Enantioselective synthesis of γ-tetrasubstituted nitrosulfonyl carboxylates and amides via L-tert-leucine-derived-squaramide catalyzed conjugate addition of nitrosulfones to acrylates and acrylamides

Article abstract of DOI:10.1039/c4ob00344f

Michael addition of α-nitrosulfones to aryl- and alkyl acrylates and acrylamides proceeds in the presence of 5-10 mol% of an amino acid derived new organocatalyst to provide γ-tetrasubstituted γ-nitro-γ- sulfonyl carboxylates and amides in excellent yield

Full text of DOI:10.1039/c4ob00344f

Organic &
Biomolecular Chemistry
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PAPER
Enantioselective synthesis of γ-tetrasubstituted
nitrosulfonyl carboxylates and amides via L-tert-
leucine-derived-squaramide catalyzed conjugate
addition of nitrosulfones to acrylates and
acrylamides†
Cite this: Org. Biomol. Chem., 2014,
12, 6425
Kalisankar Bera and Irishi N. N. Namboothiri*
Michael addition of α-nitrosulfones to aryl- and alkyl acrylates and acrylamides proceeds in the presence
of 5–10 mol% of an amino acid derived new organocatalyst to provide γ-tetrasubstituted γ-nitro-γ-sulfo-
nyl carboxylates and amides in excellent yields and enantioselectivities. Scale-up of the reaction to multi-
grams, convenient recovery of the catalyst and its recyclability without any drop in yield and selectivity are
attractive features of this methodology.
Received 14th February 2014,
Accepted 26th June 2014
DOI: 10.1039/c4ob00344f
www.rsc.org/obc
tuted chiral center exhibit activities against Alzheimer’s14 and
glaucoma.16 Enantiopure β-alkyl-β-sulfonylhydroxamates are
Introduction
Asymmetric organocatalysis has emerged in the last decade as superior MMP (matrix metalloprotease) and PDE (phosphodi-
a powerful platform for the synthesis of enantioenriched esterase) inhibitors as compared to their racemic counter-
molecules.1 Among various substrate activation strategies, parts.17 The pivotal role of organosulfones in synthesis and
H-bonding involving chiral alcohol,2 amide,3 urea,4 thiourea,3,4 biology prompted the stereoselective synthesis of organic com-
and guanidine5 has proven to be extremely effective. Recently, pounds with a key sulfone functionality.18–28 Michael addition
Rawal et al. reported cinchonine6 and cyclohexanediamine- to vinyl sulfones,18,19 nucleophilic addition of active methyl-
derived7 squaramides as superior H-bond donors paving the ene/methine sulfones,20–22 hydrogenation/reduction,23,24 ally-
way for the introduction of new squaramides derived from lation,25,26 cyclopropanation27 and [3 + 2] cycloaddition28 of
other chiral sources such as cinchona alkaloids8 and various various sulfones are the methods of choice for the diastereo-
chiral 1,2-diamines9 into the realm of H-bond assisted asym- and enantioselective synthesis of organosulfones. However,
metric organocatalysis.10 However, apart from a recent report catalytic asymmetric synthesis of sulfones attached to a chiral
on a Michael addition catalyzed by an amino acid-derived center has received only limited attention.22,25–28 In particular,
squaramide,11 there has been no development, to our knowl- catalytic asymmetric approaches to sulfones attached to a
edge, on the possible application of relatively inexpensive and tetrasubstituted chiral center are rare,22,26,27 and there are only
easily available amino acids as a chiral source for the prepa- three reports on such approaches via Michael addition.22
ration of squaramide catalysts.
In this context, we have recently reported the synthesis of
From the point of view of substrates and products, sulfones enantioenriched α-nitro-δ-ketosulfones via a quinine-squar-
belong to a unique class of compounds with versatile reactivity amide catalyzed conjugate addition of α-nitrosulfones to
as nucleophiles, electrophiles and as an activating/stabilizing enones which were further transformed to γ-tetrasubstituted
group for functional group interconversion.12 Organosulfones γ-sulfonylhydroxamic acid in two steps.29 Herein we describe
also possess a prominent pharmacological profile13 among the first enantioselective synthesis of γ-tetrasubstituted γ-nitro-
which chiral organosulfones have received particular γ-sulfonyl carboxylates and amides via conjugate addition of
attention.14–16 For instance, sulfones attached to a tetrasubsti- α-nitrosulfones to acrylates and acrylamides in the presence of
a new L-tert-leucine derived squaramide catalyst.
