A general approach to chiral building blocks via direct amino acid-catalyzed cascade three-component reductive alkylations: Formal total synthesis of HIV-1 protease inhibitors, antibiotic agglomerins, brefeldin A, and (R)-γ-hexanolide

Article abstract of DOI:10.1021/jo901799n

(Chemical Equation Presented) Multicatalysis cascade (MCC) process for the synthesis of highly substituted chiral building blocks (2-alkyl-CH-acids, 2-alkylcyclohexane-1,3-diones, 2-alkylcyclopentane-1,3-diones, andH-P ketone analogues) is presented based on the cascade three-component reductive alkylation's (TCRA) platform. Herein, we developed the high-yielding alkylation of a variety of CH-acids with (R)-glyceraldehyde acetonide/(S)-Garner aldehyde and Hantzsch ester through amino acid-catalyzed TCRA reaction without racemization at the α-position to carbonyl. Direct sequential combination of the L-proline-catalyzed TCRA reaction with other reactions like cascade alkylation/ketenization/ esterification (A/K/E), alkylation/ketenization/ esterification/alkylation (A/K/E/A), Bronsted acid-catalyzed cascade hydrolysis/lactonization/esterification (H/L/E), hydrolysis/esterification (H/E), hydrolysis/oxy-Michael/dehydration (H/OM/DH), and Robinson annulation (RA) of CH-acids, chiral aldehydes, Hantzsch ester, diazomethane, methyl vinyl ketone, various active olefins, and acetylenes furnished the highly functionalized chiral building blocks in good to high yields with excellent diastereoselectivities. In this context, many of the pharmaceutically applicable chiral building blocks were prepared via MCC reactions.

Full text of DOI:10.1021/jo901799n

pubs.acs.org/joc
A General Approach to Chiral Building Blocks via Direct Amino
Acid-Catalyzed Cascade Three-Component Reductive Alkylations:
Formal Total Synthesis of HIV-1 Protease Inhibitors, Antibiotic
Agglomerins, Brefeldin A, and (R)-γ-Hexanolide
Dhevalapally B. Ramachary* and Y. Vijayendar Reddy
School of Chemistry, University of Hyderabad, Central University (PO), Hyderabad 500 046, India
ramsc@uohyd.ernet.in
Received August 20, 2009
Multicatalysis cascade (MCC) process for the synthesis of highly substituted chiral building blocks
(2-alkyl-CH-acids, 2-alkylcyclohexane-1,3-diones, 2-alkylcyclopentane-1,3-diones, and H-P ketone
analogues) is presented based on the cascade three-component reductive alkylation’s (TCRA)
platform. Herein, we developed the high-yielding alkylation of a variety of CH-acids with (R)-
glyceraldehyde acetonide/(S)-Garner aldehyde and Hantzsch ester through amino acid-catalyzed
TCRA reaction without racemization at the R-position to carbonyl. Direct sequential combination of
the L-proline-catalyzed TCRA reaction with other reactions like cascade alkylation/ketenization/
esterification (A/K/E), alkylation/ketenization/esterification/alkylation (A/K/E/A), Brønsted acid-
catalyzed cascade hydrolysis/lactonization/esterification (H/L/E), hydrolysis/esterification (H/E),
hydrolysis/oxy-Michael/dehydration (H/OM/DH), and Robinson annulation (RA) of CH-acids,
chiral aldehydes, Hantzsch ester, diazomethane, methyl vinyl ketone, various active olefins, and
acetylenes furnished the highly functionalized chiral building blocks in good to high yields with
excellent diastereoselectivities. In this context, many of the pharmaceutically applicable chiral
building blocks were prepared via MCC reactions.
Introduction
synthesis of natural products (see Chart 1).1 As such, the
development of more general catalytic asymmetric methods
for their preparation is of significant interest.2 For example,
diethyl 2-(2,2-dimethyl[1,3]dioxolan-4-ylmethyl)malonate
was utilized as key intermediate in the total synthesis of
natural products like HIV-1 protease inhibitors A-D, phos-
pholipase A2 inhibitors E and F, antibiotic agglomerins G,
(R)-Glyceraldehyde acetonide and (S)-Garner aldehyde
derivatives from olefination/hydrogenation are an impor-
tant class of heterocycles and very good chiral building
blocks which display a very large spectrum of biological/
chemical activities and are widely used as drug intermediates
and ingredients in pharmaceuticals and also in the total
74 J. Org. Chem. 2010, 75, 74–85
Published on Web 12/02/2009
DOI: 10.1021/jo901799n
r
2009 American Chemical Society

Ramachary and Vijayendar Reddy
CHART 1. Natural Products Library Generated from (R)-Glyceraldehyde Acetonide and (S)-Garner Aldehyde Derivatives
JOCArticle
(R)-γ-hexanolide H, and (þ)-brefeldin-A I but which was
prepared only in 40% overall yield from four steps starting
from (R)-glyceraldehyde acetonide (see eq 1).1a-i Interest-
ingly, to the best of our knowledge, there is no report on the
direct catalytic asymmetric single step method for the synth-
esis of functionalized dialkyl 2-(2,2-dimethyl[1,3]dioxolan-4-
ylmethyl)malonates and dialkyl 2-(3-tert-butoxycarbonyl-
2,2-dimethyloxazolidin-4-ylmethyl)malonates, which are
good intermediates for the synthesis of biologically active
natural products as demonstrated in this work (see Chart 1).
Herein, we reported the organocatalytic single step approach
to the asymmetric synthesis of functionalized chiral building
blocks based on (R)-glyceraldehyde acetonide and (S)-Gar-
ner aldehyde via “three-component reductive alkylation
reactions”.3a-c
Recently, we discovered the amino acid-catalyzed three-
component reductive alkylation reactions of ketones/alde-
hydes with a variety of CH-acids and Hantzsch ester to
provide a general route to a variety of alkylation products
in good yields with high chemoselectivity, which is known as
the “three-component reductive alkylation (TCRA)” re-
action.3a-c The advent of amino acid-catalyzed TCRA
reaction technology triggered a burst of activity in the
synthesis of a huge variety of alkylation products through
biomimetic iminium-catalysis chemistry for the 1 ꢀ C-C
and 2 ꢀ C-H bond formations and also providing high
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J. Org. Chem. Vol. 75, No. 1, 2010 75

Ramachary and Vijayendar Reddy
JOCArticle
SCHEME 1. Direct Amino Acid-Catalyzed Cascade Three-Component Reductive Alkylations
inspiration to develop cellular type cascade reactions based
on TCRA platform.3
and amines/amino acid 4 (Scheme 1). In this paper, we
discovered the observation of no racemization at the
R-position to carbonyl at the normal amino acid-catalyzed
TCRA reaction conditions.4
Over the last 5 years, we have been interested in an amino
acid mediated multicatalysis cascade (MCC) reactions from
multiple components and multiple catalysts for the genera-
tion of highly functionalized druglike molecules through
C-C, C-H, C-O, and C-N bonds formation in one
pot.5i-k During our investigation for new reactive species
for such MCC processes, we have decided to explore the
potential ability of the chiral aldehydes 1 to participate in an
amino acid-catalyzed TCRA reaction with CH-acids 2 and
Hantzsch ester 3 (see Scheme 1). We imagine that the
reaction of (R)-glyceraldehyde acetonide 1a (>98% ee) with
Meldrum’s acid 2a and Hantzsch ester 3 under L-proline
catalysis may lead to racemic 5-(2,2-dimethyl[1,3]dioxolan-
4-ylmethyl)-2,2-dimethyl[1,3]dioxane-4,6-dione 5aa. How-
ever, TCRA product 5aa could not be racemized and instead
it is shown the >98% ee (based on HPLC analysis) under the
standard reaction conditions. This unexpected result repre-
sents a good methodology for the preparation of chiral
TCRA products and a new reactivity for amino acid cata-
lysts. Herein, we report our findings regarding these TCRA
reactions.
