Desymmetrization of meso-Dibromocycloalkenes through Copper(I)-Catalyzed Asymmetric Allylic Substitution with Organolithium Reagents

Article abstract of DOI:10.1021/jacs.8b02992

The highly regio- and enantioselective (up to >99:1 dr, up to 99:1 er) desymmetrization of meso-1,4-dibromocycloalk-2-enes using asymmetric allylic substitution with organolithium reagents to afford enantioenriched bromocycloalkenes (ring size of 5 to 7)

Full text of DOI:10.1021/jacs.8b02992

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Communication
Desymmetrization of meso-Dibromocycloalkenes through Copper(I)-
Catalyzed Asymmetric Allylic Substitution with Organolithium Reagents
Shermin S Goh, Sureshbabu Guduguntla, Takashi Kikuchi,
Martin Lutz, Edwin Otten, Makoto Fujita, and Ben L. Feringa
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02992 • Publication Date (Web): 23 May 2018
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Desymmetrization of meso-Dibromocycloalkenes through
Copper(I)-Catalyzed Asymmetric Allylic Substitution with Or-
ganolithium Reagents
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Shermin S. Goh,†,§ Sureshbabu Guduguntla,† Takashi Kikuchi,‡,¤ Martin Lutz,※ Edwin Otten,† Makoto
Fujita,‡ and Ben L. Feringa.†,*
† Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
§ Institute of Materials Research and Engineering, 2 Fusionopolis Way, Innovis #08ꢀ03, Singapore 138634.
‡ Department of Applied Chemistry, University of Tokyo, 7ꢀ3ꢀ1, Hongo, Bukyoꢀku, Tokyo, Japan 113ꢀ8656.
¤ Rigaku Corporation, 3ꢀ9ꢀ12 Matsubaraꢀcho, Akishimaꢀshi, Tokyo 196ꢀ8628, Japan.
※ Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
Supporting Information Placeholder
different metal catalysts and organometallic nucleophiles could be
used for AAS,9 the readily available organolithium reagents were
considered too reactive to be utilized in catalytic asymmetric CꢀC
bond formation until the 2011 disclosure by Feringa et al. using
allylic bromides as substrates, forming SN2' products with high
regioꢀ and enantioselectivities.10 In recent years our group has
extended this protocol,11 most notably to the use of allylicꢀ
chlorides and ꢀethers,11a,b aryllithium nucleophiles,11c,d and also to
the formation of highly challenging allꢀcarbon quaternary stereoꢀ
centers.11b,d We envisaged that the AAS strategy with organolithiꢀ
um reagents could be applied to the desymmetrization of meso
compounds. Herein, we report the highly regioꢀ and enantioselecꢀ
tive (up to >99:1 dr, up to 99:1 er) desymmetrization of mesoꢀ2ꢀ
cycloalkeneꢀ1,4ꢀdibromides using Cu(I)ꢀcatalyzed AAS with
organolithium reagents to afford enantioenriched bromocycloalꢀ
kene synthons (Scheme 1b).
ABSTRACT: The highly regioꢀ and enantioselective (up to
>99:1 dr, up to 99:1 er) desymmetrization of mesoꢀ1,4ꢀ
dibromocycloalkꢀ2ꢀenes using asymmetric allylic substitution
with organolithium reagents to afford enantioenriched bromocyꢀ
cloalkenes (ring size of 5 to 7) has been achieved. The cyclohepꢀ
tene products undergo an unusual ring contraction. The synthetic
versatility of this Cu(I)ꢀcatalyzed reaction is demonstrated by the
concise stereocontrolled preparation of cyclic amino alcohols,
which are privileged chiral structures in natural products and
pharmaceuticals, and widely used in synthesis and catalysis.
