OXIDATIVE METHODS FOR SYNTHESIS OF

(~, (~'-DIOXYGEN-CONTAINING DERIVATIVES

OF DEHYDRODESTHIOBIOTIN

S. I . Z a v ' y a l o v , N. A. R o d i o n o v a , a n d E . P . G r a e h e v a

UDC 542.91:542.943:547.78:547.9

a , a ' -Dioxygen-con ta in ingder iva t ives of dehydrodesthiobiotin (I), for example (II), are of interest as the s tar t ing mater ia ls for the synthesis of the biologically active oxygen analog of vitamin H, namely oxy- biotin (III) [1]. A known method for the prepara t ion of (II) is based on a complicated multistep scheme, which includes the intermediate step of brominat ing the ethyl es te r of N , N ' - d i a c e t y l - a - k e t o d e h y d r o d e s - thiobiotin (IV) and the subsequent replacement of the bromine atom in bromide (V) by the acetoxy group using s i lver acetate [1].

In the present paper it was shown that compounds of the (I) type can be obtained by a s impler method employing selective oxidation of the methyl group of the ethyl es te r of ei ther a-ketodehydrodesthiobiot in (Vl) o r (IV)

o o

HNfJ~NH HN~NH (CH3CO)20 CH3CON NCOCH 3 �9

CH2)4COOH (Vl) (IV) r162 ~- X~NBS

O O O

CH~/~coRHN/[I'NH CH3CON-~NCOCHs~ AgOCOCH3 CH3C~COCH3

C,~2 \COR CH2Br" COR (VII) JocoEH 3 (II) (V)

l O O O

H N"~N,H H + HNJJ'XNH HNJ~'-NH "

(VIII) OH (IX) ~ (X)

R = (CH2)4COOC2H5

The heating of (VI) with SeO 2 in dioxane gives a ' -oxo-VI (VII) in 50% yield, the s t ructure of which fol- lows from the following data. The presence of a - and a ' -oxo groups in the (VII) molecule was confirmed by the elemental analysis , the IR spect rum, which contains an additional band of the CO group at 1710 em -1 when compared with (VI), and the prepara t ion of the dioxime from (VII). The presence of an oxo group in the a ' -posi t ion of (VII) is in agreement with its aldehyde cha rac te r [the ability of (VII) to give the bisadduet with dimedon] and the resul ts of oxidation with KMnO4, which leads to the formation of adipie acid in high yield

N. D. Zelinskii Institute of Organic Chemistry , Academy of Sciences of the USSR. Transla ted from Izvest iya Akademii Nauk SSSR, Seriya Khimieheskaya, No. 9, pp. 2025-2028, September, 1972. Original ar t ic le submitted May 31, 1971.

�9 1973 Consultants Bureau, a division of Plenum Publishing Corporation, 227 West 17th Street, New York, N. Y. 10011. All rights reserved. This article cannot be reproduced for any purpose whatsoever without permission of the publisher. A copy of this article is available from the publisher for $15.00.

1966

K~nO~ (VII) ~ HOOC(CH2)4COOH I O O

II HN~,~N H

/ \ /%O O [~ CH 0

The reduction of (VII) with NaBHr gave diol (VIII), in whose IR spectrum is absent the band at 1710 cm -l. When treated with acid reagents , for example CH3COOH or p-toluenesulfonie acid and KHSO 4 in alcohol, (VIII) is converted to the ethyl es te r of a ' -oxodehydrodes th iobio t in (IX), whose s t ructure is in agreement with the elemental analysis , the close s imilar i ty in the UV spect ra of (IX) and (VI), and the fo r - mation of the monooxime from (IX). The t ransformat ion (VIII) ~ (IX) can be regarded as being the resul t of allylic migrat ion of the hydroxyl group and subsequent dehydration according to the scheme:

O

(VIII) >.- H H ~ H

I C~H 2 OH "~CHR

o l HN~NH (IX)

CHR [ OH \

(Vl)

It is interest ing to mention that the r ea r r angemen t (VIII) ~ (IX) proceeds quite selectively, since only t races of the i somer ic ketoester (VI) are formed from (VIII).