However, the amino acid-catalyzed TCRA reaction of
CH-acids 2 and Hantzsch ester 3 with functionalized (R)-
glyceraldehyde acetonide/(S)-Garner aldehyde 1 is not
known, but resulting TCRA products 5 have a wide range
of applications in pharmaceutical chemistry (see eq 1 and
Scheme 1). There is no direct methodology available to
prepare 5 by using the classical reaction strategies in a single
step. Herein, we have reported a metal-free and green
technology for the synthesis of highly substituted (R)-glycer-
aldehyde acetonide and (S)-Garner aldehyde derivatives 5
using organocatalytic TCRA reactions from commercially
available chiral aldehydes 1, CH-acids 2, Hantzsch ester 3,
Results and Discussion
Three-Component Reductive Alkylation of (R)-Glyceralde-
hyde Acetonide: Reaction Optimization. We initiated our
preliminary studies of the TCRA reactions by screening a
number of protic/aprotic solvents for the olefination/hydro-
genation (O/H) of (R)-glyceraldehyde acetonide 1a with
Meldrum’s acid 2a and Hantzsch ester 3 under L-proline 4-
catalysis, and some representative results are shown in Table
1. Interestingly, reaction of (R)-1a (>98% ee) with 1 equiv
each of 2a and 3 in CH2Cl2 under 5 mol % of 4-catalysis
furnished the TCRA product 5aa in 91% yield with >98%
ee (based on HPLC analysis of (-)-5aa derivative; see the
Supporting Information for more information) after 2.5 h
(Table 1, entry 1). The same reaction in CH2Cl2 under
10 mol % of L-proline 4-catalysis furnished the TCRA
product 5aa with increased yield (98%) and similar ee
([R]25D = -24.4) after 2.5 h (Table 1, entry 2). Interestingly,
increasing the catalyst loading from 10 to 20 mol %; yield
and ee of the TCRA product 5aa is affected negatively as
shown in Table 1, entry 3. The same TCRA reaction in DCE
solvent under 10 mol % of L-proline 4-catalysis furnished the
TCRA product 5aa as similar to CH2Cl2 (Table 1, entry 4).
Interestingly, TCRA reaction of (R)-1a, 2a, and 3 under
10 mol % of 4-catalysis in CH3CN for 1 h furnished the
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Tanaka, F.; Barbas, C. F. III. Acc. Chem. Res. 2004, 37, 580–591. For
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see: (i) Ramachary, D. B.; Ramakumar, K.; Narayana, V. V. J. Org. Chem.
2007, 72, 1458–1463. (j) Ramachary, D. B.; Sakthidevi, R. Chem.;Eur. J.
2009, 15, 4516–4522. For selected recent papers on organocatalytic cascade
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F. III. Chem.;Eur. J. 2004, 10, 5323–5331. (l) Yang, J. W.; Hechavarria
Fonseca, M. T.; List, B. J. Am. Chem. Soc. 2005, 127, 15036–15037. (m)
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Huettl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861–863. (p)
Rios, R.; Sunden, H.; Ibrahem, I.; Zhao, G.-L.; Cordova, A. Tetrahedron
Lett. 2006, 47, 8679–8682. (q) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am.
Chem. Soc. 2006, 128, 10354–10355. (r) Tejedor, D.; Gonzalez-Cruz, D.;
Santos-Exposito, A.; Marrero-Tellado, J. J.; de Armas, P.; Garcia-Tellado,
F. Chem.;Eur. J. 2005, 11, 3502–3510. (s) Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683–3686. (t) Ishikawa, H.;
Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304–1307. (u) Zhu,
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2008, 10, 4585–4588.
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TABLE 1. Preliminary Studies on Reductive Alkylation of (R)-Glyceraldehyde Acetonidea
d
)
entry
proline 4 (mol %)
solvent (0.3 M)
time (h)
conversionb (%)
yieldc (%)
specific rotation ([R]25
D
1
2
3
4
5
6
7
5
10
20
10
10
10
10
10
CH2Cl2
CH2Cl2
CH2Cl2
(CH2)2Cl2
CH3CN
DMF
DMSO
EtOH
H2O
2.5
2.5
0.75
2.0
1.0
2.0
3.0
1.0
>99
>99
>99
>99
>99
>99
>99
>99
>95
80
91
98
91
91
95
87
78
91
<5
68
-24.6
-24.4
-23.6
-24.4
-24.0
-22.6
-22.7
-11.9
8
9e
72.0
8f9
10f
10
CH3CN
-24.4
aReactions were carried out in solvent (0.3 M) with 1.0 equiv each of 2a and 3 relative to the 1a (0.5 mmol) in the presence of 5-20 mol % of catalyst 4.
bConversation is based on 1HNMR/TLC analysis. cYield refers to the column-purified product. dSpecific rotation of all entries determined as 1.0 g/100
mL in CHCl3. Only olefination product 5-(2,2-dimethyl[1,3]dioxolan-4-ylmethylene)-2,2-dimethyl[1,3]dioxane-4,6-dione (6aa) is formed. Reaction
performed in sequential manner.
