Novel enantioselective sequentially rhodium(I)/BINAPcatalyzed cycloisomerization-hydrogenation-isomerizationacetalization (CIHIA)

Article abstract of DOI:10.1002/adsc.200900494

Linear, easily accessible alkyl and (hetero)aryl-substituted alkynyl allyl alcohols are readily and enantioselectively transformed into 2,7dioxabicyclo[3.2.1]octanes by a sequential rhodiumcatalyzed process. Based on the initial cycloisomerization, the in

Full text of DOI:10.1002/adsc.200900494

FULL PAPERS
DOI: 10.1002/adsc.200900494
Novel Enantioselective Sequentially Rhodium(I)/BINAP-
Catalyzed Cycloisomerization–Hydrogenation–Isomerization–
Acetalization (CIHIA)
Nadine Kçrber,a Frank Rominger,b and Thomas J. J. Mꢀllera,*
a
Institut fꢀr Organische Chemie und Makromolekulare Chemie, Lehrstuhl fꢀr Organische Chemie,
Heinrich-Heine-Universitꢁt Dꢀsseldorf, Universitꢁtsstraße 1, 40225 Dꢀsseldorf, Germany
Fax : (+49)-(0)211-811-4324; phone: (+49)-(0)211-811-2298; e-mail: ThomasJJ.Mueller@uni-duesseldorf.de
Organisch-Chemisches Institut, Ruprecht-Karls-Universitꢁt Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg,
b
Germany
Received: July 14, 2009; Revised: October 5, 2009; Published online: November 18, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900494.
Abstract: Linear, easily accessible alkyl and (heter- complex enables a subsequent reduction with hydro-
o)aryl-substituted alkynyl allyl alcohols are readily gen and the transformation into bicyclic frameworks.
and enantioselectively transformed into 2,7-
dioxabicycloACHTUNGTRENNUNG[3.2.1]octanes by a sequential rhodium-
catalyzed process. Based on the initial cycloisomeri- Keywords: asymmetric catalysis; cyclization; homo-
zation, the in situ generated rhodium(I)-BINAP geneous catalysis; hydrogenation; rhodium
Introduction
chelating bisphosphane ligands led to the formation
of five-membered rings.[6] Further ligand screenings
Highly selective methodologies for transformations of proved the superior role of the rhodium-BINAP
linear precursors into hetero- and carbocyclic struc- system.[7] Additionally, the configuration of the new
tures represent a maximum gain in molecular com- stereogenic center was determined by anomalous dif-
plexity. The advent of transition metal-catalyzed pro- fraction in the X-ray crystal structure analysis[8] and
cesses was of paramount benefit and has revolution- indirectly by diastereoselective kinetic resolution.[9]
ized the field of organic syntheses giving access to
In the case of cycloisomerization reactions with al-
novel economically and ecologically benign processes. kynyl allyl alcohols, a reactive aldehyde functionality
In particular, the use of one catalyst for more than is generated by virtue of the tautomerism of the
one type of transformation in a one-pot fashion, gen- dienol intermediate. These resulting enals set the
erally referred to as sequential catalysis,[1] has stage for consecutive transformations, particularly in
emerged as a powerful method by catching two or sequentially catalyzed one-pot processes (Scheme 1).
even more birds with one stone.
As part of our program to design new transition
Among the numerous catalytic carbon-carbon metal-catalyzed sequences initiated by intramolecular
bond-forming processes as well as enyne cyclization cycloisomerization,[10] we are particularly interested in
and especially cycloisomerization,[2] the intramolecu- sequential metal-catalyzed one-pot processes. Within
lar and transition metal catalyzed-version of the our studies dealing with the scope and limitations of
Alder-ene reaction,[3] has become an outstanding tool different transition metal catalysts, the palladium-cat-
to form cycles bearing a diene functionality.
alyzed cycloisomerization works very well for the
In particular, rhodium(I)-catalyzed cycloisomeriza- TMS-substituted alkynic allyl alcohols and was al-
tion processes,[4] firstly published by Zhang,[5] have ready successfully applied in cycloisomerization–Wit-
taken pride of place to generate a tetrahedral stereo- tig,[10a] cycloisomerization–Leuckart–Wallach[10b] and
genic center from a planar sp2-carbon in the starting cycloisomerization–Knoevenagel[10c] sequences in a
material in a highly effective and selective manner. one-pot fashion. Notably, two sequential palladium-
The transformation of 1,6-enynes by a cationic rhodi- catalyzed processes were combined in a cycloisomeri-
um complex coordinated to enantiomerically pure zation–reductive amination sequence.[10d] Moreover
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Scheme 1. Transition metal-catalyzed cycloisomerization as entry to sequential transformations.
the iridium-catalyzed version with aryl-substituted al-
kynic allyl alcohols led to an interesting, as well two-
fold iridium-catalyzed, cycloisomerization–Murahashi
sequence under very mild reaction conditions.[11]
In spite of its great potential, the rhodium-catalyzed
cycloisomerization has not been investigated within
sequential transformations exploiting the cationic rho-
dium(I)/BINAP complex for a consecutive reaction
step. As rhodium has gained a superior role in catalyt-
ic hydrogenation reactions,[12] a sequential hydrogena-
tion step represents an interesting target.
Scheme 3. Rhodium(I)/BINAP-catalyzed cycloisomerization
of alkyl- and (hetero)aryl-substituted alkyne allyl alcohols 1
to g,d-enals 2.
Here we report on the rhodium-catalyzed intramo-
lecular cycloisomerization of alkynyl allyl alcohols to perature. Despite preceding publications, we succeed-
the corresponding enals and its elaboration into a ed in reducing the amount of catalyst to 1.0–2.5%
novel cycloisomerization–hydrogenation–isomeriza- [RhCl
ACHTUNGTERNUN(NG cod)]2 whereas the reactions still proceeded
tion–acetalization (CIHIA) sequence giving access to within 5 min at room temperature (Scheme 3,
enantioselective 2,7-dioxabicyclo
one-pot fashion.
ACHTUNGTRENNUNG
AHCTUNGTERNN(GUN cod)]2, 10%
BINAP and 10% AgBF4 the cyclization product 2c
was readily propared in a satisfying 78% yield
(Table 2, entry 1). Halving the catalyst amount
showed no effect on the isolated yield (Table 2,
Results and Discussion
The required linear allenyl substituted (Z)-alkynyl entry 2), and it even increased on going down to 1%
allyl alcohol substrates 1a and 1c were obtained by of the rhodium dimer (Table 2, entry 3). However, the
simple Williamson etherification of but-2-ene-1,4-diol higher yield does certainly not represent a higher con-
and 1-bromobut-2-yne or 3-bromoprop-1-ynylben- version but rather an advancement in the practical
zene, respectively, in good yields (55% and 85%). isolation of the sensitive aliphatic aldehydes. With the
The (hetero)aryl-substituted alkynyl allyl alcohol sub- p-anisyl substituted 1e the same parameter changes
strates 1d–o were generated by Sonogashira coupling furnished a stepwise reduced yield of 2e (Table 2, en-
reactions of (Z)-4-(prop-2-ynyloxy)but-2-en-1-ol and tries 4–6), whereas in all three cases the TLC control
the corresponding aryl halide in moderate to good displayed full conversion after 5 min reaction time.
yields (40–84%, Scheme 2, Table 1).
