Catalytic Enantioselective Allylations of Acetylenic Aldehydes via 2-Propanol-Mediated Reductive Coupling

Article abstract of DOI:10.1021/acs.orglett.8b01776

Cyclometalated π-allyliridium C,O-benzoates modified by (S)-SEGPHOS or (S)-Cl,OMe-BIPHEP catalyze enantioselective 2-propanol-mediated reductive couplings of diverse nonmetallic allyl pronucleophiles with the acetylenic aldehyde TIPSC≡CCHO. Absolute stere

Full text of DOI:10.1021/acs.orglett.8b01776

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Enantioselective Allylations of Acetylenic Aldehydes via
2‑Propanol-Mediated Reductive Coupling
Gilmar A. Brito,§,†,∥ Franco Della-Felice,§,†,∥ Guoshun Luo,§,∥ Alexander S. Burns,‡
Ronaldo A. Pilli,*,† Scott D. Rychnovsky,*,‡ and Michael J. Krische*,§
§Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
†Institute of Chemistry, University of Campinas (UNICAMP), P.O. Box 6154, CEP, 13083-970 Campinas, Sao
̃
Paulo, Brazil
‡Department of Chemistry, University of California at Irvine, 1102 Natural Sciences II, Irvine, California 92697, United States
S
* Supporting Information
ABSTRACT: Cyclometalated π-allyliridium C,O-benzoates modified
by (S)-SEGPHOS or (S)-Cl,OMe-BIPHEP catalyze enantioselective
2-propanol-mediated reductive couplings of diverse nonmetallic allyl
pronucleophiles with the acetylenic aldehyde TIPSCCCHO.
Absolute stereochemistries of the resulting secondary homoallylic−
propargylic alcohols were assigned using Rychnovsky’s competing
enantioselective conversion method.
espite decades of study on enantioselective carbonyl
(S)-Cl-MeO-BIPHEP and (S)-SEGPHOS, respectively, were
Dallylation, crotylation, and related syntheses of homo- utilized. Acetylenic aldehydes 1a and 1b bearing terminal
allylic alcohols,1 the asymmetric allylation of acetylenic alde-
phenyl and silyloxymethyl moieties, respectively, decomposed
upon exposure to the standard reaction conditions, and the
desired products of carbonyl allylation were not observed
(Table 1, entries 1−4). It was reasoned that a more sterically
demanding substituent at the alkyne terminus would mask the
alkyne and mitigate decomposition. Indeed, the acetylenic alde-
hyde 1c bearing a 2-(2-silyloxy)propyl substituent provided the
desired product of allylation 3c in modest yield but with
excellent levels of enantiomeric enrichment (Table 1, entries 5
and 6). A series of trialkylsilyl-terminated acetylenic aldehydes
1d−f were evaluated. While the TMS-substituted acetylenic
aldehyde 1d decomposed upon exposure to allylation condi-
tions (Table 1, entries 7 and 8), the TBS-substituted acetylenic
aldehyde 1e provided highly enantiomerically enriched allyla-
tion product 3e, albeit in poor yield (Table 1, entries 9 and 10).
Finally, using the TIPS-substituted acetylenic aldehyde 1f, the
targeted product of allylation 3f could be obtained in good yields
and excellent enantioselectivities (Table 1, entries 11 and 12).
Optimal results were obtained using the catalyst (S)-Ir-I
modified by (S)-Cl-MeO-BIPHEP. The optical rotation of 3f
matched the literature value,11 and its absolute stereochemical
assignment is consistent with the enantiofacial preference gener-
ally observed in related aldehyde allylations catalyzed by (S)-Ir-I
and (S)-Ir-II.6d,10
hydes (ynals) has received relatively little attention. To date,
only two systematic studies of asymmetric ynal allylation appear in
the literature,2 along with isolated examples involving reagents
based on boron,3 tin,4 and zinc.5 These methods invariably require
cryogenic conditions and the use of premetalated reagents,
which limits their utility. Our laboratory has developed the first
alcohol-mediated carbonyl reductive couplings,6 including
highly enantioselective carbonyl allylations and propargyla-
tions.6d These processes do not require cryogenic conditions
and exploit tractable nonmetallic allyl pronucleophiles, for
example, allyl acetate. In connection with collaborative efforts
toward the total synthesis of phosdiecin A,7 a systematic study
of enantioselective, iridium-catalyzed ynal reductive couplings
mediated by 2-propanol was undertaken. Here, we report that
the acetylenic aldehyde TIPSCCCHO participates in a
diverse range of allylative carbonyl additions to form highly
enantiomerically enriched secondary homoallylic−propargylic
alcohols.8 Additionally, as an inversion in enantiofacial selec-
tivity was previously observed in response to the steric features
of the allyl donor,9 Rychnovsky’s competing enantioselective
conversion (CEC) method was used to corroborate absolute
stereochemistry and, in doing so, was expanded to encompass
a diverse set of chiral propargyl alcohols.
The TIPS-substituted acetylenic aldehyde 1f was reacted
with a range of allyl pronucleophiles 2a−f to assess the diversity
of products potentially accessible (Scheme 1). Beyond
allylation,10 anti-diastereo- and enantioselective crotylation to
Due to the high kinetic reactivity of alkynes under the condi-
tions of iridium catalysis, it was necessary to evaluate terminally
substituted ynals 1a−d for their ability to participate in the
parent enantioselective reductive iridium-catalyzed carbonyl
allylation mediated by 2-propanol.10 For this purpose, the
chromatographically purified cyclometalated π-allyliridium
C,O-benzoate complexes (S)-Ir-I and (S)-Ir-II, modified by
Received: June 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Enantioselective Iridium-Catalyzed Allylation of
