N-B dative bond-induced [3.3.0] bicyclic boronate-tethered exo-selective intramolecular Diels-Alder reaction

Article abstract of DOI:10.1039/c5ob00917k

We report herein a highly exo-selective intramolecular Diels-Alder reaction of alkenyl boronates which employs an N-B dative bond-involved bicyclic rigid tether. Complex C(sp³)-rich polycyclic molecules containing up to 8 stereocenters can be readily formed via an operationally simple two-step procedure.

Full text of DOI:10.1039/c5ob00917k

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N–B dative bond-induced [3.3.0] bicyclic
boronate-tethered exo-selective intramolecular
Diels–Alder reaction†
Cite this: DOI: 10.1039/c5ob00917k
Received 6th May 2015,
Accepted 20th May 2015
Chao Feng, Hong Wang, Liang Xu and Pengfei Li*
DOI: 10.1039/c5ob00917k
www.rsc.org/obc
We report herein a highly exo-selective intramolecular Diels–Alder a convenient precursor that can be readily transformed to the
reaction of alkenyl boronates which employs an N–B dative bond- desired functional groups. Boron-substituted building blocks
involved bicyclic rigid tether. Complex C(sp3)-rich polycyclic mole- therefore provide an attractive strategy because C–B bonds may
cules containing up to 8 stereocenters can be readily formed via be reliably installed before and converted into C–O, C–N or
an operationally simple two-step procedure.
C–C bonds after the Diels–Alder reaction. Alkenyl boronates
were first used in [4 + 2] cycloadditions more than five decades
ago by Matteson4 and Woods.5 Later on, various alkenylboron
reagents including dialkyl boranes,6 boron dihalides,7 boronic
acids and boronates8 have been studied and a review has sum-
marized the important progress.9 Recently, this strategy has
been successfully applied in the total synthesis of pancratista-
tin and lycorine.10 Despite the mentioned significant advance-
ment, in many cases, the reactions suffered from low
reactivity, low endo/exo selectivity and/or low functional group
tolerance. During our studies on new organoboron reagents,11
we have been interested in the stereoselective cycloadditions of
alkenyl boronic acids taking advantage of new masking struc-
tures on boron atoms. Herein, we wish to report a highly exo-
selective intramolecular Diels–Alder reaction with a broad sub-
strate scope.
The Diels–Alder reaction, constructing six-membered rings by
stereospecific [4 + 2] cycloadditions, has shown unparalleled
efficiency in the field of chemical synthesis, especially of
natural products.1,2 Still, however, many complex biologically
important molecules, such as the ones shown in Fig. 1,3
contain highly functionalized six-membered rings that may
not be directly disconnected by the conventional [4 + 2] mode
due to the presence of multiple oxygen and/or nitrogen substi-
tuents. One possible solution to this problem would be using
N-methyliminodiacetic acid boronates (MIDA)12 and dietha-
nolamineboronates (DABO)13 are relatively stable surrogates of
boronic acids and the former, particularly, have shown great
potential in chemoselective Suzuki–Miyaura coupling.11a,12,14
Structurally, these compounds include a rigid [3.3.0] bicyclic
moiety where the bridgehead nitrogen and boron atoms are
connected by an N to B dative bond.15 Thus the two substitu-
ents R and Y (Scheme 1a) are of cis configuration with little
Fig. 1 Selected examples of six-membered carbon rings in natural
products.
Centre for Organic Chemistry, Frontier Institute of Science and Technology (FIST),
Xi’an Jiaotong University, 99 Yanxiang Road, Xi’an, Shaanxi 710054, China.
E-mail: lipengfei@mail.xjtu.edu.cn
†Electronic supplementary information (ESI) available: Experimental details,
spectroscopic data for new compounds and X-ray diffraction data. CCDC
1058696 and 1058694. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c5ob00917k
Scheme 1 N–B dative bond-tethered intramolecular Diels–Alder
reaction.