The enantioselective desymmetrization of meso compounds is
one of the most powerful strategies in organic synthesis.1 It enaꢀ
bles the formation of compounds with multiple stereocenters in a
single step from readily accessible σꢀsymmetric precursors. In the
case of mesoꢀcycloalkꢀ2ꢀeneꢀ1,4ꢀdiol derivatives, desymmetrizaꢀ
tion by asymmetric allylic substitution (AAS) is a powerful tool
for the construction of enantiomerically enriched functionalised
cyclic products,2 which have found ample use in the total syntheꢀ
ses of various natural products.3 Depending on the choice of
nucleophile (soft or hard) and metal catalyst, the reaction can
result in either αꢀ or γꢀsubstitution, with either retention or inverꢀ
sion of configuration. The most commonly employed procedure is
the Pdꢀcatalyzed desymmetrization, which is usually performed
Scheme 1. Desymmetrization of meso-1,4-cycloalkenediol
derivatives
with soft nucleophiles to give SN2ꢀproducts (Scheme 1a).2,3
A
viable alternative is the Rhꢀcatalyzed desymmetrization using
arylboronic acids,4 which give SN2 or SN2' products depending on
the ligand at Rh. These processes, albeit highly versatile at proꢀ
ducing chiral building blocks, rely on precious metal catalysts. In
contrast, there are markedly few examples of the Cu(I)ꢀcatalyzed
desymmetrization, which generally employs hard nucleophiles to
provide SN2' products.5 Sawamura and coꢀworkers have utilized
the Cuꢀcatalyzed asymmetric boryl substitution in conjuction with
allylation to afford a formal SN2 substitution with electrophiles.6
Optimization of the desymmetrization reaction began with me-
soꢀ3,6ꢀdibromocyclohexꢀ1ꢀene 1 as model electrophile and comꢀ
mercially available nꢀBuLi as nucleophile in the presence of a
catalytic amount of CuBr·SMe2 and chiral ligand. The racemic
reaction with PPh3 as ligand (Table 1, Entry 1) proceeded to full
conversion to give transꢀ4ꢀbromoꢀ3ꢀbutylcyclohexene 2d as the
major product (from SN2' substitution) in 91% yield. The double
addition product 3 (9%) was also observed; its formation most
probably occurs via a SN2ꢀtype substitution followed by a SN2'ꢀ
type substitution on the allylic bromide intermediate. Taniaphos
The Cu(I)ꢀcatalyzed AAS with organometallic nucleophiles,
pioneered by Bäckvall and van Koten in 1995,7 is an effective
method to synthesize tertiary carbon stereocenters.8 While many
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L1, which was an effective chiral ligand in the acyclic AAS,10 was
initially tested (Entry 2). Unfortunately, no conversion was obꢀ
Chiral HPLC confirmed that a single diastereomer of 5 with four
contiguous stereocenters was obtained (>99:1 dr, 99:1 er) after
Upjohn dihydroxylation of 2d.
1
2
3
4
5
6
7
8
Table 1. Screening of ligands for AAS-desymmetrization of
meso-dibromocyclohexene 1 with n-BuLi a
With the optimized conditions in hand (Entry 4), we proceeded
to examine the scope of the reaction. Continuing with the 6ꢀ
membered substrate 1 (Scheme 2), addition of commercially
available alkyllithium reagents afforded the AAS products 2a-e
with excellent enantioselectivities (up to 99:1 er). Only isopropylꢀ
bearing product 2c had a slightly lower er (95:5), possibly a result
of the steric bulk of the isopropyl group. The reaction worked
similarly well for mesoꢀ3,5ꢀdibromocyclopentene 6 to generate
products 7a-e in good yields with up to 96:4 er (Scheme 2).
9
PPh2
Ph2
P
N
O
O
10
11
12
13
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P
N
Fe
Scheme 2. Alkyllithium scope for desymmetrization of 5-
and 6-membered meso-cyclic allylic dibromides 1 and 6 a,b,c
L1
L2
Br
1.2 equiv. RLi
5 mol% CuBr•SMe2
6 mol% L3
X
X
Br
R
O
O
O
P
N
P
N
n
CH2Cl2, −80°C
O
n
Br
1: n = 1 or 6: n = 0
Br
2: n = 1 or 7: n = 0
L3 X = H
L4 X = OMe
L5
Br
Br
Br
Br
Entry
Ligand
PPh3
L1
2d:1:3:4 b
91:0:9:0
0:100:0:0
52:42:6:0
90:0:10:0
92:0:8:0
91:0:9:0
2d, er / % c
50:50
ꢀ
d
2a:
2b:
2c:
69%
95:5 er
90%
79%
2e:
86%
97:3 er
99:1 er
99:1 er
1
2
Br
Br
Br
Br
3
47:53
98:2
L2
7a: 99%d
94:6 er
7b: 99%d
96:4 er
7c: 99%d
86:14 er
7d:
96:4 er
7e:
96:4 er
66%
88%
4
L3
5
95:5
L4
a Conditions: mesoꢀ1 (9:1 cis/trans) or 6 (0.2 mmol) in CH2Cl2
(2 mL). RLi (0.24 mmol, diluted to a final concentration of 0.24
M) was added over 2 h. b Isolated yields. c Er determined by chiral
GC. d GC yields reported due to product volatility (see SI).