The transformations of 1j proceeded with comparable
For the rhodium-catalyzed cycloisomerization we isolated yield for both 2.5% and 1.0% rhodium dimer
first adopted the established reaction parameters by (Table 2, entries 7 and 8). In case of the heteroaryl al-
Zhang and Hashmi applying 5% of the [RhClACHTNUGTRNEUNG(cod)]2 kynyl allyl alcohol 1o a satisfying 85% yield was
precursor, 10% (rac)-BINAP and 10% of silver tetra- maintained under the established conditions (Table 2,
fluoroborate in dichloroethane (DCE) at room tem- entry 9), but with the low catalyst loading we ob-
served a significantly lower conversion (Table 2, en-
tries 10 and 11). In order to fall short of the rhodium
catalyst potential, we have chosen a general catalyst
loading of 2.5% [RhClACTHNUTRGNE(UNG cod)]2 dimer for the subse-
quent cycloisomerization, although we proved suffi-
cient conversion with even lower amounts of catalyst.
Applying the optimized parameters we were able
to transform alkyl- as well as (hetero)aryl-substituted
alkynyl allyl alcohol substrates 1 to furnish substituted
cyclic enals 2 in good to excellent yields (Scheme 3,
Table 3). Besides alkyl-substituted alkynyl allyl alco-
hols (Table 3, entries 1 and 2) also those with elec-
Scheme 2. Sonogashira-coupling for the syntheses of the
(hetero)aryl substituted alkynyl allyl alcohols 1d–o.
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Novel Enantioselective Sequentially Rhodium(I)/BINAP-Catalyzed Cycloisomerization
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Table 1. Sonogashira coupling reactions for the syntheses of the (hetero)aryl substituted alkynyl allyl alcohols 1d–o.
Entry
Aryl halide
Product
G
Yield [%][a]
1
1-Iodonaphthalene
1d
60
2
3
4
4-Iodoanisole
2-Iodoanisole
4-Iodotoluene
1e
1f
1g
70
40
66
5
6
Methyl 4-iodobenzoate
1-Bromo-4-iodobenzene
1i
1j
69
73
7
5-Iodo-1,2,3-trimethoxybenzene
1l
84
8
9
5-Iodobenzo
[1,3]dioxole
1m
1n
53
70
2-Iodothiophene
10
3-Iodo-1-tosyl-1H-indole
1o
68
[a]
Yields refer to isolated yields of compound 1.
Table 2. Different catalyst loads for the cycloisomerization.
Entry
Alkynyl allyl alcohol 1, R=
a) [RhCl
(cod)]2, b) BINAP, AgBF4
Product
Yield [%][a]
1
2
3
4
5
6
7
8
1c, C6H5
1c, C6H5
1c, C6H5
1e, 4-CH3OC6H5
1e, 4-CH3OC6H5
1e, 4-CH3OC6H5
1j, 4-BrC6H5
a) 5%, b) 10%
a) 2.5%, b) 5%
a) 1%, b) 2%
a) 5%, b) 10%
a) 2. 5%, b) 5%
a) 1%, b) 2%
a) 2.5%, b) 5%
a) 1%, b) 2%
a) 5%, b) 10%
a) 2.5%, b) 5%
a) 1%, b) 2%
2c
2c
2c
2e
2e
2e
2j
78
78
94
88
81
75
78
79
85
77
54
1j, 4-BrC6H5
2j
9
10
11
1o, 3-C15H13NO2S
1o, 3-C15H13NO2S
1o, 3-C15H13NO2S
2o
2o
2o
[a]
Yields refer to isolated yields of compound 2.
tronically variable aryl substituents (Table 3, en- form limitations with respect to the alkyne substitu-
tries 3–13) can be transformed into the expected ent, the rhodium-catalyzed version enables the trans-
enals. The substitution pattern plays no limiting role formation of a very broad variety of alkyne substitu-
and even heteroaryl-substituted substrates led to the ents. Alkyl as well as aryl substituents qualify for the
corresponding enals in satisfying yields (Table 3, en- cyclization reaction.
tries 14 and 15). In contrast to the palladium- and iri-
Notably, for the first time heteroaryl-substituted
dium-catalyzed cycloisomerization which both suffer tetrahydrofuran cores were generated. In addition,
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Table 3. Cycloisomerization reaction of alkyl and (hetero)aryl substituted alkynyl allyl alcohols 1 to g,d-enals 2.[a]
FULL PAPERS
Entry
1
Alkynyl allyl alcohol 1, R=
1a, CH3
Product
Yield [%][b]
2a
2b
93
2
3
1b, CH2OCH3
1c, C6H5
62
94
2c
2d
2e
4
5
1d, 1-naphthyl
1e, p-anisyl
81
88
6
1f, o-anisyl
2f
81
7
1g, p-tolyl
2g
2h
2i
94
89
68
86
76
8
1h, p-nitrophenyl
1i, methyl p-benzoate
1j, p-bromophenyl
1k, p-chlorophenyl
9
10
11
2j
2k
12
1l, 1,2,3-trimethoxyphen-5-yl
2l
73
13
14
1m, 1,3-benzodioxol-5-yl
1n, 2-thienyl
2m
2n
67
95
15
1o, 3-(N-tosyl)indolyl
2o
85[c]
[a]
Reaction conditions: 1.0 equiv. of alkynyl allyl alcohol 1 (0.2M in dichloroethane), 0.025 equiv. of RhCl
of BINAP, 0.05 equiv. of AgBF4 solution (0.05M in dichloroethane).
Yields refer to isolated yields of compound 2.
ACHTUNGTERN(NNUG cod)]2, 0.05 equiv.
[b]
[c]
0.05 equiv. of [RhClACTHNUTRGEN(UNG cod)]2, 0.1 equiv. of BINAP, 0.1 equiv. of AgBF4 solution.
the rhodium-catalyzed reaction clearly proves its su- consumption of the products. After complete conver-
perior potential with respect to the short reaction sion the mixture was stirred for additional 2 h at
times. Elongated reaction times did not result in any room temperature as well as heated up to 808C for
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Novel Enantioselective Sequentially Rhodium(I)/BINAP-Catalyzed Cycloisomerization
FULL PAPERS
conversion or isolated yield, but the determination of
the enantiomeric excess turned out to be very chal-
lenging with this type of enals. In fact, we did not suc-
ceed in separating the racemic mixtures [generated by
application of (rac)-BINAP], either by chiral GC or
by chiral HPLC. In order to enhance the interactions
between the column material and the compound, we
aimed at a more polar side chain, in detail by reduc-
ing the aldehyde functionality to the corresponding
primary alcohol.
