A versatile approach to chiral macrocycles

Article abstract of DOI:10.1039/b304170k

Head-to-tail Heck coupling of units derived from amino alcohols and iodoaryl aldehydes provides a short and versatile route to non-racemic chiral macrocycles.

Full text of DOI:10.1039/b304170k

A versatile approach to chiral macrocycles
Susan E. Gibson,*a Nello Mainolfi,a S. Barret Kalindjianb and Paul T. Wrightb
a Department of Chemistry, King’s College London, Strand, London, UK WC2R 2LS
b James Black Foundation, 68 Half Moon Lane, London, UK SE24 9JE
Received (in Cambridge, UK) 15th April 2003, Accepted 13th May 2003
First published as an Advance Article on the web 3rd June 2003
Head-to-tail Heck coupling of units derived from amino
alcohols and iodoaryl aldehydes provides a short and
versatile route to non-racemic chiral macrocycles.
proposed several modifications to the synthesis, including the
incorporation of non-racemic chiral centres. The resulting
synthetic route, which offers access to a very wide range of
chiral macrocycles in just a few steps, is reported herein.
The synthesis starts with substrates containing a substituted
iodoarene and an aldehyde. In the two examples provided here
(compounds 1 and 4) these functionalities are linked in a para
disposition by zero and three carbon atoms respectively. A large
number of analogues of 1 and 4 containing other carbon chain
lengths and meta or ortho substituted arenes are readily
available from a palladium catalysed zipper reaction8 between
an appropriate di-iodoarene and an w-hydroxyalkene.7
Macrocycles make excellent ligands for a wide range of metals.
For example, the last decade has seen the synthesis and
characterisation of many lanthanide complexes, several of
which have found important applications—of particular note is
their use as contrast-enhancing agents in diagnostic imaging
procedures.1 More recently interest has grown in the synthesis
and characterisation of lanthanide complexes of chiral macro-
cycles,2 and these are now beginning to be applied in the area of
catalysis. For example, N,O-macrocycles form lanthanide
complexes that catalyse asymmetric aldol reactions.3 Macro-
cycles also play a key role in host–guest chemistry. They bind
a wide range of entities, including anions, which are often
bound to receptors containing protonated bases,4 and small
organic molecules, which often bind through hydrogen bonds,
and/or lipophilic and aromatic stacking interactions.5
In step one, compounds 1 and 4 were subjected to reductive
amination reactions with amino alcohols derived from proteino-
genic amino acids (Scheme 1). This step introduces naturally
available chirality and the opportunity to incorporate steric
constraints or further functional groups depending on the choice
of amino acid precursor. Illustrated here are the conversions of
aldehyde 1 into (S)-valinol and (S)-prolinol derivatives 1v(Bn)
and 1p, and aldehyde 4 into its valinol derivative 4v(Bn)
(secondary amines were protected as their benzyl derivatives).
Step two primed the system ready for the Heck reaction that
it was anticipated would generate the target macrocycles. The
alcohols of 1v(Bn), 1p and 4v(Bn) were reacted with appro-
Our interest in applications of the intramolecular Heck
reaction6 recently led to our serendipitous discovery of a head-
to-tail coupling reaction that gave a range of cyclophanes
containing dehydrophenylalanine units.7 Seeing this as an
opportunity to develop a new short route to macrocycles, we
Scheme 1 Reagents and conditions: a, (S)-valinol, MgSO4, DCM, then NaBH4, MeOH; b, K2CO3, BnBr, acetone; c, (S)- prolinol, MgSO4, DCM, then
NaBH4, MeOH; d, NaH, THF, then Bu4NI, methyl 2-(bromomethyl)acrylate; e, acryloylCl, Et3N, DCM; f, NaH, THF, then Bu4NI, allylBr; g, Pd(OAc)2,
Bu4NCl, NaHCO3, DMF (0.05 M), 110 °C, 16 h.
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This journal is © The Royal Society of Chemistry 2003

