Stereoselective Synthesis of Polysubstituted Tetrahydropyranones via Acid-Promoted Cyclization of β-Silyl-γ-ethylidene-γ-butyrolactones with Aldehydes and Ketones

Article abstract of DOI:10.1021/acs.joc.1c01284

β-Silyl-γ-ethylidene-γ-butyrolactone upon one-pot treatment with aldehydes and ketones in the presence of Lewis acids underwent a tandem Hosomi-Sakurai/Prins cyclization to give polysubstituted tetrahydropyranones stereoselectively. Various aldehydes and ketones can be used in this reaction to produce the corresponding tetrahydropyranones. The optical purity of the starting γ-butyrolactone was substantially retained in the resulting tetrahydropyranones.

Full text of DOI:10.1021/acs.joc.1c01284

pubs.acs.org/joc
Article
Stereoselective Synthesis of Polysubstituted Tetrahydropyranones
via Acid-Promoted Cyclization of β‑Silyl-γ-ethylidene-γ-
butyrolactones with Aldehydes and Ketones
Shoma Ariyoshi, Kazuhiko Sakaguchi,* and Takahiro Nishimura
Cite This: https://doi.org/10.1021/acs.joc.1c01284
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: β-Silyl-γ-ethylidene-γ-butyrolactone upon one-pot treatment with aldehydes and ketones in the presence of Lewis
acids underwent a tandem Hosomi−Sakurai/Prins cyclization to give polysubstituted tetrahydropyranones stereoselectively. Various
aldehydes and ketones can be used in this reaction to produce the corresponding tetrahydropyranones. The optical purity of the
starting γ-butyrolactone was substantially retained in the resulting tetrahydropyranones.
Scheme 1. Construction of Substituted Tetrahydropyran
Systems by Prins Cyclization
INTRODUCTION
■
Since substituted tetrahydropyranones are important compo-
nents often found in biologically active natural/non-natural
compounds, developing methods for synthesizing tetrahydro-
pyranones is one of the important tasks in organic synthesis.1−5
Although many methods for constructing substituted tetrahy-
dropyran systems have been reported, developing stereo-
selective construction methods for polysubstituted tetrahy-
dropyranones remains a challenging task.1−5 Prins cyclization
is a useful method for fabricating tetrahydropyran systems.5
Chan and Loh synthesized 2,4,6-trisubstituted tetrahydropyr-
ans from an allylsilane and two molecules of aldehydes through
the Prins cyclization (Scheme 1).5b β-Silyl-γ-ethylidene-γ-
butyrolactone 1 has a structure containing both an allylsilane
and a vinyl ester. It is considered useful as an α,α′-dianion
equivalent of γ-keto carboxylic acid. In this study, we report an
efficient stereoselective one-pot synthesis of polysubstituted
tetrahydropyranones by a three-component coupling of 1,
aldehydes, and ketones.
3a accompanied by its diastereomer 3a′ in 34% yield with high
stereoselectivity (dr = 21:1, Table 1, entry 1). The yield of 3a
increased slightly at 0 °C (entry 2) and improved to 85% at
RESULTS AND DISCUSSION
■
The reaction substrate β-silyl-γ-ethylidene-γ-butyrolactone 1
was synthesized from allenylsilane 26 in two steps via gold-
catalyzed cyclization (Scheme 2).7 As the silyl group of 1, we
selected a dimethylphenylsilyl group, which is often used in the
Hosomi−Sakurai reaction.8 Treatment of 1 with benzaldehyde
(3 equiv) in the presence of BF3·OEt2 (2.5 equiv) in CH2Cl2 at
−78 °C for 13 h produced tetrasubstituted tetrahydropyranone
Received: June 2, 2021
https://doi.org/10.1021/acs.joc.1c01284
J. Org. Chem. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 2. Preparation of β-Silyl-γ-alkylidene-γ-
butyrolactone 1
Table 2. Scope of Acid-Promoted Cyclization of 1 with
Aldehydes
a
Table 1. Optimization of the Reaction Conditions for Acid-
a
Promoted Cyclization of 1 with Aldehydes
b
entry
Lewis acid
x (equiv)
yield of 3a + 3a′ (%)
3a:3a′
c
1
BF3·OEt2
2.5
2.5
2.5
0.2
0.2
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
34
42
21:1
20:1
20:1
13:1
21:1
16:1
3:1
3:1
6:1
>25:1
4:1
2.3:1
2.4:1
d
2
e
3
4
5
85
25
35
f
e
6
7
8
9
10
11
12
13
14
TMSOTf
FeCl3
InCl3
Sc(OTf)3
Cu(OTf)2
Zn(OTf)2
TiCl4
80
71
e
73
58
16
15
11
78
0
TfOH
CF3COOH
a
Reaction conditions: 1 (0.1 mmol), PhCHO (3 equiv), Lewis acid,
b
CH2Cl2 (0.1 M), −78 °C, 1.5 h, followed by 0 °C, 1.5 h. Yields were
determined by 1H NMR using triphenylmethane as an internal
c
d
standard. The reaction was performed at −78 °C, 13 h. The
reaction was performed at 0 °C, 1.5 h. Isolated yield. The reaction
was performed at −78 °C, 4 h, followed by 0 °C, 4 h.
e
f
−78 °C for 1.5 h and at 0 °C for 1.5 h (entry 3). The reaction
also proceeded with a catalytic amount of Lewis acid to give 3a
in 25% yield (entry 4), but no significant improvement in yield
was observed when the reaction time was extended (entry 5).
Trimethylsilyl trifluoromethanesulfonate (TMSOTf) as a
Lewis acid also promoted the reaction to give 3a with good
yield and high diastereoselectivity (80%, dr = 16:1, entry 6).
When FeCl3, InCl3, and Sc(OTf)3 were used as Lewis acids,
the diastereoselectivity decreased (entries 7−9). The use of
Cu(OTf)2 reduced the yield (entry 10), and both the yield and
diastereoselectivity decreased using Zn(OTf)2 and TiCl4
(entries 11 and 12). The reaction using trifluoromethanesul-
fonic acid (TfOH) as a Brønsted acid gave 3a in 78% yield;
however, the diastereoselectivity was low (entry 13). Trifluoro-
acetic acid did not promote the reaction (entry 14). The
a
Reaction conditions: 1 (0.1−0.2 mmol), aldehyde (3 equiv), BF3·
OEt2 (2.5 equiv), CH2Cl2 (0.1 M), −78 °C, 1.5 h followed by 0 °C,
1.5 h. Isolation yield of the corresponding methyl ester converted by
reaction with trimethylsilyldiazomethane.
b
3j). Among them, diastereoselectivity slightly decreased when
para-Me- or NO2-substituted benzaldehydes were employed
(3e, 3f). The use of 2-naphthaldehyde gave the corresponding
tetrahydropyranone in 70% yield (dr = 12:1, 3j). For aliphatic
aldehydes with linear alkyl groups, the corresponding
cyclization products were obtained in good yields with high
diastereoselectivity (3k, 3l). Aldehydes with branched alkyl
groups decreased the diastereoselectivity (3m). The reaction
with cyclopropanecarboxaldehyde gave the corresponding
tetrahydropyranone (33%, 3n) with a mixture of unknown
byproducts. However, for sterically bulky pivalaldehyde and
2,4,6-trimethylbenzaldehyde, and for aromatic heterocycle-
containing pyrrole-2-carboxaldehyde, the cyclization reaction
did not occur, and γ-keto carboxylic acid 4,10 which was
produced via hydrolysis of 1, was obtained (3o, 3p, and 3q).
1
relative configurations of 3a and 3a′ were determined by H
NMR spectral analysis.9 The minor isomer 3a′ was a
diastereomer at the C2, C3, and C6 positions of the major
isomer 3a (vide infra).
With the optimized reaction conditions in hand, the scope of
aldehydes was explored (Table 2). A variety of electron-
enriched and electron-deficient aromatic aldehydes with para-,
meta-, or ortho-substituents can undergo this reaction to deliver
the corresponding tetrasubstituted tetrahydropyranones in
moderate to good yields with high diastereoselectivity (3b−
B
https://doi.org/10.1021/acs.joc.1c01284
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
We then attempted the sequential introduction of two
different aldehydes into the cyclization reaction. Treatment of
1 with BF3·OEt2 and 1 equiv of benzaldehyde at −78 °C for
1.5 h followed by the reaction with 3-phenylpropanal at 0 °C
for 1.5 h in a one-pot afforded tetrahydropyranone 5 with four
different substituents in 60% yield (dr = 8:1, Scheme 3). By
changing the order of introduction of these aldehydes,
tetrahydropyranone 6, where the substituents at the C2- and
C6-positions were exchanged, could be synthesized.
after the reaction of 1 with 1 equiv of aldehydes to produce the
corresponding tetrahydropyranones. In the case of using
acetophenone, the corresponding 7d was not formed.12 This
suggests that the cyclization was difficult with sterically bulky
ketones, such as acetophenone.
We demonstrated that ketoaldehydes were successfully
involved in this acid-promoted cyclization (Table 4). The
Table 4. Acid-Promoted Cyclization of 1 with
a
Ketoaldehydes
Scheme 3. Acid-Promoted Cyclization of 1 with Two
Different Aldehydes
We attempted the acid-promoted reaction of 1 using
cyclohexanone instead of aldehydes. However, the desired
cyclization did not occur, and γ-keto carboxylic acid 4 (83−
84%) was obtained.11 However, it was found that the
cyclization involving 1, aldehyde, and ketone occurred when
the reaction was conducted in the presence of both aldehyde
and ketone (Table 3). The acidic treatment of 1 with
a
Reaction conditions: 1 (0.1−0.2 mmol), ketoaldehyde (1.4 equiv),
BF3·OEt2 (2.5 equiv), CH2Cl2 (0.1 M), −78 °C, 1.5 h, followed by 0
b
Table 3. Acid-Promoted Cyclization of 1 with Aldehydes
°C, 2 h. Isolation yield of the corresponding methyl ester converted
a
and Ketones
by reaction with trimethylsilyldiazomethane.
treatment of 1 with γ-ketoaldehyde 9 (1.4 equiv) in the
presence of BF3·OEt2 (2.5 equiv) smoothly underwent
cyclization to give the 8-oxabicyclo[3,2,1]octane derivative
8a in 71% yield as a single diastereomer (entry 1).9 A similar
conversion using δ-ketoaldehyde 10 was rather messy, but the
corresponding fused ring product could be obtained as an ester
derivative (8b, entry 2). Notably, even when a sterically bulky
phenyl ketone-containing aldehyde 11 was employed, the
corresponding fused ring product 8c was produced in excellent
yield (92%, entry 3).
