Pentadienyltitaniums as versatile intermediates: Regio- and stereoselectivities

Article abstract of DOI:10.1055/s-2001-14650

The adduct obtained upon consecutive treatment of 1,4-dienes with butyllithium in the presence of potassium tert-butoxide, chlorotri(isopropyloxy)titanium and a carbonyl compound contains the α-hydroxyalkyl group invariably and exclusively linked to the 3-position of the former diene. When chlorotri(isopropyloxy)titanium is replaced by the Duthaler-Hafner reagent [(4R,5R)-chloro(cyclopentadienyl)(2,2-dimethyl-α,α,α ′,α′-tetraphenyl-1,3-dioxolane- 4,5-dimethanolato-O,O^α)titanium] the reaction does not only occur regioselectively but also with appreciably high enantioselectivity.

Full text of DOI:10.1055/s-2001-14650

1016
LETTER
Pentadienyltitaniums as Versatile Intermediates: Regio- and Stereo-
selectivities
Armin Zellner, Manfred Schlosser*
Section de Chimie, Université, BCh, CH-1015 Lausanne, Switzerland
Fax ++41-21-6923965; E-mail: manfred.schlosser@ico.unil.ch
Received 5 February 2001
as the sole characterized products.9 With this as a back-
ground we wanted to find out how dienyl type organotita-
nium reagents behave in this respect.
Abstract: The adduct obtained upon consecutive treatment of 1,4-
dienes with butyllithium in the presence of potassium tert-butoxide,
chlorotri(isopropyloxy)titanium and a carbonyl compound contains
the -hydroxyalkyl group invariably and exclusively linked to the
3-position of the former diene. When chlorotri(isopropyloxy)titani-
um is replaced by the Duthaler-Hafner reagent [(4R,5R)-chloro(cy-
clopentadienyl)(2,2-dimethyl- , , ', '-tetraphenyl-1,3-dioxolane-
4,5-dimethanolato-O,Oα)titanium] the reaction does not only occur
regioselectively but also with appreciably high enantioselectivity.
The latter species were readily prepared by treatment of
the analogous lithium or potassium compounds with chlo-
rotri(isopropyloxy)titanium. The intermediate thus gener-
ated was allowed to react with 9 aliphatic or aromatic
aldehydes and 3 ketones (cyclohexanone, methyl pyru-
vate and methyl acetoacetate) to afford the adducts 1a de-
rived from electrophilic attack at the 3-position of the
pentadienyl entity as the sole detectable products.5 In the
same way, 3-methyl-1,4-pentadiene was converted into
the doubly vinyl-branched adducts 1b by addition of the
tri(isopropyloxy)titanium compound to 7 aliphatic, satu-
rated or unsaturated aldehydes and to a ketone (acetone),
the average yield amounting to 63% in both series.5
Key words: superbase, metal effects, regioselectivity of electro-
philic attack, stereoselectivity of carbon-carbon bond formation,
natural product synthesis
Crotyl type and prenyl type 2-alkenylpotassiums react
with most electrophiles mainly, if not exclusively at the
unsubstituted terminal position. Typical 1-/3-substitution
ratios are > 100:1 with chlorotrimethylsilane, 20:1 50:1 To demonstrate its practical utility, the method was ap-
with fluorodimethoxyborane, 5:1 10:1 with alkylating plied to the synthesis of the cis-substituted -methylene-
reagents, 1:1 5:1 with oxiranes and aldehydes and 10:1
lactone 2 starting with the metalation of 5-methyl-1,4-
20:1 with carbon dioxide.1 In contrast, the corresponding pentadiene and involving the addition of the resulting in-
