Synthesis of aromatic spiroacetals related to γ-rubromycin based on a 3H-spiro[1-benzofuran-2,2′-chromane] skeleton

Article abstract of DOI:10.1016/j.tet.2007.02.033

The synthesis of a series of aromatic 5,6-benzannelated and naphthyl-benzannelated spiroacetals related to the spiroacetal unit present in the quinonoid antibiotic γ-rubromycin is reported. The key steps include the use of Sonogashira coupling to construct an aryl acetylene that is coupled to an aryl aldehyde forming a propargyl alcohol intermediate. Hydrogenation of the resultant alkynol followed by oxidation produces a masked dihydroxyketone that upon treatment with silica-supported sodium hydrogen sulfate undergoes concomitant deprotection and cyclisation to afford the desired fused aromatic spiroacetal.

Full text of DOI:10.1016/j.tet.2007.02.033

Tetrahedron 63 (2007) 6015–6034
Synthesis of aromatic spiroacetals related to g-rubromycin based
on a 3H-spiro[1-benzofuran-2,20-chromane] skeleton
*
Kit Yee Tsang and Margaret A. Brimble
Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand
Received 13 January 2007; revised 7 February 2007; accepted 7 February 2007
Available online 13 February 2007
Abstract—The synthesis of a series of aromatic 5,6-benzannelated and naphthyl-benzannelated spiroacetals related to the spiroacetal unit
present in the quinonoid antibiotic g-rubromycin is reported. The key steps include the use of Sonogashira coupling to construct an aryl acetyl-
ene that is coupled to an aryl aldehyde forming a propargyl alcohol intermediate. Hydrogenation of the resultant alkynol followed by oxidation
produces a masked dihydroxyketone that upon treatment with silica-supported sodium hydrogen sulfate undergoes concomitant deprotection
and cyclisation to afford the desired fused aromatic spiroacetal.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
transcriptase of human immunodeficiency virus-1.3 The
presence of the unique aromatic spiroacetal ring system in
these molecules in which benzannelated furan and pyran
rings form a spiroacetal moiety is thought to be a key feature
for the observed activity. a-Rubromycin 1, which lacks this
aryl spiroacetal moiety, exhibits substantially decreased
inhibitory potency towards telomerase (IC50>200 mM).
The rubromycins 1–3 (Fig. 1) are a family of quinonoid an-
tibiotics isolated from cultures of Streptomyces1 that exhibit
activity against Gram-positive bacteria. b-Rubromycin 2
and g-rubromycin 3 exhibit potent inhibition of human telo-
merase2 (IC50 3 mM) and are active against the reverse
O
HO
O
OH
O
O
OH
O
O
CO2Me
OH
O
MeO
MeO
O
HO
O
O
O
CO2Me
OMe
O
OMe
-Rubromycin 1
-Rubromycin 2
O
HO
O
OH
R4
MeO
O
O
R1
R2 R3
O
OH
-Rubromycin 3: R1 = H, R2 = H, R3 = H, R4 = CO2Me
Purpuromycin 4: R1 = H, R2 = H, R3 = OH, R4 = CO2Me
Heliquinomycin 5: R1 = cymarose, R2 = OH, R3 = H, R4 = CO2Me
Heliquinomycinone 6: R1 = OH, R2 = OH, R3 = H, R4 = CO2Me
Griseorhodin C 7: R1 = OH, R2 = OH, R3 = OH, R4 = Me
Griseorhodin G 8: R1 = OH, R2 = OH, R3 = H, R4 = Me
Figure 1. The rubromycin family of antibiotics.
* Corresponding author. E-mail: m.brimble@auckland.ac.nz
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.033

6016
K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
Structurally related to the rubromycins are purpuromycin 4,4
a potential topical agent for vaginal infections,5 heliquino-
mycin 5,6 an inhibitor of DNA helicase and the griseor-
hodins 7 and 8.7 Importantly, all of these compounds can
also act as bioreductive alkylating agents as postulated by
Moore.8
to an olefin. The synthesis of a bis-benzannelated spiroacetal
has also recently been reported by Reissig et al.14 via addi-
tion of a lithiated methoxyallene to an aryl aldehyde fol-
lowed by hydrogenation and acid catalysed spirocylisation.
2. Results and discussion
To date the elegant total synthesis of heliquinomycinone 6
reported by Danishefsky et al.9 remains the only synthesis
of a naturally occurring bis-benzannelated spiroacetal. Elec-
trophilic spiroacetalization of a naphthofuran bearing a phe-
nolic hydroxyl group as the nucleophilic partner allowed
access to the key aromatic 5,6-spiroacetal ring system.
Several syntheses of model bis-benzannelated and naph-
thyl-benzannelated spiroacetals have also been reported.
de Koning et al.10 reported the first synthesis of the bis-benz-
annelated spiroacetal ring system present in g-rubromycin
3 using a Henry reaction to effect union of two aryl moieties,
then a Nef reaction was used to liberate the masked carbonyl
group required for generation of the spirocentre. Our re-
search group have also communicated11 the synthesis of
several bis-benzannelated 5,6-spiroacetal analogues of the
naturally occurring antibiotic g-rubromycin 3. We now
herein report the full details of the synthesis of a larger series
of bis-benzannelated and naphthyl-benzannelated 5,6-spi-
roacetals together highlighting some of the synthetic diffi-
culties encountered.
As part of our synthetic programme directed towards the
synthesis of bioactive spiroacetal-containing natural prod-
ucts, we prepared the bis-benzannelated 5,6-spiroacetals
9–12 via acid catalysed cyclisation of MOM-protected di-
phenolic ketones 13–16 (Scheme 1). The required ketones
13–16 were obtained from aryl alkynols 17–20 after hydro-
genation and oxidation. In turn, the required aryl alkynols
17–20 were constructed from the addition of the acetylides
generated from acetylenes 21 and 22 to aryl aldehydes 23
and 24. Aryl aldehydes 23 and 24 were readily prepared
from the appropriate commercially available substituted
phenols 25 and 26 whilst the acetylenes 21 and 22 were
available from the corresponding MOM-protected aryl
iodides 27 and 28 using the Sonogashira reaction.
Aryl aldehydes 23 and 24 were prepared from the readily
available phenols 25 and 26 (Scheme 2). Allylation of phe-
nols 25 and 26 afforded allylphenols, which then underwent
Claisen rearrangement to provide allyl ethers 31 and 32 in
good yield. Protection of the phenol as MOM ether followed
by either ozonolysis or dihydroxylation–oxidative cleavage
of the alkenes 33 and 34 furnished aldehydes 23 and 24.
Since the time of our original communication of this work,
Pettus et al.12 have reported the synthesis of a naphthyl-benz-
annelated spiroacetal via [3+2] cycloaddition of an enol
ether to a zwitterion. Kozlowski et al.13 have reported the
synthesis of bisphenolic spiroacetal and a naphthyl-benzan-
nelated spiroacetal via [3+2] cycloaddition of a nitrile oxide
Acetylenes 21 and 22 were prepared from MOM ethers 2715
and 3616 (Scheme 3) derived from 2-iodophenol 35 and
2-methoxyphenol 25 with subsequent ortholithiation of 36
R1
R3
R1
OMOM
O
OMOM
R3
O
O
R2
R2
13: R1 = OMe, R2 = H, R3 = H
14: R1 = H, R2 = OMe, R3 = H
15: R1 = OMe, R2 = H, R3 = OMe
16: R1 = H, R2 = OMe, R3 = OMe
9: R1 = OMe, R2 = H, R3 = H
10: R1 = H, R2 = OMe, R3 = H
11: R1 = OMe, R2 = H, R3 = OMe
12: R1 = H, R2 = OMe, R3 = OMe
R1
R1
OMOM
R3
OMOM
OH
OMOM
+
OMOM
R3
R2
R2
O
23: R1 = OMe, R2 = H
24: R1 = H, R2 = OMe
21: R3 = H
22: R3 = OMe
17: R1 = OMe, R2 = H, R3 = H
18: R1 = H, R2 = OMe, R3 = H
19: R1 = OMe, R2 = H, R3 = OMe
20: R1 = H, R2 = OMe, R3 = OMe
R1
OMOM
R3
I
OH
R2
25: R1 = OMe, R2 = H
27: R3 = H
26: R1 = H, R2 = OMe
28: R3 = OMe
Scheme 1.

K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
6017
R1
R1
R1
OH
O
OH
ii
i
R2
R2
R2
25: R1 = OMe, R2 = H
26: R1 = H, R2 = OMe
31: R1 = OMe, R2 = H
29: R1 = OMe, R2 = H
32: R1 = H, R2 = OMe
30: R1 = H, R2 = OMe
R1
R1
OMOM
OMOM
iii
iv
R2
R2
O
33: R1 = OMe, R2 = H
23: R1 = OMe, R2 = H, R3 = H
34: R1 = H, R2 = OMe
24: R1 = H, R2 = OMe, R3 = H
Scheme 2. Reagents, conditions and yields: (i) allyl bromide, K2CO3, acetone, reflux, 29, 87%; 30, 89%; (ii) 180 ꢁC, N2, 31, 70%; 32, 84%; (iii) MOMCl,
iPr2NEt, CH2Cl2, 0 ꢁC, 33, 83% or NaH, DMF, MOMCl, 34, 80%; (iv) O3, MeOH, ꢀ50 ꢁC, then Me2S, 23, 83% or cat. OsO4, NaIO4, THF–H2O (4:1),
0 ꢁC/rt, 24, 51%.
OH
OMOM
R3
OMOM
R3
OMOM
R3
OH
X
X
R3
iv
i
iii
27: X = I, R3 = H
37: R3 = H
38: R3 = OMe
21: R3 = H
35: X = I, R3 = H
25: X = H, R3 = OMe
36: X = H, R3 = OMe
28: X = I, R3 = OMe
22: R3 = OMe
ii
Scheme 3. Reagents, conditions and yields: (i) MOMCl, iPr2EtN, CH2Cl2, 0 ꢁC/rt, 27, 89%; 36, 99%; (ii) nBuLi, THF, ꢀ15 ꢁC/ꢀ45 ꢁC, I2, 28, 32%; (iii)
PPh3, PdCl2(PPh3)2, 2-methyl-3-butyn-2-ol, Et3N, CuI, 80 ꢁC 37, 88%; 38, 94%; (iv) NaOH, toluene, reflux, 21, 70%; 22, 78%.
followed by iodination affording iodide 28. Sonogashira
coupling of iodides 27 and 28 with 2-methyl-3-butyn-2-ol
followed by pyrolysis of the resultant tertiary acetylenic al-
cohols 37 and 38 under basic conditions provided acetylenes
21 and 22.
mixture of product (entry D). Heating ketone 13 with p-tolu-
enesulfonic acid in dioxane–water (3:1) at 55 ꢁC for 60 h
afforded spiroacetal 9 in 33% yield (entry E). When the
reaction was carried out at 80 ꢁC with a prolonged reaction
time of 81 h, only a complex mixture was afforded (entry F).
Changing the solvent to dichloromethane resulted in a lower
yield (22%) of spiroacetal 9 (entry G).
With both acetylenes 21 and 22 and aldehydes 23 and 24 in
hand, the synthesis continued with the coupling of these two
subunits to construct bis-benzannelated 5,6-spiroacetals 9–
12 (Scheme 4). The key step involved addition of the lithium
acetylide generated from the appropriate acetylenes 21 and
22 using butyllithium at ꢀ78 ꢁC, to the appropriate alde-
hydes 23 and 24. Hydrogenation of the resultant alkynes
17–20 in ethyl acetate buffered with potassium carbonate
over 10% palladium on carbon provided the saturated sec-
ondary alcohols 39–42 in good yield. Oxidation of the
alcohols 39–42 using tetra-n-propylammonium perruthenate
Treatment of ketone 13 with bromotrimethylsilane (4 equiv)
˚
in the presence of 4 A molecular sieves in dichloromethane
at ꢀ30 ꢁC for 2 h followed by slowly warming the reaction
mixture to room temperature and stirring for 5.5 h afforded
spiroacetal 9 in 15% yield (entry H). Using a large excess
of bromotrimethylsilane (8.4 equiv) the yield increased to
30% yield (entry I). This result suggests that the use of ex-
cess reagent with gradual warming of the reaction mixture
was critical to the success of the reaction. Treatment of
ketone 13 with bromotrimethylsilane (10 M equiv) in the
˚
(TPAP), 4-methylmorpholine N-oxide (NMO) and 4 A mo-
lecular sieves in dichloromethane then afforded the ketone
precursors 13–16 en route to the spiroacetals.
˚
presence of 4 A molecular sieves in dichloromethane at
ꢀ30 ꢁC for 1 h followed by slowly warming to 0 ꢁC and
stirring for 4 h afforded spiroacetal 9 in 56% yield (entry J).
In order to slow the sudden change in reaction temperature,
the reaction was kept at ꢀ30 ꢁC for 1 h, slowly warmed to
0 ꢁC, stirred for 10 h, then finally warmed to room tempera-
ture for 11 h. Gratifyingly, this procedure afforded the de-
sired spiroacetal 9 in 86% yield (entry K).
With spiroacetal precursors 13–16 in hand, only deprotec-
tion of the MOM groups with ensuing spirocyclisation was
required. Treatment of ketone 13 with a mixture of trifluo-
roacetic acid–water–tetrahydrohydran (4:1:1) for 30 min
afforded a diol, which spontaneously cyclised to give spiro-
acetal 9 in 28% yield (Table 1, entry A). A similar yield was
obtained when the reaction was carried out in dichloro-
methane (entry B). Attempts to effect deprotection and cyc-
lisation by heating ketone 13 with concentrated hydrochloric
acid in methanol resulted in a lower 13% yield of spiroacetal
9 together with unreacted ketone 13 (entry C). Heating
ketone 13 in 50% acetic acid in the presence of catalytic
amount of sulfuric acid at 62 ꢁC for 5.5 h afforded a complex
Having optimised the conditions for the cyclisation step us-
ing ketone 13, ketone 14 was next subjected to deprotection
and cyclisation using trimethylsilyl bromide (10 equiv) in
˚
dichloromethane in the presence of 4 A molecular sieves
affording spiroacetal 10 in moderate yield. Applying the
same conditions to ketone 15 however, afforded a single
product in 86% yield, which was identified as benzofuran

6018
K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
R1
R1
OMOM
OH
OMOM
OMOM
R3
i
OMOM
R3
R2
+
R2
O
17: R1 = OMe, R2 = H, R3 = H
18: R1 = H, R2 = OMe, R3 = H
19: R1 = OMe, R2 = H, R3 = OMe
20: R1 = H, R2 = OMe, R3 = OMe
21: R3 = H
22: R3 = OMe
23: R1 = OMe, R2 = H
24: R1 = H, R2 = OMe
ii
R1
R1
OMOM
O
OMOM
OMOM
R3
OMOM
R3
OH
iii
R2
R2
13: R1 = OMe, R2 = H, R3 = H
14: R1 = H, R2 = OMe, R3 = H
15: R1 = OMe, R2 = H, R3 = OMe
16: R1 = H, R2 = OMe, R3 = OMe
39: R1 = OMe, R2 = H, R3 = H
40: R1 = H, R2 = OMe, R3 = H
41: R1 = OMe, R2 = H, R3 = OMe
42: R1 = H, R2 = OMe, R3 = OMe
iv, v or vi
R3
R1
R1
O
O
O
+
R2
R2
9: R1 = OMe, R2 = H, R3 = H
10: R1 = H, R2 = OMe, R3 = H
11: R1 = OMe, R2 = H, R3 = OMe
12: R1 = H, R2 = OMe, R3 = OMe
HO
OMe
43: R1 = OMe, R2 = H
44: R1 = H, R2 = OMe
Scheme 4. Reagents, conditions and yields: (i) nBuLi, THF, ꢀ78 ꢁC, 2–5 h, 17, 61%; 18, 67%; 19, 69%; 20, 67%; (ii) 10% Pd–C, H2, K2CO3, EtOAc, 1 h–
˚
overnight, 39,ꢁ88%; 40, 96%; 41, 82%; 42, 97%; (iii) TPAP, NMO, 4 A MS, CH2Cl2, 0.5–3 h, 13, 89%; 14, 65%; 15, 84%; 16, 98%; (iv) TMSBr, CH2Cl2,
ꢁ
˚
4 A MS, ꢀ30 C/0 C/rt, 9, 86%; 10, 51%; 43, 86%; (v) NaHSO4$SiO2, CH2Cl2, rt, 3 h, 11, 43%; 44, 50%; (vi) NaHSO4$SiO2, CH2Cl2, rt, 5 min, 12, 60%.
43 (Scheme 4). The formation of benzofuran 43 was sup-
Table 1. Summary of reaction conditions used for the deprotection and
cyclisation of ketone 13
ported by the observation of a four proton singlet at dH
3.10 ppm in the 1H NMR spectrum assigned to the methyl-
ene groups H-10 and H-20 together with a broad OH reso-
nance at dH 5.75 ppm and a characteristic vinylic proton
H-300 at dH 6.38 ppm. It should be noted that in our earlier
communication of this work deprotection of ketone 15 to
spiroacetal 11 using trimethylsilyl bromide was reported to
proceed in 77% yield. However, this result was not found
to be reproducible despite several attempts at this reaction.
OMe
OMe
OMOM
O
OMOM
O
O
reagent
13
9
Entry
Reagents and conditions
Yield (%)
A
B
C
TFA–H2O–THF (4:1:1), rt, 30 min
TFA, CH2Cl2, rt, 22 h
Concd HCl, anhydrous MeOH,
62 ꢁC, 22 h
cat. H2SO4, 50% AcOH,
reflux, 5.5 h
p-TsOH, dioxane–H2O (3:1),
55–60 ꢁC, 60 h
p-TsOH, dioxane–H2O (3:1),
80 ꢁC, 81.5 h
28
24
13
Fortunately, treatment of ketone 15 with activated silica-
supported sodium hydrogen sulfate17 in dichloromethane
at room temperature for 3 h successfully afforded the desired
spiroacetal 11 in 43% yield. The analogous ketone 20 was
stirred in dichloromethane with activated silica-supported
sodium hydrogen sulfate at room temperature for 5 min re-
sulting in the formation of spiroacetal 12 in 60% yield. It
was also observed that use of a prolonged reaction time of
3 h resulted in the formation of the undesired benzofuran
44. This result suggests that spiroacetal 12 is the kinetic
product of the reaction with shorter reaction times resulting
in the formation of spiroacetal 12 rather than the thermody-
namically favoured benzofuran 44.
D
E
F
G
H
I
Complex mixture
33
Complex mixture
p-TsOH, CH2Cl2–H2O (3:1),
50 ꢁC, 84 h
TMSBr (4 equiv), CH2Cl2, 4 A
22
15
30
56
86
˚
MS, ꢀ30 ꢁC (2 h)/rt (5.5 h)
˚
TMSBr (8.4 equiv), CH2Cl2, 4 A
MS, ꢀ30 ꢁC (2 h)/5 ꢁC (5.5 h)
˚
TMSBr (10 equiv), CH2Cl2, 4 A
J
MS, ꢀ30 ꢁC (1 h)/0 ꢁC (4 h)
˚
TMSBr (10 equiv), CH2Cl2, 4 A
K
Having successfully synthesised the monosubstituted 9 and
10 and disubstituted bis-benzannelated spiroacetals 11 and
12, synthesis of naphthyl-benzannelated spiroacetals
MS, ꢀ30 ꢁC (1 h)/0 ꢁC
(10 h)/rt (11 h)

K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
6019
Table 2. Structures of naphthyl-benzannelated spiroacetals together with the naphthaldehydes and aryl acetylenes required for their synthesis
Naphthaldehyde
OMOM
Aryl acetylene
Aryl spiroacetal
OMOM
O
O
O
48
45
21
MeO
O
8'
OMOM
OMe
O
45
22
49
6
OMOM
O
O
MeO
MeO
21
O
50
46
OMe
OMOM
OMe
9
O
O
21
5
MeO
O
MeO
47
51
48–51 was next investigated. The required naphthaldehydes
45–47, acetylenes 21 and 22 and the corresponding spiroace-
tals 48–51 are depicted in Table 2.
Naphthyl-benzannelated 5,6-spiroacetals 48 and 49 (Scheme
7) and 50 (Scheme 8) were prepared by union of the appro-
priate aryl acetaldehyde with the appropriate acetylide
followed by hydrogenation, oxidation and cyclisation using
activated silica-supported sodium hydrogen sulfate.
With aryl acetylenes 21 and 22 in hand, attention next fo-
cused on the synthesis of naphthaldehydes 45–47. Naphth-
aldehyde 45 was synthesised from 2-naphthol 52 in five
steps via the sequence of allylation, Claisen rearrangement,
MOM protection, dihydroxylation and oxidative cleavage
(Scheme 5).
Treatment of ketones 78 with activated silica-supported so-
dium hydrogen sulfate in dichloromethane at room temper-
ature for 5 min gave benzofurans 79 and 80 in 20% and 37%
yield, respectively. The formation of benzofurans 79 and 80
in the cyclisation step is probably due to the steric hindrance
by the methoxy group at C-9 that results in the formation of
a benzofuran to alleviate unfavourable steric interactions in
the initially formed spiroacetal 51. Attempts to deprotect
the MOM ethers and effect cyclisation of ketone 78 with
Montmorillonite K1020 in benzene at room temperature
in the hope of obtaining the desired spiroacetal 51, only
afforded benzofuran 80 in 20% yield together with unreacted
ketone 78.
Naphthaldehydes 46 and 47 were also prepared from naph-
thols 57 and 58, respectively (Scheme 6), via a sequence
involving allylation, Claisen rearrangement, protection of
the naphthol and finally formation of the aldehyde via
dihydroxylation–oxidative cleavage. Naphthol 5718 was
prepared according to the method reported by Giles et al.
with a slight modification. Naphthol 58 was readily prepared
following our reported procedure.19
OH
OH
O
OMOM
i
ii
iii
52
54
55
53
iv
OMOM
OH
OMOM
v
O
OH
56
45
Scheme 5. Reagents, conditions and yields: (i) allyl bromide, K2CO3, Me2CO, reflux, 19 h, 99%; (ii) 200 ꢁC, N2, 2.5 h, 70%; (iii) NaH, DMF, MOMCl, 1 h, rt,
83%; (iv) cat. OsO4, NMO, Me2CO–H2O (8:1), 16 h, 72%; (v) NaIO4, CH2Cl2–H2O (5:3), 45 min, 62%.