When the acid-promoted cyclization was conducted using
enantiopure 1 (>99% ee)13 and benzaldehyde, the optical
purity of the obtained 3r and 3r′ (methyl esters of 3a and 3a′,
respectively) was 97% ee and 76% ee, respectively (Scheme
4).14 The major product 3r substantially retained the optical
a
Reaction conditions: 1 (0.1−0.2 mmol), PhCHO (1 equiv), ketone
(1.3−4 equiv), BF3·OEt2 (2.5 equiv), CH2Cl2 (0.1 M), −78 °C, 2 h,
b
followed by 0 °C, 2−20 h (one-pot). Cyclohexanone (1.3 equiv) was
c
used, and the reaction time at 0 °C was 2 h. Cycloheptanone (1.5
d
equiv) was used, and the reaction time at 0 °C was 20 h. Acetone
Scheme 4. Acid-Promoted Cyclization of Optically Active 1
with Aldehyde
(4.0 equiv) was used, and the reaction time at 0 °C was 2.5 h.
benzaldehyde (1 equiv) and cyclohexanone (1.3 equiv) in the
presence of BF3·OEt2 (2.5 equiv) gave pentasubstituted
tetrahydropyranone 7a stereoselectively (43%, dr = 8:1).9
Besides, cycloheptanone and acetone were used as ketone
components to give the corresponding cyclization products 7b
and 7c. These results suggested that ketones did not react with
γ-butyrolactone 1, and the introduction of ketones occurred
C
https://doi.org/10.1021/acs.joc.1c01284
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
purity of the starting compound 1. The absolute configuration
of enantiopure 1 was confirmed to be S by conversion to the
known γ-butyrolactone 1315 (Scheme 5). The low optical
Scheme 7. Stepwise Synthesis of Tetrahydropyranones from
1
a
Scheme 5. Determination of the Absolute Configuration of
1
purity of the obtained 12 (11% ee) and 13 (31% ee) suggested
that the exo/endo isomerization of the olefin moiety of 1
occurred under hydrogenation conditions.16 The absolute
configuration of the obtained 3r and 3r′ was determined
(Scheme 6). The 7:1 mixture of 3r (97% ee) and 3r′ (76% ee)
Scheme 6. Determination of the Absolute Configuration of
3r and 3r′
a
Conditions: PhCHO (1.3 equiv), BF3·OEt2 (1.3 equiv), CH2Cl2, 0
°C, 1.5 h.
occurred in a stepwise manner through the intermediates 16,
17, and/or 18.
A plausible reaction pathway of the acid-promoted
cyclization reaction of 1 with aldehydes is shown in Scheme
8. First, a nucleophilic attack of an allylsilane of 1 on the first
Scheme 8. Plausible Reaction Pathway of Acid-Promoted
Cyclization of 1 with Aldehydes
was subjected to isomerization with 1,5-diazabicyclo[4.3.0]-
non-5-ene (DBN) to give the enantiomer of 3r′ whose four
substituents were in the equatorial conformation (87%, 80%
ee). The resulting ent-3r′ was reduced with NaBH4 to give the
secondary alcohols 149 (67%, 77% ee) and 15 (30%, 78% ee).
The obtained 14 was converted to its (S)- and (R)-α-methoxy-
α-(trifluoromethyl)phenylacetic acid (MTPA) esters, respec-
tively. The absolute configuration of 14, which reflects that of
ent-3r′, was determined by the modified Mosher method
(Supporting Information).17
To investigate the reaction pathway of this acid-promoted
cyclization reaction, the stepwise conversion of 1 and
aldehydes to tetrahydropyranones was examined. γ-Butyrolac-
tone 1 was allowed to react with 1 equiv of benzaldehyde in
the presence of BF3·OEt2 at −78 °C to give the Hosomi−
Sakurai reaction products, alcohol 16 (53%), its diastereomer
17 (8%), and silyl ether 18 (29%, Scheme 7). The reaction of
the obtained 16 with 1.3 equiv of benzaldehyde at 0 °C gave
3a (77%) as a single diastereomer. Under the same reaction
conditions, a mixture of 16 and 17 (dr = 1:5) gave a mixture of
3a and 3a′ (69%, dr = 1:5), and 18 gave 3a (74%). The results
of these stereospecific conversions suggested that the
conversion from 1 with aldehydes to tetrahydropyranones 3
aldehyde activated by Lewis acid produced the intermediate B
(Hosomi−Sakurai reaction). Next, in the oxonium intermedi-
ate C obtained by reacting B with the second aldehyde
molecule, the nucleophilic attack of an intramolecular alkene
occurs through a chair-like transition state, producing cyclic
intermediate D stereoselectively (Prins cyclization). Finally,
D
https://doi.org/10.1021/acs.joc.1c01284
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
of 1 was determined by nuclear Overhauser effect spectroscopy
ring-opening of the resulting D followed by hydrolysis
produces the substituted tetrahydropyranone 3. The minor
isomer 3′ is produced via the isomeric intermediate B′.
(NOESY).
1
Compound (1′). Rf: 0.5 (n-hexane/AcOEt = 5/1); H NMR (400
MHz, CDCl3): δ 7.51−7.48 (m, 2H), 7.41−7.37 (m, 3H), 3.13 (t, J =
1.6 Hz, 2H), 2.22 (qt, J = 7.6, 1.6 Hz, 2H), 1.05 (t, J = 7.6 Hz, 3H),
0.43 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 178.2, 163.6,
137.0, 133.5, 129.6, 128.1, 105.1, 37.7, 22.5, 11.8, −2.1; HRMS
(DART+) m/z: calcd for C14H19O2Si (M + H)+, 247.1154; found,
247.1167.
EXPERIMENTAL SECTION
■
General Information. All reagents and solvents were purchased
from Aldrich Chemical Company, Inc., Nacalai Tesque Co., Ltd.,
Tokyo Kasei Kogyo Co., Ltd., Kanto Chemical Co., Ltd., and Wako
Pure Chemical Industries, Ltd. and were used without further
purification unless otherwise indicated. A Sartorius CPA224S was
General Procedure for the Synthesis of Tetrahydropyr-
anones (Carboxylic Acids) Using Aldehydes (General Proce-
dure A). To a solution of 1 (1 equiv) in anhydrous CH2Cl2 (0.1 M)
was added aldehyde (3 equiv). The reaction mixture was stirred at
−78 °C under a nitrogen atmosphere. BF3·OEt2 (2.5 equiv, 1.2 M
CH2Cl2 solution) was added slowly to the reaction mixture. The
reaction mixture was stirred at −78 °C for 1.5 h and then stirred at 0
°C for 1.5 h. The reaction was quenched with brine at 0 °C. The
reaction mixture was extracted with CH2Cl2 (×3). The combined
organic layers were dried over MgSO4 and filtered. The filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography or preparative TLC on silica gel to give
tetrahydropyranones (carboxylic acids) 3 and 3′.
1
used as a balance. H NMR spectra were recorded on a JEOL JNM-
ECZ400S (400 MHz), a Bruker Biospin AVANCE III HD 400 (400
MHz), or a Bruker Biospin AVANCE III HD 600 (600 MHz).
Chemical shifts of 1H NMR spectra were reported in parts per million
(ppm, δ) relative to CHCl3 (δ = 7.26) in CDCl3 or (CH3)2O (δ =
2.04) in (CD3)2O. 13C NMR spectra were recorded on a JEOL JNM-
ECZ400S (100 MHz), a Bruker Biospin AVANCE III HD 400 (100
MHz), or a Bruker Biospin AVANCE III HD 600 (600 MHz).
Chemical shifts of 13C NMR spectra were reported in ppm (δ)
relative to CDCl3 (δ = 77.0) or (CD3)2O (δ = 29.8). The following
abbreviations were used; s, singlet: d, doublet: t, triplet: q, quartet:
quint, quintet: sext, sextet: sept, septet: m, multiplet: br s, broad
singlet. High-resolution mass spectra were obtained on a JEOL
AccuTOF LC-Plus 4G JMS-T100LP spectrometer for electron spray
ionization (ESI) or for direct analysis in real time (DART). All
reactions were monitored by thin-layer chromatography (TLC),
which was performed with precoated plates (silica gel 60 F-254, 0.25
mm layer thickness, manufactured by Merck). TLC visualization was
accomplished using a UV lamp (254 nm) or a charring solution
(KMnO4 aq). Either Wakogel 60N (particle size, 38−100 μm) or
Daisogel IR-60 1002W (particle size, 40−63 μm) was used for flash
column chromatography on silica gel. Wakogel B-5F (particle size
pass, 45 μm) was used for preparative TLC. Compounds 2,6 9,18 10,19
and 1120 were prepared according to the literature procedure.
Compound (1). To a solution of allenylsilane 2 (1.31 g, 5.03
mmol) in 3:1 MeOH/H2O (25 mL) was added lithium hydroxide
(1.06 g, 25.3 mmol), and the solution was stirred at room temperature
for 18 h. The reaction was quenched with aq 2 N HCl. The reaction
mixture was extracted with Et2O (×3). The organic layer was dried
with MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (n-
hexane/AcOEt = 5/1) to afford 3-(dimethyl(phenyl)silyl)hexa-3,4-
dienoic acid (1.07 g, 86%) as a pale yellow oil. Rf: 0.2 (n-hexane/
AcOEt = 5/1); 1H NMR (400 MHz, CDCl3): δ 7.54−7.52 (m, 2H),
7.36−7.33 (m, 3H), 4.96 (qt, J = 6.9, 2.1 Hz, 1H), 4.1−2.8 (br s, 1H),
2.95 (t, J = 2.1 Hz, 2H), 1.64 (d, J = 6.9 Hz, 3H), 0.39 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3): δ 209.6, 178.3, 137.2, 133.7,
129.1, 127.7, 88.0, 81.5, 35.9, 13.1, −2.9, −3.0; HRMS (ESI+) m/z:
calcd for C14H18NaO2Si (M + Na)+, 269.0974; found, 269.0974. To a
solution of 3-(dimethyl(phenyl)silyl)hexa-3,4-dienoic acid (2.58 g,
10.5 mmol) in anhydrous CH2Cl2 (53 mL) was added
[(Ph3PAu)3O]BF4 (151.9 mg, 0.103 mmol). The reaction mixture
was stirred at room temperature for 3 h under a nitrogen atmosphere.
The reaction mixture was filtered through silica gel. The filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (n-hexane/AcOEt = 30/1) to
give 1 (1.91 g, 74%) as a colorless oil and its endo isomer 1′ (244.3
mg, 9%) as a colorless oil.
General Procedure for the Synthesis of Tetrahydropyr-
anones (Methyl Esters) Using Aldehydes (General Procedure
B). After performing general procedure A, to a solution of the
resulting carboxylic acids in anhydrous toluene/methanol (4/1, 0.03
M) was added trimethylsilyldiazomethane (3.2 equiv, 2.0 M diethyl
ether solution). The reaction mixture was stirred at room temperature
for 1.5 h under a nitrogen atmosphere. The reaction was quenched
with acetic acid at room temperature. The reaction mixture was
concentrated under reduced pressure. The residue was purified by
column chromatography or preparative TLC on silica gel to give
tetrahydropyranones (methyl esters) 3 and 3′.
Compound (3a, Carboxylic Acid). According to general procedure
A, the reaction of 1 (49.6 mg, 0.201 mmol) with benzaldehyde (65.4
mg, 0.616 mmol) and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.42 mL,
0.504 mmol) followed by purification by preparative TLC on silica gel
(n-hexane/AcOEt = 3/1) gave a mixture of 3a and 3a′ (55.4 mg, 85%,
3a:3a′ = 20:1) as a colorless solid: mp. 156 °C (decomp); Rf: 0.1 (n-
hexane/AcOEt = 3/1); 1H NMR (400 MHz, CDCl3): δ 11.1−8.9 (br
s, 1H), 7.49−7.24 (m, 10H), 5.02 (d, J = 2.8 Hz, 1H), 4.57 (d, J =
11.5 Hz, 1H), 3.34 (ddd, J = 11.5, 7.9, 3.6 Hz, 1H), 2.87 (qd, J = 7.2,
2.8 Hz, 1H), 2.56 (dd, J = 17.1, 7.9 Hz, 1H), 2.17 (dd, J = 17.1, 3.6
Hz, 1H), 1.10 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 209.9, 177.4, 139.0, 138.2, 128.9, 128.8, 128.3, 127.4,
127.1, 125.4, 83.7, 80.5, 51.0, 49.2, 29.5, 11.5; HRMS (ESI+) m/z:
calcd for C20H20NaO4 (M + Na)+, 347.1259; found, 347.1237. The
relative configuration of 3a was determined by NOESY.
