Stereocontrolled construction of quaternary stereocenters by inter- and intramolecular nitro-michael additions catalyzed by bifunctional thioureas

Article abstract of DOI:10.1002/adsc.201000612

A highly diastereo- and enantioselective conjugate addition of β-keto esters to nitroolefins, catalyzed by a chiral thiourea prepared from L-valine is described. The formation of two contiguous tertiary and quaternary stereocenters occurs in high yield an

Full text of DOI:10.1002/adsc.201000612

FULL PAPERS
DOI: 10.1002/adsc.201000612
Stereocontrolled Construction of Quaternary Stereocenters by
Inter- and Intramolecular Nitro-Michael Additions Catalyzed by
Bifunctional Thioureas
Rubꢀn Manzano,a Josꢀ M. Andrꢀs,a Marꢁa D. Muruzꢂbal,a and Rafael Pedrosaa,*
a
Instituto CINQUIMA and Departamento de Quꢁmica Orgꢂnica, Facultad de Ciencias, Universidad de Valladolid. 47011
Valladolid, Spain
Fax : (+34)-98-342-3013; e-mail: pedrosa@qo.uva.es
Received: July 30, 2010; Published online: December 3, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000612.
Abstract: A highly diastereo- and enantioselective troolefins have been tested. The same catalyst has
conjugate addition of b-keto esters to nitroolefins, been used to promote the first intramolecular conju-
catalyzed by a chiral thiourea prepared from l-valine gate addition leading to the cyclic adduct in moder-
is described. The formation of two contiguous terti- ate diastereoselectivity and good enantioselectivity.
ary and quaternary stereocenters occurs in high yield
and excellent diastereo- and enantioselection with Keywords: bifunctional thioureas; Michael addition;
only 2 mol% of catalyst loading. The reaction is gen- nitroolefins; organocatalysis; quaternary stereocen-
eral and different b-keto esters and aryl- and alkylni- ters
Introduction
cent tertiary-quaternary stereocenters intramolecular-
ly.
The stereocontrol in the construction of carbon-
Searching for easily accessible thioureas able to act
carbon bonds, especially the formation of quaternary as bifunctional organocatalysts, we have recently de-
stereocenters, constitutes one of the most important scribed a modular synthesis of these compounds start-
tasks in the asymmetric synthesis. To this end, a lot of ing from a-amino acids and their use in enantioselec-
chiral auxiliaries, reagents, and catalysts have been tive transformations,[3,9] and now we describe the re-
developed during the last two decades.[1] One of the sults obtained in both diastereo- and enantioselective
most studied reactions is the Michael addition of inter- and intramolecular additions to nitroalkenes.
easily enolizable substrates to nitroolefins because the For comparative purposes, we selected as nucleophiles
highly functionalized nitro compounds are versatile a-substituted b-keto esters or b-diketones because
intermediates in organic synthesis.[2] Enantioselective they are easily enolizable substrates previously used
addition of different nucleophiles to nitroolefins cata- in similar transformations.
lyzed by chiral bifunctional thioureas constitutes a
good approach, and a lot of organocatalysts have
been developed to achieve that goal.[3]
Results and Discussion
More difficult is the stereocontrolled construction
of two adjacent carbon-substituted quaternary and The additions of b-keto esters 3a–f, a-acyl lactone 3g,
tertiary stereocenters, although recently some organo- b-diketone 3h and ethyl 3-oxo-4-piperidylcarboxylate
catalyzed processes have been described leading to (3i) to trans-b-nitrostyrene catalyzed by thiourea 1,
the Michael adducts in good or excellent diastereo- derived from l-valine[3] were examined to evaluate
and enantioselectivities. In this context, especially in- the stereoselection in the intermolecular reaction. Ini-
teresting are the chiral thioureas derived from Cin- tially the reaction conditions were fixed by using
chona alkaloids,[4] trans-1,2-diaminocyclohexane,[5] 10 mol% of catalyst loading, and toluene as a solvent
amino alcohols,[6] guanidines,[7] or imidazolines[8] that at À188C, and the results are summarized in Table 1.
catalyze intermolecular additions to nitroolefins, but The enantioselection for all the reactions was excel-
there are no antecedents for the formation of adja-
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Adv. Synth. Catal. 2010, 352, 3364 – 3372

Stereocontrolled Construction of Quaternary Stereocenters
Table 1. Michael additions of compounds 3a–h to trans-b-nitrostyrene, catalyzed by thiourea 1.
Entry
Substrate
Time [h]
Product (Yield [%][a])
dr[b] (2S,3R/2R,3R)[c]
er[d]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3f
3g
3g
3g
3h
3i
14
4a (98)
4b (99)
4c (99)
4d (99)
4e (89)
4f (97)
4f (95)
4g (95)
4g (89)
4g (94)
4h (93)
4i (85)
23/77
98/2
95/5
98/2
95/5
96/4
97/3
98/2
97/3
99/1
96/4
97/3
99/1
96/4
97/3
0.5
0.5
17
98/2
72
98/2[e]
90/10
92/8
4
9[f]
0.75
1.5[g]
6[h]
2.5
20[i]
70/30
81/19
83/17
13/87
>99/1
9
10
11
12
[a]
Yields refer to isolated compounds.
Determined by H NMR in the reaction mixture.
Determined by comparison of the sign of the specific rotation previously described.
Determined by chiral HPLC.
[b]
[c]
[d]
[e]
[f]
Determined by X-ray diffraction analysis.
The reaction was performed at À508C.
[g]
[h]
[i]
The reaction was performed at À408C.
The reaction was performed at À608C.
The nitroolefin was trans-p-fluoronitrostyrene.
lent (er 95/5 to 99/1) while the diastereoselection the size or the substituents in the ring [Scheme 1, Eq.
varied depending on the structure of the nucleophile. (2)]. The reactions of cyclopentanone derivatives 3a
We first investigated the Michael addition of ethyl and 3b were faster than those of their homologous,
2-methylacetoacetate to trans-b-nitrostyrene leading leading to completion in 0.5 h at À188C in very good
to 4a [Scheme 1, Eq. (1)] in near quantitative yield, diastereo- and enantioselectivities (entries 2 and 3 in
and excellent enantioselectivity (er 98/2), although Table 1). The nature of the alkoxy group has little in-
moderate diasteroselectivity (dr 77/23). The absolute fluence in the stereoselection. Cycloheptanone deriva-
configuration of 4a (2R,3R) was established by com- tive 3f also reacted easily (4 h) but with lower diaster-
parison of the spectral data, HPLC retention time eo- and enantiocontrol (entry 6). Both the diastereo-
and specific rotation with those previously des- and enantioselectivities were improved when the re-
A
action temperature was lowered to À508C (entry 7).