e
f
product 5aa in 95% yield with sustained ee ([R]25D = -24.0)
as shown in Table 1, entry 5. But, L-proline 4-catalyzed
TCRA reaction of 1a, 2a, and 3 in DMF/DMSO solvents
for 2/3 h furnished the product 5aa in 87/78% yield with
decreased ee ([R]25D = -22.6) as shown in Table 1, entries 6
and 7, respectively. Surprisingly, L-proline 4-catalyzed
TCRA reaction of 1a, 2a, and 3 in EtOH solvent for 1 h
furnished the product 5aa in 91% yield with almost e50% ee
([R]25D = -11.9) as shown in Table 1, entry 8. This provides
strong evidence that enantiomerically pure (R)-glyceralde-
hyde acetonide 1a is racemizing through iminium-catalysis in
protic solvents like ethanol in the process of TCRA reaction.4
The solvent promoted one-pot TCRA reaction of 1a, 2a,
and 3 in H2O without catalyst furnished the expected pro-
duct 5aa in <5% conversion, but the olefination is com-
pleted with >95% yield under green reaction conditions
(Table 1, entry 9). Interestingly, performing the TCRA
reaction in a sequential one-pot manner was took longer
reaction times (8 h for olefination and 9 h for hydrogenation)
N-dimethylbarbituric acid 2e furnished the chiral TCRA
products 5ad and 5ae as single enantiomers in good yields
(Table 2). (S)-2-(2,2-Dimethyl[1,3]dioxolan-4-ylmethyl)-
cyclohexane-1,3-dione 5ag, and related chiral TCRA pro-
ducts 5ah-ak were generated as single enantiomers with
excellent yields from (R)-1a, 2g-k, and 3 at 25 °C under
L-proline-catalysis and which are very good starting materials
for steroid drug analogue synthesis (Table 2; see the Sup-
porting Information for HPLC analysis of 5af derivative).3a,b
The reaction of (R)-1a and 3 with acyclic CH-acids 2l-o
under L-proline-catalysis at 25 °C for 1-6 h in CH3CN
furnished the chiral TCRA products 5al-ao as single en-
antiomers in 2:1 to 1:1 dr ratio with good yields (Table 2).
The results in Table 2 demonstrate the broad scope of this
TCRA methodology covering a structurally diverse group of
CH-acids 2a-o with many of the yields obtained being very
good or, indeed, better than previously published four-step
alkylation reactions.2 The structure and regiochemistry of
TCRA products 5aa-ao were confirmed by NMR and mass
analysis.
with only e80% conversion and with sustained ee ([R]25
=
D
-24.4) as shown in Table 1, entry 10, this may be due to the
autocatalytic nature of the Hantzsch ester 3 in the cascade
TCRA (olefination-hydrogenation) reaction.3a-c The opti-
mized conditions for the TCRA reaction of 1a, 2a, and 3 in
CH3CN or CH2Cl2 at 25 °C to furnish 5aa with excellent
conversions and without racemization required the presence
of the catalytic amount of amino acid 4 (entries 1-5).
Diversity-Oriented Chiral Synthesis of TCRA Products
5aa-ao. With an efficient amino acid-catalyzed TCRA
protocol in hand, the scope of the L-proline-catalyzed TCRA
reactions were investigated with various CH-acids 2a-o. A
series of cyclic and acyclic CH-acids 2a-o were reacted with
each 1.0 equiv of (R)-glyceraldehyde acetonide 1a and
Hantzsch ester 3 catalyzed by 10 mol % of L-proline 4 at
25 °C for 1-6 h in CH3CN (Table 2). The (S)-5-(2,
2-dimethyl[1,3]dioxolan-4-ylmethyl)-2,2-dimethyl[1,3]diox-
ane-4,6-dione 5aa and (S)-5-(2,2-dimethyl[1,3]dioxolan-4-
ylmethyl)-2,2-dialkyl[1,3]dioxane-4,6-diones 5ab-ac were
obtained as enantiomerically pure with excellent yields.
The reaction of (R)-1a and 3 with barbituric acid 2d and N,
Chiral TCRA products 5aa-ac are an important inter-
mediates for the asymmetric synthesis of natural products
like HIV-1 protease inhibitors A-D, phospholipase A2 in-
hibitors E-F, antibiotic agglomerins G, (R)-γ-hexanolide H
and (þ)-brefeldin-A I as demonstrated in this paper,1a-i
TCRA products 5ag-ak could be an important intermedi-
ates for the synthesis of Wieland-Miescher (W-M) ketone
and Hajos-Parrish (H-P) ketone analogues which are very
good steroids drug intermediates,3a,b and TCRA product
(-)-5an could serve as useful synthon for the synthesis of
(-)-4,5-dihydroxy-D-threo-L-norvaline J and also for the
synthesis of antibiotic clavalanine K, emphasizing the value
of this cascade TCRA approach.
Diversity-Oriented Chiral Synthesis of TCRA Products
5ba-bk. With the optimized TCRA reaction conditions in
hand, the scope of the L-proline-catalyzed cascade O/H
reactions were investigated with different chiral R-amino
aldehydes 1b-d, various CH-acids 2a-k, and Hantzsch ester
3 as shown in Table 3. A series of chiral R-amino aldehydes
1b-d (1 equiv) reacted with Meldrum’s acid 2a and Hantzsch
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TABLE 2. Synthesis of Chiral Products 5aa-ao via Reductive Alkylation Reactiona
aYield refers to the column purified product. b(R)-Glyceraldehyde acetonide 1a was taken as 3 equiv.
ester 3 catalyzed by 10 mol % of L-proline at 25 °C in CH3CN
(Table 3). The (R)-4-(2,2-dimethyl-4,6-dioxo[1,3]dioxan-5-
ylmethyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl
ester 5ba, (S)-4-(2,2-dimethyl-4,6-dioxo[1,3]dioxan-5-ylmethyl)-
2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester
5ca, and (R)-5-(2-dibenzylamino-3-phenylpropyl)-2,2-dimethyl-
[1,3]dioxane-4,6-dione 5da were obtained in an enantiomerically
pure manner with excellent to good yields. The reaction of (S)-
Garner aldehyde 1b with cyclohexane-1,3-dione 2g and
Hantzsch ester 3 under L-proline-catalysis furnished the TCRA
product (R)-5bg as single enantiomer in 90% yield at 25 °C
(Table 3). In a similar manner, reaction of (S)-Garner aldehyde
1b with 5,5-dimethylcyclohexane-1,3-dione 2h/cyclopentane-1,3-
dione 2k and Hantzsch ester 3 in CH3CN at 25 °C for 1-6 h
under L-proline-catalysis furnished the TCRA products (R)-5bh
and (R)-5bk as single enantiomers in 93-95% yields, respec-
tively (Table 3). The results in Table 3 demonstrate the broad
scope of this reductive methodology covering a structurally
diverse group of chiral R-amino aldehydes 1b-d with many of
the yields obtained being very good, or indeed better, than
previously published four-step alkylation reactions.2 The struc-
ture and regiochemistry of TCRA products 5ba-bk were con-
firmed by NMR and mass analysis.
