Preparation of steroid-like compounds via acid promoted olefinic cyclizations

Preparation of steroid-like compounds via acid promoted

olefinic cyclizations

Citation for published version (APA):

Corvers, A. (1977). Preparation of steroid-like compounds via acid promoted olefinic cyclizations. Technische Hogeschool Eindhoven. https://doi.org/10.6100/IR121700

DOI:

10.6100/IR121700

Document status and date: Published: 01/01/1977

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PREPARATION OF STEROID-LIKE COMPOUNDS

VIA ACID PROMOlED OLEFINIC CYCLIZATIONS

PREPARATION OF STEROID-LIKE COMPOUNDS

VIA ACID PROMOTED OLEFINIC CYCLIZATIONS

PROEFSCHAl FT

TER VERKRIJGING VAN DE GRAAD VAN DOCTOR IN DE TECHNISCHE WETENSCHAPPEN AAN DE TECHNISCHE HOGESCHOOL EINDHOVEN, OP GEZAG VAN DE RECTOR MAGNIFICUS, PROF.DR. P. VAN DER LEEDEN, VOOR EEN COMMISSIE AANGEWEZEN DOOR HET COLLEGE VAN DEKANEN IN HET OPENBAAR TE VERDEDIGEN OP

VRIJDAG 4 MAART 1977 TE 16.00 UUR.

DOOR

ANTONIUS GORVERS

Dit proefschrift is goedgekeurd door de promotors

prof. dr. H.M. Buck en

Aan mijn ouders Aan Elly

Man bas been up against Nature;

from now on he will be up against bis own nature.

Chapter

Chapter

Chapter

I

Contents

General introduetion

1.1 The biosynthesis of stePaids

1.2 Heteroeyelie stePaids RefePenaes and Notes

11 Model reactions for A-B ring closure reactions of thiophene containing compounds

11.1 IntPoduetion

11.2 Synthesis and eyalization of A-B Ping elosure model systems

11.3 Experimental

Heferenoes and Notes

111 Synthesis of thiophene containing steroid-like molecules via olefinic cyclization reactions

III.1 Introduetion

111.2 Thiophene ineoPporation in (E)-and (Z)-alkenes: precursors for steroid-like eompounds

111.3 Aeid,promoted cyclization ex-pePiments of the (E}- and (Z)-olefinio systems

III.4 Discussion of the expePimental ratio (E/Z) of isomers obtained from the Wittig reaetion

9

16

Chap'ter

Chap'ter

Chap'ter

III.S The Stork-Eschenmaser hypo-thesis

111.6 Vivo versus vitro cycZizations

III.7 ExperimentaZ

Beferences and Notes

1\/ Alternative syntheses for precursors of tetracyclic compounds

IV.1 Introduetion

IV.2 Syrithesis of (E)-aZkene pre-cursors via the Wadsworth-Emmons reaction

IV.3 Synthesis of (E)-aZkene pcursors via the CZaisen re-arrangement

IV.4 ExperimentaZ

Referenaes and Notes

" Synthesis of thiophene analogues of estrone: 13c-NMR measurements of these compounds and their precursors

V.1 Synthesis of thiophene analogues of estrone

V.2 Evidenae for the trans~anti~trans

geometry in the tetracycZia products

V.3 EzperimentaZ

Referenaes and Notes

44

57

"I

Quanturn mechanica! calculations on 71

cyclization reactions; a MIND0/3 study VI.1 Introduetion

VI.2 Calculations on the cyclization of the 2-but-3-enyZ ayaZopentenyZ cation

SuJDJDary

SaJDenvattÎng

Levensloop

Dank-vvoord

VI.3 Cyelizations of the (E)- and (Z)-2-pent-3-enyl eyelopentenyl eation

Refe~enees and Notes

82

84

86

CHAPTER

I

General introduetion

1.1 The biosynthesis of steraids

Research in the field of olefinic cyclization reactions, occurring in vivo as well as in vitro, was particularly

stimulated by the discovery of enzymatic processes in which squalene is synthesized from activated acetic acid, present in biosystems as acetyl coenzyme A (acetyl-CoA)1_- 3_{• The in vivo} synthesis of squalene starts with a number of steps by which acetyl-CoA is converted into mevalonic acid. The latter com-pound is subsequently converted into an equilibrium mixture of dimethallyl and isopentenyl pyrophosphate. Coupling of "activa-ted" isoprene (2-methylbuta-1,3-diene) 12:, withits isomer 1È_

yields geranyl pyrophosphate (~) which on its turn is coupled with another molecule isopentenyl pyrophosphate (.:!2:,) to give

farnesyl pyrophosphate

Cl)·

In a final step squalene (~) is formed by the tail to tail linkage of two farnesyl units4

• The energy for these enzymatically catalyzed reactions is supplied by the energy-rich molecules ATP (~denosine IriEhosphate) and NADPH₂ (reduced ~icotin-amide-~denosine-ginucleotide-Ehosphate);

ATP is used for the synthesis of isopentenyl pyrophosphate, while NADPH₂ plays a crucial role in the coupling of the two farnesyl pyrophosphate units (fig. 1.1). Squalene acts as the general precursor for steroid-synthesis in animal and ve-getable life. Depending on the particular organism squalene or 2,3-epoxysqualene is enzymatically converted into one of the several classes of steroids, consisting of tetra-and pentacyclic compounds. The conversion of squalene into lanosterol is well documented (see Chapter III.6). Another

...

1 tT 3 4 OH I _ _ .,..,.. HOOC-CH-C- CH -CH OH 2 I 2 2

...

19. CH3 CH₂

'

C-CH-CH-OPP / 2 2 CH₃ 2

Fig. 1.1 Biosynthesis of squalene starting from activated acetic acid

reaction path leads to cycloartenol ~ which replaces lanos-terol as the principal triterpene in higher plants. Still

another example forms the conversion of squalene into 6-amyrin §_.

H

HO HO

5

Intriguing is the stereospecificity of these enzymatically formed steroids. In some structures the trans,anti,trans

geometry has been established (dammaradienol l), while in other systems a syn substitution pattern is found. This phe-nomenon has been explained in terms of folding on the enzyme. If 2,3-epoxysqualene is folded in a chair-chair-chair confor-mation, dammaradienol

l

is formed while

(precursor for

i)

is generated from the conformation (see also Chapter III.6).

~ H -~

.

.

-"' HO 7 protolanosterol ~ chair-boat-chair 8

From the examples given, it goes without saying that the enzyme plays an essential role in these cyclization reactions as is outlined in Chapter III.S.

1.2 Heteroeyclic steroida

Since the discovery of hormones and their function in the human body, organic chemists became interestad in the synthesis of modified steroid systems, mainly for the pur-pose to get more insight into the structure-activity

relation-ship, but also to study the biologica! activity of modified steraids as such. A special group of modified steraids are those containing hetero-atoms5

• In most cases it concerns compounds in which one or two carbon atoms from the steroidal skeleton (positions 1-17) are replaced by nitrogen, oxygen and/or sulphur atoms. The synthesis of a great number of these compounds occurs analogous to the Torgov synthesis for carbocyclic steraids (fig. 1.2).

0 HO

~

~MgB, ~

eH O

3

)lXJ__Y)

c~o

Áxv

Áv

y)

0

'fJ

base 0 0

Fig. 1.2 Synthesis of heterocyclic steroid systems according to the Torgov synthesis (X and Y are hetero-atoms)

Using 2-methylcyclohexane-1,3-dione insteadof 2-methylcyclo-pentane-1,3-dione the corresponding D-homo steraids are syn-thesized. The 13-aza-analogs become available when succinimide is used insteadof the 1,3-dione. Cyclodehydratation is

brought about by phosphorusoxychloride and subsequently hydragenation of the formed iminium salt affords the 13-aza-steroids. Other entries in the field of heterocyclic steraids

were developed by the application of the Diels-Alder reaction and condensation reactions between hydrogenated pyridazines and (di)enamines. However, no st.erochemical difficulties are encountered in the preparatien of the majority of hetero-cyclic steroids, for these compounds possess double honds between the positions C(8)-C(9) and C(14)-C(15). Conversion of these systems into the saturated structures with the spa-cial geometry most commonly found in nature (e.g. tPans~anti~ tPans on C(9), C(8) and C(14)) is achieved in only poor yield (S-101) by a five-step reduction-oxidation sequence.

