Asymmetric Synthesis of Remote Quaternary Centers by Copper-Catalyzed Desymmetrization: An Enantioselective Total Synthesis of (+)-Mesembrine

Article abstract of DOI:10.1021/acs.orglett.8b02084

Catalytic asymmetric syntheses of remote quaternary stereocenters have been developed by copper-catalyzed 1,4-hydrosilylation of ?,?-disubstituted cyclohexadienones. A variety of cyclohexenones have been synthesized in good yield and excellent enantioselectivity. Versatile 2-silyloxy diene intermediates bearing ?,?-disubstituted all carbon stereogenic centers can be isolated from the mild reaction conditions. The utility of this strategy is exemplified in a catalytic asymmetric total synthesis of (+)-mesembrine.

Full text of DOI:10.1021/acs.orglett.8b02084

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Synthesis of Remote Quaternary Centers by Copper-
Catalyzed Desymmetrization: An Enantioselective Total Synthesis of
(+)-Mesembrine
Apparao Bokka,† James X. Mao,† John Hartung,‡ Steven R. Martinez,‡ Justin A. Simanis,‡
Kwangho Nam,† Junha Jeon,*,† and Xiaoqiang Shen*,‡
†Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas 76019, United States
‡Process Research and Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
S
* Supporting Information
ABSTRACT: Catalytic asymmetric syntheses of remote
quaternary stereocenters have been developed by copper-
catalyzed 1,4-hydrosilylation of γ,γ-disubstituted cyclohexa-
dienones. A variety of cyclohexenones have been synthesized
in good yield and excellent enantioselectivity. Versatile 2-
silyloxy diene intermediates bearing γ,γ-disubstituted all
carbon stereogenic centers can be isolated from the mild
reaction conditions. The utility of this strategy is exemplified in a catalytic asymmetric total synthesis of (+)-mesembrine.
yclohexanones with remote quaternary stereogenic
centers are useful moieties in bioactive natural products
and pharmaceuticals (see Figure 1). Catalytic enantioselective
Scheme 1. Enantioselective Desymmetrization of γ,γ-
Disubstituted Cyclohexadienones
C
Figure 1. Examples of biomedically relevant molecules containing
cyclohexanones with remote quaternary stereogenic centers.
synthesis of all-carbon quaternary stereocenters has been
challenging in chemical synthesis.1 Although transition-metal-
catalyzed or organocatalytic α- or β-functionalization of
cyclohexanones to construct α,α- or β,β-disubstituted all-
carbon quaternary centers has been well-studied,1b,2,3 establish-
ing the remote γ,γ-all carbon quaternary centers in cyclo-
hexanones in an enantioselective fashion remains less
developed.
Recently, Nishiyama and co-workers reported catalytic
enantioselective desymmetrization of γ,γ-disubstituted cyclo-
hexadienones with a [Rh(Phebox-sBu)] catalyst and trimethox-
ysilane to generate remote quaternary stereogenic centers at
the γ-position (see Scheme 1a).4 Although this is an important
advance, this method uses a precious late-transition-metal
catalyst, and excellent enantioselection was only observed in
reactions with spirocarbocyclic cyclohexadienones. Alterna-
tively, copper is an Earth-abundant transition metal that has
received increased attention for organic syntheses. Conse-
quently, there continues to be interest in the development of
sustainable chemical catalysis through new asymmetric hydro-
silylation strategies harnessing copper hydride.5,6 In this
direction, Corey and co-workers developed Cu-catalyzed
enantioselective desymmetrization of γ,γ-disubstituted cyclo-
hexadienones to construct remote γ,γ-disubstituted all carbon
quaternary centers (see Scheme 1b).7 Although this pioneering
Received: July 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02084
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
method deployed an inexpensive and readily available copper
catalyst to deliver 5 with excellent enantioselectivity, it suffers
with the use of excess strong reducing agent DIBAL-H and
carcinogenic additive HMPA, which possibly limits the wide
usability of this method, because of functional group
compatibility.
enantioselectivity (entries 8 and 9 in Table 1). Encouraged by
this initial result, we then studied the effect of base on Cu-
catalyzed desymmetrization of 1a. Changing the base from
NaOtBu to KOtBu had little effect on both reactivity and
enantioselectivity (entries 9 and 10 in Table 1). Diminished
reactivity and enantioselectivity were observed with weaker
bases (entries 11 and 12 in Table 1). To further improve the
enantioselectivity, we turned our attention to the cyclic BPE
phosphine, which has been recently applied to a variety of
highly enantioselective Cu-catalyzed reactions.10,11 We were
pleased to find (R,R)-Ph-BPE L10 gave good reactivity and
excellent enantioselectivity (94% conversion, 95% ee; see entry
13 in Table 1).