Applications of Chiral TCRA Products: (A) Development of
Product-Specific MCC Reactions Based on the TCRA Plat-
form. Chiral 2-alkylmalonates are an important class of
compounds which are widely used as intermediates in the
pharmaceutical and agrochemical industries.1j-o Com-
pounds containing chiral 2-alkylmalonates have found
pharmaceutical applications as glucocorticoid receptor
modulators, peptide deformylase inhibitors, HIV-1 and
HIV-2 protease inhibitors, potent dual ACE/NEP inhibi-
tors, antidiabetic agents, ligands for the neuromodulatory
receptor, and also starting materials for the synthesis of
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TABLE 3. Synthesis of Chiral Products 5ba-bk via Reductive Alkylation Reactiona
aYield refers to the column purified product. bGarner aldehyde 1b was taken as 3 equivalents.
natural products as shown in Chart 1.1 As such, the devel-
opment of more general catalytic methods for their pre-
paration is of significant interest.2 The conventional
method to synthesize chiral 2-alkylmalonates is the alkyla-
tion of dialkyl malonates with chiral alkyl halides under the
dry reaction conditions, which has less scope with respect of
yields, diverse library generation, and experimental simpli-
city (see eq 1).2 Surprisingly, the amino acid-catalyzed
cascade O/H reaction sequence could not work with dia-
lkylmalonates 2p as CH-acid; even the first step of the
olefination itself did not take place. To overcome this
reactivity problem, herein we discovered the synthesis of
chiral 2-alkylmalonates in a sequential manner by utiliza-
tion of reactive species of methoxycarbonylketenes to gen-
erate the library of chiral 2-alkylmalonates via in situ O-
alkylation/ketenization/esterification (A/K/E) of TCRA pro-
duct 5aa with CH2N2 in one pot under ambient conditions, an
approach wecall “MCC approach to chiral 2-alkylmalonates”
(Table 4).3c
L-Proline-catalyzed TCRA reaction of (R)-1a and Mel-
drum’s acid 2a with Hantzsch ester 3 in CH3CN at 25 °C
for 1 h furnished the expected TCRA product (S)-5aa in
>99% conversion, which on in situ treatment with ethereal
diazomethane in MeOH 7a at 0 °C f 25 °C for 8 h furnished
the expected (S)-dimethyl 2-(2,2-dimethyl[1,3]dioxolan-4-
ylmethyl)malonate 5aaa with 75% yield and >98% ee
(based on HPLC analysis of 5aaa derivative; see the Support-
ing Information for more information) through the O-alkyla-
tion/ketenization/esterification (A/K/E) sequence (Table 4,
entry 1). The TCRA/A/K/E reaction of Meldrum’s acid
analogues 2b,c with (R)-1a, 3, 7a, and diazomethane catalyzed
by 4 in methanol at 0 °C f 25 °C for 24 h furnished the
expected (S)-5aaa with 55-60% yields, >98% ee, respec-
tively, and these results are not superior as compared to 2a
with respect to yields (results not shown in Table 4). After
these interesting results, we decided to investigate the scope
and limitations of the MCC reaction with other three chiral
R-amino aldehydes 1b-d with 2a, 3, 7a, and diazomethane
under L-proline-catalysis under ambient conditions (Table 4,
entries 2-4). MCC reaction of chiral R-amino aldehydes
(S)-1b, (R)-1c, and (S)-1dwith2a, 3, and 7aand diazomethane
under L-proline-catalysis furnished the expected enantiomeri-
cally pure products (-)-5baa, (þ)-5caa, and (þ)-5daa
in 80-65% yields, respectively, as shown in Table 4, entries
2-4.
After these interesting results, we further decided to
investigate the scope and limitations of the MCC reaction
with a range of chiral aldehydes 1a-f, barbituric acids 2d, 3,
and 7a, and diazomethane under L-proline-catalysis under
ambient conditions to test the diverse nature of the MCC
reaction (Table 4). As shown in Table 4, the MCC reaction
of (R)-1a, barbituric acid 2d, 3, 7a and diazomethane furn-
ished the (S)-5-(2,2-dimethyl[1,3]dioxolan-4-ylmethyl)-2,6-
dimethoxy-3-methyl-3H-pyrimidin-4-one 5ada as major sin-
gle product with 90% yield out of 24 theoretically expected
products from the designed reaction as shown in Table 4 and
Table S1 (Supporting Information). (S)-5-(2,2-Dimethyl-
[1,3]dioxolan-4-ylmethyl)pyrimidine-2,4,6-trione 5ad, which
is in situ generated from TCRA reaction, has many active
sites toward methylation with diazomethane, but interest-
ingly, we are able to obtain 5ada as single major product,
which is confirmed by NMR and UV spectral analysis. The
generality of the product-specific MCC reaction was con-
firmed by four more examples with chiral aldehydes 1b-f,
2d, 3, 7a, and diazomethane under L-proline-catalysis and
furnished the expected enantiomerically pure single MCC
products 5bda-fda with 75-80% yields, respectively, as
shown in Table 4. Pyrimidinone derivatives 5ada-fda are
useful compounds as agrochemical fungicides and potent
HIV-1 and HIV-2 inhibitors with good antiviral and anti-
bacterial activity.1j-o This product-specific MCC technol-
ogy may be suitable for development of a large number of
diverse compounds of 5 to screen and identify the suitable
bioactive products.
B. Brønsted Acid-Catalyzed Intramolecular Cyclization of
Chiral TCRA Products. Functionalized chiral γ-butyrolactones
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TABLE 4. Synthesis of Chiral Products 5aaa-fda via MCC Reactiona
aYield refers to the column purified product.
8 and protected γ-carboxy-L/D-glutamic acids 9 are very
good intermediates for the synthesis of pharmaceutically
useful natural and non-natural products as shown in
Chart 1.1 Surprisingly, to the best of our knowledge there
is no report for the high-yielding asymmetric synthesis of
useful chiral γ-butyrolactones 8 and higher analogues 10
through single step. Herein, we are presenting the asym-
metric synthesis of 8, 9, and 10 with g98% ee and 80-99%
yields via Brønsted acid-catalyzed cyclization of TCRA
products 5 in protic or aprotic solvents as shown in Table
5. With an efficient amino acid-catalyzed reductive alkyla-
tion protocol in hand, we continued our investigation for the
synthesis of functionalized chiral γ-butyrolactones 8 from
(S)-5-(2,2-dimethyl[1,3]dioxolan-4-ylmethyl)-2,2-dimethyl-
[1,3]dioxane-4,6-dione 5aa under Brønsted acid-catalysis in
MeOH/BnOH through cascade hydrolysis/lactonization/es-
terification (H/L/E) reactions as shown in Table 5, entry 1.
After complete investigation, we came to a conclusion that
p-TSA is suitable Brønsted acid-catalyst for the H/L/E
reactions compare to other Brønsted acid catalysts (results
not shown in Table 5). Interestingly, reaction of (-)-5aa with
30 mol % of p-TSA in MeOH 7a at 25 °C for 1-2 h furnished
the chemoselectively single compound chiral γ-butyrolac-
tone (þ)-8aaa with 1:1 dr in 99% yield (Table 5, entry 1).
Same H/L/E reaction under p-TSA-catalysis in BnOH 7b at
25 °C for 1-2 h furnished the expected single chiral
γ-butyrolactone product (þ)-8aab with 1:1 dr in 99% yield
(Table 5, entry 1). We envisioned that reaction of the (-)-5aa
with p-TSA catalysis in protic solvents at 25 °C for 1-2 h
furnished the chemoselectively H/L/E products (þ)-
8aaa-aab as single products in 99% yields instead of
5-hydroxy-2-oxo-tetrahydro-pyran-3-carboxylic acid alkyl
esters, which is revealed by NMR analysis and also by
DFT calculations (see the Supporting Information). The
calculated heat of formation (ΔΔE) for the (þ)-8aaa product
is 3.2 kcal/mol more than the six-membered ring formation
reaction as shown in Table 5, entry 1. This result also
strongly suggests that kinetically and thermodynamically
γ-butyrolactone products (þ)-8aaa-aab formation is more
favorable than 5-hydroxy-2-oxotetrahydropyran-3-car-
boxylic acid alkyl esters formation as revealed by experi-
mental and DFT calculations.
