Synthesis of α,β-unsaturated δ-lactones by vinyl acetate mediated asymmetric cross-aldol reaction of acetaldehyde: Mechanistic insights

Article abstract of DOI:10.1002/ejoc.201402551

A tandem asymmetric cross-aldol reaction involving the in situ generation of acetaldehyde from vinyl acetate has been developed that may resolve the challenges associated with the handling of acetaldehyde. The simple protocol, mild reaction conditions and unique harmony of an organocatalyst with a biocatalyst make this method a valuable tool for the synthesis of asymmetric β-hydroxy aldehydes. By using this methodology we have accessed α,β-unstaurated δ-lactones as well as isochromenones with high enantioselectivities from both asymmetric β-hydroxy aldehydes and ketones. Systemic density functional theory (DFT) studies were also performed to gain mechanistic insights into the role of hydrogen bonding in the asymmetric cross-aldol reaction of acetaldehyde and in the key cis/trans isomerisation step in the synthesis of δ-lactones. Copyright

Full text of DOI:10.1002/ejoc.201402551

FULL PAPER
DOI: 10.1002/ejoc.201402551
Synthesis of α,β-Unsaturated δ-Lactones by Vinyl Acetate Mediated
Asymmetric Cross-Aldol Reaction of Acetaldehyde: Mechanistic Insights
Manjeet Kumar,[a] Arvind Kumar,[a,b] Masood Rizvi,[c] Manoj Mane,[d] Kumar Vanka,[d]
Subhash C. Taneja,[a] and Bhahwal Ali Shah*[a,b]
Keywords: Asymmetric catalysis / Aldol reactions / Reaction mechanisms / Lactones
A tandem asymmetric cross-aldol reaction involving the in
situ generation of acetaldehyde from vinyl acetate has been
developed that may resolve the challenges associated with
as well as isochromenones with high enantioselectivities
from both asymmetric β-hydroxy aldehydes and ketones.
Systemic density functional theory (DFT) studies were also
the handling of acetaldehyde. The simple protocol, mild re- performed to gain mechanistic insights into the role of
action conditions and unique harmony of an organocatalyst
with a biocatalyst make this method a valuable tool for the
synthesis of asymmetric β-hydroxy aldehydes. By using this
methodology we have accessed α,β-unstaurated δ-lactones
hydrogen bonding in the asymmetric cross-aldol reaction of
acetaldehyde and in the key cis/trans isomerisation step in
the synthesis of δ-lactones.
Michael[9,10] and alkynylation[11] reactions, which have
served as an impetus to accessing scaffolds of biological sig-
nificance, for example, rolipram,[12,13] baclofen,[14] pregaba-
lin,[15,16] convolutamydines[17] and (+)-tetrahydropyreno-
phorol.[18] However, the use of acetaldehyde has proven dif-
ficult as a result of its tendency to polymerise, its low-boil-
ing point and the formation of side-products. To address
this issue, paraldehyde has recently been used as a source
of acetaldehyde in Michael reactions. Therefore we envis-
aged the use of vinyl acetate (a stable liquid generally em-
ployed in trans-esterification reactions and considered as
environmentally benign) as an alternative source of acetal-
dehyde for enantioselective cross-aldol reactions. Our ef-
forts led to the identification of an organocatalyst capable
of directing aldol reactions in high yields and enantio-
selectivities. The reactions possibly involve the lipase-cata-
lysed in situ hydrolysis of vinyl acetate to generate acetalde-
hyde, followed by organocatalysed aldol reactions with aro-
matic aldehydes.
Introduction
The synthesis of asymmetric β-hydroxy carbonyl com-
pounds has enjoyed its lion’s share of problems addressed
throughout the history of organic synthesis. Asymmetric β-
hydroxy carbonyl compounds are largely accessed through
the aldol reaction,[1] which is arguably the simplest and
most economic approach to C–C bond formation,[2] and
has flourished over the years as a powerful tool for the syn-
thesis of stereochemically complex molecules.[3,4] However,
despite many advances, acetaldehyde, the simplest aldehyde,
largely remains unexplored in this reaction owing to diffi-
culties in its handling and dual reactivity, that is, it may act
as an electrophile as well as a nucleophile. Following the
pioneering work of List[5] and Hayashi and their co-
workers,[6] a myriad of reports have appeared exploiting
acetaldehyde as a nucleophile for cross-aldol,[7] self-aldol,[8]
We also successfully extended our methodology to the
asymmetric synthesis of α,β-unsaturated δ-lactones, a motif
that is a characteristic underlying element of many antipro-
liferative agents, immunosuppressants and inhibitors of dif-
ferent enzymes.[19] In addition, α,β-unsaturated δ-lactones
are a part of a wide variety of natural scaffolds, for example,
fostriecin, callystatin, (R)-goniothalamin, asperlin, lepto-
mycin B and kazusamycin A,[20] or serve as intermediates
in the synthesis of bioactive molecules, such as tetra-
hydrolipstatin[21] and clavulactone.[22] Owing to their impor-
tance, many methods have been developed for their synthe-
[a] Natural Product Microbes, CSIR – Indian Institute of
Integrative Medicine,
Canal Road, Jammu-Tawi 180001, India
E-mail: bashah@iiim.ac.in
www.iiim.res.in
[b] Academy of Scientific and Innovative Research,
Canal Road, Jammu-Tawi 180001, India
[c] Department of Chemistry, University of Kashmir,
190006, India
[d] Physical Chemistry Division, National Chemical Laboratory,
Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008,
India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402551.
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B. A. Shah et al.
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sis, such as the hetero-Diels–Alder (HDA) reactions of the fluoromethyl-substituted diarylprolinol silyl ether (D) re-
Brassard diene with aldehydes or ketones,[23–26] solid-phase sulted in a significant decrease in yield (entry 4, Table 1).
Diels–Alder cycloaddition,[27] the annulation of open-chain We also examined the effect of various lipases, namely
precursors,[28] N-heterocyclic-carbene-catalysed reactions of CAL-B, ABL, PPL and PSL, on the reaction, only to find
α-bromo α,β-unsaturated aldehydes,[29] reactions of homo- N-435 to be the lipase of choice. Notably, N-435 leads to a
allylic alcohols with the lithium enolate of methyl acetate[30] better rate of reaction and enantioselectivity than CAL-B
and enzymatic cyclisation[31] (Figure 1). Intriguingly, most (recombinant from Aspergillus oryzae) in iPrOH (entries 3
of these methods suffer from poor enantioselectivity and and 5, Table 1). In contrast to the common assumption that
substrate scope, and often employ environmentally hazard- the use of alcoholic solvents results in low enantio-
ous metal catalysts. The biggest advantage of our method is selectivity, this reaction in methanol, ethanol, isobutanol
that virtually any aldol product with a β-hydroxy carbonyl and n-butanol gave the corresponding product with high
moiety can be converted enantioselectively into an α,β-un- enantioselectivity, which suggests its possible use in the de-
saturated δ-lactone, which may be subsequently used for the velopment of green methodologies.
synthesis of enantiopure valerolactones.[32] In this work we
have also performed a systemic density functional theory
(DFT) study to gain an understanding of the mechanism
of enantioselective cross-aldol reactions of acetaldehyde as
Table 1. Effect of various lipases, catalysts and solvents on the aldol
reaction of vinyl acetate and p-nitrobenzaldehyde.
well as the formation of lactones, which is of particular in-
trigue because it involves the thermal isomerisation of the
double bond.
