Catalytic Enantioselective Transannular Morita-Baylis-Hillman Reaction

Article abstract of DOI:10.1021/jacs.9b03679

Catalytic and enantioselective approaches to transannular reactions are very limited and mostly are based on chiral Lewis acid catalyzed pericyclic reactions. In this report, we present an efficient and straightforward methodology to access bicyclic carbo

Full text of DOI:10.1021/jacs.9b03679

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Catalytic Enantioselective Transannular Morita-Baylis-Hillman Reaction
Raquel Mato, Ruben Manzano, Efraim Reyes, Luisa Carrillo, Uxue Uria, and Jose L. Vicario
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b03679 • Publication Date (Web): 29 May 2019
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Catalytic Enantioselective Transannular Morita-Baylis-Hillman
Reaction
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Raquel Mato, Rubén Manzano, Efraim Reyes,* Luisa Carrillo, Uxue Uria and Jose L. Vicario*
Department of Organic Chemistry II, University of the Basque Country (UPV/EHU). P.O. Box 644, 48080 Bilbao (Spain).
Supporting Information Placeholder
amines or phosphines as Lewis base catalysts. Even a couple of
examples of diastereoselective transannular Rauhut-Currier
ABSTRACT: Catalytic and enantioselective approaches to
transannular reactions are very limited and mostly are based on
reactions (which is regarded as the vinylogous version of the
Morita-Baylis-Hillman reaction) used in the total synthesis of
complex natural products have been reported,11 but remarkably, no
precedent can be found in the literature regarding a transannular
chiral Lewis acid-catalyzed pericyclic reactions. In this report we
present an efficient and straightforward methodology to access
bicyclic carbo- and heterocyclic scaffolds combining different ring
sizes through transannular Morita-Baylis-Hillman reaction
catalyzed by a chiral enantiopure bifunctional phosphine. The
reaction is remarkably wide in scope and enables the use of a
variety of medium- and large size ketoenone substrates leading to
the final products in high yields and providing excellent
stereocontrol in the formation of a quaternary stereogenic centre at
the ring fusion. Moreover, its potential as a general tool in organic
synthesis has been highlighted through the accomplishment of the
Morita-Baylis-Hillman reaction either in
enantioselective fashion.
a diastereo- or
Scheme 1. The transannular Baylis-Hillman reaction.
Cat.
O
O
Transannular
reaction
Cat.
( )n
( )n
Lewis Base
Catalysis
( )m
( )m
Cat.
( )n
O
first enantioselective total synthesis of (-)--gurjunene,
a
H
O
O
sesquiterpene natural product.
O
Cat.
( )n
O
( )m
Cat.
O
( )n
( )m
( )m
The use of transannular reactions for building polycyclic
frameworks is significantly underdeveloped synthetic
OH
OH
a
methodology in comparison with the conventional cyclization or
cycloaddition approaches,1 This can be mostly attributed to the
requirement of a macrocyclic starting material, whose preparation
entails a synthetic problem by itself. However, advances in
synthetic methodology for the preparation of medium and large-
size rings2 has prompted several research groups to engage in the
application of transannular reactions to the synthesis of complex
targets, in almost all cases through diastereoselective processes that
involve the use of chiral and enantioenriched starting materials.3 In
fact, catalytic and enantioselective variants of transannular
reactions are limited to only four reports:4 Jacobsen pioneered the
field in 2007 with one example of a transannular Diels-Alder
reaction under chiral Lewis acid catalysis5 and two additional
transition metal-catalyzed transformations were reported
afterwards comprising a Claisen rearrangement6 and an ene
reaction.7 In addition to these three cases, one single example of a
catalytic and enantioselective transannular reaction under metal-
free conditions has been described by List and coworkers making
use of enamine catalysis.8
We initially surveyed the viability of our proposal by studying
the behavior of ketoenone 1a when exposed to 4-
dimethylaminopyridine (DMAP) as well-known nucleophilic
catalyst for Morita-Baylis-Hillman reactions (see Table 1). As
projected, bicyclic compound 2a was isolated in a promising 65%
yield after 24h (entry 1). With this result in hand, we next
proceeded to survey compounds 3a and 3b, which are the chiral
evolution of DMAP developed by Fu and coworkers.12
Disappointingly, these catalysts did not perform well in the reaction
(entries 2 and 3) and the same negative result was obtained under
any other conditions tested. As a consequence, we moved to
explore the performance of chiral phosphines as potential Lewis
base catalysts.13 After testing different candidates, (see supporting
information for the detailed screening of catalysts) we ended up
with the identification of peptide-like bifunctional phosphine 3c as
a
potentially effective promoter for this transformation.14
Remarkably, the performance of the reaction could be significantly
improved through the incorporation of a protic additive, which is
known to facilitate the proton transfer step required for the catalyst
turnover.15 Additional experiments led to establish that the use of a
50 mol% of phenol was optimal for the reaction to proceed with the
highest possible enantiocontrol (entry 4).16 Next, fine-tuning of the
structure of the catalyst was carried out (entries 5-13), initially
evaluating the possible matched/mismatched combination with
respect to the absolute configuration of the two stereogenic centres
present at the catalyst structure. Indeed, diastereomeric phosphine
3d provided adduct 2a in a similar yield but with a much lower e.e.
