Enantioselective synthesis of quaternary α-amino acids via l -tert-leucine-derived squaramide-catalyzed conjugate addition of α-nitrocarboxylates to enones

Article abstract of DOI:10.1021/acs.joc.6b00543

Enantioselective Michael addition of tertiary α-nitroesters to β-unsubstituted vinyl ketones has been carried out in the presence of an l-tert-leucine-derived squaramide as organocatalyst. The products, quaternary α-nitroesters, were formed in excellent yield and moderate to good ee's in most cases. Scale-up of the reaction and synthetic applications of the products, including transformation to representative quaternary α-amino acids, have also been demonstrated.

Full text of DOI:10.1021/acs.joc.6b00543

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Note
Enantioselective Synthesis of Quaternary alpha-Amino
Acids via L-tert-Leucine-Derived Squaramide Catalyzed
Conjugate Addition of alpha-Nitrocarboxylates to Enones
Kalisankar Bera, Nishikant S. Satam, and Irishi N. N. Namboothiri
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00543 • Publication Date (Web): 31 May 2016
Downloaded from http://pubs.acs.org on May 31, 2016
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Enantioselective Synthesis of Quaternary αꢀAmino Acids via LꢀtertꢀLeucineꢀDerived Squaramide
Catalyzed Conjugate Addition of αꢀNitrocarboxylates to Enones
Kalisankar Bera, Nishikant S. Satam and Irishi N. N. Namboothiri*
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India,
irishi@iitb.ac.in
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Abstract. Enantioselective Michael addition of tertiary αꢀnitroesters to βꢀunsubstituted vinyl
ketones has been carried out in the presence of an Lꢀtertꢀleucineꢀderived squaramide as
organocatalyst. The products, quaternary αꢀnitroesters, were formed in excellent yield and
moderate to good ee’s in most cases. Scaleꢀup of the reaction and synthetic applications of the
products, including transformation to representative quaternary αꢀamino acids, have also been
demonstrated.
Quaternary αꢀamino acids are considerably resistant to chemical and enzymatic degradation due
to their conformational and configurational stability and are useful building blocks in the synthesis
of novel peptides and proteins possessing wellꢀdefined biological properties.1 Quaternary αꢀamino
acids were found to be mechanismꢀbased inhibitors of pyridoxal phosphate dependent enzymes and
an integral part of bioactive natural products sphingofungins E and F, myriocin and altemicidin, to
name a few (Figure 1).2
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Figure 1. Quaternary αꢀAmino Acid Containing Bioactive Natural Products
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Approaches to enantioenriched quaternary αꢀamino acids include resolution, chiral auxiliary based
and catalytic asymmetric synthesis.3ꢀ6 Catalytic asymmetric approaches involving αꢀalkylation of
tertiary αꢀamino/iminocarboxylates, addition of Cꢀcentered nucleophiles to ketimines, αꢀamination
of tertiary αꢀcarboxylates and addition of tertiary αꢀnitrocarboxylates to various Michael acceptors
have been reviewed recently.6
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Among the above, αꢀfunctionalization of tertiary αꢀnitrocarboxylates via 1,4ꢀaddition, 1,2ꢀ
addition and alkylation in the presence of suitable chiral catalysts is a convenient means of
generating enantioenriched quaternary αꢀamino acids.6 As for 1,4ꢀaddition, catalytic asymmetric
addition of αꢀnitrocarboxylates to enones,7ꢀ9 enamides,10 nitroalkenes,11 vinyl phosphonates,12 vinyl
sulfones13 and azodicarboxylates14 afforded the corresponding quaternary αꢀamino acids or their
precursors. Addition of αꢀnitrocarboxylates to βꢀunsubstituted enones has been reported to take
place in the presence of (R)ꢀALB, resulting in the adducts with low to moderate ee (5ꢀ80%) with
only two products possessing >50% ee, and in the presence of peptides delivering just two products
with 0 and 50% ee.7 A similar reaction in the presence of a quinine derived catalyst led to the
adduct in 90% ee for which a single example exists in the literature.8 Isolated examples for the
reaction of βꢀsubstituted enones with αꢀnitrocarboxylate in the presence of chiral thiourea catalysts
giving products with moderate to good enantioselectivities and with an αꢀfluoroꢀαꢀnitrocarboxylate
in the presence of cinchoninamine providing the products in moderate diastereoselectivities but
excellent enantioselectivities have also been reported.9
Recently, we reported the enantioselective synthesis of quaternary αꢀaminophosphonates15ꢀ17 and
αꢀaminosulfones18ꢀ19 via conjugate addition of tertiary αꢀnitrophosphonates and αꢀnitrosulfones,
respectively, to various Michael acceptors such as enones, vinyl sulfones and acrylates. While
cinchona derived thiourea and squaramide catalysts turned out to be very effective in most cases,15ꢀ
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an amino acid (Lꢀtertꢀleucine) derived squaramide was the catalyst of choice for the conjugate
4
addition of nitrosulfones to acrylates and acrylamides.19 In continuation of our efforts, we intended
to investigate the synthesis of quaternary αꢀamino acids or their precursors via conjugate addition
of tertiary αꢀnitrocarboxylates to βꢀunsubstituted enones. This is also because of the limited success
encountered in such reactions earlier in terms of enantioselectivity and substrate scope.
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We envisioned that organocatalysts possessing a chiral Broensted basic core, a tertiary amine,
and a Broensted acid appendage such as thiourea20 or squaramide21 which proved their efficiency in
recent years and in our own recent endeavors would be suitable for the above purpose. To our
knowledge, there are only two reports for the application of amino acid derived squaramide in
asymmetric reactions.19,22
We began our experiments by treating pꢀtolyl αꢀnitropropanoate 2a as the nucleophile with enone
1a as the Michael acceptor in the presence of 10 mol % of quinineꢀsquaramide C1 as the catalyst in
o
toluene at ꢀ60 C (Figure 2 and Table 1). The desired Michael adduct 3a was isolated in excellent
yield (94%) and good enantioselectivity (76% ee, entry 1). Later on, several cinchonaꢀbased
squaramides C2ꢀC3, thioureas C4ꢀC8 and amino acidꢀderived squaramides C9ꢀC14 were screened
o
as organocatalysts for the reaction between enone 1a and nitroester 2a in toluene at ꢀ60 C (Figure
2 and Table 1, entries 2ꢀ14). Though all the squaramide and thiourea catalysts were quite effective
in providing the Michael adduct 3a in excellent yield (≥ 90%), the enantioselectivities were only
moderate to good in most cases (53ꢀ79% ee, entries 2ꢀ8 and 10ꢀ14). However, with tertꢀleucineꢀ
derived squaramide C9 as the catalyst, the Michael adduct 3a was isolated in excellent yield (95%)
and good ee (82%, entry 9). In order to further improve the enantioselectivity, other reaction
parameters such as temperature and solvent were evaluated (entries 15ꢀ19). Although the reaction
o
was complete in 12 h at higher temperature (ꢀ25 C), the selectivity dropped to 78% ee (entry 15).
At this juncture, possible enhancement of enantioselectivity by screening other solvents such as
xylene, mixture of mesitylene and xylene, dichloromethane and THF was attempted in presence of
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10 mol % of tꢀleucineꢀsquaramide C9 (entries 16ꢀ19). This resulted in the formation of the Michael
adduct 3a with moderate to good enantioselectivity (50ꢀ76% ee, entries 16ꢀ19). Thus, 10 mol % of
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tꢀleucineꢀderived squaramide C9 as the catalyst, in toluene at ꢀ60 C turned out to be the optimal
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conditions for our reaction (Table 1, entry 9).
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Figure 2. Catalysts Screened
Table 1. Catalyst Screening and Solvent Optimization
entry Ca
solvent
toluene
toluene
toluene
toluene
time (h) % yieldb % eec
1
2
3
4
15
15
15
15
94
93
90
94
76
73
C1
C2
C3
C4
53d
79
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toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
15
15
15
15
18
18
18
18
18
18
12
18
18
92
94
91
91
95
93
94
94
92
92
94
94
94
74d
76
70
76
82
76
65
78
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78
76
68
C5
C6
7
C7
8
C8
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9
C9
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15e
16
17
C10
C11
C12
C13
C14
C9
C9
mesitylene:
xylenef
CH2Cl2
THF
C9
18
19
18
90
92
67
50
C9
C9
18
a Catalyst. After silica gel column chromatography. ee determined by chiral HPLC. Opposite
b
c
d
enantiomer. e Reaction performed at ꢀ25 oC. Ratio 85:15.
f
Having optimized the reaction conditions, the scope of enones 1 and nitroesters 2 was
investigated (Tables 2ꢀ4). At first, taking nitroester 2a as the representative Michael donor, various
substituted enones 1aꢀm have been screened and the results are summarized in Table 2. In general,
the reactions were complete in 15ꢀ30 h to afford the quaternary αꢀnitrocarboxylates 3 in very good
to excellent yields (85ꢀ97%) and moderate to good enantioselectivities (68ꢀ82%). However, longer
reaction time (40ꢀ72 h) and moderate yield (69ꢀ76%) and low ee (27ꢀ37%) were encountered in the
case of products 3mꢀn, which resulted from alkyl vinyl ketones 1mꢀn (entries 13ꢀ14). The ee was
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low (35%), despite excellent yield (97%) for product 3d as well, which resulted from orthoꢀ
substituted aryl vinyl ketone 1d (entry 4). There was no major substituent effect as enones bearing
weakly and strongly electron withdrawing groups 1aꢀc and 1eꢀf, respectively, reacted equally well
with nitroester 2a to afford the products 3aꢀc and 3eꢀf in 88ꢀ97% yield and 69ꢀ82% ee (entries 1ꢀ3
and 5ꢀ6). Similarly, enones bearing electroneutral, weakly and strongly electron donating
substituents 1gꢀi, respectively, afforded the products 3gꢀi in excellent yield (85ꢀ97%) and good
selectivity (72ꢀ76% ee, entries 7ꢀ9). Representative examples of fused aryl, heteroaryl and styrenyl
enones, 1jꢀl, respectively, also reacted well with nitroester 2a to deliver the products 3jꢀl in 89ꢀ95%
yield and 68ꢀ73% ee (entries 10ꢀ12). Notably, the reaction between dienone 1l and nitroester 2a
was 100% regioselective in that 2a reacted selectively with the βꢀunsubstituted olefin moiety in the
presence of βꢀsubstituted olefin moiety in dienone 1l and furnished the Michael adduct 3l in 91%
yield and 73% ee (entry 12). To evaluate the practical utility of the asymmetric Michael addition of
αꢀnitrocarboxylate 2 to enone 1, a reaction of representative substrates 2a with 1h was performed
on gram scale (entry 8). Gratifyingly, the desired Michael adduct 3h was formed in 82% yield
(1.810 g) and 75% ee even with 5 mol % of catalyst C9.
