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23Macrocycles Макроциклы
Макрогэтэроцмклы
http://macroheterocycles.isuct.ru
Review Обзор
DOI: 10.6060/mhc161066i
Functionalisation of Macroheterocycles with Preserving and Changing Their Sizes
G. Yu. Ishmuratov,@ M. P. Yakovleva, V. A. Vydrina, М. A Shutova, N. M. Ishmuratova, and A. G. Tolstikov
Ufa Institute of Chemistry, Russian Academy of Sciences, 450054 Ufa, Russian Federation @Corresponding author E-mail: insect@anrb.ru
This review presents methodsforfunctionalisation ofmacroheterocycles occurring both with preservation and alteration of their core. It is shown that the most common methods do not affect the main ring. While functionalisation of macroheterocycles accompanied by both a decrease and an increase of their size is less common, the examples given in the literature indicate the prospects of macroheterocycle functionalisation by described methods in direct synthesis of substances for different purposes: pharmacologically active compounds, selective ligands for various (mainly transient and rare-earth) metals, odorants, etc.
Keywords: Macroheterocycles, macrocyclic size, functionalisation, biological activity, application.
Функционализация макрогетероциклов с сохранением и изменением их размеров
Г. Ю. Ишмуратов,@ М. П. Яковлева, В. А. Выдрина, М. А. Шутова, Н. М. Ишмуратова, А. Г. Толстиков
Федеральное государственное бюджетное учреждение науки Уфимский институт химии Российской академии наук, 450054 Уфа, Российская Федерация @Е-таИ: insect@anrb.ru
В данном обзоре литературы представлены методы функционализации макрогетероциклов, протекающие как с сохранением, так и изменением их остова. Показано, что наиболее распространенные методы не затрагивают их основного кольца. Тогда как функционализация макрогетероциклов, сопровождаемая как сокращением, так и увеличением их размеров, менее распространена, приведенные в литературе примеры свидетельствуют о перспективности функционализации макрогетероциклов описанными методами в направленном синтезе веществ различного назначения: фармакологически активных соединений, селективных лигандов для различных (в первую очередь переходных и редкоземельных) металлов, одорантов и др.
Ключевые слова: Макрогетероциклы, размер макроцикла, функционализация, биологическая активность, применение.
Introduction
Out of several hundred thousand secondary metabolites currently described that are isolated from various sources of natural origin, only a small part has the macrocyclic structure. However, compounds that have powerful antimicrobial, antiviral, antiparasitic, and antitumoral actions were detected precisely among them [1].This is driven by the relentless attention of chemists, biochemists, and pharmacologists to this class of natural metabolites and their synthetic derivatives.
Reviews[1, 2] describe in detail methods of development of macrocycles with ester, nitrogen-, and sulphur-containing functions, and also the use of these methods in streamlined synthesis of biologically active compounds was demonstrated on specific examples. This literature review presents methods for functionalisation of macroheterocycles themselves that proceed with both conservation and a change in their skeleton beginning with 1963 including 3 articles described in the review of 1999.[3]
1.1. Functionalisation of Macrocycles with Preservation of Their Sizes
The most common methods for functionalisation of macroheterocycles do not affect the size of cycles.
One of them consists in oxidation of the hydroquinone fragment that is a part of a macromolecule. Thus, compounds with high antiproliferative activities and abilities to inhibit Hsp90-dependent protein degradation that are potential
agents to cure cancer (Scheme 1)[4] are obtained in synthesis of radamicine (1a) and its seco analogues (1b-i) that represent series of macrocyclic chimeras radicicol (2) and geldana-mycin (3) that are strong inhibitors of the Hsp90 N-terminal ATP-binding - macroamidation of acyclic precursors (4a-i) under the action of HATU and oxidation of the resulting hydroquinones (5a-i) into appropriate quinones (6c-i) (Scheme 1).
Unsaturated cycles, functionalization of which occurs on multiple bonds, are often formed resulting from macrocyclization. Thus, in target synthesis of biologically active macroheterocycles, after the stage of the formation of unsaturated cycles, the reaction of reduction of multiple bonds follows: exhaustive hydrogenation of C=C, C=C and C=N bonds over Wilkinson's catalyst, Raney nickel and Pd/C,[6-11] reduction of C=N bonds using NaBH4 or LiAlH4 [6-12] and partial hydrogenation of the C-C triple bond to Z-double over Lindlar catalyst[13-18] that allow obtaining both isolated bonds, and conjugated systems.
For example, a method for hydrogenation of a double bond over palladium catalyst has been demonstrated in stere-oselective synthesis of macrolactames of fluvirucines B2-5 (7) showing properties of antibiotics and strong inhibitors of A virus with low toxicity.[19] Construction of the macrocyclic skeleton of species 7 was carried out by the metathesis reaction of acyclic precursor, i.e. diene 8 over the second generation Grubbs catalyst leading to a mixture of Z- and E-isomers 9 easily separated by silica gel flash chromatography. Hydrogenation of both isolated isomers (9E) and (9Z) and their mixture proceeds highly stereoselectively over a palladium catalyst with the formation of 6^-isomer (7) as major (after
Scheme 1. a) HATU, HOBt, i-PrNEt, DMF, 70 oC (72-80 %); b) TMSCl, Nal, MeCN, CH2Cl2 (73-90 %); c) Pd/C, MeOH, air (70-80 %). 346 МакрогетероцикJlbl /Macroheterocycles 2017 10(3) 345-379
crystallization of dr 97:3). High stereoselectivity of hydrogenation process may be explained by depicting 10Z-and 10£'-conformers of compound (7) with the minimum energy: the upper verges of the both isomers are most available (Scheme 2).
Crownophane-type macrocycles are especially attractive for selective recognition of inorganic and organic cations, anions and neutral substrates.They can also be used as a platform for the development of systems, e.g., rotaxanes and catenanes. The authors[19-21] have reported of convenient and efficient synthesis of crownophanes (10a-m) with two amide and two hydroxyl groups by direct amidation of dichlo-roanhydride (11) with a series of achiral and chiral diamines (12a-m) followed by the involvement of the resulting macrocycles (13a-m) in the tandem Claisen rearrangement. The latter reaction allows obtaining macrocycles with naphthol fragments without using special conditions (high dilution) (Scheme 3).
The study of properties of the synthesized macrocyclic bis-amldonaphthol (10) in relation to anions testifies significant effects of the sizes of macrocyclic rings. For example, macrocycle (10c) shows selectivity towards F ion that has unique chemical properties and plays a significant part in stomatology, the treatment of osteoporosis, etc. It was also demonstrated that acidity of the hydroxyl group might be controlled by ring sizes, which enables it to differentiate a subtle difference to affinities of F, CH3COO" and H2PO4" ions.
Polyazamacrocycles have attracted much attention, since they have found applications in various areas, such as ion release, extraction and catalysis. The presence of additional functional groups at one or several nitrogen atoms broadens chelating properties and allows regulating solubility and behaviour in solutions.[22-27] A-Functionalized triazamacrocycles that are prepared mostly by A-alkylation reaction[28-31] are especially attractive compounds to prepare selective ligands that coordinate transition metals.
1,5,9-Triazacyclodecane (14) is an extremely basic azacrown compound (pK3=12.3-12.7) used as an efficient extractant for gold dicyanate anion [Au(CN)2]-. Good solubility of the resulting complex in water significantly worsens its transfer to the organic phase. To increase hydro-phobicity compound (14) was transformed into mono- (15), di- (16) and tri- (17) A-dodecyl derivatives.[32] Alkylation
of triamine (14) with excess w-dodecyl iodide in DMF in the presence of NaHCO3 proceeds with the formation of disubstituted compound (16). Selective alkylation of two out of three equivalent nitrogen atoms of compound (14) may be explained by high proton affinity of the ring. Reductive amination of compound (14) with w-dodecanal yielded trisubstituted product (17). Monoalkylated macrocycle (15) was prepared using the Parker approach involving condensation of a diethylmalonate and bis(3-aminopropyl)amine (18) in the presence of catalytic amounts of sodium meth-oxide in ethanol. The presence of unequal nitrogen atoms in the resulting cyclic aminodiamide (19) allows carrying out alkylation chemoselectively and obtaining monosubstituted amine (15) after reduction of amide groups (Scheme 4).
Synthesis [33] of two optically pure ligands (20) and (21) containing the Z-lactic acid residues in side chains and used for coordination of Mn2+ ion included successive treatment of cyclic triamines (23) and (24) obtained from acyclic precursors (18) and (22)[34] with K2CO3 base in the polar aprotic solvent DMF and bromodiester (26) that is a product of chemoselective transformations of L-lactic acid (25) (Scheme 5).
Alkaline treatment of A-macrocycle (27) obtained by condensation of bis-(3-aminopropyl)amine (18) with 2,6-pyridine dialdehyde (28) followed by hydride reduction, and then with 2-chloromethylpyridine (29) leads to trisub-stituted derivative (30) able to form chelate complexes with a broad number of elements, such as Ca2+, Co2+, Ni2+, Zn2+, Cd2+, Pb2+, Ga3+, Fe3+, and In3+ (Scheme 6).[35]
The presence of four secondary amine functions in tetraazacycloalkanes allows unlimitedly obtaining their derivatives showing better analytical properties (e.g. UV spectrum, fluorescence, thermal stability, volatility, etc.). Particularly, 1,4,7,10-tetraazacyclodecane (cyclen) (31) from bis(2--aminoethyl)amine (22)[36,37] and 1,4,8,11-tetraazacy-clotetradecane (cyclame) (32) from A,A'-di-(2-aminoethyl)-1,3-diaminopropane (33)[38] are used as ligands for selective binding of metal ions into very stable complexes (Scheme 7).
Some derivatives of cyclen (31) and cyclam (32) completely substituted with identical functional groups show selective coordinative properties towards transition and heavy metal cations, lanthanide and actinide ions, and organic and inorganic anions with precise behaviour depending on cavity size and substituent nature.
