Sequential enolboration/hydroformylation/aldol addition: A new one-pot cascade reaction for the regio- and diastereoselective formation of carbocyclic quaternary centres from acyclic olefins

Article abstract of DOI:10.1039/b405120c

Starting from unsaturated carbonyl compounds a mild new cascade reaction involving enolboration, rhodium-catalysed hydroformylation and intramolecular aldol addition in a regio- and diastereoselective fashion leads to cyclic compounds containing highly-functionalised quaternary carbon centres.

Full text of DOI:10.1039/b405120c

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Sequential enolboration/hydroformylation/aldol addition: a new
one-pot cascade reaction for the regio- and diastereoselective
formation of carbocyclic quaternary centres from acyclic olefins†
Mark D. Keränen and Peter Eilbracht*
Fachbereich Chemie, Organische Chemie I, Universität Dortmund, Otto-Hahn-Str. 6,
D-44227 Dortmund, Germany. E-mail: peter.eilbracht@udo.edu; Fax: ϩ49 (0)231 755 5363;
Tel: ϩ49 (0)231 755 3857
Received 5th April 2004, Accepted 17th May 2004
First published as an Advance Article on the web 25th May 2004
Starting from unsaturated carbonyl compounds a mild
new cascade reaction involving enolboration, rhodium-
catalysed hydroformylation and intramolecular aldol
addition in a regio- and diastereoselective fashion leads
to cyclic compounds containing highly-functionalised
quaternary carbon centres.
An initial experiment was performed with dimethyl allyl-
malonate 3, which was exposed to standard conditions for
stereoselective E(O)-enolboration11 prior to a regioselective
n-hydroformylation in the presence of XANTPHOS12 ligand
to afford after oxidative workup dimethyl 2-hydroxy-cyclo-
pentane-1,1-dicarboxylate (7) in 51%, a result which further
extends the scope of the (cy-hex)2BCl/Et3N reagent com-
bination to include activated esters such as malonates.13 Now
that the conditions required for enolboration were determined
to be compatible with those required for regioselective hydro-
formylation, we proceeded to test whether the same protocol
was successful with ketoester 4 (Scheme 1). After oxidative
workup, the fragrant and volatile methyl 1-acetyl-2-hydroxy-
cyclopentane-carboxylate (8) was isolated as the sole product
in 50% yield as a 1.6 : 1 mixture of diastereoisomers as detected
by NMR (see Scheme 1).‡
The construction of quaternary carbon centres that retain a
high amount of neighboring functionality is a persistent goal in
natural product synthesis, since a good number of highly oxy-
genated, biologically active molecules like forskolin (1) (AB-
fusion) and ingenol (2) (ABC-fusion) possess these particular
structural characteristics. Methods resulting in the formation
of quaternary carbon centres are numerous, but if desiring to
perform this transformation in a diastereoselective1 or enantio-
selective2 fashion the number of available strategies drastically
decreases. Therefore, in the realm of total synthesis, new
methods resulting in the stereoselective formation of quater-
nary carbon centres are always in demand.
Scheme 1 Conditions 1.05 eq (cy-hex)2BCl, 1.05 eq. Et3N, 0 ЊC, 0.9
mol% Rh(CO)2(acac), 1.8 mol% XANTPHOS, 16 h, 60 bar CO/H2,
80 ЊC.
In our continuing investigations of C–C bond forming
reactions in tandem with Rh-catalysed hydroformylation,3
we extended our efforts to approach the issue of obtaining
carbocycles of various ring sizes bearing such functionality
via intramolecular regio- and diastereoselective aldol processes
following a regioselective n-hydroformylation in a one-pot
cascade reaction.
The absence of a 7-membered ring adduct showed that under
the conditions chosen, the enolboration does indeed proceed
with complete regioselectivity to form the α,α-disubstituted
boron enolate.14 Additionally, this cascade reaction is accom-
panied by a small but significant degree of diastereoselectivity
in the aldol addition. As depicted in Scheme 2, the amount of
1,3-diaxial interactions leading to the minor diastereoisomer is
reduced in the ring-flipped chair transition state affording the
major diastereoisomer.
In order to accomplish this feat, alternatives to the known
acid-catalysed and Mukaiyama variants4 of activation towards
aldol addition under hydroformylation conditions were neces-
sary because of selectivity problems present when using
compounds bearing more than one enolisable site. With this
problem in mind, we explored the use of dialkylboron enolates,
as they are known to affect high degrees of selectivity in
intermolecular aldol additions.5
Malonate 36 and the ketoesters 47 and 68 used in this study
were prepared through the use of proven literature methods
starting from dimethyl malonate or methyl acetoacetate.9
Ketoester 510 was prepared via Barbier-type addition of prenyl
bromide to ethyl cyano-acetate followed by methylation.
† Electronic supplementary information (ESI) available: Full analytical
data for all new compounds and NOE experiments conducted with 10.
See http://www.rsc.org/suppdata/ob/b4/b405120c/
Scheme 2 Transition states responsible for the observed diastereo-
selectivity in 5-membered ring formation.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 8 8 – 1 6 9 0
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
