Diastereoselective 1,3-dipolar cycloaddition of pyrylium ylides with chiral enamides

Article abstract of DOI:10.1039/c2ob07007c

Chiral enamides 5f-i were found to react with pyrylium ylides to give cycloadducts 6d-i in good yields with an excellent level of stereoselectivity. The chiral auxiliary was successfully removed on hydrogenolysis of compound 6f in continuous flow (H-Cube)

Full text of DOI:10.1039/c2ob07007c

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 4215
www.rsc.org/obc
PAPER
Diastereoselective 1,3-dipolar cycloaddition of pyrylium ylides with chiral
enamides†
Kirill Tchabanenko,* Colleen Sloan, Yves-Mael Bunetel and Philip Mullen
Received 29th November 2011, Accepted 19th March 2012
DOI: 10.1039/c2ob07007c
Chiral enamides 5f–i were found to react with pyrylium ylides to give cycloadducts 6d–i in good
yields with an excellent level of stereoselectivity. The chiral auxiliary was successfully removed on
hydrogenolysis of compound 6f in continuous flow (H-Cube) resulting in the first asymmetric
synthesis of complex amine 8.
fully applied as polarophiles in a number of cycloaddition reac-
Introduction
tions by Hsung and co-workers.8
1,3-Dipolar cycloaddition of pyrylium ylides 1 with activated
alkenes is a powerful synthetic tool providing direct access to the
8-oxa-bicyclo[3,2,1]octane motif 2 (Fig. 1).1–3 Common in a
number of biologically active natural products such as englerin
A4,5 3 and aspergillin PZ,6 the oxygen bridged bicycle 2 has
potential as a scaffold for the development of pharmaceuticals.
Our group became involved in finding new applications for
this interesting reaction,7 with particular attention drawn to the
discovery of new polarophiles and reaction conditions. Indeed,
the use of nitrogen as an alkene activator will allow direct syn-
thesis of the bicyclic amine 2 (X = NH2). Therefore it is pro-
posed that attachment of chiral auxiliaries on the nitrogen will
allow a stereoselective 1,3-dipolar cycloaddition. Only one
example of a diastereoselective 1,3-dipolar cycloaddition of pyr-
ylium ylides with chiral acrylic esters was reported by Chen and
Nicolaou in their total synthesis of englerin A.5 For this study it
was decided to investigate chiral enamides, which were success-
Results and discussion
All starting materials for this study were prepared according to
literature procedures. Acetoxy pyrones 4a–c were prepared from
corresponding furyl alcohols9 or fructose.10 Enamides 5a, 5f and
5g were prepared via palladium catalysed trans-vinylations;11
ynamide 5e and enamides 5b–d and 5h were prepared by copper
catalysed cross-couplings.12
At first we decided to establish the best cycloaddition con-
ditions for reactions with non-chiral enamides (Table 1).
Acetoxy pyrone 4a was reacted under triethyl amine promoted
conditions (A)2 and thermal conditions (B).1
Under both sets of conditions the reactions with the simplest
enamide 5a proceeded smoothly to give the desired product 6a.
The yield was marginally better under thermal conditions,
although this reaction required a significantly longer time to
reach complete conversion of the starting material. The slightly
lower yield of the base-promoted reaction was due to formation
of the pyrylium ylide dimer 72 as a minor byproduct. Reaction
of the trans-enamide 5b produced the product 6b but in a lower
yield, while the cis-enamide 5c gave no detectable cycloaddition.
Cycloaddition of the gem-disubstituted alkene 5d gave a differ-
ent product, which decomposed upon attempts at purification
by column chromatography. Our tentative assignment of the
structure 6c was made on the basis of the crude 1H NMR
analysis, which showed the absence of the enone double bond,
and instead the presence of resonances corresponding to the
double bond of the cyclic enol ether. Formation of this regio-
isomer is unusual and will be further investigated in a separate
study.
