From amino acids to Dihydrofurans: Functionalized allenes in modern organic synthesis

Article abstract of DOI:10.1055/s-2002-33707

In this account, recent accomplishments in the field of target-oriented synthesis involving allenes are summarized. Allenic α-amino acid derivatives 9, which are of interest as possible vitamin B₆ decarboxylase inhibitors, were prepared by 1,6-addition of the cyano-Gilman reagent t-Bu₂CuLi-LiCN to 2-amino-substituted enynoates 8, and selective deprotection at either the amino or the ester group was realized. 2,5-Dihydrofurans 18 were obtained by cyclization of the corresponding α-hydroxyallenes; for this step, new methods (treatment with hydrogen chloride gas or acidic ion exchange resin; gold(III)-chloride catalysis) were developed. The 2-hydroxy-3,4-dienoates 14 were obtained by diastereoselective oxidation of titanium enolates formed from 3,4-dienoates 12 with dimethyl dioxirane (DMDO), whereas hydroxyallenes 16 were prepared by copper-mediated S_N2′-substitution of propargylic epoxides 15.

Full text of DOI:10.1055/s-2002-33707

FEATURE ARTICLE
1759
From Amino Acids To Dihydrofurans: Functionalized Allenes in Modern
Organic Synthesis
Functionalized
All
o
enes in Mod
r
e
rn
O
rga
b
nic Synthesi
e
s
rt Krause,* Anja Hoffmann-Röder, Johannes Canisius
Organic Chemistry II, Dortmund University, 44221 Dortmund, Germany
Fax +49(231)7553884; E-mail: nkrause@pop.uni-dortmund.de
Received 10 February 2002; revised 14 March 2002
preparation of natural and non-natural products. Hence,
the stereoselective synthesis of -hydroxyallenes and
their subsequent transformation into 2,5-dihydrofurans
represent an example of allenes as potential building
Abstract: In this account, recent accomplishments in the field of
target-oriented synthesis involving allenes are summarized. Allenic
-amino acid derivatives 9, which are of interest as possible vitamin
B6 decarboxylase inhibitors, were prepared by 1,6-addition of the
cyano-Gilman reagent t-Bu2CuLi LiCN to 2-amino-substituted blocks in natural product synthesis, whereas the genera-
enynoates 8, and selective deprotection at either the amino or the es-
ter group was realized. 2,5-Dihydrofurans 18 were obtained by cy-
clization of the corresponding -hydroxyallenes; for this step, new
methods (treatment with hydrogen chloride gas or acidic ion ex-
tion of allenic -amino acid derivatives illustrates our in-
terest in the formation of new pharmacologically active
allenic compounds.
change resin; gold(III)-chloride catalysis) were developed. The 2-
hydroxy-3,4-dienoates 14 were obtained by diastereoselective oxi-
2
Synthesis of -Allenic -Amino Acids
dation of titanium enolates formed from 3,4-dienoates 12 with di-
methyl dioxirane (DMDO), whereas hydroxyallenes 16 were
prepared by copper-mediated SN2 -substitution of propargylic ep-
oxides 15.
In the course of our investigations on the synthesis of
functionalized allenes via 1,6-addition of organocuprates
to acceptor-substituted enynes,7 we became particularly
interested in allenic -amino acid derivatives due to their
potential biological activity. Allenic -amino acids (as
well as other unsaturated -amino acids) act as specific
mechanism-based inhibitors of vitamin B6 linked decar-
boxylases.8 In particular the introduction of an allenic en-
tity into an -amino acid enables the formation of a highly
specific inhibitor with promising therapeutic utility
through the additional incorporation of axial chirality into
the molecule. But despite the fact that -allenyl DOPA 1
rapidly inactivates porcine kidney aromatic group amino
acid decarboxylase,9 few attempts towards the synthesis
of further -allenic -amino acids have been reported to
date (Figure 1). Moreover, no natural -allenic -amino
acid is known so far; the only example of a naturally oc-
curing -amino acid comprising an allenic moiety is the -
allenic amino acid 2, which has been isolated from the
mushroom Amanita solitaria and other Amanita species.10
This unsaturated compound, however, shows only low bi-
ological activity.
1
2
3
4
5
Introduction
Synthesis of -Allenic -Amino Acids
Synthesis of 2,5-Dihydrofurans
Conclusion
Experimental Section
Key words: allenes, amino acids, gold catalysis, 2,5-dihydro-
furans, organocopper reagents
1
Introduction
In recent years, functionalized allenes have gained more
and more interest not only as valuable synthetic precur-
sors in the generation of complex molecules of biological
and industrial importance but also as target molecules in
natural product synthesis. Application of allenic interme-
diates in modern organic synthesis are mainly due to their
high reactivity and inherent axial chirality, thus allowing
subsequent transformations to proceed stereoselectively,
e.g., under chirality transfer.1 In this context, carbon-car-
bon, as well as carbon-heteroatom bond forming process-
es are of major interest, triggering the development of
preparatively useful methods involving functionalized al-
lenes, such as additions,2 Diels–Alder reactions,3 and pal-
ladium-catalyzed transformations.4 Moreover, the
increasing number of allenic pharmaceuticals5 and natural
products1,6 highly stimulated the investigation of allenes
in target-oriented synthesis.
H2N
CO2H
HO
HO
NH2
CO2H
•
•
2
1
Figure 1 Pharmacologically active and naturally occuring allenic
amino acids.
In this account, we will summarize recent results of our
own work on functionalized allenes and their use in the
Unfortunately, closer investigations of this interesting
class of compounds as potential pharmaceuticals were
hampered due to difficulties in their synthesis. In contrast
to - and -allenic -amino acids, which are quite easily
accessible via SN2 -substitution of propargylic electro-
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-210X,E;2002,0,12,1759,1774,ftx,en;Z03102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1760
N. Krause et al.
FEATURE ARTICLE
philes with amino acid derived organozinc reagents11 and
direct palladium-catalyzed allenylation,12 respectively,
the synthesis of -allenic -amino acids faces several
problems. The most efficient approach towards the pre-
paration of these unsaturated compounds relies upon
[3,3]-sigmatropic rearrangement reactions. However, in
the case of Ireland–Claisen rearrangements of propargylic
amino esters 313 only low chemical yields were obtained,
whereas the chelate-controlled Claisen rearrangement of
such amino esters14 suffers from limitations regarding the
substitution pattern. Due to steric hindrance in the transi-
tion state, only -allenic -amino acid derivatives 4 con-
taining a small substituent at position C-5 are accessible
via this route (Scheme 1).
R3
R3
O
O
1. LDA (2 eq.)
2. ZnCl2
R2
R1
R2
R1
O
O
Zn
NHPG
PGN
3
H
R3
R2
•
R1
HO2C
NHPG
4
Scheme 1 Synthesis of -allenic -amino acid derivatives 4 by che-
late-controlled Claisen rearrangement.
Biographical Sketches
Norbert Krause (born Saunders (Yale University, tic understanding of organo-
1959 in Wolfsburg, Germa- New Haven, USA), he ob- metallic reactions, their
ny) studied chemistry at the tained his habilitation for or- application to the synthesis
Technical University of ganic chemistry in the group of natural and unnatural
Braunschweig and obtained of K. Hafner at the Techni- products, and stereoselec-
his PhD degree in 1986 un- cal University of Darmstadt tive protonation reactions.
der the guidance of H. Hopf in 1993. He became associ- This work was recognized
for research on sterically ate professor at the Univer- through the award of the
and electronically modified sity of Bonn in 1994 and full Heinz–Maier–Leibnitz
retinoids. After one-year professor at the University prize (1991), the ADUC an-
postdoctoral appointments of Dortmund in 1998. His nual prize for lecturers
with D. Seebach (ETH research interests cover the (1993), and a Heisenberg
Zürich, Switzerland) and M. development and mechanis- scholarship (1994).
Anja
Hoffmann-Röder ing in N. Krause’s group on chen Industrie. In 2001, she
(born 1972 in Bonn, Germa- her PhD thesis about the uti- joined the groups of A. Al-
ny) became laboratory tech- lization of allenes for the exakis (University of Gene-
nician at the Degussa AG in synthesis of natural prod- va, Switzerland) and Y.
1994 and then studied ucts and pharmaceutically Yamamoto (Tohoku Uni-
chemistry at the University active compounds. Her versity, Sendai, Japan) for
of Bonn. In 1999, she ob- studies were recognized scientific short-term mis-
tained her Diploma with a through stipends from the sions, which were spon-
thesis on chiral allen- Studienstiftung des Deut- sored by the European
ophanes under the joint su- schen Volkes and the Fritz- Community and the Japa-
pervision of F. Vögtle and ter-Meer foundation, and by nese Ministry of Education,
N. Krause. She then moved a PhD scholarship from the Culture, Sports, Science and
to the University of Dort- Stiftung Stipendien-Fonds Technology
mund and is currently work- des Verbandes der Chemis- gakusho).
(Monbuka-
Johannes Canisius (born Krause. In 1998, he moved preparative aspects of cop-
1967 in Bonn, Germany) to the University of Dort- per-mediated Michael addi-
studied chemistry at the mund and obtained his PhD tions. He is now working as
University of Bonn and ob- degree in 2000 under the a research chemist at Witco
tained his Diploma in 1996 guidance of N. Krause for Crompton Corp. (Bergka-
under the supervision of N. research on mechanistic and men, Germany).
Synthesis 2002, No. 12, 1759–1774 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Functionalized Allenes in Modern Organic Synthesis
1761
In order to overcome these limitations and to initiate fur-
ther investigations on the structure-reactivity-relationship
of these interesting bioactive compounds, we decided to
develop a different strategy for the synthesis of -allenic
-amino acids. Since the 1,6-addition of organocuprates
to acceptor-substituted enynes has proven to be an effi-
cient way for the synthesis of highly functionalized al-
lenes,7 we applied this method to protected amino
enynoates 8, thus leading to the formation of trisubstituted
-allenic -amino acids 9. Alternative approaches to-
wards the introduction of an amino group into allenic es-
ters either via electrophilic azidation15 of the
corresponding ester enolate or Mitsunobu reaction16 of -
hydroxy allenic esters failed, furnishing the desired allen-
ic azido esters only in minor amounts.17
Table 1 Synthesis of -Amino Enynoates 8 and -Allenic -Amino
Acids 9
En-
try
Enyn-
oate
R
PG
Yield
of 8
Con-
figura- of 9
Yield
(%)
tion
E
(%)
0
1
2
3
4
8a
8b
8c
8d
t-Bu
t-Bu
Ph
Bz/Cbza
Boc
42
71
23
60
Z
71
54
63
Boc
Z
1-cyclo- Boc
hexenyl
Z
5
6
8e
8f
Me3Si
Boc
Ac
61
47
Z
Z
68
42
t-Bu
2-En-4-ynoates can be easily prepared through Wittig–
Horner–Wadsworth–Emmons (WHWE) reaction of acet-
ylenic aldehydes with suitably functionalized phospho-
nates.18 Extension of this method towards the synthesis of
-amino substituted enynoates 8 required protection of
the amino functionality either as an amide or a carbamate
(Scheme 2).17,19
a Nitrogen doubly protected.
en-4-ynoate21 and ethyl (Z)-2-acetyl-amino-5-phenyl-
pent-2-en-4-ynoate,22 respectively, revealed large cou-
3
pling constants of JC–H = 5.9–9.8 Hz for the E-
configurated products, whereas the corresponding
enynoates with Z-configuration of the double bond show
coupling constants in the range of 3JC–H = 3.9–4.6 Hz. Ad-
ditionally, the structures of the doubly protected amino es-
ter 8a23 and its acetyl analogue 8f24 were confirmed by X-
ray analysis.
CHO
1. nBuLi
O
2. DMF
3. H+
R
R
(EtO)2P
CO2Et
NHPG
5
6
7
tBuOK
CO2Et
NHPG
CO2Et
NHPG
1. tBu2CuLi • LiCN
2. H+
tBu
CO2Et
•
R
R
R
NHPG
8
9
8
Scheme 3 Synthesis of -allenic -amino acid derivatives 9 by 1,6-
cuprate addition.
Scheme 2 Synthesis of 2-amino-2-en-4-ynoates 8.
The reaction sequence started with alkynes 5 which were
formylated with N,N-dimethylformamide after deprotona-
tion with butyllithium.20 The resulting unsaturated alde-
hydes 6 proved to be unstable and were therefore
subjected without purification to the following WHWE
olefination. Thus, in the presence of the protected -ami-
nophosphonates 7 and potassium tert-butoxide as a base,
the desired -amino enynoates 8 were obtained in moder-
ate to good chemical yields (Table 1).
