Enantioselective synthesis of allenes by catalytic traceless petasis reactions

Article abstract of DOI:10.1021/jacs.6b11937

Allenes are useful functional groups in synthesis as a result of their inherent chemical properties and established reactivity patterns. One property of chemical bonding renders 1,3-substituted allenes chiral, making them attractive targets for asymmetric synthesis. While there are many enantioselective methods to synthesize chiral allenes from chiral starting materials, fewer methods exist to directly synthesize enantioenriched chiral allenes from achiral precursors. We report here an asymmetric boronate addition to sulfonyl hydrazones catalyzed by chiral biphenols to access enantioenriched allenes in a traceless Petasis reaction. The resulting Mannich product from nucleophilic addition eliminates sulfinic acid, yielding a propargylic diazene that performs an alkyne walk to afford the allene. Two enantioselective approaches have been developed; alkynyl boronates add to glycolaldehyde imine to afford allylic hydroxyl allenes, and allyl boronates add to alkynyl imines to form 1,3-alkenyl allenes. In both cases, the products are obtained in high yields and enantioselectivities.

Full text of DOI:10.1021/jacs.6b11937

Article
pubs.acs.org/JACS
Enantioselective Synthesis of Allenes by Catalytic Traceless Petasis
Reactions
Yao Jiang,† Abdallah B. Diagne,‡ Regan J. Thomson,*,‡ and Scott E. Schaus*,†
†Center for Molecular Discovery, Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts
02215, United States
‡Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States
S
* Supporting Information
ABSTRACT: Allenes are useful functional groups in synthesis as a
result of their inherent chemical properties and established
reactivity patterns. One property of chemical bonding renders
1,3-substituted allenes chiral, making them attractive targets for
asymmetric synthesis. While there are many enantioselective
methods to synthesize chiral allenes from chiral starting materials,
fewer methods exist to directly synthesize enantioenriched chiral
allenes from achiral precursors. We report here an asymmetric
boronate addition to sulfonyl hydrazones catalyzed by chiral biphenols to access enantioenriched allenes in a traceless Petasis
reaction. The resulting Mannich product from nucleophilic addition eliminates sulfinic acid, yielding a propargylic diazene that
performs an alkyne walk to afford the allene. Two enantioselective approaches have been developed; alkynyl boronates add to
glycolaldehyde imine to afford allylic hydroxyl allenes, and allyl boronates add to alkynyl imines to form 1,3-alkenyl allenes.
In both cases, the products are obtained in high yields and enantioselectivities.
transposition.23 Strategies using stoichiometric chiral reagents
INTRODUCTION
■
have also been developed,24 as well as those employing kinetic
Allenes first appeared in the chemical literature over 140 years
resolution of preformed racemic allenes.25 Contemporary efforts
ago when van’t Hoff predicted their existence in a now historic
have focused on devising asymmetric catalytic reactions,11
publication in 1875.1 Twelve years later, in 1887, Burton and
von Pechmann reported the first experimental preparation of an
allene, although the structure of the prepared molecule was
including useful metal-catalyzed approaches based on the
transformation of achiral dienes,26 conjugated enynes,27,28 vinyl
triflates,29 and terminal alkynes,30,31 as well as the dynamic
described incorrectly as an alkyne isomer.2 Confirmation of the
kinetic resolution of chiral racemic allenes.32 Organocatalytic
correct structure did not occur until 1954, following detailed
methods have been developed recently,33−36 such as an enan-
spectroscopic investigations by Whiting and co-workers.3 In a
tioselective alleno-Mannich reaction employing phase-transfer
curious inversion of characterization, the correct structure of a
natural product isolated from Carlina acaulis was shown to
catalysis35 and an enantioselective alkynylogous Mukaiyama
aldol reaction using a chiral phosphoric acid catalyst.36 While
be an alkyne,4 not the isomeric allene as had been originally
proposed in 1906.5 Perhaps because of such challenges in
significant advances have been made, the development of
broadly useful and convergent strategies to synthesize enan-
characterization, allenes were considered for many years to be
tioenriched chiral allenes from achiral precursors remains a
unstable entities, more structural oddities than useful com-
pounds. We now know that allenes are widely distributed in
nature and featured as key structural elements in a diverse range
significant challenge.
