O (3 ¥ 20 mL). The combined organic phases were dried over
MgSO4, filtered and concentrated in vacuo to give a dark orange
solid, which was purified by FC (SiO2; Et2O/petrol, 4 : 1) to give
diene ( )-8 as a light yellow solid (93 mg, 95%): Mp 65.7–69.2 ◦C
(Et2O/petrol); Rf 0.65 (Et2O/petrol, 1 : 1); vmax/cm-1 (KBr) 1039,
1248, 1490, 1506, 1608, 1732, 2895, 2984; dH (CDCl3, 400 MHz)
1.43 (3H, s, CH3), 1.51 (3H, s, CH3), 4.93 (2H, br s, C5H & C6H),
5.89 (1H, dd, J 9.0, 1.0, C4H), 6.00 (2H, s, OCH2O), 6.12 (1H, dd,
J 9.0, 6.0, C3H), 6.35 (1H, d, J 6.0, C2H), 6.85 (1H, d, J 7.5, CarH),
7.13 (2H, m, 2 ¥ CarH); dC (CDCl3, 100 MHz) 25.34 (q), 26.97 (q),
72.19 (d), 73.05 (d), 101.13 (t), 105.78 (d), 106.10 (d), 108.38 (d),
119.62 (d), 119.82 (d), 123.47 (d), 125.79 (d), 133.14 (s), 134.50
+
MNH4 , 336.1811, C18H26NO5, requires 336.1811 (D = 0.0 ppm).
To a suspension of Dess–Martin periodianane (21.4 g, 50.4 mmol)
in CH2Cl2 (60 mL) at RT was added a solution of alcohol 11 (5.34 g,
16.8 mmol) in CH2Cl2 (20 mL) dropwise via cannula. After stirring
(s), 147.35 (s), 147.98 (s); m/z (CI+) 273 (MH+, 60), 290 (MNH4 ,
+
21), 215 (100); Found: m/z MH+, 273.1118, C16H17O4, requires
273.1115 (D = +0.5 ppm); Calculated for C16H16O4 C, 70.57%; H,
5.92%; O, 23.50%, found C, 70.09%; H, 5.92%; O, 23.99%.
R
for 23.5 h the reaction mixture was filtered through Celiteꢀ and the
filtrate treated with NaHCO3 (sat. aq., 100 mL). The organic phase
was extracted with CH2Cl2 (2 ¥ 50 mL). The combined organic
phases were washed with NaHCO3 (sat. aq., 50 mL), dried over
Na2SO4 and concentrated in vacuo to give aldehyde ( )-12 (5.04 g,
(3R*,5S*,6R*)-5,6-Di-O-isopropyldiene-3-acetoxy-1-[3,4-(me-
thylenedioxy)phenyl]cyclohex-1-ene 9. In a flame-dried 2-neck
flask equipped with a condenser, acetate ( )-7 (0.30 mg,
0.88 mmol) was dissolved in THF (10 mL) and cooled to -78 ◦C. A
solution of LDA [9 mL, 0.10 M in THF, prepared by dropwise
addition of n-BuLi (2.5 M in hexanes, 1 equiv) to a stirred solution
of diisopropylamine (1 equiv) in THF at 0 ◦C followed by stirring
◦
95%).23 Mp 80.2–81.3 C; Rf 0.70 (Et2O/petrol, 1 : 1); vmax/cm-1
(CHCl3): 754, 850, 927, 1063, 1103, 1224, 1372, 1434, 1485, 1507,
1723, 3020; dH (CDCl3, 400 MHz) 1.41 (3H, s, CH3), 1.45 (3H, s,
CH3), 1.48–1.52 (1H, m, C4HH), 1.98 (1H, app dt, J 12.6, 5.3,
C4HH), 2.66–2.68 (2H, m, C3H2), 2.80–2.89 (1H, m, C3aH), 4.33
(1H, app quintet, J 5.3, C5H), 4.78 (1H, d, J 5.3, C6H), 5.93 (2H, s,
OCH2O), 6.03 (1H, d, J 2.8, C2H), 6.76 (1H, d, J 8.7, CArH), 7.00–
7.03 (2H, m, 2 ¥ CArH), 9.83 (1H, s, CHO); dC (CDCl3, 100 MHz)
26.16 (q), 28.49 (q), 29.02 (d), 31.98 (t), 49.34 (t), 72.25 (d), 73.89
(d), 101.05 (t), 106.57 (d), 108.24 (d), 108.94 (s), 119.71 (d), 130.47
(d), 133.31 (s), 134.92 (s), 147.16 (s), 147.82 (s), 201.02 (d); m/z
(EI+) 316 (M+, 76%); Found m/z M+, 316.1318, C18H20O5, requires
316.1305 D = +4.1 ppm).
◦
for 20 min at 0 C] was then added via syringe and the mixture
was stirred at -78 ◦C for 10 min. Freshly distilled TMSCl (136 ml,
1.06 mmol) was added dropwise. After stirring for further 10 min,
the dry ice bath was removed and the solution was allowed to reach
RT over 3 h. The solution was then refluxed for 12 h, cooled to RT
and partitioned with Et2O (50 mL) and brine (50 mL). The organic
phase was extracted with Et2O (3 ¥ 20 mL). The combined organic
phases were dried over MgSO4, filtered and concentrated in vacuo.
The residue was purified by FC (SiO2; Et2O/petrol, 1 : 4) to afford
rearranged acetate ( )-9 as a white solid (130 mg, 43%): Mp 78.5–
79.7 ◦C (Et2O/petrol); Rf 0.7 (Et2O/petrol, 1 : 1); vmax/cm-1(KBr)
1023, 1241, 1375, 1508, 1720 (C O), 2883, 2995; dH (CDCl3, 400
MHz) 1.37 (3H, s, CH3), 1.51 (3H, s, CH3), 1.80 (1H, dt, J 12.0,
9.5, C4HH), 2.02 (3H, s, CH3O), 2.16 (1H, dt, J 12.0, 5.5, C4HH),
4.33 (1H, dt, J 9.5, 5.5, C5H), 4.47 (1H, d, J 5.5, C6H), 5.34 (1H,
m, C3H), 5.89 (2H, s, OCH2O), 6.06 (1H, d, J 6.5, C2H), 6.71 (1H,
d, J 8.5, CarH), 7.01 (2H, m, 2 ¥ CarH); dC (CDCl3, 100 MHz)
21.25 (q), 26.39 (q), 28.44 (d), 31.68 (t), 68.36 (d), 72.21 (d), 72.51
(d), 100.96 (t), 106.74 (d), 108.30 (d), 109.9 (s), 120.15 (d), 126.88
(d), 132.36 (s), 136.09 (s), 147.63 (s), 147.94 (s), 179.69 (s); m/z
(CI+) 273 {[M-(AcOH)+H]+, 56}; Found: m/z [M-(AcOH)+H]+,
273.1127, C16H17O4, requires 273.1124 (D = +0.3 ppm); Calculated
(3R*,5S*,6R*)-5,6-Di-O-isopropylidene-3-(2-dimethyalcetale-
thyl)-1-[3,4-(methylenedioxy)phenyl]cyclohex-1-ene 13. To a so-
lution of aldehyde ( )-12 (377 mg, 1.06 mmol) in MeOH (15 mL) at
RT was added NH2OH·HCl (111.12 mg, 1.59 mmol), NaOAc(anh.)
