Formal synthesis of (-)-morphine from d-glucal based on the cascade Claisen rearrangement

Article abstract of DOI:10.1016/j.tetlet.2007.11.037

The formal synthesis of (-)-morphine is described. The C-ring in morphine was prepared in an optically pure form from d-glucal using Ferrier's carbocyclization reaction, and the vicinal tertiary and quaternary stereocenters in the C-ring were stereoselect

Full text of DOI:10.1016/j.tetlet.2007.11.037

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 358–362
Formal synthesis of (ꢀ)-morphine from D-glucal based
on the cascade Claisen rearrangement
Hiroki Tanimoto, Ryosuke Saito and Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
Received 15 October 2007; revised 5 November 2007; accepted 6 November 2007
Abstract—The formal synthesis of (ꢀ)-morphine is described. The C-ring in morphine was prepared in an optically pure form from
D-glucal using Ferrier’s carbocyclization reaction, and the vicinal tertiary and quaternary stereocenters in the C-ring were stereo-
selectively generated in a one-step reaction based on the cascade sequential Claisen rearrangement of an allylic vicinal diol deriva-
tive. After the one-step formation of the dibenzofuran structure, the intramolecular Friedel–Crafts type reaction effectively
constructed the ABCE-phenanthrofuran skeleton. Introduction of a tosylamide function, followed by reductive cyclization
furnished (ꢀ)-dihydroisocodeine, the known synthetic intermediate for (ꢀ)-morphine.
Ó 2007 Elsevier Ltd. All rights reserved.
(ꢀ)-Morphine 1 is a well-known principal alkaloid iso-
lated from opium poppy, Papaver Somniferum, and a
number of structurally related alkaloids, such as (ꢀ)-
codeine and (ꢀ)-thebaine, have also been discovered in
the same plant.1 Due to its significant effectiveness as
an analgesic, morphine has been used as a medicine
for a long time in spite of its serious addictive side
effects. Its important biological activity as well as its
highly challenging structure, a strained pentacyclic core
with five contiguous chiral centers including a benzylic
quaternary carbon (morphinan skeleton), has naturally
received considerable attention from the synthetic com-
munity, and a number of synthetic studies and total syn-
theses have been reported.2 In this Letter, we disclose a
new and stereoselective synthesis of (ꢀ)-dihydroisoco-
deine 2, the key intermediate of (ꢀ)-morphine,2c starting
from D-glucal, in which the vicinal tertiary and quater-
nary carbons in the C-ring were stereoselectively gener-
ated in a one-step reaction by the cascade Claisen
rearrangement.
2-nitrophenol-catalyzed Johnson–Claisen rearrange-
ment of a cyclohexenol possessing a substituted phenyl
group prepared from D-glucose by way of the Ferrier’s
carbocyclization as the key transformation is effective
for the stereoselective generation of a benzylic quater-
nary carbon.3 It was also shown that the dibenzofuran
skeleton could be easily constructed by the intramolecu-
lar dealkylating etherification of a cyclohexene bearing a
methoxyphenyl group. These successful results led us to
apply a similar methodology to the synthesis of
(ꢀ)-morphine 1 starting from carbohydrates. Our retro-
synthetic analysis (Fig. 1) suggested that (ꢀ)-dihydro-
isocodeine 2, which is the known synthetic intermediate
in Parker’s synthesis of (ꢀ)-morphine,2c would be an
appropriate target compound. The formation of the
morphinan skeleton in 2 was planned by the reductive
cyclization of tosylamide 3 reported by Parker.2c The
tetracyclic ring system in 3 was envisioned to be
prepared by the intramolecular Friedel–Crafts type
cyclization2e,4 of aryl-aldehyde 4, whose dibenzofuran
structure was expected to be constructed by the epox-
ide-mediated intramolecular dealkylating etherifica-
tion2f,g of cyclohexene 5 possessing a phenolic ether
function. For the stereoselective construction of the
vicinal tertiary and quaternary carbons in 5, the cascade
sequential Claisen rearrangement of cyclohexene-diol 6
was planned. If the cascade reaction works as expected
(6!50!5), the adjacent tertiary and quaternary carbons
could be constructed in a one-step reaction, and the two
C–O stereochemistries in the starting material 6 would
Recently, we reported the total synthesis of (+)-galan-
thamine, an alkaloid possessing the same tricyclic diben-
zofuran core as (ꢀ)-morphine, and revealed that the
Keywords: Morphine; Dihydroisocodeine; Total synthesis; Cascade
Claisen rearrangement; Friedel–Crafts type cyclization.
