Organocatalytic asymmetric synthesis of functionalized 3,4-dihydropyran derivatives

Article abstract of DOI:10.1002/chem.200800850

A study was conducted to demonstrate the organocatalytic enantioselective addition of 1,3-cycloalkanediones with α,β-unsaturated aldehydes to produce 3,4-dihydropyrans with enantioselectivies and diastereoselectivities for aromatic and aliphatic aldehydes. The study used a vial with magnetic stirring bar charged with catalyst, PhCO₂H, and CH₂Cl₂. The study found that α,β-unsaturated aldehydes is transformed by catalyst and nucleophile into the Michael adduct. The study also observed that the stereo-center formed in the catalytic cycle is controlled by a reface attack of the nucleophile on the planar iminium ion. The study also performed a single-crystal X-ray analysis of unprotected compound to determine the absolute configuration of the stereoisomer.

Full text of DOI:10.1002/chem.200800850

COMMUNICATION
DOI: 10.1002/chem.200800850
Organocatalytic Asymmetric Synthesis of Functionalized3,4-Dihydropyran
Derivatives
[a]
Patrick T. Franke, Bo Richter, andKarl Anker Jørgensen*
In the last few years, the field of organocatalysis has at-
tracted much attention in the chemical community.[1] It has
been proven to be a useful tool in the development of new
methodologies in order to obtain easy stereoselective access
to optically active molecules of, for example, biological im-
portance. Chiral secondary amines are very powerful orga-
Scheme 1. Retrosynthetic analysis.
nocatalysts giving rise to highly stereoselective transforma-
tions of carbonyl compounds, such as the enantioselective
a[2]-, b[3]-, and g[4]-functionalization of aldehydes. Further-
more, a new concept dealing with singly occupied molecular
orbital (SOMO) organocatalysis[5] has emerged recently. In
these reactions the chiral secondary amines catalyze the for-
mation of a single bond and stereocenter; however, a fur-
ther advantage of these compounds in organocatalysis is the
possibility to obtain multiple bonds and new stereocenters
in terms of diastereo- and enantioselective domino, one-pot,
and multicomponent reactions.[6]
A large group of important natural products, such as car-
bohydrates, alkaloids, polyether antibiotics, pheromones and
iridoids, contain polyfunctionalized pyran derivatives as sub-
units.[7] The common way to access 3,4-dihydropyrans is, for
example, by an inverse-electron-demanding hetero-Diels–
Alder reaction between a,b-unsaturated carbonyl com-
pounds with electron-rich alkenes.[8] We envisioned that it
might be possible to develop an organocatalytic reaction for
the formation of enantiomerically enriched 3,4-dihydropyr-
ans as outlined in Scheme 1. This strategy is based on the in-
itial Michael addition of a 1,3-cycloalkanedione to an a,b-
unsaturated aldehyde in the presence of an organocatalyst
followed by a subsequent cyclization reaction.
results in the formation of 3,4-dihydropyrans, proceeds in
toluene under slightly acidic conditions in the presence of a
secondary amine as the catalyst. With these promising find-
ings in hand, we performed a screening in order to optimize
the conditions in the reaction of cinnamaldehyde 1a with
1,3-cyclopentadione 2a.
Various organocatalysts 4a–e, solvents and reaction tem-
peratures were tested and a selection of results is presented
in Table 1. The screening of different secondary amines as
catalysts in toluene revealed that (S)-2-[bis(3,5-bistrifluoro-
methylphenyl)trimethyl-silanyloxymethyl]pyrrolidine (4a)[9]
gave full conversion affording the 3,4-dihydropyran 3a with
72% ee (Table 1, entry 1). Surprisingly, when (S)-2-(diphe-
nyl(trimethylsilyloxy)methyl)pyrrolidine (4b) was used as
the catalyst, no formation of 3a was detected (Table 1,
entry 2). Proline 4d, as well as proline amide 4e, were
unable to catalyze the reaction (Table 1, entries 4, 5). The
use of (S)-diphenyl(pyrrolidin-2-yl)methanol (4c) resulted
in 38% yield and À40% ee (Table 1, entry 4). To our sur-
prise, even though both catalyst 4a and 4c are derived from
the (S)-conformation, the opposite enantiomers of 3a are
formed in these reactions.[10]
After finding the appropriate catalyst for the reaction, dif-
ferent solvents and temperatures were screened. Choosing
CH2Cl2 at ambient temperature as the solvent increased the
yield of 3a to 59% and the enantioselectivity to 75% ee
(Table 1, entry 6). Less promising results were obtained in
EtOH and Et2O, compared with toluene (Table 1, entries 7,
8). Using CH2Cl2 and lowering the temperature to 48C al-
lowed 65% of the product to be isolated with an enantiose-
lectivity of 84% ee (Table 1, entry 9). Further improvement
was obtained by performing the reaction at À358C which af-
forded the final key parameters: temperature at À358C,
Initial studies showed that the addition of 1,3-cyclopenta-
dione to a,b-unsaturated aldehydes, which after cyclization
[a] P. T. Franke, B. Richter, Prof. Dr. K. A. Jørgensen
Danish National Research Foundation:
Center for Catalysis Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
Fax : (+45)8919-6199
E-mail: kaj@chem.au.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800850.
Chem. Eur. J. 2008, 14, 6317 – 6321
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6317

