Zinc Hydroxide-Catalyzed Asymmetric Allylation of Acetophenones with Amido-Functionalized Allylboronate in Water

Article abstract of DOI:10.1002/adsc.202000195

Enantioselective allylation of aldehydes and ketones is a widely used approach for preparing chiral homoallylic alcohols, however, most of the reactions are still mainly performed in organic solvents. Considering their environmental impact, expansion of synthetic technology in water has the highest priority in the organic chemistry field. Here, we report enantioselective reaction of water-stable amido-functionalized allylboronates with acetophenone derivatives in water. The reaction was catalyzed with zinc hydroxide and a didecylamino-functionalized chiral aminophenol reagent, affording a variety of homoallylic alcohols in up to 99% yield. There is a definite proportional correlation between the enantioselectivity and the size of an ortho-substituent on the substrate, and the enantiomeric excess of the product reached up to 98%. (Figure presented.).

Full text of DOI:10.1002/adsc.202000195

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DOI: 10.1002/adsc.202000195
Zinc Hydroxide-Catalyzed Asymmetric Allylation of
Acetophenones with Amido-Functionalized Allylboronate in
Water
Tetsuya Sengoku,a Ryunosuke Maegawa,a Hiroki Imamura,a Mitsuo Wada,a and
Hidemi Yodaa,*
a
Department of Applied Chemistry, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Naka-ku, Hamamatsu 432-8561,
Japan
+81-53-478-1150
E-mail: yoda.hidemi@shizuoka.ac.jp
Manuscript received: February 12, 2020; Revised manuscript received: March 30, 2020;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202000195
Abstract: Enantioselective allylation of aldehydes and ketones is a widely used approach for preparing chiral
homoallylic alcohols, however, most of the reactions are still mainly performed in organic solvents.
Considering their environmental impact, expansion of synthetic technology in water has the highest priority in
the organic chemistry field. Here, we report enantioselective reaction of water-stable amido-functionalized
allylboronates with acetophenone derivatives in water. The reaction was catalyzed with zinc hydroxide and a
didecylamino-functionalized chiral aminophenol reagent, affording a variety of homoallylic alcohols in up to
99% yield. There is a definite proportional correlation between the enantioselectivity and the size of an ortho-
substituent on the substrate, and the enantiomeric excess of the product reached up to 98%.
Keywords: Allylation; Amides; Amino alcohols; Boron; Zinc
Introduction
aldol reaction have become controllable to some extent
in water.[6] However, many catalytic enantioselective
Enantioselective allylation of aldehydes and ketones is carbon-carbon bond forming reactions are still mainly
an extensively studied and widely used carbon-carbon performed in organic solvents because reagents and
bond forming reaction. This type of reaction enables in situ generated reactive species are incompatible with
not only to construct a chiral alcohol unit but also to water. Development of asymmetric allylation in aque-
install a carbon-carbon double bond which can be ous media has been one of the major challenges in
readily transformed into other functional groups. these decades and reactions using allylindium species
Therefore, the products serve as chiral building blocks have attracted attention because of its water stability.[7]
for the syntheses of bioactive molecules including Loh and Zhou reported the first example of enantiose-
natural products. Great efforts have been devoted lective allylation of aldehydes using indium species in
toward the development of enantioselective allylation aqueous media, in which (S,S)-2,6-bis(4-isopropyl-2-
in past decades, and homoallylic alcohols as well as oxazolin-2-yl)pyridine was used as a chiral source.[8]
homoallylic amines are nowadays accessible with high More recently, the Nakamura’s research group reported
levels of stereocontrol through various catalytic enantioselective allylation of ketones using allylindium
systems.[1–5] Thus, allylation chemistry in organic reagent prepared from allyl bromide and indium metal
solvents is well-developed and is continuously inves- (Scheme 1a).[9] Their reaction system, to the best of
tigated.
our knowledge, provided the most successful result on
Considering environmental impact of organic sol- the reaction with ketones in pure water, giving the
vents, expansion of synthetic technology of organic adduct with up to 89% ee. However, despite of the
compounds in water has the highest priority and high ees, major drawback is the stoichiometric use of
becomes a major issue in the current synthetic relatively expensive indium metal. Besides indium
chemistry field. Biomimetic reactions represented by species, allylboronates can be used for catalytic
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sufficient reactivity without additives (Entry 1 in the
Table S1 in the Supporting Information). Variety of
alkali or alkaline-earth metal salts were first examined
as a water-soluble additive, but no or only a trace
amount of the desired product was observed (En-
tries 2–5). Then, we employed commercially available
zinc, copper, and indium salts with the expectation of
activation of the allylboronate (Entries 6–12).[22–26] Use
of ZnBr2, Zn(OTf)2, CuI, or CuBr2 resulted in almost
no reaction. On the other hand, Zn(OMe)2 and Zn
(OH)2 successfully mediated the desired nucleophilic
addition to provide 2a in 28% and 26% yields,
respectively, even though the reactions were carried
out in a suspension (Entries 8 and 9).
Next, we explored a promising chiral source for
asymmetric induction (Table 1). For this purpose, Zn
(OH)2 was chosen as a metal additive due to its easy
availability and high cost efficiency. Initially, the
Scheme 1. Enantioselective allylation in aqueous media.
enantioselective allylation in aqueous media. Kobaya- reaction was performed by employing a catalytic
shi and his co-workers realized the relevant reaction of amount of L-valine derived aminophenol L1, which
aldehydes by employing chiral zinc catalysis in water- has an efficient chiral motif for zinc-mediated asym-
acetonitrile solution (Scheme 1b).[10,11] They also suc- metric allylboration[27–29] and has been recently applied
ceeded the development of an analogous reaction using to amido-functionalized allylboration of isatins by our
imino substrates, where chiral allylglycine derivatives group in organic solvents,[21] to provide low but
were provided with up to 88% ee.[12] These results significant enantiomeric enrichment of the product
show the potential utility of allylboronates in asym- (Entry 1, 56% yield, 13% ee). On the other hand, chiral
metric allylation in water.
reagents bearing 1,2-aminoalcohol, diamine, or diol
In addition to the reaction using nonsubstituted structure (L2–6) showed almost no or poor effects on
allylmetal reagents, allylation with functionalized ones both yields and enantioselectivities (Entries 2–6).
is of great importance due to the broad utility in Promising potential of the chiral aminophenol reagent
complex molecule synthesis.[13–19] In this context, we was further affirmed through the experiments using
demonstrated the utility of allylboronate (1) bearing acetophenone (Entries 7–12), in which 2b was given
amide functionality at the β position for the construc- in 76% with 53% ee in the presence of Zn(OH)2 and
tion of spiroheterocycles and have succeeded the L1 under highly diluted conditions (0.04 M for
syntheses of four types of bisheterocyclic spiro acetophenone). Moreover, the phenol moiety of L1
compounds.[17,20,21] Moreover, we recently discovered was found to be important for asymmetric induction by
the remarkable air- and water-stability of 1, which comparing the results obtained with analogous aniline
remained intact even after exposure to air and water (L7) or pyridine (L8) derivative (Entries 13 and 14).[30]
for more than one week.[17] These synthetic utility and
With the acceptable results obtained in zinc-amino-
chemical stability of 1 motivated us to explore a new phenol catalysis, we turned our attention to structural
catalytic enantioselective amido-functionalized allyla- optimization of the aminophenol additive. Moderate
tion in water (Scheme 1c). In this paper, we report our yields in the reactions using N,N-dimethylamide
work towards the development of highly enantioselec- derivative L1 would be attributed to the fact that L1 is
tive addition of 1 to acetophenone derivatives utilizing a solid and hardly water-soluble material and gives a
water as the reaction solvent. The reaction was heterogeneous solid-solution system during the course
accomplished by using practically water-insoluble Zn of the reaction (Figure 1a). Therefore, our initial
(OH)2 and a newly prepared chiral aminophenol interest on structure modification was to introduce
derivative.
aliphatic residues on the amide moiety in order to
obtain chiral aminophenols as oily materials. Thus,
installation of dialkylamino (didecyl- and didodecyla-
mino) or monoalkylamino (benzyl-, pentyl-, decyl-,
Results and Discussion
In the preliminary stage of this research, we evaluated and tert-butylamino) groups gave several kinds of
the reactivity of amido-functionalized allylboronate in chiral aminophenols L9–14 as an oil, respectively
water in the absence/presence of additives. We chose (Figure 1b). As we expected, L9–14 were well-
2-butanone as a substrate because of its water-soluble dispersed in water by vigorous stirring, and the
property. Similar to the results obtained in the previous reaction efficiency was increased with comparable
experiment performed in toluene,[20] 1a did not show levels of stereocontrol (79–90% yields, 55–65% ee).
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Table 1. Screening of chiral additives for Zn(OH)2-catalyzed
allylation in water.[a]
Entry
ketone (R)
L
Yield [%]
Ee [% ee][b]
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Et
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
L1
L2
L3
L4
L5
L6
L1
L2
L3
L4
L5
L6
L7
L8
56
27
20
11
26
24
76
78
62
15
92
58
74
52
13
8
6
1
1
Figure 1. Screening of chiral aminophenols for Zn(OH)2-cata-
lyzed allylation of acetophenone in water. Reactions were
carried out with acetophenone (0.200 mmol), 1a (0.300 mmol),
Zn(OH)2 (10 mol%), and L (11 mol%) in water ([a] 0.04 M or
[b] 0.4 M for acetophenone, respectively) for 24 h.
3
53
12
0
22
0
1
45
14
9
10
11
12
13
14
amine moiety of L17 by preparing chiral amionophe-
nol derivatives from L-leucine, L-phenylalanine, and
3-methyl-L-valine, respectively (Figure 1d). Contrary
to our expectation, reactions using L20–22 indicated
the almost same levels of enantioselectivities (67–71%
ee), demonstrating that the steric factor of the alkyl
side chain does not influence the stereochemical
outcome. Finally, we carried out reactions using L23–
25 for evaluating the effect of electron density on
phenol moiety (Figure 1e). As a result, installation of
electron-withdrawing or electron-donating group to the
aromatic ring brings no effect on the reaction
[a] Reactions were carried out with ketone (0.200 mmol), 1a
(0.300 mmol), Zn(OH)2 (10 mol%), and L (11 mol%) in
water (1.0 mL for 2-butanone or 5.0 mL for acetophenone)
for 24 h.
[b] The ee values were determined by chiral HPLC analysis
using Daicel Chiralpak IF (for 2a) or IC (for 2b).
Additionally, this reagent property fortunately allowed efficiency to give 1a in the identical yield and
to increase the substrate concentration to 0.4 M with- stereoselectivity. Thus, we found that the reagent
out any loss of enantioselectivity (L9, 96% yield, 66% combination of Zn(OH)2 and L17 exhibited the best
ee). Subsequently, we further modified the amide performance in terms of reaction efficiency and
moiety to the corresponding amine by reduction with asymmetric induction.
LiAlH4 in order to evaluate the effect of the carbonyl
Having optimized both the metal salt and the chiral
group (Figure 1c). Tertiary amine derivatives L15–17 aminophenol reagent, we surveyed asymmetric allyla-
showed improved activity and stereoselectivity com- tion of a variety of methyl ketones with 1a in water
pared with the amide derivatives L1 and L9, providing (Scheme 2).[31] 2-Decanone gave the corresponding
2b in up to 98% yield and 70% ee (L17). Meanwhile, product in 67% yield, albeit with low asymmetric
mono-decylamine L18 and its analogous ether L19 led induction (2c: 28% ee). Substrate reactivity is strongly
to significant decrease of enantioselectivity, indicating dependent on the steric bulkiness around the keto
that the dialkylamino moiety plays a critical role in group, whereby reaction of tert-butyl methyl ketone
enantiodifferentiation of a prochiral ketone. Then, we resulted in only 10% yield of 2d (69% ee). Meanwhile,
attempted to control the steric environment around the allylation of methyl 1-naphthyl ketone with a moderate
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2 mol% of Zn(OH)2 and L17 (96% ee). On the basis
of these reaction profiles, we estimated that our
reaction system should be advantageous for the
preparation of highly enantioenriched 3,3-disubstituted
phthalides[32] possessing a synthetically useful carbonyl
functionality on its side chain. Thus, use of methyl 2-
acetylbenzoate as a substrate was found to give 3 in
one pot via spontaneous cyclization of the resulting
adduct (93% yield, 94% ee).
Furthermore, we evaluated the effect of amide
functionality on the allylboronate (Scheme 3). When
the reaction was carried out with para-substituted
phenyl derivatives 1b, c, the corresponding adducts
2ab and 2ac were given in good yields with
consistently excellent enantioselectivities (95% ee).
Our reaction system was also applicable to relatively
sterically hindered N-1-naphthyl allylboronate 1d,
providing 2ad in excellent yield and enantioselectivity
(89%, 97% ee).[33] On the other hand, the reaction
using commercially available 2-allyl-5,5-dimethyl-
1,3,2-dioxaborinane gave the corresponding product in
only 23% yield with 85% ee along with the recovery
of a substantial amount of the ketone. These results
highlight the utility of the amido-functionalized allyl-
boronates for organic synthesis in water.
Scheme 2. Reactions of ketones with 1a in water. The ee values
were determined by HPLC analysis on a chiral stationary phase.
The absolute configurations of acetophenone derivatives were
tentatively assigned to be S by analogy (see Scheme S1). [a]
Reactions were carried out for 72 h. [b] The reaction was
carried out with 2 mol% of Zn(OH)2 and L17.
We subsequently focused on the confirmation of the
absolute configuration of the newly formed stereo-
center (Scheme S1 in the Supporting Information).
Fortunately, compound 2y could be further purified by
recrystallization from ethyl acetate/hexane (99% ee) to
steric environment proceeded with high facial selectiv- afford X-ray quality crystals. The single-crystal X-ray
ity rather than the case with 2-naphthyl methyl ketone diffraction analysis showed that the molecules adopt
(2e: 72%, 42% ee), affording the desired adduct 2f in the monoclinic space group P21 with the Flack
93% yield with 86% ee. As for functional groups, this parameter of À 0.035(9), clearly demonstrating that the
protocol can tolerate not only electron-donating but absolute configuration of the newly formed stereo-
also electron-withdrawing functionalities at para- and center is S.[34,35] The iodine atom of S-2y was then
meta-positions of acetophenone derivatives, providing removed by hydrogenation with Pd/C to form 2a in
2g–2n in excellent yields with comparable enantiose- 30% yield with no erosion of stereointegrity (99% ee).
lectivities. The substrate bearing a relatively small By comparison of the HPLC profiles, the major
ortho-methyl group gave 2o with 92% ee, meanwhile enantiomer obtained in Table 1 was found to be
ortho-ethyl and ortho-isopropyl derivatives provided identical to S-2a. Furthermore, we attempted to
the corresponding adducts with remarkably high determine the stereochemistry of 2f and 2aa through
enantioselectivities, respectively (2p: 96% ee, 2q: the single-crystal X-ray diffraction analysis using the
97% ee). A similar trend in enantioselectivity was anomalous dispersion method.[35] Initially, 2f and 2aa
observed in the case of ortho-halophenyl derivatives, were recrystallized from ethyl acetate/hexane to
where the values of product ees are approximately provide the highly optically pure materials (99% ee).
proportional to the sizes of halogens (2w (F): 63% ee, γ-Hydroxylactam moiety of these compounds was
2v (Cl): 78% ee, 2x (Br): 86% ee, 2y (I): 90% ee).
Among a series of acetophenones bearing an ortho-
substituent, 2’-(trifluoromethyl)acetophenone gave the
corresponding product 2aa with the highest enantiose-
lectivity (98% ee). From these results, it is apparent
that the enantioselectivity is not influenced by the
electronic effect of substrates but is heavily influenced
by the appropriate size of ortho-substituents. The
highest performance for 2aa was almost maintained
even when the reaction was carried out with only
Scheme 3. Effect of amide functionality on 1.
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successfully cyclized in the presence of p-toluenesul- efficiency depended to a large extent on the THF-water
fonic acid in dichloromethane to give the correspond- ratio, and the reaction performed in pure water
ing lactams, which were in turn subjected to 1,4- provided 2aa in the highest yield (97%) with excellent
addition of p-chlorothiophenol in the presence of enantioselectivity (98% ee). In addition, reactions
trimethylamine. The resulting diastereomeric mixture carried out with L1 in organic solvents resulted in
(39:61) of both products 4a, b were separated by silica almost no product formation (Table S3 in the Support-
gel column chromatography, and subsequent oxidiza- ing Information). On the basis of these observations,
tion of the more polar diastereomers (major diaster- we inferred that water would support the degradation
eomers) with m-chloroperbenzoic acid generated the of the product-catalyst complex to release Zn(OH)2-
1
corresponding sulfones 5a and 5b in 81 and 74% aminophenol catalyst. Furthermore, H NMR spectra
yield, respectively (99% ee). These products afforded of a suspension of 1a and Zn(OH)2 (1:1 mixture) in
X-ray quality crystals from EtOAc-hexane and the D2O shows that the allylboronate was partly trans-
single-crystal X-ray diffraction analyses gave small formed into 2-(hydroxymethyl)-N-phenylacrylamide
Flack parameters of 0.00(5) and 0.00(2), respectively, and a new structurally unidentified species which was
allowing the unambiguous assignment of the absolute not identical to N-phenylmethacrylamide (Figure S3 in
configurations of both compounds as S.[36,37] These the Supporting Information). Notably, 1a was almost
results suggest that amido-functionalized allylation of completely converted to 2-(hydroxymethyl)-N-phenyl-
acetophenone derivatives would proceed in the same acrylamide within 10 minutes in the case of 1:1:1
manner to give the S adducts as a major enantiomer.
mixture of 1a, Zn(OH)2 and L17, clearly indicating
As mentioned in the screening of chiral amino- that the chiral aminophenol accelerated the relevant
phenols, L9–25 dispersed in water by stirring, but Zn transformation.[39] Considering these outcomes, we
(OH)2 still remained insoluble (solubility 1.0× estimated that allylboronate would be in situ trans-
10À 5 mol/LÀ H2O)[38] under all the reaction conditions formed into an allylzinc species by Zn(OH)2-amino-
discussed above. However, there is no doubt that the phenol complex and then undergo enantioselective
presence of water-insoluble Zn(OH)2 was indeed addition to the ketone as opposed to the Hoveyda’s
essential to achieve excellent reaction efficiency as allylboration[40] in an organic solvent where zinc
well as asymmetric induction. We speculated that reagent works as a Lewis acid. Furthermore, the
dispersion of Zn(OH)2, even though the amount is resultant homoallylic alkoxyzinc species should be
quite small, into water should be critical to induce the hydrolyzed in water to recover Zn(OH)2-aminophenol
reaction, and probably a chiral aminophenol would complex.
support dispersion of Zn(OH)2 by complexation. To
Facial selectivity is briefly discussed with reaction
verify this hypothesis, we next made analysis of the modes A–C, in which cyclic structure consisting of a
reaction time-product yield profiles with/without the substrate and an allylic species would be formed
chiral aminophenol reagent (Figure S1 in the Support- (Figure 2).[40] The interaction between the catalyst’s
ing Information). The yield of 2b reached a maximum didecylamino moiety and the amide hydrogen of 1
of 98% in the presence of L17 within 5 hours, whereas may be responsible for the high reaction efficiency and
only 38% yield of the product was obtained in the enantiocontrol because of the fact that the amide
absence of the chiral reagent even after 9 hour reaction hydrogen atom on 1 was essential to the success of the
time. On the other hand, the enantiomeric excess of 2b
was constant at 70% ee at any time point during the
course of the reaction. We also conducted a systematic
evaluation of the effect of catalyst loading (Scheme S2
in the Supporting Information), in which the product
enantioselectivity was 70% ee, irrespective of the
amount of Zn(OH)2 (5–100 mol%). These results
suggest that the rate of background reaction without
involvement of aminophenols L is likely to be
negligible in our reaction system and the desired
allylation reaction would be successfully accelerated
by a chiral complex composed of aminophenol reagent
and Zn(OH)2.
