Fast synthesis of complex enantiopure heterocyclic scaffolds by a tandem sequence of simple transformations on α-hydroxyaldehydes

Article abstract of DOI:10.1002/chem.201301712

Two tandems are faster than one! Properly sequenced reactions initiated by the Petasis aminoalcohol synthesis from boronic acids, diallylamine, and α-hydroxyaldehydes, including free aldoses, leads to rapid construction of complex enantiopure structures (see scheme). Copyright

Full text of DOI:10.1002/chem.201301712

COMMUNICATION
DOI: 10.1002/chem.201301712
Fast Synthesis of Complex Enantiopure Heterocyclic Scaffolds by a Tandem
Sequence of Simple Transformations on a-Hydroxyaldehydes
Alexandre Cannillo,[a] Stꢀphanie Norsikian,*[a] Pascal Retailleau,[a]
Marie-Elise Tran Huu Dau,[a] Bogdan I. Iorga,[a] and Jean-Marie Beau*[a, b]
Tandem chemical operations, in which a single product of
a much higher structural complexity is formed from very
simple building blocks, are essential issues in organic chem-
istry, particularly when taking into consideration sustainabil-
ity.[1] Novel synthetic sequences must be developed to pro-
vide easy access to new structural scaffolds in high efficiency
and high enantiomeric purity. An effective way to meet
these demanding issues of synthesis in constructing poly-
which up to six covalent bonds and five asymmetric centers
are formed, containing up to four points of diversity. The
demand is currently high for effective synthetic pathways
leading to new small molecular arrangements able to modu-
late biological systems.[3]
The borono-Mannich multicomponent reaction of aryl or
vinyl boronic acids with amines and optically pure a-
hydroxyACHTNUTRGNEaNUG ldehydes produces, in a single step, the correspond-
A
ing amino alcohol with a high degree of diastereocontrol,
cascade, or tandem transformations.[2]
leading exclusively to the anti adduct as a single enantio-
We report here two consecutive tandem processes, trans-
ferable into a simple one-pot sequence of classic transforma-
tions in which the chiral center of the starting a-hydroxy-
mer.[4,5] Elaborated compounds, such as polyfunctionalized
ACHTUNGTRENNUNG
pyrrolidines,[6] iminosugars,[7] conduramines,[8] N-acetylneur-
aminic acid,[9] or anti-influenza agents,[10] were synthesized
using this methodology. We reasoned that initiating a se-
quence of transformations by a combination of this borono-
Mannich reaction with an intramolecular Diels–Alder
(IMDA) reaction would produce new molecular constructs
with high efficiency and selectivity.[11] The stereostructure of
ACHTUNGTRENNUNGaldehyde directs with high stereoselectivity a first Petasis
borono-Mannich/intramolecular Diels–Alder tandem trans-
formation (Scheme 1, step a) and subsequently acts as the
nucleophile in the second cross-metathesis/conjugate addi-
tion tandem set of reactions (Scheme 1, step b).
The result of this sequence is the construction of enantio-
pure molecules with a common novel structural scaffold in
the aminoACTHNGUTRENNUaG lcohol product would hopefully guide the instal-
lation of additional stereocenters during ring construction in
the Diels–Alder step. When the
starting amine contains another
properly disposed unsaturation,
we also expected that this
tandem transform would then
set the stage for a second cross-
Scheme 1. Tandem sequence leading to complex enantiopure heterocyclic scaffolds from a-hydroxyaldehydes
(newly formed covalent bonds are in bold gray).
metathesis/conjugate addition
tandem set of reactions
(Scheme 1).
