Refined protocols for the preparation of 3-alkoxy-2,5-dihydrofurans, allylic oxidation to β-alkoxybutenolides and short synthesis of (±)-annularin H

Article abstract of DOI:10.1055/s-2007-977456

The 5-endo cyclization of α-allenyl alcohols derived from carbonyl compounds and lithiated alkoxyallenes was reinvestigated by comparing the known reagents KOt-Bu, AgNO₃ or AgBF₄ with the reagent system AuCl/pyridine. A variety of 3-

Full text of DOI:10.1055/s-2007-977456

1294
LETTER
Refined Protocols for the Preparation of 3-Alkoxy-2,5-dihydrofurans, Allylic
Oxidation to b-Alkoxybutenolides and Short Synthesis of ( )-Annularin H
3
-Alkoxy-2, 5-dihydrof
a
urans
a
nd A
l
llylic
t
e
on to
b
-
Alkoxybu
B
tenolides rasholz, 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 28 February 2007
OR3
OR3
R1
R2
Abstract: The 5-endo cyclization of a-allenyl alcohols derived
R1
O
from carbonyl compounds and lithiated alkoxyallenes was reinves-
tigated by comparing the known reagents KOt-Bu, AgNO3 or
AgBF4 with the reagent system AuCl/pyridine. A variety of 3-
alkoxy-2,5-dihydrofurans 4 was efficiently prepared, in some cases
with high diastereoselectivity. These product compounds were
subjected to manganese(III)-catalyzed allylic oxidation which led to
b-alkoxybutenolides with moderate to good yield. Combination of
these newly tuned methods allowed for a concise and short syn-
thesis of ( )-annularin H.
Li
2
R2
a
HO
1
3
KOt-Bu or Ag(I) or Au(I)
see Table 1
R2 = H:
DDQ
Key words: allenes, gold catalysis, dihydrofurans, allylic oxida-
tion, butenolides
Mn(III)
TBHP
base
OR3
R1
OR3
OR3
or Cr(VI)
R1
R2
R1
R2
O
see
Table 2
(refs. 7, 8)
O
O
O
O
Electrophile-induced 5-endo-trig cyclizations of a-allenyl
alcohols constitute a well-known and elegant route to syn-
thetically useful 2,5-dihydrofurans. Brønsted acids,1
bases, e.g. KOt-Bu,2 and Ag(I) salts3 have been utilized as
promoters in these reactions. More recently, the introduc-
tion of Au(I)- and Au(III)-based catalysts has set new
standards in the 5-endo and 6-endo cyclizations of various
allenic substrates.4 As part of our ongoing interest in lithi-
ated alkoxyallenes as building blocks for heterocyclic
synthesis,5 we required a new and more general protocol
for the 5-endo cyclization of alkoxyallene-derived a-alle-
nyl alcohols to 3-alkoxy-2,5-dihydrofurans.2,6a Our
progress using a Au(I) catalyst is described in this report.
Further, we have continuously been aiming for new oxi-
dative transformations of these synthetically valuable
intermediates7,8 and we present first results in their allylic
oxidation to b-alkoxybutenolides.
5
4
6
Scheme 1 Preparation and oxidative transformations of 3-alkoxy-
2,5-dihydrofurans 4, starting from carbonyl compounds 1 and lithi-
ated alkoxyallenes 2. Reagents and conditions: a) Et2O, –78 °C, 1–4 h.
