3-Alkoxy-2,5-dihydrofurans by gold-catalyzed allenyl cyclizations and their transformation into 1,4-dicarbonyl compounds, cyclopentenones, and butenolides

Article abstract of DOI:10.1055/s-0030-1258265

The addition of lithiated alkoxyallenes to carbonyl compounds furnishes allenyl alcohols, which undergo a highly efficient and chemoselective 5-endo-trig cyclization to 3-alkoxy-2,5-dihydrofurans catalyzed by gold(I) chloride. The dihydrofurans produced can be either oxidized to -alkoxy butenolides by a manganese(III) acetate catalyzed radical oxidation with tert-butyl hydroperoxide, or transformed into ,-unsaturated -keto aldehydes by an oxidative ring cleavage using DDQ in the presence of water. Treatment of the -keto aldehydes with sodium methoxide in methanol promotes a diastereoselective intramolecular aldol addition furnishing alkoxy-substituted cyclopentenone derivatives in good yield. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258265

PAPER
3855
3-Alkoxy-2,5-dihydrofurans by Gold-Catalyzed Allenyl Cyclizations and
Their Transformation into 1,4-Dicarbonyl Compounds, Cyclopentenones,
and Butenolides
3
-Alkoxy-2, 5-dihydrof
a
urans by G
l
old-Catalyzed
e
Allenyl Cyclizati
Bons rasholz, Branislav Dugovič, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 7 July 2010
Dedicated to Prof. Grzegorz Mlostoń (Łódź) on the occasion of his 60th birthday
1. n-BuLi
Abstract: The addition of lithiated alkoxyallenes to carbonyl com-
pounds furnishes allenyl alcohols, which undergo a highly efficient
R2
2.
R3
OR1
OR1
R2
R3
and chemoselective 5-endo-trig cyclization to 3-alkoxy-2,5-dihy-
OR1
H
O
•
R2
R3
drofurans catalyzed by gold(I) chloride. The dihydrofurans pro-
duced can be either oxidized to b-alkoxy butenolides by a
manganese(III) acetate catalyzed radical oxidation with tert-butyl
hydroperoxide, or transformed into a,b-unsaturated g-keto alde-
hydes by an oxidative ring cleavage using DDQ in the presence of
water. Treatment of the g-keto aldehydes with sodium methoxide in
methanol promotes a diastereoselective intramolecular aldol addi-
tion furnishing alkoxy-substituted cyclopentenone derivatives in
good yield.
5-endo-trig
2
•
O
HO
3
1
4
OR1
OR1
OR1
R2
R3
R2
R3
[ox.]
[ox.]
R3 = H
R2
O
O
O
O
O
5
4
6
OR1
Key words: allenes, dihydrofurans, cyclopentenones, gold cataly-
sis, allylic oxidation
aldol
R2 = CH2X
HO
O
X
7
The synthesis of heterocycles with lithiated alkoxyallenes
and varied electrophilic components opens access to a
great diversity of small- and medium-sized ring systems.1
In the past, we and others have developed efficient two- or
multi-component coupling protocols, leading to furan,2
pyrrole,3 or 1,2-oxazine derivatives,4 as well as to highly
functionalized pyridines,5 imidazoles,6 and oxazoles.7 The
diverse classes of alkoxyallene-based heterocycles are of-
ten versatile synthetic intermediates and have found nu-
merous applications as key building blocks in the
synthesis of natural products, small molecule libraries,
and components for supramolecular chemistry. As we
keep exploring the synthetic potential of lithiated alkoxy-
allenes, our synthetic procedures continue to evolve, and
one example is the [3+2] cyclization of alkoxyallenes 1
with carbonyl compounds 2 leading to 3-alkoxy-2,5-dihy-
drofurans 4 (Scheme 1). This method for the preparation
of 2,5-dihydrofurans is not new, since the 5-endo-trig cy-
clization of the key intermediates, alkoxyallenyl alcohols
3, has first been described by Brandsma and Arens in
1969.8 However, the investigation of different reagent
systems suitable to promote this transformation has been
ongoing, and we have just recently found a general,
chemoselective, and widely applicable set of conditions
for this important reaction employing a gold(I) catalyst.9
Scheme 1 Preparation and oxidation reactions of alkoxyallene-
derived 3-alkoxy-2,5-dihydrofurans 4 and their subsequent transfor-
mations into g-keto aldehydes 5, aldol products 7, and butenolides 6
The [3+2] cyclization approach to dihydrofurans 4 allows
for the introduction of various substituents R2 and R3 in
the 2-position of the heterocyclic product by choice of the
aldehyde or ketone 2, and therefore it is a fairly flexible
and rapid method to obtain products with this particular
substitution pattern, which complements other established
methods10 like the Birch reduction of furans,11 allylic sub-
stitutions of 2,3-dihydrofurans,12 the conversion of fura-
noses by elimination,13 ring-closing metathesis of
diallylalcohols,14 or the dehydration of cis-1,4-dihydroxy-
alkenes.15
The value of 3-alkoxy-2,5-dihydrofurans as synthetic in-
termediates is also based on their potential to undergo ox-
idative transformations. As they formally are progenitors
of furans, the same type of oxidation reactions could po-
tentially occur,16 for example, the oxidative ring opening
of furans to dicarbonyl compounds. This is a well-known
process that can be induced by many oxidants including
nitric acid,17 bromine,18 hydroperoxides with transition
metal catalysts,19 chromium(VI) reagents,20 N-bromosuc-
cinimide,21 and meta-chloroperbenzoic acid.22 Other im-
portant classes of compounds that may be obtained from
furans by oxidation are butenolides23 and tetronic acids,24
that is, by oxidation of 2-trimethylsilylfurans or the corre-
sponding 2-boryl derivatives.25
SYNTHESIS 2010, No. 22, pp 3855–3864
x
x.
x
x
.
2
0
1
0
Advanced online publication: 24.09.2010
DOI: 10.1055/s-0030-1258265; Art ID: T14910SS
© Georg Thieme Verlag Stuttgart · New York

3856
M. Brasholz et al.
PAPER
We have been investigating the oxidation chemistry of 3-
alkoxy-2,5-dihydrofurans 4, and were able to transfer
some of the oxidation modes of furans onto our substrates.
As shown in Scheme 1, substrates 4 could be oxidized to
a,b-unsaturated g-keto aldehydes 5,26 or alternatively, to
b-alkoxy butenolide derivatives 69 by choice of the reac-
tion conditions. In this account, we describe the full de-
tails and improved protocols for the preparation of
dihydrofurans 4 and their selective oxidation reactions
leading to product classes 5 and 6. In addition, we report
the intramolecular aldol reaction of g-keto aldehydes 5 to
alkoxy-substituted trans-cyclopentenones 7 that are use-
ful precursors for further transformations.26d
OMe
OMe
KOt-Bu
•
(0.5 equiv)
C
11H23
(1)
C11H23
4a 71%
DMSO, 60 °C
2 h
O
HO
3a
OMe
Ph
OMe
OMe Boc
•
•
OTBS
•
N
O
HO
HO
3c
HO
3b
3d
OMe
OMe
•
ref. 32
ref. 31
(2)
(3)
O
Synthesis of 3-Alkoxy-2,5-dihydrofurans from Lithiat-
ed Alkoxyallenes and Carbonyl Compounds
HO
3e
8
The cycloisomerization of allenyl alcohols to 2,5-dihy-
drofurans is a well-known type of reaction, and over the
past decades, a number of different reagents were found to
promote these transformations, including Brønsted
acids,27 transition metals like silver(I)28 and gold salts,29
and other electrophilic species.29b,30 The choice of reagent
is considerably limited for alkoxy-substituted allenyl al-
cohols 3, due to their acid sensitive enol ether moiety.
