Oxidation of chiral α-phenylacetate derivatives: Formation of dimers with contiguous quaternary stereocenters versus tertiary alcohols

Article abstract of DOI:10.1016/j.tetasy.2005.10.008

The menthol esters of α-phenylacetate derivatives undergo diastereoselective oxidative dimerizations (α-cyano) in the presence of oxidants, and nitrosylation (α-amido) in the presence of CAN to form products containing adjacent functionalized quaternary stereocenters and tertiary alcohols, respectively.

Full text of DOI:10.1016/j.tetasy.2005.10.008

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3599–3605
Oxidation of chiral a-phenylacetate derivatives:
formation of dimers with contiguous quaternary
stereocenters versus tertiary alcohols
Marisa C. Kozlowski,* Evan S. DiVirgilio, Krishnan Malolanarasimhan and
Carol A. Mulrooney
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, PA 19104, USA
Received 7July 2005; revised 26 July 2005; accepted 16 September 2005
Available online 9 November 2005
Abstract—The menthol esters of a-phenylacetate derivatives undergo diastereoselective oxidative dimerizations (a-cyano) in the
presence of oxidants, and nitrosylation (a-amido) in the presence of CAN to form products containing adjacent functionalized qua-
ternary stereocenters and tertiary alcohols, respectively.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
CN CN
EtO2C
Ph
CO2Et
The formation of carbon–carbon bonds by the oxidative
coupling of carbonyl compounds at the a-position is
useful and complementary to its ionic counterparts.
There are numerous reports on the syntheses of
1,4-dicarbonyl compounds,1,2 radical cyclizations,3 and
synthesis of functionalized pyrrolidines4 using metallic
oxidants. Furthermore, the diastereoselective oxidative
intermolecular coupling of monosubstituted enolates
employing chiral auxiliaries has been reported by several
groups.5 For example, Kise et al.6 have used chiral
oxazolidinones in the homocoupling of 3-arylpropanoic
acid derivatives to obtain the dimer with up to 98%
Ph
3, meso
CN
CN
Ph
CO2Et
Ph
CO2Et
2, achiral
+
1, racemic
CN CO2Et
CN
EtO2C
Ph
Ph
4, C2
(+)-enantiomer
Figure 1.
reochemistry of these quaternary carbons is established.
Under the reaction conditions reported by De Jongh,
the meso diastereomer was formed in excess with respect
to the racemic C2 diastereomer. However, upon heating
the meso diastereomer equilibrates to provide predomi-
nately the C2 compound. Due to the steric hindrance
present, these compounds are difficult to synthesize uti-
lizing ionic bond disconnections. To date, there has been
no report on the asymmetric dimerization of this sub-
strate. Herein, we report the diastereoselective oxidative
reactions of chiral phenylcyanoacetate derivatives.
de.7,8 Using chiral BINOL as an auxiliary, Csaky
´
¨
et al.9 performed intramolecular diastereoselective homo-
and heterocouplings of monosubstituted enolates. The
asymmetric coupling of disubstituted enolates, however,
remains a challenge.
Diastereoselective copper(II) amine catalyzed oxida-
tive dimerization of phenylcyanoacetate derivatives as
reported by De Jongh et al.10 resulted in the formation
of a carbon–carbon bond between two highly function-
alized quaternary carbons (Fig. 1). In forming this bond
through an achiral radical intermediate, the relative ste-
2. Diastereoselective dimerization
*
The first chiral phenylacetate, which we examined,
was the menthol phenylcyanoacetate derivative. We
Corresponding author. Tel.: +1 215 898 3048; fax: +1 215 573
2112; e-mail: marisa@sas.upenn.edu
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.10.008

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M. C. Kozlowski et al. / Tetrahedron: Asymmetry 16 (2005) 3599–3605
proposed that the chiral menthol ester would direct the
approach in the dimerization of the radical intermediate
(Scheme 1). Menthol ester 5a was made efficiently via
the ketene by heating a mixture of 1, menthol, DMAP,
and molecular sieves in toluene at reflux, overnight.
Dimerization of ester 5a using CuClÆ(TMEDA) in the
presence of air afforded three dimeric products 6a–8a
in 60% yield as well as an oligomeric material 9a in
40% yield. Two overlapping doublets of triplets for the
C–H adjacent to the menthol oxygen11 of 8a indicated
that this isomer was not symmetric, which is only consis-
tent with the meso configuration for the two central qua-
compounds 6b and 7b with the C2-core. Upon further
recrystallization, the major C2 isomer, highly functional-
ized 7b, was obtained in its pure form and the configura-
tion illustrated in Scheme 1 was established definitively
from the X-ray crystal structure (Fig. 2). Since the sepa-
ration of these compounds is straightforward and the
preparative (10–100 g) generation of precursors is
uncomplicated, this method offers a simple means of pre-
paring a highly functionalized array containing contigu-
ous quaternary centers in stereochemically pure form
(either meso or C2).
