Chromophore-supported purification in parallel synthesis

Article abstract of DOI:10.1002/ejoc.200500900

The requirement for chromatographic separation and purification of product mixtures of greater or lesser degrees of complexity slows down every synthesis and is especially unfavorable when a series of parallel reactions is carried out in order to produce

Full text of DOI:10.1002/ejoc.200500900

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200500900
Chromophore-Supported Purification in Parallel Synthesis
Ingo Aumüller[a] and Thisbe K. Lindhorst*[b]
Keywords: Separation techniques / Chromatography / Color marker / Parallel synthesis / 1,3-Dipolar cycloaddition / Carbo-
hydrates
The requirement for chromatographic separation and purifi-
cation of product mixtures of greater or lesser degrees of
complexity slows down every synthesis and is especially un-
favorable when a series of parallel reactions is carried out in
order to produce a library of structurally diverse compounds.
To speed up chromatography, we have employed guaj-
azulene derivatives to “dye” the starting material of a given
reaction. The blue color of the chromophore-marked reaction
products facilitates visual inspection of the separation pro-
cess during column chromatography, allowing many columns
to be carried out in parallel. In addition to their function as
color markers, the employed blue guajazulene derivatives
can also be used as protecting groups during the synthesis.
We have named this methodology “chromophore-supported
purification” (CSP) and have demonstrated its value in two
parallel syntheses: in parallel acylations of the 6-position of
a chromophore-marked mannoside on the one hand, and in
the employment of CSP for workup after parallel 1,3-dipolar
cycloadditions between guajazulene-marked alkynes and
sugar azides on the other.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
ture is intended, and especially when this requires chroma-
tographic steps, the separation and purification of products
and byproducts can become the bottleneck of a synthesis.
The development of carbohydrate ligands for carbo-
hydrate-binding proteins is typically affected by the de-
scribed problems, and so we sought for a method to facili-
tate workup of carbohydrates and to speed up the chroma-
tographic separation and purification of a product mixture
without any requirement for optimized reaction conditions.
We decided to tag the starting material with a suitable color
marker molecule to allow a “chromophore-supported puri-
fication” (“CSP”). As chromatographic purification of a
product mixture is essential for many reactions and com-
pound classes, especially in the areas of natural products
and bioactive compounds, CSP should be of broad advan-
tage in organic chemistry, once an appropriate color label
is found.
Introduction
In the era of combinatorial chemistry, parallel synthesis
has become an important methodology in drug research. It
is often used for the synthesis of small, focused libraries, in
which the structural diversity of a given ligand, agonist or
antagonist, is systematically varied to optimize its biochem-
ical properties.[1] Time is a critical parameter for an effective
parallel synthesis, in which each compound is prepared in
an individual well and has to be purified individually. The
parallel execution of reactions is thus not the only require-
ment for rapid production of compound libraries, workup
procedures also have to be simplified to be less time-con-
suming. This has stimulated the search for alternative stra-
tegies for workup and purification,[2] including fluorous
tagging[3] and the use of solid supports.[4] Solid-phase syn-
thesis has solved some of the separation problems, but is
associated with a number of other problems, most notably
the need for suitable linker units and limitation to certain
reactions and reaction conditions. Separation of side prod-
ucts remains a notorious problem in solid-phase synthesis,
which therefore depends on careful optimization of reaction
conditions and yields. Once the analysis of a product mix-
Results and Discussion
We selected azulenes as our color tags for CSP as they
are stable enough to be introduced into a large number of
starting materials and to survive a variety of reaction condi-
tions. Furthermore, their derivatives are well suited for ad-
sorption chromatography, thanks to their good lipophilicity.
We started with guajazulene (1), an inexpensive azulene de-
rivative, which was converted into the carboxylic acid 3 by
treatment with bromoacetic acid as described in the litera-
ture[5] and into the alcohol 4 by treatment with paraformal-
dehyde (Scheme 1). Both reactions start with the deproton-
ation of 1, to produce the resonance-stabilized guajazulene
anion 2.
[a] Viikki Drug Discovery Technology Center, Faculty of Phar-
macy, Viikki DDTC,
P. O. Box 56 (Viikinkaari 5 E), 00014 University of Helsinki,
Finland
[b] Otto Diels Institute of Organic Chemistry, Christiana Albertina
University of Kiel,
24098 Kiel, Germany
Fax: +49-431-880-7410
E-mail: tklind@oc.uni-kiel.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2006, 1103–1108
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1103

I. Aumüller, T. K. Lindhorst
SHORT COMMUNICATION
Scheme 1. a) LDA, diethyl ether, –35 °C, 40 min. b) BrAcOH, –35 °C (10 min), then 2 h room temp., 37% (61% based on conversion).
c) (CH2O)n, –35 °C (10 min), then room temp. overnight, 32% (46% based on conversion).