6020
K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
R3
R3
R3
OH
OH
O
ii
i
R2
R2
R2
R1
R1
R1
57: R1 = H, R2 = OMe, R3 = H
59: R1 = H, R2 = OMe, R3 = H
61: R1 = H, R2 = OMe, R3 = H
58: R1 = OMe, R2 = H, R3 = OMe
60: R1 = OMe, R2 = H, R3 = OMe
62: R1 = OMe, R2 = H, R3 = OMe
iii
R3
R3
R3
OMOM
OMOM
OMOM
v
iv
R2
R2
R2
O
R1
46: R1 = H, R2 = OMe, R3 = H
47: R1 = OMe, R2 = H, R3 = OMe
R1
R1
HO
65: R1 = H, R2 = OMe, R3 = H
66: R1 = OMe, R2 = H, R3 = OMe
OH
63: R1 = H, R2 = OMe, R3 = H
64: R1 = OMe, R2 = H, R3 = OMe
Scheme 6. Reagents, conditions and yields: (i) allyl bromide, K2CO3, Me2CO, reflux, 24 h, 59, 94% or allyl bromide, NaH, DMF, 2.5 h, 60, 72%; (ii) 210 ꢁC,
m-xylene, 19 h, 61, 100%; 62, 99%; (iii) NaH, DMF, MOMCl, 1 h, 63, 85%; 64, 92%; (iv) cat. OsO4, NMO, Me2CO–H2O (8:1), 24 h, 65, 89%; 66, 90%;
(v) NaIO4, CH2Cl2–H2O (5:3), 24 h, 46, 88%; 47, 40%.
OMOM
OMOM
OH
OMOM
OMOM
i
R
+
R
O
67: R = H
68: R = OMe
45
21: R = H
22: R = OMe
ii
R
OMOM
OH
OMOM
OMOM
O
O
OMOM
O
iv
iii
R
R
69: R = H
70: R = OMe
71: R = H
72: R = OMe
48: R = H
49: R = OMe
Scheme 7. Reagents, conditions and yields: (i) nBuLi, THF, ꢀ78 ꢁC, 3–4 h, 67, 81%; 68, 76%; (ii) Pd–C, H2, K2CO3, EtOAc, 3.5–10 h, 69, 86%; 70, 83%;
˚
(iii) TPAP, NMO, 4 A MS, CH2Cl2, 1.5–2.5 h, 71, 91%; 72, 83%; (iv) NaHSO4$SiO2, CH2Cl2, rt, 5 min, 48, 43%; 49, 41%.
R3
R3
OMOM
OMOM
OMOM
i
+
R2
R2
O
21
R1
HO
R1
46: R1 = H, R2 = OMe, R3 = H
73: R1 = H, R2 = OMe, R3 = H
OMOM
47: R1 = OMe, R2 = H, R3 = OMe
74: R1 = OMe, R2 = H, R3 = OMe
ii
R3
R3
OMOM
OMOM
iii
R2
R2
R1
O
OMOM
R1
HO
OMOM
77: R1 = H, R2 = OMe, R3 = H
75: R1 = H, R2 = OMe, R3 = H
78: R1 = OMe, R2 = H, R3 = OMe
76: R1 = OMe, R2 = H, R3 = OMe
iv
R3
OMe
9
+
O
O
RO
O
R2
R1
MeO
50: R1 = H, R2 = OMe, R3 = H
79: R = H
80: R = MOM
51: R1 = OMe, R2 = H, R3 = OMe
Scheme 8. Reagents, conditions and yields: (i) nBuLi, THF, ꢀ78 ꢁC, 3 h, 73, 78%; 74, 67%; (ii) 10% Pd–C, H2, K2CO3, EtOAc, 1.5–2.5 h, 75, 74%; 76, 91%;
˚
(iii) TPAP, NMO, 4 A MS, CH2Cl2, 1–4 h, 77, 92%; 78, 60%; (iv) NaHSO4$SiO2, CH2Cl2, rt, 5 min, 50, 47%; 79, 20% and 80, 37%.

K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
6021
In summary, seven aryl 5,6-spiroacetals, analogous to the
spiroacetal unit in the telomerase inhibitor g-rubromycin 3,
have been prepared starting from appropriate aryl aldehydes
and aryl acetylenes. The synthetic strategy was sufficiently
flexible to allow the preparation of a series of bis-benz-
annelated 5,6-spiroacetals as well as naphthyl-benzannelated
5,6-spiroacetals, which differ in the orientation of the naph-
thalene ring. It is postulated that in the attempted spirocy-
clisation of ketone 78, steric hindrance associated with the
peri-methoxy group at C-9 in the starting ketone 78 leads to
the formation of a benzofuran to alleviate unfavourable steric
interactions in the initially formed spiroacetal 51. Hence, the
limitation in the method developed herein is the formation
of undesired benzofurans when substituents preclude the
formation of sterically congested aryl 5,6-spiroacetals.
the solvent systems indicated. Thin layer chromatography
(TLC) was run on silica precoated aluminium plates (Merck
Kieselgel F254). Compounds were visualised under UV
fluorescence and by staining with vanillin in methanolic
acid followed by heating. Melting points were determined
on a Kofler hot-stage apparatus and are uncorrected.
3.2. Standard procedures for allylation of phenols and
naphthols
3.2.1. Procedure A—heating in acetone with K2CO3. To
a stirred solution of the appropriate phenol (1 mmol) in
acetone (5 mL) were added potassium carbonate (4 mmol)
and allyl bromide (1 mmol). The mixture was heated under
reflux for 4–24 h, cooled to room temperature, filtered and
the filtrate was concentrated under reduced pressure. The
residue was dissolved in dichloromethane (5 mL) and
washed sequentially with 1 M aqueous sodium hydroxide
(5 mL), water (5 mL) and brine (5 mL). The organic layer
was dried over magnesium sulfate and concentrated under
reduced pressure. The resultant residue was purified by flash
column chromatography.
3. Experimental
3.1. General details
Dichloromethane, toluene and triethylamine were distilled
from calcium hydride prior to use. Tetrahydrofuran was
dried over sodium/benzophenone and distilled before use.
Glassware was oven or flame-dried under an atmosphere
of nitrogen. Reactions were carried out under an atmosphere
of nitrogen unless otherwise specified. Infrared spectra (IR)
were obtained using Perkin–Elmer Spectrum 1000 Fourier
Transform Infrared spectrometer from thin films between
sodium chloride plates. Absorption peaks are expressed in
wave numbers (cmꢀ1) and were measured between 450
and 4000 cmꢀ1 and the absorption strengths are expressed
by the following abbreviations: s¼strong, m¼medium,
w¼weak, and br¼broad. NMR spectra were recorded on
a Bruker DRX300 spectrometer operating at 300 MHz for
1H nuclei and 75 MHz for 13C nuclei or on a Bruker
DRX400 spectrophotometer operating at 400 MHz for
1H nuclei and 100 MHz for 13C nuclei. Chemical shifts are
recorded as parts per million (ppm) downfield from tetra-
methylsilane (TMS) as the internal standard or relative to
the 1H in CDCl3. The 13C values were referenced to the re-
sidual chloroform peak at d 77.0 ppm. 13C shifts are reported
3.2.2. Procedure B—using sodium hydride in DMF. To
a stirred solution of the appropriate naphthol (1 mmol) in
anhydrous N,N-dimethylformamide (2 mL) at 0 ꢁC, pure
sodium hydride (1.05 mmol) was added portionwise. After
30 min, allyl bromide (1.3 mmol) was added dropwise and
the resultant reaction mixture was warmed to room temper-
ature and stirred for another 2 h. Water (5 mL) was added
and the reaction mixture was extracted with diethyl ether
(5 mL). The combined organic extracts were washed with
1 M NaOH (5 mL), 10% HCl (5 mL), brine (5 mL), dried
over MgSO4 and concentrated under reduced pressure. The
resultant residue was purified by flash column chromato-
graphy.
3.2.3. Allyl 2-methoxyphenyl ether 29.21 Pale yellow oil;
the spectral data were in agreement with the literature value.
0
dH (300 MHz, CDCl3): 3.86 (3H, s, OMe), 4.60 (2H, dt, J1 ,3
0
0
0
0
0
0
0
0
1.5 and J1 ,2 5.1 Hz, H-1 ), 5.27 (1H, dd, J3 A,1 1.5 and J3 A,2
10.5 Hz, H-30A), 5.39 (1H, dd, J3 B,1 1.5 and J3 B,2 17.3 Hz,
H-30B), 6.04–6.07 (1H, m, H-20), 6.88–6.91 (4H, m, H-3, H-
4, H-5 and H-6). dC (75 MHz, CDCl3): 55.8 (CH3, OMe),
69.8 (CH2, C-10), 111.7 (CH, Ar-C), 113.5 (CH, Ar-C),
117.9 (CH2, C-30), 120.7 (CH, Ar-C), 121.2 (CH, Ar-C),
133.4 (CH, C-20), 147.9 (quat., C-1 or C-2), 149.4 (quat.,
C-2 or C-1).
0
0
0
0
1
as chemical shift and assignment. H shifts are reported as
chemical shift, relative integral, multiplicity, coupling con-
stant and assignment. H NMR data are reported as s (sin-
1
glet); d (doublet); dd (doublet of doublets); dt (doublet of
triplets); ddd (doublet of doublets of doublets); t (triplet);
q (quartet); m (multiplet); br (broad). J values are given in
hertz. Assignments were all made with the aid of DEPT
135, COSY and HSQC experiments where required. Low-
resolution mass spectra were recorded using a VG70-SE
spectrometer operating at nominal accelerating voltage of
70 eV. High-resolution mass spectra were recorded using
a VG70-SE spectrometer operating at nominal resolution
of 5000 to 10,000 as appropriate. Fragmentation was in-
duced using desorptive electron impact (DEI+), electron
impact (EI) or fast atom bombardment (FAB+). Fast atom
bombardment (FAB) mass spectra were obtained using 3-
nitrobenzyl alcohol as the matrix. Major and significant
fragments are quoted in the form x(y), where x is the mass
to charge ratio and y is the percentage abundance relative
to the base peak. Purification by flash chromatography was
performed using Merck silica gel 0.0063–0.10 mm with
3.2.4. Allyl 4-methoxyphenyl ether 30.22 Pale yellow oil;
the spectral data were in agreement with the literature
values. dH (300 MHz, CDCl3): 3.75 (3H, s, OMe), 4.47
(2H, dt, J1 ,3 1.5 and J1 ,2 5.3 Hz, H-10), 5.26 (1H, dq,
0
0
0
0
J3 A,1 1.5, J3 A,3 B 3.1 and J3 A,2 10.5 Hz, H-30A), 5.39
0
0
0
0
0
0
(1H, dq, J3 B,1 1.7, J3 B,3 A 3.1 and J3 B,2 17.3 Hz, H-30B),
5.98–6.10 (1H, m, H-20), 6.79–6.88 (4H, m, Ar-H). dC
(75 MHz, CDCl3): 55.6 (CH3, OCH3), 69.5 (CH2, C-10),
114.6 (CH, 2ꢂAr-C), 115.7 (CH, 2ꢂAr-C), 117.4 (CH2,
C-30), 133.6 (CH, C-20), 152.7 (quat., C-1), 153.9 (quat.,
C-4).
0
0
0
0
0
0
3.2.5. 2-Allyloxynaphthalene 53.23 Yellow oil; the spectral
data were in agreement with the literature.23 dH (400 MHz,

6022
K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
CDCl3): 4.62 (2H, dt, J1 ,3 1.4 and J1 ,2 5.4 Hz, H-10), 5.30
3.3.1. 2-Methoxy-6-(prop-2-enyl)phenol 31.10 Clear oil;
the spectral data were in agreement with the literature
0
0
0
0
(1H, dt, J3 A,1 1.4, J3 A,3 B 2.8 and J3 A,2 10.6 Hz, H-30A),
0
0
0
0
0
0
5.45 (1H, dt, J3 B,1 1.5, J3 B,3 A 3.0 and J3 B,2 17.2 Hz,
H-30B), 6.02–6.15 (1H, m, H-20), 7.11 (1H, d, J1,3 2.3 Hz,
H-1), 7.17 (1H, dd, J3,1 2.3 and J3,4 8.9 Hz, H-3), 7.31
(1H, dt, J6,8 1.1 and J6,7¼J6,5 8.1 Hz, H-6), 7.41 (1H, dt,
J7,5 1.1 and J7,8¼J7,6 8.1 Hz, H-7), 7.69–7.77 (3H, m, H-8,
H-4 and H-5). dC (100 MHz, CDCl3): 68.8 (CH2, C-10),
107.0 (CH, C-1), 117.7 (CH2, C-30), 118.9 (CH, C-3),
123.6 (CH, C-6), 126.3 (CH, C-7), 126.7 (CH, C-8 or C-5
or C-4), 127.6 (CH, C-5 or C-8 or C-4), 129.0 (quat.,
C-4a), 129.4 (CH, C-4 or C-8 or C-5), 133.2 (CH, C-20),
134.5 (quat., C-8a), 156.5 (quat., C-2).
values.10 dH (300 MHz, CDCl3): 3.41 (2H, dd, J1 ,3 1.4
0
0
0
0
0
0
0 0
and J1 ,2 6.6 Hz, H-10), 3.87 (3H, s, OMe), 5.03–5.11 (2H,
m, H-30), 5.71 (1H, s, OH), 5.94–6.08 (1H, m, H-20), 6.67–
6.83 (2H, m, H-4 and H-6), 6.84–6.86 (1H, m, H-5). dC
(75 MHz, CDCl3): 33.8 (CH2, C-10), 56.0 (CH3, OMe),
108.6 (CH, C-3 or C-5), 115.4 (CH2, C-30), 119.4 (CH, C-
5 or C-3), 122.2 (CH, C-4), 125.8 (quat., C-6), 136.6 (CH,
C-20), 143.3 (quat., C-1 or C-2), 146.3 (quat., C-2 or C-1).
0
0
3.3.2. 2-Allyl-4-methoxyphenol 32. Clear oil. HRMS (EI):
Found M+, 206.09424 (recorded as acetate derivative),
C12H14O3 requires 206.09429. nmax (film)/cmꢀ1: 3400 (br,
s, OH), 3065 (CH]CH2), 2938, 2833 (s, CH, aromatic),
1637, 1602 (C]C, aromatic), 1277, 1206 (s, C–O), 1152,
3.2.6. Allyl 5-methoxynaphthalen-1-yl ether 59. Yellow
solid. Mp: 89–90 ꢁC. HRMS (EI): Found M+, 214.09902,
C14H14O2 requires 214.09938. nmax (film)/cmꢀ1: 3053 (s,
CH, aromatic), 2986 (s, CH), 1594, 1507, 1407 (s, C]C,
aromatic), 1265, 1211, 1078, 1061 (s, C–O). dH (400 MHz,
0
0
1112, 1039. dH (300 MHz, CDCl3): 3.36 (2H, d, J1 ,2
6.3 Hz, H-10), 3.74 (3H, s, OMe), 5.08–5.15 (2H, m, H-30),
5.23 (1H, br s, OH), 5.91–6.05 (1H, m, H-20), 6.63–6.73
(3H, m, Ar-H). dC (75 MHz, CDCl3): 34.9 (CH2, C-10),
55.7 (CH3, OMe), 112.5 (CH, C-5), 115.9 (CH, C-3),
116.2 (CH2, C-30), 116.3 (CH, C-6), 126.8 (quat., C-2),
136.2 (CH, C-20), 147.9 (quat., C-1), 153.5 (quat., C-4);
m/z (EI, %): 206 (M+, 11), 164 (100), 149 (42), 133 (5),
131 (4), 121 (7), 107 (4), 103 (6), 91 (8), 77 (7).
0
CDCl3): 3.93 (3H, s, OMe), 4.65 (2H, dt, J1 ,3 1.5 and
0
J1 ,2 5.1 Hz, H-10), 5.29 (1H, dd, J3A,1 1.5 and J3 A,2
0
0
0
0
0
10.6 Hz, H-30A), 5.48 (1H, dd, J3 B,1 1.5 and J3 B,2
0
0
0
0
17.3 Hz, H-30B), 6.08–6.18 (1H, m, H-20), 6.79 (2H, d,
J2,3¼J6,7 7.6 Hz, H-2 and H-6), 7.30–7.37 (2H, m, H-3
and H-7), 7.84 (1H, d, J8,7 8.5 Hz, H-8), 7.89 (1H, d, J4,3
8.5 Hz, H-4). dC (100 MHz, CDCl3): 55.4 (CH3, OMe),
68.9 (CH2, C-10), 104.5 (CH, C-2), 105.8 (CH, C-6),
114.3 (2ꢂCH, C-8 and C-4), 117.2 (CH2, C-30), 125.0
(2ꢂCH, C-3 and C-7), 126.7 (2ꢂquat., C-8a and C-4a),
133.3 (CH, C-20), 154.1 (quat., C-1), 155.2 (quat., C-5);
m/z (EI, %): 214 (M+, 42), 199 (M+ꢀMe, 9), 185 (M+ꢀ29,
42), 173 (M+ꢀCH2CH]CH2, 100), 145 (12), 143 (11),
115 (46).
3.3.3. 1-Allyl-2-naphthol 54.23 Yellow oil; the spectral data
were in agreement with the literature values.23 dH (400 MHz,
CDCl3): 3.80 (2H, d, J1 ,2 5.7 Hz, H-10), 5.02–5.89 (2H, m,
H-30), 5.32 (1H, br s, OH), 6.00–6.08 (1H, m, H-20), 7.04
(1H, d, J3,4 8.8 Hz, H-3), 7.31 (1H, t, J6,5¼J6,7 7.6 Hz, H-
6), 7.45 (1H, dt, J7,5 0.9 and J7,8¼J7,6 7.6 Hz, H-7), 7.62
(1H, d, J4,3 8.8 Hz, H-4), 7.74 (1H, d, J8,7 7.6 Hz, H-5),
7.88 (1H, d, J5,6 7.6 Hz, H-8). dC (100 MHz, CDCl3): 29.2
(CH2, C-10), 115.8 (CH2, C-30), 116.9 (quat., C-1), 117.9
(CH, C-3), 123.0 (CH, C-6), 123.1 (CH, C-8), 126.4 (CH,
C-7), 128.3 (CH, C-4), 128.5 (CH, C-5), 129.4 (quat., C-
4a), 133.2 (quat., C-8a), 135.8 (CH, C-20), 151.1 (quat., C-2).
0
0
3.2.7. Allyl 1,5-dimethoxynaphthalen-4-yl ether 60.
White powder. Mp: 95–98 ꢁC. HRMS (EI): Found M+,
244.10972, C15H16O3 requires 244.10994. nmax (film)/
cmꢀ1: 3053 (s, C–H, aromatic), 2960 (s, CH), 2252, 1597,
1459, 1409 (s, C]C, aromatic), 1272, 1076, 1048 (s, C–
O), 909, 802, 732, 650. dH (300 MHz, CDCl3): 3.93 (3H,
3.3.4. 5-Methoxy-(2-propen-1-yl)naphthalen-1-ol 61.
Pale yellow solid. Mp: 70–72 ꢁC. HRMS (EI): Found M+,
214.09901, C14H14O2 requires 214.09938. nmax (film)/
cmꢀ1: 3497 (s, br, OH), 3053 (s, CH, aromatic), 2985
(CH), 1600 (C]C, aromatic), 1264, 1059 (s, C–O), 925.
0
s, OMe), 3.94 (3H, s, OMe), 4.56 (2H, dt, J1 ,3 1.6 and
0
J1 ,2 4.9 Hz, H-10), 5.31 (1H, dd, J3 A,1 1.6 and J3 A,2
0
0
0
0
0
0
10.7 Hz, H-30A), 5.57 (1H, dd, J3 B,1 1.6 and J3 B,2
0
0
0
0
17.2 Hz, H-30A), 6.11–6.24 (1H, m, H-20), 6.83 (1H, d, J2,3
8.4 Hz, H-2), 6.86 (1H, d, J3,2 8.4 Hz, H-3), 6.90 (1H, d,
J6,7 8.1 Hz, H-6), 7.38 (1H, t, J7,8¼J7,6 8.1 Hz, H-7), 7.85
(1H, dd, J8,6 0.9 and J8,7 8.1 Hz, H-8). dC (75 MHz,
CDCl3): 55.7 (CH3, OMe), 56.2 (CH3, OMe), 72.0 (CH2,
C-10), 104.2 (CH, C-3), 107.0 (CH, C-2), 110.1 (CH, C-6),
114.6 (CH, C-8), 116.5 (CH2, C-30), 119.1 (quat., C-4a),
125.8 (CH, C-7), 128.8 (quat., C-8a), 134.1 (CH, C-20),
149.5 (quat., C-4), 150.0 (quat., C-1), 156.7 (quat., C-5);
m/z (EI, %): 244 (M+, 57%), 203 (M+ꢀCH2CH]CH2,
100), 185 (8), 175 (28), 173 (9), 160 (22), 145 (17), 130
(11), 115 (15), 102 (9), 91 (5), 41 (11).
dH (300 MHz, CDCl3): 3.52 (2H, d, J1 ,2 6.1 Hz, H-10),
3.95 (3H, s, OMe), 5.18–5.22 (2H, m, H-30), 5.51 (1H, br
s, OH), 5.98–6.11 (1H, m, H-20), 6.77 (1H, d, J6,7 8.1 Hz,
H-6), 7.18 (1H, d, J3,4 8.5 Hz, H-3), 7.35 (1H, t, J7,6¼J7,8
8.1 Hz, H-7), 7.71 (1H, d, J8,7 8.1 Hz, H-8), 7.80 (1H, d,
J4,3 8.5 Hz, H-4). dC (75 MHz, CDCl3): 35.6 (CH2, C-10),
55.5 (CH3, OMe), 103.8 (CH, C-6), 113.5 (CH, C-8),
114.4 (CH, C-4), 116.8 (CH2, C-30), 118.7 (quat., C-2),
125.3 (CH, C-7), 125.8 (quat., C-8a), 125.9 (quat., C-4a),
127.6 (CH, C-3), 136.4 (CH, C-20), 149.3 (quat., C-1),
155.3 (quat., C-5); m/z (EI, %): 214 (M+, 100), 199
(M+ꢀMe, 48), 171 (22), 128 (13), 115 (17), 107 (4).
0
0
3.3. Standard procedure for Claisen rearrangement of
allyl ethers
3.3.5. 4,8-Dimethoxy-2-(2-propen-1-yl)naphthalen-1-ol
62. Brown powder. Mp: 56–59 ꢁC. HRMS (EI): Found M+,
244.10979, C15H16O3 requires 244.10994. nmax (film)/
cmꢀ1: 3412 (s, br, OH), 2942 (s, C–H, aromatic), 2252,
1609, 1511, 1449, 1406 (s, C]C, aromatic), 1373, 1240,
1218, 1071 (s, C–O), 908, 803, 732. dH (300 MHz,
A mixture of allyl ether (1 mmol) in m-xylene (5 mL) was
heated at 180 ꢁC or 210 ꢁC under a nitrogen atmosphere.
The reaction mixture was allowed to cool and subjected to
flash column chromatography.

