Organocatalyzed enantioselective Michael addition of 2-hydroxy-1,4- naphthoquinone to β,γ-unsaturated α-ketophosphonatesθ

Article abstract of DOI:10.1021/jo2002825

By employing a cinchonine-based thiourea as catalyst, highly enantioselective Michael addition reactions of 2-hydroxy-1,4-naphthoquinone to β,γ-unsaturated α-ketophosphonates were realized. The reaction afforded the corresponding β-substituted carboxylates in excellent yields with high levels of enantioselectivities (94->99% ee) upon quenching the generated parent structures with DBU and MeOH as a second nucleophile.

Full text of DOI:10.1021/jo2002825

NOTE
pubs.acs.org/joc
Organocatalyzed Enantioselective Michael Addition of 2-Hydroxy-1,
4-naphthoquinone to β,γ-Unsaturated r-Ketophosphonatesθ
Tao Liu, Youming Wang,* Guiping Wu, Haibin Song, Zhenghong Zhou,* and Chuchi Tang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
People's Republic of China
S Supporting Information
b
ABSTRACT:
By employing a cinchonine-based thiourea as catalyst, highly enantioselective Michael addition reactions of 2-hydroxy-1,4-
naphthoquinone to β,γ-unsaturated R-ketophosphonates were realized. The reaction afforded the corresponding β-substituted
carboxylates in excellent yields with high levels of enantioselectivities (94ꢀ>99% ee) upon quenching the generated parent
structures with DBU and MeOH as a second nucleophile.
he Michael addition reaction represents one of the most
important and fundamental methods for construction of a
group will enhance activation of the substrate toward nucleo-
philic attack. (ii) Preferential binding between the catalyst and
the phosphoryl and carbonyl oxygens will lead to further activa-
tion of the substrate and also constrains it to a well-defined
orientation required for asymmetric induction. (iii) The facile
nucleophilic cleavage of the PꢀC bond enables the desired
β-branched optically active carboyxlates to be accessed in a
one-pot fashion under mild conditions. For example, using
chiral H-donor catalysts then oxazolones,8a indoles,8a,b and cyclic
1,3-dicarbonyl compounds8a were successfully introduced with
enantioselectivities up to 93%, 92%, and 95% ee, respectively.
Herein, we report another Michael donor, 2-hydroxy-1,
4-naphthaquinone,9 participated in the asymmetric Michael
addition to R,β-unsaturated acylphosphonates, generating the
corresponding β-(3-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-
2-yl)-substituted carboxylates in excellent yields with high levels
of enantioselectivities (94ꢀ>99% ee). Since naphthoquinones
are considered privileged structures in medicinal chemistry,10 the
organocatalytic additions of these valuable skeletons to electron-
deficient alkenes may provide an alternative process for some
novel optically active chemicals with potent pharmacological
properties.
T
carbonꢀcarbon bond in organic synthesis.1 As a result, with the
explosive development of organocatalysis during the past two
decades, considerable effort has been directed to the develop-
ment of the organocatalytic asymmetric version of these pro-
cesses, and a number of successful organocatalytic asymmetric
Michael additions have been reported. However, the Michael
acceptors employed in these asymmetric Michael additions
generally have been restricted to enals, enones, and nitroalkenes.2
The application of the efficient organocatalyst for Michael
addition of such acceptors to R,β-unsaturated esters seems to
be difficult because of the poorer nature of the R,β-unsaturated
ester as a Michael acceptor. Therefore, the development of
general and highly enantioselective versions of the reactions of
R,β-unsaturated acid derivatives still remains a challenging goal.
An in-direct, but equally efficient, strategy to encounter this
problem is the use of activated ester surrogates as masked
equivalents of the desired products. Various R,β-unsaturated
carbonyl compounds have been used as activated ester surrogates
in the catalytic enantioselective Michael reactions to give
products in which the desired carboxylates could be unveiled
in a subsequent step. Notable examples of such compounds
include R,β-unsaturated N-acylpyrazoles,3 alkenoyl pyrroles,4
styryloxazoles,5 R,β-unsaturated imides,6 and most recently
R,β-unsaturated acylphosphonates.7,8 Among these activated
ester surrogates, R,β-unsaturated acylphosphonates especially
deserve to be noticed owning to their unique characteristics:
(i) The electron-withdrawing capability of the phosphonate
First, a series of cinchona alkaloid derivatives 1ꢀ2 and bifunc-
tional thioureas 3ꢀ7 bearing different chiral diamine skeletons were
chosen as the catalyst candidates (Figure 1) and the conjugate
addition of 2-hydroxy-1,4-naphthaquinone (8a) to (E)-dimethyl
Received: February 9, 2011
Published: April 05, 2011
r
2011 American Chemical Society
4119
dx.doi.org/10.1021/jo2002825 J. Org. Chem. 2011, 76, 4119–4124
|

The Journal of Organic Chemistry
NOTE
Figure 1. Hydrogen bonding organocatalysts.
Table 1. Catalyst Screening a
diamine backbone of these thioureas plays a crucial role on both
the catalytic efficacy and chiral induction ability (Table 1,
entries 3ꢀ8). Takemoto’s thiourea 3a12 and cinchona alkaloid-
based thioureas 4 and 513 proved to be highly efficient for this
reaction. The reaction was complete within 5 min, giving the
corresponding conjugate addition product 10a with enantios-
electivities of 80%, 82%, and 80% ee, respectively (Table 1,
entries 3, 5, and 6). The use of catalyst 3b derived from (1R,2R)-
cyclohexane-1,2-diamine bearing a glucosyl scaffold14 and
catalyst 6 containing a (R,R)-11,12-diamino-9,10-dihydro-9,10-
ethanonanthracene skeleton led to a significant decrease in both
reaction rate and enantioselectivity (Table 1, entries 4 and 7).
