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Enantioselective Allylation of Carbonyl Compounds with Titanium-Carbohydrate Complexes.

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Enantioselective Allylation of Carbonyl Compounds
with Titanium-Carbohydrate Complexes **
By Martin Riediker* and Rudolf 0. Duthaler
Among the stereoselective reactions reported so far the
allylation of carbonyl compounds is unique in that several
stereogenic centers can be generated in one step and the
products exhibit versatile functionality.['] High enantioselectivity and double stereocontrol are achieved with allylnietal
compounds containing chiral ligands, especially good results
being obtained with allylboron compounds,['] allylstann a n e ~ [ and
~ ] allyI~ilanes.[~~
Largely due to the pioneering
work of Seebach et aI.['"] and Reefz,[sblallyltitanium compounds and other organotitanates have been established as
inexpensive, easily accessible and ecologically unobjectionable reagents. The chiral titanium complexes investigated so
far, which have mainly been developed for asymmetric alkylation, were, however, not suited for the enantioselective
transfer of ally1 groups.r6. The high diastereocontrol which
can be achieved with such allyltitanium reagents [ 5 . would,
nevertheless, lead one to expect that good enantioselectivity
should also be realizable under suitable conditions. One of
the first successes in this context was the high induction
which was achieved in the transfer of chiral allyl groups to
aldehydes.[']
By reaction of cyclopentadienyltitanium(w) trichloride
1
with commercially available 1,2: 5,6-di-O-isopropylidene-a-D-glucofuranose ("diacetone-glucose")/triethylamine we obtained the stable dialkoxy(chloro)cyclopentadienyl
titanate 2, which, in the absence of moisture, can be stored
either as stock solution in ether (0.05-0.1 M) or toluene (0.1 0.2 M) o r as crystalline solid after precipitation with hexane
. .
1
3
+ (CpTiOH.0)"
R*OH
5
Scheme 1. a) 1,2: 5.6-Di-O-isopropylidene-~-~-glucofuranosejEt~N~Et~O,
room
temperature (RT); b) Et,O, 0 T ; c) 1. -78 C. 2. H,O/THF. - 3 0 . C to RT.
(Scheme 1). Highly stereoselective reagents can be prepared
from this novel complex by exchange of the remaining chloro
ligand for transferable groups." 'I
Thus, reaction of 2 with allylmagnesium chloride affords
the allyltitanium complex 3, which is brought to reaction in
[*I
['I
[**I
Dr. M. Riediker [ '1, Dr. R. 0. Duthaler
Zentrale Forschungslaboratorien. Ciba-Geigy AG
Postfach, CH-4002 Basel (Switzerland)
Present address:
Research Laboratories, Plastics Division, Ciba-Geigy Corporation
Ardsley, NY 10502 (USA)
Enantioselective Syntheses with Titanium-Carbohydrate Complexes.
Part 1.
situ at -74°C with aldehydes; addition at the re-side leads,
with numerous substrates, to homoallyl alcohols 4 in good
yields and with high enantiomeric purity (Scheme 1,
Table 1). The temperature dependence of this reaction is asTable 1. Enantioselective allylation of aldehydes with the reagent 3 (cf.
Scheme 1).
R
Prod. Yield
"1
Phenyl
p-Nitrophenyl
2.3-Dihydro-1.4Benzodioxin-6-yl
I-Naphthyl
9-Anthryl
9-Phenanthryl
Vinyl
x-Styryl
Ethyl
n-Propyl
n-Nonyl
lsobutyl
lsopropyl
Cyclohenyl
[gl
/err-Butyl
Config. ce
["/.I
la1
Ref.
IbI [cl
[&
II
4a
4b
4c
85
82
78
R
R
R [el
90
91
90
pa]
[3]
4d
4e
4f
4g
4h
4i
R
R[e]
R[e]
R
S
S
R
R
R
88
94
92
86
90
93
93
92
85
90
92
131
4m
4n
83
80
60
61
51
67
78
88
55
67
78
[2a] -11 7
[2e]
-10.4
[15]-22.4
[2a]
1.2
[3]
+ 8.2
40
58
R
88
[2a]
4j
4k
41
R
S
(c)
[dl
+43.7
+23.6
+23.5
+76.2
+ 19.9
+53.9
[2a]
[2a]
pa]
-132
- 13.5
- 38
+
+10.3
[a] The yields are. in general. not optimized. [b] Determination of the enantiomeric excess by capillary G C (Chirasil-L-Val" 1121) after derivatization with
isopropyl isocyanate (4a, b,d, h, i, k-m, 0 ) or (R)-( +)-3.3,3-trifluoro-2methoxy-2-phenylpropionyl chloride 1131 (4g,j,n) o r by HPLC on a "Bakerbond Chiral Ionic DNBPG Column" (4c, or on cellulose triacetate [14] (4e).