K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
6023
0
3.89 (3H, s, OMe), 5.06 (1H, dd, J3 A,1 1.5 and J3 A,2
m, H-30 and OCH2O), 5.90–6.04 (1H, m, H-20), 6.66 (1H,
d, J3,5 3.1 Hz, H-3), 6.71 (1H, dd, J5,3 3.1 and J5,6 8.9 Hz,
H-5), 6.99 (1H, d, J6,5 8.7 Hz, H-6). dC (75 MHz, CDCl3):
34.4 (CH2, C-10), 55.5 (CH3, OCH2OCH3), 55.9 (CH3,
OMe), 95.3 (CH2, OCH2O), 111.6 (CH, C-5), 115.6 (CH2,
C-30), 115.7 (CH, C-3 or C-6), 115.8 (CH, C-3 or C-6),
130.7 (quat., C-2), 136.7 (CH, C-20), 149.1 (quat., C-1),
154.5 (quat., C-4); m/z (EI, %): 208 (M+, 26), 163 (33),
131 (14), 45 (100).
0
CDCl3): 3.52 (2H, d, J1 ,2 6.4 Hz, H-1 ), 3.87 (3H, s, OMe),
0
0
0
0
0
10.7 Hz, H-30A), 5.10 (1H, dd, J3 B,1 1.5 and J3 B,2
0
0
0
0
15.2 Hz, H-30B), 6.00–6.13 (1H, m, H-20), 6.65 (1H, s,
H-3), 6.70 (1H, d, J7,6 7.8 Hz, H-7), 7.21 (1H, dd, J6,7 7.8
and J6,5 8.5 Hz, H-6), 7.80 (1H, dd, J5,7 0.8 and J5,6
8.5 Hz, H-5), 9.17 (1H, br s, OH). dC (75 MHz, CDCl3):
34.3 (CH2, C-10), 55.7 (CH3, OMe), 55.8 (CH3, OMe),
104.9 (CH, C-3), 108.2 (CH, C-7), 115.0 (CH2, C-30),
115.3 (quat., C-8a), 115.6 (CH, C-5), 119.4 (quat., C-2),
124.3 (CH, C-6), 126.6 (quat., C-4a), 137.1 (CH, C-20),
144.5 (quat., C-1), 147.6 (quat., C-4), 155.6 (quat., C-8);
m/z (EI, %): 244 (M+, 100), 229 (M+ꢀMe, 76), 214 (9),
197 (9), 187 (9), 158 (8), 115 (9).
3.4.5. 1-Allyl-2-methoxymethoxy-naphthalene 55. Yellow
oil. HRMS (EI): Found M+, 228.11483, C15H16O2 requires
228.11503. nmax (film)/cmꢀ1: 3057, 3072, 2975, 2954,
2900, 2930, 2847, 2825, 1636, 1625, 1595, 1512, 1469,
1435, 1260, 1241, 1197, 1149, 1082, 1035, 995, 919, 807.
dH (400 MHz, CDCl3): 3.49 (3H, s, OMe), 3.88 (2H, dt,
3.4. Protection of allylphenols as methoxymethyl ethers
J1 ,3 1.6 and J1 ,2 5.8 Hz, H-10), 4.95–5.01 (2H, m, H-30),
5.25 (2H, s, OCH2O), 5.99–6.09 (1H, m, H-20), 7.33 (1H,
dt, J6,8 0.9 and J6,7¼J6,5 8.1 Hz, H-6), 7.41 (1H, d, J3,4
9.0 Hz, H-3), 7.45 (1H, dt, J7,5 1.2 and J7,8¼J7,6 8.1 Hz,
H-7), 7.69 (1H, d, J4,3 9.0 Hz, H-4), 7.77 (1H, d, J8,7
8.1 Hz, H-5), 7.93 (1H, d, J5,6 8.1 Hz, H-8). dC (100 MHz,
CDCl3): 29.3 (CH2, C-10), 56.1 (CH3, OMe), 95.2 (CH2,
OCH2O), 115.1 (CH2, C-30), 116.4 (CH, C-3), 122.0
(quat., C-1), 123.7 (2ꢂCH, C-6 and C-8), 126.2 (CH, C-
7), 128.0 (CH, C-4), 128.4 (CH, C-5), 129.9 (quat., C-4a),
133.1 (quat., C-8a), 136.6 (CH, C-20), 152.1 (quat., C-2);
m/z (EI, %): 228 (M+, 18), 183 (30), 181 (13), 168 (2), 165
(15), 152 (7), 45 (100).
0
0
0
0
3.4.1. Procedure A—using diisopropylethylamine in di-
chloromethane. To a stirred solution of phenol (0.07 mol)
in dichloromethane (20 mL) were added diisopropylethyl-
amine (0.13 mol) and chloromethyl methyl ether (0.10
mol) dropwise at 0 ꢁC under nitrogen. The mixture was
warmed to room temperature and stirred overnight.
Dichloromethane was removed in vacuo, the residue taken
up in diethyl ether (15 mL), washed with 10% aqueous HCl
solution (2ꢂ10 mL), water (2ꢂ10 mL), aqueous 10% NaOH
(2ꢂ10 mL), brine (25 mL), dried over MgSO4 and concen-
trated at reduced pressure. The residue was purified by flash
column chromatography.
3.4.2. Procedure B—using sodium hydride in DMF. To
a stirred solution of phenol or naphthalenol (1 mmol) in
anhydrous N,N-dimethylformamide (5 mL) at 0 ꢁC, sodium
hydride (1.1 mmol) was added portionwise. After stirring
at 0 ꢁC for 30 min, MOMCl (1.2 mmol) was added drop-
wise. The reaction mixture was warmed to room temperature
and stirred for 1 h. Water (5 mL) was added and extracted
with diethyl ether (3ꢂ5 mL). The combined organic extracts
were washed with 1 N NaOH (2ꢂ5 mL), then 10% HCl
(2ꢂ5 mL) and brine (5 mL). The organic layer was dried
over MgSO4, concentrated in vacuo and subjected to flash
column chromatography.
3.4.6. 5-Methoxy-1-(methoxymethoxy)-2-(2-propen-1-
yl)naphthalene 63. Brown oil. HRMS (EI): Found M+,
258.12545, C16H18O3 requires 258.12559. nmax (film)/
cmꢀ1: 3076 (s, CH, aromatic), 2929 (CH), 1637 (C]C,
aromatic), 1598, 1506, 1463, 1414, 1376, 1259, 1213,
1158, 1049 (s, C–O). dH (400 MHz, CDCl3): 3.60–3.61
(2H, m, H-10), 3.61 (3H, s, OCH2OCH3), 3.88 (3H, s,
OMe), 5.05–5.06 (1H, m, H-30A), 5.08–5.10 (1H, m,
H-30B), 5.09 (2H, s, OCH2O), 5.97–6.07 (1H, m, H-20),
6.70 (1H, d, J6,7 7.7 Hz, H-6), 7.27 (1H, d, J3,4 8.6 Hz,
H-3), 7.34 (1H, dd, J7,6 7.7 and J7,8 8.5 Hz, H-7), 7.65
(1H, d, J8,7 8.5 Hz, H-8), 8.00 (1H, d, J4,3 8.6 Hz, H-4).
dC (100 MHz, CDCl3): 34.2 (CH2, C-10), 55.3 (CH3,
OMe), 57.5 (CH3, OCH2OCH3), 100.1 (CH2, OCH2O),
103.5 (CH, C-6), 114.3 (CH, C-8), 115.7 (CH2, C-30),
118.3 (CH, C-4), 125.8 (quat., C-2), 125.9 (CH, C-7),
127.2 (CH, C-3), 129.0 (quat., C-8a), 130.0 (quat., C-4a),
137.1 (CH, C-20), 150.5 (quat., C-1), 155.5 (quat., C-5);
m/z (EI, %): 258 (M+, 57), 213 (37), 211 (22), 198 (14),
187 (8), 152 (12), 141 (11), 115 (17), 45 (100).
3.4.3. 1-Methoxy-2-methoxymethoxy-3-(prop-2-enyl)-
benzene 33.10 Clear oil; the spectral data were in agreement
with the literature.10 dH (400 MHz, CDCl3): 3.48 (2H, d,
J1 ,2 6.6 Hz, H-10), 3.59 (3H, s, OCH2OCH3), 3.77 (3H, s,
OMe), 5.02–5.08 (2H, m, H-30), 5.06 (2H, s, OCH2O),
5.92–6.03 (1H, m, H-20), 6.73–6.77 (2H, m, H-4 and H-6),
6.97–7.05 (1H, t, J5,4¼J5,6 7.9 Hz, H-5). dC (100 MHz,
CDCl3): 34.0 (CH2, C-10), 55.4 (CH3, OMe), 57.1 (CH3,
OCH2OCH3), 98.7 (CH2, OCH2O), 110.2 (CH, C-6 or
C-4), 115.3 (CH2, C-30), 121.8 (CH, C-4 or C-6), 123.9
(CH, C-5), 133.9 (quat., C-3), 136.9 (CH, C-20), 143.9
(quat., C-2), 152.0 (quat., C-1).
0
0
3.4.7. 4,8-Dimethoxy-1-(methoxymethoxy)-2-(2-pro-
penyl)naphthalene 64. Tan oil. HRMS (EI): Found M+,
288.13599, C17H20O4 requires 288.13616. nmax (film)/
cmꢀ1: 2942 (s, C–H, aromatic), 2252, 1637, 1464 (s,
C]C, aromatic), 1366, 1263, 1157, 1081 (s, C–O). dH
(400 MHz, CDCl3): 3.62 (3H, s, OCH2OCH3), 3.67 (2H,
3.4.4. 2-Allyl-4-methoxy-1-(methoxymethoxy)benzene
34. Clear oil. HRMS (EI): Found M+, 208.10996,
C12H16O3 requires 208.10994. nmax (film)/cmꢀ1: 3079
(CH]CH2), 3000, 2950, 2832 (s, C–H, aromatic), 1499,
1465 (OCH2O), 1280, 1223, 1195, 1150, 1077, 1008. dH
dt, J1 ,3 1.5 and J1 ,2 6.4 Hz, H-10), 3.93 (3H, s, OMe),
0
0
0
0
3.94 (3H, s, OMe), 5.01 (2H, s, OCH2O), 5.09 (1H, dd,
0
J3 A,1 1.5 and J3 A,2 10.2 Hz, H-30A), 5.14 (1H, dd, J3 B,1
0
0
0
0
0
1.5 and J3 B,2 17.1 Hz, H-30B), 6.00–6.11 (1H, m, H-20),
6.65 (1H, s, H-3), 6.88 (1H, d, J7,6 8.2 Hz, H-7), 7.31 (1H,
dd, J6,7¼J6,5 8.2 Hz, H-6), 7.84 (1H, dd, J5,7 1.0 and J5,6
0
0
(300 MHz, CDCl3): 3.37 (2H, d, J1 ,2 6.5 Hz, H-10), 3.47
(3H, s, OCH2OCH3), 3.74 (3H, s, OMe), 5.03–5.10 (4H,
0
0

6024
K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
8.2 Hz, H-5). dC (100 MHz, CDCl3): 35.0 (CH2, C-10), 55.6
(CH3, OMe), 56.0 (CH3, OMe), 57.4 (CH3, OCH2OCH3),
101.2 (CH2, OCH2O), 106.3 (CH, C-3), 106.9 (CH, C-7),
114.9 (CH, C-5), 115.6 (CH2, C-30), 120.4 (quat., C-2),
124.9 (CH, C-6), 127.8 (quat., C-8a), 129.5 (quat., C-4a),
137.6 (CH, C-20), 143.5 (quat., C-1), 151.5 (quat., C-4),
155.3 (quat., C-8); m/z (EI, %): 288 (M+, 100), 243
(M+ꢀCH2OMe, 98), 228 (20), 212 (60), 197 (12), 181 (5),
168 (6), 115 (9), 45 (41).
115.4 (CH, C-60), 117.0 (CH, C-30), 122.9 (quat., C-10),
149.5 (quat., C-20), 154.5 (quat., C-50), 199.6 (CH, C-1);
m/z (EI, %): 210 (M+, 50), 178 (M+ꢀMeOH, 62), 151
(32), 149 (38), 137 (31), 136 (27), 121 (23), 77 (19), 45
(100).
3.7. Dihydroxylation of protected naphthols
To a solution of alkene (1 mmol) in acetone–H2O (8:1,
9 mL) were added osmium tetroxide (2.5 wt % solution in
2-methyl-2-propanol) (0.3 mmol) and N-methylmorpho-
line-N-oxide (3 mmol). After stirring the mixture overnight,
sodium sulfite (0.5 g) and methanol (2.5 mL) were added.
After stirring for 2 h, the mixture was filtered and concen-
trated in vacuo. The residue was extracted with diethyl ether
(3ꢂ5 mL), the combined organic extracts were washed with
brine (10 mL), dried over MgSO4, concentrated under vac-
uum and subjected to flash column chromatography.
3.5. Ozonolysis of the protected allylphenol 33
A solution of alkene 33 (143 mg, 0.7 mmol) in dry methanol
(5.5 mL) was cooled to ꢀ50 ꢁC under nitrogen. Ozone was
bubbled through the solution for 10 min at a rate of 1 mL/
min. The mixture was flushed with nitrogen and dimethyl
sulfide (0.3 mL, 4 mmol) was added. After warming the
solution to room temperature, another portion of dimethyl
sulfide (0.3 mL, 4 mmol) was added and the mixture stirred
for 1 h. The solvent was concentrated in vacuo to give a
yellow residue, which was taken up in water (5 mL) and ex-
tracted with diethyl ether (3ꢂ10 mL). The combined organic
extracts were dried over MgSO4 and concentrated in vacuo
to give a yellow residue, which was purified by flash column
chromatography using hexane–diethyl ether (70:30) as elu-
ent to afford (3-methoxy-2-methoxymethoxyphenyl)acet-
aldehyde 23 (121 mg, 83%) as a pale yellow oil for which
the spectral data were in agreement with the literature.10
dH (300 MHz, CDCl3): 3.52 (3H, s, OCH2OMe), 3.73 (2H,
d, J2,1 2.1 Hz, H-2), 3.85 (3H, s, OMe), 5.09 (2H, s,
3.7.1. 3-[(2-Methoxymethoxy)-1-naphthalenyl]-1,2-pro-
panediol 56. Yellow powder. Mp: 110–112 ꢁC. HRMS
(EI): Found M+, 262.12057, C15H18O4 requires 262.12051.
nmax (CH2Cl2 solution)/cmꢀ1: 3574, 3054, 2986, 2829,
2685, 2305, 1625, 1596, 1512, 1421, 1265, 1242, 1197,
1150, 1062, 1010, 746. dH (300 MHz, CDCl3): 3.28 (2H,
d, J3,2 6.9 Hz, H-3), 3.34 (1H, br s, OH), 3.43 (3H, s,
OMe), 3.46–3.54 (2H, m, H-1), 3.58 (1H, br s, OH), 4.01–
4.08 (1H, m, H-2), 5.18 (2H, s, OCH2O), 7.27–7.35 (2H,
m, H-30 and H-60), 7.41 (1H, dd, J7 ,6 ¼J7 ,8 7.7 Hz, H-70),
0
0
0
0
7.65 (1H, d, J4 ,3 9.1 Hz, H-40), 7.72 (1H, d, J5 ,6 7.7 Hz,
0
0
0
0
OCH2O), 6.78 (1H, dd, J4 ,6 1.0 and J4 ,5 7.8 Hz, H-40),
H-50), 8.00 (1H, d, J8 ,7 7.7 Hz, H-80). dC (75 MHz,
CDCl3): 28.9 (CH2, C-3), 56.1 (CH3, OMe), 65.8 (CH2, H-
1), 72.3 (CH, H-2), 95.1 (CH2, OCH2O), 115.7 (CH, C-30),
120.1 (quat., C-10), 123.4 (CH, C-60), 123.7 (CH, C-80),
126.4 (CH, C-70), 128.3 (CHꢂ2, C-40 and C-50), 129.7
(quat., C-40a), 133.2 (quat., C-80a), 152.5 (quat., C-20); m/z
(EI, %): 262 (M+, 18), 230 (M+ꢀMeOH, 12), 200
(M+ꢀMOMOH, 22), 169 (21), 157 (68), 144 (12), 141
(12), 128 (18), 45 (100).
0
0
0
0
0
0
6.89 (1H, dd, J6 ,4 1.0 and J6 ,5 7.8 Hz, H-60), 7.04 (1H, t,
0
0
0
0
J5 ,4 ¼J5 ,6 7.8 Hz, H-50), 9.72 (1H, t, J1,2 2.1 Hz, H-1). dC
(75 MHz, CDCl3): 45.3 (CH2, C-2), 55.7 (CH3, OMe),
57.5 (CH3, OCH2OCH3), 99.0 (CH2, OCH2O), 111.9 (CH,
C-40), 122.9 (CH, C-60), 124.4 (CH, C-50), 126.9 (quat., C-
10), 144.9 (quat., C-20), 152.3 (quat., C-30), 200.0 (CH, C-1).
0
0
0
0
3.6. One step dihydroxylation–oxidative cleavage of
protected allylphenol 34
3.7.2. 3-(5-Methoxy-1-(methoxymethoxy)naphthalen-
2-yl)propane-1,2-diol 65. Yellow oil. HRMS (EI): Found
M+, 292.13031, C16H20O5 requires 292.13107. nmax (film)/
cmꢀ1: 3400 (br, OH), 3071 (s, C–H, aromatic), 2934 (m,
CH), 1734 (s, C–O), 1625, 1578, 1599, 1506 (C]C, aro-
matic), 1463, 1447, 1379 (s, C–H, alkane), 1259. dH
(400 MHz, CDCl3): 2.93 (1H, dd, J3A,2 5.6 and J3A,3B
13.7 Hz, H-3A), 3.02 (1H, dd, J3B,2 7.9 and J3B,3A 13.7 Hz,
H-3B), 3.12 (1H, br s, OH), 3.37 (1H, br s, OH), 3.45 (1H,
dd, J1A,2 6.2 and J1A,1B 11.3 Hz, H-1A), 3.57–3.62 (1H, m,
H-1B), 3.62 (3H, s, OCH2OCH3), 3.94 (3H, s, OMe), 3.94–
3.97 (1H, m, H-2), 5.10 (1H, d, Jgem 14.1 Hz, OCHAHBO),
To a stirred solution of alkene 34 (1 mmol) in THF–water
(5 mL, 4:1) was added osmium tetroxide (0.1 mmol). After
30 min, sodium periodate (1.82 mmol) was added portion-
wise. The reaction mixture was stirred at room temperature
for 8 h, then quenched with water. The aqueous layer was
washed with diethyl ether (4ꢂ5 mL) and the combined ethe-
real layer washed with brine (5 mL), dried over MgSO4, con-
centrated in vacuo and subjected to purification by flash
column chromatography.
3.6.1. (5-Methoxy-2-(methoxymethoxy)phenyl)acetalde-
hyde 24. Yellow oil. HRMS (EI): Found M+, 210.08915,
C11H14O4 requires 210.08921. nmax (film)/cmꢀ1: 2950,
2832 (s, C–H, aromatic), 1721 (s, C]O, aldehyde), 1504
(s, C]C, aromatic), 1475 (OCH2O), 1226, 1077 (C–O).
dH (300 MHz, CDCl3): 3.45 (3H, s, OCH2OCH3), 3.65
(2H, d, J2,1 2.1 Hz, H-2), 3.77 (3H, s, OMe), 5.12 (2H, s,
0
5.12 (1H, d, Jgem 14.1 Hz, OCHAHBO), 6.76 (1H, d, J6 ,7
0
7.7 Hz, H-60), 7.28 (1H, d, J3 ,4 8.5 Hz, H-30), 7.37 (1H,
0
0
dd, J7 ,6 7.7 and J7 ,8 8.4 Hz, H-70), 7.55 (1H, d, J8 ,7
0
0
0
0
0
0
8.4 Hz, H-80), 7.99 (1H, d, J4 ,3 8.5 Hz, H-40). dC
(100 MHz, CDCl3): 34.0 (CH2, C-3), 55.3 (CH3, OMe),
57.6 (CH3, OCH2OCH3), 66.0 (CH2, C-1), 72.6 (CH, C-2),
100.3 (CH2, OCH2O), 103.7 (CH, C-60), 114.1 (CH, C-80),
118.7 (CH, C-40), 126.0 (quat., C-20), 126.2 (CH, C-70),
127.6 (CH, C-30), 129.2 (2ꢂquat., C-80a and C-40a), 151.3
(quat., C-10), 155.6 (quat., C-50); m/z (EI, %): 292 (M+,
23), 274 (M+ꢀ18, 37), 260 (52), 230 (79), 212 (17), 199
0
0
OCH2O), 6.72 (1H, d, J6 ,4 3.0 Hz, H-60), 6.79 (1H, dd,
0
0
J4 ,6 3.0 and J4 ,3 8.9 Hz, H-40), 7.08 (1H, d, J3 ,4 8.9 Hz,
H-30), 9.70 (1H, t, J1,2 2.1 Hz, H-1). dC (75 MHz, CDCl3):
45.7 (CH2, C-2), 55.6 (CH3, OMe), 56.0 (CH3,
OCH2OCH3), 95.1 (CH2, OCH2O), 113.4 (CH, C-40),
0
0
0
0
0
0

