Super silyl stereo-directing groups for complete 1,5-Syn and -anti stereoselectivities in the aldol reactions of β-siloxy methyl ketones with aldehydes

Article abstract of DOI:10.1021/ja101076q

In this communication, we report that substrate-controlled 1,5-syn and -anti stereoinduction in the aldol reaction of β-tris(trialkylsilyl)siloxy methyl ketones can be achieved with high diastereoselectivities. Tris(trialkylsilyl)silyl groups are easily p

Full text of DOI:10.1021/ja101076q

Published on Web 03/29/2010
Super Silyl Stereo-Directing Groups for Complete 1,5-Syn and -Anti
Stereoselectivities in the Aldol Reactions of ꢀ-Siloxy Methyl Ketones with
Aldehydes
Yousuke Yamaoka and Hisashi Yamamoto*
Department of Chemistry, The UniVersity of Chicago, 5735 South Ellis AVenue, Chicago, Illinois 60637
Received February 5, 2010; E-mail: yamamoto@uchicago.edu
Polyketides are an important class of natural products, and the
1,3-polyol motif is commonly found in these biologically significant
compounds.1 Undoubtedly, the asymmetric aldol reaction provides
a straightforward route for the stereoselective construction of these
required polyol subunits. We recently introduced a cascade Mu-
kaiyama aldol reaction based on super silyl and super Brønsted
acid chemistry that gave the required polyol-carbonyls stereose-
lectively in a single step (Scheme 1A,B).2,3 To upgrade the cascade
process for even broader utility, such as rapid construction of
polyketide frameworks, we here focused on 1,5-stereoselective aldol
reactions that use our cascade products directly; these reactions
represent a series of two consecutive aldol reactions of a central
ketone with two polyol-aldehydes (Scheme 1C).4,5
1). The use of a noncoordinating solvent such as CH2Cl2 or toluene
gave low selectivities (entries 2 and 3). Gratifyingly, the use of N,N-
dimethylformamide (DMF) as the solvent gave syn-4a in 94% yield
with good selectivity (entry 4). Finally, when the TMS-type super silyl
[i.e., tris(trimethylsilyl)silyl] group was changed to a TES-type super
silyl [i.e., tris(triethylsilyl)silyl] group,9 the diastereoselectivity increased
to 96:4 (entry 5). As anticipated, the use of 3a having a much smaller
TBS protecting group gave 6a with low selectivity (entry 6). Appar-
ently, the super silyl group plays an important role in achieving high
selectivity because of its extreme steric bulk in comparison with other
silyl groups.2a
Table 1. Optimization of the Aldol Reactions of 1a-3a with
Pivalaldehyde
Scheme 1. Aldol Reactions Utilizing 1,3- and 1,5-Stereoinduction
entry
substrate
enolization reagent
T (°C)
solvent
% yielda
syn/antib
1
1a
1a
1a
1a
2a
3a
1a
1a
1a
1a
2a
3a
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
-78
-60
-60
-60
-60
-60
-78
-78
-78
-78
-78
-78
THF
89
50
70
94
82
69
82
65
72
82
79
78
40:60
60:40
60:40
87:13
96:4
2
CH2Cl2
toluene
DMF
3
4
5
DMF
DMF
6
66:34
5:95
c
7
CH2Cl2
CH2Cl2
hexane
toluene
toluene
toluene
TMSOTf/Et3N
c
General methodologies for high 1,5-stereoinduction in the aldol
reactions of methyl ketones have not been established to date
because the reaction site is far from the chiral center of the substrate
in comparison with 1,2- or 1,3-inductions. Nonetheless, several
methods for 1,5-anti asymmetric induction in aldol reactions have
been disclosed.6 The most commonly used method of 1,5-anti
induction is the boron-mediated aldol reaction of ꢀ-alkoxy methyl
ketones with aldehydes. Unfortunately, switching the protecting
group from a ꢀ-alkoxy group to a siloxy group leads to significantly
lower diastereoselectivities, with a few exceptions.7 Thus, the
method cannot be used directly on the product of Mukaiyama aldol
reactions and requires extra deprotection and protection steps. To
obtain 1,5-syn stereoselectivity in aldol reactions using methyl
ketones is even more difficult.8 Synthetic methods for achieving
1,5-asymmetric induction in the context of asymmetric synthesis
have been reported by both Denmark8a-c and Dias.8d,e However,
a general diastereoselective approach to 1,5-syn induction is still
challenging. Herein we report new methods for both high 1,5-syn
and -anti induction in the aldol reaction of ꢀ-siloxy methyl ketones
with aldehydes using substrate control.