Scheme 1. Enantioselective Iridium-Catalyzed Reductive
Ynals 1a−f with Allyl Acetate via 2-Propanol-Mediated
Couplings of Ynal 1f with Allyl Pronucleophiles 2a−f To
a
a
Reductive Coupling
Form Homoallylic−Propargylic Alcohols 3f and 4−8
a
Yields are of material isolated by silica gel chromatography.
Enantioselectivity was determined by chiral stationary phase HPLC
analysis. See the Supporting Information for further experimental
details.
form compound 4 occurred in good yield with excellent
control of relative and absolute stereochemistry.12 Similarly,
methallylation of aldehyde 1f delivered adduct 5 in good yield
with high levels of enantiomeric enrichment.13 Using dimeth-
ylallene 2d as the pronucleophile, tert-prenylation of aldehyde
1f occurs efficiently and, as anticipated on the basis of prior
observations,9 with inversion of enantiofacial selectivity. Aldehyde
1f reacts with vinyl aziridine 2e to form the product of
α-(aminomethyl)allylation 7 in an anti-diastereo- and enantio-
selective manner.14 Finally, using allyl donor 2f, which
incorporates a 3-(6-methoxypyridine) substituent, the product
of α-(aryl)allylation 8 is formed with good levels of stereo-
selectivity.15 Attempted reactions from the propargyl alcohol
oxidation level were less efficient (20% lower yields), as the
inductive effect of the alkyne raises the barrier for alcohol
dehydrogenation.16
a
Yields are of material isolated by silica gel chromatography.
Enantioselectivity was determined by chiral stationary phase HPLC
analysis. See the Supporting Information for further experimental
details. X-ray data obtained after removal of the TIPS group and
b
The configuration of the alcohol products were analyzed
using the CEC method (Scheme 2).17 Enantioselective acyla-
tion of the chiral nonracemic alcohols with (R)- or (S)-HBTM,
Birman’s catalyst,18 are anticipated to proceed with higher
conversions with the stereochemically matched catalyst. In the
event, the acylation catalyzed by (R)-HBTM was faster for
alcohols 3f, 4, 5, and 8, indicating these alcohols are of the
(S)-configuration; that is, the configuration of the alcohols are
forward, as shown. Acylation of alcohol 7 was anomalously fast
and unselective, and no assignment could be made. Alcohol 6,
the tert-prenylation product, was problematic. Acylation of
alcohol 6 was essentially unselective at room temperature. At 0 °C,
alcohol 6 showed modestly higher conversion with the
(R)-HBTM catalyst. The standard mnemonic suggests that
the alcohol should be of the (S)-configuration; however, X-ray
analysis establishes an (R)-configuration.19 Empirically, while
the CEC method is useful for alcohols that display reasonable
conversion to the 3,5-dinitrobenzoate.
selectivity at room temperature, lowering the temperature to
augment selectivity in normally unselective CEC substrates
should be avoided.
To illustrate how homoallylic−propargylic alcohols 3d and
4−8 might serve as building blocks in chemical synthesis, the
product of anti-crotylation, compound 4, was converted to the
acrylic ester and subjected to ring-closing metathesis to form
the α,β-unsaturated δ-lactone 9 (eq 1).6c Alternatively, removal
of the TIPS-protecting group of compound 4 using TBAF
followed by Sonogashira coupling of the crude terminal alkyne
with 5-bromopyrimidine provides the heteroaryl-substituted
alkyne 10 in good yield over two steps (eq 2).
To conclude, despite decades of study on asymmetric car-
bonyl allylation, only two systematic studies on ynal electrophiles
B
DOI: 10.1021/acs.orglett.8b01776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Analysis of Alcohol Configurations Using the
Competing Enantioselective Conversion (CEC) Method
conversion and selectivity data for the CEC reactions in
Scheme 2 (PDF)
a
Accession Codes
CCDC 1848630 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pilli@iqm.unicamp.br.
*E-mail: srychnov@uci.edu.
*E-mail: mkrische@mail.utexas.edu.
ORCID
a
Franco Della-Felice: 0000-0003-1131-9394
Ronaldo A. Pilli: 0000-0002-5919-7763
Scott D. Rychnovsky: 0000-0002-7223-4389
Michael J. Krische: 0000-0001-8418-9709
Author Contributions
∥G.A.B., F.D.-F., and G.L. contributed equally.
Parallel acylation reactions were run with (R)- or (S)-HBTM cata-
lyst (10 mol %), DIPEA (300 mol %) and propionic anhydride
(300 mol %) at room temperature. The conversions were analyzed by
1H NMR after 15−60 min. With the directing group to the left, faster
reactions with the (R)-HBTM indicate that the alcohol configuration
is forward. See the Supporting Information for more details. 0 °C,
HBTM (26 mol %).
b
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Acknowledgment is made to the Robert A. Welch Foundation
(M.J.K. F-0038), the NIH-NIGMS (M.J.K. RO1-GM069445),
the UT Austin Center for Green Chemistry and Catalysis
(M.J.K.), and the National Science Foundation (S.D.R. CHE
1361998 & 1764380) for partial support of this research.
̀
Fundaca̧ o de Amparo a Pesquisa do Estado de Sao Paulo
̃ ̃
(FAPESP) is acknowledged for postdoctoral fellowship
support (G.B. 2017/00734-5) and research internship scholar-
ship support (F.D.F. 2017/18487-4). The China Scholarship
Council is acknowledged for research internship scholarship
support (G.L. CSC.201707060020).
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01776.
■
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