The best results in terms of stereocontrol were ob-
bonyl ketones 3b–f as nucleophiles, which differ in tained for the reaction of six-membered derivatives
3d (98/2 dr and 97/3 er), 3e (98/2 dr and 98/2 er), and
3i (>99/1 dr and 98/2 er), although the reactions re-
quired longer times for completion (entries 4, 5 and
12). Diketone 3h was also a good nucleophile, leading
to the addition product in good er (96/4), but moder-
ate dr (87/13) after 2.5 h of reaction (entry 11). Simi-
larly, 2-acetyl butyrolactone 3g reacted very quickly
with trans-b-nitrostyrene at À188C giving 4g[10] in
good er, although moderate dr (70/30). Fortunately,
by reducing the reaction temperature to À408C or
even to À608C, a dr of 83/17 with 99/1 er was
achieved (entries 8–10 in Table 1). As previously de-
scribed, the cyclic and acyclic 2-substituted b-keto
esters afforded the adducts with contrary configura-
tions at C-2.[5c] In our case, the major diastereoisomer
(4a) obtained from the open keto esters has the R
configuration whereas adducts 4b–i, prepared from
cyclic substrates, have the S configuration at C-2.
Scheme 1. Organocatalyzed Michael additions of nucleo-
philes to trans-b-nitrostyrene by thiourea 1.
Adv. Synth. Catal. 2010, 352, 3364 – 3372
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Rubꢀn Manzano et al.
FULL PAPERS
appreciably. The reaction of the alkyl-substituted ni-
troolefin 2g was much slower, but it went to comple-
tion after 36 h in the presence of 5 mol% of catalyst
loading.
The excellent stereoselection of the reaction led us
to consider the enantioselective synthesis of pyrroli-
dine 9 (GW3600), which is a potent inhibitor of
PDE4 and closely related to rolipram. It has been
demonstrated that the activity of that type of com-
pounds is related with the presence of the acetyl
group at the pyrrolidine nucleus and the stereochem-
istry of the substituents.[11] In our case, both the terti-
Scheme 2. Reaction of different nitroolefins with methyl 2-
oxocyclopentanecarboxylate.
Next, we studied the effect of the temperature and ary and quaternary stereocenters could be established
loading of the catalyst in the process taking as a by the diastereo- and enantioselective addition of 3a
model the reaction of trans-b-nitrostyrene (2a) with to the corresponding b-nitrostyrene catalyzed by the
methyl 2-oxocyclopentanecarboxylate (3b), and the chiral thiourea 1.
results are collected in Scheme 2 and Table 2 (en-
tries 1–4). These data showed that the lowering of the
catalyst loading did not modify the diastereoselection
and slightly increased the enantioselection, although
at the expense of increasing the reaction time (en-
tries 1–3). Interestingly, total diastereoselectivity and
excellent enantioselectivity (97/3 er) were achieved
with only 2 mol% of catalyst loading when the reac-
tion was carried out at À508C (entry 4).
In the same experimental conditions (toluene,
À508C, 2 mol% of catalyst), the Michael addition was
extended to nitroolefins with aryl (2b–e), hetaryl (2f),
and alkyl (2g) substituents (Table 2, entries 5–10). The
addition of b-keto ester 3a occurred easily, furnishing
the adducts 5b–g in near quantitative yields and excel-
lent diastereo- and enantioselectivities. Interestingly,
the electronic nature of the substituent has an impor-
tant effect on the reaction rate, increasing the reac-
tion time with the electron-withdrawing effect of the
Scheme 3. Enantioselective synthesis of one diastereoisomer
substituent, but it did not modify the stereoselection of GW3600.
Table 2. Michael addition of 3b to nitroolefins 2a–g catalyzed by thiourea 1.
Entry
Substrate
x (mol%)
Temperature [8C]
Time [h]
Product (Yield [%][a])
dr[b]
er[c]
1
2
3
4
5
6
7
8
9
10
2a
2a
2a
2a
2b
2c
2d
2e
2f
2g
10
5
2
2
2
2
2
2
2
5
À18
À18
À18
À50
À50
À50
À50
À50
À50
À50
0.5
1
7
20
24
48
60
16
10
36
4b (99)
4b (95)
4b (98)
>98/2
>98/2
>98/2
>98/2
96/4
>98/2
96/4
97/3
95/5
95/5
96/4
97/3
96/4
97/3
96/4
99/1
98/2
96/4
4b (99)[d]
5b (98)[d]
5c (98)[d]
5d (96)d)
5e (97)[e]
5f (99)[e]
5g (96)[e]
97/3
>98/2
[a]
Yields refer to isolated compounds.
Determined by H NMR in the reaction mixture.
Determined by chiral HPLC.
[b]
[c]
[d]
The stereochemistry of these compounds has been assigned by comparison of the physical and spectral data with those
previously described.
[e]
The stereochemistry of these adducts has been tentatively assigned by generalization of the stereochemical outcome of
the reaction.
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Adv. Synth. Catal. 2010, 352, 3364 – 3372

Stereocontrolled Construction of Quaternary Stereocenters
The known nitroolefin 6[12] was reacted with ethyl
After separation by column chromatography, the
2-methylacetoacetate in the presence of 1 (10 mol%) relative stereochemistry was assigned by NOE experi-
at À188C in toluene leading to 7 (89% ee) and its ments. The NOESY experiment[13] of 12a showed a
epimer (91% ee) in 95% yield and 80/20 dr clear interaction between the methyl group at the
(Scheme 3). After chromatographic purification, 7 quaternary carbon and the hydrogen atom at the ter-
was reduced to a mixture of epimeric alcohols 8 by tiary stereocenter, indicating a cis relationship, while
reaction with sodium borohydride in methanol. That that NOE interaction did not appear for the corre-
mixture was transformed into 9 by reduction of the sponding diastereoisomer epi-12a. Interestingly, these
nitro group with lactamization, reduction of the results demonstrate that, from the stereochemical
lactam to the pyrrolidine derivative, Swern oxidation point of view, the intramolecular reaction occurs in
of the secondary alcohol, and treatment with dimethyl the same way as the intermolecular process when an
dicarbonate, in 31% total yield from 7.
acyclic substrate is used as nucleophile. Unfortunate-
The stereochemistry of 9 was established on the ly, compound 11b did not react, and it was recovered
basis of COSY and NOESY experiments.[13] Thus, the unchanged after stirring for 1 month in the described
COSY experiment[13] allowed the assignation of the conditions. The lack of reactivity for that compound
signals corresponding to the five protons at the pyrro- could be attributed to the sterically encumbered tran-
lidine nucleus. In the NOESY experiment it is possi- sition state due to the bulkiness of the tert-butyl
ble to observe signals corresponding to strong interac- group.
tion between the methyl group at C-3 (quaternary ste-
Because the mechanism and stereochemical out-
reocenter) and one proton at C-2 and the proton at come of the intermolecular process are well
C-4 (tertiary stereocenter). The last signal is clearly known,[5c,6b,19] we propose a model to explain the ste-
indicative of the cis relationship of the substituents at reoselectivity observed in the intramolecular reaction
the heterocycle.
