Rh-Catalyzed Asymmetric Hydrogenation of Unsaturated Medium-Ring NH Lactams: Highly Enantioselective Synthesis of N-Unprotected 2,3-Dihydro-1,5-benzothiazepinones

N ‑Unprotected 2,3-Dihydro-1,5-benzothiazepinones

Letter

Rh-Catalyzed Asymmetric Hydrogenation of Unsaturated Medium-

Ring NH Lactams: Highly Enantioselective Synthesis of

Congcong Yin, Tao Yang, Yingmin Pan, Jialin Wen,* and Xumu Zhang*

Cite This: https://dx.doi.org/10.1021/acs.orglett.9b04478

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sı Supporting Information

ABSTRACT: A straightforward method to prepare 1,5-benzothia-

zepines was reported. Catalyzed by a Rh/Zhaophos complex,

unsaturated cyclic NH lactams with a medium-size ring were

hydrogenated smoothly, giving remarkably high enantioselectivities.

The sulfur atom in the substrates did not bring an inhibition which

was observed with commercially available bisphosphine ligands.

This method was successfully applied in the scale-up synthesis of

(R)-(−)-thiazesim.

,5-Benzothiazepines are privileged heterocyclic pharmaco-

of enantioenriched 2,3-dihydro-1,5-benzothiazepinones.

−8

phores in numerous biological compounds (Figure 1 ).

While this method enjoyed functional group compatibility on

the benzene rings, the protection of the nitrogen atom of the

lactams with an alkyl group was essential to achieve reactivity.

The development of direct construction of chiral NH lactams

through asymmetric hydrogenation would be a practical

method which allows for further versatile manipulations on

the nitrogen atom, thus oﬀering promising opportunities for

drug discovery based on diverse structures.

We have recently displayed the broad applications of

ZhaoPhos which comprises a chiral ferrocene-based bi-

sphosphine unit and a tunable thiourea moiety. This ligand has

been successfully applied in asymmetric hydrogenation of a

1−31

variety of conjugate CC bonds.

In our perspective,

making use of the potential hydrogen bonding between the

thiourea moiety and the carbonyl group in the substrates

would be a practical strategy to achieve high enantioselectivity.

We envisioned that this catalytic system might contribute to

the construction of chiral 1,5-benzothiazepines.

Figure 1. 1,5-Benzothiazepines in pharmaceuticals.

−4

Considering the importance of chiral 1,5-benzothiazepines,

we were curious if the Rh/Zhaophos catalyst system was also

applicable to asymmetric hydrogenation of unsaturated

medium-ring NH lactams which contain a coordinating sulfur

atom. Herein, we reported a Rh-catalyzed asymmetric

hydrogenation of unsaturated cyclic NH lactams with a

medium-size ring, aﬀording various chiral NH-unprotected

Typical examples include the antidepressant drug thiazesim

and the antihypertension drug diltiazem. Especially, optically

active 1,5-benzothiazepines which contain a sulfur-substituted

stereocenter are among the most famous structural units in

medicinal chemistry. Therefore, asymmetric syntheses of

these chiral drugs have attracted great attention.

While early studies mostly relied on optical resolution to

realize enantio-enrichment, catalytic asymmetric approaches

have recently made great progress. The most frequently

employed approaches to control the asymmetric induction are

enabled by an intermolecular addition of 2-aminothiophenol to

2,3-dihydro-1,5-benzothiazepinones with up to 97% yield and

>99% ee (Scheme 1).

Received: December 13, 2019

1−19

a Michael acceptor before the cyclization step.

Alter-

natively, Glorius and co-workers have recently disclosed an

elegant Ru/NHC-catalyzed asymmetric hydrogenation of

readily available substrates for the straightforward synthesis

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 1. Asymmetric Catalytic Routes to 1,5-

Benzothiazepines

Table 2. Screening of Conditions for Asymmetric

Hydrogenation of 1a

entry

metal

T (°C)

solvent

conv. (%) ee (%)

[Rh(NBD) ]BF₄

DCM

DCE

trace

>99

[Rh(NBD) ]BF₄

toluene

ⁱPrOH

MeOH

dioxane

THF

EtOAc

MeCN

DCM

[Rh(NBD) ]BF₄

trace

[Rh(NBD) ]BF₄

Our initial study was carried out by investigating the ligand

eﬀect for the asymmetric hydrogenation of 2-phenylbenzo[b]-

[Rh(NBD) ]BF₄

[Rh(COD)Cl]₂

[Ir(COD)Cl]₂

Pd(TFA)₂

[1,4]thiazepin-4(5H)-one (1a) as a model substrate at room

trace

temperature with diﬀerent ligands (Table 1). Some commonly

[Rh(NBD) ]BF₄

Table 1. Screening a Series of Bisphosphine Ligands for

Asymmetric Hydrogenation of 1a

[Rh(NBD) ]BF₄

Reaction conditions: metal/ZhaoPhos/ 1a (0.1 mmol) ratio =

:1.1:100 in 0.5 mL of DCM under 70 bar H . Conversion was

determined by H NMR analysis, and ee was determined by HPLC

on a chiral stationary phase. S/C = 50, time = 36 h. Reaction carried

out under 50 bar of hydrogen.

