Facile enantioselective synthesis of a key homoallylic alcohol building block for polyketide synthesis: TiF4-BINOL catalyzed allylsilylation with allyl trimethylsilane

Article abstract of DOI:10.1039/b107995f

The titanium fluoride-BINOL catalyzed asymmetric allylsilylation of α,α-disubstituted aldehydes provides facile access to highly functionalized, chiral building blocks, which following simple recrystallization affords a key versatile starting material for

Full text of DOI:10.1039/b107995f

Facile enantioselective synthesis of a key homoallylic alcohol building
block for polyketide synthesis: TiF4–BINOL catalyzed allylsilylation
with allyl trimethylsilane
Jeffrey W. Bode,a Donald R. Gauthier Jr.a and Erick M. Carreira*a
Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich,
Switzerland. E-mail: carreira@org.chem.ethz.ch
Received (in Cambridge, UK) 5th September 2001, Accepted 1st November 2001
First published as an Advance Article on the web 22nd November 2001
The titanium fluoride–BINOL catalyzed asymmetric allylsi-
lylation of a,a-disubstituted aldehydes provides facile access
to highly functionalized, chiral building blocks, which
following simple recrystallization affords a key versatile
starting material for polyketide synthesis in 96% ee.
recurring structural isobutyrate motif found in polyketide-
derived natural products. In an effort to identify the appropriate
protecting group strategy that would provide crystalline mate-
rial in high optical purity, we prepared a number of aldehyde
substrates possessing a variety of protecting groups. Preparation
of the necessary aldehydes was readily achieved by monop-
rotection of the 2,2-dimethypropane-1,3-diol, an inexpensive
commodity chemical, followed by oxidation with either cata-
lytic TEMPO8 or catalytic TPAP.9
Polyketides constitute a large class of naturally occurring
structures with diverse, biological activities of importance to
human medicine. As a consequence of the common biosynthetic
pathways through which these structures are assembled there
are often a number of recurring structural patterns in the form of
1,3-dicarbonyls, 1,3-hydroxy carbonyls, and 1,3-diols derived
from acetate, propionate, or isobutyrate. Access to fragments
that function as building blocks for the synthesis of these
structures has resulted in many useful asymmetric synthetic
enantioselective and diastereoselective methods.1 The majority
of these address the construction of acetate and propionate
derived subunits, while many fewer are available for the
preparation of isobutyrate derived subunits. We have recently
reported the enantioselective TiF4–BINOL catalyzed allyl-
silylation of aldehydes employing allyltrimethylsilane to afford
adducts in useful selectivities and yields.2 In our initial
communication, the catalytic, enantioselective allylsilation of
iPr3Si-protected 2,2-dimethyl-3-hydroxypropanal furnished the
adduct in 93% yield, albeit in only 84% ee. The importance of
such building blocks led us to initiate a program of study aimed
at developing methods that would provide for their ready
access. Herein we report investigations of this process furnish-
ing fragments possesing the isobutyrate structural motif found
in polyketide-derived natural products (eqn. 1). Importantly,
The allylation reaction of these substrates afforded adducts in
55–97% yield and 84–91% ee as shown in eqn. (2) and Table
1.10,11 It is interesting to note that O-silyl, O-benzyl, and ester
protecting groups all proved to be stable to and compatible with
the allylation reaction. Also noteworthy is the ability to utilize
both acetate (entry 6) and nitro (entry 5) moieties without
complication by potentially competing reactions. Of the various
adducts isolated, the 2-naphthoate protected adduct 5g was
isolated as a white crystalline solid in 91% ee and in 97% yield,
following desilylation of the adduct. Importantly, after simple
recrystallization, product was isolated enriched to 96% ee, as
determined by chiral HPLC analysis. Additionally, the same
reaction could be carried out with 5 mol% of the titanium
catalyst on an 80 mmol scale, with the product isolated in 92%
ee and in 72% yield.
(2)
In an effort to demonstrate the versatility of these adducts, we
have carried out a number of facile, high yielding transforma-
tions. Hydrolysis of the naphthoate esters with potassium
carbonate in methanol led to diol 6, which following protection
(1)
the approach described herein furnishes optically active,
crystalline adducts from commercially available reagents, and
as such should find use in the ongoing studies towards the
development of efficient routes and strategies to polyketide-
derived natural products, such as aplasmomycin3 byrostatins4
epothilones,5 mycalamides,6 and boromycin.7
Among the critical advantages offered by the allylation
reaction we have developed are: (1) the commercial availability
of the ligand ((R)- or (S)- BINOL), metal (TiF4), and allyl-
trimethylsilane; (2) the single step, in situ, preparation of the
active catalyst from BINOL, TiF4; (3) the low toxicity of allyl-
silane as compared to the alternative and often utilized allyl-
stannane reagents; and (4) the volumetric efficiency of the
process. In our preliminary laboratory screening of substrate
scope for this transformation it was noted that the method was
particularly effective for the enantioselective allylation of
hindered, aliphatic non-enolizable aldehydes, affording adducts
consistently in useful levels of enantiopurity.
Table 1 TiF4–BINOL catalyzed allyl silylation of 5a–g
Entry Substrate
Product
5a
% ee
Yield
93%
48%
55%
85%
69%
85%
97%
i
1
2
3
4
5
6
7
R = Pr3Si
84%a
4a
t
R = BuMe2Si
5b
86%a
4b
R = PhCH2
5c
89%b
4c
R = PhCO
5d
88%a
4d
R = p-NO2C6H4CH2
5e
88%c
4e
R = MeCO
5f
90%c
4f
R = 2-Naphthoyl
5g
91%c (96%)d
4g
a Determined by GC analysis of the Mosher ester. b Determined by 1H NMR
analysis of the Mosher ester. c Determined by chiral HPLC analysis
(Chiradex OD). d Following recrystallization.
The specific use of protected 2,2-dimethyl-3-hydroxypropio-
naldehyde in the allylation reaction provides access to the
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Chem. Commun., 2001, 2560–2561
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b107995f