1
ternary centers (meso core). The H NMR spectra of
dimeric products 6a and 7a showed two well-resolved
doublets of triplets around 5 ppm for the C–H adjacent
to menthol oxygen. The integrals of these two signals
were different, indicating the presence of two different
compounds. Each of these compounds is symmetrical,
as would be expected, for 6a and 7a (i.e., C2 with respect
to the two quaternary centers; C2 core).
10 mol%
menthol
CuCl.TMEDA
DMAP, MS
Ar
PhCH3 , ∆
i-Pr
O2
Me
O
1
NC
90%
6a : 7a: 8a: 9a
5
O
8 : 16 : 36 : 40
6b : 7b : 8b : 9b
13 : 27 : 60 : 0
a Ar = Ph
b Ar = p-MePh
(C2 core)
menthol α-H
are equivalent
O Ar
R
CN
i-Pr
Hb
R
Me
O
O
R
Me
R
Hb
i-Pr
Ar CN
O
6
O NC
S
Ar
Ha
R
i-Pr
Me
O
Figure 2. X-ray structure of 7b. For clarity, only the hydrogens on
stereogenic centers are illustrated.
S
O
Me
R
i-Pr
Ha
O
NC Ar
7
O
Ar
S
CN
i-Pr
Ha
R
Me
(meso core)
menthol α-H
are not equivalent
O
R
O
Me
R
Hb
3. b-Dicarbonyl reactions: oxidative coupling versus
nitrosylation
i-Pr
NC Ar
O
8
Scheme 1.
Although, the above results using 5 were encouraging,
the low meso:C2 selectivity prompted further explora-
tion. From the structure of menthol ester 5, selectivity
was induced by an isopropyl group blocking one face
of the radical formed during the reaction. However,
there were two orientations possible in the carbon radi-
cal (nitrile syn or anti to the ester). In order to ensure
that a single isomer of the radical intermediate was
formed, the cyano group was replaced with an amide.
The resultant substrate 11 should thus form a single iso-
meric radical species in the presence of a chelating metal
(Scheme 2).
Due to the formation of oligomeric material 9a via reac-
tion at the para-phenyl position10, the chiral para-meth-
ylphenylcyanoacetate was also investigated. Starting
from benzyl cyanide, acylation was accomplished with
NaH and dimethyl carbonate to yield 1b. The menthol
ester was then formed following the procedure for 5a.
Dimerization was undertaken using CuClÆ(TMEDA) in
the presence of air. A quantitative yield of diastereomers
6b–8b was obtained indicating that oligomerization was
effectively suppressed (Scheme 1). Unfortunately, a mix-
ture of a 13:27:60 of 6b:7b:8b was still obtained. Similar
ratios were observed for 6a–8a compared to 6b–8b indi-
cating a similar stereochemical course for 5a and 5b.
Based upon the success of De Jongh in equilibrating a
mixture of 3 and 4 to predominantly one isomer under
thermal conditions,10 we were surprised to find no
change in the composition of the 6b:7b:8b mixture upon
prolonging heating.
The treatment of 1 with concentrated H2SO4 afforded
10, which was converted into compound 11 following
the same procedure for 5 (Scheme 2). Since the treat-
ment of 10 with CuClÆ(TMEDA) catalyst in the presence
of oxygen caused the formation of the a-keto products
12 and 13 (ꢀ1:1) exclusively, several other oxidants were
screened. Potassium ferricyanide and manganese(III)
acetate provided no new compounds even after several
hours, although ceric ammonium nitrate (CAN) proved
to be an effective oxidant. However, the nitrosylation12
However, the major compound 8b with the meso core
could be separated chromatographically from the two

M. C. Kozlowski et al. / Tetrahedron: Asymmetry 16 (2005) 3599–3605
3601
menthol
tively low selectivity shown for 15a and 15b with CAN
may be a consequence of poor chelation within 11 such
that a single conformationally defined reactive species is
not formed. To determine if this was the case, stoichio-
metric amounts of Lewis acids were screened in the
CAN/CH3CN reactions. Little or no improvement was
seen with TiCl4 (1.3:1), Ti(Oi-Pr)4 (1.3:1), LiCl (1.3:1),
ZnCl2 (1.4:1), or MgSO4 (1.5:1)13 indicating that the
generation of a chelated adduct with an external Lewis
acid does not provide superior facial control. With other
chiral auxiliaries, including the 8-phenyl menthol and
borneol chiral esters, a 1:1 ratio of diastereomers was
realized when subjected to CAN/MgSO4.
