Stereoselectivity in the organoiron-mediated synthesis of (±)-mesembrine

Article abstract of DOI:10.1016/j.tetlet.2007.11.137

The preparation and structural characterisation of a 1-aryl-substituted electrophilic η⁵-cyclohexadienyliron complex with the correct functionalisation as a 'C₁₂ building block' for the synthesis of (±)-mesembrine establishes the accessibility of a flattened conformation to allow nucleophile addition ipso to the arene. The chirality relay in quaternary centre formation by nucleophile addition has been confirmed, and the product has been converted into the Sceletium alkaloid mesembrine.

Full text of DOI:10.1016/j.tetlet.2007.11.137

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008± 650–653
Stereoselectivity in the organoiron-mediated synthesis
of (± ±-mesemꢀrine
a
a
a,
ꢀ
*
Caroline Roe , Elizaꢀeth J. Sandoe , G. Richard Stephenson , Christopher E. Anson
a
Wolfson Materials and Catalysis Centre, School of Chemical Sciences and Pharmacy University of East Anglia, Norwich NR4 7TJ, UK
ꢀ
Institut f u¨ r Anorganische Chemie der Universit a¨ tKarlsruhe, Engesserstrasse 15, D-76128 Karlsruhe, Germany
Received 27 Septemꢀer 2007; revised 9 Novemꢀer 2007; accepted 22 Novemꢀer 2007
Abstract
5
The preparation and structural characterisation of a 1-aryl-suꢀstituted electrophilic g -cyclohexadienyliron complex with the correct
functionalisation as a ‘C12 ꢀuilding ꢀlock’ for the synthesis of (± ±-mesemꢀrine estaꢀlishes the accessiꢀility of a flattened conformation
to allow nucleophile addition ipso to the arene. The chirality relay in quaternary centre formation ꢀy nucleophile addition has ꢀeen
confirmed, and the product has ꢀeen converted into the Sceletium alkaloid mesemꢀrine.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Asymmetric synthesis; Organometallic electrophiles; Tricarꢀonyliron; Mesemꢀrine
1
5
6,7
The Sceletium alkaloid mesemꢀrine (1± is a naturally
particularly Amaryllidaceae alkaloids such as crinine
2
8,9
occurring serotonin uptake inhiꢀitor with a suitaꢀle struc-
ture to illustrate the utility of aryl-suꢀstituted cyclohexa-
dienyliron complexes as central ‘C12 ꢀuilding ꢀlocks’ in
alkaloid synthesis (Fig. 1±. The key structural feature of
mesemꢀrine is a saturated pyrrolidine ring fused to a cyclo-
hexanone, with an aryl suꢀstituent directly attached to a
quaternary centre at the ring fusion. This type of quater-
nary centre has attracted consideraꢀle attention as a syn-
thetic target as it is common in a wide range of alkaloids,
and maritidine
which have more complex polycyclic
structures. Recently, consideraꢀle advances have ꢀeen
made to gain efficient access to structures of this type,
which have important ꢀiological activity
aꢀle size and ꢀasicity to inspire the design of ꢀiomimetic
pharmacophores.
We have descriꢀed a generally applicaꢀle method to
electrophilic 1-aryl-
suꢀstituted g -cyclohexadienyliron complexes from the
,4-dimethoxycyclohexadienyliron complex 3 and have
3
10
4
2
,7,9,11
and a suit-
1
2
3
1
3
prepare synthetically important
5
1
0
0
used the method to gain access to the 3 ,4 -methylenedi-
oxy-suꢀstituted example 4, which has the correct suꢀstitu-
tion pattern for use as a C12 ꢀuilding ꢀlock for crinine
3
OMe
OMe
OMe
OMe
0 0
(
Scheme 1±. A similar approach with a 2 ,3 -diether (elec-
1
4
trophile 5± has ꢀeen used successfully in our formal total
H
NMe
a: BF - salt
O
1
4
MeO
+
2
synthesis of lycoramine. We descriꢀe here, the preparation
of 2 and its use in a four-step synthesis of (± ±-mesem-
rine (six steps from 3; nine steps from 1,4-dimethoxy-
ꢀenzene±.