In 2012, we reported an approach to the direct synthesis of
allenes through what we termed a traceless Petasis reaction.37,38
The reaction proceeds by the addition of an alkynyltrifluor-
oborate salt into a sulfonylhydrazone to generate an inter-
mediate propargylic hydrazide. Fragmentation with loss of
sulfinic acid produces an unstable propargylic diazene species
that decomposes by a retro-ene reaction to form the cor-
responding allene as a racemate. Prior work by the Myers lab
had shown that the retro-ene reaction of enantioenriched
propargylic diazenes derived from the corresponding prop-
argylic alcohols proceeds with complete chirality transfer to
of natural products, bioactive small molecules, and materials.5,6
Allenes are highly versatile intermediates for synthesis, par-
ticipating in numerous powerful chemical transformations.7,8
The development of methods for the concise synthesis of
allenes has therefore been an area of intense research for many
years.9 As predicted by van’t Hoff in 1875,1 the orthogonal
relationship between the adjacent π systems within the allene
structure gives rise to the possibility of axial chirality, which has
inspired the development of methods that enable the enantio-
selective synthesis of allenes.10−12 Traditional approaches have
typically involved the stereospecific transformation of chiral
propargylic precursors, such as [3,3]13,14 and [2,3]15 sigma-
tropic rearrangements, SN2′ displacements,16−22 and reductive
Received: November 18, 2016
© XXXX American Chemical Society
A
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Figure 1. Development of an enantioselective allene synthesis reaction. Asymmetric routes to chiral allenes from (A) alkynyl boronate addition to
glycolaldehyde imine and (B) allylation of alkynyl hydrazones.
a
Table 1. Substrate Scope of Enantioselective Allene Synthesis via Alkynyl Boronates
a
Under each product the percent yield and enantiomeric ratio (e.r.) or diastereomeric ratio (d.r.) are given. Yields are isolated yields (0.4 mmol
scale). The e.r. or d.r. was determined by HPLC analysis using a chiral stationary phase. Abbreviations: Bn, benzyl; n-Bu, n-butyl; t-Bu, tert-butyl.
b
See the Supporting Information for experimental details. 20 mol % catalyst was used at −10 °C for 48 h.
produce enantioenriched allenes.23 We reasoned that it should be
possible to develop an enantioselective traceless Petasis reaction
by leveraging the known ability of chiral diols to catalyze regular
Petasis reactions with high levels of asymmetric induction.39−42
B
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When R2 = vinyl, the alternative disconnection of bond B
(blue) within hydrazide 3 generates propargylic hydrazone 4
and nucleophilic allyl boronate component 5 as potential
reaction partners. For this latter reaction, activation of the
boronate by a hydroxyl substituent on the hydrazone was con-
sidered unnecessary because of the capacity of allylboron
reagents to add via closed transition states, as observed in the
corresponding asymmetric allylation of imines.41,44 In a sense,
this particular reaction is truly traceless in that the allene
products obtained do not contain the remnants of functional
groups required for the reaction to proceed (cf. the previous
case that requires the hydroxyl group). The ease with which
these simple chiral allenes can be accessed in a convergent
manner is an especially powerful aspect of the reaction.
Herein we report the successful development of both
approaches outlined in Figure 1, enabling direct access to two
classes of enantioenriched allenes, 6 and 7, from readily
available precursors.
Figure 2. Isolation of hydrazide intermediate 3a.