Scheme 4. Cycloisomerization–reduction sequence of (heter-
o)aryl substituted alkynyl allyl alcohols 1 to 4-arylidene-
We designed a novel cycloisomerization–reduction
sequence in a one-pot fashion simply by adding a con-
secutive borohydride reduction step. After reacting
ACHTUNGTRENNUNGtetrahydrofuran-3-ylethanols 3.
1 h. Neither additional precipitation (besides the ini- the alkynyl allyl alcohols 1 in the presence of 2.5%
tial silver chloride formation) nor a change in color of [Rh(COD)Cl]2, 5% BINAP and 5% AgBF4 in di-
the catalyst product solution could be detected. chloroethane for 5 min, a slight excess of sodium bor-
The structures of the products 2 were unambigu- ohydride was added to give the tetrahydrofuran-3-yl-
ously supported by 1H, 13C, DEPT-135 and COSY
ethanols 3 in good to excellent yields (Scheme 4,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
NMR experiments as well as IR and mass spectrome- Table 4). Moreover, ethanol was applied to raise the
try. The molecular composition was confirmed either solubility of the hydride species.
by HR-MS or elemental analysis (see Supporting In-
The structures of the products 3 were also unambig-
1
formation). Switching to the enantioselective cycloiso- uously supported by H, 13C, DEPT-135 and COSY
merization did not show any significant changes in NMR experiments as well as IR and mass spectrome-
Table 4. Cycloisomerization–reduction sequence of alkyl- and (hetero)aryl-substituted alkyne allyl alcohols 1 to arylidenete-
trahydrofuran-3-ylethanols 3.[a]
Entry
Alkyne allyl alcohol 1, R=
Product
ee
Yield [%][b]
1
1c, C6H5
3a
3b
3c
3d
3e
3f
3g
>99%
85
[c]
2
3
4
5
6
7
1d, 1-naphthyl
1e, p-anisyl
–
78
68
95
53
64
87
>99%
>99%
1g, p-tolyl
[c]
1h, p-nitrophenyl
1j, p-bromophenyl
1n, 2-thienyl
–
>99%
[c]
–
8
1o, 3-(N-tosyl)indolyl
3h
>99%
83
[a]
Reaction conditions: 1.0 equiv. of alkynyl allyl alcohol 1 (0.2M in dichloroethane), 0.025 equiv. of [RhCl
0.05 equiv. of BINAP, 0.05 equiv. of AgBF4 solution (0.05M in dichloroethane).
Yields refer to isolated yields of compound 3.
ACHTUNGTRENNUNG(cod)]2,
[b]
[c]
The ee could not been estimated, no separation of racemic mixture on chiral GC or HPLC.
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try. The molecular composition was confirmed either ly be separated using chiral HPLC and the ee of the
by HR-MS or elemental analysis (see Supporting In- enantiomerically pure (R)-configured products ex-
formation). Excluding substrate 1h, all sequential ceeded 99%.
transformations led to the expected arylidenetetra-
To synthesize these novel enantioselective products
ACHTUNGTRENNUNGhydrofuran-3-ylethanols 3. The transformation of 1h in a more elegant way we considered to substitute the
yielded the compound 3e with 53% bearing an amino stoichiometric reduction step by a catalytic carbonyl
substituent at the aromatic system (Table 4, entry 5). hydrogenation. Referring to the cycloisomerization
Apparently, a reduction of the initial nitro group took reactions, neither precipitation nor a change in color
place. Referring to literature the reduction of aromat- of the catalyst product solution could be detected.
ic nitro compounds to the corresponding anilines has This observation encouraged us to test the possibility
been accomplished with various combinations of stoi- of performing sequential catalysis with the obviously
chiometric amounts of sodium borohydride and metal intact rhodium catalyst system. The concept was to
catalysts, for example, NiCl2,[13] (py)3RhCl3,[14] Cu(II) transform the alkynyl allyl alcohols based on the opti-
acetylacetonate,[15] Pd/C,[16] phthalocyanatoiron(II)[17] mized rhodium-catalyzed cycloisomerization and to
and Raney Ni.[18] To check whether the reduction is use the cationic rhodium system sequentially for a
induced by an in situ generated rhodium hydride spe- second catalytic hydrogenation reaction.
cies we did a cross-check experiment and isolated the
Practically, after reacting the alkynyl allyl alcohols
enal 2h. The transformation of 2h with 2 equivalents 1 in the optimized cycloisomerization we set the reac-
of sodium borohydride in dichloroethane and ethanol tion vessel under hydrogen pressure (5 bar) and
gave a non-separable mixture of 3e and the corre- stirred the mixture for 24 h at room temperature. Un-
sponding nitro-substituted tetrahydrofuran-3-yletha- expectedly, we neither observed a reduction of the
nol. The reduction of the nitro group is therefore at newly formed carbonyl side-chain to the correspond-
least to a certain degree initiated by the sodium boro- ing alcohol functionality nor an olefin hydrogenation
hydride species without any rhodium catalyst interfer- of the exo double bond. The enals 2 undergo an enan-
ence. Studies addressing the scope and limitations of tioselective sequential hydrogenation–isomerization–
this unusual reduction of the aromatic nitro group are acetalization domino reaction. Thus we performed a
currently underway.
Concerning the ee determination of compounds 3, talization (CIHIA) sequence forming 2,7-dioxa-
(rac)-3a, (rac)-3c, (rac)-3d, 3f and 3g could successful- bicyclo[3.2.1]octanes 4 in moderate to good yields
cycloisomerization–hydrogenation–isomerization–ace-
AHCTUNGTRENNUNG
(Scheme 5).
First of all we varied and optimized parameters
such as catalyst loading, hydrogen pressure and reac-
tion time in screening experiments (Table 5).
Unfortunately, a catalyst loading of 2.5% rhodium
dimer, which worked very well in case of the initial
cycloisomerization, did not produce a yield exceeding
50% (Table 5, entries 1–5) for the CIHIA sequence.
By application of 5% rhodium precursor, a lower hy-
drogen pressure did not lead to a consecutive hydro-
genation reaction, but isolation of the cycloisomeriza-
Scheme 5. Enantioselective CIHIA sequence of alkyl- and
aryl-substituted alkynyl allyl alcohols 1 to 2,7-dioxabicyclo-
ACHTUNGTRENNUNG[3.2.1]octanes 4.