Brønsted acid-catalyzed cascade hydrolysis/esterification
(H/E) reaction of (-)-5ba at 25 °C for 2 h in MeOH 7a
furnished the chemoselectively protected γ-carboxy-L-gluta-
mic acid [L-Gla] (þ)-9baa with 97% yield as a single com-
pound (Table 5, entry 2). In a similar manner, reaction of
(þ)-5ca under p-TSA-catalysis at 25 °C for 2.5 h in MeOH 7a
furnished the protected D-Gla (-)-9caa with 95% yield as a
single compound (Table 5, entry 3). Formation of 9baa-caa
as single products/isomers from a cascade H/E reaction
could be explained on the basis of the relatively weak
nucleophilic nature of in situ generated primary OH and
NHBoc groups toward ester. H/E products of protected L-
Gla and D-Gla 9baa-caa are an important component of
several vitamin K dependent blood clotting factors, includ-
ing prothrobin, and also potentially useful building blocks in
the total synthesis of quinocarcin and related bioactive
natural products,1p,q which emphasizes the pioneering role
of the cascade H/E approach.
With an efficient Brønsted acid-catalyzed H/L/E and H/E
protocol in hand, we continued our investigation for the
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TABLE 5. Brønsted Acid-Catalyzed Intramolecular Cyclization of Chiral TCRA Products 5a
aYield refers to the column purified product.
synthesis of functionalized chiral 3-hydroxy-2,3,4,6,7,8-hexa-
hydrochromen-5-ones 10af-ak from chiral TCRA pro-
ducts 5af-ak under Brønsted acid-catalysis through cascade
hydrolysis/oxy-Michael/dehydration (H/OM/DH) reactions
as shown in Table 5, entries 4-8. Interestingly, reaction of
(-)-5af with 30 mol % of p-TSA in CH2Cl2 at 25 °C for 2-3 h
furnished the chemoselectively single chiral product (-)-10af
with 88% yield through H/OM/DH reactions (Table 5,
entry 4). In a similar manner, reaction of (-)-5ag with
30 mol % of p-TSA in CH2Cl2 at 25 °C for 3-5 h furnished
the chemoselectively single chiral product (-)-10ag
with 93% yield through H/OM/DH reactions (Table 5,
entry 5). The generality of the product-specific H/OM/DH
reaction was confirmed by four more examples with
chiral TCRA compounds 5ah-ak under p-TSA-catalysis
and furnished the expected enantiomerically pure single
H/OM/DH products 10ah-ak with 80-91% yields,
respectively, as shown in Table 5, entries 5-8. Unexpected
chemoselectivity of H/OM/DH reactions could be explained
on the basis of the more nucleophilic nature of in situ
generated primary OH group than secondary OH in the
oxy-Michael step.
(6) (a) Trenor, S. R.; Shultz, A. R.; Love, B. J.; Long, T. E. Chem. Rev.
2004, 104, 3059–3077. (b) Atwal, K. S.; Wang, P.; Rogers, W. L.; Sleph, P.;
Monshizadegan, H.; Ferrara, F. N.; Traeger, S.; Green, D. W.; Grover, G. J.
ꢀ ꢀ
J. Med. Chem. 2004, 47, 1081–1084. (c) Frederick, R.; Robert, S.; Charlier,
C.; Ruyck, J.; Wouters, J.; Pirotte, B.; Masereel, B.; Pochet, L. J. Med. Chem.
2005, 48, 7592–7603. (d) Kang, Y.; Mei, Y.; Du, Y.; Jin, Z. Org. Lett. 2003, 5,
4481–4484. (e) Ross, S. A.; Sultana, G. N. N.; Burandt, C. L.; ElSohly, M. A.;
Marais, J. P. J.; Ferreira, D. J. Nat. Prod. 2004, 67, 88–90. (f) Burlison, J. A.;
Neckers, L.; Smith, A. B.; Maxwell, A.; Blagg, B. S. J. J. Am. Chem. Soc.
2006, 128, 15529–15536. (g) Shi, Y.-L.; Shi, M. Org. Biomol. Chem. 2007, 5,
1499–1504. (h) Wijeratne, E. M. K.; Turbyville, T. J.; Fritz, A.; Whitesell, L.;
Gunatilaka, A. A. L. Bioorg. Med. Chem. 2006, 14, 7917–7923. (i) Rezanka,
T.; Sigler, K. J. Nat. Prod. 2007, 70, 1487–1491. (j) Nicolaou, K. C.;
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TABLE 6. Synthesis of Chiral Products 11 with Quaternary Carbons via MCC Reactiona
aYield refers to the column purified product.
Functionalized chromanes and chromenes are of consider-
able importance in a variety of industries. These heterocyclic
analogues 10af-ak are widespread elements in natural pro-
ducts and have attracted much attention from a wide area of
science, including physical chemistry, medicinal chemistry,
natural product chemistry, synthetic organic chemistry, and
polymer science.6 As such, the development of more general
catalytic asymmetric methods for their preparation is of sig-
nificant interest and our presently developed cascade chemistry
will be useful to develop library of chiral chromanes and
chromenes in very good yields with high selectivity.
C. Sequential Cascade Synthesis of Asymmetric Com-
pounds with Quaternary Carbons through MCC Reactions
Based on TCRA Platform. Stereoselective synthesis of highly
functionalized chiral compounds with quaternary carbons
are evergreen task in synthetic organic chemistry.7 As part of
our research program to engineer direct MCC reactions in
sequential manner to deliver the highly functionalized chiral
molecules with quaternary carbons and also on the demand
of pharmaceutical applications, we extended the five-com-
ponent TCRA/A/K/E reactions into L-proline-HMPT-cat-
alyzed six-component TCRA/A/K/E/A reaction of (R)-
glyceraldehyde acetonide 1a, Meldrum’s acid 2a, Hantzsch
ester 3, diazomethane, and methanol 7a with various active
olefins and acetylenes (a-d) in one pot (Table 6). MCC
products 11 were constructed in very good yields with high
selectivity, and this method will have a great impact on the
synthesis of functionalized small chiral molecules with a
quaternary carbon as shown in Table 6. Highly substituted
asymmetric 2,2-dialkylated malonates 11 have gained
importance in recent years as starting materials and
intermediates for the synthesis of biologically active compounds,
for example, M2-selective muscarinic receptor antagonists and
isozyme-selective glutathione S-transferase inhibitors.1j-o
The TCRA reaction of (R)-1a, 2a, and 3 under 10 mol % of
L-proline-catalysis furnished the compound (-)-5aa with
>99% conversion, which on in situ treatment with ethereal
diazomethane at 0-25 °C for 8 h furnished the chemoselec-
tive TCRA/A/K/E product (-)-5aaa with >99% conver-
sion, which on in situ treatment with methyl acrylate (a)
under 10 mol % of hexamethylphosphorous triamide
(HMPT) catalysis in CH3CN at 25 °C for 0.5-1.0 h furn-
ished the TCRA/A/K/E/A product (-)-11a3a with 95%
yield as shown in Table 6.8 The generality of the L-proline-
HMPT-catalyzed chemoselective sequential one-pot TCRA/
A/K/E/A reaction is further confirmed by three more ex-
amples using methyl vinyl ketone (b), acrylonitrile (c), and
methyl propiolate (d) to furnish the expected (-)-11a3b in
90% yield, (-)-11a3c in 90% yield, and (-)-11a3d in 90%
yield with >60% de, respectively, as shown in Table 6. For
the pharmaceutical applications, diversity-oriented library
of chiral malonates 11 could be generated by using this MCC
technology.
