Nickel-Catalyzed Enantioselective Synthesis of Pre-Differentiated Homoallylic syn- or anti-1,2-Diols from Aldehydes and Dienol Ethers

Article abstract of DOI:10.1021/jacs.1c07042

Nickel catalysis allied with cyclodiphosphazane or VAPOL-derived phosphoramidite ligands provides selective access to monoprotected vicinal diols by reductive coupling of dienol ethers and aldehydes. The observed regioselectivity is unprecedented, in that the diene reacts at the least nucleophilic and most hindered C atom that is attached to the oxygen substituent rather than at the terminal position. Notably, both syn and anti diastereomers of the products can be accessed depending on the configuration of the diene partner with usually excellent diastereo- and enantioselectivity.

Full text of DOI:10.1021/jacs.1c07042

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Nickel-Catalyzed Enantioselective Synthesis of Pre-Differentiated
Homoallylic syn- or anti-1,2-Diols from Aldehydes and Dienol Ethers
̈
Thomas Q. Davies, John J. Murphy, Maxime Dousset, and Alois Furstner*
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ABSTRACT: Nickel catalysis allied with cyclodiphosphazane or VAPOL-derived phosphoramidite ligands provides selective access
to monoprotected vicinal diols by reductive coupling of dienol ethers and aldehydes. The observed regioselectivity is unprecedented,
in that the diene reacts at the least nucleophilic and most hindered C atom that is attached to the oxygen substituent rather than at
the terminal position. Notably, both syn and anti diastereomers of the products can be accessed depending on the configuration of
the diene partner with usually excellent diastereo- and enantioselectivity.
Scheme 1. (A) The Original Intermolecular Nickel-
Catalyzed “Tamaru Reaction;” (B) the First
Enantioselective Variant (ref 12); (C) a Silylative
Asymmetric Variant (ref 13); (D) This Work:
Unprecedented Regioselectivity Enables Enantioselective
Access to Monoprotected 1,2-Diols
n the 1990s, the groups of Tamaru and Mori pioneered the
nickel-catalyzed reductive coupling of aldehydes with 1,3-
I
dienes, notably isoprene.1−5 The benefits of this “isoprenyla-
tion,” or in its generalized format homoallylation reaction,
include generally mild conditions and high levels of
diastereoselectivity (Scheme 1A). Later, it was shown that
different functional groups such as aryl substituents,6 boronic
esters,7,8 silanes,9 or stannanes10 can be placed on the carbon
chain, expanding the utility of the transformation. However,
enantioselective variants remain relatively unexplored and were
described in a recent review as a “largely unresolved
challenge”.11 The first two intermolecular examples use a
SPINOL-derived phosphoramidite (3, Scheme 1B) or a chiral
N-heterocyclic carbene to couple symmetrical 1,4-diaryl dienes
with aldehydes.12,13 Likewise, the asymmetric coupling of
diene 4 with certain aldehydes in the presence of a silylborane
to give products such as 5 is known (Scheme 1C), but the
scope is again rather limited.9
The lack of catalyst control also surfaced during a recent
total synthesis campaign, where we tried to take advantage of
nickel-catalyzed isoprenylations of sugar-derived aldehydes;
however, the inability to overwrite the stereochemical bias of
some substrates with the aid of chiral nickel complexes marked
an inherent limitation of this approach.14,15 Confronted with
this impasse, we embarked into a more systematic inves-
tigation, during which an unexpected and, to the best of our
knowledge, unprecedented reactivity mode was discovered.16
The preliminary results of this new diastereo- and
enantioselective approach to monoprotected vicinal diols are
summarized below (Scheme 1D).
Our studies began with the coupling of silyloxydiene 7 with
hydrocinnamaldehyde using Ni(cod)2 as a catalyst and
triethylborane as reductant. No conversion was observed in
the absence of a ligand.17 With triphenylphosphine added, we
observed not only the expected “Tamaru product” 8 but also
the 1,2-diol derivative 9a in a 1.2:1 ratio (Figure 1).
Received: July 7, 2021
This outcome is striking as it implies attack of the silyloxy
diene 7 at C1 rather than C4, which is the least nucleophilic
and, at the same time, arguably most hindered site.18 If this
© XXXX The Authors. Published by
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first studied the racemic reaction using L6 to see if there was
any relevant scope.
