Efficient Enantioselective Syntheses of (+)-Dalesconol A and B

Article abstract of DOI:10.1021/jacs.7b00783

We herein report the first enantioselective syntheses of immunosuppressants (+)-dalesconol A and B in a highly efficient and concise manner, which features an efficient palladium-catalyzed enantioselective dearomative cyclization-kinetic resolution cascade to install the chiral all-carbon quaternary center, an effective sterically hindered Stille coupling, a powerful 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) oxidation to furnish all requisite unsaturation, and a tandem hydrolysis-ring closure sequence.

Full text of DOI:10.1021/jacs.7b00783

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Communication
Efficient Enantioselective Syntheses of (+)-Dalesconol A and B
Guoqing Zhao, Guangqing Xu, Chao Qian, and Wenjun Tang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b00783 • Publication Date (Web): 22 Feb 2017
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Efficient Enantioselective Syntheses of (+)-Dalesconol A and B
Guoqing Zhao,§ Guangqing Xu,§ Chao Qian, Wenjun Tang*
State Key Laboratory of BioꢀOrganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai 200032, China
an unprecedented enantioselective dearomative cyclization affectꢀ
9
ABSTRACT: We herein report the first enantioselective synꢀ
ed by a chiral palladium catalyst. The stereocenter at position 8
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theses of immunosuppressants (+)ꢀdalesconol A and B in a
could be eliminated by a subsequent oxidation. The bromo naphꢀ
highly efficient and concise manner, which features an effiꢀ
cient palladiumꢀcatalyzed enantioselective dearomative cyꢀ
clizationꢀkinetic resolution cascade to install the chiral allꢀ
carbon quaternary center, an effective sterically hindered Stille
coupling, a powerful DDQ oxidation to furnish all requisite
unsaturation, and a tandem hydrolysisꢀring closure sequence.
thol 5 would be easily prepared from readily available aromatic
compounds 6, 7, and 8 by a FriedelꢀCrafts reaction and a nucleoꢀ
philic addition.
a. Retrosynthetic analysis
OH
OPG
O
O
Initially isolated by Tan and coworkers1 in 2008 from mantisꢀ
B
C
Michael
addition
associated fungus Daldinia eschscholzii, Dalesconol A (1, IC50
=
1
0.16 ꢁg mLꢀ1, SI > 500) and B (2, IC50 = 0.25 ꢁg mLꢀ1, SI >320)
are two unusual polyketides that exhibit strong immunosuppresꢀ
sive activities comparable to that of clinically used cyclosporine
A2 (IC50 = 0.06 ꢁg mLꢀ1, SI = 187), but with superior selective
index (SI) values for their noncytotoxic nature. Interestingly, both
natural dalesconol A & B are scalemic mixtures with excess of
their (ꢀ)ꢀenantiomers (ratios of (ꢀ)/(+) ~2/1), a consequence dictatꢀ
ed by laccase during the atropselective coupling of naphthol radiꢀ
cals in their biosynthesis.3 Intriguingly, both scalemic mixtures of
natural dalesconol A & B provided more potent immunosuppresꢀ
sive activities than their enantiomers.1 Subsequently, these two
compounds were also isolated by She, Lin, and coworkers from a
mangrove endophtic fungus (Sporothrix sp. #4335) and named as
sporothrin A and B.4 Compound 1 exhibited strong inhibition of
acetylcholine esterase (IC50 = 1.05 ꢁM) while both compounds
showed modest antitumor activities. Structurally, dalesconol A
and B possess an architecturally unique and highly dense carbon
skeleton containing seven fused rings of various sizes and two
stereogenic centers including one sterically congested allꢀcarbon
quaternary center. The only total syntheses of racemic dalesconol
A and B were accomplished beautifully by Snyder and coworkers5
by employing a key oneꢀpot cationic cyclizationꢀintramolecular
oxidative coupling cascade through a sequence of 15 linear steps
and 25 overall steps. Later, Shi and coworkers reported a concise
method for constructing the dalesconol skeleton by using a carboꢀ
cationꢀmediated dearomatizationꢀcyclization strategy.6 An effiꢀ
cient enantioselective syntheses of dalesconol A and B would not
only help provide ample optically pure samples for further eluciꢀ
dation of their biological mechanism, but also provide valuable
analogs for discovering new immunosuppressants. Herein we
report the concise and first enantioselective syntheses of (+)ꢀ
dalesconol A and B (1 and 2).