5 steps

Fig. 1.3 Preparatien of 6-aza-, 6-oxa- and 6-thiaestrone methyl ether

From this point of view the synthesis of heterocyclic analogs of steraids is not attractive.

This thesis deals with the synthesis of the two possible estrogens, having thiophene as A ring. In Chapter II the reactivity of thiophene towards electrophiles is discussed, foliowed by the synthesis and cyclization of two thiophene derivatives under mild reaction conditions.

Chapter III describes the synthesis of thiophene con-taining steroid-like molecules. The required precursors were prepared via a modified Wittig reaction, with special atten-tion on the dependenee of the E/Z ratio on the base used. The most favourable conditions were applied for the prepara-tion of (E)- and (Z)-alkene precursors. It was found experi-mentally that only the (E)-alkene derivatives could be converted into tetracyclic compounds.

In Chapter IV two alternative routes are discussed, which both yield pure (E)-alkene precursors, in contrast to the methad given in Chapter III (via the Wittig-Schlosser reac-tion), which yields products contaminated with 5-10% of the other isomer.

Special attention is paid to the stereogeometry of the epoxide ring during the desired

0

,2] methyl shift from C(17) to C(13): "estrone" formation takes place in case of the a-epoxide, while a mixture of dienes was isolated under the same reaction conditions starting from the ~-epoxide. The

t~ans~anti>t~ans contiguration on the junction atoms, most commonly for natura! steroids, was confirmed by the 13c-NMR measurements.

In order to obtain more quantitative data, quanturn roe-ehanical calculations were performed on model systems for D-C ring closure. The results confirm the Stork-Eschenmoser hypothesis: cyclization takes place via the chair conforma-tion and ring closure of (E)-alkenes is energetically favoured with respect to (Z)-alkenes.

Referenaes and Notes

1. R.B. Clayton, Quart. Rev •• lQ_, 168 (1965) and references therein

2. J.W. Cornforth and G. Popják, Biochem. J.,

lQl,

553 (1966); J.W. Cornforth, Quart. Rev., ~. 125 (1969)

3. I.D. Frantz and G.J. Schroepfer Jr., Ann. Rev. Biochem., 36, 691 (1967); C.J. Sih and H.W. Whitlock, Ann. Rev. Biochem., 37, 661 (1968)

4. L.J. Mulheirn and P.J. Ramm, Chem. Soc. Rev., .!_, 259 (1972)

5. H.O. Huisman, Bull. Soc. Chim. Fr., (1968) 13; Angew. Chem. ,

g,

511 ( 19 71)

CHAPTER

11

Model react:ions :tor A-B ring ciosure react:ions

o:f t:hiophene. cont;aining coiD.pounds

II.1 Introduetion

Soon after the discovery of thiophene1 _{its reactivity in} electrophilic reactions was established. Thiophene reacts very rapidly with a number of electrophilic reagents (chlorine, bromine, pyrosulphonic acid, sulphuric acid and nitric acid) to yield mono- and polysubstituted thiophenes1 _{depending on the}

reaction conditions. No catalyst is required for these reac-tions. On the other hand, acyl- and alkylthiophenes are formed only under Friedel-Crafts conditions. Lewis acids, such as aluminum chloride, stannic chloride and boron trifluoride com-plexes, and Br~nsted acids as 85% orthophosphoric acid, hydro-fluoric acid or sulphuric acid bring about these reactions1_•

The sequence of addition of the reactants is very important. Aluminum chloride, for example, rapidly polymerizes thiophene. During the aluminum chloride catalyzed acylation of thiophene, special conditions must be maintained to avoid resinification. The acyl group is selectively introduced on the 2-position in contrast to alkylation in which a 1:1 mixture of 2- and 3-alkylthiophenes is formed. Intramolecular ring closures starting from acid chlorides were carried out by Fieaep et al.2

and Cagniant et aZ.3

• They found that thienylbutanoyl and

thienylpentanoyl chloride are converted into the fused six-and sevenmembered ring compounds (fig. 2.1) under Friedel-Crafts conditions.

Recently, Loozen,. found that benzo

[Q.]

thiophenes are easily accessible from suitable functionalized thiophenes.

("o

n

R

O~MgBr

"-sy

THF . 0

~

's~

R=H,alkyt

Fig. 2. 2 Synthes is of ben zo

[Q.]

thiophenes, s tarting from alkanoylthiophenes

R

Treatment of alkanoylthiophenes with the Grignard derivative of 1-(1,3-dioxolan-2-yl)-2-bromoethane ( . 2.2) yielded the expected alcohols which were subrnitted to the action of 10% refluxing sulphuric acid tobring about hydrolysis, cyclization and aromatization to the benzo

[Q.]

thiophenes.

In 1970 Gourier and Canonne5 _{reported the ring closure}

of substituted 5-(2-thienyl)pent-1-enes under rather drastic conditions (acetic acid with 5 vol. % sulphuric acid at reflux)

R=H,olkyl

Fig. 2. 3 Synthesis of tetrahydrobenzo

[Q.]

thiophenes

to gi ve the corresponding 4, 5, 6, 7 -tetrahydrobenzo

[Q.]

thiophenes

via the secondary carbocation interrnediates (fig. 2.3). This once more emphasizes the reactivity of thiophene in electro-philic reactions.

II.2 Synthesis and ayaLization of A-B Ping aLosuPe modeL systems

In order to establish the reactivity of thiophene towards relatively mild electrophiles, ring ciosure of the easily accessible compounds 3a and 3b was studied. Their preparation and cyclization is outlined in fig. 2.4 and fig. 2.5.

0

1. BuLi S

~J

1

THF

2.Br o 4a

n

oJ

H,O+

1 a H 0

( 0

2a 3a

Fig. 2.4 Synthesis of 4,4-dimethyl-4,5,6,7-tetrahydrobenzo[~J­ thiophene

Thiophene was lithiated in tetrahydrofuran at -20° to afford 2-thienyllithium which on treatment with 1-(1,3-dioxolan-2-yl)-2-bromoethane yielded acetal ~· Hydralysis of the acetal moiety of~ produced 3-(2-thienyl)propan-1-al (Za) which was converted into alkene 3a after reaction with isopropylidene triphenylphosphorane. Compound 3a failed to cyclizise in cold formic acid, but was rapidly converted into the bicyclic

pro-duct~ in formic acid with 10 vol. % trifluoroacetic acid or in methylene chloride with 25-50 vol. l trifluoroacetic acid. In a similar reaction sequence alkene 3b was prepared starting from 3-bromothiophene6 _{as precursor for 3-thienyllithium}7

0

l Buli

oJ

Ha+

((Jo

!.

3

A

Br

~J,THF

2. Br o 1 b 2 b

(rPPh,

oO

CF3 COOH

ö)

CH 2Ciz 4 b 3 b

Fig. 2.5 Synthesis of 7,7-dimethyl-4,5,6,7-tetrahydrobenzo[~J­ thiophene

Again in methylene chloride with 25 vol. % trifluoroacetic acid a rapid ring closure led to 4b. These results are in good agreement with the observations of Gourier5

(vide supra). !1.3 Experimental

General remarks

1H-NHR data were obtained on a Varian A60 using TMS (8=0.0) as internal standard. 13c-NMR data were recorded on a Varian HA 100 equipped with a Digilab FTS-NMR-3. IR spectra were measured on a Perkin-Elmer 237. Microanalyses were

carried out in our laboratories by Messrs. P. van den Bosch and H. Eding.