6
7 d
8 f
88:12
99:1
L5
92:8:0:0 (80%) e
L3
48:30:12:10
54:46
L3
When mesoꢀ3,7ꢀdibromoꢀcycloheptene 8 was used in the
desymmetrization reaction with alkyllithium reagents (Scheme 3),
the expected products 9a-e (>99:1 dr) were initially obtained with
er values ranging from 90:10 to 97:3, based on NMR and chiral
GC. However, when purification of these 7ꢀmembered rings 9a-e
was attempted by flash column chromatography on silica, only
their corresponding cyclohexene analogs 10a-e were isolated with
complete stereospecificity. A detailed structural analysis, mechaꢀ
nistic and theoretical study to elucidate this remarkable ring conꢀ
traction is reported separately.14
a
Conditions: mesoꢀ1 (0.2 mmol) in CH2Cl2 (2 mL). nꢀBuLi
(0.24 mmol, 1.6 M solution in hexanes diluted to a final concenꢀ
tration of 0.24 M) was added over 2 h. b Determined by GC–MS
1
c
d
and H NMR. Er determined by chiral GC. A 9:1 cis/transꢀ
e
mixture of 1 was used. Isolated yield of 2d on 0.2 mmol scale;
increases to 89% on 10 mmol scale (see SI). f Racemic transꢀ1
was used. Inset: Ballꢀandꢀstick representation of the Xꢀray crystal
structure of diol 5.
served which (based on models) was attributed to steric interacꢀ
tions between L1 and cyclohexene 1. We then switched to the
phosphoramidite ligand class,12 which have previously been used
in the desymmetrization of mesoꢀcyclic bis(diethyl phosphates) by
CuꢀAAS using organozinc reagents.5b,c With (S,R,R)ꢀ
phosphoramidite L2, only partial conversion was observed, and
the desired product had low er (Entry 3). When (S,S,S)ꢀ
phosphoramidite L3 was tested, 90% conversion (98:2 er) to the
desired product was found (Entry 4). When this transformation
was performed on multigram scale, analytically pure 2d was
obtained in 89% yield and 99:1 er. Neither a more electronꢀrich
phosphoramidite L4 nor a more flexible octahydrophosphoꢀ
ramidite L5 could enhance this result (Entries 5 & 6). When a 9:1
cis/trans mixture of starting material was subjected to the optiꢀ
mized conditions with L3, the enantioselectivity was maintained
(99:1 er) and the product 2d could be isolated in 80% yield (Entry
7); transꢀ1 was almost entirely recovered. This prompted us to
investigate the reaction with racemic transꢀ1 under the same
conditions (Entry 8). Unsurprisingly, the reaction did not proceed
to full conversion and formation of some cisꢀ4ꢀbromoꢀ3ꢀ
butylcyclohexꢀ1ꢀene 4 was also observed. The absolute configuraꢀ
tion of 2d was determined by Xꢀray crystallography of diol 5
(Table 1, inset),13 resulting in a Flack parameter of x = 0.04(2).
Scheme 3. Desymmetrization-rearrangement of 7-
membered meso-cyclic allylic dibromide 8 a,b,c
1.2 equiv. RLi
5 mol% CuBr•SMe2
6 mol% L3
Br
Br
Br
H
R
silica
R
>99% es
CH2Cl2, −80°C
Br
8
10a-e
9a-e
R = Me, Et, i-Pr,
n-Bu, n-Hex
57 to 81% yield
90:10 to 97:3 er
a Conditions: (i) mesoꢀ8 in CH2Cl2 (2 mL). RLi (0.24 mmol, diꢀ
luted to a final concentration of 0.24 M) was added over 2 h; (ii)
silica, pentane. b Isolated yields. c Er of 9a-e and 10a-e determined
by chiral GC to be the same, so es >99%.
We hypothesized that a phenyl substituent would stabilize the
desymmetrization product i.e. chiral cycloheptene 9, enabling its
isolation. We have previously reported that Nꢀheterocyclic carꢀ
benes (NHC) are the most suitable ligand class for asymmetric
allylic arylation (AAAr).11c,d As such, we screened, besides achiꢀ
ral L6 as control, several chiral NHC ligands for the desymmetriꢀ
zation of dibromocycloheptene 8 by with phenyllithium (Table 2).