These harsh conditions do not tolerate siloxy groups, a-
aryl substituents and functionalities that undergo elimina-
tion, isomerization, or radical9 side reactions. For in-
stance, a-allenols derived from lithiated methoxyallene
and aldehydes 1d, 1e and 1f decomposed or gave modest
yields (1e → 4e). On the other hand, allenols 3 incorporat-
ing the alkoxyallene moiety prohibit the use of Brønsted
acid promoters due to their enol ether reactivity. These se-
vere limitations may be overcome by employing Ag(I)
salts. We have previously adopted Claesson’s conditions3a
(10–30 mol% AgNO3 and 1–2 equiv of CaCO3) for the cy-
clization of allenyl amines derived from alkoxyallenes
and N-alkyl, N-tosyl and N-Boc imines.10 In the case of al-
cohols 3, however, this protocol led to rapid decomposi-
tion when base was present (K2CO3 was used in acetone
or in acetonitrile). In the absence of the base, the desired
cyclizations proceeded more cleanly but very slowly even
at elevated temperatures, and high loading of the metal
salt was necessary (25–50 mol% AgNO3 or AgBF4, see
entries 4–6, methods C and D). Thus, TBS-protected di-
hydrofuran 4d was isolated in 61% yield over two steps
after five days with 50 mol% of AgNO3. The conversion
of 4e was very low even after three days, and the notori-
ously difficult derivative 4f did not react cleanly.7
Nucleophilic addition of lithiated alkoxyallenes 2 towards
aldehydes and ketones 1 quantitatively furnishes a-allenyl
1
alcohols 3 (purity generally >95% by H NMR) and in
some cases with high diastereoselectivity (Scheme 1,
Table 1).6a,b The 5-endo cyclization of crude adducts 3
with KOt-Bu (0.25–0.50 equiv, DMSO solution, 50–
60 °C) was first reported by Brandsma and Arens2a and
this system operates cleanly for simple substrates (see
Table 1, entries 1–3, method A). Yields for dihydrofurans
4 typically range between 50% and 85% over two steps
and, if diastereomers are employed in the reaction, their
ratio is usually preserved (see conversions 1b → 4b and
1c → 4c).
Improvements to all of these cyclization processes were
overdue and we were pleased that, after some experimen-
tation, gold catalysis ultimately also matched our allenic
substrates. We could perform cycloisomerizations of sub-
strates 3 with 5 mol% of AuCl and 15 mol% of pyridine
SYNLETT 2007, No. 8, pp 1294–1298
1
6.
0
5.
2
0
0
7
Advanced online publication: 08.05.2007
DOI: 10.1055/s-2007-977456; Art ID: G04607ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
3-Alkoxy-2,5-dihydrofurans, Allylic Oxidation to b-Alkoxybutenolides
1295
Table 1 Two-Step Preparation of Dihydrofurans 4 Derived from Aldehydes or Ketones 1 and Lithiated Alkoxyallenes (Scheme 1)a,16
Entry Electrophile
2 R3
dr
Cyclization
conditions
Yield
(%)b
Product
dr
–
(adduct 3)
OMe
C11H23
1
2
1a
1b
Me
–
A
A
65
70
4a
O
O
C11H23
OMOM
O
O
O
65:35
(anti/syn)
MOM
4b
67:33
O
O
O
OMe
OMe
OMe
OTr
70:30
(anti/syn)
A
B
86
70
70:30
70:30
3
4
1c
Me
Me
4c
OTr
O
O
O
O
O
A
B
C
dec.
66
61
OTBS
88:12
(anti/syn)
83:17
84:16
1d
4d
OTBS
Boc
N
A
B
D
37
78
19
83:17
82:18
84:16
Boc
N
82:18
(anti/syn)
5
1e
Me
4ec
O
O
O
O
OMe
A
B
C
mixture
75
Ph
6
7
8
1f
Me
Me
Me
–
–
–
4f
–
–
–
31d
Ph
O
O
OMe
O
O
O
O
1g
1he
B
B
85
70
4g
4h
O
O
OMe
N Tr
N Tr
O
a Conditons A: KOt-Bu (0.50 equiv), DMSO, 60 °C, 1.5 h. Conditions B: AuCl (5 mol%), pyridine (15 mol%), CH2Cl2, r.t., 30 min to 3 h.
Conditions C: AgNO3 (0.25–0.50 equiv), MeCN, r.t. or 50 °C, 1–5 d. Conditions D: AgBF4 (0.30 equiv), MeCN, 35 °C to 50 °C, 72 h.
b Yield over two steps.
c Stereochemistry proven by X-ray crystal structure analysis of the main diastereomer.
d Result taken from ref. 7.
e Addition reaction performed in THF.