The guajazulene derivatives 3 and 4 are both deep blue a DBU-catalyzed reaction to deliver the blue ester 8. Thi-
in color, which is typical for azulenes and qualifies both olysis of the diacetal protecting group with dimercaptopro-
compounds as markers for CSP. Their potential was evalu- pane (DMP) gave the azido-functionalized diol 9, the sub-
ated in the context of two parallel synthetic sequences, both strate for the subsequent parallel syntheses, in which ten
aimed at the structural variation of mannose ligands to in- commercially available carboxylic acid anhydrides carrying
crease their affinity for mannose-specific lectins.[6]
alkyl, alkenyl, or aryl residues (Scheme 3) were used to
The first synthetic sequence started with the 6-azido-6- modify the 6-position of the α-mannoside. Trimethylphos-
deoxymannoside 5,[7] which can be obtained from mannose phane was employed in these reactions, causing activation
in three steps. The terminal azido function is needed for the both of the OH groups in the 3- and 4-positions and of the
regioselective modification of the 6-position of the sugar azide group in the 6-position of the sugar ring. Accordingly,
ring with so-called “enhancer moieties” in order to investi- these reactions afforded mixtures of products, consisting of
gate and improve interaction with carbohydrate-binding the di-O-acylated N-acylamides 10a–19a, the corresponding
proteins.[8] Treatment with diacetyl in methanol gave the di-O-acylated N,N-diacylamides 10b–19b, and the mono-O-
3,4-O-protected mannoside 6, ready for the introduction of acylated N-acylamides 10c–19c (Scheme 3).
the guajazulene chromophore in the 2-position. The guaj-
For the evaluation of the CSP methodology with this
azulene derivative 3 was first converted into its imidazolide small library of mannosides it was less important to opti-
7 with the aid of 1,1Ј-carbonyldiimidazole (CDI) in DMF mize the Staudinger-type reaction with 9 than it was to de-
(Scheme 2), and this was then treated with the alcohol 6 in termine whether CSP would allow rapid parallel purifica-
Scheme 2. a) 1. Butane-2,3-dione, HC(OMe)3, BF3 etherate, MeOH, room temp., 20 h. b) CDI, DMF, room temp., 1 h. c) DBU, DMF,
0 °C, overnight, 46% starting with 5. d) DMP, H[BF4], dichloromethane, room temp., 2 h, 78%.
1104
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Chromophore-Supported Purification in Parallel Synthesis
SHORT COMMUNICATION
Scheme 3. a) P(Me)3, (RCO)2O, THF, room temp., overnight. b) NaOMe, MeOH, room temp., 1 h.
tion of the product mixtures without further optimization chemical outcome of the reaction affording the differently
attempts. Thus, after the acylation reactions with 9 were O-acylated products 10c–19c, was not determined by mass
complete, the solvent was removed in vacuo and the ob- spectrometry and is of minor interest with regard to the
tained product mixtures were subjected to parallel column eventual deacylation step to provided the deprotected prod-
chromatography. During column chromatography the sepa- ucts of the d-series. Table 1 shows that in most cases the
ration of products and byproducts could be followed by vis- triacylated mannosides of the a-series (10a–19a) were the
ible inspection, and collection of the colored fractions was predominantly formed products of the acylation reaction
easily accomplished with ten columns running in parallel. with the mannoside 9, whilst the N,N-diacylated derivative
The collected fractions were examined by MALDI-TOF (b-series; Scheme 3) never constituted the major product.
mass spectrometry, revealing an additional advantage of the
O-Deprotection of the products of the a- and c-series as
guajazulene label: all guajazulene-conjugated compounds described by Zemplén[9] also removed the chromophore in
were amenable to laser desorption without an additional the 2-position to yield the unprotected amides 10d–19d,
matrix, giving very clean mass spectra reflecting only the which could be unequivocally characterized by NMR spec-
molecular peaks.
troscopy (see Supporting Information).
The results of mass spectrometric analysis of the reaction
In addition to the conversion of the chromophore-
products are summarized in Table 1. Naturally, the regio- marked mannoside 9, we have also tested the value of CSP
Table 1. Results of the parallel acylations of mannoside 9 with ten different carboxylic acid anhydrides in the acylation entries 10 to 19
(cf. Scheme 3). O-Deprotection of the products of the a- and c-series gave amides of type d (10d to 19d).
