A novel synthesis of the 2-aminoimidazol-4-carbaldehyde derivatives, versatile synthetic intermediates for 2-aminoimidazole alkaloids

Article abstract of DOI:10.1055/s-2006-950250

The title synthesis was achieved by the reaction of t- butoxycarbonylguanidine with 3-bromo-1,1-dimethoxypropan-2-one as a key step. Starting with 1-tert-butoxycarbonyl-2-tert-butoxycarbonylaminoimidazol-4- carbaldehyde thus obtained expeditious synthesis of oroidin, hymenidin, dispacamide and monobromodispacamide, the representative 2-aminoimidazole alkaloids, was accomplished. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950250

2836
LETTER
A Novel Synthesis of the 2-Aminoimidazol-4-carbaldehyde Derivatives,
Versatile Synthetic Intermediates for 2-Aminoimidazole Alkaloids
N
ovel Synthesis of
a
the 2-Ami
o
noimidazol-4
k
-
carbaldehy
i
de
D
erivative
A
s
ndo,*a Shiro Terashimab
a
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, nogi-machi, shimotsuga-gun, Tochigi 329-0114, Japan
Fax +81(280)571293; E-mail: naoki.andou@mb.kyorin-pharm.co.jp
b
Sagami Chemical Research Center, Hayakawa 2743-1, Ayase, Kanagawa 252-1193, Japan
Received 15 August 2006
two categories. One is the synthetic step where the 2-ami-
noimidazole ring is produced by condensing a guanidine
derivative with an a-haloketone3 or by reacting cyan-
amide with an a-aminoketone.2a The other step features
Abstract: The title synthesis was achieved by the reaction of t-but-
oxycarbonylguanidine with 3-bromo-1,1-dimethoxypropan-2-one
as a key step. Starting with 1-tert-butoxycarbonyl-2-tert-butoxycar-
bonylaminoimidazol-4-carbaldehyde thus obtained expeditious
synthesis of oroidin, hymenidin, dispacamide and monobromodis- amination of the 2-position of the preformed imidazole
ring by the use of explosive azide or diazonium reagents.4
pacamide, the representative 2-aminoimidazole alkaloids, was ac-
complished.
In both syntheses, the construction of the 2-aminoimida-
Key words: 2-aminoimidazol-4-carbaldehydes, alkaloids, cycliza-
tions, total synthesis, heterocycles
zole moiety is usually carried out at the later synthetic
stages. Accordingly, it is obvious that a number of the
congeners for natural 2-aminoimidazole alkaloids in
which the structures except for the 2-aminoimidazole
Various structural types of 2-aminoimidazole alkaloids moiety are replaced with various structural motifs differ-
including oroidin (1), hymenidin (2), dispacamide (3), ent from those involved in natural products, cannot be
monobromodispacamide (4), sceptrin (5) and ageladine A readily prepared in a large scale by applying the reported
(6), have been isolated from marine sources (Figure 1).1 methods.
Their intriguing structures as well as diverse biological
Considering these facts delineated above, a novel synthet-
activities, some of which are of interest from the pharma-
ic strategy was sought which can afford not only natural
ceutical points of view, make these alkaloids attractive
2-aminoimidazole alkaloids but also their congeners more
synthetic targets, and numerous total syntheses have hith-
efficiently than the methods reported.1 We have now
erto been reported.1,2
found that the 2-aminoimidazol-4-carbaldehyde deriva-
Taking into account the synthetic steps for constructing tives I (Figure 2) would be the best starting material for
their characteristic 2-aminoimidazole moieties, the total the novel strategy. In addition to the characteristic 2-ami-
syntheses so far achieved can be roughly classified into noimidazole moieties, I carry the 4-aldehyde groups that
O
H
N
NH2
Br
NH
Br
NH
NH
N
N
H
NH2
R
N
N
Br
N
H
O
R = Br: oroidin (1)
R = H: hymenidin (2)
NH2
NH
N
N
H
H
O
sceptrin (5)
Br
Br
O
NH
H
Br
NH2
N
R
N
N
N
N
H
O
H
N
R = Br: dispacamide (3)
R = H: monobromodispacamide (4)
NH
H2N
ageladine A (6)
Figure 1 Structures of representative 2-aminoimidazole alkaloids
SYNLETT 2006, No. 17, pp 2836–2840
1
7
.1
0
.2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950250; Art ID: U09806ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Synthesis of the 2-Aminoimidazol-4-carbaldehyde Derivatives
2837
NAc
can be elaborated to various structural motifs. However, a
search of the literature soon disclosed that the synthesis of
I is scarcely explored. The only method reported by
Alain5 is anticipated to lack practicality due to its harsh re-
action conditions such as thermolysis. Therefore, we em-
barked on exploring a novel synthetic route to I more
efficient than that reported.5
O
H
N
7 (3 equiv)
X
H2N
NH2
R
NHAc
8
DMF, r.t. or MeCN, 80 °C
31–78%
N
R
R = alkyl, aryl
X = Br, Cl
9
Scheme 1 Synthesis of the 4-substituted-2-acetamidoimidazole de-
rivatives reported by Webber et al.6
R1
N
R1, R2 = H and/or protecting groups
NHR2
N
OHC
I
Figure 2 Structures of 2-aminoimidazol-4-carbaldehyde derivati-
ves.
