Organoytterbium ate complexes extend the value of cyclobutenediones as isoprene equivalents

Article abstract of DOI:10.1002/anie.201307193

Changing course: While organolithium and Grignard reagents favor addition to C1 of A (R=Me), the corresponding organoytterbium reagents add to C2 (R=tBu). Computational studies provide insights into the nature of organoytterbium species and their reactivity, and a total synthesis of (-)-mansonone B illustrates the utility of the method in terpenoid synthesis. Tf=trifluoromethanesulfonyl.

Full text of DOI:10.1002/anie.201307193

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Angewandte
Communications
DOI: 10.1002/anie.201307193
Synthetic Methods
Organoytterbium Ate Complexes Extend the Value of
Cyclobutenediones as Isoprene Equivalents**
Emma Packard, David D. Pascoe, Jacques Maddaluno, Thꢀo P. GonÅalves, and
David C. Harrowven*
In memory of Margaret Harrowven
3-Methyl-4-methoxycyclobuten-1,2-dione (1a) has long been
recognized as a valuable isoprene equivalent in natural
products total synthesis, particularly for the preparation of
hydroquinones, quinones, and their benzannulated analogues
(e.g. Scheme 1).[1,2a] It is readily introduced to a substrate as
the electrophilic component in organolithium or Grignard
addition reactions, for example, 1a!2. Here, the differential
reactivity of the C1 and C2 carbonyl groups in 1a adds to its
value as a synthon by providing a reliable and predictable
means of achieving the ubiquitous head to tail connectivity of
isoprene units.[1,2a]
imposes a severe limitation. As evidenced by the example in
Scheme 1, while the method is convenient for the synthesis of
benzohydroquinones such as 3, it proves cumbersome when
targeting the regioisomeric series 7. In this case addition of
a carbon nucleophile to the vinylogous ester carbonyl (C2) of
1a is required to achieve the desired outcome. Consequently,
a protecting group strategy must be invoked to mask the more
reactive C1 carbonyl (e.g. 1a!4).[2] Addition of the Grignard
or organolithium reagent to C1 is then followed by depro-
tection (e.g. 5!6), which can be difficult to achieve efficiently
because of the presence of the acid sensitive tertiary alcohol
and enol ether functions.
Herein we report an expedient solution to that long-
standing problem and reveal some hitherto unknown facets of
organoytterbium reactivity. In essence, while organolithium
and Grignard reagents favor addition to the C1 carbonyl of
cyclobutenedione (1a), the corresponding organoytterbium
reagents give exclusive addition to the C2 carbonyl of 1b
(Scheme 2).[3]
Though regiocontrol in the addition of Grignard and
organolithium reagents to 1a is of critical importance, it also
The discovery was made during an optimization study
aimed at reducing side reactions resulting from deprotonation
of the C3 methyl substituent in 1a. In the addition of PhLi, for
example (Scheme 3), these appeared to limit the yield of the
Scheme 1. Use of 1a as an isoprene equivalent in the synthesis of
benzohydroquinones.
[*] E. Packard, Dr. D. D. Pascoe, T. P. GonÅalves, Prof. D. C. Harrowven
Chemistry, University of Southampton
Highfield, Southampton, SO17 1BJ (United Kingdom)
E-mail: dch2@soton.ac.uk
Scheme 2. Dichotomous regioselectivity in the addition of organo-
lithium and organoytterbium reagents to cyclobutenediones. Tf=tri-
fluoromethanesulfonyl.
Dr. J. Maddaluno
FR CNRS 3038, IRCOF, Universitꢀ de Rouen
76821 Mont St. Aignan Cedex (France)
[**] Financial support from the EPSRC and ERDF (IS:CE-Chem &
InterReg IVa program 4061) is gratefully acknowledged. We would
also like to acknowledge Dr. Edmund Lee, the IRIDIS High
Performance Computing Facility, the EPSRC National Service for
Computational Chemistry Software (NSCCS), and their associated
support staff for help in the completion of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307193.
ꢁ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Scheme 3. Regioselectivity in the additions of various phenyl organo-
metallics to 1a and 1b. THF=tetrahydrofuran.
