Chromium-mediated aldol and homoaldol reactions on solid support directed towards an iterative polyol strategy

Article abstract of DOI:10.1016/j.tetlet.2004.10.038

Chromium-Reformatsky and chromium-homoaldol reactions run under neutral and mild reaction conditions. They are highly chemoselective, tolerant towards most common functional groups, and are not prone to retroaldol reactions. Initial studies directed to transfer these homogeneous chromium-mediated solution-phase reactions to solid phase are presented. The main objective was to develop a methodology to aid a combinatorial iterative strategy to polyols (polyketides) on solid phase. A general reactivity problem was observed with polystyrene based resins compared to the solution-phase reactions, independent if the electrophilic (aldehyde) or nucleophilic (bromide) end of the polyol chain was supported to the resin. A complicated penetration, or loss of the polar solvent environment after penetration into the resin, might be responsible for the reduced reactivity. Application of either a soluble polystyrene resin or a polystyrene resin with a polar polyethylene glycol tether resulted in improved yields.

Full text of DOI:10.1016/j.tetlet.2004.10.038

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9073–9078
Chromium-mediated aldol and homoaldol reactions on solid
support directed towards an iterative polyol strategy
b,
Ludger A. Wessjohann,a,b, Harry Wild and Henri S. Schrekkera
*
aLeibniz-Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany
bLudwigs Maximilian Universita¨t Mu¨nchen, Butenandtstrasse 5-13, D-081377 Mu¨nchen, Germany
Received 1 July 2004; revised 6 October 2004; accepted 6 October 2004
Abstract—Chromium-Reformatsky and chromium-homoaldol reactions run under neutral and mild reaction conditions. They are
highly chemoselective, tolerant towards most common functional groups, and are not prone to retroaldol reactions. Initial studies
directed to transfer these homogeneous chromium-mediated solution-phase reactions to solid phase are presented. The main objec-
tive was to develop a methodology to aid a combinatorial iterative strategy to polyols (polyketides) on solid phase. A general reac-
tivity problem was observed with polystyrene based resins compared to the solution-phase reactions, independent if the electrophilic
(aldehyde) or nucleophilic (bromide) end of the polyol chain was supported to the resin. A complicated penetration, or loss of the
polar solvent environment after penetration into the resin, might be responsible for the reduced reactivity. Application of either a
soluble polystyrene resin or a polystyrene resin with a polar polyethylene glycol tether resulted in improved yields.
Ó 2004 Elsevier Ltd. All rights reserved.
A method of crucial importance for the construction of
carbon–carbon bonds in natural and artificial synthetic
chemistry is the aldol reaction.1,2 One of the oldest selec-
tive methods for cross-coupling aldol reactions is the
Reformatsky reaction.3 This redox-initiated aldol reac-
tion allows the enolate formation at a predefined posi-
tion, independent of thermodynamic and kinetic C–H
acidities. Especially attractive is the chromium-Refor-
matsky4,5 reaction, which tolerates most common func-
tional groups, and has a high chemoselectivity towards
aldehydes.6 Even more, this reaction, performed under
mild and neutral reaction conditions, is not effected by
retroaldol reactions.7,8 The kinetic anti-aldol products
of esters are the result of a Ôkinetic quenchÕ of the formed
chromium-alcoholate, and are normally difficult to ob-
tain.4,8 Chromium-Reformatsky reactions using Evans-
type oxazolidinones as chiral auxiliaries combine this
high anti-selectivity with a high stereoselectivity, and
have been successfully applied in the total synthesis of
epothilone B.9–11 By this method one is able to overcome
the limitations of the classical Evans syn-aldol chemistry
allowing direct access to anti-Evans aldols with Ônon-
EvansÕ absolute orientation. In addition, the highly ste-
reoselective transfer of carboxylmethyl groups (so called
Ôacetate anionÕ transfer of CH2–CO2R) is possible.4,9,10
A
closely related and complementary chromium-mediated
reaction to form 1,n-polyols is the Takai–Utimoto reac-
tion, which allows the direct formation of chromium alk-
yls under cobalt-catalysis in the presence of many
functional groups including homoenolates.4,12 Transfer
of these powerful chromium reactions from solution to
solid phase would be an enrichment of the present aldol
chemistry for solid-phase reactions,13–17 and result in the
first homoaldol method available for solid-phase reac-
tions. Here we wish to report our progress to transfer
the solution-phase chromium-Reformatsky and Takai–
Utimoto reaction to solid phase, which consists of opti-
mization of the resin, linker and reaction conditions.
