3*s 'Ihus. the problem of non-chelation conttol has been solved in ... We now describe a simple and general method for chelation controlled addition reactions of ...
Teadw&on Letters.Vol. 35. No. 13.pp. 1969-1972. 1994 Elsevii.schww PIhtCdillomtBZiuin 00404039~ 56.ooto.~
tMMo-4039(94)RO194-3
A Simple Method for Chelation Controlled Additions to a -Amino Aldehydes bfadkd
T. Reefz: Karfn R(pilwg and Nils Grfebenow
Max-Planck-Institut ftir Kohlerrfomchung. Kaiser-Wilhelm-Platz 1.45470 MUlheimIRuhr, Germany
Ab&ack BOG and Cbz-pmtected a-amino akMydcs &rived from amino acids un&?rgo stereoselective aoVition reactions with al&l cuprates and manganese reagents, the ch&tbn-contrvlled odducrs being the major akstereomers (generally a3 > 9096). Unhired racemization is not observed Ice > 99%).
~Amino alcohols constitute a pharmace utically and biologically imemsting class of compounds as such and as constituents of more complex molecules.1 A popular synthetic approach involves the use of natural and unnatural amino acids as chiral non-racemic building blocks.1-3 Accordingly, amino acids are converted into the corxesponding protected amino aldehydes which am then reacted with C-nucleophiles. The basic problem is to coatrol diastereoselectivity under conditions which do not lead to undesired racemization. The most comtnonly used protective groups are BGC (t-butyloxycarbonyl) and Cbz (benzyloxycarbonyl) residues. However, Grignard and L¬ate additions to BGC or Cbz-protected a-amino aldehydes usually afford 1 : 2 or 1 : 3 mixtures of diat~temornem,~ partial racemization being possible.s*6 The 9-phenyl-9-fluomnyl protective group imparts a high degree of configurational stability, but Grignard and Lienolate additions provide 1: 3 mixtures of diastere~mem.~ The Garner aldehyde derived from serine is a notable exception in that high levels of diastemoselectivity and little racemization (0 - 3%) result7 We have previously shown that N&dibenzylamino aldehydes react with RMgK, RLi, R&t&i, Me$iCN/ZnKz. Li-enolates, and enolsilam&LiC!lO~ to provide the concsponding &amino alcohols with SO% non-chelation control and no racemization. 3*s‘Ihus. the problem of non-chelation conttol has been solved in a general way, but inducing the opposite diastereoselectivity in favor of chelation control remains a challenge. Pelt’s one-pot use of a-imino esters derived from amino acids and benzophenone (O’Do~ell’s Scbiff bases) in combination with ~Bu~(I!Ru)~AI and a three molar excess of RMgK or RLi is currently the most efficient way to obtain chelation controlled adducts for phenyl and vinyl-type additions (86 : 14 to ~95 : d diasmmomer ratios with essentially no racemization),g but g&&ttetaI reagents were not employed. We now describe a simple and general method for chelation controlled addition reactions of BOC- and Cbz-pro&ted u-amino aldehycks 1 withalkyl cuprates and alkyl manganeseto ruagenta Transmetalation of organolithium compounds with Cu- or A&t-saltspaovides reagents which add to aldehydes 1 withchelation control (Tables 1 and 2). Alkyl (but not vinyl or phenyl) reagents gem-ally show diaste!reoselectitiries of HI%.