(140.42 mg, 1.59 mmol) and MgSO4 (190 mg, 1.59 mol) and
the resulting suspension was then refluxed overnight. MgSO4
was filtered and reaction mixture concentrated in vacuo. The
solid residue was then partitioned between CH2Cl2 (10 mL) and
brine (5 mL). The organic phase was extracted with CH2Cl2
(3 ¥ 10 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
FC (SiO2; petrol/Et2O, 1 : 1) to give acetal ( )-13 as colourless
needles (95 mg, 39%): Mp 102.3–104.1 ◦C (Et2O/petrol); Rf 0.75
2814 | Org. Biomol. Chem., 2011, 9, 2809–2820
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©

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(Et2O/petrol, 1 : 1); vmax/cm-1 (KBr) 980, 1039, 1253, 1494, 1510,
1612, 1742, 2901, 2959; dH (CDCl3, 400 MHz) 1.47 (3H, s, CH3),
1.52 (3H, s, CH3), 1.75 (1H, ddd, J 12.0, 10.5, 6.0, C4HH), 1.89
(2H, m, C3H2), 2.01 (1H, dt, J 12.0, 5.5, C4HH), 2.39 (1H, m,
C3aH), 3.38 (6H, s, 2 ¥ OCH3), 4.31 (1H, dt, J 10.5, 5.5, C5H),
4.58 (1H, t, J 6.0, C2HH), 4.82 (1H, d, J 5.5, C6H), 5.98 (2H, s,
OCH2O), 6.17 (1H, d, J 2.5, C2HH), 6.82 (1H, d, J 8.5, CarH),
7.09 (2H, m, 2 ¥ CarH); dC (CDCl3, 100 MHz) 26.26 (q), 28.65
(q), 31.16 (t), 32.80 (d), 38.13 (t), 52.78 (d), 53.06 (2 ¥ CH3),
72.28 (d), 74.29 (d), 101.03 (t), 102.84 (d), 106.46 (d), 108.26
(d), 108.80 (s), 119.54 (d), 132.62 (s), 133.55 (s), 147.01 (s),
Crystal data for 16: C21H27NO5·H2O, M = 391.45, monoclinic,
˚
P21/n (no. 14), a = 7.2818(1), b = 33.8728(3), c = 8.3252(1) A,
◦
3
-3
˚
b = 104.148(1) , V = 1991.17(4) A , Z = 4, Dc = 1.306 g cm ,
m(Cu-Ka) = 0.784 mm-1, T = 173 K, colourless blocks, Oxford
Diffraction Xcalibur PX Ultra diffractometer; 3808 independent
measured reflections (Rint = 0.0259), F2 refinement, R1(obs) =
0.0424, wR2(all) = 0.1248, 3426 independent observed absorption-
corrected reflections [|Fo| > 4s(|Fo|), 2qmax = 143◦], 263 param-
eters. CCDC 792817.
(3aR,5S,6R,7S,7aR)-5,6-Di-O-isopropylidene-1-carbomethoxy-
7-[3,4-(methylenedioxy)phenyl]-2,3,3a,4,5,6,7,7a-octahydroindole
18. To a stirred solution of amine (+)-6 (13 mg, 0.041 mmol)
and a crystal of 4-DMAP in CH2Cl2 (2 mL) at 0 ◦C were
added sequentially and dropwise triethylamine (17 mL, 12.5 mg,
0.12 mmol) and then a solution of methylchloroformate in CH2Cl2
(100 mL, 1 M, 0.1 mmol). The solution was stirred for 2 h at 0 ◦C
and for 16 h at RT. The reaction mixture was partitioned between
CH2Cl2 and sat. aq. NaHCO3, the aqueous phase extracted with
CH2Cl2 (3 ¥ 10 mL), the combined organic phases washed with
sat. aq. NH4Cl (10 mL), the aqueous phase extracted with CH2Cl2
(3 ¥ 20 mL), the combined organic phases dried over Na2SO4 and
the solvent evaporated in vacuo. The residue was purified by FC
(SiO2; Et2O/pentane, 1 : 1) to give methyl carbamate (+)-18 as a
white solid (15.0 mg, 98%): Mp 49 ◦C (Et2O/pentane); [a]D +17.7
(c. 0.88, CHCl3); vmax/cm-1 (CHCl3) 3007, 2952, 1683, 1604, 1504,
1491, 1451, 1383, 1234, 1206, 1120, 1074, 1043, 938, 864, 779, 745;
dH (CDCl3, 400 MHz) 1.31 (3H, s), 1.45 (3H, s), 1.83 (2H, m),
2.12 (2H, m), 2.38 (1H, sextet, J 8), 2.64 (1H, dd, J 10.5, 11.5),
3.21 (3H, broad s), 3.34 (1H, m), 3.63 (1H, m), 3.97 (1H, t, J 8.5),
4.30 (1H, m), 4.40 (1H, dd, J 10.5, 6.5), 5.91 (2H, ABq, J 1.5),
6.67 (1H, dd, J 6.5, 1), 6.74 (1H, d, J 8), 6.78 (1H, d, J 1.5); dC
(CDCl3, 100 MHz) 24.90 (q), 27.80 (q), 30.20 (t), 31.00 (t), 35.06
(d), 44.70 (t), 47.60 (d), 51.86 (d), 59.90 (q), 73.10 (d), 77.82 (d),
100.76 (t), 107.91 (d), 108.64 (d), 108.82 (s), 122.29 (d), 133.51 (s),
146.30 (s), 147.40 (s), 155.46 (s); m/z (EI) 375 (15), 360 (10), 317
(100), 299 (50), 242 (10), 215 (15), 190 (10), 177 (15), 140 (100),
126 (10), 88 (10); Found: m/z M+, 375.1682, C20H25NO6, requires
375.1675 (D = +1.9 ppm).
+
147.81 (s); m/z (CI+) 380 (MNH4 , 40), 273 (100); Found: m/z
+
MNH4 , 380.2074, C20H30NO6, requires 380.2073 (D = +0.2 ppm);
Calculated for C20H16O6 C, 66.28%; H, 7.23%; O, 26.49%, found C,
66.53%; H, 7.28%; O, 26.19%. For a single crystal X-ray structure
determination on this compound see ESI.†
Crystal data for 13: C20H26O6, M = 362.41, monoclinic, P21/c
˚
(no. 14), ◦a = 14.5941(4), b = 9.4049(2), c = 13.8121(3) A, b =
3
-3
˚
91.949(2) , V = 1894.70(8) A , Z = 4, Dc = 1.270 g cm , m(Mo-
Ka) = 0.093 mm-1, T = 173 K, colourless plates, Oxford Diffraction
Xcalibur 3 diffractometer; 6105 independent measured reflections
(Rint = 0.0455), F2 refinement, R1(obs) = 0.0448, wR2(all) = 0.1191,
3310 independent observed absorption-corrected reflections [|Fo|
> 4s(|Fo|), 2qmax = 64◦], 235 parameters. CCDC 792816.
