Catalytic Enantioselective Desymmetrization of Norbornenoquinones via C(sp2)-H Alkylation

Article abstract of DOI:10.1021/acs.orglett.6b03168

The enantioselective Diels-Alder (DA) reaction with monosubstituted p-benzoquinones is an unmet challenge. A new approach for the enantioselective synthesis of monosubstituted quinone-DA adducts is presented based on C(sp²)-H alkylative desymmetrization of meso-DA adducts. Catalyzed by a tertiary amino-thiourea derivative, this reaction utilizes nitroalkanes as the alkylating agents and generates densely functionalized products bearing at least four contiguous stereogenic centers remote from the reaction site with excellent enantioselectivities.

Full text of DOI:10.1021/acs.orglett.6b03168

Letter
pubs.acs.org/OrgLett
Catalytic Enantioselective Desymmetrization of
Norbornenoquinones via C(sp2)−H Alkylation
Rahul Sarkar and Santanu Mukherjee*
Department of Organic Chemistry, Indian Institute of Science, Bangalore-560012, India
S
* Supporting Information
ABSTRACT: The enantioselective Diels−Alder (DA) reaction with monosubstituted p-benzoquinones is an unmet challenge. A
new approach for the enantioselective synthesis of monosubstituted quinone-DA adducts is presented based on C(sp2)−H
alkylative desymmetrization of meso-DA adducts. Catalyzed by a tertiary amino-thiourea derivative, this reaction utilizes
nitroalkanes as the alkylating agents and generates densely functionalized products bearing at least four contiguous stereogenic
centers remote from the reaction site with excellent enantioselectivities.
orbornenoquinones, obtained from a Diels−Alder (DA)
reaction between cyclopentadiene (CP) and p-benzoqui-
Scheme 1. Catalytic Enantioselective Synthesis of
Monosubstituted Norbornenoquinones
N
nones, are not only important historically1 but also because of the
presence of this core structure in various natural products and
biologically active compounds (Figure 1).2 In addition, they have
Figure 1. Norbornenoquinone and examples of natural products and
bioactive compounds containing this scaffold.
beenusedasbuildingblocksforthesynthesisofseveralquinonoid
natural products, such as epoxyquinones, jesterone, phyllostine,
ambuic acid, cycloepoxydone, etc.3 The importance of
norbornenoquinone scaffold makes their enantioselective syn-
thesis highly desirable.
Even though quinones are considered to be a very reactive class
ofdienophiles, enantioselective quinone−DA reactions are rather
limited.2e,4 In fact, enantioselective DA reactions between CP and
monosubstitutedp-benzoquinonesremainelusive(Scheme1A).5
Inspired by the synthetic value of enantiopure norbornenoqui-
nones and dearth of useful methods for the enantioselective
synthesisofmonosubstituted norbornenoquinones, wesoughtan
alternative strategy for their enantioselective synthesis. We
recognized that any symmetry-breaking operation on meso-
norbornenoquinone would generate chiral norbornenoquinones
(Scheme 1B). Enantioselective desymmetrization of this type is a
powerful strategy, a unique advantage of which is the possibility of
creating stereogenic centers remote from the reaction site.6
We recently developed an organocatalytic enantioselective
alkylation of olefinic C(sp2)−H bonds using inexpensive and air-
stable nitroalkanes as the alkylating agents.7 We envisioned that a
Received: October 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03168
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
similar C(sp2)−H alkylative desymmetrization of meso-norbor-
nenoquinones would circumvent the limitations associated with
the direct enantioselective synthesis of monosubstituted
norbornenoquinones. Herein, we present a distinct method for
the catalytic enantioselective synthesis of monosubstituted
norbornenoquinones, which proceeds via C(sp2)−H alkylation
of meso-norbornenoquinones (Scheme 1C).
