Asymmetric Traceless Petasis Borono-Mannich Reactions of Enals: Reductive Transposition of Allylic Diazenes

Article abstract of DOI:10.1002/anie.201708784

The traceless Petasis borono-Mannich reaction of enals, sulfonylhydrazines, and allylboronates, catalyzed by chiral biphenols, results in an asymmetric reductive transposition of the in situ generated allylic diazene. Acyclic 1,4-diene products bearing either alkyl- or aryl-substituted benzylic stereocenters are afforded in excellent yields and enantiomeric ratios of up to 99:1. The use of crotylboronates in the reaction results in concomitant formation of two stereocenters in either a 1,4-syn or anti relationship from the corresponding E- or Z-crotylboronate used in the reaction. The use of β-monosubstituted enals in the asymmetric traceless Petasis borono-Mannich reaction of crotylboronates installs tertiary methyl-bearing stereocenters in good yields and high enantioselectivities.

Full text of DOI:10.1002/anie.201708784

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Accepted Article
Title: Asymmetric Traceless Petasis Borono-Mannich Reactions of
Enals: Reductive Transpositions of Allylic Diazenes
Authors: Scott E. Schaus, Yao Jiang, and Regan J Thomson
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10.1002/anie.201708784
Angewandte Chemie International Edition
COMMUNICATION
Asymmetric Traceless Petasis Borono-Mannich Reactions of
Enals: Reductive Transpositions of Allylic Diazenes
Yao Jiang,[a] Regan J. Thomson*[b] and Scott E. Schaus*[a]
Abstract: The traceless Petasis borono-Mannich reaction of enals,
X
sulfonylhydrazines, and allylboronates catalyzed by chiral biphenols
results in an asymmetric reductive transposition of the in situ
generated allylic diazene. Acyclic 1,4-diene products bearing alkyl-
or aryl- substituted benzylic stereocenters are afforded in excellent
yields and enantiomeric ratios up to 99:1. The use of crotylboronates
in the reaction results in concomitant formation of two stereocenters
in a 1,4-syn or anti relationship from the corresponding E- or Z-
crotylboronate used in the reaction. The use of beta mono-
substituted enals in the asymmetric traceless Petasis borono-
Mannich reaction of crotylboronates installs tertiary methyl-bearing
stereocenters in good yields and high enantioselectivities.
OH
OH
1a, X = Ph
1b, X = Br
H
N
O
Ar
S
N
H
O
X
H
H
catalyst
O
B
R2
R1
R2
+
O
R3
O
3 R4
R1
R
H
R4
allylic diazene
rearrangement
- H2O
- N2
Ar
N
O
S
N
O
H
R1
R4
N
R2
H
H
- ArSO2H
R2
N
H
The retro-ene[1] rearrangement of diazenes proceeds with the
loss of dinitrogen via a concerted pericyclic reaction pathway.[2]
The stereospecific nature of the transformation results in the
efficient transfer of chirality in a 1,3-atom transfer process.[3] We
reported the catalytic enantioselective traceless Petasis reaction,
R1
R3
R3 R4
Scheme 1. Asymmetric traceless Petasis borono-Mannich reactions of enals
resulting in the reductive transpositions of allylic diazenes. The reaction
generates 1,4-dienes bearing tertiary carbon stereocenters with high levels of
enantioselectivity.
a
reaction that uses 1,3-chirality transfer from an
enantioenriched propargylic diazene to generate an axially chiral
allene.[4] Herein we describe the reaction of allylic diazenes to
give rise to products bearing tertiary alkyl stereocenters,[5]
following the allylic diazene rearrangement. The intermediate
diazene is formed in situ by fragmentation of the corresponding
reduction controlled by cyclic substrates,[8d-j] and Diels–Alder
cycloadditions of 1-hydrazino dienes.[8k, 8l] While these advances
are significant, an enantioselective catalytic reaction that
provides access to acyclic allylic diazenes has been elusive.