• 1-(1 ,3-Dioxolan-2-yl)-2-(2 thienyl)ethane (la)

To a salution of 17 g (0.2 mol) of thiophene in 60 ml of tetra-hydrofuran, 100 ml of n-butyllithium (20% in hexane) was added dropwise at -20° under a nitrogen atmosphere. The mixture was stirred for 2 hr, whereupon 36 g (0.2 mol) of 1-(1,3-dioxolan-2-yl)-2-bromoethane8 was added. After 1 hr the reaction mixture

was allowed to warm up to room temperature and left overnight. The reaction was quenched with water and the product isolated by ether extraction. Drying, remaval of the solvent and dis-tillation gave 24.1 g (75%) of product, bp 65-68° (0.005 mm). NMR (CC1

4): 6 1.80-2.20 (m,2,C~

2

CH

2

Th); 2.82-3.15 (m,2,C~

2

Th); 3.70-4.10 (m,4,dioxolane protons); 4.88 (t,1,C~); 6.75-7.15

(m,3,Th-~).

• 1-(1,3-Dioxolan-2-yl)-2-(3-thienyl)ethane (~)

Under a nitrogen atmosphere a salution of 66.0 g (0.4 mol) of 3-bromothiophene in 100 ml of tetrahydrofuran was added drop-wise to ZOOmlof n-butyllithium (20% in hexane) at -70°. After 1 hr 72.5 g (0.4 mol) of 1-(1,3-dioxolan-2-yl)-2-bromo-ethane8 was added. The reaction mixture was stirred for 4 hr at -70° and for 1} hr at 25°. Water was carefully added to destray organolithium compounds. Aqueous work-up yielded 33.2 g (45%) of product, bp 75-80° (0.005 mm).

~ 3-(2-Thienyl)propan-1-al (Za)

A mixture of 18.4 g (0.1 mol) of~. 60 ml of tetrahydrofuran and 140 ml of N hydrochloric acid was stirred vigorously under reflux. After 1! hr the reaction mixture was poured into water and extracted with ether. Drying and evaporating of the ether yielded crude aldehyde which was distilled to give 11.2 g

0 -1

(80%) of product, bp 60 (0.7 mm). IR (nujol): 1720 cm (C=O). NMR (CC1₄): 6 2.60-2.92 (m,2,C~

₂

CHO); 2.95-3.35 (m,2,C~

₂

Th);

6.73-7.22 (m,3,Th-~); 9.79 (t,1,C~O).

~ 3-(3-Thienyl)propan-1-al (2b)

This compound was prepared analogous to 2a, bp 65° (0.5 mm).

~ 2-Methyl-5-(2-thienyl)pent-2-ene (3a)

To a suspension of 21.6 g (0. OS mol) isopropyltriphenylphos-phonium bromide9 _{in 40 ml of tetrahydrofuran was added 34 ml of} n-butyllithium (15% in hexane) at 15° (nitrogen atmosphere). To the clear deep-red salution 6.6 g (0.05 mol) of Za in 10 ml of tetrahydrofuran was added. Aqueous work-up afforded 5.5 g

(d,6,2x C~

₃

); 2.13-2.62 (m,2,C~

₂

CH

₂

Th); 2.73-3.17 (m,2,ThC~

₂

);

5.10-5.45 (m,1,C~); 6.72-7.25 (m,3,Th-~).

• 2-Methyl-5-(3-thienyl)pent-2-ene (3b) Preparedas for 3a, bp 72-74° (3 mm).

• 4, 4-Dimethyl-4 ,5 ,6, 7-tetrahydrobenzo

[2J

thiophene ( 4a) A salution of 2.0 g (0.012 mol) of 3a in 5 ml of methylene chloride was added to a mixture of 15 ml methylene chloride and 5 ml of trifluoroacetic acid at room temperature. After

!

hr the reaction mixture was poured into water and the pro-~

duet extracted into petroleum ether 40-65. Drying and stripping off the solvent yielded 2.0 g of crude product. Filtration over a silica column (petroleum ether 40-65 as eluens) gave 1.8 g (90%) of pure 4a, bp 88-90° (10 mm). NHR (CC1₄): ó 1.34 (s,6,2x C~

₃

); 1.48-2.06 (m,4,2x C~

₂

); 2.35-2.75 (m,2,ThC~

₂

);

6.83 (AB pattern,2,Th-~).

• 7, 7-Dimethyl-4, 5 ,6, 7-tetrahydrobenzo

[!?.]

thiophene ( 4b) Preparedas for 4a, bp 90-92° (10 mm).

RefePenaes and Notes

1. A. Weissberger, "The Chemistry of Heterocyclic Compounds", Volume III, H.D. Hartough, Thiophene and lts Derivatives,

Interscience Publishers Inc., New York, N.Y., 1952, Chapters 6, 7 and 8 and references cited therein.

2. L.F. Fieser and R.G. Kennelly, J. Amer. Chem. Soc.,~.

1611 (1935).

3. P. Cagniant and J. Deluzarche, Compt. Rend., 222, 1301 (1946); P. Cagniant and D. Cagniant, Bull. Soc. Chim. France, 1152 (1956); ibid. 62 (1953); ibid. 680 (1955). 4. H.J.J. Loozen and E.F. Godefroi, J. Org. Chem., ~. 1056 5. 6. 7. 8. 9. (1973). J.

s.

P. G. G.

Gourier and P. Canonne, Can. J. Chem., ~. 2587 (1970). Gronowitz, Acta Chem. Scan.,~. 1045 (1959).

Hoses and S. Gronowitz, Arkiv. Kemi., ~. 119 (1962). Buchi and H. Wuest, J. Org. Chem., 34, 1121 (1969). Wittig and D. Wittenberg, Ann. Chem., 606, 1 (1957).

CHAPTER

111

Synthesis of thiophene containing steroid-like

Inolecules via olefinic cyclization reactions

III.1 Introduation

In the last two decades much progress has been made in the field of steroid synthesis. The elucidation of the mecha-nism of the biosynthesis of lanosterol from 2,3-epoxysqualene strongly accelerated the development of model compounds. On the whole acid promoted cyclization reactions (one of the basic concepts of the in vivo synthesis) afford a general approach for the synthetic preparatien of estrogens. The strategy for this type of cyclization is outlined in Chapter I. Recently, progesterone1 _{and estrone}2 _{have been synthesized} in this way. In a multi-step sequence P.A. Barttett and

w.s.

Johnson prepared

1

and converted this compound in one step to the basical structure ~. a precursor for estrone (fig. 3.1).

RO RO

2

Fig. 3.1 Olefinic cyclization reaction as key-step in the synthesis of estrone

Based on the outlined synthetic approach, modified compounds of type

1

(fig. 3.1) were prepared with thiophene as A-ring, as will be described in Section III.Z.

III.2 Thiophene incoPpoPation in (E)- and (Z)-alkenes: pPeaursors for steroid-like aompounds

Thiophene was taken as A-ring for several reasons: (i) The ring is iso-electronic with benzene.

(ii) The presence of sulphur creates an active site which may be of importance for model studies under vivo conditions. Since the cyclization can be generated via a 2- and 3-sub-stituted thiophene, the presence of sulphur can manifest itself in quite different ways.

(iii) The high reactivity för electrophilic substitution reaction which is well documented.

As a start the preparatien of compounds

1

was undertaken following the method of P.A. Bartlettand

w.s.

Johnson2 _•

1\

-Y

o

r)o

o

.

+

Th ~ Ph/ 0 0 1g, Th=2-thienyl ~Q. Th=3-thienyl Th 7a- d

\_/

H OH

1 \

0 0 Rli THF Th (R=o-Bu,Ph)

lÖ

Th~

1 -6a-d Fig. 3.2 Preparation of thiophene containing precursors

for olefinic cyclization reactions

Surprisingly, the Wittig reaction of 3a and 3b with ylid _!3 under Schlosser conditions (see Section 111.4) with n-butyl-lithium as base (fig. 3.2, R=n-butyl) afforded in excess

the (Z)-disubstituted olefins Sc and Sd, respectively (E/Z=O.l). The (Z)-configuration was firmly established with 13c-NMR

spectroscopy by the method of de Haan and van de Ven4 •5•

However, the (E)-alkenes are necessary to obtain complete cyclization as will be shown in Section 11!.3. It has been claimed2 _{that the Wittig Schlosser reaction, performed with}

3-phenylpropan-1-al and ylid _!, yields the (E)-alkene con-taminated with only 2% (Z)-isomer. Our finding prompted us to reinvestigate this reaction; the results are gathered in Table III.l.