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Table 2. Scope of Enones 1
entry 1, R
time (h) % yielda % eeb
3
1
2
3
4
5
1a, 3ꢀBrC6H4
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20
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20
15
95
97
94
97
90
82
75
77
35
74
3a
3b
3c
3d
3e
1b, 4ꢀBrC6H4
1c, 4ꢀClC6H4
1d, 2ꢀClC6H4
1e, 4ꢀCNC6H4
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1f, 4ꢀNO2C6H4
1g, Ph
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3g
3h
3i
8c
9
1h, 4ꢀMeC6H4
1i, 4ꢀOMeC6H4
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10 1j, 2ꢀNaphthyl
11 1k, 2ꢀthienyl
12 1l, Styrenyl
13 1m, cꢀC6H11
14 1n, CH3
3j
3k
3l
3m
3n
a After silica gel column chromatography. ee determined by chiral HPLC.c Also performed in
gram scale between 1h (9.3 mmol, 1.357 g) and 2a (6.2 mmol, 1.297 g) in the presence of C9 (5
mol %) at ꢀ60 oC to afford 3h in 82% (1.810 g) yield and 75% ee.
b
Subsequently, the scope of αꢀnitrocarboxylates 2 was investigated with a representative enone 1a
(Table 3). Thus, αꢀnitrocarboxylates bearing a linear alkyl chain reacted smoothly with enone 1a to
furnish quaternary αꢀnitrocarboxylates 4aꢀc in high yields (87ꢀ94%) and good enantioselectivities
(83ꢀ86%, entries 1ꢀ3). However, αꢀnitrocarboxylate 2e bearing a branched alkyl chain provided the
desired Michael adduct 4d only in moderate enantioselectivity (69% ee) albeit in very good yield
(88%, entry 4).
Table 3. Scope of αꢀAlkyl Group in Nitroesters 2
entry 2, R
Ar1
3ꢀBrC6H4
time (d) % yielda % eeb
4
1
2
2b, Et
2
3
87
92
83
86
4a
4b
2c, nꢀPr 3ꢀBrC6H4
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2d, nꢀBu 3ꢀBrC6H4
3
4
3
94
88
85
83
69
77
4c
4d
4e
2e, iꢀPr
2b, Et
3ꢀBrC6H4
4ꢀMeC6H4
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a After silica gel column chromatography. b ee determined by chiral HPLC.
Further scope of nitroester 2 was investigated by changing the ester group from pꢀtolyl to other
representative aryl (oꢀtolyl), arylꢀalkyl (Bn) and alkyl (Et) groups (Table 4). While the yields in
these cases remained consistently excellent (93ꢀ98%), the enantioselectivities varied appreciably
(43ꢀ78%). For instance, as in the case of most of the entries in Tables 2ꢀ3, aryl ester 2f furnished
the product 5a with good enantioselectivity (78%, entry 1). On the other hand, the ee dropped to
61% in the case of benzyl ester 5b (entry 2) and 43% in the case of alkyl ester 5c (entry 3).
Table 4. Scope of Ester Group in Nitroesters 2
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entry 2, R
time (h) % yielda % eeb
5
1
2
3
2f, 2ꢀMeC6H4
18
18
24
93
97
98
78
61
43
5a
5b
5c
2g, Bn
2h, Et
a After silica gel column chromatography. b ee determined by chiral HPLC
In the proposed mechanism, the nitrocarboxylate 2, after deprotonation by the piperidine
moiety of the catalyst C9, is stabilized by the squaramide moiety through Hꢀbonding. At the
same time, the protonated piperidine activates the enone 1 by hydrogen bonding giving rise to
the favored transition state (Figure 3). Michael addition of the stabilized nitronate 2 through its
Reꢀface to the activated enone 1 delivers the desired conjugate adduct 3, 4 or 5 in
enantioenriched form and regenerates the catalyst C9.23
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O
O
CF3
H
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N
N
H
C9
N
H
H
CF3
O
N
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ArO
O
O
R1
2
R
Re face addition
1
Figure 3. Proposed Transition State
Finally, the synthetic applications of the products were demonstrated using representative
quaternary αꢀnitroesters 3h and 4e (Scheme 1). BaeyerꢀVilliger oxidation of 3h and 4e provided the
nitrodiesters 6aꢀb in excellent (84ꢀ92%) yield. Treatment of diesters 6a with excess (4 equiv)
benzylamine in THF under reflux led to the formation of diamide 8 again in 92% yield. On the
other hand, while attempts to synthesize monoamide using 1.2 equiv of benzylamine, under
otherwise identical conditions, furnished a mixture of 7 and 8, selective synthesis of cyclic imide 7
in 62% yield could be achieved by carrying out the reaction in toluene under reflux. The nitroimide
7 was further subjected to reduction using Zn/HCl at room temperature to afford aminoimide 9 in
85% yield. It may be noted that the enantioselectivities remained similar within experimental error
for all these compounds. More importantly, the diesters 6aꢀb were transformed in one pot to their
amino acids 11aꢀb, as their hydrochloride salts, via base mediated hydrolysis followed by nitro
group reduction using Zn/HCl in 63ꢀ68% overall yield for two steps.
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Scheme 1. Synthetic Applications of the Michael Adducts
The absolute configuration of 3h was assigned as R based on its conversion to (R)ꢀ2ꢀ
methylglutamic acid 11a (Scheme 1). The absolute configuration of other analogs was assigned by
analogy.
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In conclusion, we have developed the first general and efficient method for the enantioselective
Michael addition of αꢀnitrocarboxylates to various αꢀunsubstituted vinyl ketones in the presence of
a tertꢀleucineꢀderived squaramide organocatalyst. The conjugate adducts, quaternary αꢀnitroesters,
were isolated in high yields and moderate to good enantioselectivities in most cases. The feasibility
of scale up of the enantioselective conjugate addition without any appreciable drop in yield and
selectivity and transformation of the products to quaternary αꢀamino acids and cyclic quaternary αꢀ
amino imides have been successfully demonstrated. Design and synthesis of more efficient chiral
organocatalysts that would further improve the enantioselectivities will be part of our future
endeavors.
Experimental Section
1
13
General. The melting points recorded are uncorrected. NMR spectra (1H and H decoupled C)
were recorded with TMS as the internal standard. The coupling constants (J values) are given in
Hz. High resolution mass spectra were recorded under ESI QꢀTOF conditions. Enantioselectivities
were determined using chiral HPLC equipped with a PDAꢀdetector. Specific rotations were
measured for solutions of samples of known concentrations in a suitable solvent using a
polarimeter equipped with a sodium vapor lamp. Catalysts C1ꢀC11 were prepared by literature
methods.24ꢀ25 Bromoesters 14aꢀg and nitroesters 2aꢀg are new and were prepared by a general
procedure reported in the literature.26 Nitroester 2h and its precursor bromoester 14h26 as well as
enones 1aꢀn27 are known compounds.
General procedure for the preparation of catalysts C12ꢀ14. To a solution of 3ꢀmethoxyꢀ4ꢀ
(arylamino) cyclobutꢀ3ꢀeneꢀ1,2ꢀdione 15 (1.017 g, 3.00 mmol) in dry DCM (15 mL) was slowly
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added a solution of amine 1625 (3.00 mmol) in dry DCM (10 mL) at rt. The reaction mixture was
stirred for 4 h and the resulting precipitate was isolated by filtration. The residue was washed with
ether (10 ml) and dried in vacuo to afford catalyst C as a white solid.
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3ꢀ(3,5ꢀBis(trifluoromethyl)phenylamino)ꢀ4ꢀ((2S,3R)ꢀ3ꢀmethylꢀ1ꢀ(piperidinꢀ1ꢀyl)pentanꢀ2ꢀ
ylamino)cyclobutꢀ3ꢀeneꢀ1,2ꢀdione (C12). Colorless solid; Yield 1.208 g, 82%; mp 215ꢀ216 oC; IR
(film, cmꢀ1) 3200 (m), 3150 (m), 2939 (vs), 2790 (w), 1799 (s), 1663 (s), 1583 (vs), 1456 (vs),
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1379 (vs), 1327 (w), 1276 (vs), 1183 (s), 1170 (m), 1129 (s), 942 (m), 882 (m), 748 (m); H NMR
(400 MHz, DMSOꢀd6) δ 0.87 (t, overlaps with d, J = 8.2 Hz, 3H), 0.88 (d, overlaps with t, J = 7.2
Hz, 3H), 1.05ꢀ1.19 (m, 1H), 1.23ꢀ1.52 (m, 7H), 1.53ꢀ1.65 (m, 1H), 2.12ꢀ2.27 (unresolved m, 2H),
2.29ꢀ2.40 (m, 2H), 2.39ꢀ2.50 (m, 2H), 4.15 (br unresolved, 1H), 7.50ꢀ7.65 (br unresolved, 2H),
8.04 (s, 2H), 10.07 (br s, 1H); 13C NMR (100 MHz, DMSOꢀd6) δ 11.3, 15.2, 23.9, 24.2, 25.7, 37.6,
54.4, 56.2, 60.4, 114.5, 117.9, 123.2 (q, JCꢀF = 271.0 Hz), 131.4 (q, JCꢀF = 33.0 Hz), 141.2, 161.8,
170.4, 180.2, 184.6; MS (ES+, Ar) m/z (rel intensity) 493 ([MH+1]+, 21), 492 ([MH]+, 100);
HRMS (ES+, Ar) calcd for C23H28F6N3O2 (MH+, 100) 492.2083, found 492.2080; [α]25 +7.03 (c
D
0.5, acetone).
(Sꢀ3ꢀ(3,5ꢀBis(trifluoromethyl)phenylamino)ꢀ4ꢀ(1ꢀphenylꢀ3ꢀ(piperidinꢀ1ꢀyl)propanꢀ2ꢀylamino)ꢀ
o
cyclobutꢀ3ꢀeneꢀ1,2ꢀdione (C13). Colorless solid; Yield 1.024 g, 65%; mp 248ꢀ250 C; IR (film,
cmꢀ1) 3180 (m), 3140 (m), 3026 (w), 2940 (s), 1800 (s), 1661 (s), 1575 (vs), 1463 (vs), 1377 (vs),
1280 (vs), 1223 (w), 1189 (s), 1130 (s), 944 (w), 884 (m), 749 (m); 1H NMR (400 MHz, DMSOꢀd6)
δ 1.25ꢀ1.35 (m, 2H), 1.36ꢀ1.46 (m, 4H), 2.19ꢀ2.32 (br unresolved, 2H), 2.34ꢀ2.47 (m, 4H), 2.76
(ABqd, J = 13.8, 8.3 Hz, 1H), 2.94 (ABqd, J = 13.8, 5.0 Hz, 1H), 4.47 (br unresloved, 1H), 7.11ꢀ
7.32 (m, 5H), 7.60 (s overlap with br s, 1H), 7.61 (br s overlap with singlet, 1H), 8.00 (s, 2H),
10.09 (br s, 1H); 13C NMR (100 MHz, DMSOꢀd6) δ 23.9, 25.6,53.7, 54.4, 62.7, 114.7, 118.0, 123.2
(q, JCꢀF = 271.0 Hz), 126.4, 128.4, 129.3, 131.4 (q, JCꢀF = 34.0 Hz), 137.8, 141.1, 161.9, 170.0,
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180.2, 184.5; MS (ES+, Ar) m/z (rel intensity) 527 ([MH+1]+, 36), 526 ([MH]+, 100); HRMS (ES+,
Ar) calcd for C26H26F6N3O2 (MH+, 100) 526.1924, found 526.1923; [α]25 ꢀ49.65 (c 0.5, DMSO).