Table 1. Screening of reaction conditions for the addition of 2a to a,b-
unsaturated aldehyde 1a with subsequent cyclization in the presence of
secondary amines 4 as catalyst.[a]
Table 2. Scope, yield and enantioselectivity of the organocatalytic asym-
metric synthesis of optically active dihydropyrans.[a]
Entry
R
d.r.[b]
3
Product Yield [%][c] ee [%][d]
1
2
Ph (1a)
p-F-Ph (1b)
3a
3b
3c
3d
3e:1
3 f
:185[e]
82
90
88
82
93
92
92
91
95
84
93
94
96
88
88
7:2
9:2
5:1
3
2:1
5:2
2:1
7:2
5:2
32-furyl (
4
5
6
7
8
9
10
11
12
13CO
14
1c)
85[e]
95
2-thiophene (1d)
o-Br-Ph (1e)
o-NO2-Ph (1 f)
o-CF3-Ph (1g)
Bn (1h)
Me (1i)
Et (1j)
iPr (1k)
hex-3-en-1-yl (1l)
2Et (1m)
Entry
Solvent
Catalyst
T
Yield [%][b]
d.r.[c]
ee [%][d]
59
65[e]
69
1
2
toluene
toluene
4a
4b
4c
4d
4e
4a
4a
4a
4a
4a
RT
RT
RT
RT
RT
RT
RT
RT
42
n.r.
38
n.r.
n.r.
59
4:1
n.r.
4:1
n.r.
n.r.
3:1
72
3g
3h
3i
n.r.
À40[e]
n.r.
n.r.
75
85
74
3toluene
4
5
6
7
8
9
10
toluene
toluene
CH2Cl2
EtOH
Et2O
CH2Cl2
CH2Cl2
3j
74
5:2
2:1
3k
3l
74
81
66
n.d.
67
>20:1[f]
3
3m
3a
48
635:1
65
64
Ph (1a)
:171[g]
48C
À358C
3:1
3:1
84
90
85[f]
[a] Performed with 1a (0.25 mmol), 2a (0.30 mmol), 4 (0.025 mmol) and
PhCO2H (0.025 mmol) in toluene (0.5 mL) at À358C; after complete con-
version of 2a (ca. 24 h) the acetylation was performed (2 h) at room tem-
perature. [b] Diastereomeric ratio determined by 1H NMR spectroscopy
of the crude mixture. [c] Overall yield of both diastereomers after FC.
[d] Determined by chiral-stationary-phase HPLC (see the Supporting In-
formation). [e] 0.75 mmol of the aldehyde were used. [f] Only one diaste-
reomer detected. [g] Performed on a 10 mmol scale using 5 mol% cata-
lyst with a reaction time of 72 h at À208C.
[a] Performed with 1a (0.75 mmol), 2a (0.25 mmol), 4 (0.025 mmol) and
PhCO2H (0.025 mmol) in 0.5 mL of solvent; after complete conversion of
2a (ca. 12 h) the acetylation was performed (2 h). [b] Overall yield of
both diastereomers after FC. [c] Diastereomeric ratio determined by
1H NMR spectroscopy of the crude mixture. [d] Determined by chiral-
stationary-phase HPLC (see the Supporting Information). [e] Inverted se-
lectivity was observed. [f] Reaction time increased to 24 h.
CH2Cl2 as the solvent and (S)-2-[bis(3,5-bistrifluoromethyl-
phenyl)trimethyl-silanyloxymethyl]pyrrolidine (4a) as the
catalyst. Under these conditions, dihydropyran 3a was
formed in 85% yield and with 90% ee (Table 1, entry 10).
With the optimized reaction conditions in hand, we inves-
tigated the scope of the reaction. In Table 2 the results ob-
tained for the reaction of aromatic and alkyl a,b-unsaturat-
ed aldehydes 1a–m with 1,3-cyclopentadione 2a and the
subsequent cyclization to the dihydropyrans 3 are presented.
It appears that a broad range of different types of a,b-un-
saturated aldehydes are tolerated under the reaction condi-
tions used. Among these tolerated substituents are aliphat-
ics, esters, aromatic and heteroaromatic groups, and double
bonds. Employing aromatic groups resulted in a mixture of
diastereomers in the range from 2:1 to 5:1 in good yields
and with enantioselectivities up to 92% ee (Table 2, en-
tries 1, 2 and 5–7).
10 mmol, only with a slight decrease in yield, but maintain-
ing the enantio- and diastereoselectivity at high levels
(Table 2, entry 14).
After varying the substituents of the a,b-unsaturated alde-
hydes we also varied the ring size of the nucleophile. For
the addition of 1,3-cyclohexanedione 2b to cinnamaldehyde
1a, the product 3n was obtained in a 4:1 mixture of diaste-
reomers and with an excellent enantioselectivity of 97% ee
(Scheme 2). Even better results with respect to diastereose-
lectivity and yield were achieved by using the seven-mem-
bered cyclic dione 2c where 77% yield, a d.r. of >8:1 and
97% ee of the major diastereomer are obtained.
(Scheme 2).
Performing the reaction with heteroaromatic substituents
increased the diastereoselectivity providing a d.r. of up to
5:1 and in the case of (E)-3-(thiophen-2-yl)acrylaldehyde
(1d), dihydropyran 3d could be isolated in 95% yield and
with 93% ee (Table 2, entries 3, 4). The use of alkyl a,b-un-
saturated aldehydes gave comparable diastereoselectivities
in consistently good yields and with enantioselectivities in
the range from 84–96% ee (Table 2, entries 8–13). The best
selectivity was obtained with the a,b-unsaturated aldehyde
1m where only one diastereomer could be detected
(Table 2, entry 13). The reaction could also be scaled up to
Scheme 2. Asymmetric synthesis of 3,4-dihydropyrans.
6318
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Chem. Eur. J. 2008, 14, 6317 – 6321

