Synthesis of benzannulated spiroketals using an oxidative radical cyclization

Article abstract of DOI:10.1055/s-0030-1259981

The synthesis of both mono and bisbenzannulated spiroketals using an oxidative radical cyclization approach is investigated. Although unsuccessful in uncovering a novel route toward bisbenzannulated spiroketals, the oxidative radical cyclization does faci

Full text of DOI:10.1055/s-0030-1259981

PAPER
1383
Synthesis of Benzannulated Spiroketals Using an Oxidative Radical
Cyclization
Synthesis
oof Benzannu
n
lated Spiroke
a
tals than Sperry, Yen-Cheng (William) Liu, Zoe E. Wilson, Jonathan G. Hubert, Margaret A. Brimble*
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland 1142, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
Received 20 January 2011; revised 17 February 2011
heliquinomycin (4) by Danishefsky5a in which spiroketal-
ization of a hemiketal took place under Mitsunobu condi-
tions, the total synthesis of ( )-g-rubromycin (3) by Kita6
that utilized a double aromatic Pummerer-type reaction to
Abstract: The synthesis of both mono and bisbenzannulated
spiroketals using an oxidative radical cyclization approach is inves-
tigated. Although unsuccessful in uncovering a novel route toward
bisbenzannulated spiroketals, the oxidative radical cyclization does
facilitate a new approach to monobenzannulated spiroketals such as effect spiroketalization, and our own formal synthesis of
those found in berkelic acid and in the chaetoquadrins.
( )-g-rubromycin (3) which involved the spirocyclization
of a carefully chosen diphenolic ketone precursor.7
Key words: spiroketals, berkelic acid, chaetoquadrin, radical cy-
clization, cross-metathesis
HO
O
MeO
HO
OH
O
O
Spiroketals are a common structural element in several
natural products of medicinal and environmental impor-
tance.1 One such set of compounds, the rubromycins
(Figure 1), are a class of natural antibiotics that display a
broad range of biological activity2 including inhibition of
human telomerase as exemplified by b-rubromycin (2)
and g-rubromycin (3) (IC50 3.06 0.85 mM and 2.64
0.09 mM, respectively). Intriguingly, a-rubromycin (1),
derived from ring-opening of the spiroketal core of b-ru-
bromycin (2), exhibits much lower inhibition of telom-
erase (IC50 >200 mM) than other members of the family,
implying that the bisbenzannulated spiroketal core is an
essential structural unit for inhibition of telomerase.3
Structurally related to the rubromycins is heliquinomycin
(4), an inhibitor of DNA helicase.4
O
MeO
HO
O
O
α-rubromycin (1)
CO2Me
O
HO
O
CO2Me
MeO
O
O
(S)
MeO
O
β-rubromycin (2)
O
HO
O
O
O
OH
CO2Me
MeO
O
O
*
R1
Upon initial consideration, the acid-catalyzed cyclization
of a diphenolic precursor appears to offer a straightfor-
ward route toward the synthesis of the bisbenzannulated
spiroketal core of the aforementioned rubromycin family
of antibiotics 2–4. However, difficulties in executing this
classical spirocyclization protocol have been reported by
numerous research groups5 during synthetic efforts to-
ward this family of natural products. The reasons for these
difficulties were ascertained through a series of detailed
model studies by Kozlowski5b and Reißig,5c who showed
independently that the presence of the electron-withdraw-
ing moieties on the isocoumarin fragment significantly re-
duce the nucleophilicity of the phenolic hydroxy group, a
key factor in hindering the key spiroketalization step, and
hence formation of benzofuran (a-rubromycin type) prod-
ucts.5b,c Because of these difficulties in assembling the
bisbenzannulated spiroketal core, only three successful
syntheses have been achieved to date. The aglycon of ( )-
R2
OH
γ-rubromycin (3): * = (S), R1 = R2 = H
heliquinomycin (4): * = (R), R1 = O-cymarose, R2 = OH
Figure 1 The rubromycin family of natural products
Despite our formal synthesis featuring an acid-catalyzed
spiroketalization, its success hinged on the delicate bal-
ancing of the electronic properties of the substituents
present on the naphthazarin and isocoumarin fragments
present in the spiroketalization precursor.7
Several published model studies towards the bisbenzan-
nulated spiroketal core of the rubromycins feature acid-
catalyzed spiroketalization steps,8 but numerous alterna-
tive methods have been disclosed, including intramolecu-
lar alkyne hydroalkoxylations9 and cycloaddition-type
approaches.8d,10 Despite these worthwhile advances, alter-
native synthetic methods for the efficient construction of
bisbenzannulated spiroketals related to the rubromycins
would be a welcome addition to the synthetic repertoire.
SYNTHESIS 2011, No. 9, pp 1383–1398
Advanced online publication: 04.04.2011
DOI: 10.1055/s-0030-1259981; Art ID: N13311SS
x
x
.
x
x
.2
0
1
1
Our research group has a long-standing interest in the syn-
thesis of aliphatic spiroketals using the oxidative radical
© Georg Thieme Verlag Stuttgart · New York

1384
J. Sperry et al.
PAPER
cyclization of cyclic ethers containing a hydroxyalkyl side ether 10 (path A) or dihydrobenzofuran 11 (path B) with
chain (Scheme 1).11 Due to the inherently mild nature of the common ortho-substituted styrene 12 (Scheme 2).
this cyclization protocol, we set out to investigate if this
strategy could be successfully applied to the synthesis of
the bisbenzannulated spiroketal core of the rubromycins
It was presumed that formation of the five-membered ring
of the [6,5]-spiroketal 5 would require an intramolecular
hydrogen abstraction to occur through a more favorable
(Scheme 1). This previously unexplored transformation
six-membered transition state,11 and thus we focused our
would provide a worthy alternative to the troublesome
initial attention on path A. The synthesis of the cross-
metathesis coupling partners 10 and 12 was conducted as
follows: styrene 12 was prepared on a large scale by
acid-catalyzed spirocyclization commonly encountered
during the synthesis of the spiroketal core 5 of the rubro-
mycin family of antibiotics.
Wittig methylenation of salicylaldehyde followed by ben-
zylation,12 and enol ether 10 was prepared from dihydro-
I
coumarin using the reported Tebbe procedure.13
HO
O
O
H
As enol ether 10 is categorized14 as a type III alkene,15 it
was employed in excess with respect to styrene 12 (Type
II) during the cross-metathesis process (Scheme 3). Dis-
appointingly, despite subjecting styrene 12 and enol ether
10 to a large variety of cross-metathesis conditions with
Grubbs’ second-generation catalyst, no heterodimer 8 was
observed. Only the isomerized product, 2-methyl-
chromene (13) and the homodimer 14 were ever isolated,
despite employing enol ether 10 in vast excess (up to 12
equivalents) and using a variety of solvents and tempera-
tures. The main contributing factor to the failure of this re-
action was the facile isomerization of enol ether 10, even
.
[O]
IHA
O
O
O
alkyl hypoiodite
OH
O
phenolic
substrate?
O
O
HO
6
5
O
7
OBn
Scheme 1 Synthesis of spiroketals by oxidative radical cyclization
(IHA = intramolecular hydrogen abstraction)
BnO
OBn
Our initial attention focused on the model bisbenzannulat-
ed spiroketal core 5 of the rubromycins (Scheme 2). The
proposed oxidative radical cyclization approach allows
for the [6,5]-spiroketal to be assembled by two distinct
pathways; formation of the five-membered ring by cy-
clization of the chroman-tethered phenol 6 (path A), or
formation of the six-membered ring by cyclization of the
dihydrobenzofuran-tethered phenol 7 (path B). Both cy-
clization precursors 6 and 7 were envisaged to be accessi-
ble via hydrogenation of 8 or 9, respectively. In turn, 8 and
9 are accessible via the cross-metathesis between enol
Grubbs II
12
+
+
14
O
13
O
10
OBn
(3–12 equiv)
O
8
Scheme 3 Failed cross-metathesis
oxidative
radical cyclization
HO
OH
O
O
O
B
A
O
B
A
7
5
6
bisbenzannulated
[6,5]-spiroketal
hydrogenation
hydrogenation
core of the rubromycins
O
BnO
OBn
O
11
O
10
O
OBn
BnO
9
8
cross-
metathesis
cross-
metathesis
12
12
Scheme 2 Retrosynthesis of the bisbenzannulated spiroketal 5
Synthesis 2011, No. 9, 1383–1398 © Thieme Stuttgart · New York

PAPER
Synthesis of Benzannulated Spiroketals
1385
when conducting the cross-metathesis reaction in base- radical cyclization conditions11 with a variety of oxidants
washed glassware.
including diacetoxyiodobenzene [PhI(OAc)2], bis(trifluo-
roacetoxy)iodobenzene [PhI(OCOCF3)2], lead tetraace-
tate [Pb(OAc)4] or mercuric oxide (HgO),11,18 only
degradation was observed in all cases, and no bisbenzan-
nulated spiroketal 5 was ever observed (Scheme 6).
With the cross-metathesis route failing, we opted to em-
ploy a Heck coupling strategy to construct the key model
cyclization precursor 8 (Scheme 4).
H-Cube®
PtO2
EtOAc–MeOH
OBn
OBn
O
OH
OH
O
O
O
79%
I
Heck
6
8
15
10
20
oxidant (2 equiv)
I2, hν (60 W)
cyclohexane
7 °C, 0.5–7 h
Scheme 4 Heck coupling strategy
outcome
oxidant
PhI(OAc)2
PhI(OCOCF3)2
Pb(OAc)4
HgO
With enol ether 10 already in hand, its attempted Heck
coupling with the protected iodophenol 15 was investigat-
ed. However, no coupled product was ever observed, pre-
sumably due to steric hindrance restricting the initial
oxidative addition step. Unperturbed, the Heck coupling
of 10 with 2-iodophenol (16) was examined. Upon sub-
jecting compounds 10 and 16 to standard Heck condi-
tions, the chroman 17 was isolated as the sole product in
moderate yield. Despite not forming the desired product 8,
the outcome of this reaction did demonstrate some inter-
esting chemistry. A similar result had been previously dis-
closed on a related glycoside system16 and can be
attributed to the undesired regiochemical outcome of the
initial addition to form the palladium s-complex 18.
Alkoxide elimination then gives diol 19 which undergoes
6-exo-trig cyclization giving chroman 17 (Scheme 5).
degradation
O
O
5
Scheme 6 Failed oxidative radical cyclization
With the failure of the oxidative radical spiroketalization
of 6 using path A, attention turned to forming the six-
membered ring of the bisbenzannulated spiroketal core
(Scheme 2, path B). Thus, the dihydrobenzofuran cou-
pling partner 11 was synthesized from phenol in two steps
using the procedure reported by Stoltz.19 The monosubsti-
tuted nature of 11 indicated a type I status in cross-met-
athesis reactions,14 and therefore, a relatively large excess
of the styrene 12 was employed. After much experimenta-
tion, heating a mixture of dihydrobenzofuran 11, styrene
12 (4.2 equivalents) and Grubbs’ second-generation cata-
lyst (2.6 mol%) in dichloromethane at reflux for 46 hours
delivered the cross-metathesis product 9 in a 71% yield.
Smooth hydrogenolysis with concomitant double bond re-
duction provided the key cyclization precursor 7 in excel-
lent yield (Scheme 7).
Pd(OAc)2, Ph3P
TBAI, Et3N
4 Å MS
DMF, 120 °C, 36 h
OH
I
O
+
40%
17
O
OH
10
16
Pd(PPh3)4
PPh3
Pd
6-exo-trig
I
Grubbs II
BnO
CH2Cl2
O
PPh3
OH
reflux, 46 h
+
Ph3P
H
PPh3
71%
Pd
PPh3
Ph3P
I
I
Pd
11
12
HO
OH
(4.2 equiv)
O
BnO
HO
Pd/C, H2
OH
18
19
EtOH
r.t., 67 h
O
O
92%
9
Scheme 5 Unexpected formation of chroman 17
7
Scheme 7 Synthesis of cyclization precursor 7
At this stage of our work, unrelated studies in our group
resulted in the serendipitous formation of the chromene
20.17 Although only produced on small scale as an undes-
ired by-product, passing a solution of 20 over Adams’ cat-
alyst through an H-Cube® hydrogenation apparatus
provided sufficient quantities of chroman-tethered phenol
6 to attempt the desired oxidative radical cyclization.
However, despite subjecting 6 to the standard oxidative
Next, the key radical cyclization could be attempted. Irra-
diating a cyclohexane solution of phenol 7 in the presence
of diacetoxyiodobenzene and iodine gave a complex mix-
ture of products, even at 0 °C. Replacing diacetoxyiodo-
benzene with lead tetraacetate as the oxidant also gave
complex mixtures from which no spiroketal 5 could be de-
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1386
J. Sperry et al.
PAPER
OH
tected. The use of mercuric oxide in the oxidative radical
spiroketalization protocol resulted in a cleaner reaction,
but disappointingly, only small amounts of the iodide 21
were isolated, arising from electrophilic iodination of the
aromatic ring. The use of bis(trifluoroacetoxy)iodoben-
zene also resulted in a relatively clean reaction, however
the only product isolated was the quinone 22 in moderate
yield. The oxygen gained in the quinone product 22 pre-
sumably originates from the trifluoroacetate anion fol-
lowed by hydrolysis during workup (Scheme 8).
