Chemodivergence in enantioselective desymmetrization of diazabicycles: Ring-opening versus reductive arylation

Article abstract of DOI:10.1002/anie.200704708

(Chemical Equation Presented) Divergent bicycle paths: A chemodivergent desymmetrization occurs after an initial enantioselective carbometalation step. The reaction brings a solution to the challenging problem of the enantioselective ring-opening of diazabicyclo-[2.2.1]heptanes to obtain arylated cyclopentenamines (see scheme, right). An alternative reaction pathway was discovered in which C-H insertion/1,4-metal migration occurs to give reductive arylation products (left).

Full text of DOI:10.1002/anie.200704708

Angewandte
Chemie
DOI: 10.1002/anie.200704708
Asymmetric Catalysis
Chemodivergence in Enantioselective Desymmetrization of
Diazabicycles: Ring-Opening versus Reductive Arylation**
Frederic Menard and Mark Lautens*
Interest in desymmetrization by asymmetric ring-opening
reactions has grown significantly in recent years.[1] Although
very efficient reactions have been developed for the desym-
metrization of oxygenated compounds, nitrogen-containing
molecules have received much less attention.[2] Given the
ubiquitous nature of chiral amines in biologically active
molecules and in natural products, a method to access chiral
functionalized amines 4 and 5 would be useful (Scheme 1).
Herein, we report a highly selective desymmetrization of
diazabicycles 1 leading to ring-opened products 4 and
dium-mediated hydroarylation reaction of strained alkenes
with boronic acids.[4]
The ring-opening of diazabicycles 1 towards 2 with
organometallic nucleophiles such as palladium[5] and cop-
per[1g,6] was reported, but either the scope of the nucleophile
was limited or the enantioselectivity was modest. Progress on
the ring-opening of 1 with a closely related chiral Rh–
bisphosphine system was recently reported by Pineschi and
co-workers, but the ee values were variable.[7] Conversely, the
racemic hydroarylation of diazabicycles using Pd was
reported by Kaufmann and co-workers, but the reaction led
to mixtures of 2 and 3.[8] We found that the hydroarylation
products are formed through a mechanism that is markedly
different from the one proposed with Pd, thus opening up new
synthetic opportunities.[9]
À
reductive arylation products 5 after cleavage of the N N
À
hydrazine bond. A C H activation/1,4-metal migration reac-
tion pathway leading to the formation of reductive arylation
products is also described.[3] To the best of our knowledge, this
is the first example of an intermolecular, asymmetric rho-
We focused on finding a solution to the challenging
problem of enantioselective ring-opening of diazabicyclo-
[2.2.1]heptanes to provide a rapid synthesis of optically active
trans-2-arylated cyclopentyl amines 4, which are known to be
biologically active small molecules (Scheme 1).[10–12] The
asymmetric ring-opening of diazabicycles 1 would comple-
ment the catalytic preparation of chiral alcohols from meso
allylic biscarbonates.[13] Furthermore, the trans stereochemis-
try would be obtained; in contrast, the same reaction with
oxa- or azabicycles always gave the cis ring-opened prod-
ucts.[14]
Bicyclic hydrazines 1 were attractive as key substrates
because of their stability, ease of preparation,[15] and the
utility of the ring-opened hydrazine as a known amine
precursor. We opted for boronic acids as ideal nucleophiles
since they are air- and moisture-tolerant. The first trials
consisted of treating diazabicycle 1a with phenylboronic acid
under our previously reported conditions.[13a] Using (S)-xylyl-
P-phos ((S)-(À)-2,2’,6,6’-tetramethoxy-4,4’-bis[di(3,5-xylyl)-
phosphino]-3,3’-bipyridine)[16] as a chiral ligand yielded 3a
in 87% ee, albeit in low yield [Eq. (1); cod = cycloocta-1,5-
diene]. The screening of ligands showed that only bidentate
P,P ligands displayed useful levels of enantioselectivity. Inter-
estingly, tBu-josiphos (josiphos = (R)-1-[(S)-2-diphenylphos-
phino)ferrocenyl]ethyldicyclohexylphosphine) [17] shows unri-
valed reactivity and enantioselectivity in Rh-catalyzed reac-
tions with bicyclic systems.[14b] Study of various solvent
systems showed THF to be a suitable solvent.
Scheme 1. Desymmetrization of strained alkenes by two competing
pathways involvingan initial enantioselective carbometalation.
Z=electron withdrawinggroup.
