Divergent Total Syntheses of Yaequinolone-Related Natural Products by Late-Stage C-H Olefination

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Divergent Total Syntheses of Yaequinolone-Related Natural

Products by Late-Stage C−H Oleﬁnation

́

̃

Wen-Liang Jia, Sabela Vega Ces, and M. Angeles Fern á ndez-Ib á nez*

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ABSTRACT: Divergent total syntheses of 10 yaequinolone-related natural products have been achieved for the ﬁrst time by late-

stage C−H oleﬁnation of 3,4-dioxygenated 4-aryl-5-hydroxyquinolin-2(1H)-ones, core structures of this family of natural products. A

robust synthetic methodology to construct the core structures has been established, and the C−H oleﬁnation reaction has been

carried out with synthetically useful yields and high levels of site-selectivity under mild reaction conditions in the presence of a Pd/

S,O-ligand catalyst.

diastereoisomers that diﬀer in the conﬁguration of the pyranyl

tertiary methyl group. The group of Christmann successfully

synthesized ( )-peniprequinolone, ( )-aﬂaquinolones E and

F, ( )-6-deoxyaﬂaquinolone E, ( )-quinolinones A and B, and

( )-aniduquinolone C by developing a general method for the

construction of N-glycolated 2-aminobenzophenone via aryne

insertions into unsymmetrical imides in ﬂow (Scheme 1c).¹⁰

In spite of this progress, a general strategy to access these

natural products in a direct and divergent manner is still

elusive.¹¹As many members of this family of natural products

(>20) only diﬀer from each other in the structure of the oleﬁn

at the 6-position, we envisioned that their syntheses can be

achieved from a key common intermediate in a divergent

manner using late-stage site-selective C−H oleﬁnation.¹²

Herein, we report a new methodology for the late-stage

C(6)−H oleﬁnation of 3,4-dioxygenated 4-aryl-5-hydroxy-

quinolin-2(1H)-ones and its successful application in the

divergent total syntheses of 10 yaequinolone-related natural

products, which are synthesized for the ﬁrst time (Scheme 1d).

INTRODUCTION

■

Yaequinolones and related compounds that comprise 3,4-

dioxygenated 4-aryl-quinolin-2(1H)-one cores represent a

growing family of biologically active alkaloids isolated from

marine and plant fungi (Figure 1a).¹The ﬁrst two members,

NTC-47A and B, were isolated from the second metabolites of

Penicillium sp. by Nakaya in 1995 and they showed promising

insecticidal activities.²Since then, many more related

compounds have been discovered and their structures,

bioactivities, and biosynthetic mechanisms have been in-

tensively studied.³⁻⁶Structurally, the two oxygenated func-

tional groups at 3- and 4-positions have a cis-conﬁguration for

most of the members.⁷Moreover, the majority of these natural

products possess a hydroxyl group at the 5-position and only

diﬀer from each other in the oleﬁn moiety present at the 6-

position (Figure 1b).

This family of natural products has attracted great attention

in the last few years due to their unique structures and

biological activities, and the total syntheses of few members of

this family of natural products have been reported. The ﬁrst

total synthesis of this family of natural products was the

synthesis of ( )-yaequinolone A2, the structurally simplest

molecule among the family (Scheme 1a).⁸The key step of this

approach is the intramolecular aldol reaction of N-glycolated 2-

aminobenzophenone to construct the quinolone core,

generating the two oxygenated functional groups in a cis-

fashion. The ﬁrst enantioselective total syntheses of (−)-yae-

quinolones J1 and J2 were reported in 2018 by the group of

Hanessian (Scheme 1b).⁹The authors used an Evans-type

chiral auxiliary to provide the syn-aldol diol as a 1:1 mixture of

Received: January 6, 2021

Published: April 22, 2021

American Chemical Society

https://doi.org/10.1021/acs.joc.1c00042

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Figure 1. Structures of yaequinolone-related natural products.

the oleﬁnated product was obtained in 48% yield with good

C(6)-selectivity.

RESULTS AND DISCUSSION

■

In 2019, we reported a highly selective C(6)−H oleﬁnation

reaction of tetrahydroquinolines (THQs) in the presence of a

Pd/S,O-ligand catalyst (Scheme 2a).¹³We hypothesized that

late-stage selective C(6)−H oleﬁnation of 3,4-dioxygenated 4-

aryl-5-hydroxy-quinolin-2(1H)-one cores could be developed

in the presence of a Pd/S,O-ligand catalyst to directly access

yaequinolone-related natural products in a divergent manner.

First, we evaluated the C−H oleﬁnation reaction of N-

methyl-3,4-dihydroquinolin-2(1H)-one (1a), the simpliﬁed

backbone of yeaquinolone-related natural products, with

ethyl acrylate under reported reaction conditions for the

oleﬁnation of THQs. As expected, because the aromatic ring is

less activated,^13,14the reaction only provided the oleﬁnated

After having proved the suitability of the C−H oleﬁnation

reaction on model substrates, we proposed the retrosynthetic

route for 3,4-dioxygenated 4-aryl-5-hydroxy-quinolin-2(1H)-

ones as outlined in Figure 2. 3,4-dioxygenated 4-aryl-5-

hydroxy-quinolin-2(1H)-one can be obtained by cyclization

as reported by the group of She.⁸The starting diarylketone can

be synthesized from the nucleophilic addition of the lithiated

3-oxygenated 2-bromonitrobenzene, which can be prepared

from commercially available 2-bromo-3-nitrophenol, to para-

anisaldehyde, followed by oxidation.

The synthesis of the core structure is shown in Scheme 4. 2-

Bromo-3-nitrophenol (8) was ﬁrst protected with a benzyl

group in 91% yield, followed by lithiation at low temperature

and reaction with para-anisaldehyde, providing the corre-

sponding alcohol 10 in 86% yield. We then reduced the nitro

group using sodium sulﬁde to form the aniline intermediate 11,

followed by amide formation with methoxyacetyl chloride. The

formed amide intermediate 12 was oxidized with PCC,

providing the ketone 13 in 94% yield. The cyclization of 13

under reported reaction conditions produced ( )-14 in 80%

yield as a single diastereoisomer.⁸Then, we decided to protect

the nitrogen atom with 2-(trimethylsilyl)ethoxymethyl (SEM),

as it can be deprotected using mild reagents, such as

tetrabutylammonium ﬂuoride (TBAF).¹⁶Then, we introduced

the SEM-protecting group to ( )-14 using LiHMDS as the

base. SEM-protected 3,4-dihydro-2(1H)-quinolinone deriva-

tive ( )-16 was obtained in 95% yield after benzyl

deprotection of ( )-15 using Pd/C and H₂(Scheme 4).

For the C−H oleﬁnation of ( )-16, we slightly optimized

the reaction conditions and found that the best conditions

1

product in less than 10% H NMR yield (Scheme 2b). When

the reaction was performed at 80 °C, a slightly higher yield of

23% was achieved (Scheme 2b).

Because all our target natural products have a hydroxyl

group at the 5-position, we decided to investigate the eﬀect of

this functional group on the reactivity of the C−H oleﬁnation

of quinolin-2(1H)-ones. We tested N-methyl-3,4-dihydro-

2(1H)-quinolinones bearing an OMe, OEt, or/and OMOM

group at the 5-position (2a−4a, Scheme 3). As expected,

because these substrates are more activated, synthetically

useful yields (45−57%) were observed and the C(6)-oleﬁnated

products were exclusively formed. The reaction of the OMe

derivative 2a without the S,O-ligand only gave a trace amount

of oleﬁnated product, highlighting the key role of the S,O-

ligand in this transformation. We also evaluated the oleﬁnation

reaction of substrate 5a bearing a free OH group at the 5-

position, but the oleﬁnated product 5b was obtained only in

27% yield due to its instability under the reaction conditions.¹⁵

Having established the beneﬁcial eﬀect of the oxygenated

moiety at the 5-position in the C−H oleﬁnation reaction, we

decided to evaluate other protecting groups at the nitrogen

atom. The reaction with the MOM-protected substrate 6a

provided the desired oleﬁnated product 6b in 46% yield with

slightly lower C(6)-selectivity. When the benzyl-protected

substrate 7a was subjected to the standard reaction conditions,

t

were 2.0 equiv of PhCO₃Bu in dichloroethane (DCE) at 80

°C for 16 h, providing the oleﬁnated product ( )-17 in 59%

isolated yield with a regioselectivity of 6:1 (A/B) together with

5% of the dioleﬁnated product (Table 1). However, the

regioisomers were not separable by ﬂash column chromatog-

raphy. We, therefore, continued the total synthesis with the

mixture of regioisomers.

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Scheme 1. Total Syntheses of Yaequinolone-Related Natural Products

Scheme 2. Reactivity Comparison of THQs and 1a

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a

,b,c

Scheme 3. C−H Oleﬁnation of 5-Oxgenated N-Methyl-3,4-dihydro-2(1H)-quinolinones

a

t

Reaction conditions: a (0.1 mmol), ethyl acrylate (0.15 mmol), Pd(OAc)₂(0.01 mmol), S,O-ligand (0.01 mmol), and PhCO₃Bu (0.1 mmol) in

b

c

DCE (0.5 mL) at 80 °C for 16 h. Isolated yield. Regioselectivity was determined based on the analysis of crude mixture.

Figure 2. Retrosynthetic analysis of 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-ones.

We performed the deprotection of the SEM group with

TBAF, and it was found out that a high concentration of TBAF

is required to obtain the desired product in good yield. For

instance, when the concentration of TBAF was 0.1 M, no

product was observed even after reﬂuxing the reaction for 20 h.

When we increased the concentration to 1.0 M, to our delight,

the reaction reached full conversion after reﬂuxing for 15 h and

( )-yaequinolone B was obtained in 60% isolated yield as a

̅

initial report from the group of Omura, we decided to ﬁrst try

the oleﬁn ( )-trans-20 (see the Experimental Section).^4cTo

our delight, the oleﬁnated product ( )-21 was isolated in 52%

yield with a regioselectivity of 7:1 (A/B) (Scheme 7a).

However, we observed the formation of four diastereoisomers,

indicating that racemization of one of the stereocenters of the

oleﬁn moiety has occurred. To prove this, we performed the

oleﬁnation of ( )-16 with a mixture of ( )-trans- and

( )-cis-20 (1:1), and we observed the formation of the same

four diastereoisomers (Scheme 7b). Moreover, we further tried

the oleﬁnation of the model substrate 5a with ( )-trans-20

and with a 1:1 mixture of ( )-trans- and ( )-cis-20 and in

both cases, the oleﬁnated product was obtained as a mixture of

diastereoisomers in almost 1:1 ratio, conﬁrming that

racemization has occurred in one of the stereocenters of the

oleﬁn moiety during the C−H oleﬁnation (Scheme 7c).¹⁷

The deprotection of the oleﬁnated product ( )-21 (A/B =

7:1) using 4.0 M of TBAF reached full conversion after

reﬂuxing overnight, providing ( )-yaequinolone C together

with three other diastereoisomers in 79% isolated yield with an

improved regioselectivity of 10.4:1 (Scheme 8). Based on the

results obtained from the reaction of ( )-16 with ( )-trans-

20 and with a 1:1 mixture of ( )-trans- and ( )-cis-20, we

proposed that the oleﬁn moiety has a trans-conﬁguration (see

Supporting Information). Therefore, the structure of ( )-yae-

quinolone C is either 22-A or 22-B.

1

single regioisomer (Scheme 5). Its H and ¹³C NMR data

matched with those reported in the literature.^4cHence, the

total synthesis of ( )-yaequinolone B was achieved in 10.6%

overall yield in 10 synthetic steps starting from commercially

available 2-bromo-3-nitrophenol.

Encouraged by these results, we moved our attention to the

total syntheses of ( )-penigequinolones A and B, which can be

accomplished by only changing the oleﬁn coupling partner

while keeping the same core structure ( )-16. Oleﬁn ( )-18

was prepared in six synthetic steps starting from ethyl

isobutyrate (see the Experimental Section). The C−H

oleﬁnation of ( )-16 using ( )-18 as the oleﬁn under

standard reaction conditions furnished the oleﬁnated product

( )-19 in 50% yield with a regioselectivity of 8.8:1 (A/B) and

a diastereoselectivity of 1:1. The SEM deprotection of ( )-19

with TBAF (4.0 M) almost quantitatively yielded a mixture of

( )-penigequinolones A and B (dr = 1:1) with improved

1

regioselectivity (13.5:1) (Scheme 6). Their H and ¹³C NMR

data matched with those reported in the literature.^4c

In an eﬀort to synthesize ( )-aspoquinolones C and D, we

performed the oleﬁnation reaction of ( )-16 with ( )-cis-23,

but no desired product was observed and ( )-16 was fully

For the synthesis of ( )-yaequinolone C, as the relative

stereochemistry of the oleﬁn moiety was not determined in the

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Scheme 4. Synthesis of the Core Structure ( )-16

Table 1. Reaction Conditions for the C−H Oleﬁnation of ( )-16

a

entry

temp. (°C)

x

time (h)

¹H NMR yield

1

2

3

4

5

80

60

80

1.5

1.0

2.0

1.5

16

6

16

49%

31%

45%

42%

b c

,

b d

,

54% (59% + 5%

55%

)

e

6

a

b

c

¹H NMR yield of the desired regioisomer was determined by using CH₂Br₂as the internal standard. Isolated yield. Regioselectivity was

d

e

determined from the crude mixture: A/B = 6:1. Dioleﬁnated product. 15 mol % of Pd(OAc)₂and S,O-ligand were used.

Scheme 5. Synthesis of ( )-Yaequinolone B

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Scheme 6. Syntheses of ( )-Penigequinolones A and B

Scheme 7. C−H Oleﬁnation of ( )-16 and 5a with ( )-19

1

recovered (Scheme 9a). Considering that the free hydroxyl

group from the oleﬁn might be the problem, we protected the

OH of ( )-cis-23 with the TMS group. The reaction of

( )-16 with TMS-protected oleﬁn ( )-cis-24 gave a mixture

of TMS-protected and unprotected oleﬁnated products with

50% conversion (Scheme 9b). To simplify the puriﬁcation, we

directly treated the crude mixture with TBAF to deprotect the

TMS group.¹⁸After puriﬁcation, the oleﬁnated product

( )-25 was isolated in 43% yield as a single regioisomer

[the other regioisomer was detected by H NMR analysis of

the crude and separated by preparative thin layer chromatog-

raphy (TLC)]. Unfortunately, like in the previous case,

epimerization also occurred and four diastereoisomers were

detected with a ratio of 2.2:2.2:1:1. The SEM deprotection of

( )-25 with TBAF led to full decomposition of the starting

material. Then, we performed the deprotection reaction using

Me₂AlCl.¹⁹This two-step deprotection procedure provided

( )-aspoquinolones C and D together with two other

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Scheme 8. Synthesis of ( )-Yaequinolone C

Scheme 9. Syntheses of ( )-Aspoquinolones C and D

diastereoisomers with diastereoselectivity (2.2:2.2:1:1) remain-

ing in 73% combined yield (Scheme 9c). As the relative

stereochemistry of the oleﬁn moieties of aspoquinolones C and

D was not determined in the initial report,^4bwe propose, based

on our results, that one has the cis-conﬁguration on the oleﬁn

moiety and the other one has the trans-conﬁguration.

After proving the synthetic power of late-stage C−H

oleﬁnation by the Pd/S,O-ligand catalyst in the divergent

synthesis of ( )-yaequinolones B and C, ( )-penigequino-

lones A and B, and ( )-aspoquinolones C and D, we decided

to move our attention to the total syntheses of another class of

closely related quinolone natural products, which all share a

slightly diﬀerent backbone (a phenyl group located at the 4-

position instead of a 4-methoxyphenyl group). We prepared

the corresponding 3,4-dihydro-2(1H)-quinolinone derivative

( )-27 in seven synthetic steps starting from 9 using the same

procedure for the preparation of ( )-16 (see Experimental

Section) (Scheme 10).

To synthesize ( )-aﬂaquinolones A, C, and D, we prepared

oleﬁn ( )-28 as a mixture of diastereoisomers (trans/cis =

5:4) in seven synthetic steps starting from ethyl 4-

oxocyclohexanecarboxylate (see the Experimental Section).²⁰

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Scheme 10. Syntheses of ( )-Aﬂaquinolones A, C, and D and ( )-Scopuquinolone B

The coupling of this unactivated oleﬁn 28 with ( )-27 gave

the oleﬁnated product ( )-29 in 34% yield with perfect

regioselectivity (>20:1) and with a diastereoselectivity of

1:1:1.6:1.6. The SEM deprotection of ( )-29 with TBAF

failed to give any desired product, while the reaction with

Me₂AlCl provided ( )-aﬂaquinolones A, C, and D together

with another diastereoisomer in near-quantitative yield with a

diastereoselectivity of 1:1:1:1. Thus, epimerization occurred

during the deprotection reaction probably at the α-position of

the ketone.

Our last target was the synthesis of ( )-scopuquinolone B

that can be synthesized by coupling the core structure ( )-27

with the trans-oleﬁn ( )-31. The oleﬁnation reaction of

( )-27 with oleﬁn ( )-31 furnished the oleﬁnated product

( )-32 in 39% yield with a diastereoselectivity of 1:1:1:1. The

SEM deprotection of ( )-32 with Me₂AlCl provided

( )-scopuquinolone B together with three other diaster-

eoisomers in 89% yield with retained diastereoselectivity of

1:1:1:1.

ligand catalyst. The power of the oleﬁnation reaction was

showcased by successfully using unactivated oleﬁns as coupling

partners. Through this synthetic approach, the relative

conﬁguration of the oleﬁn moiety of some of these natural

products has been elucidated. Our future eﬀorts will be

devoted toward the divergent enantioselective total syntheses

of this family of natural products.

EXPERIMENTAL SECTION

■

General Information. Chromatography: Silicycle Silica Flash P60

size 40−63 μm (230−400 mesh), TLC: Merck silica gel 60 (0.25

mm), and preparative TLC: Analtech silica gel G 1500 μm 20 × 20

cm. Visualization of the TLC plate was performed with

phosphomolybdic acid or KMnO4 staining reagent and UV light.

Mass spectra were recorded on AccuTOF GC v 4g, JMS-T100GCV

1

mass spectrometers. H and ¹³C were recorded on Bruker 500 AMX,

400 and Bruker DRX 300 using CDCl₃as the solvent otherwise it will

be noted. Chemical shift values are reported in ppm with the solvent

resonance as the internal standard (CDCl₃: δ 7.26 for ¹H and δ 77.16

1

for ¹³C; dimethyl sulfoxide: δ 2.50 for H and δ 39.52 for ¹³C; and

1

acetone: δ 2.05 for H and δ 206.26 for ¹³C). Data are reported as

CONCLUSIONS

follows: chemical shifts, multiplicity (s = singlet, d = doublet, dd =

doublet of doublets, t = triplet, q = quartet, and m = multiplet),

coupling constants (Hz), and integration. IR spectra were recorded on

a Bruker Alpha Fourier transform infrared machine and wavelengths

are reported in cm⁻¹. The melting point was measured in melting

■

In summary, we have developed novel divergent syntheses of

10 yaequinolone-related natural products, which are synthe-

sized for the ﬁrst time, by late-stage C−H oleﬁnation of 3,4-

dioxygenated 4-aryl-5-hydroxyquinolin-2(1H)-ones, core struc-

tures of this family of natural products. A robust synthetic

methodology is established to construct the core structures and

the C−H oleﬁnation reaction is eﬃcient and site-selective

under mild reaction conditions in the presence of a Pd/S,O-

point apparatus Buchi M-565. Tetrahydrofuran (THF) and diethyl

̈

ether were dried over Na using benzophenone as the indicator.