(3R*,5S*,6R*)-5,6-Di-O-isopropylidene-3-(2-dimethylnitrony-
lethyl)-1-[3,4-(methylenedioxy)phenyl]cyclohex-1-ene 16. A mix-
ture of oxime isomers ( )-14 (636 mg, 1.92 mmol) were transferred
into a flask containing NaBH3CN (236 mg, 3.84 mmol) using dry
MeOH (80 mL) via a cannula. The suspension was heated gently
until a clear solution was obtained, and then cooled to 0 ◦C. 6
drops of methyl orange indicator were added and the solution
was titrated rapidly dropwise with a mixture of MeOH:HCl (conc.)
3.0 mL, 10 : 1). The cooling bath was removed and the solution
was stirred for 5 min at RT, cooled again to 0 ◦C and treated with
NaOH (8 mL, 2 M). After stirring for 10 min at 0 ◦C, the mixture
was partitioned between CH2Cl2 (15 mL) and NaHCO3 (sat. aq.,
15 mL) and extracted with CH2Cl2 (4 ¥ 15 mL). The combined
organic phases were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by FC [SiO2; Et2O/petrol, 1 : 1 →
Et2O/MeOH (NH3 sat.), 97 : 3] to give nitrone ( )-16 as colourless
(3aR,5S,5aR,11bS,11cR)–5,5a–Dihydroxyisopropylidene–1,2,
3b,3a,4,5,11b,11c-octahydro-[1,3]dioxolo[4,5–f]pyrrolo-[3,2,1–de]-
phenantridin-7-one 19. (Using the Banwell modification of Bis-
chler–Napieralski49,50): To a stirred solution of methyl carbamate
(+)-18 (100 mg, 0.266 m◦mol) and 4-DMAP (98 mg, 0.80 mmol)
in CH2Cl2 (10 mL) at 0 C was added dropwise trifluoromethyl-
sulfonic anhydride (251 mL, 376 mg. 1.33 mmol). The resulting
dark suspension was allowed to warm to RT and stir for a
further 14 h. The reaction mixture was then diluted with CH2Cl2
(40 mL), washed with sat. aq. NaHCO3 (20 mL), the aqueous
phase extracted with CH2Cl2 (3 ¥ 30 mL), the combined organic
phases washed with sat. aq. NH4Cl (20 mL), the aqueous phase
extracted with CH2Cl2 (30 mL), the combined organic phases
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by FC [SiO2, Et2O/pentane/MeOH (NH3 sat.), 60 : 35 : 5]
◦
needles (344 mg, 48%): Mp 82.6–88.9 C (Et2O/petrol); Rf 0.35
[Et2O/MeOH (NH3 sat.), 9 : 1]; vmax/cm-1 (neat) 980, 1041, 1253,
1586 (C N–OH), 2930, 2984; dH (CDCl3, 400 MHz) 1.45 (3H, s,
CH3), 1.47 (1H, m, C4HH), 1.49 (3H, s, CH3), 1.98 (1H, dt, J
12.5, 5.0, C4HH), 2.05–2.22 (2H, m, C3bHH C3aH), 2.14 (3H, s,
CH3), 2.16 (3H, s, CH3), 2.38 (1H, m, C3bHH), 3.98 (2H, m, CH2),
4.29 (1H, td, J 10.5, 5.0, C5H), 4.79 (1H, d, J 5.0, C6H), 5.96
(2H, s, OCH2O), 6.12 (1H, d, J 2.0, C2H), 6.79 (1H, dd, J 8.5,
1.0, CarH), 7.05 (1H, d, 8.5, CarH), 7.07 (1H, d, 1.0, CarH); dC
(CDCl3, 100 MHz) 19.96 (q), 20.37 (q), 26.08 (q), 28.53 (q), 32.08
(t), 32.51 (d), 32.63 (t), 56.38 (t), 72.36 (d), 74.02 (d), 100.97 (t),
106.51 (d), 108.18 (d), 108.78 (s), 119.53 (d), 131.25 (d), 133.24 (s),
134.30 (s), 143.38 (s), 147.05 (s), 147.75 (s); m/z (CI+) 374 (MH+,
100); Found: m/z MH+, 374.1969, C21H28NO5, requires 374.1967
(D = +0.5 ppm); Calculated for C21H27NO5 C, 67.54%; H, 7.29%;
N 3.75%; O, 21.42%, found C, 67.58%; H, 7.31%; N, 3.70; O,
21.41%.%. For a single crystal X-ray structure determination on
this compound see ESI.†
◦
to give lactam (-)-19 as a white solid (76 mg, 82%): Mp 224 C
(Et2O/pentane); [a]D -75.4 (c. 0.92, CHCl3); vmax/cm-1 (CHCl3)
2928, 1642, 1609, 1504, 1461. 1415, 1384, 1352, 1270, 1241, 1211,
1163, 1127, 1043, 937, 874, 832; dH (CDCl3, 400 MHz) 1.44 (3H,
s), 1.53 (3H, s), 1.67 (2H, m), 2.24 (2H, m), 2.43 (1H, m), 2.96
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(1H, dd, J 14.5, 8), 3.23 (1H, dt, J 12, 5.5), 3.52 (1H, dd, J 14,
10.5), 4.22 (1H, dd, J 12, 5.5), 4.30 (2H, m), 6.01 (2H, ABq, J 1.5),
7.19 (1H,d, J 1), 7.49 (1H, s); dC (CDCl3, 100 MHz) 24.44 (q),
27.25 (q), 32.20 (t), 32.41 (t), 34.95 (d), 40.59 (d), 45.16 (t), 57.32
(d), 74.89 (d), 75.69 (d), 101.48 (t), 106.29 (d), 108.25 (d), 109.52
(s), 124.76 (s), 135.33 (s), 146.88 (s), 150.61 (s), 161.91 (s); m/z
(EI) 344 (7), 343 (10), 268 (6), 121 (26), 111 (18), 97 (29), 85 (27),
69 (56), 57 (100); Found: m/z M+, 343.1415, C19H21NO5, requires
343.1419 (D = -1.2 ppm).
