Synthesis of (±)-cartorimine

Article abstract of DOI:10.1016/j.tetlet.2004.12.007

Heating pyranulose 4 and cinnamate 2 in the presence of 2,6-di-t-butylpyridine in CH₃CN afforded the [5+2] cycloadduct, which was hydrolyzed to give 13% of cartorimine (1).

Full text of DOI:10.1016/j.tetlet.2004.12.007

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 823–825
Synthesis of ( )-cartorimine
Barry B. Snider* and James F. Grabowski
Department of Chemistry MS 015, Brandeis University, Waltham, MA 02454-9110, USA
Received 18 November 2004; accepted 1 December 2004
Available online 16 December 2004
Abstract—Heating pyranulose 4 and cinnamate 2 in the presence of 2,6-di-t-butylpyridine in CH3CN afforded the [5+2] cycloadduct,
which was hydrolyzed to give 13% of cartorimine (1).
ꢀ 2004 Elsevier Ltd. All rights reserved.
Yin, He and Ye recently isolated the oxabicyclic acid
cartorimine (1) from Carthamus tinctorius L., which is
used as a traditional Chinese medicine to promote blood
circulation. The structure was established from extensive
NMR spectral data interpretation and single crystal X-
ray analysis.1 We thought that 1 could be prepared by
the [5+2] cycloaddition of methyl 4-acetoxycinnamate
(2) with oxypyrylium zwitterion 3, which could be gen-
erated in situ from pyranulose 4 (Scheme 1). This se-
quence may be related to the biosynthesis of 1 because
4-hydroxycinnamic acid is an abundantnatural product
and 4 is generated by the dehydration and oxidation of
fructose.2
O
O
130-135 °C
or
O
CH2
X
O
Et3N, CH2Cl2, 25 °C
X
AcO H
6
5
Scheme 2.
dipolarophiles were more reactive and that the reactions
can also be carried outusing Et N to generate the oxy-
3
pyrylium zwitterion at room temperature.4 Further
examples of [5+2] cycloadditions have been reported
by Heathcock and Ohmori.5–7 Sammes reported that
reaction of 5, styrene (6 equiv) and Et3N in CH2Cl2 at
25 ꢁC afforded 65% of 6, X = endo-Ph, which lacks the
hydroxymethyl and carboxylic acid groups of cartor-
imine (1). Unfortunately, these substituents will retard
the cycloaddition of 2 and 3. The facile dimerization
of the oxypyrylium zwitterion prevents the use of
unreactive dipolarophiles so that it was not clear a
priori that the synthesis of 1 could be achieved by this
route.
Hendrickson and Farina discovered that these [5+2] cyclo-
additions can be carried out by simply heating 5 and a
dipolarophile at130–135 ꢁC to afford up to 69% of ad-
duct 6 (Scheme 2).3 This reaction has been extensively
developed by Sammes, who found that electron rich
MeO2C
O
O
HO2C
O
O
5-(Acetoxymethyl)furfural (7) was reduced with NaBH4
in EtOH for 10 min at 0 ꢁC. The solution was quenched
dropwise with HOAc and concentrated. The residue was
taken up in water and treated with bromine in MeOH to
give 80% of 8.2,8 Acetylation with Ac2O, pyridine, and
DMAP in CH2Cl2 afforded the unstable acetate 4, which
was used without purification (Scheme 3). Acetoxy ester
2 was prepared in 94% yield from 4-hydroxycinnamic
acid by esterification with methanolic HCl at reflux
and acetylation with Ac2O, pyridine, and DMAP in
CH2Cl2. Reaction of 2 and 4 with Et3N in CH2Cl2 at
25 ꢁC or with EtN(i-Pr)2 in CH3CN at80 ꢁC did not
O
O
+
OH
AcO
OAc
AcO
OAc
1 (cartorimine)
2
3
4
HO
Scheme 1. Retrosynthesis of cartorimine.
Keywords: [5+2] Cycloaddition; Oxypyrylium zwitterion; Dipolaro-
phile; Pyranose.
*
Corresponding author. Tel.: +1 781 736 2550; fax: +1 781 736
2516; e-mail: snider@brandeis.edu
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.007