Ph
Ph
DMAP, 4Å MS
i-Pr
H2SO4
93%
Me
PhCH3, ∆
OEt
H2N
H2N
O
1
84% brsm
O
O
O
O
10
11
CAN, CH3CN, 90%
Me
10%
CuCl(TMEDA)
O2
Ph CONH2
CAN
CH3CN
i-Pr
O
O2NO
Ph
Hb
O
15a
R
O
+
Ph
O2NO
CONH2
OEt
O
Ph CONH2
i-Pr
R = OEt 12
R = NH2 13
Me
O
O2NO
O
Hb
O
14
15b
Ph CONH2
H2
acetone
cat. HCl
Scheme 2.
i-Pr
Me
Raney Ni
O
HO
15a + 15b
H
O
16
83%
40%
product 14 was obtained in high yield (70%). The iden-
tity of 14 was confirmed by crystallographic analysis
(Fig. 3).
one diastereomer
O
O
Ph
HN
Ph
i-Pr
O
DIBAL
HN
HO
Me
Me
Me
OH
60%
O
H
O
18
17
Scheme 3.
To transform 15 to further derivatives, it was found that
steric congestion at the quaternary center needed to be
alleviated first by the removal of the nitro group; reduc-
tive removal was accomplished in quantitative yield
using Raney nickel (Scheme 3). Recrystallization at this
stage gave 16 in 40% yield as one diastereomer, which
was determined by crystallographic analysis to have an
(S)-configuration at the quaternary center (Fig. 4).
Reaction of 16 with acetone gave acetonide 17 in 83%
yield. DIBAL reduction of 17 gave a-hydroxy amide
18 in 60% yield as a result of menthol ester reduction
accompanied by reductive cleavage of the hemiaminal.
Figure 3. X-ray Structure of 14.
In order to determine if this nitrosylation was general,
nitrile 1 was also subjected to CAN oxidation. Dimeric
products 3 and 4 were obtained in 65% yield and the
oligomeric material in 35% yield. However, the reaction
required one day at 40 ꢁC versus 10 min at room temper-
ature for the CuClÆ(TMEDA) catalyst. No nitrosylated
product was evident indicating that the nitrile (favors
dimerization) versus amide (favors nitrosylation) substi-
tuent is key to controlling the chemoselectivity of these
oxidations. Overall, it appeared that the less electron-
withdrawing amide (vs nitrile) permits pathways with a
more positive charge character. For example, the pres-
ence of a radical cation from amides 10 and 11 accounts
for the observed decarboxylation (12 and 13) and trap-
ping with nitrate (14 and 15). In contrast, the dimeriza-
tion behavior exhibited by nitriles 1 and 5 is consistent
with reaction via a neutral radical species.
Since this reaction is an efficient entry into highly func-
tionalized tertiary alcohols, the corresponding chiral
menthol ester amide 11 was also examined. Under the
same conditions used with 10, the nitrosylated product
was obtained as a mixture of diastereomers 15a and
15b in 90% yield. Although 15a and 15b were insepara-
ble by chromatography, the ratio could be readily ascer-
Figure 4. X-ray structure of 16. For clarity, only selected hydrogens
are illustrated.
4. Conclusion
1
tained by H NMR spectroscopy. With CAN, a 1.3:1
ratio of the two diastereomers was observed. The rela-
In conclusion, we have found that the menthol esters of a-
phenyl-a-cyanoacetates undergo oxidative dimerizations

3602
M. C. Kozlowski et al. / Tetrahedron: Asymmetry 16 (2005) 3599–3605
˚
in the presence of either copper(II) catalysts or CAN.
Although the product with the meso core predominates,
an approximate 2:1 diastereoselection was seen in the for-
mation of the products with the C2 core. Both the meso
core diastereomer and the major C2 core diastereomer
were obtained in pure form to supply the compounds
containing two new adjacent functionalized quaternary
stereocenters. In contrast, the menthol esters of a-phe-
nyl-a-amidoacetates undergo decarboxylation with cop-
per(II) catalysts and oxidative nitrosylation in the
presence of CAN. In the CAN reaction, two highly func-
tionalized tertiary alcohol products are formed cleanly,
one of which was isolated in >99% de and 40% yield upon
recrystallization.
mmol), and 4 A MS (1 g). The mixture was heated at
reflux in PhCH3 overnight and then diluted with EtOAc.