Dichloromethane was dried over CaH₂and was used freshly after

distillation. Anhydrous dimethylformamide (DMF) was purchased

from Acros and used as received. Absolute ethanol was purchased

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from VWR Amsterdam and was used as received. TBAF solution (1.0

M in THF) was purchased from Fluorochem And Pd(OAc)₂was

purchased from Strem. The S,O-ligand was prepared using the

procedure reported in the literature.^13b

(dd, J = 10.8, 1.4 Hz, 1H), 3.22 (s, 2H), 1.51−1.46 (m, 2H), 1.27 (s,

3H), 1.25−1.20 (m, 2H), 0.89 (s, 9H), 0.02 (s, 6H). ¹³C{H} NMR

(75 MHz): δ 145.4, 111.8, 77.4, 73.5, 71.4, 36.5, 35.0, 32.5, 27.8, 26.1,

24.3, 24.3, 18.4, −5.4. HRMS (EI) m/z: [M]⁺calcd for C₁₆H₃₄O₂Si⁺,

286.2328; found, 286.2295.

Synthesis of Oleﬁns. 2,5,5-Trimethyl-2-vinyltetrahydro-2H-

pyran (18) was prepared using the following procedures: Step A: In

a ﬂame-dried Schlenk ﬂask were added ethyl isobutyrate (5.563 mL,

4.84 g, 41.7 mmol, 1.0 equiv) and anhydrous THF (40 mL) under N₂.

In another ﬂask, lithium diisopropylamide (LDA) (50 mmol, 1.2

equiv) was prepared and transferred to the substrate ﬂask at −78 °C

via a cannula over a period of 0.5 h. The reaction was stirred for 2 h

before 1-bromo-2-chloroethane (8.613 mL, 14.34 g, 100 mmol, 2.4

equiv) was added. The reaction was then warmed up to room

temperature and stirred overnight. The reaction was quenched by

adding saturated aqueous NH₄Cl solution and was extracted with

EtOAc three times. The combined extracts were washed with brine,

dried over Na₂SO₄, and evaporated in vacuo. The product was

puriﬁed by ﬂash column chromatography (PE/Et₂O, 100:1 to 50:1)

giving ethyl 4-chloro-2,2-dimethylbutanoate (Int-A) as a colorless oil

Step E: In a round-bottom ﬂask were added Int-D (1.00 g, 3.49

mmol, 1.0 equiv) and THF (15 mL). TBAF solution (1.0 M in THF,

8.7 mL, 8.7 mmol, 2.5 equiv) was added dropwise. The reaction was

left to stir at room temperature for 4 h before it was quenched by

adding saturated aqueous NH₄Cl solution. The mixture was extracted

with EtOAc three times. The combined extracts were washed with

brine, dried over Na₂SO₄, and evaporated in vacuo. The product was

puriﬁed by ﬂash column chromatography (n-hexane/EtOAc, 11:1)

giving 2,2,5-trimethylhept-6-ene-1,5-diol (Int-E) as a white solid

1

(0.50 g, 83%). H NMR (300 MHz): δ 5.85 (dd, J = 17.3, 10.7 Hz,

1H), 5.16 (dd, J = 17.4, 1.3 Hz, 1H), 5.01 (dd, J = 10.8, 1.3 Hz, 1H),

3.33−3.18 (m, 2H), 2.76 (br s, 2H), 1.48−1.42 (m, 2H), 1.28−1.20

(m, 2H), 1.25 (s, 3H), 0.82 (s, 3H), 0.81 (s, 3H). ¹³C{H} NMR (75

MHz): δ 145.2, 111.8, 73.4, 70.7, 35.9, 34.75, 31.6, 27.9, 24.5, 24.2.

1

+

HRMS (FD) m/z: [M]⁺calcd for C₁₀H₂₀O₂, 172.1463; found,

(6.10 g, 82%). Its H NMR data matched with those reported in the

literature.²¹¹H NMR (400 MHz): δ 4.16 (q, J = 7.1 Hz, 2H), 3.57−

3.48 (m, 2H), 2.12−2.03 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.24 (s,

6H).

172.1470.

Step F: In a ﬂame-dried Schlenk ﬂask were successively added Int-

E (200 mg, 1.16 mmol, 1.0 equiv), DCE (25 mL), and anhydrous

ZnCl₂(158 mg, 1.16 mmol, 1.0 equiv) under N₂. The reaction was

then stirred at 70 °C for 2 h before it was quenched by adding

saturated aqueous NH₄Cl solution. The mixture was extracted with

Et₂O three times. The combined extracts were passed through a short

plug of silica gel and rinsed with Et₂O. The ﬁltrate was evaporated in

vacuo giving 2,5,5-trimethyl-2-vinyltetrahydro-2H-pyran (18) as a

Step B: In a ﬂame-dried Schlenk ﬂask were added LiBH₄(0.92 g,

42 mmol, 1.5 equiv) and anhydrous DCM (20 mL). To this

suspension was then slowly added MeOH (1.7 mL). After the

evolution of H₂has ceased, Int-A (5.00 g, 28 mmol, 1.0 equiv) was

added. The reaction was then heated under reﬂux at 45 °C overnight.

The reaction was quenched by carefully adding water and the mixture

was extracted with EtOAc three times. The combined extracts were

washed with brine, dried over Na₂SO₄, and evaporated in vacuo. The

product was puriﬁed by ﬂash column chromatography (PE/Et₂O,

100:1 to 1:1) giving 4-chloro-2,2-dimethylbutan-1-ol (Int-B) as a

1

colorless oil (130 mg, 73%). H NMR (400 MHz): δ 5.78 (dd, J =

17.4, 11.4 Hz, 1H), 5.17 (s, 1H), 5.13 (dd, J = 7.9, 1.3 Hz, 1H), 3.33

(d, J = 11.3 Hz, 1H), 3.21 (dd, J = 11.3, 2.0 Hz, 1H), 1.73−1.61 (m,

2H), 1.45−1.37 (m, 1H), 1.35−1.28 (m, 1H), 1.23 (s, 3H), 0.99 (s,

2H), 0.81 (s, 2H). ¹³C{H} NMR (101 MHz): δ 143.3, 114.3, 74.2,

72.7, 33.5, 30.7, 29.8, 28.7, 26.7, 24.2. HRMS (FD) m/z: [M + Na]⁺

calcd for C₁₀H₁₈NaO⁺, 177.1255; found, 177.1268.

trans-Linalool oxide (trans-20) was prepared using the following

procedures: Linalool oxide was purchased from TCI as a mixture of

diastereoisomers (1:1) not separable by ﬂash column chromatog-

raphy. To separate the diastereoisomers, the hydroxyl group was ﬁrst

protected with TMS using the following procedure:

In a round bottom ﬂask were successively added linalool oxide (20,

dr = 1:1) (1.01 g, 5.92 mmol, 1.0 equiv), DCM (12 mL), 1-imidazole

(1.21 g, 17.8 mmol, 3.0 equiv), and TMSCl (1.13 mL, 8.88 mmol, 1.5

equiv). The reaction was then stirred at room temperature for 0.5 h

before water was added. The mixture was extracted with Et₂O three

times. The combined organic extracts were washed with brine, dried

over Na₂SO₄, and evaporated in vacuo. The product TMS-trans-

linalool oxide (TMS-trans-20) was obtained as a colorless oil after

puriﬁcation by ﬂash column chromatography using PE as the eluent.

Its ¹H NMR data matched with those reported in the literature.²⁴¹H

NMR (400 MHz): δ 5.86 (dd, J = 17.2, 10.5 Hz, 1H), 5.16 (d, J =

17.3 Hz, 1H), 4.97 (d, J = 10.6 Hz, 1H), 3.74 (t, J = 6.1 Hz, 1H),

1.94−1.76 (m, 3H), 1.71−1.63 (m, 1H), 1.30 (s, 3H), 1.21 (s, 3H),

1.20 (s, 3H), 0.11 (s, 9H).

1

colorless oil (2.50 g, 65%). Its H NMR data matched with those

reported in the literature.²²¹H NMR (300 MHz): δ 3.64−3.51 (m,

2H), 3.35 (d, J = 0.7 Hz, 2H), 1.88−1.75 (m, 2H), 0.93 (s, 6H).

Step C: In a round-bottom ﬂask were successively added Int-B

(1.37 g, 10 mmol, 1.0 equiv), DCM (15 mL), and TBSCl (3.01 g, 20

mmol, 2.0 equiv). After stirring the mixture for 5 min, 1-imidazole

(1.36 g, 20 mmol, 2.0 equiv) was then added and the stirring was

continued for another 2 h. Saturated aqueous NH₄Cl solution was

added to quench the reaction and the mixture was extracted with

EtOAc three times. The combined extracts were washed with brine,

dried over Na₂SO₄, and evaporated in vacuo. The product was

puriﬁed by ﬂash column chromatography (PE/Et₂O, 20:1) giving tert-

butyl(4-chloro-2,2-dimethylbutoxy)dimethylsilane (Int-C) as a color-

less oil (2.50 g, quantitative yield). ¹H NMR (300 MHz): δ 3.62−3.50

(m, 2H), 3.25 (s, 2H), 1.84−1.72 (m, 2H), 0.89 (s, 9H), 0.81 (s, 6H),

0.03 (s, 6H). ¹³C{H} NMR (75 MHz): δ 71.7, 42.7, 41.8, 36.0, 26.0,

24.3, 18.4, −5.4. HRMS (FD) m/z: [M − ^tBu]⁺calcd for

C₈H₁₈ClOSi⁺, 193.0815; found, 193.0854.

Step D: In a ﬂame-dried Schlenk ﬂask were added Int-C (1.50 g,

5.98 mmol, 1.0 equiv), Mg (0.18 g, 7.41 mmol, 1.24 equiv), and

anhydrous THF (2 mL) under N₂. The mixture was then heated to

reﬂux and a few drops of 1,2-dibromoethane were slowly added to the

reaction. The reaction was continued to stir for another 6 h while

reﬂuxing at 80 °C. In another ﬂame-dried Schlenk ﬂask were added

anhydrous CeCl₃(1.47 g, 5.98 mmol, 1.0 equiv) and anhydrous THF

(12 mL), and the suspension was stirred at room temperature for 1 h.

The freshly prepared Grignard reagent was transferred to the

suspension via a cannula at 0 °C. The reaction was further stirred

at 0 °C for 1 h before but-3-en-2-one (1.0 mL, 11.96 mmol, 2.0 equiv)

was added. After stirring it at 0 °C for 1 h, the reaction was quenched

by adding saturated aqueous NH₄Cl solution and the mixture was

extracted with EtOAc three times. The combined extracts were

washed with brine, dried over Na₂SO₄, and evaporated in vacuo. The

product was puriﬁed by ﬂash column chromatography (PE/EtOAc,

15:1) giving 7-[(tert-butyldimethylsilyl)oxy]-3,6,6-trimethylhept-1-en-

3-ol (Int-D) as a colorless oil (1.01 g, 59%). ¹H NMR (400 MHz): δ

5.89 (dd, J = 17.4, 10.7 Hz, 1H), 5.20 (dd, J = 17.3, 1.4 Hz, 1H), 5.04

he TMS-protecting group was then removed by using the

following step: In a round bottom ﬂask were added TMS-trans-

T

20 (2.70 g, 11.13 mmol, 1.0 equiv) and THF (50 mL). TBAF solution

(33 mL, 1.0 M in THF, 3.0 equiv) was then added slowly. The

reaction was stirred for 1 h before water was added. The mixture was

extracted with Et₂O three times. The combined organic extracts were

washed with brine, dried over Na₂SO₄, and evaporated in vacuo. The

sample was puriﬁed by ﬂash column chromatography (n-hexane/

EtOAc, 5:1) giving trans-linalool oxide (trans-20) as a colorless oil

1

(1.70 g, 89%). Its H NMR data matched with those reported in the

literature.²³¹H NMR (400 MHz): δ 5.88 (dd, J = 17.3, 10.6 Hz, 1H),

5.19 (d, J = 17.3 Hz, 1H), 5.00 (d, J = 10.7 Hz, 1H), 3.80 (t, J = 7.1

Hz, 1H), 2.10−1.79 (m, 5H), 1.78−1.67 (m, 1H), 1.32 (s, 3H), 1.23

(s, 3H), 1.14 (s, 3H).

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TMS-cis-2,2,6-trimethyl-6-vinyltetrahydropyran-3-ol (cis-24).

2,2,6-Trimethyl-6-vinyltetrahydropyran-3-ol (23) was purchased

from TCI as a mixture of diastereoisomers (1:1) not separable by

ﬂash column chromatography. The TMS protection and deprotection

strategy was used to separate them as presented for the separation of

linalool oxide (20). TMS protection was performed using the same

procedure as the TMS protection of linalool oxide, and cis-24 was

isolated as a colorless oil after puriﬁcation by ﬂash column

chromatography with PE as the eluent. ¹H NMR (400 MHz): δ

5.96 (ddd, J = 18.2, 10.9, 1.2 Hz, 1H), 4.99−4.91 (m, 2H), 3.40 (dd, J

= 11.3, 4.1 Hz, 1H), 2.10 (dt, J = 12.7, 3.3 Hz, 1H), 1.80−1.65 (m,

1H), 1.62−1.48 (m, 2H), 1.15 (s, 3H), 1.14 (s, 3H), 1.13 (s, 3H),

0.10 (d, J = 1.1 Hz, 9H). ¹³C{H} NMR (101 MHz): δ 146.6, 110.6,

76.6, 75.7, 73.5, 32.9, 32.2, 30.1, 26.4, 20.9, 0.05. HRMS (FD) m/z:

[M − Me]⁺calcd for C₁₂H₂₃O₂Si⁺, 227.1467; found, 227.1485.

cis-2,2,6-Trimethyl-6-vinyltetrahydropyran-3-ol (cis-23). Depro-

tection of cis-24 (0.60 g, 2.475 mmol) was performed using the same

procedure as the deprotection of TMS-trans-linalool oxide (TMS-

trans-20). cis-23 was isolated as a wax (0.42 g, quantitative yield) and

its ¹H NMR data matched with those reported in the literature.²⁴¹H

NMR (400 MHz): δ 5.99 (dd, J = 18.1, 11.0 Hz, 1H), 5.03 (d, J = 5.5

Hz, 1H), 4.99 (d, J = 1.1 Hz, 1H), 3.51−3.43 (m, 1H), 2.15 (dt, J =

13.6, 3.7 Hz, 1H), 1.77−1.71 (m, 2H), 1.64−1.58 (m, 1H), 1.28 (s,

3H), 1.20 (s, 3H), 1.19 (s, 3H).

2,4-Dimethyl-4-vinylcyclohexanone (28) and 2,4-dimethyl-4-vinyl-

cyclohexanol (31) were prepared using the following procedures: Step

A: In a round-bottom ﬂask were successively added ethyl 4-

oxocyclohexane-1-carboxylate (9.29 mL, 10.00 g, 58.8 mmol, 1.0

equiv), ethylene glycol (11.5 mL, 12.77 g, 205.8 mmol, 3.5 equiv), p-

toluenesulfonic acid monohydrate (137 mg, 0.012 equiv), and

anhydrous toluene (30 mL). The reaction was then stirred overnight

at room temperature. Saturated aqueous Na₂CO₃solution was added

and the reaction was extracted with EtOAc three times. The

combined organic extracts were washed with brine, dried over

Na₂SO₄, and evaporated in vacuo. The product was puriﬁed by ﬂash

column chromatography (PE/EtOAc, 15:1) giving ethyl 1,4-

dioxaspiro[4.5]decane-8-carboxylate as a colorless oil (10.94 g,

87%). Its ¹H NMR data matched with those reported in the

literature.²⁵¹H NMR (400 MHz): δ 4.05 (q, J = 7.1 Hz, 2H), 3.86 (s,

4H), 2.29−2.22 (m, 1H), 1.91−1.80 (m, 2H), 1.79−1.64 (m, 4H),

1.54−1.42 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H).

Step B: In a ﬂame-dried Schlenk ﬂask were successively added 1,4-

dioxaspiro[4.5]decane-8-carboxylate (10.94 g, 51.1 mmol, 1.0 equiv)

and anhydrous THF (70 mL). The solution was slowly transferred to

another Schlenk ﬂask containing freshly prepared LDA (66.4 mmol,

1.3 equiv) at −78 °C over a period of 0.5 h. THF (10 mL) was used

to rinse the ﬂask and was also transferred. The reaction was then

slowly warmed up to room temperature and stirred for 0.5 h before it

was cooled to −78 °C again. MeI (6.36 mL, 14.50 g, 102.2 mmol, 2.0

equiv) was added dropwise and the reaction was slowly warmed up to

room temperature. After stirring it overnight, the reaction was

quenched by adding saturated aqueous NH₄Cl solution and was

extracted with EtOAc three times. The combined organic extracts

were washed with brine, dried over Na₂SO₄, and evaporated in vacuo.

The product was puriﬁed by ﬂash column chromatography (PE/

EtOAc, 20:1) giving ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-

carboxylate as a colorless oil (9.68 g, 83%). Its ¹H NMR data

matched with those reported in the literature.²⁵¹H NMR (400

MHz): δ 4.02 (q, J = 7.1 Hz, 2H), 3.81 (s, 4H), 2.00 (dt, J = 13.0, 3.6

Hz, 2H), 1.58−1.32 (m, 6H), δ 1.13 (t, J = 7.1 Hz, 3H), 1.06 (s, 3H).

Step C: In a ﬂame-dried Schlenk ﬂask were added ethyl 8-methyl-

1,4-dioxaspiro[4.5]decane-8-carboxylate (7.20 g, 31.5 mmol, 1.0

equiv) and anhydrous DCM (70 mL). LAH (2.63 g, 69.4 mmol,

2.2 equiv) was added in small portions at 0 °C. The reaction was

stirred at 0 °C for 0.5 h before it was warmed up to room temperature

slowly. After the reaction was stirred for 1.5 h, the reaction was

diluted with DCM and saturated aqueous potassium sodium tartrate

solution was carefully added. The reaction was then stirred vigorously

for 1 h. The mixture was extracted with DCM three times. The

combined organic extracts were washed with brine, dried over

Na₂SO₄, and evaporated in vacuo to give (8-methyl-1,4-

dioxaspiro[4.5]decan-8-yl)methanol as a white solid (5.81 g, 99%),

which was pure enough to continue for the next step without further

1

puriﬁcation. Its H NMR data matched with those reported in the

literature.²⁵¹H NMR (400 MHz): δ 3.94 (d, J = 1.7 Hz, 4H), 3.39 (s,

2H), 1.73−1.49 (m, 6H), 1.45−1.34 (m, 3H), 0.96 (s, 3H).

Step D: In a round-bottom ﬂask were successively added (8-

methyl-1,4-dioxaspiro[4.5]decan-8-yl)methanol (4.90 g, 26.3 mmol,

1.0 equiv), DCM (60 mL), and PCC (12.48 g, 57.9 mmol, 2.2 equiv).

