Catalytic Enantioselective Pinacol and Meinwald Rearrangements for the Construction of Quaternary Stereocenters

Article abstract of DOI:10.1021/jacs.9b04551

The development of enantioselective pinacol rearrangement is extremely challenging due to the likelihood involvement of the carbenium intermediate that renders the stereochemical communication between catalyst and substrate difficult to achieve. Herein, we report chiral N-triflyl phosphoramide-catalyzed enantioselective pinacol rearrangement of 1,2-tertiary diols and mechanistically related Meinwald rearrangement of tetrasubstituted epoxides for the synthesis of enantioenriched 2-alkynyl-2-arylcyclohexanones and 2,2-diarylcyclohexanones, respectively. Total synthesis of (+)-mesembrane featuring the catalytic enantioselective pinacol rearrangement as a key strategic step is also documented.

Full text of DOI:10.1021/jacs.9b04551

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Communication
Catalytic Enantioselective Pinacol and Meinwald Rearrangements
for the Construction of Quaternary Stereo-centers
Hua Wu, Qian Wang, and Jieping Zhu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04551 • Publication Date (Web): 06 Jul 2019
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Journal of the American Chemical Society
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Catalytic Enantioselective Pinacol and Meinwald Rearrangements
for the Construction of Quaternary Stereocenters
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Hua Wu, Qian Wang, and Jieping Zhu*
Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lau-
sanne, EPFL-SB-ISIC-LSPN, BCH5304, CH-1015 Lausanne, Switzerland
Supporting Information Placeholder
Scheme 1. Cyclohexane bearing an all-carbon quaternary stereo-
center: occurrence and asymmetric synthesis
ABSTRACT: The development of enantioselective pinacol rearrange-
ment is extremely challenging due to the likelihood involvement of the
carbenium intermediate that renders the stereochemical communica-
tion between catalyst and substrate difficult to achieve. Herein, we re-
port chiral N-triflyl phosphoramide-catalyzed enantioselective pinacol
rearrangement of 1,2-tertiary diols and mechanistically related Mein-
wald rearrangement of tetrasubstituted epoxides for the synthesis of en-
antioenriched 2-alkynyl-2-arylcyclohexanones and 2,2-diarylcyclohexa-
nones, respectively. Total synthesis of (+)-mesembrane featuring the
catalytic enantioselective pinacol rearrangement as a key strategic step is
also documented.
(a) Natural products and pharmaceuticals with a cyclohexane core bearing an
α-all-carbon quaternary stereocenter
CO2Et
H
N
N
OMe
OMe
O
O
H
H
H
OH
N
N
H
H
O
Me
O
NMe
(+)-Mesembrane
MeO
(-)-Gracilamine
(-)-Strychnine
OH
H
O
HO
Ar1
HO
O
MeO
O
Ar2
O
MeN
NH2
OH
HO
O
HO
MeO
O
Many bioactive natural products and pharmaceuticals, such as mes-
embrane,1 gracilamine,1 strychnine,2 stephadiamine,3 hopeanol,4 and di-
hydrobenzofurans (non-steroidal estrogen receptor b (ERb) agonist,
Scheme 1a),5 contain cyclohexane bearing an all-carbon quaternary ste-
reocenter as a core structure. 2-Aryl-2-alkyl and 2,2-diaryl substituted
cyclohexanones are obvious starting materials for the synthesis of these
compounds. The Pd-catalyzed enantioselective allylation has been de-
veloped into a powerful synthetic tool for the synthesis of a,a-dialkyl
substituted cyclohexanones6,7 and elegant enantioselective arylation8,9
alkylation10 as well as Michael addition11,12 have been devised for the syn-
thesis of a-aryl-a-alkyl substituted counterparts. There is also a report
on the enantioselective vinylation of cyclopentanones. However, apply-
ing the same conditions to cyclohexanone derivatives led to the arylated
products with only moderate ee.13 Catalytic enantioselective synthesis
of 2-alkynyl-2-arylcyclohexanones and 2,2-diarylcyclohexanones re-
mains, to the best of our knowledge, unknown (Scheme 1b).