(3aR,5S,6R,7S,7aR)-5,6-Di-O·isopropylidene-1-phenoxycar-
bonyl-7-[3,4-(methylenedioxy)-6-chloromethylphenyl]-2,3,3a,4,5,6,
7,7a-octahydroindole 21. To a stirred suspension of amine (-)-20
(3.2 mg, 0.040 mmol) and NaHCO3 (50 mg) in CH2Cl2 (5 mL)
◦
at 0 C was added a solution of phenylchloroformate in CH2Cl2
(70 mL, 1 M) dropwise. The suspension was stirred for 2 h at
◦
0 C and then refluxed for 13 h. The reaction mixture was then
diluted with CH2Cl2 (30 mL), washed with aq. sat. NaHCO3,
the aqueous phase extracted CH2Cl2 (4 ¥ 10 mL), the combined
organic phases dried over Na2SO4 and concentrated in vacuo. The
residue was purified by FC (SiO2; Et2O/pentane, 1 : 1) to give
phenyl carbamate (-)-21 as a yellow waxy solid (17.4 mg, 89%):
Mp 64 ◦C (Et2O/pentane); [a]D -24.3 (c. 0.42, CHCl3); vmax/cm-1
(CHCl3) 3020, 1709, 1507, 1488, 1406, 1220, 1073, 1043, 929, 792;
dH (CDCl3, 400 MHz, 328 K) 1.30 (3H, s), 1.49 (3H, s), 1.93 (2H,
m), 2.20 (2H, m), 2.54 (1H, m), 3.31 (1H, t, J 10.5), 3.53 (1H, m),
3.82 (1H, ddd, J 8, 8, 5.5), 4.33 (3H, m), 4.62 (2H, ABq, J 11.5),
5.54 (1H, broad s), 5.81 (1H, broad s), 6.74 (2H, d, J 7), 6.75 (1H,
s), 6.94 (1H, s), 7.07 (1H, t, J 7.5), 7.22 (2H, t, J 7.5); dC (CDCl3,
100 MHz, 328 K, 1 carbon absent) 24.69 (q), 27.65 (q), 30.77 (t),
35.47 (d), 42.63 (d), 44.58 (t), 45.51 (t), 60.23 (d), 73.19 (d), 79.37
(d), 101.17 (t), 108.81 (s), 108.81 (d), 109.87 (d), 121.10 (2 ¥ d),
124.59 (d), 128.83 (2 ¥ d), 130.35 (s), 133.46 (s), 146.38 (s), 148.44
(s), 151.44 (s), 153.05 (s); m/z (EI) 487 (35),485 (100), 450 (80),
427 (90), 392 (30), 334 (100), 298 (90), 202 (75), 97 (50), 71 (60);
Found: m/z M+, 485.1614, C26H28NO635Cl, requires 485.1598 (D =
+3.3 ppm).
(3aR,5S,5aR,11bS,11cR)–5,5a–Dihydroxyisopropylidene–1,2,
3b,3a,4,5,11b,11c-octahydro-[1,3]dioxolo[4,5–f]pyrrolo-[3,2,1–de]-
phenantridine 20. Method 1 [LiAlH4reduction of lactam (-)-19]:
To a solution of lactam (-)-19 (12 mg, 0.03 mmol) in THF
(3 mL) at RT was added LiAlH4 (4 mg, 0.11 mmol). After stirring
for 2 h, the reaction mixture was quenched with brine (3 mL)
and concentrated in vacuo. The residue was partitioned between
CH2Cl2 (5 mL) and H2O (3 mL) and the organic phase was
extracted with CH2Cl2 (3 ¥ 5 mL). The combined organic phases
were dried over Na2CO3 and concentrated in vacuo to give amine
(-)-20 as white solid (11 mg, 95%): Mp 162–164 ◦C (Et2O/pentane)
[NB. sublimes 155 ◦C]; Rf 0.35 (EtOAc/MeOH, 4 : 1); [a]D -14.0
(c. 0.50, CHCl3); vmax/cm-1 (KBr) 3440, 2988, 2905, 2775, 1485,
1380, 1252, 1237, 1050, 1036, 933; dH (CDCl3, 400 MHz) 1.40 (3H,
s), 1.53 (3H, s), 1.55–1.68 (2H), 2.11 (3H, m), 2.27 (1H t, J 10), 2.47
(1H, td, J 9, 5), 2.84 (1H, t, J 10), 3.07 (1H, ddd, J 10, 6, 2), 3.70
(1H, dd, J 14.5, 1), 4.01 (1H, d, J 14.5), 4.14 (1H, dd, J 10, 7.5),
4.24 (1H, ddd, J 11, 7.5, 5), 5.91 (2H, s), 6.55 (1H, s), 7.31 (1H,
s); dC (CDCl3, 100 MHz) 24.2 (q), 27.2 (q), 31.8 (t), 32.2 (t), 33.2
(d), 41.4 (d), 53.6 (t), 55.7 (t), 62.1 (d), 75.5 (d), 76.6 (d), 100.7 (t),
106.5 (d), 107.8 (d), 108.7 (s), 129.1 (s), 132.2 (s), 145.9 (s), 146.1
(s); m/z (CI+) 330 (MH+, 100); m/z (EI+) 329 (M+, 44), 328 (100),
314 (7), 270 (4), 254 (6), 214 (2), 187 (3); Found: m/z M+, 329.1619,
C19H23NO4, requires 329.1627 (D = -2.4 ppm). For a single crystal
X-ray structure determination on this compound see ESI.†
(3aR,5S,6R,7S,7aR)-5,6-Di-O-isopropylidene-1-phenoxycar-
bonyl-7-[3,4-(methylenedioxy)-6-oxomethylphenyl]-2,3,3a,4,5,6,7,
7a-octahydroindole 22. To a stirred solution of benzylchloride
(-)-21 (10 mg, 0.0206 mmol) in DMSO (2 mL) was added
trimethylamine-N-oxide (50 mg, 0.533 mmol) and the resulting
solution stirred at RT for 24 h. The reaction mixture was then
diluted with Et2O (20 mL) and partitioned with sat. aq. NH4Cl
(20 mL). The phases were separated, the aqueous phase was
extracted with Et2O (3 ¥ 20 mL) and the combined organic phases
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by FC (SiO2; Et2O/pentane, 9 : 1) to give aldehyde (+)-22
as a white solid (7.8 mg, 81%): Mp 74 ◦C (Et2O/pentane); [a]D
+20.4 (c. 0.35, CHCl3); vmax/cm-1 (CHCl3) 3022, 2926, 1712, 1612,
1505, 1486, 1384, 1252, 1199, 1043, 937, 867, 770, 730; dH (CDCl3,
400 MHz, 331 K) 1.32 (3H, s), 1.46 (3H, s), 2.23 (4H, m), 2.51 (1H,
d, J 7.5), 3.50 (1H, m), 3.73 (1H, td, J 11.5, 7.5), 4.16 (1H, m),
4.30 (1H, m), 4.40 (1H, m), 4.48 (1H, m), 5.69 (1H, broad s), 5.92
(1H, s), 6.69 (2H, m), 7.08 (2H, m), 7.22 (3H, m), 10.10 (1H, s); dC
(CDCl3, 100 MHz, 331 K, 1 carbon absent) 25.09 (q), 27.71 (q),
29.69 (t), 30.04 (t), 31.18 (t), 35.69 (d), 39.96 (d), 45.82 (t), 61.00
(d), 73.34 (d), 78.00 (d), 101.85 (t), 108.48 (2 ¥ d), 109.13 (2 ¥
d), 120.95 (d), 124.71 (d), 128.91 (s), 130.80 (s), 139.69 (s), 147.22
(s), 151.31 (s), 152.90 (s), 189.66 (d); m/z (EI) 465 (20), 450 (10),
407 (25), 344 (100), 268 (30), 205 (25),175 (100), 77 (20). Found:
m/z M+, 465.1788, C26H27NO7, requires 465.1780 (D = +1.7 ppm).
Crystal data for 20: C19H23NO4, M = 329.38, hexagonal, P61 (no.
