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Inversion of the Configuration of Secondary Alcohols via Isourea Ethers Prepared in situ.

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I H. 4-H), 2.55 (m, 4 H, 2.3-H; 5(2,3)= 15.8 Hz).-The other reactions of 5
shown in Scheme 2 were carried out analogously (no optimization). In
each case, the reaction products were converted into the methyl esters
with CH,OH/HCI. The characterization and quantification of the ester
was carried out by GC or by GC-MS (reference compounds).
[9] B. Bogdanovic, M. Kroner, G. Wilke, Justus Liebigs Ann. Chem. 699
(1966) I .
40
la
OH
OH
Inversion of the Configuration of Secondary
Alcohols via Isourea Ethers Prepared in situ
By Johannes Kaulen*
Procedures for the inversion of the configuration of secondary alcohols,“] e.g., the Mitsunobu procedure for “inverting esterification,”[i“.b’are of considerable preparative
interest. Such methods can be employed to establish the
correct stereochemistry of secondary alcohols in those
cases where the direct synthesis only leads to the undesired, “false” stereoisomer. In connection with the resolution of racemates, inversion procedures are also of interest
as a way of utilizing the undesired enantiomer, thereby
making chiral synthesis more economical. We have now
found that the esterification of secondary alcohols via
isourea ethers,[*’ which has been known in principle for
many years, offers a new, simple procedure for the inversion of the configuration of alcohols.f31
OH
H
\ C‘2
Rl’
~
N
-
C
=
H
~,
N
O
, -c,
R‘’
CUCl
1
‘R2
0
crwi
RJ-C -0,
3
4
The secondary alcohol 1 (as the pure enantiomer or
diastereomer) is converted in situ into the isourea ether 2
by addition to dicyclohexylcarbodiimide. When 2, without
isolation, is allowed to react further with carboxylic acids
in a one-pot procedure, the esters 3 are obtained in a
smooth reaction; the dicyclohexylurea that is formed
simultaneously can be removed by filtration.
We have been able to show, for the first time, that the
esterification proceeds with practically complete inversion
of the configuration, so that the ester 3 has the opposite
configuration of the alcohol 1 (“inverting esterification”).
Saponification of the ester 3 leads to ready formation of
the inverted alcohol 4.
The new procedure can be applied to a variety of secondary alcohols, high enantiomeric excesses and good
yields141being obtained in every case (Table 1). Small
amounts of the corresponding olefins are sometimes
formed as by-products.
Of the carboxylic acids used to carry out the “inverting
esterification,” formic acid proved to be particularly useful, but other carboxylic acids can be employed as well.
[‘I Dr. J. Kaulen
Bayer AG
Zentrale Forschung ZF-FGF
D-5090 Leverkusen (FRG)
Angew. Chem. lni. Ed. Engl. 26 11987) No.
4d
Table I . “Inverting esterification” of secondary alcohols. All inverted esters
3 and alcohols 4 were formed with >99% ee (or, if applicable, >99% de).
Alcohol
1
la
la
Ib
lc
lc
lc
Id
2
1
4c
Id
NH-C6Hl
PC
‘R2
+N-C6H1
3c
lc
Conditions
2-3
la1
Invert.
ester 3
R‘[b]
A
A
B
B
B
B
CH,
H
H
C
H
CH=CH?
C(CH\)=CH?
H
Yield
1-3
Yield
3-4
[%]
Invert.
alcohol
4 [b]
50
:;]
4b
91
4c
90
75
4d
90
[Oh]
64
[a] A: dioxane, I O O T , 2 0 h; B: toluene, I I O T . 20 h; C: dioxane, I I O T ,
20 h. [b] The structures were established by IR and ‘ H - N M R spectroscopy.
The chemical purity was checked by capillary gas chromatography. The determination of the enantiomeric purity was carried out by measuring the optical rotations or, in cases in which other centers of asymmetry are present in
the molecule, by capillary gas chromatographic separation of the diastereomers.
When acrylic acid o r methacrylic acid is used, the inverted acrylates and methacrylates, respectively, are obtained directly and can be polymerized to yield optically
active polymers.
Dioxane and especially toluene are particularly advantageous as solvents for the esterification; chlorinated solvents are unsuitable, since mainly exchange of the hydroxyl group for chlorine occurs in such solvents.
