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Enantio- and anti-Diastereoselective Aldol Additions of Acetates and Propionates via O-Silyl Ketene Acetals.

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Enantio- and anti-Diastereoselective Aldol Additions
of Acetates and Propionates
via 0-Silyl Ketene Acetals**
in quantitative yield. As was to be e x p e ~ t e d , ' the
~ ] esters of
the alcohols 2a and 2b yielded enantiomeric carboxylic
acids.
By Giinter HeIrnchen,* Ulrich LeikauJ; and
Irmtraud Taufer-Knopfel
1. LICA/THF
The structural units l a - c are present in numerous natural products. For their direct construction by enantio- and
diastereoselective aldol addition, usually via carboxylic
acid derivatives, excellent solutions have been found for
the case of I c . ~ 'Methods
]
for the direct synthesis of la[']
and lbI3l have only recently been reported; as a rule, circuitous routes are chosen that can be tedious.['] In the
course of our investigations of asymmetric syntheses with
enolates of esters of the alcohols 2a and 2bL5]
we have now
found that the structural units of l a and, albeit judged on
the basis of one example only, of l b can be obtained
highly selectively by TiCl,-catalyzed addition of aldehydes
to 0-silyl ketene acetals (Mukaiyama reaction).'']
2.
0
-
80°C
a or b
IM
OM
4
3
M
= Li;
5 M = TBS
6
R'o,c?~
6H
8 R' = H;
9 R' = CH,
7
a: R = Et: b: R = iPr;
c : R = heptyl; d: R = Ph
Scheme I . Aldol addition of the acetate of 2a or 2b (R*-OH) to give Bhydroxycarboxylic acid derivatives; a : RCHO, THF, -60°C (M =Li); b:
RCHO/TiCI, ( I : l.l), CH2C12, -80°C (M=TBS).
Table I . Conversion of the acetates 3 of the reagents 2a or 2b via lithium
enolates 4 or 0-silyl ketene acetals 5 [a] into B-hydroxycarboxylates 6 and 7
(Scheme I ) [b].
R
R'
la
2a
R'
f
R
R'
lb
Reagent
M
R
lc
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
Li
SitBuMe,
Li
SitBuMe,
Li
SitBuMe,
Li
SitBuMe,
Li
SitBuMe,
Et
Et
n-Heptyl
n-Heptyl
iPr
iPr
iPr
iPr
Ph
Ph
Diastereoselectivity
6 : 7 [c]
Yield [Oh]
6
73 : 27
93: 7
72 : 28
93: 7
74 : 26
97: 3
30 : 70
5 : 95
38 : 62
6 : 94
89 (91)
67 (83)
96
59 (68)
90
51 (89)
85
62 (80)
99
69 (83)
+ 7 [dl
Abs. Config.
8 or 9 [el
S
S
S
S
R
R
S
S
S
S
Preparation: reaction of the lithium enolates 4 with 2.2 equivalents tBuMe2SiC1/2 equivalents hexamethylphosphoric triamide (HMPT) (THF,
- 63 "C-0°C)
followed by extractive work-up (pentane/water). [b] Mukaiyama reaction: dropwise addition of a solution of 0-silyl ketene acetal 5
in CH2CI, at -80°C to a mixture of aldehyde and TiCI, (molar ratio I : 1.1).
[c] HPLC peak area ratios (silica gel, petroleum etherlethyl acetate 9: I). [d] In
brackets: corrected with respect to recovered reactant 3. [el 9s: [a]" +20.4
(undiluted); T. Tannabe, Y . Izumi, Bull. Chem. SOC.Jpn. 46 (1973) 1550,
(S)-9a: [a]? + 18.6 (undiluted). 8b: [a]:' +40.2 (c= 1.2, CHCI,); D. A. Evans,
T. R. Taber, Tetrahedron Lett. 21 (1980) 4675, (R)-Sb: [a], +40.5 (c=0.6,
CHCI2). 8c: [a]" +21.3 (c= 1, CHCI,): M. Nakahata, M. Imaida, H. Ozaki,
T. Harada, A. Tai, BUN. Chem. SOC.Jpn. 55 (1982) 2186: (S)-SC: [a]E -20.8
(c= I , CHCI,). 8 d : [a]? - 17.9 (c=2.2, 95% EtOH) [ 2 ~ ] (: R ) - 8 d :[a]:'
17.9
(c=2.3, 95% EtOH).