The subsequent transformations to the allenic amino es-
ters 9 were achieved with an excess of lithium tert-butyl-
cyanocuprate (t-Bu2CuLi LiCN) in Et2O (Scheme 3,
Table 1); the doubly protected amino ester 8a, however,
did not react under these conditions. Also, less reactive or-
ganocuprates such as Me2CuLi LiCN, Me2CuLi LiI or
Ph2CuLi LiCN did not furnish any reaction product at all,
even in the presence of different Lewis acids as additives
(e.g., Me3SiOTf) or a higher cuprate-to-substrate ratio. By
contrast, the use of the tert-butylcyanocuprate enables the
preparation of even sterically encumbered allenic esters in
moderate to good chemical yields and as a mixture of both
diastereomeric products, due to a nonselective protona-
tion of the allenyl enolate formed during the 1,6-addi-
tion.25
As outlined in Table 1, the reaction is not restricted to
alkyl-substituted allenic amino esters, but tolerates beside
alkenyl even aryl and trimethylsilyl substituents. More-
over, the WHWE reaction proceeds stereoselectively, fur-
nishing the Z-configurated products exclusively. Only in
the case of the doubly protected amino ester 8a, the geom-
etry of the double bond was found to be E, indicating a
sterically induced preference for the intermediate oxa-
phosphetane with the triple bond being trans to the pro-
tected amino group. The geometry of the double bond of
the amino esters was established by NMR-spectroscopy
Last but not least, acidic treatment of the Boc-protected
amino ester 9b with hydrochloric acid (6 M) resulted in a
chemoselective cleavage of the N-butoxycarbonyl group,
furnishing the corresponding -allenic -amino ester 10 in
87% yield. Contrarily, in the case of the acetyl-protected
amino ester 9f the ester group instead of the amino-pro-
3
through determination of the JC–H coupling constants of
the carbon resonance at C-1. Comparison of these data
with the known enynoates ethyl (E)-6,6-dimethylhept-2-
Synthesis 2002, No. 12, 1759–1774 ISSN 0039-7881 © Thieme Stuttgart · New York

1762
N. Krause et al.
FEATURE ARTICLE
tecting group was cleaved, thus providing the N-protected clization to proceed stereoselectively under chirality
amino acid 11 (66% yield, Scheme 4).
transfer (Scheme 5).
R3
R5
CO2Et
HCl
CO2Et
NH2
tBu
tBu
E
R3
R5
R4
•
•
•
E+
R1
NHBoc
R1
R2
R4
•
tBu
tBu
tBu
tBu
OH
9b
9f
10
11
O
R2
E+ = H+, NBS, PhSeBr
CO2Et
NHAc
CO2H
NHAc
HCl
tBu
tBu
•
Scheme 5 Electrophilically induced cyclization of -hydroxyalle-
nes to 2,5-dihydrofurans.
Scheme 4 Selective deprotection of -allenic -amino acid deriva- The required -hydroxyallenes are mainly accessible by
tives 9b/f.
SN2 -ring opening reaction of propargylic epoxides with
organometallic compounds31 or via oxidation of in situ
formed enolates of 3,4-dienoates.32 In the latter case, al-
In summary, we have shown that the 1,6-addition of orga-
lenic esters 12, which are again provided through the
above outlined 1,6-addition of organocuprates to
enynoates,7 were (after deprotonation) transformed into
the corresponding titanium ester enolates33 and reacted
with dimethyl dioxirane (DMDO) in acetone following
Adam’s protocol.34 The resulting -hydroxy allenic esters
14 were obtained in variable yields and diastereoselectiv-
ities depending upon the substitution pattern of the parent
allene (Scheme 6, Table 2).
nocuprates to amino-substituted enynoates 8 represents an
attractive alternative for the preparation of -allenic -
amino acid derivatives. The reaction sequence outlined
above not only furnishes the desired tert-butyl-substituted
amino ester derivatives 9, 10, and 11, respectively, but
also allows for the introduction of sterically demanding
substituents at the allenic moiety.
3
Synthesis of 2,5-Dihydrofurans
OEt
Besides, the above mentioned amino-functionalized al-
lenes, -hydroxyallenes have also proven to be highly re-
warding as building blocks in natural product synthesis. In
this context, we became particularly interested in the elec-
trophilically induced cyclization of these compounds to
2,5-dihydrofurans26 since the latter represent pivotal
structural elements of a wide variety of different biologi-
cally active molecules. For instance, 2,5-dihydrofurans
can be found in mycotoxins,27 polyether antibiotics,28
spiroketals,29 and even amino acids.30 The generation of
these heterocycles from allenic precursors not only bene-
fits from the high reactivity of -hydroxyallenes but also
from their inherent axial chirality, which allows the cy-
CO2Et
R1
R1
OTiCp2Cl
•
•
1. Base
R3
2. Cp2TiCl2
3. DMDO
R3
R2
R2
O
O
12
13
CO2Et
R3 OH
R1
•
R2
14
Scheme 6 Synthesis of 2-hydroxy-3,4-dienoates 14 by enolate oxi-
dation with DMDO.
Table 2 Oxidation of 3,4-Dienoates 12 to -Hydroxyallenes 14
Entry
Enynoate
R1
R2
R3
Base
Consumption Yield of 14
of 12 (%)
ds
(%)a
1
2
3
4
5
6
7
12a
12b
12b
12c
12c
12d
12e
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
t-Bu
Me
H
LDA
46
19
32
55
53
63
30
68
90:10
80:20
80:20
60:40
60:40
50:50
60:40
Me
Me
Me
H
LDA
63
Me
LHMDS
LDA
75
n-Bu
n-Bu
n-Hex
n-Hex
67
H
LHMDS
LDA
99
H
87
Me
LDA
56
a With respect to consumed starting material 12.
Synthesis 2002, No. 12, 1759–1774 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Functionalized Allenes in Modern Organic Synthesis
1763
In the enolate oxidation reactions examined here, no com- with stoichiometric amounts of organocuprates at –20 °C
plete conversion of the starting allenic ester 12 was ob- proceeded smoothly in the case of t-Bu2CuLi LiCN fur-
served, even with a large excess of DMDO. Presumably, nishing the desired allenic alcohols 16a,b in good chemi-
the desired oxidation is competing with the protonation of cal yields (Scheme 7; Table 3, entries 1,2). Similarly,
the enolate by acetone, which (as a result of the DMDO treatment of oxirane cis-15a with n-Hex2CuLi LiCN
preparation) is present in the reaction mixture in large (Table 3, entry 3) gave the desired substitution product
amounts. Besides, the dioxirane may react with the conju- 16c, which was contaminated with 15% of the (formal) re-
gate acid of the base used for the deprotonation of the ester duction product 17a. The formation of products of this
(i.e., diisopropylamine), resulting in the decomposition of type has been observed previously and was attributed to
the oxidizing agent.34 In this regard, it is noteworthy that the protonation of a rather stable copper intermediate dur-
the use of lithium hexamethyldisilazide as a base instead ing work-up.26f In this reaction, the presence of tri-n-bu-
of LDA led to increased comsumption of substrate 12b.35 tylphosphine served to improve the ratio of substitution to
Interestingly, in the case of allene 12c an unchanged con- (formal) reduction.
version but a much higher yield were observed, indicating
less side reactions. Generally, substrate conversions in the
Me
range of 20–30% were found with allenes bearing a meth-
R3
OR2
•
•
yl group at C-2 (Table 2, entries 2,3,7), whereas substrates
without a substituent in this position gave ca 50–60% con-
version.
Me
OH
OH
O
R1
OR2
R3M, CuCN
Et2O or THF
16
+
R1
Me
15
The highest diastereoselectivities (of up to 90% in the
case of allene 12a, entry 1) were obtained with 3,4-di-
enoates bearing substituents of different size at C-5, pre-
sumably due to complexation of the DMDO to the
titanium enolate and subsequent oxygen transfer from the
less shielded diastereotopic side [cf. possible intermediate
13; the deprotonation of 3,4-dienoates with LDA is
known to produce the E(OLi)-enolates selectively7]. The
relative configuration of the major diastereomer was de-
termined by cyclization to the corresponding 2,5-dihydro-
furan (vide infra).32 However, introduction of an
additional substituent at C-2 lowered the diastereoselec-
tivity of the oxidation reaction (Table 2, entries 2,3,7).
The same trend was observed with allenes bearing longer
alkyl chains at C-5 (Table 2, entries 4–7); in the case of
substrate 12d (Table 2, entry 6), no diastereoselectivity is
expected since the alkyl groups at C-5 are virtually of the
same size.
H
OR2
R1
17
Scheme 7 Synthesis of -hydroxyallenes 16,17 from propargylic
epoxides 15
Contrarily, the (formal) reduction product 17 was ob-
tained as the major product in the corresponding reaction
of cis- or trans-15a with Me2CuLi LiCN, and this situa-
tion could neither be improved by changing the solvent
from Et2O to THF nor through addition of an alkylating
agent such as methyl iodide26f prior to work-up. Fortu-
nately, addition of n-Bu3P led again to the predominant
formation of the desired substitution product 16d with
high diastereoselectivity (entry 4). The corresponding re-
action with Grignard reagents in the presence of stoichio-
metric amounts of CuCN gave similar results, although
sometimes direct nucleophilic substitution of the epoxide
occured as a side reaction (in particular if the reaction was
The alternative route for generation of -hydroxyallenes
via SN2 -substitution reaction of propargylic epoxides 15
Table 3 Nucleophilic Ring Opening of Propargyl Oxiranes 15
Entry
Substrate
R1
R2
R3M
Additive
Major
Ratio
Yield (%)a ds of 16
Product
16:17
1
2
3
4
5
6
7
trans-15a
trans-15b
cis-15a
H
TBS
Me
t-BuLi
t-BuLi
n-HexLi
MeLi
n-Bu3P
(EtO)3P
n-Bu3P
n-Bu3P
16a
16b
16c
16d
16d
17a
16e
100:0
100:0
85:15
94:6
66
66
77
77
70
87
80
65:35
80:20
75:25
85:15
94:6
–
Me
H
TBS
TBS
TBS
TBS
Me
cis-15a
H
cis-15a
H
MeMgBr
MeLi
n-Bu3P
100:0
20:80
90:10
–b
trans-15a
trans-15b
H
–b
Me
MeLi
–
a Combined yield of 16 and 17.
b Reaction carried out at –80 °C.
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1764
N. Krause et al.
FEATURE ARTICLE
run under copper catalysis31a according to Alexakis’ pro-
tocol). Thus, treatment of the silylated epoxide cis-15a
with the magnesium cuprate Me2CuMg2(CN)Br2 fur-
nished the desired hydroxyallene with good chemical
yield and diastereoselectivity (entry 5). Last but not least,
the formal reduction product was obtained predominantly
by treating trans-15a with the cyanocuprate
Me2CuLi LiCN at low temperature (–80 °C) in the ab-
sence of any additive, resulting in the formation of an
80:20-mixture of products 17a and 16d. Unfortunately,
the corresponding reaction of the propargylic oxirane
trans-15b (which bears a methyl group at the triple bond)
demonstrates that this behavior is substrate-dependent: in
this case a 90:10 ratio of substitution vs. (formal) reduc-
tion was observed (entry 7).
R3
R3
R5
R4
R5
R1
R1
R2
R4
•
OH
O
R2
14/16/17
18
Scheme 8 Cyclization of -hydroxyallenes 14,16,17 to 2,5-dihy-
drofurans 18.
yields. The relative configurations of the major diastere-
omers of dihydrofurans 18a and 18h, respectively, were
determined with the aid of NOE experiments,32,36 con-
firming also those of the corresponding -hydroxyallenes.
With these mild and efficient cyclization methods in hand,
we searched for their application in natural product syn-
thesis. In this respect, the functionalized aldehyde citreo-
viral (21),37 which is a key intermediate in the synthesis of
two structural related antiparasitic mycotoxins, citreo-vir-
idin (19)27a and verrucosidin (20),27b represents a promis-
ing target molecule (Scheme 9). In particular,
citreoviridin (19), isolated from Penicillium citreoviride,
has gained further interest as a potent neurotoxin, due to
its highly specific inhibition of mitochondrial F1,F0-AT-
Pase causing cardiac Beriberi disease.38
All -hydroxyallenes 14 and 16, obtained either via ester
enolate oxidation or via SN2 -substitution reaction, were
smoothly converted into the corresponding 2,5-dihydro-
furans 18 under complete axis to center chirality transfer
(Scheme 8; Table 4). Whereas the 2-hydroxy-3,4-di-
enoates 14 were easily cyclized upon treatment with hy-
drogen chloride gas in chloroform or, more conveniently,
by using acidic Amberlyst 15 resin in refluxing dichlo-
romethane, the silylated hydroxyallenes 16 required mild-
er reaction conditions. Hence, such acid labile substrates
(or those which would readily undergo elimination due to
steric hindrance) were efficiently transformed using 5 to
10 mol-% of gold(III)-chloride as a catalyst.36 Again, as in
the acid-induced cyclizations, the reaction not only pro-
ceeded under complete chirality transfer, but also proved
to be of wide scope with regard to the substitution pattern
of the allenic entity, furnishing both, tri- and tetrasubsti-
tuted 2,5-dihydrofurans in good to excellent chemical
These intriguing physiological properties have attracted
several synthetic approaches towards the total synthesis of
citreoviridin (19) and its metabolite citreoviral (21),39,40
which is far less toxic. While most of these syntheses re-
quired rather long multistep reaction sequences starting
from precursors of the ‘chiral pool’, such as carbohy-
drates,41 glycerinaldehyde,42 or lactate,43 Marshall’s
group reported a formal synthesis using an -hydroxyal-
Table 4 Cyclization of Hydroxyallenes 14 and 16 to 2,5-Dihydrofurans 18
Entry
Substrate
R1
R2
R3
R4
R5
Reagent
Product
Yield of 18 ds
(%)
1
2
14a
14a
14a
14b
14c
14c
14d
16a
16b
16c
16d
17a
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
n-Bu
t-Bu
t-Bu
H
Me
H
CO2Et
H
H
H
Me
H
H
H
H
H
H
H
H
HCl
18a
18a
18a
18b
18c
18c
18d
18e
18f
18g
18h
18i
90
90:10
Me
H
CO2Et
Amberlyst 15
AuCl3
HCl
quant.