Moreover, it is quite surprising that racemic product was
obtained when thiourea 7 derived from (þ)-cis-1,2,2-trimethyl-
cyclopentane-1,3-diamine was employed as the catalyst. These
results demonstrated that cinchonine-based thiourea 4 was the
best choice as the catalyst for the model reaction.
entry
catalyst
time
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
1
84 h
4 h
52
50
40
56
74
56
48
61
36
21
80
52
82
80
77
0
2
3a
3b
4
5 min
72 h
5 min
5 min
28 h
96 h
5
6
Having confirmed thiourea 4 as the optimum catalyst for the
reaction, other factors, such as solvent, catalyst loading, and
reaction temperature, influencing the reaction were thoroughly
investigated employing the reaction between (E)-dimethyl but-
2-enoylphosphonate (9a) and 2-hydroxy-1,4-naphthoquinone
(8a) as the model. The results are listed in Table 2.
7
a Reaction conditions: (E)-dimethyl but-2-enoylphosphonate (9a) (0.2
mmol), 2-hydroxy-1,4-naphthoquinone (8a) (0.2 mmol), in 2 mL of
methylene chloride at 20 °C in the presence of 10 mol % of catalyst.
b Yield of the isolated product after chromatography on silica gel.
c Determined by chiral HPLC analysis.
With 10 mol % of 4 as the catalyst at 20 °C, various solvents
have been examined for this reaction (Table 2, entries 1ꢀ6).
Except for methanol in which no reaction occurred, the asym-
metric Michael addition could be carried out smoothly in several
conventional solvents such as methylene chloride (82% ee),
chloroform (85% ee), THF (77% ee), ethyl acetate (83% ee),
and toluene (83% ee). The use of chloroform resulted in the
highest enantioselectivity of 85% ee albeit in low yield (Table 2,
entry 2). The conjugate addition product 10a was obtained in
high yield but with a slight loss of sterercontrol in toluene
(Table 2, entry 5). Thus, further screening indicated that the
reaction conducted in a mixture of CHCl3/PhCH3 (v/v, 1:1)
offered the best result (Table 2, entry 7). Adjusting the catalyst
loading demonstrated only little influence on the outcome of the
enantioselectivity of the reaction. The use of 5 mol % of catalyst
led to a slight improvement on enantioselectivity (Table 2, entry
8, 87% ee). The reaction proceeds well even at 2.5 mol % catalyst
but-2-enoylphosphonate (9a) was selected as a model reaction. The
experimental results are summarized in Table 1.
As shown in Table 1, The reaction of (E)-dimethyl but-2-
enoylphosphonate (9a) with 2-hydroxy-1,4-naphthoquinone
(8a) in the presence of catalyst 1 in methylene chloride as
solvent at 20 °C afforded the desired C-2 addition product 10a in
36% ee upon quenching with DBU and MeOH as a second
nucleophile (Table 1, entry 1).11 The replacement of 1 with
cinchonine (2) as the catalyst resulted in a dramatic rate
acceleration with slight erosion in enantioselectivity (Table 1,
entry 2 vs entry 1). The observed rate acceleration may attribute
to the hydrogen bond interaction between the more acidic
hydroxy group and the phosphoryl and carbonyl oxygens of
(E)-dimethyl but-2-enoylphosphonate which activate it toward
nucleophilic addition. In general, bifunctional thioureas are
promising catalysts for this transformation. However, the chiral
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The Journal of Organic Chemistry
NOTE
Table 2. Optimization of the Reaction Conditions a
Table 3. Chiral Thiourea 4 Catalyzed Asymmetric Michael
Addition of 2-Hydroxy-1,4-naphthoquinones 8 to R,β-Unsa-
turated Acylphosphonates 9a
entry
solvent
CH2Cl2
temp (°C)
time
yield (%)b ee (%)c
1
2
20
20
5 min
5 min
74
55
82
85
77
83
83
entry
10 (Y, R, R1, R2)
time (h)
yield (%)b
ee (%)c
CHCl3
1
2
10a (H, Me, Me, Me)
10a (H, Me, Et, Me)
10b (H, Me, Me, Et)
10c (H, Et, Me, Me)
10c (H, Et, Et, Me)
35
7
99
95
82
81
85
96
90
50
88
58
99
95
62
59
65
92
98
3
THF
20
10 min 63
5 min 46
10 min 72
98
4
AcOEt
20
3
35
2
97
5
PhCH3
20
4
96
6
MeOH
20
24 h
NR
5
48
1
98
d
d
d
d
d
d
7
CHCl3/PhCH3
CHCl3/PhCH3
CHCl3/PhCH3
CHCl3/PhCH3
CHCl3/PhCH3
CHCl3/PhCH3
20
10 min 72
20 min 67
85
87
88
96
98
99
6
10d (H, Pr, Me, Me)
10e (H, iPr, Me, Me)
10f (H, Bu, Me, Me)
10g (H, iBu, Me, Me)
10h (H, sBu, Me, Me)
10i (H, Ph, Me, Me)
10j (MeO, Me, Me, Me)
10k (MeO, Pr, Me, Me)
10l (MeO, iPr, Me, Me)
10m (MeO, Bu, Me, Me)
10n (MeO, iBu, Me, Me)
97
8 e
9 f
10 e
11e
12e
20
7
24
144
1
98
20
20 h
15 h
35 h
4.5 d
69
96
99
98
8
94
0
9
97
ꢀ25
ꢀ40
10
11
12
13
14
15
16
144
108
96
120
96
144
96
99 (96)d
>99
99
a Reaction conditions: (E)-dimethyl but-2-enoylphosphonate (9a) (0.2
mmol), 2-hydroxy-1,4-naphthoquinone (8a) (0.2 mmol) in 2 mL of
solvent in the presence of 10 mol % of catalyst 4. b Yield of the isolated
product after chromatography on silica gel. c Determined by chiral
HPLC analysis. d v/v = 1/1. e The reaction was conducted in the
96
99
94
f
presence of 5 mol % of catalyst. The reaction was conducted in the
99
presence of 2.5 mol % of catalyst.