magnesium derivatives afford preferentially the branched termediate to isopropyl pyruvate and the subsequent iodi-
products resulting from electrophilic attack at the internal nation-cyclization as key steps. Furthermore, racemic
end of the allylic unit, typical 3-/1-substitution ratios be- santolina alcohol10–12 3 was prepared in the same way.
ing 4:1 10:1 for borylation, 2:1 3:1 for alkylation and
Organotitanium chemistry offers still a major stereochem-
50:1 for the addition to oxiranes, aldehydes and carbon
ical bonus. The metal seeking high and tight coordination
dioxide. The regioselectivity becomes total when carbon-
can be placed in a “chiral atmosphere” by employing an
yl compounds are combined with allylic boron2,3 or
enantiomerically pure alcoholate as a ligand. Judging
titanium4 derivatives. At the same time, these reagents ex-
from previous work of R.O.Duthaler, A.Hafner et al.,13
hibit high diastereoselectivities.
the simultaneous complexation of titanium with (R,R)-
An extension of the area of delocalization makes the out- TADDOL14 diolate and cyclopentadienyl is an effica-
come of trapping reactions with alkali or alkali-earth met- cious means for promoting asymmetric -hydroxy-
al compounds less predictable. Both, 2,4-penta- alkylations of organometallic allyl and crotyl derivatives.
dienylpotassium5
and
2,4-pentadienylmagnesium We have now successfully extended this option to the ac-
halide6,7 give rise to regioisomeric mixtures when treated cordingly modified 2,4-pentadienyl reagent which gave
with alkyl halides or aldehydes. On the other hand, two with trans-2-butanal and benzaldehyde the products 4a
boronates, (2Z,4E)- and (2E,4Z)-2,4-hexadienyl(dimeth- and 4b in 62% and 66% yield and 72% and 92% ee, re-
oxy)borane, were found to combine with propanal under spectively. Analogously, the 5-(4-anisyl)-3-methyl-2,4-
allylic transposition to give threo8-(E)-4-vinyl-5-hepten- pentadienyl CpTi(TADDOL) compound reacted with
3-ol and, respectively, erythro8-(Z)-4-vinyl-5-hepten-3-ol 4-methyl-3-pentenal to form the Bakuchiol congener 5 in
OH
R
R'
R''
(O
Ti
)
3
K
(1.)
R
R
R
LiC4H9
ClTi(O
)
3
R''R'C=O
(2.) H
KOC(CH3)3
1a : R = H
1b : R = CH3
Synlett 2001, SI, 1016–1018 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Pentadienyltitaniums as Versatile Intermediates
1017
O
O
O
(1.)
KOH
(2.) Ι2
(O
Ti
)
3
OH
O
OH
O
O
(1.) red.
O
(2.) elim.
Ι
CH2
(1.)
(2.) H
OCC−CH3
2
O
(1.)
LiC4H9
KOC(CH3)3
(O
Ti
)
3
(1.)
OH
+
(H3C)2C=O
(2.)
(2.) H
ClTi(O
)
3
3
H
OH
H
CpTi(TADDOLate)
CpTi(TADDOLate)
R
(1.) RCH=O
(2.) H
4a : R = H5C2
4b : R = H5C6
H
OH
O
(1.)
(2.) H
3CO
H3CO
5
colorless platelets; mp 111 112 °C; 19 g (67%). Configuration as-
signment based on 1H,1H-NOESY. cis-4,5-Dihydro-3-methylene-
5-methyl-4-vinyl-2(3H)furanone (2)15 by deiodination of the pre-
ceding lactone (14 g, 50 mmol) with tributyltin hydride (0.10 mol)
in the presence of azoisobutyronitrile (0.1 g, 0.5 mmol) in toluene
(0.30 L) followed by conversion into the xanthogenate and thermol-
ysis (refluxing toluene); colorless liquid; bp 68 69 °C/12 mmHg;
n20D 1.4713; 3.5 g (51%).
38% yield and 78% ee. The configuration at the quarter-
nary carbon atom is presumably (S); the aldehyde should
always be approached on the Si-face.13
