β-siloxy-α-haloketones through highly diastereoselective single and double mukaiyama aldol reactions

Article abstract of DOI:10.1002/chem.201204493

Double-action haloketones: A super silyl group enabled the first highly diastereoselective Mukaiyama aldol reactions of α-chloro- and α-fluoroketones with a wide range of aldehydes, providing anti-β-siloxy-α-haloketones. This process is compatible with one-pot double-aldol methodology and allows for rapid access to new halogen-modified polyketide fragments bearing up to four contiguous stereocenters (see scheme). Copyright

Full text of DOI:10.1002/chem.201204493

DOI: 10.1002/chem.201204493
b-Siloxy-a-haloketones through Highly Diastereoselective Single and Double
Mukaiyama Aldol Reactions
Jakub Saadi and Hisashi Yamamoto*[a]
Halogens, in particular, fluorine and chlorine play a pivo-
tal role in modern medicinal chemistry due to their strong
impact on the biological properties of organic molecules.[1]
In nature, organohalogens are mainly chlorine compounds
of marine origin, and many of them exhibit potent antiproli-
ferative or antibiotic properties.[2] Recently, synthetic chem-
ists turned their attention to chlorosulfolipids[3,14j] due to
their unclear biological role and curious architecture resem-
bling polyketides, which are a class of natural products that
hold a prominent position among pharmaceuticals.[4] For
these reasons, it seems especially attractive for future medic-
inal research to develop efficient synthetic methods for the
preparation of stereodefined, halogen-modified polyketide
structures. b-Oxy-a-haloketones, which are valuable inter-
mediates of epoxyketones,[5,13e,l] natural products,[6] heterocy-
cles,[7] and carbohydrate mimetics,[8] could also be very
useful building blocks for the above-mentioned task. Espe-
cially, terminal methyl ketones may potentially be utilized
as a convenient linchpin for interconnection with aldehyde
fragments, to efficiently gain molecular complexity through
bi-directional assembly of polyketide subunits.[14hÀi] Methods
for the preparation of b-oxy-a-haloketones to date include:
aldol reactions of metal enolates, which are especially effi-
cient and selective with bulkier ketones,[5,7b,9] Mukaiyama-
aldol reactions, which unfortunately generate only dia-
lent regio- and diastereoselectivities by rearrangement of
lithium carbenoid species[10a] generated from “super-silyl”-
protected trichloromethyl alcohols 1a–b, which are readily
available by the nucleophilic addition of chloroform to alde-
hydes[16a] or equivalents thereof[16b–c] (Scheme 1). The fluo-
Scheme 1. Synthesis of a-haloketone-derived silyl enol ethers. The Z/E
ratio is based on integration of the 1H NMR spectroscopic signals of the
crude material (Si=SiACTHNUTRGEN(UNG SiMe3)3).
rine-containing silyl enol ether 2c was prepared directly
from fluoroketone 3, which was accessible by sequential
monodefluorinaton[16d] of trifluoroacetophenone (Scheme 1).
In an analogous fashion, we have also prepared chloro-
AHCTUNGTREGaNNNU cetone-derived silyl enol ethers bearing few other common
silyl groups, and briefly compared their performance in the
acid-catalyzed aldol reaction with benzaldehyde under con-
ditions optimized previously for similar reactions
(Table 1).[14j] Results clearly show the superiority of the
super silyl group, which was essential for providing the prod-
uct in excellent diastereoselectivity and yield.
ACHTUNGTRENNUNG
stereoisomeric mixtures,[10] oxyhalogenation of certain unsa-
turated ketones,[11] enzymatic,[12] and organocatalytic[13] aldol
reactions, which are particularly useful for conversion of
aromatic aldehydes. Despite tremendous progress in this
field, a truly flexible and highly diastereoselective method
to access simple chloroacetone aldol products is still re-
quired.
Table 1. Influence of the silyl group on the aldol reaction.
Herein, we describe the first highly diastereoselective Mu-
kaiyama aldol reaction of chloroacetone and fluoroaceto-
phenone, as well as the implementation of these substrates
into the one-pot sequential-aldol protocol.[14]
Entry
R
Yield [%][a]
d.r.[a]
a-Chloroketone-derived “super-silyl” (tris(trimethylsilyl)-
silyl, TTMSS) enol ethers 2a–b were prepared[15] with excel-
1
2
3
4
Me
Et
iPr
SiMe3
54
74
82
97
60:40
68:32
86:14
99:1