In addressing the issues discussed above, we aimed to
develop a mild catalytic method to produce enantio-enriched
γ,γ-disubstituted cyclohexenones. Furthermore, we envisioned
the potential to isolate 2-silyloxy diene intermediates bearing
γ,γ-disubstituted all carbon stereogenic centers as being
advantageous in a variety of succeeding transformations
involving the accessible enolate or diene. Mechanistically, it
was hypothesized that alkoxy copper species generated through
enantioselective 1,4-hydrocupration of dienones could be
intercepted with an appropriately substituted hydrosilane.
Here, we report CuH-mediated enantioselective desymmetri-
zation of γ,γ-disubstituted cyclohexadienones under mild
reaction conditions. This strategy yielded both synthetically
useful 2-silyloxy diene intermediates and cyclic enones upon
desilylation, bearing all carbon quaternary stereocenters at the
γ-position.
Next, we studied the effect of hydrosilanes on reactivity and
We commenced our investigation by exploring the reactivity
and selectivity of 4-phenyl 4-methyl cyclohexadienone 1a with
chiral CuH generated in situ from CuCl, NaOtBu, PMHS
[poly(methylhydrosiloxane)]8,9 and a chiral ligand screened
from L1 to L10 (see Table 1). Cyclohexenone 2a was formed
enantioselectivity (see Table 2). Initial success was achieved
a
Table 2. Evaluation of Hydrosilanes
a
Table 1. Evaluation of Chiral Ligands
bc
,
d
entry
silane
PMHS
(MeO)2MeSiH
(EtO)2MeSiH
(TMSO)3SiH
Ph2SiH2
Et2SiH2
Et3SiH
Et3SiH
conversion (%) enantiomeric excess, ee (%)
1
2
3
4
5
6
95 (77)
79
95
93
93
92
96
96
96
96
b
c
entry ligand
base
conversion (%) enantiomeric excess, ee (%)
87
65
52
82
1
2
3
4
5
6
7
8
9
10
11
12
13
L1
L2
L3
L4
L5
L6
L7
L8
L9
L9
L9
L9
L10
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
KOtBu
97
99
96
100
96
84
5
96
94
93
51
26
94
12
37
48
−4
38
58
e
7
100 (72)
100 (87)
f
8
a
b
Conditions: dienone 1a (0.5 mmol), toluene (1.0 mL). Monitored
c
by HPLC analysis. Value given in the parentheses is isolated yield for
2a. Determined by HPLC analysis on chiral stationary phases. The
d
e
38
78
74
73
58
95
f
reaction was performed at 40 °C. The reaction was performed under
the conditions of CuCl (2 mol %), NaOtBu (2 mol %), and (R,R)-Ph-
BPE (2 mol %) at 40 °C.
LiOtBu
LiOMe
NaOtBu
with PMHS, which resulted in excellent selectivity and
reactivity (entry 1 in Table 2), but it did not allow for
isolation of the discrete 2-silyloxy diene intermediate 7a,
because of the polymeric nature of PMHS. Alkoxysilanes
provided 2a with good enantioselectivity, albeit diminished
reactivity (entries 2−4 in Table 2). Dihydrosilanes (e.g.,
Ph2SiH2 and Et2SiH2) exhibited similar enantioselectivity, but
the reactivity was modest (entries 5 and 6 in Table 2).