74
90:10
90:10
80:20
60:40
60:40
50:50
65:35
80:20
75:25
94:6
3
Me
H
CO2Et
4
Me
H
CO2Et
92
5
n-Bu
n-Bu
n-Hex
H
H
CO2Et
HCl
80
6
H
CO2Et
AuCl3
HCl
quant.
90
7
H
CO2Et
8
Me
Me
Me
Me
Me
CH2OTBS
CH2OMe
CH2OTBS
CH2OTBS
CH2OTBS
AuCl3
AuCl3
AuCl3
AuCl3
AuCl3
95
9
Me
90
10
11
12
n-Hex
Me
65
H
77
H
H
86
–
Synthesis 2002, No. 12, 1759–1774 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Functionalized Allenes in Modern Organic Synthesis
1765
OMe
O
1. nBuLi
OH
HO
2. MeCHO
mCPBA
O
24
OH
O
25
Citreoviridin (19)
O
Me2CuMg2(CN)Br2
OMe
O
•
OR
OH
O
O
HO
O
OH
OH
CHO
26
O
27 (R = H)
O
TBSCl, Et3N, DMAP
23 (R = TBS)
Citreoviral (21)
Verrucosidin (20)
AuCl3 (5 mol-%)
OTBS
O
OTBS
22
O
22
Scheme 11 Synthesis of 2,5-dihydrofuran 22 via propargylic epoxi-
de 26
Scheme 9 Retrosynthesis of mycotoxins citreoviridin (19) and ver-
rucosidin (20) via citreoviral (21).
of the desired allene was observed, thus furnishing diol 27
after column chromatography in 43% chemical yield. Fi-
nally, selective protection of the primary hydroxyl group
as a TBS-ether provided -hydroxyallene 23, which was
then converted into the dihydrofuran 22 upon treatment
with 5 mol-% AuCl3 in dichloromethane (80% yield).
Compared to Marshall’s Ag(I)-promoted cyclization,
gold(III)-catalysis here proved to be particularly advanta-
geous not only for economical and ecological reasons but
also in terms of reactivity. Thus, complete conversion of
hydroxyallene 23 was achieved in 3 hours at room tem-
perature, furnishing the spectroscopically pure cyclization
product 22 after removal of the catalyst in 80% chemical
yield as a 60:40 mixture of diastereomers. Subsequent
steps for the transformation of 22 into racemic citreoviral
(21) follow the route outlined in Marshall’s work.26f
lene for the stereoselective construction of the 2,5-dihy-
drofuran core.26f Nevertheless, this approach still covered
9 steps and relied in its key reaction upon a heterogeneous
Ag(I)-induced cyclization of hydroxyallene 23 to the cit-
reoviral precursor 22 (Scheme 10). Here, almost stoichio-
metric amounts of silver nitrate were required to achieve
a good yield of product 22.
AgNO3 (0.8 eq.)
•
CaCO3
H2O / Acetone
OTBS
OTBS
O
OH
23
22
81%
Scheme 10 Silver-promoted cyclization of -hydroxyallene 23 to
2,5-dihydrofuran 22.26f
In summary, we present a new route to -hydroxyallenes
via oxidation of allenic ester enolates with DMDO and
their conversion into functionalized 2,5-dihydrofurans
upon acid-induced cyclization. Furthermore, we devel-
oped a stereoselective and efficient cyclization method for
-hydroxyallenes bearing acid-sensitive functionalities by
making use of gold(III)-catalysis. The latter protocol
proved to be advantageous compared to the well-known
stoichiometric cyclization procedures due to its mildness
and reactivity, and last but not least, was successfully ap-
plied to a short and concise synthesis of 2,5-dihydrofuran
22, a versatile precursor for rac-citreoviral (21). A diaste-
reo- and enantioselective synthesis of citreoviral via this
route is currently under investigation in our laboratories.
Thus, based on our own work on the use of -hydroxyal-
lenes as synthetic intermediates, we were able not only to
present an efficient and considerably shorter access to 22,
but also to improve the key step of the synthesis by em-
ploying our new gold-catalyzed cyclization method.
Moreover, our route opens up a convenient access to a va-
riety of structural analogues of citreoviral (21) for further
investigations on the structure-reactivity-relationship of
this type of compounds.
The reaction sequence started with enyne 25, easily acces-
sible via addition of the lithium acetylide of 2-methylbut-
1-en-3-yne (24) to acetaldehyde,44 which after epoxida-
tion with mCPBA furnished 26 in 58% chemical yield as
a 60:40 mixture of diastereomers (Scheme 11). About the
same yield and selectivity were observed when DMDO34a
was employed as epoxidation agent. The resulting ep-
oxide 26 was then subjected to a SN2 -substitution reac-
tion with 2 equivalents of the magnesium cyanocuprate
Me2CuMg2(CN)Br2 in Et2O. In this case, clean formation
4
Conclusion
In this account, we demonstrated the versatility of func-
tionalized allenes as potent building blocks in target-ori-
ented synthesis, benefitting from their unique reactivity
and chirality. In this respect, we presented at first an im-
Synthesis 2002, No. 12, 1759–1774 ISSN 0039-7881 © Thieme Stuttgart · New York

1766
N. Krause et al.
FEATURE ARTICLE
ic layers were washed with H2O and dried with MgSO4; the solvent
was removed in vacuo, and the crude product was purified by crys-
tallization or column chromatography.
proved access to substituted -allenic -amino acids, an
interesting class of pharmacologically active allenes
which may act as inhibitors of vitamin B6 decarboxylases.
The formation of -allenic -amino acid derivatives
through 1,6-addition reaction of organocuprates to amino-
substituted enynoates thereby allowed the generation of
even sterically encumbered representatives. Such promis-
ing target molecules for investigations of structure-reac-
tivity-relationships were not accessible by traditional
methods. In the second part, we demonstrated that -hy-
droxyallenes are also highly useful synthetic tools in nat-
ural product synthesis. These molecules can be again
obtained in an elegant way using a 1,6-cuprate addition-
oxidation sequence or by copper-promoted SN2 -substitu-
tion reaction of propargylic oxiranes. Subsequent acid-in-
duced or gold(III)-catalyzed cyclization to the correspon-
ding 2,5-dihydrofurans (which are common structural el-
ements in a wide variety of natural products) enabled the
generation of these heterocycles in a highly stereoselec-
tive mode. The efficiency of this new cyclization protocol
was illustrated in a short formal synthesis of racemic cit-
reoviral. In the future, we will work on the extension of
this method to the synthesis of other dihydrofuran-based
natural products, as well as on the generation of further
pharmacologically active allenic compounds.
Ethyl (E)-2-[benzyl-(benzyloxycarbonyl)amino]-6,6-dimethyl-
hept-2-en-4-ynoate (8a):
3,3-Dimethylbutyne (287 mg, 3.5 mmol), in Et2O (10 mL), n-BuLi
(1.5 M in hexane; 2.1 mL, 3.2 mmol), DMF (0.36 mL, 4.4 mmol),
t-BuOK (336 mg, 3.0 mmol) in CH2Cl2 (5 mL), and ethyl 2-[benzyl-
(benzyloxycarbonyl)-amino]-2-(diethoxyphosphoryl)-acetate (1.39
g, 3.0 mmol) 46 in CH2Cl2 (5 mL). Purification of the crude product
by column chromatography (SiO2; cyclohexane–Et2O, 10:1) fur-
nished 8a (542 mg, 43%) as colorless needles; mp 89 °C.
IR (KBr): 2970 (s, C–H), 2195 (s, C C), 1720 (s, C=O), 1612 cm–1
(s, C=C).
1H NMR (CDCl3): = 7.34–7.28 (m, 10 H, Ph), 5.81 (s, 1 H, 3-H),
5.19 (s, 2 H, NCH2Ph), 4.77 (s, 2 H OCH2Ph), 4.15–4.02 (m, 2 H,
CH2CH3), 1.26 [s, 9 H, C(CH3)3], 1.25–1.05 (m, 3 H, CH2CH3).
13C NMR (CDCl3): = 163.8 (C-1), 155.6 (NCO), 137.6 (C-4),
136.4 (C-2), 129.0, 128.8, 128.5, 127.8 (4+, Ph), 115.5 (+, C-3),
111.1 (C-5), 77.5 (C-4), 68.4 (–, OCH2Ph), 61.6 (–, CH2CH3), 54.5
(–, NCH2Ph), 30.9 [+, C(CH3)3], 28.9 (C-6), 14.5 (+, CH2CH3).
MS (EI): m/z (%) = 419 (15, M+), 328 (70), 284 (70), 91 (100).
Anal. Calcd for C26H29NO4 (419.53): C, 74.44; H, 6.97; N, 3.34.
Found: C, 74.30; H, 7.00; N, 3.30.
Ethyl (Z)-2-[(t-Butoxycarbonyl)amino]-6,6-dimethylhept-2-en-
4-ynoate (8b)
3,3-Dimethylbutyne (3.83 g, 46.7 mmol) in Et2O (45 mL), n-BuLi
(2.0 M in hexane; 21.0 mL, 42.0 mmol), DMF (4.3 mL ,56.0 mmol),
t-BuOK (3.98 g, 35.5 mmol) in CH2Cl2 (70 mL) and ethyl 2-[(t-bu-
toxycarbonyl)amino]-2-(diethoxyphosphoryl)-acetate (12.03 g,
35.5 mmol) 47 in CH2Cl2 (50 mL). Purification of the crude product
by column chromatography (SiO2; cyclohexane–Et2O, 10:1) fur-
nished 8b (7.43 g, 71%) as colorless needles; mp 72 °C.
NMR spectra were recorded with a Bruker WM 400 spectrometer at
400 MHz (1H) and 100.6 MHz (13C) in CDCl3 as solvent and inter-
nal standard ( = 7.27 for 1H, = 77.05 for 13C). The signals of the
major component of a product mixture are marked with an asterisk
(*). IR spectra were obtained with a Perkin-Elmer 1600 FT-IR spec-
trometer, mass spectra with Finnigan MAT 8230 (EI, 70 eV), Ther-
moquest TSQ API (ESI), or JEOL SX102A (FAB) spectrometers.
GC-MS spectra were recorded with a Finnigan ITD 800 and a Finni-
gan Polaris GCQ spectrometer. GC analyses were carried out with
a Carlo Erba GC 8000 gas chromatograph with helium as the carrier
gas and an OV-1701 capillary column. Elemental analyses were ob-
tained with Perkin Elmer CHN 240 A and B analyzers. The reac-
tions were carried out in thoroughly dried glassware under argon.
Et2O was distilled from LiAlH4 prior to use. BuLi, t-BuLi and n-
HexLi were titrated with diphenylacetic acid according to the pro-
cedure of Kofron and Baclawski.45
IR (KBr): 3241 (s), 3212 (s, N–H), 2932 (s, C–H), 2194 (s, C C),
1724 (s, C=O), 1722 (s, C=O), 1616 (s, C=C), 1470 cm–1 (s, N–H).
1H NMR (CDCl3): = 6.32 (s, 1 H, NH), 6.00 (s, 1 H, 3-H), 4.20 (q,
J = 7.3 Hz, 2 H, CH2), 1.49 [s, 9 H, OC(CH3)3], 1.25 (t, 3 H, J = 7.3
Hz, CH2CH3), 1.22 [s, 9 H, CC(CH3)3].
13C NMR (CDCl3): = 164.0 (C-1), 151.8 [(CH3)3COC], 134.6 (C-
2), 112.7 (C-5), 106.9 (+, C-3), 80.9 [OC(CH3)3], 73.8 (C-4), 61.5
(–, CH2), 30.7 (+, CC(CH3)3), 28.5 (C-6), 28.0 (+, OC(CH3)3), 14.0
(+, CH2CH3).
Some -hydroxyallenes and 2,5-dihydrofurans were too unstable to
obtain correct elemental analyses or high-resolution mass spectra.
MS (EI): m/z (%): 295 (14, M+), 195 (100), 180 (49), 166 (26).
Anal. Calcd for C16H25NO4 (295.38): C, 65.06; H, 8.53; N, 4.74.
Found: C, 65.00; H, 8.40; N, 4.70.
Preparation of 2-Amino-substituted Enynoates 8; General
Procedure17,20
Ethyl (Z)-2-[(t-Butoxycarbonyl)amino]-5-phenylpent-2-en-4-
ynoate (8c)
To a soln of alkyne 5 (1.1 equiv) in Et2O was added at –40 °C
n-BuLi (hexane soln, 1 equiv). After addition of anhyd DMF (1.2
equiv), the mixture was warmed to r.t.and stirred for 30 min; it was
then added to a vigorously stirred mixture, cooled to 5 °C, of 10%
aqueous NaH2PO4 soln and Et2O (5 mL each/mmol 5). The phases
were separated and the aqueous layer was washed with Et2O. The
combined organic phases were dried with MgSO4, and the major
part of the solvent was distilled off under ambient pressure. The
crude aldehyde 6 was used without purification in the next step.
Phenylacetylene (1.33 g, 13.0 mmol) in Et2O (15 mL) , n-BuLi (2.0
M in hexane; 5.9 mL, 11.7 mmol), DMF (1.2 mL, 15.6 mmol),
t-BuOK (1.12 g, 10.0 mmol) in CH2Cl2 (20 mL), and ethyl 2-[(t-bu-
toxycarbonyl)amino]-2-(diethoxyphosphoryl)-acetate (3.38 g, 10.0
mmol)47 in CH2Cl2 (15 mL). Crystallization of the crude product
from hexane furnished 8c (737 mg, 23%) as slightly brown needles
(mp 95 °C).
