Organocatalytic Michael addition-lactonisation of carboxylic acids using α,β-unsaturated trichloromethyl ketones as α,β-unsaturated ester equivalents

Article abstract of DOI:10.1039/c4ob01788a

Isothiourea HBTM-2.1 catalyses the Michael addition-lactonisation of 2-aryl and 2-alkenylacetic acids and α,β-unsaturated trichloromethyl ketones. Ring-opening of the resulting dihydropyranones and subsequent alcoholysis of the CCl₃ ketone with

Full text of DOI:10.1039/c4ob01788a

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Organocatalytic Michael addition–lactonisation
of carboxylic acids using α,β-unsaturated
trichloromethyl ketones as α,β-unsaturated
ester equivalents†
Cite this: DOI: 10.1039/c4ob01788a
Louis C. Morrill,a Daniel G. Stark,a James E. Taylor,a Siobhan R. Smith,a
James A. Squires,a Agathe C. A. D’Hollander,a Carmen Simal,a Peter Shapland,b
Timothy J. C. O’Riordanc and Andrew D. Smith*a
Isothiourea HBTM-2.1 catalyses the Michael addition–lactonisation of 2-aryl and 2-alkenylacetic acids
and α,β-unsaturated trichloromethyl ketones. Ring-opening of the resulting dihydropyranones and sub-
sequent alcoholysis of the CCl3 ketone with an excess of methanol gives a range of diesters in high dia-
stereo- and enantioselectivity (up to 95 : 5 dr and >99% ee). Sequential addition of two different
nucleophiles to a dihydropyranone gives the corresponding differentially substituted diacid derivative.
Received 21st August 2014,
Accepted 23rd September 2014
DOI: 10.1039/c4ob01788a
www.rsc.org/obc
Introduction
Lewis base organocatalysis is a powerful method for the stereo-
selective construction of carbon–carbon bonds.1 In this
regard, catalytic asymmetric conjugate additions of
ammonium and azolium enolates to electron-deficient alkenes
have been widely explored.2,3 However, the use of α,β-unsatu-
rated esters and amides as Michael acceptors in such pro-
cesses remains
a
challenge due to the decreased
electrophilicity of such substrates. Strategies to overcome this
problem typically make use of more reactive α,β-unsaturated
ester equivalents such as N-acylpyrroles 1,4 2-acyl imidazoles
2,5 activated imides 36 and α-ketophosphonates 4 (Fig. 1i).7,8
We have previously reported a number of intra- and inter-
molecular isothiourea-catalysed Michael addition–cyclisation
cascades of electron-deficient Michael acceptors with
ammonium enolates generated from carboxylic acids.9–12 Of
particular relevance is our recent report on the use of α-keto-
β,γ-unsaturated phosphonates as ester equivalents in an inter-
molecular Michael addition–lactonisation reaction, giving
access to a range of diester products with high levels of stereo-
selectivity after ring-opening and alcoholysis.13 However, many
α-keto-β,γ-unsaturated phosphonates are not bench-stable and
Fig. 1 (i) Previously used α,β-unsaturated ester equivalents. (ii) Pro-
posed use of α,β-unsaturated trichloromethyl ketones in asymmetric
intramolecular Michael addition–lactonisations.
aEaStCHEM, School of Chemistry, University of St Andrews, North Haugh,
St Andrews KY16 9ST, UK. E-mail: ads10@st-andrews.ac.uk
cannot be stored for long periods of time. To alleviate this
problem the use of α,β-unsaturated trichloromethyl ketones
as alternative, bench-stable α,β-unsaturated ester equivalents
seemed an attractive possibility.
bGSK, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
cSyngenta, Jealott’s Hill International Research Centre, Bracknell, RG42 6EY, UK
†Electronic supplementary information (ESI) available: 1H and 13C{1H} NMR spectra
of all novel compounds and relevant HPLC traces. See DOI: 10.1039/c4ob01788a
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Trichloromethyl ketones are versatile synthetic building of the resulting trichloromethyl carbinol gave trichloromethyl
blocks and have been used as carboxylic acid, ester and amide ketone 7 in 45% yield (4.41 g, 18 mmol) over the two steps.
equivalents by utilising the leaving group ability of the CCl3 This robust protocol was used for the gram-scale preparation
group in haloform-type reactions.14,15 For example, Friedel– of a range of α,β-unsaturated trichloromethyl ketones, which
Crafts acylation of heterocycles, in particular pyrrole deriva- can be readily stored on the bench-top without undergoing
tives, using trichloroacetyl chloride followed by substitution of decomposition.21 An alternative method of synthesising 7
the CCl3 group with either alcohol or amine nucleophiles is a using (E)-cinnamaldehyde and CHCl3 in the presence of KOH,
widely used reaction sequence in natural product syn- followed by oxidation was unreliable in our hands, with the
thesis.16,17 Shibasaki and co-workers have used trichloro- formation of polymeric mixtures during the first step resulting
methyl ketones as ester and amide-enolate equivalents in in low yields.19a
diastereoselective Mannich reactions, with the electron-with-
Initial studies
drawing nature of the CCl3 group allowing catalytic α-deproto-
nation to form an enolate.18
Reaction of trichloromethyl ketone 7 with phenylacetic acid 6
(1.5 eq.), using pivaloyl chloride (2.25 eq.) to form an in situ
mixed anhydride, in the presence of isothiourea HBTM-2.1 5
(5 mol%) and i-Pr2NEt (1.5 eq.) at −78 °C gave dihydropyra-
none 8 in 82% yield as a 87 : 13 mixture of diastereoisomers,
with the major anti-diastereoisomer formed in excellent 99%
ee (Scheme 1).22–24 Attempted nucleophilic ring-opening of
dihydropyranone 8 with one equivalent of methanol and a
catalytic amount of DMAP (20 mol%) led to the unexpected
formation of pyranone 9 in 65% yield, presumably through
deprotonation to eliminate HCl followed by tautomerisation.
Pleasingly, treating dihydropyranone 8 with a large excess of
methanol in the presence of DMAP (20 mol%) led to the
desired ring-opening and alcoholysis of the resulting CCl3
ketone to give a single diastereoisomer of diester 10 in 62%
yield and 99% ee after purification by column chromatography.
The absolute and relative stereochemistry of diester 10 was con-
firmed by comparison of data with that previously reported,
with all subsequent compounds assigned by analogy.13
α,β-Unsaturated trichloromethyl ketones have previously
been used as ester and amide equivalents of Michael acceptors
in a small number of processes.19 For example, Zhao and co-
workers reported the two-step enantioselective diaryl prolinol
catalysed epoxidation of α,β-unsaturated trichloromethyl
ketones using tert-butylhydroperoxide (TBHP) followed by
either alcoholysis with methanol or aminolysis with various
amines.19a Zhao and co-workers have also reported Michael
additions of α-cyano ketones into α,β-unsaturated trichloro-
methyl ketones catalysed by a piperazine/thiourea based
bifunctional organocatalyst.19b More recently, Wang et al. have
performed enantioselective vinylogous Michael additions of
α,β-unsaturated γ-butyrolactams into α,β-unsaturated trichloro-
methyl ketones using a chiral quinine-derived squaramide
organocatalyst, followed by methanolysis of the CCl3 ketone.19c
Herein an isothiourea-catalysed Michael addition–lactonisa-
tion process using 2-aryl and 2-alkenylacetic acids and bench-
stable α,β-unsaturated trichloromethyl ketones as ester and
amide equivalents is reported (Fig. 1ii). Nucleophilic ring-
opening of the initially formed dihydropyranone products fol-
lowed by either alcoholysis or aminolysis of the CCl3 group
gives access to stereodefined diesters and diamides, respect-
ively. Furthermore in a single example, a relatively slow alcoho-
lysis of the CCl3 ketone compared to dihydropyranone ring-
opening allowed the sequential addition of two different
nucleophiles, leading to the formation of a differentially sub-
stituted diacid derivative. This is in contrast to the use of
α-keto-β,γ-unsaturated phosphonates where both ring-opening
and either alcoholysis or aminolysis of the phosphate group
proceeds rapidly and differential functionalisation is not
possible.13
Next, a one-pot Michael addition–lactonisation followed by
in situ ring-opening with methanol was trialled (Scheme 2i). In
this case major anti-diester 10 was obtained in 78% yield in
>99% ee.25 The use of alternative ring-opening nucleophiles
was then investigated. Reacting phenylacetic acid 6 with
Results and discussion
α,β-Unsaturated trichloromethyl ketone synthesis
First, the reaction of phenylacetic acid 6 with (E)-1,1,1-tri-
chloro-4-phenylbut-3-en-2-one 7 was studied. Trichloromethyl
ketone 7 was synthesised on gram-scale using a two-step pro-
cedure first described by Corey and co-workers.20 Nucleophilic
addition of the CCl3 anion, generated from trichloroacetic acid
and sodium trichloroacetate in N,N-dimethylformamide
Scheme 1 a Isolated yield of
a
mixture of diastereoisomers.
b Determined by 1H NMR spectroscopic analysis of the crude reaction
mixture. c Determined by chiral HPLC analysis of diester 10. d Isolated
(DMF), into (E)-cinnamaldehyde followed by Swern oxidation yield of major diastereoisomer (>98 : 2 dr).
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Scope and generality
With efficient reaction conditions and suitable ring-opening
protocols in hand, the scope of this Michael addition–lacto-
nisation process was evaluated through variation of the
acetic acid component (Table 1). Phenylacetic acid deriva-
tives bearing electron-donating (4-OMe), electron-withdraw-
ing (4-CF3) and halogen (4-F) substituents could be
employed in this system, affording the corresponding di-
esters 14–16 with high stereocontrol. m-Tolylacetic acid allows
formation of diester 17 in 92 : 8 dr and >99% ee, whereas
o-tolylacetic acid is not tolerated (presumably due to steric
hindrance) and gave <10% conversion into the corresponding
diester 18. Heteroaromatic substitution was possible through
use of 3-thiopheneacetic acid, with diester 19 formed in a
reduced 81 : 19 dr but with excellent ee for the major anti-dia-
stereoisomer. (E)-4-Methyl and (E)-4-benzyl alkenoic acids also
participate in this process, affording diesters 20 and 21 in
good yields and with excellent diastereo- and enantiocontrol.
Unfortunately, the use of 3-phenylpropionic acid did not lead
to any formation of diester 22 under the standard conditions.
To further examine the scope of the reaction a selection
of α,β-unsaturated trichloromethyl ketones was examined
(Table 2). Within the Michael acceptor, β-aryl groups contain-
ing electron-donating (4-OMe), electron-withdrawing (2-NO2)
and halogen (4-F) substituents were tolerated, giving the
corresponding diesters 23–25 in high yields with excellent
Table 1 Scope of 2-aryl and 2-alkenyl acetic acids
Scheme 2 (i) Ring-opening and alcoholysis with MeOH; (ii) Ring-
opening and aminolysis with isopropylamine; (iii) Ring-opening with allyl
alcohol; (iv) Sequential addition of two nucleophiles. a Isolated yield of
major diastereoisomer (>98 : 2 dr). b Determined by 1H NMR spectro-
scopic analysis of the crude reaction mixture. c Determined by chiral
HPLC analysis.
trichloromethyl ketone 7 under the standard reaction conditions,
followed by ring-opening and aminolysis with an excess of iso-
propylamine gave diamide 11 in 90 : 10 dr, >99% ee and 67%
yield (Scheme 2ii). However, the use of secondary amines such
as pyrrolidine led to a complex mixture of products.