Dihydrobenzofurans
ERβ agonists
(+)-Hopeanol
(+)-Stephadiamine
(b) Asymmetric synthesis of 2,2-disubstituted cyclohexanones by functionalization
of enolates
O
O
O
Ar'
Ar
R
Ar
I. Pd-catalyzed enantioselective allylation
II. Pd or Ni-catalyzed enantioselecitve arylation
III. Enantioselective alkylation
Inaccessible by existing methods
IV. Enantioselective Michael addition
Scheme 2. Enantioselective pinacol rearrangement: State-of-the-
art
(a) Enantioselective pinacol rearrangement developed by Antilla and coworkers
OH
Ar
OH
Ar
O
HO
Ar
Ar
Ar
CPA
Ar
R
R
R
N
R1
N
R1
N
R1
CPA-
(b) Enantioselective vinylogous pinacol rearrangement of (E)-2-butene-1,4-diols
developed by our group
Pinacol rearrangement converts 1,2-diols to aldehydes or ketones
under acidic conditions.14 As it generates a new stereocenter, it is im-
portant to control the stereochemical outcome in order to fully exploit
its synthetic potential.15 However, the priori formation of a carbenium
intermediate before the key C-C bond forming process renders the de-
velopment of enantioselective version extremely challenging.16 The clas-
sic Lewis and Brønsted acid catalysis is inefficient since the association
between the intermediate and the catalyst, a prerequisite for the chirality
transfer, is difficult to achieve.17 To date, there are only two examples of
successful enantioselective pinacol rearrangements. In their seminal
work, Antilla and coworkers developed a chiral phosphoric acid (CPA)-
catalyzed rearrangement of indolyl diols (Scheme 2a).18 Subsequently,
our group reported an enantioselective vinylogous rearrangement of
(E)-butene-1,4-diols to enantioenriched b,g-unsaturated ketones
(Scheme 2b). 19 Both reactions featured 1,2-aryl migration providing en-
antioenriched linear ketones bearing an a-tertiary stereocenter. On
OH
OH
O
Ar
Ar
Ar
Ar
CPA
Ar’
Ar’
OH
Ar’
Ar’
Ar’
Ar Ar’
Ar
CPA-
(c) This work: Enantioselective pinacol rearrangement and Meinwald rearrangement for
the synthesis of enantioenriched cyclohexanones
O
HO
R
O
HO
OH
R
Ar
R
R
CPA
1 R = alkynyl
2 R = aryl
or
Ar
Ar
Ar
CPA–
☞
* Generation of a quaternary carbon * Alkyl migration * Important building blocks
the other hand, Snyder and co-workers reported a CPA-promoted (1.0
equiv) diastereoselective pinacol rearrangement for the synthesis of a
complex a-quaternary aldehyde, a key intermediate in their elegant total
synthesis of hopeanol. 4 The catalytic enantioselective rearrangement
of vicinal tertiary diols to ketones bearing an a-quaternary stereocenter
has, to the best of our knowledge, not been realized in spite of the signif-
icant synthetic importance of the resulting chiral compounds. We report
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Journal of the American Chemical Society
herein the first examples of such enantioselective processes as well as
Page 2 of 6
Stirring a CH2Cl2 solution of 3a (R = Ph, R1 = 4-OH, c 0.05 M) in the
presence of a diverse set of CPAs (0.1 equiv, see SI for details) at room
temperature for 12 h afforded 1a as an only isolable regioisomer in ex-
cellent yield but with only moderate ee. Although the enantioselectivity
was moderate, the exclusive formation of 1a was encouraging as it indi-
cated that only one of the two possible carbocations was generated un-
der these mild conditions. The N-triflyl phosphoramide 4a stood out
from this initial screening and was chosen for further optimization of the
reaction conditions. After systematically varying the solvents, the addi-
tives and the temperature, the optimum conditions found consisted of
performing the rearrangement of 3a in toluene (c 0.05 M) at -5 oC in the
presence of 4a (0.1 equiv) and 3 Å molecular sieves. Under these condi-
tions, 2-(4-hydroxyphenyl)-2-(phenylethynyl)cyclohexan-1-one (1a)
was isolated in 99% yield with 90% ee.24 We noted that a,b-unsaturated
ketone 5 (Scheme 3) resulting from the competing Meyer-Schuster re-
arrangement25,26 was not formed under these conditions.