Only two methods describing the asymmetric synthesis of
tertiary stereocenters via acyclic allylic diazenes exist. First,
allylic sulfonylhydrazide, synthesized by
catalyzed Petasis borono-Mannich
a
chiral biphenol-
reaction of
sulfonylhydrazides, enals, and allylboronates (Scheme 1).[6][7]
Subsequent rearrangement of the enantioenriched diazene, with
concomitant extrusion of molecular nitrogen, results in the allylic
transposition of chirality from the diazene stereocenter to the
allylic, sp2 hybridized carbon center. When a γ-substituted
allylboronate (R3 or R4 = methyl) is employed, two tertiary
McIntosh and co-workers developed
a diastereoselective
reduction of an acyclic tosylhydrazone facilitated by a proximal
α-alkoxy stereocenter, resulting in a methyl-substituted tertiary
stereocenter.[9] Second, Movassaghi and co-workers reported a
palladium-catalyzed conversion of enantioenriched allylic
epoxides to diazenes, which afforded methyl-substituted tertiary
stereocenters adjacent to secondary alcohols.[10] Despite the
efficient acyclic stereocontrol achieved by these methods, the
formation of the enantioenriched allylic diazenes prior to the
chirality transfer relied on the use of optically active starting
materials containing oxygenated stereocenters. In order to
access the desired chiral secondary hydrazine, we designed an
approach that would directly generate acyclic allylic diazenes
from achiral substrates using a BINOL-catalyzed traceless
Petasis reaction.
stereocenters in
a
1,4-relationship are generated in
a
stereoselective manner.
Strategies employing 1,3-chirality transfer by the allylic
diazene rearrangement have been elegantly utilized in
asymmetric synthesis, notably for the installation of
stereocenters within cyclic systems.[8] For this approach,
methods to access the requisite sulfonyl hydrazine precursor
include trapping of carbonium ions[8a], displacement of terminal
alcohols[8b, 8c] by sulfonylhydrazides, asymmetric hydride
We began by investigating the asymmetric Petasis allylation
with β-methyl enals using chiral biphenols catalysts. The 3,3’-
Ph2-BINOL catalyst 1a proved ideal for enantiomeric control,
consistent with our previous observations in the asymmetric
allylation of imines (Scheme 2).[6a, 6e] In addition, the electron-
deficient hydrazide 2a was identified as optimal for producing
the highest yields of the desired rearranged products 5. The
multicomponent reaction proceeded with initial generation of the
hydrazone by condensation of enals 3 with hydrazide 2a in the
presence of 3 Å molecular sieves. After removal of the solvent in
vacuo, the unpurified hydrazone was dissolved in toluene and to
[a]
[b]
Y. Jiang, Prof. Dr. S. E. Schaus
Department of Chemistry, Center for Molecular Discovery
Boston University
24 Cummington Mall, Boston, Massachusetts, 02215, United States
E-mail: seschaus@bu.edu
Prof. Dr. R. J. Thomson
Department of Chemistry
Northwestern University
2145 Sheridan Road, Evanston, Illinois, 60208, United States
E-mail: r-thomson@northwestern.edu
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201708784
Angewandte Chemie International Edition
COMMUNICATION
F3C
1) CH2Cl2, 3 Å M.S.
1) CH2Cl2, 3 Å M.S.
R2
r.t., 2 h
R2
R2
H
N
R2
H
N
r.t., 2 h
O
O
O
O
+
+
S
S
R1
2) PhCH3, r.t., 48 h
t-BuOH (3 equiv)
R1
H
2) PhCH3, r.t., 48 h
t-BuOH (3 equiv)
R1
R1
N
H
N
H
H
O
O
O2N
O2N
H
5
7
H
6
3
7 mol%
(R)-Br2-BINOL 1b
2b
2a
7 mol%
(R)-Ph2-BINOL 1a
O
O
B
B
O
O
4
4
H3C
Ph
Ph
CH3
CH3
CH3
H3C
H3CO
C11H23
CH3
7a
7b
97% y, 96:4 er
7c
F
75% y, 96:4 er
82% y, 98:2 er
5a
5b
5c
83% y, 98:2 er
75% y, 97:3 er
89% y, 97:3 er
7c[b]
60% y, 94:6 er
from
Br CH3
CH3
F
CH3
Ph
F3C
H3C
CH3
(E)-8
Ph
S
7d[c]
7e[c]
5e[b]
5d
5f
Ph
O
85% y, 97:3 er
77% y, 93:7 er
60% y, 96:4 er
85% y, 95:5 er
&
73% y, 99:1 er
(S)-Br2-BINOL
CH3
CH3
CH3
Ph
Ph
Ph
Si CH3
F3C
H3C
H3C
5h
80% y, 85:15 er
5g[c]
H3CO
Br
CF3
88% y, 97:3 er
7g
7f
7h
86% y, 98:2 er
87% y, 98:2 er
87% y, 98:2 er
Scheme 2. Enantioselective reductive allylation of β-methyl enals.[a] [a] All
reactions were run on 0.4 mmol scale. Yields of isolated products are given.