.otbs
9Z
9E
Scheme 2. a) Grubbs-II, toluene, 80 oC (85 %); b) H2 Pd/C, toluene; c) TBAF, THF. Макрогетер0циmbl /Macroheterocycles 2017 10(3) 345-379
h2n-r-nh2
12
Yield of 13
13, method
Yield of 10
Ref.
NH2СН2СН2NH2 NH^)^ NH/^XN^ NH2(СН2)12NH2
h2n^.........
hn^ph nh^v-ph
nh
nh
nh
X
ph
'X)
h2n.
h2n-
h2n h2n
nh2
nh2-v
nh2 nh2
X)
.......o
"o
NHjS/S
o
JO
O
~nh2 -nh2
12a 12b 12c 12d
(R,R)-12e (S,S)-12f (R,R)-12g (S,S)-12h 12i (S,S)-12j 12k 12l 12m
43 % 86 % 69 % 60 %
30 % 38 % 30 % 35 % 66 % 52 % 83 % 74 % 52 %
13a, А 13b, B 13c, A 13d, B
13e, B 13f, B 13g, A 13h, А 13i, А 13j, B 13k, B 13l, B 13m, B
20 % 81 % 100 % 83 %
60 % 80 % 62 % 55 % 32 % 88 % 43 % 81 % 82 %
[96] [98]
[97]
[98]
[96] [96] [96] [96] [96] [96] [96] [98] [98]
2
o
Scheme 3. а) H2N-R-NH2 (12a-m), Et3N, C6H6, 50 °C; b) PhNMe3, 180 °C (method А) or 150-180 °C (method B).
Tetraphenylsulfonyl- (34) and optically pure tetraphenyl-sulfenyl- (35) substituted with cycles used for complexation with Cu2+ and Eu2+ ions are accordingly obtained by the interaction of unsubstituted cyclam (32) and a slight excess of phenyl vinyl sulfone (36) and (R)-p-tolyl vinyl sulfoxide (37) under aza-Michael reaction conditions (Scheme 8).[39]
Tetra-^-substituted cyclen with carbamide side chains (38) are readily obtained by treatment with butyl isocyanate (4 equiv) of unsubstituted cyclen (31) (Scheme 9).[40]
Aminocarboxylate derivatives turned out to be extremely valuable for obtaining highly stable chelates with lanthanoids. In turn, the latter have found applications
h2N
h2n.
18
I
r
17
w . yy° . n
.NH HNV
19
n
-nh hnv
14
^NH HNV
I
r
R-v.r^l/R
16
nh hn.
■Nv I
R 15
R = n-Dodecyl
O O
Scheme 4. a) EtO^^OEt, MeONa, EtOH, A (22 %); b) C12H23I, DMA (60 %); c) BH3-THF, A (99 % for 12, 95 % for 16); d) C12H23I, NaHCO3, DMA, 80 °C (88 %); e) C11H23CHO, NaCNBH3, H2O/MeCN, ph=4-5 (90 %).
I —
H0*^C02H AcO" 25
C02H
OH d
Br
AcO C02Et AcO C02Et AcO C02Et
26
OAc
EtO
NH,
nh-
w 18,22
2 e-g
hn nh
(()n ())n
23,24
n' h
oh
HO
O^/OH n n ^^ oh
20,21
ho1
OEt
oh
n = 1 (20,22,23) n = 2 (18,21,24)
Scheme 5. a) AcCl, Ac2O; b) EtOH (100 %); c) BH3-THF, 0 °C (70 %); d) Ph3P, Br2 (75 %); e) TsCl, NaOH, Et2O, H2O (97 % based on 18, 57 % based on 22); f) Br(CH2)nCH2Br, K2CO3, IDMF (24 % based on 18, 8 % based on 22); g) H2SO4, H2O, 100 °C (88 % based on 18, 79 % based on 22); h) 26, K2CO3, DMF (48 % based on 18, 54 % based on 22); i) HCl, H2O, 100 °C (80 %).
n
o o
28
n
nh hn
A
27
b, c
Scheme 6. a) 18, Cu(NO3)2, EtOH, H2O then NaBH4 (86 %); b) NaOH, H2O, CH2Cl2; c)
N=\
ClH2C^>
(29) (55 %).
22
a-d
r™i C ) — C )
k______z1 nh hn nh hn
nh2h2n,
nh hn
31
nh hn
u
•nh hnx nh hn"
33
32
Scheme 7. a) TsCl, Py, 50 °C; b) EtONa, EtOH; c) DMF, 100 °C; d) H2SO4, H2O, 100 °C (80 %); e) Br(CH2)3Br, KOH, EtOH (80 %).
Ph' ^/N N
°SP
....... Ph a b
-- 32 -
Ph'
pVCn
O O ............... 0 0
:n n.
Ph
34
O ^^ 6 35
V/°
Scheme 8. a) (36), i-PrOH, H2O (82 %); b)
3R-(37), i-PrOH, H2O (69 %).
'Tol
31
bu. AnA
n n^
:c )
n H
H
O O
38
Scheme 9. a) 4 Bu-NCO, CH2Cl2 (90 %).
in medicine for diagnostics and as therapeutic agents. On the other hand, separation of f-elements (lanthanoids and actinoids) is of interest in production of nuclear fuel, since treatment is very difficult due to close chemical properties, moreover, cation radius size may turn out to be the key factor. Thus, in order to assess the effect of cavity size of macrocycles for complexation with the participation of cations 14-membered macroheterocycle (39) able to form stable complexes with some lanthanoids (La, Pr, Nd, Eu, Gd, Tb, Er, Yb, Lu) at various medium acidities is synthesised. Synthesis is based on alkylation of cyclic triamine (27) with acrylic acid under aza-Michael reaction conditions (Scheme 10).[41-44]
ho2c.
27
,c02h
ho,c 39
Scheme 10. a) CH 2=CHCO2H, H2O, 70 °C (35 %).
Due to the more complex synthesis of partially substituted tetraazaalkanes, they have received much less attention. However, these compounds are becoming increasingly popular, since they are important synthons for synthesis of macropolycycles or unsymmetrically substituted
macrocycles. In fact, mixing various side substituents may increase ligand selectivity for a given ion and will allow carrying out fine tuning properties of complexes. Their use as agents for magnetic resonance therapy is one of the possible examples. Partial substitution may also include coupling complexes with antibodies for radioimmunotherapy or the attachment of ligands into organic or inorganic polymers for their use in the processes of solid-liquid extraction.
Syntheses of mono- and trisubstituted tetraazamacrocy-clic derivatives have been described in detail in the review. [3] It proposes direct functionalisation for symmetric azacrown ethers, to which cyclen (31) and cyclam (32) are referred. Selective monoalkylation of tetraazacycloalkanes assumes the use of a large excess of macrocycles (5-10 equiv of cyclam (32) and 1.5-3 equiv of cyclen (31)) in relation to electrophiles (appropriate halocarboxylic acids) in the presence of LiOH in polar solvents (DMF, toluene, ethanol, acetonitrile or chloroform) and leads to monosubstituted cyclens (40a-c) and cyclames (41a-e) with yields up to 80 % (Scheme 11).
Tri-A-substitution of tetraazacycloalkanes has been more widely studied, since such trisubstituted derivatives are precursors for synthesis of monosubstituted macrocycles. The best result (51%) in synthesis of cyclam tritosylate (43a) has been reached when using a (2.1:1:2.2) molar ratio of tosyl chloride/cyclam (32)/Et3N in dichloromethane. Tritosylcyclen (42a) was obtained with 80% yield upon the addition of tosyl chloride (5 equiv) to macrocycle (31) (1 equiv) in the presence of a large excess (17 equiv) of triethylamine. High yields of tetraazacycloalkanes (42b) and (43b) trisubstituted with tert-butyl carbonyl (Boc) groups (70% for cyclen (31) and 67% for cyclam (32)) were obtained using only 2.4 equiv of di-feri-butyl carbonate (Boc2O). Large differences in polarity of the resulting di-, tri-, and tetra-substituted azamacrocycles facilitated chromatographic isolation of trisubstituted cyclens (42a,b) and cyclams (43a,b) (Scheme 12).[3]
The interaction of cyclam (32) with a large excess of io-doacetamide (44) in acetone in the presence of /'-Pr2NEt as a base is not following the usual pattern: only pure triamide (45) as powders almost insoluble in water and acetone is obtained. Afterwards, it is transferred to triacid (46). The formation of (45) is probably related to a high proton affinity
31
a, b
/ \/R ^NH N.
NH HN
V-l
40a-c
32
a,b
n.
^NH Nv
NH HN
41a-e
Experiment R Solvent Yield of 40, % Yield of 41, %
a ch2co2h EtOH 74 77
b (CH2xCO2H EtOH 72 65
c CH2-m-Py DMF 60 80
d CH2-o-Py DMF - 74
e (CH2)2-o-Py DMF - 40
Scheme 11. a) LiOH, solvent; b) R-X, H2O. 350
31
a or b
N N.
32
a or b
N HN \_/
42a,b
R = Ts (42a, 43a), Boc (42b, 43b).
R^ I I/R
^N N;
R"
N HN
43a,b
Scheme 12. a) TsCl, Et3N, CH2Cl2; b) Boc2O, CH2Cl2.
32
n
H2NOC m HN.
n
HOOC /N HN.
H2NOC^1j^N^CONH2 HOOC^^j^Jf^cooH
45
46
Scheme 13. а) ICH2CONH2 (44), î-Pr2NEt, Me2CO (99 %); b) 25 % HCl.
of the cyclam ring and low solubility of the ion pair formed by the macrocyclic cation and iodide ion (Scheme 13).[45]
Two-step synthesis of mono-A-substituted cyclen (47) with the carbamide side chain consisting in direct func-tionalization of cyclen (31) up to trisubstituted derivative (48) and its treatment with butyl isocyanate (Scheme 14) is an illustration of correlations between mono- and trisubstituted azacrowns. [40]
The literature describes numerous examples of synthesis, in which additional fragments to the already prepared
Cbz. I \ .Cbz R4 / \ .R
,N N4 ^N N;
а С N b
31
N N4 Cbz \_I H
48
H
„N N4 /N4
R- \ / y Bu
R=Cbz
R=H 47
Scheme 14. a) ClCO2CH2Ph, CH2Cl2, Et3N (49 %); b) Bu-NCO, CH2Cl2 (86 %); c) H2, Pd/C, EtOH (98 %).
macrocyclic ring are being completed. Thus, the construction of three-membered rings is one of the methods for C=C bond functionalization.
