Axial D3-trishomocubane derivatives with potential: Dreams or reality?

29
Send Reprints Orders on [email protected] 2632 Current Organic Chemistry, 2012, 16, 2632-2660 1385-2728/12 $58.00+.00 © 2012 Bentham Science Publishers Axial D 3 -trishomocubane Derivatives with Potential: Dreams or Reality? Dmitry I. Sharapa, 1 Igor A. Levandovskiy 2 and Tatyana E. Shubina *,1 1 Computer-Chemie-Centrum and Interdisciplinary Center for Molecular Materials, Nägelsbachstr. 25, 91052 Erlangen, Germany 2 Department of Organic Chemistry, Kiev Polytechnic Institute, pr. Pobedy 37, 03056 Kiev, Ukraine Abstract: The D3-trishomocubane is a unique high symmetrical chiral stabilomeric compound. Its derivatives have great potential to be used as scaffolds for drugs, in structure-oriented design, asymmetric catalysis, light-driven systems and much more. Axial substitution is the most useful method for this purpose but the least studied. This paper critically analyzes various synthetic strategies aiming at intro- ducing substituents into C 2 /C 9 positions of D3-trishomocubane. Herein we cover formation of trishomocubane skeleton and rearrange- ment of Cs-trishomocubanes. Based on a comprehensive retrosynthetic analysis a general synthetic scheme is proposed. Keywords: C s -trishomocubane, D 3 -trishomocubane, tertiary derivatives, axial derivatives, retrosynthetic analysis, cyclopentadienes, quinones. INTRODUCTION D 3 -trishomocubane (pentacyclo[6.3.0.0 2,6 .0 3,10 .0 5,9 ]undecane, THC) is one of the few molecules that has D 3 symmetry, yet it is chiral and exists in the form of two optical isomers. Moreover, D 3 - trishomocubane is the most stable molecule among the cage struc- tures with the empirical formula C 11 H 14 . This hydrocarbon, like adamantane, possesses specific proper- ties, viz., a relatively large cage size (its diameter is 5.5Å), high lipophilicity and conformational rigidity. The two latter properties are especially valuable for novel drug design. Additionally, its axially substituted derivatives (2-, and/or 2,9-) retain three-fold symmetry and can be potentially used as nanode- vices. Analysis of the two existing reviews on the chemistry of D 3 - trishomocubane [1,2] shows that these derivatives remain virtually unexplored. This review aims at revealing perspectives of such compounds and possible synthetic pathways (with retrosynthetic analysis) to obtain them and intends to challenge and stimulate interest to this topic. (±)-D 3 -trishomocubane was first synthesized in 1970 [3], the pure R-(+)- and S-(–)- forms were synthesized few years later [4-8]. The rotation angle [] D 165° is one of the largest among chiral cage hydrocarbons [much larger than for C 2 -bishomocubane ([] D 58°) [9], but smaller than for twistane ([] D 414-440°) [10- 13] and tribblatane ([] D 617-621°) [14]. Resolution of racemates of various D 3 -trishomocubane derivatives can be via different methods (Table 1). Additionally, monoketone and alcohol can be converted from one to another by microbiological methods stereoselectively (but not stereospecifically, the ee depends on the system) [16-18]. Thus, it seems that it is possible to find appropriate conditions for the resolution of any synthesized compound. Also it has been found 5 9 10 3 6 8 1 2 11 4 7 (–) (+) Fig. (1). Different graphical representations of the D3-trishomocubane isomers. * Address correspondence to this authors at the Computer-Chemie-Centrum and Interdisciplinary Center for Molecular Materials, Nägelsbachstr. 25, 91052 Erlangen, Germany; Tel: +49(0)9131-85 26580; Fax: +49(0)9131-85 26565; E-mail: [email protected]

Transcript of Axial D3-trishomocubane derivatives with potential: Dreams or reality?

Send Reprints Orders on [email protected]

2632 Current Organic Chemistry, 2012, 16, 2632-2660

1385-2728/12 $58.00+.00 © 2012 Bentham Science Publishers

Axial D3-trishomocubane Derivatives with Potential: Dreams or Reality?

Dmitry I. Sharapa,1 Igor A. Levandovskiy2 and Tatyana E. Shubina*,1

1Computer-Chemie-Centrum and Interdisciplinary Center for Molecular Materials, Nägelsbachstr. 25, 91052 Erlangen, Germany

2Department of Organic Chemistry, Kiev Polytechnic Institute, pr. Pobedy 37, 03056 Kiev, Ukraine

Abstract: The D3-trishomocubane is a unique high symmetrical chiral stabilomeric compound. Its derivatives have great potential to be

used as scaffolds for drugs, in structure-oriented design, asymmetric catalysis, light-driven systems and much more. Axial substitution is

the most useful method for this purpose but the least studied. This paper critically analyzes various synthetic strategies aiming at intro-

ducing substituents into C2/C9 positions of D3-trishomocubane. Herein we cover formation of trishomocubane skeleton and rearrange-

ment of Cs-trishomocubanes. Based on a comprehensive retrosynthetic analysis a general synthetic scheme is proposed.

Keywords: Cs-trishomocubane, D3-trishomocubane, tertiary derivatives, axial derivatives, retrosynthetic analysis, cyclopentadienes, quinones.

INTRODUCTION

D3-trishomocubane (pentacyclo[6.3.0.02,6.03,10.05,9]undecane, THC) is one of the few molecules that has D3 symmetry, yet it is chiral and exists in the form of two optical isomers. Moreover, D3-trishomocubane is the most stable molecule among the cage struc-tures with the empirical formula C11H14.

This hydrocarbon, like adamantane, possesses specific proper-ties, viz., a relatively large cage size (its diameter is 5.5Å), high lipophilicity and conformational rigidity. The two latter properties are especially valuable for novel drug design.

Additionally, its axially substituted derivatives (2-, and/or 2,9-) retain three-fold symmetry and can be potentially used as nanode-vices.

Analysis of the two existing reviews on the chemistry of D3-trishomocubane [1,2] shows that these derivatives remain virtually unexplored. This review aims at revealing perspectives of such

compounds and possible synthetic pathways (with retrosynthetic analysis) to obtain them and intends to challenge and stimulate interest to this topic.

(±)-D3-trishomocubane was first synthesized in 1970 [3], the pure R-(+)- and S-(–)- forms were synthesized few years later [4-8]. The rotation angle [�]D�165° is one of the largest among chiral cage hydrocarbons [much larger than for C2-bishomocubane ([�]D�58°) [9], but smaller than for twistane ([�]D�414-440°) [10-13] and tribblatane ([�]D�617-621°) [14]. Resolution of racemates of various D3-trishomocubane derivatives can be via different methods (Table 1).

Additionally, monoketone and alcohol can be converted from one to another by microbiological methods stereoselectively (but not stereospecifically, the ee depends on the system) [16-18]. Thus, it seems that it is possible to find appropriate conditions for the resolution of any synthesized compound. Also it has been found

5

9 10

3

6

8 1

2

11

4

7

(–)

(+)

Fig. (1). Different graphical representations of the D3-trishomocubane isomers.

* Address correspondence to this authors at the Computer-Chemie-Centrum and Interdisciplinary Center for Molecular Materials, Nägelsbachstr. 25, 91052 Erlangen, Germany; Tel: +49(0)9131-85 26580; Fax: +49(0)9131-85 26565; E-mail: [email protected]

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2633

that the use of enantiomerically pure substrates allow one enanti-omer of D3-trishomocubane derivative to be obtained [19].

Currently, there are only two synthetic routes resulting in 2-substituted-D3-trishomocubanes. Despite the low yield, (–)-2-D3-trishomocubaneacetic acid 10 (<1% based on 2, Scheme 1) was used for preparation of first (and to the best of our knowledge

only one) optically active organic molecule with T symmetry with known absolute configuration: (–)-1,3,5,7-tetrakis [[(2-(1S,3S,5S,6S,8S,10S)-D3-trishomocubanylbuta-1,3-diynyl]tri-shomocubanyl)acetoxy]methyl]adamantane (Scheme 2) [20-23]. First attempt with (–)-1,3,5,7-tetrakis[[(2-(1S,3S,5S,6S,8S,10S)-D3-trishomocubanyl)acetoxy]methyl]adamantane was strongly criti-

Table 1.

