Jul 13, 1987 - No products of 1,2-addition were found in the Et3N-catalysed reactions. Addition .... probably a product of the aldol condensation of (1) with (4a).
I ! J.
CHEM. SOC. PERKIN TRANS. I
1988
2075
f
Synthesis o f Enantio- and D iastereo iso -m erically Pure S u b stitu te d Prolines via Condensation o f G lycine w ith O lefins A ctivated by a C arbonyl Group Y uri N. B elo ko n ',* A leksandr G. B ulychev, V iacheslav A. Ravlov, Eugenia B. Fedorova, V la d im ir A. Tsyryapkin, V la d im ir A. B akh m u to v, and Vasili M . B elikov Nesmeyanov Institute o f Organoe/ement Compounds, U.S.S.R. Academ y o f Sciences, M oscow , U.S.S.R. The glycine fragment in the nickel(II) complex (1) formed from the Schiff's base of glycine and (S )-o-[(/V -benzylprolyl)am ino]benzophenone (2) undergoes base-catalysed Michael addition to acrylaldehyde, a-methylacrylaldehyde, (£)-crotonaldehyde, (E)-cinnam aldehyde, and methyl vinyl ketone. No products of 1,2-addition were found in the Et3N-catalysed reactions. A ddition follow ed by epimerization of the isomeric complexes proceeds w ith high diastereoselectivity at Ca (90%) and C B of the corresponding amino acid side chains. After chromatographic separation, the diastereoisomerically pure complexes were decomposed and the resulting dihydropyrrole-2-carboxylic acids reduced w ith NaBH3CN to give (S )-p ro lin e, fra/7s-3-m ethyl-(S )-proline, te&A?s-5-phenyl-(S)-proline, and a mixture of cis- and fra/7s-5-m ethyl-(S)-prolines. The chiral auxiliary (2) was recovered in 80— 90% yield. N o n -proteinogen ic a-am ino acids a ttra c t ever-increasing in terest as drugs o r co m p o n en ts of m any th erap eu tic ag en ts.1 T he specific activity is generally related to one stereoisom er o r an en an tio m er of a p articu lar a-am ino acid. Since the usual m ethods of enzym ic synthesis are inapplicable to the p rep aratio n of optically p u re u n com m on a-am ino acids, asym m etric chem ical m eth o d s are req u ired to solve the problem . T his is the underlying reason for the recent progress in the field of asym m etric synthesis o f u n com m on a-am ino acids.2-5 A m ong the uncom m on a-am ino acids, С-su b stitu ted prolines are unique because o f th eir p ropensity, w hen in co rp o rated into proteins, to induce stro n g con fo rm atio n al bias. D espite recent progress in stereoselective synthesis of С -su b stitu ted prolines,6 versatile, convenient an d general m eth o d s for th eir enantio- and diastereo-selective synthesis are n o t yet available. W e set ourselves th e task o f developing such a m ethod by elab o ratio n of the M ichael a d d itio n of a N i11 com plex (1) of the SchifFs base derived from (S)-o-[(/V -benzylprolyl)am in o ]b en zo p h en o n e (2) an d glycine to su b stitu ted acrylaldehydes. E arlier we used the com plex (1) to develop asym m etric general synthetic m ethods for p-hydroxy-a-am ino acids,5b P- and у-substitu ted glutam ic acids,5c a n d a-m ethyl-a-am ino acids.5d e T he general strategy an d the co nnection of o u r w ork w ith the a-am ino acid m etal com plexes are discussed in o u r previous paper. >a'e
R
N , c = c — c:
H
(3)(a-e) a - d E t3N e MeONa
H ^U R 3C * " 4
General Procedure fo r the Condensation o f the C om plex (1) with S u b stitu ted Acrylaldehydes (3a— d) and M e th y l Vinyl Ketone (3e).— T he com plex (1) underw ent a d d itio n to sub stitu ted acrylaldehydes an d m ethyl vinyl keto n e in m eth an o l in the presence of E t3N (M eO N a in th e case o f m ethyl vinyl ketone) a t 60 °C. Initially a com plicated kinetically controlled m ixture of p ro d u cts w as form ed. U n d e r th e experim ental conditions the ra tio o f isom eric com plexes changed (12— 72 h) until equilibrium was reached, when only 1,4-addition p ro d u cts were detectable. T he reaction sequence is o utlined in Schem e 1.
