Enantioselective synthesis of seven-membered carbo- and heterocyles by organocatalyzed intramolecular Michael addition

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Enantioselective Synthesis of Seven-Membered Carbo- and Heterocyles by
Organocatalyzed Intramolecular Michael Addition.
James O. Guevara-Pulido, José M. Andrés, Deisy P. Ávila and Rafael Pedrosa.*
Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Valladolid. Paseo de Belén 7. 47011-Valladolid. Spain
E-mail: pedrosa@qo.uva.es
Web: http://sintesisasimetrica.blogs.uva.es
Abstract.
Unprecedented diastereo- and enantioselective synthesis of seven-membered rings has
been achieved by organocatalyzed intramolecular Michael addition of enals bearing
β-diketone functionality. The cyclization, leads to 2,3-disubstituted cycloheptanone
derivatives in high yield and excellent stereoselectivity. The same organocatalyzed
cyclization process has been used to prepare six-membered homologs, but with lower
stereoselectivity.
Key words: Asymmetric synthesis, Cyclization, Cycloheptanones, Intramolecular
Michael reaction, Organocatalysis.

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Enantioselective organocatalyzed synthesis of five- and six-membered rings have
1
been extensively studied in the last decade but, in spite of their biological interest,
the synthesis of both carbo- and heterocyclic seven-membered structures has been less
developed, probably as a consequence of the difficult intramolecular reaction leading
2
to cycles with seven members. Thus, the search for the enantioselective synthesis of
that kind of cycles is an active area of research, and recently both metal and
3
organocatalyzed methodologies have been developed.
4
5
In that way, organocatalytic [4 + 3] or [5 + 2] cycloaddtions lead to seven
membered carbo- and heterocycles in good yield and stereoselection. Organocatalytic
6
7
sequential [3 + 2] cycloadditions, Michael-Frieldel Crafts reactions, and Michael-
8
aldol tandem processes followed by opening of the formed bicyclic intermediates
have been also applied to the enantioselective synthesis of cycloheptane derivatives.
Additionally, chiral phosphoric acids are able to promote three components reactions
9
10
to enantioenriched diazepine derivatives, and chiral azepanes have also been
obtained by domino Michael-cyclization reaction catalyzed by prolinol derivatives.
Based on these antecedents and our previous experience on enantioselective
1
1
organocatalyzed Michael additions, we envisaged a way to synthesize seven-
1
2
membered carbo- and heterocycles by iminium activation of easily accessible enals
bearing an enolizable methylene group in their structure.
1
3
Starting compounds 3a-g were prepared by cross-metathesis of the corresponding
dicarbonyl compounds 2a-g with crotonaldehyde in the presence of second generation
1
4
Hoveyda-Grubbs catalyst in methylene chloride at reflux. Keto ester 2a and diketo
olefins 2b-e were obtained by alkylation of the corresponding dianions derived from
1
5
benzyl acetoacetate 1a or β-diketones 1b-e with 5-bromo-1-pentene. Amide 2f was
1
6
synthesized by aminolysis of ethyl acetoacetate with benzyl 4-pentenyl amine 1f,
1
7
whereas 2g was prepared by transesterification of ethyl benzoylacetate with 4-
penten-1-ol (Scheme 1).

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O
O
O
O
1
mol% Hoveyda-
1
2
. NaH
. BuLi
O
O
Grubbs catal.
R
R
O
R
Br
O
3
.
1a-e
DCM, reflux
3a-e
2a-e
1
OBn
-3a
1-3b
Me
1-3c
Ph
1-3d
Ph-4-Me
1-3e
Ph-4-OMe
R
O
O
O
O
O
R
R
1 mol% Hoveyda-
Grubbs catal.
X
CO Et
2
X
R
X
O
Toluene
reflux
O
DCM, reflux
1
1
f X = NHBn
g X = O
3f X = NBn, R = Me
3g X = O, R = Ph
2
2
f X = NBn, R = Me
g X = O, R = Ph
Scheme 1. Synthesis of the starting enals 3a-f.
In order to study the best catalyst and conditions for the intramolecular Michael
reaction, we subjected β-ketoester 3a to the cyclization process in DCM at rt in the
presence of 10 mol% of three different catalysts and 20 mol% of p-nitrobenzoic acid
1
8
(
(
PNBA) as co-catalyst (Scheme 2). Quinidine-derived primary amine A and (S)-1-
1
9
2-pyrrolidinylmethyl) pyrrolidine B are very active, but a very complex mixture of
products was formed in the reactions promoted by both catalysts. On the contrary, the
2
0
monofunctional Jörgensen-Hayashi catalyst C was able to promote the cyclization
of 3a to an unseparable equimolar mixture of cis- and trans- 2,3-disubstituted
cycloheptanones 4a in very good ee for trans diastereoisomer (entry 1 in Table 1).
The yield was improved and the reaction time shortened, maintaining the
stereoselection, by using ethereal solvents (entries 2, 3 in Table 1), but the best results
were obtained in toluene as solvent (entries 4-7 in Table 1). In this solvent, no
important variations in both the yield and ee were observed by modifying the
concentration (entry 5), and the temperature (entry 6), but the ee dropped to 70%
when the reaction was carried out in the absence of PNBA as co-catalyst (entry 7 in
Table 1). The variation of stereoselection with the nature of the counterion, which is
dependent on the acid used as co-catalyst is a very well known act in organocatalytic
2
1
transformations. The acid additive accelerates the formation of iminium ion, and in
the present case the drop in the enantioselection could be attributed to the extension in
which the uncatalyzed background cyclization occurs.