It was reported by Webber et al.6 that, as shown in
Scheme 1, the 2-acetamido-4-alkyl- or 4-arylimidazole
derivatives 9 can be prepared in good yields by the reac-
tion of acetylguanidine (7) and a-haloketones 8 in N,N-
dimethylformamide or acetonitrile. Expecting that apply-
ing the Webber reaction can readily produce I, we treated
3-bromo-1,1-dimethoxypropan-2-one (10) with 7 under
the same conditions as employed by Webber et al.6 How-
ever, as shown in Scheme 2, the desired product 117 was
obtained only in 1% yield along with complex reaction
products.8 Aiming to improve the disappointing results,
the same reaction was next examined by using tert-but-
oxycarbonylguanidine (12a)9 in place of 7. While it was
reported that 12a is usable for the Webber reaction simi-
larly to 7,3a the reaction of 10 with 12a had not been ex-
amined. To our delight, the reaction was found to take
place smoothly, affording 2-amino-1-tert-butoxycarbon-
yl-4-dimethoxymethylimidazole (14a)7 as the sole prod-
uct in 47% yield.8 Formation of the expected 2-tert-
butoxycarbonylamino-4-dimethoxymethylimidazole
(13a) corresponding to 9 and 11 was not observed at all.
This result distinctly differs from that reported.3a
Figure 3 X-ray crystal structure of compound 14a
The structure of 14a was verified by its spectral data7 and
single-crystal X-ray analysis (Figure 3).10 Interestingly,
when phenacyl bromide (15) being one of the typical sub-
strates for the Webber reaction6 was used in place of 10, a
mixture of 2-amino-1-tert-butoxycarbonyl-4-phenylimi-
dazole (16) and its 2-phenacyl derivative 17 was similarly
obtained in 22% and 37% yields, respectively.11 In this re-
action too, formation of the 2-tert-butoxycarbonylamino
derivative corresponding to 9 and 11 could not be detect-
ed. The reason why 12a gave the results obviously differ-
ent from those obtained with 7 is presently quite unclear.
However, an electronic effect rather than a steric effect
may account for the observed results.
H
N
O
7 (3 equiv)
NHAc
MeO
Br
MeO
N
DMF, r.t., 144 h8
OMe
OMe
11 (1%)
10
NBoc
NH2
H
Boc
N
N
H2N
NHBoc
NH2
12a (3 equiv)
MeO
MeO
N
N
DMF, r.t., 72 h8
OMe
OMe
13a (0%)
14a (47%)
O
Boc
N
Boc
N
O
12a (3 equiv)
NH2
Br
+
NH
Ph
Ph
DMF, r.t.
24 h8
N
N
Ph
Ph
15
16 (22%)
17 (37%)
Scheme 2 Reactions of the acylguanidine derivatives (7 and 12a) with 3-bromo-1,1-dimethoxymethylpropan-2-one (10)
Synlett 2006, No. 17, 2836–2840 © Thieme Stuttgart · New York

2838
N. Ando, S. Terashimab
LETTER
The novel reaction to cleanly afford 14a from 10 and 12a As shown in Scheme 3, 14a which becomes readily avail-
was further studied by employing various alkoxycarbon- able in a large quantity was converted to 2-acylaminoim-
ylguanidines 12b–e and changing the reaction conditions. idazo-4-carbaldehydes 18 corresponding to
I
by
These results are summarized in Table 1 and 2. It ap- sequential acylation and deacetalization. Further protec-
peared evident that 12a is the best alkoxycarbonylguani- tion of the 1-imino group in 18 with a tert-butoxycarbonyl
dine of choice and the chemical yield is almost unaffected group furnished 2-acylamino-1-tert-butoxycarbonylimi-
by the nature of the reaction solvent. The best yield real- dazol-4-carbaldehyde 19 which also corresponds to I. At-
ized by using 12a is probably due to its stability under the tempted introduction of protective groups other than the
basic reaction conditions intensified by the increased ster- tert-butoxycarbonyl group into the 1-imino group of 18a
ic hindrance. Under the optimized conditions (Table 1, turned out fruitless.13
run 2),12 14a could be produced in more than 60% yield.
