Diastereoconvergent synthesis of chiral sulfoxides containing vicinal amino alcohol framework

Journal Pre-proofs Diastereoconvergent Synthesis of Chiral Sulfoxides Containing Vicinal Amino Alcohol Framework Yan-Xue Zhang, Ling-Yan Chen, Bang-Guo Wei PII: DOI: Reference:

S0040-4039(19)31265-1 https://doi.org/10.1016/j.tetlet.2019.151466 TETL 151466

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

11 September 2019 23 November 2019 29 November 2019

Please cite this article as: Zhang, Y-X., Chen, L-Y., Wei, B-G., Diastereoconvergent Synthesis of Chiral Sulfoxides Containing Vicinal Amino Alcohol Framework, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet. 2019.151466

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© 2019 Published by Elsevier Ltd.

Diastereoconvergent Synthesis of Chiral Sulfoxides Containing Vicinal Amino Alcohol Framework Yan-Xue Zhang, † Ling-Yan Chen,* † Bang-Guo Wei‡ †College

of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, China ‡Department

of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China E-mail: [email protected]

Abstract A highly diastereoconvergent synthesis of chiral sulfoxides containing vicinal amino alcohol framework has been achieved in moderate to good yield with up to 99:1 dr. Different from the previous work, the stereochemistry of the new chiral center was determined solely by the configuration of benzyl tert-butyl sulfoxide, while both the chiral sulfinyl group and the tert-butyldimethylsilyl ether (α-OTBS) group at the α-position of imine were not involved in the stereo induction. This approach also provides an efficient synthesis of chiral building blocks of pyrrolidinones. Keywords: chiral sulfoxides, N-sulfinyl aldimine, pyrrolidinones, amino alcohol

Introduction Chiral sulfoxides are valuable compounds in synthetic chemistry. As shown in Figure 1, it is well known that they can be used as chiral reagents or auxiliaries such as (S)-menthyl p-toluenesulfinates by Anderson,1 N-sulfinyl sultams by Oppolzer2 and tert-butyl tert-butanethiosulfinates and tert-butanesulfinamide by Ellman.3 Meanwhile, the application of chiral sulfoxides as chiral ligands4 and organocatalysts5 in asymmetric transformations have also been explored. In addition, chiral sulfoxides are useful

structural

moiety

in

various

bioactive

compounds.6

For

example,

Esomeprazole7 and Lansoprazole,8 had a good effect on the treatment of gastric ulcer as a proton pump inhibitor, which aroused the interest of researchers in drug synthesis to modify more sulfoxide structures in order to improve the pharmacodynamic

activity. Therefore, the synthesis of sulfoxide compounds, especially for the nonracemic sulfoxides, has attracted more and more attention.9 O S p-Tol

H3CO O

(S)-mentyhl p-toluenesulfinate O S

O S

S

tert-butyl tert-butanethiosulfinate

N H

N-sulfinyl sultam

CH3

N

O S Tol S N O O

S O

OCH3 N

CH3

Esomeprazole CH3 F3C

NH2

(R)-tert-butyl sulfinamide

O N

HN S O

N

(R)-Lansoprazole

Figure 1 Examples of chiral sulfoxides Chiral N-tert-butanesulfinyl imines is now widely applied in organic synthesis.10 In our previous work, we have demonstrated the asymmetric reduction of N-tert-butanesulfinyl ketimines by the NHC-BH3 complex in good yields with up to 99% de.11 Recently, we discovered intramolecular cascade reactions between the N-tert-butanesulfinyl aldimines and Grignard reagents (or acetophenones) towards the highly diastereoselective synthesis of trans-5-hydroxy-6-substituted 2-piperidinones and trans-4-hydroxy-5-substituted 2-pyrrolidinones (Figure 2, eq. (1) and (2)). The stereochemistry of the generated stereogenic center at the C-6 or C-5 position was solely controlled by the tert-butyldimethylsilyl ether (α-OTBS) group of imine.12b-e When Grignard reagent benzyl magnesium bromide were involved in this reaction, the synthetically important chiral benzyl sulfoxide was isolated as the byproduct (eq. (1)). We envisioned that the isolated chiral benzyl sulfoxide could react with N-tert-butanesulfinyl aldimines and give chiral amines bearing chiral sulfoxide frameworks. In continuation of our efforts to explore utility of N-tert-butanesulfinyl imines, herein we describe a highly diastereoconvergent reaction of benzyl chiral sulfoxides with N-tert-butanesulfinyl aldimine 1. The obtained product could be converted to piperidinones or pyrrolidinones containing chiral sulfoxides (Figure 2, eq. (3)). It is worth noting that the stereochemistry of the new chiral center in this work was determined solely by the configuration of benzyl tert-butyl sulfoxide, and both the chiral sulfinyl group and the tert-butyldimethylsilyl ether (α-OTBS) group at the α-position of imine were not involved in the stereo induction.

