Stereoselective Synthesis of Highly Substituted Tetrahydrofurans through Diverted Carbene O-H Insertion Reaction

Article abstract of DOI:10.1002/anie.201502484

Copper- or rhodium-catalyzed reactions of diazocarbonyl compounds with β-hydroxyketones give highly substituted tetrahydrofurans with excellent diastereoselectivity. Under mild conditions, the single-step process starts as a carbene O-H insertion reaction, but is diverted by an intramolecular aldol reaction. Gone astray: Copper- or rhodium-catalyzed reactions of diazocarbonyl compounds with β-hydroxyketones give highly substituted tetrahydrofurans with excellent diastereoselectivity. The single-step reaction proceeds under mild conditions, starting as a carbene O-H insertion reaction, but then diverting to an intramolecular aldol reaction.

Full text of DOI:10.1002/anie.201502484

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International Edition: DOI: 10.1002/anie.201502484
German Edition: DOI: 10.1002/ange.201502484
Tetrahydrofurans Very Important Paper
Stereoselective Synthesis of Highly Substituted Tetrahydrofurans
À
through Diverted Carbene O H Insertion Reaction**
Simon M. Nicolle, William Lewis, Christopher J. Hayes, and Christopher J. Moody*
In memory of Adam David Przeslak
Abstract: Copper- or rhodium-catalyzed reactions of diazo-
carbonyl compounds with b-hydroxyketones give highly sub-
stituted tetrahydrofurans with excellent diastereoselectivity.
Under mild conditions, the single-step process starts as
À
a carbene O H insertion reaction, but is diverted by an
intramolecular aldol reaction.
T
he tetrahydrofuran ring is a commonly found motif in
naturally occurring bioactive compounds, and occurs in
structural classes such as lignans,[1] acetogenins,[2] iono-
phores,[3] and macrolides.[4] Examples include (+)-fragran-
sin A2[5] and amphidinolide F[6] (Figure 1). As a consequence,
Scheme 1. Synthetic approaches toward tetrahydrofurans involving
metallocarbenes.
[12]
À
locarbene O H insertion/Michael addition,
and on car-
bonyl ylide cycloadditions,[13] have also been developed to
prepare tetrahydrofurans (Scheme 1).
Figure 1. Some naturally occurring tetrahydrofurans.
a number of strategies have been developed for the stereo-
selective synthesis of tetrahydrofurans.[7–9] However, despite
advances in synthetic methodology, highly substituted tetra-
hydrofurans remain difficult to access, and new approaches
are needed. We now describe a new route to highly
substituted tetrahydrofurans that proceeds with excellent
diastereoselectivity under mild conditions in a single step
Our initial investigation focused on the reaction of ethyl
phenyl diazoacetate (1) with 4-hydroxybutanone (2) under
À
the conditions of classical transition-metal-catalyzed O H
insertion reactions. Although the use of copper(I) iodide or
copper(II) acetate as catalyst resulted in very slow reactions,
À
copper(II) trifluoroacetate led to a mixture of the O H
insertion product 3 and the cyclized tetrahydrofuran 4, for
À
À
(Scheme 1) by a process initiated by metallocarbene O H
insertion, but diverted by intramolecular aldol reaction.