Owing to the mild reaction conditions, the simple workup, and the relatively inexpensive reagents, the “inverting
esterification” via isourea ethers promises to be an interesting alternative to the known inversion procedures.
General Experimental Procedure
2 121: 1 (0.5 mol) was allowed to stir with dicyclohexylcarbodiimide (0.6 mol)
and copper(1) chloride (50 mg) for 3 d in the absence of moisture at room
temperature IS]. Solid, high-melting alcohols were allowed to stir in a small
amount of anhydrous dioxane for 3 d at 40-50°C.
3: Crude 2 (0.5 mol) was dissolved in 200 mL of dry solvent (preferably toluene) and the carboxylic acid (0.6 mol, preferably formic acid) was added to
the stirred solution at room temperature. The resulting mixture was heated at
8
0 VCH Verlagsgesellschaji mbH. 0-6940 Weinheim, 1987
0044-8249/87/0808-0773 3! 02.50/0
773
reflux for 20 h and allowed to cool, and the nearly quantitatively precipitated
dicyclohexylurea was filtered off and washed with a small amount of dichloromethane. The combined organic phases were concentrated in vacuum
and the residue was dissolved in ether. The ether solution was washed with
NaHCO, solution to a final pH of 7 and then dried over Na2SOI and concentrated once again. The crude 3 was purified by distillation (or by column
chromatography).
4 : 3 (0.5 mol) was allowed to stir in 250 mL of methanol with 5 mL of 30%
NaOCH, for 12 h. After concentration in vacuum, the residue was distilled
without further workup.
Example- Neomenthyl.formate 3 c : The isourea ether 2c obtained from (-)menthol Ic (156 g, 1.0 mol) and dicyclohexylcarbodiimide(248 g, 1.2 mol)
was allowed to stir with 45 mL (1.2 mol) of formic acid in 400 mL of dry
toluene for 20 h at 1IO”C. The reaction mixture was then worked up according to the general procedure described above. After distillation, 147 g (80%)
of 3c was obtained, b.p.=52-6O0C/0.25 mbar, [a]gl= +51.9” (neat)
([a]?= 5 I 161).
+
Received: April 13, 1987 (2 2199 IE]
German version: Angew. Chem. 99 (1987) 800
[ I ] a) 0. Mitsunobu, Synrhesis 1981. I : b) 0. Mitsunobu, M. Eguchi, Bull.
Chem. Soc. Jpn. 44 (1971) 3427: c) B. Raduchel, Synthesis 1980. 292; d )
G. Cainelli, F. Manescalchi, G. Martelli, M. Panunzio, L. Plersi, Terrahedron Lert. 26 (1985) 3369: e) W. H. Kruizinga, B. Strijtveen, R. M. Kellogg, J . Org. Chem. 46 (1981) 4321; f) Y. Torisawa, H. Okabe, S. Ikegami,
Chem. Lett. 1984, 1555; g) E. J. Corey, K. C . Nicolaou, M. Shibasaki, Y.
Machida, C. S. Shiner, Tetrahedron Let,. 1975. 3183; h) J. S . Filippo. G I .
Chern J. S. Valentine, J . Org. Chem. 40 (1975) 1678; i) D. M. Floyd, G. A.
Crosby, N. M. Weinshenker, Tetrahedron Lett. 1972. 3265, 3269; j) A. K.
Bose, B. Lal, W. A. Hoffmann, M. S . Manhas, ibid. 1973. 1619; k) H.
Vorbriiggen, Justus Liebigs Ann. Chem. 1974. 821.
[2] E. Dabritz, Angew. Chem. 78 (1966) 483; Angew. Chem. Inr. Ed. Engl. 5
(1966) 470; E. Vowinkel, Chem. Ber. 100 (1967) 16; L. J. Mathias, Synthesis 1979. 561.
[3] For the synthesis of iodides from alcohols (with inversion) via carbodiimidium salts, see R. Scheffold, E. Saladin, Angew. Chem. 84 (1972)
158; Angew. Chem. Int. Ed. Engl. I 1 (1972) 229.
141 Yields for the “inverting esterification” of (S)-2-octanol l a : 20% [la, b],
75% [lhl, 86% [le]; many procedures [ I ] fail for sterically hindered alcohols such as (-)-menthol lc or afford large amounts of olefins as byproducts.