than that provided by catalyst 3c, working under the optimized
In view of the state of the art, we envisioned that a macrocyclic
keto-enone substrate such as the one shown in Scheme 1 would be
suitable to undergo a transannular Morita-Baylis-Hillman reaction9
through catalytic activation by a Lewis base. Moreover, achieving
enantiocontrol in the formation of the new stereogenic centre
formed at the final adduct should also be possible using a chiral
catalyst. There are many examples of catalytic and enantioselective
versions of the Morita-Baylis-Hillman reaction in either intra- or
intermolecular way,10 which in general make use of chiral tertiary
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Page 2 of 6
c
reaction conditions (entry 5 vs 4). This indicates that both
stereocentres play significant role in controlling the
to isolated pure product 2a. Calculated by HPLC on chiral
d
1
2
3
4
5
6
7
8
a
stationary phase (see supporting information).
determined.
n.d. not
stereochemical outcome of the reaction. Catalysts related to 3c but
with different N-protecting groups at the amine moiety were
surveyed (entries 6 and 7), again showing that catalyst 3c was the
best performing one in terms of enantiocontrol. Finally, we
proceeded to evaluate a variety of related catalysts with different
substituents at both stereocentres (entries 7-13). While substituting
the side chain at the aminophosphine moiety (R3 group) did not
have any important influence on the stereocontrol (catalysts 3g-i,
entries 8-10), modifying the alkyl substituent at the aminoacid
With an optimized experimental protocol in hand, we next
evaluated the scope and limitations of this transformation. As it can
be seen in table 2, those substrates leading to the
bicyclo[5.3.0]decane scaffold (m=1, n=1 in 1a-f) proceeded to
react efficiently, providing the corresponding adducts 2a-f in
excellent yield and e.e. The reaction worked even better with those
starting materials that led to the formation of adducts with a general
bicyclo[5.4.0]undecane architecture (m=1 and n=2 in 1g-n).
Moreover, substrates incorporating fused aromatic systems with
different substitution patterns were also suitable for this
transformation, maintaining an excellent level of enantiocontrol
(see for example adducts 2c-f and 2h-m). The reaction also
proceeds efficiently when a heteroatom is incorporated within the
structure of the starting material, as exemplified with compounds
2b and 2n. On the contrary, the possibility of using an -
unsaturated lactone as substrate was also evaluated but it was found
to be unreactive, presumably due to the poorer ability of the enoate
moiety to act as Michael acceptor towards the catalyst.
9
substructure (R2 group) had
a profound effect on the
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enantioselectivity of the process (entries 11-13), leading to an
excellent 90% e.e. with the bulkiest catalyst 3k (entry 12).
Moreover, this catalyst proved to be more active than the other
ones, observing complete consumption of starting material in only
three hours, compared to the average of 16 hours required before.
Catalysts 3m and 3n in which the amide NH moiety had been
replaced by N-Me groups were also tested, requiring for much
longer reaction time and especially providing a very poor
enantioselectivity in the case of 3n, which points towards the key
role played by the NH moiety as stereodirecting element.