We sought to devise a strategy to access optically enriched
propargylic hydrazides (i.e., 3) by the addition of an appro-
priate boron reagent (Figure 1). An analysis of the two possible
carbon−carbon bond disconnections on either side of the
hydrazide functionality within 3 reveals the possibility of two
distinct approaches to develop an enantioselective, catalytic
traceless Petasis reaction depending on the nature of the R2
substituent. When R2 = OH, disconnection of bond A (red)
within 3 leads back to alkynyl boronate 1 and hydrazone 2 as
potential reaction partners in a manner that closely resembles
the initial traceless Petasis reaction37 and to the previously
reported enantioselective alkynylation of acyl imines.40 Like
almost all Petasis-type reactions, including our initial traceless
variant, the presence of the hydroxyl functional group within 2
is required for an effective reaction to proceed via coordina-
tion to the boron nucleophile.43 Thus, path A (red) provides
a direct and convenient method for accessing enantioenriched
α-allenols that complements existing procedures.10−12
RESULTS AND DISCUSSION
■
Traceless Petasis Reaction of Alkynyl Boronates and
Glycolaldehyde. We began by designing experiments to
develop the asymmetric traceless Petasis Mannich reaction of
alkynyl boronates catalyzed by chiral biphenols. Two param-
eters were determined to be most important: the identity of the
sulfonyl hydrazide used to make the hydrazone and the chiral
biphenol catalyst employed in the reaction. A two-dimensional
evaluation of both parameters identified 2,5-dibromophenyl-
sulfonyl hydrazide (8) and 3,3′,6,6′-(CF3)4-BINOL (10) to be
optimal for the reaction, with enhanced selectivity observed
using a toluene/mesitylene solvent mixture (see the Supporting
Information for details). We found that quenching the reaction
with aqueous NaOH and allowing the reaction mixture to warm
a
Table 2. Diastereoselective Allene Synthesis
a
Under each product, the percent yield and diastereomeric ratio (anti:syn) are given. Yields are isolated yields (0.4 mmol scale). The d.r. was
1
determined by H NMR spectroscopic analysis of the unpurified reaction mixture. Abbreviations: n-Bu, n-butyl; Ph, phenyl. See the Supporting
Information for experimental details and stereochemical proofs.
C
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a
Table 3. Substrate Scope of Enantioselective Allene Synthesis from Alkynyl Aldehydes
a
Under each product the percent yield and enantiomeric ratio (e.r.) or diastereomeric ratio (d.r.) are given. Yields are isolated yields (0.4 mmol
scale). The e.r. or d.r. was determined by HPLC analysis using a chiral stationary phase. Abbreviations: Bn, benzyl; Ph, phenyl. See the Supporting
b
c
Information for experimental details and stereochemical proofs. 3 equiv of boronate was used. 40 h.
to room temperature facilitated efficient conversion of any
undecomposed intermediate propargylic hydrazide to the
desired allene product (see Figure 2). Under our optimized
conditions, the reaction of phenylalkynyl boronate 1 (R = Ph)
with glycolaldehyde using 10 mol % chiral biphenol catalyst 10
afforded the chiral allene in 85% isolated yield with 93:7
enantiomeric ratio (e.r.). The reaction proved general for
electron-rich and electron-poor arylalkynyl boronates (6a−f)
with enantioselectivities ranging from 90:10 to 93:7 (Table 1).
Similarly, aliphatic and unsaturated boronates could be used in
the reaction (6g−k), achieving commensurate levels of enan-
tioselectivity. A trialkylsilylalkynyl boronate performed the
reaction well, achieving the highest level of enantioselectivity
(6m, 62% yield with 95:5 e.r.). α-Hydroxyacetone (11) could
also be used as an electrophile to generate trisubstituted allene
6n (91% yield with 90:10 e.r.). The reaction could also be
adapted for more complex substrates requiring multistep
synthesis of the boronates. Cyclic boronates such as 12 are
stable toward chromatographic conditions but are less reac-
tive toward exchange with the biphenol catalyst. We there-
fore developed a set of conditions that facilitates boronate
exchange of cyclic boronate 12 by the addition of trialkoxy-
borate. These modified reaction conditions could be used to
promote the catalyst-controlled diastereoselective traceless
Petasis reaction of chiral alkynyl boronates (e.g., 12) with
good selectivity and yields (6o, 71% yield, 93:7 d.r. and 6p, 68%
yield, 91:9 d.r. for (S)-10 and (R)-10, respectively).
