Stereoselective [4+2]-Cycloaddition with Chiral Alkenylboranes

Article abstract of DOI:10.1002/anie.202000652

A method for the stereoselective [4+2]-cycloaddition of alkenylboranes and dienes is presented. This transformation was accomplished through the introduction of a new strategy that involves the use of chiral N-protonated alkenyl oxazaborolidines as dieneophiles. The reaction leads to the formation of products that can be readily derivatized to more complex structural motifs through stereospecific transformations of the C?B bond such as oxidation and homologation. Detailed computation evaluation of the reaction has uncovered a surprising role of the counterion on stereoselectivity.

Full text of DOI:10.1002/anie.202000652

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Cycloaddition
Hot Paper
Stereoselective [4+2]-Cycloaddition with Chiral Alkenylboranes
Dongshun Ni, Brittany P. Witherspoon, Hong Zhang, Chen Zhou, K. N. Houk,* and
M. Kevin Brown*
Abstract: A method for the stereoselective [4+2]-cycloaddi-
tion of alkenylboranes and dienes is presented. This trans-
formation was accomplished through the introduction of a new
strategy that involves the use of chiral N-protonated alkenyl
oxazaborolidines as dieneophiles. The reaction leads to the
formation of products that can be readily derivatized to more
complex structural motifs through stereospecific transforma-
bond.[10] For example, enantioselective [4+2]-cycloadditions
of alkenylarenes and dienes are unknown, but could be
formally accomplished through [4+2]-cycloaddition with
alkenylboranes and subsequent stereospecific cross-coupling
with aryl halides (Scheme 1B).
Several reports have described the development of
stereoselective [4+2]-cycloadditions with chiral vinylboranes
(Scheme 2B).[5h,r,z,ab,6e] In 1997, Avery and co-workers report-
ed the reaction of vinylborane 1 with isoprene to provide the
cycloadduct in 63:33 er after oxidation. Due to the use of
a boronate ester, high reaction temperature was necessary,
which may be detrimental to selectivity.[5r] More recently,
Pisanao and Pellegrinet described the cycloaddition of (+)-2-
carene derived vinylborane 2 with cyclopentadiene to gen-
erate the product in 70:30 er after oxidation.[5z] Since the more
reactive alkylhalovinylborane was used, the reaction temper-
atures were significantly lower compared to use of a boronate
À
tions of the C B bond such as oxidation and homologation.
Detailed computation evaluation of the reaction has uncovered
a surprising role of the counterion on stereoselectivity.
Introduction
The [4+2]-cycloaddition is an important method in
modern organic chemical synthesis due to the facility with
which a diverse range of cyclohexene rings can be construct-
ed.[1] A key milestone in the development of [4+2]-cyclo-
additions was the identification of chiral auxiliaries with
acrylate-based dieneophiles that allow control of absolute
stereochemistry.[2] These advances ultimately paved the way
for the introduction of chiral catalysts to control the
enantioselectivity of the cycloaddition (Scheme 1A).[3]
À
ester. However, the lack of rigidity due to the rotatable alkyl
B bond may be, in part, the source of the moderate facial
selectivity.[6e]
Additional progress in the field of [4+2]-cycloadditions Results and Discussion
led to the realization that other electron-deficient alkenes
would undergo reaction at reasonable rates.[4] This ultimately
led to the development of alkenylborane cycloadditions,
which was first described by Matteson and Waldbilling in 1963
(Scheme 1B).[5–9] In sharp contrast to reaction of unsaturated
carbonyls, the translation of alkenylborane [4+2]-cycloaddi-
tions to the realm of enantioselective synthesis has yet to be
achieved with high selectivity. Development of such a process
would render unknown enantioselective [4+2] cycloadditions
To develop an auxiliary that combines the characteristics
of high reactivity (low-lying LUMO) and rigidity, the strategy
shown in Scheme 2B was explored. It was reasoned that if an
alkenyl oxazaborolidine could be protonated with a Brønsted
acid, cationic adduct 5 would be generated that would possess
À
attainable through stereospecific transformation of the C B
[*] D. Ni, C. Zhou, Prof. M. K. Brown
Department of Chemistry, Indiana University
800 E. Kirkwood Ave., Bloomington, IN 47401 (USA)
E-mail: brownmkb@indiana.edu
B. P. Witherspoon
Current Address: Janssen Research & Development, LLC
3210 Merryfield Row, San Diego, CA 92121 (USA)
H. Zhang, Prof. K. N. Houk
Department of Chemistry and Biochemistry
University of California, Los Angeles, CA 90095 (USA)
E-mail: houk@chem.ucla.edu
H. Zhang
Current Address: College of Chemistry and Chemical Engineering
Xiamen University, Xiamen 361005 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202000652.