D
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(S)ꢀ3ꢀ(3,5ꢀBis(trifluoromethyl)phenylamino)ꢀ4ꢀ(1ꢀphenylꢀ2ꢀ(piperidinꢀ1ꢀyl)ethylamino)ꢀ
cyclobutꢀ3ꢀeneꢀ1,2ꢀdione (C14). Colorless solid; Yield 1.196 g, 78%; mp 230ꢀ233oC; IR (film,
cmꢀ1) 3205 (s), 3032 (w), 2938 (vs), 2855 (w), 2791 (w), 1797 (vs), 1667 (s), 1575 (vs), 1455 (vs),
1376 (vs), 1330 (m), 1274 (vs), 1174 (s), 1124 (s), 997 (w), 941 (m), 884 (m), 746 (w), 728 (w),
698 (m), 683 (w); 1H NMR (400 MHz, DMSOꢀd6) δ 1.29ꢀ1.38 (m, 2H), 1.38ꢀ1.50 (m, 4H), 2.35 (br
unresolved, 2H), 2.50ꢀ2.63 (m, 3H), 2.73ꢀ2.82 (m, 1H), 5.36 (br unresloved, 1H), 7.28ꢀ7.34 (br m,
1H), 7.36ꢀ7.41 (m, 4H), 7.65 (s, 1H), 8.04 (s, 2H), 8.16 (br s, 1H), 10.19 (br s, 1H); 13C NMR (100
MHz, DMSOꢀd6) δ 23.8, 25.5, 54.1, 55.6, 64.2, 114.7, 118.1, 123.2 (q, JCꢀF = 271.0 Hz), 126.5,
127.7, 128.7, 131.3 (q, JCꢀF = 33.0 Hz), 140.6, 141.0, 162.3, 169.6, 180.5, 184.5; MS (ES+, Ar) m/z
(rel intensity) 513 ([MH+1]+, 36), 512 ([MH]+, 100), 293 (5), 217 (7); HRMS (ES+, Ar) calcd for
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C25H24F6N3O2 (MH+, 100) 512.1767, found 512.1766; [α]26 ꢀ17.08 (c 0.5, Acetone).
D
Preparation of 2ꢀbromoesters 14.26 To a stirred solution of 2ꢀbromocarboxylic acid 12 (23.0
mmol) was added oxalyl chloride (4.0 ml, 46.0 mmol) slowly and the reaction mixture was stirred
for 2 h at 60°C. Then the excess oxalyl chloride was removed by distillation and the desired 2ꢀ
°
bromoacid chloride 13 was isolated. Pyridine (1.89 ml, 23.5 mmol) was added dropwise at ꢀ10 C
to the stirred solution of 2ꢀbromoacid chloride 13 (19.5 mmol) and phenol or benzyl alcohol (17.5
mmol) in toluene (50 ml). The reaction mixture was stirred overnight. After the completion of
reaction (as monitored by TLC), the mixture was diluted with ice water (100 ml). The aqueous
layer was extracted with toluene (2 × 50 ml). The combined organic layer was washed with water
(50 ml) and dried over anhyd sodium sulfate. The solvent was removed in vacuo and the crude 2ꢀ
bromoester 14 was purified by silica gel column chromatography using ethyl acetateꢀpet ether (4%)
as eluent.
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pꢀTolyl 2ꢀbromopropanoate (14a). Colorless liquid; Yield 3.201 g, 78%; IR (neat, cmꢀ1) 2927
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(w), 1739 (vs), 1615 (w), 1514 (s), 1448 (m), 1339 (w), 1242 (m), 1198 (m), 1167 (w), 1073 (w),
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985 (w), 818 (s), 509 (w); H NMR (500 MHz, CDCl3) δ 1.97 (d, J = 6.9 Hz, 3H), 2.39 (s, 3H),
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4.63 (q, J = 6.9 Hz, 1H), 7.04 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H); C NMR (125 MHz,
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CDCl3) δ 21.0, 21.6, 39.9, 120.8, 130.2, 136.1, 148.4, 169.1; MS (ES+, Ar) m/z (rel intensity) 268
([MNa+3]+, 10), 267 ([MNa+2]+, 97), 266 ([MNa+1]+, 10), 265 ([MNa]+, 100), 221 (75), 223 (15);
HRMS (ES+, Ar) calcd for C10H11BrO2Na (MNa+, 100) 264.9835, found 264.9831.
pꢀTolyl 2ꢀbromobutanoate (14b). Colorless liquid; Yield 3.701 g, 70%; IR (neat, cmꢀ1) 2959 (s),
2928 (vs), 2859 (m), 1760 (vs), 1507 (w), 1254 (w), 1222 (w), 1198 (m), 1166 (w), 1133 (w), 1108
(w), 1019 (m); 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J = 7.3 Hz, 3H), 2.17 (dquin, J = 14.7, 7.3
Hz, 1H), 2.29 (dquin, J = 14.7, 7.3 Hz, 1H), 2.39 (s, 3H), 4.40 (t, J = 7.3 Hz, 1H), 7.03 (d, J = 8.3
Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 12.1, 21.1, 28.5, 47.4, 120.9,
130.2, 136.1, 148.4, 168.6; MS (ES+, Ar) m/z (rel intensity) 282 ([MNa+3]+, 11), 281 ([MNa+2]+,
99), 280 ([MNa+1]+, 11), 279 ([M+Na]+, 100), 275 (15), 259 (15); HRMS (ES+, Ar) calcd for
C11H13BrO2Na (MNa+, 100) 278.9991, found 278.9998.
pꢀTolyl 2ꢀbromopentanoate (14c). Colorless liquid; Yield 3.999 g, 73%; IR (neat, cmꢀ1) 2928 (vs),
2859 (m), 1760 (vs), 1508 (w), 1464 (w), 1251 (w), 1198 (m), 1166 (w), 1133 (w), 1105 (w), 1019
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(m), 813 (w); H NMR (400 MHz, CDCl3) δ 1.01 (t, J = 7.4 Hz, 3H), 1.44ꢀ1.56 (m, 1H), 1.56ꢀ1.68
(m, 1H), 2.04ꢀ2.25 (m, 2H), 2.36 (s, 3H), 4.44 (t, J = 7.9 Hz, 1H), 7.01 (d, J = 8.3 Hz, 2H), 7.20 (d,
13
J = 8.3 Hz, 2H); C NMR (100 MHz, CDCl3) δ 13.5, 20.8, 21.0, 36.8, 45.6, 120.9, 130.1, 136.1,
148.4, 168.7; MS (ES+, Ar) m/z (rel intensity) 296 ([MNa+3]+, 14), 295 ([MNa+2]+, 97), 280
([MNa+1]+, 14), 279 ([M+Na]+, 100), 285 (14), 249 (10); HRMS (ES+, Ar) calcd for
C12H15BrO2Na (MNa+, 100) 293.0148, found 293.0146.
pꢀTolyl 2ꢀbromohexanoate (14d). Colorless liquid; Yield 4.299 g, 78%; IR (neat, cmꢀ1) 2956
(vw), 1742 (vs), 1498 (w), 1447 (m), 1380 (w), 1336 (m), 1270 (m), 1218 (m), 1156 (s), 1072 (w),
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993 (w), 948 (vw), 752 (m), 698 (w), 603 (vw); H NMR (500 MHz, CDCl3) δ 0.98 (t, J = 7.0 Hz,
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3H), 1.36ꢀ1.52 (m, 3H), 1.53ꢀ1.64 (m, 1H), 2.05ꢀ2.17 (m, 1H), 2.18ꢀ2.29 (m, 1H), 2.37 (s, 3H),
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4.43 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H); C NMR (100 MHz,
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CDCl3) δ 14.0, 21.0, 22.1,29.5, 34.6, 45.8, 120.9, 130.1, 136.0, 148.4, 168.7; MS (ES+, Ar) m/z
(rel intensity) 310 ([MNa+3]+, 13), 309 ([MNa+2]+, 96), 308 ([MNa+1]+, 13), 307 ([M+Na]+, 100),
281 (10), 263 (10); HRMS (ES+, Ar) calcd for C13H17BrO2Na (MNa+, 100) 307.0304, found
307.0304.
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pꢀTolyl 2ꢀbromoꢀ3ꢀmethylbutanoate (14e). Colorless liquid; Yield 4.011 g, 73%; IR (neat, cmꢀ1)
2928 (vs), 1760 (vs), 1507 (w), 1464 (w), 1198 (m), 1166 (w), 1133 (w), 1019 (m), 813 (w), 509
(w); 1H NMR (500 MHz, CDCl3) δ 1.18 (d, J = 6.6 Hz, 3H), 1.22 (d, J = 6.6 Hz, 3H), 2.38 (s
overlaps with m, 3H), 2.36ꢀ2.45 (m overlaps with s, 1H), 4.26 (d, J = 8.1 Hz, 1H), 7.02 (d, J =8.4
Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 20.2, 20.2, 21.1, 32.6, 54.3,
120.9, 130.2, 136.1, 148.4, 168.4; MS (ES+, Ar) m/z (rel intensity)) 296 ([MNa+3]+, 14), 295
([MNa+2]+, 99), 294 ([MNa+1]+, 14), 293 ([M+Na]+, 100), 281 (5); HRMS (ES+, Ar) calcd for
C12H15BrO2Na (MNa+, 100) 293.0148, found 293.0144.
oꢀTolyl 2ꢀbromopropanoate (14f). Colorless liquid; Yield 3.501 g, 74%; IR (neat, cmꢀ1) 3030 (w),
2982 (w), 2929 (w), 2866 (w), 1760 (vs), 1584 (vw), 1490 (w), 1462 (vw), 1445 (w), 1380 (vw),
1339 (m), 1246 (m), 1223 (s), 1173 (m), 1141 (s), 1111 (m), 1071 (vw), 1043 (w), 985 (vw), 942
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(vw), 895 (vw), 840 (vw), 773 (m), 748 (s), 713 (w), 678 (vw), 532 (vw); H NMR (400 MHz,
CDCl3) δ 1.98 (d, J = 6.9 Hz, 3H), 2.24 (s, 3H), 4.63 (q, J = 6.9 Hz, 1H), 7.04 (dd, J = 7.9, 0.9 Hz,
1H), 7.13ꢀ7.30 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 16.2, 21.8, 39.7, 121.5, 126.6, 127.2,
130.3, 131.5, 149.0, 168.7; MS (ES+, Ar) m/z (rel intensity) 268 ([MNa+3]+, 8), 267 ([MNa+2]+,
96), 266 ([MNa+1]+, 8), 265 ([M+Na]+, 100), 243 (1), 221 (10); HRMS (ES+, Ar) calcd for
C10H11BrO2Na (MNa+, 100) 264.9835, found 264.9831.
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Benzyl 2ꢀbromopropanoate (14g). Colorless liquid; Yield 3.599 g, 76%; IR (neat, cmꢀ1) 3066
(vw), 3035 (vw), 2955 (vw), 2930 (vw), 2869 (vw), 1741 (vs), 1498 (vw), 1447 (m), 1380 (m),
1336 (m), 1270 (m), 1218 (m), 1155 (s), 1096 (w), 1072 (m), 1058 (m), 1029 (vw), 993 (w), 948
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(vw), 916 (vw), 752 (m), 698 (m); H NMR (400 MHz, CDCl3) δ 1.85 (d, J = 6.9 Hz, 3H), 4.41 (q,
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J = 6.9 Hz, 1H), 5.20 (s, 2H), 7.32ꢀ7.43 (m, 5H); C NMR (100 MHz, CDCl3) δ 21.7, 40.0, 67.6,
128.2, 128.5, 128.7, 135.2, 170.1; MS (ES+, Ar) m/z (rel intensity) 268 ([MNa+3]+, 9), 267
([MNa+2]+, 99), 266 ([MNa+1]+, 9), 265 ([M+Na]+, 100), 250 (5), 221 (3); HRMS (ES+, Ar) calcd
for C10H11BrO2Na (MNa+, 100) 264.9835, found 264.9839.