Interestingly, use of allyl alcohol as the ring-opening
nucleophile afforded monoester product 12 in 60% yield,
89 : 11 dr and 99% ee, with no substitution of the CCl3 ketone
observed (Scheme 2iii). This led to the possibility of forming
differentially protected diacid derivatives through the sequen-
tial addition of two nucleophiles. To test this, the reaction
between phenylacetic acid 6 and trichloromethyl ketone 7 was
firstly ring-opened with three equivalents of isopropylamine.26
Upon the disappearance of the initial dihydropyranone
product as judged by TLC analysis a large excess of methanol
and catalytic DMAP (20 mol%) was added. Pleasingly, γ-ester
amide 13 was isolated in 42% yield over the three one-pot reac-
tion steps as a single diastereoisomer in 99% ee (Scheme 2iv).
a Isolated yield of major diastereoisomer (>98 : 2 dr). b Determined by
1H NMR spectroscopic analysis of the crude reaction mixture.
c Determined by chiral HPLC analysis.
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Table 2 Scope of α,β-unsaturated trichloromethyl ketones
a Isolated yield of major diastereoisomer (>98 : 2 dr). b Determined by
1H NMR spectroscopic analysis of the crude reaction mixture.
c Determined by chiral HPLC analysis. d Isolated yield of major
Fig. 2 Proposed mechanism for Lewis base catalysed process.
diastereoisomer (96 : 4 dr). e Isolated yield of
diastereoisomers. f Steps (i) and (ii) only.
a
mixture of
Conclusions
In conclusion, the Michael addition–lactonisation of a range
of 2-aryl and 2-alkenylacetic acids and bench-stable α,β-unsatu-
rated trichloromethyl ketones has been demonstrated. Upon
alcoholysis, the initially formed dihydropyranone products are
converted into stereodefined diesters, representing a formal
conjugate addition into an α,β-unsaturated ester. Slow substi-
tution of the CCl3 ketone after ring-opening allowed the for-
mation of a γ-ester amide through sequential addition of two
nucleophiles. Further studies within our laboratory are
focused towards the continued development of isothioureas in
catalysis.
stereocontrol. A Michael acceptor bearing a heteroaromatic
β-2-furyl substituent also participates, giving diester 26 with
reduced diastereoselectivity (80 : 20 dr), although the major
diastereoisomer again forms in excellent ee (98%). The incor-
poration of a β-alkyl substituent proved to be more challen-
ging, with the reaction of a β-pentyl trichloromethyl ketone
followed by in situ methanolysis giving a complex mixture of
products. Further investigation revealed that the Michael
addition–lactonisation worked well, with dihydropyranone 27
isolated in 71% yield albeit in a reduced 86% ee. Attempts to
ring-open isolated dihydropyranone 27 with either methanol
or isopropylamine were also unsuccessful, with a complex
mixture of products observed in both cases.
Experimental
General information
Proposed mechanism
Anhydrous CH2Cl2 was obtained from an Mbraun SPS-800
The proposed mechanism for this process initiates via N-acyla- system. Petrol is defined as petroleum ether 40–60 °C. All
tion of HBTM-2.1 5 with in situ formed mixed anhydride 28, other solvents and commercial reagents were used as supplied
forming acyl ammonium 29 (Fig. 2). Subsequent deprotona- without further purification unless stated otherwise.
tion gives the key (Z)-ammonium enolate 30, allowing either
Room temperature (rt) refers to 20–25 °C. Temperatures of
an no to σ*C–S interaction or favourable electrostatic stabili- 0 °C and −78 °C were obtained using ice/water and CO2(s)/
sation between the enolate oxygen and the sulfur atom of the acetone baths, respectively. Temperatures between 0 °C and
isothiourea.27 Stereoselective Michael addition to α,β-unsatu- −60 °C for overnight reactions were obtained using an immer-
rated trichloromethyl ketone 31 followed by lactonisation gives sion cooler (HAAKE EK 90).
dihydropyranone 33 and regenerates the catalyst. Ring-opening
Analytical thin layer chromatography was performed on pre-
of dihydropyranone 33 with a nucleophile generates keto-ester coated aluminium plates (Kieselgel 60 F254 silica). TLC visuali-
34, with further alcoholysis of the trichloromethyl ketone into sation was carried out with ultraviolet light (254 nm), followed
diester 35 proceeding at a slower rate.
by staining with a 1% aqueous KMnO4 solution and heating.
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Flash column chromatography was performed on Kieselgel 60 was added dropwise followed by stirring for 15 min at −60 °C.
silica in the solvent system stated. Et3N (20 eq.) was added dropwise and the reaction mixture was
Melting points were recorded on an Electrothermal 9100 stirred and allowed to warm to rt. The reaction mixture was
apparatus, dec refers to decomposition, sub refers to quenched with 2 M HCl and extracted with CH2Cl2 (×3). The
sublimation.
combined organic fraction was dried (MgSO4), filtered and
Optical rotations were measured on a Perkin Elmer Pre- concentrated under reduced pressure to give the crude
cisely/Model-341 polarimeter operating at the sodium D line product, which was purified by flash silica column
with a 100 mm path cell at 20 °C.
chromatography.
HPLC analyses were obtained on a Shimadzu HPLC consist-
ing of a DGU-20A5 degasser, LC-20AT liquid chromatograph,
SIL-20AHT autosampler, CMB-20A communications bus
General procedure C: intermolecular Michael addition–
lactonisation followed by in situ ring-opening
module, SPD-M20A diode array detector and a CTO-20A i-Pr2NEt (2.25 eq.) and pivaloyl chloride (2.25 eq.) were added
column oven which allowed the temperature to be set from to a solution of the appropriate carboxylic acid (1.5 eq.) in
25–40 °C. Separation was achieved using Chiralcel OD-H and CH2Cl2 (to give 0.1 M trichloromethyl ketone) at rt and the
OJ-H columns or Chiralpak AD-H, AS-H, IA, and IB columns.
reaction mixture was stirred for 5 min before cooling to
Infrared spectra (νmax) were recorded on a Shimadzu −78 °C. HBTM-2.1 (2S,3R)-5 (5 mol%), the appropriate α,β-
IRAffinity-1 Fourier transform IR spectrophotometer as thin unsaturated trichloromethyl ketone (1 eq.) and i-Pr2NEt (1.5 eq.)
films using Pike MIRacle ATR accessory. Analysis was carried were added in succession and the reaction mixture was stirred
out using Shimadzu IRsolution v1.50 and only characteristic at −78 °C for 16 h. The appropriate nucleophile (excess) and
peaks are reported.
DMAP (20 mol%) were added and the reaction mixture was
1H, 13C{1H}, and 19F {1H}NMR spectra were acquired on stirred at rt for 24 h. The reaction mixture was diluted with
either a Bruker Avance 300 {δH (300 MHz), δC (75 MHz), δF CH2Cl2 and washed with 1 M HCl and brine. The organic layer
(282 MHz)}, a Bruker Avance II 400 {δH (400 MHz), δC was dried (MgSO4), filtered and concentrated under reduced
(100 MHz), δF (376 MHz)} or a Bruker Ultrashield 500 {δH pressure to give the crude product, which was purified by flash
(500 MHz), δC (125 MHz), δF (471 MHz)} spectrometer at silica column chromatography.
ambient temperature in the deuterated solvent stated. Chemi-
Authentic racemic samples were prepared in an analogous
cal shifts, δ, are quoted in parts per million (ppm) and are fashion using racemic isothiourea catalyst (rac)-HBTM-2.1 5.
referenced to the residual solvent peak. Coupling constants, J,
Preparation of trichloromethyl carbinols
are quoted in Hertz (Hz) to the nearest 0.1 Hz. The following
abbreviations are used: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; and br, broad.
(E)-1,1,1-Trichloro-4-phenylbut-3-en-2-ol
general procedure A, cinnamaldehyde (5.03 mL, 40.0 mmol),
36. Following
Mass spectrometry (m/z) data were acquired by electrospray DMF (30 mL), trichloroacetic acid (9.80 g, 60.0 mmol) and
ionisation (ESI), electron impact (EI), chemical ionisation (CI), sodium trichloroacetate (11.1 g, 60.0 mmol) gave, after column
atmospheric solids analysis probe (ASAP), atmospheric chromatography (90 : 10 Petrol–Et2O, Rf = 0.20), the title com-
pressure chemical ionisation (APCI) or nanospray ionisation pound 36 (4.78 g, 48%) as an orange oil with spectroscopic
(NSI) at the EPSRC UK National Mass Spectrometry Facility at data in accordance with the literature.28 1H NMR (400 MHz,
Swansea University.
CDCl3) δH: 2.92 (1H, d, J 5.6, OH), 4.75–4.80 (1H, m, C(2)H),
6.37 (1H, dd, J 15.9, 6.1, C(3)H), 6.91 (1H, d, J 15.9, C(4)H),
7.28–7.39 (3H, m, ArC(3,5)H and ArC(4)H), 7.43–7.47 (2H, m,
General procedure A: synthesis of trichloromethyl carbinols
Following a literature procedure,19c trichloroacetic acid (1.5 ArC(2,6)H).
eq.) and sodium trichloroacetate (1.5 eq.) were added to a solu-
(E)-1,1,1-Trichloro-4-(4-methoxyphenyl)but-3-en-2-ol 37. Fol-
tion of the appropriate aldehyde (1 eq.) in DMF at 0 °C. The lowing general procedure A, 4-methoxycinnamaldehyde
reaction mixture was stirred in the ice/water bath and allowed (6.49 mL, 40.0 mmol), DMF (30 mL), trichloroacetic acid
to warm slowly to rt over 16 h before being diluted with water (9.80 g, 60.0 mmol) and sodium trichloroacetate (11.1 g,
and extracted with EtOAc (×3). The combined organic fraction 60.0 mmol) gave, after column chromatography (80 : 20 Petrol–
was washed with water (×3), sat. aq. NaHCO3, dried (MgSO4), Et2O, Rf = 0.20), the title compound 37 (9.04 g, 80%) as a white
filtered and concentrated under reduced pressure to give the solid; mp 66–68 °C; νmax (ATR) 3356 (O–H), 2967 (C–H), 1653,
1
crude product, which was purified by flash silica column 1605, 1514; H NMR (500 MHz, CDCl3) δH: 2.98 (1H, d, J 5.8,
chromatography.
OH), 3.82 (3H, s, OCH3), 4.74 (1H, app t, J 6.1, C(2)H), 6.22
(1H, dd, J 15.9, 6.3, C(3)H), 6.83 (1H, d, J 15.9, C(4)H),
6.87–6.91 (2H, m, ArC(3,5)H), 7.37–7.39 (2H, m, ArC(2,6)H);
13C{1H} NMR (125 MHz, CDCl3) δC: 55.5 (OCH3), 83.7 (C(2)),
General procedure B: synthesis of α,β-unsaturated
trichloromethyl ketones
Following a literature procedure,20 a solution of DMSO (8 eq.) 103.1 (C(1)), 114.2 (ArC(3,5)), 120.4 (C(3)), 128.4 (ArC(2,6)),
in CH2Cl2 was added dropwise to a solution of oxalyl chloride 128.5 (ArC(1)), 136.5 (C(4)), 160.1 (ArC(4)); HRMS (APCI+)
(4 eq.) in CH2Cl2 at −60 °C followed by stirring for 2 min at C11H1235Cl3O2 [M + H]+, found 280.9894, requires 280.9897
−60 °C. A solution of the appropriate alcohol (1 eq.) in CH2Cl2 (−1.2 ppm).
