Enantioselective construction of remote quaternary stereocentres

Article abstract of DOI:10.1038/nature13231

Small molecules that contain all-carbon quaternary stereocentres - carbon atoms bonded to four distinct carbon substituents - are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for synthesizing quaternary stereocentres that are remote from other functional groups are underdeveloped. Here we report a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids. This method provides direct access to quaternary all-carbon-substituted β, γ, δ, ε or ζ-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group. The scope of the process also includes incorporation of pre-existing stereocentres along the alkyl chain, which links the alkene and the alcohol, in which the stereocentre is preserved. The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre.

Full text of DOI:10.1038/nature13231

ARTICLE
doi:10.1038/nature13231
Enantioselective construction of remote
quaternary stereocentres
Tian-Sheng Mei1, Harshkumar H. Patel1 & Matthew S. Sigman1
Smallmolecules thatcontainall-carbon quaternarystereocentres—carbon atoms bonded to fourdistinctcarbonsubstituents—
are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an
enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for
synthesizing quaternary stereocentres that are remote from other functional groups are underdeveloped. Here we report
a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic
acids. This method provides direct access to quaternary all-carbon-substituted b-, c-, d-, e- or f-aryl carbonyl com-
pounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group.
The scope of the process also includes incorporation of pre-existing stereocentres along the alkyl chain, which links the
alkene and the alcohol, in which the stereocentre is preserved. The method described allows access to diverse molecular
building blocks containing an enantiomerically enriched quaternary centre.
The quaternary stereocentre is a common structural motif in many
We had several concerns at the outset of this work, including ques-
natural products and pharmaceuticals1–3. However, the synthesis of these tions regarding reactivity, site selectivity and enantioselectivity when
using trisubstituted alkenes in intermolecular Heck-type reactions.
Acyclic, non-conjugated trisubstituted alkenes are rare substrates in
stereocentres in a catalytic and enantioselectivemanner is a formidable
challenge, especially in acyclic systems4. Typically, quaternary stereocen-
tres are prepared from substrates with pre-existing functional groups
adjacent to the site of reaction, whereas methods to access quaternary
stereocentres distant fromsuch groupspresenta considerable, ongoing
synthetic hurdle. The most common enantioselective and catalytic appro-
achesuse a carbonylas a functionalhandle, wherein a-functionalization,
by means of alkylation or aldol reactions4,5, can be accomplishedthrough
the reaction of enolate equivalents6–11 (I in Fig. 1a). Enantioselective
b-functionalization of a carbonyl can be accomplished through 1,4-
conjugate-addition-type processes using various transition metals and
coupling partners12–16 (II in Fig. 1a). A powerful alternative to the car-
bonyl as a pre-installed functional group is the allylic electrophile17–19
or nucleophile20, whichyields a quaternarycentre adjacent to an alkene21–23
(III in Fig. 1a). However, in all of these approaches, the location of C–C
bond formation relative to the functional group is strictly defined, which
makes it difficult to install a quaternary chiral centre at more remote sites.
On the basis of our group’s recent success in developing asymmetric
a Conventional enantioselective, catalytic approaches
α-functionalization
of carbonyls
O
β-functionalization
α-quaternary centres
adjacent to alkenes
of carbonyls
R1
R1
R2
O
α
β
R1
α
R
R3
R3
R2
R
R3
R2
O
R1
R1
X
O
R1
+ ‘R3’
+ ‘R3’
+ ‘R3’
R
R2
R2
R
R2
I
II
III
b Proposed modular strategy using trisubstituted alkenes
Preferred
insertion?
Ar–B(OH)2
Pd(II), O2
Pd(II)Ln
Redox
relay
redox-relay Heck-type reactions of disubstituted alkenyl alcohols24,25
,
A
OH
R
OH
O
n
n
n
B
C
Ar
Ar
we surmised that a site-selective and enantioselective transformation
oftrisubstitutedalkenescouldaddressthissyntheticlimitation(Fig. 1b).