19
O
O
D
F
G
2
8
HO
PGO
OH
E
OPG
A
O
O
R
R
1:
2:
3
R = H, (+)-dalesconol A
R = OH, (+)-dalesconol B
cross-coupling
Pd/L
OPG
OH
OPG
O
enantioselective
dearomative
cyclization
Br
Br
Pd/L*
F
8
PGO
PGO
OPG
OPG
A
O
HO
R
5
R
4
Friedel-Crafts reaction
nucleophilic addition
OMe OMe
OMe OH
OHC
OMe
+
+
R
Br Br
6
7
8
b. Asymmetric dearomative cyclization
R
R X
L*
Pd-
Ar
Ar
O
HO
up to 99% yield
up to 99% ee
OMe
OH
O
The major challenge in synthesizing 1 and 2 (Figure 1a) is to
establish the highly congested allꢀcarbon quaternary center within
the densely fused ring systems. Instead of using an oxidative or
cationic cyclization approach adopted by Snyder5 or Shi6 in their
synthetic studies, we envisioned to implement a palladiumꢀ
catalyzed intramolecular enantioselective dearomative cyclizaꢀ
tion,7,8 a strategy that had been applied successfully for the synꢀ
thesis of terpenes and steroids in our laboratory (Figure 1b).9
Thus, dalesconol A and B could be derived from spiroenone 3
through an intramolecular Michael addition to fuse the 7ꢀ
membered G ring. The installation of the acetyl group in 3 could
be accomplished by a palladiumꢀcatalyzed sterically demanding
crossꢀcoupling from aryl bromide 4. The key spiroenone skeleton
in 4 could be constructed from a racemic aryl bromide 5 through
O
O
HO
H
O
kaurene intermediate
boldenone skeleton
(-)-totaradiol
Figure 1. Retrosynthetic analysis of dalesconol A (1) and B (2)
on the basis of an enantioselective dearomative cyclization
We commenced our synthesis from commercially available startꢀ
ing material 1,8ꢀdimethoxynaphthalene (9), which was treated
with NBS to provide the dibromo compound 7 in 78% yield
(Scheme 1). Lithiumꢀbromide exchange of 7 with 1.05 equiv Buꢀ
Li followed by an in situ nucleophilic addition with aldehyde 10
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(a) asymmetric dearomative cyclization (b) kinetic resolution by Heck cyclization
provided alcohol 11 in 85% yield. The next step was to install
another naphthalene moiety on 11. This was accomplished by a
(14 14a/15)
(12 13a/b)
O
1
2
3
4
5
6
O
O
O
P
P
Scheme 1. Enantioselective synthesis of spiroenone 14a’
O
O
O
Pd
OMe OMe
OMe OMe
OHC
OMe
A
Pd
S
1. NBS
78%
2. BuLi,
85%
O
S
19
19
O
O
7
8
9
OMe
10
Br Br
O
O
9
7
O
A
B
O
OMe
OMe
OMe OH
10
11
12
13
14
15
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OH
Figure 2. (a) Stereochemical model of asymmetric dearomative
cyclization during reductive elimination: The formation of 19S
isomers was favored with (R)ꢀAntPhos. (b) Stereochemical model
of kinetic resolutionꢀHeck cyclization: The Heck cyclization of
the 19Sꢀenantiomer was slower due to the less favorable conforꢀ
mation of the Pd complex B during insertion.
