The construction of quaternary stereocenters by the Henry reaction: Circumventing the usual reactivity of substituted glyoxals

Article abstract of DOI:10.1002/chem.201002888

The enantioselective Henry reaction between alkyl- and arylglyoxal hydrates and nitromethane catalyzed by Cu^II-iminopyridine complexes takes place regioselectively on the ketone carbonyl group to give chiral tertiary nitroaldols with high functional group density and enantiomeric excesses of up to 96 %. Both aromatic and aliphatic glyoxals are suitable substrates for this reaction.

Full text of DOI:10.1002/chem.201002888

DOI: 10.1002/chem.201002888
The Construction of Quaternary Stereocenters by the Henry Reaction:
Circumventing the Usual Reactivity of Substituted Glyoxals
Gonzalo Blay,* Vꢀctor Hernꢁndez-Olmos, and Josꢂ R. Pedro*[a]
Dedicated to the memory of Professor Rafael Suau, University of Malaga, former president of the RSEQ Organic Division
Abstract: The enantioselective Henry reaction between alkyl- and arylglyoxal hy-
drates and nitromethane catalyzed by CuII–iminopyridine complexes takes place
regioselectively on the ketone carbonyl group to give chiral tertiary nitroaldols
with high functional group density and enantiomeric excesses of up to 96%. Both
aromatic and aliphatic glyoxals are suitable substrates for this reaction.
Keywords: asymmetric catalysis ·
copper · Henry reaction · N ligands ·
nucleophilic addition
Introduction
tromethane to ketones has been only achieved with highly
electrophilic compounds. Thus, the groups of Saa[7] and Ban-
dini[8] have described the enantioselective reaction between
nitromethane and ketones activated by a strong electron-
withdrawing CF3 group using rare earths and organocataly-
sis, respectively. a-Ketoesters, with a ketone carbonyl group
activated by a less-reactive vicinal ester group, have been re-
acted successfully with nitromethane under catalytic condi-
tions to give tertiary nitroaldols with remarkable enantio-
meric excess (ee) values in some cases.[9] However, the prod-
ucts that result from these reactions have little chance of
functional modification due to the moderate reactivity of
the ester group. Therefore, the search for new procedures
toward new highly functionalized and modifiable tertiary ni-
troaldols with chirality control is still challenging.
a-Oxoaldehydes (glyoxals) are interesting reaction sub-
strates because of the presence of two different vicinal car-
bonyl groups. Arylglyoxals usually are sticky oily or semi-
solid compounds that are difficult to handle and prone to di-
merize or polymerize. Nevertheless, these compounds are
normally prepared and stored as their corresponding mono-
hydrates, which are stable solids. Arylglyoxals have been
used as substrates in a number of catalytic enantioselective
nucleophilic addition reactions,[10] especially carbonyl–ene
reactions.[10a–d] Most of these reactions were catalyzed by
water-sensitive Lewis acids, and therefore, arylglyoxals had
to be used in their anhydrous form. Furthermore, arylglyox-
al hydrates have been used as electrophiles in several enan-
tioselective reactions. Examples include the enantioselective
synthesis of mandelic acid derivatives by a Cannizaro reac-
tion,[11] carbonyl–ene reactions with water-tolerant PdII and
PtII complexes,[12] and organocatalytic cross-aldol reactions
with aldehydes.[13] In all cases, the reaction takes place at
the more-reactive aldehyde carbonyl group if anhydrous or
hydrated glyoxals were used. As a matter of fact, the only
two examples of nucleophilic addition (cyanosilylation reac-
tions) to the ketone carbonyl group of arylglyoxals reported
so far required previous protection of the aldehyde as an
The enantioselective construction of quaternary stereocen-
ters is a challenging goal that has attracted much attention
during recent years.[1] Asymmetric nucleophilic additions to
prochiral ketones provide one of the most attractive ap-
proaches toward chiral building blocks containing oxygenat-
ed quaternary stereocenters. On the other hand, enantio-
merically enriched nitroalkanols, which can be obtained by
condensation of nitroalkanes with carbonyl compounds
(Henry or nitroaldol reaction), have a high scientific and
commercial value as building blocks for pharmaceuticals
and agrochemicals.[2] During recent years, considerable prog-
ress on the development of catalytic enantioselective proce-
dures for the Henry reaction with aldehydes[3] and aldi-
mines[4] as electrophiles has been achieved. However, the
most challenging enantioselective Henry reaction with pro-
chiral ketones still has to be developed. In fact, even for the
nonenantioselective version, only a few methodologies are
available with limited substrate scopes.[5] These difficulties
arise from the attenuated reactivity of the ketone carbonyl
group and the high tendency of the tertiary nitroaldol prod-
ucts to undergo a retro-Henry reaction under basic condi-
tions. As a consequence, no examples of direct enantioselec-
tive condensation of nitroalkanes with simple ketones have
been described so far, although enantiomerically enriched
tertiary nitroaldols derived from simple ketones have been
obtained by Shibashaki et al. upon kinetic resolution of rac-
emic mixtures.[6] So far, the direct asymmetric addition of ni-
[a] Dr. G. Blay, Dr. V. Hernꢀndez-Olmos, Prof. Dr. J. R. Pedro
Departament de Quꢁmica Orgꢂnica, Facultat de Quꢁmica
Universitat de Valꢃncia
C/Dr. Moliner 50, Burjassot (Valꢃncia) (Spain)
Fax : (+34)963544328
E-mail: gonzalo.blay@uv.es
jose.r.pedro@uv.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002888.
