Strain release in C-H bond activation?

Article abstract of DOI:10.1002/anie.200904474

What a relief ! In 1955, strain release was put forward as a reactivity factor to explain the differing reactivity of axial and equitorial alcohols during oxidation. The same rationale may account for the differing rates of activation between axial and equitorial C-H bonds in C-H activation processes (see scheme)

Full text of DOI:10.1002/anie.200904474

Angewandte
Chemie
DOI: 10.1002/anie.200904474
Synthetic Methods
À
Strain Release in C H Bond Activation?**
Ke Chen, Albert Eschenmoser,* and Phil S. Baran*
À
The field of C H activation and the logic that underlies its use
in complex-molecule synthesis are developing at a rapid
pace.[1] This is due, in part, to the great potential that such
transformations could have on the various “economies” of
synthesis.[2] Comprehensive observations have pointed to the
importance of steric and electronic factors governing the
relative rates and selectivities of such reactions.[3] Yet, in order
to plan complex-molecule total syntheses that utilize one or
À
multiple C H activation steps, a profound understanding of
even the subtlest reactivity trends is needed. In particular, it
À
has been observed on multiple occasions that equatorial C H
bonds react more rapidly than those oriented axially
(Scheme 1).[4] This curious axial–equatorial rate ratio appears
to be independent of the reagent system employed and in
À
some cases can be exploited to achieve site-specific C H
activation.[4c,f,5] So far, explanations for these scattered
observations have remained ambiguous. Here, a reactivity
factor that apparently has been ignored thus far in this context
is proposed, one that we suspect, besides steric hindrance to
[6]
À
reagent approach and C H bond nucleophilicity, to be co-
responsible for the more rapid activation of equatorial vs.
À
axial C H bonds in these tertiary settings.
In 1955, one of us proposed strain release (Scheme 2A) to
explain the relative rates of reactions in which an equatorial
hydrogen is also removed more rapidly than its axial counter-
part, namely, in the oxidation of steroidal secondary alcohols
with chromic acid (see Supporting Information for an English
translation of this paper).[7] The rate enhancement in these
reactions is attributed to a release of strain (1,3-diaxial
interactions) in the transition state of going from an sp3 to an
sp2 carbon. At the time, this work convincingly contradicted
and corrected the theory[8] according to which the difference
in oxidation rate of axial and equatorial alcohols was due to
Scheme 1. Observations from the literature. LAH=lithiumaluminum
hydride; TFDO=methyl(trifluoromethyl)dioxirane; TBAC=tetrabuty-
lammoniumcyanoborohydride.
steric hindrance to proton abstraction by a base. In a later
paper, the strain release hypothesis was corroborated in
collaboration with Westheimer and Rozek,[9a] as well as by
work by Wilcox et al.[9b]
[*] Dr. K. Chen, Prof. P. S. Baran
A key step in the total synthesis of eudesmane terpenes[5]
caused us to revisit this principle, one that has so far mainly
been used to explain differences in the rates of alcohol
oxidation[7,9a,b] and solvolysis.[10] As shown in Scheme 2B, the
power of the Curci (TFDO) oxidation[4c] was vividly demon-
strated by the conversion of 1 to 2. Among five tertiary
centers present in 1, H1 was selectively activated, leading the
alcohol 2 in 82% isolated yield on a gram scale. Purely
electronic considerations might have led one to predict that
the tertiary center of the isopropyl group (H5 in Scheme 2B)
would be oxidized first since its 13C NMR shift is 0.9 ppm
more upfield than the carbon attached to H1.[11] Steric
considerations might also support the supposition that H5
will react first. Such unusual efficiency and site-selectivity led
Department of Chemistry, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7375
E-mail: pbaran@scripps.edu
Prof. A. Eschenmoser
Laboratory of Organic Chemistry, Swiss Federal Institute of
Technology, Hꢀnggerberg HCI H309
Wolfgang-Pauli-Strasse 10, 8093 Zꢁrich (Switzerland)
E-mail: eschenmoser@org.chem.ethz.ch
[**] We thank Tanja Gulder for the translation of ref. [7] and Jun Shi for
technical assistance. Financial support for this work was provided
by Amgen, Bristol-Myers Squibb, the Skaggs Institute, and the NIH
(Grant CA184785).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904474.
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Figure 1. The design of an eudesmane-based probe to account for the
À
enhanced reactivity of equatorial C H bonds.
À
Scheme 2. A) Strain release in alcohol oxidation. B) Site-selective C H
oxidation: a strain release phenomenon?