(Figure 1).
Finally, we tested the unprecedented intramolecular
reaction leading to enantioenriched cyclic substrates.
To this end, compounds 11a and 11b were prepared
by reaction of o-hydroxy-trans-b-nitrostyrene[14] with
the hemiesters of 2-methyl- and 2-tert-butyl malonic
acid in the presence of DCC (Scheme 4). The intra-
molecular addition was much slower and less diaster-
eo- and enantioselective than the intermolecular reac-
tion. Compound 11a led to 12a in 65% yield after stir-
ring for 240 h at À188C in toluene and 10 mol% of
catalyst 1. Moreover, the product was a mixture (3/2)
of epimers 12a and epi-12a at the quaternary stereo-
Figure 1. Proposed complex for the intramolecular reaction.
As generally accepted, the thiourea behaves as bi-
center, and the major diastereoisomer was obtained functional catalyst activating both the nucleophile and
in a moderate er (89/11), whereas the minor isomer the electrophile. The amino group will deprotonate
was isolated as a racemate.
the acidic hydrogen leading to an enolate near the ni-
trogen atom, whereas the thiourea will activate the ni-
troolefin by hydrogen bonding leading to complex I.
The intramolecular attack of the enolate to the
double bond yields 12a as major stereoisomer. The
proposed model could also explain why the reaction
did not take place with compound 10b (R=t-Bu).
The sterically demanding substituent probably pre-
vents the deprotonation of the substrate.
Conclusions
In summary, the described results show that thiourea
1, easily prepared from natural l-valine, is an excel-
lent catalyst for the construction of adjacent tertiary
and quaternary stereocenters by enantioselective Mi-
chael addition of b-keto esters to nitroolefins. The re-
actions occur with very good yields and excellent dia-
stereo- and enantioselectivities (dr up to >98/2 and er
Scheme 4. Diastereo- and enantioselective intramolecular
Michael additions to nitroolefins.
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Rubꢀn Manzano et al.
FULL PAPERS
(CH3), 47.3 (CH), 61.9 (C), 62.0 (CH2), 76.9 (CH2), 128.3
(CH), 128.7 (2CH), 129.2 (2CH), 135.4 (C), 170.7 (C), 205.3
(C); HPLC (Chiralcel OD, hexane/2-propanol, 90:10,
0.9 mLminÀ1, l=220 nm): tR =12.8 min (major), 18.6 min
(minor); HR-MS: m/z=316.1151, calcd. for (C15H19NO5 +
Na): 316.1161.
up to 99/1). The unprecedented intramolecular Mi-
chael reaction, leading to cyclic addition products, is
also catalyzed by 1 although with moderate diastereo-
selection and good enantioselection.
AHCTUNGTREG(NNUN 2S,3R)-Methyl 1-(2-nitro-1-phenylethyl)-2-oxocyclopen-
Experimental Section
tanecarboxylate (4b): [a]2D5: +36.4 (c 1.1, CHCl3, 90% ee)
1
(lit.[10] [a]D25: +36.5, 99% ee, dr 95:5); H NMR (300 MHz,
General Remarks
CDCl3): d=1.80–2.09 (m, 4H), 2.31–2.43 (m, 2H), 3.76 (s,
3H), 4.09 (dd, J=10.7, 4.0 Hz, 1H), 5.02 (dd, J=13.6,
10.9 Hz, 1H), 5.17 (dd, J=13.7, 4.0 Hz, 1H), 7.21–7.35 (m,
5H); 13C NMR (75 MHz, CDCl3): d=19.2 (CH2), 31.0
(CH2), 37.8 (CH2), 46.1 (CH), 52.9 (CH3), 62.3 (C), 76.3
(CH2), 128.2 (CH), 128.7 (2CH), 129.2 (2CH), 135.2 (C),
169.7 (C), 212.2 (C); HPLC (Chiralcel OD, hexane/2-propa-
nol, 80:20, 1.0 mLminÀ1, l=220 nm): tR (major diastereoiso-
mer)=10.7 min (major), 14.8 min (minor); HR-MS: m/z=
291.1114, calcd. for C15H17NO5: 291.1107.
1H NMR (300 MHz or 400 MHz) and 13C NMR (75 MHz)
spectra were recorded in CDCl3. Chemical shifts for protons
are reported in ppm from tetramethylsilane with the residu-
al CHCl3 resonance as internal reference. Chemical shifts
for carbons are reported in ppm from tetramethylsilane and
are referenced to the carbon resonance of the solvent. Data
are reported as follows: chemical shift, multiplicity (s=sin-
glet, d=doublet, t=triplet, q=quartet, sp=septet, m=mul-
tiplet, br=broad), coupling constants in Hertz, and integra-
tion. Specific rotations were measured using a 5 mL cell
with a 1-dm path length, and a sodium lamp, and concentra-
tion is given in g per 100 mL. Flash chromatography was
carried out using silica gel (230–240 mesh). Chemical yields
refer to pure isolated substances. TLC analysis was per-
formed on glass-backed plates coated with silica gel 60 and
an F254 indicator, and visualized by either UV irradiation or
by staining with I2 or phosphomolybdic acid solution. Chiral
HPLC analysis was performed using a Daicel Chiralcel OD
column (250ꢄ4.6 mm) or Chiralpak AS-H or AD-H column
(250ꢄ4.6 mm). UV detection was monitored at 220 nm or at
254 nm. Unless otherwise indicated, all compounds were
purchased from Aldrich and used as received. Nitroolefins
2g[15] and 6[12] were prepared according to literature proce-
dures. b-Keto ester 3i·HCl is commercially available and
was liberated to 3i prior to use by treatment with a saturat-
ed solution of sodium bicarbonate, and extracted with di-
chloromethane. Monomethyl 2-methylmalonate (10a) was
prepared by selective mono-hydrolysis according to the liter-
ature procedure.[16] Monomethyl 2-tert-butylmalonate (10b)
was prepared by a-carboxylation of methyl 3,3-dimethylbu-
tanoate,[17a] readily prepared from 3,3-dimethylbutyric
acid.[17b] Solvents were dried and stored over microwave-ac-
tivated 4 ꢅ molecular sieves.