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adduct 2a to approximately 70–80% when employing stan-
dard protocols (e.g. THF at ꢀ788C).[4] Inspired by reports
from the groups of Molander and Procter on the efficient
addition of organoytterbium reagents to carbonyl com-
pounds,[5] we decided to examine the addition of phenyl-
ytterbium triflate to 1a.[2] The result we attained was quite
unexpected, as the reaction led to the formation of both C1
and C2 adducts, 2a and 11a, respectively, in the correspond-
ing yields of 50% and 41% (Scheme 3). Having noted similar
anomalies in the additions of PhLi and PhMgBr to 1b, we
were delighted to find that the addition of phenylytterbium
triflate to 1b resulted in a complete reversal of the normal
regiochemical course, thus giving the C2 adduct 12a in
a remarkable 92% yield upon isolation.[5,6]
Scheme 5. Synthesis of regioisomeric series of hydroquinones by vinyl-
lithium and vinylytterbium additions to 1a and 1b.
To demonstrate the value of the method, a series of
arylytterbium reagents were prepared and reacted with 1b.
These included ortho-,[7] meta-,[7] and para-substituted aro-
matics with a variety of substituents (+ I, ꢀI, and + M), and
a heteroaromatic example[7] (see Scheme 4 and the Support-
ing Information). In each case the C2 adducts 12 were formed
Scheme 6. Alkylytterbium additions to 1b for the synthesis of 5H-
furanones and diorganylcyclobutenediones.
The addition of methylytterbium triflate to 1b also proved
facile (Scheme 6). In contrast, the analogous sequence with
nBuLi required a 2:1 equivalence with ytterbium(III) triflate
to achieve a high yield of the C2 adduct 28b.[8] The photo-
chemical rearrangement of the adduct 28a into the furanone
29,[9] and the facile generation of the diorganylcyclobuten-
diones 30 by exposure of these adducts to acid, provide
further illustrations of the methodꢀs utility.
For completeness, the addition of phenylalkynylytterbium
triflate to 1b was examined (Scheme 7). The reaction proved
sluggish (9 h at ꢀ788C) in comparison with other additions
and regioselectivity was attenuated, with the formation of
cyclobutenones 34 and 33 in 69% and 15% yield, respec-
tively. In contrast, the addition of the organolithium 31 to 1a
gave the cyclobutenone 32 as the sole isolated product.
Scheme 4. Synthesis of regioisomeric series of benzoquinones using
aryllithium and arylytterbium additions to 1a and 1b.
in excellent yield. This result was in stark contrast to the
corresponding organolithium additions to 1a where the major
product 2 resulted from addition to the C1 carbonyl.[7] For
completeness, all adducts were subjected to thermolysis and
aerial oxidation, thus leading to the complementary series of
benzoquinones 15 and 16.
The complementary reactivity extended to vinyllithium
and vinylytterbium triflate additions to 1a and 1b as
demonstrated by the syntheses of the hydroquinones 23–25
and 27 (Scheme 5).[1] Notably, vinylytterbium triflate derived
from vinylmagnesium bromide displayed the same regio-
chemical preference as those derived from vinyllithium
intermediates. Interestingly, the addition of the vinyllithium
18 to 1a proved unusual in that it gave 27 directly after
a bicarbonate quench at ꢀ788C and warming to ambient
temperature. The minor product of the reaction was the C2
adduct 21b,[7] rather than the corresponding hydroquinone.
Scheme 7. Phenylalkynyllithium and ytterbium additions to 1a and 1b,
respectively.
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Figure 1. Calculated free energy barriers for C1 and C2 addition in the reactions of 1b with PhYb(OTf)2 and [PhYb(OTf)3]ꢀ in THF.
Thermolyses of the adduct 32 and 34 exposed a further
anomaly, with the former giving a 5:4 mixture of the quinone
35 and cyclopentenedione (E)-36, while the a latter gave only
the cyclopentenedione (Z)-37.
product whose identity has yet to be determined with rigor
but seemed likely to be as depicted in 43.[13] Our synthesis
began with (ꢀ)-menthone (39; Scheme 8), which was readily
To gain insights into the mechanistic course of organo-
ytterbium addition reactions we decided to initiate a computa-
tional study of the reaction of PhYb(OTf)2 with 1b. However,
these investigations proved fruitless, with DFT calculations
predicting a preference for reaction at the ketonic C1
carbonyl (i.e. DG°A < DG°D, Figure 1).[10] The results led us
to question the nature of the organometallic reagent. Based
on limited literature precedent,[11] we had assumed that the
reaction of PhLi with Yb(OTf)3 would first give the ate
complex PhYb(OTf)3Li, which in turn would collapse to
PhYb(OTf)2 and LiOTf. When this premise was tested
computationally, our calculations indicated that loss of
a triflate ligand from the ate complex would cost approx-
imately 25 kcalmolꢀ1 at ꢀ788C! Moreover, when the reac-
tivity of [PhYb(OTf)3]ꢀ towards 1b was examined, the
predicted outcome mirrored our experimental findings by
revealing a kinetic preference for phenyl addition to the C2
carbonyl (i.e. DG°H < DG°E, Figure 1).
