Direct catalytic asymmetric synthesis of highly functionalized (2-ethynylphenyl)alcohols via Barbas-List aldol reaction: Scope and synthetic applications

Article abstract of DOI:10.1039/c2ob25563d

A high-yielding asymmetric synthesis of functionalized (2-ethynylphenyl) alcohols 5/6 with good diastereo- and enantioselectivities was achieved by Barbas-List aldol (BLA) reaction of 2-alkynylbenzaldehydes 1 with various ketones 2 in the presence of trans-4-OH-l-proline or l-prolinamide derivative 3/4 as catalyst at the ambient temperature or -35 °C. This method also gives first time access to the novel double aldol addition compounds 6, which are of medicinal importance. Chiral functionalized (2-ethynylphenyl)alcohols 5/6 were transformed into acyclic and cyclic 1,4-triazoles 8/9 and cis-1,3-diols 10 in good yields with high selectivity through double click-reaction and Lewis acid-mediated NaBH₄ reduction respectively. Chiral products 8-10 may become good ligands and inhibitors in medicinal chemistry.

Full text of DOI:10.1039/c2ob25563d

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PAPER
Direct catalytic asymmetric synthesis of highly functionalized
(2-ethynylphenyl)alcohols via Barbas–List aldol reaction:
scope and synthetic applications†‡
Dhevalapally B. Ramachary,* Rumpa Mondal and R. Madhavachary
Received 15th March 2012, Accepted 25th April 2012
DOI: 10.1039/c2ob25563d
A high-yielding asymmetric synthesis of functionalized (2-ethynylphenyl)alcohols 5/6 with
good diastereo- and enantioselectivities was achieved by Barbas–List aldol (BLA) reaction of
2-alkynylbenzaldehydes 1 with various ketones 2 in the presence of trans-4-OH-L-proline or
L-prolinamide derivative 3/4 as catalyst at the ambient temperature or −35 °C. This method also gives
first time access to the novel double aldol addition compounds 6, which are of medicinal importance.
Chiral functionalized (2-ethynylphenyl)alcohols 5/6 were transformed into acyclic and cyclic 1,4-triazoles
8/9 and cis-1,3-diols 10 in good yields with high selectivity through double click-reaction and Lewis
acid-mediated NaBH4 reduction respectively. Chiral products 8–10 may become good ligands and
inhibitors in medicinal chemistry.
or nucleophile. The scope of a large number of aliphatic and aro-
matic aldehydes has been explored so far as the acceptor in the
BLA reaction with both acyclic and cyclic ketone donors, pro-
viding aldol products with high diastereo- and enantioselec-
tivities using different organocatalysts.3 As expected, aromatic
aldehydes containing electron withdrawing groups at the ortho
or para position are “highly reactive” towards in situ generated
enamines and furnished the aldol adducts with high yields and
high selectivities. Whereas, the presence of electron donating
groups at the ortho or para position decreases both the reactivity
and selectivity. Moreover, the reactivity of the aldehydes, in
some instances, considerably affect the product ratio leading to
the formation of double aldol addition products along with
the mono aldol addition products from “highly-reactive” aro-
matic aldehydes.5 But high yielding asymmetric synthesis of
1,5-dihydroxy-pentan-3-one (double aldol addition) products
from “less-reactive” aromatic aldehydes are rare in organocatalysis.
As a matter of fact, aromatic aldehydes containing electron
donating or neutral ortho groups are much less explored in orga-
nocatalytic BLA reactions. It was envisaged that both the elec-
tronic and stereochemical properties of the group at the ortho
position of aromatic aldehyde play a crucial role as neighboring
group participation in the transition state of the organocatalytic
BLA reaction and therefore can significantly control the selectiv-
ity of the aldol products.3q Hence, aldol reactions of aromatic
aldehydes containing ortho groups could be an interesting
subject to study in organocatalysis.
