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Diastereoselective Synthesis of -Methyl Homoallyl Alcohols.

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The structures derived from spectra for a 4-oxooctanoic,
a 4-oxononanoic, and a 4-oxodecanoic methyl ester were confirmed by synthesis and subsequent comparative measurements of mass spectra and retention indices (Table 1).
Table I. 4-0x0- and w-formylcarboxylic methyl esters.
Name
4-Oxooctanoic
methyl ester
( M = 172)
Retention
index [a]
--____
1236
4-Oxononanoic
methyl ester
(M = 186)
1336
4-Oxodecanoic
methyl ester
( M= 200)
1436
7-Formylheptanoic
methyl estex
(M=172)
1288
8-Formyloctanoic
methyl ester
(M=186)
1387
Key ions in
mass spectrum
29 (47 %), 41 (42 %), 55 (60 %), 57
(100 %),59(28 %), 71 (5 %),85(67 %j,
87 (16%), 98 (50%j, 1 1 1 (9%), 115
(61 %), 130 (36 %), 141 (23 %)
41 (32%), 43 (loo%), 55 (56%), 59
(26%),71 (50%),87(16 %),98(73 %),
99(48~),111(10%),115(58%), 130
(41 %), 155 (19%)
41 (34 %). 43 (100 %), 55 (46 %), 57
(36 %), 59(18 %), 71 (10 %), 85 (22 %),
87 (24 %), 98 (59 %), 113 (25 %), 115
(45%), 130(34%), 1 6 9 ( l l % j
41 (100%). 43 (81 %), 55 (76 %), 57
(51 %j, 59(45 %),69(72 %j,74 (89 %j,
81 (31 %). 87 (88 %), 97 (39 %), 101
(17%), 111 (26%), 129 (44%), 141
(23 %), 144 (10%)
29 (42%), 41 (74%), 43 (63%), 55
(81 %), 59 (37 %), 69 (33%,), 74
(100 %), 83 (43 %), 87 (64 %), 97
(lo%), 111 (21%). 115 (7%), 136
( S % ) , 143 (29%), 155 (19%), 158
( I 1 %)
Diastereoselective Synthesis of p-Methyl Homoallyl
Alcohols
By Reinhard W Hofinann and Hans-Joachim Zeissp]
Dedicated to Professor Horst Pommer on the occasion of his
60th birthday
The diastereoselective synthesis of the 0-methyl alcohol
units of macrolide antibiotics represents a similar challenge[']
to preparative organic chemistry today as did the stereoselective synthesis of carotenoids twenty years agoL2].Significant
achievements have been the threo-selective addition of (4-2butenyl-metal derivative^'^^ and the erythro-selective addition
of (Z)-metal en01atesI~~
to aldehydes. Starting from the effective
addition of allylboronates to aldehydesL5* we have found
an erythro-selective addition of (2)-2-butenylboronates (3)
to aldehydes.
(3)
[a] Stationary phase OV-101, temperature program 2"C/min, initial temperature 80°C.
R
Two further compounds in the chromatogram were identified as acid aldehydes (a-formylcarboxylic acids). Their mass
spectra, like those of the long-chain fatty acid methyl esters,
are characterized by key ions of mass 74 and 87. The molecular
weight can be determined from an M - 31 ( M - OCH3) fragment and an M - 2 8 ion. These ions, as well as an M-43
fragment, are typical for methyl o-formylcarboxylates[', 'I. The
structures of both the C8 and the C9 acid aldehydes were
likewise confirmed by synthesis and comparative measurements (Table 1).
Isolation and workup
Blood plasma (5ml) was diluted with five times its volume
of physiological saline solution, and the resulting solution
adjusted to pH = 1 with 6 N hydrochloric acid and extracted
with 3 x 25 ml diethyl ether. The organic phase was concentrated to 1 ml and esterified with ethereal diazomethane solution. The dicarboxylic methyl ester fraction, which also contains the o-formyl- and 4-oxocarboxylic methyl esters, can
be isolated by chromatography on a silica gel column with
petroleum ether/diethyl ether as eluent13]. After separation
in a coupled glass-capillary gas chromatograph/mass spectrometer, the compounds listed in Table 1 were identified by
retention indices and mass spectra.
Received: January 8, 1979 [ Z 171 IE]
German version: Angew. Chem. 91, 321 (1979)
CAS Registry numbers:
Table 1, from top to bottom: 4316-48-7; 33566-57-3; 7011-82-7; 3884-92-2;
1931-63-1
[l] A . C . Noble, W W Nabvar, J. Agric. Food Chem. 19, 1039 (1971).
[2] W GBrtner, G. Spifeller, unpublished.
[ 3 ] S. Lindstrdt, K . Norherg. G. Stern, E. Wuhl, Clin. Chem. 22, 1330 (1976).
306
erythro: threo
Only in the absence of Lewis acids do 2-butenylboronates
prove to be E/Z-stable on heatingC6"'. This is presumably
the reason why direct reaction of (Z)-2-butenylpotassium
(I
with chloro(dia1koxy)boranes led to E/Z mixtures of
the 2-butenylboronates. We therefore used the weaker Lewis
acid chlorobis(dimethylamino)boraneL7~
in tetrahydrofuran/
hexane (-120 to O T ) to convert ( I ) into 2-butenylbis(dimethy1amino)borane ( 2 ) , which was shown by I3C-NMR
to be more than 95 % Z-configurated. (2) could be separated
from minor amounts of the methylallylborane derivative also
formed by distillation (70°C/1 5 torr) over a Spaltrohr@column.
Reaction of (2) with pinacol followed by removal of dimethylamine led almost quantitatively to (3) ( > 9 5 % Z), which was
of aldehydes via ( 4 )
used immediately for the
into the P-methyl homoallyl alcohols ( 5 ) in crude yields of
up to 92%. The erythro/threo ratioL8]of the alcohols ( 5 )
has been determined by gas chromatography.
The reaction of E/Z mixtures of 2-butenyl(dimethoxy)borane with acetaldehyde or benzaldehyde gave P-methyl homoallyl alcohols in erythrolthreo ratios['] corresponding exactly
to the Z/E ratios of the boronates used. It can therefore
be concluded that not only the (Z)-2-butenylboronate but
also the ( E ) isomer reacts diastereospecifically.
Received: December 27, 1978 [Z 170 IE]
German version: Angew. Chem. 91, 329 (1979)
Publication delayed at authors' request
____
[*] Prof. Dr. R. W. Hoffmann, Dip!.-Chem. H. J . Zeiss
Fachbereich Chemie der Universitat
Postfach 1929, D-3550 Marburg 1 (Germany)
Angew. Chrm. Int. Ed. Enyl. 1ii (19791 No. 4
0 Verluy Chemie, GnihH, 6940 Weinheirn, 1979
0570-0833,79;o404-030h
< 07
Toin
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
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