Fig. 1 1,3-Dipolar cycloaddition approach to 8-oxa-bicyclo[3,2,1]-
octanes.
School of Chemistry and Chemical Engineering, Queen’s University
Belfast, David Keir Building, Stranmillis Road, Belfast BT9 5AG,
United Kingdom. E-mail: k.tchabanenko@qub.ac.uk
The ynamide 5e gave no cycloaddition products under either
thermal or base catalysed conditions.
Having established that the mono-substituted double bond
gave the best yields of the cycloadduct, we proceeded to
†Electronic supplementary information (ESI) available: 1H and 13C
spectra for cycloadducts 6a–i and acetamide 8. CCDC reference number
856583. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob07007c
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4215–4219 | 4215

View Article Online
Table 1 Cycloadditions with simple enamides 5a–e
Enamide
Conditions
A
Time (d)
1.5
Product
Yield
72%
B
A
4
2
85%
32%
—
A
A
2
—
1.5
ca. 25% (decomposed on purification)
A or B
2
—
—
investigate the reactions of chiral enamides 5f–h under base pro-
moted milder reaction conditions (Table 2).
preferred conformation8 and the endo cycloaddition13 happens
on the least hindered face of the alkene giving rise to the
observed stereochemistry of the adducts.
Gratifyingly, cycloaddition reactions of terminal enamides
5f–h proceeded in moderate to good yields and the products
were formed as single diastereoisomers. Chiral trans-enamide
5i gave cycloadduct 6i in a lower yield as was expected
from our initial experiments. The relative stereochemistry
of the cycloadducts was established via X-ray analysis of 6d
(Fig. 2) and further correlation of the NMR data for the
products.
To conclude this study we decided to demonstrate possible
cleavage of the chiral auxiliary. Cycloadduct 6f was reduced on
a continuous flow hydrogenation setup (H-Cube) to give both
reduction of the enone double bond and cleavage of the chiral
auxiliary. We discovered that direct purification of the primary
amine by column chromatography was problematic due to its
high polarity and the crude product was converted into an aceta-
mide 8, which was isolated in a 50% yield after two steps
(Scheme 1).
The stereochemical outcome of the reactions can be rational-
ized by the model presented in Fig. 3. The enamide assumes the
4216 | Org. Biomol. Chem., 2012, 10, 4215–4219
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 2 Cycloadditions with chiral enamides 5f–i
Pyrone
Enamide
Temp
rt
Time (h)
24
Product
Yield (%)
59
rt
rt
48
48
45
51
50 °C
48
63
rt
24
87
rt
48
21
reactions of pyrylium ylides. The use of chiral oxazolidinones
as chiral auxiliaries leads to highly stereoselective cyclo-
additions and the first asymmetric synthesis of the bicyclic
amine 8.
Conclusions
In summary, we have demonstrated the first example of the use
of amides as alkene activators in the 1,3-dipolar cycloaddition
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4215–4219 | 4217

View Article Online
12 h when TLC analysis indicated complete consumption of the
starting material 4. Solvents and volatiles were removed under
reduced pressure and the residue was purified by column chrom-
atography (40–60 petroleum ether–ethyl acetate 3 : 1) to give the
cycloadducts 6.
Thermal cycloadditions (method B)
A solution of acetoxy pyrones 4 (1.28 mmol) and enamides 5
(6.4 mmol) in toluene (7 mL) was placed in a sealed tube con-
taining a Teflon stirrer bar. The sealed tube was flushed with N2,
sealed with a Teflon screw-cap and heated in an oil bath
(150 °C) under stirring until TLC indicated complete consump-
tion of the starting material 4 (usually after a period of 4 days).
The reaction mixture was allowed to cool down, volatiles were
removed under reduced pressure and the residue was purified by
column chromatography (40–60 petroleum ether–ethyl acetate
3 : 1) to give the cycloadducts 6.