Table 5. CIHIA optimization for the reaction with 1c.
Entry
a) [RhCl
(cod)]2, b) BINAP,[a] AgBF4
Hydrogen pressure
T, t
Yield of 4b
1
2
3
4
5
6
7
8
9
a) 2.5%, b) 5%
a) 2. 5%, b) 5%
a) 2.5%, b) 5%
a) 2.5%, b) 5%
a) 2.5%, b) 5%
a) 5%, b) 10%
a) 5%, b) 10%
a) 5%, b) 10%
a) 5%, b) 10%
1 bar
2 bar
4 bar
5 bar
5 bar
1 bar
2 bar
5 bar
5 bar
r.t., 24 h
r.t., 24 h
r.t., 24 h
r.t., 12 h
r.t., 24 h
r.t., 24 h
r.t., 24 h
r.t., 18 h
r.t., 24 h
no reaction
no reaction
30%[b])
13%[b])
50%[b]
no reaction
no reaction
49%[c]
69%[c]
[a]
(rac)-BINAP.
Yields via GC.
Yields refer to isolated yields of compound 4b.
[b]
[c]
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Novel Enantioselective Sequentially Rhodium(I)/BINAP-Catalyzed Cycloisomerization
FULL PAPERS
Scheme 6. Formation of intermediate vinyl ether (significant 13C NMR shifts in parentheses).
1
tion product 2c (Table 5, entries 6 and 7). Raising the
Most characteristically in all H NMR spectra the
hydrogen pressure up to 5 bar the CIHIA sequence signal of the acetal proton H1 gives a significant sin-
reaches a maximum yield of 69% for compound 4c glet between d=5.07–5.24. The protons of the four
after 24 h reaction time (Table 5, entry 9). Looking at methylene groups H3, H5, H6, and H9 and appear as
the reaction control via TLC only one single product discrete signal sets due to their diastereotopic charac-
spot of the newly formed bicyclic acetal structure was ter. In most cases the signals of the two stereogenic
detected after 24 h reaction time. Interestingly, when centered protons H4 and H8 cannot be clearly identi-
the CIHIA sequence was stopped after 4–6 h under fied but are located as combined multiplets in the
hydrogen pressure, an unknown intermediate bearing range of d=1.81–2.85. The enantioselectivity of the
a relative polarity between those of the cycloisomeri- reaction under application of the enantiomerically
zation product 2c and the corresponding acetal 4b pure BINAP ligand and the enantiomeric excess of
could be detected via TLC. Although the intermedi- the resulting compounds 4b–e, 4i, and 4k could be ob-
ate just occurs in very minor concentrations during tained by chiral HPLC experiments (spectra see Sup-
the domino sequence, we successfully isolated a small porting Information). All compounds, excluding 4k,
amount of it and the 13C as well as a DEPT-135 NMR gave excellent ees exceeding 99% (Table 6). As a
experiment unambiguously supported the structure of matter of fact, the enantiomers of (rac)-4i could not
the isomerized vinyl ether, a dihydrofuran derivative. be separated on chiral GC and the absence of UV
(Scheme 6, spectra see Supporting Information).
active molecule fragments excludes separation via
Based upon these parameters (5 bar hydrogen pres- chiral HPLC. The racemic mixtures of the remaining
sure for 24 h) the CIHIA sequence for alkynyl allyl aryl-substituted compounds 4g, 4h, 4j and 4l could not
alcohols 1 was probed for some representative exam- be separated with the chiral HPLC column on hand.
ples (Table 6). To the best of our knowledge these bi-
The unexpected formation of the bicyclic acetals 4
cyclic acetal structures have not been reported in the prompted us to investigate the CIHIA sequence
literature and, therefore, the structures of the prod- mechanistically and to propose a mechanistic ration-
ucts 4 were unambiguously supported by 1H, 13C, ale of this domino sequence.
DEPT-135 and COSY NMR experiments as well as
Looking at the differences in mass of the intermedi-
IR, mass spectrometry and later by X-ray crystal ate enals and the acetal product, an addition of mo-
structure analyses of (rac)-4b and (R,R,R)-4i lecular hydrogen takes place. Therefore, it is reasona-
(Figure 1).[19] The molecular composition was con- ble to assume a hydrogenation key step, presumably
firmed either by HR-MS or elemental analysis (see of the aldehyde functionality, generating an alcohol
Supporting Information). For the determination of intermediate within the domino sequence. Hence, we
the absolute configuration by anomalous diffraction carried out H/D-exchange experiments (Scheme 7) to
we used crystals of (R,R,R)-4i bearing the feasible gain an insight in the reduction key step by analyzing
heavy atom at the bromine-substituted aryl system. In the position of the deuterium atoms in the final prod-
complete accord with Zhang and Hashmi the cyclo- ucts. Besides the synthesis of 4b (Scheme 7, A), we
ACHTUNGTRENNUNGisomerization of 1 with (R)-BINAP as chelating also conducted using 1c in a CIHIA sequence but ap-
ligand leads to (R)-configured enals 2. In the CIHIA plying deuterium instead of hydrogen (Scheme 7, B).
sequence this initial stereocenter induces the orienta- The isolated mixture contained the bis-deuterated
tion of the stereo centers C4 and C8, whereas in the compound 5a and the mono-deuterated compound 5b
final 2,7-dioxabicycloACHTGNUTERN[UNNG 3.2.1]octanes 4 all three contigu- in a 1:1 ratio (determined by mass spectrometry).
1
ous stereocenters feature the same configuration. In
The H NMR data showed a simplified couple of
short, the CIHIA sequence of 1 with (R)-BINAP pro- signals for the a-methylene group C6. In comparison
vides the (R,R,R)-2,7-dioxabicyclo[3.2.1]octanes 4. to the characteristic signal of the acetal-bridged hy-
AHCTUNGTRENNUNG
For the subsequent description of the bicyclic acetal drogen H1 the set of integrals H6 have decreased to a
structures, especially within the discussion of the relative value of approximately 0.5 (Figure 1). The
mechanistic rationale, we will refer to the numeration deuterium substituent is therefore located at both the
shown in Figure 1.
axial and equatorial positions with a 50% distribution
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Table 6. Rhodium(I)/BINAP-catalyzed CIHIA sequence.[a]
Entry
1
Alkynyl allyl alcohol, R=
1a, CH3
Product
ee
Yield
[%][b]
[c]
4a
4b
–
34[d]
2
3
1c, C6H5
>99%
69
35
1d, 1-naphthyl
4c
4d
4e
4f
>99%
4
5
6
1e, p-anisyl
1f, o-anisyl
1g, p-tolyl
>99%
>99%
>99%
38
38
55
[c]
7
8
9
1h, p-nitrophenyl
4g
4h
4i
–
70
60
54
[c]
1i, methyl p-benzoate
1j, p-bromophenyl
–
>99%
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Adv. Synth. Catal. 2009, 351, 2921 – 2935

Novel Enantioselective Sequentially Rhodium(I)/BINAP-Catalyzed Cycloisomerization
FULL PAPERS
Table 6. (Continued)
Entry
Alkynyl allyl alcohol, R=
Product
ee
Yield
[%][b]
[c]
10
1m, 1,3-benzodioxol-5-yl
4j
–
58
11
1n, 2-thienyl
4k
4l
63%
52
68
[c]
12
1o, 3-(N-tosyl)indolyl
–
[a]
Reaction conditions: 1) cycloisomerization: 1.0 equiv. of 1 (0.2M in DCE), 0.05 equiv. of [RhCl
BINAP, 0.1 equiv. of AgBF4 solution (0.05M in DCE). 2) H2 pressure (5 bar).