( 5) ( b - d)
/
o — c'
Ni R e su lts Synthesis o f the C om plex (1).—‘T he com plex (1) w as obtain ed via co ndensatio n o f (.S)-o-[(Ar-benzylprolyl)am ino]benzophenone w ith glycine in the presence of N i( N 0 3)2 in m ethanol, as described earlier.51’
R2
II 0
j
: h r 1- c h r - c r 3
; c^ N •.
и 0 H
(6)(a-e)
а
R1 H
R2 H
R3 H H
b
H
Me
с
Me
H
H
d
Ph
H
H
e
H
H
Me
Scheme 1.
D iastereoisom ers were easily sep arated chrom atographically on S i 0 2 w ith th e аЛ -isom ers eluted first. As expected, they have th e sam e set of p ro to n signals, differing only in chemical shifts, a n d sim ilar u.v.-visible an d i.r. spectra. T heir o.r.d. curves
2076
J. CHEM. SOC. PERKIN TRANS. I
1988
Figure 3. O.r.d. curves at 25 °C (M eOH) equilibrium ratio otS: j.R w as greater th a n 9 5 :5 for all the olefins studied. T he configurations o f the P- and y-carb on atom s o f the side chains in the case of diastereoisom eric com plexes form ed via c o n d en satio n o f (1) w ith (3 b —d) were established by ‘H n.m.r. Acid hydrolysis of th e pure isom ers liberated the initial benzophenones (2) in chem ical yields o f 80— 90% an d the interm ed iate (2S )-d ih y d ro p y rro le carboxylic acids. T he latter, w ith o u t isolation, were reduced w ith N a B H 3C N in H 20 to the su b stitu ted prolines (60— 90% yield) (M eth o d A, Schem e 2). T he stru ctu res o f th e a-am ino acids were established by their 1H n.m.r. an d m ass spectra. E nantiom eric p urity w as determ ined ch iroptically o r by chiral h.p.l.c. A detailed description of the co nd en satio n p ro ced u re for every olefin (3) is given separately.
Figure 2. O.r.d. curves at 25 °C (M eOH); (6b) is a mixture of diastereoisomers
(Figures 1— 3) could be used to assign the ab so lu te configur ations o f the a-carb o n atom s of the am ino acid side chains, as discussed e a rlie r;5c C o tto n effects in the 400— 500 nm regions were positive for xR - and negative for aS-form s. The
Condensation with Acrylaldehyde; Synthesis o f (R)- and (S)-Prolines.— T h e com plex (1) u nderw ent ad d itio n to (3a) according to Scheme 1 in 95% chem ical yield. The ratios of the diastereoisom eric p ro d u cts o f 1,4-addition are presented in the Table. T reatm en t o f th e diastereoisom ers as o utlined in Scheme 2 furnished (Л )-Рго [from (6a)] a n d (S )-P ro [from (4a)] with enan tio m eric excess (e.e.) > 98%. A ddition catalysed by M eO N a in M eO H a t 25 °C p roduced a m ixture of com pounds, as show n in Scheme 3. Flash c h ro m ato g rap h y o f the m ixture pro d u ced , as well as the usual 1,4-addition pro d u cts, co m p o u n d s (8) a n d (9). T he form er was pro b ab ly a p ro d u ct of the aldol co n d en satio n of (1) with (4a) a n d (6a); th e la tte r (9) originated from th e aldol co ndensation of (1) w ith the 1,4-addition p ro d u c t o f M eO H an d acrylaldehyde. C o n d en satio n o f (1) w ith (3a) catalysed by concentrated M e O N a in M eO H a t —78 °C gave, besides (8) an d (9). a n 18% yield of th e p ro d u ct (10) of 1,2-addition of (1) to acrylaldehyde. C ondensation with (E)-C rotonaldehyde (3c); Synthesis o f tra.ns-3-M etliyl-(S)-proline.— T he com plex (1) underw ent
J. CHEM. SOC. PERKIN TRANS. I
2077
1988
Table. Michael addition of the complex (1) to substituted acrylaldehydes and methyl vinyl ketone (Scheme 1)“
Yield (°/„) of (4) + (5) + (6)
Olefin C H 2=CH CH O (3a)
73
C H 2=CM eCH O (3b)
98
(£ )-C H 3C H =CH CH O (3c)
96
(£> P hC H = C H C H O (3d)
100
C H 2= C H C (0)M e (3e)
100
Yields (%) of individual diastereoisomeric complexes (4a) (6a) (4b) (5b) (6b) (4c) (6c) (4d) (5d) (6d) (4e)
68.5 (58.4)c 4.3 (14.6)c 29 61 8 91.3 4.6 82 (73)c 10 (10.7)c 8 (16)' 96 (86)'
,
Amino acids *------Optical purity (% е е.)