Department of Chemistry, Indian Institute of Technology, Bombay, Mumbai 400 076,
India. E-mail: irishi@iitb.ac.in
†Electronic supplementary information (ESI) available: Complete characteriz-
Results and discussion
ation data, CIF for 4c copies of NMR spectra and HPLC profiles. CCDC 971336.
In order to identify the suitable reaction conditions, we com-
menced our studies by evaluating the catalytic activity of cinch-
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ob00344f
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ona alkaloid and amino acid derived bifunctional catalysts in squaramide C5 provided Michael adduct 3a in similar yields,
the reaction between p-tolyl acrylate 1a and (1-nitroethylsulf- the enantioselectivity remained low (entries 2–5). However,
onyl)benzene 2a in mesitylene at room temperature (Fig. 1 and cinchonine-squaramide C6, cinchonidine-squaramide C7 and
Table 1). At the outset, quinine-thiourea C1, recently reported quinine-squaramide C8 provided Michael adduct 3a with
from our laboratory,30 was employed in the Michael addition, better selectivities (61–79% ee, entries 6–8) when compared to
and gratifyingly, the Michael adduct, γ-nitro-γ-sulfonyl ester their thiourea derivatives (entries 1–4). At this juncture,
3a, was obtained in excellent yield (96%) albeit with poor further improvement in the selectivity was explored by employ-
enantioselectivity (48% ee, entry 1). Although the use of other ing amino acid-derived bifunctional catalysts. Thus, although
bifunctional catalysts such as quinine-thiourea C2, cincho- there was no substantial improvement in the yield and the
nidine-thiourea C3, cinchonine-thiourea C4 and quinine- selectivity with L-tert-leucine-derived-thiourea C9 (entry 9), the
performance of the new squaramides C10–12 derived from
different L-amino acids appeared to be very promising. To our
delight, the reaction of nitrosulfone 2a with vinyl ester 1a in
mesitylene at room temperature took place in the presence of
squaramide C10 to afford the Michael adduct 3a in excellent
yield and enantioselectivity (97%, 93% ee, entry 10). However,
other amino acid derived squaramides C11 and C12 did not
improve the selectivity (entries 11 and 12). Further solvent
screening confirmed that mesitylene was the best (entries
13–20) which furnished the Michael adduct 3a in 97% yield
and 93% ee (entry 10). Though lowering the reaction tempera-
ture to 0 °C caused a marginal increase in the selectivity (93%
ee to 94% ee), the rate of the reaction decreased drastically (12
to 48 h, entries 10 and 21). More importantly, a comparable
result (98% yield and 92% ee) was still obtained even when
the catalyst loading was reduced to 5 mol% at room tempera-
ture (entry 22).
Fig. 1 Catalysts screened.
Having optimized the reaction conditions (i.e. 5 mol% of
catalyst C10, in mesitylene at room temperature), we explored
the scope of the aforementioned method by treating a variety
of substituted acrylates 1 with nitrosulfone 2a and the results
Table 1 Catalyst screening and optimization of reaction conditions
are summarized in Table 2. Thus, the reaction of nitrosulfone
Table 2 Scope of acrylates 1
Temp.
