Enantioselective Ir-Catalyzed Bidirectional Reductive Coupling

Article abstract of DOI:10.1021/acs.orglett.8b03669

In the presence of a chiral iridium complex, commercially available 3-chloro-2-chloromethyl-1-propene (1) was selectively activated for various reductive couplings. Depending on the reaction conditions it allows a selective mono- or bidirectional condensa

Full text of DOI:10.1021/acs.orglett.8b03669

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Ir-Catalyzed Bidirectional Reductive Coupling
Adrien Quintard* and Jean Rodriguez
Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille 13397, France
S
* Supporting Information
ABSTRACT: In the presence of a chiral iridium complex,
commercially available 3-chloro-2-chloromethyl-1-propene (1) was
selectively activated for various reductive couplings. Depending on
the reaction conditions it allows a selective mono- or bidirectional
condensation with one or two external aldehydes with excellent
enantiocontrol (>90% ee). This approach occurring simply under
mild conditions and avoiding premetalated reagents constructs
rapidly chiral homoallylic alcohols, key precursors of important
molecular fragments such as furans, pyrans, ketodiols, or 1,3,5-polyols.
diols, 1,3,5-polyols or spiroketals (Scheme 1b).2 As a result of
ssembling simple building blocks into elaborate complex
this pivotal synthetic interest, numerous methods have been
Achiral chemical architectures with good stereocontrol
developed for their stereoselective preparation3 mainly relying
while limiting waste generation represents a priority for
on stoichiometric metal activation and chiral additives.4 The
only chiral Lewis-acid-catalyzed strategy to access alcohols 3
from 1 involved allylic stannanes obtained after initial Cl−Li
exchange.5 Access to parent ketodiols A can also be based on
bidirectional aldolization by condensing two molecules of
aldehydes with a ketone equivalent, however the direct
enantioselective variant on aliphatic aldehydes still represents
a challenge.6 As a result, it is clear that the development of a
modular enantioselective catalytic synthesis of 3 and 4 starting
from aliphatic aldehydes, occurring without the use of
stoichiometric prematallated reagents and under mild conditions
is highly desirable.
modern organic synthesis.1 Notably, the discovery of greener
and easy to use enantioselective catalytic methods should
enhance the application potential of organic transformations
facilitating their transposition in the synthesis of elaborated
drugs or materials. Among crucial synthetic building blocks
necessary for the construction of divers chemical architectures,
homoallylic alcohols 3 and 4 stand out (Scheme 1.a). They
constitute privileged precursors for the synthesis of molecular
patterns found in a number of natural products and drugs. For
example, 3 provides a direct access to furans and pyrans while
preparation of 4 constitutes a straightforward route to keto-
To circumvent waste and hazards associated with the use of
stoichiometric premetalated nucleophiles, the group of Krische
has proposed a wide array of coupling reactions based on the
concept of alcohol mediated carbonyl addition.7,8 In a typical
reaction, dehydrogenation of an alcohol by a catalytic metal
complex (Ru or Ir) generates a carbonyl and a metal hydride.
The formed metal hydride then inserts in the allyl
pronucleophile, forming a reactive metal−allyl complex able
to stereoselectively add to an electrophilic carbonyl generating
the desired chiral alcohol.
Scheme 1. State of the Art and Proposed Bidirectional
Reductive Coupling
This type of reductive coupling is illustrated in Scheme 1c
where two allyl donors 5 are condensed to a pivotal 1,3-diol 6,
providing enantioenriched diols 7.9 Interestingly, this reductive
coupling chemistry can be performed by starting from an
alcohol or from an aldehyde. In the latter case, addition of an
environmentally friendly reductant such as 2-propanol initiates
the formation of the required catalytic metal-hydride.
Continuing with our interest on bidirectional condensations, we
hypothesized that 2-propanol might be used to activate
commercially available 3-chloro-2-(chloromethyl)-1-propene (1)
Received: November 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03669
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
as pivotal pronucleophile addition to an aldehyde. This would
allow for a rapid and selective generation of 3 and subsequently 4
through a bidirectional condensation with a second external
aldehyde (Scheme 1d). However, the development of this
bidirectional chemistry using a pivotal bis-donor might be
hampered by numerous challenges. First of all, 1 should be
selectively monoactivated through the use of greener hydride
donors such as 2-propanol, generating 3 after addition to an
aldehyde. Moreover, to apply the allylic chloride 3 in other
derivatizations, it should be stable enough under the reaction
conditions to avoid direct decomposition. Finally, advancing
intermediate 3 to diol 4 will require an additional metal
hydride insertion, resulting in a particularly sensitive hydroxy-
functionalized Ir−π-allyl complex10 prompt to evolve by a 5-
endo cyclization to form a methylene tetrahydrofuran 8. This
trimethylene methane (TMM) like-cycloaddition popularized
by the group of Trost has, however, no efficient enantiose-
lective version as far as aliphatic aldehydes are concerned.11
Therefore, of utmost importance for the success of our
approach is that the presence of the unprotected alcohol
function should neither inhibit the reactivity of the metal−allyl
complex through intramolecular coordination12 nor influence
the stereochemical outcome of the second nucleophilic
addition allowing for a catalyst-controlled diastereodivergent
process.