*
Corresponding author. Tel./fax: +81 45 566 1573; e-mail: chida@
applc.keio.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.037

H. Tanimoto et al. / Tetrahedron Letters 49 (2008) 358–362
359
1) NaOMe, MeOH
2) p-anisaldehyde
dimethylacetal
PMP
O
CH2OAc
O
AcO
AcO
PPTS, DMF, 45 ºC
reduced pressure
O
O
3) TBSCl, imidazole
TBSO
DMF (45% for 3 steps)
tri-O-acetyl-
9
D-glucal
R
1) DIBAL, toluene
—20 ºC to rt
PMBO
O
t-BuOK
2) Ph3P•HBr, MeOH
THF
TBSO
OMe
NaBr, DME, 0 °C
(87%)
I2, imidazole
10 R = OH
11 R = I
Ph3P, THF
(69% for 3 steps)
1) Hg(OCOCF3)2
O
(20 mol%)
acetone /
PMBO
TBSO
PMBO
O
acetate buffer
2) MsCl, Et3N,
DMAP, CH2Cl2
OMe
TBSO
MeO
12
13
(91% for 2 steps)
L-Selectride®
THF, —78 °C
8
Pd(OAc)2, Ph3P
MeO
PMBO
7
then Comins
aq Na2CO3
/
reagent
1,4-dioxane
(89%)
(100%)
TBSO
14
6
MeO
MeO
HO
DDQ
CH2Cl2 / H2O
(83%)
Bu4NF
THF
(100%)
TBSO
15
Figure 1. Structure of morphine and its retrosynthetic analysis.
TBS = –SiMe2(t-Bu), Tf = –SO2CF3, PMB = –CH2C6H4(p-OMe).
Scheme 1. PMP = –C6H4(p-OMe), L-SelectrideÒ = Li[CH(CH3)-
CH2CH3]3BH.
be effectively transferred to the C–C stereogenic centers
in 5 by the sequential chirality transfer. Although a
number of examples of the stereoselective C–C bond
formation via chirality transfer utilizing the Claisen
rearrangement have been reported,5 its cascade versions
have received little attention.6 The cyclohexene-diol 6, in
turn, was envisioned to be prepared by the Suzuki–
Miyaura coupling of vinyl triflate 7 with arylboronic
acid 8. The planned formation of the cyclohexene ring
in 7 was to be prepared in optically active form starting
from D-glucal utilizing Ferrier’s carbocyclization
reaction.7
carbocyclization reaction7c of 12 in acetone–acetate
buffer and subsequent b-elimination of the hydroxy
function cleanly generated cyclohexenone 13 in 91%
yield. The 1,4-reduction of 13 with L-SelectrideÒ,
followed by trapping of the resulting enolate with
Comins reagent11 provided the vinyl triflate 7 in 89%
yield. Suzuki–Miyaura coupling12 of 7 with 2,3-dimeth-
oxyphenylboronic acid 8 smoothly proceeded at room
temperature to quantitatively give 14. Deprotection of
the PMB group in 14 by the action of DDQ produced
allylic alcohol 15 (83% yield). Removal of the O-TBS
group in 15 provided the precursor of the cascade
Claisen rearrangement, the vicinal allylic–homoallylic
diol 6,13 in quantitative yield.