A
1-(2-nitro-1-phenylethyl)-2-oxocyclopen-
tanecarboxylate (4c): [a]2D5: +30.8 (c 1.0, CHCl3, 92% ee);
1H NMR (300 MHz, CDCl3): d=1.28 (t, J=7.1 Hz, 3H),
1.80–2.09 (m, 4H), 2.30–2.42 (m, 2H), 4.08 (dd, J=10.8,
3.9 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 5.02 (dd, J=13.5,
11.0 Hz, 1H), 5.18 (dd, J=13.5, 3.9 Hz, 1H), 7.21–7.35 (m,
5H); 13C NMR (75 MHz, CDCl3): d=13.8 (CH3), 19.2
(CH2), 31.0 (CH2), 37.8 (CH2), 46.1 (CH), 62.1 (CH2), 62.3
(C), 76.3 (CH2), 128.1 (CH), 128.7 (2 CH), 129.2 (2 CH),
135.3 (C), 169.2 (C), 212.3 (C); HPLC (Chiralcel OD,
hexane/2-propanol, 80:20, 1.0 mLminÀ1, l=220 nm): tR
(major
diastereoisomer)=9.5 min
(major),
12.9 min
(minor); HR-MS: m/z=305.1267, calcd. for C16H19NO5:
305.1263.
A
1-(2-nitro-1-phenylethyl)-2-oxocyclohex-
anecarboxylate (4d): [a]2D5: À86.5 (c 1.0, CHCl3, 93% ee)
(lit.[10] [a]D25: À91.5, 99% ee, dr>98:2); H NMR (300 MHz,
1
CDCl3): d=1.26 (t, J=7.1 Hz, 3H), 1.42–1.52 (m, 1H),
1.57–1.75 (m, 3H), 2.00–2.18 (m, 2H), 2.41–2.56 (m, 2H),
4.01 (dd, J=11.3, 3.2 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 4.80
(dd, J=13.4, 11.4 Hz, 1H), 5.07 (dd, J=13.4, 3.3 Hz, 1H),
7.14–7.17 (m, 2H), 7.25–7.31 (m, 3H); 13C NMR (75 MHz,
CDCl3): d=13.8 (CH3), 22.2 (CH2), 27.8 (CH2), 36.9 (CH2),
41.3 (CH2), 47.6 (CH), 61.8 (CH2), 62.8 (C), 77.4 (CH2),
128.0 (CH),128.3 (2CH), 129.4 (2CH), 135.3 (C), 169.5 (C),
207.0 (C); HPLC (Chiralcel OD, hexane/2-propanol, 95:5,
1.0 mLminÀ1, l=220 nm): tR (major diastereoisomer)=
12.0 min (major), 16.7 min (minor); HR-MS: m/z=319.1406,
calcd. for C17H21NO5: 319.1420.
Typical Procedure for Enantioselective Michael
Addition of b-Keto Esters to Nitroolefins
To a stirred solution of trans-b-nitrostyrene 2a (0.30 mmol,
45.6 mg) and catalyst 1 (0.03 mmol) in toluene (0.6 mL) was
added methyl 2-oxocyclopentanecarboxylate 3b (0.60 mmol,
0.08 mL) at À188C. The reaction mixture was stirred until
disappearance of the nitroolefin by TLC. The solvent was
removed under vacuum and the residue was purified by
flash chromatography (hexane/AcOEt=10/1 as eluent) to
afford the desired product 4b.
AHCTUNGERTG(NNUN 2S,3R)-Methyl 2-(2-nitro-1-phenylethyl)-1-oxo-1,2,3,4-tet-
rahydronaphthalene-2-carboxylate (4e): [a]2D5: À47.9 (c 1.1,
CHCl3, 97% ee) (lit.[5c] [a]2D5: +51.0, 95% ee, dr>98:2);
1H NMR (300 MHz, CDCl3): d=2.00–2.09 (m, 1H), 2.42 (dt,
J=13.9, 5.1 Hz, 1H), 2.96–3.00 (m, 2H), 3.65 (s, 3H), 4.22
(dd, J=10.4, 4.0 Hz, 1H), 5.07 (dd, J=13.5, 10.3 Hz, 1H),
5.17 (dd, J=13.5, 4.1 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H),
7.26–7.40 (m, 6H), 7.51 (td, J=7.5, 1.4 Hz, 1H), 8.05 (dd,
J=8.0, 1.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=25.5
(CH2), 30.7 (CH2), 47.1 (CH), 52.7 (CH3), 59.7 (C), 77.8
(CH2), 127.0 (CH), 128.2 (CH), 128.4 (CH), 128.6 (2CH),
128.7 (CH), 129.8 (2CH), 131.5 (C), 134.1 (CH), 135.9 (C),
142.4 (C), 170.2 (C), 194.2 (C); HPLC (Chiralcel OD,
hexane/2-propanol, 90:10, 1.0 mLminÀ1, l=254 nm): tR
ACHTUNGTRENNUNG(2R,3R)-Ethyl 2-acetyl-2-methyl-4-nitro-3-phenylbutano-
ate (4a): Major diastereoisomer; [a]2D5: +43.9 (c 0.6, CHCl3,
95% ee) (lit.[5c] [a]D25: À41.0, 91% ee, dr>98:2); 1H NMR
(300 MHz, CDCl3): d=1.19 (t, J=7.2 Hz, 3H), 1.43 (s, 3H),
2.11 (s, 3H), 3.98–4.17 (m, 2H), 4.20–4.25 (m, 1H), 4.94–
4.97 (m, 2H), 7.19–7.24 (m, 2H), 7.26–7.31 (m, 3H);
13C NMR (75 MHz, CDCl3): d=13.8 (CH3), 18.0 (CH3), 27.5
3368
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Adv. Synth. Catal. 2010, 352, 3364 – 3372

Stereocontrolled Construction of Quaternary Stereocenters
(major diastereoisomer)=17.4 min (major), 35.6 min
(minor); HR-MS: m/z=376.1154, calcd. for (C20H19NO5 +
Na): 376.1161.
75.0 min (minor); HR-MS: m/z=451.1634, calcd. for
(C23H25FN2O5 +Na): 451.1645.