Fig. 2 Ortep plot of the X-ray structure of 6d.
Cycloadduct 6a a white solid: m.p. 76 °C; λmax(KBr) 1740
(m), 1686 (s); m/z (ES+) found 208.0974 (MH+) C11H14NO3
1
requires 208.0974; H (500 MHz, CDCl3) δ 1.82 (1H, ddd, J
14.0, 6.0, 1.5 Hz), 2.04 (2H, m), 2.40 (2H, t, J 8.5 Hz), 2.67
(1H, ddd, J 14.0, 9.0, 6.0 Hz), 3.28 (2H, m), 4.56 (1H, d, J 9.0
Hz), 4.70 (1H, dt, J 10.0, 6.0 Hz), 5.40 (1H, dd, J 6.0, 4.5 Hz),
Fig. 3 Cycloaddition model.
6.15 (1H, dd, J 10.0, 1.5 Hz), 7.22 (1H, dd, J 10.0, 4.5 Hz). 13
C
(125 MHz, CDCl3) 0.0, 8.7, 12.6, 28.2, 36.4, 55.1, 62.1, 105.9,
132.5, 157.8, 177.9.
Cycloadduct 6b a white solid: m.p. 90–91 °C; λmax(KBr)
1752 (s), 1697 (m); m/z (ES+) found 221.1121 (MH+)
1
C12H16NO3 requires 222.1130; H (500 MHz, CDCl3) δ 1.38
(3H, d, J 6.0 Hz), 2.01 (2H, m), 2.27 (1H, m), 2.41 (2H, t, J
9.0), 3.29 (2H, m), 4.13 (1H, s), 4.23 (1H, app t, J 6.0 Hz), 5.13
(1H, dd, J 6.0, 5.0 Hz), 6.11 (1H, dd, J 10.0, 1.5 Hz), 7.21 (1H,
dd, J 10.0, 5.0 Hz). 13C (125 MHz, CDCl3) 0.0, 0.9, 12.6, 17.5,
28.2, 44.7, 56.3, 69.2, 109.2, 132.5, 157.8, 177.5.
Cycloadduct 6d a white solid: m.p. 131 °C; [α]2D0 = +370.1 (c
= 0.95, CHCl3); λmax(KBr) 1750 (s), 1696 (s); m/z (ES+) found
Scheme 1 Cleavage of the chiral auxiliary.
1
300.1236 (MH+) C17H18NO4 requires 300.1236; H (500 MHz,
CDCl3) δ 1.80 (1H, dd, J 13.5, 1.5 Hz), 2.70 (2H, m), 3.10 (1H,
dd, J 13.5, 4.0 Hz), 3.88 (1H, ddd, J 14.0, 9.0, 8.5 Hz), 4.09
(1H, app s), 4.10 (1H, app s), 4.20 (1H, ddd, J 10.0, 6.0, 4.5
Hz), 4.50 (1H, dd, J 8.5, 1.5 Hz), 5.50 (1H, dd, J 6.0, 4.5 Hz),
6.10 (1H, dd, J 10.0, 1.5 Hz), 7.10 (1H, d, J 10.0 Hz), 7.3 (5H,
m); 13C (125 MHz, CDCl3) 29.7, 37.9, 55.7, 58.9, 66.6; 74.9,
80.2, 127.5, 127.7, 129.1, 129.2, 135.1, 151.1, 157.7, 196.4.