The modeling also exposed some seminal facets of
organoytterbium reactivity (Figure 1). In particular, the pre-
reaction complexes of [PhYb(OTf)3]ꢀ·1b (F and G) each
showed single ytterbium–carbonyl interactions leading to
trapezoidal transition states. The strength of those interac-
tions was a key factor in determining the regiochemical
course of addition, with DGG less than DGF by about
2.5 kcalmolꢀ1. Additionally, steric interactions in the addition
phase play an important role, as evidenced by 1) the need to
rotate the tBu ether during C1 addition (F!E, Figure 1) at
a cost of about 2.6 kcalmolꢀ1 [12] and 2) the low selectivity
observed for addition of [PhYb(OTf)3]ꢀ to 1a compared to
that for 1b (Scheme 3).
Scheme 8. First total synthesis of (ꢀ)-mansonone B. TMEDA=
N,N,N’,N’-tetramethylethylenediamine, Trisyl=2,4,6-triisopropylphenyl-
sulfonyl.
transformed into the required vinyllithium reagent 41 by
means of a
Shapiro reaction.[14] Transmetallation with
ytterbium triflate, and subsequent addition of the resulting
vinylytterbium intermediate to 1b, gave a 7:3 diastereomeric
mixture of the C2 adduct 42 in 94% yield. Thermolysis of that
mixture under continuous flow at 1108C with concomitant
aerial oxidation, gave the quinone 44, from which our target
43 was readily derived. Pleasingly, the physical and spectral
characteristics displayed by our synthetic sample (ꢀ)-43
matched those reported for mansonone B in its isolation
paper,[13a] thus confirming the regiochemical and relative
stereochemical identity of the natural product. Its absolute
configuration remains uncertain because of a lack of available
optical rotation data for comparison.
Finally, to demonstrate the methodꢀs potential in terpe-
noid synthesis we decided to target mansonone B, a natural
In conclusion, we have shown that organoytterbium
additions to 1b are easy to effect, proceed in excellent
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[4] a) S. L. Xu, H. W. Moore, J. Org. Chem. 1992, 57, 326 – 338;
yield, and follow a complementary regiochemical course to
related organolithium additions to 1a. Alkyl, aryl, hetaryl,
vinyl, and alkynyl ytterbium reagents participate in the
reaction, greatly extending the utility of cyclobutenone
rearrangements by providing a predictable means of intro-
ducing this isoprene unit in a regioselective manner. High-
level computational studies have provided seminal insights
into the nature of organoytterbium intermediates and their
reactivity. Of particular note is the realization that reactions
proceed via ytterbium ate complexes.
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1642 – 1643. See the Supporting Information for additional
references.
[6] At the request of a reviewer, the reactivity of PhLi/CeCl3
towards 1b was examined and shown to favor C1 addition
(Scheme 3).
[7] Additions of ortho-, meta-, and hetero-arylytterbium reagents to
1b are detailed in the Supporting Information along with further
examples of organolithium additions to 1a and 1b and the
thermal rearrangements of 21b and 33.
[8] For a possible explanation of 2:1 stoichiometry required with
alkyl Yb reagents see: S.-i. Fukuzawa, K. Mutoh, T. Tsuchimoto,
T. Hiyama, J. Org. Chem. 1996, 61, 5400 – 5405, and references
therein.
[9] D. C. Harrowven, M. Mohamed, T. P. GonÅalves, R. J. Whitby,
D. Bolien, H. F. Sneddon, Angew. Chem. 2012, 124, 4481 – 4484;
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[10] DFT calculations were performed using B3LYP with a mixed
basis set of MWB59 for Yb. Pre-optimization was carried out
with MOPAC PM7/SPARKLE [a) J. J. P. Stewart, J. Mol. Model.
2013, 19, 1 – 32; b) J. D. L. Dutra, M. A. M. Filho, G. B. Rocha,
R. O. Freire, A. M. Simas, J. J. P. Stewart, J. Chem. Theory
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calculated at the M06-2x/6-311 + G(d,p)/MWB59 level [c) Y.
Zhao, D. Truhlar, Theor. Chem. Acc. 2008, 120, 215 – 241] using
Received: August 15, 2013
Published online: October 23, 2013
Keywords: density functional calculations · flow chemistry ·
.
natural products · rearrangement · ytterbium
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