IR (KBr): 3227 (s, N–H), 2932 (s, C–H), 2200 (s, C C), 1722 (s,
C=O), 1708 (s, C=O), 1623 (s, C=C), 1477 cm–1 (s, N–H).
1H NMR (CDCl3): = 7.36–7.21 (m, 5 H, Ph), 6.54 (br s, 1 H, NH),
6.17 (s, 1 H, 3-H), 4.17 (q, 2 H, J = 7.0 Hz, CH2), 1.38 [s, 9 H,
C(CH3)3], 1.21 (t, 3 H, J = 7.0 Hz, CH2CH3).
A suspension of t-BuOK (1 equiv) in CH2Cl2 was cooled to –78 °C,
a soln of phosphonate 7 in CH2Cl2 was added dropwise. After stir-
ring for 30 min at –78 °C, a soln of the crude aldehyde 5 (1 equiv)
in THF (1 mL/mmol 5) was added dropwise, and the mixture was
stirred for 1 h at –78 °C. After hydrolysis, the layers were separated
and the aqueous phase was washed with Et2O. The combined organ-
Synthesis 2002, No. 12, 1759–1774 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Functionalized Allenes in Modern Organic Synthesis
1767
13C NMR (CDCl3): = 163.8 (C-1), 151.7 [(CH3)3COC], 135.6 (C-
2), 131.6, 128.9, 128.3 (3+, Ph), 122.5 (Ph), 105.5 (+, C-3), 102.3
(C-5), 84.1 (C-4), 81.1 [C(CH3)3], 61.8 (–, CH2), 28.0 [+, C(CH3)3],
14.0 (+, CH2CH3).
IR (KBr): 3212 (s), 3175 (s, N–H), 2970 (s, C–H), 2180 (s, C C),
1720 (s, C=O), 1680 (s, C=O), 1610 (s, C=C), 1529 cm–1 (s, N–H).
1H NMR (CDCl3): = 7.33 (br s, 1 H, NH), 6.18 (s, 1 H, 3-H), 4.17
(q, 2 H, J = 7.3 Hz, CH2), 2.03 (s, 3 H, CH3CO), 1.22–1.17 [m, 12
H, CH2CH3, C(CH3)3].
MS (EI): m/z (%) = 315 (16, M+), 259 (9), 215 (19), 57 (100).
Anal. Calcd for C18H21NO4 (315.37): C, 68.55; H, 6.71; N, 4.44.
Found: C, 68.60; H, 6.70; N, 4.40.
13C NMR (CDCl3): = 168.1 (CH3CO), 163.7 (C-1), 134.6 (C-2),
114.1 (C-5), 110.9 (+, C-3), 74.5 (C-4), 61.5 (–, CH2), 30.5 [+,
C(CH3)3], 28.5 [C(CH3)3], 22.8 (+, CH3CO), 13.9 (+, CH2CH3).
Ethyl (Z)-2-[(t-Butoxycarbonyl)amino]-5-(cyclohex-1-en-1-yl)-
pent-2-en-4-ynoate (8d)
MS (EI): m/z (%) = 237 (30, M+), 195 (12), 180 (100), 166 (48).
Anal. Calcd for C13H19NO3 (237.30): C, 65.80; H, 8.07; N, 5.90.
Found: C, 65.70; H, 8.00; N, 5.90.
1-Ethynylcyclohexene (1.38 g, 13.0 mmol) in Et2O (15 mL),
n-BuLi (2.0 M in hexane; 5.9 mL, 11.7 mmol), DMF (1.2 mL, 15.6
mmol), t-BuOK (1.12 g, 10.0 mmol) in CH2Cl2 (20 mL), and ethyl
2-[(t-butoxycarbonyl)amino]-2-(diethoxyphosphoryl)-acetate (3.38
g, 10.0 mmol)47 in CH2Cl2 (15 mL). Purification of the crude prod-
uct by column chromatography (SiO2; cyclohexane–Et2O, 10:1)
furnished 8d (1.90 g, 60%) as a red oil.
1,6-Addition of t-Bu2CuLi LiCN to 2-Amino-substituted
Enynoates; General Procedure
To a suspension of CuCN (2–4 equiv) in Et2O was added at –30 °C
t-BuLi (4–8 equiv) in pentane. After stirring for 15 min at –30 °C, a
soln of Michael acceptor 8 (1 equiv) in Et2O was added, and the
mixture was stirred for 2 h at –10 °C. Then, a sat. aq NH4Cl soln was
added, and the mixture was filtered through Celite. The solvent was
removed in vacuo, and the crude product purified by column chro-
matography (SiO2; cyclohexane–Et2O, 1:1-10:1).
IR (neat): 3334 (s, N–H), 2979 (s), 2934 (s, C–H), 2184 (s, C C),
1727 (s, C=O), 1708 (s, C=O), 1631 (s), 1609 (s, C=C), 1481 cm–1
(s, N–H).
1H NMR (CDCl3): = 6.40 (br s, 1 H, NH), 6.19 (m, 1 H, 2 -H),
6.15 (s, 1 H, 3-H), 4.24 (q, 2 H, J = 7.3 Hz, CH2), 2.15–2.11 (m, 4
H, 3 -H, 6 -H), 1.65–1.56 (m, 4 H, 4 -H, 5 -H), 1.46 [s, 9 H,
C(CH3)3], 1.28 (t, 3 H, J = 7.3 Hz, CH2CH3).
Ethyl 2-[(t-butoxycarbonyl)amino]-5-t-butyl-6,6-dimethylhep-
ta-3,4-dienoate (9b)
CuCN (1.78 g, 20.0 mmol) in Et2O (50 mL), t-BuLi (1.5 M in pen-
tane; 26.7 mL, 40.0 mmol), and 8b (1.50 g, 5.0 mmol) in Et2O (25
mL) furnished 9b (1.25 g, 71%) as a yellow oil.
13C NMR (CDCl3): = 164.0 (C-1), 151.8 [(CH3)3COC], 137.2 (+,
C-2 ), 134.3 (C-2), 120.6 (C-1 ), 106.5 (+, C-3), 104.8 (C-5), 81.7
(C-4), 81.1 [C(CH3)3], 61.7 (–, CH2), 28.9, 25.9 (2 –, C-3 , C-6 ),
28.1 [+, C(CH3)3], 22.1, 21.3 (2 –, C-4 , C-5 ), 14.1 (+, CH2CH3).
IR (KBr): 3448 (s, N–H), 2972 (s), 2908 (s), 2871 (s, C–H), 1944
(w, C=C=C), 1745 (s, C=O), 1721 (s, C=O), 1500 (s, N–H) cm–1
.1H NMR (CDCl3): = 5.21 (d, 1 H, J = 5.8 Hz, 3-H), 5.04 (br s, 1
H, NH), 4.75 (d, 1 H, J = 5.8 Hz, 2-H), 4.17 (m, 2 H, CH2), 1.42 [s,
9 H, OC(CH3)3], 1.25 (t, 3 H, J = 7.0 Hz, CH2CH3), 1.15 [s, 18 H,
CC(CH3)3].
MS (EI): m/z (%) = 319 (46, M+), 263 (15), 219 (38), 57 (100).
Anal. Calcd for C18H25NO4 (319.40): C, 67.69; H, 7.89; N, 4.39.
Found: C, 67.60; H, 7.90; N, 4.30.
Ethyl (Z)-2-[(t-Butoxycarbonyl)amino]-5-trimethylsilylpent-2-
en-4-ynoate (8e)
13C NMR (CDCl3):
= 201.4 (C-4), 171.1 (C-1), 154.8
Trimethylsilylacetylene (1.28 g, 13.0 mmol) in Et2O (15 mL),
n-BuLi (2.0 M in hexane; 5.9 mL, 11.7 mmol), DMF (1.2 mL, 15.6
mmol), t-BuOK (1.12 g, 10.0 mmol ) in CH2Cl2 (20 mL), and ethyl
2-[(t-butoxycarbonyl)amino]-2-(diethoxyphosphoryl)-acetate (3.38
g, 10.0 mmol)47 in CH2Cl2 (15 mL). Purification of the crude prod-
uct by column chromatography (SiO2; cyclohexane–Et2O, 10:1)
and crystallization from hexane furnished 8e (1.90 g, 61%) as col-
orless needles; mp 85 °C.
[(CH3)3COC], 127.0 (C-5), 89.8 (+, C-3), 79.7 [OC(CH3)3], 61.3
(–, CH2), 52.7 (+, C-2), 35.1 [CC(CH3)3], 32.0 [+, C(CH3)3], 28.3
[+, OC(CH3)3], 14.1 (+, CH2CH3).
MS (EI): m/z (%) = 353 (2, M+), 297 (90), 224 (100), 168 (60), 151
(45).
Anal. Calcd for C20H35NO4 (353.51): C, 67.96; H, 9.98; N, 3.96.
Found: C, 68.00; H, 9.90; N, 4.20.
IR (KBr): 3231 (s, N–H), 2977 (s), 2964 (s, C–H), 2129 (s, C C),
1731 (s, C=O), 1711 (s, C=O), 1639 (s, C=C), 1477 cm–1 (s, N–H).
1H NMR (CDCl3): = 6.45 (br s, 1 H, NH), 5.95 (s, 1 H, 3-H), 4.25
(q, 2 H, J = 7.0 Hz, CH2), 1.47 [s, 9 H, C(CH3)3], 1.29 (t, 3 H,
J = 7.0 Hz, CH2CH3), 0.20 [s, 9 H, Si(CH3)3].
Ethyl 2-[(t-Butoxycarbonyl)amino]-6,6-dimethyl-5-phenylhep-
ta-3,4-dienoate (9c)
CuCN (356 mg, 4.0 mmol) in Et2O (10 mL), t-BuLi (1.5 M in pen-
tane; 5.3 mL, 8.0 mmol), and 8c (315 mg, 1.0 mmol) in Et2O (5 mL)
furnished 9c (200 mg, 54%) as a yellow oil.
13C NMR (CDCl3): = 163.8 (C-1), 151.6 [(CH3)3COC], 136.8 (C-
2), 108.8 (C-5), 104.4 (+, C-3), 98.9 (C-4), 81.4 [C(CH3)3], 61.8
(–, CH2), 28.1 [+, C(CH3)3], 14.1 (+, CH2CH3), –0.2 [+, Si(CH3)3].
IR (KBr): 3444 (s), 3368 (s, N–H), 2971 (s), 2933 (s), 2904 (s),
2869 (s, C–H), 1960 (w, C=C=C), 1743 (s, C=O), 1719 (s, C=O),
1492 cm–1 (s, N–H).
MS (EI): m/z (%) = 311 (15, M+), 255 (7), 211 (100), 196 (23), 103
(35).
1H NMR (CDCl3): = 7.31–7.20 (m, 5 H, Ph), 5.13 (br s, 1 H, NH),
5.42, 5.40 (2 d, 1 H, J = 5.5 Hz, 3-H), 4.88/4.82 (2 dd, 1 H, J = 5.5,
5.8 Hz, 2-H), 4.27–4.07 (m, 2 H, CH2), 1.43, 1.42 [2 s, 9 H,
OC(CH3)3], 1.25, 1.19 (2 t, 3 H, J = 7.0 Hz, CH2CH3), 1.13 [s, 9 H,
CC(CH3)3].
Anal. Calcd for C15H25NO4Si (311.46): C, 57.85; H, 8.09; N, 4.50.
Found: C, 57.90, H, 8.00, N, 4.50.
Ethyl (Z)-2-(Acetylamino)-6,6-dimethylhept-2-en-4-ynoate (8f)
3,3-Dimethylbutyne (2.92 g, 35.6 mmol) in Et2O (40 mL), n-BuLi
(2.3 M in hexane;13.9 mL, 32.0 mmol), DMF (3.3 mL, 43.0 mmol),
t-BuOK (2.99 g, 26.7 mmol) in CH2Cl2 (50 mL), and ethyl 2-
(acetylamino)-2-(diethoxyphosphoryl)-acetate (7.50 g, 26.7
mmol)47 in CH2Cl2 (40 mL). Crystallization of the crude product
from hexane furnished (2.97 g, 47%) 8f as colorless needles; mp
128 °C.
13C NMR (CDCl3): = 200.9, 200.6 (C-4), 170.7, 170.6 (C-1),
154.8, 154.7 [(CH3)3COC], 136.4 (Ph), 129.1, 127.8, 127.7, 126.9
(4 +, Ph), 120.8, 120.7 (C-5), 89.9, 89.7 (2 +, C-3), 79.8
[OC(CH3)3], 61.4 (–, CH2), 52.5 (+, C-2), 34.5 [CC(CH3)3], 29.6,
29.5 [2 +, C(CH3)3], 28.3,28.2 [2 +, OC(CH3)3], 14.0, 13.9 (2 +,
CH2CH3).
Synthesis 2002, No. 12, 1759–1774 ISSN 0039-7881 © Thieme Stuttgart · New York

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N. Krause et al.
FEATURE ARTICLE
MS (EI): m/z (%) = 373 (12, M+), 317 (100), 244 (72), 188 (54), 122
CH2), 1.91 (s, 3 H, COCH3), 1.16 (t, 3 H, J = 7.0 Hz, CH2CH3), 1.06
(34).
[s, 18 H, C(CH3)3].
Anal. Calcd for C22H31NO4 (373.50): C, 70.75; H, 8.37; N, 3.75.
Found: C, 70.80; H, 8.40; N, 3.80.
13C NMR (CDCl3): = 201.3 (C-4), 170.7 (COCH3), 169.1 (C-1),
126.6 (C-5), 89.1 (+, C-3), 61.2 (+, C-2), 61.2 (–, CH2), 34.8
[C(CH3)3], 31.8 [+, C(CH3)3], 22.7 (+, COCH3), 13.9 (+, CH2CH3).