(entry 7). Variation in reaction temperature failed to offer any
beneficial effect on either yield or enantioselectivity (entries 8−
9). A number of other bifunctional (thio)ureas (II−VI) derived
from either cinchona alkaloids or trans-1,2-diaminocyclohexane
were also tested as catalyst under the same reaction conditions
(entries 10−14). However, thiourea derivative I emerged as the
catalyst of choice.
The catalyst and the reaction conditions optimized for endo-
norbornenoquinone 1a (Table 1, entry 7) were then applied to
other meso-DA adducts (1b−m) toward C(sp2)−H methylation
with nitromethane. As illustrated in Table 2, this protocol is
As in our previous report,7a an enantioposition-selective
conjugate addition of nitroalkanes to the electron-deficient olefin
of meso-norbornenoquinones was reasoned to be the key to the
success of this approach (Scheme 1B). Accordingly, tertiary
amino-(thio)urea-based bifunctional compounds8 were once
again selected as the catalyst candidate.
Table 2. Scope of the Desymmetrization with Regard to meso-
a
We chose endo-norbornenoquinone 1a as the model substrate
and nitromethane 2a as the alkylating agent (Table 1).
Diels−Alder Adducts
a
Table 1. Catalyst Screening and Reaction Optimization
b
c
entry
cat.
solvent
temp (°C) t (h) yield (%)
er
1
2
3
4
5
6
−
I
PhCF3
PhCF3
CH2Cl2
CHCl3
PhF
25
25
25
25
25
25
25
0
12
6
8
8
6
6
6
6
6
6
6
6
6
6
n.d.
33
26
37
32
42
58
41
53
57
37
45
37
−
91.5:8.5
I
91:9
I
91.5:8.5
91:9
I
I
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
94.5:5.5
95:5
d
7
I
d
8
d
I
96:4
9
I
50
25
25
25
25
25
94.5:5.5
94.5:5.5
83:17
d
10
II
III
IV
V
VI
d
11
d
12
93:7
a
Reactions were carried out on a 0.1 mmol scale. Yields correspond to
d
13
9:91
the isolated yield. Er was determined by HPLC analysis on a chiral
d
b
14
32
13.5:86.5
stationary phase. After 48 h, reaction mixture was passed through
a
b
Celite, concentrated, and treated with KOAc/18-crown-6 in THF for 3
Reactions were carried out on a 0.1 mmol scale. Yields correspond
c
c
h. After 12 h, reaction mixture was passed through Celite,
to the isolated yield; n.d. = not determined. Enantiomeric ratio (er)
was determined by HPLC analysis on a chiral stationary phase. 4 Å
d
concentrated, and treated with KOAc/18-crown-6 in THF for 3 h.
MS (50 mg) was used as an additive.
applicable to DA adducts derived from p-benzoquinone and a
variety of dienes including those having different ring sizes (1a−
c), spiro-fused dienes (1d−g), fulvene (1h), and highly
substituted cyclopentadienes (1j−m). The corresponding
methylated products (3aa−am) were obtained generally with
good to excellent enantioselectivities. Both the tetra- and penta-
substituted norbornenoquinones 1j and 1k, under the optimum
reaction conditions, resulted in a mixture of desired C−H
alkylated product and the corresponding Michael adduct (see
Scheme 3). When these mixtures in each case were treated with
KOAc (1.2 equiv) and 18-crown-6 (1.2 equiv) in THF for 3 h, the
desired products (3ja and 3ka) containing two all-carbon
quaternary stereocenters were formed with 60% yield and 99:1
er. The yields of the reactions are modest in most cases due to the
innate instability of both the quinone-DA adducts and the
Identification of a suitable terminal base incapable of catalyzing
the conjugate addition was crucial before undertaking the catalyst
optimization. After screening several bases,9 (NH4)2CO3 turned
out to be the optimum as no product formation was observed
when the reaction was carried out in the absence of any catalyst in
trifluorotoluene at 25 °C (Table 1, entry 1). When 10 mol % of
dihydroquinine-derived thiourea I was used as the catalyst under
the same reaction conditions, the desired monosubstituted
norbornenoquinone 3aa was formed in 33% yield after 6 h with
a promising er of 91.5:8.5 (entry 2). A solvent screening9 at this
point revealed toluene as the optimal solvent both in terms of
reaction efficiency and enantioselectivity (entries 3−6). The
product yield could be improved by using 4 Å MS as an additive
B
DOI: 10.1021/acs.orglett.6b03168
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
methylated products. The desymmetrized products obtained
from fulvene and tetrachloro cyclopentadienone-ketals derived
DA adducts (3ha and 3la−ma, respectively) are particularly
unstable and formed with poor yield, albeit with high er.