As for the effect of water in our reaction system,
the enantiomeric excess of the product was found to be
independent of the amount of water added since 2aa
was constantly given with 98% ee in all reactions
carried out in various aqueous THF media (Figure S2
in the Supporting Information). Meanwhile, reaction
Figure 2. Plausible transition states for enantioselective amido-
functionalized allylation in water.
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reaction.[33,11] Modes B and C would be destabilized
due to the steric repulsion between the catalyst’s aryl
group and the substrate phenyl group (mode B) or the
catalyst’s side chain (mode C). The high enantiomeric
excess of 2aa can be explained with mode A (R=CF3)
in consideration of the increased steric repulsion
observed on B’ in which the ortho substituent is
oriented toward the aryl group to minimize nonbonded
interaction with the methyl group.
Experimental Section
General methods
All solvents and reagents were of reagent grade quality and
used without further purification unless otherwise stated.
Chloroform, acetonitrile, toluene and dichloromethane were
dried over MS 4 Å or MS 3 Å prior to use, respectively.
Tetrahydrofuran was dried over Na wire under a nitrogen
1
atmosphere. The H and 13C{1H} nuclear magnetic resonance
(NMR) spectra operating at the frequencies of 300 and 75 MHz,
respectively, on a JEOL JNM-AL300 spectrometer were
recorded in chloroform-d (CDCl3) unless otherwise noted.
Chemical shifts are reported in parts per million (ppm) relative
to TMS and the solvent used as internal standards, and the
coupling constants are reported in hertz (Hz). Thin layer
chromatography (TLC) was performed using Merck TLC silica
gel 60F254, visualized by irradiation with UV light and/or by
treatment with phosphomolybdic acid or p-anisaldehyde stain
followed by heating. Column chromatography was performed
using silica gel 60 N (spherical neutral) from Kanto Chemical
Co. and eluting with the indicated solvent system. Fourier
transform infrared (FTIR) spectra were recorded on a JASCO
FT/IR-550 spectrometer. Optical rotations were measured in
1 dm path length cell of 2 mL capacity using a JASCO Model
DIP-1000 and P-2200 polarimeter at a wavelength of 589 nm.
Elemental analyses were performed by JSL Model JM 10
instruments. Allylboronates 1 were prepared according to the
literature procedure.[17] Aminophenols (L11, L12, and L14)
were prepared according to the literature procedure.[21,41]
Synthetic schemes are summarized in the Supporting Informa-
tion (Schemes S3–S7).
Finally, we attempted to render our protocol more
environmentally friendly by testing reusability and
reducibility of the chiral catalyst. The chiral amino-
phenol L17 could be separated from the reaction
mixture of 2aa by silica gel column chromatography
(hexane/EtOAc=7/1 as an eluent) and was obtained
with sufficiently high purity (recovery yields on three
cycles: 40–60%). Recovered L17 was used for the next
cycles to afford 2aa in comparable yields and
enantioselectivities (the second cycle: 93% yield, 94%
ee; the third cycle: 97% yield, 95% ee). As for the
effect of catalyst amounts, 2aa was given in 79% yield
with 96% ee, even when the reaction was performed in
the presence of 2.5 mol% of Zn(OH)2 and L17 (Fig-
ure S4 in the Supporting Information). In addition to
these investigations, we tried to simplify the work-up
procedure by skipping the extraction step. The reaction
mixture including 2aa obtained under the optimum
reaction conditions was concentrated under the reduced
pressure, and the resultant was transferred directly to
the silica gel column. As a result, the desired product
was successfully isolated in 91% yield with 95% ee.
Thus, from the viewpoint of reuse and reduction, we
could provide more environmentally benign protocol
for amido-functionalized allylation with this chiral
reagent.
Synthesis and characterization of (S)-
2-((2-aminobenzyl)amino)-N,N,3-trimeth-
ylbutanamide (L7)
To a solution of N-Boc-L-valine (928 mg, 4.27 mmol) in
anhydrous dichloromethane (17 mL), dimethylamine (ca. 50%
in water, 1.1 mL, 11 mmol, 2.5 equiv.), 1-(2-dimeth-
ylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI,
901 mg, 4.70 mmol, 1.1 equiv.) and 1-hydroxybenzotriazole
(HOBt, 635 mg, 4.70 mmol, 1.1 equiv.) were added at room
temperature. After stirring the mixture at the same temperature
for 16 hours, the reaction was quenched by addition of saturated
aqueous citric acid (20 mL). The resulting solution was filtered
through a pad of celite and the filtrate was extracted with
dichloromethane (20 mL). The organic extract was washed with
brine (20 mL), dried over Na2SO4, filtered and concentrated in
vacuo to give a crude material (1.04 g), which was used without
Conclusion
In conclusion, we have succeeded in the development
of a catalytic enantioselective allylation of acetophe-
nones in water. Our reaction system consists of water-
stable allylboronate bearing an amide functionality and
Zn(OH)2-chiral aminophenol catalyst and gave the
corresponding allyl adducts with up to 98% ee. There
is a definite proportional correlation between the
reaction enantioselectivity and the size of an ortho-
substituent on a substrate. Water would work as not further purification: Rf =0.43 (silica gel, hexane/EtOAc=1/1).
only the reaction solvent but also a reagent for the
To a solution of the crude material (1.04 g) in 1,4-dioxane
(8.5 mL), conc. hydrochloric acid (2.6 mL, 25 mmol, 6.0 equiv.)
degradation of the ZnÀ O bond in the product-catalyst
complex. The present work providing chiral homo-
°
was added at 0 C. The solution was warmed to room temper-
allylic alcohols bearing an amide unit under organic
solvent-free reaction conditions will be valuable for
future pharmaceutical development and can open new
ature and stirred for 4 hours. The reaction mixture was
concentrated in vacuo and the resulting material was dissolved
in anhydrous dichloromethane (14 mL). Triethylamine (1.8 mL,
perspectives in stereoselective organic synthesis in 13 mmol, 3.0 equiv.), 2-(Boc-amino)benzaldehyde (924 mg,
4.18 mmol, 1.0 equiv.) and magnesium sulfate (1.54 g,
12.8 mmol, 3.0 equiv.) were added to the solution at room
temperature. After stirring the mixture at the same temperature
water.
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°
for 12 hours, the resulting mixture was concentrated in vacuo.
The resulting material was roughly purified by column
chromatography (silica gel, hexane/EtOAc=1/1) to give a
crude material (1.71 g), which was used without further
purification: Rf =0.23 (silica gel, hexane/EtOAc=2/1).
21 mmol, 6.0 equiv.) was added at 0 C. The solution was
warmed to room temperature and stirred for 4 hours. The
reaction mixture was concentrated in vacuo and the resulting
material was dissolved in anhydrous dichloromethane (11 mL).
Triethylamine (1.4 mL, 10 mmol, 3.0 equiv.), picolinaldehyde
(440 mg, 4.11 mmol, 1.2 equiv.) and magnesium sulfate (1.23 g,
10.2 mmol, 3.0 equiv.) were added to the solution at room
temperature. After stirring the solution at the same temperature
for 18 hours, the reaction mixture was concentrated in vacuo.
The resulting material was roughly purified by column
chromatography (silica gel, hexane/EtOAc=1/3) to give a
crude material (451 mg), which was used without further
purification: Rf =0.15 (silica gel, hexane/EtOAc=1/3).
To a solution of the crude material (1.71 g) in methanol
(11 mL), sodium borohydride (646 mg, 17.0 mmol, 4.0 equiv.)
°
and conc. hydrochloric acid (1 drop) were added at 0 C. The
solution was warmed to room temperature and stirred for
2 hours. The reaction was quenched by addition of saturated
aqueous NaHCO3 (5.0 mL), and the resulting mixture was
extracted with dichloromethane (20 mL×2). The combined
organic extracts were dried over Na2SO4, filtered and concen-
trated in vacuo to give a crude material (1.20 g), which was
used without further purification: Rf =0.31 (silica gel, hexane/
EtOAc=2/1).
To a solution of the crude material (451 mg) in methanol
(11 mL), sodium borohydride (516 mg, 13.6 mmol, 4.0 equiv.)
and conc. hydrochloric acid (1 drop) were added at 0 C. The
°
solution was warmed to room temperature and stirred for
1 hour. The reaction was quenched by addition of saturated
aqueous NaHCO3 (10 mL), and the resulting mixture was
extracted with dichloromethane (20 mL×2). The combined
organic extracts were dried over Na2SO4, filtered and concen-
trated in vacuo to give a crude material. The crude material was
purified by column chromatography (silica gel, hexane/
EtOAc=1/2 to 1/3) to give L8 (34.9 mg, 4.3% in 4 steps) as a
pale yellow oil: Rf=0.33 (silica gel, hexane/EtOAc=1/3);
To a solution of the crude material (1.20 g) in 1,4-dioxane
(12 mL), conc. hydrochloric acid (2.0 mL, 21 mmol, 6.0 equiv.)
°
was added at 0 C. The solution was warmed to room temper-
ature and stirred for 2 hours. The reaction was quenched by
addition of saturated aqueous NaHCO3 (30 mL), and the
resulting mixture was extracted with EtOAc (30 mL). The
organic extract was washed with brine (20 mL), dried over
Na2SO4, filtered and concentrated in vacuo to give a crude
material. The crude material was purified by column chroma-
tography (silica gel, hexane/EtOAc=6/1 to 2/1) to give L7
(439 mg, 41% in 5 steps) as a white solid: Rf=0.60 (silica gel,
23
[α]D À 30.7 (c 0.48 in CHCl3); IR (NaCl) 3433 (NÀ H), 1632
(C=O) cmÀ 1; 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J=5.7 Hz,
1H), 8.06 (d, J=7.8 Hz, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.32 (m,
1H), 4.22 (d, J=18.3 Hz, 1H), 3.99 (d, J=18.3 Hz, 1H), 3.28
(d, J=6.0 Hz, 1H), 3.03 (s, 3H), 3.02 (s, 3H), 2.31 (brs, 1H),
1.88 (sextet, J=6.3 Hz, 1H), 1.03 (d, J=6.9 Hz, 3H), 0.99 (d,
J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.9, 160.4,
148.7, 136.4, 122.2, 121.7, 62.4, 54.0, 37.0, 35.6, 31.5, 19.7,
18.3. Anal. Calcd for C13H21N3O: C, 66.35; H, 8.99; N, 17.86.
Found: C, 66.00; H, 8.66; N, 17.48.
22
hexane/EtOAc=1/2); [α]D À 58.1 (1.01 in CHCl3); IR (NaCl)
3386 (NÀ H), 3304 (NÀ H), 1631 (C=O) cmÀ 1; 1H NMR
(300 MHz, CDCl3) δ 7.07 (dt, J=7.5, 1.5 Hz, 1H), 6.93 (d, J=
7.8, 1.2 Hz, 1H), 6.66–6.61 (m, 2H), 4.79 (brs, 1H), 3.83 (d, J=
12.6 Hz, 1H), 3.43 (d, J=12.6 Hz, 1H), 3.20 (d, J=6.3 Hz,
1H), 3.03 (s, 3H), 2.91 (s, 3H), 1.77 (m, 1H), 0.91 (t, J=
6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 174.6, 147.0, 130.0,
128.2, 123.4, 117.4, 115.5, 61.3, 51.1, 36.8, 35.5, 31.3, 19.9,
18.1. Anal. Calcd for C14H23N3O: C, 67.43; H, 9.30; N, 16.85.
Found: C, 67.35; H, 9.45; N, 16.79.
Characterization of (S)-N,N-didecyl-
2-((2-hydroxybenzyl)amino)-3-methylbutanamide
(L9)
Synthesis and characterization of (S)-N,
N,3-trimethyl-2-((pyridin-2-ylmethyl)amino)buta-
namide (L8)
According the synthetic procedure of L8, L9 (900 mg, 52% in 4
steps) was obtained from N-Boc-L-valine (1.08 g, 4.98 mmol),
didecylamine (1.76 g, 5.91 mmol, 1.2 equiv.) and salicylalde-
hyde (608 mg, 4.98 mmol, 1.0 equiv.) as a colorless oil after
chromatographic purification (silica gel, hexane/EtOAc=15/1
To a solution of N-Boc-L-valine (741 mg, 3.41 mmol) in
anhydrous dichloromethane (14 mL), dimethylamine (ca. 50%
in water, 1.0 mL, 8.5 mmol, 2.5 equiv.), 1-(2-dimeth-
ylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI,
719 mg, 3.75 mmol, 1.1 equiv.) and 1-hydroxybenzotriazole
(HOBt, 507 mg, 3.75 mmol, 1.1 equiv.) were added at room
temperature. After stirring the mixture at the same temperature
for 24 hours, the reaction was quenched by addition of saturated
aqueous citric acid (20 mL). The resulting solution was filtered
through a pad of celite and the filtrate was extracted with
dichloromethane (20 mL). The organic extract was washed with
brine (20 mL), dried over Na2SO4, filtered and concentrated in
vacuo to give a crude material (932 mg), which was used
without further purification: Rf =0.33 (silica gel, hexane/
EtOAc=1/1).
23
to 8/1): Rf=0.16 (silica gel, hexane/EtOAc=10/1); [α]D À 7.0
(c 1.07 in CHCl3); IR (NaCl) 3287 (OÀ H), 1634 (C=O) cmÀ 1;
1H NMR (300 MHz, CDCl3) δ 7.15 (dt, J=7.8, 1.2 Hz, 1H),
6.91 (dd, J=7.8, 1.2 Hz, 1H), 6.84 (dd, J=7.8, 0.9 Hz, 1H),
6.74 (dt, J=7.8 Hz, 0.9 Hz, 1H), 4.05 (d, J=14.0 Hz, 1H),
3.73–3.64 (m, 1H), 3.54 (d, J=14.0 Hz, 1H), 3.28–3.17 (m,
2H), 3.11–2.93 (m, 2H), 1.84 (sext, J=5.1 Hz, 1H), 1.57–1.21
(m, 32H), 1.01 (d, J=6.9 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H),
0.88 (t, J=6.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 172.3,
158.1, 128.7, 128.5, 122.3, 118.9, 116.3, 61.6, 51.2, 47.2, 45.9,
31.81, 31.79, 31.4, 29.53, 29.45, 29.4, 29.3, 29.22, 29.17, 29.1,
27.6, 27.0, 26.7, 22.6, 20.4, 17.2, 14.0. Anal. Calcd for
C32H58N2O2: C, 76.44; H, 11.63; N, 5.57. Found: C, 76.27; H,
11.28; N, 5.68.
To a solution of the crude material (932 mg) in anhydrous
dichloromethane (6.8 mL), trifluoroacetic acid (2.1 mL,
Adv. Synth. Catal. 2020, 362, 1–23
7
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1H), 3.69 (m, 1H), 3.55 (d, J=14.0 Hz, 1H), 3.40–3.06 (m,
Characterization of (S)-N,N-dihexadecyl-
2-((2-hydroxybenzyl)amino)-3-methylbutanamide
(L10)
4H), 1.85 (m, 1H), 1.17 (t, J=6.9 Hz, 3H), 1.12 (t, J=6.9 Hz,
3H), 1.00–0.97 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 172.1,
158.2, 128.9, 128.5, 122.4, 119.1, 116.3, 61.6, 51.2, 41.4, 40.3,
31.6, 20.2, 17.7, 14.6, 13.0. Anal. Calcd for C16H26N2O2: C,
69.03; H, 9.41; N, 10.06. Found: C, 68.78; H, 9.09; N, 9.93.
According the synthetic procedure of L8, L10 (1.35 g, 47% in 4
steps) was obtained from N-Boc-L-valine (928 mg, 4.27 mmol),
dipalmitoylamine (3.69 g, 7.92 mmol, 1.9 equiv.) and salicylal-
dehyde (521 mg, 4.27 mmol, 1.0 equiv.) as a colorless oil after
chromatographic purification (silica gel, hexane/EtOAc=10/1):
Characterization of (S)-N,N-didecyl-
2-((2-hydroxybenzyl)amino)-4-methylpentanamide
(pre-L20)
23
Rf=0.50 (silica gel, hexane/EtOAc=5/1); [α]D À 5.4 (c 1.00
in CHCl3); IR (NaCl) 3280 (OÀ H), 1636 (C=O) cmÀ 1; 1H NMR
(300 MHz, CDCl3) δ 7.16 (dt, J=7.5, 1.2 Hz, 1H), 6.91 (dd,
J=7.5, 1.2 Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.74 (d, J=
7.5 Hz, 1H), 4.05 (d, J=13.8 Hz, 1H), 3.70 (quintet, J=7.5 Hz,
1H), 3.54 (d, J=13.8 Hz, 1H), 3.28–3.17 (m, 2H), 3.11–2.93
(m, 2H), 1.84 (sext, J=6.6 Hz 1H), 1.57–1.26 (s, 56H), 1.01 (d,
J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H), 0.88 (t, J=6.6 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 172.3, 158.1, 128.8, 128.6,
122.4, 119.0, 116.3, 61.6, 51.2, 47.3, 46.0, 31.9, 31.4, 29.7,
29.63, 29.59, 29.52, 29.46, 29.3, 29.1, 27.7, 27.0, 26.8, 22.7,
20.4, 17.3, 14.1. Anal. Calcd for C44H82N2O2: C, 78.74; H,
12.32; N, 4.17. Found: C, 78.37; H, 12.06; N, 4.11.