in CH2Cl2. These conditions have been reported by Oxidative transformations of dihydrofurans 4 lead to
Krause for the 6-endo cyclization of b-allenyl alcohols to multifunctional building blocks which are highly useful
4a
dihydropyrans4b (in turn, AuCl3 in CH2Cl2 again led to intermediates in natural product synthesis. Treatment of
decomposition). Results were now clearly superior to all substrates 4 with wet DDQ7,8 or CrO3–dimethylpyrazole
aforementioned reagent systems, since reactions are com- complex yields a,b-unsaturated g-ketoaldehydes
5
plete very rapidly and products are formed with high (Scheme 1) which served us as precursors in the synthesis
yields and perfect chemoselectivity (see conversions 1d– of rare deoxy sugars.8 Alternatively, their allylic oxidation
h → 4d–h, method B). The short reaction time of the gold- would furnish unsaturated g-lactones 6 and we have
catalyzed reaction is a distinct feature – in some cases, screened many reagents for this purpose. After some fail-
conversion was complete after 15–30 min at room temper- ures, we succeeded in the allylic oxidation by modifying
ature. On the other hand, a precatalyst loading of 5 mol% Shing’s conditions11 using TBHP and catalytic amounts
was mandatory since substrates 3 have to be used in the re- of manganese(III) acetate dihydrate (Table 2). When di-
action as crude materials (chromatographic purification hydrofuran 4a was reacted under the exact conditions re-
inevitably leads to decomposition). The purity should be ported by Shing, we isolated butenolide 6a in 32% yield,
ca. 95% or higher (1H NMR) for the catalyst to operate along with several side products and some polymeric ma-
since no reaction occurred with slightly more impure terial. In the subsequent optimization attempts, we varied
starting materials.
solvent, tested basic and acidic additives and the influence
Synlett 2007, No. 8, 1294–1298 © Thieme Stuttgart · New York

1296
M. Brasholz, H.-U. Reissig
LETTER
of temperature. These optimizations slightly improved the We prepared a series of butenolides 6 and also g-lactam
yield of 6a, ultimately up to moderate 46%. Under these 13 by our method and the results were similar for systems
optimum conditions (solvent MeCN, 0.50 equiv Cs2CO3, analogous to 4a (Table 2, entries 2 and 3). A minor shift
4 Å MS, O2 atmosphere, 0 °C, 72 h), trace amounts (1– of the diastereomeric ratio was observed during prepara-
5%) of furan 8 and ketoaldehyde 11 were formed along- tion of lactone 6e. Gratifyingly, reactions of spiro di-
side of 6a (see Scheme 2). Without added base, yields of hydrofurans 4g–i proceeded more straightforward and
8 and 11 were much higher (ca. 20–40% each). A mecha- lactones 6g–i were isolated in good yields (entries 4–6).
nistic rationale is depicted in Scheme 2: Compound 4a is The transformation of 4i required no base additive and
first converted into the intermediate peroxide 7, which ei- butenolide 6i was the sole product (73% yield). The anal-
ther undergoes fragmentation to 6a via abstraction of Ha ogous reaction of 4g in turn gave 6g in only 43% yield,
or, alternatively, elimination to furan 8 via abstraction of along with 11% of the 1,4-elimination product (3-furan-
Hb. Furan 8 may then react to intermediate epoxide 9 one), which was isolable in this case. Addition of car-
which rearranges to ketoaldehyde 11.12 The amount and bonate base again improved the yield, up to 66% for 6g.
strength of base additive was critical for balancing the Remarkably, the presence of the electron-rich nitrogen is
reaction and we applied K3PO4, Cs2CO3,13 NaOAc and tolerated under these conditions as shown by the con-
NaH2PO4 at 0.5–3.0 molar equivalents. However, among version 4h → 6h. The conversion of 12 into lactam 13
all parameters, temperature had the greatest impact on the demonstrates that the reaction is also applicable to dihy-
yield of 6a. Carrying out the reaction at 0 °C for 72 hours dropyrroles.
increased the yield by 10% compared to room tempera-
ture. Temperatures lower than 0 °C might further improve
yield but reaction times and experimental inconvenience
would increase accordingly. By the aforementioned mea-
sures, we could suppress the formation of 8 and 11 to a
minimum but the major side reaction was still polymeriza-
The utility of these findings was demonstrated by a short
synthesis of the polyketide annularin H (17,15a Scheme 3).
Commercially available methyl 3-oxovalerate (14) was
converted into protected aldehyde 15 within three steps.
