Highly enantioselective construction of a quaternary carbon center of dihydroquinazoline by asymmetric Mannich reaction and chiral recognition

Article abstract of DOI:10.1002/adsc.200800039

The highly enantioselective construction of a quaternary carbon center of dihydroquinazoline by an asymmetric Mannich reaction and chiral recognition are described. The key transformation was to establish the chiral trifluoromethyl quaternary carbon center bya diamine-Bronsted acid-catalyzed enantioselective and regioselective Mannich reaction of a methyl ketone and 4-trifluoromethyldihydroquinazoline. An unusual phenomenon of self-discrimination of enantiomers in hydrogen-bonded dimers was observed. A valuable intermediate was transformed into the enantiopure HIV reverse transcriptase inhibitor DPC 083 (>99.9 ee) simplyby reduction of the carbonyl group and elimination of the hydroxy group in hexamethylphosphoric tramide (HMPA).

Full text of DOI:10.1002/adsc.200800039

FULL PAPERS
DOI: 10.1002/adsc.200800039
Highly Enantioselective Construction ofa Quaternary Carbon
Center ofDihydroquinazoline by Asymmetric Mannich Reaction
and Chiral Recognition
Biao Jiang,a,* Jia Jia Dong,a Yu Gui Si,a Xiao Long Zhao,a Zuo Gang Huang,a
and Min Xua
a
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, Peopleꢀs
Republic of China
Fax : (+86)-21-6416-6128; e-mail: jiangb@mail.sioc.ac.cn
Received: January19, 2008; Revised: March 4, 2008; Published online: May9, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The highlyenantioselective construction of
a quaternarycarbon center of dihydroquinazoline by
of enantiomers in hydrogen-bonded dimers was ob-
served. A valuable intermediate was transformed
an asymmetric Mannich reaction and chiral recogni- into the enantiopure HIV reverse transcriptase in-
tion are described. The keytransformation was to es- hibitor DPC 083 (>99.9 ee) simplybyreduction of
tablish the chiral trifluoromethyl quaternary carbon the carbonyl group and elimination of the hydroxy
center bya diamine -Brønsted acid-catalyzed enantio- group in hexamethylphosphoric tramide (HMPA).
selective and regioselective Mannich reaction of a
À
methyl ketone and 4-trifluoromethyldihydroquinazo- Keywords: C C coupling; HIV therapeutics; hydro-
line. An unusual phenomenon of self-discrimination gen bonds; organocatalysis; self-discrimination
Introduction
Chiral nitrogen-containing compounds are widelydis-
tributed in nature and include manybiologicallyim-
portant molecules. The generation of tertiaryalcohol
stereocenters can be achieved easilyin most cases by
using the appropriate chiral auxiliary, reagent, or cata-
lyst. However, the approach to complex compounds
bearing quaternarystereocenters, such as tertiary
amines and related systems, is still a challenge for syn-
thetic organic chemists, and everyenantioselective
procedure for the construction of a fullysubstituted
carbon center is of great value.[1]
In recent years, a number of dihydroquinazolines
bearing a chiral trifluoromethyl group have occupied
a central role in fighting AIDS. For example, DPC
961 and DPC 083 are second-generation non-nucleo-
side HIV reverse transcriptase inhibitors (NNRTIs)
Figure 1. Structures of Efavirenz, DPC 961 and DPC 083
and retrosynthesis of DPC 083.