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Next, the generation of 6- and 7-membered ring carbocycles
was attempted by applying the same conditions to ketoesters 5
and 6. In the case of 5, the desired cyclization product ethyl
of 5-, 6-, and 7-membered carbocycles bearing functionalised
quaternary carbon centres starting from easily available
unsaturated carbonyl compounds. The generation of the alde-
hyde from its olefin precursor allows for the initial enolboration
of the preexisting carbonyl group to proceed selectively, which
circumvents the more laborious construction of protected alde-
hyde substrates necessary to accomplish this transformation
via intramolecular Lewis acid-mediated acetal cyclisation tech-
niques.16 Notably, the boron enolate tolerates the hydroformyl-
ation conditions and reacts immediately with the aldehyde
group, thus preventing unwanted side reactions.
6-hydroxy-1,3,3-trimethyl-2-oxo-cyclohexanecarboxylate
(9)
was obtained in 82% isolated yield as a 2.5 : 1 mixture of
diastereoisomers. This product is potentially useful as a stereo-
defined building block, offering direct access to the A-ring
system of forskolin (1) in one step.
Another encouraging result was obtained when ketoester 6
was subjected to the same conditions, resulting in the formation
of the 7-membered ring of methyl 2-hydroxy-1-methyl-7-oxo-
cycloheptane-carboxylate (10) as the sole product in 89% yield
as a 6 : 1 mixture of diastereoisomers (Scheme 3). The suitability
of this method to form functionalized β-hydroxycyclo-
heptanones bearing α-quaternary centres in high yields and
good diastereoselectivities is particularly attractive, since stereo-
selective methods leading to substituted 7-membered rings—
such as the central B-ring of ingenol (2)15—are much less
commonplace.
Acknowledgements
Many thanks for performing the NOE studies go to
Dr. Burkhard Costisella of the Universität Dortmund. We
thank Bayer AG, Leverkusen and Degussa AG, Düsseldorf
for donation of chemicals, and the Deutsche Forschungs-
gemeinschaft for financial support.
Notes and references
‡ Procedure for sequential enolboration/hydroformylation/aldol addition
reactions. Et3N (1.05 eq. to carbonyl compound) was pre-complexed
under an argon atmosphere with (cy-hex)2BCl (1.05 eq.) in dry CH2Cl2
(5 mL) at 0 ЊC for 15 min. The unsaturated carbonyl compound in
approx. 1 mL of solvent was then added slowly via syringe and the
enolboration was allowed to stir for an additional 30 min before being
transferred into the autoclave containing 0.9 mol% Rh(CO)2(acac),
10–15 mL of solvent and 1.8 mol% XANTPHOS. The autoclave was
then pressurised to 60 bar with equal pressures of CO and H2 CAU-
TION! and heated overnight to 80 ЊC. Upon cooling the autoclave to
RT, the reaction mixture was removed and concentrated under reduced
pressure. Enough MeOH was added to dissolve the solid residue (∼25
mL) along with 2 mL of conc. pH 7 phosphate buffer and 1 mL of 30%
H2O2, and the reaction was allowed to stir overnight before being
extracted with ether (100 mL), washed with sat. aq. NaHCO3 (1 × 75
mL), dried and concentrated prior to further purification when neces-
sary via flash chromatography or Kugelrohr distillation.
Scheme 3 Conditions 1.05 eq (cy-hex)2BCl, 1.05 eq. Et3N, 0 ЊC, 0.9
mol% Rh(CO)2(acac), 1.8 mol% XANTPHOS, 16 h, 60 bar CO/H2,
80 ЊC.
The relative configuration of the two stereogenic centres of
compounds 9 and 10 was established by 1D gradient NOE
experiments. A summary of the characteristic NOE inter-
actions observed are shown for 10—the compound obtained in
the highest diastereoselectivity—in Fig. 1.
1 Some recent examples of the diastereoselective construction of qua-
ternary carbon centres: E. D. Burke and J. L. Gleason, Org. Lett.,
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3 Tandem C–C bond formation/hydroformylation: L. Bärfacker,
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T. Rische, R. Roggenbuck, A. Schmidt and P. Eilbracht, Chem. Rev.,
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Fig. 1 Characteristic NOE interactions present in 10.
The aldol addition in the latter cases proceeds with a con-
siderably higher degree of diastereoselectivity when compared
to the conversion of 4. A potential transition state assembly
that accounts for this can be seen in Scheme 4. The enolate
geometry here again is determined by chelation during the
enolboration prior to hydroformylation. After hydroformyl-
ation, chelation switches from the ester group to the aldehyde,
resulting in a rigid bicyclic transition state for the aldol
addition.
4 C. Hollmann and P. Eilbracht, Tetrahedron Lett., 1999, 40, 4313;
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Scheme 4 Transition state responsible for the diastereoselectivity
observed in 6- and 7-membered ring formation.
In summary, we herein report a new one-pot enolboration/
hydroformylation/aldol addition cascade reaction, and demon-
strate its utility in the regio- and diastereoselective synthesis
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 8 8 – 1 6 9 0
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13 (cy-hex)2BCl was previously believed to be ineffective for the
enolboration of an ester functionality. H. C. Brown and
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 8 8 – 1 6 9 0
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