Ethyl 2-[(t-Butoxycarbonyl)amino]-6,6-dimethyl-5-(cyclohex-
1-en-1-yl)-hepta-3,4-dienoate (9d)
CuCN (1.42 g, 16.0 mmol) in Et2O (50 mL) , t-BuLi (1.5 M in pen-
tane; 21.3 mL, 32.0 mmol ), and 8d (1.30 g, 4.0 mmol) in Et2O (25
mL) furnished 9d (950 mg, 63%) as a red oil.
MS (EI): m/z (%) = 295 (85, M+), 222 (53), 180 (48), 166 (100).
Anal. Calcd for C17H29NO3 (295.43): C, 69.12; H, 9.89; N, 4.74.
Found: C, 69.00; H, 9.90; N, 4.70.
Ethyl 2-Amino-5-t-butyl-6,6-dimethylhepta-3,4-dienoate (10)
To a soln (700 mg, 2.0 mmol) of 9b in dioxane (3 mL) and THF (6
mL) was added HCl (6 N, 8 mL), and the mixture was heated to 80
°C for 6 h and stirred for another 50 h at r.t. After addition of EtOAc
(10 mL), the layers were separated, the aqueous phase was washed
with EtOAc (3 10 mL), the combined organic phases were dried
over MgSO4, and the solvent was removed in vacuo to furnish 10
(435 mg, 87%) as colorless needles; mp 113 °C.
IR (KBr): 3446 (s), 3369 (s, N–H), 2966 (s), 2931 (s), 2868 (s),
2837 (s, C–H), 1953 (w, C=C=C), 1743 (s, C=O), 1721 (s, C=O),
1497 cm–1 (s, N–H).
1H NMR (CDCl3): = 5.05 (br s, 1 H, NH), 5.59 (m, 1 H, 2 -H),
5.27 (d, 1 H, J = 5.0 Hz, 3-H), 4.79–4.72 (m, 1 H, 2-H), 4.23–4.08
(m, 2 H, CH2), 2.04–2.02 (m, 4 H, 3 -H, 6 -H), 1.59–1.49 (m, 4 H,
4 -H, 5 -H), 1.40 [s, 9 H, OC(CH3)3], 1.24, 1.23 (2 t, 3 H, J = 7.0
Hz, CH2CH3), 1.06, 1.05 [2 s, 9 H, CC(CH3)3].
13C NMR (CDCl3): = 200.7, 200.4 (C-4), 170.9 (C-1), 154.8
[(CH3)3COC], 132.7, 132.5 (C-1 ), 125.9, 125.8 (2 +, C-2 ), 122.8,
122.5 (C-5), 89.4, 89.2 (2 +, C-3), 79.7 [OC(CH3)3], 61.3 (–, CH2),
52.6, 52.5 (2 +, C-2), 34.2 [CC(CH3)3], 30.0 [+, C(CH3)3], 28.3 [+,
OC(CH3)3], 26.8, 25.5 (2 –, C-3 , C-6 ), 23.0, 21.8 (2 –, C-4 , C-5 ),
14.1 (+, CH2CH3).
IR (KBr): 3434 (s, N–H), 2957 (s), 2911 (s), 2872 (s, C–H), 1946
(w, C=C=C), 1746 (s, C=O), 1482 cm–1 (s, N–H).
1H NMR (CDCl3): = 8.79 (br s, 2 H, NH), 5.44 (d, 1 H, J = 7.0 Hz,
3-H), 4.50 (dd, 1 H, J = 7.0 Hz, 2-H), 4.26–4.14 (m, 2 H, CH2), 1.27
(t, 3 H, J = 7.3 Hz, CH2CH3), 1.16 [s, 18 H, C(CH3)3].
13C NMR (CDCl3): = 203.8 (C-4), 167.9 (C-1), 126.7 (C-5), 85.6
(+, C-3), 62.4 (–, CH2), 53.4 (+, C-2), 35.1 [C(CH3)3], 31.9 [+,
C(CH3)3], 13.9 (+, CH2CH3).
MS (EI): m/z (%) = 377 (5, M+), 321 (15), 275 (22), 248 (100), 187
(14).
MS (EI): m/z (%) = 253 (21, M+), 180 (8), 164 (100).
Anal. Calcd for C22H35NO4 (377.53): C, 69.99; H, 9.34; N, 3.71.
Found: C, 69.80; H, 9.20; N, 3.80.
Anal. Calcd for C15H27NO2 (253.39): C, 71.10; H, 10.74; N, 5.53.
Found: C, 71.10; H, 10.70; N, 5.50.
Ethyl 2-[(t-Butoxycarbonyl)amino]-6,6-dimethyl-5-trimethyl-
silylhepta-3,4-dienoate (9e)
CuCN (356 mg, 4.0 mmol) in Et2O (10 mL), t-BuLi (1.5 M in pen-
tane; 5.3 mL, 8.0 mmol), and 8e (311 mg, 1.0 mmol) in Et2O (5 mL)
furmished 9e (250 mg, 68%) as a yellow oil.
2-(Acetylamino)-5-t-butyl-6,6-dimethylhepta-3,4-dienoic Acid
(11)
To a soln of 9f (590 mg, 2.0 mmol) in dioxane (3 mL) and THF (6
mL) was added HCl (6 N, 8 mL), and the mixture was stirred at r.t.
for 50 h. After addition of EtOAc (10 mL), the layers were separat-
ed, the aqueous phase was washed with EtOAc (3 10mL), the
combined organic phases were dried with MgSO4, and the solvent
was removed in vacuo to furnish 11 (350 mg, 66%) as colorless nee-
dles; mp 196 °C/decomp.
IR (KBr): 3447 (s), 3369 (s, N–H), 2965 (s), 2903 (s), 2871 (s, C–
H), 1940 (w, C=C=C), 1744 (s, C=O), 1721 (s, C=O), 1500 cm–1 (s,
N–H).
1H NMR (CDCl3): = 5.31 (br s, 1 H, NH), 5.13–4.64 (m, 2 H, 2-
H, 3-H), 4.19–4.02 (m, 2 H, CH2), 1.35 [s, 9 H, OC(CH3)3], 1.18 (t,
J = 7.0 Hz, 3 H, CH2CH3), 1.02 [s, 9 H, CC(CH3)3], 0.08, 0.07 (2
s, 9 H, Si(CH3)3].
13C NMR (CDCl3): = 203.3, 203.1 (C-4), 171.1, 171.0 (C-1),
154.6 [(CH3)3COC], 115.6 (C-5), 85.0, 84.9 (2 +, C-3), 79.6, 79.5
[OC(CH3)3], 61.1 (–, CH2), 52.1, 52.0 (2 +, C-2), 35.1 [CC(CH3)3],
31.1 [+, C(CH3)3], 28.2 [+, OC(CH3)3], 14.0 (+, CH2CH3), 0.9 [+,
Si(CH3)3].
IR (KBr): 3600–3300 (m, O–H), 3320 (s, N–H), 2968 (s), 2956 (s),
2922 (s), 2871 (s, C–H), 1942 (w, C=C=C), 1721 (s, C=O), 1610 (s,
C=O), 1545 cm–1 (s, N–H).
1H NMR (THF-d8): = 7.25 (s, 1 H, CO2H), 6.52 (br s, 1 H, NH),
5.21 (d, 1 H, J = 6.0 Hz, 3-H), 5.02 (dd, 1 H, J = 5.8, 6.0 Hz, 2-H),
1.91 (s, 3 H, COCH3), 1.21 [s, 18 H, C(CH3)3].
13C NMR (THF-d8): = 203.9 (C-4), 173.4 (COCH3), 170.2 (C-1),
126.9 (C-5), 92.6 (+, C-3), 53.7 (+, C-2), 36.9 [C(CH3)3], 33.7 [+,
C(CH3)3], 23.7 (+, COCH3).
MS (EI): m/z (%) = 369 (5, M+), 313 (48), 268 (60), 240 (100).
Anal. Calcd for C19H35NO4Si (369.58): C, 61.75; H, 9.55; N, 3.79.
Found: C, 61.80; H, 9.50; N, 3.70.
MS (EI): m/z (%) = 267 (18, M+), 210 (7), 193 (15), 152 (100).
Anal. Calcd for C15H25NO3 (267.37): C, 67.38; H, 9.42; N, 5.24.
Found: C, 67.30; H, 9.30; N, 5.20.
Ethyl 2-(Acetylamino)-5-t-butyl-6,6-dimethylhepta-3,4-dien-
oate (9f)
CuCN (1.34 g, 15.0 mmol) in Et2O (50 mL), t-BuLi (1.5 M in pen-
tane; 20.0 mL, 30.0 mmol), and 8f (1.18 g, 5.0 mmol) in Et2O (25
mL); column chromatography furnished 9f (621 mg, 42%) as a yel-
low oil, along with starting material 8f (533 mg).
2-Hydroxy-3,4-dienoates 14; General Procedure32
To a soln of i-Pr2NH or hexamethyldisilazane in THF was added at
–20 °C n-BuLi in hexane. After stirring for 15 min, the mixture was
cooled to –80 °C, and a soln of the -allenic ester 12 in THF was
added dropwise. The mixture was stirred for 20 min at –80 °C, and
solid Cp2TiCl2 was added. The mixture was warmed to –30 °C with-
in 1 h. After cooling to –80 °C, a freshly prepared cold (–20 °C) soln
of DMDO in acetone (ca. 0.1 M)34a was added rapidly, the cooling
bath was removed, and the mixture was warmed to 0 °C. The reac-
tion was then quenched by addition a sat. aq NH4F soln (2 mL/mmol
12), and the mixture was stirred for 16 h at r.t. After filtration
IR (KBr): 3292 (s, N–H), 2969 (s), 2957 (s), 2907 (s), 2870 (s, C–
H), 1944 (w, C=C=C), 1745 (s, C=O), 1656 (s, C=O), 1536 cm–1 (s,
N–H).
1H NMR (CDCl3): = 6.35 (br s, 1 H, NH), 5.11 (d, 1 H, J = 6.0 Hz,
3-H), 4.90 (dd, 1 H, J = 6.0, 6.3 Hz, 2-H), 4.07 (q, 2 H, J = 7.0 Hz,
Synthesis 2002, No. 12, 1759–1774 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Functionalized Allenes in Modern Organic Synthesis
1769
through Celite, the solvent was removed in vacuo, and the crude
product was purified by column chromatography (SiO2; cyclohex-
ane–EtOAc, 10:1).
furnished 12c (241 mg) and 14c (287 mg, 99% yield with respect to
53% consumption of 12c) as a yellow oil (ds 60:40 according to GC
and NMR analysis).
IR (neat): 3502 (br, O–H), 2962 (s), 2932 (s), 2871 (s, C–H), 1958
(w, C=C=C), 1739 (s, C=O), 1733 cm–1 (s, C=O).
Ethyl 2-Hydroxy-5,6,6-trimethylhepta-3,4-dienoate (14a)
i-Pr2NH (0.29 g, 2.9 mmol) in THF (15 mL), n-BuLi (1.6 M in hex-
ane; 2.0 mL, 3.2 mmol), 12a (470 mg, 2.4 mmol) 48 in THF (5 mL),
Cp2TiCl2 (800 mg, 3.2 mmol), and DMDO (35 mL, 3.5 mmol) fur-
nished 12a (255 mg), and 14a (157 mg, 68% yield with respect to
46% consumption of 12a) as a yellow oil (ds 90:10 according to GC
and NMR analysis).
1H NMR (C6D6): = 5.53–5.48 (m, 1 H, 3-H), 4.72 (br s, 1 H, 2-H),
4.05–4.00 (m, 2 H, OCH2), 3.20, 3.19 (2 br s, 1 H, OH), 2.06–1.94
(m, 2 H, 6-H), 1.63–1.51 (m, 2 H, 7-H), 1.42 (m, 2 H, 8-H), 1.17,
1.15 [2 s, 9 H, C(CH3)3], 1.01 (2 t, J = 7.3 Hz, 6 H, 9-H,
OCH2CH3).
13C NMR (C6D6): = 200.4*, 200.3 (C-4), 174.2*, 174.1 (C-1),
119.1, 118.8* (C-5), 94.5, 94.5 (2 +, C-3), 70.5*, 70.4 (2 +, C-2),
61.7 (–, OCH2), 34.3, 34.2 [C(CH3)3], 31.0, 31.0 (2 –, C-6), 29.7 [+,
C(CH3)3], 27.5, 27.4 (–, C-7), 23.2 (–, C-8), 14.7, 14.6, 14.4, 14.4
(4 +, C-9, OCH2CH3).
MS (EI): m/z (%) = 254 (<1, M+), 237 (13), 212 (8), 179 (13), 151
(15), 139 (32), 107 (23), 57 (100).
IR (neat): 3600–3200 (s, O–H), 2964 (s), 2940 (s), 2911 (s), 2868
(s, C–H), 1962 (w, C=C=C), 1737 cm–1 (s, C=O).
1H NMR (C6D6): = 5.17 (dq, 1 H, J = 6.4, 3.0 Hz, 3-H), 4.56 (d, 1
H, J = 6.4 Hz, 2-H), 4.20/4.19 (2 q, 2 H, J = 7.2 Hz, CH2), 2.88
(s, 1 H, OH), 1.69 (d, 3 H, J = 3.0 Hz, 5-CH3), 1.26 (t, 3 H, J = 7.2
Hz, CH2CH3), 1.02 [s, 9 H, C(CH3)3].