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(E)-1,1,1-Trichloro-4-(2-nitrophenyl)but-3-en-2-ol 38. Follow- 19.0 mmol) in CH2Cl2 (20 mL) and Et3N (53.0 mL, 380 mmol)
ing general procedure A, 2-nitrocinnamaldehyde (7.09 mL, gave, after column chromatography (95 : 5 Petrol–Et2O, Rf =
40.0 mmol), DMF (100 mL), trichloroacetic acid (9.80 g, 0.30), the title compound 7 (4.41 g, 93%) as a yellow solid; mp
1
60.0 mmol) and sodium trichloroacetate (11.1 g, 60.0 mmol) 56–58 °C; νmax (ATR) 3059, 3030 (C–H), 1707 (CvO); H NMR
gave, after column chromatography (70 : 30 Petrol–Et2O, Rf = (500 MHz, CDCl3) δH: 7.35 (1H, d, J 15.7, C(3)H), 7.43–7.49 (3H,
0.30), the title compound 38 (3.12 g, 26%) as a white solid; mp m, ArC(3,5)H and ArC(4)H), 7.65–7.66 (2H, m, ArC(2,6)H), 8.01
114–116 °C; νmax (ATR) 3291 (O–H), 2973 (C–H), 1607, 1518; 1H (1H, d, J 15.7, C(4)H); 13C{1H} NMR (125 MHz, CDCl3) δC: 96.6
NMR (300 MHz, DMSO-d6) δH: 4.83 (1H, app t, J 5.8, C(2)H), (C(1)), 115.9 (C(3)), 129.1 (ArC), 129.3 (ArC), 131.9 (ArC(4)),
6.44 (1H, dd, J 15.6, 5.9, C(3)H), 7.15–7.23 (2H, m, C(4)H and 133.9 (ArC(1)), 149.8 (C(4)), 180.2 (C(2)); HRMS (APCI+)
ArCH), 7.56–7.60 (1H, m, ArCH), 7.71–7.76 (2H, m, ArCH), 7.99 C10H835Cl3O [M + H]+, found 248.9634, requires 248.9635
(1H, d, J 8.2, ArC(3)H); 13C{1H} NMR (75 MHz, DMSO-d6) δC: (−0.5 ppm).
81.5 (C(2)), 103.5 (C(1)), 124.3 (ArC(3)), 128.6 (ArC), 129.3
(E)-1,1,1-Trichloro-4-(4-methoxyphenyl)but-3-en-2-one
(ArC), 129.8 (C(4)), 130.0 (C(3)), 130.6 (ArC(1)), 133.6 (ArC), 42. Following general procedure B, oxalyl chloride (6.43 mL,
147.8 (ArC(2)); HRMS (APCI+) C10H1235Cl3NO3 [M + NH4]+, 76.0 mmol) in CH2Cl2 (300 mL), DMSO (10.8 mL, 152 mmol)
found 312.9907, requires 312.9908 (−0.3 ppm).
(E)-1,1,1-Trichloro-4-(4-fluorophenyl)but-3-en-2-ol
in CH2Cl2 (35 mL), (E)-1,1,1-trichloro-4-(4-methoxyphenyl)but-
39. Fol- 3-en-2-ol 37 (5.35 g, 19.0 mmol) in CH2Cl2 (20 mL) and Et3N
lowing general procedure A, 4-fluorocinnamaldehyde (5.00 g, (53.0 mL, 380 mmol) gave, after column chromatography
33.3 mmol), DMF (30 mL), trichloroacetic acid (8.17 g, (90 : 10 Petrol–Et2O, Rf = 0.20), the title compound 42 (4.63 g,
50.0 mmol) and sodium trichloroacetate (9.27 g, 50.0 mmol) 87%) as a yellow solid; mp 98–100 °C; νmax (ATR) 3013, 2835
gave, after column chromatography (85 : 15 Petrol–Et2O, Rf = (C–H), 1699 (CvO), 1587 1562, 1508; 1H NMR (500 MHz,
0.25), the title compound 39 (4.71 g, 52%) as an orange solid CDCl3) δH: 3.87 (3H, s, OCH3), 6.95 (2H, d, J 8.7, ArC(3,5)H),
with spectroscopic data in accordance with the literature.19a 7.21 (1H, d, J 15.5, C(3)H), 7.60–7.63 (2H, m, ArC(2,6)H), 7.97
mp 66–64 °C; {Lit.19a mp 60–62 °C}; 1H NMR (400 MHz, (1H, d, J 15.5, C(4)H); 13C{1H} NMR (125 MHz, CDCl3) δC: 55.6
CDCl3) δH: 2.92 (1H, d, J 5.7, OH), 4.76 (1H, td, J 5.9, 1.3, C(2)H), (OCH3), 96.8 (C(1)), 113.2 (C(3)), 114.7 (ArC(3,5)), 126.7 (ArC(1)),
6.29 (1H, ddd, J 15.9, 6.1, 0.6, C(3)H), 6.87 (1H, d, J 15.9, C(4)H), 131.1 (ArC(2,6)), 149.7 (C(4)), 162.8 (ArC(4)), 180.3 (C(2));
7.01–7.08 (2H, m, ArC(3,5)H), 7.38–7.46 (2H, m, ArC(2,6)H); HRMS (APCI+) C11H1035Cl3O2 [M + H]+, found 278.9747,
19F{1H} NMR (376 MHz, CDCl3) δF: −113.18 (ArC(4)F).
requires 278.9741 (+2.2 ppm).
(E)-1,1,1-Trichloro-4-(furan-2-yl)but-3-en-2-ol 40. Following
(E)-1,1,1-Trichloro-4-(2-nitrophenyl)but-3-en-2-one 43. Fol-
general procedure A, 3-(furan-2-yl)acrylaldehyde (5.00 g, lowing general procedure B, oxalyl chloride (2.85 mL,
40.9 mmol), DMF (30 mL), trichloroacetic acid (10.1 g, 33.6 mmol) in CH2Cl2 (150 mL), DMSO (4.78 mL, 67.2 mmol)
61.4 mmol) and sodium trichloroacetate (11.4 g, 61.4 mmol) in CH2Cl2 (20 mL), (E)-1,1,1-trichloro-4-(2-nitrophenyl)but-3-
gave, after column chromatography (85 : 15 Petrol–Et2O, Rf = en-2-ol 38 (2.49 g, 8.40 mmol) in CH2Cl2 (100 mL) and Et3N
1
0.25), the title compound 40 (4.00 g, 40%) as a yellow oil; H (23.4 mL, 168 mmol) gave, after column chromatography
NMR (400 MHz, CDCl3) δH: 2.89 (1H, d, J 5.9, OH), 4.75 (1H, (75 : 25 Petrol–Et2O, Rf = 0.30), the title compound 43 (2.13 g,
td, J 5.9, 1.3, C(2)H), 6.33 (1H, dd, J 15.8, 5.8, C(3)H), 6.37 (1H, 86%) as a white solid; mp 56–58 °C; νmax (ATR) 3103, 2857 (C–
1
d, J 3.3, ArC(3)H), 6.41 (1H, dd, J 3.3, 1.8, ArC(4)H), 6.72 (1H, H), 1715 (CvO), 1605, 1570, 1520; H NMR (400 MHz, CDCl3)
dd, J 15.8, 1.3, C(4)H), 7.40 (1H, d, J 1.6, ArC(5)H). The title δH: 7.24 (1H, d, J 15.5, C(3)H), 7.60–7.66 (1H, m, ArCH),
compound was carried forward immediately without further 7.70–7.75 (2H, m, ArCH), 8.10–8.12 (1H, m, ArC(3)H), 8.43 (1H,
characterisation due to instability.
d, J 15.5, C(4)H); 13C{1H} NMR (100 MHz, CDCl3) δC: 96.1
(E)-1,1,1-Trichloronon-3-en-2-ol 41. Following general pro- (C(1)), 120.7 (C(3)), 125.3 (ArC(3)), 129.5 (ArC), 130.1 (ArC(1)),
cedure A, (E)-oct-2-enal (5.00 mL, 39.6 mmol), DMF (30 mL), 131.5 (ArC), 133.9 (ArC), 144.9 (C(4)), 148.6 (ArC(2)), 179.1
trichloroacetic acid (9.76 g, 59.4 mmol) and sodium trichloro- (C(2)); HRMS (APCI+) C10H735Cl3NO3 [M + H]+, found 293.9491,
acetate (11.1 g, 59.4 mmol) gave, after column chromatography requires 293.9486 (+1.7 ppm).
(95 : 5 Petrol–Et2O, Rf = 0.20), the title compound 41 (4.71 g,
(E)-1,1,1-Trichloro-4-(4-fluorophenyl)but-3-en-2-one 44. Fol-
48%) as a yellow oil with spectroscopic data in accordance lowing general procedure B, oxalyl chloride (3.17 mL,
with the literature.29 1H NMR (400 MHz, CDCl3) δH: 0.81–0.95 37.4 mmol) in CH2Cl2 (150 mL), DMSO (5.32 mL, 74.7 mmol)
(3H, m, CH3), 1.24–1.48 (6H, m, 3 × CH2), 2.08–2.17 (2H, m, in CH2Cl2 (20 mL), (E)-1,1,1-trichloro-4-(4-fluorophenyl)but-3-
C(5)H2), 2.72 (1H, d, J 5.9, OH), 4.51–4.56 (1H, m, C(2)H), 5.65 en-2-ol 39 (2.52 g, 9.34 mmol) in CH2Cl2 (10 mL) and Et3N
(1H, ddt, J 15.5, 6.5, 1.5, C(3)H), 6.02 (1H, dtd, J 15.5, 6.9, 1.0, (26.1 mL, 187 mmol) gave, after column chromatography
C(4)H).
(95 : 5 Petrol–Et2O, Rf = 0.25), the title compound 44 (2.38 g,
95%) as a white solid with spectroscopic data in accordance
Preparation of α,β-unsaturated trichloromethyl ketones
1
with the literature.19a mp 59–61 °C; {Lit.19a mp 58–60 °C}; H
(E)-1,1,1-Trichloro-4-phenylbut-3-en-2-one
7. Following NMR (500 MHz, CDCl3) δH: 7.10–7.18 (2H, m, ArC(3,5)H), 7.26
general procedure B, oxalyl chloride (6.43 mL, 76.0 mmol) in (1H, d, J 15.6, C(3)H), 7.62–7.70 (2H, m, ArC(2,6)H), 7.97 (1H,
CH2Cl2 (300 mL), DMSO (10.8 mL, 152 mmol) in CH2Cl2 d, J 15.6, C(4)H); 19F{1H} NMR (471 MHz, CDCl3) δF: −106.65
(35 mL), (E)-1,1,1-trichloro-4-phenylbut-3-en-2-ol 36 (4.78 g, (ArC(4)F).
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(E)-1,1,1-Trichloro-4-(furan-2-yl)but-3-en-2-one 45. Following
HPLC or GC analysis not achieved in our hands, ee deter-
general procedure B, oxalyl chloride (5.62 mL, 66.3 mmol) in mined through derivatisation into diester 10.