TABLE 2. Scope of the reaction.a
TABLE 1. Screening for best reaction conditions.a
O
O
O
3k
(10 mol%)
PhOH (50 mol%)
CHCl3, 25ºC
Catalyst (10 mol%)
O
additive
n
n
Solvent, 25ºC
OH
O
m
X
OH
X
O
m
1a
2a
1a-s
2a-s
NR2
Bn
Bn
O
2
O
H
N
H
O
O
N
BocHN
PPh2 BocHN
PPh2
PPh2
N
iPr
O
iPr
Fe
R1
O
R1
R1
R1
3c
3d
OH
OH
2b
Yield: 98% (3h) Yield: 93% (2h)
R1
OH
OH
O
tBu
H
2a
2c
2d
1
2
3 i
1
2
3e
3f
3g
3h
3i
3j
3k
3l
(R =Fmoc, R =Bn, R = Pr)
Boc
N
3a
(R =Ph; R =Me)
(R =Me; R =-(CH2)4-)
Yield: 88% (2h)
84% e.e.
O
Yield: 90% (6h)
88% e.e.
O
N
1
2
3 i
1
2
(R =Ts, R =Bn, R = Pr)
3b
90% e.e.
O
95% e.e.
Me
O
iPr
3m
1
2
3
s
(R =Boc, R =Bn, R =(S)- Bu)
R2
PPh2
1
2
3 t
H
(R =Boc, R =Bn, R = Bu)
tBu Me PPh2
N
MeO
1
2
3
R1HN
(R =Boc, R =Bn, R =Ph)
Boc
N
1
2
i
3 i
(R =Boc, R = Pr, R = Pr)
O
R3
N
H
OH
1
2
t
3 i
OH
OH
O
iPr
(R =Boc, R = Bu, R = Pr)
2gb
1
2
3 i
2f
3n
MeO
2e
(R =Boc, R =Ph, R = Pr)
Yield: 90% (20h)
Yield: 88% (2h)
78% e.e.
Yield: 98% (6h)
87% e.e.
entry Catalyst Solvent Additive Time Yield e.e.(%)c
82% e.e.
O
(%)b
65
<5
<5
86
87
77
89
80
87
99
83
98
91
82
21
O
(h)
24
96
96
16
24
16
16
16
16
16
16
3
O
1
DMAP
3a
EtOH
none
OH
OH
2
EtOH
none
n.d.d
n.d.d
84
OH
2h
2i
2j
MeO
3
3b
3c
EtOH
none
Yield: 99% (3h)
98% e.e.
Yield: 99% (7h)
>98% e.e.
Yield: 99% (4h)
97% e.e.
O
4
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
O
Br
5
3d
3e
68
MeO
6
72
OH
OH
2k
Yield: 99% (7h)
>98% e.e.
2l
Yield: 95% (2h)
97% e.e.
O
7
3f
76
8
3g
84
O
O
9
3h
3i
82
F
10
11
12
13
14
15
80
OH
OH
OH
O
3j
86
2m
2n
2o
Yield: 73% (8h)
74% e.e.
O
Yield: 99% (2h)
98% e.e.
Yield: 99% (1h)
97% e.e.
O
3k
3l
90
O
16
40
72
81
O
3m
3n
82
OH
OH
10
OH
2q
2p
2r
2s
a All reactions were carried out at 0.06 mmol scale of 1a, using
10 mol% of catalyst, 50 mol% of PhOH in 0.8 mL of CHCl3 at r.t.
until consumption of starting material (TLC analysis). bYields refer
Yield: <5% (96h) Yield: 72% (5h) Yield: 82% (10h) Yield: 73% (28h)
92% e.e. 70% e.e.
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a All reactions were carried out at 0.20 mmol scale of 1a-t, using
Finally, we also decided to demonstrate the potential of this
methodology as a general tool in total synthesis. In particular, this
reaction has shown to be particularly effective for the construction
of the bicyclo[5.3.0]decane structure, which is the central motif of
the general architecture of many natural products of sesquiterpene
and diterpene origin.18 In particular, we focused on the application
of this methodology on the synthesis of -gurjunene (see Scheme
4), a sesquiterpenoid natural product isolated from the gurjun
balsams of several species of Dipterocarpus.19 In view of its
structure and observing the presence of a methyl substituent at C-4
(which is also generally found in most of the natural products with
this architecture isolated up to date), we envisaged that chiral
ketoenone 4 should be a very appropriate starting material.