Scheme 1. Key developments in [4+2]-cycloadditions.
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Scheme 2. Strategies for stereoselective [4+2]-cycloaddition with chiral
alkenylboranes.
the features of high reactivity and rigidity. Initial efforts were
directed towards the use of diphenylprolinol (6)-derived
alkenylboranes for several reasons: 1) related aryl and alkyl
oxazaborolidines are known to be stable since they have been
used as pre-catalysts for a variety of enantioselective trans-
formations.[3b,11] 2) Activation of aryl oxazaborolidine with
Lewis acids or Brønsted acids has been demonstrated.[11]
3) Diphenylprolinol is commercially available and costs less
than $2gÀ1 from a variety of suppliers; furthermore deriva-
tives are easily prepared from proline.
Synthesis of alkenyl oxazaborolidine 8 was readily ach-
ieved in high yield through azeotropic removal of water from
an equimolar mixture of alkenylboroxine pyridine complex
7[12] and diphenylprolinol (6). The generated alkenyl oxaza-
borolidine 8 was used without purification as a solution in
dichloromethane. Early studies revealed that addition of
Tf2NH to oxazaborolidine 8 and myrcene led to formation of
the cycloadducts 10 and 11 after oxidation. While the
enantioselectivity for the major regioisomer 11 is moderate
(75:25), it was encouraging and served as a proof of concept
and starting point for further optimization. Based on the
absolute stereochemistry of product 11, it was proposed that
the major stereoisomer is generated when the diene ap-
proaches the bottom face of the alkenylborane as shown in 12
(Scheme 3B). Conversely, the minor stereoisomer is likely
formed by approach of the diene from the top face (13). To
design a more effective chiral auxiliary, we hypothesized that
placement of a substituent on the concave face of the 5/5-ring
system could further disfavor approach from the top face, thus
enhancing facial selectivity (see 14).
Scheme 3. Initial Studies.
the aid of chromatographic purification (Scheme 4A). The
simplicity of this synthesis enables facile derivatization of the
chiral auxiliary. Condensation with the alkenylboroxine
pyridine complex 7 led to formation of the oxazaborolidine
18 in good yield.
With access to alkenylborane 17, cycloaddition with
myrcene led to the formation of product 11 with good yield,
and importantly, improved selectivity (Scheme 4B, entry 1)
when compared to reactions with 8. While reactions per-
formed at lower temperatures resulted in higher selectivity,
the yield was diminished due to incomplete conversion
(Scheme 4B, entries 2–3). Reaction optimization through
modulation of the Brønsted or Lewis acid activator was
ineffective (Scheme 4B, entries 4–7). Steric modulation of the
aryl units resulted in an increase in enantioselectivity, but with
a concomitant decrease in yield (Scheme 4B, entry 8).
Fortunately, the yield was improved through the use of
1.0 equiv of Tf2NH (Scheme 4B, entry 9).