D. Sequential Cascade Asymmetric Synthesis of Ha-
jos-Parrish Ketone Analogues through MCC Reactions
Based on the TCRA Platform. Higher alkyl-substituted chiral
Wieland-Miescher (W-M) and Hajos-Parrish (H-P) ke-
tone analogues 13/14 are good intermediates for the synth-
esis of natural products like steroids, and also higher alkyl
W-M and H-P ketone analogues 13/14 are very good
intermediates for the synthesis of pharmaceutically accepta-
ble salts or hydrates of heterocycles, which are shown as
selective glucocorticoid receptor modulators for treating a
variety of autoimmune and inflammatory diseases.9 Inter-
estingly, to the best of our knowledge, there is no report
for the asymmetric synthesis of useful higher alkyl sub-
stituted H-P ketone analogues 13/14. In this paper, we are
(7) For the selected reviews on quaternary carbon generation, see: (a)
Austeri, M.; Buron, F.; Constant, S.; Lacour, J.; Linder, D.; Muller, J.;
Tortoioli, S. Pure Appl. Chem. 2008, 80, 967–977. (b) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186. (c)
Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363–
5367. (d) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105–10146. (e)
Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591–4597. (f)
Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388–401. (g)
Srikrishna, A.; Krishnan, K.; Nagaraju, S. J. Indian Inst. Sci. 1994, 74, 157–
168. (h) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503–9569.
(8) For HMPT-catalyzed Michael reactions, see: Grossman, R. B.;
Comesse, S.; Rasne, R. M.; Hattori, K.; Delong, M. N. J. Org. Chem.
2003, 68, 871–874.
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TABLE 7. Asymmetric Synthesis of H-P Ketone Analogues 13 and 14 via MCC Reactiona
aYield refers to the column purified product.
presenting the asymmetric synthesis of H-P ketone analo-
gues 13/14 with very good ee/de and yields through MCC
reactions based on TCRA platform as shown in Table 7.
We were surprised to know that L-proline-catalyzed
TCRA reaction of 3 equiv of (R)-glyceraldehyde acetonide
1a with cyclohexane-1,3-dione 2g and Hantzsch ester 3 in
(9) Applications of Wieland-Miescher (W-M) ketone analogues; see:
(a) Paquette, L. A.; Wang, H.-L. J. Org. Chem. 1996, 61, 5352–5357. (b)
Deng, W.; Jensen, M. S.; Overman, L. E.; Rucker, P. V.; Vionnet, J.-P. J.
Org. Chem. 1996, 61, 6760–6761. (c) Katoh, T.; Nakatani, M.; Shikita, S.;
Sampe, R.; Ishiwata, A.; Ohmori, O.; Nakamura, M.; Terashima, S. Org.
Lett. 2001, 3, 2701–2704. (d) Inomata, K.; Barrague, M.; Paquette, L. A. J.
Org. Chem. 2005, 70, 533–539. (e) Nagamine, T.; Inomata, K.; Endo, Y.;
Paquette, L. A. J. Org. Chem. 2007, 72, 123–131. Applications of
Hajos-Parrish (H-P) ketone analogues; see: (f) Majetich, G.; Song, J. S.;
Ringold, C.; Nemeth, G. A.; Newton, M. G. J. Org. Chem. 1991, 56, 3973–
3988. (g) Ruprah, P. K.; Cros, J. -P.; Pease, J. E.; Whittingham, W. G.;
Williams, J. M. J. Eur. J. Org. Chem. 2002, 3145–3152. (h) Cao, L.; Sun, J.;
Wang, X.; Zhu, R.; Shi, H.; Hu, Y. Tetrahedron 2007, 63, 5036–5041. (i)
Kasch, H.; Liedtke, B.; U. S. Pat. Appl. Publ. 2006, 24 pp, CODEN: USXXCO
US 2006089340 A1 20060427, CAN 144:433022 (patent written in English). (j)
Sevillano, L. G.; Melero, C. P.; Boya, M.; Lopez, J. L.; Tome, F.; Caballero, E.;
Carron, R.; Montero, M. J.; Medarde, M.; San Feliciano, A. Bioorg. Med. Chem.
1999, 7, 2991–3001. For the pharmaceutical applications of W-M and H-P
ketone analogues, see: (k) Thompson, C. F.; Quraishi, N.; Ali, A.; Mosley, R. T.;
Tata, J. R.; Hammond, M. L.; Balkovec, J. M.; Einstein, M.; Ge, L.; Harris, G.;
Kelly, T. M.; Mazur, P.; Pandit, S.; Santoro, J.; Sitlani, A.; Wang, C.; Williamson,
J.; Miller, D. K.; Yamin, T. D.; Thompson, C. M.; O'Neill, E. A.; Zaller, D.; Forrest,
M. J.; Carballo-Jane, E.; Luell, S. Bioorg. Med. Chem. Lett. 2007, 17, 3354–
3361. (l) Smith, C. J.; Ali, A.; Balkovec, J. M.; Graham, D. W.; Hammond, M. L.;
Patel, G. F.; Rouen, G. P.; Smith, S. K.; Tata, J. R.; Einstein, M.; Ge, L.; Harris, G.
S.; Kelly, T. M.; Mazur, P.; Thompson, C. M.; Wang, C. F.; Williamson, J. M.;
Miller, D. K.; Pandit, S.; Santoro, J. C.; Sitlani, A.; Yamin, T. D.; O'Neill, E. A.;
Zaller, D. M.; Carballo-Jane, E.; Forrest, M. J.; Luell, S. Bioorg. Med. Chem.
Lett. 2005, 15, 2926–2931. (m) Ali, A.; Balkovec, J. M.; Beresis, R.; Colletti, S.
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FIGURE 1. Crystal structure of 4-(7a-hydroxy-3,6-dioxooctahy-
droinden-3a-ylmethyl)-2,2-dimethyloxazolidine-3-carboxylic acid
tert-butyl ester (13bkb).