Cycloadduct 6e a white solid; m.p. 168–170 °C; [α]2D0 = +8.8
(c = 1.0, CHCl3); λmax(KBr) 1755 (s), 1708 (s), 1409 (s); m/z
(ES+) found 286.1089 (MH+) C16H16NO4 requires 286.1079; 1H
(400 MHz, CDCl3) δ 1.68 (1H, dd, J 13.5, 1.5 Hz), 2.28 (1H,
ddd, J 13.5, 10.0, 8.5 Hz), 4.02 (1H, ddd, J 10.0, 8.5, 4.5 Hz),
4.21 (1H, dd, J 8.5, 3.0 Hz), 4.38 (1H, dd, J 8.0, 1.5 Hz), 4.61
(1H, dd, J 8.5, 8.5 Hz), 4.68 (1H, dd, J 8.5, 3.0 Hz), 5.36 (1H,
dd, J 6.0, 4.5), 6.17 (1H, dd, J 10.0, 1.5 Hz), 7.20–7.45 (6H, m).
13C (125 MHz, CDCl3) 29.3, 56.0, 61.5, 70.4, 74.5, 80.1, 126.2,
127.9, 129.5, 129.7, 138.3, 150.9, 158.3, 190.4.
Experimental section
All reactions were carried out under an inert atmosphere (N2)
unless stated otherwise. Reaction solvents (toluene, CH2Cl2)
were freshly distilled from calcium hydride under a N2 atmos-
phere prior to use. All NMR spectral data was collected on
Bruker DRX-500 or Bruker AV-400 spectrometers. IR spectra
were collected on
a Perkin-Elmer Spectrum One FT-IR
spectrometer, optical rotations were measured on a Perkin-
Elmer Model 341 polarimeter and mass-spec data was collected
on
a Waters GCT-Premier spectrometer with NanoMate
attachment.
Base promoted cycloadditions (method A)
To a stirred solution of acetoxy pyrones 4 (1.28 mmol) and
enamides 5 (6.4 mmol) in DCM (5 mL) was added triethylamine
(696 μL, 5.12 mmol) in three equal portions over a period of
36 h at room temperature. Stirring was continued for another
Cycloadduct 6f a white solid; m.p. 195–199 °C; [α]D20
=
+25.9 (c = 2.8, CHCl3); λmax(KBr) 1742 (s), 1685 (s), 1400 (s);
m/z (ES+) found 384.1230 (MNa+) C22H19NO4Na requires
4218 | Org. Biomol. Chem., 2012, 10, 4215–4219
This journal is © The Royal Society of Chemistry 2012

View Article Online
384.1212; 1H (400 MHz, CDCl3) δ 1.65 (1H, dd, J 13.5,
2.0 MHz), 2.26 (1H, ddd, J 13.5, 9.5, 8.5 Hz), 4.20 (1H, ddd, J
10.0, 9.5, 6.0 Hz), 4.40 (1H, dd, J 8.5, 1.5 Hz), 4.86 (1H, d, J
7.0 Hz), 5.48 (1H, dd, J 6.0, 4.5 Hz), 5.82 (1H, d, J 7.0 Hz),
6.23 (1H, dd, J 10.0, 1.5 Hz), 5.95–7.16 (10H, m), 7.46 (1H, dd,
J 10.0, 4.5 Hz). 13C (125 MHz, CDCl3) 12.1, 38.8, 49.6, 57.1,
62.7, 63.0, 108.3, 110.3, 110.5, 110.6, 111.2, 11.3, 115.7, 115.8,
139.5, 178.8.
in full hydrogenation mode until TLC indicated disappearance of
compounds running mid-plate in hexane–EtOAc 2 : 1 mixture.
Solvents were removed under vacuum and to the residual
ammonium acetate salt was added DCM (10 mL), Et3N (0.5 mL,
excess) and acetic anhydride (0.2 mL, excess). The resulting
mixture was stirred for 6 h and concentrated. The residue was
purified by flash column chromatography (40–60 petrol–EtOAc
3 : 1) to give the product 8 (17.4 mg, 50%) as a colourless oil:
[α]2D0 = +115.5 (c = 1.01, CHCl3); λmax(thin film) 3490 (br m),
2950 (m), 1720 (s), 1650 (s); m/z (ES+) found 184.0981 (MH+)
C9H14NO3 requires 184.0974; 1H (500 MHz, CDCl3) δ 1.68
(1H, dd, J 14.0, 1.5 Hz), 2.09 (3H, s), 2.13 (1H, m), 2.28 (1H,
dd, J 13.0, 7.5 Hz), 2.41 (1H, dd, J 17.0, 8.0 Hz), 2.58–2.76
(2H, m), 4.20 (1H, d, J 8.0 Hz), 4.44 (1H, app t, J 6.5 Hz), 4.52
(1H, ddd, J 13.0, 10.0, 6.5 Hz). 13C (125 MHz, CDCl3) 3.35,
6.7, 15.1, 20.4, 53.8, 58.8, 63.8, 157.2, 197.9.