Brandsma and co-workers have described the first 5-
OMe
OMe
•
O
HO
3f
9
Scheme 2 Cyclization of allenyl alcohols 3 to 3-alkoxy-2,5-dihy-
drofurans 4 with KOt-Bu and DMSO
endo-trig cyclizations of these substrates using a substo- drawbacks are the high loading of catalyst and the slug-
ichiometric amount of potassium tert-butoxide (0.1 to 0.5 gish conversion in some cases. The use of a base additive
equiv) in DMSO at 50–60 °C.8 These basic reaction con- like potassium carbonate along with silver(I) has an accel-
ditions often provide good yields of dihydrofurans 4 in the erating effect on cyclizations of various alkoxyallenyl
range of 40–80%. In a subsequent report, it has been sug- amines,3 but is not effective in case of alkoxyallenyl alco-
gested by Magnus et al. that the reaction proceeds via a hols 3.
radical mechanism.31 However, the method is limited to
fairly simple substrates such as allenyl alcohol 3a, which
(1)
AgNO3
(0.5 equiv)
OMe
OMe
was converted into dihydrofuran 4a as shown in Scheme 2
(transformation 1). Aryl-substituted allenyl alcohols like
3b as well as substrates bearing sensitive protecting
groups, for example, compounds 3c and 3d, tend to under-
go decomposition under the reaction conditions. More-
over, base-promoted isomerization processes may occur
during the reaction, as exemplified by the cyclization of
allenyl alcohol 3e to furan derivative 8 (Scheme 2, trans-
formation 2),32 and sterically demanding substrates such
as adamantanone-derived adduct 3f may react to vinyl ep-
oxide products like 9 (Scheme 2, transformation 3).31
•
OTBS
OTBS
MeCN, 50 °C
5 d
61% (dr 84:16)
O
HO
3c
(dr 88:12)
4c
AuCl (0.05 equiv)
pyridine (0.15 equiv)
(2)
CH2Cl2, r.t.,1 h
66% (dr 83:17)
Scheme 3 Cyclization of allenyl alcohol 3c to 3-alkoxy-2,5-dihy-
drofuran 4c with Ag(I) or Au(I)
As part of our ongoing interest in alkoxyallene-derived
2,5-dihydrofurans 4 and 2,5-dihydropyrroles as useful in-
termediates in natural product synthesis,1 we kept search-
ing for more general reaction conditions for cyclization of
the allenic precursors. As we have previously reported,
many functionalized alkoxyallenyl alcohols 3 and alkoxy-
allenyl amines undergo cyclization with silver(I) salts in
acetone or acetonitrile,3 a protocol which is complemen-
tary to Brandsma’s method. Usually, a substoichiometric
amount of silver(I) (0.1 to 0.3 equiv) is required, and heat-
ing may be necessary to achieve full conversion. This
method allows for the cyclization of some substrates that
are incompatible with KOt-Bu in DMSO, as shown for al-
lenyl alcohol 3c in Scheme 3 (transformation 1), but its
Gold catalysts have been extensively studied in the activa-
tion of carbon–carbon multiple bonds,33 and the intramo-
lecular hydroamination and hydroalkoxylation of allenic
double bonds proceed readily with gold(I) and gold(III)
species in many examples.29,33 Our own investigations
showed that for the cyclization of alkoxy-substituted sub-
strates 3, gold(III) chloride as well as cationic gold(I)
complexes were too reactive, and we observed mostly de-
composition of the starting materials. However, the re-
agent system of gold(I) chloride and pyridine previously
reported by Gockel and Krause34 turned out to be the ideal
and most general catalyst for substrates 3. These condi-
tions left the sensitive enol ether moiety intact, and many
Synthesis 2010, No. 22, 3855–3864 © Thieme Stuttgart · New York

PAPER
3-Alkoxy-2,5-dihydrofurans by Gold-Catalyzed Allenyl Cyclizations
3857
R2
OR1
OR1
R2
R3
R3
OR1
H
OR1
Li
•
R2
R3
O
methods A–C
(see below)
2
n-BuLi
•
•
THF or Et2O
–40 °C
THF or Et2O
–78 °C
O
HO
3
1a–c
4
(1a R1 = Me, 1b R1 = MOM, 1c R1 = Bn)
OMe
OBn
OMe
OMOM
C11H23
C11H23
C11H23
O
O
O
O
4a
4g
4h
4i
A: 63%
A: 36%a
OMe
A: 71%
A: 47%
OMe
OMe
OMe
Ph
OBn
O
O
O
O
4j
A: 91%
4k
C: 76%
4l
C: 69%
4b
A: dec.
B: 31%b
C: 75%
OMe
OMe
OMe
OMe
Boc
O
O
OTBS
N
N
Tr
O
O
O
O
O
4cc
A: dec.
B: 61%
4m
C: 85%
4n
C: 70%
4d
A: 37%
B: 19%d
C: 78% (dr 82:18)
C: 66% (dr 83:17)
Scheme 4 Scope of dihydrofuran synthesis from alkoxyallenes 1 and carbonyl compounds 2. Method A: 0.5 equiv KOt-Bu, DMSO, 60 °C,
1–2 h. Method B: 0.3–0.5 equiv AgNO3, MeCN, r.t. or 50 °C. Method C: 0.05 equiv AuCl, 0.15 equiv pyridine, CH2Cl2, r.t., 30 min to 1 h.
a Allenyl alcohol 3h used in the cyclization step contained benzyloxyallene (1c). b Result taken from ref. 26a. c Yield of the crude allenyl alcohol
3c was 89%. d AgBF4 was used instead of AgNO3 and the reaction was stopped after 72 h with incomplete conversion.
functional groups were tolerated. Complete conversion substrates that earlier could only be cyclized with moder-
was achieved with 5% of catalyst loading and in short re- ate success employing Brandsma’s conditions or AgNO3
action times, as shown for substrate 3c in Scheme 3 (method B). Cyclizations of allenic precursors 3 derived
(transformation 2).
from ketones also proceeded efficiently using AuCl, as
shown by examples 4m and 4n.
A summary of the described transformations is given in
Scheme 4. Alkoxyallenes 1 (typically 3.5 equiv) were Oxidative Cleavage to a,b-Unsaturated g-Keto
deprotonated at –40 °C with n-butyllithium (3.0 equiv) in Aldehydes
THF or diethyl ether and then treated with aldehydes and
Alkoxy-substituted 2,5-dihydrofurans 4 are prone to oxi-
dative degradation. An early observation we made was the
ketones 2 (1.0 equiv) at –78 °C. a-Chiral aldehydes pref-
erentially led to the anti-adducts in all cases.35 After ex-
oxidative ring cleavage of compound 4a when kept in the
tractive workup and removal of the excess of alkoxyallene
open air, slowly generating a,b-unsaturated g-keto alde-
hyde 5a (Scheme 5).
1 in vacuo, crude allenyl alcohols 3 were mostly obtained
in quantitative yield and were directly cyclized under dif-
ferent reaction conditions. When diastereomeric mixtures
of allenyl alcohols 3 were employed in the cyclization
step, the syn/anti ratio was essentially retained under all
reaction conditions employed.
OMe
OMe
C11H23
5a + 4a
air
O
C11H23
6 weeks
O
O
4a
The examples 4a and 4g–j show that cyclizations with
KOt-Bu and DMSO (method A) smoothly proceeded with
allenyl substrates 3 that bear simple aliphatic substituents
R2/R3 and different alkoxy substituents R1 are also well
tolerated. In the case of product 4h, the yield was lowered
to 36% due to the presence of nonvolatile benzyloxyallene
(1c) in the cyclization step, leading to the formation of un-
known side products. The examples 4b–d illustrate that
AuCl and pyridine (method C) is the reagent of choice for
3%
84%
OMe
OMe
C11H23
HOO
C11H23
O
O
10
11
Scheme 5 Aerobic oxidation of 2,5-dihydrofuran 4a
Synthesis 2010, No. 22, 3855–3864 © Thieme Stuttgart · New York

3858
M. Brasholz et al.
PAPER
The oxidation had most likely proceeded via the hydro- The formal four-electron oxidation of 2,5-dihydrofurans 4
peroxide 10 and furan 11 as intermediates, and in order to to g-keto aldehydes 5 with DDQ in the presence of water
verify this assumption, we tried to prepare a sample of fu- is applicable to a wide range of substrates 4 and a scope of
ran 11 by oxidation of substrate 4a in the presence of var- the method is shown in Scheme 8.
ious oxidants. To our surprise, we were unable to
deliberately induce this oxidation. While reagents like
manganese(IV) oxide and DDQ gave only minimal con-
version even at reflux temperature in anhydrous dichlo-
romethane or chlorobenzene, other reagents like the acidic
pyridinium chlorochromate or platinum on carbon exclu-
sively led to cleavage of the enol ether moiety of 4a yield-
ing 3-furanone 12 (Scheme 6). On the other hand, the
OR1
OR1
DDQ (2 equiv)
R2
O
R2
CH2Cl2/H2O (20:1)
r.t., 2 h
O
O
4
5
OMe
C11H23
OMOM
OBn
C11H23
chromium(VI) oxide dimethylpyrazole complex 13,36
a
O
O
O
C11H23
reagent known for allylic oxidation of 2,5-dihydro-
furans,37 gave g-keto aldehyde 5a as the sole product in
48% yield (Scheme 6).