a Reaction conditions: acyl phosphonates 9 (0.2 mmol), 2-hydroxy-1,4-
naphthoquinones 8 (0.2 mmol), in 2 mL of CHCl3/PhCH3 (v/v = 1:1)
at ꢀ25 °C in the presence of 5 mol % of catalyst 4. b Yield of the
isolated product after chromatography on silica gel. c Determined by
chiral HPLC analysis. d The ratio of the two diastereomers is 72/28. Data
in parentheses is the enantiomeric excess value of the minor
diastereomer.
loading at the expense of reaction time, without any erosion in
the observed ee value (Table 2, entry 9, 88% ee). It was gratifying
that decreasing the reaction temperature had a markedly positive
effect on the enantioselectivity of the reaction with a catalyst
loading of 5 mol % (Table 2, entries 8 and 10ꢀ12). Lowering the
temperature from 20 to ꢀ25 °C led to a sharp increase in
enantioselectivity (Table 2, entry 8, 87% ee vs entry 11, 98% ee).
Although almost perfect enantioselectivity was achieved, the
reaction became quite sluggish by further lowering the tempera-
ture to ꢀ40 °C (Table 2, entry 12).
Moreover, the use of ethanol instead of methanol as the
quenching nucleophile also led to the corresponding ethyl ester
adduct 10b with almost the same level of enantioselectivity
(Table 3, entry 3 vs entry 1). Diethyl acylphosphonates rather
than dimethyl acylphosphonates also worked well to furnish the
desired product with unaltered or even improved ee values
(Table 3, entries 2, 5 vs entries 1, 4). In addition, a substituted
2-hydroxy-1,4-naphthoquinone, such as 2-hydroxy-6-methoxyl-
1,4-naphthoquinone (8b), was also proved to be a suitable
reaction partner with different aliphatic R,β-unsaturated acyl
phosphonates, furnishing the desired products 10jꢀn with
94ꢀ99% ee albeit with decreased yields and prolonged reaction
times (Table 3, entries 12ꢀ16). Similarly, a bulkier substituent
on the β-position of R,β-unsaturated acyl phosphonates means
the higher ee values of the desired product (Table 3, entry 14 vs
entry 13; entry 16 vs entry 15).
With a set of optimized reaction conditions in hand (5 mol %
of 4 as the catalyst, at ꢀ25 °C in a 1:1 mixture of chloroform and
toluene), we then investigated the scope and limitations of this
asymmetric Michael addition reaction. The results are collected
in Table 3.
As shown in Table 3, in the case of 2-hydroxy-1,4-naphtho-
quinone (8a), the reaction tolerated both aliphatic and
aromatic substituents R on the R,β-unsaturated acyl phospho-
nates (Table 3, entries 1ꢀ11), affording the desired optically
active β-(3-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-sub-
stituted carboxylates 10aꢀi in 50ꢀ99% yield and 94ꢀ>99% ee.
With respect to the alkyl-substituted R,β-unsaturated acyl phos-
phonates, generally, the introduction of bulky alkyl substituent to
some extent favored the enantioselectivity of the reaction.
For example, the reaction of a linear alkyl group, such as propyl
and butyl, substituted substrates led to the addition product
with 97% and 94% ee, respectively (Table 3, entries 6 and 8).
However, the use of the corresponding branched alkyl group,
such as isopropyl, isobutyl, and second butyl, substituted ones
resulted in obviously improved enantioselectivities (Table 3,
entries 7, 9, and 10, 98%, 97%, and 99% ee, respectively).
The absolute configuration of the product 10a is unequivo-
cally established to be R by X-ray analysis (see the Supporting
Information, the absolute configuration of compound 10a was
determined by the Flack parameter ꢀ0.20(19), and further
examination was done by BijvoetPair check in platon) and the
remaining configurations are assumed by analogy.
To account for the observed high enantioselectivity of the
reaction, a ternary complex of thiourea catalyst 4, 1,4-dioxo-1,
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The Journal of Organic Chemistry
NOTE
For 7: white solid, 0.66 g, 75% yield, mp 166ꢀ167 °C, [R]20D ꢀ46.7
(c 0.3, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.89 (s, 3 H), 1.02 (s, 3
H), 1.66 (s, 3 H), 1.77ꢀ1.86 (m, 9 H), 2.23ꢀ2.27 (m, 1 H), 2.87 (br s,
1 H), 7.64 (s, 1 H), 7.69 (s, 2 H), 8.83 (br s, 2 H); 13C NMR (CDCl3,
100.6 MHz) δ 18.5, 24.3, 25.4, 33.2, 45.0, 49.4, 69.5, 74.6, 118.5 (br
signal, J = 3.6 Hz), 122.8 (q, J = 272.7 Hz), 124.1, 132.7 (q, J = 33.6 Hz),
139.7, 179.4; HRMS (ESI) m/z calcd for C19H25F6N3S [M ꢀ H]ꢀ
440.1601, found 440.1606.
General Procedure for the Catalytic Asymmetric Addition
of 2-Hydroxy-1,4-naphthoquinones to β,γ-Unsaturated
r-Ketophophonates. A 10 mL Schlenk tube was charged with
β,γ-unsaturated R-ketophophonate 9 (0.2 mmol), thiourea catalyst 4
(5 mol %), and a mixture of PhCH3/CHCl3 (2 mL, v/v = 1/1). After 30
min of stirring at ꢀ25 °C, 2-hydroxy-1,4-naphthonuinone (8, 0.2 mmol)
was added in one portion. The stirring was maintained at the same
temperature until the total consumption of 2-hydroxy-1,4-naphthonui-
none (8) (monitored by TLC). Upon completion the reaction mixture
was allowed to warm to room temperature and then methanol (0.2 mL)
and DBU (61 mg, 0.4 mmol) were added in the described sequence.
After an additionally 30 min of stirring, the crude reaction mixture was
diluted with saturated aqueous NH4Cl, extracted with EtOAc (3 ꢁ
5 mL), dried over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (200ꢀ300 mesh,
eluted with methylene chloride) to afford the desired optically active
3-substituted carboxylate 10.