For example, the cyclopropanation reaction is applicable in case of enantiomeric pure R-muscone (49) that is an odorous substance (muscus) isolated from glands of musk deer Moschus moschiferus.[46,47] Asymmetrically catalysed cyclization of 14-pentadecinal (50) consisting in hydroboration of its triple bond followed by transmeta-lation and interaction with the aldehyde functional group in the presence of (-)-3-exo-(dimethylamino) isoborneol (51) yielded E-allyl alcohol (52) with high (92% ee) enantiomeric purity. Hydroxy-directed cyclopropnation by the Denmark method followed by recrystallization yielded the sole dias-terereomer of alcohol (53), the Swern oxidation of which and reduction of the cyclopropyl functional group completed the synthesis (Scheme 15).
Oxidation of the double bond to epoxide is another option for the construction of a three-membered ring. This approach has been successfully carried out upon the action of meta-chloroperbenzoic acid on olefins in synthesis of ionophor units[48,49] and representatives of a very large family of chemically bound mycotoxins (trichothecins)[50] or 2,2'-dimethyl-
dioxirane (DMDO) in synthesis of epothilone A and B,[51] their analogues,1521 and antibiotic erythromycin derivatives A.[53] Thus, synthesis of erythronolide A (54) derivatives that are macroheterocycles (55-58) with potentially antibiotic properties^^ was carried out by the interaction between DMDO and cyclic èis-allenes (59) and (60) that led to appropriate èis[spirodiepoxides] (61) and (62). Subsequent addition of methyl cuprate to compound (61) leads to chiral macro-heterocycle (55) with four stereocenters and side rearrangement product with C4-C6 oxetane fragments (63). Reduction of èis[spirodiepoxides] (61) and (62) with thiobenza-mide (64) forms thiazoline rings into C-5 and C-11 positions of macrocycles (56) and (57) with 78 % and 74 % yields,
respectively. A decrease in the amount of dimethyldioxirane in 3 times upon epoxidation of (60) leads to the selective formation of keto-alcohol (65) that is further transformed into mono-thiazoline (58) (Scheme 16).
The formation of the epoxide ring is possible under Sharpless conditions. This process has been carried out in stereselective synthesis[54-56] of amphidinolide B (66) that is a representative of a family of amphidinolides that are isolated from dinoflagellates Amphidinium sp. and show anticancer activity. Thus, the generation of macrocyclic structure (67) happens upon spontaneous cyclization by the intramolecular Wittig-Horner reaction of compound (68) that is an oxidation product of acyclic precursor (69) (Scheme 17).
Scheme 16. a) DMDO (6 eq.), CHCl3, -40 °C; b) MeCuCNLi, Et2O, -40 °C (22 % for 55, 17 % for 63); c) PhCSNH2 (64), 0 °C (78 % for 56, 78 % for 57, 78 % for 58); d) i. DMDO (3 eq.), CHCl3, -40 °C, H2O; ii. TESCl, imide, DMAP, CH2Cl2, 0 °C (77 %).
Scheme 17. a) TPAP, CH2Cl2; b) Ba(OH)28H2O, THF/H2O. 352
The introduction of the epoxide ring into macrocycle (67) was carried out in two steps. The first one consisted in stereoselective (dr 10:1) reduction with cathehol borane into allyl alcohol (70) involved in the stereoselective Sharpless epoxidation. In the presence of diisopropyltartrate, dr-selectivity of the latter reaction is 10:1,[54] and in its absence, it is drastically decreased to 1.5:1.[55] Dehydration was carried out via intermediate ortho-nitrophenyl selenide (71) (Scheme 18).
The formation of a four-membered ring was described in synthesis[57] of macrocyclic èis-azetidines (72-74) as convenient chelating agents for a series of metals, particularly, Co2(CO)6. It consists in transformations of diimines (77) and (78) readily available from dialdehydes (75) and (76), respectively, using the double Staudinger reaction accompanied by the formation of two additional four-membered rings. It is noteworthy that diimine (77) with closely located
functional groups reacted low-selectively yielding a mixture (1:1) of cys-syn-cys (72) and cys-anti-cys (73) diastereomers, and diimine (78) almost exclusively turned into cys-anti-cys diastereomer (74) (Scheme 19).
The formation of a five-membered oxazol ring was carried out, for instance, in synthesis of the macrolide ulapual-ide A isolated from marine nudibranch[58] and oxygen analog (79) of the anti-inflammatory thiazole-containing drug halipeptin D (80) of sea sponges Leiosella cf. arenifibrosa. Synthesis of the latter includes cyclization of aminoacid (81) under the action of HATU and macrocycle (82) and the formation of the oxazole ring under the action of DAST on compound (83) (Scheme 20).[59]
We managed to generate highly-stressed 13-membered macrocycle (86) by the intramolecular Ullmann etherifica-tion of compound (85) in synthesis of hirsutellone B (84) isolated from the pathogenic fungus Hirsutella nivea BCC
TT3C
,X>PMB
69
TES
XY Ô
X=OH, Y=H - 71 X=H, Y=Se(o-N02C6H4) HO/ OH o
dy
Scheme 18. a) k , CH2Cl2, -20 °C, (56 %); b) (i-PrO)4Ti, (+)-DIPT, THBP, CH2Cl2, 0 °C (54 %); c) (50 %); d) TPAP, NMO, Et3N, CHC (48 %).
no2 , PBu, THF
75 n = 0
76 n= 1
77 n = 0
78 n=l
PhO
PhO.
>OPh
Scheme 19. a) H2N^^NH2, MeOH, A (94 % for 75), (95 % for 76); b) PhOCH2COCl, Et3N, CH2Cl2, -78 °C (23 % for 72, 27 % for 73, 78 % for 74).
81
, I— 82 R=TBS ° 83 R = H
79 X = 0
80 X = S
Scheme 20. a) HATU, HOAt, /-PrNEt, CH.Cl. (74 %); b) TBAF, THF, -10 °C; c) DAST, CH2Cl2, -78 °C (74 %).
2594 and showing antituberculous activity, and spontaneous stereoselective cyclization into desired five-membered y-hydroxylactam (84) proceeded after the removal of protective groups in cyclophane (87) (Scheme 21).[60]
Another method to generate a five-membered ring was carried out in synthesis of natural danielid (88), i.e. oxygenated furan lactone-containing cembranoid[61] isolated from gorgonian. Treatment of a-siloxy aldehyde (89) with Li-HMDS proceeds with intramolecular cycliza-tion to intermediate (90) that is accompanied with in situ lactonization with migration of the acyl group and leads to the sole diastereomer of furanocenbranoid (91). The removal of ethylene ketal protection and chemoselective ac-
ylation of secondary hydroxyl groups leads to macrocycle (92) that is semiproduct in synthesis of (88) (Scheme 22).
The intramolecular stereoselective Michael addition is one of the key steps in synthesis of leinamicyne (93) with the unique spiro-1-oxo-1,2-dithiolane-3-one structure. This compound is a new antitumor antibiotic. The intermediate thiolane fragment formed under the action of H2S on bromo-ketone (94) is added to the third position of 18-membered a,p-unsaturated lactam yielding a mixture (10:1) of spirosul-phides (95a) and (95b).[62] Isomer (95a) was the chiral intermediate for synthesis of leinamicyne (93) (Scheme 23).[63]
There are examples in the literature when six-mem-bered rings, e.g. hexanolide [64] or tetrahydropyrane-4-one [65]
MOMO
I—{ >—-""""OTBS
85
, , conh2
b, c V/-W h N=< d
-~ HQMOMC
°*OTBS
86
ÇONH
2 e
"ONE,
- . H V< J Hd o
87
84
Scheme 21. a) CuI, Cs2CO3, 1,10-phenanthroline, toluene, 160 °C (42 %); b) TBAF, THF; c) DMP, CH2Cl2 (90 %); d) KOH, t-BuOH; e) HCl aq., i-PrOH, 60 °C (85 %).
co2Et
,co2Et
Scheme 22. a) LiHMDS, LiCl, THF, -78 °C (51 %); b) H2O/HOAc, 100 °C (98 %); c) TBAF, THF, 0 °C (90 %); d) Ac2O/Py (65 %). 354 Макрогетероцикnbl /Macroheterocycles 2017 10(3) 345-379
MOMÛ DMPM 94
10:1
MOMÛ ÛMPM 95b
Scheme 23. a) H2S, Et3N (88 %).
are being completed in macrocyclic species during syntheses of biological objects.Thus, in synthesis of highly function-alised macrocyclic peptidomimetics (96-98) containing nonprotein structural elements that are able to copy or counteract to biological activity of natural protein species, enyne (99) cross-metathesis reaction over catalyst (100) and function-alisation of the resulting diene (101) by the Diels-Alder reaction [66] that allows the formation of additional six-membered rings of compounds (96) and (97) are used (Scheme 24).
Since antibiotic resistance of pathogenic bacteria has become the challenge of the last decade, the study of new approaches to transformations of potentially biologically active compounds is relevant. For example, the nitroso Diels-Alder reaction, i.e. a heteroreaction with nitroso dienophiles was applicable for synthesis of some 10,13-di-substituted 16-membered macrolides (103 a-i) from the antibiotic leucomycin A7 (102).[67] Despite wide functionalities
of the latter, heterocycloaddition proceeded highly regio-and stereoselectively:compounds (103a-i) were obtained as a sole isomer. As demonstrated in the carried out experiments, 2-nitrosopyridines (104a-i) were efficient dienophiles with selective sensitivities to electron and space structures of macrolide (102) with the diene system, which is probably related to their asymmetry. Low yields of compounds (103b and 103c) can be explained by the labile nature of nitroso compounds (104b and 104c), and also instability of leucomycin A7 (102) under oxidative conditions. Derivatives (103a-i) retained antibiotic properties similar to leucomycin (102), however unlike it, they additionally showed antipro-liferative and cytoxic properties, which broadened biological activity profile (Scheme 25).