Racemate Reagent [�]D of (+)-isomer [�]D of (–)-isomer Ref

O

l-ephedrine +98.8° –98.8° [4]

HO

Phtalic acid

NH2

+143°

Note: corresponding

ketone [�]D = +83°,

hydrocarbon [�]D = +155°

No data [5]

Directly after resolution ester was reduced and hydrolyzed to alcohol HO

I

(–)-camphanic acid

No data –147°

[6]

HOOC

NH2

+105° for acid,

+94° for methyl ester,

100% ee

–74° for acid,

–47° for methyl ester,

80% ee

[15]

O

O

O

R,R-2,3-butanediol

+949°

Note: dextrorotary isomer was obtained from levo-

rotary ketal and was reduced to levorotary hydro-

carbon

–923°

(probably 97% ee) [7]

O

O

COOCH3

OO

COOMe

OO

COOMe

OHHO

CH2OR

O

CH2X

6 X = CN

7 X = COOH

a b c e g

f

O

CH2COOH

O

CH2COOMeO

CH2COOMe

O

O CH2COOMe

COOH

O

O

O

O

CH2COOH

g h, i, j, k

l

4 R = H

5 R = OTsd321

7(-)

8(-)

9(+) 10(-)

Scheme 1. a) cyclopentadiene, ether, 0°C–r.t., 45%; b) hv, ether, 55%; c) LiAlH4, THF, reflux, 6 hrs, 62%; d) TsCl, pyridine, 0°C, 3 hrs, r.t., overnight, e) NaCN, DMFA, 120°C, 12 hrs, comb. yield by two steps 28%; f) KOH, ethylene glycol, 150-160°C, then HCl, 86%; g) resolution by cinchonidine salt, yield of (–)-isomer 32%; h) AcOH, H2SO4, sealed tube, 42 hrs, 150-160°C; i) KOH, MeOH, reflux 4 hrs, then aq.HCl; j) etheral diazomethane; k) PCC, CH2Cl2, com-bined yield of pure (+)-9 based on (–)-7 15%, ratio of (–)-8: (+)-9 = 1:1; l) Wolf-Kishner reduction, 91%;

2634 Current Organic Chemistry, 2012, Vol. 16, No. 22 Sharapa et al.

cized [24], also in both papers 2-derivatives of (1S,3S,5S,6S, 8S,10S)-D3-trishomocubane were referred as (1S,3S,5R,6S,8R,10R)-D3-trishomocubane [24].

Also 2-substituted-D3-trishomocubanes (25 - 27, Scheme 3) were used for NMR relaxation studies, as they are 'pseudo-symmetric tops' ”since complete characterization of the dynamic behaviour of completely asymmetric molecules in solution is very

difficult” [25]. The pathway depicted on Scheme 3 results in much better yield (<7% based on 1, can be improved up to �14%), but the procedure still looks rather complicated and some yields are poorly reproduced (see below) [25].

Until now, no synthetic methods which obtain 2,9-substituted-D3-trishomocubane were reported, or concepts on how to synthesize it. Yet such compounds can be used as:

CH2OH

HOH2C

HOH2C

CH2OH

C CH

HC C

HC C

C CH

C C-Br

R

R

R

R

CH2COOH

-C C-C CR=

11 ([�]D = +19.6°)

unstable

8-step procedure

9-step procedure

a

R+

10 ([�]D = –68.2°)

12 13

14 15

Scheme 2. a) CuCl, aq. EtNH2, THF, mixture contains unreacted 11:15:14 in ratio � 2:4,5:3, respectively; yield of pure 14 (after recrystallization) - 13%

OO OHHO

X X

OHHO

X

OHO

OHO

X

X

+

HO

OH

X

X

+

8%

66%

18

19 21

20

X = COOMe

a b c d

2 16 17

OH

COOMe COOH

OHOH

COOH

OH

COOMe

O

COOMe COOH COOMe CH2OH

e f g

g h i j

20 22 23

24 25 26 27

Scheme 3. a) NaBH4, CeCl3·7H2O, MeOH, –10°C – r.t., 12 hrs., 61%); b) hv, acetone, 81%; c) PDC, CH2Cl2, r.t., overnight, 88%; d) Wolff-Kishner reduc-tion, then CH2N2, Et2O; e) glacial AcOH, conc. H2SO4, 150°C, 36 hrs., then KOH/EtOH, reflux, 3.5 hrs., 85%; f) (MeO)2SO2, K2CO3, acetone, reflux, 4 hrs, 95%; g) PCC, CH2Cl2, r.t., 5 hrs., 80%; h) Wolff-Kishner reduction, 91%; i) (MeO)2SO2, K2CO3, acetone, reflux, 4 hrs, 96%; j) LiAlH4, THF, 0°C, then reflux, 4 hrs, 88%.

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2643

• Rotors of molecular gyroscopes. Currently only achiral rotors

are known, but it was shown (based on the example of diamantane

rotor) that “higher symmetry rotors should have significantly faster

dynamics” (rates of rotation) [26]. According to the latest research

chiral molecules can be unidirectional rotated by polarized light

[27,28], thus this can be a way to light-driven motors, one of

the most rapidly developing field of modern science [29,30]. An idea that unidirectional rotation

of a “molecular ratchet” “… can be induced by the implementation of suitable chirality elements”

was proposed independent by Schalley [31]. While the topic of rotation of chiral ratchet wheel is

also interesting [32,33], one should note that chiral cage rotor of gyroscope (or ratchet) cannot be

C2/D2-symmetrical, because such rotors cannot have a single bond coaxial with rotational axe.

C2/D2-symmetrical chiral rotor can only be built based on substituted aryl (see the following

point).

• Part of chiral catalyst, with or without high symmetry. For example, a THC unit can replace chiral aryl substituent in porphyrine catalyst,

used for the asymmetric epoxidation of aromatic-substituted alkenes [34].

• Main part of (self-assembled) monolayers on metal surfaces, which will specifically react to light [35].

• Chiral nanorods, which combine the properties of usual nanorods and chirality [36,37].

• Girochiral biologically active compounds that can interact with ion channels (like a bolt with a nut), DNA helixes, proteins etc. (A

strange idea at first glance, but was nevertheless employed for the “Screw and Nut”-type interaction between �-Cyclodextrin and polylac-

tides of different chirality) [38].

2644 Current Organic Chemistry, 2012, Vol. 16, No. 22 Sharapa et al.

PLLA - poly(L-lactide); PDLA - poly(D-lactide)

Table 2. Relative stabilities of D3-trishomocubane +C

1,

+C

2 and

+C

4 cations and �C

1, �C

2 and

�C4

radicals (�E + ZPE, kcal/mol, relative to +C

1 and �C

4,

respectively).

Cations Radicals

+

+C1=+C3=+C6

+

+C2=+C9

+

+C4=+C7=+C11

�C1=�C3=�C6

�C2=�C9

�C4=�C7=�C11

B3PW91/6–31G(d) 0.0 5.6 1.2 4.0 2.6 0.0

B3PW91/6–311+G(d,p) 0.0 6.1 0.9 4.7 3.5 0.0

MP2/cc–pVDZ 0.0 7.9 0.8 2.4 2.4 0.0

I. RETROSYNTHETIC ANALYSIS

How can one introduce functional groups in 2 and/or 2,9 posi-tions in D3-trishomocubane? The seemingly obvious answer would be – by standard chemical reactions (i.e. halogenation). Unfortu-nately, in most cases the direct methods of functionalization lead to formation of 4-derivatives. The reason for that is preferred forma-tion of either +C1/+C4 cations (in electrophilic reactions) or �C1/�C4 radicals (in radical transformations). As implied by our calcula-tions, Table 2) [39], the D3-trishomocubane +C1 cation and �C4 radi-cal are most stable. The other D3-trishomocubane cations and radi-

cals are less stable [MP2/cc-pVDZ]: +C1 (0.0 kcal/mol) < +C4 (0.8

kcal/mol) < +C2 (7.9 kcal/mol) and �C1 (0.0 kcal/mol) < �C4 (2.4 kcal/mol) � �C2 (2.4 kcal/mol), respectively. Hence, under electro-philic conditions one would expect formation of 4-derivatives and under radical conditions - 1-derivatives, which was shown experi-mentally [40,41] (Scheme 4).

E

EE E

2829 30

Scheme 4. Radical pathway: (COCl)2, (PhCOO)2, 80-90°C, 24 hrs, then MeOH, 5 hrs, 56% (E = COOMe); electrophilic pathway: Br2, AlBr3, r.t., 1.5 hrs, 41% (E = Br).

Another approach – is the formation of the D3-trishomocubane skeleton via the expansion of the C2-bishomocubane due to the reaction with chlorodicarbonylrhodium dimer (Scheme 5) [42,43]. This rearrangement was reported only twice by the same group of authors and resulted in low yields for several substituted substrates.

It is unclear whether it is possible to use this method for the synthesis of the target compound (Scheme 6).

R1 R2 Yield,

%

H H 100

OH H 100

O H 65

OAc H 34

Cl H 0

R1 R1

O

a

31 32

R2 R2

Me Me 0

Scheme 5. a) Rh2(CO)4Cl2, benzene, in a sealed pressure tube under N, at 68°C.

OY

YX X

?

33

Scheme 6.

Hence, we will only focus on the rearrangement of Cs-trishomocubane skeleton to D3-trishomocubane catalyzed by H+ or Lewis acids with already existing substituents which will be at positions 2 and 2,9 in D3-trishomocubane.

The chemistry of Cs-THC derivatives is much more rich com-pared to D3-trishomocubane, but no suitable direct methods for the functionalization of the positions 2,6,9,10 (that would become axial after the rearrangement) exist (Scheme 7).

5

9 10

3

6

7 1

2

8 11

4

A

B

H

H

A

B

Y

A

B

XH

H

Scheme 7.

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2637

Apart from the widely used formation of Cs-trishomocubane skeleton via photocyclization of the Diels-Alder adduct (vide infra), a non-photochemical synthesis of the 2-substituted Cs-trishomocubane is also known [44]. Diendiol 35, which can be readily obtained from the well-known adduct 34, yields under basic condition the keto-olefin 36 [45], which is than reduced by SmI2 to the Cs-compound 37 (Scheme 8). Such a reaction between the keto- and the olefin group is rather remarkable, but known for the chem-istry of trishomocubanes [46]. The very important outcome of this synthesis is the selective introduction of the hydroxyl group in 11C position. This suggests that 37 can be rearranged selectively to the derivative of 2-hydroxy-D3-THC in one step (vide infra). However, this method has several disadvantages:

• The reaction is rather sensitive to the conditions and the struc-ture of substrate.

