Experiments directed towards the synthesis of anthracyclinones. XXXIV hetero-diels-alder reactions using chiral boron and titanium reagents

Article abstract of DOI:10.1071/ch98181

Reactions between benzaldehyde or o-anisaldehyde and a series of silyloxy dienes catalysed by the chiral acyloxyborane (CAB) complex (4) give high yields of enantioselective products from a Mukaiyama aldol rather than a hetero-Diels-Alder reaction. Attempts to effect a similar catalytic reaction with anthraquinone aldehydes were unsuccessful but use of 2 equiv. of the CAB complex (1) followed by cyclization promotes a formal heteroDiels-Alder reaction between the aldehyde (7) and the diene (12) to give the dihydropyrone (24) in 45% yield and with a 79% e.e. in favour of the 2′R enantiomer. Hetero-Diels-Alder reactions between the aldehyde (7) and the diene (12) using the chiral titanium complexes Ti[(R)-BINOL]Cl₂, Ti[(R,R)-TADDOL]Cl₂ and Ti[(R)-BINOL]₂ have been investigated. The first two complexes promote the reaction at -30 and -78° respectively but with low induced enantioselectivities.

Full text of DOI:10.1071/ch98181

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Australian Journal
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Volume 52, 1999
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Aust. J. Chem., 1999, 52, 851–859
Experiments Directed Towards the
Synthesis of Anthracyclinones. XXXIV*
Hetero-Diels–Alder Reactions Using
Chiral Boron and Titanium Reagents
A
A
A,B
Mark D. Bercich, Richard C. Cambie and Peter S. Rutledge
A
Department of Chemistry, University of Auckland,
Private Bag 92019, Auckland, New Zealand.
B
Author to whom correspondence should be addressed.
Reactions between benzaldehyde or o-anisaldehyde and a series of silyloxy dienes catalysed by the chiral acyl-
oxyborane (CAB) complex (4) give high yields of enantioselective products from a Mukaiyama aldol rather than a
hetero-Diels–Alder reaction. Attempts to effect a similar catalytic reaction with anthraquinone aldehydes were
unsuccessful but use of 2 equiv. of the CAB complex (1) followed by cyclization promotes a formal hetero-
Diels–Alder reaction between the aldehyde (7) and the diene (12) to give the dihydropyrone (24) in 45% yield and
with a 79% e.e. in favour of the 2´R enantiomer.
Hetero-Diels–Alder reactions between the aldehyde (7) and the diene (12) using the chiral titanium complexes
Ti[(R)-BINOL]Cl
2
, Ti[(R,R)-TADDOL]Cl
2
and Ti[(R)-BINOL] have been investigated. The first two complexes
2
promote the reaction at –30 and –78° respectively but with low induced enantioselectivities.
Introduction
aldehyde (6), while a similar reaction employing (1) (2.5
equiv.) afforded the hydroxy ketone (13) (63%) with an
e.e. of 60% (Scheme 1). It was assumed that (13) arose from
a Mukaiyama aldol-like reaction and the failure to observe
any reaction with catalytic quantities of the CAB complex was
rationalized by assuming that coordination of the complex to
other basic sites of the anthraquinone molecule, such as the
oxygens of the quinone carbonyl and the peri methoxy
groups, was inhibiting the desired reaction between the C2
formyl group of (6) and the diene (9).
1
In the previous paper in this series we established that in
many respects Togni’s catalyst, (+)-bis[3-(heptafluoro-
2
butyryl)camphorato]vanadium(IV) [(+)-VO(hfc)
2
], was an
effective catalyst for hetero-Diels–Alder reactions between
several anthraquinone aldehydes and a variety of silyloxy
dienes. However, the enantioselectivities of these reactions
were smaller than those observed by Togni for simple alde-
hydes such as benzaldehyde. In a search for greater enan-
tioselectivities the potential of several members of the chiral
acyloxyborane (CAB) class of Lewis acids as catalysts for
hetero-Diels–Alder reactions has also been examined. In
addition, a brief investigation of the potential of three chiral
titanium Lewis acids as hetero-Diels–Alder catalysts has
been undertaken.
Subsequent to our initial investigations, Yamamoto
reported the successful catalysis of hetero-Diels–Alder reac-
tions between simple aldehydes and dienes using CAB com-
1
2,13
plexes.
Yamamoto’s procedure involved stirring a
solution of the aldehyde, an excess of a diene, and 10 mole
% of a CAB catalyst in propionitrile at –78 for 4–9 h, fol-
lowed by workup and treatment of the crude reaction product
with trifluoroacetic acid, with no attempt to isolate or char-
acterize the initial adducts. The enantioselectivity of a reac-
tion was dependent on both the aldehyde used and the nature
of the substituent on the CAB catalyst. The best results were
obtained with aromatic aldehydes, and with CAB complexes
such as (5) with bulky groups attached to boron which gen-
erally led to higher enantioselectivities, but the yield of a
product tended to decrease as the bulk of this group was
increased. The reactions all favoured formation of a dihy-
dropyrone with an R configuration at C2´, which was con-
Yamamoto has demonstrated the potential of tartrate-
derived chiral acyloxyboranes, such as (1)–(5), to serve as
highly efficient enantioselective catalysts for a variety of
3
–7
Lewis acid mediated processes including the Diels–Alder,
8
,9
10,11
Mukaiyama aldol,
Sakurai–Hosomi,
reactions. The potential of CAB catalysis for
a hetero-Diels–Alder reaction between the keto aldehyde (6)
and hetero-
1
2,13
Diels–Alder
1
4
and the diene (9) was recognized by us in 1992. In a brief
investigation, a solution of (6), (9), and the CAB (1) (0.1
equiv.) in dichloromethane was stirred at –78 for 18 h.
However, this resulted only in recovery (89%) of the keto
*
Part XXXIII, Aust. J. Chem., 1999, 52, 303.
Manuscript received 12 December 1998
© CSIRO 1999
10.1071/CH98181
0004-9425/99/090851

8
52
M. D. Bercich, R. C. Cambie and P. S. Rutledge
sistent with attack of the diene at the re face of the aldehyde
carbonyl group, and implied a shielding of the si face by the
catalyst. This observation was consistent with the enantio-
facial selectivities in CAB catalysed Diels–Alder, Mukaiyama
aldol, ene, and Sakurai–Hosomi reactions in which delivery
of the nucleophile to the re face of the electrophile was also
strongly favoured. To account for this re face selectivity,
Yamamoto proposed the transition state assembly shown in
Fig. 1. This model proposes coordination of the CAB catalyst
by the lone pair of electrons on the carbonyl oxygen that is
anti to the phenyl ring, and that -stacking of the aryl rings
of the catalyst and the substrate favours a transition state
where the si face of the aldehyde is strongly shielded by the
however, an alternative model for explaining the enantiofa-
cial selectivity of reactions mediated by chiral boron Lewis
1
5-17
acids has been proposed by Corey,
who notes that com-
plexes of formyl compounds with B–F or B–O containing
Lewis acids show a conformational preference for an
eclipsed geometry in which the formyl group and a B–F or
1
5
B–O bond are coplanar (Fig. 2). This preference, which
results from a novel type of hydrogen bond between the alde-
hydic proton and either an oxygen or fluorine atom on boron,
is supported by X-ray crystallographic studies of several
complexes of formyl compounds with boron Lewis acids.
1
6,17
Corey
has used his hypothesis to postulate that the
favoured mode of coordination of benzaldehyde to the (R,R)-
tartrate-derived CAB complexes (3)–(5) is that which allows
a bifurcated hydrogen bond between the aldehydic proton
2
,6-diisopropoxybenzoyl moiety, forcing the diene to attack
the less congested re face of the carbonyl group. Recently,
Scheme 1. CAB catalysed reaction of (6) and (9).

Synthesis of Anthracyclinones. XXXIV
853
and the oxygens corresponding to the carbonyl oxygen of the
C1 carboxy group and the C3 alcohol oxygen of the ligand
of (3)–(5) (Fig. 3a). This mode of coordination in combina-
tion with a favourable -stacking interaction between the
aromatic rings of benzaldehyde and the 2,6-diisopropoxy-
benzoyl moiety on the ligand results in strong shielding of
the si face of the benzaldehyde carbonyl group. Nucleophilic
attack at the less hindered re face of this carbonyl group is
therefore favoured by this arrangement. Corey argues that
the alternative mode of coordination of benzaldehyde to
Discussion
Chiral Acyloxyborane Complexes
Attempted hetero-Diels–Alder reactions of the keto alde-
hyde (6) and the diene (10) using the CAB catalyst (4) (0.5 or
1
3
1
equiv.) and following Yamamoto’s procedure were
unsuccessful, returning only the starting keto aldehyde (6)
after 24 h. Use of 2 equiv. of the CAB complex afforded the
hydroxy ketone (13) (10%) along with recovered (6) (82%).