The e.r. values were determined by HPLC analysis using chiral stationary
phases. [b] Reaction was run at 1 M concentration. [c] 5 equivalents of t-BuOH
were used in the absence of toluene. The (Z)-silyl enal 3g was used in the
reaction. See Supplementary Information for experimental details and
stereochemical proof.
F
Ph
Ph
OCH3
7j
7i
H3CO
7k
99% y, 98:2 er
87% y, 95:5 er
85% y, 98:2 er
this mixture was added t-BuOH (3 equivalents), catalyst (R)-1a
(7 mol%) and allyl boronate 4 at room temperature.The reaction
generated the corresponding enantioenriched 1,4-dienes 5 after
stirring at room temperature for 48 hours. The reaction tolerated
β-aryl-β-methyl enal substrates, furnishing allylated products
bearing benzylic stereocenters in good yields and with excellent
enantioselectivities (Scheme 2, 5a-5e). The observed absolute
stereochemistry was consistent with the previously reported
biphenol-catalyzed borono-Mannich allylation reaction (see
Scheme 3. Enantioselective reductive allylation of β,β-disubstituted enals.[a]
[a] All reactions were run at 0.4 mmol scale. Yields of isolated products are
given. The e.r. values were determined by HPLC analysis using chiral
stationary phases. [b] (S)-Br2-BINOL (ent-1b) and enal (E)-8 were used. [c] 5
equivalents of t-BuOH was employed in the absence of toluene. See
Supplementary Information for experimental details.
and with reduced enantioselectivity (41% yield, 82:18 e.r.). The
nature of the sulfonylhydrazide and the biphenol catalyst proved
crucial to the reactivity and selectivity of the traceless Petasis
Supporting
Information
for
absolute
stereochemical
allylation. In
a two-dimensional evaluation of arylsulfonyl
[6e]
determination).
3-(Thiophen-2-yl)but-2-enal (3f) was also a
hydrazides and catalysts (see Supplementary Information for
details), 2-NO2-benzenesulfonyl hydrazide 2b and 3,3’-Br2-
BINOL catalyst 1b proved to be optimal for β,β-disubstituted
enals with substituents larger than a methyl group (Scheme 3).
Under these conditions, the corresponding products were
thereby accessed with excellent enantioselectivity (Scheme 3,
7a-7c). The allylation product 7d containing a stereogenic
benzylic CF3 group was formed in good yield and with high
selectivity (85% yield, 97:3 e.r.), an approach complementary to
existing strategies.[13] The monofluoromethyl-substituted product
7e was also produced in good yield and with high enantiopurity.
Under these reaction conditions, the olefin geometry of the enals
determined the stereochemical outcome. Thus, the reaction of
the Z-enal catalyzed by (R)-Br2-BINOL (1b) afforded the (S)-
product 7c in 82% yield and with a 98:2 enantiomeric ratio, while
the same product [i.e., (S)-7c] was obtained by using (E)-enal 8
with the enantiomeric catalyst (S)-1b, albeit in lower yield and
with slightly diminished enantiomeric purity (60% yield, 94:6 e.r.).
suitable substrate, affording the product 5f in 73% isolated yield
and an enantiomeric ratio (e.r.) of 99:1. (Z)-β-Silyl-β-methyl enal
3g yielded the corresponding chiral silane 5g in high
enantiomeric purity with the use of 5 equivalents of t-BuOH in
the absence of toluene. The addition of t-BuOH as an additive
was found to accelerate the catalytic pathway while impeding
the
uncatalyzed
reaction,
consistent
with
previous
observations.[11] Geranial (3h), a β-alkyl-β-methyl enal, proved to
be a challenging substrate, affording product 5h with modest
enantioselectivity (85:15 e.r.). The lack of enantioselectivity
observed was due to facile E/Z isomerization of the
corresponding hydrazone intermediate, as either hydrazone
isomer would give rise to opposite enantiomers.[12]
We sought to expand the scope of the reaction by placing
other functional groups at the β-position of the enal (Scheme 3).