The treatment of D-glucal, prepared from the commer-
cially available tri-O-acetyl-D-glucal by de-O-acetyl-
ation, with p-anisaldehyde dimethylacetal produced a
4,6-O-anisylidene derivative, whose hydroxy group was
protected as a TBS ether to afford the known 98 in
45% overall yield (Scheme 1). Cleavage of the anisyl-
idene acetal in 9 with DIBAL gave a primary alcohol
derivative, which was transformed into methyl glycoside
10 by the action of methanol in the presence of
Ph3PÆHBr.9 The primary hydroxy group in 10 was
replaced with iodide to give 1110 in 69% overall yield
from 9. The treatment of 11 with t-BuOK provided 5-
enopyranoside 12 in 87% yield. Catalytic Ferrier’s
With the desired diol 6 in hand, the crucial step, the
cascade sequential Claisen rearrangement was then
explored (Scheme 2). After several attempts, it was
found that when 6 was heated at 140 °C in triethyl
orthoacetate in the presence of 2-nitrophenol in a sealed
tube, the cascade Johnson–Claisen rearrangement
successfully took place to provide the doubly rearranged
product 513 in moderate (36%) yield.14 It is important to
note that the vicinal tertiary and quaternary carbons in
morphine were stereoselectively constructed in
a

360
H. Tanimoto et al. / Tetrahedron Letters 49 (2008) 358–362
MeO
MeO
MeO
DIBAL
2-nitorophenol
mCPBA
(2 equiv)
(5 mol% to 6)
O
5
CO2Et
CO2Et
CO2Et
CO2Et
4
6
CH2Cl2
(74%)
toluene
–78 ºC
CH3C(OEt)3
140 ºC, 72 h
in a sealed tube
RO
5
(36%)
TBSCl
18 R = H
19 R = TBS
imidazole
DMF
2-nitorophenol
(5 mol% to 17)
(57%)
CH3C(OEt)3
140 ºC, 120 h
in a sealed tube
(99%)
(17: 14% recovery)
MeO
1) Montmorillonite
K-10
OH
CHO
MeO
MeO
(CH2Cl)2
O
2) TBSOTf
2,6-lutidine
CH2Cl2
EtCOOH
CO2Et
(45 mol% to 15)
H
15
CH3C(OEt)3
140 ºC, 24 h
RO
(75% for 3 steps)
in a sealed tube
R = TBS, H
RO
(87%)
Bu4NF
THF
(97%)
16 R = TBS
17 R = H
MeO
1) MeNH2, MeNH3Cl
MS 3A, THF, 0 ºC
CHO
then LiBH4
O
3
Scheme 2.
2) TsCl, DMAP
pyridine, 80 ˚C
3) Bu4NF, THF
H
TBSO
one-step reaction by this cascade rearrangement. On the
other hand, the stepwise version was also investigated.
Claisen rearrangement of allylic alcohol 15 in triethyl
orthoacetate in the presence of propionic acid at
140 °C in a sealed tube for 24 h gave the rearranged
product 16 in 87% yield.15 After removal of the
O-TBS group (97% yield), the resulting allylic alcohol
17 was heated in triethyl orthoacetate in the presence
of 2-nitrophenol at 140 °C to provide 5 in 57% yield
along with the recovery of 17 (14%). Thus, the stepwise
approach provided the rearranged product 5 in 48%
overall yield (56% overall yield based on the recovered
starting material) from 15.16
(86% for 3 steps)
20
MeO
known
Li, t-BuOH
(–)-morphine 1
O
liq NH3, THF
–78 ºC
N
H
Me
(92%)
HO
(–)-dihydroisocodeine 2
Scheme 3. mCPBA = m-chloroperbenzoic acid.
cleanly provided (ꢀ)-dihydroisocodeine 213 in 92% yield.
The 1H and 13C NMR data of 2 were totally identical to
those reported by Parker,2c and the [a]D value of the syn-
Having established the preparation of diester 5 by way
of the cascade or stepwise Claisen rearrangement, we
next turned our attention to the transformation of 5 into
dihydroisocodeine 2 (Scheme 3). The reaction of 5 with
mCPBA induced the intramolecular dealkylating etherfi-
cation via an epoxide intermediate2g to give hydroxy-
dibenzofuran derivative 18 in 74% yield in one-step.