After washing three times with 1 M HCl, the organic
layer was dried over anhydrous Na2SO4 and concen-
trated to a solid. Chromatography (50% CH2Cl2/
hexanes) afforded the two diastereomers of 5a
(875 mg) in 90% yield as a white solid: mp 80–82 ꢁC;
23
½aŠ ¼ À83:3 (c 1.71, CHCl3); IR (film) 2364,
D
1742 cmÀ1; H NMR (250 MHz, CDCl3): d 7.47–7.38
(m, 5H), 4.74–4.62 (m, 2H), 2.00–1.85 (m, 1H), 1.67–
1.20 (m, 5H), 1.10–0.90 (m, 2H), 0.87(d, J = 6.5 Hz,
3H), 0.86–0.83 (m, 1H), 0.77 (d, J = 7Hz, 3H), 0.58
(d, J = 7Hz, 3H); 13C NMR (62.5 MHz, CDCl3): d
164.5, 130.3, 129.1, 129.0, 127.8, 115.6, 77.6, 46.8,
44.0, 40.1, 33.9, 31.2, 25.8, 23.1, 21.8, 20.5, 15.8; HRMS
(ES) calcd for C19H25NO2 (MNa+) 322.1787, found
322.1861.
1
5. Experimental
5.1. General considerations
5.3. Dimerization of 5a
Unless otherwise noted, all non-aqueous reactions were
carried out under an atmosphere of dry N2 in dried
glassware. When necessary, solvents and reagents were
dried prior to use. Toluene was de-oxygenated by purg-
ing with N2 and then dried by passing through activated
alumina. CH3CN, MeOH, TMEDA, dimethoxyethane,
and hexanes were distilled from CaH2. Cu(TMEDA)-
Cl(OH) was prepared by sonicating CuCl with TMEDA
in CH3CN under aerobic conditions. Removal of the
solvent yielded Cu(TMEDA)Cl(OH) as a blue-purple
crystalline powder.
To a solution of 5a (300 mg, 0.9509 mmol) in MeOH
was added Cu(TMEDA)Cl(OH) (43 mg, 10 mol %).
After stirring for 5 min, the reaction mixture was
quenched with 1 M HCl and extracted with EtOAc.
Chromatography (50% CH2Cl2/hexanes) afforded 6a
and 7a (110 mg), 8a (180 mg), and 9a (120 mg) in 22%,
36%, and 40% yields, respectively as white solids.
Compounds 6a and 7a (1:2 mixture): mp 191–193 ꢁC;
23
½aŠ ¼ À129:6 (c 0.47, CHCl3); IR (film) 2362,
D
1736 cmÀ1
;
1H NMR (500 MHz, CDCl3): d 7.44 (t,
J = 7.2 Hz, 1H), 7.29 (t, J = 7.2 Hz, 2H), 7.12 (d,
J = 7.6 Hz, 2H), 4.88 (dt, J = 4.2, 10.6 Hz, 1H), 2.22–
2.14 (m, 1H), 1.75–0.75 (m, 11H), 0.65 (d, J = 6.8 Hz,
3H), 0.62 (d, J = 6.8 Hz, 3H); 13C NMR (62.5 MHz,
CDCl3): d 165.7, 165.5, 130.0, 128.9, 128.7, 128.4,
128.3, 115.6, 79.1, 78.9, 60.6, 46.6, 46.5, 39.8, 39.5,
34.0, 31.5, 31.4, 25.7, 25.6, 23.2, 23.0, 21.9, 21.8, 20.7,
20.3, 15.9; HRMS (ES) calcd for C38H24N2O4 (MNa+)
619.3510, found (MNa+) 619.3513.
Analytical thin layer chromatography (TLC) was per-
formed on EM reagents 0.25 mm Silica Gel 60-F plates.
Preparative thin layer chromatography was performed
on EM reagents 1.00 mm Silica Gel plates. Visualization
was accomplished with UV light. Chromatography on
Silica Gel was performed using a forced flow of the indi-
cated solvent system on EM reagents Silica Gel 60 (230–
400 mesh).14 1H NMR spectra were recorded on Bruker
AM-500 (500 MHz), AM-250 (250 MHz), or AM-200
(200 MHz) spectrometers. Chemical shifts are reported
in ppm from tetramethylsilane (0 ppm) or from the sol-
vent resonance (CDCl3 7.26 ppm, DMSO-d6 2.49 ppm).
Data are reported as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, br =
broad, m = multiplet), coupling constants, and number
of protons. Mass spectra were obtained on a low reso-
nance Micromass Platform LC in electron spray mode
and high resonance VG autospec with an ionization
mode of either CI or ES. IR spectra were taken on a Per-
kin–Elmer FT-IR spectrometer using a thin film on
NaCl plates. Melting points were obtained on Thomas
Scientific Unimelt apparatus and are uncorrected. Opti-
cal rotations were measured on a Perkin–Elmer Polar-
23
Compound 8a: mp 184–186 ꢁC; ½aŠ ¼ À45:1 (c 0.61,
D
CHCl3); IR (film) 1743, 1582 cmÀ1
;
1H NMR
(250 MHz, CDCl3): d 7.40–7.30 (m, 5H), 4.80 (m, 1H),
2.00–1.80 (m, 1H), 1.79–0.70 (m, 11H), 0.60 (d,
J = 6.8 Hz, 3H), 0.49 (d, J = 6.8 Hz, 3H); 13C NMR
(62.5 MHz, CDCl3): d 163.7, 129.9, 129.3, 128.7, 128.2,
116.1, 116.0, 78.9, 78.8, 46.5, 44.8, 39.8, 39.5, 33.9,
31.4, 31.3, 29.7, 25.7, 23.2, 22.9, 21.8, 20.6, 20.3, 15.9,
15.7; HRMS (ES) calcd for C38H24N2O4 (MNa+)
619.3510, found (MNa+) 619.3513.
