IP Library › Granted Patent US 11,866,398

Granted Patent B2

US 11,866,398 · App. 17/055,970 · Granted Jan 9, 2024

Total synthesis of prostaglandin J natural products by stereoretentive metathesis

Inventors: Jiaming Li (Pasadena, CA); Xu Chen (Pasadena, CA); Tonia S. Ahmed (Pasadena, CA); Brian M. Stoltz (Pasadena, CA); Robert H. Grubbs (Pasadena, CA)

Assignee: California Institute of Technology

C07C405/0016 B01J23/462 C07C2601/10

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Quick Facts

Patent No.: US 11,866,398
App. No.: 17/055,970
Granted: Jan 9, 2024
Kind: B2

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Abstract

This invention relates generally to the synthesis of Δ 12 -Prostaglandin J product using stereoretentive ruthenium olefin metathesis catalysts supported by dithiolate ligands. Δ 12 -Prostaglandin J products were generated with excellent selectivity (>99% Z) and in moderate to high/good yields (47% to 80% yield; 58% to 80% yield).

Claims (109)

1. A method for producing at least one Δ 12 -Prostaglandin J product represented by Formula (IV),

wherein: R z is selected from

and wherein at least one carbon-carbon double bond has a Z/E-selectivity of 95/5, or 96/4, or 97/3, or 98/2, or 99/1, or >99/<1;

comprising, submitting an alcohol product of Formula (III)

to oxidation conditions; wherein the alcohol product of Formula (III) is formed during a cross-metathesis reaction between a substrate represented by Formula (II)

and cis-5-octen-1-ol in the presence of a ruthenium olefin metathesis catalyst; and wherein R v is selected from

2. The method according to claim 1 , wherein the ruthenium catalyst is a stereoretentive ruthenium olefin metathesis catalyst represented by Formula (I) is

X is O or S;

Y is O or S;

Z is N or CR 32 ;

W is O, halogen, NR 33 or S;

R 1 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl, or together with R 2 can form a spiro compound or together with R 3 or together with R 4 can form a polycyclic ring;

R 2 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl or together with R 1 can form a spiro compound or together with R 3 or together with R 4 can form a polycyclic ring;

R 3 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl or together with R 2 or together with R 1 can form a polycyclic ring or together with R 4 can form a spiro compound;

R 4 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl, or together with R 3 can form a spiro compound or together with R 2 or together with R 1 can form a polycyclic ring;

R 5 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl, or together with R 6 can form an optionally substituted polycyclic ring;

R 6 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl, or together with R 5 or together with R 7 can form an optionally substituted polycyclic ring;

R 7 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl optionally substituted C 3-8 cycloalkenyl, or together with R 6 or together with R 8 can form an optionally substituted polycyclic ring;

R 8 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl, or together with R 7 or together with R 9 can form an optionally substituted polycyclic ring;

R 9 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl, or together with R 8 can form an optionally substituted polycyclic ring;

R 10 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl, or together with R 11 can form an optionally substituted polycyclic ring;

R 11 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl or together with R 10 or together with R 12 can form an optionally substituted polycyclic ring;

R 12 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl, or together with R 11 or together with R 13 can form an optionally substituted polycyclic ring;

R 13 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl, or together with R 14 or together with R 12 can form an optionally substituted polycyclic ring;

R 14 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl, or together with R 13 can form a polycyclic ring;

R 15 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl, or together with R 16 can form an optionally substituted polycyclic ring;

R 16 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl, or together with R 15 or together with R 17 can form an optionally substituted polycyclic ring;

R 17 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl, or together with R 18 or together with R 16 can form an optionally substituted polycyclic ring;

R 18 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl, or together with R 17 can form an optionally substituted polycyclic ring;

R 19 is H, optionally substituted C 1-24 alkyl, —C(R 34 )(R 35 )COOR 36 , —C(R 34 )(R 35 )C(O)H, —C(R 34 )(R 35 )C(O)R 37 , —C(R 34 )(R 35 )CR 38 (OR 39 )(OR 40 ), —C(R 34 )(R 35 )C(O)NR 41 R 42 , —C(R 34 )(R 35 )C(O)NR 41 OR 40 , —C(O)R 25 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl, or together with R 33 can form an optionally substituted heterocyclic ring or is nil when W is halogen;

R 20 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl or together with R 21 can form a polycyclic ring;

R 21 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl or together with R 20 or together with R 22 can form a polycyclic ring;

R 22 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl or together with R 21 or together with R 23 can form a polycyclic ring;

R 23 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl or together with R 22 can form a polycyclic ring;