(S)-Proline (/?)-Proline ?ranj-4-Methyl-(S)-proline m -4-M ethyl-(S)-proline
>95 > 95 > 95 > 95
Chemical yield (% )‘ 73 73 70 74
/rani-3-M ethyl-(S)-proline /ra«.s-3-Methyl-( Z?)-proline (ra«,v-3-Phenyl-(S)-proline c«-3-Phenyl-(S)-proline /ranj-3-Phenyl-(/?)-proline 1:1 cis- and /гаил-5-methyl(S)-proline
> 95 >95 > 95 > 95 > 95 >95r
70 72 75 71 69 69
Designation
M ethod A A В В A A A A A A
(6e) 4 (14)c “ Reaction conditions: M eO H solution, E t3N [M eO N a in the case of (3e)], 60 °C, under argon, ratio of olefin to (1) 1:1 to 1:4, 12— 72 h . b Based on the initial pure diastereoisomer. ‘ Kinetically controlled ratio of diastereoisomers (E t3N as catalyst).
(1)
+
( 3a)
MeO N a 25 ° C { - 7 8 °C)>
i. N aB H jC N .M eO H
1ii.D o w ex-
50H +
(7) a i R1= R 2 = H с ; R1 = Me, R2 = H d i R1 = P h . R2= H e ; R 1 = H , R 2 = Me
Scheme 2.
addition to (3c) in m ethanol in the presence of E t3N. Isom ers of types (8) and (9)were form ed in the initial stages o f the reaction, but after 72 h at 60 °C the m ixture consisted m ainly of tw o individual isom ers (see Table). T he ab so lu te configurations of their side-chain x-carbon ato m s were assigned from o.r.d. curves (F igure 1). T he m in o r isom er (6c) (4.6%) was found to have V al.7 T he n.m.r. signal of the m ethyl p ro to n s o f the m ajor isom er the аЛ -configuration; the m ajo r isom er (91.4%) h ad the (8 2.07) testified to th eir stro n g deshielding, as observed in the xS-configuration an d could be designated either (4c) o r (5c). case o f o th e r alkyl g roups located above o r u n d er the N i11 co M olecular m odels indicated th a t in the case of (4c) the m ost o rd in atio n p lan e.7-8 T hus, the ab so lu te configuration o f the side stable conform ation of the side chain h ad its Р-M e su b stitu en t chain could be assigned a t (2 S,3S), an d the m ajo r isom er was under the N i11 ion (see Figure 4). A sim ilar co n fo rm atio n was (4c). observed earlier for analogously co n stru cted com plexes of (5)-
2078
J. CHEM. SOC. PERKIN TRANS. I
1988
(5B)
H
(4B)
(5c)
Figure 5. Conform ations of the amino acid side chain in (5b) and (4b) and schematic representation of the shielding of the protons of the 3-methyl group in (5b), or the formyl proton in (4b) due to the diam agnetic ring current of the phenyl ring
Figure 4. Conform ations of (he amino acid side chain in (4c) and (5c)
T reatm en t of (4c) as o utlined in Scheme 2 gave initially benzophenone (2) and then p u re (25,3S )-isom er (7c) in 70% chem ical yield and with m ore th a n 95% optical purity. Condensation with (E)-Cinnam aldehyde (3d); Synthesis o f trans- andcis-3-Phenyl-(S)-prolines.— The ad d itio n catalysed by E t3N in M eO H a t 60 °C for 72 h gave a m ixture of three m ajo r diastereoisom eric com plexes in yields of 8, 80, an d 10% in the o rd er of their em ergence from a c h ro m ato g rap h ic colum n. The «-configuration could be assigned to the first isom er (6d), an d the aS-configuration to the second an d th ird from th eir o.r.d. curves (Figure 3). T he configuration at C„ of the latter tw o isom ers could be easily established by the n.m.r. m ethod as for the analogous com plexes o f (2S,3R )- an d (25,3S)-3-phenylglutam ic acids.51 A ccording to this analysis, the side-chain am ino acid configuration of the m ajo r isom ers was 2 