Four-Step Total Synthesis of (+)-Euphococcinine and (&#177;)-Adaline

Sopan P. Khandare and Kavirayani R. Prasad*

Note

Four-Step Total Synthesis of (+)-Euphococcinine and (± )-Adaline

Cite This: https://doi.org/10.1021/acs.joc.1c00938

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ABSTRACT: A four-step enantiospeciﬁc total synthesis of bicyclic homotropinone

alkaloid euphococcinine and a racemic synthesis of adaline were reported. Key

reactions in the synthesis are the diastereoselective addition of a Wittig phosphorene

to the ketimines derived from Davis−Ellman sulﬁnamides, ring-closing metathesis, and

intramolecular Michael reactions.

iperidine, quinolizidine, indolizidine, and pyrrolidine

alkaloids bearing the α-tertiary amine (attached to chiral

addition of lithium enolate of (acetylmethylene) triphenyl

phosphorane 7 to nonracemic aldimines obtained from

quaternary carbon center) are structural units prevalent in

aldehydes and Ellman sulﬁnamide. Herein, we report the

bioactive natural products. Some examples of these alkaloids

addition of (acetylmethylene) triphenyl phosphorane to

ketimine derived from acetophenone and its application to

the synthesis of (+)-euphococcinine 2 and (±)-adaline 3.

Our investigation began with the addition of lithium enolate

of (acetyl methylene) triphenyl phosphorane 7 to the

sulﬁnimine 8 derived from acetophenone (Scheme 1). The

reaction of 2 equiv of the lithium enolate of 7 to sulﬁnimine 8

proceeded well. However, it was cumbersome to purify the

product phosphorane 9 at this stage and also diﬃcult to

evaluate the diastereomeric ratio of 9. Hence, 9 was subjected

to Wittig oleﬁnation with various aldehydes to aﬀord the β-

sulﬁnamido enones 10, which were puriﬁed by silica gel

column chromatography. Thus, the reaction of crude 9 with

diﬀerent aldehydes such as acetaldehyde, benzaldehyde, para-

bromo- and nitro-substituted benzaldehydes, and ethyl

glyoxylate furnished the corresponding β-sulﬁnamido enones

include simple piperidinones such as adalinine 1, bicyclic

compounds ephococcinine 2, adaline 3, and complex natural

products such as cyclindricine C 4, porantherine 5, and

lycopodine 6 (Figure 1 ).

0a−e having a quaternary chiral center in moderate yields. It

Figure 1. Alkaloids bearing α-tertiary amines attached to a chiral

quaternary center.

is important to note that the Wittig reaction of 9 with ketones

did not proceed at all. Deprotection of the sulﬁnyl group in

0a−e using saturated ethereal HCl followed by treatment

with triethylamine aﬀorded a separable mixture of cis and trans-

,2,6-trisubstituted piperidinones 11a−d and 11a′−d′ in good,

Among the several methods described in the literature for

the synthesis of chiral amines, the addition of nucleophiles to

ketimines either in a Mannich fashion or by the addition of

2b,e

Received: April 22, 2021

organometallic reagents is a frequently used reaction. Chiral

sulﬁnimines pioneered by Davis and Ellman served as excellent

substrates for the addition of various nucleophiles to aldimines

and ketimines. The addition of a variety of nucleophiles to the

sulﬁnimines consistently provided the product amines with

excellent diastereoselectivities. We recently found that the

XXXX American Chemical Society

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

Scheme 1. Addition of the Lithium Enolate of 7 to

Sulﬁnimine 8 and Elaboration of Piperidinones 11a−d

elegantly applied this intramolecular Mannich reaction strategy

for the synthesis of euphococcinine and adaline from N-sulﬁnyl

amino ketone. We envisioned the synthesis of 2 and 3 by

intramolecular Michael addition of the amine obtained by the

deprotection of the sulﬁnyl group in 13a and 13b, respectively.

The formation of 13a and 13b was planned by RCM of the

diene in 12a and 12b, the synthesis of which was anticipated

by the addition of the lithium enolate of 7 to sulﬁnimine 8a,b

derived from pent-1-en-5-one or undec-1-en-6-one and

subsequent Wittig oleﬁnation (Scheme 2).

Scheme 2. Retrosynthesis for (+)-Euphococcinine and

(

± )-Adaline

Thus, the addition of lithium enolate of 7 to sulﬁnimine 8a

and further Wittig oleﬁnation with formalin aﬀorded a

separable mixture of diastereomers 12a′ and 12a in 14% and

3% yields, respectively. Ring-closing metathesis of compound

2a using Grubbs second generation catalyst (5 mol %)

furnished the cyclooctenone 13a in 71% yield along with the

dimer 14 in 18% yield, respectively. Deprotection of the

sulﬁnyl group in 13a and further neutralization with Et N gave

euphococcinine 2 in 83% yield. The spectral and physical

properties were in complete agreement with that reported for

the natural product in literature. However, the addition of

lithium enolate of 7 to sulﬁnimine 8b was found to be

nonselective. This can be attributed to the structure of the

imine (which existed in a 1:1 mixture of E/Z isomers as

evidenced from the C NMR) in which both alkyl

substitutions do not oﬀer steric bias required for diﬀerentiation

of the substituents in the addition of lithium enolate. The

product 12b was isolated in a 68% yield. We were not able to

estimate the diastereomeric ratio of the product at this stage.

Ring-closing metathesis of 12b with Grubbs’ second

generation catalyst (5 mol %) formed the cyclooctenone 13b

in 69% yield (87% BRSM). The diastereomeric ratio of 13b

combined yields (Scheme 1). cis/trans-Stereochemistry of the

formed piperidinones 11a−d was established by comparison

with that reported in the literature. The origin of the

diastereoselectivity in the addition reaction can be explained by

a transition state similar to that proposed for the addition of

phosphorene to aldimines.

was found to be 1:1 from the H NMR analysis. The removal

of the sulﬁnyl group followed by intramolecular Michael

After a short survey of the reaction of sulﬁnamido

phosphorane 9 with aldehydes, the strategy was applied for

addition reaction after neutralization with Et N aﬀorded

the synthesis of homotropinone alkaloids euphococcinine and

(±)-adaline 3 in 80% yield (Scheme 3).

adaline containing the bicyclic keto amine attached to a

In conclusion, the addition of lithium enolate of (acetyl-

methylene) triphenyl phosphorene to nonracemic sulﬁnylke-

timines was described. A Wittig reaction of the formed

phosphorene with aldehydes aﬀorded the β-sulﬁnamido

enones with good diastereoselectivity in good to moderate

yields. The β-sulﬁnamido enones were used in the synthesis of

homotropinone alkaloids (+)-euphococcinine and (±)-adaline.

quaternary chiral center. Several syntheses of ephococcinine

were reported in the literature. Most of the syntheses were

based on the nitro cycloaddition reaction reported by Holmes

et al., while the biomimetic synthesis involving the

intramolecular Mannich reaction of a suitably substituted

piperidine is a practical approach. The Davis group has

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

Oleﬁnation Reaction of Resultant Sulﬁnamido Keto Phosphoranes

with Aldehydes.