1
2
3
4
5
6
7
8
mechanistically related Meinwald rearrangement20 of epoxides for the
synthesis of enantioenriched 2-alkynyl-2-arylcyclohexanones 1 and 2,2-
diarylcyclohexanones 2 (Scheme 2c). We also document the transfor-
mation of the hydroxylated aromatic ring, the alkynyl and the carbonyl
groups which allowed easy access to a diverse set of synthetic building
blocks. A concise total synthesis of (+)-mesembrane is also accom-
plished featuring the catalytic enantioselective pinacol rearrangement as
a key strategic step.
Scheme 3. Scope of the catalytic enantioselective pinacol rear-
rangement a
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Ar
O
P
O
O
R
HO
OH
O
R
NHTf
4a (10 mol%)
R1
Ar
3 Å MS, toluene
With the optimized conditions in hand, the scope of this catalytic
enantioselective pinacol rearrangement was next examined. As shown in
Scheme 3, arylalkyne moieties bearing an electron-donating (Me, MeO)
and an electron-withdrawing group (F, Cl) at different positions (para,
meta and ortho) are compatible with the reaction conditions (adducts
1a-1i). Heterocycle could also be incorporated into the chiral cyclohex-
anone product (1j). Pleasingly, alkynes with aliphatic substituents such
as tBu (1k), nBu (1l) and functionalized alkyls (1n, 1p) were also well
tolerated affording the desired products in excellent yields and enanti-
opurities. The presence of a free phenol group is not an obligation since
other electron-rich arenes, such as 4-methoxyphenyl (1m), 3,4-di-
methoxyphenyl (1n-1q), benzo[d][1,3]dioxole (1r), dihydrobenzofu-
ran (1s), and 2-thiophene group (1t) and benzofuran (1u), were com-
patible with the reaction conditions to give the corresponding rear-
ranged products in high ees. The enantioselective pinacol rearrange-
ment of indole C-2 substituted diol could not be examined due to its
instability. It is worth noting that, alkynes containing various types of
functional groups such as halide, TMS and OBn were compatible with
the reaction conditions to afford the functionalized enantioenriched cy-
clohexanones (1n-1p and 1r). The (S)-absolute configuration of 1a was
determined by X-ray crystallographic analysis, and the configuration of
the other cyclohexanones were assigned by analogy.