O
MeO2C
CO2H
OH
O
H
O
O
HO
OH
HO
O
O
H
OH
O
OH
(–)-berkelic acid (24)
aquilarinoside A (23)
[5,5]-spiroketal
[6,5]-spiroketal
OH
HO
I
O
O
O
O
O
O
HgO
13%
O
21
I2, hν (60 W)
cyclohexane
7 °C, 0.5–7 h
OMe
chaetoquadrin A (25)
[6,6]-spiroketal
PhI(OCOCF3)2
35%
7
O
Figure 2 Examples of natural products containing a monobenzan-
22
nulated spiroketal
O
O
see
text
chain length of the heterocyclic alkenes 11 or 41, or the al-
iphatic alcohol coupling partner 42–44 (Scheme 9). The
full details of this study25 are provided herein, providing a
strategy that is readily amenable to analogue production.
5
Scheme 8 Attempted oxidative radical cyclizations
The synthesis of the two heterocyclic alkenes 11 and 41
was undertaken. Heterocyclic alkene 11 was readily avail-
able from phenol (45),19 and alkene 41 was obtained by
the palladium-catalyzed annulation of 2-iodophenol (16)
The disappointing finding that phenols 6 and 7 were un-
suitable substrates for the oxidative radical cyclization
was attributed to either their reduced nucleophilicity or
the increased stabilization of the phenoxy radical by the
aromatic ring preventing the key intramolecular hydrogen
abstraction (IHA) step. Nevertheless, we sought to em-
ploy our cross-metathesis–oxidative radical cyclization
approach to the synthesis of monobenzannulated spiroket-
als, thus offering a novel route to this key moiety.1a Such
O
O
O
O
O
O
O
O
natural products possessing
a monobenzannulated
spiroketal include the agarwood component aquilarino-
side A (23),20 the extremophile-derived (–)-berkelic acid
(24),21,22 a potent matrix metalloprotease-3 (MMP) inhib-
itor (GI50 1.87 mM), and chaetoquadrin A (25), a member
of the chaetoquadrin family which exhibit promising
monoamine oxidase (MAO) inhibitory properties23
(Figure 2). Several novel approaches to this ring system
have been reported.24
oxidative
radical cyclization
O
O
O
y
OH
y
x
R
x
R
26; R = H, x = 1, y = 2
27: R = Me, x = 1, y = 2
28: R = Me, x = y = 1
29: R = Me, x = 2, y = 1
30; R = Me, x = y = 2
31; R = H, x = 1, y = 2
32; R = Me, x = y = 1
33; R = Me, x = 1, y = 2
34; R = Me, x = 2, y = 1
35; R = Me, x = y = 2
Thus, our retrosynthetic strategy to access various
monobenzannulated spiroketals is outlined in Scheme 9
and is based on our earlier proposed route to access bis-
benzannulated spiroketals. It was envisaged that
monobenzannulated spiroketals 26–30 could be synthe-
sized by oxidative radical cyclization of alcohols 31–35,
which in turn could be formed by concomitant hydrogena-
tion of the alkene and hydrogenolysis of the benzyl group
in alkenes 36–40. Each of the alkenes 36–40 could be as-
sembled via cross-metathesis of the appropriate heterocy-
clic coupling partner 11 or 41 with the appropriate alkene
42–44 (Scheme 9). This convergent approach should al-
low for the synthesis of monobenzannulated [5,5]-, [6,5]-
and [6,6]-spiroketals by simple alteration of the alkyl
O
hydrogenation
x
O
cross-metathesis
OBn
11 x = 1
41 x = 2
x
+
y
R
OBn
36; R = H, x = 1, y = 2
37; R = Me, x = y = 1
38; R = Me, x = 1, y = 2
39; R = Me, x = 2, y = 1
40; R = Me, x = y = 2
y
R
42–44
Scheme 9 Retrosynthesis of monobenzannulated spiroketals
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PAPER
Synthesis of Benzannulated Spiroketals
1387
with 1,4-pentadiene.26 The alkene coupling partners 42– With the appropriate starting materials in hand, attention
4427 were obtained by benzylation of the commercially was turned to the cross-metathesis step (Table 1). Not sur-
available alcohol precursors under standard conditions prisingly, cross-metathesis of 11 with alkene 42 only af-
(Scheme 10).
forded a low yield of heterodimer 36, as both 11 and 42
are classified as type I alkenes (Table 1, entry 1).14 As a
result of this observation, disubstituted type III alkenes 43
and 44 were envisioned to be more suitable coupling part-
ners for heterocyclic alkenes 11 and 41. This was indeed
the case and it was found that heating a neat mixture of 11
(one equivalent) and alkene 43 (four equivalents) in the
presence of Grubbs’ second-generation catalyst (5 mol%)
provided the best yield of the desired heterodimer 37 as an
inconsequential mixture of E/Z isomers (Table 1, entry 2).
OBn
OH
O
O
2 steps19
4227a
OBn
45
11
41
OH
4327b
ref. 26
I
OBn
16
Based on this result, the synthesis of heterodimers 38–40
could thus be carried out in a similar fashion in moderate
yields. Careful monitoring of the reaction time for each in-
dividual example was necessary to minimize the forma-
tion of homodimeric products (Table 1). Thus, compound
4427c
Scheme 10 Cross-metathesis coupling partners
Table 1 Cross-Metathesis
Grubbs II
neat
60 °C
O
O
OBn
OH
+
y
x
x
R
y
R
Entry
1
Heterocyclic alkene
Alkene
Time (h) Product
Yield (%)(E/Z) ratio Notes
O
O
O
OBn
a
OBn
48
19
57
1:0
4:1
11
42
36
37
O
OBn
OBn
b,c
2
3
37
48
11
43
44
O
O
OBn
OBn
c,d
e,f
–
58
2.1:1
11
38
39
40
O
O
OBn
OBn
4
5
70
14
51
38
3.5:1
1.1:1
43
44
41
O
OBn
O
OBn
41
a A 7% yield of heterocycle dimer and 16% yield of alcohol dimer were obtained.
b A 41% yield of heterocycle dimer was obtained.
c Product A was observed.
d A 30% yield of heterocycle dimer was obtained.
e A 30% yield of heterocycle dimer was obtained.
f Product B was observed.
O
Ph
O
Ph
A
B
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1388
J. Sperry et al.
PAPER
38 was obtained from the alkene coupling partners 11 and cross-metathesis adducts 36, 38 and 40 (Table 2, entries 1,
44, 39 from 41 and 43, and 40 from 41 and 44, respective- 3 and 5).28 The over-reduction could be eliminated by
ly (Table 1, entries 3–5). Heterodimers 37–40 were all conducting the hydrogenation with 10% palladium on car-
produced as inconsequential mixtures of E/Z isomers bon in ethyl acetate (conditions B). The shorter chain
which were nearly always accompanied by the formation cross-metathesis adducts 37 and 39 underwent smooth hy-
of the homodimer of the heterocyclic alkene (Table 1).
drogenation with Pearlman’s catalyst to give the desired
aliphatic alcohols 32 and 34, respectively (Table 2, entries
2 and 4).
Next, hydrogenation of the cross-metathesis adducts was
conducted using heterodimer 36 as our initial substrate
(Table 2). Thus, hydrogenation of 36 over Pearlman’s cat- With the spiroketalization precursors 31–35 in hand, the
alyst in methanol (conditions A) afforded the desired key oxidative radical cyclization was attempted (Table 3).
product 31, but in poor yield. Much to our surprise, we Thus, to a solution of 31 in cyclohexane was added iodine
also observed trace amounts of the hydrogenolysis prod- and diacetoxyiodobenzene at 5 °C. The resulting solution
uct 46 (Table 2, entry 1), and even more puzzlingly, this was maintained at this temperature for two hours whilst
over-reduction was only observed in the longer chain being irradiated with a desk lamp (60 W). Gratifyingly,
Table 2 Hydrogenation Conditionsa
conditions
A or B
O
O
O
OBn
OH
+
x
y
x
x
y
y
R
R
R
x = 1, 2
y = 0, 1
x = 1, 2
y = 1, 2
Entry
1
Substrate
Hydrogenation conditions, product(s), yield (%)
O
O
O
OH
OBn
31
46
36
A
B
44
52
4
0
(E/Z = 100:0)
O
O
OH
OBn
2
3
32
(dr = 1:1)
83
37
(E/Z = 4:1)
A
O
O
OH
O
OBn
47
33
(dr = 1:1)
38
(dr = 1:1)
~10%
0
(E/Z = 2.1:1)
A
B
40
100
O
O
OH
OBn
4
5
34
39
(dr = 1:1)
(E/Z = 3.5:1)
A
76
O
OH
O
O
OBn
35
(dr = 1:1)
48
(dr = 1:1)
40
A
B
37
63
(E/Z = 1.1:1)
63
0
a Conditions A: H2, Pd(OH)2/C, MeOH, r.t., 2.5 h. Conditions B: H2, Pd/C, EtOAc, r.t., 3.5 h.
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PAPER
Synthesis of Benzannulated Spiroketals
1389
Table 3 Oxidative Radical Cyclization
PhI(OAc)2, I2, hν
cyclohexane
7 °C, 2 h
O
O
O
OH
y
x
y
R
x
R
Entry
1
Spiroketalization precursor
Product
Yield (%)
40
dr
–
O
O
O
OH
O
O
31
26
O
OH
O
2
3
42
73
1:0
+
O
4'
4'
32
(dr = 1:1)
28a (major)
28b (minor)
O
OH
O
O
1.4:1
33
(dr = 1:1)
27
O
OH
O
O
4
92
1.4:1
+
O
O
34
(dr = 1:1)
29b (minor)
29a (major)
O
OH
5
58
1:0
O
O
35
(dr = 1:1)
30
the desired monobenzannulated spiroketal 26 was ob- spiroketal 28a was more upfield than the corresponding
tained in moderate yield (Table 3, entry 1). Spiroketal 26 methyl group in 28b where it occupied a position syn to
was isolated as a single racemic conformer wherein the the oxygen atom of the dihydrobenzofuran moiety. Simi-
C–O bond of the five-membered ring adopts an axial po- larly, the resonance for H-4¢ in spiroketal 28a was further
sition with respect to the six-membered ring.
PhI(OAc)2, I2, hν
O
cyclohexane
7 °C, 2 h
The methyl substituted precursors 32–35 were subjected
to the same spiroketalization conditions, delivering
spiroketals 27–30 in variable yields. Higher yields were
observed for the formation of the five-membered rings (28
and 29) compared to their six-membered counterparts (26,
27 and 30). This was attributed to the fact that the intramo-
lecular hydrogen abstraction proceeds through an unfa-
vored seven-membered transition state, 49 when forming
six-membered rings (Scheme 11).
O
O
OH
n = 1, 2
R = H, Me
n
n
R
R
(31, 32 and 35)
(26, 27 and 30)
‡
O
IHA
then [O]
H
O
n
With spiroketals 28 and 29, two inseparable racemic dia-
stereomers were observed for each spiroketal. With re-
spect to diastereomeric spiroketals 28a and 28b
(Figure 3), it was found that the methyl group at C-4¢ in
R
seven-membered
transition state
49
Scheme 11 Oxidative radical cyclization
Synthesis 2011, No. 9, 1383–1398 © Thieme Stuttgart · New York

1390
J. Sperry et al.
PAPER
All reactions were carried out in oven-dried or flame-dried glass-
ware under a nitrogen atmosphere unless otherwise stated. Analyti-
cal thin-layer chromatography was performed using 0.2 mm
Kieselgel F254 (Merck) silica plates and compounds were visual-
ized under 365 nm UV irradiation followed by staining with either
alkaline permanganate or ethanolic vanillin solution. Column chro-
matography was carried out using 0.063–0.1 mm silica gel. IR spec-
tra were obtained using a Perkin–Elmer Spectrum One Fourier
Transform IR spectrometer with a universal attenuated total refrac-
tance (ATR) attachment installed. Absorption maxima are ex-
pressed as wavenumbers (cm–1). NMR spectra were recorded as
indicated on either a Bruker DRX-400 spectrometer operating at
400 MHz for 1H nuclei and 100 MHz for 13C nuclei, or on a Bruker
Avance 300 spectrometer operating at 300 MHz and 75 MHz for 1H
and 13C nuclei, respectively. Chemical shifts are reported in parts
per million (ppm) relative to the tetramethylsilane peak recorded at
d = 0.00 ppm in CDCl3–TMS solvent, the residual chloroform peak
O
O
H
H
Me
O
O
H
H
H
H
4'
4'
Me
H
H
H
H
28a (major)
28b (minor)
= NOE correlation
Figure 3 NOE correlations observed for spiroketal 28
downfield than that for H-4¢ in 28b due to H-4¢ in 28a be-
ing syn to the oxygen atom of the dihydrobenzofuran moi-
ety. Based on this and NOE evidence, spiroketal 28a was
assigned as the major diastereomer with the methyl group
adopting a pseudoequatorial position (Figure 3). A similar
rationale was used to assign the major and minor diaste-
reomers of the [6,5]-spiroketal 29.
1
at d = 7.25 ppm or the residual acetone peak at d = 2.05 ppm. H
NMR data are reported as chemical shift (d), relative integral, mul-
tiplicity, coupling constant (J in Hz) and assignment. The 13C NMR
values were referenced to the residual chloroform peak at d = 77.0
ppm or the residual acetone peak at d = 29.8 ppm. 13C NMR data are
reported as chemical shift (d) and assignment. Assignments were
made with the aid of DEPT 135, COSY, NOESY and HSQC exper-
iments. Atom-numbering is shown in Figure 4 for compounds 26–
30. High-resolution mass spectra were recorded on a VG-70SE
mass spectrometer at a nominal accelerating voltage of 70 eV. H-
Cube® continuous hydrogenation equipment (Thompson Scientific)
used a flow rate of 1 mL·min–1, a block temperature of 20 °C and
pressure of 10 bar.
