Hydrometallation-asymmetric conjugate addition: Application to complex molecule synthesis

Article abstract of DOI:10.1039/c2cc37155c

Copper catalysis allows alkyl zirconium species, generated in situ from alkenes, to undergo conjugate addition reactions. A hydrometallation-catalytic asymmetric 1,4-addition was used to synthesize either enantiomer of a natural product in one step from commercially available materials. Hydrometallation- addition sequences applied to steroids containing a cross-conjugated dienone or 1,6-acceptor give highly functionalized products.

Full text of DOI:10.1039/c2cc37155c

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Hydrometallation-asymmetric conjugate addition:
application to complex molecule synthesis†‡
Cite this: Chem. Commun., 2013,
49, 4211
Rebecca M. Maksymowicz, Philippe M. C. Roth, Amber L. Thompsony and
Stephen P. Fletcher*
Received 1st October 2012,
Accepted 19th November 2012
DOI: 10.1039/c2cc37155c
www.rsc.org/chemcomm
Copper catalysis allows alkyl zirconium species, generated in situ compound isolated from the New Zealand liverwort Balantiopsis
from alkenes, to undergo conjugate addition reactions. A hydro- rosea.8 Using the conditions shown in Scheme 1, natural (ꢀ)-1
metallation-catalytic asymmetric 1,4-addition was used to synthe- was synthesized in one step (53% yield, 95% ee) using catalyst
size either enantiomer of a natural product in one step from (S,S,S)-A at 0 1C. These conditions gave slightly better results
commercially available materials. Hydrometallation-addition than experiments carried out at room temperature (37%, 90% ee).
sequences applied to steroids containing
a cross-conjugated The unnatural enantiomer of the natural product ((+)-1) was
dienone or 1,6-acceptor give highly functionalized products.
synthesized (one step, 45% yield, 94% ee) using the other
enantiomer (R,R,R, not shown) of the catalyst complex.‡ The
The copper-catalyzed asymmetric 1,4-addition of unstabilized CD spectrum of (ꢀ)-1,‡ is consistent with the natural material8
alkyl nucleophiles such as Grignard reagents, dialkylzincs and and the absolute configuration shown.9
alkyl aluminiums has emerged as a powerful method for
We decided to examine the method on more challenging
forming C–C bonds.1–4 We recently reported that alkenes can substrates – commercially available steroids that contain
be used as equivalents of premade alkylmetal species in additional functional groups, which could potentially interfere
catalytic asymmetric reactions via a process where an alkene with conjugate addition processes (Fig. 1). 1,4-Androstadiene-
undergoes hydrometallation, and the resulting organometallic 3,17-dione (2) is a cross-conjugated dienone capable of 1,4-
species is used as a nucleophile in conjugate additions addition reactions, 1,2-additions to the dienone and ketone
(eqn (1)).5 Using the
moieties, as well as other possibilities, such as rearrangement.
Canrenone 3, contains a lactone, and is capable of 1,2-, 1,4-,
and 1,6-addition reactions. The products of hydrometallation-
addition to 2 and 3 would be functionalized steroids, which are
valuable compounds, for example cholesteryl benzoate was the first
compound found to form chiral nematic liquid crystals,10 and
fulvestrant (Faslodex)11 is an established breast cancer drug.11–14
Hydrometallation-addition of 1-hexene to 2, catalyzed by
copper complex (S,S,S)-A at room temperature, was found to
ð1Þ
Schwartz reagent6 as the hydrometallating agent, the resulting
alkyl zirconium species7 undergo copper-catalyzed enantio-
selective 1,4-addition at room temperature.5 Here, we explore
the application of this approach in the context of complex
molecule synthesis.
We selected 1 as a simple target, for proof of concept that
natural products could be synthesized using hydrometallation-
asymmetric conjugate addition (HM-ACA). 1 is an aromatic
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
12 Mansfield Road, Oxford OX1 3TA, UK. E-mail: stephen.fletcher@chem.ox.ac.uk;
Tel: +44 (0)18652 75642
† This article is part of the ChemComm ‘Emerging Investigators 2013’ themed
issue.
‡ Electronic supplementary information (ESI) available: Materials and methods,
all procedures, characterization data and spectra. CCDC 904095. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2cc37155c
§ To whom correspondence regarding the X-ray crystallography should be
addressed.
Scheme 1 One step synthesis of natural (ꢀ)-1 and its enantiomer (+)-1.
Chem. Commun., 2013, 49, 4211--4213 4211
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Fig. 1 Selected steroid derivatives.
proceed in a 1,4-fashion to give a crude B3.5 : 1 ratio¶ of
diastereoisomers in favour of the 1-a-isomer 4, which was
isolated in 50% yield by flash column chromatography
(Scheme 2). The 1-b-isomer could also be isolated in 16% yield.
Hydrometallation-addition of functionalized alkenes to 2 illustrates
that reactive functional groups such as bromides and benzyl
chlorides are tolerated (see compounds 5 and 6).
In the case of canrenone 3, hydrozirconation of 1-hexene,
followed by (S,S,S)-A catalyzed addition, favoured8 the a-1,6-
addition product 7, which was isolated in 59% yield. A minor,
b-isomer, 1,6-addition product could also be isolated in
21% yield.
We examined the possibility of adding functionalized
alkenes to canrenone, and found that, while the yields are
lower, alkenes and styrenes bearing reactive groups are surpris-
ingly well tolerated. These reactions give steroids containing
groups that should be useful handles for further derivatization –
primary alkyl bromides (8), benzyl chlorides (9), and boronic
esters (10). In the case of benzyl chloride 9 single crystal X-ray
diffraction studies** confirmed the stereochemistry of the
product (Fig. 2).
The addition of hard organometallic nucleophiles to steroids
in 1,4-additions to cross conjugated enones15–18 and 1,6-addition
processes,19–23 has previously been reported, but as far as we
are aware, the functional group compatibility of reported
procedures is much more limited than demonstrated
here.11,12,15–23 In comparison to relevant procedures, the hydro-
metallation – addition approach is operationally simple,
convenient, and tolerates important functional groups – factors
that may make these procedures useful24,25 in the synthesis of
Scheme 2 1,4- and 1,6-addition reactions to steroids. Conditions: alkene
(2.5 eq.), Cp2ZrHCl (2 eq.), CH2Cl2;(S,S,S)-A (10 mol%), steroid (1 eq.), Et2O, room
a
temperature. Crude diastereomeric ratio determined by 1H NMR spectroscopy.
b
Isolated yields.
medically important derivatives. We are also unaware of any We applied a hydrometallation-asymmetric conjugate addition
reported procedures that use alkenes as the equivalents to sp3 sequence in the highly enantioselective one-step synthesis of a
hybridized nucleophiles in conjugate addition reactions to natural product. In the case of unsaturated steroids we
steroids.
examined a hydrometallation-addition sequence and found
In conclusion, we have used alkenes as equivalents to that copper catalyzed conjugate addition reactions readily
premade alkyl-metal species in conjugate addition reactions. occur, and functional groups are tolerated.
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** Single crystal X-ray diffraction data were collected at 150 K with an
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