P A R T I
RECENT ADVANCES IN THE FIELD
OF MACRCCYCLIC COMPOUNDS - 2 -
ABSTRACT
The stereochemistry of alicyclic compounds along v/ith the modern concept of conformational analysis have
been discussed.
Various methods for the preparation of macro-
cyclic compounds involving the high-dilution principle,
the acyloin condensation and the recently developed
method for the oxidative couplinj^ of terminal diacetylenes
have been described. The practical methods developed in
this Laboratory for the preparation of civetone, dihydro-
civetone, exaltone and exaltollde from indigenous raw
materials are mentioned as well.
The odour and constitution of macrocycllc
compounds have been correlated. In addition, the possible
biogenetlc pathways of these compounds along with their
occurrence in nature have been presented. - 3 -
The chemistry of alicyclic compounds is of interest primarily because of stereochemical properties inherent in the ring form as opposed to open chain structures, prior to about 1880, no compound containing a ring structure of other than six members had been isolated from a natural source or synthesised in the laboratory, and it was generally agreed that ring structures of other sizes were incapable of existence. > It is evident from the personal reminiscences of Perkin" that such eminent organic chemists of the period as A.von
Baeyer, Victor Meyer, and Emil Fischer considered it highly improbable that three-, four-, and five- membered carbon rings should be capable of existence.
The Early Syntheses of Small Rings
During the period 1881-1885, the incorrectness of this view was clearly demonstrated by the synthesis of compounds containing three-, four-, and five-membered carbonrings. The first such synthesis was that of
1,3-cyclobutane-dicarboxylic acid by Markovnikov and
Krestovnikov,^ which surprisingly excited no comment in chemical circles. It was only after the elegant synthetic work on small ring compounds by Perkin, this 4 ,5 conception of the finite existence of small ring compounds received a firmer support and subsequently aroused enough interest in this field. - 4 -
Baeyer* s Strain Theory
In order to explain the prevalence of six- raembered carbon rings in nature, the difficulty in formation of the small rings, and the great reactivity of such unsaturated linkages as the carbon-carbon double and triple bonds, Bieyer brought forth his famous Strain Theory,^ Baeyer based his theory upon the Van’ t Hoff^ and Le Bel^ conception of the tetrahydral distribution of carbon valences in space.
Bayer concluded from this concept that?” the four valences of the c'^rbon atom act in directions which connect the centre of the sphere with the corners of an inscribed tetrahydron, and form an angle of 109°
2B' with each other. The direction of attraction
(valence) can undergo a bending or distortion, which
results in a tension (spannung) proportional to the amount of this bending.”® Any deviation from the normal valence angle was supposed to set up a
condition of strain which exhibited itself by a corresponding decrease in the stability of the molecule.
Baeyer's conception of this strain theory was based on
the assumption that the rings under consideration were
planar. However, this conception later on underwent considerable modifications (vide infra).
Seeming confirmation of the general concept
of the strain theory was immediately obtained by Perkin," - 5 -
who succeeded in preparing cyclopentane-l,!^-dicarboxylic acid, which was found to be extremely stable, and the yield in the cyclisation step was very high,in distinct contrast to the low yields obtained during the formation of three- and four- mernbered rings.
Limitations of the Strain Theory
Many other early observations give general support to Bayer’ s strain theory as applied tc smaller ring systems, although the physical nature of this strain is not yet fully understood. The theory,however, breaks down completely when employed for interpreting the properties of macrocyclic rings. Thus cyclopenta- decane (muscane) with a negative valency deflection of
“^3® 16’ might be expected to possess the same order of stability as cyclopropane with a positive valence deflection of 24® 44’ . Infact muscane approximates in stability to cyclohexane and tne same is true for all the macrocyclic ring systems.
Strainless Rings
Sachse^® furnished an explanation for this anomaly but his conceptions remained neglected until revived and elaborated by Mohr^^ thirty years later.
They showed that the erroneous conclusions stemmed from the assumption that all rings must necessarily be uniplanar. This is indeed true for rings upto - 6
and including five-merabered systems, but from cyclo- hexane upwards, puckered, raultiplanar configurations can be envisaged which involve little or no distortion of the tetrahydral valence angles.
Boat- and Chair- qoniormatlons
Thus cyclohexane ma- exist in two ’’strainless” configurations in wnich four of the carbon atoras are coplanar and two other carbon atoms occupy a second plane; these are commonly referred to as the boat- forra(I), and the chair form(II),
IlgC CH2 H2 C
-CHg'"'/ ...... HgC------CHg Crf2--- CH2. \ N. CH2
(I) (II)
Examination of the individual structures (I) and (II) suggests the eiistence of several stereoisomers of each of the monosubstitution derivatives of cyclo hexane. No such isomers, hOFever, have been isolated, probably due to the fact that the various steric forms of the cyclohexane ring are easily interconvertible,
Mohr^^ pointed out that, whereas the simple cyclohexane - 7 -
derivatives may fail to exhibit ” boat-chair’* conformation fused ring systems might afford better opportunity for the isolation of stereo-isomeric forms. This prediction has been amply verified experimentally. Thus decalin
(decahydronaphthalene) has been shown to exist in two forms, which are cis- trans isomers.