AHCTUNGERTG(NNUN 2S,3R)-Methyl 1-[1-(4-chlorophenyl)-2-nitroethyl]-2-oxo-
A
cyclopentanecarboxylate (5b): [a]2D5: +36.2 (c 1.6, CHCl3,
91% ee) (lit.[8] [a]D25: À39.6, 96% ee, dr>20:1); 1H NMR
(300 MHz, CDCl3): d=1.82–2.13 (m, 4H), 2.35–2.45 (m,
2H), 3.75 (s, 3H), 4.04 (dd, J=11.0, 3.9 Hz, 1H), 4.98 (dd,
J=13.6, 11.0 Hz, 1H), 5.15 (dd, J=13.8, 4.0 Hz, 1H), 7.20–
7.24 (m, 2H), 7.28–7.32 (m, 2H); 13C NMR (75 MHz,
CDCl3): d=19.2 (CH2), 31.2 (CH2), 37.8 (CH2), 45.5 (CH),
53.0 (CH3), 62.1 (C), 76.1 (CH2), 128.9 (2CH), 130.6 (2CH),
133.8 (C), 134.2 (C), 169.6 (C), 212.1 (C); HPLC (Chiralcel
OD, hexane/2-propanol, 90:10, 1.0 mLminÀ1, l=220 nm): tR
(major diastereoisomer)=19.1 min (major), 32.2 min
(minor); HR-MS: m/z=348.0604, calcd. for (C15H16ClNO5 +
Na): 348.0615.
tanecarboxylate (4f): The diastereomers could not be sepa-
rated. 1H NMR (300 MHz, CDCl3): d=1.40–1.94 (m, 8H),
2.49–2.66 (m, 2H), 3.78 (s, 3H), 4.07 (dd, J=9.3, 4.9 Hz,
1H), 4.88–4.99 (m, 2H), 7.14–7.21 (m, 2H), 7.27–7.34 (m,
3H); 13C NMR (75 MHz, CDCl3): d=24.4 (CH2), 25.0
(CH2), 28.8 (CH2), 32.8 (CH2), 41.3 (CH2), 48.4 (CH), 52.3
(CH3), 65.4 (C), 77.7 (CH2), 128.2 (CH), 128.6 (2CH), 129.3
(2CH), 135.5 (C), 171.2 (C), 208.1 (C); HPLC (Chiralcel
OD, hexane/2-propanol, 95:5, 1.0 mLminÀ1, l=220 nm): tR
(major diastereoisomer)=14.6 min (major), 32.8 min
(minor); HR-MS: m/z=319.1428, calcd. for C17H21NO5:
319.1420.
A
ACHTUNGERTN(NUNG 2S,3R)-Methyl 1-[1-(4-fluorophenyl)-2-nitroethyl]-2-oxo-
(4g): The major diastereoisomer was purified by recrystalli-
zation (hexane/AcOEt); [a]2D5: +4.2 (c 0.6 CHCl3, 99% ee);
1H NMR (300 MHz, CDCl3): d=2.25–2.35 (m, 1H), 2.51 (s,
3H), 2.86 (ddd, J=13.3, 7.8, 4.1 Hz, 1H), 3.87 (td, J=8.9,
4.1 Hz, 1H), 4.01–4.09 (m, 1H), 4.51–4.57 (m, 2H), 4.86 (dd,
J=14.2, 12.4 Hz, 1H), 7.32–7.39 (m, 5H); 13C NMR
(75 MHz, CDCl3) d 25.6 (CH2), 26.2 (CH3), 45.6 (CH), 64.6
(C), 65.9 (CH2), 74.9 (CH2), 129.0 (CH), 129.1 (4 CH), 133.0
(C), 173.1 (C), 201.2 (C); HPLC (Chiralcel OD, hexane/2-
propanol, 70:30, 1.0 mLminÀ1, l=220 nm): tR (major diaste-
reoisomer)=20.2 min (major), 51.0 min (minor); HR-MS:
m/z=277.0945, calcd. for C14H15NO5: 277.0950.
cyclopentanecarboxylate (5c): [a]2D5: +30.5 (c 1.5, CHCl3,
95% ee) (lit.[8] [a]D25: À31.3, 94% ee, dr>20:1); 1H NMR
(300 MHz, CDCl3): d=1.81–2.11 (m, 4H), 2.32–2.44 (m,
2H), 3.75 (s, 3H), 4.05 (dd, J=11.0, 4.0 Hz, 1H), 4.97 (dd,
J=13.6, 11.0 Hz, 1H), 5.15 (dd, J=13.6, 4.0 Hz, 1H), 6.96–
7.04 (m, 2H), 7.22–7.29 (m, 2H); 19F NMR (282 MHz,
CDCl3): d=À113.9 (m, 1F); 13C NMR (75 MHz, CDCl3):
d=19.2 (CH2), 31.1 (CH2), 37.8 (CH2), 45.4 (CH), 53.0
2
(CH3), 62.3 (C), 76.3 (CH2), 115.7 (d, JC,F =22.0 Hz, 2 CH),
1
131.0 (C), 131.0 (d, 3JC,F =8.5 Hz, 2CH), 162.4 (d, JC,F
=
247.8 Hz, C), 169.7 (C), 212.2 (C); HPLC (Chiralcel OD,
hexane/2-propanol, 90:10, 1.0 mLminÀ1, l=220 nm): tR
(major diastereoisomer)=15.7 min (major), 28.0 min
(minor); HR-MS: m/z=332.0910, calcd. for (C15H16FNO5 +
Na): 332.0910.
ACHTUNGTRENNUNG(2R,3R)-2-Acetyl-2-(2-nitro-1-phenylethyl)-cyclopentan-
one (4h): The major diastereoisomer was purified by flash
chromatography; [a]D25: À33.3 (c 1.2, CHCl3, 92% ee) (lit.[10]
[a]2D5: À43.3, 99% ee, dr>98:2); 1H NMR (300 MHz,
CDCl3): d=1.67–1.76 (m, 3H), 1.92–2.02 (m, 1H), 2.11–2.22
(m, 1H), 2.32 (s, 3H), 2.52–2.59 (m, 1H), 4.38 (dd, J=11.6,
3.9 Hz, 1H), 4.50 (dd, J=13.6, 3.9 Hz, 1H), 4.86 (dd, J=
13.5, 11.5 Hz, 1H), 7.23–7.34 (m, 5H); 13C NMR (75 MHz,
CDCl3): d=19.3 (CH2), 26.5 (CH3), 27.3 (CH2), 38.5 (CH2),
46.2 (CH), 71.0 (C), 75.5 (CH2), 128.3 (CH), 128.7 (2 CH),
129.4 (2 CH), 134.3 (C), 202.7 (C), 213.1 (C); HPLC (Chiral-
cel OD, hexane/2-propanol, 70:30, 1.0 mLminÀ1, l=
220 nm): tR (major diastereoisomer)=11.4 min (major),
39.2 min (minor); HR-MS: m/z=275.1152, calcd. for
C15H17NO4: 275.1158.