HO
Br
OMe
Br
6
8
3. TFA
52%
MeO
MeO
OMe
OMe OMe
O
P
FriedelꢀCrafts alkylation of naphthol 6 with alcohol 11 in the
presence of TFA to afford bromo naphthol 12 in 52% yield. The
stage was set for the crucial enantioselective intramolecular
dearomative cyclization of racemic 12 with a chiral palladium
catalyst. We envisioned that a Pꢀchiral monophosphorus ligand
developed in our laboratory could be effective for this unpreceꢀ
dented enantioselective intramolecular cyclization to afford the
spiroenones 13a and 13b. The challenge was the highly acidic
nature of proton at position 8 in 12, which might complicate the
outcome of the cyclization. After many experimentations,10 we
found that both the enantioselectivities and the diastereomeric
ratios of 13a/b were highly sensitive to the choice of the ligand as
well as the base. (R)ꢀAntPhos11 proved to be most effective and
provided preferentially the 19S isomers 13a (63% ee) and 13b
(70% ee). This palladiumꢀcatalyzed asymmetric reaction was proꢀ
posed to proceed through the conformation A depicted in Figure
2a during reductive elimination, favoring the formation of 19S
products. With K2CO3 as the base, a good combined yield (80%
yield) was achieved. Employment of a stronger base such as
Cs2CO3 (~40% ees) and KOtBu (~20% ees) led to preferentially
the formation of the thermodynamically more stable isomer 13b,
however with a diminished ee (~20% ees). We thus chose K2CO3
as the base for the synthesis. Interestingly, the diastereomeric
mixture of 13a and 13b (~1:1.3) was transformed to a single diaꢀ
stereomeric aryl bromide 14a in 95% yield and in 67% ee upon
the treatment of Bu4NBr3. Apparently, a facile proton shift took
place at position 8 during the electrophilic aromatic substitution,
resulting in the sole formation of the thermodynamically more
stable isomer 14a.12 The next challenge was to enhance the optiꢀ
cal purity of 14a. We considered that the sterically hindered aryl
bromide 14a bearing a vicinal enone moiety could proceed an
intramolecular Heck cyclization by employing a chiral palladium
catalyst through a kinetic resolution fashion. Excitingly, when 14a
was treated with the same chiral catalyst (Pdꢀ(R)ꢀAntPhos) used
for dearomative cyclization, an effective kinetic resolution (S = 15)
was observed13 and the 19S enantiomer proceeded at a much lowꢀ
er rate than its antipode, resulting in the formation of bromide
14a’ in 96% ee and in 80% isolated yield along with the heptacyꢀ
clic Heck product 15 in 13% yield and 99% ee. It was believed
that the steric interaction between the A ring and the tertꢀbutyl
group of AntPhos caused the less favorable conformation of the
Pd complex B required for olefin insertion (Figure 2b), leading to
a relatively lower rate of the 19S enantiomer for Heck cyclization.
The absolute configuration of 14a’ was confirmed by Xꢀray crysꢀ
tallography.14
12
11
MeO
tBu
4. Pd2(dba)3
(R)-AntPhos
K2CO3
OMe
OMe
O
O
(R)-AntPhos
19
8
19
8
MeO
MeO
OMe
OMe
MeO
13a
MeO
13b
MeO
O
MeO
35%, 63% ee
45%, 70% ee
5. Bu4NBr3
95%
OMe
OMe
O
6. Pd2(dba)3
(R)-AntPhos
K2CO3
19
Br
Br
8
80%
MeO
MeO
MeO
MeO
OMe
OMe
MeO
MeO
14a
14a'
67% ee
OMe
96% ee
O
OMe
MeO
MeO
OMe
15
99% ee, 13%
aReagents and conditions: (1) NBS (1.05 equiv), DCM, ꢀ15 oC;
o
then NBS (1.05 equiv), DMF, 20 C (78%); (2) nBuLi (1.05 equiv),
o
o
THF, ꢀ78 C; then 10 (1.1 equiv), ꢀ78 C (85%); (3) 6 (1.1 equiv),
TFA (1.8 equiv), DCM, ꢀ40 oC to rt (52%); (4) Pd2(dba)3 (3.0 mol %),
o
(R)ꢀAntPhos (8.0 mol %), K2CO3 (2.0 equiv), toluene, 80 C (80%);
(5) Bu4NBr3 (1.05 equiv), rt (95%, 67% ee); (6) Pd2(dba)3 (3.0 mol
%), (R)ꢀAntPhos (8.0 mol %), K2CO3 (2.0 equiv), toluene, 80 oC
(80%, 96% ee); NBS = Nꢀbromosuccinimide, dba = dibenzylidene
acetone.
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tion with BBr3 completed the enantioselective synthesis of (+)ꢀ
Scheme 2. Completion of (+)ꢀdalesconol B (2)
1
2
dalesconol B (2) from 1,8ꢀdimethoxynaphthalene (9) through 11
linear steps and in 10% overall yield.