K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
6025
(22), 187 (65), 174 (6), 171 (8), 159 (15), 129 (13), 115 (14),
45 (100).
d, J2,1 1.9 Hz, H-2), 3.97 (3H, s, OMe), 5.11 (2H, s,
OCH2O), 6.82 (1H, d, J6 ,7 7.7 Hz, H-60), 7.24 (1H, d,
0
0
J3 ,4 8.6 Hz, H-30), 7.42 (1H, dd, J7 ,6 7.7 and J7 ,8 8.4 Hz,
0
0
0
0
0
0
H-70), 7.61 (1H, d, J8 ,7 8.4 Hz, H-80), 8.06 (1H, d, J4 ,3
0
0
0
0
3.7.3. 3-(4,8-Dimethoxy-1-(methoxymethoxy)naphtha-
len-2-yl)propane-1,2-diol 66. Yellow oil. HRMS (EI):
Found M+, 322.14168, C17H22O6 requires 322.14164. nmax
(film)/cmꢀ1: 3430 (s, br, OH), 3156, 2938 (s, CH, aromatic),
2844, 1602, 1580, 1509, 1465 (s, OCH2O), 1416, 1369,
1264, 1157, 1080. dH (300 MHz, CDCl3): 2.52 (1H, br s,
OH), 2.99 (1H, dd, J3A,2 5.3 and Jgem 13.7 Hz, H-3A), 3.13
(1H, dd, J3B,2 8.2 and Jgem 13.7 Hz, H-3B), 2.96–3.15 (1H,
br, OH), 3.55 (1H, dd, J1A,2 6.0 and Jgem 11.2 Hz, H-1A),
3.63 (3H, s, OCH2OCH3), 3.68 (1H, dd, J1B,2 3.6 and Jgem
11.2 Hz, H-1B), 3.96 (6H, s, OMe), 4.02–4.08 (1H, m, H-
2), 5.04 (1H, d, Jgem 16.6 Hz, OCHAHBO), 5.06 (1H, d,
Jgem 16.6 Hz, OCHAHBO), 6.68 (1H, s, H-30), 6.91 (1H, d,
8.6 Hz, H-40), 9.77 (1H, t, J1,2 1.9 Hz, H-1). dC (75 MHz,
CDCl3): 45.6 (CH2, C-2), 55.5 (CH3, OMe), 57.5 (CH3,
OCH2OCH3), 100.3 (CH2, OCH2O), 104.1 (CH, C-60),
114.1 (CH, C-80), 119.0 (CH, C-40), 122.3 (quat., C-2),
126.5 (CH, C-70), 126.6 (quat., C-40a or C-80a), 127.4 (CH,
C-30), 129.3 (quat., C-80a or C-40a), 152.1 (quat., C-10),
155.7 (quat., C-50), 199.9 (CH, C-1); m/z (EI, %): 260
(M+, 24), 228 (18), 201 (14), 187 (14), 155 (4), 144 (4),
128 (6), 115 (11), 45 (100).
3.8.3. (4,8-Dimethoxy-1-(methoxymethoxy)naphthalen-
2-yl)acetaldehyde 47. Yellow oil. HRMS (EI): Found M+,
290.11564, C16H18O5 requires 290.11542. nmax (film)/
cmꢀ1: 3054, 2986 (s, C–H, aromatic), 1732 (C]O, alde-
hyde), 1601, 1551, 1511 (w, C]C, aromatic), 1265, 1156,
1080 (s, C–O), 738, 705. dH (400 MHz, CDCl3): 3.55 (3H,
s, OCH2OCH3), 3.90 (2H, d, J1,2 2.1 Hz, H-1), 3.91 (3H, s,
OMe), 3.92 (3H, s, OMe), 5.02 (2H, s, OCH2O), 6.57 (1H,
J7 ,6 7.7 Hz, H-70), 7.35 (1H, dd, J6 ,5 8.2 and J6 ,7 8.1 Hz,
0
0
0
0
0
0
H-60), 7.86 (1H, dd, J5 ,7 0.9 and J5 ,6 8.4 Hz, H-50). dC
(75 MHz, CDCl3): 34.6 (CH2, C-3), 55.7 (CH3, OMe),
56.0 (CH3, OMe), 57.4 (CH3, OCH2OCH3), 66.4 (CH2,
C-1), 72.9 (CH, C-2), 101.5 (CH2, OCH2O), 106.6 (CH,
C-30), 107.2 (CH, C-70), 115.0 (CH, C-50), 120.2 (quat.,
C-20), 125.2 (CH, C-60), 127.6 (quat., C-80a), 128.0 (quat.,
C-40a), 144.5 (quat., C-10), 151.8 (quat., C-40), 155.1
(quat., C-80); m/z (EI, %): 322 (M+, 45), 304 (M+ꢀ 18, 3),
290 (29), 260 (30), 229 (13), 217 (100), 189 (10), 174
(10), 45 (37).
0
0
0
0
s, H-30), 6.89 (1H, d, J7 ,6 8.2 Hz, H-70), 7.34 (1H, dd,
0
0
J6 ,7 ¼J6 ,5 8.2 Hz, H-60), 7.86 (1H, dd, J5 ,7 1.0 and J5 ,6
0
0
0
0
0
0
0
0
8.2 Hz, H-50), 9.78 (1H, t, J2,1 2.1 Hz, H-2). dC (100 MHz,
CDCl3): 46.1 (CH2, C-1), 55.5 (CH3, OMe), 55.8 (CH3,
OMe), 57.2 (CH3, OCH2OCH3), 101.5 (CH2, OCH2O),
106.3 (CH, C-30), 107.1 (CH, C-70), 114.9 (CH, C-50),
120.1 (quat., C-20), 122.2 (quat., C-80a), 125.5 (CH, C-60),
128.3 (quat., C-40a), 145.1 (quat., C-10), 151.7 (quat., C-
40), 155.1 (quat., C-80), 200.4 (CH, C-2); m/z (EI, %): 290
(M+, 100), 245 (M+ꢀCH2OCH3, 58), 229 (M+ꢀOMOM,
29), 217 (92), 202 (27), 174 (20), 115 (22), 45 (94).
3.8. Oxidative cleavage of diols
To a solution of diol (1 mmol) in dichloromethane (6 mL)
was added sodium periodate (2 mmol) in water (5 mL) to
give an immiscible mixture. The reaction mixture was stirred
for 45 min at room temperature. The organic layer was sep-
arated and the aqueous layer was extracted with dichloro-
methane (4ꢂ5 mL). The combined organic extracts were
dried over MgSO4, concentrated in vacuo and subjected to
flash column chromatography.
3.9. Protection of aryl phenols as MOM ethers
To a stirred solution of 2-iodophenol (4.86 mmol) in di-
chloromethane (5 mL) at 0 ꢁC were added chloromethyl
methyl ether (7.24 mmol) and diisopropylethylamine
(9.45 mmol) under a nitrogen atmosphere and the mixture
stirred for 1 h, then warmed to room temperature overnight.
Water (6 mL) was added to the reaction mixture, two layers
were separated and aqueous layer was extracted with diethyl
ether (4ꢂ6 mL). The combined organic extracts were
washed with brine (2ꢂ5 mL), dried over MgSO4, concen-
trated in vacuo and subjected to flash column chromato-
graphy.
3.8.1. (2-Methoxymethoxy-naphthalen-1-yl)acetalde-
hyde 45. Colourless oil. Mp: 65–68 ꢁC. HRMS (EI): Found
M+, 230.09444, C14H14O3 requires 230.09429. nmax (film)/
cmꢀ1: 3054, 2986, 2827, 2724, 2305, 1722, 1625, 1596,
1513, 1470, 1420, 1381, 1265, 1243, 1198, 1150, 1062,
1020, 999, 743. dH (400 MHz, CDCl3): 3.44 (3H, s, OMe),
4.12 (2H, d, J2,1 2.1 Hz, H-2), 5.23 (2H, s, OCH2O), 7.33
(1H, t, J6 ,7 ¼J6 ,5 7.6 Hz, H-60), 7.40–7.46 (2H, m, H-30
and H-70), 7.3–7.78 (3H, m, H-40, H-50 and H-80), 9.66
(1H, t, J1,2 2.1 Hz, CHO). dC (100 MHz, CDCl3): 40.4
(CH2, C-2), 56.0 (CH3, OMe), 94.8 (CH2, OCH2O), 114.5
(quat., C-10), 115.5 (CH, C-30), 122.6 (CH, C-40 or C-50 or
C-80), 123.9 (CH, C-60), 126.8 (CH, C-70), 128.5 (CH, C-50
or C-40 or C-80), 129.3 (CH, C-80 or C-40 or C-50), 129.6
(quat., 40a), 133.1 (quat., C-80a), 152.9 (quat., C-20), 199.5
(CH, CHO); m/z (EI, %): 230 (M+, 13), 185 (20), 169 (14),
168 (20), 141 (11), 128 (13), 115 (4), 45 (100).
0
0
0
0
3.9.1. 2-(Methoxymethoxy)iodobenzene 27.15 Orange-yel-
low oil. dH (300 MHz, CDCl3): 3.51 (3H, s, OMe), 5.23 (2H,
s, OCH2O), 6.75 (1H, dt, J5,3 1.4 and J5,4¼J5,6 7.6 Hz, H-5),
7.06 (1H, dd, J3,5 1.4 and J3,4 8.3 Hz, H-3), 7.24–7.30 (1H,
m, H-4), 7.77 (1H, dd, J6,4 1.6 and J6,5 7.6 Hz, H-6). dC
(75 MHz, CDCl3): 56.3 (CH3, OCH3), 87.1 (quat., C-1),
94.9 (CH2, OCH2O), 114.9 (CH, C-3), 123.6 (CH, C-5),
129.4 (CH, C-4), 139.4 (CH, C-6), 156.0 (quat., C-2).
3.8.2. (5-Methoxy-1-(methoxymethoxy)naphthalen-2-
yl)acetaldehyde 46. Yellow oil. HRMS (EI): Found M+,
260.10451, C15H16O4 requires 260.10486. nmax (film)/
cmꢀ1: 3053, 2937, 2830, 2305, 1722, 1599, 1579, 1507,
1416, 1377, 1264, 1159, 1054, 965, 807, 704. dH
(300 MHz, CDCl3): 3.60 (3H, s, OCH2OCH3), 3.90 (2H,
3.9.2. 1-Methoxy-2-(methoxymethoxy)benzene 36.16
Orange-yellow oil. dH (300 MHz, CDCl3): 3.51 (3H, s,
OMe), 3.86 (3H, s, OMe), 5.22 (2H, s, OCH2O), 6.84–7.01
(3H, m, H-4, H-5 and H-6), 7.15 (1H, dd, J3,5 1.6 and J3,4
8.0 Hz, H-3). dC (75 MHz, CDCl3): 55.8 (CH3, OMe), 56.1
(CH3, OMe), 95.5 (CH2, OCH2O), 111.8 (CH, C-6), 116.6

6026
K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
(CH, C-3), 120.8 (CH, C-4), 122.5 (CH, C-5), 146.5 (quat.,
C-2), 149.8 (quat., C-1).
cmꢀ1: 3689, 3584 (s, br, OH), 3054 (s, C–H, aromatic),
2305 (m, C^C), 1598, 1575, 1511 (C]C, aromatic),
1469 (OCH2O), 1265, 1208, 1160 (s, C–O). dH (300 MHz,
CDCl3): 1.60 (6H, s, CMe2OH), 2.88 (1H, br s, OH), 3.65
(3H, s, OCH2OMe), 3.82 (3H, s, OMe), 5.22 (2H, s,
OCH2O), 6.84–6.90 (1H, m, H-40), 6.97–6.99 (2H, m, H-50
and H-60). dC (75 MHz, CDCl3): 31.3 (6ꢂCH3, C-1), 55.8
(CH3, OMe), 57.4 (CH3, OCH2OMe), 65.4 (quat., C-2),
84.0 (quat., C-4), 98.0 (quat., C-3), 98.3 (CH2, OCH2O),
112.8 (CH, C-40), 117.8 (quat., C-10), 124.0 (CH, C-60),
125.2 (CH, C-50), 146.8 (quat., C-30), 152.4 (quat., C-20);
m/z (EI, %): 250 (M+, 2), 203 (5), 188 (100), 175 (5), 173
(7), 160 (14), 145 (14), 131 (15), 115 (7), 45 (49).
3.10. Iodination of 36
To a solution of 36 (23.4 mmol) in THF (20 mL) at ꢀ15 ꢁC
was added n-butyllithium (24.0 mmol) dropwise. The mix-
ture was warmed to room temperature and stirred for 2 h.
The solution was cooled at ꢀ45 ꢁC and a solution of iodine
(23.7 mmol) in THF (10 mL) added. The reaction mixture
was stirred at 20 ꢁC for 2 h. The solution was concentrated
in vacuo and the residue extracted with diethyl ether. The or-
ganic layer was washed with 20% sodium thiosulfate solu-
tion (3ꢂ35 mL), saturated sodium bicarbonate solution
(3ꢂ35 mL), dried over MgSO4 and concentrated in vacuo.
The resultant residue was purified by flash column chroma-
tography using hexane–ethyl acetate (90:10) as eluent to
afford 3-methoxy-2-(methoxymethoxy)-1-iodobenzene 28
(1.915 g, 30%) as a tan oil. HRMS (EI): Found M+,
293.97546, C9H11IO3 requires 293.97530. nmax (film)/
cmꢀ1: 2960, 2938, 1569, 1580, 1464, 1434, 1290, 1259,
1157, 1030, 948, 828, 766, 735. dH (300 MHz, CDCl3):
3.67 (3H, s, OCH2OMe), 3.83 (3H, s, OMe), 5.16 (2H, s,
OCH2O), 6.79 (1H, t, J5,4¼J5,6 8.0 Hz, H-5), 6.88 (1H, dd,
J4,6 1.3 and J4,5 8.2 Hz, H-4), 7.37 (1H, dd, J6,4 1.5 and
J6,5 7.9 Hz, H-6). dC (75 MHz, CDCl3): 55.9 (CH3, OMe),
58.3 (CH3, OCH2OCH3), 92.6 (quat., C-1), 98.7 (CH2,
OCH2O), 112.8 (CH, C-4), 125.9 (CH, C-5), 131.0 (CH,
C-6), 145.9 (quat., C-3), 152.4 (quat., C-2); m/z (EI, %):
294 (M+, 20), 264 (M+ꢀ30, 7), 249 (M+ꢀCH2OCH3, 7),
167 (M+ꢀI, 21), 107 (6), 94 (4), 51 (7), 45 (100).
3.12. Standard procedure for pyrolysis of the tertiary
alcohols
A mixture of the alcohol (0.38 mmol) and solid sodium
hydroxide (1.92 mmol) in dry toluene (10 mL) was heated
under reflux for 3.5 h. The reaction was quenched by the
addition of saturated ammonium chloride solution (4 mL)
and extracted with diethyl ether (10 mL). The solvents
were removed under reduced pressure and the resultant
residue purified by flash column chromatography.
3.12.1. 1-Ethynyl-2-(methoxymethoxy)benzene 21. Yel-
low oil. HRMS (EI): Found M+, 162.06773, C10H10O2 re-
quires 162.06812. nmax (film)/cmꢀ1: 3282 (C–H, alkyne),
2107 (C^C), 1488 (OCH2O), 1238 (C–O). dH (300 MHz,
CDCl3): 3.20 (1H, s, H-20), 3.44 (3H, s, OMe), 5.18 (2H,
s, OCH2O), 6.88 (1H, dt, J5,3 1.0 and J5,4¼J5,6 7.6 Hz, H-
5), 7.04 (1H, dd, J3,5 1.0 and J3,4 8.4 Hz, H-3), 7.18–7.24
(1H, m, H-4), 7.38 (1H, J6,4 1.7 and J6,5 7.6 Hz, H-6). dC
(75 MHz, CDCl3): 56.2 (CH3, OMe), 80.0 (CH, C-20),
81.0 (quat., C-10), 94.9 (CH2, OCH2O), 112.5 (quat., C-1),
115.0 (CH, C-3), 121.7 (CH, C-5), 130.1 (CH, C-4), 134.1
(CH, C-6), 158.3 (quat., C-2); m/z (EI, %): 162 (M+, 11),
147 (1), 132 (19), 131 (34), 89 (8).
3.11. Standard procedure for Sonogashira couplings
A mixture of protected iodophenol (1.2 mmol), 2-methyl-
3-butyn-2-ol (1.6 mmol), triphenylphosphine (0.02 mmol)
and
bis(triphenylphosphine)palladium(II)
dichloride
(0.01 mmol) in dry triethylamine (3 mL) was heated at
80 ꢁC for 15 min. Copper(I) iodide (0.02 mmol) was added
and the reaction mixture was kept at 80 ꢁC overnight. The
reaction mixture was cooled, filtered through CeliteÒ and
concentrated in vacuo and purified by flash column chroma-
tography.
3.12.2. 1-Ethynyl-3-methoxy-2-(methoxymethoxy)benz-
ene 22. Brown oil. HRMS (EI): Found M+, 192.07864,
C11H12O3 requires 192.07801. nmax (film)/cmꢀ1: 3075 (s,
C–H, aromatic), 2999, 2961, 2936, 2901, 2839 (m, CH),
2268 (s, C^C), 1596, 1574, 1509, 1469, 1438 (m, C]C,
aromatic), 1306, 1266, 1230, 1200, 1183, 1157, 1132, 1073
(s, C–O). dH (300 MHz, CDCl3): 3.25 (1H, s, C^CH), 3.64
(3H, s, OCH2OCH3), 3.84 (3H, s, OMe), 5.23 (2H, s,
OCH2OMe), 6.91 (1H, dd, J4,6 1.8 and J4,5 7.9 Hz, H-4),
7.00 (1H, t, J5,4¼J5,6 7.9 Hz, H-5), 7.06 (1H, dd, J6,4 1.8
and J6,5 7.9 Hz, H-6). dC (75 MHz, CDCl3): 55.9 (CH3,
OMe), 57.5 (CH3, OCH2OCH3), 80.1 (quat., C-10), 81.1
(CH, C-20), 98.5 (CH2, OCH2O), 113.4 (CH, C-4), 117.3
(quat., C-1), 124.1 (CH, C-6), 125.7 (CH, C-5), 147.6
(quat., C-3), 152.4 (quat., C-2); m/z (EI, %): 192 (M+, 5),
191 (M+ꢀH, 6), 162 (30), 161 (MꢀOMe, 22), 147 (6), 131
(MꢀOMOM, 11), 119 (8), 91 (7), 76 (7), 45 (100).
3.11.1. 4-(2-Methoxymethoxyphenyl)-2-methyl-3-butyn-
2-ol 37. Tan oil. HRMS (EI): Found M+, 220.10958,
C13H16O3 requires 220.10994. nmax (film)/cmꢀ1: 3400 (br,
O–H), 2230 (C^C), 1490 (OCH2O), 1230 (C–O). dH
(300 MHz, CDCl3): 1.63 (6H, s, CMe2OH), 2.47 (1H, br s,
OH), 3.53 (3H, s, OMe), 5.23 (2H, s, OCH2O), 6.94 (1H,
dt, J5 ,3 1.0 and J5 ,4 ¼J5 ,6 7.7 Hz, H-50), 7.07 (1H, dd,
0
0
0
0
0
0
J3 ,5 1.0 and J3 ,4 8.3 Hz, H-30), 7.19–7.27 (1H, m, H-40),
0
0
0
0
7.38 (1H, dd, J6 ,4 1.7 and J6 ,5 7.7 Hz, H-60). dC
(75 MHz, CDCl3): 31.5 (CH3, CMe2OH), 56.2 (CH3,
OMe), 65.6 (quat., C-2), 78.3 (quat., C-4), 95.1 (quat.,
C-3), 97.9 (CH2, OCH2O), 113.5 (quat., C-10), 115.6 (CH,
C-30), 121.9 (CH, C-50), 129.5 (CH, C-40), 133.5 (CH,
C-60), 157.6 (quat., C-20); m/z (EI, %): 220 (M+, 0.5), 158
(M+ꢀOMOM, 100), 143 (18).
0
0
0
0
3.13. Standard procedure for union of acetylenes with
aryl aldehydes
3.11.2. 4-(3-Methoxy-2-(methoxymethoxy)phenyl)-2-
methyl-but-3-yn-2-ol 38. Tan oil. HRMS (EI): Found M+,
250.12083, C14H18O4 requires 250.12051. nmax (film)/
n-Butyllithium (1.50 mmol) was added dropwise to a stirred
solution of the acetylene (1.50 mmol) in tetrahydrofuran
(2 mL) at ꢀ78 ꢁC under nitrogen. The solution was stirred