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conformational flexibility. We therefore wondered if such a
structural preorganization might be employed in intra-
molecular Diels–Alder reaction to promote the reaction of elec-
tronically unactivated substrates and to induce not only high
regioselectivity but also high stereoselectivity. To forge this
well-defined framework in a highly modular manner, we
planned to condense an alkenyl boronic acid and an amino-
diacetic acid or an aminodiethanol on which a diene is prein-
stalled (Scheme 1b).
We firstly chose to use an iminodiacetic acid tether, i.e.
where X is O in Scheme 1b. The diene-incorporated iminodi-
acetic acid 1 and the alkenyl boronic acids 2 were readily pre-
pared by routine methods (for Experimental details, see the
ESI†). We then tested the design by a two-step process invol-
ving intermolecular dehydrative condensation and intra-
molecular cycloaddition. Thus, heating a mixture of (E)-styryl
boronic acid (2a, 1.0 equiv.) and N-dienyliminodiacetic acid (1,
1.1 equiv.) in toluene and DMSO (10 : 1, v/v) containing 4 Å
molecular sieves at 80 °C cleanly gave the desired MIDA boro-
nate-type compound 3a, as evidenced by the characteristic AB-
1
type –CH2– signals in H NMR spectrum of the crude product
(chemical shift 4.06, 4.16 ppm, coupling constant 16.8 Hz).
This crude compound can be used without further purification
for the key [4 + 2] cycloaddition reaction. Thus, simply heating
a solution of 3a in 1,2-dichlorobenzene at 160 °C for 8 hours
led to full conversion, affording a single observable isomer
according to 1H NMR analysis of the crude product. After puri-
fication by flash chromatography on silica gel, extensive NMR
experiments including 1H–1H COSY, HSQC and HMBC sup-
ported an exo-[4 + 2] cycloaddition product 4a (64% yield over
Scheme 2 Substrate scope of MIDA-type boronate tethered intra-
molecular Diels–Alder reactions.
two steps based on (E)-styryl boronic acid). The structure was densation process. Therefore, in a single step, the final
further confirmed by X-ray diffraction analysis of a single product was readily prepared.
crystal of 4a.16 Notably, this compact cage-like heteropropel-
Encouraged by the above results, we extended the process
lane structure contains five rings and four of them are annu- to DABO boronate-like substrates. Literature studies have indi-
lated non-aromatic rings. cated that the DABO structures are less rigid than the MIDA
We next explored the scope of this tethered D–A reaction. counterparts.12b In this work, nevertheless, we were able to
The results are shown in Scheme 2. Remarkably, in all cases, employ the DABO-type N–B coordination tether for successful
only one stereoisomer was observed, in sharp contrast to pre- intramolecular [4 + 2] reaction. The dehydration step could be
vious DA reactions of alkenyl boronates where a mixture of smoothly done under mild conditions. Thus, the two com-
endo and exo products were usually formed.9,17 Various substi- ponents (5 and 2, Scheme 3) were stirred with anhydrous mag-
tuents on the phenyl ring (Me, OMe, SMe, F, Cl and Br) were nesium sulphate in dichloromethane at ambient temperature
well tolerated, affording the respective cycloaddition products to complete the condensation step. After the removal of the
(4b–4i) in two steps in good to excellent yields. 2-Thiophenyl solids by filtration, the crude product was immediately used in
was also compatible in this D–A approach (4j), giving the the intramolecular [4 + 2] reaction with conditions similar to
product in 80% yield. In addition, aliphatic alkenyl boronic the MIDA-like cases. Again, only the exo-stereoisomer was
acids could be successfully used in this process and the pro- obtained. The substrate scope was briefly surveyed. In all cases,
ducts were isolated in high yields and high exo-selectivity (4k a very good exo-selectivity was achieved. Substituents such as
and 4l). These results suggest that the generally excellent methyl, methoxy, methylmercapto, nitro and chlorine groups on
stereocontrol is governed by the N–B dative bond-induced the phenyl rings (7b–7f), and a phthalimide group (7g) were all
rigid [3.3.0] bicyclic moiety. Alkenyl boronic acids bearing elec- tolerated and the corresponding cycloaddition products were
tron-withdrawing groups are often prone to decomposition isolated in moderate to good yields. It is worth noting that cyclo-
due to protodeboronation, thus posing challenges for further hexenone-3-boronic acid (2o), which had led to low yield of the
transformations. To our satisfaction, β-carbonyl alkenyl product (4o) in the MIDA-type case, now served as an efficient
boronic acids were also viable in our system, although only dienophile, giving a D–A product 7h in good yield. This
moderate yields were obtained (4m–4o). Interestingly, in the outcome might be attributable to the mild condensation con-
case of 4m, D–A reaction occurred during the dehydrative con- ditions that prevent the decomposition of 2o.