The separation of the indubitable els- trans isomers of decalin^^ afforded Incontrovertible evidence that the Sachse-Mohr conception of strainless nonplanar rings is essentially correct. Ruzicka’ s discovery that muscone and civetone, the odourous principles of natural musk and civet respectively were representatives of the group of large ring ketones, gave the final blow to
Baeyer's strain theory and put the strainless ring theory on firmer fccting. These large rings show no strain in the Baeyer sense. However, there is certain evidence that "strain” exists in higher ring systems^^ due to steric rppulsions, as described in the sequel.
Conformational Analysis
A somewhat different approach to an understanding of the effects that steric factors exert on the properties of organic substances has led to the valuable new concept that is now described as conformational analysis ,which has been established in recent years as a valuable approach to the solution of a wide variety oi problems in structural organic chemistry.^'^ - 8 -
By ’ conformation' is meant any arrangement in space of the atoms of a molecule that can arise by rotation about a single bond and that is capable of finite existence.^® Such arrangements would correspond to a potential minimum with respect to all types of small displacements in bond lengths, in bond angles, or in angles of rotation about single bonds (or double bonds). Defined in this way, confor mations are rotational isomers entirely analogous to isomers, related by rotation about a double bond.
However, since the potential barriers associated with rotation about single bonds are relatively low,isolation of such isomers is not likely to be feasible. Neverthe less, each potential isomer or conformation has finite and distinct physical properties, and the seperate spectra of various conformations h^ve been identified in a number of cases. preferred Conformations of some Hydrocarbons
In the last two decades many of the powerful methods of modern chemical physics including electron and x-ray diffraction, infrared, Raman and microwave spectroscopy and statistical mechanics, have been used to demonstrate the existence and nature of preferred conformations in simple molecules. - s -
n-Batane
The conformation of n-batane with lowest energy is the fully transoid, staggered conformation (III), whereas the energies for the fully eclipsed (IV), eclipsed (V ), and skew (VI) conformations are about
3.6, 2.9 and 0.8 kcal. per mole respectively graater than that of the staggered conformation.
(H) H H(H) (Me)H H(H)
Me Me (Ke)
Staggered Fully eclipsed Eclipsed Skew
(III) (IV) (V) (VI)
In the aliphatic as well as alicyclic compounds, the most stable conformation is usually that in which the
substituents on adjacent tetrahydral carbon atoms adopt
the fully staggered confoi^nation as ( I I I ) , the two
largest groups (or, in qualification, the two most
strongly repelling dipoles) taking up the 180°arrangement. 16 Eclipsed conformations are always avoided whenever possible. - 10 -
In cycloalkanes, the possibility of attaining the favourable staggered conformation will be severely conditioned by the size of the ring.
Cyclohexanes
The conclusion by Sachse and Mohr that
cyclohexane can exist in only two conforraations
free from anglo-strain has long been accepted by
chemists. That the chciir confornation (VII), is more stable than the boat (VIII), is attested by
considerable physical evidence including infrared and
Raman spectroscopy, and electron diffraction^'^ and by
thermodynamic considerations, 1 9
a e
(VII) (VIII)
Derivatives of cyclohexane always tend to take
up the chair conformation, whenever this is stereo- po chemically possible. In the chair conformation," it
is possible to distinguish two types of carbon - hydrogen bonds; those which are parallel to the axis
of symmetry of the ring and are called axial,designated -li
as (a), and those which radiate more or less in the plane o ' the ring are designated as equitorial (e).
Decalins
Tile nrnnber of geometrically possible confor mations becomes very much greater when the fusion of tvrc cyolohexane rings to give trans- and els- decalin is consiaerod. i’ortunately, if chair conformations are accepted as being more stable than boat conformations, then there is a imique conformation for both trans- (IX) and cis-decalin (X), The conformation (IX) of trans- decalin has been accepted for many years, whereas (X) differs from the two boat Sachse - Mohr cis-decalin configuration (XI) which is usually depicted in the text books.
H
.H A
(IX) (XI)
Ejqierimental evidence that (X) is the correct represen tation of cls-decnlln has been obtained by the electron diffraction studies of Hassel and his colleagues and - 1^? -
is supported by a wealth of ohaiaical evidence.
Reasons for the existence of preferred conformations
In general, it can be said that the energy of p pr'.rticular conformation of a molecule depends on the presence or in specially formed cases, the absence of repulsive interactions between non-bonded atoms. To a certain extent these repulsive interactions can be modified by bond-angle deformation. Modification by bond extension is not important because of the relatively large onergy requirements for such a process. In the absence of a direct physical evidence the most stable conformation of a molecule may then be selected by the principle of minimisation of (repulsive) non bonded interactions.
General Rules
A.S a consequence of conformational analysis of various sj^ems, Barton^^ has generalised certain rules governing a reaction in the light of conformation.