K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
6027
at ꢀ78 ꢁC for 30 min, then a solution of the aldehyde
(1.26 mmol) in tetrahydrofuran (0.5 mL) was added drop-
wise and the mixture stirred for 1 h. The mixture was al-
lowed to warm to room temperature and stirred for 2.5 h.
Water (3 mL) was added and the mixture extracted with
ethyl acetate (3ꢂ2 mL). The combined organic extracts
were washed with brine (1 mL), dried over magnesium
sulfate and concentrated in vacuo. The resultant residue
was purified by flash chromatography.
402.16728, C22H26O7 requires 402.16785. nmax (film)/
cmꢀ1: 3435 (s, br, O–H), 2936, 2838 (s, C–H, aromatic),
2225 (C^C), 1735, 1574 (s, C]C, aromatic), 1510, 1472
(s, OCH2O), 1266 (s, C–O), 1157, 1075. dH (300 MHz,
CDCl3): 3.09 (1H, s, OH), 3.18 (1H, dd, J1A,2 5.7 and Jgem
13.6 Hz, H-1A), 3.27 (1H, dd, J1B,2 7.9 and Jgem 13.6 Hz,
H-1B), 3.60 (3H, s, OCH2OCH3), 3.61 (3H, s, OCH2OCH3),
3.80 (3H, s, OMe), 3.82 (3H, s, OMe), 4.89 (1H, dd, J2,1A 5.7
and J2,1B 7.9 Hz, H-2), 5.11–5.14 (2H, m, OCH2O), 5.15
(2H, s, OCH2O), 6.76–6.89 (2H, m, Ar-H), 6.92–7.06 (4H,
m, Ar-H). dC (75 MHz, CDCl3): 38.6 (CH2, CH2CHO,
C-1), 55.6 (CH3, OMe), 55.8 (CH3, OMe), 57.3 (CH3
2ꢂOCH2OCH3), 63.1 (CH, C-2), 81.2 (quat., C-4), 94.3
(quat., C-3), 98.5 (CH2, OCH2O), 99.1 (CH2, OCH2O),
111.0 (CH, Ar-C), 112.8 (CH, Ar-C), 117.8 (quat., C-100),
123.1 (CH, Ar-C), 123.9 (CH, Ar-C), 124.3 (CH, Ar-C),
125.2 (CH, Ar-C), 131.1 (quat., C-10), 145.0 (quat., C-30 or
C-300), 147.0 (quat., C-300 or C-30), 151.9 (quat., C-20 or
C-200), 152.5 (quat., C-200 or C-20); m/z (EI, %): 402 (M+,
0.4), 372 (0.6), 357 (0.5), 326 (2.9), 325 (3), 308 (8), 307
(5), 296 (35), 265 (6), 161 (17), 137 (16), 45 (100).
3.13.1. 1-(3-Methoxy-2-methoxymethoxyphenyl)-4-(2-
methoxymethoxyphenyl)but-3-yn-2-ol 17. Pale yellow
oil. HRMS (EI): Found M+, 372.15690, C21H24O6 requires
372.15729. nmax (film)/cmꢀ1: 3433 (br, s, OH), 3070
(C–H, aromatic), 2937, 2837 (s, CH), 2229 (C^C), 1597,
1585 (ArC]C), 1488 (OCH2O), 1079, 1049 (C–O). dH
(300 MHz, CDCl3): 2.86 (1H, br s, OH), 3.21 (1H, dd,
J1A,2 5.5 and Jgem 13.6 Hz, H-1A), 3.29 (1H, dd, J1B,2 8.0
and Jgem 13.6 Hz, H-1B), 3.51 (3H, s, 200-OCH2OCH3),
3.64 (3H, s, 20-OCH2OCH3), 3.87 (3H, s, OMe), 4.90–4.94
(1H, m, H-2), 5.13 (1H, d, Jgem 10.9 Hz, OCHAHBO), 5.15
(1H, d, Jgem 10.8 Hz, OCHAHBO), 5.22 (2H, s, OCH2O),
6.84 (1H, dd, J4 ,6 1.7 and J4 ,5 7.9 Hz, H-40), 6.92–6.99
3.13.4. 4-(3-Methoxy-2-(methoxymethoxy)phenyl)-1-(5-
methoxy-2-(methoxymethoxy)phenyl)but-3-yn-2-ol 20.
Yellow oil. HRMS (EI): Found M+, 402.16755, C22H26O7
requires 402.16785. nmax (film)/cmꢀ1: 3450 (s, br, O–H),
2936, 2837 (s, C–H, aromatic), 2228 (s, C^C), 1594,
1574 (s, C]C, aromatic), 1500, 1470 (s, OCH2O), 1261
(s, C–O), 1222, 1197. dH (300 MHz, CDCl3): 3.12 (1H, d,
J1A,2 7.0 Hz, H-1A), 3.13 (1H, d, J1B,2 6.5 Hz, H-1B), 3.44
(3H, s, OCH2OCH3), 3.56 (3H, s, OCH2OCH3), 3.69 (1H,
s, OH), 3.71 (3H, s, OMe), 3.79 (3H, s, OMe), 4.87 (1H,
dd, J2,1A 7.0 and J2,1B 6.5 Hz, H-2), 5.11 (2H, s, OCH2O),
0
0
0
0
(2H, m, H-500 and H-60), 7.05 (1H, t, J5 ,4 ¼J5 ,6 7.8 Hz, H-
0
0
0
0
50), 7.07–7.11 (1H, dd, J3 ,5 0.9 and J3 ,4 7.9 Hz, H-300),
00 00
00 00
7.24 (1H, td, J4 ,6 1.7 and J4 ,3 ¼J4 ,5 7.9 Hz, H-400),
00 00
00 00
00 00
7.38 (1H, dd, J6 ,4 1.7 and J6 ,5 7.6 Hz, H-600). dC
(75 MHz, CDCl3): 38.7 (CH2, C-1), 55.7 (CH3, OMe),
56.2 (CH3, 200-OCH2OCH3), 57.4 (CH3, 20-OCH2OCH3),
63.2 (CH, C-2), 81.0 (quat., C-4), 94.2 (quat., C-3), 94.9
(CH2, 200-OCH2O), 99.1 (CH2, 20-OCH2O), 111.0 (CH,
C-40), 113.4 (quat., C-100), 115.2 (CH, C-300), 121.7 (CH,
C-500), 123.1 (CH, C-60), 124.2 (CH, C-50), 129.5 (CH, C-
400), 131.3 (quat., C-10), 133.6 (CH, C-600), 145.1 (quat.,
C-20), 152.0 (quat., C-30), 157.7 (quat., C-200); m/z (EI, %):
372 (M+, 0.1), 310 (9), 277 (9), 266 (8), 205 (8), 150 (11),
137 (18), 45 (100).
00 00
00 00
00 00
00 00
5.15 (2H, s, OCH2O), 6.71 (1H, dd, J4 ,6 3.1 and J4 ,3
00 00
8.9 Hz, H-400), 6.83–6.87 (1H, m, H-50), 6.87 (1H, J6 ,3
3.1 Hz, H-600), 6.94–6.95 (2H, m, H-40 and H-60), 7.01
(1H, d, 1H, J3 ,4 8.9 Hz, H-300). dC (75 MHz, CDCl3):
00 00
39.0 (CH2, C-1), 55.3 (CH3, OMe), 55.6 (CH3, OMe), 55.7
(CH3, OCH2OCH3), 57.1 (CH3, OCH2OCH3), 62.5 (CH,
C-2), 81.2 (quat., C-4), 94.1 (quat., C-3), 95.1 (CH2,
OCH2O), 98.2 (CH2, OCH2O), 112.7 (CH, C-400), 112.8
(CH, C-40)0, 115.3 (CH, C-600), 117.1 (CH, C-300), 117.6
(quat., C-1 ), 123.8 (CH, C-50), 125.0 (CH, C-60), 127.2
(quat., C-100), 146.8 (quat., C-30), 149.4 (quat., C-500),
152.3 (quat., C-20), 154.1 (quat., C-200); m/z (EI, %): 402
(M+, 2), 372 (1), 340 (5), 308 (8), 296 (15), 281 (3), 267
(6), 210 (7), 178 (9), 161 (11), 137 (12), 45 (100).
3.13.2. 1-(5-Methoxy-2-(methoxymethoxy)phenyl)-4-(2-
(methoxymethoxy)phenyl)but-3-yn-2-ol 18. Yellow oil.
HRMS (EI): Found M+, 372.15750, C21H24O6 requires
372.15729. nmax (film)/cmꢀ1: 3432 (br, s, OH), 2955,
2934, 2830 (s, CH), 2229 (C^C), 1596, 1575 (ArC]C),
1499 (OCH2O), 1280, 1254, 1222 (C–O). dH (300 MHz,
CDCl3): 2.96 (1H, br s, OH), 3.09–3.22 (2H, m, H-1), 3.46
(6H, s, OCH2OCH3ꢂ2), 3.71 (3H, s, OMe), 4.91–4.93
(1H, m, H-2), 5.12 (2H, s, OCH2O), 5.18 (2H, s, OCH2O),
6.72 (1H, dd, J4 ,6 3.0 and J4 ,3 8.8 Hz, H-40), 6.90–6.94
0
0
0
0
(2H, m, H-30 and H-60), 7.01–7.09 (2H, m, H-300 and H-
3.13.5. 1-(2-Methoxymethoxy-naphthalen-1-yl)-4-(2-
methoxymethoxyphenyl)but-3-yn-2-ol 67. Yellow oil.
HRMS (EI): Found M+, 392.16275, C24H24O5 requires
392.16237. nmax (film)/cmꢀ1: 2958, 2252, 1730, 1625,
1596, 1514, 1490, 1470, 1374, 1242, 1197, 1152, 1114,
1081, 1048, 1019, 910, 810, 738. dH (300 MHz, CDCl3):
2.96 (1H, br s, OH), 3.40 (3H, s, OCH2OCH3), 3.47 (3H,
s, OCH2OCH3), 3.64–3.77 (1H, m, H-1), 5.01–5.05 (1H,
m, H-2), 5.09 (1H, s, 20-OCH2O), 5.25 (2H, s, 200-
500), 7.20–7.25 (1H, m, H-400), 7.35 (1H, d, J6 ,5 7.6 Hz,
00 00
H-600). dC (75 MHz, CDCl3): 39.1 (CH2, C-1), 55.4 (CH3,
OMe), 55.9 (CH3, OCH2OCH3), 56.0 (CH3, OCH2OCH3),
62.8 (CH, C-2), 81.3 (quat., C-4), 94.0 (quat., C-3), 94.9
(CH2, OCH2O), 95.2 (CH2, OCH2O), 112.5 (CH, C-40),
113.2 (quat., C-100), 115.2 (CH, C-300), 115.4 (CH, C-600),
117.5 (CH, C-30), 121.7 (CH, C-500), 127.4 (quat., C-10),
129.5 (CH, C-400), 133.5 (CH, C-600), 149.6 (quat., C-20),
154.2 (quat., C-50), 157.7 (quat., C-200); m/z (EI, %): 372
(M+, 3), 310 (M+ꢀMOMOH, 11), 278 (14), 266 (10), 166
(13), 137 (19), 131 (13), 45 (100).
00 00
00 00
00 00
OCH2O), 6.86 (1H, dt, J5 ,3 1.0, J5 ,6 ¼J5 ,4 7.4 Hz, H-
500), 7.03 (1H, d, J3 ,4 8.0 Hz, H-300), 7.16 (1H, d, J6 ,5
00 00
00 00
7.4 Hz, H-600), 7.15–7.21 (1H, m, H-400), 7.32 (1H, dt, J6 ,8
0
0
1.0, J6 ,7 ¼J6 ,5 7.5 Hz, H-60), 7.41 (1H, d, J3 ,4 9.0 Hz, H-
0
0
0
0
0
0
0 0
3.13.3. 1,4-Bis-(3-methoxy-2-(methoxymethoxy)phenyl)-
but-3-yn-2-ol 19. Yellow oil. HRMS (EI): Found M+,
30), 7.41–7.46 (1H, m, H-70), 7.71 (1H, d, J4 ,3 9.0 Hz, H-
40), 7.76 (1H, d, J5 ,6 7.5 Hz, H-50), 8.13 (1H, d, J8 ,7
0
0
0
0

6028
K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
8.5 Hz, H-80). dC (75 MHz, CDCl3): 33.7 (CH2, C-1), 56.0
(CH3, 2ꢂOMe), 62.9 (CH, C-2), 81.0 (quat., C-4), 94.3
(quat., C-3), 94.8 (CH2, 200-OCH2OCH3), 95.1 (CH2, 20-
OCH2OCH3), 113.2 (quat., C-10), 115.2 (CH, C-300), 115.8
(CH, C-30), 119.4 (quat., C-100), 121.6 (CH, C-500), 123.6
(CH, C-50 or C-80), 123.7 (CH, C-80 or C-50), 126.2 (CH,
C-60), 128.3 (CH, C-70), 128.6 (CH, C-600), 129.4 (CH, C-
40), 129.8 (quat., C-40a), 133.4 (quat., C-80a), 133.5 (CH,
C-400), 153.2 (quat., C-20), 157.6 (quat., C-200); m/z (EI, %):
392 (M+, 2), 330 (4), 315 (3), 297 (5), 285 (4), 202 (21),
171 (10), 157 (17), 131 (9), 45 (100).
(quat., C-80a), 129.6 (CH, C-400), 133.6 (CH, C-600), 152.0
(quat., C-10), 155.7 (quat., C-50), 157.8 (quat., C-200); m/z
(EI, %): 422 (M+, 3), 392 (3), 360 (M+ꢀMOMOH, 15),
328 (16), 260 (8), 228 (9), 216 (11), 199 (10), 187 (24),
131 (9), 115 (8), 45 (100).
3.13.8. 1-[4,8-Dimethoxy-1-(methoxymethoxy)naphtha-
len-2-yl]-4-(2-(methoxymethoxy)phenyl)but-3-yn-2-ol
74. Yellow oil. HRMS (EI): Found M+, 452.18381,
C26H28O7 requires 452.18350. nmax (film)/cmꢀ1: 3435 (s,
OH), 3054, 2987 (s, C–H, aromatic), 2685, 2521, 2410,
2305 (C–H, alkane), 2126 (C^C, alkyne), 1421 (C–H
alkane), 1265 (s, C–O), 742. dH (400 MHz, CDCl3): 3.31
(1H, dd, J1A,2 5.2 and Jgem 13.6 Hz, H-1A), 3.44 (3H, s,
OCH2OCH3), 3.55 (1H, dd, J1B,2 8.7 and Jgem 13.6 Hz, H-
1B), 3.63 (1H, d, J 6.3 Hz, OH), 3.71 (3H, s, OCH2OCH3),
3.89 (3H, s, OMe), 3.93 (3H, s, OMe), 5.01–5.04 (1H, m,
H-2), 5.07 (1H, d, Jgem 16.6 Hz, OCHAHBO), 5.08 (1H, d,
Jgem 16.6 Hz, OCHAHBO), 5.16 (2H, s, OCH2O), 6.82
3.13.6. 4-(3-Methoxy-2-methoxymethoxyphenyl)-1-(2-
methoxymethoxy-naphthalen-1-yl)but-3-yn-2-ol 68.
Yellow oil. HRMS (EI): Found M+, 422.17327, C25H26O6
requires 422.17294. nmax (film)/cmꢀ1: 3454 (s, br, OH),
2936, 2840, 1736, 1625, 1595, 1574, 1470, 1438, 1373,
1261, 1242, 1261, 1185, 1151, 1047. dH (400 MHz,
CDCl3): 2.84 (1H, br s, OH), 3.50 (3H, s, 20-OCH2OCH3),
3.53 (3H, s, 200-OCH2OCH3), 3.64–3.74 (1H, m, H-1), 3.78
(3H, s, 30-OMe), 5.00–5.02 (1H, m, H-2), 5.09 (2H, s, 20-
OCH2O), 5.28 (2H, s, 200-OCH2O), 6.80–6.83 (2H, m, H-40
(1H, s, H-30), 6.88 (1H, d, J7 ,6 8.1 Hz, H-70), 6.91 (1H, dt,
0
0
J5 ,3 0.7, J5 ,6 ¼J5 ,4 7.5 Hz, H-500), 7.07 (1H, d, J3 ,4
00 00
00 00
00 00
00 00
8.4 Hz, H-300), 7.23 (1H, dt, J4 ,6 1.6, J4 ,5 7.5, J4 ,3
00 00
00 00
00 00
and H-50), 6.92 (1H, d, J6 ,5 7.9 Hz, H-60), 7.34 (1H, t,
8.4 Hz, H-400), 7.33 (1H, t, J6 ,7 ¼J6 ,5 8.1 Hz, H-60), 7.38
0
0
0
0
0
0
J6 ,7 ¼J6 ,5 7.8 Hz, H-600), 7.42 (1H, d, J3 ,4 9.0 Hz, H-
(1H, dd, J6 ,4 1.6 and J6 ,5 7.6 Hz, H-600), 7.85 (1H, d,
00 00
00 00
00 00
00 00
00 00
300), 7.46 (1H, t, J7 ,6 ¼J7 ,8 7.8 Hz, H-700), 7.42 (1H, d,
J5 ,6 8.1 Hz, H-50). dC (100 MHz, CDCl3): 39.2 (CH2, C-
1), 55.5 (CH3, OMe), 56.0 (CH3, OMe), 56.0 (CH3,
OCH2OCH3), 57.1 (CH3, OCH2OCH3), 63.2 (CH, C-2),
80.8 (quat., C-4), 94.8 (quat., C-3), 94.9 (CH2, OCH2O),
101.4 (CH2, OCH2O), 106.8 (CH, C-70), 107.0 (CH, C-50),
113.4 (quat., C-100), 115.0 (CH, C-300), 115.2 (CH, C-30),
120.1 (quat., C-20), 121.7 (CH, C-500), 125.1 (CH, C-60),
126.7 (quat., C-80a), 128.1 (quat., C-40a), 129.5 (CH, C-
400), 133.5 (CH, C-600), 145.1 (quat., C-80), 151.5 (quat.,
C-40), 155.1 (quat., C-10), 157.7 (CH, C-200); m/z (EI, %):
452 (M+, 23), 390 (M+ꢀOMOM, 20), 375 (8), 358 (7),
343 (13), 217 (100), 201 (14), 69 (21), 57 (34), 45 (82).
00 00
00 00
0
0
J4 ,3 9.0 Hz, H-400), 7.77 (1H, d, J5 ,6 7.8 Hz, H-500), 8.10
00 00
00 00
(1H, d, J8 ,7 7.8 Hz, H-800). dC (100 MHz, CDCl3): 33.7
00 00
(CH2, C-1), 55.7 (CH3, 200-OCH2OMe), 56.1 (CH3, 20-
OCH2OMe), 57.3 (CH3, OMe), 63.0 (CH, C-2), 81.2
(quat., C-4), 94.3 (quat., C-3), 95.2 (CH2, 20-OCH2O),
98.4 (CH2, 200-OCH2O), 112.8 (CH, C-40), 115.8 (CH,
C-300), 117.7 (quat., C-100), 119.3 (quat., C-10), 123.6 (CH,
C-60), 123.7 (CH, C-800 or C-600), 123.9 (CH, C-600 or C-800),
125.1 (CH, C-50), 126.4 (CH, C-700), 128.4 (CH, C-400),
128.8 (CH, C-500), 129.8 (quat., C-400a), 133.4 (quat., C-800a),
146.9 (quat., C-20), 152.4 (quat., C-30), 153.2 (quat., C-200);
m/z (EI, %): 422 (M+, 1), 392 (1), 360 (7), 328 (7), 316
(8), 202 (15), 157 (16), 77 (1), 45 (100).
3.14. Standard procedure for hydrogenation
of acetylenes
3.13.7. 1-(5-Methoxy-1-(methoxymethoxy)naphthalen-2-
yl)-4-(2-(methoxymethoxy)phenyl)but-3-yn-2-ol 73. Tan
oil. HRMS (EI): Found M+, 422.17338, C25H26O6 requires
422.17294. nmax (film)/cmꢀ1: 3428 (s, br, OH), 2997,
2956, 2934, 2850, 2247 (s, C^C), 1598, 1577 (s, C]C, aro-
matic), 1506, 1490, 1449, 1415, 1378, 1258, 1155, 1051 (s,
C–O). dH (400 MHz, CDCl3): 3.18 (br s, OH), 3.34 (1H, dd,
J1A,2 5.7 and Jgem 13.6 Hz, H-1A), 3.45 (3H, s, OCH2OCH3),
3.47–3.52 (1H, m, H-1B), 3.72 (3H, s, OCH2OCH3), 3.96
(3H, s, OMe), 5.00 (1H, m, H-2), 5.16 (2H, s, OCH2O),
A mixture of the acetylene (80 mg, 0.17 mmol), 10% palla-
dium on carbon (67 mg, 0.63 mmol) and potassium bicar-
bonate (86 mg, 0.63 mmol) in ethyl acetate (2 mL) was
stirred under an atmosphere of hydrogen at room temperature
for 2 h. The resulting mixture was filtered through a plug of
CeliteÒ and the filtrate concentrated in vacuo. The resulting
residue was purified by flash column chromatography.
3.14.1. 1-(3-Methoxy-2-methoxymethoxyphenyl)-4-(2-
methoxymethoxyphenyl)butan-2-ol 39. Colourless solid.
Mp: 41–42 ꢁC. HRMS (EI): Found M+, 376.18842,
C21H28O6 requires 376.18859. nmax (film)/cmꢀ1: 3460 (br,
s, OH), 3064 (C–H, aromatic), 2998, 2836 (s, CH), 1600,
1585 (ArC]C), 1493 (OCH2O), 1070, 1049 (C–O), 753
(ArC–H). dH (400 MHz, CDCl3): 1.77–1.84 (2H, m, H-3),
2.58 (1H, br s, OH), 2.71–2.93 (4H, m, H-4 and H-1), 3.42
(3H, s, 200-OCH2OCH3), 3.53 (3H, s, 20-OCH2OCH3), 3.78
(3H, s, OMe), 5.07 (2H, m, 20-OCHAHBO), 5.15 (2H, s,
200-OCH2O), 6.75–6.80 (2H, m, H-40 and H-60), 6.90 (1H,
0
0
5.16–5.23 (2H, m, OCH2O), 6.79 (1H, d, J6 ,7 7.8 Hz, H-
00 00
60), 6.93 (1H, ddd, J5 ,3 0.8, J5 ,4 7.4 and J5 ,6 7.6 Hz,
00 00
00 00
H-500), 7.07 (1H, d, J3 ,4 7.7 Hz, H-300), 7.20–7.26 (1H, m,
00 00
H-400), 7.37 (1H, dd, J6 ,4 1.6 and J6 ,5 7.6 Hz, H-600),
00 00
00 00
7.39 (1H, dd, J7 ,6 7.8 and J7 ,8 8.4 Hz, H-70), 7.49 (1H, d,
0
0
0
0
J3 ,4 8.7 Hz, H-30), 7.58 (1H, d, J8 ,7 8.4 Hz, H-80), 8.03
0
0
0
0
(1H, d, J4 ,3 8.7 Hz, H-40). dC (100 MHz, CDCl3): 38.7
(CH2, C-1), 55.5 (CH3, OMe), 56.1 (CH3, OMe), 56.2
(CH3, OCH2OCH3), 57.5 (CH3, OCH2OCH3), 63.2 (CH,
C-2), 81.2 (quat., C-4), 94.2 (quat., C-3), 94.8 (CH2,
OCH2O), 100.3 (CH2, OCH2), 103.9 (CH, C-60), 113.2
(quat., C-100), 114.2 (CH, C-80), 115.1 (CH, C-500), 118.6
(CH, C-40), 121.7 (CH, C-300), 126.2 (CH, C-70), 126.3
(quat., C-20), 126.8 (quat., C-40a), 127.8 (CH, C-30), 129.3
0
0
t, J5 ,6 ¼J5 ,4 7.2 Hz, H-500), 6.97 (1H, t, J5 ,4 ¼J5 ,6
00 00
00 00
0
0
0
0
7.9 Hz, H-50), 7.03 (1H, dd, J3 ,4 8.1 Hz, H-300), 7.10–7.14
(1H, m, H-400), 7.15 (1H, d, J6 ,5 7.2 Hz, H-600). dC
(100 MHz, CDCl3): 26.5 (CH2, C-4), 37.6 (CH2, C-3),
00 00
00 00