824
B. B. Snider, J. F. Grabowski / Tetrahedron Letters 46 (2005) 823–825
Acknowledgements
O
MeO2C
CHO
1) NaBH4, EtOH, 0 °C
2) Br2, MeOH/H2O
We are grateful to the National Institutes of Health
(GM-50151) for generous financial support.
O
O
3) Ac2O, pyr, DMAP
RO
CH2OAc
AcO
OAc
8, R = H (80%)
2
7
References and notes
4, R = Ac
1) CH3CN, 175 °C
1. Yin, H.-B.; He, Z.-S.; Ye, Y. J. Nat. Prod. 2000, 63, 1164–
1165. The 1H NMR data1 were referenced to CD2HOD at
d 3.50 rather than d 3.31. Private communication from
Prof. Ye, September 10, 2004.
2. Lichtenthaler, F. W.; Brust, A.; Cuny, E. Green Chem.
2001, 3, 201–209.
3. (a) Hendrickson, J. B.; Farina, J. S. J. Org. Chem. 1980,
45, 3359–3361; (b) Hendrickson, J. B.; Farina, J. S. J. Org.
Chem. 1980, 45, 3361–3363.
2,6-di-t-butylpyridine
2) KOH, EtOH, H2O, ∆
O
HO2C
H7
H5
H6
O
HO
+
O
H5
O
H6
OH
H7
OH
CO2H
HO
1 (cartorimine, 13% from 8)
9 (3% from 8)
4. (a) Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem.
Commun. 1982, 1056–1057; (b) Sammes, P. G.; Street, L. J.
J. Chem. Soc., Perkin Trans. 1 1983, 1261–1265; (c)
Sammes, P. G.; Street, L. J.; Kirby, P. J. Chem. Soc.,
Perkin Trans. 1 1983, 2729–2734; (d) Sammes, P. G.;
Street, L. J. J. Chem. Res. Synop. 1984, 196–197; (e)
Sammes, P. G. Gazz. Chim. Ital. 1986, 116, 109–114.
5. Marshall, K. A.; Mapp, A. K.; Heathcock, C. H. J. Org.
Chem. 1996, 61, 9135–9145.
O
O
Me
H
Ph
O
H
CH3CN, 175 °C
2,6-di-t-butylpyridine
O
H
Ph
AcO
OAc
10 (31% from 8)
AcO
4
Scheme 3. Synthesis of cartorimine.
6. (a) Ohmori, N.; Miyazaki, T.; Kojima, S.; Ohkata, K.
Chem. Lett. 2001, 906–907; (b) Ohmori, N. J. Chem. Soc.,
Perkin Trans. 1 2002, 755–767.
7. For a review see: Ohkata, K.; Akiba, K.-Y. In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic:
New York, 1996; Vol. 65, pp 354–364.
afford the desired cycloadduct. Thermal reaction in
CH3CN in a sealed tube at 150–175 ꢁC was more suc-
cessful, but not completely reproducible. Eventually,
we concluded that residual pyridine from the prepara-
tion of 4 was important for the success of the reaction.
Heating a 0.2 M solution of crude 4 in CH3CN with
6 equiv of 2 and 1 equiv of 2,6-di-t-butylpyridine in a
175 ꢁC oil bath for 14 h afforded the crude bis acetoxy
methyl ester of 1. Hydrolysis with KOH in 4:1 EtOH/
H2O atreflux for 20 h and preparaitve TLC afforded
16% (from 8) of a 4:1 mixture of cartorimine (1) and
the stereoisomer 9, which were separated by reverse
phase HPLC.9 A similar reaction using pyridine, instead
of 2,6-di-t-butylpyridine, afforded only 4% of a 3:1 mix-
ture of 1 and 9. The analogous cycloaddition of 4 with
trans-b-methylstyrene provided 31% (from 8) of 1010
regio- and stereospecifically, indicating that the elec-
tron-withdrawing carbomethoxy group of 2 retards the
reaction.
8. Kuo, Y.-H.; Shih, K.-S. Heterocycles 1990, 31, 1941–
1949.
9. 2,6-Di-tert-butylpyridine (0.45 mL, 2.01 mmol) was added
to a solution of crude 4 (459 mg, 2.01 mmol) and 2
(2.664 g, 12.1 mmol, 6 equiv) in dry CH3CN in a Schlenk
vacuum tube with PTFE valve (10 mL). The resulting
solution was degassed using the freeze–thaw method and
heated in a 175 ꢁC oil bath for 14 h. The reaction was
cooled and concentrated to give 3.119 g of a black solid.
Most of the unreacted 2 was removed by filtration through
50 g of silica gel (3:2 hexanes/EtOAc) to afford 239 mg of
crude bis acetoxy ester, which was dissolved in 4:1 EtOH/
H2O (50 mL). KOH (178 mg, 3.18 mmol) was added and
the resulting red solution was heated at reflux for 20 h and
cooled. The solution was acidified to pH 3 using saturated
NaH2PO4 solution and concentrated to remove EtOH.
The resulting aqueous solution was extracted with CH2Cl2
(3 · 50 mL) to remove less polar impurities. The resulting
aqueous solution was saturated with NaCl and extracted
with EtOAc (4 · 50 mL). The EtOAc solution was dried
(MgSO4) and concentrated to give 159 mg of crude 1.
PTLC (7:3 CHCl3/acetone) gave 110 mg (16% from 2) of a
4:1 mixture of 1 and 9, which were separated by HPLC on
a Zorbex Eclipse XDB-C18 4.6 · 250 mm column, 9:1
H2O/MeOH, flow rate = 1 mL/min with 0.5 mg of sample:
tR = 12.3 (9), tR = 18.3 (1). Data for 1: 1H NMR (CD3OD)
7.07 (d, 2, J = 8.5), 6.80 (d, 1, J = 10.4), 6.71 (d, 2, J = 8.5),
6.18 (br d, 1, J = 10.4), 4.70 (br s, 1), 3.84 (d, 1, J = 6.7),
3.82 (d, 1, J = 12.5), 3.73 (d, 1, J = 12.5), 3.13 (br d, 1,
J = 6.7); 13C NMR (CD3OD) 197.9, 158.2, 155.6, 131.1 (2
C), 128.9, 128.4, 116.4 (2 C), 88.4, 86.1, 64.2, 54.2 (2 C)
(one quaternary C not observed). Data for 9: 1H NMR
(CD3OD) 7.47 (d, 1, J = 9.5), 7.09 (d, 2, J = 7.6), 6.73 (d,
2, J = 7.6), 6.05 (d, 1, J = 9.5), 3.83–3.64 (m, 2), 3.19 (d, 1,
J = 12.2) (one H is under the OH peak at d 4.8 and one H
is under the MeOH peak at d 3.31); 1H NMR ((CD3)2CO)
The spectral data of 1 are identical to those previously
reported.1 Small NOEs from the aromatic hydrogens
to the hydroxymethyl group of both 1 and 9 established
that the minor product is a stereo- rather than a regio-
isomer. The vicinal coupling constants support this
assignment. JH5,H6 = 1.5 Hz in 1 and 7.9 Hz in 9, while
JH6,H7 = 7.5 Hz in 1 and 4.3 Hz in 9. These coupling
constants are consistent with those expected from
MM2 calculations and analogous to those in the related
stereoisomeric adducts formed from oxypyrylium zwit-
terions and dimethyl fumarate.6
In conclusion, we have completed the first synthesis of
cartorimine (1) using a possibly biomimetic [5+2] cyclo-
addition to efficiently construct the fully functionalized
8-oxabicyclo[3.2.1]octenone skeleton.

