Total synthesis of (+)-galanthamine starting from d-glucose

Article abstract of DOI:10.1016/j.tetlet.2007.07.042

The stereoselective total synthesis of (+)-galanthamine (+)-1 starting from d-glucose is described. The cyclohexene ring in (+)-1 was prepared in an optically active form from d-glucose using Ferrier's carbocyclization reaction, and the critical quaternar

Full text of DOI:10.1016/j.tetlet.2007.07.042

Tetrahedron Letters 48 (2007) 6267–6270
Total synthesis of (+)-galanthamine starting from D-glucose
Hiroki Tanimoto, Tomoaki Kato and Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
Received 20 June 2007; accepted 5 July 2007
Available online 30 July 2007
Abstract—The stereoselective total synthesis of (+)-galanthamine (+)-1 starting from D-glucose is described. The cyclohexene ring in
(+)-1 was prepared in an optically active form from D-glucose using Ferrier’s carbocyclization reaction, and the critical quaternary
carbon was stereoselectively generated via chirality transfer based on the Claisen rearrangement of a cyclohexenol. The dibenzofu-
ran skeleton was effectively constructed by the bromonium ion-mediated intramolecular cyclization of a cyclohexene possessing a
phenolic ether function. After the introduction of a carbon–carbon double bond, the Pictet–Spengler type cyclization, followed
by the reduction of the amide function completed the chiral synthesis of (+)-1.
Ó 2007 Elsevier Ltd. All rights reserved.
(ꢀ)-Galanthamine (ꢀ)-1, an alkaloid isolated from some
species of the Amaryllidaceae family,1,2 has been
reported to be a centrally acting acetylcholinesterase
inhibitor3 and an allosteric modulator of the neuronal
nicotinic receptor for acetylcholine.4 On the basis of
these biological activities, (ꢀ)-galanthamine was devel-
oped as a medicine for Alzheimer’s disease and has been
clinically used in Europe and the USA.2c Its important
and significant biological activity as well as its interest-
ing structure have naturally received considerable atten-
tion from the synthetic community, and several
synthetic approaches to 1 have been reported to
date.2,5,6 A number of successful total syntheses of
galanthamine, employing the biomimetic oxidative
bisphenol coupling,2,5a,6a intramolecular Heck reac-
tion,2,5b,6d,h,i and semipinacol rearrangement5c for the
construction of the characteristic tetracyclic skeleton
possessing a spiro quaternary carbon, have appeared,
however, reports of the chiral syntheses of 1 are rather
limited.6 Due to the scarce supplies of galanthamine
from natural sources7 and the necessity for preparing
structural analogues for the development of more potent
drugs, it is still important to establish a chiral and effec-
tive synthetic route to the alkaloid from readily avail-
able materials. In this Letter, we report a new and
stereoselective total synthesis of (+)-galanthamine (+)-
1, an enantiomer of the natural product, starting from
D-glucose, which is readily utilized for the preparation
of natural (ꢀ)-galanthamine and would be applicable
for the synthesis of structural analogues that are not
available through the biomimetic synthetic approach
nor the chemical modification of the natural product.
Recently, we have reported the total synthesis of (+)-
vittatine and (+)-haemanthamine, Amaryllidaceae alka-
loids possessing the hexahydroindole skeleton with a
1,3-dioxolane ring at m- and p-positions in the phenyl
group as the core structure, starting from D-glucose,
and revealed that the methodology involving Claisen
rearrangement on the chiral cyclohexenol derived from
carbohydrates is effective for the stereoselective genera-
tion of quaternary carbons.8 Our retrosynthetic analysis
for (+)-galanthamine (+)-1, taking the successful syn-
thesis of vittatine and haemanthamine into account,
suggested that tetracyclic lactam 2, which had been uti-
lized in the synthesis of the racemic galanthamine by
Guillou,5b would be a suitable intermediate for the total
synthesis (Fig. 1). The dibenzofuran skeleton in 2 was
expected to be constructed by the bromonium ion-
mediated intramolecular dealkylating etherification of
cyclohexene possessing a phenolic ether function9 3,
whose crucial quaternary carbon preparation was
planned using the Claisen rearrangement8,10 of cyclo-
hexenol derivative 4. Cyclohexenol 4, in turn, was
envisioned to be synthesized by the coupling reaction
of an aryl metal species with cyclohexenone (+)-5, which
is a known compound11 and has been prepared in the
optically pure form starting from D-glucose utilizing
Ferrier’s carbocyclization12 as the key transformation.
