Copper-Catalyzed Asymmetric Synthesis of Bicyclo[3. n.1]alkenones

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Copper-Catalyzed Asymmetric Synthesis of Bicyclo[3.n.1]alkenones

Zhehui Liao, Jiantao Zhang, Tongxiang Cao,* and Shifa Zhu*

Cite This: J. Org. Chem. 2021, 86, 5388 −5400

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sı Supporting Information

ABSTRACT: A series of highly strained bicyclo[3.n.1]alkenones have been

successfully constructed in good-to-excellent enantioselectivities and moderate-to-

good yields via copper-catalyzed formal [3+3] cycloaddition. The versatile chiral

cycloadducts could be selectively converted into various valuable bridge systems,

which hold considerable potential for the construction of natural and bioactive

compounds containing a [3.n.1] moiety.

he highly strained bicyclo[3.n.1] system is an important

through aminocatalysis. For examples, Barluenga and Hu

structure that exists in a large number of bioactive natural

products (Scheme 1). For example, hyperforin has been

independently developed a transition-metal catalytic system to

access such skeleton by desymmetrization of enamine.

Similarly, Jia and their co-workers introduced an amine/

copper dual catalytic protocol to synthesize a benezo-fused

Scheme 1. Natural Products Containing Bicyclo[3.n.1]

Skeletons

bicyclo compound via desymmetrization of cyclohexone. In

addition, a double activation strategy by combining amino-

catalysis and N-heterocyclic carbene catalysis was adopted by

Rodriguez and Coquerel, which enabled a direct enantiose-

lective entry to such bridged bicyclic compound. Lately,

several enantioselective versions by using other organo-

catalysts, such as phosphoric acid, dihydroquinine, bifunc-

tional aminoquinine-thiourea, and transition metal, were

reported as well. Considering the limited ability of the

organocatalyst in substrate activation and a relative high

catalyst loading, we envisioned that transition-metal catalysis

might be able to circumvent these challenges in a

complementary way.

Structurally, the bicyclo[3.n.1]octene 4 could be regarded as

a formal [3+3] cycloaddition adduct via a bridge-type

Robinson annulation of 2 with 1 via intermediate 3. The

proved versatile biological properties including antidepression

and inhibition of tumor invasion. Huperzine A, a natural

cholinesterase inhibitor from a Chinese herb, was recently

unveiled that it might be used as a disease-modifying treatment

for Alzheimer’s disease (AD), and the phase II trial is under

critical γ-quaternary chiral center, which was less studied,

comparing to the corresponding β-carbon stereocenter,

could be established by a regio- and enantioselective

intermolecular Michael addition reaction (Scheme 2).

As part of our continuous eﬀort in asymmetrical synthesis by

c,d

way.

N-Methylwelwitindolinone D and its congeners

display a wide variety of biological activities, ranging from

antifungal eﬀects to microtubule depolymerization and reversal

of P-glycoprotein-mediated multidrug resistance in human

using a chiral bisoxazoline (Box) ligand, the combination of

bisoxazoline and several triﬂate salts were tested ﬁrst using

methyl-β-ketoester 1a and enone 2a as model substrates

e,f

carcinoma cells. Therefore, developing methods to construct

such bicyclo [3.n.1] skeleton is highly desired, especially the

asymmetric version by using simple materials.

(

Table 1, entries 1−3). The results showed that the

bisoxazoline L1/Cu(OTf) catalytic system functioned better

During the past decades, diverse synthetic methods have

been accumulated in the construction of this important

skeleton. Typically, these methods were based on conia-ene-

than others, which aﬀorded intermediate 3a in a promising

Received: January 19, 2021

Published: March 23, 2021

type cyclization, pinacol rearrangement, tandem Michael/

aldol reaction, biomimic dearomatization annulation, trans-

annulation, double Tsuji−Trost cycloaddition, and Eﬀen-

berger cyclization. Nevertheless, the methods for the

enantioenriched bicyclo[3.n.1] system with a quaternary

stereocenter are still limited, and most of them proceeded

2021 American Chemical Society

388

J. Org. Chem. 2021, 86, 5388−5400

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Note

Scheme 2. Access to the Bicyclo[3.n.1] System with a γ-

Quaternary Chiral Stereocenter

dismal enantioselectivities were obtained (entries 8−10).

However, the racemic product was obtained using bulky

ligand L7 (entry 11). Based on the above feedbacks, the side

arm-Box L1 was chosen as the chiral ligand for further

optimization. It was found that decreasing the temperature had

slightly beneﬁcial eﬀect on enantioselectivity (entries 12 and

3). Finally, the inﬂuence of steric eﬀect was explored (entries

4 and 15). The enantioselectivity could be further enhanced

to 92% ee with good yield when isopropyl ester 1c was used as

substrate (entry 15). Other ligands and solvents were screened

as well, but no further improvements were obtained. It is

noteworthy that the superiority of side arm-Box L1 in

asymmetric induction might result from its ability to form a

compact octahedral intermediate with the branch side arm

Table 1. Optimization of Reaction Conditions

posed in d_Zdirection (see Supporting Information, page S5,

14c,15b,c

for the proposed induction model).

After the method for enantiomerically enriched 1,5-

dicarbonyl product 3 was established, we set out to identify

a suitable catalytic system that can achieve the intramolecular

cyclization easily and economically. It is exciting to ﬁnd that

when the simple Brønsted acid (TfOH) was employed as

catalyst, the desired product 4 was obtained in a high yield, and

the ee value remained. (Table 2)

Table 2. Optimization of Reaction Conditions

The reaction was performed with 3 (0.1 mmol), TfOH (15 mol %),

and DCE (0.1 M) under an air atmosphere for 0.5 h

Under the optimal conditions (Table 1, entry 15, and Table

), the substrate scope of the reaction was then explored. As

shown in Table 3, the catalytic system worked smoothly with a

series of β-ketoesters 1 and enones 2 to aﬀord 4a−u in

moderate to good yields and excellent enantioselectivities

(

87%−95%). The reaction was compatible with both electron-

withdrawing and electron-donating groups on the aromatic

rings (4g and 4l). Furthermore, the substrates with

heteroaromatic substituents (4s−u) generated the products

in moderate yields and good enantioselectivies. Other β-

ketoesters with diﬀerent ring sizes could also be successfully

employed to aﬀord the expected structure; however, the

enantioselectivity decreased when the ring size increased (4v−

w).

Catalyst (20 mol %) and L1 (24 mol %) were stirred in DCE (0.1

M) for 5 min, and then 1 (0.2 mmol) and 2a (0.24 mmol) were

added; The mixture was tirred for 24 h, isolated yield. 20 mol % (R)-

BNP acid was added. 20 mol % TfOH was added. 10 mol %

Cu(OTf) , 12 mol %, 72 h. 10 mol % Cu(OTf) , 12 mol % L, 48 h.

yield and enantiomeric excess (entry 1). For the purpose of

merging Michael addition, aldol cyclization, and dehydration in

one operation, several acids as cocatalyst were also screened.

However, instead of the desired bicyclic adduct 4a, the

intermediate 3a was obtained in a compromised yield and

enantioselectivity (entries 4 and 5).

Consequently, more attention was paid to developing a

consequential stepwise process, which was initiated by

evaluating the ligands eﬀects in the construction of

intermediate 3a. The Box ligands (L2, L3) without side arm

could promote the Michael addition process eﬃciently at

ambient temperature to give 3a in a slightly improved yield,

but in moderate enantioselectivity (entries 6 and 7). When the

coplanar tridentate Pyboxes (L4, L5, and L6) were used,

Encouraged by the above success, we turned to exploit a new

type of substrate with two diﬀerent enone motifs owing to the

potential application of the diene products. The cinnamalde-

hyde derivative 5a was ﬁrst tested. Surprisingly, the reaction

displayed excellent regio- and enantioselectivity to give 7a as a

single product in 93% ee. As shown in Table 4, most substrates

gave moderate-to-good yields and excellent enantioselectivities

(7a−e). However, the enone bearing strong electron-donating

group (−OCH ) failed to provide the corresponding

cyclization product in a good yield (7f) under the acid

condition. We have investigated several Lewis acids and found

that, when the TfOH was replaced by Sc(OTf) , the

bicyclo[3.2.1] product (7f) was obtained in a higher yield

with a slightly decreased enantioselectivity.

389

J. Org. Chem. 2021, 86, 5388−5400

The Journal of Organic Chemistry

Note

Table 3. Scope of the Substrates

Table 4. Scope of the Substrates

The Cu(OTf) (10 mol %) and L1 (12 mol %) in DCE (0.1 M)

were stirred for 5 min. Then, 1c (0.2 mmol) and 5 (0.24 mmol) were

added, and the mixture was stirred at 0 °C for 35−96 h. Puriﬁed 6

(

0.1 mmol) was treated with TfOH (5 mol %) in DCE (0.1M) at 100

C for 10−120 min. The reaction was conducted with 6f (0.1 mmol)

and Sc(OTf) (5 mol %) in 100 °C for 10 min.

Table 5. One-Pot Relay Catalytic Annulation

The Cu(OTf) (10 mol %) and L1 (12 mol %) in DCE (0.1 M)

were stirred for 5 min; then, 1 (0.1 mmol) and 2/5 (0.12 mmol) were

added, and then stirred at 0 °C until the reaction had ﬁnished. Finally,

TfOH (50 mol %) was added, and the mixture was heated at 100 °C

for 5−60 min.

The Cu(OTf) (10 mol %) and L1 (12 mol %) in DCE (0.1 M)

were stirred for 5 min. Then, 1 (0.2 mmol) and 2 (0.24 mmol) were

added, and the mixture was stirred at 0 °C for 35−96 h. Puriﬁed 3

(

0.1 mmol) was treated with TfOH (15 mol %) in DCE (0.1 M) at

00 °C for 10−120 min. The reaction was conducted with 3 (0.1

With the chiral bicyclo[3.2.1] products 4 and 7 in hand,

further transformations were carried out to demonstrate the

potential applications of these products (Scheme 3). The C

O and carbon−carbon double bond of 4c could be easily

reduced to produce 8 and 9 independently, and the

stereostructure was conﬁrmed by the NOE spectrum.

Considering the importance of the bridged CC bond in a

natural product (Scheme 1), the diene 10 was then synthesized

via Wittig oleﬁnation from 4c. Inspired by the architecture of

the bioactivity-enriched huperzine A, further chemical trans-

formation of 10 was performed. The ester group of 10 could

be eﬃciently converted to a carboxyl group, which was used

directly without puriﬁcation for the following copper-catalyzed

mmol) and Sc(OTf) (20 mol %) in 100 °C for 10−120 min.

For the purpose of simplifying the processes, a sequential

one-pot synthesis was tried. As shown in Table 1, directly

introducing TfOH to the reaction system at the initial process

not only failed to give the desired bicyclo[3.2.1] product but

also was detrimental to the yield and enantioselectivity of the

Michael addition reaction. So, a sequential addition procedure

by adding TfOH when the ﬁrst process had ﬁnished was

applied. Gratifyingly, this one-pot catalytic relay annulation

exhibited superior eﬃciency with the corresponding

bicyclo[3.2.1]alkenones obtained in equally well enantioselec-

tivities (Table 5).

Curtius rearrangement the protocol disclsoed by Lu lately,

and the carbamate product 11 was eventually obtained in an

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J. Org. Chem. 2021, 86, 5388−5400

The Journal of Organic Chemistry

Note

Procedure for the Preparation of 1e. LDA (10 mmol, 2.5

mmol/L in THF) was added dropwise to a solution of cyclo-

heptanone (560 mg, 5 mmol) in dry THF (8 mL) at −78 °C, and

then the solution was stirred for 1 h. Isobutyryl chloride (612 mg, 6

mmol) in 5 mL of dry THF was added via syringe. The mixture was

warmed to room temperature over 4 h. The reaction was quenched

Scheme 3. Diversiﬁcation of the Bicyclo[3.n.1]alkenones

with saturated NH Cl solution (10 mL). The organic phase was

washed with NaCl solution (3 × 20 mL), dried with Na SO , and

concentrated under a reduced vacuum. The residue was chromatog-

raphy with EtOAc/petroleum ether (1:15) to give the desired product

(

380 mg, 40%) as a colorless oil. H NMR (500 MHz, CDCl ): δ

2.83 (s, 0.3 H), 5.29−4.91 (m, 0.9 H), 3.49 (dd, J = 10.2, 3.9 Hz,

.6H), 2.84−2.51 (m, 1.3H), 2.51−2.34 (m, 1.3H), 2.07 (m, 0.7H),

.98−1.80 (m, 2.7H), 1.77−1.65 (m, 0.7H), 1.56−1.62 (m,1.6H),

.58−1.37 (m, 2H), 1.37−1.14 (m, 6H). C{ H} NMR (126 MHz,

CDCl ): δ 209.1, 179.3, 172.7, 170.1, 102.0, 69.0, 67.7, 59.1, 43.1,

5.4, 32.0, 29.7, 27.9, 27.6, 27.4, 24.6, 24.4, 24.3, 21.9, 21.7, 21.6. IR

−

(KBr, cm ): 2950, 1737, 1706, 1453, 1306, 1242, 1106, 937, 909.

HRMS (ESI-TOF): m/z [M + H] calcd for C H O , 199.1329;

found, 199.1324.

General Procedure for the Preparation of 3/6. Copper(II)

triﬂuoromethanesulfonate (7.0 mg) and L1 (12 mg) in 1 mL of dry

DCE were stirred for 5 min in a 25 mL Schlenk tube. Ketene 2/5

(0.24 mmol) and β-Ketoesters (0.2 mmol) 1 were dissolved in 1 mL

of dry DCE and added dropwise to the tube. The reaction was stirred

at 0 °C until substrate 1 was completely consumed. The solvent was

removed under a reduced vacuum, and the resulting mixture was

puriﬁed by silica gel chromatography (EtOAc/petroleum ether =

1:10) to give the product 3/6. Racemic samples were prepared by

using the same procedure with copper(II) triﬂuoromethanesulfonate

as a catalyst.

overall yield of 63% for two steps. Furthermore, dienone 7a

could be used as a valid diene for the Diels−Alder reaction

with p-benzoquinone, giving the unexpected oxidized adduct

2 in 50% yield. The stereochemistry was well retained in all of

these transformations.

Methyl 2-Oxo-1-(3-oxo-3-phenylpropyl)cyclopentane-1-carbox-

In summary, we have developed a copper-catalyzed formal

3+3] cycloaddition, which delivered a series of chiral

ylate (3a). Yield: 81% (44 mg), colorless oil, R = 0.6 (EtOAc/

[

petroleum ether = 1:10). H NMR (500 MHz, CDCl ): δ 7.96 (d, J =

bicyclo[3.n.1]alkenone frameworks with an all-carbon quater-

nary stereocenter in moderate yields and good-to-excellent

enantioselectivities. In addition, a one-pot catalytic relay

annulation was also established. The reaction was proposed

to proceed through a tandem of Michael addition and

intramolecular aldol cyclization. The functional group enriched

chiral bicyclo[3.n.1] products could be selectively transformed

into various value-added bridged systems via Curtius

rearrangement, DA-reaction, oleﬁnation, and reduction,

which hold considerable potential for the construction of

natural or bioactive compounds containing the bicyclo[3.n.1]

skeletons.