with enhanced potencyin comparison with Efavirenz
(SustivaTM) (Figure 1).[2] The challenge for synthesiz- nones containing a chiral auxiliaryN-substituent,
ing this class of NNRTIs is to form a tertiarycarbina- 1,2-enantioselective addition of a lithium acetylide to
mine with absolute stereocontrol. Previously, tremen- cyclic N-acylketimines using lithium Cinchona alka-
dous efforts mainlyfocused on the synthesis of this
loids as the chiral moderator.[4] Our group also devel-
tion of a magnesium acetylide to 2(3H)-quinazoli-
[3]
class of compounds via formation of the chiral propar- oped a mild and efficient method for the asymmetric
gylamine, for example, the diastereoselective 1,4-addi- synthesis of DPC 961, in which a highly enantioselec-
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HighlyEnantioselective Construction of a QuaternaryCarbon Center
FULL PAPERS
tive addition of zinc acetylide to a cyclic N-acylketi- strates, and the direct Mannich reactions were carried
mine in the presence of the chiral chloramphenicol out using a catalytic amount of l-proline (30 mol%)
ligand was employed as the key step.[5] In contrast to in DMSO at room temperature. It was found that the
DPC 961, little work has been done on the synthesis reaction proceeded rapidlyand the desired products 2
of DPC 083. The onlymethod developed for DPC
083 was reduction of DPC 961 bylithium aluminum
hydride,[3] which is obviouslynot suitable in large-
(P=H, P=PMB) were afforded in quantitative yields
within 2 h. However, the enantioselectivities were
quite low (20–30% ee) (Table 1, entries 1–3). A more
scale synthesis. Therefore, it is highly desirable to bulky protecting group, 2,4,6-trimethylbenzyl (TMB),
seek a practical and scalable alternative for the con- seemed to prolong the reaction time to 12 h, with no
struction of the tertiarycarbinamine stereogenic
beneficial effect on the enantioselectivity. A number
center and asymmetric synthesis of DPC 083 and its of solvents were tested, onlyDMSO and DMF could
analogues to meet clinical demands. We envisioned give good yields. Decreasing the amount of the cata-
that DPC 083 could be prepared bythe reduction-de-
lyst or lowering the temperature (<108C) had little
hydration sequence from a b-amino ketone intermedi- effect on the enantioselectivity, however, the reaction
ate, which could be regarded as a potential asymmet- was slowed down and this resulted in loss of the yield.
ric Mannich adduct (Figure 1).
All of the optimization conditions did not lead to sig-
It is well known that the catalytic asymmetric Man- nificant improvements in enantioselectivityunder the
À
nich reaction is an effective C C bond forming pro- catalysis of l-proline.
cess for the construction of chiral b-amino carbonyl
Then we turned to screening other structurallydi-
compounds. In recent years, a tremendous amount of verse amine catalysts (3b–3g) (Table 1, entries 4–9).
work and effort has been devoted to the development a-Methylproline (3c) provided moderate yield and
of efficient and versatile organocatalyzed asymmetric enantioselectivity. However, the major product had
Mannich reactions,[6] but the structure of the electro- an opposite absolute configuration (entry5). The
phile has been restricted to imines derived from alde- more soluble catalyst, 4-siloxyproline (3d),[8] gave
hydes. The organocatalytic enantioselective Mannich good yield but with poor enantioselectivity (entry 6).
reaction of imines derived from ketones (ketimines) The MacMillan chiral imidazolidinone[9] (HCl salt)
is verylimited, although the substrates would consti-
(3e) could not catalyze the reaction at all (entry 7).