In synthesis of ^-methylmaysenin (105) i.e. a macrolide that is isolated from several species of Maytenus and represents an extremely promising antitumour drug,
R-N=O
Adducts Yield, %
R-N=O
Adducts Yield, %
O,N-
,JO
N^
^ 104b
LA-o
"n" 104c
^^ 104d
103a
103b
103c
103d
88
26
13
91
Cl.
N N 104f
B,TX
'N^ N"
104g
^ -N<*O104h r^N^S
N 104i
103f
103g
103h
103i
88
86
89
78
104e
103e
90
Scheme 25. a) R-N=O (104a-i), CH2Cl2, 0 °C.
P(OEt)2
MeO.
OMe
MeO
OMe
106
MeO
X e.f
'OX
OMe
C
I— x =
X = EE
X = H 107
X = C02Ph 108
MeO.
= N X> /HO H MeO
105
Scheme 26. a) t-BuOK, THF, -78 °C (74 %); b) HgCl2-CaCO3, MeCN-H2O; c) HCl, THF-H2O (81 %); d) ^ O Cl, THF: e) liq. NH3, -78 °C (50 %); f) HPLC.
I
F
macrocyclization of compound (106) was carried out under Wadsworth-Emmons conditions to form an additional six-membered ring treatment of the hydroxy functional group of compound (107) with phenyl chloroformate was used. The resulting mixed carbonate (108) was transformed into a mixture of epimers (105) at C10 under the action of excess liquid ammonia. The required diastereomer was isolated using HPLC (Scheme 26).[68]
The formation of cys-bridged cycles (109-113) though with low yields during the interaction of unsubstituted cyclen (31) and cyclam (32) with bis-electrophiles (114-118) (Scheme 27) seems to be surprising.[3]
Locking two macro rings[69-73] is required in synthesis of some bicyclic compounds, including and biologically active.
Thus, the development of the bicyclic structure in synthesis of antitumor agents of spiruchostatin A (119 )[7475] and FK228 depsipeptide (FR901228) (120)[76-82] was carried out by consecutive macrocyclization reactions of hydroxy acids (121) or (122) by the Shiina's method or under Mit-sunobu conditions, correspondingly, followed by the formation of the disulphide fragment in oxidation with iodine (Scheme 28).
In synthesis[83,84] of the complex macrocyclic spermine alkaloid (-)-ephedradine A (123) that is one of the hypotensive
components of the traditional Chinese drug Mao-con, the closure of the 16-membered ring of polyamine (124) was also carried out under Mitsunobu conditions, and construction of the 13-membered ring of macro-lactam (125) included cycli-zation of precursor (126) with an activated ester group using the Staudinger/intramolecular aza-Wittig reaction (Scheme 29).
Macrocyclic tetraazaparacyclophanes are an unique class of compounds that have found broad applications in studies of the "guest-host" interaction,[85] moreover, their structure itself has a high potential for modification. Thus, 1,8,22,29-dibridged derivatives of tetraaza[8,1,8,1] paracyclophane (127) and (128) are obtained by consecutive reactions of 1,8,22,29-tetraaza[8,1,8,1]paracyclo-phane (129) with 6-bromohexanoyl chloride (130) and resulting 1,8,22,29-tetra(6-bromohexanoyl)-1,8,22,29-tetra-aza[8.1.8.1]paracyclophane (131) with benzene sulphona-mide (132) (Scheme 30).[86]
Many crown ethers show high selectivities of complex-ation against series of alkali metals. Thus, to improve binding metal cations due tothe expansion of macromolecule cavity, synthesis of bis-crown ethers (133) and (134) was carried out by the interaction of tri- (135) and tetra- (136) ethylene glycol ditosylates with tetramethoxy resorcinarene (137) (Scheme 31).[87]
31
109
32
110(X = CH), 111 (X = N)
32
112 (X = O, n = 1); 113(X = CH2,n = 4)
Scheme 27. a) Br(CH2)8Br (114), Na2CO3, MeCN (17 %); b) BrCH2 X CH2Br (115 (X=CH), 116 (X=N)), Na2CO3, CHCl3, (37 % for 110, 14 % for 111); c) Br(CH2)2-X-CH2(CH2)nBr (117 (X=O, n=1), 118 (X=CH2, n=4), (30 % for 112, 35 % for 113).
OTBS
OTBS
HN
^co2H
Y™ st
OR
O^ /NH
HN
Scheme 28. a) MNBA, DMAP, CH2Cl2 (89 %); b) I2, MeOH, CH2Cl2 (80 %); c) HF^Py, Py (92 %); d) DIAD, PPh3, TsOH, THF, 0 °C (24 %); e) I2, MeOH (81 %).
H-f C02Me CbzN
OBn
o;
H-f—C02Me CbzN.
CbzN-
126
NNs
CbzN-
OH
NNs
i,J
123
Scheme 29. a) PPh,, DEAD, toluene (77 %); b) K2CO3, MeOH/THF (96 %); c) MsCl, Et3N, CH2Cl2, 0 °C; d) NaN3, DMF, 60 °C (82 %); e) LiOH, MeOH/THF/H2O (97 %); f) pentafluorophenol, WSCDaHCl, CH2Cl2 (93 %); g) PPh3, toli2ene, A; h) MeCN/H2O, A (73 %); i) PhSH, KOH, MeCN, 50 °C (75 %); j) BCl3, CH2Cl2, -78 to 0 °C (73 %).
S02Ph
HN..... 6NH
/4 )~\
/~л /л
HN -NH
129
Br(H2C)5OC , . /CO(CH2)5Br N..... g N
/ \ У \
f\ лл
Br(H2C)5OC 6 CO(CH2)5Br
131
127
128
Scheme 30. a) Br(CH2)5COCl (130), CHCl z-Pr2NEt (61 %); b) PhSO2NH2 (132), K2CO3, DMF (13 %).
o-^A
MeO
"OMe 133 n=l 134 n=2
Scheme 31. a) Tsi
us (135 (n=1), 136 (n=2)), Cs2CO3, DMF (18 % for 133), (22 % for 134).
Sisfpolyazamacrocycles) have attracted considerable attention due to their ability to form binuclear complexes. [88-90] Over the past decades, there has been an increase in the use of saturated bis-macrocyclic ligands instead of bis-porphyrin compounds containing two polyazamacrocycles coupled to each other by aliphatic or aromatic spacers. Some derivatives of bis-cyclams that are two macrocycles coupled by a spacer are able to strongly and selectively inhibit the human immunodeficiency virus (HIV-1 and HIV-2) with a unique mechanism of action.
Introducing diisocyanate (138) into condensation allows "stitching" two cyclen (48) molecules with dicarbamide spacer in compound (139). The resulting cyclen derivatives (38), (47) and (139) are readily chelated with Cu2+ and Zn2+ ions (Scheme 32).[91]
Monoalkylation of trisubstituted cyclen (42b) and cyclam (43b) allows introducing such substituents as xylyl groups. Various bis-macrocycles coupled to each other ortho- (140a, 141a, 140b, 141b), meta- (140c, 141c, 140d, 141d) or para- (140e, 141e, 140f, 141f) xylyl or anthracene-
I \ /R
R\ / \ /R
2 eq. 48
H H ^
n n:
n n.
\_/ Y 6 T ^_1
R=Cbz R=H 139
Scheme 32. a) OCN(CH2)6NCO (138), CH2Cl2 (69 %); b) H2, Pd/C, EtOH (97 %).
42b
Boc
A /
;n n-
* Boc \_\ Boc
X-
Boc
/
;n n-
Boc \_\ Boc
TV /
Ar
-n hn-
140a-h
-nh hn
nh hn
^Boc
43b
X-^N
AK
Boc
Boc ^Boc
x-"^n hn—__
nh hn
ArC
x-pn
Boc
Boc
X-HN-—
nh hn
141a-f
Experiment
142
X
140
141
^C^Br
rr
CH2Br 142a COC1
BrCH.
COC1 142b CH2Br
142e
142f
CH
CO
CH
CO
CH
CO
CH
CO
140a
140b
140c
140d
140e
140f
140g
140h
141a
141b
141c
141d
141e
141f
Scheme 33. a) Y-Ar-Y (142a-h); b) BH3/THF when X=CO or HCl (6M).
a
b
c
d
e
g
h
1,8-dimethylene (140g, 140h) groups were synthesised in high yields during the interaction of compounds (42b) and (43b) with a number of electrophilic compounds (115, 142a,b,d-h) (Scheme 33).[3]
Direct Pd-catalysed arylation of cyclen (31) and cyclam (32) to obtain £is-polyaazamarocycles directly coupled with the aryl group is a complex task, since these cyclic tetraamines readily reduce halogen atoms in aryl halogenides. Therefore, trimethylcyclam (144) and trimethylcyclen (145) were introduced into reactions with rn-dibromobenzene (143) during catalysis with Pd(dba)2/DavePHOS that was most applicable for amine arylation, as a whole, and for diamination of 1,3-dibromobenzene, particularly, in the presence of sodium tret-butylate as a base yielding bis-macrocycles (146) and (147) (Scheme 34).[92]
The coupling reaction of two cyclam (32) species and diamide spacer under the action of methylene- (148), ethylene- (149) or hexamethylene- (150) 6is-acrylamides
in the presence of acid catalysts proceeds highly selectively with obtaining solely monosubstituted cyclams (151-153) (Scheme 35).[93]
Lately, heteroditopic receptors containing binding sites of anions and cations various by nature have attracted much attention, which enables their capture of substrates as ion pairs (ion-pair recognition), thus, increasing lipophilicity and solubility of ion pairs in a non-polar medium and ensuring an opportunity of their efficient use in extraction systems and membrane transport processes. Bis(crown ethers), in which two crown ether cycles (cation binding sites) are connected by a relatively rigid chain containing urea fragments (anion binding sites) appear to be promising as ion pair receptors. Synthesis of compounds (154-156) was carried out by the interaction of 1,2-6is(2,2,2-trichloro-1-isocyanatoethoxy)benzene (157) and appropriate azacrown ether (2 equiv) (158-160) at room temperature (Scheme 36).[94]
\l 1 /
,-n n.
n hn'
n n:
144
jsf hn.
n n 145
:n n^
\ c
) C J
/Y /T T^
146
nn n n'
CyjR
NMej
147
Scheme 34. а) br
Br (143), Pd(dba)2/DavePHOS, t-BuONa, dioxane (22 % for 146, 32 % for 147).
o o
32 + 0,5 CH2=CH-C-NH-(CH2)n-NH-C-CH=CH2 148 n=l; 149 n=2; 150 n=6
nh hn
X . n un h h
151 n= 1
152 n = 2
153 n = 6
:n hn.
vnh hn
)
Scheme 35. а) TsOH, CHCl3 (90 % for 151, 82 % for 152, 86 % for 153).