Preparation of nitroesters 2.26 To a stirred solution of NaNO2 (0.945 g, 14.2 mmol) in DMSO (20
ml) was added phloroglucinol (1.034 g, 8.7 mmol), followed by 2ꢀbromoester 14 (8.27 mmol) at 0
°C. After completion of the reaction (as monitored by TLC), the mixture was diluted with diethyl
ether (50 ml) and ice water (50 ml). The aqueous layer was extracted with diethyl ether (3 × 50 ml).
The combined organic layer was washed with water (50 ml) and dried over anhyd sodium sulfate.
The solvent was removed in vacuo and the crude 2ꢀnitroester 2 was purified by silica gel coloumn
chromatography using ethyl acetate and pet ether (8%) as eluent.
pꢀTolyl 2ꢀnitropropanoate (2a). Colorless liquid; Yield 1.249 g, 69%; IR (neat, cmꢀ1) 2926 (w),
1770 (vs), 1561 (vs), 1506 (m), 1450 (m), 1389 (w), 1359 (w), 1315 (w), 1194 (vs), 1175 (s), 1112
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(w), 1084 (w), 1019 (w), 904 (w), 874 (w), 843 (w), 816 (w); H NMR (400 MHz, CDCl3) δ 1.93
(d, J = 7.1 Hz, 3H), 2.36 (s, 3H), 5.41 (q, J = 7.1 Hz, 1H), 7.01 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 15.9, 21.0, 83.3, 115.2, 120.7, 130.1, 130.3, 136.7, 147.8,
164.0; MS (ES+, Ar) m/z (rel intensity) 233 ([MNa+1], 3), 232 ([MNa]+, 100), 221 (1), 201 (1),
181 (1); HRMS (ES+, Ar) calcd for C10H11NO4Na (MNa+, 100) 232.0580, found 232.0581.
pꢀTolyl 2ꢀnitrobutanoate (2b). Colorless liquid; Yield 1.299 g, 67%; IR (neat, cmꢀ1) 3037 (w),
2979 (s), 2944 (m), 2884 (w), 1770 (vs), 1561 (vs), 1507 (s), 1460 (m), 1439 (m), 1373 (w), 1289
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(m), 1192 (vs), 1174 (vs), 1103 (m), 1091 (m), 962 (m), 841 (s), 812 (s), 790 (s), 510 (s); H NMR
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(400 MHz, CDCl3) δ 1.17 (d, J = 7.1 Hz, 3H), 2.29ꢀ2.55 (m overlaps with s, 2H), 2.38 (s, overlaps
with m, 3H), 5.28 (dd, J = 8.8, 5.9 Hz, 1H), 7.01 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 10.3, 21.1, 24.2, 89.4, 120.7, 130.3, 136.7, 147.8, 163.4; MS (ES+, Ar)
m/z (rel intensity) 247 ([MNa+1], 3), 246 ([MNa]+, 53), 153 (100); HRMS (ES+, Ar) calcd for
C11H13NO4Na (MNa+) 246.0737, found 246.0739.
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pꢀTolyl 2ꢀnitropentanoate (2c). Colorless liquid; Yield 1.499 g, 73%; IR (neat, cmꢀ1) 2927 (vs),
1771 (vs), 1564 (vs), 1508 (w), 1374 (w), 1265 (w), 1195 (m), 1170 (w), 1109 (m), 1020 (w), 804
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(w); H NMR (400 MHz, CDCl3) δ 1.04 (t, J = 7.4 Hz, 3H), 1.46ꢀ1.59 (m, 2H), 1.99ꢀ2.31 (m, 1H),
2.35 (s, overlaps with m, 3H), 2.34ꢀ2.47 (m, overlaps with s, 1H), 5.32 (dd, J = 9.2, 5.8 Hz, 1H),
6.99 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 13.5, 19.2, 21.1,
32.4, 88.0, 120.7, 130.3, 136.7, 147.9, 163.5; MS (ES+, Ar) m/z (rel intensity) 260 ([MNa]+, 100),
216 (49), 102 (10); HRMS (ES+, Ar) calcd for C12H15NO4Na (MNa+, 100) 260.0893, found
260.0893.
pꢀTolyl 2ꢀnitrohexanoate (2d). Colorless liquid; Yield 1.511 g, 73%; IR (neat, cmꢀ1) 2927 (s),
1771 (s), 1564 (s), 1507 (vw), 1374 (vw), 1266 (vw), 1196 (w), 1169 (w), 1108 (w), 1019 (w), 803
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(vw), 508 (vw); H NMR (500 MHz, CDCl3) δ 0.98 (t, J = 7.1 Hz, 3H), 1.37ꢀ1.53 (m, 4H), 2.24ꢀ
2.35 (m, 1H), 2.38 (s, overlaps with m, 3H), 2.36ꢀ2.48 (m, overlaps with s, 1H), 5.33 (dd, J = 9.1,
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5.7 Hz, 1H), 7.02 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H); C NMR (100 MHz, CDCl3) δ
13.8, 21.0, 22.1, 27.8, 30.2, 88.2, 120.7, 130.3, 136.7, 147.9, 163.5; MS (ES+, Ar) m/z (rel
intensity) 274 ([MNa]+, 100), 164 (1), 132 (4); HRMS (ES+, Ar) calcd for C13H17NO4Na (MNa+,
100) 274.1050, found 274.1043.
pꢀTolyl 3ꢀmethylꢀ2ꢀnitrobutanoate (2e). Colorless liquid; Yield 1.295 g, 63%; IR (neat, cmꢀ1)
2927 (vs), 1771 (vs), 1564 (vs), 1508 (w), 1374 (w), 1266 (w), 1196 (m), 1170 (w), 1109 (w), 1020
(w), 804 (w); 1H NMR (400 MHz, CDCl3) δ 1.18 (d, J = 6.9 Hz, 3H), 1.20 (d, J = 6.9 Hz, 3H), 2.35
(s, 3H), 2.73ꢀ2.86 (m, 1H), 5.12 (d, J = 8.9 Hz, 1H), 7.01 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz,
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2H); 13C NMR (100 MHz, CDCl3) δ 18.6, 18.9, 21.0, 30.5, 93.5, 120.7, 130.3, 136.6, 147.8, 162.7;
MS (ES+, Ar) m/z (rel intensity) 276 ([M+K]+, 10), 260 ([M+Na]+, 100), 216 (50), 132 (5), 102
(9); HRMS (ES+, Ar) calcd for C12H15NO4Na (MNa+, 100) 260.0893, found 260.0892.
9
oꢀTolyl 2ꢀnitropropanoate (2f). Colorless liquid; Yield 1.299 g, 72%; IR (neat, cmꢀ1) 2982 (m),
1770 (vs), 1563 (vs), 1490 (m), 1449 (m), 1389 (m), 1360 (w), 1316 (w), 1222 (s), 1172 (vs), 1110
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60
1
(m), 1084 (w), 750 (s); H NMR (400 MHz, CDCl3) δ 1.96 (d, J = 7.1 Hz, 3H), 2.20 (s, 3H), 5.46
(q, J = 7.1 Hz, 1H), 7.05 (dd, J = 7.9, 1.7 Hz, 1H), 7.17ꢀ7.27 (m, 3H); 13C NMR (100 MHz, CDCl3)
δ 16.0, 16.0, 83.2, 121.3, 127.1, 127.3, 130.1, 131.6, 148.6, 163.5; MS (ES+, Ar) m/z (rel intensity)
233 ([MNa+1], 8), 232 ([MNa]+, 100), 221 (4); HRMS (ES+, Ar) calcd for C10H11NO4Na (MNa+,
100) 232.0580, found 232.0582.
Benzyl 2ꢀnitropropanoate (2g). Colorless liquid; Yield 1.402 g, 78%; IR (neat, cmꢀ1) 3035 (w),
2965 (w), 1753 (vs), 1562 (vs), 1498 (w), 1455 (m), 1392 (w), 1361 (w), 1315 (w), 1267 (w), 1195
(m), 1121 (w), 1085 (w), 1027 (m), 874 (w), 751 (m), 698 (m); 1H NMR (400 MHz, CDCl3) δ 1.80
(d, J = 7.1 Hz, 3H), 5.24 (q, J = 7.1 Hz, 1H), 5.25 (s, 2H), 7.32ꢀ7.42 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 15.9, 68.6, 83.3, 128.5, 128.9, 129.0, 134.4, 165.1; MS (ES+, Ar) m/z (rel intensity) 233
([MNa+1], 12), 232 ([MNa]+, 100), 221 (20), 204 (22), 181 (31), 162 (45), 145 (32), 125 (10), 102
(14); HRMS (ES+, Ar) calcd for C10H11NO4Na (MNa+, 100) 232.0580, found 232.0581.
General procedure for the addition of nitroesters 2 to enones 1. To a solution of nitroester 2
(0.5 mmol) and catalyst C9 (24.55 mg, 0.05 mmol) in toluene (0.5 ml) was added enone 1 (0.75
o
mmol, dissolved in 0.5 ml toluene) at ꢀ60 C. The reaction mixture was stirred at the same
temperature and monitored by TLC. The solvent was evaporated in vacuo and the residue was
purified by silica gel column chromatography using EtOAcꢀpet ether (10ꢀ30%, gradient elution) as
eluent to afford pure 3, 4 or 5. All the fractions containing the product were combined and the
solvent was removed in vacuo in order to avoid any selfꢀdisproportionation of enantiomers (SDE)
during column chromatography.28
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pꢀTolyl (R)ꢀ5ꢀ(3ꢀbromophenyl)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxopentanoate (3a). Colorless solid; Yield
200 mg, 95%; mp 77ꢀ78oC; IR (film, cmꢀ1) 3040 (w), 2919 (w), 1771 (vs), 1694 (s), 1550 (s), 1506
(w), 1416 (vw), 1387 (vw), 1349 (w), 1311 (vw), 1251 (s), 1224 (m), 1204 (m), 1117 (m), 1068
9
1
(w), 914 (vw), 890 (vw), 778 (m), 683 (w), 556 (vw), 508 (m); H NMR (400 MHz, CDCl3) δ 2.01
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(s, 3H), 2.35 (s, 3H), 2.73, 2.80 (ABqdd, J = 12.6, 9.2, 5.9 Hz, 2H), 3.13, 3.20 (ABqdd, J = 15.0,
9.2, 5.9 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.70
(ddd, J = 7.9, 1.8, 0.9 Hz, 1H), 7.87 (ddd collapsed to dt, J = 7.9, 1.4 Hz, 1H), 8.07 (dd collapsed to
t, J = 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.1, 22.5, 30.9, 33.4, 92.2, 120.7, 123.3, 126.7,
130.3, 130.5, 131.2, 136.5, 136.7, 138.1, 147.9, 166.0, 196.1; MS (ES+, Ar) m/z (rel intensity) 445
([MNa+3]+, 16), 444 ([MNa+2]+, 99), 443 ([MNa+1]+, 16), 442 ([MNa]+, 100), 439 (24), 437 (24),
422(11), 420 (12); HRMS (ES+, Ar) calcd for C19H18BrNO5Na (MNa+, 100) 442.0261, found
442.0261; [α]25 ꢀ8.49 (c 1.0, CHCl3); HPLC: Chiralcel ODꢀH (pet ether/iꢀPrOH = 90/10, flow rate
D
0.5 mL/min, λ = 216 nm), tR (major) = 22.0 min, tR (minor) = 23.8 min; 82% ee.