(

.6 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 3.73

d, J = 2.1 Hz, 3H), 3.28−3.19 (m, 1H), 3.08−2.95 (m, 1H), 2.57−

.50 (m, 1H), 2.47−2.40 (m, 1H), 2.39−2.33 (m, 1H), 2.33−2.26

(

m, 1H), 2.16−2.08 (m, 1H), 2.07−1.95 (m, 3H). C{ H} NMR

(126 MHz, CDCl ): δ 214.7, 199.3, 171.9, 136.7, 133.1, 128.6, 128.1,

−

59.2, 52.6, 38.0, 34.4, 34.1, 27.8, 19.6. IR (KBr, cm ): 3064, 1731,

1684, 1446, 1217, 1157, 992, 842, 765, 745, 692. HRMS (ESI-TOF):

m/z [M + Na] calcd for C H O Na, 297.1097; found, 297.1101.

16 18

HPLC: OJH column, 90:10 hexanes/isopropanol, 0.80 mL/min, t =

(major) 34.7 min, (minor) 38.1 min, 90% ee. [α] +13.1° (c 0.98,

EtOAc)

Ethyl 1-(3-(4-Methoxyphenyl)-3-oxopropyl)-2-oxocyclopentane-

-carboxylate (3b). Yield: 83% (48 mg), colorless oil, R = 0.6

(EtOAc/petroleum ether = 1:10). H NMR (500 MHz, CDCl ): δ

EXPERIMENTAL SECTION

General Information. All reactions were carried out under N in

.96 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.6 Hz,

■

2H), 4.19 (q, J = 7.2 Hz, 2H), 3.30−3.19 (m, 1H), 3.05−2.95 (m,

a Schlenk tube under otherwise noted, H, C, F NMR, and 2D

NMR spectra were recorded on a Bruker AVANCE 400 and Bruker

1H), 2.57−2.48 (m, 1H), 2.48−2.39 (m, 1H), 2.39−2.23 (m, 2H),

2.16−1.92 (m, 4H), 1.26 (t, J = 7.2 Hz, 3H). C{ H} NMR (126

AVANCE 500. H NMR and C NMR chemical shifts were

determined relative to an internal standard, TMS at δ 0.0. Chemical

shifts (δ) are reported in ppm, and coupling constants (J) are in hertz

MHz, CDCl ): δ 214.8, 199.4, 171.5, 136.7, 133.1, 128.6, 128.1, 61.5,

−

59.2, 38.0, 34.4, 34.1, 27.8, 19.6, 14.10. IR (KBr, cm ): 3064, 2960,

1731, 1684, 1463, 1217, 1157, 1217, 1157, 992, 745, 692. HRMS

(ESI-TOF): m/z [M + Na] calcd for C H O Na, 311.1254; found,

(

Hz). The following abbreviations were used to explain the

multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m =

multiplet. HRMS spectra were recorded on an Agilent UHD-Accurate

Mass Q-TOF LC/MS. HPLC analysis was performed on WHELK-

O1, OD-H, OJ-H, and IA columns. X-ray crystallographic analysis was

performed on an Agilent SuperNova, Dual, Cu at zero, AtlasS2

diﬀractometer. Melting points were determined on a JH30 melting

point apparatus bought from JIAHANG. Optical rotations were

measured on ADP440+B+S. Infrared (IR) spectra were recorded on a

Nicolet 210 spectrophotometer and were recorded in a potassium

bromide (KBr) pellet.

311.1257. HPLC: OJH column, 90:10 hexanes/isopropanol, 0.80

mL/min, t = (major) 21.7 min, (minor) 23.0 min, 91% ee. [α]

+24.3° (c 0.64, DCM).

Isopropyl 2-Oxo-1-(3-oxo-3-phenylpropyl)cyclopentane-1-car-

boxylate (3c). Yield: 84% (48 mg), colorless oil, R

petroleum ether = 1:10). H NMR (400 MHz, CDCl

= 0.6 (EtOAc/

): δ 7.95 (d, J =

7.6 Hz, 2H), 7.53 (t, 1H), 7.44 (t, J = 7.6 Hz, 2H), 5.04 (hept, J = 6.3

Hz, 1H), 3.25 (ddd, J = 16.1, 10.2, 5.3 Hz, 1H), 2.98 (ddd, J = 17.5,

10.2, 5.1 Hz, 1H), 2.52−2.21 (m, 4H), 2.13−1.91 (m, 4H), 1.25−

1.22 (m, 6H). C{ H} NMR (101 MHz, CDCl ): δ 214.8, 199.5,

Compounds 1a, 1b, and L1−L26 and solvents were commercial

171.0, 136.7, 133.0, 128.6, 128.1, 69.0, 59.2, 38.0, 34.4, 34.0, 27.7,

21.7, 21.6, 19.6. IR (KBr, cm ): 3062, 2978, 1748, 1719, 1685, 1460,

−1

and used without puriﬁcation. Compound 1c, 1d, 2, and 5

were synthesized according to the literature procedures. All of these

compounds are known.

1372, 1260, 1236, 1104, 745, 693. HRMS (ESI-TOF): m/z [M +

Na] calcd for C H O Na, 325.1410; found, 325.1415. HPLC:

391

J. Org. Chem. 2021, 86, 5388−5400

The Journal of Organic Chemistry

Note

WHELK column, 95:5 hexanes/isopropanol, 0.80 mL/min, t

9.1 Hz), 115.8 (C−F, J

= 19.1 Hz), 115.5 (C−F, J

= 19.1

C−F

major) 34.2 min, (minor) 31.6 min, 92% ee. [α]²−4.3° (c 0.80,

Hz), 69.0, 59.1, 38.0, 34.5, 34.0, 27.7, 21.7, 21.6, 19.6. F NMR (376

MHz, CDCl ): δ −105.40. IR (KBr, cm ): 3075, 2979, 1749, 1720,

1478, 1267, 1104, 996, 826, 763 HRMS (ESI-TOF): m/z [M + Na]

calcd for C H FO Na, 343.1316; found, 343.1314.

Isopropyl 1-(3-(4-Chlorophenyl)-3-oxopropyl)-2-oxocyclopen-

tane-1-carboxylate (3j). Yield: 68% (46 mg), colorless solid, m.

(

−

EtOAc)

Isopropyl 2-Oxo-1-(3-oxo-3-(p-tolyl)propyl)cyclopentane-1-car-

boxylate (3d). Yield: 67% (42 mg), colorless oil, R = 0.6 (EtOAc/

18 21

petroleum ether = 1:10). H NMR (400 MHz, CDCl ): δ 7.86 (d, J =

.9 Hz, 2H), 7.25 (d, J = 7.8 Hz, 2H), 5.05 (hept, 1H), 3.27−3.13 (m,

H), 3.04−2.86 (m, 1H), 2.54−2.44 (m, 1H), 2.45−2.37 (m, 4H),

p.=53−57 °C, R = 0.6 (EtOAc/petroleum ether = 1:10). H NMR

(400 MHz, CDCl ): δ 7.91 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz,

.38−2.21 (m, 2H), 2.13−1.91 (m, 4H), 1.24 (d, J = 6.2 Hz, 6H).

C{ H} NMR (101 MHz, CDCl ): δ 214.9, 199.2, 171.0, 143.8,

2H), 5.04 (hept, J = 6.2 Hz, 1H), 3.31−3.18 (m, 1H), 3.03−2.90 (m,

34.3, 129.3, 128.2, 69.0, 59.3, 38.0, 34.3, 33.9, 27.8, 21.7, 21.6, 19.6.

1H), 2.54−2.38 (m, 2H), 2.38−2.19 (m, 2H), 2.15−1.89 (m, 4H),

−

IR (KBr, cm ): 3032, 2978, 1748, 1718, 1607, 1374, 1233, 1104,

1.28−1.20 (m, 6H). C{ H} NMR (101 MHz, CDCl ): δ 214.9,

18, 568. HRMS (ESI-TOF): m/z [M + Na] calcd for C H O Na,

198.3, 171.0, 139.5, 135.1, 129.5, 128.9, 69.1, 59.0, 38.0, 34.6, 34.0,

−

39.1567; found, 339.1572.

Isopropyl 1-(3-(4-Isopropylphenyl)-3-oxopropyl)-2-oxocyclopen-

tane-1-carboxylate (3e). Yield: 75% (47 mg), colorless oil, R = 0.6

27.6, 21.7, 21.6, 19.6. IR (KBr, cm ): 3042, 2968, 2777, 1717, 164,

150, 137, 1099, 829, 754, 526. HRMS (ESI-TOF): m/z [M + Na]⁺

calcd for C H ClO Na 359.1021; found, 359.1013.

Isopropyl 1-(3-(4-Bromophenyl)-3-oxopropyl)-2-oxocyclopen-

tane-1-carboxylate (3k). Yield: 82% (62 mg), yellow solid, mp

56−60 °C, R = 0.6 (EtOAc/petroleum ether = 1:10). H NMR (400

MHz, CDCl ): δ 7.82 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 7.9 Hz, 2H),

18 21

(EtOAc/petroleum ether = 1:10). H NMR (500 MHz, CDCl ): δ

7.90 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.05 (hept, J = 6.3

Hz, 1H), 3.28−3.17 (m, 1H), 3.02−2.89 (m, 2H), 2.53−2.38 (m,

H), 2.36−2.22 (m, 2H), 2.11−1.93 (m, 4H), 1.28−1.23 (m, 12H).

C{ H} NMR (126 MHz, CDCl ): δ 214.8, 199.1, 171.0, 154.5,

5.04 (hept, J = 12.5, 6.3, 5.7 Hz, 1H), 3.29−3.17 (m, 1H), 3.00−2.88

34.6, 128.4, 126.6, 69.0, 59.3, 38.0, 34.3, 34.2, 34.0, 27.8, 23.7, 21.7,

(m, 1H), 2.54−2.38 (m, 2H), 2.37−2.27 (m, 1H), 2.27−2.16 (m,

−

1.6, 19.6. IR (KBr, cm ): 2967, 1748, 1720, 1606, 1460, 1260,

1H), 2.14−1.92 (m, 4H), 1.27−1.20 (m, 6H). C{ H} NMR (101

104, 831, 751. HRMS (ESI-TOF): m/z [M + Na] calcd for

MHz, CDCl ): δ 214.9, 198.5, 171.0, 135.4, 131.9, 129.6, 128.2, 69.1,

−

C H O Na, 367.1880; found, 367.1882.

59.0, 38.0, 34.6, 34.0, 27.6, 21.7, 21.6, 19.6. IR (KBr, cm ): 3090,

2973, 1749, 1682, 1580, 1241, 1157, 822, 735, 566. HRMS (ESI-

Isopropyl 1-(3-(4-(tert-Butyl)phenyl)-3-oxopropyl)-2-oxocyclo-

pentane-1-carboxylate (3f). Yield: 91% (64 mg), colorless oil, R =

TOF): m/z [M + H] calcd for C H BrO , 381.0696; found,

18 22

.6 (EtOAc/petroleum ether = 1:10). H NMR (500 MHz, CDCl ):

381.0698.

δ 7.91 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 5.11−4.97 (m,

Methyl 4-(3-(1-(Isopropoxycarbonyl)-2-oxocyclopentyl)-

H), 3.33−3.12 (m, 1H), 3.04−2.81 (m, 1H), 2.58−2.19 (m, 4H),

propanoyl)benzoate (3l). Yield: 65% (46 mg), Yellow solid,

.17−1.88 (m, 4H), 1.34 (s, 9H), 1.27−1.15 (m, 6H). C{ H} NMR

m.p.=75−79 °C, R

= 0.4 (EtOAc/petroleum ether = 1:10).

(

126 MHz, CDCl ): δ 214.9, 199.2, 171.0, 156.8, 134.1, 128.1, 125.5,

NMR (500 MHz, CDCl

): δ 8.11 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 8.3

9.0, 59.3, 38.0, 35.1, 34.3, 34.0, 31.1, 27.8, 21.7, 21.6, 19.6. IR (KBr,

Hz, 2H), 5.05 (hept, J = 6.3 Hz, 1H), 3.95 (s, 3H), 3.36−3.26 (m,

−

cm ): 3066, 2971, 1752, 1604, 1463, 1408, 1265, 996, 837, 736.

HRMS (ESI-TOF): m/z [M + Na] calcd for C H O Na, 381.2036;

1H), 3.08−2.98 (m, 1H), 2.54−2.39 (m, 2H), 2.38−2.21 (m, 2H),

2.15−1.95 (m, 4H), 1.27−1.22 (m, 6H). C{ H} NMR (126 MHz,

found, 381.2033.

CDCl ): δ 214.9, 199.0, 171.0, 166.2, 139.9, 133.8, 129.8, 128.0, 69.1,

−

Isopropyl 2-Oxo-1-(3-oxo-3-phenylpropyl)cyclopentane-1-car-

59.0, 52.4, 38.0, 34.6, 34.4, 27.5, 21.7, 21.6, 19.6. IR (KBr, cm ):

2978, 1723, 1690, 1441, 1406, 1280, 1107, 996, 756. HRMS (ESI-

TOF): m/z [M + Na] calcd for C H O Na, 383.1465; found,

boxylate (3g). Yield: 86% (57 mg), white solid, mp 75−80 °C, R

0.6 (EtOAc/petroleum ether = 1:10). H NMR (400 MHz,

CDCl ): δ 7.95 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 5.05 (p,

383.1467.

J = 6.3 Hz, 1H), 3.86 (s, 3H), 3.19 (ddd, J = 16.1, 10.4, 5.3 Hz, 1H),

Isopropyl 2-Oxo-1-(3-oxo-3-phenylpropyl)cyclopentane-1-car-

.92 (ddd, J = 16.2, 10.4, 5.1 Hz, 1H), 2.56−2.44 (m, 1H), 2.44−2.38

boxylate (3m). Yield: 64% (49 mg), white solid, m.p.=114−117

(

m, 1H), 2.37−2.31 (m, 1H), 2.31−2.19 (m, 1H), 2.14−1.92 (m,

°C, R = 0.4 (EtOAc/petroleum ether = 1:10). H NMR (400 MHz,

H), 1.20−1.27 (m, 6H). C{ H} NMR (101 MHz, CDCl ): δ

CDCl ): δ 8.06 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.65 (d,

14.9, 198.1, 171.0, 163.5, 130.4, 129.8, 113.7, 69.0, 59.3, 55.5, 38.0,

J = 7.6 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.42 (t, 1H), 5.15−5.00 (m,

−

4.3, 33.7, 28.0, 21.7, 21.6, 19.6. IR (KBr, cm ): 3309, 2975, 2844,

1H), 3.38−3.25 (m, 1H), 3.11−2.98 (m, 1H), 2.59−2.24 (m, 4H),

747, 1718, 1675, 1605, 1259, 1028, 990, 907, 766. HRMS (ESI-

2.21−1.95 (m, 4H), 1.30−1.25 (m, 6H). C{ H} NMR (101 MHz,

TOF): m/z [M + Na] calcd for C H O Na, 355.1516; found,

CDCl ): δ 215.0, 199.2, 171.1, 145.8, 139.9, 135.5, 128.9, 128.7,

55.1507.