Yields refer to isolated yields of compound 4.
The ee could not been estimated, no separation of racemic mixture on chiral GC or HPLC.
Highly volatile compound.
ACHTUNGTERN(NNUG cod)]2, 0.1 equiv. of
[b]
[c]
[d]
allyl alcohol 1c-D2, was also conducted generating a
mixture of two mono-deuterated compounds 6a and
6b and the bis-deuterated compound 6c (Scheme 7,
C). The ratio of the mono-deuterated compound vs.
the bis-deuteration products showed a 1:8 excess of 6c
(determined by mass spectrometry). In contrast, the
deuterium substituents are found at the acetal bridge
atom C1 and in the a-position to the phenyl moiety
(C9). Interestingly, looking at the sets of signals of H9
in the a-position to the phenyl moiety, only the inte-
gral of one of the two signals decreases to a relative
value of 0.3 whereas the other integral area remained
at 1.0. This means the methylene group next to the
phenyl moiety has selectively been deuterated at one
of the diastereotopic positions. After the cycloisome-
Figure 1. Molecular structure of (S,S,S)-4b (left) and rization reaction the CD2 group next to the exo-cyclic
(R,R,R)-4i (right). Most hydrogen atoms have been omitted
for clarity.
double bond forms the only deuterium source, there-
fore, an isomerization reaction from allyl ether to the
corresponding vinyl ether seems to be reasonable. As
no deuterium was found at the stereo center C8 the
each. For compound 5b the second deuterium sub- stereosepecific deuterium transfer excludes a possible
stituent can be found at the stereocenter C8 with a hydrorhodation step. The minor hydrogen content at
relative integral of 0.4 amounting to approximately carbon atom C9 indicates a hydrogen/deuterium
50% deuteration. As the deuterated carbon atom cor- scrambling.
relates with the former carbon center of the aldehyde
Assuming a combination of a rhodium-catalyzed
functionality, this indicates an intermediate deutera- hydrogenation as well as an allyl ether-vinyl ether iso-
tion of the carbonyl group to the corresponding deu- merization, we synthesized specially modified model
terated alcohol side-chain.
compounds, derived from compound 1c to selectively
The counter experiment, the hydrogenation se- block out one of the above-mentioned reaction steps.
quence with the corresponding deuterated alkyne Firstly we converted the ester tethered analogue 7 in
Adv. Synth. Catal. 2009, 351, 2921 – 2935
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Nadine Kçrber et al.
FULL PAPERS
Scheme 7. CIHIA experiments with H/D exchange.
the cycloisomerization under the established condi- formed compounds, whereas twice m/z=218 (Rf =
tions into the corresponding lactone. Application of 23.7 min and 25.9 min, 10a and 10b) and once m/z=
the hydrogenation sequence resulted in the reduction 220 (Rf =24.6 min, 10c) were detected (ratio [218]:
of the carbonyl functionality to give the alcohol 8[20] [218]:
ACHTNUTRGNE[NUG 220]=1:2.3:8.8). For comparison, the starting
(Scheme 8). As expected the Michael system within material 9 was also analyzed by GC-MS under the
the lactone core prevents any migration of the exo- same conditions (Rf =26.8 min). Unfortunately, the
ACHTUNGTRENNUNG
alcohol side chain.
The main product 10c was derived from a rhodium-
In another approach we methylated the cycloisome- catalyzed hydrogenation. Although the NMR data of
rization-reduction product 3a and subjected the re- the mixture were not very significant they clearly
sulting methyl ether 9 to the standard hydrogenation proved the migration of the benzylic double bond. By
1
conditions (Scheme 9). The GC-MS analysis of the comparison of the H NMR spectra of starting materi-
product mixture (70% yield based on recovered start- al 9 with product mixture 10a–c, the singlet signal of
ing material) revealed the peaks of three newly the former exo-olefinic hydrogen atom (d=6.34) has
disappeared. Similarly, the signal of the methylene
group between the oxygen atom and the exo-cyclic
double bond, formerly appearing as singlet signal at
1
d=4.61, dropped out. However, the H NMR spec-
trum of 10a–c bears a multiplet (d=5.01–5.10) and
hereby gives a considerable indication for the hydro-
gen atom of a vinyl ether. We ascribe the formation
of the vinyl ether 10a and the achiral dihydrofuran
10b to a rhodium-catalyzed isomerization reaction.
As we have observed no subsequent domino reac-
tion after the cycloisomerization without any parame-
ter changes, we believe that the active rhodium hy-
Scheme 8. Cycloisomerization–hydrogenation sequence of 7
to 8.
Scheme 9. Hydrogenation experiment with 9.
2930
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Adv. Synth. Catal. 2009, 351, 2921 – 2935

Novel Enantioselective Sequentially Rhodium(I)/BINAP-Catalyzed Cycloisomerization
FULL PAPERS
dride catalyst species for the subsequent domino se- hydride species implies the generation of a rho-
quence is generated by the application of increased dium(V) hydride allyl intermediate. Examples of rho-
hydrogen pressure. To further prove our postulate of dium(V) intermediates and complexes, although they
an active rhodium
ACHTUNGTRNE(NUNG III) hydride species within the still remain limited, can be found within studies by
scope of the isomerization key step, we subjected al- Maitlis et al. and Beckett et al.[22]
cohol 3a first to the cationic rhodium-BINAP species
Based on the presented H/D exchange experiments
under an argon atmosphere and secondly under a hy- and additional hydrogenation and isomerization in-
drogen atmosphere. In the first case we only observed vestigations, respectively, we propose the following
a very minor formation of the corresponding acetal mechanistic rationale (Scheme 10). After the cycloiso-
4b via GC. Application of the hydrogen atmosphere, merization reaction and generation of the (R)-config-
hence generation of a rhodiumACHTNUTRGNE(NUG III)-hydride species, ured enal, the cationic rhodium/(R)-BINAP complex
led to quantitative formation of 4b. We conclude a A, coordinated to the carbonyl and the allyl ether
very slow isomerization rate of the rhodium(I), but in double bonds, undergoes an oxidative addition with
the case of the rhodium
cant acceleration can be observed. The general iso- um hydride catalyst B. The newly formed rhodium-
merization potential of rhodium hydride complexes (III) hydride species catalyzes an isomerization of the
ACHTUNGTRNE(NUNG III) hydride species a signifi- molecular hydrogen to give the active cationic rhodi-
AHCTUNGTRENNUNG
via an allyl rhodium species has already been report- allyl ether compound B to the corresponding vinyl
ed.[21] In our case, the isomerization of the allyl ether ether analogue D, which we were able to isolate, via
to the vinyl ether by means of an active rhodiumACTHNUGRTENUNG(III) formation of a rhodium(V) allyl intermediate. The al-
Scheme 10. Proposed mechanism for the rhodium/(R)-BINAP-catalyzed CIHIA sequence.
