J. Am. Chem. SOC.1980, 102, 7026-7032
7026
Table V. Partition Coefficients for 6-STC and Sa-epi-6-STC in the CHC1,-H,O System 6-STC Sa-epi-6-STC ~~
~
PH 7
6 5
KD' 28.0 >50b >50
KD" 30.8 >50 12.0
PH 7
6 5
KD = (concentration in CHCl,)/(concentration in H,O). The lipophilicity of the thiatetracycline was so high that accurate determination of the concentration in the aqueous phase was not practical. Table VI. Intramolecular Hydrogen Bonding in the Thiatetracyclines' 1la-OH12a-DOH6-STC(O)
6-STC(O)
5a-epi-6STC(0)
O(2am)-H( 3) 0(3)-H(3) O(2am)-H( 3)-0( 3) O(2am). . . O(3)
1.48 (3) 0.99 (3) 158 (3) 2.431 (1)
0.79 (7) 1.65 (6) 171 (9) 2.427 (3)
0.98 (3) 1.55 (3) 150 (3) 2.450 (2)
O( 10)-H( 10) 0(11)-H(10) 0(10)-H(10)-0(11) 0 ( 1 0 ) . . . O(11)
0.86 (3) 1.74 (3)
0.82 (5) 1.89 (5)
0.84 (3) 1.82 (3) 146 (3) 2.559 (2)
O( 12)-H( 12) O( 11)-H( 1 2 )
0.87 (2) 1.68 (2) 152 (2) 2.494 (1)
0(1l)-H(lO)-0(12) 0 ( 1 1 ) ' . . O(12)
152 (3) 2.534 (1)
144 (5)
2.598 (4) 0.72 (5) 1.85 (5) 155 (5) 2.523 (3)
0(12)-H(12) 0(1)-H( 12) 0(12)-H( 12)-O( 1) O( 12) . ' . O( 1)
N(2am)-H(2 1) 0.86 (2) 0.77 (5) 0(1)-H(21) 2.03 (2) 2.12 (4) O( 1)-H(2 l)-N(2am) 136 (4) 137 (2) O( 1) . * * N(2am) 2.717 (1) 2.726 (5) a Distances in angstroms, angles in degrees.
0.97 (3) 1.56 (3) 158 (3) 2.488 (2) 0.92 (3) 1.97 (2) 133 (2) 2.681 (2)
The enol moiety of the tricarbonylmethane system is of considerable interest not only because it sustains a central role in the equilibrium between the two forms of the free base but also because it presents an unusually short intramolecular hydrogen bond. We have reported examples where the hydrogen atom was
found to be primarily associated with atom 0 ( 3 ) 4 d and others in which it was localized primarily on atom 0(2am).'9I6 Emphasis should be placed on the word primarily, since in an unusually short hydrogen bond the hydrogen atom is expected to bind to either oxygen atom with nearly equivalent bond energy. Difference electron density plots19 for the appropriate region of the A ring are presented in Figure 2 for 6-STC(O) and Sa-epi-6-STC(O), These plots provide indications of partial, but not equivalent, occupancy for the hydrogen atom on each oxygen of the enol. Comparison of the appropriate C-0 bond distances in Table I11 supports the validity of the plotted electron density. The intramolecular hydrogen-bonding geometry of the three thiatetracyclines is presented in Table VI. It is clear from Tables 111 and VI that the extension of the A-ring chromophore in 1 l a - O H 12a-DOH-6-STC(O) has not altered the hydrogen-bonding character of the A-ring enol significantly. The extension of the A-ring chromophore in the 1 la-hydroxyl derivative results in the carbonyl group a t C ( 1) being part of an enolic /3-diketone in which this group serves as an acceptor in two intramolecular hydrogen bonds. The observed carbonyl C - O bond distance closely resembles that at C ( 11) in the tetracyclines with the usual BCD chromophore.' In 1 la-OH-12a-DOH-6-STC(O), the carbonyl group at C( 1 1) also reflects the change in chemical structure. It is shortened significantly when compared with the usual value' but is very similar to that in 5a,l la-DH-7-ClTC(O)' in which the carbonyl group serves as an acceptor in only one hydrogen bond, that from the phenolic hydroxyl group. These observations and the general trend in bond distances from the high-resolution crystal structure determinations demonstrate that the tetracyclines display a high degree of integrity in their bonding geometry.