tute an interesting template for the synthesis of qua- The tetrazole catalyst (3g)[10] behaved similarlyto l-
ternary b-amino carbonyl compounds. To the best of proline with a rapid reaction rate and good yield, but
our knowledge, the onlyexample of an organocatalyt-
poor enantioselectivity(entry9). The chiral diamine
ic enantioselective Mannich reaction of ketimines and (S)-2-(1-pyrrolidinylmethyl)pyrrolidine (3f), a catalyst
unmodified aldehydes was reported by the Jorgensen of choice in the Mannich reaction of ketimines and
group,[7] while the asymmetric synthesis of tertiary unmodified aldehydes reported by the Jorgensen
carbinamines bythe organocatalyzed Mannich reac-
group,[7] also promoted the reaction and gave a better
tion of unsymmetrical ketones with ketimines has enantioselectivity(51% ee) (entry8), but the yield
generated considerable frustration. Thus, the develop- was verylow (38%). It is known that the proper
ment of an efficient protocol for an enantioselective design of acid-base catalysis has been shown to be ef-
direct Mannich reaction of a ketimine with a ketone fective for achieving high reactivityand selectivityin
remains challenging, especiallywhen the Mannich ad-
ducts could be applied in the practical synthesis of opment of diamine-Brønsted acid types of catalyst.[11]
pharmaceuticallyimportant compounds. Thus, we attempted to optimize the reaction through
Herein, we present a novel and efficient protocol the addition of Brønsted acids. The combinations of
for the construction of a chiral quaternarycarbon diamine 3f with different Brønsted acids in a ratio of
the asymmetric direct aldol reaction during the devel-
center of dihydroquinazoline (cyclic N-acylketimine) 1:1.1 were employed as catalysts in the direct Man-
bya diamine -Brønsted acid-catalyzed enantioselective nich reactions (Table 1, entries 10–17). Indeed,
and regioselective Mannich reaction of a methyl Brønsted acids could accelerate the reaction dramati-
ketone and 4-trifluoromethyldihydroquinazoline and callyand a few of the 3f-Brønsted acid salts (1:1.1)
self discrimination of enantiomers in the hydrogen- were found to catalyze the formation of 2ba in good
bonded dimers, which was applied to the preparation yields. Interestingly, the diacid, dibenzoyl-l-tartaric
of the HIV reverse transcriptase inhibitor DPC 083 acid (l-DBT, 0.55 equiv.), proved to be superior
with excellent enantiopurity( >99.9 ee).
(entry15) and the chiralityof tartaric acid seemed to
have no influence on the stereoselectivityof the reac-
tion (entry16). When switching the protecting group
from PMB to more the bulkyTMB, 2ca was obtained
in 92% yield with an improved enantioselectivity
Results and Discussion
Initially, 4-trifluoromethyldihydroquinazolines (1a– (71% ee). Using 1a as a substrate, the activityof the
1c)[3a] and acetone were investigated as model sub- diamine-Brønsted acid catalysts was quite poor (yield
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Table 1. Direct Mannich reaction of 4-trifluoromethyldihydroquinazolines 1a–1c and acetone.[a]
EstntryCataly Substrate
t [h]
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3a
3a
1a
1b
1c
1b
1b
1b
1b
2
2
2aa
2ba
2ca
2ba
2ba
2ba
2ba
2ba
2ba
2ba
2ba
2ba
2ba
2ba
2ba
2ba
2ca
quant.
quant.
97
80
65
82
N.R
38
98
91
64
76
88
89
95
89
92
23
30
20
<2
55[e]
21
nd
51
25
18
55
17
47
49
54
49
71
3a
12
24
72
48
24
120
2
12
24
48
72
72
12
12
24
3b[d]
3c
3d
3e
3f1b
3g
9
1b
1b
1b
1b
1b
1b
1b
1b
1c
10
11
12
13
14
15
16
17
3f+1[f]
3f+2[f]
3f+3[f]
3f+4[f]
3f+5[f]
3f+6[f]
3f+7[f]
3f+6[f]
[a]
All reactions were performed on 0.14 mmol scale in DMSO (1 mL) and acetone (0.25 mL) at room temperature (PMB=
p-methoxybenzyl, TMB=2,4,6-trimethylbenzyl).
Isolated yield.
Determined bychiral HPLC analysis.
50 mol% l-alanine was used.
Opposite stereoselectivitywas obtained.
1:1.1 mixture of diamine and Brønsted acid was used.
