1. ENZYME-CATALYZED REACTIONS Assoc. Prof. Dr. Devrim Özdemirhan

2. Spirocyclic compounds found in the structure of natural products that have biological activities.
The structures contain cyclopentenone-pyran ring composed of cyclopentenone ring known as cyclopentenone PG’s (prostaglandins) which are used in the treatment of many psychological desease.
Dihydropyran ring containing compounds found in the structure of molecules used in the anti-cancer treatment drugs.
Pauson-Khand Reaction (PKR) and Ring Closing Methatesis (RCM) are frequently used methods in the literature for the synthesis of spiro-cyclic units.
Chiral tertiary alcohols are valuable building blocks for these spiro-cyclic units

3. Spirocyclic compounds that will be synthesized

4. Retrosynthetic analysis of synthesis of spiro cyclopentenone-pyran
and -furan compounds

5. Retrosynthetic analysis of synthesis of spiro -dihyropyran and -dihydrofuran
compounds

6. Enzyme-catalyzed resolution of allylic, homoallyl and homopropargyl tertiary alcohols

7. natural product synthesis and pharmaceuticals
The construction of building blocks that contain chiral tertiary alcohol moieties
has great importance
in the field of
natural product synthesis and pharmaceuticals
It has been reported that various hydrolases PLE (Pig liver esterase),
PPL (Porcine pancreatic lipase),
CRL (Candida rugosa lipase)
and CAL-A (Lipase A from Candida antarctica)
are active biocatalysts toward tertiary alcohols and corresponding esters.

8. Conversion 35% E =65
CAL-A catalyzed kinetic resolution of (±)-2-phenylbut-3-yn-2-ol with vinyl acetate as acyl donor.
S. Hari Krishna, M. Persson, U.T. Bornscheuer, Tetrahedron: Asymmetry, 2002, 13,

9. F. Coope, B. G. Main, Tetrahedron: Asymmetry, 1995, 6,1393-1398
PLE-catalyzed enantioselective hydrolysis of (±)-3-ethynyl-3-oxbutyryl quinuclidine
F. Coope, B. G. Main, Tetrahedron: Asymmetry, 1995, 6,

10. Transesterification of (±)-1-methyl-2,3-dihydro-1H-inden-1-ol 1a
and (±)-1-methyl-1,2,3,4 tetrahydro napthalen-1-ol 1b
rac-1a-b (S)-(+)- 1a-b (S)-(+)-2a
(S)-(-)-2a-b
1a; n= a; n=1
1b; n= b; n=2
Özdemirhan D., Sezer S., Sönmez Y., Tetrahedron:Asymmetry 19 (2008)

11. the best biocatalyst for 1b
Transesterification of these tertiary alcohols; CAL-A (Candida antarctica Lipase A) was found to be
the best biocatalyst for 1b
and CAL-A-CLEA (Lipase A, C. antarctica, cross-linked enzyme aggregate) for 1a,
obtained with ee values of 20% and 45%, respectively,
and the corresponding esters 2b and 2a with the ee values of 99% and 71%, respectively.

12. Enzyme-catalyzed resolution of allylic, homoallyl and
homopropargyl tertiary alcohols

13. Optimization reactions done by (±)-1-allyl-cyclohex-2-en-1-ol
By changing substrate/enzyme ratio (1:0.25 to 1:1)
Various hydrolases CAL-A-CLEA, CRL, CAL-A, CAL-B and Amano PS-C II were tested.
cosolvent ( i.e:THF, hexane, 1,4 dioxane, diisopropylether)
temperature (25 to 32ºC)

14. a Conversions were determined by HPLC analysis
The results of transesterification of (±) allylic, homoallyl and homopropargyl tertiary alcohols
Entry
Substrate
Product
Time (day)
Conv.a (%)
eebs (%)
eep(%)
[α]25D
( subs.)
( prod.) 1 3 50 42 56
-1.50 (c=0.7 CHCl3)
+7.14 (c=.1
CHCl3) 2 4 60 71
-3.89
c =1.42 CHCl3)
-6.62
c=0.50
CHCl3 5 90 98
-4.69
( c=1.1 CHCl3)
+5.72
( c=1.2
2.5 55
+5.86
( c=1 CHCl3)
-5.17
(c =0.7 7 25 35 43
-5.73 (c=1 CHCl3)
+9.58 (c=.0.5 6 65 82
+2.5 (c=1, MeOH)
+5.2 (c=1,
MeOH)
a Conversions were determined by HPLC analysis
b Enantiomeric excesses were determined by Daicel Chiralcel OD-H and OJ-H column HPLC analysis

15. CONCLUSION
Enantioselective resolution of tertiary allylic, homoallyl and homopropargyl cyclopentenols and cyclohexenols were performed with high ee varying between 35 % and 90 % ee and corresponding esters up to 98 % ee by commercially available enzyme CAL-CLEA, between ºC
The substituents on the quaternary center drastically influence the enantioselectivity of the enzyme
Temperature factor is crucial for high enantioselectivity

16. Pauson-Khand Reaction (PKR) and Ring Closing Methatesis (RCM) are
frequently used methods in the literature for the construction of spiro-cyclic units.
Pauson-Khand reaction is [2+2+1] cycloaddition reaction
Proposed mechanism for Pauson-Khand reaction

17. Synthesis of fused tricyclic compounds have aromatic side chains
PEREZ-SERRANO L., Blanco-Urgoiti J., Casarrubios L., Dominguez G., Perez-Castells J. P.,
Journal of Organic Chemistry (J. Org. Chem), 65, 11, , (2000).