• The expenses due to the reagent SmI2 could be a problem for synthesizing 2-substituted D3-THC in multigram quantity.

Thus, we describe and analyse only retrosynthetic pathways leading to D3-trishomocubane (THC) derivatives that include the next principle steps:

• Rearrangement of Cs-THC derivatives to the corresponding substituted D3-THC (Scheme 9)

• Photocyclization of diene derivatives IIIa to functionalized Cs-THC IIb (Scheme 10)

• Diels-Alder reaction between cyclopentadiene moiety and qui-none fragment (Scheme 11).

These 3 steps completely describe the formation and the change of the carbon skeleton, but without the introduction of any func-tional group into the “required” position - these functional groups must be already present from the beginning, either in cyclopentadi-ene or quinone compounds or be introduced upon functionalization of the adduct.

X, Y – target groups, which are described in this chapter; equal to the X and Y on the corresponding substituted CPD and quinone (in this case they play a determining role in the outcome of the reac-tion, see Chapters IV and V), or equal to H, if the unsubstituted adduct were functionalized later (see Chapters VI, VII).

Z- – non-target groups, which are introduced for the selectivity of rearrangement or for other purposes, or appeared during rear-rangement, are described in this chapter;

Nu – group that replaces A throughout the rearrangement, is de-scribed in Chapter II;

A, B – substituents that in combination with X,Y,Z ensure the selective rearrangement; positions 8, 11 in IIb and IIIa can be sub-stituted not only by carbonyls but also by hydroxyls [25,47,48].

O

O

OMeMeO

Cl

ClCl

ClOH

HO

OMeMeO

Cl

ClCl

Cl

OH

OMeMeO

Cl

ClO

Cl

OH

OMeMeO

Cl

Cl

HO

OH

ClCl

MeO OMe

HO

34 35 36 37

a b c

Scheme 8. a) NaBH4·CeCl3, MeOH, 85%; b) t-BuOH/t-BuOK, 84%; c) SmI2 (5.5 eqiv), THF/MeOH (2:1), –78°C, then r.t. overnight (16 hrs), 70%.

Z

XYZ

Preparation for

rearrangementSelective

rearrangement

Deleting of all

unwanted parts

IbIa IIa

AB

XY

Nu

X

Y Z

IIb

OO

X

Y

B

Scheme 9.

O

O

ZPhotocyclization,

Substituents do not change

IIIa

Z

IIb

OO

X

Y

Y

X

Scheme 10.

O

O

Z1,2

O

O

Z2Z1

Diels-Alder reaction

Functionalization

of adduct III

CPD

moiety

Quinone

moietyIIIa IIIb

O

O

ZY

X X

Y

X

Y

+

Scheme 11.

2638 Current Organic Chemistry, 2012, Vol. 16, No. 22 Sharapa et al.

According to the expected application, one has to choose which substituents can be in axial positions. Evidently, targeted substitu-ents X and Y can be alkyl or aryl groups (although they can be barely converted further or used in previously mentioned systems, see Introduction), as well as halogen or hydroxyl (thiols) groups (it was shown that OH group is non-reactive in tertiary position of THC systems, Scheme 12) [49,50]. This leads to to the assumption that groups such as –COOAlk, –C(O)Me, –C=CH2, –CH2OH, –CH2Hal, –CH2COOAlk, etc might be more suitable.

HO HOOC

Br

38 40

39

a

b

c

Scheme 12. a) HCOOH, H2SO4, 20°C, 30 min, 27%; b) HBr, reflux, 15 hrs, 50%; c) HCOOH, H2SO4, 3.5 hrs, 52%.

Since the substituents A and B in IIb originate from adduct IIIb (A=B=O) and take part in the rearrangement (see chapter Re-arrangement), these groups (in forms of ketones or reduced to hy-droxyls) should exist after photocyclization and must be removed after selective rearrangement, together with all the other unwanted substituents. These substituents can also be defined at this point: since the removal of functional group from the tertiary positions of the cage is an extremely complicated task, only halogens should be present on the tertiary positions of structures Ib, IIa, IIb (Scheme

13) [51]. Possible substitutions on the 4C- atom (secondary posi-tion) are described in chapter IV.

Br

O

O

O

O

41 42

Scheme 13. Li/tBuOH, 84%.

II. SELECTIVE REARRANGEMENT OF THE CS-CAGE TO

D3

The problem of selectively rearranging Cs-trishomocubane is obvious: if the functional groups in the positions 8 and 11 are the same (usually after photocyclization they are either keto- or hy-droxyl- groups), there are two possible ways for the rearrangement to occur (Scheme 14). Thus, from a molecule with a plane of sym-metry the two enantiomers (R and S) are always obtained while a chiral Cs-substrate yields two different isomers.

Nu is the nucleophile that attacks the rearranged cation, A is the group that causes the rearrangement (either a hydroxyl or a car-bonyl), note that A=B in accordance with the numbering on the previous schemes.

To obtain the single product one of the two strategies can be applied:

• The rearrangement must be selective for the substituents (A=B),

• The substrate must have only one possibility for rearrange-ment (A�B). The synthesis of such compounds requires selective changing of the A or B groups, which can be done only based on the presence of specific target groups.

5

9 10

3

6

8 1

2

11

4

7 10

3

1

2

11

4

9

5

7

6

8

front sideback side

(R) (S)A

A AA

NuNu

5

9 10

3

6

8 1

2

11

4

710

3

1

2

11

4

9

5

7

6

8

A

AAA

NuNu Y

Y

Y

axial isomernonaxial isomer

Chiral substrate

Achiral substrate

Scheme 14.

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2639

The influence of the substituents on the reactivity of groups A and B plays a major role and is different for diols and diketones.

Mild oxidation was found to be the one method, which can dif-ferentiate the two hydroxyl groups according to the substituents on the “frontside” or the “backside” (the less hindered hydroxyl is more reactive) of the Cs-trishomocubane (Scheme 15 [52] and Scheme 16 steps a-c). The rearrangement of the ether 7 was non-selective, therefore it is expected that the situation with the diol would be the same. Unfortunately, no attempts on the rearrange-ment of 17 were made. Yet substituted diketo- compounds have high selectivity in various reactions. For example, the hindrance of carbonyl group decreases its reactivity Scheme 17 [53,54], Scheme

16 steps d-f [55]. Even when the frontside and the backside sub-stituents are the same their influence is quite different (Scheme 18)

[56,57]. Both pathways were used to synthesize 18 and its corresponding ketal 46 (Scheme 16).

Rearrangement of the Cs-THC-alcohol in acidic media is the most popular method for rearranging this cage. According to the classical idea, 8Cs-THC-cation 53a undergoes rearrangement to 4D3-THC-cation 53b, followed by a reaction with a nucleophile [59]. Our ab initio and DFT study showed that the reaction proceeds via the formation of only one D3-nonclassical cation instead (Scheme 19) [39]. Hence, this method seems to be suitable to form substi-

tuted D3-skeleton based on Cs-THC. However, the rearrangement of Cs-THC-alcohol in acidic media only yields a single isomer (vide

supra), when the second group is not a hydroxyl (A=OH, B�OH).

The effect of the B-substituent on this rearrangement was found to be essential. The cation, which is formed on a first step by the removal of the hydroxyl group (Scheme 20), successfully rear-ranges when there is no substituent in position 11 (B1 = H,H), or the substituent is another hydroxyl group (B1 = OH, H).

It was also found that complex carbon substituent (B = Me, CH2OH) does not affect the rearrangement (Scheme 21) [62].

However, the presence of a keto group in this position com-pletely prevents rearrangement (different substrates and acids were tried by several authors, Scheme 22) [58,62-66]. The reduction of the carbonyl group is a possible solution for this problem (see for

HOOH

Ph

HOO

Ph

Me Me

43 44

a

Scheme 15. a) PCC, CH2Cl2, 0–25°C.

OO

MeOOC

O O

OMeOOC

OO

MeOOC

HOOH

MeOOC

HOOH

MeOOC

a

b c (selective)

d

e f

selective

HOO

MeOOC

HO O

OMeOOC

2

16 17 18

3 45 46

Scheme 16. a, b, c – see Scheme 3; d) hv, EtOAc, 88%[55] (compare with step b, Scheme 1); e) ethylene glycol, TsOH, 85%;[55] f) NaBH4, MeOH, r.t., 48 hrs., 95% [58].

OO

O

R R

a

OH

O

OEt

b

OCH2

R

4748 49

R = Me

Ph

R = Ph

Scheme 17. a) Ph3P–CH3-Br+, n-BuLi, 0°-25°C, 48%[53]; b) ethyl diazoacetate (EDA), BF3·Et2O, 0°C–r.t., 2 hrs., 25% for both substituents [54].

OOO

Br

BrBr

HOOH

Br

a b

O

Br

Br

O

Br

Br

O OO

O

+

5051 52a 52b

Scheme 18. a) moist air;[56] b) ethylene glycol, TsOH · H2O, ratio 52a:52b = 1:5, also bisethylenketal formed, which can be converted back to a mixture 52a+52b by hydrolysis 10% H2SO4, THF, total yield � quant.