Having optimized the conditions for this reaction, a variety
of dienes were evaluated with alkenylborane 18. As shown in
Scheme 5, 2-alkyl- and 2-aryl-substituted dienes underwent
reaction with high selectivity (products 11, 21—23, and 25–
31). Cyclopentadiene also functioned well to generate 24 with
high levels of diastereo- and enantioselectivity. Vinyl oxaza-
borolidine 20 could also be used and enabled the highly
enantioselective synthesis of products 32–36. Particularly
successful was the use of 2-phenyl butadiene, since product 35
Based on the hypothesis outlined in Scheme 3B (14), an
auxiliary based on commercially available l-octahydroindole-
2-carboxylic acid (15) was selected. The amino alcohol 16 was
easily prepared in three steps on a multigram scale without
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Scheme 4. A) Synthesis octahydroindole-derived reagents.[21] B) Opti-
mization of the [4+2]-cycloaddition. [a] Regioisomeric ratio (rr) of para
(11) to meta (10) isomers. [b] Yield of product after isolation by silica
gel column chromatrogaphy. [c] Yield determined by analysis of the
unpurified reaction mixture by 1H NMR. [d] Enantiomeric ratio (er) is
of the para isomer (11) and was determined by HPLC analysis with
a chiral column after derivatization.
Scheme 5. Substrate scope. Yield of product after isolation by silica gel
column chromatrogaphy are shown and are the average of two runs.
Regioisomeric ratio (rr) is of para to meta isomers. Enantiomeric ratio
(er) is of the para isomer and was determined by HPLC analysis with
a chiral column after derivatization. [a] Due to sample volatility, yield
was generated in 99:1 er. In the case of cyclopentadiene,
a mixture of endo- and exo-diastereomers 37a and 37b was
formed. This stands in contrast to the reaction of isopropenyl
borane 18 with cyclopentadiene, in which a single observable
diastereomer was formed (product 24). While high levels of
enantioselectivity are achieved for many examples, limita-
tions were uncovered when the alkenylborane was substituted
for any group other than a methyl at the 1-position, likely for
steric reasons. For example, reaction of an oxazaborolidene in
which R1 = nBu or substitution at the 2-position did not give
product formation. In addition, 1-substiuted or 2,3-disubsti-
tuted dienes were not tolerated.
Cycloadditions of 1,2-disubstituted diene 38 with 18 or 20
enabled the synthesis of 39 or 40, respectively, with high levels
of enantio- and diastereoselectivity (Scheme 6). The absolute
configuration of each was confirmed by X-ray crystallogra-
phy.
1
determined by analysis of the unpurified reaction mixture by H NMR
with an internal standard.
Due to the availability of the starting materials, the ease of
the alkenylborane preparation, and the subsequent cyclo-
addition conditions, this approach was amenable to gram-
scale synthesis (Scheme 7). Starting from 5.0 mmol of octa-
hydrodindole 16, cycloadducts 42 and 43 could be isolated
with good yield and selectivity. In these cases, the reaction was
treated with pinacol to provide direct access to the pinacol-
boronate ester. In addition, for larger scale operations,
octahydroindole 16 could be recovered in 85% and 92%
yield, respectively. Thus, while this process does use stoichio-
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Scheme 6. Cycloaddition with 1,2-disubstituted dienes.[21]
Scheme 8. Transformations of products. See the Supporting Informa-
tion for details.
manipulation of the ester- or ketone-based products that are
typically derived from known [4+2]-cycloadditions.
To provide support for the role of Tf2NH in this reaction,
NMR analysis of the oxazaborolidine was carried out
(Scheme 9). Upon treatment of 20 with 1.0 equiv of Tf2NH,
significant downfield shifts for many of the signals were
Scheme 7. Preparative-scale reactions and synthesis of boronates.
metric quantities of a chiral component, it can be easily
recycled.