The specific rotation of (13) was only –1.1 (cf. [ ] –41.5
D
1
4
equivalent to 60% e.e. for the earlier reaction ) indicating
that this reaction proceeded with a very small degree of enan-
tioselection.
(
3)–(5) (Fig. 3b), in which the -stacking interactions
between the 2,6-diisopropoxybenzoyl moiety of the ligand
and benzaldehyde would result in shielding of the re face of
the aldehyde carbonyl group, is somewhat less favoured as
this arrangement would allow only a single hydrogen bond
between the aldehydic proton and a somewhat less basic car-
boxylate oxygen.
Further investigations were made to determine if the
limited degree of reactivity, and the favouring of a
Mukaiyama aldol-like reaction pathway, were a consequence
of the structure of the anthraquinone aldehyde or of the
dienes (9) and (10) which lack a C1 alkoxy substituent, or
were due to a combination of these factors. Reaction of ben-
zaldehyde and the diene (10) with the CAB complex (4) (0.25
equiv.) in propionitrile at –78 for 7 h and then warming to
room temperature over 12 h afforded the triethylsilyl ether
(14) (34%) and the hydroxy ketone (15) (58%). Formation
of each of these products can be attributed to the operation of
a Mukaiyama aldol-like reaction pathway. Presumably,
transfer of the triethylsilyl group from the C2 oxygen of the
diene to the C1 oxygen of the aldehyde occurs via a six-
membered transition state (Scheme 2). The alcohol (15)
could arise either from loss of the triethylsilyl group from
(
14) or from a nucleophilic displacement of this group during
Fig. 1. Yamamoto’s proposed transition state assembly.
the Mukaiyama aldol reaction. However, the nature of the
nucleophile responsible for this displacement is not clear.
A high-resolution mass spectrum of the ether (14) con-
tained an ion at m/z 304.1856 consistent with the molecular
formula C18
1
H
28
O Si. The i.r. spectrum contained a band at
2
–
1
670 cm attributable to an
-unsaturated ketone car-
bonyl, but lacked any absorbance due to a hydroxy group.
1
The H n.m.r. spectrum contained a six-proton quartet at
Fig. 2. Corey’s formyl C---H---O hydrogen bond postulate.
0
.48 and a nine-proton triplet at 0.83 indicative of the pres-
ence of a triethylsilyl group, as well as a five-proton multi-
plet centred at 7.29 corresponding to the protons of the
aromatic ring. A spin system consisting of one-proton dou-
blets of doublets at 2.62 and 3.09 corresponding to the
diastereotopic methylene protons at C2, and a one-proton
doublet of doublets at 5.22 corresponding to the benzylic
proton at C1, along with a second spin system consisting of
Publication of Yamamoto’s results, which suggested that
CAB complexes bearing alkyl or aryl substituents directly
attached to boron are efficient catalysts for the hetero-
Diels–Alder reaction of simple aldehydes and dienes under
mild conditions, prompted our renewed investigations.
Fig. 3. Corey’s proposed CAB–aldehyde transition state assemblies.

8
54
M. D. Bercich, R. C. Cambie and P. S. Rutledge
a three-proton doublet of doublets at 1.87 corresponding to
the C6 methyl group, was only consistent with the triethylsi-
lyloxy group being located at C1 and the carbonyl group at
C3. A coupling constant of 15.8 Hz between the olefinic
protons indicated an E geometry for the double bond. The
lated any cycloadducts from his reported hetero-Diels–Alder
reactions it is possible that these also gave Mukaiyama aldol
products which were converted into the formal cycloaddition
products by treatment of the crude reaction mixtures with tri-
fluoroacetic acid.
In an attempt to decide between these two possibilities the
CAB catalysed reaction between benzaldehyde and the diene
(11) was investigated. This afforded the trimethylsilyl ether
(16) (13%) and the alcohol (17) (56%), the structures of
which were assigned by comparison with those of (14) and
(15). This result demonstrated that the reaction favoured a
Mukaiyama aldol-like reaction pathway rather than a peri-
cyclic pathway, and that the formation of the dihydropyrone
1
3
C n.m.r. spectrum contained the expected 12 resonances
and included signals at 4.7 and 6.6 corresponding to the
carbons of the triethylsilyl group, a signal at 198.1 corre-
sponding to the C3 ketone carbon, as well as resonances for
the aromatic carbons and the rest of the hex-4-en-3-one side
chain.
(
20) reported by Yamamoto from this reaction was formed as
a result of the acidic workup. This was verified when treat-
ment of each of the compounds (16) and (17) with trifluo-
roacetic acid afforded the dihydropyrone (20) in high
(
94–98%) yield. In each case the dihydropyrone had a spe-
cific rotation of –89 which, when compared with that of the
1
3
pure R enantiomer of (20) corresponded to a 74% e.e. in
favour of the R enantiomer and agreed well with the 75% e.e.
reported by Yamamoto for his overall reaction. The enan-
tiopurity of the alcohol (17) was also determined by using a
1
chiral solvating agent— H n.m.r. methodology similar to
that employed for measuring the enantiopurity of products
from hetero-Diels–Alder reactions of 1-methoxyan-
Scheme 2. Formation of (14) and (15) via a Mukaiyama aldol reac-
tion.
1
thraquinone aldehydes. However, in the case of (17) it was
the C5 methoxy protons that were observed to be
anisochronous in the presence of (S)-(+)-2,2,2-trifluoro-1-
(9-anthryl)ethanol (TFAE). A best separation (5.5 Hz) of the
resonances due to these protons was obtained in the presence
of 5 equiv. of (S)-(+)-TFAE, and integration of these signals
also revealed an enantiomeric excess of 74%. The sense of
the anisochrony created in the resonances of the C5 methoxy
group of (17) was opposite to that observed for the reso-
nances of the C5 methoxy groups of the anthraquinone
hetero-Diels–Alder adducts with the resonance of the major
R enantiomer being shifted downfield relative to that of the
minor S enantiomer.
A high-resolution mass spectrum for the alcohol (15) con-
tained a molecular ion at m/z 190.0993 consistent with the
molecular formula C12
H
14
O . The i.r. spectrum contained
2
–
1
strong bands at 3448 and 1654 cm commensurate with the
presence of alcohol and
-unsaturated ketone carbonyl
1
functions. The H n.m.r. spectrum contained a five-proton
multiplet centred at 7.30 corresponding to the protons of
the aromatic ring, and a broad one-proton singlet at 3.68
which exchanged with deuterium oxide, confirming the pres-
ence of a hydroxy group. The remaining signals in the spec-
trum were consistent with an (E)-1-hydroxy-hex-4-en-3-one
1
3
side chain on the aromatic ring. The C n.m.r. spectrum
contained the expected 10 resonances including one at
00.1 attributable to the C3 ketone carbon.
The acid-catalysed cyclizations of (16) and (17) to the
dihydropyrone (20) presumably occur via processes similar
1
8–20
2
to those outlined in Scheme 3.
Cleavage of the
The reaction between benzaldehyde and the diene (10)
was clearly catalysed by the CAB (4) as it gave a 92% com-
bined yield of (14) and (15), which indicated that for
complex aldehyde substrates, such as anthraquinones that
possess other Lewis-basic sites, it may be difficult to achieve
a catalytic reaction with CAB complexes. The specific rota-
tions of the products (14) and (15) were +64 and +60.7
respectively, indicating some degree of enantioselection. It
was also clear that CAB catalysed or promoted reactions
involving benzaldehyde or anthraquinone aldehydes and the
diene (10) favoured the initial formation of Mukaiyama aldol
products rather than the desired hetero-Diels–Alder
cycloadducts. In contrast to the dienes used by Yamamoto,
the diene (10) lacks a C1 alkoxy group and it was considered
that this structural difference may account for the difference
in reaction pathway. However, since Yamamoto never iso-
Scheme 3. A mechanism for the cyclization of (16) and (17).

Synthesis of Anthracyclinones. XXXIV
855
trimethylsilyl ether group of (16) would give the alcohol
workup indicated the formation of a multiplicity of products.
The dihydropyrone (22) had a specific rotation of –52.2
revealing that the reaction proceeded with some degree of
enantioselection. However, the lack of a methoxy group on
(
17), the enol ether group of which could undergo facile acid
cleavage to generate a hydroxy dicarbonyl compound. This
could then undergo an intramolecular cyclization to give a -
hydroxy ketone which, under the acidic conditions, would
readily eliminate water to give dihydropyrone (20). These
pathways would preserve the stereochemistry at C1 of (16)
and (17) generated via the asymmetric CAB catalysed
Mukaiyama aldol reaction.
