Simple strategy for synthesis of optically active allylic alcohols and amines by using enantioselective organocatalysis

Article abstract of DOI:10.1073/pnas.0914523107

A simple organocatalytic one-pot protocol for the construction of optically active allylic alcohols and amines using readily available reactants and catalyst is presented. The described reaction is enabled by an enantioselective enone epoxidation/aziridination-Wharton-reaction sequence affording two highly privileged and synthetically important classes of compounds in an easy and benign way. The advantages of the described sequence include easy generation of stereogenic allylic centers, also including quaternary stereocenters, with excellent enantio- and diastereomeric-control and high product diversity. Furthermore, using monosubstituted enones as substrates, having moderate enantiomeric excess, the one-pot reaction sequence proceeds with an enantioenrichment of the products and high diastereoselectivity was achieved.

Full text of DOI:10.1073/pnas.0914523107

Simple strategy for synthesis of optically active
allylic alcohols and amines by using
enantioselective organocatalysis
Hao Jiang, Nicole Holub, and Karl Anker Jørgensen1
Center for Catalysis, Department of Chemistry, Aarhus University, Langelandsgade 140, DK-8000, Aarhus C, Denmark
Edited by David W. C. MacMillan, Princeton University, Princeton, NJ, and accepted by the Editorial Board April 29, 2010 (received for review December
16, 2009)
A simple organocatalytic one-pot protocol for the construction of
optically active allylic alcohols and amines using readily available
reactants and catalyst is presented. The described reaction is
enabled by an enantioselective enone epoxidation/aziridination-
Wharton-reaction sequence affording two highly privileged and
synthetically important classes of compounds in an easy and benign
way. The advantages of the described sequence include easy
generation of stereogenic allylic centers, also including quaternary
stereocenters, with excellent enantio- and diastereomeric-control
and high product diversity. Furthermore, using monosubstituted
enones as substrates, having moderate enantiomeric excess, the
one-pot reaction sequence proceeds with an enantioenrichment
of the products and high diastereoselectivity was achieved.
asymmetric catalysis ∣ allylic amines ∣ enantioselectivity
llylic alcohols and amines represent two of the most abun-
A
dant and fundamental building blocks in contemporary
organic synthesis. The possible transformations of these impor-
tant compounds are numerous and proceed often with excellent
stereoinduction (1–3). Consequently, optically active allylic
alcohols and amines have appeared innumerable times as key
intermediates in asymmetric total syntheses, showing the need
for efficient and benign methods of their formation.
One of the traditional synthetic approaches to optically active
allylic alcohols is the catalytic kinetic resolution applying enzymes
(4). In addition, Sharpless and coworkers have successfully estab-
lished an asymmetric titanium-catalyzed resolution of racemic
secondary allylic alcohols via the Sharpless-Katsuki epoxidation
(5), resulting in a mixture of epoxy-alcohols and optically active
allylic alcohols (Scheme 1, expression 1). However, the fact that
the resolution method is restricted to a theoretical yield of 50%,
makes other direct routes to optically active allylic alcohols highly
desirable. With the dynamic kinetic resolution (6), a procedure
that allows full conversion of the starting compound to one
desired product with excellent stereocontrol was established.
In this process, a fast and efficient in situ racemization reaction
of the undesired enantiomer of the starting material is the key to
overcome the 50%-yield limit of the traditional resolution meth-
od. However, the scope of this reaction is limited to mainly acyclic
substrates and the combined use of transition metal and enzyme
is necessary (Scheme 1, expression 2).
As an alternative to the resolution method, several different
enantioselective reduction protocols of enones have been
developed. Examples are the Corey-Bakshi-Shibata reduction
(7), applying a borane-prolinol complex, and the catalytic enan-
tioselective hydrogenation, applying BINAP [2,2'-Bis(diphenyl-
phosphino)-1,1'-binaphthyl]-diamine ruthenium complexes de-
veloped by Noyori and coworkers (8) (Scheme 1, expression 3).