O
O
O
5a
79%
5ga
61%
5h
60%
OMe
OMe
OMe
O
HO Cr
O
N
O
O
O
N
O
O
O
O
OMe
PCC
13
BnO
(5 equiv)
(8 equiv)
5i
76%
5j
93%
5l
67%
5a
48%
C11H23
C11H23
CH2Cl2
r.t., 16 h
CH2Cl2
–20 °C, 2 h
O
12
O
4a
82%
Boc
N
OMe
OMe
OTBS
Scheme 6 Reactions of 3-alkoxy-2,5-dihydrofuran 4a with chromi-
um(VI) reagents
O
O
O
O
O
5c
72%
5d
While we could not selectively oxidize substrate 4a to the
3-alkoxyfuran 11, we recognized the oxidation to g-keto
aldehyde 5a as the transformation of much higher synthet-
ic value, and this process was studied in detail.26 Prior to
our investigations, DDQ in wet dichloromethane had been
used as a reagent for the oxidation of 2,5-diaryl-substitut-
ed 3-alkoxyfurans 14 to 1,4-diketones 15 (Scheme 7,
transformation 1).38 When 2,5-dihydrofuran 4a was react-
ed under the same conditions, g-keto aldehyde 5a and un-
consumed starting material 4a were obtained in a ratio of
approximately 1:1. This experiment showed that the pre-
sumed intermediate furan species 11 is too short-lived to
be isolated. Treatment of 4a with a total of two equiva-
lents of DDQ in the presence of water resulted in complete
conversion of dihydrofuran 4a into g-keto aldehyde 5a
(transformation 2).
90%
Scheme 8 Oxidative cleavage of 2,5-dihydrofurans 4 leading to
a,b-unsaturated g-keto aldehydes 5. a Reaction mixture buffered at pH
7 with aqueous phosphate buffer.
The method is well compatible with different acid-sensi-
tive protecting groups such as TBS ethers as well as ox-
azolidinyl groups, and oxidation-prone benzyl ethers are
also left intact. Only in case of MOM ether 5g, buffering
of the reaction mixture at pH 7 was necessary to avoid hy-
drolysis of the protective group. When employing chiral
dihydrofuran substrates in the reaction, g-keto aldehyde
products were obtained without noticeable racemiza-
tion.39 It should be noted that the transformations leading
to compounds such as 5c and 5d resemble the Achmatowicz
reaction, the oxidation of a-hydroxy or a-amino furan de-
rivatives to 4-enuloses,40 which in turn are versatile build-
ing blocks in the de novo synthesis of carbohydrates and
other functionalized six-membered-ring structures.41 Fi-
nally, water could be replaced by methanol as co-solvent
in the DDQ-mediated oxidation, leading to cyclic bis-
acetals such as compound 16 in Scheme 9.
OR
OR
DDQ
(1 equiv)
Ar
O
Ar
(1)
(2)
Ar
Ar
CH2Cl2/H2O
ref. 38
O
O
15
O
14
OMe
OMe
C11H23
DDQ
(2 equiv)
C11H23
OMe
OMe
OMe
C11H23
CH2Cl2/H2O
(20:1)
r.t., 2 h
O
DDQ
O
(3 equiv)
4a
5a
79%
C11H23
4a
MeO
CH2Cl2–MeOH
(20:1)
O
O
16 (dr 67:33)
Scheme 7 DDQ-promoted oxidations of furans 14 and 3-methoxy-
2,5-dihydrofuran 4a
r.t., 2 h
62%
Scheme 9 DDQ-mediated oxidation in the presence of methanol to
cyclic bis-acetal 16
Synthesis 2010, No. 22, 3855–3864 © Thieme Stuttgart · New York

PAPER
3-Alkoxy-2,5-dihydrofurans by Gold-Catalyzed Allenyl Cyclizations
3859
We already demonstrated the synthetic utility of dicarbo- Allylic Oxidation of Dihydrofurans to b-Alkoxy-
nyl compounds 5 by converting them into heterocyclic butenolides
products like pyridazine and tetronic acid derivatives,26a
The oxidation of 2,5-dihydrofurans in allylic position can
as well as their use as templates for the synthesis of rare
lead to butenolides, however, the only example of this
carbohydrates.26b,c A more recent application of these ver-
transformation known in the literature37 employs chromi-
satile intermediates is the intramolecular aldol addition
um(VI) oxide dimethylpyrazole complex 1336 as the oxi-
dizing reagent. As shown in Scheme 6, 3-alkoxy-2,5-
dihydrofurans 4 react with complex 13 via a different
mechanism and undergo oxidative cleavage to g-keto al-
dehydes 5. We continued investigating alternative oxida-
tion methods for the desired allylic oxidation, and reaction
conditions reported by Shing and co-workers using tert-
leading to cyclopentenone derivatives.26d As shown in
Scheme 10, the primary product of the DDQ-mediated
oxidation of dihydrofuran 4k readily cyclized during
chromatography on silica gel, to give cyclopentenone de-
rivative 7k with high diastereoselectivity (trans/cis =
94:6).
butyl hydroperoxide and catalytic amounts of manga-
nese(III) acetate43 led to the formation of butenolide 6a
OMe
O
OMe
1. DDQ
CH2Cl2/H2O
from dihydrofuran 4a in a moderate yield of 36%. In an at-
tempt to improve this result, the influence of the solvent,
the reaction temperature, and of various acidic and basic
additives were investigated. As shown in Scheme 12, we
could improve the yield of butenolide 6a to 46%, by using
0.5 molar equivalents of cesium carbonate44 as a basic ad-
ditive, and performing the reaction at 0 °C under an atmo-
sphere of oxygen. Along with the desired product 6a, we
isolated trace amounts of g-keto aldehyde 5a and furan 11.
When no base was added, the yields of 5a and 11 were
much higher (20–40%).
Ph
HO
2. silica gel
O
Ph
4k
7k 76%
(dr 94:6)
Scheme 10 Oxidation of 3-methoxy-2,3-dihydrofuran 4k and sub-
sequent silica gel promoted intramolecular aldol addition to cyclopen-
tenone 7k
A number of different enolizable g-keto aldehydes 5 were
deliberately converted into cyclopentenone products, and
the reactions proceeded readily using a catalytic amount
of sodium methoxide in methanol as the base. As shown
in Scheme 11, dialkyl-substituted 7i and 7j were obtained
in good yields. In cases with an a-methylene substructure,
the aldol addition gave the trans-configured products with
high preference (examples 7a and 7l), very likely as a re-
sult of thermodynamic control.42
Mn(OAc)3⋅2H2O
(0.05 equiv)
OMe
OMe
TBHP (5 equiv)
Cs2CO3 (0.50 equiv)
C11H23
O
C11H23
4 Å MS
MeCN, O2, 0 °C, 72 h
O
O
4a
6a
46%
OMe
OMe
O
+
+
C11H23
OMe
C11H23
11
O
OMe
O
NaOMe
(0.2 equiv)
R1
5a
O
HO
O
MeOH, r.t.
Scheme 12 Allylic oxidation of 3-methoxy-2,5-dihydrofuran 4a to
butenolide 6a
O
R2
R1 R2
5
7
OMe
O
OMe
O
A mechanistic rationale for these observations is depicted
in Scheme 13. The dihydrofuran substrate is first convert-
ed into peroxide 17, which may undergo rearrangement to
butenolide 6a by abstraction of Ha or, alternatively, elim-
ination to furan 11 by abstraction of Hb. Furan 11 may
then react to epoxide 18, which rearranges to g-keto alde-
hyde 5a. The amount and strength of the basic additive
was critical for balancing the reaction and we used K3PO4,
Cs2CO3, NaOAc, and NaH2PO4 at 0.5–3.0 molar equiva-
lents. However, temperature had the greatest impact on
the yield of 6a. Carrying out the reaction at 0 °C for 72
hours increased the yield by 10% compared to the reaction
at room temperature. Peroxide 17 may also undergo 1,4-
elimination to furan-3(2H)one 19 and we could isolate
this intermediate in one case. This side reaction becomes
increasingly important at elevated temperatures, and as
enolizable compounds like 19 are prone to oligomeriza-
tion,45 it may account for the observed loss of material in
the overall process.
HO
HO
7i
83%
7j
76%
OMe
O
OMe
O
HO
HO
C10H21
OBn
7l (dr 92:8)
7a (dr 94:6)
78%a
77%
Scheme 11 Intramolecular aldol reactions yielding cyclopenten-
ones 7. a Reaction performed with aq Na2CO3 in THF.