Scheme 3. Total Synthesis of Alkaloids (+)-Euphococcinine

and (± )-Adaline 3

S )-(S,E)-6-((tert-Butyl(λ -oxidaneyl)-λ -sulfaneyl)amino)-6-phe-

nylhept-2-en-4-one (10a ). To

a stirred solution of

(acetylmethylene)triphenylphosphorane 7 (0.86 g, 2.7 mmol) in dry

THF (20 mL) at −78 °C was added dropwise LDA (2.7 mL of 1 M

solution in THF, 2.7 mmol). The reaction mixture was stirred for 30

min at the same temperature. A solution of sul ﬁ nimine 8 (0.30 g, 1.34

mmol) in THF (5 mL) was added dropwise to the reaction mixture at

−

78 °C. It was stirred for 2 h at the same temperature. After

completion of the reaction (TLC), it was quenched by the addition of

sat. NH Cl solution (20 mL) and extracted with ethyl acetate (3 × 20

mL). The combined organic layers were washed with brine (20 mL)

and dried over anhydrous Na SO . Evaporation of the solvent gave

the crude residue, which was puri ﬁ ed by short silica gel column

chromatography to remove excess of unreacted (acetylmethylene)-

triphenylphosphorane 7 .

The addition product (obtained above) was dissolved in toluene

(

15 mL), and acetaldehyde (0.6 mL, 10 mmol) was added at room

temperature. The resulting solution was stirred at 80 °C (oil bath) for

h. After completion of the reaction (TLC), most of the solvent was

removed under reduced pressure. The crude residue thus obtained

was puriﬁed by silica gel column chromatography using EtOAc/

petroleum ether (2:3) as an eluent to furnish 10a in 64% yield (0.26 g

for 2 steps) (recovered sulﬁnimine 8, 0.11 g) (94% yield of 10a

BRSM) as a colorless oil: R 0.5 (petroleum ether/EtOAc, 3:2); [α]

17.4 (c 0.7, CHCl ); IR (neat) ν 3432, 3270, 2973, 2922, 1659,

3 max

−

1 1

1626, 1444, 1380, 1061 cm ; H NMR (400 MHz, CDCl ) δ 7.37

(d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 2H), 7.22 (t, J = 8.4 Hz, 1H),

.84 (ddd, J = 16.0 Hz, 12.4 Hz, 8.0 Hz, 1H), 6.10 (dd, J = 16.0 Hz,

.0 Hz, 1H), 5.64 (s, 1H), 3.41 (AB , J = 17.6 Hz, 1H), 3.32 (AB J =

7.6 Hz, 1H), 1.88 (dd, J = 6.8 Hz, 1.6 Hz, 3H), 1.71 (s, 3H), 1.29 (s,

H); C{ H} NMR (100 MHz, CDCl ) δ 199.2, 146.5, 143.7, 132.4,

28.3 (2C), 126.9, 125.2 (2C), 59.4, 56.0, 50.8, 29.0, 22.9 (3C), 18.3;

HRMS (ESI-TOF) m/z [M + Na] calcd for C H NO SNa

330.1504, found 330.1506.

EXPERIMENTAL SECTION

■

(

S )-(S,E)-5-((tert-Butyl(λ -oxidaneyl)-λ -sulfaneyl)amino)-1,5-di-

General Procedures. Column chromatography was performed on

phenylhex-1-en-3-one (10b). Compound 10b was prepared from

acetylmethylene)triphenylphosphorane 7 (1.14 g, 3.60 mmol), LDA

1 M solution in THF, 3.60 mL, 3.60 mmol), sulﬁnimine 8 (0.40 g,

.80 mmol), and benzaldehyde (0.95 mL, 9 mmol) using the general

procedure described above 10b in 54% yield (0.36 g for 2 steps)

recovered sulﬁnimine 8, 0.157 g, 86% yield of 10b BRSM) as a

silica gel, Acme grade 100−200 mesh. TLC plates were visualized

either with UV, in an iodine chamber, or with phosphomolybdic acid

spray, unless noted otherwise. All reagents were purchased from

commercial sources and used without additional puriﬁcation. THF

was freshly distilled over Na-benzophenone ketyl. Melting points were

(

measured in open glass capillary tubes using a Bu

chi B-540 melting

colorless oil: R 0.4 (petroleum ether/EtOAc, 7:3); [α] +18.0 (c

point apparatus, and values are uncorrected. Unless stated otherwise,

0.65, CHCl ); IR (neat) ν 3271, 2962, 2923, 1649, 1606, 1449,

3 max

H NMR (400 MHz) and C NMR (100 MHz) spectra were

−

380, 1062 cm ; H NMR (400 MHz, CDCl ) δ 7.56−7.47 (m,

recorded on 400 MHz ultrashield Bruker spectrophotometers in

CDCl as a solvent with TMS or residual CHCl as a reference. High-

H), 7.42 (d, J = 8.0 Hz, 2H), 7.39−7.36 (m, 3H), 7.33 (t, J = 8.0 Hz,

H), (7.26−7.21 (m, 1H), 6.66 (d, J = 16.0 Hz, 1H), 5.72 (s, 1H),

.57 (d, J = 17.6 Hz, 1H), 3.49 (d, J = 17.6 Hz, 1H), 1.76 (s, 3H),

resolution mass spectra (HRMS) were recorded on a Waters XEVO

G2-XS Q-TOF micromass spectrometer using electron spray

ionization mode. Sulﬁnimine 8 was prepared according to the

.32 (s, 9H); C{ H} NMR (100 MHz, CDCl ) δ 199.1, 146.3,

43.3, 134.1, 130.6, 128.8 (2C), 128.3 (4C), 126.9, 126.4, 125.2

(2C), 59.6, 56.0, 51.8, 28.9, 22.9 (3C); HRMS (ESI-TOF) m/z [M +

Na] calcd for C H NO SNa 392.1660, found 392.1652.

procedure described in the literature.

General Procedure for the Addition of (Acetylmethylene)-

triphenylphosphorane 7 to Sulﬁnimines 8 and Successive Wittig

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

General Procedure for Intramolecular aza-Michael Cyclization

Reaction: The Following Synthesis of 11a and 11a′ Is

Representative.