While the dihydroimidazoliumꢀbased ligands L7 and L8 gave
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excellent conversion, the er was poor to moderate (Entries 2 and
aminoalcohol derivative 12 in 60% yield over two steps. SN2
substitution of bromide 12 with sodium azide followed by hydroꢀ
genation yielded transꢀ1,4ꢀdiaminoꢀ2ꢀalcohol 13 with four conꢀ
tiguous stereocenters (Scheme 4a). The 7ꢀmembered analog cyꢀ
cloheptene 9f undergoes diastereoselective Upjohn dihydroxylaꢀ
tion (88:12 dr) to afford cisꢀ1,2ꢀdiol 11 in 80% yield, which was
readily transformed into aminodiol 14 via substitution and hydroꢀ
genation (Scheme 4b).
1
2
3
4
5
6
7
8
3). In contrast, triazoliumꢀbased ligands L9 and L10 gave poorer
conversions (Entries 4 and 5). Gratifyingly, we found that imidazꢀ
olium salt L12 was a suitable NHC precursor; in conjunction with
CuBr·SMe2 and NaOtꢀBu, this catalytic system afforded the deꢀ
sired 4ꢀbromoꢀ3ꢀphenylcycloheptene 9f in 83% isolated yield with
95:5 er (Entry 7). In accordance with our prediction, and in sharp
contrast with alkyl analogs 9a-e, this product was stable to baseꢀ
treated silica and could be isolated. The absolute configuration of
9f was determined to be (R,R) by Xꢀray crystallography of diol 11
(Table 2, inset),15 which was obtained via diastereoselective
Upjohn dihydroxylation (88:12 dr, 96:4 er as determined by chiral
HPLC).
Scheme 4. Derivatization of desymmetrization products
towards cyclic aminoalcohols.
9
NH2
Br
10
11
12
13
14
15
16
17
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60
Br
(a)
Bu
Bu
i, ii
iii, iv
68%
Bu
60%
HO
HO
Table 2. Screening of ligands for AAAr-desymmetrization
NH2
13
of meso-dibromocycloheptene 8 with PhLi a
NHBn
12
2d
Br
NH2
Br
Ph
HO
Ph
(b)
Ph
v
iii, iv
72%
HO
80%
HO
HO
14
Ph
Ph
9f
11
N
N
N
N
Conditions: (i) mꢀCPBA (1.2 equiv.), PhMe, RT; (ii) BnNH2
(1.2 equiv.), silica (10 wt%), 80 °C; (iii) NaN3 (3 equiv.), DMF,
80 °C; (iv) H2 (1 atm), Pd/C (20 mol%), EtOAc; (v) OsO4 (4
mol%), NMO (1.5 equiv.), acetone/H2O (3:1).
BF4
L7
Cl
L6
Ph
Ph
O
N
N
N
N
N
Aminodiol 14 is a direct precursor to 2ꢀphenylꢀtropanꢀ6αꢀol usꢀ
ing the cyclization strategy described by Pollini et al.17 These 8ꢀ
azabicyclo[3.2.1]octanes18 represent an important scaffold of
bioactive tropane alkaloids natural products such as schizanthines,
baogongtengs and calystegines.16b,19 Thus, our synthesis of amiꢀ
nodiol 14 represents an efficient route to phenylꢀsubstituted anaꢀ
logs of these natural products and drug targets (see Figure 1).
BF4
BF4
L9
L8
F
F
F
F
Ph Ph
Ar
N
N
N
F
N
N
Ar
N
N
I
Ph
Ph
BF4
BF4
O
L12
Ar = 1-Napth
L13 Ar = o-MePh
L10
L11
Me
Me
N
N
H
N
Entry
Ligand
L6
9f:8 b
9f, er / % c
50:50
12:88
53:47
41:59
21:79
23:77
5:95
O
OH
O
OH
O
O
O
1
2
3
4
5
6
7
8
>99:1
>99:1
>99:1
82:18
68:32
86:14
O
O
O
O
L7
atrophine
schizanthine A
bao gong teng A
L8
Figure 1. Examples of tropane alkaloids with the 8ꢀ
L9
azabicyclo[3.2.1]octane framework
L10
L11
L12
L13
In summary, the highly regioꢀ and enantioselective desymmeꢀ
trization of mesoꢀdibromocycloalkenes with ring size ranging
from 5 to 7 via CuꢀAAS with organolithium reagents has been
demonstrated. Phosphoramidite L3 is the preferred ligand for
alkyllithium reagents while for arylation NHC was found to be the
ligand of choice. These findings represent an efficient method to
access enantioenriched cyclic bromoalkenes; the synthetic utility
of the products is demonstrated by the concise synthesis of chiral
multifunctional cyclic aminoalcohols, which are a privileged
scaffold for natural products, pharmaceuticals and asymmetric
synthesis.