According the synthetic procedure of L8, pre-L20 (318 mg,
38% in 4 steps) was obtained from N-Boc-L-leucine (391 mg,
1.69 mmol), didecylamine (855 mg, 2.87 mmol, 1.7 equiv.) and
salicylaldehyde (206 mg, 1.69 mmol, 1.0 equiv.) as a colorless
oil after chromatographic purification (silica gel, hexane/
EtOAc=30/1 to 20/1 to 15/1): Rf=0.43 (silica gel, hexane/
23
EtOAc=10/1); [α]D À 26.7 (c 0.99 in CHCl3); IR (NaCl) 3286
1
(OÀ H), 1729 (C=O) cmÀ 1; H NMR (300 MHz, CDCl3) δ 7.16
(dt, J=7.5, 1.2 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 6.84 (d, J=
7.5 Hz, 1H), 6.75 (dt, J=7.5, 1.2 Hz, 1H), 4.07 (d, J=13.8 Hz,
1H), 3.61–3.44 (m, 3H), 3.14 (m, 2H), 2.97 (m, 1H), 1.94 (m,
1H), 1.56–1.19 (m, 32H), 0.94–0.85 (m, 12H); 13C NMR
(75 MHz, CDCl3) δ 173.5, 158.3, 128.8, 128.6, 122.4, 119.0,
116.3, 54.6, 51.0, 47.2, 46.3, 42.9, 31.9, 29.6, 29.4, 29.3, 29.3,
29.2, 29.1, 27.7, 27.0, 26.8, 24.6, 23.8, 22.6, 21.0, 14.1. Anal.
Calcd for C33H60N2O2: C, 76.69; H, 11.70; N, 5.42. Found: C,
76.32; H, 11.34; N, 5.48.
Characterization of (S)-N-decyl-
2-((2-hydroxybenzyl)amino)-3-methylbutanamide
(L13)
According the synthetic procedure of L8, L13 (881 mg, 94% in
4
steps) was obtained from N-Boc-L-valine (563 mg,
2.59 mmol), decylamine (1.02 g, 6.48 mmol, 2.5 equiv.) and
salicylaldehyde (316 mg, 2.59 mmol, 1.0 equiv.) as a colorless
oil after chromatographic purification (silica gel, hexane/
Characterization of (S)-N,N-didecyl-
2-((2-hydroxybenzyl)amino)-3-phenylpropanamide
(pre-L21)
24
EtOAc=3/1): Rf=0.60 (silica gel, hexane/EtOAc=1/1); [α]D
À 26.3 (c 1.12 in CHCl3); IR (NaCl) 3311 (OÀ H), 1648 (C=O)
According the synthetic procedure of L8, pre-L21 (193 mg,
22% in 4 steps) was obtained from N-Boc-L-phenylalanine
(424 mg, 1.60 mmol), didecylamine (809 mg, 2.72 mmol,
1.7 equiv.) and salicylaldehyde (195 mg, 1.60 mmol, 1.0 equiv.)
as a colorless oil after chromatographic purification (silica gel,
hexane/EtOAc=30/1 to 20/1 to 15/1): Rf=0.17 (silica gel,
1
cmÀ 1; H NMR (300 MHz, CDCl3) δ 7.18 (m, 1H), 6.94 (m,
1H), 6.85 (dd, J=8.1, 0.9 Hz, 1H), 6.77 (dt, J=7.2, 0.9 Hz,
1H), 5.52 (d, J=5.7 Hz, 1H), 4.10 (d, J=13.8 Hz, 1H), 3.64 (s,
J=13.8 Hz, 1H), 3.33 (q, J=6.0 Hz, 2H), 2.66 (d, J=7.2 Hz,
1H), 1.89 (q, J=3.6 Hz, 1H), 1.52 (q, J=6.9 Hz, 2H), 1.36–
1.23 (m, 14H), 1.01 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.6 Hz,
3H), 0.88 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 172.6, 157.6, 128.8, 128.6, 122.4, 119.1, 116.0, 67.2, 50.7,
39.4, 31.8, 31.4, 29.6, 29.49, 29.46, 29.22, 29.19, 26.9, 22.6,
19.6, 18.8, 14.0. Anal. Calcd for C22H38N2O2: C, 72.88; H,
10.56; N, 7.73. Found: C, 72.66; H, 10.95; N, 7.45.
24
hexane/EtOAc=10/1); [α]D À 3.2 (c 1.10 in CHCl3); Rf=0.33
(silica gel, hexane/EtOAc=15/1); IR (NaCl) 3289 (OÀ H), 1637
(C=O) cmÀ 1; 1H NMR (300 MHz, CDCl3) δ 7.29 (m, 1H), 7.25–
7.21 (m, 2H), 7.17–7.12 (m, 3H), 6.89 (dd, J=7.5, 1.5 Hz, 1H),
6.80 (dd, J=8.1, 1.2 Hz, 1H), 6.73 (dt, J=7.5, 1.2 Hz, 1H),
4.02 (d, J=14.1 Hz, 1H), 3.66 (t, J=1.2 Hz, 1H), 3.60 (d, J=
14.1 Hz, 1H), 3.49 (m, 1H), 3.09 (m, 1H), 2.95–2.78 (m, 3H),
2.62 (m, 1H), 1.57–1.28 (m, 32H), 0.91–0.87 (m, 6H); 13C
NMR (75 MHz, CDCl3) δ 172.1, 158.1, 136.8, 129.3, 128.8,
128.6, 128.5, 126.9, 121.9, 119.0, 116.5, 57.7, 50.6, 47.0, 46.6,
40.4, 31.9, 29.6, 29.53, 29.46, 29.37, 29.28, 29.22, 29.1, 29.0,
27.6, 27.1, 26.7, 22.6, 14.1. Anal. Calcd for C36H58N2O2:
C,78.49; H, 10.61; N, 5.09. Found: C, 78.47; H, 10.24; N, 5.37.
Characterization of (S)-N,N-diethyl-
2-((2-hydroxybenzyl)amino)-3-methylbutanamide
(pre-L16)
According the synthetic procedure of L8, pre-L16 (2.03 g 71%
in
4 steps) was obtained from N-Boc-L-valine (2.22 g,
10.2 mmol), dimethylamine (1.87 g, 25.5 mmol, 2.5 equiv.) and
salicylaldehyde (1.25 g, 10.2 mmol, 1.0 equiv.) as a colorless oil
after chromatographic purification (silica gel, hexane/EtOAc=
Characterization of (S)-N,N-didecyl-
2-((2-hydroxybenzyl)amino)-3,3-dimeth-
ylbutanamide (pre-L22)
22
4/1): Rf=0.27 (silica gel, hexane/EtOAc=2/1); [α]D À 3.3 (c
0.78 in CHCl3); IR (NaCl) 3446 (OÀ H), 3294 (NÀ H), 1633
1
(C=O) cmÀ 1; H NMR (300 MHz, CDCl3) δ 7.17 (dt, J=8.1,
According the synthetic procedure of L8, pre-L22 (677 mg,
63% in 4 steps) was obtained from N-Boc-L-tert-leucine
(500 mg, 2.16 mmol), didecylamine (770 mg, 2.59 mmol,
1.5 Hz, 1H), 6.92 (dd, J=8.1, 1.5 Hz, 1H), 6.85 (dd, J=8.1,
0.9 Hz, 1H), 6.75 (dt, J=8.1, 0.9 Hz, 1H), 4.05 (d, J=14.0 Hz,
Adv. Synth. Catal. 2020, 362, 1–23
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1.2 equiv.) and salicylaldehyde (227 mg, 1.86 mmol, 0.9 equiv.)
as a pale yellow oil after chromatographic purification (silica
gel, hexane/EtOAc=15/1 to 8/1 to 5/1): [α]D22 +16.0 (c 0.97 in
Characterization of (S)-2-(((1-(didecylamino)-
3-methylbutan-2-yl)amino)methyl)phenol (L17)
1
CHCl3); IR (NaCl) 3293 (OÀ H), 1634 (C=O) cmÀ 1; H NMR
According the synthetic procedure of L15, L17 (582 mg, 71%
yield) was obtained from L9 (849 mg, 1.73 mmol) as a colorless
oil after chromatographic purification (silica gel, hexane/
EtOAc=80/1 to 30/1 to 20/1): Rf=0.20 (silica gel, hexane/
EtOAc=20/1); [α]D24 +82.4 (c 1.10 in CHCl3); IR (NaCl) 3249
(300 MHz, CDCl3) δ 7.16 (m, 1H), 6.92 (d, J=7.5 Hz, 1H),
6.85 (d, J=8.1 Hz, 1H), 6.74 (dt, J=7.5, 1.5 Hz, 1H), 3.94 (d,
J=13.5 Hz, 1H), 3.74 (m, 1H), 3.57 (d, J=13.5 Hz, 1H), 3.43
(m, 1H), 3.32 (s, 1H), 3.09–2.94 (m, 2H), 1.60–1.25 (m, 32H),
1.02 (s, 9H), 0.88 (t, J=6.5 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 171.8, 158.1, 128.8, 128.5, 122.4, 118.9, 116.3, 63.7,
51.4, 48.2, 46.2, 34.8, 31.8, 29.6, 29.5, 29.3, 29.24, 29.20,
29.17, 27.7, 27.2, 27.1, 26.9, 22.6, 14.1. Anal. Calcd for
C33H60N2O2: C, 76.69; H, 11.70; N, 5.42. Found: C, 76.60; H,
12.06; N, 5.44.
1
(OÀ H) cmÀ 1; H NMR (300 MHz, CDCl3) δ 7.15 (dt, J=8.1,
1.5 Hz, 1H), 6.98 (dd, J=7.5, 1.5 Hz, 1H), 6.83 (dd, J=7.8,
1.2 Hz, 1H), 6.75 (dt, J=7.2, 0.9 Hz, 1H), 4.02 (d, J=13.5 Hz,
1H), 3.78 (d, J=13.5 Hz, 1H), 2.52–2.39 (m, 3H), 2.35–2.26
(m, 4H), 2.05–1.93 (m, 1H), 1.40–1.24 (m, 32H), 0.97–0.94 (m,
6H), 0.88 (t, J=6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 158.3, 128.4, 127.9, 123.9, 118.7, 116.4, 60.9, 54.5, 54.4,
51.5, 31.9, 29.7, 29.62, 29.59, 29.3, 28.5, 27.6, 27.0, 22.7, 19.0,
17.4, 14.1. Anal. Calcd for C32H60N2O: C, 78.62; H, 12.37; N,
5.73. Found: C, 79.01; H, 12.64; N, 5.74.
Synthesis and characterization of (S)-
2-(((1-(dimethylamino)-3-methylbutan-2-yl)amino)
methyl)phenol (L15)
To a solution of pre-L15[2] (201 mg) in tetrahydrofuran (THF, Characterization of (S)-2-(((1-(decylamino)-3-meth-
2.7 mL), LiAlH4 (76.2 mg, 2.01 mmol, 2.5 equiv.) was added at
ylbutan-2-yl)amino)methyl)phenol (L18)
°
0 C. The solution was then stirred at reflux for 19 hours. The
According the synthetic procedure of L15, L18 (28.1 mg, 13%
yield) was obtained from L13 (217 mg, 0.600 mmol) as a
colorless oil after chromatographic purification (silica gel,
hexane/EtOAc=3/1 to 1/3): Rf=0.17 (silica gel, hexane/
EtOAc=1/1); [α]D22 +24.6 (c 0.66 in CHCl3); IR (NaCl) 3266
reaction was quenched by addition of water (0.08 mL and
0.24 mL) and aqueous NaOH (ca. 10% in water, 0.08 mL). The
resulting solution was filtered through a pad of celite and dried
over Na2SO4, filtered and concentrated in vacuo to give a crude
material. The crude material was purified by column chroma-
tography (silica gel, hexane/EtOAc=2/1 to 1/1) to give L15
(139 mg, 73%) as a white solid: Rf=0.17 (silica gel, hexane/
EtOAc=2/1); [α]D19 +108.4 (c 0.80 in CHCl3); IR (NaCl) 3231
1
(OÀ H) cmÀ 1; H NMR (300 MHz, CDCl3) δ 7.16 (m, 1H), 7.00
(dd, J=7.2, 1.8 Hz, 1H), 6.84 (dd, J=8.1, 0.9 Hz, 1H), 6.77
(dt, J=7.2 Hz, J=1.2 Hz, 1H), 3.98 (d, J=13.5 Hz, 1H), 3.88
(d, J=13.5 Hz, 1H), 2.76 (d, J=12.0, 3.8 Hz, 1H), 2.65–2.51
(m, 3H), 2.45 (m, 1H), 1.93 (m, 1H), 1.48–1.26 (m, 16H), 0.97
(d, J=7.1 Hz, 3H), 0.94 (d, J=7.1 Hz, 3H), 0.88 (t, J=6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 158.1, 128.6, 128.2, 123.8,
118.8, 116.5, 62.6, 50.9, 50.1, 49.1, 31.9, 29.9, 29.59, 29.56,
29.51, 29.3, 28.9, 27.3, 22.7, 19.1, 18.1, 14.1. Anal. Calcd for
C22H40N2O: C, 75.81; H, 11.57; N, 8.04. Found: C, 75.90; H,
11.21; N, 7.85.
1
(OÀ H), 1599 (C=O) cmÀ 1; H NMR (300 MHz, CDCl3) δ 7.16
(dt, J=7.5, 1.2 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.84 (d, J=
7.5 Hz, 1H), 6.76 (dt, J=7.5, 1.2 Hz, 1H), 4.01 (d, J=13.4 Hz,
1H), 3.83 (d, J=13.4 Hz, 1H) 2.54 (m, 1H), 2.35 (t, J=
12.0 Hz, 1H), 2.23 (s, 6H), 2.16 (dd, J=12.0 Hz, 3.9 Hz, 1H),
2.04–1.91 (m, 1H), 0.97 (d, J=5.1 Hz, 3H), 0.94 (d, J=5.1 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 158.1, 128.6, 128.2, 124.1,
118.8, 116.5, 60.3, 59.8, 50.9, 45.7, 28.9, 19.0, 17.7. Anal.
Calcd for C14H24N2O: C, 71.14; H, 10.24; N, 11.85. Found: C,
71.23; H, 9.84; N, 11.57.
Characterization of (S)-2-(((1-(didecylamino)-
4-methylpentan-2-yl)amino)methyl)phenol (L20)
Characterization of (S)-2-(((1-(diethylamino)-
3-methylbutan-2-yl)amino)methyl)phenol (L16)
According the synthetic procedure of L15, L20 (126 mg, 59%
yield) was obtained from pre-L20 (221 mg, 0.428 mmol) as a
colorless oil after chromatographic purification (silica gel,
hexane/EtOAc=30/1 20/1 10/1): Rf=0.17 (silica gel, hexane/
EtOAc=10/1); [α]D24 +83.3 (c 1.04 in CHCl3); IR (NaCl) 3257
According the synthetic procedure of L15, L16 (1.19 g, 62%
yield) was obtained from pre-L16 (2.03 g, 7.29 mmol) as a
yellow oil after chromatographic purification (silica gel,
hexane/EtOAc=2/1 to 1/3): Rf=0.17 (silica gel, hexane/
EtOAc=2/1); [α]D21 +116.5 (c 1.09 in CHCl3); IR (NaCl) 3250
1
(OÀ H) cmÀ 1; H NMR (300 MHz, CDCl3) δ 7.15 (m, 1H), 6.98
(d, J=7.2 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 6.76 (m, 1H), 4.00
(d, J=13.7 Hz, 1H), 3.83 (d, J=13.7 Hz, 1H), 2.67 (sep, J=
4.8 Hz, 1H), 2.49–2.27 (m, 6H), 1.71 (sep, J=6.5 Hz, 1H),
1.23 (s, 34H), 0.93–0.87 (m, 12H); 13C NMR (75 MHz, CDCl3)
δ 158.3, 128.4, 127.8, 123.8, 118.6, 116.4, 58.8, 54.5, 53.7,
50.1, 42.0, 31.9, 29.7, 29.6, 29.3, 27.5, 27.0, 25.0, 23.3, 22.7,
22.6, 14.1. Anal. Calcd for C33H62N2O: C, 78.82; H, 12.43; N,
5.57. Found: C, 78.82; H, 12.52; N, 5.60.
1
(OÀ H) cmÀ 1; H NMR (300 MHz, CDCl3) δ 7.16 (m, 1H), 6.99
(d, J=7.4 Hz, 1H), 6.83 (dd, J=8.0, 1.2 Hz, 1H), 6.76 (m, 1H),
4.01 (d, J=13.5 Hz, 1H), 3.80 (d, J=13.5 Hz, 1H), 2.65–2.29
(m, 6H), 1.98 (m, 1H), 0.99 (d, J=7.2 Hz, 6H), 0.95 (d, J=
6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 158.2, 128.4, 127.9,
123.9, 118.6, 116.3, 60.5, 53.0, 51.2, 47.1, 28.6, 18.9, 17.4,
11.7. Anal. Calcd for C16H28N2O: C, 72.68; H, 10.67; N, 10.59.
Found: C, 72.36; H, 10.50; N, 10.53.
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To a solution of the crude material (1.48 g) in ethanol (5.8 mL),
sodium borohydride (439 mg, 11.6 mmol, 4.0 equiv.) and conc.
Characterization of (S)-2-(((1-(didecylamino)-
3-phenylpropan-2-yl)amino)methyl)phenol (L21)
°
hydrochloric acid (1 drop) were added at 0 C. The solution was
According the synthetic procedure of L15, L21 (87.0 mg, 34%
yield) was obtained from pre-L21 (264 mg, 0.479 mmol) as a
colorless oil after chromatographic purification (silica gel,
hexane/EtOAc=30/1 to 20/1 to 10/1): Rf=0.17 (silica gel,
hexane/EtOAc=10/1); [α]D24 +53.6 (c 0.97 in CHCl3); IR
warmed to room temperature and stirred for 2 hours. The
reaction was quenched by addition of saturated aqueous
NaHCO3 (5.0 mL), and the resulting mixture was extracted with
dichloromethane (20 mL×2). The combined organic extracts
were dried over Na2SO4, filtered and concentrated in vacuo to
give a crude material (834 mg). The crude material was purified
by column chromatography (silica gel, hexane/EtOAc=20/1 to
15/1) to give L19 (474 mg, 47% in 3 steps) as a colorless oil:
Rf=0.33 (silica gel, hexane/EtOAc=10/1); [α]D23 +11.7 (c
1.13 in CHCl3); IR (NaCl) 3303 (OÀ H) cmÀ 1; 1H NMR
(300 MHz, CDCl3) δ 7.15 (t, J=6.6 Hz, 1H), 6.98 (d, J=
7.5 Hz, 1H), 6.84 (d, J=8.7 Hz, 1H), 6.76 (t, J=7.2 Hz, 1H),
4.01 (d, J=13.7 Hz, 1H), 3.94 (d, J=13.7 Hz, 1H), 3.56 (dd,
J=9.0 Hz, J=3.0 Hz, 1H), 3.44–3.36 (m, 3H), 2.56 (q, J=
5.1 Hz, 1H), 1.93 (sextet, J=6.9 Hz, 1H), 1.55 (s, 2H), 1.27 (s,
16H), 1.01–0.84 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 158.2,
128.5, 128.0, 123.2, 118.7, 116.2, 71.4, 69.2, 62.2, 50.8, 31.8,
31.5, 29.53, 29.50, 29.46, 29.3, 29.2, 29.1, 26.1, 22.6, 19.1,
18.7, 14.0. Anal. Calcd for C22H39NO2: C, 75.59; H, 11.25; N,
4.01. Found: C, 75.19; H, 10.94; N, 4.12.
1
(NaCl) 3249 (OÀ H) cmÀ 1; H NMR (300 MHz, CDCl3) δ 7.31–
7.26 (m, 2H), 7.22–7.11 (m, 4H), 6.95 (d, J=7.5 Hz, 1H), 6.82
(d, J=9.0 Hz, 1H), 6.74 (dt, J=7.4 Hz, J=1.2 Hz, 1H), 3.97
(d, J=13.7 Hz, 1H), 3.86 (d, J=13.7 Hz, 1H), 2.95–2.84 (m,
2H), 2.65 (sext, J=6.4 Hz, 1H), 2.42–2.23 (m, 6H), 1.23 (s,
32H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 158.2, 138.7, 129.1, 128.5, 127.8, 126.3, 123.7, 118.8, 116.5,
58.2, 57.8, 54.4, 51.0, 39.4, 31.9, 31.5, 29.7, 29.6, 29.3, 27.5,
27.0, 22.7, 14.1. Anal. Calcd for C36H60N2O: C, 80.54; H,
11.26; N, 5.22. Found: C, 80.33; H, 10.91; N, 5.27.
