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Economic Synthesis of Activated N-tert-Butyloxycarbonyl Amino Acid Esters.

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CAS Registry numbers:
( Z ) - (I). 59304-72-2; (E)-(I ), 60647-48-5; (2)-(2), 69610-99-7; (E)-(2),
6961 1-00-3; (Z)-(3), 69611-01-4; ( E ) - ( 3 ) , 69611-02-5; (R*,R*)-14aJ,
6961 1-03-6; (R*.S')-(4a),
6961 1-04-7;
(R*, R*)-(4 b),
69611-05-8;
(R*,S*)-(4b), 6961 1-06-9; (R*,R*)-(4c),
69611-07-0; (R*,S*)-(4c),
(R*,R*)-(4d),
69611-09-2;
(R*,S*)-(4d),
6961 1-10-5;
69611-08-1;
(R*,R*)-(5u), 1538-23-4; (R*,S*)-(5a), 1538-22-3; (R*, R')-(5b), 1538-21-2;
(R*,S*)-(5b), 1589-07-7; (R*,R*)-(5c), 1502-91-6; (R*,S*)-fSc), 1502-90-5;
(R*,R*)-(5 d), 52922-10-8; (R*,S*)-(5d), 52922-19-7; chlorobis(dimethy1amino)borane, 6562-41-0; acetaldehyde, 75-07-0; henzaldehyde, 100-52-7;
propanal, 123-38-6; 2-methylpropanal, 78-84-2; pinacol, 76-09-5
[l] S . Masamune, G. S . Bates, 3 . W Corcoran, Angew. Chem. 89, 602 (1977);
Angew. Chem. Int. Ed. Engl. 16, 585 (1977).
[2] H. Pommer, Angew. Chem. 72, 811, 911 (1960).
131 Y. Okude, S. Hiruno, 7: Hiyama, H. Nozaki, J. Am. Chem. Soc. 99,
3179 (1977); C . 7: Buse, C . H. Heathcock, Tetrahedron Lett. 1978, 1685;
cf. also C . Servens, M. Pereyre, J. Organomet. Chem. 35, C20 (1972).
[4] W A . Kleschick, C . 7: Euse, C . H. Heathcock, J. Am. Chem. Soc. 99,
247 (1977); C. 7: Buse, C. H. Heathcock, ibid. 99, 8109 (1977); W Fenzl,
R. Kiister, H. J. Zimniermann, Justus Liehigs Ann. Chem. 1975, 2201;
E. A . Jefiery, A . Mcisters, 7: Mole, J. Organomet. Chem. 74, 373 (1974);
H. 0 . House, D. S. Crumrine, A . Y Teranishi, H. D. Olmstead, J. Am.
Chem. Soc. 95, 3310 (1973).
[ 5 ] a) Cf. B. M. Mikhaiioc, Organomet. Chem. Rev. A 8 , 1 (1972); b) 7:
Herold, R. W Hofmann, Angew. Chem. 90, 822 (1978); Angew. Chem.
Int. Ed. Engl. 17, 768 (1978).
[6] a) J . Blais, A . L'Honore, J . Soulie, P. Cudiot, J. Organomet. Chem.
78,323 (1974);cf. H. C . Brown, N. R. De Lue, Y Yumamoto. K. Maruyama,
7: Kusohara, S . Murahashi, A . Sonodu, J . Org. Chem. 42, 4089 (1977);
M. Schlosser, G. Rauchschwalbe, J. Am. Chem. Soc. 100, 3258 (1978);
h) cf. G. Ruuchschwalbe,M. Schlosser, Helv. Chim. Acta 58, 1094 (1975).
[7] H. Niith, P. Fritz, 2. Anorg. Allg. Chem. 322, 297 (1963).
[8] Our assignment is based on the rule (H. Felkin, Z Gault, G. Roussi,
Tetrahedron 26, 3761 (1970)), that the threo-isomer shows the shorter
retention time on gas chromatography. This has been secured by further
transformations in the case o f( 5 ) , R = CH3: P. A. Bartlett, K . J. Jernstedt,
J. Am. Chem. Soc. 99,4829 ( 1 977); P. A. Bartlett, personal communication
1977.