pꢀTolyl (R)ꢀ5ꢀ(4ꢀbromophenyl)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxopentanoate (3b). Colorless solid; Yield
204 mg, 97%; mp 86ꢀ88oC; IR (film, cmꢀ1) 2921 (w), 1774 (vs), 1692 (vs), 1584 (w), 1551 (vs),
1507 (w), 1421 (vw), 1388 (m), 1348 (w), 1314 (w), 1249 (m), 1201 (m), 1162 (w), 1117 (m), 1064
1
(w), 989 (vw), 888 (vw), 802 (m), 786 (w), 755 (w); H NMR (500 MHz, CDCl3) δ 2.02 (s, 3H),
2.37 (s, 3H), 2.75, 2.81 (ABqdd, J = 15.0, 9.4, 5.7 Hz, 2H), 3.14, 3.22 (ABqdd, J = 17.7, 9.4, 5.7
Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 7.84 (d, J =
8.6 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.1, 22.6, 31.1, 33.3, 92.3, 120.7, 128.9, 129.7, 129.7,
130.3, 132.3, 135.1, 136.7, 147.9, 166.0, 196.5; MS (ES+, Ar) m/z (rel intensity) 445 ([MNa+3]+,
19), 444 ([MNa+2]+, 100), 443 ([MNa+1]+, 19), 442 ([MNa]+, 100), 437 (9); HRMS (ES+, Ar)
calcd for C19H18BrNO5Na (MNa+, 100) 442.0261, found 442.0261; [α]25 ꢀ11.68 (c 1.0, CHCl3);
D
HPLC: Chiralpack IC (pet ether/iꢀPrOH = 95/5, flow rate 0.5 mL/min, λ = 258 nm), tR (major) =
27.4 min, tR (minor) = 29.4 min; 75% ee.
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pꢀTolyl (R)ꢀ5ꢀ(4ꢀchlorophenyl)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxopentanoate (3c). Colorless solid; Yield
176 mg, 94%; mp 108ꢀ109oC; IR (film, cmꢀ1) 2920 (vw), 1778 (vs), 1690 (vs), 1587 (w), 1572 (w),
1549 (vs), 1509 (m), 1389 (m), 1314 (vw), 1242 (s), 1209 (s), 1166 (w), 1116 (m), 1104 (w), 1091
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(m), 979 (w), 889 (w), 804 (m), 788 (m); H NMR (400 MHz, CDCl3) δ 1.99 (s, 3H), 2.35 (s, 3H),
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2.72, 2.79 (ABqdd, J = 15.0, 9.1, 6.0 Hz, 2H), 3.12, 3.20 (ABqdd, J = 17.7, 9.1, 6.0 Hz, 2H), 6.99
(d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.6 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 21.1, 22.5, 31.0, 33.3, 92.3, 120.7, 129.2, 129.6, 130.3, 134.7, 136.7,
140.1, 147.9, 166.0, 196.3; MS (ES+, Ar) m/z (rel intensity) 400 ([MNa+2]+, 29), 399 ([MNa+1]+,
16), 398 ([MNa]+, 100), 393 (11), 376 (25), 329 (8); HRMS (ES+, Ar) calcd for C19H18ClNO5Na
(MNa+, 100) 398.0766, found 398.0766; [α]25 ꢀ12.32 (c 1.0, CHCl3); HPLC: Chiralpack IC (pet
D
ether/iꢀPrOH = 95/5, flow rate 0.5 mL/min, λ = 258 nm), tR (major) = 25.5 min, tR (minor) = 27.4
min; 77% ee.
p-Tolyl (R)ꢀ5ꢀ(2ꢀchlorophenyl)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxopentanoate (3d). Colorless oil; Yield 182
mg, 97%; IR (neat, cmꢀ1) 2935 (m), 1768 (vs), 1703 (s), 1590 (w), 1553 (vs), 1507 (m), 1434 (w),
1389 (vw), 1347 (w), 1265 (m), 1240 (m), 1194 (vs), 1172 (s), 1115 (m), 1074 (w), 985 (vw), 805
1
(vw), 757 (s), 739 (s), 705 (w); H NMR (400 MHz, CDCl3) δ 1.98 (s, 3H), 2.35 (s, 3H), 2.78
(ABqdd, J = 15.0, 8.0, 6.6 Hz, 2H), 3.17 (ABqdd, J = 18.0, 8.0, 6.6 Hz, 2H), 6.99 (d, J = 8.6 Hz,
2H), 7.19 (d, J = 8.6 Hz, 2H), 7.33 (ddd, J = 7.5, 6.3, 2.3 Hz, 1H), 7.37ꢀ7.44 (m, 2H), 7.48 (ddd, J
13
= 7.5, 1.3, 0.9 Hz, 1H); C NMR (100 MHz, CDCl3) δ 21.0, 22.3, 31.0, 37.6, 92.2, 120.7, 127.3,
129.2, 130.3, 130.8, 131.1, 132.3, 136.7, 138.7, 147.9, 166.0, 200.5; MS (ES+, Ar) m/z (rel
intensity) 401 ([MNa+3]+, 6), 400 ([MNa+2]+, 32), 399 ([MNa+1]+, 19), 398 ([MNa]+, 100), 393
(28), 376 (27), 329 (15); HRMS (ES+, Ar) calcd for C19H18ClNO5Na (MNa+, 100) 398.0766, found
398.0765; [α]25 ꢀ4.64 (c 1.0, CHCl3); HPLC: Chiralpack IC (pet ether/iꢀPrOH = 97/3, flow rate
D
0.5 mL/min, λ = 216 nm), tR (major) = 32.7 min, tR (minor) = 34.4 min; 35% ee.
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pꢀTolyl (R)ꢀ5ꢀ(4ꢀcyanophenyl)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxopentanoate (3e). Colorless solid; Yield
165 mg, 90%; mp 75.5ꢀ77.5 oC; IR (film, cmꢀ1) 2926 (w), 2232 (w), 1768 (vs), 1696 (s), 1607 (vw),
1554 (vs), 1507 (m), 1459 (w), 1405 (w), 1390 (w), 1348 (w), 1292 (w), 1243 (m), 1194 (s), 1172
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(m), 1116 (m), 1062 (vw), 1019 (vw), 992 (w), 846 (m), 808 (m), 737 (w); H NMR (400 MHz,
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CDCl3) δ 2.00 (s, 3H), 2.34 (s, 3H), 2.72, 2.79 (ABqdd, J = 15.0, 9.1, 5.9 Hz, 2H), 3.17, 3.26
(ABqdd, J = 18.0, 9.1, 5.9 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H) 7.18 (d, J = 8.3 Hz, 2H), 7.76 (d, J =
8.6 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.0, 22.6, 30.9, 33.7, 92.1,
116.9, 117.9, 120.6, 128.6, 130.3, 132.8, 136.8, 139.2, 147.8, 165.9, 196.2; MS (ES+, Ar) m/z (rel
intensity) 390 ([MNa+1]+, 19), 389 ([MNa]+, 100), 221 (9), 181 (9); HRMS (ES+, Ar) calcd for
C20H18N2O5Na (MNa+, 100) 389.1108, found 389.1108; [α]25 ꢀ15.36 (c 1.0, CHCl3); HPLC:
D
Chiral cell ADꢀH (pet ether/iꢀPrOH = 95/5, flow rate 0.5 mL/min, λ = 216 nm), tR (major) = 64.7
min, tR (minor) = 55.2 min; 74% ee.
p-Tolyl (R)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀ(4ꢀnitrophenyl)ꢀ5ꢀoxopentanoate (3f). Colorless solid; Yield 170
mg, 88%; mp 94ꢀ95oC; IR (film, cmꢀ1) 2925 (w), 1768 (s), 1697 (m), 1604 (w), 1555 (vs), 1528 (s),
1508 (m), 1389 (w), 1347 (s), 1319 (w), 1244 (m), 1194 (s), 1171 (m), 1116 (m), 1019 (vw), 991
1
(vw), 856 (m), 806 (w), 742 (m); H NMR (500 MHz, CDCl3) δ 2.01 (s, 3H), 2.35 (s, 3H), 2.74,
2.81 (ABqdd, J = 15.0, 9.2, 5.7 Hz, 2H), 3.21, 3.30 (ABqdd, J = 18.0, 9.2, 5.7 Hz, 2H), 6.99 (d, J =
8.3 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 8.10 (d, J = 8.9 Hz, 2H), 8.30 (d, J = 8.9 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 21.0, 22.7, 31.0, 34.0, 92.1, 120.6, 124.1, 129.3, 130.3, 136.8, 140.7, 147.9,
150.7, 165.9, 196.1; MS (ES+, Ar) m/z (rel intensity) 410 ([MNa+1]+, 21), 409 ([MNa]+, 100), 404
(14), 387 (3); HRMS (ES+, Ar) calcd for C19H18N2O7Na (MNa+, 100) 409.1006, found 409.1009;
[α]25 ꢀ15.51 (c 1.0, CHCl3); HPLC: Chiralpack IC (pet ether/iꢀPrOH = 90/10, flow rate 0.5
D
mL/min, λ = 216 nm), tR (major) = 60.7 min, tR (minor) = 72.3 min; 69% ee.
p-Tolyl 2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxoꢀ5ꢀphenylpentanoate (3g). Colorless solid; Yield 160 mg, 94%;
mp 93ꢀ94 oC; IR (film, cmꢀ1) 3036 (vw), 2926 (w), 1775 (vs), 1688 (vs), 1598 (w), 1582 (w), 1550
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(vs), 1506 (w), 1459 (w), 1421 (vw), 1389 (w), 1347 (vw), 1321 (vw), 1247 (m), 1210 (m), 1200
1
(m), 1186 (m), 1161 (w), 1118 (m), 1102 (w), 888 (w), 747 (m), 690 (w); H NMR (500 MHz,
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CDCl3) δ 2.02 (s, 3H), 2.37 (s, 3H), 2.78, 2.84 (ABqdd, J = 15.0, 9.2, 5.9 Hz, 2H), 3.18, 3.24
(ABqdd, J = 17.6, 9.2, 5.9 Hz, 2H), 7.02 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.49 (t, J =
7.3 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.98 (d, J = 7.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.1,
22.5, 31.1, 33.3, 92.4, 120.7, 128.2, 128.9, 130.3, 133.7, 136.4, 136.7, 148.0, 166.1, 197.5; MS
(ES+, Ar) m/z (rel intensity) 364 ([MNa]+, 100), 301 (15); HRMS (ES+, Ar) calcd for
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C19H19NO5Na (MNa+, 100) 364.1155, found 364.1154; [α]25 ꢀ10.58 (c 1.0, CHCl3); HPLC:
D
Chiralpack IC (pet ether/iꢀPrOH = 95/5, flow rate 0.5 mL/min, λ = 216 nm), tR (major) = 27.4 min,
tR (minor) = 29.9 min; 72% ee.
