Enantioselective Addition of Alkynes to α,α-Dichlorinated Aldehydes

Article abstract of DOI:10.1021/acs.orglett.6b03692

Enantioselective addition of terminal alkynes to α,α-dichlorinated aldehydes employing Zn(OTf)₂/NME is disclosed. The propargylic alcohols obtained are accessed in good yields and high enantioselectivity from easily accessible α,α-dichloroaldeh

Full text of DOI:10.1021/acs.orglett.6b03692

Letter
pubs.acs.org/OrgLett
Enantioselective Addition of Alkynes to α,α-Dichlorinated Aldehydes
Yeshua Sempere Molina, Jonathan Ruchti, and Erick M. Carreira*
Laboratorium fur Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland
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* Supporting Information
ABSTRACT: Enantioselective addition of terminal alkynes to α,α-
dichlorinated aldehydes employing Zn(OTf)2/NME is disclosed. The
propargylic alcohols obtained are accessed in good yields and high
enantioselectivity from easily accessible α,α-dichloroaldehydes. The
method opens new strategic opportunities for the synthesis of chlorinated
natural products, such as the chlorosulfolipids.
here are numerous bioactive natural products that
The first addition of an alkyne to α,α-dichlorinated aldehyde
was reported by Maruoka and co-workers in 1998.11 They
employed an aluminum-based alkynylation using phenyl-
acetylene and 2,2-dichlorodecanal to give adducts as racemates.
An asymmetric version of this reaction was also disclosed using
aluminum alkoxides, although α,α-dichlorinated aldehydes were
not tested.12
In approaching the methodological studies described herein,
the strong electrophilic nature and low stability of these
aldehydes were of concern, in particular, whether the initial
conditions reported for the sole example of Zn-mediated
addition4a would be extendable to other substrates. Addition-
ally, we were interested in investigating whether the additions
would give rise to adducts that in turn would be amenable to
further synthetic elaboration.
The α,α-dichlorinated aldehydes in this study were
synthesized from the corresponding aldehydes via dichlorina-
tion of their enamines following a known procedure.13,14
However, they were not amenable to purification by silica gel
chromatography, and accordingly, they were either purified by
distillation or used without purification. We were pleased to
find that conditions employed in the mytilipin B synthesis4a
could be employed with a wide range of substrates, as shown in
Scheme 2.
sp3-bound chlorides.1 These have served as
a source of inspiration for the development of methods
enabling their stereoselective synthesis.2 An often-occurring
structural motif in chlorinated lipids is gem-dichlorides in
proximity to a stereogenic center, such as a secondary alcohol.
We have previously reported the implementation of ZnII-
mediated enantioselective alkyne additions to aldehydes3 in the
total synthesis of undecachlorosulfolipid A, also known as
mytilipin B (Scheme 1).4,5 Herein, we document that the
reaction can be extended to a collection of other α,α-
dichloroaldehydes to furnish products in useful yields and
high enantiocontrol.
Tincorporate C
Scheme 1. Example of Asymmetric Addition of an Alkyne to
a Dichlorinated Aldehyde in the Synthesis of Mytilipin B
This method exhibits wide substrate scope and is compatible
with various functional groups on both the alkyne and the
aldehyde moieties (Scheme 2). The 1H NMR of the unpurified
product always showed conversion to a greater extent than
85%.15 The method shows tolerance for a wide range of
protecting groups and functional groups, including primary
chlorides. The configuration of product 3c was confirmed by X-
ray crystallography, and for all other adducts, the absolute
configurations were determined by analogy.16 In the study, the
addition to give 3c was carried out at 1 mmol scale to give
products in equally high yield and selectivity, consistent with
the use of the reaction in the total synthesis of mytilipin B.
The method tolerates olefins (3d) and arenes in the aldehyde
substrate (3e), giving good results in yields and enantiose-
The presence of chiral propargylic alcohols in synthetic
routes to natural products and pharmaceuticals makes them
highly valuable buildings blocks.6 Various methods for the
asymmetric synthesis of propargylic alcohols have been
disclosed. These include direct addition of metalated
nucleophilic acetylenes to prochiral aldehydes7 or the
asymmetric reduction of alkynyl ketones.8 Since the ZnII-
mediated enantioselective addition of alkynes to aldehydes was
described by our group,3 there has been widespread use of this
method by the synthetic community.9 This simple and mild
reaction constitutes a powerful means to access intermediates
employed in the synthesis of complex molecules.10
Received: December 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
A range of functionalized alkynes was also examined, and the
appended side chains serve as a second point for further
synthetic elaboration of the products. In this regard, the
substitution in the α-position to the alkyne moiety was well
tolerated to furnish adducts in up to 96% ee and in good yields
(3h,i,k−n). Likewise, the alkyne can bear an ether or silyl ether
group without any adverse effect on enantioselectivity (for
example, 3b, 3g, or 3j). However, when free alcohols were
present in the alkyne the reaction did not proceed well (yields
lower than 40%). The use of 6-chloro-1-pentyne (1f)
demonstrates that primary chlorides can be present in both
fragments of the molecule.
Scheme 2. Asymmetric Alkynylations of α,α-Dichlorinated
Aldehydes
a,b
In summary, we have disclosed a substantive expansion of the
ZnII-mediated asymmetric addition of alkynes to include
additions to α,α-dichlorinated aldehydes, which proceed to
furnish adducts in greater than 86% ee. The scope as well as
attendant yield and enantiomeric excesses observed are
promising for the application of the method in the synthesis
of a variety of chlorinated natural products.
ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03692.
Experimental procedures, characterization data, and
NMR spectra (PDF)
X-ray data for compound 3c (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: carreira@org.chem.ethz.ch.
ORCID
Yeshua Sempere Molina: 0000-0002-4953-4666
Erick M. Carreira: 0000-0003-1472-490X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dr. Nils Trapp (ETH Zurich) and Michael Solar (ETH Zurich)
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are acknowledged for X-ray analysis. Mr. Roger Geisser and Mr.
Christian Nilewski of ETH Zurich are acknowledged for the
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initial prospecting experiments.
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■
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