(

S )-(S,E)-5-((tert-Butyl(λ -oxidaneyl)-λ -sulfaneyl)amino)-1-(4-

nitrophenyl)-5-phenylhex-1-en-3one (10c). Compound 10c was

prepared from (acetylmethylene)triphenylphosphorane 7 (430 g, 1.34

mmol), LDA (1 M solution in THF, 1.4 mL, 1.35 mmol), sulﬁnimine

2S,6R)-2,6-Dimethyl-2-phenylpiperidin-4-one (11a ). To stirred

(0.15 g, 0.67 mmol), and 4-nitrobenzaldehyde (0.51 g, 3.35 mmol)

using the general procedure described above 10c in 59% yield

recovered sulﬁnimine 8 0.044 g) (83% yield of 10c BRSM) (0.165 g

for 2 steps) as a colorless oil: R 0.4 (petroleum ether/EtOAc, 7:3);

solution of 10a (0.075 g, 0.24 mmol) in Et O (2 mL) at 0 °C was

added a saturated solution of ethereal HCl (w/v) (0.8 mL). The

reaction mixture was stirred for 0.45 h at the same temperature. After

completion of the reaction (TLC), the solvent was evaporated o ﬀ and

the resultant amine hydrochloride salt was dissolved in MeOH (5

(

[

α] +31.6 (c 0.50, CHCl ); IR (neat) ν 3279, 2976, 2363, 1688,

D 3 max

−

1 1

596, 1520, 1344, 1058 cm ; H NMR (400 MHz, CDCl ) δ 8.21

mL) and Et N (0.16 mL, 1.2 mmol) was added. The reaction mixture

(

d, J = 7.6 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 16.0 Hz,

H), 7.39 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.23 (t, J = 8.4

Hz, 1H), 6.75 (d, J = 16.4 Hz, 1H), 5.44 (s, 1H), 3.63 (AB J = 18.0

was stirred for 12 h at room temperature. The solvent was evaporated

o ﬀ and water (5 mL) was added to the residue and was extracted with

EtOAc (2 × 5 mL). The organic layers were washed with brine (1 × 5

Hz, 1H), 3.56 (AB J = 18.0 Hz, 1H); C NMR 1.73 (s, 3H), 1.30 (s,

_H₎_;₁3C{ H} NMR (100 MHz, CDCl ) δ 198.3, 148.5, 146.2, 140.4,

mL) and dried over anhydrous Na SO . Evaporation of solvent

2 4

followed by silica gel column chromatography of the resulting crude

residue with petroleum ether/EtOAc as an eluent a ﬀ orded the

separable diastereomers 11a in 27% (0.013 g) and 11a ′ in 60% (0.029

39.8, 129.6, 128.8 (2C), 128.4 (2C), 127.0, 124.9 (2C), 124.0 (2C),

9.2, 56.0, 52.2, 29.3, 22.8 (3C); HRMS (ESI-TOF) m/z [M + H]

calcd for C H N O SNa 437.1511, found 437.1512.

g) yields, respectively, as a colorless oil: 11a R 0.5 (petroleum ether/

EtOAc, 8:2); [α ] +10.0 (c 0.5, CHCl ); IR (neat) ν 2965, 2924,

363, 2329, 1710, 1494, 1446, 1285 cm ; H NMR (400 MHz,

max

−

CDCl ) δ 7.57 (d, J = 84 Hz, 2H), 7.37 (t, J = 8.0 Hz, 2H), 7.27 (t, J

8.0 Hz, 1H), 3.46 −3.37 (m, 1H), 2.64 (dd, J = 16.0 Hz, 4.0 Hz,

H), 2.57 (d, J = 16.0 Hz, 1H), 2.44 (dq, J = 8.0 Hz, 4.0 Hz, 1H),

2.09 (dd, J = 12.0 Hz, 1.6 Hz, 1H), 1.63 (brs, 1H), 1.43 (s, 3H), 1.28

(

S )-(S,E)-1-(4-Bromophenyl)-5-((tert-butyl(λ -oxidaneyl)-λ -

(d, J = 8.0 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 209.7,

sulfaneyl)amino)-5-phenylhex-1-en-3-one (10d). Compound 10d

was prepared from (acetylmethylene)triphenylphosphorane 7 (0.86 g,

48.1, 128.5 (2C), 127.1, 124.7 (2C), 59.0, 54.1, 50.2, 47.3, 25.7,

3.1; HRMS (ESI-TOF) m /z [M + H] calcd for C H NOH

.69 mmol), LDA (1 M solution in THF, 2.7 mL, 2.69 mmol),

sulﬁnimine 8 (0.30 g, 1.34 mmol), and 4-bromobenzaldehyde (1.22 g,

.73 mmol) using the general procedure described above 10d in 52%

13 17

04.1388, found 204.1387.

(

2S,6S)-2,6-Dimethyl-2-phenylpiperidin-4-one (11a′): R 0.4

(

petroleum ether/EtOAc, 7:3); [α] −13.4 (c 1.2, CHCl ); IR

yield (0.27 g for 2 steps) (recovered sulﬁnimine 8, 0.093 g) (84%

neat) ν 3293, 2967, 2925, 2365, 2330, 1708, 1447, 1376, 1023

yield of 10d BRSM) as a colorless oil: R 0.4 (petroleum ether/

max

−

1 1

_E_t_O_A_c_,₇_:₃₎_;_[_α_]2 +24.0 (c 1.0, CHCl ); IR (neat) ν 3160, 2958,

cm ; H NMR (400 MHz, CDCl ) δ 7.36 (d, J = 8.0 Hz, 2H), 7.31

max

−

(t, J = 8.4 Hz, 2H), 7.20 (t, J = 7.8 Hz, 1H), 3.17 (dd, J = 16.0 Hz, 4.0

Hz, 1H), 2.78−2.67 (m, 1H), 2.44 (d, J = 12.0 Hz, 1H), 2.22 (dq, J =

923, 1649, 1608, 1449, 1380, 1060 cm ; H NMR (400 MHz,

CDCl ) δ 7.50 (d, J = 8.0 Hz, 2H), 7.47−7.38 (m, 3H), 7.35 (d, J =

6.0 Hz, 4.0 Hz, 1H), 2.01 (dd, J = 12.0 Hz, 1.6 Hz, 1H), 1.88 (brs,

H), 1.48 (s, 3H), 1.13 (d, J = 8.0 Hz, 3H); C{ H} NMR (100

.8 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 8.0 Hz, 1H), 6.63

(

d, J = 16.0 Hz, 1H), 5.59 (s, 1H), 3.56 (ABq, J = 18.0 Hz, 1H), 3.48

ABq, J = 18.0 Hz, 1H), 1.75 (s, 3H), 1.30 (s, 9H); C{ H} NMR

100 MHz, CDCl ) δ 198.8, 146.3 (2C), 141.8, 133.1 (2C), 132.2,

MHz, CDCl ) δ 209.2, 145.0, 128.6 (2C), 126.8, 125.9 (2C), 59.6,

1.6, 49.6, 47.1, 34.0, 22.5; HRMS (ESI-TOF) m/z [M + H] calcd

for C H NOH 204.1388, found 204.1385.

29.9 (2C), 128.4 (2C), 126.9 (2C), 125.1, 124.9, 59.4, 56.0, 51.9,

13 17

9.1, 22.8 (3C); HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C H BrNO SH 448.0946, found 448.0946.

