Enantioselective syn- and anti-Alkoxyallylation of Aldehydes via Br?nsted Acid Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b02653

A diastereo- and enantioselective alkoxyallylation via phosphoric acid catalysis was reported. Under the developed conditions, either 1,2-syn- or 1,2-anti-alkoxyallylation adducts were obtained in good yields with high enantioselectivities.

Full text of DOI:10.1021/acs.orglett.8b02653

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective syn- and anti-Alkoxyallylation of Aldehydes 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: A diastereo- and enantioselective alkoxyallyla-
tion via phosphoric acid catalysis was reported. Under the
developed conditions, either 1,2-syn- or 1,2-anti-alkoxyallyla-
tion adducts were obtained in good yields with high
enantioselectivities.
nantioenriched 1,2-syn- and anti-3-ene-diols are important
building blocks in organic synthesis. In particular, they are
Enantioselective addition of γ-alkoxyallylboron reagents to
imines was recently disclosed by the Hoveyda group.6c In
comparison to the available methods to synthesize 1,2-anti-3-
ene-diols, catalytic asymmetric approaches that allow access to
analogous 1,2-syn-3-ene-diols are underdeveloped. One notable
example is the addition of chiral, nonracemic γ-alkoxy-
substituted allylstannanes to aldehydes developed by Marshall
and co-workers (Scheme 1, eq 3).7 The toxicity and sensitive
nature associated with the organo-tin reagents, however, make
them less desirable in a practical scale. Therefore, development
of nontoxic reagents and practical methods to synthesize
enantioenriched 1,2-syn-3-ene-diols is an important objective
in organic synthesis.
E
key structural motifs in numerous biologically active natural
products (Figure 1).1 Consequently, many efforts have been
In 2010, the Antilla group reported the first chiral phosphoric-
acid-catalyzed enantioselective allylboration to obtain homo-
allylic alcohols with high enantiomeric excess.8 It is well-
established that the reaction of an aldehyde with either (Z)- or
(E)-crotylboronate proceeds through a chair-like transition state
to give either syn- or anti-homoallylic alcohol with high fidelity of
stereochemistry.9 Therefore, it was envisaged that 1,2-syn- and
1,2-anti-3-ene-diols should be accessible with high diastereo-
and enantioselectivities through the reaction of aldehydes with
either a (Z)- or (E)-(γ-alkoxyallyl)boron reagent by proper
selection of a chiral phosphoric acid catalyst. To our surprise,
there is only a single example of chiral phosphoric-acid-catalyzed
addition of (E)-(γ-silyloxyallyl)boronate to benzaldehyde to
give monosilyl-protected 1,2-anti-3-ene-diol with 17% ee.10 To
the best of our knowledge, there is no report for the phosphoric-
acid-catalyzed enantioselective syntheses of 1,2-syn-3-ene-diols
with achiral (γ-alkoxyallyl)boronates. Inspired by the previous
work on chiral phosphoric-acid-catalyzed enantioselective
carbonyl addition reactions,11−13 we report herein asymmetric
γ-alkoxyallylation of aldehydes with (Z)- or (E)-γ-alkoxyallyl-
boronate, 1 or 3, to provide 1,2-syn- or 1,2-anti-alkoxyallylation
Figure 1. Selected natural products containing 1,2-syn and anti-3-ene-
diols.
devoted to diastereo- and enantioselective syntheses of 3-ene-
1,2-diols.2 The addition of enantioselective γ-alkoxyallyl
organometallic reagents to carbonyl compounds is one classic
approach to synthesize these 1,2-diols, although a stoichiometric
amount of chiral auxiliaries is often required for the asymmetric
induction.3,4 Similarly, reactions of carbonyl compounds with
masked enantioselective γ-alkoxy allylmetal reagents, such as γ-
boryl or γ-silyl reagents, also produce chiral 3-ene-1,2-diols upon
oxidation of the resulting adducts.5 Recently, several key
advances have been achieved to access enantioenriched 1,2-
anti-3-ene-diols without resorting to chiral auxiliaries. For
example, Krische and co-workers developed an elegant Ir-
catalyzed allylation strategy for the syntheses of bisbenzoyl-
protected 1,2-anti-3-ene-diols (Scheme 1, eq 1).6a A chirality-
transfer approach was reported by the Ito group using
enantioenriched γ-alkoxyallylboron reagents,6b and monopro-
tected 1,2-anti-3-ene-diols were obtained with excellent
conservation of enantioselectivities (Scheme 1, eq 2).