Surprisingly, spiroketals 27 and 30 were obtained as a sin-
gle racemic diastereomer. It was established that the
methyl substituent adopted an equatorial position on the
six-membered ring, and the corresponding spiroketal
bearing a methyl group in the axial position was not ob-
served. Presumably, once spiroketal formation had taken
place, ring-opening and ring-closure resulted in formation
of the thermodynamically favored spiroketal in which the
methyl group was equatorial and the C–O bond of the
five-membered ring was axial with respect to the six-
membered ring, thus gaining maximum stability from the
anomeric effect. Therefore, the formation of two racemic
diastereomers for each of spiroketals 28 and 29 can be ra-
tionalized by the fact that the anomeric effect is weaker in
five-membered ring systems (spiroketals 28 and 29) than
in six-membered ring systems (spiroketals 27 and 30).29
6
7
6
7
7a
5
1
O
5
7a
O1
2
2'
4'
4
3a
2
1'
O
6'
4
3a
1'
O
2'
6'
3
7
4'
3
3' Me
5'
3'
5'
26
27
6
6
7
Unfortunately, as neither the diastereomeric mixtures of
spiroketals 28a,b nor 29a,b were separable by chromatog-
raphy, subjecting the minor diastereomer to the reaction
conditions was not possible and we were unable to un-
equivocally confirm that equilibration did occur in this
case. It is equally feasible that the transition state for for-
mation of these products simply minimizes diaxial inter-
actions, which in the [6,5] and [5,5] systems is not as
destabilizing, and thus the formation of two diastereomers
is observed for 28 and 29.
5
5
7a
7a
1
O
1
O
4
4
3a
3a
H
Me
2
2
1'
3
3
O
O1'
2'
2'
HA
HA
HA
HA
4'
4'
3'
5'
3'
5'
Me
H
HB
HB
HB
HB
28a (major)
28b (minor)
7
7
6
6
8
8
5
5
8a
8a
4a
4a
4
O1
2
O1
4
In conclusion, we have investigated the synthesis of both
mono and bisbenzannulated spiroketals using a mild oxi-
dative radical cyclization approach. Although this strate-
gy proved elusive to provide a novel route toward
bisbenzannulated spiroketals, it did offer a new approach
to monobenzannulated spiroketals such as those observed
in (–)-berkelic acid (24). Studies toward the synthesis of
the monobenzannulated spiroketal natural products 23–25
and analogues thereof, using this methodology are ongo-
ing.
H
2'
4'
Me
2
1'
O
O1'
2'
HA3
HA
HA3
HA
4'
3'
5'
3'
5'
Me
H
HB
HB
HB
HB
29a (major)
29b (minor)
7
6
8
5
8a
4a
1
O
4
2
1'
6'
2'
3
O
4'
3' Me
5'
30
Figure 4 Numbering of atoms for compounds 26–30
Synthesis 2011, No. 9, 1383–1398 © Thieme Stuttgart · New York

PAPER
Synthesis of Benzannulated Spiroketals
1391
Cross-Metathesis; General Procedure A
13C NMR (75 MHz, CDCl3): d = 22.2 (CH2), 27.6 (Me), 31.2 (CH2),
81.3 (C), 117.0 (CH), 117.9 (CH), 119.8 (CH), 121.6 (CH), 125.6
(CH), 127.5 (CH), 127.9 (C), 129.2 (CH), 129.7 (CH), 152.0 (C),
155.6 (C), (1 × C not observed).
Grubbs II catalyst (5 mol%) was added to a mixture of heterocyclic
alkene 11 or 41 and alkene 42, 43 or 44 (4 or 6 equiv) at r.t. and the
neat reaction mixture was heated at 60 °C under N2 for 14–70 h. Af-
ter cooling to r.t., purification by column chromatography on silica
gel (hexanes–CH2Cl2, 1:1, then 100% CH2Cl2) gave the hetero-
dimeric product.
MS (EI, 70 eV): m/z (%) = 263 (100) [M + Na+], 241 (10), 209 (9),
147 (8), 121 (10).
HRMS (EI): m/z [M + Na+] calcd for C16H16NaO2: 263.1040; found:
263.1043.
Hydrogenation/Hydrogenolysis; General Procedure B
Conditions A
2-(Chroman-2-ylmethyl)phenol (6)
Pd(OH)2 [20 wt% Pd (dry basis) on carbon, 5–26 mg] was added to
a soln of heterodimer in MeOH (1–2 mL). H2 was bubbled through
the reaction mixture at r.t. for 2.5–5 h after which the mixture was
filtered through Celite®. The catalyst was washed with EtOAc (5 ×
10 mL) and the filtrate was concentrated in vacuo. The crude prod-
uct was purified by column chromatography on silica gel (hexanes–
EtOAc, 3:1) to give the alcohol product.
Alkene 20 (10 mg, 0.04 mmol) was dissolved in EtOAc (4 mL) and
MeOH (4 mL) before hydrogenation employing a H-Cube® contin-
uous hydrogenation apparatus (Thompson Scientific) using a flow
rate of 1 mL·min–1, a block temperature of 20 °C and pressure of 10
bar. The solvent was removed in vacuo and the resulting oil was pu-
rified via preparatory thin layer chromatography (hexanes–EtOAc,
4:1) to afford the title compound.
Conditions B
Colorless oil; yield: 8 mg, 0.03 mmol (79%).
IR (neat): 2926, 2857, 1595, 1231, 752 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.94–2.17 (m, 2 H, 3-H2), 2.77–
2.93 (m, 2 H, 2¢¢-H2), 3.09 (br s, 1 H, OH), 3.25–3.31 (m, 1 H, 4-Ha),
4.71–4.80 (m, 1 H, 4-Hb), 6.81–6.90 (m, 3 H, Ar-H), 7.08–7.23 (m,
4 H, Ar-H), 7.31–7.52 (m, 1 H, Ar-H).
13C NMR (75 MHz, CDCl3): d = 25.9 (CH2, C-4), 35.4 (CH2, C-3),
36.3 (CH2, C-2¢¢), 82.2 (CH, C-2), 109.5, 116.1, 120.6, 120.9, 125.1,
127.6, 128.0, 130.5 (8 × CH, C-5, C-6, C-7, C-8, C-3¢¢¢, C-4¢¢¢, C-
5¢¢¢, C-6¢¢¢), 140.7, 149.9, 154.1, 156.9 (4 × C, C-4a, C-8a, C-1¢¢¢, C-
2¢¢¢).
As above, except Pd/C (10 wt%, 6–14 mg) and EtOAc (1–2 mL)
were used as catalyst and solvent, respectively.
Oxidative Radical Cyclization; General Procedure C
A mixture of alcohol (1 equiv), PhI(OAc)2 (2 equiv) and I2 (2.25–
2.28 equiv) in cyclohexane (1 mL per 0.012 mmol of alcohol sub-
strate) was degassed with Ar at r.t. for 15 min. The resulting soln
was cooled in an ice-H2O bath (5 °C) and irradiated with a desk
lamp (60 W) for 2–3 h. The soln was diluted with Et2O (10 mL),
then sat. aq Na2S2O3 soln (10 mL) and sat. aq NaHCO3 soln (10 mL)
were added. After separation of both phases, the aq phase was ex-
tracted with Et2O (4 × 15 mL). The organic phases were combined,
dried over anhyd MgSO4, filtered and the solvents concentrated in
vacuo. The crude product was purified by column chromatography
on silica gel (100% n-pentane, then n-pentane–Et2O, 12:1) to give
the spiroketal product.
MS (EI, 70 eV): m/z (%) = 263 (3) [M + Na+], 237 (5), 174 (100),
146 (35).
HRMS (EI): m/z [M + Na+] calcd for C16H16NaO2: 263.1040; found:
263.1048.
The following compounds were prepared according to reported lit-
erature procedures: 2-methylenechroman (10),13 ( )-2-ethenyl-2,3-
dihydrobenzofuran (11),19 1-(benzyloxy)-2-ethenylbenzene (12),12
1-(benzyloxy)-2-iodobenzene (15),30 ( )-2-ethenylchroman (41),26
[(but-3-enyloxy)methyl]benzene (42),27a {[(2-methylprop-2-en-
yl)oxy]methyl}benzene (43),27b {[(3-methylbut-3-enyl)oxy]meth-
yl}benzene (44).27c 2-Methylchromene (13) is a known compound31
and was identified from its spectroscopic data.
( )-(E)-2-[2-(Benzyloxy)styryl]-2,3-dihydrobenzofuran (9)
Grubbs II catalyst (3 mg, 0.004 mmol, 2.6 mol%) and a soln of sty-
rene 12 (119 mg, 0.57 mmol) in CH2Cl2 (2.5 mL) were added to neat
alkene 11 (20 mg, 0.14 mmol) under N2 at r.t. The reaction mixture
was heated under reflux at 50 °C for 46 h after which it was concen-
trated in vacuo. The crude product was purified by column chroma-
tography on silica gel (hexanes–CH2Cl2, 4:1, then 1:1) to give the
title compound.
2-(2-Methylchroman-2-yl)phenol (17)
Yellow oil; yield: 32 mg, 0.097 mmol (71%).
To a base-washed, oven-dried, thick-walled sealed tube containing
freshly degassed DMF (5 mL) were added 4 Å MS (200 mg), TBAI
(1.26 mmol, 465 mg), Et3N (1.26 mmol, 175 mL), enol ether 10 (31
mg, 0.21 mmol), aryl iodide 16 (0.42 mmol, 131 mg), Pd(OAc)2 (10
mol%, 0.021 mmol, 5 mg) and Ph3P (10 mol%, 0.021 mmol, 6 mg).
The reaction mixture was covered with a blanket of Ar, the tube
tightly sealed and placed on a sand bath pre-heated to 120 °C, and
the contents stirred vigorously for 36 h. The reaction mixture was
cooled, diluted with H2O (20 mL) and extracted with EtOAc (3 × 20
mL). The combined organic extracts were washed with brine (2 ×
20 mL), dried (MgSO4), filtered and concentrated in vacuo. Purifi-
cation by column chromatography on silica gel (hexanes–EtOAc,
3:1) gave the title compound.
IR (neat): 3066, 3033, 2925, 2854, 1688, 1649, 1629, 1598, 1479,
1461, 1451, 1379, 1293, 1229, 1162, 1099, 1015, 909, 733, 696
cm–1.
1H NMR (400 MHz, CDCl3): d = 3.06 (dd, J = 15.6, 7.8 Hz, 1 H, 3-
Ha), 3.41 (dd, J = 15.6, 9.2 Hz, 1 H, 3-Hb), 5.09 (s, 2 H, OCH2Ph),
5.35 (dddd, J = 8.3, 8.3, 8.3, 1.0 Hz, 1 H, 2-H), 6.40 (dd, J = 15.9,
7.6 Hz, 1 H, OCHCH=CH), 6.79–6.86 (m, 2 H, 5-H, 7-H), 6.90–
6.94 (m, 2 H, 3¢-H, 5¢-H), 7.08–7.22 (m, 4 H, OCHCH=CH, 4-H, 4¢-
H, 6-H), 7.31–7.43 (m, 5 H, OCH2Ph), 7.48 (dd, J = 7.5, 1.2 Hz, 1
H, 6¢-H).
13C NMR (75 MHz, CDCl3): d = 36.3 (CH2, C-3), 70.3 (CH2,
OCH2Ph), 84.1 (CH, C-2), 109.4 (CH, C-5 or C-7), 112.5 (CH, C-
3¢ or C-5¢), 120.3 (CH, C-5 or C-7), 121.0 (CH, C-3¢ or C-5¢), 124.8
(CH, C-6), 125.6 (C, C-1¢), 126.8 (C, C-3a), 127.1 (CH, C-6¢), 127.2
(2 × CH, C-2¢¢, C-6¢¢), 127.3 (CH, OCHCH=CH), 127.9 (CH, C-4¢¢),
128.0 (CH, C-4), 128.5 (2 × CH, C-3¢¢, C-5¢¢), 128.9 (CH,
OCHCH=CH), 129.0 (CH, C-4¢), 137.0 (C, C-1¢¢), 156.0 (C, C-2¢),
159.4 (C, C-7a).
Pale-yellow oil; yield: 20 mg, 0.083 mmol (40%).
IR (neat): 3299, 3100, 2928, 2830, 1684, 1658, 1630, 1577, 1479,
1461, 1456, 1379, 1229, 1176, 1100, 1020, 922, 731, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.72 (s, 3 H, Me), 2.10–2.20 (m,
1 H, 3-Hb), 2.58–2.90 (m, 3 H, 3-Ha, 4-Ha, 4-Hb) 6.84–6.93 (m, 4 H,
Ar-H), 7.03–7.19 (m, 4 H, Ar-H), 8.25 (s, 1 H, OH).
Synthesis 2011, No. 9, 1383–1398 © Thieme Stuttgart · New York

1392
J. Sperry et al.
PAPER
MS (EI, 70 eV): m/z (%) = 328 (16) [M+], 237 (67), 221 (8), 209 (7),
197 (3), 189 (4), 178 (3), 165 (3), 144 (5), 131 (33), 119 (12), 107
(3), 91 (100), 77 (6), 65 (12), 51 (4), 39 (5).