Finally, we hope that this work will form a basis for
the implementation of an iterative polyol strategy to syn-
thesize polyketides.
Keywords: Chromium; Solid phase; Aldol; Homoaldol; Polyol;
Polyketide.
An iterative polyol synthesis consists of a sequence of al-
dol reactions in combination with the reestablishment of
a key reactive functionality (Fig. 1). Development of an
iterative polyol strategy is highly challenging and com-
plicated, which is evident from the pioneering works
*
Corresponding author. Tel.: +49 345 5582 1301; fax: +49 345 5582
1309; e-mail: wessjohann@ipb-halle.de
Present address: Metanomics, Tegeler Weg 33, D-10589 Berlin,
Germany.
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.038

9074
L. A. Wessjohann et al. / Tetrahedron Letters 45 (2004) 9073–9078
Functionalization
FG
CHO
Br
FG
O
OPG
OPG O
Resin
Linker
R
FG
n cycles
H
H
Rn-1 Rn
Rn-1 Rn
CrCl2
R
CrCl2
Br
FG
Iteration
Rn
Figure 1. Principle of the iterative polyol synthesis utilizing chromium(II)-mediated reactions.
of Reggelin et al.,18–20 and Paterson et al.21,22 An impor-
tant advantage of the stereoselective chromium-Refor-
matsky reaction is its insensitivity to matched and
mismatched interactions, that is, the induction usually
is not much effected by the chirality in the aldehyde.4
For practical purposes it is also important that many
chromium(II)-mediated reactions to some extent toler-
ate residual water or OH-groups, and do not react with,
for example, keto, ester, amide or other groups impor-
tant for natural products like polyketides. In principle,
two inverse strategies are possible for chromium(II)-
mediated reactions on solid phase: the iteration of the
aldehyde (electrophile) or that of the bromide (to be
converted to the organochromium nucleophile) sup-
ported to the resin. Theoretical considerations suggest
to use the aldehyde supported strategy. The aldehyde
key functionality can be reestablished directly from the
activating carbonyl functional group, for example,
Evans amide (Fig. 1). Other advantages are better yields
through the suppression of pinacol coupling by spatial
separation of the aldehyde groups, and a better accept-
ance of traces of water since the chromium(III) enolate
is present in excess.
with sodium hydride to the Merrifield resin followed by
an oxidation with Dess–Martin Periodinane resulted in
the formation of aldehyde-functionalized resin 1 (FT-IR:
1721cmÀ1).23 Introduction of the aldehyde functionality
together with an easy cleavable linker on the Merrifield
resin was achieved in three steps. A nucleophilic substi-
tution with the sodium salt of 2,2-dimethyl-4-hydroxy-
methyl-1,3-dioxolane, cleavage of the acetal in a one
to one mixture of 1M-HCl (aq) and dioxane, and a con-
densation with terephthaldehyde afforded 2 (0.86mmol/
g).24 The direct coupling of p-hydroxybenzaldehyde with
2-chlorotrityl chloride resin in the presence of pyridine
gave resin 3. Resin 4 was synthesized by an etherification
of the trityl chloride resin with p-bis(hydroxy-
methyl)benzene, followed by an oxidation with the pyr-
idine complex of sulfur trioxide.25 Functionalization of
soluble chloromethyl polystyrene (1.04mmol/g based
on chlorine analysis)26 via a nucleophilic substitution
with the sodium salt of 2-(4-hydroxyphenyl)-1,3-dioxa-
lane, and acid catalyzed cleavage of the acetal afforded
resin 5, which was confirmed by NMR.