Introduction
Although the potential of L-proline-catalyzed asymmetric intra-
molecular aldol reactions has been known since long back,1 the
pioneering discovery of L-proline-catalyzed direct intermolecular
asymmetric aldol reactions of aldehydes with acetone by Barbas
et al.,2 opened a new gateway for green asymmetric reactions.
Following this pioneering “Barbas–List aldol (BLA)” reaction,
the last decade has seen a tremendous development in the field
of “amine-/amino acid-catalyzed asymmetric aldol reactions”
both in terms of catalyst design as well as reaction engineering.3
A vast number of organocatalysts, mostly based on the L-proline
moiety has been synthesized and utilized under finely tuned
reaction conditions to provide aldol products with high selec-
tivities in both aqueous and organic media with broad range of
substrates.3 The transition state of the BLA reaction has been
studied extensively providing evidences for an enamine based
mechanism where hydrogen-bonding plays a key role to achieve
the high enantioselectivity.4
In BLA reactions, mainly an aldehyde acts as the acceptor or
the electrophile and ketone or another aldehyde acts as the donor
Catalysis Laboratory, School of Chemistry, University of Hyderabad,
Hyderabad-500 046, India. E-mail: ramsc@uohyd.ernet.in,
ramchary.db@gmail.com; Fax: +91-40-23012460
†This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
‡Electronic supplementary information (ESI) available: Experimental
procedures and analytical data (1H NMR, 13C NMR, HRMS and HPLC)
for all new compounds. CCDC 804553. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2ob25563d
As a part of ongoing research in our laboratory on organocata-
lytic asymmetric synthesis,6 the scope of 2-alkynylbenzalde-
hydes 1 as acceptor in organocatalytic BLA reaction with
5094 | Org. Biomol. Chem., 2012, 10, 5094–5101
This journal is © The Royal Society of Chemistry 2012

Table 1 Preliminary optimization of the BLA reaction of 1a with 2a
Scheme 1 Direct organocatalytic BLA reaction of 2-alkynylbenzalde-
hydes 1 with ketones 2 and their synthetic applications.
Catalyst Solvent
Entry 3/4
(0.125–0.3 M) Time (h) Yielda (%) ee 5aab (%)
1c
3a
3a
3a
3a
3b
3c
3d
3d
3d
3e
3d
3f
3g/4b
3h/4a
3i/4a
DMSO
DMF
NMP
1
2
2
24
24
30
24
19
24
7
84
87
85
35
25
75
85
87
83
82
74
<10
<10
60
61
60
65
68
59
71
85
73
67
74
66
71
—
—
54
−43
Fig. 1 Important compounds to study from the double BLA
products 6.
2c
3c
4c
CH3CN
DMSO
DMSO
DMSO
DMF
NMP
DMSO
DMSO
DMSO
DCM
—
5c
6c
various cyclic and acyclic ketones 2 was studied and the findings
are disclosed in the next section (Scheme 1). The expected BLA
adducts 5 were obtained with high yields and high ee and de’s,
as well as in some cases 1,5-dihydroxy-pentan-3-one (double
aldol addition) derivatives 6 were isolated as the major product
with >99% ee and >99% de. Therefore these studies also give an
insight into the highly enantioselective synthesis of 1,5-dihy-
droxy-pentan-3-one derivatives 6 from “less reactive” aromatic
aldehydes 1 through BLA reaction. These double aldol addition
products 6 can be utilized as chiral synthons for the analogues
synthesis of potent HIV-1 protease inhibitors A, B and natural
products diarylheptanoids C–F from the male flowers of Alnus
sieboldiana (Fig. 1).7
7c
8c
9c
10c
11d
12c
13e
14f
15f
9
24
72
2
—
3
a Yield refers to the column purified products. b Ee was determined
by CSP HPLC analysis. c Reactions were carried out in solvent
(0.125 M) with 34 equiv. of 2a relative to 1a (0.3 mmol) in the presence
of 20 mol% of catalyst 3. d Reaction was carried out in solvent (0.25 M)
with 14 equiv. of 2a relative to 1a (0.3 mmol) in the presence of
20 mol% of catalyst 3. e Reaction was carried out in DCM (0.3 M) with
28 equiv. of 2a relative to 1a (0.3 mmol) in the presence of each
10 mol% of catalyst 3g and co-catalyst 4b. f Reactions were carried out
in neat acetone (0.3 M) with each 10 mol% of catalyst 3h–i and co-
catalyst 4a.
