Rapid, one-pot synthesis of β-siloxy-α-haloaldehydes

Article abstract of DOI:10.1021/ja2066169

The Mukaiyama cross-aldol reaction of α-fluoro-, α-chloro-, and α-bromoacetaldehyde-derived (Z)-tris(trimethylsilyl)silyl enol ethers is described, furnishing anti-β-siloxy-α-haloaldehydes. A highly diastereoselective, one-pot, sequential double-aldol process is developed, affording novel β,δ-bissiloxy-α,γ-bishaloaldehydes. Reactions are catalyzed by C₆F₅CHTf₂ and C ₆F₅CTf₂AlMe₂ (0.5-1.5 mol %) and provide access to halogenated polyketide fragments.

Full text of DOI:10.1021/ja2066169

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Rapid, One-Pot Synthesis of β-Siloxy-r-haloaldehydes
Jakub Saadi,† Matsujiro Akakura,‡ and Hisashi Yamamoto*,†
†Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
‡Department of Chemistry, Aichi University of Education, Igaya-cho, Kariya, Aichi 448-8542, Japan
S Supporting Information
b
Scheme 1. Synthesis of the Halogenated Silyl Enol Ethers
ABSTRACT: The Mukaiyama cross-aldol reaction of R-
fluoro-, R-chloro-, and R-bromoacetaldehyde-derived (Z)-
tris(trimethylsilyl)silyl enol ethers is described, furnishing
anti-β-siloxy-R-haloaldehydes. A highly diastereoselective,
one-pot, sequential double-aldol process is developed, af-
fording novel β,δ-bissiloxy-R,γ-bishaloaldehydes. Reac-
tions are catalyzed by C6F5CHTf2 and C6F5CTf2AlMe2
a Z/E ratio based on integration of the 1H NMR signals of crude
material.
(0.5ꢀ1.5 mol %) and provide access to halogenated poly-
ketide fragments.
ecently our group has actively developed a highly efficient
methodology employing catalytic, sequential one-pot
R
Mukaiyama aldol reactions of “super-silyl” [tris(trimethyl-
silyl)silyl, TTMSS] enol ethers.1 High steric shielding pro-
vided by the super-silyl group and its unique electronic
properties allowed us to tame the reactivity of an acetalde-
hyde-derived enol ether in mono, double,1a,c,e,f and triple1g
cross-aldol processes. Furthermore, it enabled spectacularly
rapid construction of a few naturally occurring polyketides.1c,i
The prospect of introducing halogen atoms into these biolo-
gically relevant structures seems especially exciting, as halo-
gens often have a high impact on a molecule’s activity in biological
settings.2 Recently, halogenated polyketide-like structures have also
received a lot of attention among the synthetic community.3
In addition, halogen atoms could also be potentially exploited as
chemically reactive functional groups as a means to introduce more
complex functionalities.
1
aYield and dr based on integration of the H NMR signals of crude
material.
and with excellent anti stereoselectivity (eq 1).
Further experiments indicated that the conditions established
for benzaldehyde work well with various aromatic aldehydes;
however, reactions with aliphatic aldehydes proved sluggish.
Thus, we performed an additional screening of other potential
catalysts for this reaction to also enable high reactivity with
aliphatic aldehydes. Gratifyingly, pentafluorophenylbis(triflyl)-
methane8 (0.5 mol %) afforded the desired R-chloroaldehyde
from octanal in good yield and excellent anti stereoselec-
tivity (eq 2).
Herein, we describe the first cross-aldol reactions of
R-haloacetaldehyde-derived silyl enol ethers, affording
β-siloxy-R-haloaldehydes4ꢀ6 with excellent anti-stereoselec-
tivities, and the first sequential double-aldol reaction of such
enol ethers, furnishing novel β,δ-bissiloxy-R,γ-bishaloalde-
hydes in a one-pot reaction.
aIsolated yield of the corresponding alcohols obtained after NaBH4
reduction. Dr based on integration of the H NMR signals of crude
material obtained after NaBH4 reduction.
b
1
The halogenated silyl enol ethers 3aꢀc were prepared via
highly stereoselective rearrangement of lithium carbenoid
species7 generated from readily available silylated trihaloethanols
2aꢀc (Scheme 1).
Employing the conditionsoptimized for antiselectivity, wehave
systematically prepared a series of anti-β-siloxy-R-haloaldehydes
4ꢀ17 using the starting materials 3aꢀc (Table 1). Most aromatic
aldehydes reacted smoothly with compounds 3aꢀc, affording
products in good yields and excellent stereoselectivities. Sterically
hindered 2-methylbenzaldehyde afforded products 6aꢀc. Halides
at the 2-, 3-, and 4-positions were very well tolerated, giving
products 7ꢀ9. 4-Nitro- and 4-trifluoromethyl-substituted
With the starting materials in hand, we screened for the
best reaction conditions using benzaldehyde and 3b as model
substrates and 0.3 mol % HNTf2 as catalyst (eq 1). The
reaction in dichloromethane afforded the desired R-chloro-
aldehyde with high efficiency but with modest diastereose-
lectivity. Remarkably, switching the solvent to toluene fur-
nished the 3-siloxy-2-chloro-3-phenylpropanal quantitatively
Received: July 15, 2011
Published: August 04, 2011
r
2011 American Chemical Society
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|

