Desymmetrisation of meso propargylic diols

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Tekbxlnm Letters, Vol. 34, No. 29. PP. 46314634.1993 Printed in Great Britain

Desymmetrisation of Meso Propargyiic Diols N. Adjk, P. Breullles, and

D. Uguen*

Laboratoire de Synthtke Organique, associ6 eu CNRS Emle Europbnne

des Hautes Etudes des Industries Chimiques de .Strasbourg

1. Rue Blake Paxal; 67008 Strasbourg (France)

Abatmet: Meso ace@& diok, conveniently separated from their threo isomers via the cor~~ponding addrtcts with bromine, have been conwtied into optkal& pum derivatives iy e&her [email protected]~sed hrydmlysis 01 the corresponding diacetates or ketakation of (+) - menthone.

We recently described a highly stemoselective preparation of the C-3/C-7 unit of pristinamycin PIIA, 1, starting from syn meSO 2,4dimethyl-3-hydroxy-15pentanedioll. The next goal of our planned total synthesis of 1 was to obtain the C-9/C-16 segment which could also be considered as potentially derived, via the olefinic intermediate 2, from a meso polyol, m-3a (scheme12.

P=prolt3ctinggroup

1

considering infer alia the possibility to build the entim C-9/C-16 framework in a single step by twice condensing a suitably protected 3-hydroxy-ptopanal derivative with acetylene. Achievement of the planned synthesis implied however several critical steps, namely: l- isolation of the pure me.90 isomer from the mixture of diastereomets normally fonned in condensing acetylene with aldehydes3; 2- stereoselective derivation of the resulting me.so polyol in order to generate the (14s) chit-al centre; 3- steteo and mgioselective addition of a methyl group to the carbon-carbon triple bond. Herein is described how the first two of these challenging steps have been This remsynthetic

analysis seemed attractive

ptXfOITllC!d.

Following Midland’s procedures condensation of acetylene with 3-t-butyldimethylsilyloxy-propanal, 4b4, or the corresponding 3-p-methoxybenzyloxy derivative, 4c, prcceeded well. giving the corresponding diols 3b and 3c (65% and 73% mspectively). A slightly better yield (78%) was obtained with the less sensitive 3-phenyl-propanaL 4d. Neither NMR (1H, 13C) nor TLC (silica gel) proved to be very helpful in determining the presence of diasteteomers in the resulting mixtures. Analysis was however achieved by IiPL@. Fractional crystallisation has been used to separate diaskmomen in some related case$. Unfortunately, the present mixtures resisted crystallisation using various solvent conditions. We addmssed this problem of separation in working first with a model substrate, 3e (R=Me). which is commercially available as a 1:l mixture of meSOand three isomers. Previously it has been shown7 that treating 3e with bromine gave a crystalline dibromo derivative of the meso diol and indeed, adding bromine to a solution of 3e in chloroform resulted in the formation of crystals of m-5e (m.p. 143’C. ethanol). 4631

4632

Due to the sensitivity of diols 3b-d with bromine in chloroform, the protocol of the bromination step had to be modified. Slow addition of bromine in CH$& to mixtures of diols 3bd (cooled to -1O’C) with Hiinig’s base (2 eq.) and 4Amolecular sieves in CH$ls resulted in quantitative formation of the cotmsponding dibtomo derivatives 5b-d. The separation was easily performed by flashchromatography on silica gel (CH$&/etherL In all cases studied, the dibtomo derivatives formed from the mesc dials, m-5bd, eluted first.

R-Cl-IO + 4b, 4~. 4d, 4..

-

note 5b

R=CH.&Hz_OTBDMS bCHrCHz-OPMB R&H&i&‘h Fldal~

mbb. msc. mad. mba.

m.p. rrl.p. nl.p. rap.

124% 116% 12!5% 142°C

I

6 l- a) m5e: Brx (1 eq.), CH&, r.t. ovemipht, followed by filtration, and recrystallisation (EtOH); b) m-5b-d: Bra (1.6 eq.), 4A-molecular sreves (lS~/mmd),.Hfinig baaa (2 eq.), CH2C12,-lo%, 1Oh, then flash-chromatography (silica gel, CH2Cl#her); 2- activated Zn powder (O.iPg/mmol), in erther refluxing THF, 1h (for I??&) or refluxing glyme, 6h (for m3b-d). followed by work-up according to note 7b.