Scheme 2
(2H, m, NCH2CH2), 2.49–2.59 (2H, m, ArCH2CH2), 2.6–2.75 (1H, m,
priate halides to give 2-carboxyprop-2-enyl, prop-2-enoyl and
allyl derivatives 1v(Bn)c, 1v(Bn)p, 1pp, 4v(Bn)c, 4v(Bn)a and
4v(Bn)p.
NCHCH), 3.58 (1H, d, J 14, NCHAr), 3.73 (1H, d, J 14, NCHAr), 4.19 (1H,
dd, J 12 and 7, CHHOCNO), 4.40 (1H, dd, J 12 and 2, CHHOCNO), 6.25
(1H, d, J 16, CHCNO), 6.92 (2H, m, H-2,6), 7.08–7.21 (5H, m, H-8–12),
7.26 (2H, m, H-3,5), 7.50 (1H, d, J 16, ArCHNC); dC{1H}(90.4 MHz,
CDCl3) 20.9 (CH3), 22.2 (CH3), 27.9 (CH3CHCH3), 28.8 (NCH2CH2) 29.8
(ArCH2CH2), 36.1 (ArCH2), 51.3 (NCH2CH2), 55.6 (NCH2Ar), 62.4
(CHCH2O), 64.1 (NCH), 117.7 (CHNCHCNO), 127.1 (C-3,5), 128.53,
128.55, 129.0, 129.2 (C-2,6,8–12), 132.1 (C-4), 141.3 (C-7), 145.1
(ArCHNCH), 146.2 (C-1), 167.4 (CNO); m/z (ESI) 755.5 (M+, 98%), 452.4
(M 2 (CH2)4(NBn)CH(CH3)2CHCH2OCNOCHNCH 2 2H, 50), 410.4 (M
2 (CH2)4(NBn)CH(CH3)2CHCH2OCNOCHNCH 2 (CH3)2CH 2 H, 35),
242.4 (CH2CH(CH3)2CHN(CH2)4C6H4CHNCH, 69), 119.1 (CH2NBn,
100). Data for m3–4v(Bn)p: (Found: C, 79.3; H, 8.1; N, 3.5. C75H93N3O6
requires C, 79.54; H, 8.28; N, 3.71%); [a]2D0 = 259.4 (c 0.05, CH2Cl2);
nmax(neat)/cm21 1711s (CNO), 1634m (CNC); dH(360 MHz, CDCl3) 0.84
(3H, d, J 6.5, CHCH3), 0.95 (3H, d, J 6.5, CHCH3), 1.32–1.50 (4H, m,
NCH2CH2 and ArCH2CH2), 1.77–1.80 (1H, m, CH3CHCH3), 2.43–2.59
(5H, m, NCH2CH2, ArCH2CH2 and NCHCH), 3.50 (1H, d, J 14, NCHAr),
3.77 (1H, d, J 14, NCHAr), 4.22 (1H, dd, J 12 and 7, CHHOCNO), 4.34 (1H,
dd, J 12 and 2, CHHOCNO), 6.25 (1H, d, J 16, CHCNO), 6.95 (2H, m, H-
2,6), 7.08–7.21 (5H, m, H-8–12), 7.31 (2H, m, H-3,5), 7.57 (1H, d, J 16,
ArCHNC); dC{1H}(90.4 MHz, CDCl3) 19.3 (CH3), 20.4 (CH3), 27.3
(NCH2CH2), 27.6 (CH3CHCH3), 27.7 (ArCH2CH2), 34.6 (ArCH2), 49.9
(NCH2CH2), 54.2 (NCH2Ar), 62.1 (CHCH2O), 62.8 (NCH), 116.1
(CHNCHCNO), 125.6 (C-3,5), 127.1, 127.6 3 2, 128.2 (C-2,6,8–12), 130.8
(C-4), 139.9 (C-7), 143.8 (ArCHNCH), 144.5 (C-1), 166.1 (CNO); m/z (ESI)
1132.9 (M+, 12.5%), 510.3 (C6H4(CH2)4(NBn)CH(CH3)2CHCH2OC-
Subjecting the six iodoarene-alkene substrates to Heck
reaction conditions generated macrocycles in all cases except
for the substrate bearing the relatively unactivated alkene
4v(Bn)a.†‡ In the reactions where the 2-carboxyprop-2-enyl
group was used as the Heck acceptor alkene, only the products
of two head-to-tail couplings [m2-1v(Bn)c and m2-4v(Bn)c]
were isolated.§ In contrast, it proved possible to isolate both the
products of two head-to-tail couplings and the products of three
head-to-tail couplings from all the reactions that used the prop-