Economic Synthesis of Activated N-tert-Butyloxycarbony1 Amino Acid Esters"]
By Gerd Schnorrenberg and Wolfgang Steglich"]
Dedicated to Professor Horst Pommer on the occasion of his
60th birthday
We have found that 4,6-diphenylthieno[3,4-d][l,3]dioxol-2one 5,Sdioxide (1)['I permits an economic synthesis of activated Boc-amino acid esters ( 5 a ) if the reagent is used not only
for activation of the Boc-amino acid (3a)I2] but also for
introduction of the Boc group. To this end, activated tert-butyl
0
[*] Prof. Dr. W. Steglich, Dip1.-Chem. G. Schnorrenberg
Institut fur Organische Chemie und Biochemie der Universitat
Gerhard-Domagk-Strasse I , D-5300 Bonn (Germany)
carbonate (2a)['] is heated with the amino acid and one
equivalent of 1,1,3,3-tetramethylg~anidine[~~
in tetrahydrofuran (THF) until the amino acid has dissolved (variant A).
In the case of sparingly soluble amino acids, the components
are stirred in dioxane/water at room temperature (variant
B). After removal of the base with aqueous citric acid the
Boc-amino acid ( 3 a ) , together with the sulfone ( 4 ) , is again
treated with equimolar amounts of ( 1 ) and pyridine15! The
sulfone ( 4 ) can be readily removed, and the crystalline activated ester ( 5 a ) (Table 1) is usually obtained analytically
pure.
Table I . Activated Boc- ( 5 a ) and Z(0Me) amino acid ester ( S h ) [a]
________
Activated ester
( 5 ) of
t [h]
Boc-Ala
Boc-Cys(S-Bzl)
Boc-Gly
Boc-Leu
Boc-Phe
Boc-Pro
Boc-Ser(0-Bzl)
Boc-Trp
Boc-Val
Z(OMe)-Leu
Z(0Me)-Pro
24
12
48
7
12
3
4
12
18
4
3
PI
B
A
B
A
A
A
A
A
A
A
A
Yield
["/.I [.I
[dl
M.p. r C ]
82
90
72
83
84
92
87
72
87
85
76
95
153
138
158
178
1 66
145
147
160
138
I46
[a] All compounds gave correct elemental analyses. [b] For reaction o f
the amino acids with ( 2 a j or ( 2 b ) . [ c ] Based on amino acid. [d] Diastereomeric mixtures except for Boc-glycine derivative.
Unlike similar one-pot preparations of activated Boc-amino
acid esterst41,our method avoids activation with dicyclohexylcarbodiimide and hence the difficulties of removing dicyclohexylurea. The yields are often higher than for conventional introduction of the Boc group. The activated esters ( 5 a ) are well
suited for peptide syntheses['!
Preparation of the esters (5 a ) was shown by gas chromatogr a p h ~ [and
~ ] polarimetry to proceed without racemization.
Reaction of ( 1 ) with p-methoxybenzyl alcohol gives the
activated carbonate (2b) (m. p. 226°C after prior sintering
with red coloration above 85°C) in 82% yield. Like (Za ),
(2 b) can be used for preparing the activated Z(0Me)-amino
acid esters (5 b). Highly acid-labile alcohols such as triphenylmethanol or cc,sc-dimethyl-3,5-dimethoxybenzylalcoholI61
cannot be converted into carbonates of ( 2 ) .
Procedure
Synthesis of ( 2 a ) : Compound
(3.26g, IOmmol), dry
tert-butanol(O.89 g, 12 mmol), and pyridine (0.81 ml, 10mmol)
are stirred together at 20°C for 1.5 h in dry dichloromethane
(80ml). The mixture is then washed twice with saturated
N a H C 0 3 solution, once with 20% citric acid solution. and
once with water, dried over MgSOb, and evaporated to dryness
in uacuo; yield 3.60 g (90 %), m. p. 158°C (dec.).
Synthesis of ( 5 a ) : variant A: Compound (2a) (4.00g,
IOmmol), finely powdered amino acid (lOmmol), and 1,1,3,3tetramethylguanidine (1.85 ml, 15 mmol) are heated under reflux in dry THF (100ml) until the amino acid has dissolved.
After evaporation in vacuo, the residue is taken up in dichloromethane, extracted four times with saturated N a H C 0 3 solution; the pH of the aqueous extracts is then adjusted to
3 with solid citric acid or cold 1 N HCI before extracting
three times with ethyl acetate. After washing with H 2 0 , drying
over MgS04, and evaporation in vacua the mixture is stirred
with(1)(3.26g, lOmmol)andpyridine(0.81 mi, 10mmol)indry
CH2CI2(80ml) at 20°C for 30min. The mixture is shaken three
times each with 20% citric acid solution and saturated
307
Angew. Chem. Int. Ed. Engl. 18 (1979) N o . 4
0 firlag Chemie, GmbH, 6940 Weinheim, I979
Variant
0570-0833/79/O404-O307 S 02.5010
N a H C 0 3 solution, washed once more with citric acid solution
and water, dried over MgS04, and evaporated. The esters
( 5 0 ) can be used without further purification for peptide
synthesis. For analysis, the product can be crystallized, if
necessary, from ethyl acetate/light petroleum.-Variant
B:
The components are stirred in dioxane/water ( 2 :1) (150ml)
at 20°C for 1-2 days, the mixture evaporated down and
treated as for variant A.