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Chem. Eur. J. 2011, 17, 3768 – 3773

FULL PAPER
acetal.[14] As a part of our research addressed toward the de-
velopment of the Henry reaction with ketones,[9d] we have
considered the possibility of carrying out the addition of ni-
troalkanes to the ketone group of glyoxals to obtain tertiary
nitroaldols with a reactive aldehyde group. To achieve this
goal, we need to circumvent the normal reactivity shown by
glyoxals with nucleophiles, that is, the preferential attack of
nitromethane to the aldehyde carbonyl. It is known that, in
alcohol solvents, arylglyoxals and their hydrates are almost
quantitatively converted into the corresponding hemiace-
tals.[11] Therefore, our hypothesis was that direct nitrome-
thane addition to the ketone should be possible in these sol-
vents if it was faster than the equilibration between the
hemiacetal and dicarbonyl forms of the glyoxal (Scheme 1).
Scheme 2. Henry reaction with glyoxal hydrates and ligands used in this
study.
this moderate ee value was the result of a competitive non-
AHCTUNGTREGeNNNU nantioselective background reaction promoted by DIPEA
(1 equiv), we tested the reaction in the absence of any
added base (Table 1, entry 2). However, under these condi-
tions only a sluggish reaction was observed. Encouraged by
the initial result, we examined the related iminopyridine 6
under similar conditions and obtained compound 3a in
81% ee (Table 1, entry 3). Iminopyridines 7–9 were also
tested, although none of them provided better results than
ligand 6 (Table 1, entries 4–6). Further optimization was
then carried out with ligand 6 by changing CuII salt, base,
and solvent (Table 1, entries 8–13). The best result was ob-
Scheme 1. Competitive pathways for nucleophilic addition to arylglyoxal
hydrates.
Herein, we report the catalytic enantioselective addition of
nitromethane to substituted glyoxal hydrates, with an unpre-
cedented regioselectivity, to give 2-substituted-2-hydroxy-3-
nitropropanals with an oxygenated quaternary stereogenic
center.
tained by performing the reaction with ligand 6, CuACHTUNGTRENNUNG(OTf)2,
and DIPEA in iPrOH as the solvent at À508C (Table 1,
entry 13). In this way compound 3a was obtained in 99%
yield and 91% ee. It should be mentioned that when we at-
tempted the reaction with the “privileged ” bis-oxazoline
(BOX) ligand 10 for comparative purpose, the reaction did
not proceed at temperatures below 08C and in this way the
reaction took place to give compound 4a as the major prod-
Results and Discussion
In this scenario, a highly active
Lewis acid catalyst tolerant to
hydroxylic solvents was re-
quired. Our group has devel-
oped imino- and aminopyridine
ligands (5–9) that, in the pres-
ence of CuII salts, catalyze the
Henry reaction with aldehydes
Table 1. Optimization of the reaction conditions between phenylglyoxal hydrate (1a, R=Ph) and nitrome-
thane (2).[a]
Entry[b]
Ligand
CuII salt
Base
Solvent
t [h]
Yield[c] [%]
ee[d] [%]
1
2
3
4
5
6
7
8
5
5
6
7
8
9
10
6
6
6
6
6
6
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
N
DIPEA
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
nPrOH
iPrOH
26
–
99
–
57
–
81
34
3
63
8[e]
85
82
85
76
73
91
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
DIPEA
DIPEA
DIPEA
DIPEA
22
22
26
24
24
16
20
16
16
22
22
98
94
93
99
60[e]
99
98
99
99
98
99
at
low
temperatures
in
EtOH.[15] To our delight, under
similar conditions, nitrome-
thane and phenylglyoxal hy-
drate 1a (Ar=Ph) reacted in
the presence of ligand 5 and
9
10
11
12
13
CuACHTUNGTRENNUNG(OAc)2 to give a crude prod-
uct that consisted almost exclu-
sively of 3a in 57% ee
[a] DIPEA=diisopropylethylamine, Tf=triflate. [b] 1a (0.25 mmol), ligand (11 mol%), CuII salt (10 mol%),
CH3NO2 (10 equiv), base (1 equiv), solvent (1.5 mL), À508C. [c] Isolated yield of 3a after extraction. [d] De-
(Scheme 2
and
Table 1,
entry 1). To find out whether termined by chiral HPLC. [e] Yield and ee referred to product 4a.
