Regiodirecting effects in difunctionalised tricarbonyl[(1,2,3,4,5-η)- cyclohexadienyl]iron(1+) salts: Building blocks for alkaloids

Article abstract of DOI:10.1016/j.tetlet.2012.09.086

Electrophilic tricarbonyl[(1,2,3,4,5-η)-cyclohexadienyl]iron(1+) salts that incorporate methoxy and 2-ethanoyl ester substituents have been prepared, and the regiochemistry of their reactions with nucleophiles in arylation reactions has been examined using the model nucleophile diphenylzinc. The 1-carbomethoxymethyl-2-methoxy salt 1 reacts selectively by the ω addition pathway, but the 2-carbomethoxymethyl-3-methoxy salt 9 gave a 6:1 mixture of ω and α addition products. The 1-carbomethoxymethyl-2-methoxy regioisomer 1 was prepared in >95% purity without recourse to chromatography and shows the correct regiocontrol for use as a starting material in organoiron-mediated routes to alkaloids such as lycorine and parkacine.

Full text of DOI:10.1016/j.tetlet.2012.09.086

Tetrahedron Letters 54 (2013) 123–127
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Tetrahedron Letters
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Regiodirecting effects in difunctionalised tricarbonyl[(1,2,3,4,5-
cyclohexadienyl]iron(1+) salts: building blocks for alkaloids
g)-
⇑
G. Richard Stephenson , Ian M. Palotai
School of Chemistry, University of East Anglia, Norwich NR4 7TJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Electrophilic tricarbonyl[(1,2,3,4,5-g)-cyclohexadienyl]iron(1+) salts that incorporate methoxy and
2-ethanoyl ester substituents have been prepared, and the regiochemistry of their reactions with
nucleophiles in arylation reactions has been examined using the model nucleophile diphenylzinc.
Received 4 August 2012
Revised 11 September 2012
Accepted 20 September 2012
Available online 6 October 2012
The 1-carbomethoxymethyl-2-methoxy salt
1
reacts selectively by the
x
addition pathway, but
the 2-carbomethoxymethyl-3-methoxy salt 9 gave a 6:1 mixture of
x
and
a addition products. The
1-carbomethoxymethyl-2-methoxy regioisomer 1 was prepared in >95% purity without recourse to chro-
matography and shows the correct regiocontrol for use as a starting material in organoiron-mediated
routes to alkaloids such as lycorine and parkacine.
Dedicated to Professor Philip J. Parsons,
Senior Research Investigator, Chemistry
Department, Imperial College London,
SW7 2AZ, UK to mark his 60th birthday
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Stereodominant
Organoiron
Regioselectivity
Lycorine
Parkacine
Cyclohexadienyliron
Our work to establish the use of stereodominant organoiron
control groups1 as a general method of asymmetric synthesis
has, over the last decade, focused on a series of alkaloids2 which
are structurally diverse and yet, through related biogenesis, con-
tain the same substructure components. For example, lycorine3
and hippeastrine4 differ from lycoramine5,6 and maritidine6,7 in
the relative positions of the arene and a two-carbon side-chain
(Fig. 1). Conventional synthesis design would analyse the activa-
tion effects of substituents in each of these structures to choose
disconnections based on natural or umpolung polarities,8 or radical
methods. Strategies for stereocontrol are typically based on the
properties of the substitution pattern in intermediates, or external
chiral auxiliaries. When transition metal control groups are used,
substituents on the ‘working ligand’9 remain important, but in a
different way. The chirality is present in the planar chirality of me-
tal complex, and the substituents are crucial for regiocontrol, but
stereocontrol is entirely derived from the metal.10 Understanding
the regiodirecting effects of substituents in new combinations on
the working ligand is a prerequisite for the reliable planning of
new synthetic routes to incorporate efficiently the working ligand
into the target structure.
We describe here a series of studies that explore the properties
of electrophilic tricarbonyl[(1,2,3,4,5-g)-cyclohexadienyl]-iron(1+)
salts that incorporate methoxy and 2-ethanoyl ester substituents
in different relative positions on the cyclohexadienyl ligand. For
example, the isomers 1 and 2 (Fig. 2) are expected to be suitable
for synthetic routes to lycorine3 and parkacine,11 based on the
x-
directing property of the OMe group at C-2. The regioisomer 1 is
known from our earlier work12 that studied the ipso directing ef-
fect of a 1-methoxy substituent in the g5 series, but was obtained
by an inconvenient route that required separation of regioisomers
of the intermediate neutral g4 diene complexes.