Treatment of m-5e with zinc powder in ethanol as described’s gave the expected meso diol m-3e effectively but contaminated with the corresponding Z-olefinic dial, 6. In our hands, use of acetic acid, recommended in order to minimise the formation of that overreduction pmduct,7b proved detrimental, 6 being the major product. Obviously some protons were needed in this side-reaction and indeed, using hot THP instead of ethanol resulted only in the formation of the acetylenic diol m-3e (m.p. 70-71’0. Submitting m-3e to the acidic debtomination conditions gave the pure dio16. With bromides m-5b and m-5c the debromination step proved mote difficult, requiring tefluxing glyme to teach completion. Acetylation of pure m-3e with acetic anhydride eventually gave the known diacetate 7 (m.p. 37’C)7b which was submitted to an enzymecatalysed hydrolysis (PPL, phosphate buffer, pH adjusted periodically to 7 by addition of 1N aqueous NaOH. 18’, 2 weeks). The only product was the (2RSs) monoacetate 8 (83% yield, e.e. 97%) of which both the absolute configuration and optical purity were established as summa&xl in the scheme!

wY----foAc -L-D 7

6, [aID- 03 c-5

23 (see note 9)

“9-T

*

[r&+173 c-6 (dioxan). from (R)- butynol [do+74 c-6.1

l- FFL, pH7 PhbaPhate buffer, 5 days, 16%; 2- DFTBBCI, imtdazole. DMF, r.t., 14h; 3. K&Oa, MeOH, -10°C. lh; 4- FCC (2rW), CHaClx, r.t., 2h; 5- n-BuLi (laq.) in THFIhexana, -76%. 0.5h, than CH&HO, -76°C. 20 mn

Such high stemoselectivitylu led us to directly submit the crude mixture of bis-acetates derived from 3b-d to these hydrolytic conditions, with, the hope that in each case easily fractionated mixtures of &%diacetate, (RS)-monoacetate, and (RR)-diol would form. Should this happen, the result would be a substantially shortened overall synthetic scheme.

4633

To our great disappointment, b&acetates of compounds 3b-d were not substrates using various enzymes. Furthermore, low diastereoselectivity was observed in the hydrolysis of the diacetates formed from 3e itself. Submitting 3b to an esterification process (Candida cyhdmceu lipase. vinyl acetate, hexane) after several weeks resulted however in the fotmation of a monoacetate fraction but which proved to be derived, mainly, from the (WWiol ([aID-23, c=O.6). The initial assumption that the high stereoselectivity observed in the hydrolysis of 7 would imply a clear-cut difference in reactivity of each isomeric diacetates is probably false. Obviously respective stereochemical shapes of either meso, d or I isomers are quite different, so binding affinities to the catalyst differ from one isomer to the other. As a matter of fact, only the (RR) isomer compound is a convenient substrate in the esterification of 3b. whereas the meso (RS diol teacts much more slowly, as shown by independently submitting m-3b to the CCL-catalysed esterification process. Owing to these somewhat unexpected difficulties in the asymmetrisation process, we turned our attention to the ketalisation of me&one by m-3a. Deprotection of m-3b (MeOH. Amberlyst 15, r.t.. 14h. 87%) gave the corresponding tetraol m-3a which was fully silylated (HMDS) then treated with,(+)-menthonet. The resulting ketal mixture (67%) upon flash-chromatography (silica gel, CH$Zl#exane) gave two optically active diastereomeric ketals 10 and 11 (10: 35%. [aID +18 ~0.7; 11: 27%. [aID +20 c=OS). Stmcture determination was facilitated by conversion of 10. after silylation (TBDMSCI), into the ketone 12 by oxidation (PCC, CH&) and identification with an authentic sample ptepamd from (s)- malic acidll. 0

1.2

OTBDMS

12

10, [a]0 +18 C-0.7 * w&

i 1, [a]L,+20 -0.5 1- (+)-menthcne,TMSOTf, CHaCIz,-18%, overnight (see ref.1); 2- Silicagel (hexedether); 3- TBDMSCI (leq.), imidezole (leq.), DMF, r.t., 10h; 4- PCC, CH,C&, WC-r.t., 2h. In conclusion, an improved btomination/debromination procedure for separating meso acetylenic diols from their fhreo isomers has been set up. The efficiency of the enzyme-catalysed asymmetrisation of these diols appeared highly dependent on the substitution pattern of the pmpargylic carbon atoms. In the simplest case -i.e. m-3e- a perfect deacylation of the corresponding diacetate has been achieved using PFL. The resulting synthon could be of interest for pmparing useful olefinic diol derivatives12, as shown above. DPTBSO Red-Al, toluene!ether w -WC, 3h

DPTwoMH [aID+

C-1 0

6H [I&+28 C-8

Chemical asymmetrisation with menthone has conveniently supplemented the enzymatic process, hence furnishing two synthons well-equipped for further transformation into the targeted C-9/C-16 fragment of pristinamycin. Results along this line will be disclosed in due course. Acknowledgments : Our thanks are due to Rh&te-Poulenc company for a grant (to N.A.) and especially to Dr J.P. Corbet (Rh&-Poulenc, C.R.C. - St Fons) for discussions.