Entry Catalyst Lipase[a]
Solvent[b] Time [h] Yield[c] [%] ee [%]
1
2
3
4
5
6
7
8
A
B
C
D
C
C
C
C
C
C
C
C
N-435
N-435
N-435
N-435
CAL-B
ABL
PPL
PSL
N-435
N-435
N-435
N-435
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
MeOH
EtOH
72
96
48
72
96
120
120
96
72
72
20
Ͻ10
94
Ͻ10
28
Ͻ10
Ͻ10
25
60
72
86
88
15
–
95
–
72
–
–
64
92
90
92
95
9
10
11
12
Figure 1. Methods for the synthesis of α,β-unsaturated δ-lactones.
iBuOH
nBuOH
72
72
[a] Lipase: 1 mg per mmol of aromatic aldehyde. [b] Solvent/vinyl
acetate (1:1). [c] Isolated yields.
Results and Discussions
The aldol reaction of p-nitrobenzaldehyde and vinyl acet-
ate (10 equiv.) as a test reaction was carried out in the pres-
Having optimised the conditions, we next investigated the
ence of lipase Novozym435 (N-435, 0.5%, w/w). From our substituent effects of the aldehydes on the aldol reaction to
previous work we knew that proline as an organocatalyst in identify its scope and limitations (Table 2). The reactions
tandem with lipase can catalyse vinyl acetate mediated aldol with aromatic aldehydes bearing electron-withdrawing
reaction but with low enantioselectivity, and reaction with groups (entries 1–3, Table 2) proceeded smoothly to afford
N-435 in the absence of catalyst gives the aldol product in the corresponding aldol products in excellent yields and
25% yield.[33] Initially, we examined the impact of catalysts enantioselectivities. Halogen-substituted benzaldehydes (en-
on the enantioselectivity of the resulting products. The reac- tries 4–8, Table 2) also gave the corresponding products in
tion with diphenylprolinol (A) and diphenylprolinol silyl good yields and with excellent enantioselectivities. Al-
ether (B) with lipase N-435 in 2-propanol (iPrOH) gave the though the reaction of the electron-donating aldehyde p-
corresponding products in low yields and enantioselectivit- methoxybenzaldehyde proceeded slowly and in low yield, a
ies. The reaction with the trifluoromethyl-substituted di- good enantioselectivity was observed (entry 9, Table 2). On
arylprolinol (C) provided the cross-aldol product in good the other hand, reactive aldehydes, such as heteroaromatic
yield and high enantioselectivity (entry 3, Table 1). The tri- and pentafluoro-substituted aromatic aldehydes (entries 10–
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Synthesis of α,β-Unsaturated δ-Lactones
13, Table 2), were found to be suitable electrophiles, giving
high enantioselectivities and yields. Naphthaldehyde (en-
try 14, Table 2), which is less active towards cross-aldol re-
actions, also provided the corresponding product with high
enantiopurity. Because we had been using the R isomer of
the catalyst, we were interested to know whether the reac-
tion system could be successfully extended to the S isomer.
Therefore we carried out the reactions of p-nitro- and m-
nitrobenzaldehyde in the presence of catalyst E (S isomer
of catalyst C, Figure 2) under similar conditions. As ex-
pected, the reactions resulted in the formation of the corre-
sponding products with comparably high enantiopurities
and yields (entries 15 and 16, Table 2).
Table 2. Aldol reactions of various aromatic aldehydes with vinyl
acetate.
Entry
R
Product
t [h] Yield[a] [%] ee [%]
1
2
3
4
5
6
7
8
4-NO2C6H4
2-NO2C6H4
3-NO2C6H4
3-BrC6H4
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
48
48
48
96
96
72
72
72
108
72
96
72
48
120
48
48
94
92
89
66
74
76
75
78
60
84
80
74
80
64
95
82
95
97
93
99
87
99
99
99
94
99
90
90
99
94
94
94
3-ClC6H4
2,4-Cl2C6H4
2,4-F2C6H4
3-Br-4-FC6H4
4-CH3OC6H4
quinolin-4-yl
quinolin-2-yl
4-pyridyl
2,3,4,5,6-pentafluoro
1-naphthyl
4-NO2C6H4
9
10
11
12
13
14
15
16
Figure 2. Optimised structures of the different transitions states for
the cross-aldol reaction of acetaldehyde at the TZVP/PBE/B3LYP
level of theory.
[b]
[b]
3-NO2C6H4
[a] Yields obtained after the reduction of the aldol product. [b]
Reaction was performed with catalyst E and resulted in the cross-
aldol product with the R configuration.
nificant observation from the energy-minimised molecular
orientations is that the bulky aryl rings discriminate the en-
antiofaces on the basis of steric hindrance; in the attack at
the Re face, the aryl rings of the aldehyde and catalyst are
sufficiently far apart for a stable adduct of low energy to
Furthermore, to shed light on the mechanism of the reac- form (20.9 kcal/mol), whereas in the case of the approach
tion we performed DFT calculations. The reaction starts on the Si face, the aromatic groups of the two substrates
with the interaction between acetaldehyde and catalyst E to are sufficiently close that they interact sterically leading to
form TS1 (32.1 kcal/mol), which tautomerises to the ener- a less stable adduct with a higher energy (25.6 kcal/mol),
getically more stable enamine (11.8 kcal/mol; see Figure S1 and hence this approach is less favourable for bond forma-
in the Supporting Information). The resultant enamine tion. The results of the DFT studies are in agreement with
adopts two different configurations, with the anti-enamine the experimental results (Figure 2).
more stable than the syn-enamine. Furthermore, each en-
Our next aim was to extend this methodology to the syn-
amine intermediate can approach the aldehyde in two dif- thesis of enantiopure α,β-unsaturated δ-lactones. Thus,
ferent ways, resulting in four different transition states: anti- first, the reduced cross-aldol product 2 was protected by
Re face (TS1), anti-Si face (TS2), syn-Re face (TS3) and using TBDMSCl and imidazole in DCM at 0 °C to give the
syn-Si face (TS4; Figure 2). On the basis of the DFT calcu- TBDMS-protected diol, which was then selectively depro-
lations, we propose that the transition state involves tected by using HF·pyridine in THF and subsequently
hydrogen bonding between the acidic OH group of the tri- oxidised by using Dess–martin periodinane in DCM. The
fluoromethyl-substituted catalyst E and the carbonyl of resulting product was then subjected to Wittig reaction with
acetaldehyde, which activates the substrate for reaction as (tert-butoxycarbonylmethylene)triphenylphosphorane
in
well as controlling the direction of approach. The other sig- DCM, followed by deprotection of the secondary alcohol
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B. A. Shah et al.
