Towards configurationally stable [4]helicenes: Enantioselective synthesis of 12-substituted 7,8-dihydro[4]helicene quinones

Article abstract of DOI:10.1002/chem.200700762

The synthesis of enantiopure C-12 methoxy- or alkyl-substituted 5,7,8,12b-tetrahydro[4]helicene quinones 16 and 17 and the 7,8-dihydroaromatic analogues 4 and 5 has been achieved from (SS)-2-(p-tolylsulfinyl)-1,4- benzoquinone. In the first series, with a structure containing both central and helical chiralities, the R absolute configuration of the stereogenic carbon atom was defined after the asymmetric cycloaddition step, whereas the P or M helicity was shown to be dependent on the nature of the C-12 substituent. The size of this group was also defining the configurational stability of the final (P)-7,8-dihydro[4]helicene quinones 4and 5. The interconversion barriers between the P and M helimers in the latter, computed with a DFT B3LYP method, matched well with the experimentally observed stability. Our study provided evidence that, in addition to steric effects, a small but significant role of electronic effects is governing the configurational stability of such helical quinones.

Full text of DOI:10.1002/chem.200700762

FULL PAPER
DOI: 10.1002/chem.200700762
Towards Configurationally Stable [4]Helicenes: Enantioselective Synthesis of
12-Substituted 7,8-Dihydro[4]helicene Quinones
M. Carmen CarreÇo,*[a] lvaro Enríquez,[a] Susana García-Cerrada,[a]
M. Jesffls Sanz-Cuesta,[a] Antonio Urbano,*[a] Feliu Maseras,[b, c] and
Alfons Nonell-Canals[b]
Abstract: The synthesis of enantiopure
C-12 methoxy- or alkyl-substituted
cycloaddition step, whereas the P or M
helicity was shown to be dependent on
the nature of the C-12 substituent. The
size of this group was also defining the
configurational stability of the final
(P)-7,8-dihydro[4]helicene quinones 4
and 5. The interconversion barriers be-
tween the P and M helimers in the
latter, computed with a DFT B3LYP
method, matched well with the experi-
mentally observed stability. Our study
provided evidence that, in addition to
steric effects, a small but significant
role of electronic effects is governing
the configurational stability of such
helical quinones.
5,7,8,12b-tetrahydro[4]helicene
qui-
nones 16 and 17 and the 7,8-dihydroar-
omatic analogues 4 and 5 has been ach-
ieved from (SS)-2-(p-tolylsulfinyl)-1,4-
benzoquinone. In the first series, with a
structure containing both central and
helical chiralities, the R absolute con-
figuration of the stereogenic carbon
atom was defined after the asymmetric
Keywords: asymmetric synthesis ·
cycloaddition · helical structures ·
quinones · sulfoxides
Introduction
terconversion barrier between them is high enough. Phenan-
threne itself shows helical distortion in the solid structure[2]
and can be considered the smallest helicene;[3] however, the
enantiomers are not stable enough to be isolated because
they interconvert quickly at room temperature. Although
their half lives have been shown to increase with the pres-
ence of alkyl substituents at C-4 and C-5, the enantiomers
of more strained 4,5-disubstituted phenanthrenes can be
separated only at low temperatures.[3] To the best of our
knowledge, configurationally stable [3]helicenes have never
been isolated at room temperature. The larger [5,6]- and
[7]helicenes can be configurationally stable at room temper-
ature and the isolated helimers can be stored for long peri-
ods without significant loss of enantiomeric purity, due to
the higher values of their interconversion barriers.[4] The hel-
ical distortion of the planarity in the case of benzo[c]phe-
nanthrene derivatives, [4]helicenes, is reinforced by over-
crowding of the substituents at the 1- and 12-positions of the
terminal rings (Scheme 1). In comparison with higher homo-
logues, the diminution of the number of aromatic rings de-
termines a lower interconversion barrier between the two
helical forms[4] which is highly dependent on the substituents
at the terminal rings. Small substituents facilitate the ther-
mal racemisation of such compounds. When these substitu-
ents are large enough, the molecules become configuration-
ally stable and can be resolved into their corresponding en-
Phenanthrene and the higher homologues, bearing a series
of ortho-condensed aromatic rings, exist in a chiral non-
planar disposition due to the steric hindrance of the hydro-
gens in positions four and five in the former and the exter-
nal rings and their substituents in the latter. The helical
structures resulting from this distortion of planarity, called
helicenes,[1] can be resolved into their enantiomers if the in-
[a] Prof. Dr. M. C. CarreÇo, . Enríquez, Dr. S. García-Cerrada,
Dr. M. J. Sanz-Cuesta, Dr. A. Urbano
Departamento de Química Orgµnica (C-I)
Universidad Autónoma Madrid
Cantoblanco, 28049 Madrid (Spain)
Fax : (+34)914-973-966
E-mail: carmen.carrenno@uam.es
antonio.urbano@uam.es
[b] Dr. F. Maseras, A. Nonell-Canals
Institut of Chemical Research of Catalonia (ICIQ)
Av. Països Catalans 16
43007 Tarragona (Spain)
[c] Dr. F. Maseras
Unitat de Química Física, Edifici Cn
Universitat Autònoma, Bellaterra
08193 Barcelona (Spain)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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603