4634

REFERENCES AND NOTES

l- Adje N.. Breuilles P., and Uguen D.. Tetrahedron Letf., 1992,33.2151-2154. 2- For leading references on related synthetic studies, see: a) Gangloff A.R., Akermark B., and Helquist P., J. Org. Chem., 1992,57,4797-4799; b) Paris J.M., Bar&e J.C., Smith C., and Bost P.E., the chemistry of pristinamycins, in Recent Progress in the Chemical Synthesis of Antibiotics, Springer: Berlin, Heidelberg, 1990, 185-245. 3- Sudweeks W.B., and Broadbent H., J. Org. Chem., 1975,40,1131-l 136. 4- Aldehyde 4b (Bpce9 37’C) was prepared by DIBA-H reduction of the corresponding nitrile (Bpo.9 57-58°C) in CH$$ at -78’C. followed by hydrolysis in mild conditions (tartarichartrate pH6 buffer, O’C, 83%). Thep-methoxybenzyloxy (PMBO) derivative, 4c (Bp0.1~ 95°C). was prepamd from the acetal of 4methoxybenzaldehyde with 13-propanediol by DIBA-H reduction (CH$$, -78X 97%), followed by PCC oxidation (CH&. O’C, 7%) of the resulting 3-PMBO-ptopanol. 5- a) Midland M.M., J. Org. Chem., 1975.40.2250-2252; b) optimal yields and purities were obtained in performing a two step condensation: the alcohol formed in condensing lithio acetylene with the aldehyde (1 eq.lsa was silylated (HMDS, Me$iCl, t&l=). The resulting bis-protected diol was distilled, anionised with n-BuLi (1 eq.) in THF at -78.C. then condensed with the aldehyde (1 eq.). Quenching with saturated aqueous NH&l was followed by extraction (ether). Stirring the extract with 0.5 N aqueous tartaric acid for 2 hours at O’C,washing (brine). drying (Na#04), then evaporation left an oil which was then purified (silica gel, CH$&&/ether) to give the diols 3b-d; c) 4d was prepared as model substrate for experiments with enzymes. 6- Pirkle (naphtyl-alanine) column, using a refractometer as detector and a 3:2 isopropanovhexane mixture as eluant (flow rate: 0.5 mL/mn). In each case the mesoldll ratio was about 2:1:1, the meso isomer being eluted first. 7- a) Dupont G., C.R. Acud. Sci., Paris, 1909, 249, 1381; these, Paris, 1912; b) Lett R., Bory S., Momau B., and Maquet A., Bull. Sot. Chim. Fr., 1972,2299-2306. 8- Selected NMR data: a) lH (200 MHz, MeGD): m-3a: 1.73-2 (m, 4H) 3.62-3.8 (m, 4H), 4.52 (t, J6H2, 2H), 4.95 (4H, OH); b) l3C (50MHz, CDC13):m-3b: -5.44, 18.20, 25.90, 39.18, 60.74, 61.02, 85.43; m-5b: -5.47, 18.12, 25.85, 36.78, 60.81, 72.86, 125.79; 9: 19.28, 24.38, 26.90, 59.81, 83.28, 93.40, 127.76, 127.90, 130.03, 130.12, 133.13, 133.21. 135.82, 136.00, 184.39; 10: 18.92, 21.82, 22.32, 23.89, 24.46, 28.93, 32.25, 34.88, 37.08, 38.91, 51.31, 58.61, 59.15, 60.56, 61.90,84.13, 85.04, 101.18. Except otherwise stated, [a]D values have been recorded on solutions in CHzC12. 9- Pure (RI-(+)-1-butyn-3-ol (Bps,-,46’C, [c&+4. c=6 in dioxan) was prepared by the phthalate method using (+)-l-phenyl-ethylamine as described (Weidmann R., Schoofs A., and Homau A., Bull. Sot. Chim. Fr., 1976.645-648; [a], +41, c=3.2 in dioxan). The amine salt was recrystallised 20 times from moist acetone (m.p. 142’C). lo- Enzyme (or microorganism)-mediated hydrolysis of 3-acetoxy-1-alkyne in most cases am not so stemoselective (see, for instance: Gllnzer B.I., Faber K., and Griengl H., Tetrahedron, 1987,43,57915796; Mori K.. and Akao H., Tetrahedron, 1980,36,91-96 ; Oritani T., and Yamashita K., Agric. Biol. Chem., 1980,44, 2407-2411; Shimizu M., Kawanami H., and Fujisawa T., Chem. Letters, 1992, 107110). This was confirmed by submitting 3-acetoxy-1-butyne to PFL-catalysed hydrolysis. The resulting 1-butyn-3-01 had [aID +17, c=6 (dioxan)(e.e. 3%). ll- Breuilles P., Kaspar K., and Uguen D., to be published. 12- Compare with: BIckvall J-E., No&erg R.E., and Wilhelm D., J. Am. Chem. Sot., 1985, 107, 6892-6898.

(Receivedin France 14 April 1993; accepted 27 May 1993)