(

2S,6S)-2-Methyl-2,6-diphenylpiperidin-4-one (11b). Compounds

1b and 11b′ were prepared from the keto enone 10b (0.090 g, 0.24

(

S )-Ethyl (S,E)-6-((tert-Butyl(λ -oxidaneyl)-λ -sulfaneyl)amino)-

mmol) using the general procedure described above in 32% (0.021 g)

-oxo-6-phenylhept-2-enoate (10e). Compound 10e was prepared

and 57% (0.037 g) yields, respectively, as a colorless oil: 11b R 0.5

from (acetylmethylene)triphenylphosphorane 7 (0.85 g, 2.69 mmol),

LDA (1 M solution in THF, 2.7 mL, 2.69 mmol), sulﬁnimine 8 (0.30

g, 1.34 mmol), and ethyl glyoxalate (50% solution in toluene) (1.37

mL, 6.73 mmol) using the general procedure described above 10e in

(petroleum ether/EtOAc, 8:2); [α] +5.7 (c 0.4, CHCl ); IR (neat)

D 3

−

1 1

ν_m_a_x2968, 2932, 1712, 1498, 1447, 1289, 1027 cm ; H NMR (400

MHz, CDCl ) δ 7.67 (dd, J = 8.8 Hz, 1.2 Hz, 2H), 7.53 (d, J = 7.6 Hz,

2H), 7.40 (t, J = 8.0 Hz, 4H), 7.35−7.27 (m, 2H), 4.43 (dd, J = 11.2

5% yield (0.173 g for 2 steps) (recovered sulﬁnimine 8, 0.157 g, 73%

Hz, 3.6 Hz, 1H), 2.75 (d, J = 13.2 Hz, 1H), 2.66−2.58 (m, 2H),

yield of 10e BRSM) as a colorless oil: R 0.4 (petroleum ether/EtOAc,

2.57−2.50 (m, 1H), 1.72 (brs, 1H), 1.59 (s, 3H); C{ H} NMR

:2); [α]²+7.1 (c 2.0, CHCl ); IR (neat) ν 3405, 2986, 2947,

678, 1494, 1107 cm ; H NMR (400 MHz, CDCl ) δ 7.36−7.28

(100 MHz, CDCl ) δ 208.8, 148.1, 143.1, 128.7 (2C), 128.5 (2C),

max

−

1 1

127.9, 126.7 (2C), 124.9 (2C), 58.7, 55.9, 54.8, 50.2, 24.8; HRMS

(

m, 4H), 7.25−7.20 (m, 1H), 6.96 (d, J = 16.0 Hz, 1H), 6.62 (d, 16.0

(ESI-TOF) m/z [M + H] calcd for C H NOH 266.1545, found

Hz, 1H), 5.28 (s, 1H), 4.23 (q, J = 8.0 Hz, 2H), 3.57 (ABq, J = 16.0

266.1545.

Hz, 1H), 3.51 (ABq, J = 16.0 Hz, 1H), 1.69 (s, 3H), 1.31−1.26 (m,

(2S,6R)-2-Methyl-2,6-diphenylpiperidin-4-one (11b′): R 0.5

2H); ¹³C{ H} NMR (100 MHz, CDCl ) δ 198.6, 165.2, 146.0,

(petroleum ether/EtOAc, 7:3); [α] −11.2 (c 0.6, CHCl ); IR

−

1 1

39.3, 131.3, 128.5 (2C), 127.1, 124.8 (2C), 61.4, 59.2, 56.0, 52.2,

(neat) ν_m_a_x3027, 2968, 2924, 1714, 1495, 1446, 1289, 1028 cm ; H

9.3, 22.8 (3C), 14.0; HRMS (ESI-TOF) m/z [M + Na] calcd for

NMR (400 MHz, CDCl ) δ 7.43−7.33 (m, 8H), 7.32−7.23 (m, 2H),

C H NO SNa 388.1558, found 388.1554.

3.72 (dd, J = 11.2 Hz, 4.0 Hz, 1H), 3.27 (dd, J = 13.2 Hz, 1.6 Hz,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

H), 2.64 (d, J = 14.4 Hz, 1H), 2.51 (dd, J = 12.4 Hz, 8.0 Hz, 1H),

(2C), 125.8, 121.5, 59.6, 55.1, 51.5, 48.9, 34.0; HRMS (ESI-TOF) m/

.43 (dq, J = 12.0 Hz, 4.0 Hz, 1H), 2.21 (brs, 1H), 1.60 (s, 3H);

z [M + H] calcd for C H BrNOH 344.0650, found 344.0647.

C{ H} NMR (100 MHz, CDCl ) δ 208.7, 144.9, 142.5, 128.8 (2C),

28.7 (2C), 127.8, 126.9, 126.5 (2C), 125.9 (2C), 59.7, 55.6, 51.6,

9.1, 34.0; HRMS (ESI-TOF) m/z [M + H] calcd for C H NOH

66.1545, found 266.1549.

(

S )-(E)-N-(tert-Butyl(λ -oxidaneyl)-λ -sulfaneyl)hept-6-en-2-

11a

imine (8a). To a stirred solution of hept-6-en-2-one (0.70 g, 6.19

mmol) in THF at room temperature were added tert-

butylsulﬁnamide(0.50 g, 4.13 mmol) and tetraethoxytitanium (1.37

mL, 6.19 mmol). The reaction mixture was reﬂuxed for 12 h. After

completion of the reaction (TLC), it was quenched by the addition of

water (0.5 mL), and the solid residue thus formed was ﬁltered

through a short pad of Celite. The Celite pad was washed with

(

2S,6S)-2-Methyl-6-(4-nitrophenyl)-2-phenylpiperidin-4-one

11c). Compounds 11c and 11c′ were prepared from the keto enone

0c (0.14 g, 0.33 mmol), saturated ethereal HCl (w/v) (1.4 mL), and

(

Et N (0.23 mL, 1.65 mmol) using the general procedure described

above 11c in 38% yield (0.040 g) as a white solid and 11c′ 52%

CH Cl (2 × 5 mL). Evaporation of the solvent under reduced

pressure and silica gel column chromatography of the crude residue

thus obtained using EtOAc/petroleum ether (1:9) as an eluent gave

2 2

(

0.056 g) yields as colorless oils: 11c R 0.5 (petroleum ether/EtOAc,

:3); [α]²+8.7 (c 0.4, CHCl ); mp 95−97 °C; IR (neat) ν 3306,

max

−1 1

969, 2924, 1713, 1601, 1520, 1347, 768 cm ; H NMR (400 MHz,

the imine 8a in 73% yield (0.671 g) as a colorless oil: R

0.6

); IR (neat)