128.2, 127.2, 127.3, 69.1, 59.3, 38.0, 34.5, 34.3, 27.8, 21.7, 21.6, 19.7.

−

-(3-(4-(Methylthio)phenyl)-3-oxopropyl)-2-oxocyclopentane-1-

IR (KBr, cm ): 3052, 1979, 1746, 171, 1462, 1406, 1263, 1108, 997,

932, 763, 698. HRMS (ESI-TOF): m/z [M + Na]⁺calcd for

C H O Na, 401.1723; found, 401.1722.

carboxylate (3h). Yield: 64% (47 mg), colorless oil, R = 0.6 (EtOAc/

petroleum ether = 1:10). H NMR (500 MHz, CDCl ): δ 7.88 (d, J =

24 26

.6 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 5.04 (hept, J = 6.3 Hz, 1H),

.26−3.15 (m, 1H), 2.99−2.88 (m, 1H), 2.52 (s, 4H), 2.47−2.38 (m,

Isopropyl 2-Oxo-1-(3-oxo-3-(m-tolyl)propyl)cyclopentane-1-car-

boxylate (3n). Yield: 60% (38 mg), colorless oil, R = 0.6 (EtOAc/

H), 2.38−2.19 (m, 2H), 2.13−1.90 (m, 4H), 1.27−1.21 (m, 6H).

petroleum ether = 1:10). H NMR (400 MHz, CDCl ): δ 7.80−7.72

C{ H} NMR (126 MHz, CDCl ): δ 214.9, 198.5, 171.0, 145.8,

(m, 2H), 7.41−7.30 (m, 2H), 5.05 (hept, J = 6.3 Hz, 1H), 3.31−3.18

(m, 1H), 3.05−2.89 (m, 1H), 2.54−2.46 (m, 1H), 2.45−2.38 (m,

4H), 2.37−2.20 (m, 2H), 2.15−1.91 (m, 4H),, 1.25 (d, J = 6.1 Hz,

33.0, 128.5, 125.0, 69.0, 59.2, 38.0, 34.4, 33.9, 3.8, 21.7, 21.6, 19.6,

4.8. IR (KBr, cm ): 2978, 2930, 1748, 1718, 1678, 1589, 1446,

−

370, 1236, 1184, 1099, 994, 820. HRMS (ESI-TOF): m/z [M +

6H). C{ H} NMR (101 MHz, CDCl ): δ 214.9, 199.7, 171.0, 138.3,

Na] calcd for C H O SNa, 371.1288; found, 371.1284.

136.8, 133.8, 128.6, 128.5, 125.3, 69.0, 59.2, 38.0, 34.4, 34.1, 27.7,

−

Isopropyl 1-(3-(4-Fluorophenyl)-3-oxopropyl)-2-oxocyclopen-

21.7, 21.6, 21.4, 19.6. IR (KBr, cm ): 3044, 2975,2931, 1747, 1683,

tane-1-carboxylate (3i). Yield: 83% (53 mg), colorless oil, R = 0.6

1509, 1454, 1161, 1036, 982, 825. HRMS (ESI-TOF): m/z [M +

(EtOAc/petroleum ether = 1:10). H NMR (400 MHz, CDCl ): δ

Na] calcd for C H O Na, 339.1567; found, 339.1569.

19 24

.92 (dd, J = 8.4, 5.5 Hz, 2H), 7.04 (t, J = 8.4 Hz, 2H), 4.97 (hept, J =

.4 Hz, 1H), 3.17 (ddd, J = 16.1, 10.2, 5.3 Hz, 1H), 2.89 (ddd, J =

6.4, 10.2, 5.1 Hz, 1H), 2.52−2.31 (m, 2H), 2.30−2.11 (m, 2H),

Isopropyl 1-(3-(2-Fluorophenyl)-3-oxopropyl)-2-oxocyclopen-

tane-1-carboxylate (3o). Yield: 56% (34 mg), colorless oil, R =

0.6 (EtOAc/petroleum ether = 1:10). H NMR (400 MHz, CDCl ):

.09−1.78 (m, 4H), 1.19−1.14 (m, 6H). C{ H} NMR (101 MHz,

δ 7.75 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 9.5 Hz, 1H), 7.52−7.39 (m,

1H), 7.34−7.13 (m, 1H), 5.05 (hept, J = 6.3 Hz, 1H), 3.37−3.13 (m,

1H), 3.07−2.80 (m, 1H), 2.53−2.20 (m, 4H), 2.15−1.89 (m, 4H),

CDCl ): δ 214.9, 198.0, 171.0, 167.0 (C−F, J

= 255.5 Hz), 164.5

C−F

(

C−F, J

= 255.5 Hz), 133.19 (C−F, J

= 3.0 Hz), 133.16 (C−

C−F

F, J

= 3.0 Hz), 130.8 (C−F, J

= 9.1 Hz), 130.7 (C−F, J

1.29−1.19 (m, 6H). C{ H} NMR (101 MHz, CDCl ): δ 214.8,

C−F

392

J. Org. Chem. 2021, 86, 5388−5400

The Journal of Organic Chemistry

Note

F, J

98.2, 171.0, 164.1 (C−F, J

= 249.5 Hz),161.6 (C−F, J

Isopropyl 1-(3-(Benzo[b]thiophen-3-yl)-3-oxopropyl)-2-oxocy-

C−F

49.5 Hz), 138.9 (C−F, J

= 6.1 Hz), 138.8(C−F, J

= 6.1 Hz),

clopentane-1-carboxylate (3u). Yield: 59% (42 mg), colorless oil,

C−F

30.2(C−F, J

= 8.1 Hz), 130.3 (C−F, J

= 3.0 Hz), 123.8 (C−F, J

= 8.1 Hz), 123.9 (C−

C−F

= 0.5 (EtOAc/petroleum ether = 1:10). H NMR (500 MHz,

C−F

= 3.0 Hz), 120.1 (C−F, J =

C−F

CDCl ): δ 8.73 (d, J = 8.2 Hz, 1H), 8.42 (s, 1H), 7.85 (d, J = 8.0 Hz,

C−F

1.2 Hz)120.0 (C−F, J

= 21.2 Hz), 114.9 (C−F, J

= 17.1

1H), 7.47 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 5.06 (hept, J =

6.2 Hz, 1H), 3.40−3.16 (m, 1H), 3.10−2.90 (m, 1H), 2.58−2.24 (m,

C−F

Hz), 114.7 (C−F, J

= 17.1 Hz), 69.1, 59.0, 38.0, 34.5, 34.2, 27.6,

C−F

1.6, 21.6, 19.6. F NMR (376 MHz, CDCl ): δ −111.96, IR (KBr,

4H), 2.22−1.91 (m, 4H), 1.31−1.17 (m, 6H). C{ H} NMR (126

−

cm ): 3075, 2979, 1749, 1720, 1478, 1267, 1104, 996, 826, 763.

MHz, CDCl ): δ 214.9, 194.8, 171.1, 139.8, 137.3, 136.6, 134.7,

HRMS (ESI-TOF): m/z [M + Na]⁺calcd for C H FO Na,

125.8, 125.6, 125.4, 122.2, 69.1, 59.3, 38.0, 35.8, 34.3, 28.2, 21.7, 21.6,

−

43.1316; found, 343.1314.

Isopropyl 1-(3-(2,4-Dimethylphenyl)-3-oxopropyl)-2-oxocyclo-

pentane-1-carboxylate (3p). Yield: 76% (51 mg), colorless oil, R

19.7. IR (KBr, cm ): 3097, 2977, 1747, 1717, 1668, 1494, 1260,

1171, 1103, 765. HRMS (ESI-TOF): m/z [M + Na]⁺calcd for

C H O SNa, 381.1131; found, 381.1128.

20 22

0.6 (EtOAc/petroleum ether = 1:10). H NMR (500 MHz,

Isopropyl 2-Oxo-1-(3-oxo-3-phenylpropyl)cyclohexane-1-car-

CDCl ): δ 7.53 (d, J = 7.7 Hz, 1H), 7.03−6.91 (m, 2H), 4.96 (hept, J

boxylate (3v). Yield: 53% (32 mg), colorless oil, R

petroleum ether = 1:10). H NMR (400 MHz, CDCl

= 0.6 (EtOAc/

): δ 7.97 (d, J =

(

12.5, 6.2 Hz, 1H), 3.18−3.01 (m, 1H), 2.87−2.72 (m, 1H), 2.44−

.37 (m, 4H), 2.34−2.24 (m, 5H), 2.19−2.12 (m, 1H),, 2.01−1.90

7.7 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.18−

5.03 (m, 1H), 3.26−3.08 (m, 1H), 2.94−2.78 (m, 1H), 2.67−2.37

(m, 3H), 2.33−2.16 (m, 1H), 2.14−1.91 (m, 2H), 1.84−1.76 (m,

1H), 1.67 (t, J = 9.4 Hz, 2H), 1.57−1.42 (m, 1H), 1.27 (d, J = 6.2 Hz,

m, 3H), 1.90−1.81 (m, 1H), 1.18−1.12 (m, 6H). C{ H} NMR

126 MHz, CDCl ): δ 214.9, 202.6, 171.0, 141.9, 138.6, 134.6, 132.8,

29.1, 126.3, 69.0, 59.3, 38.0, 36.5, 34.3, 27.9, 21.7, 21.6, 21.5, 21.3,

9.6. IR (KBr, cm ): 2973, 2930, 1748, 1719, 1681, 1450, 1259,

234, 1145, 985, 935, 756. HRMS (ESI-TOF): m/z [M + Na] calcd

for C H O Na, 353.1723; found, 353.1718.

Isopropyl 1-(3-(3,5-Dimethylphenyl)-3-oxopropyl)-2-oxocyclo-

pentane-1-carboxylate (3q). Yield: 65% (42 mg), colorless oil, R

0.6 (EtOAc/petroleum ether = 1:10). H NMR (400 MHz,

CDCl ): δ 7.57 (s, 2H), 7.19 (s, 1H), 5.06 (hept, J = 6.2 Hz, 1H),

−

6H). C{ H} NMR (101 MHz, CDCl

): δ 208.2, 199.5, 171.6, 136.8,

133.0, 128.6, 128.1, 69.1, 60.3, 41.1, 36.9, 34.0, 29.3, 27.6, 22.6, 21.7,

−

21.6. IR (KBr, cm ): 2939, 2866, 1711, 1597, 1448, 1370, 1300,

1214, 983, 693. HRMS (ESI-TOF): m/z [M + Na]⁺calcd for

C H O Na, 339.1567; found, 339.1572.

19 24

Isopropyl 2-Oxo-1-(3-oxo-3-phenylpropyl)cycloheptane-1-car-

boxylate (3w). Yield: 64% (38 mg), colorless oil, R

petroleum ether = 1:10). H NMR (500 MHz, CDCl

= 0.6 (EtOAc/

): δ 7.97 (d, J =

(

.33−3.13 (m, 1H), 3.06−2.89 (m, 1H), 2.55−2.47 (m, 1H), 2.44−

.30 (m, 8H), 2.29−2.20 (m, 1H), 2.13−1.91 (m, 4H), 1.27−1.20

7.7 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 5.14−

5.02 (m, 1H), 3.15 (ddd, J = 16.2, 10.8, 4.9 Hz, 1H), 2.91 (ddd, J =

16.4, 10.9, 4.8 Hz, 1H), 2.68 (td, J = 10.2, 7.9, 5.1 Hz, 1H), 2.52 (dd,

J = 13.9, 7.3 Hz, 1H), 2.34 (ddd, J = 15.2, 10.8, 4.9 Hz, 1H), 2.21−

2.13 (m, 1H), 2.07 (ddd, J = 14.6, 10.8, 4.7 Hz, 1H), 1.83−1.75 (m,

2H), 1.72−1.61 (m, 3H), 1.59−1.47 (m, 2H), 1.28−1.23 (m, 6H).

m, 6H). ¹³C{ H} NMR (101 MHz, CDCl ): δ 214.9, 199.9, 171.0,

38.2, 136.9, 134.7, 125.9, 69.0, 59.3, 38.0, 34.4, 34.1, 27.7, 21.7, 21.6,

1.2, 19.6. IR (KBr, cm ): 3042, 2967, 1746, 1717, 1678, 1315,

262, 854, 814, 752. HRMS (ESI-TOF): m/z [M + Na] calcd for

C H FO Na, 353.1723; found, 353.1725.

Isopropyl 1-(3-(Naphthalen-1-yl)-3-oxopropyl)-2-oxocyclopen-

tane-1-carboxylate (3r). Yield: 62% (42 mg), yellow oil, R = 0.6

EtOAc/petroleum ether = 1:10). H NMR (400 MHz, CDCl ): δ

−

C{ H} NMR (126 MHz, CDCl ): δ 209.7, 199.5, 172.0, 136.8,

133.0, 128.5, 128.1, 68.9, 61.9, 42.3, 34.4, 34.3, 30.2, 29.8, 25.4, 25.0,

−1

(

21.7, 21.6. IR (KBr, cm ): 3061, 1978, 2934,1689, 1597, 1450, 1373,

.56 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 7.1 Hz,

H), 7.85 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.53−7.45 (m,

H), 5.03 (hept, J = 6.4 Hz, 1H), 3.35 (ddd, J = 16.1, 9.9, 5.4 Hz,

H), 3.06 (ddd, J = 16.3, 9.9, 5.1 Hz, 1H), 2.55−2.45 (m, 1H), 2.44−

.27 (m, 3H), 2.22−2.12 (m, 1H), 2.08−1.91 (m, 3H), 1.23 (t, J =

1231, 1179, 1105, 1004, 938, 752, 693. HRMS (ESI-TOF): m/z [M +

Na] calcd for C H O Na, 353.1723; found, 353.1720.

Isopropyl (E)-2-Oxo-1-(3-oxo-5-phenylpent-4-en-1-yl)-

cyclopentane-1-carboxylate (6a). Yield: 83% (54 mg), colorless

oil, R = 0.6 (EtOAc/petroleum ether = 1:10). H NMR (500 MHz,

.3 Hz, 6H). ¹³C{ H} NMR (101 MHz, CDCl ): δ 214.9, 203.6,

CDCl ): δ 7.61−7.52 (m, 3H), 7.42−7.37 (m, 3H), 6.72 (d, J = 16.2

71.0, 135.8, 133.9, 132.6, 130.1, 128.4, 127.9, 127.6, 126.4, 125.8,

Hz, 1H), 5.05 (hept, J = 6.2 Hz, 1H), 3.01−2.88 (m, 1H), 2.78−2.65

(m, 1H), 2.52−2.38 (m, 2H), 2.37−2.28 (m, 1H), 2.23−2.15 (m,

1H), 2.07−1.98 (m, 3H), 1.96−1.88 (m, 1H), 1.27−1.22 (m, 6H).