MS (EI, 70 eV): m/z (%) = 366 (96) [M+], 272 (1), 259 (52), 246 (2),
233 (24), 145 (7), 133 (100), 119 (14), 107 (29), 91 (27), 77 (24), 65
(10), 51 (16), 39 (12).
HRMS (EI): m/z [M+] calcd for C23H20O2: 328.1463; found:
HRMS (EI): m/z [M+] calcd for C16H15IO2: 366.0117; found:
328.1461.
366.0124.
( )-2-[2-(2,3-Dihydrobenzofuran-2-yl)ethyl]phenol (7)
Pd/C (10 wt%, 84 mg) was added to a soln of alkene 9 (249 mg, 0.76
mmol) in EtOH (7 mL). The reaction mixture was evacuated and
back-filled with H2 (× 3, balloon), then stirred at r.t. under H2 for 67
h after which it was filtered through Celite® and the catalyst washed
with EtOAc (4 × 10 mL). The filtrates were combined and the sol-
vents concentrated in vacuo. The crude product was purified by col-
umn chromatography on silica gel (hexanes–EtOAc, 9:1) to give the
title compound.
( )-2-[2-(2,3-Dihydrobenzofuran-2-yl)ethyl]cyclohexa-2,5-di-
ene-1,4-dione (22)
A mixture of phenol 7 (26 mg, 0.108 mmol), PhI(OCOCF3)2 (93
mg, 0.216 mmol) and I2 (62 mg, 0.244 mmol) in cyclohexane (9.0
mL) was degassed with Ar at r.t. for 10 min. The resulting soln was
cooled in an ice-H2O bath (7 °C) and irradiated with a desk lamp (60
W) for 2.5 h after which it was diluted with Et2O (15 mL), then sat.
aq Na2S2O3 soln (12 mL) and sat. aq NaHCO3 soln (12 mL) were
added. After separation of both phases, the aq phase was extracted
with Et2O (4 × 15 mL). The organic phases were combined, dried
over anhyd MgSO4, filtered and the solvents concentrated in vacuo.
The crude product was purified by column chromatography on sili-
ca gel (hexanes–Et2O, 3:1) to give the title compound.
Colorless oil; yield: 167 mg, 0.69 mmol (92%).
IR (neat): 3390, 3033, 2921, 2851, 1595, 1479, 1456, 1374, 1229,
1170, 1096, 1043, 1014 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.91–2.00 (m, 1 H, 2¢-Ha), 2.06–
2.15 (m, 1 H, 2¢-Hb), 2.76–2.86 (m, 3 H, 1¢-H, 3¢¢-Ha), 3.20 (dd, J =
15.5, 8.9 Hz, 1 H, 3¢¢-Hb), 4.72 (dddd, J = 8.2, 8.2, 8.2, 5.1 Hz, 1 H,
2¢¢-H), 6.22 (br s, 1 H, OH), 6.77–6.86 (m, 4 H, 4-H, 5¢¢-H, 6-H, 7¢¢-
H), 7.03–7.12 (m, 4 H, 3-H, 4¢¢-H, 5-H, 6¢¢-H).
13C NMR (75 MHz, CDCl3): d = 25.9 (CH2, C-1¢), 35.4 (CH2, C-
3¢¢), 36.2 (CH2, C-2¢), 82.2 (CH, C-2¢¢), 109.5 (CH, C-6 or C-7¢¢),
116.0 (CH, C-6 or C-7¢¢), 120.6 (CH, C-4 or C-5¢¢), 120.8 (CH, C-4
or C-5¢¢), 125.0 (CH, C-4¢¢), 126.8 (C, C-3¢¢a), 127.1 (C, C-2), 127.6
(CH, C-5 or C-6¢¢), 128.0 (CH, C-5 or C-6¢¢), 130.4 (CH, C-3), 154.1
(C, C-1), 158.8 (C, C-7¢¢a).
MS (EI, 70 eV): m/z (%) = 240 (46) [M+], 145 (5), 133 (100), 131
(12), 119 (8), 107 (39), 105 (15), 103 (5), 91 (20), 77 (25), 65 (6),
51 (7), 39 (8).
HRMS (EI): m/z [M+] calcd for C16H16O2: 240.1150; found:
240.1151.
Orange oil; yield: 9.5 mg, 0.037 mmol (35%).
IR (neat): 3049, 2921, 2851, 1657, 1598, 1480, 1461, 1264, 1230
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.88–2.04 (m, 2 H, 2¢-H), 2.55–
2.63 (m, 1 H, 1¢-Ha), 2.67–2.74 (m, 1 H, 1¢-Hb), 2.90 (dd, J = 15.5,
7.4 Hz, 1 H, 3¢¢-Ha), 3.33 (dd, J = 15.4, 9.0 Hz, 1 H, 3¢¢-Hb), 4.77–
4.84 (m, 1 H, 2¢¢-H), 6.61 (s, 1 H, 3-H), 6.71–6.76 (m, 2 H, 5-H, 7¢¢-
H), 6.77 (d, J = 10.1 Hz, 1 H, 6-H), 6.83 (t, J = 7.2 Hz, 1 H, 5¢¢-H),
7.10 (t, J = 7.7 Hz, 1 H, 6¢¢-H), 7.15 (d, J = 7.2 Hz, 1 H, 4¢¢-H).
13C NMR (100 MHz, CDCl3): d = 25.5 (CH2, C-1¢), 34.2 (CH2, C-
2¢), 35.3 (CH2, C-3¢¢), 82.0 (CH, C-2¢¢), 109.4 (CH, C-7¢¢), 120.4
(CH, C-5¢¢), 125.0 (CH, C-4¢¢), 126.4 (C, C-3¢¢a), 128.1 (CH, C-6¢¢),
132.8 (CH, C-3), 136.4 (CH, C-5), 136.8 (CH, C-6), 148.7 (C, C-2),
159.2 (C, C-7¢¢a), 187.3 (C, C-1), 187.6 (C, C-4).
MS (EI, 70 eV): m/z (%) = 254 (17) [M+], 252 (7), 240 (1), 235 (1),
149 (4), 147 (8), 131 (100), 123 (14), 119 (6), 115 (4), 107 (16), 105
(7), 91 (18), 77 (13), 65 (7), 57 (7), 51 (7), 39 (11).
( )-2-[2-(2,3-Dihydrobenzofuran-2-yl)ethyl]-6-iodophenol (21)
A mixture of HgO (23 mg, 0.106 mmol) and I2 (27 mg, 0.106 mmol)
in cyclohexane (1.5 mL) was degassed with Ar at r.t. for 10 min.
Next, a soln of phenol 7 (25 mg, 0.104 mmol) in cyclohexane (1.5
mL) was added. The reaction mixture was further degassed with Ar
at r.t. for 5 min after which it was cooled in an ice-H2O bath (7 °C)
and irradiated with a desk lamp (60 W) for 3 h. The mixture was
quenched with sat. aq Na2S2O5 soln (10 mL), and Et2O (20 mL) and
sat. aq NaHCO3 soln (10 mL) were added. After separation of both
phases, the aq phase was extracted with Et2O (4 × 15 mL). The or-
ganic phases were combined, dried over anhyd MgSO4, filtered and
the solvents concentrated in vacuo. The crude product was purified
by column chromatography on silica gel (hexanes–Et2O, 5:1) to
give the title compound.
HRMS (EI): m/z [M+] calcd for C16H14O3: 254.0943; found:
254.0942.
( )-(E)-2-[4-(Benzyloxy)but-1-enyl]-2,3-dihydrobenzofuran
(36)
According to general procedure A, the title compound was obtained
from reaction of alkene 42 (200 mg, 1.233 mmol) and Grubbs II cat-
alyst (9 mg, 0.011 mmol, 5 mol%) with alkene 11 (30 mg, 0.205
mmol) for 48 h.
Pale-yellow oil; yield: 11 mg, 0.039 mmol (19%).
IR (neat): 3032, 2923, 2853, 1598, 1558, 1479, 1460, 1361, 1229,
1172, 1097, 1027, 1015, 965, 910, 872, 747, 733, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.41 (q, J = 6.6 Hz, 2 H, 3¢-H),
2.98 (dd, J = 15.5, 8.0 Hz, 1 H, 3-Ha), 3.33 (dd, J = 15.4, 9.1 Hz, 1
H, 3-Hb), 3.54 (t, J = 6.7 Hz, 2 H, 4¢-H), 4.51 (s, 2 H, OCH2Ph), 5.15
(q, J = 8.1 Hz, 1 H, 2-H), 5.75 (dd, J = 15.1, 7.7 Hz, 1 H, 1¢-H), 5.87
(dt, J = 15.3, 6.6 Hz, 1 H, 2¢-H), 6.77 (d, J = 7.9 Hz, 1 H, 7-H), 6.83
(t, J = 7.3 Hz, 1 H, 5-H), 7.10 (t, J = 7.8 Hz, 1 H, 6-H), 7.15 (d, J =
7.1 Hz, 1 H, 4-H), 7.26–7.34 (m, 5 H, OCH2Ph).
13C NMR (100 MHz, CDCl3): d = 32.6 (CH2, C-3¢), 36.1 (CH2, C-
3), 69.4 (CH2, C-4¢), 72.9 (CH2, OCH2Ph), 83.6 (CH, C-2), 109.3
(CH, C-7), 120.3 (CH, C-5), 124.8 (CH, C-4), 126.8 (C, C-3a),
127.6 (CH, C-4¢¢), 127.7 (2 × CH, C-2¢¢, C-6¢¢), 128.0 (CH, C-6),
128.4 (2 × CH, C-3¢¢, C-5¢¢), 130.7 (CH, C-2¢), 131.1 (CH, C-1¢),
138.3 (C, C-1¢¢), 159.3 (C, C-7a).
Pale-yellow oil; yield: 5 mg, 0.014 mmol (13%).
IR (neat): 3479, 2927, 2848, 1596, 1480, 1442, 1373, 1264, 1231,
1166, 1106, 1044, 1015 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.95–2.03 (m, 1 H, 2¢-Ha), 2.07–
2.17 (m, 1 H, 2¢-Hb), 2.81–2.92 (m, 3 H, 1¢-H, 3¢¢-Ha), 3.29 (dd, J =
15.4, 8.9 Hz, 1 H, 3¢¢-Hb), 4.73–4.80 (m, 1 H, 2¢¢-H), 5.64 (s, 1 H,
OH), 6.62 (t, J = 7.6 Hz, 1 H, 4-H), 6.79–6.85 (m, 2 H, 5¢¢-H, 7¢¢-
H), 7.09–7.16 (m, 3 H, 3-H, 4¢¢-H, 6¢¢-H), 7.52 (d, J = 7.9 Hz, 1 H,
5-H).
13C NMR (100 MHz, CDCl3): d = 27.4 (CH2, C-1¢), 35.4 (CH2, C-
3¢¢), 35.8 (CH2, C-2¢), 82.3 (CH, C-2¢¢), 86.6 (C, C-6), 109.4 (CH,
C-5¢¢ or C-7¢¢), 120.3 (CH, C-5¢¢ or C-7¢¢), 122.4 (CH, C-4), 125.0
(CH, C-4¢¢), 126.8 (C, C-3¢¢a), 128.0 (CH, C-6¢¢), 128.3 (C, C-2),
130.9 (CH, C-3), 136.3 (CH, C-5), 152.8 (C, C-1), 159.3 (C, C-7¢¢a).
Synthesis 2011, No. 9, 1383–1398 © Thieme Stuttgart · New York

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Synthesis of Benzannulated Spiroketals
1393
MS (EI, 70 eV): m/z (%) = 280 (8) [M+], 189 (5), 174 (4), 171 (3),
159 (24), 146 (8), 131 (7), 119 (6), 115 (4), 107 (6), 91 (100), 77 (8),
65 (10), 55 (5), 51 (5), 41 (9).
E-Isomer
Clear oil; yield: 23.7 mg, 0.081 mmol (39% of 58%).
IR (neat): 3029, 2920, 2853, 1674, 1596, 1478, 1460, 1379, 1361,
1228, 1097, 961, 870, 747, 697 cm–1.
HRMS (EI): m/z [M+] calcd for C19H20O2: 280.1463; found:
280.1456.
1H NMR (400 MHz, CDCl3): d = 1.80 (s, 3 H, 2¢-Me), 2.39 (td, J =
6.7, 2.6 Hz, 2 H, 3¢-H), 2.93 (dd, J = 15.4, 7.7 Hz, 1 H, 3-Ha), 3.33
(dd, J = 15.4, 8.1 Hz, 1 H, 3-Hb), 3.60 (t, J = 6.9 Hz, 2 H, 4¢-H), 4.51
(s, 2 H, OCH2Ph), 5.44–5.52 (m, 2 H, 1¢-H, 2-H), 6.76 (d, J = 7.9
Hz, 1 H, 7-H), 6.83 (t, J = 7.3 Hz, 1 H, 5-H), 7.10 (t, J = 7.7 Hz, 1
H, 6-H), 7.15 (d, J = 7.2 Hz, 1 H, 4-H), 7.25–7.33 (m, 5 H,
OCH2Ph).
13C NMR (100 MHz, CDCl3): d = 17.1 (CH3, 2¢-Me), 36.6 (CH2, C-
3), 39.4 (CH2, C-3¢), 68.6 (CH2, C-4¢), 72.9 (CH2, OCH2Ph), 79.6
(CH, C-2), 109.4 (CH, C-7), 120.2 (CH, C-5), 124.8 (CH, C-4),
126.0 (CH, C-1¢), 127.1 (C, C-3a), 127.56 (CH, C-4¢¢), 127.64 (2 ×
CH, C-2¢¢, C-6¢¢), 128.0 (CH, C-6), 128.4 (2 × CH, C-3¢¢, C-5¢¢),
138.2 (C, C-2¢), 138.4 (C, C-1¢¢), 159.4 (C, C-7a).