3
4
Scheme 3. Completion of (+)ꢀdalesconol A (1)
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
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60
o
aReagents and conditions: (7) PtO2 (30 mol %), H2 (10 atm), 25 C
(84%); (8) TMSC≡CSnBu3 (3.0 equiv), Pd2(dba)3 (2.5 mol %), BIꢀ
DIME (5 mol %), toluene, 100 oC (89%); (9) DDQ (2.2 equiv), DCE,
80 oC (90%); (10) TBAF (2.0 equiv), THF, rt; then Fe2(SO4)3 (10
mol %), AcOH/DCE, 60 C (77%); (11) BBr3 (1.5 M in DCM, 43
equiv), DCM, 35 C (91%); DDQ = 2, 3–dichloroꢀ5,6–dicyanoꢀ1,4ꢀ
o
o
benzoquinone, TBAF = tetrabutylammonium fluoride.
aReagents and conditions: (1) MeI (3.0 equiv), K2CO3 (2.0 equiv),
acetone, rt (98%); (2) 7 (1.0 equiv), nBuLi (1.05 equiv), THF, ꢀ78 oC;
then 21 (1.1 equiv), ꢀ78 oC (85%); (3) 6 (1.1 equiv), TFA (1.8 equiv),
To complete the synthesis of dalesconol B, the next mission was
to install a two carbon unit at C2 position (Scheme 2). To avoid a
Heck sideꢀreaction, the carbonꢀcarbon double bond in 14a’ was
hydrogenated over PtO2 to form 16 in 84% yield. It should be
noted that the spirocyclic unit of 14a’ underwent a Wagnerꢀ
Meerwein rearrangement to form a planar aromatized sideꢀproduct
under conditions of H2/Pd/C.15 Next, a sterically hindered Stille
o
DCM, ꢀ40 C to rt (52%); (4) Pd2(dba)3 (3.0 mol %), (R)ꢀAntPhos
o
(8.0 mol %), K2CO3 (2.0 equiv), toluene, 100 C (52%); (5) PtO2 (30
o
mol %), H2 (10 atm), 25 C (84 %); (6) TMSC≡CSnBu3 (3.0 equiv),
o
Pd2(dba)3 (2.5 mol %), BIꢀDIME (5 mol %), toluene, 100 C (89%);
(7) DDQ (2.2 equiv), DCE, 80 oC (90%); (8) TBAF (2.0 equiv), THF,
o
coupling
between
bromide
16
and
trimeꢀ
rt; then Fe2(SO4)3 (10 mol %), AcOH/DCE, 70 C (77%); (11) BBr3
(1.5 M in DCM, 40 equiv), DCM, 35 oC (91%).
thyl((tributylstannyl)ethynyl)silane proceeded smoothly with a
PdꢀBIꢀDIME catalyst16 (5 mol %) to form compound 17 in 89%
yield. Low conversions were observed when ligands PPh3, tBuꢀ
DPPF and tBu3P were employed. A powerful DDQ oxidation17 of
17 formed both the enone and the pꢀnaphthoquinone methide
moieties of 18 in an excellent yield. Treatment with TBAF folꢀ
lowed by hydrolysis under conditions of Fe2(SO4)3/HOAc18 autoꢀ
matically forged the sevenꢀmembered ring and formed 19 containꢀ
ing the full skeleton of dalesconol B. Finally, a global demethylaꢀ
We then pursued the synthesis of (+)ꢀdalesconol A (1), whose
structure lacked only one hydroxyl group compared to that of
dalesconol B (Scheme 3). However, the strategy of cyclizationꢀ
brominationꢀkinetic resolution to form the enantiomerically pure
allꢀcarbon quaternary center employed in the synthesis of
dalesconol B would not be well suitable for the synthesis of
dalesconol A due to a regioselectivity issue during the brominaꢀ
tion step. Because of the same catalyst employed in both catalytic
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4. Wen, L.; Cai, X.; Xu, F.; She, Z.; Chan, W. L.; Vrijmoed, L. L.
steps, we therefore implemented a oneꢀpot enantioselective cyꢀ
clizationꢀkinetic resolution cascade of dibromide 23 by using a
Pdꢀ(R)ꢀAntPhos catalyst. Thus, aldehyde 21 was prepared in 98%
yield from phenol 20 by methylation. A nucleophilic addition
followed by a FriedelꢀCrafts reaction with 6 furnished the dibroꢀ
mide 23 in 52% yield. Gratifyingly, the cyclizationꢀkinetic resoluꢀ
P.; Jones, E. B. G.; Lin, Y. J. Org. Chem. 2009, 74, 1093.
5. Snyder, S. A.; Sherwood, T. C.; Ross, A. G. Angew. Chem., Int.
Ed. 2010, 49, 5146.
6. Fan, Y.; Feng, P.; Liu, M.; Pan, H.; Shi, Y. Org. Lett. 2011, 13,
4494.