Figure 2. Proposed transition state.
4-dihydronaphthalen-2-olate, and (E)-dimethyl but-2-enoylpho-
sphonate is proposed as a plausible transition state for this
transformation (Figure 2). In the proposed transition state,
1,4-dioxo-1,4-dihydronaphthalen-2-olate and (E)-dimethyl but-
2-enoylphosphonate coordinate to the thiourea moiety and
tertiary amino group of catalyst 4 by hydrogen bonding interac-
tion, respectively. Then nucleophilic attack of the 1,4-dioxo-1,4-
dihydronaphthalen-2-olate from the Re-face of (E)-dimethyl but-
2-enoylphosphonate leads to the formation of the (R)-enantio-
mer as the major product.
In conclusion, cinchonine-based thiourea 4 has proven to be
an efficient catalyst for the asymmetric Michael addition of
2-hydroxy-1,4-naphthoquinones to R,β-unsaturated acylpho-
sphonates. Subsequent treatment of the resulting conjugate
addition product with methanol in the presence of DBU
afforded β-(3-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-
substituted carboxylates in excellent yields and enantioselectiv-
ities (up to >99% ee). The presented approach allows for an
efficient route to formal β-functionalization of simple esters.
(R)-Methyl 3-(1,4-dihydro-2-hydroxy-1,4-dioxonaphtha-
len-3-yl)butanoate (10a): yellow solid, 54 mg, 99% yield, mp
1
98ꢀ99 °C, [R]20 ꢀ7.0 (c 1.0, CHCl3), 98% ee; H NMR (CDCl3,
D
400 MHz) δ 1.32 (d, J = 7.2 Hz, 3H), 2.73 (dd, J = 6.8 and 16.0 Hz, 1 H),
2.97 (dd, J = 8.4 and 16.0 Hz, 1 H), 3.61 (s, 3 H), 3.71ꢀ3.80 (m, 1 H),
7.51 (br s, 1 H), 7.67 (t, J = 7.6 Hz, 1 H), 7.75 (t, J = 7.6 Hz, 1 H), 8.06 (d,
J = 7.6 Hz, 1 H), 8.12 (d, J = 7.6 Hz, 1 H); 13C NMR (CDCl3, 100.6
MHz) δ 18.2, 26.7, 38.2, 51.5, 126.0, 127.0, 129.2, 132.9, 133.0, 135.0,
152.8, 173.0, 181.6, 184.1; HRMS (ESI) m/z calcd for C15H14O5 [M þ
Na]þ 297.0733, found 297.0724; HPLC analysis (Chiralpak OJ-H
column, hexane:2-propanol = 75:25, flow rate = 1.0 mL/min, wave-
length = 220 nm) Rt = 13.96 (major) and 20.12 min (minor).
(R)-Ethyl 3-(1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-
3-yl)butanoate (10b): yellow solid, 47 mg, 82% yield, mp 90ꢀ91 °C,
[R]20D ꢀ4.0 (c 1.0, CHCl3), 97% ee; 1H NMR (CDCl3, 400 MHz) δ
1.17 (t, J = 7.2 Hz, 3 H), 1.32 (d, J = 7.2 Hz, 3H), 2.71 (dd, J = 6.8 and
16.0 Hz, 1 H), 2.96 (dd, J = 8.8 and 16.0 Hz, 1 H), 3.71ꢀ3.81 (m, 1 H),
4.05 (dq, J = 2.8 and 7.2 Hz, 2 H), 7.48 (br s, 1 H), 7.67 (dt, J = 1.2 and
7.6 Hz, 1 H), 7.76 (dt, J = 1.2 and 7.6 Hz, 1 H), 8.06 (dd, J = 1.2 and 7.6
Hz, 1 H), 8.12 (dd, J = 0.8 and 7.6 Hz, 1 H); 13C NMR (CDCl3, 100.6
MHz) δ 14.1, 18.2, 26.7, 38.5, 60.2, 126.0, 126.2, 127.0, 129.2, 132.8,
133.0, 135.0, 152.8, 172.5, 181.6, 184.1; HRMS (ESI) m/z calcd for
C16H16O5 [M ꢀ H]ꢀ 287.0925, found 287.0925; HPLC analysis
(Chiralpak OJ-H column, hexane:2-propanol = 75:25, flow rate =
1.0 mL/min, wavelength = 220 nm) Rt = 9.51 (major) and 14.20 min
(minor).
’ EXPERIMENTAL SECTION
All reagents and solvents were commercial grade and purified prior to
use when necessary. NMR spectra were acquired on either a 300 or 400
MHz instrument. Chemical shifts are measured relative to residual
solvent peaks as an internal standard set to δ 7.26 and 77.0 (CDCl3).
Enantiomeric excesses were determined on a HPLC instrument (chiral
column; mobile phase: hexane/i-PrOH). Column chromatography was
performed on silica gel (200ꢀ300 mesh).
Preparation of Thioureas 6 and 7. To a solution of chiral parent
diamine (2 mmol) in methylene chloride (4 mL) was added dropwise a
solution of the 3,5-bis(trifluoromethyl)phenyl isothiocyanate (0.54 g,
2 mmol) in methylene chloride (4 mL) under a nitrogen atmosphere.
The resulting mixture was stirred at room temperature until total
consumption of the isothiocyanate (monitored by TLC). After removal
of solvent, the residue was purified through column chromatography on
silica gel (200ꢀ300 mesh, eluted with ethyl acetate/petroleum ether:
1/2) to give the thiourea catalyst as a white solid.