pꢀTolyl (R)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxoꢀ5ꢀpꢀtolylpentanoate (3h). Colorless solid; Yield 151 mg,
85%; mp 101ꢀ102 oC; IR (film, cmꢀ1) 2925 (w), 1779 (s), 1682 (s), 1606 (w), 1552 (vs), 1510 (w),
1
1420 (w), 1389 (w), 1308 (vw), 1245 (m), 1214 (m), 1115 (w), 890 (w), 784 (m); H NMR (400
MHz, CDCl3) δ 1.99 (s, 3H), 2.35 (s, 3H), 2.41 (s, 3H), 2.74, 2.81 (ABqdd, J = 15.0, 9.0, 6.2 Hz,
2H), 3.12, 3.19 (ABqdd, J = 17.4, 9.0, 6.2 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H) 7.19 (d, J = 8.0 Hz,
2H), 7.24 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.0, 21.8,
22.4, 31.1, 33.1, 92.4, 120.7, 128.3, 129.5, 130.3, 133.9, 136.6, 144.5, 147.9, 166.1, 197.1; MS
(ES+, Ar) m/z (rel intensity) 379 ([MNa+1]+, 17), 378 ([MNa]+, 100), 373 (11), 356 (21), 309(5);
HRMS (ES+, Ar) calcd for C20H21NO5Na (MNa+, 100) 378.1312, found 378.1315; [α]25 ꢀ11.25 (c
D
1.0, CHCl3); HPLC: Chiralpack IC (pet ether/iꢀPrOH = 90/10, flow rate 0.5 mL/min, λ = 216 nm),
tR (major) = 23.6 min, tR (minor) = 25.5 min; 75% ee.
pꢀTolyl (R)ꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxopentanoate (3i). Colorless solid; Yield
180 mg, 97%; mp 94ꢀ95 oC; IR (film, cmꢀ1) 2937 (w), 1778 (vs), 1679 (s), 1603 (s), 1577 (s), 1550
(vs), 1510 (m), 1424 (w), 1390 (w), 1313 (w), 1256 (vs), 1247 (vs), 1213 (s), 1179 (s), 1116 (m),
1
1061 (vw), 1034 (w), 892 (w), 808 (m); H NMR (400 MHz, CDCl3) δ 1.99 (s, 3H), 2.35 (s, 3H),
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2.74, 2.80 (ABqdd, J = 15.0, 9.1, 6.1 Hz, 2H), 3.09, 3.16 (ABqdd, J = 17.3, 9.1, 6.1 Hz, 2H), 3.87
(s, 3H), 6.94 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.9
7
8
13
Hz, 2H); C NMR (100 MHz, CDCl3) δ 21.0, 22.4, 31.2, 32.8, 55.7, 92.5, 114.0, 120.7, 129.5,
9
130.3, 130.5, 136.6, 148.0, 163.9, 166.1, 196.0; MS (ES+, Ar) m/z (rel intensity) 395 ([MNa+1]+,
19), 394 ([MNa]+, 100), 373 (8), 372 (40), 325 (7); HRMS (ES+, Ar) calcd for C20H21NO6Na
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(MNa+, 100) 394.1261, found 394.1258; [α]25 ꢀ13.55 (c 1.0, CHCl3); HPLC: Chiral cell ADꢀH
D
(pet ether/iꢀPrOH = 95/5, flow rate 0.5 mL/min, λ = 258 nm), tR (major) = 39.3 min, tR (minor) =
37.5 min; 76% ee.
p-Tolyl (R)ꢀ2ꢀmethylꢀ5ꢀ(naphthalenꢀ2ꢀyl)ꢀ2ꢀnitroꢀ5ꢀoxopentanoate (3j). Colorless solid; Yield
o
186 mg, 95%; mp 117ꢀ118.2 C; IR (film, cmꢀ1) 3060 (w), 2924 (w), 1778 (vs), 1681 (vs), 1628
(vw), 1596 (vw), 1548 (vs), 1508 (m), 1470 (vw), 1439 (vw), 1418 (vw), 1389 (w), 1352 (w), 1254
(m), 1240 (m), 1206 (m), 1185 (w), 1117 (m), 1062 (w), 866 (w), 825 (w), 814 (w), 798 (w), 745
1
(w); H NMR (500 MHz, CDCl3) δ 2.06 (s, 3H), 2.37 (s, 3H), 2.84, 2.90 (ABqdd, J = 15.0, 9.3, 5.8
Hz, 2H), 3.32, 3.38 (ABqdd, J = 17.4, 9.3, 5.8 Hz, 2H), 7.04 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3
Hz, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.90 (d, partially overlaps with d, J = 8.0
Hz, 1H), 7.92 (d, partially overlaps with d, J = 8.7 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 8.04 (dd, J =
13
8.7, 1.6 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H); C NMR (125 MHz, CDCl3) δ 21.0, 22.5, 31.2, 33.3,
92.4, 120.7, 123.8, 127.1, 127.9, 128.8, 129.8, 130.0, 130.3, 132.6, 133.7, 135.9, 136.7, 148.0,
166.1, 197.4; MS (ES+, Ar) m/z (rel intensity) 415 ([MNa+1]+, 24), 414 ([MNa]+, 100), 409 (4);
HRMS (ES+, Ar) calcd for C23H21NO5Na (MNa+) 414.1312, found 414.1313; [α]25 ꢀ12.52 (c 1.0,
D
CHCl3); HPLC: Chiralpack IC (pet ether/iꢀPrOH = 95/5, flow rate 0.5 mL/min, λ = 216 nm), tR
(major) = 41.6 min, tR (minor) = 43.8 min; 71% ee.
p-Tolyl (R)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxoꢀ5ꢀ(thiophenꢀ2ꢀyl)pentanoate (3k). Colorless solid; Yield 154
mg, 89%; mp 111ꢀ112oC; IR (film, cmꢀ1) 3093 (vw), 2925 (vw), 1778 (vs), 1668 (vs), 1551 (vs),
1519 (m), 1506 (m), 1442 (w), 1423 (m), 1413 (m), 1389 (m), 1347 (w), 1311 (w), 1245 (vs), 1203
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(s), 1162 (w), 1117 (m), 1103 (w), 1083 (w), 887 (vw), 860 (vw), 813 (vw), 802 (vw), 732 (m), 726
(m); 1H NMR (400 MHz, CDCl3) δ 1.98 (s, 3H), 2.35 (s, 3H), 2.74, 2.80 (ABqdd, J = 15.0, 9.0, 6.2
Hz, 2H), 3.09, 3.16 (ABqdd, J = 17.0, 9.0, 6.2 Hz, 2H), 6.99 (d, J = 8.3 Hz, 2H), 7.13 (dd, J = 5.0,
3.8 Hz, 1H), 7.19 (d, J = 8.3 Hz, 2H), 7.66 (dd, J = 5.0,1.1 Hz, 1H), 7.74 (dd, J = 3.8, 1.1 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 21.0, 22.4, 31.1, 33.9, 92.3, 120.7, 128.4, 130.3, 132.4, 134.3,
136.7, 143.4, 147.9, 166.0, 190.4; MS (ES+, Ar) m/z (rel intensity) 371 ([MNa+1]+, 40), 370
([MNa]+, 100), 365 (11), 349 (6), 348 ([MH]+, 19); HRMS (ES+, Ar) calcd for C17H18NO5S (MH+)
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348.0900, found 348.0904; [α]25 ꢀ10.42 (c 1.0, CHCl3); HPLC: Chiralcel ODꢀH (pet ether/iꢀPrOH
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= 95/5, flow rate 0.5 mL/min, λ = 258 nm), tR (major) = 36.1 min, tR (minor) = 38.1 min; 68% ee.
(E)ꢀpꢀTolyl (R)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxoꢀ7ꢀphenylheptꢀ6ꢀenoate (3l). Colorless solid; Yield 167
mg, 91%; mp 129ꢀ130oC; IR (film, cmꢀ1) 2918 (w), 1776 (s), 1659 (s), 162 (m), 1544 (vs), 1574
(vw), 1508 (m), 1389 (w), 1241 (m), 1206 (m), 1179 (m), 1117 (m), 979 (w), 744 (m), 690 (w); 1H
NMR (400 MHz, CDCl3) δ 1.98 (s, 3H), 2.35 (s, 3H), 2.65ꢀ2.80 (m, 2H), 2.81ꢀ2.97 (m, 2H), 6.74
(d, J = 16.3 Hz, 1H), 7.0 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.37ꢀ7.45 (m, 3H), 7.55 (dd,
13
J = 6.8, 2.9 Hz, 2H), 7.59 (d, J = 16.3 Hz, 1H); C NMR (100 MHz, CDCl3) δ 21.1, 22.4, 30.9,
35.3, 92.4, 120.7, 125.6, 128.6, 129.2, 130.3, 130.9, 134.3, 136.7, 143.6, 147.9, 166.1, 197.3; MS
(ES+, Ar) m/z (rel intensity) 391 ([MNa+1]+, 17), 390 ([MNa]+, 100), 385 (10), 381 (6), 368 (33),
321 (4) 221 (6); HRMS (ES+, Ar) calcd for C21H21NO5Na (MNa+) 390.1312, found 390.1309;
[α]25 ꢀ12.64 (c 1.0, CHCl3); HPLC: Chiralcel ODꢀH (pet ether/iꢀPrOH = 97/3, flow rate 0.5
D
mL/min, λ = 216 nm), tR (major) = 54.3 min, tR (minor) = 48.9 min; 73% ee.
p-Tolyl (R)ꢀ5ꢀcyclohexylꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxopentanoate (3m). Colorless solid; Yield 120
mg, 69%; mp 64ꢀ66oC; IR (film, cmꢀ1) 2932 (vs), 2856 (m), 1773 (vs), 1710 (vs), 1533 (vs), 1508
(m), 1450 (m), 1388 (w), 1347 (w), 1237 (m), 1195 (m), 1169 (m), 1146 (w), 1114 (m), 1081 (w),
1
1019 (w), 887 (w), 859 (w), 844 (w), 809 (w); H NMR (400 MHz, CDCl3) δ 1.11ꢀ1.41 (m, 5H),
1.61ꢀ1.71 (m, 1H), 1.72ꢀ1.88 (m, 4H), 1.91 (s, 3H), 2.29ꢀ2.41 (m, overlaps with singlet, 1H), 2.35
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(s, overlaps with m, 3H), 2.49ꢀ2.73 (m, 4H), 6.97 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 21.0, 22.3, 25.7, 25.9, 28.6, 28.6, 30.6, 35.0, 51.0, 92.3, 120.7, 130.3,
136.6, 147.9, 166.0, 211.3; MS (ES+, Ar) m/z (rel intensity) 371 ([MNa+1]+, 21), 370 ([MNa]+,
100), 348 ([MH]+, 6), 301 (4); HRMS (ES+, Ar) calcd for C19H26NO5(MH+) 348.1805, found
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348.1805; [α]25 ꢀ3.64 (c 1.0, CHCl3); HPLC: Chiralpack IC (pet ether/iꢀPrOH = 98/2, flow rate
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0.25 mL/min, λ = 216 nm), tR (major) = 64.3 min, tR (minor) = 68.1 min; 37% ee.