Scheme 2. Synthetic Elaboration of the Desymmetrized
Products
We next examined the scope of this C(sp2)−H alkylative
desymmetrization with regard to other nitroalkanes (Table 3).
Table 3. Scope of the Desymmetrization with Respect to
a
Nitroalkane
tively. Treatment of 3aa with benzyl or allyl bromide in the
presence of K2CO3 under reflux furnished the chiral dihydroqui-
none derivatives 5a−b in high yields. Selective reduction of the
electron deficient olefin of 3aa was possible using Zn/AcOH.
However, the product (6) was obtained with poor diastereose-
lectivity (1.6:1 dr). Reduction of 3aa and 3la under Luche
conditions11 was found to be completely regio- and diaster-
eoselective and furnished the corresponding diols 7 and 8,
respectively, in high yields.12 The relative and absolute stereo-
chemistry of 8 was established from its single crystal X-ray
diffraction analysis.13 The absolute configurations of 7 and the
desymmetrized products (3, Tables 2 and 3) were inferred in
analogy with 8. The endo,endo-cis-diol 7 found its application in
the synthesis of the carbocyclic core of bioactive natural products
antroquinonols.3b In all these cases, the reactions proceeded
without any erosion of enantioselectivity.
While exploring the scope of the reaction, endo-norborneno-
quinone derivative 1j under the optimized reaction conditions
delivered, along with the desired methylated analogue 3ja, the
Michael adduct 9 as a single diastereomer in 55% yield with 99:1
er (Scheme 3). Exposure of 9toKOAc/18-crown-6 generated 3ja
with identical er as that of 9 and 3ja obtained directly from 1j.
These results provide direct evidence in support of the
intermediacy of 9 in this C(sp2)−H alkylation reaction. This
experiment also suggests that the conjugate addition of
nitroalkanes (2) to endo-norbornenoquinone derivatives (1) is
a
Reactions were carried out on a 0.1 mmol scale. Yields correspond to
the isolated yield. Er was determined by HPLC analysis on a chiral
stationary phase. Reaction was conducted at 25 °C using the one-step
protocol as in Table 2.
b
Surprisingly, when 1a was subjected to alkylation with nitro-
ethane (2b) under our standard reaction conditions, formation of
a complex mixture was observed instead of the desired product.
To our relief, conducting the reaction at 0 °C using 4.0 equiv of
nitroethane resulted the Michael adduct, which could be
converted to the desired product 3ab on treatment with
KOAc/18-crown-6 in 40% yield with 95:5 er. This modified
two-step protocol was then followed for alkylation with other
nitroalkanes. endo-Norbornenoquinone 1a could be alkylated
with a number of nitroalkanes, furnishing the alkylated products
(3ab−ai) in moderate to decent yields with up to 99:1 er. In the
case of ester- or keto-functionalized nitroalkanes (2g−i), the
productswereobtainedinmoderatetogoodyieldsundertheone-
stepprotocol, albeitwithsignificantlyreduceder. Cyclohexadiene
and tetrasubstituted cyclopentadiene-derived DA adducts (1b
and 1j) were also alkylated with phenylnitromethane (2c) and
nitroethane (2b), respectively, with good to excellent enantiose-
lectivities.
Scheme 3. Identification and Isolation of the Intermediate
It must be noted that, for majority of these products, this is the
first example of their enantioselective synthesis.