Adv. Synth. Catal. 2009, 351, 2921 – 2935
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Nadine Kçrber et al.
FULL PAPERS
values are listed with the corresponding solvent mixtures.
ternative hydrorhodation mechanism can be excluded
by the results of the hydrogenation experiment lead-
ing to the acetals 6a–c. The isomerization via the allyl
complex is accompanied by a primary isotope effect
as well as a favored stereospecific-syn hydrogen trans-
fer. This concept delivers a reasonable explanation
for the exclusive H-transfer in case of the deuterium
experiment (product 5a, b) and the H/D scrambling
for the hydrogenation of the deuterated starting mate-
rial (6a–c). Coordination to the carbonyl double bond
(E) sets the stage for the aldehyde reduction by inser-
1
The H and 13C NMR spectra were recorded on a Bruker
DRX 500 and an Avance DRX 250 spectrometer. TMS was
used as reference (d=0.0) or the resonance of CDCl3 was
locked as internal standard (1H: d=7.24, 13C: d=77.0). The
multiplicities of signals are abbreviated as s (singlet), d
(doublet), t (triplet), dd (doublet of doublets), m (multiplet)
and corresponding combinations. The type of carbon atoms
(CH3, CH2, CH, Cquat) was determined on the basis of
DEPT-135 NMR spectra. EI-mass spectra were measured
on a Finnigan MAT 8200 spectrometer. IR spectra were ob-
tained on a Bruker Vector 22 FT-IR. The solids were mea-
sured as KBr pellets and the oils in the form of films on
KBr plates. The intensity of signals is abbreviated as s
(strong), m (medium) and w (weak). The melting points
(uncorrected) were measured on a Bꢀchi Melting Point B-
540. Combustion analyses were carried out on a Perkin–
Elmer Series II Analyser 2400 in the microanalytical labora-
tory of the Institut fꢀr Pharmazeutische und Medizinische
Chemie der Heinrich Heine Universitꢁt Dꢀsseldorf.
tion of the rhodiumACHTNUGRTENUNG(III) hydride (F). By final reduc-
tive elimination and acetalization the (R,R,R)-config-
ured bicyclic acetal G and the original cationic rhodi-
um/(R)-BINAP species are released. As we could not
prove whether the cyclizing acetalization takes place
under rhodium catalysis, a formal Lewis or Brønsted
acid-catalyzed cyclization cannot be excluded. The
facial attack of the hydroxy functionality within the
acetalization step derives from the configuration of
the stereocenter generated in the preceding cycloiso-
merization reaction whereas in the acetal product 4b
the phenyl substituent points into the direction of the
five-membered ring system, the former tetrahydrofur-
an system.
Typical Procedure for the Sonogashira Coupling
Reaction of the Aryl-Substituted Alkynyl Allyl
Alcohols 1
(Z)-4-[3-(3,4,5-Trimethoxyphenyl)prop-2-ynyloxy]but-2-en-
1-ol (1l): In a 100-mL Schlenk flask 2.0 g (6.8 mmol) 5-iodo-
1,2,3-trimethoxybenzene and 0.88 g (1.03 equiv., 7.0 mmol)
(Z)-4-(prop-2-ynyloxy)but-2-en-1-ol were dissolved in
20 mL absolute THF under an argon atmosphere at room
temperature. To the yellowish solution 49 mg (1%,
Conclusions
0.07 mmol)
dichlorobis(triphenylphosphane)palladium(II)
Starting from a rhodium/BINAP-catalyzed cycloiso-
merization of alkynyl allyl alcohols 1 to novel substi-
tuted alkylidene and arylidene tetrahydrofurans 2, we
have developed a cycloisomerization–reduction se-
quence giving arylidene tetrahydrofuran-3-ylethanols
3 in good yields and with excellent ee > 99%. In par-
ticular, we elaborated an enantioselective one-pot
and 14 mg (1%, 0.07 mmol) copper(I) iodide were added re-
sulting in a yellow suspension The reaction was finally start-
ed by addition of 30 mL of distilled triethylamine whereby
the suspension turned into a brown solution immediately.
The reaction mixture was stirred at room temperature over-
night (18 h) and the conversion checked via TLC and/or
GC-MS.
CIHIA sequence to 2,7-dioxabicyclo
and investigated the mechanism of this novel reaction
sequence.
[3.2.1]octanes 4
The precipitate was filtered off and the filtrate poured
into water. After several extraction steps with diethyl ether
the combined organic phases were washed with water and
brine. Finally the organic phase was dried with anhydrous
magnesium sulfate and the solvents were removed under
vacuum and the residual crude product was chromatograph-
ed on silica gel (n-hexane/diethyl ether 1:2, Rf =0.35) to give
the analytically pure product 1l in the form of a yellow
solid; yield: 1.73 g (5.9 mmol, 84%); mp 548C. 1H NMR
(CDCl3, 300 MHz): d=1.73 (s, 1H), 3.82 (s, 9H), 4.20 (d,
J=6.5 Hz, 2H), 4.24 (d, J=6.5 Hz, 2H), 4.35 (s, 2H), 5.69–
5.73 (m, 1H), 5.82–5.87 (m, 1H), 6.67 (s, 2H); 13C NMR
(CDCl3, 75.5 MHz): d=56.3 (CH3), 58.3 (CH2), 58.9 (CH2),
61.2 (CH3), 65.3 (CH2), 84.0 (Cquat), 86.8 (Cquat), 109.2 (CH),
117.6 (Cquat), 127.9 (CH), 133.2 (CH), 139.2 (Cquat), 153.2
(Cquat); EI-MS (70 eV): m/z (%)=292 ([M]+, 22), 261
Experimental Section
The catalysis reactions were performed in degassed di-
chloroethane which was dried using an MBraun system MB-
SPS-800. All rhodium-catalyzed cycloisomerization reactions
were carried out in oven-dried Schlenk glassware using
septa and syringes under an argon atmosphere. All rhodi-
um-catalyzed one-pot sequences based on the cycloisomeri-
zation reaction were performed in purpose-made Schlenk
tubes (6 mL volume, 4 mm wall thickness to resist the excess
hydrogen pressure). The purification of products was per-
formed on silica gel 60 (0.015–0.040 mm) using the flash
technique and under pressure of 2 bar. The crude mixtures
were adsorbed on Celite 545 (0.02–0.10 mm) before chroma-
tographic purification. The reaction progress was monitored
qualitatively using TLC silica gel 60 F254 aluminium sheets.