CH3CN at 25 °C for 5.0 h furnished the expected TCRA
product (-)-5ag with good conversion, which on further
removing the solvent CH3CN by vacuum pump, adding
solvent DMSO, 30 mol % of L-proline 4, and 3 equiv of
methyl vinyl ketone (b) to the reaction mixture, and stirring
at 25 °C for 2 days furnished the only Michael adduct (-)-
12agb with 75% yield and >98% ee instead of the expected
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Ramachary and Vijayendar Reddy
SCHEME 2. High-Yielding Synthesis of Chiral Building Block 80aaa: Formal Synthesis of Natural Products (A-I)
JOCArticle
W-M ketone analogue 13agb as shown in Table 7. In a
similar manner, L-proline-catalyzed TCRA reaction of
3 equiv of (R)-1a with cyclopentane-1,3-dione 2k and
Hantzsch ester 3 in CH3CN at 25 °C for 3.0 h furnished
the expected TCRA product (-)-5ak with good conversion,
which on further removing the solvent CH3CN by vacuum
pump and adding solvent DMSO, 30 mol % of L-proline 4
and 3 equiv of methyl vinyl ketone (b) to the reaction mixture
and stirring at 25 °C for 2 days furnished only the Michael
adduct (-)-12akb with 95% yield and >98% ee instead of
expected H-P ketone analogue 13akb as shown in Table 7.
Interestingly, treatment of (-)-12akb with 20 mol % of L-
proline 4-catalysis in DMSO at 50 °C for 24.0 h furnished the
expected bicyclic alcohol (þ)-13akb in 95% yield with
>98% ee and 99% de. Hydrolysis of bicyclic alcohol (þ)-
13akb obtained from L-proline-catalysis with L-proline (30
mol %) in DMSO at 25 °C for 96 h furnished the expected
bicyclic H-P ketone analogue (þ)-14akb in good yield with
>98% ee and 99% de as shown in Table 7.
With an efficient organocatalytic asymmetric sequential
cascade Robinson annulation (RA) protocol in hand, the
scope of the L-proline-L-proline-catalyzed sequential asym-
metric RA reactions was investigated with Garner aldehyde
(S)-1b. A series of cyclohexane-1,3-dione 2g/cyclopentane-
1,3-diones 2k were reacted with 3.0 equiv of Garner aldehyde
(S)-1b and Hantzsch ester 3 under 10 mol % of L-proline at
25 °C in CH3CN for 4-5 h followed by treatment with
3.0 equiv of methyl vinyl ketone (b) catalyzed by 30 mol % of
L-proline at 25 °C in DMSO for 48 h (Table 7). In the case of
2g, the expected Michael adduct (-)-12bgb was only ob-
tained in good yields with >98% ee as shown in Table 7. But
interestingly, sequential RA reaction with 2k furnished the
bicyclic alcohol (-)-13bkb in 90% yield with >98% ee and
99% de along with Michael adduct 12bkb as byproduct in
<8% yield. The absolute configuration of product (-)-
13bkb prepared under L-proline-L-proline-catalysis was
established by using X-ray crystallography and also by
comparison with the L-proline-catalyzed Hajos-Parrish-
Eder-Sauer-Wiechert reaction.10 The X-ray crystal struc-
ture of product (-)-13bkb is depicted in Figure 1.11
E. High-Yielding Synthesis of Chiral Building Blocks for
Natural Products Synthesis: Formal Total Synthesis of HIV-1
Protease Inhibitors, Phospholipase A2 Inhibitors, Antibiotic
Agglomerins, Brefeldin A, and (R)-γ-Hexanolide. After suc-
cessful demonstration of the L-proline-catalyzed asymmetric
TCRA reactions followed by development of MCC reactions
with the combination of A/K/E, A/K/E/A, H/L/E, H/E, H/
OM/DH, and RA reactions, we further decided to synthesize
the chiral building blocks for natural products synthesis
from MCC reactions as shown in Scheme 2. The design
and implementation of MCC reactions is a challenging task
of organic chemistry, yet one that can impart striking
novelty, elegance, and efficiency to synthetic strategies.
The application of MCC reactions to natural products
synthesis represents a particularly demanding task, but the
results can be both stunning and instructive. Herein, we
highlight the design and execution of the combination of
MCC reactions for the high-yielding synthesis of key inter-
mediates in the total synthesis with minimum synthetic steps
as demonstrated with selected natural product examples.12
Recently, chiral (5S)-5-hydroxymethyl-2-oxotetrahydro-
furan-3-carboxylic acid 80aaa was used as a key intermediate
for the total synthesis of HIV-1 protease inhibitors A-D,
phospholipase A2 inhibitors E and F, antibiotic agglomerins
G, (R)-γ-hexanolide H, and (þ)-brefeldin A I as shown in
Scheme 2.1a-i Ohta et al. and Kitahara et al. prepared the key
intermediate 80aaa in six steps starting from (R)-glyceralde-
hyde acetonide 1a with an overall yield of 40% in their total
synthesis of A-F and I, respectively.1a-i Herein, by the
combination of cascade TCRA and H/L/E reactions, we
prepared the key intermediate of chiral acid (5S)-80aaa by
using only three synthetic steps [TCRA, H/L/E, and hydro-
genation] with overall yield of 83% with >98% ee as shown
in Scheme 2. We also developed the other alternative method
to prepare (5S)-8’aaa with overall yield of 60% with >98%
ee by using again three synthetic steps [TCRA/A/K/E,
hydrolysis (H) and lactonization (L)], which is similar to
the previous approach for cyclization as shown in Scheme 2.
Herein, we have demonstrated the successful combination of
two cascades TCRA and H/L/E with hydrogenation; or/and
(10) (a) Zhong, G.; Hoffmann, T.; Lerner, R. A.; Danishefsky, S.; Barbas,
C. F. III. J. Am. Chem. Soc. 1997, 119, 8131–8132. (b) Bahmanyar, S.; Houk,
K. N. J. Am. Chem. Soc. 2001, 123, 11273–11283. (c) Bahmanyar, S.; Houk,
K. N. J. Am. Chem. Soc. 2001, 123, 12911–12912. (d) Hoang, L.; Bahmanyar,
S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16–17. (e) Bahmanyar,
S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475–
2479. (f) List, B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5839–5842. (g) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P.
H-Y.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558–569.
(11) CCDC-743987 for (-)-13bkb contains the supplementary crystal-
lographic data for this paper. This data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ, UK;
fax: (þ44)1223-336-033; or mail to: deposit@ccdc.cam.ac.uk.
(12) For the total synthesis of natural products through cascade reac-
tions, see: Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993–3009.
and references cited therein.
84 J. Org. Chem. Vol. 75, No. 1, 2010

Ramachary and Vijayendar Reddy
JOCArticle
TCRA/A/K/E with hydrolysis (H)/lactonization (L) to
furnish the (5S)-80aaa with overall yield of >83% with
>98% ee, which is utilized as key chiral building block for
the total synthesis of natural products A-I as shown in
Scheme 2.