By applying the proposed method, it is possible to position the alcohol
at different chain lengths from the alkene to obtain a diverse range of
functionalized carbonyl products. This is a mechanistic consequence
of the process. Specifically, site-selective migratory insertion26,27 of an
alkene into the organometallic intermediate produces a Pd alkyl, B,
that can migrate towards the alcohol through a sequential b-hydride
elimination/migratory-insertion process (Fig. 1b, D R E) ultimately
to release the desired carbonyl product, C28,29. Although well-known
Heck cyclization reactions havebeen developed and extensively applied
to the formation of quaternary centres by intramolecular reaction of
trisubstituted alkenes30–32, no examples of catalytic, asymmetric, qua-
ternary stereocentres synthesized through intermolecular Heck-type
Accessible products
R
R
R2
R2
R2
R1
R2
β
γ
δ
ε
O
O
R1
R1
O
R1
O
Ar
n = 0
R
Ar
n = 1
Ar
n = 2
Ar
n = 3
Mechanistic proposal
H
γ
γ
B
C
OH
OH
Migratory
insertion
β-hydride
Ar Pd(II)–H
Ar
Pd(II)
E
D
elimination
Figure 1
|
Approaches to constructing acyclic all-carbon quaternary
stereocentres. a, Conventional enantioselective, catalytic approaches:
a-functionalization of carbonyls (I); b-functionalization of carbonyls (II);
a-quaternary centres adjacent to alkenes (III). b, Proposed modular strategy
using a redox-relay enantioselective Heck reaction of trisubstituted alkenes and
reactions of isolated (non-conjugated) trisubstituted alkenes are known2. resulting mechanistic analysis. Ar, aryl.
1Department of Chemistry, The University of Utah, 315 South, 1400 East, Salt Lake City, Utah 84112, USA.
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ARTICLE RESEARCH
intermolecular Heck-type reactions, probably because of poor bind- Reaction optimization and scope
ing tothe catalyst or slow migratory insertion33. Ifa reaction does occur,
We began our investigation by revisiting our previously developed cata-
lytic system24 for enantioselective oxidative Heck reactions36–40 of disub-
stituted alkenes. A trisubstituted homoallylic alcohol (1), whichhasethyl
and methyl groups at the terminus of the alkene, was selected as a model
substrate (Fig. 2). Any success with this substrate would bode well for
expanding the scope of the reaction to substrates containing other sub-
stituents on the alkene with more pronounced differences. Our initial
efforts resultedinpoor conversiontothedesiredproduct, 2a(40%con-
version, 23% yield). Nevertheless, migratory insertionoccurred to install
the aryl group predominantly at the c-position (.15 times more likely
than at the b-position) and the product was generated in a high enan-
tiomeric ratio (e.r.) of 97:3 (Supplementary Table 1). Encouraged by
this initial result, we explored various changes to the reaction condi-
tions, yettheseafforded littlenoticeableimprovementsinyield. During
our previous studies, we observed that the arylboronic acid coupling part-
ner was consumed by various side reactions, such as decomposition of
the question of site selectivity is intriguing because the ability to forge a
quaternary centre relies on addition to the more substituted carbon. In
our study of the redox-relay Heck reaction of disubstituted alkenes,
subtle electronic variance of the alkenyl carbons, as determined by 13
C
chemical shift differences, correlates with site selectivity, with the aryl
nucleophile addingtothecarbonthat ismore downfield-shifted24. Addi-
tional support for electronically influenced site selectivity was revealed
by recent density functional theory calculations on this reaction34,35
.
These studies show that site selectivity is controlled by remote dipole
interactionsoftheattached alcohol. Taken together, theseobservations
suggested that, in the case of a trisubstituted alkene, insertion should
occur preferentially at the more substituted carbon (the hindered and
downfield-shiftedcarbon). Thiswouldpossiblyalsorelievestericstrain
because the bulky Pd catalyst is positioned at the less hindered carbon.