Addition of lithiated methoxyallene and 5-endo cycliza-
tion with AuCl/pyridine provided dihydrofuran 16, which
tion. Peroxide 7 may also undergo 1,4-elimination to fu-
upon allylic oxidation and deprotection furnished the ra-
ran-3(2H)-one 1013 and we could isolate this intermediate
cemic natural product 1717 with good overall efficiency.
in one case (see below). This side reaction becomes
increasingly dominant at elevated temperatures and
enolizable compounds 10 are known to be very prone to
polymerization.14 Yet, we did not succeed in suppressing
this undesired process satisfactorily, at least for substrates
of type 4a.
O
O
a–c
O
O
93% (3 steps)
OMe
O
14
15
d, e
OMe
72% (2 steps)
Ha
R'OO
Hb
a
4a
R
O
OMe
OMe
O
7
f, g
R = C11H23
R' = t-Bu or H
O
O
O
51% (2 steps)
O
17
16
base
O
(±)-annularin H
OMe
OMe
R
Scheme 3 Preparation of ( )-annularin H (17). Reagents and condi-
tions: a) 2,2-dimethylpropane-1,3-diol, HC(OMe)3, amberlyst (H+
form), CH2Cl2, r.t., overnight; b) LiAlH4, Et2O, 0 °C, 2 h; c) oxalyl
chloride, DMSO, CH2Cl2, –60 °C to –40 °C, 30 min, then i-Pr2NEt;
d) methoxyallene (3.5 equiv), n-BuLi (3.0 equiv), Et2O, –78 °C, 2.5
h; e) AuCl (5 mol%), pyridine (0.15 equiv), CH2Cl2, r.t., 1 h; f)
Mn(OAc)3·2H2O (5 mol%), TBHP (5.0 equiv), Cs2CO3 (0.5 equiv), 4
Å MS, MeCN, O2, 0 °C, 72 h; g) HCl aq, acetone, r.t., 22 h.
+
C11H23
O
O
O
via
6a
46%
8
trace
OMe
R
O
(for base = Cs2CO3)
O
O
OMe
9
+
+
O
R
R
O
O
10
11
trace
We will further investigate and improve the allylic and
other oxidative transformations of alkoxyallene-based
heterocycles. In fact, the protocols presented here should
be useful for the synthesis of pyrrolidine alkaloids and
iminosugars and our progress in these areas will be report-
ed in due course.
polymeric
products
Scheme 2 Products formed in the TBHP oxidation of substrates 4
(see text). Reagents and conditions: a) Mn(OAc)3·2H2O (5 mol%),
TBHP (5–6 equiv), base additive, O2 atmosphere, 0 °C, 72 h.
Synlett 2007, No. 8, 1294–1298 © Thieme Stuttgart · New York

LETTER
3-Alkoxy-2,5-dihydrofurans, Allylic Oxidation to b-Alkoxybutenolides
1297
Table 2 Oxidation of Dihydrofurans 417 (Dihydropyrrole 12) to Butenolides 6 (Lactam 13)a
Entry
1
Substrate
Additive
Cs2CO3 (equiv)
Conditions
0 °C, 72 h
Yield
(%)
Product
OMe
OMe
4a
0.50
0.50
46
50
6a
C11H23
OMe
O
O
C11H23
OMe
O
O
O
O
OTBS
OTBS
2
3
4d
4e
0 °C, 72 h
6d
6e
dr = 83:17
dr = 85:15
OMe
OMe
Boc
N
Boc
N
0.50
0 °C, 72 h
r.t., 48 h
47
73
O
O
O
O
O
dr = 73:27
dr = 82:18
OMe
OMe
4
5
6
4ib
4g
4h
–
6i
O
O
O
O
O
OMe
OMe
OMe
OMe
–
0.50
r.t., 48 h
r.t., 48 h
43
66
O
O
O
6g
6h
O
O
OMe
0.50
0.50
r.t., 48 hc
53
35
N Tr
N Tr
O
O
O
O
OMe
7
12d
0 °C, 72 h
13
N
N
Tos
Tos
a Conditions: Mn(OAc)3·2H2O (5 mol%), TBHP (5–6 equiv), 4 Å MS, O2 atmosphere, MeCN.
b Compound prepared according to ref. 2b.
c Reaction carried out in CH2Cl2–MeCN (1:1).
d Compound prepared by cyclization of the parent allenyl amine with AgNO3 and K2CO3.
reviews on homogenic gold catalysis: (d) Hoffmann-Röder,
A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387.