Thfcs> aret
(1) At a given carbon atom in a cyclohexane ring system an equitcrial substit lent is in general more stable than an axial substituent,
(2) For r-jlatlvel;/- readily Ir^-elimination re-ction or ionic type tho necessary geometric condition is that the four centres of importance in tho reaction should lie in one plane. - 13 -
(3) For rearrangement reactions of the Nametkin type or related reactions in which the ring carbon atoms are not (formally) involved, reaction proceeds in cyclohexane rin^ systems, most readily if the groups which are eliminated or migrated are in axial confor mations,
(4) For rearrangement reactions in a cyclohexane ring system in which a change in the number of ring atoms is involved, the reaction proceeds with greater facility (and often exclusively) v/hen the group elimi nated possesses an equatorial orientation. The enhanced reactivity of isobornyl compounds is an illustrative example of this generalisation,^®
(5) When an oxide ring is opened, the product of ring opening has the carbon-hydroxyl bond and the newly formed carbon-addend bond both axial.
(6 ) At a given carbon atom in a cyclohexane ring system an axial, is more hindered for acylation reactions than an equitorial hydroxyl group.
All these generalisations have been found tf much help in explaining various reactions particularly 16 28 in steroid series. ’ present the subject has developed in three different directions. First, conformational analysis of unsaturated and of aliphatic 29 systems has become customary. Secondly, the study of conformational equilibria and of the effect of such 30 31 equilibria on reactivity has been initiated. » - 14 -
Thirdly, exploration has begun of the more subtle influences exerted by minor changes in conformation upon changes in reactivity.
Occurrence of Macrocyclic Musks
Musk as it is commonly known in commerce, is
the dried gland obtained from musk deer, Moschus moschiferus. This egg-sized gland is situated beneath
the abdomen of the male musk deer, a small wild animal found in the mountaineous regions of Centr il Asia, particularly the Himalayasj the apparent function of
the musk is to attr:ict the female animal. From about
60.000 deer killed per year, there results an average
2.000 kg. of the valuable musk pod.^^ Walbaum^ first
isolated from musk a ketone in the form of an o il,
b.p. 145-7°/3-4 mm., obtained in an yield of a little
over and named it as muscone.
Civet is similarly found in a peculiar sac
situated near the anus of the civet cat, the Abyssimian
Yiverra civetta and the Asiatic Viverra zibetha.^^
This natural excretion is collected every nine days from
both male and female animals specially bred for the
purpose, the average yield from one cat being about 25 g.
at a time. It is a yellowish to light brown paste with
a characteristic odour which is due mainly to two
compounds, skatole and civetone, both of which were
isolated by Sack.^ - 15 -
The pioneering work of Ruaicka^'^ led to the establishiE,ent of the constitution of civetone (XII) and muscone (X III) as derivatives of cyclcheptadecaite and cyclopentadecane respectively.
Cil, (C H ^ )^ ^ CH3
PH CH.(CH2 )7 '
(Cilo)np CH2 \ V CO
(XII) (XIII)
The North American musk rat, Ondatra zibethicus rivalicius has recently become a commercial source of pure musk compounds. Stevens and Erickson have found that 98^ of the potential musk in the natural secretion of the musk rat is in the form of odourifer- cusly uninteresting alcohols, dihydrocivetol (cyclohepta- decanol) and normuscol (cyclopentadecanol) with only traces of the corresponding ketones. For these ketones, viz., dihydrocivetone (XIV) and exaltone (XV), the above authors gave the following structures v/hich have been supported by their syntheses,
(CUo)i4 CO
\ ch/
(XIV) (XV) , 16 -
It is interesting to note that the musk odour is found in other animals also,^® as in the flesh of musk ox, Vibus moschatus; the dried blood of the alpine goat, Capra ibex; the feces of marten, Mustela folna; the urine of the rock-badger, Hyrax capensis; and in certain organs of the zebu, Bos indicus; jjecari, Dicotvles torquatus; musk duck, Ana moschatus; desma, Moygal moschata; crocodile, Crocodilus vulgaris; turtle, beetle, etc. Cf these, the urine of rock-badger in concentrated form is occasionally marketed as hyraceum.
Apart from the above-mentioned animal sources, a number of plant products also possess musk-odourous principles. The two important products belonging to this class are angelica root. Archangelica officinalis
Hoffm. and ambrette seed. Hibiscus abelmoschus L. ; the former contains exaltolide (XVI) as its odoriferous principle and the latter owes its musk odour to ambrett- olide (XVII), Kerschbaum'^® assigned the following structures to these lactones.
CH2.(CH2)g.GCv^ CH. (C%)5,C0>. 0 I © CH. (CHg)7.CH/^
(XVI) (XVII) - 17 -
In addition, the common musk plant, musk mallow,
Malva moschatus; musk melon, Curcumus melo ] musk
thistle. Cardans nlctaus ; musk orchis, Herminicum
monorchls; and the roots of the sumbul plant found
in Bokharo, Ferula sumbul, are all reported to possess
musk odours.
Methods for the Preparation of Macrocyclic Compounds
Tho fact that nature produces a stable compound
having seventeen carbon atoms in the ring (i.e. civetone),
encouraged Ruzicka to attempt synthesis of compounds of
a type traditionally regarded as incapable of existence.
Ruzicka’ s Method
Up to 1926, the largest rinj, compound known was
cyclooctanone, which had been obtained in minute quanti
ties by pyrolysis of the calcium salts of azelaic acid.