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N
Ph
Ph
N
H
N
H
NH2
N
OTMS
MeO
A
B
C
N
O
O
O
O
O
O
OBn
OBn
1
0 mol % C
OBn
+
O
20 mol % PNBA
O
O
3
a
trans-4a
cis-4a
Scheme 2. Cyclization of 3a promoted by catalyst C.
Table 1. Screening of conditions for the cyclization of 3a promoted by 10 mol% of
catalyst C.
o
a
b
Entry
Solvent
DCM
THF
Conc [M] T ( C)
Time (h)
35
Yield (%)
Ee (%)
1
2
3
4
5
6
7
0.1
0.1
0.1
0.1
0.05
0.1
0.1
0
0
30
37
35
45
43
45
90
26
92
Et
2
O
0
24
90
Toluene
Toluene
Toluene
Toluene
0
24
93
0
38
92
- 18
0
40
92
c
25
45
70
a
b
Isolated yields as a mixture (1:1) of cis and trans diastereoisomers. Determined by
c
chiral HPLC for the trans diastereoisomer. Reaction without PNBA as co-catalyst.
o
The reaction in toluene at 0 C in the presence of 10 mol% of catalyst C and 20 mol%
of PNBA as co-catalyst was selected as the best reaction conditions, and the reaction
extended to different enals bearing β-diketones or β-ketoamides (3b-f) in their
structure, and the results are summarized in Scheme 3 and Table 2.
Acetylacetone-derived enal 3b (entry 2 in Table 2) cyclized in much better yield than
ketoester 3a, but leading to an unseparable equimolar mixture of cis and trans-
cycloheptanone derivative 4b and hemiacetal 5b in a ratio 3:1. Fortunately, an

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important improvement in both yield and the diastereoselection was achieved for the
cyclization of the enal derived from benzoyl acetone 3c. The cyclization of 3c gave
the 2,3-disubstituted cyloheptanone in 77% yield, as a mixture (1:2.5) of hemiacetal
5
c and trans-4c as a single diastereoisomer in excellent enantioselectivity (90% ee)
(entry 3 in Table 2). The behavior of p-tolyl substituted derivative 3d was similar to
that showed by 3c (entry 4), whereas the para-methoxy substituted 3e was less
reactive increasing the reaction time to 30 h, but leading to the cyclization product in
good yield (73%) and total diastereoselectivity and very good enantioselectivity (84%
ee) (entry 5 in Table 2).
We then tried to extend the methodology to the preparation of heterocycles with one
nitrogen or oxygen in their structure starting from amide 3f or ester 3g.
Acetylacetamide derived enal 3f easily cyclized to a mixture (1:2) of hemiacetal 5f
and trans α,β-disubstituted caprolactam 4f as a single diastereoisomer in a total 78%
yield and excellent enantioselectivity (92%) (entry 6). The ester derived from
benzoylacetic acid 3g also reacted in the presence of 10 mol% of catalyst C, but
leading to a very complex mixture of products where it was not possible to isolate the
cyclization products 4g or 5g.
O
R
O
O
O
O
C 10 mol%
PNBA 20 mol%
Toluene, 0 C
O
R
+
OH
X
R
X
X
o
O
O
3
a-g
4a-f
5b-f
g
3
, 4, 5
a
b
c
d
e
f
X
CH2 CH2 CH2
OBn Me Ph
CH2
CH2
BnN
Me
O
R
Me-4-Ph MeO-4-Ph
Ph
Scheme 3. Synthesis of seven-membered rings by intramolecular Michael addition.

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Table 2. Synthesis of enantioenriched disubstituted seven-membered ring by
intramolecular Michael reaction catalyzed by diphenyl prolinol derivative C.
a
b
b
c
Entry
Reagent T (h) Yield
Ratio (4/5) (cis-4/trans-4)
Ee
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
24
24
16
20
30
20
15
45
80
77
76
73
78
--
-
1:1
1:1
93
88
90
93
84
92
--
3/1
2.5/1
2.2/1
2/1
2/1
--
>1:<99
>1:<99
>1:<99
>1:<99
--
3g
a
b
c
Total yield of 4 and 5. Determined by HNMR of the reaction mixture. The values
were determined by chiral HPLC, and refer to the trans-isomer.
The good results obtained in the formation of cycloheptanone derivatives led us to
explore the synthesis of six-membered rings from enals 6c, 6e and 6f for comparative
purposes. Starting compounds were prepared by sequential alkylation cross-
metathesis as described above, and subjected to intramolecular Michael addition in
the same conditions used for the cyclization of 3a-g (Scheme 4 and Table 3).
O
O
O
O
O
O
Ph
Bn
N
OCH3
O
O
6
c
O
6
e
6
f
C 10 mol%
PNBA 20 mol%
Toluene, 0 C
C 10 mol%
PNBA 20 mol%
Toluene, 0 C
OMe
C 10 mol%
PNBA 20 mol%
Toluene, 0 C
o
o
o
O
O
O
Ph
O
O
O
O
O
O
Ph
Bn
Bn
N
O
O
N
OCH3
O
OH
OH
O
O
O
OH
7
c
8c
7e
8e
7f
8f
Scheme 4. Intramolecular Michael addition leading to six-membered rings.