3
˚
˚
169), a = b = 10.695(1), c = 25.134(4) A, V = 2489.7(5) A , Z = 6,
Dc = 1.318 g cm-3, m(Mo-Ka) = 0.092 mm-1, T = 298 K, colourless
prisms, Stoe Stadi-4 diffractometer; 2331 independent measured
reflections (Rint = 0.0), F2 refinement, R1(obs) = 0.0446, wR2(all) =
0.0846, 1415 independent observed absorption-corrected reflec-
tions [|Fo| > 4s(|Fo|), 2qmax = 46◦], 218 parameters. The absolute
structure of 20 could not be determined by either an R-factor test
[R1 = 0.0446, R1- = 0.0446] or by use of the Flack parameter [x+ =
+
0.0(17), x- = 2.6(17)], and so was assigned by internal reference on
C(7), C(8), C(12), C(14) and C(22). CCDC 792818.
Method 2 [Pictet–Spengler reaction46,47 using Eschenmoser’s salt
on hydrindane (+)-6]: To a solution of amine (+)-6 (173 mg,
0.54 mmol) in THF (20 mL) was added Eschenmoser’s salt66
(151 mg, 0.82 mmol, 1.5 equiv) and the suspension stirred at
40 ◦C. After 40 h the solution was quenched with NH4OH (10%
aq. 10 mL) and the resulting biphasic solution concentrated in
vacuo. The residue was suspended in CH2Cl2 (30 mL), washed with
water (10 mL), dried over MgSO4 and concentrated in vacuo. The
residue was purified by FC (Et2O/pentane, 1 : 1→Et2O; column
presaturated with Et3N/Et2O, 1 : 9) to give amine (-)-20 as a white
solid (95.2 mg, 53%) and recovered amine (+)-6 (12.0 mg, 7%).
Spectroscopic data as above.
(3aR,5S,6R,7S,7aR)-5,6-Di-O-isopropyfidene-l-methyl-7-[3,
4-(methylendioxy)-6-hydroxymethylphenyl]-2,3,3a,4,5,6,7,7a-octa-
hydroindole 23. To a solution of aldehyde (+)-22 (55 mg,
0.118 mmol) in THF (8 mL) was added a solution of LiAlH4
(64 mg, 1.88 mmol) in Et2O (12 mL) and the reaction mixture
heated at reflux for 4.5 h. The reaction mixture was cooled to RT
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and MeOH (1 mL) added dropwise. The reaction mixture was then
partitioned between CH2Cl2 (25 mL) and sat. brine (25 mL). The
phases were separated, the aqueous phase extracted with CH2Cl2
(5 ¥ 20 mL), the combined organic phases dried over Na2SO4
and concentrated in vacuo. The residue was purified by FC (SiO2;
Et2O/pentane/MeOH (NH3 sat.), 58 : 40 : 2] to give benzyl alcohol
(+)-23 as a colourless oil (38 mg, 89%): [a]D +15.4 (c. 1.14, CHCl3);
6.65–6.75 (3H, 3 ¥ CarH), 6.81 (1H, d, J 1.5, CarH), 7.09 (1H, t, J
7.0, CarH), 7.23 (2H, t, J 7.0, CarH), 7.28 (1H, CarH); dC (CDCl3,
125 MHz, 328 K) 24.95 (q), 27.85 (q), 29.85 (t), 30.63 (t), 34.63
(d), 45.01 (t), 47.52 (d), 60.42 (d), 73.74 (d), 78.68 (d), 100.82
(t), 108.13 (d), 108.49 (d), 108.75 (s), 120.99 (2 ¥ d), 122.75 (d),
124.74 (d), 129.28 (2 ¥ d), 133.09 (s), 146.65 (s), 147.79 (s), 151.02
(s), 153.07 (s); m/z (CI+) 438 (MNH+, 90), 455 (MNH4 , 100);
+
v
max/cm-1 (CHCl3) 3521, 2987, 2889, 1616, 1502, 1480, 1458, 1382,
Found: m/z MH+, 438.1920, C25H28NO6, requires 438.1917 (D =
+0.8); Calculated for C25H27NO6 C, 68.63%; H, 6.22%; N, 3.20%;
O, 21.94%, found C, 68.60%; H, 6.21%; N, 3.18%; O, 22.01%.
1262, 1229, 1077, 1044, 930, 870, 793, 750; dH (CDCl3, 400 MHz)
1.31 (3H, s), 1.42 (3H, s), 1.64 (5H, broad s), 2.06 (1H, m), 2.17
(1H, td, J 13, 5.5), 2.32 (3H, m), 3.08 (1H, m), 3.21 (1H, t, J 10.5),
4.23 (1H, d, J 12), 4.31 (1H, m), 4.43 (1H, dd, J 10, 7.5), 4.82
(1H, d, J 11.5), 5.95 (2H, ABq, J 1), 6.85 (1H, s), 6.89 (1H, s); dC
(CDCl3, 100 MHz) 24.35 (q), 27.29 (q), 32.07 (t), 32.53 (t), 36.28
(d), 43.16 (d), 43.74 (d), 56.98 (t), 63.18 (t), 68.47 (q), 74.23 (d),
77.86 (d), 101.11 (t), 106.05 (2 ¥ d), 108.85 (2 ¥ d), 111.02 (d),
132.89 (s), 135.46 (s), 146.15 (s), 147.97 (s).
(3aR*,5S*,6R*,7S*,7aR*)-5,6-Di-O-isopropylidene-1-methyl-
7-[3,4-(methylenedioxy)phenyl]-2,3,3a,4,5,6,7,7a-octahydroindole
26. To a solution of phenyl carbamate ( )-25 (199 mg,
0.45 mmol) in THF (20 mL) at RT was added LiAlH4 (258 mg,
0.68 mmol). The resulting suspension was refluxed in the dark
for 3 h and then allowed to cool to RT. The reaction mixture
was then partitioned between brine (10 mL) and EtOAc (15 mL)
and the organic phase was extracted with EtOAc (3 ¥ 15 mL).
The combined organic phases were dried over Na2CO3, filtered
and concentrated in vacuo to afford N-methylindoline ( )-26 as
a colourless oil (130 mg, 88%). Rf 0.35 (SiO2; petrol/Et2O, 1 : 4);
(3aR,5S,6R,7S,7aR)-5,6-Di-O-isopropylidene-l-methyl-7-[3,4-
(methylenedioxy)-6-oxomethylphenyl]-2,3,3a,4.5,6,7,7a-octahydr-
oindole 24. To a stirred solution of benzyl alcohol (+)-23 (24 mg,
0.066 mmol) in CH2Cl2 (8 mL) at RT was added a solution of
Dess–Martin periodinane (35 mg, 0.083 mmol) in CH2Cl2 (7 mL)
dropwise. After 75 min a further portion of periodinane (20 mg,
0.047 mmol) was added and the reaction mixture was stirred for
further 2.5 h at RT. The reaction mixture was then diluted with
CH2Cl2 (30 mL), washed with sat. aq. NaHCO3 (20 mL), the
phases separated, the aqueous phase re-extracted with CH2Cl2
(3 ¥ 10 mL), the combined organic phases dried over Na2SO4 and
the solvent evaporated in vacuo. The residue was purified by (SiO2;
Et2O/pentane/MeOH (NH3 sat.), 60 : 37 : 3] to give aldehyde (+)-
24 as a pale yellow solid (8.8 mg, 37%): vmax/cm-1 (CHCl3) 2921,
2780, 1671, 1616, 1480, 1458, 1382, 1365, 1284, 1251, 1158, 1044,
935, 864, 641; dH (CDCl3, 200 MHz) 1.29 (3H, s), 1.40 (3H, s), 1.57
(1H, m), 1.72 (3H, s), 2.11 (1H, m), 2.97 (1H, dd, J 8, 7.5), 3.71
(1H, t, J 9), 4.28 (2H, m), 6.01 (2H, ABq, J 1), 6.94 (1H, s), 7.40
(1H, s), 10.26 (1H, s); dC (CDCl3, 50 MHz, diagnostic peaks only)
24.21 (q), 27.12 (q), 31.15 (d), 32.74 (t), 35.78 (t), 41.29 (d), 42.32
(d), 57.11 (t), 67.89 (q), 74.16 (d), 78.25 (d), 101.82 (t), 106.12 (d),
107.30 (d).