The role of the 2.2 equiv of K3PO4 was crucial since use of a
lower amount (1.1 equiv) or alternatively of Cs2CO3
considerably reduced the reactivity (entries 3 and 4). Turning
to the use of Segphos Ir-cat2 dramatically improved the
efficiency of the 2-propanol-promoted reductive coupling
forming 3a in excellent 70% yield and 98% ee (entry 5). To
promote the formation of 3a and avoid its decomposition, an
excess of 1 and of 2-propanol is required in the process (entry
5 vs entries 6 and 7). It must be noticed that the use of 3.5
equiv of 2-propanol also provides higher enantiocontrol
(entries 5 and 7, 98 vs. 93% ee). Finally, use of more
electron-poor aromatic ligand on the iridacycle as in Ir-cat3
reduced the reactivity forming only around 15% of 3a (entry
8). Given previous reports on reductive couplings, the
presence of traces amount of inorganic salts in Ir-cat3
reducing the reactivity cannot be excluded.14
With the optimized conditions of entry 5 in hand, we then
scrutinized the scope of the monodirectional reductive
coupling (Scheme 2). The 2-propanol-promoted coupling
Scheme 2. Scope of the Ir-cat2 Condensation of 1 with 2a-h
To initiate our study, we started investigating the reactivity
of 1 with isovaleraldehyde (2a) as the electrophile for the
selective synthesis of monoaddition product 3a (Table 1).13 2-
Table 1. Optimization of the Iridium-Catalyzed Addition of
1 to 2a
a
b
Using 2 mol % of Ir-cat2 starting from 10 mmol of 1. Using
additional 20 mol % 4-NO2-BzOH.
tolerated aldehydes with various steric substitution patterns.
Aliphatic isobutyl, isopropyl, or neopentyl substituents led to
the formation of the expected adducts 3a−c in 70−80% yields.
Moreover, the Ir-cat2 was able to induce an excellent
enantiofacial discrimination during the addition providing
these products in very high 96 to 98% ee. Starting from
enantiopure (S)-citronellal, the terpenoid chain could be
introduced in 3d with 85% yield and excellent diastereocontrol
(>95:5 dr). Use of less sterically demanding hydrocinnamalde-
hyde 2e or trans-2-pentenal 2f decreased the reaction efficiency
providing 3e and 3f in 37% and 43% yield, respectively but
again with a high level of stereocontrol (97 and 92% ee).15
Finally, 2-substituted enal 2g or Boc-protected amine 2h were
well tolerated, providing 3g and 3h in 71 and 61% yields and
>90% ee. Interestingly, demonstrating the synthetic potential of
this approach, it must be pointed out that 3b could be
prepared starting from 10 mmol of 1 and using only 2 mol %
Ir-cat2.
1/2/i-
yield
a
ee
b
entry
1
cat
base (equiv)
K3PO4 (2.2)
PrOH
(%)
(%)
in situ formed
5/1/3.5
trace
nd
Ir-cat
Ir-cat1
Ir-cat1
2
3
K3PO4 (2.2)
Cs2CO3
(2.2)
K3PO4 (1.1)
K3PO4 (2.2)
K3PO4 (2.2)
K3PO4 (2.2)
K3PO4 (2.2)
5/1/3.5
5/1/3.5
38
trace
90
nd
c
4
5
6
7
8
Ir-cat1
Ir-cat2
Ir-cat2
Ir-cat2
5/1/3.5
5/1/3.5
3/1/3
5/1/2
5/1/3.5
15
nd
98
nd
93
nd
70
c
10
51
15
c
Ir-cat3
a
b
Isolated yields. Enantiomeric excess determined by chiral gas
chromatography. NMR yield. Nd = not determined.
c
Propanol was chosen as the green activator in the presence of
various easily accessible iridium complexes. When the active
iridium complex was generated in situ from [Ir(COD)Cl]2,
phosphine ligand, and the corresponding acid, only a trace
amount of the adduct 3a was observed and 1 was mostly
recovered (entry 1).14 However, use of 5 mol % preformed
Binap complex Ir-cat1 restored the reductive coupling
providing 3a in promising 38% yield and 90% ee (entry 2).