1
2
3
4
5
6
7
8
o
7. For recent reviews on dearomatization, see: (a) Wu, W.ꢀT.;
Zhang, L.; You, S.ꢀL. Chem. Soc. Rev. 2016, 45, 1570. (b) Sun,
W.; Li, G.; Hong, L.; Wang, R. Org. Biomol. Chem. 2016, 14,
2164. (c) Zhuo, C.ꢀX.; Zhang, W.; You, S.ꢀL. Angew. Chem., Int.
Ed. 2012, 51, 12662. (d) Roche, S. P.; Porco, J. A., Jr. Angew.
Chem., Int. Ed. 2011, 50, 4068. (e) Pouýegu, L.; Deffieux, D.;
Quideau, S. Tetrahedron 2010, 66, 2235.
8. For selected recent examples, see: synthesis (a) Douki, K.; Ono,
H.; Taniguchi, T.; Shimokawa, J.; Kitamura, M.; Fukuyama, T. J.
Am. Chem. Soc. 2016, 138, 14578. (b) Qi, J.; Beeler, A. B.;
Zhang, Q.; Porco, J. A., Jr. J. Am. Chem. Soc. 2010, 132, 13642.
methodology (c) Zhuo, C.ꢀX.; You, S.ꢀL. Angew. Chem., Int. Ed.
2013, 52, 10056. (d) Rousseaux, S.; GarciaꢀFortanet, J.; Sanchez,
M. A. D. A.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 9282.
(e) GarciaꢀFortanet, J.; Kessler, F.; Buchwald, S. L. J. Am. Chem.
Soc. 2009, 131, 6676.
tion cascade proceeded smoothly at 100 C for 20 h with K2CO3
as the base provided product 24 in 52% yield and 96% ee. It
should be noted that the formation of only a single diastereomer
24 was observed in the reaction and its optical purity started at
~50% ee and reached to 96% ee after the kinetic Heck process
proceeded. The following steps for the synthesis of (+)ꢀdalesconol
A were similar to those for (+)ꢀdalesconol B. Thus, a sequence of
hydrogenationꢀStille couplingꢀDDQ oxidationꢀhydrolysis cyclizaꢀ
tion cascadeꢀglobal demethylation completed the enantioselective
synthesis of dalesconol A, which consisted of 9 linear steps and
11% overall yield from commercially available starting material
20. Furthermore, the oneꢀpot enantioselective cyclizationꢀkinetic
resolution cascade was also successfully applied to the synthesis
of (+)ꢀdalesconol B, leading to only 9 linear steps of its overall
synthesis.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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40
41
42
43
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49
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51
52
53
54
55
56
57
58
59
60
9. Du, K.; Guo, P.; Chen, Y.; Cao, Z.; Wang, Z.; Tang, W. Angew.
Chem., Int. Ed. 2015, 54, 3033.
In conclusion, we have accomplished the first enantioselective
syntheses of immunosuppressants (+)ꢀdalesconol A and B in a
highly efficient and concise manner, which features an unpreceꢀ
dented enantioselective palladiumꢀcatalyzed dearomative cyclizaꢀ
tionꢀkinetic resolution cascade to install the sterically congested
chiral allꢀcarbon quaternary center, an effective sterically hinꢀ
dered Stille coupling, a powerful DDQ oxidation to furnish all
requisite unsaturation, and a tandem hydrolysisꢀMichael addition
ring closure sequence. Both Dalesconol A and B can be prepared
within 9 steps from commercially available starting materials with
a scalable synthetic route, which should facilitate the discovery
and the development of new immunosuppressants.
10. A series of chiral monophosphorus ligands, bases, and solvents
were screened, and see Supporting Information for more details.
11. (a) Fu, W.; Nie, M.; Wang, A.; Cao, Z.; Tang, W. Angew. Chem.,
Int. Ed. 2015, 54, 2520. (b) Nie, M.; Fu, W.; Cao, Z.; Tang, W.
Org. Chem. Front. 2015, 2, 1322. (c) Hu, N.; Li, K.; Wang, Z.;
Tang, W. Angew. Chem., Int. Ed. 2016, 55, 5044. (d) Cao, Z.; Du,
K.; Liu, J.; Tang, W. Tetrahedron 2016, 72, 1782. (e) Fu, W.;
Tang, W. ACS Catal. 2016, 6, 4814.
12. See Supporting Information for a rationale.
13. Racemic 14a was also subjected for kinetic resolution with a Pdꢀ
(R)ꢀAntPhos catalyst. At 61% conversion of Heck cyclization, the
enantiomerically enriched aryl bromide 14a’ was collected in
96% ee (S = 15).