[b]
[c]
[d]
[e]
[f]
<50%), probablydue to the influence of the active
proton on the distal nitrogen of 1a.
and 13). Isopropyl methyl ketone and the more bulky
tert-butyl methyl ketone were found to be inert
To expand the scope of the reaction, various ke- donors for this reaction. Furthermore, worthyof note
tones were tested as Mannich donors under the catal- is the unique regioselectivityobserved in our cases.
ysis of 3f-DBT. l-Proline 3a was also tested for com- Generally, the regioselectivity in an organocatalyzed
parison. The results are illustrated in Table 2. It was enantioselective direct Mannich reaction was affected
found that the bulkiness of the ketone substituent bythe structure and electronic properties of both the
(R1) could dramaticallyinfluence the reaction out-
unsymmetrical ketone and imine. The highly regiose-
comes. The reactions of linear alkyl methyl ketones lectivities reported so far were obtained onlywhen an
(4c, 4d, 4f) or cyclopropyl methyl ketone (4b) with a-hydroxy ketone as a donor or an electron-deficient
the dihydroquinazolines (1a–1c) proceeded smoothly imine derived from a-imino glyoxylate as an acceptor
À
and gave the desired products 2 in high yields (91– were used, and the C C bond formation occurred ex-
95%) (Table 2, entries 1–10, 14, 15). However, the clusivelyon the more substituted side of the ketone
bulky isobutyl methyl ketone gave only 51–75% yield to afford branched b-amino carbonyl compounds. In
in reactions under the catalysis of 3f-DBT (entries 12 contrast, nucleophilic addition of a non-oxygen-substi-
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Table 2. Reaction of 4-trifluoromethyldihydroquinazolines 1a–1c with unsymmetrical methyl ketones.
[a]
EntryKetone
st Cataly
Ketimine
Product
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4b
4b
4b
4b
4c
4c
4c
4c
4d
4d
4e
4e
3a
3a
1a
1b
1b
1c
1a
1b
1b
1c
1b
1b
1b
1b
1c
2bf
1b
1c
2ab
2bb
2bb
2cb
2ac
2bc
2bc
2cc
2bd
2bd
2be
2be
2ce
96
72
72
96
24
24
48
72
72
72
72
120
192
48
72
96
94
89
94
95
95[d]
95
95
94
96
91
89
75
51
91
92
87
44
40
57
75
30
58
69
78
47
74
66
76
66
61
78
79
3f+DBT
3f+DBT
3a
3a
3f+DBT
3f+DBT
3a
3f+DBT
3a
3f+DBT
3f+DBT
1b
9
10
11
12
13
14
15
16
4e
4f3a
4f3f
4f3f
+DBT
+DBT
2bf
2cf
[a]
l-DBT was used.
Isolated yield.
[b]
[c]
[d]
Determined bychiral-phase HPLC.
Total yield of the two regioisomers (11:1), ee of major product is shown.
tuted unsymmetrical ketone to other imines often re- enantiomers in the hydrogen-bonded dimers provided
sulted in a mixture of regioisomers.[12] To our surprise, an efficient alternative for rapid access to a series of
high regioselectivities were observed in most of our enantiopure compounds 2. Initially, we tried to im-
cases. The dihydroquinazoline was regiospecifically prove the enantiopurityof this series of compounds 2
attacked by the methyl side of unsymmetrical methyl byrecrsytallization, however, it was found that the
ketones to give the linear b-amino ketone as the sole crystals we collected were racemates in all cases. X-
product. Only in the case of ethyl methyl ketone 4c ray crystallography of representative racemic crystals
and dihydroquinazoline 1a were regioisomers ob- revealed that two enantiomers with opposite absolute
tained in the ratio of 11:1 (entry5). Regarding enan-
configurations bind to each other through multiple
tioselectivity, diamine-Brønsted acid catalyst 3f-DBT hydrogen bonds in a C2-symmetric heterochiral dimer-
showed much higher ee than l-proline 3a (entries 2/3, ic form (Figure 2).[13] On the other hand, since the sol-
6/7, 9/12, 14/15). In addition, the bulkier TMB pro- ubilityof heterochiral dimers were extremelypoor in
tecting group in the dihydroquinazoline substrate ethanol, the ee value of compounds 2 can be easily
gave enhanced enantioselectivities (69–79% ee) in enhanced from 57–75% to >99% bya single recrys-
most cases (entries 7, 8, 15, 16). To our delight, under tallization, and the yield was approximately equal to
the catalysis of 3f-DBT, the Mannich donor cyclo- the enantiomeric excess (ee) before crystallization
propyl methyl ketone 4b (entries 1–4) reacted with 1c (Table 3). Enantiopure compounds 2 remained in the
to afford 2cb in 95% yield with 75% ee, which could mother liquor and racemic crystals were removed by
be considered as a valuable intermediate to synthesize simple filtration (see Experimental Section). Howev-
DPC 083.