After the reaction was stirred at room temperature for 1 h, it was

ﬁltrated through a plug of silica gel and rinsed with EtOAc. The

ﬁltrate was evaporated and puriﬁed by ﬂash column chromatography

(PE/EtOAc, 5:1) giving 8-methyl-1,4-dioxaspiro[4.5]decane-8-carbal-

dehyde a colorless oil (4.20 g, 87%). Its ¹H NMR data matched with

those reported in the literature.²⁶¹H NMR (400 MHz): δ 9.46 (s,

1H), 3.93 (s, 4H), 2.07−1.92 (m, 2H), 1.70−1.49 (m, 6H), 1.04 (s,

3H).

Step E: In a ﬂame-dried Schlenk ﬂask were added methyl

triphenylphosphonium bromide (13.44 g, 37.6 mmol, 1.65 equiv)

and anhydrous THF (75 mL) at 0 °C under N₂. n-BuLi (13.7 mL, 2.5

M in hexanes, 34.25 mmol, 1.5 equiv) was then added dropwise. The

reaction was warmed up to room temperature and stirred for 0.5 h

before it was cooled to 0 °C again. In another ﬂask, a solution of 8-

methyl-1,4-dioxaspiro[4.5]decane-8-carbaldehyde (4.20 g, 22.8 mmol,

1.0 equiv) in anhydrous THF (20 mL) was prepared and the solution

was slowly transferred to the Wittig reagent ﬂask via a cannula over a

period of 0.5 h. 10 mL of anhydrous THF was used to rinse the ﬂask

and was also transferred. The reaction was then stirred at room

temperature for 3 h. Acetone (5 mL) was added to quench the Wittig

reagent. The mixture was ﬁltrated and washed with Et₂O. The ﬁltrate

was evaporated and puriﬁed by ﬂash column chromatography (n-

pentane/Et₂O, 15:1) giving 8-methyl-8-vinyl-1,4-dioxaspiro[4.5]-

1

decane as a pale yellow oil (3.46 g, 83%). Its H NMR data matched

with those reported in the literature.²⁶¹H NMR (400 MHz): δ 5.79

(dd, J = 17.8, 10.7 Hz, 1H), 5.01 (d, J = 4.6 Hz, 1H), 4.98 (s, 1H),

3.93 (s, 4H), 1.69−1.61 (m, 6H), 1.53−1.44 (m, 2H), 1.01 (s, 3H).

Step F: 8-Methyl-8-vinyl-1,4-dioxaspiro[4.5]decane (3.40 g, 18.7

mmol) was dissolved in acetone (60 mL). 10% HCl (24 mL) was

then added dropwise. The reaction was stirred for 2.5 h before brine

was added. The mixture was extracted with DCM/Et₂O (1:2) three

times. The volatiles were carefully evaporated in vacuo giving 4-

methyl-4-vinylcyclohexan-1-one as a colorless oil (2.57 g, quantitative

yield). Its ¹H NMR data matched with those reported in the

literature.²⁶¹H NMR (400 MHz): δ 5.89 (dd, J = 17.5, 11.0 Hz, 1H),

5.18−5.08 (m, 2H), 2.45−2.25 (m, 4H), 1.97−1.90 (m, 2H), 1.74−

1.67 (m, 2H), 1.12 (d, J = 0.9 Hz, 3H).

Step G: In a ﬂame-dried Schlenk ﬂask was added LiHMDS (7.6

mL, 1.0 M in THF, 7.6 mmol, 1.05 equiv) under N₂and 4-methyl-4-

vinylcyclohexan-1-one (1.00 g, 7.2 mmol, 1.0 equiv) in DMF (4 mL)

was added dropwise at −78 °C. The reaction was then left to stir for

1.5 h before MeI (446 μL, 7.2 mmol, 1.0 equiv) was added dropwise.

The reaction was slowly warmed up to room temperature and stirred

overnight. The reaction was quenched by adding saturated aqueous

NH₄Cl solution and was extracted with Et₂O three times. The

combined extracts were washed with water three times and brine,

dried over Na₂SO₄, and evaporated in vacuo. The product was

puriﬁed by ﬂash column chromatography (n-pentane/Et₂O, 20:1)

giving 2,4-dimethyl-4-vinylcyclohexan-1-one (28) as a pale yellow oil

(0.82 g, 74%, dr: trans/cis = 5:4). ¹H NMR (400 MHz): δ 5.98 (dd, J

= 17.6, 10.9 Hz, 1H_trans), 5.84 (dd, J = 17.5, 10.7 Hz, 1H_cis), 5.26−

5.19 (m, 1H_transand 1H_cis), 5.04−4.95 (m, 1H_transand 1H_cis), 2.66−

2.41 (m, 2H_transand 2H_cis), 2.34 (dt, J = 14.4, 3.8 Hz, 1H_cis), 2.25

(ddd, J = 14.0, 4.5, 2.5 Hz, 1H_trans), 2.10−2.01 (m, 1H_transand 1H_cis),

1.81−1.77 (m, 1H_trans), 1.73−1.65 (m, 1H_cis), 1.51 (t, J = 13.4 Hz,

1H_cis), 1.44 (m, t, J = 13.4 Hz, 1H_trans), 1.33 (s, 3H_cis), 1.06 (s,

3H_trans), 1.04 (d, J = 6.5 Hz, 2H_cis), 1.01 (d, J = 6.5 Hz, 3H_trans).

¹³C{H} NMR (75 MHz): δ 213.9, 213.5, 148.3, 144.8, 113.5, 110.6,

47.0, 46.4, 41.3, 40.7, 38.5 (trans and cis), 37.9 (trans and cis), 37.7,

37.5, 30.3, 22.1, 14.7, 14.5. HRMS (FD) m/z: [M]⁺calcd for

C₁₀H₁₆O⁺, 152.1201; found, 152.1211.

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Step H: In a ﬂame-dried Schlenk ﬂask were added 37 (dr = 5:4,

0.36 g, 2.36 mmol, 1.0 equiv) and anhydrous Et₂O (70 mL). LAH

(0.18 g, 4.74 mmol, 2.0 equiv) was added in small portions at 0 °C.

The reaction was stirred for 0.5 h before it was warmed up to room

temperature slowly. After the reaction was stirred for 1.5 h, the

reaction was diluted with Et₂O and saturated aqueous potassium

sodium tartrate solution was carefully added. The reaction was then

stirred vigorously for 1 h. The mixture was extracted with Et₂O three

times. The combined organic extracts were washed with brine, dried

over Na₂SO₄, and evaporated in vacuo. The product was puriﬁed by

ﬂash column chromatography (n-pentane/Et₂O, 5:1) giving 2,4-

dimethyl-4-vinylcyclohexanol (31) as a pale yellow oil (0.35 g, 96%,

dr: A/B = 5:4). ¹H NMR (300 MHz): δ 5.78 (dd, J = 17.6, 10.8 Hz,

1H_Aand 1H_B), 5.07−4.84 (m, 2H_Aand 2H_B), 3.14−3.05 (m, 1H_A

and 1H_B), 1.87−1.22 (m, 7H_Aand 7H_B), 1.05 (s, 3H_B), 0.99 (d, J =

6.5 Hz, 3H_B), 0.97 (d, J = 6.7 Hz, 3H_A), 0.95 (s, 3H_A). ¹³C{H} NMR

(75 MHz): δ 150.4, 146.2, 112.5, 109.4, 45.4, 44.4, 37.2, 36.5, 36.4,

36.1, 35.5, 35.5, 31.9 (A and B), 31.2, 31.1, 22.4 (A and B), 18.8, 18.7.

HRMS (FD) m/z: [M]⁺calcd for C₁₀H₁₈O⁺, 154.1358; found,

154.1360.

equiv), EtBr (0.7 mg, 6.42 mmol, 1.5 equiv), and anhydrous DMF (5

mL) under N₂. The reaction was then stirred at 70 °C for 5 h. Water

was then added and the mixture was extracted with EtOAc three

times. The combined organic extracts were washed with water three

times and brine two times, dried with MgSO₄, ﬁltrated, and

concentrated in vacuo to yield 5-ethoxy-3,4-dihydroquinolin-2(1H)-

one as a white solid (800 mg, 98%), which was pure enough to be

1

directly used for the next step. Its H NMR data matched with those

reported in the literature.²⁹¹H NMR (400 MHz): δ 7.58 (br s, 1H),

7.10 (t, J = 8.1 Hz, 1H), 6.56 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 7.9 Hz,

1H), 4.05 (q, J = 7.0 Hz, 2H), 2.97 (t, J = 7.7 Hz, 2H), 2.60 (dd, J =

8.4, 6.9 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H).

5-Ethoxy-N-methyl-3,4-dihydroquinolin-2(1H)-one (3a). In a

ﬂame-dried Schlenk ﬂask were added 5-ethoxy-3,4-dihydroquinolin-

2(1H)-one (191 mg, 1.0 mmol, 1.0 equiv) and anhydrous DMF (2

mL) under N₂. NaH (60 mg, 60% in mineral oil, 1.5 mmol, 1.5 equiv)

was then added at 0 °C and stirred for 0.5 h. MeI (170 mg, 1.2 mmol,

1.2 equiv) was then added dropwise at 0 °C. The reaction was then

warmed up to room temperature and stirred overnight. The reaction

was quenched by adding water and extracted with EtOAc three times.

The combined organic extracts were washed with water three times

and brine two times, dried with MgSO₄, ﬁltrated, and concentrated in

Synthesis of Model Substrates. 5-Methoxy-N-methyl-3,4-

dihydroquinolin-2(1H)-one (2a). In a ﬂame-dried Schlenk ﬂask

were added 5-hydroxy-3,4-dihydroquinolin-2(1H)-one (326 mg, 2.0

mmol, 1.0 equiv) and anhydrous DMF (10 mL) under N₂. NaH (240

mg, 60% in mineral oil, 6.0 mmol, 3.0 equiv) was then added at 0 °C

and stirred for 0.5 h. MeI (500 μL, 8.0 mmol, 4.0 equiv) was then

added dropwise at 0 °C. The reaction was then warmed up to room

temperature and stirred overnight. The reaction was quenched by

adding water and extracted with EtOAc three times. The combined

organic extracts were washed with water three times and brine two

times, dried with Na₂SO₄, ﬁltrated, and concentrated in vacuo to give

1

vacuo to give 3a as a white solid (200 mg, 98%). Its H NMR data

matched with those reported in the literature.²⁹¹H NMR (400

MHz): δ 7.20−7.15 (m, 1H), 6.63−6.61 (m, 2H), 4.05 (q, J = 7.0 Hz,

2H), 3.34 (s, 3H), 2.93−2.88 (m, 2H), 2.60 (t, J = 7.3 Hz, 2H), 1.42

(t, J = 7.0 Hz, 3H).

5-Ethoxy-N-(methoxymethyl)-3,4-dihydroquinolin-2(1H)-one

(6a). In a ﬂame-dried Schlenk ﬂask were added 5-ethoxy-3,4-

dihydroquinolin-2(1H)-one (150 mg, 0.78 mmol, 1.0 equiv) and

freshly distilled THF (3 mL) under N₂. NaH (47 mg, 60% in mineral

oil, 1.17 mmol, 1.5 equiv) was then added at 0 °C. After stirring it for

0.5 h at 0 °C, MOMCl (70 μL, 0.94 mmol, 1.2 equiv) was added to

the reaction at 0 °C dropwise. After stirring it for 2 h at room

temperature, the reaction was quenched by slowly adding water and

extracted with EtOAc three times. The combined organic extracts

were washed with brine, dried over Na₂SO₄, and evaporated in vacuo.

The product was puriﬁed by ﬂash column chromatography (PE/

EtOAc, 4:1) giving 6a as a pale yellow solid (99 mg, 54%). ¹H NMR

(300 MHz): δ 7.21−7.12 (m, 1H), 6.93 (d, J = 7.9 Hz, 1H), 6.63 (d, J

= 8.2 Hz, 1H), 5.30 (s, 2H), 4.05 (q, J = 6.5 Hz, 2H), 3.40 (s, 3H),

2.93 (t, J = 7.5 Hz, 2H), 2.68−2.62 (m, 2H), 1.42 (t, J = 7.0 Hz, 3H).

¹³C{H} NMR (101 MHz): δ 171.7, 155.7, 140.9, 127.9, 114.7, 108.8,

1

2a as a pale yellow solid (380 mg, 99%). Its H NMR data matched

with those reported in the literature.²⁷¹H NMR (400 MHz): δ 7.21

(t, J = 8.2 Hz, 1H), 6.64 (d, J = 8.3 Hz, 2H), 3.85 (s, 3H), 3.35 (s,

3H), 2.89 (dd, J = 8.6, 6.4 Hz, 2H), 2.60 (dd, J = 8.6, 6.4 Hz, 2H).

5-Hydroxy-N-methyl-3,4-dihydroquinolin-2(1H)-one (5a). In a

ﬂame-dried Schlenk ﬂask were added 2a (1.15 g, 6.0 mmol, 1.0 equiv)

and anhydrous DCM (10 mL) under N₂. A solution of BBr₃in DCM

(18 mL, 1.0 M, 18.0 mmol, 3.0 equiv) was added dropwise at −78 °C.

After stirring the reaction for another 1 h at −78 °C, the reaction was

slowly warmed up to room temperature and stirred for additional 3 h.

Water was slowly added to quench the reaction and the reaction was

extracted with DCM three times. The combined organic extracts were

washed with water and brine, dried with MgSO₄, ﬁltrated, and

concentrated in vacuo to give 5a as a pale yellow solid (1.02 g, 96%).

Its ¹H NMR data matched with those reported in the literature.²⁸¹H

NMR (400 MHz): δ 7.11 (t, J = 8.2 Hz, 1H), 6.61 (d, J = 8.2 Hz,

1H), 6.54 (d, J = 7.9 Hz, 1H), 3.35 (s, 3H), 2.90 (dd, J = 8.7, 6.3 Hz,

2H), 2.64 (dd, J = 8.5, 6.4 Hz, 2H).

107.1, 74.2, 64.1, 56.4, 31.5, 18.3, 15.0. HRMS (FD) m/z: [M]⁺calcd

+

for C₁₃H₁₇NO₃, 235.1208; found, 235.1219.

4-{[5-Ethoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl]methyl}phenyl

Acetate (7a). In a ﬂame-dried Schlenk ﬂask were added 5-ethoxy-3,4-

dihydroquinolin-2(1H)-one (215 mg, 1.12 mmol, 1.0 equiv) and

anhydrous DMF (3 mL) under N₂. NaH (54 mg, 60% in mineral oil,

1.35 mmol, 1.2 equiv) was then added at 0 °C and stirred for 0.5 h at

0 °C. 4-(Bromomethyl)phenyl acetate (332 mg, 1.46 mmol, 1.3

equiv) was then added at 0 °C. The reaction was then warmed up to

room temperature and stirred overnight. The reaction was quenched

by adding water and extracted with EtOAc three times. The combined

organic extracts were washed with water three times and brine two

times, dried over MgSO4, ﬁltrated, and concentrated in vacuo. The

product was puriﬁed by ﬂash column chromatography (n-hexane/

EtOAc, 3:1) giving 7a as a pale yellow solid (250 mg, 66%). mp

5-(Methoxymethoxy)-N-methyl-3,4-dihydroquinolin-2(1H)-one

(4a). In a ﬂame-dried Schlenk ﬂask were added 5a (532 mg, 3.0

mmol, 1.0 equiv) and freshly distilled THF (10 mL) under N₂. NaH

(156 mg, 60% in mineral oil, 3.9 mmol, 1.3 equiv) was then added

portionwise at 0 °C. After stirring it at room temperature for 0.5 h,

MOMCl (1.127 g, 15.1 mmol, 1.2 equiv) was added to the reaction

dropwise at 0 °C. After stirring it for 3 h at room temperature, the

reaction was quenched by slowly adding water and extracted with

EtOAc three times. The combined organic extracts were washed with

brine, dried over Na₂SO₄, and evaporated in vacuo. The product was

puriﬁed by ﬂash column chromatography (n-hexane/EtOAc, 3:1)

giving 4a as a pale yellow solid (500 mg, 75%). ¹H NMR (400 MHz):

δ 7.18 (t, J = 8.3 Hz, 1H), 6.85 (dd, J = 8.4, 0.9 Hz, 1H), 6.68 (d, J =

8.2 Hz, 1H), 5.21 (s, 2H), 3.49 (s, 3H), 3.35 (s, 3H), 2.93 (dd, J =

8.6, 6.4 Hz, 2H), 2.61 (dd, J = 8.6, 6.4 Hz, 2H). ¹³C{H} NMR (75

MHz): δ 170.6, 154.1, 141.9, 127.8, 115.5, 109.3, 108.8, 94.8, 56.3,

1

102.0−103.3 °C. H NMR (400 MHz): δ 7.22 (d, J = 8.2 Hz, 2H),

7.07−7.01 (m, 3H), 6.58 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 8.2 Hz,

1H), 5.15 (s, 2H), 4.04 (q, J = 6.9 Hz, 2H), 2.98 (dd, J = 8.6, 6.3 Hz,

2H), 2.73 (dd, J = 8.7, 6.3 Hz, 2H), 2.27 (s, 3H), 1.42 (t, J = 6.9, 3H).

¹³C{H} NMR (101 MHz): δ 170.8, 169.6, 155.9, 149.7, 141.0, 135.0,

127.8, 127.6, 121.9, 114.8, 108.5, 106.8, 64.1, 46.0, 31.5, 21.3, 18.3,

15.0. IR ν: 2977, 1758, 1671, 1594, 1467, 1188, 728 cm⁻¹. HRMS

+

31.2, 29.9, 18.3. HRMS (FD) m/z: [M]⁺calcd for C₁₂H₁₅NO₃,

+

(FD) m/z: [M]⁺calcd for C₂₀H₂₁NO₄, 339.1471; found, 339.1471.

221.1052; found, 221.1061.

Synthesis of Core Structures ( )-16 and ( )-27 of

Yaequinolone-Related Natural Products. Synthesis of ( )-16.

1-(Benzyloxy)-2-bromo-3-nitrobenzene (9). In a round-bottom ﬂask

were added 2-bromo-3-nitrophenol (8) (2.18 g, 10.0 mmol, 1.0

5-Ethoxy-3,4-dihydroquinolin-2(1H)-one. In a ﬂame-dried

Schlenk ﬂask were added 5-hydroxy-3,4-dihydroquinolin-2(1H)-one

(0.70 g, 4.29 mmol, 1.0 equiv), K₂CO₃(1.23 mg, 8.93 mmol, 2.1

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equiv), K₂CO₃(4.15 g, 30.0 mmol, 3.0 equiv), benzyl chloride (2.3

mL, 20 mmol, 2.0 equiv), and EtOH (15 mL) successively. The

mixture was then reﬂuxed at 85 °C overnight. The volatiles were

removed in vacuo. The product was puriﬁed by ﬂash column

chromatography (PE/EtOAc, 3:1) giving 9 as a yellow solid (2.80 g,

91%). mp 73.0−74.0 °C. ¹H NMR (400 MHz): δ 7.49 (d, J = 7.6 Hz,

2H), 7.48−7.26 (m, 5H), 7.17−7.09 (m, 1H), 5.25 (s, 2H). ¹³C{H}

NMR (101 MHz): δ 156.6, 135.6, 128.9, 128.7, 128.5, 127.2, 117.0,

equiv) was then added portionwise. After stirring it at room

temperature for 1 h, TLC showed full conversion of the reaction.