The needs of bulky functional groups, different substitution
patterns at the enone functionality, and inert reaction conditions
for obtaining high selectivities are some of the drawbacks of these
methods. Another protocol for the enantioselective synthesis of
allylic alcohols is the 1,2-addition of vinylic metal species, gener-
Scheme 1. Different methods for synthesis of allylic alcohols and amines;
X ¼ O, NH.
ated either by transmetallation of boronates or by rhodium- or
iridium-catalyzed
reductive coupling of acetylenes (9) (Scheme 1, expression 4).
While the transmetallation strategy requires the preparation of
a “primary organometallic reagent,” the reductive coupling of
acetylenes is usually performed under high pressure of hydrogen.
Foreshadowed by the pioneering work of Trost et al., metal-cat-
alyzed π-allyl substitutions of racemic allylic carbonates or esters
have been extensively investigated in the last years (Scheme 1,
expression 5). These methods provide straightforward and widely
applied synthetic routes to nonterminal allylic alcohols (10–15).
Nevertheless, despite the wide applicability, significant challenges
remain yet to be solved. Among them is the restriction of π-allyl
substitutions to symmetrically disubstituted π-allyl systems, which
excludes certain substitution patterns in the allylic products.
Author contributions: H.J., N.H., and K.A.J. designed research; H.J. and N.H. performed
research; and H.J., N.H., and K.A.J. wrote the paper.
The authors declare no conflict of interest.
This article is
a PNAS Direct Submission. D.W.C.M. is a guest editor invited by the
Editorial Board.
1To whom correspondence should be addressed. E-mail: kaj@chem.au.dk.
This article contains supporting information online at www.pnas.org/lookup/suppl/
doi:10.1073/pnas.0914523107/-/DCSupplemental.
20630–20635 ∣ PNAS ∣ November 30, 2010 ∣ vol. 107 ∣ no. 48
www.pnas.org/cgi/doi/10.1073/pnas.0914523107

Scheme 3. Enantioselective organocatalytic synthesis of allylic alcohols.
Scheme 2. An organocatalytic approach to allylic alcohols and amines.
corresponding allylic alcohols and maintaining the high enantios-
electivity.
Moreover, the formation of quaternary allylic centers is, to the
best of our knowledge, not possible using these methods.
Optically active allylic amines have so far been synthesized by
almost similar protocols. While the metal-catalyzed π-allyl substi-
tution for the synthesis of allylic amines (Scheme 1, expression 5)
is restricted by the same issues mentioned above (16, 17), the 1,2-
addition of vinylic metal species to imines (Scheme 1, expression4)
often applies an additional chiral auxiliary attached to the nitrogen
atom in order to obtain high stereocontrol (9). An efficient
transformation with complete stereoinversion, is the Mitsunobu
reaction (Scheme 1, expression 6) which has been applied numer-
ous times for the synthesis of optically active allylic amines (18).
However, this process requires optically active allylic alcohols
as starting materials and thus provides an indirect route to this
important class of compounds.
Despite the achievements published so far for the synthesis of
optically active allylic alcohols and amines, there is still need for
developments of general, robust, and easy synthetic approaches
to these classes of compounds. Incorporation of organocatalytic
functionalizations in complex one-pot reactions has recently
emerged as an efficient strategy for the formation of many impor-
tant optically active compounds, otherwise difficult to obtain
(19–25). The present work shows the development of an organo-
catalytic synthetic process, making use of a single amino-catalyst
(26–31) in combination with cheap and readily available starting
materials, for the formation of allylic alcohols and amines in mod-
erate to good yields and excellent enantioselectivities (Scheme 2).
The described reactions are enabled by an enantioselective enone
epoxidation/aziridination-Wharton-reaction sequence. While the
organocatalytic epoxidation of cyclic and acylic enones has been
recently described by List et al. (32, 33) and Deng et al. (34), the
organocatalytic aziridination of enones has been mainly limited
to acyclic substrates (35, 36). We envisioned that a merger of the
catalytic enone functionalizations with the hydrazine mediated
1,3-transposition following the Wharton protocol (37) could
allow simple access to a broad spectrum of optically active allylic
products under metal-free conditions, and preferably in an
one-pot process (Scheme 2).