[c] The signs of the rotations in benzene correspond to the configurational
assignments in the cited works. [d] Concentration in benzene. [el New compound: the configuration was assigned on the basis ofanalogies. [f'J I n Et,O. [g]
In EtOH.
n
tonishingly small; thus, reaction with benzaldehyde at 0 "C
furnishes the product 4 a with 80 % ee. By controlled hydrolysis the filterable titanate 5 can be precipitated and by treatment with HCI (g) reconverted into CpTiC1, l.[l6]In the
process the chiral auxiliary diisopropylideneglucose can either be recovered or, after hydrolysis with 0.1 N HCI, be
separated by aqueous extraction.
As exemplified in Scheme 2 with the reactions of 6a, b,
titanates such as 7a-c with substituted allyl groups are
also highly enantioselective allylating reagents. These compounds are prepared from the corresponding lithium or
Grignard reagents. As in the case of achiral allyltitanates['. 81
the diastereomeric purity of the products 8b,c is near the
limit of detection ( 2 99%).['21
Reaction of racemic hydratopaldehyde 9 with 0.5 equivalents of allyl titanate 3 leads to formation of the stereoisomeric homoallyl alcohols 10-13 (80% based on 3) in the
ratio 70.8:0.9:24.2:4.1, whereby loll1 are the products
from (R)-9 and 12/13 those from ( 3 - 9 (Scheme 2). The moderate differentiation of enantiomers (2.5: 1) as well as the
higher diastereoselectivity in the case of the more reactive
enantiomer (R)-9 (97% de, matched case) would indicate a
certain Cram selectivity of the reagent 3, which, however, is
outweighed by the enantiofacial differentiation (71 % de in
the case of (59-9, mismatched case).
The titanium reagent 3 exhibits the usual chemoselectivity:''] at -74°C it does not react with ketones. At O'C,
however, aryl ketones are transferred smoothly into tertiary
homoallyl alcohols, but the asymmetric induction is, as expected, small (ca. 50% ee; 80% ec, however, in the case of
acetophenone). In contrast to the allyl compounds, analogous alkyl- and aryltitanates d o not react with aldehydes,
even at elevated temperatures.
CpTi(OR*),
0
R I A H
+
6 a , R ' = lsobutyl
6a,
6b,
R'=
lsobutyl
R'=
lsopropyl
R
2
9"
___c
d
-78%
R
l
T
?a, R Z - V i n y l
8 a , 6 8 %(90%
7b,
7c,
8b,
8c,
R Z = C,H,
R 2 = CH,
EH,
ee)
5 9 % ( 8 8 %ee j
46%(83%ee)
CH,
10 (56.6%)
11
(0.7%)
12
13
(3.3%)
(19.4%)
Scheme 2.
With the chiral reagents 3 and 7a-c the enantioselective
allylation of aldehydes has been achieved for the first time
with organotitanium compounds. Boron reagentsI2' exhibit
a similar stereoselectivity, but the advantage of titanium
must not be overlooked, e.g. simple preparation, chemoselectivity, inexpensive auxiliaries, as well as
the possibility of recovering diisopropylideneglucose and
CpTiCI, 1. Still a drawback of this method is, however, that
the high price of L-glucose impedes an equally good access to
the other enantiomers of the homoally1 alcohols 4. Concerted efforts are therefore currently directed a t solving this
problem with other ligands.
E.uperirnen tnl
Stock solution of 2 in ether: A solution/suspension of 1 (11.0g. 50mmol.
i n Et,O (400 mL. distilled over Naihenzophenone) was
freshly
treated with 26.0 g (0.1 mol) of 1.2: 5,6-di-O-isopropylidene-a-o-glucofuranose
(R*OH, crystallized from cyclohexane) under argon in the absence of moisture.