Results and discussion
Structure–activity relationships of amino acid catalysts on
BLA reaction of 1a with 2a: reaction optimization. The study
was initiated by employing a number of known and novel orga-
nocatalysts on BLA reaction of 1a with 2a in variety of solvents
at 25 °C and L-proline 3a being the first choice as it is unequivo-
cally accepted as the universal asymmetric catalyst (Table 1).
It was observed that 20 mol% of L-proline 3a was able to cata-
lyze the reaction between 2-ethynylbenzaldehyde 1a and 34
equiv. of acetone 2a in DMSO at 25 °C to give the desired BLA
adduct 5aa in 84% yield with only 60% ee within 1 h (Table 1,
entry 1). The same BLA reaction of 1a with 2a under 20 mol%
of 3a catalysis at 25 °C for 2 h using DMF or NMP as solvent,
also gave similar results. In DMF, 5aa was furnished in 87%
yield with 65% ee while in NMP the yield and ee were 85% and
68% respectively (Table 1, entries 2 and 3). CH3CN proved to
be inferior as compared to other polar aprotic solvents in the
above reaction and afforded 5aa in only 35% yield with 59% ee
under similar reaction conditions even after longer reaction time
(Table 1, entry 4). Replacing the catalyst L-proline 3a with L-thia-
proline 3b (20 mol%) for the reaction of 1a with 2a in DMSO
for 24 h at 25 °C furnished 5aa in low yield albeit with 71% ee
(Table 1, entry 5). Interestingly, the same reaction using
the costly catalyst 5,5-dimethyl-thiazolidinium-4-carboxylate
(DMTC) 3c furnished the 5aa in 75% yield with 85% ee, signifi-
cantly better than L-proline 3a-catalysis (Table 1, entry 6). When
the BLA reaction of 1a with 34 equiv. of 2a was catalyzed by
20 mol% of trans-4-OH-L-proline 3d in DMSO at 25 °C, the
aforesaid product 5aa was isolated with 85% yield and 73% ee
(Table 1, entry 7). The BLA adduct 5aa was isolated with com-
parable yields and ee’s when reaction catalyzed by trans-4-OH-
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5094–5101 | 5095

L-proline 3d under similar reaction conditions in both DMF and
NMP solvents (Table 1, entries 8 and 9). Trans-4-OTBDMS-L-
proline 3e (20 mol%) also afforded the product 5aa in 82% yield
with only 66% ee in DMSO solvent within 7 h. When the
amount of acetone 6a was reduced from 34 equiv. to 14 equiv.,
then also the BLA adduct 5aa was obtained with an optical
purity of 71% but at the expense of yield (74%) under 3d cataly-
sis in DMSO (Table 1, entry 11). Use of O-tBu-L-threonine 3f as
a catalyst in the above BLA reaction in DMSO, did not appear
to be promising and furnished 5aa in only <10% yield even
after 24 h (entry 12).3l–n The bifunctional catalyst Q-NH2
3g/Ph2CHCO2H 4b also gave similar result in the above reaction
(Table 1, entry 13). After moderate to good selectivity with
L-proline based catalysts on BLA reaction of 1a with 2a, we
further showed interest to screen L-prolinamide catalysts as
shown in Table 1, entries 14–15.
Among the various L-prolinamide catalysts developed for
BLA reaction till date, the best results were achieved by
Yun-Dong Wu, Liu-Zhu Gong and V. K. Singh et al. by using a
small class of prolinamides 3h and 3i where the acidity and
strong hydrogen-bonding capacity of the catalysts 3h/3i guided
the selectivity.8 Inspired by these results, the catalyst 3h was
chosen for testing the BLA reaction of 2-ethynylbenzaldehyde
1a with acetone 2a under the neat conditions. Unexpectedly,
when 1a was treated with 2a (0.3 M) using 10 mol% 3h/4a as
catalyst at 25 °C, the BLA product 5aa was formed in only 60%
yield with 54% ee (Table 1, entry 14). The same reaction
under 10 mol% of 3i/4a-catalysis also furnished the BLA
product 5aa in 61% yield with reduced (43%) ee as shown in
Table 1, entry 15.