MeCN (Table 2, entries 2−9). While cationic [Rh(NBD) ]-

BF was identiﬁed as the optimal precursor (60% conversions,

9% ee, Table 2, entry 10), neutral [Rh(cod)Cl] , iridium, and

palladium failed to catalyze this reaction eﬃciently. The

conversion could be improved when we increased the catalyst

loading (S/C = 50) and elongated the reaction time to 36 h

(

99% conversions, 99% ee, Table 2, entry 14). While

increasing the reaction temperature led to higher conversion,

the reduction of hydrogenation pressure to 50 bar resulted in

incompletion (entry 15).

Encouraged by these promising results, we turned our

attention to the investigation of reaction scope, using the

Reaction conditions: [Rh(NBD) ]BF /ligand/substrate 1a (0.1

optimized reaction conditions ([Rh(NBD) ]BF /ZhaoPhos in

mmol) ratio of 1:1.1:100 in 0.5 mL of DCM at 30 °C under 70

bar of H for 20 h. Conversion was determined by H NMR analysis,

and ee was determined by HPLC with a chiral stationary phase. The

conﬁguration of 2a was determined by comparing the optical rotation

DCM under 70 bar hydrogen pressure and 45 °C). These

results were summarized in Table 3. Hydrogenation of the N-

methyl-protected substrate 1b and N-benzyl-protected sub-

strate 1c gave the corresponding hydrogenation products with

excellent enantioselectivity (91−97% yield, 98−>99% ee). The

inﬂuence of electronic properties of the substituents on the

fused benzene ring was investigated: substrates with no matter

electron-withdrawing (1d−1e) or electron-donating (1f−1h)

substituent groups performed smoothly in this reaction (81−

96% yield, 98−>99% ee). The introduction of various

substituents on the phenyl group had a minimal inﬂuence on

the reactivity and enantioselectivity (2i−2m, 81−92% yield,

95−>99% ee). The disubstituted substrate 1n displayed high

conversion but moderate enantioselectivity (92% yield, 76%

ee). Furthermore, the alkyl-substituted substrate 1o was

hydrogenated to produce a chiral product with desired

reactivity and selectivity (95% yield, 95% ee).

data with that reported in the literature.

used commercially available ligands, such as BINAP, SegPhos,

JosiPhos, MeO-BIPHEP, DuanPhos, and f-BINAPHANE, did

not show activity in the reaction. This failure probably could

be attributed to the stable conjugate structure and the potential

coordination of the sulfur atom. Indeed, limited reports on the

transition-metal-catalyzed asymmetric hydrogenation of vinyl-

2−34

thioethers.

Gratefully, the reaction could proceed with

ZhaoPhos, giving an outstanding enantioselectivity (55%

conversions, >99% ee).

Subsequently, metal precursors and other reaction param-

eters were investigated. Among diﬀerent types of solvents,

dichloromethane was selected as the optimal solvent (55%

conversion, >99% ee, Table 2, entry 1). Poor conversions were

The gram-scale asymmetric hydrogenation of 1a was

performed smoothly with S/C = 100, aﬀording the product

(R)-2-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one

with 99% yield and 99% ee (Scheme 2). This successfully

observed in toluene, PrOH, THF, and EtOAc, while no

reactivity was observed in DCE, EtOH, MeOH, dioxane, and

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

The Supporting Information is available free of charge at

Letter

Table 3. Substrate Scope Study of Rh-Catalyzed Asymmetric

Hydrogenation of Unsaturated Medium-Ring NH Lactams

ASSOCIATED CONTENT

sı Supporting Information

■

https://pubs.acs.org/doi/10.1021/acs.orglett.9b04478 .

Experimental details and characterization data (PDF)

AUTHOR INFORMATION

Corresponding Authors

■

Jialin Wen − Southern University of Science and

Technology, Shenzhen, China; Email: wenjl@

sustech.edu.cn

Xumu Zhang − Southern University of Science and

Technology, Shenzhen, China; orcid.org/0000-0001-

700-0608; Email: zhangxm@sustech.edu.cn

Other Authors

Congcong Yin − Southern University of Science and

Technology, Shenzhen, China

Tao Yang − Southern University of Science and

Technology, Shenzhen, China

Yingmin Pan − Southern University of Science and

Technology, Shenzhen, China

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.9b04478

Author Contributions

Reaction conditions: [Rh(NBD) ]BF /ZhaoPhos/substrate 1 (0.1

^§Congcong Yin and Dr. Tao Yang contributed equally.

mmol) ratio of 1:1.1:50 in 0.5 mL of DCM at 45 °C under 70 bar H₂

for 36 h. The catalyst was precomplexed in DCM (0.1 mL for each

reaction vial). Yield is isolated yield, and ee was determined by HPLC

with a chiral stationary phase.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

Scheme 2. Gram-Scale Asymmetric Hydrogenation of 1a

and the Synthesis of the Antidepressant Drug (R)-

We are grateful for the ﬁnancial support from the NSF of

China (21801118) and the Science, Technology, and

I n n o v a t i o n C o m m i s s i o n o f S h e n z h e n

(−)-Thiazesim

(

JCYJ20170817104350391 and KQTD20150717103157174).

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