Products and Protocols
Metalation, transmetalation and adddition to carbonyls : At 0 °C,
the 1,4-diene (25 mmol) and butyllithium (25 mmol) in hexanes (15
mL) were added to a suspension of potassium tert-butoxide (2.8 g,
25 mmol) in hexanes (25 mL). After 30 min of vigorous stirring, the
solvent was evaporated under reduced pressure and the residue dis-
solved at 75 °C in precooled tetrahydrofuran (125 mL). The color
of the red solution intensified when chlorotri(isopropyloxy)titanium
(6.5 g, 25 mmol) in tetrahydrofuran (25 mL) was added drop-
wise in the course of 60 min before the mixture was treated,
still at 75 °C, with the aldehyde or ketone (25 mmol). The mix-
ture was allowed to warm to 25 °C and was then poured into a sat-
urated aqueous solution of ammonium chloride (0.10 L). After
extraction with diethyl ether (3 50 mL), the product was purified
by distillation or column chromatography (silica gel; diethyl
ether/hexanes 1:4). Examples : 1-(1-Vinyl-2-propenyl)-1-cyclo-
hexanol15 (1a : R = H, R'+R'' = -(CH2)5-) from cyclohexanone (2.6
Santolina alcohol : 1,1,4-Trimethyl-2-vinyl-3-penten-1-ol (3)15
from 5-methyl-1,4-hexadiene16 (25 mmol) and acetone (25 mmol);
colorless liquid; bp 70 72 °C/12 mmHg; n20 1.4632 (lit.12 n20
D
D
1.4640); 2.6 g (67%).
Enantioselective reactions: The ee-values of (E)-3-vinyl-1,5-hep-
tadien-4-ol15 (4a; bp 72 74 °C/12 mmHg; n20D 1.4730; 62%, 72%
ee), 1-phenyl-2-vinyl-3-buten-1-ol17 (4b; 66%, 92% ee) and
(3S,4R,E)-1-(4-anisyl)-3,7-dimethyl-3-vinyl-1,7-octadien-4-ol15
(5; viscous colorless liquid; mp 21 °C to 19 °C; bp 146
148 °C/0.1 mmHg; n20D 1.4771; 38% yield, 78% ee; diastereomeric
ratio 95:5) were determined after esterification with Mosher's
reagent18 by 19F-nmr. Compound 5 was prepared by consecutive
treatment of (E)-5-(4-anisyl)-3-methyl-1,3-pentadiene (10 mmol;
from 4-anisylmagnesium bromide and 3-methyl-2,4-pentadienyl
acetate in the presence of the dilithiotetrachlorocuprate catalyst in
tetrahydrofuran at 30 °C19) with butyllithium in the presence of
potassium tert-butoxide, the Duthaler-Hafner complex13 and 4-me-
thyl-3-pentenal.20
mL, 2.5 g, 25 mmol); colorless liquid; bp 94–96 °C/8 mmHg; n20
D
1.4895 (lit.15 n20 1.4903); 3.0 g (71%). Isopropyl 2-hydroxy-2-
D
methyl-3-vinyl-4-pentenoate15 from 1,4-pentadiene and methyl
pyruvate (2.3 ml, 2.6 g, 25 mmol); colorless liquid; bp 56 58 °C/
1 mmHg; n20D 1.4440; 3.0 g (60%).
Lactones : 4,5-Dihydro-r-3-hydroxy-5,c-iodomethyl-3-methyl-
4,c-vinyl-2(3H)furanone:15 From the latter ester (0.20 mol) by sa-
ponification to the acid15 (colorless needles, mp 57 58 °C; 92%)
followed by simultaneous treatment with iodine (0.10 mol) and a
saturated aqueous solution (0.30 L) of sodium hydrogen carbonate;
Acknowledgement
This work was supported by the Swiss National Science Foundati-
on, Bern (grant 20-49'307-96).
Synlett 2001, SI, 1016–1018 ISSN 0936-5214 © Thieme Stuttgart · New York

1018
A. Zellner, M. Schlosser
LETTER
(13) Hafner, A.; Duthaler, R.O.; Marti, R.; Rihs, G.; Rothe-Streit,
P.; Schwarzenbach, F.; J. Am. Chem. Soc. 1992, 114, 2321
2336.
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Article Identifier:
1437-2096,E;2001,0,SI,1016,1018,ftx,en;Y04801ST.pdf
Synlett 2001, SI, 1016–1018 ISSN 0936-5214 © Thieme Stuttgart · New York