During our experiments to optimize the reaction conditions,
we identified and characterized the initial Petasis borono-
Mannich reaction product (Figure 2). When the reaction
mixture was kept at −5 °C, the addition of alkynyl boronate 1a
to the glycolaldehyde hydrazone derived from 8 and 9 formed
the corresponding hydrazide 3a and allenyl alcohol 6a as a
separable mixture (see the Supporting Information for details).
Attempts to directly determine the enantiopurity of 3a were
unsuccessful; subjecting hydrazide 3a to chiral HPLC analysis
resulted in concomitant diazene formation and rearrangement
to afford chiral allenyl alcohol 6a in a 92:8 enantiomeric ratio.
Furthermore, treating hydrazide 3a with aqueous NaOH also
resulted in the formation of allenyl alcohol 6a in a 92:8 enan-
tiomeric ratio. These observations support the original hypo-
thesis that a stereoselective Petasis borono-Mannich reaction of
sulfonyl hydrazones would result in the formation of enan-
tioenriched chiral allenes via the formation of propargylic
hydrazide intermediates. The isolation of hydrazide 3a also
clearly defines the developed reaction as mechanistically
distinct from the reaction recently reported by Wang and
co-workers, wherein sulfonyl hydrazones are transformed into
enantioenriched allenes by initial conversion of the hydrazone
to a diazo intermediate that undergoes a subsequent copper-
catalyzed coupling with a terminal alkyne.31
D
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Diastereoselective Traceless Petasis Reaction of
Alkynyl Boronates and Chiral α-Hydroxy Aldehydes.
We next investigated the use of chiral α-hydroxy aldehydes in
the traceless Petasis reaction catalyzed by chiral biphenols
(Table 2). For ease of preparation, stability, and general utility,
the reaction employed 2,2-dimethyl-1,3-dioxolan-4-ol, a
synthetic precursor that readily decomposes to the α-hydroxy
imine in the presence of amines.42 Our hope was that the
diastereomeric outcome of the reaction could be controlled
by the catalyst rather than by the substrate. The inherent
selectivity, as we have shown before, ranges from 2−5 to 1 in
the formation of the anti product, anti-15.42 As we anticipated,
one catalyst enantiomer, (S)-10, gave rise to enhanced
selectivity in the formation of anti-15 from the (S)-α-hydroxy
aldehyde precursor 13. Selectivities as high as 20:1 (anti:syn)
could be achieved under optimal conditions in good overall
yields (>70% isolated yield) for this matched scenario.
However, the use of the (R)-10 catalyst only resulted in a
1:1 mixture of diastereomers; the catalyst was unable to
completely overturn the inherent selectivity. Correspondingly,
the yields were lower for this case than for the (S)-10-catalyzed
reaction, supporting the hypothesis of a catalyst-mediated
process, albeit slower as a result of a diastereomeric transition
state that does not promote the reaction because of mis-
matched steric constraints. Finally, the reaction of enantiopure
α-hydroxy ketone 16 also resulted in excellent diastereose-
lectivity (anti-15e; Table 2); the anti product was obtained with
>20:1 selectivity in 70% isolated yield. Unfortunately, the
enantiomeric catalyst (R)-10 was unable to affect the anti
selectivity when used in the reaction, resulting in 9:1 dia-
stereomeric ratio still favoring the anti diastereomer. While we
were unable to achieve our desired goal of a completely
catalyst-controlled diastereoselective process, the method
reported herein will be useful for synthetic plans that require
the anti isomer of an α-allenol.
propiolaldehydes were also good substrates for the reaction
(7j−l). Likewise, aliphatic propiolaldehydes were also effec-
tively converted to the corresponding enantioenriched allenes
(7m and 7n) with >98:2 enantiomeric ratio. Finally, the dia-
stereoselective reaction of a protected chiral 1,2-diol-substituted
propionaldehyde afforded the product 7o in good yield (79%)
with excellent diastereoselectivity (99:1 d.r.). Overall, the
asymmetric allylation of propiolaldehyde hydrazones in the
traceless Petasis reaction is an excellent method to access struc-
turally simple enantioeneriched allenes.