2640 Current Organic Chemistry, 2012, Vol. 16, No. 22 Sharapa et al.

example Scheme 3), while masking of the carbonyl group by a ketal moiety has no effect, because of the potential hydrolysis of the pro-tecting group hydrolysis.

Also a thioketal protecting group, which is stable under acidic conditions, was used the rearrangement did not occur (it should be noted that conditions are different to commonly used acidic rear-

rangement, Scheme 23) [67]. However, rearrangement (under rather hard conditions) occurs when an alkyl group is connected to the same carbon atom as the hydroxyl (A= –Me, –OH), (Scheme 24) [68].

OH

a

O O

MeMe

X

63 64 X = Cl, Br

Scheme 24 a) aq. HCl, 140-150°C (autoclave), 3 hrs., 63% (X = Cl) or 48% HBr, reflux, 3 hrs., 57% (X = Br).

Nevertheless, exploration of the dithioethyleneketals is motivat-ing, because it can be used not only to distinguish between ke-

HO

H Nu

-H2ONu

53a 53b

Scheme 19.

B1 Acid B2 Nu Yield, % Ref

a H AcOH H OAc 79 [19]

b OH MsOH OH OMs quant [60]

c OH HI OH I 44-86 [6,59]

d OH AcOH OAc OAc 70 [61] HO

HNu

B1 B2

Nu

54a-e 55a-e

e OH HI I I 87 [61]

Scheme 20.

OOH

XCH2OAc

56 57

a

OH

Scheme 21. a) glacial HOAc, conc. H2SO4 (cat), reflux 12 hrs, X = OAc.

HO

a

HO

b

O

O

MeOOC

BrO

EtCOOO

MeOOC

58 59 6046

O

O

Scheme 22. a) typical conditions: stirring it in a large excess of 48% hydrobromic acid at 80° for 3 hrs, yield 90%; b) propionic acid, conc. H2SO4 (cat), reflux, 42 hrs., 80%.

HO S

S

RO S

S

61 62

aR = acryloyl

Scheme 23. a) acrylic acid, NEt3, THF, 0°C-r.t., 1 hr.

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2641

togroups (like ethyleneketals), but also for the reduction of the non-targeted keton in one step under mild condition (compared to widely used Wolf-Kishner reaction), Scheme 25.

Some methods allow the formation of some “unwanted” keto-alcohols (Scheme 26) [69].

This result, however, can also be used: by converting such compounds into bromo-ketones without rearrangement (Scheme

22), with the possibility that after reduction to bromo-alcohols these compounds can successfully undergo rearrangement (Scheme 27).

Since dienetriol 70 (obtained from acid 16 by multistep synthe-

sis involving reductions and resolutions) can be converted to ace-

tonide 71 (Scheme 28) [70], we can expect that the same can be

done with the cage-triol 4.

OO

X

HO

X

HO

X

S

S

O

X

S

S

X

HO

Ni/Ra

Scheme 25.

O

O

O

TBSOH2CO

OH

O

TBSOH2C

81%

H H

O

O

MeOOCO

OH

MeOOC

H H

O

OH

TBSOH2C

H

OOH

MeOOC

65 662

68 6967

a b

c

Scheme 26. a) NaBH4 (1.1 equiv), CeCl3·7H2O, -30°–0°C, 30 min; b) hv, acetone, 90%; c) NaBH4, MeOH, 15°C, 81%.

O

OH

X

OOH

X

OBr

X

HOBr

X

X

HO

Br

Scheme 27.

OH

H

HOH

CH2OH

O

H

HOH

O

O

H

O

O

OH

H

HOH

COOMe

OH

H

HOH

CH2OH

O

H

HOH

O

O

H

O

O

16 70 71 72

4

Scheme 28. a) LiAlH4, THF, 0°C, 1 hr, r.t. 2 hrs.; b) acetone, PPTS (cat), r.t., 12 hrs., overall yield from 16 51%; c) PDC, CH2Cl2, 0°C–r.t. 2 hrs.

2642 Current Organic Chemistry, 2012, Vol. 16, No. 22 Sharapa et al.

Based on the selectivity of the reactions with diketones it is an-

ticipated that these compounds can undergo rearrangement in one

step to form a single product. The previously reported rearrange-

ment of �-diketone by chlorosulphonic acid [39,71-73] is studied

much less than the rearrangement of alcohols, but is characterized

by rather promising features:

• The rearrangement occurs under low temperature (this usually

corresponds to higher selectivity)

• The rearrangement is selective towards “frontside” substitution

(reaction with “backside”-substituted diketones was never at-

tempted, Scheme 29).

OO

Br

Br

HSO3Cl

?

50

We propose that this rearrangement (Scheme 29) and the rear-

rangement shown on Scheme 24 occur via the formation of the

analogous intermediates 77b-d, which reactivity differ from the

unsubstituted 77a (Table 3).

We also expect that polysubstituted Cookson diketones, (for

example 50) will rearrange in only one possible way (probably by

the less hindered carbonyl). Contrary to the first method (rear-

rangement of alcohols), chlorosulfation does not require removal of

a substituent near 11

C, so it can be used for the synthesis of 4,7,11-

substituted-THC with functional groups in position 2/9. Thus, this

method can be useful for diketones, which are obtained from halo-

substituted quinones (see chapter V).

In the case of synthesis of mono-axial-substituted D3-THC the

problem of the selective rearrangement could be omitted by using

type II compounds, which have same functional group in positions

9 and 10 (for example 116) or 2 and 7 (based on dicarboxyfulvene

120b), Scheme 30.

Also this method solves the problem of the selective synthesis

of 2-X,9-Y-substituted III. No compounds of this type are known at

the moment, since the selectivity of functionalization of these two

positions is in general independent from each other and in the case

of high sensitivity for the individual reaction – unpredictable (thus

its possible to form IIIa or IIIc by functionalization, while using a

“trisubstituted strategy” suggests the synthesis of 2,9-substituted

compounds of type IIId, IIIe, Scheme 31).

OO

HO

ClO

OO

HO

ClO

MeMe

HSO3Cl HSO3Cl

73 74 75 76

Scheme 29. a) HSO3Cl, CH3Cl, 0°C, overnight, 75%;[39] b) HSO3Cl, 0°C, 57% [73].

Table 3.

X Rearrangement Conditions Ref.

H – Any acid [58,62-66]

Me + HBr, (or HCl), reflux, P [68] X

O

77 Cl + HSO3Cl [39,71-73]

2

7

A

B

X

X

10

9

A

B

H

Y

Y

HA B

X X

AB

YYZZ

nonselective rearrangament

Scheme 30.

2

7

6

5

4

31

10

9

8

A

B

X

Y

IIIa

H

H

2

7

10

9

A

B

X

H

IIIc

Y

H

210

9

A

B

X

Y

IIId

Y

H

2

7

10

A

B

X

H

IIIe

Y

X

Scheme 31.

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2643

However such simplification causes another problem: the re-gioselective reduction of a functional group that appears on a non-axial position. This problem would be even more complicated than searching for a pathway for compound IIIa.

III. CYCLOPENTADIENE DERIVATIVES (9-

SUBSTITUTED III)

In general several types of starting compounds with CPD-fragment can be used:

• 2-Substituted cyclopentadienes • 2-Substituted cyclopentadienone or its ketal • 2-Substituted fulvenes • 2-Substituted cyclopentadienes with two substituents at the

atom C5

3 2

1

5

4

RO OR R1 R2

X X X X

The main problem of substituted cyclopentadiens is the equi-librium of several isomers. The structure of a product depends on the substituent pattern in CPD, the structure of the dienophile, and the presence of a Lewis acid catalyst and is generally unpredictable (e.g. Scheme 32) [74-80].

Very often the product is a mixture of several adducts (Scheme 33). In some cases it is a mixture of endo- and exo- adducts, but more often a mixture of regioisomers (1 or 9) [81,82].

Cyclopentadiene derivatives usually exist in their dimer form, and the respective monomer (that participates in the DA reaction) can be obtained by distillation, whereby the yields are often low (e.g. monomerization of Thiele ester (Carbomethoxycyclopentadi-ene dimer) to methylcyclopenadienecarboxylate 85 – 50%[81]).

The presence of heterosubstituents poses additional problems, because possible structures are in equilibrium with each other and undergo very fast rearrangement. For example, bistrimethylsylil-CPD has 7 equilibrium structures, with 5,5-isomer being major one (�95% in mixture). But its reactivity in the DA reaction is rather low, and in all reported cases the 2,5-isomer is the reactive one [83]. The adduct with quinone was then readily photocyclized into

O

O

O

O

O

O

O

O

O

O

O

O

Ph

O

O

Ph

Me

Me

Me

Me

Me

Me

Me

78

79 80

81 82

83 84

a

b

c

Scheme 32. a) benzene, sealed tube, 90°C, 5 hrs, 77%; [74] b) benzene, 0-5°C, 4 hrs., 40%; [76] c) no experimental data is available [75].

41

8

O

O

O

O

+

MeOOC

2

59

O

O

MeOOC

MeOOC

+

O

O

+

(MeO)3C

O

O

MeOOC

+

O

O

MeOOC

H

H

H

H

85 86 87 88

89 86 88 90

a

b

Scheme 33. a) CH2Cl2/benzene, -75°C-r.t., overnight, ratio 87:88 = 3:1, total yield unknown, 87 was isolated in 30% yield;[81] b) no experimental data is available; ratio 88:90 = 3:2 [82].