(R)-Methyl 3-(1,4-dihydro-2-hydroxy-1,4-dioxonaphtha-
len-3-yl)pentanoate (10c): yellow oil, 47 mg, 81% yield and 49
mg, 85% yield (from (E)-diethyl pent-2-enoylphosphonate), [R]20
D
þ4.0 (c 1.0, CHCl3), 96% ee and 98 ee (from (E)-diethyl pent-2-
enoylphosphonate); 1H NMR (CDCl3, 400 MHz) δ 0.88 (t, J = 7.2 Hz,
3 H), 1.68ꢀ1.76 (m, 1 H), 1.80ꢀ1.89 (m, 1 H), 2.74 (dd, J = 6.0 and
15.6 Hz, 1 H), 2.99 (dd, J = 9.2 and 16.0 Hz, 1 H), 3.59 (s, 2 H),
3.54ꢀ3.61 (m, 1 H), 7.51 (br s, 1 H), 7.67 (t, J = 7.6 Hz, 1 H),
7.75 (t, J = 7.6 Hz, 1 H), 8.07 (d, J = 7.6 Hz, 1 H), 8.12 (d, J = 7.6 Hz, 1
H); 13C NMR (CDCl3, 100.6 MHz) δ 12.2, 25.7, 33.8, 36.9, 51.5,
124.8, 126.0, 127.0, 129.3, 132.8, 133.0, 135.0, 153.3, 173.2, 181.4,
184.3; HRMS (ESI) m/z calcd for C16H16O5 [M ꢀ H]ꢀ 287.0925,
found 287.0926; HPLC analysis (Chiralpak AS-H column, hexane:
For 6: white solid, 1.06 g, 99% yield, mp 116ꢀ117 °C, [R]20D þ48.4
1
(c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 2.29 (s, 6 H), 3.00
(s, 1 H), 3.86 (s, 1 H), 4.29 (s, 1 H), 4.62 (s, 1 H), 6.23 (s, 1 H),
7.16ꢀ7.22 (m, 4 H), 7.32ꢀ7.40 (m, 4 H), 7.58 (s, 1 H), 7.98 (s, 2 H),
12.04 (s, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 41.4, 42.9, 48.4, 57.9,
72.9, 117.9 (br signal, J = 3.2 Hz), 122.8, 123.1 (q, J = 273.3 Hz), 123.6,
125.8, 126.0, 126.7, 126.9, 127.4, 131.7 (q, J = 33.5 Hz), 137.5, 140.2,
140.4, 141.7, 142.7, 181.3; HRMS (ESI) m/z calcd for C27H23F6N3S
[M ꢀ H]ꢀ 534.1444, found 534.1446.
4122
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The Journal of Organic Chemistry
NOTE
2-propanol = 75:25, flow rate = 1.0 mL/min, wavelength = 220 nm) Rt =
10.95 (minor) and 14.48 min (major).
(R)-methyl 3-(1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-
75.0 MHz) δ 10.9 (minor isomer), 11.2 (major isomer), 16.8 (major
isomer), 17.1 (minor isomer), 26.9 (minor isomer), 27.5 (major
isomer), 34.8 (major isomer), 35.0 (minor isomer), 36.6, 37.4 (minor
isomer), 37.9 (major isomer), 51.4, 125.3, 126.0, 127.1, 129.3, 132.8,
133.0, 134.9, 153.2, 173.5, 181.3, 184.3; HRMS (ESI) m/z calcd for
C18H20O5 [M ꢀ H]ꢀ 315.1238, found 315.1236; HPLC analysis
(Chiralpak AD-H column, hexane:2-propanol = 85:15, flow rate =
1.0 mL/min, wavelength = 220 nm) Rt = 9.40 (minor, major isomer),
10.15 (major, major isomer), 11.20 (major, minor isomer), and 12.34
min (minor, minor isomer).
(S)-Methyl 3-(1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-
3-yl)-3-phenylpropanoate (10i): yellow oil, 67 mg, 99% yield,
[R]20D ꢀ15 (c 1.0, CHCl3), >99% ee; 1H NMR (CDCl3, 400 MHz) δ
3.21 (dd, J = 6.4 and 16.4 Hz, 1 H), 3.55 (dd, J = 9.6 and 16.8 Hz, 1 H),
3.62 (s, 3 H), 5.00 (dd, J = 6.4 and 9.6 Hz, 1 H), 7.19 (t, J = 7.2 Hz, 1 H),
7.28 (t, J = 7.6 Hz, 2 H), 7.47 (d, J = 7.6 Hz, 1 H), 7.63 (s, 1 H), 7.73 (t, J
= 7.2 Hz, 1 H), 8.03 (d, J = 7.2 Hz, 1 H), 8.11 (d, J = 7.6 Hz, 1 H); 13C
NMR (CDCl3, 100.6 MHz) δ 36.3, 36.9, 51.7, 124.3, 126.0, 127.1, 128.1,
128.5, 129.1, 132.8, 132.9, 135.1, 141.2, 152.7, 172.7, 181.6, 184.0;
HRMS (ESI) m/z calcd for C20H16O5 [M ꢀ H]ꢀ 335.0925, found
335.0929; HPLC analysis (Chiralpak OJ-H column, hexane:2-propanol
= 75:25, flow rate = 1.0 mL/min, wavelength = 220 nm) Rt = 42.17 min
(major).
(R)-Methyl 3-(1,4-dihydro-2-hydroxy-6-methoxy-1,4-dioxo-
naphthalen-3-yl)butanoate (10j): yellow oil, 58 mg, 95% yield,
[R]20D ꢀ8.0 (c 1.0, CHCl3), 99% ee; 1H NMR (CDCl3, 300 MHz) δ
1.31 (d, J = 7.2 Hz, 3 H), 2.72 (dd, J = 6.9 and 15.9 Hz, 1 H), 2.95 (dd, J =
8.4 and 16.0 Hz, 1 H), 3.61 (s, 3 H), 3.67ꢀ3.77 (m, 1 H), 3.95 (s, 3 H),
7.11 (dd, J = 2.4 and 8.4 Hz, 1 H), 7.58 (d, J = 2.7 Hz, 1 H), 7.60 (br s, 1
H), 8.00 (d, J = 8.4 Hz, 1 H); 13C NMR (CDCl3, 75.0 MHz) 18.2, 26.7,
38.3, 51.5, 56.0, 111.0, 119.2, 122.4, 125.3, 128.7, 135.6, 153.1, 165.4,
180.2, 184.0; HRMS (ESI) m/z calcd for C16H16O6 [M ꢀ H]þ
303.0874, found 303.0873; HPLC analysis (Chiralpak AD-H column,
hexane:2-propanol = 90:10, flow rate = 1.0 mL/min, wavelength =
220 nm) Rt = 38.29 (minor) and 50.42 min (major), 99% ee.