( )-(E/Z)-2-[3-(Benzyloxy)-2-methylprop-1-enyl]-2,3-dihydro-
benzofuran (37)
According to general procedure A, reaction of alkene 43 (133 mg,
0.820 mmol) and Grubbs II catalyst (9 mg, 0.011 mmol, 5 mol%)
with alkene 11 (30 mg, 0.205 mmol) for 37 h gave the title com-
pound as a mixture of E/Z isomers in the ratio 4:1 (as determined by
1H NMR spectroscopy). These isomers were separated for charac-
terization purposes.
Clear oil; yield: 33 mg, 0.118 mmol (57%).
E-Isomer
Viscous oil; yield: 26.4 mg, 0.094 mmol (46% of 57%).
MS (EI, 70 eV): m/z (%) = 294 (15) [M+], 203 (10), 185 (17), 173
(33), 160 (10), 145 (8), 131 (9), 119 (5), 107 (12), 91 (100), 81 (8),
71 (10), 57 (16), 41 (13).
IR (neat): 3031, 2916, 2848, 1596, 1479, 1461, 1377, 1354, 1228,
1096, 1071, 963, 909, 872, 731, 697 cm–1
1H NMR (400 MHz, CDCl3): d = 1.82 (s, 3 H, 2¢-Me), 2.96 (dd, J =
15.3, 8.4 Hz, 1 H, 3-Ha), 3.37 (dd, J = 15.3, 8.9 Hz, 1 H, 3-Hb), 3.96
(s, 2 H, 3¢-H), 4.50 (s, 2 H, OCH2Ph), 5.51 (q, J = 8.6 Hz, 1 H, 2-
H), 5.77 (d, J = 8.6 Hz, 1 H, 1¢-H), 6.77 (d, J = 7.9 Hz, 1 H, 7-H),
6.83 (t, J = 7.3 Hz, 1 H, 5-H), 7.10 (t, J = 7.8 Hz, 1 H, 6-H), 7.15
(d, J = 7.1 Hz, 1 H, 4-H), 7.25–7.34 (m, 5 H, OCH2Ph).
13C NMR (100 MHz, CDCl3): d = 14.3 (CH3, 2¢-Me), 36.5 (CH2, C-
3), 72.0 (CH2, OCH2Ph), 75.0 (CH2, C-3¢), 79.2 (CH, C-2), 109.4
(CH, C-7), 120.3 (CH, C-5), 124.8 (CH, C-4), 126.6 (CH, C-1¢),
126.9 (C, C-3a), 127.6 (CH, C-4¢¢), 127.7 (2 × CH, C-2¢¢, C-6¢¢),
128.0 (CH, C-6), 128.4 (2 × CH, C-3¢¢, C-5¢¢), 137.2 (C, C-2¢), 138.2
(C, C-1¢¢), 159.3 (C, C-7a).
MS (EI, 70 eV): m/z (%) = 280 (9) [M+], 189 (2), 175 (4), 161 (4),
159 (7), 145 (3), 131 (17), 119 (3), 115 (3), 107 (5), 91 (100), 77 (6),
65 (7), 55 (5), 51 (4), 39 (8).
HRMS (EI): m/z [M+] calcd for C19H20O2: 280.1463; found:
280.1463.
HRMS (EI): m/z [M+] calcd for C20H22O2: 294.1620; found:
294.1626.
Z-Isomer
Pale-yellow oil; yield: 11.3 mg, 0.038 mmol (19% of 58%).
1H NMR (400 MHz, CDCl3): d = 1.81 (d, J = 1.2 Hz, 3 H, 2¢-Me),
2.39 (ddd, J = 13.4, 6.6, 6.6 Hz, 1 H, 3¢-Ha), 2.62 (ddd, J = 13.4,
7.5, 7.6 Hz, 1 H, 3¢-Hb), 2.89 (dd, J = 15.5, 8.3 Hz, 1 H, 3-Ha), 3.23
(dd, J = 15.5, 8.7 Hz, 1 H, 3-Hb), 3.54 (ddd, J = 9.1, 7.2, 7.2 Hz, 1
H, 4¢-Ha), 3.60 (ddd, J = 9.2, 5.8, 7.4 Hz, 1 H, 4¢-Hb), 4.51 (d, J =
12.1 Hz, 1 H, OCHaHbPh), 4.55 (d, J = 12.1 Hz, 1 H, OCHaHbPh),
5.47 (q, J = 8.7 Hz, 1 H, 2-H), 5.55 (d, J = 8.7 Hz, 1 H, 1¢-H), 6.75
(d, J = 7.9 Hz, 1 H, 7-H), 6.82 (td, J = 7.5, 0.8 Hz, 1 H, 5-H), 7.07–
7.12 (m, 2 H, 4-H, 6-H), 7.26–7.35 (m, 5 H, OCH2Ph).
13C NMR (100 MHz, CDCl3): d = 24.0 (CH3, 2¢-Me), 32.9 (CH2, C-
3¢), 36.6 (CH2, C-3), 68.6 (CH2, C-4¢), 73.0 (CH2, OCH2Ph), 79.5
(CH, C-2), 109.3 (CH, C-7), 120.2 (CH, C-5), 124.7 (CH, C-4),
126.9 (CH, C-1¢), 127.2 (C, C-3a), 127.57 (CH, C-4¢¢), 127.61 (2 ×
CH, C-2¢¢, C-6¢¢), 127.9 (CH, C-6), 128.4 (2 × CH, C-3¢¢, C-5¢¢),
138.1 (C, C-2¢), 138.4 (C, C-1¢¢), 159.4 (C, C-7a).
Z-Isomer
Pale-yellow oil; yield: 6.6 mg, 0.024 mmol (11% of 57%).
1H NMR (400 MHz, CDCl3): d = 1.88 (d, J = 1.0 Hz, 3 H, 2¢-Me),
2.94 (dd, J = 15.5, 8.2 Hz, 1 H, 3-Ha), 3.30 (dd, J = 15.5, 8.9 Hz, 1
H, 3-Hb), 4.06 (d, J = 11.8 Hz, 1 H, 3¢-Ha), 4.19 (d, J = 11.9 Hz, 1
H, 3¢-Hb), 4.51 (s, 2 H, OCH2Ph), 5.48 (q, J = 8.7 Hz, 1 H, 2-H),
5.66 (d, J = 9.0 Hz, 1 H, 1¢-H), 6.76 (d, J = 7.9 Hz, 1 H, 7-H), 6.83
(t, J = 7.3 Hz, 1 H, 5-H), 7.10 (t, J = 7.8 Hz, 1 H, 6-H), 7.14 (d, J =
7.3 Hz, 1 H, 4-H), 7.26–7.36 (m, 5 H, OCH2Ph).
13C NMR (100 MHz, CDCl3): d = 21.7 (CH3, 2¢-Me), 36.7 (CH2, C-
3), 68.6 (CH2, C-3¢), 72.1 (CH2, OCH2Ph), 78.7 (CH, C-2), 109.4
(CH, C-7), 120.3 (CH, C-5), 124.8 (CH, C-4), 126.9 (C, C-3a),
127.7 (CH, C-4¢¢), 127.8 (2 × CH, C-2¢¢, C-6¢¢), 128.0 (CH, C-6),
128.4 (2 × CH, C-3¢¢, C-5¢¢), 128.7 (CH, C-1¢), 137.5 (C, C-2¢),
138.1 (C, C-1¢¢), 159.3 (C, C-7a).
( )-(E/Z)-2-[3-(Benzyloxy)-2-methylprop-1-enyl]chroman (39)
According to general procedure A, reaction of alkene 43 (122 mg,
0.75 mmol) and Grubbs II catalyst (8 mg, 0.009 mmol, 5 mol%)
with alkene 41 (30 mg, 0.19 mmol) for 70 h gave the title compound
as a mixture of E/Z isomers in the ratio 3.5:1 (as determined by 1H
NMR spectroscopy). These isomers were separated for character-
ization purposes.
Clear oil; yield: 28 mg, 0.095 mmol (51%).
E-Isomer
Clear oil; yield: 21.8 mg, 0.074 mmol (40% of 51%).
IR (neat): 3060, 3027, 2923, 2850, 1581, 1522, 1487, 1455, 1231,
1094, 1068, 1045, 750, 735, 697 cm–1.
( )-(E/Z)-2-[4-(Benzyloxy)-2-methylbut-1-enyl]-2,3-dihydro-
benzofuran (38)
1H NMR (400 MHz, CDCl3): d = 1.77 (s, 3 H, 2¢-Me), 1.83–1.93
(m, 1 H, 3-Hax), 2.01 (dddd, J = 16.5, 5.9, 3.0, 3.0 Hz, 1 H, 3-Heq),
2.79 (dt, J = 16.6, 4.4 Hz, 1 H, 4-Heq), 2.91 (ddd, J = 16.6, 10.8, 6.0
Hz, 1 H, 4-Hax), 3.97 (s, 2 H, 3¢-H), 4.50 (s, 2 H, OCH2Ph), 4.81 (td,
J = 9.0, 2.5 Hz, 1 H, 2-H), 5.68 (d, J = 7.8 Hz, 1 H, 1¢-H), 6.81–6.85
(m, 2 H, 6-H, 8-H), 7.04–7.10 (m, 2 H, 5-H, 7-H), 7.27–7.35 (m, 5
H, OCH2Ph).
According to general procedure A, reaction of alkene 44 (217 mg,
1.231 mmol) and Grubbs II catalyst (9 mg, 0.011 mmol, 5 mol%)
with alkene 11 (30 mg, 0.205 mmol) for 48 h gave the title com-
pound as a mixture of E/Z isomers in the ratio 2.1:1 (as determined
by 1H NMR spectroscopy). These isomers were separated for char-
acterization purposes.
13C NMR (100 MHz, CDCl3): d = 14.4 (CH3, 2¢-Me), 24.5 (CH2, C-
4), 27.8 (CH2, C-3), 72.0 (CH2, OCH2Ph), 72.5 (CH, C-2), 75.3
Clear oil; yield: 35 mg, 0.119 mmol (58%).
Synthesis 2011, No. 9, 1383–1398 © Thieme Stuttgart · New York

1394
J. Sperry et al.
PAPER
(CH2, C-3¢), 116.9 (CH, C-6 or C-8), 120.1 (CH, C-6 or C-8), 121.7
(C, C-4a), 126.7 (CH, C-1¢), 127.2 (CH, C-7), 127.6 (CH, C-4¢¢),
127.7 (2 × CH, C-2¢¢, C-6¢¢), 128.4 (2 × CH, C-3¢¢, C-5¢¢), 129.5 (CH,
C-5), 136.4 (C, C-2¢), 138.3 (C, C-1¢¢), 154.7 (C, C-8a).
MS (EI, 70 eV): m/z (%) = 294 (11) [M+], 235 (4), 217 (7), 199 (3),
187 (6), 174 (6), 160 (10), 145 (8), 131 (8), 107 (68), 91 (100), 81
(8), 77 (11), 65 (9), 44 (8), 41 (8).
1H NMR (400 MHz, CDCl3): d = 1.76–1.86 (m, 1 H, 3-Hax), 1.82 (s,
3 H, 2¢-Me), 1.90–1.96 (m, 1 H, 3-Heq), 2.38 (ddd, J = 13.2, 6.5, 6.5
Hz, 1 H, 3¢-Ha), 2.57 (ddd, J = 13.7, 7.1, 7.1 Hz, 1 H, 3¢-Hb), 2.72
(dt, J = 16.6, 4.0 Hz, 1 H, 4-Heq), 2.83 (ddd, J = 16.4, 11.0, 5.7 Hz,
1 H, 4-Hax), 3.52–3.62 (m, 2 H, 4¢-H), 4.51 (s, 2 H, OCH2Ph), 4.75
(td, J = 9.3, 1.9 Hz, 1 H, 2-H), 5.46 (d, J = 8.4 Hz, 1 H, 1¢-H), 6.78–
6.84 (m, 2 H, 6-H, 8-H), 7.02–7.09 (m, 2 H, 5-H, 7-H), 7.27–7.33
(m, 5 H, OCH2Ph).
13C NMR (100 MHz, CDCl3): d = 24.0 (CH3, 2¢-Me), 24.7 (CH2, C-
4), 28.2 (CH2, C-3), 33.1 (CH2, C-3¢), 68.6 (CH2, C-4¢), 72.6 (CH,
C-2), 72.9 (CH2, OCH2Ph), 116.9 (CH, C-6 or C-8), 120.0 (CH, C-
6 or C-8), 121.8 (C, C-4a), 126.8 (CH, C-1¢), 127.1 (CH, C-7), 127.5
(CH, C-4¢¢), 127.6 (2 × CH, C-2¢¢, C-6¢¢), 128.3 (2 × CH, C-3¢¢, C-
5¢¢), 129.5 (CH, C-5), 137.5 (C, C-2¢), 138.4 (C, C-1¢¢), 154.9 (C, C-
8a).
HRMS (EI): m/z [M+] calcd for C20H22O2: 294.1620; found:
294.1612.
Z-Isomer
Pale-yellow oil; yield: 6.2 mg, 0.021 mmol (11% of 51%).