With paving the way to 19 completed, the total synthesis
of representative 2-aminoimidazole alkaloids, oroidin (1),
Table 1 Synthesis of Various 2-Amino-1-alkoxycarbonyl-4-
hymenidin (2), dispacamide (3) and monobromodispac-
amide (4), was next examined to explore the synthetic
utility of 19. Thus, as outlined in Scheme 4, Julia
dimethoxymethylimidazole Derivatives (14a,b,d,e) in THF or DMFa
COOR
N
COOR
N
H2N
NH2
Boc
N
H
N
NH2
a, b
c
MeO
N
14a
NHCOR
NHCOR
12a–e (3 equiv)
10
N
N
OHC
OHC
OMe
14a,b,d,e
THF or DMF
r.t., 72 h
18
19
a: R = Ot-Bu: 90%
b: R = OBn: 41%
c: R = OMe: 44%
d: R = Oallyl: 51%
e: R = Me: 52%
a: R = Ot-Bu: 88%
b: R = OBn: 78%
c: R = OMe: 21%
d: R = Oallyl: 75%
e: R = Me: 22%
Entry
Product R
t-Bu (14a)
t-Bu (14a)
Me (14b)
Yield (%)b in THF in DMF
1
2c
3
4
5
6
51
47
Scheme 3 Synthesis of various 2-aminoimidazole-4-carbaldehyde
derivatives (18a–e and 19a–e) from 2-amino-1-tert-butoxycarbonyl-
4-dimethoxymethylimidazole (14a). Reagents and conditions: (a)
(RCO)2O or RCOCl, NaHMDS (2 equiv)–THF, 0 °C–r.t., 15 min; (b)
PPTS (cat.)–acetone–H2O (3:2), r.t., overnight; (c) Boc2O, TEA–
THF–MeCN (1:1), r.t., 8 h.
62 (64d)
<24e
<8e
n.d.f
26
CH2CCl3 (14c)
n.d.f
24
Allyl (14d)
Benzyl (14e)
37
26
O
O
O
SH
S
N
N
a All reactions were carried out on 0.25–1.0-mmol scale.
b Isolated yield.
N
a, b
N
N
N
N
N
N
c The reaction was performed at 50 °C for 6 h.
d The reaction was carried out on 10-mmol scale.
Ph
Ph
O
20
21
e This sample was contaminated by a minute amount of the unidenti-
fied byproduct.
O
f Not detected.
NBoc
d
c
19a
NHBoc
N
N
O
22
Table 2 Synthesis of 2-Amino-1-tert-butoxycarbonyl-4-dimeth-
oxymethylimidazole (14a) in Various Solventsa
NH
e
NHBoc
H2N
12a (3 equiv), r.t., 72 h
N
10
14a
23
Entry Solvent
Yield (%)b Entry
Solvent
MeCN
DMAc
DMF
Yield (%)b
Br
1
2
3
4
5
PhMe
EtOAc
THF
42
50
51
40
44
6
7
38
47
47
44
51
NH
f
oroidin (1)
hymenidin (2)
H
N
R
NHBoc
N
N
H
O
8
24a: R = Br
24b: R = H
CH2Cl2
EtOH
9
NMPd
DMSO
Scheme 4 Total synthesis of oroidin (1) and hymenidin (2).
Reagents and conditions: (a) N-(2-bromoethyl)phthalimide, K2CO3,
acetone, reflux, 3 h; (b) MCPBA, NaHCO3–CH2Cl2, r.t., overnight,
79% (2 steps from 20); (c) 21, NaHMDS–THF, –78 °C, 30 min, 62%;
(d) H2NNH2–EtOH, 50 °C, 2 h, 92%; (e) 4,5-dibromo- or 4-bromo-2-
trichloroacetylpyrrole, Na2CO3–DMF, r.t., overnight, 79% for 24a,
83% for 24b; (f) 20% HCl–EtOH, r.t., 1 h, 92% for 1, 99% for 2.