(a) Previous work

n

OTBS

O MeO

n

N OTBS

g RM

O S

X

O

N H

R

O

R

+

S O

(1)12b-d

OTBS O

R O

(2)12e

R

N H

(b) This work O MeO

n

N OTBS

O S

S O

R LDA

O O

O

R

S

n TBSO

O

NH S

(3)

Figure 2 Strategies of conjugated addition to access sulfoxides related compounds

Results and Discussion At the outset of our investigation, the starting material -chiral N-sulfinyl aldimine 1 was easily prepared following the previous reported method, and the chiral sulfoxides 2 were prepared through the reaction of aldimine 1 with Grignard reagents towards the synthesis of 2-piperidinones or 2-pyrrolidinones12b (see supporting information). (R, SR)-1a and (R)-benzyl tert-butyl sulfoxide 2a was initially treated with freshly prepared lithium diisopropylamide (LDA, 1.0 equiv.) at -78oC in THF, and the desired product was obtained in 43% yield with high diastereoselectivity (up to 99:1, Table 1, entry 1). In order to improve the yield of the reaction, we screened reaction parameters including the amount of LDA (1.2, 1.5 and 2.0 equiv.) and reaction time. It showed that if 2.0 equiv. of LDA was used in the reaction for 1.5 h, the yield could be up to 80% with 99:1 dr (Table 1, entry 5). In addition, when n-BuLi or NaHMDS was used as the base, the yield decreased without loss of diastereoselectivity (Table 1, entries 7-8). However, if DCM was used as the solvent in the reaction, the yield dramatically decreased to 18% (Table 1, entry 6). Table 1 Screening of different conditions for the reactiona

O MeO

N OTBS 1a

Entry 1 2 3 4 5 6 7 8

O S

Solvent THF THF THF THF THF DCM THF THF

O

S O (R)-2a

O

S

O

MeO

TBSO

Base, -78℃

O

NH S

Base (equiv.) LDA (1.0) LDA (1.2) LDA (1.2) LDA (1.5) LDA (2.0) LDA (2.0) n-BuLi (2.0) NaHMDS (2.0)

S

+ MeO

3a

Time (h) 0.5 0.5 1 1 1.5 1.5 1.5 1.5

O

TBSO

O

NH S

3a'

Yield (%)b 43 48 57 67 80 18 63 54

drc (3a/3a’) 99:1 99:1 99:1 99:1 99:1 99:1 99:1 99:1

a

Unless otherwise noted, all reactions were carried out using 1a (0.9 mmol), 2a (0.6 mmol), in solvent (2.0 mL) at -78oC. b Isolated yield. c Determined by 1HNMR.

Afterwards, the effect of configuration of N-sulfinyl aldimine 1 and benzyl tert-butyl sulfoxide 2a were also investigated. As shown in Table 2, when the imine substrate 1 with different configurations ((S, SS)-1, (R, SR)-1, or (R, Ss)-1), the same product 3a was generated with high diastereoselectivities (Table 2, entries 1-3). Furthermore, if there was no OTBS group on the imine substrate, the stereochemistry of desired product remained the same. In contrast, (S)-benzyl tert-butyl sulfoxide gave 3a’ with opposite configuration at the same position under the identical reaction conditions (Table 2, entry 6). Therefore, both the chiral sulfinyl group and the tert-butyldimethylsilyl ether (α-OTBS) group at the α-position of imine did not involve in the stereo induction of the reaction process. The stereochemistry of the newly formed chiral center was determined solely by the configuration of benzyl tert-butyl sulfoxide, although the chiral sulfinyl group or the -OTBS were suggested determining the stereochemistry of the products in the previous literature reports.12 Table 2 Investigation of the effect of different configuration in N-sulfinyl aldimine 1a

(R or S) O MeO

N

O (R or S) S

2a

S O

O

R

1

3a

Entry 1 2 3 4 5 6

sulfoxide

R OTBS OTBS OTBS H H OTBS

O

MeO

LDA, THF, -78℃

R

O

(R or S)

S

O

imine (S,SS)-1 (R,SR)-1 (R,SS)-1 SR-1 SS-1 (R,SR)-1

(R)-2a (R)-2a (R)-2a (R)-2a (R)-2a (S)-2a

O

+ MeO NH S (R or S)

S

R 3a'

Yieldb (%) 51 80 62 77 73 50

O

NH S (R or S)

drc (3a/3a’) 99:1 99:1 99:1 99:1 99:1 1:99

a Unless

otherwise noted, all reactions were carried out using 1a (0.9 mmol), 2a (0.6 mmol), LDA (1.2 mmol) in solvent (2.0 mL) at -78oC. b Isolated yield. c Determined by 1HNMR.