The enantioenriched products obtained in these newly
developed C(sp2)−H alkylative desymmetrization reactions are
densely functionalized and can be further transformed into
potentially useful building blocks. For example, Weitz−Scheffer-
type epoxidation10 of 3aa provided the epoxynorbornenoqui-
none 4 as a single diastereomer with 64% yield (Scheme 2). The
exo-epoxide 4 and its prenyl analogue have been utilized for the
synthesis of the core structure of bioactive kinamycin natural
products3a and antifungal natural product jesterone,3j respec-
C
DOI: 10.1021/acs.orglett.6b03168
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Letter
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the enantiodetermining step of the reaction, as conceived at the
outset of this study (Scheme 1B).
Notwithstanding the tremendous progress in catalytic
asymmetric Diels−Alder reactions during the past several
decades, enantioselective synthesis of DA adducts from
monosubstituted p-benzoquinones remains elusive. Here we
have offered an alternative solution to this problem, more
specifically for the enantioselective synthesis of monosubstituted
endo-norbornenoquinones and related polycyclic compounds.
Our approach is based on the C(sp2)−H alkylative desymmet-
rization of meso-norbornenoquinones and related polycyclic
compounds using inexpensive and air-stable nitroalkanes as the
alkylating agents. These reactions are catalyzed by a dihydroqui-
nine-based tertiary amino-thiourea derivative and deliver highly
functionalized quinone-DA adducts bearing at least four
contiguous stereocenters remote from the reaction site in
moderate to good yields with excellent enantioselectivities.
ASSOCIATED CONTENT
* Supporting Information
(5) For direct approaches, see refs 4b and 4d. For selected indirect
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■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b03168.
(6) For selected reviews, see: (a) Borissov, A.; Davies, T. Q.; Ellis, S. R.;
Fleming, T. A.; Richardson, M. S. W.; Dixon, D. J. Chem. Soc. Rev. 2016,
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Experimental details (PDF)
Characterization data (PDF)
Crystallographic data for 8 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sm@orgchem.iisc.ernet.in.
ORCID
(7) (a) Manna, M. S.; Mukherjee, S. J. Am. Chem. Soc. 2015, 137, 130.
Also see: (b) Manna, M. S.; Sarkar, R.; Mukherjee, S. Chem. - Eur. J. 2016,
22, 14912.
(8) (a) Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sgarzani, V.
Tetrahedron 2006, 62, 375. (b) McCooey, S. H.; Connon, S. J. Angew.
Chem., Int. Ed. 2005, 44, 6367. (c) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem.
Rahul Sarkar: 0000-0003-3700-6580
Santanu Mukherjee: 0000-0001-9651-6228
Notes
The authors declare no competing financial interest.
́ ́
Commun. 2005, 4481. (d) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T.
ACKNOWLEDGMENTS
■
Org. Lett. 2005, 7, 1967. (e) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding,
L.-S.; Wu, Y. Synlett 2005, 603. (f) Okino, T.; Hoashi, Y.; Takemoto, Y. J.
Am. Chem. Soc. 2003, 125, 12672. For selected reviews, see: (g) Siau, W.-
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Commun. 2008, 2499.
Financial supports fromSERB [Grant No. SB/S1/OC-63/2013],
CSIR [Grant No. 02(0207)/14/EMR-II], and DAE-BRNS
[Grant No. 2013/37C/56/BRNS/2440] are gratefully acknowl-
edged. R.S. thanks the Council of Scientific and Industrial
Research(CSIR), NewDelhiforadoctoralfellowship. Wewishto
thank Mr. Prodip Howlader (Department of Inorganic and
Physical Chemistry, IISc, Bangalore) for his help with the X-ray
structure analysis.
(9) For comprehensive optimization studies, see the Supporting
Information.
(10) Weitz, E.; Scheffer, A. Ber. Dtsch. Chem. Ges. B 1921, 54, 2344.
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(12) Wu, H.-J.; Chao, C.-S.; Lin, C.-C. J. Org. Chem. 1998, 63, 7687.
(13) CCDC 1510668 contains the crystallographic data for 8. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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