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3769

G. Blay, J. R. Pedro, and V. Hernꢀndez-Olmos
Table 2. Reaction of aryl- and alkylglyoxal hydrates 1 and nitromethane
(2).
uct with a low ee value, together with compound 3a and
other byproducts (Table 1, entry 7).
Entry[a]
1
R
t [h]
Yield[b] [%]
ee[c] [%]
The role of the protected aldehyde group was also consid-
ered. Ketoacetal 11 and a-hydroxyketone 12 were recovered
unaltered after being subjected to the reaction conditions
given in entry 1 in Table 1. These results suggest that the
presence of two electronegative oxygen atoms on the neigh-
boring carbon is necessary to provide sufficient electrophilic
activation to the ketone carbonyl group. Furthermore, at
least one of them should be present as a free OH group;
most probably indicating the participation of a strongly che-
lated species in the mechanism of the reaction. Anyway, al-
though simple a-hydroxyketones do not react under our re-
action conditions, the nitroaldol products that would result
from this reaction can be formally prepared from com-
pounds 3 by selective aldehyde reduction (see Scheme 3,
conversion of 3a into 15).
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
22
22
23
22
20
17
24
17
22
19
24
24
24
99
96
98
81
91
89
85
89
89
81
15
86
86
93
90
96
94
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
4-NO2C6H4
4-MeOC6H4
3-BrC6H4
2-naphthyl
2-thiophenyl
99
90
60[d]
99
9
99
10
11
12
13
1j
1k
1l
99[e]
82
CH
(CH3)2CH
(CH3)2CH
(CH2)2
T
A
83
1m
T
70[f]
[a] 1 (0.25 mmol),
6
(11 mol%), CuACTHUNGTER(UNNG OTf)2 (10 mol%), MeNO2
(10 equiv), DIPEA (1 equiv), iPrOH (1.5 mL), À508C. [b] Isolated yield
of 3 after extraction. [c] Determined by HPLC. [d] Incomplete reaction
(in EtOH). [e] Compound 3j contained about 30% of 4j. [f] A 5:2 mix-
ture of 3m and 4m was obtained.
yphenylglyoxal hydrate (1g), with a strong electron-donat-
ing group on the aromatic ring, was the reaction (in EtOH)
was incomplete and gave a mixture of compound 3g (ca.
60%, 15% ee) and unreacted 1g (ca. 30%, as ethyl hemi-
AHCTUNGTREGaNNNU cetal). On the other hand, compound 1j, with a thiophene
ring gave compound 3j with 93% ee, although it was conta-
minated with about 30% of hydroxyketone 4j (Table 2,
entry 10). We would like to remark that these reactions for-
mally involve the preferential attack of nitromethane to the
ketone in the “presence” of a more electrophilic aldehyde
group, since the reaction does not require separate protec-
tion and deprotection steps.
Although our research was initially focused on arylglyox-
als, we extended our study to enolizable aliphatic alkylglyox-
al hydrates. We found that these were also very suitable sub-
strates for this reaction and gave even better results than ar-
ylglyoxal hydrates. Thus, compounds 1k and 1l provided the
corresponding products 3k and 3j in good yields and with
90 and 96% ee, respectively, in an almost completely regio-
selective manner (Table 2, entries 11 and 12). With com-
pound 1m, in which the ketone carbonyl group was hin-
dered by an isopropyl group, the regioselectivity was poorer
and a mixture of about 5:2 of compounds 3m and 4m was
obtained. Even so, compound 3m was obtained as the major
regioisomer and with 94% ee.