stable and their configurational integrity is preserved up to
2008C.[10] Although not systematically studied, these data
provide evidence that the racemisation barriers of [4]heli-
cenes are highly dependent on the particular structure.
Among the applications found for these [4]helicenes, it is
worth mentioning those for 1,12-dimethylbenzo[c]phenan-
threne-5,8-dicarboxylic acid (1b), described by Yamaguchi
et al.[11a] This compound has shown interesting properties in
chiral catalysis,[11a,13] chiral recognition in the complexation
with cyclodextrins,[14] chiral LB film formation,[15] charge-
transfer complexation,[16] chiral macrocyclic anhydride and
amide formation,[8c,17] optically active acyclic and cyclic poly-
amine synthesis,[18] chiral macrocyclic alkynes,[19a] cycloal-
kyne dimer and oligomer formation,[19b–c] optically active bi-
helicenol synthesis[20] and in the preparation of helicenedia-
mine oligomers.[21] The high non-planarity of helical ben-
zo[c]phenanthrenes induced by a methyl group at C-12 was
shown to decrease their DNA-damaging effect if compared
with the unsubstituted derivative.[22] Moreover, Kelly et al.
described a [4]helicene structure as a part of the first ration-
ally designed chemically powered molecular motor.[23] Al-
though the interest of synthesizing such helical molecules in
optically active form is evident, to the best of our knowl-
edge, only a single asymmetric approach has been described
so far for the enantioselective construction of the lactone-
type chiral tetrahelicene 2,[24] with the resolution of racemic
structures the most frequently used method to enantiopure
[4]helicenes.
In connection with a program devoted to asymmetric syn-
thesis mediated by sulfoxides,[25] we recently described a
new asymmetric approach to [5]helicene bisquinones based
on the domino Diels–Alder reaction/sulfoxide elimination/
oxidation process that occurred when enantiopure (SS)-2-(p-
tolylsulfinyl)-1,4-benzoquinone reacted with vinyl naphtha-
lenes and phenanthrenes.[26] Nevertheless, due to the poor
reactivity of these aromatic derivatives as dienes, Diels–
Alder reactions took place only upon reflux of high boiling
solvents or under high pressure conditions, with low chemi-
cal and optical yields. This problem was later circumvented
by the use of non-fully aromatised more reactive dienes,
such as dihydroarylethenes.[27] This slight structural modifi-
cation of the diene allowed the Diels–Alder reaction be-
tween enantiopure (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone
and differently substituted vinyl dihydrophenanthrenes to
proceed under very mild conditions, opening an easy access
to new helically chiral dihydro[5]helicene quinones and bis-
quinones with good chemical yields and excellent optical pu-
rities.[28] Moreover, the presence of a central hydroaromatic
ring in the resulting helicenes is known to increase the race-
misation barrier in comparison with that of the whole aro-
matic derivatives.[29] More recently, enantiopure [7]helicene
bisquinones were prepared in a more efficient and conver-
gent one-pot six-step domino process by using 3,6-divinyl-
1,2,7,8-tetrahydrophenanthrenes as dienes.[30]
Scheme 1. [4]Helicenes previously synthesized in an optically active form.
antiomers with
(Scheme 1).[5]
P
or
M
absolute configurations
Although the first reference about the helical chirality of
such tetracyclic systems was reported by Newman et al. in
1948,[6a] the first configurationally stable 1,12-dimethyl-sub-
stituted [4]helicene 1a was not prepared and resolved until
1956 by the same author[6b] (Scheme 1). Since then, several
synthetic methods have been exploited for the assembly of
the tetrahelicene framework,[7] but only a few derivatives,
such as 1b, 2 and 3 have been resolved into their optical iso-
mers either by chemical[8–10,11] or chromatographic[3a,8b,12]
methods. Thus, 1,12-dimethyl-substituted [4]helicene deriva-
tives 1[8] are configurationally stable even at high tempera-