The spots were detected using ethanolic solution and the Rf
([MÀCH3O]+,
12),
231
([MÀC2H5O]+,
34),
222
([MÀC4H6O]+, 15), 215 (20), 206 (30), 205 ([MÀC4H7O2]+,
100), 195 (35), 193 (11), 192 (18), 191 ([MÀC5H9O2]+, 84),
189 ([C11H9O3]+, 18), 181 ([C10H13O3]+, 27), 176 (18), 175
([C11H11O2]+, 15), 173 ([C11H9O2]+, 12), 172 (42), 169 (19),
168 ([C9H12O3]+, 16), 163 (37), 162 (22), 161 (20), 160
([C10H8O2]+, 18), 145 (13), 131 (20), 119 (19), 115
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Novel Enantioselective Sequentially Rhodium(I)/BINAP-Catalyzed Cycloisomerization
FULL PAPERS
([C6H11O2]+, 12), 105 (18), 103 (25), 102 ([C5H10O2]+, 18), 91
(31), 89 ([C4H9O2]+, 19), 77 (21), 71 ([C4H7O]+, 6). IR
2 mL degassed dichloroethane were added and the solution
was stirred for several minutes, until a dark red solution was
formed. Then 108 mg (0.5 mmol) 1g was added, the solution
stirred for another minute and finally the reaction was start-
ed by addition of 0.5 mL AgBF4 (dissolved in dichloro-
ethane, c 0.5M). The reaction was monitored by TLC and
showed a complete conversion after 5 min at room tempera-
ture. Then 38 mg (1.0 mmol) sodium borohydride and
0.5 mL ethanol were added and the mixture stirred at room
temperature for 30 min. The reaction was again checked by
TLC. The excess of sodium borohydride was destroyed by
dropwise addition of 2N hydrochloric acid. After addition
of water and extraction with diethyl ether the combined or-
ganic layers were dried with anhydrous sodium sulfate, fil-
tered, the solvents removed under vacuum and the residue
was chromatographed on silica gel (diethyl ether, Rf =0.20)
to give the analytically pure product 3d in the form of a
yellow oil; yield: 104 mg (0.48 mmol, 95%). 1H NMR
(CDCl3, 500 MHz): d=1.70–1.76 (m, 2H), 1.94–2.00 (ddd,
J=13.5 Hz, J=12.0 Hz, J=6.7 Hz, 1H), 2.32 (s, 3H), 2.94–
2.99 (m, 1H), 3.64 (dd, J=8.5 Hz, J=5.3 Hz, 1H), 3.73 (t,
J=6.4 Hz, 2H), 3.99 (dd, J=8.5 Hz, J=6.5 Hz, 1H), 4.57–
4.65 (m, 2H), 6.33 (d, J=2.1 Hz, 1H), 7.01 (d, J=8.1 Hz,
2H), 7.13 (d, J=7.9 Hz, 2H); 13C NMR (CDCl3, 125 MHz):
d=21.3 (CH3), 36.3 (CH2), 42.9 (CH), 61.2 (CH2), 70.3
(CH2), 72.9 (CH2), 121.1 (CH), 128.1 (CH), 129.4 (CH),
˜
(KBr): n=3364 (br), 2943 (m), 2838 (m), 2365 (w), 2345
(w), 2228 (w), 1577 (s), 1543 (w), 1508 (s), 1459 (m), 1438
(w), 1411 (m), 1341 (m), 1238 (s), 1184 (w), 1130(s), 1082
(m), 1026 (m), 99À31 (m), 933 (w), 834 (m), 772 (w), 676 (w),
631 (m), 527 cm
(w); anal. calcd. for C16H20O5 (292.13):
[%] C 65.74, H 6.90; found: C 65.70, H 6.73.
Typical Procedure for the Rhodium-BINAP-
Catalyzed Cycloisomerization of Alkyl- and Aryl-
Substituted Alkynyl Allyl Alcohols 1 to g,d-Enals 2
(Z)-2-[4-(Thiophen-2-ylmethylene)tetrahydrofuran-3-yl]-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(0.05 mmol) (R)-BINAP ligand were placed in a Schlenk
tube. Then 4 mL dried, degassed dichloroethane was added
and the solution was stirred for several minutes, until a dark
red solution was formed. Then 208 mg (1.0 mmol) alkyne
allyl alcohol 1n were added, the solution stirred for another
minute and finally the reaction was started by addition of
1 mL (0.05 mmol) of AgBF4 solution (c 0.05M, dissolved in
dichloroethane). The reaction was monitored by TLC and
full conversion was observed after 5 min at room tempera-
ture. After dilution with diethyl ether the crude product was
filtered, the solvents removed under vacuum, and the resi-
due was chromatographed on silica gel (n-hexane/diethyl
ether 1:2, Rf =0.43) to give the analytically pure product 2n
in form of a yellow oil; yield: 197 mg (0.95 mmol, 95%).
1H NMR (CDCl3, 300 MHz): d=2.70 (ddd, J=18.2 Hz, J=
8.4 Hz, J=1.1 Hz, 1H), 2.84 (ddd, J=18.2 Hz, J=5.1 Hz,
J=1.2 Hz, 1H), 3.30–3.39 (m, 1H), 3.59 (dd, J=8.8 Hz, J=
5.5 Hz, 1H), 3.81 (s, 3H), 4.13 (dd, J=8.8 Hz, J=6.5 Hz,
1H), 4.59–4.61 (m, 2H), 6.55–6.58 (m, 1H), 6.88 (d, J=
3.6 Hz, 1H), 7.03 (dd, J=5.1 Hz, J=3.6 Hz, 1H), 7.26–7.29
(m, 1H), 9.84 (t, J=1.1 Hz, 1H); 13C NMR (CDCl3,
75.5 MHz): d=39.2 (CH), 47.4 (CH2), 70.4 (CH2), 73.1
(CH2), 114.3 (CH), 125.6 (CH), 126.2 (CH), 127.5 (CH),
140.6 (Cquat), 142.0 (Cquat), 200.5 (CH); EI MS (70 eV):, m/z
˜
134.6 (Cquat), 136.7 (Cquat), 143.7 (Cquat). IR (film): n=3385
(s), 2939 (s), 2865 (s), 1653 (w), 1610 (w), 1514 (s), 1456
(m), 1361 (m), 1183 (m), 1054 (s), 927 (m), 882 (w), 810 (m),
435 (s), 427 cmÀ1 (s); EI-MS (70 eV): m/z=218 ([M]+, 4),
201 ([MÀOH]+, 2), 145 ([C10H11O]+, 14), 136 (33), 132 (11),
131 (11), 129 ([C10H9]+,12), 121 (65), 120 (83), 119 ([C9H11]+,
100), 118 (13), 117 (10), 115 (15), 114 (20), 113 (13), 106
(65), 105 (85), 99 (20), 93 (16), 92 (16), 91 ([C7H7]+, 96), 83
(18), 77 (15), 71 ([C4H7O]+,15); HR-MS: m/z=218.1285,
calcd. for C14H18O2: 218.1307; (R)-enantiomer: [a]20: À0.58
(c 1.0M, CHCl3); chiral HPLC (n-hexane/2-PrODH 95:5,
0.6 mLminÀ1, 254 nm): tR =40.0 min (major), tS =46.0 min
(minor): ee> 99%.