[*] F. Menard, Prof. M. Lautens
Davenport Chemistry Laboratories
University of Toronto
80 St. George Street, Toronto, ON, M5S 3H6 (Canada)
Fax: (+1)416-946-8185
E-mail: mlautens@chem.utoronto.ca
[**] This work was supported by NSERC, Merck-Frosst, and the
University of Toronto. F.M. thanks the Government of Ontario for a
postgraduate scholarship. Solvias Inc, Takasago, and Digital
Specialty Chemicals are thanked for generous gifts of chiral ligands.
We acknowledge A. Martins for the preparation of some substrates,
a referee for useful comments, as well as Y. Bolshan for checkingour
experimental procedure.
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: RhI-catalyzed ring-opening of diazabicycles with substituted
The stereochemical assignment is challenging in substi-
boronic acids.[a]
tuted five-membered ring systems because of removed
rotamers. Different substituents (benzyloxy carbonyl (Cbz),
t-butyl carbonyl (Boc), phthalyl) on the nitrogen centers were
examined; notably, the phthalyl substituted substrate 1b
yielded product 3b quantitatively and the trans stereochem-
istry was confirmed by X-ray crystallographic analysis
[Eq. (2)].[18] Bis(Boc)-protected diazabicycle 1c was selected
as the substrate of choice for this study because of the ease of
deprotection and practical reasons.[19]
Entry
1[e]
Product
Ar
Yield [%][b]
53
ee [%][c,d]
6
99
2
7
7
52
99
97
97
3[e]
4
5
6
7
8
8
55
75
96
54
91
99
99
9
10
11
12
99
The reaction is ideally suited for the addition of ortho-
substituted, electron-rich aryl boronic acids (ee > 96%,
Table 1, entries 1–9).[20] Steric hindrance close to the reacting
center appears necessary to achieve good selectivity (Table 1,
entries 10–13). Electron-rich boronic acids generally led to
higher yields and lower ee values, whereas electron-deficient
systems proved less reactive and more selective (Table 1,
entries 10–13). The reaction tolerates a range of functional
groups on the boronic acid substrate. A vinylboronic acid also
reacted with ring-opened 1c in high yield but with poor
enantioselectivity (i.e. trans-styrylboronic acid gave 99%
yield, 44% ee).
>99
96
9
13
14
68
49
99
84
10
11
12
13
15
3c
16
58
85
80
86
68
50
A novel enantioselective reductive arylation reaction was
revealed when the boronic acids were changed to heteroaryl
derivatives (Table 2). When the boronic acid bore a suffi-
ciently activated hydrogen atom in the 2-position, the hydro-
arylated diazabicycles 17–20 were isolated. It is thought that
the sigma inductive effect of neighboring heteroatoms
À
facilitates a C H insertion reaction (see below). 2-Fluorobor-
[a] Reaction conditions: The {Rh}2 catalyst (5 mol%) and ligand
(12 mol%) were in THF/water (50:1) and under an Ar atmosphere.[20]
[b] Yields of isolated products. [c] Enantiomeric excess determined by
chiral HPLC. [d] Absolute configuration determined by derivatization of
3c. [e] Reaction conducted in toluene/THF/H2O (7:2:1).
onic acid seems to lie at the inflection point of the competing
reaction pathways, as both products 6 and 19 were obtained
(53% and 47% yield, respectively). The trend in enantiose-
lectivities observed for hydroarylated products 17–20 matches
that for the ring-opened products, suggesting that both
pathways are subject to the same stereodifferentiating factors.
The outcome of the reaction can be biased by changing
the solvent system. For example, in preliminary studies, we
found that running the reaction in a mixture of toluene/THF/
water (7:2:1) rather than THF/water (50:1) gave the ring-
opened product 7 as the sole product (Table 1, entry 3). In
pure THF, the hydroarylated product was observed in
approximately 12% yield (the remainder being unreacted
1c).
Correlation of the observed enantioselectivities of the
ring opened hydrazines 6–16 and those of the arylated
diazabicycles 17–20 suggest that a plausible mechanism
would involve a common intermediate. As depicted in
Scheme 2, the preformed active catalyst A undergoes a fast
transmetalation to form the Ar–RhI complex B. The alkene of
diazabicycle 1 is activated by coordination to the metal center
and inserts into the metal–carbon bond of B in the enantio-
discriminating step to give the key carbometalated inter-
mediate C. Ring-opening of C can occur through anti-b-
nitrogen elimination of the hydrazide leaving group to give
the trans-cyclopentene 2. Carborhodation of the alkene
occuring on the more accessible exo face of the diazabicycle
accounts for the trans diastereoselectivity observed in the
ring-opened products 2. Alternatively, if the ortho-hydrogen
The reductive arylation is sensitive to steric effects. When
an ortho-hydrogen atom was flanked by a bulky group
attached to the meta position (Table 1, entries 6 and 8), only
the ring-opening reaction was observed. Notably, in all cases
in which the ortho-hydrogen atom was accessible, the hydro-
arylated products were observed when THF was used as the
solvent, but only in poor yield (2–15%).