1
(22) precluded use of the usual chiral solvating agent— H
n.m.r. protocols to establish the enantiopurity of this com-
2
pound. Togni has obtained the same dihydropyrone (22) in
18% e.e. in favour of the (R)-(–) enantiomer from the (+)-
VO(hfc) catalysed hetero-Diels–Alder reaction of benzalde-
2
The present results have important implications for the
use of CAB complexes as catalysts in the asymmetric synthe-
sis of olivose C-glycosides. As the CAB catalysed reaction
favours an initial Mukaiyama aldol pathway rather than a
pericyclic hetero-Diels–Alder route there is no cycloadduct
that can be elaborated via hydroboration in the manner of
Danishefsky to generate the olivose sugar. Furthermore,
the Mukaiyama aldol products from reactions involving
dienes such as (10), which lack a C1 oxygen, cannot be
readily cyclized to the corresponding dihydropyrone. This
limits the utility of CAB catalysts to reactions involving
dienes with both the C1 functionality necessary for cycliza-
tion to the dihydropyrone and a C1 methyl group required to
generate the olivose sugar.
hyde and (12) but did not report the magnitude of the specific
rotation. However, the observation of a negative sign of rota-
tion in both cases indicates that the CAB catalysed reaction
also favoured formation of the R enantiomer.
Reaction of o-anisaldehyde with the diene (12) was inves-
tigated to ascertain what effect the presence of an ortho
methoxy group would have on the yield and enantioselectiv-
ity of the reaction. The reaction, catalysed by 20 mole % of
the CAB complex (4) followed by acid workup, gave only
31% of the dihydropyrone (23) along with starting aldehyde
(54%). The specific rotation of (23) was +4 which corre-
2
1
1
sponded with a 7% e.e. for the reaction as determined by H
n.m.r. in the presence of (S)-(+)-TFAE. The reasons for
reduced reactivity and enantioselectivity in reactions involv-
ing o-anisaldehyde are not clear, but they may result from a
specific interaction between the o-methoxy group and the
catalyst in the activated complex, or may simply be the result
of increased steric congestion about the boron centre forcing
the CAB–aldehyde complex to adopt a conformation in which
the energy differential for attack of the diene at the prochiral
faces of the aldehyde is smaller.
Attempts were next made to establish why a catalytic
reaction with anthraquinone aldehydes could not be
achieved. It was considered that the methoxy group ortho to
the formyl group in the keto aldehyde (6) may interact
unfavourably with the CAB complex and prevent a catalytic
reaction, and thus it was of interest to determine if a CAB
catalysed reaction of o-anisaldehyde and the diene (11) could
be achieved. In the event, reaction afforded the trimethylsi-
lyl ether (18) (11%), the alcohol (19) (59%), and starting
aldehyde (21%). The combined yield (70%) of the two
Mukaiyama aldol products (18) and (19) showed that the
presence of an o-methoxy group in the anthraquinone (6)
may not be an important factor in preventing a CAB catalysed
reaction between the substrate and the diene (10).
Compounds (18) and (19) were each optically active and the
Attempts to achieve a CAB promoted reaction between the
anthraquinone aldehyde (7) and the diene (12) at 0 or room
temperature using the CAB complexes (1), (2), (3), or (4) were
largely unsuccessful, with all returning high yields of start-
ing material. A significant reaction was achieved only with
the least sterically demanding CAB complex (1) and only
when 2 equiv. of the complex were present. This reaction
1
afforded the dihydropyrone (24) (45%) with a 79% e.e. in
enantiopurity of the alcohol (19) was readily determined
favour of the R enantiomer. This result parallels that of the
reaction between the keto aldehyde (6) and diene (9) in the
presence of the same CAB complex (2.5 equiv.), which
afforded a 63% yield of the product (13) in 60% e.e. The
failure to observe any reaction between (7) and (12) when the
analogous CAB complex (3) (2.5 equiv.) was used indicates
that the extra steric bulk arising from replacement of the
methoxy groups of (1) with isopropoxy groups is sufficient
to inhibit reaction. This suggests that steric congestion about
the formyl group in the aldehyde–CAB complex may be one
of the factors responsible for the poor reactivity of
anthraquinone aldehydes. It is also possible that the confor-
mation of the anthraquinone aldehyde–CAB complexes
differs from that postulated for complexes between CABs and
simple aromatic aldehydes because of interactions between
Lewis basic sites on the anthraquinone molecule and sites on
the CAB such as the boron atom or the free carboxy group of
the ligand. The observation that 1.1 equiv. of the CAB (1) was
insufficient to promote any reaction indicates that reactions
were occurring between this CAB and the aldehyde (7) at sites
1
from a H n.m.r. spectrum in (D
6
)benzene in the presence of
(
R)-(–)-TFAE, the addition of which induced detectable
anisochrony in the signals of the C5 and C2 methoxy groups
which appeared in regions of the spectrum free from overlap
with other signals. However, integration revealed an enan-
tiomeric excess of only 5% in favour of the R enantiomer.
1
No useful anisochrony was observed in the H n.m.r. spectra
of the ether (18) in the presence of (R)-(–)-TFAE following the
sequential addition of up to 10 equivalents. Compounds (18)
and (19) each cyclized to the dihydropyrone (21) in high
yield (91–94%) when treated with trifluoroacetic acid. The
specific rotations of the dihydropyrone (21) derived from the
alcohol (19) and the trimethylsilyl ether (18) were –3.8 and
–
3.5 respectively, indicating that, within the limits of error,
(
18) and (19) were of similar enantiopurity.
Reaction of benzaldehyde with the diene (12) and 20 mole
of the CAB complex (4) followed by acid workup gave the
%
dihydropyrone (22) (62%). No attempt was made to isolate
the aldol products of this reaction since t.l.c. prior to acid

8
56
M. D. Bercich, R. C. Cambie and P. S. Rutledge
other than the formyl group. It could also be expected that
interactions between the aromatic ring of the CAB ligand
strated that Ti[(R)-BINOL]Cl promoted a formal hetero-
2
–
Diels–Alder reaction between (7) and (12) the combination
of slow reaction rates at low temperatures and poor enan-
tioselectivity indicated that the development of a syntheti-
cally useful catalytic reaction was unlikely.
and the relatively electron-deficient aromatic rings of the
anthraquinone would differ significantly in strength from the
equivalent interactions proposed by Yamamoto and Corey
for benzaldehyde–CAB complexes.
The complex Ti[(R,R)-TADDOL]Cl (1.2 equiv.), prepared
2
2
6
Reaction of the anthracene aldehyde (26) with the diene
12) in the presence of the CAB complex (4) was investigated
from (R,R)-TADDOL (29), also promoted the reaction
between (7) and an excess of (12). Reactions employing this
complex proceeded more readily at low temperature (–30 or
–78 for c. 24 h) with the same facial selectivity but with
lower enantioselectivities (17–20%) than the analogous
(
in the hope that using a more electron-rich aldehyde, in
which the quinone carbonyls had been masked as their
methyl ethers, would result in greater reactivity than with the
equivalent aldehyde (7). However, no reaction was observed
with either 0.5 or 2.5 equiv. of the CAB complex (4) at 0 in
propionitrile for 19 h.