Table III.l E/Z ratio of the product from the reaction of 3-phenylpropan-1-al with ylid ±in dependenee of the base (reaction carried out in THF at specified temperature)

base (solvent) temperature time a) ratio E:Zb)

n-BuLi (hexane} 20° 70 h 50:50

n-BuLi (hexane) -50° 24 h 10:90

n-BuLi (hexane) -30° 3 h 50:50

n-BuLi (hexane) -30° ~ h 50:50

n-BuLi (hexane) -30° 1 5 min 60:40

2 n-BuLi (hexane) -30° 5 min 40:60

2 tert-BuLi (hexane) -30° 5 min 75:25

2 tert-BuLi (hexane)c) -30° 1 h 90:10

PhLi (benzene/ether) -78° 5 min 95: 5

a)time between the extra addition of base and quenching of. the betaine anion (25, fig. 3.9) with methanol; b)as deter-mined with 13c-NMR;-c)2.5 equivalents lithium perchlorate are added before the addition of the extra base

The results clearly demonstrate a considerable influence of the base used. Also a salt effect is established. Sehtosser and ao-workers6_•7_{paid no attention to the influence of the} base in the oxaphosphetane (~, fig. 3.9) isomerization pro-cess. Corey8

, on the other hand, obtained the best results

using n-BuLi or sea-BuLi in the Wittig-Schlosser reaction.

Andereon et at.9 _{observed no isomerization of the}

interme-diate oxaphosphetane in the synthesis of gossyplure by em-ploying sodium diisopropylamide as base, whereas Zeeten10

obtained good results by using phenyllithium. From Table III.1 it may be concluded that the Wittig-Schlosser reaction, performed at -78° with phenyllithium as base, gives a rather high yield of the (E)-alkenes. This condition for the re-action of the aldehyde and 3b with ylid

i

yielded 90% of the (E)-isomers Sa and Sb and 10% of (Z)-isomers Sc and Sd (determined by 11"ë-NMR:-:ee fig. 3.2). Hydrolysis-;;-f diketals ~ foliowed by cyclodehydratation gave cyclopen-tenones 6a-~. Lithium aluminum hydride reduction at -30° afforded the cyclopentenals 7a-~ in almest quantitative yield which, due to their susceptibility to dehydratation, were used without further purification.

III.3 Aeid promoted eyatization experiments of the (E)-and (Z)-otefinia systems

The (E)-olefinic compounds 7a and 7b could be converted into the tetracyclic products and (see fig. 3.3).

Tin tetrachloride promoted cyclization (in methylene chloride) proved to be the most effective procedure. The use of excess tin tetrachloride lowered the yield as could be confirmed by performing the reaction at higher temperatures.

Lower yields were also found in the formolysis of compounds 7a and 7b (at 0°, or at room temperature) and in cyclization experiments with nitromethane.

70 7b

!

Sn Ct₄ CH 2

ct

2 CH₃ 8a 8 b Fig. 3.3 SnC1

4 promoted ring ciosure of (E)-alkene precursors The moderate yield of tetracyclic products Cabout 50%) may be due to polymerization of the thiophene nucleus, caused by the action of Lewis acids on thiophene. Furthermore, it was observed, that (E)-isomers 7a and 7b, containing about 10% of (Z)-isomer ~ and 7d, gave relatively low yields of tetra-cyclic compounds as was the case with the products, free of (Z)-isomer.

The behaviour of alkene precursors 7c and 7d in cycli-zation experiments was quite different from that of the eer-responding (E)-isomers. The farmer substances failed to give tetracyclic compounds when treated with formic acid at 0° or with tin tetrachloride in methylene chloride at various temperatures. Low temperature NMR studies revealed that neither cyclopentenol 7c nor cyclopentenene 6c could be converted into tetracyclic compounds, even in the presence of the very streng fluoro sulphonic acid. In the case of 6c the carbonyl group was protonated. Excess acid only brought about protonation and polymerization of the thio-phene with the (Z)-double bond unaffected. The conversion of cyclopentenol 7c into the corresponding chloride was

0

achieved with thionyl chloride at -20 (S0

2ClF or cn2c12 as solvent). Addition of aluminum chloride caused

resini-fication of the product. No tetracyclic compound was observed. In the literature, little attention is paid to the cycliza-tion of polyenes. Only small ring cyclizacycliza-tions of (Z)-alkenes are reported11_{• Formalysis of (Z)-sulphonate ester}

~12 _,1 _{3 gives the cis-monocyclic alcohol~ and the epimeric}

mixture of the cis-2-decalols

l l

(fig. 3.4 eq (1)).

H

.

ct)

+

: H H

QY--w

\ _ ) 0 H

+

12 13 15

Fig. 3.4 Cyclizations of (Z)-alk'enes

!;I I

ctrOH(1)

.

.

H 11 H

w

(2) 0 H 14 (3)

Another example of (Z)-alkene cyclization is given by

w.s.

Johnson14 _{and D.J. Goldsmith}15 _{(fig. 3.4 eq. (2)), who}

per-formed the cyclization of the (Z)-dienic acetal ~ which -after a degradation and oxidation sequence- yields a mixture of cis-decalones and • An unexpected result was obtained by Eschenmoser16 _{(fig. 3.4 eq. (3)) by ring closure of 15}

Stork17

, however, proved that the boron trifluoride

cata-lyzed cyclization of the closely related farnesic acid pro-ceeds by a two step mechanism. After cyclization and depro-tonation a monocyclic product was isolated which was fully identical with the product acquired from the ring ciosure of the (E)-isomer cyclization. Reprotonation and ring closure yielded the trans bicyclic product ~· It is evident, that the last mentioned reaction mechanism must be quite different from the other two reactions mentioned in fig. 3.4. Cycli-zation of the all (E)-isomers of the alkenes of fig. 3.4 (eq. (1) and (2)) yields products with the opposite stereo-geometry. The high stereoselectivity o~ the discussed re-actions are in full agreement with the predictions of the Stork-Eschenmoser hypothesis (Section III.S).

III.4 Diseussion of the experimentaZ ratio (E/ZJ of isomers obtained from the Wittig reaation

Undoubtedly, the Wittig reaction18 _{is one of the most} im-portant methods for the synthesis of olefinic systems. This reaction has been used for the preparation of di-, tri- and tetrasubstituted olefins. The sequence of the reaction con-sists of three steps. Addition of a phosphorane

lL

to an aldehyde (or ketone) gives the intermediate betaines 18a and 18b (fig. 3.5). After the formation of the phosphorus-oxygen bond a fast eliminatien of trialkylphosphine oxide from the oxaphosphetanes 19a and 19b occurs by syn-elimi-nation leading to the (E)- and (Z)-olefins. Certain features of the reaction are well established. Non-stabilized phos-phoranes (e.g. ~) give an excess of (Z)-olefins, contrary to stabilized phosphoranes and phosphonoacetates (e.g. ~

and ~. fig. 3.6) which yield (E)-alkenes predominantly. Kinetic studies have shown a slow and reversible formation of the betaines 23a and 23b from resonance stabilized phos-phoranes. Preferential formation of the threo betaine 23a is observed in the reaction of stabilized phosphoranes with

l

Fig. 3.5 Reaction mechanism for the Wittig reaction

+-Ph3 P-CHMe - - - +-Ph3 P=CHMe 20 •0

+

- / I Ph 3P-èH-C-0Et _,. _____ .,. .... Ph3 P= CH-COOEt

n

o

•o

( ) 11 __ -,' l RO P-CH-C -OEt 2

l l

/

R3-cHO + R1 ₃-P= CHR 2 23o

'

H R3 R2 H

Fig. 3.7 Wittig reaction with stabilized phosphoranes

aldehydes. Due to the relatively slow eliminatien of tri-phenylphosphine oxide, the intermediate betaines 23a and 23b have a better chance to equilibrate leading .to the for-mation of the most stable isomer

(e.g.

