Synthesis of desosamines

Patent metadata

Field	Value
Publication number	US-10544182-B2
Application number	US-201615558910-A
Country	US
Kind code	B2
Filing date	Mar 25, 2016
Priority date	Mar 25, 2015
Publication date	Jan 28, 2020
Grant date	Jan 28, 2020

Abstract

The present invention provides desosamine and mycaminose analogs and nitro sugars and methods for their preparation. The invention also provides methods of cyclizing a compound of Formula (A′) with glyoxal to give a nitro sugar of Formula (B). Methods for the preparation of compound of Formula (D′) are provided comprising cyclization of a nitro alcohol to give a nitro sugar and reduction and alkylation of the nitro sugar to give a desosamine, mycaminose, or an analog thereof.

First claim

What is claimed is:

1. A method of preparing a compound of Formula (D′):

or salt thereof, comprising cyclizing a compound of Formula (A):

or salt thereof, with glyoxal:

 to yield a compound of Formula (B), or salt thereof:

reducing a compound of Formula (B), or salt thereof, to yield a compound of Formula (C′), or salt thereof; and alkylating or protecting a compound of Formula (C′):

or salt thereof, with an alkylating or protecting agent;
wherein:
R 1 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR S , —N(R S ) 2 , —NR S (OR S ), —SR S , —SSR S , —Si(R S ) 3 , —OSi(R S ) 3 , or of formula:

each of R 2 and R 3 is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, —OR SO , or —N(R SN ) 2 ;
L S1 is independently a bond, —NR S —, —O—, or —S—, or a linking group selected from the group consisting of optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, and optionally substituted heteroalkynylene, and combinations thereof;
X S is independently a bond, —C(═O)—, —C(═NR SN ), —S(═O)—, or —S(═O) 2 ;
L S2 is independently a bond, —NR S —, —O—, or —S—, or a linking group selected from the group consisting of optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, and optionally substituted heteroalkynylene, and combinations thereof;
each R S is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or a sulfur protecting group when attached to a sulfur atom, or two R S attached to the same nitrogen atom are taken together to form ═N 2 , an optionally substituted heterocyclyl, or heteroaryl ring;
each of R 7 and R 8 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or R 7 and R 8 are joined to form an optionally substituted heterocyclyl or heteroaryl ring;
each R SN is independently hydrogen, optionally substituted C 1 -C 6 alkyl, or a nitrogen protecting group, or two R SN attached to the same nitrogen atom are joined to form an optionally substituted heterocyclyl or heteroaryl ring;
each of R 4a and R 4b is independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, or —OR SO ; and
each of R 5 , R 6 and R SO is independently hydrogen, optionally substituted C 1 -C 6 alkyl, a carbohydrate, or an oxygen protecting group.

2. The method of claim 1 , wherein the salt of Formula (C′) is of Formula (C-X′):

wherein the step of alkylating or protecting is performed in the presence of a base, and
wherein X c − is an anion selected from the group consisting of halide, H 3 C(C═O)O − , NO 3 − , ClO 4 − , OH − , H 2 PO 4 —, HCO 3 − , HSO 4 − , sulfonates, carboxylates, carboranes, BF 4 − , PF 4 − , PF 6 − , AsF 6 − , SbF 6 − , B[3,5-(CF 3 ) 2 C 6 H 3 ] 4 ] − , BPh 4 − , and Al(OC(CF 3 ) 3 ) 4 − .

3. The method of claim 1 , wherein the alkylating agent is formaldehyde, benzyl bromide, or di-tert-butyl dicarbonate.

4. The method of claim 1 , wherein the step of reducing is performed in the presence of H 2 and a catalyst.

5. The method of claim 1 , wherein R 5 and R 6 are hydrogen.

6. The method of claim 1 further comprising protecting a compound of Formula (B):

or salt thereof, to yield a compound of Formula (B′):

 or salt thereof,
and reducing a compound of Formula (B′), or salt thereof, to yield a compound of Formula (C′), or salt thereof.

7. The method of claim 1 further comprising reducing a compound of Formula (R):

or salt thereof, to yield a compound of Formula (A), or salt thereof.

8. The method of claim 7 further comprising adding a nitro group to a compound of Formula (Q):

or salt thereof, to yield a compound of Formula (R), or salt thereof.

9. The method of claim 8 , wherein the step of adding a nitro group is performed in the presence of pyridinium trifluroacetic acid and a nitrite salt.

10. The method of claim 1 further comprising the steps of:
protecting a compound of Formula (D′), or salt thereof, to yield a compound of Formula (E′):

or salt thereof, and
contacting a compound of Formula (E′), or salt thereof, with a thiol to form a compound of Formula (F-1′):

or salt thereof, wherein each of P O1 and P O2 is independently optionally substituted C 1 -C 6 alkyl, or an oxygen protecting group, and R TG is optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

11. The method of claim 10 , wherein P O1 and P O2 are —C(═O)OMe.

12. The method of claim 10 , wherein —SR TG is:

13. The method of claim 1 , wherein the compound of Formula (D′) is of Formula (D-1′), (D-d-1′), (D-m-1′), or (D-m-1′-A):

or salt thereof.

14. The method of claim 1 , wherein R 7 and R 8 are methyl.

15. The method of claim 1 , wherein R 2 is hydrogen or methyl.

16. The method of claim 1 , wherein the alkylating agent is formaldehyde.

17. The method of claim 1 , wherein R 1 is —OR S .

Assignees

• Harvard College
• Presidents and Fellow of Harvard College

Inventors

• Myers Andrew G
• Zhang Ziyang

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• C07H15/18

  Acyclic radicals, substituted by carbocyclic rings · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07H11/02

  Nitrates; Nitrites · CPC title

• C07H17/02

  Heterocyclic radicals containing only nitrogen as ring hetero atoms · CPC title