Compounds 3 are highly functionalized building blocks
that can be transformed into different small-sized multifunc-
tional products with a quaternary stereogenic center owing
to the presence of three different functional groups
(Scheme 3). For instance, we have carried out the oxidation
of aldehyde 3a with NaClO2–TEMPO followed by esterifi-
cation of the resulting acid with diazomethane to give the
known compound (S)-14,[9] which allowed the absolute ste-
reochemistry of 3a to be established. For the rest of the
products, stereochemistry was assigned on the assumption of
a uniform mechanistic pathway. Selective reduction of the
Scheme 3. Synthetic transformations of compound 3a. i) NaClO2, 2,2,6,6-
tetramethylpiperidine N-oxyl (TEMPO), phosphate buffer, CH3CN;
ii) CH2N2, Et2O, 0 8C, 61% (two steps); iii) LiAlH4, THF, À508C, 75%;
iv) H2, Pd/C, EtOH, 71%; v) Me3SiOMe, Me3SiOTf, CH2Cl2, À788C to
RT, 95 %; vi) H2, Pd/C, EtOH, 99%; vii) 9-fluorenylmethoxycarbonyl
chloride (FmocCl), Et3N, CH2Cl2, 64%, viii) 5% HCl, acetone, 81%.
A representative number of arylglyoxals were tested
under the optimized reactions. In most cases, almost pure
compounds 3 were obtained by extraction and fast filtration
through silica gel in high yields and with high ee values rang-
ing from 81 to 93% (Table 2). Only in the case of 4-methox-
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Chem. Eur. J. 2011, 17, 3768 – 3773

Constructing Quaternary Stereocenters
FULL PAPER
1 mLminÀ1, major enantiomer (S) tr =20.6 min, minor enantiomer (R)
tr =33.9 min.
aldehyde in the presence of the nitro group was possible
with LiAlH4 at low temperature to give 15. This compound
could be transformed into 16 by catalytic hydrogenation on
Pd/C. Finally, compound 20 was obtained in four steps from
3a in an overall yield of 49%. We did not observe loss of
optical purity during these transformations.
(S)-Methyl 2-hydroxy-3-nitro-2-phenylpropanoate (14): TEMPO (9.8 mg,
0.0061 mmol) and NaClO2 (52 mg, 0.46 mmol) were added to a solution
of 3a (45 mg, 0.23 mmol, 81% ee) in acetonitrile (2.5 mL) and sodium
phosphate buffer (pH 6.5, 1 mL), and the mixture was heated at 558C for
3 h. After this time, the reaction was allowed to cool to RT, was diluted
with water (15 mL), and was then acidified with 2m HCl. The resulting
mixture was extracted with diethyl ether (4ꢅ20 mL). The combined or-
ganic layers were evaporated under reduced pressure. The crude acid ob-
tained in the first step was dissolved in diethyl ether and the solution was
cooled to 08C. A solution of CH2N2 in diethyl ether was added in small
portions until the reaction was complete (TLC). Removal of the solvent
under reduced pressure followed by purification by flash chromatography
eluting with hexane/diethyl ether (9:1 to 8:2) gave 31.1 mg (61% for the
two steps) of a compound that was identified as (S)-14 after comparison
with literature data.[9d] The ee value (80%) was determined by HPLC
(Chiralcel OD-H), hexane/iPrOH 90:10, 1 mLminÀ1, major enantiomer
(S) tr =12.4 min, minor enantiomer (R) tr =16.3 min.
Conclusion
We have reported the first example of a direct Henry reac-
tion on the ketone carbonyl group of aryl- and alkylglyoxals
with high yields and enantioselectivities. The reaction pro-
vides chiral tertiary nitroaldols with high functional group
density, with a reactive aldehyde, nitro, and hydroxyl groups.
To the best of our knowledge, this is an unprecedented ex-
ample in which the normal reactivity pattern of glyoxals
with nucleophiles is overcome to allow nucleophilic attack
on the ketone instead of the aldehyde without separate pro-
tection and deprotection steps. The success of the reaction is
probably due to the high electrophilic activation of the car-
bonyl group by the iminopyridine–CuII complexes, which
can promote the nucleophilic attack of nitromethane at a
low temperature in which equilibration of the in situ formed
hemiacetal to the dicarbonyl form of the glyoxal is prevent-
ed.