The reaction was then quenched by a saturated solution of Na₂SO₃

and extracted with DCM three times. The combined organic extracts

were washed with brine, dried over Na₂SO₄, and evaporated in vacuo.

The product was puriﬁed by ﬂash column chromatography (n-

hexane/EtOAc, 1.5:1) giving 13 as a pale yellow oil (1.30 g, 94%). ¹H

NMR (400 MHz): δ 9.32 (br s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.82−

7.75 (m, 2H), 7.37 (t, J = 8.4 Hz, 1H), 7.19−7.06 (m, 3H), 6.91−

6.82 (m, 4H), 6.78 (d, J = 8.3 Hz, 1H), 4.89 (s, 2H), 3.87 (s, 2H),

3.78 (s, 3H), 3.32 (s, 3H). ¹³C{H} NMR (101 MHz): δ 194.9, 168.1,

163.7, 156.6, 136.3, 136.0, 131.7, 131.5, 128.0, 127.4, 126.5, 119.1,

114.8, 113.5, 108.3, 71.9, 70.0, 59.2, 55.3. IR ν: 3359, 2935, 2837,

1692, 1592, 1461, 1253, 927 cm⁻¹. HRMS (FD) m/z: [M]⁺calcd for

+

116.4, 105.5, 71.8. HRMS (FD) m/z: [M]⁺calcd for C₁₃H₁₀BrNO₃,

306.9844; found, 306.9816.

[2-(Benzyloxy)-6-nitrophenyl](4-methoxyphenyl)methanol (10).

In a ﬂame-dried Schlenk ﬂask were added 9 (4.00 g, 13.0 mmol,

1.0 equiv) and freshly distilled THF (50 mL) under N₂. At −95 °C, n-

BuLi (6.24 mL, 2.5 M in hexanes, 15.6 mmol, 1.2 equiv) was then

added dropwise. The reaction was continued to stir at −95 °C for 1.5

h before a solution of p-anisaldehyde (3.54 g, 26.0 mmol, 2.0 equiv)

in THF (10 mL) was added dropwise. After stirring the reaction for

another 2 h, the reaction was quenched by slow addition of saturated

solution of NH₄Cl and extracted with EtOAc three times. The

combined organic extracts were washed with brine, dried over

Na₂SO₄, and concentrated in vacuo. The sample was puriﬁed by ﬂash

column chromatography (n-hexane/EtOAc, 5:1 to 3:1) giving 10 as a

pale yellow oil (2.20 g, 46%). Another reaction using 4.00 g of 9 (13.0

mmol) with 0.95 equiv of n-BuLi and 0.5 equiv of para-anisaldehyde

was also performed, and 2.06 g of 10 was obtained (86% based on

para-anisaldehyde). ¹H NMR (400 MHz): δ 7.44−7.36 (m, 2H),

7.31−7.27 (m, 3H), 7.24−7.18 (m, 3H), 7.02 (dd, J = 7.5, 2.1 Hz,

2H), 6.86−6.82 (m, 2H), 6.23 (d, J = 10.5 Hz, 1H), 5.07 (d, J = 11.5

Hz, 1H), 4.99 (d, J = 11.5 Hz, 1H), 3.81 (s, 3H). ¹³C{H} NMR (101

MHz): δ 158.8, 157.1, 150.7, 135.1, 134.6, 129.2, 128.6, 128.4, 127.5,

127.1, 126.4, 116.6, 116.5, 113.5, 71.2, 69.4, 55.3. IR ν: 3545, 2934,

1604, 1509, 1356, 1246, 1025, 737 cm⁻¹. HRMS (FD) m/z: [M]⁺

+

C₂₄H₂₃NO₅, 405.1576; found, 405.1591.

(3R*,4R*)-5-(Benzyloxy)-4-hydroxy-3-methoxy-4-(4-methoxy-

phenyl)-3,4-dihydroquinolin-2(1H)-one [( )-14]. In a ﬂame-dried

Schlenk ﬂask were added 13 (0.94 g, 2.32 mmol, 1.0 equiv) and

freshly distilled THF (50 mL) at 0 °C under N₂. A solution of KO^tBu

(16.2 mL, 1.0 M in THF, 16.2 mmol, 7.0 equiv) was then added

dropwise. After stirring it at 0 °C for 2 h, TLC showed full conversion

of the reaction. The reaction was quenched by adding water and

extracted with EtOAc (three times). The combined organic extracts

were washed with brine, dried over Na₂SO₄, and evaporated in vacuo.

The product was puriﬁed by ﬂash column chromatography (n-

hexane/EtOAc, 1:1.5) giving ( )-14 as a single diastereoisomer:

1

white solid (0.75 g, 80%). H NMR (400 MHz): δ 8.80 (br s, 1H),

7.32−7.25 (m, 3H), 7.25−7.16 (m, 3H), 7.12 (dd, J = 6.3, 2.7 Hz,

2H), 6.86−6.77 (m, 2H), 6.73 (d, J = 8.4 Hz, 1H), 6.55 (dd, J = 8.1,

0.9 Hz, 1H), 5.33 (s, 1H), 5.07 (d, J = 11.5 Hz, 1H), 4.99 (d, J = 11.5

Hz, 1H), 3.83 (s, 1H), 3.77 (d, J = 1.0 Hz, 3H), 3.61 (s, 3H). ¹³C{H}

NMR (101 MHz): δ 168.3, 159.7, 158.0, 137.1, 135.7, 133.6, 129.9,

128.7, 128.4, 127.6, 127.5, 115.3, 114.0, 109.6, 108.7, 85.1, 78.1, 71.1,

59.7, 55.3. IR ν: 3509, 2932, 1692, 1607, 1509, 1259, 1103 cm⁻¹.

+

calcd for C₂₁H₁₉NO₅, 365.1263; found, 365.1248.

[2-Amino-6-(benzyloxy)phenyl](4-methoxyphenyl)methanol

(11). In a round bottom ﬂask were added 10 (2.00 g, 5.5 mmol, 1.0

equiv), EtOH (30 mL), and Na₂S (1.28 g, 16.4 mmol, 3.0 equiv)

successively. The reaction was then reﬂuxed at 85 °C for 15 min

before water was added to quench the reaction. The mixture was then

extracted with EtOAc three times. The combined organic extracts

were washed with brine, dried over Na₂SO₄, and evaporated in vacuo.

+

HRMS (FD) m/z: [M]⁺calcd for C₂₄H₂₃NO₅, 405.1576; found,

405.1591.

(3R*,4R*)-5-(Benzyloxy)-4-hydroxy-3-methoxy-4-(4-methoxy-

phenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydroquinolin-

2(1H)-one [( )-15]. In a ﬂame-dried Schlenk ﬂask were added ( )-14

(1.20 g, 2.96 mmol, 1.0 equiv) and anhydrous THF (50 mL) under

N₂. LiHMDS solution in THF (3.26 mL, 1.0 M, 3.26 mmol, 1.1

equiv) was then added dropwise at 0 °C. After stirring it for 0.5 h,

SEMCl (0.59 g, 3.55 mmol, 1.2 equiv) was added dropwise. The

reaction was continued to stir at 0 °C for 2 h before water was added

to quench the reaction. The mixture was extracted with EtOAc three

times. The combined organic extracts were washed with brine, dried

over Na₂SO₄, and evaporated in vacuo. The product was puriﬁed by

ﬂash column chromatography (PE/EtOAc, 3:1) giving ( )-15 as a

white solid (1.40 g, 88%). ¹H NMR (400 MHz): δ 7.33 (t, J = 8.3 Hz,

1H), 7.30−7.26 (m, 3H), 7.19−7.11 (m, 5H), 6.84−6.80 (m, 3H),

5.67 (d, J = 11.0 Hz, 1H), 5.49 (s, 1H), 5.10 (d, J = 11.5 Hz, 1H),

5.01 (d, J = 11.5 Hz, 1H), 4.96 (d, J = 11.0 Hz, 1H), 3.92 (s, 1H),

3.78 (s, 3H), 3.67−3.54 (m, 2H), 3.58 (s, 3H), 0.98−0.94 (m, 2H),

0.00 (s, 9H). ¹³C{H} NMR (101 MHz): δ 167.6, 159.8, 157.4, 139.8,

135.7, 133.5, 129.7, 128.8, 128.4, 127.7, 127.5, 116.9, 114.0, 110.0,

109.3, 85.3, 77.4, 72.2, 71.2, 66.0, 59.4, 55.3, 18.1, −1.3. IR ν: 3508,

2952, 1693, 1594, 1465, 1385, 1247, 1064, 832 cm⁻¹. HRMS (FD)

m/z: [M]⁺calcd for C₃₀H₃₇NO₆Si⁺, 535.2390; found, 535.2383.

(3R*,4R*)-4,5-Dihydroxy-3-methoxy-4-(4-methoxyphenyl)-1-{[2-

(trimethylsilyl)ethoxy]methyl}-3,4-dihydroquinolin-2(1H)-one

[( )-16]. In a Schlenk ﬂask were added ( )-15 (430 mg), EtOH (5

mL), EtOAc (5 mL), and Pd/C (100 mg, 10 wt %) under N₂. The

ﬂask atmosphere was then changed to H₂by using a balloon ﬁlled

with H₂. The reaction was then stirred for 2 h under H₂(1 atm.

pressure). The reaction was ﬁltrated and evaporated in vacuo. The

product was puriﬁed by ﬂash column chromatography (n-hexane/

EtOAc, 3:1) giving ( )-17 as a white solid (446 mg, 95%). 430 mg of

( )-15 (0.80 mmol) and 100 mg Pd/C (10% wt) were used.

Puriﬁcation was performed using PE/EtOAc (3:1) as an eluent.

Product ( )-16 was isolated as a white solid in 95% yield (340 mg).

1

The obtained 11 was directly used for the next step. H NMR (400

MHz): δ 7.38−7.30 (m, 8H), 7.04 (t, J = 8.1 Hz, 1H), 6.87−6.82 (m,

2H), 6.49 (s, 1H), 6.45 (dd, J = 8.3, 1.0 Hz, 1H), 6.32 (dd, J = 8.0, 0.9

Hz, 1H), 5.08 (d, J = 11.7 Hz, 1H), 5.02 (d, J = 11.7 Hz, 1H), 3.78 (s,

3H). ¹³C NMR (101 MHz): δ 158.7, 156.9, 146.4, 137.1, 135.0,

129.1, 128.6, 128.0, 127.5, 127.2, 116.6, 113.7, 111.1, 102.7, 70.6,

68.4, 55.4.

N-{3-(Benzyloxy)-2-[hydroxy(4-methoxyphenyl)methyl]phenyl}-

2-methoxyacetamide (12). In a ﬂame-dried Schlenk ﬂask were added

i

crude 11 obtained from the previous step, Pr₂NEt (853 mg, 6.6

mmol, 1.2 equiv), and freshly distilled DCM (25 mL). 2-

Methoxyacetyl chloride (657 mg, 6.05 mmol, 1.1 equiv) was then

added dropwise at 0 °C. The reaction was stirred for another 40 min

at room temperature before it was quenched by adding water. The

reaction was extracted with DCM three times and the combined

extracts were washed with brine, dried over Na₂SO₄, and concentrated

in vacuo. The product was puriﬁed by ﬂash column chromatography

(n-hexane/EtOAc, 2:1) giving 12 as a pale yellow oil (1.40 g, 61%

over two steps). ¹H NMR (400 MHz): δ 10.09 (br s, 1H), 7.95 (d, J =

8.3 Hz, 1H), 7.38−7.22 (m, 8H), 6.82−6.78 (m, 3H), 6.65 (s, 1H),

5.11 (d, J = 11.7 Hz, 1H), 5.04 (d, J = 11.7 Hz, 1H), 3.87 (d, J = 15.4

Hz, 1H), 3.77 (s, 3H), 3.69 (d, J = 15.5 Hz, 1H), 3.28 (s, 3H).

¹³C{H} NMR (101 MHz): δ 168.2, 158.3, 155.4, 137.6, 136.6, 134.4,

128.5, 128.3, 127.7, 127.1, 127.0, 121.1, 115.2, 113.2, 108.0, 72.0,

70.3, 67.4, 59.1, 54.9. IR ν: 3282, 2934, 2834, 1665, 1593, 1472, 1249,

+

1116 cm⁻¹. HRMS (FD) m/z: [M]⁺calcd for C₂₄H₂₅NO₅, 407.1733;

found, 407.1746.

N-[3-(Benzyloxy)-2-(4-methoxybenzoyl)phenyl]-2-methoxyace-

tamide (13). In a round bottom ﬂask were added 12 (1.40 g, 3.44

mmo, 1.0 equiv) and DCM (30 mL). PCC (1.48 g, 6.88 mmol, 2.0

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¹H NMR (400 MHz): δ 8.86 (s, 1H), 7.28 (t, J = 8.2 Hz, 1H), 7.17−

115.2, 109.6, 108.7, 85.0, 78.3, 71.0, 59.8. Its NMR data matched with

those reported in the literature.^10a

7.15 (m, 2H), 6.98 (d, J = 8.3 Hz, 1H), 6.85−6.82 (m, 2H), 6.74 (d, J

= 8.3 Hz, 1H), 5.65 (d, J = 11.0 Hz, 1H), 5.00 (d, J = 10.9 Hz, 1H),

4.53 (s, 1H), 3.85 (s, 1H), 3.77 (s, 3H), 3.63−3.53 (m, 2H), 3.59 (s,

3H), 0.96 (t, J = 8.3 Hz, 2H), 0.00 (s, 9H). ¹³C{H} NMR (101

MHz): δ 166.1, 160.4, 157.6, 138.1, 130.4, 129.0, 128.2, 114.3, 113.8,

112.3, 107.7, 84.6, 78.1, 72.2, 66.1, 58.8, 55.3, 18.1, −1.3. IR ν: 3353,

2953, 1677, 1613, 1470, 1243, 1073, 834 cm⁻¹. HRMS (FD) m/z:

[M]⁺calcd for C₂₃H₃₁NO₆Si⁺, 445.1921; found, 445.1939.

(3R*,4R*)-5-(Benzyloxy)-4-hydroxy-3-methoxy-4-phenyl-1-{[2-

(trimethylsilyl)ethoxy]methyl}-3,4-dihydroquinolin-2(1H)-one

[( )-Int-K]. In a ﬂame-dried Schlenk ﬂask were added ( )-Int-J (0.90

g, 2.40 mmol, 1.0 equiv) and anhydrous THF (35 mL). LiHMDS

solution in THF (3.12 mL, 1.0 M, 3.12 mmol, 1.3 equiv) was then

added dropwise at 0 °C. After stirring it for 0.5 h, SEMCl (0.60 g,

3.60 mmol, 1.5 equiv) was added dropwise. The reaction was ﬁrst

stirred at 0 °C for 0.5 h and then 2 h at room temperature. Water was

added to quench the reaction. The mixture was extracted with EtOAc

three times. The combined organic extracts were washed with brine,

dried over Na₂SO₄, and evaporated in vacuo. The sample was puriﬁed

by ﬂash column chromatography (PE/EtOAc, 4:1) giving ( )-Int-K

as a white solid (1.15 g, 94%). ¹H NMR (400 MHz): δ 7.31 (t, J = 8.3

Hz, 1H), 7.29−7.20 (m, 8H), 7.16 (d, J = 8.4 Hz, 1H), 7.08−6.99 (m,

2H), 6.80 (d, J = 8.4 Hz, 1H), 5.64 (d, J = 11.0 Hz, 1H), 5.47 (br s,

1H), 5.05 (d, J = 11.5 Hz, 1H), 4.97−4.94 (m, 2H), 3.91 (s, 1H),

3.66−3.53 (m, 2H), 3.56 (s, 3H), 0.98−0.93 (m, 2H), −0.02 (s, 9H).

¹³C{H} NMR (101 MHz): δ 167.5, 157.4, 141.7, 139.9, 135.7, 129.8,

Synthesis of ( )-27. [2-(Benzyloxy)-6-nitrophenyl](phenyl)-

methanol (Int-F). The procedure for the preparation of 10 was

followed. 4.00 g of 9 (13.0 mmol) was used and puriﬁcation was

performed using PE/EtOAc (7:1 to 3:1) as an eluent. Product Int-F

was isolated as a yellow oil in 48% yield (2.10 g). Another reaction

using 4.00 g of 9 (13.0 mmol) with 0.95 equiv of n-BuLi and 0.5 equiv

of anisaldehyde was also performed, and 1.93 g of Int-F was obtained

(88% based on anisaldehyde). ¹H NMR (400 MHz): δ 7.41−7.36 (m,

2H), 7.34−7.20 (m, 8H), 7.15 (d, J = 7.9 Hz, 1H), 6.94−6.87 (m,

2H), 6.26 (s, 1H), 5.02 (dd, J = 11.6, 2.8 Hz, 1H), 4.92 (d, J = 11.5

Hz, 1H). ¹³C{H} NMR (101 MHz): δ 157.3, 151.0, 142.6, 135.0,

129.4, 128.8, 128.6, 128.3, 127.6, 127.3, 126.6, 125.8, 116.8, 77.4,

71.5, 69.6. IR ν: 3031, 1528, 1452, 1356, 1023, 737, 697 cm⁻¹. HRMS

128.7, 128.6, 128.5, 128.3, 127.4, 126.3, 116.7, 109.9, 109.2, 85.2,

77.6, 72.2, 71.2, 66.0, 59.5, 18.1, −1.3. IR ν: 3507, 2951, 1693, 1593,

1469, 1376, 1247, 1062, 833, 730, 696 cm⁻¹. HRMS (FD) m/z: [M]⁺

calcd for C₂₉H₃₅NO₅Si⁺, 505.2284; found, 505.2302.

+

(EI) m/z: [M − OH]⁺calcd for C₂₀H₁₆NO₃, 318.1130; found,

318.1110.

(3R*,4R*)-4,5-Dihydroxy-3-methoxy-4-phenyl-1-{[2-

(trimethylsilyl)ethoxy]methyl}-3,4-dihydroquinolin-2(1H)-one

[( )-27]. The procedure for the preparation of ( )-16 was followed.

0.90 g of ( )-Int-K (2.17 mmol) was used and puriﬁcation was

performed using PE/EtOAc (4:1) as an eluent. Product ( )-27 was

isolated as a white solid in 94% yield (0.70 g). ¹H NMR (400 MHz):

δ 8.80 (br s, 1H), 7.32−7.29 (m, 3H), 7.28−7.20 (m, 3H), 6.98 (d, J

= 8.2 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 5.65 (d, J = 10.9 Hz, 1H),

5.00 (d, J = 10.9 Hz, 1H), 4.54 (s, 1H), 3.82 (s, 1H), 3.60−3.54 (m,

2H), 3.58 (s, 3H), 0.97−0.92 (m, 2H), −0.02 (s, 9H). ¹³C{H} NMR

(101 MHz): δ 165.9, 157.6, 138.3, 137.3, 130.6, 129.5, 129.0, 126.7,

113.9, 112.2, 107.8, 84.6, 78.3, 72.3, 66.2, 58.9, 18.1, −1.3. IR ν: 3325,

2952, 1680, 1470, 1241, 1070, 834 cm⁻¹. HRMS (FD) m/z: [M]⁺

calcd for C₂₂H₂₉NO₅Si⁺, 415.1815; found, 415.1836.