13C NMR (C6D6): = 200.3 (C-4), 173.6 (C-1), 113.0 (C-5), 90.5
(+, C-3), 70.0 (+, C-2), 61.6 (–, CH2), 33.5 (C-6), 28.9 [+, C(CH3)3],
14.7 (+, 5-CH3), 14.1 (+, CH2CH3).
HRMS (FAB) Calcd for C15H26O3 (254.37): 254.1882. Found
254.1863.
MS (EI): m/z (%) = 212 (4, M+), 195 (31), 139 (11), 84 (51), 57
(100).
Ethyl 2-Hydroxy-5-butylundeca-3,4-dienoate (14d)
i-Pr2NH (0.23 g, 2.3 mmol) in THF (25 mL), n-BuLi (1.6 M in hex-
ane; 1.5 mL, 2.4 mmol), 12d (500 mg, 1.9 mmol) in THF (5 mL),
Cp2TiCl2 (573 mg, 2.3 mmol), and DMDO (40 mL, 4.0 mmol) fur-
nished 12d (186 mg) and 14d (290 mg, 87% yield with respect to
63% consumption of 12d) as a yellow oil (ds 50:50 according to GC
and NMR analysis).
HRMS (EI) Calcd for C12H20O3 (212.29): 212.1415. Found
212.1414.
Ethyl 2-Hydroxy-2,5,6,6-tetramethylhepta-3,4-dienoate (14b)
i-Pr2NH (0.56 g, 5.5 mmol) in THF (25 mL), n-BuLi (1.6 M in hex-
ane; 3.5 mL, 5.5 mmol), 12b (1.00 g, 4.8 mmol)49 in THF (15 mL),
Cp2TiCl2 (1.37 g, 5.5 mmol), and DMDO (55 mL, 5.5 mmol) fur-
nished 12b (813 mg) and 14b (127 mg) (63% yield with respect to
19% consumption of 12b) as a brown oil (ds 80:20 according to GC
and NMR analysis). The analogous reaction with hexamethyldi-
silazane (342 mg, 2.1 mmol) in THF (35 mL), n-BuLi (1.5 M in
hexane; 1.7 mL, 2.5 mmol), 12b (442 mg, 2.1 mmol)49 in THF (5
mL), Cp2TiCl2 (627 mg, 2.5 mmol), and DMDO (35 mL, 3.5 mmol)
furnished 12b (300 mg) and 14b (115 mg; 75% yield with respect
to 32% consumption of 12b) as a brown oil (ds 80:20 according to
GC and NMR analysis).
IR (neat): 3483 (br, O–H), 2958 (s), 2929 (s), 2858 (s, C–H), 1964
(w, C=C=C), 1738 cm–1 (s, C=O).
1H NMR (C6D6): = 5.53–5.48 (m, 1 H, 3-H), 4.75 (m, 1 H, 2-H),
4.05–4.00 (m, 2 H, OCH2), 3.19, 3.17 (2 br s, 1 H, OH), 2.04–1.99
(m, 4 H, =CCH2), 1.61–1.39 (m, 12 H, 6 CH2), 1.03-0.99 (m, 9 H,
3
CH3).
13C NMR (C6D6): = 201.0, 201.0 (C-4), 173.8, 173.8 (C-1), 109.4,
109.3 (C-5), 92.9 (+, C-3), 70.0/70.0 (2 +, C-2), 61.4 (–, OCH2),
32.9, 32.6, 32.1, 32.1, 30.0, 30.0, 29.4, 27.4, 23.0, 22.8, 22.7 (11 –,
CH2) 14.3, 14.2, 14.1, 14.0 (4 +, CH3).
MS (ESI): m/z (%) = 283 (100, M++1), 265 (99), 242 (87).
IR (neat): 3515 (br, O–H), 2966 (s), 2907 (s), 2870 (s, C–H), 1963
(w, C=C=C), 1732 cm–1 (s, C=O).
1H NMR (C6D6): = 5.37, 5.36* (2 q, 1 H, J = 2.7 Hz, 3-H), 3.91,
3.90* (2 q, 2 H, J = 7.2 Hz, CH2), 3.51 (s, 1 H, OH), 1.63, 1.60*
(2 d, 3 H, J = 2.7 Hz, 5-CH3), 1.58 (s, 3 H, 2-CH3), 1.02*, 1.01 [2
s, 9 H, C(CH3)3], 0.90 (t, J = 7.2 Hz, 3 H, CH2CH3).
13C NMR (C6D6): = 199.1 (C-4), 175.8*, 175.6 (C-1), 113.4,
113.2* (C-5), 97.3, 97.2* (2 +, C-3), 73.8*, 73.6 (C-2), 61.6, 61.5
(–, CH2), 33.7*, 33.7 (C-6), 29.1 [+, C(CH3)3], 25.2, 24.9* (2 +, 2-
CH3), 14.9, 14.9* (+, 5-CH3), 14.0 (+, CH2CH3).
Hydroxyallenes 16,17; General Procedure
To a suspension of CuCN in Et2O was added n-Bu3P or (EtO)3P.
The mixture was stirred for 1 h at r.t. and then cooled to –50 °C. The
organometallic reagent was added dropwise, and the mixture was
stirred for 30 min at –30 °C. After cooling to –80 °C, a soln of the
propargylic epoxide 15 in Et2O was added dropwise, and the mix-
ture was stirred for 1–2 h at –20 °C. Quenching with a sat. NH4Cl
soln (ca. 1 mL/mmol 15) was followed by filtration through Celite.
The filtrate was dried with MgSO4, the solvent was removed in vac-
uo, and the crude product was purified by column chromatography
(SiO2; cyclohexane–EtOAc, 10:1).
MS (EI): m/z (%) = 226 (<1, M+), 209 (20), 169 (20), 153 (18), 111
(22), 97 (22), 57 (72), 43 (100).
HRMS (FAB) Calcd for C13H22O3 (226.32): 226.1569. Found
226.1593.
1-(t-Butyldimethylsilyloxy)-3,6,6-trimethylhepta-3,4-dien-2-ol
(16a)
CuCN (595 mg, 6.7 mmol) in Et2O (20 mL), n-Bu3P (1.34 g, 6.7
mmol), t-BuLi (1.5 M in pentane; 8.9 mL, 13.3 mmol), and trans-
15a (1.25 g, 5.5 mmol)50 in Et2O (15 mL) furnished 16a (1.04 g,
66%) as a pale yellow liquid (ds 65:35 according to GC and NMR
analysis).
Ethyl 2-Hydroxy-5-t-butylnona-3,4-dienoate (14c)
i-Pr2NH (0.56 g, 5.5 mmol) in THF (20 mL), n-BuLi (1.6 M in hex-
ane; 3.5 mL, 5.5 mmol)), 12c (1.27 g, 5.0 mmol)48 in THF (15 mL),
Cp2TiCl2 (1.37 g, 5.5 mmol), and DMDO (55 mL, 5.5 mmol) fur-
nished 12c (573 mg) and 14c (494 mg, 67% yield with respect to
55% consumption of 12c) as an orange oil (ds 60: 40 according to
GC and NMR analysis). The analogous reaction with hexamethyld-
isilazane (342 mg, 2.1 mmol) in THF (15 mL), n-BuLi (1.5 M in
hexane;1.7 mL, 2.5 mmol), 12c (513 mg, 2.2 mmol)48 in THF (5
mL), Cp2TiCl2 (627 mg, 2.5 mmol), and DMDO (32 mL, 3.2 mmol)
IR (neat): 3447 (br, O–H), 2958 (s), 2929 (s), 2858 (s, C–H), 1965
cm–1 (w, C=C=C).
1H NMR (C6D6): = 5.20 (m, 1 H, 5-H), 4.17 (m, 1 H, 2-H), 3.47
(dd, J = 10.0, 4.0 Hz, 1 H, 1-H), 3.66 (m, 1 H 1-H), 2.59*, 2.56 (2
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1770
N. Krause et al.
FEATURE ARTICLE
s, 1 H, OH), 1.80 (s, 3 H, 3-CH3), 1.04, 1.03* [2 s, 9 H, 5-
C(CH3)3], 0.93 [s, 9 H, SiC(CH3)3], 0.04, 0.04 [2 s, 6 H, Si(CH3)2].
1H NMR (C6D6): = 5.17 (m, 1 H, 5-H), 4.24 (m, 1 H, 2-H), 3.80–
3.69 (m, 2 H 1-H), 2.50 (s, 1 H, OH), 1.86, 1.85 (2 × s, 3 H, 3-CH3),
1.64, 1.62 (2 s, 3 H, 6-H), 1.02, 1.01 [2 s, 9 H, C(CH3)3], 0.12
[s, 6 H, Si(CH3)2].
13C NMR (C6D6): = 202.0, 201.9 (C-4), 100.0 (C-3), 87.5, 87.4 (2
+, C-5), 73.0, 72.8 (2 +, C-2), 66.5, 66.4 (2 –, C-1), 26.0 [+,
C(CH3)3], 18.5 [C(CH3)3], 15.6, 15.5 (2 +, C-6, 3-CH3), –5.3 [+,
Si(CH3)2].
13C NMR (C6D6): = 198.4, 198.2* (C-4), 104.9, 104.8* (2 +, C-5),
102.5, 102.3* (C-3), 73.0*, 72.9 (2 +, C-2), 66.9, 66.8* (2 –, C-1),
32.2, 32.2* (C-6), 30.4, 30.3 [2 +, 5-C(CH3)3], 26.1 [+, SiC(CH3)3],
18.5, 18.5* [SiC(CH3)3], 16.0*, 15.8 (2 +, 3-CH3), –5.5*, –5.5 [2 +,
Si(CH3)2].
MS (EI): m/z (%) = 283 (<1, M+–1), 171 (15), 135 (60), 119 (30),
107 (60), 91 (50), 75 (100).
MS (FAB): m/z (%) = 245 (5, M+–1), 73 (100).
1-Methoxy-3,5,6,6-tetramethylhepta-3,4-dien-2-ol (16b)
CuCN (595 mg, 6.7 mmol) in Et2O (20 mL), (EtO3)P (1.10 g, 6.7
mmol), t-BuLi (1.3 M in pentane; 10.1 mL, 13.3 mmol), and trans-
15b (777 mg, 5.5 mmol)51 in Et2O (15 mL) furnished 16b (723 mg,
66%) as a pale yellow liquid (ds 80:20 according to GC and NMR
analysis).
1-(t-Butyldimethylsilyloxy)-3-methylpenta-3,4-dien-2-ol (17a)
From CuCN (297 mg, 3.3 mmol) in Et2O (25 mL), MeLi (1.6 M in
Et2O; 4.1 mL, 6.6 mmol), and trans-15a (500 mg, 2.2 mmol)50 in
Et2O (5 mL). Deviating from the general procedure, no phosphine
or phosphite was added, and the mixture was stirred for 2 h at –80
°C before quenching with NH4Cl soln at this temperature. This fur-
nished 17a (437 mg, 87%) as a yellow liquid, containing 20% of the
corresponding substitution product 16d.
IR (neat): 3447 (br, O–H), 2963 (s, C–H), 1964 cm–1 (w, C=C=C).
1H NMR (C6D6): = 4.37 (m, 1 H, 2-H), 3.51–3.43 (m, 2 H 1-H),
3.19 (s, 3 H, OCH3), 2.73 (br s, 1 H, OH), 1.89*, 1.88 (2 s, 3 H, 3-
CH3), 1.75, 1.74 (2 s, 3 H, 5-CH3), 1.15, 1.14 [2 s, 9 H, 5-
C(CH3)3].
13C NMR (C6D6): = 197.5*, 197.3 (C-4), 110.4, 110.0* (C-3),
99.9, 99.6* (C-5), 76.3 (–, C-1), 71.7, 71.6 (2 +, C-2), 58.6 (+,
OCH3), 34.0, 33.9 (C-6), 29.3 [+, C(CH3)3], 16.1, 16.0*, 15.2, 15.1*
(4 +, 3-CH3, 5-CH3).
IR (neat): 3442 (br, O–H), 2955 (s), 2929 (s), 2858 (s, C–H), 1960
cm–1 (w, C=C=C).
1H NMR (C6D6): = 4.64–4.62 (m, 2 H, 5-H), 4.15 (m, 1 H, 2-H),
3.67 (dd, 1 H, J = 10.0, 3.2 Hz, 1-H), 3.61 (dd, J = 10.0, 7.0 Hz, 1
H, 1-H), 2.54 (s, 1 H, OH), 1.73 (t, 3 H, J = 3.2 Hz, 3-CH3), 0.91 [s,
9 H, C(CH3)3], 0.01 [s, 6 H, Si(CH3)2].
13C NMR (C6D6): = 206.0 (C-4), 99.6 (C-3), 76.0 (–, C-5), 72.5
(+, C-2), 66.0 (–, C-1), 26.0 [+, C(CH3)3], 18.5 [C(CH3)3], 15.0 (+,
3-CH3), –5.3 [+, Si(CH3)2].
MS (FAB): m/z (%) = 198 (10, M+), 181 (100).
HRMS (FAB) Calcd for C12H22O2 (198.31): 198.1620. Found
198.1641.
MS (FAB): m/z (%) = 229 (3, M+ + 1), 73 (100).
