Rhodium-catalyzed domino enantioselective synthesis of bicyclo[2.2.2] lactones

Article abstract of DOI:10.1002/anie.201101773

Once, twice, three times a catalyst! A novel domino rhodium(I)-catalyzed asymmetric transformation of substituted oxabicyclic alkenes into bicyclo[2.2.2]lactones proceeded with good yields (up to 78 %) and excellent stereoselectivity (>97 % ee; see scheme; cod=1,5-cyclooctadiene, Tf=trifluoromethanesulfonyl). Mechanistic investigations suggest that this process proceeds by rhodium-catalyzed asymmetric ring opening, allylic alcohol isomerization and oxidation. Copyright

Full text of DOI:10.1002/anie.201101773

Communications
DOI: 10.1002/anie.201101773
Domino Reactions
Rhodium-Catalyzed Domino Enantioselective Synthesis of Bicyclo-
[2.2.2]lactones**
Alistair Boyer and Mark Lautens*
Increasing focus is placed upon achieving efficiency in
processes and syntheses in organic chemistry. The combina-
tion of multiple reactions into domino sequences is an
excellent way to achieve efficiency, with several operations
proceeding in concert without recourse to expensive and
wasteful purification at each intermediate stage.[1] The
rhodium-catalyzed asymmetric ring-opening (ARO) reaction
of strained oxabicyclic alkenes using heteroatom nucleophiles
has been well-studied and been demonstrated to be a highly
efficient enantioselective process (e.g. 1!2, Scheme 1).[2–4]
alkaloids is an aminotetralin core (Scheme 1; dashed box),
which we reasoned could be created efficiently with ARO
chemistry. Previously, the ARO reaction of bridgehead
unsubstituted oxabicyclic alkenes has been demonstrated to
be effective for a wide range of nucleophiles, to give products
in excellent yield and enantioselectivity.[2–4] The incorporation
of one symmetry-breaking substituent at the bridgehead has
been demonstrated to be tolerated, resulting in regiodiver-
gent resolution to two products, each in approximately 50%
yield. Recognizing that the aminotetralin core of the ergoline
natural product family is highly substituted, we sought a
more-functionalized building block and selected the doubly
bridgehead substituted oxabicyclic alkene 3. This substrate
was readily available in two steps from furfuryl alcohol.[7]
The increased steric demand of the two hydroxymethyl
groups coupled with their inductive electron-withdrawing
nature meant that many of the catalysts previously employed
in the ARO reaction[3] failed to induce ring opening (Table 1;
Table 1: Effect of counter-ion and reaction conditions.
Scheme 1. An overview of the nucleophilic asymmetric ring-opening
reaction. (R,Sp)-Josiphos=(R)-(ꢀ)-1-[(SP)-2-(diphenylphosphino)-ferro-
cenyl]-ethyldi-tert-butylphosphine.
Entry
Additive
Conditions[a]
Yield [%]
Yield [%]
(ee [%])[b]
(ee [%])[c]
However, rhodium is also capable of many other catalytic
transformations owing to its reactivity with p bonds, alcohols,
aldehydes, and boronic acids.[5] Herein, we report a novel
domino process in which rhodium is demonstrated to perform
three distinct roles: ARO, allylic alcohol isomerization, and
oxidation (3!5, Scheme 1).
1
2
3
4
nBu4NI[d]
0.1m, 608C, 1 h
0.1m, 608C, 1 h
0.1m, 608C, 1 h
0.3m, 608C, 18 h
no reaction
[e]
NH4BF4
20 (n.d.)
65 (98)
–
–
–
[f]
–
–
[g]
65 (98)
[a] Oxabicyclic alkene diol (0.2 mmol, 1 equiv), amine nucleophile
(1.1 equiv). [b] Yield of the isolated product after column chromato-
graphy on silica gel. [c] The ee value was determined by HPLC using a
chiral stationary phase. [d] 20 mol%. [e] 1 equiv. [f] A comparable yield of
4a was obtained with 1 equiv of water. [g] Molecular sieves (4 ꢀ) were
used in catalyst preparation. cod=1,5-cyclooctadiene, n.d.=not deter-
mined, THF=tetrahydrofuran, Tf=trifluoromethanesulfonyl.
The ergoline alkaloids are often described as the most
potent family of natural products.[6] The core motif of these
[*] Dr. A. Boyer, Prof. Dr. M. Lautens
Department of Chemistry
University of Toronto
80 St. George St., Toronto, Ontario, M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
Homepage: http://www.chem.utoronto.ca/staff/ML/
entries 1 and 2). Conversely, the cationic RhOTf/Josiphos
system was able to promote the desired transformation in
only 1 hour. At low concentrations, the reaction gave only the
product resulting from the ARO reaction (4a) with good yield
and excellent enantioselectivity (Table 1; entry 3). However,
upon an increase in the reaction concentration, an extension
of the reaction time, and with the exclusion of moisture, we
observed the clean formation of a new compound whose IR
and 13C NMR spectra indicated the presence of a lactone
[**] We gratefully acknowledge Steven G. Newman for valuable
mechanistic studies, Dr. Alan Lough for single crystal X-Ray
structure analysis; the University of Toronto and NSERC for
financial support; and Solvias AG for the generous gift of chiral
ligands.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101773.
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Angew. Chem. Int. Ed. 2011, 50, 7346 –7349