(S)-(À)-3-Nitro-2-phenylpropane-1,2-diol (15): A 2m solution of LiAlH4
in THF (76 mL, 0.15 mmol) was added to a solution of compound 14
(30 mg, 0.15 mmol, 80% ee) in dry THF (1 mL) under nitrogen at
À508C. The reaction was stirred at this temperature for 1 h. After this
time, the reaction was quenched by the addition of 1m HCl (15 mL) and
the resulting solution was extracted with CH2Cl2 (3ꢅ15 mL). The com-
bined organic layers were washed with brine, dried over anhydrous
MgSO4, and evaporated under reduced pressure. Column chromatogra-
phy eluting with CH2Cl2/EtOAc (95:5 to 50:50) gave nitrodiol 15
(22.5 mg, 75%). M.p. 81–838C; [a]2D5 =À7.0 (c=0.89 in CH2Cl2, 80% ee);
1H NMR (300 MHz, CDCl3): d=7.46–7.35 (m, 5H), 5.00 (d, J
ACHTUNGTRENNUNG
13.2 Hz, 1H), 4.95 (d, JACHTUGNTRENNNUG
A
ACHTUNGTRENNUNG
(75.5 MHz, CDCl3): d=138.8 (C), 128.9 (CH), 128.6 (CH), 125.0 (CH),
80.9 (CH2), 76.4 (C), 68.9 ppm (CH2); HRMS (ESI): m/z calcd for
C9H10NO4 [M+ÀH]: 196.0610; found: 196.0608; the ee value (80%) was
determined by HPLC (Chiralpak AD-H), hexane/iPrOH 90:10,
1 mLminÀ1, major enantiomer (S) tr =16.1 min, minor enantiomer (R)
tr =15.3 min.
Experimental Section
General: Commercial reagents were used as purchased. Reagent-quality
absolute EtOH and iPrOH were used without additional drying for all
enantioselective reactions. Reactions were monitored by TLC using
Merck Silica Gel 60 F-254 thin-layer plates. NMR spectra were recorded
in the deuterated solvents stated, using the residual nondeuterated sol-
vent as internal standard. J values are given in Hz. The carbon type was
determined by DEPT experiments. Specific optical rotations were mea-
sured by using sodium light (D line 589 nm). Mass spectra (ESI) were re-
corded on a mass spectrometer equipped with an electrospray source
with a capillary voltage of 3.3 kV. Chiral HPLC analyses were performed
in a chromatograph equipped with a UV diode-array detector using
chiral stationary columns from Daicel. Ligand 6 was prepared according
to our reported procedure.[15a] Racemic compounds were prepared by fol-
lowing the general procedure using racemic iminopyridine 6.
(S)-(+)-3-Amino-2-phenylpropane-1,2-diol (16): 10% Pd/C (5 mg) was
added to a solution of 15 (20 mg, 0.101 mmol) in ethanol (1 mL). The
mixture was vigorously stirred at RT under a H2 atmosphere (balloon)
for 20 h. The catalyst was removed upon filtration through a short pad of
Celite, eluting with ethanol. The solvent was removed under reduced
pressure and the residue was purified by chromatography through a short
pad of silica gel eluting with EtOAc/EtOH (100:0 to 0:100) to give 15
(12.1 mg, 71%). [a]2D5 =+0.4 (c=0.37 in MeOH, 80% ee); 1H NMR
(300 MHz, MeOD): d=7.49 (dd, J
(H,H)=7.8 Hz, 2H), 7.26 (td, J(H,H)=7.8, 1.2 Hz, 1H), 3.73 (d, J-
(H,H)=11.4 Hz, 1H), 3.78 (d, J(H,H)=11.4 Hz, 1H) 3.04 (d, J(H,H)=
13.5 Hz, 1H), 2.94 ppm (d, J
(H,H)=13.5 Hz, 1H); 13C NMR (75.5 MHz,
ACHTUNGTRNE(NUNG H,H)=8.7, 1.5 Hz, 2H), 7.36 (t, J-
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
MeOD): d=44.3 (C), 129.3 (CH), 128.1 (CH), 126.9 (CH), 78.0 (C), 69.3
(CH2), 48.5 ppm (CH2); HRMS (ESI): m/z calcd for C9H12NO2 [M+ÀH]:
166.0868; found: 166.0866.
General procedure for the catalytic Henry reaction with glyoxals: Cu-
ACHTUNGTRENNUNG(OTf)2 (9.0 mg, 0.025 mmol) was added to a solution of 6 (6.6 mg,
0.025 mmol) in isopropanol (1.5 mL) in a Schlenk tube under nitrogen.