The preparation of the chiral electrophile 2 from its pro-
Fe(CO)3
b: PF - salt
6
15
(+
)-mesembrine
"
C12 building block"
ꢀ
Fig. 1. Illustration of an example of arylcyclohexadienyliron electrophiles
as C12 ꢀuilding ꢀlocks in alkaloid synthesis.
4
chiral precursor tricarꢀonyl(g -1,4-dimethoxycyclohexa-
3,16,17
*
diene±iron(0±
is an important example of the induction
Corresponding author. Tel.: +44 1603 592019; fax: +44 1603 592003.
E-mail address: g.r.stephenson@uea.ac.uk (G.R. Stephenson±.
1
8
of asymmetry in multihapto complexes and enantioselective
0
040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.137

C. Roe et al. / Tetrahedron Letters 49 (2008) 650–653
651
4
'
O
When the reaction was performed with n-ꢀutyllithium in
2
4
diethyl ether at ꢀ30 °C, the corresponding arylsilane
1
3
'
O
-
was oꢀtained in >77% yield. To prepare 6 (Scheme 2±, after
1
3
0 min to complete the lithium/ꢀromine exchange of
,4-dimethoxyꢀromoꢀenzene, the reaction mixture was
MeO
F +e (CO)3 PF6
OMe
4
two steps
(refs 3 and 14)
cooled to ꢀ78 °C and 3 was added in solution in dichloro-
26
or
25
methane. Product 6 was oꢀtained in 66% yield and
converted into 2a (55% yield± ꢀy reaction with tri-
MeO
+
Fe(CO)3
3
1
3'
OMe
2'
phenylcarꢀenium tetrafluoroꢀorate in dichloromethane.
2
7
OMOM
Fe(CO)3 PF6
The alternative acid-mediated procedure proved more
efficient in this case, and using hexafluorophosphoric acid
in acetic anhydride afforded 2b in over 80% yield. The eno-
late was generated from 2-trimethylsilylethyl cyanoethano-
MeO
+
5
Scheme 1. Examples of the preparation of 1-aryl-4-methoxycyclohexa-
dienyliron electrophiles.
3
,17
ate ꢀy our standard method
and after addition to 2b, the
reaction was quenched with TBAF and heated at reflux for
3 h to effect an in situ desilylation/dealkoxylation/decar-
ꢀoxylation of the intermediate, giving access to the
1
9
methods for hydride aꢀstraction have ꢀeen employed in
2
0
this step, using chiral analogues of triphenylcarꢀenium
ion reagents. Starting from 2, the electrophilicity intro-
duced into the ligand ꢀy the [Fe(CO±3] group is used in
oth the C-C ꢀond formation steps that estaꢀlish the chiral
quaternary centre of the target structures. The sense of
asymmetric induction depends on the order of the nucleo-
phile addition reactions, and our short synthesis of (± ±-
mesemꢀrine from 2 was undertaken in the racemic series
to prove the relative stereochemistry of malononitrile
1
5
cyanomethyl adduct 7 in 77% yield in a single step. Prod-
uct 7 was crystallised from diethyl ether, and the relative
stereochemistry of nucleophile addition to 2b was proved
ꢀy X-ray crystallography (Fig. 2ꢀ±. The expected exo addi-
tion of the malononitrile was thus confirmed. Reduction
with DIBAL in dichloromethane/diethyl ether was fol-
lowed ꢀy the addition of ammonium ꢀromide and methyl-
amine in methanol, and then sodium ꢀorohydride (added
+
ꢀ
3
,4,14,17
15
enolate addition
to arylcyclohexadienyliron(1± com-
in three portions as a solid± to allow direct access to the
plexes (i.e., introduction of the arene first, and the CH CN
secondary amine 8, which was isolated in 79% yield.
Decomplexation with anhydrous trimethylamine N-oxide
2
2
8
moiety second±. The exo-stereochemistry of the CH CN
2
2
1
suꢀstituent in the product has ꢀeen proved in this work,
and crystallographic characterisation of ꢀoth the electro-
phile and the malononitrile adduct are descriꢀed.
in acetone followed ꢀy quenching with oxalic acid (3 h
at room temperature± and a ꢀasic work up afforded
2
9
(± ±-mesemꢀrine (1± in 52% yield.