Other possible products, such as an a-epoxide or lac-
tones, could not be isolated in this reaction.17 The
hydroxy group in 18 was protected as a TBS ether to
give 19 in 99% yield. The reduction of 19 with DIBAL
(2 equiv) at ꢀ78 °C afforded dialdehyde 4, which was
then treated with Montmorillonite K-10 in 1,2-dichloro-
ethane at room temperature. Under these acidic condi-
tions, the Friedel–Crafts type cyclization18 took place,
and subsequent dehydration of the resulting benzylic
hydroxy group gave a mixture (ca. 1:1) of phenanthrofu-
ran 2013 and its de-O-TBS derivative. After O-silylation
of the mixture, tetracyclic aldehyde 20 was obtained in
75% yield from 19. It is noteworthy that the cycliz-
ation/dehydration process proceeded in a high yield
under relatively mild reaction conditions.19 The reduc-
tive amination of 20, followed by N-tosylation and
de-O-silylation afforded tosylamide 3, which is known
as the intermediate for the synthesis of morphine
reported by Parker2c in 86% yield. Finally, the treatment
of 3 with Li in liq. NH3 in the presence of t-BuOH2c
28
thetic compound {½aꢁD ꢀ132 (c 0.32, CHCl3)} showed
good accordance with those reported by Ginsburg20
28
{½aꢁD ꢀ136 (c 2.55, CHCl3)}.
In summary, a new synthetic route to (ꢀ)-dihydroisoco-
deine 2 starting from D-glucal, representing the formal
synthesis of (ꢀ)-morphine 1 has been established. This
stereoselective synthesis demonstrated that the cascade
Claisen rearrangement is highly effective for the stereo-
selective one-step construction of the vicinal tertiary and
quaternary carbons. This novel method, that is, the cas-
cade sigmatropic rearrangement of allylic vicinal diols,
would be applicable to the synthesis of a variety of natu-
ral products. It is also shown that the combination of the
intramolecular dealkylating etherfication via an epoxide
intermediate and the Friedel–Crafts type cyclization of
the aryl-aldehyde are useful for the construction of the
ABCE-tetracyclic skeleton of morphinan alkaloids.
Acknowledgements
We thank the Ministry of Education, Culture, Sports,
Science, and Technology, Japan (Grant-in-Aid for
Scientific Research on Priority Area ‘Creation of Biolo-
gically Functional Molecules’ and Grant-in-Aid for the

H. Tanimoto et al. / Tetrahedron Letters 49 (2008) 358–362
361
250.1205, calcd for C14H18O4, M+, 250.1205. Anal. Calcd
for C14H18O4: C, 67.18; H, 7.25. Found: C, 67.28; H, 7.14.
Data of 5: syrup; ½aꢁD ꢀ54 (c 0.61, CHCl3); IR mmax (neat)
21st Century COE program ‘KEIO LCC’) for financial
assistance.