2-enoyl group as the Heck acceptor. It was assumed that the
remaining material was polymeric in nature.
Finally, one of the Heck products obtained, m2-4v(Bn)p, was
hydrogenated. Gratifyingly, it proved possible to identify
conditions that led to the reduction of the two alkenes to give
m2-4v(Bn)p-H4 and conditions that led to both alkene reduction
and amine deprotection to give m2-4vp-H4 (Scheme 2).
In summary, we have designed a new approach to non-
racemic chiral macrocycles that is short and flexible. Our initial
studies readily generated 0.25–1.00 g quantities of the macro-
cycles and we are now in a position to start to investigate the
catalytic and host–guest properties of our macrocycles.
The authors thank James Black Foundation for generous
studentship support (NM).
NOCHNCHC6H4(CH2)4
+
H,
27),
326.4
(CH2OC-
NOCHNCHC6H4(CH2)4NCHCH2OCNOCHNCH
(CH2NBn, 100).
2 H, 25), 119.2
Notes and references
§ The stereochemistry of the trisubstituted double bonds was assigned using
NOESY experiments which revealed a throughspace interaction between
the protons of the CH2O and the aryl substituents.
† All compounds reported gave satisfactory spectroscopic (IR, 1H NMR,
13C NMR, and low resolution MS) and microanalytical data.
‡
The head-to-tail Heck reaction of 4v(Bn)p is typical: A 250 cm3 flask
containing a stirrer bar and fitted with a condenser was placed under an inert
atmosphere of nitrogen and charged with 4v(Bn)p (2.53 g, 5 mmol, 1 eq.),
palladium(II) acetate (0.11 g, 0.5 mmol, 0.1 eq.), sodium hydrogencarbonate
(1.05 g, 12.5 mmol, 2.5 eq.) and tetra-n-butylammonium chloride (1.39 g,
5 mmol, 1 eq.). Dry dimethylformamide (100 cm3, 0.05 M) was added and
the mixture was saturated with nitrogen. The flask was lowered into a
preheated oil bath held at 110 °C and stirred for 16 h. After cooling, the
product mixture was diluted with diethyl ether (200 cm3) and the precipitate
filtered. The filtrate was concentrated in vacuo and subjected to flash
column chromatography (SiO2; hexane–diethyl ether 3 : 1) to afford m2-
4v(Bn)p as a white solid (0.47 g, 0.62 mmol, 25%) and m3-4v(Bn)p as a
bright yellow solid (0.28 g, 0.25 mmol, 15%). Data for m2-4v(Bn)p:
(Found: C, 79.4; H, 8.0; N, 3.6. C50H62N2O4 requires C, 79.54; H, 8.28; N,
3.71%); [a]2D0 = 243.5 (c 0.08, CH2Cl2); nmax(neat)/cm21 1709s (CNO),
1635m (CNC); dH(360 MHz, CDCl3) 0.87 (3H, d, J 6.5, CHCH3 ), 0.97 (3H,
d, J 6.5, CHCH3), 1.28–1.38 (1H, m, NCH2CHH), 1.39–1.52 (3H, m,
ArCH2CH2 and NCH2CHH), 1.89–1.95 (1H, m, CH3CHCH3), 2.38–2.45
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