Characterization of (S)-2-(((1-(didecylamino)-
3,3-dimethylbutan-2-yl)amino)methyl)phenol (L22)
According the synthetic procedure of L15, L22 (121 mg, 38%
yield) was obtained from pre-L22 (677 mg, 1.35 mmol) as a
yellow oily material after chromatographic purification (silica
gel, hexane/EtOAc=15/1 to 8/1): Rf=0.43 (silica gel, hexane/
EtOAc=8/1); [α]D23 +77.4 (c 1.08 in CHCl3); IR (NaCl) 3188
Synthesis and characterization of (S)-
2-(((1-(didecylamino)-3-methylbutan-2-yl)amino)
methyl)-4-nitrophenol (L23)
1
(OÀ H) cmÀ 1; H NMR (300 MHz, CDCl3) δ 7.15 (t, J=7.5 Hz,
1H), 6.96 (d, J=7.5 Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.70 (t,
J=7.5 Hz, 1H), 4.06 (d, J=13.2 Hz, 1H), 3.92 (d, J=13.2 Hz,
1H), 2.56–2.42 (m, 3H), 2.34–2.23 (m, 4H), 1.45–1.14 (m,
33H), 0.99 (s, 9H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 158.3, 128.4, 127.9, 124.1, 118.7, 116.4, 64.7, 55.6,
55.1, 54.2, 34.5, 31.9, 29.7, 29.6, 29.3, 27.6, 27.3, 26.8, 22.7,
14.1. Anal. Calcd for C33H62N2O: C, 78.82; H, 12.43; N, 5.57.
Found: C, 78.69; H, 12.07; N, 5.81.
According the synthetic procedure of L8, a crude material
including A was obtained from N-Boc-L-valine (350 mg,
1.61 mmol) and didecylamine (0.4 mL, 4.0 mmol, 2.5 equiv.).
The crude material was purified by column chromatography
(silica gel, hexane/EtOAc=10/1 to 4/1 to 0/1) to give A
(542 mg, 82% in 2 steps) as a yellow oil: Rf=0.40 (silica gel,
hexane/EtOAc=6/1); [α]D23 +18.0 (c 0.91 in CHCl3); IR
1
(NaCl) 3384 (NÀ H), 1641 (C=O) cmÀ 1; H NMR (300 MHz,
CDCl3) δ 8.18 (brs, 1H), 4.16 (d, J=4.2 Hz, 1H), 3.66 (m, 1H),
3.28 (m, 1H), 3.11 (m, 1H), 2.97 (m, 1H), 2.16 (m, 1H), 1.57–
1.26 (m, 32H), 1.11 (d, J=7.2 Hz, 3H), 1.02 (d, J=7.2 Hz,
3H), 0.88 (t, J=6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 173.8, 55.6, 46.7, 45.2, 31.6, 31.1, 28.8, 28.7, 28.6, 28.5,
26.9, 26.2, 26.0, 21.8, 19.2, 16.2, 13.2; Anal. Calcd for
C25H52N2O: C, 75.69; H, 13.21; N, 7.06. Found: C, 75.42; H,
12.82; N, 6.86.
Synthesis and characterization of (S)-
2-(((1-(decyloxy)-3-methylbutan-2-yl)amino)methyl)
phenol (L19)
To a solution of L-valinol (330 mg, 3.19 mmol) in THF
(5.8 mL), sodium hydride (136 mg, 3.40 mmol, 1.2 equiv.) was
°
added at 0 C. After stirring the mixture at the same temperature
for 30 min, 1-bromodecane (0.6 mL, 2.9 mmol, 0.9 equiv.) was
added. The resulting solution was stirred at reflux for 7 hours.
The reaction was quenched by addition of water (0.2 mL), and
the resulting mixture was filtered through a pad of celite
(washed with EtOAc). The organic solution was dried over
Na2SO4, filtered and concentrated in vacuo to give a crude
material (872 mg), which was used without further purification:
Rf =0.26 (silica gel, hexane/EtOAc=3/1).
To a solution of A (542 mg) in THF (4.6 mL), LiAlH4 (140 mg,
°
3.43 mmol, 2.5 equiv.) was added at 0 C. The solution was
warmed to room temperature and stirred for 2 hours. The
reaction was quenched by addition of water (0.14 mL and
0.42 mL) and aqueous NaOH (ca. 10% in water, 4.6 mL). The
resulting solution was filtered through a pad of celite and dried
over Na2SO4, filtered and concentrated in vacuo to give a crude
material. The crude material was purified by column chroma-
tography (silica gel, hexane/EtOAc=5/1 to 2/1 to 0/1) to give
B (440 mg, 84%) as a yellow oil: Rf=0.27 (silica gel, hexane/
EtOAc=0/1); [α]D23 +47.9 (c 0.44 in CHCl3); IR (NaCl) 3388
(NÀ H) cmÀ 1; 1H NMR (300 MHz, CDCl3) δ 2.58 (m, 1H),
2.50–2.12 (m, 6H), 1.51 (m, 1H), 1.42–1.26 (m, 32H), 0.93–
0.86 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 59.5, 54.7, 54.2,
32.1, 31.9, 31.6, 29.7, 29.6, 29.3, 27.5, 27.3, 22.7, 19.4, 18.4,
To a solution of the crude material (872 mg) in ethanol
(5.8 mL), salicylaldehyde (346 mg, 2.83 mmol, 1.0 equiv.) was
added at room temperature. After stirring the mixture at reflux
for 3 hours, the resulting mixture was concentrated in vacuo to
give a crude material (1.48 g), which was used without further
purification: Rf =0.30 (silica gel, hexane/EtOAc=3/1).
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14.1; Anal. Calcd for C25H54N3: C, 78.46; H, 14.22; N, 7.31.
Found: C, 78.06; H, 13.92; N, 7.13.
Rf=0.30 (silica gel, hexane/EtOAc=5/1); [α]D23 +49.7 (c 0.40
in CHCl3); IR (NaCl) 3245 (OÀ H), 3058 (NÀ H) cmÀ 1; 1H NMR
(300 MHz, CDCl3) δ 7.76 (t, J=9.0 Hz, 2H), 7.66 (d, J=
8.7 Hz, 1H), 7.41 (dd, J=7.2, 1.5 Hz, 1H), 7.26 (m, 1H), 7.09
(d, J=8.7 Hz, 1H), 4.53 (d, J=14.2 Hz, 1H), 4.22 (d, J=
14.2 Hz, 1H), 2.61–2.28 (m, 8H), 2.06 (m, 1H), 1.21 (s, 31H),
1.01–0.99 (m, 6H), 0.87 (t, J=6.6 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 156.9, 132.2, 128.81, 128.76, 128.3, 126.1, 122.2,
121.0, 119.7, 113.2, 61.4, 54.6, 46.7, 31.9, 29.64, 29.62, 29.6,
29.3, 28.8, 27.6, 27.1, 22.7, 19.2, 17.4, 14.1. Anal. Calcd for
C36H62N2O2: C, 80.24; H, 11.60; N, 5.20. Found: C, 80.05; H,
11.48; N, 4.86.
To a solution of B (440 mg) in dichloromethane (3.8 mL), 2-
hydroxy-5-nitrobenzaldehyde (231 mg, 1.38 mmol, 1.2 equiv.)
was added at room temperature. After stirring the mixture for
12 hours, the resulting mixture was concentrated in vacuo to
give a crude material (726 mg), which was used without further
purification: Rf =0.60 (silica gel, hexane/EtOAc=3/1).
To a solution of the crude material (726 mg) in ethanol
(5.8 mL), sodium borohydride (348 mg, 9.21 mmol, 4.0 equiv.)
°
and conc. hydrochloric acid (1 drop) were added at 0 C. The
solution was warmed to room temperature and stirred for
4 hours. The reaction was quenched by addition of saturated
aqueous NaHCO3 (20 mL), and the resulting mixture was
extracted with dichloromethane (20 mL×2). The combined
extracts were dried over Na2SO4, filtered and concentrated in
vacuo to give a crude material (683 mg). The crude material
was purified by column chromatography (silica gel, hexane/
General procedure for amido-functionalized allyla-
tion of ketones
To a suspension of zinc hydroxide (2.0 mg, 0.020 mmol,
0.10 equiv.) and L17 (10.9 mg, 0.0220 mmol, 0.11 equiv.) in
water (0.50 mL). After stirring the mixture at the same temper-
ature for 1 hour, 1a (0.300 mmol, 1.5 equiv.) and ketone
(0.200 mmol) were added at room temperature. After stirring
the mixture at the same temperature for 24 hours, the reaction
was quenched by addition of saturated aqueous sodium period-
ate (3.0 mL). The resulting mixture was extracted with dichloro-
methane (8.0 mL×2). The combined organic extracts were
washed with brine (10 mL), dried over Na2SO4, filtered and
concentrated in vacuo to give a crude material. This material
was purified by column chromatography to give 2.
EtOAc=10/1 to 5/1) to give L23 (483 mg, 57% in 5 steps) as a
23
yellow oil: Rf=0.43 (silica gel, hexane/EtOAc=3/1); [α]D
+
65.0 (c 1.08 in CHCl3); IR (NaCl) 3224 (OÀ H) cmÀ 1; H NMR
(300 MHz, CDCl3) δ 8.05 (dd, J=9.0, 2.7 Hz, 1H), 7.93 (d, J=
2.7 Hz, 1H), 7.64 (brs, 1H), 6.80 (d, J=9.0 Hz, 1H), 4.03 (d,
J=13.8 Hz, 1H), 3.87 (d, J=13.8 Hz, 1H), 2.58–2.33 (m, 7H),
1.96 (m, 1H), 1.50–1.20 (s, 33H), 0.99 (d, J=7.2 Hz, 3H), 0.95
(d, J=6.9 Hz, 3H), 0.88 (t, J=7.2 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 166.2, 139.0, 125.3, 124.3, 123.8, 116.8,
60.5, 54.3, 54.1, 54.0, 50.1, 31.8, 29.6, 29.5, 29.41, 29.36, 29.3,
28.6, 27.5, 26.6, 22.6, 19.1, 17.4, 14.0. Anal. Calcd for
C32H59N3O3: C, 72.00; H, 11.14; N, 7.87. Found: C, 72.09; H,
11.06; N, 7.88.
1
Synthesis and characterization of (À )-4-hydroxy-
4-methyl-2-methylene-N-phenylhexanamide (2a)
According to the general procedure, the reaction of 2-butanone
(23.5 mg, 0.326 mmol) with 1a (134 mg, 0.489 mmol) was
performed for 24 hours. The crude material was purified by
column chromatography (silica gel, hexane/EtOAc=4/1) to
give 2a (42.3 mg, 56%, 13% ee) as a colorless oil: Rf=0.37
Characterization of (S)-2-(((1-(didecylamino)-
3-methylbutan-2-yl)amino)methyl)-4-meth-
oxyphenol (L24)
22
According the synthetic procedure of L23, L24 (98.7 mg, 45%
in 5 steps) was obtained from N-Boc-L-valine (91.3 mg,
0.420 mmol) as a colorless oil after chromatographic purifica-
tion (silica gel, hexane/EtOAc=15/1 to 8/1): Rf=0.40 (silica
gel, hexane/EtOAc=8/1); [α]D23 +69.0 (c 1.15 in CHCl3); IR
(silica gel, hexane/EtOAc=1/1); [α]D À 0.83 (c 0.64 in
°
CHCl3); m.p. 83–85 C; IR (NaCl) 3214 (OÀ H), 3120 (NÀ H),
1
1647 (C=O) cmÀ 1; H NMR (300 MHz, CDCl3) δ 9.19 (brs,
1H), 7.55 (d, J=6.9 Hz, 2H), 7.30 (t, J=6.9 Hz, 2H), 7.09 (t,
J=6.9 Hz, 1H), 6.11 (s, 1H), 5.41 (s, 1H), 3.46 (s, 4H), 2.62 (d,
J=14.3 Hz, 1H), 2.46 (d, J=14.3 Hz, 1H), 1.58 (q, J=7.5 Hz,
2H), 1.20 (s, 3H), 0.96 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.8, 141.9, 138.1, 128.9, 124.7, 124.2, 120.2, 72.8,
44.0, 35.3, 26.1, 8.4. Anal. Calcd for C14H19NO2: C, 72.07; H,
8.21; N, 6.00. Found: C, 72.40; H, 8.04; N, 6.00. The
enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IF column (hexane/EtOH=95/5), flow rate 0.5 mL/
min, UV detection 254 nm, tR (major)=30.0 min, tR (minor)=
32.8 min.
1
(NaCl) 3399 (OÀ H), 3255 (NÀ H) cmÀ 1; H NMR (300 MHz,
CDCl3) δ 6.76–6.69 (m, 2H), 6.57 (d, J=2.7 Hz, 1H), 3.98 (d,
J=13.5 Hz, 1H), 3.76–3.72 (m, 4H), 2.51–2.40 (m, 3H), 2.34–
2.26 (m, 4H), 1.98 (m, 1H), 1.43–1.25 (s, 32H), 0.96–0.93 (m,
6H), 0.89 (t, J=6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 152.3, 152.0, 124.6, 116.6, 113.9, 113.2, 60.9, 55.7, 54.5,
54.4, 51.7, 31.9, 29.7, 29.6, 29.3, 28.5, 27.6, 27.0, 22.7, 19.0,
17.3, 14.0. Anal. Calcd for C33H62N2O2: C, 76.39; H, 12.04; N,
5.40. Found: C, 76.01; H, 11.67; N, 5.36.
Characterization of (S)-1-(((1-(didecylamino)-
3-methylbutan-2-yl)amino)methyl)naphthalen-2-ol
(L25)
Synthesis and characterization of (S)-4-hydroxy-
2-methylene-N,4-diphenylpentanamide (2b)
According to the general procedure, the reaction of acetophe-
none (24.0 mg, 0.200 mmol) with 1a (81.9 mg, 0.300 mmol)
was performed for 24 hours. The crude material was purified by
column chromatography (silica gel, hexane/EtOAc=7/1 to 4/1)
to give 2b (547 mg, 98%, 70% ee) as a white solid: Rf=0.30
According the synthetic procedure of L23, L25 (98.2 mg, 5.5%
in 5 steps) was obtained from N-Boc-L-valine (516 mg,
2.38 mmol) as
a pale yellow oil after chromatographic
purification (silica gel, hexane/EtOAc=18/1 to 15/1 to 10/1):
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18
(silica gel, hexane/EtOAc=2/1); [α]D À 32.6 (c 1.00 in
Synthesis and characterization of (S)-4-hydroxy-
2-methylene-4-(naphthalen-2-yl)-N-phenylpentana-
mide (2e)
°
CHCl3); m.p. 114–116 C; IR (KBr) 3271 (OÀ H), 3158 (NÀ H),
3134 (NÀ H), 1650 (C=O) cmÀ 1; H NMR (300 MHz, CDCl3)
1
δ 8.53 (brs, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.45 (d, J=7.8 Hz,
2H), 7.31 (m, 1H), 7.21 (t, J=7.2 Hz 1H), 7.11 (t, J=7.2 Hz
1H), 5.79 (s, 1H), 5.10 (s, 1H), 4.73 (brs, 1H), 2.81 (s, 2H),
1.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.5, 147.3, 141.2,
137.7, 128.9, 128.0, 126.6, 125.0, 124.5, 120.2, 74.4, 47.5,
29.7. Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98.
Found: C, 76.55; H, 6.43; N, 4.88. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak IC column
(hexane/EtOH=90/10), flow rate 0.5 mL/min, UV detection
254 nm, tR (major)=16.3 min, tR (minor)=14.9 min.
According to the general procedure, the reaction of 2’-
acetonaphthone (34.2 mg, 0.201 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=5/1 to 4/1) to give 2e (42.8 mg, 72%, 42% ee) as a
23
white solid: Rf=0.23 (silica gel, hexane/EtOAc=3/1); [α]D
°
À 62.8 (c 1.00 in CHCl3); m.p. 174–176 C; IR (KBr) 3195
1
(OÀ H), 3135 (NÀ H), 1649 (C=O) cmÀ 1; H NMR (300 MHz,
CDCl3) δ 8.17 (brs, 1H), 7.97 (s, 1H), 7.83–7.78 (m, 3H), 7.54–
7.43 (m, 5H), 7.30 (t, J=7.8 Hz, 2H), 7.11 (t, J=7.2 Hz, 1H),
5.71 (s, 1H), 5.10 (s, 1H), 4.84 (s, 1H), 2.93 (s, 2H), 1.72 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 168.6, 144.7, 141.5, 137.5,
133.1, 132.2, 129.0, 128.2, 127.7, 127.4, 126.0, 125.7, 124.6,
123.8, 123.7, 123.6, 120.2, 74.5, 47.3, 30.1. Anal. Calcd for
C22H21NO2: C, 79.73; H, 6.39; N, 4.23. Found: C, 79.84; H,
6.66; N, 4.30. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=95/
5), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
36.4 min, tR (minor)=32.9 min.
Synthesis and characterization of (À )-4-hydroxy-
4-methyl-2-methylene-N-phenyldodecanamide (2c)
According to the general procedure, the reaction of 2-decanone
(31.3 mg, 0.200 mmol) with 1a (81.9 mg, 0.300 mmol) was
performed for 24 hours. The crude material was purified by
column chromatography (silica gel, toluene/EtOAc=20/1 to
10/1) to give 2c (42.8 mg, 67%, 28% ee) as a colorless solid:
20
Rf=0.21 (silica gel, toluene/EtOAc=10/1); [α]D À 0.72 (c
0.77 in CHCl3); IR (NaCl) 3297 (OÀ H), 3137 (NÀ H), 1661
(C=O) cmÀ 1; 1H NMR (300 MHz, CDCl3) δ 9.19 (brs, 1H),
7.57–7.53 (m, 2H), 7.33–7.27 (m, 2H), 7.09 (tt, J=7.4, 1.2 Hz,
1H), 6.10 (s, 1H), 5.40 (s, 1H), 3.43 (brs, 1H), 2.62 (d, J=
14.1 Hz, 1H), 2.46 (d, J=14.1 Hz, 1H), 1.56–1.50 (m, 2H),
1.28 (s, 12H), 1.21 (s, 3H), 0.88 (t, J=6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 167.8, 141.8, 138.2, 128.8, 124.9, 124.2,
120.1, 72.6, 44.4, 42.9, 31.8, 30.1, 29.6, 29.2, 26.6, 24.0, 22.6,
14.0. Anal. Calcd for C20H31NO2: C, 75.67, H, 9.84; N, 4.41.
Found: C, 75.49; H, 9.59; N, 4.54. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak IG column
(hexane/EtOH=95/5), flow rate 0.5 mL/min, UV detection
254 nm, tR (major)=23.0 min, tR (minor)=27.1 min.