Brønsted Acid-Catalyzed Cascade H/L/E and H/OM/DH
Reactions. In an ordinary glass vial equipped with a magnetic
stirring bar, to 0.1 mmol of the chiral TCRA product 5aa-ak
was added 1.0 mL of solvent followed by the catalyst p-TSA
(0.03 mmol, 30 mol %), and the reaction mixture was stirred at
25 °C for the time indicated in Table 5. The crude reaction
mixture washed with water, and the aqueous layer was extracted
with dichloromethane (3 ꢀ 15 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated. Pure
cascade H/L/E and H/OM/DH products 8-10 were obtained by
column chromatography (silica gel, mixture of hexane/ethyl
acetate).
L-Proline-HMPT-Catalyzed Sequential TCRA/A/K/E/A
Reactions. In an ordinary glass vial equipped with a magnetic
stirring bar, to 0.3 mmol of the chiral aldehyde 1, 0.3 mmol of
Meldrum’s acid 2a, and 0.3 mmol of Hantzsch ester 3 was
added 1.0 mL of CH3CN followed by the catalyst amino acid
4 (0.03 mmol, 10 mol %), and the reaction mixture was stirred
at 25 °C for the time indicated in Table 6. To the crude reaction
mixture was added 15 equiv of an ethereal solution of
diazomethane followed by methanol 7a (1.0 mL), and the
reaction mixture was stirred at room temperature for the time
indicated in Table 6. After evaporation of the solvent and excess
diazomethane completely in a fume hood, to the crude reaction
mixture were added 3 equiv of active olefins/acetylenes (a-d),
hexamethylphosphorous triamide (HMPT, 10 mol %),
and CH3CN (1.0 mL) and the mixture stirred at 25 °C for
0.5 h. The crude reaction mixture was directly loaded onto a
silica gel column with or without aqueous workup, and
pure one-pot chiral MCC products 11 were obtained by
column chromatography (silica gel, mixture of hexane/ethyl
acetate).
L-Proline-L-Proline-Catalyzed Sequential Double-Cascade
TCRA/Robinson Annulation Reactions. In an ordinary glass vial
equipped with a magnetic stirring bar, to 0.9 mmol of the
aldehyde 1, 0.3 mmol of CH-acids 2 g/k, and 0.3 mmol of
Hantzsch ester 3 was added 1.0 mL of CH3CN followed by the
catalyst amino acid 4 (0.03 mmol), and the reaction mixture was
stirred at 25 °C for the time indicated in Table 7. After
evaporation of the solvent completely, to the crude reaction
mixture were added 0.9 mmol of methyl vinyl ketone (b), 1.0 mL
of DMSO solvent, and 0.09 mmol of L-proline 4a, and the
reaction mixture was stirred at 25 °C for 2 days. The crude
reaction mixture was worked up with aqueous NH4Cl solution,
and the aqueous layer was extracted with dichloromethane (3 ꢀ
20 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated. Pure one-pot MCC products 12-14
were obtained by column chromatography (silica gel, mixture of
hexane/ethyl acetate).
Conclusions
In summary, we have developed the metal-free and MCC
process for the asymmetric synthesis of highly substituted
chiral building blocks (2-alkyl-CH-acids, 2-alkylcyclohex-
ane-1,3-diones, 2-alkylcyclopentane-1,3-diones, and H-P
ketone analogues) based on the three-component reductive
alkylation’s (TCRA) platform. We developed the single-step
alkylation of variety of CH-acids with (R)-glyceraldehyde
acetonide/(S)-Garner aldehyde and Hantzsch ester through
amino acid-catalyzed TCRA reaction without racemization
in very good yields. Direct combination of L-proline-cata-
lyzed TCRA reaction with other reactions like alkylation/
ketenization/esterification (A/K/E), alkylation/keteniza-
tion/esterification/alkylation (A/K/E/A), hydrolysis/lacto-
nization/esterification (H/L/E), hydrolysis/esterification
(H/E), hydrolysis/oxy-Michael/dehydration (H/OM/DH),
and Robinson annulation (RA) of CH-acids, chiral alde-
hydes, Hantzsch ester, diazomethane, and methyl vinyl
ketone furnished the highly functionalized chiral building
blocks with good to high yields and with excellent diaster-
eoselectivities. Many of the chiral building blocks [5aa, 5ba,
5ca, 5ag, 5ak, 5bg, 5bk, 5am, 5an, 5aaa, 8aab, 9baa, and 9caa]
prepared via MCC reactions are illustrated direct applica-
tion in pharmaceutical chemistry. Further work is in pro-
gress to utilize TCRA reactions in synthetic chemistry.
Experimental Section
General Experimental Procedures for the MCC Reactions. L-
Proline-Catalyzed Cascade TCRA Reactions. In an ordinary
glass vial equipped with a magnetic stirring bar, to 0.3 mmol
of the chiral aldehyde 1, 0.3 mmol of CH-acid 2a-o, and 0.3
mmol of Hantzsch ester 3 was added 1.0 mL of solvent followed
by the catalyst amino acid 4 (0.03 mmol, 10-mol %), and the
reaction mixture was stirred at 25 °C for the time indicated in
Tables 1-3. The crude reaction mixture was directly loaded
onto a silica gel column with or without aqueous workup, and
pure TCRA products 5 were obtained by column chromato-
graphy (silica gel, mixture of hexane/ethyl acetate).
L-Proline-Catalyzed Sequential TCRA/A/K/E Reactions. In
an ordinary glass vial equipped with a magnetic stirring bar, to
0.3 mmol of the chiral aldehyde 1, 0.3 mmol of Meldrum’s acid
2a or barbituric acid 2d, and 0.3 mmol of Hantzsch ester 3 was
added 1.0 mL of solvent followed by the catalyst amino acid 4
(0.03 mmol, 10 mol %), and the reaction mixture was stirred at
25 °C for the time indicated in Table 4. To the crude reaction
mixture added 15 equiv of an ethereal solution of diazomethane
followed by methanol 7a (1.0 mL), and the reaction mixture was
stirred at room temperature for the time indicated in Table 4.
After evaporation of the solvent and excess diazomethane com-
pletely in fume hood, the crude reaction mixture was directly
loaded onto a silica gel column with or without aqueous workup,
and pure one-pot MCC products 5 were obtained by column
chromatography (silica gel, mixture of hexane/ethyl acetate).
Acknowledgment. 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). Y.V.R.
thanks Council of Scientific and Industrial Research (CSIR),
New Delhi for a senior research fellowship. We thank Dr. P.
Raghavaiah for his help in X-ray structural analysis.
Supporting Information Available: Complete experimental
procedures, compound characterization, X-ray crystal struc-
tures, and analytical data (1H NMR, 13C NMR, HRMS, and
elemental analysis) for all new compounds. Copies of 13C NMR
spectra of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 1, 2010 85