Our final concern was whether this process would be highly enantio-
selective, given that cis- and trans-disubstituted alkenes have previously
yieldedenantiomers asproducts24,25. Consideringthattrisubstitutedalkenes
the boronic acid into a phenol and homocoupling of this reagent41–43
Indeed, we detected that the arylboronic acid was consumed after 24 h,
.
contain both of these stereochemical relationships, the outcome is not with corresponding poor conversion of the alkene. We speculated that
easily predicted.
slow addition of the arylboronic acid would suppress the undesired
F3C
Pd(CH3CN)2(OTs)2 (6 mol%)
O
γ
β
Cu(OTf)2 (3 mol%), ligand (9 mol%)
O
N
Ar–B(OH)2
(3.0 equiv.)
+
OH
3 Å MS, DMF
O2 (balloon), RT, 24 h
N
Ar
1
Ligand
t-Bu
a Arylation with different arene boronic acids
O
O
O
O
O
O
O
2c, 74%
2d, 78%
2e, 73%
2f, 77%
97:3 e.r.
2g, 76%
2a, 65%
97:3 e.r.
2b, 81%
98:2 e.r.
98:2 e.r.
97:3 e.r.
97:3 e.r.
97:3 e.r.
(gram scale)
OMe
O
MeO2C
MeO
Me
Cl
OMe
OBn
OMe
O
O
O
O
O
O
2h, 68%
97:3 e.r.
2k, 55%
99:1 e.r.
2i, 52%
96:4 e.r.
2j, 61%
99:1 e.r.
2l, 70%
98:2 e.r.
2m, 35%
99:1 e.r.
2n, 25%
97:3 e.r.
Me
O
MeO
OMe
Cl
OMe
CO2Me
b Effect of chain length using racemic secondary alcohols
O
O
O
β
TBSO
δ
TBSO
Cl
δ
ε
ε
ε
O
O
O
TBSO
3a, 75%
96:4 e.r.
(from
(E)-alkene)
3b, 61%
93:7 e.r.
(from
(E)-alkene)
3c, 45%
94:6 e.r.
(from
(E)-alkene)
3d, 61%
94.5:5.5 e.r.
3e, 60%
97:3 e.r.
3f, 41%
99:1 e.r.
OMe
CO2Me
OMe
c Effect of alkene substitution
O
O
O
O
O
TBSO
3g, 51%
99:1 e.r.
3h, 56%
99:1 e.r.
(from
3i, 73%
97:3 e.r.
(from
3j, 75%
98:2 e.r.
Ent-3j, 73%
98:2 e.r.
(from
(E)-alkene)
(E)-alkene)
(E)-alkene)
d Analysing origin of enantioselectivity
(Z)-alkene
(E)-alkene
O
O
Ph–B(OH)2
relay Heck
OH
Ph–B(OH)2
relay Heck
OH
3j
Ent-3j
(S), 73%
97:3 e.r.
F3C
F3C
OH
OH
O
O
(R), 75%
98:2 e.r.
N
N
N
N
Pd
Pd
Ph
Ph
(Z)-1a
Me
(E)-1a
Bu
Ph
Me
Ph
Bu
A
B
Bu
Me
Bu
Me
Me
Bu
Bu
Me
Figure 2
|
Enantioselective construction of remote quaternary
a, Exploration of scope of process using various arylboronic acids. Me, methyl.
b, Evaluation of various chain lengths between the alkene and the alcohol
on the substrate. TBS, t-butyldimethylsilyl. c, Exploration of the alkene
stereocentres. Conditions for 2a, 2i–2n, 3c, 3f, 3i–3j: 10 mol%
Pd(CH3CN)2(OTs)2, 4 mol% Cu(OTf)2, 14 mol% ligand, 3 equiv. ArB(OH)2
(two-batch addition, 12 h between additions). t-Bu, t-butyl; OTs, tosylate; OTf, substituents. d, Proposed origin of enantioselectivity as a function of alkene
trifluoromethanesulphonate; MS, molecular sieves; RT, room temperature.