Access to bromide-functionalized resins was more con-
venient and straightforward compared to the synthesis
of aldehyde resins, because the desired substrates are
commercially available. Synthesis was achieved in a
straightforward manner by an acylation of OH- or
NH2-functionalized resins with an activated acid. Thus,
A set of aldehyde- and bromide-functionalized resins
(Fig. 2) were synthesized to screen the potential of the
chromium-Reformatsky- and Takai–Utimoto reaction
in solid-phase assisted reactions. Coupling of butanediol
Merifield-Trityl-Resin
Aldehyde-Functionalized
Bromide-Functionalized
O
O
O
Cl-Trt
Wang-Resin
O
Tentagel S
PEG
Merrifield-Resin
3
O
Br
Br
Merifield-Trityl-Resin
O
6
O
O
O
1
8
Trt
O
MHBA-Resin
MHBA-Resin
Merrifield-Resin
O
4
O
O
O
Br
Rink
N
Br
n
Soluble Polystyrene
PS
Rink
N
O
O
H
H
2
9
a: n = 1
b: n = 6
c: n = 9
7
O
O
5
Figure 2. Functionalized resins.

L. A. Wessjohann et al. / Tetrahedron Letters 45 (2004) 9073–9078
9075
reaction of the Wang resin with 2-bromoisobutyryl bro-
mide and diisopropylethylamine afforded 6 with a load-
ing of 0.68mmol/g based on bromide analysis. The same
reaction was performed on the deprotected MHBA-
Rink amide- and Tentagel S OH resin, to yield 7
(Kaisertest: negative, 0.61mmol/g) and 8 (0.25mmol/
g). Aliphatic bromide-functionalized resin 9 (Kaisertest:
negative. a: 0.59mmol/g; b: 0.61mmol/g; c: 0.61mmol/g)
was synthesized by amidation of the corresponding
diisopropylcarbodiimide activated acid with the depro-
tected MHBA-Rink amide resin.
only in the recovery of unreacted aldehyde, which might
be explained by the low electrophilicity of p-methoxy-
benzaldehyde. Trityl resin 4 was chosen to overcome this
reactivity problem, and resulted into a mixture of cou-
pling product 10c (6% isolated yield) and aldehyde 11c
(Table 1, entry 3). The low absolute yields do not corre-
spond to our experience in solution phase with yields
>95%. They might indicate that the reactivity of the
aldehyde as such or the linker/cleavage properties are
not the only reason for the low purity and yield. An-
other reason might be the apolar polystyrene backbone
of the resins. Chromium(II)-mediated reactions require
polar reaction media like THF and DMF. Even the
addition of 10% toluene inhibits the chromium reaction
efficiently. Thus, soluble polystyrene support 5 was ap-
plied to assure a higher interaction with the polar sol-
vent without loss of the advantages of solid-phase
synthesis.27 Coupling product 10a was the only isolated
product in an absolute yield of 44% (Table 1, entry 4),
supporting our notion that the polymer backbone bears
importance for the reactivity. Unexpectedly, the soluble
resin became insoluble after the first chromium-Refor-
matsky reaction was performed, rendering this princi-
pally suitable system useless for further iterative steps.
Reaction of Merrifield resin 1 (Scheme 1) with 2-bro-
moisobutyronitrile resulted into successful coupling,
based on the disappearance of the carbonyl- and appear-
ance of the nitrile-band. Unfortunately, the ether linker
was too stable, and the product could not be cleaved
from the resin without severe decomposition.
Methyl-2-bromoisobutyrate was chosen as model sub-
strate for the further development of the chromium-Ref-
ormatsky reaction (Table 1). Introduction of a suitable
linker was necessary to enable cleavage of the product.
The 1,3-dioxolane linker in Merrifield resin 2 is stable
towards many reaction conditions and could be cleaved
with 2M aqueous HCl/dioxane (1:1). A mixture of cou-
pling product 10b and aldehyde 11b was isolated in a
ratio of 60:40. The absolute isolated yield, based on
the theoretical loading as given by the producer of the
resin is calculated to 23% of 10b (Table 1, entry 1).
Cleavage from trityl resin 3 (Table 1, entry 2) resulted
The complementary Takai–Utimoto reaction of methyl-
3-bromopropionate with trityl resin 4 resulted in the
same reaction profile as for the chromium-Reformatsky
reaction (Scheme 2). An incomplete reaction with a
30:70 ratio of product 12 to aldehyde, and a low abso-
lute yield of 17%.
