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Synthesis of α-azido aldehydes. Stereoselective formal access to the immunosuppressant myriocin
Tchuhcdmn Lcfter~,Vol. 35. No. 27, pp. 4783-4786,1994 l3lwvkscialmLm Ril&dillatartB&&l
oo4o4039194 s7.oo4o.al
00404039(94)00!219-8
Synthesis of a=Azido Aldehydes. Stereoselective Formal to the Immunosuppressant Myriocin. Sandrim
Deloisy*, Ton Tbrt Tbmgb,
Inslitut&chimicdess~
Cbimk Biwqanique,
Alain Ok&e+*
Access
and Gabor LukacSr
N~&CN~S.,91198cfifaaYvettc,Frmceamd~~de assock?au CNRS.. PIaceE Bataillon,34095 Montpellk, Fraaoeb.
The mctabolitc myriocin, isolated in 1972 from the tbamojthilic funp kQri0wccun1 aibomyces, was shown to exhibit a potent kmmmosupprWdveactivityl. very rccult bio@ical rwults lWcalal that myrkia 1 (thamozymocidin)wasalmosttwoadaof~~~~tthan~~~A2~.Inviewoftbese
fmdin~myriocinisbcingcom&rcdasa~fbrcliniccllrpplicatoas4. lllCfhttOQllQ7lthCSiSOfl@OCh,repated
&stereoselcctivity, due to a Sacka
marcthaatulycarSago5.qwaS~mpliSbcdwithpolx
reaction-basedstrategy in farming the crucial a,u-dk~bstituted amino
nitie precursor. A subsequent. very elegant formal synthesis of myriocia 1, using W(0) catalysed cishydmxyaminationof a ca&ob* derivedvinyl cpoxkk as its key step, was also disclosai~. Howevcq io this scheme, the transfarmation of 288intotheinmte 6b required 13 stcps7. In this letter, we report the stcxcoselective convasion
of h into 6b in only 6 steps (overall yield 21%) making optically active myxiocin
!synwwuymorere3dilyav8ilnbk.
Afewyerrsaeo,~have~thu~roaadenrprion,in~pnsenceofpotagsiumt-b9ltoxide,of samecarbohydrueketoawwithchloromzhypptdylstllfom~~s~~y~xysulfonres9.In~ ptience of aaide ion, the latter afT6rdadbra~~&ukbain functiunalkd aizkio-sugan59_ The same reaction sequence on ketones. 28 and 2b led only to rapid dceomposition. However, treatment of 2r with dicbloromcthyllithilun.as described by Sato and al.lOJl, afforded a,+poxy chkxidcs 3 which+without isolatiolzinthe~~ofa;cideionfurnirhedcleurly,bySN2r#ctiaaattbe&crrbwrelrtinaotbechlaine, the key a-a&lo
lldehyde 4 [a]D - 25 (c 1.03. CHCl3) of (Q-coafigumtioa (55% ovaall yicld)l2. A similar
l)isaaK&atC-5.
t3apmccfromkaone2b13gavctwo~rldehyder(2:
Hydrogenolysis of 4 @‘d-C, H2. &OH, 3 bars) was fdowed by bcnzoylation of tbc intumediate !!a
leadingtoSbasamixtunafrwouKwar(~from4).Swan~d5bgavethe~60(8646) 4783
4784
28 R=TMMS 2bR=Bn
1
[a&‘) + 32 (c 0.72, CEKl3), whose configuration at C-2 was ascertained by a 400 MHz NOESY expuirxmt~4 (Figure).
Desilylatim
@I’Bu4+ F-, 97%) of 6a afforded 6b, [a]~ + 33 (c 1.0, CHC13); lit? [a]p + 19 (c 0.3,
C!HC13)15. The 1H ?MR spectrum of 6b exhibits chemical shifts and coupling constants identical with its spcctmm7. Rama Rae et al.7 have describedthe trmsfommtion of lactone 6b into aldehyde 7 whi& had &.lrcadybeen commtcd into myriocin I 6. Thus, the present work can be consMcrcd as a relatively shoat,
m
iWW&ctive
f&
synthesis ofmyriocin 1.