R1
4a Ar = 2,4,6-iPr3C6H2
3
1
R
R
O
O
O
OH
OH
OH
1b R = Me, 98% yield, 94% eea
1c R = Ph, 75% yield, 91% eea
1d R = F, 97% yield, 92% eea
1e R = OMe, 81% yield, 87% eea
1f R = F, 94% yield, 91% eea
1g R = Cl, 98% yield, 88% eea
1h R = OMe, 93% yield, 92% eea
1a 99% yield, 90% eea
Me
Me
Me
S
Me
O
O
O
OH
OH
OH
1i 97% yield, 90% eea
1j 96% yield, 84% eeb
1k 99% yield, 94% eea
Cl
Ph
Me
O
O
O
OMe
OMe
OMe
OH
1l 91% yield, 94% eea
1m 95% yield, 84% eec
1n 95% yield, 91% eec
OBn
Ph
Scheme 4. Synthesis of 2,2-diarylcyclohexanones from tetrasubsti-
TMS
O
O
O
tuted epoxides a
OMe
OMe
OMe
OMe
OMe
OMe
Ar1
O
4a (10 mol%)
1o 94% yield, 92% eed 1p 90% yield, 87% eec
1q 85% yield, 90% eec
O
Ph
Ar1
Ar2
4 Å MS, toluene, -78 o
C
Ph
Ar2
TMS
O
O
O
6
2
O
F
S
O
O
O
O
O
1r 82% yield, 83% eee
1s 84% yield, 82% eec
1t 90% yield, 83% eec
OMe
OMe
OH
Ph
OH
O
O
HO
2a 97% yield, 84% ee
2b 98% yield, 72% ee
2c 97% yield, 89% ee
Ph
Me
Cl
Me
O
O
O
O
5
Me
OH
1u 83% yield, 81% ee
1a
OMe
OMe
OMe
a Optimum conditions: 3 (0.1 mmol), 4a (0.01 mmol, 0.1 equiv), toluene (2.0
mL, c 0.05 M), 3 Å molecular sieves, -5 °C. b The reaction was performed at -10
OMe
OMe
OMe
d
°C. c The reaction was performed at -50 °C. The reaction was performed at -40
2d 96% yield, 91% ee
2e 99% yield, 91% ee
2f 95% yield, 87% ee
°C. e The reaction was performed at -30 °C. All the reactions were performed on
a 0.1 mmol scale. Enantiomeric excess (ee) was determined by SFC or HPLC
analysis on a chiral stationary phase.
aThe reaction was performed on a 0.1 mmol scale. Enantiomeric excess (ee) was
determined by SFC or HPLC analysis on a chiral stationary phase.
We began our studies using 3a as a test substrate and chiral phos-
phoric acids21,22 and N-triflyl phosphoramides (CPA) 423 as catalysts.
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Journal of the American Chemical Society
We next turned our attention to the mechanistically relevant Mein-
The phenyl substituted epoxide 6j underwent Meinwald rearrange-
ment at -90 °C to afford 1w in 76% yield with 65% ee, while the pinacol
rearrangement of diol 3w took place sluggishly to provide 1w in only 7%
yield (34% ee). These results are important as it not only clearly illus-
trated the higher reactivity of the epoxide than diol towards the rear-
rangement, but also indicated that the presence of an extra cation stabi-
lizing group (OH, OMe) might not be absolutely needed for the devel-
opment of enantioselective Meinwald rearrangement (Scheme 5c).
1
2
3
4
5
6
7
8
wald rearrangement.20,24,27 Tetrasubstituted epoxides 6 were readily syn-
thesized by a two-step sequence involving McMurry cross-coupling of
two different ketones28 followed by epoxidation of the resulting
tetrasubstituted alkenes. Gratifyingly, treatment of a toluene solution of
6 in the presence of catalyst 4a and 4 Å molecular sieves (MS) at -78 °C
afforded the 2,2-diarylcyclohexanones 2a-2f in excellent yields with
high ees (Scheme 4). Although water was not generated in this reaction,
the presence of MS was important for the reaction outcome and we ob-
served that 4 Å MS was a better additive than the 3 Å counterpart in
terms of both the yield and the ee of the rearranged product.29 Since the
two aryl substituents in 6 are similar in size, the observed enantioselec-
tivity could be attributed to the stereoelectronic effect. The presence of
hydroxyl or methoxy group at the para position in one of the aryl groups
fixed effectively, via resonance effect, the geometry of the transient car-
benium intermediate leading to the observed enantioselectivity.
Scheme 6. Desymmetrizative Meinwald rearrangement
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mCPBA (1.2 equiv)
O
MeO
MeO
OTBS
O
MeO
MeO
OTBS
DCM, 0 o
C
9 91% yield, d.r. = 2:1a
8
OTBS
OMe
It is worth noting that epoxide 6g bearing an alkynyl substituent was
unstable and was readily hydrolyzed to diol 3q during workup and puri-
fication processes, while the cyclobutane derivatives 6h and 6i under-
went spontaneous rearrangement during their preparation to afford the
corresponding cyclopentanone derivatives 7h and 7i (Scheme 5a). For
the sake of comparison, we also prepared a diaryl substituted diol 3v and
found that it was more stable than the epoxide counterpart 6e towards
the rearrangement. Stable at -78 °C, the diol 3v underwent rearrange-
ment only at -10 °C to afford cyclohexanone 2e in excellent yield with
77% ee (Scheme 5b).