We initially focused on the three-component coupling be-
tween the readily available (E)-(3-methylbuta-1,3-dien-1-yl)-
boronic acid (1),[12] diallylamine (2), and (S)-2-hydroxyhep-
tanal (3a; Table 1). The latter compound was obtained by
regioselective oxidation of the corresponding (S)-1,2-diol 4a
and used directly after the oxidation workup in the next Pe-
tasis condensation.[12,13] The optimal conditions were found
in CH2Cl2/HFIP at 508C for 12 h (entry 2) or under micro-
wave irradiation (1208C,[14] 30 min, entry 1), with the reac-
tion leading only to the formation of the cyclized compound
6a (R=nBu) in 84 and 91% yield, respectively. In CH2Cl2
alone, the reaction was less effective (entries 3 and 5), pro-
viding the Petasis/Diels–Alder adduct 6a in lower yields. In-
terestingly, the intramolecular cycloaddition reaction occur-
red even at room temperature (entries 4 and 5) with no
trace of uncyclized 5a (R=nBu) being detected. Only hexa-
[a] A. Cannillo, Dr. S. Norsikian, Dr. P. Retailleau, Dr. M.-E. T. H. Dau,
Dr. B. I. Iorga, Prof. J.-M. Beau
Centre de Recherche de Gif
Institut de Chimie des Substances Naturelles du CNRS
CNRS UPR 2301, Avenue de la Terrasse
91198 Gif-sur-Yvette (France)
Fax : (+33)1-69-07-72-47
E-mail: stephanie.norsikian@icsn.cnrs-gif.fr
jean-marie.beau@icsn.cnrs-gif.fr
[b] Prof. J.-M. Beau
Universitꢀ Paris-Sud and CNRS
Laboratoire de Synthꢁse de Biomolꢀcules
Institut de Chimie Molꢀculaire et des Matꢀriaux d’Orsay
91405 Orsay (France)
Fax : (+33)1-69-85-37-15
E-mail: jean-marie.beau@u-psud.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301712.
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Table 1. Selected experimental conditions for the tandem Petasis Diels–
Alder reaction starting from boronic acid 1, diallylamine (2) and a-hy-
droxyaldehyde 3a.
Table 2. Scope for the tandem Petasis Diels–Alder reaction.
Entry
Substrates
Product[a]
Yield [%][b]
1
2
1+2+3b
1+2+3c
6b, R=iPr
6c, R=Ph
71
75
Entry
Solvent[a]
T [8C]
t [h]
Yield 6a [%][b]
1
2
3
4
5
CH2Cl2/HFIP[c]
CH2Cl2/HFIP[c]
CH2Cl2
120 (MW)
50
50
RT
RT
0.5
12
12
12
96
91
84
42
61
24
CH2Cl2/HFIP[c]
CH2Cl2
3
4
1+2+3e[c]
6e
6 f
73
64
[a] The reaction was carried out with 1 (1 equiv), 2 (2 equiv), and 3a
(2 equiv based on the starting diol 4a). [b] Isolated yield following chro-
matography, based on boronic acid. [c] As a 9:1 mixture. HFIP=hexa-
fluoroisopropanol.
1+2+3 f[c]
hydroisoindole 6a was obtained, which suggested a very fa-
vorable preorganization of the two partners of the intramo-
lecular Diels–Alder reaction as very recently quantified in a
“proximity-induced” example.[15] Moreover, of the four pos-
sible diastereoisomers that could be obtained from the cycli-
zation, we observed the formation of a unique isomer with
complete stereocontrol at all the newly formed asymmetric
centers.[16,17]
5
6
7
9+2+3a
9+2+3b
9+2+3c
11a, R=nBu[d]
11b, R=iPr
11c, R=Ph
83
66
86
The configuration of 6a was unambiguously determined
through the X-ray crystal diffraction analysis of 8, obtained
after deallylation of 6a and p-nitrobenzoylation of the re-
sulting free amine 7 (Scheme 2). The crystal structure of 8
8
9
10+2+3a[c]
10+2+3d[c]
12a, R=nBu[d]
12b, R=nPr
94
78
[a] The reaction was carried out with boronic acid (1 equiv), a-hydroxy-
AHCTUNGTRENGaNNU ldehyde (2 equiv), and amine (2 equiv) in a 9:1 mixture of CH2Cl2/HFIP
under microwave radiation (1208C, 30 min) unless otherwise stated.
[b] Isolated yield following chromatography, based on boronic acid. [c] A
1:1 mixture of CH2Cl2/HFIP was used. [d] X-ray analysis of the corre-
sponding N-p-nitrobenzamide is available (compounds 16 and 17, see the
Supporting Information).
IMDA was obtained, showing the addition of the diene on
the Re face of the dienophile in the endo TS.