8
15:85
15:85
3:97
2:98
45:55
TESOTf/Et3N
c
9
TMSOTf/Et3N
c
10
11
12
TMSOTf/Et3N
c
TMSOTf/Et3N
c
TMSOTf/Et3N
a Isolated yield. b Determined by 1H NMR or GC analysis. c After
isolation of the silyl enol ether of 1a-3a, the aldol reaction was carried
out using 0.2 mol % Tf2NH in the indicated solvent.
Since metallocyclic and acyclic transition states frequently give
opposite stereoselectivities in aldol reactions,10 we evaluated the
possibility of a 1,5-anti aldol reaction with 1a under acidic conditions.
Thus, the aldol reactions of the silyl enol ethers of 1a and pivalaldehyde
catalyzed by Tf2NH were investigated (Table 1, entries 7-12). The
use of the trimethylsilyl enol ether of 1a in CH2Cl2 gave anti-4a in
82% yield with high selectivity (95:5; entry 7). The selectivity
decreased when the triethylsilyl enol ether of 1a was used (entry 8).
The use of hexane caused a decrease in the yield of 4a (entry 9),
whereas the use of toluene gave an 82% yield of anti-4a almost
exclusively (97:3; entry 10). When the TES-type super silyl derivative
2a was tested, the selectivity increased to 98:2 with a slight decrease
in yield (entry 11). As anticipated, the use of TBS-protected 3a gave
6a with a very low selectivity (entry 12).11
To examine whether the use of bulky ꢀ-super siloxy groups could
lead to high 1,5-stereoinduction in the aldol reaction, compounds 1a
and 2a were prepared using our reported methodology.2 Simple
treatment of the lithium enolate of 1a with pivalaldehyde in tetrahy-
drofuran (THF) at -78 °C gave 4a with low selectivity (Table 1, entry
Plausible transition-state structures for the 1,5-syn and 1,5-anti
selectivities are shown in Figure 1. Both transition states should adopt
conformation A because avoids the unfavorable steric interaction
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10.1021/ja101076q  2010 American Chemical Society

C O M M U N I C A T I O N S
between the R1 group and the olefin of the enolate that is present in
conformation B. In the case of the lithium-mediated aldol reaction,
the syn selectivity can be attributed to the unfavorable 1,3-diaxial
interactions found in transition state D, which are absent in transition
state C. A bulkier coordinating solvent such as THF destabilizes
conformation A as a result of the repulsion between R1 and the
coordinated solvent molecules, leading to lower syn selectivity. In the
case of the acid-catalyzed aldol reaction, anti selectivity is observed
because transition state E has less interaction between the R2 group
and the methylene group than exists in transition state F. Switching
to a bulkier silyl group in the silyl enol ether destabilizes conformation
A as a result of the repulsion between the R1 group and the siloxy
group, leading to lower anti selectivity.
Table 2. Substrate Scope of 1,5-Syn Aldol Reactions with 2a-d
entry
R1 (2)
R2
product (% yielda)
syn/antib
1
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
i-Pr (2b)
t-Bu
i-Pr
5a (82)
5b (82)
5c (77)
5d (70)
5e (72)
5f (70)
5g (83)
5h (84)
5i (80)
5j (84)
5k (82)
5l (85)
5m (80)
96:4
95:5
96:4
93:7
89:11
88:12
85:15
96:4
95:5
97:3
97:3
93:7
92:8
2
3
c-Hex
4
n-Hept
4-MeO-Ph
4-NO2-Ph
PhCHdCH (E)
t-Bu
5
6
7
8
9
i-Pr (2b)
c-Hex
10
11
12
13
c-Hex (2c)
c-Hex (2c)
n-Hept (2d)
n-Hept (2d)
t-Bu
c-Hex
t-Bu
c-Hex
a Isolated yield. b Determined by 1H NMR analysis of the crude
product.