Moreover, we decided to use this substrate in a racemic form,
provided that conditions were found that enable kinetic resolution
during the projected catalytic enantioselective transannular Morita-
Baylis-Hillman reaction. Indeed, when this compound was
subjected to reaction in the presence of catalyst 3k under slightly
modified conditions,20 bicyclic adduct 5 was isolated in 42% yield
and 90% e.e. together with the resolved starting material (R)-4 in
56% yield and 76% e.e.21 Next, this adduct was protected as the
1
2
3
4
5
6
7
8
10 mol% of 3k, 50 mol% of PhOH in 2.0 mL of CHCl3 at r.t. Yields
refer to isolated pure product 2a-s and e.e. was calculated by HPLC
on chiral stationary phase (See supporting information for details).
b Reaction carried out at 0ºC in CCl4
Those substrates that require the formation of larger ring
structures at the cycloalkanone moiety of the final adduct (m>1)
were found to be less reactive. In fact, a longer reaction time was
required for the synthesis of the bicyclo[6.3.0]undecane scaffold
(adduct 2o), even though still providing acceptable yield and e.e.
but substrate 1p failed to undergo the desired transannular process
that would eventually lead to the formation of compound 2p. This
reaction design can also be used for the construction of decalone-
type scaffolds (m=0, n=2 in adducts 2q and 2r) but provides the
corresponding dehydration product when trying to build up the
bicyclo[4.3.0]nonane scaffold (m=0, n=1; substrate 1s). Finally, we
also scaled up the reaction leading to 2a, obtaining similar results
(98% yield, 90% e.e. at 2.0 mmol scale).
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The absolute stereostructure of the adducts obtained by this
protocol was established by single-crystal X-ray analysis of an
enantiopure sample of compound 2k. The configuration of all other
adducts 2a-r, was established based on mechanistic analogy.
Accordingly, we can tentatively propose a model to explain the
stereochemical outcome of the reaction through the formation of an
intermediate such as the one depicted in Scheme 2. In this sense,
once the activation of the substrate by the catalyst by conjugate
addition of the phosphine has taken place, the stereodefining step
would rely on the presence of H-bonding interactions between the
NH moieties of the catalyst and the electrophilic ketone during the
transannular aldol reaction step. This type of arrangement has also
been proposed in the literature for other reactions in which his type
of bifunctional phosphines have been involved.17
corresponding TMS ether (TMS=trimethylsilyl)
6
and
subsequently subjected to conjugate addition with Gilman cuprate.
Disappointingly, this reaction provided the corresponding
conjugate addition product with the wrong stereochemistry at the
-stereocentre. As an alternative, the enolate intermediate arising
after the conjugate addition of Gilman cuprate to 6 was trapped in
situ as the corresponding TMS enol ether, followed by treatment
with N-bromosuccinimide (NBS), which led to the formation of
brominated adduct 7. Base-promoted elimination followed by
hydrogenation provided compound 8 with the correct relative
stereochemistry. The lateral 2-propenyl unit was introduced
through standard aldol chemistry followed by dehydration,
providing key synthetic intermediate 9 in excellent yield. Finally,
installation of the endocyclic C=C double bond was accomplished
by reduction of the ketone moiety followed by elimination under
standard conditions, leading to the target product (-)--gurjunene,
whose spectroscopic and analytical data matched with those
reported in the literature.22
Scheme 2. Proposed stereochemical model.
O
O
O
N
Ph
2k
H
P
Ph
O
N
O
n
H
O
tBuO
OH
m
n
m
H
n
O
Scheme 4. Total synthesis of (-)--gurjunene..
H
m
O
O
O
3k
(10 mol%)
In addition, we also tested substrate 1t (m=1, n=0 in Table 2) that
should lead to the formation of a cycloheptanone structure with a
fused four-membered ring. However, this compound showed a
particular behavior, forming compound 2t in an excellent yield and
high enantiocontrol (see Scheme 3). The formation of this
structurally different adduct can be explained by assuming
isomerization of the intermediate enolate formed after the
activation of the substrate. The reason for this behavior should rely
on the less strained nature of 2t in comparison with the
bicyclo[5.2.0]nonane architecture expected to be formed through
the conventional pathway.