AHCTUNGTREG(NNUN 2S,3R)-Methyl 1-[1-(4-methoxyphenyl)-2-nitroethyl]-2-
oxocyclopentanecarboxylate (5d): [a]2D5: +34.7 (c 1.5, CHCl3,
92% ee) (lit.[8] [a]D25: À38.9, 93% ee, dr>20:1); 1H NMR
(300 MHz, CDCl3): d=1.79–2.07 (m, 4H), 2.29–2.43 (m,
2H), 3.75 (s, 3H), 3.77 (s, 3H), 4.06 (dd, J=11.0, 4.2 Hz,
1H), 4.96 (dd, J=13.4, 11.0 Hz, 1H), 5.11 (dd, J=13.4,
4.0 Hz, 1H), 6.82 (ps d, J=8.8 Hz, 2H), 7.16 (ps d, J=
8.8 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=19.2 (CH2),
30.8 (CH2), 37.9 (CH2), 45.4 (CH), 52.9 (CH3), 55.1 (CH3),
62.5 (C), 76.4 (CH2), 114.0 (2 CH), 126.8 (C), 130.3 (2 CH),
159.2 (C), 169.8 (C), 212.3 (C); HPLC (Chiralpak AS-H,
hexane/2-propanol, 90:10, 1.0 mLminÀ1, l=220 nm): tR
(major diastereoisomer)=22.0 min (minor), 25.8 min
(major); HR-MS: m/z=344.1109, calcd. for (C16H19NO6 +
Na): 344.1110.
ACHTUNGTRENNUNG(2S,3R)-Ethyl 1-benzyl-4-[1-(4-fluorophenyl)-2-nitroeth-
yl]-3-oxopiperidine-4-carboxylate (4i): 1H NMR (300 MHz,
CDCl3): d=1.15 (t, J=7.1 Hz, 3H), 1.54–1.64 (m, 1H),
2.22–2.31 (m, 1H), 2.45 (ddd, J=11.7, 7.5, 4.2 Hz, 1H),
2.70–2.80 (m, 1H), 2.97 (d, J=16.7 Hz, 1H), 3.31 (d, J=
16.7 Hz, 1H), 3.46 (d, J=13.0 Hz, 1H), 3.56 (d, J=13.0 Hz,
1H), 3.95 (dd, J=11.4, 3.5 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H),
4.73 (dd, J=13.3, 11.7 Hz, 1H), 5.05 (dd, J=13.3, 3.4 Hz,
1H), 6.95–7.02 (m, 2H), 7.15–7.25 (m, 4H), 7.27–7.34 (m,
3H); 19F NMR (282 MHz, CDCl3): d=À114.1 (m, 1F);
13C NMR (75 MHz, CDCl3): d=13.8 (CH3), 31.0 (CH2), 45.8
(CH), 48.1 (CH2), 59.0 (C), 60.9 (CH2), 61.9 (CH2), 62.2
AHCTUNGTREG(NNUN 2S,3R)-Methyl 1-[2-nitro-1-(2-nitrophenyl)ethyl]-2-oxo-
cyclopentanecarboxylate (5e): [a]2D5: +108.0 (c 1.7, CHCl3,
97% ee); 1H NMR (300 MHz, CDCl3): d=1.87–2.07 (m,
3H), 2.15–2.23 (m, 2H), 2.42–2.52 (m, 1H), 3.73 (s, 3H),
4.65 (dd, J=10.8, 3.5 Hz, 1H), 5.04 (dd, J=14.3, 10.8 Hz,
1H), 5.34 (dd, J=14.5, 3.5 Hz, 1H), 7.40–7.46 (m, 1H),
7.56–7.61 (m, 1H), 7.77–7.82 (m, 2H); 13C NMR (75 MHz,
CDCl3): d=19.1 (CH2), 33.2 (CH2), 37.5 (CH2), 38.8 (CH),
53.0 (CH3), 61.4 (C), 76.9 (CH2), 124.8 (CH), 129.0 (CH),
129.5 (CH), 131.4 (C), 133.2 (CH), 151.1 (C), 170.3 (C),
212.6 (C); HPLC (Chiralpak AD-H, hexane/2-propanol,
80:20, 0.2 mLminÀ1, l=220 nm): tR (major diastereoiso-
mer)=52.8 min (major), 66.5 min (minor); HR-MS: m/z=
359.0841, calcd. for (C15H16N2O7 +Na): 359.0855.
(CH2), 77.2 (CH2), 115.3 (d, 2JC,F =22.0 Hz, 2CH), 127.5
(CH), 128.3 (2CH), 128.7 (2CH), 130.8 (C), 131.2 (d, JC,F
8.5 Hz, 2CH), 136.6 (C), 162.4 (d, JC,F =247.8 Hz, C), 168.4
(C), 204.3 (C); HPLC (Chiralpak AS-H, hexane/2-propanol,
90:10, 0.2 mLminÀ1, l=220 nm): tR =69.7 min (major),
Adv. Synth. Catal. 2010, 352, 3364 – 3372
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3369

Rubꢀn Manzano et al.
FULL PAPERS
A
phase was extracted with EtOAc (3ꢄ3 mL). The combined
organic extracts were dried over anhydrous MgSO4. After
removal of the solvent at reduced pressure the crude prod-
uct was passed through a plug of silica gel to afford 8 as col-
orless oil; yield: 75%. The diastereoisomers could be sepa-
rated by flash chromatography (hexane/ethyl acetate 5:1).
pentanecarboxylate (5f): [a]2D5: +68.8 (c 1.1, CHCl3, 95%
ee); 1H NMR (300 MHz, CDCl3): d=1.65–1.80 (m, 1H),
1.92–2.04 (m, 2H), 2.08–2.18 (m, 1H), 2.30–2.41 (m, 1H),
2.44–2.52 (m, 1H), 3.76 (s, 3H), 4.43 (dd, J=9.1, 5.4 Hz,
1H), 4.85–4.98 (m, 2H), 6.19 (dd, J=3.3, 0.4 Hz, 1H), 6.30
(dd, J=3.3, 2.0 Hz, 1H), 7.33 (dd, J=2.0, 0.9 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=19.3 (CH2), 30.1 (CH2), 37.8
(CH2), 40.3 (CH), 53.1 (CH3), 61.8 (C), 74.3 (CH2), 110.0
(CH), 110.7 (CH), 142.6 (CH), 148.9 (C), 169.4 (C), 211.9
(C); HPLC (Chiralcel OD, hexane/2-propanol, 90:10,
1.0 mLminÀ1, l=220 nm): tR (major diastereoisomer)=
12.6 min (major), 19.5 min (minor); HR-MS: m/z=304.0797,
calcd. for (C13H15NO6 +Na): 304.0797.