4a (10 mol%)
4 Å MS, toluene
-78 oC, 2 days
OMe
10 99% yield, 87% ee
aOnly the major diastereomer 9 was shown for the sake of clarity.
Desymmetrizative Meinwald rearrangement was next explored to
extend further its application scope (Scheme 6). Epoxidation of alkene
8 with mCPBA afforded the epoxide 9 in 91% yield as a mixture of two
diastereomers. Under standard conditions, rearrangement of epoxide 9
furnished 10 in 99% yield with 87% ee. The 3,3-diaryl substituted oc-
tahydronaphthalen-2-(1H)-one harboring three stereocenters would
not be easily prepared by the known methodologies.
Scheme 5. Stability and reactivity of epoxides vs diols
(a)
Br
O
Ph
O
HO
OH
Ph
Li
H2O
Ph
Scheme 7. Possible reaction pathway of the pinacol rearrangement
THF, 0 °C
OMe
OMe
OMe
O
O
O
O
OMe
3q 43%
OMe
OMe
6g
P
P
O
NTf
TfN
O
H2O
H
H
H
O
H
MeO
OMe
MeO
OMe
4a
H
O
OMe
H
O
3
O
R
O
R
O
mCPBA
DCM, 0 °C
H2O
OMe
Cl
A
B
OR'
OR'
Cl
6h
7h 58%
Cl
O
O
O
O
P
P
H
H
Ph
O
4a
OMe
O
NTf
NTf
O
O
Br
O
Ph
Li
O
H2O
O
OMe
OR'
OR'
THF, 0 °C
OMe
OMe
OMe
OMe
C
C'
Ph
R
R
6i
7i 63%
O
Me
(b)
O
O
R
R
P
H
O
O
HO
NTf
HO
OH
O
Me
OMe
OMe
H2O
Me
O
X
C
R
OR'
Me
Me
OMe
OR'
6e
3v
5
C’’
1
OMe
O
R'O
Me
OMe
4a (10 mol%)
4 Å MS, toluene
-78 o
4a (10 mol%)
4 Å MS, toluene
C
-10 o
C
While no detailed mechanistic studies were carried out,30 a plausible
99% yield , 91% ee
98% yield , 77% ee
OMe
Ph
2e
reaction pathway for the enantioselective pinacol rearrangement was
proposed as illustrated in Scheme 7. The N-triflyl phosphoramide 4a
would act as a bifunctional catalyst to form a 9-membered ring interme-
diate A and B with the 1,2-diol 3 via hydrogen bonding. The selective
dehydration of B delivering the carbocation C would be kinetically and
thermodynamically favored. Indeed, the presence of an alkynyl and an
electron-rich aryl group would be capable of stabilizing the carbenium
(c)
4a (10 mol%)
4 Å MS, toluene
-90 o
Ph
O
4a (10 mol%)
HO
OH
O
C
toluene, rt
Ph
7% yield
76% yield
34% ee
6j
65% ee
1w
3w
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Journal of the American Chemical Society
intermediate C via the resonance structures C’ and C”. Although ion-
Page 4 of 6
The alkynyl group is also amenable to a diverse set of chemical trans-
formations. Treatment of 1o with tert-butyldimethylsilyl trifluoro-
methanesulfonate (TBSOTf) afforded silylenol ether 15 in 93% yield.