2 ~23b). This thermodynamically controlled reaction course is in contrast with the kinetically controlled reaction products generated

from non-stabilized phosphoranes. Phosphonoacetates (~)

behave in a similar manner as the phosphoranes

ll·

In the presence of lithium salts, the betaines are strongly solvated with lithium ions, so that the rate of the forward reaction is lowered to such an extend that it becomes determining for the over-all rate of formation. Betaine re-versibility becomes important; interconversion to the most stabie betaine (the threo form) is favoured which leads to the (E)-olefin. A considerable dependenee on salt cation concentratien is found for the Wittig reaction in non-polar solvents, thus increases the amount of (E)-isomer. Exclusion of metal salts in non-polar solutions of ylids during the

Wittig reaction affords (Z)-olefins. This is in good agree-ment with the observations of Vedejs and Snoble19• They

suggest that in the absence of salts the Wittig reaction can be described as a TIZ + TI 2 cycloaddition according to the

s a

rules of Woodward and Hoffmann. Orthogonal approach of the TI-honds of the ylid and the aldehyde would lead directly to the most hindered oxaphosphetane (e.g. the

erythro form) which results in the formation of the (Z)-alkene:

a{<"----

. R CH₃ H H H

H

CH 3 R

Fig. 3.8 TI; + TI! cycloaddition of an ylid and aldehyde

in the Wittig reaction

Reaction of pivalaldehyde (fig. 3.8 R= tert-butyl) with ethylidenephosphorane resulted in the formation of the eer-responding alkene with an E:Z ratio of 1:99. Salteffects

I

are explained by the formation of betaine-lithium halide adduct as a competing reaction. Bahlosser and ao-workers1

showed that the betaine-lithium halide adducts which are formed during the Wittig reaction, rapidly equilibrate when treated with another equivalent of phenyllithium or n-butyl-lithium. The following adoption was made for explanation of the stereochemical course of the reaction: the initially formed erythro betaine-lithium halide adduct 24a is con-verted into anion 25a after treatment with an extra equiva-lent base (fig. 3.9). A rapid equilibrium between the two possible forms of~ is reached, in which 25b predominates. Protonation and eliminatien of triphenylphosphine oxide gives the (E)-olefin. The above described mechanism for the modified Wittig reaction was further elaborated by

P~PK+

Oli ' ' ' , ', 1 2 H R H R erythro Rli rapid

---

---ROH threo

Fig. 3.9 Schlosser modification of the Wittig reaction

Bahlosser and aollaborators7 _{in 1970. They concluded that}

only (E)-alkenes çould be obtained via the modified Wittig reaction in the presence of soluble lithium salts. Only in that case the betaines exist in the threo form.

III.S The Stork-Esahenmoser hypothesis

It is striking that many of the natural occurring steroirlal compounds derived from the (in general most stable (E)-poly-enes) consist of trans,anti.trans structures. Basedon the stereochemistry of some polyene cyclizations Stork17 _and

Esahenmoser20 developed a stereoelectronic theory explaining and predicting the course and stereoselectivity of polyene cyclizations. They postulated that the concerted formation of

a cyclohexane ring in cationic cyclization reactions of open chain polyenes must proceed via an anti-parallel mechanism.

In fig. 3.10 this is illustrated for the ring A/B cyclization of a squalene fragment.

OH

Fig. 3.10 Ring A/B cyclization of squalene according to the Stork-Eschenmoser

hypothesis

Electrophilic attack of the generated C(2) cation on the C(6)-C(7) double bond and a simultaneous nucleophilic attack of the C(10)-C(11) double bond occurs in such a way, that the first mentioned addition takes place in a tPans manner with regard to the other one. Extension of this postulate would always result in a polycyclic product having the tPans,anti~tPans,

anti,tPans geometry. This postulate, however, cannot account for the in vivo cationic cyclization of 2,3-epoxysqualene into lanosterol, because in the intermediate protolanosterol the methyl group on C(lO) is expected to be situated syn towards the hydrogen atom on C(9), as can be concluded from the confi-guration of lanosterol. This suggests that the vivo cycliza-tion brings the 2,3-epoxysqualene in a coiled conformacycliza-tion from which the configuration of lanosterol can be generated21

•22•

An other hypothetical model for this vivo cyclization is out-lined in Section III.6.

III.6 Vivo vePsus vitPo eyelizations

In the previous Sectien it was outlined that the Stork-Eschenmoser hypothesis is probably valid only for non-enzymatic cyclization reactions. The suggestion was made that under vivo

conformation which can only be obtained under these specific conditions23

• First of all the accepted substrate folding will be more specified. Finally, another approach is offered which is developed by W. de Loos of our department2_~.

Model-studies are in prögress to support this hypothesis.

Two fundamental routes can be distinguished for the squa-lene conversion: an oxidative and a non-oxidative route. BZoah and Tahen25 _{verified that the oxidative cyclization of}

squa-lene in the presence of 2H₂0 or H₂18

o

did not result in the formation of labeled lanosterol, whereas the enzymatically ca-talyzed cyclization in the presence of 18

o

₂ yielded lanosterol labeled with 180 in the hydroxyl group. Corey and van TameZen23

showed that 2,3-epoxysqualene is an intermediate which can be converted anaerobically to lanosterol. The enzymes squalene-epoxidase and epoxysqualene-cyclase are believed to catalyze these reactions. Another intriguing feature concerns the ste-reochemistry of this reaction. Squalene which possesses no asym-metrical carbon atoms is converted into a molecule with

seven asymmetrical centers. However, one stereoisomer is formed only. This is explained by assuming that the 2,3-epoxysqualene chain is folded and held in such a manner that its conformation in the substrate-cyclase complex favours the formation of

protolanosterol by proper w-orbital interactions. This orienta-tion on the enzyme is believed to occur in a chair-boat-chair conformation, visualized in fig. 3.11.

R

Fig. 3.11 Orientation of 2,3-epoxy-squalene on the enzyme

A concerted cyclization will yield protolanosterol as inter-mediate which rearranges to lanosterol by two consecutive 1 ,2-hydride and two 1,2-methide shifts foliowed by proton elimina-tion on C(9) (steroidal numbering):

HO HO \ ~

CH3 èH3

Fig. 3.12 Enzymatically controlled rearrangement of proto-lanosterol to proto-lanosterol

Note, that during the cyclization the cationic center moves via C(6) and C(10) which are tertiary cent~rs to C(14) which is a secondary center (squalene numbering). This must be due tosome unknown interaction of the enzyme and C(14), most probably a favourable orientation on the enzyme. The favour-able orientation of the C(15)-n-lobe, which is directed to-wards the C(10)-n-lobe may be of importance for the

forma-tion of a C-C bond between the atoms C(15) and C(10). It is at this stage that the non-enzymatic process differs from the enzymatic one. The vitro reaction stops at the formation of a tricyclic compound having a five-membered C ring23

•

R

1.§.

It must be clear that there is a pronounced influence of th~

enzyme on the cyclization process. Thermodynamically a five-membered ring is the most favoured one. In spite of this fact the reaction proceeds via a less stable secondary cation to

a tertiary one in the final D ring closure. In order to ex-plain this feature, W. de Loos2~ proposes a two-step mechanism. The cyclization process is interrupted after the chair-boat cyclization of the A/B ring system by trapping the cation at the a side with an active site of the cyclase enzyme (for in-stance the nitrogen atoms in histidine). This site creates a leaving group or back-shielding via the enzyme which forces the incoming (entering) double bond in a chair-cyclohexenyl conformation, generating a six-membered C ring with the right configuration.

Fig. 3.13 Two-step mechanism for the cyclization of 2,3-epoxysqualene to protolanosterol

On the other hand,

w.s.

Johnson and aollaborators11 took profit from the possibility that relatively stable tertiary carbenium ions generated during the reaction, can be used for weli-con-trolled cyclization reactions under non-enzymatic conditions leading to steroids as is outlined in the Introduetion (III.l).