Gratifyingly, linear (9a−9d) and branched (9e−9f) alkyl
aldehydes performed well, and even sterically hindered
pivaldehyde still gave an acceptable 40% yield (9g; Scheme
2). Likewise, aromatic and heteroaromatic aldehydes proved
Scheme 2. Scope of the (Virtually) Racemic Reaction42
Figure 1. Initial ligand screening.
reactivity pattern can be generalized, however, a new and
potentially highly enabling entry into vicinal diols is gained; on
top of the stereochemical virtues, it allows the two hydroxy
groups to be rigorously discriminated in that one of them is
delivered as the free alcohol, whereas the other one carries a
protecting group. For this trait, such an approach nicely
complements the traditional arsenal.19−34
a
Using Ni(cod)2 and L4 (5 mol % each).
compliant and allowed the compatibility of the reaction with
various polar substituents such as esters, nitriles, and ketones
to be demonstrated (for additional functionality, see Scheme
5). Furfural also led to excellent results, whereas thiophene-2-
carbaldehyde reacted sluggishly because of the thiophilicity of
the nickel catalyst. Unsurprisingly, perhaps, pyridine-2-
carbaldehyde failed to react under standard conditions, also
likely because the heteroatom donor site functions as a
competitive ligand for Ni(0). An α,β-unsaturated aldehyde was
also transformed more slowly but did eventually give product
9k in 46% yield and 20:1 dr.41 With regard to the reaction
partner, excellent yields and remarkably high diastereoselectiv-
ities were maintained using dienyl ethers with −OTES and
−OTBS groups; the latter proved particularly adequate when
working with dienes lacking the methyl substituent at C3,
where the −OTIPS derivative led to a slightly lower dr
(compare 9i/9j).
Increasing the donor strength of the ligand (PCy3, NHC,35
L1) or moving to a bidentate phosphine (BINAP) suppressed
any conversion; more electron-deficient ligands, including
phosphoramidite L2 and bulky TADDOL-derived phosphon-
ite L3,36 fared better, giving good or even complete selectivity
in favor of diol 9a, although the conversion and ee were low.
Switching to the cyclodiphosphazane ligand L4 proved
key,37,38 with the diol product obtained with excellent
regioselectivity, diastereoselectivity, and quantitative yield
(NMR), though in virtually racemic form. Extensive efforts
were made to improve the level of induction by (i) placing
substituents at the 3,3′-positions of the ligand’s BINOL
subunit (L5 and L6), (ii) varying the amine part (L7), (iii)
using octahydro-BINOL (L8), and (iv) replacing BINOL with
VANOL (L9).39 Even though approximately 40 different chiral
cyclodiphosphazanes were prepared and screened, many of
which are synthetically quite challenging, ee’s were generally
poor, and no result with both >40% conversion and >40% ee
could be obtained (for full details, see the SI).40 Therefore, we
The major diastereomer formed was confirmed as the 1,2-
anti diol by comparison of product 9j derived from heptanal
with authentic material prepared by a known literature route
(see the SI).43
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The use of (Z)-configured silyloxydienes (10) led to a stark
reversal of diastereoselectivity as shown by the formation of the
syn-configured diol derivatives 11a and 11b (Scheme 3).
Coordination of Lewis-acidic triethylborane aids the
cyclization by reducing the electron density of the carbonyl
group; moreover, the subsequent ethyl transfer to nickel is
rendered quasi-intramolecular and hence more facile. β-
Hydride elimination then gives ethylene and the nickel hydride
species 15, which undergoes reductive elimination to release
product 16 (leading to 17 upon hydrolysis of the B−O bond
during workup) and regenerate the catalytically active
nickel(0) species.
Scheme 3. Stereochemical Effects of Alternative Dienes
Convinced by these results of the utility of the reaction, we
redoubled our efforts to develop an enantioselective variant
(Figure 2). For the lack of any real hit, cyclodiphosphazanes
Furthermore, the trisubstituted diene 12 furnished product 13
in 91% yield as a single diastereomer (for the enantioselective
version, see Scheme 5); this result proves that the high 1,3-anti
selectivity characteristic of the original Tamaru isoprenylation4
is retained in the new diol synthesis even though C−C-bond
formation now occurs at the head- rather than the tail-end of
the dienolsilane partner.
In analogy to the mechanism of the Tamaru homoallyla-
tion,4,44 we propose that the new reaction proceeds through
nickel-induced oxidative cyclization of the dienyl ether45 and
the aldehyde to give nickelacycle 14 (Scheme 4). The bulky
Scheme 4. Proposed Mechanism
Figure 2. Optimization of the enantioselective reaction. a72 h reaction
b
time. 3.0 equiv diene, 10 mol % Ni/L17.