Acknowledgment. W e thank the Institut fur Organische Chemie, Biochemie und Isotopenforschung der Universitat Stuttgart for making this research possible.
Supplementary Material Available: Anisotropic temperature factors for the C, N, 0,and S atoms, fractional atomic coordinates and isotropic temperature factors for the H atoms, bond angles between C, N, and 0 atoms, and calculated and observed structure factors for each structure (1 11 pages). Ordering information is given on any current masthead page. (19) Program JIMPLAN, an oblique-plane Fourier plotting program in which the slant-plane Fourier transform routine of van de Waal has been incorporated by Hansen.
Synthesis of @-Lactamsfrom Substituted Hydroxamic Acids Marvin J. Miller,* Phillip G. Mattingly, Marjorie A. Morrison, and James F. Kerwin, Jr. Contribution from the Department of Chemistry, University of Notre Dame, Notre Dame, Indiana 46556. Received May 28, 1980
Abstract: An efficient biomimetic p-lactam synthesis has been developed on the basis of cyclization of substituted 8-hydroxyhydroxamic acids. The method is experimentally simple and, by appropriate choice of amino acid starting material, allows complete control of the stereochemistry at all positions of the p-lactam. The method is also compatible with the incorporation of sensitive peripheral functionality required for potential elaboration to biologically useful @-lactamderivatives. The key to the process is the low N-H pK of the intermediate 0-alkylhydroxamic acid which facilitates diethylazodicarboxylatetriphenylphosphine (DEAD/Ph3P) or Ph,P/CCL/Et,N mediated N-C4 bond closure to N-alkoxy-2-azetidinones.The sequential reduction of the latter by H,/Pd-C followed by N-0 cleavage with TiCI3 leads to N-unsubstituted 8-lactams.
The p-lactam antibiotics are the most widely used antimicrobial agents. However, the bacterial development of p-lactamase en0002-7863/80/ 1502-7026$01.OO/O
zymes' which render some of the antibiotics ineffective has prompted a persistent search for modified antibiotic forms. While 0 1980 American Chemical Society
J. Am. Chem. SOC.,Vol. 102, No. 23, 1980 1021
Synthesis of @-Lactams Scheme I1
Scheme I
13, 16, 17
a
7
6
0
II
II
Scheme 111. Chiral Models
RCNH R’
CH20H
I L-H2N--CH-C02CH, 9
P N H y I l
II
2 HCI, H 2 0
protect N
21 HZNOCH2Ph ( 2 4 i
P N H P c ’
NOH
--
N
~
R
~
~
22, P = CBZ 23, P = t-BOC
NHR3
0
c
CHzClz
0 25, P = CBZ 26, P = t-BOC
0 C
-
I
L-NH2-CH-CO2H
NHOCH2Ph DMFv
U
R
CH2CI
20
11 (racemized)
10
15,18,19
16,18, R=CH,Ph, R’ = RZ= CH,, R’ = R 4 = H 17,19, R = CW(CH,),, R’ = R Z =CH,, R’ = R4 = H
n
0
14
pNHj2-ocH
12
0
traditionally most modifications have been derived from peripheral changes on the penicillins 1 and cephalosporins 2, the recent discovery and structural elucidation of the nocardicins (3),* thienamycin (4),3clavulanic acid (5),4 and others indicate that
27, P = CBZ 28, P = t-BOC
synthesis of @-lactamson the basis of the cyclization of substituted @-hydroxyhydroxamicacids5 Synthesis of the 2-azetidinone ring system by N-C4 bond closure (Scheme I, 7 8) is especially attractive because of its biosynthetic analogy and the conceptual ability to use chiral amino acid derivatives as starting materials. Indeed, several elegant biomimetic @-lactam syntheses have been devised.69 However, the required protection of the peripheral amino acid functionality and chirality, the need for a multistep incorporation of a @-leaving group, and the use of strong base in the cyclization steps decrease their utility. Ideally a biomimetic @-lactam synthesis should proceed by direct cyclization without the need for elaborate prior manipulations. While conceptually such a process is represented in Scheme I (6 8), experimentally it is not feasible. The similarity of the pK values of the ultimate C3-H and the peripheral N-H bonds would lead to detrimental proton transfers and subsequent reactions with little desired cyclization. The problem, therefore, became one of differentiating the pK values at the three potentially ionizable positions to allow selective ionization to 7.
