Efficient syntheses of korupensamines A, B and michellamine B by asymmetric Suzuki-Miyaura coupling reactions

Article abstract of DOI:10.1021/ja409669r

Efficient asymmetric Suzuki-Miyaura coupling reactions are employed for the first time in total syntheses of chiral biaryl natural products korupensamine A and B in combination with an effective diastereoselective hydrogenation, allowing ultimately a concise and stereoselective synthesis of michellamine B. Chiral monophosphorus ligands L1-3 are effective for the syntheses of a series of functionalized chiral biaryls by asymmetric Suzuki-Miyaura coupling reactions in excellent yields and enantioselectivities (up to 99% ee). The presence of a polar-π interaction between the highly polarized BOP group and the extended π system of arylboronic acid coupling partner is believed to be important for the high enantioselectivity.

Full text of DOI:10.1021/ja409669r

Communication
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Efficient Syntheses of Korupensamines A, B and Michellamine B by
Asymmetric Suzuki-Miyaura Coupling Reactions
Guangqing Xu,‡ Wenzhen Fu,‡ Guodu Liu,‡ Chris H. Senanayake,† and Wenjun Tang*,‡
‡State Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, China
†Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut CT06877, United States
S
* Supporting Information
syntheses of both 2 and 3 is still lacking. Consequently, a concise
and stereoselective synthesis of 1 is yet to be reported.
ABSTRACT: Efficient asymmetric Suzuki-Miyaura cou-
pling reactions are employed for the first time in total
syntheses of chiral biaryl natural products korupensamine
A and B in combination with an effective diastereoselective
hydrogenation, allowing ultimately a concise and stereo-
selective synthesis of michellamine B. Chiral mono-
phosphorus ligands L1−3 are effective for the syntheses
of a series of functionalized chiral biaryls by asymmetric
Suzuki-Miyaura coupling reactions in excellent yields and
enantioselectivities (up to 99% ee). The presence of a
polar-π interaction between the highly polarized BOP
group and the extended π system of arylboronic acid
coupling partner is believed to be important for the high
enantioselectivity.
While various methods for constructing chiral biaryls are
available including chiral auxiliaries,7 asymmetric transforma-
tions of “pro-chiral” biaryls,5,8 asymmetric aryl formations,9
asymmetric oxidative homocouplings,10 the catalytic asymmetric
cross-couplings,11 particularly Suzuki-Miyaura couplings,12
remains one of most attractive and versatile methods due to its
mild reaction conditions, the ability of tolerating various
functionalities, and the availability and nontoxic nature of
starting materials. Despite the recent advances in this field, the
current substrate scope of asymmetric Suzuki-Miyaura couplings
remains very narrow. Limited results were achieved on substrates
with synthetically interesting functionalities. To our knowledge,
efficient asymmetric Suzuki-Miyaura coupling is yet to be applied
in natural product syntheses. In addition, most current methods
still suffer from high catalyst loadings and prolonged reaction
time. We herein report an asymmetric Suzuki-Miyaura coupling
methodology for chiral ortho-biaryl-ol derivatives with chiral
monophophorus ligands (Figure 2) and applications in total
synthesis of 1−3.
ichellamine B (1),1 originally isolated from tropical liana
M
Ancistrocladus korupensis in Cameroon, has gained
significant interest as a strong anti-HIV-1 and anti-HIV-2 agent
(Figure 1). Structurally, it derives from heterodimerization of
Figure 2. Chiral monophosphorus ligands.