Organocatalytic Asymmetric Synthesis
COMMUNICATION
The proposed mechanism for the reaction course is sum-
marized in Scheme 3. The Michael addition follows the
common path previously reported in the literature.[3f,p,6p,r,u]
same as the major diastereomer.
The configuration of the re-
maining compounds is assumed
by analogy.
Scheme 4 outlines some trans-
formations of the optically
active dihydropyrans formed. A
desymmetrization of one ketone
affording aldehyde 9 was ach-
ieved when the unprotected 3,4-
dihydropyran 8a (R=H) was
treated with methanesulfonyl
chloride. Furthermore, by react-
ing the TBS-protected com-
Figure 1. X-ray structure of un-
protected derivative of com-
pound 3e. C gray, H white, O
red, Br brown.
pound 10 (R=TBS) with
a
Grignard reagent a,b-functionalized cyclopent-2-enone 11
could be accessed in 40% yield. The lactone 12 can be ob-
tained according to the procedure developed recently by
Rueping et al.[3s]
Scheme 3. Proposed mechanism for the organocatalytic one-pot Michael
addition of a,b-unsaturated aldehydes 1 and 1,3-cyclopentadione 2 to
afford chiral dihydropyrans 3.
Scheme 4. Elaboration of the 3,4-dihydropyrans.
The a,b-unsaturated aldehyde 1 is transformed by catalyst
4a and nucleophile 2 into the Michael adduct 6. The stereo-
center formed in the catalytic cycle is controlled by a Re-
face attack of the nucleophile on the planar iminium ion 5.
The Re face of the b-carbon atom in the iminium-ion inter-
mediate is favored for approach of the nucleophile owing
to the bulk of the C2-substituent in the pyrrolidine ring of
the catalyst which shields the Si face, previously reported
for the use of TMS-protected prolinols as organocata-
lysts.[3f,p,6p,r,u] After the formation of the stereocenter, the cat-
alyst is released by cyclization to form the hemi-acetal 7.
For separation purposes 7 is easily acetylated to afford 3.
Finally, we determined the absolute configuration of the
major stereoisomer by single-crystal X-ray analysis of the
unprotected compound 8b derived from 3e, where the
chiral centers were determined as 2S/4R (Figure 1).[11] The
absolute configuration of the initially formed stereocenter
indicates that the addition of the nucleophile approaches
from the Re face through the control of the catalyst. The ini-
tially formed stereocenter for the minor diastereomer is the
In conclusion, we have developed the organocatalytic
enantioselective addition of 1,3-cycloalkanediones to a,b-un-
saturated aldehydes obtaining 3,4-dihydropyrans with excel-
lent enantioselectivies and good diastereoselectivities for a
broad range of aromatic and aliphatic aldehydes. These
compounds could afterwards be transformed to various in-
teresting derivatives.
Experimental Section
Synthesis of adducts 3: An ordinary vial equipped with a magnetic stir-
ring bar was charged with catalyst 3a (0.025 mmol, 10 mol%), PhCO2H
(0.025 mmol, 10 mol%) and CH2Cl2 (0.50 mL). Then, the solution was
cooled to À358C and the a,b-unsaturated aldehyde 1 (0.25 mmol) and
the 1,3-cyclodione 2 (0.25 mmol) were added. The stirring was main-
tained at À358C for about 24 h until completion of the reaction. To the
reaction mixture CH2Cl2 (1.5 mL), Ac2O (0.75 mmol), Et3N (0.10 mL)
and DMAP (catalytic amount) were added and stirred at ambient tem-
perature for about 2 h. The reaction mixture was poured into H2O
(10 mL), extracted with EtOAc (3”10 mL), dried over MgSO4, evaporat-
Chem. Eur. J. 2008, 14, 6317 – 6321
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6319