Large-Scale Synthesis of 3a. According to general procedure A,
the reaction was performed using 1 (615 mg, 2.50 mmol),
benzaldehyde (797 mg, 7.50 mmol), and BF3·OEt2 (1.2 M CH2Cl2
solution, 5.2 mL, 6.24 mmol) followed by purification by column
chromatography on silica gel (n-hexane/AcOEt = 3/1−1/1) to give a
mixture of 3a and 3a′ (640 mg, 79%, 3a:3a′ = 15:1) as a colorless
solid.
Compound (3r, Methyl Ester of 3a). According to general
procedure B, the reaction was performed using (S)-1 (24.0 mg,
0.0974 mmol), benzaldehyde (31.1 mg, 0.293 mmol), BF3·OEt2 (1.2
M CH2Cl2 solution, 0.20 mL, 0.240 mmol), and TMSCHN2 (2.0 M
diethyl ether solution, 0.16 mL, 0.320 mmol) followed by purification
by preparative TLC on silica gel (n-hexane/AcOEt = 3/1) to give a
mixture of methyl-esterified 3r and 3r′ (25.2 mg, 77%, 3r (97%
ee):3r′ (76% ee) = 7:1) as a colorless solid. [α]2D5: +37 (c 0.72,
CHCl3, 7:1 mixture of 3r (97% ee) and 3r′ (76% ee)); Rf: 0.4 (n-
Compound (1). [α]D25: +97 (c 1.01, CHCl3, >99% ee, R), [α]2D5:
−98 (c 1.01, CHCl3, >99% ee, S); Rf: 0.6 (n-hexane/AcOEt = 5/1);
1H NMR (400 MHz, acetone-d6): δ 7.58−7.56 (m, 2H), 7.43−7.35
(m, 3H), 4.30 (qd, J = 6.8, 1.7 Hz, 1H), 2.94 (dd, J = 18.2, 11.8 Hz,
1H), 2.83−2.78 (m, 1H), 2.45 (dd, J = 18.2, 4.2 Hz, 1H), 1.57 (dd, J
= 6.8, 1.8 Hz, 3H), 0.38 (s, 3H), 0.35 (s, 3H); 13C{1H} NMR (100
MHz, acetone-d6): δ 175.0, 151.9, 136.4, 134.8, 130.5, 128.8, 96.8,
30.6, 26.5, 10.6, −5.2, −5.3; HRMS (DART+) m/z: calcd for
C14H19O2Si (M + H)+, 247.1154; found, 247.1148. Compound 1 was
gradually isomerized to compound 1′ in CDCl3. The stereochemistry
1
hexane/AcOEt = 5/1); H NMR (400 MHz, CDCl3): δ 7.52−7.24
(m, 10H), 5.04 (d, J = 2.8 Hz, 1H), 4.59 (d, J = 11.6 Hz, 1H), 3.58 (s,
3H), 3.39 (ddd, J = 11.6, 7.6, 3.8 Hz, 1H), 2.87 (qd, J = 7.1, 2.8 Hz,
1H), 2.57 (dd, J = 17.0, 7.6 Hz, 1H), 2.16 (dd, J = 17.0, 3.8 Hz, 1H),
1.12 (d, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 210.1,
172.2, 139.1, 138.2, 128.7 (×2), 128.2, 127.3, 127.2, 125.4, 83.8, 80.5,
E
https://doi.org/10.1021/acs.joc.1c01284
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
51.7, 51.1, 49.3, 29.4, 11.5; HRMS (DART+) m/z: calcd for C21H23O4
(M + H)+, 339.1596; found, 339.1595.
137.1, 132.0, 131.5, 128.8, 127.1, 122.9, 121.4, 83.1, 79.9, 51.9, 50.7,
49.1, 29.3, 11.5; HRMS (ESI+) m/z: calcd for C21H20Br2NaO4 (M +
Na)+, 516.9626; found, 516.9646.
Compound (ent-3r′, Methyl Ester of 3a′). To a solution of a
mixture of methyl-esterified 3r (97% ee) and 3r′ (76% ee) (14.4 mg,
0.0426 mmol, 3r:3r′ = 7:1) in anhydrous CH2Cl2 (53 mL) was added
1,5-diazabicyclo[4.3.0]non-5-ene (DBN) (6.8 mg, 0.0548 mmol).
The reaction mixture was stirred at room temperature for 16 h under
a nitrogen atmosphere. The reaction mixture was filtered through
silica gel. The filtrate was concentrated under reduced pressure to give
methyl-esterified ent-3r′ (12.5 mg, 87%, 80% ee, dr = 17:1) as a
colorless solid: [α]2D0: +3 (c 0.63, CHCl3, 80% ee); Rf: 0.4 (n-hexane/
AcOEt = 5/1); 1H NMR (400 MHz, CDCl3): δ 7.49−7.26 (m, 10H),
4.57 (d, J = 10.2 Hz, 1H), 4.37 (d, J = 11.5 Hz, 1H), 3.59 (s, 3H),
3.38 (ddd, J = 11.5, 8.5, 3.0 Hz, 1H), 2.96 (dq, J = 10.2, 6.5 Hz, 1H),
2.59 (dd, J = 16.7, 8.5 Hz, 1H), 2.07 (dd, J = 16.7, 3.0 Hz, 1H), 0.88
(d, J = 6.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 207.3,
172.3, 139.4, 138.7, 128.73, 128.71, 128.6, 128.5, 127.2, 127.1, 86.5,
84.2, 53.8, 51.82, 51.76, 29.9, 9.7; HRMS (ESI+) m/z: calcd for
C21H22NaO4 (M + Na)+, 361.1416; found, 361.1422.
Compound (3e). According to general procedure A, the reaction of
1 (49.3 mg, 0.200 mmol) with p-tolualdehyde (73.1 mg, 0.608 mmol)
and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.42 mL, 0.504 mmol)
followed by preparative TLC on silica gel (n-hexane/AcOEt = 3/1)
gave a mixture of 3e and 3e′ (40.1 mg, 53%, 3e:3e′ = 6:1) as a
colorless solid. Rf: 0.1 (n-hexane/AcOEt = 3/1); mp: 161 °C
(decomp); 1H NMR (400 MHz, CDCl3): δ 12.3−9.5 (br s, 1H), 7.35
(d, J = 8.4 Hz, 2H), 7.23−7.21 (m, 4H), 7.14 (d, J = 7.6 Hz, 2H),
4.97 (d, J = 2.5 Hz, 1H), 4.50 (d, J = 11.3 Hz, 1H), 3.33 (ddd, J =
11.3, 8.3, 3.4 Hz, 1H), 2.83 (qd, J = 7.1, 2.5 Hz, 1H), 2.54 (dd, J =
17.2, 8.3 Hz, 1H), 2.37 (s, 3H), 2.33 (s, 3H), 2.15 (dd, J = 17.2, 3.4
Hz, 1H), 1.10 (d, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 210.2, 177.7, 138.6, 136.9, 136.1, 135.2, 129.4, 128.9,
127.0, 125.3, 83.5, 80.4, 51.1, 49.2, 29.6, 21.2, 21.1, 11.4; HRMS
(ESI+) m/z: calcd for C22H24NaO4 (M + Na)+, 375.1572; found,
375.1545.
Compound (3b). According to general procedure A, the reaction of
1 (49.2 mg, 0.200 mmol) with p-fluorobenzaldehyde (74.8 mg, 0.602
mmol) and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.42 mL, 0.504 mmol)
followed by purification by preparative TLC on silica gel (n-hexane/
AcOEt = 5/2) gave a mixture of 3b and 3b′ (46.2 mg, 64%, 3b:3b′ =
16:1) as a colorless solid. Rf: 0.1 (n-hexane/AcOEt = 5/1); mp: 145
Compound (3f). According to general procedure B, the reaction of
1 (24.5 mg, 0.0994 mmol) with p-nitrobenzaldehyde (90.0 mg, 0.596
mmol) and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.42 mL, 0.504 mmol)
followed by purification by preparative TLC on silica gel (n-hexane/
AcOEt = 3/1) gave a diastereomeric mixture of carboxylic acids.
Then, the reaction of the mixture with TMSCHN2 (2.0 M diethyl
ether solution, 0.15 mL, 0.300 mmol) followed by purification by
preparative TLC on silica gel (n-hexane/AcOEt = 4/1) gave a mixture
of 3f and 3f′ (26.7 mg, 31%, 3f:3f′ = 2.5:1) as a colorless solid. Rf: 0.5
(n-hexane/AcOEt = 5/1); mp: 92−93 °C; 1H NMR (400 MHz,
CDCl3): δ 8.31 (d, J = 8.8 Hz, 2 H), 8.24 (d, J = 8.4 Hz, 2 H), 7.68
(d, J = 8.8 Hz, 2 H), 7.52 (d, J = 8.8 Hz, 2 H), 5.20 (d, J = 2.8 Hz,
1H), 4.88 (d, J = 10.9 Hz, 1H), 3.61 (s, 3H), 3.26 (ddd, J = 10.9, 6.9,
4.2 Hz, 1H), 2.96 (qd, J = 7.0, 2.8 Hz, 1H), 2.51 (dd, J = 17.0, 6.9 Hz,
1H), 2.29 (dd, J = 17.0, 4.2 Hz, 1H), 1.09 (d, J = 7.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 207.5, 171.7, 148.2, 147.4,
145.5, 145.0, 128.1, 126.2, 124.1, 123.7, 82.4, 79.7, 52.0, 50.1, 48.8,
29.1, 11.6; HRMS (ESI+) m/z: calcd for C21H20N2NaO8 (M + Na)+,
451.1117; found, 451.1125.
Compound (3g). According to general procedure A, the reaction of
1 (24.5 mg, 0.0994 mmol) with m-tolualdehyde (35.8 mg, 0.298
mmol) and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.21 mL, 0.252 mmol)
followed by purification by preparative TLC on silica gel (n-hexane/
AcOEt = 3/1) gave a mixture of 3g and 3g′ (26.6 mg, 76%, 3g:3g′ =
16:1) as a colorless solid. Rf: 0.1 (n-hexane/AcOEt = 3/1); mp: 110−
112 °C; 1H NMR (400 MHz, CDCl3): δ 11.0−8.1 (br s, 1H), 7.33−
7.06 (m, 8H), 4.97 (d, J = 2.5 Hz, 1H), 4.50 (d, J = 11.1 Hz, 1H),
3.35 (ddd, J = 11.1, 8.1, 3.5 Hz, 1H), 2.85 (qd, J = 7.2, 2.5 Hz, 1H),
2.55 (dd, J = 17.2, 8.1 Hz, 1H), 2.41 (s, 3 H), 2.35 (s, 3 H), 2.16 (dd,
J = 17.2, 3.5 Hz, 1H), 1.12 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 210.1, 177.5, 138.9, 138.6, 138.1, 137.8, 129.6,
128.7, 128.1 (×2), 127.8, 126.0, 124.3, 122.5, 83.8, 80.6, 51.1, 49.1,
29.6, 21.50, 21.48, 11.5; HRMS (ESI+) m/z: calcd for C22H24NaO4
(M + Na)+, 375.1572; found, 375.1580.