The synthesis of 3 was conducted in a similar fashion as
the preparation of 1,[5] as shown in Scheme 3. Thus, the
us to consider that their origin be related to strain release in
going to the electrophilic transition state of the oxidation. In
fact, numerous mechanistic studies of carbene,[12a–c] nitr-
ene,[12d] dioxirane,[12e] and other[12f,g] intermolecular C H
À
oxidations have suggested a somewhat “flattened tetrahe-
drality” of the tertiary carbon center in the rate-determining
transition states of such reactions (not an actual radical or
cation formation but an electrophilic carbon that is bent as if
to become trigonal).
Of special interest in this context are Houkꢀs calculations
on the mechanism of dioxirane-mediated oxidations.[13] They
À
point to “a concerted transition state with O H abstraction
À
much more advanced than O C bond formation”, and to a
Scheme 3. Synthesis of eudesmane 3.
“polarized nature of the transition state [that] cause[s] the
concerted oxygen insertions into tertiary CH bonds to be highly
favored” [see Eq. (1)]. These conclusions seem perfectly
compatible with a participation of strain release as rate-
influencing co-factor; they qualitatively combine concerted-
ness with the structural prerequisite for strain release to
operate in the formation of the transition state.
decalin framework of enone 4 was forged using methyl vinyl
ketone, 3-methylbutyraldehyde, lithium dimethylcuprate, and
5-bromopentene in six steps with 44% overall yield. Stereo-
selective hydrogenation then delivered intermediate 5 in 80%
yield as the major isomer. The establishment of three
requisite steric centers of demethyl dihydrojunenol 6 was
achieved in the subsequent Birch reduction in 73% yield.
Lastly, carbamate formation smoothly delivered desired
eudesmane probe 3 in nearly quantitative yield. The structure
and stereochemical assignment were verified by X-Ray
crystallography (see Figure 1). Notably, probe 3 exhibits an
identical conformation in the solid state and nearly identical
13C NMR chemical shifts relative to 1 (the 13C NMR shift at
the key tertiary carbon atom differ by 0.1 ppm).[11a,b,15] Not
surprisingly, probe 3 reacted rapidly with TFDO in high yield
to give the tertiary alcohol 7.
The dihydrojunenol system with its steric repulsion
between two 1,3-diaxial methyl groups offers a rare oppor-
tunity to determine whether strain release may be a contri-
buting factor in oxidations by an electrophilic oxidant besides
À
the factors of C H bond nucleophilicity and steric hindrance
In order to establish the presence of any reactivity
difference between 1 and 3 (Scheme 4), the following two
experiments were conducted on a 1:1 mixture of 1 and 3 and
halted before reaching full conversion (both experiments
were run in triplicate and on scales ranging from 5–25 mg).
Standard Curci conditions[4c] led to a 3.0–3.1:1 ratio of tertiary
alcohols 2 and 7, along with recovered starting materials. To
confirm that this result is not reagent-specific, the mixture was
absorbed to silica gel and exposed to a stream of ozone[16] at
to reagent approach.[3] It is for this very purpose that a specific
eudesmane-based probe—demethyl dihydrojunenol carba-
mate (3)—was designed (Figure 1). In such a probe, any
decrease in reactivity as compared to 1 would reflect the
importance of strain release in going to the transition state,
À
since the electronic reactivity factors (C H bond nucleophi-
licity) in both settings are as nearly identical as they possibly
can be,[14] as is the steric environment at the site of oxidation.
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À
Scheme 5. Strain release is a minor factor in methylene C H activa-
tion. H2esp=a,a,a’,a’-tetramethyl-1,3-benzenedipropionic acid.
reactions at methylene groups and, therefore, less sensitive to
the strain release factor. Furthermore, the repulsion between
CH3 (axial) and H (axial) in the 3-position is roughly four
times smaller (0.9 vs 3.7 kcalmolÀ1) than the corresponding
repulsion between two axial methyl groups (8 vs 1) and so the
effect on oxidation rates should be correpondingly smaller.[3e]
However, it is in more complex systems containing
methylene groups where the strain release factor might be
operative, such as the case of sclareolide (15) (Scheme 6).
Scheme 4. TFDO- and Ozone-mediated oxidation of a 1:1 mixture of 1
À
and 3 points to the strain-release phenomenon in tertiary C H
oxidation (sm: starting materials).