2644 Current Organic Chemistry, 2012, Vol. 16, No. 22 Sharapa et al.

2,4-bis-TMS-derivative of the Cookson diketone [84] (Scheme 34),

however attempts to control the DA-reaction by a TMS group was

in general unsuccessful (Scheme 35) [85].

The derivatives of cyclopentadienone and their ketals exist

as one isomer, but are usually very reactive (ethyl ketal of cy-

clopentadienone dimerizes about 465 times more rapidly than cy-

clopentadiene; the ethylene ketal dimerizes nearly 5�105

times

faster than cyclopentadiene) [86]. The dimerization rate can be

decreased by introducing steric or electron-accepting substituents:

while ketals of nonsubstituted cyclopentadienone are usually used

without isolation [87,88], e.g. dimethyl ketal of tetrachlorocy-

clopentadienone is stable [89], and ethylene ketal of 3-t-butyl-

cyclopentadienone 101 dimerizes slowly enough to obtain adducts

with p-benzoquinone [90] (Scheme 36). Annulated 2,5-

bis(trimethylsilyl)cyclopentadienone 104 is stable even without any

ketal protection [91]. However, the problem of low yield still exists:

dehydrobromination of 2,5-dibromo-3-t-butyl-cyclopentanone ketal

100 produces only 50% of 3-t-butyl-cyclopentadienone ketal 101

(after distillation) and 40% are lost to dimerisation (conditions for

the monomerization are unknown) [92]. The yield of the adduct 109

is even lower – 30% [93].

Me3Si SiMe3SiMe3

Me3Si

COOMe

COOMe

Me3Si

SiMe3

SiMe3

Me3SiCN

CN

CN

CN

O

Me3Si

O

Me3Si

H

H

SiMe3

SiMe3

OO

O

O

MeOOC COOMe

CN

NC CN

NC91

92

93 94

95

a

d

b

c

Scheme 34. a) CCl4, 20°C, 24 hrs (or xylene, reflux, 2 hrs); b) MeOH, r.t., 89%; c) hv, EtOAc, quant.; d) CH2Cl2, 20°C, 24 hrs., 94%

SiMe3

MeN

O

O

Ph

SiMe3

N

O

O

Ph

SiMe3

N

O

O

Ph

++

96 97a 97b

a

Scheme 35. a) Et2O, r.t., 1 hr., 97a:97b = 9:11 (the same result obtained for methylCPD).

X

X

X

X

OMe

OMe

ButO

O

ButO

O

Br

BrO

O

But

O

O

endo/exo

stereochemistry

is unknown

OMeMeO

X

O

O

X

X

X Cl

Cl ClCl

MeOOMe

OO

98 X=H

34 X=Cl

99

100 101 102

a b

dc

5,5-dimethoxycyclopentadiene X=H

tetrachloro-5,5-dimethoxyCPD X=Cl

Scheme 36. a) toluene, 0-70°C, 12 hrs., 74% (X = H) [94], toluene, reflux, 24 hrs., 83% (X = Cl); [89] b) hv, acetone, 90%; [89] c) MeONa, DMSO, 25°C, 40

hrs., 50%; [92] d) benzoquinone, MeOH, r.t., 12 hrs., quant [90].

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2645

O

RR

O

X Scheme 38.

Unfortunately, the compounds that are relevant to our main topic (Scheme 38, X described in chapter II) are unknown. Never-theless, this way is rather promising and we want to stress that the popular ethylene ketals are too reactive (and therefor useless for us) and need to be changed to dimethoxy (R = Me) or propylene ketals (R,R = –(CH2)3–) [86].

Fulvenes – compounds with fixed substituent pattern and a

lower reactivity than ketones and ketals (Scheme 39). The “weak place” of the fulvene pathway is the obtained mixture of endo- and exo- adducts in the Diels-Alder reaction, even with such reactive dienophile as quinone. It should to be noted that the exo-adducts of a majority of CPD-derivatives are thermodynamically more stable (and endo-adducts are formed due to kinetic control). In the case of fulvenes this become extremely important. The reaction is very sensitive to the substituent pattern on both fulvene and quinone, the solvent and the method used as well as the order of the addition of reagents, the reaction temperatureand timeand the following workup. This leads to a large variety of different yields (Scheme 39).

X

+

O

O

X

O

O Scheme 39.

Despite of the above mentioned issues, this way can still be successfully deployed: the easily accessible dimethylfulvene reacts with several quinones forming only endo- isomer with substituents in positions 2,5 [99] and 2,7 [100,101] in high yields (Scheme 40). Also methods are known to obtain 2 and 2,3 substituted fulvenes that readily react in the DA reaction (Scheme 41, reports on stabil-ity of diester 120b differ in different papers) [102,103].

Table 4.

X Ratio endo:exo Yield Ref

CMe2

88:12

50:50

up to 0:100

81%

unknown

quant

[95]

[96,97]

[98]

CHMe 90:10 91% [95]

CH(i-Pr) 96:4 84% [95]

CH(t-Bu) 97:3 86% [95]

SiMe3

SiMe3

O

SiMe3

SiMe3

Me3Si

Me3Si

O

O

OR

R

OO

O

OMe

OMe

OMe

OMe

Br

Br

OMeMeO

O

O

Br Br

Br

Br

MeO OMe

OO

104103 105 106

107 108 109 110

a, b

e

c

f

d

g

Scheme 37. a) Fe2(CO)5, glyme, 140°C, 15 hrs, 82%; b) Me3NO·2H2O, acetone, 15°C, 66%; c) benzoquinone, CH2Cl2, 25°C, 90%; d) hv, benzene, quant; e) t-BuOK/tBuOH, t < 20°C; f) benzoquinone, EtOAc/petroleum ether, overall yield for two steps 30%; g) hv, EtOAc, 70%.

+

O

O

X

O

O

O

O

X

O

O

O

O

X

O

O

+

O

O

Br

Br

O

O

Br

O

O

Br

BrBr O

O

Br

Br

111 2,5-dibromquinone 112 113

111 114 115 116

a b

c d

Scheme 40. a) H2O, 5°C-r.t., 2 days, quant.; b) hv, EtOAc, 60%; c) CHCl3, r.t., 10 min., quant.; d) hv, 90%.

2646 Current Organic Chemistry, 2012, Vol. 16, No. 22 Sharapa et al.

The last type of compounds that should be mentioned here are

5,5-disubstituted cyclopentadienes. These compounds are not

well studied, although it was shown that they readily react with

benzoquinone and yield endo-adducts like unsubstituted CPD 121a

(Schemes 42, 43) [104-107].

The synthesis of 2,5,5-substituted cyclopentadiens (relevant to

the topic of this review) was also described (Scheme 44) [108].

Thus it can be suggested that the synthesis of compounds 131 –

134 (Scheme 45) is possible and the only difficulties that may occur

are associated with the removal of Y,Z-substituents from the cage.

R

E

R R

EE

R E

+

E = COOMe

111 117a,b 118a,b 119a,b 120a,b

a b c 117-120a R=H

117-120b R=COOMe

Scheme 41. a) heating in sealed tube, 50% for 118a or heating without solvent, 90% for 118b; b) H2/Pd, MeOH, 60% for 119a, 90% for 119b; c) flash vacuum

pyrolysis 68% for 120a, quant. for 120b.

121-123 n

a 0 (H,H)

b 2

c 4

+

(CH2)n

O

O

O

OO

O

(CH2)n (CH2)n

122a-c 123a-c121a-c benzoquinone

a b

Scheme 42. a) benzene, r.t.; b) CH2Cl2, 0°C, 20°C or 40°C.

+

Me CH2OH

O

O

O

O

CH2OH

Me

O

O

HOH2CMe

+

124 125 126

c

Scheme 43. a) benzene, r.t., 5 days, 81%, ratio 125:126 = 5.25:1.

O

Me COOMe Me COOMe

Me CN

Me COOMe

127 128

129a

130a

a, b, c

d, e

f, g, h, i, j, k

Me COOMe

129b

+

+

Me CN

130b

Scheme 44. a) NaH, MeI, b) NaBH4, MeOH, 81%; c) P4O10, benzene, 76%; d) NBS, AIBN, 87%; e) quinoline, 69%, ratio 129a:129b = 71:29; f) alkaline

hydrolysis - 95%; g) SOCl2, 92%; h) ammonolysis - 95%; i) dehydratation – 87%; j) NBS-bromination - 62%; k) t-BuOK, THF, reflux, 15 min., 84%, ratio

130a:130b = 90:10.

O

O OO

O

O

ZY

OO

YZ

X X

X X

131 132 133 134

Scheme 45. Z = Me, Y = CN, COOR, CH2OH, etc; X described in chapter II.

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2647

Additionally, the steric influence of substituent on the regiose-lectivity of Diels-Alder reactions (Scheme 46, Table 5) Scheme 46, Table 5) will play an important role [109].

O

O

XX

COOR

+

X X

O

O

O

O

XX

COOR

+

COOR

121a-c 1 135a-c 136a-c

Scheme 46.

Table 5.

X,X Ratio 135:136 Ref

a H,H (CPD) 100:0 [21,70,110,111]

b –CH2CH2– 50:50 [109]

c –CH2(CH2)2CH2– 38:62 [109]

IV. SUBSTITUTED QUINONES (2-SUBSTITUTED III)

The previously described methods for the synthesis of 9-substituted IV are based on Diels-Alder reaction of alkyl-carboxy-quinone 1 with CPD, followed by a photocyclization step. Firstly, it should be noted that the majority of monosubstituted quinones react via the unsubstituted side.