10
a All reactions were performed on 0.25-mmol scale.
b Isolated yield.
c N,N-Dimethylacetamide.
d N-Methylpyrrolidone.
Synlett 2006, No. 17, 2836–2840 © Thieme Stuttgart · New York

LETTER
Novel Synthesis of the 2-Aminoimidazol-4-carbaldehyde Derivatives
2839
olefination14 of 19a with sulfone 21 gave E olefin 22 in dimethoxymethylpropan-2-one (10) as a key step. Start-
62% yield along with the undesired Z olefin (10% yield). ing with 1-tert-butoxycarbonyl-2-tert-butoxycarbonyl-
Wittig reaction to produce 22 resulted in low yield and de- aminoimidazol-4-carbaldehyde (19a) thus obtained,
creased E selectivity. Sulfone 21 was readily obtained expeditious synthesis of oroidin (1), hymenidin (2), dis-
from commercially available 1-phenyl-5-mercapto-1H- pacamide (3) and monobromodispacamide (4), the repre-
tetrazole (20) and N-(2-bromoethyl) phthalimide in 79% sentative 2-aminoimidazole alkaloids, was accomplished,
yield (2 steps). Deprotection of 22 with hydrazine accom- realizing the synthetic utility of I.
panied complete removal of the 1-tert-butoxycarbonyl
group and subsequent treatment with 4,5-dibromo-2-
Acknowledgment
trichloroacetylpyrrole15 afforded the protected oroidin de-
We are grateful to Dr. T. Ishizaki and Dr. Y. Fukuda, Kyorin Phar-
maceutical Co. Ltd., for many valuable suggestions and encourage-
ment. We would also like to thank Dr. Y. Kohno, Kyorin
Pharmaceutical Co. Ltd., for helpful suggestions and discussions.
We are also indebted to Prof. K. Yamaguchi, Tokushima Bunri Uni-
versity, for single-crystal X-ray crystallographic analysis.
rivative 24a in 79% yield (2 steps). Final removal of the
tert-butoxycarbonyl group under acidic conditions gave
rise to oroidin (1) in 92% yield.4a,6,16,17 In a similar man-
ner, hymenidin (2)18 was prepared from 23 by way of
24b.19 Spectral and physical properties of 1 and 2 were
identical to those reported.4a,6,17,20
Finally, the synthesis of dispacamide (3) and monobromo-
dispacamide (4) was examined starting with 22. As shown
in Scheme 5, catalytic reduction of 22 followed by depro-
tection with hydrazine and complete removal of the 1-tert-
butoxycarbonyl group in the imidazole moiety gave
amine 25 in 64% yield (3 steps). This was converted to 3
and 4 following the procedure reported by Horne et al.21
with some modifications. Thus, after oxidation of 25 with
tetra-n-butylammonium tribromide, the aliphatic primary
amino group of the product was selectively protected with
the tert-butoxycarbonyl group to simplify the purification,
affording the 2-amino-D1-imidazolin-4-one derivative 26
in 40% yield (2 steps). Sequential deprotection and acyla-
tion with the pyrrole derivatives15,19 furnished dispacam-
ide (3) and monobromodispacamide (4) both as an
amorphous solids in 85% and 69% yields (2 steps), re-
spectively.22 Spectral data of 3 and 4 were in good agree-
ment with those reported.23
References and Notes
(1) (a) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753.
(b) Jacquot, D. E. N.; Lindel, T. Curr. Org. Chem. 2005, 9,
1551. (c) Mourabit, A. A.; Portier, P. Eur. J. Org. Chem.
2001, 237.
(2) (a) Baran, P. S.; Zografos, A. L.; O’Malley, D. P. J. Am.
Chem. Soc. 2004, 126, 3726. (b) Meketa, M. L.; Weinreb, S.
M. Org. Lett. 2006, 8, 1443.
(3) For example: (a) Birman, V. B.; Jiang, X.-T. Org. Lett.
2004, 6, 2369. (b) Papeo, G.; Frau, M. A. G.-Z.; Borghi, D.;
Varasi, M. Tetrahedron Lett. 2005, 46, 8635. (c) Yang, C.-
G.; Wang, J.; Jiang, B. Tetrahedron Lett. 2002, 43, 1063.
(4) For example: (a) Lindel, T.; Hochgürter, M. J. Org. Chem.
