Enantioselective syntheses of 1,4-pentadien-3-yl carbinols via br?nsted acid catalysis

Article abstract of DOI:10.1021/acs.orglett.9b04089

An asymmetric addition of substituted 1,3-pentadienylboronates to aldehydes via Br?nsted acid catalysis is reported. Under the developed conditions, a variety of synthetically useful 1,4-pentadien-3-yl carbinols were obtained in good yields with high enan

Full text of DOI:10.1021/acs.orglett.9b04089

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Syntheses of 1,4-Pentadien-3-yl Carbinols via
Brønsted Acid Catalysis
Shang Gao and Ming Chen*
Department of Chemistry and Biochemistry, Auburn University, Auburn, Alabama 36849, United States
S
* Supporting Information
ABSTRACT: An asymmetric addition of substituted 1,3-pentadienylboronates to aldehydes via Brønsted acid catalysis is
reported. Under the developed conditions, a variety of synthetically useful 1,4-pentadien-3-yl carbinols were obtained in good
yields with high enantioselectivities in the presence of a catalytic amount of a chiral phosphoric acid.
nantioenriched 1,4-pentadien-3-yl carbinols (e.g., A and 2
in Scheme 1) are important building blocks in organic
conjugated trienes, which readily participate in sequential
Diels−Alder reactions to generate polycyclic structures.2
Several methods are available for the syntheses of racemic
1,4-pentadien-3-yl carbinols (2).3 Shibasaki reported a
pentadienylchromium complex-mediated coupling of penta-
dienyl esters with carbonyl compounds to give racemic 1,4-
pentadien-3-yl carbinols 2 with high γ-selectivity.3a Nishigaichi
developed a ZnCl2-promoted γ-selective addition of 1,3-
pentadienyl stannanes to aldehydes to generate racemic
carbinols 2.3b The Araki and Fallis groups showed that
racemic carbinols 2 can also be synthesized via regioselective
aldehyde allylation with pentadienyl indium reagents generated
from bromo-pentadienes and indium metal.2a,3c A Ti-mediated
carbonyl addition with pentadienyl titanium reagents was
disclosed by the Sato and Schlosser groups independently.3d,e
By contrast, very few methods are known to produce
enantioenriched 1,4-pentadien-3-yl carbinols 2, in particular
the catalytic asymmetric variants. Yamamoto and co-workers
reported a BINAP·Ag(I) complex-catalyzed asymmetric γ-
selective addition to aldehydes with pentadienyl stannanes,4
and carbinols 2 were obtained with moderate to high
enantioselectivities (58−90% ee). However, the toxicity of
organotin reagents poses a severe limit on their synthetic
utilities on a practical scale. Therefore, the development of
nontoxic reagents and practical methods to synthesize
enantioenriched 1,4-pentadien-3-yl carbinols is highly desirable
in chemical synthesis.
E
Scheme 1. Proposed Approach to Enantioenriched 1,4-
Pentadien-3-yl Carbinols 2
synthesis.1−4 They are valuable intermediates not only in
natural product synthesis1 but also in the preparation of small-
molecule probes for biological evaluations.2 For instance,
compound A, which contains a 1,4-pentadien-3-yl carbinol
moiety, underwent a highly diastereoselective intramolecular
Pauson−Khand reaction to give ketone B (Scheme 1a).1a
Ketone B was a key intermediate in the total synthesis of
natural product penostatin B.1a Additionally, 1,4-pentadien-3-
yl carbinols can serve as precursors to generate cross-
In connection with an ongoing synthesis project, we became
interested in developing catalytic asymmetric methods to
generate enantioenriched 1,4-pentadien-3-yl carbinols.5 We
Received: November 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04089
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
envisioned that these structural entities should be readily
available from the addition of 1,3-pentadienylboronate [e.g., 1a
(Scheme 1b)] to aldehydes. Given the well-established
Zimmerman−Traxler transition states in allylboration chem-
istry,6 such additions should be highly γ-selective to generate
1,4-pentadien-3-yl carbinols. An external chiral catalyst should
be able to control the absolute configuration of the secondary
alcohol group. Inspired by prior work on chiral phosphoric
acid-catalyzed asymmetric carbonyl addition with unsaturated
organoboron compounds,7−10 we report herein our studies of
enantioselective syntheses of 1,4-pentadien-3-yl carbinols via
chiral phosphoric acid-catalyzed asymmetric allylboration.