[a]
Reaction of the acetates 3, R*-OH = 2a or 2b, with lithium cyclohexylisopropylamide (LICA) in tetrahydrofuran (THF) affords the lithium enolates 4, which on subsequent reaction with t-butyldimethylsilyl chloride (TBSCI)
furnish the 0-silyl ketene acetals 5 in good yields."] The
latter react with TiCI4-complexes of achiral aldehydes to
give the crystalline B-hydroxycarboxylates 6 and 7 with a
diastereoselectivity of > 93 :7 (yield : 50-70%),['] whereas
the lithium enolates 4 react unselectively with aldehydes
(Table 1). The diastereomers 6 and 7 can be separated by
liquid chromatography, thus enabling determination of the
diastereomeric ratio by high performance liquid chromatography (HPLC) and purification by medium pressure liquid chromatography. In the case of the Mukaiyama reaction the main product 6 can also be obtained in essentially
pure form by recrystallization. Hydrolysis of the esters 6
(1.5 N methanolic KOH, room temperature) affords the
carboxylic acids 8a-d with known absolute configuration
[*I Prof. Dr. G . Helmchen ['I, DipLChem. U. Leikauf [+I,
DipLChem. I. Taufer-Knopfel
lnstitut fur Organische Chemie der UniversitBt
Am Hubland, D-8700 Wiirzburg (FRG)
[+I Present address: Organisch-chemisches Institut der Universitat
Im Neuenheimer Feld 270, D-6900 Heidelberg (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie. We thank F. Lippert for carrying
out some of the experiments, Prof. R. Baker, Southampton, for data on
the optical rotation of 19, and Prof. B. Ganem, Cornell University, for a
sample o f ent-20. For definition of the descriptors syn and anti see
Val.
874
0 VCH Veriagsyeseliscliafl mbH, 0-6940 Weinheim, 1985
+
According to Chan et al.I9l the Mukaiyama reaction with
(E)-O-silyl ketene acetals leads preferably to anti-3-hydroxy-2-methylcarboxylates. Since, under the conditions
employed for acetates, the propionates 10 of the alcohols
2a and 2b furnish (E)-0-t-butyldimethylsilyl ketene acetals with a selectivity of 98 :2, the 0-silyl ketene acetal 12
was reacted with isobutyraldehyde-TiC14 complex in order
to test the diastereoselectivity. The four diastereomeric adducts 13-16 can be readily separated by chromatography.
In this case also, the Mukaiyama reaction is remarkably
diastereoselective, whereas the reaction of the corresponding lithium enolate 11 once again proceeded unselectively
(Table 2).
Surprisingly, the reactions of the 0-silyl ketene acetals 5
and 12 proceed with configuratively inverse enantiofacedifferentiation of the aldehyde, i.e. with Re attack in the
case of 5 and Si attack in the case of 12. The diastereoface-differentiation at C-2 of 12 corresponds configura-
0570-0833/85/1010-0874 $ 02.50/0
Angew. Chem. Int. Ed. Enyl. 24 (1985) No. 10
1. LICA/THF
2.
0
- 8OoC
a or b
w
11 M =
10
OM
Li; 12 M
13
=
Reviews: a) D. A. Evans, J. V. Nelson, T. R. Taber. Top. Srereochem. 13
(1982) I ; h) C. H. Heathcock in 7.Durst, E. Bunce (Eds.): Comprehensiue Carbanion Chemisfcv, Vol. 2. Elsevier, Amsterdam 1983, p. 177; c)
C. H. Heathcock in J. D. Morrison (Ed.): Asyrnmerric Synrhesis, Vol. 3.
Academic Press, New York 1984, p. 111; d j R. W. Hoffmann, Angew.