Reported yield and e.r. values are an average of at least two experiments.
geometry. Ph, phenyl.
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RESEARCH ARTICLE
pathways and favour product formation. Batchwise addition of the observed when ortho-substituted arenes are used, as illustrated by 2m
arylboronic acid did improve the yield to 50%. Increasing the catalyst and 2n, although enantioselectivity remains high. The absolute config-
loading led to 65% yield (2a in Fig. 2a), with .15:1 site selectivity (c/b) uration of a derivative of 2f was determined to be (R) by X-ray crystal-
and excellent enantioselectivity (e.r. 97:3). A series of control experi- lography (Supplementary Information).
ments verified the importance of the various reaction components: the
The effect of chain length (the distance from the alcohol to the alkene)
45
˚
absence of either Cu(OTf)2 (ref. 44) or 3 A molecular sieves substan- using various racemic, trisubstituted alkenyl secondary alcohols was eval-
tially reduced the yield, and when the palladium catalyst was excluded, uated (Fig. 2b). Of particular note, high site selectivity and enantios-
no reactionwas observed(SupplementaryTable 1). Both of theseaddi- electivity is observed irrespective of the chain length, enabling access
tives are frequently used in oxidative Pd catalysis to facilitate reoxida- to b- (3a), d- (3b, 3c) and e-quaternary (3d23f) functionalized ketone
tion of Pd(0), although their precise role in this transformation is not products. Alkenes bearing another oxygen substituent are well toler-
currently understood.
ated (3a23c), although substrates with a styrene unit are unreactive
under the present reaction conditions. Substrates were also selected to
probe the effect of differential size of the alkene aliphatic substituents
(3g23j in Fig. 2c). Excellent site selectivity and enantioselectivity is
again observed in all cases. To highlight this, an alkene featuring an ethyl
group and a butyl group, which have negligible steric differences, per-
forms well, yielding 3i in 97:3 e.r.
The scope of arylboronic-acid coupling partners was investigated
with homoallylic alcohol 1 (Fig. 2a). A wide array of arylboronic acids
were found to be compatible, delivering the corresponding all-carbon
quaternary c-aryl aldehyde products with uniformly high enantios-
electivity (e.r. up to 99:1) and in moderate to good yields (2a22n).
High site selectivity (c/b $ 15:1) is observed with both electron-deficient
and electron-rich arylboronic acids. This stands in contrast to our pre-
vious reports on enantioselective redox-relay Heck-type reactions of
disubstituted alkenes, where only modest site selectivity was achieved
for electron-rich aryl boronic acids24. Thisobserved difference suggests
that the electronic nature of the alkene dictates site selectivity. Higher
yields are achieved with electron-rich arylboronic acids, as compared
Mechanistic experiments
From analysis of the scope of the reaction, it seems that the enantios-
electivity is essentially independent of the steric and electronic nature
of both reaction partners, which is atypical in enantioselective reac-
tions. To explore this further, we probed the effect of alkene geometry
with their electron-poor counterparts (compare 2e with 2k), which is on enantioselection by comparing the reaction of (Z)-1a and (E)-1a
consistentwiththeir greaternucleophilicityfacilitatingmigratoryinser- (Fig. 2d). The magnitude of the enantioselectivity is the same for both
tion of the presumed alkene complex. In all cases, excellent enantios- substrates, again suggesting a robust enantioselective reaction. However,
electivityisobservedandthe reactioncanbescaledto10 mmol, yielding the major enantiomer produced in the two cases differ. This is consistent
.2 g as demonstrated by example 2f. Not surprisingly, lower yields are with the binding orientation of the alkene not changing. Specifically,
a Preservation of preinstalled stereocentre
b Control of two remote chiral centres
Ph–B(OH)2
relay Heck
Ph–B(OH)2
relay Heck
Me 7
OH
O
O
OH
S
O
O
Me
7
S
3
Me
3
O
Me
(R)-4, >99:1 e.r.