Although enantioselective Suzuki-Miyaura couplings are
achieved on a few functionalized substrates with alkoxy,12e,f
phosphonate,12a,h,i bulky amides,12b and carbonylbenzooxazoli-
dinone13 at ortho positions, it is particularly important to develop
a highly efficient method for synthesizing chiral ortho-hydroxyl
biaryls because such structures exist ubiquitously in numerous
natural products. We thus focused on developing efficient
asymmetric Suzuki-Miyaura couplings of aryl halides with an
ortho-OPG group. Our previous work13 on asymmetric Suzuki-
Miyaura coupling with a Pd-L1 catalyst showed the importance
of a second interaction between two coupling partners for high
enantioselectivity. We thus exploited this strategy to explore the
enantioselective Suzuki-Miyaura couplings between O-protected
Figure 1. Axially chiral biaryl natural products.
antimalarial atropdiastereomeric natural products korupens-
amine A (2) and korupensamine B (3).2 Due to their interesting
biological activities and unique molecular architectures contain-
ing both axial and central chirality, there has been considerable
study3 toward diastereoselective syntheses of 2 or 3 led by
Bringmann,4a−c Lipshutz,4d,e Uemura,4f,g and Hoye.4h−k Notable
strategies in constructing the axial chirality include kinetic
asymmetric transformation of “lactone”,5 atropselective inter-
moleculare biaryl coupling,4e and chiral chromium complexes.6
Despite these methods, an efficient route for catalytic asymmetric
Received: September 18, 2013
© XXXX American Chemical Society
A
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1-bromonaphthalen-2-ol and naphthalen-1-ylboronic acid. The
reactions were carried out under nitrogen in toluene/water (5/1
v/v) with K3PO4 as the base at 30−35 °C for 12 h (Table 1). It
was found that the PG group exerts a significant impact on the
enantioselectivity. While excellent yields (90−97% yield) were
all obtained with various PG groups, only medium ee’s (65−
74%) were achieved with -COtBu, -COPh, -CO(1-Np), and
-P(O)Ph2 groups (entries 1−3, 5). The carbonyl-oxazolidinone
protection also led to only 65% ee (entry 4). Interestingly, an
excellent enantioselectivity (94% ee) was achieved when a bis(2-
oxo-3-oxazolidinyl)phosphinyl (BOP) protection was applied
(entry 6). Further employment of the new ligand L2, with an
isopropyl group on the top aryl ring, led to the coupling product
6f in an almost perfect ee (99%). Exploration of the substrate
scope found that this protocol is tolerable with various
substituents and functionalities on both coupling partners
(entries 8−13). A variety of chiral functionalized biaryls could
be efficiently synthesized in excellent ee’s and yields under mild
conditions by using these chiral monophosphorus ligands.
We attributed to a possible noncovalent interaction between
two coupling partners for the high stereoselectivity. The sharp
increase of enantioselectivity from OP(O)Ph2 (entry 5) to
OBOP (entry 6) functionality indicated the important effect
posed by the oxazolidinone moieties in BOP. Observation from
its substrate scope showed the necessity of an extended π system
of arylboronic acid for the high enantioselectivity. For example,
excellent enantioselectivities were achieved with 1-naphthylbor-
onic acid, 2-formylphenylboronic acid, and ortho-phenylphenyl-
boronic acid as shown in Table 1. In contrast, a poor selectivity
(20% ee) was observed with 2-methylphenylboronic acid. It was
thus proposed the presence of a significant polar-π inter-
action14,15 between the highly polarized BOP group and the
extended π system of the boronic acid partner during reductive
elimination step (Figure 3).
Table 1. Asymmetric Suzuki-Miyaura Coupling
Figure 3. A proposed model of Pd(II)-L2 catalyst for the synthesis of 6f
during the reductive elimination step.