24.4, 69.0, 59.2, 38.0, 37.5, 34.4, 28.0, 21.7, 21.6, 19.7. IR (KBr,

−

cm ): 3051, 2978, 1748, 1717, 1591, 1508, 1459, 1369, 1234, 1102,

938, 802, 780, 598. HRMS (ESI-TOF): m/z [M + Na] calcd for

C{ H} NMR (126 MHz, CDCl ): δ 214.9, 199.4, 171.0, 142.8,

C H O Na, 375.1567; found, 375.1562.

134.5, 130.5, 128.9, 128.3, 126.0, 69.0, 59.2, 38.0, 36.1, 34.3, 27.5,

−

Isopropyl 2-Oxo-1-(3-oxo-3-(thiophen-2-yl)propyl)cyclopentane-

-carboxylate (3s). Yield: 76% (43 mg), colorless oil, R = 0.6

EtOAc/petroleum ether = 1:10). H NMR (500 MHz, CDCl ): δ

21.7, 21.6, 19.6. IR (KBr, cm ): 3030, 2978, 1747, 1718, 1662, 1495,

1258, 1180, 1031, 753, 693. HRMS (ESI-TOF): m/z [M + Na]⁺

calcd for C H O Na, 351.1567; found, 351.1568.

(

.73−7.65 (m, 1H), 7.60−7.49 (m, 1H), 7.09−6.97 (m, 1H), 5.03−

.90 (m, 1H), 3.17−3.04 (m, 1H), 2.92−2.81 (m, 1H), 2.46−2.30

Isopropyl (E)-2-Oxo-1-(3-oxo-5-(p-tolyl)pent-4-en-1-yl)-

cyclopentane-1-carboxylate (6b). Yield: 70% (47 mg), colorless

(

m, 2H), 2.30−2.11 (m, 2H), 2.04−1.83 (m, 4H), 1.20−1.13 (m,

oil, R = 0.5 (EtOAc/petroleum ether = 1:10). H NMR (500 MHz,

H). ¹³C{ H} NMR (126 MHz, CDCl ): δ 214.8, 192.4, 170.9, 143.9,

CDCl ): δ 7.55 (d, J = 16.2 Hz, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.20

33.6, 132.1, 128.1, 69.0, 59.2, 37.9, 34.8, 34.2, 27.9, 21.7, 21.6, 19.6.

(d, J = 7.8 Hz, 2H), 6.68 (d, J = 16.2 Hz, 1H), 5.09−5.00 (m, 1H),

2.97−2.87 (m, 1H), 2.74−2.64 (m, 1H), 2.52−2.45 (m, 1H), 2.45−

2.37 (m, 3H), 2.37−2.27 (m, 2H), 2.24−2.14 (m, 1H), 2.08−1.97

−

IR (KBr, cm ): 3097, 2977, 1747, 1717, 1668, 1494, 1260, 1171,

103, 765. HRMS (ESI-TOF): m/z [M + Na] calcd for

C H O SNa, 331.0975; found, 331.0977.

(m, 3H), 1.97−1.88 (m, 1H), 1.27−1.21 (m, 6H). C{ H} NMR

Isopropyl 1-(3-(Benzo[b]thiophen-2-yl)-3-oxopropyl)-2-oxocy-

clopentane-1-carboxylate (3t). Yield: 71% (45 mg), white solid,

(126 MHz, CDCl ): δ 214.94, 199.48, 170.97, 142.86, 140.97, 131.72,

29.68, 128.32, 125.06, 68.99, 59.26, 38.00, 36.04, 34.26, 27.54, 21.68,

−

mp = 79−81 °C, R = 0.5 (EtOAc/petroleum ether = 1:10). H NMR

21.60, 21.50, 19.62. IR (KBr, cm ): 3051, 1978, 1749, 1665, 1612,

(

500 MHz, CDCl ): δ 8.01 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.85 (d,

1490, 1450, 1403, 1373, 1319, 1177, 1013, 982, 817, 735. HRMS

J = 8.0 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H),

(

ESI-TOF): m/z [M + Na] calcd for C H O Na, 365.1723; found,

.06 (hept, J = 6.2 Hz, 1H), 3.41−3.20 (m, 1H), 3.14−2.98 (m, 1H),

65.1725.

.56−2.23 (m, 4H), 2.21−1.93 (m, 4H), 1.31−1.18 (m, 6H).

Isopropyl (E)-1-(5-(4-Fluorophenyl)-3-oxopent-4-en-1-yl)-2-oxo-

C{ H} NMR (126 MHz, CDCl ): δ 214.9, 194.0, 171.0, 143.3,

cyclopentane-1-carboxylate (6c). Yield: 66% (45 mg), colorless oil,

R = 0.5 (EtOAc/petroleum ether = 1:10). H NMR (500 MHz,

42.5, 139.2, 129.3, 127.4, 126.0, 125.0, 123.0, 69.1, 59.2, 38.0, 34.7,

4.4, 27.9, 21.7, 21.6, 19.7. IR (KBr, cm ): 3061, 2978, 1747, 1718,

−

CDCl ): δ 7.54−7.41 (m, 3H), 7.01 (t, J = 8.4 Hz, 2H), 6.57 (d, J =

666, 1558, 1258, 1233, 1166, 1103, 752. HRMS (ESI-TOF): m/z

16.2 Hz, 1H), 4.97 (hept, J = 6.1 Hz, 1H), 2.94−2.80 (m, 1H), 2.74−

2.54 (m, 1H), 2.47−2.19 (m, 3H), 2.19−2.04 (m, 1H), 2.03−1.82

[

M + Na] calcd for C H O SNa, 381.1131; found, 381.1126.

393

J. Org. Chem. 2021, 86, 5388−5400

The Journal of Organic Chemistry

Note

2.07 (m, 3H). ¹³C{ H} NMR (101 MHz, CDCl ): δ 210.5, 171.6,

(

m, 4H), 1.24−1.10 (m, 6H). C{ H} NMR (126 MHz, CDCl ): δ

15.0, 199.2, 171.0, 165.0 (C−F, J

= 256.0 Hz), 163.0 (C−F,

143.0, 138.7, 128.6, 127.8, 125.5, 120.9, 55.7, 52.6, 48.9, 43.2, 31.0,

C−F

−1

= 256.0 Hz), 141.4, 130.73 (C−F, J

= 3.8 Hz), 130.70 (C−

29.0. IR (KBr, cm ): 3051, 1978, 1749, 1665, 1612, 1490, 1450,

C−F

F, J

= 3.8 Hz), 130.2 (C−F, J

= 8.8 Hz), 130.1 (C−F, J

1403, 1373, 1319, 1177, 1013, 982, 817, 735. HRMS (ESI-TOF): m/

z [M + Na] calcd for C16

HPLC: OD-H column, 95:5 hexanes/isopropanol, 1.00 mL/min, t =

(major) 12.3 min, (minor) 11.5 min. 90% ee. [α] −17.5° (c 0.55,

C−F

= 2.5

.8 Hz), 125.70 (C−F, J

= 2.5 Hz), 125.68 (C−F, J

Na, 279.0992; found, 279.0995.

C−F

Hz), 116.2 (C−F, J

= 21.4 Hz), 116.0 (C−F, J

= 21.4 Hz),

C−F

9.0, 59.2, 38.0, 36.2, 34.4, 27.5, 21.7, 21.6, 19.6. F NMR (471

−

MHz, CDCl ): δ −109.28. IR (KBr, cm ): 3047, 2978, 1743, 1719,

509, 1232, 1162, 1104, 826. HRMS (ESI-TOF): m/z [M + H]

calcd for C H FO , 347.1653; found, 347.1657.

Isopropyl (E)-1-(5-(4-Chlorophenyl)-3-oxopent-4-en-1-yl)-2-oxo-

cyclopentane-1-carboxylate (6d). Yield: 77% (54 mg), colorless oil,

R = 0.5 (EtOAc/petroleum ether = 1:10). H NMR (500 MHz,

EtOH).

Ethyl (1S,5S)-8-Oxo-4-phenylbicyclo[3.2.1]oct-3-ene-1-carboxy-

late (4b). Yield: 85% (23 mg), colorless oil, R = 0.6 (EtOAc/

petroleum ether = 1:20). H NMR (400 MHz, CDCl ): δ 7.35−7.23

(m, 5H), 5.96−5.89 (m, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.40 (dd, J =

17.9, 3.1 Hz, 1H), 3.22−3.09 (m, 1H), 2.87−2.70 (m, 2H), 2.33−

CDCl ): δ 7.56−7.43 (m, 3H), 7.36 (d, J = 8.5 Hz, 2H), 6.69 (d, J =

2.12 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H). C{ H} NMR (101 MHz,

(

6.2 Hz, 1H), 5.15−4.97 (m, 1H), 3.05−2.89 (m, 1H), 2.76−2.62

CDCl ): δ 210.3, 171.1, 143.1, 138.8, 128.6, 127.7, 125.5, 120.9, 61.4,

55.5, 49.0, 43.2, 31.0, 29.0, 14.2. IR (KBr, cm ): 2980, 1725, 1635,

1494, 1448, 1234, 1085, 1030, 760, 698, 529.HRMS (ESI-TOF): m/z

[M + Na] calcd for C17

−

m, 1H), 2.55−2.29 (m, 3H), 2.27−2.11 (m, 1H), 2.07−1.86 (m,

H), 1.32−1.19 (m, 6H). C{ H} NMR (126 MHz, CDCl ): δ

14.9, 199.1, 171.0, 141.2, 136.3, 133.0, 129.4, 129.2, 126.4, 69.0,

Na, 293.1148; found, 293.1141.

−1

9.1, 38.0, 36.3, 34.4, 27.4, 21.7, 21.6, 19.6. IR (KBr, cm ): 3051,

978, 1749, 1665, 1612, 1490, 1450, 1403, 1373, 1319, 1177, 1013,

82, 817, 735. HRMS (ESI-TOF): m/z [M + Na] calcd for

HPLC: WHELK-O1 column, 95:5 hexanes/isopropanol, 0.70 mL/

min, t

= (major) 17.9 min, (minor) 31.3 min, 91% ee. [α] −58.3°

(c 0.60, DCM).

C H ClO Na, 385.1177; found, 385.1180.

Isopropyl (E)-1-(5-(4-Bromophenyl)-3-oxopent-4-en-1-yl)-2-oxo-

cyclopentane-1-carboxylate (6e). Yield: 62% (52 mg), colorless oil,

Isopropyl (1S,5S)-8-Oxo-4-phenylbicyclo[3.2.1]oct-3-ene-1-car-

boxylate (4c). Yield: 86% (24 mg), white solid, mp = 96−100 °C,

= 0.6 (EtOAc/petroleum ether = 1:20). H NMR (500 MHz,

R = 0.5 (EtOAc/petroleum ether = 1:10). H NMR (500 MHz,

CDCl ): δ 7.35−7.30 (m, 4H), 7.30−7.26 (m, 1H), 5.93 (t, 1H),

CDCl ): δ 7.55−7.47 (m, 3H), 7.41 (d, J = 8.4 Hz, 2H), 6.70 (d, J =

5.16−5.07 (m, 1H), 3.38 (dt, J = 18.1, 2.6 Hz, 1H), 3.16−3.11 (m,

6.2 Hz, 1H), 5.04 (hept, J = 6.3 Hz, 1H), 3.00−2.89 (m, 1H), 2.75−

1H), 2.84−2.70 (m, 2H), 2.32−2.24 (m, 2H), 2.23−2.15 (m, 1H),

.64 (m, 1H), 2.52−2.28 (m, 3H), 2.21−1.98 (m, 4H), 1.97−1.88

1.32−1.26 (m, 6H). C{ H} NMR (126 MHz, CDCl ): δ 210.5,

(

m, 1H), 1.26−1.21 (m, 6H). C{ H} NMR (126 MHz, CDCl ): δ

170.7, 142.9, 138.8, 128.6, 127.7, 125.5, 121.0, 68.9, 55.5, 49.0, 43.2,

−

15.0, 199.2, 171.0, 141.3, 133.4, 132.2, 129.6, 126.4, 124.7, 69.0,

9.1, 38.0, 36.3, 34.4, 27.4, 21.7, 21.6, 19.6. IR (KBr, cm ): 2976,

30.9, 29.0, 21.8, 21.8. IR (KBr, cm ): 3062, 2981, 1720, 1636, 1494,

1460, 1273, 1104, 831, 761, 700. HRMS (ESI-TOF): m/z [M + Na]⁺

calcd for C H O Na, 307.1305; found, 307.1307. HPLC: WHELK-

−1

842, 1747, 1781, 1601, 1249, 1170, 1104, 1024, 756. HRMS (ESI-

TOF): m/z [M + Na] calcd for C H BrO Na, 429.0672; found,

O1 column, 85:15 hexanes/isopropanol, 0.80 mL/min, t = (major)

29.0667.

8.6 min, (minor) 13.4 min, 92% ee. [α] −32.8° (c 0.13, DCM).

Isopropyl (E)-1-(5-(2-Methoxyphenyl)-3-oxopent-4-en-1-yl)-2-ox-

Isopropyl (1S,5S)-8-Oxo-4-(p-tolyl)bicyclo[3.2.1]oct-3-ene-1-car-

ocyclopentane-1-carboxylate (6f). Yield: 74% (53 mg), colorless oil,

boxylate (4d). Yield: 78% (23 mg), colorless oil, R = 0.6 (EtOAc/

R = 0.4 (EtOAc/petroleum ether = 1:10). H NMR (500 MHz,

petroleum ether = 1:20). H NMR (400 MHz, CDCl ): δ 7.27−7.20

CDCl ): δ 7.83 (d, J = 16.4 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.28 (t,

(m, 1H), 7.19−7.08 (m, 3H), 5.93 (t, J = 3.5 Hz, 1H), 5.14 (hept, J =

6.0 Hz, 1H), 3.40 (d, J = 18.1 Hz, 1H), 3.15 (d, J = 3.7 Hz, 1H),

2.86−2.71 (m, 2H), 2.38 (s, 3H), 2.33−2.14 (m, 3H), 1.35−1.28 (m,

J = 7.8 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H),

6.71 (d, J = 16.2 Hz, 1H), 4.97 (hept, J = 5.6 Hz, 1H), 3.82 (t, J = 1.6

Hz, 3H), 2.92−2.81 (m, 1H), 2.69−2.58 (m, 1H), 2.44−2.30 (m,

6H). C{ H} NMR (101 MHz, CDCl ): δ 210.7, 170.7, 143.1, 138.8,

H), 2.30−2.20 (m, 1H), 2.18−2.10 (m, 1H), 1.99−1.90 (m, 3H),

138.2, 128.5, 126.3, 122.6, 120.8, 68.9, 55.5, 49.1, 43.2, 30.9, 29.0,

−1

.89−1.82 (m, 1H), 1.17 (d, J = 6.3 Hz, 6H). C{ H} NMR (126

21.8, 21.8, 21.5. IR (KBr, cm ): 2962, 1758, 1729, 1584, 1472, 1442,

MHz, CDCl ): δ 214.9, 199.9, 170.9, 158.5, 138.1, 131.7, 128.7,

1234, 1104, 1035, 499. HRMS (ESI-TOF): m/z [M + Na] calcd for

26.7, 123.4, 120.8, 111.1, 69.0, 59.4, 55.5, 38.0, 35.8, 34.1, 27.6, 21.7,

C H O Na, 321.1461; found, 321.1463. HPLC: WHELK-O1

−

1.6, 19.6. IR (KBr, cm ): 2976, 1747, 1718, 1660, 1601, 1462,

column, 95:5 hexanes/isopropanol, 0.80 mL/min, t = (major) 11.5

249, 1170, 1104, 1024, 756. HRMS (ESI-TOF): m/z [M + Na]

min, (minor) 24.3 min, 92% ee. [α]_D+83.3° (c 0.24, EtOH).

calcd for C H O Na, 381.1672; found, 381.1676.