Synthesis 2010, No. 22, 3855–3864 © Thieme Stuttgart · New York

3860
M. Brasholz et al.
PAPER
OMe
Hb
1)
HO
OH
Ha
Amberlyst A-15,
HC(OMe)3
O
O
t-BuOO
R
O
O
O
17
OMe
2) LiAlH4
3) Swern oxidation
93% (3 steps)
O
21
– Ha
OMe
– Hb
20
OMe
Li
1)
•
OMe
R
+
22
O
R
O
O
11
2) AuCl, pyridine
72% (2 steps)
6a
OMe
O
OMe
O
OMe
1) Mn(OAc)3⋅2H2O
TBHP, Cs2CO3
2) aq HCl
R
O
18
O
O
O
51% (2 steps)
O
OMe
O
O
+
O
R
24
R
O
O
5a
( )-annularin H
23
19
R = C11H23
Scheme 15 Synthesis of the natural product annularin H (24)
Scheme 13 Mechanistic rationale for the fragmentation of hydro-
peroxide 17
acetal protection of the keto group, reduction with lithium
aluminum hydride and Swern oxidation47 of the resulting
alcohol. Addition of lithiated methoxyallene 22 to alde-
hyde 21 and subsequent cyclization of the allenyl alcohol
with gold(I) chloride and pyridine led to dihydrofuran 23
in good overall yield. Allylic oxidation of this substrate
and subsequent hydrolysis of the acetal protecting group
furnished the natural product with good overall efficiency.
Mn(OAc)3⋅2H2O (0.05 equiv)
OMe
OMe
TBHP (5–6 equiv)
R1
R2
R1
R2
Cs2CO3 (0.50 equiv), 4 Å MS
O
MeCN, O2, 0 °C, 72 h
O
O
4
6
OMe
OMe
OMe
Boc
By way of their reactions with diverse electrophilic spe-
cies, lithiated alkoxyallenes deliver heterocyclic products
of high synthetic value. While the known preparation of 3-
alkoxy-2,5-dihydrofurans has been re-shaped employing
gold catalysis, the examination of 2,5-dihydrofurans in
oxidation reactions led to new procedures for their oxida-
tive cleavage to g-keto aldehydes and their allylic oxida-
tion to butenolides. The intramolecular aldol reactions of
suitably substituted g-keto aldehydes readily furnished
highly functionalized cyclopentenone derivatives, which
could be versatile intermediates for further synthetic elab-
orations.
OTBS
N
O
C11H23
O
O
O
O
O
O
6a
46%
6c (dr 85:15)
6d (dr 73:27)
50%
47%
OMe
OMe
OMe
O
O
N
Tr
O
O
O
O
6oa,b
O
O
6ma
6na
66%
53%
73%
Scheme 14 Scope of allylic oxidation of 3-methoxy-2,5-dihydro-
a
furans 4 leading to b-alkoxybutenolides 6. Reaction performed at
room temperature for 48 h. b No base was used.
Reactions were performed under exclusion of air and moisture, in
flame-dried glassware and under an atmosphere of argon (oxygen,
respectively). Anhydrous solvents were prepared by standard pro-
cedures, and commercial reagents were used without further purifi-
cation, with the exception of aldehydes which were either distilled
freshly or chromatographed prior to use. AuCl (99.9%) was pur-
chased from Sigma Aldrich. Column chromatography was per-
A small scope of the allylic oxidation of substrates 4 is
shown in Scheme 14. Yields of butenolides 6 ranged from
45–50% (examples 6a, 6c, 6d). In the case of compound
6d, a minor shift of the original ratio of diastereomers was
observed, after chromatographic purification. When
spirodihydrofurans were employed as precursors, yields
of up to 73% were obtained (examples 6m, 6n, 6o), and
the reaction could well be performed at room temperature
without a noticeable difference in yield.
1
formed using silica gel 60 (230–400 mesh, 40–63 mm, Merck). H
and 13C NMR spectra were recorded on JEOL (Eclipse 500) and
Bruker (AMX 500 and AC 250) instruments. Chemical shifts are
reported relative to the resonances of CHCl3 at d = 7.25 ppm (1H
NMR) and d = 77.0 ppm (13C NMR). IR spectra were recorded with
a Nicolet 5SXC FTIR spectrometer, EI mass spectra with Finnigan
MAT 711 (80 eV, 8 kV) and Finnigan MAT CH7A (80 eV, 3 kV)
instruments. FAB mass spectra were obtained using a Finnigan
CH5DF instrument (3 kV) and ESI mass spectra with an Agilent
ESI-TOF 6210 instrument (4 mL/min, 1 bar, 4000 V). Elemental
analyses were obtained from Perkin-Elmer and Vario EL analyzers.
The utility of our new protocols for the preparation of di-
hydrofurans and their allylic oxidation could be demon-
strated by a short synthesis of the natural product ( )-
annularin H (24)46 as shown in Scheme 15. Methyl 3-oxo-
valerate (20) was readily converted into aldehyde 21 by
Synthesis 2010, No. 22, 3855–3864 © Thieme Stuttgart · New York

PAPER
3-Alkoxy-2,5-dihydrofurans by Gold-Catalyzed Allenyl Cyclizations
3861
Melting points were measured with a Büchi MP 510 apparatus and
are uncorrected. Optical rotation values were determined using
Perkin-Elmer (241-P) and IBZ (POLAR-LmP) polarimeters (l =
589 nm, sodium D-emission, quartz cuvette, thickness 10 cm).
MS (EI, 50 °C): m/z (%) = 258 ([M]+, 2), 157 ([C8H17OSi]+, 100),
115 ([C6H15Si]+, 25).
HRMS (EI, 40 °C): m/z calcd for [C13H26O3Si]+: 258.1651; found:
258.1672.
Addition of Lithiated Alkoxyallenes to Aldehydes and Ketones
and Gold-Catalyzed Cyclization to 2,5-Dihydrofurans; Prepa-
ration of Compound anti/syn-4c; Typical Procedure 1
Methoxyallene48 (1a; 0.90 mL, 756 mg, 10.8 mmol) was dissolved
in Et2O (15 mL) and n-BuLi (3.70 mL, 2.50 M in hexanes,
9.25 mmol) was added at –40 °C. After 30 min, the mixture was
cooled to –78 °C and a solution of (S)-2-(tert-butyldimethylsil-
oxy)propanal49 (590 mg, 3.13 mmol) in Et2O (7 mL) was added.
The mixture was stirred for 3 h, H2O (20 mL) was added, and after
warming to r.t., the layers were separated. The aqueous layer was
extracted with Et2O (3 × 20 mL), and the combined organic layers
were dried (MgSO4), filtered, and evaporated to dryness to provide
the intermediate allenyl alcohol anti/syn-3c (721 mg, 89%, anti/
syn = 88:12) as a yellowish oil, which was directly used in the next
step.
DDQ-Mediated Oxidative Cleavage of 2,5-Dihydrofurans to g-
Keto Aldehydes; (S,E)-5-tert-Butyldimethylsiloxy-3-methoxy-4-
oxohex-2-enal (5c); Typical Procedure 2
H2O (0.11 mL) was added to a solution of dihydrofuran anti/syn-4c
(150 mg, 0.58 mmol) in CH2Cl2 (2.30 mL) followed by DDQ
(264 mg, 1.16 mmol). The mixture was stirred at r.t. for 2 h, then aq
NaHCO3 (2 mL) and H2O (2 mL) were added. The layers were sep-
arated and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL).
The combined organic layers were dried (MgSO4), filtered, concen-
trated in vacuo and chromatographed (silica gel, EtOAc–
hexanes, 1:4) to provide keto aldehyde 5c (114 mg, 72%) as a yel-
lowish liquid; [a]D22 –6.8 (c = 0.22, CHCl3).
IR (film): 2955–2860 (=C–H, C–H), 1730, 1670, 1605 cm–1 (C=O,
C=C).
1H NMR (500 MHz, CDCl3): d = 0.04 (s, 6 H, SiMe2t-Bu), 0.84 (s,
9 H, SiMe2t-Bu), 1.34 (d, J = 6.8 Hz, 3 H, 6-H), 3.75 (s, 3 H, OMe),
4.69 (q, J = 6.8 Hz, 1 H, 5-H), 5.53 (d, J = 7.3 Hz, 1 H, 2-H), 9.66
(d, J = 7.3 Hz, 1 H, 1-H).
13C NMR (126 MHz, CDCl3): d = –5.1, –4.9 (2 q, SiMe2t-Bu), 19.5
(q, C-6), 18.0, 25.6 (s, q, SiMe2t-Bu), 56.4 (q, OMe), 71.8 (d, C-5),
108.3 (d, C-2), 170.0 (s, C-3), 190.2 (d, C-1), 199.0 (s, C-4).
MS (pos. FAB): m/z (%) = 295 ([M + Na]+, 1), 273 ([M + H]+, 7),
215 ([M – C4H9]+, 5), 159 ([C8H19OSi]+, 56), 115 ([C6H15Si]+, 14),
73 ([C3H9Si]+, 100).
anti-3c
1H NMR (500 MHz, CDCl3): d = 0.01, 0.03 (2 s, 2 × 3 H, SiMe2t-
Bu), 0.81 (s, 9 H, SiMe2t-Bu), 1.13 (d, J = 6.0 Hz, 3 H, 1-H), 2.39
(d, J = 5.8 Hz, 1 H, OH), 3.37 (s, 3 H, OMe), 3.91–3.99 (m, 2 H, 2-
H, 3-H), 5.50 (mc, 2 H, 6-H).