2000, 65, 2806. (b) Danios-Zeghal, S.; Mourabit, A. A.;
Ahond, A.; Poupat, C.; Potier, P. Tetrahedron 1997, 53,
7605. (c) Commerçon, A.; Paris, J. M. Tetrahedron Lett.
1991, 32, 4905. (d) Nanteuil, G. D.; Ahond, A.; Poupat, C.;
Thoison, O.; Potier, P. Bull. Soc. Chim. Fr. 1986, 813.
(5) Alain, C. Fr. Patent FR2681323, 1991; Chem. Abstr. 1993,
119; 139229a.
(6) Little, T. L.; Webber, S. E. J. Org. Chem. 1994, 59, 7299.
(7) Physical and spectral data of the representative compounds.
Compound 11: amorphous solid. IR (KBr): 3295, 1686,
1625, 1113, 1052 cm–1. 1H NMR (400 MHz, DMSO-d6): d =
2.02 (s, 3 H, Ac), 3.18 (s, 6 H, OMe), 5.24 [s, 1 H,
NH
a, b, c
d, e
22
NHBoc
H2N
N
25
CH(OMe)2], 6.65 (s, 1 H, 4-CH), 11.08 (br s, 1 H, NHAc),
11.40 (br s, 1 H, 1-NH). LRMS (EI+): m/z = 199 [M+], 168,
126, 96. HRMS (EI+): m/z calcd for C8H13N3O3: 199.0957;
found: 199.0947. Compound 14a: mp 134–136 °C (EtOAc).
IR (KBr): 3463, 1740, 1637, 1342, 1121, 1060 cm–1. 1H
NMR (400 MHz, CDCl3): d = 1.59 (s, 9 H, t-Bu), 3.37 (s, 6
H, OMe), 5.27 [d, J = 1.2 Hz, 1 H, CH(OMe)2], 5.56 (br s, 2
H, NH2), 6.86 (d, J = 1.2 Hz, 1 H, 4-CH). 13C NMR (400
MHz, CDCl3): d = 28.0, 52.7, 85.0, 99.4, 109.3, 135.6,
149.4, 150.6. LRMS (EI+): m/z = 257 [M+], 226, 125, 96.
Anal. Calcd for C11H19N3O4: C, 51.35; H, 7.44; N, 16.33.
Found: C, 51.20; H, 7.33; N, 16.36. Compound 16: mp 156–
158 °C (hexane–EtOAc). IR (KBr): 3417, 1736, 1640, 1372,
1358, 1127 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 1.57
(s, 9 H, t-Bu), 6.58 (br s, 2 H, NH2), 7.21 (t, J = 7.3 Hz, 1 H,
Ph), 7.33 (t, J = 7.3 Hz, 2 H, Ph), 7.33 (s, 1 H, 4-CH), 7.71
(d, J = 7.3 Hz, 2 H, Ph). 13C NMR (400 MHz, CDCl3): d =
28.0, 85.1, 106.1, 125.0, 127.3, 128.5, 133.2, 137.7, 149.4,
150.8. LRMS (EI+): m/z = 259 [M+], 203, 159. Anal. Calcd
for C14H17N3O2: C, 64.85; H, 6.61; N, 16.21. Found: C,
64.72; H, 6.57; N, 16.21. Compound 18a: mp 155–157 °C
(dec.) (hexane–EtOAc). IR (KBr): 3409, 1711, 1648, 1604,
O
NH
NH2
f, g
dispacamide (3)
monobromodispacamide (4)
BocHN
N
26
Scheme 5 Total synthesis of dispacamide (3) and monobromodis-
pacamide (4). Reagents and conditions: (a) H2 (4 kg/cm2), 10% Pd–
C–EtOH, 50 °C, 13 h; (b) H2NNH2–EtOH, 50 °C,6 h; (c) 20% HCl–
EtOH, r.t., overnight, 64% (3 steps from 22); (d) tetra-n-butylammo-
nium tribromide–DMSO, r.t., 1.5 h; (e) Boc2O–MeOH, r.t., overnight,
40% (2 steps from 25); (f) 20% HCl–EtOH, r.t., overnight; (g) 4,5-di-
bromo-2-trichloroacetylpyrrole or 4-bromo-2-trichloroacetylpyrrole,
Na2CO3–DMF, r.t., overnight, 85% for 3 (2 steps from 26), 69% for 4
(2 steps from 26).