(R)-Methyl 3-(1,4-dihydro-2-hydroxy-6-methoxy-1,4-di-
3-yl)hexanoate (10d): yellow oil, 58 mg, 96% yield, [R]20 ꢀ4.6
D
(c 1.0, CHCl3), 97% ee; 1H NMR (CDCl3, 300 MHz) δ 0.88 (d, J = 7.2
Hz, 3 H), 1.21ꢀ1.34 (m, 2 H), 1.56ꢀ1.67 (m, 1 H), 1.78ꢀ1.91
(m, 1 H), 2.72 (dd, J = 6.0 and 15.9 Hz, 1 H), 2.97 (dd, J = 9.3 and
15.9 Hz, 1 H), 3.59 (s, 3 H), 3.64ꢀ3.72 (m, 1 H), 7.50 (br s, 1 H), 7.67
(dt, J = 1.2 and 7.5 Hz, 1 H), 7.75 (dt, J = 1.5 and 7.5 Hz, 1 H), 8.06 (dd, J
= 1.2 and 7.5 Hz, 1 H), 8.12 (dd, J = 0.9 and 7.5 Hz, 1 H); 13C NMR
(CDCl3, 75.0 MHz) δ 14.0, 20.9, 31.9, 34.9, 37.2, 51.5, 125.0, 126.0,
127.0, 129.2, 132.8, 133.0, 135.0, 153.2, 173.1, 181.4, 184.3; HRMS
(ESI) m/z calcd for C17H18O5 [M ꢀ H]ꢀ 301.1081, found 301.1082;
HPLC analysis (Chiralpak OJ-H column, hexane:2-propanol = 75:25,
flow rate = 1.0 mL/min, wavelength = 220 nm) Rt = 7.81 (major) and
24.18 min (minor).
(S)-Methyl 3-(1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-
3-yl)-4-methylpentanoate (10e): yellow oil, 54 mg, 90% yield,
[R]20D ꢀ1.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.84 (d,
J = 6.8 Hz, 3 H), 1.03 (d, J = 6.8 Hz, 3 H), 2.13ꢀ2.22 (m, 1 H), 2.79 (dd,
J = 4.8 and 16.0 Hz, 1 H), 3.01 (dd, J = 10.8 and 16.0 Hz, 1 H),
3.30ꢀ3.36 (m, 1 H), 3.55 (s, 3 H), 7.51 (br s, 1 H), 7.67 (t, J = 7.6 Hz, 1
H), 7.75 (t, J = 7.6 Hz, 1 H), 8.06 (d, J = 7.6 Hz, 1 H), 8.12 (d, J = 7.6 Hz,
1 H); 13C NMR (CDCl3, 100.6 MHz) 21.1, 21.3, 30.3, 35.2, 39.3, 51.5,
125.2, 126.0, 127.1, 129.3, 132.8, 132.9, 135.0, 153.2, 181.3, 184.4;
HRMS (ESI) m/z calcd for C17H18O5 [M ꢀ H]ꢀ 301.1081, found
301.1082; HPLC analysis (Chiralpak OJ-H column, hexane:2-propanol
= 75:25, flow rate = 1.0 mL/min, wavelength = 220 nm) Rt = 8.45
(major) and 13.89 min (minor).
(R)-Methyl 3-(1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-
3-yl)heptanoate (10f): yellow solid, 32 mg, 50% yield, mp
1
60ꢀ61 °C, [R]20 ꢀ0.6 (c 1.0, CHCl3), 94% ee; H NMR (CDCl3,
D
400 MHz) δ 0.84 (t, J = 6.0 Hz, 3 H), 1.18ꢀ1.29 (m, 4 H), 1.64 (br s, 1
H), 1.84 (br s, 1 H), 2.73 (dd, J = 5.6 and 15.6 Hz, 1 H), 2.96 (dd, J = 10.0
and 15.6 Hz, 1 H), 3.59 (s, 3 H), 3.63ꢀ3.64 (m, 1 H), 7.50 (br s, 1 H),
7.67 (t, J = 7.2 Hz, 1 H), 7.76 (t, J = 7.2 Hz, 1 H), 8.07 (d, J = 7.6 Hz, 1 H),
8.12 (d, J = 7.6 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 13.9, 22.6,
29.9, 32.1, 32.4, 37.2, 51.5, 125.1, 126.0, 127.1, 129.3, 132.8, 132.9, 133.0,
135.0, 153.2, 173.1, 181.4, 184.3; HRMS (ESI) m/z calcd for C18H20O5
[M þ Na]þ 339.1203, found 339.1199; HPLC analysis (Chiralpak OJ-H
column, hexane:2-propanol = 85:15, flow rate = 1.0 mL/min, wave-
length = 220 nm) Rt = 9.77 (major) and 13.77 min (minor).
oxonaphthalen-3-yl)hexanoate (10k): yellow oil, 41 mg, 62%
1
yield, [R]20 ꢀ3.8 (c 1.0, CHCl3), 96% ee; H NMR (CDCl3, 400
D
MHz) δ 0.88 (t, J = 7.2 Hz, 3 H), 1.25ꢀ1.32 (m, 2 H), 1.59ꢀ1.63 (m,
1 H), 1.79ꢀ1.88 (m, 1 H), 2.71 (dd, J = 6.0 and 15.6 Hz, 1 H), 2.95 (dd,
J = 9.2 and 15.6 Hz, 1 H), 3.59 (s, 3 H), 3.62ꢀ3.68 (m, 1 H), 3.95 (s, 3
H), 7.11 (dd, J = 2.4 and 8.4 Hz, 1 H), 7.58 (d, J = 2.8 Hz, 1 H), 7.60 (br s,
1 H), 8.00 (d, J = 8.4 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 14.0,
20.9, 31.9, 34.8, 37.2, 51.5, 56.0, 110.9, 119.2, 122.5, 124.1, 128.7, 135.5,
153.5, 165.3, 173.2, 180.0, 184.2; HRMS (ESI) m/z calcd for C18H20O6
[M þ Na]þ 355.1152, found 355.1155; HPLC analysis (Chiralpak
AD-H column, hexane:2-propanol = 85:15, flow rate = 1.0 mL/min,
wavelength = 220 nm) Rt = 33.40 (minor) and 45.05 min (major).