Notes and references
1 (a) Catalytic Asymmetric Synthesis, ed. I. Ojima, VCH, New York,
1993; (b) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley,
New York, 1994.
2 D. R. Gauthier and E. M. Carreira, Angew. Chem., Int. Ed. Engl., 1996,
35, 2363–2365.
3 F. Matsuda, N. Tomiyoshi, M. Yanagiya and T. Matsumoto, Tetra-
hedron Lett., 1986, 27, 6345–6347.
4 M. Kageyama, T. Tamura, M. H. Nantz, J. C. Roberts and P. Somfai, J.
Am. Chem. Soc., 1990, 112, 7407–7409.
5 G. H. Höfle, N. Bedorf, H. Steinmetz, D. Schonburg, K. Gerth and H.
Reichenbach, Angew. Chem., Int. Ed. Engl., 1996, 35, 1567–1569.
6 N. B. Perry, J. W. Blunt, M. H. G. Munro and L. K. Pannell, J. Am.
Chem. Soc., 1988, 110, 4850–4851.
Scheme 1 Elaboration of adduct 6g to diol 7.
7 H. Maehr, L. Leach, L. Yarmchuk and L. M. Mitrouic, J. Antibiot.,
1979, 32, 361–367.
8 P. L. Anelli, C. Biffi, F. Montanari and S. Quici, J. Org. Chem., 1987,
52, 2559–2562.
9 W. P. Griffith, S. V. Ley, G. P. Whitcombe and A. D. White, J. Chem.
Soc., Chem. Commun., 1987, 1625–1627.
as the corresponding acetonide and ozonolytic cleavage of the
olefin afforded chiral aldehyde 7 in 80% overall yield (Scheme
1). Alternatively, ozonolysis could be performed directly on the
allyl adduct and the resulting aldehyde protected in situ as
dioxolane 8 in 80% yield. Following saponification and
selective oxidation of the primary hydroxy moiety, aldehyde 9
was obtained in 80% yield (Scheme 2).
10 Experimental procedure for naphthalene-2-carboxylic acid (3S)-hy-
droxy-2,2-dimethylhex-5-enyl ester. To a suspension of TiF4 (0.25 g,
2.0 mmol, 5.0 mol%) in 10 ml CH3CN was added (S)-BINOL (1.15 g,
4.00 mmol, 10.0 mol%) and the mixture stirred 15 min before the
solvent was removed under reduced pressure. After 10 min at 1.0 torr,
the residue was dissolved in 10 ml CH2Cl2 and cooled to 0 °C. To this
solution was added allyltrimethylsilane (12.7 ml, 80.0 mmol, 2.00
equiv.) and stirred 1 h to give a dark precipitate to which aldehyde 4g
(10.3 g, 40.0 mmol, 1.00 equiv.) was added neat in two portion to give
a dark red-orange solution. This solution was allowed to stir 5 days at
0 °C at which time analysis by 1H NMR showed the reaction to be
complete. The reaction mixture was diluted with 2+1 pentane+ether
(500 ml), filtered over silica gel and eluted with 2+1 pentane+Et2O (500
ml). Following rotary evaporation, the resulting residue was treated with