Keywords: Galanthamine; Chiral synthesis; Claisen rearrangement.
*
Corresponding author. Tel./fax: +81 455661573; e-mail: chida@
applc.keio.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.042

6268
H. Tanimoto et al. / Tetrahedron Letters 48 (2007) 6267–6270
MeO
MeO
Ph
O
O
O
MgBr
THF
—78 ºC
8 steps
(38%)
(ref. 11)
(+)-5
HO
OMe
OH
(85%)
6
(4:1 diastereomeric mixture)
MeO
MeO
MeO
MeO
OH
OBn
PCC
NaOAc
NaBH4
CeCl3 7H2O
OBn
(CH2Cl)2
60 ºC
(75%)
MeOH / CH2Cl2
(2 / 3)
O
OTBS
8
OTBS
—78 ºC
(89%, epimer 9%)
7
MeO
2-nitrophenol
(150 mol% to 4)
NBS
CO2Et
OBn
O
3
4
DMF
CH3C(OEt)3
140 ºC, 60 h
(80%)
0 ºC
(84%)
Br
OTBS
9
MeO
H2, 10% Pd/C
EtOH
CO2Et
OR
O
then H2, 10% Pd/C
K2CO3, EtOH
9a
7
5a
9
8
10 R = H
11 R = Bz
6
BzCl
pyridine
(100%)
(85%)
Figure 1. Structure of galanthamine and its retrosynthetic analysis.
Bn = –CH2Ph, TBS = –SiMe2(t-Bu).
OTBS
MeO
J5a,6ax = 8.9 Hz
J5a,6eq = 6.5 Hz
J6ax,7 = 10.2 Hz
J7,8ax = 10.4 Hz
J8ax,9 = 11.9 Hz
J8eq,9 = 3.9 Hz
O
5a
6
9a
CO2Et
The treatment of (4R,6S)-6-benzyloxy-4-(tert-butyldim-
ethylsilyloxy)-2-cyclohexenone11 (+)-5, prepared from
commercially available methyl 4,6-O-benzylidene-a-D-
glucopyranoside 6 utilizing the catalytic Ferrier’s carbo-
cyclization12c as the key transformation in a total of
eight steps with 38% overall yield, with 2,3-dimethoxy-
phenylmagnesium bromide at ꢀ78 °C gave 1,2-adducts
7 in 85% yield as a diastereomeric mixture (4:1) (Scheme
1).13 The oxidation of 7 with pyridinium chlorochro-
mate (PCC) afforded cyclohexenone 8 in 75% yield,
which was reduced under the conditions of Luche14 at
ꢀ78 °C to give cyclohexenol 4 and its C-1 epimer in 89
and 9% isolated yields, respectively. The observed cou-
pling constants in 4 (J1,2 = 7.8 Hz) and its C-1 epimer
(J1,2 = 4.1 Hz) supported their assigned configurations.
8
TBSO
2'
O
H 9
H
7
H
H
Bz
H
NOE
Scheme 1. Bz = –C(O)Ph.
Selected NMR data of 11
the decomposition of the substrate, but could catalyze
the formation of a ketene acetal.