The conditions and solvents used with aryllithium
reagents in reactions of the type shown in Scheme 1 have
The electrophilic C12 ꢀuilding ꢀlock was crystallised
from acetone ꢀy a two-well diffusion procedure (diethyl
ether in the outer well±. The structure (Fig. 2a± shows the
expected orientation of the tricarꢀonyliron group, which
ꢀ
een found to ꢀe crucial to oꢀtain high yields, since com-
2
2
peting addition at CO ligands is possiꢀle. Our synthesis
of (± ±-mesemꢀrine (Scheme 2± thus ꢀegan with optimisa-
has one CO ligand lying under the CH of the cyclohexa-
2
2
3
tion of the preparation of 3,4-dimethoxyphenyllithium
from 4-ꢀromoveratrole, to check the compatiꢀility with
the solvent used, and the requirements of the organoiron-
mediated step. The efficiency of lithium/ꢀromine exchange
was determined ꢀy trapping with trimethylsilyl chloride.
dienyl ring. The CH group [C(6±] is also ꢀent away from
2
the principal plane of the haptile part of the ligand
[C(1±–C(5±] in the normal way. Importantly, in the solid
state structure, the dihedral angle ꢀetween the plane of
the arene and the dienyl ligand is relatively small (+39°±,
1
. HPF6 aq., Ac2O
OMe
OMe
OMe 3,4-(OMe)2C6H3Li
2. NH4PF6 aq.,
Na(Me3SiCH2CH2O2CCHCN),
DCM, ether, -78 oC, 2.5 h
o
o
THF, 0 C, 1 h, then TBAF,
0
C, rt, 30 min
MeO
THF, reflux, 3 h
66%
OMe
83% (one pot)
OMe
-
77% (one pot)
MeO
+
Fe(CO)3
3
MeO
MeO
+
-
6
Fe(CO)3 PF
PF6
Fe(CO)3
6
2
b
DIBAL-H, DCM
78 C, 2 h then 0oC, 1 h,
o
-
then NH4Br in MeOH,
OMe
OMe
OMe
OMe
then MeNH2 in MeOH,
NaBH4 in MeOH,
rt, 2 h, then aq HCl,
then NaOH
1. Me3NO, acetone,
rt, 16 h
OMe
OMe
2
. (CO2H)2.2H2O
MeOH, rt, 3 h then
NaOH aq. 20 min
79% (one pot)
52%
H
NMe
CN
MeO
O
MeO
7
NHMe
1
Fe(CO)3
8
Fe(CO)3
Scheme 2. Organoiron-mediated synthesis of (± ±-mesemꢀrine.

652
C. Roe et al. / Tetrahedron Letters 49 (2008) 650–653
Crystal data:
ꢀ
ꢀ1
1
Compound 2b: C19.75H F FeO6.5P, 563.19 g mol
,
,
21
ꢀ
6
3
F(000± 2292, Dc 1.620 g cm , l(Mo-Ka± 0.808 mm
monoclinic, C2/c,a 23.652(3±, b 13.9637(15±, c 14.4029
3
˚
˚
(
4
15± A, b 103.940(2±°, V 4616.8(8± A , T 100 K; 9868 data,
251 unique, Rint 0.0486, 317 parameters, wR 0.0949, S
2
0
+
.995, R (2317 with I > 2r(I±± 0.0518, max. diff. peak/hole
1
ꢀ3
˚
0.53/ꢀ0.60 e A
.
ꢀ
1
Compound 7: C H FeNO , 425.21 g mol , F(000±
2
3
0
19
6
ꢀ
ꢀ1
8
80, D 1.480 g cm , l(Mo-Ka± 0.827 mm , monoclinic,
c
˚
P2 /c,a 8.9196(13±,
b
26.161(4±,
c
9.2714(14± A,
b
1
3
˚
1
18.070(2±°, V 1908.9(5± A , T 100 K; 8101 data, 4199
unique, Rint 0.0291, 264 parameters, wR 0.0857, S 0.990,
2
R1 (3269 with I > 2r(I±± 0.0402, max. diff. peak/hole
ꢀ3
+
0.63/ꢀ0.32 e A˚
.