B. B. Snider, J. F. Grabowski / Tetrahedron Letters 46 (2005) 823–825
825
7.57 (d, 1, J = 10.1), 7.15 (d, 2, J = 8.5), 6.81 (d, 2, J = 8.5),
6.01 (br d, 1, J = 10.1), 4.89 (br d, 1, J = 7.9), 3.83–3.79
(m, 1), 3.77 (d, 1, J = 4.3), 3.37 (d, 1, J = 11.6), 3.26 (d, 1,
J = 11.6); 13C NMR (CD3OD) 157.8, 156.8, 132.1, 131.2
(2 C), 127.8, 116.3 (2 C), 88.7, 85.2, 65.5 (four C not
observed).
10. Data for 10: 1H NMR (CDCl3) 7.32–7.26 (m, 3), 7.14 (dd,
2, J = 7.0, 1.8), 6.70 (d, 1, J = 9.8), 6.26 (d, 1, J = 9.8), 4.46
(d, 1, J = 11.9), 4.27 (br s, 1), 4.21 (d, 1, J = 11.9), 3.00 (d, 1,
J = 6.7), 2.54 (br dq, 1, J = 6.7, 6.7), 1.36 (d, 3, J = 6.7); 13
C
NMR (CDCl3) 195.8, 170.6, 151.1, 135.6, 128.9 (2 C), 128.7
(2 C), 128.3, 127.9, 88.0, 84.7, 65.3, 59.4, 43.0, 20.7, 19.6.