As described above, we have succeeded in exploring a
novel synthetic route to 2-aminoimidazol-4-carbaldehyde
derivatives I, the versatile synthetic intermediates for 2-
aminoimidazole alkaloids, by featuring the reaction of
tert-butoxycarbonylguanidine (12a) with 3-bromo-1,1-
Synlett 2006, No. 17, 2836–2840 © Thieme Stuttgart · New York

2840
N. Ando, S. Terashimab
LETTER
1170 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.58 (s, 9 H, t-
Bu), 7.49 (s, 1 H, 4-CH), 9.59 (s, 1 H, CHO). 13C NMR (400
MHz, CDCl3): d = 28.2, 82.6, 128.8, 137.6, 147.7, 153.1,
176.9. LRMS (EI+): m/z = 211 [M+], 155, 111. Anal. Calcd
for C9H13N3O3: C, 51.18; H, 6.20; N, 19.89. Found: C,
51.07; H, 6.11; N, 19.93. Compound 19a: mp 112–114 °C
(hexane–EtOAc). IR (KBr): 1755, 1697, 1532, 1305, 1152
cm–1. 1H NMR (400 MHz, CDCl3): d = 1.55 (s, 9 H, t-Bu),
1.64 (s, 9 H, t-Bu), 7.70 (s, 1 H, 4-CH), 9.10 (br s, 1 H,
BocNH), 9.92 (s, 1 H, CHO). 13C NMR (400 MHz, CDCl3):
d = 27.8, 28.1, 82.5, 88.5, 117.2, 138.1, 142.8, 148.7, 149.6,
187.2. LRMS (EI+): m/z = 311 [M+], 211, 155, 111. Anal.
Calcd for C14H21N3O5: C, 54.01; H, 6.80; N, 13.50. Found:
C, 53.76; H, 6.63; N, 13.70.
analytical sample of 14a was prepared by recrystallization
from EtOAc.
(13) We subjected 18a to tritylation, acetylation, triisopropyl-
silylation and methoxymethylation under the standard
reaction conditions. Although formation of the desired
compounds corresponding to 19a was observed in
tritylation, acetylation and triisopropylsilylation, these
products were found to be too unstable to be isolated in pure
states. In the case of methoxymethylation, a complex
mixture was obtained as the reaction product.
(14) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26.
(15) Bailey, D. M.; Johnson, R. E. J. Med. Chem. 1973, 16, 1300.
(16) Mp 218–220 °C (dec.) [Lit.6 202–205 °C (dec.)].
(17) Forenza, S.; Minale, L.; Riccio, R.; Fattorusso, E. J. Chem.
Soc., Chem. Commun. 1971, 1129.
(8) The reaction was continued until complete consumption of
the starting material was ascertained by TLC analysis.
(9) Buchinska, T. V. J. Pept. Res. 1999, 53, 314.
(10) The crystallographic data was deposited at the Cambridge
Crystallographic Data Centre. The deposition number is
CCDC 605791.
(11) When the reaction of 15 and 12a was examined in THF at 50
°C for 3 h (see below), 16 was obtained as an almost sole
product in 68% yield along with a trace amount of 17.
(12) To a solution of 12a (478 mg, 3.0 mmol) in anhyd THF (3
mL) was added a solution of 10 (197 mg, 1.0 mmol) in anhyd
THF (2 mL) under an argon atmosphere. After heating at 50
°C for 6 h, the solvent was removed in vacuo. Purification of
the residue by column chromatography (SiO2, EtOAc)
afforded 14a as a colorless solid (159 mg, 62%). An
(18) Amorphous solid (Lit.19 amorphous solid).
(19) Kitamura, C.; Yamashita, Y. J. Chem. Soc., Perkin Trans. 1
1997, 1443.
(20) Kobayashi, J.; Ohizumi, Y.; Nakamura, H.; Hirata, Y.
Experientia 1986, 42, 1176.
(21) Olofson, A.; Yakushijin, K.; Horne, D. A. J. Org. Chem.
1998, 63, 1248.
(22) 1H NMR spectra of 3 and 4 synthesized by us clearly showed
that both samples were contaminated by small amounts of
the unnatural Z isomers (ca. 5%).
(23) Cafieri, F.; Fattorusso, E.; Mangoni, A.; Taglialatela-
Scafati, O. Tetrahedron Lett. 1996, 37, 3587.
Synlett 2006, No. 17, 2836–2840 © Thieme Stuttgart · New York