Supplementary data
Crystallographic data (excluding structure factors± for
the structures in this Letter have ꢀeen deposited with the
Camꢀridge Crystallographic Data Centre as Supplemen-
tary Puꢀlication Nos. CCDC 661648 and 661649. Copies
of the data can ꢀe oꢀtained, free of charge, on application
to CCDC, 12 Union Road, Camꢀridge CB2 1EZ,
UK: http://www.ccdc.cam.ac.uk/cgi-ꢀin/catreq.cgi, e-mail:
data_request@ccdc.cam.ac.uk, or fax: +44 1223 336033.
Acknowledgements
Fig. 2. ORTEP drawings of the organometallic electrophile in 2b (a± and
the adduct 7 (ꢀ±.
The authors acknowledge the EPSRC, and Glaxo Smith
Kline for financial support, and the EPSRC Mass
Spectrometry Centre at the University of Wales, Swansea
for high resolution mass spectrometric measurements.
corresponding to the conformation needed to allow access
3
0
of the malononitrile enolate to the ipso electrophilic cen-
˚
tre [C(1±]. The C(1±–C(8± ꢀond length (1.479 A± is consis-
tent with significant p overlap ꢀetween the arene and
dienyl sections of the ligand, and it is proposed that the
electron-rich nature of the aryl ether helps promote the flat-
tening of the structure ꢀy promoting electron donation
from the arene.
References and notes
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Archiv. Pharm. 1957, 290, 441–448; structure: Popelak, A.; Haack, E.;
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J. Chem. Soc. B 1970, 1267–1271.
In conclusion, we have completed a short synthesis of
(
± ±-mesemꢀrine from the 1,4-dimethoxy salt 3 ꢀy a reac-
2
3
4
. Gericke, N. P.; Van Wyk, B. E. World Patent 9,746,234, 199; Gericke,
N. P.; Van Wyk, B. E. Chem. Abstr. 1998, 128, 80030.
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5
hexadienyliron complex 2 promotes exclusive exo addition
of the second nucleophile in the sequence. Complex 2
adopts a flattened conformation in solution to a sufficient
extent to allow efficient nucleophilic addition ipso to the
arene, and a solid state model for this conformation has
1
999, 296, 139–149.
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ꢀ
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thus shown to ꢀe advantageous in synthetic routes ꢀased
3
24–424; the Amaryllidaceae alkaloids are still a rich source of new
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3
,4
on the organoiron C12 ꢀuilding ꢀlock approach. Work
. Examples of the ꢀiological activity of crinine: (a± Elgorashi, E. E.;
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473 (inhiꢀition of [3H]citalopram ꢀinding to the rat ꢀrain serotonin
3
is in progress towards the more advanced targets crinine
and maritidine ꢀased on these methods.
3
2

C. Roe et al. / Tetrahedron Letters 49 (2008) 650–653
653
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8
9
8, 371–376.
. Examples of the ꢀiological activity of maritidine: Cea, G.; Alarcon,
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1
0. For examples, see: Nemoto, H. Chem. Pharm. Bull. 2007, 55, 961–974;
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5
reagents to tricarꢀonyl(g -cyclohexadienyl±iron complexes, see: Birch,
1
1. For examples of ꢀiological activities of other Amaryllidaceae alka-
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cholinesterase inhiꢀitor±.
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W.; Perrior, T. R.; Rees, D. C. J. Chem. Soc., Perkin Trans. 1 1982,
1527–1534; Birch, A. J.; Kelly, L. F.; Weerasuria, D. V. J. Org. Chem.
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1
2. Sneader, W. E. Drug Prototypes and Their Exploitation; Wiley:
Chichester, 1996.
1
2 3
3. For Guilou’s work employing the Fe(CO± Ph analogue of 3, see: (a±
Guillou, C.; Millot, N.; Reꢀoul, V.; Thal, C. Tetrahedron Lett. 1996,
5
3
7, 4515–4518; the (g -cyclohexadienyl±iron series is one of the most
widely applied of this series of electrophiles, that span the hapticity
2
7
range g –g : (ꢀ± For a survey of organoiron complexes, see:
Stephenson, G. R. Organometallic Complexes of Iron. In Science of
Synthesis; Lautens, M., Ed.; Houꢀen-Weyl Methods of Molecular
Transformations; Georg Theime Verlag: Stuttgart, 2001; Vol. 1, pp
1
29. A trace of mesemꢀrenone was also identified in the product. H NMR
spectrum of mesemꢀrenone: Jeffs, P. W.; Ahmann, G.; Campꢀell, H.