which O H insertion was diverted by an intramolecular aldol
reaction, in moderate yield. Several reaction parameters, such
as temperature, catalyst loading, addition of Lewis or
Brønsted acid, were varied (Table S1, Supporting Informa-
tion), but the key advance was the use of an increased
stoichiometric ratio of the diazo compound. This was further
improved by switching to the copper(I) triflate/toluene
complex as the catalyst, resulting in the desired isolated
tetrahydrofuran 4 in 82% yield as a single diastereoisomer,
with the yield of a-alkoxyester 3 below 10%. The rhodium
octanoate dimer was also a competent catalyst (Scheme 2),
although in this case the products were obtained in a higher
ratio of 3:4. Interestingly, the addition of triethylamine to this
À
In continuation of our longstanding interest in O H
insertion reactions of metallocarbenes,[10,11] we now report
that b-hydroxyketones and metallocarbenes derived from
diazocarbonyl compounds can lead directly to substituted
tetrahydrofurans by a process that we term “diverted carbene
À
O H insertion”. Recently, related methods based on metal-
[*] S. M. Nicolle, Dr. W. Lewis, Prof. Dr. C. J. Hayes,
Prof. Dr. C. J. Moody
School of Chemistry, University of Nottingham
University Park, Nottingham NG7 2RD (UK)
E-mail: c.j.moody@nottingham.ac.uk
À
system led to the isolation of O H insertion product 3
exclusively. In this tetrahydrofuran synthesis, two contiguous
stereocenters are created in a highly stereoselective manner,
with the hydroxy group and the carbonyl moiety in a cis
configuration as shown by 1H NOESY NMR spectroscopy.
[**] We thank the University of Nottingham for support.
Supporting information for this article (including full details of all
experiments) is available on the WWW under http://dx.doi.org/10.
1002/anie.201502484.
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Scheme 2. Synthesis of 3-hydroxytetrahydrofuran 4 by the copper- or
rhodium-catalyzed reaction of ethyl phenyl diazoacetate (1) with 4-
hydroxybutan-2-one (2).
Having found the optimal conditions for tetrahydrofuran
formation, we set out to determine the scope of the reaction.
A wide range of highly substituted tetrahydrofurans was
accessible in modest to excellent yield, accompanied in some
À
cases by small amounts of the corresponding O H insertion
product (Schemes 3 and 4). Electron rich 4-methoxyphenyl
diazoacetate 5 gave tetrahydrofuran 15 in only 49% yield
with copper(I) triflate as the catalyst, while the same reaction
using the rhodium octanoate dimer as the catalyst gave 15 in
an improved yield of 80% (Scheme 3). Similarly, the reaction
of 4-methylphenyl diazoacetate 6 proceeded better under
rhodium catalysis than under copper catalysis. The opposite
trend was observed with nitro-substituted compound 7, which
gave isolated tetrahydrofuran 17 in 61% yield with copper(I)
catalyst, but only in trace quantities when the rhodium
catalyst was used. It is noteworthy that no product resulting
from intramolecular cyclopropanation was observed. The
results obtained with diazo compounds 5–8 suggest that
rhodium(II) and copper(I) are complementary catalysts for
À
the diverted O H insertion reaction. On the other hand, 4-
bromophenyl-substituted diazo compound 8 gave similar
results under both catalytic systems, while thienyl diazo
compound 9 gave tetrahydrofuran 19 in modest yield. Diazo
compounds that lack the aryl group also participated: for
example, commercially available ethyl diazoacetate 10 gave
tetrahydrofuran 20 under rhodium catalysis (along with
carbene dimerization products). Diazo compound 11, which
Scheme 3. Synthesis of 3-hydroxytetrahydrofurans by rhodium- and
À
copper-catalyzed diverted O H insertion reaction. Ratios of tetrahydro-
À
furan to O H insertion products (for higher-yielding reactions) as
À
possesses a C H bond in a position to the diazo group, gave
determined by NMR analysis of the initial products are given in
parentheses.
tetrahydrofuran 21 in moderate yield as a result of a compet-
ing 1,2-H shift.[14] When no a-C H bond was present, as in
À
diazo compound 12, spiro-tetrahydrofuran 22 was obtained in
an excellent yield (91%). Additionally, cyclic diazo com-
pound 13 gave spiro compound 23 in good yield (77%), but
only under rhodium catalysis. Finally, the complementary
aspect of rhodium(II) and copper(I) catalysis was further
illustrated by the reaction of diazoketone 14, which gave
To extend the scope of the process, we surveyed the
reaction of ethyl phenyl diazoacetate (1) with various b-
hydroxyketones under both sets of catalytic conditions to give
a
diverse set of highly substituted tetrahydrofurans
(Scheme 4). b-Hydroxyketone 25 behaved similarly to its
methyl analogue 2 under copper(I) or rhodium(II) catalysis.