>99:1 (83) d
71
18:82
a Conditions: mesoꢀ8 (0.2 mmol) in CH2Cl2 (2 mL). PhLi (0.30
mmol, 1.9 M solution in diꢀnꢀbutyl ether diluted with hexanes to a
final concentration of 0.30 M) was added over 2 h. b Determined
by GC–MS and 1H NMR. c Er determined by chiral GC. d Isolated
yield of 9f. Inset: Ballꢀandꢀstick representation of the Xꢀray strucꢀ
ture of diol 11.
Cyclic amino alcohols are structural elements found in numerꢀ
ous natural products e.g. tropane alkaloids,16 and are privileged
scaffolds in medicinal chemistry e.g. atropine and cocaine.18b
Having access to a variety of enantioenriched bromocycloalkenes
of various ring sizes via the AASꢀdesymmetrization protocol, we
next demonstrated the versatility of these products by the concise
stereocontrolled synthesis of cyclic amino alcohols (Scheme 4).
Reaction of cyclohexene 2d with mꢀCPBA afforded a 71:29 diaꢀ
stereomeric mixture of epoxides. Ring opening of the epoxide
with benzylamine catalyzed by silica under neat conditions was
selective for the major epoxide isomer, affording transꢀ1,2ꢀ
ASSOCIATED CONTENT
Supporting Information
Experimental details and characterisation data are provided
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
†,*Eꢀmail: b.l.feringa@rug.nl
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5
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7
8
Notes
The authors declare no competing financial interests.
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jita, M.; Houk, K. N.; Feringa, B. L. J. Am. Chem. Soc. 2018, 140, 4986ꢀ
4990.
(15) CCDC 1575122 contains the supplementary crystallographic data
for this structure. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
(16) (a) Lounasmaa, M.; Tamminen, T. The Tropane Alkaloids. In The
Alkaloids: Chemistry and Pharmacology; Cordell, G. A., Ed.; Academic
Press, Inc.: San Diego, 1993; Vol. 44, pp 1–115. (b) Grynkiewicz, G.;
Gadzikowska, M. Pharmacol. Rep. 2008, 60, 439ꢀ463.
ACKNOWLEDGMENT
B.L.F acknowledges The Netherlands Organization for Scientific
Research (NWOꢀCW), the Royal Netherland Academy of Arts
and Sciences (KNAW), and the Ministry of Education Culture
and Science (Gravitation program 024.601035) for funding. S.S.G
acknowledges A*STAR (NSS) for a postꢀdoctoral fellowship and
SERC (1527200020) for support. M.F and T.K acknowledge JSTꢀ
ACCEL project in which M.F is a principal investigator.
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REFERENCES
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(2) For reviews of enantioselective desymmetrizations via transitionꢀ
metal catalyzed asymmetric allylic substitution, see: (a) Ma, S.; Lu, Z.
Angew. Chem. Int. Ed. 2008, 47, 258ꢀ297. (b) Pfaltz, A.; Lautens, M. in
Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
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Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395ꢀ422.
(3) For reviews of natural product synthesis by enantioselective
desymmetrizations via AAS, see: (a) Trost, B. M.; Crawley, M. L. In
Transition Metal Catalyzed Allylic Substitution in Organic Synthesis;
Kazmaier, U., Ed.; SpringerꢀVerlag, Berlin, 2012; pp. 321ꢀ340. (b) Trost,
B. M. J. Org. Chem. 2004, 69, 5813ꢀ5837. (c) Trost, B. M.; Crawley, M.
L. Chem. Rev. 2003, 103, 2921ꢀ2944. (d) Graening, T.; Schmalz, H.ꢀG.
Angew. Chem. Int. Ed. 2003, 42, 2580ꢀ2584. (e) Wang, M.; Feng, M.;
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(5) The only examples of desymmetrization by CuꢀAAS with hard nuꢀ
cleophiles are highly substrate and nucleophile specific, see: (a) Piarulli,
U.; Daubos, P.; Claverie, C.; Roux, M.; Gennari, C. Angew. Chem. Int.
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(17) Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.;
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(18) For
a
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Zanirato, V. Chem. Rev. 2006, 106, 2434ꢀ2454.
(19) Biastoff, S.; Dräger, B. In The Alkaloids: Chemistry and Biology;
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