(°C)
Time
(h)
Yieldb
(%)
eec
(%)
Entry
Ca
Solvent
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C7
C8
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Toluene
Xylene
PhCF3
CH2Cl2
CHCl3
(CH2)2Cl2
THF
MeCN
Mesitylene
Mesitylene
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
16
16
16
16
12
48
16
96
94
95
93
98
95
95
98
97
97
95
96
96
96
95
86
93
97
91
92
98
98
48
50
52
45d
39
61d
79
78
80
93
89
90
90
91
84
82
85
81
83
53
94
92
Entry
R
Time (h)
3
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
4-MeC6H4
3,5-(Me)2C6H3
4-OMeC6H4
3,4-(OCH2O)C6H3
2-MeC6H4
C6H5
16
16
16
24
16
16
9
10
10
12
14
12
16
16
24
24
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
98
97
94
99
98
97
97
96
99
86
94
94
90
94
91
99
92
91
91
90
84
89
86
85
84
92
94
91
86
93
94
95
9
C9
10
11
12
13
14
15
16
17
18
19
20
21
22e
C10
C11
C12
C10
C10
C10
C10
C10
C10
C10
C10
C10
C10
4-FC6H4
4-ClC6H4
4-BrC6H4
3-NO2C6H4
2-ClC6H4
2-BrC6H4
2-Naphthyl
1-Naphthyl
Me
9
10
11
12
13
14
15
16
rt
Et
a Catalyst. b After silica gel column chromatography. c Determined by a After silica gel column chromatography. b Determined by chiral
chiral HPLC. d Opposite enantiomer. e 5 mol% catalyst.
HPLC.
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2a with a variety of para-substituted aryl acrylates such as 1a,
1c and 1g–i showed that although the substitution does not
have any appreciable influence on the yield (94–99%), the
selectivities are higher for acrylates with electron donating sub-
stituents 1a and 1c (91–92% ee, entries 1 and 3) than for those
with electron withdrawing substituents 1g–i (84–86% ee, entries
7–9). As for ortho-substituted aryl acrylates, the selectivities were
higher for those with electron withdrawing substituents on the
aromatic ring 1k and 1l (91–94% ee, entries 11–12) as compared
to the one with electron donating substituent 1e (84% ee, entry
5). Acrylates with multiple electron donating aryl groups 1b and
1d also gave the products 3b and 3d, respectively, in excellent
yield and selectivity (97–99%, 90–91% ee, entries 2 and 4).
While the yields and selectivities were high for 1-naphthyl acry-
late 3n and alkyl acrylates 3o–p (91–99%, 93–95% ee, entries
14–16), slightly lower selectivities were encountered for phenyl-
and 2-naphthyl acrylates 1f and 1m, respectively (89% and 86%
ee, respectively, entries 6 and 13).
Table 4 Scope of electron deficient olefins 5
Entry 5, EWG, R
Time (h)
6
Yielda (%) eeb (%)
1
2
5a, 4-MeC6H4CO, H
5b, CO2Me, Me
5c, CONMe(OMe), H
5d, CONPh(Me), H
5e, 4-NO2C6H4NHCO, H 72
1
72
48
72
6a 98
6b
6c 91
6d 53
6e
6f
6g 91
96
c
d
—
—
92
96
3
4e
5
c
c
d
—
—
—
—
d
6
5f, CONH2, H
5g, SO2Ph, H
5h, CN, H
72
24
72
7
10
14
8e, f
6h 51
a After silica gel column chromatography. b Determined by chiral
HPLC. c No reaction. d Not determined. e ∼20% of 2a was recovered.
f Due to slow reaction rate, 20 mol% catalyst was used.
leucine-derived squaramide C10 is clearly superior for acrylate
(see Table 1 and also vide infra).
The high yields and enantioselectivities observed for
α-nitrosulfones 3 derived from nitrosulfone 2a and a variety of
acrylates 1 (Table 2) prompted us to investigate the scope of
the reaction further with other sterically and electronically
different nitrosulfones 2b–g (Table 3). Thus, a number of alkyl,
allyl and benzyl substituted nitrosulfones 2b–g were treated
with a representative 1-naphthyl acrylate 1n in the presence of
10 mol% of catalyst C10. Generally, the Michael adducts 4a–f
were obtained in excellent yields and high enantioselectivities
(entries 1–5) except in the case of benzyl nitrosulfone 2g where
the selectivity dropped to 83% (entry 6).