3h and co-catalyst 4a in neat acetone (0.3 M) at −35 °C for
24 h, the BLA adduct 5aa was furnished with an improved yield
(34%) and ee (93%) accompanied by 6aa in 38% yield with
>99% de and >99% ee (Table 2, entry 3). The catalyst 3i
(10 mol%) in combination with 4a (10 mol%) also catalyzed the
same reaction under identical reaction conditions to afford the
opposite enantiomers of 5aa and 6aa with high ee and de’s
albeit with less yields (Table 2, entry 4). The structure of the
double BLA product (R,R)-(+)-6aa was determined by NMR
analysis and the absolute configuration was confirmed by X-ray
structure analysis (Fig. 2).9 Therefore, two optimized reaction
conditions were finalized for the BLA reaction of 2-ethynylben-
zaldehyde 1a with acetone 2a. Method-B involved the usage
of 20 mol% of 3c or 3d as the catalyst at 25 °C in DMSO
(0.125 M) solvent, whereas in Method-A, the reaction was
carried out at −35 °C using each 10 mol% of the catalyst 3h or
3i and co-catalyst 4a in neat acetone 2a (0.3 m). The overall
structure–activity relationship garnered from the catalyst screen
on the asymmetric BLA reaction of 1a and 2a was similar to that
basic aldol reaction2 with optimal yield and enantioselectivity
being provided by proline-like catalysts.
Synthetic scope of L-DMTC, trans-4-OH-L-proline and
L-prolinamide catalyzed BLA reactions. With the optimized
reaction conditions in hand, the scope of other acyclic and cyclic
ketones 2b–h as donors in the BLA reaction with 1a and 1b was
explored and the results are summarized in Table 3. The reaction
of 2-ethynylbenzaldehyde 1a with 2-butanone 6b (0.3 M) cata-
lyzed by 3h/4a, each 10 mol% at −35 °C for 24 h furnished
only the mono aldol addition products 5ab and 5′ab in 3.1 : 1
ratio. Interestingly, even though double aldol addition product
was not observed in the above reaction, the regioselectivity,
BLA reaction of 1a with 2a under only 3h-catalysis furnished
the product 5aa with improved yield and ee at 25 °C for 6 h as
shown in Table 2, entry 1. Surprisingly, lowering the reaction
temperature from 25 °C to −35 °C, had a profound impact on
the outcome of the above reaction. We were pleased to find that
the reaction of 1a with 2a (0.3 M) catalyzed by 10 mol% of 3h
at −35 °C, not only furnished the expected BLA adduct 5aa in
moderate yield and ee but also furnished the double aldol
addition product 6aa in 44% yield with >99% de and >99% ee,
which is so far the highest optical purity obtained for the 1,5-
dihydroxy-pentan-3-one derivatives (Table 2, entry 2).5 When
the reaction was carried out using each 10 mol% of the catalyst
Fig. 2 Crystal structure of 1,5-bis-(2-ethynylphenyl)-1,5-dihydroxy-
pentan-3-one (6aa).
Table 2 General optimization of the BLA reaction of 1a with 2a
Yielda (%)
eeb (%)
deb (%)
Entry
Catalyst 3 (10 mol%)
Co-catalyst 4a (10 mol%)
Temp (°C)
Time (h)
5aa
6aa
5aa
6aa
6aa
1c
2c
3d
4d
3h
3h
3h
3i
—
—
4a
4a
25
6
68
20
34
16
—
44
38
30
65
65
93
−95
—
—
−35
−35
−35
28
24
24
>99
>99
>−99
>99
>99
>99
a Yield refers to the column-purified products. b ee and de was determined by CSP-HPLC analysis. c Reactions were carried out in neat acetone
(0.3 M) with 10 mol% of catalyst 3h. d Reactions were carried out in neat acetone (0.3 M) with each 10 mol% of catalysts 3h or 3i and co-catalyst 4a.