1H NMR (400 MHz, CDCl3): d = 1.82–1.91 (m, 1 H, 3-Hax), 1.89 (s,
3 H, 2¢-Me), 1.92–1.99 (m, 1 H, 3-Heq), 2.75 (dt, J = 16.4, 4.4 Hz,
1 H, 4-Heq), 2.83 (ddd, J = 16.6, 10.9, 5.9 Hz, 1 H, 4-Hax), 4.05 (d,
J = 11.8 Hz, 1 H, 3¢-Ha), 4.16 (d, J = 11.7 Hz, 1 H, 3¢-Hb), 4.47 (d,
J = 11.9 Hz, 1 H, OCHaHbPh), 4.51 (d, J = 11.9 Hz, 1 H, OCHaHb-
Ph), 4.74 (td, J = 9.2, 2.1 Hz, 1 H, 2-H), 5.58 (d, J = 8.5 Hz, 1 H,
1¢-H), 6.79–6.85 (m, 2 H, 6-H, 8-H), 7.03–7.10 (m, 2 H, 5-H, 7-H),
7.27–7.36 (m, 5 H, OCH2Ph).
13C NMR (100 MHz, CDCl3): d = 21.7 (CH3, 2¢-Me), 24.5 (CH2, C-
4), 28.2 (CH2, C-3), 68.6 (CH2, C-3¢), 71.97 (CH, C-2), 71.99 (CH2,
OCH2Ph), 116.9 (CH, C-6 or C-8), 120.1 (CH, C-6 or C-8), 121.7
(C, C-4a), 127.2 (CH, C-7), 127.6 (CH, C-4¢¢), 127.7 (2 × CH, C-2¢¢,
C-6¢¢), 128.4 (2 × CH, C-3¢¢, C-5¢¢), 128.6 (CH, C-1¢), 129.5 (CH, C-
5), 137.1 (C, C-2¢), 138.2 (C, C-1¢¢), 154.6 (C, C-8a).
The cross-metathesis side products ( )-(E)-2-styryl-2,3-dihy-
drobenzofuran and (E)-2-styrylchroman (Table 1) were assigned
according to comparison with the literature.32
( )-4-(2,3-Dihydrobenzofuran-2-yl)butan-1-ol (31)33
According to general procedure B (conditions B), the title com-
pound was obtained from reaction of Pd/C (10 wt%, 14 mg) with
heterodimer 36 (33 mg, 0.118 mmol) in EtOAc (2 mL) for 4 h.
Pale-yellow oil; yield: 12 mg, 0.061 mmol (52%).
IR (neat): 3352, 2918, 2850, 1598, 1480, 1461, 1377, 1264, 1231,
1173, 1057, 1028, 1015, 869, 738 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.47–1.67 (m, 4 H, 2-H, 3-H),
1.70–1.77 (m, 1 H, 4-Ha), 1.81–1.92 (m, 1 H, 4-Hb), 2.86 (dd, J =
15.4, 7.8 Hz, 1 H, 3¢-Ha), 3.28 (dd, J = 15.5, 8.9 Hz, 1 H, 3¢-Hb),
3.68 (t, J = 6.2 Hz, 2 H, 1-H), 4.77 (tdd, J = 9.0, 7.4, 5.4 Hz, 1 H,
2¢-H), 6.75 (d, J = 8.0 Hz, 1 H, 7¢-H), 6.81 (td, J = 7.4, 0.8 Hz, 1 H,
5¢-H), 7.09 (t, J = 7.8 Hz, 1 H, 6¢-H), 7.14 (d, J = 7.3 Hz, 1 H, 4¢-H).
13C NMR (100 MHz, CDCl3): d = 21.7 (CH2, C-3), 32.6 (CH2, C-2),
35.5 (CH2, C-3¢), 35.8 (CH2, C-4), 62.8 (CH2, C-1), 83.1 (CH, C-
2¢), 109.3 (CH, C-7¢), 120.1 (CH, C-5¢), 124.9 (CH, C-4¢), 126.8 (C,
C-3¢a), 127.9 (CH, C-6¢), 159.5 (C, C-7¢a).
MS (EI, 70 eV): m/z (%) = 192 (65) [M+], 174 (6), 159 (12), 145
(23), 133 (34), 131 (35), 119 (31), 107 (78), 92 (8), 91 (65), 39 (23),
85 (100), 77 (28), 65 (17), 51 (14), 41 (15).
HRMS (EI): m/z [M+] calcd for C12H16O2: 192.1150; found:
192.1156.
( )-(E/Z)-2-[4-(Benzyloxy)-2-methylbut-1-enyl]chroman (40)
According to general procedure A, reaction of alkene 44 (198 mg,
1.12 mmol) and Grubbs II catalyst (8 mg, 0.009 mmol, 5 mol%)
with alkene 41 (30 mg, 0.19 mmol) for 14 h gave the title compound
as a mixture of E/Z isomers in the ratio 1.1:1 (as determined by 1H
NMR spectroscopy). These isomers were separated for character-
ization purposes.
Clear oil; yield: 22 mg, 0.071 mmol (38%).
E-Isomer
Clear oil; yield: 11.5 mg, 0.037 mmol (20% of 38%).
IR (neat): 3060, 3028, 2920, 2851, 1670, 1581, 1487, 1455, 1361,
1230, 1103, 1069, 1043, 750, 734, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.77 (s, 3 H, 2¢-Me), 1.82–1.89
(m, 1 H, 3-Hax), 1.94–2.00 (m, 1 H, 3-Heq), 2.37 (ddd, J = 13.9, 6.9,
6.9 Hz, 1 H, 3¢-Ha), 2.42 (ddd, J = 13.3, 6.7, 6.7 Hz, 1 H, 3¢-Hb),
2.77 (dt, J = 16.4, 4.3 Hz, 1 H, 4-Heq), 2.89 (ddd, J = 16.4, 10.9, 5.8
Hz, 1 H, 4-Hax), 3.61 (t, J = 6.9 Hz, 2 H, 4¢-H), 4.52 (s, 2 H,
OCH2Ph), 4.76 (td, J = 9.0, 2.0 Hz, 1 H, 2-H), 5.43 (d, J = 8.2 Hz,
1 H, 1¢-H), 6.81–6.85 (m, 2 H, 6-H, H-8), 7.03–7.09 (m, 2 H, 5-H,
7-H), 7.26–7.34 (m, 5 H, OCH2Ph).
13C NMR (100 MHz, CDCl3): d = 17.1 (CH3, 2¢-Me), 24.7 (CH2, C-
4), 27.9 (CH2, C-3), 39.5 (CH2, C-3¢), 68.7 (CH2, C-4¢), 72.8 (CH,
C-2), 72.9 (CH2, OCH2Ph), 116.9 (CH, C-6 or C-8), 120.0 (CH, C-
6 or C-8), 121.8 (C, C-4a), 125.9 (CH, C-1¢), 127.2 (CH, C-7), 127.5
(CH, C-4¢¢), 127.6 (2 × CH, C-2¢¢, C-6¢¢), 128.3 (2 × CH, C-3¢¢, C-
5¢¢), 129.5 (CH, C-5), 137.2 (C, C-2¢), 138.4 (C, C-1¢¢), 154.9 (C, C-
8a).
No 1H NMR or 13C NMR data were reported in the literature.33
( )-3-(2,3-Dihydrobenzofuran-2-yl)-2-methylpropan-1-ol (32)
According to general procedure B (conditions A), reaction of
Pd(OH)2 [20 wt% Pd (dry basis) on carbon, 5 mg] with heterodimer
37 (21 mg, 0.075 mmol) in MeOH (2 mL) for 2.5 h gave the title
compound as a mixture of inseparable diastereomers in the ratio 1:1.
Pale-yellow oil; yield: 12 mg, 0.062 mmol (83%).
IR (neat): 3392, 3045, 2923, 2848, 1597, 1480, 1461, 1373, 1264,
1230, 1033 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.03 (d, J = 6.6 Hz, 3 H, 2-Me, 2-
Me*), 1.54 (ddd, J = 13.6, 6.9, 3.5 Hz, 0.5 H, 3-Ha), 1.79 (t, J = 6.5
Hz, 1 H, 3-Ha*, 3-Hb*), 1.89–2.01 (m, 1.5 H, 2-H, 2-H*, 3-Hb), 2.85
(dd, J = 15.4, 7.9 Hz, 1 H, 3¢-Ha, 3¢-Ha*), 3.29 (dd, J = 14.9, 8.9 Hz,
0.5 H, 3¢-Hb), 3.33 (dd, J = 13.2, 9.0 Hz, 0.5 H, 3¢-Hb*), 3.51–3.59
(m, 2 H, 1-H, 1-H*), 4.86–4.95 (m, 1 H, 2¢-H, 2¢-H*), 6.75 (d, J =
7.9 Hz, 1 H, 7¢-H, 7¢-H*), 6.83 (t, J = 7.3 Hz, 1 H, 5¢-H, 5¢-H*), 7.10
(t, J = 7.6 Hz, 1 H, 6¢-H, 6¢-H*), 7.15 (d, J = 7.2 Hz, 1 H, 4¢-H, 4¢-
H*).
MS (EI, 70 eV): m/z (%) = 308 (11) [M+], 235 (4), 217 (7), 199 (3),
187 (6), 174 (6), 160 (10), 145 (8), 131 (8), 107 (68), 91 (100), 81
(8), 77 (11), 65 (9), 44 (8), 41 (8).
HRMS (EI): m/z [M+] calcd for C21H24O2: 308.1776; found:
308.1778.
13C NMR (100 MHz, CDCl3): d = 17.0, 17.2 (2 × CH3, 2-Me), 32.8,
33.7 (2 × CH, C-2), 35.9, 36.4 (2 × CH2, C-3¢), 39.6, 40.7 (2 × CH2,
Z-Isomer
Clear oil; yield: 10.5 mg, 0.034 mmol (18% of 38%).
Synthesis 2011, No. 9, 1383–1398 © Thieme Stuttgart · New York

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Synthesis of Benzannulated Spiroketals
1395
C-3), 67.6, 68.4 (2 × CH2, C-1), 81.4, 81.8 (2 × CH, C-2¢), 109.35,
109.39 (2 × CH, C-7¢), 120.3, 120.4 (2 × CH, C-5¢), 124.91, 124.93
(2 × CH, C-4¢), 126.8 (2 × C, C-3¢a), 128.0 (2 × CH, C-6¢), 159.1,
159.3 (2 × C, C-7¢a).
MS (EI, 70 eV): m/z (%) = 192 (14) [M+], 174 (1), 161 (4), 159 (6),
145 (4), 133 (14), 131 (10), 119 (15), 115 (3), 107 (25), 105 (6), 91
(30), 85 (100), 77 (11), 65 (8), 57 (19), 51 (7), 41 (16), 39 (14).
C-6¢), 121.98, 122.01 (2 × C, C-4¢a), 127.2 (2 × CH, C-7¢), 129.6 (2
× CH, C-5¢), 154.6, 154.7 (2 × C, C-8¢a).
MS (EI, 70 eV): m/z (%) = 206 (1) [M+], 185 (7), 149 (5), 147 (6),
133 (5), 131 (7), 121 (11), 111 (6), 105 (11), 92 (11), 83 (18), 77
(19), 69 (33), 57 (85), 55 (64), 43 (100), 38 (5).
HRMS (EI): m/z [M+] calcd for C13H18O2: 206.1307; found:
206.1311.
HRMS (EI): m/z [M+] calcd for C12H16O2: 192.1150; found:
192.1156.
( )-4-(Chroman-2-yl)-3-methylbutan-1-ol (35)
According to general procedure B (conditions B), reaction of Pd/C
(10 wt%, 6 mg) with heterodimer 40 (7 mg, 0.023 mmol) in EtOAc
(1 mL) for 3.5 h gave the title compound as a mixture of inseparable
diastereomers in the ratio 1:1.
( )-4-(2,3-Dihydrobenzofuran-2-yl)-3-methylbutan-1-ol (33)
According to general procedure B (conditions B), reaction of Pd/C
(10 wt%, 14 mg) with heterodimer 38 (11 mg, 0.037 mmol) in
EtOAc (1 mL) for 3.5 h gave the title compound as a mixture of in-
separable diastereomers in the ratio 1:1.
Pale-yellow oil; yield: 3.13 mg, 0.014 mmol (63%).
IR (neat): 3359, 2925, 2848, 1582, 1488, 1456, 1379, 1264, 1232,
1105, 1048, 735, 703 cm–1.
Yellow oil; yield: 7.7 mg, 0.037 mmol (100%).
IR (neat): 3364, 2925, 2848, 1597, 1480, 1460, 1378, 1264, 1230,
1053, 1015 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.99 (d, J = 6.2 Hz, 1.5 H, 3-Me),
1.00 (d, J = 6.2 Hz, 1.5 H, 3-Me*), 1.30–1.38 (m, 0.5 H, 4-Ha*),
1.42–1.83 (m, 4.5 H, 2-H, 2-H*, 3¢-Hax, 3¢-Hax*, 4-Ha*, 4-Hb, 4-
Hb*), 1.89–2.06 (m, 2 H, 3-H, 3-H*, 3¢-Heq, 3¢-Heq*), 2.74 (dt, J =
16.2, 4.3 Hz, 1 H, 4¢-Heq, 4¢-Heq*), 2.81–2.90 (m, 1 H, 4¢-Hax, 4¢-
Hax*), 3.67–3.78 (m, 2 H, 1-H, 1-H*), 4.05–4.13 (m, 1 H, 2¢-H, 2¢-
H*), 6.77–6.84 (m, 2 H, 6¢-H, 6¢-H*, 8¢-H, 8¢-H*), 7.02–7.09 (m, 2
H, 5¢-H, 5¢-H*, 7¢-H, 7¢-H*).