reactions with Ti[(R)-BINOL]Cl
2
. Like most Ti[BINOL]Cl
catalysed reactions the enantioselectivity of Ti[TADDOL]Cl
2
2
4
2
reactions increased (28%) when the reaction was carried out
in the absence of 4 Å molecular sieves used in the prepara-
tion of the complex. Reaction of the phenolic anthraquinone
aldehyde (8) and the diene (12) in the presence of Ti[(R,R)-
Chiral Titanium Complexes
The use of chiral titanium complexes to catalyse or
promote hetero-Diels–Alder reactions between aldehydes
and silyloxy dienes has received little attention, despite the
TADDOL]Cl was also attempted since it was envisaged that
2
chelation of the titanium complex by the formyl group and
2
2,23
pioneering work of Danishefsky,
which showed that
the ortho phenolic oxygen of (8) might alter both the enan-
tioselectivity and facial selectivity of the hetero-Diels–Alder
reaction. In the event, reaction with Ti[(R,R)-TADDOL]Cl
(2 equiv.) in the absence of molecular sieves at –78 for 24 h
followed by addition of trifluoroacetic acid afforded the
dihydropyrone (25) (82%). The specific rotation of (25) was
–26.7 , and in order to assess the degree of enantioselectiv-
ity the phenolic group of (25) was methylated to give the
dihydropyrone (24) (95%). The specific rotation of (24) was
–3.8 which is opposite in sign to that observed previously
for this compound resulting from the Ti[(R,R)-TADDOL]Cl
promoted reaction of the dimethoxy aldehyde (7) and the
diene (12). Confirmation of this reversal of enantiofacial
selectivity was provided by a reversal in the sense of
simple titanium Lewis acids such as titanium(IV) chloride
are efficient catalysts of such reactions. Two reports have
appeared which suggest that chiral titanium(IV) complexes
have potential for the catalysis of enantioselective hetero-
2
2
4
Diels–Alder reactions. Mikami has demonstrated that 10
mole % of the complex Ti[(R)-BINOL]Cl , derived from the
2
reaction of (R)-BINOL (27) (1 equiv.) and bis(chloro)bis(iso-
propoxy)titanium(IV), catalyses the reaction between methyl
1
2
3
glyoxylate and dienes of the type (28) (R ,R ,R = H or OMe)
in dichloromethane at –30 to afford predominantly the cis
cycloadducts indicative of the operation of an endo-selective
pericyclic reaction. The enantioselectivities were typically
greater than 90%, and reaction favoured formation of
adducts having a 2´R configuration. Recently, Keck has
reported that 10% of a complex derived from titanium(IV)
tetraisopropoxide and BINOL (2 equiv.) catalyses the reaction
between a variety of aldehydes and the diene (11) in
2
1
anisochrony observed in the H n.m.r. spectrum of this
sample of (24) in the presence of (S)-(+)-TFAE. The enantio-
facial selectivity of the formal hetero-Diels–Alder reaction
was only 15% in favour of (S)-(25). The change in enantio-
facial selectivity from attack of the diene at the re face of the
aldehyde (7) to one of attack at the si face is considered to
2
5
dichloromethane at –20 . The degree of enantioselection
was dependent on the nature of the aldehyde although the
reaction with benzaldehyde proceeded with lower enantio-
selectivity than reactions employing aliphatic aldehydes.
Keck assumed, on the basis of previous studies which
showed that this complex catalyses Mukaiyama aldol reac-
tions, that these formal hetero-Diels–Alder reactions
involved an aldol reaction followed by an acid-catalysed
cyclization.
result from chelation of the Ti[(R,R)-TADDOL]Cl to the phe-
2
nolic and C2 formyl groups of (8).
Finally, several attempts were made to achieve a reaction
between (7) and (12) by using the Ti[(R)-BINOL] complex of
2
2
5
Keck, but use of 0.5, 1.2, and 2 equiv. of this complex
returned only the starting aldehyde.
Experimental
In the present study reaction of the aldehyde (7) with an
For general experimental details see ref. 27.
excess of the diene (12) and Ti[(R)-BINOL]Cl (1.5 equiv.) at
2
–
30 for 40 h followed by addition of trifluoroacetic acid
CAB Promoted Reaction of 2-Formyl-1,5-dimethoxy-6-(2 -
oxopropyl)anthraquinone (6) and 2-[(Triethylsilyl)oxy]penta-1,3-
diene (10)
afforded the dihydropyrone (24) (68%) along with starting
aldehyde (20%). The specific rotation of (24) was +6.4
which corresponded to an enantiomeric excess of 26% in
A solution of the keto aldehyde (6) (25 mg, 0.07 mmol) in propioni-
1
favour of the R enantiomer based on the use of H n.m.r.
trile (4 ml) was added to a stirred solution of mono(2,6-diisopropoxy-
1
3
benzoyl)tartaric acid [CAB (4)] (58 mg, 0.16 mmol) and phenylboronic
acid (19 mg, 0.07 mmol) in propionitrile (2 ml) under nitrogen, at room
temperature. The mixture was stirred for 10 min, the diene (10) (31 mg,
spectroscopy in the presence of (S)-(+)-TFAE. A similar
sequence using the titanium complex (1 equiv.) at –78 for
2
4 h and then at room temperature for 24 h gave only 28% of
0
.16 mmol) was added and the mixture was stirred at room temperature
the dihydropyrone (24) with an e.e. of 31%, along with start-
ing aldehyde (69%). While these two reactions demon-
for 24 h, poured into saturated aqueous sodium hydrogencarbonate
(20 ml), and extracted with CH Cl . The extracts were washed with sat-
2
2

Synthesis of Anthracyclinones. XXXIV
857
urated aqueous sodium hydrogencarbonate, and water, dried, and the
solvent was removed under reduced pressure. P.l.c. of the residue gave
starting material (20 mg, 82%) and (E)-1-[1 ,5 -dimethoxy-6 -(2 -oxo-
propyl)anthraquinon-2 -yl]-1-hydroxy-hex-4-en-3-one (13) (3 mg,
water, dried, and concentrated under reduced pressure to give an oil,
p.l.c. (hexanes/ether, 2:1) of which gave the following. (i) (E)-5-
Methoxy-1-phenyl-1-[(trimethylsilyl)oxy]pent-4-en-3-one (16) (17 mg,
+
13%) was obtained as a colourless oil (Found: M , 278.4420.
+
1
0%) as an orange solid, m.p. 152–154 , [ ]
D
–1.1 (c, 0.29 in CHCl
3
)
C
15
H
22
O
3
Si requires M , 278.4425). max (neat) 2957, 1684 (CO),
+
+
–1
(
(
(
Found M , 436.1511. C25
H
42
O
7
requires M , 436.1522). max 236
1621, 1595, 1251, 1086, 948, 843, 701 cm .
H
0.01, s, 9H, (CH ) Si;
3
3
log 4.88), 261 (4.97), 345 (4.73). max 3448br (OH), 2925, 1718
2.60, dd, J2a,2b 14.5, J2a,1 3.9 Hz, H2a; 2.96, dd, J2b,2a 14.5, J2b,1 8.8 Hz,
H2b; 3.68, s, 5-OCH ; 5.20, dd, J1,2b 8.8, J1,2a 3.9 Hz, H1; 5.89, d, J4,5
12.7 Hz, H4; 7.20–7.39, m, 5H, H2 ,3 ,4 ; 7.58, d, J5,4 12.7 Hz, H5.
–
1
CO), 1670 (quinone CO), 1384, 1260, 1076 cm .
H
1.91, dd, J6,5 6.9,
3
J
3
3
6,4 1.6 Hz, H6; 2.29, s, H3 ; 2.75, dd, J2a,2b 17.6, J2a,1 9.4 Hz, H2a;
C
.24, dd, J2b,2a 17.6, J2b,1 2.3 Hz, H2b; 3.26, d, J1a ,1b 16.5 Hz, H1a ;
–0.01, (CH
3
)
3
Si; 52.0, C2; 57.4, 5-OCH ; 71.8, C1; 106.9, C 4; 125.6,
3
.32, d, J1b ,1a 16.5 Hz, H1b ; 3.67, s, 1 -OCH
3
; 3.70, s, 5 -OCH
3
; 5.53,
C2 or C3 ; 127.2, C4 ; 128.2, C2 or C3 ; 144.6, C1 ; 163.4, C5;
197.6, C3. m/z 278 (M, 12%), 206 (10), 188 (15), 179 (34), 173 (10),
157 (33), 142 (16), 120 (25), 105 (30), 100 (28), 85 (100). (ii) (E)-1-
unresolved dd, J1,2a 9.4 Hz, H1; 6.16, dd, J4,5 15.8, J4,6 1.6 Hz, H4; 6.91,
dq, J5,4 15.8, J5,6 5.9 Hz, H5; 7.56, d, J7 ,8 7.9 Hz, H7 ; 8.03, d, J3 ,4
8
4
.1 Hz, H 3 ; 8.06, d, J8 ,7 7.9 Hz, H8 ; 8.12, d, J4 ,3 8.1 Hz, H4 . m/z
Hydroxy-5-methoxy-1-phenylpent-4-en-3-one (17) (55 mg, 56%) was
+
36 (M), 418 (M–H
2
O), 352, 310, 295, 267, 165, 69, 43.
obtained as a colourless oil, [ ]
D
+56 (c, 4.11 in CH
2
Cl
2
) (Found: M ,
+
A similar reaction using CH
2
Cl
2
instead of propionitrile as solvent
206.0945. C12
1669 (CO), 1653, 1457, 1073, 1001, 996, 970, 811, 741 cm .
2.83–2.87, m, 2H, H2; 3.69, s, 5-OCH ; 3.84, br s, 1-OH; 5.17, dd, J1,2 b
7.1, J1,2 a 5.2 Hz, H1; 5.58, d, J4,5 12.7 Hz, H4; 7.24–7.39, m, 5H,
H
14
O requires M , 206.0943). max (neat) 3451, 2951,
3
-1
returned starting material (98%).