5096 | Org. Biomol. Chem., 2012, 10, 5094–5101
This journal is © The Royal Society of Chemistry 2012

Table 3 Direct BLA reaction of 2-ethynylbenzaldehydes 1a/1b with various acyclic and cyclic ketones 2b–h
eec(%)
anti
drb
anti : syn
Entry
1d
Ketone 2
Time (h)
24
Products (5/5′)
Yielda (%)
71 (23)e
syn
>99 : 1
1 : 1
99(>99)f
—
2d
3g
4d
5d
6d
30
24
24
60
24
61 (30)e
61
41(90)f
93
53
26
91
0
3 : 1
83
11.6 : 1
1 : 1.9
>99 : 1
96
72
95
80
96
—
7h
8g
24
72
85
90
>99 : 1
1.4 : 1
96
—
—
77(53)i
9d
24
24
83
73
8.2 : 1
1 : 1
93
0
6
0
10g
11j
72
24
40
92
>99 : 1
>99 : 1
88
86
—
—
12d
13h
24
85
>99 : 1
90
—
a Yield refers to the column-purified products. b dr was determined by NMR analysis on crude products. c ee was determined by CSP-HPLC analysis.
d Method-A: Reactions were carried out in neat ketone (0.3 M) with each 10 mol% of 3h and 4a at −35 °C. e Values in parentheses refer to the yields
f
of the minor regioisomers. Value in parentheses refers to the ee of the minor regioisomer. g Method-B: Reaction was carried out in DMSO (0.25 M)
in presence of 20 mol% of 3d at 25 °C. h Reaction performed with each 10 mol% of 3i/4a as catalyst. i Value in parentheses refers to the ee of the
minor diastereomer. j Reaction were carried out in THF (0.3 M) with each 10 mol% of 3h/4a at −35 °C.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5094–5101 | 5097

diastereoselectivity, yields and optical purities of the BLA pro-
ducts 5ab and 5′ab were excellent (Table 3, entry 1). Similarly,
hydroxyacetone 2c also reacted with 1a under identical reaction
conditions to afford the mono aldol addition products 5ac and 5′
ac in 30% and 61% yields respectively (Table 3, entry 2). Minor
BLA product 5ac furnished with 90% ee, but major product 5′ac
were in 1 : 1 isomeric mixture with moderate ee’s as shown in
Table 3, entry 2. Interestingly, same BLA reaction of 2c with 1a
under the catalysis of 3d (20 mol%) in DMSO at 25 °C for 24 h
furnished the selectively anti-5′ac and syn-5′ac in 61% yield
with 3 : 1 dr ratio and 93/26% ee respectively (Table 3, entry 3).
When 2-ethynylbenzaldehyde 1a was treated with neat
cyclohexanone 2d (0.3 M) in the presence of 10 mol% of 3h/4a
at −35 °C, the only mono BLA adduct 5ad was formed in 83%
yield with a diastereomeric ratio of 11.6 : 1 in favour of anti-5ad.
The ee’s of the BLA products anti-5ad and syn-5ad were 96%
and 91% respectively (Table 3, entry 4). In a similar manner,
cyclopentanone 2e (0.3 M) also reacted with 1a following
Method-A to afford the only mono BLA products anti-5ae and
syn-5ae in 72% yield with 1 : 1.9 dr respectively (Table 3, entry
5). Interestingly the optical purity of anti-5ae was 95% ee, but
syn-5ae was found to be almost racemic (Table 3, entry 5). Struc-
ture and regioselectivity of products 5 were obtained based
on the NMR analyses and also by correlation with previous
L-proline catalyzed BLA reactions.3
Scheme 2 Proposed pre-transition states for the ADS of 2f with 1a/1b
through BLA reaction.