[2-Amino-6-(benzyloxy)phenyl](phenyl)methanol (Int-G). The

procedure for the preparation of 11 was followed. 1.80 g of Int-F

(5.4 mmol) was used and the reaction was reﬂuxed for 0.5 h. Product

1

Int-G was used for the next step without puriﬁcation. H NMR (400

MHz): δ 7.46 (d, J = 7.5 Hz, 2H), 7.42−7.16 (m, 8H), 7.08 (t, J = 8.2

Hz, 1H), 6.57 (s, 1H), 6.49 (d, J = 8.3 Hz, 1H), 6.35 (d, J = 7.9 Hz,

1H), 5.17−5.02 (m, 2H). ¹³C{H} NMR (101 MHz): δ 156.9, 146.1,

143.0, 137.1, 129.2, 128.6, 128.3, 128.0, 127.5, 127.0, 125.9, 116.7,

111.2, 102.9, 70.6, 68.5.

N-{3-(Benzyloxy)-2-[hydroxy(phenyl)methyl]phenyl}-2-methox-

yacetamide (Int-H). The procedure for the preparation of 12 was

followed. The crude sample Int-G from the previous step was used

and puriﬁcation was performed using PE/EtOAc (2.5:1) as an eluent.

Product Int-H was isolated as a yellow oil in 67% yield (2.10 g) over

two steps. ¹H NMR (400 MHz): δ 9.76 (s, 1H), 7.89 (d, J = 8.3 Hz,

1H), 7.41−7.16 (m, 11H), 6.82 (d, J = 8.4 Hz, 1H), 6.67 (s, 1H),

5.13 (d, J = 11.6 Hz, 1H), 5.05 (d, J = 11.6 Hz, 1H), 3.89 (d, J = 15.4

Hz, 1H), 3.67 (d, J = 15.3 Hz, 1H), 3.29 (s, 3H). ¹³C{H} NMR (101

MHz): δ 168.3, 156.0, 142.0, 137.7, 136.7, 129.3, 128.7, 128.2, 128.2,

127.6, 127.2, 125.8, 121.4, 116.1, 108.7, 72.4, 71.0, 68.2, 59.5. IR ν:

3293, 2934, 1665, 1592, 1443, 1261, 1117, 736 cm⁻¹. HRMS (EI) m/

C(6)−H Oleﬁnation of 3,4-Dihydro-2(1H)-quinolinone De-

rivatives. General Procedure. In a pressure tube containing a

suitable stirring bar were added the corresponding 3,4-dihydro-

2(1H)-quinolinone derivative (1.0 equiv), Pd(OAc)₂(10 mol %),

t

PhCO₃Bu (1.0−2.0 equiv), oleﬁn (1.5 equiv), S,O-ligand stock

solution in DCE (0.1 M, 10 mol %), and DCE. The tube was

introduced into an oil bath preheated at 80 °C and was stirred for 16

h. The tube was then removed from the oil bath and cooled to room

temperature. The reaction was ﬁltrated through Celite and rinsed with

DCM. The ﬁltrate was then washed with a saturated solution of

Na₂CO₃, dried with MgSO₄, ﬁltrated, and concentrated in vacuo. The

product was puriﬁed by ﬂash column chromatography.

+

z: [M − H₂O]⁺calcd for C₂₃H₂₁NO₃, 359.1521; found, 359.1513.

N-[2-Benzoyl-3-(benzyloxy)phenyl]-2-methoxyacetamide (Int-I).

The procedure for the preparation of 13 was followed. 1.46 g of Int-H

(3.87 mmol) was used and puriﬁcation was performed using PE/

EtOAc (2:1) as eluent. Product Int-I was isolated as a pale yellow

solid in 89% yield (1.29 g). ¹H NMR (400 MHz): δ 9.53 (s, 1H), 8.04

(d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.59−7.50 (m, 3H),

7.46−7.40 (m, 3H), 7.20−7.11 (m, 3H), 6.81 (d, J = 8.4 Hz, 1H),

6.76 (d, J = 7.6 Hz, 2H), 4.88 (d, J = 2.0 Hz, 2H), 3.92 (d, J = 1.9 Hz,

2H), 3.39 (d, J = 2.3 Hz, 3H). ¹³C{H} NMR (101 MHz): δ 197.0,

168.4, 157.3, 139.3, 137.0, 135.9, 133.0, 132.4, 129.2, 128.4, 128.2,

127.7, 126.7, 118.6, 115.0, 108.4, 72.2, 70.3, 59.5. IR ν: 3354, 2936,

1692, 1581, 1466, 1274, 1070, 923, 697 cm⁻¹. HRMS (EI) m/z: [M]⁺

(E)-Ethyl 3-(1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-

acrylate (1b). Substrate 1a (16.1 mg, 0.1 mmol) was oleﬁnated

t

using ethyl acrylate (16.3 μL, 0.15 mmol, 1.5 equiv) and PhCO₃Bu

(18.6 μL, 0.1 mmol, 1.0 equiv) for 16 h following the general

procedure, and the sample was puriﬁed by preparative TLC (PE/

EtOAc, 5:1) to give 1b as a yellow oil (9.0 mg, 35%) as a mixture of

regioisomers (para/others 4.3:1). ¹H NMR (400 MHz): δ 7.63 (d, J =

16.1 Hz, 1H), 7.42 (dd, J = 8.4, 2.1 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H),

6.98 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 16.0 Hz, 1H), 4.26 (q, J = 7.1

Hz, 2H), 3.37 (s, 3H), 2.93 (dd, J = 8.6, 6.1 Hz, 2H), 2.68 (dd, J =

8.7, 6.0 Hz, 3H), 1.34 (t, J = 7.1 Hz, 4H). HRMS (FD) m/z: [M]⁺

+

calcd for C₂₃H₂₁NO₄, 375.1471; found, 375.1464.

(3R*,4R*)-5-(Benzyloxy)-4-hydroxy-3-methoxy-4-phenyl-3,4-di-

hydroquinolin-2(1H)-one [( )-Int-J]. The procedure for the prep-

aration of ( )-14 was followed. 1.15 g of Int-I (3.06 mmol) was used

and puriﬁcation was performed using PE/EtOAc (1:1) as an eluent.

Product ( )-Int-J was isolated as a white solid in 95% yield (1.10 g).

¹H NMR (400 MHz): δ 8.76 (br s, 1H), 7.27−7.18 (m, 9H), 7.06−

+

calcd for C₁₅H₁₇NO₃, 259.1208; found, 259.1184.

(E)-Ethyl 3-(5-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquino-

lin-6-yl)acrylate (2b). Substrate 2a (19.1 mg, 0.1 mmol) was

oleﬁnated using ethyl acrylate (16.3 μL, 0.15 mmol, 1.5 equiv) and

t

PhCO₃Bu (18.6 μL, 0.1 mmol, 1.0 equiv) following the general

7.03 (m, 2H), 6.70 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H), 5.28

(br s, 1H), 5.03 (d, J = 11.6 Hz, 1H), 4.93 (d, J = 11.6 Hz, 1H), 3.83

(s, 1H), 3.59 (s, 3H). ¹³C{H} NMR (101 MHz): δ 168.1, 158.0,

141.9, 137.2, 135.7, 130.0, 128.7, 128.7, 128.4, 128.3, 127.4, 126.2,

procedure, and the sample was puriﬁed by ﬂash column

chromatography (PE/EtOAc, 3:1) to give 2b as a yellow oil (13.0

mg, 45%, C6/others > 20:1). H NMR (400 MHz): δ 7.88 (d, J =

1

16.1 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.45

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(d, J = 16.1 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 3.36 (s,

3H), 2.97 (dd, J = 8.6, 6.3 Hz, 2H), 2.63 (dd, J = 8.6, 6.2 Hz, 2H),

1.34 (t, J = 7.1 Hz, 3H). ¹³C{H} NMR (101 MHz): δ 170.3, 167.4,

156.7, 143.7, 139.0, 127.2, 123.1, 120.1, 118.3, 111.4, 62.0, 60.6, 31.1,

29.9, 18.8, 14.5. IR ν: 2923, 2852, 1675, 1628, 1596, 1265, 1167

2H), 1.44 (t, J = 7.0 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H). ¹³C{H} NMR

(101 MHz) (6b-c): δ 171.4, 167.0, 156.0, 144.7, 141.3, 134.5, 118.5,

117.2, 109.0, 106.1, 74.2, 64.2, 60.7, 56.5, 31.2, 18.5, 15.0, 14.5. IR

(6b−c) ν: 2979, 2931, 1690, 1601, 1270, 1177 cm⁻¹. HRMS (6b−c)

+

(FD) m/z: [M]⁺calcd for C₁₈H₂₃NO₅, 333.1576; found, 333.1575.

+

cm⁻¹. HRMS (FD) m/z: [M]⁺calcd for C₁₆H₁₉NO₄, 289.1314;

(E)-Ethyl 3-[1-(4-Acetoxybenzyl)-5-ethoxy-2-oxo-1,2,3,4-tetrahy-

droquinolin-6-yl]acrylate (7b). Substrate 7a (33.9 mg, 0.1 mmol)

was oleﬁnated using ethyl acrylate (16.3 μL, 0.15 mmol, 1.5 equiv)

found, 289.1319. A parallel reaction was performed without using the

S,O-ligand and only a trace amount of desired product was detected.

(E)-Ethyl 3-(5-Ethoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquino-

lin-6-yl)acrylate (3b). Substrate 3a (20.5 mg, 0.1 mmol) was

oleﬁnated using ethyl acrylate (16.3 μL, 0.15 mmol, 1.5 equiv) and

t

and PhCO₃Bu (18.6 μL, 0.1 mmol, 1.0 equiv) following the general

procedure, and the sample was puriﬁed by ﬂash column

chromatography (PE/EtOAc, 3:1 to 2:1) to give 7b as a yellow oil

(21.0 mg, 48%, C6/others > 20:1). ¹H NMR (400 MHz): δ 7.87 (d, J

= 16.1 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.23−7.21 (m, 2H), 7.05−

7.03 (m, 2H), 6.69 (d, J = 8.7 Hz, 1H), 6.37 (d, J = 16.1 Hz, 1H),

5.15 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.87 (q, J = 7.0 Hz, 2H), 3.02

(dd, J = 8.6, 6.1 Hz, 2H), 2.78−2.72 (m, 2H), 2.28 (s, 3H), 1.44 (t, J

= 7.0 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H). ¹³C{H} NMR (101 MHz): δ

170.4, 169.6, 167.3, 155.8, 149.9, 142.8, 139.1, 134.4, 127.7, 126.8,

123.6, 122.0, 120.5, 118.1, 112.0, 70.8, 60.6, 45.9, 31.4, 21.3, 19.2,

15.7, 14.5. IR ν: 2927, 1761, 1681, 1371, 1166 cm⁻¹. HRMS (FD) m/

t

PhCO₃Bu (18.6 μL, 0.1 mmol, 1.0 equiv) following the general

procedure, and the sample was puriﬁed by ﬂash column

chromatography (PE/EtOAc, 3:1) to give 3b as a yellow oil (17.3

1

mg, 57%, C6/others > 20:1). H NMR (400 MHz): δ 7.90 (d, J =

16.1 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.42

(d, J = 16.1 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.86 (q, J = 7.0 Hz,

2H), 3.35 (s, 3H), 2.95 (dd, J = 8.6, 6.2 Hz, 2H), 2.61 (dd, J = 8.5, 6.2

Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H). ¹³C{H}

NMR (101 MHz): δ 170.3, 167.3, 155.7, 143.7, 139.3, 126.8, 123.3,

120.3, 118.0, 111.3, 70.7, 60.5, 31.2, 29.9, 19.0, 15.6, 14.5. IR ν: 2977,

1679, 1598, 1441, 1352, 1177, 1125, 1044 cm⁻¹. HRMS (FD) m/z:

+

z: [M]⁺calcd for C₂₅H₂₇NO₆, 437.1838; found, 437.1837.

(E)-5-Hydroxy-6-{2-[5-(2-hydroxypropan-2-yl)-2-methyltetrahy-

drofuran-2-yl]vinyl}-1-methyl-3,4-dihydroquinolin-2(1H)-one (5c)

and 2-[5-(2-Hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl]-

6-methyl-8,9-dihydrofuro[2,3-f ]quinolin-7(6H)-one (5d). Substrate

5a (44.3 mg, 0.25 mmol) was oleﬁnated using trans-29 (63.8 mg,

+

[M]⁺calcd for C₁₇H₂₁NO₄, 303.1471; found, 303.1488.

(E)-Ethyl 3-[5-(Methoxymethoxy)-1-methyl-2-oxo-1,2,3,4-tetra-

hydroquinolin-6-yl]acrylate (4b). Substrate 4a (22.1 mg, 0.1

mmol) was oleﬁnated using ethyl acrylate (16.3 μL, 0.15 mmol, 1.5

t

0.375 mmol, 1.5 equiv) and PhCO₃Bu (86.0 μL, 0.45 mmol, 1.8

equiv) and PhCO₃Bu (18.6 μL, 0.1 mmol, 1.0 equiv) following the

equiv) for 16 h following the general procedure, and the sample was

puriﬁed by preparative TLC (PE/EtOAc, 3:1) to give 5c as a yellow

oil (41.4 mg, 48%, dr = 1.3:1) and 5d as a yellow oil (15.4 mg, 18%,

dr not determined). Another reaction was also performed using a

mixture of trans-29 and cis-29 as the oleﬁn, and the same results were

general procedure, and the sample was puriﬁed by ﬂash column

chromatography (PE/EtOAc, 3:1) to give 4b as a yellow oil (15.0 mg,

47%, C6/others > 20:1). H NMR (400 MHz): δ 7.93 (d, J = 16.1

1

Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 6.38 (d, J

= 16.2 Hz, 1H), 4.97 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 3.62 (s, 3H),

3.35 (s, 3H), 2.97 (dd, J = 8.6, 6.2 Hz, 2H), 2.61 (dd, J = 8.6, 6.3 Hz,

2H), 1.33 (t, J = 7.1 Hz, 3H). ¹³C{H} NMR (101 MHz): δ 170.3,

167.2, 154.2, 143.7, 139.4, 126.5, 123.5, 120.5, 118.0, 111.8, 100.7,

60.6, 58.1, 31.2, 30.0, 19.6, 14.5. IR ν: 2852, 1677, 1598, 1354, 1251,

1

obtained regarding both the yield and diastereoselectivity. H NMR

(5c) (300 MHz) (two diastereoisomers: A/B = 1:1.3): δ 7.17 (d, J =

8.5 Hz, 1H_B), 7.15 (d, J = 8.5 Hz, 1H_A), 6.83 (d, J = 16.0 Hz, 1H_A),

6.71 (d, J = 15.9 Hz, 1H_B), 6.55 (d, J = 8.5 Hz, 1H_B), 6.54 (d, J = 8.5

Hz, 1H_A), 6.12 (d, J = 15.9 Hz, 1H_A), 6.10 (d, J = 15.9 Hz, 1H_B),

3.96−3.90 (m, 1H_Aand 1H_B), 3.33 (s, 3H_B), 3.33 (s, 3H_A), 2.93−

2.86 (m, 2H_Aand 2H_B), 2.63−2.57 (m, 2H_Aand 2H_B), 2.04−1.81

(m, 4H_Aand 4H_B), 1.42 (s, 3H_B), 1.32 (s, 3H_A), 1.18 (s, 3H_A), 1.16

(s, 3H_B). ¹³C{H} NMR (5c) (75 MHz): δ 170.6 (A and B), 150.3 (A

and B), 141.0 (A and B), 137.7 (A or B), 137.1 (A or B), 125.7 (A or

B), 125.6 (A or B), 122.0 (A or B), 121.1 (A or B), 120.3 (A or B),

120.0 (A or B), 113.2 (A and B), 107.5 (A and B), 86.1 (A or B), 86.0

(A or B), 83.6 (A or B), 83.1 (A or B), 72.1 (A or B), 72.0 (A or B),

38.7 (A or B), 38.3 (A or B), 31.2 (A and B), 29.9 (A and B), 27.5 (A

and B), 27.0 (A or B), 26.9 (A or B), 26.7 (A or B), 26.5 (A or B),

25.3 (A or B), 23.9 (A or B), 18.4 (A and B). IR (5c) ν: 3306, 2972,

2929, 1652, 1624, 1472, 1372, 1126, 1041, 729 cm⁻¹. HRMS (5c)

(FD) m/z: [M]⁺calcd for C₂₀H₂₅NO₄, 343.1784; found, 343.1771.

¹H NMR (5d) (400 MHz) (two diastereoisomers: A and B. Ratio was

not determined): δ 7.38 (d, J = 8.5 Hz, 1H_Aand 1H_B), 6.94 (d, J = 8.5

Hz, 1H_Aand 1H_B), 6.57 (s, 1H_Aand 1H_B), 4.05−4.01 (m, 1HA and

1HB), 3.44 (s, 3H_Aand 3H_B), 3.19−3.14 (m, 2H_Aand 2H_B), 2.77−

2.72 (m, 2H_Aand 2H_B), 2.52−2.43 (m, 1H_Aand 1H_B), 2.10−1.97

(m, 3H_Aand 3H_B), 1.70 (s, 3H_A), 1.69 (s, 3H_B), 1.31 (s, 3H_A), 1.30

(s, 3H_B), 1.21 (s, 3H_B), 1.20 (s, 3H_A). ¹³C{H} NMR (5d) (75 MHz):

δ 170.2 (A and B), 162.4 (A and B), 152.4 (A or B), 152.2 (A or B),

137.8 (A or B), 137.6 (A or B), 124.0 (A or B), 123.8 (A or B), 119.0

(A or B), 118.9 (A or B), 110.9 (A or B), 110.8 (A or B), 109.7 (A

and B), 101.5 (A or B), 101.3 (A or B), 86.7 (A and B), 81.0 (A or

B), 80.7 (A or B), 71.5 (A or B), 71.3 (A or B), 38.6 (A or B), 37.5 (A

or B), 31.3 (A and B), 30.3 (A and B), 27.9 (A and B), 27.4 (A or B),

27.1 (A or B), 26.7 (A or B), 26.6 (A or B), 24.7 (A or B), 24.4 (A or

B), 18.7 (A or B), 18.6 (A or B). IR (5d) ν: 3444, 2975, 2928, 1671,

1632, 1470, 1375, 1127, 1026, 819 cm⁻¹. HRMS (5d) (FD) m/z:

+

1124, 812 cm⁻¹. HRMS (FD) m/z: [M]⁺calcd for C₁₇H₂₁NO₅,

319.1420; found, 319.1415.

(E)-Ethyl 3-(5-Hydroxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquino-

lin-6-yl)acrylate (5b). Substrate 5a (17.7 mg, 0.1 mmol) was

oleﬁnated using ethyl acrylate (16.3 μL, 0.15 mmol, 1.5 equiv) and

t

PhCO₃Bu (18.6 μL, 0.1 mmol, 1.0 equiv) following the general

procedure, and the sample was puriﬁed by preparative TLC (PE/

EtOAc, 2:1) to give 5b as a yellow oil (7.4 mg, 27%). (The product is

not stable, as after the sample solution in CDCl₃was stored overnight

at room temperature and was measured again, many new peaks

1

appeared.) H NMR (300 MHz): δ 7.97 (d, J = 16.0 Hz, 1H), 7.40

(d, J = 8.6 Hz, 1H), 6.64 (d, J = 8.6 Hz, 1H), 6.45 (d, J = 15.9 Hz,

1H), 5.88 (s, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.36 (s, 3H), 2.96−2.83

(m, 2H), 2.67 (dd, J = 8.8, 6.2 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).