Synthesis and characterization of (S)-4-hydroxy-
2-methylene-4-(naphthalen-1-yl)-N-phenylpentana-
mide (2f)
According to the general procedure, the reaction of 1’-
acetonaphthone (34.1 mg, 0.201 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=5/1 to 4/1) to give 2f (61.8 mg, 93%, 86% ee) as a
17
white solid: Rf=0.21 (silica gel, hexane/EtOAc=4/1); [α]D
°
À 126.3 (c 1.00 in CHCl3); m.p. 123–125 C; IR (KBr) 3285
1
(OÀ H), 3191 (NÀ H), 3139 (NÀ H), 1650 (C=O) cmÀ 1; H NMR
(300 MHz, CDCl3) δ 8.51 (d, J=8.4 Hz, 1H), 8.18 (brs, 1H),
7.86 (d, J=7.5 Hz, 1H), 7.77 (dd, J=7.5, 1.5 Hz, 1H), 7.75
(dd, J=8.4, 0.9 Hz, 1H), 7.53–7.29 (m, 7H), 7.12 (t, J=7.5 Hz,
1H), 5.69 (s, 1H), 5.12 (s, 1H), 4.82 (s, 1H), 3.45 (d, J=
14.7 Hz, 1H), 3.08 (d, J=14.7 Hz, 1H), 1.89 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 168.4, 142.5, 141.8, 137.5, 134.7, 130.3,
129.4, 128.9, 128.5, 126.1, 125.4, 125.0, 124.9, 124.6, 124.0,
123.7, 120.3, 75.4, 45.7, 29.7. Anal. Calcd for C22H21NO2: C,
79.73; H, 6.39; N, 4.23. Found: C, 79.54; H, 6.22; N, 4.18. The
enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IG column (hexane/EtOH=80/20), flow rate 0.5 mL/
min, UV detection 254 nm, tR (major)=19.4 min, tR (minor)=
14.0 min.
Synthesis and characterization of (+)-4-hydroxy-
4,5,5-trimethyl-2-methylene-N-phenylhexanamide
(2d)
According to the general procedure, the reaction of 3,3-dimeth-
yl-2-butanone (19.8 mg, 0.198 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, toluene/
EtOAc=20/1 to 10/1) to give 2d (5.2 mg, 10%, 69% ee) as a
21
colorless oil: Rf=0.21 (silica gel, toluene/EtOAc=10/1); [α]D
+6.1 (c 0.75 in CHCl3); IR (NaCl) 3299 (OÀ H), 3136 (NÀ H),
1
1661 (C=O) cmÀ 1; H NMR (300 MHz, CDCl3) δ 8.93 (brs,
1H), 7.56 (d, J=7.5 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.10 (t,
J=7.5 Hz, 1H), 6.15 (s, 1H), 5.43 (s, 1H), 2.80 (d, J=13.8 Hz,
1H), 2.78 (brs, 1H), 2.41 (d, J=13.8 Hz, 1H), 1.17 (s, 3H),
1.03 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 167.7, 142.5, 138.2,
128.9, 124.8, 124.2, 120.0, 39.1, 38.4, 25.2, 21.2, 14.1. Anal.
Calcd for C16H23NO2: C, 73.53; H, 8.87; N, 5.36. Found: C,
73.85; H, 8.91; N, 5.32. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak IF column
(hexane/EtOH=95/5), flow rate 0.5 mL/min, UV detection
254 nm, tR (major)=22.9 min, tR (minor)=26.4 min.
Synthesis and characterization of (S)-4-hydroxy-
4-(4-methoxyphenyl)-2-methylene-N-phenylpenta-
namide (2g)
According to the general procedure, the reaction of 4’-meth-
oxyacetophenone (29.8 mg, 0.198 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=7/1 to 5/1) to give 2g (51.9 mg, 84%, 66% ee) as a
18
white solid: Rf=0.13 (silica gel, hexane/EtOAc=3/1); [α]D
Adv. Synth. Catal. 2020, 362, 1–23
12
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°
À 76.9 (c 1.00 in CHCl3); m.p. 120–122 C; IR (KBr) 3286
min, UV detection 254 nm, tR (major)=39.7 min, tR (minor)=
36.3 min.
1
(OÀ H), 3192 (NÀ H), 3136 (NÀ H), 1650 (C=O) cmÀ 1; H NMR
(300 MHz, CDCl3) δ 8.81 (brs, 1H), 7.50 (d, J=7.5 Hz, 2H),
7.37–7.25 (m, 4H), 7.09 (tt, J=7.5, 1.2 Hz, 1H), 6.82 (tt, J=
8.7, 2.7 Hz, 1H), 5.80 (s, 1H), 5.07 (s, 1H), 4.81 (brs, 1H), 3.75
(s, 3H), 2.75 (s, 2H), 1.59 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 168.4, 158.2, 141.7, 139.5, 137.7, 129.0, 126.2, 124.5, 123.9,
120.1, 113.3, 74.2, 55.2, 47.6, 30.0. Anal. Calcd for C19H21NO3:
C, 73.29; H, 6.80; N, 4.50. Found: C, 72.89; H, 6.66; N, 4.74.
The enantiomeric excess was determined by HPLC with a
Daicel Chiralpak IC column (hexane/EtOH=90/10), flow rate
0.5 mL/min, UV detection 254 nm, tR (major)=22.8 min, tR
(minor)=20.8 min.
Synthesis and characterization of (S)-4-hydroxy-
2-methylene-N-phenyl-4-(4-(trifluoromethyl)
phenyl)pentanamide (2j)
According to the general procedure, the reaction of 4’-
(trifluoromethyl)acetophenone (37.4 mg, 0.199 mmol) with 1a
(81.9 mg, 0.300 mmol) was performed for 24 hours. The crude
material was purified by column chromatography (silica gel,
hexane/EtOAc=6/1 to 4/1) to give 2j (66.1 mg, 99%, 58% ee)
as a white solid: Rf=0.28 (silica gel, hexane/EtOAc=3/1);
19
°
[α]D À 62.5 (c 1.00 in CHCl3); m.p. 93–95 C; IR (KBr) 3276
(OÀ H), 3187 (NÀ H), 3140 (NÀ H), 1649 (C=O) cmÀ 1; H NMR
1
Synthesis and characterization of (S)-4-(4-((tert-
butyldimethylsilyl)oxy)phenyl)-4-hydroxy-2-meth-
ylene-N-phenylpentanamide (2h)
(300 MHz, CDCl3) δ 8.52 (brs, 1H), 7.55 (s, 4H), 7.47 (d, J=
7.5 Hz, 2H), 7.29 (t, J=7.5 Hz, 2H), 7.12 (t, J=7.5 Hz, 1H),
5.74 (s, 1H), 5.69 (brs, 1H), 5.07 (s, 1H), 2.81 (d, J=14.0 Hz,
1H), 2.75 (d, J=14.0 Hz, 1H), 1.60 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 168.7, 151.5, 140.9, 137.3, 129.0, 128.7 (q,
J=32.0 Hz), 125.6, 124.9, 124.207 (q, J=270.1 Hz), 124.205,
120.5, 74.0, 47.4, 29.8. Anal. Calcd for C19H18F3NO2: C, 65.32;
H, 5.19; N, 4.01. Found: C, 65.16; H, 5.48; N, 4.06. The
enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IC column (hexane/EtOH=97/3), flow rate 0.5 mL/
min, UV detection 254 nm, tR (major)=29.2 min, tR (minor)=
25.5 min.
According to the general procedure, the reaction of 4’-tert-
butyldimethylsiloxyacetophenone (50.1 mg, 0.200 mmol) with
1a (81.9 mg, 0.300 mmol) was performed for 24 hours. The
crude material was purified by column chromatography (silica
gel, hexane/EtOAc=8/1 to 5/1) to give 2h (60.2 mg, 73%,
69% ee) as a white solid: Rf=0.28 (silica gel, hexane/EtOAc=
18
°
5/1); [α]D À 60.0 (c 1.00 in CHCl3); m.p. 139–141 C; IR
(KBr) 3196 (OÀ H), 3134 (NÀ H), 1650 (C=O) cmÀ 1; H NMR
1
(300 MHz, CDCl3) δ 8.61 (brs, 1H), 7.52 (d, J=7.5 Hz, 2H),
7.33–7.26 (m, 4H), 7.11 (tt, J=7.2, 1.2 Hz, 1H), 6.78 (tt, J=
8.4, 2.4 Hz, 1H), 5.80 (s, 1H), 5.06 (s, 1H), 4.51 (brs, 1H), 2.80
(d, J=14.3 Hz, 1H), 2.74 (d, J=14.3 Hz, 1H), 1.61 (s, 3H),
0.97 (s, 9H), 0.17 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 168.4,
154.3, 141.5, 140.0, 137.8, 128.9, 126.2, 124.5, 124.2, 120.1,
119.5, 74.3, 47.6, 29.8, 25.7, 18.2, À 4.4. Anal. Calcd for
C24H33NO3Si: C, 70.03; H, 8.08; N, 3.40. Found: C, 70.41; H,
7.73; N, 3.59. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=97/
3), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
29.8 min, tR (minor)=27.6 min.
Synthesis and characterization of (S)-4-hydroxy-
4-(3-methoxyphenyl)-2-methylene-N-phenylpenta-
namide (2k)
According to the general procedure, the reaction of 3’-meth-
oxyacetophenone (31.3 mg, 0.208 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=7/1 to 4/1) to give 2k (54.7 mg, 84%, 69% ee) as a
22
white solid: Rf=0.20 (silica gel, hexane/EtOAc=3/1); [α]D
°
À 74.7 (c 1.06 in CHCl3); m.p. 114–116 C; IR (KBr) 3273
1
(NÀ H), 3197 (OÀ H), 3135 (NÀ H), 1650 (C=O) cmÀ 1; H NMR
Synthesis and characterization of (S)-
4-(4-chlorophenyl)-4-hydroxy-2-methylene-N-phe-
nylpentanamide (2i)
(300 MHz, CDCl3) δ 8.66 (brs, 1H), 7.50 (d, J=8.1 Hz, 2H),
7.31–7.20 (m, 3H), 7.12–6.98 (m, 3H), 6.74 (dd, J=8.1,
2.6 Hz, 1H), 5.80 (s, 1H), 5.12 (s, 1H), 4.94 (s, 1H), 3.76 (s,
3H), 2.78 (s, 2H), 1.60 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 168.5, 159.4, 149.2, 141.2, 137.7, 129.0, 128.9, 124.5, 124.3,
120.2, 117.5, 111.6, 111.2, 74.3, 55.1, 47.3, 29.8. Anal. Calcd
for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.03; H,
6.77; N, 4.57. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=97/
3), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
88.4 min, tR (minor)=83.5 min.
According to the general procedure, the reaction of 4’-
chloroacetophenone (156 mg, 1.00 mmol) with 1a (410 mg,
1.50 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=6/1 to 4/1) to give 2i (312 mg, 99%, 65% ee) as a
18
white solid: Rf=0.35 (silica gel, hexane/EtOAc=2/1); [α]D
°
À 88.6 (c 1.00 in CHCl3); m.p. 118–120 C; IR (KBr) 3280
1
(OÀ H), 3171 (NÀ H), 3140 (NÀ H), 1649 (C=O) cmÀ 1; H NMR
(300 MHz, CDCl3) δ 8.44 (brs, 1H), 7.48 (dd, J=8.6, 1.1 Hz,
2H), 7.39–7.24 (m, 6H), 7.12 (tt, J=7.3, 1.5 Hz, 1H), 5.75 (s,
1H), 5.29 (s, 1H), 5.07 (s, 1H), 2.80 (d, J=14.1 Hz, 1H), 2.72
(d, J=14.1 Hz, 1H), 1.59 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 168.6, 145.9, 141.1, 137.4, 132.3, 129.0, 128.0, 126.7, 124.8,
124.0, 120.3, 73.9, 47.5, 29.9. Anal. Calcd for C18H18ClNO2: C,
68.46; H, 5.75; N, 4.44. Found: C, 68.44; H, 5.80; N, 4.50. The
enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IC column (hexane/EtOH=97/3), flow rate 0.5 mL/
Synthesis and characterization of (S)-
4-(3-chlorophenyl)-4-hydroxy-2-methylene-N-phe-
nylpentanamide (2l)
According to the general procedure, the reaction of 3’-
chloroacetophenone (31.2 mg, 0.202 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
Adv. Synth. Catal. 2020, 362, 1–23
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EtOAc=7/1 to 4/1) to give 2l (61.1 mg, 96%, 65% ee) as a
white solid: Rf=0.23 (silica gel, CHCl3/EtOAc=15/1); [α]D
66.25; H, 5.56; N, 8.58. Found: C, 66.63; H, 5.61; N, 8.36. The
enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IF column (hexane/EtOH=90/10), flow rate 0.5 mL/
min, UV detection 254 nm, tR (major)=29.0 min, tR (minor)=
43.2 min.
21
°
À 71.0 (c 0.72 in CHCl3); m.p. 107–109 C; IR (KBr) 3274
1
(OÀ H), 3184 (NÀ H), 3136 (NÀ H), 1645 (C=O) cmÀ 1; H NMR
(300 MHz, CDCl3) δ 8.45 (brs, 1H), 7.51–7.46 (m, 3H), 7.33–
7.18 (m, 5H), 7.12 (tt, J=7.5, 1.2 Hz, 1H), 5.77 (s, 1H), 5.38
(brs, 1H), 5.11 (s, 1H), 2.80 (d, J=14.1 Hz, 1H), 2.73 (d, J=
14.1 Hz, 1H), 1.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.7,
149.7, 141.0, 137.4, 134.0, 129.3, 129.0, 126.7, 125.5, 124.8,
124.1, 123.4, 120.4, 73.9, 47.4, 29.7. Anal. Calcd for
C19H18F3NO2: C, 68.46; H, 5.75; N, 4.44. Found: C, 68.26; H,
5.62; N, 4.48. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=95/
5), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
25.1 min, tR (minor)=22.7 min.
Synthesis and characterization of (S)-4-hydroxy-
2-methylene-N-phenyl-4-(o-tolyl)pentanamide (2o)
According to the general procedure, the reaction of 2’-meth-
ylacetophenone (26.8 mg, 0.200 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=6/1 to 4/1) to give 2o (53.5 mg, 90%, 92% ee) as a
18
white solid: Rf=0.39 (silica gel, hexane/EtOAc=2/1); [α]D
°
À 102.1 (c 1.00 in CHCl3); m.p. 88–90 C; IR (KBr) 3276
1
(OÀ H), 3199 (NÀ H), 3136 (NÀ H), 1648 (C=O) cmÀ 1; H NMR
Synthesis and characterization of (S)-4-hydroxy-
2-methylene-N-phenyl-4-(3-(trifluoromethyl)
phenyl)pentanamide (2m)
(300 MHz, CDCl3) δ 8.66 (brs, 1H), 7.54–7.47 (m, 3H), 7.32–
7.26 (m, 2H), 7.15–7.07 (m, 4H), 5.86 (s, 1H), 5.23 (s, 1H),
4.49 (brs, 1H), 3.05 (d, J=14.7 Hz, 1H), 2.78 (d, J=14.7 Hz,
1H), 2.55 (s, 3H), 1.68 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 168.2, 144.7, 142.0, 137.7, 134.8, 132.6, 128.9, 127.1, 126.1,
125.8, 124.5, 123.8, 120.2, 75.4, 45.0, 28.9, 22.6. Anal. Calcd
for C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C, 77.09; H,
7.52; N, 4.76. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=95/
5), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
31.7 min, tR (minor)=25.1 min.
According to the general procedure, the reaction of 3’-
(trifluoromethyl)acetophenone (37.6 mg, 0.200 mmol) with 1a
(81.9 mg, 0.300 mmol) was performed for 24 hours. The crude
material was purified by column chromatography (silica gel,
hexane/EtOAc=8/1 to 4/1) to give 2m (68.6 mg, 98%, 66%
ee) as a white solid: Rf=0.30 (silica gel, hexane/EtOAc=2/1);
19
°
[α]D À 70.0 (c 1.00 in CHCl3); m.p. 77–79 C; IR (KBr) 3281
(OÀ H), 3140 (NÀ H), 1660 (C=O) cmÀ 1; H NMR (300 MHz,
1
CDCl3) δ 8.31 (brs, 1H), 7.73 (s, 1H), 7.64 (d, J=7.2 Hz, 1H),
7.50–7.39 (m, 4H), 7.33–7.28 (m, 2H), 7.13 (tt, J=7.2, 1.2 Hz,
1H), 5.74 (s, 1H), 5.56 (brs, 1H), 5.09 (s, 1H), 2.83 (d, J=
14.1 Hz, 1H), 2.76 (d, J=14.1 Hz, 1H), 1.62 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 168.7, 148.6, 141.0, 137.3, 130.2 (q, J=
31.6 Hz), 129.0, 128.7, 128.5, 124.9, 124.3 (q, J=270.2 Hz),
124.0, 123.4, 122.0, 120.4, 73.9, 47.5, 29.8. Anal. Calcd for
C19H18F3NO2: C, 65.32, H, 5.19; N, 4.01. Found: C, 65.06; H,
5.44; N, 4.08. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=95/
5), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
17.2 min, tR (minor)=15.5 min.
Synthesis and characterization of (S)-
4-(2-ethylphenyl)-4-hydroxy-2-methylene-N-phenyl-
pentanamide (2p)
According to the general procedure, the reaction of 2’-ethyl-
acetophenone (29.4 mg, 0.198 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 h. The crude material was
purified by column chromatography (silica gel, chloroform/
EtOAc=40/1 to 10/1) to give 2p (40.9 mg, 67%, 96% ee) as a
19
white solid: Rf=0.25 (silica gel, hexane/EtOAc=3/1); [α]D
°
À 91.0 (c 1.00 in CHCl3); m.p. 117–119 C; IR (KBr) 3267
1
(OÀ H), 3134 (NÀ H), 1662 (C=O), 1637 (C=O) cmÀ 1; H NMR
(300 MHz, CDCl3) δ 8.67 (brs, 1H), 7.50 (d, J=7.8 Hz, 3H),
7.30 (t, J=8.0 Hz, 2H), 7.23–7.08 (m, 4H), 5.89 (s, 1H), 5.25
(s, 1H), 4.38 (brs, 1H), 3.09–2.79 (m, 4H), 1.69 (s, 3H), 1.27 (t,
J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 168.2, 144.1,
142.0, 141.6, 137.8, 131.0, 129.0, 127.2, 126.0, 125.5, 124.5,
123.9, 120.1, 75.4, 45.9, 29.6, 27.2, 16.9. Anal. Calcd for
C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.79; H,
7.10; N, 4.45. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=95/
5), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
24.4 min, tR (minor)=21.0 min.
