Direct catalytic asymmetric synthesis of highly functionalized 2-methylchroman-2,4-diols via Barbas-list aldol reaction

Article abstract of DOI:10.1002/chem.200900066

A study was conducted to demonstrate the organocatalytic approach to the asymmetric synthesis of functionalized 2-methylchroman-2,4-diol products through 'Barbas-List aldol (BLA) reactions'. Investigations were conducted on the BLA reactions by screening

Full text of DOI:10.1002/chem.200900066

DOI: 10.1002/chem.200900066
Direct Catalytic Asymmetric Synthesis of Highly Functionalized
2-Methylchroman-2,4-diols via Barbas–List Aldol Reaction
Dhevalapally B. Ramachary* and Rajasekar Sakthidevi[a]
Chromanes and chromenes are an important class of het-
erocycles, which display a very large spectrum of biological
activities and are widely used as drug intermediates and in-
gredients in pharmaceuticals [see Eq. (1)].[1] As such, the de-
velopment of new and more general catalytic asymmetric
methods for their preparation is of significant interest.[2] In-
terestingly, to the best of our knowledge there is no report
on the direct catalytic asymmetric method for the synthesis
of functionalized 2-methylchroman-2,4-diols, which can
serve as good intermediates for the functionalized chro-
manes and chromenes. Herein, we reported for the first
time the organocatalytic approach to the asymmetric synthe-
sis of functionalized 2-methylchroman-2,4-diol products via
“Barbas–List aldol reactions”.[3]
triggered a burst of activity in the synthesis of a huge variety
of chiral pool of aldol products through biomimetic enamine
chemistry thus providing a high potential for the develop-
ment of cellular-type cascade reactions.[4]
The amino acid catalyzed aldol reaction of ketones/alde-
hydes 1 with functionalized 2-hydroxybenzaldehydes 2 has
not been described thus far although the resulting aldol
products 4 and 5 have a wide range of potential applications
in pharmaceutical chemistry [see Eq.(1) and (2)]; also, there
is no direct methodology available to date to prepare these
compounds by classical reaction strategies. We report herein
a metal-free, novel and green technology for the synthesis of
highly substituted 2-methylchroman-2,4-diols 5 using orga-
nocatalytic BLA reactions from commercially available 2-
hydroxybenzaldehydes 2, ke-
tones 1 and amines/amino acid
3 [Eq. (2)]. We describe the
existence of fast dynamic equi-
librium between 2-methylchro-
man-2,4-diols [lactol] 5 and 4-
hydroxy-4-(2-hydroxyphenyl)-
butan-2-one [d-hydroxyketone]
4 under the normal reaction
conditions.[5]
Recently Barbas, List and co-workers discovered the
novel technology of amino acid catalyzed intermolecular
aldol reactions of ketones/aldehydes with a variety of car-
bonyls to provide a general route to several diverse aldol
products in good yields with high enantioselectivity, which is
known as the Barbas–List aldol (BLA) reaction.[3] The
advent of amino acid catalyzed aldol reaction technology
Over the last few years, we have been interested in
amine/amino acid mediated multicatalysis reactions from
multiple components and multiple catalysts for the genera-
ꢀ
ꢀ
ꢀ
tion of highly functionalized molecules via C C, C H, C O
[6]
ꢀ
and C N bonds formation in one-pot reactions. During
our investigations of new reactive species for such multicata-
lytic processes, we decided to explore the potential ability of
2-hydroxybenzaldehydes 2 to participate in an amine/amino
acid catalyzed BLA reaction with acetone 1a. We expected
that the reaction of 2-hydroxybenzaldehyde 2a with in situ
generated enamine from acetone 1a would lead to 4-hy-
droxy-4-(2-hydroxyphenyl)butan-2-one (4aa). However,
aldol product 4aa was not only detected; instead product
4aa showed the existence of a fast dynamic equilibrium with
2-methylchroman-2,4-diol 5aa under standard reaction con-
ditions. This unexpected result represents a novel methodol-
[a] Prof. Dr. D. B. Ramachary, R. Sakthidevi
School of Chemistry, University of Hyderabad
Hyderabad 500046 (India)
Fax : (+91)40-23012460
E-mail: ramsc@uohyd.ernet.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900066: Experimental proce-
dures, X-ray crystal structures and analytical data for all new com-
pounds.
