Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether

Younggyu Kong; Pulla Reddy Boggu; Gi Min Park; Yeon Su Kim; Seong Hwan An; In Su Kim; Young Hoon Jung

doi:10.3390/molecules27082603

Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether

Younggyu Kong
, Pulla Reddy Boggu
, Gi Min Park
, Yeon Su Kim
, Seong Hwan An
, In Su Kim
, Young Hoon Jung

Department of Pharmacy

Sungkyunkwan University

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Eliglustat (Cerdelga®, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihy-droxylation and diastereoselective amination of chiral para-methoxycinnamyl benzyl ethers using chlorosulfonyl isocyanate as the key steps. Notably, the reaction between syn-1,2-dibenzyl ether 6 and chlorosulfonyl isocyanate in the mixture of toluene and hexane (10:1) afforded syn-1,2-amino alcohol 5 at a 62% yield with a diastereoselectivity > 20:1. This observation can be explained by competition between the S_Ni and the S_N1 mechanisms, leading to the retention of stereochemistry.

Original language	English
Article number	2603
Journal	Molecules
Volume	27
Issue number	8
DOIs	https://doi.org/10.3390/molecules27082603
State	Published - 1 Apr 2022

Keywords

amination
chlorosulfonyl isocyanate
eliglustat
Sharpless asymmetric dihydroxylation
total synthesis

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10.3390/molecules27082603

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@article{5dcfbb4ac04c45cbaf884a1267b6377e,

title = "Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether",

abstract = "Eliglustat (Cerdelga{\textregistered}, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihy-droxylation and diastereoselective amination of chiral para-methoxycinnamyl benzyl ethers using chlorosulfonyl isocyanate as the key steps. Notably, the reaction between syn-1,2-dibenzyl ether 6 and chlorosulfonyl isocyanate in the mixture of toluene and hexane (10:1) afforded syn-1,2-amino alcohol 5 at a 62\% yield with a diastereoselectivity > 20:1. This observation can be explained by competition between the SNi and the SN1 mechanisms, leading to the retention of stereochemistry.",

keywords = "amination, chlorosulfonyl isocyanate, eliglustat, Sharpless asymmetric dihydroxylation, total synthesis",

author = "Younggyu Kong and Boggu, \{Pulla Reddy\} and Park, \{Gi Min\} and Kim, \{Yeon Su\} and An, \{Seong Hwan\} and Kim, \{In Su\} and Jung, \{Young Hoon\}",

note = "Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = apr,

day = "1",

doi = "10.3390/molecules27082603",

language = "English",

volume = "27",

journal = "Molecules",

issn = "1420-3049",

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TY - JOUR

T1 - Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether

AU - Kong, Younggyu

AU - Boggu, Pulla Reddy

AU - Park, Gi Min

AU - Kim, Yeon Su

AU - An, Seong Hwan

AU - Kim, In Su

AU - Jung, Young Hoon

PY - 2022/4/1

Y1 - 2022/4/1

N2 - Eliglustat (Cerdelga®, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihy-droxylation and diastereoselective amination of chiral para-methoxycinnamyl benzyl ethers using chlorosulfonyl isocyanate as the key steps. Notably, the reaction between syn-1,2-dibenzyl ether 6 and chlorosulfonyl isocyanate in the mixture of toluene and hexane (10:1) afforded syn-1,2-amino alcohol 5 at a 62% yield with a diastereoselectivity > 20:1. This observation can be explained by competition between the SNi and the SN1 mechanisms, leading to the retention of stereochemistry.

AB - Eliglustat (Cerdelga®, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihy-droxylation and diastereoselective amination of chiral para-methoxycinnamyl benzyl ethers using chlorosulfonyl isocyanate as the key steps. Notably, the reaction between syn-1,2-dibenzyl ether 6 and chlorosulfonyl isocyanate in the mixture of toluene and hexane (10:1) afforded syn-1,2-amino alcohol 5 at a 62% yield with a diastereoselectivity > 20:1. This observation can be explained by competition between the SNi and the SN1 mechanisms, leading to the retention of stereochemistry.

KW - amination

KW - chlorosulfonyl isocyanate

KW - eliglustat

KW - Sharpless asymmetric dihydroxylation

KW - total synthesis

UR - https://www.scopus.com/pages/publications/85128801438

U2 - 10.3390/molecules27082603

DO - 10.3390/molecules27082603

M3 - Article

C2 - 35458801

AN - SCOPUS:85128801438

SN - 1420-3049

VL - 27

JO - Molecules

JF - Molecules

IS - 8

M1 - 2603

ER -

Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether

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Keywords

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