H
1
4
In an earlier (1992) experiment the keto aldehyde (6) (20 mg, 0.06
3
mmol) in CH
added to a stirred solution of diborane (0.16 mmol) in tetrahydrofuran
1 ml) and the tartrate precursor of the CAB (1) (50 mg, 0.15 mmol) in
CH Cl (1 ml) under argon at –78 . The mixture was stirred for 18 h
and worked up as above to give (6) (2 mg, 12%) and (13) (17 mg, 63%),
–41.5 (c, 0.05 in CHCl ).
2
Cl
2
(1 ml) and the diene (9) (39 mg, 0.25 mmol) were
H2 ,3 ,4 ; 7.60, d, J5,4 12.7 Hz, H5.
C
48.9, C2; 57.6, 5-OCH ; 70.1,
3
(
C1; 105.8, C 4; 125.6, C2 or C3 ; 127.4, C4 ; 128.4, C2 or C3 ; 143.0,
C1 ; 163.7, C5; 199.3, C3. m/z 206 (M, 8%), 174 (10), 120 (26), 105
(28), 100 (12), 87 (10), 85 (100).
2
2
[
]
D
3
Cyclization of (E)-5-Methoxy-1-phenyl-1-[(trimethylsilyl)oxy]pent-4-
CAB Catalysed Reaction of Benzaldehyde and
en-3-one (16)
2
-[(Triethylsilyl)oxy]penta-1,3-diene (10)
Benzaldehyde (50 mg, 0.47 mmol) followed by the diene (10)
Trifluoroacetic acid (2 drops) was added to a stirred solution of the
2
1
pentenone (16) (15 mg, 0.06 mmol) in CH
2
Cl (2 ml) at 0 and the
2
(
0.19 g, 0.94 mmol) were added to a cooled (–78 ) solution of the tar-
mixture was stirred at 0 for 30 min, diluted with CH
2
Cl (10 ml), and
2
trate precursor of the CAB (4) (44 mg, 0.2 mmol) and phenylboronic acid
14 mg, 0.12 mmol) in dry, freshly distilled propionitrile (1 ml) which
poured into saturated aqueous sodium hydrogencarbonate (20 ml). The
organic layer was washed with water, dried, and the solvent was
removed under reduced pressure. P.l.c. (hexanes/ether, 9:1) of the
(
had been stirred at room temperature for 1 h. The mixture was stirred
for 7 h, warmed to room temperature, stirred for a further 12 h, and then
poured into saturated aqueous sodium hydrogencarbonate (10 ml). The
mixture was extracted with ether and the solvent was removed from the
dried extracts under reduced pressure to give a colourless oil, p.l.c.
resulting oil gave 2-phenyl-2,3-dihydro-4H-pyran-4-one (20) (9 mg,
1
94%) as a colourless oil, [ ]
D
–89 (c, 0.82 in CHCl
3
) (correct H n.m.r.
2
spectrum).
Cyclization of (E)-1-Hydroxy-5-methoxy-1-phenylpent-4-en-3-one (17)
(
hexanes/ether, 2:1) of which gave the following. (i) (E)-1-Phenyl-1-
[
(triethylsilyl)oxy]hex-4-en-3-one (14) (48 mg, 34%) was obtained as a
Trifluoroacetic acid (2 drops) was added to a solution of the pentenone
+
colourless oil, [ ]
D
+64 (c, 4.25 in CHCl
3
) (Found: M , 304.1856.
(17) (24 mg, 0.12 mmol) in CH
2
Cl (2 ml) at 0 and the mixture was stirred
2
+
C
18
H
28
O
2
Si requires M , 304.1859). max (neat) 2954, 2876, 1670
at 0 for 30 min, diluted with CH
2
Cl (10 ml), and poured into saturated
2
–
1
(
CO), 1631, 1454, 1070, 1006, 970, 802, 744, 700 cm .
J 7.6 Hz, (MeCH ; 0.83, t, 9H, J 7.6 Hz, (CH CH )Si; 1.87, dd, J6,5
.8, J6,4 1.3 Hz, H6; 2.62, dd, J2a,2b 14.9, J2a,1 4.2 Hz, H2a; 3.09, dd,
2b,2a 14.9, J2b,1 8.5 Hz, H2b; 5.22, dd, J1,2 b 8.5, J1,2 a 4.2 Hz, H1; 6.11,
H
0.48, q, 6H,
aqueous sodium hydrogencarbonate (20 ml). The organic layer was
washed with water, dried, and the solvent was removed under reduced
pressure to give an oil, p.l.c. (hexanes/ether, 1:1) of which yielded 2-
phenyl-2,3-dihydro-4H-pyran-4-one (20) (20 mg, 98%) as a colourless oil,
2
)
3
3
2
6
J
1
2
dq, J4,5 15.8, J4,6 1.3 Hz, H4; 6.81, dq, J5,4 15.8, J5,6 6.8 Hz, H5;
[ ]
D
3
–89 (c, 1.27 in CHCl ) (expected H n.m.r. spectrum).
7
.20–7.37, m, 5H, H2 ,3 ,4 .
C
4.65, (MeCH
2
)
3
; 6.63, (CH
3
CH ) Si;
2
3
CAB Catalysed Reaction of o-Anisaldehyde with 1-Methoxy-3-
1
8.2, C6; 50.8, C2; 71.7, C1; 125.7, C2 or C3 ; 127.2, C4 ; 128.2, C2
[(trimethylsilyl)oxy]buta-1,3-diene (11)
or C 3 ; 124.0, C4; 143.4, C5; 145.3, C1 ; 198.1, C3. m/z 304 (M, 1%),
2
75 (65), 221 (10), 169 (100), 103 (18), 75 (26). (ii) (E)-1-Hydroxy-1-
A solution of o-anisaldehyde (50 mg, 0.37 mmol) in propionitrile
phenylhex-4-en-3-one (15) (52 mg, 58%) was obtained as a colourless
(1 ml) followed by the diene (11) (0.19 g, 1.10 mmol) were added to a
cooled (–78 ) solution of the tartrate precursor of the CAB (4) (27 mg,
0.07 mmol) and phenylboronic acid (9 mg, 0.07 mmol) in dry, freshly
distilled, propionitrile (1 ml) which had been stirred under argon for 1 h.
The mixture was stirred at –78 for 17 h, poured into saturated aqueous
sodium hydrogencarbonate (10 ml) and extracted with ether. The
extracts were dried and concentrated under reduced pressure to give an
oil, p.l.c. (hexanes/ether, 1:1) of which afforded the following. (i) o-
Anisaldehyde (10 mg, 21%). (ii) (E)-5-Methoxy-1-(2 -methoxyphenyl)-
+
oil, [ ]
D
+60.7 (c, 4.34 in CHCl
3
) (Found: M , 190.0993. C12
H
14
O
2
+
requires M , 190.0994). max (neat) 3448 (OH), 1654 (CO), 1628,
–
1
1
441, 1056, 969, 756, 701, 548 cm .
H
1.89, dd, J6,5 6.8, J6,4 1.6 Hz,
H6; 2.90–2.94, m, 2H, H2; 3.68, br s, 1-OH; 5.17, t, J1,2 5.9 Hz, H1;
6
.11, dq, J4,5 15.8, J4,6 1.6 Hz, H4; 6.86, dq, J5,4 15.8, J5,6 6.8 Hz, H5;
7
.21–7.38, m, 5H, H2 ,3 ,4 .
C
18.3, C6; 48.0, C2; 69.9, C1; 125.6,
C2 or 3 ; 127.4, C4 ; 128.4, C2 or C3 ; 132.0, C4; 143.0, C1 ; 144.4,
C5; 200.1, C3. m/z 190 (M, 10%), 171 (10), 162 (12), 120 (18), 105
(100), 84 (22), 77 (52), 69 (80).
1-[(trimethylsilyl)oxy]pent-4-en-3-one (18) (11 mg, 11%) was obtained
+
as a colourless oil, [ ]
D
–5.8 (c, 0.97 in CH
2
Cl
2
) (Found: M ,
CAB Catalysed Reaction of Benzaldehyde and 1-Methoxy-3-
+
3
08.1448. C16
CO), 1622, 1598, 1490, 1464, 1248, 1085, 843, 756 cm .