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Chem. Eur. J. 2009, 15, 4516 – 4522

COMMUNICATION
TFA (3b) and l-thiaproline
(3c) also catalyzed the BLA
reaction of 1a with 2a in NMP
at ꢀ10 or 258C to furnish 4aa/
5aa with moderate yields and
increased ee values compared
with 3a as shown in Table 1,
entries 6–7. Interestingly, reac-
tion of 2a with 14 equiv of 1a
and 20 mol% of trans-4-OH-l-
proline (3d) in NMP for 24 h
furnished a 1:1 ratio of (+)-
4aa/5aa in 70% yield with
77% ee; but the same reaction
ogy for the preparation of 2-methylchroman-2,4-diols and a
new reactivity for amino acid catalysts. Herein, we report
our results of these new BLA reactions.
under trans-4-OTBS-l-proline (3e) catalysis furnished 4aa/
5aa and byproduct 6aa with low results (50% yield/33% ee
and 40% yield, Table 1, entries 8–11). We also tested a
number of primary and secondary amines such as l-Trp-OH
(3 f), l-Ala-OH (3g), l-Val-OH (3h), l-aminophenylacetic
We started our original studies on the BLA reactions by
screening a number of known and novel organocatalysts for
the aldolization of 2-hydroxybenzaldehyde 2a by 14 to 28
equivalents of acetone 1a. A few representative results are
shown in Table 1. Interestingly, reaction of 2a with 28 equiv
of acetone 1a in DMF under 20 mol% of l-proline (3a) cat-
alysis furnished a 1:1 ratio of the aldol$lactol product 4aa/
5aa in 50% yield with only 17% ee and byproduct enone
6aa in 20% yield (Table 1, entry 1). The same reaction in
DMSO with 20 mol% of 3a also furnished a 1:1 ratio of al-
dol$lactol product 4aa/5aa in 50% yield with only 19% ee
and enone 6aa in 30% yield (Table 1, entry 2). Reaction of
2a with 28 equiv of 1a in N-methylpyrrolidone (NMP) with
20 mol% 3a furnished a 1:1 ratio of 4aa/5aa in 50% yield
with increased an (36%) ee value and enone 6aa in 20%
yield (Table 1, entry 3). Reaction of 2a with 14 equiv of 1a
with 20 mol% d- 3a in NMP
acid (3i), l-ThrACHTUNTRGNEUNG(OtBu)-OH (3j), 4-benzyl-1-methylimidazoli-
dine-2-carboxylic acid (3k), l-DPP (3l) and l-DPPOTMS
(3m) as catalysts for the BLA reaction of 1a with 2a in
NMP or H2O though the conversion was very poor (results
not shown in Table 1). We envisioned the optimized condi-
tion as 258C in NMP using 20 mol% 3d to furnish highly
substituted 1:1 ratio of (+)-4aa/5aa in 70% yield with 77%
ee (Table 1, entry 8).
After successful demonstration of the asymmetric BLA
reaction of 1a with 2a under amino acid catalysis, we decid-
ed to investigate the amino acid catalyzed BLA reaction of
1a with the other functionalized 2-hydroxybenzaldehydes
2b–k in H2O to study the library generation of achiral 4/5 in
good yields and also to furnish the further support for the
for 38 h furnished the 1:1 ratio
Table 1. Reaction optimization for the BLA reaction of 1a, 2a and 3.
of 4aa/5aa in 60% yield with
decreased (11%) ee and by-
product 6aa in 20% yield
(Table 1, entry 4). Interestingly,
l-proline-catalyzed BLA reac-
tion of 1a with 2a in H2O fur-
nished the expected aldol$lac-
tol product 4aa/5aa in 50%
yield with 0% ee (Table 1,
entry 5).
Proline-catalyzed BLA reac-
tion of 1a with 2a is a solvent-
dependent reaction, which per-
forms well in aprotic and protic
polar solvents such as DMSO,
DMF, NMP, and H2O; however,
only <5% conversion was ob-
served in other solvents such as
CH3CN, CH2Cl2, CH3C6H5, and
[bmim]BF4 (results not shown).