1
°C (decomp); H NMR (400 MHz, CDCl3): δ 12.0−9.4 (br s, 1H),
7.45 (dd, J = 8.8, 5.6 Hz, 2H), 7.29 (dd, J = 8.6, 5.4 Hz, 2H), 7.12 (t, J
= 8.8 Hz, 2H), 7.05 (t, J = 8.8 Hz, 2H), 4.99 (d, J = 2.6 Hz, 1H), 4.57
(d, J = 10.8 Hz, 1H), 3.28 (ddd, J = 10.8, 7.7, 3.8 Hz, 1H), 2.83 (qd, J
= 6.9, 2.6 Hz, 1H), 2.55 (dd, J = 17.2, 7.7 Hz, 1H), 2.17 (dd, J = 17.2,
3.8 Hz, 1H), 1.08 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 209.3, 177.0, 162.9 (d, J = 246 Hz), 162.1 (d, J = 244 Hz),
134.7, 133.8, 128.9 (d, J = 8 Hz), 127.0 (d, J = 8 Hz), 115.9 (d, J = 21
Hz), 115.3 (d, J = 22 Hz), 83.0, 80.0, 50.9, 49.2, 29.4, 11.4; HRMS
(ESI−) m/z: calcd for C20H17F2O4 (M − H)−, 359.1095; found,
359.1094.
Compound (3c). According to general procedure B, the reaction of
1 (23.3 mg, 0.0946 mmol) with p-chlorobenzaldehyde (40.2 mg,
0.286 mmol) and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.20 mL, 0.240
mmol) followed by purification by preparative TLC on silica gel (n-
hexane/AcOEt = 4/1) gave a diastereomeric mixture of carboxylic
acids. Then, the reaction of the mixture with TMSCHN2 (2.0 M
diethyl ether solution, 0.16 mL, 0.320 mmol) followed by purification
by preparative TLC on silica gel (n-hexane/AcOEt = 4/1) gave a
mixture of 3c and 3c′ (22.6 mg, 59%, 3c:3c′ = 25:1) as a colorless
1
solid. Rf: 0.5 (n-hexane/AcOEt = 5/1); mp: 90−92 °C; H NMR
(400 MHz, CDCl3): δ 7.40−7.3 (m, 6H), 7.25 (d, J = 8.4 Hz, 2H),
5.00 (d, J = 2.8 Hz, 1H), 4.59 (d, J = 10.8 Hz, 1H), 3.59 (s, 3H), 3.29
(ddd, J = 10.8, 7.4, 4.2 Hz, 1H), 2.83 (qd, J = 7.0, 2.8 Hz, 1H), 2.52
(dd, J = 17.2, 7.4 Hz, 1H), 2.16 (dd, J = 17.2, 4.2 Hz, 1H), 1.08 (d, J
= 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.2, 172.0,
137.4, 136.6, 134.7, 133.3, 129.0, 128.5 (×2), 126.8, 83.0, 79.9, 51.8,
50.7, 49.1, 29.3, 11.5; HRMS (ESI+) m/z: calcd for C21H20Cl2NaO4
(M + Na)+, 429.0636; found, 429.0616.
Compound (3h). According to general procedure A, the reaction of
1 (49.7 mg, 0.202 mmol) with m-anisaldehyde (83.0 mg, 0.610
mmol) and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.42 mL, 0.504 mmol)
followed by purification by preparative TLC on silica gel (n-hexane/
AcOEt = 3/1) gave a mixture of 3h and 3h′ (59.2 mg, 74%, 3h:3h′ =
15:1) as a colorless solid. Rf: 0.1 (n-hexane/AcOEt = 3/1); mp: 63−
65 °C; 1H NMR (400 MHz, CDCl3): δ 11.8−8.9 (br s, 1H), 7.33 (t, J
= 8.2 Hz, 2H), 7.26 (t, J = 8.2 Hz, 2H), 7.04−7.02 (m, 2H), 6.91−
6.89 (m, 3H), 6.80 (dd, J = 8.2, 2.2 Hz, 1H), 4.98 (d, J = 2.5 Hz, 1H),
4.53 (d, J = 10.8 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.31 (ddd, J =
10.8, 8.1, 3.6 Hz, 1H), 2.85 (qd, J = 7.2, 2.5 Hz, 1H), 2.55 (dd, J =
17.2, 8.1 Hz, 1H), 2.21 (dd, J = 17.2, 3.6 Hz, 1H), 1.10 (d, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.9, 177.5, 159.8,
159.5, 140.4, 139.8, 129.8, 129.3, 119.4, 117.7, 113.7, 113.0, 112.3,
111.5, 83.4, 80.3, 55.3, 55.2, 50.9, 49.1, 29.5, 11.5; HRMS (ESI+) m/
z: calcd for C22H24NaO6 (M + Na)+, 407.1471; found, 407.1473.
Compound (3d). According to general procedure B, the reaction of
1 (24.5 mg, 0.0994 mmol) with p-bromobenzaldehyde (55.2 mg,
0.298 mmol) and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.21 mL, 0.252
mmol) followed by purification by preparative TLC on silica gel (n-
hexane/AcOEt = 4/1) gave a diastereomeric mixture of carboxylic
acids. Then, the reaction of the mixture with TMSCHN2 (2.0 M
diethyl ether solution, 0.16 mL, 0.320 mmol) followed by purification
by preparative TLC on silica gel (n-hexane/AcOEt = 4/1) gave a
mixture of 3d and 3d′ (28.2 mg, 57%, 3d:3d′ = >25:1) as a colorless
1
solid. Rf: 0.5 (n-hexane/AcOEt = 5/1); mp: 59−61 °C; H NMR
(400 MHz, CDCl3): δ 7.55 (d J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz,
2H), 7.34 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 4.98 (d, J =
2.6 Hz, 1H), 4.58 (d, J = 10.8 Hz, 1H), 3.11 (s, 3H), 3.28 (ddd, J =
10.8, 7.5, 4.0 Hz, 1H), 2.83 (qd, J = 7.3, 2.6 Hz, 1H), 2.52 (dd, J =
16.9, 7.5 Hz, 1H), 2.16 (dd, J = 16.9, 4.0 Hz, 1H), 1.08 (d, J = 7.3 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.1, 172.0, 137.9,
F
https://doi.org/10.1021/acs.joc.1c01284
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Compound (3i). According to general procedure A, the reaction of
1 (49.6 mg, 0.201 mmol) with o-tolualdehyde (73.5 mg, 0.612 mmol)
and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.42 mL, 0.504 mmol)
followed by purification by preparative TLC on silica gel (n-hexane/
AcOEt = 3/1) gave a mixture of 3i and 3i′ (55.2 mg, 78%, 3i:3i′ =
10:1) as a colorless solid. Rf: 0.1 (n-hexane/AcOEt = 3/1); mp: 143
J = 7.2 Hz, 3H), 1.08−0.94 (m, 9H), 0.79 (d, J = 6.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 212.2, 177.9, 84.9, 84.3, 47.2,
45.4, 29.8, 29.25, 29.15, 20.5, 20.0, 17.7, 14.0, 10.4; HRMS (ESI+) m/
z: calcd for C14H24NaO4 (M + Na)+, 279.1572; found, 279.1567.
Compound (3n). According to general procedure B, the reaction of
1 (25.1 mg, 0.102 mmol) with cyclopropanecarboxaldehyde (21.3 mg,
0.304 mmol) and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.21 mL, 0.252
mmol) followed by purification by preparative TLC on silica gel (n-
hexane/AcOEt = 4/1) gave a diastereomeric mixture of carboxylic
acids. Then, the reaction of the mixture with TMSCHN2 (2.0 M
diethyl ether solution, 0.16 mL, 0.320 mmol) followed by purification
by preparative TLC on silica gel (n-hexane/AcOEt = 4/1) gave a
mixture of 3n and 3n′ (9.0 mg, 33%, 3n:3n′ = 6:1) as a yellow oil. Rf:
1
°C (decomp); H NMR (400 MHz, CDCl3): δ 11.1−8.9 (br s, 1H),
7.61−7.13 (m, 8H), 5.15 (d, J = 2.5 Hz, 1H), 4.85 (d, J = 10.9 Hz,
1H), 3.56 (ddd, J = 10.9, 8.7, 3.2 Hz, 1H), 2.87 (qd, J = 7.0, 2.5 Hz,
1H), 2.63 (dd, J = 17.0, 8.7 Hz, 1H), 2.42 (s, 3 H), 2.30 (s, 3 H), 2.11
(dd, J = 17.0, 3.2 Hz, 1H), 1.15 (d, J = 7.0 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 210.3, 177.6, 136.1, 135.8, 133.0, 130.8, 130.3,
128.5, 127.3, 127.0, 126.9, 126.7, 125.8, 125.7, 78.6 (×2), 48.6 (×2),
29.3, 19.6, 19.0, 12.0; HRMS (ESI+) m/z: calcd for C22H24NaO4 (M
+ Na)+, 375.1572; found, 375.1592.
1
0.5 (n-hexane/AcOEt = 5/1); H NMR (400 MHz, CDCl3): δ 3.68
(s. 3H), 3.17 (ddd, J = 11.8, 7.0, 4.1 Hz, 1H), 2.73 (dd, J = 8.6, 2.6
Hz, 1H), 2.70 (dd, J = 17.0, 7.0 Hz, 1H), 2.60−2.50 (m, 3H), 1.33 (d,
J = 7.6 Hz, 3H), 1.12−0.98 (m, 2H), 0.70−0.57 (m, 2H), 0.50 (m,
1H), 0.43−0.33 (m, 3H), 0.28 (sext, J = 4.5 Hz, 1H), 0.13 (sext, J =
5.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 211.0, 172.8, 85.4,
84.1, 51.8, 49.3, 49.2, 29.4, 15.4, 12.1, 11.7, 4.3 (×2), 2.2, 1.3; HRMS
(ESI+) m/z: calcd for C15H22NaO4 (M + Na)+, 289.1416; found,
289.1403.
Compound (3j). According to general procedure A, the reaction of
1 (24.0 mg, 0.0974 mmol) with 2-naphthaldehyde (45.3 mg, 0.290
mmol) and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.20 mL, 0.240 mmol)
followed by purification by preparative TLC on silica gel (n-hexane/
AcOEt = 4/1) gave a mixture of 3j and 3j′ (29.1 mg, 70%, 3j:3j′ =
12:1) as a colorless solid. Rf: 0.1 (n-hexane/AcOEt = 3/1); mp: 176
1
°C (decomp); H NMR (400 MHz, CDCl3): δ 11.5−9.6 (br s, 1H),
Compound (4).10 According to general procedure A, the reaction
of 1 (49.5 mg, 0.201 mmol) with cyclohexanone (59.0 mg, 0.601
mmol) and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.42 mL, 0.504 mmol)
followed by preparative TLC on silica gel (n-hexane/AcOEt = 2/1)
gave 4 (21.7 mg, 83%) as a colorless oil. Rf: 0.1 (n-hexane/AcOEt =
3/1); 1H NMR (400 MHz, CDCl3): δ 10.3−7.9 (br s, 1H), 2.71 (t, J
= 6.3 Hz, 2H), 2.63 (t, J = 6.3 Hz, 2H), 2.47 (q, J = 7.4 Hz, 2H), 1.06
(t, J = 7.4 Hz, 3H).