Table 2: (Continued)
Entry[a]
Nucleophile
(Table 1, entry 4). Full analysis of the spectral data revealed
the product to be the [2.2.2]bicyclic compound 5a.
Product
Yield
[%][b]
ee
[%][c]
To investigate this process, the reaction between a range
of secondary amine nucleophiles and a selection of substi-
tuted oxabicyclic alkenes was explored. The reaction gave the
lactone products 5 with uniformly high levels of stereoselec-
tivity for all the amines that were investigated, including those
with hydrocarbon substituents (5a–f, Table 2) as well as
amines bearing ether, acetal and ester functionalities (5g–i,
Table 2). Although chiral amine nucleophiles such as (S)-N-
methyl-1-phenylethanamine j have been demonstrated to
induce selectivity in many organic transformations,[8] the
powerful rhodium catalyst/ligand system was unaffected by
9
60
>98
10
48
45
>20:1 d.r.
>20:1 d.r.
Table 2: Domino formation of bicycle[2.2.2]lactones with dialkylamine
nucleophiles.
11[e]
Entry[a]
Nucleophile
Product
Yield
[%][b]
ee
[%][c]
[a] Reagents and reaction conditions: oxabicyclic alkene diol (ca.
0.2 mmol, 1 equiv), amine nucleophile (1.1 equiv), [Rh(cod)2OTf] (5
mol%), (R,Sp)-Josiphos (6 mol%), THF (0.3m), 608C, 16–18 h. [b] Yield
of the isolated product after flash column chromatography on silica gel.
[c] The ee value was determined by HPLC using a chiral stationary phase
and the d.r. determined by 1H NMR analysis of the reaction mixture.
[d] Approximately 0.6 mmol of oxabicyclic alcohol was used and the yield
is an average over three experiments. [e] (S,Rp)-Josiphos (6 mol%) was
used as the ligand.
1
65[d]
98[d]
2
3
58
>98
>98
the stereochemistry of the amine nucleophile, and by choos-
ing an appropriate ligand we were able to access each of the
diastereomeric products 5j and 7j with exquisite selectivity.
The use of a different oxabicyclic alkene substrate with an
extended aromatic backbone was well-tolerated and the
bicyclic lactone product 9j was formed in > 20:1 d.r.
(Scheme 2).
64
4
5
6
7
64
62
65
62
>98
97
Scheme 2. Domino reaction with substituted benzo-oxabicyclic alkene
substrates.
>98
>98
Aniline nucleophiles have been previously demonstrated
to be competent nucleophiles in the ARO reaction, and often
give more favorable results than alkylamines.[3c] However,
applying the reaction conditions used for the alkylamines to
the aniline nucleophiles (i.e. N-methylaniline) led to exclusive
formation of the ARO product (4k) in high yield and
enantioselectivity (Scheme 3). There are substantial differ-
ences in the basicity of an aniline nitrogen atom versus an
alkylamine nitrogen atom, therefore triethylamine (1.1 equiv)
was added to the reaction mixture and we were pleased to
obtain the lactone product (5k) with comparable yield and
8
78
>98
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Communications
conditions (Scheme 5). The triol 4a underwent an isomeri-
zation/oxidation domino sequence to give the lactone 5a,
however the addition of triethylamine was also required for
Scheme 3. Domino formation of bicycle[2.2.2]lactones with aniline
nucleophiles. Reagents and reaction conditions: oxabicyclic alkene diol
(ca. 0.2 mmol; 1 equiv), amine nucleophile (1.1 equiv), triethylamine
(1.1 equiv), [Rh(cod)2OTf] (5 mol%), (R,Sp)-Josiphos (6 mol%), THF
(0.3m), 608C, 16–18 h.
Scheme 5. Experiments to support the proposed domino mechanism
for the lactone formation.
selectivity to those achieved with dialkylamines. Again the
reaction proved general for several different anilines (5k–n)
and furthermore, the crystalline products 5k and 5n allowed
us to unequivocally confirm the bicyclic lactone structure and
absolute stereochemistry.[9]
When considering the mechanism for the formation of
these unexpected and interesting products, it was reasoned
that the ARO reaction would be the first step in the sequence
(Scheme 4, A), since under milder reaction conditions it
occurred rapidly and efficiently (Table 1, entry 3). The
resulting intermediate 4 contains an alkene that could be
isomerized to the corresponding aldehyde 11’ (Scheme 4,
B).[10] The aldehyde (11’) thus formed would be in close
proximity[11] to the tertiary alcohol and lead to the formation
of a hemiacetal,[12] which could be oxidized under the
optimized reaction conditions to give the observed product