Synthesis and characterization of (S)-4-hydroxy-
2-methylene-4-(3-nitrophenyl)-N-phenylpentana-
mide (2n)
According to the general procedure, the reaction of 3’-nitro-
acetophenone (32.9 mg, 0.199 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=6/1 to 3/1) to give 2n (56.0 mg, 86%, 56% ee) as a
19
white solid: Rf=0.24 (silica gel, hexane/EtOAc=2/1); [α]D
°
À 78.6 (c 1.00 in CHCl3); m.p. 109–111 C; IR (KBr) 3283
1
(OÀ H), 3192 (NÀ H), 3138 (NÀ H), 1649 (C=O) cmÀ 1; H NMR
(300 MHz, CDCl3) δ 8.33 (brs, 1H), 8.06 (tt, J=8.1, 1.2 Hz,
2H), 7.85 (dd, J=7.8, 0.9 Hz, 1H), 7.49 (t, J=8.1 Hz, 3H),
7.33 (t, J=7.7 Hz, 2H), 7.15 (m, 1H), 5.85 (s, 1H), 5.74 (s,
1H), 5.15 (s, 1H), 2.89 (d, J=14.1 Hz, 1H), 2.80 (d, J=
14.1 Hz, 1H), 1.66 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.8,
150.0, 148.0, 140.9, 137.1, 131.6, 129.0, 125.0, 123.9, 121.6,
120.4, 120.4, 73.7, 47.5, 29.9. Anal. Calcd for C18H18N2O4: C,
Synthesis and characterization of (S)-4-hydroxy-
4-(2-isopropylphenyl)-2-methylene-N-phenylpenta-
namide (2q)
According to the general procedure, the reaction of 2’-
isopropylacetophenone (32.4 mg, 0.200 mmol) with 1a
(81.9 mg, 0.300 mmol) was performed for 24 h. The crude
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material was purified by column chromatography (silica gel,
chloroform/EtOAc=40/1 to 20/1) to give 2q (43.3 mg, 67%,
120.9, 120.0, 111.1, 74.8, 55.2, 44.3, 27.8. Anal. Calcd for
C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.06; H,
6.44; N, 4.48. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=90/
10), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
24.2 min, tR (minor)=16.8 min.
97% ee) as a white solid: Rf=0.20 (silica gel, hexane/EtOAc=
18
°
3/1); [α]D À 89.5 (c 1.00 in CHCl3); m.p. 151–153 C; IR
(KBr) 3238 (OÀ H), 3135 (NÀ H), 1663 (C=O) cmÀ 1; H NMR
1
(300 MHz, CDCl3) δ 8.64 (brs, 1H), 7.56–7.51 (m, 3H), 7.38–
7.22 (m, 4H), 7.15–7.09 (m, 2H), 5.95 (s, 1H), 5.29 (s, 1H),
4.11 (s, 1H), 3.69 (sept, J=6.9 Hz, 1H), 3.08 (d, J=14.4 Hz,
1H), 2.87 (d, J=14.4 Hz, 1H), 1.70 (s, 3H), 1.29 (d, J=6.9 Hz,
3H), 1.26 (d, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 168.1, 146.7, 143.4, 141.9, 137.8, 128.9, 127.5, 125.6, 125.4,
124.5, 124.3, 120.1, 75.1, 45.7, 29.6, 29.5, 24.9, 24.6. Anal.
Calcd for C21H25NO2: C, 77.98; H, 7.79; N, 4.33. Found: C,
77.58; H, 7.76; N, 4.62. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak IC column
(hexane/EtOH=90/10), flow rate 0.5 mL/min, UV detection
254 nm, tR (major)=12.6 min, tR (minor)=11.6 min.
Synthesis and characterization of (S)-4-(2-((tert-
butyldimethylsilyl)oxy)phenyl)-4-hydroxy-2-meth-
ylene-N-phenylpentanamide (2t)
According to the general procedure, the reaction of 2’-tert-
butyldimethylsiloxyacetophenone (50.3 mg, 0.201 mmol) with
1a (81.9 mg, 0.300 mmol) was performed for 24 hours. The
crude material was purified by column chromatography (silica
gel, chloroform/EtOAc=40/1) to give 2t (60.0 mg, 72%, 72%
ee) as a white solid: Rf=0.33 (silica gel, hexane/EtOAc=5/1);
21
°
[α]D À 21.5 (c 0.59 in CHCl3); m.p. 124–126 C; IR (KBr)
3283 (OÀ H), 3198 (NÀ H), 3138 (NÀ H), 1650 (C=O) cmÀ 1; H
1
Synthesis and characterization of (S)-4-([1,1’-bi-
phenyl]-2-yl)-4-hydroxy-2-methylene-N-phenylpen-
tanamide (2r)
NMR (300 MHz, CDCl3) δ 8.81 (brs, 1H), 7.53–7.45 (m, 3H),
7.34–7.28 (m, 2H), 7.16–7.07 (m, 2H), 6.94 (dt, J=7.5, 1.2 Hz,
1H), 6.84 (dd, J=8.1, 1.2 Hz, 1H), 5.89 (s, 1H), 5.41 (s, 1H),
5.24 (s, 1H), 3.20 (d, J=13.8 Hz, 1H), 2.92 (d, J=13.8 Hz,
1H), 1.67 (s, 3H), 1.04 (s, 9H), 0.37 (s, 3H), 0.36 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 168.0, 152.4, 142.1, 138.1, 135.5,
128.9, 128.1, 127.4, 124.2, 121.2, 120.0, 118.4, 75.2, 44.2, 28.2,
26.1, 18.5, À 3.6, À 3.8. Anal. Calcd for C24H33NO3Si: C, 70.03;
H, 8.08; N, 3.40. Found: C, 70.41; H, 7.80; N, 3.37. The
enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IC column (hexane/EtOH=90/10), flow rate 0.5 mL/
min, UV detection 254 nm, tR (major)=13.1 min, tR (minor)=
10.9 min.
According to the general procedure, the reaction of 2’-phenyl-
acetophenone (39.3 mg, 0.200 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 72 h. The crude material was
purified by column chromatography (silica gel, chloroform/
EtOAc=40/1 to 20/1) to give 2r (27.5 mg, 38%, 93% ee) as a
17
white solid: Rf=0.20 (silica gel, hexane/EtOAc=3/1); [α]D
°
À 97.4 (c 1.00 in CHCl3); m.p. 156–158 C; IR (KBr) 3276
1
(OÀ H), 3199 (NÀ H), 3136 (NÀ H), 1649 (C=O) cmÀ 1; H NMR
(300 MHz, CDCl3) δ 8.68 (brs, 1H), 7.69 (dd, J=8.1, 1.2 Hz,
1H), 7.43–7.22 (m, 11H), 7.12–7.07 (m, 2H), 5.96 (s, 1H), 5.09
(s, 1H), 3.41 (brs, 1H), 2.89 (d, J=14.4 Hz, 1H), 2.78 (d, J=
14.4 Hz, 1H), 1.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.6,
144.3, 143.7, 141.4, 139.8, 138.0, 132.2, 129.8, 128.8, 127.8,
127.4, 127.1, 126.7, 126.3, 125.1, 124.2, 120.0, 76.3, 46.7,
30.6. Anal. Calcd for C24H23NO2: C, 80.64; H, 6.49; N, 3.92.
Found: C, 80.25; H, 6.84; N, 3.85. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak IC column
(hexane/EtOH=95/5), flow rate 0.5 mL/min, UV detection
254 nm, tR (major)=27.3 min, tR (minor)=25.7 min.
Synthesis and characterization of (S)-4-(2-(dimeth-
ylamino)phenyl)-4-hydroxy-2-methylene-N-phenyl-
pentanamide (2u)
According to the general procedure, the reaction of 2’-(dimeth-
ylamino)acetophenone (32.6 mg, 0.200 mmol) with 1a
(81.9 mg, 0.300 mmol) was performed for 24 hours. The crude
material was purified by column chromatography (silica gel,
hexane/EtOAc=3/1 to 1/1) to give 2u (35.1 mg, 54%, 73% ee)
as a colorless oil: Rf=0.10 (silica gel, hexane/EtOAc=3/1);
Synthesis and characterization of (S)-4-hydroxy-
4-(2-methoxyphenyl)-2-methylene-N-phenylpenta-
namide (2s)
22
[α]D À 103.5 (c 0.41 in CHCl3); IR (KBr) 3272 (OÀ H), 3128
1
(NÀ H), 1675 (C=O) cmÀ 1; H NMR (300 MHz, CDCl3) δ 12.52
(brs, 1H), 11.10 (brs, 1H), 7.66 (d, J=7.5 Hz, 2H), 7.36–7.25
(m, 6H), 7.08 (m, 1H), 6.12 (d, J=1.8 Hz, 1H), 4.93 (d, J=
1.8 Hz, 1H), 2.94 (s, 2H), 2.70 (s, 3H), 2.59 (s, 3H), 1.70 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 167.0, 150.9, 141.4, 139.3,
139.1, 128.8, 128.2, 127.9, 126.9, 126.6, 123.5, 123.4, 119.5,
78.9, 48.3, 46.3, 32.6. Anal. Calcd for C20H24N2O2: C, 74.05; H,
7.46; N, 8.63. Found: C, 74.20; H, 7.34; N, 8.73. The
enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IC column (hexane/EtOH=90/10), flow rate 0.5 mL/
min, UV detection 254 nm, tR (major)=25.2 min, tR (minor)=
29.4 min.
According to the general procedure, the reaction of 2’-meth-
oxyacetophenone (29.9 mg, 0.199 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=7/1 to 4/1) to give 2s (56.4 mg, 91%, 70% ee) as a
18
white solid: Rf=0.17 (silica gel, hexane/EtOAc=4/1); [α]D
°
À 42.8 (c 1.00 in CHCl3); m.p. 109–111 C; IR (KBr) 3299
1
(OÀ H), 3138 (NÀ H), 1658 (C=O) cmÀ 1; H NMR (300 MHz,
CDCl3) δ 8.53 (brs, 1H), 7.52–7.47 (m, 3H), 7.33–7.27 (m, 2H),
7.23 (m, 1H), 7.10 (t, J=7.5 Hz, 1H), 6.95 (dt, J=7.5, 1.2 Hz,
1H), 6.89 (d, J=8.3 Hz, 1H), 5.83 (s, 1H), 5.21 (s, 1H), 5.02 (s,
1H), 3.89 (s, 3H), 3.20 (d, J=13.8 Hz, 1H), 2.91 (d, J=
13.8 Hz, 1H), 1.66 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.0,
156.1, 142.2, 138.0, 134.2, 128.8, 128.4, 126.7, 124.2, 123.7,
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1649 (C=O) cmÀ 1; H NMR (300 MHz, CDCl3) δ 8.16 (brs,
1H), 7.90 (dd, J=7.8, 1.8 Hz, 1H), 7.55 (d, J=7.8, 1.2 Hz,
1H), 7.49–7.46 (m, 2H), 7.34–7.23 (m, 3H), 7.12 (tt, J=7.5,
1.3 Hz, 1H), 7.06 (m, 1H), 5.79 (s, 1H), 5.69 (s, 1H), 5.39 (s,
1H), 3.41 (d, J=14.4 Hz, 1H), 2.95 (d, J=14.4 Hz, 1H), 1.80
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.0, 145.4, 141.8,
137.2, 134.7, 129.0, 128.9, 128.5, 127.5, 124.9, 123.2, 120.4,
120.1, 75.1, 42.9, 27.7. Anal. Calcd for C18H18BrNO2: C, 60.01;
H, 5.04; N, 3.89. Found: C, 59.94; H, 5.24; N, 3.86. The
enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IC column (hexane/EtOH=90/10), flow rate 0.5 mL/
min, UV detection 254 nm, tR (major)=16.9 min, tR (minor)=
12.7 min.
1
Synthesis and characterization of (S)-
4-(2-chlorophenyl)-4-hydroxy-2-methylene-N-phe-
nylpentanamide (2v)
According to the general procedure, the reaction of 2’-
chloroacetophenone (31.3 mg, 0.202 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, chloroform/
EtOAc=30/1) to give 2v (62.0 mg, 97%, 78% ee) as a white
22
solid: Rf=0.21 (silica gel, hexane/EtOAc=4/1); [α]D À 123.1
(c 1.27 in CHCl3); IR (KBr) 3288 (OÀ H), 3162 (NÀ H), 1649
(C=O) cmÀ 1; 1H NMR (300 MHz, CDCl3) δ 8.44 (brs, 1H), 7.66
(d, J=8.7, 1.1 Hz, 2H), 7.39–7.24 (m, 6H), 7.12 (tt, J=7.4,
1.2 Hz, 1H), 5.75 (s, 1H), 5.29 (s, 1H), 5.07 (s, 1H), 2.80 (d,
J=14.1 Hz, 1H), 2.72 (d, J=14.1 Hz, 1H), 1.59 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 169.0, 143.9, 141.9, 137.2, 131.0,
130.5, 129.0, 128.7, 128.2, 127.0, 124.9, 123.0, 120.4, 74.7,
43.3, 27.8. Anal. Calcd for C18H18ClNO2: C, 68.46; H, 5.75; N,
4.44. Found: C, 68.74; H, 5.96; N, 4.58. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak IC
column (hexane/EtOH=90/10), flow rate 0.5 mL/min, UV
detection 254 nm, tR (major)=15.3 min, tR (minor)=11.7 min.
Synthesis and characterization of (S)-4-hydroxy-
4-(2-iodophenyl)-2-methylene-N-phenylpentana-
mide (2y)
According to the general procedure, the reaction of 2’-
iodoacetophenone (49.2 mg, 0.201 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, chloroform/
EtOAc=40/1 to 10/1) to give 2y (81.0 mg, 99%, 90% ee) as a
22
white solid: Rf=0.27 (silica gel, hexane/EtOAc=3/1); [α]D
Synthesis and characterization of (S)-
4-(2-fluorophenyl)-4-hydroxy-2-methylene-N-phe-
nylpentanamide (2w)
À 124.7 (c 0.47 in CHCl3); IR (KBr) 3254 (OÀ H), 3232 (NÀ H),
3136 (NÀ H), 1659 (C=O) cmÀ 1; H NMR (300 MHz, CDCl3)
1
δ 8.07 (brs, 1H), 7.95 (dd, J=7.8, 1.4 Hz, 1H), 7.90 (dd, J=
8.1, 1.8 Hz, 1H), 7.51–7.47 (m, 2H), 7.36–7.28 (m, 3H), 7.13
(tt, J=7.4, 1.2 Hz, 1H), 6.86 (dt, J=7.5, 1.8 Hz, 1H), 5.75 (s,
1H), 5.47 (brs, 1H), 5.45 (s, 1H), 3.57 (d, J=14.4 Hz, 1H),
2.93 (d, J=14.4 Hz, 1H), 1.82 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 168.9, 148.2, 142.4, 141.7, 137.3, 129.0, 128.5, 128.3,
128.2, 124.8, 123.6, 120.3, 93.9, 75.1, 42.6, 27.7. Anal. Calcd
for C18H18INO2: C, 53.09; H, 4.46; N, 3.44. Found: C, 52.97; H,
4.45; N, 3.40. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=90/
10), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
17.4 min, tR (minor)=13.4 min.
According to the general procedure, the reaction of 2’-
fluoroacetophenone (27.7 mg, 0.201 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, chloroform/
EtOAc=1/0 to 30/1 to 10/1) to give 2w (59.6 mg, 99%, 63%
ee) as a white solid: Rf=0.30 (silica gel, hexane/EtOAc=3/1);
23
[α]D À 74.8 (c 0.97 in CHCl3); IR (KBr) 3238 (OÀ H), 1649
(C=O) cmÀ 1; 1H NMR (300 MHz, CDCl3) δ 8.04 (brs, 1H), 7.67
(dt, J=8.1, 1.8 Hz, 1H), 7.49–7.46 (m, 2H), 7.34–7.29 (m, 2H),
7.24–7.07 (m, 3H), 6.99 (ddd, J=12.0, 8.1, 1.2 Hz, 1H), 5.68
(s, 1H), 5.65 (s, 1H), 5.27 (s, 1H), 3.08 (d, J=14.1 Hz, 1H),
2.92 (d, J=14.1 Hz, 1H), 1.66 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 168.9, 159.0 (d, J=242.3 Hz), 141.8, 137.3, 133.8 (d,
J=12.9 Hz), 129.0, 128.6 (d, J=8.6 Hz), 128.0 (d, J=4.3 Hz),
124.9, 124.1 (d, J=3.2 Hz), 123.1, 120.4, 115.4 (d, J=
24.1 Hz) 73.4, 45.1, 29.1. Anal. Calcd for C18H18FNO2: C,
72.22, H, 6.06; N, 4.68. Found: C, 72.41; H, 6.22; N, 4.94. The
enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IC column (hexane/EtOH=95/5), flow rate 0.5 mL/
min, UV detection 254 nm, tR (major)=26.6 min, tR (minor)=
20.0 min.
Synthesis and characterization of (S)-4-hydroxy-
2-methylene-4-(2-nitrophenyl)-N-phenylpentana-
mide (2z)
According to the general procedure, the reaction of 2’-nitro-
acetophenone (33.5 mg, 0.203 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=5/1 to 3/1) to give 2z (60.3 mg, 91%, 88% ee) as a
18
white solid: Rf=0.14 (silica gel, hexane/EtOAc=3/1); [α]D
À 65.1 (c 1.00 in CHCl3); IR (KBr) 3303 (OÀ H), 3137 (NÀ H),
Synthesis and characterization of (S)-
4-(2-bromophenyl)-4-hydroxy-2-methylene-N-phe-
nylpentanamide (2x)
1
3088 (NÀ H), 1655 (C=O) cmÀ 1; H NMR (300 MHz, CDCl3)
δ 8.05 (brs, 1H), 7.60 (dd, J=8.1, 1.2 Hz, 1H), 7.53–7.43 (m,
3H), 7.38–7.28 (m, 4H), 7.13 (tt, J=7.5, 1.3 Hz, 1H), 5.89 (s,
1H), 5.40 (s, 1H), 5.13 (brs, 1H), 3.22 (d, J=14.1 Hz, 1H),
2.88 (d, J=14.1 Hz, 1H), 1.65 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 168.2, 149.7, 140.8, 139.5, 137.4, 130.7, 128.9, 128.4,
127.9, 124.7, 124.6, 123.6, 120.3, 74.4, 46.1, 28.7. Anal. Calcd
for C18H18INO2: C, 66.25; H, 5.56; N, 8.56. Found: C, 66.02; H,
5.83; N, 8.42. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=90/
According to the general procedure, the reaction of 2’-
bromoacetophenone (39.6 mg, 0.199 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, chloroform/
EtOAc=40/1 to 10/1) to give 2x (68.1 mg, 95%, 86% ee) as a
white solid: Rf=0.31 (silica gel, hexane/EtOAc=3/1); [α]D
À 144.4 (c 1.00 in CHCl3); IR (KBr) 3262 (OÀ H), 3137 (NÀ H),
18
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10), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
27.4 min, tR (minor)=22.5 min.