Ruzicka and his co-workers'^^ examined the preparation
of cyclic ketones by pyrolysis of the motal salts of
dicarboxylic acids with extended chains in vacuum at
about 300®. They found th.^t the thorium, cerium or
yttrium salt mixed with copper powder (which aids
heat conduction) gave comparitively good yields of
large ring ketones containing one carbon atom
less than the starting acid. Following this method,
Ruzicka, etal. prepared large rings containing upto
thirty-four carbon atoms. A number of products were obtained by the distillation of a particular acid, viz., a cyclic hydrocarbon, a cyclic monoketone (XVIj.I) and a cyclic diketone (XIX),
(CH2 )n CO -•-- (CH2 )n -- ^ (CH^)n (0^2 )n CCOH | _ --
(XVIII) (XIX)
The yields obtained wore as follows*
C7 and Cg ketones - Fair ('^0-40$^)
C9 to Ci3 kotones - Kot more than 0,5%
From C]_3 upwards the yield improves, reaching
a maximum of 5% for Cis ketone and then falls
again to about 2%,
Ziegler* s Method
Ziegler^^ pointed out that the method employed
by Ruzicka, for the synthesis of the higher cycloalkanones was inherently unfavourable to rinis formation, because
the reaction occurs in a condensed phase which favours
intermolecular as opposed to intramolecular reaction
(i.e. polymerisation rather than cyclisation), He applied
to the problem a principle enunciated earlier by Ruggn,'^^
that the intramolecular ring closure is favoured when the
reaction is carried out at high-dilution in a homogeneous medium, under which conditions the competing intermolecular - 19 -
reaction of the second order yielding polymeric products remains suppressed,
Z ie g l e r ^ applied the Thorpe-iraino-reaction to dinitriles using the ether-soluble lithium salt of ethyl aniline, CgHs - N - CgHsLi^ as the reagent* The reaction product seperates out as the lithium compound insoluble in the ether used as solvent; the reaction thus becoming practically irreversible, as shown in
Scheme I ,
Scheme I
^ C H o .C N Li.N.(C6H5)>(C2H5)
Li •Cil.CK (Siiq)n + CgH . NH.G-^Hq '^C H o.C N
•GH.CN (pa \ acid ^Ql^GN
Giig hydrol. ' '"CHg
(0rf5)n CO ' ^0K 2 - 20 -
A rather elaborate apparatus was used in order th^t the reaction could be effected at exceedingly high- dllution. A solution of 0.2 mole of dinitrile in 500-700ml., of benzene was added at the rate of about 2 ml/hr. to a sol tion of the catalyst in 3 l.of ether with effective stirring. The solution of dinitrile could not be added dropwise, since even a single drop causes too high a local concentratior^ rather, the dinitrile solution was continuously displaced with mercury through a capillary tube whose orifice was immersed in the solution of the catalyst.
This general method has been used by Ziegler and his co-workers to synthesise large ring cyclo- alkanones in remarkably high yields as siimmarized in
Table I .
TABLS I
I i i 115 i Gycloalkanone]( C7 j Gg j C9 to C ii j C12 i C1 3 j C1 4 , C1 5 j ------j---j j ------j--- j---- j------j
Yield io { 95 i 8 8 J fiegligible J 8 { 15 { Ca. 60 { A i i X A i i
For higher ring system, a distinct alternation effect was observed; even members of the homologous series were obtained in yields noticeably higher than add members. In all cases, however, the yields of the - 21 -
higher cycloalkanones were jood, a maximum yield of
80^ being obtained for the eighteen-membered ring.
This method for the preparation of large rin^" compounds is very much superior to Ruzicka’ s, but an yield minima exists in this refined technique of c;>clisation also* \n interpretation based on conforma tional analysis has been sug^iested by Prelog,
The high-dilution principle may be applied to any cyclisation reaction which can be effected in solution, and several such applications have been made; those relevant to the subject are by Hunsdiecker, and Blomquist,
Hunsdiecker*s Method 46 This procedure involves an intramolecular condensation of an 6o-halo->S-ke toes ter by the action of potassium carbonate in dilute solution of methyl ethyl ketone to yield a cyclic >S-ketoester, which on hydrolysis and»decirboxylation furnishes the corres ponding cyclic ketone, as per Scheme II.
K2 CC3 ,MeEtCC X.GHg. (Gii2 )n.C 0 .CH2 .C 0 g.Et high dilution
^ G O (CHq)n Cti.GO<^.Et -- - - 22 -
Macroc^clic ketones fourteen to seventeen carbon atoms have been thus obtained in good yields.
Blomqulst' s Method
47 Blomquist and his coworkers have recently applied the dilution principle to the synthesis of large ring ketones by an internal ’’dimerisation" of bifunctional ketenes. The acid chloride of an
“dicarboxylic acid on treatment with triethylamine in ether solution, employing the high-dilution conditions, furnished the bifunctional oc, co-diketenes, which readily undergo Intramolecular condensation to a product analo gous to a ketenedimer, and this on alkaline hydrolysis and decarboxylation gave cyclic ketones, v iz. the macrocyclic ketone, the diketone, together with polymeric products as depicted in Scheme III.