pꢀTolyl (R)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxohexanoate (3n) . Colorless solid; Yield 106 mg, 76%; mp 64ꢀ
66 oC; IR (film, cmꢀ1) 2366 (vw), 1773 (vs), 1718 (s), 1546 (s), 1507 (m), 1353 (w), 1238 (s), 1197
1
(vs), 1197 (vs), 1162 (m), 1117 (m), 1056 (vw), 886 (vw), 803 (w), 511 (w); H NMR (400 MHz,
CDCl3) δ 1.91 (s, 3H), 2.18 (s, 3H), 2.35 (s, 3H), 2.49ꢀ2.73 (m, 4H), 6.99 (d, J = 8.9 Hz, 2H), 7.19
(d, J = 8.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.1, 22.4, 30.2, 30.5, 38.0, 92.2, 120.7, 130.3,
136.7, 147.9, 166.0, 205.8; MS (ES+, Ar) calcd for C14H17NO5Na (MNa+) 302.0999, found
302.0988; [α]25 ꢀ2.05 (c 1.0, CHCl3); HPLC: Chiralpack ADH (pet ether/iꢀPrOH = 97/3, flow rate
D
0.5 mL/min, λ = 220 nm), tR (major) = 30.5 min, tR (minor) = 39.9 min; 27% ee.
pꢀTolyl (R)ꢀ5ꢀ(3ꢀbromophenyl)ꢀ2ꢀethylꢀ2ꢀnitroꢀ5ꢀoxopentanoate (4a). Colorless solid; Yield 188
o
mg, 87%; mp 84ꢀ85 C; IR (film, cmꢀ1) 3066 (vw), 2968 (m), 2935 (m), 2877 (w), 1767 (s), 1693
(s), 1552 (vs), 1507 (m), 1421 (w), 1349 (w), 1264 (w), 1194 (vs), 1168 (m), 1125 (w), 1068 (vw),
1019 (vw), 997 (vw), 878 (vw), 783 (m), 739 (w), 680 (w); 1H NMR (400 MHz, CDCl3) δ 1.08 (t, J
= 7.5 Hz, 3H), 2.35 (s, 3H), 2.45 (ABqq, J = 15.1, 7.6 Hz, 2H), 2.71, 2.78 (ABqdd, J = 15.1, 9.6,
5.5 Hz, 2H), 3.06, 3.17 (ddd, J = 17.9, 9.6, 5.5 Hz, 1H), 3.17 (ddd, J = 17.9, 9.6, 5.5 Hz, 1H), 6.98
(d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.70 (ddd, J = 7.9, 1.7, 0.9
Hz, 1H), 7.85 (ddd collapsed to dt, J = 7.9, 1.3 Hz, 1H), 8.06 (dd collapsed to t, J = 1.3 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 8.4, 21.1, 28.1, 28.9, 33.3, 96.1, 120.8, 123.3, 126.8, 130.3, 130.5,
131.2, 136.5, 136.7, 138.1, 147.9, 165.5, 196.2; MS (ES+, Ar) m/z (rel intensity) 459 ([MNa+3]+,
15), 458 ([MNa+2]+, 76), 457 ([MNa+1]+, 15), 456 ([MNa]+, 77), 367 (18), 302 (17), 301 (100),
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149 (7); HRMS (ES+, Ar) calcd for C20H20BrNO5Na (MNa+) 456.0417, found 456.0412; [α]25
ꢀ
D
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7
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8.77 (c 0.75, CHCl3); HPLC: Chiralpack IC (pet ether/iꢀPrOH = 97/3, flow rate 0.3 mL/min, λ =
244 nm), tR (major) = 56.4 min, tR (minor) = 59.5 min; 83% ee.
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pꢀTolyl (R)ꢀ5ꢀ(3ꢀbromophenyl)ꢀ2ꢀnitroꢀ5ꢀoxoꢀ2ꢀpropylpentanoate (4b). Colorless solid; Yield
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o
206 mg, 92%; mp 86ꢀ87 C; IR (film, cmꢀ1) 3066 (w), 2968 (m), 2935 (m), 2877 (w), 1767 (s),
1693 (s), 1591 (w), 1552 (vs), 1507 (m), 1421 (m), 1348 (w), 1299 (w), 1264 (w), 1194 (vs), 1168
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(m), 1125 (m), 1068 (w), 1019 (w), 997 (w), 878 (vw), 783 (m), 739 (w), 680 (w); H NMR (400
MHz, CDCl3) δ 1.05 (t, J = 7.3 Hz, 3H), 1.38ꢀ1.52 (m, 2H), 2.32ꢀ2.41 (m, overlaps with s, 2H),
2.35 (s, overlaps with m, 3H), 2.71, 2.79 (ABqdd, J = 15.2, 9.6, 5.6 Hz, 2H), 3.06, 3.17 (ABqdd, J
= 17.8, 9.6, 5.6 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 7.9 Hz, 1H),
7.70 (ddd, J = 7.9, 1.9, 0.9 Hz, 1H), 7.86 (ddd collapsed to dt, J = 7.9, 1.4 Hz, 1H), 8.06 (dd
13
collapsed to t, J = 1.4 Hz, 1H); C NMR (125 MHz, CDCl3) δ 14.2, 17.4, 21.0, 28.6, 33.3, 37.5,
95.6, 120.7, 123.3, 126.7, 130.3, 130.5, 131.2, 136.5, 136.7, 138.1, 147.9, 165.6, 196.2; MS (ES+,
Ar) m/z (rel intensity) 473 ([MNa+3]+, 18), 472 ([MNa+2]+, 100), 471 ([MNa+1]+, 19), 470
([MNa]+, 93), 395 (8), 367 (27), 301 (18); HRMS (ES+, Ar) calcd for C21H22BrNO5Na (MNa+)
470.0574, found 470.0577; [α]25 ꢀ5.44 (c 1.0, CHCl3); HPLC: Chiralpack IC (pet ether/iꢀPrOH =
D
97/3, flow rate 0.5 mL/min, λ = 244 nm), tR (major) = 30.3 min, tR (minor) = 32.1 min; 86% ee.
pꢀTolyl (R)ꢀ2ꢀ(3ꢀ(3ꢀbromophenyl)ꢀ3ꢀoxopropyl)ꢀ2ꢀnitrohexanoate (4c). Colorless solid; Yield
o
217 mg, 94%; mp 84ꢀ86 C; IR (film, cmꢀ1) 3066 (vw), 2968 (m), 2934 (m), 2877 (w), 1767 (s),
1693 (vs), 1591 (vw), 1552 (vs), 1507 (m), 1441 (w), 1421 (m), 1348 (m), 1264 (w), 1194 (vs),
1
1168 (m), 1125 (m), 1068 (w), 1019 (w), 997 (w), 878 (w), 783 (m), 739 (w), 680 (w); H NMR
(400 MHz, CDCl3) δ 0.96 (t, J = 7.0 Hz, 3H), 1.32ꢀ1.49 (m, 4H), 2.34ꢀ2.41 (m, overlaps with s,
2H), 2.35 (s, overlaps with m, 3H), 2.71, 2.78 (ABqdd, J = 15.2, 9.6, 5.6 Hz, 2H), 3.05, 3.17
(ABqdd, J = 17.8, 9.6, 5.6 Hz, 2H), 6.99 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 7.34 (t, J =
7.9 Hz, 1H), 7.70 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 7.86 (ddd collapsed to dt, J = 7.9, 1.5 Hz, 1H),
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8.06 (dd collapsed to t, J = 1.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 13.9, 21.0, 22.7, 25.9, 28.6,
33.3, 35.2, 95.7, 120.7, 123.3, 126.7, 130.3, 130.5, 131.2, 136.5, 136.7, 138.1, 147.9, 165.6, 196.2;
MS (ES+, Ar) m/z (rel intensity) 487 ([MNa+3]+, 22), 486 ([MNa+2]+, 93), 485([MNa+1]+, 21),
484 ([MNa]+, 100); HRMS (ES+, Ar) calcd for C22H24BrNO5Na (MNa+) 484.0730, found
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484.0731; [α]25 ꢀ5.30 (c 0.8, CHCl3); HPLC: Chiralpack IC (pet ether/iꢀPrOH = 97/3, flow rate
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0.5 mL/min, λ = 244 nm), tR (major) = 26.6 min, tR (minor) = 28.5 min; 83% ee.
pꢀTolyl (R)ꢀ5ꢀ(3ꢀbromophenyl)ꢀ2ꢀisopropylꢀ2ꢀnitroꢀ5ꢀoxopentanoate (4d). Colorless oil; Yield
197 mg, 88%; IR (neat, cmꢀ1) 3066 (w), 2968 (m), 2935 (m), 2877 (w), 1767 (s), 1693 (s), 1592
(w), 1552 (vs), 1507 (m), 1467 (w), 1441 (w), 1422 (m), 1349 (w), 1264 (w), 1194 (vs), 1168 (m),
1125 (m), 1068 (w), 1019 (w), 784 (m), 739 (w), 680 (w); 1H NMR (400 MHz, CDCl3) δ 1.20 (d, J
= 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H), 2.34 (s, 3H), 2.71ꢀ2.78 (m, 2H), 2.82 (septet, J = 6.8 Hz,
1H), 3.12, 3.23 (ABqdd, J = 17.9, 8.9, 6.4 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.3 Hz,
2H), 7.34 (t, J = 7.9 Hz, 1H), 7.69 (ddd, J = 7.9, 1.9, 0.9 Hz, 1H), 7.86 (ddd collapsed to dt, J = 7.9,
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1.4 Hz, 1H), 8.06 (dd collapsed to t, J = 1.4 Hz, 1H); C NMR (125 MHz, CDCl3) δ 18.0, 18.3,
21.1, 28.5, 33.8, 35.1, 99.3, 120.8, 123.3, 126.7, 130.3, 130.5, 131.2, 136.5, 136.7, 138.2, 147.8,
165.1, 196.5; MS (ES+, Ar) m/z (rel intensity) 473 ([MNa+3]+, 23), 472 ([MNa+2]+, 94), 471
([MNa+1]+, 22), 470 ([MNa]+, 100), 465 (9); HRMS (ES+, Ar) calcd for C21H22BrNO5Na (MNa+)
470.0574, found 470.0570; [α]25 ꢀ8.26 (c 1.0, CHCl3); HPLC: Chiralpack IC (pet ether/iꢀPrOH =
D
97/3, flow rate 0.5 mL/min, λ = 244 nm), tR (major) = 23.0 min, tR (minor) = 30.5 min; 69% ee.
pꢀTolyl 2ꢀethylꢀ2ꢀnitroꢀ5ꢀoxoꢀ5ꢀ(pꢀtolyl)pentanoate (4e). Colorless solid; Yield 467 mg, 85%;
o
mp 75ꢀ77 C; IR (film, cmꢀ1) 2981 (vw), 2368 (vw), 1762 (vs), 1552 (m), 1508 (w), 1356 (vw),
1194 (vs), 1167 (s), 1018 (vw), 799 (w), 738 (m), 511 (vw); 1H NMR (400 MHz, CDCl3) δ 1.07 (t,
J = 7.5 Hz, 3H), 2.35 (s, 3H), 2.39ꢀ2.52 (m, 2H), 2.68, 2.82 (ddd, J = 19.2, 9.5, 6.0 Hz, 2H), 3.02,
3.19 (ddd, 19.2, 9.5, 6.0 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.0
Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 8.4, 21.1, 21.9, 28.3, 28.8, 33.0,
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96.3, 120.8, 126.5, 128.4, 129.6, 130.3, 134.0, 136.6, 144.8, 147.9, 165.6, 197.2; MS (ES+, Ar)
calcd for C21H23NO5Na (MNa+) 392.1468, found 392.1468; [α]25 ꢀ8.59 (c 1.0, CHCl3); HPLC:
D
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Phenomenex Celluoseꢀ1 (pet ether/iꢀPrOH = 97/3, flow rate 0.5 mL/min, λ = 220 nm), tR (major) =
40.6 min, tR (minor) = 43.6 min; 77% ee.