À
Owing to the versatility of the C B bond, the pinacolbor-
onate ester products can be elaborated in various ways. In
addition to the oxidative workups shown in Schemes 5–6 that
À
led to formation of the corresponding alcohol, various C C
bond-forming processes were investigated. Starting from 43,
homologation (44),[13] olefination (45),[14] and arylation (46
and 47)[15,16] processes were achieved. In each case, the
reactions were stereospecific since only a single diastereomer
was observed. In addition, the derived secondary alcohol can
also be used to generate secondary fluoride 48 with inversion
of configuration.[17] The transformation of a Bpin-substituted
quaternary carbon proved to be more difficult with estab-
lished reaction methods. However, arylation with 2-lithiofur-
an did lead to the formation of 49 from 42.[15] We expect that
with additional innovations in the transformation of Bpin-
substituted quaternary carbons, the utility of these products
beyond oxidation and arylation will be improved.[10] Finally, it
is important to note that all of the products illustrated in
Scheme 8 would be challenging to prepare with traditional
enantioselective [4+2]-cycloadditions. For example, enantio-
selective preparation of furan 49 would require extensive
Scheme 9. 1H NMR spectra of oxazaborolidine and N-protonated
oxazaborolidine.
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Figure 1. DFT studies of the [4+2]-cycloaddition with the counterion omitted. Energies reported in kcalmolÀ1, interatomic distances are in
ꢀngstrçms.
observed in the 1H NMR spectrum, thus indicating the likely
formation of 50. In addition, downfield shift for the boron
atom and the C2-alkene carbon (the C1 carbon of the alkene
could not be detected by 13C NMR due to quadrupolar
relaxation of the boron) were also observed. In particular, the
resonances were shifted downfield, thus suggesting that
protonation with Tf2NH decreases the electron density at
these positions.
To probe the basis for the observed enantioselectivity, we
investigated the energy landscape with density functional
theory (DFT) calculations at the CPCM(dichloromethane)-
wB97X-D/def2-QZVPP//B3LYP/6-31G level of theory (see
the Supporting Information).[18] There are four possible
[4+2]-cycloaddition transition structures (TS) that lead to
the observed regioisomer. In addition, the N-protonated
alkenyl oxazaborolidine can adopt two conformations (oxy-
gen-syn-to-vinyl and nitrogen-syn-to-vinyl). Thus, a total of
eight TS structures were located for the [4+2] cycloaddition
between chiral N-protonated alkenyl oxazaborolidine 20 and
2-phenyl butadiene. The computed potential energy profiles
are summarized in Figure 1A. For the oxygen-syn-to-vinyl TS
conformers, the endo TSA was the lowest in energy, which
follows traditional [4+2]-cycloaddition endo paradigms and
leads to formation of the observed enantiomer. TSE is close in
energy to TSA (DDG° = 0.6 kcalmolÀ1), but leads to forma-
tion of the minor enantiomer (Figure 1B).[19] Given the high
levels of enantioselectivity observed in this reaction (99:1 er),
a DDG° of at least 2.5 kcalmolÀ1 would be expected. There-
fore, a key aspect of the reaction that is crucial for selectivity
must have been omitted from the model chosen for calcu-
lations.
The component of the reaction that was absent from the
calculations was the counterion, bis(trifluoromethane)sulfo-
namide. To further explore the effects of the counterion on
the stereoselectivity, we re-computed TSA and TSE, but now in
the presence of the counterion (Figure 2). In the case TSA-
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Figure 2. DFT studies of the [4+2]-cycloaddition with the counterion included. Energies reported in kcalmolÀ1, interatomic distances are in
ꢀngstrçms.