The facile construction of a series of functionalized chiral
biaryls under mild conditions by using this methodology
prompted us to pursue the syntheses of both 2 and 3 through
catalytic asymmetric Suzuki-Miyaura couplings. Because of the
diastereomeric nature of 2 and 3 containing both axial chirality
and central carbon chirality, a key challenge is to install the chiral
elements in highly selective fashion and without interfering with
each other. Our strategy is to construct the axial chirality using
the developed asymmetric Suzuki-Miyaura coupling method-
ology followed by asymmetric hydrogenation to furnish the
chiral tetrahydroisoquinoline moiety (Scheme 1).16 Thus, diol 7
was sequentially protected with TBS and BOP followed by
bromination to provide 8. Asymmetric Suzuki-Miyaura coupling
of 8 with arylboronic acid 1417 in the presence of 1 mol %
Pd(OAc)2 and 1.2 mol % L2 in toluene/water at 35 °C for 8 h
provided the coupling product 9 in 96% yield and 93% ee at a
gram scale. Subsequent basic removal of both BOP and TBS
groups followed by benzyl protection yielded 10, which was
further transformed to enamide 11 through nitroaldol and
reductive acetylation.18 Asymmetric hydrogenation of 11 with a
Rh-WingPhos catalyst developed in our group19 unfortunately
led to the formation of 12 at a low d.r. ratio (2:1). A Rh-MeO-
BIBOP catalyst20 also provided a mediocre ratio (3:1). Further
engineering of the hydrogenation catalyst led to the development
of L421 with a chiral bisphosphoindole structure, providing 12 at
a good d.r. ratio of 92:8 in 99% overall yield. Subsequent
a
Conditions unless otherwise specified: 1.0 equiv of aryl bromide, 1.5
equiv of boronic acid, 1 mol % Pd(OAc)2, 1.2 mol % of chiral ligand, 3
equiv of K3PO4, toluene/H2O (5/1, v/v), rt, 4−12 h, isolated yield,
enantiomeric excesses were determined by chiral HPLC on a chiralcel
b
OD-H or chiralPak AD-H column. The absolute configurations of
6a−f were determined by conversion to 1,1′-binaphthalen-2-ol and by
comparison of their optical rotations to reported data. The absolute
configurations of 6g−i were assigned by analogy. The absolute
c
configurations of 6j−l were not determined. BuOH/H2O (4/1, v/v)
d
was employed the solvent and K2CO3 was used as the base. BuOH/
H2O (4/1, v/v) was employed the solvent.
B
dx.doi.org/10.1021/ja409669r | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 1. Syntheses of 2
Scheme 2. Syntheses of 3
+
−
Conditions: (g) EtNO2, HO(CH2)NH3 HCO2 , 60 °C, 93%; (h) Fe,
AcOH, Ac2O, DMF, 70 °C, 61%; (i) 1 mol % [Rh(NBD)2]BF4/L4, H2
(20 atm), 0 °C, 12 h, 99%, d.r. = 90/10; (j) BnBr, NaH, DMF, 96%;
(k) POCl3, 2,4,6-Collidine, toluene, 100 °C, 4 h; (l) NaBH4, EtOH,
−78 °C to rt, 78% (over 2 steps, trans/cis = 4/1); (m) Pd/C (5%), H2
(1 atm), 3 h, MeOH/DCM = 2/1, 3 h, 86%.
Conditions: (a) TBSCl, TEA, DCM, −78 °C to rt, 59%; (b) NBS,
DCM, −15 °C, 86%; (c) BOPCl, TEA, DCM, 98%; (d) 14,
Pd(OAc)2/L2, K3PO4, toluene/H2O = 5/1, 96%, 93% ee; (e) NaOH,
MeOH, 97%; (f) BnBr, K2CO3, DMF, 95%; (g) EtNO2, HO(CH2)-
NH3 HCO2 , 60 °C, 92%; (h) Fe, AcOH, Ac2O, DMF, 70 °C, 60%;
(i) 1 mol % Rh(nbd)2BF4/L4, H2 (20 atm), DCM, 0 °C, 12 h, 99%,
d.r. 92/8; (j) BnBr, NaH, DMF, 96%; (k) POCl3, 2,4,6-collidine,
toluene, 100 °C, 4 h; (l) NaBH4, EtOH, −78 °C to rt, 85% (over 2
steps, trans:cis = 6/1); (m) Pd/C (5%), H2 (1 atm), MeOH/DCM =
2/1, 3 h, 95%.