5.4. Cyano-p-tolyl-acetic acid menthyl ester 5b
4-Methylbenzylcyanide (0.990 g, 7.55 mmol) was added
to a suspension of NaH (60% in mineral oil, 0.4526 g,
11.32 mmol) in 1,2-dimethoxyethane (5 mL). After stir-
ring for 30 min at 60 ꢁC, dimethyl carbonate (1.36 g,
15.1 mmol) was added. After completion, the reac-
tion mixture was neutralized with 1 M HCl and
extracted with ether. The extracts were concentrated
and the resultant material used in the next step without
purification.
imeter 341 with a sodium lamp and are reported as
T
k
follows ½aŠ (c = g/100 mL, solvent).
5.2. Cyano-phenyl-acetic acid menthyl ester 5a
To a solution of ethyl phenylcyanoacetate (584 mg,
3.09 mmol) in PhCH3 were added (1R,2S,5R)-(À)-
menthol (1.27g, 8.11 mmol), DMAP (990 mg, 8.11

M. C. Kozlowski et al. / Tetrahedron: Asymmetry 16 (2005) 3599–3605
3603
Toluene (5 mL), menthol (1.18 g, 7.55 mmol), and cata-
lytic DMAP (0.75 mmol) were combined and the mix-
ture heated at reflux for 48 h. After cooling and
concentrating, chromatography (7.5% EtOAc/hexanes)
46.8, 40.2, 39.9, 34.3, 31.8, 31.7, 26.1, 26.0, 23.6, 23.3,
22.2, 21.5, 21.4, 21.1, 20.7, 16.3, 16.0; HRMS (ES) calcd
for C40H52N2O4Na (MNa+) 647.3825, found (MNa+)
647.3821.
yielded 5b (950 mg) in 40% yield from 4-methyl benzyl
23
D
1
cyanide as a white solid: mp 78–79 ꢁC; ½aŠ ¼ À50:4 (c
5.6. 2-Phenyl-malonamic acid ethyl ester 10
1.21, CHCl3); IR (film) 2358.9, 1741.5 cmÀ1; H NMR
(500 MHz, CDCl3): d 7.35 (d, J = 8 Hz, 2H), 7.24 (d,
J = 8 Hz, 2H), 4.70 (dt, J = 11 Hz, 1H), 4.67(s, 1H),
2.38 (s, 3H), 1.97(d, J = 12 Hz, 1H), 1.71–1.67 (m,
2H), 1.63–1.57(m, 1H), 1.51–1.40 (m, 2H), 1.07–0.99
(m, 2H), 0.92 (d, J = 6.5 Hz, 3H), 0.89–0.85 (m, 1H),
0.81 (d, J = 7Hz, 3H), 0.64 (d, J = 7Hz, 3H); 13C
NMR (126 MHz, CDCl3): d 165.5, 139.5, 130.2, 128.1,
127.7, 116.2, 77.9, 47.2, 44.1, 40.6, 34.4, 31.7, 26.2,
23.5, 22.2, 21.4, 20.9, 16.3; HRMS (ES) calcd for
C20H27NO2 (MNa+) 336.1940, found 336.1934.
Ethyl phenylcyanoacetate 1 (5.3 g, 28 mmol) was stirred
with 96% H2SO4 (15 mL) for 3 h. The mixture was
neutralized with aqueous NaHCO3 and the product
extracted with EtOAc (3 · 50 mL). The organic extracts
were dried over anhydrous Na2SO4 and concentrated to
give 10 (5.2 g) in 93% yield as a white powder: mp 132–
135 ꢁC; IR (film) 3394, 1737, 1655 cmÀ1 1H NMR
;
(200 MHz, CDCl3): d 7.51–7.28 (m, 5H), 6.87 (br s,
1NH), 6.02 (br s, 1NH), 4.50 (s, 1H), 4.20 (q,
J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR
(62.5 MHz, CDCl3): d 170.8, 170.3, 134.0, 124.4, 128.6,
128.4, 62.2, 58.4, 14.1; HRMS (ES) calcd for
C11H14NO3 (MH+) 208.0973, found 208.0976.