To launch a major synthetic route to our chosen target mole-
cules, we wanted access to the difunctionalised cyclohexadienyl-
iron complexes that could be performed without chromatography.
Starting from 2-methoxybenzyl cyanide (3), we used a Pinner reac-
tion (Scheme 1) to prepare 1-methoxy-2-(2,2,2-trimethoxyeth-
yl)benzene13 on
a 20 g scale. Birch reduction followed by
complexation of 1,4-diene with pentacarbonyliron at reflux in
di-n-butyl ether gave the expected mixture of two 1,3 diene com-
plexes 4 and 5 (box: Scheme 1) in a 2:1 ratio. Hydride abstraction
followed by hydrolysis was performed on the mixture of regioisom-
ers to produce 114,15 (>95% purity16) which was separated from the
⇑
Corresponding author. Tel.: +44 1 603 456161; fax: +44 1 603 259396.
E-mail address: g.r.stephenson@uea.ac.uk (G.R. Stephenson).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.086

124
G. R. Stephenson, I. M. Palotai / Tetrahedron Letters 54 (2013) 123–127
OH
"meta"
relationship
"meta"
relationship
MeN
HO
O
O
O
O
OH
N
O
O
lycorine
hippeastrine
MeN
MeO
"ipso"
relationship
MeO
"ipso"
relationship
MeO
HO
O
HO
H
N
H
H
maritidine
lycoramine
Figure 1. Structural features of target alkaloids for iterative organoiron-mediated synthetic routes (the ring to be introduced as the ‘working ligand’ is highlighted in bold).
MeO
+
O
O
HO
Fe(CO)3
PF6
MeO
O
O
O
O
N
N
1
CO2Me
lycorine
OH
+
O
Fe(CO)3
PF6
MeO
OH
H
HO
MeO
MeO
MeO
MeO
N
N
O
2
CO2Me
parkacine
Figure 2. Proposed retrosyntheses for lycorine and parkacine.
major 1-methoxy regioisomer by the standard hydrolysis method.17
In this way, the required salt can be precipitated and the neutral die-
none (presumably 618) is separated by extraction into ether. The
reaction sequences described here were performed on the racemic
series.19
The well-established regiocontrolled demethoxylation ap-
proach21 offers a more iterative alternative, starting from the 2,4-
dimethoxycyclohexadienyl complex 722 (Scheme 2), reaction with
1-trimethylsilyloxy-1-methoxyethene23 gave 815 which was
demethoxylated using trifluoroacetic acid at 0 °C. The product
915,24 was precipitated as a single regioisomer with ammonium
hexafluorophosphate. Reduction of 9 (NaBH4 in MeCN) gave a 1:1
mixture of the regioisomeric diene complexes 10 and 1115 (box:
Scheme 2). Hydride abstraction gave the alternative regioisomer
225 of the target salts (Fig. 2) as a mixture with 1 and 9.
Both salts 1 and 2 have 2-methoxy substituents, so unlike the 1-
methoxy series used in our syntheses of O-methyl joubertiamine,
mesembrine, lycoramine, and maritidine, which employed arylli-
thium reagents as nucleophiles, organozinc reagents were ex-
pected26 to be more suitable in this study. The simple
diphenylzinc nucleophile was chosen as a benchmark to investi-
gate the regiocontrol effects in the series of dienyl cations 1, 2,
a
b
1.