13C NMR (126 MHz, CDCl3): d = –5.1, –4.6 (2 q, SiMe2t-Bu), 17.9
(q, C-1), 18.5, 26.7 (s, q, SiMe2t-Bu), 55.9 (q, OMe), 69.5 (d, C-2),
75.0 (d, C-3), 91.8 (t, C-6), 133.6 (s, C-4), 198.4 (s, C-5).
syn-3c
1H NMR (500 MHz, CDCl3): d (characteristic signals) = 1.23 (d,
J = 6.9 Hz, 3 H, 1-H), 2.55 (d, J = 8.0 Hz, 1 H, OH).
13C NMR (126 MHz, CDCl3): d (characteristic signals) = 56.0 (q,
OMe), 68.7 (d, C-2), 74.2 (d, C-3), 92.5 (t, C-6), 135.0 (s, C-4),
198.3 (s, C-5).
Anal. Calcd for C13H24O4Si (272.4): C, 57.32; H, 8.88. Found: C,
57.32; H, 8.90.
Intramolecular Aldol Reaction of g-Keto Aldehydes; cis/trans-
5-Decyl-4-hydroxy-2-methoxycyclopent-2-enone (7a); Typical
Procedure 3
A mixture of keto aldehyde 5a (100 mg, 0.37 mmol) and NaOMe
(0.5 M in MeOH, 0.14 mL, 0.07 mmol) in MeOH (5 mL) was
stirred at r.t. for 2 h. The mixture was concentrated to dryness and
the residue was chromatographed (silica gel, EtOAc–hexanes, 1:1)
to provide cyclopentenone 7a (77 mg, 77%, trans/cis = 94:6) as a
colorless solid; mp 44 °C.
The allenyl alcohol anti/syn-3c (721 mg, max. 2.79 mmol) was dis-
solved in CH2Cl2 (40 mL) and pyridine (40 mL, 39 mg, 0.49 mmol)
was added, followed by AuCl (33 mg, 0.14 mmol). After stirring for
1 h at r.t., conversion was complete as indicated by TLC, and the
mixture was concentrated in vacuo and chromatographed
(silica gel, EtOAc–hexanes, 1:8) to provide 2,5-dihydrofuran anti/
syn-4c (533 mg, 66% over 2 steps, anti/syn = 83:17) as a yellowish
liquid. The diastereomers could not be separated.
Major Isomer, trans-7a
IR (KBr): 3410 (OH), 3080–2850 (=C–H, C–H), 1705 (C=O), 1635
(S)-2-[(S)-1-(tert-Butyldimethylsiloxy)ethyl]-3-methoxy-2,5-di-
hydrofuran (anti-4c)
cm–1 (C=C).
1H NMR (500 MHz, CDCl3): d = 0.06 (mc, 6 H, SiMe2t-Bu), 0.88
(s, 9 H, SiMe2t-Bu), 1.11 (d, J = 6.4 Hz, 3 H, 2¢-H), 3.63 (s, 3 H,
OMe), 3.94 (dq, J = 2.3, 6.4 Hz, 1 H, 1¢-H), 4.50–4.53 (m, 1 H, 2-
H), 4.60–4.65 (m, 3 H, 4-H, 5-H).
1H NMR (500 MHz, CDCl3): d = 0.88 (t, J = 7.0 Hz, 3 H, 10¢-H),
1.26–1.36, 1.41–1.49 (2 m, 18 H, 9 × CH2), 1.79–1.87 (m, 1 H, 5-
H), 2.15 (br s, 1 H, OH), 3.75 (s, 3 H, OMe), 4.60 (br s, 1 H, 4-H),
6.23 (d, J = 2.9 Hz, 1 H, 3-H).
13C NMR (126 MHz, CDCl3): d = –4.9, –4.6 (2 q, SiMe2t-Bu), 17.3
(q, C-2¢), 18.2, 25.9 (s, q, SiMe2t-Bu), 57.4 (q, OMe), 70.2 (d, C-1¢),
73.5 (t, C-5), 85.7 (d, C-2), 91.3 (d, C-4), 156.5 (s, C-3).
13C NMR (125 MHz, CDCl3): d = 14.1 (q, C-10¢), 22.6, 27.1, 29.0,
29.3, 29.4, 29.5, 29.6, 31.9 (8 t, 9 × CH2), 55.0 (d, C-5), 57.1 (q,
OMe), 72.1 (d, C-4), 125.0 (d, C-3), 157.6 (s, C-2), 201.4 (s, C-1).
MS (EI, 50 °C): m/z (%) = 268 (67, [M]+), 253 (7, [M – CH3]+), 239
(R)-2-[(S)-1-(tert-Butyldimethylsiloxy)ethyl]-3-methoxy-2,5-di-
hydrofuran (syn-4c)
(10) [M – C2H5]+, 128 (100).
1H NMR (500 MHz, CDCl3): d (characteristic signals) = 0.85 (s, 9
H, SiMe2t-Bu), 1.21 (d, J = 6.5 Hz, 3 H, 2¢-H), 3.63 (s, 3 H, OMe),
3.90 (dq, J = 2.0, 6.5 Hz, 1 H, 1¢-H), 4.28-4.32 (m, 1 H, 2-H).
Anal. Calcd for C16H28O3 (268.4): C, 71.60; H, 10.52. Found: C,
71.13; H, 10.21.
Manganese(III) Acetate Catalyzed Allylic Oxidation of 2,5-Di-
hydrofurans with tert-Butyl Hydroperoxide; Preparation of
Compound anti/syn-6c: Typical Procedure 4
Molecular sieves (4 Å, powder, 570 mg) were suspended in a solu-
tion of dihydrofuran anti/syn-4c (302 mg, 1.17 mmol) and Cs2CO3
(190 mg, 0.58 mmol) in MeCN (13 mL). TBHP solution (1.15 mL,
13C NMR (126 MHz, CDCl3): d (characteristic signals) = 20.0 (q,
C-2¢), 25.7 (q, SiMe2t-Bu), 57.1 (q, OMe), 68.3 (d, C-1¢), 73.7 (t, C-
5), 85.6 (d, C-2), 91.4 (d, C-4), 155.8 (s, C-3).
anti/syn-4c
IR (film): 2960–2855 (=C–H, C–H), 1665 cm–1 (C=C).
Synthesis 2010, No. 22, 3855–3864 © Thieme Stuttgart · New York

3862
M. Brasholz et al.
PAPER
5.50 M in nonane, 6.33 mmol) was added at 0 °C, followed by
Mn(OAc)3·2H2O (16 mg, 60 mmol) and the mixture was stirred at
this temperature, under an atmosphere of O2, for 72 h. The mixture
was poured into an aqueous solution of FeSO4·7H2O (3.00 g in
30 mL H2O) and diluted with EtOAc (20 mL). After filtration of the
mixture through Celite (with EtOAc), the layers were separated and
the aqueous layer was extracted with EtOAc (3 × 30 mL). The com-
bined organic layers were dried (MgSO4), filtered, concentrated in
vacuo, and chromatographed (silica gel, EtOAc–hexanes,
1:2 → 1:1) to provide butenolide anti/syn-6c (158 mg, 50%, anti/
syn = 85:15) as a yellowish oil. HPLC separation afforded analyti-
cal samples of the single diastereomers.
was added. Filtration over silica gel (with EtOAc) and concentra-
tion of the filtrate in vacuo provided an oil, which was taken up in
pentane (40 mL). After stirring for 20 min, the mixture was filtered
(excess 2,2-dimethylpropanediol was thereby removed) and con-
centrated to dryness to provide the intermediate alcohol (3.60 g) as
a colorless liquid.
1H NMR (500 MHz, CDCl3): d = 0.79 (s, 3 H, Me), 0.85 (t, J = 7.5
Hz, 3 H, 5-H), 1.12 (s, 3 H, Me), 1.82 (q, J = 7.5 Hz, 2 H, 4-H), 1.86
(t, J = 5.4 Hz, 2 H, 2-H), 3.10 (t, J = 5.4 Hz, 1 H, OH), 3.38, 3.60 (2
d, J = 11.6 Hz, 2 × 2 H, 4¢-H, 6¢-H), 3.83 (q, J = 5.4 Hz, 2 H, 1-H).
13C NMR (126 MHz, CDCl3): d = 7.8 (q, C-5), 22.3, 23.0 (2 q,
2 × Me), 23.6 (t, C-4), 29.6 (s, C-5¢), 37.7 (t, C-2), 58.6 (t, C-1), 69.9
(t, C-4¢, C-6¢), 101.9 (s, C-3).