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Table 1. Aldol Reactions with Siloxy-vinyl Halides 3aꢀca
Table 2. One-Pot Sequential Reactions with
r-Haloaldehydes
a All reactions performed directly on crude mixtures of R-haloaldehyde;
therefore, yields are given over two steps. b Yields of isolated material.
1
c Dr based on integration of the H NMR signals of crude material.
d Purified directly; dr of isolated material.
of acetone, as well as with acetone silyl enol ether, furnished the
desired δ-chloro-β-hydroxyketones 21 and 22 with good yields
and good, complementary antiꢀanti and synꢀanti stereoselec-
tivities, respectively. Reaction of 4b with RawalꢀKozmin’s
diene12 smoothly afforded the hetero-DielsꢀAlder product 23
as a single stereoisomer.
a Yields of isolated alcohols after NaBH4 reduction. Dr based on
integration of the 1H NMR signals of crude alcohols. b Reaction
conditions for 5b0 and 15b0: C6F5C(Tf)2AlMe2 (1.5 mol %), CH2Cl2,
ꢀ78 °C to RT, 8 h.
Taking advantage of the unique reactivity enabled by the super-
silyl group, we tried to expand this reaction to the sequential double
Mukaiyama aldol reaction with the halogenated silyl enol ethers in a
single pot. Remarkably, the second aldol step works exclusively in
dichloromethane rather than toluene. Thus, after the first aldol
reaction (anti-selective), the toluene was evacuated under vacuum
from the crude R-haloaldehyde reaction mixtures, followed by the
addition of 1.5 equiv of a second halogenated silyl enol ether in
dichloromethane at ꢀ78 °C. Addition of freshly prepared C6F5C-
(Tf)2AlMe2 (1.5 mol %) was essential to ensure good yields.
The results are summarized in Table 3. Novel β,δ-bis-
siloxy-R,γ-bishaloaldehydes 24ꢀ31 having four stereocenters
were isolated with remarkably high stereoselectivities. Signifi-
cantly, this sequential process offers the possibility to introduce
two different halogen atoms into the polyketide fragment in a
regiocontrolled fashion. The secondaldol addition of(Z)-halosilyl
enol ether to the mono-aldol intermediates is, as expected, Felkin-
selective and furnishes synꢀsynꢀanti-configured products.9ꢀ11
Amazingly, if both aldol steps were performed only in
dichloromethane as solvent, all-syn product 32 was obtained in
high diastereoselectivity and good yield; this was probably due to
benzaldehyde reacted remarkably efficiently and selectively
(products 10 and 11). Electron-rich 4-methoxybenzaldehyde and
heterocyclic 2-furylcarboxyaldehyde gave R-haloaldehydes 12 and 13
with high stereoselectivity and slightly lower yields. Racemic 2-phe-
nylpropanal afforded mixtures of stereoisomers 14aꢀc in good
yields and stereoselectivities. Cyclohexylcarboxyaldehyde afforded
15a,b with very good anti/syn ratios but only moderate yields.
Reaction of octanal and pivaloaldehyde with 3b furnished chlori-
nated 16b and 17b with excellent stereoselectivities. Pivaloaldehyde
also reacted well with 3a, but the fluorinated product 17a was formed
with only moderate stereoselectivity. In addition, two syn-selective
aldol reactions were accomplished in dichloromethane using alumi-
num catalyst (see Table 1, footnote b), giving products 5b0 and 15b0,
albeit with moderate diastereoselectivities.
Next, a few possibilities of subsequent, one-pot transform-
ations of the obtained β-siloxy-R-haloaldehydes were briefly
investigated (Table 2). Addition of vinyl and aryl Grignard
reagents to 6c and 17b was very efficient, furnishing pro-
ducts 18ꢀ20 in good yields and quite unexpected synꢀanti
diastereoselectivities.9ꢀ11 Reaction of 4b with the lithium enolate
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Table 3. One-Pot Sequential Double-Aldol Reactionsa
stereoselective construction of novel halogenated polyketide-like
fragments. The first aldol addition of the (Z)-halo silyl enol
ethers furnishes anti-β-siloxy-R-haloaldehydes. The subsequent
addition is Felkin-selective and yields synꢀsynꢀanti-configured
β,δ-bissiloxy-R,γ-bishaloaldehydes. Moreover, by switching sol-
vent, all-syn double-aldol product was also obtained.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures;
b
1
characterization of all compounds shown, including their H,
13C, and if applicable 19F NMR spectra; crystallographic data;
computational details; and complete ref 15. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
yamamoto@uchicago.edu
a Yields of isolated alcohols after NaBH4 reduction. Dr based on
’ ACKNOWLEDGMENT
integration of the 1H NMR signals of purified alcohols.
This work was supported by the NIH (grant P50 GM086 145-01).
J.S. thanks the Deutsche Forschungsgemeinschaft for a post-
doctoral fellowship (Sa 2108/1-1). The authors thank
Dr. Ian Steele for X-ray crystallography and Dr. Antoni Jurkiewicz
for NMR expertise. The computations were performed using the
Research Center for Computational Science, Okazaki, Japan.
the exceptionally efficient kinetic resolution of the initially
formed mono-aldol product (eq 3).13
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