Finally, the important concept of asymmetric desymmetriza-
tion (ADS) of 4-methylcyclohexanone 2f was studied using the
BLA reaction of 1a/1b with 2f following both Method-A and B
to furnish optically pure highly functionalized (2-ethynylphenyl)
alcohols 5af–bf. Surprisingly, neat reaction of 1a with 2f under
the catalysis of 3h/4a at −35 °C, led to the formation of the
single diastereomer (2S,4S,1′R)-5af in 80% yield with 96% ee
(Table 3, entry 6). Same neat reaction of 1a with 2f under the
catalysis of 3i/4a at −35 °C, led to the formation of the single
diastereomer of opposite enantiomer (2R,4R,1′S)-5af in 85%
yield with 96% ee (Table 3, entry 7). But when the same reaction
was carried out following Method-B, the diastereomers (2S,4R,1′R)-
5af and (2S,4S,1′R)-5af were formed in 1.4 : 1 ratio in 90% yield
with 77% and 53% ee’s respectively (Table 3, entry 8). In a
similar manner, neat reaction of 1a with tetrahydropyran-4-one
2g under the catalysis of 3h/4a at −35 °C, led to the formation
of the BLA products anti-5ag and syn-5ag in 83% yield with
8.2 : 1 dr and 93 and 6% ee’s respectively (Table 3, entry 9). But
surprisingly, same reaction through Method-B conditions furn-
ished the BLA products anti-5ag and syn-5ag in 73% yield with
1 : 1 dr and 0/0% ee respectively (Table 3, entry 10). In a further
support, BLA reaction of 1a with tetrahydrothiopyran-4-one 2h
under the catalysis of 3h/4a at −35 °C for 72 h in THF led to the
formation of the single diastereomer anti-5ah in 40% yield with
88% ee (Table 3, entry 11). Interestingly, BLA reaction of 2-phe-
nylethynyl-benzaldehyde 1b with 2f under the catalysis of 3h/4a
at −35 °C for 24 h furnished the single diastereomer (2S,4S,1′R)-
5bf in 92% yield with 86% ee (Table 3, entry 12). Same neat
reaction of 1b with 2f under the catalysis of 3i/4a at −35 °C for
24 h, led to the formation of the single diastereomer of opposite
enantiomer (2R,4R,1′S)-5bf in 85% yield with 90% ee (Table 3,
entry 13).
Scheme 3 Direct BLA reaction of 2-phenylethynylbenzaldehyde 1b
with acetone 2a.
assigned based on analogy with the literature reports.8,10 The
possible pre-transition states for the ADS of 4-methylcyclohexa-
none 2f with 1a/1b through enamine-based BLA reaction and
also for the structures of all possible stereoisomers of the BLA
adduct 5af under the simple L-proline catalysis are depicted in
Scheme 2.10 The most favorable pre-transition states for the
ADS of 2f with 1a/1b through 3/4-catalysis were re–re face
approach, in which formation of the enantiomer G is thermody-
namically stable as shown in Scheme 2.
After successful synthesis of the asymmetric mono BLA pro-
ducts 5ab–ah/5′ab–ah from 1a with various acyclic and cyclic
ketones 2a–h, we further showed interest to screen different sub-
stituted alkynylbenzaldehydes 1b–c as acceptors for the BLA
reaction with acetone 2a to check the formation of double BLA
products 6 as shown in Schemes 3 and 4. As expected, BLA
reaction of 2-phenylethynylbenzaldehyde 1b with 34 equiv. of
acetone 2a under 3d-catalysis at 25 °C for 27 h in DMSO furn-
ished the desired mono BLA product 5ba in 93% yield with
76% ee. Interestingly, the same reaction when catalyzed by each
10 mol% of the catalyst 3h/4a at −35 °C for 46 h under neat
condition (0.3 M) furnished the mono BLA adduct 5ba in only
13% yield with 66% ee, which is accompanied by 6% of the
double BLA product 6ba with >99% ee and >99% de as shown
in Scheme 3.