5.5. Dimerization of 5b
Oxygen was bubbled into a round bottom flask contain-
ing MeOH (11 mL). To this solution was added 5b
(500 mg, 1.60 mmol) and, upon dissolution, Cu(TME-
DA)Cl(OH) (72.8 mg, 0.16 mmol) was added. After stir-
ring for 15 min, the reaction mixture was quenched with
1 M HCl. Cold water was added and the resulting pre-
cipitate was filtered. The crude reaction mixture was
chromatographed twice (30% CH2Cl2/hexanes) to give
6b and 7b (158.6 mg, 32%), 8b (234.7mg, 47%), and
unseparated 6b, 7b, and 8b (94.6 mg, 19%). Compounds
6b and 7b mixture was further recrystallized from
EtOAc/hexanes to provide X-ray quality crystals of 7b
(70.0 mg, 14% from 5b).15
5.7. 2-Phenyl-malonamic acid menthyl ester 11
To a solution of 10 (1.00 g, 4.8 mmol) in PhCH3 was
added (1R,2S,5R)-(À)-menthol (800 mg, 5.1 mmol),
˚
DMAP (1.20 g, 1 mmol), and 4 A MS (1 g). After heat-
ing at reflux in PhCH3 overnight, the mixture was
cooled, diluted with EtOAc, and washed with 1 M
HCl. The organic layer was dried over anhydrous
Na2SO4 and concentrated to a solid. Chromatography
(98% CH2Cl2/EtOAc) afforded 11 (900 mg) in 43% yield
(84% brsm) as a 1:1 ratio of diastereomers in the form of
23
a white solid: mp 162–168 ꢁC; ½aŠ ¼ À53:7 (c 0.57,
D
CHCl3); IR (film) 3413, 1735, 1656 cmÀ1
;
1H NMR
Compounds 6b and 7b: mp 167–170 ꢁC; IR (film) 1740,
1613 cmÀ1; 1H NMR (500 MHz, CDCl3): d 7.1 (m, 2H),
7.0 (m, 2H), 4.9 (m, 1H), 2.36 (s, 3H), 2.16 (d,
J = 12.5 Hz, 1H), 1.72–1.25 (m, 5H), 1.09–1.01 (m,
1H), 0.98–0.92 (m, 3H), 0.90–0.84 (m, 2H), 0.67–0.64
(m, 6H); 13C NMR (126 MHz, CDCl3): d 166.4, 166.1,
140.5, 129.4, 129.3, 129.0, 126.5, 126.4, 116.2, 116.1,
79.3, 79.0, 60.9, 47.0, 46.8, 40.2, 39.9, 34.4, 31.9, 31.8,
31.7, 26.1, 26.0, 23.5, 23.4, 22.3, 22.2, 21.5, 21.1, 20.7,
16.3, 16.2; HRMS (ES) calcd for C40H52N2O4Na
(MNa+) 647.3825, found (MNa+) 647.3835.
(250 MHz, CDCl3): d 7.39–7.31 (m, 10H), 7.13 (br s,
1NH), 6.99 (br s, 1NH), 6.09 (br s, 2NH), 4.74 (dt,
J = 4.2, 11 Hz, 1H), 4.66 (dt, J = 4.5 10 Hz, 1H), 4.47
(s, 1H), 4.45 (s, 1H), 2.03 (br s, 2H), 1.85–1.95 (m,
2H), 1.79–1.61 (m, 4H), 1.60–1.20 (m, 5H), 1.20–0.80
(m, 5H), 1.10–0.90 (m, 6H), 0.90 (d, J = 7Hz, 3H),
0.87(d, J = 8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H), 0.49
(d, J = 7Hz, 3H); 13C NMR (62.5 MHz, CDCl3): d
170.6 170.1, 134.4, 129.2, 129.1, 128.4, 128.4, 128.3,
76.3, 58.7, 58.6, 47.2, 47.0, 40.3, 34.3, 31.62, 31.55,
26.3, 25.9, 23.49, 23.4, 22.1, 20.9, 20.7, 16.4, 16.0;
HRMS (ES) calcd for C19H27NO3 (MH+) 340.2252,
found 340.2234.
23
Compound 7b: mp 171–173 ꢁC; ½aŠ ¼ À148:5 (c 0.90,
D
CHCl3); IR (film) 1740, 1613 cmÀ1
;
1H NMR
(500 MHz, CDCl3): d 7.1 (d, J = 8.2 Hz, 2H), 7.0 (d,
J = 8.2 Hz, 2H), 4.9 (m, 1H) 2.36 (s, 3H), 2.16 (d,
J = 12.5 Hz, 1H), 1.72–1.25 (m, 5H), 1.09–1.01 (m,
2H), 0.98–0.92 (m, 3H), 0.90–0.84 (m, 1H), 0.67–0.64
(m, 6H); 13C NMR (126 MHz, CDCl3): d 166.0, 140.1,
128.9, 126.1, 126.5, 115.8, 78.9, 60.5, 46.5, 39.8, 34.0,
31.5, 25.6, 23.2, 21.9, 21.1, 20.3, 15.9.