Isopropyl (1S,5S)-4-([1,1′-Biphenyl]-4-yl)-8-oxobicyclo[3.2.1]oct-

Typical Procedure for the Synthesis of 4/7. Condition A.

Compound 3 (0.1 mmol), TfOH (15 mol %), and 1 mL of DCE were

added to a 25 mL Schlenk tube under air. The reaction was heated to

3-ene-1-carboxylate (4e). Yield: 72% (23 mg), colorless oil, R

(EtOAc/petroleum ether = 1:20). H NMR (500 MHz, CDCl

= 0.6

): δ

7.27 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 5.89 (t, J = 4.4, 2.8

Hz, 1H), 5.11 (hept, J = 6.3 Hz, 1H), 3.37 (dt, J = 18.0, 2.6 Hz, 1H),

3.13 (d, J = 4.4 Hz, 1H), 2.90 (hept, J = 6.7 Hz, 1H), 2.84−2.68 (m,

2H), 2.33−2.21 (m, 2H), 2.21−2.10 (m, 1H), 1.32−1.27 (m, 6H),

00 °C in an oil bath and then stirred for 5−60 min. When the

reaction was ﬁnished, the solvent was removed under a reduced

vacuum. The mixture was puriﬁed by silica gel chromatography

(EtOAc/petroleum ether = 1:20) to aﬀord product 4. The racemic

1.24 (d, J = 6.9 Hz, 6H). C{ H} NMR (126 MHz, CDCl

): δ 210.7,

samples were prepared by using the same procedures with TfOH as a

catalyst.

170.7, 148.6, 142.8, 136.3, 126.6, 125.4, 120.2, 68.8, 55.5, 49.0, 43.1,

−

33.8, 30.9, 29.0, 23.9, 21.8, 21.8. IR (KBr, cm ): 2961, 1758, 1724,

Condition B. Compound 6 (0.1 mmol), TfOH (5 mol %), and 1

mL of DCE were added to a 25 mL Schlenk tube under air. The

reaction was heated to 100 °C in an oil bath and then stirred for 5−60

min. When the reaction was ﬁnished, the solvent was removed under

a reduced vacuum. The mixture was puriﬁed by silica gel

chromatography (EtOAc/petroleum ether = 1:20) to aﬀor product

1510, 1460, 1350, 1285, 1106, 959, 843. HRMS (ESI-TOF): m/z [M

+ Na] calcd for C21

Na 349.1774; found, 349.1771. HPLC:

WHELK-O1 column, 85:15 hexanes/isopropanol, 0.80 mL/min, t =

(major) 7.2 min, (minor) 11.6 min, 90% ee. [α] −28.8° (c 0.32,

DCM).

Isopropyl (1S,5S)-4-(4-(tert-Butyl)phenyl)-8-oxobicyclo[3.2.1]oct-

. Racemic samples were prepared by using the same procedures with

3-ene-1-carboxylate (4f). Yield: 72% (24 mg), colorless oil, R

(EtOAc/petroleum ether = 1:20). H NMR (400 MHz, CDCl

= 0.6

): δ

TfOH as a catalyst.

Methyl (1S,5S)-8-Oxo-4-phenylbicyclo[3.2.1]oct-3-ene-1-carbox-

7.35 (d, J = 7.5 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 5.91 (t, 1H), 5.11

(dt, J = 12.8, 6.1 Hz, 1H), 3.37 (d, J = 18.1 Hz, 1H), 3.13 (s, 1H),

2.84−2.68 (m, 2H), 2.33−2.22 (m, 2H), 2.23−2.12 (m, 1H), 1.35−

ylate (4a). Yield: 74% (19 mg), white solid, mp = 90−92 °C, R = 0.6

(

EtOAc/petroleum ether = 1:20). H NMR (400 MHz, CDCl ): δ

.22 (dd, J = 21.8, 4.1 Hz, 5H), 5.91−5.80 (m, 1H), 3.71 (s, 3H),

.31 (d, J = 18.0 Hz, 1H), 3.07 (s, 1H), 2.80−2.60 (m, 2H), 2.25−

1.25 (m, 15H). C{ H} NMR (101 MHz, CDCl ): δ 210.7, 170.8,

150.8, 142.7, 135.8, 125.5, 125.1, 120.2, 68.8, 55.5, 49.0, 43.2, 34.6,

394

J. Org. Chem. 2021, 86, 5388−5400

The Journal of Organic Chemistry

Note

−

1.3, 31.0, 29.0, 21.8. IR (KBr, cm ): 2959, 2870, 1758, 1724, 1462,

210.2, 170.5, 141.9, 137.7, 131.7, 127.1, 121.7, 69.0, 55.4, 48.9, 43.1,

−

882, 1235, 1181, 1106, 1082, 811, 561. HRMS (ESI-TOF): m/z [M

Na] calcd for C H O Na, 363.1931; found, 363.1929. HPLC:

30.9, 28.9, 21.8. IR (KBr, cm ): 2960, 2937, 1759, 1723, 1488, 1287,

1235, 1182, 1148, 1105, 836. HRMS (ESI-TOF): m/z [M + Na]⁺

calcd for C H BrO Na, 385.0409; found, 385.0410. HPLC:

WHELK-O1 column, 95:5 hexanes/isopropanol, 0.70 mL/min, t =

18 19

major) 11.8 min, (minor) 23.6 min, 95% ee. [α]²−17.9° (c 0.28,

(

WHELK-O1 column, 95:5 hexanes/isopropanol, 0.80 mL/min, t =

EtOH).

(major) 12.2 min, (minor) 19.2 min, 91% ee. [α] −25.7° (c 0.46,

Isopropyl (1S,5S)-4-(4-Methoxyphenyl)-8-oxobicyclo[3.2.1]oct-3-

EtOH).

ene-1-carboxylate (4g). Yield: 84% (26 mg), colorless oil, R = 0.5

Isopropyl (1S,5S)-4-(4-(Methoxycarbonyl)phenyl)-8-oxobicyclo-

(

EtOAc/petroleum ether = 1:20). H NMR (500 MHz, CDCl ): δ

[3.2.1]oct-3-ene-1-carboxylate (4l). Yield: 72% (25 mg), white

.19 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 5.75 (t, J = 3.5 Hz,

H), 5.19−4.90 (m, 1H), 3.72 (s, 3H), 3.28 (d, J = 17.9 Hz, 1H),

.02 (d, J = 5.2 Hz, 1H), 2.85−2.56 (m, 2H), 2.27−1.98 (m, 3H),

solid, mp = 58−64 °C, R

= 0.4 (EtOAc/petroleum ether = 1:20). H

NMR (500 MHz, CDCl

): δ 7.99 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2

Hz, 2H), 6.06 (t, J = 3.6 Hz, 1H), 5.12 (hept, J = 6.5 Hz, 1H), 3.92 (s,

3H), 3.41 (d, J = 18.4 Hz, 1H), 3.14 (d, J = 5.6 Hz, 1H), 2.88−2.73

.25−1.08 (m, 6H). C{ H} NMR (126 MHz, CDCl ): δ 210.7,

70.7, 159.3, 142.4, 131.3, 126.6, 119.2, 113.9, 68.8, 55.5, 55.3, 49.1,

(m, 2H), 2.36−2.15 (m, 3H), 1.32−1.27 (m, 6H). C{ H} NMR

−

3.1, 30.9, 28.9, 21.81, 21.77. IR (KBr, cm ): 2973, 2840, 1888,

835, 1512, 1282, 1223, 1181, 1106, 1103, 837. HRMS (ESI-TOF):

m/z [M + Na] calcd for C H O Na, 337.1410; found, 337.1412.

HPLC: WHELK-O1 column, 85:15 hexanes/isopropanol, 0.80 mL/

(126 MHz, CDCl ): δ 210.0, 170.4, 166.7, 143.0, 142.2, 129.9, 129.3,

125.3, 123.4, 69.0, 55.4, 52.1, 48.7, 43.2, 30.9, 29.0, 21.8, 21.8. IR

−1

(KBr, cm ): 2983, 2951, 1759, 1721, 1606, 1439, 1282, 1186, 1108,

919, 862, 739. HRMS (ESI-TOF): m/z [M + Na]⁺calcd for

min, t = (major) 12.3 min, (minor) 22.3 min, 88% ee. [α] −12.1°

Na, 365.1359; found, 365.1354. HPLC: WHELK-O1

(c 0.38, EtOH).

column, 85:15 hexanes/isopropanol, 0.80 mL/min, t = (minor)

19.9 min, (major) 31.0 min, 93% ee. [α] −17.1° (c 0.03, DCM).

Isopropyl (1S,5S)-4-(4-(Methylthio)phenyl)-8-oxobicyclo[3.2.1]-

oct-3-ene-1-carboxylate (4h). Yield: 64% (21 mg), white solid, mp

92−96 °C, R = 0.5 (EtOAc/petroleum ether = 1:20). H NMR

500 MHz, CDCl ): δ 7.25 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 8.2 Hz,

Isopropyl (1S,5S)-4-([1,1′-Biphenyl]-4-yl)-8-oxobicyclo[3.2.1]oct-

(

3-ene-1-carboxylate (4m). Yield: 73% (28 mg), white solid, mp =

156−158 °C, R

(400 MHz, CDCl

= 0.5 (EtOAc/petroleum ether = 1:20). H NMR

H), 5.90 (t, J = 3.6 Hz, 1H), 5.11 (hept, J = 6.1 Hz, 1H), 3.37 (d, J =

8.1 Hz, 1H), 3.10 (d, J = 5.4 Hz, 1H), 2.83−2.69 (m, 2H), 2.48 (s,

H), 2.33−2.24 (m, 2H), 2.22−2.14 (m, 1H), 1.29 (d, J = 6.0 Hz,

): δ 7.57 (t, J = 8.6 Hz, 4H), 7.47−7.38 (m, 4H),

7.34 (t, J = 7.3 Hz, 1H), 5.99 (t, J = 3.6 Hz, 1H), 5.12 (hept, J = 6.0

Hz, 1H), 3.41 (d, J = 18.1 Hz, 1H), 3.18 (d, J = 3.8 Hz, 1H), 2.89−

H). ¹³C{ H} NMR (126 MHz, CDCl ): δ 210.5, 170.6, 142.3, 138.1,

2.68 (m, 2H), 2.41−2.12 (m, 3H), 1.30 (d, J = 6.3 Hz, 6H). C{ H}

35.5, 126.6, 125.8, 120.5, 68.9, 55.5, 48.9, 43.1, 30.9, 29.0, 21.8, 21.8,

5.8. HRMS (ESI-TOF): m/z [M + Na] calcd for C H O SNa,

53.1182; found, 353.1176. HPLC: WHELK-O1 column, 85:15

hexanes/isopropanol, 0.80 mL/min, t = (major) 13.5 min, (minor)

NMR (101 MHz, CDCl

): δ 210.5, 170.7, 142.5, 140.6, 140.4, 137.6,

128.8, 127.5, 127.3, 127.0, 125.8, 121.0, 68.9, 55.5, 48.9, 43.2, 31.0,

−

29.0, 21.8. IR (KBr, cm ): 3030, 2980, 1754, 1722, 1485, 1454,

1349, 1285, 1149, 812. HRMS (ESI-TOF): m/z [M + Na] calcd for

3.9 min, 93% ee. [α]_D−43.1° (c 0.23, EtOH).

Na, 383.1618; found, 383.1613. HPLC: OD-H column,

95:5 hexanes/isopropanol, 0.80 mL/min, t = (major) 17.0 min,

−63.5° (c 0.40, DCM).

Isopropyl (1S,5S)-8-Oxo-4-(m-tolyl)bicyclo[3.2.1]oct-3-ene-1-car-

boxylate (4n). Yield: 78% (23 mg), colorless oil, R = 0.6 (EtOAc/

petroleum ether = 1:20). H NMR (500 MHz, chloroform-d): δ 7.22

Isopropyl (1S,5S)-4-(4-Fluorophenyl)-8-oxobicyclo[3.2.1]oct-3-

ene-1-carboxylate (4i). Yield: 74% (22 mg), colorless oil, R = 0.6

(minor) 32.7 min, 92% ee. [α]

(

EtOAc/petroleum ether = 1:20). H NMR (400 MHz, CDCl ): δ

.31−7.14 (m, 2H), 6.93 (t, J = 8.5 Hz, 2H), 5.79 (t, J = 3.4 Hz, 1H),

.03 (hept, J = 8.1, 7.6 Hz, 1H), 3.29 (d, J = 18.0 Hz, 1H), 3.00 (d, J

5.1 Hz, 1H), 2.79−2.58 (m, 2H), 2.28−2.04 (m, 3H), 1.21 (d, J =

.3 Hz, 6H). C{ H} NMR (101 MHz, CDCl ): δ 210.3, 170.6,

(

t, J = 7.5 Hz, 1H), 7.16−7.06 (m, 3H), 5.93−5.88 (m, 1H), 5.11

13 1

(hept, J = 6.3 Hz, 1H), 3.37 (d, J = 18.0 Hz, 1H), 3.13 (d, J = 4.1 Hz,

−

H), 2.83−2.69 (m, 2H), 2.35 (s, 3H), 2.32−2.24 (m, 2H), 2.22−

13 1

63.6 (C−F, J

= 248.5 Hz), 161.1 (C−F, J

= 248.5 Hz),

C−F

.12 (m, 1H), 1.32−1.26 (m, 6H). C{ H} NMR (126 MHz,

42.0, 134.94 (C−F, J

= 3.1 Hz), 134.91 (C−F, J

= 3.1 Hz)

C−F

CDCl ): δ 210.7, 170.7, 143.1, 138.8, 138.2, 128.5, 126.23, 122.6,

27.2 (C−F, J

= 8.0 Hz), 127.1 (C−F, J

= 8.0 Hz), 121.0,

= 21.2 Hz), 68.9,

C−F

20.8, 68.9, 55.5, 49.1, 43.2, 30.9, 29.0, 21.8, 21.8, 21.5.IR (KBr,

15.5 (C−F, J

= 21.2 Hz), 115.3 (C−F, J

C−F

−

cm ): 3027, 2980, 2874, 1758, 1724, 1457, 1286, 1241, 1105, 784.