Ethyl
3-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-(1-hy-
droxyethyl)-2-methyl-4-nitrobutanoate
(8a):
1H NMR
(300 MHz, CDCl3): d=1.09 (s, 3H), 1.21 (d, J=6.4 Hz, 3H),
1.24 (t, J=7.1 Hz, 3H), 1.57–1.64 (m, 2H), 1.77–1.98 (m,
6H), 3.12 (br d, J=11.0 Hz, 1H), 3.61–3.71 (m, 1H), 3.82 (s,
3H), 4.04 (dd, J=11.9, 4.0 Hz, 1H), 4.15 (q, J=7.2 Hz, 1H),
4.72–4.79 (m, 1H), 4.78 (dd, J=12.8, 3.8 Hz, 1H), 5.04 (ps t,
J=12.4 Hz, 1H), 6.69–6.80 (m, 3H); 13C NMR (75 MHz,
CDCl3): d=14.1 (CH3), 18.1 (CH3), 19.2 (CH3), 24.0
(2CH2), 32.7 (2CH2), 48.5 (CH), 53.6 (C), 55.9 (CH3), 61.3
(CH2), 69.9 (CH), 77.0 (CH2), 80.4 (CH), 111.5 (CH), 116.2
(CH), 121.6 (CH), 127.1 (C), 147.2 (C), 149.8 (C), 175.1 (C);
HR-MS: m/z=432.1975, calcd. for (C21H31NO7 +Na):
432.1998.
To a mixture of epimers 8 (286 mg, 0.7 mmol) and 10%
Pd-C (80 mg) in methanol (2 mL) anhydrous ammonium
formate (442 mg, 7 mmol) was added in a single portion.[18]
The resulting reaction mixture was stirred at room rempera-
ture for 2–3 h (TLC) under nitrogen, and then it was re-
fluxed for 20 min. The catalyst was removed by filtration
through a celite pad and washed with dry methanol. The fil-
trate was evaporated under reduced pressure and the result-
ing residue was partitioned between water (1 mL) and di-
chloromethane (2 mL). The aqueous phase was extracted
with dichloromethane (4ꢄ2 mL) and the combined organic
layers were dried over anhydrous MgSO4. After removal of
the solvent, the crude diastereoisomeric hydroxy lactams
were subjected to further reduction with lithium aluminum
hydride, as follows.
To a suspension of LiAlH4 (106 mg, 2.8 mmol, 4 equiv.) in
dry tetrahydrofuran (7 mL) at 08C a solution of the previ-
ously obtained hydroxylactams in THF (3 mL) was added.
The reaction mixture was refluxed for 16 h until disappear-
ance of the starting material and carefully quenched by se-
quential addition of water (0.11 mL), 15% NaOH (0.11 mL)
and water (0.32 mL). The solids were filtered off and
washed with ethyl acetate, and the filtrate was dried over
anhydrous MgSO4. The solvent was removed in vacuo and
the crude product was subjected to the Swern oxidation con-
ditions.
To a stirred solution of 0.08 mL (0.95 mmol) of oxalyl
chloride in 2 mL of dichloromethane at À788C under nitro-
gen was added 0.14 mL (2.0 mmol) of dimethyl sulfoxide.
After 15 min, a solution of the hydroxypirrolydine in 2 mL
of dichloromethane was added. After 30 min, 0.28 mL of
triethylamine (2.0 mmol) was added and the resulting mix-
ture was gradually warmed to room temparature. The mix-
ture was partitioned between dichloromethane and water.
The organic phase was dried over anhydrous MgSO4 and
then evaporated to yield the crude keto lactam, which was
redissolved in dichloromethane and treated with 1.5 equiv.
of dimethyl pyrocarbonate at room temperature for 30 min.
The solvent was removed at reduced pressure and the prod-
uct was purified by flash chromatography (hexane/ethyl ace-
tate 1:3) to afford desired product 9; overall yield: 31% (4
steps).
ACHTUNGTRENNUNG(2S,3R)-Methyl 1-(1-nitro-4-phenylbutan-2-yl)-2-oxocyclo-
pentanecarboxylate (5g): [a]2D5: +76.1 (c 1.2, CHCl3, 91%
ee); 1H NMR (300 MHz, CDCl3): d=1.56–1.68 (m, 1H),
1.74–2.03 (m, 4H), 2.22–2.48 (m, 2H), 2.51–2.61 (m, 2H),
2.70–2.79 (m, 1H), 2.82–2.90 (m, 1H), 3.70 (s, 3H), 4.46 (dd,
J=14.3, 5.3 Hz, 1H), 4.97 (dd, J=14.2, 5.2 Hz, 1H), 7.13–
7.32 (m, 5H); 13C NMR (75 MHz, CDCl3): d=19.2 (CH2),
31.1 (CH2), 32.4 (CH2), 33.8 (CH2), 38.0 (CH2), 39.9 (CH),
52.7 (CH3), 62.7 (C), 76.1 (CH2), 126.3 (CH), 128.3 (2CH),
128.5 (2CH), 140.5 (C), 169.8 (C), 213.2 (C); HPLC (Chiral-
pak AS-H, hexane/2-propanol, 90:10, 1.0 mLminÀ1, l=
220 nm): tR =11.6 min (major), 12.8 min (minor); HR-MS:
m/z=342.1327, calcd. for (C17H21NO5 +Na): 342.1317.
Conjugate Addition of b-Keto Ester 2a to Nitroolefin
6
Product 7 was obtained following the general procedure for
nitro-Michael additions described above for 4b starting from
3-cyclopentyloxy-4-methoxy-b-nitrostyrene (6)[12] and ethyl
2-methylacetoacetate (3a), and using thiourea 1 as catalyst
(48 h). The mixture of diasteroisomers was obtained with
95% yield and the major diastereoisomer (7) was separated
(ca. 80:20) by flash chromatography (hexane/ethyl acetate
8:1 to 4:1).
ACHTUNGTRENNUNG(2R, 3R)-Ethyl 2-acetyl-3-[3-(cyclopentyloxy)-4-methoxy-
phenyl]-2-methyl-4-nitrobutanoate (7): H NMR (300 MHz,
CDCl3): d=1.22 (t, J=7.1 Hz, 3H), 1.44 (s, 3H), 1.59–1.66
(m, 2H), 1.79–1.97 (m, 6H), 2.11 (s, 3H), 3.81 (s, 3H), 4.02–
4.22 (m, 1H), 4.69–4.74 (m, 1H), 4.93 (ABX, J=14.6,
13.3 Hz, 1H), 4.96 (ABX, J=19.5, 13.2 Hz, 1H), 6.71–6.78
(m, 3H); 13C NMR (75 MHz, CDCl3): d=13.6 (CH3), 18.3
(CH3), 23.8 (2CH2), 27.6 (CH3), 32.5 (CH2), 32.5 (CH2), 47.1
(CH), 55.6 (CH3), 61.7 (CH2), 61.8 (C), 77.4 (CH2), 80.2
(CH), 111.5 (CH), 115.9 (CH), 121.5 (CH), 127.2 (C), 147.1
(C), 149.7 (C), 170.8 (C), 205.6 (C); HPLC (Chiralpak OD,
hexane/2-propanol, 90:10, 1.0 mLminÀ1, l=220 nm): tR =
11.7 min (major), 14.3 min (minor); HR-MS: m/z=430.1823,
calcd. for (C21H29NO7 +Na): 430.1842.