K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
6029
38.1 (CH2, C-1), 55.5 (CH3, OMe), 55.8 (CH3, 200-
OCH2OCH3), 57.2 (CH3, 20-OCH2OCH3), 71.4 (CH, C-2),
94.2 (CH2, 200-OCH2O), 98.9 (CH2, 20-OCH2O), 110.4
(CH, C-40 or C-60), 113.7 (CH, C-300), 121.5 (CH, C-500),
122.8 (CH, C-60 or C-40), 124.0 (CH, C-50), 126.8 (CH, C-
400), 130.0 (CH, C-600), 131.0 (quat., C-100), 132.8 (quat.,
C-10), 144.6 (quat., C-20), 151.9 (quat., C-30), 154.9 (quat.,
C-200); m/z (EI, %): 376 (M+, 2), 344 (M+ꢀMeOH, 9), 314
(M+ꢀMOMOH, 9), 300 (2), 282 (10), 270 (4), 150 (28),
133 (22), 45 (100).
br, O–H), 3061, 2995, 2936, 2836 (s, C–H, aromatic),
1736, 1601, 1585 (s, C]C, aromatic), 1499, 1475 (s,
OCH2O), 1439, 1403, 1372, 1305, 1266 (s, C–O), 1221,
1196, 1152, 1119, 1073, 1045, 1005. dH (300 MHz,
CDCl3): 1.72–1.89 (2H, m, H-3), 2.46 (1H, br s, OH),
2.68–2.94 (4H, m, H-4 and H-1), 3.39 (3H, s, OCH2OCH3),
3.44–3.53 (1H, m, H-2), 3.57 (3H, s, OCH2OCH3), 3.73 (3H,
s, OMe), 3.81 (3H, s, OMe), 5.06 (2H, s, OCH2O), 5.08 (20H0 ,
00 00
00
00 00
s, OCH2O), 6.69 (1H, dd, J4 ,6 3.1 and J4 ,3 8.8 Hz, H0-4 ),
00 00
6.73 (1H, d, J6 ,4 3.1 Hz, H-6 ), 6.74–6.80 (2H, m, H-4 and
H-50), 6.96 (1H, d, J6 ,5 7.9 Hz, H-60), 6.98 (1H, d, J3 ,4
8.5 Hz, H-300). dC (75 MHz, CDCl3): 26.1 (CH2, C-4), 37.9
(CH2, C-3), 38.7 (CH2, C-1), 55.5 (CH3, OMe), 55.6 (CH3,
OMe), 55.8 (CH3, OCH2OCH3), 57.4 (CH3, OCH2OCH3),
70.9 (CH, C-2), 95.1 (CH2, OCH2O), 99.0 (CH2, OCH2O),
109.9 (CH, C-4000), 112.0 (CH, C-400), 115.4 (CH, C-600),
117.0 (CH, C-3 ), 122.0 (CH, C-50), 124.1 (CH, C-60),
129.3 (quat., C-100), 136.1 (quat., C-10), 144.2 (quat., C-30),
149.4 (quat., C-500), 152.0 (quat., C-20), 154.3 (quat., C-
200); m/z (EI, %): 402 (M+, 2), 374 (7), 344 (4), 342 (3),
330 (5), 300 (12), 298 (3), 175 (20), 163 (38), 150 (31),
137 (34), 57 (21), 45 (100).
0
0
00 00
3.14.2. 1-(5-Methoxy-2-(methoxymethoxy)phenyl)-4-(2-
(methoxymethoxy)phenyl)butan-2-ol 40. Pale yellow oil.
HRMS (EI): Found M+, 376.18807, C21H28O6 requires
376.18859. nmax (film)/cmꢀ1: 3452 (br, s, OH), 3062 (C–
H, aromatic), 2932, 2829, 2788 (s, CH), 1601, 1587
(ArC]C), 1495 (OCH2O), 1283, 1221, 1150, 1113, 1006
(C–O). dH (300 MHz, CDCl3): 1.76–1.84 (2H, m, H-3),
2.35 (1H, br s, OH), 2.71–2.89 (4H, m, H-4 and H-1), 3.39
(3H, s, OCH2OCH3), 3.43 (3H, s, OCH2OCH3), 3.73 (3H,
s, OMe), 3.83–3.88 (1H, m, H-2), 5.07 (2H, s, OCH2O),
0
0
0
0
5.17 (2H, s, OCH2O), 6.69 (1H, dd, J4 ,6 3.0 and J4 ,3
8.8 Hz, H-40), 6.74 (1H, d, J6 ,4 3.0 Hz, H-60), 6.89–6.94
(1H, m, H-30), 6.98–7.05 (2H, m, H-300 and H-500), 7.10–
7.24 (2H, m, H-400 and H-600). dC (75 MHz, CDCl3): 26.4
(CH2, C-4), 37.2 (CH2, C-3), 38.7 (CH2, C-1), 55.5 (CH3,
OMe), 55.9 (CH3, OCH2OCH3), 57.4 (CH3, OCH2OCH3),
71.1 (CH, C-2), 94.3 (CH2, OCH2O), 95.1 (CH2, OCH2O),
111.9 (CH, C-40), 113.9 (CH, C-300), 115.4 (CH, C-60),
117.1 (CH, C-30), 121.7 (CH, C-500), 127.0 (CH, C-400),
129.2 (quat., C-100), 130.1 (CH, C-600), 131.0 (quat., C-10),
149.4 (quat., C-20), 154.3 (quat., C-50), 155.0 (quat., C-200);
m/z (EI, %): 376 (M+, 6), 344 (11), 314 (17), 282 (8), 270
(5), 175 (11), 163 (18), 137 (18), 13 (18), 107 (12), 45 (100).
0
0
3.14.5. 1-(2-Methoxymethoxy-naphthalen-1-yl)-4-(2-
methoxymethoxyphenyl)butan-2-ol 69. Pale yellow oil.
HRMS (EI): Found M+, 396.19360, C24H28O5 requires
396.19367. nmax (film)/cmꢀ1: 2933, 2354, 2251, 1730,
1624, 1595, 1513, 1491, 1469, 1374, 1240, 1197, 1151,
1061, 1010, 909, 808, 649. dH (400 MHz, CDCl3): 1.88–
1.93 (2H, m, H-3), 2.35 (1H, br s, OH), 2.72–2.91 (2H, m,
H-4), 3.31–3.32 (2H, m, H-1), 3.32 (3H, s, OMe), 3.38
(3H, s, OMe), 3.99 (1H, m, H-2), 5.07 (2H, s, 20-OCH2O),
5.17 (1H, d, Jgem 9.6 Hz, 200-OCHAHBO), 5.19 (1H, d, Jgem
9.6 Hz, 200-OCHAHBO), 6.87 (1H, dt, J5 ,3 0.9 Hz,
00 00
J5 ,6 ¼J5 ,4 7.4 Hz, H-500), 6.99 (1H, d, J3 ,4 7.5 Hz, H-
00 00
00 00
00 00
3.14.3. 1,4-Bis-(3-methoxy-2-methoxymethoxyphenyl)-
butan-2-ol 41. Colourless oil. HRMS (EI): Found M+,
406.19883, C22H30O7 requires 406.19915. nmax (film)/
cmꢀ1: 3470 (br, s, OH), 2936, 2838 (C–H, aromatic),
1599, 1584 (s, C]C, aromatic), 1475 (s, OCH2O), 1439,
1402, 1307, 1267 (s, C–O). dH (300 MHz, CDCl3): 1.74–
1.88 (2H, m, H-3), 2.78–2.94 (4H, m, H-4 and H-1), 3.41–
3.50 (1H, m, H-2), 3.53 (3H, s, OCH2OCH3), 3.55 (3H, s,
OCH2OCH3), 3.77 (3H, s, OMe), 3.78 (3H, s, OMe), 3.86
(1H, br s, OH), 5.02–5.06 (2H, m, OCH2O), 5.06 (2H, s,
300), 7.06–7.13 (2H, m, H-400 and H-600), 7.30 (1H, t,
J6 ,7 ¼J6 ,5 7.8 Hz, H-60), 7.35 (1H, d, J3 ,4 9.0 Hz, H-30),
0
0
0
0
0
0
7.42 (1H, dt, J7 ,5 1.1, J7 ,6 ¼J7 ,8 7.8 Hz, H-70), 7.65 (1H,
0
0
0
0
0
0
d, J4 ,3 9.0 Hz, H-40), 7.73 (1H, d, J5 ,6 7.8 Hz, H-50), 7.98
0
0
0
0
(1H, d, J8 ,7 7.8 Hz, H-80). dC (100 MHz, CDCl3): 26.6
(CH2, C-4), 33.2 (CH2, C-3), 37.5 (CH2, C-1), 56.0
(2ꢂCH3, OMe), 71.6 (CH, C-2), 94.1 (CH2, 200-OCH2O),
94.8 (CH2, 20-OCH2O), 113.7 (CH, C-300), 115.6 (CH, C-
30), 121.1 (quat., C-10), 121.5 (CH, C-500), 123.5 (CH, C-50
or C-80), 123.6 (CH, C-80 or C-50), 126.2 (CH, C-60), 126.8
(CH, C-70), 128.0 (CH, C-600), 128.3 (CH, C-40), 129.7
(quat., C-100), 130.0 (CH, C-400), 131.0 (quat., C-40a), 133.4
(quat., C-80a), 152.6 (quat., C-20), 154.9 (quat., C-200); m/z
(EI, %): 396 (M+, 6), 364 (6), 334 (8), 289 (4), 202 (20),
195 (9), 183 (5), 181 (6), 170 (38), 157 (34), 133 (26), 129
(8), 121 (9), 45 (100).
0
0
0
0
0
0
OCH2O), 6.71–6.84 (4H, m, Ar-H), 6.95 (1H, t, J5 ,4 ¼J5 ,6
7.9 Hz, H-50), 6.97 (1H, t, J5 ,4 ¼J5 ,6 7.9 Hz, H-500). dC
(75 MHz, CDCl3): 26.3 (CH2, C-4), 38.2 (CH2, C-3), 38.3
(CH2, C-1), 55.6 (CH3, OMe), 55.6 (CH3, OMe), 57.4
(CH3, OCH2OCH3), 57.4 (CH3, OCH2OCH3), 71.5 (CH,
C-2), 99.0 (CH2, OCH2O), 99.1 (CH2, OCH2O), 110.0
(CH, Ar-C), 110.6 (CH, Ar-C), 118.7 (quat., C-100), 122.1
(CH, Ar-C), 122.9 (CH, Ar-C), 124.1 (CH, Ar-C),
124.2 (CH, Ar-C), 133.0 (quat., Ar-C), 136.3 (quat.,
Ar-C), 144.2 (quat., Ar-C), 144.7 (quat., Ar-C), 152.1
(quat., Ar-C); m/z (EI, %): 406 (M+, 0.1), 374 (M+ꢀMeOH,
4), 342 (5), 330 (8), 312 (12), 300 (14), 175 (19), 163 (47),
137 (35), 45 (100).
00 00
00 00
3.14.6. 4-(3-Methoxy-2-methoxymethoxyphenyl)-1-(2-
methoxymethoxy-naphthalen-1-yl)butan-2-ol 70. Pale
yellow oil. HRMS (EI): Found M+, 426.20424, C25H30O6 re-
quires 426.20424. nmax (film)/cmꢀ1: 3435 (s, br, OH), 2935,
2840, 2251, 1730, 1625, 1585, 1475, 1438, 1401, 1382,
1265, 1241, 1197, 1151, 1063, 1018, 909, 733. dH
(400 MHz, CDCl3): 1.90–1.96 (2H, m, H-3), 2.41 (1H, br
s, OH), 2.83–2.91 (2H, m, H-4), 3.30–3.33 (2H, m, H-1),
3.41 (3H, s, 20-OCH2OMe), 3.52 (3H, s, 200-OCH2OMe),
3.77 (3H, s, OMe), 3.96–3.99 (1H, m, H-2), 5.05 (2H, s,
20-OCH2O), 5.20 (1H, d, Jgem 9.8 Hz, 200-OCHAHBO), 5.22
3.14.4. 4-(3-Methoxy-2-(methoxymethoxy)phenyl)-1-(5-
methoxy-2-(methoxymethoxy)phenyl)butan-2-ol 42.
Pale yellow oil. HRMS (EI): Found M+, 406.19948,
C22H30O7 requires 406.19915. nmax (film)/cmꢀ1: 3466 (s,

6030
K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
(1H, d, Jgem 9.8 Hz, 200-OCHAHBO), 6.71–6.76 (2H, m, H-40
H-60), 7.85 (1H, d, J5 ,6 8.0 Hz, H-50). dC (100 MHz,
CDCl3): 26.6 (CH2, C-4), 38.2 (CH2, C-3), 38.7 (CH2, C-
1), 55.6 (CH3, OMe), 55.9 (CH3, OMe), 56.0 (CH3,
OCH2OCH3), 57.2 (CH3, OCH2OCH3), 71.9 (CH, C-2),
94.3 (CH2, OCH2OCH3), 101.4 (CH2, OCH2OCH3),
106.8 (CH, C-70), 107.0 (CH, C-50), 113.8 (CH, C-300),
114.9 (CH, C-30), 120.2 (quat., C-20), 121.6 (CH, C-500),
124.9 (CH, C-60), 126.9 (CH, C-400), 127.8 (quat., C-80a),
128.5 (quat., C-40a), 130.1 (CH, C-600), 131.2 (quat., C-100),
144.6 (quat., C-80), 151.5 (quat., C-40), 155.0 (quat., C-10),
155.1 (CH, C-200); m/z (EI, %): 456 (M+, 24), 424 (14),
394 (51), 350 (8), 243 (31), 217 (100), 45 (67).
0
0
0
and H-60), 6.93 (1H, t, J5 ,4 ¼J5 ,6 7.6 Hz, H-5 ), 7.32 (1H, t,
0
0
0
0
00
00
00 00
00 00
00 00
J6 ,7 ¼J6 ,5 7.6 Hz, H-6 ), 7.37 (1H, d, J3 ,4 9.0 Hz, H-3 ),
7.43 (1H, dt, J7 ,5 1.0 and J7 ,6 ¼J7 ,8 7.6 Hz, H-700), 7.060 8
00 00
00 00
00 00
00
00 00
(1H, d, J4 ,3 9.0 Hz, H-4 ), 7.74 (1H, d, J5 ,6 7.6 Hz, H-5 ),
00 00
00
00 00
8.00 (1H, d, J8 ,7 7.6 Hz, H-8 ). dC (100 MHz, CDCl3): 26.3
(CH2, C-4), 33.2 (CH2, C-1), 38.2 (CH2, C-3), 55.5 (CH3, 200-
OCH2OMe), 56.0 (CH3, 20-OCH2OMe), 57.3 (CH3, OMe),
71.6 (CH, C-2), 94.9 (CH2, 20-OCH2O), 98.9 (CH2, 200-
OCH2O), 109.9 (CH, C-40 or C-60), 115.7 (CH, C-300),
121.2 (quat., C-100), 121.9 (CH, C-60 or C-40), 123.6
(2ꢂCH, C-800 and C-600), 124.0 (CH, C-50), 126.2 (CH, C-
700), 128.1 (CH, C-400), 128.3 (CH, C-500), 129.8 (quat., C-
400a), 133.4 (quat., C-800a), 136.1 (quat., C-10), 144.1 (quat.,
C-20), 152.0 (quat., C-30), 152.7 (quat., C-200); m/z (EI, %):
426 (M+, 3), 394 (10), 364 (9), 322 (5), 320 (8), 246 (7),
201 (17), 181 (9), 170 (44), 163 (34), 157 (23), 151 (16),
137 (12), 128 (4), 45 (100).
3.15. Standard procedure for oxidation of secondary
alcohols to ketones
Tetra-n-propylammoniumperruthenate(0.3 mg, 0.008 mmol)
was added to a stirred mixture of the secondary alcohol
(74 mg, 0.16 mmol), 4-methylmorpholine N-oxide (3 mg,
˚
3.14.7. 1-(5-Methoxy-1-(methoxymethoxy)naphthalen-2-
yl)-4-(2-(methoxymethoxy)phenyl)butan-2-ol 75. Pale
yellow oil. HRMS (EI): Found M+, 426.20403, C25H30O6 re-
quires 426.20424. nmax (film)/cmꢀ1: 3435 (s, br, OH), 3054,
2986 (CH, aromatic), 1637, 1601, 1420, 1333, 1265, 1154,
1079, 1006 (s, C–O), 896, 739, 705. dH (400 MHz,
CDCl3): 1.78–1.90 (2H, m, H-3), 2.60 (1H, br s, OH),
2.74–2.90 (2H, m, H-4), 2.99–3.09 (2H, m, H-1), 3.39
(3H, s, OCH2OCH3), 3.64 (3H, s, OCH2OCH3), 3.95 (3H,
s, OMe), 3.95–3.98 (1H, m, H-2), 5.11–5.15 (4H, m,
0.24 mmol) and 4 A molecular sieves (45 mg) in dichloro-
methane (1 mL). The reaction was stirred at room tempera-
ture for 1.5 h, then filtered through a plug of silica gel and
the filtrate concentrated in vacuo. The resultant residue was
purified by flash column chromatography.
3.15.1. 1-(3-Methoxy-2-methoxymethoxyphenyl)-4-
(2-methoxymethoxyphenyl)butan-2-one 13. Colourless
solid. Mp: 65–68 ꢁC. HRMS (EI): Found M+, 374.17320,
C21H26O6 requires 374.17294. nmax (film)/cmꢀ1: 3054 (C–
H, aromatic), 2905, 2840 (s, CH), 1711 (C]O), 1601,
1585 (ArC]C), 1492 (OCH2O), 1077 (C–O). dH
(300 MHz, CDCl3): 2.72–2.79 (2H, m, H-4), 2.85–2.91
(2H, m, H-3), 3.42 (3H, s, 200-OCH2OCH3), 3.51 (3H, s,
20-OCH2OCH3), 3.76 (2H, s, H-1), 3.83 (3H, s, OMe),
5.06 (2H, s, 20-OCH2O), 5.15 (2H, s, 200-OCH2O), 6.72
2ꢂOCH2O), 6.77 (1H, d, J6 ,7 7.7 Hz, H-60), 6.92 (1H, dt,
0
0
J5 ,3 0.9, J5 ,4 ¼J5 ,6 7.3 Hz, H-500), 7.04 (1H, d, J3 ,4
00 00
00 00
00 00
00 00
7.6 Hz, H-300), 7.11–7.17 (2H, m, H-400 and H-600), 7.31
(1H, d, J3 ,4 8.6 Hz, H-30), 7.38 (1H, dd, J7 ,6 7.7 and J7 ,8
0
0
0
0
0
0
8.5 Hz, H-70), 7.58 (1H, d, J8 ,7 8.5 Hz, H-80), 7.99 (1H, d,
0
0
J4 ,3 8.6 Hz, H-40). dC (100 MHz, CDCl3): 26.6 (CH2, C-
4), 37.9 (CH2, C-3), 38.2 (CH2, C-1), 55.5 (CH3, OMe),
55.9 (CH3, OCH2OCH3), 57.5 (CH3, OCH2OCH3), 71.7
(CH, C-2), 94.3 (CH2, OCH2O), 100.3 (CH2, OCH2O),
103.7 (CH, C-60), 113.9 (CH, C-80), 114.3 (CH, C-500),
118.6 (CH, C-40), 121.7 (CH, C-300), 126.0 (quat., C-20),
126.2 (CH, C-70), 127.0 (CH, C-30), 127.8 (CH, C-400),
128.4 (quat., C-40a), 129.4 (quat., C-80a), 130.1 (CH, C-
600), 131.1 (quat., C-100), 151.5 (quat., C-10), 155.0 (quat.,
C-50), 155.7 (quat., C-200); m/z (EI, %): 426 (M+, 9), 394
(21), 364 (38), 332 (12), 225 (24), 213 (31), 211 (30), 187
(43), 133 (13), 107 (13), 45 (100).
0
0
(1H, dd, J4 ,6 1.4 and J4 ,5 7.6 Hz, H-40), 6.83 (1H, dd,
0
0
0
0
J6 ,4 1.4, J6 ,5 8.2 Hz, H-60), 6.89 (1H, dt, J5 ,3 1.4 and
0
0
0
0
00 00
J5 ,6 ¼J5 ,4 7.3 Hz, H-500), 6.97–7.03 (2H, m, H-300 and H-
50), 7.06–7.19 (2H, m, H-400 and H-600). dC (75 MHz,
CDCl3): 24.9 (CH2, C-4), 41.8 (CH2, C-1), 44.9 (CH2, C-
3), 55.7 (CH3, OMe), 55.9 (CH3, 200-OCH2OCH3), 57.5
(CH3, 20-OCH2OCH3), 94.2 (CH2, 200-OCH2O), 98.9
(CH2, 20-OCH2O), 111.4 (CH, C-40), 113.7 (CH, C-300),
121.6 (CH, C-500), 122.9 (CH, C-60), 124.3 (CH, C-50),
127.3 (CH, C-400), 129.1 (quat., C-100), 130.0 (quat., C-10),
130.2 (CH, C-600), 144.5 (quat., C-20), 152.2 (quat., C-30),
155.1 (quat., C-200), 208.1 (quat., C-2); m/z (EI, %): 374
(M+, 0.2), 342 (M+ꢀMeOH, 4), 297 (6), 280 (5), 268 (31),
161 (34), 150 (14), 107 (9), 45 (100).
00 00
00 00
3.14.8. 1-[4,8-Dimethoxy-1-(methoxymethoxy)naphtha-
len-2-yl]-4-[(2-methoxymethoxy)phenyl]butan-2-ol 76.
Pale yellow oil. HRMS (EI): Found M+, 456.21485,
C26H32O7 requires 456.21480. nmax (film)/cmꢀ1: 3435 (s,
br, OH), 3054, 2986 (CH, aromatic), 1637, 1601, 1420,
1333, 1265, 1154, 1079, 1006 (s, C–O), 896, 739, 705. dH
(400 MHz, CDCl3): 1.83–1.94 (2H, m, H-3), 2.76–2.94
(3H, m, H-2 and H-4), 3.01–3.12 (2H, m, H-1), 3.41 (3H,
s, OCH2OCH3), 3.60 (3H, s, OCH2OCH3), 3.91 (3H, s,
OMe), 3.92 (3H, s, OMe), 4.02 (1H, br s, OH), 5.01 (1H,
d, Jgem 17.7 Hz, OCHAHBO), 5.03 (1H, d, Jgem 17.7 Hz,
OCHAHBO), 5.16 (2H, s, OCH2O), 6.67 (1H, s, H-30), 6.87
3.15.2. 1-(5-Methoxy-2-(methoxymethoxy)phenyl)-4-(2-
(methoxymethoxy)phenyl)butan-2-one 14. Yellow oil.
HRMS (EI): Found M+, 374.17355, C21H26O6 requires
374.17294. nmax (film)/cmꢀ1: 2949, 2826 (s, CH), 1712
(C]O), 1588 (C]C, aromatic), 1496, 1455 (OCH2O),
1080 (C–O). dH (300 MHz, CDCl3): 2.76 (2H, t, J4,3
5.9 Hz, H-4), 2.90 (2H, t, J3,4 5.9 Hz, H-3), 3.39 (3H, s,
OCH2OCH3), 3.41 (3H, s, OCH2OCH3), 3.65 (2H, s, H-1),
3.72 (3H, s, OMe), 5.03 (2H, s, OCH2O), 5.14 (2H, s,
(1H, d, J7 ,6 8.0 Hz, H-70), 6.92 (1H, dd, J5 ,6 ¼J5 ,4
OCH2O), 6.67 (1H, d, J6 ,4 3.0 Hz, H-60), 6.72 (1H, dd,
0
0
00 00
00 00
0
0
7.4 Hz, H-500), 7.05 (1H, d, J3 ,4 8.0 Hz, H-300), 7.13 (1H,
J4 ,6 3.0 and J4 ,3 8.2 Hz, H-40), 6.89 (1H, td, J3 ,6 0.9 and
00 00
0
0
0
0
0
0
ddd, J4 ,6 1.5, J4 ,5 7.4 and J4 ,3 8.0 Hz, H-400), 7.18 (1H,
J3 ,4 8.2 Hz, H-30), 7.01 (1H, d, J3 ,4 8.9 Hz, H-300), 7.02
00 00
00 00
00 00
0
0
0
0
0
0
d, J6 ,5 7.4 Hz, H-600), 7.31 (1H, t, J6 ,7 ¼J6 ,5 8.0 Hz,
(1H, d, J5 ,4 ¼J5 ,6 7.8 Hz, H-500), 7.10–7.15 (2H, m,
00 00
0
0
0
0
00 00
00 00