TMS·imidazole
TMSCl
PhOH (50 mol%)
CCl4, 5ºC, 30 min.
Yield: 42%; 90% e.e.
neat. r.t.
OH
OTMS
53%
(±)-4
5
6
O
(R)-4
+
(56%;76% e.e.)
1) MeLi, CuI/TMSCl
Et3N, THF, -78ºC
75%
(2 steps)
2) NBS, THF, 0ºC
O
1) Li2CO3, LiBr
DMF, 130ºC
1) LDA, THF, -78ºC
2) acetone, ZnCl2,
THF, -40ºC
O
O
Br
H
H
H
3) Burgess reagent
C6H6, 60ºC
2) H2, Pd/C
OTMS
H
42% (2 steps)
55% (3 steps)
9
8
7
96%
(1:1 d.r.)
DIBAL-H
CH2Cl2, -78ºC
Scheme 3. Proposed pathway for the formation of 2t.
R1
R2
O
O
O
3k
(10 mol%)
H
H
PhOH (50 mol%)
Burgess reagent
CHCl3, 60ºC
CHCl3, 25ºC
OH
not formed
O
1t
61%
OH
2t
H
H
Yield: 86% (96h)
87% e.e. (d.r. 17:1)
10´
)
(from
1
2
(-)--gurjunene
10
(R =OH, R =H)
PR3
PR3
1
2
10'
(R =H, R =OH)
O
O
O
H
In conclusion, we have established a solid and direct synthetic
approach to polycyclic carbo- and heterocyclic scaffolds using
transannular reactivity as an unconventional entry to this type of
complex molecular architectures. Through the activation of a
PR3
PR3
PR3
O
O
O
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lactones: Recent advancements in medium-sized ring formation. Chem.
medium-sized ketoenone substrate with a chiral enantiopure
multifunctional phosphine catalyst, a transannular Morita-Baylis-
Hilman reaction takes place with excellent yield and
enantioselectivity for a variety of different substrates, enabling the
generation of bicyclic structures containing fused rings of different
sizes and with an excellent degree of stereocontrol in the generation
of the stereogenic tertiary alcohol moiety placed at the ring
junction. Moreover, this new reaction has been used as the key step
in the first enantioselective total synthesis of a sesquiterpene
natural product, which highlights the synthetic utility and
performance of this transformation as a powerful tool in organic
synthesis. For instance, the straightforward access to the
hydroazulene core opens additional possibilities for the application
of this methodology to other relevant examples of total synthesis.
In addition, this type of reactivity will be further developed to other
mechanistically related transformations in order to further widen
the potential of transannular reactions as an alternative
disconnection when planning the total synthesis of complex
molecules.
Rev. 2007, 107, 239. (g) Hassan, H. M. A. Recent applications of ring-
closing metathesis in the synthesis of lactams and macrolactams. Chem.
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macrocyclizations as an efficient ring-closing strategy in natural product
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products. Chem. Rev. 2006, 106, 911. (j) Yet, L. Metal-mediated synthesis
of medium-sized rings Chem. Rev. 2000, 100, 2963. (k) Maier, M. E.
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1
2
3
4
5
6
7
8
(3) Reyes, E.; Uria, U.; Carrillo, L.; Vicario, J. L. Transannular reactions
in asymmetric total synthesis. Tetrahedron 2014, 70, 9461.
9
10
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(4) There is one example of an enantioselective transannular aldol
reaction using stoichiometric amounts of a chiral metal alkoxide as
Bronsted base. Knopff, O.; Kuhne, J.; Fehr, C. Enantioselective
intramolecular aldol addition/dehydration reaction of a macrocyclic
diketone: Synthesis of the musk odorants (R)-muscone and (R,Z)-5-
Muscenone. Angew. Chem. Int. Ed. 2007, 46, 1307.
(5) Balskus, E. P.; Jacobsen , E. N. Asymmetric catalysis of the
transannular Diels-Alder reaction. Science 2007, 317 , 1736.