4785
In our earlier investigations9.
the method using Moromethyl
p-tolylsulfoae
followal
by aaide ion
treatmntrevealedfarfrosl~~in~@branchd-chrrin~sulprs.Fa~artmentoflcetoae and ketone 1117 ~pveonlytheelimination product 12 ca]D + 33 (c0.74,
816 lad oat~y to wtion
==l3).
I R,-bMe;R2=H 9 Rl=H
10 RI =OMe;
;R2=Ct&
13 R1 -OW;R2=H 14R,=H
:R2=OMe
11 R,=H
Rz=H ;R2=OMe
IS R1+OMe:R2=H: R, =CWO:R4=N3
16 Ill-H Rs=N3
In view of the good results obtained on ulose 2a when applying
;R2-OMa ;R4=CH0
Sato’s procedurel0~ 11, four
carbohydrate ketones 8l6,9**.
1019ad 1117were-withdichl~thyllithillmmandcnldereactioil produa weletreated withazidenucleoj4lile. The following cc-a&o akkhydes wex obtaiW& tWpectively, as theonlyisomrs: l3 (52%)[a]D - 54 (c0.98, CHCl3),14(50%)[aID - 22 (c 1.03, CHCl3). 15 (46%) [a]D 119 (c 1.03, CHClg),l6(54%)[a]D + 43 (c 0.95, CHC13). compound l5, whose absolute configuration at C2 is identical to that in the su-disubstituted amino acid 1,appears to be a further UUM&& as starting ma&al for an enantioselective synthesis of myriocin and its analogues. The configuration at the qmuemary carbon was easy to determine by 13C NMR s pectroscopy as described9, only in case of 14.For allthebrmched-chain sugars the stmctures were unambiguously
ascertained by means of nGe results by selective irradiation of the
respective aldehyde ptutons and inspection of tht behaviourof the neighboring hydtogen atans. The new branched-chain a-azido aldehydes may prove to be highly useful synthons
for the
enantioselective synthesis of a variety of biologically impoxtant ga-dimbstitmdamino acidsa. Ackrwwledgments.
‘I%e authors thank Professors A. V. Rama Rao and M. K. Gear.
fa stimulating discussions and CEFXPRA. New Delhi, for financial support.
Hyderabad, India,
4786
References 1
2. 3. :: 6. 7. 8. 9. ::: 12.
13. 14. 15.
16.
and Notar
l, D.; Baglit J.; Baker, E; Chalet, M-P.; Kudclski, A.; Schga&S. N.; Vu&m, C. J. (a)Kl Anti’ cs 1972.25,109-115; (b) Cr&mi. R; Manachiui, P. L.; Arasolmnq F. Eq&m&z l.9’72, 28.867-868; (c) Kuo, C. H, Wendler, N. L. Tefmhcclron fm 1978.21 l-214; (d) Fujita, T.; Inouu, k; Yamamoto, S.; Ikumoto, T.; Sasaki. S.; Toyama, R.; Chiba, K.; Hoshiio, Y.; Okumoto, T. Absttautsof Papers of the 17 th NPAC International Synqwsiaunon tk Ckmistry ofNatuml Pro&&r, 1990, p. 68, New Delhi, Feb. 4-9. Fujita, T.; Moue. K.; Yamamuto. S.; Ikumoto, T.; Sasaki, S.; Toyama. R; Chiba, K.; Hosbino, Y.; Ohuuoto, T. J. Antibiotics 1994,47,208-215. Fuji@ T.; Moue, K.; Ymamoto, S.; Ikumuto, T.; Sasaki, S.; Toyama, R, Yoncta, M.; Chiba, K.; Hoshiuo, Y.; Gkumoto, T. J. Anribi&x 1994,47,216-224. p Data Repott, l991,I3,506 (Article No 169735). au!i, L.; Berem M. 0.; colombo, L.; German, C.; Scolastico, C. J. Ckm. Sot., Ckm. Conunun. 