The treatment of 3 with N-bromosuccinimide (NBS) in
DMF induced the intramolecular dealkylating etherifi-
cation via a bromonium ion intermediate9 to give bro-
mo-dibenzofuran derivative 917 in 84% yield. The
formation of other possible products such as bromohyd-
rins or lactones was not observed in the cyclization reac-
tion. The hydrogenolysis of 9 in the presence of Pd on
carbon and potassium carbonate in EtOH at room tem-
perature under atmospheric pressure of H2 caused the
debromination as well as the deprotection of the O-
benzyl group to provide 10. However, under these basic
conditions, the de-O-benzylation process was found to
be very sluggish, and resulted in the low yield of 10 (less
than 40%). In contrast, under similar hydrogenolytic
conditions without potassium carbonate, deprotection
of the O-benzyl group smoothly proceeded, but the
debromination process became slow. After some
attempts, it was found that the two-steps in a one-pot
reaction gave satisfactory results. Thus, deprotection
of the O-benzyl group in 9 under neutral conditions
(Pd on carbon, atmospheric pressure of H2 in EtOH)
was first carried out. After completion of the de-O-ben-
Johnson–Claisen rearrangement15 of
4 in triethyl
orthoacetate in the presence of 2-nitrophenol8b,16 in a
sealed tube at 140 °C for 60 h successfully afforded the
rearranged product 317 in 80% yield. It is important to
note that the Johnson–Claisen rearrangement of 4, pos-
sessing an o-methoxy substituent in the phenyl group,
proceeded in a high yield when 2-nitrophenol was em-
ployed as the acid catalyst.18 It has been reported that
the conventional Johnson–Claisen rearrangement (using
propionic acid as the catalyst) of the simple cyclohexe-
nol systems similar to 4 resulted in the very poor yields
of the rearranged products, probably due to the acid
sensitivity of the substrates and the steric congestion at
the reaction center caused by the presence of the o-meth-
oxy substituent in the phenyl group.9,10b,19 The acidity
of 2-nitrophenol (pKa 7.04) would be appropriate for
the Johnson–Claisen rearrangement of 4; its weaker
acidity than that of propionic acid (pKa 4.62) suppressed

H. Tanimoto et al. / Tetrahedron Letters 48 (2007) 6267–6270
6269
zylation (TLC monitoring), potassium carbonate was
added to the reaction mixture and the hydrogenolysis
of the C–Br bond was further continued in the same
reaction vessel to give 10 in 85% yield. The structure
of compound 10 was confirmed by NMR analyses of
the derived benzoate 11 (Scheme 1); the observed large
rearrangement on chiral cyclohexenol derived from
D-glucose is effective for the stereoselective generation
of the quaternary carbon. The effectiveness of 2-nitro-
phenol as the acid catalyst for the Johnson–Claisen
rearrangement is particularly noteworthy. It was also
shown that the intramolecular dealkylating etherifica-
tion using NBS is a useful procedure for the construc-
tion of benzofuran skeletons, which are commonly
found in galanthanmine-type and morphine-type bio-
logically significant alkaloids.
coupling constants (J5a,6ax, J6ax,7, J7,8ax and J8ax,9
)
revealed that the substituents at C-5a, C-7 and C-9 are
all in the equatorial positions, and NOE experiments
(correlations between H-5a and C-20 methylene, and
H-9 and C-20 methylene) clearly assigned the stereo-
chemistry of the quaternary carbon at C-9a as R.
Acknowledgments
To introduce the requisite carbon–carbon double bond,
compound 10 was treated with (thiocarbonyl)diimidaz-
ole and DMAP in dichlorobenzene at 180 °C20 to afford
12 in 72% yield from 10 (Scheme 2). Hydrolysis of the
ethyl ester function in 12, followed by condensation with
methylamine under the conditions of Shioiri21 success-
fully provided amide 1317 in 93% yield. The Pictet–Spen-
gler type reaction of 13 with paraformaldehyde in
the presence of TFA5b,c generated the ethano-bridge
between the amide nitrogen and C-1, and induced the
deprotection of the O-TBS group to give the tetracyclic
lactam 2, which is known as the intermediate for the
synthesis of racemic galanthamine reported by the Guil-
lou5b and the Tu5c groups in 67% yield. Finally, the
reduction of 2 with LiAlH4 cleanly afforded (+)-galan-
We thank the Ministry of Education, Culture, Sports,
Science, and Technology, Japan (Grant-in-Aid for Sci-
entific Research on Priority Area ‘Creation of Biologi-
cally Functional Molecules’ and Grant-in-Aid for the
21st Century COE program ‘KEIO LCC’) for financial
assistance.
References and notes
1. (a) Proskurnina, N. F.; Yakovleva, A. P. Zhur. Obschchei.