(e) Hashmi, A. S. K. Angew. Chem. Int. Ed. 2005, 44, 6990;
Angew. Chem. 2005, 117, 7150. (f) Hashmi, A. S. K.;
Hutchings, G. J. Angew. Chem. Int. Ed. 2006, 45, 7896;
Angew. Chem. 2006, 118, 8064.
Acknowledgment
The authors thank the Fonds der Chemischen Industrie (PhD fel-
lowship for M.B.) and Schering AG for financial support.
References and Notes
(5) Overview on the chemistry of donor-substituted allenes:
(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.
(1) (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.
(6) (a) For a previous account on diastereoselective syntheses
of 3-alkoxy-2,5-dihydrofurans, see: Hormuth, S.; Reissig,
H.-U. J. Org. Chem. 1994, 59, 67. (b) The addition of
lithiated alkoxyallenes to a-chiral aldehydes produces the
Felkin–Anh (anti-configured) products in preference.
(7) Flögel, O.; Reissig, H.-U. Eur. J. Org. Chem. 2004, 2797.
(8) Brasholz, M.; Reissig, H.-U. Angew. Chem. Int. Ed. 2007,
46, 1634; Angew. Chem. 2007, 119, 1659.
(2) (a) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. Trav. Chim.
Pays-Bas 1969, 88, 609. (b) Gange, D.; Magnus, P. J. Am.
Chem. Soc. 1978, 100, 7746. (c) Magnus, P.; Albaugh-
Robertson, P. J. Chem. Soc., Chem. Commun. 1984, 804.
(3) (a) Olsson, L.-I.; Claesson, A. Synthesis 1979, 743.
(b) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1990, 55,
2995.
(4) (a) Hoffmann-Röder, A.; Krause, N. Org. Lett. 2001, 3,
2537. (b) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485.
(c) Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121. Recent
(9) It was proposed that the KOt-Bu-promoted cyclizations
proceed via a SET mechanism, see ref. 2c.
Synlett 2007, No. 8, 1294–1298 © Thieme Stuttgart · New York

1298
M. Brasholz, H.-U. Reissig
LETTER
(10) (a) Okala Amombo, M. G.; Hausherr, A.; Reissig, H.-U.
Synlett 1999, 1871. (b) Flögel, O.; Okala Amombo, M. G.;
Reissig, H.-U.; Zahn, G.; Brüdgam, I.; Hartl, H. Chem. Eur.
J. 2003, 9, 1405. (c) Kaden, S.; Brockmann, M.; Reissig, H.-
U. Helv. Chim. Acta 2005, 88, 1826. (d) Kaden, S.; Reissig,
H.-U. Org. Lett. 2006, 8, 4763. (e) Chowdhury, M. A.;
Reissig, H.-U. Synlett 2006, 2383.
J = 1.7 Hz, 2 H, 5-H) ppm. 13C NMR (126 MHz, CDCl3):
d = 30.7, 31.8 (2 t, 4 × CH2), 57.4 (q, OCH3), 64.1, 64.2 (2 t,
2 × CH2), 70.2 (t, C-5), 82.5 (s, C-2), 88.2 (d, C-4), 108.3 [s,
C(OR)2], 161.4 (s, C-3) ppm. IR (KBr): n = 2960–2850
cm–1 (=CH, CH). ESI-TOF: 249.1095 [M + Na]+, 227.1277
[M + H]+. Anal. Calcd for C12H18O4 (226.3): C, 63.70; H,
8.02. Found: C, 63.47; H, 8.11.
(11) Shing, T. K. M.; Yeung, Y. Y.; Su, P. L. Org. Lett. 2006, 8,
3149.
(17) Typical Procedure for the Allylic Oxidation: Preparation
of ( )-Annularin H (17)
(12) For a related furan oxidation with TBHP/VO(acac)2, see:
Yang, Z. C.; Zhou, W.-S. J. Chem. Soc., Perkin Trans. 1
1994, 3231.
(13) Yu, J.-Q.; Wu, H.-C.; Corey, E. J. Org. Lett. 2005, 7, 1415
1415.
(14) Meister, C.; Scharf, H.-D. Synthesis 1981, 737.