Scheme 2 shows the prepared 1,3-pentadienylboronate
reagents with different substitution patterns. Reagent 1b was
Scheme 3. Scope of Aldehydes for Asymmetric Allylation
with 1,3-Pentadienylboronate 1a
a−c
Scheme 2. Synthesized 1,3-Pentadienylboronate Reagents
a
synthesized by adopting the reported literature methods.11
Reagents 1a, 1c, and 1d were obtained via a Matteson
homologation approach12 from the corresponding 1,3-dienyl
boronates (see the Supporting Information for details).13,14
With several 1,3-pentadienylboronate reagents in hand,
subsequent chiral phosphoric acid-catalyzed allyl addition to
aldehydes was conducted. In initial experiments, treatment of
benzaldehyde (1 equiv) with 1,3-pentadienylboronate 1a (1.3
equiv) in the presence of 5 mol % phosphoric acid (R)-A
(Scheme 1) and 4 Å molecular sieves at −45 °C in toluene for
48 h provided 1,4-pentadien-3-yl carbinol 2a in 75% yield with
97% ee.
Reaction conditions: allyl boronate 1a (0.13 mmol, 1.3 equiv),
aldehyde (0.1 mmol, 1.0 equiv), phosphoric acid (R)-A (5 mol %), 4
Å molecular sieves (50 mg), toluene (0.3 mL), −45 °C, 48 h.
b
Enantioselectivities were determined by HPLC analysis using a chiral
c
stationary phase. Yields of the isolated product.
in 92−96% yields with 93−98% ee. Finally, reaction of 1a with
an aliphatic aldehyde substrate, hydrocinnamaldehyde, also
worked well to produce 2m in 88% yield with 91% ee. The
absolute configuration of the secondary hydroxyl group in
alcohols 2 was determined by modified Mosher ester
analyses.15
Reactions of reagent 1b with a variety of aldehydes were
conducted under the standard reaction conditions, and the
results are summarized in Scheme 4. Reagent 1b readily added
to aromatic aldehydes in the presence of 5 mol % phosphoric
acid (R)-A at −45 °C to form products 3a−i in 84−97% yields
with 93−99% ee. α,β-Unsaturated aldehydes and heterocycle-
containing aldehydes were suitable substrates for asymmetric
allylation with 1b, and secondary alcohols 3j−l were isolated in
71−96% yields with 95−99% ee. Hydrocinnamaldehyde also
reacted with 1b to afford carbinol 3m in 84% yield with 94% ee
(Scheme 4).
The results of aldehyde allylation with reagent 1c in the
presence of 5 mol % phosphoric acid (R)-A are summarized in
Scheme 5. Reactions of 1c with various aldehydes, including
aromatic, α,β-unsaturated, heteroaromatic, and aliphatic
aldehydes, occurred to deliver carbinol products 4a−m in
84−97% yields with 92−99% ee and >20:1 dr (Scheme 5).16
Asymmetric allylboration of aldehydes with reagent 1d was
also conducted. As summarized in Scheme 6, the reactions
worked well with several representative aldehydes under
We next explored the scope of aldehyde that underwent
asymmetric allyl addition with 1,3-pentadienylboronate 1a, and
the results are summarized in Scheme 3. Under the developed
reaction conditions, a variety of aldehydes with diverse
electronic properties participated in reactions with 1a to give
alcohols 2 in good yields with high enantioselectivities.
Aromatic aldehydes with an electron-donating group at the
para position reacted with 1a to deliver products 2b and 2c in
93−98% yields with 99% ee. Reactions of aromatic aldehydes
with an electron-withdrawing group at the para position
proceeded smoothly to give carbinol products 2d−f in 92−
96% yields with 94−95% ee. Halogen-substituted aldehydes
also reacted with boronate 1a to afford products 2g−i in 90−
96% yields with 91−95% ee. α,β-Unsaturated aldehydes and
aldehydes containing a heterocycle were tolerated under the
reaction conditions, and carbinol products 2j−l were generated
B
DOI: 10.1021/acs.orglett.9b04089
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Letter
Scheme 4. Scope of Aldehydes for Asymmetric Allylation
with 1,3-Pentadienylboronate 1b
Scheme 5. Scope of Aldehydes for Asymmetric Allylation
with 1,3-Pentadienylboronate 1c
a−
c
a−c
a
Reaction conditions: allyl boronate 1b (0.13 mmol, 1.3 equiv),
aldehyde (0.1 mmol, 1.0 equiv), phosphoric acid (R)-A (5 mol %), 4
Å molecular sieves (50 mg), toluene (0.3 mL), −45 °C, 48 h.