Khim. 1952, 22, 1899–1902; (b) Kobayashi, S.; Shingu, T.;
Uyeo, S. Chem. Ind. 1956, 177–178; (c)The Merck Index;
Budavari, S., Ed., 12th ed.; Merck & CO.: Newyork, 1996;
p 736, monograph number 4357.
2. For comprehensive reviews on biological activities and
synthetic studies of galanthamine-type Amaryllidaceae
alkaloids, see: (a) Martin, S. F. In The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, NY, 1987; Vol. 30,
pp 251–376; (b) Hoshino, O. In The Alkaloids; Cordell, G.
A., Ed.; Academic Press: New York, NY, 1998; Vol. 51,
pp 323–424; (c) Marco-Contelles, J.; Carreiras, M. D. C.;
Rodriguez, C.; Villarroya, M.; Garcia, A. G. Chem. Rev.
2006, 106, 116–133.
3. (a) Rainer, M. Drugs Today 1997, 33, 273–279; Mucke, H.
A. M. Drugs Today 1997, 33, 259–264; Giacobini, E.
Neurochem. Int. 1998, 32, 413–419; Weinstock, M. CNS
Drugs 1999, 12, 307–323; Sramek, J. J.; Frackiewicz, E. J.;
Culter, N. R. Expert Opin. Invest. Drugs 2000, 9, 2393–
2402.
4. Lilienfeld, S. CNS Drug Rev. 2002, 8, 159–176.
5. Recent reports on racemic syntheses of galanthamine, see:
(a) Node, M.; Kodama, S.; Hamashima, Y.; Baba, T.;
Hamamichi, N.; Nishide, K. Angew. Chem., Int. Ed. 2001,
40, 3060–3062; (b) Guillou, C.; Beunard, J.-L.; Gras, E.;
Thal, C. Angew. Chem., Int. Ed. 2001, 40, 4745–4746; (c)
Hu, X.-D.; Tu, Y. Q.; Zhang, E.; Gao, S.; Wang, S.;
Wang, A.; Fan, C.-A.; Wang, M. Org. Lett. 2006, 8, 1823–
1825.
6. For chiral total syntheses of (+)- and (ꢀ)-galanthamine,
see: (a) Tomioka, K.; Shimizu, K.; Yamada, S.-i.; Koga,
K. Heterocycles 1977, 6, 1752–1756; (b) Shimizu, K.;
Tomioka, K.; Yamada, S.-i.; Koga, K. Heterocycles 1977,
8, 277–282; (c) Shimizu, K.; Tomioka, K.; Yamada, S.-i.;
Koga, K. Chem. Pharm. Bull. 1978, 26, 3765–3771; (ꢀ)-
Galanthamine, see: (d) Trost, B. M.; Tang, W. Angew.
Chem., Int. Ed. 2002, 41, 2795–2797; (e) Trost, B. M.;
Tang, W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
14785–14803; (f) Kodama, S.; Hamashima, Y.; Nishide,
K.; Node, M. Angew. Chem., Int. Ed. 2004, 43, 2659–2661;
(g) Node, M.; Kodama, S.; Hamashima, Y.; Katoh, T.;
Nishide, K.; Kajimoto, T. Chem. Pharm. Bull. 2006, 54,
1662–1679; (h) Satcharoen, V.; McLean, N. J.; Kemp, S.
1
thamine (+)-117 in 88% yield. The H and 13C NMR
data of the synthetic 1 were totally identical with those
for natural (ꢀ)-galanthamine and the [a]D value of the
24
synthetic compound {½aꢁD +111.5 (c 0.50, EtOH): lit.1c
20
½aꢁD ꢀ118.8 (c 1.378, EtOH)} confirmed its unnatural
absolute configuration. Since we have already reported
the preparation of the enantiomeric cyclohexenone
(ꢀ)-5 from the same starting material 6,11 the synthesis
of (ꢀ)-galanthamine in the formal sense has also been
achieved.
In summary, a new and non-biomimetic synthetic route
to optically active galanthamine starting from D-glucose
has been established. This synthesis, required 11 steps
with a 12.8% overall yield from (+)-5 (19 steps with a
4.9% overall yield from commercially available 6), dem-
onstrated that the methodology involving the Claisen
MeO
4
N
C S
1
8
5
N
1) LiOH, MeOH-H2O
2
O
10
CO2Et
.