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oꢀTolyl (R)ꢀ5ꢀ(3ꢀbromophenyl)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxopentanoate (5a). Colorless solid; Yield
o
78 mg, 93%; mp 60ꢀ61 C; IR (film, cmꢀ1)3066 (w), 2936 (w), 1767 (s), 1693 (s), 1554 (vs), 1491
(vw), 1448 (vw), 1422 (w), 1389 (vw), 1347 (w), 1300 (vw), 1242 (w), 1222 (w), 1170 (m), 1120
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(s), 1069 (w), 780 (w), 750 (m), 706 (w); H NMR (400 MHz, CDCl3) δ 2.03 (s, 3H), 2.20 (s, 3H),
2.75, 2.84 (ABqdd, J = 15.1, 9.0, 6.0 Hz, 2H), 3.14, 3.21 (ABqdd, J = 17.8, 9.0, 6.0 Hz, 2H), 7.05
(dd, J = 8.0, 1.6 Hz, 1H), 7.15ꢀ7.26 (m, 3H), 7.36 (t, J = 7.9 Hz, 1H), 7.71 (dt, J = 7.9, 1.1 Hz, 1H),
13
7.87 (dt, J = 7.9, 1.1 Hz, 1H), 8.07 (t, J = 1.1 Hz, 1H); C NMR (100 MHz, CDCl3) δ 16.1, 22.5,
31.0, 33.4, 92.2, 121.3, 123.3, 126.7, 127.1, 127.3, 130.1, 130.5, 131.2, 131.7, 136.6, 138.1, 148.6,
165.6, 196.1; MS (ES+, Ar) m/z (rel intensity) 445 ([MNa+3]+, 77), 444 ([MNa+2]+, 100), 443
([MNa+1]+, 72), 442 ([MNa]+, 100), 441 (46), 439 (28), 437(74), 432 (22); HRMS (ES+, Ar) calcd
for C19H18BrNO5Na (MNa+, 100) 442.0261, found 442.0261; [α]25 ꢀ5.32 (c 1.0, CHCl3); HPLC:
D
Chiralpack IC (pet ether/iꢀPrOH = 98/2, flow rate 0.5 mL/min, λ = 216 nm), tR (major) = 29.9 min,
tR (minor) = 31.7 min; 78% ee.
Benzyl (R)ꢀ5ꢀ(3ꢀbromophenyl)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxopentanoate (5b). Colorless sticky oil;
Yield 81 mg, 97%; IR (neat, cmꢀ1) 3065 (w), 1751 (m), 1691 (m), 1552 (vs), 1456 (w), 1422 (vw),
1348 (w), 1300 (w), 1266 (m), 1202 (w), 1184 (w), 1127 (m), 1099 (w), 776 (m), 739 (s), 701 (m);
1H NMR (400 MHz, CDCl3) δ 1.85 (s, 3H), 2.56ꢀ2.70 (m, 2H), 2.95ꢀ3.01 (m, 2H), 5.24 (s, 2H),
7.27ꢀ7.37 (m, 6H), 7.69 (ddd, J = 7.9, 1.8, 0.9 Hz, 1H), 7.76 (ddd collapsed to dt, J = 7.9, 1.4 Hz,
1H), 7.98 (dd collapsed to t, J = 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.6, 30.8, 33.4, 68.7,
92.1, 123.2, 126.7, 128.6, 128.9, 129.0, 130.4, 131.2, 134.5, 136.4, 138.1, 167.0, 196.1; MS (ES+,
Ar) m/z (rel intensity) 445 ([MNa+3]+, 9), 444 ([MNa+2]+, 42), 443 ([MNa+1]+, 9), 442 ([MNa]+,
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43), 393 (5), 302 (16), 301 (100), 279(3), 149 (3); HRMS (ES+, Ar) calcd for C19H18BrNO5Na
(MNa+, 100) 442.0261, found 442.0266; [α]25 +1.71 (c 0.57, CHCl3); HPLC: Chiral cell ODꢀH
D
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(pet ether/iꢀPrOH = 90/10, flow rate 0.5 mL/min, λ = 216 nm), tR (major) = 19.8 min, tR (minor) =
20.8 min; 61% ee.
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Ethyl (R)ꢀ5ꢀ(3ꢀbromophenyl)ꢀ2ꢀmethylꢀ2ꢀnitroꢀ5ꢀoxopentanoate (5c). Colorless solid; Yield 70
o
mg, 98%; mp 58.5ꢀ60 C; IR (film, cmꢀ1) 2987 (w), 2944 (w), 1750 (s), 1684 (s), 1549 (vs), 1466
(w), 1443 (w), 1416 (w), 1389 (w), 1348 (w), 1299 (w), 1267 (m), 1228 (w), 1187 (m), 1132 (w),
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1115 (w), 1013 (w), 773 (s), 745 (w), 680 (w); H NMR (400 MHz, CDCl3) δ 1.29 (t, J = 7.1 Hz,
3H), 1.85 (s, 3H), 2.60, 2.68 (ABqdd, J = 15.0, 8.5, 6.4 Hz, 2H), 3.05, 3.10 (ABqdd, J = 17.8, 8.5,
6.4 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.70 (ddd, J = 8.0, 1.8, 1.0 Hz, 1H),
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7.86 (ddd collapsed to dt, J = 8.0, 1.4 Hz, 1H), 8.06 (dd collapsed to t, J = 1.4 Hz, 1H); C NMR
(100 MHz, CDCl3) δ 14.0, 22.4, 30.8, 33.4, 63.2, 92.1, 123.3, 126.7, 130.5, 131.2, 136.5, 138.1,
167.2, 196.3; MS (ES+, Ar) m/z (rel intensity) 383 ([MNa+3]+, 15), 382 ([MNa+2]+, 99), 381
([MNa+1]+, 17), 380 ([MNa]+, 100), 360 (19), 358 (19), 313(9), 311 (9), 301 (8); HRMS (ES+, Ar)
calcd for C14H16BrNO5Na (MNa+, 100) 380.0104, found 380.0106; [α]25 +1.58 (c 1.0, CHCl3);
D
HPLC: Chiralpack IC (pet ether/iꢀPrOH = 90/10, flow rate 0.5 mL/min, λ = 216 nm), tR (major) =
19.4 min, tR (minor) = 20.5 min; 43% ee.
General procedure for the BaeyerꢀVilliger oxidation of 3h and 4e. To a stirred solution of mꢀ
chloroperbenzoic acid (55ꢀ75%, 11.25 mmol, 1.94 g) in dichloromethane (9 mL) at rt was added
TFA (7.3 mmol, 562 ꢁl) and the stirring was continued for 6 h. A solution of ketone 3h (483 mg,
1.36 mmol) or 4e (502 mg, 1.36 mmol) in dichloromethane (3 mL) was added to the reaction
mixture and stirring was continued for another 14 h at rt. The reaction mixture was diluted with
ether (15 mL), washed with sat aqueous sodium sulphite (20 mL), sodium bicarbonate (20 mL),
brine (10 mL) and dried over anhyd sodium sulfate. The organic layer was concentrated in vacuo
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and the residue was purified by silica gel column chromatography using EtOAcꢀpet ether (5%) as
eluent to afford the ester 6.
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Diꢀpꢀtolyl (R)ꢀ2ꢀmethylꢀ2ꢀnitropentanedioate (6a). Colorless solid; Yield 461 mg, 92%; mp 120
oC; IR (film, cmꢀ1) 2921 (w), 1764 (vs), 1555 (s), 1507 (m), 1446 (vw), 1389 (vw), 1347 (vw),
1296 (vw), 1196 (s), 1167 (m), 1147 (w), 1115 (w), 1046 (vw), 1017 (vw), 942 (vw), 841 (w), 809
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(w); H NMR (500 MHz, CDCl3) δ 2.0 (s, 3H), 2.34 (s, 3H), 2.44 (s, 3H), 2.69ꢀ2.86 (m, 4H), 6.94
(d, J = 8.4 Hz, 2H), 7.0 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.25 Hz, 2H), 7.20 (d, J = 8.25 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 21.1, 21.1, 22.2, 29.3, 31.8, 92.0, 120.7, 121.2, 130.2, 130.4, 135.9,
136.8, 148.0, 148.4, 165.8, 170.6; MS (ES+, Ar) m/z (rel intensity) 394 (MNa+, 100), 241 (45);
HRMS (ES+, Ar) calcd for C20H21NO6Na (MNa+, 100) 394.1261, found 394.1261; [α]25 ꢀ10.98 (c
D
0.5, CHCl3); HPLC: Chiralpack celluloseꢀ2 (pet ether/iꢀPrOH = 90/10, flow rate 0.5 mL/min, λ =
216 nm), tR (minor) = 16.7 min, tR (major) = 18.5 min; 71% ee.
Diꢀpꢀtolyl (R)ꢀ2ꢀethylꢀ2ꢀnitropentanedioate (6b). Colorless solid; Yield 439 mg, 84%; mp 122ꢀ
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124 C; IR (film, cmꢀ1) 2982 (w), 1762 (vs), 1552 (s), 1507 (m), 1355 (vw), 1194 (vs), 1167 (s),
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824 (w), 508 (w); H NMR (400 MHz, CDCl3) δ 1.08 (t, J = 7.5 Hz, 3H), 2.35 (s, 3H), 2.36 (s,
3H), 2.49 (ABqq, J = 14.5, 7.3 Hz, 2H), 2.68ꢀ 2.79 (m, 4H), 6.95 (d, J = 8.5 Hz, 2H), 7.01 (d, J =
8.5 Hz, 2H), 7.19 (t, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H);13C NMR (125 MHz, CDCl3) δ 8.3,
21.0, 21.1, 28.4, 28.8, 29.2, 95.8, 120.8, 121.2, 130.2, 130.4, 135.9, 136.7, 148.0, 148.4, 165.8,
170.6; MS (ES+, Ar) calcd for C21H23NO6Na (MNa+, 100) 408.1418, found 408.1420; [α]25 ꢀ7.110
D
(c 1.0, CHCl3); HPLC: Phenomenex celluloseꢀ2 (pet ether/iꢀPrOH = 90/10, flow rate 1.0 mL/min, λ
= 216 nm), tR (major) = 23.6 min, tR (minor) = 25.5 min; 75% ee.
(R)ꢀ1ꢀBenzylꢀ3ꢀmethylꢀ3ꢀnitropiperidineꢀ2,6ꢀdione (7). To a solution of ester 6 (200 mg, 0.54
mmol) in toluene (5 mL) was added benzylamine (70 ꢁL, 0.64 mmol, 1.2 equiv) and the mixture
was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was dissolved in
EtOAc (15 mL), the organic layer was washed with 1 N HCl (2 × 5 mL), dried over anhyd sodium
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