CH2Cl2 (300 mL), DMSO (9.43 mL, 133 mmol) in CH2Cl2
6-(Dichloromethyl)-3,4-diphenyl-2H-pyran-2-one 9. MeOH
(30 mL), (E)-1,1,1-trichloro-4-(furan-2-yl)but-3-en-2-ol 40 (9 μL) in CH2Cl2 (2.4 mL) was added to a solution of lactone 8
(4.00 g, 16.6 mmol) in CH2Cl2 (20 mL) and Et3N (46.3 mL, (81 mg, 0.22 mmol) and DMAP (5 mg, 0.04 mmol) in CH2Cl2
331 mmol) gave, after column chromatography (90 : 10 Petrol– (2 mL) at rt and the reaction stirred for 6 h. Column chromato-
Et2O, Rf = 0.35), the title compound 45 (1.00 g, 25%) as a light graphy (85 : 15 Petrol: EtOAc, Rf = 0.25) gave the title com-
yellow solid with spectroscopic data in accordance with the lit- pound 9 (47 mg, 65%) as a white solid; mp 196–197 °C; νmax
1
erature.19b mp 40–42 °C; {Lit.19b mp 42–44 °C}; 1H NMR (ATR) 1348, 1647, 1709, 3001, 3030, 3090; H NMR (500 MHz)
(400 MHz, CDCl3) δH: 6.56 (1H, dd, J 3.5, 1.8, ArC(4)H), 6.84 δH: 6.40 (1H, s, CHCl2), 6.73 (1H, s, C(5)H), 7.10–7.12 (2H, m,
(1H, d, J 3.6, ArC(3)H), 7.21 (1H, d, J 15.3, C(3)H), 7.57–7.60 ArH), 7.16 (2H, m, ArH), 7.23–7.30 (6H, m, ArH); 13C{1H} NMR
(1H, m, ArC(5)H), 7.73 (1H, d, J 15.3, C(4)H).
(125 MHz) δC: 65.2 (CHCl2), 107.2 (C(5)H), 126.2 (C(3)), 128.3
(E)-1,1,1-Trichloronon-3-en-2-one 46. Following general pro- (ArCH), 128.4 (ArCH), 128.7 (ArCH), 128.8 (ArCH), 129.3
cedure B, oxalyl chloride (6.51 mL, 76.7 mmol) in CH2Cl2 (ArCH), 130.8 (ArCH), 133.1 (ArC(4)), 136.8 (C(3)ArC(1)), 151.2
(300 mL), DMSO (10.9 mL, 154 mmol) in CH2Cl2 (30 mL), (E)- (C(4)ArC(1)), 155.2 (C(2)), 161.2 (C(6)); HRMS (NSI+)
1,1,1-trichloronon-3-en-2-ol 41 (4.71 g, 19.2 mmol) in CH2Cl2 C18H1335Cl2O2 [M + H]+, found 331.0296, requires 331.0287
(200 mL) and Et3N (53.7 mL, 384 mmol) gave, after column (+2.7 ppm).
chromatography (97 : 3 Petrol–Et2O, Rf = 0.35), the title com-
pound 46 (4.11 g, 88%) as a yellow oil; νmax (ATR) 2928 (C–H),
1722 (CvO), 1625 (CvC); 1H NMR (400 MHz, CDCl3) δH:
0.87–0.93 (3H, m, CH3), 1.28–1.38 (4H, m, 2 CH2), 1.48–1.56
(2H, m, C(6)H2), 2.34 (2H, app qd, J 7.2, 1.6, C(5)H2), 6.73 (1H,
dt, J 15.3, 1.6, C(3)H), 7.34 (1H, dt, J 15.4, 7.0, C(4)H); 13C{1H}
NMR (100 MHz, CDCl3) δC: 14.1 (CH3), 22.5 (CH2), 27.6
(C(6)H2), 31.5 (CH2), 33.2 (C(5)H2), 96.5 (C(1)), 119.7 (C(3)),
156.0 (C(4)), 179.8 (C(2)); HRMS (APCI+) C9H1435Cl3O [M + H]+,
found 243.0104, requires 243.0105 (−0.3 ppm).
Dimethyl (2R,3R)-2,3-diphenylpentanedioate 10
Method A. MeOH (6 mL) was added to a solution of lactone
8 (140 mg, 0.38 mmol) and DMAP (9 mg, 0.076 mmol) in
CH2Cl2 (6 mL) and reaction stirred at rt for 16 h. Concentration
of reaction under reduced pressure gave crude product (87 : 13
dr anti : syn). Column chromatography (80 : 20 Petrol–Et2O, Rf =
0.25) gave the title compound 9 (74 mg, 62%) as a white solid
(>98 : 2 dr anti : syn). All data in accordance to that provided for
method B below.
Method B. Following general procedure C, phenylacetic acid
(81.6 mg, 0.60 mmol), i-Pr2NEt (156 μL, 0.90 mmol), pivaloyl
chloride (111 μL, 0.90 mmol) in CH2Cl2 (4 mL), HBTM-2.1
(2S,3R)-5 (6.16 mg, 0.02 mmol, 5 mol%), (E)-1,1,1-trichloro-4-
Preparation of products
(3R,4R)-3,4-Diphenyl-6-(trichloromethyl)-3,4-dihydro-2H-
pyran-2-one 8. Phenyl acetic acid (164 mg, 1.2 mmol), i-Pr2NEt
(312 μL, 1.8 mmol), pivaloyl chloride (222 μL, 1.8 mmol), in
CH2Cl2 (8 mL), followed by HBTM-2.1 (2S,3R)-5 (12 mg,
phenylbut-3-en-2-one
7 (99.8 mg, 0.40 mmol), i-Pr2NEt
(104 μL, 0.60 mmol), MeOH (4 mL) and DMAP (9.76 mg,
0.08 mmol) gave the crude product (89 : 11 dr anti : syn).
Column chromatography (80 : 20 Petrol–Et2O, Rf = 0.25) gave
the title compound 10 (97.0 mg, 78%) as a white solid (>98 : 2
dr anti : syn) with spectroscopic data in accordance with the lit-
erature.13 mp 68–70 °C; {Lit.13 mp 62–63 °C}; [α]2D0 −116.6 (c
1.0 CHCl3); {Lit.13 [α]D20 −125.7 (c 0.3 CHCl3) for 97% ee (2R,3R)
stereoisomer}; Chiral HPLC analysis, Chiralpak AD-H
(95 : 5 hexane–IPA, flow rate 1 mL min−1, 211 nm, 30 °C) tR
(2S,3S): 10.2 min, tR (2R,3R): 11.7 min, >99% ee; 1H NMR
(500 MHz, CDCl3) δH: 2.78–2.86 (2H, m, C(4)HH and C(4)HH),
3.51 (3H, s, C(5)O2CH3), 3.69 (3H, s, C(1)O2CH3), 3.84–3.90
(2H, m, C(2)H and C(3)H), 7.00–7.02 (2H, m, ArCH), 7.03–7.06
(1H, m, ArCH), 7.08–7.14 (7H, m, ArCH).
0.04 mmol), (E)-1,1,1-trichloro-4-phenylbut-3-en-2-one
7
(200 mg, 0.8 mmol), i-Pr2NEt (208 μL, 1.2 mmol) gave crude
product (87 : 13 dr anti : syn). Column chromatography
(92.5 : 7.5 Petrol–EtOAc, Rf = 0.25) gave title compound 8
(244 mg, 82%) as a white solid (87 : 13 dr anti : syn) mp
86–88 °C; νmax (ATR) 1003, 1119, 1454, 1773, 2031, 3063;
[α]2D0 −0.986 (c 0.5 CHCl3); Data for major anti diastereoisomer:
1H NMR (500 MHz, CDCl3) δH 3.97–4.01 (1H, m, C(4)H), 4.05–4.07
(1H, m, C(3)H), 6.37 (1H, d, J 4.1, C(5)H), 7.09 (2H, d, J 6.7,
ArH), 7.16 (2H, d, J 6.4, ArH), 7.27–7.35 (6H, m, ArH); 13C{1H}
NMR (125 MHz, CDCl3) δC 45.2 (C(3)H), 52.6 (C(4)H), 90.1
(CCl3), 107.8 (C(5)H), 127.5 (ArCH), 128.1 (ArCH), 128.2
(ArCH), 128.3 (ArCH), 129.0 (ArCH), 129.3 (ArCH), 135.4 (ArC),
(2R,3R)-N1,N5-Diisopropyl-2,3-diphenylpentanediamide
139.4 (ArC), 149.0 (ArC), 166.4 (C(2)); Data for minor syn diaster- 11. Following general procedure C, phenylacetic acid (81.6 mg,
1
eoisomer; H NMR (500 MHz, CDCl3) δH 3.73 (1H, br s, C(4)H), 0.60 mmol), i-Pr2NEt (156 μL, 0.90 mmol), pivaloyl chloride
4.28 (1H, d, J 7.0, C(3)H), 6.54 (1H, d, J 6.0, C(5)H), 6.76 (2H, d, (111 μL, 0.90 mmol) in CH2Cl2 (4 mL), HBTM-2.1 (2S,3R)-5
J 6.8, ArH), 6.81 (2H, d, J 6.9, ArH), 7.27–7.35 (6H, m, ArH); 13C (6.16 mg, 0.02 mmol, 5 mol%), (E)-1,1,1-trichloro-4-phenylbut-
{1H} NMR (125 MHz, CDCl3) δC 44.6 (C(3)H), 50.9 (C(4)H), 91.2 3-en-2-one
7 (99.8 mg, 0.40 mmol), i-Pr2NEt (104 μL,
(CCl3), 108.6 (C(5)H), 127.2 (ArCH), 128.0 (ArCH), 128.4 0.60 mmol), isopropylamine (4 mL) and DMAP (9.76 mg,
(ArCH), 128.7 (ArCH), 128.9 (ArCH), 128.9 (ArC), 129.6 (ArC), 0.08 mmol) gave the crude product (90 : 10 dr anti : syn).