Bifunctional catalyst (S)-1-(2-
pyrrolidinylmethyl)pyrrolidine·
Entry
Catalyst 3 [ 20 mol%]
Solvent [1.0m–0.25m]
t [h]
Product yield [%][a]
ee 4aa/5aa[b]
4aa/5aa
6aa
1[c]
2[c]
l-proline 3a
l-proline 3a
l-proline 3a
d-proline 3a
l-proline 3a
DMF
DMSO
NMP
NMP
H2O
NMP
NMP
NMP
DMSO
DMF
NMP
–
24
6
4
50
50
50
60
50
50
20
70
45
20
50
<5
20
30
20
20
5
30
2
2
10
6
40
–
17
19
36
11
0
50
69
77
50
63
33
–
3[c]
4[d]
38
24
48
24
24
17
23
12
72
5[d]
6[d,e]
7[d]
diamine·TFA 3b
l-thiaproline 3c
8[d]
trans-4-OH-l-proline 3d
trans-4-OH-l-proline 3d
trans-4-OH-l-proline 3d
trans-4-OTBS-l-proline 3e
trans-4-OH-l-proline 3d
9[d]
10[d]
11[d]
12[d]
[a] Yield refers to the column-purified product. [b] ee determined by CSP HPLC analysis. [c] Reactions were
carried out in solvent (0.25m) with 28 equiv of 1a relative to the 2a (0.5 mmol) in the presence of 20 mol% of
catalyst 3. [d] Reactions were carried out in solvent (1.0m) with 14 equiv of 1a relative to the 2a (0.5 mmol) in
the presence of 20 mol% of catalyst 3. [e] (S)-1-(2-Pyrrolidinylmethyl)pyrrolidine·TFA 3b and reaction was
carried out at ꢀ108C.
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D. B. Ramachary and R. Sakthidevi
existence of fast dynamic equilibrium between 4 and 5 as
shown in Table 2. The results in Table 2 give strong support
to the existence of rapid equilibrium between aldol 4 and
lactol 5 products in solution and also provide the best
method to synthesize racemic 4/5 in good yields. Rapid equi-
librium between aldol 4 and lactol 5 products in solution
was confirmed by NMR analysis on 4ad/5ad and also finally
confirmed by X-ray structure analysis (see next section).
1H NMR analysis on 4ad/5ad in CDCl3 at different temper-
atures (50, 25, 0, ꢀ15, ꢀ30, and ꢀ458C) and also in CDCl3 +
D2O at 258C indicate that the resulting compound is bearing
four OH groups, that is, two secondary, one tertiary and one
phenolic OH. Interestingly, equilibrium between aldol 4 and
lactol 5 products were controlled by electronic factors as
shown in Table 2 (entries 3 and 9). Reaction of 2-hydroxy-
naphthalene-1-carbaldehyde (2c) with acetone 1a under
ee (Table 3, entry 12). Equilibrium between aldol 4 and
lactol 5 of BLA products 4aa–ak/5aa–ak was confirmed by
NMR analysis and also finally confirmed by X-ray structure
analysis on (+)-5ag and (+)-4ai as shown in Figures S1 and
S2 (see Supporting Information).[7]
After successful demonstration of the trans-4-OH-l-pro-
line-catalyzed asymmetric BLA reactions of 1 with 2, we de-
cided to explore the utilization of the aldol$lactol isomeri-
zation in the synthesis of functionalized molecules via acid/
base catalysis in a one-pot reaction as shown in Equations
(3–4). BLA reaction of 1a with 2a under 3d catalysis at
258C in NMP furnished (+)-4aa/5aa in 70% yield with
77% ee, which upon treatment with p-TsCl and Et3N in a
one-pot reaction furnished the selectively tosylated product
(+)-7aa in 50% yield with 77% ee as shown in Equa-
tion (3). In a similar manner, treatment of reaction inter-
proline
catalysis
furnished
lactol 5ac as the major product
and 2-hydroxy-5-nitrobenzalde-
hyde (2i) with acetone 1a
under proline catalysis pro-
duced aldol 4ai as the major
product (Table 2, entries 3 and
9).