Ligand
Ph
Me
TBSO
Me
F3C
S
TBSO
(S)-6, 99:1 e.r.
(R)-5, 65% yield
N
N
t-Bu
t-Bu
7, 44%, 93:6:1 d.r.
(3S, 7S:3S, 7R:3R, 7S)
Ligand
>99:1 e.r.
Ph–B(OH)2
relay Heck
Ph–B(OH)2
relay Heck
Me 7
OH
OH
S
Me
S
7
3
Me
Ent-ligand
Ph
Me
O
TBSO
Me
R
3
Me
F3C
TBSO
(R)-4, >99:1 e.r.
(R)-5, 62% yield
(S)-6, 99:1 e.r.
N
N
>99:1 e.r.
8, 45%, 6:93:1 d.r.
(3S, 7S:3S, 7R:3R, 7R)
Ent-ligand
c Mechanistic analysis for the formation of 5
Pd(II)
[Pd]
H
[Pd]
Pd(II)
Me
Ph–B(OH)2
Ph
Ph
Ph
OH
OH
4
Migratory
insertion
β-hydride
elimination
Relay
Me
Me
OH
Migratory
insertion
[Pd]
Me
Ph
Ph
Ph
Me
OH
Me
Pd(II)–H
5
Migratory
insertion
β-hydride
elimination
Relay
OH
OH
[Pd]
d Isotopic labelling experiment
Pd(II)
Ph
Ph
Me
OH
[Pd]
Me
OH Ph–B(OH)2
Ph
OH
OH
Migratory
insertion
β-deuteride
elimination
D
D
Me
[Pd]
Relay
Me D
D
D–Pd(II)
D
9
10
D D
11
Migratory
insertion
95%
D
Ph
Ph–B(OH)2
relay Heck
Ph
Me
OH
[Pd]
Me
O
CD2OH
α
O
Me
D
35–40%
9
13
Me
D
Ph
D
13
12
D
[Pd]
D
>98%
Figure 3
|
Evaluation of alkene substrates containing a branch point.
b, Accessing distinct diastereomers using a combination of catalyst- and
substrate-controlled asymmetric synthesis. d.r., diastereomeric ratio.
c, Proposed mechanistic origin for the observed formation of 5 from
4. d, Isotopic labelling experiment and analysis.
Conditions: 10 mol% Pd(CH3CN)2(OTs)2, 4 mol% Cu(OTf)2, 14 mol%
ligand, 3 equiv. PhB(OH)2. a, Independence of catalyst enantiomer on the
conservation of the chiral centre during the proposed chain-walking process.
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ARTICLE RESEARCH
triethylamine to yield an aldehyde product. Full experimental details and char-
acterization of new compounds can be found in the Supplementary Information.
comparison of the proposed intermediates A and B (Fig. 2d) shows
that the alkenyl carbon closer to the alcohol remains fixed, leading to
the observed stereochemical outcomes. This conclusion is supported
by the relative insensitivity of the process to the group that appears on
the terminal end of the trisubstituted alkenes. Although the precise details
of why this catalyst is exceptionally selective are under further inves-
tigation, these results indicate that few synthetic limitations should be
encountered in variation of the alkenyl aliphatic substituents.
As suggested in the initial mechanistic proposal, the Pd catalyst pre-
sumably migrates along the alkyl chain until the aldehyde is formed.