__ III
^0Il,.CC01 on = 00
^CUp.COCl ^ ^C ii = GO
GH OH' .dimer is at ion ^ 0 — 0 I I -COo CH-CO
CO -f (GHc?)nfo ^C drf ^ 0 0 - ^ - 23 -
The yields are lower than the Ziegler's or
Hunsdiecker's process, owing to considerable linear polymerisation, but the starting materials are claimed to be more readily available,
Acyloin Method
Hansley^^ found that oc, cu-dicar boxy lie acids, on treatment with finely divided sodium in hot xylene, gave cyclic acyloins. Prelog,and Stoll,applied this procedure independently and simultaneously, for the preparation of higher-membered cyclic acyloins with excellent results. The process involved vigorous stirring of a sc lution of the ester of , co-dicarboxylic acid ii'i hot xylene with molten sodium. An intratnolecular acyloin condensation takes place to give cyclic -hydroxy- ketones. It is important that the reaction be carried out in the absence of any freealcohol and oxygen.
In recent years the electronic concept of the free radical aifion (XX) formation has been used to explain the acyloin formation as presented in Scheme IV. - 24 -
Scheme IV
Na + RCCH' -- ► RC — OR’ + iia
o: ;o:
(XX)
^6 : 0 n T RG-CR'RC--CR --- ^ RC-CR + ^ R'0
^CtV '‘CR’
0 0 :E: ^ «l HO - OH + 1 Ha ^ RC = CR 4. 3 Na'" HC=CH==RC-CR
The yields by this oiethod exceed those by any other described earlier, and an added advojitage is that the reaction does not have to be carried out at high- dilution. Even in the low yield region (Cg to C1 3 ), yields of about 40^ v;ere realized by the acyloin cyclisation. This new teclmitiUe, Xirhich has superseded the earlier methods, undoubtedly represents the major single advance in the field of macrocyclic compounds.
The acyloins were reduced to the ketone with zinc and hydrochloric acid or by dehydration (passing over artiininium oxide at 330®) followed by hydrogenation of theoc, /3 -unsaturated ketone. - 2 5 -
Gram^^ has developed a new method lOx’ the redaction of an ac/loin to the corresponding ketone.
The acyloin or its acetate on treatment with propane- ditniol gave the mercaptal, which was converted to the ketone by ordinary hydrolytic methods. Yields of about SOfc were realised at each, stage.
Those methods for the reduction of acyloins are, however, not applicable for unsaturated acyloins, and in such cases metal-,amine reduction has been employed in the present investigations.
Large Ring Lactones
The formation of large rln^ lactones by direct ring-closure of -hydroxyacids has been studied by
Stoll and Rouve' working at high-dilution in boiling benzene using benzene-sulphonic acid as a catalyst. Water was removed progressively during the reaction, the reversal of waich was thus largely prevented. In this way the sixteen- and seventeen-membered rings were obtained in yields of 87 and 94^ respectively. 53 Recently, Carothers has developed an improved method for the preparation of these lactones, involving thermal depolymerisation in vacuum of the polyester of
w-hydroxy acids.
These methods will be discussed in detail in
Partlllof the thesis. - 26 -
NEWLY DEVELOPED METHODS
Macrocycllc Compounds from Acetylenes
Recent years have witnessed a remarkable growth
in both the industrial and academic applications of
acetylenic compounds
Medium-sized carbocyclic compounds containing
n acetylenic linkage are v/ell-known,^^ cyclooctyne
being the smallest so far obtained. However, cyclic o(,)f-diynes have been only recently prepared by Eglinton
and G a lb r a it h ,^ and Sondheimer and his co-workers
Eglinton and Galbraith found the intramolecular
oxidative coupling of (x, w-diynes to be a convenient
route for the preparation of cyclic conjugated diynes,
the formation of olymeric diynes,— [c = C-(CH2 )>n—CsCj-jf
being largely avoided under high dilution conditions.