A plethora of cyclic enones of various ring-size and substitu-
tion patterns were evaluated as substrates in this one-pot
sequence and the results are outlined in Table 1. The obtained
yields ranged from moderate to good, while the enantiomeric
excess remained high in all cases (87–99% ee). Seven-membered
allylic alcohols were formed in similar high enantioselectivity,
while for the application of cyclopentenone a significant decrease
in reactivity was observed, as expected in analogy to previous
reports (32). Substitutions at 5-, 4-, and 3-position of the enone
were all well tolerated. With respect to use of enones with sub-
stitutions at 3- and 4-positions it is noteworthy that they represent
substitution patterns difficult to obtain using conventional meth-
ods, such as palladium-catalyzed π-allyl substitution or dynamic
kinetic resolution. The formation of quaternary allylic stereo-
genic centers with good enantio-control by nonresolution meth-
ods is a highly challenging task (38). Using the present conditions,
a variety of allylic alcohols carrying a quaternary allylic center are
formed with enantioselectivities up to 99% ee. Finally, it is also
demonstrated that acyclic enones (Table 1, entry 9) are valid
substrates for this reaction. However, for the acyclic product
4h an E∕Z ratio of 1∶1 is observed, which is in accordance with
the mechanism of the Wharton rearrangement (39–41).
The traditional Wharton reaction is facilitated with a α-carbo-
nyl leaving group, which typically is an epoxy motif as applied in
the one-pot reaction sequence for the formation of the optically
active allylic alcohols, by which the chirality is set during the first
organocatalytic step. Intuitively, we propose that an electron-
poor aziridine should be equally effective as the “chiral leaving
group,” thereby facilitating the formation of the corresponding
optically active allylic amines. To the best of our knowledge, such
a reaction for this class of compounds has not yet been described.
As mentioned previously, the organocatalytic aziridination of
cyclic enones has only been rarely described, whereas acyclic
enones have been studied more frequently (35, 36). Differently
substituted hydroxylamine derivatives were tested as nucleophilic
reagents, in which the hydroxy functionality serves as the leaving
group and enables therefore the formation of the three-mem-
bered heterocycle after the nucleophilic 1,4-addition of the amine
moiety. We chose 4-methyl-N-(tosyloxy)benzenesulfonamide 5 as
a suitable nucleophile, because of its easy and simple access via
ditosylation of hydroxylamine and the two-step sequence was
initially performed separately (Scheme 4). We were pleased to
observe, that the subjection of the synthesized and isolated azir-
idines to the Wharton transposition conditions led smoothly to
the formation of optically active allylic N-tosyl amines in good
yields and excellent enantioselectivities.
Results and Discussion
To find the optimal reaction conditions, we started our investiga-
tions for the synthesis of optically active allylic alcohols by
using cyclohexenone 1a as a model substrate and performing
the envisaged sequence in two separate steps (Scheme 3). Both
the epoxidation and Wharton transposition reactions could
be achieved providing the desired allylic alcohol 4a with high
enantioselectivity. Comparable results could be attained for
3-methyl cyclohexenone 1e allowing the formation of the tertiary
allylic alcohol 4e, otherwise difficult to obtain, with excellent
enantiomeric excess.
Although the products 7b, d proved to be nonvolatile, an
one-pot sequence is highly desirable, reducing purification steps,
However, the volatility of the optically active epoxy ketones 3a,
e and allylic alcohols 4a, e (Scheme 3) makes the development of
an one-pot protocol, and therefore a minimization of purification
steps, desirable. We have found that sequential addition of hydra-
zine, methanol, and acetic acid to the reaction mixture of the
epoxidation process, after full conversion of the organocatalytic
step has been achieved, resulted in higher isolated yields of the
Scheme 4. Enantioselective organocatalytic synthesis of allylic amines.
Jiang et al.