(E)-Ethyl 3-[5-Ethoxy-1-(methoxymethyl)-2-oxo-1,2,3,4-tetrahy-

droquinolin-6-yl]acrylate (6b). Substrate 6a (81.6 mg, 0.35 mmol)

was oleﬁnated using ethyl acrylate (57.0 μL, 0.525 mmol, 1.5 equiv),

t

PhCO₃Bu (67.0 μL, 0.35 mmol, 1.0 equiv) following the general

procedure, and the sample was puriﬁed by ﬂash column

chromatography (PE/EtOAc, 3:1) to give a mixture of 6b-a and

6b-b as a yellow oil (50.8 mg, 44%, 6b−a/6b−b = 9.1:1) and 6b−c as

a yellow oil (1.7 mg, 1.5%). ¹H NMR (400 MHz) (6b−a): δ 7.91 (d,

J = 16.2 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H),

6.43 (d, J = 16.1 Hz, 1H), 5.31 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.86

(q, J = 6.4 Hz, 2H), 3.41 (s, 3H), 2.97 (t, J = 7.2 Hz, 2H), 2.76−2.63

(m, 2H), 1.43 (t, J = 6.3 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H). ¹³C{H}

NMR (101 MHz) (6b−a): δ 171.1, 167.3, 155.6, 142.6, 139.2, 126.9,

123.9, 120.3, 118.2, 112.5, 74.0, 70.8, 60.5, 56.5, 31.3, 19.1, 15.6, 14.4.

IR (6b−a) ν: 2976, 1711, 1680, 1626, 1598, 1393, 1166, 1041 cm⁻¹.

HRMS (6b−a) (FD) m/z: [M]⁺calcd for C₁₈H₂₃NO₅, 333.1576;

1

+

[M]⁺calcd for C₂₀H₂₇NO₄, 345.1940; found, 345.1944.

found, 333.1575. H NMR (400 MHz) (6b−c): δ 7.64 (d, J = 16.0

Hz, 1H), 7.12 (d, J = 1.3 Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 6.41 (d, J

= 15.9 Hz, 1H), 5.31 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 4.08 (q, J = 7.0

Hz, 2H), 3.41 (s, 3H), 2.95−2.92 (m, 2H), 2.66 (dd, J = 8.4, 6.3 Hz,

(3R*,4R*)-4,5-Dihydroxy-3-methoxy-4-(4-methoxyphenyl)-6-

[(E)-3-oxobut-1-en-1-yl]-1-{[2-(Trimethylsilyl)ethoxy]methyl}-3,4-di-

hydroquinolin-2(1H)-one [( )-17]. The substrate ( )-16 (44.5 mg,

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0.1 mmol) was oleﬁnated using but-3-en-2-one (12.5 μL, 0.15 mmol,

1.5 equiv) and PhCO₃Bu (38.0 μL, 0.2 mmol, 2.0 equiv) following

found two groups of peaks. That is because the H NMR spectra of

t

1

( )-21-A and ( )-21-B were highly identical, while the H NMR

the general procedure, and the sample was puriﬁed by ﬂash column

chromatography (n-hexane/EtOAc, 3:1) to give ( )-17 as a mixture

of regioisomers [30.3 mg, 59%, yellow oil, ( )-17-A/( )-17-B =

spectra of ( )-21-C and ( )-21-D were also highly identical.

Therefore, we were not able to determine the ratios of ( )-21-A/

( )-21-B and ( )-21-C/( )-21-D, but we assumed that they were

both 1:1. Also, because of overlapping of these two groups of peaks,

we were not able to determine their ratio. A reaction using a mixture

of trans- and cis-20 (1:1) as the oleﬁn was also performed [0.1 mmol

scale for ( )-16], and the product 21 was isolated as a mixture of

regioisomers (A/B = 5.3:1) (30.0 mg, 50%, mixture of four

1

6:1], and ( )-17-di (2.9 mg, 5%, yellow oil). H NMR (300 MHz)

[( )-17-A]: δ 9.52 (s, 1H), 7.82 (d, J = 16.5 Hz, 1H), 7.55 (d, J = 8.7

Hz, 1H), 7.15−7.10 (m, 2H), 6.99 (d, J = 8.6 Hz, 1H), 6.84−6.78 (m,

2H), 6.72 (d, J = 16.5 Hz, 1H), 5.61 (d, J = 10.9 Hz, 1H), 5.01 (d, J =

11.1 Hz, 1H), 4.62 (s, 1H), 3.84 (s, 1H), 3.75 (s, 3H), 3.58−3.52 (m,

5H), 2.34 (s, 3H), 0.96−0.93 (m, 2H), −0.03 (s, 9H). ¹³C{H} NMR

(75 MHz) [( )-17-A]: δ 199.3, 165.9, 160.6, 156.9, 139.9, 138.1,

129.5, 128.4, 128.1, 127.0, 119.5, 114.5, 112.6, 108.2, 84.4, 78.2, 72.0,

66.4, 58.9, 55.4, 27.0, 18.1, −1.3. IR [( )-17-A] ν: 3259, 2953, 2926,

1692, 1605, 1369, 1252, 1081, 834 cm⁻¹. HRMS [( )-17-A] (FD)

1

diastereoisomers). H NMR (400 MHz): δ 9.19 (br s, 1H_A, 1H_B,

1H_Cand 1H_D), 7.43 (d, J = 8.6 Hz, 1H_Aand 1H_B), 7.41 (d, J = 8.6

Hz, 1H_Cand 1H_D), 7.16−7.11 (m, 2H_A, 2H_B, 2H_Cand 2H_D), 6.93 (d,

J = 8.6 Hz, 1H_A, 1H_B, 1H_Cand 1H_D), 6.82−6.77 (m, 3H_A, 3H_B, 3H_C

and 3H_D), 6.33 (d, J = 16.4 Hz, 1H_Cor 1H_D), 6.32 (d, J = 16.4 Hz,

1H_Cor 1H_D), 6.28 (d, J = 16.3 Hz, 1H_Aor 1H_B), 6.27 (d, J = 16.3 Hz,

1H_Aor 1H_B), 5.62 (d, J = 10.9 Hz, 1H_Aand 1H_B), 5.61 (d, J = 10.9

Hz, 1H_Cand 1H_D), 4.98 (d, J = 11.0 Hz, 1H_Aand 1H_B), 4.97 (d, J =

11.0 Hz, 1H_Cand 1H_D), 4.47 (s, 1H_A, 1H_B, 1H_Cand 1H_D), 3.91−

3.82 (m, 1H_A, 1H_B, 1H_Cand 1H_D), 3.80 (s, 1H_A, 1H_B, 1H_Cand

1H_D), 3.75 (s, 3H_A, 3H_B, 3H_Cand 3H_D), 3.59−3.52 (m, 2H_A, 2H_B,

2H_Cand 2H_D), 3.57 (s, 3H_Aand 3H_B), 3.56 (3H_Cand 3H_D), 2.05−

1.73 (m, 4H_A, 4H_B, 4H_Cand 4H_D), 1.41 (s, 3H_Cand 3H_D), 1.40 (s,

3H_Aand 3H_B), 1.24 (s, 3H_Aand 3H_B), 1.23 (s, 3H_Cand 3H_D), 1.14

(s, 3H_Cand 3H_D), 1.13 (s, 3H_Aand 3H_B), 0.95−0.91 (m, 2H_A, 2H_B,

2H_Cand 2H_D), −0.03 (s, 9H_A, 9H_B, 9H_Cand 9H_D). ¹³C{H} NMR

(101 MHz): δ 165.9 (A, B, C, and D), 160.4 (A, B, C, and D), 154.9

(A, B, C, and D), 137.2 (C or D), 137.1 (C or D), 137.0 (A and B),

136.0 (C or D), 135.9 (C or D), 135.6 (A or B), 135.5 (A or B),

128.9 (A and B), 128.8 (C and D), 128.2 (A, B, C, and D), 127.8 (A

or B), 127.7 (A or B), 127.6 (C and D), 122.3 (A, B, C, and D), 121.3

(C and D), 120.9 (A and B), 114.4 (A, B, C, and D), 112.2 (A, B, C,

and D), 107.7 (A, B, C, and D), 85.8 (C and D), 85.7 (A and B), 84.7

(A, B, C, and D), 83.4 (A and B), 83.2 (C and D), 78.3 (A, B, C, and

D), 72.1 (A, B, C, and D), 71.3 (A and B), 71.2 (C and D), 66.2 (A,

B, C, and D), 58.9 (A, B, C, and D), 55.4 (A, B, C, and D), 38.7 (C or

D), 38.6 (C or D), 38.1 (A and B), 27.5 (A, B, C, and D), 26.6 (A, B,

C, and D), 24.3 (A, B, C, and D), 18.1 (A, B, C, and D), −1.3 (A, B,

C, and D). IR ν: 3295, 2967, 2929, 1688, 1611, 1511, 1441, 1374,

1082, 835 cm⁻¹. HRMS (FD) m/z: [M]⁺calcd for C₃₃H₄₇NO₈Si⁺,

613.3071; found, 613.3064.

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m/z: [M]⁺calcd for C₂₇H₃₅NO₇Si⁺, 513.2183; found, 513.2208. H

NMR (400 MHz) [( )-17-di]: δ 9.41 (s, 1H), 7.82 (d, J = 16.5 Hz,

1H), 7.75 (d, J = 16.5 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.53 (d, J =

2.4 Hz, 1H), 7.05 (dd, J = 8.8, 2.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H),

6.81 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 16.5 Hz, 1H), 6.67 (d, J = 16.5

Hz, 1H), 5.64 (d, J = 10.9 Hz, 1H), 5.01 (d, J = 10.8 Hz, 1H), 4.59 (s,

1H), 3.86 (s, 3H), 3.81 (s, 1H), 3.60 (s, 3H), 3.60−3.53 (m, 2H),

2.37 (s, 2H), 2.36 (s, 3H), 0.96−0.92 (m, 2H), −0.03 (s, 9H).

¹³C{H} NMR (101 MHz) [( )-17-di]: δ 199.2, 199.1, 165.7, 159.1,

156.8, 139.8, 138.2, 137.9, 129.9, 129.8, 128.9, 128.7, 127.2, 127.2,

124.2, 119.8, 112.1, 111.6, 108.4, 84.3, 78.0, 72.1, 66.4, 59.0, 55.8,

27.4, 27.2, 18.1, −1.3. IR [( )-17-di] ν: 3251, 2954, 1692, 1604,

1368, 1253, 1082, 836 cm⁻¹. HRMS [( )-17-di] (FD) m/z: [M]⁺

calcd for C₃₁H₃₉NO₈Si⁺, 581.2445; found, 581.2443.

(E)-4,5-Dihydroxy-3-methoxy-4-(4-methoxyphenyl)-1-{[2-

(trimethylsilyl)ethoxy]methyl}-6-[2-(2,5,5-trimethyltetrahydro-2H-

pyran-2-yl)vinyl]-3,4-dihydroquinolin-2(1H)-one (19). Substrate

( )-16 (111.2 mg, 0.25 mmol) was oleﬁnated using oleﬁn 18

t

(57.8 mg, 0.375 mmol, 1.5 equiv) and PhCO₃Bu (86.0 μL, 0.45

mmol, 1.8 equiv) following the general procedure, and the sample was

puriﬁed by preparative TLC (n-hexane/acetone, 6:1) to give 19 as a

mixture of regioisomers (75.0 mg, 50%, yellow oil, regioselectivity:

1

8.8:1, dr = 1:1). H NMR (400 MHz) (two diastereoisomers: A and

B): δ 9.18 (br s, 1H_Aor 1H_B), 9.17 (br s, 1H_Aor 1H_B), 7.48 (d, J =

8.6 Hz, 1H_Aand 1H_B), 7.18−7.13 (m, 2H_Aand 2H_B), 6.96 (d, J = 8.6

Hz, 1H_Aand 1H_B), 6.83−6.80 (m, 2H_Aand 2H_B), 6.77 (d, J = 16.7

Hz, 1H_Aand 1H_B), 6.18 (d, J = 16.7 Hz, 1H_Aor 1H_B), 6.17 (d, J =

16.7 Hz, 1H_Aor 1H_B), 5.63 (d, J = 10.9 Hz, 1H_Aand 1H_B), 4.99 (d, J

= 10.9 Hz, 1H_Aand 1H_B), 4.45 (s, 1H_Aand 1H_B), 3.81 (s, 1H_Aor

1H_B), 3.80 (s, 1H_Aor 1H_B), 3.76 (s, 3H_Aor 3H_B), 3.75 (s, 3H_Aor

3H_B), 3.59−3.53 (m, 2H_Aand 2H_B), 3.58 (s, 3H_Aor 3H_B), 3.57 (s,

3H_Aor 3H_B), 3.41−3.36 (m, 1H_Aand 1H_B), 3.25−3.21 (m, 1H_Aand

1H_B), 1.86−1.79 (1H_Aand 1H_B), 1.75−1.67 (1H_Aand 1H_B), 1.52−

1.44 (1H_Aand 1H_B), 1.36−1.32 (1H_Aand 1H_B), 1.31 (s, 3H_Aand

3H_B), 1.01 (s, 3H_Aor 3H_B), 1.00 (s, 3H_Aor 3H_B), 0.95−0.91 (2H_A

and 2H_B), 0.79 (s, 3H_Aand 3H_B), −0.03 (s, 9H_Aand 9H_B). ¹³C{H}

NMR (101 MHz): δ 165.9 (A and B), 160.5 (A and B), 154.7 (A and

B), 137.1 (A and B), 134.8, 134.7, 128.8 (A and B), 128.2 (A and B),

127.4, 127.3, 123.3 (A and B), 122.4 (A and B), 114.4 (A and B),

112.3 (A and B), 107.7 (A and B), 84.7 (A and B), 78.3 (A and B),

74.5 (A and B), 73.0, 72.9, 72.1 (A and B), 66.2 (A and B), 58.9 (A

and B), 55.4 (A and B), 33.7 (A and B), 31.3, 31.1, 29.9 (A and B),

29.4, 29.2, 26.8 (A and B), 24.2, 24.1, 18.2 (A and B), −1.3 (A and

B). IR ν: 3314, 2950, 1690, 1611, 1511, 1441, 1390, 1250, 1083, 834

cm⁻¹. HRMS (FD) m/z: [M]⁺calcd for C₃₃H₄₇NO₇Si⁺, 597.3122;

found, 597.3134.

(E)-4,5-Dihydroxy-6-[2-(5-hydroxy-2,6,6-trimethyltetrahydro-2H-

pyran-2-yl)vinyl]-3-methoxy-4-(4-methoxyphenyl)-1-{[2-

(trimethylsilyl)ethoxy]methyl}-3,4-dihydroquinolin-2(1H)-one (25).

Substrate ( )-16 (44.5 mg, 0.1 mmol) was oleﬁnated using oleﬁn cis-

t

24 (36.4 mg, 0.15 mmol, 1.5 equiv) and PhCO₃Bu (34.2 μL, 0.18

mmol, 1.8 equiv) following the general procedure.

Before performing puriﬁcation, the crude sample was deprotected

by using the following procedure: The sample was dissolved in THF

(2 mL) and TBAF solution (1.0 mL, 1.0 M in THF) was added

dropwise. After stirring it for 4 h, the reaction was quenched by

adding water. The mixture was extracted with EtOAc three times. The

combined extracts were washed with brine, dried with MgSO₄, and

evaporated in vacuo. the sample was puriﬁed by preparative TLC (n-

hexane/EtOAc, 4:1) to give 25 as a single regioisomer (26.3 mg, 43%,

1

yellow oil, dr = 2.2:2.2:1:1). H NMR (300 MHz) [two groups of

diastereoisomers: (A + B)/(C + D), 2.2:1] 9.21−9.19 (m, 1H_A, 1H_B,

1H_C, and 1H_D), 7.45 (d, J = 8.6 Hz, 1H_A), 7.45 (d, J = 8.6 Hz, 1H_A

and 1H_B), 7.44 (d, J = 8.6 Hz, 1H_Cand 1H_D), 7.19−7.14 (m, 2H_A,

2H_B, 2H_C, and 2H_D), 6.96 (d, J = 8.7 Hz, 1H_A, 1H_B, 1H_C, and 1H_D),

6.89−6.79 (m, 3H_A, 3H_B, 3H_C, and 3H_D), 6.38−6.26 (m, 1H_A, 1H_B,

1H_C, and 1H_D), 5.64 (d, J = 10.9 Hz, 1H_A, 1H_B, 1H_C, and 1H_D), 5.01

(d, J = 10.9 Hz, 1H_A, 1H_B, 1H_C, and 1H_D), 4.48 (s, 1H_Aand 1H_B),

4.47 (s, 1H_Cand 1H_D), 3.95−3.88 (m, 1H_A, 1H_B, 1H_C, and 1H_D),

3.78 (s, 3H_A, 3H_B, 3H_C, and 3H_D), 3.62−3.54 (m, 2H_A, 2H_B, 2H_C,

and 2H_D), 3.59 (s, 3H_A, 3H_B, 3H_C, and 3H_D), 2.08−1.70 (m, 4H_A,

4H_B, 4H_C, and 4H_D), 1.44 (s, 3H_Cand 3H_D), 1.42 (3H_Aand 3H_C),

1.26 (s, 3H_A, 3H_B, 3H_C, and 3H_D), 1.16 (s, 3H_A, 3H_B, 3H_C, and

3H_D), 0.98−0.92 (m, 2H_A, 2H_B, 2H_C, and 2H_D), −0.01 (s, 9H_A, 9H_B,

9H_C, and 9H_D). ¹³C{H} NMR (75 MHz): δ 167.2 (A, B, C, and D),

(E)-4,5-Dihydroxy-6-{2-[5-(2-hydroxypropan-2-yl)-2-methyltetra-

hydrofuran-2-yl]vinyl}-3-methoxy-4-(4-methoxyphenyl)-1-{[2-

(trimethylsilyl)ethoxy]methyl}-3,4-dihydroquinolin-2(1H)-one (21).