R 24 is H, optionally substituted C 1-24 alkyl, halogen, —C(O)R 25 , —OR 26 , CN, —NR 27 R 28 , NO 2 , —CF 3 , —S(O) x R 29 , —P(O)(OH) 2 , —OP(O)(OH) 2 , —SR 31 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 25 is OH, OR 30 , NR 27 R 28 , optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl,

R 26 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 27 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 28 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 29 is H, optionally substituted C 1-24 alkyl, OR 26 , —NR 27 R 28 , optionally substituted heterocycle, optionally substituted C 3-8 cycloalkyl, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 30 is optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 31 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 32 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 33 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl, optionally substituted C 3-8 cycloalkenyl, or together with R 19 can form an optionally substituted heterocyclic ring;

R 34 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 35 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 36 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 37 is optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 38 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 39 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 40 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 41 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl;

R 42 is H, optionally substituted C 1-24 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted heterocycle, optionally substituted C 5-24 aryl or optionally substituted C 3-8 cycloalkenyl; and

x is 1 or 2.

3. The method according to claim 1 , wherein the ruthenium catalyst is a Z-selective ruthenium olefin metathesis catalyst represented by Formula (V) is

wherein:

W is O, halogen, NR 33 or S;

X 1 is hydrogen, halide, nitrate, optionally substituted C 1 -C 20 alkyl, optionally substituted C 5 -C 24 aryl, optionally substituted C 1 -C 20 alkoxy, optionally substituted C 1 -C 20 alkylcarboxylate, optionally substituted C 5 -C 24 aryloxy, optionally substituted C 2 -C 20 alkoxycarbonyl, optionally substituted C 6 -C 24 aryloxycarbonyl, optionally substituted C 6 -C 24 arylcarboxylate, optionally substituted C 2 -C 24 acyl, optionally substituted C 2 -C 24 acyloxy, optionally substituted C 1 -C 20 alkylsulfonato, optionally substituted C 5 -C 24 arylsulfonato, optionally substituted C 1 -C 20 alkylsulfanyl, optionally substituted C 5 -C 24 arylsulfanyl, optionally substituted C 1 -C 20 alkylsulfinyl, or optionally substituted C 5 -C 24 arylsulfinyl;

x is 1 or 2.

4. The method according to claim 1 , wherein the oxidation takes place in the presence of tetrapropylammonium perruthenate and 4-methylmorpholine N-oxide monohydrate.

5. The method according to claim 1 , wherein the oxidation takes place in the presence of pyridinium chlorochromate and sodium chlorite.

6. The method according to claim 4 , wherein R z is

R v is

and the ruthenium catalyst is a stereoretentive catalyst represented by Formula (I) wherein: X is S; Y is S; Z is N; W is O; R 1 is H; R 2 is H; R 3 is H; R 4 is H; R 5 is i-Pr; R 6 is H; R 7 is H; R 8 is H; R 9 is i-Pr; R 10 is i-Pr; R 11 is H; R 12 is H; R 13 is H; R 14 is i-Pr; R 15 is Cl; R 16 is H; R 17 is H; R 18 is Cl; R 19 is i-Pr; R 20 is H; R 21 is H; R 22 is H; R 23 is H; and R 24 is H.

7. The method according to claim 4 , wherein R z is

R v is

and the ruthenium catalyst is a Z-selective catalyst represented by Formula (V) wherein W is O; X 1 is nitrate; R 1 is H; R 2 is H; R 3 is H; R 4 is H; R 5 is i-Pr; R 6 is H; R 7 is H; R 8 is H; R 9 is i-Pr; R 19 is i-Pr; R 20 is H; R 21 is H; R 22 is H; R 23 is H; R 24 is H.

8. The method according to claim 5 , wherein R z is

R v is

9. The method according to claim 5 , wherein R z is

R v is

10. The method according to claim 5 , wherein R z is

R v is

Assignments (2)

CONFIRMATORY LICENSE Recorded Oct 26, 2023

From: CALIFORNIA INSTITUTE OF TECHNOLOGY

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 065356/0695 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 17, 2021

From: LI, JIAMING; CHEN, XU; AHMED, TONIA S.; STOLTZ, BRIAN M.; GRUBBS, ROBERT H.

To: CALIFORNIA INSTITUTE OF TECHNOLOGY

Reel/Frame 057199/0738 →

Continuity (3)

Provisional Application 62803603 · Feb 11, 2019

Provisional Application 62671891 · May 15, 2018

Related Publication 20210332011A1 · Oct 28, 2021