Acylation
entry
Major product Mcalcd.
(% yield)
Side product Deprotected product MALDI-TOF-MS
MALDI-TOF-MS
Mcald.
(% yield)
(d-series), % yield
[M + Na]+
[M +K]+
10
11
12
13
14
15
16
17
18
19
a (60)
a (70)
a (61)
a (54)
2× c (47)
a (49)
c (54)
a (77)
a (46)
a (53)
599.31
641.36
683.40
641.36
599.35
683.40
627.38
683.40
677.36
833.34
–
95
94
85
80
88
79
88
78
272.1
286.0
300.1
286.1
300.1
300.1
314.1
300.1
298.1
350.0
288.1
302.0
316.0
302.1
316.0
316.0
330.0
316.0
314.0
365.9
249.12
263.14
277.15
263.14
277.15
277.15
291.17
277.15
275.14
327.13
b (12)
–
b (13)
a (10)
c (27)
a (20)
b (8)
c (21)
–
97
quant.
Eur. J. Org. Chem. 2006, 1103–1108
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I. Aumüller, T. K. Lindhorst
SHORT COMMUNICATION
Scheme 4. a) 7 (freshly prepared), DBU, 5 h, 94%. b) 1. DCC, diethyl ether, 0 °C, 0.5 h, 2. 4, TEA, 0 °C, 71%. c) 4, DCC, DMAP, THF,
–20 °C (4 h), then room temp., overnight, 47%.
in a series of parallel reactions in which 1,3-dipolar cycload-
ditions between azides and alkynes have been employed for
the introduction of molecular diversity in carbohydrate de-
rivatives.[10] The alkyne component was chromophore-lab-
eled either with the carboxylic acid derivative 3 or with the
guajazulene alcohol 4. Thus, the propargylic ester 20 was
obtained with 3 in a CDI-mediated reaction, as described
for the synthesis of 8, while the alcohol 4 was used together
with DCC as the coupling reagent for the preparation of
the color-labeled alkynes 21 und 22 (Scheme 4). As azide
components for the cycloaddition reaction the mannose de-
Scheme 5. 1,3-Dipolar cycloadditions between sugar azides and
rivatives 23,[11] 24,[11] and 25,[12] and the GlcNAc derivative
guajazulene-marked alkynes. a) 70 °C, 3–10 d. G = guajazulene
26[13] were selected and prepared by known literature pro-
chromophore; x = molecular moiety linking the chromophore to
cedures.
the alkyne (cf. Scheme 4).
The guajazulene-protected alkynes 20, 21, and 22 were
combined with the sugar azides 23–26 in 12 parallel reac-
Out of the 24 theoretically possible products of the 12
tions, to yield two regioisomeric triazoles in each case; parallel syntheses carried out, 22 were obtained after se-
these were named 4-G and 5-G, corresponding to the veral days’ reaction time. The azide 23 and alkyne 21 did
position of the guajazulene moiety in the five-membered not undergo the expected reaction.
triazole ring (Scheme 5). Again, our goal was not to im-
The parallel chromophore-supported separation of 11 re-
prove the regioselectivity of this reaction,[14] but we in- gioisomeric mixtures thus became the key step of this series
tended rather to test whether CSP would allow the sepa- of reactions. In eight cases, separation of the regioisomeric
ration of the regioisomeric products of this cycloaddition products was visible on the column and fractioning of the
reaction.
products was easy. Cycloaddition products arising from the
Table 2. Twelve parallel 1,3-dipolar cycloadditions were carried out with the carbohydrate azides 23, 24, 25, and 26 and the guajazulene-
marked alkynes 20, 21, and 22 (cf. Scheme 4 and Scheme 5), forming two regioisomeric products in each reaction (the protected 4-G and
the 5-G isomers, listed with their isolated yields after chromatography). If not otherwise indicated, the purities of the products were
1
assumed to be Ͼ95% on the basis of their clean H NMR spectra.