129.8 (ArCH), 149.7 (ArC), 166.1 (C(2)); HRMS (NSI+) Column chromatography (EtOAc, Rf = 0.35) gave the title com-
C18H1335Cl3O2Na [M + Na]+, found 388.9880, requires 388.9873 pound 11 (100 mg, 67%) as a white solid (>98 : 2 dr anti : syn)
(+1.7 ppm).
with spectroscopic data in accordance with the literature.13
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mp 250–252 °C; {Lit.13 mp 264–266 °C}; [α]D20 −26.0 (c 0.1 (>98 : 2 dr anti : syn). mp 110–112 °C; [α]D20 −84.3 (c 0.4 CHCl3);
CHCl3); {Lit.13 [α]D20 −20.0 (c 0.1 CHCl3) for 99% ee (2R,3R) Chiral HPLC analysis, Chiralpak AD-H (95 : 5 hexane–IPA, flow
stereoisomer}; Chiral HPLC analysis, Chiralpak AD-H rate 1 mL min−1, 211 nm, 30 °C) tR (2S,3S): 23.6 min, tR
(95 : 5 hexane–IPA, flow rate 1 mL min−1, 211 nm, 30 °C) tR (3R,4R): 26.7 min, 99% ee; νmax (ATR) 3378, 3308, 2974, 1740,
(2S,3S): 7.1 min, tR (2R,3R): 23.5 min, >99% ee; 1H NMR 1722, 1659, 1636, 1533, 1452, 1369; 1H NMR (300 MHz, CDCl3)
(400 MHz, CD3OD) δH: 0.72 (3H, d, J 6.6, CH3), 0.94 (3H, d, J δH: 1.02 (3H, d, J 6.54, NCH(CH3)2), 1.12 (3H, d, J 6.54, NCH-
6.6, CH3), 1.03 (3H, d, J 6.6, CH3), 1.18 (3H, d, J 6.6, CH3), 2.50 (CH3)2), 2.80 (1H, dd, J 15.4, 9.3, C(2)HH), 2.92 (1H, dd, J 15.4,
(1H, dd, J 13.3, 11.3, C(4)HH), 2.64 (1H, dd, J 13.3, 4.1, C(4) 4.5, C(2)HH), 3.50 (3H, s, OCH3), 3.58 (1H, d, J 10.3, C(4)H),
HH), 3.64–3.73 (2H, m, C(2)H and CH(CH3)2), 3.83 (1H, td, J 3.89 (1H, ddd, J 10.3, 9.8, 4.5, C(3)H), 4.00–4.11 (1H, m, NCH-
11.3, 4.1, C(3)H), 3.95 (1H, heptet, J 6.5, CH(CH3)2), 6.97–7.10 (CH3)2), 5.42 (1H, br d, J 7.6, NH), 7.00–7.16 (10H, m, ArCH);
(8H, m, ArCH), 7.21–7.24 (2H, m, ArCH).
Allyl (2R,3R)-6,6,6-trichloro-5-oxo-2,3-diphenylhexanoate (NCH(CH3)2), 38.9 (C(2)H2), 41.7 (C(3)H), 45.5 (NCH), 51.6
13C{1H} NMR (100 MHz, CDCl3) δC: 22.6 (NCH(CH3)2), 22.9
12. Following general procedure C, phenylacetic acid (81.6 mg, (OCH3), 58.4 (C(4)H), 126.7 (ArCH), 127.1 (ArCH), 128.2
0.60 mmol), i-Pr2NEt (156 μL, 0.90 mmol), pivaloyl chloride (ArCH), 128.3 (ArCH), 128.4 (ArCH), 128.5 (ArCH), 138.0 (ArC),
(111 μL, 0.90 mmol) in CH2Cl2 (4 mL), HBTM-2.1 (2S,3R)-5 140.9 (ArC), 171.3 (C(5)), 172.6 (C(1); HRMS (NSI+) C21H26NO3
(6.16 mg, 0.02 mmol, 5 mol%), (E)-1,1,1-trichloro-4-phenylbut- [M + H]+, found 340.1909, requires 340.1907 (+0.5 ppm).
3-en-2-one
7
(99.8 mg, 0.40 mmol), i-Pr2NEt (104 μL,
Dimethyl (2R,3R)-2-(4-methoxyphenyl)-3-phenylpentanedio-
0.60 mmol), allyl alcohol (4 mL) and DMAP (9.76 mg, ate 14. Following general procedure C, 4-methoxyphenylacetic
0.08 mmol) gave the crude product (89 : 11 dr anti : syn). acid (99.7 mg, 0.60 mmol), i-Pr2NEt (156 μL, 0.90 mmol), piva-
Column chromatography (95 : 5 Petrol–Et2O, Rf = 0.25) gave the loyl chloride (111 μL, 0.90 mmol) in CH2Cl2 (4 mL), HBTM-2.1
title compound 12 (102 mg, 60%) as a white solid (>98 : 2 dr (2S,3R)-5 (6.16 mg, 0.02 mmol, 5 mol%), (E)-1,1,1-trichloro-4-
anti : syn). mp 90–92 °C; [α]2D0 −50.8 (c 0.25 CH2Cl2); Chiral phenylbut-3-en-2-one
7 (99.8 mg, 0.40 mmol), i-Pr2NEt
HPLC analysis, Chiralpak AD-H (95 : 5 hexane–IPA, flow rate (104 μL, 0.60 mmol), MeOH (4 mL) and DMAP (9.76 mg,
1 mL min−1, 211 nm, 30 °C) tR (2S,3S): 8.1 min, tR (2R,3R): 0.08 mmol) gave the crude product (92 : 8 dr anti : syn). Column
9.5 min, 99% ee; νmax (ATR) 3030, 2945 (C–H), 1746 (CvO), chromatography (75 : 25 Petrol–Et2O, Rf = 0.25) gave the
1726 (CvO); 1H NMR (500 MHz, CDCl3) δH: 3.35 (1H, dd, J title compound 14 (105 mg, 77%) as a white solid (>98 : 2 dr
17.7, 3.1, C(4)HH), 3.67 (1H, dd, J 17.7, 10.2, C(4)HH), 3.96 anti : syn) with spectroscopic data in accordance with the litera-
(1H, d, J 10.9, C(2)H), 4.02 (1H, td, J 10.5, 3.1, C(3)H), 4.56–4.67 ture.13 mp 96–98 °C; {Lit.13 mp 99–101 °C}; [α]D20 −126.8 (c 0.5
(2H, m, CO2CHH and CO2CHH), 5.18–5.23 (2H, m, vCHH and CHCl3); {Lit.13 [α]D20 −135.1 (c 0.2 CHCl3) for >99% ee (2R,3R)
vCHH), 5.85 (1H, app ddt, J 17.1, 10.5, 5.7, vCH), 7.03–7.16 stereoisomer}; Chiral HPLC analysis, Chiralpak AD-H
(10H, m, ArH); 13C{1H} NMR (125 MHz, CDCl3) δC: 38.8 (C(4)), (95 : 5 hexane–IPA, flow rate 1 mL min−1, 211 nm, 30 °C) tR
45.0 (C(3)), 57.1 (C(2)), 65.8 (CO2CH2), 118.8 (CHvCH2), 127.1 (2S,3S): 16.7 min, tR (2R,3R): 22.9 min, >99% ee; 1H NMR
(ArC), 127.6 (ArC), 128.3 (ArC), 128.5 (ArC), 128.5 (ArC), 128.6 (400 MHz, CDCl3) δH: 2.73–2.82 (2H, m, C(4)HH and C(4)HH),
(ArC), 131.8 (CHvCH2), 136.4 (ArC), 139.3 (ArC), 172.6 (C(1)), 3.51 (3H, s, C(5)O2CH3), 3.69 (3H, s, CH3), 3.70 (3H, s, CH3),
188.1 (C(5)); HRMS (NSI+) C21H2035Cl3O3 [M + H]+, found 3.78–3.83 (2H, m, C(2)H and C(3)H), 6.64–6.68 (2H, m, C(2)
425.0474, requires 425.0473 (+0.3 ppm).
Methyl (3R,4R)-5-(isopropylamino)-5-oxo-3,4-diphenylpen-
ArC(3,5)H), 6.99–7.14 (7H, m, ArCH).
Dimethyl (2R,3R)-3-phenyl-2-(4-(trifluoromethyl)phenyl)-
tanoate 13. Phenylacetic acid (81.7 mg, 0.60 mmol) was dis- pentanedioate 15. Following general procedure C, 2-(4-(tri-
solved in CH2Cl2 (4 mL) before i-Pr2NEt (156 μL, 0.90 mmol) fluoromethyl)phenyl)acetic acid (122.5 mg, 0.60 mmol),
and pivaloyl chloride (111 μL, 0.90 mmol) were added. After i-Pr2NEt (156 μL, 0.90 mmol), pivaloyl chloride (111 μL,
stirring at rt for 5 min the solution was cooled to −78 °C and 0.90 mmol) in CH2Cl2 (4 mL), HBTM-2.1 (2S,3R)-5 (6.16 mg,
HBTM-2.1 (2S,3R)-5 (6.16 mg, 0.02 mmol, 5 mol%), (E)-1,1,1- 0.02 mmol, 5 mol%), (E)-1,1,1-trichloro-4-phenylbut-3-en-2-one
trichloro-4-phenylbut-3-en-2-one
7 (99.8 mg, 0.40 mmol), 7 (99.8 mg, 0.40 mmol), i-Pr2NEt (104 μL, 0.60 mmol), MeOH
i-Pr2NEt (104 μL, 0.60 mmol) were added in succession. The (4 mL) and DMAP (9.76 mg, 0.08 mmol) gave the crude
reaction mixture was stirred at −78 °C for 16 h before i-PrNH2 product (85 : 15 dr anti : syn). Column chromatography (90 : 10
(111 μL, 1.30 mmol) was added and the mixture warmed to rt. Hexane–EtOAc, Rf = 0.15) gave the title compound 15 (99.0 mg,
Upon consumption of the intermediate dihydropyranone by 65%) as a white solid (>98 : 2 dr anti : syn). mp 96–98 °C;
TLC analysis, MeOH (4 mL) and DMAP (9.8 mg, 0.08 mmol) [α]2D0 −84.8 (c 0.8 CHCl3); Chiral HPLC analysis, Chiralpak
were added and the reaction stirred overnight at rt. The solu- AD-H (95 : 5 hexane–IPA, flow rate 1 mL min−1, 211 nm, 30 °C)
tion was diluted with CH2Cl2 and washed with 1 M HCl (2 × tR (2S,3S): 11.4 min, tR (2R,3R): 12.9 min, 91% ee; νmax (ATR)
20 mL) and brine (2 × 20 mL) before being dried over MgSO4, 2954, 1732, 1439, 1325, 1246, 1111; 1H NMR (400 MHz, CDCl3)
filtered and concentrated under reduced pressure. The crude δH: 2.79–2.82 (2H, m, C(4)HH and C(4)HH), 3.52 (3H, s,
product was purified by column chromatography (hexane to C(5)O2CH3), 3.71 (3H, s, C(1)O2CH3), 3.83–3.95 (2H, m, C(2)H
60 : 40 hexane–EtOAc, Rf = 0.21). The resulting solid was and C(3)H), 6.97–7.00 (2H, m, C(3)ArC(2,6)H), 7.03–7.15 (3H, m,
further purified by recrystallisation from Et2O and hexane to C(3)ArC(3,4,5)H), 7.25 (2H, d, J 8.2, C(2)ArC(2,6)H), 7.39 (2H, d,
give the title compound 13 (57 mg, 42%) as a white solid J 8.2, C(2)ArC(3,5)H); 13C{1H} NMR (125 MHz, CDCl3) δC: 39.4
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(C(4)), 45.5 (C(3)), 51.8 (C(5)O2CH3), 52.5 (C(1)O2CH3), 57.0 (C(2)), Rf = 0.25) gave the title compound 19 (81 mg, 64%) as a white
1
3
124.1 (q, JCF 271.9, CF3), 125.3 (q, JCF 3.7, C(2)ArC(3,5)) solid (>98 : 2 dr anti : syn) with spectroscopic data in accord-
127.1 (ArC), 128.1 (ArC), 128.5 (ArC), 129.1 (ArC), 129.6 (q, JCF ance with the literature.13 Mp 61–64 °C {Lit.13 60–64 °C}; [α]2D0
2
32.4, C(2)ArC(4)), 139.7 (C(2)ArC(1)), 140.7 (C(3)ArC(1)), 171.8 −72.0 (c 0.5 CHCl3); {Lit.13 [α]D20 −69.0 (c 0.5 CHCl3) for 97% ee
(C(5)), 172.8 (C(1)); 19F{1H} NMR (470 MHz, CDCl3) δF: −62.6; (2R,3R) stereoisomer}; Chiral HPLC analysis, Chiralpak AD-H
HRMS (NSI+) C20H20O4F3 [M + H]+, found 381.1309, requires (95 : 5 hexane–IPA, flow rate 1 mL min−1, 211 nm, 30 °C) tR
381.1308 (+0.2 ppm).