Electron-rich triethylsilane afforded 2a in complete conversion
and excellent enantioselectivity at slightly elevated temperature
(96% ee; see entry 7 in Table 2). However, under the reaction
conditions with 5 mol % catalyst, 10%−15% of over-reduction
product (i.e., cyclohexanone) was formed. By reducing the
catalyst loading to 2 mol %, the over-reduction product was
formed within <5% and the desired product 2a was isolated in
a
b
Conditions: dienone 1a (0.5 mmol), toluene (1.0 mL). Monitored
c
by HPLC analysis. Determined by HPLC analysis on chiral
stationary phases.
with poor enantioselectivity with (S)-Tol-BINAP L1 (entry 1
in Table 1), the enantioselectivity was slightly improved with
(S)-DM-BINAP L2 (entry 2 in Table 1). In the Josiphos series,
L3 further improved the enantioselectivity (entry 3 in Table
1), but other ligands (L4 and L5) in that series were poorly
selective (entries 4 and 5 in Table 1). The ligand (S)-DTBM-
MeOBIPHEP (L6) resulted in moderate enantioselectivity
(entry 6 in Table 1). While (S)-SegPhos L7 gave a poor
conversion to 2a (entry 7 in Table 1), (S)-DM-SegPhos L8
and (S)-DTBM-SegPhos L9 notably improved conversion and
B
DOI: 10.1021/acs.orglett.8b02084
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
87% yield with identical enantioselectivity (entries 7 and 8 in
Table 2), which indicates that there was no secondary
resolution due to over-reduction. Notably, under the
triethylsilane conditions, we were able to isolate the
intermediate 7a, which is a useful synthon for a variety of
transformations.12,13
Having arrived at the optimal conditions to produce and
isolate both synthetically useful γ,γ-disubstituted 2-silyloxy
dienes 7 and cyclohexenone products 2 upon desilylation, we
examined the scope of γ,γ-disubstituted cyclohexadienones, as
presented in Scheme 2. The enantioselective desymmetrization
phenolic TBS ether, and N-substituted indole-containing
substrates proceeded in good yield and high enantioselectivity
(2g−2i). In the reaction of 1h, the TBS group was tolerated
during the desymmetrization and removed during the
subsequent TBAF treatment. When the methyl group in
substrate 1a was replaced with ethyl, enantioselectivity was
further improved (99% ee, 2j). Note that 37% ee was observed
for this substrate in Rh−H catalysis.4 With recognition of
biologically privileged all carbon spirocyclic scaffolds, cyclo-
hexadienone 1k was tested under the optimized reaction
conditions. The product 5,6-spirocycle 2k was obtained in 86%
ee, which is an improvement over Nishiyama’s catalyst system
(78% ee).4 Finally, we tested the cyclohexadienones with two
alkyl substituents, the catalyst distinguishes cyclohexyl and
methyl in 1l well, and product 2l formed in 94% ee and 82%
yield. For one of the most challenging substrates 1m, which
has two minimally differentiated substituents Et and Me, the
product 2m was obtained in decent enantioselectivity (54%
ee).
abc
, ,
Scheme 2. Scope of the Desymmetrization Reaction
To gain further insight into the enantio-determining step of
the desymmetrization process (see Figure 2a), we performed
density functional theory (DFT) calculations for the hydro-
cupration of 1a with the presumed catalyst (L10CuH). Our
computational studies predict that, during the hydrocupration,
1a can approach two sterically accessible quadrants (II and IV)
in the C2 symmetric catalyst, where four diastereotopic olefin
faces of two enantiotopic olefins were differentiated within the
asymmetric environment of L10CuH via TS1 to TS4. Among
them, TS3 avoids the most severe steric interactions of the
unreacted olefin moiety and two substituents (i.e., Ph and Me)
at the γ-position of 1a with the phenyl substituents (quadrants
I and III) on the phospholane moieties in the CuH/Ph-BPE
catalyst, leading to the preferential formation of the hydro-
cupration intermediate shown in TS3 with an activation free
energy of 18.4 kcal/mol, which is 2.7 kcal/mol lower than that
from the second lowest barrier shown in TS1 (Figures 2b and
2c). Additions of L10CuH to two other diastereotopic faces of
two olefins through TS2 and TS4 experiences the unfavorable
steric repulsions of the olefin moiety and substituents at the γ-
position of 1a with two quadrants in the catalyst, with the
formation of relevant reacting complexes disfavored by 3.8 and
3.3 kcal/mol relative to TS3, respectively (Figure 2c). These
calculated results offer a plausible mechanistic basis for the
CuH/Ph-BPE catalyst to induce enantioselective desymmetri-
zation of the remotely substituted cyclohexadienones.