Only nitroquinone, acetylquinone and ethers of quinone-carboxilic acid react at the activated side (Scheme 48). Nitroqui-none is very unstable and should be prepared in situ, although the yield is unsatisfactory [112]. The adduct 141 was mentioned only twice before [113,114] and was drawn in a second paper in the exo-form, contrary to obvious endo-configuration. No data for the iden-tification of the configuration was presented.

The Diels-Alder reaction of 2-(carbomethoxy)-1,4-benzo-quinone was studied in more details, but the yields are not repro-ducible (Scheme 49 Table 6) [21,70,110].

The catalysis with strong Lewis acids leads to the formation of a different product [111]. Nevertheless, the ZnCl2-catalysed cy-cloaddition to (1’R,2’S,5’R)-(–)-menthyl-1,4-benzoquinone-2-carboxylate results in high yield (80%) and the selective formation of two diastereomers (3:1) [111] that can be used for the selective synthesis of single enantiomer of Cs- and D3- THC (Scheme 50). Thus, the use of chiral quinone at the beginning of the scheme re-

O

O

O

O

+

X X X = Alk

Ar,

Hal

Scheme 47.

O

O

O

O

NO2

O2NOH

OH

NO2 a

O

O

O

O

Me(O)CO

137 138 139

140 141

b

Scheme 48. a) Ag2O, CPD, benzene, 0°C-r.t., 8 hrs., 25%; b) CPD, benzene, r.t., 81%.

O

O

O

O

COOMe

MeOOCOH

OH

COOMe Ag2O

142 1 2

Scheme 49.

2648 Current Organic Chemistry, 2012, Vol. 16, No. 22 Sharapa et al.

sults in non-equivalent amount of the R- and S- isomers of the tar-geted trishomocubanes, without a resolution of a racemate on any step. Such substrate enantioselectivity is extremely important and has never been reviewed before in any work on D3-THC.

There is no information about the adduct of the mono-nitrile-quinone (except for the statement concerning the formation of the endo-adduct at the substituted side in the original paper [115], the reference to this statement is incorrect and the compound has never been mentioned in the Scifinder® database). The information about the adduct of dicyanoquinone is also contradictory, Scheme 51

[116-118]. The authors of first two publications claimed that the adduct, synthesized under 0°C, cannot undergo photocyclization and suggested the exo-configuration for the adduct (148a, based on

“double melting point” and analysis of 1H NMR) [116,117]. How-ever, later Marchand et al. reported the successful photocyclization after the reduction of the carbonyls to hydroxyls, followed by an esterification (and thus endo-configuration, 148b). The structure of the final product 149 was confirmed by X-ray analysis [118].

Nonetheless, the Diels-Alder reaction of 2-�yano-3-(p-tolylsulfinyl)-1,4-benzoquinone (Scheme 52) affords the adducts with a complete chemo- (the reaction only takes place at the the sulfinyl-substituted double bond), regio- (controlled by the cyano group), and endo-selectivity (with respect to the quinone moiety) [119]. Quinone 152 is chiral (because of the sulfinyl-group), which leads to substrate enantioselectivity as described before. The overall yield for the 2 isomers is 60%.

Table 6.

Yield, %

1 2

Ref Notes

91 45 [21] The product was photocyclizied with 55% yield. No information about the mixture.

in situ 86 [70] A 9:1 mixture of endo- and exo- isomers was separated after 3 steps.

57 21 [110] A lot of other pathways were tried (unsuccessfully).

60 57-66 [111] ZnCl2, Ti(OiPr)4 or TiCl2(OiPr)2 were deployed as catalyst. The utilization of TiCl4or SnCl4 leads to fragmentation product.

O

O

COX

OMe

OMe

COX

O

O

COX

O

O

XOC

MeOOC COOMe

ratio �1:1

X = O

143 144

a b

145R 145S

26R 26S

Scheme 50. a) Ag2O2, HNO3, dioxane, 10 min, 89%; b) CPD, CH2Cl2, ZnCl2, –78°C, 3 hrs., 80%.

O

O

CN

CN

O

O

CN

CN

O

O

CN

CN

O

O

NC

NC

a

b

c

d,e

OAc

OAc

CN

CN

146147

148a

148b 149

Scheme 51. a) CPD, benzene, reflux, 3 hrs, 64%; b) CPD, MeOH, 0°C, 70%;[117] c) CPD, MeOH, 0°C, 70%;[118] d) NaBH4, CeCl3·7H2O, MeOH, 5°C, 0.5 hr., then r.t. 4 hrs. 77%; e) Ac2O, pyridine, r.t., 30 hrs., 57%.

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2649

The idea to change carbometoxyquinone to stable car-bomethoxycyclohexenone (Scheme 53) is also unsuitable, since exo-addition takes place [120,121]. The corresponding aldehyde will most likely have the same problems [122].

In some cases the structure of the product can also depend on the diene used (Scheme 54) [100,101].

Another possible way is to use 2,5- and 2,6- substituted qui-

nones, which result in 2,5- and 2,4- substituted III, respectively. The impractical substitution 5/4 in III results in the redundant sub-stitution 1/7 in II, respectively. It can then be either useful or prob-

lematic for the selective rearrangement (vide supra), and needs to be removed after forming the hydrocarbon cage without destroying the “wanted” functional groups. Also it is a necessary requirement that the side with the “redundant” substituent would be less reactive (in Diels-Alder reaction) than the side with the “wanted” functional

groups.

These requirements are rather contradictory, e.g. the adducts of the symmetrical, stable and available diesters 160a-c [123,124] (Scheme 55) clearly have a carboxylic group on an appropriate position, but the selective removal of the other carboxylic group is a

O

O

S

CN O

O

CN

S(O)Tol

Tol

O

O

O

NC

Tol(O)S

+

OH

OH

S

CN

Tol

O

a

151 152 153R 153S

Scheme 52. a) PhI(OAc)2, CH2Cl2, 20-40 min., 153R - 28%, 153S - 37%.

O

+

COOMe

COOMe

O

O

+

O

H

CHO

OCHO

O

+

154 155

156 157 158

a

b

Scheme 53. a) Et2O, SnCl4, –25°C, 3 hrs., 29%; [120,121] b) Et2O, ZnCl2, r.t., 10 min., 52%, ratio 157:158 = 20:1 [122].

O

O

X

O

O

O

O

CO

OC

X

O

OCO

OC

X

114 115159

a b

Scheme 54. a) benzene, r.t., 10 min., 91%; b) CHCl3, r.t., 10 min., 96%.

O

O

O

O

COOR

COORX

X

ROOC

X

X

COORX

ROOCX

OO

ROOC

160a X=H

b Cl

c Br

161a-c 162a-c

a b

Scheme 55. a) 160a obtained in situ by oxidizing of corresponding hydroquinone by PhI(O2CCF3)2 [123] acetone, 0°C, 84.4% (X=H), ethanol, reflux for 10 min or r.t. for 24 hrs., 90% (X=Cl), 95% (X=Br); b) hv, EtOAc, 76% (X=H), 77% (X=Cl), 85% (X=Br) [124].

2650 Current Organic Chemistry, 2012, Vol. 16, No. 22 Sharapa et al.

big problem, while the presence of two different substituents al-ways opens the question “which side is preferable for the Diels-Alder reaction”.

Since the requirements, which are outlined above, eliminate al-

kyl and aryl groups from the list of substituents, there are not many

suitable di- and poly-substituted quinones left. From our point of

view the most appropriate “redundant” substituent are halogens.

The Diels-Alder reaction of such quinones is not described well

[125,126] (Scheme 56) but methods of their synthesis (or the corre-

sponding hydroquinones) are known [127-130] (Scheme 57).

Apart from methods based on the functionalization of benzo- and tolu- quinones, or their corresponding hydroquinones and their methylated derivatives, there is a universal method that can be used to synthesize different 2,3-dichloro-4-substituted-benzoquinons (Scheme 58) [131,132].

One should be aware that similar quinones might have different stability or react in unpredictable way (Scheme 59) [133,134].

V. FUNCTIONALIZATION OF C9 IN ADDUCT III

All methods that were described beforehand suggest the synthe-sis of III with the substituents in the correct position directly after

O

O

O

O

CH2Br

CH2Br

Br

CH2Br

Br

OO

Br

O

O

O

O

C(O)Me

Cl

C(O)Me

Cl

OO

Cl

Me

O

Cl

ClCl

163 164 165

166 167 168

a

b

c

d

Scheme 56. a) benzene, 0°C-r.t., 2 days, 60%; b) hv, EtOAc, 32%; [126] c) benzene, r.t., 96%, mixture 23:2 of endo- and exo- adducts; d) hv, EtOAc, quant

[125]. OMe

OMe

CH2XBr

169a X = OH,

b Br

OMe

OMe

CH2XCl

170a X = OH

b CN

c COOH

O

O

CH2CH2OHX

Y

171a X = Br, Y = H

b X = H, Y = Cl

Scheme 57.