CI-CI
ci-CI
CI
-n=c"0
CI
n=c=0
157
CI-
C1~>L HN^N R
ci-^f
X)
Cil HN-
CI
■n r
r= r^ r^r^ . . O O, O O 0,0 O
154 155 156
on.
NH O
Scheme 36. a) ^'vJ' (158) or (159) or
(160), CHCl3, (73 % for 154, 71 % for 155, 84 % for 156).
Cryptands comprising of two or more cycles containing O, S or N atoms coupled by ethylene bridges constitute a class of macrocyclic compounds.[95-97] They form stable complexes with alkali, alkaline earth, and some other metal cations. The former are cryptates, in which a metal ion is strongly shielded by the surrounding atoms from solvent and counterion species. Cryptands are used as catalysts, selective sorbents for extraction of metals, such exotic compounds as alkaloids comprising of alkaline metal cations ([Na(2,2,2-crypt]+Na-) were obtained using them.
The literature presents two approaches for synthesis of cryptands. The first one is based on consecutive reactions of cyclen- (161) or cyclam- (162) -glyoxal-bis-aminals (2 equiv) with a number of electrophilic compounds (1,2-(142a), 1,3- (142c) and 1,4- (142e) bis(bromomethyl)ben-
zenes and 2,6-b/s(bromomethyl)pyridine (116)), and the resulting diammonium salts (163-168) - with the same reactants in a 1:1 ratio. Deprotection of the resulting tetraamonium salts (169-174) leads to cryptands (175-180) (Scheme 37).[9S-100]
The reaction of b/s-aminal (161) or b/s-formaldehyde cyclam (181)[10U02] (1 equiv.) with 3-bromobenzyl- (182) and 4-bromobenzyl- (183) 1-bromides that have unequal substituents with obtaining tetraazaphenyl-substituted macrocycles (184-187) (Scheme 38) is the first step of the first approach to synthesis of cryptands.[103,104]
The subsequent reaction catalyzed by Pd salts of equi-molar amounts of diphenyl-substituted macrocycle (184) with a number of diamines (188a-e) leads to the formation of a mixture of cryptands (189a-e) and their cyclodimers (190a-e) (Scheme 39).[103]
31
i6i
163-166
175-178
32
Bisaminal Y-Ar-Y Diammonium salt, Y-Ar-Y Tetraammonium salt, Macrocycle, yield, %
161 116 163, X = CH2, o- 116 169, X = CH2, o-, o- 175,60
161 142a 164, X = CH2, m- 142a 170, X = CH2, m-, m- 176, 98
161 142c 165, X = CH2, p- 142c 171, X = CH2, p-, p- 177, 91
161 142e 166, X = N 142e 172, X = N 178, 98
162 142c 167, X = CH2, m- 142c 173, X = CH2, m-, m- 179, 68
162 142e 168, X = CH2, p- 142e 174, X = CH2, p-, p- 180, 61
Scheme 37. a) OHC-CHO, MeOH; b) Y-Ar-Y, MeCN; c) NH2OH, EtOH.
161
32
Br 184 (m-), 185 (p-)
Br 186 (m-), 187 (p-)
Br—<\ /)—CH,Br
Scheme 38. a) Bf "CH2Br (182) or V^ (183), MeCN; b) NaOH, H2O, 80 °C (94 % for 184, 91 % for 185, 78 % for 186, 98 % for 187); c) CH20, H2O (90 %).
184
189a-e
Experiment 188 189, yield % 190, yield %
a 188a, NH2-(CH2)3-NH2 189a, 13 190a, 5
b 188b, NH2-(CH2)3-NH-(CH2)3-NH2 189b, 26 190b, 53
c 188c, NH2-(CH2)2-NH-(CH2)3-NH-(CH2)2-NH2 189c, 38 189c, 44
d 188d, NH2-(CH2)3-NH-(CH2)2-NH-(CH2)3-NH2 189d, 45 190d, 34
e 188e, NH2-(CH2)3-O-(CH2)4-O-(CH2)3-NH2 189e, 29 190e, 36
Scheme 39. a) H2N-CH2-X-CH2-NH2 (188), Pd(dba)2/BINAP, t-BuONa, dioxane, A.
187
184
185
191
193
194
m
o H
° H 0
Scheme 40. a) ^n^J (192), Pd(dba)2 / DavePHOS, t-BuONa, dioxane (12 %, for 191, 30 % for 193, 27 % for 194).
One-step synthesis of a macrocyclic cryptand with cylindrical shape (191) used the reaction of equimolar amounts tetraazaphenyl substituted macrocycle (187) and diazacrown ether (192) with Pd(dba)2/DavePHOS catalysis.[105 106] The yield of cryptands (193) and (194) based on cyclen derivatives (184) and (185) was somewhat higher (Scheme 40).
Macrobicycles containing 1,8-disubstituted cyclam fragment may be planar-chiral under the condition that
a chain of atoms that form the second macrocycle cannot freely rotate around cyclam fragment. Hindered rotation can be achieved by two additional substituents on nitrogen atoms provided that a small chain length of the second cycle. A,A',A",A'"-Tetrasubstituted cyclam (195) synthesised from è/'s-formaldehyde-cyclam (181)[101] by consecutive interactions with benzyl bromide (196) and 1-bromo-3-(bromomethyl)benzene (182) was introduced into Pd-catalysed amination reaction with 1,3-diaminopropane
(188a) with the formation of appropriate macrobicycle (197). This reaction explored chiral diphosphine ligands (198) and (199) based on 1,2-disubstituted ferrocene, and low asymmetric induction was noted (Scheme 41).[107]
Cryptand (200) that forms a stable complex with the herbicide paraquat (201) was obtained by the interaction of c/s(4,4')-di(carbomethoxybenzo)-30-crown-10 (202) and 2,6-piridinecarboxylic acid dichloroanhydride (203) (Scheme 42).[108]
In addition to the above examples of functionalisa-tion of macrocycles that consist in the formation of covalent bonds, there are synthetic methods for compounds with to-pological bonds that comprise of two or several independent parts not bound with each other by any valence bonds but nevertheless, held together. Catenanes comprised oftwo or several cycles bound as chain fragments and rotaxanes, the linear part of which is threaded through a macrocyclic ring and cannot slip out of it due to the presence of bulky end groups are referred to them. Species built without chemical bonding are found in animate and inanimate nature. Rotaxane and catenane forms of deoxyribonucleic acid (DNA) have been detected. It is interesting that an increase in the content of catenane DNA is observed during leukemia
and various forms of cancer.[109] Rotaxanes are of interest as objects for information storage, and also can be used as molecular machines that operate during rotation of macrocycles around a linear axis or transition from one edge of the molecule to another.
When considering opportunities for synthesis of cat-enanes cases, when they are obtained as side or sole reaction products should be distinguished. The first method may be defined as statistical, and the second one - asa directed method, in which there are conditions, upon which the formation of catenane is inevitable. The statistical method may be illustrated by the following scheme: cyclization of a molecule with a long chain (204) containing terminal functional groups X in the presence of macrocycle (205) may lead to catenane (207), if in the moment of cycle closure the chain of (204) takes the intra-annular position (206) (Scheme 43).
Thus, macrocyclization of aromatic dibasic acid chloro-anhydride (208) and aromatic diamine (209) in the presence of macrocycle (210) were most preferable for the formation of catenane (211)[110111] that was able to enter into the Diels-Alder reaction (Scheme 44).
The probability of formation of catenane using the above method is low; however, it can be increased
2Br"
181
n..
" " ™ N HN
u
Ph. ,N N'
Ph. ,N HN
Ligand L
Fe
P(t-Bu)2
7T pfv> ^ lb*
198
199
Yield of macrocycle (197), %
ee %
50 11
41 12
Scheme 41. a) CH2O, H2O (90 %); b) PhCH2Br (196), MeCN (78 %); c) NaOH, 80 °C (90 %); d) 182, CH2Cl2/NaOH/H2O (95 %); e) H2N(CH2)3NH2 (188a), Pd(dba)2/L, t-BuONa, dioxane (50 %).
Me \ h—4 ,N~Me
201
(PF6)2
O \ O /n <X ^-R
•Q / Q \ O
n= 3, R= Œ)OMe 202 n=3,R=CH2OH
J1
200
Scheme 42. a) Ts(OCH2CH2)4OTs, KPF6, K2CO3, MeCN (93 %); b) LiAlH4, THF (94 %); c) Cl Макрогeтeр0циmbl /Macroheterocycles 2017 10(3) 345-379
Cl (203), CH2Cl2/Py (44 %).
204 205 206 207
Scheme 43.
due to additional steric factors and through a temporary bond of macrocycle (205) with long-chain molecule (204). Compound with an open long chain (204) is added to (205) through an auxiliary bond (indicated by the dotted line) with the formation of adducts (212) and (213). Thus, the forced close convergence of two species is reached. By selecting a suitable auxiliary bond, one can affect the conformational
equilibrium between adducts (212) and (213). Cyclization leads to the formation of cycles (214) and precatenane (215) coupled to each other that turn into two isolated macrocycles
(216) and catenane (207), respectively, when breaking auxiliary bonds (Scheme 45).[109]
This was realised in synthesis of [2]catenane
(217) when using Pd(II) directed cyclization of triden-tate ligand (218) with monodentate macrocycle (219) (Scheme 46).[112]
Similarly to catenanes, rotaxanes can be synthesized by both statistical and directed methods.[109] Rotaxanes are formed in statistic synthesis along with molecular components in a ratio defined by statistic laws. Thus, in the presence of macrocycle (205), bulky end groups of (220) are added to the chain of (204). Consequently, alongside with the initial macrocycle (205), some amounts of rotaxane (221) and molecular barbells of (222) are formed (Scheme 47).
i-Bu
Scheme 44. a) Et3N, CHCl3/THF (45 %); b) 140 °C; c) O , 1,2-dichlorobenzene, 140 °C (63 %).