5 ,ЗЛ, as in (4d), while th a t of the last eluted was 25,35, as in (5d). T reatm en t of the pure isom ers as show n in Scheme 2 gave (2S,3R )-3phenylproline [//Y//i,v-3-phenyl-(S)-proline] and (25,35)-3phenylproline [c/.s-3-phenyl-(.S')-proline], from (4d) and (5d), respectively. C om p o u n d (6d) after the usual treatm en t gave a sam ple of 3-phenylproline w ith R r value on cellulose an d n.m.r. spectrum identical w ith those of (25,3^)-3-phenylproline. H ence, the configuration o f th e initial am ino acid side chain in (6d) w as 2Л ,35 an d thus the resulting p roline h ad the 2R ,35configuration. C o ndensation o f (1) w ith (3d) is reversible. U n d er the experim ental cond itio n s (6d) w as converted in to an equilibrium m ixture of all three isom ers (6d), (5d), a n d (4d), an d the com plex (1) and cinnam aldehyde ( E : Z 19:1) were also detected. Condensation with M e th y l Vinyl Ketone (3e); Synthesis o f a m ixture o f cis- and\.rans-5-M ethyl-(S)-proline.— T he ad d itio n of
the com plex (1) to (3e) (catalysed by E t3N ) occurred readily in M eO H w ithin 2 h. T he diastereoisom eric com plexes were sep arated as before a n d the side-chain ab so lu te configurations (Figure 1) were determ ined in the usual m anner. T he initial kinetically controlled ra tio o f diastereoisom ers (4e):(6e) (Schem e 1) was estim ated as 5 :1 , and n o p ro d u cts of side reactions were obtained. E q u ilib ratio n of the isom ers could be effected by keeping the m ixture in tact for an o th e r 72 h, but the reactio n o ccurred m ore readily if catalysed by M eO N a in M eO H . In this case the equilibrium ratio [(4 e ): (6e)] of 25:1 was reached w ithin 20 min. T reatm en t of (4e) according to Scheme 2 gave a m ixture of cis- an d rra«.v-5-m ethyl-(5)-prolines in the ratio 1:1. T he ratio increased to 10:1 if the interm ediate dihydropyrrole-2-carboxylic acid w as catalytically hydrogen ated over P d -C .6b'9 Condensation with y.-M ethylacrylaldehyde (3b); Synthesis o f cis- and trans-4-M ethyl-(S)-proline.— A ddition of the com plex (1) to (3b) catalysed by Et ,N in M eO H gave after 36 h at 60 °C an equilibrium m ixture of three isom ers in yields of 11, 28, and 60.5% in o rd er o f th eir em ergence from a ch ro m ato g rap h ic colum n. T he аЛ -configuration could be assigned to the first isom er (6b), and the a5 -co n lig u ratio n to th e second and the third ones according to th eir o.r.d. curves (F igure 2). A nalysis of the n.m.r. spectrum of (6b) suggested th a t the isom er was a m ixture of tw o аЛ -isom ers differing in th eir -/-configuration. T he y-configurations o f the o th er tw o isom ers could be established by n.m.r. as discussed later. M olecular m odels of (4b) an d (5b), as well as the A"-ray crystal stru ctu re of the an alo g o u s N i" com plex o f th e SchifFs base from (25,4A )-4-m ethylglutam ic acid an d the b en zophenone (2),5c indicate th a t the m ost favoured conform ation of the am ino acid side chain displaces the P,y-bond outside the m ain co o rd in atio n plane an d positions the C H 3 a n d C H O groups as show n in Figure 5.
J. CHEM. SOC. PERKIN TRANS. I
1988
2079
HO—
H
I
4 c C
™
d2o | o c i
CH,
CH3
(D)H
" 4
N
>
C0>H
'-H
CO,H D+
4 N''Ч ,
С" 3" ) ^ У 'N i
С 0 1Н -H
D
N0 BH3 CN
NaBHjCN
CH, D ""
,co2H
CH0
'H
,C02H N
1
Scheme 4.