For example, tetradeca-1,13-diyne(XXI) on treatment with excess of cupric acetate in methanolic pyridine
in high-dilution, formed cyclotetradeca-l,3-diyne(X in 20-405? yield and also some of the cyclic dimer cyclo-octacosa-l,3,15,17-tetrayne(XXIII), The combined yield of pure monomer and dimer was around 50$^, the relative proportions depending on the experimental conditions. CH = C-(Cfi,)io-c=GH (XXI) ^ ’ rc = c-~c=c-i /-G = c~cscs^ (('^ )l O ^*^^^^10 ■(CHo)2 >'10 / C = C —CC = GG '^ IXXII) (XXIII) - 'Tl - From a study of molecular models, Eglinton, et al. concluded that the smallest reasonably stable ring containing two acetylenic bonds would have twelve- members. Suca a compound, namely, cyclododeca-1,7- 58 diyne has been prepared by Cram and Allinger via an acyloin type cyclisation. Tile cyclisation procedure employed by Sondheimer 57 and Amiel involved the oxidative coupling of terminal diacetylenes in aqueous ethanol at 55® in the presence of c®uprous chloride and armnoniura chloride, oxygen being bubbled through the mixture. Thus octa-l|7~diyne (XXIV a) furnished about 10% of the cyclic dimer, cyclohexadeca-1,3»9,11-tetrayne (XXV a), besides the linear dimer and tetramer. pCsG~C = C-i HC = C~(CH2)n~C=CH ---- ^ I (Cd2 )n *-C = C-C = C- (XXIV) • (XXY) a, n = 4 b, n = ^ Sondheimer et al.^® have studied the scope of their method and fcfund that diacetylenes in wnich the terminal acetylenic groupings were seperated by at least ten methylene groups (XXIV, n=l^^) failed to give cyclic products. Further the yield of cyclic tetrayne(XKV) increases as n decreases as far as n=3. Oxidation of hexa-1,5-diyne (XXIV b) yielded some polymeric material and no c clododeca-1,3, 7, 9-tetrayne (X.CV b). Furth'r investigations,®^ on the oxidative ccupling of terminal diacetylenes of the type (XXVI) by simply heating in pyridine solution with neutral cupric acetate, led to a very significint discovery, that.not only the cyclic dimers (XXVll) were formed, but also the cyclic trimers (XXVIII) tetramers (XXIX), pentamers (JLiX.) ^ hexamers (XXXI) and higher cyclic polyacetylenes were obtained as shown in Fig.l. Except in the case of (XXVI d^, only small amounts of the linear coupling products resulted. For example, 1 part of nona-l,B-diyne(XXVI a) in 1 0 0 parts of pyridine was heated and stirred with 15 parts of neutral cupric acetate at 55® for 3 hours. The product on elaborative chromatography was resolved into: (i) the ClS-tetrayne (XXVII a) (10^); ( i i ) the Cq7 -hexayne (XXVIII a) (13?2); ( i i i ) the Gsg-octayne (XXIX a) (11^)-, (iv) the C4 5 «decayne (XXX a) (4^) i and (v) probably the C5 4 ~dodecayne (XXXI a) (4^)* Sondheimer and his co-workers have made a glorious contribution in this field through their extensive studies leading to the synthesis of a series of hitheito unknovm large ring poly-enynescyclo- polyenes,^^ and polyoxygenated macrocyclic compoxmds,®^ such as the Ci4 -dione, Coi trione and the in addition to the large ring poly-acetylenes described above. HC:EC-(CH 2 )n-C = CH pC=C-C5C-| (Ch.^;n iCH2 )n "XXSZK (CH2)n (CHp) -CEC-CHC-(CH2)n / \ ! I C C C C /^y \\\ (II HI c c c c / \ 1 I ■ V c C c c V/ \\\ 111 III c c c c (CH2)n-C5C-CEC-(Cho)n iCH^)-C=C-C~C-iCH2i^ xxyiir XXIX (CHJn C''' '^C c (CHgin ("cHgln C C III C c / c Q ■ 'c . Q (GH2)ri-C£C-CEC-(CH2)n CH.Jn-C=C-CEC-{CH2)n C '"c ■ ■ ■ c XXX C "c '// ,N\ c c ( CHJn > CHJn a, n=5 C > C b,u n=4 ^ C c, '1=3 xxzr d, n - 2 (''cH^n~C^C-CEC-(CH2 )n F m . 1 - q9 - This method makes available in one step xiighly urisaturatGd large ring alicyolic compounds, and by hy-rogenaticn, the corI’espending saturated ones, over a vride range of size. These compounds, however, have no perfumery value 5 but are extremely interesting for academic studies. Exaltellde from A^cetylanes Eglinton and his co-workers^*^ have reported a new synthesis of exaltolide in which the sixteen- membered ring was closed by a high-dilution intra molecular oxidative coupling, involving the terminal ethynyl groups of but-4-ynyl'-undec-10-ynoate (XXXII), to produce an 8 8 ^ yield of crystalline 1,15-pentadec- 10,12-diynolide (XXXIII). Catalytic hydrogenation of compound (XXXIII) gave pure exaltolide (XXXIV) according to Scheme V, Scheme V CH = C. (Cxl3)2.0.C0. (CHg)g. CsQH Cu(0 Ac )2 in pyridine-ether ^XXXII) tig - PtOg in G • (Gi]o)g. (G sc )g . (CH2)8.C0 ethyl acetate (x ;a i i i ) 0 . (C CO (XXXIV) - 30 - Vlith the object of studying ways for the s3mthesis of macrolide and polyenlc antibiotics, Bergelson and his collaborators®^ have developed a method similar to that of Eglinton described above, for the preparation of diacetylenic macrocyclic lactones, by the cyclisation of terminal diacetylenic esters in high-diration conditions, Macrocyclic Musks from Ustilaglc Acid Ustilagic acid®® is a metabolic product of corn smut in artificial culture. On degradation, it liberates the hydroxy hexadecanoic acids, termed ustilic acids, which serve as starting materials for COgH CO2H (CH2),o HCOH I I HCOH (CH9)tp 