X
47% HBr / AcOH
CN
OH
CrCl2, LiI
X
CN
Br
CN
O
O
O
THF, 20ºC, 2h
1
X = OH or Br
Scheme 1. Chromium-Reformatsky reaction of 2-bromoisobutyronitrile (3.6equiv) with resin 1 (1.0equiv), CrCl2 (7.5equiv) and LiI (0.5equiv).
Table 1. Chromium-Reformatsky reaction of methyl-2-bromoisobutyrate with aldehyde-functionalized resins
O
OH
a: R = CO2H
b: R = OH
c: R = CH2OH
O
CO2Me
CrCl2, LiI
Cleavage
Br
CO2Me
Resin
R
R
2-5
10
11
Entry
Resin
T (°C)
t (h)
10
Purity (%)a
1
2
3
4
2b
3d
4f
20
4
6
10a
60c
e
0
1610b
10c
10b
—
47g
100i
20–45
20
1–1.25
2
5h
a Purity of 10 related to 11.
b 2 (1.0equiv), methyl-2-bromoisobutyrate (2.7equiv), CrCl2 (5.9equiv) and LiI (0.3equiv) in DMF.
c Product cleaved by a 1:1 mixture of 2M HCl and dioxane.
d 3 (1.0equiv), methyl-2-bromoisobutyrate (3.2equiv) and CrCl2 (7.2equiv) in DMF.
e Product cleaved with 30% trifluoroacetic acid in DCM.
f 4 (1.0equiv), methyl-2-bromoisobutyrate (2.7equiv) and CrCl2 (6.6equiv) in THF. Resin 4 was pretreated with TMSCl and NEt3 in THF to protect
non-oxidized free alcohol groups.
g Product cleaved with 5% trifluoroacetic acid in dichloromethane.
h 5 (1.0equiv), methyl-2-bromoisobutyrate (2.5equiv), CrCl2 (4.5equiv) and LiI (0.3equiv) in THF.
i Product cleaved with TMSI in chloroform.28

9076
L. A. Wessjohann et al. / Tetrahedron Letters 45 (2004) 9073–9078
O
O
CrCl2, B12, LiI
5% TFA
CH2Cl2
Trt
O
MeO2C
4
HO
Br
DMF, 40oC, 19h
CO2Me
12
OH
Scheme 2. Takai–Utimoto reaction of methyl-3-bromopropionate (2.1equiv) with aldehyde resin 4 (1.0equiv), CrCl2 (5.2equiv), cyanocobalamine
(0.1equiv) and LiI (0.7equiv).
The nucleophile supported strategy has the disadvan-
tage that inorganic Cr(II) has to penetrate the polymer
and that the bromide key functionality is troublesome
to reestablish when applied in an iterative synthesis.
Advantages are the direct accessability to bromide-func-
tionalized resins, the usually cheaper aldehydes are ap-
plied in excess, and the loading of the bromide-
functionalized resins can be determined conveniently
by elemental analysis. The methyl-2-bromoisobutyrate
functionalized resins for the Reformatsky reaction were
screened for their efficiency in the coupling with benzal-
dehyde. A first attempt with Wang resin 6 resulted in the
isolation of 24% of the desired product 13a (Table 2,
entry 1), but with the presence of a considerable amount
of unreacted bromide. Higher temperature and longer
reaction time led to complete reaction of the bromide
(Table 2, entry 2) at the cost of a lower absolute yield
of 11%. Application of MHBA resin 7 resulted in the
same trend (Table 2, entry 3), a low absolute yield of
12%, without complete consumption of the bromide.
These observations are in agreement with the previously
obtained results of the aldehyde-functionalized resins.
The apolarity of the polystyrene backbone seems to re-
duce the reactivity of the chromium reagent. Tentagel
S resin 8 offers the possibility to study this reaction in
the more polar, cation complexing environment of poly-
ethylene glycol side chains, with the reactive centre re-
mote from the polystyrene backbone. This resulted in
a complete conversion of the bromide, an increased yield
(35% over all steps, based on theoretical loading) and
high purity of the desired product (Table 2, entry 4).
Substitution of the bulk solvent DMF by THF did not
effect the reaction (Table 2, entry 5).