T he 2S,4/?-isom er (5b) has its side-chain y-m ethyl su b stitu en t situated above the phenyl su b stitu en t o n the C=N bond. Hence, one m ight expect the 1H n.m.r. signals of the m ethyl p ro to n s in (5b) to be shifted upfield vs. (4b), ow ing to the d iam agnetic cu rren t o f the phenyl ring. O n the o th e r h an d , (4b) (2S,4S) should have its aldehyde p ro to n signal shifted upfield vs. (5b). R elative upfield shifts were observed for the resonances of the m ethyl grou p in the m ajo r isom er (60.5%) a n d the aldehyde p ro to n in the second isom er (28%). T he isom ers could be thus designated (5b) an d (4b), respectively. This assignm ent is additionally su p p o rted by the close sim ilarity betw een the ‘H n.m.r. spectrum of (5b) an d th a t of the previously studied com plex of (2S,4/?)-4-m ethylglutam ic acid, unam biguously identified earlier.5' T reatm en t o f (4b) an d o r (5b) as indicated in Scheme 2 p ro du ced a 1:1 m ixture of cis- an d r/w w -4-m ethyl-(S)-prolines from either isom er. If the diastereoisom eric com plexes were cleaved in DC1 solution in D 20 , subsequent reduction with N a B H 3C N p roduced a m ixture of cis- and /ra«.v-4-methyl-(S)[4 -2H ]prolines. W e assum e th a t the form atio n of the interm ediate dihydropyrrole-2-carboxylic acid is accom panied by racem ization a n d hydrogen exchange at the 4-position according to Scheme 4. T o avoid racem ization an o th e r ap p ro a c h (M eth o d B) to the synthesis o f 4-substituted prolines w as developed as outlined in Schem e 5. T he first stage is the reduction o f the carbonyl gro u p in (5b) o r (4b) with M SA resin (B H 4_ form ) in M eO H at 25 °C to give the com plexes (11) and (12). T he corresp o n d in g enantioand diastereoiso-m erically p u re y-hydroxy-a-am ino acids could be recovered in the usual m anner. C o m p o u n d s (11) an d (12) could be further treated w ith M e S 0 2Cl to give the corresponding O -M es derivatives (15) an d (16). C leavage o f the com plexes w ith aq. HC1, followed by n eu tralizatio n of the reaction m ixture and extraction o f th e benzophenone (2), p ro duced cis-4-m ethyl-(S)-proline from (16) an d /гшм-4-m ethyl-
(S)-proline from (15) in a chem ical yield o f 70% an d with en antiom eric p urity of 95%.
D iscu ssio n The glycine fragm ent in the com plex (1) has significant C H acidity, w ith p K a 18.8 as m easured in M e2S 0 . 10 T he carb an io n generated in M eO H by E t3N o r M eO N a is reactive enough to ad d to the activated C=C b o n d s o f the olefins (3). T he C=C bonds of the acrylaldehydes (3) con stitu te the only reactive sites of these bifunctional m olecules even in the case of the sterically hindered cro to n ald eh y d e and cinnam aldehyde, w ith catalysis by E t3N . A large phenyl su b stitu en t on th e C=N bond of (1) prevents intram o lecu lar cy cliza tio n 11 o r any bis-addition, as discussed earlier.5e T he p ro d u cts o f type (8) were probably form ed via aldol co n d en satio n of (4), (5), o r (6) with the com plex (1). A significant am o u n t (18%) of 1,2-addition p ro d u ct from acrylaldehyde and the com plex (1) was detected only at low tem p eratu re ( —78 °C) a n d w ith a high co n cen tratio n of M eO N a. U n d er these cond ition s the aldol p ro d u cts are stabilized by the form atio n of a new type o f com plex w ith a co -o rd inated sidechain hydroxy g ro u p .56 H ow ever a t low pH the 1,2-addition p ro d u cts are highly u nstable therm odynam ically, and in the presence of E t3N rearran g e to the corresp o n d in g 1,4-addition com pounds, o r in the case of (8) dissociate to (1) and a m ixture of (4) an d (5). T he stereochem ical course of the M ichael reaction is initially co ntrolled by steric h indrance to the ap p ro ac h of an electrophile to the carb an io n o f (1).5