III.7 Experimental

• 2,5-Bis(1,3-dioxolan-2-yl)-12-(2-thienyl)(E)dodec-9-ene (Sa) To'a solution of

i,

prepared from 6.3 g (0.01 mol) of the corresponding iodide and 5 ml phenyllithium (2 N in benzene/ ether mixture, 70/30) in 30 ml tetrahydrofuran at 0°, 1.4 g

(0.01 mol) of aldehyde 3a in 5 ml tetrahydrofuran was added dropwise at -78° (nitrogen atmosphere). After ~ha ser.ond equivalent of phenyllithium was added, followed by excess of methanol (after 5 min). Aqueous work-up foliowed by

chromato-graphy over silica (chloroform as eluens), gave 2.S9 g (70\) of pure Sa. NMR (CC1_{4): 6 1.24 (s,3,C!:!3); 1.33-2.60 (m,8,} 4x C!:! 2); 1.61 (s,4,o 2cc!:!2-c!:!2co2); 2.7S-3.10 (m,2,Th-C!:!2); 3.90 (s,8,dioxolane protons); S.40-S.60 (m,2,C!:!=C!:!); 6.6S-7.16 ( m, 3 , Th-!:!) • • 2,S-Bis(1,3-dioxolan-2-yl)-12-(3-thienyl)(E)-dodec-9-ene (Sb)

Prepared as for Sa.

• 2,S-Bis(1,3-dioxolan-2-yl)-12-(2-thienyl)(Z)dodec-9-ene (Sc)

To a salution of!, prepared from 6.3 g (0.01 mol) of the corresponding iodide and 6 ml of n-butyllithium (20\) in hexane) in 30 ml of tetrahydrofuran at 15°, 1.4 g (0.01 mol) of aldehyde 3a in 5 ml of tetrahydrofuran was added dropwise at -78° (nitrogen atmosphere). After! h the temperature was raised to -30°; then a secend equivalent of n-butyllithium was added foliowed by excess of methanol. Aqueous work-up as

for Sa yielded 2.64 g (72\) of product. lts speetral data were fully identical with these of •

c

₂₀H₃₀o₄

s

(366.52): Calcd C 65.54, H 8.25; found C 65.71, H 8.37.

• 2,5-Bis(1,3-dioxolan-2-yl)-12-(3-thienyl)(Z)dodec-9-ene (Sd) Preparedas for Sc.

c

₂₀H₃₀o₄

s

(366.52): Calcd C 6S.S4, H 8.25; found C 65.71, H 8.37.

• 12-(2-Thienyl)(E)dodec-9-ene-2,5-dione

A salution of 1.65 g (0.045 mol) of in a mixture of 30 ml of methanol and 60 ml of 0.5 N hydrochloric acid was stirred for

l

h at 50-60° under nitrogen. The reaction mixture was diluted with water and the product extracted into ether. Drying and remaval of the solvent left 1.15 g (92%) of crude oily product which was used without purification.

• 12-(3-Thienyl)(E)dodec-9-ene-2,5-dione • 12-(2-Thienyl)(Z)dodec-9-ene-2,5-dione ... 12-(3-Thienyl)(Z)dodec-9-ene-2,5-dione

were prepared as described in the previous experimental . ... 2- [6-(2-Thienyl) (E)hex-3-eny~ -3-methylcyclopent-2-enone

(6a)

A mixture of 7.5 g (0.027 mol) of dione (see preceding syn-thesis), 60 ml of ethanol and 20 ml of 0.1 N aqueous sodium hydroxide was refluxed for! h (nitrogen atmosphere). The salution was poured into water and the product isolated by ether extraction. Drying and stripping off the solvent gave crude product. Column chromatography (Si0

2,CHC13) gave 6.1 g (87%) of pure product. NMR (CC1

4):

o

1.97 (s,3,C!:!3); 2.00-2.60 (m, 10,5x C!:!₂); 2.62-2.98 (m,2,ThC!:!₂); 5.23-5.52 (m,2, C!:!=C!:!); 6.60-7.08 (m,3,Th-!:!) .

... 2- [6-(3-Thienyl) (E)hex-3-eny:j] -3-methylcyclopent-2-enone (6b)

Prepared as for 6a .

... 2-

[§-

(2-Thienyl)

(Z)hex-3-eny~

-3-methylcyclopent-2-enone (6c)

Preparedas for 6a.

c

₁₆H₂₀

os

(260.40): Calcd C 73.80, H 7.74; found C 73.91, H 7.92 .

... 2-~-(3-Thienyl)(Z)hex-3-eny~ -3-methylcyclopent-2-enone (6d)

Preparedas for 6a.

c

₁₆H₂₀

os

(260.40): Calcd C 73.80, H 7.74; found C 73.87, H 7.84 .

... 2- [6- (2-Thienyl) (E)hex-3-enyi) -3-methylcyclopent-2-en-1-ol (7a)

To a salution of 520 mg (2 mmol) of 6a in 10 ml of ether 78 mg (2 mmol) lithium aluminum hydride was added portions-wise at -30°. After ! h 1 N aq~eous sodium hydroxide salution was added. Drying and evaparatien of the ether layer gave

480 mg (92%) of product. No saturated alcohol could be de-tected by 1H-NMR spectroscopy. This product was used without purification for cyclization experiments. NMR (CC1₄):

o

1.63

5.27-5.63 (m,2,C~=C~); 6.67-7.12 (m,3,Th-~). • 2- ~-(3-Thienyl)(E)hex-3-enyD -3-methylcyclopent-2-en-1-ol (7b) • 2- @-(2-Thienyl)(Z)hex-3-eny~ -3-methylcyclopent-2-en-1-ol (7c) •

Z~~-(3-Thienyl)(Z)hex-3-eny~

-3-methylcyclopent-2-en-1-ol (7d)

were prepared as for ?a.

• 5-Methyl-12, 13-lli} thienotricyclo

[7.

4. 0. 0 4' 8] tridec-4-ene (Sa) Toa salution of 480 mg (1.8 mmol) of 7a in 10 ml of methylene chloride was added dropwise 460 mg (1.8 mmol) of $tannic

chloride at -95° (nitrogen atmosphere). After 1 h the mixture was poured into a saturated ammonium chloride solution. The water layer was extracted twice with methylene chloride and .the çombined organic layers were dried and concentrated.

Column chromatography (Si0₂, pet. ether 40-65) yfelded 215 mg (0.9 mmol} of product (49%), mp 73.5-75.5°~

c

₁₆H 20

s

(244.40): Calcd C 78.63, H 8.25; found C 78.70, H 8.37. NMR (CC1 4): ö 1.65 (s,3,C~

₃

); 0.83-3.10 (m,1S,aliphatic protons}; ~.02 (AB pattern,2,Th-~).

• 5-Methyl-13, 12-

[Q]

thienotricyclo [7. 4. 0.

o

4 '8) tridec-4-ene

(Sb)-Preparedas for Sa, mp 59.5-61.5°.

c

₁₆H

20

s

(244.40): Calcd C 78.63, H 8.25; found C 78.45, H 8.50. NMR (CC1

4):

o

1.65

(s,3,C~

₃

); 0.90-3.00 (m,15,aliphatic protons); 6.78 (AB pattern,

2,Th-~).

BefePences and Notes

1. W.S. Johnson, H.B. Gravestock and B.E. HcCarry, J. Amer. Chem. Soc.,

21.,

4330 (1971).

2. P.A. Bartlettand W.S. Johnson, J. Amer. Chem. Soc., 95, 7501 (1973).

3. ~.S. Johnson, M.B. Gravestock and B.E. McCarry, J. Amer. Chem. Soc., 93, 4332 (1971).

4. J.W. de Haan and L.J.M. van de Ven, Org. Magn. Resonance,

~. 147 (1973).

5. The assignment of the (E) and (Z) structure of alkenes is based on the difference in chemical shift of the allylic carbon atoms. Comparison of the spectra of Sc and Sd with those of 4-(2-thienyl)but-1-ene and 2,5-bis(1,3-dioxolan-2-yl)nonane revealed the (Z) conformation as can be seen from the subjoined Table.

1 3 5.

0 / c , / c ~ _rl'"c

Th/ C

~t,-2 4

compound values for the allylic carbon atoms (in ppm downfield from TMS)

c

₂(E) C₂(Z) Me

c

₅(E)

c

₅(Z) Me Scb 35.71 30.54 5. 17 33.80 28.50 5.30

5d?