A longer distance to the polystyrene backbone appears
to be the key to higher yields in chromium-mediated
reactions on solid phase. Reaction of MHBA resins
9a–c with benzaldehyde resulted, after cleavage with tri-
fluoroacetic acid, in a mixture of alcohol and trifluoro-
acetate products (Scheme 3). The increased total yields
Table 2. Chromium-Reformatsky reaction of benzaldehyde with bromide-functionalized resins
O
O
OH
Ph
O
CrCl2, LiI
DMF
Cleavage
Br
Br
PhCHO
Resin
HX
HX
a: X = O
b: X = NH
6-8
13
14
Entry
Resin
T (°C)
t (h)
13
Purity (%)a,b
1
2
3
4
5
6c
6e
7f
8h
8h
20
60
20
40
40
1.50
3.00
1.50
13a
13a
13b
13a
13a
65d
100d
34g
100i
100i,j
17.0
17.0
a Purity of 13 related to 14.
b Low isolated yields are probably the result of low active loading or the volatility of debrominated 14.
c 6 (1.0equiv), PhCHO (5.6equiv) and CrCl2 (4.8equiv) in DMF.
d Cleavage performed with 60% trifluoroacetic acid in dichloromethane. Transesterification/cleavage did not succeed with catalytic NaOMe in
MeOH/THF.
e 6 (1.0equiv), PhCHO (3.9equiv), CrCl2 (3.9equiv) and LiI (1.0equiv) in DMF.
f 7 (1.0equiv), PhCHO (6.2equiv) and CrCl2 (5.2equiv) in DMF.
g Cleavage performed with 80% trifluoroacetic acid in dichloromethane. Transamidation/cleavage did not occur with n-butylamine.
h 8 (1.0equiv), PhCHO (8.0equiv), CrCl2 (9.8equiv) and LiI (1.12equiv) in DMF. Treated 8 with TMSCl/NEt3 to remove H2O.
i Cleavage performed with 1M-NaOH. Elemental analysis of 8 after Reformatsky reaction: 0% Br.
j Reaction performed in THF, THF/DMF mixture formed in a ratio of 3/1 to 4/1 as the CrCl2 was added as a DMF-solution.
Scheme 3. Takai–Utimoto reaction of benzaldehyde (5.0equiv) with resins 9 (1.0equiv), CrCl2 (6.0equiv), cyanocobalamine (0.1equiv) and LiI
(0.5equiv). Yields are based on theoretical loading and thus should only be considered in relative terms.

L. A. Wessjohann et al. / Tetrahedron Letters 45 (2004) 9073–9078
9077
(based on theoretical loading) of alcohol and trifluoro-
acetate products with an increased length of the ali-
phatic chain again indicate that the presence of the
polar solvent medium is crucial for high conversion
and purity (and higher yields).
applied washing procedure, with the exception of Tenta-
gel S. If removal of chromium occurs under cleavage
conditions, this resulted in considerably decreased yield
because of additional purification requirements.
Methyl-2,2-dimethyl-3-hydroxy-3-(4-formylphenyl)-prop-
1
Chromium-Reformatsky and chromium-homoaldol
reactions performed on solid phase are severely effected
by polymer backbone, spacer and linker type. The reac-
tivity generally depends very much on the polarity and
complexation properties of the polymer and spacer.
Also, an electron poor linker is preferred. This is inde-
pendent of the substrate directionality, that is, from
the bromide or aldehyde functionality being attached
to the solid support. Three possible reasons may explain
this effect. First, penetration of the chromium reagent
into the resin may be the problem. Second, chromium-
mediated reactions do not work in apolar solvents like
toluene or even in polar solvents mixed with toluene,
whereby toluene is a good mimic for the Merrifield resin
environment. Third, chromium complexes and reactions
are extremely sensitive to steric effects, and thus may be
effected by substrates close to the backbone. The pres-
ence of the very lipophilic polystyrene backbone,
together with an eventual loss of coordinating polar
solvent molecules after penetration into the solid phase
may cause the reduced reactivity. Application of a solu-
ble linear polystyrene supported aldehyde (5) in the
chromium-Reformatsky reaction released the steric
strain and allowed somewhat more influence of polar
solvent, and solved the reactivity problem. The insolu-
bility of the soluble polystyrene resin after reaction,
however, constitutes a severe disadvantage with respect
to its application in an iterative polyol strategy.
ionate (10a): H NMR (300MHz): d 9.93 (s, 1H), 7.77
(d, J = 7.9, 2H), 7.39 (d, J = 7.9, 2H), 4.89 (s, 1H),
3.63 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H).