The absolute configuration of the ADS products (2S,4S,1′R)-
5af, (2R,4R,1′S)-5af, (2S,4S,1′R)-5bf and (2R,4R,1′S)-5bf were
5098 | Org. Biomol. Chem., 2012, 10, 5094–5101
This journal is © The Royal Society of Chemistry 2012

Table 4 Direct application of chiral BLA products 5aa/6aa in click
reactionsa
Entry
1
Product
Yieldb (%)
55
Scheme 4 Direct BLA reaction of dialdehyde 1c with acetone 2a.
The BLA reaction of the diyne-dialdehyde 1c with 34 equiv.
of acetone 2a catalyzed by 20 mol% of 3d at 25 °C for 5 h in
DMSO afforded the novel BLA products (R,R)-5ca and (R,S)-
5ca in 66% yield with 3.7 : 1 dr and 97% ee respectively. Inter-
estingly, when the same reaction was carried out under the cata-
lysis of 3h/4a at −35 °C for 24 h furnished the BLA products
(R,R)-5ca and (R,S)-5ca in 65% yield with 21 : 1 dr and >99%
ee respectively as shown in Scheme 4. Interestingly, in both reac-
tion conditions, optically inactive BLA product (R,S)-5ca furni-
shed as minor isomer. The structure of the BLA products (R,R)-
5ca and (R,S)-5ca was confirmed by NMR analysis and also by
high resolution mass spectral analysis.
2
3
55
65
4c
30
a See Experimental section. b Yield refers to the column purified product.
c Reaction performed with 2 equiv. of 7b in the presence of CuSO4
(1 equiv.) and Cu powder (5 mol%) in EtOH (0.15 M) at RT for 8 h.
Applications of chiral BLA products
Synthesis of functionalized chiral acyclic and cyclic 1,2,3-tri-
azole compounds 8–9 and syn-diols 10 based on the asymmetric
BLA platform. In order to explore the utility of the chiral BLA
products 5 and 6, we subjected them to simple reactions like
copper-catalyzed azide-alkyne cycloaddition (CuAAC) or click
and reduction protocol to furnish the highly functionalized mole-
cules 8–10 (Table 4 and Scheme 5). Fascinatingly, [Cu]-induced
click reaction on chiral product (+)-5aa (95% ee) with 1,2-bis-
(azidomethyl)benzene 7a in tBuOH + H2O for 8–12 h at 25 °C
resulted in the formation of double click product (+)-8aaa in
55% yield with 95% ee (Table 4, entry 1). The selective double
click strategy was demonstrated with two more substrates of
bis(azides) 7b and 7c with (+)-5aa (95% ee) to furnish the pro-
ducts (+)-8aab and (+)-8aac in 55% and 65% yields with 95%
ee respectively (Table 4, entries 2–3). Interestingly, [Cu]-induced
click reaction of chiral product (+)-6aa (99% ee) with 1,3-bis
(azidomethyl)benzene 7b in EtOH for 8 h at 25 °C furnished the
22-membered cyclic double click product (+)-9aab in 30% yield
without racemization (Table 4, entry 4). The acyclic and cyclic
chiral 1,2,3-triazole compounds 8–9 may become good candi-
dates to study in medicinal chemistry,11 which is highlighting the
importance of sequential BLA-double click approach to syn-
thesize these important compounds.
selective NaBH4 reduction of (+)-5aa as shown in Scheme 5.