With a practically convenient and highly enantioselective
access to hydroxyl functionalized allylic chlorides 3, we next
turned our attention to the development of the challenging
second functionalization. Preliminary experiments (see the
Supporting Information) were conducted mixing 3d under the
conditions of Scheme 1 and in the absence of aldehyde. Of
B
DOI: 10.1021/acs.orglett.8b03669
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Letter
importance, removing any external electrophile, evolution of
3d notably through cyclization was noticed possibly through
the formation of the corresponding catalytic Ir-π-allyl complex.
This is in agreement with the reactivity observed in Table 1
showing that an excess of 1 was required to improve the yield.
To promote the bidirectional addition process, we thus
reduced the temperature to 50 °C while placing 3 in the
presence of an excess of aldehydes. Under the reductive
conditions, Ir-cat2 efficiently reacted with 3b providing the
unprotected diols 4b,d,g in 44−70% yield without racemiza-
tion of the initial stereocenter (Scheme 3). Gratifyingly,
desymmetrizable substrates.17 For example, anti4a could be
converted through reductive ozonolysis to 1,3,5-poyol 9a, a
polyol whose synthesis was only disclosed in the racemic series
(Scheme 5.a).6d To prove the feasibility of a direct catalytic
Scheme 5. Examples of Bidirectional Synthetic Applications
and Reductive Coupling from the Alcohol Level
Scheme 3. Diastereodivergent Reductive Coupling of 3b
stereoselective TMM like-cycloaddition on aliphatic aldehydes,
we performed the one-pot direct preparation of methylene
tetrahydrofuran 8d. Directly in situ treating the reductive
coupling adduct with NaH, the resulting TMM like-adduct
could be formed in 73% overall yield (Scheme 5.b). Of
importance, the reductive coupling can also be performed from
the alcohol oxidation state. Preliminary experiment condensing
1 with 10d provided the expected adduct 3d in 49% yield and
>95:5 dr. Finally, determination of the absolute configuration
of compounds 3 and 4 supports the enantioselection model
proposed for allylation reactions using (S)-Ir-cat2.18
In conclusion, activation of commercially available 3-chloro-
2-chloromethyl-1-propene (1) by the appropriate use of a
catalytic chiral iridium complex provides an innovative
enantioselective reductive coupling avoiding the use of
premetalated reagents. This constitutes a straightforward
access to synthetically valuable bis-functionalized homoallylic
alcohols with high levels of stereocontrol. The second allylic
chloride functionalization involves a peculiar Ir-π-allyl complex
possessing an adjacent unprotected alcohol function. Despite
the poor stability of this complex, the second carbonyl addition
occurs with perfect catalyst control allowing for an efficient
diastereodivergent process. The discovery of an efficient way to
selectively generate and react functionalized chloro-allylic
alcohols opens strong perspectives for the development of
other cascade reactions. It should allow a rapid and
environmentally friendly construction of a broad range of
valuable building blocks with important implications notably in
the synthesis of natural products or drugs. Finally, we are
currently investigating the strong potential of using 2-propanol
reductive coupling to promote other TMM like-cycloadditions.
despite the presence of the unprotected alcohol in the starting
material, the Ir-cat2 was able to independently control the
formation of the newly formed stereogenic center. Indeed,
using the appropriate enantiomer of the catalyst, either anti or
syn diols could be prepared with more than 80% diastereocon-
trol.
With a method able to selectively functionalize allylic
chlorides 3, we focused on a last challenge, the development of
a cascade direct synthesis of symmetric bis-alcohols 4. This
bidirectional reductive coupling would constitute an alternative
to the ones already reported in the literature such as the
condensation of two pro-nucleophiles on a central bis-alcohol
(Scheme 1.b). In the present approach, an internal
stoichiometric pro-nucleophile would have to react directly
with two external electrophiles. As a result, for the success of
this cascade, the in situ generated hydroxy functionalized allylic
chloride 3, should directly react again with another aldehyde.
Gratifyingly, the selective use of Ir-cat2 allowed for the
efficient condensation of structurally different aldehydes
(Scheme 4). Use of 2 equiv of aldehydes with respect to
each chlorine at 50 °C provided the bidirectional products 4a−
d in 65−74% yield. Interestingly, the diols could be obtained
with almost perfect enantiocontrol and >95:5 dr for 4d. As a
result, this cascade rapidly assembles simple substrates into
valuable diols key direct precursors of 1,3,5-polyols,16 easily
Scheme 4. Cascade Bidirectional Reductive Coupling of 1
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03669.