5 (Scheme 4; C).[13,14]
this transformation.[7] Most importantly, we prepared the
deuterium-labelled substrate [D4]-3 and this reacted to give
the product [D3]-5a, which is consistent with the proposed
mechanism.
In summary, we have achieved the first intermolecular
rhodium-catalyzed ARO reaction of doubly bridgehead
substituted oxabicyclic alkenes. Furthermore, we discovered
a domino reaction which affords bicyclo[2.2.2]lactone pro-
ducts in good yield and with excellent enantioselectivity. Our
preliminary mechanistic investigations suggest that rhodium
plays three distinct roles in the reaction. We are currently
performing further experiments to fully elucidate the mech-
anism of the process and investigate the application of these
novel intermediates to natural product synthesis. Further-
more, the lactone products themselves are of particular
interest as bicyclic lactones can be found at the core of several
bioactive natural products.[15]
To study the reaction mechanism, the intermediate 4a,
which was formed after the first step of the proposed three-
step sequence, was subjected to the optimized reaction
Experimental Section
Gemeral procedure: To
a mixture of [Rh(cod)2OTf] (55 mg,
0.12 mmol, 5 mol%), (R,Sp)-Josiphos (76 mg, 0.14 mmol, 6 mol%)
and molecular sieves (4 ꢀ) was added THF (3 cm3). The reaction
vessel was flushed with Ar and stirred at ambient temperature for
10 min. The catalyst solution was added to a solution of 3 (480 mg,
2.4 mmol, 1.0 equiv) and N-benzylmethylamine (a; 313 mg, 2.6 mmol,
1.1 equiv) in THF (3.5 cm3). The reaction vessel was sealed and the
contents heated to 608C for 16 h. The reaction mixture was allowed to
reach ambient temperature and then transferred to a round-bottomed
flask with ethyl acetate. The crude solution was concentrated and
purified by flash column chromatography on silica gel (gradient from
10 to 50% ethyl acetate in pentane) to give 5a (490 mg, 65%) as a
pale yellow oil.
Received: March 11, 2011
Scheme 4. Proposed mechanism for the lactone formation.
Published online: June 22, 2011
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[10] This process is remarkable owing to the high level of steric
congestion at the alkene and the regioselective isomerization of
the double bond away from the amine nitrogen atom. For recent
reviews on rhodium-catalyzed isomerization of allylic alcohols,
see: a) L. Mantilli, C. Mazet, Chem. Lett. 2011, 40, 341 – 344;
b) R. Uma, C. Crꢂvisy, R. Gree, Chem. Rev. 2003, 103, 27 – 52;
c) R. C. van der Drift, E. Bouwman, E. Drent, J. Organomet.
Chem. 2002, 650, 1 – 24.
[11] We suggest that the aldehyde a stereocentre rapidly epimerized
under the reaction conditions. For a similar aldehyde, see: M. C.
Clasby, S. Chackalamannil, M. Czarniecki, D. Doller, K. Eagen,
W. J. Greenlee, Y. Lin, J. R. Tagat, H. Tsai, Y. Xia, H.-S. Ahn, J.
Agans-Fantuzzi, G. Boykow, M. Chintala, Y. Hsieh, A. T.
McPhail, Bioorg. Med. Chem. Lett. 2007, 17, 3647 – 3651.
[12] There is only a trace of aldehydic protons in the 1H NMR spectra
of 11a, indicating that the equilibrium lies towards the lactol
form.
[13] There was no erosion of yield when oxygen was rigorously
excluded from the reaction. See the Supporting Information for
more details. For a similar example of oxidation within a
rhodium-catalyzed domino sequence, see: a) S. Shin, A. K.
Gupta, C. Y. Rhim, C. H. Oh, Chem. Commun. 2005, 4429 –
4431; b) Z. Ye, G. Lv, W. Wang, M. Zhang, J. Cheng, Angew.
Chem. 2010, 122, 3753 – 3756; Angew. Chem. Int. Ed. 2010, 49,
3671 – 3674; c) F. Luo, S. Pan, C. Pan, P. Qian, J. Cheng, Adv.
Synth. Catal. 2011, 353, 320 – 324.
[14] For recent reviews in the subject of transition-metal catalyzed
hydrogen transfer, see: a) M. H. S. A. Hamid, P. A. Slatford,
J. M. J. Williams, Adv. Synth. Catal. 2007, 349, 1555 – 1575; b) F.
Alonso, F. Foubelo, J. C. Gonzꢃlez-Gꢄmez, R. Martꢅnez, D. J.
Ramꢄn, P. Riente, M. Yus, Mol. Diversity 2010, 14, 411 – 424;
c) G. E. Dobereiner, R. H. Crabtree, Chem. Rev. 2010, 110, 681 –
703.
Keywords: asymmetric catalysis · domino reactions · lactones ·
oxidation · rhodium
.
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[9] CCDC 816868 (5k) and 816869 (5n) contain the supplementary
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