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Table 3. Synthesis of enantioenriched disubstituted six-membered ring by
intramolecular Michael reaction catalyzed by diphenyl prolinol derivative C.
a
b
b
c
Entry
Reagent T (h) Yield
Ratio (7/8) (cis-7/trans-7)
Ee
1
2
3
6c
6e
6f
23
50
17
80
83
50
3/1
>1:<99
>1:<99
1:3.5
78
89
64
4.5/1
1.5/1
a
b
c
Total yield of 4 and 8. Determined by HNMR of the reaction mixture. The values
were determined by chiral HPLC, and refer to the trans-isomer.
The best result, in terms of yield and enantioselection, was obtained for diketone 6e,
leading to the cyclization product in 83% as a mixture (1:4.5) of hemiketal 8e and
trans-disubstituted cyclohexanone 7e as a single diastereomer in very good 89% ee
(entry 2 in Table 3). On the contrary, benzoylacetone-derived enal 6c reacted faster
than 6e, leading to a mixture (1:3) of hemiketal 8c and trans-7c, but in worse
enantioselection (78% ee) than its homolog 3c (compare entry 1 in Table 3 versus
entry 3 in Table 2). In the same way, amide 6f easily cyclized, in moderate yield, to a
mixture (1:1.5 ratio) 8f and 7f as a mixture (1:3.5) of cis and trans diastereoisomers,
but the stereoselection dropped a lot with respect to the cyclization of 3f to the seven-
membered lactam 4f (compare entry 3 in Table 3 versus entry 6 in Table 2).
The relative trans stereochemistry of the compounds was determined by COSY and
1
3
NOESY experiments for compound 7e, and the absolute configuration was
established by chemical correlation of 7c with the known (2S,3R)-2-benzoyl-3-ethyl
2
2
cyclohexanone (10), and extended for all the compounds. The conversion of 7c into
1
0 was done in two steps, in mild conditions, by chemoselective thioacetalization
2
3
catalyzed by scandium triflate to 9, followed by hydrogenolysis of the thioacetal by
stirring with Ni-Raney in ethanol at rt (Scheme 5). The process occurred with
negligible loss of enantiopurity.
O
O
O
O
O
O
Ph Ni-Raney
Ph
Ph
SH SH
4
mol% Sc(OTf)3
EtOH, rt
S
DCM, rt
O
S
7
c (78% ee)
9
10 (76% ee)

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Scheme 5. Chemical correlation of 7c with (2S,3R)-2-benzoyl-3-ethyl cyclohexanone.
On the basis of the absolute configuration of the final compounds a plausible model
for the cyclization process is depicted in Figure 1. The activation of the enal occurs by
2
4
formation of iminium ion A, which cyclizes to enamine B by intr-Michael si-face
attack of the nucleophile from the less hindered face. The hydrolysis of the enamine
in the last step of the catalytic cycle lead to the cylcoalkanones.
n
H
H
O
N
N
R
H
O
H
H
n
n
R
O
O
O
R
O
O H
A
B
H
4a-f : n = 1, 7c-f : n = 0
Figure 1. Plausible stereoselective formation of cycloalkanones.
In summary, we have described the unprecedented synthesis of enantioenriched
seven-membered rings by stereoselective intramolecular Michael addition of
dicarbonyl functionalized enals. The reaction worked very well by using the
Jorgensen-Hayashi catalyst, leading to a mixture of trans 2,3-disubstituted cyclic
derivatives and their corresponding hemiacetals, with good yields and excellent
stereoselection. The same protocol can be used for the preparation of six-membered
rings, but the cyclization occurred in lower diastereo- and enantioselectivities.
Acknowledgements
We acknowledge the financial support provided by the Spanish MINECO (Project
CTQ2014-59870-P) and Junta de Castilla y León (Project, VA064U13). J. O. G.-P.
thanks the Universidad de Valladolid for a predoctoral fellowship.
1
13
Electronic supplementary Information Available: Copies of H-NMR and C-
NMR spectra for all new compounds and copies of the HPLC chromatograms.
Notes and References.
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TABLE OF CONTENTS
Enantioenriched seven membered rings have been prepared in high yields and
stereoselectivities by intramolecular Michael addition of functionalized enals
catalyzed by Jorgensen-Hayashi catalyst.