1982, 488-490. Baufi, L; Buretta,M. G.; Colombo, L.; Gennari, C.; Suolastico, C. J. Ckm. Sot., Perkin Trant I. 1983, 1613-1619. Rama Rae, A. V.; Gtujar, M. K.; Rama Dcvi, T.; Ravi Kumar, K. TezruhedronLtlr. 1993,1653-1656. Liang, D.; Pauls, H. W.; Fraser-Reid, B.; Geoqcs, M.; Mubarak, A. M.; Jamsz, S. Can. J. Ckm. 1986,64, 1800-1809. Ton That, T.; Labonle, M. de 10s A.; Olesker, A.; Lukacs, G. J. Ckrn. Sm., Ckm. Ccwnmun. 1988, 1581-1582. Sam K.; Ucda, M.; Katayama, M.; Kajihata, Y. Clrem.Ltxz. 1991,1469-1472. Sam K; Kajihara, Y.; Nakamura,Y.; Yoshimura, J. Ckm. f&r. 1991.1559-1562. QXIIRQ& 4 : lH NMR (400 MHz, CDCl3) 6 9.60 (s, lH, CHO), 7.42-7.28 (m. 5H, Ph). 6.00 (d, HI, lH.Jl2=3.6H.z, Jl2 = 3.6 Hz, H-l), 4.66 and 4.45 (2d, 2H, J au, =11.7Hz,CX&Ph),4.64(d, H-2), 4.49 and 4.05 (2d,2H, J3 4 = 3.8 Hz. 83 and H-4). 4.07 and 3.90 (2d, 2H, J a,n ‘, 10.8Hz, W-6). 1.47 and 1.34 [2s. 6H. &X3)2], 0.86 [s, 9H. SiC(CH3)3], 0.03 and 0.01 [5:s, 6H.
bs?
Si(CH3)2]; 13C NMR (62.9 MHz, CDC13) 8 196.7 (CHO), 136.4, 128.7 128.3 (Ph), 112.5 E(CH3)fl. 105.1 (C-l), 82.1, 82.1 and 81.0 (C-2, -3. -4). 72.3 -2ph). 71.6 (C-5). 64.2 (C-6), 27.0 and 26.6 [C(gI3)2]. 25.7 [SiCcH3)3], 18.1 E(CH3)2]. - 5.6 Si(CH3)2. Yamamoto, H.; Hosoyatuada, C.; Kawamoto. l-L; Inokawa, S.. Yamashita, M.; Artuour, M-A.; Nakashima, T.T. Curb&&. Res. 1982.102, 159-167. It has been reported (Hauser, F. M.; Adams, Jr, T. C. J. Org. C/ma. 1984.49.22962297.) (see also nf. 7) thatGr@ud nactions on ketone 2a pmxcds via a stum&ctive qqmmh giving alcohols of (s)-mf@ratiou in agnemnt with our fiudin8s iu the tea&on with dichlommcthyllithium. No cxplauationis advatxxd for the dismpaucy between our and the mp9rtcd [a]~ value far 6b. The lH-lH NMR NOF!SY cxpcrimunton out uompound6b m&cd a rcvurscd signal assignmeatfor H3 aud H-4 relative to the signal attributionpmpuscd carlicr7. Qmlp~~& 6b : *H NMR (400 MHz, CDCl3) 6 7.79-7.38 (m. SH, Ph). 6.79 (s, IH, NH), 5.92 (d, 1H. J1.2 = 3.6 Hz. H-6), 5.27 (d. H-I, J3 4 = 3.6 Hz, H-3), 5.07 (d, lH, J3,4 = 3.6 Hz, H-4), 4.86 (d, lH, Jl 2 = 3.6 Hz, H-5), 4.43 (m, = 11.4 Hz, CH2). 1.50 and 1.33 [2s, 6H. CXCH3)2]; lH, OH), 4.15 aud 3.91 (2d, 2H, J Anal. Calud for Cl7Hl9NG7 : C,s% H, 5.48; N, 4.01. Found : C, 58.58; H, 5.43; N, 3.94. El LagMach, A.; Echatri, R.; Matheu, M. I.; Barrena,M. I.; Garuia,J.; Castillon, S. J. Org. Ckm, 1991,56. 45564559. T&uwto. T.; Sudoh, R Bull. Cktn. Sot. Jpn 1975.48. 3413-3414. Klumer, A.; Klaffke, W. Ucbigs Ann. Chin. m, 759-763. Luu, L. L.; Keavcney, 0.; O’Cctlla, P. S, Carbohydr, Res. 1977.59, 268-273. O’Leary. M. H.; Baugh, R. L J. Biol. Ckm. 1977,252, 7168-7173.