27
2940 and 1730 cmꢀ1; 1H NMR d 6.94 (dd, 1H, J = 8.1 and
8.1 Hz), 6.85 (dd, 1H, J = 8.1 and 2.1 Hz), 6.83 (dd, 1H,
J = 8.1 and 2.1 Hz), 6.13 (d, 1H, J = 10.5 Hz), 5.85 (ddd,
1H, J = 10.5, 3.3 and 3.3 Hz), 4.03 (q, 2H, J = 7.2 Hz),
3.92 (q, 2H, J = 7.2 Hz), 3.89 (s, 3H), 3.84 (s, 3H), 3.64 (d,
1H, J = 15.0 Hz), 2.89 (d, 1H, J = 15.0 Hz), 2.73 (dddd,
1H, J = 12.0, 5.4, 3.3 and 3.3 Hz), 2.09 (dd, 1H, J = 15.3
and 3.3 Hz), 1.91 (dd, 1H, J = 15.3 and 12.0 Hz), 1.77–
2.18 (m, 3H), 1.53 (dddd, 1H, J = 14.1, 5.4, 5.4 and
5.4 Hz), 1.18 (t, 3H, J = 7.2 Hz), 1.02 (t, 3H, J = 7.2 Hz);
13C NMR d 173.6, 171.8, 152.8, 148.1, 135.8, 132.5, 126.1,
122.6, 122.3, 111.38, 60.3, 60.0, 59.7, 55.7, 45.3, 44.6, 37.8,
35.3, 21.9, 21.2, 14.2, 14.0; HRMS (FAB) m/z 413.1932,
calcd for C22H30NaO6, (M+Na)+, 413.1940. Data of 20:
syrup; ½aꢁ2D4 +21 (c 0.54, CHCl3); IR mmax (neat) 2920, 2860,
1720 and 1500 cmꢀ1; 1H NMR d 9.55 (dd, 1H, J = 2.5 and
2.2 Hz), 6.74 (d, 1H, J = 8.0 Hz), 6.66 (d, 1H, J = 8.0 Hz),
6.42 (dd, 1H, J = 9.5 and0.8 Hz), 5.81 (dd, 1H, J = 9.5
and 5.9 Hz), 4.61 (d, 1H, J = 7.1 Hz), 3.90 (s, 3H), 3.43
(ddd, 1H, J = 11.9, 7.1 and 4.6 Hz), 2.64 (dd, 1H, J = 15.6
and 2.2 Hz), 2.52 (dd, 1H, J = 15.6 and 2.5 Hz), 2.51
(dddd, 1H, J = 11.5, 5.9, 4.4 and 0.8 Hz), 1.80 (dddd, 1H,
J = 13.7, 4.7, 4.4 and 2.5 Hz), 1.58 (m, 1H), 1.38 (dddd,
1H, J = 13.7, 13.4, 11.9 and 2.5 Hz), 0.85–1.01 (m, 1H),
0.96 (s, 9H), 0.12 (s, 3H), 0.03 (s, 3H); 13C NMR d 201.2,
145.5, 144.7, 130.0, 127.9, 123.7, 123.3, 117.9, 114.3, 97.6,
73.6, 56.8, 50.3, 44.8, 39.4, 29.6, 26.9, 25.8, 18.1, ꢀ4.6,
ꢀ5.0; LRMS (EI) m/z 400 (M+, 30), 356 (27), 343 (56), 299
(100). HRMS (EI) m/z 400.2074, calcd For C23H32O4Si,
M+, 400.2070. Data of 2: white crystals; mp 201–202 °C;
References and notes
1. For a review of morphine and related alkaloids, see: (a)
Kapoor, L. D. Opium Poppy: Botany, Chemistry and
Pharmacology; Food Products Press: New York, 1995; (b)
Butora, G.; Hudlicky, T.. In Organic Synthesis: Theory
and Applications; Hudlicky, T., Ed.; JAI Press: Stamford,
CT, 1998; Vol. 4, pp 1–51.
2. (a) Omori, A. T.; Finn, K. J.; Leisch, H.; Carroll, R. J.;
Hudlicky, T. Synlett 2007, 2859–2862; (b) Uchida, K.;
Yokoshima, S.; Kan, T.; Fukuyama, T. Org. Lett. 2006, 8,
5311–5313; (c) Parker, K. A.; Fokas, D. J. Org. Chem.
2006, 71, 449–455; (d) Trost, B. M.; Tang, W.; Toste, F.
D. J. Am. Chem. Soc. 2005, 127, 14785–14803; (e) Nagata,
H.; Miyazawa, N.; Ogasawara, K. Chem. Commun. 2001,
1094–1095; (f) Trauner, D.; Bats, J. W.; Werner, A.;
Mulzer, J. J. Org. Chem. 1998, 63, 5908–5918; (g) Mulzer,
J.; Bats, J. W.; List, B.; Opatz, T.; Trauner, D. Synlett
1997, 441–444; For reviews and other syntheses, see: (h)
Mascavage, L. M.; Wilson, M. L.; Dalton, D. R. Curr.