Under the same conditions used for β-methyl enals, however, β-
ethyl enal 6a afforded the corresponding product in lower yield
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10.1002/anie.201708784
Angewandte Chemie International Edition
COMMUNICATION
F3C
1) CH2Cl2, 3 Å M.S.
O
B
H
N
r.t., 2 h
O
O
H3C
R2
O
+
R2
O
R
S
9
N
H
R
H
2) PhCH3, r.t., 48 h
t-BuOH (3 equiv)
1) CH2Cl2
O
R1
CH3
O2N
R1
3 Å M.S.
r.t., 2h
H
H
13
14
2) PhCH3, 40 °C, 48 h
t-BuOH (3 equiv)
7 mol% (S)-Br2-BINOL
(ent-1b)
CH3
CH3
11
12
2a
7 mol%
(R)-Ph2-BINOL 1a
+
F3C
R2
H
N
O
O
S
R1
N
H
O
H3C
B
O
O2N
O
H
B
2a
9
O
CH3
10
CH3
CH3
CH3
CH3
14b[b]
65% y, 97:3 er
CH3
H3CO
F
14a
14c[b]
CH3
85% y, 97:3 er
81% y, 98:2 er
CH3
11a
12a
O
59% y, 98:2 er, 16:1 dr
54% y, >99:1 er, 9:1 dr
CH3
CH3
CH3
F
F
OCH3
NO2
14d[b]
79% y, 98:2 er
14f
14e
81% y, 99:1 er
73% y, 99:1 er
CH3
CH3
14g[c]
54% y, 98:2 er
14h[d]
53% y, 99:1 er
CH3
CH3
H3CO
H3CO
11b[b]
12b[b]
62% y, 98:2 er, 15:1 dr
81% y, 98:2 er, 9:1 dr
Scheme 5. Enantioselective reductive crotylation of non-branched enals.[a] [a]
All reactions were run on 0.4 mmol scale. Yields of isolated products are given.
The e.r. values were determined by HPLC analysis using chiral stationary
phases. [b] Reactions were run at 50 oC for 24 h. [c] 14 mol% of catalyst was
Scheme 4. Diastereoselective reductive crotylations of β,β-disubstituted
enals.[a] [a] All reactions were run on 0.4 mmol scale. Yields of isolated
products are given. The values of e.r. and diastereomeric ratio (d.r.) were
determined by HPLC analysis using chiral stationary phases. [b] 10 mol%
catalyst was employed. See Supplementary Information for experimental
details.
employed. [d] 14 mol
% of (R)-1b was employed. See Supplementary
Information for experimental details and stereochemical proofs.
crotylboronate was presumably due to an unfavorable 1,3-diaxial
interaction between the terminal methyl group from the boronate
and the arylsulfonyl group on the nitrogen arising from a cyclic
transition state.[16] Notably, this method achieved high levels of
stereocontrol in acyclic hydrocarbons bearing 1,4-stereocenters
without using any directing functional groups. The results
compare favorably with existing methods to directly access
Tertiary diarylmethane stereocenters are a moiety that
appears in natural products and pharmaceuticals.[14] While there
have been recent notable advances in accessing these
structures enantioselectively,[15] we envisaged that use of the
traceless Petasis reaction would provide access to
diarylmethane tertiary stereocenters through a complementary
strategy. β,β-Diaryl enals proved to be good substrates for the
optimized reductive allylation conditions. The corresponding 1,4-
dienes bearing diaryl-substituted tertiary stereocenters were
obtained with excellent yields and enantioselectivities,
irrespective of the steric or electronic properties of the aryl
substituents (Scheme 3, 7f-7k).