Received: January 31, 1979 [Z 173 IE]
German version- Angew. Chem. 91. 326 (1979)
[I]
[2]
[3]
[4]
[5]
[6]
Activated Carboxylic Acid Derivatives, Part 4.-Part 3: H . Schmidt,
0. Hullirzer, A . Seewald, W Steglidi, Chem. Ber., in press.
0. Hollifzer, A . Seewald, W Stegiich, Angew. Chem. 88, 480 (1976);
Angew. Chem. Int. Ed. Engl. 15,444 (1976).
Cf. A . Ali, B. Weinsrein,J. Org. Chem. 36,3022(1971); A. Ali, F. Fahrenholz,
B. Weinstein, Angew. Chem. 84, 259 (1972): Angew. Chem. lnt. Ed.
Engl. 11, 289 (1972); U . Ragnarson, S. M . Karlsson, B. E. Sandberg,
Acta Chem. Scand. 26, 2550 (1972); W Steglich, S. Hinre. Synthesis
1976, 399.
Examples: M. Frankel, D. Ladkany, C. Gillon, Y Whmn, Tetrahedron
Lett. 1966, 4765; E Wolman, D. Ludkany, M. Frankel, J. Chem. SOC.
C 1967. 689: W Broadhent, J . S . Morley, 8. E. Stone, ihid. 1967, 2632.
F. Weygand, A . Prox, L. Schmidhnmmer, W Konig, Angew. Chem. 75,
282 (1963); Angew. Chem. Int. Ed. Engl. 2, 183 (1963).
C. Birr, W Lochinyer, G. Slahnke,P. Lung, Justus Liebigs Ann. Chem.
763, 162 (1972).
Electrophilic Behavior of
diene“]
Tri-revr-butylcyclobuta-
By Giintker Maier and Fritz Kohler[*l
Dedicated to Professor Horst Pommer on the occasion of his
60th birthday
The cyclobutadiene ( I ) , which is readily accessible from
2,3,4-tri-tert-butylcyclopentadienonevia the corresponding
“housenone”[2], is extremely versatile in its reactions. It
behaves both as a diene and as a dienophilel3”1,as a nucleophile
and as a base[3b1,and as a potential diradicalr3‘! No evidence
of electrophilic properties has yet been reported for ( I ) , but
our latest studies now close this gap. This chemical omnipotence of the cyclobutadiene 4rr-system confirms its exceptional
nature.
dianion (6) occurs. The H/D NMR coupling constant in
D1-(3) proves the trans c~nfigurationl~l.
A hydride ion is also added to (1 ) I 6 ] . Both the direct action
of lithium aluminum hydride on ( 1 ) and the circuitous route
oia the halogen adducts ( 4 ~ 1 ) ‘ ’I~ sor ( 4 b ) [‘H-NMR (CDC13):
6=1.18 (9H), 1.20 (9H), 1.36 (9H), 5.13 (1 H); I3C-NMR
(CDC13):6=28.24,30.04,31.10,33.62,34.31,40.48,
58.60, 85.53,
149.89, 155.791 lead to 1,2,3-tri-tert-butylcyclobutene
(5)141.
Nucleophilicity and basicity of ( I ) parallel the excellent
donor properties of unsubstituted cyclobutadiene and its alkyl
derivatives[81.It is therefore all the more surprising that ( 1 )
should also show pronounced electrophilic character. The
reason for this dualism is to be found in the pseudo-Jahn-Teller
effectigaJwhich gives rise to a low-lying LUMO and a highenergy HOMO, and thus endows ( I ) with the properties
of a nucleophile and of an electrophilefgbl.The addition of
tert-butyllithium-also known in the case of open-chain butadiene[’ol-is even able to overcome the kinetic hindrance
of three tert-butyl groups as a result of the energetic destabilization of the x-system.