7.99 (d, J = 8.8 Hz, 1H), 7.91−7.82 (m, 6H), 7.76 (d, J = 8.0 Hz,
1H), 7.53−7.41 (m, 6H), 5.24 (d, J = 2.2 Hz, 1H), 4.80 (d, J = 11.0
Hz, 1H), 3.50 (ddd, J = 11.0, 7.9, 3.5 Hz, 1H), 3.03 (qd, J = 7.1, 2.2
Hz, 1H), 2.60 (dd, J = 17.2, 7.9 Hz, 1H), 2.21 (dd, J = 17.2, 3.5 Hz,
1H), 1.17 (d, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
209.8, 176.9, 136.2, 135.6, 133.6, 133.1, 133.0, 132.7, 129.1, 128.1,
128.04, 128.01, 127.8, 127.6, 126.9, 126.5 (×2), 126.2, 125.9, 124.4,
124.3, 123.2, 84.0, 80.7, 51.0, 49.1, 29.6, 11.6; HRMS (ESI+) m/z:
calcd for C28H24NaO4 (M + Na)+, 447.1572; found, 447.1537.
Compound (3k). According to general procedure A, the reaction of
1 (51.7 mg, 0.210 mmol) with butyraldehyde (44.9 mg, 0.623 mmol)
and BF3·OEt2 (71.5 mg, 0.503 mmol) followed by flash column
chromatography on silica gel (n-hexane/AcOEt = 5/3) gave a mixture
of 3k and 3k′ (44.6 mg, 83%, 3k:3k′ = >25:1) as a pale yellow oil. Rf:
0.2 (n-hexane/AcOEt = 3/1); 1H NMR (400 MHz, CDCl3): δ 11.0−
8.4 (br s, 1H), 3.54 (ddd, J = 8.8, 4.1, 2.5 Hz, 1H), 3.32 (ddd, J =
11.0, 7.6, 3.2 Hz, 1H), 2.88 (ddd, J = 11.0, 7.6, 4.0 Hz, 1H), 2.67 (dd,
J = 17.2, 7.6 Hz, 1H), 2.42 (qd, J = 7.0, 2.5 Hz, 1H), 2.31 (dd, J =
17.2, 4.0 Hz, 1H), 1.70−1.24 (m, 8H), 1.15 (d, J = 7.0 Hz, 3H), 0.92
(t, J = 7.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 211.3,
178.0, 80.4, 78.9, 49.0, 47.9, 36.2, 33.8, 29.5, 19.0, 18.6, 13.9, 13.8,
10.7; HRMS (ESI+) m/z: calcd for C14H24NaO4 (M + Na)+,
279.1572; found, 279.1569.
Compound (5). To a solution of β-silyl-γ-ethylidene-γ-butyrolac-
tone 1 (26.0 mg, 0.106 mmol) in anhydrous CH2Cl2 (1 mL) was
added benzaldehyde (11.2 mg, 0.106 mmol). The reaction mixture
was stirred at −78 °C under a nitrogen atmosphere. BF3·OEt2 (1.2 M
CH2Cl2 solution, 0.22 mL, 0.264 mmol) was added slowly to the
reaction mixture. The reaction mixture was stirred at −78 °C for 1.5
h. 3-Phenylpropionaldehyde (16.9 mg, 0.126 mmol) was added to the
reaction mixture. The reaction mixture was warmed to 0 °C and
stirred for 1.5 h. The reaction was quenched with brine at 0 °C and
then extracted with CH2Cl2 (×3). The combined organic layers were
dried over MgSO4 and filtered. The filtrate was concentrated under
reduced pressure. The residue was purified by preparative TLC on
silica gel (n-hexane/AcOEt = 5/1) to give a diastereomeric mixture of
carboxylic acids. Then, to a solution of the mixture in anhydrous
toluene (2.8 mL) and methanol (0.7 mL) was added trimethylsi-
lyldiazomethane (2.0 M diethyl ether solution, 0.16 mL, 0.320 mmol).
The reaction mixture was stirred at room temperature for 1.5 h under
a nitrogen atmosphere. The reaction was quenched with acetic acid at
room temperature and then concentrated under reduced pressure.
The residue was purified by preparative TLC on silica gel (n-hexane/
AcOEt = 5/1) to give 5 (23.3 mg, 60%, dr = 8:1) as a colorless solid.
Compound (3l). According to general procedure A, the reaction of
1 (26.7 mg, 0.108 mmol) with 3-phenylpropionaldehyde (46.0 mg,
0.343 mmol) and BF3·OEt2 (1.2 M CH2Cl2 solution, 0.23 mL, 0.276
mmol) followed by preparative TLC on silica gel (n-hexane/AcOEt =
4/1) gave a mixture of 3l and 3l′ (29.5 mg, 72%, 3l:3l′ = >25:1) as a
colorless solid. Rf: 0.1 (n-hexane/AcOEt = 3/1); mp: 98−100 °C; 1H
NMR (400 MHz, CDCl3): δ 12.0−8.2 (br s, 1H), 7.33−7.28 (m,
4H), 7.22 (d, J = 7.6 Hz, 6H), 3.57 (ddd, J = 9.4, 3.1, 2.6 Hz, 1H),
3.32 (ddd, J = 11.0, 7.9, 3.1 Hz, 1H), 3.05−2.86 (m, 3H), 2.81−2.62
(m, 3H), 2.44 (qd, J = 7.4, 2.6 Hz, 1H), 2.26 (dd, J = 17.6, 4.0 Hz,
1H), 2.07 (m, 1H), 1.97−1.92 (m, 2H), 1.66 (m, 1H), 1.21 (d, J = 7.4
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 210.7, 177.6, 141.43,
141.39, 128.5 (×2), 128.4 (×2), 126.0 (×2), 79.6, 78.0, 49.0, 47.8,
35.9, 33.6, 32.1, 31.5, 29.4, 10.9; HRMS (ESI+) m/z: calcd for
C24H28NaO4 (M + Na)+, 403.1885; found, 403.1864.
Compound (3m). According to general procedure A, the reaction
of 1 (49.5 mg, 0.201 mmol) with isobutyraldehyde (44.0 mg, 0.610
mmol) and BF3·OEt2 (71.5 mg, 0.503 mmol) followed by preparative
TLC on silica gel (n-hexane/AcOEt = 3/1) gave a mixture of 3m and
3m′ (40.1 mg, 78%, 3m:3m′ = 4:1) as a colorless solid. Rf: 0.2 (n-
hexane/AcOEt = 3/1); mp: 103−105 °C; 1H NMR (400 MHz,
CDCl3): δ 12.4−10.4 (br s, 1H), 3.18 (J = 11.0, 1.2 Hz, 1H), 3.05
(ddd, J = 11.0, 7.8, 3.7 Hz, 1H), 2.99 (dd, J = 9.9, 2.1 Hz, 1H), 2.64
(dd, J = 17.0, 7.8 Hz, 1H), 2.59 (qd, J = 7.2, 2.1 Hz, 1H), 2.26 (dd, J
= 17.0, 3.7 Hz, 1H), 1.89−1.82 (m, 1H), 1.79−1.73 (m, 1H), 1.13 (d,
1
Rf: 0.4 (n-hexane/AcOEt = 5/1); mp: 99−101 °C; H NMR (400
MHz, CDCl3): δ 7.4−7.1 (m, 10H), 4.83 (d, J = 2.6 Hz, 1H), 3.69 (s,
3H), 3.56 (ddd, J = 11.1, 8.1, 2.9 Hz, 1H), 3.11 (ddd, J = 11.1, 7.2, 4.2
Hz, 1H), 3.02 (ddd, J = 13.8, 8.6, 5.2 Hz, 1H), 2.84 (m, 1H), 2.78
(qd, J = 7.5, 2.6 Hz, 1H), 2.70 (dd, J = 17.0, 7.2 Hz, 1H), 2.32 (dd, J
= 17.0, 4.2 Hz, 1H), 2.1−1.9 (m, 2H), 0.96 (d, J = 7.5 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 210.7, 172.5, 141.5, 138.6,
128.43, 128.41, 128.3, 127.3, 125.9, 125.3, 79.7, 79.6, 51.9, 50.6, 47.4,
35.8, 31.4, 29.4, 11.3; HRMS (ESI+) m/z: calcd for C23H26NaO4 (M
+ Na)+, 389.1729; found, 389.1703.
Compound (6). To a solution of β-silyl-γ-ethylidene-γ-butyrolac-
tone 1 (24.4 mg, 0.0990 mmol) in anhydrous CH2Cl2 (1 mL) was
added 3-phenylpropionaldehyde (13.4 mg, 0.0990 mmol). The
reaction mixture was stirred at −78 °C under a nitrogen atmosphere.
BF3·OEt2 (1.2 M CH2Cl2 solution, 0.10 mL, 0.120 mmol) was added
slowly to the reaction mixture. The reaction mixture was stirred at
−45 °C for 1.5 h. Benzaldehyde (12.9 mg, 0.122 mmol) was added to
the reaction mixture. The reaction mixture was warmed to 0 °C and
stirred for 3.5 h. The reaction was quenched with brine at 0 °C and
G
https://doi.org/10.1021/acs.joc.1c01284
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
then extracted with CH2Cl2 (×3). The combined organic layers were
dried over MgSO4 and filtered. The filtrate was concentrated under
reduced pressure. The residue was purified by preparative TLC on
silica gel (n-hexane/AcOEt = 3/1) to give a diastereomeric mixture of
carboxylic acids. Then, to a solution of mixture in anhydrous toluene
(2.8 mL) and methanol (0.7 mL) was added trimethylsilyldiazo-
methane (2.0 M diethyl ether solution, 0.16 mL, 0.320 mmol). The
reaction mixture was stirred at room temperature for 1.5 h under a
nitrogen atmosphere. The reaction was quenched with acetic acid at
room temperature and then concentrated under reduced pressure.
The residue was purified by preparative TLC on silica gel (n-hexane/
AcOEt = 3/1) to give 6 (20.3 mg, 56%, dr = 10:1) as a colorless oil.
colorless oil. Rf: 0.6 (n-hexane/AcOEt = 3/1); H NMR (400 MHz,
CDCl3): δ 7.40−7.25 (m, 5H), 4.91 (d, J = 3.0 Hz, 1H), 3.69 (s, 3H),
3.33 (dd, J = 10.8, 2.8 Hz, 1H), 2.75 (dd, J = 16.6, 10.8 Hz, 1H), 2.71
(qd, J = 7.0, 3.0 Hz, 1H), 2.25 (dd, J = 16.6, 2.8 Hz, 1H), 1.92−1.35
(m, 12H), 0.95 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 211.8, 172.8, 128.2, 127.3, 127.1, 125.5, 82.1, 72.9, 53.2,
51.9, 50.7, 42.4, 30.3, 29.0, 28.5, 28.1, 22.8, 21.0, 11.5; HRMS (ESI+)
m/z: calcd for C21H28NaO4 (M + Na)+, 367.1885; found, 367.1862.