tertiary alkyl stereocenters in
asymmetric
cycloadditions.[8l,
a
1,4-relationship using
17]
The
observed
diastereoselectivity was consistent with the previously reported
biphenol-catalyzed borono-Mannich allylation reaction.[6e]
The methyl-substituted stereocenters generated in the
crotylation reaction (Scheme 4) encouraged us to further explore
the possibility of introducing branched methyl groups in 1,4-
dienes. We investigated this strategy by subjecting
cinnamaldehyde 13a to the crotylboration conditions using
hydrazide 2a, 3,3’-Ph2-BINOL catalyst 1a, and (E)-
crotylboronate 9 (Scheme 5). The desired methyl-branched
hydrocarbon product 14a was isolated in 85% yield with a 97:3
enantiomeric ratio. Other cinnamaldehyde derivatives were
successfully converted to the corresponding enantioenriched
1,4-dienes with excellent selectivities (Scheme 5, 14b-14e).
Enantioenriched 1,4,7-triene (14g) was also obtained under
similar conditions albeit in moderate yield (54% yield, 98:2 e.r.).
Similarly, β-alkyl enal 13h displayed attenuated reactivity,
affording the diene product 14h in modest yield but with
excellent enantioselectivity when using 1b as the catalyst (54%
yield, 99:1 e.r.). Given the operational ease of the reaction and
the generally high level of selectivities, we anticipate that this
methodology will find useful applications in the total synthesis of
We have previously disclosed that both syn and anti α-
methyl amines were accessible by an asymmetric Petasis
borono-Mannich crotylation of aldehydes and amines.[6e] To
investigate related reactivity in the reductive allylation, β-methyl
cinnamaldehyde 3a was subjected to the crotylation conditions
using either (E)-crotylboronate
9 or (Z)-crotylboronate 10
(Scheme 4). The Petasis products were postulated to provide
access to both syn and anti α-methyl diazene intermediates after
the elimination of sulfinic acid. As anticipated, the reaction
afforded diene products bearing two methyl-substituted tertiary
stereogenic centers with a 1,4-syn or anti stereochemistry
(Scheme 4, 11a and 12a). β,β-Diaryl enal 6k also proved to be a
viable substrate, providing access to both 1,4-disubstituted
acyclic products 11b and 12b with good selectivity. The
observed sense of enantio- and diastereoselectivity was
consistent with the stereochemical outcome from the previously
reported asymmetric Petasis crotylations.[6e] The lower
diastereoselectivity for 12a and 12b resulting from (Z)-
the
natural
products
bearing
the
methyl-substituted
stereocenters.[18]
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10.1002/anie.201708784
Angewandte Chemie International Edition
COMMUNICATION
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In summary, we have developed an asymmetric reductive
allylation of aldehydes that affords tertiary alkyl stereocenters
using chiral biphenol catalysts. The reaction proceeds via the
sigmatropic rearrangement of a transient enantioenriched allylic
diazene intermediate; a process mechanistically distinct from the
reductive coupling of boronic acids with tosylhydrazones via
diazo intermediates.[19] Both allylation and crotylation reactions
provide access to 1,4-dienes bearing tertiary alkyl-substituted
stereocenters in excellent yields and high enantioselectivities.
Key aspects of the methodology include the exclusive
generation of (E)-alkenes by allylic transposition, and the
traceless installation of two stereocenters within acyclic systems.
Further exploration of the observed reactivity within the context
of asymmetric catalysis is underway and will be reported in due
course.
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The research was supported by the National Institutes of Health
(R01 GM078240 to SES) and the National Science Foundation
(CHE1361173 to RJT).
Keywords: asymmetric synthesis • organocatalysis • diazene •
allylation • hydrazones
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Asymmetric Traceless Petasis
Borono-Mannich Reactions of Enals:
Reductive Transpositions of Allylic
Diazenes
Leave no trace: Tertiary stereogenic centers are installed by an asymmetric
traceless reductive allylboration catalyzed by chiral biphenols. The reaction
proceeds via transient enantioenriched allyic diazene species that break down
through a sigmatropic rearrangement to generate 1,4-dienes bearing aryl- or alkyl-
substituted tertiary stereocenters with high enantio- and diastereoselectivities.
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