Table 2. Synthesis of achiral aldol$lactol products 4/5.[a]
Entry
2-Hydroxybenzaldehydes 2
Products [4/5]
4aa/5aa
Ratio[b] [4/5]
Products yield [%][c]
With the optimized reaction
conditions in hand, the scope of
the amino acid catalyzed asym-
metric BLA reactions was in-
vestigated. A series of substitut-
ed 2-hydroxybenzaldehydes 2a–
k was reacted with 14 equiva-
lents of 1a catalyzed by
20 mol% 3d at 258C in NMP
(Table 3). Neutral, electron-
withdrawing and electron-do-
nating compounds generated
the expected BLA products 4/5
with excellent yields and ee
values (Table 3). BLA reaction
byproducts 6aa–ad were ob-
tained in very poor yields and
6ae–ak were not observed. Fas-
cinatingly, reaction of 2-hydrox-
ynaphthalene-1-carbaldehyde
(2c) with acetone 1a and 3d
furnished lactol (ꢀ)-5ac as the
major product, but unfortunate-
ly only 26% ee were observed
(Table 3, entry 3). Interestingly,
BLA reaction of 2-hydroxy-5-
nitrobenzaldehyde (2i) with 1a
and 3d furnished aldol (+)-4ai
as major product with 85%
yield and 52% ee (Table 3,
entry 9). A deuterated 1:1 ratio
of chiral (+)-4bg/5bg was fur-
4/5
6
1
2
1:1
1:1
50
5
4ab/5ab
56
50
4
5
3
4ac/5ac
1:99
4
5
6
7
8
9
4ad/5ad
4ae/5ae
4af/5af
4ag/5ag
4ah/5ah
4ai/5ai
1:1
1:1
65
85
65
70
70
85
–
-
1:1
3
2
2
–
1:1
1:1
99:1
10
11
4aj/5aj
3:1
5:1
90
40
–
–
4ak/5ak
[a] Reactions were carried out in H2O (1.0m) with 14 equiv of 1a relative to the 2a–k (0.5 mmol) in the pres-
ence of 20 mol% of catalyst 3a. [b] Ratio is based on NMR analysis. [c] Yield refers to the column purified
nished in 50% yield with 86% product.
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Catalytic Asymmetric Synthesis
COMMUNICATION
Table 3. Synthesis of chiral aldol$lactol products 4/5.[a]
mediate (+)-4aa/5aa with p-
TSA in MeOH (a) at 258C in
a one-pot reaction furnished
selectively trans-2-methoxy-2-
methylchroman-4-ol
[(+)-
8aaa] in 55% yield with 77%
ee and >95% de as shown in
Equation (3).
With synthetic and pharma-
ceutical applications in mind,
we further extended the appli-
cation of acid-catalyzed lacto-
nization methodology to pure
isolated (+)-4ag/5ag with vari-
ous alcohols a–c, CH acids and
[d]
Entry
1[e]
2-Hydroxy-
benzaldehydes 2
Products [4/5]
4aa/5aa
Ratio[b] [4/5]
Yield [%][c] 4/5
ee 4/5
1:1
1:1
70
65
77
90
2[e]
4ab/5ab
3[e]
4ac/5ac
1:99
50
26
2,2-dimethoxypropane
as
shown in Equation (4). All ex-
pected 2-alkoxy-2-methylchro-
man-4-ols (+)-8aga–(+)–agc
were furnished in very good
yields with good de values
from the reaction of (+)-4ag/
5ag with methanol a, ethanol b
and allyl alcohol c under acid
catalysis [see Eq. (4)]. Acid-
catalyzed lactonization of al-
dol$lactol product (+)-4ag/
5ag is further applied in the
presence of CH acids like di-
medone and cyclohexane-1,3-
dione. Interestingly, reaction of
(+)-4ag/5ag with 2 equiv of
dimedone under p-TSA cataly-
sis in toluene at 1208C for 4–
6 h furnished the unexpected
tetracyclic product 9aga in
90% yield with <5% ee and
>99% de instead of simple
chiral addition product and
there is no reaction observed
at 258C. Generation of unex-
pected tetracyclic product from
acid catalysis on (+)-4ag/5ag
4[e]
4ad/5ad
4ae/5ae
4af/5af
4ag/5ag
4ah/5ah
4ai/5ai
1:1
1:1
65
65
65
70
70
85
89
87
88
86
87
52
5
6
1:1
7
1:1
8
1:1
9
99:1
10
4aj/5aj
3:1
90
86
11
4ak/5ak
4bg/5bg
5:1
1:1
40
50
75
86
12[f]
[a] Reactions were carried out in NMP (1.0m) with 14 equiv of 1a relative to the 2a–k (0.5 mmol) in the pres-
ence of 20 mol% of catalyst 3d. [b] Ratio is based on NMR analysis. [c] Yield refers to the column-purified
product. [d] ee determined by CSP HPLC analysis (see SI). [e] Byproducts 6aa–6ad was obtained in 5–10%
yields. [f] CD3COCD3 1b (14 equiv) was used and reaction time is 48 h.