K. A. Jørgensen et al.
ed and then loaded onto silica gel and the products 3a–o were obtained
by flash chromatography.
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Representative example: (2R,4S)-5-oxo-4-phenyl-2,3,4,5,6,7-hexahydrocy-
clopenta[b]pyran-2-yl acetate (3a) was isolated by FC using silica gel (n-
hexane/AcOEt 3:1) as an oil in 85% yield as a mixture of diastereomers
(3:1). Major diastereomer: 1H NMR (400 MHz, CDCl3): d = 7.33–7.29
(m, 2H), 7.27–7.21 (m, 1H), 7.19–7.13(m, 2H), 6.38 (dd, J=6.1, 2.5 Hz,
1H), 3.85 (t, J=6.5 Hz, 1H), 2.78–2.58 (m, 2H), 2.55–2.43(m, 2H), 2.32–
2.20 (m, 1H), 2.16 (s, 3H), 2.06–2.00 pppm (m, 1H); 13C NMR (100 MHz,
CDCl3): d = 202.1, 182.0, 169.0, 140.9, 128.6, 127.3, 126.9, 116.7, 91.3,
34.4, 33.4, 31.9, 26.0, 20.9 ppm; HRMS: m/z: calcld for C16H16O4Na:
295.0946; found: 295.0952 [M+H]+. The ee was determined by HPLC
analysis using a Chiralpak AD column (hexane/iPrOH 90:10); flow rate
1.0 mLminÀ1; tmajor =6.5, tminor =8.1 min (90% ee). [a]RDT = +24.6 (c=
1.0, CH2Cl2).
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Acknowledgements
This work was made possible by a grant from Danish National Research
Foundation. Thanks are expressed to Dr. Jacob Overgaard for perform-
ing X-ray analysis.
Keywords: asymmetric synthesis
· conjugate addition ·
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cyclization · organocatalysis · pyrans
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[11] CCDC-687038 (3e) 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
Received: May 5, 2008
Published online: June 5, 2008
Chem. Eur. J. 2008, 14, 6317 – 6321
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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