1970
0
0
Rob”
Rok
()
R’
W-M
0
‘NH OH
)
tc(
+ t( R’
H 1 a:R=rBu
l&H
b:R=PhC&
t+
X
R’
2
OH
R*
3
Table1. Reactions of Organocopper Reagents with Aldehydes 1 in Diethylethef? hkhyde la la 10 la la 18 la la 18 la lb lb lb lb lb la la la 18 la 1P la la la la la la la la la la la
R’ CH3 m3 a3 CH3 CH3 CH3 a3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 KHz
PhCH2 PhCH, pM3H2 PhcH, =H2
PhCH2 MH2 WI42 (CH,),cHCH, (CH3)2cHcH2 (CW2cHCH2 (CQCWH2 (cH3)2cHc~ (CH3)1cHcH? (cH3)2cHCH2 (CH3)2~~2
Reagentb) 3 CH3Li 1 (aJ3)&ti 3 nBuLi 1.2 (nBu)&uLi 3 tBuLi 2.2 (~Bu)~C~L~ 3 CH#(CH3)Li 2.2 [CH&CH,)],CuLi 3Fw.J 2.2 Ph2CuLi 3 CH,Li 2 (CH3>&ti 2 [(CH3CuCN)Li - 2 LiCIl 3nBuLi 2.2 (nBu)#Li 3 CH&i 1.5 (CH3>2CuLi 4.4 [(cw,cllcN)Li * 2 La] 3 nBuLi 1.5 (rrB~)~CuLi 3tBuLi 2.2 (rBt~)~CuLi 3PhLi 2.2 P!t2CuLi 3 CH3Li 1.5 (CH3)2cuLi 3 (CH3,PLi 4.4 [(CH3CuCN&i * 2 LiCll 3nBuLi 22 (nBu)&uLi 3 2BuLi 2.2 (tBu)&uLi
TempJIIme (Oclh) -1813 -5513 -7813 -7814 -7813 -7813 -1813 -1813 -1813 -1813 -1813 -5515 -5513 -7813 -7813 -7813 -7813 -1813 -7813 -7814 -7813 -1814 -7813 -7813 -5513 -5513 -5513 -7813 -1813 -1813 -7813 -7814
% Convetsionc) (yield)
91 93 (82) 82 94 (69) 93 94 92 98 14 90 (62) 85 86 98 80 80 (68) 92 92 96 (80) 77 49 (26) 71 94 81 94 (73) 99 92 87
2 : 3c)
44 : 56 r-1 58 : 42 jxq 48 : 52 80 : 20 66:34 71:29 49 : 51
48 : 52 (92:8j 42 : 58 88 : 12 1-1 38 : 62 78 : 22
41:59 69:31
94 (80) 82 84
a)CuBr-SMe, was used to pam R&t&i. b, ‘Ilk? numbers in front of the reagents indicate the amount of reageat used wi tr twpect to 1.c,Convemioiianddiatmmmer ratioswee determined byacBIlalvninofthecrudeproducts.Thenuarbersinparenthe#arefertoisolatedpureproducts.
1971
Reagents with Aldchydes 1 in TEE.
Table 2. Reactions of Organov Aldehyde la
la
Reagent.)
R’
T
2.2 cH3Ii
c
/Ii Ih)
7 (
%Convexsionb~ (yield)
40:60
-78/2
76
-7812
71
62:38
97
194:61 195:51
c
2.2 CH3MgI
la
a3
2.2 (CH&i/MnCl~
la
a3
2.2
(cH3LilMnBr2)
-5513
90
la
a3
2.2
(cH3LminI2)
-78 / 3.5
41
la
-78-U)
I4
81: 19
a3
2.2 (2 CH3Li/h4nBr~
-7815
97 (66)
la
c
2.2 (nBuLi/MoBr2)
-7815
82
la
.2 LiBr]
2:3b)
c
2.1 [(nBuLiMnBr2)
la
CH3
2.2 (PhLiMSrz)
-78-25i3 -55/ 17
lb
194:6) 86: 14
95 (63)
(88:12) 78 : 22
88
m3
2.2 (CH3LUMllBQ
-78 15.5
84
lb
m3
2.2 CH2=CHMgBr
-7814
77
lb
a3
2.2 (CH2=CH?klgBrJMnBr~
-7815
62
lb
CH3
2.2 (nBuLi/MnBr2)
-78 13.5
82
la
-2
2.2 CH3MgI
-7813
66
la
19a:I 56:44 I= [E,
WH2
2.1 (CH3Li/Mn3ri)
-5512
85
la
WCH,
2.2 (2 CH3LiMlCl~)
-78 / 2.5
93
89: 11
la
-2
2.2 [(nBuLiA4nBr2) .2 LiBr]
-78 / 26
60
85: 15
la
(CH3hcHcH2
3 CH&i
-78f 3
85
39:61
la
(CH3~HCH2
2.1 (CH3LVMnBr~
-5013
97
2.2 (n-BuLiinBr~
-7813
68
la
(CH3)&HCH2
/Gq 84: 16
a)The numbers in front of the reagents indicate the amount of reagent used with respect to 1. b, Conversion and diastereomer ratios were determined by GC analysis of the crude products. The numbers in parentheses refer to isolated pure products.
Contml experiments
show
that the reactions proceed without any appreciable racemization
S!9%).11 ConfiQurational assignment
(ee
of adducts 2 was made by comparison with known compounds,
chemical correlation and/or x-ray structural anslysis. In summary, al.Qlcopper and -manganese compounds chelation conrrolled Grigna&type without any l7Semiznlion.
ate curmntly the most efficient reagents for
additions to N-BOC or IV-C& amino ahkhydes.
Diastereoselectivity
is considerably
the captions
proceeding
lower in the case of phenyl snd vinyl-type
reagents, which means that our protocolt2 is complementary to POWsmethod.9
This work was supported by the Deutsche Forsclumgsgemeit.tschaft (LeibnM’rogramm).