(2R,3R): 16.9 min, tR (2S,3S): 18.3 min, >99% ee; 1H NMR
Dimethyl (2R,3R)-2-(4-fluorophenyl)-3-phenylpentanedioate (500 MHz, CDCl3) δH: 2.75–2.83 (2H, m, C(4)HH and C(4)HH),
16. Following general procedure C, 2-(4-fluorophenyl)acetic 3.52 (3H, s, C(5)O2CH3), 3.71 (3H, s, C(1)O2CH3), 3.77–3.82
acid (92.5 mg, 0.60 mmol), i-Pr2NEt (156 μL, 0.90 mmol), piva- (1H, m, C(3)H), 4.00 (1H, d, J 10.2, C(2)H), 6.85 (1H, dd, J 1.1,
loyl chloride (111 μL, 0.90 mmol) in CH2Cl2 (4 mL), HBTM-2.1 5.0, C(2)ArH), 6.91 (1H, dd, J 1.0, 2.9, C(2)ArH), 7.00–7.02 (2H,
(2S,3R)-5 (6.16 mg, 0.02 mmol, 5 mol%), (E)-1,1,1-trichloro-4- m, C(3)ArH), 7.09–7.12 (2H, m, ArH), 7.14–7.17 (2H, m, ArH).
phenylbut-3-en-2-one
7
(99.8 mg, 0.40 mmol), i-Pr2NEt
Dimethyl
(2S,3R)-3-phenyl-2-((E)-prop-1-en-1-yl)pentane-
(104 μL, 0.60 mmol), MeOH (4 mL) and DMAP (9.76 mg, dioate 20. Following general procedure C, 3-pentenoic acid
0.08 mmol) gave the crude product (90 : 10 dr anti : syn). (61 μL, 0.6 mmol), i-Pr2NEt (156 μL, 0.90 mmol, pivalolyl chlor-
Column chromatography (80 : 20 Hexane–EtOAc, Rf = 0.27) ide (111 μL 0.90 mmol), in CH2Cl2 (4 mL), HBTM-2.1 (2S,3R)-5
gave the title compound 16 (91.0 mg, 69%) as a white solid (6.16 mg, 0.02 mmol), (E)-1,1,1-trichloro-4-phenylbut-3-en-2-
(>98 : 2 dr anti : syn) with spectroscopic data in accordance one 7 (99.8 mg, 0.40 mmol), i-Pr2NEt (104 μL, 0.60 mmol) and
with the literature.13 mp 84–85 °C; {Lit.13 mp 86–88 °C}; MeOH (5 mL) gave the crude product (85 : 15 dr anti : syn).
[α]2D0 −114.3 (c 0.7 CHCl3); {Lit.13 [α]D20 −119.5 (c 0.2 CHCl3) for Column chromatography (90 : 10 Petrol: EtOAc, Rf = 0.25) gave
98% ee (2R,3R) stereoisomer}; Chiral HPLC analysis, Chiralpak the title compound 20 (86 mg, 78%) as a colourless oil (>98 : 2
AD-H (95 : 5 hexane–IPA, flow rate 1 mL min−1, 211 nm, 30 °C) dr anti : syn) with spectroscopic data in accordance with the lit-
tR (2S,3S): 11.7 min, tR (2R,3R): 13.5 min, 99% ee; 1H NMR erature.13 [α]2D0 −67.3 (c 0.5 CHCl3); {Lit.13 [α]2D0 −69.0 (c 0.5
(300 MHz, CDCl3) δH: 2.74–2.83 (2H, m, C(4)HH and C(4)HH), CHCl3) for >99% ee (2S,3R) stereoisomer}; Chiral HPLC analy-
3.51 (3H, s, C(5)O2CH3), 3.70 (3H, s, C(1)O2CH3), 3.80–3.86 sis, Chiralpak OD-H (97 : 3 hexane–IPA, flow rate 1 mL min−1
,
(2H, m, C(2)H and C(3)H), 6.77–6.85 (2H, m, ArCH), 6.95–6.99 220 nm, 30 °C) tR (2R,3S): 9.82 min, tR (2S,3R): 15.5 min, >99%
(2H, m, ArCH), 7.03–7.15 (5H, m, ArCH); 19F{1H} NMR ee; 1H NMR (500 MHz, CDCl3) δH 1.55 (3H, dd, J 1.3, 6.3,
(282 MHz, CDCl3) δF: −115.6.
C(2)C(3′)H), 2.69 (2H, d, J 7.6, C(4)H), 3.27 (1H, d, J 8.7, C(3)H),
Dimethyl (2R,3R)-3-phenyl-2-(3-tolyl)pentanedioate 17. Fol- 3.52–3.62 (4H, m, C(2)H and C(5)O2CH3), 3.67 (C(1)O2CH3),
lowing general procedure C, m-tolylacetic acid (90 mg, 5.22–5.44 (2H, m, C(2)C(1′)H and C(2)C(2′)H), 7.09–7.12 (2H,
0.6 mmol), i-Pr2NEt (156 μL, 0.90 mmol, pivalolyl chloride m, C(3)ArH), 7.18–7.29 (3H, m, C(3)ArH).
(111 μL 0.90 mmol), in CH2Cl2 (4 mL), HBTM-2.1 (2S,3R)-5
Dimethyl
(2S,3R)-3-phenyl-2-((E)-3-phenylprop-1-en-1-yl)-
(6.16 mg, 0.02 mmol), (E)-1,1,1-trichloro-4-phenylbut-3-en-2- pentanedioate 21. Following general procedure C, (E)-5-phe-
one 7 (99.8 mg, 0.40 mmol), i-Pr2NEt (104 μL, 0.60 mmol) and nylpent-3-enoic acid (106 mg, 0.60 mmol), i-Pr2NEt (156 μL,
MeOH (5 mL) gave the crude product (92 : 8 dr anti : syn). 0.90 mmol), pivaloyl chloride (111 μL, 0.90 mmol) in CH2Cl2
Column chromatography (90 : 10 Petrol: EtOAc, Rf = 0.22) gave (4 mL), HBTM-2.1 (2S,3R)-5 (6.16 mg, 0.02 mmol, 5 mol%), (E)-
the title compound 17 (79 mg, 60%) as a white solid (>98 : 2 dr 1,1,1-trichloro-4-phenylbut-3-en-2-one 7 (99.8 mg, 0.40 mmol),
anti : syn) with spectroscopic data in accordance with the litera- i-Pr2NEt (104 μL, 0.60 mmol), MeOH (4 mL) and DMAP
ture.13 Mp 72–74 °C {Lit.13 73–75 °C}; [α]2D0 −135.0 (c 0.1 (9.76 mg, 0.08 mmol) gave the crude product (95 : 5 dr anti :
CHCl3); {Lit.13 [α]D20 −127.4 (c 0.1 CHCl3) for 99% ee (2R, 3R) syn). Column chromatography (80 : 20 Petrol–Et2O, Rf = 0.25)
stereoisomer}; Chiral HPLC analysis, Chiralpak AD-H gave the title compound 21 (105 mg, 74%) as a colourless oil
(95 : 5 hexane–IPA, flow rate 1 mL min−1, 211 nm, 30 °C) tR (>98 : 2 dr anti : syn) with spectroscopic data in accordance with
(2S, 3S): 8.7 min, tR (2R, 3R): 10.4 min, 99% ee; 1H NMR the literature.13 [α]2D0 −6.7 (c 1.0 CHCl3); {Lit.13 [α]2D0 −6.9 (c 1.0
(500 MHz, CDCl3) δH: 2.21 (3H, s, ArCH3), 2.79–2.84 (2H, m, CHCl3) for >99% ee (2S,3R) stereoisomer}; Chiral HPLC analy-
C(4)HH and C(4)HH), 3.51 (3H, s, C(5)O2CH3), 3.68 (3H, s, sis, Chiralcel OJ-H (99 : 1 hexane–IPA, flow rate 1 mL min−1
,
C(1)O2CH3), 3.80–3.88 (2H, m, C(2)H and C(3)H), 6.90–6.92 211 nm, 40 °C) tR (2S,3R): 44.0 min, tR (2R,3S): 48.4 min, 99%
(2H, m, ArH), 6.94 (1H, br s, C(2)Ar(2)H), 7.00–7.07 (4H, m, ee; 1H NMR (400 MHz, CDCl3) δH: 2.69 (2H, app. d, J 7.5,
ArH), 7.10–7.13 (2H, m, ArH).
C(4)HH and C(4)HH), 3.20 (2H, app. d, J 6.3, C(2)C(3′)HH and
Dimethyl (2R,3R)-3-phenyl-2-(thiophen-3-yl)pentanedioate C(2)C(3′)HH), 3.33 (1H, t, J 9.3, C(2)H), 3.53 (3H, s, C(5)O2CH3),
19. Following general procedure C, 3-thiophene acetic acid 3.57–3.63 (1H, m, C(3)H), 3.71 (3H, s, C(1)O2CH3), 5.34 (1H,
(85 mg, 0.6 mmol), i-Pr2NEt (156 μL, 0.90 mmol, pivalolyl ddt, J 15.3, 9.3, 1.3, C(2)C(1′)H), 5.42–5.53 (1H, m, C(2)C(2′)H),
chloride (111 μL 0.90 mmol), in CH2Cl2 (4 mL), HBTM-2.1 6.75–6.79 (2H, m, ArCH), 7.11–7.32 (8H, m, ArCH).
(2S,3R)-5 (6.16 mg, 0.02 mmol), (E)-1,1,1-trichloro-4-phenylbut-
Dimethyl
(2R,3R)-3-(4-methoxyphenyl)-2-phenylpentane-
3-en-2-one (99.8 mg, 0.40 mmol), i-Pr2NEt (104 μL, dioate 23. Following general procedure C, phenylacetic acid
7
0.60 mmol) and MeOH (5 mL) gave the crude product (81 : 19 (81.75 mg, 0.60 mmol), i-Pr2NEt (156 μL, 0.90 mmol), pivaloyl
dr anti : syn). Column chromatography (90 : 10 Petrol: EtOAc, chloride (111 μL, 0.90 mmol) in CH2Cl2 (4 mL), HBTM-2.1
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(2S,3R)-5 (6.16 mg, 0.02 mmol, 5 mol%), (E)-1,1,1-trichloro-4- min−1, 211 nm, 30 °C) tR (2R,3R): 10.2 min, tR (2S,3S):
(4-methoxyphenyl)but-3-en-2-one 42 (112 mg, 0.40 mmol), 11.1 min, 99% ee; 1H NMR (500 MHz, CDCl3) δH: 2.75 (1H, dd,
i-Pr2NEt (104 μL, 0.60 mmol), MeOH (4 mL) and DMAP J 15.4, 10.0, C(4)HH), 2.82 (1H, dd, J 15.4, 4.4, C(4)HH), 3.52
(9.76 mg, 0.08 mmol) gave the crude product (90 : 10 dr anti : (3H, s, C(5)O2CH3), 3.69 (3H, s, C(1)O2CH3), 3.79 (1H, d, J 10.9,
syn). Column chromatography (80 : 20 Hexane–EtOAc, Rf
=
C(2)H), 3.86 (1H, app. td, J 10.4, 4.4, C(3)H), 6.77–6.82 (2H, m,
0.29) gave the title compound 23 (99.0 mg, 73%) as a thick col- C(3)ArC(3,5)H), 6.94–6.97 (2H, m, C(3)ArC(2,6)H), 7.08–7.17
ourless oil (96 : 4 dr anti : syn) with spectroscopic data in (5H, m, ArCH); 19F{1H} NMR (470 MHz, CDCl3) δF: −115.92
accordance with the literature.13 [α]D20 −98.5 (c 0.5 CHCl3); (C(3)ArC(4)F).