Substrate ( )-16 (44.5 mg, 0.1 mmol) was oleﬁnated using trans-20

t

(25.5 mg, 0.15 mmol, 1.5 equiv) and PhCO₃Bu (34.2 μL, 0.18 mmol,

1.8 equiv) following the general procedure, and the sample was

puriﬁed by ﬂash column chromatography (n-hexane/EtOAc, 3:1) to

give 21 as a mixture of regioisomers (32.0 mg, 52%, yellow oil, A/B =

7:1, dr: not determined). From the ¹H NMR spectra of 21, we mainly

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https://doi.org/10.1021/acs.joc.1c00042

J. Org. Chem. 2021, 86, 6259−6277

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

161.7 (A, B, C, and D), 156.1 (A, B, C, and D), 138.4 (C and D),

136.8 (A and B), 137.3 (C or D), 137.1 (C or D), 136.8 (A and B),

130.1 (A, B, C, and D), 129.4 (A, B, C, and D), 129.1 (A or B), 129.0

(A or B), 128.9 (C or D), 128.8 (C or D), 123.6 (A or B), 123.5 (A

or B), 123.51 (C and D), 122.6 (C or D), 122.5 (C or D), 122.2 (A

or B), 122.1 (A or B), 115.6 (A, B, C, and D), 113.5 (A, B, C, and D),

109.0 (A, B, C, and D), 87.1 (C and D), 86.9 (A and B), 85.9 (A, B,

C, and D), 84.7 (A and B), 84.4 (C and D), 79.5 (A, B, C, and D),

73.4 (A, B, C, and D), 72.6 (A, B, C, and D), 67.5 (A and B), 67.4 (C

and D), 60.1 (A, B, C, and D), 56.6 (A, B, C, and D), 40.0 (C or D),

39.9 (C or D), 39.4 (A and B), 29.0 (C or D), 28.9 (C or D), 28.8 (A

and B), 28.7 (A, B, C, and D), 28.0 (C and D), 27.8 (A and B), 25.8

(C and D), 25.6 (A and B), 19.4 (A, B, C, and D), 0.0 (A, B, C, and

D). IR ν: 3296, 2956, 2927, 1688, 1611, 1511, 1441, 1250, 1082, 834

cm⁻¹. HRMS (FD) m/z: [M]⁺calcd for C₃₃H₄₇NO₈Si⁺, 613.3071;

found, 613.3084.

[d, J = 8.6 Hz, (1H_Aand 1H_B) or (1H_Cand 1H_D)], 7.31−7.21 (m,

5H_A, 5H_B, 5H_C, and 5H_D), 6.95 [d, J = 8.6 Hz, (1H_Aand 1H_B) or

(1H_Cand 1H_D)], 6.93 [d, J = 8.6 Hz, (1H_Aand 1H_B) or (1H_Cand

1H_D)], 6.63 [d, J = 16.7 Hz, (1H_Aand 1H_B) or (1H_Cand 1H_D)], 6.59

[d, J = 16.7 Hz, (1H_Aand 1H_B) or (1H_Cand 1H_D)], 6.17 [d, J = 16.4

Hz, (1H_Aand 1H_B) or (1H_Cand 1H_D)], 6.16 [d, J = 8.6 Hz, (1H_A

and 1H_B) or (1H_Cand 1H_D)], 5.63 (d, J = 10.9 Hz, 1H_A, 1H_B, 1H_C,

and 1H_D), 5.00 (d, J = 10.9 Hz, 1H_A, 1H_B, 1H_C, and 1H_D), 4.55 (s,

1H_A, 1H_B, 1H_C, and 1H_D), 3.79 (s, 1H_A, 1H_B, 1H_C, and 1H_D), 3.57

(s, 3H_A, 3H_B, 3H_C, and 3H_D), 3.59−3.53 (m, 2H_A, 2H_B, 2H_C, and

2H_D), 3.15−3.06 (m, 1H_A, 1H_B, 1H_C, and 1H_D), 1.88−1.73 (m, 3H_A,

3H_B, 3H_C, and 3H_D), 1.66−1.20 (m, 4H_A, 4H_B, 3H_C, and 3H_D), 1.14

(s, 3H_Cand 3H_D), 1.07 (t, J = 12.9 Hz, 1H_Aand 1H_B), 1.06 (s, 3H_A

and 3H_B), 1.01−0.98 (m, 3H_A, 3H_B, 3H_C, and 3H_D). ¹³C{H} NMR

(101 MHz): δ 165.8 (A, B, C, and D), 154.4 [(A and B) or (C and

D)], 154.3 [(A and B) or (C and D)], 142.3 (A, B, C, and D), 138.0

(A, B, C, and D), 137.2 (A, B, C, and D), 129.5 (A, B, C, and D),

129.0 (A, B, C, and D), 127.1 [(A and B) or (C and D)], 127.0 [(A

and B) or (C and D)], 126.7 (A, B, C, and D), 123.3 (A, B, C, and

D),121.6 (A, B, C, and D), 112.1 (A, B, C, and D), 107.8 [(A and B)

or (C and D)], 107.7 [(A and B) or (C and D)], 84.6 (A, B, C, and

D), 78.5 (A, B, C, and D), 76.3 (A, B, C, and D), 72.1 (A, B, C, and

D), 66.2 (A, B, C, and D), 58.9 (A, B, C, and D), 46.0 [(A and B) or

(C and D)], 44.8 [(A and B) or (C and D)], 37.4 (A, B, C, and D),

37.4 (A, B, C, and D), 37.2 (A, B, C, and D), 34.0 (C and D), 32.9 (A

and B), 32.1 [(A and B) or (C and D)], 32.0 [(A and B) or (C and

D)], 18.8 [(A and B) or (C and D)], 18.7 [(A and B) or (C and D)],

18.2 (A, B, C, and D), −1.3 (A, B, C, and D). IR ν: 3338, 2952, 2926,

2855, 1689, 1612, 1440, 1375, 1247, 1080, 1043, 804 cm⁻¹. HRMS

(FD) m/z: [M]⁺calcd for C₃₂H₄₅NO₆Si⁺, 567.3016; found, 567.3011.

Deprotection of SEM to Complete the Total Syntheses of

Yaequinolone Natural Products. General Procedure for the

Deprotection of SEM with TBAF. In a 10 mL round bottom ﬂask

containing the substrate (1.0 equiv) was added a solution of TBAF

(1.0 M in THF, 10−15 equiv) (in cases where more concentrated

TBAF was required, after mixing TBAF solution with the substrate in

the ﬂask, the THF was quickly evaporated using a rotary evaporator

and the right amount of THF was then added). The reaction was then

left to stir under reﬂux at 80 °C overnight. The reaction was then

quenched by adding water. The mixture was extracted with EtOAc

three times. The combined extracts were washed with brine, dried

with Na₂SO₄, and concentrated in vacuo. The sample was puriﬁed by

ﬂash column chromatography.

(E)-6-[2-(1,3-Dimethyl-4-oxocyclohexyl)vinyl]-4,5-dihydroxy-3-

methoxy-4-(4-methoxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]-

methyl}-3,4-dihydroquinolin-2(1H)-one (29). Substrate ( )-27

(103.9 mg, 0.25 mmol) was oleﬁnated using oleﬁn 28 (dr = 5:4,

t

57.1 mg, 0.375 mmol, 1.5 equiv) and PhCO₃Bu (86.0 μL, 0.45 mmol,

1.8 equiv) following the general procedure, and the sample was

puriﬁed by ﬂash column chromatography (n-hexane/EtOAc, 2.5:1) to

give 29 as a yellow oil (48.0 mg, 34%, regioselectivity > 20:1, dr =

1

1:1:1.6:1.6). H NMR (400 MHz) [two groups of diastereoisomers:

(A + B)/(C + D), 1:1.6]: δ 9.18 (s, 1H_Aand 1H_B), 9.17 (C and D),

7.49 (d, J = 8.7 Hz, 1H_Aand 1H_B), 7.42 (d, J = 8.6 Hz, 1H_Cand

1H_D), 7.31−7.21 (m, 5H_A, 5H_B, 5H_Cand 5H_D), 6.98 (d, J = 8.7 Hz,

1H_Aand 1H_B), 6.95 (d, J = 8.6 Hz, 1H_Cand 1H_D), 6.82 (d, J = 16.6

Hz, 1H_Aand 1H_B), 6.65 (d, J = 16.5 Hz, 1H_Cand 1H_D), 6.31 (d, J =

16.6 Hz, 1H_Aand 1H_B), 6.18 (d, J = 16.4 Hz, 1H_Cand 1H_D), 5.65 (d,

J = 10.9 Hz, 1H_Aand 1H_B), 5.63 (d, J = 10.9 Hz, 1H_Cand 1H_D), 5.02

(d, J = 10.8 Hz, 1H_Aand 1H_B), 5.00 (d, J = 10.8 Hz, 1H_Cand 1H_D),

4.59 (s, 1H_Aand 1H_B), 4.58 (s, 1H_Cand 1H_D), 3.80 (s, 1H_A, 1H_B,

1H_C, and 1H_D), 3.59−3.53 (m, 2H_A, 2H_B, 2H_C, and 2H_D), 3.58 (s,

3H_Aand 3H_B), 3.57 (s, 3H_Cand 3H_D), 2.66−2.46 (m, 2H_A, 2H_B,

2H_C, and 2H_D), 2.37−2.09 (m, 2H_A, 2H_B, 2H_C, and 2H_D), 1.91−1.84

(m, 1H_A, 1H_B, 1H_C, and 1H_D), 1.76−1.68 (m, 1H_Cand 1H_D), 1.63−

1.55 (m, 1H_Aand 1H_B), 1.51−1.43 (m, 1H_A, 1H_B, 1H_C, and 1H_D),

1.40 (s, 3H_Cand 3H_D), 1.11 (s, 3H_Aand 3H_B), 1.02 (d, J = 6.4 Hz,

3H_Cand 3H_D), 0.99 (d, J = 6.5 Hz, 3H_Aand 3H_B), 0.95−0.91 (m,

2H_A, 2H_B, 2H_C, and 2H_D), −0.03 (s, 9H_A, 9H_B, 9H_C, and 9H_D).

¹³C{H} NMR (75 MHz): δ 213.9 (A and B), 213.5 (C and D), 165.8

(A, B, C, and D), 154.5 (A, B, C, and D), 139.9 (A, B, C, and D),

137.2 (A or B), 137.1 (C or D), 137.1 (A or B), 137.0 (C or D),

136.2 (A, B, C, and D), 129.5 (A and B), 129.0 (C and D), 129.0 (A,

B, C, and D), 127.2 (A, B, C, and D), 126.6 (A, B, C, and D), 122.8

(C and D), 122.6 (A and B), 119.8 (A, B, C, and D), 112.3 (A and B),

112.2 (C and D), 107.8 (A, B, C, and D), 84.6 (A, B, C, and D), 78.5

(A, B, C, and D), 72.1 [(A and B) or (C and D)], 71.5 [(A and B) or

(C and D)], 66.3 [(A and B) or (C and D)], 66.0 [(A and B) or (C

and D)], 58.9 (A, B, C, and D), 47.7 (A and B), 46.9 (C or D), 46.8

(C or D), 41.4 (A and B), 40.8 (C and D), 38.7 (A, B, C, and D),

38.5 (A and B), 38.2 (C or D), 38.1 (C or D), 38.0 (C and D), 37.5

(A and B), 30.6 (A, B, C, and D), 18.2 (A, B, C, and D), 14.7 (C and

D), 14.6 (A and B), −1.3 (A, B, C, and D). IR ν: 3294, 2955, 2926,

1689, 1612, 1439, 1376, 1246,1079, 836 cm⁻¹. HRMS (FD) m/z:

[M]⁺calcd for C₃₂H₄₃NO₆Si⁺, 565.2860; found, 565.2885.

(E)-4,5-Dihydroxy-6-[2-(4-hydroxy-1,3-dimethylcyclohexyl)-

vinyl]-3-methoxy-4-(4-methoxyphenyl)-1-{[2-(trimethylsilyl)-

ethoxy]methyl}-3,4-dihydroquinolin-2(1H)-one (32). Substrate

( )-27 (41.6 mg, 0.1 mmol) was oleﬁnated using oleﬁn 31 (dr =

5:4, 23.1 mg, 0.15 mmol, 1.5 equiv) and PhCO₃tBu (34.2 μL, 0.18

mmol, 1.8 equiv) using the following the general procedure, and the

sample was puriﬁed by ﬂash column chromatography (n-hexane/

EtOAc, 3:1 to 1:1) to give 32 as a yellow oil (22.0 mg, 39%,

regioselectivity: >20:1, dr = 1:1:1:1). ¹H NMR (400 MHz) [two

groups of diastereoisomers: (A + B)/(C+ D), 1:1]: δ 9.13 [s, (1H_A

and 1H_B) or (1H_Cand 1H_D)], 9.11 [s, (1H_Aand 1H_B) or (1H_Cand

1H_D)], 7.45 [d, J = 8.6 Hz, (1H_Aand 1H_B) or (1H_Cand 1H_D)], 7.43

General Procedure for the Deprotection of SEM with Me₂AlCl. In

a ﬂame-dried Schlenk ﬂask were added substrate (1.0 equiv) and

anhydrous DCM (0.4−0.5 M) under N₂. A solution of Me₂AlCl (1.0

in hexanes, 6.0 equiv) was then added dropwise at −78 °C and the

reaction was stirred for 1 h before it was warmed up to 0 °C. After

stirring it for another 1 h, the reaction was quenched by adding water.

The mixture was extracted with EtOAc three times. The combined

extracts were washed with brine, dried with Na₂SO₄, and concentrated

in vacuo to give the hydroxymethyl protected intermediate, which was

i

then mixed with MeOH (0.4−0.5 M) and Pr₂NEt (7.0 equiv) and

heated at 55 °C overnight. The reaction was quenched by adding

saturated solution of NH₄Cl and extracted with EtOAc three times.

The combined extracts were washed with brine, dried with Na₂SO₄,

and concentrated in vacuo. The sample was puriﬁed by ﬂash column

chromatography.

( )-Yaequinolone B. SEM Deprotection of ( )-17 with TBAF. 20

mg of ( )-17 [regioisomers (6:1), 0.039 mmol, 1.0 equiv] and 600

μL TBAF (1.0 M in THF, 15 equiv) solution were used. Puriﬁcation

was performed using n-hexane/EtOAc (1:1) as an eluent to give

( )-yaequinolone B as a single regioisomer (pale yellow solid, 9.0

mg, 60%). ¹H NMR (400 MHz): δ 9.44 (s, 1H), 7.80 (d, J = 16.5 Hz,

1H), 7.70 (br s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.20−7.13 (m, 2H),

6.86−6.78 (m, 2H), 6.70 (d, J = 16.5 Hz, 1H), 6.40 (d, J = 8.3 Hz,

1H), 4.62 (s, 1H), 3.77 (s, 3H), 3.73 (s, 1H), 3.62 (s, 3H), 2.35 (s,

3H). ¹³C{H} NMR (101 MHz): δ 199.3, 165.5, 160.6, 157.5, 138.1,

137.2, 129.8, 128.6, 127.9, 126.8, 119.3, 114.5, 111.2, 107.5, 84.0,

6274

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78.8, 59.1, 55.5, 27.1. IR ν: 3251, 2926, 1691, 1599, 1257, 1079, 805

cm⁻¹. Its data matched with those reported in the literature.^4c

( )-Penigequinolones A and B. Deprotection of 19 with TBAF.

23 mg of 19 [regioisomers (8.8:1), dr = 1:1, 0.0385 mmol, 1.0 equiv]

and 385 μL TBAF (1.0 M in THF, 10 equiv) solution were ﬁrst mixed

in the reaction ﬂask. After quickly removing the THF using a rotary

evaporator, 90 μL THF was added. Puriﬁcation was performed using

n-hexane/EtOAc (2:1) as an eluent to give the product as a mixture of

regioisomers (A/B = 13.5:1, dr = 1:1) (pale yellow solid, 16.9 mg,

(A or B or C or D), 38.6 (A or B or C or D), 38.1 [(A and B) or (C

and D)], 27.5 (A, B, C, and D), 26.7 (A, B, C, and D), 26.6 (A, B, C,

and D), 24.6 (A or B or C or D), 24.5 (A or B or C or D), 24.3 [(A

and B) or (C and D)]. IR ν: 3249, 2966, 2927, 1686, 1602, 1419,

1373, 1254, 1030, 804 cm⁻¹. HRMS (FD) m/z: [M]⁺calcd for

+

C₂₇H₃₃NO₇, 483.2257; found, 483.2262.

( )-Aspoquinolones C and D. Deprotection of 25 with Me₂AlCl.

38 mg of 25 (dr = 2.2:2.2:1:1, 0.062 mmol) was used and the product

26 was isolated as a mixture of diastereoisomers (A/B/C/D =

2.2:2.2:1:1) (pale yellow solid, 22.0 mg, 73%) after puriﬁcation with

n-hexane/EtOAc (1:1) as an eluent. ¹H NMR (400 MHz), two

groups of diastereoisomers: (A + B)/(C + D) = 2.2:1.

Aspoquinolones C and D were reported as a mixture and we found

out that one of the mixtures matched with the NMR data of group A

and the other one matched with those of Group B.^4bTherefore, we

concluded that one of the natural products has a cis-conﬁguration for

the oleﬁn moiety and the other has a trans-conﬁguration for the oleﬁn

moiety. δ 9.13 (br s, 1H_Aor 1H_B), 9.13 (br s, 1H_Cor 1H_D), 9.12 (br

s, 1H_Aor 1H_B), 9.11 (br s, 1H_Cor 1H_D), 8.12 (br s, 1H_Cand 1H_D),

8.08 (br s, 1H_Aand 1H_B), 7.35−7.31 (m, 1H_A, 1H_B, 1H_C, and 1H_D),

7.18−7.14 (m, 2H_A, 2H_B, 2H_C, and 2H_D), 6.82−6.73 (m, 3H_A, 3H_B,

3H_C, and 3H_D), 6.34−6.21 (m, 2H_A, 2H_B, 2H_C, and 2H_D), 4.59−4.57

(m, 1H_A, 1H_B, 1H_C, and 1H_D), 3.90−3.83 (m, 1H_A, 1H_B, 1H_C, and

1H_D), 3.75−3.74 (m, 3H_A, 3H_B, 3H_C, and 3H_D), 3.69−3.68 (m, 1H_A,

1H_B, 1H_C, and 1H_D), 3.60−3.59 (m, 3H_A, 3H_B, 3H_C, and 3H_D),

2.03−1.74 (m, 4H_A, 4H_B, 4H_C, and 4H_D), 1.40−1.38 (m, 3H_A, 3H_B,

3H_C, and 3H_D), 1.25−1.23 (m, 3H_A, 3H_B, 3H_C, and 3H_D), 1.13 (s,

3H_A, 3H_B, 3H_C, and 3H_D). ¹³C{H} NMR (75 MHz): δ 165.9 (A, B,

C, and D), 160.4 (A, B, C, and D), 155.4 (A, B, C, and D), 135.7 (C

or D), 135.6 (C or D), 135.3 (A or B), 135.2 (A or B), 134.4 (C and

D), 134.4 (C and D), 129.2 (A and B), 129.1 (C and D), 128.0 (A

and B), 127.9 (C or D), 127.8 (C or D), 122.0 (C and D), 121.9 (A

and B), 121.4 (C or D), 121.3 (C or D), 121.0 (A or B), 120.9 (A or

B), 114.4 (A, B, C, and D), 110.9 (A, B, C, and D), 107.0 (A, B, C,

and D), 85.8 (C and D), 85.7 (A and B), 84.3 (A, B, C, and D), 83.4

(A and B), 83.2 (C and D), 78.9 (A and B), 78.8 (C and D), 71.4 (C

and D), 71.3 (A and B), 59.0 (A, B, C, and D), 55.4 (A, B, C, and D),

38.7 (C and D), 38.6 (A and B), 27.7 (C and D), 27.5 (A, B, C, and

D), 27.4 (A and B), 26.8 (C or D), 26.7 (C or D), 26.7 (A or B), 26.6

(A or B), 24.6 (C or D), 24.5 (C or D), 24.3 (A and B). IR ν: 3261,

2924, 1686, 1600, 1377, 1262, 1077, 1026, 734 cm⁻¹. HRMS (FD)