(Received in France 14 April 1994, accepted 8 May 1994)
oo4o4039194 s7.oo4o.al
00404039(94)00!219-8
Synthesis of a=Azido Aldehydes. Stereoselective Formal to the Immunosuppressant Myriocin. Sandrim
Deloisy*, Ton Tbrt Tbmgb,
Inslitut&chimicdess~
Cbimk Biwqanique,
Alain Ok&e+*
Access
and Gabor LukacSr
N~&CN~S.,91198cfifaaYvettc,Frmceamd~~de assock?au CNRS.. PIaceE Bataillon,34095 Montpellk, Fraaoeb.
The mctabolitc myriocin, isolated in 1972 from the tbamojthilic funp kQri0wccun1 aibomyces, was shown to exhibit a potent kmmmosupprWdveactivityl. very rccult bio@ical rwults lWcalal that myrkia 1 (thamozymocidin)wasalmosttwoadaof~~~~tthan~~~A2~.Inviewoftbese
fmdin~myriocinisbcingcom&rcdasa~fbrcliniccllrpplicatoas4. lllCfhttOQllQ7lthCSiSOfl@OCh,repated
&stereoselcctivity, due to a Sacka
marcthaatulycarSago5.qwaS~mpliSbcdwithpolx
reaction-basedstrategy in farming the crucial a,u-dk~bstituted amino
nitie precursor. A subsequent. very elegant formal synthesis of myriocia 1, using W(0) catalysed cishydmxyaminationof a ca&ob* derivedvinyl cpoxkk as its key step, was also disclosai~. Howevcq io this scheme, the transfarmation of 288intotheinmte 6b required 13 stcps7. In this letter, we report the stcxcoselective convasion
of h into 6b in only 6 steps (overall yield 21%) making optically active myxiocin
!synwwuymorere3dilyav8ilnbk.
Afewyerrsaeo,~have~thu~roaadenrprion,in~pnsenceofpotagsiumt-b9ltoxide,of samecarbohydrueketoawwithchloromzhypptdylstllfom~~s~~y~xysulfonres9.In~ ptience of aaide ion, the latter afT6rdadbra~~&ukbain functiunalkd aizkio-sugan59_ The same reaction sequence on ketones. 28 and 2b led only to rapid dceomposition. However, treatment of 2r with dicbloromcthyllithilun.as described by Sato and al.lOJl, afforded a,+poxy chkxidcs 3 which+without isolatiolzinthe~~ofa;cideionfurnirhedcleurly,bySN2r#ctiaaattbe&crrbwrelrtinaotbechlaine, the key a-a&lo
lldehyde 4 [a]D - 25 (c 1.03. CHCl3) of (Q-coafigumtioa (55% ovaall yicld)l2. A similar
l)isaaK&atC-5.
t3apmccfromkaone2b13gavctwo~rldehyder(2:
Hydrogenolysis of 4 @‘d-C, H2. &OH, 3 bars) was fdowed by bcnzoylation of tbc intumediate !!a
leadingtoSbasamixtunafrwouKwar(~from4).Swan~d5bgavethe~60(8646) 4783
4784
28 R=TMMS 2bR=Bn
1
[a&‘) + 32 (c 0.72, CEKl3), whose configuration at C-2 was ascertained by a 400 MHz NOESY expuirxmt~4 (Figure).
Desilylatim
@I’Bu4+ F-, 97%) of 6a afforded 6b, [a]~ + 33 (c 1.0, CHC13); lit? [a]p + 19 (c 0.3,
C!HC13)15. The 1H ?MR spectrum of 6b exhibits chemical shifts and coupling constants identical with its spcctmm7. Rama Rae et al.7 have describedthe trmsfommtion of lactone 6b into aldehyde 7 whi& had &.lrcadybeen commtcd into myriocin I 6. Thus, the present work can be consMcrcd as a relatively shoat,
m
iWW&ctive
f&
synthesis ofmyriocin 1.
4785
In our earlier investigations9.
the method using Moromethyl
p-tolylsulfoae
followal
by aaide ion
treatmntrevealedfarfrosl~~in~@branchd-chrrin~sulprs.Fa~artmentoflcetoae and ketone 1117 ~pveonlytheelimination product 12 ca]D + 33 (c0.74,
816 lad oat~y to wtion
==l3).