1-Methoxy-3,6-dimethylhexa-3,4-dien-2-ol (16e)
1-(t-Butyldimethylsilyloxy)-3-methylundeca-3,4-dien-2-ol (16c)
CuCN (595 mg, 6.7 mmol) in Et2O (20 mL), n-Bu3P (1.34 g, 6.7
mmol), n-HexLi (2.5 M in hexane; 5.3 mL, 13.3 mmol), cis-15a
(1.25 g, 5.5 mmol)50 in Et2O (15 mL) furnished 16c (1.32 g, 77%)
as a pale yellow liquid (ds 75:25 according to GC and NMR analy-
sis), containing 15% of the corresponding reduction product 17a.
From CuCN (383 mg, 4.3 mmol) in Et2O (30 mL), MeLi (1.6 M in
Et2O; 5.4 mL, 8.6 mmol), and trans-15b (500 mg, 3.8 mmol) in
Et2O (5 mL). Deviating from the general procedure, no phosphine
or phosphite was added, and the mixture was stirred for 2 h at –80
°C before quenching with NH4Cl soln at this temperature. This fur-
nished 16e (469 mg, 88%) as a pale yellow liquid, containing 10%
of the corresponding reduction product 17b.
IR (neat): 3374 (br, O–H), 2957 (s), 2928 (s), 2857 (s, C–H), 1962
cm–1 (w, C=C=C).
IR (neat): 3439 (br, O–H), 2986(s), 2981 (s), 2906 (s, C–H), 1970
cm–1 (w, C=C=C).
1H NMR (C6D6): = 4.38 (m, 1 H, 2-H), 3.50–3.43 (m, 2 H 1-H),
3.20 (s, 3 H, OCH3), 2.82 (br s, 1 H, OH), 1.88 (s, 3 H, 3-CH3), 1.70,
1.70 (2 s, 6 H, 5-CH3).
13C NMR (C6D6): = 198.8 (C-4), 98.3, 96.7 (C-3, C-5), 76.3 (–, C-
1), 71.7 (+, C-2), 58.6 (+, OCH3), 20.8, 20.7 (2 +, 5-CH3), 15.9 (+,
3-CH3).
1H NMR (C6D6): = 5.18 (m, 1 H, 5-H), 4.20 (m, 1 H, 2-H), 3.74
(dd, 1 H, J = 10.0, 4.3 Hz, 1-H), 3.67 (dd, 1 H, J = 10.0, 6.8 Hz, 1-
H), 2.61 (s, 1 H, OH), 1.96 (m, 2 H, 6-H), 1.81, 1.81 (2 s, 3 H, 3-
CH3), 1.44–1.25 (m, 8 H, 7-H, 8-H, 9-H, 10-H), 0.94–0.89 [m, 12
H, 11-H, SiC(CH3)3], 0.05, 0.04 [2 s, 6 H, Si(CH3)2].
13C NMR (C6D6): = 201.3, 201.2* (C-4), 100.6 (C-3), 92.9, 92.9
(2 +, C-5), 73.1, 72.9* (2 +, C-2), 66.7*, 66.7 (2 –, C-1), 32.3*, 32.0
(2 –, C-6), 30.2, 30.1, 29.8, 29.6, 29.5, 29.2, 23.1, 23.0 (8 –, C-7, C-
8, C-9, C-10), 26.1 [+, SiC(CH3)3], 18.5 [SiC(CH3)3], 15.8 (+, 3-
CH3), 14.4*, 14.3 (2 +, C-11), –5.3, –5.2 [2 +, Si(CH3)2].
MS (FAB): m/z (%) = 156 (13, M+), 73 (100).
HRMS (FAB) Calcd for C9H16O2 (156.22): 156.1150. Found
156.1156.
MS (EI): m/z (%) = 312 (<1, M+), 297 (<1), 255 (10), 171 (35), 107
(30), 93 (40), 75 (100).
Cyclization of -Hydroxyallenes 14,16,17 to 2,5-Dihydrofurans
18: General Procedure
Method A
Into a soln of the hydroxyallene 14 in anhyd CHCl3 or CDCl3, HCl
gas was introduced for 2 min. The reaction was monitored by TLC;
after complete consumption (usually 1 h), the solvent was removed
under reduced pressure, giving spectroscopically pure dihydrofuran
18. This material can be further purified by flash chromatography
(SiO2; cyclohexane–EtOAc, 10:1). Attention: Long exposure to sil-
ica gel may cause considerable decomposition of the dihydrofuran.
1-(t-Butyldimethylsilyloxy)-3-methylhexa-3,4-dien-2-ol (16d)
CuCN (238 mg, 2.7 mmol) in Et2O (30 mL), n-Bu3P (537 mg, 2.7
mmol), MeLi (1.6 M in Et2O; 3.3 mL, 5.3 mmol), and cis-15a (500
mg, 2.2 mmol)50 in Et2O (5 mL) furnished 16d (414 mg, 77%) as a
yellow liquid (ds 85:15 according to GC and NMR analysis). Alter-
natively, CuCN (238 mg, 2.7 mmol) in Et2O (20 mL), n-Bu3P (537
mg, 2.7 mmol), MeMgBr (3.0 M in Et2O; 1.8 mL, 5.3 mmol), and
cis-15a (500 mg, 2.2 mmol)50 in Et2O (5 mL) furnished 16d (373
mg, 70%) as a pale yellow liquid (ds 94:6 according to GC and
NMR analysis).
Method B
IR (neat): 3436 (br, O–H), 2930 (s), 2885 (s), 2858 (s, C–H), 1968
cm–1 (w, C=C=C).
To a soln of the hydroxyallene 14 in anhyd CH2Cl2 was added Am-
berlyst 15 resin, and the mixture was heated to reflux for 1–2 h. Af-
Synthesis 2002, No. 12, 1759–1774 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Functionalized Allenes in Modern Organic Synthesis
1771
ter cooling to r.t. and filtration, the solvent was removed in vacuo,
giving spectroscopically pure dihydrofuran 18. This material can be
further purified by flash chromatography (SiO2; cyclohexane–
EtOAc, 10:1). Attention: Longer exposure to silica gel may cause
considerable decomposition of the dihydrofuran.
Method C: Compound 14c (100 mg, 0.39 mmol) in CH2Cl2 (5 mL),
and AuCl3 (10 mg, 0.03 mmol) furnished 18c (100 mg, quant.) as an
orange liquid (ds 60:40 according to GC and NMR analysis).
IR (neat): 3084 (w, =C–H), 2959 (s), 2872 (s, C–H), 1761 (s), 1732
cm–1 (s, C=O).
1H NMR (CDCl3): = 5.86 (m, 1 H, 3-H), 5.73 (m, 1 H, 4-H), 5.15
(m, 1 H, 2-H), 4.17 (m, 2 H, OCH2), 1.84–1.52 (m, 2 H, 5-CH2),
1.30–1.20 (m, 7 H, CH2CH2, OCH2CH3), 0.90 [s, 9 H, C(CH3)3],
0.83 (t, 3 H, J = 7.2 Hz, CH2CH2CH3).
13C NMR (CDCl3): = 170.6*, 170.3 (CO2CH2), 132.9*, 132.5 (+,
C-4), 125.0*, 124.6 (+, C-3), 100.6*, 100.3 (C-5), 85.1*, 85.0 (+, C-
2), 60.8*, 60.7 (–, CH2), 39.3*, 37.3 [C(CH3)3], 33.5, 32.7* (–, 5-
CH2), 26.9, 26.2 (–, 5-CH2CH2), 26.4, 26.1* [+, C(CH3)3], 22.6*,
21.5 (+, 5-CH3), 14.1, 14.1 (2 +, CH2CH2CH3, OCH2CH3).
Method C
To a soln of the hydroxyallene under argon in anhyd CH2Cl2 was
added AuCl3 (5–10 mol%) (99%, Aldrich), and the mixture was
stirred at r.t. After completion (TLC control), the solvent was evap-
orated in vacuo. Flash column chromatography (SiO2; cyclohex-
ane–EtOAc, 10:1) afforded the 2,5-dihydrofuran 18. Attention:
Long exposure to silica gel may cause considerable decomposition
of the dihydrofuran. Gold(III)-chloride is hygroscopic; the reaction
proceeds sluggishly with material that has been exposed to mois-
ture.
MS (EI): m/z (%) = 255 (10, M+ – 1), 197 (70), 181 (15), 125 (20),
81 (45), 57 (100).
Ethyl 5-t-Butyl-5-methyl-2,5-dihydrofurancarboxylate (18a)
Method A: Compound 14a (124 mg, 0.58 mmol) in CDCl3 (2 mL)
furnished 18a (112 mg, 90%) as a yellow liquid (ds 90:10 according
to GC and NMR analysis).
Ethyl 5-Butyl-5-hexyl-2,5-dihydrofurancarboxylate (18d)
Method A: Compound 14d (50 mg, 0.18 mmol) in CDCl3 (1 mL)
furnished 18d (45 mg, 90%) as a yellow liquid (ds 50:50 according
to GC and NMR analysis).
Method B: Compound 14a (90 mg, 0.42 mmol) in CH2Cl2 (15 mL),
and Amberlyst 15 (200 mg) furnished 18a (90 mg, quant.) as a yel-
low liquid (ds 90:10 according to GC and NMR analysis).
IR (neat): 3080 (w, =C–H), 2976 (s), 2872 (s, C–H), 1758 (s), 1733
cm–1 (s, C=O).
Method C: Compound 14a (134 mg, 0.63 mmol) in CH2Cl2 (5 mL),
and AuCl3 (9.6 mg, 0.03 mmol) furnished 18a (98 mg, 74%) as a
yellow liquid (ds 90:10 according to GC and NMR analysis).
1H NMR (C6D6): = 5.66 (d, 1 H, J = 5.9 Hz, 4-H), 5.44 (dd, 1 H,
J = 5.9, 2.7 Hz, 3-H), 5.21 (m, 1 H, 2-H), 3.93 (m, 2 H, OCH2),
1.85–0.85 (m, 25 H, CH2, CH3).
13C NMR (C6D6): = 170.7 (CO2CH2), 135.5, 135.5 (2 +, C-3),
124.8 (+, C-4), 95.2 (C-5), 84.8 (+, C-2), 60.65 (–, OCH2), 40.4,
40.1, 39.5, 39.3 (4 –, C-1 , C-1 ), 32.3, 32.3, 30.3, 30.2, 26.7, 26.5,
24.5, 24.3, 23.6, 23.5, 23.0 (11 –, CH2), 14.4, 14.3, 14.2 (3 +, CH3).
IR (neat): 3084 (w, =C–H), 2972 (s), 2909 (s), 2873 (s, C–H), 1758
(s), 1732 cm–1 (s, C=O).
1H NMR (C6D6): = 5.56 (m, 2 H, 3-H, 4-H), 5.13 (m, 1 H, 2-H),
3.91 (m, 2 H, CH2), 1.41 (s, 3 H, 5-CH3), 0.91 [m, 12 H, C(CH3)3,
CH2CH3].
MS (EI): m/z (%) = 282 (<1, M+), 225 (75), 209 (100), 197 (65), 153
(40), 125 (35), 81 (55).
NOESY: Crosspeak between = 5.13 (5-H) and 1.41 (5-CH3).
13C NMR (C6D6): = 171.0*, 170.1 (CO2CH2), 135.2 (+, C-4),
124.4*, 124.2 (+, C-3), 97.7*, 97.1 (C-5), 85.3*, 83.5 (+, C-2),
60.6*, 60.5 (–, CH2), 38.0*, 37.1 [C(CH3)3], 26.2, 25.7* [+,
C(CH3)3], 22.6*, 21.5 (+, 5-CH3), 14.1 (+, CH2CH3).
MS (EI): m/z (%) = 212 (<1, M+), 171 (7), 155 (10), 125 (16), 98
(100).
5-t-Butyl-2-(t-butyldimethylsilyloxymethyl)-3-methyl-2,5-dihy-
drofuran (18e)
Method C: Compound 16a (250 mg, 0.88 mmol) in CH2Cl2 (5 mL)
and AuCl3 (19 mg, 0.06 mmol) furnished 18e ( 238 mg, 95%) as a
yellow liquid (ds 65:35 according to GC and NMR analysis).
IR (neat): 3069 (w, = C–H), 2955 (s), 2929 (s), 2858 cm–1 (s, C–H).
1H NMR (C6D6): = 5.29*, 5.24 (dd, 1 H, J = 3.0, 1.5 Hz, 4-H),
4.64, 4.59* (m, 1 H, 2-H), 4.49*, 4.42 (m, 1 H, 5-H), 3.74–3.60 (m,
2 H, CH2), 1.62, 1.61* (d, 3 H, J = 0.5 Hz, 3-CH3), 0.98–0.94 [m,
18 H, 5-C(CH3)3, SiC(CH3)3], 0.08–0.05 [m, 6 H, Si(CH3)2].
13C NMR (C6D6): = 139.0, 138.4* (C-3), 123.4, 123.3 (+, C-4),
94.0, 93.5 (2 +, C-5), 88.9*, 88.1 (+, C-2), 66.4, 65.5* (–, CH2),
35.9*, 34.5 [5-C(CH3)3], 26.1, 25.3 [2 +, 5-C(CH3)3, SiC(CH3)3],
18.5, 18.4 [SiC(CH3)3], 13.0, 12.8* (+, 3-CH3), –5.2, –5.3 [+,
Si(CH3)2].
Ethyl 5-t-Butyl-2,5-dimethyl-2,5-dihydrofurancarboxylate
(18b)
Method A: Compound 14b (50 mg, 0.22 mmol) in CDCl3 (1 mL)
furnished 18b (46 mg, 92%) as brown liquid (ds 80:20 according to
GC and NMR analysis).
IR (neat): 3079 (w, =C–H), 2978 (s), 2872 (s, C–H), 1750 (s), 1730
cm–1 (s, C=O).
