“Chemoenzymatic Synthesis of Scytonemin A and HPA-12 Synthons”ABSTRACTA chemoenzymatic protocol was efficient, yet environmentally benign syntheses of the target compound.The lipase-catalyzed acylation of several secondary carbinols in organic solvents was adopted for their kinetic resolution.The reactions proceeded with varying enantiomeric excesses, depending on the substrate structure and the nature of lipases.

Presented By:Paulami Bose, NIT-RourkelaRoll: 412CY2006

A Presentation On:

Guided By :Dr. S. ChattopadhyayaBio-organic Div.,BARC, Mumbai

OBJECTIVE Enantiomerically pure secondary carbinols are reported as useful

synthons for many natural products with useful biological activities. The project was primarily aimed (Figure 1) at formulating asymmetric

syntheses of:i. the aryl-alkyl segment of of the cyclic peptide scytonemin A andii. N-(3-Hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-

12), an inhibitor of ceramide trafficking.

NH OHO

ONH

OO

OH

OH

O

ON OHN

O

HO

NH

O

OHN

O

HO

O O NH

NO

OHO

Scytonemin A (I)

Figure. Chemical structures of scytonemin A and 12-HPA, and their segments.

NH2OOHHO

OHOH

Aryl-alkyl segment (1)

HONH OH

Ph

C11H23 OH

HOHN OH

Ph12-HPA segment (2)

Pg

12-HPA (II)

INTRODUCTION Enantioselective Synthesis: is a chemical reaction (or reaction

sequence) in which one or more new elements of chirality are formed in a substrate molecule and which produces the stereoisomeric (enantiomeric or diastereoisomeric) products in unequal amounts.

The enantiomerically pure compounds are important as the enantiomer can show useful biological activity.

One important strategy in the preparation of enantiomerically pure compounds is the kinetic resolution of racemic substrates by enzymatic or chemical protocols.

Why Enzymes..?? As they catalyze many reactions under very mild conditions, and show high enantio-selectivity as well as substrate specificity.

SCYTONEMIN A SEGEMENTImportance of Targeted MoleculeIsolated from the marine organism, Scytonemin sp. (Scytonematacea).The cyclic peptide Scytonemin A (I) is a potent calcium antagonistDistinctive feature : Sphingosine component with terminal phenyl group.

Retrosynthetic Path Suggested:

NH2O

OHHO

OHOH

OPg OPg

1 A Pg = prot. gr.

OPg

B

PART OF SCHEME DONE SO FAR ON ASSYMETRIC SYNTHESES OF SCYTONEMIN A SEGEMENT :

HO OH HO OTBS TBSO CHO

OH

OTBS

OTHP

OTBS

OTHP

OH

OTHPCHO

OTHP OH OH OH

3 4 5

(+)-6 7 8

9 10 (+)11

i ii

iii iv v

vi viiii

i) NaH/TBSCl/THF/0 oC/1 h, ii) PCC/NaOAc (cat.)/CH2Cl2/25 oC/3h, iii) PhCH2Br/Mg/THF/25 oC/5 h, iv) DHP/PPTS/CH2Cl2/25 oC/12h, v) Bu4NF/THF/0 oC/3h, vi) CH2=CHMgBr/THF/25 oC/3 h, vii) PPTS/MeOH/25 oC/12h.

OH

OTBS(+)-6

OH

OTBS(R)-6

OAc

OTBS(S)-12

+i

OH OH

(+)11

i OH OH

(2RS,6R)-11

OH OAc+

(2RS,6S)-13

i) CH2=CHOAc/diisopropyl ether/25 oC/lipase.

N-(3-Hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12)Importance of Targeted Molecule Shingolipids present in mammalian cells has active role in cell

growth, differentiation, and apoptosis. Its misregulation leads to variety of disease states. Sphingomylin (SM) is produced from ceramide on transportation

from endoplasmic reticulum (ER) to the Golgi Apparatus. This transportation is mediated by cytosolic protein, CERT and N-(3-Hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12) acts an inhibitor of ceramide trafficking.

HPA-12 is now known as direct antagonist of CERT, and is used for various biological in vitro studies.

PART OF THE SCHEME DONE SO FAR ON ASSYMETRIC SYNTHESES OF HPA-12:

CHO

(+)-1514

i

OH

ii

OH

+

OAc(R)-15 (S)-16

i) CH2=CHCH2Br/Zn/aqueous THF/25 oC/3 h, ii) CH2=CHOAc/diisopropyl ether/25 oC/lipase, iii) K2CO3/MeOH/25 oC/3 h, iv) AD-mix /tert-BuOH-H2O/24 h/0 oC .

OAc(S)-16

iii

OH(S)-15

iv

OHOH

OH17

OAcOH

OH18

iv

CHARACTERIZATION

[α]D25 -5.4206 (c 1.07, CHCl3); 1H NMR: δ 1.24-1.53 (m, 6H), 2.05 (s, 3H), 2.58-2.69 (m, 1H), 2.76-2.86 (m, 1H), 3.77-3.80 (m, 1H), 5.13-5.26 (m, 3H), 5.67-5.85 (m, 1H), 7.18-7.34 (m, 5H); 13C NMR: δ 21.0, 33.8, 36.1, 43.8, 72.1, 74.5, 116.4, 126.1, 128.2, 129.2, 136.2, 138.4, 170.2.

[α]D28 51.667 (c 1.20, φH); 1H NMR: δ 2.32 (broad s, 1H), 2.46-2.53 (t, J = 6.2 Hz, 2H), 4.70 (t, J = 6.2 Hz, 1H), 5.10-5.18 (m, 2H), 5.70-5.90 (m, 1H), 7.37 (s, 5H); 13C NMR: δ 43.3, 73.1, 76.4, 77.0, 77.6, 117.5, 125.6, 127.1, 128.0, 134.3, 143.7.

OH OAc

(2RS,6S)-13

Scytonemin A

HPA-12

OAc(S)-16

CONCLUSION Chemoenzymatic step was found to be substrate and enzyme

dependent. In the synthesis of Scytonemin A, both the isomers of 13 are the

required precursor.

In the synthesis on HPA-12, ADH reaction with AD mix –β yields 17 which is the required precursor for the Targeted Molecule.

OH OH

(+)11

OH OH

(2R,6S)-13

OH OH+

(2S,6S)-13

OHOH

OH17

HOHN OH

Ph12-HPA segment

Pg

HONH OH

Ph

C11H23 OH

12-HPA (II)