DMAP
9a
7
2) MeNH2 HCl, Et3N
5a
1,2-dichlorobenzene
rt - reflux
(EtO)2P(O)CN
THF, —10 ºC
(72%)
OTBS
(93%)
12
4
MeO
1
O
5a
NHMe
(CH2O)n
LiAlH4
(+)-galanthamine
2
O
THF
reflux
(88%)
TFA
(CH2Cl)2
(67%)
(+)-1
7
OTBS
13
Scheme 2.

6270
H. Tanimoto et al. / Tetrahedron Letters 48 (2007) 6267–6270
C.; Camp, N. P.; Brown, R. C. D. Org. Lett. 2007, 9,
1867–1869; For preparation of (ꢀ)-galanthamine via
spontaneous resolution of racemic narwedine, see: (i)
Shieh, W.-C.; Carlson, J. A. J. Org. Chem. 1994, 59, 5463–
5465; (j) Kuenburg, B.; Czollner, L.; Fro¨hlich, J.; Jordis,
¨
U. Org. Process Res. Dev. 1999, 3, 425–431.
C, 68.85; H, 8.20. Found: C, 68.74; H, 8.19. Data of 9:
26
Colorless syrup; ½aꢁD +26.1 (c 1.78, CHCl3); mmax (neat)
1730, 1640 and 1590 cmꢀ1; 1H NMR (CDCl3, 300 MHz) d
7.44–7.28 (m, 5H), 7.22 (dd, 1H, J = 1.4 and 6.8 Hz),
6.82–6.76 (m, 2H), 5.18 (br d, 1H, J = 7.6 Hz), 4.71 and
4.52 (2d, each 1H, J = 11.6 Hz), 4.19–4.00 (m, 3H), 3.87
(s, 3H), 3.76–3.62 (m, 2H), 2.89 and 2.48 (2d, each 1H,
J = 16.1 Hz), 2.27 (ddd, 1H, J = 3.4, 3.4 and 12.7 Hz),
1.53 (m, 1H), 1.22 (t, 3H, J = 7.2 Hz), 0.86 (s, 9H), 0.13
and 0.07 (2s, each 3H); 13C NMR (CDCl3, 75 MHz) d
171.0, 146.6, 145.9, 138.1, 132.0, 128.5, 127.81, 127.78,
122.3, 118.8, 113.2, 90.2, 75.4, 72.1, 69.8, 60.5, 60.1, 56.3,
54.5, 39.7, 36.3, 25.7, 18.0, 14.1, ꢀ4.4, ꢀ4.5; LRMS (EI)
m/z 606 (M+, 4.0%), 604 (M+, 4.0), 549 (3.7), 547 (3.7),
531 (3.5), 529 (3.4), 337 (42.2), 247 (93.3), 91 (100), 73
(39.4); HRMS (EI) m/z 604.1857, Calcd for
C30H4179BrO6Si, M+ 604.1856. Data of 13: Crystalline
´
7. Bastida, J.; Viladomat, F.; Llabres, J. M.; Quiroga, S.;
Codina, C.; Rubiralta, M. Planta Med. 1990, 56, 123–124.
8. (a) Bohno, M.; Imase, H.; Chida, N. Chem. Commun.
2004, 1086–1087; (b) Bohno, M.; Sugie, K.; Imase, H.;
Yusof, Y. B.; Oishi, T.; Chida, N. Tetrahedron 2007, 63,
6977–6989.
9. Construction of benzofuran skeletons by way of the
bromonium ion-mediated cyclization using Br2, see: Mul-
zer, J.; Bats, J. W.; List, B.; Opatz, T.; Trauner, D. Synlett
1997, 441–444.
10. For utilization of Claisen rearragement in the synthesis of
related alkaloids, see: (a) Keck, G. E.; Webb, R. R., II. J.
Org. Chem. 1982, 47, 1302–1309; (b) Labidalle, S.; Min, Z.