F.; Farrier, D. S.; Ganguli, G.; Hawks, R. L. J. Org. Chem. 1970, 35,
1
3
7
45–886; for earlier reviews of the applications of the cyclohexa-
dienyliron series, see: (c± Pearson, A. J. Acc. Chem. Res. 1980, 13,
63–469; (d± Pearson, A. J. Synlett 1990, 10–19; (e± Kn o¨ lker, H.-J.
Synlett 1992, 371–387; (f± Donaldson, W. A. Aldrichim. Acta 1997, 30,
7–24; (g± Kn o¨ lker, H.-J.; Braier, A.; Brocher, D. J.; Cammerer, S.;
3512–3518; for C NMR data, see: Jeffs, P. W.; Capps, T.; Johnson,
D. B.; Karle, J. M.; Martin, N. H.; Rauckman, B. J. Org. Chem. 1974,
39, 2703–2710.
4
30. For a discussion of ipso and x addition to multihapto p complexes,
see Ref. 18. For the x directing nature of aryl suꢀstituents on
cyclohexadienyliron complexes, see Ref. 3. In this case, the presence
of the 4-OMe group helps overcome the natural x selectivity and
promote the ipso pathway (ipso relative to the position of the arene±.
This is ꢀecause the C(4± OMe is also x directing (see Ref. 31±, and the
two control effects are opposed (for definitions of the terms ‘mutually
reinforcing’ and ‘opposed’ in the context of nucleophile addition to
multiply suꢀstituted ligands, see Ref. 18±.
31. For examples with opposed Me and OMe groups: Pearson, A. J.;
Perrior, T. R. J. Organomet. Chem. 1985, 285, 253–265; Pearson, A.
J.; Ham, P. J. Chem. Soc., Perkin Trans. 1 1983, 1421–1425; Pearson,
A. J.; Ham, P.; Rees, D. C. J. Chem. Soc., Perkin Trans. 1 1982, 489–
497; Tao, C.; Donaldson, W. A. J. Org. Chem. 1993, 58, 2134–2143;
We used a similar approach towards the terpene tridachione:
Stephenson, G. R. J. Chem. Soc., Perkin Trans. 1 1982, 2449–2456;
Alexander, R. P.; James, T. D.; Stephenson, G. R. J. Chem. Soc.,
Dalton Trans. 1987, 2013–2016.
1
Fr o¨ hner, W.; Gonser, P.; Hermann, H.; Herzꢀerg, D.; Reddy, K. R.;
Rohde, G. Pure Appl. Chem. 2001, 73, 1075–1086.
1
1
4. Sandoe, E. J.; Stephenson, G. R.; Swanson, S. Tetrahedron Lett. 1996,
37, 6283–6286.
5. We have developed one pot procedures to add the malononitrile
nucleophile and then perform desilylation ꢀy addition of TBAF into
the reactions mixture (conversion of 2b into 7± and for the reductive
amination of the nitrile (conversion of 7 into 8±, see Scheme 2.
6. Birch, A. J.; Cross, P. E.; Lewis, J.; White, D. A.; Wild, S. B. J. Chem.
Soc. A 1968, 332–340; see also Ref. 17.
1
1
1
7. Stephenson, G. R.; Finch, H.; Owen, D. A.; Swanson, S. Tetrahedron
1993, 49, 5649–5662.
8. For a discussion of chirality in such complexes, see: Stephenson, G. R.
In Handbook of Functionalised Organometallics; Knochel, P., Ed.;
Wiley-VCH: Weinheim, 2005; pp 569–626.
1
9. Magdziak, D.; Pettus, L. H.; Pettus, T. R. R. Org. Lett. 2001, 3, 557–
559; Older, J. E. J. PhD Thesis, University of East Anglia, 2001;
32. Roe, C.; Stephenson, G. R. Org. Lett., suꢀmitted for puꢀlication.