HRMS (ESI-TOF): m/z [M + Na] calcd for C H O Na, 321.1461;

5.4, 49.1, 43.1, 30.9, 28.9, 21.8. F NMR (376 MHz, CDCl ): δ

−

114.41. IR (KBr, cm ): 3073, 2980, 2908, 1757, 1723, 1601, 1510,

285, 1232, 1104, 838. HRMS (ESI-TOF): m/z [M + Na] calcd for

C H FO Na, 325.1210; found, 325.1208. HPLC: WHELK-O1

column, 95:5 hexanes/isopropanol, 0.80 mL/min, t = (major) 11.0

19 22

found, 321.1459. HPLC: WHELK-O1 column, 95:5 hexanes/

isopropanol, 0.80 mL/min, t = (major) 12.0 min, (minor) 22.7

min, 91% ee. [α] −25.7° (c 0.42, EtOH).

Isopropyl (1S,5S)-4-(2-Fluorophenyl)-8-oxobicyclo[3.2.1]oct-3-

min, (minor) 16.9 min, 92% ee. [α]_D−32.8° (c 0.13, DCM).

ene-1-carboxylate (4o). Yield: 78% (24 mg), colorless oil, R = 0.6

Isopropyl (1S,5S)-4-(4-Chlorophenyl)-8-oxobicyclo[3.2.1]oct-3-

(

EtOAc/petroleum ether = 1:20). H NMR (500 MHz, CDCl ): δ

ene-1-carboxylate (4j). Yield: 75% (22 mg), yellow solid, mp =

7.32−7.27 (m, 1H), 7.11 (d, J = 7.9 Hz, 1H), 7.02 (dt, J = 10.3, 2.1

Hz, 1H), 6.97 (td, J = 8.4, 2.6 Hz, 1H), 5.97 (t, J = 3.6 Hz, 1H), 5.12

9−83 °C, R = 0.6 (EtOAc/petroleum ether = 1:20). H NMR (400

MHz, CDCl ): δ 7.31−7.22 (m, 4H), 5.91 (t, J = 3.6 Hz, 1H), 5.15−

(hept, J = 6.2 Hz, 1H), 3.38 (dt, J = 18.2, 2.7 Hz, 1H), 3.09 (d, J = 5.5

.05 (m, 1H), 3.37 (d, J = 18.1 Hz, 1H), 3.06 (d, J = 5.4 Hz, 1H),

.85−2.69 (m, 2H), 2.36−2.10 (m, 3H), 1.29 (d, J = 6.3 Hz, 6H).

Hz, 1H), 2.85−2.71 (m, 2H), 2.33−2.14 (m, 3H), 1.31−1.27 (m,

6H). C{ H} NMR (126 MHz, CDCl ): δ 210.0, 170.5, 163.9 (C−F,

C{ H} NMR (101 MHz, CDCl ): δ 209.9, 170.4, 142.0, 137.2,

^JC−F = 247.0 Hz), 162.0 (C−F, J

= 247.0 Hz), 141.88 (C−F,

(

33.6, 128.7, 126.8, 121.6, 68.9, 55.4, 48.9, 43.1, 30.9, 28.9, 21.7. IR

KBr, cm ): 3073, 2980, 2908, 1757, 1723, 1601, 1510, 1285, 1232,

104, 838. HRMS (ESI-TOF): m/z [M + Na] calcd for

C H ClO Na 341.0915; found, 341.0911. HPLC: WHELK-O1

C−F

−

^JC−F = 2.5 Hz), 141.86 (C−F, J

= 2.5 Hz), 141.03 (C−F, J

C−F

= 8.8

= 3.8

C−F

.6 Hz), 140.91 (C−F, J

= 7.6 Hz), 130.08 (C−F, J

C−F

Hz), 130.01 (C−F, J

= 8.8 Hz), 122.2, 121.1 (C−F, J

C−F

Hz), 121.0 (C−F, J

= 3.8 Hz), 114.6 (C−F, J

= 21.4 Hz),

= 22.7 Hz), 112.3

column, 95:5 hexanes/isopropanol, 0.80 mL/min, t = (major) 11.6

C−F

14.4 (C−F, J

= 21.4 Hz), 112.5 (C−F, J

min, (minor) 18.0 min, 91% ee. [α]_D−32.0° (c 0.67, EtOH).

C−F

(

C−F, J

= 22.7 Hz), 69.0, 55.4, 48.9, 43.0, 30.9, 29.0, 21.8, 21.8.

Isopropyl (1S,5S)-4-(4-Bromophenyl)-8-oxobicyclo[3.2.1]oct-3-

C−F

−1

ene-1-carboxylate (4k). Yield: 69% (25 mg), yellow solid, mp =

F NMR (376 MHz, CDCl ): δ −112.87. IR (KBr, cm ): 2982,

7−92 °C, R = 0.6 (EtOAc/petroleum ether = 1:20). H NMR (400

MHz, CDCl ): δ 7.45 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H),

2909, 2878, 1758, 1724, 1489, 1462, 1284, 1223, 1150, 814, 761.

HRMS (ESI-TOF): m/z [M + Na] calcd for C H FO Na,

18 19

.94 (d, J = 3.6 Hz, 1H), 5.17−5.06 (m, 1H), 3.36 (d, J = 18.2 Hz,

325.1210; found, 325.1209. HPLC: WHELK-O1 column, 95:5

H), 3.07 (d, J = 5.4 Hz, 1H), 2.84−2.70 (m, 2H), 2.33−2.13 (m,

hexanes/isopropanol, 0.80 mL/min, t = (major) 11.2 min, (minor)

H), 1.29 (d, J = 6.3 Hz, 6H). C{ H} NMR (101 MHz, CDCl ): δ

17.4 min, 91% ee. [α]_D−61.2° (c 0.32, DCM).

395

J. Org. Chem. 2021, 86, 5388−5400

The Journal of Organic Chemistry

Note

Isopropyl (1S,5S)-4-(2,4-Dimethylphenyl)-8-oxobicyclo[3.2.1]oct-

Isopropyl (1S,5S)-4-(Benzo[b]thiophen-3-yl)-8-oxobicyclo[3.2.1]-

(

-ene-1-carboxylate (4p). Yield: 71% (23 mg), colorless oil, R = 0.4

oct-3-ene-1-carboxylate (4u). Yield: 70% (21 mg), yellow solid, mp

EtOAc/petroleum ether = 1:20). H NMR (500 MHz, CDCl ): δ

= 109−114 °C. R = 0.6 (EtOAc/petroleum ether = 1:20). H NMR

.04−7.00 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 5.47 (t, 1H), 5.12 (hept,

(500 MHz, CDCl ): δ 7.73 (d, J = 6.8 Hz, 1H), 7.68 (d, J = 8.6 Hz,

J = 6.3 Hz, 1H), 3.41 (d, J = 17.8 Hz, 1H), 2.79−2.70 (m, 3H), 2.31

1H), 7.38−7.28 (m, 2H), 7.13 (s, 1H), 6.11−5.97 (m, 1H), 5.18−

5.08 (m, 1H), 3.41 (d, J = 18.5 Hz, 1H), 3.28 (d, J = 4.2 Hz, 1H),

2.92−2.67 (m, 2H), 2.35−2.14 (m, 3H), 1.34−1.26 (m, 6H).

(

s, 3H), 2.26 (s, 3H), 2.24−2.17 (m, 2H), 2.16−2.10 (m, 1H), 1.29

13 1

d, J = 6.3 Hz, 6H). C{ H} NMR (126 MHz, CDCl ): δ 210.7,

70.8, 144.7, 137.4, 135.2, 131.2, 128.7, 126.3, 122.7, 68.8, 55.5, 51.2,

C{ H} NMR (126 MHz, CDCl ): δ 209.7, 170.4, 142.1, 139.9,

−

3.4, 30.9, 28.3, 21.8, 21.8, 21.0, 19.9.IR (KBr, cm ): 2975, 2929,

138.8, 137.3, 124.9, 124.6, 123.6, 122.2, 122.0, 119.4, 69.0, 55.2, 48.6,

−1

755, 1726, 1603, 1447, 1406, 1238, 1104, 817. HRMS (ESI-TOF):

43.0, 30.8, 28.5, 21.8, 21.8. IR (KBr, cm ): 2980, 2937, 1758, 1723,

m/z [M + Na] calcd for C H O Na, 335.1618; found, 335.1617.

1456, 1283, 1240, 1150, 1106, 804. HRMS (ESI-TOF): m/z [M +

HPLC: WHELK-O1 column, 95:5 hexanes/isopropanol, 0.80 mL/

Na] calcd for C H O SNa, 363.1025; found, 363.1022. HPLC:

min, t = (major) 9.1 min, (minor) 7 min, 91% ee. [α] +12.4° (c

WHELK-O1 column, 90:10 hexanes/isopropanol, 0.70 mL/min, t =

.04, DCM).

(major) 13.9 min, (minor) 19.3 min, 87% ee. [α] −26.7° (c 0.33,

Isopropyl (1S,5S)-4-(3,5-Dimethylphenyl)-8-oxobicyclo[3.2.1]oct-

EtOH).

(

-ene-1-carboxylate (4q). Yield: 57% (23 mg), colorless oil, R = 0.6

Isopropyl (1S,5S)-9-Oxo-4-phenylbicyclo[3.3.1]non-3-ene-1-car-

EtOAc/petroleum ether = 1:20). H NMR (500 MHz, CDCl ): δ

boxylate (4v). Yield: 90% (26 mg), colorless oil, R = 0.6 (EtOAc/

.96−6.90 (m, 3H), 5.88 (s, 1H), 5.16−5.08 (m, 1H), 3.36 (d, J =

petroleum ether = 1:20). H NMR (500 MHz, CDCl ): δ 7.37−7.24

8.0 Hz, 1H), 3.11 (s, 1H), 2.81−2.70 (m, 2H), 2.3 (s, 6H), 2.25 (s,

(m, 5H), 6.29 (t, J = 3.8 Hz, 1H), 5.12 (p, J = 6.3 Hz, 1H), 3.54 (d, J

= 19.6 Hz, 1H), 3.46 (s, 1H), 2.66 (dd, J = 19.3, 4.0 Hz, 1H), 2.47−

2.37 (m, 1H), 2.06−1.99 (m, 3H), 1.72−1.65 (m, 1H), 1.33−1.27

H), 2.22−2.13 (m, 1H), 1.29 (d, J = 6.3 Hz, 6H). C{ H} NMR

126 MHz, CDCl ): δ 210.7, 170.8, 143.2, 138.8, 138.1, 129.4, 123.4,

20.6, 68.8, 55.5, 49.1, 43.2, 30.9, 29.0, 21.8, 21.8, 21.3. IR (KBr,

(m, 6H). C{ H} NMR (126 MHz, CDCl ): δ 209.8, 171.5, 138.8,

−

cm ): 2979, 2924, 1757, 1724, 1601, 1281, 1243, 1184, 1103, 850,

136.2, 128.6, 127.6, 125.6, 124.6, 69.0, 57.4, 49.2, 39.0, 38.3, 32.4,

−1

01. HRMS (ESI-TOF): m/z [M + Na]⁺calcd for C H O Na,

21.8, 17.5. IR (KBr, cm ): 2929, 2862, 1716, 1637, 1256, 1234,

35.1618; found, 335.1614. HPLC: WHELK-O1 column, 95:5

1108, 1070, 755, 693. HRMS (ESI-TOF): m/z [M + Na] calcd for

hexanes/isopropanol, 0.80 mL/min, t = (major) 11.6 min, (minor)

C H O Na, 321.1461; found, 321.1460. HPLC: WHELK-O1

19 22

3.7 min, 91% ee. [α]_D−11.2° (c 0.41, EtOH).

column, 95:5 hexanes/isopropanol, 0.80 mL/min, t = (major) 10.3

Isopropyl (1S,5S)-4-(Naphthalen-1-yl)-8-oxobicyclo[3.2.1]oct-3-

min, (minor) 14.8 min, 85% ee. [α] −61.0° (c 0.19, EtOH).

ene-1-carboxylate (4r). Yield: 56% (17 mg), colorless oil, R = 0.6

Isopropyl (1S,6S)-10-Oxo-7-phenylbicyclo[4.3.1]dec-7-ene-1-car-

(

EtOAc/petroleum ether = 1:20). H NMR (400 MHz, CDCl ): δ

boxylate (4w). Yield: 86% (23 mg), colorless oil, R = 0.6 (EtOAc/

.83 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.2 Hz,

H), 7.47−7.37 (m, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 6.9 Hz,

H), 5.62 (t, J = 3.4 Hz, 1H), 5.07 (hept, J = 6.2 Hz, 1H), 3.44 (d, J =

7.7 Hz, 1H), 2.90 (d, J = 5.8 Hz, 1H), 2.81−2.66 (m, 2H), 2.28−

petroleum ether = 1:20). H NMR (500 MHz, CDCl ): δ 7.27 (dd, J

= 15.5, 8.4 Hz, 5H), 5.93 (d, J = 6.1 Hz, 1H), 5.06 (dt, J = 12.2, 5.7

Hz, 1H), 3.57 (t, 1H), 3.10 (d, J = 18.0 Hz, 1H), 2.52−2.39 (m, 2H),

1.83−1.75 (m, 2H), 1.57−1.50 (m, 2H), 1.46−1.39 (m, 1H), 1.26−

.15 (m, 2H), 2.14−2.00 (m, 1H), 1.24 (d, J = 6.2 Hz, 6H). C{ H}

1.19 (m, 8H). C{ H} NMR (126 MHz, CDCl ): δ 209.7, 172.9,

NMR (101 MHz, CDCl ): δ 210.9, 170.8, 144.2, 138.2, 133.7, 131.0,

139.7, 139.3, 128.5, 127.6, 126.4, 124.3, 68.7, 59.4, 51.8, 36.7, 34.0,

−1

28.4, 128.2, 126.5, 126.0, 125.8, 125.6, 125.2, 124.2, 68.9, 55.6, 51.5,

29.7, 27.2, 26.3, 21.8, 21.7. IR (KBr, cm ): 3061, 2978, 2903, 1705,

1597, 1450, 1373, 1231, 1179, 1106, 1004, 903, 752, 693. HRMS

−

3.7, 30.9, 28.6, 21.8, 21.8. IR (KBr, cm ): 3055, 2979, 2874, 1756,

723, 1468, 1348, 1186, 1106, 800. HRMS (ESI-TOF): m/z [M +

(ESI-TOF): m/z [M + Na] calcd for C H O Na, 335.1618; found,

Na] calcd for C H O Na, 357.1461; found, 357.1462. HPLC:

335.1610. HPLC: WHELK-O1 column, 85:15 hexanes/isopropanol,

WHELK-O1 column, 95:5 hexanes/isopropanol, 0.80 mL/min, t =

0.80 mL/min, t = (major) 10.3 min, (minor) 14.8 min, 57% ee. [α]

(

major) 11.6 min, (minor) 13.5 min, 91% ee. [α]_D+11.6° (c 0.5,

EtOH).