Cycloadduct 6g a white solid; m.p. 136–138 °C; [α]D20
=
−267 (c = 0.4, CHCl3); λmax(KBr) 1755 (s), 1721 (m); m/z
(ES+) found 336.1221 (MNa+) C18H19NO4Na requires
336.1212; 1H (500 MHz, CDCl3) δ 1.51 (3H, s), 1.98 (1H, dd, J
12.0, 6.5 Hz), 2.26 (1H, dd, J 12.0, 9.0 Hz), 2.70 (1H, dd, J
13.5, 10.0 Hz), 3.06 (1H, dd, J 13.5, 4.0 Hz), 3.84 (1H, app t, J
5.0 Hz), 4.10 (2H, app d, J 5.0 Hz), 4.32 (1H, ddd, J 9.0, 6.5,
6.0 Hz), 6.41 (1H, dd, J 6.0, 5.0 Hz), 6.13 (1H, d, J 9.5 Hz),
7.10–7.33 (6H, m). 13C (125 MHz, CDCl3) 18.5, 35.2, 36.8,
55.0, 57.7, 64.5, 74.5, 83.0, 126.4, 128.1, 128.2, 134.1, 149.8,
156.6, 196.8.
Acknowledgements
Cycloadduct 6h a white solid; m.p. 138–140 °C; [α]D20
=
We would like to thank DEL NI for studentships (CS and PM),
Almac for a studentship (YMB), Dr P Nockemann (QUB) for
the X-ray analysis and Dr G Trevitt (Almac) for the use of the
H-Cube.
+110.5 (c = 1.0, CHCl3); λmax(KBr) 1776 (m), 1720 (s), 1680
(m), 1257 (s); 1240 (s); m/z (ES+) found 380.1068 (MNa+)
1
C19H19NO6Na requires 380.1110; H (500 MHz, CDCl3) δ 1.55
(1H, ddd, J 13.5, 6.0, 1.5 Hz), 2.11 (3H, s), 2.36 (1H, ddd, J
13.5, 10.0, 8.5 Hz), 4.10 (1H, dd, J 8.5, 2.5 Hz), 4.34 (1H, d, J
13.0 Hz), 4.40 (1H, dd, J 8.5, 1.5 Hz), 4.54 (1H, app t, J 8.5
Hz), 4.61 (1H, dd, J 10.0, 6.0 Hz), 4.65 (1H, dd, J 8.5, 2.5 Hz),
4.72 (1H, d, J 13.0 Hz), 6.30 (1H, dd, J 10.0, 1.5 Hz),
7.10–7.40 (6H, m). 13C (125 MHz, CDCl3) 3.11, 11.2, 39.9,
42.0, 47.4, 52.9, 62.4, 64.8, 108.0, 111.7, 111.9, 115.5, 121.9,
132.1, 140.6, 152.8, 177.6.
Notes and references
1 Original report of high temperature conditions: J. B. Hendrickson and
J. S. Farina, J. Org. Chem., 1980, 45, 3359.
2 Base promoted reactions: J. B. Hendrickson and J. S. Farina, J. Org.
Chem., 1980, 45, 3361; P. G. Sammes and L. J. Street, J. Chem. Soc.,
Perkin Trans. 1, 1983, 1261.