(15) (a) Li, C.; Nitka, M. V.; Gloer, J. B. J. Nat. Prod. 2003, 66,
1302. (b) For syntheses of annularins B and F, see:
Kurdyumov, A. V.; Munoz, R. L. P.; Hsung, R. P. Synthesis
2006, 1787.
Dihydrofuran 16 (520 mg, 2.03 mmol) was dissolved in
MeCN (22 mL). Then, Cs2CO3 (335 mg, 1.03 mmol) and
powdered 4 Å MS (1.02 g) were added. After cooling to
0 °C, TBHP (1.90 mL, 5.5 M solution in nonane, 10.5 mmol)
and Mn(OAc)3·2H2O (27 mg, 101 mmol) were added and the
flask was equipped with a balloon of O2. The mixture was
vigorously stirred at 0 °C for 72 h, then poured into an
aqueous solution of FeSO4·7H2O (ca. 2.5 g in 30 mL H2O),
rinsing with EtOAc (10 mL). After 10 min of stirring, the
mixture was filtered through Celite® with the aid of EtOAc
(50 mL). The filtrate layers were separated and the aqueous
layer was extracted with EtOAc (5×). The combined organic
layers were dried (MgSO4), filtered, and evaporated to
dryness. The residue was dissolved in acetone–H2O (8 mL/
0.50 mL) and HCl (0.20 mL, 37% aq) was added. After 22 h
of stirring at r.t., the mixture was poured into pH 7 phosphate
buffer solution (10 mL). The layers were separated and the
aqueous layer was extracted with EtOAc (3×). The
combined organic layers were dried (MgSO4), filtered,
concentrated, and chromatographed (silica gel, 100%
EtOAc, Rf = 0.6) to provide 192 mg (51% over 2 steps) of 17
as a yellowish oil that solidified to a light yellow solid in the
refrigerator. Analytical data for 17: mp 55–57 °C (lit.15 oil).
1H NMR (500 MHz, CDCl3): d = 1.02 (t, J = 7.3 Hz, 3 H,
CH3), 2.46 (q, J = 7.3 Hz, 2 H, CH2), 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, OCH3), 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) ppm. 13C NMR (126 MHz,
CDCl3): d = 7.29 (q, CH3), 36.7 (t, CH2), 43.7 (t, C-1¢), 59.5
(q, OCH3), 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¢) ppm. Anal. Calcd for C9H12O4
(184.2): C, 58.69; H, 6.57. Found: C, 58.25; H, 6.56. The
analytical data are in agreement with those given in ref. 15.
(16) Typical Procedure for the Au(I)-Catalyzed Cyclization:
Preparation of Compound 4g
Methoxyallene (0.35 mL, 294 mg, 4.19 mmol) was
dissolved in Et2O (5 mL) at –40 °C. n-BuLi (1.40 mL, 2.5 M
in hexane, 3.50 mmol) was added, the mixture was stirred for
20 min and then cooled to –78 °C. A solution of ketone 1g
(180 mg, 1.15 mmol) in Et2O (2 mL) was slowly added and
the mixture was stirred at –78 °C for 2.5 h. Then, H2O (10
mL) was added and the mixture was warmed to r.t. The
layers were separated and the aqueous layer was extracted
with Et2O (3×). The combined organic layers were dried
(MgSO4), filtered, and evaporated. Drying at 0.1 mbar
provided the allenyl alcohol as a yellow oil (285 mg, quant.).
The crude product (max. 1.15 mmol) was dissolved in
CH2Cl2 (17 mL). Pyridine (15 mL, 15 mg, 190 mmol) and
AuCl (13 mg, 56 mmol) were added with rapid stirring. After
1 h, TLC showed complete conversion. The mixture was
concentrated in vacuo and directly chromatographed (silica
gel, EtOAc–hexane = 1:3) to provide 222 mg (85% over 2
steps) of 4g as a colorless solid. Analytical data for 4g: mp
72–74 °C. 1H NMR (500 MHz, CDCl3): d = 1.59–1.67,
1.86–1.91 (2 m, 2 × 4 H, 4 × CH2), 3.61 (s, 3 H, OCH3), 3.92
(mc, 4 H, 2 × CH2), 4.50 (t, J = 1.7 Hz, 1 H, 4-H), 4.52 (d,
Synlett 2007, No. 8, 1294–1298 © Thieme Stuttgart · New York

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