"N-Pd—N
218
219
217
Scheme 46. a) CH2Cl2 (69 %); b) Grubbs catalyst I, CH2Cl2 then H2, Pd-C, THF (78 %); c) KCN, MeOH, CH2Cl2, 40 °C (97 %); d) Pd(OAc)2, MeCN, 60 °C (79 %).
—Y + X-X + Y—
220
204
220 205
205
Scheme 47.
Ar N R1 OH H2
PFfi"
22Sa-d
(^0 O O O
224
r
■O O PF6-
/ o N* RW> R2
H2 oJ
VJ^ 223a-d
225
Ar
R1
R2
Rotaxane
Yield, %
225a
225b
225c
225a
-CH2-
-CH2-
ivic
O-
Me Me
Me Me
O
Me
Me
Me-
223a
223b
223c
223d
90
78
82
85
Me
Scheme 48. a) (R3CO)2O, cat. Bu3P, CH2Cl2. МакрогетерaцикJU /Macroheterocycles 2017 10(3) 345-379
Catalysed acylation with bulky acid anhydrides of pseudo-rotaxanes that have a hydroxyl group at the end of the axis is one of the most methods of synthesis of [2]rotaxanes comprising of crown ethers and secondary ammonium salts. Thus, a series of [2]rotaxanes (223a-d) were synthesized from dibenzo-24-crown-8 (224) and dibenzylammonium salts (225a-d) under catalysis by Bu3P (Scheme 48).[113-115]
When a catalyst is a strong acid, e.g. triflic acid, the corresponding amine can be used as a base, since ammonium salts can be produced in sutu.[116] When using natural amino acids racemised in acid medium, and also for synthesis [3]rotaxanes as acylating agentsas the axis 2-pyridylthioesters are being applied successfully. Thus, acylation of alcohol (225a) with 2-pyridylthioesters (226)
and (227) proceeds under neutral conditions under catalysis by Bu3P and leads to [2]rotaxane (228) (without amino acid residue racemization) and [3]rotaxane (229) in good yields (Scheme 49).[117]
Disulphide-containing rotaxanes (230a-c) have been obtained by the interaction of symmetric dumbbell-like compounds (231a-c) containing by two secondary ammonium centers and the central disulphide fragment with crown ether (224) under catalysis by benzenethiol (Scheme 50).[118] It is known that urethanes are more stable than esters and disulphides towards chemical reagents, heating, light, and radiation. Rotaxane (232) with a urethane functional group in the axis can be readily obtained in a high yield[119] from dibenzo-24-crown-8 (224) and benzylammonium salt (225a) by the interaction with
ÇH2Ph
225a + 224 + f^Y^™™00
Scheme 49. a) Bu3P, CH2Cl2 (82 %)
Ar N H2
2PFfi'
231a-c
N Ar H2
2PF,
Q
C
± _ c_<5 ___© Vis,
Ar-f^N"-—JS ------N-^J
p H2 o o H2 o
Xn J3
230a-c
Ar
231 Ar T, °C Yield of 230, %
Bui 50 65
231a tv> Bu' 20 81
/=\ 50 63
231b 20 81
Me 50 61
231c Me 20 79
Scheme 50. a) 224, PhSH.
3,5-dimethylphenylisocyanate (233) under soft conditions: «-Bu2Sn(OCO-«-C11H23)2 in CDCl3 at room temperature (Scheme 51).
The yield of rotaxane (221) increases in temporary binding chain (204) with macrocycle (205). Herewith, extra- and intraannular isomers (234) and (235) should exist in the conformational equilibrium. A mixture containing rotaxane (221), compound (222) and macrocycle (205) is formed after the addition of bulky end groups (220) and cleavage of a temporary bond (Scheme 52).[109]
This approach was implemented in highly selective synthesis of rotaxanes (236a-c) using aminoly-sis of their precursors (237a-c) obtained by substitution
233
Scheme 51. a) «-Bu2Sn(OCO-«-C11H23)2, CDCl3 (90 %).
of the hydroxyl group in phenols (238a-c) with bulky groups: the kinetically controlled approach of the amine (239) from the back part of the ring of pseudorotaxanes (237a-c)
(Scheme 53).[120]
Another method of synthesis of [2]rotaxane (240) includes reactions occurring in sequence of treatment of tri-dentate palladium(II) complex obtained from macrohetero-cycle (241) with 2,6-disubstituted pyridine (245), protection of hydroxyl groups in the resulting (243) bulky isocyanate (246) and destruction of palladium complex (244) with carbon monoxide (Scheme 54).[121-123]
0234
— OCT H-H-O-O
204 205 ^ „ /_\ 220 222 221 205
Scheme 52.
o o
o }
r1" ^o oho-' r1
238a-e
r2 237a-e
236a-e
Experiment R1 R2 Yield of 236, %
a H Br 82
b Ph Br 81
c H NO2 81
0,N
G 0
ci
C6D6.
Scheme 53. a) o2n
1.2. Functionalisation of Macrocycles with Decrease in Their Sizes
Functionalisation of macroheterocycles, including into synthesis of biologically active compounds may be accompanied by their cyclecontraction.
Thus, the key steps in synthesis of cavicularin (247) that is related to phenolic secondary metabolites isolated from Cavicularia Densa and representing the first natural compound with optical activity exclusively due to the presence of axial and planar chirality are macrocyclization of di-aldehyde (248) into macrocycle (249) catalysed by a low valency titanium salt and a radical-induced transannular ring contraction in compound (250). The resulting target cavicularin (247) and riccardin C (251) that is present in Chinese liverwort Plagiochasma intermedium are readily separated using column chromatography (Scheme 55). [124]
The formation of the dihydropyran fragment occurs in the intramolecular interaction of the triple bond with the hydroxyl group, which is applicable to synthesis of bry-
astatines of sea mats Bigula neritina[125] and polycavernoside (252) that is glycosylated macrolide of poisonous red algae Gracilaria edulis (Polycavernosa tsudai).[126] Thus, metathesis cyclization of diyne (253) over a molybdenum catalyst (254) forms the required macrocycle (255), and transannu-lar reaction therein over alkynophile gold catalyst (256) -an additional six-membered cycle. Further transformations of the resulting tricycle (257) (oxidation of the double bond and decreasing the pyranone cycle to hydroxyfurane) proceeded stereoselectively (Scheme 56).
The generation of 2-hydroxytetrahydropyran happens in the intramolecular interaction of keto- and hydroxy-groups, which is presented in synthesis of bryostatins of sea mats Bigula neritina[l21] and the natural polyfunctional bicy-clic immunosuppressant rapamycin (258) isolated from Streptomyces hydroscopicus and showing antifungal proper-ties.[128] To form its 35-membered precursor that is macro-heterocycle (260) DCC-initiated cyclization of bromo acid (259) was carried out. The intramolecular template Dieckmann condensation of two ester groups in macrolide (260) lead to a decrease in the cycle, and the removal of TES-pro-
YnV
HOH2C I I I rCH2OH L C^....... Pd.................cfC
A A 0 ° A
RUN OH2C „ I I I _CH20....... NHR RHN OH2C „ „ХН20 NHR
.....N Pd..........%......с
244
НОН,С.
Scheme 54. а) Pd(OAc)2, MeCN (86 %); b)
•CH,OH
(245), CH2Cl2 (100 %); с) R-N=C=O (246),
n-Bu3Sn(OCOC11H23)2, CH2Cl2 (96 %); d) CO (50 atm), MeOH, 80 °C (100 %).
MeO.
MeO
Scheme 55. a) TiCl4, Mg, THF, -78 °C (35 %); b) TsNHNH2 aq.THF, NaOAc (91 %); c) TTMSS, AlBN then BBr3, CH2Cl2, toluene, 90 °C (95 %).
OTBS 253 R = C(0)CHC12
X = TBS —I c d 255 X = Ac —I '
¿K-^-OMe Прмс
Ar
ill
Ar,SiO..........Mo........OSiAr3
J \
Ar3Si(J OSffl3Ar3
"к©
Ar = />МеОС6Н4" 254
Bu/.
e
SbF6
e
Bui-P-Au-NCMe 256
Scheme 56. a) 254, toluene, MS 5Â, 80 °C (91 %); b) K2CO3, MeOH, 40 °C (80 %); c) TFA, CH2Cl2, 40 °C (76 %); d) Ac2O, Py, CH2Cl2; 40 °C (97 %); e) 256, MS 4Â, CH2Cl2 (84 %); f) DMDO, PPTS, MeOH then TPAP, NMO (72 %); g) O3, PPh3 then CHI3, CrCl2 then K2CO3 (54 %).
Aj-i-v"0 ! >OTES
I ft I Ó Alloc
OTES
259
'OTES
260
.OTES
258
ОН
Scheme 57. а)
он
, DCC, DMAP, CH2Cl2, 0 °C (88 %); b) K2CO3, DMF (81 %); c) LiHMDS, THF, -78 °C (78 %); d) [Pd(PPh3)4
4), THF (80 %); e) PhI(OAc)2, MeCN/H2O, 0 °C; f) DMP, Py, CH2Cl2 (61 %); g) HFPy, THF, 50 °C (61 %).
tection in compound (261) was accompanied by the spontaneous formation of a six-membered lactol ring of compound (258) (Scheme 57).