2.
c
OMe
OMe
OMe
N
C
3
OMe
OMe
Fe(CO)3
OMe
OMe
CO2Me
and
CO2Me
Fe(CO)3
4
5
+
Fe(CO)3
PF6
OMe
O
d
and
(CO)3Fe
37%
11%
CO2Me
CO2Me
1
6
(with a trace of 2)
and 9. Reaction of 1 with diphenylzinc gave the expected
tion product 1227 (mp 62–66 °C; found m/z found 399.0530
[M+H]+; C19H19FeO6 requires 399.0531). The strong
directing ef-
fect of the OMe group, and the weaker (steric) directing effect of
x addi-
Scheme 1. Reagents and conditions: (a) AcCl, MeOH, 4 °C, collect the imino ether
by filtration, then dry MeOH, hexane, 6 d; (b) Li, IPA, THF, liq. NH3; (c) Fe(CO)5, n-
Bu2O, reflux, 16 h; 11% for three steps from 3 (allowing for recovered diene20); (d)
Ph3CBF4, K2CO3, CH2Cl2, reflux, 1 h, NH4PF6, 48%.
x
x

G. R. Stephenson, I. M. Palotai / Tetrahedron Letters 54 (2013) 123–127
125
+
+
-
PF6
Fe(CO)3
PF6
Fe(CO)3
OMe
Fe(CO)3
OMe
MeO
b
MeO
OMe
a
CO2Me
74%
CO2Me
84%
9
8
7
Fe(CO)3
OMe
Fe(CO)3
OMe
c
and
d
CO2Me
CO2Me
11
10
+
+
+
Fe(CO)3 PF6
OMe
PF6
Fe(CO)3
Fe(CO)3
PF6
OMe
OMe
and
and
CO2Me
CO2Me
CO2Me
9
2
1
Scheme 2. Reagents and conditions: (a) H2C@C(OMe)(OSiMe3), MeCN, exothermic reaction followed by 80 °C, 15 min; (b) TFA, 0 °C, 6 h, NH4PF6; (c) NaBH4, MeCN, rt, 83%
(1:1 mixture); (d) Ph3CBF4, CH2Cl2, NH4PF6, 57% (7:1:2 mixture).
+
so are suitable for scale-up.16 The salt 9 lacked complete regiose-
lectivity when used in combination with diphenylzinc.
-
Fe(CO)3
OMe
PF6
Fe(CO)3
Ph2Zn
OMe
CO2Me
THF,0 oC,
15 min
CO2Me
Acknowledgments
12
1
We thank the Lilly Research Centre, Earl Wood Manor, Windle-
sham and the EPSRC for financial support, and the EPSRC Mass
Spectrometry Centre at the University of Wales, Swansea for high
resolution mass spectrometric measurements.
54%
Scheme 3. Regiocontrol studies using diphenylzinc in THF at 0 °C.
CH2CO2Me are mutually supporting in this example. A trace (<4%)
of a second regioisomer was observed in the 1H NMR spectrum of
the product. To identify it, NMR spectra were recorded for products
obtained by diphenylzinc addition to salt 9 and to the mixture of
salts 1, 2, and 9 shown in Scheme 2. From 9, a 6:1 mixture of regioi-
somers28,29 was obtained, with the major product resulting, as ex-
References and notes
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x addition
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and 9, gave 12 as the major product (Scheme 3). The minor prod-
uct30 (7:2 ratio) from this reaction corresponded to the trace impu-
rity from the reaction of 1. This product is formed by the addition
of the phenyl group
The differences in regioselectivity reported here are consistent
with the strong
directing influence of 2-methoxy groups on g5
x to the 2-methoxy directing group in 2.
x
working ligands, and confirm that salt 1 is suitable as a starting
point for synthetic applications provided that deprotonation of
the methylene group next to the ester in the C-1 substituent can
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strong
regiocontrol of the reaction.
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x directing effect of the C-2 methoxy group influences the
x
group from diphenylzinc to the cyclohexadienyliron complex 1
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tricarbonyl[(1,2,3,4,5-g)-cyclohexadie-
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reaction sequences that avoid the need for chromatography and

126
G. R. Stephenson, I. M. Palotai / Tetrahedron Letters 54 (2013) 123–127
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g
4-diene complex). The expected ester
(1735 cmÀ1) and ketone (1660 cmÀ1) vibrations were also observed.
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enantiomerically pure complexes for use in applications of the stereodominant
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iron particles, and then concentrated on a rotary evaporator fitted with a dry
ice cooled condenser (caution: pentacarbonyliron in distillate) and then
Kugelrohr distilled. In practice, the recovered diene can be recycled by
returning it to the blackened reaction vessel (in our experience this is more
effective than using a clean flask, and also more convenient), adding additional
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Stephenson, G. R. J. Chem. Soc., Perkin Trans.