Using the optimized conditions (MW, 1208C, 30 min), we
studied the reaction scope with a series of substrates and the
results are shown in Table 2. The reaction of boronic acid 1,
diallylamine (2), optically pure a-hydroxyaldehydes 3b–c,[12]
carbohydrates d-ribose (3e), and d-fucose (3 f) gave com-
pounds 6b–c and 6e–f, respectively (Table 2, entries 1–4).
As observed previously, only one isomer was observed for
each compound and their absolute configurations were
given in analogy to that of 6a. In the case of the more polar
aldoses 3e and 3 f, the proportion of HFIP was increased
(1:1 mixture of CH2Cl2/HFIP) for solubility. Other dienic
boronic acids, such as 9 and 10,[12] in combination with dif-
ferent aldehydes 3a–d and allyl amine 2 (entries 5–9) pro-
Scheme 2. Derivatization of hexahydroisoindole (+)-6a and X-ray struc-
ture of nitrobenzamide 8: a) NMBA, cat. [PdACTHNUGTRNEUNG(PPh3)4], CH2Cl2, 458C,
12 h; b) 4-nitrobenzoyl chloride, pyridine, RT, 48 h then MeOH, K2CO3
(77%). NMBA=N,N’-dimethylbarbituric acid.
confirmed the anti relationship of the amino alcohol pro-
duced during the borono-Mannich reaction.[18] It also re-
vealed a cis-ring junction geometry, which suggested that
the IMDA reaction proceeded through an endo transition
state. Moreover, an excellent p-facial selectivity of this
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Fast Synthesis of Complex Enantiopure Heterocyclic Scaffolds
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duced the corresponding hexahydroisoindole adducts[19] as
single enantiomers.[20,21] In the case of 11a and 12a, endo
and facial selectivities were the same as previously observed
and were confirmed by X-ray analysis of the corresponding
p-nitrobenzamide derivatives.[22,23]
The N-allyl appendage in hexahydroisoindole 6a then
served as the starting point to install the subsequent tandem
transformation. Thus, after ammonium tosylate salt forma-
tion[24] and ruthenium–alkylidene-catalyzed cross metathe-
sis[25] with methyl vinyl ketone, the resulting enone under-
went directly 1,4-addition[26] of the properly positioned hy-
droxyl group. Hexahydroisoindole 6a provided, in good
yield (86%) with high diastereoselectivity, the tricyclic 2,6-
trans-substituted morpholine compound 13a (Table 3).[27]
Similar results were obtained with hydroxyhexahydroiso-
A further increase of the conciseness of the synthesis was
ultimately implemented by completing the entire sequence
of transformations on three examples, by starting from the
boronic acid, amine, and a-hydroxyaldehyde in the same re-
action vessel (Table 3). Although a notable reduction of the
overall efficiency was noticed when compared to the two-
pot procedure, the need for workup and product isolation of
the intermediate products was avoided.
The cornerstone of the entire sequence was the remark-
AHCTUNGTREGaNNUN bly facile and highly selective intramolecular Diels–Alder
reaction that insured the overall 3D geometry of the scaf-
fold. To better understand this key experimental result, a
molecular modeling study of the reaction was undertaken
starting from the simplified structures Sa and Sb that would
result from the borono-Mannich reaction (the hydroxyl
group was considered in either a free form or a borate
ester).[28] The two endo (TS1 and TS2) and two exo (TS3
and TS4) possible transition states (TSs) were built, leading
to products with a cis and trans junction, respectively
(Scheme 3). The energy diagram for this reaction (see the
ACHTUNGTRENNUNGindoles 6b–c, 11a–b, and 12b leading to enantiopure tri- or
tetracyclic scaffolds 13b–c, 14a–b, and 15.
Table 3. Examples of the cross-metathesis/Michael addition tandem
transformation on hexahydroisoindoles 6a–c, 11a–b, and 12b and results
of the one-pot process from the starting boronic acid 1, 9, or 10, diallyl-
ACHTUNGTRENNUNGamine (2), and a-hydroxyaldehydes 3a or 3d.
Entry
Hexahydroisoindole
substrate
Product
AHCTUNGTRENNUNG
(yield [%])[a,b]
Combined
yield [%][c]
1
2
3
6a
6b
6c
13a, R=nBu (86)
13b, R=iPr (82)
13c, R=Ph (84)
78 (53)[d]
58
63
Scheme 3. Transition structures for the intramolecular Diels–Alder reac-
tion of model Sa and its borate ester Sb resulting from the three-compo-
nent Petasis borono-Mannich reaction. C1–4a,b are the near-attack con-
formers. Details are given in the Supporting Information.