Macroheterocycles are successfully used to form polycyclic compounds using intramolecular reactions, e.g. Diels-Alder.[129]
A macrocyclization reaction of compound (264) in synthesis of [(11R)-(-)-8-epi-11-hydroxyaphidicolin]
(262) that is an unnatural derivative of tetracyclic diterpene (+)-aphidicolin (263) isolated from Cephalosporium aphidicola fungus as a potential anticancer agent led to the formation of polyfunctional E,E,Z-triene (265) involved in a tandem of highly stereoselective reactions, such as the trans-annular Diels-Alder sequence and aldolization into tetracyclic compound (266) as a precursor of (262) (Scheme 58).[130131]
The Diels-Alder reaction is also used in the key step of the formation of hexaphenylene (267) as a representative with the carbon allotropie modification "cubic graphite", the conical cavity of which can be used as the "host" in molecular associates, and compound (267) itself - as a building block for porous solids.[132] Condensation of cyclo-pentadienone (268) with tribenzohexahydro[12]annulene (269) under high-temperature reflux conditions (300 °C) in diphenyl ether leads to the desired the triple addition product (267) of the Diels-Alder reaction in a mixture with com-
pound (270) that are formed during the Bergman cyclization of intermediate adduct (271) (Scheme 59).
A highly-efficient method for the construction of tetracyclic organic species consists in the use of a domino process that combines the ewe-reaction of two alkynes and the Diels-Alder cycloaddition. Thus, nitrogen-containing 15-membered triacetylene (272), enediyne (273) and (274) macrocycles were involved into [2+2+2] cycloisomerization processes that are catalysed by PhCl(CO)(PPh3)2 and lead to tetracyclic compounds (275-277) in high yields. Moreover,
TIPSO
f-Bu02l Mi
264
. I- R = C02l-
0 I—». 265 R = H
Bu
R = CH2OAc —| d CHÖ
. R = CH2 OH
TiPSO'
HO
OH
262
HO
OH
263
OH OH
Scheme 58. а) Cs2CO3, Csl, Me2CO (79 %); b) Lil, 2,4,6-collidine, 100 "C (72 %); c) Me2BBr, Nal, 15-crown-5, CH2Cl2, -78 "C then AcONa, DMF, 50 "C; d) K2CO3, MeOH (75 %), e) Dess-Martin periodinane, CH2Cl2 (88 %); f) Et3N, PhMe, sealed tube , 230 "C (81 %).
269
271
267
Ph Ph
270
If
Scheme 59. а) p/ph (268), 300 "C
Ar02S. / VS02Ar
N N
/ \
\ / S02AT
272
A«2S4i/ — VSOjAr
N N
ArOjS-N
275
S02Ar
S02Ar
S02Ar
S02Ar
AtOjS^/ \T.S02Ar
273
274 277
Scheme 60. a) PhCl(CO)(PPh3)2, toluene, 65 "C (96 % for 275, 80 % for 276, 68 % for 277).
Pr\
Ar02S-N
Ar =
P/
S02Ar
S02Ar
276
the reaction proceeds stereospecifically in case of enediyne macrocycles (Scheme 60).[133 134]
Other products (278) and (279) have been obtained in thermally induced [2+2+2] cycloisomerisation, though in moderate yields but high stereoselectivities: only isomers in cys-location of hydrogen atoms in unsaturated azacyclo-pentyl rings have been formed (Scheme 61).[133 134]
The [2+2] cycloaddition reaction of stilbenes during their UV irradiation is one of the most efficient methods of synthesis of cyclobutane-substituted derivatives. Thus, UV irradiation of both cis- (280) and trans- (281) macrolide stilbenes obtained from commercially available cis- (282) or trans- (283) stilbene-4,4'-dicarbolylic acid dimethyl ester led to the formation of the sole product (287) by their transfer in two steps to dibromides (284) and (285) followed
by cyclization with triazinone (286) in the presence of NaOH in THF and the removal of protective groups under the action of diethanolamine. This can be explained by ready transfer of cis-stilbene (280) into its trans-isomer (281) that enters into a cycloaddition reaction (Scheme 62).[135]
Enantioselective synthesis of phomactin (283) that is a natural compound isolated from a marine fungus Phoma sp. that grows in Chinoecetes opiloi crab shells is based on consecutive reactions of iodoacetylene and conjugated aldehyde functional group of compound (284) through the Nozaki-Hiyama-Kishi reaction with obtaining 12-membered macroheterocycle (285) and MgI2-catalysed iodoallenoate cyclization of the latter into a precursor of phomactin (283) that is a tricyclic compound (286) (Scheme 63).[136 137]
272
ArOjS-N
278
S02Ar
S02Ar
273
Ar02S-N
279
S02Ar
S02Ar
Pr\
Ar =
w
-Pr1
Pr1
Scheme 61. a) A, toluene (32 % for 278, 45 % for 279).
ÔMe OMe
282 or 283
x
284,285 x=Br
t-Bu-:
%
x=oh n .
:=Br -J b
N^ 0=( N—Bu-t N^
<K
nh
HN
nh
HN
280
281
280, 281
Scheme 62. a) LiAlH4, THF (95 %, 99 %); b) NBS, PPh,, THF (78 % for 284, 74 % for 285); c) or 20 %); d) HO(CH2)2N(CH2)2OH, MeOH (90 % for 280, 92 % for 281); e) hv, DMSO-rf6 (100 %).
/—NH i-Bu-N )=0
(286), NaH, THF (12 %
Scheme 63. a) CrCl2, NiCl2, THF (63 %); b) MnO2, CH2Cl2 (69 %) (250); c) SiO2; d) HF-pyridine, THF, 0 °C (98%); e) n-Pr4N+RuO4", NMO, MS 4 A, CH2Cl2 (73 %); e) MgI2, THF, 0 °C (60 %); g) PNBOH, PPh3, DEAD, benzene; h) K2CO3, MeOH (52%); i) TBSOTf, 2,6-lutidine, toluene (54 %).
1.3 Functionalisation of Macrocycles with an Increase in Their Sizes
Functionalisation of biologically active macroheterocycles may also be accompanied by an increase in their sizes. One of the methods of transforming antibiotic erythromycin species (287) is the Beckmann rearrangement, that is the key step in highly efficient synthesis of a series of novel 6-O-sub-stituted 8a-aza-8a-homoerythromycin A ketolides (288a,b) as epimers at the 2nd center. 3-0-Decladinosyl-6-0-allyl-erythromycin A (Z)-oxime (289) required for its implemen-
tation has been obtained by alkaline treatment of initially formed £-oxime (290).[138,139] In vitro testing of antibacterial activity of macrocycles (288a,b) against a series of erythro-mycin-sensitive and erythromycin-stable strains has demonstrated their high activity (Scheme 64).
^-^-Rearrangement accompanied by ring expansion with the formation of compound (292) may proceed in acidified solutions of cyclic peptide containing the amino acid residue of threonine (291). Amines (293-297) obtained by acylation of the latter with various carboxylic acids are characterised by high membrane permeabilities and conformations similar to the initial peptide (291) (Scheme 65).[140]
HO,
287
290
289
HO
HtrCH2CH2Ph O J1" N(CH3)2
HtrCH2CH2Ph
288a
Scheme 64. a) LiOH-RO, EtOH (80 %); b)^-TsCl, NaHCO Me2CO, H2O (90 %)
288b
h
„oh
ho'
h
291
„.. w
AnaO 0 (¿YY 0 0
N "1 h
292 b , 293
294 - 297
Compound R Yield, %
292 H
293 Ac 62
294 ^Y^NHBoc O 41
295 0 56
296 O 43
297 43
Scheme 65. a) EtOH, HCl, 50 °C; b) Ac2O, CH2Cl2, 30 °C; c) RCOOH, DIC, 2,6-lutidine, CH2Cl2, 30 °C.
It is known that many macrocyclic imides show fungicide and bactericide properties may also are used as compositions for bleaching of textile products and the suppression of adsorption and desorption of pollutions or colourants. One of the methods[141] for obtaining macrocyclic imides (298) consists in the interaction of isocyanates (300) with cycloalkanols (209) substituted in the 2nd position with electron-acceptor groups that stabilize carbanion (301). Ring expansion proceeds by the following probable mechanism (Scheme 66).
Thus, 2-cyano-substituted dodecanone (302) enters into reactions with various /»-substituted aryl isothiocy-anates (303a-c) accompanied by ring expansion with obtaining appropriate CN-substituted cyclic imides (304a-c) (Scheme 67).[141]
The use of CO2R-substituted derivatives of cycloal-kanones allows synthesizing both A-unsubstituted and vari-
ous ^-substituted cycloalkane dicarboximides. Thus, treatment of cyclododecanone (305) with sodium hydride and diallyl carbonate leads to oxoester (306),[141-144] in which the a-position to the (allyloxy)carbonyl group is activated under the influence of base, and ring expansion with obtaining 14-membered amide (308) happens in the interaction with various isocyanates (307). Its Pd(0)-catalysed A-deallylcarboxylation leads to both A-unsubstituted (310), and also A-alkyl and A-phenyl substituted (309) cyclic car-boxyimides (Scheme 68).
The resulting derivatives may enter into repeated ring expansion reactions. For example, A-alkyl substituted cyclic carboxyimides (311) and (312) are rearranged into macrocyclic diamides (313) and (314) under the interaction with sodium azide and triphenylphosphine (Scheme 69).[144]
If reactive groups (Br, OH) are present in the orthoposition of aromatic isothiocyanate species; resulting A-aryl
299
+ R-N=C=0
300
R N=C=0 O f
301
298
n = 3, 5,7; R = Ar; E = CN, C02R'
Scheme 66.
^CN
302
/—\ O 304 R Yield, %
a,b a H 76
WjrT^
b Cl 79
wCNO
304a-c c MeO 78
Scheme 67. a) NaH, THF; b) \=
rv-s««
(303a-c); c) HCl, H2O.
o o
b-d r^^N'* —-
305
306
308
R = Alkyl, Ar, Ts
u
309
310
Scheme 68. a) NaH, CO(OCH2CH=CH2)2, benzene, A (70 %); b) NaH, THF; c) R-N=C=O (307); d) HCl, H2O; e) Pd(PPh,)4, HCOOH, Et3N, THF (100 %); f) Pd(PPh,)4, HCOOH, Et3N, dioxane, 100 °C (100 %).