Compound (7c). According to general procedure C, the reaction of
1 (24.3 mg, 0.0986 mmol) with benzaldehyde (10.2 mg, 0.0961
mmol), acetone (23.7 mg, 0.408 mmol), and BF3·OEt2 (1.2 M
CH2Cl2 solution, 0.21 mL, 0.252 mmol) followed by purification by
preparative TLC on silica gel (n-hexane/AcOEt = 4/1) gave a
diastereomeric mixture of carboxylic acids. Then, the reaction of the
mixture with TMSCHN2 (2.0 M diethyl ether solution, 0.16 mL,
0.320 mmol) followed by purification by preparative TLC on silica gel
(n-hexane/AcOEt = 4/1) gave 7c (10.1 mg, 35%, dr = 6:1) as a
1
Rf: 0.4 (n-hexane/AcOEt = 5/1); H NMR (400 MHz, CDCl3): δ
7.40−7.32 (m, 3H), 7.26−7.22 (m, 3H), 7.19−7.15 (m, 2H), 7.13−
7.11 (m, 2H), 4.28 (d, J = 11.4 Hz, 1H), 3.71 (ddd, J = 8.2, 4.8, 2.4
Hz, 1H), 3.51 (s, 3H), 3.26 (ddd, J = 11.4, 7.6, 3.7 Hz, 1H), 2.72 (m,
1H), 2.60 (m, 1H), 2.52 (qd, J = 7.1, 2.4 Hz, 1H), 2.46 (dd, J = 16.8,
7.6 Hz, 1H), 2.06 (m, 1H), 2.00 (dd, J = 16.8, 3.7 Hz, 1H), 1.69 (m,
1H), 1.32 (d, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
210.3, 172.2, 141.5, 139.2, 128.71, 128.68, 128.5, 128.4, 127.2, 126.0,
84.0, 78.7, 51.7, 49.4, 49.1, 33.3, 31.8, 29.5, 11.0; HRMS (ESI+) m/z:
calcd for C23H26NaO4 (M + Na)+, 389.1729; found, 389.1700.
General Procedure for the Synthesis of Tetrahydropyr-
anones Using Ketones (General Procedure C). To a solution of
β-silyl-γ-ethylidene-γ-butyrolactone 1 (1 equiv) in anhydrous CH2Cl2
(0.1 M) were added aldehyde (1.0 equiv) and ketone (1.3−4.0
equiv). The reaction mixture was stirred at −78 °C under a nitrogen
atmosphere. BF3·OEt2 (2.5 equiv, 1.2 M CH2Cl2 solution) was added
carefully to the reaction mixture. The reaction mixture was stirred at
−78 °C for 1.5 h and then the reaction mixture was stirred at 0 °C for
2−20 h. The reaction was quenched with brine at 0 °C and then
extracted with CH2Cl2 (×3). The combined organic layers were dried
over MgSO4 and filtered. The filtrate was concentrated under reduced
pressure. The residue was purified by preparative TLC on silica gel to
give a diastereomeric mixture of carboxylic acids. Then, to a solution
of mixture in anhydrous 4:1 toluene/methanol (0.03 M) was added
trimethylsilyldiazomethane (2.0 M diethyl ether solution, 3.2 equiv).
The reaction mixture was stirred at room temperature for 1.5 h under
a nitrogen atmosphere. The reaction was quenched with acetic acid at
room temperature and then concentrated under reduced pressure.
The residue was purified by preparative TLC on silica gel to give
tetrahydropyranone 7.
1
colorless solid. Rf: 0.5 (n-hexane/AcOEt = 5/1); mp: 79−81 °C; H
NMR (400 MHz, CDCl3): δ 7.49−7.24 (m, 5H), 5.04 (d, J = 3.2 Hz,
1H), 3.70 (s, 3H), 3.39 (dd, J = 10.4, 3.2 Hz, 1H), 2.76 (dd, J = 16.6,
10.4 Hz, 1H), 2.68 (qd, J = 7.0, 3.2 Hz, 1H), 2.19 (dd, J = 16.6, 3.2
Hz, 1H), 1.51 (s, 3H), 1.14 (s, 3H), 0.96 (d, J = 7.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 211.6, 172.6, 138.9, 128.2,
127.2, 125.6, 78.3, 74.0, 51.9, 51.7, 50.7, 29.5, 29.2, 20.3, 11.5; HRMS
(ESI+) m/z: calcd for C17H22NaO4 (M + Na)+, 313.1416; found,
313.1442.
General Procedure for the Synthesis of Tetrahydropyr-
anones (Carboxylic Acids) Using Ketoaldehydes (General
Procedure D). To a solution of β-silyl-γ-ethylidene-γ-butyrolactone
1 (1 equiv) in anhydrous CH2Cl2 (0.1 M) was added keto-containing
aldehyde (1.4 equiv). The reaction mixture was stirred at −78 °C
under a nitrogen atmosphere. BF3·OEt2 (2.5 equiv, 1.2 M CH2Cl2
solution) was added slowly to the reaction mixture. The reaction
mixture was stirred at −78 °C for 1.5 h and then stirred at 0 °C for 2
h. The reaction was quenched with brine at 0 °C. The reaction
mixture was extracted with CH2Cl2 (×3). The combined organic
layers were dried over MgSO4 and filtered. The filtrate was
concentrated under reduced pressure. The residue was purified by
preparative TLC on silica gel to give tetrahydropyranone 8.
General Procedure for the Synthesis of Tetrahydropyr-
anones (Methyl Esters) Using Ketoaldehydes (General
Procedure E). After performing general procedure D, to a solution
of the resulting carboxylic acids in anhydrous toluene/methanol (4/1,
0.03 M) was added trimethylsilyldiazomethane (3.2 equiv, 2.0 M
diethyl ether solution). The reaction mixture was stirred at room
temperature for 1.5 h under a nitrogen atmosphere. The reaction was
quenched with acetic acid at room temperature. The reaction mixture
was concentrated under reduced pressure. The residue was purified by
column chromatography or preparative TLC on silica gel to give
tetrahydropyranone 8.
Compound (8a). According to general procedure D, the reaction
of 1 (25.2 mg, 0.102 mmol) with 9 (14.4 mg, 0.144 mmol) and BF3·
OEt2 (1.2 M CH2Cl2 solution, 0.21 mL, 0.252 mmol) followed by
purification by flash column chromatography on silica gel (n-hexane/
AcOEt = 3/1) gave 8a (15.3 mg, 71%) as a colorless solid. Rf: 0.1 (n-
hexane/AcOEt = 3/1); mp: 51−52 °C; 1H NMR (400 MHz,
CDCl3): δ 11.8−9.0 (br s, 1H), 4.46 (dd, J = 6.7, 4.8 Hz, 1H), 3.09
(dd, J = 8.9, 4.3 Hz, 1H), 2.87 (dq, J = 6.5, 6.5 Hz, 1H), 2.77 (dd, J =
16.8, 8.9 Hz, 1H), 2.15 (dd, J = 16.8, 4.3 Hz, 1H), 1.95 (m, 1H),
1.70−1.59 (m, 2H), 1.50 (m, 1H), 1.44 (s, 3H), 0.94 (d, J = 6.5 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 208.3, 177.7, 85.4, 80.5,
56.9, 50.0, 32.1, 29.9, 26.2, 24.5, 9.6; HRMS (ESI+) m/z: calcd for
C11H16NaO4 (M + Na)+, 235.0946; found, 235.0941. The relative
configuration of 8a was determined by NOESY.
Compound (7a). According to general procedure C, the reaction
of 1 (26.7 mg, 0.108 mmol) with benzaldehyde (55.2 mg, 0.298
mmol), cyclohexane (13.5 mg, 0.138 mmol), and BF3·OEt2 (1.2 M
CH2Cl2 solution, 0.23 mL, 0.276 mmol) followed by purification by
preparative TLC on silica gel (n-hexane/AcOEt = 3/1) gave a
diastereomeric mixture of carboxylic acids. Then, the reaction of the
mixture with TMSCHN2 (2.0 M diethyl ether solution, 0.16 mL,
0.320 mmol) followed by purification by preparative TLC on silica gel
(n-hexane/AcOEt = 10/1) gave 7a (15.5 mg, 43%, dr = 8:1) as a
1
colorless solid. Rf: 0.6 (n-hexane/AcOEt = 5/1); mp: 80−81 °C; H
NMR (400 MHz, CDCl3): δ 7.43−7.34 (m, 4H), 7.28 (m, 1H), 4.94
(d, J = 2.8 Hz, 1H), 3.69 (s, 3H), 3.30 (dd, J = 10.4, 2.9 Hz, 1H),
2.79−2.70 (m, 2H), 2.21 (dd, J = 16.7, 2.9 Hz, 1H), 2.01−1.05 (m,
10H), 0.95 (d, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
211.6, 172.8, 139.2, 128.2, 127.1, 125.4, 79.1, 72.3, 52.1, 51.9, 50.5,
37.1, 28.9, 26.8, 25.3, 21.7, 20.3, 11.6; HRMS (ESI+) m/z: calcd for
C20H26NaO4 (M + Na)+, 353.1729; found, 353.1720. The relative
1
configuration of 7a was determined by NOESY and J values in H
NMR.
Compound (7b). According to general procedure C, the reaction
of 1 (25.2 mg, 0.102 mmol) with benzaldehyde (10.2 mg, 0.0961
mmol), cycloheptanone (17.6 mg, 0.157 mmol) and BF3·OEt2 (1.2 M
CH2Cl2 solution, 0.22 mL, 0.264 mmol) followed by purification by
preparative TLC on silica gel (n-hexane/AcOEt = 3/1) gave a
diastereomeric mixture of carboxylic acids. Then, the reaction of the
mixture with TMSCHN2 (2.0 M diethyl ether solution, 0.16 mL,
0.320 mmol) followed by purification by preparative TLC on silica gel
(n-hexane/AcOEt = 5/1) gave 7b (8.2 mg, 23%, dr = 4.5:1) as a
Compound (8b). According to general procedure E, the reaction of
1 (28.1 mg, 0.114 mmol) with 10 (19.6 mg, 0.172 mmol) and BF3·
OEt2 (1.2 M CH2Cl2 solution, 0.23 mL, 0.276 mmol) followed by
purification by preparative TLC on silica gel (n-hexane/AcOEt = 3/1)
gave a carboxylic acid. Then, the reaction of the mixture with
TMSCHN2 (2.0 M diethyl ether solution, 0.16 mL, 0.32 mmol)
H
https://doi.org/10.1021/acs.joc.1c01284
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
followed by purification by preparative TLC on silica gel (n-hexane/
AcOEt = 3/1) gave 8b (3.5 mg, 12%) as a colorless oil. Rf: 0.5 (n-
hexane/AcOEt = 3/1); 1H NMR (400 MHz, CDCl3): δ 4.31 (ddd, J
= 6.5, 4.5, 1.9 Hz, 1H), 3.72 (s, 3H), 3.03 (dd, J = 10.4, 1.8 Hz, 1H),
2.91 (quint, J = 6.5 Hz, 1H), 2.69 (dd, J = 16.1, 10.4 Hz, 1H), 2.10
(dd, J = 16.1, 1.8 Hz, 1H), 1.70−1.42 (m, 5H), 1.32 (s, 3H), 1.13 (m,
1H), 1.00 (d, J = 6.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
210.9, 172.9, 77.2, 75.3, 54.8, 52.0, 46.9, 32.7, 30.3, 29.4, 24.4, 16.3,
10.3; HRMS (ESI+) m/z: calcd for C13H20NaO4 (M + Na)+,
263.1259; found, 263.1258.
a nitrogen atmosphere. The reaction mixture was stirred at 40 °C for
16 h. The reaction mixture was filtered through silica gel. The filtrate
was concentrated under reduced pressure. The residue was purified by
preparative TLC on silica gel (n-hexane/AcOEt = 3/1) to give (S)-
MTPA-14 (2.3 mg, 73%). Rf: 0.2 (n-hexane/AcOEt = 10/1); 1H
NMR (400 MHz, CDCl3): δ 7.60−7.56 (m, 2H), 7.40−7.24 (m,
13H), 5.34 (t, J = 11.3 Hz, 1H), 4.74 (d, J = 10.2 Hz, 1H), 4.26 (d, J
= 10.4 Hz, 1H), 3.54 (d, J = 1.6 Hz, 3H), 3.44 (s, 3H), 2.49 (dddd, J
= 11.3, 10.2, 4.9, 1.6 Hz, 1H), 2.18 (dd, J = 17.0, 6.2 Hz, 1H), 2.12−
2.03 (m, 2H), 0.60 (d, J = 6.4 Hz, 3H); HRMS (ESI+) m/z: calcd for
C31H31F3NaO6 (M + Na)+, 579.1970; found, 579.1967.