(6) Jaschinski, T.; Hiersemann, M. {1,6}-Transannular Catalytic
Asymmetric Gosteli–Claisen Rearrangement. Org. Lett. 2012, 14, 4114.
(7) Rajapaksa, N. S.; Jacobsen, E. N. Enantioselective catalytic
transannular ketone-ene reactions. Org. Lett. 2013, 15, 4238.
(8) Chandler, C. L.; List, B. Catalytic, asymmetric transannular
aldolizations: Total synthesis of (+)-Hirsutene. J. Am. Chem. Soc. 2008,
130, 6737.
(9) Ciganek, E. The catalyzed α‐hydroxyalkylation and
α‐aminoalkylation of activated olefins (the Morita-Baylis-Hillman
reaction). Org. React. 1997, 51, 201.
(10) (a) Pellissier, H. Recent developments in the asymmetric
organocatalytic Morita-Baylis-Hillman reaction. Tetrahedron 2017, 73,
2831. (b) Wei, Y.; Shi, M. Recent Advances in organocatalytic asymmetric
Morita-Baylis-Hillman/aza-Morita-Baylis-Hillman reactions. Chem. Rev.
2013, 113, 6659. (c) Marinetti, A.; Voituriez, A. Enantioselective
phosphine organocatalysis. Synlett 2010, 174. (d) Masson, G.; Housseman,
C.; Zhu, J. The enantioselective Morita-Baylis-Hillman reaction and its aza
counterpart. Angew. Chem. Int. Ed. 2007, 46, 4614. (e) Krishna, P. R.;
Sachwani, R.; Reddy, P. S. Asymmetric Baylis-Hillman reaction: an
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ASSOCIATED CONTENT
Supporting Information
Survey of the performance of a variety of chiral Lewis base
catalysts and additives in the model reaction. Characterization
of all new compounds and copies of 1H and 13C NMR spectra.
HPLC traces of all adducts prepared (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
efraim.reyes@ehu.es; joseluis.vicario@ehu.es
Author Contributions
All authors have given approval to the final version of the
manuscript.
(11) (a) Han, J.; Li, F.; Li, C. Collective synthesis of Humulanolides
using a metathesis cascade reaction. J. Am. Chem. Soc. 2014, 136, 13610.
(b) Mergott, D. J.; Frank, S. A.; Roush, W. R. Total synthesis of (–)-
Spinosyn A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11955. (c) Winbush,
S. M.; Mergott, D. J.; Roush, W. R. Total synthesis of (−)-Spinosyn A:ꢀ
Examination of structural features that govern the stereoselectivity of the
key transannular Diels-Alder reaction. J. Org. Chem. 2008, 73, 1818. For a
seminal work on the Rauhut-Currier reaction: (d) Wang, L.-C.; Luis, A. L.;
Agapiou, K., Jang, H.-Y.; Krische, M. J. Organocatalytic Michael
Cycloisomerization of Bis(enones): The Intramolecular Rauhut−Currier
Reaction. J. Am. Chem. Soc. 2002, 124, 2402.
(12) Fu, G. C. Asymmetric catalysis with "planar-chiral" derivatives of
4-(dimethylamino)pyridine. Acc. Chem. Res. 2004, 37, 542.
(13) Ni, H.; Chan, W.-L.; Lu, Y. Phosphine-catalyzed asymmetric
organic reactions. Chem. Rev. 2018, 118, 9344.
(14) For an excellent discussion on this topic see Wei, Y.; Shi, M.
Multifunctional chiral phosphine organocatalysts in catalytic asymmetric
Morita-Baylis-Hillman and related reactions. Acc. Chem. Res. 2010, 43,
1005.
(15) For a complete description of the mechanism of Morita-Baylis-
Hillman reaction and the role of protic additives see (a) Plata, R. E.;
Singleton, D. A. A case study of the mechanism of alcohol-mediated Morita
Baylis-Hillman reactions. The importance of experimental observations. J.
Am. Chem. Soc. 2015, 137, 3811. (b) Isenegger, P. G.; Bachle, F.; Pfaltz, A.
Asymmetric Morita-Baylis-Hillman Reaction: Catalyst development and
mechanistic insights based on mass spectrometric back-reaction screening.