Chem. 94 (1982) 569; Angenz. Chem. lnt. Ed. Engl. 21 (1982) 555.
a) T. Mukaiyama, N. Iwasawa, R. W. Stevens, T. Haga, Tetrahedron 40
(1984) 1381; b) G. Solladie, Chimia 38 (1984) 2 3 3 ; c) M. Braun, R. Devant, Angew. Chem. 95 (1983) 802; Angew. Chem. I n t . Ed. Engl. 22
(1983) 788; d) K. Narasaka, T. Miwa, H. Hayashi, M. Ohta, Chem. Left.
1984. 1399; e) J. D. Elliott. J. Steele, W. S . Johnson, TefrahedronLett. 26
(1985) 2535.
A. I. Meyers, Y. Yamamoto, Terrahedron 40 (1984) 2309.
a) S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem. 97
(1985) I ; Angew. Chem. I n t . Ed. Engl. 24 (1985) I ; b j G. Frater, U. Miiller, W. Gunter, Tetrahedron 40 (1984) 1269: c) R. Baker, C. J. Swain, J. C.
Head, J. Chem. Soc. Chem. Commun. 1985, 309; d) V. J. Jephcote, A. F.
Pratt, E. J. Thomas, ibid. 1984. 800.
G. Helmchen, A. Selim, D. Dorsch, 1. Taufer, Tetrahedron Lett. 24
(1983) 3213, and references cited therein.
T. Mukaiyama, Org. React. 28 (1982) 203.
With chlorotrimethylsilane under the same conditions the C-silylated
product is obtained.
The acetates 3 and u-tert-butyldimethylsilyl acetates of the alcohols Za
and 2b are formed as by-products.
T. H. Chan, T. Aida, P. W. K. Ldu, V. Gorys, D. N. Harpp, Tetrahedron
Lett. 1979, 4029; for analogous results with thiol esters: C. Gennari, A.
Bernardi, S. Cardani, C. Scolastico, ibid. 26 (1985) 797.
The relative configuration at C-2/C-3 of the acyl groups of 13- 16 was
assigned on the basis of the 'H-NMR coupling constants. For determination of the absolute configuration, 14 was converted into 19 and 16
into 20. 19 from 14: In]$ -9.4 (c=0.6, CHCI,); 19 (cf. I4cl): [a10 -7.5
(c= 1.8, CH2CIZ);20 from 16: [a]g + 11.3 (c=0.6, CHCI,): ent-20 (vgl.
[I I]): [a12 - 10.3 (c=0.2, CHCII).
R. D. Wood, B. Ganem, Tetrahedron Lett. 23 (1982) 707; due to a printing error the optical rotation quoted for enr-20 is erroneous.
TBS
14
15
16
Scheme 2. Aldol reaction of the propionate 10, R*-OH
dehyde; a, b: a s in Scheme 1.
= 2a
with isobutyral-
Table 2. Conversion of the propionate 10 of the alcohol 2a via the lithium
enolate 11 or 0-silyl ketene acetal 12 with isobutyraldehyde into the Bhydroxy esters 13-16 (Scheme 2) [a].
Reagent
M
13
2a
2a
Li
SitBuMe,
Diastereoselectivity
: 14 : 15 : 16[b)
: 13 : 0 : 60
1.5 : 92 : 1.5 : 5
Yield [%I
13-16
[c]
94
66 (89)
27
[a] For reaction conditions see Table I.(b] [c] as in Table I.
tively to that of the alkylation of the corresponding lithium
enolate 11. If one assumes a transition state of the Zimmermann-Traxler type and addition of the electrophile
from the sterically more favorable half space of C-2, the
configurational relationships can be rationalized on the
basis of the transition states 17 and 18.