O

O

ClXX = Me

O

O

X

O

O

OTMS

X

OTMS

Cl

O

O

ClX

Cl

Cl

Cl Cl

TMS-Cl

overall yield ~50%

172 173 174 175

a b c

Scheme 58. a) NEt3, ZnCl2, MeCN, r.t., quant; b) epoxybutane, sealed tube, 145°C, 64 hrs, without isolation; c) MeOH, r.t., 1.5 hrs., overall yield for two steps 50%.

O

O

CH2Cl

O

O

CH2Cl

ClH2CClH2C

CH2Cl

ClH2C

OO

CH2Br

BrH2C

OO

CH2Br

H2C

O

O

Br

O

O

CH2Br

O

O

CH2Br

BrH2CBrH2C

176 177 178

179180

181 182

+

Scheme 59. a) benzene, 0°C–r.t., 20 hrs., 87%; b) hv (sunlight), EtOAc, 83%; [133] c) benzene, 10°C–r.t., 15 hrs., 88%; d) hv (sunlight), EtOAc, 181 - 18%, 182 - 63% [134].

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2651

the Diels-Alder reaction. The functionalization of the non-substituted Diels-Alder adduct 183 is very difficult as the presence of different functional groups (conjugated double bond and keto groups) significantly limits the possibilities for further synthesis. For example (Scheme 60), the conjugated double bond is readily

oxidized in mild conditions to the corresponding epoxide 184

[135,136], or reduced by Zn/AcOH and related systems – to the enedion 185 [137,138]. The double bond is also susceptible to dif-ferent types of nucleophiles [139,140] and it can take part in a [3+2]cycloaddition [141]. Additionally the system readily converts into the hydroquinone form 189 [110,142-144].

The non-conjugated bond usually is unreactive, however, there is at least one reaction that has to be mentioned.

The [3+2]cycloaddition of nitrile-oxides [145] (generated in

situ) to norbornene double bond is an efficient synthetic method to obtain isoxazolines (Scheme 61). This heterocycle can then be transformed into substituted norbornene derivatives in different ways (Scheme 62) [146-148].

Advantages of this method are:

• High yields • Available substrate (with no problem in respect to the exo-

/endo-isomers) • Variety of different available nitrile oxides (Table 7) • A high selectivity of the reaction, which can be used for in-

troducing functional groups to particular position of the norbornene moiety, Scheme 63) [150-152].

It was found that the conjugated system (O=C–CH=CH–C=O) undergoes de-aromatization under the same condition as this reac-tion (Scheme 64) [153,154], but the transformation to the hydroqui-none can be prevented, e.g. by masking of C=C bond with an epox-ide [155,156] or a hydroxyl group, or the transformation of the

O

O

O

O

O

O

O

O

O

O

Et

SPh

OH

OH

O

O

S

RR

184 185

186

187188

189183

O

Scheme 60.

A

BA

B

X

C

A

B

XO

N

Y

A

B

X

ZC

Z

X

C

Y

N

O

Scheme 61. A,B - keto-groups, ketals, hydroxyl groups (if they would not react under condition of pathway); C - protecting group that prevents any undesir-able reactions of the conjugated double bond, obligatory; X - substituent that will present in the resulting compound, obligatory; Y - COOEt, H, Br, etc; Z – a functional group, obtained based on Y, by different treatment.

O

N O

H

N

NO

N

N

NHO

NC

N

N

CN

O

N

O

N

Me

O

H

Me

N

O

c d e

f g, h

O

N

Me

OH

O

Me

a

190 191

O

Me

b

192

193 194 195 196

197 198 199

MeOSO3

Scheme 62. a) W-2 Raney Ni, AlCl3, MeOH/H2O (5:1); [146] b) PTSA (cat), acetone, reflux, 6 hrs, 64%; [149] c) Me2SO4, toluene, 50°C, 2-8 hrs.; d) NaNO2, H2O, r.t., 1-8 hrs.; e) TMG, toluene, r.t., overall yield for 3 steps 72%; [147] f) NEt3, reflux, 2days, 88%; g) BsCl, pyridine, 6.5 days, r.t., quant.; h) t-BuOK, THF, 30 min, quant [148].

2652 Current Organic Chemistry, 2012, Vol. 16, No. 22 Sharapa et al.

keto-groups to ketals or hydroxyls or the use of a 2-substituted ad-duct (Scheme 65).

Additionally, it was found that nitroalkanes can yield the same isoxazolines [168], but this method is more complicated due to reactivity of the nitroalkanes towards other functional groups in the adduct.

VI. FUNCTIONALIZATION OF C2 IN ADDUCT III

Treatment of epoxide 184 by a mixture of acetic and sulfuric

acid produces the acetoxy-adduct 205 [169]. Since the configura-

tion of the adduct does not change, it can undergo photocyclization to form the acetate of 9-hydroxy-Cookson diketone (Scheme 67). This is, perhaps, the simplest possible way to synthesis 9-substituted Cs-THC. The disadvantage of this scheme is similar to that of Scheme 8: the substituents of the THC-cage hardly change from one to another.

Different nucleophiles can react with trienedione 209, resulting

in the endo- adducts (Scheme 68) [170].

The question of the individual reactivity for adducts with dif-ferent substituents is still open. It was shown that the addition of

an arylsulfonyl group to the phenyl-substituted adduct 212 can successfully take place (Scheme 69) [172,173]. However, such addition is very sensitive to the solvent – the formation of the hy-

droquinone product (210, 213) is a concurrent process.

Despite the fact that the arylsulphuric substituents are probably not the best one, they can be useful for retrieving the endo- configu-

CH2OH CH2OHON CH2OH

O

N

Ph

Ph

+CH2OH

O

N

(EtO)2P

200201 202 203

O

a b

Scheme 63. a) (i-PrO)2P(O)C(Cl)NOH, NEt3, CH2Cl2, 12 hrs, 75%; b) PhC(Cl)NOH, NEt3, DMF, 1 min, 82%, 202:203=3:2.

Table 7.

N-oxide Precursor Ref

carbethoxyformonitrile oxide (CEFNO) EtO2C–C�N+–O-

O

O

N

Cl

OH

[157]

Cyanogens N-oxide (CNO). N�C–C�N+–O- NC N

Cl

OH

[158]

2-oxopropanenitrile oxide CH3–C�N+–O- Acetone + CAN [159,160]

trifluoroacetonitrile oxide CF3–C�N+–O- F3C N

Cl

OH

[161]

1,3-Dithiane of 2-Oxopropanenitrile Oxide

N

S S

Me C O N OH

S S

Me C

H

[162]

bromonitrile oxide Br–C�N+–O- Br N

Br

OH

[163]

benzenesulfonylcarbonitrile oxide PhSO2–C�N+–O- O

S

O

N

Br

OHPh

[164]

Me3Si C N O from Hg(CNO)2 and TMS-Br [165,166] fulminic acid HCNO

H N

I

OH

from Hg(CNO)2 and HI, KI

[167]

O

N

C

R

C

N

R

O

+

O

O OH

OH183 204

a

Scheme 64. a) Ethyl chloroximidoacetate, NaHCO3, [bmim]BF4, ionic liquid, r.t., 3-4 hrs., 72% (R = COOEt).

Table 8.

R Ref

Ph [153]

COOEt [154]

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2653

O

OX

OH

O

O

O

O

OO

O

OH

O

OH

RO

Adding substituents to C2 or C7

Transformation of keto-groups

O

Masking of double bond Combination of methods

H H

Scheme 65.

O

O

O

OAcO

OAc

OO

O

O

O

183 184 205 206

a b

Scheme 67. a) H2O2, NaHCO3, acetone/water, 10 min, 90%; [135] b) AcOH, H2SO4, r.t., 3 days, 50% [169].

O

O

Y

MeS

MeS

O

O

SMe

SMe

OH

OH

SMe

SMe

O

O

Cl

Cl

nucleophile

endo-isomer207 208 209 210

a, b c

Table 8

Scheme 68. a) NaSMe, MeOH, r.t., 87%; b) KHCO3, MeOH/H2O, reflux, 1 hr., 68%; [171] c) oxidation, no information is available.

Table 9.

Nucleophile

NaSMe Aziridine methanol Nitromethane, sodium salt Carbanion of acetamidomalonate

Y –SMe N

–OMe –CH2NO2 –C(COOEt)2NHCOMe

Endo, yield % 81 49 68 34 71

Exo, yield % – 12 23 6 –

OSO2Ph

OH

O

O

SO2Ph

SMe

SMe

MeS

MeS

O

O

SMe

SMe

OH

OH

O

O

SO2Tol

Ph

Ph

O

O

Ph

SO2Tol

a b

209210 211

212 214213

c d

TolO2S

OO

Ph

215

e

Scheme 69. a) PhSO2Na, DMSO r.t., 1 hr., 79%; [173] b) PhSO2Na, DME, 67%; [173] c) TolSO2Na·7H2O, AcOH, 80°C, 30 min, 68%, ratio 213:214 = 2.5:1 [172]; d) TolSO2H, THF, r.t., 5 hrs, 67%, ratio 213:214 = 1:7.3 [172]; e) hv, benzene, quant [172].

2654 Current Organic Chemistry, 2012, Vol. 16, No. 22 Sharapa et al.

O

O

O

O OO

OO

O

O

HOH2C HOH2C

O

O

O

O

CH2OH

OO

O

HOH2C HOH2C

HOH2C

HOH2C

HOH2C HOH2C

H

H

95%

quant

184

216a 216b

217

Scheme 70. a) DBU (0.1 equiv), 40% formalin, THF, 0°C, 95% [178]; b) DBU (2.1 equiv.), 40% formalin (excess), 0°C, quant.; compare 70 and 216b.