er, compounds 2aa, 2ab, 2ac without a protecting
Although the enantioselectivityof the reaction was
group on the distal nitrogen (P=H) did not display
not satisfactory for a practical asymmetric synthesis, self-discrimination under various conditions.
an interesting phenomenon of self-discrimination of
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Figure 2. X-ray crystallography of the heterochiral hydrogen-bonded dimers (RS)-2bb.
Table 3. A single recrystallization increases the enantiomeric purity of these series of compounds.[a]
1
EntryR
P
Compound[b]
ee [%][c] before recrystallization
ee [%][c] after recrystallization
Yield [%][d]
1
2
3
4
5
6
7
Et
Et
Et
c-C3H5
c-C3H5
i-Bu
n-Hex
PMB
PMB
TMB
PMB
TMB
PMB
PMB
2bc
2bc
2cc
2bb
2cb
2be
2bf
58
69
57
57
75
66
61
99.1
99.6
99.7
99.3
>99.9
99.5
>99.9
55
67
53
53
67
60
58
[a]
All reactions and single recrystallizations were performed on 1–2 g scale.
Compounds were purified bycolumn chromatography(silica, CH 2Cl2/EtOAc).
Determined bychiral-phase HPLC analysis.
[b]
[c]
[d]
Yield=the isolated pure enantiomers, all before recrystallization (In theory, the yield should be equal to the ee values
before recrystallization).
With enantiopure 2cb in hand, we then focused on
the synthesis of DPC 083. As shown in Scheme 1, the
TMB protecting group was removed under TFA/ani-
sole conditions to afford 2ab in quantitive yield. Re-
duction of the carbonyl group in 2ab byKBH gave
4
two diastereoisomers 5a and 5b in a 98% yield with a
ratio of 2:1. The isomeric mixture was directlydehy-
drated in HMPA[14] to give DPC 083. Recrystalliza-
tion from CHCl3/hexane gave enantiopure DPC 083
[>99.9% ee, containing 3.5% (Z)-isomer] with a spe-
cific rotation of [a]D20: À22.5 (c 0.40 in CH3OH), which
Scheme 1. The synthesis of DPC 083 from enantiopure 2cb:
a) i. TFA, anisole, 708C, 20 min, quant.; ii. 4 equiv. KBH4,
MeOH, room temperature, overnight, 98%; b) HMPA,
was in accordance with the optical rotation data[15] of 2308C, 7–10 min, 60%.
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layers were washed with brine, dried over Na2SO4. Concen-
tration under vacuum and purification byflash chromatogra-
phyon silica gel (for P =PMB, TMB, CH2Cl2:EtOAc=20:1
or hexane:EtOAc=4:1 to 3:1; for P=H, hexane:EtOAc=
2:1 to 1:1) provided product 2aa–2cf.
(S)-DPC 083 synthesized from (S)-DPC 961 bylithi-
um aluminum hydride reduction.[2a] Therefore, the
stereochemistryof the final product and the keyorga-
nocatalyzed direct Mannich adduct 2cb were assigned
as the S configuration.
Typical Procedure for the Recrystallization to
Increase the Enantiomeric Purity
Conclusions
Compound 2cb (1.75 g, ee=75%) was dissolved in boiling
ethanol, then the mixture was slowlyconcentrated within
1 h and the volume of solvent was reduced to ca.15 mL.