13C NMR (100 MHz, CDCl3): d = 19.7, 20.3 (2 × CH3, 3-Me), 24.7,
24.8 (2 × CH2, C-4¢), 25.9, 26.2 (2 × CH, C-3), 27.6, 28.2 (2 × CH2,
C-3¢), 39.6, 40.3 (2 × CH2, C-2), 42.5, 42.8 (2 × CH2, C-4), 60.9,
61.0 (2 × CH2, C-1), 73.7, 74.0 (2 × CH, C-2¢), 116.7 (2 × CH, C-6¢
or C-8¢), 120.0 (2 × CH, C-6¢ or C-8¢), 122.0 (2 × C, C-4¢a), 127.1
(2 × CH, C-7¢), 129.5 (2 × CH, C-5¢), 154.9 (2 × C, C-8¢a).
MS (EI, 70 eV): m/z (%) = 220 (50) [M+], 185 (11), 173 (4), 167 (4),
159 (4), 149 (12), 147 (9), 133 (40), 131 (10), 120 (39), 107 (100),
105 (15), 95 (30), 91 (14), 85 (14), 77 (18), 71 (23), 69 (21), 57 (32),
55 (24), 43 (29), 39 (10).
HRMS (EI): m/z [M+] calcd for C14H20O2: 220.1463; found:
220.1465.
1H NMR (400 MHz, CDCl3): d = 1.01 (d, J = 6.8 Hz, 1.5 H, 3-Me),
1.03 (d, J = 6.9 Hz, 1.5 H, 3-Me*), 1.42–1.55 (m, 1.5 H, 2-Ha, 2-
Ha*, 4-Ha), 1.60–1.69 (m, 1.5 H, 2-Hb, 2-Hb*, 4-Ha*), 1.72–1.82 (m,
0.5 H, 4-Hb*), 1.87–1.99 (m, 1.5 H, 3-H, 3-H*, 4-Hb), 2.83 (dd, J =
15.1, 7.7 Hz, 0.5 H, 3¢-Ha), 2.84 (dd, J = 15.3, 7.9 Hz, 0.5 H, 3¢-
Ha*), 3.29 (dd, J = 15.3, 8.3 Hz, 0.5 H, 3¢-Hb), 3.30 (dd, J = 15.4,
7.1 Hz, 0.5 H, 3¢-Hb*), 3.67–3.79 (m, 2 H, 1-H, 1-H*), 4.84–4.92
(m, 1 H, 2¢-H, 2¢-H*), 6.75 (d, J = 8.0 Hz, 1 H, 7¢-H, 7¢-H*), 6.82
(t, J = 7.3 Hz, 1 H, 5¢-H, 5¢-H*), 7.10 (t, J = 7.8 Hz, 1 H, 6-H, 6¢-
H*), 7.15 (d, J = 7.2 Hz, 1 H, 4¢-H, 4¢-H*).
13C NMR (100 MHz, CDCl3): d = 19.6, 20.1 (2 × CH3, 3-Me),
26.67, 26.69 (2 × CH, C-3), 35.8, 36.2 (2 × CH2, C-3¢), 39.6, 40.2
(2 × CH2, C-2), 43.3, 43.7 (2 × CH2, C-4), 60.85, 60.90 (2 × CH2,
C-1), 81.4, 81.6 (2 × CH, C-2¢), 109.3, 109.4 (2 × CH, C-7¢), 120.2
(2 × CH, C-5¢), 124.9 (2 × CH, C-4¢), 126.8, 126.9 (2 × C, C-3¢a),
127.9 (2 × CH, C-6¢), 159.4, 159.5 (2 × C, C-7¢a).
MS (EI, 70 eV): m/z (%) = 206 (31) [M+], 185 (4), 173 (8), 159 (6),
149 (9), 145 (10), 133 (48), 119 (31), 107 (80), 99 (100), 91 (64), 81
(37), 69 (21), 55 (33), 41 (40).
HRMS (EI): m/z [M+] calcd for C13H18O2: 206.1307; found:
( )-2-(2-Methylbutyl)chroman (48)
206.1312.
According to general procedure B (conditions A), reaction of
Pd(OH)2 [20 wt% Pd (dry basis) on carbon, 20 mg] with het-
erodimer 40 (38 mg, 0.123 mmol) in MeOH (2 mL) for 2.5 h gave
the title compound as a mixture of inseparable diastereomers in the
ratio 1:1.
( )-3-(Chroman-2-yl)-2-methylpropan-1-ol (34)
According to general procedure B (conditions A), reaction of
Pd(OH)2 [20 wt% Pd (dry basis) on carbon, 26 mg] with het-
erodimer 39 (28 mg, 0.095 mmol) in MeOH (2 mL) for 5 h gave the
title compound as a mixture of inseparable diastereomers in the ra-
tio 1:1.
Yellow oil; yield: 15.9 mg, 0.078 mmol (63%).
IR (neat): 2954, 2922, 2869, 2848, 1582, 1488, 1456, 1377, 1299,
1271, 1232, 1108, 1067, 1046, 991, 887 cm–1.
Light-brown oil; yield: 15 mg, 0.073 mmol (76%).
1H NMR (400 MHz, CDCl3): d = 0.90 (t, J = 7.4 Hz, 1.5 H, 4¢-H),
0.91 (t, J = 7.4 Hz, 1.5 H, 4¢-H*), 0.937 (d, J = 6.6 Hz, 1.5 H, 2¢-
Me), 0.943 (d, J = 6.3 Hz, 1.5 H, 2¢-Me*), 1.17–1.49 (m, 2.5 H, 1¢-
Ha, 3¢-H, 3¢-H*), 1.51–1.81 (m, 3.5 H, 3-Hax, 3-Hax*, 1¢-Ha*, 1¢-Hb,
1¢-Hb*, 2¢-H, 2¢-H*), 1.92–2.02 (m, 1 H, 3-Heq, 3-Heq*), 2.74 (ddd,
J = 16.5, 5.6, 3.5 Hz, 1 H, 4-Heq, 4-Heq*), 2.84 (ddd, J = 16.6, 11.0,
5.7 Hz, 0.5 H, 4-Hax), 2.85 (ddd, J = 16.6, 11.2, 5.6 Hz, 0.5 H, 4-
Hax*), 4.04–4.10 (m, 1 H, 2-H, 2-H*), 6.77–6.83 (m, 2 H, 6-H, 6-
H*, 8-H, 8-H*), 7.02–7.08 (m, 2 H, 5-H, 5-H*, 7-H, 7-H*).
13C NMR (100 MHz, CDCl3): d = 11.17, 11.24 (2 × CH3, C-4¢),
18.9, 19.6 (2 × CH3, 2¢-Me), 24.7, 24.8 (2 × CH2, C-4), 27.6, 28.2 (2
× CH2, C-3), 29.3, 30.0 (2 × CH2, C-3¢), 30.5, 30.9 (2 × CH, C-2¢),
42.2, 42.5 (2 × CH2, C-1¢), 73.7, 74.3 (2 × CH, C-2), 116.77, 116.79
(2 × CH, C-6 or C-8), 119.8 (2 × CH, C-6 or C-8), 122.1 (2 × C, C-
4a), 127.1 (2 × CH, C-7), 129.5 (2 × CH, C-5), 155.08, 155.10 (2 ×
C, C-8a).
IR (neat): 3362, 2924, 2872, 1581, 1487, 1456, 1380, 1231, 1107,
1039, 751 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.00 (d, J = 6.8 Hz, 1.5 H, 2-Me),
1.01 (d, J = 6.9 Hz, 1.5 H, 2-Me*), 1.44 (ddd, J = 14.3, 7.5, 2.9 Hz,
0.5 H, 3-Ha), 1.68–1.72 (m, 1 H, 3-Ha*, 3-Hb*), 1.74–1.87 (m, 1.5
H, 3-Hb, 3¢-Hax, 3¢-Hax*), 1.93–2.02 (m, 2 H, H-2, H-2*, 3¢-Heq, 3¢-
Heq*), 2.75 (ddd, J = 16.6, 5.7, 3.4 Hz, 1 H, 4¢-Heq, 4¢-Heq*), 2.81–
2.92 (m, 1 H, 4¢-Hax, 4¢-Hax*), 3.50–3.61 (m, 2 H, 1-H, 1-H*), 4.07–
4.18 (m, 1 H, 2¢-H, 2¢-H*), 6.78 (d, J = 8.1 Hz, 1 H, 8¢-H, 8¢-H*),
6.83 (t, J = 7.4 Hz, 1 H, 6¢-H, 6¢-H*), 7.03–7.09 (m, 2 H, 5¢-H, 5¢-
H*, 7¢-H, 7¢-H*).
13C NMR (100 MHz, CDCl3): d = 17.2, 17.3 (2 × CH3, 2 × 2-Me),
24.7 (2 × CH2, C-4¢), 27.8, 28.4 (2 × CH2, C-3¢), 32.4, 33.3 (2 × CH,
C-2), 38.9, 39.9 (2 × CH2, C-3), 67.7, 68.5 (2 × CH2, C-1), 73.9,
74.4 (2 × CH, C-2¢), 116.7 (2 × CH, C-8¢), 120.20, 120.24 (2 × CH,
Synthesis 2011, No. 9, 1383–1398 © Thieme Stuttgart · New York

1396
J. Sperry et al.
PAPER
MS (EI, 70 eV): m/z (%) = 204 (7) [M+], 203 (8), 165 (7), 120 (16),
(4.8 mL) for 2 h gave the title compound as a mixture of inseparable
105 (27), 89 (27), 71 (13).
major (28a) and minor* (28b) diastereomers in the ratio 1.4:1.
HRMS-FAB: m/z [M+] calcd for C14H20O: 204.1514; found:
Pale-yellow oil; yield: 8 mg, 0.042 mmol (73%).
204.1521.
IR (neat): 2954, 2924, 2855, 1598, 1479, 1462, 1377, 1241, 1120,
1082, 1010, 830, 779, 747, 706 cm–1.
( )-3¢,4¢,5¢,6¢-Tetrahydro-3H-spiro(benzofuran-2,2¢-pyran)
(26)9
According to general procedure C, the title compound was obtained
from reaction of PhI(OAc)2 (34 mg, 0.106 mmol) and I2 (30 mg,
0.118 mmol) with alcohol 31 (10 mg, 0.052 mmol) in cyclohexane
(4.3 mL) for 2.5 h.
1H NMR (400 MHz, CDCl3): d = 1.13 (d, J = 6.8 Hz, 3 H, 4¢-Me),
1.20 (d, J = 6.6 Hz, 2.1 H, 4¢-Me*), 1.73 (dd, J = 12.9, 10.1 Hz, 1
H, 3¢-HB), 2.12 (dd, J = 13.6, 6.0 Hz, 0.7 H, 3¢-HA*), 2.38 (dd, J =
13.4, 9.4 Hz, 0.7 H, 3¢-HB*), 2.45–2.54 (m, 0.7 H, 4¢-H*), 2.51 (dd,
J = 12.9, 7.0 Hz, 1 H, 3¢-HA), 2.69–2.82 (m, 1 H, 4¢-H), 3.23–3.32
(m, 3.4 H, 3-H, 3-H*), 3.56 (t, J = 8.0 Hz, 1 H, 5¢-HB), 3.68 (t, J =
8.2 Hz, 0.7 H, 5¢-HA*), 4.13 (t, J = 7.9 Hz, 0.7 H, 5¢-HB*), 4.25 (t,
J = 8.0 Hz, 1 H, 5¢-HA), 6.76 (d, J = 8.4 Hz, 1 H, 7-H), 6.79 (d, J =
8.9 Hz, 0.7 H, 7-H*), 6.85 (t, J = 7.4 Hz, 1.7 H, 5-H, 5-H*), 7.11 (t,
J = 7.9 Hz, 1.7 H, 6-H, 6-H*), 7.16 (d, J = 7.4 Hz, 1.7 H, 4-H, 4-
H*).
13C NMR (100 MHz, CDCl3): d = 17.7 (CH3, 4¢-Me), 18.0 (CH3, 4¢-
Me*), 32.3 (CH, C-4¢), 32.9 (CH, C-4¢*), 39.0 (CH2, C-3), 40.1
(CH2, C-3*), 44.6 (CH2, C-3¢*), 45.2 (CH2, C-3¢), 75.3 (CH2, C-
5¢*), 75.5 (CH2, C-5¢), 109.4 (CH, C-7), 109.5 (CH, C-7*), 118.6
(C, C-2*), 118.7 (C, C-2), 120.46 (CH, C-5), 120.51 (CH, C-5*),
124.49 (CH, C-4*), 124.53 (CH, C-4), 125.7 (C, C-3a), 125.8 (C, C-
3a*), 127.89 (CH, C-6*), 127.94 (CH, C-6), 157.7 (C, C-7a), 158.0
(C, C-7a*).
Colorless oil; yield: 4 mg, 0.021 mmol (40%).