max 2924, 2853, 2364, 1630, 1582 cm ; H NMR (400 MHz,

CDCl ) δ 8.25 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.67 (d, J

(petroleum ether/EtOAc, 9:1); [α] +56.4 (c 1.2, CHCl

−

8.8 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 4.55

(

dd, J = 11.2 Hz, 3.2 Hz, 1H), 2.78 (d, J = 13.6 Hz, 1H), 2.67−2.59

CDCl ) δ 5.78 (ddd, J = 16.4 Hz, 9.6 Hz, 6.4 Hz, 1H), 5.07−4.94 (m,

m, 2H), 2.49 (dd, J = 12.0 Hz, 4.0 Hz, 1H), 1.78 (brs, 1H), 1.61

2H), 2.48−2.39 (m, 2H), 2.31 (s, 3H), 2.16−2.01 (m, 2H), 1.76−

3H); ¹³C{ H} NMR (100 MHz, CDCl ) δ 207.3, 150.3, 147.5,

1.62 (m, 2H), 1.23 (s, 9H); C{ H} NMR (100 MHz, CDCl

185.2, 138.0, 115.2, 56.2, 42.6, 33.0, 24.6, 23.1, 22.1 (3C); HRMS

) δ

47.4, 128.6 (2C), 127.6 (2C), 127.4, 124.8 (2C), 124.0 (2C), 58.8,

5.4, 54.7, 49.6, 24.6; HRMS (ESI-TOF) m/z [M + H] calcd for

(ESI-TOF) m/z [M + H] calcd for C11H21NOSH 216.1422, found

C H N O H 311.1396, found 311.1396.

216.1425.

(

2S,6R)-2-Methyl-6-(4-nitrophenyl)-2-phenylpiperidin-4-one

(

11c′): R 0.5 (petroleum ether/EtOAc, 6:4); [α] −73 (c 0.76,

CHCl ); IR (neat) ν 3323, 2970, 2924, 1716, 1601, 1520, 1347,

71 cm ; H NMR (400 MHz, CDCl ) δ 8.18 (dd, J = 8.8 Hz, 4.0

max

−1 1

Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.45−7.32 (m, 4H), 7.29−7.23 (m,

H), 3.81 (dd, J = 10.4 Hz, 4.4 Hz, 1H), 3.28 (d, J = 16.0 Hz, 1H),

.65 (d, J = 16.4 Hz, 1H), 2.47−2.36 (m, 2H), 2.17 (brs, 1H), 1.57 (s,

H); ¹³C{ H} NMR (100 MHz, CDCl ) δ 207.3, 149.7, 147.3, 144.3,

Preparation of 12a′ and 12a. To a stirred solution of

acetylmethylene)triphenylphosphorane 7 (0.61 g, 1.92 mmol) in

dry THF (20 mL) at −78 °C was added LDA (1 M solution in THF,

2.0 mL, 1.92 mmol) dropwise. The reaction mixture was stirred for 45

min at the same temperature. A solution of the sulﬁnimine 8a (0.20 g,

28.9 (2C), 127.4 (2C), 127.2, 125.7 (2C), 123.9 (2C), 59.7, 55.1,

(

1.4, 48.6, 33.9; HRMS (ESI-TOF) m/z [M + H] calcd for

C H N O H 311.1396, found 311.1395.

.96 mmol) in THF (5 mL) was added dropwise to the reaction

mixture at −78 °C. It was stirred for 2 h at the same temperature.

After completion of the reaction (TLC), it was quenched by the

addition of sat. NH Cl solution (20 mL) and extracted with ethyl

acetate (3 × 20 mL). The combined organic layers were washed with

(

2S,6S)-6-(4-Bromophenyl)-2-methyl-2-phenylpiperidin-4-one

brine (20 mL) and dried over anhydrous NaSO . Evaporation of the

(

11d). Compounds 11d and 11d′ were prepared from the keto enone

solvent gave the crude residue, which was puriﬁed on short silica gel

column chromatography to remove excess of unreacted

(acetylmethylene)triphenylphosphorane 7.

0d (0.085 g, 0.19 mmol) using the general procedure described

above in 26% yield (0.017 g) as a colorless oil and 58% yield (0.035

g) as a white solid: 11d R 0.5 (petroleum ether/EtOAc, 8:2); [α]

The addition product obtained above was dissolved in toluene (15

14 (c 0.71, CHCl ); IR (neat) ν 2967, 2924, 1711, 1486, 1443,

mL), and formalin (37% solution in H O) (0.75 mL, 9.6 mmol) was

max

−

1 1

288, 1008 cm ; H NMR (400 MHz, CDCl ) δ 7.66 (dd, J = 8.0

added at room temperature. The resulting solution was stirred at 80

°C for 4 h. After completion of the reaction (TLC), most of the

solvent was removed under reduced pressure. The crude residue thus

obtained was puriﬁed by silica gel column chromatography using

EtOAc/petroleum ether (2:3) as an eluent to furnish 12a′ in 14%

(0.039 g for 2 steps) and 12a in 63% (0.173 g for 2 steps) yields,

Hz, 4.0 Hz, 2H), 7.52 (dd, J = 6.8 Hz, 1.6 Hz, 2H), 7.40 (t, J = 8.0

Hz, 4H), 7.30 (t, J = 7.2 Hz, 1H), 4.39 (dd, J = 11.2 Hz, 3.2 Hz, 1H),

.74 (d, J = 13.2 Hz, 1H), 2.62−2.54 (m, 2H), 2.47 (dd, J = 12.8 Hz,

13 1

1.2 Hz, 1H), 1.68 (brs, 1H), 1.58 (s, 3H); C{ H} NMR (100

MHz, CDCl ) δ 208.3, 147.8 (2C), 142.1 (2C), 131.9, 131.8, 128.5,

28.4, 127.3, 124.9, 124.7, 121.6, 58.6, 55.3, 54.8, 50.0, 24.7; HRMS

respectively, as a colorless oil: 12a′ R

0.5 (petroleum ether/EtOAc,

+51.0 (c 1.0, CHCl ); IR (neat) νmax 2949, 2924, 1690,

D 3

(

ESI-TOF) m/z [M + H] calcd for C H BrNOH 344.0650, found

7:3); [α]

1611, 1462, 1402, 1056 cm ; H NMR (400 MHz, CDCl ) δ 6.31

−

1 1

44.0651.