Stereodivergent and Diastereoselective Traceless
Petasis Reaction of Alkynyl Aldehydes. In order to
develop a stereodivergent approach toward the synthesis of
α-substituted enantioenriched allenes (i.e., 23 and 24), we
investigated the use of crotyl boronates as nucleophiles. The
reaction of propiolaldehyde 18a with hydrazide 17 using
(E)-crotyldioxaborinane (21) provided the syn diastereomer
23a with excellent enantio- and diastereoselectivity. Disappoint-
ingly, under the same conditions, (Z)-crotyldioxaborinane (22)
afforded the anti diastereomer 24a with lower enantioselectivity
(64:36 e.r.). Changing the hydrazide structure had a remarkable
impact on the reaction generality, however. The use of hydra-
zide 20 with phenylpropiolaldehye and catalyst (R)-19 enable
highly stereoselective reactions with both 21 and 22 to deliver
allenes (Ra,S)-23a and (Ra,R)-24a, respectively (Table 4).
The reactions also worked well for hept-2-ynal to produce the
corresponding aliphatic allenes (Ra,S)-23b and (Ra,R)-24b. Thus,
under a standard set of reaction conditions, either diastereomeric
a
Table 4. Stereodivergent Synthesis of Chiral Allenes
Traceless Petasis Reaction of Alkynyl Aldehydes. We
next sought to pursue a strategy that uses alkynyl aldehydes
in the traceless Petasis Mannich reaction with allyl boronates
as the nucleophile. Similar to our observations of alkynyl
boronates reacting with glycolaldehyde, the identities of the
sulfonyl hydrazide and the chiral biphenol catalyst employed in
the traceless Petasis reaction proved to be important for the
yield and selectivity. 2-Nitro-4-trifluoromethylphenylsulfonyl
hydrazide (17) afforded the desired products in the highest
yields and enantioselectivities (Table 3). The 3,3′-Ph2-BINOL
catalyst 19 proved to be ideal for the enantioselectivity, an
observation we have also made in asymmetric imine allyl-
boration reactions.41 Typical reaction conditions involved the
reaction of the alkynyl aldehyde 3-phenylpropiolaldehyde (18a)
with hydrazide 17 at room temperature for in situ formation of
the hydrazone. After concentration, the crude hydrazone was
dissolved in toluene with the addition of t-BuOH (3 equiv),
catalyst (R)-19 (7 mol %), and allyl boronate 5 at room
temperature for 24 h, affording the enantioenriched allene in
87% isolated yield with 99:1 enantiomeric ratio. The reaction
was general for both electron-rich and electron-poor aryl-
propiolaldehyde substrates, affording the products (7a−f) with
>98:2 enantiomeric ratio. Heterocyclic propiolaldehydes were
also good substrates for the reaction (>98:2 e.r.), although the
pyridylpropiolaldehyde resulted in a low yield (7h, 27% yield,
98:2 e.r.), presumably because the nitrogenated heterocycle acts
as a Lewis base to inhibit the reaction. Silylpropiolaldehyde
(7i, 73% yield, 98:2 e.r.) and propargylic heteroatom-bearing
a
Under each product the percent yield, diastereomeric ratio (d.r.), and
enantiomeric ratio (e.r.) are given. Yields are isolated yields (0.4 mmol
scale). The e.r. and d.r. were determined by HPLC analysis using chiral
stationary phases. Ph, phenyl. See the Supporting Information for
experimental details and stereochemical proofs.
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Figure 3. Utility of the chiral allene products prepared from traceless Petasis reactions. (a) Stereospecific cycloetherifications yield substituted
dihydrofurans. (b) An efficient synthesis of laballenic acid (35), a major constituent of Leonotis nepetaefolia seed oil. (c) A formal total synthesis of
39, an odor-active lactone component of oranges and wasabi, intercepting Ma’s intermediate (i.e., 38).
product, (Ra,S)-23 or (Ra,R)-24, could be obtained simply by
changing the olefin geometry of the boronate, indicating that
transfer of chirality from the catalyst to the product most likely
proceeds through a closed six-membered transition state. Use
of the antipodal catalyst (S)-19 under these conditions would
provide access to the enantiomeric pair of diastereomeric allene
products in this new stereodivergent traceless Petasis reaction.
