# US 2008/0188651 A1 · Analogs of dictyostatin, intermediates therefor and methods of systhesis thereof

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- Number: US 2008/0188651 A1
- Document ID: US20080188651A1
- Status: Published application
- Kind: A1
- Application number: 12/006,364
- Filed: 2008-01-02
- Published: 2008-08-07
- Earliest claimed: 2002-09-06
- Inventors: Dennis P. Curran; Youseung Shin; Jean-Hugues Fournier; John Mancuso; Billy W. Day; Arndt Bruckner; Yoshikazu Fukui
- Web page: https://patentgrep.com/patent/US20080188651A1

## CPC

- C07C 33/02: Acyclic alcohols with carbon-to-carbon double bonds
- C07C 59/10: Polyhydroxy carboxylic acids
- C07C 59/42: containing hydroxy or O-metal groups
- C07C 69/732: of unsaturated hydroxy carboxylic acids
- C07C 69/734: Ethers
- C07D 309/10: Oxygen atoms
- C07D 309/30: Oxygen atoms, e.g. delta-lactones
- C07D 313/00: Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D 319/06: not condensed with other rings
- C07D 407/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07F 7/1804: {Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896)}
- C07B 2200/07: Optical isomers
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

Dictyostatin and its analogs show great promise as new anticancer agents. The present invention provides dictyostatin analogs, synthetic intermediates for the synthesis of dictyostatin analogs, and synthetic methods for the synthesis of such analogs and intermediates. Dictyostatin analogs can have the following structure or its enantiomer wherein R1 is H, an alkyl group, an aryl group, an alkenyl group, an alkynyl group, or a halogen atom; R2 is H, a protecting group, an alkyl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, or CORe; Ra, Rb and Rc are independently an alkyl group or an aryl group; Rd is an alkyl group, an aryl group, an alkoxylalkyl group, —RiSiRaRbRc or a benzyl group, wherein Ri is an alkylene group; Re is an alkyl group, an allyl group, a benzyl group, an aryl group, an alkoxy group, or —NRgRh, wherein Rg and Rh are independently H, an alkyl group or an aryl group; R3 is (CH2)n where n is and integer in the range of 0 to 5, —CH2CH(CH3), —CH═CH—, —CH═C(CH3), or —C≡C—; R4 is wherein R23a is H, a protecting group, an alkyl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, or CORe, R23b is H, a protecting group, an alkyl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, or CORe, or R23a and R23b together form a portion of six-membered acetal ring incorporating CRtRu; Rt and Ru are independently H, an alkyl group, an aryl group or an alkoxyaryl group; and R5 is H or OR2b, wherein R2b is H, a protecting group, an alkyl group, an aryl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, or CORe; provided that the compound is not dictyostatin 1.

## Claims

### Claim 1

A compound having the following formula, or its enantiomer
R2 is H, a protecting group, an alkyl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, or CORe;
Ra, Rb and Rc are independently an alkyl group or an aryl group;
Rd is an alkyl group, an aryl group, an alkoxylalkyl group, —RSiRaRbRc or a benzyl group, wherein Ri is an alkylene group;
Re is an alkyl group, an allyl group, a benzyl group, an aryl group, an alkoxy group, or —NRgRh, wherein Rg and Rh are independently H, an alkyl group or an aryl group;
R3 is (CH2), where n is and integer in the range of 0 to 5, —CH2CH(CH3)—, —CH═CH—, —CH═C(CH3)—, or —C≡C—;
R11a and R11b are independently H, a protecting group, an alkyl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, CORe, or R11a and R11b together form a portion of six-membered acetal ring containing CRtRu;
Rt and Ru are independently H, an alkyl group, an aryl group or an alkoxyaryl group;
R12 is a halogen atom, CH2OR2c, CHO, CO2R10, CH═CHCH2OR2c, CH═CHCHO or CH═CHCO2R10, wherein R2c is H, a protecting group, an alkyl group, an aryl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, or CORe, and R10 is H or alkyl; and
R14a and R14b are independently H, an alkyl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, CORe, or R14a and R14b together form a six-membered ring containing CRvRw, wherein Rv and Rw are independently H, an alkyl group, an aryl group or an alkoxyaryl group.

### Claim 2 (depends on 1)

The compound of claim 1 with the following stereostructure, or its enantiomer
wherein R3 is CH2CH(CH3)CH2CH2, CH═CH, or CH═C(CH3); and R11a and R11b are H or together form a portion of a six-membered acetal ring containing C(H)(p-C6H40CH3) or C(CH3)2.

### Claim 3

A compound having the following formula, or its enantiomer
wherein X is H, NCH3(OCH3), or a leaving group;
R11 is H, a protecting group, an alkyl group, and aryl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, or CORE,
Rt and Ru are independently H, an alkyl group or an aryl group;
R12 is a halogen atom, CH2OR2c, CHO, CO2R10, CH═CHCH2OR2c, CH═CHCHO or CH═CHCO2R10, wherein R2c is H, a protecting group, an alkyl group, an aryl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, or CORe, and R10 is H or alkyl.

### Claim 4

A process for reacting a first compound of the following formula, or its enantiomer
wherein R2 a protecting group, an alkyl group, an aryl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, or CORe;
Ra, Rb and Rc are independently an alkyl group or an aryl group;
Rd is an alkyl group, an aryl group, an alkoxylalkyl group, —RiSiRaRbRc or a benzyl group, wherein Ri is an alkylene group;
Re is an alkyl group, an allyl group, a benzyl group, an aryl group, an alkoxy group, or —NRGRh wherein Rg and Rh are independently H, an alkyl group or an aryl group;
R16 is H or alkyl; and
R17 is CH2OR2f, CHO, CO2Rv, wherein R2f is H, an alkyl group, an aryl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, or CORe;
R25CH═CX2, C≡CH or C═CSiRaRbR;
X is Cl, Br or I with a second compound of the following formula, or its enantiomer
wherein X is NCH3(OCH3), or a leaving group;
R11 an alkyl group, and aryl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, CORe;
R12 is a halogen atom, CH2OR2c, CO2Rv, CH═CHCH2OR2c or CH═CHCO2Rv, wherein R2c is an alkyl group, an aryl group, a benzyl group, a trityl group, —SiRaRbRc, CH2ORd, or CORe, and Rv is alkyl, comprising metalation of the first compound and addition of the second compound to produce a compound of the following formula, or its enantiomer
wherein R24 is C≡C.