a
Conditions: Dienone (0.5 mmol), silane (0.55 mmol), toluene (1.0
Since mesembrine was first isolated in 1957,14 this alkaloid
has attracted a great deal of interest from chemists,15 because
of its interesting biological activity.16 We were interested in
demonstrating the versatility of the Cu-catalyzed enantiose-
lective desymmetrization strategy to access the octahydro-
indole skeleton core bearing an all-carbon quaternary center
(see Scheme 3). Pd-catalyzed α-arylation of Boc-protected
amino aldehyde 9 with 3,4-dimethoxy-1-bromobenzene 10
provided aldehyde 11 in 52% yield.17 Base-catalyzed Robinson
annulation18 of 11, followed by DDQ-mediated dehydrogen-
ation19 afforded dienone 12 in 56% yield (two steps). The key
Cu-catalyzed desymmetrization of 12 delivered enone 13 (82%
yield, 97% ee). The completion of this synthesis was achieved
by removal of the Boc group, followed by concomitant amine
conjugate addition under the acidic conditions to furnish
(+)-mesembrine 8 in 81% yield and 97% ee.
b
c
mL). Yields of isolated products. The % ee values were determined
by chiral HPLC analysis. The absolute configurations of 2a, 2b, 2c,
2e, 2g, 2k, and 2l were determined by comparing the optical rotations
with literature-reported values.4 The configurations of other enones
were assigned by analogy. dYields of isolated 2-siloxy dienes (7).
eTBS-protected phenol as substrate. fLow isolated yield due to
product volatility.
of a variety of substrates, with various electronic and steric
natures, generally gave 2 in good to excellent yield and with
good to excellent enantioselectivity (77%−99% ee). A few
representative siloxy dienes were isolated in high yields (86%−
92%) and excellent enantioselectivities (91%−96% ee, 7a, 7b,
7c, and 7f; see the Supporting Information). Under these
conditions, varying the electronic properties of the aryl group
consistently gave good to excellent yields and enantioselectiv-
ities (2a−2e; see Scheme 2). Ortho-substitution in 1f was
compatible with the process. Reactions with 2-naphthyl,
In summary, we have developed a protocol involving Cu-
catalyzed enantioselective desymmetrization of γ,γ-disubsti-
C
DOI: 10.1021/acs.orglett.8b02084
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Figure 2. (a) Approaches of CuH to four diastereotopic faces of two enantiotopic olefins. (b) Quadrant diagram model for the hydrocupration of
L10CuH with cyclohexadienones 1a in TS3. (c) DFT calculations of transition states of hydrocupration of 1a with L10CuH catalyst. Energies were
calculated at the M06/SDD−def2TZVP/SMD(toluene) level of theory with geometries optimized at the B3LYP-D3(BJ)/SDD−6-31G(d) level
(see the Supporting Information for more details and references).
a
ASSOCIATED CONTENT
Scheme 3. Total Synthesis of (+)-Mesembrine
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02084.
1
Detailed experimental procedures, H and 13C NMR
spectra of all new compounds, and HPLC trace analysis
of enantio-enriched compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: jjeon@uta.edu (J. Jeon).
*E-mail: xiaoqiang.shen@abbvie.com (X. Shen).
ORCID
Junha Jeon: 0000-0001-8632-8098
Xiaoqiang Shen: 0000-0002-2746-4484
Notes
a
Data taken from ref 20.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
tuted cyclohexadienones to provide chiral cyclohexenones
bearing remote all carbon quaternary stereogenic centers at a γ-
position. Under the mild catalytic conditions, reactions with
chiral CuH complex generated in situ from CuCl, NaOtBu,
(R,R)-Ph-BPE, and Et3SiH exhibited a relatively broad scope
with good to excellent enantioselectivity. In addition, the use of
Et3SiH allowed for the isolation of synthetically useful 2-
silyloxy dienes which can be utilized for further trans-
formations. Finally, the utility of this approach was exemplified
in an asymmetric total synthesis of (+)-mesembrine.
The design, study conducted, analysis, and financial support of
the study were provided by AbbVie. The NSF (CHE-0234811
and CHE-0840509) is acknowledged for partial funding of the
purchases of the NMR spectrometers used in this work. The
authors acknowledge Parham Asgari (University of Texas,
Arlington) and Scott W. Krabbe, Daniel D. Caspi, Gregory E.
Storer, Anthony R. Haight, and Steven J. Wittenberger
(AbbVie) for insightful discussions and advice on the
preparation of this manuscript.
D
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Letter
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