“““jj..... 0
R‘
0 C02H
C02H
1
2 N-OH
-+
3 (Nocardicin A)
I
C02H
4
COzH
5
compounds structurally quite diverse from the normal penicillins and cephalosporins might be effective antibiotics or 0-lactamase inhibitors. Such structural variety has made apparent the need for an efficient synthesis of the core 2-azetidinone ring in a manner compatible with complete control and versatile incorporation of chirality and peripheral functionality. Of the many methods available for 0-lactam synthesis, no single method is generally applicable to the variety of synthetic targets now being approached. Described here is the development of an efficient and versatile (1) Hamilton-Miller, J. M. T., Smith, J. T., Eds. “Beta-Lactamases”; Academic Press: New York, 1979. (2) Hashimoto, M.; Komori, T.; Kamiya, T. J. Am. Chem. SOC.1976,98, 3023. Kamiya, T. “Recent Advances in the Chemistry of 8-Lactam Antibiotics”; Chemical Society: Cambridge, England, 1976; pp 287-294. (3) Albers-Schbnberg, G.; Arison, B. H.; Hensens, 0. D.; Hirshfield, J.; Hoogsteen, K.; Kaczka, E. A,; Rhodes, R. E.; Kahan, J. S.; Kahan, F. M.; Ratcliffe, R. W.; Walton, E.; Ruswinkle, L. J.; Morin, R. B.; Christensen, B.
G. J. Am. Chem. SOC.1978, 100,6491-6499. (4) Howarth, T. T.; Brown, A. G.; King, T. J. J. Chem. Soc., Chem. Commun. 1976, 266.
Models Cyclization of &Chlorohydroxamates. The N H bonds of 0acyl- and 0-alkylhydroxamic acids have pK values of 6-10,10-11 yet the corresponding anions can be alkylated inter-12 or intramolecularly13 without competitive Lossen rearrangement.” Although such intermolecular alkylations often give mixtures of Nor O-alkylation products,’*the preparation of substituted N-alkoxy (5) Mattingly, P. G.; Kerwin, J. F., Jr.; Miller, M. J. J. Am. Chem. SOC. 1979,101,3983-3985. See also: Chem. Eng. News Oct 1,1979, pp 25-26. (6) Baldwin, J. E.; Christie, M. A. J . Am. Chem. SOC.1978, 100, 4597. Baldwin, J. E.; Christie, M. A,; Haber, S. B.; Hessan, D. Ibid. 1975, 97, 5957. (7) Nakatsuka, S.; Tanio, H.; Kishi, Y. J. Am. Chem. Soc. 1975,97,5008,
5010. (8) Koppel, G. A.; McShane, J. J.; Cooper, R. D. G. J. Am. Chem. SOC. 1978, 100, 3933. (9) Wasserman, H. H.; Hlasta, D. J. J. Am. Chem. SOC.1978, 100, 6780. Wasserman, H. H.; Hlasta, D. J.; Tremper, A. W.; Wu, J. S. Tetrahedron Lett. 1979, 549.
(IO) Exner, 0.;Simon, W. Collect. Czech. Chem. Commun. 1965, 30, 4078. (1 1) Miller, M. J.; DeBons, F. E.; Loudon, G. M. J. Org. Chem. 1977, 42, 175C-1761. Miller, M. J.; Loudon, G. M. J. Am. Chem. SOC.1975, 97, 5295-5297. (12) Johnson, J. E.; Springfield, J. R.; Hwang, J. S . ; Hayes, L. J.; Cunningham, W. C.; McClaugherty, D. L. J. Org. Chem. 1971,36, 284. (13) Nicolaus, B. J. R.; Bellasio, E.; Pogani, G.; Testa, E. Gazz. Chim. Ital. 1963, 93, 618.
7028 J. Am. Chem. SOC.,Vol. 102, No. 23, 1980
Miller et al.