18. Retrosynthetic analysis of synthesis spiro cyclopentenone-pyran
and - furan compounds

19. Synthesis of spiro cyclopentenone-pyran compounds by Pauson-Khand
Reaction
Synthesis of 4a',5'-dihydro-1'H- spiro[cyclopent[2]ene-1,3‘cyclopenta[c]pyran-6'(4'H)-one
Synthesis of 7’,7a’-dihydro-2’H-spiro[cyclopent[2]ene-1,3’-[cyclopenta[b]pyran]-6’(4’H)-one

20. Synthesis of spiro cyclopentenone-furan compounds by Pauson-Khand
Reaction
Synthesis of 6’,6a’-dihydrospiro[cyclopent[2]en-1,1’cyclopenta[c]furan]-5’(3’H)-one

21. Synthesis of spiro cyclopentenone-pyran compounds by Pauson-Khand Reaction
Synthesis of 4a’, 5’-dihydro-2’H-spiro[siklohex[2]ene-1,3’-cyclopenta[b]pyran]-6’(4’H)-one
Synthesis of 7’,7a’-dihydro-2’H-spiro[siklohekz[2]en-1,3’-cylopenta[b]pyran
6’(4’H)-one

22. Synthesis of spiro cyclopentenone-furan compounds by Pauson-Khand
Reaction
Synthesis of 6’,6a’-dihydrospiro[cyclohex[2]en-1,1’-cyclopenta[c]furan-5’(3’H)-one

23. Retrosynthetic analysis of synthesis of spiro –dihyropyran and -dihydrofuran compounds

24. General Survey to Metathesis
Ring-Closing Methatesis (RCM)
Cross Methatesis (CM)
Acyclic Dien Methatesis Polymerization (ADMEP)
Ring-Opening Methatesis Polymerization (ROMP)
Enyn Methatesis (EYN)
Ring-Opening Cross Methatesis (ROCM)

25. Various Methatesis reactions

26. Some typical Methatesis catalysts

27. Ring-Closing Metathesis is the most popular method in the natural product synthesis
We can explain the success of Ring Closing Methathesis (RCM) by three ways
Variety of functional groups
Ability to make macrocyclization reactions
Ability to use pre-molibyden and ruthenium catalysts that satisfy easy binding to unsaturated groups

28. General mechanism for Ring-Closing Methatesis

29. natural products such as (-)-pentanomycin synthesized by using
Ring-Closing Methathesis (RCM) can be an important step in the synthesis of
natural products such as (-)-pentanomycin synthesized by using
1st generation Grubbs catalysts.
Synthesis of (-)-pentanomycin by Ring Closing Methatesis

30. Retrosynthetic analysis of synthesis of spiro -dihyropyran and -dihydrofuran compounds

31. Synthesis of spiro- dihydofuran compounds by Ring Closing Methatesis
Synthesis of 1-oxaspiro[4,4]nona-3,6-dien
Synthesis of 1-oxaspiro[4,5]deca-3,6-dien

32. Synthesis of 6-oxaspiro[4,5]deca-1,8-dien
Synthesis of spiro -dihydropyran compounds by Ring Closing Methatesis
Synthesis of 6-oxaspiro[4,5]deca-1,8-dien
Synthesis of 1-oxaspiro[5,5]undeca-3,7-dien

33. CONCLUSION
Spiro-dihyropyran compounds 6-oxaspiro[4,5]deca-1,8-dien and 1-oxaspiro[5,5]undeca-3,7-dien were obtained by Ring Closing Metatesis reaction with high chemical yields 83 % and 89 % overall yield respectively, also spiro-dihydrofuran compounds 1-oxaspiro[4,4]nona-3,6-dien and 1-oxaspiro[4,5]deca-3,6-dien were obtained with 90 % and 93 % chemical yield respectively.

34. Cylopentene based spiro cyclopentenone-pyran compounds 4a',5'-dihydro-1'H- spiro[cyclopent[2]ene-1,3‘cyclopenta[c]pyran-6'(4'H)-one and 7’,7a’-dihydro-2’H-spiro[cyclopent[2]ene-1,3’-[cyclopenta[b]pyran]-6’(4’H)-one were synthesized by Pauson-Khand Reaction with 87 % and 85 % chemical yields.
In the same manner cyclohexene based spiro cyclopentenone-pyran compounds 4a’, 5’-dihydro-2’H-spiro[siklohex[2]ene-1,3’-cyclopenta[b]pyran]-6’(4’H)-one and 7’,7a’-dihydro-2’H-spiro[siklohekz[2]en-1,3’-cylopenta[b]pyran-6’(4’H)-one obtained by 87 % and 89 % chemical yield.

35. Spiro cyclopentenone-furan compounds, 6’,6a’-
dihydrospiro[cyclopent[2]en-1,1’-cyclopenta[c]furan]-5’(3’H)-one
and 6’,6a’-dihydrospiro[cyclohex[2]en-1,1’-cyclopenta[c]furan-
5’(3’H)-one were synthesized by Pauson-Khand Reaction obtained
with 83 % and 79 % chemical yield respectively.

36. ACKNOWLEDGEMENTS Prof. Dr. Cihangir Tanyeli Msc. Ayça Güzel
Scientific and Technological Research Council of grant [TBAG-110T169]

37. THANKS FOR
YOUR
ATTENTION!