1H NMR (CDCl3): = 5.75 (d, 1 H, J = 6.0 Hz, 3-H), 5.61 (d, 1 H,
J = 6.0 Hz, 4-H), 4.13–3.96 (m, 2 H, CH2), 1.40 (s, 3 H, 2-CH3),
1.19 (s, 3 H, 5-CH3), 1.14 (t, 3 H, J = 7.1 Hz, CH2CH3), 0.82 [s, 9
H, C(CH3)3].
MS (EI): m/z (%) = 283 (15, M+ – 1), 269 (25, M+ – CH3), 227 (35),
157 (10), 135 (45), 111 (25), 89 (100).
13C NMR (CDCl3): = 174.1 (CO2CH2), 134.2, 133.4* (2 +, C-4),
128.7, 128.4* (2 +, C-3), 96.7*, 96.1 (C-5), 89.8, 89.2* (C-2),
61.0*, 60.8 (2 –, OCH2), 37.2, 36.7* [C(CH3)3], 26.1 [+,C(CH3)3],
24.0*, 23.5 (2 +, 2-CH3), 21.9 (+, 5-CH3), 14.1, 14.0* (2 +,
CH2CH3).
MS (EI): m/z (%) = 180 (<1, M+ – C2H6O), 169 (2, M+ – C4H9), 127
(20), 109 (20), 97 (100).
5-t-Butyl-3,5-dimethyl-2-methoxymethyl-2,5-dihydrofuran
(18f)
Method C: Compound 16b (269 mg, 1.36 mmol) in CH2Cl2 (5 mL),
and AuCl3 (20.6 mg, 0.07 mmol) furnished 18f (242 mg, 90%) as
yellow liquid (ds 80:20 according to GC and NMR analysis).
IR (neat): 3075 cm–1 (w, =C–H), 2966 (s), 2931 (s), 2857 (s, C–H).
1H NMR (CDCl3): = 5.46 (m, 1 H, 4-H), 4.69, 4.61* (m, 1 H, 2-
H), 3.52–3.37 (m, 2 H, CH2), 3.38, 3.37* (s, 3 H, OCH3), 1.70*,
1.68 (s, 3 H, 3-CH3), 1.23*, 1.18 (s, 3 H, 5-CH3), 0.95, 0.89 [s, 9 H,
C(CH3)3].
Ethyl 5-Butyl-5-t-butyl-2,5-dihydrofurancarboxylate (18c)
Method A:Compound 14c (100 mg, 0.39 mmol) in CDCl3 (1 mL)
furnished 18c (80 mg, 80%) as an orange liquid (ds 60:40 according
to GC and NMR analysis).
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1772
N. Krause et al.
FEATURE ARTICLE
13C NMR (CDCl3): = 134.6 (C-3), 128.7, 128.4* (+, C-4), 94.4*,
94.0 (C-5), 87.5*, 85.0 (+, C-2), 75.1*, 74.9 (–, CH2), 59.3*, 59.2
(+, OCH3), 38.5 [C(CH3)3], 26.1, 25.6* [+, C(CH3)3], 22.9*, 21.3
(+, 5-CH3), 12.4 (+, 3-CH3).
soln (100 mL), the layers were separated and the aqueous layer was
washed with CH2Cl2 (2
30 mL). The combined layers were
washed with 1% NaOH (50 ML), a sat. Na2CO3 soln (3 25 mL),
and brine (25 mL). After drying with MgSO4, the solvent was re-
moved under reduced pressure, to give crude 26 (1.65 g, 58%;
ds 60:40 according to NMR analysis) which was used without puri-
fication in the next step.
MS (EI): m/z (%) = 183 (5, M+-CH3), 141 (100), 154 (7), 109 (30).
2-(t-Butyldimethylsilyloxymethyl)-5-hexyl-3-methyl-2,5-dihy-
drofuran (18g)
IR (neat): 3403 (br, O–H), 2984 (s), 2934 cm–1 (s, C–H).
Method C: Compound 16c (257 mg, 0.82 mmol) in CH2Cl2 (5 mL),
and AuCl3 (12.5 mg, 0.04 mmol) furnished 18g (166 mg, 65%) as a
yellow liquid (ds 75:25 according to GC and NMR analysis).
IR (neat): 3070 (w, =C–H), 2956 (s), 2926 (s), 2856 cm–1 (s, C–H).
1H NMR (CDCl3): = 5.43 (m, 1 H, 4-H), 4.74, 4.67* (m, 1 H, 5-
H), 4.55 (m, 1 H, 2-H), 3.68-3.65 (m, 2 H, OCH2), 1.72 (s, 3 H, 3-
CH3), 1.26 [m, 10 H, (CH2)5], 0.99–0.94 [m, 12 H, CH2CH3,
C(CH3)3], 0.06–0.03 [m, 6 H, Si(CH3)2].
13C NMR (CDCl3): = 136.7, 136.6* (C-3), 125.5, 125.4* (+, C-4),
88.1*, 87.9 (+, C-2), 85.5, 85.4* (+, C-5), 65.7*, 65.1 (–, CH2),
37.2*, 36.6 (–, 5-CH2), 31.9*, 31.9, 29.7*, 29.7, 29.4, 29.4*, 22.7*,
22.6 [4–, (CH2)4], 25.8 [+, C(CH3)3], 18.3 [C(CH3)3], 14.1 [+,
CH2CH3], 12.8 (+, 3-CH3), –5.4, –-5.5 [+, Si(CH3)2].
1H NMR (C6D6): = 4.47 (q, 1 H, J = 6.6 Hz, 2-H), 3.00 (br s, 1 H,
OH), 2.95 (d, 1 H, J = 5.5 Hz, 6-H), 2.71 (d, 1 H, J = 5.5 Hz, 6-H),
1.48 (s, 3 H, 5-CH3), 1.37 (d, 3 H, J = 6.6 Hz, 1-H).
13C NMR (C6D6): = 84.1, 83.3 (C-3, C-4), 57.8 (+, C-2), 55.3 (–,
C-6), 47.2 (C-5), 23.9 (+, C-1), 22.7 (+, 5-CH3).
2,4-Dimethylhexa-2,3-dien-1,5-diol (27)26f
CuCN (887mg, 9.9 mmol) in Et2O (25 mL), MeMgBr (3.0 M in
Et2O; 6.6 mL, 19.8 mmol), and 26 (625 mg, 5.0 mmol) in Et2O (15
mL) according to the general procedure for the preparation hy-
droxyallenes 16,17 (no phosphine added) furnished 27 (300 mg,
43%) as a yellow oil (ds 60:40 according to NMR analysis).
1H NMR (C6D6): = 4.54–4.47 (m, 2 H, OH), 4.34, 4.14 (2 q,
J = 6.5 Hz, 1 H, 5-H), 4.08–4.01 (m, 2 H, 1-H), 1.75, 1.74 (2 d, 3
H, 2-CH3, 4-CH3), 1.66 (s, 3 H, 2-CH3, 4-CH3), 1.35, 1.33 (2 d, 3
H, J = 6.5 Hz, 6-H).
2-(t-Butyldimethylsilyloxymethyl)-3,5-dimethyl-2,5-dihydrofu-
ran (18h)
Method C: Compound 16a (362 mg, 1.50 mmol) in CH2Cl2 (10
mL), and AuCl3 (45 mg, 0.15 mmol) furnished 18h (279 mg, 77%)
as a yellow liquid (ds 94:6 according to GC and NMR analysis).
IR (neat): 3065 (w, =C–H), 2956 (s), 2929 (s), 2885 (s), 2858 cm–1
(s, C–H).
1H NMR (C6D6): = 5.20, 5.16 (m, 1 H, 4-H), 4.91, 4.83* (m, 1 H,
5-H), 4.64, 4.59* (m, 1 H, 2-H), 3.69–3.59 (m, 2 H, CH2), 1.56 (s,
3 H, 3-CH3), 1.23 (d, 3 H, J = 6.3 Hz, 5-CH3), 0.97–0.93 [m, 9 H,
C(CH3)3], 0.06–0.03 [m, 6 H, Si(CH3)2].
13C NMR (C6D6): = 196.8*, 196.3 ( C-3), 106.9, 106.1*, 103.1,
101.5* (C-2, C-4), 69.5*, 69.1 (2 +, C-5), 64.2, 64.0 (2 –, C-1), 22.3,
21.7* (2 +, C-6), 16.7, 16.1*, 14.2 (3 +, 2-CH3, 4-CH3).
2-(t-Butyldimethylsilyloxymethyl)-2,4,5-trimethyl-2,5-dihydro-
furan (22)26f
A soln of 27 (300 mg, 2.1 mmol) in CH2Cl2 (30 mL) was treated
successively with a small amount DMAP, Et3N (0.35 mL, 2.5
mmol), and TBSCl (350 mg, 2.3 mmol). After stirring for 4 h at r.t.,
a sat. NaHCO3 soln (10 mL) was added, the layers were separated,
the aqueous layer was washed CH2Cl2 (2 10 mL) and the com-
bined organic layers were washed brine (2 10 mL) and dried with
MgSO4. Removal of the solvent in vacuo followed by column chro-
matography (SiO2; cyclohexane–EtOAc, 5:1) furnished 23 (307
mg, 57%) as a colorless liquid. This was immediately dissolved in
CH2Cl2 (5 mL), and treated with AuCl3 (17.6 mg, 0.06 mmol) ac-
cording to the general procedure for the cyclization of -hydroxyal-
lenes 14,16,17 to 2,5-dihydrofurans 18 (Method C) to give 22 (245
mg, 80%) as a pale yellow liquid (ds 60:40 according to GC and
NMR analysis).
NOESY: Crosspeak between = 4.83 (5-H, major diastereomer)
and 4.59 (2-H, major diastereomer).
13C NMR (C6D6): = 136.6 (C-3), 127.4, 127.2* (+, C-4), 88.6*,
88.2 (+, C-2), 81.5, 81.3* (+, C-5), 65.9*, 65.3 (–, CH2), 26.1 [+,
C(CH3)3], 23.0*, 22.5 (+, 5-CH3), 18.5 [C(CH3)3], 12.7 (+, 3-CH3),
–5.2, –5.3 [+, Si(CH3)2].
MS (EI): m/z (%) = 241 (20, M+ – 1), 227 (35, M+ – CH3), 185
(100), 155 (12), 141 (27), 109 (48), 97 (100).
2-(t-Butyldimethylsilyloxymethyl)-3-methyl-2,5-dihydrofuran
(18i)
Method C: Compound 17a (230 mg, 1.01 mmol) in CH2Cl2 (5 mL),
and AuCl3 (12 mg, 0.04 mmol) furnished 18i ( 198 mg, 86%) as a
pale yellow liquid.
1H NMR (C6D6): = 5.32, 5.27 (2 s, 1 H, 4-H), 4.70 (q, J = 6.2
Hz, 5-H), 3.58 (s, CH2), 1.42, 1.40 (2 s, 3-CH3), 1.38, 1.37 (2 s,
2-CH3), 1.20, 1.19 (2
d, J = 6.2 Hz,, 5-CH3), 0.98 [s, 9 H,
C(CH3)3], 0.07, 0.06 [2 s, Si(CH3)2].
13C NMR (C6D6): = 140.3, 139.8 ( C-3), 126.8, 126.7 (2 +, C-4),
89.3, 89.0 ( C-2), 83.7, 83.2 (2 +, C-5), 71.5, 70.4 (2 –, CH2), 26.1,
26.0 [2 +, C(CH3)3], 24.9, 23.7 (2 +, 5-CH3), 21.9, 21.6 (2 +, 2-
CH3), 18.6, 18.5 [C(CH3)3], 12.2, 12.1 (2 +, 3-CH3), –5.2, –5.3 [+,
Si(CH3)2].
IR (neat): 3063 cm (w, =C–H), 2955 (s), 2929 (s), 2857 –1 (s, C–H).
1H NMR (C6D6): = 5.20 (m, 1 H, 4-H), 4.57–4.47 (m, 3 H, 2-H, 5-
H), 3.69 (dd, 1 H, J = 11.0, 3.8 Hz, 2-CH2), 3.62 (dd, 1 H, J = 11.0,
3.5 Hz, 2-CH2), 1.55 (s, 3 H, 3-CH3), 0.96 [s, 9 H, C(CH3)3], 0.07
[s, 6 H, Si(CH3)2].
13C NMR (C6D6): = 136.6 (C-3), 122.1 (+, C-4), 88.6 (+, C-2),
74.9 (–, C-5), 65.2 (–, 2-CH2), 26.0 [+, C(CH3)3], 18.5 [C(CH3)3],
12.7 (+, 3-CH3), –5.3 [+, Si(CH3)2].
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft,
the European Community (COST D12/0022/99 and D24/0003/01)
and the Fonds der Chemischen Industrie. We thank Dr. Jürgen
Fenske (Roche AG, Basel, Switzerland) for gifts of chemicals, and
Ms. Anne Biernat, Mr. Carl Deutsch, and Mrs. Claudia God for lab-
oratory assistance.
5,6-Epoxy-5-methylbut-3-yn-2-ol (26)
To a soln of 25 (2.50 g, 22.7 mmol)44 in CH2Cl2 (120 mL) was add-
ed successively at 0 °C Na2HPO4 (6.06 g, 34.0 mmol) and (8.39 g,
34.0 mmol) of mCPBA (70%). The mixture was stirred and warmed
up gradually to r.t. within 16 h; after hydrolysis with a sat. Na2CO3
Synthesis 2002, No. 12, 1759–1774 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
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