Org. Synth. 2006, 3, 99–120; (i) Zezula, J.; Hudlicky, T.
Synlett 2005, 388–405; (j) Novak, B. H.; Hudlicky, T.;
Reed, J. W.; Mulzer, J.; Trauner, D. Curr. Org. Chem.
2000, 4, 343–362.
3. Tanimoto, H.; Kato, T.; Chida, N. Tetrahedron Lett.
2007, 48, 6267–6270.
4. (a) Yamada, O.; Ogasawara, K. Org. Lett. 2000, 2, 2785–
2788; (b) Hanada, K.; Miyazawa, N.; Ogasawara, K. Org.
Lett. 2002, 4, 4515–4517.
5. Castro, A. M. M. Chem. Rev. 2004, 104, 2939–3002.
6. For reports of the successful cascade Claisen rearrange-
ment, see: (a) Curran, D. P.; Suh, Y.-G. Carbohydr. Res.
1987, 171, 161–191; (b) Tisdale, E. J.; Vong, B. G.; Li, H.;
Kim, S. H.; Chowdhury, C.; Theodorakis, E. A. Tetra-
hedron 2003, 59, 6873–6887.
7. (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.
28
28
½aꢁD ꢀ132 (c 0.32, CHCl3) {lit.18 mp 199–200 °C; ½aꢁD
ꢀ136 (c 2.55, CHCl3)}; IR mmax (neat) 3400, 2920, 2860,
1640, 1620 and 1500 cmꢀ1 1H NMR d 6.73 (d, 1H,
;
J = 8.3 Hz), 6.65 (d, 1H, J = 8.3 Hz), 4.38 (d, 1H,
J = 6.6 Hz), 3.87 (s, 3H), 3.44 (ddd, 1H, J = 12.4, 6.6
and 4.9 Hz), 3.28 (br s, 1H), 3.02 (d, 1H, J = 18.5 Hz),
2.70 (dd, 1H, J = 12.2 and 4.1 Hz), 2.52 (s, 1H), 2.49 (dd,
1H, J = 18.5 and 5.1 Hz), 2.40 (br d, 1H, J = 12.9 Hz),
2.28 (ddd, 1H, J = 12.4, 12.4 and 3.9 Hz), 2.01 (ddd, 1H,
J = 12.4, 12.4 and 4.1 Hz), 1.82 (dddd, 1H, J = 12.9, 4.9,
2.7 and 2.7 Hz), 1.74 (dd, 1H, J = 12.4 and 3.9 Hz), 1.61
(dddd, 1H, J = 12.9, 2.7, 2.7 and 2.7 Hz), 1.39 (dddd, 1H,
J = 12.9, 12.9, 12.4 and 2.7 Hz), 0.97 (dddd, 1H, J = 12.9,
12.9, 12.9 and 2.7 Hz); 13C NMR d 144.2, 143.9, 129.9,
125.2, 119.1, 113.8, 96.9, 73.1, 59.9, 56.5, 47.2, 42.8, 42.4,
41.8, 34.7, 29.8, 23.5, 20.5; LRMS (EI) m/z 301 (M+, 100),
286 (1). HRMS (EI) m/z 301.1677. Calcd For C18H23NO3,
M+, 301.1678.
8. Boulineau, F. P.; Wei, A. Carbohydr. Res. 2001, 334, 271–
279.
9. (a) Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J.
Org. Chem. 1990, 55, 5812–5813; (b) France, C. J.;
McFarlane, I. M.; Newton, C. G.; Pitchen, P.; Webster,
M. Tetrahedron Lett. 1993, 34, 1635–1638.
14. Attempted Eschenmoser–Claisen rearrangement (N,N-
dimethylacetamide dimethylacetal, toluene, reflux) and
Ireland–Claisen rearrangement {(1) Ac2O, pyridine (2)
LHMDS then TMSCl/Et3N} of 6 produced no cascade
rearranged products.