14. CCDC 1528560 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Camꢀ
bridge Crystallographic Data Centre, 12 Union Road, Cambridge
Supporting Information
Full experimental details, characterization data, NMR spectra of
1, 2 and related intermediates, chiral HPLC trace of 1 and related
chiral intermediates, crystallographic data of 14a’. This inforꢀ
mation is available free of charge via the Internet at
http://pubs.acs.org/.
Corresponding Author
tangwenjun@sioc.ac.cn
Notes
G. Zhao and G. Xu contributed equally.
The authors declare no competing financial interest.
Acknowledgments
This work is dedicated to Professor K.C. Nicolaou on occasion of
his 70th birthday. The work is supported by the Strategic Priority
Research Program of the Chinese Academy of Sciences
XDB20000000, CAS (QYZDYꢀSSWꢀSLH029), NSFCꢀ21432007,
21272254, 21572246, and China Postdoctoral Science Foundaꢀ
tion 2015M571622, 2016T90397 (GZ).
CB21EZ,
UK;
fax:
(+44)1223ꢀ336ꢀ033;
or
deposꢀ
it@ccdc.cam.ac.uk)
15. The formation of a rearrangement product was observed during
hydrogenation when Pd/C was used as the catalyst.
16. (a) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel,
N. D.; Savoie, J.; Gao, J. J.; Rodriguez, S.; Qu, B.; Haddad, N.;
Lu, B. Z.; Krishnamurthy, D.; Yee, N. K.; Senanayake, C. H. An-
gew. Chem., Int. Ed. 2010, 49, 5879. (b) Zhao, Q.; Li, C.; Senaꢀ
nayanke, C. H.; Tang, W. Chem. Eur. J. 2013, 19, 2261. (c)
Tang, W.; Patel, N. D.; Xu, G.; Xu, X.; Savoie, J.; Ma, S.; Hao,
M.ꢀH.; Keshipeddy, S.; Capacci, A. G.; Wei, X.; Zhang, Y.; Gao,
J. J.; Li, W.; Rodriguez, S.; Lu, B. Z.; Yee, N. K.; Senanayake, C.
H. Org. Lett. 2012, 14, 2258. (d) Xu, G.; Fu, W.; Liu, G.;
Senanayanke, C. H.; Tang, W. J. Am. Chem. Soc. 2014, 136, 570.
(e) Li, C.; Chen, D.; Tang, W. Synlett 2016, 27, 2183.
17. (a) Huang, J.; Yang, T.; Shia, K. Org. Lett. 2015, 17, 4248. (b)
Ospina, F.; Hidalgo, W.; Cano, M.; Schneider, B.; Otalvaro, F. J.
Org. Chem. 2016, 81, 1256.
18. Bassetti, M.; Ciceri, S.; Lancia, F.; Pasquini, C. Tetrahedron
Lett. 2014, 55, 1608.
References
1. (a) Zhang, Y. L.; Ge, H. M.; Zhao, W.; Dong, H.; Xu, Q.; Li, S.
H.; Li, J.; Zhang, J.; Song, Y. C.; Tan, R. X. Angew. Chem., Int.
Ed. 2008, 47, 5823. (b) Zhang, Y. L.; Zhang, J.; Jiang, N.; Lu, Y.
H.; Wang, L.; Xu, S. H.; Wang,W.; Zhang,G. F.; Xu, Q.; Ge, H.
M.; Ma,J.; Song, Y. C.; Tan, R. X. J. Am. Chem. Soc. 2011, 133,
5931.
2. For a recent total synthesis of cyclosporin A, see: Wu, X.;
Stockdill, J. L.; Wang, P.; Danishefsky, S. J. J. Am. Chem. Soc.
2010, 132, 4098.
3. Fang, W.; Ji, S.; Jiang, N.; Wang, W.; Zhao, G. Y.; Zhang, S.;
Ge, H. M.; Xu, Q.; Zhang, A. H.; Zhang, Y. L.; Song, Y. C.;
Zhang, J.; Tan, R. X. Nat. Commun. 2012, 3, 1039.
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Table of Contents:
1
2
OH
O
OMe
OMe
OH
O
3
4
Pd2dba3
(R)-AntPhos
K2CO3
Br
O
Br
5
6
7
8
Br
HO
MeO
MeO
MeO
MeO
OH
OMe
OMe
O
96% ee
52% yield
(+)-dalesconol A
enantioselective cyclization-kinetic resolution cascade
9 linear steps, 11% overall yield
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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55
56
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60
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ACS Paragon Plus Environment