(R)-MTPA-14. To a solution of 14 (2.3 mg. 0.0068 mmol),
triethylamine (3.5 mg, 0.035 mmol) and DMAP (1.6 mg, 0.013
mmol) in anhydrous CH2Cl2 (0.9 mL) were added (S)-(−)-MTPA
chloride (5.1 mg) at room temperature under a nitrogen atmosphere.
The reaction mixture was stirred at 40 °C for 16 h. The reaction
mixture was filtered through silica gel. The filtrate was concentrated
under reduced pressure. The residue was purified by preparative TLC
on silica gel (n-hexane/AcOEt = 3/1) to give (R)-MTPA-14 (2.3 mg,
61%). Rf: 0.2 (n-hexane/AcOEt = 10/1); 1H NMR (400 MHz,
CDCl3): δ 7.60−7.58 (m, 2H), 7.43−7.22 (m, 13H), 5.41 (t, J = 11.3
Hz, 1H), 4.79 (d, J = 10.4 Hz, 1H), 4.28 (d, J = 10.0 Hz, 1H), 3.56
(d, J = 0.8 Hz, 3H), 3.48 (s, 3H), 2.39 (dddd, J = 11.3, 10.4, 4.2, 1.4
Hz, 1H), 2.15−2.06 (m, 2H), 1.91 (dd, J = 17.2, 2.8 Hz, 1H), 0.70 (d,
J = 6.4 Hz, 3H); HRMS (ESI+) m/z: calcd for C31H31F3NaO6 (M +
Na)+, 579.1970; found, 579.1959.
Compounds (16), (17), and (18). To a solution of β-silyl-γ-
ethylidene-γ-butyrolactone 1 (252.4 mg, 1.02 mmol) in anhydrous
CH2Cl2 (9 mL) was added benzaldehyde (110.4 mg, 1.04 mmol).
The reaction mixture was stirred at −78 °C under a nitrogen
atmosphere. BF3·OEt2 (1.2 M CH2Cl2 solution, 1.1 mL, 1.32 mmol)
was added slowly to the reaction mixture. The reaction mixture was
stirred at −78 °C for 1.5 h and then quenched with brine. The
reaction mixture was extracted with CH2Cl2 (×3). The combined
organic layers were dried over anhydrous MgSO4 and filtered. The
filtrate was concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (n-hexane/AcOEt =
3/1) to give 16 (118.7 mg, 53%) as a colorless oil, 17 (16.7 mg, 8%,
16:17 = 1:5) as a colorless oil, and 18 (104.0 mg, 29%) as a pale
yellow oil.
Compound (8c). According to general procedure D, the reaction of
1 (26.3 mg, 0.107 mmol) with 11 (24.1 mg, 0.149 mmol) and BF3·
OEt2 (1.2 M CH2Cl2 solution, 0.22 mL, 0.264 mmol) followed by
purification by preparative TLC on silica gel (n-hexane/AcOEt = 3/1)
gave 8c (26.9 mg, 92%) as a colorless solid. Rf: 0.1 (n-hexane/AcOEt
1
= 3/1); mp: 118 °C (decomp); H NMR (400 MHz, CDCl3): δ
12.0−9.0 (br s, 1H), 7.42−7.26 (m, 5H), 4.61 (t, J = 6.2 Hz, 1H),
3.21 (dd, J = 10.0, 3.6 Hz, 1H), 3.06 (quint, J = 6.2 Hz, 1H), 2.59 (dd,
J = 16.8, 10.0 Hz, 1H), 2.11−1.97 (m, 3H), 1.84 (dd, J = 16.8, 3.6 Hz,
1H), 1.76 (m, 1H), 1.01 (d, J = 6.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 207.5, 177.2, 141.7, 128.4, 128.0, 126.2, 89.2, 80.3,
58.5, 50.4, 30.6, 29.9, 25.6, 9.5; HRMS (ESI+) m/z: calcd for
C16H18NaO4 (M + Na)+, 297.1103; found, 297.1099.
Compounds (12) and (13). A suspension of 1 (>99% ee, 18.7 mg,
0.0759 mmol) and 10% Pd/C (55% water, 9.8 mg, 0.00416 mmol) in
AcOEt (3.4 mL) was stirred under H2 for 20 h. The mixture was
filtered on silica, and the filtrate was concentrated under reduced
pressure to give a mixture of 12 and 13 [23%, 12:13 = 1.9:1 by NMR;
Rf, 0.3 (n-hexane/AcOEt = 5/1)]. The formation of 13 was confirmed
by comparing the 1H NMR spectra of the obtained mixture with that
of 13 described in the literature.15 HPLC analysis with a chiral
stationary phase column of the mixture showed that 12 and 13 were
11% ee and 31% ee, respectively. The absolute configuration of the
obtained 13 was determined to be 4S,5R by comparison with the
retention time of (4R,5S)-13 (80% ee) described in the literature.15
These results indicated that the absolute configuration of the starting
1 was S.
Compounds (14) and (15). To a solution of ent-3a′ (80% ee, 12.5
mg, 0.0369 mmol) in dry MeOH (0.9 mL) was added NaBH4 (2.9
mg, 0.0763 mmol) at 0 °C, and the mixture was stirred at the same
temperature for 0.5 h. The reaction was quenched by addition of
water, and the mixture was concentrated under vacuum to remove
methanol. The remained mixture was filtered through silica gel. The
filtrate was concentrated under reduced pressure. The residue was
purified by preparative TLC on silica gel (n-hexane/AcOEt = 30/1)
to give 14 (8.4 mg, 67%, 77% ee) as a pale yellow oil and 15 (3.8 mg,
30% 78% ee) as a pale yellow oil.
Compound (16). Rf: 0.1 (n-hexane/AcOEt = 5/1); 1H NMR (400
MHz, CDCl3): δ 7.39−7.26 (m, 5 H), 5.12 (dd, J = 3.2, 2.4 Hz, 1H),
5.03 (d, J = 4.8 Hz, 1H), 3.19 (dt, J = 24.4, 2.1 Hz, 1H), 3.13 (dt, J =
24.4, 2.4 Hz, 1H), 2.79 (m, 1H), 1.94 (br s, 1H), 1.14 (d, J = 6.8 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 176.5, 158.3, 142.1,
128.3, 127.6, 125.8, 99.7, 73.8, 41.3, 33.7, 10.7; HRMS (ESI+) m/z:
calcd for C13H14NaO3 (M + Na)+, 241.0841; found, 241.0826.
Compound (17). Rf: 0.1 (n-hexane/AcOEt = 5/1); 1H NMR (400
MHz, CDCl3): δ 7.37−7.28 (m, 5H), 5.25 (s, 1H), 4.74 (d, J = 7.5
Hz, 1H), 3.21 (d, J = 24.8 Hz, 1H), 3.18 (d, J =24.8 Hz, 1H), 2.83
(quint, J = 7.5 Hz, 1H), 2.36 (br s, 1H), 0.95 (d, J = 7.5 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 176.6, 158.0, 141.5, 128.4,
128.1, 126.6, 100.0, 75.5, 41.5, 33.8, 14.0; HRMS (DART+) m/z:
calcd for C13H15O3 (M + H)+, 219.1021; found, 219.1032.
Compound 14. [α]2D0: −12 (c 0.42, CHCl3, 77% ee); Rf: 0.33 (n-
1
hexane/AcOEt = 3/1); H NMR (400 MHz, CDCl3): δ 7.44−7.26
(m, 10H), 4.35 (d, J = 9.6 Hz, 1H), 4.15 (d, J = 10.0 Hz, 1H), 3.54 (s,
3H), 3.44 (t, J = 9.0 Hz, 1H), 2.36 (m, J = 6.0 Hz, 1H), 2.31 (d, J =
6.0 Hz, 2H), 2.17 (br s, 1H), 1.88 (m, 1H), 0.85 (d, J = 6.4 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 173.8, 140.2, 139.5, 128.4,
128.3 (×2), 127.9, 127.7, 127.4, 85.0, 82.8, 78.1, 51.7, 47.2, 45.7, 33.7,
13.4; HRMS (ESI+) m/z: calcd for C21H24NaO4 (M + Na)+,
363.1572; found, 363.1567. The relative configuration of 14 was
determined by NOESY.
Compound (18). Rf: 0.5 (n-hexane/AcOEt = 5/1); 1H NMR (400
MHz, CDCl3): δ 7.51−7.20 (m, 10 H), 5.01 (d, J = 4.4 Hz, 1H),
4.96−4.95 (m, 1H), 2.98 (dt, J = 24.2, 2.8 Hz, 1H), 2.88 (dt, J = 24.2,
2.0 Hz, 1H), 2.64 (m, 1H), 1.07 (d, J = 7.2 Hz, 3H), 0.25 (s, 3H),
0.23 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 176.6, 158.3,
142.9, 137.7, 133.4, 129.6, 128.0, 127.7, 127.2, 126.0, 99.5, 74.5, 42.3,
33.6, 10.5, −1.2, −1.9; HRMS (ESI+) m/z: calcd for C21H24NaO3Si
(M + Na)+, 375.1392; found, 375.1365.
Compound 15. [α]2D51 +1 (c 0.38, CHCl3, 78% ee); Rf: 0.36 (n-
hexane/AcOEt = 3/1); H NMR (400 MHz, CDCl3): δ 7.39−7.36
(m, 4H), 7.33−7.29 (m, 4H), 7.26−7.25 (m, 2H), 4.67 (d, J = 9.6 Hz,
1H), 4.59 (d, J = 10.8 Hz, 1H), 4.04 (s, 1H), 3.57 (s, 3H), 2.48−2.39
(m, 2H), 2.09−2.00 (m, 3H), 0.78 (d, J = 6.8 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 173.2, 140.9, 140.1, 128.4, 128.2, 128.1,
127.7, 127.5, 127.3, 80.1, 78.6, 70.9, 51.6, 44.7, 42.3, 33.0, 14.0;
HRMS (ESI+) m/z: calcd for C21H24NaO4 (M + Na)+, 363.1572;
found, 363.1571.