b
a
Enantioselectivities were determined by HPLC analysis using a chiral
Reaction conditions: allyl boronate 1c (0.13 mmol, 1.3 equiv),
aldehyde (0.1 mmol, 1.0 equiv), phosphoric acid (R)-A (5 mol %), 4
Å molecular sieves (50 mg), toluene (0.3 mL), −45 °C, 48 h.
c
stationary phase. Yields of isolated product.
b
Enantioselectivities were determined by HPLC analysis using a chiral
standard reaction conditions, and carbinols 5a−f bearing two
different alkene groups were obtained in 77−95% yields with
93−99% ee and excellent diastereoselectivities (Scheme 6).
Again, the absolute configuration of the secondary hydroxyl
group in alcohols 3−5 was determined by modified Mosher
ester analyses.15
c
stationary phase. Yields of isolated product.
Scheme 6. Scope of Aldehydes for Asymmetric Allylation
with 1,3-Pentadienylboronate 1d
a−c
The 1,4-pentadien-3-yl carbinol products 4 and 5 obtained
from allylboron reagents 1c and 1d contain two different
alkene units, which underwent several transformations with
excellent chemoselectivity. As depicted in Scheme 7, hydro-
boration of 6 with (dIpc)2BH occurred at the monosubstituted
alkene unit. Oxidation of the borane intermediate followed by
deprotection of the TES group with TBAF gave diol 7 in 56%
yield. Ir-catalyzed hydroboration of 8 with HBpin also
occurred at the terminal alkene unit to produce boronate 9
in 72% yield.17 By contrast, the more electron-rich, internal
alkene group of alcohol 4e participated in an iodoetherification
reaction to form tetrahydrofuran derivative 10a in 61% yield
with 3:1 diastereoselectivity (see the Supporting Information
for the assignment of the relative configuration of 10 with
NOE studies). Pt-catalyzed asymmetric alkene diboration of 6
occurred at the monosubstituted alkene group to furnish
diboronate 11 in 76% yield with excellent diastereoselectiv-
ity.18 A detectable amount of product generated from
diboration of the 1,1-substituted alkene group in 6 was not
formed.
a
Reaction conditions: allyl boronate 1d (0.13 mmol, 1.3 equiv),
aldehyde (0.1 mmol, 1.0 equiv), phosphoric acid (R)-A (5 mol %), 4
Å molecular sieves (50 mg), toluene (0.3 mL), −45 °C, 48 h.
b
Enantioselectivities were determined by HPLC analysis using a chiral
c
stationary phase. Yields of isolated product.
C
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Letter
ligand PCy3, the Pt-catalyzed diboration generated a mixture of
four diastereomers with low selectivity. Therefore, the
asymmetric alkene diborations with Pt(dba)3/L as the catalyst
system are completely catalyst-controlled reactions. The
absolute configuration of the secondary alcohol in 12 did
not impact the stereochemical outcomes of asymmetric
diboration. The relative configuration of 13 and 15 was
Scheme 7. Transformation of Reaction Products
1
assigned by NOE, H NMR, and 13C NMR studies of the
corresponding acetonide derivatives 14 and 16 (see the
Supporting Information for the details of structural assign-
ment).19 It is worth noting that the asymmetric diboration
reaction not only sets one stereogenic center at the terminal
alkene group but also generates a stereocenter α to the alkene
group (highlighted in 13 and 15).
In summary, asymmetric syntheses of a variety of 1,4-
pentadien-3-yl carbinols via Brønsted acid catalysis were
developed. In the presence of a catalytic amount of phosphoric
acid (R)-A, allylboration of a broad range of aldehydes with
reagents 1 bearing different substitution patterns occurred to
give various 1,4-pentadien-3-yl carbinols in good yields with
high enantioselectivities. Subsequent alkene functionalization
of the TES ethers of 1,4-pentadien-3-yl carbinols 2 proceeded
with high diastereoselectivities. Functionalization of the
derivatives of carbinols 4 and 5 occurred with excellent
chemoselectivities to generate synthetically useful intermedi-
ates. Synthetic application of this method is currently ongoing.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04089.
Experimental procedures and spectra for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mzc0102@auburn.edu.
ORCID
Shang Gao: 0000-0001-8166-5503
Ming Chen: 0000-0002-9841-8274
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support provided by Auburn University is gratefully
acknowledged.
■
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E
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