Under the optimized reaction conditions (Table 1, entry 5), the scope of current addition was examined (Table 3). As shown in Table 3, various substituted benzyl tert-butyl sulfoxides 2 were used for the reaction. The reaction could tolerate para- or meta- substituted benzyl tert-butyl sulfoxides, affording the corresponding products in moderate to good yields with high diastereoselectivities (Table 3, entries 3-4 and 6-7). However, when ortho-fluoro and ortho-methyl benzyl tert-butyl sulfoxides were used, the reaction could not occur due to the steric hindrance in the ortho-position. Additionally, the α-chiral aldimine with one less carbon in the chain was also investigated. The reaction also proceeded smoothly and resulted in high diastereoselectivities, albeit in slightly lower yields (Table 3, entries 8-12). However, alkyl tert-butyl sulfoxides (such as ethyl, hexyl and cyclopropyl tert-butyl sulfoxides) failed to enable the reaction to proceed. Table 3 The scope of the reaction between N-sulfinyl aldimines 1 and benzyl tert-butyl sulfoxides 2a

O MeO

n

N OTBS 1

O S

R

S O 2

O

LDA THF,-78℃

MeO

O

S

n TBSO

R

O 3

NH S

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

R phenyl o-Methylphenyl m-Methylphenyl p-Methylphenyl o-Fluorophenyl p-Fluorophenyl p-t-Butylphenyl phenyl m-Methylphenyl p-Methylphenyl p-Fluorophenyl p-t-Butylphenyl Ethyl Hexyl cyclopropyl

n 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0

product 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o

Yieldb (%) 80 81 68 46 51 45 53 53 61 58 -

drc (3/3’) 99:1 99:1 99:1 99:1 99:1 99:1d 99:1 99:1 99:1 99:1 -

a Unless

otherwise noted, all reactions were carried out using 1a (0.9 mmol), 2a (0.6 mmol), LDA (1.2 mmol) in solvent (2.0 mL) at -78oC. b Isolated yield. c Determined by 1HNMR. d The configuration was confirmed by X-ray analysis of the cyclized compound 4h. Other products 3a-l were accordingly assigned by analogy.

The obtained product 3a−l can be easily transformed into the corresponding trans-5-hydroxy-6-substituted

2-piperidinones

or

trans-4-hydroxy-5-substituted

2-pyrrolidinones after cleaving the sulfinyl group under mild acidic conditions, followed by sodium hydroxide. We chose product 3h for example to give the pyrrolidinone 4h in 40% yield after two steps. The stereochemistry of 4h was unambiguously determined as the trans form by X-ray crystallography (Figure 3).13 Other products 3a-l were accordingly assigned by analogy.

O MeO

S

(S)

1.HCl/1,4-Dioxane (R)

OTBSO

(R)

O

NH S

O

H N

2.NaOH

3h

Scheme 1 Preparation of the corresponding pyrrolidinone 4h

(R)

(S)

(R)

S O

OH 4h

Figure 3 The X-ray crystallography of 4h On the basis of our experimental results and the reported relative literatures,12a,12b,14 a mechanism is tentatively proposed (Figure 4). In the case of the reaction of (R)-2a with (R, SR)-1a, as the Si-face of N-sulfinyl aldimine 1a in TS2 was hindered due to the steric repulsion, the anion IR derived from (R)-2a would attack the Re-face of the imine 1a and gave the favored product 3a. In contrast, (S)-2a would prefer to attack the Si-face of the imine 1a (TS4), affording the favored product 3a’. (R)-2a

(S)-2a

LDA

t-Bu

LDA

Ph R

S O Li IR

H

TBSO

O S t-Bu N S R O Ph O Li TBSO t-Bu S t-Bu H S N R O Li TS TS 2 1 TBSO

MeO

Ph t-Bu

(R, SR)-1a

H

S (R)

OTBSO

(S)

(R)

O

O NH S

3a (favored)

MeO

S (R)

OTBSO

Ph

S O Li t-Bu O H S R N TBSO TS3 t-Bu

(S)

O (S)

O

NH S

(unfavored)

S O Li IS O

Ph

t-Bu

O

O S t-Bu N

MeO

S (R)

OTBSO

R

O

N

(unfavored)

t-Bu

Ph S t-Bu O Li TS4

O NH S

S

TBSO

(S)

(R)

H

MeO

S (R)

OTBSO

(S)

(S)

O

NH S

3a' (favored)

Figure 4 Proposed mechanism for the reaction of (R, SR)-1a with (R)-2a and (S)-2a

Conclusion In summary, we have demonstrated a convenient approach for highly diastereoconvergent synthesis of chiral sulfoxides containing vicinal amino alcohol

framework in moderate to good yield with up to 99:1 dr. The stereochemistry of the new chiral center was determined solely by the configuration of benzyl tert-butyl sulfoxides, while both the chiral sulfinyl group and the tert-butyldimethylsilyl ether (α-OTBS) group at the α-position of imine were not involved in the stereo induction. This approach also provides an efficient synthesis of chiral building blocks of pyrrolidinones containing chiral sulfoxides.

Conflicts of interest There are no conflicts of interest to declare.

Acknowledgments We are thankful for the financial support from the National Natural Science Foundation of China (21772027) and the students Innovation Program in Shanghai University of Engineering Science (18KY0417).

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Declaration of interests

☒

The authors declare that they have no known competing financial interests or

personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Graphic Abstract

O MeO

n

N OTBS

O S

R

S O

O

LDA MeO THF,-78℃

O

R

S

n TBSO

O

NH S

15 examples 46-81% yield, 99:1 dr

Highlights 1. Diastereoselective synthesis of chiral sulfoxides was achieved. 2. The stereochemistry was determined solely by chiral sulfoxides. 3. The approach is accessible to pyrrolidinones.