(S)-5-[(S)-1-(tert-Butyldimethylsiloxy)ethyl]-4-methoxyfuran-
2(5H)-one (anti-6c)
A solution of DMSO (5.80 mL, 6.38 g, 81.7 mmol) in CH2Cl2 (10
mL) was added at –78 °C to a solution of oxalyl chloride (3.40 mL,
5.03 g, 39.6 mmol) in CH2Cl2 (60 mL). The mixture was warmed to
–60 °C over 15 min, then a solution of the crude alcohol (3.60 g,
max 17.5 mmol) in CH2Cl2 (15 mL) was added dropwise. The mix-
ture was warmed to –40 °C over 30 min, i-Pr2NEt (30.0 mL, 23.5 g,
182 mmol) was added, before warming to 0 °C over 20 min. The
mixture was poured onto aq NaHCO3 (100 mL), the layers were
separated, and the aqueous layer was extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were dried (MgSO4),
filtered, concentrated in vacuo and chromatographed (silica gel,
EtOAc–hexanes, 1:4) to provide aldehyde 21 (3.02 g, 93% over 3
steps) as a yellowish liquid.
IR (film): 2960–2870 (C–H), 2740, 2690 (=C–H), 1725 cm–1
(C=O).
1H NMR (500 MHz, CDCl3): d = 0.88 (s, 3 H, Me), 0.90 (t, J = 7.5
Hz, 3 H, 5-H), 1.01 (s, 3 H, Me), 1.83 (q, J = 7.5 Hz, 2 H, 4-H), 2.65
(d, J = 3.0 Hz, 2 H, 2-H), 3.44, 3.57 (2 d, J = 11.7 Hz, 2 × 2 H, 4¢-
H, 6¢-H), 9.84 (d, J = 3.0 Hz, 1 H, 1-H).
Yellowish oil; [a]D22 +65.0 (c = 0.80, CHCl3).
1H NMR (500 MHz, CDCl3): d = 0.043, 0.046 (2 s, 2 × 3 H,
SiMe2t-Bu), 0.84 (s, 9 H, SiMe2t-Bu), 1.23 (d, J = 6.6 Hz, 3 H, 2¢-
H), 3.85 (s, 3 H, OMe), 4.17 (dq, J = 2.5, 6.6 Hz, 1 H, 1¢-H), 4.62
(dd, J = 0.8, 2.5 Hz, 1 H, 5-H), 5.06 (d, J = 0.8 Hz, 1 H, 3-H).
13C NMR (126 MHz, CDCl3): d = –5.1, –4.9 (2 q, SiMe2t-Bu), 18.6
(q, C-2¢), 20.1, 25.6 (s, q, SiMe2t-Bu), 59.2 (q, OMe), 67.9 (d, C-1¢),
82.5 (d, C-5), 90.0 (d, C-3), 172.5 (s, C-2), 180.5 (s, C-4).
(R)-5-[(S)-1-(tert-Butyldimethylsiloxy)ethyl]-4-methoxyfuran-
2(5H)-one (syn-6c)
Colorless solid; mp 57–58 °C; [a]D22 –9.5 (c = 0.75, CHCl3).
1H NMR (500 MHz, CDCl3): d = –0.02, 0.04 (2 s, 2 × 3 H, SiMe2t-
Bu), 0.82 (s, 9 H, SiMe2t-Bu), 1.31 (d, J = 6.4 Hz, 3 H, 2¢-H), 3.85
(s, 3 H, OMe), 4.12 (dq, J = 2.1, 6.4 Hz, 1 H, 1¢-H), 4.56 (dd,
J = 0.9, 2.1 Hz, 1 H, 5-H), 5.07 (d, J = 0.9 Hz, 1 H, 3-H).
13C NMR (126 MHz, CDCl3): d = –5.4, –4.4 (2 q, SiMe2t-Bu), 17.9
(q, C-2¢), 17.8, 25.5 (s, q, SiMe2t-Bu), 59.0 (q, OMe), 66.2 (d, C-1¢),
82.5 (d, C-5), 89.9 (d, C-3), 172.7 (s, C-2), 179.9 (s, C-4).
13C NMR (126 MHz, CDCl3): d = 7.5 (q, C-5), 22.4, 23.0 (2 q, Me),
26.2 (t, C-4), 29.6 (s, C-5¢), 48.2 (t, C-2), 70.2 (t, C-4¢, C-6¢), 99.4
(s, C-3), 201.2 (d, C-1).
anti/syn-6c
IR (film): 3020–2860 (=C–H, C–H), 1760, 1630 cm–1 (C=O, C=C).
MS (ESI-TOF): m/z (%) = 209 ([M + Na]+, 25), 143 ([C8H15O2]+,
MS (EI, 50 °C): m/z (%) = 257 ([M – CH3]+, 10), 228 (12), 215
([M – C4H9]+, 100), 143 ([M + H – CH3 – C6H15Si]+, 62), 73
([C3H9Si]+, 46).
44).
HRMS (ESI-TOF): m/z calcd [M + Na]+ for [C10H18O3 + Na]+:
209.1154; found: 209.1162.
Anal. Calcd for C13H24O4Si (272.4): C, 57.32; H, 8.88. Found: C,
57.43; H, 9.01.
2-Ethyl-2-[(3-methoxy-2,5-dihydrofuran-2-yl)methyl]-5,5-di-
methyl-1,3-dioxane (23)
In an experiment analogous to typical procedure 1, methoxyallene
(1a, 2.00 mL, 1.68 g, 24.0 mmol, dissolved in 30 mL Et2O), n-BuLi
(8.00 mL, 2.50 M in hexanes, 20.0 mmol), and aldehyde 21 (1.46 g,
7.84 mmol, dissolved in 10 mL Et2O) gave the intermediate allenyl
alcohol (2.13 g, quant) as an orange oil.
1H NMR (500 MHz, CDCl3): d = 0.78 (s, 3 H, Me), 0.86 (t, J = 7.6
Hz, 3 H, 8-H), 1.14 (s, 3 H, Me), 1.77 (q, J = 7.6 Hz, 2 H, 7-H), 1.90
(mc, 1 H, 5-H), 2.01 (dd, J = 10.0, 14.9 Hz, 1 H, 5-H), 3.39, 3.62 (2
d, J = 11.6 Hz, 2 × 2 H, 4¢-H, 6¢-H), 3.42 (s, 3 H, OMe), 4.71 (mc, 1
H, 4-H), 5.52 (d, J = 1.8 Hz, 2 H, 1-H).
13C NMR (126 MHz, CDCl3): d = 7.8 (q, C-8), 22.3, 23.0 (2 q, Me),
23.7 (t, C-7), 29.6 (s, C-5¢), 40.3 (t, C-5), 56.3 (q, OMe), 67.2 (d, C-
4), 69.96, 70.03 (2 t, C-4¢, C-6¢), 91.9 (t, C-1), 101.4 (s, C-6), 136.3
(s, C-3), 197.6 (s, C-2).
Synthesis of ( )-Annularin H
(2-Ethyl-5,5-dimethyl[1,3]dioxane-2-yl)acetaldehyde (21)
Amberlyst A-15 (SO3H-form, 0.98 g, 1.1 mmol/g) was added at r.t.
to a solution of methyl 3-oxovalerate (2.28 g, 17.5 mmol), 2,2-di-
methylpropanediol (2.63 g, 25.3 mmol) and HC(OMe)3 (4.00 mL,
3.88 g, 36.6 mmol) in CH2Cl2 (30 mL). The suspension was stirred
for 16 h, then filtered, and evaporated to dryness to provide the
crude intermediate ketal (4.55 g) as a colorless liquid.
1H NMR (500 MHz, CDCl3): d = 0.89 (s, 3 H, Me), 0.94 (t, J = 7.5
Hz, 3 H, 5-H), 0.97 (s, 3 H, Me), 1.86 (q, J = 7.5 Hz, 2 H, 4-H), 2.77
(s, 2 H, 2-H), 3.45, 3.56 (2 d, J = 11.6 Hz, 2 × 2 H, 4¢-H, 6¢-H), 3.66
(s, 3 H, OMe).
13C NMR (126 MHz, CDCl3): d = 7.4 (q, C-5), 22.4, 22.6 (2 q,
2 × Me), 28.4 (t, C-4), 29.7 (s, C-5¢), 38.2 (t, C-2), 51.7 (q, OMe),
70.4 (t, C-4¢, C-6¢), 98.9 (s, C-3), 170.0 (s, C-1).