Scheme IV
Table I. Intermolecular Alkylations of Substituted 0
-
Hydroxamic Acids
I1
Ph3P
t
EtOzC-N=N-C02Et
Et0 C
-1
DEAD
0
RCNHOR'
N-fi-COZEt
0
Ph3P'
I
U
R
t Ph3PtOR
COPh COPh
analogues 13 of the P-lactam precursor 6 was anticipated to allow selective NH ionization to 14 (Scheme 11). That such mildly formed anions would be nucleophilic enough to displace a 0-leaving group and form a four-membered ring had apparently been demonstrated by the reaction of 2,2-dialkyl-3-bromo acid chlorides with 0-alkylhydroxylamines in pyridine a t 70-100 " C which afforded N-alkoxy-3,3-dialkyl-2-azetidinones (15) (R3 = R4 = H).13 However, under these conditions, whether the ring formation 15) or resulted from acylation then N-C4 bond closure (14 alkylation at the @ position followed by N-Cz bond formation was not clear. In order to test the effectiveness of an N-C4 closure, we synthesized model compounds 16 and 17 by reaction of the corresponding @-chloro acids with 0-benzylhydroxylamine and 0-pivaloylhydroxylamine,respectively, in DMF/HzO (1 :4) at pH 4-4.5 with a water-soluble carbodiimide. The prdoucts generally precipitated from the reaction mixture. Both compounds cyclized readily (16 18, NaH, DMF, 20 "C, 1 h, 94%; 17 19, Li2C03, DMF, 20 'C, 24 h, 76%). These results encouraged the synthesis of chiral models to test the differentiation of the hydroxamate nitrogen anion and potential anions at C 3 or side-chain amide. @-Chloro-L-alanine hydroxamates were considered appropriate models since intermolecular displacement reactions on @-chloro-L-alanine derivatives with benzylmercaptan (pK = 9.4)14 have previously been used to prepare S-benzyl-L-cysteine derivatives without r a c e m i z a t i ~ n . ' ~ The N - C B Z - and N-t-BOC-@-chloro-L-alanine 0-benzylhydroxamates 25 and 26 were prepared by the procedure outlined in Scheme 111. Thus, L-serine methyl ester (20) was treated with PCI5 followed by hydrolysis to give 6-chloro-L-alanine (21).16 Reaction with carbobenzoxy chloride ((CBZ)Cl) gave 22 ( [aI2'D = +23.8', as the dicyclohexylammonium salt). The t-BOC derivative 23 ( [aI2OD = +22.9') was prepared by reaction of 21 with di-tert-butyl dicarbonate.]' Carbcdiimide mediated coupling of 22 and 23 with 0-benzylhydroxylamine (24) in aqueous solvent gave the desired optically active hydroxamates 25 ([a30= -32.4") and 26 ([a],,= -43.8') essentially quantitatively. Base-initiated cyclization provided the lactams 27 (74-86%, [aI2OD = -9 f 3") and 28 (75-88%, [ a ] % D = -3.3 f 0.05') as anticipated. Although 27 and 28 had optical rotations, the possibility of partial racemization was not completely excluded at this point. However, no dehydrohalogenation products were detected, and stopping the reaction before completion allowed recovery of starting material with complete retention of optical activity. Direct Cyclization of j3-Hydroxyhydroxamates. With the facility of the cyclization process demonstrated, a more convenient process which would avoid the prior preparation of intermediate ~-chloro-~-alanine derivatives was sought. Needed was a method of converting the @-hydroxygroup of a serine hydroxamate to a good leaving group while simultaneously forming the desired
-
h
CH,Ph 25
20
CH,
6 20
50 25 25 25 50 25 25
ORZ
% % % N-alkyla 0-alkyl' yield 65 76 63 78 100
35 24 37 22 0 0 0 0
82 88 51 62 66 71 91