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by using TBAF in THF to give 3. Compound 3 was depro-
The synthesis of α,β-unsaturated δ-lactones involves a
tected with TFA, which, after drying, was stirred at 70 °C very important step, namely, the thermally induced trans/cis
for 4 h in the presence of p-dimethylaminopyridine isomerisation of the alkene. Therefore we envisioned per-
(DMAP) and 1-ethyl-3-(3-dimethylaminopropyl)carbodi- forming DFT calculations to gain an insight into the mech-
imide (EDCI) to accomplish the synthesis of δ-lactones anistic aspects of this step. The calculations revealed that
4a–d [Scheme 1, Equation (I)]. The methodology with β-hy- the rate of the lactonisation reaction mainly depends upon
droxy ketone gave access to δ-lactones in two high-yielding the concentration of the Z isomer as well as the relative rate
steps, circumventing the need for any protection/deprotec- of cyclisation compared with the reverse isomerisation of
tion [4e–i, Scheme 1, Equation (II)]. The methodology was the E isomer to the Z isomer during the progress of the
also used for the synthesis of asymmetric isochromenone reaction. The availability of the requisite Z isomer of the
4k and hence can be used to synthesize a library of isochro- alkene is best achieved by heating at 70 °C because the E
menones, which are of immense biological importance, and isomer cannot be populated thermally due to the high EǞZ
indeed a number of methods over the years have appeared thermal isomerisation barrier (3.3 kcal/mol). Thus, by pro-
for their synthesis.[34,35] It is also imperative to mention here viding constant heating at 70 °C the Z isomer state estab-
that these α,β-unsaturated δ-lactones are also precursors for lishes a high constant Z/E ratio that favours the formation
the synthesis of δ-valerolactones.[32]
of the cyclised product (Figure 3).
Scheme 1. Reagents and conditons: a) imidazole, TBDMSCl, CH2Cl2, 0 °C to r.t.; b) HF/pyridine, THF; c) Dess–Martin periodinane,
CH2Cl2, r.t.; d) (tert-butoxycarbonylmethylene)triphenylphosphorane, CH2Cl2, –10 °C; e) TBAF, THF; f) TFA, CH2Cl2, 0 °Cto r.t.;
g) EDCI, DMAP, CH2Cl2, 70 °C. *Aromatic aldehydes (1 mmol), acetone (10 equiv.), d-proline (20 mol-%), DMSO, r.t.; **p-nitrobenzal-
dehyde (1 mmol), cyclohexanone (10 equiv.), cinchona amine (10 mol-%), TfOH (15 mol-%), r.t.. Note: * and ** asterisked compounds
were synthesised by Equation (II); the asymmetric β-hydroxy ketones were synthesised following reported protocols.[36] The given yields
correspond to overall yields of lactones 4a–k.
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Synthesis of α,β-Unsaturated δ-Lactones
Figure 3. DFT-calculated free energy surfaces for the lactonisation process [kcal/mol].
(151 mg, 1.0 mmol) in a sealed glass tube and agitated at room
temperature. After 24 h, further vinyl acetate (276 μL, 4.0 mmol)
and 2-propanol (306 μL, 4.0 mmol) were added to the reaction mix-
Conclusions
The inherent challenges associated with the handling of
acetaldehyde can be addressed by using vinyl acetate as its ture. The reaction mixture was agitated for 48 h, then cooled to
0 °C, and then MeOH (2.0 mL) and NaBH4 (226.5 mg, 6 mmol)
were added. The mixture was stirred for a further 1 h at 0 °C. The
reaction was quenched with pH 7.0 phosphate buffer solution, the
organic materials were extracted with ethyl acetate (3ϫ), and then
the combined organic extracts were dried with anhydrous sodium
sulfate and concentrated under vacuum. Purification by column
chromatography gave (S)-1-(4Ј-nitrophenyl)propane-1,3-diol (1a) in
94% yield and 95% ee.
precursor. The β-hydroxy carbonyls generated by the cross-
aldol reaction can give facile access to libraries of α,β-un-
saturated δ-lactones in high yields and enantioselectivities.
DFT calculations have provided mechanistic support for
the role of hydrogen bonding between catalyst and aldehyde
in the asymmetric aldol reactions and also for the cis/trans
isomerisation step that occurs in the lactonisation reactions,
thereby expanding our knowledge of their mechanisms.
Further efforts to amplify the scope of vinyl acetate in other
organocatalytic reactions are underway.
(S)-1-(2,4-Dichlorophenyl)propane-1,3-diol: (Table 2, entry 6): 1H
NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 8.4 Hz, 1 H), 7.26 (d,
J = 2.1 Hz, 1 H), 7.19 (dd, J = 8.4, 2.0 Hz, 1 H), 5.18 (dd, J = 9.0,
3.0 Hz, 1 H), 3.87–3.41 (m, 1 H), 3.65 (m, 1 H), 1.82–1.74 (m, 1
H), 1.67–1.59 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
140.2, 133.4, 131.8, 129.0, 128.1, 127.4, 70.8, 61.7, 38.2 ppm.
Experimental Section
General Methods: 1H and 13C NMR spectra were recorded with
400 and 500 MHz spectrometers with TMS as internal standard.
Chemical shifts (δ) are expressed in parts per million (ppm) and J
values are given in Hz. The reagents and solvents used were mostly
AR-grade. Aluminium plates coated with silica gel were used for
TLC. LC-ESI-MS/MS analysis was carried out with a Triple-Quad
LC–MS/MS spectrometer (model 6410).
(S)-1-(2,4-Difluorophenyl)propane-1,3-diol: (Table 2, entry 7): 1H
NMR (400 MHz, CDCl3): δ = 7.60–7.58 (m, 1 H), 7.30–7.27 (m, 1
H), 7.09 (t, J = 8.4 Hz, 1 H), 4.97–4.93 (m, 1 H), 3.91–3.85 (m, 2
H), 1.98–1.94 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
140.4, 134.7, 132.1, 129.7, 129.1, 127.0, 68.8, 61.3, 38.8 ppm.
(S)-1-(3-Bromo-4-fluorophenyl)propane-1,3-diol: (Table 2, entry 8):
1H NMR (400 MHz, CDCl3): δ = 7.60 (dd, J = 6.7, 1.9 Hz, 1 H),
7.31–7.26 (m, 1 H), 7.08 (t, J = 8.5 Hz, 1 H), 4.93–4.89 (m, 1 H),
3.87–3.77 (m, 2 H), 1.92–1.85 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.3, 156.4, 143.1, 130.2, 126.3, 115.8, 108.0, 69.9,
69.2, 58.9, 55.5, 49.2, 41.2 ppm.
General Procedure for the Cross-Aldol Reaction: Vinyl acetate
(276 μL, 4.0 mmol) was added to a mixture of trifluoromethyl-sub-
stituted diarylprolinol (C; 78 mg, 15 mol-%), 2-propanol (306 μL,
4.0 mmol), Novozym435 lipase (1 mg), and p-nitrobenzaldehyde
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B. A. Shah et al.