were not pursued any further.40 Because of the literature
precedent12 (see Scheme 1B), ligands L10 and L11 comprising
a SPINOL backbone seemed promising; their use, however,
was to no avail either. Likewise, BINOL-based phosphor-
amidites including L12−L14 were rapidly ruled out, despite
their excellent track record in asymmetric catalysis.46
For these systematic failures, we were prompted to revisit
the design. Rather than forging a chiral cleft on the “backside”
of the ligands as, e.g., in the case of BINOL-derived
phosphoramidites, it seemed warranted to enlarge the “major
groove” on the front side in the hope of crafting an effective
(helically) chiral environment about the nickel center. Indeed,
a first promising result was obtained with the VANOL-
phosphoramidite derivative L15,39 which gave product 18a
with 55% ee. Extending the π-system further, as manifested in
cyclodiphosphazane backbone dictates the relative orientation
of the reaction partners on the loaded catalyst, such that a
steric clash between the bulky ligand and the oxygen
substituent on the dienyl ether is avoided; this array explains
the formation of the 1,2-diol product. In line with this notion,
sterically less demanding (but still reactive) ligands such as
PPh3 lead to product mixtures. The diastereoselectivity results
from the position of the R group of the aldehyde: when
equatorially oriented, unfavorable 1,3-diaxial interactions
across the metallacyclic ring are prevented; this likely includes
transannular collisions with the ligand L on nickel, since the
bulky cyclophosphazane L6 entails a better dr than slimmer
PPh3.
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the VAPOL derivative L16,39 improved the outcome to 72%
ee. The yield, dr, and ee were all boosted using the
diethylamino analogue L17; further changes to the amine
substituents, however, did not lead to any significant
improvements (for details, see the SI). Varying the solvent
had little effect, whereas lowering the temperature to 0 °C or
−20 °C resulted in 81% and 84% ee, respectively; the decrease
in conversion could be compensated by using an excess of the
diene and a higher catalyst loading of 10 mol % (entry 11).
Under these conditions, 18a was obtained in 77% yield, 20:1
dr, and 84% ee.47 To the best of our knowledge, this represents
the first use of a VAPOL-phosphoramidite in nickel
catalysis.48−50
Scheme 5. Scope of the Enantioselective Reaction
These conditions were then used to survey the scope of the
enantioselective reaction. Hydrocinnamaldehyde, which had
been chosen for the initial screening, actually turned out to be
one of the more recalcitrant substrates, as evident from the
results for compounds 13, 18a, and 18b. Changing the O-
protecting group on the dienyl ether hardly altered the attained
ee’s (compare 18a/18b, 18c/18d, and 19a/19b). In contrast,
further lowering of the temperature to −40 °C had a notable
effect for aryl aldehydes, though at the expense of a drop in
yield (see 18e and 19f). Various aryl aldehydes with different
steric and electronic properties were tested. Excellent ee’s were
obtained for substrates bearing electron-donating, neutral, and
weakly electron-withdrawing substituents. Even the presence of
an ortho-methyl group is well tolerated (18g). The
compatibility of the nickel-based catalyst system with an aryl
chloride is also noteworthy (18j), as is the ability to run the
reaction in the presence of an arylboronate group (18l), which
opens numerous possibilities for downstream functionalization.
The poorer result caused by the strongly electron-withdrawing
4-CF3 group (18k, 78% ee) reveals a limitation of the current
catalyst system, which could not be ameliorated even by
running the reaction at −60 °C (30% yield, 82% ee). In
contrast, electron-rich furfural fared very well, furnishing
product 18m in excellent yield and selectivity.
Another interesting observation pertains to the syn-diol
series. Whereas the results for aliphatic aldehydes were rather
uniform, we were surprised to find that 4-phenylbenzyldehyde
reacted less selectively with (Z)-configured dienes than with
(E)-dienes (cf. 18e versus 19e, 74% versus 87/93% ee).
Fortunately, recourse to a benzyl protecting group improved
the outcome to a respectable 92% ee at −40 °C (19f); this
result mandates further systematic survey. Finally, it is
emphasized that the diastereoselectivity was invariably
excellent in the anti as well as syn series; in many cases, the
attained dr’s approach the limits of detection (NMR).
In conclusion, we have discovered a synthesis of
monoprotected vicinal diols based on a nickel-catalyzed
reductive coupling of dienol ethers and aldehydes that exhibits
an unusual regioselective course and can selectively access
either diastereomer of the product. The use of bulky, relatively
electron-deficient phosphorus ligands including cyclodiphos-
phazane L6 and VAPOL phosphoramidite L17 proved key to
unlocking this transformation. The presence of a silyl or benzyl
group on one oxygen of the diol products should allow for
selective functionalization; therefore, the new method nicely
complements the traditional catalytic asymmetric toolbox
which usually affords two unprotected vicinal hydroxy groups.
Importantly, both anti and syn diol products can be obtained in
invariably outstanding diastereoselectivity and often excellent
enantioselectivity with a range of alkyl and aryl aldehydes.