9H, (CH) Si; 2.73–2.76, m, 2H, H2; 3.70, s, 5-OCH ; 3.84, s, 2 -OCH ;
H
24
O Si requires M , 308.1444). max (neat) 2957, 1685
4
[(trimethylsilyl)oxy]buta-1,3-diene (11)
–1
(
H
0.01, s,
Benzaldehyde (50 mg, 0.47 mmol) and then the diene (11) (0.24 g,
3
3
3
1
.41 mmol) were added to a cooled (–78 ) solution of the tartrate pre-
5.54, t, J5 ,4 6.1 Hz, H5 ; 5.62, d, J4,5 12.8 Hz, H4; 6.83, dd, J6 ,5 8.2,
cursor of the CAB (4) (35 mg, 0.09 mmol) and phenylboronic acid
12 mg, 0.09 mmol) in dry, freshly distilled propionitrile (1 ml) which
had been stirred at 0 under argon for 1 h. The mixture was stirred at
78 for 19 h, poured into saturated aqueous sodium hydrogencarbon-
ate (10 ml), and extracted with ether. The extracts were washed with
J
J
6 ,4 1.1 Hz, H 6 ; 6.96, ddd, J4 ,3 = J4 ,5 7.5, J4 ,6 1.1 Hz, H4 ; 7.22, ddd,
5 ,6 8.2, J5 ,4 7.5, J5 ,3 1.8 Hz, H5 ; 7.49, dd, J3 ,4 7.5, J3 ,5 1.8 Hz, H3 ;
(
7.62, d, J5,4 12.8 Hz, H5.
C
–0.07, (CH
3
)
3
Si; 50.0, C2; 55.2, 2 -OCH ;
3
–
57.3, 5-OCH
3
; 66.3, C1; 106.9, C4; 109.9, C3 ; 120.5, C5 ; 126.5, C4 ;
127.9, C6 ; 132.9, C1 ; 155.2, C2 ; 163.1, C5; 197.8, C3. m/z 308 (M,

8
2
58
M. D. Bercich, R. C. Cambie and P. S. Rutledge
0%), 209 (100), 187 (45), 157 (33), 142 (14), 135 (28), 119 (10), 100
stirred at room temperature for 30 min, extracted with ether, and the
extracts were washed with saturated aqueous sodium hydrogencarbon-
ate, water, and brine. Solvent was removed from the dried solution
under reduced pressure, and p.l.c. (hexanes/ether, 2:1) of the residue
gave o-anisaldehyde (27 mg, 54%) and 2-(2 -methoxyphenyl)-6-
(
16). (iii) (E)-1-Hydroxy-5-methoxy-1-(2 -methoxyphenyl)pent-4-en-3-
one (19) (51 mg, 59%) was obtained as a colourless oil, [ ]
D
–6.0 (c,
+
+
3
2
1
.14 in CH
2
Cl
2
) (Found: M , 236.1043.
C
13
H
16
O
4
requires M ,
36.1049). max (neat) 3444 (OH), 2939, 1674 (CO), 1620, 1589, 1492,
–1
241, 1049, 757 cm .
H
2.74, dd, J2a,2b 16.5, J2a,1 9.1 Hz, H2a; 2.98,
; 3.82, s, 2 -OCH ; 5.44,
methyl-2,3-dihydro-4H-pyran-4-one (23) (25 mg, 31%) as a colourless
+
dd, J2b,2a 16.5, J2b,1 3.0 Hz, H2b; 3.69, s, 5-OCH
3
3
oil, [ ]
D
+4 (c, 1.97 in CH
2
Cl
2
) (Found: M , 218.0943. C13
H
14
O
3
+
dd, J1,2a 9.1, J1,2b 3.0 Hz, H1; 5.58, d, J4,5 12.7 Hz, H4; 6.85 dd, J6 ,5 8.2,
requires M , 218.0943). max 1667 (CO), 1612, 1495, 1396, 1247,
–
1
J
6 ,4 1.0 Hz, H6 ; 6.97, ddd, J4 ,3 = J4 ,5 7.5, J4 ,6 1.0 Hz, H4 ; 7.23, ddd,
5 ,6 8.2, J5 ,4 7.5, J5 ,3 1.7 Hz, H5 ; 7.48, dd, J3 ,4 7.5, J3 ,5 1.8 Hz, H 3 ;
1027, 1006, 953, 766 cm .
2H, H3ax,3eq; 3.83, s, 2 -OCH
H
(CDCl
3
) 2.08, s, 6-CH ; 2.62–2.67, m,
3
J
3
; 5.43, s, H5; 5.76, dd, J2,3ax 10.0, J2,3eq
7
6
1
.61, d, J5,4 12.7 Hz, H5.
C
47.3, C2; 55.2, 2 -OCH
3
; 57.5, 1-OCH
3
;
7.7 Hz, H2; 6.91, dd, J6 ,4 8.2, J6 ,4 0.7 Hz, H6 ; 7.02, ddd, J4 ,5 8.1, J4 ,3
7.6, J4 ,6 0.7 Hz, H4 ; 7.33, ddd, J5 ,6 8.2, J5 ,4 8.1, J5 ,3 1.5 Hz, H5 ;
5.7, C1; 106.1, C4; 110.1, C3 ; 120.8, C5 ; 126.4, C4 ; 128.2, C6 ;
31.2, C1 ; 155.7, C2 ; 163.5, C5; 199.8, C3. m/z 236 (M, 12%), 187
7.50, dd, J3 ,4 7.6, J3 ,5 1.5 Hz, H 3 .
H
(C
6
D
6
) 1.48, s, 6-CH ; 2.51, dd,
3
(
22), 150 (20), 135 (49), 119 (16), 107 (22), 100 (24), 85 (100).
J
3ax,3eq 16.6, J2,3ax 14.1 Hz, H3ax; 2.70, dd, J3eq,3ax 16.6, J2,3eq 3.4 Hz,
H3eq; 3.09, s, 2 -OCH
3
; 5.36, s, H5; 5.72, dd, J2,3ax 14.1, J2,3eq 3.4 Hz,
Cyclization of (E)-5-Methoxy-1-(2 -methoxyphenyl)-1-
H2; 6.40, dd, J 8.2, J 0.9 Hz, H6 ; 6.85, ddd, J 8.1, J 7.5,
6
,5
6 ,4
4 ,5
4 ,3
[(trimethylsilyl)oxy]pent-4-en-3-one (18)
J
0.9 Hz, H4 ; 7.04, ddd, J 8.2, J 8.1, J 1.7 Hz, H5 ; 7.37,
4
,6
5 ,6
5 ,4
5 ,3
Trifluoroacetic acid (2 drops) was added to a stirred solution of the
dd, J3 ,4 7.5, J3 ,5 1.7 Hz, H3 .
C
21.1, 6-CH
3
; 41.3, C3; 55.3, 2 -OCH ;
3
pentenone (18) (9 mg, 0.03 mmol) in CH
2
Cl
2
(1 ml) at 0 and the
76.0, C2; 105.0, C5; 110.5, C3 ; 120.7, C5 ; 126.3, C4 ; 126.9, C2 ;
129.5, C6 ; 155.8, C1 ; 174.8, C6; 193.2, C4. m/z 218 (M, 20%), 200
(12), 187 (10), 175 (38), 134 (78), 119 (100), 91 (70), 77 (14).
mixture was stirred for 30 min, diluted with CH
2
Cl (10 ml), and poured
2
into saturated aqueous sodium hydrogencarbonate (20 ml). The organic
layer was washed with water, and concentrated under reduced pressure
to give an oil, p.l.c. (hexanes/ether, 1:1) of which afforded 2-(2 -
CAB Promoted Reaction of 2-Formyl-1,5-dimethoxyanthraquinone (7)
and 2,4-Bis[(trimethylsilyl)oxy]penta-1,3-diene (12)
methoxyphenyl)-2,3-dihydro-4H-pyran-4-one (21) (5 mg, 91%) as a
+
–1
colourless oil, [ ]
D
–3.5 (c, 0.51 in CH
2
Cl
2
) (Found: M , 204.0783.
Borane–tetrahydrofuran complex (0.10 ml, 1 mol l solution in
+
C
12
H
12
O
3
requires M , 204.0786). max 1664 (CO), 1609, 1498, 1393,
tetrahydrofuran) was added to a stirred suspension of the tartrate pre-
cursor of the CAB (1) (32 mg, 0.10 mmol) in CH Cl (1 ml) under argon
–
1
1
247, 1031, 1005, 944, 756 cm .