23
24
25
26
20
21
22
4-G isomer: 63%
5-G isomer: 8%
4-G isomer: –
5-G isomer: –
4-G isomer: 78%
5-G isomer: 5%
4-G isomer: 44%
5-G isomer: 32%[a]
4-G isomer: 9%[d]
5-G isomer: 10%
4-G isomer: 73%
5-G isomer: 14%[e]
4-G isomer: 40%
5-G isomer: 25%[b]
4-G isomer: 45%
5-G isomer: 41%
4-G isomer: 81%
5-G isomer: 17%
4-G isomer: 60%
5-G isomer: 31%[c]
4-G isomer: 41%
5-G isomer: 19%
4-G isomer: 67%
5-G isomer: 1%
1
1
[a] Purity according to the 1H NMR spectrum: 83%. [b] Purity according to the H NMR spectrum: 87%. [c] Purity according to the H
1
1
NMR spectrum: 91%. [d] Purity according to the H NMR spectrum: 92%. [e] Purity according to the H NMR spectrum: 88%.
1106 Eur. J. Org. Chem. 2006, 1103–1108
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Chromophore-Supported Purification in Parallel Synthesis
SHORT COMMUNICATION
12.6 mmol) was then added at –35 °C. After 10 min the mixture
was allowed to attain room temp., satd. aq. NaCl solution (300 mL)
and diethyl ether (300 mL) were added after 2 h, the phases were
separated, the organic phase was extracted with satd. aq. NaCl
solution (100 mL), and the combined aqueous phases were washed
with diethyl ether (3×, 100 mL). Diethyl ether was then carefully
layered over the aqueous phase and aq. hydrochloric acid (2 ) was
added until the blue product had been completely transported into
the organic phase. The organic phase was then washed neutral and
dried (Na2SO4), and the solvent was removed in vacuo after fil-
combinations 20/24, 20/25, and 22/26 had to be separated
by repeated column chromatography. Table 2 summarizes
the yields of the 12 parallel cycloaddition reactions carried
out. The purities of the separated products were assumed
1
to be greater than 95% from their clean H NMR spectra.
Twenty triazoles were thus obtained in significant yields
and subjected to deprotection under Zemplén conditions,[9]
which removed the sugar protecting groups together with
the guajazulene chromophore. The structures of the depro-
tected triazoles were unequivocally assigned by MALDI- tration. Chromatographic purification (toluene/ethyl acetate, 3:1)
afforded the title compound (2.40 g, 9.34 mmol, 37%), in the form
of blue crystals. m.p. 138 °C. H NMR (300.13 MHz, CDCl3): δ =
TOF mass spectrometry and NMR spectroscopy, in par-
ticular by NOESY und HMBC NMR experiments (see
Supporting Information).
1
8.14 (d, J6,8 = 2.0 Hz, 1 H, 8-H), 7.66 (dq, J2,3 = 3.8 Hz, 1 H, 2-
H), 7.43 (dd, J5,6 = 10.6 Hz, J2,Me = 0.6 Hz, 1 H, 6-H), 7.29 (d, 1
H, 3-H), 7.03 (d, 1 H, 5-H), 3.49 (mc, 2 H, CH2CH2COOH), 3.08
[sept, 1 H, (CH3)2CH], 2.90 (mc, 2 H, CH2COOH), 2.67 (d, 3 H,
aryl-CH3), 1.36 [d, Jisopropyl = 6.9 Hz, 6 H, CH(CH3)2] ppm. 13C
NMR (75.47 MHz, CDCl3): δ = 179.4 (COOH), 146.0 (C-4), 140.5
(C-7), 136.8 (C-2), 136.5 (C-8a), 136.4 (C-3a), 135.3 (C-6), 133.6
(C-8), 125.6 (C-1), 124.2 (C-5), 112.1 (C-3), 38.3 [CH(CH3)2], 35.3
(CH2COOH), 32.9 (CH2CH2COOH), 24.7 [CH(CH3)2], 12.9 (aryl-
CH3) ppm. IR (KBr): 3093–2507 (COOH), 2962, 2926, 2866
(CHaliph), 1701 (C=O) cm–1. HR-MS: m/z = 256.14630 (m/z =
256.14633 calcd. for C17H20O2).
Conclusions
In conclusion, it has been shown that a methodology in
which reaction partners are marked with a suitable chromo-
phore moiety allows parallel separation and purification of
products and byproducts during column chromatography.
Column chromatography of colored products is greatly fa-
cilitated in comparison to the separation of a colorless
product mixture as the separation can be visually inspected.