08C for 20 min delivering a mixture of tertiary alcohols 2 and
7 in a 3.9–4.1:1 ratio (in addition to recovered starting
materials). Whereas the reaction of TFDO with both 1 and 3
was selective (only trace quantities of byproducts were
observed), the reaction of 1 with ozone proceeded more
efficiently (74% 2 based on recovered 1) than with 3
(numerous uncharacterized byproducts were observed and
the product was formed in 30% based on recovered 3). Thus,
1 not only reacts faster with ozone than 3, it also reacts with
greater selectivity.
The observed rate ratio of 3:1 to 4:1 in these experiments
might seem modest (DG# ꢀ 0.6 kcalmolÀ1) for serving as
evidence for the operation of a reactivity factor, particularly
when compared with corresponding ratios in chromic acid
oxidations of secondary alcohols. Yet there is a mechanistici-
cally significant difference between the latter reaction and an
Scheme 6. Strain release may be an important contributor in methyl-
ene activation in complex settings.
Although 15 contains 26 hydrogen atoms (2 tertiary and 12
À
À
oxidative hydroxylation of a tertiary C H bond, in the
product of which the carbon remains tetrahedral. Such rate
methylene), it should be possible to predict which C H bond
will react first with an electrophilic oxidant. On electronic
grounds, CH2 positions at ring A may be considered most
reactive since they are furthest away from the electron-
withdrawing lactone ring C. Taking into account strain
release, the equatorial a-CH bond at position C-2 of ring A
is both the least sterically hindered and, due to the presence of
two 1,3-diaxial interactions of the axial hydrogen at position
C-2, expected to be most prone to the effects of strain release
in the transition state of oxidation. Indeed, when commer-
cially available sclareolide (15) was submitted to Du Boisꢀ
nitrene insertion chemistry,[3l] product 16 (verified by NMR
spectroscopy, see Supporting Information for details) was
obtained in nearly quantitative yield (based on sulfonamide).
The reactivity comparison of 1 and eudesmane probe 3
brings to light the previously unrecognized importance of a
À
ratios in oxidative C H activations are expected to be much
smaller than in chromic acid oxidations of secondary alcohols
(see Scheme 2A), leading us to consider the observed ratios
of Scheme 4 as significant. There is a parallel between these
observations and those of classical solvolysis studies wherein
similar rate differences are observed.[10] As alluded to above,
these results suggest that strain release considerations can
help to predict not only relative rate but also selectivity in
complex settings.
In an attempt to delineate the scope of this conclusion, a
series of experiments involving dioxirane, carbene, and
nitrene C H activation were conducted on 1,1-dimethylcy-
clohexane (8). If the strain release factor was operative also in
methylene C H activation, one would expect these condi-
À
À
À
tions to favor activation at the C-3 carbon. As shown in
Scheme 5, after correcting for statistics, TFDO and carbene
activation show little to no site specificity (ca. 1:1) while
nitrene activation shows a small effect (ca. 1.5:1 favoring C-
3). The transition state is likely to be more tight in insertion
reactivity factor in C H activation that is in all likelihood
attributable to strain release, since both the steric and
electronic characteristics of these two substrates are nearly
identical at the reacting site. The corroboration of these
results in other settings will of course require more experi-
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Polo, X. Sala, X. Ribas, M. Costas, Angew. Chem. 2009, 121,
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[5] K. Chen, P. S. Baran, Nature 2009, 459, 824 – 828.
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is tempting to consider that the remarkably consistent rate
À
differences in C H activation of equatorial versus axial
À
[6] We use the term “C H bond nucleophilicity” when referring to
À
tertiary C H bonds (see Scheme 1) may result from a
the “electronic reactivity factor”. It seems to us that this term
pragmatically denotes the effect of what hyperconjugative and
inductive electronic effects might transmit from neighboring
substituents to the reaction site. Thus, this term can refer to both
À
cooperation of reactivity factors that involve 1) C H bond
nucleophilicity, 2) steric hindrance to reagent approach, and
3) strain release in transition state formation. Most impor-
tantly, the work presented here may aid in the planning and
execution of total syntheses that rely on the simplifying power
À
activation as well as deactivation of the C H bond by
À
neighboring substituents towards electrophilic “C H activation”
insertion reactions.
À
of C H activation logic.
[7] J. Schreiber, A. Eschenmoser, Helv. Chim. Acta 1955, 38, 1529 –
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Received: August 11, 2009
Revised: October 29, 2009
Published online: November 24, 2009
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À
Keywords: C H functionalization · conformational analysis ·
natural products · strain release
.
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À
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À
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