Isopropyl (1S,5S)-8-Oxo-4-(thiophen-2-yl)bicyclo[3.2.1]oct-3-

ene-1-carboxylate (4s). Yield: 85% (23 mg), colorless oil, R = 0.6

+10.0° (c 0.40, DCM).

Isopropyl (1S,5S)-8-Oxo-4-((E)-styryl)bicyclo[3.2.1]oct-3-ene-1-

carboxylate (7a). Yield: 75% (21 mg), colorless oil. R = 0.6

(EtOAc/petroleum ether = 1:20). H NMR (500 MHz, CDCl ): δ

(

EtOAc/petroleum ether = 1:20). H NMR (500 MHz, CDCl ): δ

7.39 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.23 (t, J = 7.3 Hz,

1H), 6.67 (d, J = 16.2 Hz, 1H), 6.47 (d, J = 16.1 Hz, 1H), 5.70 (t, J =

3.8 Hz, 1H), 5.17−5.04 (m, 1H), 3.36 (d, J = 18.7 Hz, 1H), 3.14 (d, J

= 5.7 Hz, 1H), 2.85−2.67 (m, 2H), 2.31−2.08 (m, 3H), 1.32−1.25

.17 (d, J = 4.6 Hz, 1H), 6.99−6.92 (m, 2H), 5.98−5.92 (m, 1H),

.14−5.06 (m, 1H), 3.36 (d, J = 18.3 Hz, 1H), 3.18−3.13 (m, 1H),

.81−2.70 (m, 2H), 2.30−2.22 (m, 2H), 2.22−2.13 (m, 1H), 1.31−

.26 (m, 6H). ¹³C{ H} NMR (126 MHz, CDCl ): δ 209.9, 170.5,

(m, 6H). C{ H} NMR (126 MHz, CDCl ): δ 210.9, 170.6, 142.0,

42.4, 136.8, 127.4, 124.5, 122.8, 119., 69.0, 55.2, 49.2, 42.9, 30.8,

136.8, 128.7, 127.7, 127.1, 126.4, 124.9, 68.9, 55.5, 45.9, 43.1, 30.9,

−

−1

8.5, 21.8, 21.8. IR (KBr, cm ): 2925, 1755, 1722, 1456, 1277, 1241,

28.3, 21.8, 21.78. IR (KBr, cm ): 3059, 3030, 2981, 2936, 1758,

103, 1030, 754, 703. HRMS (ESI-TOF): m/z [M + Na] calcd for

1723, 1493, 1275, 1183, 1106, 740, 699. HRMS (ESI-TOF): m/z [M

C H O SNa, 313.0869; found, 313.0870. HPLC: WHELK-O1

+ Na] calcd for C H O Na, 333.1461; found, 333.1464. HPLC:

20 22

column, 95:5 hexanes/isopropanol, 1.00 mL/min, t = (major) 10.2

WHELK-O1 column, 95:5 hexanes/isopropanol, 0.60 mL/min, t =

(major) 14.5 min, (minor) 18.3 min, 93% ee. [α]_D+23.8° (c 0.63,

EtOH).

min, (minor) 21.1 min, 90% ee. [α]_D+15.7° (c 0.23, EtOH).

Isopropyl (1S,5S)-4-(Benzo[b]thiophen-2-yl)-8-oxobicyclo[3.2.1]-

oct-3-ene-1-carboxylate (4t). Yield: 69% (22 mg), colorless oil, R =

Isopropyl (1S,5S)-4-((E)-4-Methylstyryl)-8-oxobicyclo[3.2.1]oct-3-

.6 (EtOAc/petroleum ether = 1:20). H NMR (500 MHz, CDCl ):

ene-1-carboxylate (7b). Yield: 78% (23 mg), colorless oil. R = 0.6

δ 7.87−7.82 (m, 2H), 7.42−7.32 (m, 2H), 7.27 (s, 1H), 5.92 (t, 1H),

(EtOAc/petroleum ether = 1:20). H NMR (500 MHz, CDCl ): δ

.20−5.07 (m, 1H), 3.48 (dt, J = 18.0, 2.6 Hz, 1H), 3.07 (d, J = 5.2

7.28 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 6.62 (d, J = 16.1

Hz, 1H), 6.44 (d, J = 16.2 Hz, 1H), 5.66 (t, J = 3.7 Hz, 1H), 5.15−

5.06 (m, 1H), 3.35 (d, J = 18.2 Hz, 1H), 3.13 (d, J = 5.7 Hz, 1H),

2.79−2.67 (m, 2H), 2.33 (s, 3H), 2.27−2.20 (m, 1H), 2.19−2.09 (m,

Hz, 1H), 2.86−2.74 (m, 2H), 2.31−2.20 (m, 3H), 1.31 (d, J = 6.2 Hz,

H). ¹³C{ H} NMR (126 MHz, CDCl ): δ 210.2, 170.6, 140.4, 138.8,

37.4, 135.8, 124.6, 124.5, 123.5, 123.1, 123.0, 122.9, 69.0, 55.6, 50.6,

−

3.3, 30.9, 29.0, 21.8, 21.8. IR (KBr, cm ): 3048, 2978, 2923, 1812,

2H), 1.31−1.25 (m, 6H). C{ H} NMR (126 MHz, CDCl ): δ

757, 1586, 1257, 1239, 757. HRMS (ESI-TOF): m/z [M + Na]

211.0, 170.7, 142.1, 137.6, 134.0, 129.4, 127.0, 126.7, 126.4, 124.3,

68.9, 55.5, 45.9, 43.1, 30.9, 28.3, 21.8, 21.8, 21.2. IR (KBr, cm ):

2981, 1758, 1721, 1511, 1440, 1277, 1182, 1105, 1206, 963, 819.

−

calcd for C H O SNa, 363.1025; found, 363.1020. HPLC:

WHELK-O1 column, 90:10 hexanes/isopropanol, 0.80 mL/min, t

(major) 14.3 min, (minor) 31.1 min, 88% ee. [α]_D+11.6° (c 0.50,

HRMS (ESI-TOF): m/z [M + Na] calcd for C H O Na, 347.1618;

EtOH).

found, 347.1610. HPLC: WHELK-O1 column, 85:15 hexanes/

396

J. Org. Chem. 2021, 86, 5388−5400

The Journal of Organic Chemistry

Note

isopropanol, 0.80 mL/min, t = (major) 9.3 min, (minor) 16.5 min,

bar. Ketone 2/5 (0.12 mmol) and β-ketoesters 1 (0.1 mmol) were

added to the tube, and the reaction was stirred at 0 °C until substrate

1 was completely consumed (monitored by TLC). When the reaction

was ﬁnished, 0.5 equiv of TfOH was added, and the reaction was

stirred at 100 °C in an oil bath. When the reaction was ﬁnished

2% ee. [α]³−23.5° (c 0.34, EtOH).

Isopropyl (1S,5S)-4-((E)-4-Fluorostyryl)-8-oxobicyclo[3.2.1]oct-3-

ene-1-carboxylate (7c). Yield: 86% (26 mg), colorless oil. R = 0.6

(EtOAc/petroleum ether = 1:20). H NMR (500 MHz, CDCl ): δ

.35 (dd, J = 8.6, 5.5 Hz, 2H), 7.01 (t, J = 8.7 Hz, 2H), 6.58 (d, J =

6.1 Hz, 1H), 6.42 (d, J = 16.1 Hz, 1H), 5.69 (t, J = 3.7 Hz, 1H),

.14−5.07 (m, 1H), 3.36 (d, J = 18.7 Hz, 1H), 3.12 (d, J = 5.8 Hz,

H), 2.80−2.68 (m, 2H), 2.29−2.18 (m, 1H), 2.18−2.09 (m, 2H),

(monitored by TLC), NaHCO (2.0 equiv) was added to neutralize

the acidic solution at room temperature. The mixture was ﬁltered

through a short pad of silica gel. The ﬁltrate was removed under

reduced pressure to give a residue, which was puriﬁed by silica gel

chromatography (EtOAc/petroleum ether = 1:20) to aﬀord the

desired product.

Gram Scale Synthesis of 4c. Copper(II) triﬂuoromethanesulfonate

(5 mol %) and L1 (6 mol %) in 15 mL of dry DCE were stirred for 5

min in a 50 mL Schlenk tube. 1-Phenylprop-2-en-1-one (7.2 mmol,

953 mg) and β-ketoesters (6 mmol, 1.02 g) 1c were dissolved in 5 mL

of dry DCE and added dropwise to the mixture. The reaction was

stirred at 0 °C for 4 days until 1c was completely consumed. The

solvent was removed under reduced a vacuum, and the mixture was

puriﬁed by silica gel chromatography (EtOAc/petroleum ether =

.31−1.25 (m, 6H). C NMR (126 MHz, CDCl ) δ C{ H} NMR

(

126 MHz, CDCl ): δ 210.8, 170.6, 163.3 (C−F, J

= 248.1 Hz),

= 2.7 Hz),

C−F

61.1 (C−F, J

= 248.1 Hz), 141.9, 133.04 (C−F, J

C−F

33.02 (C−F, J

= 2.7 Hz), 127.95 (C−F, J

= 7.6 Hz), 127.85

C−F

(

C−F, J

= 7.6 Hz), 127.53 (C−F, J

= 2.7 Hz), 125.83, 125.01, 115.7 (C−F, J

= 2.7 Hz), 127.51 (C−F,

C−F

= 21.4 Hz), 115.5

C−F

(

C−F, J

= 21.4 Hz), 68.9, 55. 5, 45.9, 43.1, 30.9, 28.3, 21.8, 21.8.

F NMR (376 MHz, CDCl ): δ −114.05. IR (KBr, cm ): 3039,

C−F

−1

981, 1759, 1722, 1507, 1282, 1231, 1105, 961, 831. HRMS (ESI-

TOF): m/z [M + Na] calcd for C H FO Na, 351.1367; found,

:10) to give product 3c (1.08 g, 60%).

Compound 3c (1.08 g), 5 mol % TfOH, and 15 mL of DCE were

51.1360. HPLC: WHELK-O1 column, 85:15 hexanes/isopropanol,

.80 mL/min, t = (major) 9.1 min, (minor) 14.8 min, 93% ee. [α]

added to a Schlenk tube under air; the reaction was heated to 100 °C

in an oil bath and then stirred for 30 min. When the reaction was

ﬁnished, the solvent was removed under a reduced vacuum. The

mixture was puriﬁed by silica gel chromatography (EtOAc/petroleum

ether = 1:20) to aﬀord the product in 651 mg (92% ee, 64%).

Typical Procedure for the Synthesis of 8. To a solution of 4 (0.1

54.2° (c 0.45, EtOH).

Isopropyl (1S,5S)-4-((E)-4-Chlorostyryl)-8-oxobicyclo[3.2.1]oct-3-

ene-1-carboxylate (7d). Yield: 73% (33 mg, 0.13 mmol), yellow

solid, mp = 104−109 °C. R = 0.6 (EtOAc/petroleum ether = 1:20).

H NMR (500 MHz, CDCl ): δ 7.24−7.18 (m, 4H), 6.56 (d, J = 16.2

Hz, 1H), 6.33 (d, J = 16.1 Hz, 1H), 5.64 (t, J = 3.8 Hz, 1H), 5.06−

mmol, 1.0 equiv) in THF (1 mL) was added NaBH (0.12 mmol,

.00 (m, 1H), 3.29 (d, J = 18.8 Hz, 1H), 3.04 (d, J = 5.8 Hz, 1H),

.71−2.63 (m, 2H), 2.20−2.13 (m, 1H), 2.09−2.02 (m, 2H), 1.21 (d,

1.2eq) in portion. Then MeOH (100 μL) was added dropwise at 0

°C. The mixture was stirred for 5 min and quenched by water. The

organic phase was combined and concentrated in vacuo to give the

J = 6.3 Hz, 6H). C{ H} NMR (126 MHz, CDCl ): δ 210.7, 170.6,

41.8, 135.4, 133.3, 128.9, 128.3, 127.6, 125.8, 125.6, 68.9, 55.5, 45.9,

3.1, 30.9, 28.3, 21.8, 21.8. IR (KBr, cm ): 3025, 2980, 2936, 1759,

723, 1511, 1281, 1184, 961, 817. HRMS (ESI-TOF): m/z [M +

−

desired product 8. Yield: 84% (24 mg, 0.1 mmol), colorless liquid. R

0.6 (EtOAc/petroleum ether = 1:10). H NMR (400 MHz,

CDCl ): δ 7.38 (d, J = 7.2 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.23 (t, J

Na] calcd for C H O Na, 367.1071; found, 367.1076. HPLC:

WHELK-O1 column, 85:15 hexanes/isopropanol, 0.80 mL/min, t =

7.2 Hz, 1H), 6.02 (t, J = 3.6 Hz, 1H), 5.07 (p, J = 6.2 Hz, 1H), 4.52

(d, J = 4.4 Hz, 1H), 3.03 (t, J = 5.0 Hz, 1H), 2.92−2.77 (m, 1H),

(

major) 9.9 min, (minor) 15.8 min, 93% ee. [α]_D+142° (c 0.45,

EtOH).

Isopropyl (1S,5S)-4-((E)-4-Bromostyryl)-8-oxobicyclo[3.2.1]oct-3-

ene-1-carboxylate (7e). Yield: 87% (29 mg), yellow solid, mp = 96−

.44−2.25 (m, 2H), 2.25−2.10 (m, 1H), 2.08−1.94 (m, 1H), 1.94−

13 1

.79 (m, 2H), 1.31−1.18 (m, 6H). C{ H} NMR (101 MHz,

): δ 175.9, 140.7, 139.4, 128.4, 127.1, 125.4, 121.2, 75.1, 68.0,

CDCl

−1

9.2, 43.6, 34.5, 33.0, 29.9, 21.8, 21.8. IR (KBr, cm ): 3479, 2977,

722, 1495, 1464, 1373, 1281, 1240, 1240, 763, 696. HRMS (ESI-

8 °C. R = 0.6 (EtOAc/petroleum ether = 1:20). H NMR (500

MHz, CDCl ): δ 7.43 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H),

TOF): m/z [M + H] calcd for C H O , 287.1642; found,

.65 (d, J = 16.2 Hz, 1H), 6.39 (d, J = 16.1 Hz, 1H), 5.72 (t, J = 3.7

18 23

87.1637. HPLC: OD-H column, 99:1 hexanes/isopropanol, 0.10

Hz, 1H), 5.15−5.06 (m, 1H), 3.35 (d, J = 18.8 Hz, 1H), 3.11 (d, J =

mL/min, t = (major) 7.9 min, (minor) 9.9 min, 91% ee [α] −35.7°

.8 Hz, 1H), 2.80−2.68 (m, 2H), 2.28−2.19 (m, 1H), 2.18−2.09 (m,

(

c 1.4, EtOAc).