(The major part of the RS dimer has alreadyprecipitated at
this time). The mixture was cooled to room temperature
and allowed to stand overnight, then further cooled to
À208C and allowed to stand for 2 h. After quick filtration,
the mother liquor was concentrated under vacuum to give
2cb (yield: 1.18 g, 67%, ee=99.9%) as a white solid, and the
filter cake was dried to afford (RS)-2cb (yield: 470 mg,
ee<4%). The ee value was determined byHPLC using
In summary, a highly enantioselective construction of
a quaternarycarbon center of trifluoromethyldihydro-
quinazoline byan asymmetric Mannich reaction and
chiral recognition is described. The keytransforma-
tion was to establish the chiral trifluoromethyl quater-
narycarbon center bya diamine -Brønsted acid-cata-
lyzed enantioselective and regioselective direct Man-
nich reaction of a methyl ketone and a 4-trifluorome-
thyldihydroquinazoline. Particularly, special regiose-
lectivities were observed in all cases. An unusual Chiralcel AD-H column, i-PrOH/hexane=40:60, flow rate=
0.7 mLminÀ1, tmajor =7.39 min, tminor =19.62 min, 254 nm.
phenomenon of self-discrimination of enantiomers in
the hydrogen-bonded dimers was observed, and by
(S)-6-Chloro-4-(2-cyclopropyl-2-oxoethyl)-4-
(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one
[(S)-2ab]
taking advantage of the unique spontaneous chiral
recognition of the Mannich adducts, a rapid access to
enantipure DPC 083 (>99.9% ee) was demonstrated.
Compared with the reported process, our process was
carried out under extremelymild conditions, simple
manipulation and short reaction steps with higher
enantiopurity.
A mixture of (S)-2cb (100 mg, 0.216 mmol, ee>99.9%),
TFA (2 mL) and anisole (1 mL) was heated at 708C for
10 min. After cooling to room temperature. Water (10 mL)
was added and the mixture was extracted with EtOAc
(5 mL”5). The combined organic layers were washed with
1N NaOH, brine and dried over Na2SO4. Concentration
under vacuum gave the crude product, which was purified
byflash chromatographyon silica gel (hexane:EtOAc =2:1)
to give (S)-2ab as a white solid; yield: 71 mg (quant.); [a]2D0:
+ 5.29 (c 0.48 in acetone); ee>99.9%; the ee value was de-
termined byHPLC using Chiralcel AD-H column, i-PrOH/
hexane=10:90, flow rate=0.5 mLminÀ1, tr(S)=46.79 min,
tr(R)=50.39 min, 254 nm.
Experimental Section
General Procedure for the Organocatalytic Enantio-
selective Direct Mannich Reactions of4-Trifluoro-
methyldihydroquinazolines 1a–1c and Methyl Ketones
4a-4f
(a) l-Proline as the catalyst: To a solution of 4-trifluorome-
thyldihydroquinazolines (1a–1c) (0.14 mmol) and l-proline
(4.8 mg, 0.04 mmol) in dryDMSO (1 mL), was added the
ketone (0.25 mL) in one portion under an argon atmos-
phere. The reaction mixture was stirred at room tempera-
ture until the ketimine disappeared (monitored by 19F NMR
or TLC). Water (4 mL) was added, the mixture was extract-
ed with EtOAc (5 mL”4), the combined organic layers
were washed with brine and dried over Na2SO4. Concentra-
tion under vacuum and purification byflash chromatogra-
phyon silica gel (for P =PMB, TMB, CH2Cl2:EtOAc=20:1
or hexane:EtOAc=4:1 to 3:1; for P=H, hexane:EtOAc=
2:1 to 1:1) provided product 2.