H
2.72–2.76, m, 2H, H2ax,2eq;
2
2
3
.84, s, 2 -OCH ; 5.51, d, J5,6 6.5 Hz, H5; 5.80, dd, J2,3ax 10.7, J2,3eq 7.1
3
at room temperature and the mixture was stirred for 1 h, cooled to –30 ,
and treated with a solution of the aldehyde (7) (15 mg, 0.06 mmol) in
CH Cl (2 ml) and the diene (12) (37 mg, 0.15 mmol). Stirring was con-
Hz, H2; 6.91, dd, J6 ,5 8.1, J6 ,4 1.0 Hz, H6 ; 7.02, ddd, J4 ,5 8.2, J4 ,3 7.6,
J
4 ,6 1.0 Hz, H4 ; 7.34, ddd, J5 ,4 8.2, J5 ,6 8.1, J5 ,3 1.7 Hz, H5 ; 7.48,
dd, J3 ,4 7.6, J3 ,5 1.5 Hz, H3 ; 7.51, d, J6,5 6.5 Hz, H6. 42.3, C3;
5.3, 2 -OCH ; 76.4, C2; 107.2, C5; 110.5, C3 ; 120.8, C5 ; 126.3,
C4 ; 126.5, C2 ; 129.6, C6 ; 155.8, C1 ; 163.5, C6; 192.9, C 4. m/z 204
M, 44%), 175 (12), 134 (100), 119 (99), 91 (98), 77 (18).
2
2
C
tinued for 24 h, trifluoroacetic acid (2 drops) was added, and the
mixture was warmed slowly to room temperature. The mixture was
stirred for 10 min, poured into saturated aqueous sodium hydrogencar-
bonate (20 ml), and the organic layer was washed with saturated
aqueous sodium hydrogencarbonate, water, and dried. Solvent was
5
3
(
Cyclization of (E)-1-Hydroxy-5-methoxy-1-(2 -methoxyphenyl)pent-4-
removed under reduced pressure to give a solid, p.l.c. (CH
2
Cl /ether) of
2
en-3-one (19)
which gave starting aldehyde (7) (6 mg, 37%) and 1,5-dimethoxy-2-(6 -
Trifluoroacetic acid (2 drops) was added to a stirred solution of the
methyl-4 -oxo-2´,3´-dihydro-4´H-pyran-2 -yl)anthraquinone (24) (9
pentenone (19) (23 mg, 0.1 mmol) in CH
2
Cl
2
(1 ml) at 0 , and the
mg, 45%) as a yellow solid, [ ]
D
+18 (c, 0.36 in CH
2
Cl ) (expected
2
1
1
mixture was stirred for 30 min at 0 , diluted with CH
2
Cl
2
(10 ml), and
t.l.c. behaviour and H n.m.r. spectrum).
poured into saturated aqueous sodium hydrogencarbonate (20 ml). The
organic layer was washed with water, dried, and the solvent was
removed under reduced pressure. P.l.c. (hexanes/ether, 1: 1) of the
Similar reactions at room temperature or 0 returned starting mate-
rial. An attempted reaction using phenylboronic acid instead of
borane–tetrahydrofuran complex at room temperature also returned
starting material (94%).
residue afforded the dihydropyrone (21) (19 mg, 94%) as a colourless
1
oil, [ ]
D
–3.8 (c, 1.03 in CH
2
Cl
2
) (correct H n.m.r. spectrum).
Ti[(R)-BINOL]Cl Promoted Reactions of 2-Formyl-1,5-dimethoxy-
2
CAB Catalysed Reaction of Benzaldehyde and
anthraquinone (7) and 2,4-Bis[(trimethylsilyl)oxy]penta-
2
,4-Bis[(trimethylsilyl)oxy]penta-1,3-diene (12)1
1,3-diene (12)
Benzaldehyde (75 mg, 0.71 mmol) and the diene (12) (0.26 g, 1.06
A solution of the aldehyde (7) (10 mg, 0.03 mmol) in CH Cl (2 ml)
2
2
mmol) were added to a solution of the tartrate precursor of the CAB (4)
was added to a mixture of (R)-(+)-BINOL (27) (15 mg, 0.05 mmol),
(
52 mg, 0.14 mmol) and phenylboronic acid (17 mg, 0.14 mmol) in pro-
Ti(O
crushed activated 4 Å molecular sieves (0.25 g), and CH Cl (1 ml)
i
Pr) Cl (61 l of a 0.83 mol l–1 solution in toluene, 0.05 mmol),
2
2
pionitrile (1 ml) which had been stirred at 0 , under argon, for 30 min
and then cooled to –78 . The mixture was stirred at –78 for 24 h,
poured into 20% aqueous hydrochloric acid, stirred at room tempera-
ture for 30 min, and then extracted with ether. The extracts were
washed with water, dried, and the solvent was removed under reduced
pressure. P.l.c. (hexanes/ether, 2:1) of the residue afforded 6-methyl-
2
2
which had been stirred under argon for 2 h. The mixture was cooled
to –30 , stirred for 10 min, the diene (12) (25 mg, 0.10 mmol) was
added, and the mixture was stirred for a further 40 h. Trifluoroacetic
acid (2 drops) was added and the mixture was warmed to room temper-
ature, stirred for 30 min, and then poured into saturated aqueous sodium
hydrogencarbonate (10 ml). The organic layer was washed with water,
dried, and the solvent was removed under reduced pressure. P.l.c.
2
-phenyl-2,3-dihydro-4H-pyran-4-one (22) (83 mg, 62%) as a colour-
1
2
less oil, [ ]
D
–52.2 (c, 3.67 in CH
2
Cl
2
) (correct H n.m.r. spectrum).
(
CH
2
Cl
2
/ether, 49:1) of the residue gave starting aldehyde (2 mg, 20%)
+6.4
) (correct t.l.c. behaviour and H n.m.r. spectrum).
In a similar experiment a solution of the aldehyde (7) (10 mg, 0.03
CAB Catalysed Reaction of o-Anisaldehyde and
,4-Bis[(trimethylsilyl)oxy]penta-1,3-diene (12)
A solution of o-anisaldehyde (50 mg, 0.37 mmol) in propionitrile
1 ml) was added to a cooled (–78 ) solution of the tartrate precursor of
and the dihydropyrone (24) (9 mg, 68%) as a yellow solid, [ ]
D
2
1
(c, 0.75 in CH
2
Cl
2
(
mmol) in CH
2
Cl
2
(2 ml) was added to a mixture of (R)-(+)-BINOL (11 mg,
i
–1
the CAB (4) (27 mg, 0.07 mmol) and phenylboronic acid (9 mg, 0.07
mmol) in propionitrile (1 ml) which had been stirred at 0 under argon
for 1 h. The mixture was stirred for 10 min, the diene (12) (27 mg, 1.1
mmol) was added, and the mixture was stirred at –78 for 25 h, and then
poured into 20% aqueous hydrochloric acid (10 ml). The mixture was
0.04 mmol), Ti(O Pr)
2
Cl
2
(41 l) of a 0.83 mol l solution in toluene,
0.03 mmol), crushed activated 4 Å molecular sieves (0.25 g), and
CH
2
Cl (1 ml) which had been stirred, under argon, at room temperature
2
for 2 h. The mixture was cooled to –78 , stirred for 10 min, and the diene
(12) (25 mg, 0.10 mmol) was added. The mixture was stirred at –78 for

Synthesis of Anthracyclinones. XXXIV
859
2
4 h and then at room temperature for 24 h before trifluoroacetic acid (2
Methylation of 1-Hydroxy-5-methoxy-2-(6 -methyl-4 -oxo-2Ј,3 -
drops) was added. Workup and p.l.c. yielded starting material (7 mg,
dihydro-4 -pyran-2 -yl)anthraquinone (25)
6
9%) and the dihydropyrone (24) (4 mg, 28%), [ ]
D
+7.4 (c, 0.34 in
A mixture of the hydroxyanthraquinone (25) (8 mg, 0.02 mmol),
potassium carbonate (31 mg, 0.23 mmol), dimethyl sulfate (14 mg, 0.11
mmol), and acetone (5 ml) was heated at reflux, under argon, for 1.5 h,
cooled, and poured onto ice. The solid was filtered off, washed with
1
CH
Cl
2 2
) (correct t.l.c. behaviour and H n.m.r. spectrum).