Received: August 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02653
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a−c
Scheme 1. Approaches for Catalytic, Asymmetric Synthesis of
Scheme 2. Scope of syn-Alkoxyallylation
1,2-syn- or anti-3-Ene-diols
a
Reaction conditions: allylboronate 1 (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.
b
Enantioselectivities were determined by HPLC analysis using a
c
chiral stationary phase. Yields of isolated products are listed.
92−94% ee. Aldehydes with an electron-donating group, an
electron-withdrawing group, or a halogen atom at either the
para- or meta-position are also suitable substrates for the
reaction. Alcohols 2d−i were obtained in 56−94% yields with
92−94% ee. The reaction of allylboronate 1 with heteroaromatic
aldehyde, for example, 3-thiophene carboxaldehyde, proceeded
smoothly to give product 2j in 62% yield with 86% ee.
Significantly, aliphatic aldehyde, such as hydrocinnamic
aldehyde, also reacted to give product 2k in 60% yield with
90% ee. The absolute configuration of the secondary hydroxyl
groups in the products was determined by modified Mosher
ester analysis of 2e.15 In general, aldehydes bearing an electron-
withdrawing group showed a reactivity much higher than that of
aromatic aldehydes substituted with an electron-donating group
in the arene.
products, 2 or 4, in good yields with high enantiomeric excess
(Scheme 1).
We began our studies on asymmetric syn-alkoxyallylation by
examining the reaction between (Z)-(γ-methoxymethoxyallyl)-
boronate 1 and benzaldehyde.14 In the presence of 4 Å
molecular sieves with 5 mol % of phosphoric acid (R)-A as the
catalyst, the reaction of benzaldehyde with (Z)-allylboronate 1
at −45 °C in toluene provided the syn-adduct 2a in 73% yield
with 91% ee as a single diastereomer.
To access 1,2-anti-alkoxyallylation products, we then
examined reactions of various aldehydes with (E)-γ-ethox-
yallylboronate 3.16 As summarized in Scheme 3, the standard
reaction conditions tolerated a broad scope of aldehydes, and
anti-ethoxyallylation products 4 were formed as a single
diastereomer in 74−97% yield with high enantioselectivities.
Benzaldehyde and aromatic aldehydes containing an aryl, an
electron-donating group, or an electron-withdrawing group at
the para-position reacted with (E)-allylboronate 3 to give
products 4a−f in excellent yields with 94−97% ee. Reactions
with para-halogen-substituted aromatic aldehydes afforded
alcohols 4g−i in 93−97% yields with 96−97% ee. These
halogen-containing adducts provide a platform for further
elaborations (e.g., cross-coupling reactions). Similar results were
The reaction without the addition of 4 Å molecular sieves gave
product 2a with much lower enantioselectivity. In addition, it is
crucial to conduct the reaction at temperatures below −40 °C to
obtain homoallylic alcohol 2a with high enantioselectivity.
Product 2a was formed with low enantiomeric excess when the
reaction was performed at ambient temperature.
We next explored the scope of aldehydes that underwent the
syn-alkoxyallylation reaction with allylboronate 1 (Scheme 2).
Under the standard reaction conditions, a variety of aldehydes
with diverse electronic properties participated in the reaction to
give syn-products 2 in good yields with high enantioselectivities.
Aromatic aldehydes with an alkyl or aryl group at the para-
position reacted to give products 2b,c in 70−86% yields with
B
DOI: 10.1021/acs.orglett.8b02653
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a−c
allylic boronate 3 with an enantioenriched aldehyde was
conducted. The anti,anti-stereoisomer 4u was obtained in 89%
yield with a synthetically useful diastereoselectivity (8:1). We
also prepared (E)-γ-benzyloxyallylboronate 5, and the reaction
of 5 with benzaldehyde under the standard conditions gave
product 6 in 89% yield with 95% ee (Scheme 4).