(98.8 mg, 0.300 mmol) was performed for 24 hours. The crude
material was purified by column chromatography (silica gel,
hexane/EtOAc=6/1) to give 2ac (63.8 mg, 74%, 95% ee) as a
22
white solid: Rf=0.33 (silica gel, hexane/EtOAc=3/1); [α]D
Synthesis and characterization of (S)-4-hydroxy-
2-methylene-N-phenyl-4-(2-(trifluoromethyl)
phenyl)pentanamide (2aa)
°
À 76.5 (c 1.03 in CHCl3); m.p. 174–176 C; IR (KBr) 3304
1
(OÀ H), 3159 (NÀ H), 1651 (C=O) cmÀ 1; H NMR (300 MHz,
CDCl3) δ 8.36 (brs, 1H), 7.75 (dd, J=8.1, 0.9 Hz, 1H), 7.71 (d,
J=8.1 Hz, 1H), 7.52–7.43 (m, 3H), 7.36–7.31 (m, 3H), 5.92 (s,
1H), 5.30 (s, 1H), 4.77 (brs, 1H), 3.07 (d, J=14.3 Hz, 1H),
2.82 (d, J=14.3 Hz, 1H), 1.73 (s, 3H), 1.31 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 168.0, 147.7, 146.9, 141.4, 135.0, 131.5,
128.9, 127.9 (q, J=7.2 Hz), 127.1 (q, J=30.8 Hz), 127.0,
125.8, 124.3, 120.0, 75.2, 46.6, 34.4, 31.3, 29.9. Anal. Calcd for
C23H26F3NO2: C, 68.13, H, 6.46; N, 3.45. Found: C, 67.84; H,
6.32; N, 3.63. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=95/
5), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
16.7 min, tR (minor)=14.6 min.
According to the general procedure, the reaction of 2’-
(trifluoromethyl)acetophenone (37.2 mg, 0.198 mmol) with 1a
(81.9 mg, 0.300 mmol) was performed for 24 hours. The crude
material was purified by column chromatography (silica gel,
hexane/EtOAc=7/1 to 4/1) to give 2aa (64.6 mg, 97%, 98%
ee) as a white solid: Rf=0.30 (silica gel, hexane/EtOAc=3/1);
17
°
[α]D À 76.1 (c 1.00 in CHCl3); m.p. 125–127 C; IR (KBr)
3274 (OÀ H), 3139 (NÀ H), 1656 (C=O) cmÀ 1; 1H NMR
(300 MHz, CDCl3) δ 8.39 (brs, 1H), 7.76 (d, J=8.1 Hz, 1H),
7.70 (d, J=8.1 Hz, 1H), 7.56–7.49 (m, 3H), 7.37–7.30 (m, 3H),
7.13 (t, J=7.5 Hz, 1H), 5.97 (s, 1H), 5.34 (s, 1H), 4.50 (s, 1H),
3.10 (d, J=14.3 Hz, 1H), 2.84 (d, J=14.3 Hz, 1H), 1.75 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 167.9, 146.9, 141.0, 137.8,
131.5, 128.9, 127.9, 127.05 (q, J=30.5 Hz), 127.02, 125.3,
125.2, 124.5, 123.0, 120.1, 75.3, 46.5, 29.7. Anal. Calcd for
C19H18F3NO2: C, 65.32, H, 5.19; N, 4.01. Found: C, 65.27; H,
5.13; N, 3.97. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=95/
5), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
19.8 min, tR (minor)=17.7 min.
Synthesis and characterization of (S)-4-hydroxy-
2-methylene-N-(naphthalen-1-yl)-
4-(2-(trifluoromethyl)phenyl)pentanamide (2ad)
According to the general procedure, the reaction of 2’-
(trifluoromethyl)acetophenone (37.2 mg, 0.198 mmol) with 1d
(97.0 mg, 0.300 mmol) was performed for 24 hours. The crude
material was purified by column chromatography (silica gel,
hexane/EtOAc=6/1 to 4/1) to give 2ad (70.3 mg, 89%, 97%
ee) as a white solid: Rf=0.22 (silica gel, hexane/EtOAc=3/1);
22
Synthesis and characterization of (S)-4-hydroxy-
2-methylene-N-(p-tolyl)-4-(2-(trifluoromethyl)
phenyl)pentanamide (2ab)
°
[α]D À 59.2 (c 1.03 in CHCl3); m.p. 130–132 C; IR (KBr)
3297 (OÀ H), 3057 (NÀ H), 1661 (C=O) cmÀ 1; 1H NMR
(300 MHz, CDCl3) δ 8.71 (brs, 1H), 7.86–7.83 (m, 3H), 7.76–
7.68 (m, 3H), 7.50–7.40 (m, 4H), 7.33 (t, J=7.7 Hz, 1H), 6.01
(s, 1H), 5.31 (s, 1H), 4.82 (s, 1H), 3.10 (d, J=14.4 Hz, 1H),
2.88 (d, J=14.4 Hz, 1H), 1.72 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 168.9, 146.8, 141.2, 134.0, 132.2, 131.5, 128.9, 128.6,
127.8 (q, J=7.0 Hz), 127.4, 127.1 (q, J=30.2 Hz), 127.0,
126.3, 126.1, 126.0, 125.6, 124.7, 123.0, 121.2, 121.0, 75.4,
46.6, 30.1. Anal. Calcd for C23H20F3NO2: C, 69.16, H, 5.05; N,
3.51. Found: C, 68.84; H, 4.94; N, 3.68. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak IC
column (hexane/EtOH=90/10), flow rate 0.5 mL/min, UV
detection 254 nm, tR (major)=23.0 min, tR (minor)=17.6 min.
According to the general procedure, the reaction of 2’-
(trifluoromethyl)acetophenone (36.8 mg, 0.196 mmol) with 1b
(86.2 mg, 0.300 mmol) was performed for 24 hours. The crude
material was purified by column chromatography (silica gel,
hexane/EtOAc=6/1) to give 2ab (53.6 mg, 76%, 95% ee) as a
22
white solid: Rf=0.23 (silica gel, hexane/EtOAc=3/1); [α]D
°
À 76.8 (c 1.02 in CHCl3); m.p. 134–136 C; IR (KBr) 3344
1
(OÀ H), 3125 (NÀ H), 1651 (C=O) cmÀ 1; H NMR (300 MHz,
CDCl3) δ 8.36 (brs, 1H), 7.73 (dd, J=14.7, 7.8 Hz, 2H), 7.50 (t,
J=7.7 Hz, 1H), 7.41 (t, J=8.4 Hz, 2H), 7.34 (t, J=7.7 Hz,
1H), 7.12 (t, J=8.4 Hz, 2H), 5.92 (s, 1H), 5.30 (s, 1H), 4.80 (s,
1H), 3.07 (d, J=14.4 Hz, 1H), 2.81 (d, J=14.4 Hz, 1H), 2.32
(s, 3H), 1.73 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.9,
146.9, 141.2, 135.1, 134.2, 131.5, 129.4, 128.8, 127.8 (q, J=
7.2 Hz), 127.1 (q, J=30.8 Hz), 127.0, 124.6, 123.0, 120.2,
75.2, 46.6, 29.8, 20.8. Anal. Calcd for C20H20F3NO2: C, 66.11,
H, 5.55; N, 3.85. Found: C, 66.04; H, 5.88; N, 4.03. The
enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IC column (hexane/EtOH=95/5), flow rate 0.5 mL/
min, UV detection 254 nm, tR (major)=22.2 min, tR (minor)=
20.4 min.
Synthesis and characterization of (S)-
2-(2-(trifluoromethyl)phenyl)pent-4-en-2-ol[42]
According to the general procedure, the reaction of 2’-
(trifluoromethyl)acetophenone (37.3 mg, 0.198 mmol) with 2-
allyl-5,5-dimethyl-1,3,2-dioxaborinane (43.2 mg, 0.280 mmol)
was performed for 24 hours. The crude material was purified by
column chromatography (silica gel, hexane/EtOAc=15/1 to
10/1) to give (S)-2-(2-(trifluoromethyl)phenyl)pent-4-en-2-ol
22
(10.3 mg, 23%, 85% ee) as a colorless oil: [α]D À 75.4 (c
1
0.0082 in CHCl3); H NMR (300 MHz, CDCl3) δ 7.76 (d, J=
Synthesis and characterization of (S)-N-(4-(tert-
butyl)phenyl)-4-hydroxy-2-methylene-
4-(2-(trifluoromethyl)phenyl)pentanamide (2ac)
7.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.52–7.47 (m, 1H), 7.34
(t, J=7.8 Hz, 1H), 5.65 (m, 1H), 5.20–5.14 (m, 2H), 2.92 (dd,
J=14.1, 6.3 Hz, 1H), 2.54 (dd, J=14.1, 8.3 Hz, 1H), 2.38 (s,
1H), 1.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 146.7, 133.2,
131.4 (q, J=1.2 Hz), 128.5, 128.0 (q, J=7.3 Hz), 127.3 (q, J=
According to the general procedure, the reaction of 2’-
(trifluoromethyl)acetophenone (40.3 mg, 0.214 mmol) with 1c
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30.8 Hz), 126.8, 124.8 (q, J=271 Hz), 120.1, 74.6, 48.3 (q, J=
1.9 Hz), 30.6 (q, J=1.8 Hz). The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak IG column
(hexane/EtOH=90/10), flow rate 0.5 mL/min, UV detection
254 nm, tR (major)=8.1 min, tR (minor)=9.8 min.
EtOAc=40/1) to give II (44.9 mg, 58%, 13% ee) as a white
solid: Rf=0.20 (silica gel, hexane/EtOAc=3/1); [α]D23 +8.0 (c
°
0.41 in CHCl3); m.p. 165–167 C; IR (KBr) 3285 (OÀ H), 1648
1
(C=O), 1617 (C=O) cmÀ 1; H NMR (300 MHz, CDCl3) δ 8.15
(dt, J=9.3, 2.1 Hz, 2H), 7.67 (dt, J=9.3, 2.1 Hz, 2H), 7.59
(brs, 1H), 7.50–7.46 (m, 4H), 7.38–7.14 (m, 6H), 5.95 (s, 1H),
5.61 (s, 1H), 4.96 (s, 1H), 3.46 (d, J=13.8 Hz, 1H), 3.37 (d,
J=13.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 169.0, 154.2,
146.6, 145.6, 140.7, 136.9, 129.1, 128.3, 127.5, 127.4, 126.23,
126.17, 125.2, 123.2, 120.4, 77.3, 44.8. Anal. Calcd for
C23H20N2O4: C, 71.12, H, 5.19; N, 7.21. Found: C, 70.72; H,
5.35; N, 6.87. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IA column (hexane/EtOH=70/
30), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
17.6 min, tR (minor)=22.7 min.
Synthesis and characterization of (+)-2-((1-methyl-
3-oxo-1,3-dihydroisobenzofuran-1-yl)methyl)-N-
phenylacrylamide (3)
According to the general procedure, the reaction of methyl 2-
acetylbenzoate (35.6 mg, 0.200 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=3/1 to 1/1) to give 3 (57.3 mg, 93%, 94% ee) as a
22
white solid: Rf=0.38 (silica gel, hexane/EtOAc=3/2); [α]D
+
°
16.4 (c 0.77 in CHCl3); m.p. 139–141 C; IR (KBr) 3352
Synthesis and characterization of (S)-2-((3-hydroxy-
1-methyl-2-oxoindolin-3-yl)methyl)-N-phenylacryla-
mide (III)[21]
1
(NÀ H), 1753 (C=O), 1672 (C=O) cmÀ 1; H NMR (300 MHz,
CDCl3) δ 7.81 (d, J=7.5 Hz, 1H), 7.55–7.36 (m, 3H), 7.31–
7.23 (m, 4H), 7.07 (m, 1H), 5.70 (s, 1H), 5.49 (s, 1H), 3.29 (d,
J=14.1 Hz, 1H), 3.05 (d, J=14.1 Hz, 1H), 1.73 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 169.7, 166.7, 151.8, 139.9, 137.5,
134.1, 129.2, 128.7, 126.2, 125.1, 124.3, 123.1, 122.4, 120.1,
86.6, 41.2, 25.9. Anal. Calcd for C19H17NO3: C, 74.25, H, 5.58;
N, 4.56. Found: C, 74.41; H, 5.79; N, 4.83. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak IE
column (hexane/EtOH=85/15), flow rate 0.5 mL/min, UV
detection 254 nm, tR (major)=30.8 min, tR (minor)=28.5 min.
According to the general procedure, the reaction of N-meth-
ylisatin (31.9 mg, 0.198 mmol) with 1a (81.9 mg, 0.300 mmol)
was performed for 24 hours. The crude material was purified by
column chromatography (silica gel, hexane/EtOAc=3/2 to
CHCl3/MeOH=20/1) to give III (23.0 mg, 36%, 38% ee) as a
white solid: Rf=0.23 (silica gel, hexane/EtOAc=2/3); 1H
NMR (300 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.47 (d, J=8.7 Hz,
2H), 7.30–7.18 (m, 4H), 7.02 (m, 1H), 6.93–6.87 (m, 2H), 6.19
(s, 1H), 5.72 (s, 1H), 5.27 (s, 1H), 3.10–3.06 (m, 4H), 2.73 (d,
J=12.9 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 176.8,
166.5, 143.1, 139.3, 138.9, 130.0, 129.0, 128.3, 124.4, 123.3,
122.6, 121.8, 120.3, 108.3, 75.4, 25.8. The enantiomeric excess
was determined by HPLC with a Daicel Chiralpak IC column
(hexane/EtOH=70/30), flow rate 0.5 mL/min, UV detection
254 nm, tR (major)=20.2 min, tR (minor)=17.0 min.
Synthesis and characterization of (+)-4-hydroxy-
4-(4-methoxyphenyl)-2-methylene-
N,4-diphenylbutanamide (I)
According to the general procedure, the reaction of 4-meth-
oxybenzophenone (42.4 mg, 0.200 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=7/1 to 4/1) to give I (13.4 mg, 18%, 9% ee) as a white
solid: Rf=0.20 (silica gel, hexane/EtOAc=3/1); [α]D24 +57.2
Synthesis and characterization of (À )-methyl
2-hydroxy-2-phenyl-4-(phenylcarbamoyl)pent-
4-enoate (IV)[19]
°
(c 0.011 in CHCl3); m.p. 56–58 C; IR (KBr) 3261 (OÀ H), 1654
(C=O) cmÀ 1; 1H NMR (300 MHz, CDCl3) δ 7.77 (brs, 1H),
7.48–7.27 (m, 10H), 7.23–7.09 (m, 2H), 6.83 (m, 2H), 5.62 (s,
1H), 4.94 (s, 1H), 4.59 (s, 1H), 3.76 (s, 3H), 3.41 (d, J=
13.8 Hz, 1H), 3.35 (d, J=13.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 168.9, 158.3, 146.7, 141.6, 138.7, 137.6, 129.0, 127.9,
127.6, 126.8, 126.3, 124.7, 123.0, 120.2, 113.3, 77.7, 55.2, 45.0.
Anal. Calcd for C24H23NO3: C, 77.19, H, 6.21; N, 3.75. Found:
C, 77.51; H, 5.81; N, 3.80. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak IC column
(hexane/EtOH=80/20), flow rate 0.5 mL/min, UV detection
254 nm, tR (major)=17.1 min, tR (minor)=14.6 min.
According to the general procedure, the reaction of methyl
benzoylformate (32.8 mg, 0.200 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=7/1 to 4/1) to give IV (38.1 mg, 59%, 79% ee) as a
18
white solid: Rf=0.47 (silica gel, hexane/EtOAc=2/1); [α]D
À 13.5 (c 0.60 in CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.53 (s,
1H), 7.66–7.53 (m, 4H), 7.40–7.26 (m, 5H), 7.11 (t, J=7.5 Hz,
1H), 5.96 (s, 1H), 5.38 (s, 1H), 5.15 (s, 1H), 3.77 (s, 3H), 3.38
(d, J=14.1 Hz, 1H), 3.08 (d, J=14.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 174.3, 167.5, 140.7, 140.2, 137.8, 128.9,
128.3, 128.1, 125.5, 125.1, 124.4, 120.0, 79.1, 53.3, 42.4. The
enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IA column (hexane/EtOH=90/10), flow rate 0.5 mL/
min, UV detection 254 nm, tR (major)=46.2 min, tR (minor)=
41.5 min.
Synthesis and characterization of (+)-4-hydroxy-
2-methylene-4-(4-nitrophenyl)-
N,4-diphenylbutanamide (II)
According to the general procedure, the reaction of 4-nitro-
benzophenone (45.4 mg, 0.200 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, CHCl3/
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lization (EtOAcÀ hexane) to give Bz-1a (448 mg, 64%) as a
white solid: Rf=0.27 (silica gel, hexane/EtOAc=2/1); m.p.
Synthesis and characterization of (À )-4-cyclopentyl-
4-hydroxy-2-methylene-N-phenylpentanamide (V)
À 1
1
°
123–125 C; IR (KBr) 1700 (C=O), 1662 (C=O) cm ; H NMR
(300 MHz, CDCl3) δ 7.71 (d, J=7.3 Hz, 2H), 7.48–7.27 (m,
6H), 7.18 (d, J=7.7 Hz, 2H), 5.71 (s, 1H), 5.46 (s, 1H), 3.58 (s,
4H), 1.74 (s, 2H), 0.93 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 174.8, 173.4, 143.7, 140.1, 135.4, 132.0, 129.3, 129.1, 128.4,
127.5, 127.4, 122.8, 72.1, 31.6, 21.8. Anal. Calcd for
C22H24BNO4: C, 70.04; H, 6.41; N, 3.71. Found: C, 69.93; H,
6.77; N, 3.76.
According to the general procedure, the reaction of cyclopentyl
methyl ketone (22.4 mg, 0.200 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, hexane/
EtOAc=7/1 to 4/1) to give V (30.5 mg, 56%, 54% ee) as a
22
colorless oil: Rf=0.23 (silica gel, hexane/EtOAc=3/1); [α]D
À 45.5 (c 0.020 in CHCl3); IR (NaCl) 3295 (OÀ H), 1658 (C=O)
cmÀ 1; 1H NMR (300 MHz, CDCl3) δ 9.29 (brs, 1H), 7.56 (d, J=
7.5 Hz, 2H), 7.32–7.27 (m, 2H), 7.08 (t, J=7.5 Hz, 1H), 6.13
(s, 1H), 5.40 (s, 1H), 3.23 (brs, 1H), 2.70 (d, J=14.1 Hz, 1H),
2.39 (d, J=14.1 Hz, 1H), 2.08–1.97 (m, 1H), 1.84—1.22 (m,
8H), 1.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.6, 141.9,
138.5, 128.8, 125.0, 124.1, 120.0, 74.3, 50.7, 43.6, 27.5, 26.8,
25.9, 25.9, 24.2. Anal. Calcd for C17H23NO2: C, 74.69, H, 8.48;
N, 5.12. Found: C, 74.95; H, 8.58; N, 5.22. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak IC
column (hexane/EtOH=98/2), flow rate 0.5 mL/min, UV
detection 254 nm, tR (major)=40.4 min, tR (minor)=47.4 min.