5.8. 2-Nitrooxy-2-phenyl-malonamic acid ethyl ester 14
A solution of 10 (55.2 mg, 0.2663 mmol) in CH3CN
(10 mL) was stirred with CAN (292 mg, 0.5326 mmol)
for 4 h. Water was added, and the resultant mixture
extracted with EtOAc. The organic layer was dried
over anhydrous MgSO4 and concentrated to a solid.
Chromatography (10% hexanes/CH2Cl2) afforded 14
(51.3 mg) in 70% yield as a white solid: mp 116–
23
Compound 8b: mp 169–171 ꢁC; ½aŠ ¼ À50:2 (c 0.96,
CHCl3); IR (film) 1745, 1613 DcmÀ1
;
1H NMR
117 ꢁC; IR (film) 3409, 1735, 1710, 1598 cmÀ1 1H
;
(500 MHz, CDCl3): d 7.40 (s, 2H), 7.13 (m, 2H), 4.71
(m, 1H), 2.37(d, J = 5.5 Hz, 3H), 1.88 (s, 1H), 1.63
(m, 2H), 1.36 (m, 2H), 0.94–0.78 (m, 7H), 0.63 (d,
J = 6.5 Hz, 3H), 0.51 (s, 3H); 13C NMR (126 MHz,
CDCl3): d 164.2, 140.4, 129.2, 126.9, 116.6, 79.1, 46.9,
NMR (500 MHz, CDCl3): d 8.01 (br s, 1H), 7.58–7.53
(m, 2H), 7.46–7.41 (m, 3H), 6.80 (br s, 1H), 4.43–4.33
(m, 2H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d 168.6, 166.6 130.8, 129.5, 126.5,
87.5, 64.1, 14.1; HRMS (ES) calcd for C11H12N2O6

3604
M. C. Kozlowski et al. / Tetrahedron: Asymmetry 16 (2005) 3599–3605
(MNa+) 291.0593, found 291.0590. Compound 14 was
further recrystallized from EtOAc/hexanes to provide
X-ray quality crystals.15
NMR (500 MHz, CDCl3): d 7.98 (s, 1H), 7.70–7.68
(m, 2H), 7.37–7.30 (m, 3H), 4.78–4.73 (m, 1H), 1.99–
1.97(m, 1H), 1.69–1.63 (s, 6H), 1.48–1.38 (m, 5H),
1.05–0.98 (m, 2H), 0.89 (d, J = 7Hz, 3H), 0.86–0.84
(m, 1H), 0.79 (d, J = 7Hz, 3H), 0.67 (d, J = 7Hz,
3H); 13C NMR (125 MHz, CDCl3): d 168.8, 168.0,
136.4, 128.3, 127.9, 125.7, 91.5, 84.9, 46.8, 40.1, 34.1,
31.3, 29.6, 29.0, 25.7, 23.1, 21.9, 20.6, 15.9; HRMS
(ES) calcd for C22H31NO4 (MNa+) 396.2151, found
396.2153.
5.9. 2-Nitrooxy-2-phenyl-malonamic acid menthyl ester
15
A solution of 11 (140 mg, 0.419 mmol) in CH3CN was
stirred with MgSO4 (101 mg, 0.837mmol) at room tem-
perature. After 20 min, CAN (459 mg, 0.837mmol) was
added. After 6 h, water was added and the resultant
mixture extracted with EtOAc. The organic layer was
dried over anhydrous MgSO4 and concentrated to a
solid. Chromatography (98% CH2Cl2/EtOAc) afforded a
5.12. 2,3-Dihydroxy-N-isopropyl-2-phenyl-propionamide
18
1.5:1 mixture of 15a:15b (149 mg) in 90% yield as a white
DIBAL (1.0 M in hexanes, 0.75 mL, 0.75 mmol) was
added to 17 (55 mg, 0.15 mmol) in THF (5 mL) and
the resultant clear solution stirred at À78 ꢁC overnight.
The mixture was then treated with a saturated solution
of Rochelleꢀs salt in water (5 mL) and stirred for 3 h.