K
A Previously Unrecognized 1H-Azepine Synthesis**
18
17
By Hartwig Perst, * Werner Massa, Michael Lumrn, and
Gerhard Baum
Dedicafed to Professor Karl Dimroth on the occasion
of his 75th birthday
In 1963 the N-ethoxycarbonyl derivative 1 was described as the first monocyclic, 1-substituted 1 H-azepine."]
. .
HY
iPr
+
I9
OH OTBS
Me
20
OH OH
The assignment of configuration with regard to C-2 and
C-3 of the adducts 13-16"'] was combined with an application in natural product synthesis, in that the TBS derivative of the ester 14 was reduced to the alcohol 19, which,
as building block for a synthesis of avermectin, was recently prepared via a different route.
Received: June 19, 1985 [Z 1357 IE]
German version: Angew. Chem. 97 (1985) 874
CAS Registry numbers:
2a (n-t-butyldimethylsilylacetate), 98269- 18-2; 2b (u-1-butyldimethylsilyl acetate), 98391-90-3; 3 (R*==Za), 98269-08-0; 3 (R* =Zb), 98391-79-8; 4
(R*=2a), 98269-09-1; 4 (R*=Zb), 98391-80-1; 5 (R*=Za), 98269-10-4; 5
(R*=2b),98391-81-2: 6a (R*=2a), 98269-11-5; 6b (R*=2a), 98269-13-7; 6b
(R*=Zb), 98391-82-3; 6c (R*=2a), 98269-12-6; 6d (R*=2b), 98269-14-8; 7a
(R* =2a). 98391-83-4; 7b (R*=Zaj, 98391-85-6; 7b (R*=Zb), 98391-86-7; 7c
(R*=2a), 98391-84-5; Id (R*=2b), 98391-87-8; (R)-Sb, 77981-87-4; (R)-8c,
19525-80-5: (S)-Sc, 19526-23-9: (R)-Sd, 2768-42-5: (.S)-8d, 36567-72-3; (S)-9a,
42558-50-9; 10 (R*=2a), 76529-59-4; 11 (R*=2a), 98269-15-9; 12 (R*=2a),
98269-16-0; 13 (R*=2a), 98269-17-1; 14 (R*=2a), 98391-88-9; 15 (R*=2a),
9839 1-89-0; 16 (R* =2a), 98392-66-6; 19, 97848-37-8; 20, 98391-91-4; EtCHO, 123-38-6; 1-PrCHO, 78-84-2; CHI(CH2),CH0, 124-13-0; PhCHO, 10052-7: r-hutyldimethylsilyl chloride, 18 162-48-6.
Angew Chem. Int. Ed. Engl 24 (1985) N o . 10
1
2a
An entry to the monocyclic IH-azepine 2a first reported
as long ago as 1956 by Adams and Brower seems to have
been overlooked, because the authors could not, at the
time, elucidate the structure of 2a. Upon reaction of triethylammonium cyanide with the linearly conjugated 6benzenesulfonyliminocyclohexadienyl acetate 3a they obtained-apart from the expected 3-cyanoanilide derivative
5a (18.5% yield)-a pale yellow compound (55% yield).121
The structure 6-cyanocyclohexadienylideneamide 4a proposed for this substance131should, according to our recent
findings, be replaced by the lH-azepine structure 2a.
[*] Prof. Dr. H. Perst, Priv.-Doz. Dr.
W. Massa, DipLChem.
M. Lumm,
G. Baum
Fachbereich Chemie der Universitat
Hans-Meerwein-Strasse, D-3550 Marburg (FRG)
[**I
This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
0 YCH Verlagsgesellscha~
mhH. 0-6940 Wernheim. 1985
0570-0833/85/1010-0875 $ 02.50/0
875
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diastereoselective, propionate, acetals, ketene, aldon, additional, sily, anti, via, acetate, enantio
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