1
1982, 2449–2456; (f) Alexander, R. P.; Morley, C.;
1988, 2069–2074; (g)
1
Alexander, R. P.; Stephenson, G. R. J. Chem. Soc., Dalton Trans. 1987, 885–888;
(h) Pearson, A. J.; O’Brien, M. K. J. Org. Chem. 1989, 54, 4663–4673; (i) Chandler,
M.; Mincione, E.; Parsons, P. J. J. Chem. Soc., Chem. Commun. 1985, 1233–1234;
(j) Pearson, A. J.; Heywood, G. C.; Chandler, M. J. Chem. Soc., Perkin Trans. 1 1982,
2631. terpene synthesis; (k) Dunn, M. J.; Jackson, R. F. W.; Stephenson, G. R.
Synlett 1992, 905–906. amino acid synthesis; (l) Tao, C.; Donaldson, W. A. J. Org.
Chem. 1993, 58, 2134–2143; (m) Franck-Neumann, M.; Colson, P.-J. Synlett
1991, 891–894; (n) Gigou, A.; Beaucourt, J.-P.; Lellouche, J.-P.; Grée, R.
Tetrahedron Lett. 1991, 32, 635–638; (o) Birch, A.; Dahler, J. P.; Narula, A. S.;
Stephenson, G. R. Tetrahedron Lett. 1980, 21, 3817–3820. prostaglandins and
leukotrienes; (p) Börger, C.; Krahl, M. P.; Gruner, M.; Kataeva, O.; Knölker, H.-J.
Org. Biomol. Chem. 2012, 10, 5189–5193; (q) Thomas, C.; Kataeva, O.; Knölker,
H.-J. Synlett 2011, 2663–2666; (r) Knott, K. E.; Auschill, S.; Jäger, A.; Knölker, H.-
J. Chem. Commun. 2009, 1467–1469; (s) Choi, T. A.; Czerwonka, R.; Forke, R.;
Jäger, A.; Knöll, J.; Krahl, M. P.; Krause, T.; Reddy, K. R.; Franzblau, S. G.; Knölker,
H.-J. Med. Chem. Res. 2008, 17, 374–385; (t) Kataeva, O.; Krahl, M. P.; Knölker,
H.-J. Org. Biomol. Chem. 2005, 3, 3099–3101; (u) Knölker, H.-J.; Bauermeister, M.
Tetrahedron: Asymmetry 1993, 49, 11221–11236; (v) Knölker, H.-J.;
Bauermeister, M. Chem. Commun. 1990, 664–665; (w) Birch, A. J.; Liepa, A. J.;
Stephenson, G. R. J. Chem. Soc., Perkin Trans. 1 1982, 1, 713–717. carbazole
alkaloids.
10. This is illustrated in our synthesis of O-methyl joubertiamine: Stephenson, G.
R.; Finch, H.; Owen, D. A.; Swanson, S. Tetrahedron: Asymmetry 1993, 49, 5649–
5662.
11. Isolation of parkacine: Doepke, W. Naturwissenschaft 1963, 50, 645.
pancratistatin is
parkacine.
a
more simple structure because it lacks the
D
ring of
21. (a) Birch, A. J.; Haas, M. A. J. Chem. Soc. C 1971, 2465–2467; (b) Meng, W. D.;
Stephenson, G. R. J. Organomet. Chem 1989, 371, 355–360; (c) Stephenson, G. R.;
Owen, D. A.; Finch, H.; Swanson, S. Aust. J. Chem. 1992, 45, 121–134.
22. Birch, A. J.; Kelly, L. F.; Thompson, D. J. J. Chem. Soc., Perkin Trans. 1 1981, 1006–
1012.
12. Palotai, I. M.; Stephenson, G. R.; Ross, W. J.; Tupper, D. E. J. Organomet. Chem.
1989, 364, C11–C14.
13. 1-Methoxy-2-(2,2,2-trimethoxyethyl)benzene is commercially available in
gram quantities from specialist suppliers.
23. (a) Ainsworth, C.; Chen, F.; Kuo, Y.-N. J. Organomet. Chem. 1972, 46, 59–71; (b)
Burlachenko, G. S.; Baukov, Yu. I.; Lutsenko, I. F. Zh. Obshch. Khim. 1972, 42,
387–391; Examples of recent use: (c) Palmieri, A.; Petrini, M. Org. Biomol. Chem.