The mixture was stirred for 1 h at RT. After this time, compound 1a
(38 mg, 0.25 mmol) was added and the tube was introduced into a bath at
À508C. Then, compound 2 (2.5 mmol, 136 mL) was added, followed by
DIPEA (43.6 mL, 0.25 mmol). The reaction was stirred at À508C over-
night and was then quenched with 1m HCl (15 mL). The aqueous layer
was extracted with dichloromethane (3ꢅ15 mL) and the combined organ-
ic layers were washed with brine, dried over anhydrous magnesium sul-
fate, and evaporated under reduced pressure to afford product 3a
(48 mg, 99%). [a]2D5 =À72.7 (c=0.55 in CH2Cl2, 91% ee); 1H NMR
(S)-(+)-1,1-Dimethoxy-3-nitro-2-phenylpropan-2-ol (17): Me3SiOMe
(426 mL, 3.0 mmol) and Me3SiOTf (15 mL) were added to a solution of 3a
(150 mg, 0.76 mmol) in dry CH2Cl2 (2 mL) at À788C under N2. After stir-
ring at À788C for 1 h, the reaction mixture was allowed to reach RT and
stirring was continued for 1.5 h. At this point the reaction was cooled
again to À788C and pyridine (150 mL) was added. After stirring at
À788C for 10 min, a saturated aqueous solution of NaHCO3 (25 mL) was
added and the mixture was extracted with diethyl ether (3ꢅ20 mL). The
combined organic layers were dried over anhydrous MgSO4 and evapo-
rated under reduced pressure to give 17 (177.0 mg, 96%). [a]2D5 =+17.3
(c=1.33, CH2Cl2 in 81% ee); 1H NMR (300 MHz, CDCl3): d=7.58–7.54
(300 MHz, CDCl3): d=9.80 (s, 1H), 7.49–7.38 (m, 5H), 5.23 (d, J
13.8 Hz, 1H) 4.80 (d,
ACHTUNGTRENNUNG
JACHTUNGTRENNUNG
13C NMR (75.5 MHz, CDCl3): d=195.6 (CH), 133.1 (C), 129.4 (CH),
129.4 (C), 125.3 (CH) 79.9 (CH2), 79.8 ppm (C); HRMS (ESI): m/z calcd
for C9H8NO4 [M+ÀH]: 194.0451; found: 194.0453; the ee value (91%)
was determined by HPLC (Chiralcel OD-H), hexane/iPrOH 90:10,
(m, 2H), 7.47–7.30 (m, 3H), 4.99 (d, JACTHNUGTRNEUNG(H,H)=12.9 Hz, 1H), 4.91 (d, J-
AHCTUNGERTG(NNUN H,H)=12.9 Hz, 1H), 4.31 (s, 1H), 3.79 (brs, 1H), 3.52 (s, 3H), 3.32 ppm
(s, 3H); 13C NMR (75.5 MHz, CDCl3): d=138.3 (C), 128.29 (2ꢅCH),
128.25 (CH), 126.1 (2ꢅCH), 109.1 (CH), 79.3 (CH2), 77.4 (C), 58.4
Chem. Eur. J. 2011, 17, 3768 – 3773
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3771

G. Blay, J. R. Pedro, and V. Hernꢀndez-Olmos
(CH3), 58.2 ppm (CH3); HRMS (ESI): m/z calcd for C11H15NNaO5
[M+Na]+: 264.0848; found: 264.0845.
Synthesis (Eds.: J. Christoffers, A. Baro), Wiley-VCH, Weinheim,
2006.
[2] V. Farina, J. T. Reeves, C. H. Senanayake, J. J. Song, Chem. Rev.
2006, 106, 2734–2793.
(S)-(+)-3-Amino-1,1-dimethoxy-2-phenylpropan-2-ol (18): 10% Pd/C
(20 mg) was added to a solution of 17 (53 mg, 0.22 mmol) in methanol
(2 mL). The mixture was vigorously stirred at RT under a H2 atmosphere
(balloon) for 20 h. The catalyst was removed upon filtration through a
short pad of Celite, eluting with methanol. The solvent was evaporated
under reduced pressure to give 18 (46.2 mg, 99%). [a]2D5 =+9.5 (c=1.15,
[3] For reviews on the Henry reaction, see: a) F. A. Luzzio, Tetrahedron
2001, 57, 915–945; b) C. Palomo, M. Oiarbide, A. Mielgo, Angew.