The resultant mixture was concentrated and diluted with
water (2 mL). After extraction with EtOAc (3 · 5 mL),
the combined organic layers were dried over Na2SO4
and concentrated. Chromatography (50% hexanes/
23
solid: mp 101–118 ꢁC; ½aŠ ¼ À38:5 (c 2.70, CHCl3); IR
D
(film) 3471, 1713, 1694 cmÀ1
;
1H NMR (500 MHz,
CDCl3): d 8.13 (d, J = 23 Hz, 2H), 7.57–7.55 (m, 4H),
7.43–7.38 (m, 6H), 6.56 (d, J = 26 Hz, 2H), 4.88–4.81
(m, 2H), 2.02–1.98 (m, 2H), 1.73–1.68 (m, 6H), 1.57–
1.44 (m, 6H), 1.07–0.96 (m, 8H), 0.94–0.86 (m, 9H),
0.77–0.72 (m, 6H), 0.64–0.62 (d, J = 7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3): d 168.35, 168.22, 166.82,
166.78, 131.01, 130.87, 130.68, 130.64, 129.47, 129.34,
126.50, 126.25, 87.61, 87.41, 79.36, 78.90, 47.04, 46.89,
40.16, 40.09, 34.23, 31.80, 26.09, 25.87, 23.35, 23.01,
22.24, 22.21, 21.14, 20.84, 16.03, 15.66; HRMS (ES)
calcd for C19H26N2O6 (MNa+) 401.1698, found
401.1701.
EtOAc) afforded the product diol in 60% yield as a white
23
powder: mp 87–89 ꢁC; ½aŠ ¼ þ3:5 (c 0.38, CHCl3); IR
(film) 2974, 1644, 1530 DcmÀ1
;
1H NMR (500 MHz,
CDCl3): d 7.60 (d, J = 7.6 Hz, 2H), 7.38–7.30 (m, 3H),
4.44–4.41 (m, 1H), 4.1 (s, 1H), 4.05–4.00 (m, 1H),
3.59–3.56 (m, 1H), 3.31–3.28 (m, 1H), 1.17, (d,
J = 7Hz, 3H), 1.07 (d, J = 7Hz, 3H); 13C NMR
(125 MHz, CDCl3): d 172.6, 138.8, 128.4, 128.0, 125.2,
79.4, 67.9, 41.5, 22.6, 22.3; MS (ES) m/z HRMS (ES)
calcd for C12H17NO3 (MH+) 224.1286, found 224.1281.
5.10. (À)-2-Hydroxy-2-phenyl-malonamic acid menthyl
ester (16)
To a solution of 15a and 15b (1.0 g, 2.6 mmol) in MeOH
(25 mL) was added activated Raney nickel catalyst (50%
slurry in H2O, 1.0 g). After stirring at room temperature
overnight under an atmosphere of H2, the mixture was
diluted with H2O and EtOAc. The Raney Ni was care-
fully filtered away through a column of Celite. The
organic layer was separated and concentrated to a white
solid. Recrystallization from CH2Cl2/hexanes afforded
Acknowledgements
Financial support was provided by the University of
Pennsylvania Research Foundation and the National
Science Foundation (CHE-0094187). We thank the
Department of Education, for a GAANN fellowship
(E.S.D.). We gratefully acknowledge the efforts of Dr.
Patrick Carroll in determining the crystallographic
structures.
16 in 40% yield as white crystals suitable for X-ray dif-
23
fraction:15 ½aŠ ¼ À88:7 (c 0.62, CHCl3); IR (film)
D
1710, 1588 cmÀ1
;
1H NMR (500 MHz, CDCl3): d
7.70–7.67 (m, 2H), 7.40–7.30 (m, 3H), 6.94 (s, 1H),
5.48 (s, 1H), 4.82 (s, 1H), 4.81–4.76 (m, 1H), 2.05–2.02
(m, 1H), 1.69–1.65 (m, 2H), 1.49–1.44 (m, 3H), 1.18–
1.11 (m, 1H), 1.03–1.00 (m, 1H), 0.92–0.89 (m, 1H),
0.87(d, J = 7Hz, 3H), 0.74 (d, J = 7Hz, 3H), 0.59 (d,
J = 7Hz, 3H); 13C NMR (125 MHz, CDCl3): d 171.6,
171.1, 138.0, 128.9, 128.6, 126.5, 80.2, 78.6, 47.l, 40.5,
34.4, 31.8, 26.1, 23.5, 22.3, 21.0, 16.2; HRMS (ES) calcd
for C19H27NO4 (MNa+) 356.1838, found 356.1847.
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5.11. 2,2-Dimethyl-4-oxo-5-phenyl-oxazolidine-5-carb-
oxylic acid menthyl ester 17
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chromatography (90% hexanes/EtOAc) provided 17 in
23
83% yield as a white solid: ½aŠ ¼ À53:42 (c 0.72,
D
CHCl3); IR (film) 2955, 2869, 1743, 1643 cmÀ1
;
1H

M. C. Kozlowski et al. / Tetrahedron: Asymmetry 16 (2005) 3599–3605
3605
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´
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13. Et2O, THF, CH2Cl2, and PhCH3 were also screened as
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15. Crystallographic data for compounds 7b, 14, and 16 have
been deposited at the Cambridge Crystallographic Data
Centre: CCDC numbers 285462 (14), 285463 (7b), and
285464 (16).