C02CH2PhCH,Ph COPh CH2Ph 20 (CH,),CH CH,Ph CH,Ph 20 (CH,),CH CH,Ph CH,Ph 6 100 Ph CH,W CH,W 20 100 Ph CH,Ph CH, 20 100 67 ' The relative percent of N- and 0-alkylated isomers was determined by NMR analysis and comparison with the literature chemical shift values.12 Scheme V R'
R
P
OHR2
R OH
3
-;p$ R1
OH
wsc
method D and€
HZNOCHzPh
NHOC H 2P h
0
33, 34, 3 8 , 4 1 , 4 4
35, 36, 37, 3 9 , 4 2 , 4 5 R*R3
-
(14) Jencks, W. P. In "Handbook of Biochemistry"; Sober, H. A,, Ed.; CRC Press: Cleveland, Ohio 1970; p J-150. (15) Wilchek, M.; Zioudrou, C.; Patchornik, A. J . Org. Chem. 1966,31,
T, time,
"C
CH,
H,DEAD
-
R2
R'
Ph Ph Ph
IR~-OH EtOzC-NH-NH-COzEt
I
RZ
I1
&N-OCHzPh 0
27, 28, 18, 4 0 , 4 3 , 4 6
initial reactant
first second prod- meth- prodR R' R2 R3 uct oda uct 33 (CBZ)NH H H H 35 D 27 34 @OC)NH H H H 36 D/E 28 H 37 D/E 18 CH, H CH, 38 (B0C)NH H CH, H 39 D/E 40 41 (CBZ)NH H CH, 4 2 D/E 43 H 44 @OC)NH H CH, 45 D 46 H 'Method D = DEAD/Ph,P; E = Ph,P/CCI,/Et,N.
nitrogen anion to initiate cyclization. Because of the nucleophilicity of the hydroxamate nitrogen, classical hydroxyl modification methods such as tosylation were not anticipated to be effective. However, the combination of triphenylphosphine (Ph!P) and diethyl azodicarboxylate (DEAD) has mediated the alkylation of several acidic groups (carboxylic acids, phenols, imides, and others) with alcohols.18 The only apparent limitation of this reaction is that the acidic component should have a pK I 13. Since, as previously indicated, the N-H bonds of the 0-substituted hydroxamates fulfill this criterion, a mechanism based on literature analogy for other systems could be written for the DEAD/Ph,P alkylation of substituted hydroxamates with alcohols (Scheme IV). The alkylation process was tested intermolecularly with several different alcohols and hydroxamic acids (Table I). T h e results indicated that while Oacylhydroxamates (pK = 6-7) gave typical mixtures of N- or 0-alkylation products, the less acidic (pK = 9-10) 0-alkylhydroxamates gave only the desired N-alkyl products. An extension, the attempted intermolecular alkylation of either Obenzoyl- or Gbenzylbenzohydroxamic acids 29 or 30 with N-CBZ-L-serine benzyl esters (31), gave only the dehydroalanine elimination product 32 (eq l ) . I 9 While this apparent inability of intermolecular alkylation to compete with 0-elimination was disappointing, we rationalized that the cyclization reaction still might proceed. Formation of an intramolecular nitrogen anion
2865.
(16) Fischer, E.; Raske, K. Chem. Reo. 1907, 40, 3717. Wood, J. L.; Middlesworth, L. V. J . Biol. Chem. 1949, 179, 529. (17) Maroder, L.; Hallet, A.; Wunsch, E.; Keller, D.; Wersin, G. Hoppe-Seyler s Z . Physiol. Chem. 1976, 357, 1651,
(18) Wada, M.; Mitsunobu, 0. Tetrahedron Lett. 1972, 1279. (19) Wojciechowska, H.; Pawlowicz,R.;Andruszkiewicz, R.; Grzybowska, J. Tetrahedron Lett. 1978, 4063.
J . Am. Chem. SOC.,Vol. 102, No. 23, 1980 7029
Synthesis of @-Lactams
Fi II
PhC-NHOR
29, R = COPh 30, R = CH,Ph
Scheme VI
C H$H I
I
t CBZNH-CH-CO2CH2Ph
DEAD
31 &NHOCH*Ph
kNHOCH2Ph
0
0 I1
CBZNH-C-C02CH2Ph
32 was anticipated to decrease the acidity of the a-C-H bond and thereby discourage elimination. Thus, N-CBZ- and N-t-BOCL-serine (33 and 34) were each converted to the corresponding hydroxamates 35 (carbodiimide, H2NOCH2Ph;DMF/H20 (1 :4); p H 4.5;