Y.; Reynet, A.; Moskowitz, H.; Vierfond, J.-M.; Miocque,
M. Tetrahedron 1988, 44, 1159–1169; (c) Parsons, P. J.;
Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195–206;
(d) Schkeryantz, J. M.; Pearson, W. H. Tetrahedron 1996,
52, 3107–3116; (e) Chida, N.; Sugihara, K.; Amano, S.;
Ogawa, S. J. Chem. Soc., Perkin Trans. 1 1997, 275–280;
(f) Mulzer, J.; Trauner, D. Chirality 1999, 11, 475–482, see
also Ref. 9; (g) Ng, F. W.; Lin, H.; Danishefsky, S. J.
J. Am. Chem. Soc. 2002, 124, 9812–9824.
24
residue; mp 58–60 °C; ½aꢁD ꢀ3.5 (c 0.98, CHCl3); mmax
(KBr disk) 3395, 3310, 1650 and 1645 cmꢀ1 1H NMR
;
(CDCl3, 300 MHz) d 6.83 (dd, 1H, J = 7.3 and 8.0 Hz),
6.74 (dd, 1H, J = 1.5 and 8.0 Hz, 1H, H-1), 6.71 (dd, 1H,
J = 1.5 and 7.3 Hz), 5.99 (dd, 1H, J = 2.0 and 10.1 Hz),
5.82 (ddd, 1H, J = 1.2, 1.9 and 10.1 Hz), 5.18 (br s), 4.37
(dddd, 1H, J = 1.9, 2.0, 4.9 and 10.4 Hz), 3.86 (s, 3H), 2.69
(d, 3H, J = 4.9 Hz), 2.48 and 2.34 (2d, each 1H,
J = 13.8 Hz), 2.31 (dddd, 1H, J = 1.2, 2.0, 4.9 and
11.7 Hz), 1.69 (ddd, 1H, J = 10.4, 11.6 and 11.7 Hz),
0.84 (s, 9H), 0.054 and 0.047 (2s, each 3H); 13C NMR
(CDCl3, 75 MHz) d 170.0, 145.9, 145.4, 134.2, 133.3,
127.1, 121.4, 115.4, 111.7, 84.9, 65.2, 56.0, 48.4, 47.0, 36.9,
26.2, 25.7, 18.0, ꢀ4.6, ꢀ4.8; LRMS (EI) m/z 403 (M+,
9.0%), 346 (41.9), 328 (100), 254 (22.8), 181 (19.2), 158
(16.1), 75 (44.7), 73 (39.6); HRMS (EI) m/z 403.2165,
Calcd for C22H33NO4Si, M+, 403.2179. Data of (+)-1:
Crystalline residue; mp 124–125 °C (lit.1c mp 126–127 °C);
11. Imuta, S.; Tanimoto, H.; Momose, K. M.; Chida, N.
Tetrahedron 2006, 62, 6926–6944.
12. (a) Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93,
2779–2831; (b) Ferrier, R. J.; Middleton, S. Top. Curr.
Chem. 2001, 215, 277–291; (c) Chida, N.; Ohtsuka, M.;
Ogura, K.; Ogawa, S. Bull. Chem. Soc. Jpn. 1991, 64,
2118–2121.
13. All new compounds described in this Letter were charac-
terized by 300 MHz 1H NMR, 75 MHz 13C NMR, IR,
and mass spectrometric and/or elemental analyses.
14. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103,
5454–5459.
23
½aꢁD +111.5 (c 0.50, EtOH); mmax (neat) 3360, 2920, 1505,
1440, 1280 and 1050 cmꢀ1; 1H NMR (CDCl3, 300 MHz) d
6.66 and 6.62 (2d, each 1H, J = 8.3 Hz), 6.06 (dd, 1H,
J = 1.2 and 10.3 Hz), 6.00 (ddd, 1H, J = 1.3, 4.9 and
10.3 Hz), 4.61 (br s, 1H), 4.14 (br dd, 1H, J = 4.9 and
4.9 Hz), 3.83 (s, 3H), 4.08 and 3.68 (2d, each 1H,
J = 15.1 Hz), 3.26 (ddd, 1H, J = 1.7, 13.0 and 14.6 Hz),
3.05 (ddd, 1H, J = 3.2, 3.9 and 14.6 Hz), 2.68 (dddd, 1H,
J = 1.3, 1.5, 3.2 and 15.6 Hz), 2.40 (s, 3H), 2.08 (ddd, 1H,
J = 3.2, 13.0 and 13.7 Hz), 2.00 (ddd, 1H, J = 2.4, 4.9 and
15.6 Hz), 1.85 (br s, 1H), 1.57 (ddd, 1H, J = 1.7, 3.9 and
13.7 Hz); 13C NMR (CDCl3, 75 MHz) d 145.8, 144.2,
133.0, 128.5, 127.7, 126.7, 122.2, 111.2, 88.7, 62.0, 60.4,
55.9, 53.7, 48.1, 41.8, 33.6, 29.9; LRMS (EI) m/z 288
(18.1%), 287 (M+, 100), 286 (84.1), 269 (14.1), 244 (14.0),
230 (19.6), 215 (11.3), 174 (18.8); HRMS (EI) m/z
287.1521; Calcd for C17H19NO4, M+, 287.1521.
15. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brock-
som, T. J.; Li, T.-T.; Faulkner, D. J.; Petersen, M. R. J.
Am. Chem. Soc. 1970, 92, 741–743; Castro, A. M. M.
Chem. Rev. 2004, 104, 2939–3002.
16. Fukazawa, T.; Shimoji, Y.; Hashimoto, T. Tetrahedron:
Asymmetry 1996, 7, 1649–1658.
26
17. Data of 3: Colorless syrup; ½aꢁD ꢀ7.2 (c 0.38, CHCl3); mmax
(neat) 1730 and 1470 cmꢀ1; 1H NMR (CDCl3, 300 MHz) d
7.35–7.21 (m, 6H), 6.95 (dd, 1H, J = 8.0 and 8.0 Hz), 6.83
(dd, 1H, J = 1.4 and 8.0 Hz), 6.03 (dd, 1H, J = 1.7 and
10.2 Hz), 5.66 (ddd, 1H, J = 1.0, 1.5 and 10.2 Hz), 4.66
and 4.53 (2d, each 1H, J = 11.7 Hz), 4.30 (dddd, 1H,
J = 1.5, 1.7, 6.8 and 9.3 Hz), 4.00 (q, 2H, J = 7.1 Hz), 3.83
(dd, 1H, J = 2.7 and 12.2 Hz), 3.82 and 3.75 (2s, each 3H),
3.26 and 3.03 (2d, each 1H, J = 14.9 Hz), 2.06 (dddd, 1H,
J = 1.0, 2.7, 12.2 and 12.2 Hz), 1.83 (ddd, 1H, J = 9.3,
12.2 and 12.2 Hz), 1.13 (t, 3H, J = 7.1 Hz), 0.87 (s, 9H),
0.05 and 0.03 (2s, each 3H); 13C NMR (CDCl3, 75 MHz) d
171.9, 153.2, 149.5, 138.7, 134.2, 133.0, 130.4, 128.1, 127.9,
127.4, 124.01, 122.1, 111.5, 78.6, 71.7, 68.2, 60.3, 59.8,
55.8, 48.2, 42.4, 33.2, 25.9, 18.2, 14.1, ꢀ4.5, ꢀ4.6; LRMS
(EI) m/z 540 (M+, 4.7%), 483 (4.4), 406 (40.5), 175 (30.9),
91 (76.6), 75 (100); HRMS (EI) m/z 540.2908, Calcd for
C31H44O6Si, M+, 540.2907. Anal. Calcd for C31H44O6Si:
18. When propionic acid was employed as the acid in the
Johnson–Claisen rearrangement of 4, the yield of 3 was
found to be low (less than 25%) and the formation of
significant amount of unidentified by-products was
observed.
19. Trauner, D.; Bats, J. W.; Werner, A.; Mulzer, J. J. Org.
Chem. 1998, 63, 5908–5918.
20. Williams, D. R.; Coleman, P. J.; Henry, S. S. J. Am.
Chem. Soc. 1993, 115, 11654–11655.
21. Yamada, S.-i.; Kasai, Y.; Shioiri, T. Tetrahedron Lett.
1973, 14, 1595–1598; Shioiri, T.; Yokoyama, Y.; Kasai,
Y.; Yamada, S.-i. Tetrahedron 1976, 32, 2211–2217.