v
max (neat)/cm-1 983, 1050, 1187, 1504, 2875, 2942; dH (CDCl3, 400
MHz) 1.30 (3H, s, CH3), 1.46 (3H, s, CH3), 1.53 (1H, ddd, J 12.0,
10.0, 6.0, C4HH), 1.68 (1H, dt, J 13.0, 10.5, C3HH), 1.82 (3H, s,
NCH3), 2.03 (1H, ddd, J 12.0, 8.5, 6.0, C4HH), 2.13–2.25 (2H,
C11bH, C3HH), 2.25 (1H, m, C3aH), 2.32 (1H, t, J 10.0, C2HH),
2.72 (1H, t, J 10.0, C2HH), 2.99 (1H, dd, J 10.5, 7.5, C11cH), 4.15
(1H, dd, J 11.0, 7.0, C5aH), 4.33 (1H, dt, J 10.5, 7.0, C5H), 5.97
(2H, AB, J 1.5, OCH2O), 6.70 (3H, m, 3 ¥ CarH); dC (CDCl3, 100
MHz) 24.63 (q), 27.54 (q), 30.70 (t), 32.98 (t), 35.40 (q), 42.77
(d), 49.95 (d), 57.84 (t), 68.59 (d), 74.31 (d), 79.61 (d), 100.92 (t),
108.31 (d), 108.44 (s), 108.72 (d), 121.89 (d), 135.88 (s), 146.34 (s),
147.75 (s); m/z (CI+) 332 (MH+, 100); Found: m/z MH+, 332.1867,
C19H26NO4, requires 332.1862 (D = +1.6).
(3aR*,5S*,6R*,7S*,7aR*)-5,6-Di-O-isopropylidene-1-N-meth-
yl-7-[3,4-(methylenedioxy)-6-bromophenyl]-2,3,3a,4,5,6,7,7a-octa-
hydroindole 27. To a solution of carbamate ( )-25 (200 mg,
0.46 mmol) and K2CO3 (69 mg, 0.50 mmol) in CH2Cl2 (15 mL)
at -78 ◦C was added Br2 dropwise. After stirring for 6 h at
-78 ◦C, the reaction mixture was allowed to warm-up to RT
over 14 h. 1H-NMR of the crude suggested a partial deprotection
of the acetonide. Hence, DMP (61 mL, 0.50 mmol) and p-TSA
(5 mg, 0.03 mmol) were added at RT. After stirring for 40 min,
the reaction mixture was partitioned between NaHCO3 (sat. aq.,
10 mL) and CH2Cl2 (10 mL) and the organic phase was extracted
with CH2Cl2 (10 mL). The combined organic phases were dried
over Na2SO4, filtered and concentrated in vacuo. The residue was
dissolved in degassed THF (5 mL) and LiAlH4 (52 mg, 1.38 mmol)
was added. The suspension was refluxed in the dark at 80 ◦C
for 5 h and quenched with MeOH (2 mL). The reaction mixture
was partitioned between brine (15 mL) and Et2O (15 mL) and
the organic phase was extracted with Et2O (3 ¥ 15 mL). The
combined organic phases were dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by FC (SiO2;
Et2O/petrol, 5 : 1 → Et2O 100%) to give bromo-N-methyl indoline
( )-27 as a yellow oil (38 mg, 21%). Rf 0.70 (Et2O/MeOH, 4 : 1);
vmax (neat)/cm-1 983, 1078 (Car–Br), 1187, 1504, 2875, 2942; dH
(CDCl3, 400 MHz) 1.29 (3H, s, CH3), 1.52 (3H, s, CH3), 1.71 (1H,
(3aR*,5S*,6R*,7S*,7aR*)-5,6-Di-O-isopropylidene-1-phenyl-
carbamate-7-[3,4-(methylenedioxy)phenyl]-2,3,3a,4,5,6,7,7a-octa-
hydroindole 25. To a solution of pyrrolidine ( )-6 (620 mg,
1.96 mmol), Et3N (1 mL, 7.82 mmol) and DMAP (17 mg,
0.02 mmol) in CH2Cl2 (10 mL) at RT was added phenyl chlo-
roformate (736 mL, 5.87 mmol). After stirring for 10 min, the
reaction mixture was quenched with NaHCO3 (sat. aq., 5 mL)
and the organic phase was extracted with CH2Cl2 (3 ¥ 10 mL).
The combined organic phases were dried over Na2SO4, filtered
and concentrated in vacuo. The residue was purified by FC (SiO2;
petrol/Et2O, 1 : 1) to give carbamate ( )-25 as a white solid
◦
(670 mg, 78%): Mp 231.5–234.7 C. Rf 0.30 (SiO2; petrol/Et2O,
1 : 1); vmax (neat)/cm-1 987, 1043, 1178 (C–O), 1504, 1689 (C O),
2861, 2942; dH (CDCl3, 500 MHz, 328 K) 1.35 (3H, s, CH3), 1.50
(3H, s, CH3), 1.89 (1H, m, C4HH), 1.99 (1H, m, C3HH), 2.18–
2.24 (2H, C4HH & C3HH), 2.54 (1H, app sext, J 7, C3aH), 2.78
(1H, dd, J 11.5, 10.5, C11bH), 3.48 (1H, m, C2HH), 3.81 (1H, m,
C2HH), 4.19 (1H, m, C11cH), 4.35 (1H, td, J 8.5, 6.0, C5H), 4.48
(1H, m, C5aH), 5.71 (1H, br s, OCHHO), 5.85 (1H, br s, OCHHO),
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m, C4HH), 1.82 (1H, m, C3HH), 1.90 (3H, s, NCH3), 1.96–2.14
(3H, C2HH, C3HH, C4HH), 2.15–2.22 (2H, C2HH & C3aH), 2.99
(1H, t, J 11.0, C11bH), 3.54 (1H, m, C11cH), 4.08 (1H, dd, J 11.0,
7.0, C5aH), 4.38 (1H, dt, J 10.0, 7.0, C5H), 5.96 (1H, d, J 1.5,
OCHHO), 6.00 (1H, d, J 1.5, OCHHO), 6.80 (1H, s, CarH), 7.04
(1H, s, CarH); dC (CDCl3, 100 MHz) 24.80 (q), 27.33 (q), 29.98 (t),
33.03 (t), 35.10 (q), 41.87 (d), 47.26 (d), 57.61 (t), 70.03 (d), 74.21
(d), 79.99 (d), 101.72 (t), 107.56 (d), 109.10 (s), 112.85 (d), 116.78
(s), 135.10 (s), 146.73 (s), 147.59 (s); m/z (CI+) 410 [MH+(79Br),
100], 412 [MH+(81Br), 97]; Found: m/z [MH+(79Br)], 410.0973,
C19H2579BrNO4, requires 410.0967 (D = +1.5).
deprotection of the acetonide so 2,2-dimethoxypropane (54 mL,
0.44 mmol) and p-TSA (5 mg, 0.03 mmol) were added at RT. After
stirring for 40 min, the reaction mixture was partitioned between
NaHCO3 (sat. aq., 10 mL) and CH2Cl2 (10 mL) and the organic
phase was extracted with CH2Cl2 (10 mL). The combined organic
phases were dried over Na2SO4, filtered and concentrated in vacuo.