Indeed, computational studies34,35 of the redox-relay Heck reaction of
disubstituted alkenesshowsgenerally lowenergybarriersfor the ‘chain-
walking’ events46–48. Therefore, a key question, with implications for the
applicability of this method in more complex settings, is whether the
catalyst disengages during the chain-walking process. To explore this
possibility, a natural-product-derived substrate, (R)-4, containing a pre-
installed stereogenic centre in the alkyl chain was evaluated using both
enantiomers of the catalyst. Preservation of the enantiomeric composi-
tion was observed when treating this substrate with either catalyst enan-
tiomer under redox-relay Heck conditions, toyield (R)-5 (Fig. 3a). This
implies that as the catalyst proceeds through the iterative b-hydride
elimination/migratory-insertion events depicted in Fig. 3c, the catalyst
remains both ligated to the substrate and on the same face of the alkene
throughout the relay process. As a more striking example, alkene (S)-6
was treated with both enantiomers of catalyst to yield the relay pro-
ducts 7 and 8 in high diastereoselectivity (Fig. 3b). Two distinct dia-
stereomers are producedbythe useofdifferentenantiomersof catalyst,
Received 22 November 2013; accepted 4 March 2014.
Published online 9 April 2014.
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Conclusion
We have described a catalytic and enantioselective addition of aryl-
boronic acids to trisubstituted alkenes that is highly site selective for
the more hindered position. The method does not rely on a defined
relationship between the site of addition and an adjacent functional group,
and thus provides a modularmethod toaccess quaternary stereocentres
in high enantioselectivity. Furthermore, we anticipate that the mecha-
nistic implications of both site-selective addition of an organometallic
to atrisubstituted alkene and theability of thecatalystto migrate through
existing chiral centres will inspire further studies in this area.
METHODS SUMMARY
To a dry, 100-ml Schlenk flask equipped with a stir bar, we added Pd(CH3CN)2(OTs)2
(15.9mg, 0.030mmol,6.0 mol%), Cu(OTf)2 (5.4mg, 0.015mmol,3.0 mol%), ligand
(12.3mg, 0.045 mmol, 9.0 mol%), 3 A molecular sieves (75.0 mg, 150mg mmol
21
˚
)
anddimethylformamide(DMF;8 ml). Tothisflask, athree-way adaptorfittedwith
a balloon of O2 wasadded, andtheflaskwasevacuatedviahousevacuumand refilled
with O2 three times while stirring. The resulting mixture was stirred for 10 min. To
this, a DMF solution (2 ml) of the alkenyl alcohol (0.5 mmol) and corresponding
boronic acid (1.5 mmol, 3 equiv.) was added by syringe. The resulting mixture was
stirred for 24 h at room temperature (23–25 uC). The mixture was diluted with
diethyl ether (200 ml) and water (50 ml). The aqueous layer was extracted with diethyl
ether (2350 ml). The combined organic layers were washed with water (3320 ml)
and brine (20 ml) and dried over sodium sulphate. The organic extracts were con-
centrated under reduced pressure, and the resulting residue was purified by silica
gel flash chromatography using 2–10% ethyl acetate in hexanes containing 0.1%
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Supplementary Information is available in the online version of the paper.
Acknowledgements We thank the US National Institutes of Health (NIGMS
GM063540) for financial support.
Author Contributions T.-S.M. and H.H.P. performed the experiments and analysed the
data. T.-S.M. and M.S.S. designed the experiments. T.-S.M. and M.S.S. prepared this
manuscript with feedback from H.H.P.
Author Information Data for the crystallized product (a derivative of 2f) have been
deposited in the Cambridge Crystallographic Data Centre under accession number
CCDC988090. Reprints and permissions information is available at www.nature.com/
reprints. The authors declare no competing financial interests. Readers are welcome to
comment on the online version of the paper. Correspondence and requests for
materials should be addressed to M.S.S. (sigman@chem.utah.edu).
41. Werner, E. W. & Sigman, M. S. A highly selective and general palladium catalyst for
the oxidative Heck reaction of electronically nonbiased olefins. J. Am. Chem. Soc.
132, 13981–13983 (2010).
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