Cyclization was also successful with hydroxyketoester 26, and
the tetrahydrofuran 37 was obtained in 55% yield under
copper(I) catalysis and in a similar yield of 53% with
rhodium(II) catalysis. Cyclization also occurred with cin-
namyl hydroxyethyl ketone (27) and furylketone 28. In both
cases, the rhodium(II) catalyst was superior to the copper(I)
catalyst.
À
predominantly the O H insertion product under rhodium(II)
catalysis, while the use of copper(I) triflate led to the isolation
of tetrahydrofuran 24 in 56% yield. In the majority of cases,
À
any traces of an O H insertion product were readily removed
by chromatography. The use of dimethyl diazomalonate
under rhodium catalysis led to the isolation of the corre-
À
sponding O H insertion product exclusively, while diethyl a-
phenyl diazophosphonate did not give any tetrahydrofuran
Aldol 29, which possesses an a-methyl substituent, under-
went the reaction to give the cis/cis tetrahydrofuran 40 in
product under conditions A or B.
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furan 43 was obtained with a similar enantiomeric excess of
84%, which could be readily improved to enantiopurity by
crystallization.
The reaction sequence was relatively insensitive to steric
bulk around the alcohol functionality, for example, tertiary
alcohol 33 gave tetrahydrofuran 44 in 67% yield. Both a,b-
disubstituted b-hydroxyketone diastereoisomers 34 and 35
were subjected to rhodium catalysis with diazo compound 1 to
give single diastereoisomers 45 and 46, respectively. The latter
results show that, when stereocontrol over positions 4 and 5 of
the final tetrahydrofuran product can be achieved, the
substituent at C4 has a greater effect on the stereocontrol
than that at C5. Additionally, the structures of cyclic
compounds 38 and 43 were confirmed by X-ray crystallog-
raphy (Figures S1 and S2, Supporting Information).
The examples shown in Scheme 3 and 4 clearly establish
the wide scope of this tetrahydrofuran synthesis. However, in
order to rationalize the formation of tetrahydrofurans such as
À
4, as opposed to O H insertion (e.g. 3) products, we
performed a series of control experiments. First, in order to
establish whether the tetrahydrofuran 4 was formed through
À
an initial O H insertion reaction and subsequent intra-
À
molecular aldol cyclization, the ketoester O H insertion
product 3 was exposed to the reaction conditions (i.e. rhodium
octanoate or copper(I) triflate/toluene complex in CH2Cl2 at
reflux; Scheme 5). Under these conditions, no conversion to
Scheme 5. Control experiments. Reagents and conditions: a) [Rh2-
(oct)4] (1 mol%), CH2Cl2 at reflux; b) [Rh2(oct)4] (1 mol%), NEt3
excess, CH2Cl2 at reflux; c) (CuOTf)2·Tol (5 mol%), CH2Cl2 at reflux;
d) NaOMe, MeOH, 08C!RT.