The residue (150 mg, 0.28 mmol) was dissolved in degassed THF
(5 mL) and LiAlH4 (55 mg, 1.43 mmol) was added. The suspension
was refluxed in the dark at 80 ◦C for 5 h and quenched with
MeOH (2 mL). The reaction mixture was partitioned between
brine (15 mL) and Et2O (15 mL) and the organic phase was
extracted with Et2O (3 ¥ 15 mL). The combined organic phases
were dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by FC (SiO2; petrol/Et2O, 3 : 1) to give the
intermediate aryl bromide as a white solid (154 mg, 0.29 mmol,
80%): Rf 0.55 (Et2O/petrol, 1 : 2); dH (CDCl3, 400 MHz) 1.27
(3H, s, CH3), 1.49 (1H, m, C4HH), 1.49 (3H, s, CH3), 1.80 (1H,
app td, J 13.6, 10.2, C4HH), 1.92 (2H, m, C3H2), 2.09 (1H, ddd, J
11.1, 6.4, 4.4, C2HH), 2.21 (1H, m, C3aH), 2.52 (1H, app t, J 11.1,
C2HH), 2.61 (1H, d, J 12.6 CarCHHN), 2.75 (1H, m, C11cH), 3.35
(1H, d, J 12.6, CarCHHN), 3.64 (1H, t, J 10.7, C11bH), 4.12 (1H,
dd, J 10.7, 7.1, C5aH), 4.34 (1H, app dt, J 10.2, 7.1, C5H), 5.91
(1H, AB, J 1.3, OCHHO), 5.95 (1H, ABq, 1.3, OCHHO), 6.76
(1H, s, CarH), 6.97 (1H, s, CarH), 7.11 (2H, d, J 8.4, 2 ¥ CarH), 7.17
(2H, d, J 8.4, 2 ¥ CarH); dC (CDCl3, 100 MHz) 24.72 (q), 27.35 (q),
30.36 (t), 32.88 (t), 34.97 (d), 47.70 (d), 53.79 (t), 59.56 (t), 67.94
(d), 74.11 (d), 79.73 (d), 101.77 (t), 107.37 (d), 108.96 (s), 112.91
(d), 116.92 (s), 128.11 (2 ¥ d), 130.21 (2 ¥ d), 132.23 (s), 134.87 (s),
138.55 (s), 146.80 (s), 147.77 (s); m/z (CI+) 520 [MH+ (79Br, 35Cl),
75], 522 [MH+ (79Br, 37Cl), (81Br, 35Cl), 100], 524 [MH+ (81Br, 35Cl),
25]; Found: m/z [MH+ (79Br, 35Cl)], 520.0884, C25H28NO435Cl79Br,
requires 520.0890 (D = -1.2 ppm). The bromide was immediately
dissolved in THF (4 mL) and cooled to -78 ◦C. To this solution was
added tert-BuLi (367 mL, 1.5◦M in hexanes, 0.55 mmol) dropwise.
After stirring for 1 h at -78 C, DMF (341 mL, 4.43 mmol) was
added dropwise and the reaction mixture was allowed to warm
to RT over 14 h. The resulting suspension was then partitioned
between NaHCO3 (sat. aq., 10 mL) and CH2Cl2 (10 mL) and
the organic phase was extracted with CH2Cl2 (3 ¥ 10 mL). The
combined organic phases were dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by FC (SiO2;
petrol/Et2O, 2 : 1) to give:
(3aR*,5S*,6R*,7S*,7aR*)-5,6-Di-O-isopropylidene-1-(4-chlo-
robenzoyl)methyl-7-[3,4-(methylenedioxy)phenyl]-2,3,3a,4,5,6,7,
7a-octahydroindole 28. To a solution of hydrindane ( )-6
(620 mg, 1.96 mmol), Et3N (1 mL, 7.82 mmol) and 4-DMAP
(12 mg, 0.1 mmol) in CH2Cl2 (15 mL) at RT was added 4-
chlorobenzoyl chloride (441 mg, 2.52 mmol) dropwise. After
stirring for 18 h, the reaction mixture was partitioned between
NaHCO3 (sat. aq., 10 mL) and CH2Cl2 (5 mL) and the aqueous
phase extracted with CH2Cl2. The combined organic phases were
dried over Na2SO4, filtered and concentrated in vacuo. The residue
was purified by FC (SiO2; Et2O) to give amide ( )-28 as a white
solid (545 mg, 61%): Mp 186.4–188.3 ◦C. Rf 0.45 (Et2O); vmax/cm-1
(neat) 987, 1081, 1192, 1516, 1648 (C O), 2878, 2939; dH (CDCl3,
400 MHz) 1.30 (3H, s, CH3), 1.41 (3H, s, CH3), 1.55 (1H, m,
C4HH), 1.86–1.97 (2H, C4HH & C3HH), 2.03–2.18 (2H, C3HH
& C2HH), 2.48 (1H, m, C3aH), 2.74 (1H, m, C2HH), 3.54 (2H, m,
C11bH & C11cH), 4.30 (2H, m, C5H & C5aH), 5.85 (1H, d, J 1.5,
OCHHO), 5.90 (1H, d, J 1.5, OCHHO), 6.65 (2.3 H, m, CarHs),
7.07 (1.7 H, m, CarHs), 7.26 (3H, m, 3 ¥ CarH); dC (CDCl3, 100
MHz) 24.91 (q), 27.84 (q), 29.70 (t), 30.02 (t), 31.32 (d), 34.36
(t), 47.24 (2 ¥ d), 73.08 (d), 78.21 (d), 100.92 (t), 108.47 (2 ¥
d), 108.70 (s), 122.34 (d), 128.22 (2 ¥ d), 128.73 (2 ¥ d), 132.74
(s), 134.98 (s), 135.81 (s), 146.84 (s), 147.81 (s), 168.90 (s); m/z
(CI+) 456 [MH+(35Cl), 100], 458 [MH+(37Cl), 35]; Found: m/z
[MH+(35Cl)], 456.1567, C25H2635ClNO5, requires 456.1578 (D =
+1.1 ppm); Calculated for C25H26ClNO5: C, 65.86%; H, 5.75%;
Cl, 7.78%; N, 3.07%; O 17.55%, found C, 65.90%; H, 5.72%; Cl,
7.79%; N, 3.05%; O 17.54%. For a single crystal X-ray structure
determination on this compound see ESI.†
¯
Crystal data for 28: C25H26ClNO5, M = 455.92, triclinic, P1 (no.