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Table 2: RhI-catalyzed reductive arylation of diazabicycles with substi-
tuted boronic acids.[a]
Entry
1
Product
Yield [%][b]
89
ee [%][c]
We observed exclusive deuterium incorporation on the
aromatic moiety of 18 ([D1]-18, 91% deuteration). This
17
18
62
À
experiment supports a rhodium migration occuring by a C H
insertion. This oxidative pathway allows selective electro-
philic functionalization at the more hindered ortho position of
the heteroaromatic ring, a process that is not easily accom-
plished by other means.
2
66
99
3[d]
ent-19
47
39
98
83
An example demonstrating the synthetic value of sub-
stituted cyclopentenes 6–16 is the synthesis of glycosydase
inhibitor derivatives.[21] This class of compounds was reported
to be accessible by stereoselective transformations of the
cyclopentyl core of 3.[22] In addition, conversion of the
hydrazine moiety of the desymmetrized products 2 and 3
into the amines 4 and 5 can be accomplished by several
established reduction methods.[23] It should be noted that this
method provides a good
4
20
[a] Reaction conditions are as described in Table 1. [b] Yields of isolated
products. [c] Enantiomeric excess determined by chiral HPLC. [d] (S,R)-
josiphos ligand was used.
way to access enantiopure
building blocks bearing
1,2,4- and 1,2,5-substituted
benzene rings.[24] The abso-
lute and relative stereo-
chemistry of the Boc-pro-
tected ring-opened prod-
ucts was confirmed by full
reduction of 3c and com-
parison of the optical rota-
tion of 21 with literature
values [Eq. (4); TFA = tri-
fluoroacetic acid].[25] Ongo-
ing efforts are focused on
ways to influence the reac-
tion rate constants k1 and
k2, to alter the course of the
reaction, and to obtain
products 2 or 3 selectively
(Scheme 2).
Scheme 2. Proposed catalytic cycle for the chemodivergent RhI-catalyzed desymmetrization of diazabicycle 1.
atom is sufficiently activated, the RhI center of intermediate
III
À
C can undergo an oxidative C H insertion to give the Rh
À
complex D. Reductive elimination leads to the Rh Csp2
complex E, which is thermodynamically more stable than
À
Rh Csp3 complex C. Subsequent proto-demetalation with
boronic acid as the proton source leads to the observed
reductive arylation product 3. A working hypothesis suggests
À
that if the C H bond insertion rate is slow, a water molecule
can fill the free coordination site in C and therefore prevent
the formation of D. Thus, excess water in a less polar solvent
system may favor the ring-opened products 2 (Table 1,
entry 3).
In summary, the enantioselective RhI-catalyzed ring-
opening of diazabicycles provides a rapid synthesis of chiral
arylcyclopentenamine precursors and complements our
related approach to chiral cyclopentenols. It is ideally suited
for the addition of aryl boronic acids bearing ortho substitu-
ents and provides a good method to access interesting
enantiopure building blocks.[24] Furthermore, we identified a
To test whether the arylated bicycles 3 arise from simple
protonation of the carbometalated intermediate C, the
reaction was conducted in the presence of D2O [Eq. (3)].
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À
[9] In previous work we observed that organoboron reagents add to
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diazabicycles enantioselectively, thereby setting three stereo-
centers in one reaction.
[10] P. E. Finke et al.
, (Merck),WO 9714671, 1997; see the
Received: October 11, 2007
Revised: December 14, 2007
Published online: February 7, 2008
Supporting Information.
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[18] CCDC 661282 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre at www.ccdc.
cam.ac.uk/data request/cif.
[19] Compund 1c is a free-flowing powder, making for easy handling.
Its preparation on scale is also the most convenient one,
involving simple filtration of the reaction mixture to obtain
analytically pure material.
[20] See the Supporting Information for full experimental details.
Strictly anhydrous conditions are not appropriate for this
reaction and we thank the referee for this finding.
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Keywords: asymmetric catalysis · C–H activation ·
desymmetrization · rhodium · ring-opening reactions
.
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