Cyclization of the crude product (2.13 g, max 7.84 mmol) with
AuCl (91 mg, 0.39 mmol) and pyridine (100 mL, 97 mg,
1.23 mmol) in CH2Cl2 (120 mL), followed by column chromatogra-
phy (silica gel, EtOAc–hexanes, 1:5), provided 2,5-dihydrofuran 23
(1.45 g, 72% over 2 steps, purity ~95% by 13C NMR) as a yellowish
solid; mp 41–43 °C.
A solution of the crude ketal (4.55 g, max 17.5 mmol) in Et2O
(15 mL) was added dropwise to a suspension of LiAlH4 (1.52 g,
40.2 mmol) in Et2O (35 mL) at 0 °C. The mixture was stirred for 2 h
at this temperature, then EtOAc (30 mL) was added dropwise over
20 min, followed by the addition of aq 2 M NaOH (5 mL). The mix-
ture was warmed to r.t., diluted with EtOAc (100 mL), and MgSO4
IR (KBr): 2955–2875 (=C–H, C–H), 1750, 1640 cm–1 (C=C).
Synthesis 2010, No. 22, 3855–3864 © Thieme Stuttgart · New York

PAPER
3-Alkoxy-2,5-dihydrofurans by Gold-Catalyzed Allenyl Cyclizations
3863
1H NMR (500 MHz, CDCl3): d = 0.90 (t, J = 7.4 Hz, 3 H, 9-H), 0.93
(br s, 6 H, 2 × Me), 1.79 (dd, J = 8.6, 15.1 Hz, 1 H, 6-H), 1.83 (q,
J = 7.4 Hz, 2 H, 8-H), 2.17 (dd, J = 1.2, 15.1 Hz, 1 H, 6-H), 3.47,
3.53 (AB-system, JAB = 12.0 Hz, 2 × 2 H, 4¢-H, 6¢-H), 3.64 (s, 3 H,
OMe), 4.54–4.63 (m, 3 H, 4-H, 5-H), 4.71–4.76 (m, 1 H, 2-H).
13C NMR (126 MHz, CDCl3): d = 7.5 (q, C-9), 22.7, 22.8 (2 q,
2 × Me), 27.4 (t, C-8), 29.7 (s, C-5¢), 36.9 (t, C-6), 57.5 (q, OMe),
69.9, 70.1 (2 t, C-4¢, C-6¢), 72.6 (t, C-5), 77.5 (d, C-2), 89.6 (d, C-
4), 99.8 (s, C-7), 158.2 (s, C-3).
(3) (a) Okala Amombo, M. G.; Hausherr, A.; Reissig, H.-U.
Synlett 1999, 1871. (b) Breuil-Desvergnes, V.; Compain, P.;
Vatèle, J.-M.; Goré, J. Tetrahedron Lett. 1999, 40, 5009.
(c) Breuil-Desvergnes, V.; Compain, P.; Vatèle, J.-M.; Goré,
J. Tetrahedron Lett. 1999, 40, 8789. (d) Breuil-Desvergnes,
V.; Goré, J. Tetrahedron 2001, 57, 1939. (e) Breuil-
Desvergnes, V.; Goré, J. Tetrahedron 2001, 57, 1951.
(f) Flögel, O.; Okala Amombo, M. G.; Reissig, H.-U.; Zahn,
G.; Brüdgam, I.; Hartl, H. Chem. Eur. J. 2003, 9, 1405.
(g) Kaden, S.; Brockmann, M.; Reissig, H.-U. Helv. Chim.
Acta 2005, 88, 1826. (h) Kaden, S.; Reissig, H.-U. Org. Lett.
2006, 8, 4763. (i) Chowdhury, M. A.; Reissig, H.-U. Synlett
2006, 2383.
MS (pos. FAB): m/z (%) = 143 ([C8H15O2]+, 67), 69 (60), 57
([C3H5O]+, 100).
Anal. Calcd for C14H24O4 (256.3): C, 65.60; H, 9.44. Found: C,
65.06; H, 9.23.
(4) (a) Schade, W.; Reissig, H.-U. Synlett 1999, 632.
(b) Helms, M.; Schade, W.; Pulz, R.; Watanabe, T.;
Al-Harrasi, A.; Fišera, L.; Hlobilová, I.; Zahn, G.; Reissig,
H.-U. Eur. J. Org. Chem. 2005, 1003.
( )-Annularin H [4-Methoxy-5-(2-oxobutyl)furan-2(5H)-one,
24]
(5) (a) Flögel, O.; Dash, J.; Brüdgam, I.; Hartl, H.; Reissig,
H.-U. Chem. Eur. J. 2004, 10, 4283. (b) Dash, J.; Lechel,
T.; Reissig, H.-U. Org. Lett. 2007, 9, 5541. (c) Lechel, T.;
Dash, J.; Hommes, P.; Lentz, D.; Reissig, H.-U. J. Org.
Chem. 2010, 75, 726.
(6) Gwiazda, M.; Reissig, H.-U. Synthesis 2008, 990.
(7) Lechel, T.; Lentz, D.; Reissig, H.-U. Chem. Eur. J. 2009, 15,
5432.
In an experiment analogous to typical procedure 4, 2,5-dihydrofu-
ran 23 (520 mg, 2.03 mmol), Cs2CO3 (335 mg, 1.03 mmol),
Mn(OAc)3·2H2O (27 mg, 0.10 mmol), TBHP (1.90 mL, 5.50 M in
nonane, 10.5 mmol), and molecular sieves (4 Å, powder, 1.02 g) in
MeCN (22 mL) gave a crude product, which was dissolved in ace-
tone (8 mL) and H2O (0.50 mL) and treated with aq 37% HCl (0.20
mL) for 22 h. The mixture was poured onto pH 7 phosphate buffer
(20 mL) and the layers were separated. The aqueous layer was ex-
tracted with EtOAc (3 × 20) and the combined organic layers were
dried (MgSO4), filtered, evaporated, and chromatographed (silica
gel, EtOAc) to afford ( )-annularin H 24 (192 mg, 51% over 2
steps) as a yellowish oil, which solidified upon storage at –20 °C;
mp 55–57 °C (Lit.46 oil).
(8) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. Trav. Chim. Pays-
Bas 1969, 88, 609.
(9) Brasholz, M.; Reissig, H.-U. Synlett 2007, 1294.
(10) For a review, see: Kilroy, T. G.; O’Sullivan, T. P.; Guiry, P.
J. Eur. J. Org. Chem. 2005, 4929.
(11) For an example, see: Donohoe, T. J.; Helliwell, M.;
Stevenson, C. A. Tetrahedron Lett. 1998, 39, 3071.
(12) Selected examples: (a) Ozawa, F.; Kubo, A.; Hayashi, T.
Tetrahedron Lett. 1992, 33, 1485. (b) Pearce, A. J.; Ramaja,
S.; Thorn, S. N.; Bloomberg, G. B.; Walter, D. S.; Gallagher,
T. J. Org. Chem. 1999, 64, 5453. (c) Glorius, F.
Tetrahedron Lett. 2003, 44, 5751.
(13) For an example, see: Guindon, Y.; DeLorme, D.; Lau, C. K.;
Zamboni, R. J. Org. Chem. 1988, 53, 267.
(14) Selected examples: (a) Baylon, C.; Heck, M. P.;
Mioskowski, C. J. Org. Chem. 1999, 64, 3354. (b) Heck,
M. P.; Baylon, C.; Nolan, S. P.; Mioskowski, C. Org. Lett.
2001, 13, 1989. (c) Duffy, M. G.; Grayson, D. H. J. Chem.
Soc., Perkin Trans. 1 2002, 1555.
1H NMR (500 MHz, CDCl3): d = 1.02 (t, J = 7.3 Hz, 3 H, 4¢-H),
2.46 (q, J = 7.3 Hz, 2 H, 3¢-H), 2.67 (dd, J = 8.5, 16.9 Hz, 1 H, 1¢-
H), 2.85 (dd, J = 3.6, 16.9 Hz, 1 H, 1¢-H), 3.86 (s, 3 H, OMe), 5.05
(d, J = 1.0 Hz, 1 H, 3-H), 5.21 (ddd, J = 1.0, 3.6, 8.5 Hz, 1 H, 5-H).
13C NMR (126 MHz, CDCl3): d = 7.3 (q, C-4¢), 36.7 (t, C-3¢), 43.7
(t, C-1¢), 59.5 (q, OMe), 74.4 (d, C-5), 88.7 (d, C-3), 171.8 (s, C-2),
181.8 (s, C-4), 206.1 (s, C-2¢).
The NMR data match those previously reported.46
Anal. Calcd for C9H12O4 (184.2): C, 58.69; H, 6.57. Found: C,
58.25; H, 6.56.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
(15) For an example, see: Barry, C. N.; Evans, S. A. Jr. J. Org.
Chem. 1983, 48, 2825.