˚
2), a = 6.0988(2), b = 11.8551(4), c = 16.3205(5) A, a = 102.804(3),
Aldehyde ( )-29 ◦as a white solid [86 mg, 51% from amide ( )-
◦
3
˚
b = 98.740(3), g = 102.130(3) , V = 1100.31(6) A , Z = 2, Dc =
28]: Mp 43.4-46.1 C (Et2O/petrol); Rf 0.45 (petrol/Et2O, 2 : 1);
1.376 g cm-3, m(Cu-Ka) = 1.854 mm-1, T = 298 K, colourless
plates, Oxford Diffraction Xcalibur PX Ultra diffractometer; 4218
independent measured reflections (Rint = 0.0256), F2 refinement,
R1(obs) = 0.0368, wR2(all) = 0.1087, 3060 independent observed
absorption-corrected reflections [|Fo| > 4s(|Fo|), 2qmax = 143◦],
290 parameters. CCDC 792819.
v
max/cm-1 (neat) 983, 1078, 1187, 1206, 1697 (C O), 2875, 2930;
dH (CDCl3, 400 MHz) 1.33 (3H, s, CH3), 1.44 (3H, s, CH3),
1.55–1.71 (2H, C4HH & C3HH), 2.00–2.38 (3H, C3HH, C2HH
& C4HH), 2.34 (1H, m, C3aH), 2.69 (1H, app t, J 10.0, C2HH),
2.80 (2H, m, CarCHHN & C11cH), 3.11 (1H, d, J 13.0, CarCHHN),
3.90 (1H, t, J 10.0, C11bH), 4.37 (2H, m, C5H & C5aH), 6.03 (1H,
AB, J 1.0, OCHHO), 6.07 (1H, ABq, 1.0, OCHHO), 6.91 (2H,
d, J 8.5, 2 ¥ CarH), 6.94 (1H, s, CarH) 7.16 (2H, d, J 8.5, 2 ¥
CarH), 7.40 (1H, s, CarH), 10.41 (1H, s, CHO); dC (CDCl3, 100
MHz) 24.29 (q), 27.18 (q), 31.24 (t), 32.59 (t), 35.47 (d), 41.39
(d), 53.66 (t), 59.87 (t), 66.68 (d), 74.02 (d), 78.27 (d), 101.97 (t),
106.13 (d), 107.44 (d), 108.87 (s), 128.19 (2 ¥ d), 129.89 (2 ¥ d),
130.96 (s), 132.44 (s), 137.65 (s), 141.60 (s), 146.98 (s), 152.72
(s), 188.95 (d); m/z (CI+) 470 [MH+(35Cl), 100], 472 [MH+(37Cl),
40]; Found: m/z [MH+(37Cl)], 470.1749, C26H29NO537Cl, requires
(3aR*,5S*,6R*,7S*,7aR*)-5,6-Di-O-isopropylidene-1-(4-chlo-
robenzyl)-7-[3,4-(methylenedioxy)-6-oxomethylphenyl]-2,3,3a,4,5,
6,7,7a-octahydroindole 29 and (3aR*,5S*,6R*,7S*,7aR*)-5,6-di-
O-isopropylidene-1-(4-chlorobenzyl)-7-[3,4-(methylenedioxy)phen-
yl]-2,3,3a,4,5,6,7,7a-octahydroindole 30. To a solution of amide
( )-28 (164 mg, 0.36 mmol) and K2CO3 (102 mg, 0.74 mmol)
in CH2Cl2 (15 mL) at -78 ◦C was added Br2 dropwise. After
stirring for 6 h at -78 ◦C, the reaction mixture was allowed to
warm to RT over 14 h. 1H-NMR of the crude suggested a partial
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470.1734 (D = +3.2 ppm); Calculated for C26H28ClNO5: C, 66.45%;
H, 6.01%; Cl, 7.54%; N, 2.98%; O, 17.02%, found C, 66.47%; H,
6.03%; Cl, 7.52%; N, 2.97%; O, 17.01%.
Dr G. Whited (Genencor Inc.) for a generous gift of (+)-(2S,3S)-
1-chloro-4,6-cyclohexadiene-2,3-diol.
Reduced product ( )-30 as a white solid [41 mg, 26% from amide
( )-28]: Mp 34.2–38.6 ◦C (Et2O/petrol); Rf 0.35 (petrol/Et2O,
2 : 1); vmax/cm-1 (neat) 983, 1078, 1187, 1206, 1505, 2875, 2930;
dH (CDCl3, 400 MHz) 1.33 (3H, s, CH3), 1.48 (4H, s, CH3 &
C4HH), 1.68 (1H, m, C3HH), 1.95–2.16 (3H, C3HH, C2HH &
C4HH), 2.26 (1H, m, C3aH), 2.64 (1H, t, J 10.0, C2HH), 2.71 (1H,
d, J 13.0, CarCHHN), 2.82 (2H, m, C11bH,C11cH), 3.25 (1H, d, J
13.0, CarCHHN), 4.26 (1H, dd, J 10.5, 7.5, C5aH), 4.34 (1H, m,
C5H), 5.92 (1H, d, J 1.5, OCHHO), 5.95 (1H, d, J 1.5, OCHHO),
6.77–6.85 (3H, 3 ¥ CarH), 7.03 (2H, d, J 8.5, CarH), 7.20 (2H, d,
J 8.5, CarH); dC (CDCl3, 100 MHz) 24.53 (q), 27.49 (q), 30.91
(t), 32.83 (t), 35.38 (d), 50.15 (d), 54.06 (t), 59.77 (t), 66.62 (d),
74.25 (d), 79.25 (d), 100.95 (t), 108.38 (s), 108.49 (d), 108.62
(d), 121.98 (d), 128.25 (2 ¥ d), 129.56 (2 ¥ d), 132.21 (s), 135.67
(s), 138.60 (s), 146.41 (s), 147.88 (s); m/z (CI+) 442 [MH+(35Cl),
100], 444 [MH+(37Cl), 40]; Found: m/z [MH+(35Cl)], 442.1786,
C25H29NO435Cl, requires 442.1786 (D = +0.2 ppm); Calculated
for C25H28ClNO4: C, 67.94%; H, 6.39%; Cl, 8.02%; N, 3.17%;
O, 14.48%, found C, 67.89%; H, 6.41%; Cl, 8.01%; N, 3.15%; O,
14.54%.
Notes and references
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R
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(d), 49.94 (t), 60.81 (t), 67.38 (d), 68.90 (d), 81.82 (d), 101.95 (t),
107.12 (s), 109.36 (d), 118.67 (s), 128.25 (2 ¥ d), 129.68 (2 ¥ d),
132.21 (s), 137.93 (s), 140.63 (s), 146.77 (s), 152.67 (s), 164.63
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-2.0 ppm); Calculated for C23H22ClNO5: C, 64.56%; H, 5.18%; Cl,
8.29%; N, 3.27%; O, 18.70%, found C, 64.60%; H, 5.19%; Cl,
8.27%; N, 3.26%; O, 18.68%.
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