Work is underway to gain more mechanistic insights and
increase the level of induction as well as the scope of the
reaction even further.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c07042.
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Experimental procedures and supporting characteriza-
tion data and spectra (PDF)
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(9) Saito, N.; Kobayashi, A.; Sato, Y. Nickel-Catalyzed Enantio- and
Diastereoselective Three-Component Coupling of 1,3-Dienes,
Aldehydes, and a Silylborane Leading to α-Chiral Allylsilanes.
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(10) Sato, Y.; Saito, N.; Mori, M. Ni(0)-catalyzed bismetallative
cyclization of 1,3-diene and a tethered aldehyde in the presence of
Bu3SnSiMe3. Chem. Lett. 2002, 31 (1), 18−19.
AUTHOR INFORMATION
■
Corresponding Author
Alois Fu
45470 Mu
0098-3417; Email: fuerstner@kofo.mpg.de
̈
rstner − Max-Planck-Institut fu
̈
r Kohlenforschung,
̈
lheim/Ruhr, Germany; orcid.org/0000-0003-
Authors
Thomas Q. Davies − Max-Planck-Institut fu
Kohlenforschung, 45470 Mulheim/Ruhr, Germany;
orcid.org/0000-0003-1054-1161
John J. Murphy − Max-Planck-Institut fu
45470 Mulheim/Ruhr, Germany; orcid.org/0000-0001-
8411-9540
Maxime Dousset − Max-Planck-Institut fu
45470 Mulheim/Ruhr, Germany
(11) Holmes, M.; Schwartz, L. A.; Krische, M. J. Intermolecular
Metal-Catalyzed Reductive Coupling of Dienes, Allenes, and Enynes
with Carbonyl Compounds and Imines. Chem. Rev. 2018, 118 (12),
6026−6052.
(12) Yang, Y.; Zhu, S. F.; Duan, H. F.; Zhou, C. Y.; Wang, L. X.;
Zhou, Q. L. Asymmetric reductive coupling of dienes and aldehydes
catalyzed by nickel complexes of spiro phosphoramidites: Highly
enantioselective synthesis of chiral bishomoallylic alcohols. J. Am.
Chem. Soc. 2007, 129 (8), 2248−2249.
(13) Sato, Y.; Hinata, Y.; Seki, R.; Oonishi, Y.; Saito, N. Nickel-
catalyzed enantio- and diastereoselective three-component coupling of
1,3-dienes, aldehydes, and silanes using chiral N-heterocyclic carbenes
as ligands. Org. Lett. 2007, 9 (26), 5597−5599.
̈
r
̈
̈
r Kohlenforschung,
̈
̈
r Kohlenforschung,
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c07042
(14) Heinrich, M.; Murphy, J. J.; Ilg, M. K.; Letort, A.; Flasz, J. T.;
Philipps, P.; Furstner, A. Chagosensine: A Riddle Wrapped in a
Mystery Inside an Enigma. J. Am. Chem. Soc. 2020, 142 (13), 6409−
6422.
Funding
Open access funded by Max Planck Society.
Notes
(15) Heinrich, M.; Murphy, J. J.; Ilg, M. K.; Letort, A.; Flasz, J.;
Philipps, P.; Furstner, A. Total Synthesis of Putative Chagosensine.
Angew. Chem., Int. Ed. 2018, 57 (41), 13575−13581.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(16) Tamaru and co-workers had studied silyloxydienes of the type
used herein in their pioneering study but did not observe any 1,2-diol
formation, see ref 4.
Generous financial support by Alexander-von-Humboldt
Foundation (fellowship to T.Q.D.) and the Max-Planck-
Society is gratefully acknowledged. We thank Dr. M. Heinrich
for collaboration in the early phase of this project, C. Wille for
preparing multigram amounts of VAPOL, and all service
groups of our Institute, most notably the HPLC department,
for excellent service.
(17) In the original Tamaru reaction, four equivalents of the diene
and a reaction time of almost two days were required for full
conversion under similar conditions (with benzaldehyde), see refs 1
and 2.
(18) In an interesting case study, reductive coupling at the different
sites of 2-substituted 1,3-dienes with formaldehyde was accomplished
by changing the catalyst from nickel to ruthenium, see: Köpfer, A.;
Sam, B.; Breit, B.; Krische, M. J. Regiodivergent reductive coupling of
2-substituted dienes to formaldehyde employing ruthenium or nickel
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(19) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroder, G.;
Sharpless, K. B. Asymmetric Dihydroxylation Via Ligand-Accelerated
Catalysis. J. Am. Chem. Soc. 1988, 110 (6), 1968−1970.
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(42) Where investigated, the ee’s were < 40%.
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F
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