The BLA adduct (+)-5aa was converted into the diol anti-10aa
as major product in 90% yield with 43% de by 2 equiv. of
NaBH4 in dry MeOH (0.25 M) at −5 °C within 0.5 h
(Scheme 5). Interestingly, the same reduction on (+)-5aa in the
presence of 1.1 equiv. of BEt2(OMe) as Lewis acid furnished the
diol syn-(−)-10aa as single product in 75% yield with 99% de
and 95% ee by 1.1 equiv. of NaBH4 in dry THF + MeOH (4 : 1,
0.2 M) at −78 °C for 4 h (Scheme 5). In a similar manner,
highly functionalized chiral syn-diols (1S,2S,4R,1′S)-10af and
(1R,2R,4S,1′R)-10bf were furnished in very good yields with
excellent ee and de’s from chiral BLA products (2R,4R,1′S)-5af
(96% ee) and (2S,4S,1′R)-5bf (86% ee) respectively as shown in
Scheme 5. Stereochemistry of the newly generated hydroxyl
group in the major diols 10aa–10bf from 5aa–5bf was tenta-
tively assigned as syn-selective based on the chelating action of
diethylmethoxyborane12 and cyclohexanone conformational
strain. Outcome of the high stereoselectivity from the simple
NaBH4 reduction on 5af and 5bf can be readily explained via
the approach of the hydride from the less crowded equatorial
side of the hydroxyl-ketone 5af/5bf. These chiral syn-diols 10
will be suitable starting materials for the synthesis of oxa-cyclic
natural and unnatural products through Lewis acid-catalysis.13
To further demonstrate the synthetic application of the chiral
BLA products 5 in the synthesis of analogous natural products
of diarylheptanoids C–F, (+)-5aa was successfully transformed
into the both isomers of syn-10aa and anti-10aa through the
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5094–5101 | 5099

1
ppm downfield to TMS (δ = 0) for H NMR and relative to the
central CDCl3 resonance (δ = 77.0) for 13C NMR. In the
13C NMR spectra, the nature of the carbons (C, CH, CH2 or
CH3) was determined by recording the DEPT-135 experiment,
and is given in parentheses. The coupling constants J are given
in Hz. Column chromatography was performed using Acme’s
silica gel (particle size 0.063–0.200 mm). High-resolution mass
spectra were recorded on micromass ESI-TOF MS. GCMS mass
spectrometry was performed on Shimadzu GCMS-QP2010
mass spectrometer. Elemental analyses were recorded on a
Thermo Finnigan Flash EA 1112 analyzer. LCMS mass spectra
were recorded on either VG7070H mass spectrometer using EI
technique or Shimadzu-LCMS-2010A mass spectrometer. IR
spectra were recorded on JASCO FT/IR-5300 and Thermo
Nicolet FT/IR-5700. The X-ray diffraction measurements were
carried out at 298 K on an automated Enraf-Nonious MACH 3
diffractometer using graphite monochromated, Mo-Kα (λ =
0.71073 Å) radiation with CAD4 software or the X-ray intensity
data were measured at 298 K on a Bruker SMART APEX CCD
area detector system equipped with a graphite monochromator
and a Mo-Kα fine-focus sealed tube (λ = 0.71073 Å). For thin-
layer chromatography (TLC), silica gel plates Merck 60 F254
were used and compounds were visualized by irradiation with
UV light and/or by treatment with a solution of p-anisaldehyde
(23 mL), conc. H2SO4 (35 mL), acetic acid (10 mL), and ethanol
(900 mL) followed by heating.
Materials
All solvents and commercially available chemicals were used as
received.
Acknowledgements
This work was made possible by a grant from the Department
of Science and Technology (DST), New Delhi [Grant No.:
DST/SR/S1/OC-65/2008]. RM and RM thank Council of Scien-
tific and Industrial Research (CSIR), New Delhi for their
research fellowship. We thank Dr P. Raghavaiah for his help in
X-ray structural analysis.
Scheme 5 High-yielding stereoselective reduction of BLA products 5
to syn-1,3-diols 10.
Conclusions
In summary, the organocatalytic asymmetric BLA reaction of
2-alkynylbenzaldehydes with various ketone donors was studied.
In some cases, the formation of expected BLA adducts was
accompanied by some novel double aldol addition products in
moderate to good yields with high de and ee’s. The potential of
the BLA adducts has been demonstrated in the stereoselective
synthesis of chiral acyclic and cyclic 1,2,3-triazole compounds
8–9 and syn-diols 10. The 1,5-dihydroxy-pentan-3-one deriva-
tives 6 can be utilized as intermediates for the development of
potential HIV-1 protease inhibitors.
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