(b) 3f-DBT as the catalyst: To a solution of l-DBT (8 mg,
0.022 mmol) in dryDMSO (1 mL), was added diamine 3f
(6.9 uL, 0.042 mmol) in one portion under argon. After the
reaction mixture had been stirred for 15 min, ketone
(0.25 mL) and 4-trifluoromethyldihydroquinazoline (1b, 1c)
(0.14 mmol) were added. The reaction mixture was stirred
at room temperature until the 4-trifluoromethyldihydroqui-
nazolines disappeared. Water (4 mL) was added, the mixture
was extracted with EtOAc (5 mL x 4), the combined organic
(4S)-6-Chloro-4-(2-cyclopropyl-2-hydroxyethyl)-4-
(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one
(5a) and (5b)
To a solution of (S)-2ab (580 mg, 1.7 mmol) in methanol
(20 mL), was added KBH4 (424 mg, 7.86 mmol) in portions
at room temperature. After being stirred at room tempera-
ture overnight, the mixture was concentrated; the residue
was partitioned between H2O and EtOAc. The organic layer
was separated, washed with brine, and dried over Na2SO4.
Concentration under vacuum provided the crude product,
which was purified byflash chromatographyon silica gel
(hexane:EtOAc=2:1 to 1:1) to provided a mixture of 5a
and 5b (570 mg, 5a/5b=2/1), yield: 98%.
A
methyl)-3,4-dihydroquinazolin-2(1H)-one (DPC 083)
A solution of 5a and 5b (480 mg, 1.44 mmol) in dryHMPA
(5 mL) was heated to 225–2308C under argon. After being
kept gentlyboiling for 7–10 min, the solution was then
quicklycooled to room temperature. The mixture was dilut-
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Biao Jiang et al.
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ed with water (20 mL) and extracted with EtOAc (20 mL”
6). The combined organic layers were washed with brine
and dried over Na2SO4. Concentration under vacuum pro-
vided the crude product, which was purified byflash chro-
matographyon silica gel (hexane:EtOAc =4:1) and re-
crystallization from CHCl3/hexane then cyclohexane to give
DPC 083 as colorless crystals; yield: 270 mg (60%);
[6] For recent reviews on organocatalyzed asymmetric
Mannich reactions, see: a) J. M. M. Verkade, L. J. C.
van Hemert, P. J. L. M. Quaedflieg, F. P. J. T. Rutjes,
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Barbas III, Acc. Chem. Res. 2004, 37, 580–591; e) A.
Cordova, Acc. Chem. Res. 2004, 37, 102–112.
ee>99.9%, (E, S)/
mined byHPLC using Chiralcel AD-H column, i-PrOH/
hexane=5:95, flow rate=0.7 mLminÀ1, tr
(Z,S)=23.95 min,
tr(E,R)=26.54 min, tr
(E,S)=30.44 min, 254 nm; [a]2D0: À22.5
(c 0.40 in CH3OH).
A
AHCTREUNG
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A
ACHTREUNG
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ushima, M. Shoji, D. Hashizume, H. Koshino, Adv.
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Angew. Chem. 2004, 116, 6890–6892; Angew. Chem.
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Supporting Information
Characterization data for all compounds are available as
Supporting Information.
[10] A. J. A. Cobb, D. M. Shaw, S. V. Ley, Synlett 2004, 558–
560.
[11] For review in acid-base organocatalyzed asymmetric
aldol reactions, see: S. Saito, H. Yamamoto, Acc.
Chem. Res. 2004, 37, 570–579.
Acknowledgements
Financially support of this work by the Science & Technology
Commission of Shanghai Municipality, the National Natural
Science Foundation of China and Chinese Academy of Scien-
ces is gratefully acknowledged.
[12] For examples of organocatalyzed Mannich reaction of
ketones with imines, see: a) H. Zhang, S. Mitsumori, N.
Utsumi, M. Imai, N. Garcia-Delgado, M. Mifsud, K.
Albertshofer, P. H. Cheong, K. N. Houk, F. Tanaka,
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Adv. Synth. Catal. 2008, 350, 1360 – 1366