I R,-bMe;R2=H 9 Rl=H
10 RI =OMe;
;R2=Ct&
13 R1 -OW;R2=H 14R,=H
:R2=OMe
11 R,=H
Rz=H ;R2=OMe
IS R1+OMe:R2=H: R, =CWO:R4=N3
16 Ill-H Rs=N3
In view of the good results obtained on ulose 2a when applying
;R2-OMa ;R4=CH0
Sato’s procedurel0~ 11, four
carbohydrate ketones 8l6,9**.
1019ad 1117were-withdichl~thyllithillmmandcnldereactioil produa weletreated withazidenucleoj4lile. The following cc-a&o akkhydes wex obtaiW& tWpectively, as theonlyisomrs: l3 (52%)[a]D - 54 (c0.98, CHCl3),14(50%)[aID - 22 (c 1.03, CHCl3). 15 (46%) [a]D 119 (c 1.03, CHClg),l6(54%)[a]D + 43 (c 0.95, CHC13). compound l5, whose absolute configuration at C2 is identical to that in the su-disubstituted amino acid 1,appears to be a further UUM&& as starting ma&al for an enantioselective synthesis of myriocin and its analogues. The configuration at the qmuemary carbon was easy to determine by 13C NMR s pectroscopy as described9, only in case of 14.For allthebrmched-chain sugars the stmctures were unambiguously
ascertained by means of nGe results by selective irradiation of the
respective aldehyde ptutons and inspection of tht behaviourof the neighboring hydtogen atans. The new branched-chain a-azido aldehydes may prove to be highly useful synthons
for the
enantioselective synthesis of a variety of biologically impoxtant ga-dimbstitmdamino acidsa. Ackrwwledgments.
‘I%e authors thank Professors A. V. Rama Rao and M. K. Gear.
fa stimulating discussions and CEFXPRA. New Delhi, for financial support.
Hyderabad, India,
4786
References 1
2. 3. :: 6. 7. 8. 9. ::: 12.
13. 14. 15.
16.
and Notar
l, D.; Baglit J.; Baker, E; Chalet, M-P.; Kudclski, A.; Schga&S. N.; Vu&m, C. J. (a)Kl Anti’ cs 1972.25,109-115; (b) Cr&mi. R; Manachiui, P. L.; Arasolmnq F. Eq&m&z l.9’72, 28.867-868; (c) Kuo, C. H, Wendler, N. L. Tefmhcclron fm 1978.21 l-214; (d) Fujita, T.; Inouu, k; Yamamoto, S.; Ikumoto, T.; Sasaki. S.; Toyama, R.; Chiba, K.; Hoshiio, Y.; Okumoto, T. Absttautsof Papers of the 17 th NPAC International Synqwsiaunon tk Ckmistry ofNatuml Pro&&r, 1990, p. 68, New Delhi, Feb. 4-9. Fujita, T.; Moue. K.; Yamamuto. S.; Ikumoto, T.; Sasaki, S.; Toyama. R; Chiba, K.; Hosbino, Y.; Ohuuoto, T. J. Antibiotics 1994,47,208-215. Fuji@ T.; Moue, K.; Ymamoto, S.; Ikumuto, T.; Sasaki, S.; Toyama, R, Yoncta, M.; Chiba, K.; Hoshiuo, Y.; Gkumoto, T. J. Anribi&x 1994,47,216-224. p Data Repott, l991,I3,506 (Article No 169735). au!i, L.; Berem M. 0.; colombo, L.; German, C.; Scolastico, C. J. Ckm. Sot., Ckm. Conunun. 