This chromophore-supported purification (CSP) was shown
to be efficient in the acylation of mannoside 9, in which ten
4-(2-Hydroxyethyl)-7-isopropyl-1-methylazulene (4): A solution of
LDA (12.6 mL, 25.2 mmol) in cyclohexane/ethylbenzene/THF was
diluted with dry diethyl ether (60 mL) and cooled to –35 °C. A
columns were run in parallel, allowing the isolation of ten solution of guajazulene (5.00 g, 25.2 mmol) in dry diethyl ether
(15 mL) was added dropwise under argon. The mixture was stirred
for 40 min, and paraformaldehyde (756 mg, 25.2 mmol formalde-
hyde) was then added. After 10 min the cooling was removed and
the reaction mixture was stirred overnight at room temp. Diethyl
ether (100 mL) was added and the system was washed three times
with satd. aq. NaCl. The organic phase was dried (Na2SO4), fil-
tered, and concentrated, and the residue was purified by flash col-
umn chromatography (toluene/ethyl acetate, 6:1) to yield the title
compound (1.53 g, 7.74 mmol, 32%) as a blue oil. 1H NMR
(300.13 MHz, CDCl3): δ = 8.20 (d, J6,8 = 2.1 Hz, 1 H, 8-H), 7.65
major products and seven side products in less than one
day. In a second example, CSP was successfully employed
for the parallel purification of 11 reaction mixtures, al-
lowing the separation of 22 chemically very similar re-
gioisomeric products of 1,3-dipolar cycloaddition reactions
during a single day.
CSP requires an additional synthetic step for the intro-
duction of the color marker, but the chromophores used for
CSP can also be regarded and utilized as protecting groups
and thus offer an additional advantage. CSP requires no (dq Ϸ dd, J2,3 = 3.8 Hz, J2,Me = 0.6 Hz, 1 H, 2-H), 7.43 (dd, J5,6
= 10.7 Hz, 1 H, 6-H), 7.30 (d, 1 H, H-3), 7.02 (d, 1 H, 5-H), 4.04
(t, Ja,b = 6.5 Hz, 2 H, CH2OH), 3.38 (t, 2 H, CH2CH2OH), 3.07
[sept, Jisopropyl = 6.9 Hz, 1 H, CH(CH3)2], 2.67 (d, 3 H, aryl-CH3),
1.36 [d, 6 H, CH(CH3)2] ppm. 13C NMR (75.47 MHz, CDCl3): δ
= 144.3 (C-4), 140.2 (C-7), 137.6 (C-2), 136.7, 136.1 (C-3a, C-8a),
135.1 (C-6), 133.6 (C-8), 125.6 (C-1), 124.8 (C-5), 112.4 (C-3), 63.6
(CH2O), 41.3 (CH2CH2O), 38.3 [CH(CH3)2], 24.7 [CH(CH3)2], 12.9
(aryl-CH3) ppm. IR (film): 3346 (br.s, OH), 2958 (CHaliph) cm–1.
HRMS: m/z = 228.15120 (m/z = 228.15141 calcd. for C16H20O).
MALDI-TOF MS (no matrix required): m/z = 228.1 [M]+ (228.15
challenging know-how nor sophisticated equipment and, in
contrast to solid-phase synthesis, is compatible with reac-
tions that produce mixtures of regioisomers or dia-
stereomers. CSP facilitates reaction control and allows in-
process optimization of the synthesis. With CSP a parallel
synthesis approach might also become reasonable for a
number of reactions previously regarded as not suited for
parallel synthesis. CSP should be a feasible method to sup-
port purification of focused libraries of up to 100 com-
pounds. In addition, this method can be employed on a calcd. for C16H20O).
scale of up to several grams, which is rather unusual for
Supporting Information (see also the footnote on the first page of
solid-phase chemistry.
this article): The experimental procedures for the synthesis of the
guajazulene derivatives 20–22 and full NMR and MS analytical
data for all synthesized unprotected amides (cf. Scheme 3) and
glyco-triazoles (cf. Scheme 5) are provided.
Experimental Section
3-(7-Isopropyl-1-methylazulen-4-yl)propanoic Acid (3): A solution
of LDA (12.6 mL, 25.2 mmol) in cyclohexane/ethylbenzene/THF
was diluted with diethyl ether (60 mL) and cooled to –35 °C, and
a solution of guajazulene (5.00 g, 25.2 mmol) in dry diethyl ether
(15 mL) was then added dropwise under argon. The reaction mix-
ture was stirred for 40 min and bromoacetic acid (1.75 g,
Acknowledgments
This work was supported by the DFG (SFB 470) and the Fonds
of the German Chemical Industry (FCI). We are indepted to Dr.
Christian Wolff for extensive NMR experiments.
Eur. J. Org. Chem. 2006, 1103–1108
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Received: November 17, 2005
Published Online: January 19, 2006
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