2S,6R)-6-(4-Bromophenyl)-2-methyl-2-phenylpiperidin-4-one

(

(dd, J = 17.6 Hz, 10.4 Hz, 1H), 6.18 (d, J = 17.6 Hz, 1H), 5.85−5.71

(m, 2H), 5.00 (d, J = 17.2 Hz, 1H), 4.94 (d, J = 10.0 Hz, 1H), 4.62 (s,

1H), 3.06 (AB , J = 17.6 Hz, 1H), 2.65 (AB , J = 17.6 Hz, 1H), 2.04

(

11d′): R 0.5 (petroleum ether/EtOAc, 7:3); [α] −19.0 (c 0.86,

CHCl ); mp 115−119 °C; IR (neat) ν 3461, 3316, 2923, 2363,

max

−

713, 1486, 1442, 1289, 1238, 1078, cm ; H NMR (400 MHz,

(quart., J = 6.8 Hz, 2H), 1.82 (ddd, J = 18.0 Hz, 14.0 Hz, 4.4 Hz, 1H),

1.67 (ddd, J = 17.2 Hz, 12.0 Hz, 5.2 Hz, 1H), 1.51−1.32 (m, 2H),

CDCl ) δ 7.56 (d, J = 8.4 Hz, 2H), 7.39−7.32 (m, 4H), 7.28−7.24

(

m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 3.66 (dd, J = 9.6 Hz, 5.6 Hz, 1H),

1.30 (s, 3H), 1.18 (s, 9H); C{ H} NMR (100 MHz, CDCl ) δ

.24 (d, J = 14.4 Hz, 1H), 2.61 (d, J = 14.4 Hz, 1H), 2.45−2.32 (m,

199.7, 138.4, 137.2, 128.2, 114.8, 56.7, 55.5, 49.7, 40.0, 33.8, 26.0,

22.9, 22.6 (3C); HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C H NO SH 286.1841, found 286.1841.

H), 2.04 (brs, 1H), 1.53 (s, 3H); C{ H} NMR (100 MHz, CDCl )

δ 208.2, 144.6 (2C), 141.5 (2C), 131.8, 128.9, 128.3 (2C), 127.0

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

(

S )-(S)-5-((tert-Butyl(λ -oxidaneyl)-λ -sulfaneyl)amino)-5-meth-

eluent furnished euphococcinine (2) in 83% yield (0.034 g) as a white

yldeca-1,9-dien-3-one (12a): R 0.5 (petroleum ether/EtOAc, 6:4);

α] +28 (c 1.0, CHCl ); IR (neat) ν 3422, 2927, 2363, 1671,

610, 1460, 1402, 1053 cm ; H NMR (400 MHz, CDCl ) δ 6.31

dd, J = 17.6 Hz, 10.4 Hz, 1H), 6.20 (dd, J = 17.6 Hz, 0.8 Hz, 1H),

.83−5.69 (m, 2H), 5.02−4.89 (m, 2H), 4.77 (s, 1H), 3.02 (AB , J =

7.6 Hz, 1H), 2.78 (AB , J = 17.6 Hz, 1H), 2.02 (quart., J = 6.8 Hz,

H), 1.69 (ddd, J = 18.4 Hz, 13.6 Hz, 4.8 Hz, 1H), 1.63 (ddd, J = 16.4

Hz, 11.6 Hz, 5.2 Hz, 1H), 1.48−1.38 (m, 1H), 1.36 (s, 3H), 1.33−

.27 (m, 1H), 1.20 (s, 9H); C NMR (100 MHz, CDCl ) δ 200.2,

38.4, 137.2, 128.5, 114.8, 56.6, 55.6, 49.3, 40.4, 38.8, 25.7, 23.0, 22.7

3C); HRMS (ESI-TOF) m/z [M + Na] calcd for C H NO SNa

solid: R 0.5 (MeOH/EtOAc, 0.5:4.5); [α] +6.8 (c 0.7, MeOH) [lit.

f D

[

(

[α]_D+5.4 (c 0.65, MeOH)]; mp 31−33 °C (lit. 32−34 °C); IR

−1 1

max

−

(neat) ν_m_a_x3430, 2978, 2930, 1717, 1471, 1201, 1147, 1025 cm ; H

NMR (400 MHz, CDCl ) δ 3.68−3.57 (m, 1H), 2.52 (dd, J = 16.0

Hz, 6.8 Hz, 1H), 2.36 (t, J = 15.6 Hz, 2H), 2.18 (d, J = 16.0 Hz, 1H),

2.07 (brs, 1H), 1.72−1.37 (m, 6H), 1.16 (s, 3H); C{ H} NMR

(100 MHz, CDCl ) δ 210.9, 53.4, 52.4, 49.7, 46.1, 38.4, 31.5, 31.1,

18.0; HRMS (ESI-TOF) m/z [M + H] calcd for C H NOH

(

154.1232, found 154.1232.

08.1660, found 308.1661.

(

S )-N-(tert-Butyl(λ -oxidaneyl)-λ -sulfaneyl)undec-1-en-6-imine

(

8b). The compound 8b prepared using a procedure described for 8a

11b

from undec-1-en-6-one (0.83 g, 4.96 mmol), tert-butylsulﬁnamide

0.50 g, 4.13 mmol), and tetraethoxytitanium (0.90 mL, 4.96 mmol)

gave 7b in 67% yield (0.671 g) as a colorless oil: R 0.6 (petroleum

ether/EtOAc, 9:1); [α]

927, 2862, 1620, 1456, 1360, 1076 cm ; H NMR (400 MHz,

CDCl ) (E/Z 1:1) δ 5.74 (ddd, J = 16.0 Hz, 8.0 Hz, 4.0 Hz, 1H),

(

+5.8 (c 1.0, CHCl ); IR (neat) νmax 2957,

D 3

(

S )-(S,Z)-7-((tert-Butyl(λ -oxidaneyl)-λ -sulfaneyl)amino)-7-

−1

methylcyclooct-2-en-1-one (13a). To a solution of 12a (0.15 g, 0.52

mmol) in CH Cl (0.002 M, 260 mL) was added Grubbs’ second

.01−4.86 (m, 2H), 2.71−2.48 (m, 2H), 2.42−2.28 (m, 2H), 2.11−

generation catalyst (0.022 g, 0.026 mmol), and the mixture was stirred

under reﬂux for 48 h. After completion of the reaction (TLC), most of

the solvent was evaporated oﬀ, and the crude residue thus obtained

was puriﬁed by silica gel column chromatography using petroleum

ether/EtOAc (2:3) as an eluent to furnish 13a 71% (0.096 g) and 14

.95 (m, 3H), 1.68−1.59 (m, 2H), 1.57−1.47 (m, 2H), 1.41−1.35

(m, 2H), 1.18 and 1.17 (s, 9H), 1.09 (brs, 1H), 0.83 (t, J = 8.0 Hz,

H); C{ H} NMR (100 MHz, CDCl ) (E/Z 1:1) δ 188.7 and 188.6

(

1C), 138.7 and 138.1 (1C), 115.5 and 115.1 (1C), 56.23 and 56.19

1C), 41.3, 40.9, and 40.1 (1C), 36.6 and 36.0 (1C), 34.2 and 33.7

in 18% (0.024 g) yields, respectively, as a colorless oil: 13a R 0.4

(1C), 33.1, 31.9, and 31.3 (1C), 27.1 and 26.6 (1C), 25.3 and 24.6

(1C), 22.2, 22.1 (3C), 13.94 and 13.90 (1C); HRMS (ESI-TOF) m/z

(

petroleum ether/EtOAc, 1:1); [α]_D+39.0 (c 1.0, CHCl ); IR (neat)

ν_m_a_x2953, 2926, 1685, 1657, 1467, 1051 cm ; H NMR (400 MHz,

−

[M + H] calcd for C H NOSNa 294.1868, found 294.1869.