Chem. 2004, 116, 5558–5560; Angew. Chem. Int. Ed. 2004, 43, 5442–
5444; c) J. Boruwa, N. Gogoi, P. P. Saikia, N. C. Barua, Tetrahedron:
Asymmetry 2006, 17, 3315–3326; d) C. Palomo, M. Oiarbide, A.
Laso, Eur. J. Org. Chem. 2007, 2561–2574.
MeOH) in 81% ee); 1H NMR (300 MHz, CDCl3): d=7.48 (d, J
7.8 Hz, 2H), 7.35–7.22 (m, 3H), 4.25 (s, 1H), 3.38 (s, 3H), 3.35 (s, 3H),
ACHTUNGTRNE(NUNG H,H)=
[4] For a review of the aza-Henry reaction, see: E. Marques-Lꢆpez, P.
Merino, T. Tejero, R. P. Herrera, Eur. J. Org. Chem. 2009, 2401–
2420.
[5] a) M. N. Elinson, A. I. Ilovaisky, V. M. Merkulova, F. Barba, B. Ba-
tanero, Tetrahedron 2008, 64, 5915–5919; b) C. Gan, X. Chen, G.
Lai, Z. Wang, Synlett 2006, 387–390; c) P. B. Kisanga, J. G. Verkade,
J. Org. Chem. 1999, 64, 4298–4303; d) M. Eyer, D. Seebach, J. Am.
Chem. Soc. 1985, 107, 3601–3606; e) D. Seebach, F. Lehr, Angew.
Chem. 1976, 88, 540–541; Angew. Chem. Int. Ed. Engl. 1976, 15,
505–506.
[6] a) K. Hara, S. Tosaki, V. Gnanadesikan, H. Morimoto, S. Harada,
M. Sugita, N. Yamagiwa, S. Matsunaga, M. Shibashaki, Tetrahedron
2009, 65, 5030–5036; b) S. Tosaki, K. Hara, V. Gnanadesikan, H.
Morimoto, S. Harada, M. Sugita, N. Yamagiwa, S. Matsunaga, M.
Shibashaki, J. Am. Chem. Soc. 2006, 128, 11776–11777.
3.10 (d, JACHTUNGTRENNUNG(H,H)=12.9 Hz, 1H), 3.00 (d, JACHTUTGNREN(NUGN H,H)=12.9 Hz, 1H), 2.43 ppm
(brs, 3H); 13C NMR (75.5 MHz, CDCl3): d=141.0 (C), 128.1 (2ꢅCH),
127.2 (CH), 126.2 (2ꢅCH), 110.1 (CH), 77.4 (C), 57.9 (CH3), 57.8 (CH3),
46.6 ppm (CH2); HRMS (ESI): m/z calcd for C11H17NNaO4 [M++Na]:
234.1106; found: 234.1109.
(S)-(+)-(9H-Fluoren-9-yl)methyl-2-hydroxy-3,3-dimethoxy-2-phenylpro-
pylcarbamate (19): A solution of 18 (15 mg, 0.095 mmol) in CH2Cl2
(1 mL) was added to a solution of Fmoc-Cl (24.6 mg, 0.095 mmol) and
triethylamine (19.8 mL, 0.14 mmol) in CH2Cl2 (1 mL) precooled in an ice
bath. After 20 min, the ice bath was removed and stirring was continued
at RT for 2 h. The reaction was quenched with a saturated aqueous solu-
tion of NaHCO3 (20 mL) and extracted with CH2Cl2 (3ꢅ15 mL). The
combined organic layers were washed with brine, dried over anhydrous
MgSO4, and evaporated under reduced pressure. Column chromatogra-
phy, eluting with hexane/EtOAc (8:2), gave 19 (26.1 mg, 64%). [a]D25
10.7 (c=1.0 in CHCl3, 81% ee); H NMR (300 MHz, CDCl3): d=7.75 (d,
+
1
[7] a) J. M. Saꢀ, F. Tur, J. Gonzalez, Chirality 2009, 21, 836–842; b) F.
Tur, J. M. Saa, Org. Lett. 2007, 9, 5079–5082.
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4360–4362.