5+95+1.5 HF+MeCN+H2O (80 ml) for 0.5 h, dissolved in Et2O (200
ml), washed with 2 M NaOH (2 3 50 ml), brine (100 ml), dried over
Na2SO4, and concentrated to give a yellow oil (11.65 g, 98% yield).
Purification by crystallization from hexanes provided 5g (8.30 g, 72%
yield) as a white solid in 92% ee. (Determined by chiral HPLC analysis
Chiradex OD), 98+2 hexanes–iPrOH. [a]2D5 (c 0.950, CHCl3) = +11.9;
mp 46.5 °C; 1H NMR (300 MHz, CDCl3) d 8.61 (s, 1H), 8.06 (dd, J =
8.7, 1.6, 1 H), 7.97 (d, J = 7.78, 1 H), 7.92 (d, J = 8.7, 1 H), 7.60–7.53
(m, 2 H), 5.97-5.83 (m, 1 H), 5.19 (d, J = 8.6, 1 H), 5.14 (s, 1 H), 4.48
(d, J = 10.9, 1 H), 4.13 (d, J = 10.9, 1 H), 3.59 (td, J = 8.4, 3.4, 1 H),
2.45–2.39 (m, 1 H), 2.20 (d, J = 3.4, 1 H), 2.17–2.12 (m, 1 H), 1.10 (s,
3H), 1.07 (s, 3H); 13C NMR (75 MHz, CDCl3): 167.0, 136.1, 135.6,
132.5, 131.1, 129.4, 128.3, 128.2, 127.8, 127.5, 126.7, 125.2, 118.0,
74.1, 71.2, 38.7, 36.2, 21.8, 19.4; IR (KBr) 3493, 3068, 2971, 2892,
1683, 1475, 1373, 1274, 1230, 1198, 905, 776; EI-MS: 298.1 (M)+;
Anal. Calcd. for (C19H22O3) C, 76.48; H, 7.43%; found, C, 76.64; H,
7.26%.
Scheme 2 Elaboration of adduct 6g to aldehyde 10.
In summary, the TiF4–BINOL catalyzed allylsilylation of
protected aldehydes provides facile access to highly function-
alized building blocks in high enantiopurity. These results
demonstrate the possibility of employing this reaction for the
preparation of significant quantities of chiral starting materials
and attests to the tolerance of this catalyst towards a number of
potentially reactive functionalities. Importantly, the synthesis
study described herein furnishes optically active, crystalline
adducts from commercially available reagents, and as such
should find applications in the development of increasingly
efficient strategies to polyketide-derived natural products.
Support has been provided by generous funds from the ETH,
the Kontaktgruppe für Forschungsfragen (KGF), Hoffmann-La
Roche, and Merck. J. W. B. is grateful to the National Science
Foundation (USA) for a predoctoral fellowship.
11 At the current level of development the process works optimally with
non-enolizable aldehydes. Enolizable aldehydes furnish adducts, albeit
in reduced yields and selectivities.
Chem. Commun., 2001, 2560–2561
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