2012, 10, 3486–3493; (d) Chua, S.-S.; Alni, A.; Chan, L.-T. J.; Yamane, M.; Loh, T.-
P. Tetrahedron: Asymmetry 2011, 67, 5079–5082; Nucleophilicity: (e) Deuri, S.;
Phukan, P. Indian J. Chem. 2010, 49A, 1206–1211; Deuri, S.; Phukan, P. J. Mol.
Struct. THEOCHEM 2010, 945, 64–70.
14. Salt 1 1H NMR dH (400 MHz, CD3CN) 6.95 (1H, d, J = 6 Hz, H-3), 5.84 (1H,
apparent t, J = 6 Hz, H-4), 4.33 (1H, apparent t, J = 6 Hz, H-5), 4.04 (3H, s,
CO2Me), 3.66 (3H, s, OMe), 3.09 (1H, d, J = 17 Hz, CH2CO2), 3.02 (1H, dd, J = 15,
6 Hz, H-6b), 2.91 (1H, d, J = 17 Hz, CH2CO2), 2.32 (1H, d, J = 15 Hz, H-6a); dC
199.6 (FeCO), 169.7 (CO2–), 148.4 (C-2), 98.1 (C-4), 72.7 (C-3), 66.9 (C-5), 58.4
(OMe), 56.2 (C-1), 52.9 (OMe), 37.3 (CO2–), 33.1 (C-6) ppm.
15. Microanalytical data: Salt 1: Found: C, 33.3; H, 2.7. C13H13F6FeO6P requires C,
33.5; H, 2.8. Regioisomeric diene complexes 4 and 5: Found: C, 48.9; H, 4.4.
24. Salt 9: 1H NMR dH (400 MHz, CD3CN) 6.05 (1H, d, J = 8 Hz, H-4), 4.14 (3H, s,
OMe), 4.00 (1H, m, H-1), 3.88 (1H, m, H-5), 3.86 (1H, d, J = 16 Hz, CH2CO2), 3.73
(3H, s, CO2Me), 3.03 (1H, d, J = 16 Hz, CH2CO2), 2.93 (dt, J = 15, 6 Hz, H-6b), 1.83
C13H14FeO6 requires C, 48.5; H, 4.4. Salt 8: Found: C, 47.7; H, 4.6. C14H16FeO7
requires C, 47.8; H, 4.6. Salt 9: Found: C, 33.4; H, 2.6. C13H13F6FeO6P requires C,
33.5; H, 2.8. Regioisomeric diene complexes 10 and 11: Found: C, 48.1; H, 4.3.
(dt, J = 15, 1.8 Hz, H-6a) ppm.
25. Salt 2: 1H NMR dH (400 MHz, CD3CN) 6.00 (1H, d, J = 7 Hz, H-4), 3.80 (3H, s,
CO2Me), 3.64 (3H, s, OMe), other signals obscured by signals of 1; 13C NMR dC
199.6 (FeCO), 171.7 (CO2–), 154.3 (C-2), 101.6 (C-4), 91.2 (C-3), 62.0 (C-5), 58.4
(OMe), 53.2 (OMe) 41.5 (C-1), 33.5 (CH2CO2), 27.3 (C-6) ppm.
C13H14FeO6 requires C, 48.5; H, 4.4.
16. The salt 1 was purified by simple precipitation from acetonitrile by addition of
diethyl ether, and appeared pure by NMR, However, a trace amount (ca. 4%) of
the regioisomeric phenyl derivative 13 was identified in the NMR spectrum of
the products from reaction with diphenylzinc. When 1 is prepared on a large
scale, repeated precipitation improves the purity. It is anticipated that the
route described here will be more suitable than the original procedure (Ref. 12)
for access on a large scale.