Ti[(R,R)-TADDOL]Cl Promoted Reactions of 2-Formyl-1,5-
2
dimethoxyanthraquinone (7) and 2,4-Bis[(trimethylsilyl)oxy]penta-
water, and dissolved in CH
2
Cl (20 ml). The organic solution was
2
1
,3-diene (12)
washed with water, dried, and the solvent was removed under reduced
A solution of the aldehyde (7) (10 mg, 0.03 mmol) in CH
2
Cl
2
(2 ml)
pressure to give (24) (8 mg, 95%), [ ]
D
–3.8 (c, 0.81 in CH
2
Cl ) as a
2
1
was added to a cooled (–78 ) mixture of (R,R)-TADDOL (29) (19 mg,
yellow solid (expected t.l.c. behaviour and H n.m.r. spectrum).
i
–1
0
0
.04 mmol), Ti(O Pr)
2
Cl
2
(49 l of a 0.83 mol l solution in toluene,
.04 mmol), crushed activated 4 Å molecular sieves (0.25 g), and
References
CH
2
Cl
2
(1 ml) under argon. Stirring was continued for 10 min, the
1
Bercich, M. D., Cambie, R. C., and Rutledge, P. S., Aust. J. Chem.,
diene (12) (25 mg, 0.10 mmol) was added, and the mixture was stirred
at –78 for 20 h before trifluoroacetic acid (2 drops) was added. The
mixture was warmed to room temperature, stirred for 30 min, and
poured into saturated aqueous sodium hydrogencarbonate (10 ml). The
organic layer was washed with water, dried, and the solvent was
removed under reduced pressure. P.l.c. of the resulting solid gave the
1
999, 52, 303.
2
3
Togni, A., Organometallics, 1990, 9, 3106.
Furuta, K., Miwa, Y., Iwanaga, K., and Yamamoto, H., J. Am. Chem.
Soc., 1988, 110, 6254.
4
5
6
Furuta, K., Shimizu, S., Miwa, Y., and Yamamoto, H., J. Org.
Chem., 1989, 54, 1481.
dihydropyrone (24) (11 mg, 86%) as a yellow solid, [ ]
D
+4.9 (c, 0.94
Ishihara, K., Gao, Q., and Yamamoto, H., J. Org. Chem., 1993, 58,
1
in CH
2
Cl
2
) (correct t.l.c. behaviour and H n.m.r. spectrum).
6
917; J. Am. Chem. Soc., 1993, 115, 10412.
In a similar experiment the molecular sieves were removed before
the addition of the diene (12). Workup gave starting aldehyde (28%)
Furuta, K., Kanematsu, A., Takaoka, S., and Yamamoto, H.,
Tetrahedron Lett., 1989, 30, 7231.
and (24) (59%), [ ]
D
+6.8 (c, 0.72 in CH
2
Cl
2
).
7
8
Furuta, K., Gao, Q., and Yamamoto, H., Org. Synth., 1995, 72, 86.
Furuta, K., Maruyama, T., and Yamamoto, H., J. Am. Chem. Soc.,
Reactions in the presence of molecular sieves at higher temperature
–30 ) or with less Lewis acid (0.5 equiv.) gave lower yields of (24) (74
(
1
991, 113, 1041.
and 37% respectively).
9
Ishihara, K., Maruyama, T., Mouri, M., Gao, Q., Furuta, K., and
Yamamoto, H., Bull. Chem. Soc. Jpn, 1993, 66, 3483.
Furuta, K., Mouri, M., and Yamamoto, H., Synlett, 1991, 561.
Ishihara, K., Mouri, M., Gao, Q., Maruyama, T., Furuta, K., and
Yamamoto, H., J. Am. Chem. Soc., 1993, 115, 11490.
Gao, Q., Maruyama, T., Mouri, M., and Yamamoto, H., J. Org.
Chem., 1992, 57, 1951.
Ti[(R,R)-TADDOL]Cl
2
Promoted Reaction of 2-Formyl-1-hydroxy-5-
10
11
methoxyanthraquinone (8) and 2,4-Bis[(trimethylsilyl)oxy]penta-1,3-
diene (12)
i
12
A mixture of (R,R)-TADDOL (33 mg, 0.07 mmol), Ti(O Pr)
2
Cl (85 l
2
–1
of a 0.83 mol l solution in toluene, 0.07 mmol), activated crushed 4 Å
molecular sieves (0.25 g), and CH Cl (1 ml) was stirred, under argon, at
room temperature for 2 h. Stirring was discontinued and once the sieves
1
3
2
2
Gao, Q., Ishihara, K., Maruyama, T., Mouri, M., and Yamamoto, H.,
Tetrahedron, 1994, 50, 979.
1
1
4
5
had settled, the supernatant liquid and CH
Cl
2 2
washings were cen-
Bercich, M. D., M.Sc. Thesis, University of Auckland, 1992.
Corey, E. J., Rohde, J. J., Fischer, A., and Azimioara, M. D.,
Tetrahedron Lett., 1997, 38, 33.
trifuged until the supernatant liquid was clear. This solution was added
dropwise to a stirred solution of the aldehyde (8) (10 mg, 0.04 mmol) in
1
1
6
7
CH
Cl
2 2
(3 ml) under argon. The mixture was stirred at –78 for 10 min,
Corey, E. J., Rohde, J. J., Tetrahedron Lett., 1997, 38, 37.
Corey, E. J., Barnes-Seeman, D., and Lee, T. W., Tetrahedron Lett.,
1997, 38, 1699.
the diene (12) (26 mg, 0.11 mmol) was added, the mixture was stirred at
–
78 for 24 h, and then trifluoroacetic acid (2 drops) was added. The
1
8
mixture was warmed to room temperature, stirred for 10 min, poured
into saturated aqueous sodium hydrogencarbonate (10 ml) and the
organic layer was washed with water, dried, and concentrated under
Corey, E. J., Cywin, C. L., and Roper, T. D., Tetrahedron Lett., 1992,
38, 6907.
1
2
9
0
Oppolzer, W., and Rodriguez, I., Helv. Chim. Acta, 1993, 76, 1282.
Bednarski, M., Maring, C., and Danishefsky, S. J., Tetrahedron
Lett., 1992, 33, 6907.
vacuum to give a solid. P.l.c. (CH
2
Cl /ether, 49:1) afforded 1-hydroxy-
2
5
-methoxy-2-(6 -methyl-4 -oxo-2 ,3 -dihydro-4 H-pyran-2 -
2
1
yl)anthraquinone (25) (11 mg, 82%) which crystallized from
Danishefsky, S. J., Uang, B. J., and Quallich, G., J. Am. Chem. Soc.,
1985, 107, 1285.
CH
2
Cl
2
/hexanes as small yellow needles, m.p. 210–212 , [ ]
D
–26.7 (c,
+
+
22
23
0
.79 in CH
2
Cl
2
) (Found: M , 364.0938.
C H O
21 16 6
requires M ,
Danishefsky, S. J., Harvey, D. F., Pearson, W. H., Maring, C. J., and
Springer, J. P., J. Am. Chem. Soc., 1985, 107, 1256.
Danishefsky, S. J., Harvey, D. F., and Pearson, W. H., J. Am. Chem.
Soc., 1984, 106, 2455, 2456.
3
64.0937). max 228 (log 4.43), 256 (4.37), 409 nm (3.86). max 3446
–1
(
OH), 1670, 1629, 1607, 1397, 1268, 1004, 814 cm .
H
2.13, s, 6 -CH
3
;
2
.62, dd, J3 ax,3 eq 16.8, J2 ,3 ax 13.8 Hz, H3 ax; 2.85, ddd, J3 eq,3 ax 16.8,
2
2
2
2
4
5
6
7
J
J
J
2 3 eq 3.8, J3 eq,5 0.9 Hz, H3 eq; 4.06, s, 5-OCH
3
; 5.48, br s, H5 ; 5.86, dd,
Mikami, K., Motoyama, Y., and Terada, M., J. Am. Chem. Soc.,
1994, 116, 2812.
2 ,3 ax 13.8, J2 ,3 eq 3.8 Hz, H2 ; 7.39, dd, J6,7 8.5, J6,8 1.0 Hz, H6; 7.76, dd,
7,6 8.5, J7,8 7.7 Hz, H7; 7.85, d, J3,4 8.0 Hz, H3; 7.93, d, J4,3 8.0 Hz, H4;
Keck, G. E., Krishnamurthy, D., and Xiang-Yi, L., J. Org. Chem.,
1995, 60, 5998.
7
.99, dd, J8,7 7.7, J8,6 1.0 Hz, H8; 12.88, s, 1-OH.
C
21.5, 6 -CH ; 41.1,
3
C3 ; 57.0, 5-OCH
3
; 75.8, C2 ; 106.0, C5 ; 115.8, 119.2, 119.6, 120.0,
21.8, 133.0, 134.0, 135.0, 135.6, 135.7, 158.8, 161.0, 174.5, 181.8,
89.3, 189.3, 192.3. m/z 364 (M, 54%), 321, 306 (12), 293 (16), 280
Seebach, D., Hayakawa, M., Sakaki, J., and Schweizer, W. B.,
Tetrahedron, 1993, 49, 1711.
1
1
Cambie, R. C., Holroyd, S. E., Larsen, D. S., Rutledge, P. S., and
Woodgate, P. D., Aust. J. Chem., 1992, 45, 1589.
(
100), 265 (30), 251 (12), 165 (16), 148 (18).