After 2 min at room temperature (RT) a solution of 15.2mL ( l l 0 m m o l ) of
Et,N in 125 m L of Et,O was added dropwise to the stirred mixture within 1 h.
The resulting suspension was stirred for ca. 15 h ; the E t , N . HCI was then
filtered off under argon and washed three times with ca. 50 mL of Et,O (14 2 g
o f E t , N . HCIvacuumdried).ThecontentofZin theyellowfiltrate(0.09
calculated from the volume of the solution assuming a quantitative conversion.
was
(R)-l-Phenyl-3-huten-l-ol(4a):
7.2 mL of a 1.25 M solution of allylmagnesium
chloride in T H F (Aldrich, 9 mmol) was added dropwise within 10 min at O'C
under argon to 110 mL of a ca. 0.09 M solution of 2 in Et,O (9.9 mmol). After
stirring for 1 h at 0 C the orange suspension was cooled to - 74 C and treated
within 5 niin with 0.8 m L (8 mmol) of henzaldehyde. The mixture was stirred
for 2 h at - 74 C . warmed to ca. - 3 0 ' C and hydrolyzed by addition of 16 m L
of a ca. 5 M solution of H,O in T H F (1 h, RT). Filtration, washing with Et,O
and drying (high vacuum) yielded 4.2 g of 5 (yellowish solid). The filtrate was
evaporated and the solid residue stirred with 100 m L of hexane. Subsequent
filtration furnished 4.4 g of R*OH. Chromatography (80 g silica gel, hexane:
AcOEt 3.1) finally afforded 1.01 g (85%) of 4 a (90% w, determined as described in (121).
Received: December 21. 1Y88 [Z 3095 IE]
German version: Angeir. Chern. 101 (1989) 488
[ I ] a ) R. W. Hoffmann, Angew. Cltenr. Y4 (1982) 569; Angeir. Cliern. Inr. Ed.
Gig /. 21 (1982) 555: b) Y. Yamamoto. A c r . C/rc,m. Rrs. 20 (1987) 243.
[2] a ) R W Hoffmann. T. Herold. Chrm. Ber. 114(1981) 375; b) R . W. Hoffmann. Pure Appl. Chem. 60 (1988) 123; c ) H. C. Brown. P. K.Jadhav. 1
Am. C h m . SJC..
105 (1983) 2092; d ) H. C. Brown. P. K.Jadhav. K. S.
Bhat. hid. /10(1988) 1535;e) W. R. Roush. A. E. Walts, L. K. Hoong, ;bid
107 (1985) 8186; 0 W. R. Roush, L. Banfi, ihM. 110 (1988) 3979: g) W. R.
Roush. K.Ando. D. B. Powers, R. L. Halterman. A. D. Palkowitz. Ewuhedron Let!. 29 (1988) 5579: h) M. T. Reetz, T. Zierke, Chon. Ind. (London) 1988. 663
(31 a ) N.Minowa. T. Mukaiyama, BUN. Chem. S o c . J p . (50 (1987) 3697; h)
G. P. Boldrini, L. Lodi. E.Tagliavini, C. Tarasco. C Trombini. A. UmaniRonchi. J. Org. Chem. 51 (1987) 5441.
141 a) T. Hayashi, Y. Matsumoto. T. Kiyoi, Y. Ito, S. Kohra. Y. Tominaga. A.
Hosomi. Tc.fru/fedronLerr. 29 (1988) 5667; b) R. lmwinkelried. D. Seehach. Angew. Cliem. 97 (1985) 781 :A n g e ~ Chern.
.
In/. Ed. Engl. 24 (1985)
765; c) A. Hosomi, Arc. Clwm. Res. 11 (1988) 200.
[5] a) D. Seebach, B. Weidmann, L. Widler in R. Scheffold (Ed.): Motlwn
STnrhrrir Merhods, Vo/. 3, Salle. Frankfurt am Main, Sauerlinder. Aarau
1983. p. 217; b) M. T. Reetz: Orgnno/itunium Rwgenr.\ in Orguwk Ssnr/leSLY, Springer, Berlin 1986.
[6] D. Seebach, A. K. Beck, R. Imwinkelried, S. Roggo, A. Wonnacott, H c h .
Chrm. Arru 70 (1987) 954.