[S] The reaction times were not optimized; at higher temperatures and with
reaction control (IR or GC), shorter reaction times are possible.
[6] Beilsteins Handbuch der Organischen Chemie. Bd. 6 . 4. Erganzungsband.
Springer, Berlin 1978, p. 153.
to mass 2500). In our experience, the amounts of small,
unknown peptides thus required are hardly obtainable.
In order to investigate peptides having molecular
weights between 2000 and 3000 dalton, which we isolate
from biological material, we employ the following strategy: We carry out tryptic and chymotryptic cleavage of the
peptide, separate the fragments by HPLC (since the highest degree of purity possible is necessary for subsequent
sequencing by MS), and then determine the molecular
weights of these fragments by LSIMS.[”*’ Only in optimal
cases-usually when the peptide has a molecular weight of
< 1000 dalton-is a direct and unequivocal structure derivation of the fragments appearing in the LSIMS spectrum
possible. Only a very small amount of the sample used for
the LSIMS measurement (ca. I pg) is consumed. So far,
the remainder of the sample had been discarded. We have
now found, however, that the remainder of the sample can
be eluted unchanged from the target and separated from
the matrix substance (glycerol) by HPLC. Part of the remaining sample is then treated with a drop of C H 3 0 H / 2 N
HCI. After 12 h standing, all COOH and all CONH,
groups have been converted into COOCH3 groups. An
LSIMS determination of this sample gives the number of
COOH and CONH, groups originally present. The greater
part of the remaining sample is subject to sequencing by
double Edman degradation according to the modified procedure of Chang and Wittmann-Liebold et a1.[31 Each
cleaved amino-acid fragment is subjected to both thinlayer chromatography and HPLC (to be certain of the results). The recovered sample can, if necessary, be used for
determination of the N terminus by dansylation. Either an
LSIMS analysis of the whole peptidef4]or hydrolytic cleavage of the peptide followed by determination of the derivatized N-terminal amino acids by HPLC is possible.
The application of the procedure outlined above is exemplified by the sequencing of a new 20-amino-acid peptide that we isolated in 300-pg amounts from human semen. Determination of the molecular weight of the whole
peptide by LSIMS was not successful. The amount of sample used for the measurement was approximately 20 +g
Structure Elucidation of a New Icosapeptide from
Human Semen**
4
By Maus Schneider, Josef Reiner, and Gerhard Spitellere
The Edman degradation as modified by Chang and Wittmann-Liebold has proved extremely useful in the structure
elucidation of peptides.“’ The only disadvantage of this
method is the uncertainty in determining the C terminus,
since, once the peptide has been degraded to two or three
residues, the extraction of the hydantoin can result in partial loss of the remaining peptide. Therefore, at the very
least, an amino-acid determination is necessary.
This determination may no longer be necessary when
the exact molecular weight of the peptide is known; the
molecular weight, in turn, can be determined by “soft ionization methods.”12’ However, the amount of sample required increases greatly with increasing molecular weight
(by a factor of approximately 10 in going from mass 1500
S0
I00
150
200
250
300
400
350
8 0 5 806
I
40
7L8
[*] Prof. Dr. G. Spiteller, Dr. K. Schneider, J. Reiner
450
Lehrstuhl fur Organische Chemie I der Universitat
Postfach lO1251, D-8580 Bayreuth (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft.
[***I LSIMS = liquid secondary ion mass spectrometry. In this method,
charged molecules are ejected from a liquid matrix by bombardment
with Cs +,thereby making mass spectrometry possible. FAB mass spectrometry functions similarly, Xe atoms, instead of C s + , being used.
774
0 V C H VerlagsgesellschaftmbH. 0-6940 Weinheim. 1987
580
550
600
650
700
-
800
750
m/z
Fig. 1. LSI mass spectrum of positive ions of the fragment C l : Cly-Argm/z
Leu-Pro-Ser-Glu-Phe; in the one-letter code, G-R-L-P-S-E-F,
805=MHe. The signals marked with “G” are due to the matrix material
(glycerol). The peptide fragment ions (A,,.. . Z,,) are denoted according to the
system of RoepstofJ et al. 171. In the scheme above the spectrum, the oneletter code applies only to the side chains of the amino acids.
0570-0833/87/0608-0774 $ 02.50/0
Angew. Chem. Inr. Ed. Engl. 26 (1987) No. 8
850
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