Synthetic Utility of the Enantioenriched Allene
Products. The enantioenriched allenes available through
either one of the methods reported herein are versatile inter-
mediates that may be further elaborated into a number of
useful products (Figure 3). For example, when treated with
either Au(III) or Ag(I) catalysts, the allenols formed by the
traceless Petasis reaction with glycolaldehyde dimer underwent
smooth cycloetherification to deliver enantioenriched dihy-
drofurans with complete transfer of stereochemical information
(Figure 3a).25,45,46 In some cases we noticed that the choice of
catalyst was critical for complete stereochemical transfer. As an
illustration, the attempted cyclization of phenyl-substituted
The allene products generated through the enantioselective
allylation route (see Tables 3 and 4) were also converted to
interesting natural products (Figure 3b,c). A key transforma-
tion that demonstrates the utility of these products is the
chemoselective hydroboration of the terminal alkene over the
less reactive internal allene π system using 9-borabicyclo[3.3.1]-
nonane (9-BBN). Thus, allene 31 was transformed to alcohol
32 in 75% yield, and subsequent cyanation and hydrolysis
delivered laballenic acid (35) in a highly efficient manner.47,48
Similarly, allene 24b could be converted to alcohol 37 by
hydroboration with 9-BBN, and then carboxylic acid 38 was
obtained from 37 by treatment with Jones reagent. Ma and co-
workers previously demonstrated that acid 38 could be
transformed in two steps to lactone 39 through a novel
stereoselective iodolactonization,49 and thus, access to acid 38
through our methodology completes a six-step formal synthesis
of this natural product.50
CONCLUSIONS
■
45
allene 6a using AuCl3 led to significant erosion of the enan-
Reactions that result in the direct formation of carbon−carbon
bonds with the simultaneous generation of elements of stereo-
chemistry are particularly powerful in synthetic pursuits. When
applied in a rational manner to the synthesis of complex targets,
such reactions enable the rapid generation of complexity from
simple starting materials. The two catalytic enantioselective
traceless Petasis reactions reported herein are powerful new
examples of such fragment-coupling reactions that enable the
tiopurity, while AgNO3 (10 mol % on silica gel)25 induced
cyclization of 6a with no change in the enantiomeric ratio. The
use of AgNO3 (20 mol %) in acetone/water46 was the most
effective for the cyclization of 6g, while AuCl3 (1 mol %)45 was
effective for most of the other substrates investigated (i.e., 6o,
6p, and 15b) (see the Supporting Information for additional
examples).
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efficient asymmetric synthesis of chiral allenes from achiral
precursors. Both reaction manifolds utilize boron nucleophiles
that add to sulfonyl hydrazones to generate chiral propargylic
hydrazides, which decompose to form unstable diazene
intermediates. Retro-ene fragmentation of the enantioenriched
diazene intermediates results in a stereospecific point-to-axial
transfer of chirality, generating the allene products with
concomitant loss of dinitrogen. The catalytic and enantiose-
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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/jacs.6b11937.
■
S
All experimental procedures, complete characterization
(NMR, MS, IR, and optical rotation) of all new com-
pounds, and HPLC assays for determination of enan-
tiopurity (PDF)
135, 4970.
AUTHOR INFORMATION
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Wang, J. J. Am. Chem. Soc. 2016, 138, 14558.
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2005, 127, 14186.
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18020.
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2009, 131, 7212.
■
Corresponding Authors
*r-thomson@northwestern.edu
*seschaus@bu.edu
ORCID
Yao Jiang: 0000-0002-6137-1126
Regan J. Thomson: 0000-0001-5546-4038
Notes
The authors declare no competing financial interest.
(35) Hashimoto, T.; Sakata, K.; Tamakuni, F.; Dutton, M. J.;
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ACKNOWLEDGMENTS
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S.E.S. and Y.J. gratefully acknowledge the NIH for research sup-
port (R01 GM078240) and instrumentation (P50 GM067041).
R.J.T. and A.B.D. gratefully acknowledge the NSF for research
support (CHE1361173) and the ARCS Foundation for the
Daniel D. and Ada L. Rice Foundation Scholarship to A.B.D.
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