The scope of our methodology was further extended to
other electron deficient alkenes (Table 4). First of all, our
recently reported quinine-squaramide C8 catalyzed reaction of
nitrosulfones 2 with vinyl ketones29 was revisited using our
new tert-leucine-derived squaramide C10. Accordingly, nitro-
sulfone 2a was treated with vinyl ketone 5a under our opti-
mized conditions to afford α-nitro-δ-ketosulfone 6a in
excellent yield (98%) and enantioselectivity (96%) in a short
reaction time (1 h, entry 1) which were comparable to those
reported with C8 (99% yield, 96% ee).29 This shows that while
both catalysts are equally efficient for vinyl ketones, tert-
Subsequently, other Michael acceptors such as crotonate
5b, amides 5c–f, sulfone 5g and nitrile 5h were screened.
While a β-substituted acceptor such as 5b remained unreactive
even after 72 h (entry 2), we were pleased to note the formation
of adduct 6c from Weinreb amide 5c in excellent yield (91%)
and selectivity (92% ee) in 48 h (entry 3). Tertiary amide 5d
also reacted satisfactorily with nitrosulfone 2a to afford adduct
6d in moderate yield (53%) and excellent selectivity (96%,
entry 4). However, secondary and primary amides, 5e and 5f,
respectively, were not amenable to Michael addition of nitro-
sulfone 2a under our experimental conditions (entries 5–6).
Further scope of our methodology investigated using vinyl
sulfone 5g and acrylonitrile 5h led to the formation of adducts
6g and 6h in 91% and 51% yields, respectively, and in low, but
measurable, enantioselectivities (10–14% ee, entries 7–8).
The absolute configuration of the Michael adduct 4c was
unambiguously assigned as R from its single crystal X-ray ana-
lysis (Fig. 2) and that of other Michael adducts 3, 4 and 6 was
assigned by analogy. The proposed mechanism based on
model studies involves deprotonation of nitrosulfone 2 by the
piperidine moiety, stabilization of the nitronate by the squar-
amide moiety of catalyst C10 and activation of ester 1 by the
protonated piperidine moiety (Fig. 2). This is consistent with a
recent report by Pedrosa et al.,31 who suggested a similar
mechanism for the addition of nitromethane to vinyl ketones
through DFT calculations that amino acid derived thiourea
catalyst stabilizes the nitronate nucleophile by hydrogen
bonding while the protonated tertiary amine activates the carb-
onyl group. Although in both models I and II, the squaramide
moiety co-ordinates with the nitro and the sulfone groups, and
the piperidinum moiety coordinates with the ester group,
model I that enables nucleophilic addition of the nitrosulfone
anion from the Re-face to the acrylate ester 1, affording (R)-
nitrosulfone 3, 4 or 6, appears to be favored. This is because
there are no severe steric interactions in this approach and
there exists the possibility of a favorable π–π interaction
Table 3 Scope of nitrosulfones 2a
Entry
2, R1
Time (h)
4
Yieldb (%)
eec (%)
1
2
3
4
5
6
2b, Et
2c, Allyl
2d, n-Bu
2e, n-C5H11
2f, n-C7H15
2g, Benzyl
20
16
36
36
36
36
4a
4b
4c
4d
4e
4f
99
99
97
95
93
98
92
93
92
92
92
83
a Due to slow reaction rate, 10 mol% catalyst was used. b After silica gel
column chromatography. c Determined by chiral HPLC.
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Scheme 2 Synthetic applications of nitrosulfone 4b.
tion, gratifyingly, provided nitrosulfonyl ester 4b in 97% yield
(1.7 g) and 94% selectivity.
The synthetic applications of nitrosulfonylesters 3 and 4
were demonstrated by the transformation of a representative
substrate 4b to carboxylic acid 7 and hydroxamic acid 8
(Scheme 2). Thus, lithium hydroxide mediated hydrolysis of 4b
afforded quaternary γ-nitro-γ-sulfonyl carboxylic acid 7 in 90%
yield. Similarly, hydroxamic acid 8 was synthesized in 82%
yield by treating 4b with hydroxylamine hydrochloride. In our
previous work with vinyl ketones,29 an additional step, Baeyer–
Villiger oxidation of the Michael adducts, was necessary to
obtain the same carboxylate derivatives.