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Scheme 5 Computational study of the endo/exo selectivity of 3a.
An enantiopure aminodiol (8, Scheme 4) was prepared from
D-phenylglycinol and (S)-(−)-propylene oxide by epoxide
opening and alkylation. When 8 was heated with (E)-styryl
boronic acid at 80 °C, the condensation proceeded smoothly
and was accompanied by concomitant partial intramolecular
[4 + 2] reaction. Without separation, the crude product was
subjected to the next reaction at 160 °C. Theoretically, de-
hydrative condensation of 8 with (E)-styryl boronic acid may form
two cis diastereomers, (2R,4SN,5R,8SB)-6o and (2R,4RN,5R,8RB)-6i
that are thermodynamically interconvertible via N–B bond
cleavage, ring flipping and N–B bond reformation.15a Isomer 6i
should be disfavoured because the steric collapsing between
2-methyl and 5-phenyl groups would lead to significant struc-
tural distortion. Further [4 + 2] cycloaddition of 6o and 6i there-
fore might form four stereoisomers (7io, 7i′o, 7ii and 7i′i). In
practice, two isomers of the final product were observed in a
1 : 1 NMR ratio and isolated in high overall yield (80%). A
single crystal of one isomer was obtained and its relative and
absolute configuration was thus identified as 7io (shown in
Scheme 4) by X-ray diffraction analysis.18 The other isomer was
therefore deduced to be 7i′o. Remarkably, in this operationally
simple two-step procedure, complex sp3-rich polycyclic mole-
cules containing up to 8 stereocenters were readily formed.
In order to understand the origin of the exceptionally high
exo/endo selectivity in this tethered intramolecular [4 + 2] reac-
tion, density functional theory (DFT) calculations were per-
formed at the M06/6-31G* level of theory (Scheme 5). The
intramolecular [4 + 2] reaction of 3a was selected as the model
reaction. TSen and TSex represent the transition states of endo-
selective and exo-selective reaction channel respectively. Com-
pared with the lowest-lying conformation of 3a, the gas phase
activation free energy barrier for TSex is 26.1 kcal mol−1, and
TSen is located 3.2 kcal mol−1 higher than TSex. This energy
difference indicates the intramolecular [4 + 2] reaction to be
highly exo-selective, in consistence with the experimental
results.
Scheme 3 Substrate scope of DABO-type boronate tethered intra-
molecular Diels–Alder reactions.
Conclusions
In summary, a highly exo-selective intramolecular Diels–Alder
reaction has been developed which utilizes an N–B dative
bond-induced [3.3.0] bicyclic boronate unit as the structurally
well-defined tether. In an operationally simple two-step
process, various readily available alkenyl boronic acids were
Scheme 4 NB tether-induced stereoselective intramolecular [4 + 2]
reaction.
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successfully used as the dienophile, affording the [4 + 2] cyclo-
addition products in high yields and stereoselectivity. We are
currently studying to extend this reaction for asymmetric syn-
thesis of complex biologically important molecules.
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Acknowledgements
We are grateful for financial support by the National Science
Foundation of China (no. 21202129 and 21472146) and the
Ministry of Science and Technology of PRC (973 program for
young scientists, no. 2014CB548200). We thank Yousong Ding
for the X-ray crystallography analyses.
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