(71 a) M. T. Reetz. S.-H. Kyung, J. Westermann, Orgonofnefu/lic\3 (1984)
1716: b) H . Takahashi. A. Kawabata, K. Higashiyama. Chm?. Phunn.
BUN.35 ( 1987) 1604.
[8] a) F. Sato, K. Iida. S. Iijima. H. Moriya. M. Sato, 1 C/?em.So<..Cilrm.
Commim. I Y N I , 1140: h) M. T. Reetz. M. Sauerwald. J. Org. Chon. 4Y
(1984) 2292: c) S. Collins, W P. Dean, D. G. Ward. Orgunonrr/u//ir.~
7
(1988) 2289: d ) D. Seebach, L. Widler, Hrlv. Chin?.Arro 65 (1982) 1972;
e) M. T. Reetz. R. Steinbach, J. Westermann, R. Peter, B. Wenderoth,
C h ~ mBer.
.
I18 (1985) 1441.
[9] a) H. Roder. G Helmchen, E. M. Peters, K. Peters, H.-G. von Schnering.
Angcw. Clirm. 96 (1984) 895; Angew. Cltem. In,. Ed. Engl 23 (1984) 898:
b) T. Krimer, D. Hoppe. l?/roheilron Lerr. 28 (1987) 5149.
[lo] R . D. Gorsich, 1 An?. Chon. S o l . 82 (1960) 421 1.
[I11 M. Riediker, R. W. Lang, R. Duthaler. P. Herold, K. Oertle. G. Bold,
Eur. Pat.-Anm. 0254685 (27. Jan. 1988). Ciba-Geigy AG.
[12] H. Frank, G. J. Nicholson, E. Bayer, Angeti. Chern. 90 (1978) 396: Angriv.
Ch(,m. I n f . Ed. Engl. 1 7 (1978) 363.
[I31 J. A. Dale, H. S. Mosher. J. Am. Chetn. Sor. Y5 (1973) 512.
[14] H. Koller, K:H. Rimhock, A. Mannschreck.1 Chromutogr. 282(1983) 89.
[15] B. Cazes, C.Verniere, J. Gore, SJ,n/h.Cotnmun. 13 (1983) 73.
[16] With one equivalent of conc. HCI a crystalline tetramer is formed; A. C.
Skapski. P. G . H. Troughton, Arru Cry.s/u//ngr.S ~ r r8. 2 6 (1970) 716.
Enantioselective Aldol Reaction of
tevt-Butyl Acetate using
Titanium-Carbohydrate Complexes **
By Rudolf 0. Duthaler,* Peter Herold, Willy Lottmhuch,
Konrad Oertle, and Murtin Riediker
The Aldol reaction is one of the most important methods
for the stereoselective construction of complex acyclic
molecules.~']Covalently bound chiral auxiliaries readily induce high stereoselectivity in the case of propionate enolates.
whereas in the case of acetate enolates this could hitherto
only be achieved via a circuitous route involving auxiliary
substituents.l2] More recently, methods have been developed
which enable the stereoselective addition of a-unsubstituted
enolate~.[~
AI particularly efficient approach makes use of
metal complexes with chiral l i g a n d ~ . [It~should,
]
however, be
mentioned, that many j3-hydroxy esters (such as 4) are accessible by enantioselective reduction of the corresponding
j3-0x0 esters as ~ e I 1 . [ ~ ]
The successful asymmetric allylation of carbonyl compounds with novel cyclopentadienyltitanium-carbohydrate
motivated us to apply this principle also to the
acetate-Aldol rea~tion!'~ We have found that, in this way, a
variety of j3-hydroxycarboxylic acids are accessible in 9095 o/o optical purity (Scheme 1 , Table 1).
[*I
[ '1
[**I
Dr. R. 0. Duthaler. Dr. P. Herold, Dr. W. Lottenbach. Dr. K. Oertle.
Dr. M. Riediker [ + ]
Zentrale Forschungslaboratorien. Ciba-Geigy AG
Postfach. CH-4002 Bascl (Switzerland)
Present address:
Research Laboratories, Plastics Division. Ciba-Geigy Corporation
Ardsley. NY 10502 (USA)
Enantioselective Syntheses with Titanium-Carbohydrate Complexes.
Part 2.--Part 1 : 161.
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