[a] Dr. J. Saadi, Prof. Dr. H. Yamamoto
Department of Chemistry, The University of Chicago
5735 South Ellis Avenue, Chicago, IL 60635 (USA)
Fax : (+1)773-702-5059
[a] Yield and d.r. by integration of the 1H NMR spectroscopic signals of
the crude material.
With the starting materials in hand, we systematically ex-
plored the scope of the Mukaiyama aldol reaction with silyl
enol ether 2a, which reacted smoothly with a remarkably
E-mail: yamamoto@uchicago.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204493.
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COMMUNICATION
Table 2. Synthesis of b-siloxy-a-chloroketones.[a]
with excellent diastereoselectivities and in very good yields.
The chloroacetaldehyde furnished bishalogenated 10 in very
good yield and with a diatstereomeric ratio (d.r.) of 10:1.
The 2-phenylpropanal provided 11a containing three contig-
uous stereocenters with a remarkably high diastereoselectiv-
ity. The reaction was also applicable to a,b-unsaturated and
heterocyclic aldehydes giving products 12–15 in good yields
and with excellent diastereoselectivities. Indole-2-carboxyal-
dehyde, bearing an unprotected indole nitrogen atom, re-
quired two equivalents of enol ether to achieve the full con-
version to 16, albeit with only a 6:1 d.r.. Aromatic alde-
hydes, regardless of their steric or electronic properties, re-
acted very smoothly with 2a affording products 17–30 in
good to excellent yields and with excellent diastereoselectiv-
ities.
To further demonstrate the flexibility of this method, piv-
alaldehyde, 2-naphthaldehyde, methyl benzaldehyde-4-car-
boxylate, and 3,5-dibromobenzaldehyde were reacted with
the silyl enol ether 2c yielding fluorinated ketones 31–34,
respectively. Furthermore, benzaldehyde was also reacted
with the silyl enol ether 2b, furnishing chlorinated heptyl
ketone 35 (Table 3). Silyl enol ethers 2b and 2c showed sim-
ilarly good reactivity to 2a, albeit the corresponding prod-
ucts were afforded with slightly eroded diastereoselectivi-
ties.
Table 3. Synthesis of b-siloxy-a-haloketones.[a]
[a] Yields of isolated ketones are shown. The d.r. is based on integration
of the 1H NMR spectroscopic signals of the crude reaction mixture (Si=
SiACTHNUTRGNE(UNG SiMe3)3).
[a] Yields of isolated ketones are shown. The d.r. is based on the integra-
tion of the 1H NMR spectroscopic signals of the crude reaction mixture
(Si=Si
dition to 2-phenylpropanal,[14a,f,k] we expect 11 to be the anti,syn dia-
stereoisomer; however, the stereochemical assignment was not per-
formed in this case. [c] Two equivalents of the silyl enol ether 2a were
used.
ACHTUNGTRENNUNG(SiMe3)3). [b] From previous examples of super-silyl enol ether ad-
Finally, we set out to establish if halogenated ketone-de-
rived silyl enol ethers could be implemented into the one-
pot sequential aldol reaction[14] and thus provide a rapid
access to a new type of halogen-modified polyketide frag-
ment. To demonstrate the utility of this protocol silyl enol
ethers derived from chloro- and fluoroacetaldehyde[14j] and
propanal[14k] were chosen as partners in the first aldol step.
To our delight, the one-pot sequential reaction of the thus
preformed anti-3-siloxy-2-functionalized aldehydes with 2a
or 2c as second aldol partners provided new syn,syn,anti-
configured 3,5-bissiloxy-2,4-bishaloketones 36–42 and a 3,5-
ACHTUNGTRENNUNG
broad range of aldehydes, furnishing b-siloxy-a-chloroke-
tones 4–30 with exceptionally high anti-diastereoselectivities
(Table 2).
Reactions with propanal and longer-chain, as well as bulk-
ier, a-branched aliphatic aldehydes afforded products 4–9
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H. Yamamoto and J. Saadi
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Acknowledgements
This work was supported by the NIH (P50 GM086 145-01) and the Uni-
versity of Chicago. J.S. is grateful to the Deutsche Forschungsgemein-
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Keywords: aldol
diastereoselectivity · haloketones · polyketides
reactions
·
cascade
reactions
·
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Single and Double Mukaiyama Aldol Reactions
COMMUNICATION
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Received: December 17, 2012
Published online: February 19, 2013
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