H), 1.31−1.25 (m, 6H). C{ H} NMR (126 MHz, CDCl ): δ

Typical Procedure for the Synthesis of 9. Tributylsilane (0.6

mmol, 3.0 equiv) was added to a solution of DCE/H O (10:1, 1 mL),

10.7, 170.5, 141.8, 135.8, 131.8, 128.4, 127.9, 125.8, 125.7, 121.4,

−1

8.9, 55.5, 45.8, 43.1, 30.9, 28.3, 21.8, 21.8. IR (KBr, cm ): 3034,

979, 1758, 1721, 1485, 1279, 1184, 1147, 1009, 822, 755. HRMS

c (0.2 mmol, 1.0 equiv) and Pd(OAc) (0.02 equiv) under air. The

(

ESI-TOF): m/z [M + Na]⁺calcd for C H BrO Na, 411.0566;

reaction was stirred at room temperature for 2 h. When the reaction

was ﬁnished, the mixture was ﬁltered through a short pad of Celite.

The ﬁltrate was concentrated and the resulting residue puriﬁed by

column chromatography. Yield: 80% (38 mg, 2.6:1 dr), colorless

liquid.

20 21 3

found, 411.0563. HPLC: WHELK-O1 column, 85:15 hexanes/

isopropanol, 0.80 mL/min, t = (major) 9.7 min, (minor) 15.3

_m_i_n_,₉₀_%_e_e_._[_α_]31 +43.2° (c 0.35, EtOH).

Isopropyl (1S,5S)-4-((E)-4-Methoxystyryl)-8-oxobicyclo[3.2.1]oct-

-ene-1-carboxylate (7f). Yield: 68% (25 mg), yellow solid, mp =

Compound 9a (Major). R

= 0.6 (EtOAc/petroleum ether = 1:20).

H NMR (400 MHz, CDCl ): δ 7.38−7.32 (m, 2H), 7.27 (d, J = 6.7

5−58 °C R = 0.6 (EtOAc/petroleum ether = 1:20). H NMR (400

MHz, CDCl ): δ 7.47 (d, J = 6.7 Hz, 1H), 7.24 (t, J = 7.1 Hz, 1H),

Hz, 3H), 5.12 (hept, J = 6.2 Hz, 1H), 3.48−3.28 (m, 1H), 2.71−2.49

(m, 2H), 2.40−2.28 (m, 1H), 2.24−2.10 (m, 2H), 2.06−1.92 (m,

.95 (t, J = 7.5 Hz, 1H), 6.91−6.82 (m, 2H), 6.70 (d, J = 16.3 Hz,

H), 5.70 (t, J = 3.7 Hz, 1H), 5.13 (hept, J = 6.2 Hz, 1H), 3.88 (s,

H), 3.38 (d, J = 18.7 Hz, 1H), 3.23 (d, J = 5.5 Hz, 1H), 2.83−2.67

2H), 1.91−1.82 (m, 2H), 1.30 (d, J = 6.3 Hz, 6H). C{ H} NMR

(101 MHz, CDCl ): δ 213.9, 171.0, 141.6, 128.6, 127.2, 126.8, 68.6,

−1

(

m, 2H), 2.34−2.05 (m, 3H), 1.31 (d, J = 6.2 Hz, 6H). C{ H}

57.4, 52.5, 50.0, 36.1, 27.3, 22.6, 21.8, 21.8, 17.7. IR (KBr, cm ):

NMR (101 MHz, CDCl ): δ 211.2, 170.7, 156.8, 142.7, 128.8, 128.0,

2928, 1750, 1719, 1652, 1400, 1384, 1267, 1175, 1106, 751, 698.

26.3, 125.9, 124.3, 121.9, 120.7, 110.9, 68.9, 55.6, 46.0, 43.1, 31.0,

8.4, 21.81, 21.77. IR (KBr, cm ): 2977, 2934, 1755, 1721, 1599,

490, 1247, 1103, 1025, 755. HRMS (ESI-TOF): m/z [M + Na]

HRMS (ESI-TOF): m/z [M + Na] calcd for C18

Na, 287.1642;

−

found, 287.1643. HPLC: OD-H column, 95:5 hexanes/isopropanol,

0.80 mL/min, t

= (major) 13.4 min, (minor) 12.8 min, 92% [α]

calcd for C H O Na, 363.1567; found, 363.1565. HPLC: WHELK-

−109.8° (c 0.41, EtOAc).

O1 column, 85:15 hexanes/isopropanol, 0.80 mL/min, t = (major)

Compound 9b (Minor). R

= 0.5 (EtOAc/petroleum ether = 1:20).

4.5 min, (minor) 18.3 min, 86% ee. [α]_D+17.7° (c 0.34, EtOH).

One-Pot Synthesis. Copper(II) triﬂuoromethanesulfonate (3.5 mg,

0 mol %) and L1 (6 mg, 12 mol %) were stirred for 5 min in 0.5 mL

H NMR (400 MHz, CDCl ): δ 7.34−7.26 (m, 4H), 7.23−7.17 (m,

1H), 5.06 (hept, J = 6.2 Hz, 1H), 3.50−3.34 (m, 1H), 2.75−2.53 (m,

3H), 2.44−2.19 (m, 2H), 2.18−2.00 (m, 3H), 1.98−1.88 (m, 1H),

of dry DCE in a 25 mL Schlenk tube charged with a magnetic stirring

1.26−1.22 (m, 6H). C{ H} NMR (101 MHz, CDCl ): δ 212.4,

397

J. Org. Chem. 2021, 86, 5388−5400

The Journal of Organic Chemistry

pubs.acs.org/doi/10.1021/acs.joc.1c00146 .

Note

71.0, 142.4, 128.5, 127.1, 126.5, 68.6, 56.8, 52.3, 50.6, 35.8, 26.4,

3.0, 22.7, 21.8, 21.8. IR (KBr, cm-1) 2926, 1749, 1719, 1452, 1384,

CDCl ): δ 208.2, 186.8, 185.7, 170.1, 142.0, 141.3, 139.9, 136.5,

136.4, 135.3, 128.8, 128.6, 127.1, 122.1, 69.1, 58.3, 54.9, 42.7, 41.7,

−1

274, 1237, 1207, 1179, 1101, 1042, 698, 635. HRMS (ESI-TOF):

31.0, 27.1, 21.8, 21.8, 21.5. IR (KBr, cm ): 2979, 1758, 1722, 1656,

1451, 1295, 1270, 1106, 735, 701. HRMS (ESI-TOF): m/z [M + H]⁺

calcd for C H O Na, 439.1516; found, 439.1514. HPLC: OD-H

m/z [M + Na] calcd for C H O Na, 287.1642; found, 287.1639.

HPLC: OD-H column, 95:5 hexanes/isopropanol, 0.80 mL/min, t =

26 25

(

major) 11.5 min, (minor) 14.8 min, 92% [α]_D+30.73° (c 0.41,

EtOAc).

Typical Procedure for the Synthesis of 10. At 0 °C, potassium

column, 90:10 hexanes/isopropanol, 0.80 mL/min, t = (major) 24.9

min, (minor) 56.9 min, 93% ee. [α] −28.6° (c 0.05, DCM).

tert-butoxide (0.4 mmol, 2.0 equiv) was added in portion to the

suspention of methyltriphenylphosphonium bromide (0.4 mmol, 2.0

equiv) in 2 mL dry THF in a 25 mL Schlenk tube and stirred for 1 h.

ASSOCIATED CONTENT

sı Supporting Information

X-ray crystallographic data (ORTEP diagrams) of product 4k

CCDC: 2042797) along with its important crystal data, table

■

c (0.2 mmol, 1.0 equiv) was dissolved in 0.5 mL THF and added to

(

the stirred mixture dropwise at −20 °C and then warmed to room

temperature slowly. The reaction was quenched by H O after stirred

of experimental conditions for optimization studies, asym-

metric induction model, HPLC traces for all products of this

for 12 h. The organic phase was collected and washed with brine (3 ×

mL). The mixture was puriﬁed by silica gel chromatography

paper, H NMR, C{ H} NMR spectra for all the new

compounds and NOE spectra for 8, 9, 12 (PDF). The

Supporting Information is available free of charge at https://

(EtOAc/petroleum ether = 1:30) to aﬀord 10 as a yellow solid (33

mg, 58%), mp = 48−49 °C. H NMR (400 MHz, CDCl ): δ 7.42 (d,

J = 7.7 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.31−7.25 (m, 1H), 5.84 (t,

J = 3.6 Hz, 1H), 5.27−5.11 (m, 1H), 4.93 (s, 1H), 4.76 (s, 1H), 3.41

(PDF )

(

d, J = 4.7 Hz, 1H), 3.09 (d, J = 17.8 Hz, 1H), 2.66−2.44 (m, 2H),

.21−2.07 (m, 2H), 2.03−1.88 (m, 1H), 1.40−1.28 (m, 6H).

Accession Codes

C{ H} NMR (101 MHz, CDCl ): δ 174.1, 153.7, 144.0, 140.1,

CCDC 2042797 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/data_request/cif , or by emailing

data_request@ccdc.cam.ac.uk , or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

28.4, 127.0, 125.2, 120.2, 100.7, 68.0, 52.4, 47.5, 42.7, 34.7, 33.8,

−

1.9, 21.8. IR (KBr, cm ): 3025, 2979, 1222, 1493, 1447, 1350,

274, 1243, 118, 1108, 894, 759. HRMS (ESI-TOF): m/z [M + H]

calcd for C H O , 283.1693; found, 283.1702. HPLC: IA column,

9:1 hexanes/isopropanol, 0.60 mL/min, t = (major) 6.9 min,

(minor) 8.4 min, 92% ee. [α]_D+36.1° (c 0.41, DCM).

Typical Procedure for the Synthesis of 11. A mixture of 10 (0.1

mmol, 1.0eq) and 1 mL NaOH (2N)/THF/MeOH (2:1:2) was

added to a 25 mL Schlenk tube, the tube was sealed and the reaction

was heated to 90 °C in oil bath overnight. The solution was quenched

by HCl (2M) and extracted with EtOAc (3 × 1 mL). The combined

organic phases were washed with brine (2 mL), dried over Na SO ,

AUTHOR INFORMATION

Corresponding Authors

■

Tongxiang Cao − Key Laboratory of Functional Molecular

Engineering of Guangdong Province, School of Chemistry and

Chemical Engineering, South China University of Technology,

Guangzhou 510640, People ’s Republic of China;

orcid.org/0000-0003-4246-4340; Email: caotx@

scut.edu.cn

and concentrated under vacuum to give the white solid which was

used without further puriﬁcation. To a solution of the white solid in

CH CN (0.5 mL), Cu(OAc) (0.05 equiv) and DMAP (0.1 equiv)

was added azidoformate (0.12 mmol, 1.2 equiv) which was dissolved

in 0.5 mL CH CN. The tube was sealed and stirred under 80 °C in oil

Shifa Zhu − Key Laboratory of Functional Molecular

Engineering of Guangdong Province, School of Chemistry and

Chemical Engineering, South China University of Technology,

Guangzhou 510640, People ’s Republic of China;

orcid.org/0000-0001-5172-7152; Email: zhusf@

scut.edu.cn

bath for 8 h. The reaction was monitored by TLC. When the reaction

was ﬁnished, the solvent was removed and the residue was puriﬁed by

silica gel chromatography. Yield: 63% (20 mg, 0.1 mmol), white solid,

mp = 117−120 °C R = 0.7 (EtOAc/petroleum ether = 1:10). H

NMR (400 MHz, CDCl ): δ 7.42 (d, J = 7.3 Hz, 2H), 7.36 (t, J = 7.5

Hz, 2H), 7.31−7.28 (m, 1H), 5.83 (t, J = 3.7 Hz, 1H), 5.30 (s, 1H),

4.96 (s, 1H), 4.84 (d, J = 11.7 Hz, 1H), 4.74 (s, 2H), 3.47 (d, J = 5.6

Authors

Hz, 1H), 3.01 (d, J = 14.1 Hz, 1H), 2.66 (d, J = 16.8 Hz, 1H), 2.39−

Zhehui Liao − Key Laboratory of Functional Molecular

Engineering of Guangdong Province, School of Chemistry and

Chemical Engineering, South China University of Technology,

Guangzhou 510640, People’s Republic of China

Jiantao Zhang − College of Chemistry, Guangdong University

of Petrochemical Technology, Maoming 525000, People’s

Republic of China

(

.32 (m, 1H), 2.32−2.24 (m, 1H), 2.24−2.10 (m, 1H), 2.10−2.01

_m_,₁_H₎_.1 C{ H} NMR (101 MHz, CDCl ): δ 153.3, 152.9, 144.4,

39.6, 128.5, 127.2, 125.2, 119.7, 98.2, 95.8, 74.2, 60.3, 46.1, 45.6,

5.1, 32.5. IR (KBr, cm-1) 3346, 2951, 1749, 1501, 1235, 1214, 1148,

114, 1038, 817, 757, 730, 695. HRMS (ESI-TOF): m/z [M + H]

calcd for C H C NO , 386.0476; found, 386.0473. HPLC: OD-H

19 l3

column, 99:1 hexanes/isopropanol, 1 mL/min, t = (major) 14.0 min,

(

minor) 16.0 min, 92% ee [α]_D+27.5° (c 0.56, EtOAc).

Typical Procedure for the Synthesis of 12. To a 25 mL Schlenk

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00146

tube charge with a magnetic stir bar was added 7a (0.1 mmol, 1.0

equiv), benzoquinone (0.3 mmol, 3.0 equiv), zinc iodide (0.05 mmol,

0.5 equiv) and 1 mL toluene. The reaction was stirred at 80 °C in oil

Notes

bath overnight. Then the mixture was ﬁltered with a short pad of silica

gel, the solvent was evaporated. The residue was puriﬁed by ﬂash

The authors declare no competing ﬁnancial interest.

chromatography to aﬀord the product as brown solid (50%, 21 mg).

ACKNOWLEDGMENTS

We appreciate ﬁnancial support from Ministry of Science and

Technology of the People’s Republic of China

2016YFA0602900), the NSFC (22071062, 22001077,

1871096), Guangdong Science and Technology Department

(2018B030308007, 2018A030310359), China Postdoctoral

Science Foundation (2018M643062, 2019T120723).

■

mp = 78−90 °C. H NMR (500 MHz, CDCl ): δ 7.26 (d, J = 7.2 Hz,

H), 7.18 (t, J = 7.3 Hz, 1H), 7.11 (d, J = 7.5 Hz, 2H), 6.74 (d, J =

0.0 Hz, 1H), 6.62 (d, J = 10.1 Hz, 1H), 5.59 (d, J = 3.9 Hz, 1H),

.15−5.02 (m, 1H), 4.62 (t, J = 4.9 Hz, 1H), 3.92−3.77 (m, 1H),

.06 (d, J = 6.6 Hz, 1H), 2.89 (dd, J = 12.7, 5.6 Hz, 1H), 2.72 (td, J =

3.3, 4.5 Hz, 1H), 2.43−2.31 (m, 1H), 2.27−2.14 (m, 1H), 2.10−

(

.92 (m, 2H), 1.28 (d, J = 6.3 Hz, 6H). C{ H} NMR (126 MHz,

398

J. Org. Chem. 2021, 86, 5388−5400

The Journal of Organic Chemistry

Note

versatile platform to access methanobenzo[7]annulenes. Angew.

Chem., Int. Ed. 2017, 56, 12930.

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