1

94%). H NMR (400 MHz) (Two diastereoisomers): δ 9.12 (br s,

1H_Aand 1H_B), 7.84 (br s, 1H_Aand 1H_B), 7.40 (d, J = 8.3 Hz, 1H_Aor

1H_B), 7.39 (d, J = 8.3 Hz, 1H_Aor 1H_B), 7.21−7.16 (m, 2H_Aand

2H_B), 6.84−6.80 (m, 2H_Aand 2H_B), 6.73 (d, J = 16.3 Hz, 1H_Aand

1H_B), 6.35 (d, J = 8.3 Hz, 1H_Aor 1H_B), 6.34 (d, J = 8.3 Hz, 1H_Aor

1H_B), 6.14 (d, J = 16.7 Hz, 1H_Aor 1H_B), 6.13 (d, J = 16.7 Hz, 1H_Aor

1H_B), 4.56 (br s, 1H_Aand 1H_B), 3.76 (s, 3H_Aand 3H_B), 3.70 (d, J =

1.5 Hz, 1H_Aor 1H_B), 3.69 (d, J = 1.5 Hz, 1H_Aor 1H_B), 3.60 (s, 3H_A

and 3H_B), 3.38 (d, J = 11.3 Hz, 1H_Aor 1H_B), 3.37 (d, J = 11.3 Hz,

1H_Aor 1H_B), 3.24−3.20 (m, 1H_Aand 1H_B), 1.84−1.76 (m, 1H_Aand

1H_B), 1.73−1.66 (m, 1H_Aand 1H_B), 1.51−1.46 (m, 1H_Aand 1H_B),

1.30 (s, 3H_Aand 3H_B), 1.00 (s, 3H_Aand 3H_B), 0.79 (s, 3H_Aand

3H_B). ¹³C{H} NMR (101 MHz): δ 165.8 (A and B), 160.4 (A and

B), 155.3 (A and B), 134.5, 134.43, 134.37 (A and B), 129.1 (A and

B), 127.6, 127.5, 123.3 (A and B), 122.1 (A and B), 114.4 (A and B),

110.9 (A and B), 107.0 (A and B), 84.3 (A and B), 74.5 (A and B),

72.9 (A and B), 59.0 (A and B), 55.4 (A and B), 33.7 (A and B), 31.2,

31.1, 29.9 (A and B), 29.3 (A and B), 26.8, 26.7, 24.2 (A and B). IR ν:

3269, 2927, 1686, 1616, 1508, 1256, 1079, 806 cm⁻¹. HRMS (FD)

+

m/z: [M]⁺calcd for C₂₇H₃₃NO₆, 467.2308; found, 467.2287. The

data matched with those reported in the literature.^4c

( )-Yaequinolone C. Deprotection of 21 with TBAF. 24 mg of 21

[regioisomers (6.8:1), dr not determined, 0.039 mmol, 1.0 equiv] and

400 μL TBAF (1.0 M in THF, 10 equiv) solution were ﬁrst mixed in

the reaction ﬂask. After quickly removing the THF using a rotary

evaporator, 100 μL THF was added. Puriﬁcation was performed using

n-hexane/EtOAc (1.5:1) as an eluent to give the product 22 as a

mixture of regioisomers (10:1, dr = 1:1:0.6:0.6) (pale yellow solid,

15.0 mg, 79%). ¹H NMR (400 MHz), two groups of diaster-

eoisomers: (A + B)/(C + D) = 1:0.6. The NMR data of groups A and

B matched with those of yaequinolone C reported in the literature.^4c

Therefore, either ( )-22-A or ( )-22-B is ( )-yaequinolone C.

The oleﬁn moiety of ( )-yaequinolone C has a trans-conﬁguration]:

δ 9.16 (A and/or B and/or C and/or D), 9.15 (A and/or B and/or C

and/or D), 7.84 (A, B, C, and D), 7.37 [d, J = 8.2 Hz, (1H_Aand 1H_B)

or (1H_Cand 1H_D)], 7.36 [d, J = 8.2 Hz, (1H_Aand 1H_B) or (1H_Cand

1H_D), 7.22−7.17 (m, 2H_A, 2H_B, 2H_C, and 2H_D), 6.85−6.83 (m, 2H_A,

2H_B, 2H_C, and 2H_D), 6.79 [d, J = 16.4 Hz, (1H_Aand 1H_B) or (1H_C

and 1H_D)], 6.78 [d, J = 8.2 Hz, (1H_Aand 1H_B) or (1H_Cand 1H_D)],

6.34−6.21 (m, 2H_A, 2H_B, 2H_C, and 2H_D), 4.56 [s, (1H_Aand 1H_B) or

(1H_Cand 1H_D)], 4.57 [s, (1H_Aand 1H_B) or (1H_Cand 1H_D)], 3.91−

3.83 (m, 1H_A, 1H_B, 1H_C, and 1H_D), 3.76 [s, (3H_Aand 3H_B) or (3H_C

and 3H_D)], 3.75 [s, (3H_Aand 3H_B) or (3H_Cand 3H_D)], 3.69−3.68

(m, 1H_A, 1H_B, 1H_C, and 1H_D), 3.60 (s, 3H_A, 3H_B, 3H_C, and 3H_D),

2.04−1.75 (m, 4H_A, 4H_B, 4H_C, and 4H_D), 1.40 [s, (3H_Aand 3H_B) or

(3H_Cand 3H_D)], 1.39 [s, (3H_Aand 3H_B) or (3H_Cand 3H_D)], 1.24

(s, 3H_A, 3H_B, 3H_C, and 3H_D), 1.14 (s, 3H_A, 3H_B, 3H_C, and 3H_D).

¹³C{H} NMR (101 MHz): δ 165.7 (A, B, C, and D), 160.4 (A, B, C,

and D), 155.4 (A, B, C, and D), 135.7 (A or B or C or D), 135.6 (A

or B or C or D), 135.3 (A and/or B and/or C and/or D), 134.5 (A or

B or C or D), 134.4 (A or B or C or D), 134.3 (A and/or B and/or C

and/or D), 129.2 [(A and B) or (C and D)], 129.1 [(A and B) or (C

and D)], 128.0 (A, B, C, and D), 127.9 [(A and B) or (C and D)],

127.8 [(A and B) or (C and D)], 122.0 [(A and B) or (C and D)],

121.9 [(A and B) or (C and D)], 121.3 [(A and B) or (C and D)],

121.0 (A or B or C or D), 120.9 (A or B or C or D), 114.4 (A, B, C,

and D), 110.9 (A, B, C, and D), 107.0 (A, B, C, and D), 85.8 [(A and

B) or (C and D)], 85.7 [(A and B) or (C and D)], 84.3 (A, B, C, and

D), 83.4 [(A and B) or (C and D)], 83.2 [(A and B) or (C and D)],

78.9 (A, B, C, and D), 71.4 [(A and B) or (C and D)], 71.3 [(A and

B) or (C and D)], 59.0 (A, B, C, and D), 55.4 (A, B, C, and D), 38.7

+

m/z: [M]⁺calcd for C₂₇H₃₃NO₇, 483.2257; found, 483.2272.

( )-Aﬂaquinolones A, C, and D. Deprotection of 29 with

Me₂AlCl. 40 mg of 29 (dr = 1:1:1.6:1.6, 0.071 mmol) was used and

the product 30 was isolated as a mixture of diastereoisomers (dr =

1:1:1:1) (pale yellow solid, 30.0 mg, 97%) after puriﬁcation with n-

hexane/EtOAc (1.5:1) as an eluent. ¹H NMR (400 MHz) [two

1

groups of diastereoisomers: (A + B)/(C + D) = 1:1, The H NMR

data of ( )-aﬂaquinolones A, C, and D matched with those reported

in the literature.:^5bδ 9.11 [br s, (1H_Aand 1H_B) or (1H_Cand 1H_D)],

9.09 [br s, (1H_Aand 1H_B) or (1H_Cand 1H_D)], 8.35 [br s, (1H_Aand

1H_B) or (1H_Cand 1H_D)], 8.33 [br s, (1H_Aand 1H_B) or (1H_Cand

1H_D)], 7.39 (d, J = 8.3 Hz, 1H_Aand 1H_B), 7.34−7.25 (m, 5H_A, 5H_B,

6H_C, and 6H_D), 6.78 (d, J = 16.6 Hz, 1H_Cand 1H_D), 6.61 (d, J = 16.5

Hz, 1H_Aand 1H_B), 6.39 (d, J = 8.1 Hz, 1H_Cand 1H_D), 6.36 (d, J =

8.2 Hz, 1H_Aand 1H_B), 6.27 (d, J = 16.6 Hz, 1H_Aand 1H_B), 6.13 (d, J

= 16.4 Hz, 1H_Cand 1H_D), 4.69 [s, (1H_Aand 1H_B) or (1H_Cand

1H_D)], 4.67 [s, (1H_Aand 1H_B) or (1H_Cand 1H_D)], 3.69 (d, J = 1.6

Hz, 1H_A, 1H_B, 1H_C, and 1H_D), 3.61 (s, 3H_A, 3H_B, 3H_C, and 3H_D),

2.65−2.44 (m, 2H_A, 2H_B, 2H_C, and 2H_D), 2.36−2.31 (m, 1H_Cand

1H_D), 2.28−2.21 (m, 1H_Aand 1H_B), 2.21−2.08 (m, 2H_A, 2H_B, 2H_C,

and 2H_D), 1.76−1.68 (m, 1H_Aand 1H_B), 1.62−1.54 (m, 1H_Cand

1H_D), 1.43−1.39 (m, 1H_A, 1H_B, 1H_C, and 1H_D) 1.39 (s, 3H_Cand

3H_D), 1.10 (s, 3H_Aand 3H_B), 1.02 (d, J = 6.5 Hz, 3H_Cand 3H_D),

0.93 (d, J = 6.5 Hz, 3H_Aor 3H_B), 0.92 (d, J = 6.5 Hz, 3H_Aor 3H_B).

¹H NMR (400 MHz, acetone-d₆): δ 9.62 (br s, 1H_Aor 1H_Bor 1H_Cor

1H_D), 9.61 (br s, 1H_Aor 1H_Bor 1H_Cor 1H_D), 9.59 [br s, (1H_Aand

1H_B) or (1H_Cand 1H_D)], 9.37 [br s, (1H_Aand 1H_B) or (1H_Cand

1H_D)], 9.36 [br s, (1H_Aand 1H_B) or (1H_Cand 1H_D)], 7.53 (d, J =

8.3 Hz, 1H_Aor 1H_B), 7.52 (d, J = 8.3 Hz, 1H_Aor 1H_B), 7.43 (d, J =

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8.4 Hz, 1H_Cand 1H_D), 7.37−7.32 (m, 5H_A, 5H_B, 5H_C, and 5H_D),

6.84 (d, J = 16.7 Hz, 1H_Aand 1H_B), 6.65 (d, J = 16.5 Hz, 1H_Cand

1H_D), 6.60 [d, J = 8.6 Hz, (1H_Aand 1H_B) or (1H_Cand 1H_D)], 6.57

[d, J = 8.6 Hz, (1H_Aand 1H_B) or (1H_Cand 1H_D)], 6.44 (d, J = 16.6

Hz, 1H_Aand 1H_B), 6.37 (s, 1H_Aor 1H_Bor 1H_Cor 1H_D), 6.36 (s, 1H_A

or 1H_Bor 1H_Cor 1H_D), 6.36 [s, (1H_Aand 1H_B) or (1H_Cand 1H_D)],

6.23 (d, J = 16.4 Hz, 1H_Cand 1H_D), 3.68 (d, J = 1.4 Hz, 1H_A, 1H_B,

1H_Cand 1H_D), 3.52 [s, (3H_Aand 3H_B) or (3H_Cand 3H_D)], 3.51 [s,

(3H_Aand 3H_B) or (3H_Cand 3H_D)], 2.73−2.47 (m, 2H_A, 2H_B, 2H_C,

and 2H_D), 2.22−2.09 (m, 1H_A, 1H_B, 1H_C, and 1H_D), 1.91−1.81 (m,

2H_A, 2H_B, 2H_C, and 2H_D), 1.75−1.67 (m, 1H_Aand 1H_B), 1.58−1.49

(m, 1H_Cand 1H_D), 1.42 (s, 3H_Cand 3H_D), 1.11 (s, 3H_Aand 3H_B),

0.95 (d, J = 6.5 Hz, 3H_Cand 3H_D), 0.93 (d, J = 6.5 Hz, 3H_Aor 3H_B),

0.92 (d, J = 6.5 Hz, 3H_Aor 3H_B). ¹³C{H} NMR (101 MHz): δ 214.0

[(A and B) or (C and D)], 213.6 [(A and B) or (C and D)], 165.9

(A, B, C, and D), 155.0 (A, B, C, and D), 137.4 (A, B, C, and D),

136.0 (A, B, C, and D), 134.5 [(A and B) or (C and D)], 134.4 [(A

and B) or (C and D)], 129.4 (A, B, C, and D), 129.1 [(A and B) or

(C and D)], 129.0 [(A and B) or (C and D)], 127.4 [(A and B) or (C

and D)], 127.3 [(A and B) or (C and D)], 126.4 (A, B, C, and D),

122.6 (A, B, C, and D), 122.5 [(A and B) or (C and D)], 122.4 [(A

and B) or (C and D)], 110.9 [(A and B) or (C and D)], 110.8 [(A

and B) or (C and D)], 107.2 (A, B, C, and D), 84.2 (A, B, C, and D),

79.0 (A, B, C, and D), 59.1 (A, B, C, and D), 47.7 (A or B), 47.6 (A

or B), 46.9 (C or D), 46.8 (C or D), 41.5 (A and B), 40.8 (C and D),

38.7 (A, B, C, and D), 38.5 [(A and B) or (C and D)], 38.2 [(A and

B) or (C and D)], 38.0 (C and D), 37.4 (A and B), 30.6 (A, B, C, and

D), 14.7 (A or B or C or D), 14.6 (A or B or C or D), 14.3 [(A and

B) or (C and D)]. IR ν: 3221, 2923, 1689, 1377, 1260, 1080, 1026,

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00042.

■

sı

General schemes for the synthesis of 18, trans-20, 28,

31, and ( )-27; comparison of the H NMR spectra of

oleﬁnated product 21 when using trans-20 or a mixture

of trans- and cis-20; comparison of the NMR data of

natural and synthetic products; and copies of the ¹H and

¹³C NMR spectra for all new compounds (PDF)

1

AUTHOR INFORMATION

■

Corresponding Author

́

M. Angeles Fernández-Ibánez − Van’t Hoﬀ Institute for

̃

Molecular Sciences, University of Amsterdam, 1098 XH

Amsterdam, The Netherlands; orcid.org/0000-0002-

7694-5911; Email: m.a.fernandezibanez@uva.nl

Authors

Wen-Liang Jia − Van’t Hoﬀ Institute for Molecular Sciences,

University of Amsterdam, 1098 XH Amsterdam, The

Netherlands

Sabela Vega Ces − Van’t Hoﬀ Institute for Molecular Sciences,

University of Amsterdam, 1098 XH Amsterdam, The

Netherlands

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00042

+

800 cm⁻¹. HRMS (FD) m/z: [M]⁺calcd for C₂₆H₂₉NO₅, 435.2046;

found, 435.2047.

Notes

( )-Scopuquinolone B. Deprotection of 32 with Me₂AlCl. 19 mg

of 32 (dr = 1:1:1:1, 0.0335 mmol) was used and the product 33 was

isolated as a mixture of daistereosiomers (dr = 1:1:1:1) (pale yellow

solid, 13.0 mg, 89%) after puriﬁcation with n-hexane/EtOAc (1:1) as

an eluent. ¹H NMR (400 MHz, acetone-d₆) [two groups of

diastereoisomers: (A + B)/(C + D) = 1:1. The NMR data of groups

C and D matched with those of scopuquinolone B reported in the

literature.:^6cδ 9.55 (br s, 1H_A, 1H_B, 1H_C, and 1H_D), 9.33 (br s, 1H_A,

1H_B, 1H_C, and 1H_D), 7.44 [d, J = 8.3 Hz, (1H_Aand 1H_B) or (1H_C

and 1H_D)], 7.42 [d, J = 8.3 Hz, (1H_Aand 1H_B) or (1H_Cand 1H_D)],

7.37−7.32 (m, 5H_A, 5H_B, 5H_C, and 5H_D), 6.65−6.55 (m, 2H_A, 2H_B,

2H_C, and 2H_D), 6.20 [d, J = 16.5 Hz, (1H_Aand 1H_B) or (1H_Cand

1H_D)], 6.17 [d, J = 16.5 Hz, (1H_Aand 1H_B) or (1H_Cand 1H_D)], 3.66

(d, J = 1.5 Hz, 1H_A, 1H_B, 1H_C, and 1H_D), 3.52 [s, (3H_Aand 3H_B) or

(3H_Cand 3H_D)], 3.51 [s, (3H_Aand 3H_B) or (3H_Cand 3H_D)], 3.06−

2.97 (m, 1H_A, 1H_B, 1H_C, and 1H_D), 1.81−1.68 (m, 3H_A, 3H_B, 3H_C,

and 3H_D), 1.64−1.27 (m, 3H_A, 3H_B, 4H_C, and 4H_D), 1.13 (s, 3H_A

and 3H_B), 1.07 (t, J = 12.9 Hz, 1H_cand 1H_d), 1.01 (s, 3H_Cand 3H_D),

0.98 (d, J = 6.4 Hz, 3H_Aand 3H_B), 0.96 (d, J = 6.4 Hz, 3H_Aand 3H_B).

¹³C{H} NMR (101 MHz, acetone-d₆): δ 166.3 (A, B, C, and D),

156.1 (C and D), 155.9 (A and B), 141.8 (A and B), 140.3 (C and

D), 137.6 (A, B, C, and D), 136.9 (A, B, C, and D), 129.7 (A, B, C,

and D), 129.6 (A, B, C, and D), 127.5 [(A and B) or (C and D)],

127.5 [(A and B) or (C and D)], 127.4 [(A and B) or (C and D)],

127.3 [(A and B) or (C and D)], 122.6 (A, B, C, and D), 122.3 (A, B,

C, and D), 112.1 (A, B, C, and D), 107.7 (A, B, C, and D), 85.8 (A, B,

C, and D), 80.0 (A, B, C, and D), 76.8 (A, B, C, and D), 59.0 (A, B,

C, and D), 46.9 (C and D), 45.9 (A and B), 37.7 (A, B, C, and D),

37.7 (A, B, C, and D), 37.0 [(A and B) or (C and D)], 36.9 [(A and

B) or (C and D)], 34.0 (A and B), 33.1 (C and D), 31.9 [(A and B)

or (C and D)], 31.8 [(A and B) or (C and D)], 19.5 [(A and B) or

(C and D)], 19.4 [(A and B) or (C and D)]. IR ν: 3274, 2926, 1687,

1620, 1452, 1378, 1261, 1082, 1039, 803 cm⁻¹. HRMS (FD) m/z:

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We acknowledge ﬁnancial support from NWO through a VIDI

grant (723.013.006). W.L.J. gratefully acknowledges ﬁnancial

support from the China Scholarship Council (CSC) (File no.

201606180020).

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Article Doi

Divergent Total Syntheses of Yaequinolone-Related Natural Products by Late-Stage C-H Olefination

DOI: 10.1021/acs.joc.1c00042

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