NTf2, the counterion optimizes close to the HN+, forming
a hydrogen-bonded tight-ion pair. In TSE-NTf2, the hydrogen-
bonding and close association of the cation of N-protonated
alkenyl oxazaborolidine 20 and the anion is unachievable due
to steric pressure with the diene, and instead, conformations
without NÀ-HN+ hydrogen bond have to be adopted. There-
fore, the counterion was positioned at the most electro-
between the methyl group of the alkenylborane and the
methylene unit of cyclopentadiene disfavors the endo ap-
proach. The observations made here with cyclopentadiene
and 20 are consistent with those made in related [4+2]-
cycloadditions with 2-substituted acrolein derivatives.[3]
positive regions of TSE with two different orientations, TSE- Conclusion
NTf2(1) and TSE-NTf2(2). Thus, TSA-NTf2 is substantially
lower in energy (DDG° = 8.1 kcalmolÀ1 and 8.6 kcalmolÀ1)
than TSE-NTf2(1) and TSE-NTf2(2). The trend observed from
these data shows that the strong association of the counterion
with the TS structure greatly influences the stereoselectivity
of the reaction.[20]
Based on the computed transition structures shown in
Figure 2, we can confidently illustrate models to rationalize
the observed selectivity for the other substrate classes (Fig-
ure 3). In the case of isopropenyl oxazaborolidine 18, TSI is
likely operative. Regarding the reaction of cyclopentadiene
with vinylborane 20, endo-approach TSJ appears to be slightly
favored (See Scheme 5, products 37a,b). However, with
isopropenyl borane 18, the exo-approach TSK is preferred
(See Scheme 5, product 24). It is likely that steric pressure
In conclusion, we have introduced a method that ad-
dresses the long-standing challenge of stereoselective [4+2]-
cycloadditions with chiral alkenylboranes. This was achieved
through the introduction of a new strategy that enables in situ
generation of a highly reactive dienophile. The products of
these reactions enable the formal synthesis of cycloadducts
that would be challenging to access with existing [4+2]-
cycloaddition strategies. In addition, mechanistic investiga-
tions uncovered a significant role of the counterion in
influencing the conformation of the dienophile and the
stereoselectivity of the reaction. Finally, the approach out-
lined here introduces a strategy that suggests that achiral
oxazaborolidines in combination with chiral Brønsted acids
could enable the development of catalytic enantioselective
variants, and studies along these lines are currently under
investigation.
Acknowledgements
We thank Indiana University and a NSF CAREER award
(CHE1554760) for financial support. This project was parti-
ally funded by the Vice Provost for Research through the
Research Equipment Fund and the NSF (CHE1726633 and
Figure 3. Transition structures for other substrates classes.
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Conflict of interest
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The authors declare no conflict of interest.
Keywords: alkenylboranes · chiral auxiliaries · cycloaddition ·
dienes · synthetic methods
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[19] A similar observation was also made with isoprene. See the
Supporting Information for details.
[20] While the tight hydrogen bond interaction in TSA-NTf2 slightly
raises the LUMO relative to conformations that lack a tight
hydrogen bond, as is reflected in the 1 kcalmolÀ1 higher
&&&&
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Angewandte
Research Articles
Chemie
activation energy in the contact ion pair, the energy to separate
the ions is much larger than this small increase in activation
energy.
are provided free of charge by The Cambridge Crystallographic
Data Centre.
[21] CCDC 2001031 (18), 2001033 (39), and 2001034 (40) contain the
supplementary crystallographic data for this paper. These data
Manuscript received: January 14, 2020
Revised manuscript received: March 21, 2020
Version of record online: && &&
,
&&&&
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ꢀ 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
&&&&
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Research Articles
Cycloaddition
D. Ni, B. P. Witherspoon, H. Zhang,
C. Zhou, K. N. Houk,*
M. K. Brown*
&&&& — &&&&
Stereoselective [4+2]-Cycloaddition with
Chiral Alkenylboranes
Stereoselective [4+2]-cycloaddition of
alkenylboranes and dienes was accom-
plished through the introduction of chiral
N-protonated alkenyl oxazaborolidines as
dieneophiles. The reaction gives products
that can be readily derivatized to more
complex structural motifs through ste-
À
reospecific transformations of the C B
bond such as oxidation and homologa-
tion. DFT calculations uncovered a sur-
prising effect of the counterion on ste-
reoselectivity.
&&&&
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ꢀ 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2020, 59, 2 – 10
These are not the final page numbers!