{Lit.13 [α]D20 −105.7 (c 0.2 CHCl3) for 99% ee (2R,3R) stereo-
Dimethyl
(2R,3R)-3-(furan-2-yl)-2-phenylpentanedioate
isomer}; Chiral HPLC analysis, Chiralpak AD-H (95 : 5 hexane– 26. Following general procedure C, phenylacetic acid (81.7 mg,
IPA, flow rate 1 mL min−1, 211 nm, 30 °C) tR (2S,3S): 18.7 min, 0.60 mmol), i-Pr2NEt (156 μL, 0.90 mmol), pivaloyl chloride
1
tR (2R,3R): 20.1 min, >99% ee; H NMR (300 MHz, CDCl3) δH: (111 μL, 0.90 mmol) in CH2Cl2 (4 mL), HBTM-2.1 (2S,3R)-5
2.70–2.84 (2H, m, C(4)HH and C(4)HH), 3.51 (3H, s, C(5) (6.16 mg, 0.02 mmol, 5 mol%), (E)-1,1,1-trichloro-4-(furan-2-yl)
O2CH3), 3.68 (6H, s, C(1)O2CH3 and C(3)ArOCH3), 3.77–3.84 but-3-en-2-one 45 (95.8 mg, 0.40 mmol), i-Pr2NEt (104 μL,
(2H, m, C(2)H and C(3)H), 6.64 (2H, d, J 8.7, C(3)ArC(3,5)H), 0.60 mmol), MeOH (4 mL) and DMAP (9.76 mg, 0.08 mmol)
6.91 (2H, d, J 8.7, C(3)ArC(2,6)H), 7.10–7.15 (5H, m, C(2)ArCH). gave the crude product (80 : 20 dr anti : syn). Column chromato-
Dimethyl (2R,3R)-3-(2-nitrophenyl)-2-phenylpentanedioate graphy (90 : 10 Hexane–EtOAc, Rf = 0.14) gave the title com-
24. Following general procedure C, phenylacetic acid (81.6 mg, pound 26 (97.0 mg, 80%) as a colourless oil (80 : 20 dr
0.60 mmol), i-Pr2NEt (156 μL, 0.90 mmol), pivaloyl chloride anti : syn). [α]2D0 −75.6 (c 0.6 CHCl3); νmax (ATR) 2953, 1730, 1454,
(111 μL, 0.90 mmol) in CH2Cl2 (4 mL), HBTM-2.1 (2S,3R)-5 1435, 1350, 1269, 1148; Data for major anti diastereoisomer:
(6.16 mg, 0.02 mmol, 5 mol%), (E)-1,1,1-trichloro-4-(2-nitro- Chiral HPLC analysis, Chiralpak AD-H (95 : 5 hexane–IPA, flow
phenyl)but-3-en-2-one 43 (118 mg, 0.40 mmol), i-Pr2NEt rate 1 mL min−1, 211 nm, 30 °C) tR (2S,3S): 10.9 min, tR
(104 μL, 0.60 mmol), MeOH (4 mL) and DMAP (9.76 mg, (2R,3R): 12.3 min, 98% ee; 1H NMR (500 MHz, CDCl3) δH:
0.08 mmol) gave the crude product (95 : 5 dr anti : syn). Column 2.71–2.74 (1H, m, C(4)HAHB), 2.81–2.89 (1H, m, C(4)HAHB),
chromatography (65 : 35 Petrol–Et2O, Rf = 0.25) gave the title 3.61 (3H, s, C(5)O2CH3), 3.69 (3H, s, C(1)O2CH3), 3.97–4.02
compound 24 (114 mg, 80%) as a light yellow solid (>98 : 2 dr (2H, m, C(2)H and C(3)H), 5.81 (1H, dd, J 3.3, 0.6, C(3)ArC(3)
anti : syn). mp 76–78 °C; [α]2D0 −106.6 (c 1.0 CHCl3); Chiral H), 6.06 (1H, dd, J 3.3, 1.9, C(3)ArC(4)H), 7.15–7.25 (6H, m,
HPLC analysis, Chiralpak AD-H (95 : 5 hexane–IPA, flow rate C(2)ArCH and C(3)ArC(5)H); 13C{1H} NMR (125 MHz, CDCl3)
1 mL min−1, 211 nm, 30 °C) tR (2S,3S): 29.0 min, tR (2R,3R): δC: 36.9 (C(4)), 39.4 (C(3)), 51.8 (C(5)O2CH3), 52.3 (C(1)O2CH3),
31.1 min, >99% ee; νmax (ATR) 2957 (C–H), 1725 (CvO), 1526 55.0 (C(2)), 107.5 (C(3)ArC(3)), 110.0 (C(3)ArC(4)), 127.5
(N–O), 1354 (N–O); 1H NMR (400 MHz, CDCl3) δH: 2.88 (1H, (C(2)ArC), 128.3 (C(2)ArC), 128.4 (C(2)ArC), 136.5 (C(2)ArC(1)), 141.4
dd, J 15.9, 4.4, C(4)HH), 2.98 (1H, dd, J 15.9, 10.0, C(4)HH), (C(3)ArC(5)), 153.3 (C(3)ArC(1)), 171.8 (C(5)), 173.0 (C(1)); Data
3.52 (3H, s, C(5)O2CH3), 3.67 (3H, s, C(1)O2CH3), 4.14 (1H, d, J for minor syn diastereoisomer: Chiral HPLC analysis, Chiralpak
9.5, C(2)H), 4.56 (1H, td, J 9.7, 4.4, C(3)H), 7.13–7.26 (6H, m, AD-H (95 : 5 hexane–IPA, flow rate 1 mL min−1, 211 nm, 30 °C)
ArCH), 7.37–7.47 (2H, m, ArCH), 7.63 (1H, dd, J 8.1, 1.3, tR (major): 13.8 min, tR (minor): 16.9 min, 23% ee; 1H NMR
C(3)ArC(3)H); 13C{1H} NMR (125 MHz, CDCl3) δC: 38.1 (C(4)), (500 MHz, CDCl3) δH: 2.38 (1H, dd, J 15.7, 4.4, C(4)HAHB), 2.46
39.4 (C(3)), 51.9 (C(5)O2CH3), 52.4 (C(1)O2CH3), 57.8 (C(2)), (1H, dd, J 15.7, 9.6, C(4)HAHB), 3.50 (3H, s, C(5)O2CH3), 3.51
124.6 (C(3)ArC(3)H), 127.8 (C(2)ArC(4)H), 128.6 (C(2)ArC(3,5)H (3H, s, C(1)O2CH3), 4.03–4.09 (2H, m, C(2)H and C(3)H), 6.16
and C(3)ArC(4)H), 128.7 (C(2)ArC(2,6)H and C(3)ArC(6)H), (1H, d, J 3.2, C(3)ArC(3)H), 6.27 (1H, dd, J 3.2, 1.9, C(3)ArC(4)H),
132.5 (C(3)ArC(5)H), 135.2 (C(3)ArC(1)), 136.0 (C(2)ArC(1)), 7.27–7.42 (6H, m, C(2)ArCH and C(3)ArC(5)H); 13C{1H}
150.7 (C(3)ArC(2)), 171.5 (C(5)), 172.8 (C(1)); HRMS (NSI+) NMR (125 MHz, CDCl3) δC: 36.1 (C(4)), 38.7 (C(3)), 51.6
C19H20NO6 [M + H]+, found 358.1285, requires 358.1285 (0.0 ppm). (C(5)O2CH3), 52.1 (C(1)O2CH3), 55.2 (C(2)), 106.8 (C(3)ArC(3)),
Dimethyl (2R,3R)-3-(4-fluorophenyl)-2-phenylpentanedioate 110.3 (C(3)ArC(4)), 128.1 (C(2)ArC), 128.7 (C(2)ArC), 129.0
25. Following general procedure C, phenylacetic acid (81.6 mg, (C(2)ArC), 136.0 (C(2)ArC(1)), 141.8 (C(3)ArC(5)), 154.4 (C(3)ArC(1)),
0.60 mmol), i-Pr2NEt (156 μL, 0.90 mmol), pivaloyl chloride 171.9 (C(5)), 172.8 (C(1)); HRMS (NSI+) C17H19O5 [M + H]+,
(111 μL, 0.90 mmol) in CH2Cl2 (4 mL), HBTM-2.1 (2S,3R)-5 found 303.1228, requires 303.1227 (+0.3 ppm).
(6.16 mg, 0.02 mmol, 5 mol%), (E)-1,1,1-trichloro-4-(4-fluoro-
(3R,4R)-4-Pentyl-3-phenyl-6-(trichloromethyl)-3,4-dihydro-
phenyl)but-3-en-2-one 44 (107 mg, 0.40 mmol), i-Pr2NEt 2H-pyran-2-one 27. Phenylacetic acid (81.7 mg, 0.60 mmol)
(104 μL, 0.60 mmol), methanol (4 mL) and DMAP (9.76 mg, was dissolved in CH2Cl2 (4 mL) before i-Pr2NEt (156 μL,
0.08 mmol) gave the crude product (87 : 13 dr anti : syn). 0.90 mmol) and pivaloyl chloride (111 μL, 0.90 mmol) were
Column chromatography (75 : 25 Petrol–Et2O, Rf = 0.25) gave added. After stirring at rt for 5 min the solution was cooled to
the title compound 25 (92.0 mg, 70%) as a colourless oil −78 °C and HBTM-2.1 (2S,3R)-5 6.16 mg, 0.02 mmol, 5 mol%),
(>98 : 2 dr anti : syn) with spectroscopic data in accordance with (E)-1,1,1-trichloronon-3-en-2-one 46 (97 mg, 0.40 mmol),
the literature.13 [α]D20 −119.6 (c 0.75 CHCl3); {Lit.13 [α]D20 −114.3 i-Pr2NEt (104 μL, 0.60 mmol) were added in succession. The
(c 0.1 CHCl3) for 98% ee (2R,3R) stereoisomer}; Chiral HPLC reaction mixture was stirred at −78 °C for 16 h before being
analysis, Chiralcel OD-H (95 : 5 hexane–IPA, flow rate 1 mL concentrated under reduced pressure and purified by column
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chromatography (neat hexane to 96 : 4 hexane–EtOAc, Rf
=
J. E. Taylor, T. B. Brown, D. Pryde, T. Lébl, A. M. Z. Slawin
and A. D. Smith, Synlett, 2013, 1243–1249.
9 For a review on isothiourea catalysis, see: J. E. Taylor,
S. D. Bull and J. M. J. Williams, Chem. Soc. Rev., 2012, 41,
2109–2121.