Methyl-2,2-dimethyl-3-(4-hydroxyphenyl)-propionate
(10b): 1H NMR (300MHz): d 7.12 (d, J = 8.7, 2H), 6.82
(d, J = 8.7, 2H), 4.41 (s, 1H), 3.72 (s, 3H), 1.11 (s, 3H),
1.01 (s, 3H).
Methyl-2,2-dimethyl-3-hydroxy-3-(4-hydroxymethylphen-
yl)-propionate (10c): H NMR (250MHz): d 7.40–7.10
(m, 5H), 4.9 (s, 1H), 4.8 (s, 2H), 3.7 (s, 3H), 1.1 (s, 6H).
1
4-[4-(Hydroxymethyl)phenyl]-butyrolactone (12): 1H
NMR (250MHz): d 7.5–7.2 (m, 4H), 5.6–5.5 (m, 1H),
4.75 (s, 2H), 2.8–2.6 (m, 3H), 2.3–2.1 (m, 1H).
2,2-Dimethyl-3-hydroxy-3-phenyl propionic acid (13a):
1H NMR (250MHz): d 7.40–7.30 (m, 5H), 4.91 (s,
1H), 4.60 (br, 1H), 1.17 (s, 3H), 1.15 (s, 3H).
2,2-Dimethyl-3-hydroxy-3-phenylpropionamide (13b):
MS-ESI (positive), m/z (%): 194(22) [M+H] , 211 (29)
+
[M+NH4]+.
4-Hydroxy-4-phenyl-butanamide (15a): 1H NMR
(250MHz): d 7.5–7.3 (m, 5H), 5.52 (t, J = 8, 1H), 2.8-
2.6 (m, 3H), 2.3–2.1 (m, 1H).
Separation of the polystyrene backbone and the bro-
mide functionality by a polar polyethylene glycol spacer
(8), or an apolar aliphatic spacer (9c), resulted in both
cases in an increased yield, and a completely converted
bromide substrate. These first results will be used for a
further development of chromium-mediated reactions
on solid support, and optimized reaction conditions will
be used to introduce the enantioselective chromium-Ref-
ormatsky reaction on solid phase. The future focus will
be on the application of novel polar resins and easily
cleavable linkers to bring this method to a level at which
it can be applied in an iterative polyol strategy.29
9-Hydroxy-9-phenyl-nonaamide (15b): 1H NMR
(250MHz): d 7.4–7.2 (m, 5H), 4.85 (t, J = 9, 1H), 2.20
(t, J = 8, 2H), 2.1–1.6 (m, 4H), 1.4–1.1 (m, 8H).
12-Hydroxy-12-phenyl-dodecanamide (15c): 1H NMR
(250MHz): d 7.4–7.2 (m, 5H), 5.9 (br, 1H), 5.7 (br,
1H), 4.67 (t, J = 8, 1H), 2.24(t, J = 8, 2H), 1.8–1.5 (m,
4H), 1.5–1.2 (m, 14H).
Acknowledgements
The authors wish to thank Dr. Alexander Chucholowski
from F. Hoffmann-La Roche A. G. (Basel) for the
opportunity to perform part this research in his group.
H.S. was supported by the state of Saxony-Anhalt
(HWP).
General reaction procedure for the chromium-mediated
reactions with a resin supported substrate: All reactions
were carried out under an argon atmosphere in flame-
dried glassware using standard syringe, septa and glove-
box techniques. Absolute solvent (10mL/g resin) was
added to the resin, followed by benzaldehyde or bro-
mide. The required quantities of CrCl2, LiI and cya-
nocobalamine were dissolved in DMF (1mL/g CrCl2)
and added to the resin. This mixture was shaked at the
temperature and time mentioned in the article. The resin
was filtered, and washed several times with DMF,
DMF/H2O, THF/H2O and THF. Standard reaction
conditions were used for each linker type to cleave the
products from the resins. A general problem was the re-
moval of chromium residues from the resin under the
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