(16) Reviews of furan chemistry: (a) König, B. In Science of
Synthesis, Vol. 9; Maas, G., Ed.; Thieme: Stuttgart, 2002,
183–285. (b) Brown, R. C. D. Angew. Chem. Int. Ed. 2005,
44, 850; Angew. Chem. 2005, 117, 872. (c) Senning, A.;
Wong, H. N. C.; Yeung, K.-S.; Yang, Z.; Graening, T.;
Thrun, F.; Keay, B. A.; Hopkins, J. M.; Dibble, P. W. In
Comprehensive Heterocyclic Chemistry III; Katritzky, A.
R.; Ramsden, C. A.; Scriven, E. F. C.; Taylor, R. J. K., Eds.;
Elsevier: Amsterdam, 2008.
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft, the Fonds der
Chemischen Industrie (Ph.D. fellowship for MB), the Alexander
von Humboldt Foundation (Postdoctoral fellowship for BD), and
Bayer Schering Pharma AG for generous support of this research.
References
(17) Bailey, P. S.; Christian, J. D. J. Am. Chem. Soc. 1949, 71,
4122.
(1) For reviews, see: (a) Zimmer, R. Synthesis 1993, 165.
(b) Zimmer, R.; Reissig, H.-U. In Modern Allene Chemistry,
Vol. 1; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004, 425–492. (c) Brasholz, M.; Reissig, H.-
U.; Zimmer, R. Acc. Chem. Res. 2009, 42, 45. (d) Pfrengle,
F.; Reissig, H.-U. Chem. Soc. Rev. 2010, 39, 549.
(2) Hormuth, S.; Reissig, H.-U. J. Org. Chem. 1994, 59, 67;
references 8 and 9.
(18) Raczko, J. Tetrahedron 2003, 59, 10181.
(19) (a) Antonioletti, R.; Arista, L.; Bonadies, F.; Locati, L.;
Scettri, A. Tetrahedron Lett. 1993, 34, 7089. (b) Yang, Z.
C.; Zhou, W.-S. J. Chem. Soc., Perkin Trans. 1 1994, 3231.
(c) Finlay, J.; McKervey, M. A.; Gunaratne, H. Q. N.
Tetrahedron Lett. 1998, 39, 5651. (d) Massa, A.; Acocella,
M. R.; De Rosa, M.; Soriente, A.; Villano, R.; Scettri, A.
Tetrahedron Lett. 2003, 44, 835.
Synthesis 2010, No. 22, 3855–3864 © Thieme Stuttgart · New York

3864
M. Brasholz et al.
PAPER
(20) (a) Piancatelli, G.; Scettri, A.; D’Auria, M. Tetrahedron Lett.
1977, 18, 2199. (b) Piancatelli, G.; Scettri, A.; D’Auria, M.
Tetrahedron 1980, 36, 661. (c) Antonioletti, R.; D’Auria,
M.; De Mico, A.; Piancatelli, G.; Scettri, A. Synthesis 1984,
280.
(21) Georgiadis, M. P.; Couladouros, E. A. J. Org. Chem. 1986,
51, 2725.
(22) Lefevre, Y. Tetrahedron Lett. 1972, 13, 133.
(23) For a review, see: Knight, D. W. Contemp. Org. Synth. 1994,
1, 287.
(24) For reviews, see: (a) Zografos, A. L.; Georgiadis, D.
Synthesis 2006, 3157. (b) Schobert, R.; Schlenk, A. Bioorg.
Med. Chem. 2008, 16, 4203.
(25) (a) Shono, T.; Matsumura, Y.; Yamane, S. Tetrahedron Lett.
1981, 22, 3269. (b) Kuwajima, I.; Urabe, H. Tetrahedron
Lett. 1981, 22, 5191. (c) Pelter, A.; Rowlands, M.
Tetrahedron Lett. 1987, 28, 1203.
(26) (a) Flögel, O.; Reissig, H.-U. Eur. J. Org. Chem. 2004,
2797. (b) Brasholz, M.; Reissig, H.-U. Angew. Chem. Int.
Ed. 2007, 46, 1634; Angew. Chem. 2007, 119, 1659.
(c) Brasholz, M.; Reissig, H.-U. Eur. J. Org. Chem. 2009,
3595. (d) Dugovič, B.; Reissig, H.-U. Synlett 2008, 769.
(27) (a) Krause, N.; Laux, M.; Hoffmann-Röder, A. Tetrahedron
Lett. 2000, 41, 9613. (b) Berry, C. R.; Hsung, R. P.;
Antoline, J. E.; Petersen, M. E.; Challepan, R.; Nielson, J. A.
J. Org. Chem. 2005, 70, 4038.
(34) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485.
(35) (a) Our results have shown that the addition of lithiated
alkoxyallenes to a-chiral aldehydes predominantly proceeds
via the Felkin–Anh mode in all cases (also see ref. 2).
Assignment of syn- and anti-isomers was based on NMR
data for most compounds, at the stage of the allenyl alcohol
intermediates, and according to guidelines by Landmann and
Hoffmann. (b) Landmann, B.; Hoffmann, R. W. Chem. Ber.
1987, 120, 331. (c) The assignment for compound 4d could
be confirmed by an X-ray analysis of the main isomer.
(d) Brasholz, M. Ph.D. Dissertation; Freie Universität
Berlin: Germany, 2007.
(36) (a) Corey, E. J.; Fleet, G. W. J. Tetrahedron Lett. 1973,
4499. (b) Salmond, W. G.; Barta, M. A.; Havens, J. L.
J. Org. Chem. 1978, 43, 2057.
(37) Marco, J. A.; Carda, M.; Rodríguez, S.; Castillo, E.;
Kneeteman, M. N. Tetrahedron 2003, 59, 4085.
(38) Sayama, S.; Inamura, Y. Heterocycles 1996, 43, 1371.
(39) This was demonstrated for closely related compounds, see
refs. 26b, 26c.
(40) Achmatowicz, O. Jr.; Bukowski, P.; Szechner, B.;
Zwierzchowska, Z.; Zamojki, A. Tetrahedron 1971, 27,
1973.
(41) For reviews, see: (a) Holder, N. L. Chem. Rev. 1982, 82,
287. (b) Harris, J. M.; Li, M.; Scott, J. G.; O’Doherty, G. A.
In Strategies and Tactics in Organic Synthesis, Vol. 5;
Harmata, M., Ed.; Elsevier: London, 2004, 221–253.
(42) Attempted asymmetric organocatalytic variants of the
reaction have so far been unsuccessful.
(28) (a) Olsson, L.-I.; Claesson, A. Synthesis 1979, 743.
(b) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1990, 55,
2995.
(29) (a) Hoffmann-Röder, A.; Krause, N. Org. Lett. 2001, 3,
2537. (b) Krause, N.; Hoffmann-Röder, A.; Canisius, J.
Synthesis 2002, 1759. (c) Hoffmann-Röder, A.; Krause, N.
Org. Biomol. Chem. 2005, 3, 387.
(30) Beaulieu, P. L.; Morisset, V. M. Tetrahedron Lett. 1980, 21,
129.
(43) Shing, T. K. M.; Yeung, Y.-Y.; Su, P. L. Org. Lett. 2006, 8,
3149.
(44) (a) Yu, J.-Q.; Corey, E. J. J. Am. Chem. Soc. 2003, 125,
3232. (b) Yu, J.-Q.; Wu, H.-C.; Corey, E. J. Org. Lett. 2005,
7, 1415.
(45) Meister, C.; Scharf, H.-D. Synthesis 1981, 737.
(46) Li, C.; Nitka, M. V.; Gloer, J. B. J. Nat. Prod. 2003, 66,
1302.
(31) Magnus, P.; Albaugh-Robertson, P. J. Chem. Soc., Chem.
Commun. 1984, 804.
(32) Flögel, O. Ph.D. Dissertation; Freie Universität Berlin:
Germany, 2003.
(47) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(48) Pérez, M.; Canoa, P.; Gómez, G.; Teijeira, M.; Fall, Y.
Synthesis 2005, 411.
(49) (a) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org.
Chem. 1983, 48, 5180. (b) Smith, N. D.; Kocienski, P. J.;
Street, S. Synthesis 1996, 652.
(33) Selected reviews: (a) Hashmi, A. S. K. Angew. Chem. Int.
Ed. 2005, 44, 6990; Angew. Chem. 2005, 117, 7150.
(b) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem. Int. Ed.
2006, 45, 7896; Angew. Chem. 2006, 118, 8064.
(c) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
(d) Bongers, N.; Krause, N. Angew. Chem. Int. Ed. 2008, 47,
2178; Angew. Chem. 2008, 120, 2208.
Synthesis 2010, No. 22, 3855–3864 © Thieme Stuttgart · New York