CDCl ) δ 6.48 (dt, J = 12.0, 8.4 Hz, 1H), 6.18 (d, J = 12.0 Hz, 1H),

15 29

.39 (s, 1H), 3.12−2.86 (m, 2H), 2.78−2.56 (m, 2H), 1.83−1.61 (m,

H), 1.40 (s, 3H), 1.17 (s, 9H); C{ H} NMR (100 MHz, CDCl ) δ

98.8, 142.8, 136.0, 55.9, 55.7, 55.3, 34.5, 29.3, 25.6, 22.5 (3C), 19.8;

HRMS (ESI-TOF) m/z [M + Na] calcd for C H NO SNa

80.1347, found 280.1346.

(

S )-5-((tert-Butyl(λ -oxidaneyl)-λ -sulfaneyl)amino)-5-pentylde-

ca-1,9-dien-3-one (12b). The compound 12b was prepared using a

procedure similar to that described for the synthesis of 12a. Thus, the

reaction of 7 (0.70 g, 2.20 mmol), LDA (1 M solution in THF, 2.20

mL, 2.20 mmol), and sulﬁnimine 8b (0.30 g, 1.1 mmol) aﬀorded 12b

(

S )-(2E,7S,10E,15S)-7,15-Bis((tert-butyl(λ -oxidaneyl)-λ -

in 67% (0.196 g for 2 steps) yield as a colorless oil: R 0.5 (petroleum

sulfaneyl)amino)-7,15-dimethylcyclohexadeca-2,10-diene-1,9-

dione (14): R 0.3 (petroleum ether/EtOAc, 2:3); [α] + 45.4 (c 0.7,

CHCl ); IR (neat) ν 2981, 2953, 2926, 1685, 1651, 1618, 1467,

051 cm ; H NMR (400 MHz, CDCl ) δ 6.76−6.62 (m, 1H), 6.09

d, J = 15.6 Hz, 1H), 4.60 (s, 1H), 2.84 (d, J = 13.6 Hz, 1H), 2.73 (d,

ether/EtOAc, 3:2); [α]

+14.5 (c 1.5, CHCl

); IR (neat) νmax 3433,

927, 2863, 1675, 1610, 1460, 1403, 1064 cm ; H NMR (400 MHz,

−1 1

max

−

CDCl ) δ 6.30 (dd, J = 16.0 Hz, 8.0 Hz, 1H), 6.19 (dd, J = 16.0 Hz,

(

.0 Hz, 1H), 5.84−5.71 (m, 2H), 5.03−4.92 (m, 2H), 4.79 (s, 1H),

.02 (dd, J = 16.0 Hz, 4.0 Hz, 1H), 2.76 (d, J = 16.0 Hz, 1H), 2.09−

J = 13.6 Hz, 1H), 2.48−2.26 (m, 1H), 2.18−2.11 (m, 1H), 1.76−1.59

1.98 (m, 2H), 1.84−1.71 (m, 1H), 1.70−1.62 (m, 3H), 1.44−1.21

(

m, 1H), 1.37 (s, 3H), 1.35−1.26 (m, 3H), 1.23 (s, 9H); C{ H}

13 1

(

m, 6H), 1.20 (s, 9H), 0.85 (t, J = 8.0 Hz, 3H); C{ H} NMR (100

MHz, CDCl ) (diastereomeric mixture 1:1) δ 200.20 and 200.17

1C), 138.3, 137.1, 128.2, 114.9, 59.07, and 59.04 (1C), 55.70 and

NMR (100 MHz, CDCl ) δ 199.8, 148.2, 132.7, 57.4, 55.7, 51.6, 40.6,

2.2, 24.4, 22.8 (3C), 21.9; HRMS (ESI-TOF) m/z [M + Na] calcd

(

for C H N O S Na 537.2797, found 537.2798.

4 2

55.69 (1C), 47.4 and 47.3 (1C), 36.9 and 36.6 (1C), 36.4 and 36.2

(

1C), 33.85 and 33.81 (1C), 32.03 and 31.98 (1C), 22.8 and 22.7

1C), 22.5 (3C), 14.0; HRMS (ESI-TOF) m/z [M + Na] calcd for

C H NO SNa 364.2286, found 364.2285.

(+)-Euphococcinine (2). To a stirred solution of 13a (0.070 g, 0.27

mmol) in Et O (2 mL) was added saturated ethereal HCl (0.7 mL) at

°C. The reaction mixture was stirred for 45 min at 0 °C. After

completion of the reaction (TLC), most of the solvent was

evaporated oﬀ, the crude amine hydrochloride salt was dissolved in

MeOH (5 mL), and Et N (0.2 mL, 1.35 mmol) was added. The

reaction mixture was stirred for 48 h at room temperature. After

completion of the reaction (TLC), most of solvent was evaporated

oﬀ, and the residue was diluted with water (5 mL) and extracted with

EtOAc (2 × 10 mL). The organic layers were washed with brine (1 ×

(S )-(Z)-7-((tert-Butyl(λ -oxidaneyl)λ -sulfaneyl)amino)-7-pentyl-

cyclooct-2-en-1-one (13b). Using a procedure similar to that

described for the synthesis of 12a, the compound 13b was prepared

from 12b (0.10 g, 0.28 mmol), CH Cl (0.002 M, 140 mL), and

Grubbs’ second generation catalyst (0.012 g, 0.014 mmol) in 69%

(0.061 g) yield, with recovery of the starting material 12b (0.013 g)

0 mL) and dried over anhydrous Na SO . Evaporation of the solvent

followed by silica gel column chromatography of the resulting crude

residue with methanol/ethyl acetate (MeOH/EtOAc 0.5:4.5) as an

(77% yield of 13b BRSM) as a colorless oil: R 0.4 (petroleum ether/

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Rev. 2016 , 116 (7), 4441 −4557. (b) Zhou, P.; Chen, B.-C.; Davis, F.

Note

EtOAc, 1:1); [α] +6.1 (1.0, CHCl ); IR (neat) ν 3434, 3273,

max

stereoselective construction of C −N bonds in total synthesis. Chem.

A. Recent advances in asymmetric reactions using sulfinimines (N -

sulfinyl imines). Tetrahedron 2004 , 60 , 8003−8030. (c) Davis, F. A.

Adventures in sulfur-nitrogen chemistry. J. Org. Chem. 2006, 71,

8993 −9003. (d) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A.

tert-Butanesulfinimines: structure, synthesis, and synthetic applica-

tions. Chem. Soc. Rev. 2009, 38 , 1162 −1186. (e) Robak, M. T.;

Herbage, M. A.; Ellman, J. A. Synthesis and applications of tert -

butanesulfinamide. Chem. Rev. 2010, 110, 3600−3740.