Scheme 3. Scope of anti-Alkoxyallylation
Scheme 4. Transformation of the Reaction Products
a
Reaction conditions: allylboronate 3 (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.
b
Enantioselectivities were determined by HPLC analysis using a
c
d
chiral stationary phase. Yields of isolated products are listed. The ee
was determined by modified Mosher ester analysis.15
To demonstrate the synthetic utility of this method, further
derivatization of the syn- or anti-alkoxyallylation products was
conducted. As shown in Scheme 4, hydroboration of TBS ether
7 followed by oxidative workup gave alcohol 8 in 91% yield.
Cross-metathesis18 of 7 with (Z)-2-butene-1,4-diol in the
presence of 10 mol % of Grubbs second generation catalyst
and subsequent TBS deprotection with TBAF gave diol 9 in 64%
yield in two steps.
The syn-alkoxyallylation adduct ent-2a was used as the starting
material for the synthesis of the C1−7 fragment of natural
product, aetheramide A (Scheme 4).19 First, the methoxymethyl
ether (MOM group) of ent-2a was deprotected under acidic
conditions to give diol 10. In the presence of 10 mol % of
Hoveyda-Grubbs second generation catalyst, cross-metathesis18
of 10 with acrolein generated aldehyde 11. Horner−Wads-
obtained with aromatic aldehydes with various substitutions at
the meta- or ortho-position to furnish products 4j−m in 74−93%
yield with 93−97% ee. Reactions with 2-naphthaldehyde and
piperonal occurred to provide alcohols 4n,o in 76−91% yields
with 96% ee. α,β-Unsaturated aldehydes and heteroaromatic
aldehydes were also tolerated under the reaction conditions to
generate alcohol products 4p−s in 80−93% yields with 94−97%
ee. The reaction of hydrocinnamic aldehyde with allylboronate 3
gave product 4t in 89% yield with 87% ee. The absolute
configuration of the secondary hydroxyl groups in the products
was determined by modified Mosher ester analysis15 of 4a, 4m,
and 4r. Additionally, double stereodifferentiation reaction17 of
C
DOI: 10.1021/acs.orglett.8b02653
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In summary, we developed a chiral phosphoric-acid-catalyzed
syn- and anti-alkoxyallylation of aldehydes. The syn- and anti-3-
ene-1,2-diol derivatives are useful building blocks in organic
synthesis as illustrated in the synthesis of the C1−7 fragment of
aetheramide A. Other synthetic applications of this method are
currently ongoing.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02653.
́
́
Gonzalez-Gomez, J. C.; Foubelo, F. Chem. Rev. 2011, 111, 7774.
(10) Miura, T.; Nishida, Y.; Morimoto, M.; Murakami, M. J. Am.
Chem. Soc. 2013, 135, 11497.
1H and 13C NMR spectra for all new compounds (PDF)
(11) For selected examples, see: (a) Xing, C.-H.; Liao, Y.-X.; Zhang,
Y.; Sabarova, D.; Bassous, M.; Hu, Q.-S. Eur. J. Org. Chem. 2012, 2012,
1115. (b) Incerti-Pradillos, C. A.; Kabeshov, M. A.; Malkov, A. V.
Angew. Chem., Int. Ed. 2013, 52, 5338. (c) Huang, Y.; Yang, X.; Lv, Z.;
Cai, C.; Kai, C.; Pei, Y.; Feng, Y. Angew. Chem., Int. Ed. 2015, 54, 7299.
(d) Barrio, P.; Rodríguez, E.; Saito, K.; Fustero, S.; Akiyama, T. Chem.
Commun. 2015, 51, 5246. (e) Clot-Almenara, L.; Rodríguez-Escrich,
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mzc0102@auburn.edu.
ORCID
Ming Chen: 0000-0002-9841-8274
Notes
̀
C.; Osorio-Planes, L.; Pericas, M. A. ACS Catal. 2016, 6, 7647.
(f) Miura, T.; Nakahashi, J.; Murakami, M. Angew. Chem., Int. Ed. 2017,
56, 6989. (g) Miura, T.; Nakahashi, J.; Zhou, W.; Shiratori, Y.; Stewart,
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(12) For computational studies, see: (a) Grayson, M. N.; Pellegrinet,
S. C.; Goodman, J. M. J. Am. Chem. Soc. 2012, 134, 2716. (b) Wang, H.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support provided by Auburn University is gratefully
acknowledged. We thank AllylChem for a generous gift of
B2Pin2.
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