10. All new compounds described in this Letter were charac-
terized by 300 MHz 1H NMR (in CDCl3), 75 MHz 13C
NMR (in CDCl3), IR, and mass spectrometric and/or
elemental analyses.
11. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33,
6299–6302.
15. When the Claisen rearrangement was carried out in the
presence of 2-nitorophenol (53 mol %), the rearranged
product was obtained in a less satisfactory yield (53%).
16. The moderate yields of the cascade rearrangement and the
second rearrangement of the stepwise version were mainly
due to the decomposition of the substrates. The decom-
position would be induced by the formation of stabilized
conjugated carbocations generated from cyclohexenol
derivatives 6, 17 and/or 50 by elimination of water or
ethyl acetate under the acidic reaction conditions. For the
acid sensitivity of the structurally related cyclohexenol,
see: Chida, N.; Sugihara, K.; Amano, S.; Ogawa, S. J.
Chem. Soc., Perkin Trans. 1 1997, 275–280.
12. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
24:5
13. Data of 6: white crystals; ½aꢁD ꢀ41 (c 0.87, CHCl3); mp
110.5–111.5 °C; IR mmax (KBr) 3350, 2930 and 1580 cmꢀ1
;
1H NMR d 7.04 (dd, 1H, J = 12.0 and 12.0 Hz), 6.88 (d,
1H, J = 12.0 Hz), 6.80 (d, 1H, J = 12.0 Hz), 5.82 (ddd,
1H, J = 3.6, 3.6 and 1.8 Hz), 4.45 (m, 1H), 3.88 (s, 3H),
3.81 (s, 3H), 3.84 (m, 1H), 2.89 (d, 1H, J = 5.1 Hz), 2.59
(br, 1H), 2.30–2.36 (m, 2H), 2.08 (dddd, 1H, J = 12.9, 4.5,
4.5 and 4.2 Hz), 1.81 (m, 1H); 13C NMR d 152.5, 145.6,
137.7, 134.3, 128.5, 124.7, 122.4, 111.5, 74.5, 72.2, 60.9,
55.8, 27.4, 24.5; LRMS (EI) m/z 250 (M+, 29), 232 (83),
214 (100), 199 (64), 184 (43), 159 (39); HRMS (EI) m/z

362
H. Tanimoto et al. / Tetrahedron Letters 49 (2008) 358–362
17. Although the exact reasons for the observed stereoselec-
tivity in the epoxidation of 5 have not been clear so far, it
may be reasonable to suppose that the steric factor (steric
hindrance caused by the presence of an a-aromatic ring
and an a-ethoxycarbonylmethyl group) as well as the
stereoelectronic effects associated with an a-dimethoxy-
phenyl group would be responsible for the stereoselective
formation of a b-epoxide. As a possible stereoelectronic
effect, the concepts of the Cieplak postulate might be
extended to explain the observed p-facial selectivity. In the
transition state for epoxidation of 5 by the b-attack of
the a-aromatic ring. These through-space stabilizing
interactions (remote no–rꢂ interactions) would lead to
¼
form the b-epoxide intermediate. For reviews of stereo-
electronic effects in p-facial selectivities, see (a) Cieplak, A.
S. Chem. Rev. 1999, 99, 1265–1336; (b) Ohwada, T. Chem.
Rev. 1999, 99, 1337–1375.
18. For solid catalyst-based Friedel–Crafts reaction, see:
Sartori, G.; Maggi, R. Chem. Rev. 2006, 106, 1077–1104.
19. The similar Friedel–Crafts type cyclization of aryl-mono-
aldehyde derivatives first developed by Ogasawara2e,4
required a higher reaction temperature (p-TsOH, ethyl-
eneglycol, benzene or toluene, reflux).
mCPBA, the vacant orbitals (rꢂ ) that develop in the a-
¼
face along with formation of the incipient C–O bonds may
20. Elad, D.; Ginsburg, D. J. Am. Chem. Soc. 1956, 78, 3691–
3693.
interact with n-electrons on the o-methoxy group (no) in