(%)=208 ([M]+, 59), 179 ([MÀ
149 ([C8H6OS]+, 21), 138 ([C7H6OS]+, 22), 135 ([C8H7S]+,
67), 123 ([C7H7S]+, 15), 113 ([C6H9O2]+, 100), 110 ([C6H6S]+,
36), 109 ([C6H5S]+, 16), 97 ([C5H5S]+, 96), 91 ([C7H7]+, 18),
85 ([C4H5S]+, 20), 84 ([C4H4S]+,17), 69 ([C4H5O]+, 27); IR
(CHO)]+, 6), 165
ACHTUNGTRENNUNG
Typical Procedure for the Enantioselective
Cycloisomerization–isomerization–hydrogenation–
acetalization Sequence to 2,7-
([C9H9O2]+, 15), 164 ([MÀ
(CO2)]+, 84), 151 ([C8H7OS]+, 18),
ACHTUNGTRENNUNG
DioxabicycloACTHNUTRGENUGN[3.2.1]octanes
8-(4-Nitrobenzyl)-2,7-dioxabicyclo
an argon atmosphere 12.3 mg (0.025 mmol) of the
[RhCl(cod)]2 precursor and 31.1 mg (0.05 mmol) (R)-
ACHTUNGERTN[NUNG 3.2.1]octane (4g): Under
˜
(film): n=3411 (s), 3104 (m), 2939 (s), 2846 (s), 2727 (m),
2364 (w), 2248 (w), 1722 (s), 1675 (m), 1514 (w), 1474 (w),
1429 (m), 1403 (m), 1385 (m), 1310 (m), 1231 (m), 1065 (s),
933 (s), 854 (m), 702 (s), 666 (w), 509 cmÀ1 (m); UV/Vis
(CH2Cl2): lmax (e)=272 nm (11200), 282 nm (14700), 292
(11000); HR-MS: m/z=208.0564, calcd. for [C11H12O2S]:
208.0558; (R)-enantiomer: [a]2D0: À14.48 (c 1.0M, CHCl3).
A
ACHTUNGTRENNUNG
BINAP ligand were placed in a Schlenk tube (8 mL volume,
4 mm wall thickness). Then 4 mL degassed dichloroethane
were added and the solution was stirred for several minutes,
until
a dark red solution was formed. Then 124 mg
(0.5 mmol) alkyne allyl alcohol 1h were added, the solution
stirred for another minute and finally the reaction was start-
ed by addition of 1 mL (0.05 mmol) of AgBF4-solution (c
0.05M, dissolved in dichloroethane). The solution was
stirred for 10 min at room temperature before the reaction
vessel was set under hydrogen pressure (5 bar) for 24 h.
After dilution with diethyl ether the crude product was fil-
tered, the solvents removed under vacuum and the residue
was chromatographed on silica gel (n-hexane/diethyl ether
1:2) to give the analytically pure product 4g in the form of a
Typical Procedure for the Enantioselective
Cycloisomerization-Reduction Sequence to
Tetrahydrofuran-3-yl)ethanols
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
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Nadine Kçrber et al.
FULL PAPERS
colorless solid; yield: 87 mg (0.35 mmol, 70%); mp 1038C.
1H NMR (CDCl3, 500 MHz): d=1.55 (dt, J=13.1 Hz, J=
4.3 Hz, 1H), 1.80 (dd, J=19.6 Hz, J=12.8 Hz, 1H), 2.20 (t,
J=8.0 Hz, 1H), 2.30 (s, 1H), 2.50 (dd, J=14.0 Hz, 3J=
8.1 Hz, 1H), 2.68 (dd, J=14.0 Hz, J=7.8 Hz, 1H), 3.71 (dd,
J=11.7 Hz, J=6.8 Hz, 1H), 3.82 (td, J=12.2 Hz, J=
12.1 Hz, J=4.5 Hz, 1H), 4.03 (d, J=8.5 Hz, 1H), 4.08 (m,
1H), 5.09 (s, 1H), 7.31 (d, J=8.6 Hz, 2H), 8.14 (d, J=
8.7 Hz, 2H); 13C NMR (CDCl3, 125 MHz): d=31.3 (CH2),
34.8 (CH2), 36.2 (CH), 51.4 (CH), 59.0 (CH2), 70.7 (CH2),
102.0 (CH), 123.8 (CH), 129.6 (CH), 146.7 (Cquat), 147.1
(Cquat). EI MS (70 eV): m/z (%)=249 ([M]+, 7), 203
([MÀNO2)]+, 6), 186 (19), 158 (8), 156 (10), 149
([C8H7NO2]+, 15), 142 (16), 137 ([C7H5NO2]+, 15), 129 (43),
128 (51), 127 ([C7H11O2]+, 14), 119 (30), 116 (23), 115
([C6H11O2]+, 46), 107 (21), 103 (24), 102 (13), 91 (42), 90
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(KBr): n=3109 (m), 3081 (s), 2990 (m), 2957 (s), 2882 (s),
2451 (s), 2217 (w), 1942 (m), 1810 (m), 1721 (m), 1602 (s),
1508 (s), 1447 (m), 1385 (w), 1342 (s), 1283 (w), 1243 (s),
1229 (m), 1205 (m), 1188 (m), 1160 (m), 1094 (s), 1042 (s),
997 (s), 9245 (s), 857 (s), 832 (m), 818 (m), 781 (w), 746 (m),
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Acknowledgements
Financial support of the Deutsche Forschungsgemeinschaf
(SFB 623) and Fond der Chemischen Industrie is gratefully
acknowledged. We also cordially thank the BASF SE for the
generous donation of chemicals.
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