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Table 1. One-pot synthesis of allylic alcohols using an organocatalytic epoxidation-Wharton sequence
N
(i) 2a (10 mol%)
H2O2, dioxane
O
2 TFA
H
35-50 o
C
NH2
R2
R2
OMe
R1
OH
∗
(ii) AcOH, MeOH
hydrazine
R1
n
n
4
N
1
2a
Entry
1
Enone (1)
Product (4)
Yield (%)*
50 (32)§
ee (%)†
93 (93)§
O
O
1a
1b
4a
4b
OH
2
3
45
58
92
87
OH
O
1c
4c
OH
O
4
1d
4d
47
94
OH
O
O
O
5
6
7
1e
1f
4e
4f
40 (35)§
94 (94)§
Me
OH
Me
40
98
Bn
OH
Bn
1g
4g
45
99
Bn
OH
Bn
O
8‡
1g
1h
ent-4g
42
54
96
96
OH
Bn
Bn
O
OH
9
4h
nBu
nBu
*Yields of isolated products.
†Determined by chiral stationary phase GC or HPLC.
‡The quasienantiomer of the catalyst is used (2b, see Scheme 5).
§Results for the sequence performed in two separate steps.
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Table 2. One-pot synthesis of allylic amines using an organocatalytic aziridination-Wharton sequence
O
(i) 2a (20 mol%)
TsONHTs (5)
NaHCO3, CHCl3
R2
R2
∗
R1
NHTs
(ii) AcOH, MeOH
hydrazine, 50 °C
R1
n
n
7
1
Entry
1
Enone (1)
Product (7)
Yield (%)*
56
ee (%)†
O
O
O
1a
1a
7a
96
NHTs
NHTs
2‡
ent-7a
52
95
3
1b
1d
7b
7d
48 (37)§
98 (98)§
NHTs
O
4
50 (50)§
97 (97)§
NHTs
O
O
5
1e
1f
1f
7e
7f
57
61
69
99
99
99
Me
NHTs
Me
6
Bn
NHTs
Bn
Bn
O
O
7‡
ent-7f
NHTs
Bn
8
9
1g
1h
7g
7h
42
52
94
97
Bn
NHTs
Bn
O
NHTs
nBu
nBu
*Yields of isolated products.
†Determined by chiral stationary phase HPLC.
‡The quasi-enantiomer of the catalyst was used (2b, see Scheme 5).
§Results for the sequence performed in two separate steps.
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mentary method to the palladium-catalyzed reactions for the
formation of both cis and trans-substituted allylic products.
The mechanistic proposal of the reported one-pot reactions
for the formation of optically active allylic alcohols and amines
is outlined in Scheme 6. Condensation of the 9-amino-9-deoxye-
piquinine ditrifluoroacetic acid salt catalyst 2a and enone 1 leads
to the formation of an activated iminium species 10, which is
subjected to nucleophilic attack of H2O2 or TsONHTs (4-
Methyl-N-(tosyloxy)benzenesulfonamide) under formation of in-
termediate 11. Spontaneous ring closure and hydrolysis provided
the optically active epoxy-ketone 3 and aziridine 6 intermediates
and liberation of the amino-catalyst. Next, condensation of 3 or 6
with hydrazine under acidic conditions afforded the short-lived
iminium species 12, which upon subsequent ring opening rear-
range to intermediate 13. Final release of volatile N2 and proto-
nation of the formed vinyl anions provided the desired optically
active allylic alcohols 4 and amines 7. Despite the elevated tem-
peratures and acidic conditions, no racemization was observed,
furnishing the products in excellent enantioselectivities.
Scheme 5. Diastereoselective synthesis of allylic alcohols and amines.
material costs, and time. By increasing the amount of acetic acid
used in the reductive elimination step, the allylic amines could be
synthesized in an one-pot fashion in equally good or higher yields
and without affecting the high enantioselectivity (Table 2).
Both six- and seven-membered enones participate in the reac-
tion with satisfactory results and 95–99% ee. As expected, substi-
tution at 4- and 3-position of the enone is tolerated. However,
enones bearing substituents in 5-position resulted only in low
conversion in the organocatalytic aziridination step. Although
the aziridination of 3-substituted cyclic enones has been reported
with only moderate enantioselectivity, we accomplished the
generation of quaternary allylic centers (7e, f, g) with excellent
enantio-control, using the nucleophile 5. The use of acyclic sub-
strates (entry 9) furnished again the desired product 7h in high
enantiomeric excess (97% ee); however also in this case a 1∶1
mixture of E∕Z isomers was obtained.