1 I ^ CHpOH HCOH I GHgOH Ustilic Acid ‘A* Ustilic icid »B' the preparation oi a variety of macrocyclic musk, of i/hich exdltoliae is most desirable. Musk-like Compounds f rom Diketones The readily available diametric diketones 1,9-cyclohexadecane-dione (.OCXVI) and 1,10-cyclo- octadecane-dione (XXXVII) have been reduced, by - 31 - Blomquist and his co-workers^'^ to the musk-like compounds, cyclohexadecancne and cyclcoctadecanone in good yields by catalytic hydrogenolysis of their monoethylene dithioketals. ( d i g ^ ( C H g ) g ^ CO CO CO CO (XiCCVI) (XXXVII ) Further, the diones (XXXVI) and (XXXVII) have been converted to 8 -cyclohexadecen-l-one and 9-cyclo- octadecen-l-one respectively, by partial hydrogenation 68 followed by dehydration. Russian Work 69 Belov dt al. have reported a production - feasible synthesis of lactones having fifteen to seven- teen carbon atoms by cyclising w-hydroxy acids. A 70 recent soviet patent disclosed the preparation of raacrocyclic lactones and oxalactones from tetrachl6 ro- alkanes with nine to seventeen carbon atoms. Electrolysis of a mixture of «•>-acetoxy-undecanoic acid and monoethyl adipate has been reported to yield ethyl Hbout 16^ / -w-acetoxy pentadecanoate, which could be used for the preparation of cyclopentadecanolide,'^^ 3^ Japanese Work Yonetani and Kubo'^^ h ’Ve described the synthesis ci' cyclopenfcadecanone usin-^ undecylenic acid as the starting material. Macrocycllc Ureas and Amides Iwakura and Uno'^3 reported the sjtithesis of macrocyclic N-alkyl amides and N,N'-dialkyl uroas, 2-Methyl-2-aza“ cyclohexadecanone (XXXVIII) was s:,Tithe- sised from tetradecane-l,14-dicarboxylic acid and was found to have a muslv-like odour. CH^ - N ------C * 0 -(Cri2)i4 — (XXXVIII) Work dene at the National Chemical Laboratory,Poona A mjmber of syntheses have been developed in this Laboratory, for the practical preparation of raacrocyelic compounds starting with cheap and indigenous raw materials. These include the preparation of civetone dic'irboxylic acid from oleic acid,"^"^ dihydrocivetone and exaltone from karalolenic acid,?5 exaltone and exaltolide from erucic acid Those processes have been patented in India and some of the leading countries of the West. - 33 - Interlocking Rings Wasserman'^2 has recently reported the formation of a macrocyclic acyloin in the presence of a macrocyclic hydrocarbon, to give a small but demonstrable yield of a catenane, a species comprised of two interlocking but otherwise non-bonded rings. The preparation involved the acyloin condensation of diethyl tetratriacontanedioate (XXXIX) to form the cyclic acyloin (XL), which on Clemmensen reduction with deuterated hydrochloric acid produced the cyclic hydro carbon (XLI), The transformation of (XXXIX) to (XL) was then carried out with a 1 :1 mixture of (XLI) and xylene as solvent. From the reaction product, the pure acyloin fraction was obtained by elaborate chromatography and this fraction was proposed to contain the catenane(XLIII), Oxidation of (XLIII) cleaved the acyloin containing ring followed by unthreading to give (XLI), the presence of which v/;\s demonstrated by its chromatographic behaviour, infrared dpectrum, m.p. and mixed m.p.; the diacid(XLII)from the acyloin ring was also obtained as shown in Scheme VI. - 34 - Scheme__ Y1 EtO^C •(CH2)32-G02Et (XXXIX) = 0 Zn(H2 ) (CHo )32 HGl (XL) \cxIOH DCl i HOg C (C ) 22 cop H Gs4^i63D5 (XLII) (XLI) 0 II H ,^C I ■OH '(Clip) 32 (XLIII) The catenane (XLIII) is the first demonstrated ex mple of a compound in which the topology of the system must be considered in describing its structure. Such compounds are potentially important poljnners, Odour and Constitution The odour of synthetic alicyclic ketones and lactones is related to ring size'^^ as listed in Table II. - 35 - TABLE II No.of Carbon 0 D C U R Atoms in Ring Ketones Lactones 5 Almoniy and minty Fruity 6 Alracndy and minty Weak odour 7 Minty Weak spicy 8 Minty • • 9 to 1 1 Camphor • • 1 2 Camphoraceous • 9 13 Cedar, faint musk • • 14 Musk 15 Pure musk Musk and amber 16 Musk-civet Musk 17 Civet Civet 18 Civet, iireak Weak civet 19 V/eak odour • • 20 C dour lass • • By lar the largest group of compounds possessing a somewhat uniform odour type are the musks. At present no less tnan six different structural classes of compounds possessing a musk odour are known, v iz. (i) the macrocyclic musks, (ii) the steroid musks, (iii) the nitromusks, (iv) the indane musks, (v) the tetralene musks, and (vi) the benzene musks. - 36 - Various theories^' * have been propounded to correlate odour and constitution. However, such theories have their limitations. For the sake of brevity, we shall confine this discussion to macrocyclic compounds only. Stoll®^ has drawn the following conclusions regarding the relation between odour and structure of macrocyclic compounds: (a'; In order for the musk odour to be present in any form, the basic ring struci:ure must contain at least fourteen and less than nineteen members and at least one functional group, as to the influence of the latter upon tne intensity of the odour, the lactone group (XLIV) gives the strongest odour, followed by the c rbonyl group (XLV). Anhydride (XLVI) and carbonate groups (XLVII) give weaker odours, whereas hetero-atoms like oxygen, sulphur and nitrogen®^ (XLVIII) can only create very weak musk character. ■Gfio G= 0 0=0 '"- 0=0 (a LIV) (XLV) (XLVI) Gii;, X = 0, S, WH X (XLVII) (XLVIII) - 37 - (b) The introduction of a second carbonyl group completely destroys the odour (X L IX ), a second ester group only i^eakens it (L) or (L I). 