Scheme 4. Synthesis of polysubstituted tetrahydrofurans by rhodium-
the tetrahydrofuran 4 was observed, thus showing that the
metal catalysts were not capable of mediating the intra-
molecular aldol reaction. The reaction was repeated, but this
time in the presence of an excess of triethylamine to
encourage the formation of a reactive aldol intermediate
(enol/enolate), but once again, no tetrahydrofuran 4 was
formed. Finally, we treated the ketoester 3 with a stronger
base (NaOMe) in an attempt to force the aldol process, but
under these conditions only methyl mandelate (44%) was
formed as a result of a retro-Michael elimination of methyl
vinyl ketone and transesterification, and no trace of the
tetrahydrofuran 4 was observed. In order to assess the
reversibility of the formation of the five-membered ring, we
exposed tetrahydrofuran 4 to the original reaction conditions
(Scheme 5). Tetrahydrofuran 4 was stable in the presence of
the metal catalysts, and no retro-aldol product 3 was
observed. Even with the addition of an excess of triethyl-
amine, the tetrahydrofuran 4 was stable, and a stronger base
(NaOMe) was required to cause decomposition of 4. Under
these conditions, methyl mandelate (73%) was formed,
presumably through a retro-aldol reaction to give 3, elimi-
nation of methyl vinyl ketone, and transesterification.
À
and copper-catalyzed diverted O H insertion reaction. Ratios of
À
tetrahydrofuran to O H insertion products (for higher-yielding reac-
tions) as determined by NMR analysis of initial products are given in
parentheses.
85% yield, thus showing that the stereoselectivity of the
reaction could be extended to the substituent at position 4 of
the cyclic ether ring. a-Disubstituted aldol 30 did not give the
desired tetrahydrofuran 41 under copper(I) catalysis, while
single diastereoisomer 41 was obtained in 48% yield under
rhodium catalysis. When allylic alcohol 31 was subjected to
rhodium catalysis, the desired tetrahydrofuran 42 with an
exocyclic double bond was obtained in 67% yield.
Secondary and tertiary alcohols also underwent the
À
diverted O H insertion/cyclization reaction, and in these
cases, the rhodium catalyst was superior. Alcohol 32 gave
a single diastereoisomer of tetrahydrofuran 43 in good yield,
showing that the stereocontrol could be extended to the
position 5 of the tetrahydrofuran product. When enantioen-
riched (R)-aldol 32 (77% ee) was used, no erosion of
stereochemistry was observed, and the product tetrahydro-
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À
Having established that the O H insertion product 3 is
not on the reaction pathway to tetrahydrofuran 4, we propose
is required to establish the details of the pathway, transition
states D or E predict the observed stereochemical outcome,
and by placing substituents at C4 or C5 in pseudoequatorial
positions, also explains the diastereocontrol shown in the
formation of 40 and 43.
À
that the tetrahydrofurans result from a diversion from the O
H insertion reaction through an intramolecular aldol cycliza-
tion. This proposal is in line with the finding of Hu and others,
who found that in a number of cases, transient oxonium and
In conclusion, we have developed a strategy for the
stereoselective construction of highly substituted tetrahydro-
À
ammonium ylide intermediates in X H insertion (X = O, N)
pathways can be trapped by electrophiles.[15–18] The widely
furans by a diverted metallocarbene O H insertion/intra-
À
À
accepted mechanism for metallocarbene O H insertion is
molecular aldol reaction process using both copper(I) and
rhodium(II) catalysis. This convergent and highly selective
approach tolerates a wide range of b-hydroxyketones, easily
available by aldol reactions,[29] including diastereo- and
enantioselective variants, and diazo compounds. The high
stereoselectivities observed in the formation of tetrahydro-
furans were rationalized by a mechanistic proposal involving
an intramolecular aldol reaction.
a stepwise process initiated by the attack of an alcohol (e.g. 2)
onto the electrophilic metallocarbene A, which is generated
by metal-catalyzed decomposition of the corresponding diazo
compound, to give a metal-associated oxonium ylide B
(Scheme 6).[19–24] The metal-associated oxonium ylide B can
Keywords: aldol reaction · carbenes · diazo compounds ·
tetrahydrofurans · transition-metal catalysis
How to cite: Angew. Chem. Int. Ed. 2015, 54, 8485–8489
Angew. Chem. 2015, 127, 8605–8609
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Scheme 6. Proposed mechanism to rationalize the stereoselective
À
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À
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Received: March 17, 2015
Revised: May 6, 2015
Published online: June 9, 2015
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