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D. B. Ramachary and R. Sakthidevi
with CH acid was confirmed by one more example as shown
in Equation (4) and furnished 9agb in 85% yield with <5%
ee and >99% de. Structure and regiochemistry of cascade
products 9 were confirmed by X-ray structure analysis on
9aga (Figure S3, see Supporting Information).[7]
2,2-Dimethoxypropane is known to serve as a source of
methyl esterification, methylation, acetonation of acids and
alcohols, respectively,[8] and herein we utilized this reagent
for the acetonation of BLA product (+)-4ag/5ag. Interest-
ingly, reaction of (+)-4ag/5ag with 5 equiv of 2,2-dimeth-
oxypropane and 1.2 equiv of NMP under p-TSA catalysis in
acetone (0.5m) at 258C for 4 h furnished acetonation prod-
uct
(+)-10aga in 65% yield with 70% ee as shown in Equa-
tion (4). In this reaction, 17% of trans-2-methoxy-2-methyl-
chroman-4-ol [(+)-8aga] was isolated as byproduct with
50% de [see Eq. (4)]. The same reaction without NMP as
co-solvent furnished three products as trans-6-bromo-2,4-di-
methoxy-2-methylchroman [(+)-11aga] in 50% yield with
>99% de and 67% ee, trans-2-methoxy-2-methylchroman-
4-ol [(+)-8aga] in 25% yield with 80% de and acetonation
product (+)-10aga in 6% yield as shown in Equation (4).
The 2,2-disubstituted 2H-1-benzopyran structural unit [com-
pounds 8 and 11] is found in many natural products and de-
signed products which exhibit a wide range of biological ac-
tivities.[1q] This reaction is an ideal example for the trapping
of both forms of aldol 4 and lactol 5 from fast dynamic equi-
librium and utilization of 1.2 equiv of NMP as co-solvent is
crucial for the generation of acyclic product (+)-10aga in
good yield as shown in Equation (4) and Scheme 1. Unfortu-
nately the optical purity of products 8, 10 and 11 was de-
creased by 10–20% and products 9 were decreased by 80%
starting from 86% optical purity of (+)-4ag/5ag under acid
catalysis as shown in Equation (4).
The possible reaction mechanism for the synthesis of
functionalized compounds 8–11 through reaction of BLA
product (+)-4ag/5ag with alcohols, CH acids, and 2,2-dime-
thoxypropane under p-TSA catalysis is illustrated in
Scheme 1. In the first step, catalyst p-TSA selectively reacts
with (+)-4ag/5ag to generate substituted chroman oxonium
ion 12 via a dehydration reaction in the solvents such as al-
cohols, toluene and acetone (4/5!12). In the following
second step, in situ generated chroman ion 12 selectively
reacts with different nucleophiles as shown in Scheme 1.
Direct selective addition of variety of alcohols to chroman
ion 12 leads to the formation of compounds 8. In situ reac-
tion of 12 with p-TSA at 1208C in toluene generates racemic
6-bromo-2-methylbenzopyrylium tosylate (13), which upon
treatment with 1,3-diones at 1208C in toluene generates the
cyclic intermediates 15 via transition state 14, which upon
further treatment with p-TSA furnishes the expected prod-
ucts 9. Reaction of 12 with 2,2-dimethoxypropane generates
compounds 8 and methyloxonium ion via methoxy-transfer
reaction (see 16), which on further intermolecular methyl-
transfer reaction through 17 generates 11aga with high se-
lectivity. Interestingly, the reaction of (+)-4ag/5ag with p-
TSA in 2,2-dimethoxypropane and NMP as the co-solvent
gave different results than without NMP, so that we assume
that the 1:1 ratio of 4ag $ 5ag is shifted towards aldol com-
pound 4ag due to the basic nature of NMP and major
isomer diol 4ag is transformed into acetonation product
10aga via 18 as shown in Scheme 1. Minor isomer 5ag is
also transformed into compounds 8aga via 12!16!8aga
sequence as shown in Scheme 1.
In summary, we describe for the first time the synthesis of
the trans-4-OH-l-proline 3d catalyzed asymmetric BLA re-
action of acetone with 2-hydroxybenzaldehydes at ambient
conditions. The BLA reaction proceeds in good yields with
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Catalytic Asymmetric Synthesis
COMMUNICATION
Keywords: aldol reaction
·
amino acids · heterocycles ·
organocatalysis
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Experimental procedures, characterization data for new products, X-ray
crystal structures and complete details about the synthesis of new prod-
ucts are available in the Supporting Information.
Acknowledgements
This study was supported by the Department of Science and Technology
(DST), New Delhi. R.S. thanks Council of Scientific and Industrial Re-
search (CSIR), New Delhi for her research fellowship. We thank Prof.
M. V. Rajasekharan, Mr. A. R. Biju and Dr. P. Raghavaiah for their help
in the X-ray structural analysis.
Chem. Eur. J. 2009, 15, 4516 – 4522
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Received: January 11, 2009
Published online: March 23, 2009
4522
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Chem. Eur. J. 2009, 15, 4516 – 4522