Synthesis and characterization of (5S)-
3-(((4-chlorophenyl)thio)methyl)-5-methyl-
5-(naphthalen-1-yl)dihydrofuran-2(3H)-one (4a)
To a solution of 2f (107 mg, 0.323 mmol) in anhydrous
dichloromethane (5.4 mL) was added p-toluenesulfonic acid
(67.6 mg, 0.355 mmol, 1.1 equiv.) at room temperature. After
stirring the mixture at the same temperature for 14 hours, the
reaction was quenched by addition of saturated aqueous
NaHCO3 (15 mL). The resulting mixture was extracted with
dichloromethane (25 mL). The organic extract was washed with
brine (10 mL), dried over Na2SO4, filtered and concentrated in
vacuo to give a crude material. The resulting material was
roughly purified by column chromatography (silica gel, hexane/
EtOAc=8/1) to give a crude material (76.5 mg), which was
used without further purification: Rf =0.40 (silica gel, hexane/
EtOAc=3/1).
Synthesis and characterization of (+)-4-ethyl-
4-hydroxy-2-methylene-N-phenyldodecanamide
(VI)
According to the general procedure, the reaction of 3-
undecanone (34.1 mg, 0.200 mmol) with 1a (81.9 mg,
0.300 mmol) was performed for 24 hours. The crude material
was purified by column chromatography (silica gel, CHCl3/
EtOAc=20/1 to 15/1) to give VI (16.7 mg, 49%, 4% ee) as a
To a solution of the crude material (76.5 mg) in anhydrous
chloroform
(0.88 mL),
p-chlorothiophenol
(49.8 mg,
23
0.345 mmol, 1.3 equiv.) and triethylamine (16 mg, 0.159 mmol,
0.2 equiv.) were added at room temperature. After stirring the
mixture at the same temperature for 20 hours, the reaction
mixture was diluted with water (10 mL). The resulting mixture
was extracted with dichloromethane (20 mL). The organic
extract was dried over Na2SO4, filtered and concentrated in
vacuo to give a crude material. The crude material was purified
by column chromatography (silica gel, hexane/EtOAc=20/1 to
7/1) to give 4a (109 mg, 88% in 2 steps, diastereomer ratio
39:61) as a colorless oil: Rf=0.38, 0.33 (silica gel, hexane/
EtOAc=5/1); IR (NaCl) 1769 (C=O) cmÀ 1; 1H NMR
(300 MHz, CDCl3) δ 8.05 (d, J=9.2 Hz, 1H, major), 8.04–8.01
(m, 1H, minor), 7.89–7.86 (m, 1H), 7.81–7.78 (d, J=8.1 Hz,
1H), 7.67 (d, J=6.9 Hz, 1H, major), 7.60 (d, J=7.2 Hz, 1H,
minor), 7.57–7.40 (m, 3H), 7.21–7.14 (m, 4H), 3.48 (dd, J=
13.5, 3.6 Hz, 1H major), 3.46–3.41 (m, 1H, minor), 3.29 (dd,
J=12.6, 8.7 Hz, 1H, minor), 3.18–3.02 (m, 2H, minor), 2.76
(dd, J=13.5, 9.6 Hz, 1H, major), 2.70–2.64 (m, 1H, minor),
2.57 (dd, J=12.3, 9.3 Hz, 1H, major), 2.40 (t, J=12.0 Hz, 1H,
minor), 2.03 (s, 3H, minor), 1.89 (s, 3H, major); 13C NMR
(75 MHz, CDCl3) δ 176.1, 175.5, 140.0, 138.2, 134.7, 134.5,
133.4, 133.1, 132.8, 132.6, 131.2, 131.0, 129.6, 129.4, 129.2,
129.14, 129.11, 129.0, 128.82, 128.77, 126.0, 125.9, 125.44,
125.41, 125.0, 124.8, 124.5, 122.2, 122.1, 86.1, 85.9, 41.3,
41.1, 40.5, 40.3, 35.2, 34.6, 29.8, 28.7. Anal. Calcd for
C22H19ClO2S: C, 69.01, H, 5.00; N, 0.00. Found: C, 69.28; H,
5.26; N, 0.00. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=95/
5), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
32.9 min, tR (minor)=27.3 min.
colorless oil: Rf=0.30 (silica gel, CHCl3/EtOAc=10/1); [α]D
+14.7 (c 0.0098 in CHCl3); IR (NaCl) 3282 (OÀ H), 1658
(C=O) cmÀ 1; 1H NMR (300 MHz, CDCl3) δ 9.07 (brs, 1H), 7.56
(d, J=8.7 Hz, 2H), 7.33–7.26 (m, 2H), 7.09 (t, J=7.5 Hz, 1H),
6.13 (s, 1H), 5.42 (s, 1H), 3.04 (brs, 1H), 2.56 (s, 2H), 1.59–
1.47 (m, 4H), 1.28 (s, 12H), 0.94–0.86 (m, 6H); 13C NMR
(75 MHz, CDCl3) δ 167.7, 141.9, 138.1, 128.9, 124.7, 124.2,
120.0, 74.7, 42.1, 38.5, 31.8, 31.5, 30.1, 29.6, 29.3, 23.6, 22.6,
14.1, 8.1. Anal. Calcd for C21H33NO2: C, 76.09, H, 10.03; N,
4.23. Found: C, 76.37; H, 9.63; N, 4.11. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak IG
column (hexane/EtOH=95/5), flow rate 0.5 mL/min, UV
detection 254 nm, tR (major)=27.3 min, tR (minor)=31.2 min.
Synthesis and characterization of N-(2-((5,5-dimeth-
yl-1,3,2-dioxaborinan-2-yl)methyl)acryloyl)-N-phe-
nylbenzamide (Bz-1a)
To a solutin of 1a (507 mg, 1.86 mmol) in anhydrous dichloro-
methane (3.7 mL) were added triethylamine (563 mg,
5.57 mmol, 3.0 equiv.) and benzoyl chloride (523 mg,
°
3.72 mmol, 2.0 equiv.) at 0 C. The solution was warmed to
room temperature and stirred for 3 hours, the reaction was
quenched by addition of saturated aqueous NaHCO3 (15 mL).
The resulting mixture was extracted with dichloromethane
(20 mL). The organic extract was washed with brine (10 mL),
dried over Na2SO4, filtered and concentrated in vacuo to give a
crude material. The crude material was purified by column
chromatography (silica gel, hexane/EtOAc=8/1) and recrystal-
Adv. Synth. Catal. 2020, 362, 1–23
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Major diastereomer of 4a was isolated by further purification
by column chromatography (silica gel, hexane/EtOAc=12/1):
Rf=0.33 (silica gel, hexane/EtOAc=5/1); [α]D23 +21.5 (c 1.12
10), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
23.3 min, tR (minor)=18.0 min.
Major diastereomer of 4b was isolated by further purification
by column chromatography (silica gel, hexane/EtOAc=12/1):
Rf=0.37 (silica gel, hexane/EtOAc=5/1); [α]D21 +62.6 (c 0.56
1
in CHCl3); IR (NaCl) 1769 (C=O) cmÀ 1; H NMR (300 MHz,
CDCl3) δ 8.06 (d, J=9.2 Hz, 1H), 7.90 (m, 1H), 7.81 (d, J=
8.1 Hz, 1H), 7.68 (d, J=7.3 Hz, 1H), 7.56–7.41 (m, 3H), 7.22–
7.18 (s, 4H), 3.50 (dd, J=13.5, 3.6 Hz, 1H), 3.22–3.05 (m,
2H), 2.76 (dd, J=13.5, 9.6 Hz, 1H), 2.59 (dd, J=12.3, 9.6 Hz,
1H), 1.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 175.6, 140.0,
134.6, 133.1, 132.9, 131.3, 129.5, 129.2, 129.1, 128.9, 126.1,
125.5, 125.1, 124.8, 122.2, 86.2, 41.4, 40.4, 35.3, 28.8. Anal.
Calcd for C22H19ClO2S: C, 69.01, H, 5.00; N, 0.00. Found: C,
68.74; H, 5.31; N, 0.00.
1
in CHCl3); IR (NaCl) 1773 (C=O) cmÀ 1; H NMR (300 MHz,
CDCl3) δ 7.76 (t, J=8.3 Hz, 2H), 7.57 (t, J=7.5 Hz, 1H), 7.44
(t, J=7.5 Hz, 1H), 7.30–7.24 (m, 4H), 3.51 (dd, J=13.2,
3.6 Hz, 1H), 3.16–3.05 (m, 1H), 2.99–2.81 (m, 2H), 2.35 (t, J=
12.0 Hz, 1H), 1.74 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 175.1,
142.7, 133.1, 133.0, 132.2, 131.4, 129.3, 128.0, 127.9 (q, J=
6.8 Hz), 127.1, 125.8 (q, J=31.0 Hz), 124.1 (q, J=271.5 Hz),
85.5, 40.9, 40.2, 34.9, 28.7. Anal. Calcd for C19H16ClF3O2S: C,
56.93, H, 4.02; N, 0.00. Found: C, 56.96; H, 4.12; N, 0.00.
Synthesis and characterization of (5S)-
3-(((4-chlorophenyl)thio)methyl)-5-methyl-
5-(2-(trifluoromethyl)phenyl)dihydrofuran-2(3H)-
one (4b)
Synthesis and characterization of (3S,5S)-
3-(((4-chlorophenyl)sulfonyl)methyl)-5-methyl-
5-(naphthalen-1-yl)dihydrofuran-2(3H)-one (5a)
To a solution of 2aa (314 mg, 0.899 mmol) in anhydrous
dichloromethane (15 mL) was added p-toluenesulfonic acid
(188 mg, 0.989 mmol, 1.1 equiv.) at room temperature. After
stirring the mixture at the same temperature for 14 hours, the
reaction was quenched by addition of saturated aqueous
NaHCO3 (15 mL). The resulting mixture was extracted with
dichloromethane (25 mL). The organic extract was washed with
brine (10 mL), dried over Na2SO4, filtered and concentrated in
vacuo to give a crude material. The resulting material was
roughly purified by column chromatography (silica gel, hexane/
EtOAc=8/1) to give a crude material (227 mg), which was
used without further purification: Rf =0.50 (silica gel, hexane/
EtOAc=3/1).
To a solution of the major diastereomer of 4a (52.3 mg,
0.137 mmol) in anhydrous dichloromethane (2.3 mL), m-chlor-
operbenzoic acid (35% water suspension, 109 mg, 0.411 mmol,
°
3.0 equiv.) was added at 0 C. The solution was warmed to
room temperature and stirred for 15 hours. The reaction was
quenched by addition of saturated aqueous Na2S2O3 (15 mL),
and the resulting mixture was extracted with dichloromethane
(30 mL). The organic extract was washed with brine (20 mL),
dried over Na2SO4, filtered and concentrated in vacuo to give a
crude material. The crude material was purified by recrystalliza-
tion (EtOAc-hexane) to give 5a (45.8 mg, 81%, 99% ee) as a
22
white solid: Rf=0.30 (silica gel, hexane/EtOAc=3/1); [α]D
°
À 81.6 (c 1.27 in CHCl3); m.p. 164–166 C; IR (KBr) 1766
1
(C=O), 1310 (S=O), 1151 (S=O) cmÀ 1; H NMR (300 MHz,
To a solution of the crude material (227 mg) in anhydrous
chloroform (2.6 mL), p-chlorothiophenol (149 mg, 1.03 mmol,
1.3 equiv.) and triethylamine (16 mg, 0.159 mmol, 0.2 equiv.)
were added at room temperature. After stirring the mixture at
the same temperature for 20 hours, the reaction mixture was
diluted with water (10 mL). The resulting mixture was extracted
with dichloromethane (20 mL). The organic extract was dried
over Na2SO4, filtered and concentrated in vacuo to give a crude
material. The crude material was purified by column chroma-
tography (silica gel, hexane/EtOAc=20/1 to 7/1) to give 4b
(317 mg, 88% in 2 steps, diastereomer ratio 39:61) as a
colorless oil: Rf=0.39, 0.37 (silica gel, hexane/EtOAc=5/1);
IR (NaCl) 1773 (C=O) cmÀ 1; 1H NMR (300 MHz, CDCl3)
δ 7.76 (t, J=8.3 Hz, 2H, major), 7.74–7.67 (m, 2H, minor),
7.57 (t, J=7.5 Hz, 1H, major), 7.57–7.52 (m, 1H, minor), 7.44
(t, J=7.5 Hz, 1H, major), 7.30–7.22 (m, 4H), 3.51 (dd, J=
13.2, 3.6 Hz, 1H, major), 3.49–3.44 (m, 1H, minor), 3.16–2.82
(m, 3H), 2.67 (m, 1H, minor), 2.37–2.28 (m, 1H, minor), 2.35
(t, J=12.0 Hz, 1H, major), 1.85 (s, 3H, minor), 1.74 (s, 3H,
major); 13C NMR (75 MHz, CDCl3) δ 175.7, 175.0, 142.7,
141.5, 133.18, 133.15, 132.8, 132.1, 131.29, 131.26, 129.2,
129.1, 128.5 (q, J=6.5 Hz), 128.2, 128.0, 127.9 (q, J=6.5 Hz),
127.1, 126.7, 126.3 (q, J=30.8 Hz), 125.8 (q, J=31.0 Hz),
124.2 (q, J=271.3 Hz), 124.1 (q, J=271.9 Hz), 85.6, 85.4,
41.8, 40.9, 40.2, 40.1, 34.8, 34.7, 30.2, 28.6. Anal. Calcd for
C19H16ClF3O2S: C, 56.93, H, 4.02; N, 0.00. Found: C, 57.25; H,
3.88; N, 0.00. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IG column (hexane/EtOH=90/
CDCl3) δ 8.10 (d, J=7.8 Hz, 1H), 7.91–7.81 (m, 4H), 7.66 (dd,
J=7.2, 0.9 Hz, 1H), 7.58–7.41 (m, 5H), 3.73 (dd, J=13.8,
2.1 Hz, 1H), 3.58 (m, 1H), 3.43 (dd, J=12.9, 9.0 Hz, 1H), 3.00
(dd, J=13.8, 11.1 Hz, 1H), 2.63 (dd, J=12.8, 11.1 Hz, 1H),
1.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.3, 141.1, 139.5,
137.3, 134.6, 129.9, 129.44, 129.36, 129.3, 128.9, 126.4, 125.6,
125.0, 124.9, 122.2, 87.3, 57.1, 42.1, 35.1, 28.2. Anal. Calcd for
C22H19ClO4S: C, 63.69; H, 4.62; N, 0.00. Found: C, 63.79; H,
4.64; N, 0.00. The enantiomeric excess was determined by
HPLC with a Daicel Chiralpak IC column (hexane/EtOH=60/
40), flow rate 0.5 mL/min, UV detection 254 nm, tR (major)=
22.4 min, tR (minor)=25.6 min.
Synthesis and characterization of (3S,5S)-
3-(((4-chlorophenyl)sulfonyl)methyl)-5-methyl-
5-(2-(trifluoromethyl)phenyl)dihydrofuran-2(3H)-
one (5b)
To a solution of the major diastereomer of 4b (87.2 mg,
0.218 mmol) in anhydrous dichloromethane (3.6 mL), m-chlor-
operbenzoic acid (35% water suspension, 174 mg, 0.654 mmol,
°
3.0 equiv.) was added at 0 C. The solution was warmed to
room temperature and stirred for 15 hours. The reaction was
quenched by addition of saturated aqueous Na2S2O3 (15 mL),
and the resulting mixture was extracted with dichloromethane
(30 mL). The organic extract was washed with brine (20 mL),
dried over Na2SO4, filtered and concentrated in vacuo to give a
Adv. Synth. Catal. 2020, 362, 1–23
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crude material. The crude material was purified by recrystalliza-
[16] Y. Murata, M. Takahashi, F. Yagishita, M. Sakamoto, T.
Sengoku, H. Yoda, Org. Lett. 2013, 15, 6182–6185.
[17] T. Sengoku, A. Shirai, A. Takano, T. Inuzuka, M.
Sakamoto, M. Takahashi, H. Yoda, J. Org. Chem. 2019,
84, 12532–12541.
tion (EtOAc-hexane) to give 5b (69.5 mg, 74%, 99% ee) as a
22
white solid: Rf=0.32 (silica gel, hexane/EtOAc=3/1); [α]D
°
À 27.4 (c 1.06 in CHCl3); m.p. 123–125 C; IR (KBr) 1774
1
(C=O), 1309 (S=O), 1119 (S=O) cmÀ 1; H NMR (300 MHz,
CDCl3) δ 7.87 (d, J=8.4 Hz, 2H), 7.77–7.69 (m, 2H), 7.60–
7.55 (m, 3H), 7.45 (t, J=7.5 Hz, 1H), 3.76 (dd, J=14.1,
2.1 Hz, 1H), 3.53–3.41 (m, 1H), 3.18 (m, 1H), 3.07 (m, 1H),
2.40 (t, J=12.3 Hz, 1H), 1.81 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 173.9, 142.2, 141.1, 137.3, 132.2, 129.9, 129.4, 128.2,
128.0 (q, J=6.8 Hz), 127.1, 126.0 (q, J=31.0 Hz), 122.2, 86.1,
57.0, 41.8, 35.1, 28.4. Anal. Calcd for C19H16ClF3O4S: C, 52.72;
H, 3.73; N, 0.00. Found: C, 52.42; H, 4.02; N, 0.00. The
enantiomeric excess was determined by HPLC with a Daicel
Chiralpak IC column (hexane/EtOH=60/40), flow rate 0.5 mL/
min, UV detection 254 nm, tR (major)=18.0 min, tR (minor)=
21.1 min.
[18] M. Takahashi, Y. Murata, F. Yagishita, M. Sakamoto, T.
Sengoku, H. Yoda, Chem. Eur. J. 2014, 20, 11091–
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We thank Professor Mitsuru Kondo (Shizuoka University) for
assistance with X-ray analysis. We also thank Mr. Wataru Anze
(Shizuoka University) for partial support of this research. This
work was supported in part by JSPS Kakenhi Grant number
17 K05858 from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
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Adv. Synth. Catal. 2020, 362, 1–23
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[32] M. Okada, K. Kaneko, M. Yamanaka, S. Shirakawa, Org. [37] Crystal data for 5b: monoclinic, space group P21, a=
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4519 reflections and 254 parameters (CCDC deposition
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Zinc Hydroxide-Catalyzed Asymmetric Allylation of Aceto-
phenones with Amido-Functionalized Allylboronate in Water
Adv. Synth. Catal. 2020, 362, 1–23
T. Sengoku, R. Maegawa, H. Imamura, M. Wada, H. Yoda*