Fig. 2 X-ray structure of 4c and the proposed mechanistic model.
between the phenyl group of sulfone 2 and the aryl group of
catalyst C10. On the other hand, the alternative model II
appears to be disfavored due to severe steric interactions
between the phenyl group of the sulfone and the tert-butyl
group of catalyst C10 as well as due to the absence of the
above mentioned π–π interaction. It may be noted that a mech-
anism in which activation of the ester carbonyl group by the
squaramide moiety and stabilization of the nitronate by the
protonated amine was not considered. This is due to the poor
Michael acceptor ability of acrylate and its activation by the
squaramide moiety did not appear sufficient for the reaction
to proceed well and provide high selectivity. The reason for
lower ee’s observed with catalysts C1–C8 (the best being 79%
with C7, entry 7, Table 1) is attributable to insufficient acti-
vation of the ester carbonyl in the sterically crowded TS.
A practical synthetic utility of our method was demon-
strated by the synthesis of 2.45 g of γ-tetrasubstituted γ-nitro-
γ-sulfonyl ester 4b in 98% yield and 94% ee via Michael
addition of 1.37 g of nitrosulfone 2c to 1.69 g of 1-naphthyl
acrylate 1n in the presence of 5 mol% (140 mg) of catalyst C10
(Scheme 1). Notably, in the reaction mixture, the catalyst C10
existed in the form of a suspension and was completely preci-
pitated out from the mixture on addition of petroleum ether
and then was recovered (up to 80%, 112 mg) by filtration.
Further use of the recovered catalyst C10 in a gram scale reac-
Conclusions
Conjugate addition of α-nitrosulfones to aryl and alkyl acry-
lates as well as unsaturated amides in the presence of
5–10 mol% of an L-tert-leucine-derived squaramide organocata-
lyst afforded quaternary α-nitrosulfones in good to excellent
yields and enantioselectivities. Similar additions to vinyl
sulfone and acrylonitrile, though afforded the products in
moderate to excellent yields, encountered poor selectivity. The
feasibility of scale up of the enantioselective conjugate
addition, recovery of the catalyst by simple filtration and sub-
sequent use of the recovered catalyst in a multi-gram scale
reaction have been successfully demonstrated without any
drop in yield and selectivity. Furthermore, the conjugate
adduct was successfully converted into the corresponding
carboxylic and hydroxamic acid derivatives.
Experimental
General experimental details
The melting points recorded are uncorrected. NMR spectra (1H
and 1H decoupled 13C) 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 Q-TOF
conditions. Enantioselectivities were determined using a chiral
HPLC equipped with a PDA-detector. Specific rotations were
measured for solutions of samples of known concentrations in
CHCl3 using a polarimeter equipped with a sodium vapor
lamp. X-ray data were collected on a diffractometer equipped
with Mo Kα radiation. The structure was solved by direct
Scheme 1 Scale-up reaction.
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methods using shelxs97 and refined by full-matrix least (1)2(1), a = 10.600(4) Å, b = 12.434(5) Å, c = 16.898(6) Å, α = 90°,
squares against F2 using the shelxl97 software. General pro- β = 90°, γ = 90°, V = 2227.2(15) Å3, Z = 4, ρcald = 1.358 Mg m−3
cedures and representative characterization data are given F(000) = 960, λ = 0.71073 Å, μ = 0.186 mm−1, total/unique
,
below. For complete characterization data, see the ESI.†
reflections = 17 141/4049, final R [I > 2σ(I)]: R1 = 0.0381, wR2 =
0.0867, R (all data): R1 = 0.0419, wR2 = 0.0885 Absolute struc-
ture parameter 0.01(7).
General procedure for the synthesis of catalysts C10–12
To a solution of 3-methoxy-4-(arylamino)cyclobut-3-ene-1,2-
(S)-4-Nitro-4-(phenylsulfonyl)hept-6-enoic acid (7). To a
dione (678 mg, 2.00 mmol) in dry DCM (10 ml) was slowly solution of 4b (220 mg, 0.50 mmol) in THF (5.0 ml) and H2O
added a solution of diamine32 (2.00 mmol) in dry DCM (5.0 ml) was added LiOH·H2O (42 mg, 1.0 mmol) and the
(10 ml) at rt. The reaction mixture was stirred for 4 h and the mixture was stirred at room temperature for 15 min. The
resulting precipitate was isolated by filtration. The residue was mixture was acidified with 1 N HCl and extracted with Et2O
washed with ether (10 ml) and dried in vacuo to afford catalyst (3 × 15 ml). The combined extract was dried over anhydrous
C as a white solid.