(S)-Methyl 3-(3-hydroxy-7-methoxy-1,4-dioxo-1,4-dihydro-
naphthalen-2-yl)-4-methylpentanoate (10l): yellow solid, 39
mg, 59% yield, mp 63ꢀ64 °C, [R]20D ꢀ1.8 (c 1.0, CHCl3), 99% ee; 1H
NMR (CDCl3, 400 MHz) δ 0.84 (d, J = 6.8 Hz, 3 H), 1.03 (d, J = 6.8 Hz,
3 H), 2.12ꢀ2.21 (m, 1 H), 2.78 (dd, J = 4.0 and 16.0 Hz, 1 H), 3.01 (dd, J
= 10.8 and 16.0 Hz, 1 H), 3.28ꢀ3.34 (m, 1 H), 3.55 (s, 3 H), 3.95 (s, 3
H), 7.12 (dd, J = 2.4 and 8.4 Hz, 1 H), 7.59 (br s, 2 H), 8.01 (d,
J = 8.8 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) 21.1, 21.3, 30.3, 35.2,
39.3, 51.5, 56.0, 111.0, 119.3, 122.5, 124.3, 128.7, 135.5, 153.5, 165.3,
173.5, 180.0, 184.3; HRMS (ESI) m/z calcd for C18H20O6 [M þ Na]þ
355.1152, found 355.1152; HPLC analysis (Chiralpak AD-H column,
hexane:2-propanol = 75:25, flow rate = 1.0 mL/min, wavelength =
220 nm) Rt = 32.38 (major) and 37.18 min (minor).
(R)-Methyl 3-(1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-
3-yl)-5-methylhexanoate (10g): yellow oil, 56 mg, 88% yield,
[R]20D ꢀ5.0 (c 1.0, CHCl3), 97% ee; 1H NMR (CDCl3, 400 MHz) δ
0.80 (br s, 3 H), 0.85 (br s, 3 H), 1.35 (br s, 2 H), 1.79ꢀ1.83 (m, 1 H),
2.62 (d, J = 15.6 Hz, 1 H), 2.88 (dd, J = 10.0 and 15.2 Hz, 1 H), 3.52 (s, 3
H), 3.67ꢀ3.69 (m, 1 H), 7.46 (br s, 1 H), 7.61 (t, J = 6.8 Hz, 1 H), 7.69
(t, J = 6.4 Hz, 1 H), 7.99 (d, J = 6.8 Hz, 1 H), 8.05 (d, J = 7.2 Hz, 1 H);
13C NMR (CDCl3, 100.6 MHz) δ 22.1, 23.3, 26.3, 30.2, 37.5, 41.8, 51.5,
125.1, 126.0, 127.0, 129.2, 132.8, 133.0, 135.0, 153.3, 173.0, 181.4, 184.2;
HRMS (ESI) m/z calcd for C18H20O5 [M ꢀ H]ꢀ 315.1238, found
315.1236; HPLC analysis (Chiralpak OJ-H column, hexane:2-propanol
= 85:15, flow rate = 1.0 mL/min, wavelength = 220 nm) Rt = 8.57
(major) and 11.12 min (minor).
(3S)-Methyl 3-(1,4-dihydro-2-hydroxy-1,4-dioxonaphtha-
len-3-yl)-4-methylhexanoate (10h): yellow oil, 37 mg, 58% yield,
[R]20D ꢀ10.4 (c 1.0, CHCl3), 72/28 dr, 99% ee for major diastereomer
1
and 96% ee for minor diastereomer; H NMR (CDCl3, 300 MHz) δ
0.83 (t, J = 8.1 Hz, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.05ꢀ1.20 (m, 1 H),
1.32ꢀ1.38 (m, 1 H), 1.95ꢀ2.03 (m, 1 H), 2.77 (dd, J = 6.4 and 15.6 Hz,
1 H), 3.03 (dd, J = 10.8 and 15.6 Hz, 1 H), 3.39ꢀ3.48 (m, 1 H), 3.55 (s, 3
H), 7.51 (br s, 1 H), 7.67 (t, J = 7.2 Hz, 1 H), 7.75 (t, J = 7.2 Hz, 1 H),
8.06 (d, J = 7.5 Hz, 1 H), 8.12 (d, J = 7.5 Hz, 1 H); 13C NMR (CDCl3,
(R)-Methyl 3-(1,4-dihydro-2-hydroxy-6-methoxy-1,4-dioxo-
naphthalen-3-yl)heptanoate (10m): yellow oil, 45 mg, 65% yield,
[R]20D ꢀ2.2 (c 1.0, CHCl3), 94% ee; 1H NMR (CDCl3, 400 MHz) δ
4123
dx.doi.org/10.1021/jo2002825 |J. Org. Chem. 2011, 76, 4119–4124

The Journal of Organic Chemistry
NOTE
0.84 (d, J = 6.8 Hz, 3 H), 1.25ꢀ1.33 (m, 4 H), 1.60ꢀ1.66 (m, 1 H),
1.80ꢀ1.86 (m, 1 H), 2.71 (dd, J = 6.0 and 15.6 Hz, 1 H), 2.95 (dd,
J = 9.6 and 15.6 Hz, 1 H), 3.61 (s, 3 H), 3.62ꢀ3.65 (m, 1 H), 3.95
(s, 3 H), 7.12 (dd, J = 2.4 and 8.4 Hz, 1 H), 7.58 (s, 1 H), 7.59 (br s, 1 H),
8.01 (d, J = 8.4 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 14.0, 22.6,
29.9, 32.1, 32.4, 37.2, 51.5, 56.0, 110.9, 119.3, 122.4, 124.1, 128.7, 135.5,
153.5, 165.3, 173.2, 180.0, 184.2; HRMS (ESI) m/z calcd for C19H22O6
[M þ Na]þ 369.1309, found 369.1304; HPLC analysis (Chiralpak
AD-H column, hexane:2-propanol = 75:25, flow rate = 1.0 mL/min,
wavelength = 220 nm) Rt = 32.38 (major) and 37.18 min (minor).