Compound (IV) also undergoes selective oxidation at the methyl group when it is treated with Pb(OAc)~ in glacial acetic acid. The s t ructure of the thus formed aeetoxy derivative (II) was proved by the counter syntheses: ei ther by react ing CH3COOAg with (V) [1] or by heating the ethyl es te r of a - k e t o - a ' -p iper id ino- dehydrodesthiobiotin (X) with (CH3CO)20. In turn, (X) is obtained by treat ing (V) with excess piperidine.

E X P E R I M E N T A L M E T H O D

Ethyl Es te r of a , a ' -Dioxodehydrodes th iob io t in (VII). A mixture of 10 g of the ethyl es te r of o~-keto- dehydrodesthiobiotin (VI) [2] and 5 g of SeO 2 in 100 ml of dioxane was refluxed for 2 h, after which the hot solution was fi l tered, evaporated in vaeuo to dryness , and the residue was t reated with alcohol. We ob- tained 7.7 g (70%) of (VII) with mp 110-112 ~ After reerys ta l l iza t ion from alcohol the yield of (VII) was 5.5 g (50%), mp 135-136~ Rf 0.60 (here and subsequently TLC on silica gel G, system ace tone-hep tane , 4: 1, development of the spot with iodine vapors) . Infrared spectrum (KBr) (v, era-t): 1730, 1710, 1680, 1668. Ultraviolet spectrum (alcohol):)~max 348 rim. Found: N 9.79%. C~2H~OhN 2 .H20. Calculated: N 9.78%.

Dioxime of (VII). To a solution of 0.75 g of (VII) in 15 ml of pyridine and 5 ml of alcohol was added 0.5 g of hydroxylamine hydrochlor ide, after which the mixture was heated at 80-100~ for 2 h and then evaporated in vacuo. The residue was t reated with water and the precipitate was fi l tered. We obtained 0.63 g (86%) of the (VII) dioxime with mp 237-238 ~ (from alcohol). Infrared spectrum (KBr) 0', era-t): 1710, 1620. Found: C 48.17; H 5.83%. C12H12OhN 4. Calculated: C 43.31; H 6.08%.

Bisadduct of (VII) with Dimedon. To 0.4 g of (VH) in 25 ml of aqueous alcohol (1 : 1) was added 0.9 g of dimedon, the mixture was refluxed for 10 rain, and the obtained precipi tate was fil tered. We obtained 0.8 g of the (VII) bisadduct with mp 192-193 ~ (from aqueous alcohol). Found: C 63.25; H 7.32%. C2sH38 �9 OsN 2. Calculated: C 63.38; H 7.22%.

Ethyl Es te r of a , a ' -Dioxodehydrodesthiobiot in (VIII). With s t i r r ing, to 0.7 g of (VII) in 30 ml of a lco- hol was added 0.1 g of NaBH4, followed by the addition of 0.5 ml of CH3COOH after 1 h, and then the mixture was evaporated in vacuo, the residue was t reated with water , and the obtained precipitate was filtered. We

1967

obtained 0.35 g (50%) of (VIII) with mp 130-131 ~ (from alcohol); Rf 0.52 ( ace tone -wa te r , 9 :1) . Infrared spectrum (KBr} (v, cm-J}: 1730, 1680, 1650. Found: C 52.92; H 7.31%. C12H20ObN 2. Calculated: C 52.92; H 7.400/o.

Ethyl Es te r of ol ' -Oxodehydrodesthiobiotin (IX). A solution of 2.8 g of (VIII) in 30 ml of CH3COOH was refluxed for 5 h, the acetic acid was vacuum-dist i l led, the residue was ehromatographed on SiO2, and the react ion product was eluted with a 1 : 1 benzene -e thy l acetate mixture. After removal of the solvent the residue was t reated with ether and the obtained white powder was fil tered. We obtained 1.9 g {75%) of (IX) with mp 145-147 ~ (from water); Rf 0.33 (ethyl a ce t a t e - ace tone , 9 : 1). Infrared spectrum (KBr) (v, cm-1}: 1730, 1690, 1660. Ultraviolet spectrum (alcohol}: kma x 300 rim. Found: C 56.45; H 7.12; N 11.15%. C12H1804N2. Calculated: C 56.67; H 7.13; N 11.08%. Ultraviolet spectrum of (VI} (alcohol): Xma x 299 nm.