(S)-1-(Quinolin-4-yl)propane-1,3-diol: (Table 2, entry 10): H NMR (S)-3-[(tert-Butyldimethylsilyloxy)-3-(4-nitrophenyl)propan-1-ol: A
FULL PAPER
1
(400 MHz, CDCl3): δ = 8.82 (d, J = 4.4 Hz, 1 H), 8.09–8.06 (m, 2
solution of HF/pyridine was prepared by the addition of
H), 7.75–7.69 (m, 2 H), 7.61–7.56 (m, 1 H), 5.72–5.69 (m, 1 H),
HF·pyridine (1.3 g) to pyridine (3.1 mL) and THF (10 mL). This
3.92–3.83 (m, 2 H), 2.16–2.14 (m, 1 H), 1.95–1.93 (m, 1 H) ppm. solution (6 mL) was added to a solution of (S)-1-[1,3-bis(tert-butyl-
13C NMR (100 MHz, MeOD): δ = 154.3, 151.1, 148.6, 130.7, 129.8,
127.9, 126.9, 124.7, 118.7, 67.5, 59.8, 42.3 ppm.
dimethylsilyloxy)propyl]-4-nitrobenzene (700 mg, 1.65 mmol) in
THF (24 mL) and the mixture was stirred for 18 h at room tem-
perature. The reaction was quenched by the addition of a saturated
solution of NaHCO3, and the aqueous layer was extracted with
Et2O. The organic layer was dried with Na2SO4, the solvent was
removed in vacuo and the residue was purified by column
chromatography to give 480 mg (1.54 mmol, 94%) of (S)-3-(tert-
butyldimethylsilyloxy)-3-(4-nitrophenyl)propan-1-ol as a colourless
liquid. [α]2D3 = –38.0 (c = 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 8.32 (d, J = 8.6 Hz, 2 H), 7.63 (d, J = 8.5 Hz, 2 H),
5.17 (dd, J = 7.0, 4.7 Hz, 1 H), 3.93–3.76 (m, 2 H), 2.05 (m, 2 H),
1.03 (s, 9 H), 0.21 (s, 3 H), 0.01 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 152.4, 147.1, 126.5, 123.7, 77.3, 77.1, 76.8, 72.6, 59.5,
42.3, 25.8, 18.1, –4.7, –5.1 ppm.
1
(S)-1-(Quinolin-2-yl)propane-1,3-diol: (Table 2, entry 11): H NMR
(400 MHz, CDCl3): δ = 8.19 (d, J = 8.5 Hz, 1 H), 8.08 (d, J =
8.4 Hz, 1 H), 7.84 (d, J = 8.1 Hz, 1 H), 7.77–7.72 (m, 1 H), 7.59–
7.54 (m, 1 H), 7.39 (d, J = 8.5 Hz, 1 H), 5.15 (dd, J = 8.8, 3.5 Hz,
1 H), 4.02–3.87 (m, 2 H), 2.28–2.20 (m, 1 H), 1.99–1.89 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.5, 146.3, 137.2,
129.8, 128.4, 127.6, 127.4, 125.4, 118.2, 72.3, 60.1, 39.9 ppm.
General Procedure for the Silyl Protection of the Reduced Cross-
Aldol Products
(S)-1-[1,3-Bis(tert-butyl-dimethylsilyloxy)propyl]-4-nitrobenzene:
Imidazole (431 mg, 6.33 mmol) followed by tert-butyldimethylsilyl
chloride (838 mg, 5.57 mmol) were added to a rapidly stirred solu-
tion of (S)-1-(4-nitrophenyl)propane-1,3-diol (500 mg, 2.53 mmol)
in dichloromethane. The resulting mixture was stirred at room tem-
perature until TLC showed complete consumption of the starting
material, and the reaction was quenched by the addition of water.
The aqueous layer was extracted with Et2O and the organic extract
was washed with brine. The organic layer was dried with Na2SO4,
the solvent was removed in vacuo and the residue was purified
by column chromatography to give 950 mg (2.23 mmol, 88%) of a
colourless liquid. [α]2D3 = –7.2 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.13 (d, J = 8.7 Hz, 2 H), 7.43 (d, J =
8.6 Hz, 2 H), 4.93 (dd, J = 7.9, 4.7 Hz, 1 H), 3.70 (m, 1 H), 3.50
(m, 1 H), 1.84 (m, 1 H), 1.66 (m, 1 H), 0.84 (s, 18 H), –0.02 (m, 9
H), –0.18 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.3,
145.8, 125.4, 122.4, 69.7, 57.8, 42.7, 24.7, 24.6, 24.5, 17.1, 17.0,
16.9, –4.1, –4.2, –5.8, –6.2, –6.4, –6.5 ppm.
(S)-3-(tert-Butyldimethylsilyloxy)-3-(3-nitrophenyl)propan-1-ol:
Yield 92%. [α]2D3 = –40.0 (c = 1.00, CHCl3). H NMR (400 MHz,
1
CDCl3): δ = 8.33 (s, 1 H), 8.24 (dd, J = 8.1, 1.2 Hz, 1 H), 7.80 (d,
J = 7.7 Hz, 1 H), 7.63 (t, J = 7.9 Hz, 1 H), 5.18 (dd, J = 7.2, 4.7 Hz,
1 H), 3.85 (m, 2 H), 2.06 (m, 2 H), 1.03 (s, 9 H), 0.21 (s, 3 H),
–0.01 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.2, 147.2,
131.8, 129.3, 122.2, 120.7, 72.5, 59.5, 42.3, 25.7, 18.0, –4.6,
–5.1 ppm.
(S)-3-(tert-Butyldimethylsilyloxy)-3-(2-nitrophenyl)propan-1-ol:
Yield 88%. [α]2D3 = +41.2 (c = 1.00, CHCl3). H NMR (400 MHz,
1
CDCl3): δ = 8.07 (dd, J = 17.7, 8.0 Hz, 2 H), 7.84 (t, J = 7.6 Hz,
1 H), 7.61 (dd, J = 11.4, 4.1 Hz, 1 H), 5.73 (dd, J = 8.0, 3.3 Hz, 1
H), 3.98 (m, 2 H), 2.32 (m, 1 H), 2.10 (m, 1 H), 1.08 (s, 9 H), 0.25
(s, 3 H), –0.00 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
147.0, 140.4, 133.2, 128.7, 128.0, 124.1, 68.9, 60.2, 41.5, 25.7, 18.0,
–4.9, –5.3 ppm.
(S)-3-(tert-Butyldimethylsilyloxy)-3-(2,4-dichlorophenyl)propan-1-
ol: Yield 92%. [α]2D3 = –40.1 (c = 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.65 (d, J = 8.4 Hz, 1 H), 7.45 (d, J = 2.1 Hz, 1 H),
7.40 (m, 1 H), 5.43 (m, 1 H), 3.86 (m, 2 H), 2.15 (m, 1 H), 2.94
(m, 1 H), 1.02 (s, 9 H), 0.21 (s, 3 H), –0.00 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 140.6, 133.3, 131.3, 128.9, 128.8, 127.2,
70.1, 60.1, 40.0, 25.7, 18.0, –4.8, –5.2 ppm.
(S)-1-[1,3-Bis(tert-butyldimethylsilyloxy)propyl]-3-nitrobenzene:
Yield 89%. [α]2D3 = –7.5 (c = 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 8.16 (s, 1 H), 8.05 (m, 1 H), 7.60 (d, J = 7.6 Hz, 1 H),
7.44 (t, J = 7.9 Hz, 1 H), 4.93 (dd, J = 7.8, 4.8 Hz, 1 H), 3.70 (m,
1 H), 3.49 (m, 1 H), 1.86 (m, 1 H), 1.71 (m, 1 H), 0.86 (s, 18 H),
0.01 (s, 9 H), –0.18 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 147.5, 147.2, 131.2, 128.3, 121.0, 119.9, 69.9, 58.2, 43.3, 25.1,
25.0, 17.4, 17.4, –5.3, –5.7, –6.0, –6.0 ppm.