(R)-Methyl 3-(3-hydroxy-7-methoxy-1,4-dioxo-1,4-dihy-
dronaphthalen-2-yl)-5-methylhexanoate (10n): yellow oil, 64
mg, 92% yield, [R]20D ꢀ4.0 (c 1.0, CHCl3), 99% ee; 1H NMR (CDCl3,
300 MHz) δ 0.87 (d, J = 6.3 Hz, 3 H), 0.91 (d, J = 6.0 Hz, 3 H),
1.35ꢀ1.46 (m, 2 H), 1.80ꢀ1.92 (m, 1 H), 2.67 (dd, J = 6.3 and 15.9 Hz,
1 H), 2.92 (dd, J = 9.3 and 15.9 Hz, 1 H), 3.59 (s, 3 H), 3.67ꢀ3.77
(m, 1 H), 3.94 (s, 3 H), 7.11(dd, J = 2.7 and 8.7 Hz, 1 H), 7.58 (d, J = 2.4
Hz, 1 H), 7.63 (br s, 1 H), 7.99 (d, J = 8.4 Hz, 1 H); 13C NMR (CDCl3,
100.6 MHz) δ 22.1, 23.3, 26.3, 30.2, 37.5, 41.8, 51.5, 56.0, 110.9, 119.2,
122.5, 124.2, 128.7, 135.6, 153.6, 165.3, 173.1, 180.0, 184.2; HRMS
(ESI) m/z calcd for C19H22O6 [M þ Na]þ 369.1309, found 369.1307;
HPLC analysis (Chiralpak AD-H column, hexane:2-propanol = 75:25,
flow rate = 1.0 mL/min, wavelength = 220 nm) Rt = 18.4 (minor) and
26.54 min (major), 99% ee.
(7) (a) For pioneering work on the use of these Michael acceptors in
asymmetric catalysis, see: (a) Telan, L. A.; Poon, C.-D.; Evans, S. A.
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Campos, K. R. Tetrahedron Lett. 1999, 40, 2879. (d) Evans, D. A.;
Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635. (e) Evans,
D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem.
Soc. 2003, 125, 10780. (f) Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc.
2006, 128, 7442. (g) Takenaka, N.; Abell, J. P.; Yamamoto, H. J. Am.
Chem. Soc. 2007, 129, 742. (h) Samanta, S.; Krause, J.; Mandai, T.; Zhao,
C.-G. Org. Lett. 2007, 9, 2745.
(8) (a) Jiang, H.; Paix~ao, M. W.; Monge, D.; Jørgensen, K. A. J. Am.
Chem. Soc. 2010, 132, 2775. (b) Bachu, P.; Akiyama, T. Chem. Commun.
2010, 4112.
(9) For works on the use of 2-hydroxy-1,4-naphthoquinones as
Michael donors, see: (a) Rueping, M.; Sugiono, E.; Merino, E. Angew.
Chem., Int. Ed. 2008, 47, 3046. (b) Zhou, W.-M.; Liu, H.; Du, D.-M. Org.
Lett. 2008, 10, 2817. (c) Wang, Y.-F.; Zhang, W.; Luo, S.-P.; Zhang,
G.-C.; Xia, A.-B.; Xu, X.-S.; Xu, D.-Q. Eur. J. Org. Chem. 2010, 4981.
(10) Ravelo, A.; Estꢀevez-Braun, A.; Chꢀavez-Orellana, H.; Pꢀerez-
Sacau, E.; Mesa-Silverio, D. Curr. Top. Med. Chem. 2004, 4, 241.
(11) Sekine, M.; Kume, A.; Hata, T. Tetrahedron Lett. 1981,
37, 3617.
(12) Okino, T.; Nakamura, A.; Furukawa, T.; Takemoto, Y. Org. Lett.
2004, 6, 625.
(13) Vakulya, B.; Varga, S.; Csampai, A.; Soꢀos, T. Org. Lett. 2005,
7, 1967.
’ ASSOCIATED CONTENT
(14) (a) Wang, C. G.; Zhou, Z. H.; Tang, C. C. Org. Lett. 2008,
10, 1707. (b) Gao, P.; Wang, C. G.; Wu, Y.; Zhou, Z. H.; Tang, C. C. Eur.
J. Org. Chem. 2008, 4563.
S
Supporting Information.
Copies of NMR spectra,
b
HPLC analysis, as well as complete data for the reported crystal
structure. This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: z.h.zhou@nankai.edu.cn and youmingwang@eyou.
com.
’ ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of
China (Nos. 20772058 and 20972070), the National Basic
research Program of China (973 program 2010CB833300),
and the Key laboratory of Elemento-Organic Chemistry for
generous financial support for our programs.
’ REFERENCES
(1) For review, see: Perlmutter, P. Conjugate addition reactions in
organic synthesis; Pergamon: Oxford, UK, 1992.
(2) For selected reviews on organocatalytic asymmetric conjugate
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(e) Enders, D.; Wang, C.; Liebich, J. X. Chem.—Eur. J. 2009, 15, 11058
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dx.doi.org/10.1021/jo2002825 |J. Org. Chem. 2011, 76, 4119–4124