Table 3. Substrate Scope of 1,5-Anti Aldol Reactions with 1a′-d′
entry
R1 (1′)
R2
product (% yielda)
anti/synb
1
t-Bu (1a′)
t-Bu (1a′)
t-Bu (1a′)
t-Bu (1a′)
t-Bu (1a′)
t-Bu (1a′)
t-Bu (1a′)
i-Pr (1b′)
t-Bu
i-Pr
4a (82)
4b (87)
4c (80)
4d (91)
4e (85)
4f (92)
4g (83)
4h (90)
4i (87)
4j (77)
4k (74)
4l (71)
4m (78)
97:3
95:5
97:3
95:5
97:3
95:5
98:2
98:2
97:3
95:5
97:3
94:6
97:3
2
3
c-Hex
4
n-Hept
4-MeO-Ph
4-NO2-Ph
PhCHdCH (E)
t-Bu
5
6
7
8
9
i-Pr (1b′)
c-Hex
10
11
12
13
c-Hex (1c′)
c-Hex (1c′)
n-Hept (1d′)
n-Hept (1d′)
t-Bu
c-Hex
t-Bu
c-Hex
a Isolated yield. b Determined by 1H NMR analysis of the crude
product.
Scheme 2. Syntheses of 1,3,5-Triols
Figure 1. Plausible transition states for 1,5-syn and 1,5-anti inductions.
Under the optimized reaction conditions, the 1,5-syn-selective aldol
reaction was achieved using various aldehydes and methyl ketones,
and the results are summarized in Table 2. The reactions of 2a with
various aliphatic aldehydes gave syn-5a-d with high diastereoselec-
tivities (entries 1-4). The aldol reactions of 2a with aromatic and
conjugated aldehydes gave syn-5e-g with slightly lower diastereose-
lectivities (entries 5-7). Methyl ketones bearing various ꢀ-alkyl
substituents (2b-d) produced syn-5h-m with high diastereoselec-
tivities (entries 8-13). Thus, the 1,5-syn aldol reaction using the TES-
type super silyl group proved to be rather general in scope.
Furthermore, the substrate scope for the 1,5-anti-selective aldol
reaction was also investigated (Table 3). The aldol reactions of 1a′
with various aldehydes gave anti-4a-g with high diastereoselec-
tivities (entries 1-7), and methyl ketones bearing various ꢀ-alkyl
substituents (1b′-d′) also gave anti-4h-m without exception
(entries 8-13). Thus, the anti-selective acidic aldol process also
proved to be very general.
Next, we investigated the conversion of anti- and syn-5a to 1,3,5-
triol motifs (Scheme 2). 1,3,5-Triol syn/anti-7 was obtained by the
simple NaBH4 reduction of anti-5a with excellent selectivity (Scheme
2A).12 1,3,5-Triol syn/syn-7 was also obtained by the NaBH4 reduction
of syn-5a with high selectivity (Scheme 2B). These selectivities
depended heavily on the tris(triethylsilyl)siloxy group because of its
overwhelming steric hindrance. It should be noted that the TES-type
super silyl group was also cleanly cleaved in MeOH/CH2Cl2 upon
irradiation with UV light.13 1,3,5-Triol anti/anti-8 was obtained from
syn-5a by an intramolecular hydrosilylation/scandium triflate-catalyzed
reduction/desilylation sequence (Scheme 2C).14-16
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C O M M U N I C A T I O N S
Scheme 3. Doubly Stereodifferentiating Aldol Reactions
(3) Akakura, M.; Boxer, M. B.; Yamamoto, H. ARKIVOC 2007, (x), 337.
(4) For reviews of 1,5-asymmetric induction in the aldol reaction, see: (a)
Yeung, K.; Paterson, I. Chem. ReV 2005, 105, 4237. (b) Dias, L. C.; Aguilar,
A. M. Chem. Soc. ReV. 2008, 37, 451.
(5) Selected papers utilizing 1,5-induction in the aldol reaction for total
synthesis: (a) Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Roberts,
J. C.; Somfai, P.; Whritenour, D. C.; Masamune, S.; Kageyama, M.;
Tamura, T. J. Org. Chem. 1989, 54, 2817. (b) Claffey, M. M.; Heathcock,
C. H. J. Org. Chem. 1996, 61, 7646. (c) Paterson, I.; Oballa, R. M.;
Norcross, R. D. Tetrahedron Lett. 1996, 37, 8581. (d) Paterson, I.; Wallace,
D. J.; Gibson, K. R. Tetrahedron Lett. 1997, 38, 8911. (e) Evans, D. A.;
Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.; Rajapakse, H. A.;
Tyler, A. N. Tetrahedron 1999, 55, 8671. (f) Evans, D. A.; Fitch, D. M.;
Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033. (g) Paterson,
I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187. (h) Kulkarni, B. A.;
Roth, G. P.; Lobkovsky, E.; Porco, J. A., Jr. J. Comb. Chem 2002, 4, 56.