26. Stephenson, G. R.; Palotai, I. M.; Ross, W. J.; Tupper, D. E. Synlett 1991, 586–588.
27. Phenylation product 12 from the
x
addition pathway to 1: 1H NMR dH
(400 MHz, CDCl3) 7.20 (5H, m, Ar-H), 5.05 (1H, d, J = 6.5 Hz, H-3), 3.77 (3H,
OMe), 3.72 (3H, OMe), 3.23 (1H, dt, J = 11, 6.5 Hz, H-5), 3.04 (2H, s, CH2CO2),
2.71 (1H, dd, J = 6.5, 3.5, H-4), 2.45 (1H, dd, J = 14.5, 11 Hz, H-6b), 1.94 (1H, dd,

G. R. Stephenson, I. M. Palotai / Tetrahedron Letters 54 (2013) 123–127
127
J = 14.5, 3.5 Hz, H-6
a
); dC 211.0 (FeCO), 171.3 (CO2–), 146.8 (Ar), 139.3 (C-2),
OMe or CO2Me), 3.67 (1H, dd, J = 11, 3.7 Hz, H-5), 2.91 (1H, d, J = 15.3 Hz,
CH2CO2), 2.71 (1H, ddd, 6.7, 3.7, 2.4 Hz, H-1), 2.37 (1H, d, J = 15.3 Hz, CH2CO2),
2.18 (1H, ddd, J = 14.7, 11, 3.7 Hz, H-6b), 1.61 (1H, ddd, J = 14.7, 3.7, 2.4 Hz, H-
128.6 (Ar), 126.8 (Ar), 126.2 (Ar), 65.7 (C-1), 63.1 (C-3), 55.9 (C-4), 54.8 (OMe),
51.7 (OMe), 44.7 (C-5), 39.1 (CH2), 38.6 (CH2) ppm.
28. Product from
x
addition pathway to 9: 1H NMR dH (400 MHz, CDCl3) 7.02 (5H,
6a); dC 211.1 (FeCO), 171.9 (CO2–), 174.2 (Ar), 145.0 (C-3), 128.6 (Ar), 127.3
m, Ar-H), 4.03 (1H, d, J = 17 Hz, CH2CO2), 3.83 (3H, s, OMe or CO2Me), 3.38 (1H,
d, J = 3.5, H-4). 3.31 (3H, s, OMe or CO2Me), 3.28 (1H, dt, J = 11, 3.5 Hz, H-5),
3.08 (1H, d, J = 17 Hz, CH2CO2), 2.82 (1H, dd, J = 3.5, 2 Hz, H-1), 2.18 (1H, ddd,
J = 14.5, 11, 3.5 Hz, H-6b), 2.38 (1H, ddd, J = 11, 3.5, 2 Hz, H-5), 1.67 (1H, ddd,
(Ar), 126.4 (Ar), 69.9 (C-4), 64.6 (C-2), 54.9 (OMe), 51.6 (OMe), 48.1 (C-1), 46.5
(C-5), 35.9 (CH2), 35.7 (CH2) ppm.
30. Product from
x
addition pathway to 2: 1H NMR dH (400 MHz, CDCl3) 7.20 (5H,
m, Ar-H), 3.83 (1H, J = 15 Hz, CH2CO2), 3.68 (3H, s, OMe), 3.51 (3H, s, OMe), 3.49
(1H, dd, J = 4, 2 Hz, H-1), 3.15 (1H, dt, J = 11, 3.8 Hz, H-5), 2.95 (1H, d J = 15 Hz,
CH2CO2), 2.90 (1H, d, J = 3.8 Hz, H-4), 2.35 (1H, ddd, J = 14.6, 11, 4 Hz, H-6b),
J = 14.5, 3.5, 2 Hz, H-6a); dC 211.1 (FeCO), 171.4 (CO2–), 147.1 (Ar), 138.3 (C-3),
128.8 (Ar), 126.8 (Ar), 126.3 (Ar), 84.5 (C-2), 55.4 (OMe), 54.5 (C-4 or C-1), 53.9
(C-4 or C-1), 52.1 (OMe), 46.8 (C-5), 36.9 (CH2), 34.3 (CH2) ppm.
1.73 (1H, ddd, J = 14.4, 3.8, 2 Hz, H-6a) ppm.
29. Product from
m, Ar-H), 5.23 (1H, d, J = 6.7 Hz, H-2), 3.77 (3H, s, OMe or CO2Me), 3.76 (3H, s,
a
addition pathway to 9: 1H NMR dH (400 MHz, CDCl3) 7.20 (5H,