O

O

O

O

HOH2C

O

O

O

HOH2C

H

H

O

O

O

H

H

O

O

O

OTES

O

HOH2C

O

O

H

H

O

O

H

R R

OTESXY XY

O O O O

HOH2C

218 219 220 221

222 223 224 225

a

b

c

d

Scheme 71. a) DBU, 40% formalin, THF, 0°C, 65% (X,Y=O), 86% (X=OH, Y=H), 91% (X=H, Y=OH); b) DBU, 35% formalin, THF, 0 °C, 2 h, 92%; [183]

c) HCHO (3 equiv), DBU (0.5 equiv), THF, rt, 5 h, 94% [187]; also see [188] d) DBU, 37% formalin, THF, 0°C-25°C, 98% [181].

O

O

O

HOH2C

O

OH

O

TBSOH2C

O

OH

O

TBSOH2C

OAc

O

O

TBSOH2C

45%

46%

H

H

H

H

OH

O

O

HOH2C

H

215

226

228

(–)-227

(+)-227

a, b

c

d

Scheme 72. a) TBSCl, imid. DMAP, DMF, rt, 92%; b) NaBH4, MeOH, 15°C, 81%; c) Lipase PS-D (Amano), vinyl acetate, rt, 28h. [178]; d) DIBAL-H, THF,

–78°C, 65% [189].

ration of adduct once it is turned into the hydroquinone form (by

functionalization in the intended position). Another way is to use

the triene 209, followed by the removal of the methylsulfanyl sub-

stituents. For example, this can be done by changing the groups to

halogens [174] or by oxidizing and removing them after the forma-

tion of the cage [175-177]. Anyway, this pathway seems to be too

complicated and long.

The hydroxymethylation of epoxide 184 (Scheme 70) is a

much shorter and more interesting pathway, from our point of view

[178,179].

This high yield procedure can be applied to monoalcohols [180]

and monoketals [181] (only �-keto position is then functionalized),

adducts of fulvenes [182] and substituted quinones [183] (Scheme

71). The deoxygenation of the epoxide to the olefin is also not a

problem [184-186].

Regioselective reduction of one carbonyl group and the separa-

tion of the optical isomers can be done at this step as well (Scheme

72) [189]. This can simplify the Cs–D3 rearrangement (Scheme 27)

and the separation of the final compounds into the corresponding

enantiomers.

Furthermore the introduction of a halogen substituent in posi-

tion 7 can be useful for the following selective rearrangement

(Scheme 73) [190].

We suggest that this pathway can be successfully combined

with the [3+2]-cycloaddition of nitrile-oxides.

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2655

OH

O

O

TBSOH2C

H

228

OH

O

O

TBSOH2C

BrR R

229

a

OO

Br

HO

OCl

HO

BrHOH2C

Scheme 73. a) 1,2-dibromotetrachloroethane (2.0 equiv) DBU, CH2Cl2, r.t., 10 hrs, quant. R = allyl.

O

O

O

O

O

O

CH2

RO

O

OH

O

CH2

RO

O

OH

O

CH2

RO

O

N

C

Z

O

OH

OH

CH2

RO

HO

Y

O

OH

CH2

RO

Y

O

O

O

CH2

RO

O

N

C

Z

O

O

CH2

RO

Y

OH

OH

O

CH2

RO

OH

OH

CH2

RO

O

N

C

Z

OH

OH

CH2

RO

Y

OH

OH

CH2

RO

O

O

CH2

RO

CH2OR

O

O

Y

COOMe

O

Y O

O

COOMe

OH

Y

H2C

YOH

OH

OR

H2C

Y

O

O

O

CH2OH

OH

Y

CH2OR

OH

O

Y

CH2OR

Br

O

Y

CH2OR

Br

OH

Y

YX

Nu

YX

photocyclization

rearrangement

introduction of first target group

introduction

of

second

target

group

V

VI

VII

IX

VIII

XII

XIII

XIX

XIV

XV XVI XVII

XVIII XIX XX

XXVXXIIIXXI

XXII XXIV XXVI

XXVII

XXVIII

Scheme 74.

2656 Current Organic Chemistry, 2012, Vol. 16, No. 22 Sharapa et al.

O

O

HOH2C

H

OH

O

HOH2C

BrO

O

Br

HO

OCl

HOBr

HOH2C

O

O

O

H

H

O

N

Z

O

O

O

HOH2C

H

O

N

Z

Y

Y

Y

Ias it was described on previous

scheme

Y

XI XVIXXIX

XXX XXXI XXXII Scheme 75.

O

OR

R

Br

Br

O

OR

RO

O

R R

O

O

hindered

positionhindered

position

OO

R R

O

O

Y

CH2OHR = Me, Ph, etc XXXIII

XXXIV

OEt

OEt

OEtEtO

O

O

O

O

O

XXXV Scheme 76.

VII. GENERAL SYNTHESIS SCHEME

Hence, based on the reviewed methods and pathways above, the general pathways to 2,9-D3-trishomocubane can be drawn (Scheme 74). As a starting compound the readily available epoxide V can be used. First the substituent can be introduced into position 2 via hydroxymethylation. After that several options are possible: the [3+2]cycloaddition of nitrile-oxides can be done directly, either after the reduction of one carbonyl or after the deoxygenation of epoxide and the reduction of both carbonyls. The opening of the heterocycles followed by a dehydration of the alcohols should result in disubstituted adducts (XV-XVII), and adduct XVI, which can be converted into the other two (XV and XVII).

The Cs-trishomocubane derivatives XVII-XX (obtained by pho-tocyclization of adducts XV-XVI, respectively), can be converted into one another by reduction-oxidation steps. Thus, independently from the first synthetic steps, at least three independent pathways for the formation of suitable monoalcohol derivative for the rear-rangement can be proposed:

1) Selective ketalization or thioketalization of 9-substituted diketone XIX, followed by reduction of the second carbonyl group and removal of the protecting one (via Ni-Ra for thioketal or via deprotection and Wolf-Kishner reduction);

2) Changing of the hydroxyl group into ketoalcohol XX to bromine followed by reduction of the carbonyl;

3) Protection of one hydroxyl group in XVIII by the formation of an acetonide XXI, followed by the oxidation of the second hy-droxyl group and the reduction of the carbonyl as it was described before.

The monoalcohols XXII, XXIV, XXVI can undergo rear-rangement to form the D3-THC-derivative XXVII, which after removal of all useless halo- and hydroxy- groups gives the targeted “diaxial-substituted D3-THC” XXVIII.

Certainly, lots of disadvantages of this general scheme can be found during the synthesis itself, for example the lack of selectivity during cycloaddition of nitrile-oxides, or some problems with the rearrangement. If the first problem cannot be solved by the change of substrates (VI, IX, XII) and/or nitrile-oxides, then changing the order of steps can be used – addition of nitrile oxides to epoxide V followed by a selective hydroxymethylation (Scheme 75). Also rearrangement of the Cs-diketones by chlorsulfonic acid can be tried, with or without C10 substitution (XIX, XXXI). The big vari-ety of methods and substrates, described in this review give hope that any difficulties can be avoided.

Another possibility to increase the selectivity of the nitrile-oxide addition and the hydroxymethylation is by using the chiral ketals XXXIV (Scheme 76). Although, adducts of such type have never been reported before, one can expect that the corresponding cyclopentadienoneketals XXXIII could be less reactive than CPD

Axial D3-trishomocubane Derivatives with Potential Current Organic Chemistry, 2012, Vol. 16, No. 22 2657

ethylene ketal because of steric hindrance. Also the ketal XXXIV can possibly be synthesized from the triketone XXXV.

VIII. CONCLUSIONS AND FUTURE PERSPECTIVES

The D3-trishomocubane is one of the few molecules belonging to the D3 point symmetry group and despite the high symmetry has a chiral cage structure. C3-symmetry axe is also retained in 2- and 2,9- derivatives of D3-trishomocubane. While such derivatives have great potential to be used as scaffolds for drugs, in structure-oriented design, asymmetric catalysis, rigid axial rods, light-driven systems etc., they still remain to be elusive. The direct functionali-zation of D3-trishomocubane usually leads to formation of 4-derivatives. As an alternative methodology rearrangement of Cs-trishomocubane derivatives to corresponding D3-trishomocubane can be used. However, in such case the major problem is also func-tionalization of Cs-trishomocubane. Consequently, functional groups should be already present from the beginning, either in cy-clopentadiene or quinone or to be introduced upon functionalization of the adduct.

Based on the extensive retro-synthetic analysis a general scheme for the synthesis of 2- and 2,9- derivatives of D3-trishomocubane is suggested. All steps of the proposed scheme are reviewed and discussed.

Although D3-trishomocubane is known for more than four dec-ades, its chemistry is still insufficiently studied. Further investiga-tions on the chemistry, reactivity and biological properties of such compounds are required. We hope that this review will instigate such studies.

CONFLICT OF INTEREST

The author(s) confirm that this article content has no conflicts of interest.

ACKNOWLEDGEMENTS

This work was supported by the State Basic Research Fund of Ukraine (grants from the President of Ukraine to young scientists 2005-2011). We thank “Macrochem” and “UkrOrgSynthesis” for their support.

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