1982, 488-490. Baufi, L; Buretta,M. G.; Colombo, L.; Gennari, C.; Suolastico, C. J. Ckm. Sot., Perkin Trant I. 1983, 1613-1619. Rama Rae, A. V.; Gtujar, M. K.; Rama Dcvi, T.; Ravi Kumar, K. TezruhedronLtlr. 1993,1653-1656. Liang, D.; Pauls, H. W.; Fraser-Reid, B.; Geoqcs, M.; Mubarak, A. M.; Jamsz, S. Can. J. Ckm. 1986,64, 1800-1809. Ton That, T.; Labonle, M. de 10s A.; Olesker, A.; Lukacs, G. J. Ckrn. Sm., Ckm. Ccwnmun. 1988, 1581-1582. Sam K.; Ucda, M.; Katayama, M.; Kajihata, Y. Clrem.Ltxz. 1991,1469-1472. Sam K; Kajihara, Y.; Nakamura,Y.; Yoshimura, J. Ckm. f&r. 1991.1559-1562. QXIIRQ& 4 : lH NMR (400 MHz, CDCl3) 6 9.60 (s, lH, CHO), 7.42-7.28 (m. 5H, Ph). 6.00 (d, HI, lH.Jl2=3.6H.z, Jl2 = 3.6 Hz, H-l), 4.66 and 4.45 (2d, 2H, J au, =11.7Hz,CX&Ph),4.64(d, H-2), 4.49 and 4.05 (2d,2H, J3 4 = 3.8 Hz. 83 and H-4). 4.07 and 3.90 (2d, 2H, J a,n ‘, 10.8Hz, W-6). 1.47 and 1.34 [2s. 6H. &X3)2], 0.86 [s, 9H. SiC(CH3)3], 0.03 and 0.01 [5:s, 6H.
bs?
Si(CH3)2]; 13C NMR (62.9 MHz, CDC13) 8 196.7 (CHO), 136.4, 128.7 128.3 (Ph), 112.5 E(CH3)fl. 105.1 (C-l), 82.1, 82.1 and 81.0 (C-2, -3. -4). 72.3 -2ph). 71.6 (C-5). 64.2 (C-6), 27.0 and 26.6 [C(gI3)2]. 25.7 [SiCcH3)3], 18.1 E(CH3)2]. - 5.6 Si(CH3)2. Yamamoto, H.; Hosoyatuada, C.; Kawamoto. l-L; Inokawa, S.. Yamashita, M.; Artuour, M-A.; Nakashima, T.T. Curb&&. Res. 1982.102, 159-167. It has been reported (Hauser, F. M.; Adams, Jr, T. C. J. Org. C/ma. 1984.49.22962297.) (see also nf. 7) thatGr@ud nactions on ketone 2a pmxcds via a stum&ctive qqmmh giving alcohols of (s)-mf@ratiou in agnemnt with our fiudin8s iu the tea&on with dichlommcthyllithium. No cxplauationis advatxxd for the dismpaucy between our and the mp9rtcd [a]~ value far 6b. The lH-lH NMR NOF!SY cxpcrimunton out uompound6b m&cd a rcvurscd signal assignmeatfor H3 aud H-4 relative to the signal attributionpmpuscd carlicr7. Qmlp~~& 6b : *H NMR (400 MHz, CDCl3) 6 7.79-7.38 (m. SH, Ph). 6.79 (s, IH, NH), 5.92 (d, 1H. J1.2 = 3.6 Hz. H-6), 5.27 (d. H-I, J3 4 = 3.6 Hz, H-3), 5.07 (d, lH, J3,4 = 3.6 Hz, H-4), 4.86 (d, lH, Jl 2 = 3.6 Hz, H-5), 4.43 (m, = 11.4 Hz, CH2). 1.50 and 1.33 [2s, 6H. CXCH3)2]; lH, OH), 4.15 aud 3.91 (2d, 2H, J Anal. Calud for Cl7Hl9NG7 : C,s% H, 5.48; N, 4.01. Found : C, 58.58; H, 5.43; N, 3.94. El LagMach, A.; Echatri, R.; Matheu, M. I.; Barrena,M. I.; Garuia,J.; Castillon, S. J. Org. Ckm, 1991,56. 45564559. T&uwto. T.; Sudoh, R Bull. Cktn. Sot. Jpn 1975.48. 3413-3414. Klumer, A.; Klaffke, W. Ucbigs Ann. Chin. m, 759-763. Luu, L. L.; Keavcney, 0.; O’Cctlla, P. S, Carbohydr, Res. 1977.59, 268-273. O’Leary. M. H.; Baugh, R. L J. Biol. Ckm. 1977,252, 7168-7173.
(Received in France 14 April 1994, accepted 8 May 1994)