IR (neat): 2923, 2848, 1598, 1479, 1461, 1366, 1239, 1089, 1071,
1046, 867, 809, 793, 771, 746, 707 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.60–1.73 (m, 2 H, 5¢-Hax, 5¢-Heq),
1.75–1.80 (m, 1 H, 4¢-Heq), 1.88 (dd, J = 13.6, 4.5 Hz, 1 H, 3¢-Heq),
1.98–2.08 (m, 2 H, 3¢-Hax, 4¢-Hax), 3.05 (d, J = 16.2 Hz, 1 H, 3-Ha),
3.11 (d, J = 16.2 Hz, 1 H, 3-Hb), 3.72 (dddd, J = 11.4, 4.3, 2.0, 2.0
Hz, 1 H, 6¢-Heq), 4.08 (td, J = 11.7, 2.9 Hz, 1 H, 6¢-Hax), 6.81–6.88
(m, 2 H, 5-H, 7-H), 7.11–7.17 (m, 2 H, 4-H, 6-H).
13C NMR (100 MHz, CDCl3): d = 19.7 (CH2, C-4¢), 24.7 (CH2, C-
5¢), 34.1 (CH2, C-3¢), 42.7 (CH2, C-3), 62.8 (CH2, C-6¢), 109.6 (C,
C-2), 109.7 (CH, C-7), 120.6 (CH, C-5), 125.0 (CH, C-4), 126.0 (C,
C-3a), 127.9 (CH, C-6), 158.2 (C, C-7a).
MS (EI, 70 eV): m/z (%) = 190 (1) [M+], 120 (2), 118 (3), 85 (65),
83 (100), 47 (33), 37 (11).
HRMS (EI): m/z [M+] calcd for C12H14O2: 190.0994; found:
190.0991.
MS (EI, 70 eV): m/z (%) = 190 (30) [M+], 175 (9), 134 (4), 131 (6),
107 (21), 85 (66), 83 (100), 78 (10), 47 (42), 37 (21).
HRMS (EI): m/z [M+] calcd for C12H14O2: 190.0994; found:
190.0990.
No 1H NMR or 13C NMR data were reported in the literature.9
( )-4¢-Methyl-4¢,5¢-dihydro-3¢H-spiro(chroman-2,2¢-furan)
(29a and 29b)
According to general procedure C, reaction of PhI(OAc)2 (41 mg,
0.127 mmol) and I2 (36 mg, 0.142 mmol) with a 1:1 mixture of
diastereomeric alcohols 34 (13 mg, 0.063 mmol) in cyclohexane
(5.25 mL) for 3 h gave the title compound as a mixture of insepara-
ble major (29a) and minor* (29b) diastereomers in the ratio 1.4:1.
( )-4¢-Methyl-3¢,4¢,5¢,6¢-tetrahydro-3H-spiro(benzofuran-2,2¢-
pyran) (27)
According to general procedure C, the title compound was obtained
from reaction of PhI(OAc)2 (53 mg, 0.165 mmol) and I2 (47 mg,
0.185 mmol) with a 1:1 mixture of diastereomeric alcohols 33 (17
mg, 0.082 mmol) in cyclohexane (6.9 mL) for 3 h.
Yellow oil; yield: 11.9 mg, 0.058 mmol (92%).
Pale-yellow oil; yield: 7 mg, 0.034 mmol (42%).
IR (neat): 2957, 2928, 2872, 1582, 1490, 1455, 1364, 1219, 1134,
1094, 1034, 1013, 838, 751 cm–1.
IR (neat): 2946, 2925, 2869, 1597, 1479, 1461, 1377, 1238, 1216,
1121, 1096, 1084, 1034, 869, 826, 810, 791, 776, 747, 706 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.10 (d, J = 6.9 Hz, 3 H, 4¢-Me),
1.18 (d, J = 6.9 Hz, 2.1 H, 4¢-Me*), 1.52 (dd, J = 12.7, 9.2 Hz, 1 H,
3¢-HB), 1.91 (dd, J = 13.4, 7.1 Hz, 0.7 H, 3¢-HA*), 1.99–2.06 (m, 3.4
H, 3-H, 3-H*), 2.20 (dd, J = 13.3, 9.5 Hz, 0.7 H, 3¢-HB*), 2.37 (dd,
J = 12.6, 7.5 Hz, 1 H, 3¢-HA), 2.41–2.49 (m, 0.7 H, 4¢-H*), 2.68–
2.84 (m, 2.7 H, 4-Heq, 4-Heq*, 4¢-H), 3.00–3.08 (m, 1.7 H, 4-Hax, 4-
Hax*), 3.51 (t, J = 7.5 Hz, 1 H, 5¢-HB), 3.64 (t, J = 8.6 Hz, 0.7 H, 5¢-
HA*), 4.05 (t, J = 7.9 Hz, 0.7 H, 5¢-HB*), 4.21 (t, J = 8.0 Hz, 1 H,
5¢-HA), 6.76 (d, J = 8.0 Hz, 1 H, 8-H), 6.79 (d, J = 8.0 Hz, 0.7 H, 8-
H*), 6.84 (t, J = 7.5 Hz, 1 H, 6-H), 6.85 (t, J = 7.4 Hz, 0.7 H, 6-H*),
7.05–7.10 (m, 3.4 H, 5-H, 5-H*, 7-H, 7-H*).
13C NMR (100 MHz, CDCl3): d = 17.6 (CH3, 4¢-Me*), 18.3 (CH3,
4¢-Me), 22.4 (CH2, C-4*), 22.7 (CH2, C-4), 30.4 (CH2, C-3), 30.6
(CH2, C-3*), 32.0 (CH, C-4¢), 33.2 (CH, C-4¢*), 45.4 (CH2, C-3¢*),
45.6 (CH2, C-3¢), 74.6 (CH2, C-5¢*), 75.1 (CH2, C-5¢), 107.2 (2 × C,
C-2, C-2*), 117.0 (CH, C-8), 117.1 (CH, C-8*), 120.3 (CH, C-6),
120.5 (CH, C-6*), 121.7 (C, C-4a), 121.8 (C, C-4a*), 127.15 (CH,
C-7*), 127.18 (CH, C-7), 129.08 (CH, C-5), 129.10 (CH, C-5*),
153.0 (C, C-8a), 153.1 (C, C-8a*).
1H NMR (400 MHz, CDCl3): d = 0.98 (d, J = 6.6 Hz, 3 H, 4¢-Me),
1.33 (qd, J = 12.8, 4.9 Hz, 1 H, 5¢-Hax), 1.47 (dd, J = 13.1, 12.5 Hz,
1 H, 3¢-Hax), 1.64 (dtd, J = 13.2, 3.8, 1.9 Hz, 1 H, 5¢-Heq), 2.03 (ddd,
J = 13.4, 3.8, 1.8 Hz, 1 H, 3¢-Heq), 2.08–2.24 (m, 1 H, 4¢-Hax), 3.05
(d, J = 16.3 Hz, 1 H, 3-Ha), 3.12 (d, J = 16.3 Hz, 1 H, 3-Hb), 3.74
(ddd, J = 11.4, 4.9, 1.5 Hz, 1 H, 6¢-Heq), 4.06 (ddd, J = 13.0, 11.3,
2.4 Hz, 1 H, 6¢-Hax), 6.80 (d, J = 7.9 Hz, 1 H, 7-H), 6.85 (td, J = 7.4,
0.9 Hz, 1 H, 5-H), 7.10–7.17 (m, 2 H, 4-H, 6-H).
13C NMR (100 MHz, CDCl3): d = 22.1 (CH3, 4¢-Me), 26.2 (CH, C-
4¢), 33.3 (CH2, C-5¢), 42.5 (CH2, C-3¢), 42.8 (CH2, C-3), 62.6 (CH2,
C-6¢), 109.7 (CH, C-7), 109.8 (C, C-2), 120.6 (CH, C-5), 124.9 (CH,
C-4), 126.0 (C, C-3a), 127.9 (CH, C-6), 158.2 (C, C-7a).
MS (EI, 70 eV): m/z (%) = 204 (100) [M+], 203 (5), 189 (60), 145
(3), 134 (10), 131 (21), 121 (5), 115 (4), 107 (29), 97 (70), 91 (12),
78 (41), 69 (16), 55 (15), 51 (12), 41 (30).
HRMS (EI): m/z [M+] calcd for C13H16O2: 204.1150; found:
204.1146.
MS (EI, 70 eV): m/z (%) = 204 (100) [M+], 189 (53), 187 (9), 174
(7), 159 (16), 148 (23), 131 (45), 120 (27), 115 (8), 107 (94), 98
(19), 91 (88), 83 (33), 77 (27), 69 (13), 57 (28), 55 (27), 40 (44).
HRMS (EI): m/z [M+] calcd for C13H16O2: 204.1150; found:
204.1153.
( )-4¢-Methyl-4¢,5¢-dihydro-3H,3¢H-spiro(benzofuran-2,2¢-fu-
ran) (28a and 28b)
According to general procedure C, reaction of PhI(OAc)2 (37 mg,
0.115 mmol) and I2 (33 mg, 0.130 mmol) with a 1:1 mixture of
diastereomeric alcohols 32 (11 mg, 0.057 mmol) in cyclohexane
Synthesis 2011, No. 9, 1383–1398 © Thieme Stuttgart · New York

PAPER
Synthesis of Benzannulated Spiroketals
1397
( )-4¢-Methyl-3¢,4¢,5¢,6¢-tetrahydrospiro(chroman-2,2¢-pyran)
(30)
According to general procedure C, the title compound was obtained
from reaction of PhI(OAc)2 (53 mg, 0.165 mmol) and I2 (47 mg,
0.185 mmol) with a 1:1 mixture of diastereomeric alcohols 35 (18
mg, 0.082 mmol) in cyclohexane (6.8 mL) for 3 h.
Hanaoka, F.; Ishizuka, M.; Takeuchi, T. J. Antibiot. 1998,
51, 480.
(5) (a) Siu, T.; Qin, D. H.; Danishefsky, S. J. Angew. Chem. Int.
Ed. 2001, 40, 4713. (b) Waters, S. P.; Fennie, M. W.;
Kozlowski, M. C. Org. Lett. 2006, 8, 3243. (c) Venkatesh,
C.; Reißig, H. U. Synthesis 2008, 3605.
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Pale-yellow oil; yield: 10.3 mg, 0.047 mmol (58%).
IR (neat): 2926, 2869, 1583, 1492, 1455, 1372, 1244, 1216, 1172,
1142, 1110, 1088, 1038, 837, 751 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.97 (d, J = 6.6 Hz, 3 H, 4¢-Me),
1.23 (t, J = 13.0 Hz, 1 H, 3¢-Hax), 1.28 (qd, J = 13.1, 4.8 Hz, 1 H,
5¢-Hax), 1.62 (dtd, J = 13.2, 3.7, 1.9 Hz, 1 H, 5¢-Heq), 1.82 (td, J =
13.3, 6.2 Hz, 1 H, 3-Hax), 1.90 (ddd, J = 13.3, 3.9, 1.8 Hz, 1 H, 3¢-
Heq), 1.96 (ddd, J = 13.5, 6.5, 2.1 Hz, 1 H, 3-Heq), 2.18–2.31 (m, 1
H, 4¢-Hax), 2.62 (ddd, J = 16.2, 6.1, 2.1 Hz, 1 H, 4-Heq), 3.03 (ddd,
J = 16.3, 13.0, 6.5 Hz, 1 H, 4-Hax), 3.63 (ddd, J = 11.0, 5.2, 1.4 Hz,
1 H, 6¢-Heq), 3.81 (ddd, J = 12.9, 11.4, 2.4 Hz, 1 H, 6¢-Hax), 6.83 (dd,
J = 8.2, 0.8 Hz, 1 H, 8-H), 6.87 (td, J = 7.4, 1.2 Hz, 1 H, 6-H), 7.06
(d, J = 7.6 Hz, 1 H, 5-H), 7.10 (t, J = 8.1 Hz, 1 H, 7-H).
13C NMR (100 MHz, CDCl3): d = 21.1 (CH2, C-4), 22.2 (CH3, 4¢-
Me), 24.8 (CH, C-4¢), 31.9 (CH2, C-3), 33.9 (CH2, C-5¢), 43.4 (CH2,
C-3¢), 61.7 (CH2, C-6¢), 96.3 (C, C-2), 116.9 (CH, C-8), 120.5 (CH,
C-6), 122.7 (C, C-4a), 127.0 (CH, C-7), 129.2 (CH, C-5), 152.3 (C,
C-8a).
(9) Zhang, Y.; Xue, J. J.; Xin, Z. J.; Xie, Z. X.; Li, Y. Synlett
2008, 940.
(10) (a) Lindsey, C. C.; Wu, K. L.; Pettus, T. R. R. Org. Lett.
2006, 8, 2365. (b) Wu, K. L.; Wilkinson, S.; Reich, N. O.;
Pettus, T. R. R. Org. Lett. 2007, 9, 5537.
MS (EI, 70 eV): m/z (%) = 218 (1) [M+], 203 (1), 107 (5), 97 (30),
91 (78), 83 (32), 77 (30), 69 (47), 57 (77), 55 (80), 41 (100).
HRMS (EI): m/z [M+] calcd for C14H18O2: 218.1307; found:
218.1305.
(11) (a) Sperry, J.; Liu, Y.-C.; Brimble, M. A. Org. Biomol.
Chem. 2010, 8, 29. (b) For an enantioselective route to
dihydrobenzofurans using chiral ammonium(hypo)iodite
catalyzed oxidative cyclizations, see: Uyanik, M.; Okamoto,
H.; Yasui, T.; Ishihara, K. Science 2010, 328, 1776.
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Acknowledgment
We thank the Tertiary Education Committee, New Zealand for the
award of a Bright Futures Top Achiever Doctoral Scholarship (Y.-
C. Liu). Financial support from the Royal Society of New Zealand
Marsden Fund is gratefully acknowledged.
(14) Chatterjee, A.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360.
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