J
N
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(s, 3H), 3.40 (s, 3H), 3.19 ppm (brs, 1H); 13C NMR (75.5 MHz, CDCl3):
d=157.1 (C), 144.0 (C), 143.9 (C), 141.2 (C), 140.1 (C), 128.1 (CH), 127.6
(CH), 127.0 (CH), 126.3 (CH), 125.14 (CH), 125.07 (CH), 119.9 (CH),
109.6 (CH), 77.9 (C), 66.8 (CH2), 58.3 (CH3), 58.1 (CH), 47.1 (CH),
46.2 ppm (CH2); HRMS (ESI): m/z calcd for C26H27NNaO5 [M++Na]:
456.1787; found: 456.1786.
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2009, 38, 1052–1053; b) K. Takada, N. Takemura, K. Cho, Y. Soh-
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2008, 6, 468–476; e) B. Qin, X. Xiao, X. Liu, J. Huang, Y. Wen, X.
Feng, J. Org. Chem. 2007, 72, 9323–9328; f) H. Li, B. Wang, L.
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T. Fang, J. Xu, J. Org. Chem. 2005, 70, 3712–3715; h) S. F. Lu, D. M.
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3441C; i) C. Christensen, K. Juhl, R. G. Hazell, K. A. Jørgensen, J.
Org. Chem. 2002, 67, 4875–4881. See also diastereoselective addi-
tion to a-keto lactams: j) B. Alcaide, P. Almendrꢆs, A. Luna, M. R.
Torres, Org. Biomol. Chem. 2008, 6, 1635–1640.
[10] a) K. Zheng, J. Shi, X. Liu, X. Feng, J. Am. Chem. Soc. 2008, 130,
15770–15771; b) S. Doherty, P. Goodrich, C. Hardacre, H.-K. Luo,
M. Niewehuyzen, R. K. Rath, Organometallics 2005, 24, 5945–5955;
c) H.-K. Luo, H. Schumann, J. Mol. Catal. A 2006, 248, 42–47; d) S.
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f) R. Matsubara, T. Doko, R. Uetake, S. Kobayashi, Angew. Chem.
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5116–5125; h) R. Matsubara, N. Kawai, S. Kobayashi, Angew.
Chem. 2006, 118, 3898–3900; Angew. Chem. Int. Ed. 2006, 45, 3814–
3816; i) R. R. Huddleston, H.-Y. Jang, M. J. Krische, J. Am. Chem.
Soc. 2003, 125, 11488–11489.
(S)-(À)-(9H-Fluoren-9-yl)methyl 2-hydroxy-3-oxo-2-phenylpropylcarba-
mate (20): A solution of 19 (20.0 mg, 0.0464 mmol) and aqueous 5% HCl
(0.1 mL) in acetone (1 mL) was heated at reflux for 3 h. The reaction was
quenched with a saturated aqueous solution of NaHCO3 (15 mL) and ex-
tracted with CH2Cl2 (3ꢅ15 mL). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, and evaporated under
reduced pressure. Purification by flash chromatography, eluting with
hexane/EtOAc (8:2), gave 20 (14.6 mg, 81%). [a]2D5 =À43.4 (c=0.43,
CHCl3, 81% ee); 1H NMR (300 MHz, CDCl3): d=9.68 (s, 1H), 7.77 (d, J-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
CDCl3): d=198.8 (CH), 157.2 (C), 143.7 (C), 143.6 (C), 141.3 (C), 136.2
(C), 129.0 (CH), 128.5 (CH), 127.8 (CH), 127.1 (CH), 125.6 (CH), 125.02
(CH), 124.96 (CH), 120.0 (CH), 82.5 (C), 67.3 (CH2), 47.2 (CH2),
47.1 ppm (CH); HRMS (ESI): m/z calcd for C24H21KNO4 [M++K]:
426.1108; found: 426.1109.
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3185–3188; b) K. Ishihara, T. Yano, M. Fushimi, J. Fluorine Chem.
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shino, A. Nishinaga, J. Chem. Soc. Chem. Commun. 1992, 1617–
1618.
Acknowledgements
Financial support from the Ministerio de Ciencia e Innovaciꢆn and
FEDER (Grants CTQ2006-14199 and CTQ2009-13083) and Generalitat
Valenciana (ACOMP/2009/338) is acknowledged. V.H.-O. thanks the
Universitat de Valꢃncia for a pre-doctoral grant (V Segles program).
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3772
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ꢄ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 3768 – 3773

Constructing Quaternary Stereocenters
FULL PAPER
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Received: October 7, 2010
Revised: December 30, 2010
Published online: February 23, 2011
Chem. Eur. J. 2011, 17, 3768 – 3773
ꢄ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3773