Received: January 19, 1979 [Z 175 IE]
German version: Angew. Chem. 9 / . 327 (1979)
CAS Registry numbers:
( I ) , 51067-53-9; (2), 69631-78-3; ( 3 ) , 69631-79-4; ( 4 a ) , 69631-80-7; ( 4 h ) ,
69631-81-8; (5),37715-08-5
[I]
[2]
[3]
[4]
[5]
61
71
81
[9]
[lo]
Small Rings, Part 26. This work was supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen 1ndustrie.-Part
25: C. M a i e r , S. Pfriem, U . Schafer, R. Mafusch, Angew. Chem. YO,
552 (1978): Angew. Chem. Int. Ed. Engl. 17, 520 (1978).
G. Maier, U . Schafer, W Sauer, H. Harran, R. Matuach, J . F . M .
O h , Tetrahedron Lett. 1978, 1837.
a) Review: C. Maier, Angew. Chem. 86, 491 (1974); Angew. Chem.
Int. Ed. Engl. 13,425 (1974): b) G. Maier, W Suuer, ibid. 87. 675 (1975)
and 14, 648 (1975): c) ibid. 89, 49 (1977) and 16, 51 (1977).
A . E. Feirirtg, J . Ciabattoni, J. Am. Chem. SOC. 95. 5266 (1973).
JHDis ca. 0.4 Hz for D,-(3). This gives JHH-2.5 Hz,which corresponds
more closely to the trans coupling (1.7 Hz) typical of allylic cyclobutene
protons than to cis coupling (4.9Hz). We are grateful to Dr. H . - 0 .
Knliizoicski for this configurational assignment.
This reaction is not very clear-cut; gas chromatography shows the
crude product t o contain about 18 % of (S).
Presumably, the halogen adducts are also tmns-configurated. In the
compound 3,4-dichlorotetramethylcyclobutene
f ~ r m e r l y ‘used
~ ’ as reference substance the chlorine atoms are also trans-oriented contrary
to the original assumption: R. Criegee. Angew. Chem. 80,585 (1968);
Angew. Chem. Int. Ed. Engl. 7 , 559 (1968).
G. Muier, H . P. Rcisennuer, Tetrahedron Lett. 1976, 3591: C. Maier,
W Mayer, C . Haucke, R. Askaiii, Angew. Chem. 85, 1057 (1 973); Angew.
Chem. Int. Ed. Engl. 12, 1016 (1973).
a) L. Salem: The Molecular Orbital Theory of Conjugated Systems.
Benjamin, Reading 1966, pp, 4 8 6 8 ; b) I . Fleming: Frontier Orbitals
and Organic Chemical Reactions. Wiley, New York 1976.
W H . Glaze, D. J . Berry, D. R. Duncan, J. Organomet. Chem. 52,
233 (1973).
Ester and Lactone Formation with the Reagent 1 , s
Dihydro-4,6-dimethyl-2-thioxo-3-pyridinecarbonitrile
(4n). x
=
c1
(5)
16)
(46), X = Br
Reaction of ( I ) with tert-butyllithium in diethyl ether in
the presence of N,N,N’,N’-tetramethylethylenediamineat
-78°C smoothly affords the adduct (2). Aqueous work-up
gives a high yield (94 % based on the cyclopentadienone reactant) of 1,2,3,4-tetra-tert-butylcyclobutene
(3)[41. Treatment
with D2O gives only the monodeuterated derivative D,-(3).
This means that addition does not proceed beyond the
monoanion (2) ; no deprotonation to give the “aromatic”
[*] Prof. Dr. G. Maier, F. Kohler
lnstitut fur Organische Chemie der Universitat
Heinrich-Buff-Ring 58, D-6300 Lahn-Giessen 1 (Germany)
308
By Ulrich Schmidt and Dieter Heermann[*l
Dedicated to Professor Horst Pommer on the occasion of his
60th birthday
Several synthetic routes affording entry to macrolactones
have been described in recent years[‘-4! So far, however,
no single method has proven universally satisfactory for the
synthesis of complex macrolides.
We report here on the formation of esters with the readily
accessible reagent 1,2-dihydro-4,6-dimethyl-2-thioxo-3-pyri[*] Prof. Dr. U. Schmidt, Dr. D. Heermann
Institut fur Organische Chemie, Biochemie und Isotopenforschung der
Universitat
Pfaffenwaldring 55, D-7000 Stuttgart 80 (Germany)
Angew. Chem Int. Ed. Engl. 18 ( 1 9 7 9 ) N o . 4
0 firlag Chemie, GmbH, 6940 Weinheim, 1979
0570-0833179/0404-03O8 $ 02.5010
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acid, synthesis, butyloxycarbonyl, esters, amin, economic, tert, activated
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