To further challenge the robustness of the developed reaction
sequence, we decided to evaluate the process applying the
enantioenriched monosubstituted cyclohexenone 8 (42). As de-
monstrated in Scheme 5, the synthesis of optically active cyclic
allylic alcohol and amine having two stereogenic centers was
accomplished with good yields and diastereoselectivities. By
employing catalyst 2b, the trans-substituted product 9a is formed
in good yield and diastereomeric ratio, and an enantio-enrichment
from75% to92% eeis achieved becauseof double stereoselection.
However, by applying catalyst 2a, the cis-product is formed prefer-
ably, as demonstrated for compound 9b formed in 95% ee.
A review of literature shows that methods for catalytic asymmetric
synthesis of disubstituted cyclic allylic alcohols and amines are
limited. Among the simplest and most applied methods is the
palladium-catalyzed π-allyl substitution. However, stereo-selec-
tive π-allyl substitution is mostly carried out on cis-substituted
substrates giving retention of the relative stereochemistry of the
products, while the corresponding trans-product is obtained usual-
ly by Mitsunobu inversion (43). Consequently, we believe that
the described diastereoselective reaction can serve as a comple-
Conclusion
In conclusion, we have developed a simple and metal-free one-pot
protocol for construction of optically active allylic alcohols and
amines using readily available starting materials. The advantages
of the described sequence include easy formation of quaternary
allylic centers and expanded product diversity. It should therefore
serve as practical complementary to presently available methods.
Materials and Methods
Unless otherwise stated, all commercially available reagents were purchased
and used as received without further purification. The amino catalysts 2a, b,
enones 1c, f, g and 8 were synthesized according to literature procedures
(32, 42).
Typical Procedure for One-Pot Synthesis of Allylic Alcohols. An ordinary glass
vial equipped with a magnetic stirring bar was charged with the enone 1
(0.25 mmol, 1.0 equivalent), the catalyst 2 (0.025 mmol, 0.1 equivalent),
and dioxane (1.0 mL). After 30 min of stirring at room temperature, H2O
(50 wt% in H2O, 0.30 mmol, 1.2 equivalent) was added. The reaction was
heated to 35–50 °C (see individual entries) and kept under vigorous stirring
until complete conversion of the enone as monitored by TLC (usually
24–72 h). MeOH (5.0 mL), hydrazine monohydrate (1.25 mmol, 5.0 equivalent),
and AcOH (0.63 mmol, 2.5 equivalent) were then added in the described
sequence. After an additional 0.5–1 h of stirring at room temperature, the
crude reaction mixture was diluted with NaHCO3 (sat.), extracted with
CH2Cl2 (3 × 10 mL), dried over MgSO4, and most of the excess solvents were
carefully removed in vacuo. The remaining volume (ca. 1–2 mL) was charged
on silica gel and purified by FC (gradient: pentane to pentane∕Et2 2∶1).
Typical Procedure for One-Pot Synthesis of Allylic Amines. An ordinary glass vial
Scheme 6. Mechanistic proposal of the formation of allylic alcohols and amines.
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Jiang et al.

equipped with
a
magnetic stirring bar was charged with TsONHTs
5
to room temperature, diluted with NaHCO3 (sat.), extracted with CH2Cl2
(3 × 10 mL), dried over MgSO4, concentrated in vacuo, and purified by FC
on silica gel (gradient: pentane to pentane/EtOAc 1∶1).
(0.38 mmol, 1.5 equivalent), the catalyst 2 (0.05 mmol, 0.2 equivalent),
and CHCl3 (1.0 mL). After 10 min of stirring at room temperature, enone
1 (0.25 mmol, 1.0 equivalent) and NaHCO3 (0.5 mmol, 2 equivalent) were
added sequentially. The reaction was kept under vigorous stirring until
complete conversion of the enone as monitored by TLC (usually 24–72 h).
MeOH (5.0 mL), hydrazine (1.25 mmol, 5.0 equivalent), and AcOH (1.13 mmol,
4.5 equivalent) were then added in the described sequence. After an
additional 1 h of stirring at 50 °C, the crude reaction mixture was cooled
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Danish National Research Foundation, the Carlsberg Foundation, Deutsche
Forschungsgemeinschaft, and OChemSchool.
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