1.
2. 3.
4.
5. 6. 7. 8. 9. 10. 11.
12.
See for example: Me& Index, 8th Ed., Merck: R&way, NJ/USA, 1968, p. 233; Rich, D. 8. J; Med CIicm I!&!% 28, 264: &?Medy, J. E; White, C. A. Biuuc&e Ckbhydrraks, Eliis Horwood~ ChichesterrlEngland 1983; Petit, G. R.; Singh. S. B.; Hogan, F.; Lloyd-Wi&ms, P.: Herald, D. L.; Burke% D. D.; Clewlow, P. J. J, Am C%em Sue. 1989,111,5463. Junzzak, J.; Golebiowski. A. C&em.Rev. lS9.89, 149. Reviews of reactions of ~~-~~y~o aid~hydes and other N-pro&c!@ analogs: Reetz, M, T. Angcw, Chem 1991,103. 1559; Angnv, chcnr. In& Ed EslgL 1991,30, 1531;Reetz, M. T. Pure &pl C&m 19!&64,35L Examples: Hanson, G. J.; mdberg, T. J, Org. Chcm 198S, 50.5399; Rosenberg. S. H.; Platmer, J. J.; Woods, K. W.; S&in, H. H.; Marcotte, P. A.; Cohn, J.; &run, T. J. J. Med Chem 1!387.30.1978; Rich, D. H.; Sun, E. T.; Boparai, A. S. J. Org. Chem. 1978,43, 3624; Della& J. F.; Maki, R. G. Te@&ecdron Lctt X=,2?, 2337. Fehrentz, J. A.; Castro, B. S’yn&csis, 19S3,676; RiUIe, K. E. Hornnick, C, F.; Punticello, G. S.; Evans? B. E. J. Org. C&em. 1982,47,3016. Lube& W. D.: Rapoport, H. J. Am. Chem Sue. 1988, X10,7447. Gamer, P.: Park, J. M. J. Org. C&em 1987, 52. 2361; Gamer, P.; Park, J. M.; Male&i, E. J. Org. Churn. 1988,53,4395; Herold, P. Helv. Chim Acta 198R71.354. Reetz, M. T.; Fox, D. N. A. ~e~~dr~n Len. 1993,34,1I 19. PO&,R.; Peterson, M. A.; &Young, L. J. Org. Chem 1992,57,54&t see also: Ibuktt,T.; Habaahita, H.; Gtaka, A; Fujii, N.; Oguchii K.; Uyehsra, T.; Yukon, Y. J. Org. C&em Z@91,56,4370. Cahiez, G.; Normant, J.F. in Modem Synthetic Me&a!% Scheffold, R. Ed.; Wiley: New York, 1983; Reetz, M. T.; Hauing, H.; Stanchev, S. Te~~ed~n Left. 1992,33,6963. This was checked by GC @ii phase) in the z~%tions of aldehyde la (RI = CH& We thank F. Kobor and U. H&wig for heIp in the &~~~tio~ of the ee values and F. Sagheb for all other GC analyses. TypIcal procedure: Cuprae adze: To a suspension of CuBpSMe, (3.8 mmoi) in dry ether (30 ml) is ad&d RLi (7.6 mmol, 1.6 M in ether or hexane) at -786c under argon-atmosphere. After warming up until a clear solution is obtained the mixture is cooled to the given ornate and stirred for 30 min. ‘I%en the a-aminoa.l&hyde 1 (1.7 mmol) dissolved in 8 lal dry ether is ad&d. After 3 - 4 h fhe reaction mixture is quenched with sat. NH&l, diluted with ether, extracted once again with sat. NH&l, sat. NaHC4, brine and dried over MgSO+ The products am purified by flash c~m~~hy. Manganese reagent additions: To a swqensiot~ of atthydroua MI& (2.2 nunol) (and 4.4 mm01 anhydrous LiX) in dry THF (10 ml) is added RLi (2.2 or 4.4 mmol, 1.6 M in ether or hexane) at 25oC under argon-atmosphere. The clear redbrown solution obtained is stirxed for 30 min (for R = n-Bu; 1 min). After that the mixture is cooled to the given temperature and the u-~~o~dehy& 10 mmol) dissolved in 8 ml dry THF is added. After the given time the reaction mixture is quenched with sat NH&l, diluted with ether, extracted. witi sat. aq. EDTA soltion, sat. NaHCOs, brine and dried over MgSO.,. -cation aa above.
(Received in Gerwny 19 Junuqy 1994; acceptird 20 JWWW @94