General Procedure for the Oxidation of the Primary Alcohols
(S)-3-[(tert-Butyldimethylsilyloxy)-3-(4-nitrophenyl)propanal: Dess–
Martin periodinane (851 mg, 2.00 mmol) was added to a cooled
(0 °C) solution of (S)-3-(tert-butyldimethylsilyloxy)-3-(4-ni-
trophenyl)propan-1-ol (500 mg, 1.61 mmol) in dry CH2Cl2
(20 mL). The mixture was stirred at room temperature for 1 h and
then treated with a saturated solution of NaHCO3 and 20% aque-
ous solution of Na2S2O3. The aqueous layer was extracted with
Et2O and the organic extract was washed with brine. The organic
layer was dried with Na2SO4, the solvent removed in vacuo, and
the residue was purified by column chromatography to give 450 mg
(1.45 mmol, 91 %) of (S)-3-(tert-butyldimethylsilyloxy)-3-(4-ni-
trophenyl)propanal as a colourless liquid. [α]2D3 = –48.2 (c = 1.00,
(S)-1-[1,3-Bis(tert-butyldimethylsilyloxy)propyl]-2-nitrobenzene:
1
Yield 92%. [α]2D3 = +7.9 (c = 1.00, CHCl3). H NMR (400 MHz,
CDCl3): δ = 7.81 (dd, J = 12.6, 8.0 Hz, 2 H), 7.57 (t, J = 7.6 Hz,
1 H), 7.35 (t, J = 7.7 Hz, 1 H), 5.42 (dd, J = 8.8, 2.8 Hz, 1 H), 3.80
(m, 1 H), 3.70 (m, 1 H), 1.95 (m, 1 H), 1.78 (m, 1 H), 0.85 (m, 18
H), 0.03 (m, 9 H), –0.22 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 146.1, 140.1, 131.7, 127.6, 126.4, 122.7, 65.5, 58.4,
42.0, 24.7, 24.6, 24.5, 17.1, 16.9, –6.1, –6.3, –6.4, –6.5 ppm.
(S)-1-[1,3-Bis(tert-butyldimethylsilyloxy)propyl]-2,4-dichlorobenz-
ene: Yield 84%. [α]2D3 = –7.8 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.45 (d, J = 8.4 Hz, 1 H), 7.26 (d, J =
2.1 Hz, 1 H), 7.19 (dd, J = 8.4, 2.0 Hz, 1 H), 5.18 (dd, J = 9.0,
3.0 Hz, 1 H), 3.73 (m, 1 H), 3.60 (m, 1 H), 1.78 (m, 1 H), 1.63 (m,
1 H), 0.84 (m, 18 H), 0.01 (s, 3 H), –0.20 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 142.1, 132.8, 131.5, 128.8, 128.7, 127.1,
67.4, 59.2, 53.4, 42.2, 25.8, 25.8, 25.7, 18.1, 18.1, –4.8, –5.2, –5.30,
–5.36 ppm.
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 9.70 (t, J = 1.7 Hz, 1
H, CHO), 8.13 (d, J = 8.7 Hz, 2 H), 7.47 (d, J = 8.7 Hz, 2 H), 5.27
(dd, J = 7.7, 4.3 Hz, 1 H), 2.81 (m, 1 H), 2.61 (m, 1 H), 0.81 (s, 9
H), 0.00 (s, 3 H), –0.19 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 199.9, 151.3, 147.4, 126.5, 123.9, 69.6, 53.7, 25.6, 18.0, –4.7,
–5.1 ppm.
General Procedure for the Selective Deprotection of the Primary
Silyl Ethers
(S)-3-(tert-Butyldimethylsilyloxy)-3-(3-nitrophenyl)propanal: Yield
87%. [α]2D3 = –56.3 (c = 1.00, CHCl3). 1H NMR (400 MHz, CDCl3):
5252
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5247–5255

Synthesis of α,β-Unsaturated δ-Lactones
δ = 9.67 (m, 1 H), 8.15 (s, 1 H), 8.03 (m, 1 H), 7.60 (d, J = 7.7 Hz,
1H NMR (400 MHz, CDCl3): δ = 7.63 (m, 1 H), 7.44 (d, J =
1 H), 7.44 (m, 1 H), 5.24 (dd, J = 7.7, 4.3 Hz, 1 H), 2.81 (m, 1 H), 2.1 Hz, 1 H), 7.37 (dd, J = 7.8, 2.6 Hz, 1 H), 6.97 (dt, J = 15.3,
2.60 (m, 1 H), 0.78 (s, 9 H), –0.02 (s, 3 H), –0.21 (s, 3 H) ppm. 13C 7.5 Hz, 1 H), 5.86 (m, 1 H), 5.23 (dd, J = 8.0, 3.6 Hz, 1 H), 2.64
NMR (100 MHz, CDCl3): δ = 192.8, 149.0, 133.5, 130.8, 130.2,
125.3, 123.04, 69.3, 53.7, 25.7, 17.9, –4.6, –5.1 ppm.
(m, 1 H), 2.50 (m, 1 H), 1.59 (s, 9 H), 0.99 (s, 9 H), 0.15 (s, 3 H),
–0.02 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.5, 143.4,
140.6, 133.2, 131.2, 128.8, 128.7, 127.2, 125.8, 80.0, 69.8, 41.1, 28.0,
25.5, 18.2, –4.8, –5.1 ppm.
(S)-3-(tert-Butyldimethylsilyloxy)-3-(2-nitrophenyl)propanal: Yield
90%. [α]2D3 = +58.7 (c = 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 9.76 (m, 1 H), 7.92 (d, J = 8.2 Hz, 1 H), 7.83 (d, J =
7.5 Hz, 1 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.40 (m, 1 H), 5.80 (dd, J
= 8.1, 3.3 Hz, 1 H), 2.83 (m, 1 H), 2.72 (m, 1 H), 0.80 (s, 9 H),
–0.00 (s, 3 H), –0.23 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 199.8, 146.7, 139.7, 133.3, 128.6, 128.3, 124.2, 65.6, 52.7, 25.6,
18.0, –4.8, –5.2 ppm.
tert-Butyl (S,E)-5-(4-Nitrophenyl)-5-hydroxy-3-methylpent-2-enoate
(3e): Yield 89%. 1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J =
8.7 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 2 H), 5.78 (s, 1 H), 4.90 (d, J =
9.2 Hz, 1 H), 3.02 (dd, J = 12.8, 9.5 Hz, 1 H), 2.60–2.48 (m, 1 H),
1.76 (t, J = 7.6 Hz, 3 H), 1.40 (s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 165.7, 151.0, 147.2, 142.5, 126.5, 126.2, 123.7, 80.7,
71.9, 41.7, 28.0, 18.5 ppm.