K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
6031
H-400 and H-600). dC (75 MHz, CDCl3): 24.9 (CH2, C-4), 41.8
(CH2, C-1), 45.0 (CH2, C-3), 55.5 (CH3, OMe), 55.8 (CH3,
OCH2OCH3), 55.9 (CH3, OCH2OCH3), 94.1 (CH2,
OCH2O), 95.0 (CH2, OCH2O), 112.8 (CH, C-40), 113.7
(CH, C-300), 115.3 (CH, C-60), 116.9 (CH, C-30), 121.5
(CH, C-500), 125.4 (quat., C-10), 127.3 (CH, C-400), 129.9
(quat., C-10), 130.0 (CH, C-600), 149.2 (quat., C-20), 154.3
(quat., C-50), 155.0 (quat., C-200), 207.8 (quat., C-2); m/z
(EI, %): 374 (M+, 2), 342 (M+ꢀMeOH, 3), 280 (9), 268
(19), 161 (38), 150 (14), 45 (100).
394.17802. nmax (film)/cmꢀ1: 2929, 2320, 1710, 1625,
1596, 1512, 1492, 1470, 1404, 1235, 1198, 1151, 1079,
1037, 1013, 922, 810, 752. dH (400 MHz, CDCl3): 2.72
(2H, t, J4,3 7.6 Hz, H-4), 2.86 (2H, t, J3,4 7.6 Hz, H-3),
3.26 (3H, s, OMe), 3.44 (3H, s, OMe), 4.17 (2H, s, H-1),
5.02 (2H, s, 20-OCH2O), 5.23 (2H, s, 200-OCH2O), 6.83
(1H, t, J5 ,6 ¼J5 ,4 7.3 Hz, H-500), 6.96 (1H, d, J3 ,4
00 00
00 00
00 00
8.0 Hz, H-300), 7.04 (1H, dt, J4 ,6 1.5 and J4 ,3 ¼J4 ,5
00 00
00 00
00 00
7.3 Hz, H-400), 7.06–7.11 (1H, m, H-600), 7.34 (1H, t,
J6 ,7 ¼J6 ,5 7.4 Hz, H-60), 7.41 (1H, d, J3 ,4 9.1 Hz, H-30),
0
0
0
0
0
0
7.44 (1H, t, J7 ,8 ¼J7 ,6 7.8 Hz, H-70), 7.73 (1H, J4 ,3
0
0
0
0
0
0
9.1 Hz, H-40), 7.72–7.77 (2H, m, H-80 and H-50). dC
(100 MHz, CDCl3): 24.9 (CH2, C-4), 40.5 (CH2, C-1),
41.3 (CH2, C-3), 55.8 (CH3, OMe), 56.1 (CH3, OMe), 94.0
(CH2, 200-OCH2O), 94.9 (CH2, 20-OCH2O), 113.6 (CH,
C-300), 115.7 (CH, C-30), 117.3 (quat., C-10), 121.5 (CH,
C-500), 123.1 (CH, C-80 or C-40 or C-50), 123.8 (CH, C-60),
126.8 (CH, C-70), 127.2 (CH, C-600), 128.4 (CH, C-50 or
C-80 or C-40), 128.9 (CH, C-40 or C-50 or C-80), 129.6
(quat., C-40a or C-100), 129.9 (quat., C-100 or C-40a), 130.0
(CH, C-400), 133.2 (quat., C-80a), 152.6 (quat., C-20), 154.9
(quat., C-200), 208.7 (quat., C]O); m/z (EI, %): 394 (M+,
4), 300 (5), 288 (5), 201 (10), 181 (18), 170 (25), 45 (100).
3.15.3. 1,4-Bis-(3-methoxy-2-(methoxymethoxy)phenyl)-
butan-2-one 15. Yellow oil. HRMS (EI): Found M+,
404.18331, C22H28O7 requires 404.18350. nmax (film)/
cmꢀ1: 2937, 2902, 2839 (C–H, aromatic), 1712, 1599,
1585, 1476, 1439, 1403, 1361, 1306, 1266, 1223, 1157,
1069, 968, 781, 750. dH (300 MHz, CDCl3): 2.78 (2H, t,
J4,3 7.5 Hz, H-4), 2.94 (2H, t, J3,4 7.5 Hz, H-3), 3.51 (3H,
br s, OCH2OCH3), 3.52 (3H, br s, OCH2OCH3), 3.76 (2H,
s, H-1), 3.80 (3H, br s, OMe), 3.81 (3H, br s, OMe), 5.05
(4H, s, OCH2O), 6.72–6.76 (3H, m, Ar-H), 6.82 (1H, dd,
J4 ,6 1.2 and J4 ,5 8.2 Hz, H-40 or H-400), 6.92–7.02 (2H,
m, Ar-H). dC (75 MHz, CDCl3): 24.5 (CH2, C-4), 42.4
(CH2, C-1), 44.7 (CH2, C-3), 55.6 (CH3, OMe), 55.6 (CH3,
OMe), 57.3 (CH3, OCH2OCH3), 57.4 (CH3, OCH2OCH3),
98.8 (CH2, OCH2O), 98.8 (CH2, OCH2O), 110.2 (CH,
Ar-C), 111.3 (CH, Ar-C), 121.9 (CH, Ar-C), 122.9 (CH,
Ar-C), 124.0 (CH, Ar-C), 124.2 (CH, Ar-C), 129.0 (quat.,
C-10), 135.3 (quat., C-100), 144.2 (quat., C-30 or C-300),
144.4 (quat., C-300 or C-30), 152.0 (quat., C-20 or C-200),
152.1 (quat., C-200 or C-20), 207.7 (quat., C-2); m/z (EI,
%): 404 (M+, 0.1), 372 (M+ꢀMeOH, 1), 354 (0.2), 342
(2), 328 (2), 310 (9), 298 (52), 284 (8), 191 (7), 161 (30),
150 (12), 137 (48), 45 (100).
0
0
0
0
3.15.6. 4-(3-Methoxy-2-methoxymethoxyphenyl)-1-(2-
methoxymethoxy-naphthalen-1-yl)butan-2-one 72. Yel-
low oil. HRMS (EI): Found M+, 424.18843, C25H28O6
requires 424.18859. nmax (film)/cmꢀ1: 3067, 2934, 2842,
2252, 1708, 1625, 1597, 1585, 1475, 1438, 1264, 1243,
1198, 1155, 1067, 1039, 1018, 908, 731. dH (400 MHz,
CDCl3): 2.79 (2H, t, J4,3 7.6 Hz, H-4), 2.92 (2H, t, J3,4
7.6 Hz, H-3), 3.43 (3H, s, 20-OCH2OCH3), 3.44 (3H, s, 200-
OCH2OCH3), 3.75 (3H, s, OMe), 4.18 (2H, s, C-1), 5.00
(2H, s, 200-OCH2O), 5.24 (2H, s, 20-OCH2O), 6.66 (1H, d,
J4 ,5 7.8 Hz, H-40), 6.71 (1H, d, J6 ,5 7.8 Hz, H-60), 6.89
0
0
0
0
(1H, t, J5 ,4 ¼J5 ,6 7.8 Hz, H-50), 7.33 (1H, t, J6 ,7 ¼J6 ,5
7.5 Hz, H-600), 7.40–7.46 (2H, m, H-300 and H-700), 7.72–
7.78 (3H, m, H-400, H-500 and H-800). dC (100 MHz,
CDCl3): 24.6 (CH2, C-4), 40.4 (CH2, C-1), 42.0 (CH2, C-
3), 55.5 (CH3, 200-OCH2OMe), 56.0 (CH3, 20-OCH2OMe),
57.1 (CH3, OMe), 94.9 (CH2, 20-OCH2O), 98.7 (CH2, 200-
OCH2O), 110.2 (CH, C-40), 115.6 (CH, C-300), 117.1
(quat., C-100), 121.8 (CH, C-60), 123.1 (CH, C-800 or C-600),
123.8 (CH, C-600 or C-800), 124.0 (CH, C-50), 126.7 (CH,
C-700), 128.4 (CH, C-400), 128.9 (CH, C-500), 129.6 (quat.,
C-400a), 133.2 (quat., C-800a), 135.2 (CH, C-10), 144.2
(quat., C-20), 152.0 (quat., C-), 152.5 (quat., C-30), 208.7
(quat., C-200); m/z (EI, %): 424 (M+, 1.0), 318 (8), 246
(14), 223 (6), 181 (36), 170 (29), 137 (6), 45 (100).
0
0
0
0
00 00
00 00
3.15.4. 4-(3-Methoxy-2-(methoxymethoxy)phenyl)-1-(5-
methoxy-2-(methoxymethoxy)phenyl)butan-2-one 16.
Yellow oil. HRMS (EI): Found M+, 404.18337, C22H28O7
requires 404.18350. nmax (film)/cmꢀ1: 2995, 2937, 2836 (s,
C–H, aromatic), 1715, 1666, 1599, 1585, 1499, 1476,
1439, 1404, 1361, 1266 (s, C–O), 1223, 1196, 1152, 1196,
1073, 1041, 977, 924. dH (300 MHz, CDCl3): 2.80 (2H, t,
J4,3 7.7 Hz, H-4), 2.93 (2H, t, J3,4 7.7 Hz, H-3), 3.40 (3H,
s, OCH2OCH3), 3.53 (3H, s, OCH2OCH3), 3.66 (2H, s,
H-1), 3.74 (3H, s, OMe), 3.82 (3H, s, OMe), 5.06 (4H, s,
2ꢂOCH2O), 6.67–6.78 (4H, m, H-40, H-400, H-60 and H-
600), 6.96 (1H, t, J5 ,4 ¼J5 ,6 7.9 Hz, H-50), 7.02 (1H, d,
0
0
0
0
J3 ,4 8.9 Hz, H-300). dC (75 MHz, CDCl3): 24.7 (CH2, C-
00 00
4), 42.6 (CH2, C-1), 45.0 (CH2, C-3), 55.6 (CH3, OMe),
55.7 (CH3, OMe), 56.0 (CH3, OCH2OCH3), 57.4 (CH3,
OCH2OCH3), 95.1 (CH2, OCH2O), 98.9 (CH2, OCH2O),
110.4 (CH, C-400), 113.0 (CH, C-40), 115.4 (CH, C-600),
116.9 (CH, C-300), 122.0 (CH, C-50), 124.1 (CH, C-60),
125.3 (quat., C-100), 135.3 (quat., C-10), 144.3 (quat., C-30),
149.3 (quat., C-500), 152.1 (quat., C-20), 154.3 (quat., C-
200), 207.7 (quat., C-2); m/z (EI, %): 404 (M+, 2%), 372
(2), 342 (2), 328 (2), 310 (7), 298 (38), 195 (7), 161 (42),
150 (13), 137 (33), 45 (100).
3.15.7. 1-(5-Methoxy-1-(methoxymethoxy)naphthalen-
2-yl)-4-(2-(methoxymethoxy)phenyl)butan-2-one 77. Tan
oil. HRMS (EI): Found M+, 424.18921, C25H28O6 requires
424.18859. nmax (film)/cmꢀ1: 3376, 3053, 2978, 1707,
1602, 1402, 1420, 1265, 1069 (s, C–O), 737, 705. dH
(400 MHz, CDCl3): 2.74–2.78 (2H, m, H-4), 2.88–2.91
(2H, m, H-3), 3.32 (3H, s, OCH2OCH3), 3.59 (3H, s,
OCH2OCH3), 3.93 (2H, s, H-1), 3.98 (3H, s, OMe), 5.08
(4H, m, 2ꢂOCH2O), 6.81 (1H, d, J6 ,7 7.7 Hz, H-60), 6.87
0
0
(1H, t, J5 ,4 ¼J5 ,6 7.4 Hz, H-500), 6.99 (1H, d, J3 ,4
00 00
00 00
00 00
3.15.5. 1-(2-Methoxymethoxy-naphthalen-1-yl)-4-(2-
methoxymethoxyphenyl)butan-2-one 71. Yellow oil.
HRMS (EI): Found M+, 394.17795, C24H26O5 requires
7.4 Hz, H-300), 7.09–7.11 (2H, m, H-400 and H-600), 7.21
(1H, d, J3 ,4 8.6 Hz, H-30), 7.40 (1H, d, J7 ,6 7.7 and J7 ,8
0
0
0
0
0
0
8.3 Hz, H-70), 7.61 (1H, d, J8 ,7 8.3 Hz, H-80), 8.00 (1H, d,
0
0

6032
K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
J4 ,3 8.6 Hz, H-40). dC (100 MHz, CDCl3): 25.1 (CH2, C-4),
41.9 (CH2, C-1), 45.3 (CH2, C-3), 55.6 (CH3, OMe), 55.8
(CH3, OCH2OCH3), 57.6 (CH3, OCH2OCH3), 94.1 (CH2,
OCH2O), 100.4 (CH2, OCH2O), 104.0 (CH, C-60), 113.6
(CH, C-80), 114.4 (CH, C-500), 118.8 (CH, C-40), 121.6
(CH, C-300), 124.6 (quat., C-20), 126.3 (CH, C-70), 126.5
(quat., C-100), 127.3 (CH, C-30), 127.6 (CH, C-400), 129.4
(quat., C-40a), 129.9 (quat., C-80a), 130.1 (CH, C-600),
151.6 (quat., C-10), 155.0 (quat., C-200), 155.7 (quat., C-50),
208.2 (quat., C-2); m/z (EI, %): 424 (M+, 4), 392 (3), 362
(3), 348 (6), 330 (21), 318 (16), 211 (49), 200 (18), 187
(10), 45 (100).
120 ꢁC for 48 h. The reaction mixture was stirred at room
temperature for 3 h, the catalyst was removed by filtration,
washed successively with dichloromethane (50 mL) then
concentrated and subjected to flash column chromatography.
0
0
3.16.3. 7-Methoxy-3H-spiro[1-benzofuran-2,20-chro-
mane] 9. Yellow powder. Mp: 115–118 ꢁC. HRMS (EI):
Found M+, 268.11020, C17H16O3 requires 268.10994. nmax
(film)/cmꢀ1: 3053 (CH, aromatic), 1584 (ArC]C), 1093
and 1049 (C–O). dH (300 MHz, CDCl3): 2.13–2.24 (1H,
0
0
0
0
0
m, H-3 ax), 2.37 (1H, ddd, J3 eq,4 eq 3.3, J3 eq,4 ax 5.9 and
0
0
0
0
0
Jgem 13.4 Hz, H-3 eq), 2.82 (1H, ddd, J4 eq,3 eq 3.3, J4 eq,3 ax
5.8 and Jgem 16.7 Hz, H-40eq), 3.30 (1H, d, Jgem 16.4 Hz,
0
0
0
0
H-3ax), 3.32 (1H, ddd, J4 ax,3 eq 5.9, J4 ax,3 ax 12.0, Jgem
16.7 Hz, H-40ax), 3.45 (1H, d, Jgem 16.4 Hz, H-3eq), 3.81
(3H, s, OMe), 6.76–6.79 (2H, m, H-4, H-80), 6.84–6.92
(3H, m, H-4, H-5, H-60), 7.07–7.17 (2H, m, H-50 and
H-70). dC (75 MHz, CDCl3): 22.0 (CH2, C-30), 30.5 (CH2,
C-40), 42.3 (CH2, C-3), 56.0 (CH3, OMe), 109.6 (quat., C-
2), 111.8 (CH, C-4 or C-80), 117.0 (CH, Ar-C), 117.1 (CH,
Ar-C), 121.0 (CH, C-4 or C-5 or C-60), 121.4 (quat., C-
40a), 121.7 (CH, C-5 or C-60 or C-4), 126.5 (quat., C-3a or
C-7a), 127.4 (CH, C-70 or C-50), 129.1 (CH, C-50 or C-70),
144.4 (quat., C-7), 146.3 (quat., C-7a or C-3a), 152.3
(quat., C-80a); m/z (EI, %): 268 (M+, 41), 267 (9), 167 (3),
161 (100), 149 (12), 131 (12), 107 (21), 97 (10), 77 (8), 57
(26).
3.15.8. 1-[4,8-Dimethoxy-1-(methoxymethoxy)naphtha-
len-2-yl]-4-[(2-methoxymethoxy)phenyl]butan-2-one 78.
Yellow oil. HRMS (EI): Found M+, 454.19894, C26H30O7
requires 454.19915. nmax (film)/cmꢀ1: 3054, 2987 (s, C–H,
aromatic), 2685, 2521, 2411, 2305 (C–H alkane), 1710
(C]O, ketone), 1601, 1580, 1551, 1511, 1492 (s, C]C, ar-
omatic), 1265 (s, C–O), 1155, 1079, 739, 705. dH (400 MHz,
CDCl3): 2.78–2.83 (2H, m, H-4), 2.88–2.92 (2H, m, H-3),
3.32 (3H, s, 20-OCH2OMe), 3.54 (3H, s, 10-OCH2OMe),
3.91 (3H, s, 80-OMe), 3.95 (3H, s, 40-OMe), 3.97 (2H, s,
H-1), 4.99 (2H, s, OCH2O), 5.07 (2H, s, OCH2O), 6.54
(1H, s, H-30), 6.86 (1H, dt, J5 ,3 0.7, J5 ,6 ¼J5 ,4 7.4 Hz,
00 00
00 00
00 00
H-500), 6.90 (1H, d, J7 ,6 8.0 Hz, H-70), 6.97–6.99 (1H, m,
0
0
H-300), 7.09–7.12 (2H, m, H-400 and H-600), 7.35 (1H, t,
J6 ,7 ¼J6 ,5 8.0 Hz, H-60), 7.86 (1H, d, J5 ,6 8.0 Hz, H-50).
dC (100 MHz, CDCl3): 24.9 (CH2, C-4), 41.7 (CH2, C-1),
45.5 (CH2, C-3), 55.6 (CH3, OMe), 55.7 (CH3, OMe), 55.9
(CH3, OCH2OCH3), 57.4 (CH3, OCH2OCH3), 94.0 (CH2,
OCH2O), 101.5 (CH2, OCH2O), 106.5 (CH, C-70), 107.0
(CH, C-50), 113.5 (CH, C-300), 115.0 (CH, C-30), 120.3
(quat., C-20), 121.4 (CH, C-500), 124.5 (quat., C-80a), 125.3
(CH, C-60), 127.2 (CH, C-400), 128.2 (quat., C-40a), 130.0
(quat., C-100), 130.1 (CH, C-600), 144.6 (quat., C-80), 151.5
(quat., C-40), 155.0 (quat., C-10), 155.1 (CH, C-200), 208.6
(quat., C-2); m/z (EI, %): 454 (M+, 18), 422 (6), 410 (2),
392 (26), 378 (7), 360 (9), 348 (10), 241 (100), 229 (29),
226 (11), 217 (16), 45 (66).
0
0
0
0
0
0
3.16.4. 5-Methoxy-3H-spiro[1-benzofuran-2,20-chro-
mane] 10. Colourless needles. Mp: 90–92 ꢁC. HRMS (EI):
Found M+, 268.10970, C17H16O3 requires 268.10994. nmax
(CH2Cl2 solution)/cmꢀ1: 3054, 2986, 2959, 2930, 2305,
1584, 1488, 1457, 1466, 1433, 1422, 1265, 1222, 1209,
1177, 736, 705. dH (300 MHz, CDCl3): 2.17 (1H, ddd,
0
(1H, ddd, J3 eq,4 eq 2.8, J3 eq,4 ax 6.0 and Jgem 13.3 Hz, H-
0
0
0
J3 ax,4 eq 6.0, J3 ax,4 ax 13.3 and Jgem 13.3 Hz, H-3 ax), 2.31
0
0
0
0
0
0
0
0
0
0
3 eq), 2.81 (1H, ddd, J4 eq,3 eq 2.8, J4 eq,3 ax 6.0 and Jgem
16.4 Hz, H-40eq), 3.17–3.27 (1H, m, H-40ax), 3.26 (1H, Jgem
16.6 Hz, H-3A), 3.41 (1H, Jgem 16.6 Hz, H-3B), 3.76 (3H,
s, OMe), 6.69 (2H, m, H-4 and H-6), 6.77–6.82 (2H, m, H-
7 and H-80), 6.90 (1H, dt, J6 ,8 1.1 and J6 ,5 ¼J6 ,7 7.9 Hz,
H-60), 7.07–7.13 (2H, m, H-50 and H-70). dC (75 MHz,
CDCl3): 21.9 (CH2, C-40), 30.4 (CH2, C-30), 42.3 (CH2, C-
3), 56.0 (CH3, OMe), 109.2 (quat., C-2), 109.8 (CH, C-6),
111.2 (CH, C-80), 113.0 (CH, C-4), 117.1 (CH, C-7), 121.1
(CH, C-60), 121.4 (quat., C-40a), 126.3 (quat., C-3a), 127.4
(CH, C-70), 129.1 (CH, C-50), 152.0 (quat., C-7a), 152.3
(quat., C-80a), 154.6 (quat., C-5); m/z (EI, %): 268 (M+,
32), 161 (100), 131 (6), 107 (12), 77 (6), 65 (3), 45 (3).
0
0
0
0
0
0
3.16. Standard procedure for cyclisation of ketones to
a 5,6-spiroacetal or a benzofuran
3.16.1. Procedure A—using bromotrimethylsilane in di-
chloromethane. A solution of ketone (0.17 mmol) in di-
˚
chloromethane (1 mL) containing 4 A molecular sieves
was treated with bromotrimethylsilane (1.70 mmol) at
ꢀ30 ꢁC under nitrogen and the mixture stirred for 1 h at
this temperature. The reaction mixture was warmed to
0 ꢁC and stirred for 10 h, then warmed to room temperature
and stirred for a further 11 h. The reaction mixture was
poured into a solution of saturated sodium bicarbonate
(2 mL), then extracted with ether (4ꢂ2 mL). The combined
organic extracts were washed with brine (5 mL), dried over
MgSO4 and concentrated in vacuo to give a yellow residue,
which was purified by flash column chromatography.
3.16.5. 2-Methoxy-6-(2-(7-methoxybenzofuran-2-yl)-
ethyl)phenol 43. White solid. Mp: 82–84 ꢁC. HRMS (EI):
Found M+, 298.12025, C18H18O4 requires 298.12051. nmax
(CH2Cl2 solution)/cmꢀ1: 3534 (s, br, O–H), 3053, 2985
(s, aromatic, CH), 1732, 1620, 1479, 1373, 1265 (C–O),
1096, 1079, 1046. dH (300 MHz, CDCl3): 3.10 (4H, s, H-
10 and H-20), 3.85 (3H, s, OMe), 3.99 (3H, s, OMe), 5.75
(1H, br s, OH), 6.38 (1H, s, H-300), 6.69–6.77 (4H, m, Ar-
H), 7.06–7.11 (2H, m, Ar-H). dC (75 MHz, CDCl3): 28.2
(CH2, C-10 or C-20), 28.3 (CH2, C-20 or C-10), 55.9 (CH3,
2ꢂOMe), 102.4 (CH, C-300), 105.5 (CH, Ar-C), 108.7 (CH,
Ar-C), 110.0 (CH, Ar-C), 112.8 (CH, Ar-C), 119.3 (CH,
Ar-C), 122.2 (CH, Ar-C), 122.9 (CH, Ar-C), 126.6 (quat.,
3.16.2. Procedure B—using silica-supported sodium
hydrogen sulfate in dichloromethane. To a stirred solution
of ketone (0.34 mmol) in dichloromethane (5 mL) was
added NaHSO4$SiO2 (804 mg) that had been heated at