Synthesis of 9
To a solution of b-keto ester 7 (407 mg, 1 mmol) in metha-
nol (8 mL) at 08C was added NaBH4 (76 mg, 2 mmol). The
reaction mixture was stirred until disappearance of starting
material (TLC, about 1 hour), and then acidified with HCl
(2M). The volatiles were removed under vacuum and the
residue was partitioned between H2O (2 mL) and EtOAc
(2 mL). The organic phase was separated and the aqueous
3370
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ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 3364 – 3372

Stereocontrolled Construction of Quaternary Stereocenters
A
d=19.7 (CH3), 41.5 (CH), 51.7 (C), 53.3 (CH3), 74.9 (CH2),
117.2 (CH), 121.3 (C), 125.6 (CH), 126.2 (CH), 130.1 (CH),
150.2 (C), 166.0 (C), 169.4 (C); HPLC (Chiralpak AD-H,
hexane/2-propanol, 90:10, 1.0 mLminÀ1, l=220 nm): tR =
14.8 min (major), 16.3 min (minor); HR-MS: m/z=302.0637,
calcd. for (C13H13NO6 +Na): 302.0641.
phenyl]-3-methylpyrrolidine-1-carboxylate (2 conformers)
(9): H NMR (300 MHz, CDCl3): d=1.44 (s, 3H), 1.61–1.71
(m, 2H), 1.69 (s, 3H), 1.75–1.97 (m, 6H), 3.17 (t, 1H), 3.20–
3.33 (m, 1H), 3.62–3.94 (m, 2H), 3.74 (s, 1.5H), 3.75 (s,
1.5H), 3.82 (s, 3H), 4.04 (t, J=10.8 Hz, 1H), 4.71 (br s, 1H),
6.62–6.69 (m, 2H), 6.78 (d, J=8.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=23.1 (CH3), 24.1 (2CH2), 28.1 (CH3),
28.4 (CH3), 32.8 (2 CH2), 50.4 (CH2), 50.8 (CH2), 52.5
(CH3), 52.7 (CH), 53.6 (CH), 54.0 (CH2), 54.6 (CH2), 55.9
(CH3), 57.5 (C), 58.6 (C), 80.4 (CH), 111.8 (CH), 114.3
(CH), 120.0 (CH), 129.8 (C), 130.0 (C), 147.6 (C), 149.4 (C),
155.4 (C), 210.1 (C); HR-MS: m/z=398.1931, calcd. for
(C21H29NO5 +Na): 398.1943.
AHCTUNGTREG(NNUN 3R, 4R)-Methyl 3-methyl-4-(nitromethyl)-2-oxochroman-
3-carboxylate (epi-12a): 1H NMR (400 MHz, CDCl3): d=
1.66 (s, 3H), 3.58 (s, 3H), 4.25 (dd, J=9.7, 5.2 Hz, 1H), 4.37
(dd, J=12.6, 9.8, 1H), 4.69 (dd, J=12.6, 5.0 Hz, 1H), 7.10–
7.21 (m, 3H), 7.34–7.39 (m, 1H); 13C NMR (75 MHz,
CDCl3): d=18.2 (CH), 42.0 (CH3), 52.2 (C), 53.6 (CH), 75.4
(CH2), 117.3 (CH), 120.7 (C), 125.5 (CH), 128.7 (CH), 130.6
(CH), 150.5 (C), 166.1 (C), 169.7 (C); HPLC (Chiralpak
AD-H, hexane/2-propanol, 90:10, 1.0 mLminÀ1, l=220 nm):
tR =13.1 min (minor), 14.7 min (major); HR-MS: m/z=
302.0627, calcd. for (C13H13NO6 +Na): 302.0641.
Synthesis of 2-(2-Nitrovinyl)phenyl Malonates
To a solution of trans-2-hydroxy-b-nitrostyrene (510 mg,
3 mmol) and monomethyl 2-methylmalonate 10a (436 mg,
3.3 mmol)[16] in dry THF (30 mL), DCC (681 mg, 3.3 mmol)
was added at À208C in one portion.[14] After stirring for
15 min at this temperature, the reaction mixture was allowed
to warm to room temperature and stirred for 7 days. During
Acknowledgements
We acknowledge financial support by the Spanish MICINN
(Project CTQ2008-03960/BQU) and Junta de Castilla y Leꢀn
(Project GR 168). R. M. and M.-D. M. also thank the MEC
and J C y L, respectively, for pre-doctoral fellowships.
that time
a white precipitate of dicyclohexylurea was
formed. The white solid was filtered off and the solvent was
removed in vacuo. The crude product was purified by flash
chromatography (CH2Cl2) to afford compound 11a as a
yellow solid; yield: 272 mg (0.97 mmol, 32%).
(E)-1-Methyl 3-[2-(2-nitrovinyl)phenyl] 2-methylmalonate
(11a): 1H NMR (300 MHz, CDCl3): d=1.62 (d, J=7.2 Hz,
3H), 3.81 (q, J=7.2 Hz, 1H), 3.89 (s, 3H), 7.21–7.24 (m,
1H), 7.32–7.37 (m, 1H), 7.51–7.57 (m, 1H), 7.61 (d, J=
13.8 Hz, 1H), 7.61–7.64 (m, 1H), 8.13 (d, J=13.6 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=13.5 (CH3), 45.9 (CH), 53.0
(CH3), 123.0 (C), 123.2 (CH), 126.8 (CH), 128.4 (CH), 132.4
(CH), 132.9 (CH), 138.5 (CH), 149.7 (C), 168.1 (C), 169.6
(C); HR-MS: m/z=302.0637, calcd. for (C13H13NO6 +Na):
302.0641.
(E)-1-Methyl 3-[2-(2-nitrovinyl)phenyl] 2-tert-butylmalo-
nate (11b): 1H NMR (300 MHz, CDCl3): d=1.25 (s, 9H),
3.61 (s, 1H), 3.87 (s, 3H), 7.21 (dd, J=8.2, 1.1 Hz, 1H),
7.32–7.36 (m, 1H), 7.51–7.56 (m, 1H), 7.60 (d, J=13.8 Hz,
1H), 7.61–7.63 (m, 1H), 8.12 (d, J=13.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=27.8 (3 CH3), 33.9 (C), 52.4 (CH3),
60.9 (CH), 123.1 (C), 123.2 (CH), 126.8 (CH), 128.4 (CH),
132.5 (CH), 132.9 (CH), 138.5 (CH), 149.6 (C), 166.4 (C),
167.9 (C); HR-MS: m/z=344.1108, calcd. for (C16H19NO6 +
Na): 344.1110.
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A
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