sodium sulfate. The organic layer was concentrated in vacuo
(S)-3-(3,5-Bis(trifluoromethyl)phenylamino)-4-(3,3-dimethyl-1- and the residue was purified by silica gel column chromato-
(piperidin-1-yl)butan-2-ylamino)cyclobut-3-ene-1,2-dione (C10). graphy using EtOAc–pet ether (90%) as an eluent to afford the
Colorless solid; Yield 736 mg, 75%; mp 257–259 °C; νmax(film)/ acid 7. Red oil; yield 141 mg, 90%; νmax(neat)/cm−1 3069brs,
cm−1 3205m, 3149m, 2942m, 1796m, 1662m, 1576vs, 1464s, 2987brs, 1716vs, 1582m, 1554vs, 1441s, 1334vs, 1315s, 1230vw,
1376vs, 1275vs, 1196m, 1174m, 1127vs, 940w, 882w, 749w, 1151vs, 1082m, 999w, 937m, 854w, 758w, 721w, 688w, 608m,
683w; δH(400 MHz; DMSO-d6) 0.84 (9H, s), 1.15–1.42 (6H, m), 565w, 545w; δH(400 MHz; CDCl3) 2.57–2.69 (2H, m), 2.77–2.96
2.06–2.20 (2H, m), 2.25 (1H, t, J 11.8 Hz), 2.32–2.50 (3H, m), (2H, m), 2.98–3.12 (2H, m), 5.27 (1H, dd, J 16.8, 1.2 Hz), 5.30
3.92 (1H, t, J 8.6 Hz), 7.50–7.58 (2H, br unresolved), 7.99 (2H, (1H, dd, J 10.1 1.2 Hz), 5.67 (1H, ddt, J 16.8, 10.1, 7.0 Hz), 7.62
s), 9.99 (1H, br s); δC(100 MHz; DMSO-d6) 23.9, 25.7, 26.1, (2H, t, J 7.9 Hz), 7.78 (1H, tt, J 7.9, 1.2 Hz), 7.88 (2H, dd, J 7.9,
33.8, 54.2, 58.9, 60.5, 114.6, 117.9, 123.2 (q, JC–F 271.0 Hz), 1.2 Hz); δC(100 MHz; CDCl3) 26.0, 28.5, 36.9, 107.8, 123.0,
131.4 (q, JC–F 33.0 Hz), 141.2, 161.6, 170.7, 180.1, 184.6; HRMS 128.2, 129.5, 131.2, 133.1, 135.7, 177.4; HRMS (ES+, Ar)
(ES+, Ar) calcd for C23H27F6N3O2Na (MNa+, 100), 514.1900, calcd for C13H15NO6SNa (MNa+) 336.0512, found 336.0514;
found 514.1890; [α]2D6 +49.47 (c 0.5 in DMSO).
[α]2D5 +25.00 (c 1.0 in CHCl3).
(S)-N-hydroxy-4-nitro-4-(phenylsulfonyl)hept-6-enamide (8).
To a solution of 4b (317 mg, 0.72 mmol) in EtOH–DCM
(10.5 : 4.5, 15.0 ml) were added HONH2·HCl (187 mg,
General procedure for the addition of nitrosulfone 2 to
acrylate 1 and other electron deficient alkenes 5
To a solution of nitrosulfone 2 (0.4 mmol) and catalyst C10 2.89 mmol) and pyridine (233 μl, 2.89 mmol) and the mixture
(0.02 mmol, 9.9 mg) in mesitylene (0.8 ml) was added 1 or 5 was stirred at room temperature for 12 h. The mixture was
(0.6 mmol) at rt. The reaction mixture was stirred at rt and evaporated in vacuo and the residue was purified by silica gel
monitored by TLC. The residue was purified by silica gel column chromatography using EtOAc–pet ether (60 : 40) as an
column chromatography using pet ether–EtOAc (18–40%) as eluent to afford pure amide 8. Colorless sticky liquid; yield
an eluent.