(S)-MTPA-14. To a solution of 14 (1.9 mg, 0.0056 mmol),
triethylamine (2.5 mg, 0.024 mmol) and N,N′-dimethylaminopyridine
(DMAP, 0.8 mg, 0.0065 mmol) in anhydrous CH2Cl2 (0.9 mL) were
added (R)-(−)-MTPA chloride (4.5 mg) at room temperature under
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01284.
■
sı
Spectral data for all new compounds and HPLC analyses
with a chiral stationary phase (PDF)
I
https://doi.org/10.1021/acs.joc.1c01284
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Synthetic Analogues. J. Am. Chem. Soc. 2001, 123, 9974−9983.
(e) Anada, M.; Washio, T.; Shimada, N.; Kitagaki, S.; Nakajima, M.;
Shiro, M.; Hashimoto, S. A New Dirhodium(II) Carboxamidate
Complex as a Chiral Lewis Acid Catalyst for Enantioselective Hetero-
Diels−Alder Reactions. Angew. Chem., Int. Ed. 2004, 43, 2665−2668.
(4) Construction of tetrahydropyran systems by Petasis−Ferrier
rearrangement: Smith, A. B., III; Fox, R. J.; Razler, T. M. Evolution of
the Petasis-Ferrier Union/Rearrangement Tactic: Construction of
Architecturally Complex Natural Products Possessing the Ubiquitous
cis-2,6-Substituted Tetrahydropyran Structural Element. Acc. Chem.
Res. 2008, 41, 675−687.
AUTHOR INFORMATION
Corresponding Author
Kazuhiko Sakaguchi − Division of Molecular Materials
Science, Graduate School of Science, Osaka City University,
Osaka 558-8585 Sumiyoshi, Japan; orcid.org/0000-
0002-2364-0970; Email: sakaguch@sci.osaka-cu.ac.jp
■
Authors
Shoma Ariyoshi − Division of Molecular Materials Science,
Graduate School of Science, Osaka City University, Osaka
558-8585 Sumiyoshi, Japan
Takahiro Nishimura − Division of Molecular Materials
Science, Graduate School of Science, Osaka City University,
Osaka 558-8585 Sumiyoshi, Japan; orcid.org/0000-
0002-7032-8613
(5) Construction of tetrahydropyran systems by Prins cyclization:
(a) Cloninger, M. J.; Overman, L. E. Stereocontrolled Synthesis of
Trisubstituted Tetrahydropyrans. J. Am. Chem. Soc. 1999, 121, 1092−
1093. (b) Chan, K.-P.; Loh, T.-P. Lewis acid-catalyzed one-pot
crossed Prins cyclizations using allylchlorosilane as allylating agent.
Tetrahedron Lett. 2004, 45, 8387−8390. (c) Cossey, K. N.; Funk, R.
L. Diastereoselective Synthesis of 2,3,6-Trisubstituted Tetrahydropyr-
an-4-ones via Prins Cyclizations of Enecarbamates: A Formal
Synthesis of (+)-Ratjadone A. J. Am. Chem. Soc. 2004, 126, 12216−
12217. (d) Dalgard, J. E.; Rychnovsky, S. D. Oxonia-Cope Prins
Cyclizations: A Facile Method for the Synthesis of Tetrahydropyr-
anones Bearing Quaternary Centers. J. Am. Chem. Soc. 2004, 126,
15662−15663. (e) Tu, W.; Liu, L.; Floreancig, P. E. Diastereose-
lective Tetrahydropyrone Synthesis through Transition-Metal-Free
Oxidative Carbon−Hydrogen Bond Activation. Angew. Chem., Int. Ed.
2008, 47, 4184−4187. (f) Han, X.; Peh, G.; Floreancig, P. E. Prins-
Type Cyclization Reactions in Natural Product Synthesis. Eur. J. Org.
Chem. 2013, 2013, 1193−1208.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01284
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Japan Society of the Promotion of
Science (JSPS KAKENHI grant numbers 17K05935 and
20K05515) for supporting this work.
REFERENCES
(6) Brawn, R. A.; Panek, J. S. Preparation and Use of
Enantioenriched Allenylsilanes for the Stereoselective Synthesis of
Homopropargylic Ethers. Org. Lett. 2007, 9, 2689−2692.
■
(1) Construction of tetrahydropyran systems by oxa-Michael
cyclization: (a) Reiter, M.; Turner, H.; Gouverneur, V. Intramolecular
Hetero-Michael Addition of β-Hydroxyenones for the Preparation of
Highly Substituted Tetrahydropyranones. Chem. Eur. J. 2006, 12,
7190−7203. (b) Nising, C. F.; Bräse, S. The oxa-Michael reaction:
from recent developments to applications in natural product synthesis.
Chem. Soc. Rev. 2008, 37, 1218−1228. (c) Fuwa, H.; Mizunuma, K.;
Matsukida, S.; Sasaki, M. A new strategy for the synthesis of
substituted dihydropyrones and tetrahydropyrones via palladium-
catalyzed coupling of thioesters. Tetrahedron 2011, 67, 4995−5010.
(d) Yao, H.; Ren, J.; Tong, R. A short and flexible route to
tetrahydropyran-4-ones via conjugated nitrile oxides cycloaddition
and oxa-Michael cyclization: a concise diastereoselective total
synthesis of ( )-diospongin A. Chem. Commun. 2013, 49, 193−195.
(e) Bosset, C.; Angibaud, P.; Stanfield, I.; Meerpoel, L.; Berthelot, D.;
Guérinot, A.; Cossy, J. Iron-Catalyzed Synthesis of C2 Aryl- and N-
Heteroaryl Substituted Tetrahydropyrans. J. Org. Chem. 2015, 80,
12509−12525.
(7) (a) Okada, T.; Sakaguchi, K.; Shinada, T.; Ohfune, Y. Au-
catalyzed cyclization of allenylsilanes. Regioselective conversion to 2-
amino-4-silylmethylene γ-butyrolactone. Tetrahedron Lett. 2011, 52,
5740−5743. (b) Cadierno, V. Gold-Catalyzed Addition of Carboxylic
Acids to Alkynes and Allenes: Valuable Tools for Organic Synthesis.
Catalysts 2020, 10, 1206−1241.
(8) Masse, C. E.; Panek, J. S. Diastereoselective reactions of chiral
allyl- and allenylsilanes with activated C=X π-bonds. Chem. Rev. 1995,
95, 1293−1316.
(9) The relative configuration of 3a, 7a, 8a, and 14 was determined
1
by NOESY and/or J values in H NMR (Supporting Information).
(10) Paju, A.; Kanger, T.; Pehk, T.; Lindmaa, R.; Muurisepp, A.-M.;
̈ ̈
Lopp, M. Asymmetric oxidation of 3-alkyl-1,2-cyclopentanediones.
Part 2: Oxidative ring cleavage of 3-alkyl-1,2-cyclopentanediones:
synthesis of 2-alkyl-γ-lactone acids. Tetrahedron: Asymmetry 2003, 14,
1565−1573.
(11) Markó, I. E.; Mekhalfia, A. Regiocontrol in the intramolecular
silyl modified sakurai (ISMS) reaction. An efficient synthesis of a
Dacus oleae fruit fly pheromone. Tetrahedron Lett. 1992, 33, 1799−
1802.
(2) Construction of tetrahydropyran systems by Japp−Maitland
reaction: (a) Clarke, P. A.; Martin, W. H. C. Diastereoselective
Synthesis of Highly Substituted Tetrahydropyran-4-ones. Org. Lett.
2002, 4, 4527−4529. (b) Clarke, P. A.; Martin, W. H. C. Exploiting
the Maitland−Japp reaction: a synthesis of ( )-centrolobine.
Tetrahedron 2005, 61, 5433−5438. (c) Clarke, P. A.; Martin, W. H.
C.; Hargreaves, J. M.; Wilson, C.; Blake, A. J. Revisiting the
Maitland−Japp reaction. Concise construction of highly functional-
ised tetrahydropyran-4-ones. Chem. Commun. 2005, 1061−1063.
(3) Construction of tetrahydropyran systems by hetero-Diels−Alder
cycloaddition: (a) Johannsen, M.; Joergensen, K. A. Asymmetric
Hetero Diels-Alder Reactions and Ene Reactions Catalyzed by Chiral
Copper(II) Complexes. J. Org. Chem. 1995, 60, 5757−5762.
(12) γ-Keto carboxylic acid 410 (54%) and 3a (23%) were obtained.
(13) Enantiopure 1 (>99% ee) was prepared by the optical
resolution of racemic 1 using HPLC with a chiral stationary phase
column.
(14) The diastereoselectivity of 3r (3r:3r′ = 7:1) and the decrease in
optical purity of 3r′ (76% ee) suggested that partial epimerization
from 3r to ent-3r′ (or from 3a to ent-3a′) occurred. It is unknown at
what stage the epimerization occurred during the conversion.
(15) Pace, V.; Rae, J. P.; Harb, H. Y.; Procter, D. J. NHC−Cu(I)
catalysed asymmetric conjugate silyltransfer to unsaturated lactones:
application inkinetic resolution. Chem. Commun. 2013, 49, 5150−
5152.
(16) Sakaguchi, K.; Kawamura, Y.; Saito, S.; Ohfune, Y. Pd-C
Assisted Synthesis of cis-2,4-Disubstituted γ-Butyrolactones and their
Properties for Ferroelectric Liquid Crystals. Synlett 1997, 1997, 624.
(17) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. High-field
FT NMR application of Mosher’s method. The absolute config-
̊
(b) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. Asymmetric Hetero-
Diels-Alder Reactions Catalyzed by Chiral (Salen)Chromium(III)
Complexes. J. Org. Chem. 1998, 63, 403−405. (c) Dossetter, A. G.;
Jamison, T. F.; Jacobsen, E. N. Highly Enantio- and Diastereoselective
Hetero-Diels−Alder Reactions Catalyzed by New Chiral Tridentate
Chromium(III) Catalysts. Angew. Chem., Int. Ed. 1999, 38, 2398−
2400. (d) Thompson, C. F.; Jamison, T. F.; Jacobsen, E. N.
FR901464: Total Synthesis, Proof of Structure, and Evaluation of
J
https://doi.org/10.1021/acs.joc.1c01284
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
urations of marine terpenoids. J. Am. Chem. Soc. 1991, 113, 4092−
4096.
(18) Wanner, M. J.; Boots, R. N. A.; Eradus, B.; Gelder, R.;
Maarseveen, J. H.; Hiemstra, H. Organocatalytic Enantioselective
Total Synthesis of (−)-Arboricine. Org. Lett. 2009, 11, 2579−2581.
(19) Ghobril, C.; Sabot, C.; Mioskowski, C.; Baati, R. TBD-
Catalyzed Direct 5- and 6-enolexo Aldolization of Ketoaldehydes. Eur.
J. Org. Chem. 2008, 2008, 4104−4108.
(20) Uyeda, C.; Jacobsen, E. N. Enantioselective Claisen Rearrange-
ments with a Hydrogen-Bond Donor Catalyst. J. Am. Chem. Soc. 2008,
130, 9228−9229.
K
https://doi.org/10.1021/acs.joc.1c01284
J. Org. Chem. XXXX, XXX, XXX−XXX