4
5
11a
11b
14a, R=nBu (56)
14b, R=iPr (65)
47 (33)[d]
43
Supporting Information) generated using DFT calculations
at the B3LYP/6-31GACTHNUTRGNE(NUG d,p) level led to the following major
conclusions: 1) in all structures an intramolecular hydrogen
bond between the tertiary amino group and either the hy-
droxyl or borate moieties as shown in Sa and Sb most likely
plays an important role in pre-organizing the reacting func-
tional groups in favorable positions; 2) the Diels–Alder re-
action is irreversible, the energy barrier for the retro-reac-
tion being extremely high (about 60 kcalmolÀ1), which im-
plies that the reaction is under kinetic control; and 3) the
relative rates of the reactions converting C1–4 to P1–4,
6
12b
15, R=nPr (64)
50 (24)[d]
[a] Reaction conditions: TsOH (1 equiv), CH2Cl2; methylvinylketone
(10 equiv), cat. HG-II, CH2Cl2, MW irradiation, 1008C, 4 h. [b] Isolated
yield following chromatography. [c] Combined yield of the two separated
tandem transformations based on the starting boronic acid. [d] Entire se-
quence in
a one-pot procedure. Reaction conditions: boronic acid
(1 equiv), a-hydroxyaldehyde (2 equiv), and amine (2 equiv), 9:1 mixture
of CH2Cl2/HFIP, microwave irradiation (1208C, 30 min) then conditions a
with TsOH (2 equiv).
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S. Norsikian, J.-M. Beau et al.
CHARM3AT and LERMIT Labex programs are acknowledged for their
support.
weighed by the Boltzmann distribution of the initial near-
attack conformers C1–4, are 5300:1:4:4 and 34000:1:34:89 in
both a and b series, respectively. This analysis clearly indi-
cated the highly favored formation of the endo products
P1a,b, consistent with the experimentally observed exclusive
formation of diastereoisomer 6a and of analogous com-
pounds.[29]
Keywords: borono Mannich
·
carbohydrates
·
cross
metathesis · Diels–Alder reactions · tandem reaction
In conclusion, we have successfully developed a novel se-
quence of tandem transformations, combining the Petasis
borono-Mannich, intramolecular Diels–Alder, cross meta-
thesis, and Michael reactions. This process allows the effi-
cient and totally stereocontrolled formation of new poly-
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ACHTUNGTRENNUNGheterocyclic scaffolds. The highly favored and selective in-
tramolecular Diels–Alder reaction, strategic for the stereo-
chemical outcome of this sequence, was rationalized with
DFT calculations. Variations on this theme are currently
being explored in our laboratory.
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Experimental Section
General: Detailed experimental procedures, characterization data, 1H
and 13C NMR spectra for new compounds, crystallographic data, molecu-
lar modeling details, theoretical characterization of the studied structures
and their PDF3D representations are provided in the Supporting
Information.
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Preparation of hexahydroisoindole 12a: Diallylamine (2; 1.23 mL,
10.0 mmol, 2.0 equiv) and boronic acid 10 (640 mg, 5.00 mmol, 1.0 equiv)
were added to a stirred solution of aldehyde 3a (1.30 g, 10.0 mmol,
2.0 equiv) in dichloromethane/hexafluoroisopropanol (1:1, 25 mL). The
resulting mixture was heated at 508C for 16 h. Solvent evaporation and
purification afforded hexahydroisoindole 12a (1.32 g, 4.50 mmol, 90%)
as a yellow oil. [a]2D0 =À20 (c=0.80 in CHCl3). ESI-HRMS: m/z: calcd
for C18H32NO2: 294.2433; found: 294.2434; spectroscopic details are given
in the Supporting Information.
One-pot borono-Mannich/Diels–Alder reaction followed by cross-meta-
thesis/Michael addition synthesis of morpholine 13a: Diallylamine (2;
30 mL, 250 mmol, 2.0 equiv) and then boronic acid 1 (14 mg, 125 mmol,
1.0 equiv) were added to a stirred solution of 2-hydroxyheptanal 6a
(32 mg, 250 mmol, 2.0 equiv) in dichloromethane/hexafluoroisopropanol
(9:1, 0.7 mL). The resulting mixture was heated to 1208C by microwave
irradiation for 30 min. The solvent was removed under reduced pressure.