Hydrogenation of 1o (Pd/C, H2, EtOAc) furnished the 2-(2’-trime-
thylsilylethyl)-2-aryl substituted cyclohexanone 16 in 91% yield. Re-
moval of the trimethylsilyl group from 1o followed by hydrogenation
over Lindlar’s catalyst provided the 2-vinyl-2-aryl substituted cyclohex-
anone 17 in 86% yield over two steps. Wittig reaction of the sterically
hindered carbonyl group of 1o occurred smoothly to afford methylene-
cyclohexane 18 in high yield. Finally, removal of TMS group from 1o
followed by CuI-catalyzed [3+2] cycloaddition of the resulting terminal
alkyne with benzyl azide afforded triazole 19 in 99% yield . This last ex-
ample showcased the advantage of our methodology as it is difficultly
accessible by other means (Scheme 8b).
1
2
3
4
5
6
7
8
pairing itself is non-directional, its association with the hydrogen bond
in C might be able to impose a pre-organized three-dimensional struc-
ture for the efficient chirality transfer in the subsequent 1,2-alkyl shift
process leading to ketone 1. The fact that Meyer-Schuster rearrange-
ment product 5 was not observed under our conditions indicated that
the 1,2-alkyl shift was much faster than the intermolecular nucleophilic
trapping of the intermediate C”. Although 2- and 4-hydroxybenzyl alco-
hol derivatives have been used in CPA-catalyzed asymmetric transfor-
mations, all the literature precedents involved the in situ generation of
neutral quinomethide intermediates. As the 2- and 4-methoxybenzyl al-
cohols were ineffective substrates in these literature examples, H-bond-
ing rather than ion-pairing was proposed to be responsible for the asym-
metric induction.31 It is therefore interesting to note that both pathways
are apparently operational in the present pinacol and Meinwald rear-
rangement reactions. 19, 32
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To further illustrate the synthetic potential of the present method-
ology, total synthesis of (+)-mesembrane (20) was undertaken
(Scheme 9). AlCl3-mediated Friedel-Crafts reaction of cyclopentane-
carbonyl chloride (21) with 1,2-dimethoxybenzene (22) followed by
bromination of the resulting ketone afforded a-bromoketone 23 in 91%
overall yield. Nucleophilic addition of lithium (trimethylsilyl) acetylide
(24) to ketone 23 led to an epoxide intermediate which was not stable
and was hydrolyzed directly to the 1,2-diol 3o. The CPA 4a (5 mol%)-
catalyzed enantioselective pinacol rearrangement of 3o in gram scale
(5.0 mmol) afforded, after removal of the TMS group, the enantioen-
riched cyclohexanone 25 in 92% yield with 90% ee. A ruthenium-cata-
lyzed anti-Markovnikov hydration of the triple bond following literature
procedure34 afforded the aldehyde 2610,12 which, upon intramolecular re-
ductive amination afforded (+)-mesembrane (20).35
Scheme 8. Synthetic transformations of the rearranged productsa
(a) Functionalization of the aryl substituent taking advantage of the phenol group
Me
Me
Me
O
O
O
a
b
H
12
OH
OTf
11
1b
Me
Me
c
O
O
Br
OH
d
Scheme 9. Gram scale experiment and total synthesis of (+)-mes-
embrane
Ph
14
13
Br
(b) Transformation of the alkynyl and the carbonyl groups
O
O
TMS
TMS
OMe
OMe
Cl
a) AlCl3, CH2Cl2, rt
b) Br2, CH2Cl2, 91%
Br
OMe
OMe
OTBS
O
+
OMe
OMe
OMe
21
Li
22
23
OMe
TMS
HO
OH
4a (5 mol%)
f
15
16
toluene (0.1 M), -30 oC, 3 days
e
TMS
24
O
TMS
OMe
OMe
OMe
NaHSO4, H2O, 60%
then K2CO3 (2.0 equiv)
MeOH, rt, 1 h
h
OMe
3o 5.0 mmol
1o
TMS
OMe
OMe
g
O
[CpRu(CH3CN)3]PF6 (0.1 equiv)
i
O
O
O
N
OMe
OMe
F3C
CF3
0.1 equiv
N
Bn
O
N
OMe
OMe
OMe
N
N
18
OMe
OMe
NMP/H2O (4/1), 35 oC, 24 h
17
OMe
25 92% yield
26 82% yield
Me
N
19
NaBH3CN, MeNH2, TFA
a
o
Reaction conditions: a) Tf2O, pyridine, DCM, 0 C, 98% yield; b)
Pd/C, Mg, MeOH, rt, 84% yield; c) Pd(PPh3)2Cl2, PhB(OH)2, Cs2CO3,
dioxane/H2O, 120 C, 3 h, 85% yield; d) NBS, DCM, -40 C, 81% yield;
e) TBSOTf, Et3N, DCM, rt, 93% yield; f) Pd/C, H2, EtOAc, rt, 91%
yield; g) K2CO3, MeOH; then Pd on CaCO3, H2, rt, 86%; h) MePPh3Br,
tBuOK, THF, rt, 88% yield; i) K2CO3, MeOH; then PhCH2N3, CuI (0.1
equiv), 2,2’-bipyridine (0.1 equiv), DCM, 40 °C, 12 h, 99%.