3 For a recent review and examples see: V. Singh, U. M. Krishna,
V. Vikrant and G. K. Trivedi, Tetrahedron, 2008, 64, 3405.
4 R. Ratnayake, D. Covell, T. T. Ranson, K. R. Gustafson and J. A. Beutler,
Org. Lett., 2009, 11, 57.
5 K. C. Nicolaou, Q. Kang, S. Y. Ng and D. Y.-K. Chen, J. Am. Chem.
Soc., 2010, 132, 8219.
6 Y. Zhang, T. Wang, Y. Pei, H. Hua and B. Feng, J. Antibiot., 2002, 55,
693.
7 K. Tchabanenko, P. McIntyre and J. F. Malone, Tetrahedron Lett., 2010,
51, 86.
8 H. Xiong, R. P. Hsung, L. Shen and J. M. Hahn, Tetrahedron Lett., 2002,
43, 4449; Z. Song, T. Lu, R. P. Hsung, Z. F. Al-Rashid, C. Ko and
Y. Tang, Angew. Chem., Int. Ed., 2007, 46, 4069; C. Ko, R. P. Hsung, Z.
F. Al-Rashid, J. B. Feltenberger, T. Lu, Y. Wei, J. Yang and C.
A. Zificsak, Org. Lett., 2007, 9, 4459; T. Lu, Z. Song and R. P. Hsung,
Org. Lett., 2008, 10, 541.
Cycloadduct 6i a pale grey viscous oil; [α]2D0 = −220 (c =
0.3, CHCl3); λmax(thin film) 1748 (s), 1693 (s), 1412 (m), 736
(m); m/z (ES+) found 314.1366 (MH+) C18H20NO4 requires
1
314.1392; H (500 MHz, CDCl3) δ 1.55 (1H, ddd, J 13.5, 6.0,
1.5 Hz), 2.11 (3H, s), 2.36 (1H, ddd, J 13.5, 10.0, 8.5 Hz), 4.10
1
(1H, dd H (500 MHz, CDCl3) δ 1.52 (3H, d, J 7.0 Hz), 2.38
(1H, m), 2.62 (1H, dd, J 13.5, 10.5 Hz), 3.06 (1H, dd, J 13.5,
3.5 Hz), 3.78 (1H, m), 3.92 (1H, dd, J 6.0, 4.5 Hz), 3.96 (1H,
dd, J 6.5, 1.0 Hz), 4.01 (1H, dd, J 6.0, 1.5 Hz), 4.11 (1H, s),
5.34 (1H, dd, J 6.5, 4.0 Hz), 6.06 (1H, d, J 9.5 Hz), 7.03–7.30
(6H, m); 13C (125 MHz, CDCl3) 20.7, 37.3, 38.4, 58.4, 64.1,
66.6, 76.2, 88.4, 127.6, 127.7, 129.1, 129.2, 134.9, 151.7,
157.5, 196.0.
9 O. Achmatowicz jun., P. Bukowski, B. Szechner, Z. Zwierzchowska and
A. Zamojski, Tetrahedron, 1971, 27, 1973.
10 B. B. Snider and J. F. Grabowski, Tetrahedron, 2006, 62, 5171.
11 M. Bosch and M. Schlaf, J. Org. Chem., 2003, 68, 5225.
12 T. B. Nguyen, A. Martel, R. Dhal and G. Dujardin, J. Org. Chem., 2008,
73, 2621.
13 Calculations showing endo preference for oxidopyrylium cycloadditions:
S. C. Wang and D. J. Tantillo, J. Org. Chem., 2008, 73, 1516.
Acetamide 8
A solution of cycloadduct 6f (68 mg, 0.19 mmol) in EtOAc–
AcOH (10 : 1, 5 mL) was continuously passed through a Pd/C
cartridge at 80 °C on the H-Cube hydrogenation setup working
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4215–4219 | 4219