Additional experiments, NMR spectrum, example of
literature derivatization of the obtained adducts,
C
DOI: 10.1021/acs.orglett.8b03669
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Organic Letters
proposed mechanism, experimental procedures and
Letter
Shimoda, Y.; Hu, H.; Gao, S.; Sugiura, M.; Ogasawara, M.; Nakajima,
M. Chem. - Asian J. 2016, 11, 376. (f) Quintard, A.; Rodriguez, J. ACS
Catal. 2017, 7, 5513. (g) Kotani, S.; Kai, K.; Sugiura, M.; Nakajima,
M. Org. Lett. 2017, 19, 3672. (h) Quintard, A.; Rodriguez, J. Org. Lett.
2018, 20, 5274. (i) Ricucci, A.; Rodriguez, J.; Quintard, A. Eur. J. Org.
Chem. 2018, 2018, 3697. (j) Quintard, A.; Rodriguez, J. Chimia 2018,
72, 580.
characterization of compounds, NMR and intensity
spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: adrien.quintard@univ-amu.fr.
ORCID
(7) For reviews: (a) Ngai, M.-Y.; Kong, J.-R.; Krische, M. J. J. Org.
Chem. 2007, 72, 1063. (b) Bower, J. F.; Kim, I. S.; Patman, R. L.;
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X.; Itoh, T.; Krische, M. J. Nat. Prod. Rep. 2014, 31, 504. (e) Quintard,
A.; Rodriguez, J. Chem. Commun. 2016, 52, 10456. (f) Feng, J.; Kasun,
Z. A.; Krische, M. J. J. Am. Chem. Soc. 2016, 138, 5467. (g) Kim, S.
W.; Zhang, W.; Krische, M. J. Acc. Chem. Res. 2017, 50, 2371.
(8) For leading references notably based on iridium complexes:
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6340. (b) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc.
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D. C.; Krische, M. J. Angew. Chem., Int. Ed. 2013, 52, 3195. (e) Feng,
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(9) (a) Lu, Y.; Kim, I. S.; Hassan, A.; Del Valle, D. J.; Krische, M. J.
Angew. Chem., Int. Ed. 2009, 48, 5018. (b) Hassan, A.; Lu, Y.; Krische,
M. J. Org. Lett. 2009, 11, 3112. (c) Han, S. B.; Hassan, A.; Kim, I. S.;
Krische, M. J. J. Am. Chem. Soc. 2010, 132, 15559. (d) Gao, X.; Han,
H.; Krische, M. J. J. Am. Chem. Soc. 2011, 133, 12795.
(10) For the reactivity of such iridium π-allyl towards nucleophilic
addition: Meza, T.; Wurm, T.; Smith, L.; Kim, S. W.; Zbieg, J. R.;
Stivala, C. E.; Krische, M. J. J. Am. Chem. Soc. 2018, 140, 1275.
(11) For leading references: (a) Trost, B. M.; Chan, D. M. T. J. Am.
Chem. Soc. 1979, 101, 6429. (b) Trost, B. M.; King, S. A. Tetrahedron
Lett. 1986, 27, 5971. (c) Trost, B. M.; King, S. A.; Schmidt, T. J. Am.
Chem. Soc. 1989, 111, 5902. (d) For the recent enantioselective
version, see: Trost, B. M.; Bringley, D. A.; Silverman, S. M. J. Am.
Chem. Soc. 2011, 133, 7664.
(12) (a) Zhang, Y. J.; Yang, J. H.; Kim, S. H.; Krische, M. J. J. Am.
Chem. Soc. 2010, 132, 4562. (b) Feng, J.; Garza, V. J.; Krische, M. J. J.
Am. Chem. Soc. 2014, 136, 8911. (c) Wang, G.; Franke, J.; Ngo, C. Q.;
Krische, M. J. J. Am. Chem. Soc. 2015, 137, 7915.
(13) When 1,1-disubstituted allyl donors are reacted, use of chloro
derivatives are preferred over esters derivatives: (a) Hassan, A.;
Townsend, I. A.; Krische, M. J. Chem. Commun. 2011, 47, 10028.
(b) Hassan, A.; Montgomery, T. P.; Krische, M. J. Chem. Commun.
2012, 48, 4692. (c) Manoni, F.; Rumo, C.; Li, L.; Harran, P. G. J. Am.
Chem. Soc. 2018, 140, 1280.
(14) For a discussion on the difference of reactivity between isolated
and in situ formed complexes see ref 8b and Gao, X.; Townsend, I. A.;
Krische, M. J. J. Org. Chem. 2011, 76, 2350.
(15) Use of additional carboxylic acid was required to improve the
yield, probably by avoiding undesired iridacycle decomposition.
(16) For a recent review on polyols synthesis, see: Kumar, P.;
Tripathi, D.; Sharma, B. M.; Dwivedi, N. Org. Biomol. Chem. 2017, 15,
733.
Adrien Quintard: 0000-0003-0193-6524
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The Centre National de la Recherche Scientifique (CNRS)
and the Aix-Marseille Universite are gratefully acknowledged
for financial support.
■
́
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D
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Org. Lett. XXXX, XXX, XXX−XXX