(S)-3-(tert-Butyldimethylsilyloxy)-3-(2,4-dichlorophenyl)propanal:
1
Yield 85%. [α]2D3 = –54.2 (c = 1.00, CHCl3). H NMR (400 MHz,
tert-Butyl (S,E)-5-(4-Fluorophenyl)-5-hydroxy-3-methylpent-2-eno-
ate (3f): Yield 92%. 1H NMR (500 MHz, CDCl3): δ = 7.38–7.26
(m, 2 H), 7.11–6.92 (m, 2 H), 5.68 (s, 1 H), 4.85 (dd, J = 8.8,
4.5 Hz, 1 H), 2.57–2.35 (m, 2 H), 2.17 (d, J = 1.2 Hz, 3 H), 1.55–
1.41 (m, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.0, 163.2,
161.2, 153.6, 139.5, 120.5, 115.4, 115.2, 80.0, 71.3, 50.9, 28.2, 28.1,
18.7 ppm.
CDCl3): δ = 9.71 (dd, J = 2.7, 2.0 Hz, 2 H), 7.46 (m, 1 H), 7.27
(m, 1 H), 7.20 (dd, J = 8.4, 2.0 Hz, 1 H), 5.45 (m, 1 H), 2.62 (m,
2 H), 0.80 (s, 9 H), –0.04 (s, 3 H), –0.17 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 200.4, 139.7, 133.7, 131.5, 128.7, 128.6,
127.5, 67.8, 51.6, 25.6, 17.9, –4.8, –5.3 ppm.
General Procedure for the Wittig–Horner Reactions of Aldehydes
and Ketones
tert-Butyl (S,E)-5-(4-Bromophenyl)-5-hydroxy-3-methylpent-2-eno-
1
ate (3g): Yield 89%. H NMR (500 MHz, CDCl3): δ = 7.55–7.36
tert-Butyl (S,E)-5-(tert-Butyldimethylsilyloxy)-5-(4-nitrophenyl)-
pent-2-enoate: (tert-Butoxycarbonylmethylene)triphenylphos-
phorane (584 mg, 1.55 mmol) was added to a cooled (0 °C) solu-
tion of (S)-3-(tert-butyldimethylsilyloxy)-3-(4-nitrophenyl)propanal
(400 mg, 1.29 mmol) in dry dichloromethane (20 mL) . The re-
sulting mixture was stirred at –10 °C until TLC showed complete
consumption of the starting material, and then the reaction was
quenched by the addition of water. The aqueous layer was extracted
with Et2O and the organic extract was washed with brine. The or-
ganic layer was dried with Na2SO4, the solvent was removed in
vacuo and the residue was purified by column chromatography to
give 450 mg (1.11 mmol, 85%) of tert-butyl (S,E)-5-(tert-butyldi-
methylsilyloxy)-5-(4-nitrophenyl)pent-2-enoate as a colourless li-
quid. [α]2D3 = –38.2 (c = 1.00, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 8.14 (d, J = 8.5 Hz, 2 H), 7.43 (d, J = 8.5 Hz, 2 H), 6.74 (dt,
J = 15.1, 7.4 Hz, 1 H), 5.87 (d, J = 15.6 Hz, 1 H), 4.80 (t, J =
5.9 Hz, 1 H), 2.45 (m, 2 H), 1.41 (s, 9 H), 0.82 (s, 9 H), –0.03 (s, 3
H), –0.16 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.4,
151.9, 147.3, 142.6, 126.5, 126.1, 123.7, 80.3, 73.4, 43.2, 28.1, 25.7,
18.2, –4.7, –5.0 ppm.
(m, 2 H), 7.20 (d, J = 8.4 Hz, 2 H), 5.64 (s, 1 H), 4.79 (dd, J = 8.7,
4.6 Hz, 1 H), 2.51–2.29 (m, 2 H), 2.14 (t, J = 7.2 Hz, 3 H), 1.52–
1.37 (m, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.1, 153.5,
142.9, 131.5, 127.4, 121.3, 120.4, 80.0, 71.2, 50.7, 28.2, 28.1, 27.9,
18.7 ppm.
tert-Butyl (S,E)-5-Hydroxy-3-methyl-5-(perfluorophenyl)pent-2-eno-
ate (3h): Yield 93%. 1H NMR (500 MHz, CDCl3): δ = 5.67 (s, 1
H), 5.21–5.10 (m, 2 H), 2.57 (dd, J = 13.6, 5.5 Hz, 1 H), 2.37–2.26
(m, 1 H), 2.18 (d, J = 5.5 Hz, 3 H), 1.51–1.48 (m, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 169.2, 166.1, 152.1, 144.3, 145.5,
138.4, 136.2, 121.9, 81.4, 64.8, 47.7, 28.2, 18.3 ppm.
tert-Butyl (S,E)-5-Hydroxy-3-methyl-5-phenylpent-2-enoate (3i):
1
Yield 85%. H NMR (500 MHz, CDCl3): δ = 7.41–7.20 (m, 5 H),
5.71 (s, 1 H), 4.93–4.77 (m, 1 H), 2.57–2.40 (m, 2 H), 2.18 (d, J =
3.7 Hz, 3 H), 1.56–1.39 (m, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.0, 153.9, 143.8, 128.5, 127.7, 125.6, 120.3, 79.9,
79.4, 72.0, 50.8, 28.2, 18.7 ppm.
tert-Butyl (S,E)-5-Hydroxy-3-methyl-5-(2-naphthyl)pent-2-enoate
(3j): Yield 89%. 1H NMR (500 MHz, CDCl3): δ = 7.86 (td, J =
8.3, 3.8 Hz, 4 H), 7.53–7.45 (m, 3 H), 5.78 (t, J = 8.9 Hz, 1 H),
5.15–5.04 (m, 1 H), 2.64–2.55 (m, 2 H), 2.29–2.17 (m, 3 H), 1.49
(d, J = 4.3 Hz, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.9,
154.0, 141.1, 133.2, 133.0, 128.4, 128.1, 126.0, 125.6, 124.4, 120.92,
119.7, 114.1, 80.2, 72.1, 50.8, 28.2, 18.7 ppm.
tert-Butyl (S,E)-5-(tert-Butyldimethylsilyloxy)-5-(3-nitrophenyl)-
pent-2-enoate: Yield 88%. [α]2D3 = –40.1 (c = 1.00, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 8.21 (s, 1 H), 8.11 (m, 1 H), 7.67
(m, 1 H), 7.46 (m, 1 H), 6.80 (m, 1 H), 5.74 (m, 1 H), 4.85 (dd, J
= 16.8, 10.0 Hz, 1 H), 2.54 (m, 2 H), 1.46 (s, 9 H), 0.90 (s, 9 H),
0.06 (s, 3 H), –0.10 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 165.3, 146.7, 142.7, 132.8, 131.7, 129.1, 126.1, 122.3, 120.5, 80.0,
73.2, 43.4, 27.8, 25.9, 18.2, –4.7, –4.9 ppm.