0.20) to give the title compound 27 (105 mg, 71%) as a white
solid (94 : 6 dr anti : syn). mp 42–44 °C; [α]2D0 −62.1 (c 1.0
CHCl3); Chiral HPLC analysis, Chiralpak AD-H (99 : 1 hexane–
IPA, flow rate 1 mL min−1, 211 nm, 30 °C) tR (2R,3R): 15.9 min,
tR (2S,3S): 17.7 min, 86% ee; νmax (ATR) 2955, 2928, 2859, 10 For a review on the functionalisation of carboxylic acids
1
1778, 1497, 1454, 1173, 1155, 1115, 1101; H NMR (300 MHz,
CDCl3) δH: 0.87 (3H, t, J 6.7, CH3), 1.24–1.50 (8H, m, (CH2)4),
2.81–2.89 (1H, m, C(4)H), 3.68 (1H, d, J 8.1, C(3)H), 6.20 (1H, d,
and equivalents via ammonium and azolium enolates, see:
L. C. Morrill and A. D. Smith, Chem. Soc. Rev., 2014, 43,
6214–6226.
J 4.2, C(5)H), 7.19–7.24 (2H, m, ArC(2,6)H), 7.29–7.42 (3H, m, 11 For seminal work on the in situ activation of carboxylic
ArC(3,4,5)H); 13C{1H} NMR (100 MHz, CDCl3) δC: 14.1 (CH3),
22.5 (CH2), 25.8 (CH2), 31.6 (CH2), 32.9 (CH2), 38.1 (C(4)H),
49.9 (C(3)H), 90.2 (CCl3), 108.4 (C(5)H), 128.2 (ArC(4)H), 128.2
acids for the generation of ammonium enolates, see:
G. S. Cortez, R. L. Tennyson and D. Romo, J. Am. Chem.
Soc., 2001, 123, 7945–7946.
(ArC(2,6)H), 129.1 (ArC(3,5)H), 135.7 (ArC(1)), 148.2 (C(6)), 12 (a) D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin
167.4 (C(2)); HRMS (NSI+) C17H1835Cl3O2 [M + H]+, found
359.0369, requires 359.0367 (+0.6 ppm).
and A. D. Smith, J. Am. Chem. Soc., 2011, 133, 2714–2720;
(b) L. C. Morrill, T. Lébl, A. M. Z. Slawin and A. D. Smith,
Chem. Sci., 2012, 3, 2088–2093; (c) C. Simal, T. Lébl,
A. M. Z. Slawin and A. D. Smith, Angew. Chem., Int. Ed.,
2012, 51, 3653–3657; (d) D. Belmessieri, D. B. Cordes,
A. M. Z. Slawin and A. D. Smith, Org. Lett., 2013, 15, 3472–
3475; (e) L. C. Morrill, J. Douglas, T. Lébl, A. M. Z. Slawin,
D. J. Fox and A. D. Smith, Chem. Sci., 2013, 4, 4146–4155;
(f) D. G. Stark, L. C. Morrill, P.-P. Yeh, A. M. Z. Slawin,
T. J. C. O’Riordan and A. D. Smith, Angew. Chem., Int. Ed.,
2013, 52, 11642–11646; (g) E. R. T. Robinson, C. Fallan,
C. Simal, A. M. Z. Slawin and A. D. Smith, Chem. Sci., 2013,
4, 2193–2220; (h) P.-P. Yeh, D. S. B. Daniels, D. B. Cordes,
A. M. Z. Slawin and A. D. Smith, Org. Lett., 2014, 16, 964–
967; (i) L. C. Morrill, S. M. Smith, A. M. Z. Slawin and
A. D. Smith, J. Org. Chem., 2014, 79, 1640–1655;
( j) L. C. Morrill, L. A. Ledingham, J.-P. Couturier, J. Bickel,
A. D. Harper, C. Fallan and A. D. Smith, Org. Biomol.
Chem., 2014, 12, 624–636; (k) D. Belmessieri, A. de la Hou-
pliere, E. D. D. Calder, J. E. Taylor and A. D. Smith, Chem. –
Eur. J., 2014, 20, 9762–9769.
Acknowledgements
We thank the Royal Society for a University Research Fellow-
ship (ADS), The Carnegie Trust for the Universities of Scotland
(LCM), Syngenta/EPSRC (Case award to DGS), GSK/EPSRC
(CASE award to SRS), the EU (IEF for CS), and the European
Research Council under the European Union’s Seventh Frame-
work Programme (FP7/2007-2013) ERC Grant Agreement no.
279850 (JET) for funding. We also thank the EPSRC UK
National Mass Spectrometry Facility at Swansea University.
Notes and references
1 For a comprehensive review on Lewis base catalysis, see:
S. E. Denmark and G. L. Beutner, Angew. Chem., Int. Ed.,
2008, 47, 1560–1638.
2 For a review of ammonium enolate organocatalysis, see:
M. J. Gaunt and C. C. C. Johansson, Chem. Rev., 2007, 107,
5596–5605.
3 For recent reviews on the use of azolium enolates, see:
(a) S. J. Ryan, L. Candish and D. W. Lupton, Chem. Soc.
Rev., 2013, 42, 4906–4917; (b) J. Douglas, G. Churchill and
A. D. Smith, Synthesis, 2012, 2295–2309.
4 S. Matsunaga, T. Kinoshita, S. Okada, S. Harada and
M. Shibasaki, J. Am. Chem. Soc., 2004, 126, 7559–7570.
5 D. A. Evans, K. R. Fandrick and H.-J. Song, J. Am. Chem.
Soc., 2005, 127, 8942–8943.
13 S. R. Smith, S. M. Leckie, R. Holmes, J. Douglas, C. Fallan,
P. Shapland, D. Pryde, A. M. Z. Slawin and A. D. Smith, Org.
Lett., 2014, 16, 2506–2509.
14 (a) S. C. Hess, F. Nome, C. Zucco and M. C. Rezende, Synth.
Commun., 1989, 19, 3037–3045; (b) J. R. Salim, F. Nome and
M. C. Rezende, Synth. Commun., 1989, 19, 1181–1187;
(c) I. A. Atanassova, J. S. Petrov, V. H. Ognjanova and
N. M. Mollov, Synth. Commun., 1990, 20, 2083–2090;
(d) R. N. Ram, V. K. Soni and D. K. Gupta, Tetrahedron,
2012, 68, 9068–9075; (e) S. Dohi, K. Moriyama and H. Togo,
Eur. J. Org. Chem., 2013, 7815–7822.
15 For mechanistic studies on the haloform reactivity of tri-
chloromethyl ketones, see: (a) M. Uieara, C. Zucco,
D. Zanette, M. C. Rezende and F. Nome, J. Chem. Soc.,
Perkin Trans. 2, 1987, 175–179; (b) C. Zucco, C. F. Lima,
M. C. Rezende, J. F. Vianna and F. Nome, J. Org. Chem.,
1987, 52, 5356–5359.
6 C. D. Vanderwal and E. N. Jacobsen, J. Am. Chem. Soc.,
2004, 126, 14724–14725.
7 (a) D. A. Evans, K. A. Scheidt, K. R. Fandrick, H. W. Lam
and J. Wu, J. Am. Chem. Soc., 2003, 125, 10780–10781;
(b) D. A. Evans and J. S. Johnson, J. Am. Chem. Soc., 1998,
120, 4895–4896; (c) H. Jiang, M. W. Paixão, D. Monge and 16 For seminal examples, see: (a) F. K. Signaigo and
K. A. Jørgensen, J. Am. Chem. Soc., 2010, 132, 2775–2783.
H. Adkins, J. Am. Chem. Soc., 1936, 58, 1122–1124;
(b) A. Treibs and A. Dietl, Justus Liebigs Ann. Chem., 1958,
619, 80–95; (c) D. M. Bailey, R. E. Johnson and
8 For recent example of α-keto-β,γ-unsaturated phos-
a
phonates in NHC catalysis, see: S. M. Leckie, C. Fallan,
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N. F. Albertson, Org. Synth., 1971, 51, 100; (d) D. M. Bailey 21 This is in contrast to some α-keto-β,γ-unsaturated phospho-
and R. E. Johnson, J. Med. Chem., 1973, 16, 1300–1302;
(e) P. Barker, P. Gendler and H. Rapoport, J. Org. Chem.,
1978, 43, 4849–4853.
nates, which are only stable for approximately one month
when kept in the freezer under an inert atmosphere.
22 In the absence of catalyst the reaction gives 20% conver-
sion into 8 after 18 h.
17 For selected recent applications in natural product syn-
thesis, see: (a) S. Su, R. A. Rodriguez and P. S. Baran, 23 Optimal conditions were the same as those previously
J. Am. Chem. Soc., 2011, 133, 13922–13925; (b) B. Troegel obtained in related processes, see ref. 12e.
and T. Lindel, Org. Lett., 2012, 14, 468–471; (c) Q. Zhang, 24 Authentic racemic sample of all products were prepared
X. Cui, S. Lin, J. Zhou and G. Yuan, Org. Lett., 2012, 14, using (rac)-HBTM-2.1 5 as the catalyst.
6126–6129; (d) S. Han, D. S. Siegel, K. C. Morrison, 25 The catalyst loading could be lowered to 1 mol%, giving 10
P. J. Hergenrother and M. Movassaghi, J. Org. Chem.,
2013, 78, 11970–11984; (e) T. Yoshimura, T. Kinoshita,
in 66% yield with 89 : 11 dr and >99% ee, although catalysis
was routinely carried out using 5 mol% HBTM-2.1 5.
H. Yoshioka and T. Kawabata, Org. Lett., 2013, 15, 864– 26 Three equivalents of i-PrNH2 were required due to compet-
867. ing acylation of excess pivaloyl chloride.
18 H. Morimoto, S. H. Wiedemann, A. Yamaguchi, S. Harada, 27 (a) Y. Nagao, T. Hirata, S. Goto, S. Sano, A. Kakehi,
Z. Chen, S. Matsunaga and M. Shibasaki, Angew. Chem.,
Int. Ed., 2006, 45, 3146–3150.
19 (a) C. Zheng, Y. Li, Y. Yang, H. Wang, H. Cui, J. Zhang and
G. Zhao, Adv. Synth. Catal., 2009, 351, 1685–1691;
(b) H.-F. Wang, P. Li, H.-F. Cui, X.-W. Wang, J.-K. Zhang,
W. Liu and G. Zhao, Tetrahedron, 2011, 67, 1774–1780;
K. Iizuka and M. Shiro, J. Am. Chem. Soc., 1998, 120, 3104–
3110; (b) V. I. Minkin and R. M. Minyaev, Chem. Rev., 2001,
101, 1247–1266; (c) K. A. Brameld, B. Kuhn, D. C. Reuter
and M. Stahl, J. Chem. Inf. Model., 2008, 48, 1–24; (d) P. Liu,
X. Yang, V. B. Birman and K. N. Houk, Org. Lett., 2012, 14,
3288–3291.
(c) J. Zhang, X. Liu, X. Ma and R. Wang, Chem. Commun., 28 M. K. Gupta, Z. Li and T. S. Snowden, J. Org. Chem., 2012,
2013, 49, 9329–9331. 77, 4854–4860.
20 E. J. Corey, J. O. Link and Y. Shao, Tetrahedron Lett., 1992, 29 D. Yang, G.-S. Jiao, Y.-C. Yip, T.-H. Lai and M.-K. Wong,
33, 3435–3438.
J. Org. Chem., 2001, 66, 4619–4624.
Org. Biomol. Chem.
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