K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
6033
Ar-C), 130.7 (quat., Ar-C), 143.6 (quat., Ar-C), 143.7 (quat.,
Ar-C), 144.9 (quat., C-700 or C-2), 146.3 (quat., C-2 or C-700),
159.2 (quat., Ar-C); m/z (EI, %): 298 (M+, 64), 161 (100),
146 (5), 137 (96), 118 (11), 77 (6).
solution)/cmꢀ1: 3053, 2971, 2905, 1627, 1577, 1486,
1454, 1421, 1265, 739. dH (400 MHz, CDCl3): 2.26 (1H,
0
2.39 (1H, ddd, J3 eq,4 eq 2.6, J3 eq,4 ax 6.0, Jgem 13.4 Hz,
0
ddd, J3 ax,4 eq 5.9, J3 ax,4 ax 13.0 and Jgem 13.0 Hz, H-3 ax),
0
0
0
0
0
0
0
0
13.4 Hz, H-4 eq), 2.39 (1H, ddd, J4 ax,3 eq 6.0, J4 ax,3 ax 12.6,
0
H-3 eq), 2.84 (1H, ddd, J4 eq,3 eq 2.6, J4 eq,3 ax 6.0, Jgem
0
0
0
0
0
0
0
0
3.16.6. 7-Methoxy-3H-spiro[1-benzofuran-2,20-(8-meth-
oxychromane)] 11. Off-white powder. Mp: 185–188 ꢁC.
HRMS (EI): Found M+, 298.11990, C18H18O4 requires
298.12051. nmax (CH2Cl2 solution)/cmꢀ1: 3054, 2986,
2959, 2923, 2305, 1584, 1482, 1457, 1466, 1433, 1422,
1264, 1225, 1180, 1082, 903, 747. dH (300 MHz, CDCl3):
Jgem 16.4 Hz, H-40ax), 3.51 (1H, d, Jgem 16.4 Hz, H-3A),
0
0
3.73 (1H, d, Jgem 16.4 Hz, H-3B), 6.80 (1H, d, J8 ,7
0
8.1 Hz, H-80), 6.93 (1H, t, J6 ,7 ¼J6 ,5 7.6 Hz, H-60), 7.09
0
0
0
(1H, d, J9,8 8.8 Hz, H-9), 7.08–7.13 (1H, m, H-70), 7.14
(1H, d, J5 ,6 7.6 Hz, H-50), 7.32 (1H, t, J6,5 7.7 and J6,7
8.2 Hz, H-6), 7.47 (1H, t, J5,6 7.7 and J5,4 8.2 Hz, H-5),
7.60 (1H, d, J4,5 8.2 Hz, H-4), 7.69 (1H, d, J8,9 8.8 Hz,
H-8), 7.80 (1H, d, J7,6 8.2 Hz, H-7). dC (100 MHz,
CDCl3): 21.9 (CH2, C-40), 30.6 (CH2, C-30), 40.8 (CH2,
C-3), 109.8 (quat., C-2), 112.2 (CH, C-9), 117.1 (CH, C-
80), 117.1 (quat., C-3a), 121.2 (CH, C-60), 121.4 (quat.,
C-40a), 122.7 (CH, C-4), 123.1 (CH, C-6), 126.7 (CH, C-
5), 127.5 (CH, C-70), 128.8 (CH, C-7), 129.1 (2ꢂCH, C-
50 and C-8), 129.5 (quat., C-7a), 130.6 (quat., C-4a),
152.3 (quat., C-80a), 155.3 (quat., C-9a); m/z (EI, %): 288
(M+, 23), 181 (100), 152 (10), 149 (4), 115 (1), 107 (2),
91 (2), 77 (3), 57 (6).
0
0
0
0
0
0
2.15 (1H, ddd, J3 ax,4 eq 5.7, J3 ax,4 ax 13.0 and Jgem
0
0
13.0 Hz, H-3 ax), 2.33 (1H, J3 eq,4 eq 2.7, J3 eq,4 ax 5.7 and
0
0
0
0
0
0
0
0
Jgem 13.4 Hz, H-3 eq), 2.78 (1H, ddd, J4 eq,3 eq 2.5, J4 eq,3 ax
5.6, Jgem 16.4 Hz, H-40eq), 3.31 (1H, d, Jgem 16.6 Hz, H-
3A), 3.26–3.33 (1H, m, H-40ax), 3.60 (1H, d, Jgem 16.6 Hz,
H-3B), 3.75 (3H, s, OMe), 3.79 (3H, s, OMe), 6.70–6.75
(3H, m, Ar-H), 6.82–6.87 (3H, m, Ar-H). dC (75 MHz,
CDCl3): 21.8 (CH2, C-40), 30.6 (CH2, C-30), 42.4 (CH2, C-
3), 55.9 (CH3, OMe), 56.0 (CH3, OMe), 109.5 (quat., C-2),
110.0 (CH, Ar-C), 111.6 (CH, Ar-C), 117.1 (CH, Ar-C),
120.6 (CH, Ar-C), 121.1 (CH, Ar-C), 121.5 (CH, Ar-C),
122.4 (quat., C-40a), 126.5 (quat., C-3a), 141.9 (quat., C-
80a), 144.3 (quat., C-7 or C-80), 146.3 (quat., C-7a), 148.4
(quat., C-80 or C-7); m/z (EI, %): 298 (M+, 62), 167 (8),
161 (100), 146 (7), 137 (96), 118 (8), 91 (9), 77 (8), 71
(14), 57 (23), 43 (16).
3.16.10. 80-Methoxy-3H-spiro[1-naphthofuran-2,20-chro-
mane] 49. Colourless needles. Mp: 162–164 ꢁC. HRMS
(EI): Found M+, 318.12535, C21H18O3 requires 318.12559.
nmax (film)/cmꢀ1: 3053, 2978, 2840 (CH, aromatic), 2681,
2311, 1739, 1627, 1580, 1476, 1461, 1418, 1265, 1215,
3.16.7. 2-Methoxy-6-(2-(5-methoxybenzofuran-2-yl)-
ethyl)phenol 44. Colourless oil. HRMS (EI): Found M+,
298.12072, C18H18O4 requires 298.12051. dH (300 MHz,
CDCl3): 3.07 (4H, s, H-10 and H-20), 3.82 (3H, s, OMe),
3.87 (3H, s, OMe), 5.76 (1H, br s, OH), 6.33 (1H, s,
0
0
738. dH (400 MHz, CDCl3): 2.27 (1H, ddd, J3 ax,4 eq 5.8,
0
J3 eq,4 eq 2.4, J3 eq,4 ax 5.9 and Jgem 13.2 Hz, H-3 eq), 2.85
0
J3 ax,4 ax 12.8 and Jgem 13.2 Hz, H-3 ax), 2.39 (1H, ddd,
0
0
(1H, ddd, J4 eq,3 eq 2.4, J4 eq,3 ax 5.8 and Jgem 16.5 Hz,
0
0
0
0
0
0
0
0
0
0
0
0
0
H-4 eq), 3.31 (1H, ddd, J4 ax,3 eq 6.0, J4 ax,3 ax 12.8 and Jgem
16.5 Hz, H-40ax), 3.56 (1H, d, Jgem 16.6 Hz, H-3A), 3.75
(3H, s, OMe), 3.89 (1H, d, Jgem 16.6 Hz, H-3B), 6.73–6.78
H-300), 6.75–6.79 (5H, m, Ar-H), 7.06–7.11 (1H, d, J4 ,6
00 00
2.48 Hz, H-400); m/z (EI, %): 298 (M+, 43), 161 (100), 137
(44), 118 (8), 77 (6).
(2H, m, H-50 and H-70), 6.88 (1H, t, J6 ,7 ¼J6 ,5 ¼7.8 Hz,
H-60), 7.09 (1H, d, J9,8 8.8 Hz, H-9), 7.32 (1H, dd, J6,5 8.1
and J6,7 8.2 Hz, H-6), 7.47 (1H, dd, J5,6 8.1 and J5,4
8.2 Hz, H-5), 7.60 (1H, d, J4,5 8.2 Hz, H-4), 7.68 (1H, d,
J8,9 8.8 Hz, H-8), 7.80 (1H, d, J7,6 8.2 Hz, H-7). dC
(100 MHz, CDCl3): 30.7 (CH2, C-40), 30.8 (CH2, C-30),
40.9 (CH2, C-3), 55.8 (CH3, OMe), 109.9 (quat., C-2),
109.9 (CH, C-50 or C-70), 112.1 (CH, C-9), 117.1 (quat.,
C-3a), 120.7 (CH, C-60), 121.0 (CH, C-50 or C-70), 122.3
(quat., C-40a), 122.7 (CH, C-5), 123.0 (CH, C-6), 126.6
(CH, C-5), 128.6 (CH, C-7), 128.9 (CH, C-8), 129.4
(quat., C-7a), 130.5 (quat., C-4a), 141.9 (quat., C-80a),
148.4 (quat., C-80), 155.2 (quat., C-9a); m/z (EI, %): 318
(M+, 23), 181 (100), 152 (8), 149 (37), 137 (7), 129 (27),
69 (4), 57 (46), 43 (33).
0
0
0
0
3.16.8. 5-Methoxy-3H-spiro[1-benzofuran-2,20-(8-
methoxychromane)] 12. Colourless needles. Mp: 139–
141 ꢁC. HRMS (EI): Found M+, 298.12017, C18H18O4
requires 298.12051. nmax (film)/cmꢀ1: 3053, 2986 (CH, s,
aromatic), 1586, 1482 (C]C, aromatic), 1421, 1265
(C–O), 1180, 1080, 1030, 1004, 896. dH (400 MHz,
0
J3 eq,4 ax 6.0 and Jgem 13.3 Hz, H-3 eq), 2.81 (1H, ddd,
0
0
CDCl3): 2.15–2.19 (1H, m, H-3 ax), 2.29 (1H, J3 eq,4 eq 2.6,
0
0
0
0
0
0
0
0
J4 eq,3 eq 2.5, J4 eq,3 ax 5.8, Jgem 16.4 Hz, H-4 eq), 3.20–3.30
(1H, m, H-40ax), 3.28 (1H, d, Jgem 16.5 Hz, H-3A), 3.55
(1H, d, Jgem 16.6 Hz, H-3B), 3.75 (6H, s, 2ꢂOMe), 6.62–
6.74 (4H, m, H-6, H-7, H-50 and H-70), 6.78 (1H, s, H-4),
6.84 (1H, t, J6 ,5 ¼J6 ,7 7.84 Hz, H-60). dC (75 MHz,
CDCl3): 21.9 (CH2, C-40), 30.5 (CH2, C-30), 42.3 (CH2,
C-3), 55.9 (CH3, OMe), 56.0 (CH3, OMe), 109.2 (quat.,
C-2), 109.7 (CH, Ar-C), 110.1 (CH, Ar-C), 111.0 (CH, Ar-
C), 113.0 (CH, Ar-C), 120.7 (CH, Ar-C), 121.1 (CH,
Ar-C), 122.4 (quat., C-40a), 126.3 (quat., C-3a), 142.0
(quat., C-7a), 148.5 (quat., C-80a), 152.1 (quat., C-80),
154.5 (quat., C-5); m/z (EI, %): 298 (M+, 43), 209 (9), 161
(100), 137 (47), 135 (14), 118 (6), 91 (3), 77 (4).
0
0
0
0
3.16.11. 6-Methoxy-3H-spiro[1-naphthofuran-2,20-chro-
mane] 50. Colourless solid. Mp: 166–168 ꢁC. HRMS (EI):
Found M+, 318.12535, C21H18O3 requires 318.12559. nmax
(CH2Cl2 solution)/cmꢀ1: 2980 (CH, aromatic), 1793,
1644, 1601, 1469, 1403, 1381, 1298, 1261, 1224, 1166,
1096, 1044, 1003, 907, 0733, 650. dH (400 MHz, CDCl3):
0
0
2.20–2.28 (1H, m, H-3 ax), 2.44 (1H, ddd, J3 eq,4 eq 2.7,
0
0
0
J3 eq,4 ax 5.8 and Jgem 13.4 Hz, H-3 eq), 2.86 (1H, ddd,
3.16.9. 3H-Spiro[1-naphthofuran-2,20-chromane] 48.
White powder. Mp: 153–156 ꢁC. HRMS (EI): Found M+,
288.11484, C20H16O2 requires 288.11503. nmax (CH2Cl2
J4 eq,3 eq 2.7, J4 eq,3 ax 5.8 and Jgem 16.3 Hz, H-4 eq), 3.34–
3.42 (1H, m, H-40ax), 3.46 (1H, d, Jgem 16.4 Hz, H-3A),
3.62 (1H, d, Jgem 16.4 Hz, H-3B), 3.98 (3H, s, OMe), 6.75
0
0
0
0
0

6034
K. Y. Tsang, M. A. Brimble / Tetrahedron 63 (2007) 6015–6034
(1H, d, J7,8 7.8 Hz, H-7), 6.79 (1H, d, J8 ,7 7.8 Hz, H-80),
Acknowledgements
0
0
0
0
0
0
0
0
0
0
0
6.94 (1H, t, J6 ,7 ¼J6 ,5 7.8 Hz, H-6 ), 7.12 (1H, t, J7 ,6 ¼J7 ,8
7.8 Hz, H-70), 7.17 (1H, J5 ,6 7.8 Hz, H-50), 7.29 (1H, t,
J8,7¼J8,9 7.8 Hz, H-8), 7.35 (1H, d, J4,5 8.5 Hz, H-4), 7.47
(1H, d, J9,8 7.8 Hz, H-9), 7.84 (1H, d, J5,4 8.5 Hz, H-5). dC
(100 MHz, CDCl3): 21.8 (CH2, C-40), 30.6 (CH2, C-30),
42.7 (CH2, C-3), 55.4 (CH3, OMe), 103.7 (CH, C-7),
109.7 (quat., C-2), 113.9 (CH, C-9), 114.9 (CH, C-5),
117.0 (CH, C-80), 119.0 (quat., C-3a), 121.0 (CH, C-60),
121.3 (quat., C-9a), 121.5 (quat., C-40a), 121.6 (CH, C-4),
125.4 (CH, C-8), 126.0 (quat., C-5a), 127.4 (CH, C-70),
129.0 (CH, C-50), 152.3 (quat., C-80a), 153.0 (quat., C-9b),
155.4 (quat., C-6); m/z (EI, %): 318 (M+, 19), 255 (6), 230
(4), 211 (100), 196 (5), 168 (8), 45 (8).
The authors thank the New Zealand Foundation for Re-
search, Science and Technology for the award of a Top
Achiever Doctoral Scholarship (K.Y.T) for this work.
0
0
References and notes
1. (a) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A.
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Brockmann, H.; Zeeck, A. Chem. Ber. 1970, 103, 1709.
2. Ueno, T.; Takahashi, H.; Oda, M.; Mizunuma, M.; Yokoyama,
A.; Goto, Y.; Mizushina, Y.; Sakaguchi, K.; Hayashi, H.
Biochemistry 2000, 39, 5995.
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Zerilli, L. F.; Cornelli, C. Tetrahedron 1974, 30, 2747.
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Goldstein, B. P.; Ciabatti, R. J. Med. Chem. 1997, 40, 967.
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Yamazaki, T.; Tsuchida, T.; Sawa, T.; Hamada, M.; Takeuchi,
T. J. Antibiot. 1996, 49, 752; (b) Chino, M.; Nishikawa, K.;
Tsuchida, T.; Sawa, R.; Nakamura, H.; Nakamura, K. T.;
Muraoka, Y.; Ikeda, D.; Naganawa, H.; Sawa, T.; Takeuchi,
T. J. Antibiot. 1997, 50, 143.
7. Stroshane, R. M.; Chan, J. A.; Rubalcaba, E. A.; Garetson,
A. L.; Aszalos, A. A.; Roller, P. P. J. Antibiot. 1979, 32, 197.
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Angew. Chem., Int. Ed. 2001, 40, 4709; (b) Siu, T.; Qin, D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4713.
10. (a) Capecchi, T.; de Koning, C. B.; Michael, J. P. Tetrahedron
Lett. 1998, 39, 5429; (b) Capecchi, T.; de Koning, C. B.;
Michael, J. P. J. Chem. Soc., Perkin Trans. 1 2000, 2681.
11. Tsang,K.Y.;Brimble,M.A.;Bremner,J.Org. Lett. 2003,5, 4425.
12. Lindsey, C. C.; Wu, K. L.; Pettus, T. R. R. Org. Lett. 2006,
8, 2365.
13. (a) Waters, S. C.; Fennie, M. W.; Kozlowski, M. C. Tetrahedron
Lett. 2006, 47, 5409; (b) Waters, S. C.; Fennie, M. W.;
Kozlowski, M. C. Org. Lett. 2006, 8, 3243.
14. Soergel, S.; Azap, C.; Reissig, H.-U. Org. Lett. 2006, 8, 4875.
15. Labrosse, J.-R.; Poncet, C.; Lhoste, P.; Sinou, D. Tetrahedron:
Asymmetry 1999, 10, 1069.
3.16.12. 2-[2-(5,9-Dimethoxynaphtho[1,2-b]furan-2-yl)-
ethyl]phenol 79. White powder. Mp: 107–108 ꢁC. HRMS
(EI): Found M+, 348.13687, C22H20O4 requires 348.13616.
nmax (film)/cmꢀ1: 3054, 2898 (s, C–H, aromatic), 1822,
1786, 1600, 1463, 1382, 1265, 1155, 1079, 730. dH
(400 MHz, CDCl3): 3.15–3.19 (2H, m, H-20 or H-10),
3.21–3.25 (2H, m, H-10 or H-20), 3.99 (3H, s, OMe), 4.12
(3H, s, OMe), 5.53 (1H, s, OH), 6.44 (1H, s, H-3), 6.74
(1H, d, J6 ,5 8.0 Hz, H-600), 6.85 (1H, t, J4 ,3 ¼J4 ,5
00 00
00 00
00 00
7.4 Hz, H-400), 6.91 (1H, s, H-4), 7.01 (1H, d, J8,7 8.1 Hz,
00 00
00 00
00 00
H-8), 7.06 (1H, ddd, J5 ,3 1.4, J5 ,4 7.4 and J5 ,6 8.0 Hz,
H-500), 7.17 (1H, dd, J3 ,5 1.4 and J3 ,4 7.4 Hz, H-300),
7.37 (1H, t, J7,6¼J7,8 8.1 Hz, H-7), 7.91 (1H, d, J6,7
8.1 Hz, H-6). dC (100 MHz, CDCl3): 27.9 (CH2, C-10 or C-
20), 29.2 (CH2, C-20 or C-10), 55.9 (CH3, OMe), 56.0 (CH3,
OMe), 97.8 (CH, C-4), 103.4 (CH, C-3), 106.4 (CH, C-8),
115.0 (quat.,C-9a), 115.2 (CH, C-6), 116.1 (CH, C-600),
120.8 (CH, C-400), 124.1 (CH, C-7), 124.6 (quat., C-5a),
127.2 (quat., C-200), 127.6 (CH, C-500), 129.0 (quat., C-3a),
130.3 (CH, C-300), 143.6 (quat., C-9b), 151.6 (quat., C-5),
153.8 (quat., C-9), 154.1 (quat., C-100), 157.3 (quat., C-2);
m/z (EI, %): 348 (M+, 30), 346 (27), 331 (12), 257 (10),
241 (100), 231 (27), 226 (14), 97 (10), 81 (12), 69 (27),
55 (19).
00 00
00 00
3.16.13. 5,9-Dimethoxy-2-(2-(methoxymethoxy)phen-
ethyl)naphtho[1,2-b]furan 80. Yellow solid. Mp: 145–
147 ꢁC. HRMS (EI): Found M+, 392.16283, C24H24O5
requires 392.16237. nmax (film)/cmꢀ1: 2930, 2853, 2253,
1793, 1575, 1456, 1413, 1381, 1261, 1234, 1215, 1075,
907. dH (400 MHz, CDCl3): 3.14–3.24 (2H, m, H-10 and
H-20), 3.49 (3H, s, OCH2OMe), 4.00 (3H, s, 5-OMe), 4.08
(3H, s, 9-OMe), 5.20 (2H, s, OCH2O), 5.28 (1H, s, OH),
6.46 (1H, s, H-3), 6.91–6.95 (1H, m, H-500), 6.94 (1H, s,
00 00
H-4), 6.99 (1H, d, J8,7 8.1 Hz, H-8), 7.09 (1H, d, J3 ,4
16. Rosenberg, S. H.; Rapoport, H. J. Org. Chem. 1984, 56.
17. (a) Ramesh, C.; Ravindranath, N.; Das, B. J. Org. Chem. 2003,
68, 7101; (b) Breton, G. W. J. Org. Chem. 1997, 62, 8952.
18. Giles, R. G. F.; Hughes, A. B.; Sargent, M. V. J. Chem. Soc.,
Perkin Trans. 1 1991, 1581.
19. Brimble, M. A.; Ireland, E. J. Chem. Soc., Perkin Trans. 1 1994,
3109.
20. Deville, J. P.; Behar, V. J. Org. Chem. 2001, 66, 4097.
21. Lahiri, S.; Ramarao, C.; Rao, B. V.; Rao, A. Org. Process Res.
Dev. 1999, 3, 71.
8.1 Hz, H-300), 7.16–7.22 (2H, m, H-400 and H-600), 7.36
(1H, t, J7,8¼J7,6 8.1 Hz, H-7), 7.91 (1H, dd, J6,8 0.6 and
J6,7 8.1 Hz, H-6). dC (100 MHz, CDCl3): 28.8 (CH2, C-10
or C-20), 29.0 (CH2, C-20 or C-10), 55.8 (CH3, OMe),
56.0 (CH3, 2ꢂOMe), 94.4 (CH2, OCH2O), 97.8 (CH, C-
4 or C-500), 102.7 (CH, C-3), 106.5 (CH, C-8), 113.9
(CH, C-300), 114.1 (quat., C-9a), 115.2 (CH, C-6), 121.7
(CH, C-4 or C-500), 123.9 (CH, C-7), 124.7 (quat., C-3a),
125.1 (quat., C-5a), 127.4 (CH, C-400 or C-600), 130.1
(CH, C-600 or C-400), 130.2 (quat., C-100), 143.6 (quat., C-
9b), 151.5 (quat., C-5), 154.2 (quat., C-9), 155.2 (quat.,
C-200), 158.3 (quat., C-2); m/z (EI, %): 241 (M+, 27),
226 (12), 45 (13).
22. El-Qisairi, A. K.; Qaseer, H. A.; Henry, P. M. J. Organomet.
Chem. 2002, 656, 168.
23. Gozzo, F. C.; Fernandes, S. A.; Rodrigues, D. C.; Eberlin,
M. N.; Marsaioli, A. J. J. Org. Chem. 2003, 68, 5493.