tert-Butyl (E)-2-{2-[(S)-Hydroxy(4-nitrophenyl)methyl]-
cyclohexylidene}acetate (3k): Yield 82 %. 1H NMR (400 MHz,
CDCl3): δ = 8.24–8.12 (m, 2 H), 7.53–7.40 (m, 2 H), 5.39–5.27 (m,
1 H), 5.21–5.12 (m, 1 H), 3.03–2.81 (m, 1 H), 2.79–2.59 (m, 1 H),
2.44–2.27 (m, 1 H), 2.16–1.94 (m, 1 H), 1.85–1.66 (m, 1 H), 1.69–
1.55 (m, 1 H), 1.55–1.46 (m, 1 H), 1.43–1.38 (m, 9 H), 1.38–1.23
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.3, 159.4,
149.0, 148.3, 127.9, 126.6, 123.6, 123.4, 113.3, 74.0, 70.1, 57.1, 56.8,
42.7, 42.6, 30.7, 27.8, 27.6, 25.9, 24.7, 24.6 ppm.
tert-Butyl (S,E)-5-[(tert-Butyldimethylsilyloxy)-5-(2-nitrophenyl)-
pent-2-enoate: Yield 90%. [α]2D3 = +43.2 (c = 1.00, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 8.09 (dd, J = 8.2, 1.1 Hz, 1 H), 8.01
(dd, J = 7.9, 1.0 Hz, 1 H), 7.80 (m, 1 H), 7.58 (m, 1 H), 7.07 (m,
1 H), 5.94 (d, J = 15.6 Hz, 1 H), 5.55 (dd, J = 8.0, 3.3 Hz, 1 H),
2.85 (m, 1 H), 2.63 (m, 1 H), 1.65 (s, 9 H), 1.03 (s, 9 H), 0.19 (s, 3
H), –0.00 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.5,
146.7, 143.3, 140.3, 133.0, 128.6, 128.0, 126.0, 124.1, 80.0, 69.2,
42.2, 28.0, 25.7, 18.0, –4.9, –5.1 ppm.
General Procedure for the Deprotection of the Secondary Alcohols
tert-Butyl (S,E)-5-Hydroxy-5-(4-nitrophenyl)pent-2-enoate (3a):
Tetra-n-butylammonium fluoride hydrate (TBAF, 1.06 mL,
3.68 mmol) was added to a solution of tert-butyl (S,E)-5-(tert-bu-
tert-Butyl (S,E)-5-[(tert-Butyldimethylsilyloxy)-5-(2,4-dichloro-
phenyl)pent-2-enoate: Yield 83%. [α]2D3 = –40.2 (c = 1.00, CHCl3).
Eur. J. Org. Chem. 2014, 5247–5255
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5253

B. A. Shah et al.
FULL PAPER
tyldimethylsilyloxy)-5-(4-nitrophenyl)pent-2-enoate (500 mg,
1.23 mmol) in THF (10 mL), and the mixture was stirred at room
temperature for 4 h. Then the reaction mixture was diluted with
EtOAc and washed with water. The organic layer was dried with
Na2SO4, the solvent was removed in vacuo and the residue was
purified by column chromatography to give 265 mg (0.90 mmol,
(S)-6-(2-Nitrophenyl)-5,6-dihydro-2H-pyran-2-one (4c): Yield 85%.
1
[α]2D3 = –29.8 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
7.98–7.89 (m, 1 H), 7.85 (t, J = 10.2 Hz, 1 H), 7.73–7.55 (m, 1 H),
7.56–7.36 (m, 1 H), 7.08–6.84 (m, 1 H), 5.84 (dd, J = 24.4, 10.7 Hz,
1 H), 5.15–5.07 (m, 1 H), 2.84–2.65 (m, 1 H), 2.60–2.47 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.8, 147.4, 143.1,
139.4, 133.6, 128.3, 126.0, 124.4, 80.5, 40.8 ppm. HRMS: calcd. for
C11H10NO4 [M + H]+ 220.2009; found 220.2032.
1
74%) of 3a as a colourless oil. [α]2D3 = –24.2 (c = 1.00, CHCl3). H
NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 8.4 Hz, 2 H), 7.54 (d,
J = 8.6 Hz, 2 H), 6.84 (dt, J = 15.1, 7.4 Hz, 1 H), 5.87 (d, J =
15.6 Hz, 1 H), 4.93 (t, J = 5.9 Hz, 1 H), 2.61 (m, 2 H), 1.44 (s, 9
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.8, 151.1, 147.3,
142.5, 126.9, 126.6, 126.3, 123.8, 123.6, 80.78, 71.9, 41.8, 28.1,
28.0 ppm.
(S)-6-(2,4-Dichlorophenyl)-5,6-dihydro-2H-pyran-2-one (4d): Yield
88%. [α]2D3 = –29.5 (c = 1.00, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 7.59 (t, J = 9.4 Hz, 1 H), 7.49–7.30 (m, 2 H), 6.98 (dd, J = 9.6,
6.2, Hz, 1 H), 6.16 (dd, J = 9.8, 2.7 Hz, 1 H), 5.84–5.69 (m, 1 H),
2.87–2.70 (m, 1 H), 2.50–2.31 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 163.5, 144.7, 135.0, 134.8, 131.9, 129.3, 128.5, 121.5,
75.6, 30.2 ppm. HRMS: calcd. for C11H9Cl2O2 [M + H]+ 244.0934;
found 244.0956.
tert-Butyl (S,E)-5-Hydroxy-5-(3-nitrophenyl)pent-2-enoate (3b):
1
Yield 78%. [α]2D3 = –24.6 (c = 1.00, CHCl3). H NMR (400 MHz,
CDCl3): δ = 8.21 (s, 1 H), 8.11 (m, 1 H), 7.67 (m, 1 H), 7.46 (m, 1
H), 6.81 (m, 1 H), 5.74 (m, 1 H), 4.85 (dd, J = 16.8, 10.0 Hz, 1 H),
2.4 (m, 2 H), 1.46 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 165.68, 148.13, 145.90, 142.58, 131.82, 129.27, 125.96, 122.34,
120.58, 80.54, 71.66, 41.54, 27.86 ppm.
(S)-4-Methyl-6-(4-nitrophenyl)-5,6-dihydro-2H-pyran-2-one (4e):
1
Yield 94%. H NMR (400 MHz, CDCl3): δ = 8.27 (d, J = 8.6 Hz,
2 H), 7.61 (d, J = 8.7 Hz, 2 H), 5.96 (s, 1 H), 5.54 (dd, J = 11.6,
4.2 Hz, 1 H), 2.75–2.40 (m, 2 H), 2.06 (d, J = 7.7 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 163.9, 156.6, 147.8, 145.6, 126.7,
124.0, 116.8, 77.3, 36.7, 24.1 ppm. HRMS: calcd. for C12H12NO4
[M + H]+ 234.2274; found 234.2231.
tert-Butyl (S,E)-5-Hydroxy-5-(2-nitrophenyl)pent-2-enoate (3c):
Yield 80%. [α]2D3 = +25.2 (c = 1.00, CHCl3). H NMR (400 MHz,
1
CDCl3): δ = 7.96 (d, J = 8.1 Hz, 1 H), 7.86 (d, J = 7.7 Hz, 1 H),
7.67 (t, J = 7.6 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 1 H), 6.95 (m, 1 H),
5.90 (d, J = 15.6 Hz, 1 H), 5.41 (dd, J = 8.6, 3.2 Hz, 1 H), 2.78 (m,
1 H), 2.56 (m, 1 H), 1.48 (s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 165.8, 147.4, 143.1, 139.4, 133.6, 128.3, 128.0, 126.0,
125.9, 124.4, 80.5, 68.2, 40.9, 28.0 ppm.