OMe
OMe
EtOH, rt, 12 h
76% yield
o
o
20 (+)-Mesembrane
In summary, we developed an efficient catalytic enantioselective pi-
nacol rearrangement of vicinal tertiary diols and Meinwald rearrange-
ment of tetrasubstituted epoxides. 2-Alkynyl-2-arylcyclohexanones and
2,2-diarylcyclohexanones, inaccessible using the existing synthetic
methodologies, were obtained in excellent yields and enantioselectivi-
ties. The association of two non-covalent interactions, ie, ion-pairing
and H-bonding, between the reactive carbenium intermediate and the
chiral phosphate might allow the effective chirality transfer from catalyst
to product.36 The synthetic potential was illustrated by post-functional-
ization of the rearrangement products and the development of a concise
total synthesis of (+)-mesembrane featuring the catalytic enantioselec-
tive pinacol rearrangement as a strategic transformation.
The presence of a phenol group provided a versatile handle for the
functionalization of the rearranged products. As depicted in Scheme 8a,
triflation of 1b under standard conditions (Tf2O, Py, CH2Cl2) afforded
the triflate 11 in 98% yield. Reduction of 11 under single electron trans-
fer conditions (Pd/C, Mg, MeOH) provided 12 with an unsubstituted
phenyl ring.33 Pd-catalyzed Suzuki-Miyaura cross coupling of 11 with
phenyl boronic acid provided a biphenyl substituted derivative 13. On
the other hand, treatment of 1b with N-bromosuccinimide (NBS) af-
forded the dibrominated product 14 that was armed for the further func-
tionalization.
ASSOCIATED CONTENT
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(16) (a) Wu, H.; Wang, Q.; Zhu, J. Recent Advances in Catalytic Enantioselec-
Supporting Information
Supporting Information is available free of charge on the ACS Publica-
tions Web site at DOI: xxxx
Experimental procedures and characterization data, copies of
1H and 13C NMR spectra, chrystallographic data for 1a and SFC chro-
matograms (PDF)
tive Rearrangement. Eur. J. Org. Chem. 2019, 1964. (b) Gualandi, A.; Cozzi, P.
G. Stereoselective Organocatalytic Alkylations with Carbenium Ions. Synlett
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1
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7
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Rearrangement. Angew. Chem. Int. Ed. 2010, 49, 9734.
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AUTHOR INFORMATION
Corresponding Author
*jieping.zhu@epfl.ch
ORCID
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Jieping Zhu: 0000-0002-8390-6689
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank financial support from EPFL (Switzerland) and the Swiss Na-
tional Science Foundation (SNSF 20020-155973). We thank Dr. F.-T.
Farzaneh and Dr. Rosario Scopelliti for the X-ray structural analysis of
compound 1a.
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Table of Contents
R
O
HO
OH
R
CPA
Ar1
Ar1
or
O
Ar2
O
Ar2
Ar1
or
Ar1
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