(i) Paterson, I.; Coster, M. J. Tetrahedron Lett. 2002, 43, 3285. (j) Sinz,
C. J.; Rychnovsky, S. D. Tetrahedron 2002, 58, 6561. (k) Schneider, C.;
Tolksdorf, F.; Rehfeuter, M. Synlett 2002, 2098. (l) Paterson, I.; Di
Francesco, M. E.; Ku¨hn, T. Org. Lett. 2003, 5, 599. (m) Hubbs, J.;
Heathcock, C. H. J. Am. Chem. Soc. 2003, 125, 12836. (n) Zhang, D.-H.;
Zhou, W.-S. Synlett 2003, 1817. (o) Paterson, I.; Britton, R.; Ashton, K.;
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I.; Coster, M. J.; Chen, D. Y.-K.; Oballa, R. M.; Wallace, D. J.; Norcross,
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Finally, the doubly stereodifferentiating aldol reactions of these
enolates were examined, giving us a unique opportunity to study the
absolute stereocontrol of the 1,5- versus 1,2-inductions (Scheme 3).
The aldol reaction of the lithium enolate of 917 with aldehyde 1117 in
DMF gave 12 with high selectivity (Scheme 3A). However, the
reaction of the lithium enolate of 9 with ent-11 gave 13 with low
selectivity (Scheme 3B). On the other hand, the aldol reactions of 10
with 11 and ent-11 gave 12 and 13, respectively, both with high
selectivity (Scheme 3C,D). Thus, under acidic conditions, 1,2-induction
predominates in both cases, while metalloenolate conditions give 1,5-
induction in competition with the 1,2-process (Scheme 3B).
In summary, we have developed (1) 1,5-syn-selective aldol
reactions of lithium enolates of ꢀ-super siloxy methyl ketones and
aldehydes in DMF; (2) 1,5-anti-selective aldol reactions of the
trimethylsilyl enol ethers of methyl ketones with aldehydes
catalyzed by Tf2NH in toluene; (3) a stereoselective synthesis of
1,3,5-triols syn/syn- and anti/anti-7 from syn-5a; and (4) a stereo-
selective synthesis of 1,3,5-triol syn/anti-7 from anti-5a. These
methods are advantageous in 1,5-stereoinduction, which can be
achieved from the same starting material, and all of the 1,3,5-triol
stereoisomers can easily be prepared. Applications of this meth-
odology in the synthesis of long-chain complex polyketides (Scheme
1) are currently under investigation.
´
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Acknowledgment. This work was supported by the Uehara
Memorial Foundation, the NIH (P50 GM086 145-01), and the
University of Chicago. We thank Antoni Jurkiewicz for his NMR
expertise.
(11) The use of the dicyclohexylboron enolate of substrate 1a with pivalaldehyde
gave a slightly lower anti selectivity (85:15).
(12) The reduction of anti-4a also gave a syn/anti product mixture in 89% yield
with high selectivity (91:9).
(13) Using the same procedure as reported to remove the Si(TMS)3 group. See:
(a) Brook, M. A.; Gottardo, C.; Balduzzi, S.; Mohamed, M. Tetrahedron
Lett. 1997, 38, 6997. (b) Brook, M. A.; Balduzzi, S.; Mohamed, M.;
Gottardo, C. Tetrahedron 1999, 55, 10027.
(14) Anwar, S.; Davis, A. P. Tetrahedron 1988, 44, 3761.
(15) The use of Me4NHB(OAc)3, SmI2/i-PrCHO, and DIBAL-H gave low yields
or low selectivities for anti/anti-8.
Supporting Information Available: Experimental procedures,
characterization of compounds 1a-d, 1a′-d′, 2a-d, syn-4a, anti-
1
4a-m, anti-5a, syn-5a-m, and 7-13, including their H NMR and
13C NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) The use of B(C6F5)3 as the Lewis acid instead of Sc(OTf)3 gave the 1,3,5-
syn/syn product as a single isomer. The relative configurations of products
5a, 7, and 8 were determined on the basis of the NMR spectra of these
related compounds (see the Supporting Information for full details).
(17) For the synthesis of aldehyde 11, see: Botuha, C.; Haddad, M.; Larcheveˆque,
M. Tetrahedron: Asymmetry 1998, 9, 1929. For the synthesis of ketone 9,
see ref 2b.
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