(S)-6-(4-Fluorophenyl)-4-methyl-5,6-dihydro-2H-pyran-2-one (4f):
1
Yield 92%. H NMR (500 MHz, CDCl3): δ = 7.51–7.35 (m, 2 H),
7.14–6.97 (m, 2 H), 5.94 (dd, J = 42.7, 8.5 Hz, 1 H), 5.47–5.29 (m,
1 H), 2.72–2.56 (m, 1 H), 2.55–2.38 (m, 1 H), 2.15–1.95 (m, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.8, 163.6, 161.6,
134.4, 127.9, 116.6, 115.6, 78.0, 36.8, 22.9 ppm. HRMS: calcd. for
C12H12FO2 [M + H]+ 207.2203; found 207.2190.
tert-Butyl (S,E)-5-Hydroxy-5-(2,4-dichlorophenyl)pent-2-enoate
(3d): Yield 79%. [α]2D3 = –25.0 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.52 (t, J = 7.5 Hz, 1 H), 7.33 (dd, J = 7.7,
2.0 Hz, 1 H), 7.27 (m, 1 H), 6.89 (dt, J = 15.4, 7.3 Hz, 1 H), 5.84
(d, J = 15.6 Hz, 1 H), 5.17 (dd, J = 8.4, 3.5 Hz, 1 H), 2.65 (m, 1
(S)-6-(4-Bromophenyl)-4-methyl-5,6-dihydro-2H-pyran-2-one (4g):
1
Yield 94%. H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 8.4 Hz,
2 H), 7.28 (d, J = 8.4 Hz, 2 H), 5.90 (s, 1 H), 5.36 (dd, J = 12.0,
H), 2.46 (m, 1 H), 1.47 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): 3.9 Hz, 1 H), 2.78–2.52 (m, 1 H), 2.49–2.35 (m, 1 H), 2.03 (s, 3
δ = 165.8, 143.1, 139.8, 133.6, 132.0, 129.0, 128.0, 127.4, 125.8,
80.5, 68.9, 39.9, 28.0 ppm.
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.5, 157.0, 137.7,
131.7, 127.7, 122.4, 116.7, 77.8, 36.7, 22.9 ppm. HRMS: calcd. for
C12H12BrO2 [M + H]+ 268.1259; found 268.1290.
General Procedure for the Synthesis of α,β-Unsaturated δ-Lactones
(S)-4-Methyl-6-(perfluorophenyl)-5,6-dihydro-2H-pyran-2-one (4h):
Yield 93%. 1H NMR (400 MHz, CDCl3): δ = 5.94 (s, 1 H), 5.76
(dd, J = 13.0, 3.9 Hz, 1 H), 3.16–2.89 (m, 1 H), 2.35 (dd, J = 17.8,
3.9 Hz, 1 H), 2.07 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 162.2, 156.7, 145.7, 143.7, 141.5, 137.2, 115.4, 110.8, 68.2, 32.4,
22.4 ppm. HRMS: calcd. for C12H8F5O2 [M + H]+ 279.1822; found
279.1843.
(S)-6-(4-nitrophenyl)-5,6-dihydro-2H-pyran-2-one 4a: Ester 3a
(50 mg, 0.17 mmol) was dissolved in CH2Cl2 (3 mL), and TFA
(0.5 mL) was added. After 1 h, toluene (2 mL) was added and the
reaction mixture was concentrated in vacuo. The resulting acid was
dissolved in CH2Cl2 (3 mL) and EDCI (25 mg, 0.16 mmol) and
DMAP (20 mg, 0.16 mmol) were added. The reaction mixture was
stirred at 70 °C for 3 h. A saturated aqueous solution of NaHCO3
was added and the aqueous phase was extracted with CH2Cl2. The
organic layer was dried with Na2SO4 and the residue purified by
column chromatography to give 33 mg (0.15 mmol, 90%) of 4a as
a colourless oil. [α]2D3 = –28.3 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.34–8.19 (m, 2 H), 7.62 (d, J = 8.7 Hz, 2
H), 7.01 (m, 1 H), 6.18 (m, 1 H), 5.59 (dd, J = 11.6, 4.5 Hz, 1 H),
2.82–2.54 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.2,
147.9, 145.4, 144.4, 126.7, 124.2, 121.8, 77.8, 31.5 ppm. HRMS:
calcd. for C11H10NO4 [M + H]+ 220.2009; found 220.2032.
(S)-4-Methyl-6-phenyl-5,6-dihydro-2H-pyran-2-one (4i): Yield 90%.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.29 (m, 5 H), 5.91 (s, 1
H), 5.41 (dd, J = 12.1, 3.9 Hz, 1 H), 2.73–2.56 (m, 1 H), 2.46 (dd,
J = 17.9, 3.9 Hz, 1 H), 2.03 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 164.9, 157.1, 138.6, 128.6, 128.5, 126.2, 126.0, 116.7,
78.6, 36.9, 22.7 ppm. HRMS: calcd. for C12H13O2 [M + H]+
189.2299; found 189.2273.
(S)-4-Methyl-6-(2-naphthyl)-5,6-dihydro-2H-pyran-2-one (4j): Yield
1
92%. H NMR (400 MHz, CDCl3): δ = 7.95–7.76 (m, 4 H), 7.50
(dd, J = 9.1, 3.1 Hz, 3 H), 5.96 (s, 1 H), 5.59 (dd, J = 12.0, 3.9 Hz,
1 H), 2.84–2.64 (m, 1 H), 2.55 (dd, J = 18.0, 3.9 Hz, 1 H), 2.05 (d,
J = 3.9 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.9,
157.1, 135.9, 133.3, 128.5, 128.1, 127.7, 126.5, 125.1, 123.5, 116.8,
78.7, 36.9, 23.0 ppm. HRMS: calcd. for C16H15O2 [M + H]+
239.2886; found 239.2880.
(S)-6-(3-Nitrophenyl)-5,6-dihydro-2H-pyran-2-one (4b): Yield 92%.
[α]2D3 = –28.5 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
8.37–8.17 (m, 2 H), 7.81 (d, J = 7.6 Hz, 1 H), 7.70–7.53 (m, 1 H),
7.10–6.96 (m, 1 H), 6.27–6.09 (m, 1 H), 5.57 (dt, J = 21.8, 11.0 Hz,
1 H), 2.84–2.56 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
163.1, 147.5, 144.4, 140.5, 132.0, 129.9, 123.5, 121.8, 121.0, 77.8,
31.5 ppm. HRMS: calcd. for C11H10NO4 [M + H]+ 220.2009; (1S)-1-(4-Nitrophenyl)-6,7,8,8a-tetrahydro-1H-isochromen-3(5H)-
1
found 220.2041.
one (4k): Yield 87%. H NMR (500 MHz, MeOD): δ = 8.30 (d, J
5254
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5247–5255

Synthesis of α,β-Unsaturated δ-Lactones
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= 4.6 Hz, 1 H), 3.36 (dd, J = 11.0, 9.4 Hz, 1 H), 2.71–2.53 (m, 1
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Published Online: July 15, 2014
Eur. J. Org. Chem. 2014, 5247–5255
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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