Scheme 3. Syntheses of 1
+
−
installation of the tetrahydroquinoline moiety was accomplished
through the following transformations: (i) benzyl protection at
the amide bond under conditions of NaH/BnBr; (ii) Bischler-
Napieralski reaction with POCl3; and (iii) diastereoselective
reduction of the resulting imine with NaBH4 (tans:cis = 6:1). A
final global debenzylation by hydrogenolysis provided 2, whose
characterization was identical at every aspects with reported
data.2,4 Thus, 2 was synthesized through an efficient asymmetric
Suzuki-Miyaura coupling and an effective diastereoselective
hydrogenation as key steps from compound 7 in 24% overall
yield and in 13 linear steps
Conditions: (a) C5H5NHBr3, CHCl3, AcOH, 59%; (b) C5H5NHBr3,
CHCl3, AcOH, 62%; (c) B(OiPr)3, toluene/THF = 2/1, −95 °C,
nBuLi, −95 °C to −15 °C, aq NH4Cl (87%); (d) Pd(PPh3)4, K3PO4,
DMF, 90 °C, 84%; (e) Pd/C (5%), H2 (1 atm), MeOH/DCM = 2/1,
7 h, 93%.
By using a similar route, the synthesis of 3 was also
accomplished through asymmetric catalytic technology (Scheme
2). Thus, chiral aldehyde 15 with M configuration was
synthesized from 8 and 14 with a Pd-ent-L2 catalyst in 96%
yield and in 93% ee. After two steps to install the enamide moiety,
asymmetric hydrogenation of 16 in the presence of 1 mol % Rh-
L4 catalyst provided 17 with a d.r. ratio of 90:10. The fact that
similar diastereoselecitivities were observed in preparation of
both 17 and 13 strongly demonstrated the independence of
asymmetric hydrogenation with the Rh-L4 catalyst from the axial
chirality of the substrate. 17 underwent installation of the
tetrahydroquinoline moiety and global deprotection of the
benzyl groups, yielding 3 in equal synthetic efficiency.
With the syntheses of both korupensamine A and B
accomplished, we set out to synthesize michellamine B22 (1)
from their advanced intermediates 13 and 18 by a Suzuki-
Miyaura coupling (Scheme 3).22b Thus, bromide 19 was
prepared from 13 under action of C5H5NHBr3 as the
bromination reagent. Boronic acid 20 was obtained from 18 by
bromination followed by metal−halogen exchange to react with
B(OiPr)3. Suzuki-Miyaura coupling of 19 and 20 with Pd(PPh3)4
as the catalyst led to the formation of the coupling product 21 in
84% yield. Hydrogenolysis of 21 removed all benzyl groups and
completed the synthesis of 1 in a concise and highly
stereoselective fashion.
In summary, we have developed an efficient and practical
asymmetric Suzuki-Miyaura coupling methodology for a series of
synthetically useful and functionalized chiral biaryls under mild
reaction conditions and at low catalyst loadings. The presence of
a polar-π interaction between the highly polarized BOP group
and the extended π system of arylboronic acid coupling partner is
believed to be essential for the high enantioselectivity. The
methodology has been successfully applied in natural product
syntheses and allowed for the first time the syntheses of both
korupensamine A and B through catalytic asymmetric Suzuki-
Miyaura coupling along with an effective diastereoselective
hydrogenation. Additionally, the synthesis of their heterodimer 1
is accomplished in a concise and highly stereoselective fashion.
Further applications of this methodology in constructing chiral
biaryl natural products and analogs are currently underway and
progress will be reported in due course.
C
dx.doi.org/10.1021/ja409669r | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
* Supporting Information
Full experimental details and characterization data. This
information is available free of charge via the Internet at
http://pubs.acs.org/.
■
S
AUTHOR INFORMATION
Corresponding Author
tangwenjun@sioc.ac.cn
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by NSFC-21272254, STCSM-
13PJ1410900, the “Thousand Plan” Youth program, the
Innovation Fund of State Key Laboratory of Bio-organic and
Natural Products Chemistry, and Boehringer Ingelheim. We are
grateful to Dr. Lifeng Pan for NMR assistance.
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