0«C G=0 (XLIX) 0=G-(GHo)jj — G=0 0-(G%)n-C=0 0 -(G%)jn — 0 0=C-(GH2 )ih-0 (L) (LI) (c) Introduction of an oxygen atom in the driain of a macrocyclic lactone weakens the odour. BIOGENESIS Speculations as to the formation of essential oils have always been a fascinating subject, Civetone from Oleic Acid Ruzicka^ pointed out the structural similarity betxireen civetone and oleic acid on the one hand and muscone and palmitic acid on the other and proposed that the higher fatty acids may be precursors for the macro- cyclic compounds via omega oxidation to di-acids followed by ring closure. 38 - Stevens^"^ examinod these hypotheses in the light or later Knowledge of the in vivo reactions oi the fatty acids. Scheme VII shows his conceiotion of the biological production of civetone from oleic acid. Scheme V II CrI. (CH2 )7 .CH3 CH. (CHo )7.CH0 Partial II CH. (GH.t )^.CO^H “-Oxidation CH. (CHg)7.C0oH aldol* condensation Cii, (C.Io)7.C0 CH. (CH9 )7 .CdOH II I -oxidation II I C i. (CHo)6 .CH.C0 -2 H CH.(CHo)e.CH.CO^H - - C O o Cxi. vC'i^U.GO CH. (CH9 U.CHOH II ' ’ I II ' ^ I CH. Civetone Civetol ♦Analogous to the ring closure of d in it r ile s .'^ This scheme receives support from the occurrence 01 civetol alongwith civetone in the animal extract. AS identified in Louisiana musk rat extracts, Stevens has shoivn that there is a definite correlation between the percentage distribution of potential homo logous fatty acid precursors and that of the homologous 3R macrocyclic tetones. - 39 - Fatty acids are hydroxylated at the omega position by some mechanism, presumably enzymatically. Such hydroxylation on a ^-methyl carbon has been 85 demonstrated by Wakabayashi and Shimazono in the case of sorbic amide. The methyl group in question was, however, activated by the allylic double bond, 86 S7 Earlier evidence by Kuhn et a l . , and Verkade suggests that w-oxidation may be a wide spread biolo gical phenomenon. The oxygenation of an 6o-methyl group which is not activated may perhaps take place by a mechanism 88 discovered by Bloomfield and Bloch, whereby the C9 methylene of stearyl - CoA was converted to the corres ponding 9-hydroxy compound enroute to oleic acid. This is a '’mixed function’* oxidation requiring atmospheric oxygen and TPNH, The first step in omega oxidation is undoubtedly the formation of a primary alcohol, which is then oxidi sed through the aldehyde to the acid. The occurrence of w-hydroxy pentadecanoic acid, juniperic acid and ambrett- olic acid in certain plants, and aleuritic acid in shellac, is consistent with this hypothesis. Oxidation of a w-hydroxy fatty acid to the corresponding aldehyde and acid has been demonstrated 89 in animal liver by Metz and Heinrickson giving rise to the dicarboxylic acid precursor* - 40 - The dlcarboxyllc acid or its active form may undergo dehydrogenation atoc,^to the activated carboxyl, followed by hydration by a crotonase type system and finally get converted to the ^-keto acid following the usual pajstem of degradation of fatty acids. Muscone from Palmitic Acid The problem of the biogenesis of muscone is not so straight forward and Stevens^'^ considers this ketone to be derived from stearic acid rather than from palmitic acid. This hypothesis is represented in SchemeVIII. Scheme v n I CH2 .CH2 .CCqH '^-oxidation {GH2 )iq.CHo.CHo.C0 ^H (CHg )2.2 • • CHg. COpH bilateral CO /5-oxidation CC * GH3 CO.Ctio.COpH -2 COp j (C H<-)) -j^2 • C 0»C rig (CHg) 12» CO.CHo,CO2H ketol condensation CO CO CH,^ hydrogenation \ — C — GH3 (CH2 ) i 2 — CH — CH3 Mus cone ~ 41 - The last two stiges have since been accomplished In vitro. Unlike the civetone biogenesis, this mechinism does not provide for prior carbinol formation and it is interesting to note thi,t m used does not accompany muscone in the animal secretion. The above scheme would appear more feasible than any hypothesis envisaging the rarely occurring branched-chain fatty acids as precursors. Squalene as a precursor Recent work employing tracer techniques tc study the formn.tion of sterols in plants or the animal kingdom indicates the importance of the role of squalenes which might have a bearing on the formation of terpenes in Cl plants, Polak’' has put forth a hypothesis for the biogenesis of non-terpenic constituents of essential oils involving stepwise degradation of amino and fatty acids. 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