The r ea r r angemen t (VIII) --~ (IX) also proceeds in refluxing alcohol in the presence of t races of KHSO 4 and p-toluenesulfonie acid.

Oxime of Es te r (IX). In a s imi la r manner , from 0.37 g of (IX) was obtained 0.36 g (92o/0) of the oxime with mp 220-221 ~ (from alcohol). Inf rared spectrum (KBr) (v, em-1): 1730, 1690, 1645. Found: C 53.44; H 7.14%. CI2H19N304. Calculated: C 53.52; H 7.12%.

Ethyl Es te r of N, N ' -D iaee ty l -~ -ke to -~ ' - ace toxydehydrodes th iob io t i n (II). To 1.2 g of (IV) in 20 ml of glacial acetic acid was added 1.8 g of Pb(OAc) 4, and the s t i r red mixture was heated on the steam bath for 5 h. The solution was f i l tered, evaporated, the residue was extracted with ether, and the ether solution was washed with water and evaporated. The residue was dissolved in benzene and the benzene solution was f i l tered through a column containing 10 ml of SiO 2. Removal of the solvent gave 0.8 g (53%) of (II) (pale yellow oil); Rf 0.65 (benzene-e thyl acetate, 3 : 2). Infrared spectrum (NaC1) (v, cm-1): 1730, 1380, 1310, 1230.

Ethyl Es te r of a - K e t o - ~ ' -piperidinodehydrodesthiobiotiu (X). To 0.9 g of (V) [1] in 20 ml of absolute benzene was added 1.2 ml of piperidine in 5 ml of absolute benzene and the mixture was refluxed for 3 h. The obtained piperidine hydrobromide was fil tered, the benzene was vacuum-dist i l led, and the residue was extracted with heptane and t reated with ether. The obtained precipitate was fil tered. We obtained 0.39 g (47%) of (X) with mp 106-107 ~ (from water); Rf 0.62 (ace tone-wate r , 9: 1). Infrared spectrum (KBr) (~, cm-1): 1738, 1698, 1640, 1600. Found: C 57.22; H 8.40; N 12.08%. C17H2804N 3.H20. Calculated: C 57.45; H 8.23; N 11.83%.

Reaction of (X) with Acetic Anhydride. A solution of 0.4 g of (X) in 10 ml of acetic anhydride was refluxed for 3 h, after which it was evaporated in vaeuo, the residue was treated with benzene and water, and the benzene layer was separated and fi l tered through a bed of SiO 2. Removal of the solvent gave 0.26 g (65%) of (II) (pale yellow oil); Rf 0.65 (benzene-e thyl acetate, 3 : 2). Inf rared spect rum (NaC1) (v, era-l): 1730, 1380, 1310, 1230.

We express our gratitude to T. N. Sedletska and T. A. Pe t rova for running the spectral studies.

C O N C L U S I O N S

The action of selenium dioxide in dioxane on the ethyl es te r of a-ketodehydrodesthiobiot in and of lead te t raaceta te in glacial acetic acid on its N,N' -d iace ty l derivative give the corresponding ethyl es ters of a ,a ' -dioxodehydrodesthiobiot in and a -oxo-o~ ' -acetoxy-N,N'-diaeetyldehydrodesthiobiot in .

1.

2.

LITERATURE CITED

R. Dushinsky and L A. Dolan, Jubilee Volume Emil Barell, Basle (1946), p. 146.

R. Dushinsky and L. A. Dolan, J. Am. Chem. Soc., 67, 2079 (1945).

1968