(CH^Nj
Ck
306
a-d
311 n=3, X=C1
312 n=4, X = Br
(CH2)nNPPh3 CU JsL JO
(CH2)nNH2
(CH2)n
Scheme 69. a) NaH, THF; b) X-(CH2)n-N=C=O; c) HCl, H2O (42 % or 55 %); d) Pd(PPh3)4, HCOOH, Et3N, THF (92 %); e) NaN3, H2O, C6H6 (67 % or 87 %); f) PPh3; g) H20 (94 % for 313, 84 % for 314).
substituted macrolides (317) and (318) are transformed into appropriate cyclophanes (319) and (320) after deallylation (Scheme 70).[142]
Cyclophanes were also obtained using the PhotoFries rearrangement.[143] Thus, irradiation of 12-membered A-phenylamide (321) in MeCN at 0 °C with a low pressure mercury lamp (110 W) leads to the formation of four products in the total yield of 97 %. ortho- (322) and para-(323) cyclophanes with the prevalence of the latter are main of them; moreover, bicyclic diketones (324) and (325) isomeric to them represent products of their secondary Photo-Fries rearrangement. Replacement of MeCN with EtOH allows excluding secondary processes and changes the ortho-/para-product ratio; ortho-cyclophane (322) is mainly formed (Scheme 71).
A large group of natural compounds that are metabolites of lower fungi and bacteria belongs to a class of cyclodepsipeptides. Many of them are significant antibiotics. Their synthesis consists in spontaneous isomerization of A-oxy- (326) and A-amino- (327) acyllactams and proceeds via the stage of the formation of cyclols (328) and azacyclols (329).[145-147] The latter are unstable and decompose with the formation of cyclopeptides
(330) and (331). Additionally, transformation of A-a-aminoacyllactam (326) into bicyclic acylamides (332) that are dehydration products of intermediate azacyclols (329) (Scheme 72) is also possible.
The above method was used in synthesis of cyclotet-radepsipeptides (333a-h) with regularly alternating residues of p-oxy- and a-amino acids. For this purpose, diketopip-erazines (334a-h) were acylated with p-benzyloxy acid chloroanhydrides (335a-h) in boiling toluene and resulting A,A'-di(P-benzyloxy-acyl)diketopiperazines (336a-h) were subjected to hydrogenolysis in the presence of palladium oxide, which lead to the formation of cyclotetradep-sipeptides (333a-h) in yields reaching 90 % in some cases (Scheme 73).[144-147]
Representatives of a family of macrolactam Fluviru-cines A1, A2, and B2-5 attract research attention, showing powerful activities against bacteria, fungi and especially the flu virus with their low toxicity. The aza Claisen rearrangement of amide enolate (338)[148] that proceeds stereoselectively with the formation of a mixture of diastereomeric 14-mem-bered microlactams (339) in the 10:1 ratio is the key step of synthesis of fluvirucin A2 (337). The regioselective oxidative cleavage of the exo-cyclic double bond in diyne (339)
306
315
317
319
306
CÇ
nco
316
318 0
KJ
Br
320
Scheme 70. a) NaH, THF; b) Pd(PPh,)4, HCOOH, Et3N, dioxane, 100 °C; c) BuLi, Et2O, hexane, -100 °C.
Products High pressure mercury lamp, Low pressure mercury lamp, Low pressure mercury lamp, _EtOH, 1.5 h_EtOH, 1.5 h_MeCN, 24 h
322 37 % 10 % 33 %
323 23 % 4 % 44 %
324 2 % - 2 %
325 4 % - 18 %
Total yield 66 % 14 % 97 %
Scheme 71.
он || also used in the fragrance industry have been developed.
/ у \ / _(/ " C"i)) Synthesis of natural macrocyclic ketones, such as
\c__n-.^/ " \ „-n.^/ x N__n-^/ x exaltone (341) (from the glands of muskrats) and muscone
о 326 x=o 4 328 x=o И ззо x=o (342) (from the glands of deer) is based on oxidative
327 x=nh 0 ,, 329 x=nh 33i x=nh fragmentation reactions of the double bond in macrocyclic
bicycles (343a,b) and conjugated enones (344a,b). The simplest procedure is based on ozonolysis of olefins t)'x (343a,b) followed by reduction yielding symmetrical
г
(^n
c diketones (345a,b). Partial hydrogenation of the latter
o 332 in the presence of an alkaline Raney nickel, dehydration
of intermediate hydroxyketones (346a,b) and hydrogenation Scheme 72. complete synthesis of compounds (341) and (342)
Ri Q „ Rj о
Y° P^n^a __ R2T° H Й'
Wo f^ YYt*
О R[ О Rj
334a-h 335a-h 336a-h J 333a-h
Compound R1 R2 Compound R1 R2
a H H e CH2OAc H
b Me H f CH2OCHO H
c CH(CH3)2 H g CH2OCH2Ph H
d H Me h CH2OH H
Scheme 73.
followed by stereoselective addition of a Grignard reagent to the resulting aldehyde leads to the formation of a mixture of lactam stereoisomers (340a) and (340b) in the 20:1 ratio. Its catalysed hydrogenation completes synthesis of bioactive 14-membered Fluvirucines A2 (337) (Scheme 74).
Musks are an important class of odorants and have been used in perfumery more than ten centuries. Animals whose death is sometimes a requirement to extract essence are natural sources of musks. Therefore the prices for natural musks have remained high. In this regard, various methods of synthesis and transformation of their analogs[149] that are
(Scheme 75).
Another approach assumes the impact of singlet oxygen on compounds (343a,b) with the formation of crystalline allylic hydroxyperoxides (347a,b). Hydroboration of the latter proceeds as an intramolecular redox reaction with the formation of trans- 1,3-diols transformed into monotosylates (348a,b). Treatment of the latter with potassium ferf-butylate and hydrogenation of macrocyclic precursors (349a,b) lead to target compounds (341 and 342) (Scheme 76).
One more approach consists in the generation of ketones (341) or (342) based on macrocyclic conjugated enones
Scheme 74. a) LiHMDS, toluene, Д (74 %); b) OsO4, NMO then NaIO4, Me2CO, H2O; с) MeMgl, Et2O, 0 °С (93 %); d) TBAF, THF; e) H2 Pd/C, MeOH (96 %).
343a,b 345a, b 346a,b
R = H (343a, 345a, 346a, 341), Me (343b, 345b, 346b, 342)
Scheme 75. a) O3 then H2; b) H2, Ni-Ra; c) H3O+; d) H2, Pd/C.
c, d
341, 342
343a,b --
347a,b 348a,b "OTs
R = H (347a, 348a, 349a, 341), Me (347b, 348b, 349b, 342)
Scheme 76. a) 1O2; b) BH3 then TsCl, Py; c) t-BuOK, t-BuOH; d) H2, Pd/C.
349a,b
341,342
b c -► 345a,b -► 341,342
344a,b 350a,b
R = H (344a, 345a, 350a, 341), Me (344b, 345b, 350b, 342)
Scheme 77. a) i. DIBAH; ii. m-CPBA; iii. TsCl, Py; b) CaCO3, A, 1,4-dioxane-H2O; c) i. TsNHNH2; ii. NaBH4; iii. CrO3, H2SO4, H2O, acetone.
(344a,b). Consecutive reduction, epoxidation, and tosylation reactions lead to cis-epoxy tosylates (350a,b), treatment of which with hot calcium carbonate solution allows obtaining 15-membered cyclic diketones (345a,b). The latter are transformed into ketones (341) or (342) by the Cagliotti method that is based on reduction of monotosylhydrazons of (345a,b) with excess NaBH4 followed by the Jones oxidation (Scheme 77).
The use of ozone or atomic oxygen in large scale production of natural musk-ketones (341) and (342) requires special equipment and poses a security threat. The Eschenmoser fragmentation of cyclic a,p-epoxyketones (351a,b) available from the epoxidation reaction
344a,b
of conjugated enones (344a,b) is one of the processes that allow avoiding the above issues. Tosylhydrazones (352a,b) that are subjected to a intramolecular rearrangements are obtained from keto-epoxides (351a,b).
Since the yields of reaction products in the epoxidation stage are low, another way to transform enones (344a,b) is proposed. It consists in fragmentation of bromotosylhydrazones (353a,b) obtained by consecutive treatment with tosyl hydrazide and A-bromosuccinimide followed by exhaustive hydrogenation of the resulting alkyne ketones (354a,b) (Scheme 78).
The advisability of transformation of mechanically bound ring macromolecules into more complex molecular
341,342
353a, b
R = H (344a, 351a, 352a, 353a, 354a, 341), Me (344b, 351b, 352b, 353b, 354b, 342)
354a,b
Scheme 78. a) H2O2, NaOH; b) i. TsNHNH2, ii. NBS, s-BuOH, COMe2; c) TsNHNH2, AcOH-CH2Cl2; d) warm; e) H3O+; f) H2, Pd/C. 376 Макрогетероцикnbl /Macroheterocycles 2017 10(3) 345-379
systems without structure destruction is driven by the need of studying the roles of catenanes and rotaxanes in living organisms. Thus, paper [123] demonstrated for the first time ring expansion of [2]catenane (355) without destruction of chained structures, and also the introduction of functional groups. The Diels-Alder reaction of bound ring macromolecules with dimethyl fumarate (10 equiv) proceeds under boiling with the formation of cyclohexane-condensed 4,5-disubstituted cyclohexen[2]catenane (357). The ozonolytic cleavage of the double bond in the cyclic species of the latter followed by reduction of peroxide ozonolysis products with dimethyl sulphide and further m-CPBA oxidation of sulphide groups expanded the ring of the catenane (355) macromolecule with obtaining catenane (358) (Scheme 79).
Thus, the presented review considered three approaches to functionalisation of macroheterocycles (with retaining, decreasing and increasing their sizes) in directed synthesis of compounds with various functionalities.
Acknowledgments. The work was carried out with the partial financial support of the Russian Foundation for Basic Research (Grant No. 17-03-01050-a).
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Received 06.10.2016 Accepted 28.12.2016