−

924, 2859, 2713, 2562, 1654, 1064 cm ; H NMR (400 MHz,

CDCl ) (diastereomeric mixture 1:1) δ 6.58−6.47 (m, 1H), 6.23 (d, J

12.0 Hz, 1H), 3.50 (d, J = 8.0 Hz, 1H), 3.04−2.93 (m, 1H), 2.92−

.79 (m, 1H), 2.72−2.61 (m, 1H), 2.11−1.98 (m, 1H), 1.88−1.62

(

m, 7H), 1.41−1.26 (m, 6H), 1.24 and 1.21 (s, 9H), 0.89 (t, J = 3H);

C{ H} NMR (100 MHz, CDCl ) (diastereomeric mixture 1:1) δ

00.4 and 199.4 (1C), 143.1 and 142.8 (1C), 136.3 and 136.2 (1C),

8.4 and 58.2 (1C), 56.4 and 56.3 (1C), 53.1, 52.0, 35.3, 33.4, 32.0,

5.83, and 25.77 (1C), 22.76 and 22.72 (1C), 22.58 and 22.55 (3C),

0.3 and 20.0 (1C), 14.0; HRMS (ESI-TOF) m/z [M + Na] calcd

for C H NO SH 314.2154, found 314.2154.

(3) Khandare, S. P.; Reddy, P. O.; Prasad, K. R. Addition of lithium

anion of (acetylmethylene)triphenylphosphorane to non-racemic

sulfinimines: total synthesis of (+)-241D and formal total synthesis

of (+)-preussin. Org. Lett. 2020, 22, 7273−7277.

4) Adriaenssens, L. V.; Hartley, R. C. β -Amino acids to

piperidinones by Petasis methylenation and acid-induced cyclization.

J. Org. Chem. 2007, 72, 10287−10290.

(

±)-Adaline (3). Using a procedure described for the synthesis of 2,

compound 3 was prepared from 13b (0.05 g, 0.15 mmol) in 80% yield

0.027 g) as a colorless oil: R 0.5 (MeOH/EtOAc, 0.5:4.5); IR (neat)

5) Hart, N. K.; Johns, S. R.; Lamberton, J. A. (+)-9-Aza-1-

methylbicyclo[3,3,1]nonan-3-one, a new alkaloid from Euphorbia

atoto Forst. Aust. J. Chem. 1967, 20, 561−563.

(

−

1 1

ν_m_a_x3435, 2927, 2853, 1703, 1464, 1356 cm ; H NMR (400 MHz,

CDCl ) δ 3.67 (brs, 1H), 2.54 (dd, J = 16.0 Hz, 8.0 Hz, 1H), 2.37 (d,

(6) Tursch, B.; Braekman, J. C.; Daloze, D.; Hootele, C.; Losman,

D.; Karlsson, R.; Pasteels, J. M. Chemical ecology of arthropods, VI.

adaline, a novel alkaloid from Adaliabipunctata L , (Coleoptera,

Coccinellidae ). Tetrahedron Lett. 1973, 14, 201−202.

J = 16.0 Hz, 2H), 2.19 (d, J = 16.0 Hz, 1H), 1.97 (brs, 1H), 1.76−

(

.57 (m, 4H), 1.55−1.46 (m, 1H), 1.44−1.36 (m, 3H), 1.34−1.21

13 1

m, 6H), 0.87 (t, J = 8.0 Hz, 3H); C{ H} NMR (100 MHz, CDCl )

(7) For a summary of the syntheses of adaline and euphococcinine,

δ 211.3, 54.7, 51.5, 49.6, 46.5, 44.6, 36.5, 32.3, 31.5, 22.5, 22.2, 17.8,

4.0; HRMS (ESI-TOF) m/z [M + H] calcd for C H NOH

10.1858, found 210.1861.

see: (a) Lima, D. J. P.; Santana, A. E. G.; Birkett, M. A.; Porto, R. S.

Recent progress in the synthesis of homotropane alkaloids adaline,

euphococcinine and N -methyleuphococcinine. Beilstein J. Org. Chem.

13 23

021, 17, 28−41. For a recent synthesis of N-Me-euphococcine see:

ASSOCIATED CONTENT

sı Supporting Information

■

Siitonen, J. H.; Kattamuri, P. V.; Yousufuddin, M.; Kurti, L.

Arylboronic acid-catalyzed C-allylation of unprotected oximes: total

synthesis of N -Me-euphococcine. Org. Lett. 2020, 22, 2486 −2489.

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00938.

8) (a) Davison, E. C.; Holmes, A. B.; Forbes, I. T. A Tandem

¹H and ¹³C NMR spectra of all new compounds (PDF)

synthesis of (±)-euphococcinine and (±)-adaline. Tetrahedron Lett.

995 , 36 , 9047 −9050. (b) Davis, F. A.; Edupuganti, R. Asymmetric

synthesis of substituted homotropinones from N -sulfinyl-β -amino

ketone ketals. (−)-euphococcinine and (−)-adaline. Org. Lett. 2010,

12, 848−851.

AUTHOR INFORMATION

Corresponding Author

Kavirayani R. Prasad − Department of Organic Chemistry,

Indian Institute of Science, Bangalore 560012, Inida;

orcid.org/0000-0003-1453-9798; Email: prasad@

iisc.ac.in

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(9) Arbour, M.; Roy, S.; Godbout, C.; Spino, C. Stereoselective

synthesis of (+)-euphococcinine and (−)-adaline. J. Org. Chem. 2009,

10) Liu, G.; Cogan, D. A.; Owens, T. P.; Tang, T. P.; Ellman, J. A.

4, 3806−3814.

Synthesis of enantiomerically pure N -tert -butanesulfinylimines (tert-

butanesulfinimines) by the direct condensation of tert -butane

sulfonamides with aldehydes and ketones. J. Org. Chem. 1999, 64,

Author

Sopan P. Khandare − Department of Organic Chemistry,

Indian Institute of Science, Bangalore 560012, Inida

(

278−1284.

11) (a) Baggelaar, M. P.; Huang, Y.; Feringa, B. L.; Dekker, F. J.;

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00938

Minnaard, A. J. Catalytic asymmetric synthesis of (S )-zearalenone, a

novel lipoxygenase inhibitor. Bioorg. Med. Chem. 2013 , 21 , 5271 −

5274. (b) Molander, G. A.; Cameron, K. O. Neighbouring group

Notes

participation in Lewis acid-promoted [3 + 4] and [3 + 5] annulations.

The synthesis of oxabicyclo[3.n.1]alkan-3-ones. J. Am. Chem. Soc.

The authors declare no competing ﬁnancial interest.

1993, 115, 830−846.

ACKNOWLEDGMENTS

We thank the Science and Engineering Research Board

SERB) (CRG/2018/001332), New Delhi, for funding of

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(

the project. S.P.K. thanks the Council of Scientiﬁc and

Industrial Research (CSIR), New Delhi, for a fellowship. We

thank Dr. Arava Veera Reddy of Suven Lifesciences,

Hyderabad, India, for a generous gift of the sulﬁnamide used

in this study.

REFERENCES

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