Chem. Eur. J. 2016, 22, 17595. (c) Singh, N. K.;Satpathi, B.; Balanarayan,
P.; Ramasastry S. S. V. A computational investigation of the solvent
dependent enantioselective intramolecular Morita-Baylis-Hillman reaction
of enones. Org. Biomol. Chem., 2017, 15, 10212. See also (d) Robiette, R.;
Aggarwal, V. K.; Harvey, J. N. Mechanism of the Morita-Baylis-Hillman
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors thank the Spanish MICINN (FEDER-CTQ2017-
83633-P 52107-P) and the Basque Government (Grupos IT908-
16 and fellowship to R. Mato) for financial support.
REFERENCES
(1) (a) Marsault, E.; Toro, A.; Nowak, P.; Deslongchamps, P. The
transannular Diels-Alder strategy: applications to total synthesis.
Tetrahedron 2001, 57, 4243. (b) Handa, S.; Pattenden, G. Free radical-
mediated macrocyclizations and transannular cyclizations in synthesis.
Contemp. Org. Synth. 1997, 4, 196. (c) Montana, A. M.; Batalla, C.; Barcia,
J. A. Intramolecular haloetherification and transannular hydroxycyclization
of alkenes. A synthetic methodology to obtain polycyclic ethers and amines.
Curr. Org. Chem. 2009, 13, 919. (d) Rizzo, A.; Harutyunyan, S. R.
Azabicycles construction: the transannular ring contraction with N-
protected nucleophiles. Org. Biomol. Chem. 2014, 12, 6570.
(2) (a) Donald, J. R.; Unsworth, W. P. Ring-expansion reactions in the
synthesis of macrocycles and medium-sized rings. Chem. Eur. J. 2017, 23,
8780. (b) Webster, A. M.; Cobb, S. L. Recent advances in the synthesis of
peptoid macrocycles Chem. Eur. J. 2018, 24, 7560. (c) Josse, T.; De Winter,
J.; Gerbaux, P.; Coulembier, O. Cyclic polymers by ring-closure strategies.
Angew. Chem. Int. Ed. 2016, 55, 13944. (d) Hussain, A.; Youssuf, S. K.;
Mukherjee, D. Importance and synthesis of benzannulated medium-sized
and macrocyclic rings. RSC Adv. 2014, 4, 43241. (e) White, C. J.; Yudin,
A. K. Contemporary strategies for peptide macrocyclization. Nat. Chem.
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Reaction:ꢀ A computational investigation. J. Am. Chem. Soc. 2007, 129,
15513.
(16) A detailed list of protic additives tested and the optimization of the
amount of phenol required is included at the supporting information.
(17) Wang, T.; Han, X.; Zhong, F.; Yao, W.; Lu, Y. Amino acid-derived
bifunctional phosphines for enantioselective transformations. Acc. Chem.
Res. 2016, 49, 1369.
(18) Brill, Z.G.; Condakes, M. L.; Ting, C. P.; Maimone, T. J. Navigating
the chiral pool in the total synthesis of complex terpene natural products.
Chem. Rev. 2017, 117, 11753.
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configuration: Isomerisation de l'α-gurjunene. Tetrahedron 1969, 25, 1785.
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hydrocarbons on alkali metal/aluminum oxide. Angew. Chem. Int. Ed. 1985,
24, 320.
(20) For the complete optimization study of the kinetic resolution
process (reaction time vs e.e.) see supporting information.
(21) The absolute stereostructure of both compounds (R)-4 and 5 was
determined by X-ray diffraction analysis of monocrystalline samples.
(22) Konig, G. M.; Wright, A. D. New and unusual sesquiterpenes:
kelsoene, prespatane, epi--gurjunene, and t-cadinthiol, from the tropical
marine sponge cymbastela hooperi. J. Org. Chem. 1997, 62, 3837.
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SYNOPSIS TOC
1
H
2
3
4
5
O
Boc
N
N
PPh2
R
O
O
H
O
R
(cat.)
Enantioselective
Transannular
Morita-Baylis-Hillman
X
OH( )m
X
( )n
( )m
( )n
6
7
8
20 examples
70 - >98% e.e.
Substituted Carbo- and Heterocycles
Different ring sizes
9
10
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13
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