Dry dichloromethane (2.8 mL) and anhydrous p-toluenesulphonic acid
(42 mg, 250 mmol, 2.0 equiv) were added to the residue under an argon
atmosphere. The resulting mixture was stirred at room temperature for
15 min and the solvent was removed under reduced pressure. Dry and
degassed dichloromethane (1.3 mL), methyl vinyl ketone (125 mL,
1.25 mmol, 10 equiv), and Hoveyda–Grubbs II catalyst (HG-II, 7.8 mg,
12.5 mmol, 0.1 equiv) were added to the residue under an argon atmos-
phere. The resulting mixture was heated at 1008C for 4 h by microwave
irradiation. Solvent and excess of ketone were removed under reduced
pressure (2 h at 1 mbar) and the residue was purified by flash chromatog-
raphy on silica gel (toluene/acetone/Et3N 94.9:5:0.1) to afford product
13a (21 mg, 65.7 mmol, 53%) as a yellow oil. [a]2D0 =À99 (c=0.85 in
CHCl3); ESI-HRMS: m/z: calcd for C20H34NO2: 320.2590; found:
320.2588.
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[12] For the detailed preparation, see the Supporting Information.
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[14] Under microwave irradiation with CH2Cl2 alone, by using a CEM
Discover S-Class apparatus, the temperature could only reach 908C
(not 1208C), which led after 30 min to 6a in only 20% yield.
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1
[16] Determined by H and 13C NMR spectroscopy.
Acknowledgements
[17] Enantiomeric purity of the hexahydroisoindole product was con-
firmed by chiral HPLC analysis in the case of 6c (Table 2).
We thank the ICSN-CNRS for a PhD grant for A.C. and the Institut Uni-
versitaire de France (IUF) for the financial support of this study. The
[18] The reaction is believed to proceed through a transient iminium spe-
cies followed by an intramolecular transfer of the organyl ligand
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from the activated “ate” complex of organoboronic acid: a) N.
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[19] Gram-scale synthesis was carried out with 10 (0.64 g, 5 mmol), 2,
and 3a in a 1:1 mixture of CH2Cl2/HFIP at 508C for 16 h to lead to
12a in 90% yield (1.32 g).
[20] For a recent access to an enantiopure perhydroisoindole scaffold
from fumagillol, see: B. R. Balthaser, M. C. Maloney, A. B. Beeler,
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[27] Relative stereochemistry can be deduced from 1H NMR spectrosco-
py including NOESY experiments.
[28] Derivatives with boron directly bonded to the nitrogen atom were
[21] At this stage, further diversity may be obtained by easy functionali-
zation of the cyclohexene ring. Full details will be reported in a full
paper.
[22] See the Supporting Information. CCDC-913816 (8), -913817 (16),
and -913818 (17) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
also considered in theoretical calculations but, during the optimiza-
À
tion step, the B N bond was broken.
[29] Our calculations predict the same selectivity with the hydroxyl
group in both free form or as a borate ester. Indeed, in the case of
the less favorable IMDA, the same unique diastereoisomer was
experimentally obtained by using
a one-pot protocol or by
isolating the intermediate Petasis adduct before the Diels–Alder
cycloaddition.
[23] After submission of this work, we learned that a similar borono-
Mannich/intramolecular Diels–Alder transformation with furan-2-
Received: May 3, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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S. Norsikian, J.-M. Beau et al.
Two tandems are faster than one!
Properly sequenced reactions initiated
by the Petasis aminoalcohol synthesis
from boronic acids, diallylamine, and
a-hydroxyaldehydes, including free
aldoses, provide a brief construction of
complex enantiopure structures (see
scheme).
Synthesis
A. Cannillo, S. Norsikian,*
P. Retailleau, M.-E. T. H. Dau,
B. I. Iorga, J.-M. Beau* . . . . . &&&& — &&&&
Fast Synthesis of Complex Enantio-
pure Heterocyclic Scaffolds by a
Tandem Sequence of Simple Transfor-
mations on a-Hydroxyaldehydes
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6
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www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!