35.29 30.08 5.17 33.66 28.27 5.39 - d 35.55 32.86 6a

-

-

-6bd _34.36

_-

-

32.86

-

-aTh=thiophene ring (2- or 3-substituted); bData of the (Z)-and (E)-isomers were measured in the mixtures (E/Z=O.l); cAó=C(E)-C(Z); dCompounds 6a and 6b from Chapter IV

The Aó values are in good agreement with those measured in disubstituted olefins by de Haan and van de Ven. By computer

simuiatien the coupling constants of the olefinic protons in the cliones derived from and were determined. The values found are characteristic for (Z)-alkenes, 10.85 and 11.06 Hz respectively.

6. H. Schlosser and K.F. Christmann, Angew. Chem., Intern. Ed. Eng!.,.§_, 126 (1966); Ann. Chem., 708, 1 (1967).

7. M. Schlosser, K.F. Christmann and A. Piskala, Chem. Ber., 1 3 2814 (1970).

8. E.J. Corey and H. Yamamoto, J. Amer. Chem. Soc.,~. 226 (1970) j ibid. 92, 6637 (19-70); ibid. ~. 6638 (1970).

9. R.J. Andersen and C.A. Henrick, J. Amer. Chem. Soc., 97, 147 (1975).

10. P.J. Zeelen, private communication.

11. W.S. Johnson, Acc. Chem. Res., _!_, 1 (1968).

12. W.S. Johnson, D.H. Bailey, R. Owyang, R.A. Bel!, B. Jacques and J.K. Crandell, J. Amer. Chem. Soc., 86, 1959 (1965). 13. W.S. Johnson and J.K. Crandell, J. Org. Chem., lQ, 1785

( 196 5 ).

14. W.S. Johnson, A. van der Gen and J.J. Swoboda, J. Amer. Chem. Soc.,~. 170 (1967).

15. D.J. Goldsmith, B.C. Clark, Jr. and R.J. Joines, Tetra-hedron Letters, 1211 (1967).

16. P.A. Stadler, A. Nechvatal, A.J. Frey and A. Eschenmoser, Helv. Chem. Acta,

iQ,

1373 (1957).

17. G. Sterk and A.W. Burgstahler, J. Amer. Chem. Soc.,

21.

5068 (1955).

18. Por a review see: J. Reucroft and P.G. Sammes, Quart. Rev.,

ll•

135 (1971).

19. E. Vedejs and K.A.J. Snoble, J. Amer. Chem. Soc., 95, 5778 (1973).

20. A. Eschenmoser, L. Ruzicka, 0. Jeger and D. Arigoni, Helv. Chem. Acta, 38, 1268 (1955); ibid. 38, 1890 (1955).

21. P. van Pelt, Thesis, Eindhoven (1975).

22. See for two reviews: L.J. Mulheirn and P.J. Ramm, Chem.

42

Soc. Reviews,_!_, 259 (1972); L. Zechmeister, Fortschritte der Chemie organischer Naturstoffe, Teil XXIX, R. Goldsmith,

Biogenetic Synthesis of Terpenoid Systems, p. 364,

Springer Verlag, Wien (1971) and references cited therein. 23. E.E. van Tamelen, J. Willet, M. Schwartz and R. Nadeau,

J. Amer. Chem. Soc., 88, 5937 (1966), 24. W. de Loos, forthcoming Thesis, Eindhoven.

25. T.T. Tchen and K. Bloch, J. Amer. Chem. Soc.,~' 1516 (1956); J. Biol. Chem., 226, 931 (1957).

CHA,PTER

IV

Alternative syntheses :for precursors

of tetracyclic compounds

IV.1 Introduetion

In the previous Chapter the synthesis was described of compounds of type

l

which served as precursors for tetracy-cles. These materials prepared via the Schlosser modifica-tion of the Wittig reacmodifica-tion still contained 5-10% of (Z)-isomer. In order to obtain pure (E)-compounds alternative routes towards this type of compounds were developed.

IV.Z Synthesis of (E)-aZkene precursors via the Wadsworth-Emmons reaetion

In Section 1I1.4 the E/Z ratio of isomers obtained from the Wittig reaction and its modifications is discussed. üne of these modifications concerns the reaction of resonance-stabilized phosphoranes or phosphonoacetate anions with al-dehydes and ketones known as the Wadsworth-Emmons reaction, which leads to (E)-alkenes selectively. Application of this method by reacting the aldehydes 1 and

!Q

(for their pre-paration see Sectien 11.3) with the triethylphosphonoacetate

anion afforded the thienyl substituted (E)-ethylpentenoates Za and Zb (fig. 4.1). The 1H-NMR spectra of the afore men-tioned compounds revealed a JCH=CH=16 Hz, which is charac-teristic for (E)-alkenes. Reduction of Za and 2b proved to be the most successful approach with diisobutylaluminum hydride1

yielding the allylic alcohols 3a and 3b. Applying other reducing reagents, such as lithium aluminum hydride2 _only saturated products could be isolated, due to 1,4-addition of

H 0 O Na+ Th

J+

(Eto)2

~ ~OEt

0 1 a Th=2-thienyl 1 b Th=3-thienyl 1. Buli 2.oxirane

0\'0Et

-r0

n..

Dibai-H

(OH

r0

3a,~

JO

₀ A

₀

~MgCI 5 Cu Cl

n

0

1\

HO OH p- TSA Th

Fig. 4.1 Synthesis of (E)-precursors for cyclization reactions

the hydride. Treatment of the allylic alcohols 3a and 3b with sodium hydride and excess methyl iodide afforded the methyl ethers 4a and 4b in quantitative yield. The copper promoted coupling3 _{of the farmer products with Grignard derivative ~} (vide infPa) gave compounds 6a and 6b, respectively, in ex-cellent yield. Inspeetion of-;he 13c-NMR spectra proved that the coupling had occurred with complete retentien of the

geometry of the double bond. No (Z)-isomer could be detected (see also Chapter III, note 4 and 5). Performing coupling experiments with ~ and the chlorides derived from the aleo-hals 3, in the absence of copper salts, the SN2 products

(e.g. !l and the SN2' products

(!)

were formed in a 1:1 ratio. Cl

Thj

+

_ff1

---Th

ÄO~MgBr

+ 6

The Grignard derivative was prepared starting from 2-methyl-furan. Lithiation with n-butyllithium in tetrahydrofuran and subsequent alkylation with oxirane produced 2-(5-methyl-2-furyl)ethanol. Conversion into the corresponding chloride under neutral conditions was accomplished by the action of triphenylphosphine in CC1₄ at refluxq. Grignard derivative

~ was formed by the action of magnesium on the chloride in ether (not in tetrahydrofuran). Acid catalyzed ring opening of the furan ring by the method of Johnson5 _{led to the}

di-ketals 7a and 7b. These compounds were fully identical with the (E)-alkenes, obtained from the Wittig-Schlosser reaction, in the presence of phenyllithium as base (see Section III.2).

IV.3 Synthesis of (E)-alkene preaursors via the Claisen re arrangement

The synthetic route, given in Section IV.2, for molecules of type

l

cannot be applied to prepare compounds which are prone to attach by acids, as acidic conditions are necessary for the conversion of!+

l

(e.g. a furan nucleus as A ring), Therefore, a different reaction sequence was developed

whereby the A ring compound was introduced in one of the last steps, which permits a rather quick transposition of hetero-cycles as A ring compounds. For this purpose

11

was synthe-sized as general precursor for compoundsof type

l

(fig. 4.2).

D

1.n,-Bu U 2.Br~Br 0 HO 1. EtO+OEt 0 OEt ~ I _{OH 2.} OH-11

!

1. HrOH, p-TSA 2.0W 1 \ 0 0 12

I

Pb(OAcl

liCI 1 \ 0 0 Cl 13

~Br

0 9

l1.M~

0

2.~H

~

0 10

1\

0 0 0

Fig. 4.2 Reaction sequence for the preparation of

J1.