194 mg, 82%; νmax(neat)/cm−1 3235brvs, 1662vs, 1583m,
(R)-Naphthalen-1-yl 4-nitro-4-(phenylsulfonyl)octanoate (4c). 1554s, 1448m, 1332s, 1315s, 1268m, 1150vs, 1081m, 999m,
Colorless solid; yield 176 mg, 97%; mp 108–109 °C; νmax(film)/ 937m, 894w, 853m, 757m, 739m, 689m, 607m, 543m;
cm−1 2961w, 2935w, 2873w, 1760s, 1646w, 1553s, 1509vw, δH(500 MHz; CDCl3) 2.40–2.52 (1H, m), 2.61–2.74 (2H, m),
1448w, 1385w, 1331s, 1314m, 1259vw, 1225w, 1150vs, 1079w, 2.81–2.90 (1H, m), 2.97, 3.05 (2H, ABqd, J 15.0, 7.1 Hz), 5.22
798m, 775m, 756m, 775s, 756s, 738s, 688m, 619w, 550w; (1H, d, J 15.1 Hz), 5.23 (1H, d, J 12.3 Hz), 5.60–5.70 (1H, m),
δH(400 MHz; CDCl3) 0.93 (3H, t, J 7.3 Hz), 1.16–1.27 (1H, m), 7.61 (2H, t, J 7.6 Hz), 7.76 (1H, t, J 7.6 Hz), 7.88 (2H, d, J
1.31–1.43 (2H, m), 1.54–1.65 (1H, m), 2.33 (2H, ABqdd, J 14.7, 7.6 Hz); δC(125 MHz; CDCl3) 26.7, 27.3, 36.8, 108.4, 123.1,
11.6, 4.8 Hz), 2.72–2.85 (1H, m), 3.02–3.12 (2H, m), 3.25–3.39 128.0, 129.5, 131.2, 133.1, 135.7, 169.8; HRMS (ES+, Ar) calcd
(1H, m), 7.29 (1H, dd, J 7.8, 0.9 Hz), 7.48 (1H, t, J 7.8 Hz), 7.53 for C13H16N2O6SNa (MNa+) 351.0621, found 351.0626;
(1H, td, J 6.9, 1.9 Hz), 7.55 (1H, td, J 6.9, 2.0 Hz), 7.62 (2H, t, J [α]2D5 +26.19 (c 1.0 in CHCl3); HPLC: Chiralpak IC (pet ether–i-
8.1 Hz), 7.77 (1H, tt overlap with dd, J 8.1, 1.1 Hz), 7.77 (1H, PrOH = 70/30, flow rate 1.0 mL min−1, λ = 216 nm), tR (major)
dd overlap with tt, J 7.8, 0.9 Hz) 7.84–7.91 (2H, m), 7.93 (2H, = 11.4 min, tR (minor) = 13.5 min; 94% ee.
dd, J 8.1, 1.1 Hz), confirmed by 1H–1H-COSY spectrum;
δC(100 MHz; CDCl3) 13.8, 22.8, 25.8, 26.3, 29.3, 32.5, 109.0,
118.2, 121.2, 125.5, 126.4, 126.7, 126.8 (×2), 128.3, 129.4, 131.2,
Acknowledgements
133.4, 134.8, 135.6, 146.5, 170.5; HRMS (ES+, Ar) calcd for
C24H25NO6SNa (MNa+) 478.1295, found 478.1308; [α]2D5 +19.98 INNN thanks DAE India for financial assistance. KSB thanks
(c 1.0 in CHCl3); HPLC: Lux Cellulose-1 (pet ether–i-PrOH = CSIR India for a senior research fellowship. The authors
80/20, flow rate 1.0 mL min−1, λ = 250 nm), tR (major) = thank Dr Jeyashree Ramiya, Director, Chiral Management, San
18.7 min, tR (minor) = 16.6 min; 92% ee; Selected X-ray data: Ramon, CA, USA for her support and the anonymous reviewers
C24 H25 N O6 S, M = 455.51, orthorhombic, space group P2(1)2- for their valuable suggestions.
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Organic & Biomolecular Chemistry
W. Raimondi, D. Bonne, T. Constantieux, Y. Coquerel and
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