Treatment of 5-methylfuryllithium with 1,3-dibromopropane5

at -30° afforded bromide 2_ from which a Grignard derivative could be prepared with magnesium in ether. Reaction with freshly distilled acroleine afforded allyl alcohol ~· The

crude ~was converted after treatment with excess ethyl ortho-acetate and a catalytic amount of propionic acid into the ethyl ester of (E)-alkene compound

!1,

exclusively. This Claisen rearrangement proceeds via a (u! + u; + a;) electro-cyclic process which always results in the formation of (E)-alkenes. This was confirmed by IR (streng absarptien at 970 cm- 1 ((E)-alkene) and no absarptien at 730 cm-1 ((Z)-alkene)) and 13c-N"MR spectroscopy. The crude ester was saponified to the acid under standard conditions. Acid-base extraction yielded the pure acid

ll·

Acid catalyzed furan ring opening5 produced the diketal ~ after saponification. Halodecarboxy-lation of the acid with iodine and lead tetraacetate6 result-ed in the formation of iodolactone When this reaction was performed on a model system (formed from 1-bromo-2-(1,3-dioxo-lan-2-yl)ethane via the sequence given in fig. 4.2) the desired iodide could he isolated in high yield. A modified halodecar-hoxylation with lithium chloride and lead tetraacetate7 _did result in the formation of 13 in an over-all yield of 22% starting from 2-methylfuran. It is known that compounds such as are very susceptible for basic reaction conditions8

• Reaction of

11

with thienyllithium and furyllithium in tetra-hydrofuran at low temperatures (< -30°) yielded only the ex-pected dehydrohalogenated derivative. Therefore, non-basic coupling experiments of arylcopper compounds and alkyl halides were performed on model systems. These arylcopper reagents, which are known to react with, for example, aryl halides 9_-1_~

and alkyne derivatives15 _{failed to give suhstitution products} when exposed to alkyl halides (4-bromohut-1-ene, 1-phenyl-2-bromoethane). Another methad to produce these types of com-pounds is substitution of an aryl iodide with an alkylcopper-tri-n-butylphosphine complex ar a lithium dialkylcuprate. However, it appeared that this reaction can only he used in case of methyl substitution reactions, due to the high stabili-ty of methylcapper with respect to alkylcopper compounds. This was illustrated hy the capper catalyzed coupling of

product (e.g. 2-(4-but-1-enyl)thiophene) could be isolated. The oxidative coupling, however, which proceeds via mixed cuprate complexes, afforded coupled products. This reaction is based on the formation of complexes of the type R1R2CuX in which X stands for Li or MgBr. Yields up to 75% are obtained when R1=sea-butyl or tert-butyl and R2=phenyl16

• To apply this method on chloride

ll,

this compound was converted into the corresponding iodide from which a Grignard derivative could be prepared in ether.

1\

0 0 Naf

11..----I 15 1.Mg

z.~Cu

J.

o

₂

n

7o

On the addition of this Grignard derivative to a suspension of 2-thienylcopper (from 2-thienyllithium and cuprous iodide) at -78° the mixed cuprate was formed, whereupon oxygen (dry air) was passed through the mixture resulting in the formation of 7a in yields of 10-35%. Optimization of this reaction may lead to an effective method for the synthesis of compounds of type

z

from the easily accessible heterocyclic lithium derivatives and 13.

IV.4 Experimental

~s-(2-Thienyl)(E)pent-2-enoic acid, ethyl ester (Za)

To a sodium hydride suspension (80 wt. % in paraffin) in 100 ml of dimethoxyethane (1.8 g, 0.06 mol) was added dropwise 14 g (0.06 mol) triethyl phosphonoacetate (T < 20°, nitrogen atmosphere), foliowed by a solution of 8.55 g (0.06 mol) of~

in 50 ml of tetrahydrofuran at 0° with vigorous stirring. After 3 hr the reaction mixture was refluxed for 1 hr. Aqueous work-up gave after distillation 8.2 g (65%) of product, bp

85-90° (0.005 mm).

NMR (CC1_{4): ö 1.22 (t,3,Cg3); 2.27-2.71 (m,2,ThCH2cg2);} 2.77-3.12 (m,2,Thcg_{2); 4.12 (q,z,ocg2cH3}); 5.67, 5.96 (m,1,cg= CHCOOEt); 6.70-7.23 (m,4,Th-g+cgcoOEt).

• 5-(3-Thienyl)(E)pent-2-enoic acid, ethyl ester (2b) Preparedas for 2a, bp 85-90° (0.001 mm).

• 5- (2-Thienyl) (E)pent-2-enol (3a)

A salution of 3.57 g (0.025 mol) of diisobutylaluminum hydride in 10 ml of benzene was added dropwise toa mixture of 2.1 g

(0.01 mol) of Za in 50 ml of benzene at 5° (nitrogen atmo-sphere). After 1 hr of stirring at 5-10° a saturated ammonium chloride salution was added. Filtration, separation of the organic layer gave after drying and stripping off the solvent 1.45 g (86%) of product.

NMR (CC1₄): ö _{3.60 (s,1,0g); 3.90-4.10 (m,z,cg20H); 5.50-5.75} (m,2,cg=cg).

• 5- (3-Thienyl) (E)pent-2-enol (3b)

Prepared analogous tp the 2-thienyl substituted derivative 3a.

• 1-Chloro-5.- (2-thienyl) (E).pent-2-ene

A salution of 0.45 g (0.03 mol) 3a and 1.5 g (0.003 mol) triphenylphosphine in 20 ml tetra was refluxed for 7 hr. The salution was cooled, filtrated and concentrated, whereupon the residue was stirred for

i

hr at 0° after the addition of petroleum ether 40-65. Filtratien and evaparatien of the solvent left crude product. Chromatography (Si0₂, petroleum ether 40-65) afforded 0.44 g (86%) pure material.

NMR _{(CC1 4):}

o

3.96 (m,2,cg₂Cl).

• 1-Chloro-5-(3-thienyl)(E)pent-2-ene

Prepared as the 2-thienyl substituted analogue.

... 1-Methoxy-5-(2 -thienyl) (E)pent-2-ene ( 4a)

A salution of 8.5 g (0•05 mol) of alcohol (3a) in 20 ml of dimethylformamide was added toa suspension of 1.8 g (0.06 mol) of sodium hydride (80 wt. % in paraffin) in 40 ml of dimethylformamide at 50-60°. After 3 hr 14.2 g (0.10 mol) of methyl iodide was added at room temperature. After 16 hr the reaction mixture was worked up as usual to yield 9.0 g (98%) of product (bp 70-73° (0.01 mm)).

NMR (CC1₄): ö 3.30 (s,3,0C~

₃

) .

... 1-Methoxy-5-(3-thienyl)(E)pent-2-ene (4b) Preparedas for 4a, bp 64-68° (0.005 mm) .

... 2-(5-Methyl-2-furyl)ethanol

Toa salution of 8.2 g (0.10 mol) 2-methylfuran in 45 ml of tetrahydrofuran 50 ml of n-butyllithium (20% in hexane) was added dropwise at -30° (nitrogen atmosphere). After 3 hr of stirring at -10°, a salution of 6.6 g (0.15 mol) of oxirane in 10 ml of tetrahydrofuran was added. The reaction mixture was allowed to stand overnight at room temperature and poured into water from which the alcohol was isolated by ether

extraction. Stripping off the solvent and distillation at 72-75° (4.5 mm) gave 8.2 g (65%) of product.

NMR (CC1₄):

o

2.20 (s,3,C~

₃

); 2.58-2.88 (m,2,C~

₂

0H); 3.57-3.89 (m,2,C~

₂

cH

₂

0H); 3.95 (s,l,Oli); 5.70-5.95 (m,2,furan protons).

• 1-Chloro-2-(5-methyl-2-furyl)ethane

A salution of 12.6 g (0.1 mol) of alcohol and 39.3 g (0.15 mol) of triphenylphosphine in 250 ml of tetra was stirred under reflux overnight. The mixture was cooled, filtered and concentrated. The residue was taken up in petroleum ether 40-65 and stirred for

1

hr at 0°. Filtration, evaparatien of the solventand distillation gave 11.8 g (82%) of product, bp 48-50° (4.5 mm).