tures, whereas the stability of 4-susbtituted-6H-
benzo[b]naphtha
[1,2]pyran-6-ones 2[9] is dependent on the
T
size of the substituents, with the 4-methoxy derivative being
highly unstable. By contrast, the [4]heterohelicenium cations
3, bearing two methoxy groups at C-1 and C-12, are highly
Abstract in Spanish: La síntesis asimØtrica de las 5,7,8,12b-
tetrahidro[4]heliceno quinonas metoxi o alquil sustituídas en
C-12, 16 y 17,y las anµlogas 78,-dihidroaromµticas 4 y 5 se
ha llevado a cabo a partir de la (S,S)-2-(p-tolilsulfinil)-1,4-
benzoquinona. En las quinonas 16 y 17,que poseen quirali-
dad central y helicoidal,la configuración absoluta R en el
carbono estereogØnico se define despuØs de la etapa de ci-
cloadición asimØtrica,mientras que la helicidad P o M depen-
de de la naturaleza del sustituyente en C-12. El tamaÇo de
este grupo es fundamental a la hora de definir la estabilidad
configuracional de las (P)-7,8-dihidro[4]heliceno quinonas 4
y 5. Las barreras de interconversión entre los helímeros P y
M de 4 y 5,calculadas teóricamente con el mØtodo DFT
B3LYP,coincidieron bastante bien con la estabilidad confi-
guracional observada experimentalmente. Este estudio ha evi-
denciado que,ademµs de efectos estØricos,existe una pequeÇa
pero significativa contribución de efectos electrónicos para
explicar la estabilidad configuracional de estas quinonas heli-
coidales.
Taking into account the lower racemisation barriers of
[4]helicenes (<16 kJmolꢀ1 for tetrahelicene),[4b] a similar
asymmetric approach would be applicable if mild conditions
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Synthesis of 7,8-Dihydro[4]helicene Quinones
FULL PAPER
conducive to the tetracyclic skeleton were used to avoid the
possible racemisation processes. In a preliminary communi-
cation, we reported the synthesis of a 12-(tert-butyl)-substi-
tuted [4]helicene quinone[31] and showed that the bulky tert-
butyl substituent conferred configurational stability to the
system. Because the properties of all these artificial mole-
cules are closely associated to their inherent chirality, future
applications of [4]helicene derivatives would require us to
know their configurational stability. We then decided to
extend our asymmetric approach to the synthesis of new
enantioenriched 12-substituted 7,8-dihydrobenzo[c]phenan-
threne-1,4-quinones with the aim of evaluating the influence
of such substituents on the racemisation barrier and, as a
consequence, on the configurational stability of [4]helicenes.
We describe herein the synthesis of new 12-alkyl- and 12-
methoxy-substituted 7,8-dihydro[4]helicenequinones 4 and 5
by starting from (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone.
Our previous synthesis of 12-(tert-butyl)-substituted ana-
logues[31] is also discussed in full detail, including results not
described in our earlier communication. We also report on
theoretical calculations of the energy barriers of enantiomer-
ic inversion in the [4]helicene quinone system, which match-
es with the experimental observations. The present study
shows that, although the configurational stability of the tet-
racyclic skeleton is mainly governed by steric effects, the
presence of electron-donating groups in the whole system
also increases the racemisation barrier.
matisation that should occur in the presence of an excess of
the chiral sulfinyl quinone. The dienes 6 and 7, the substitu-
ents of which at C-5 (R1 in Scheme 2) would be the precur-
sors of those at C-12 in the final helicenequinones 4 and 5,
could be accessible by a Stille coupling between a vinyl stan-
nane and the bicyclic triflates 9. These derivatives could be
formed from the corresponding 2-tetralone precursors 10,
bearing the appropriate substitution at C-8 (R1 in Scheme 2)
which will be ultimatly responsible for the configurational
stability of the final [4]helicene quinones (C-12 in 4 or 5).
Thus, a general synthesis allowing the presence of different
groups at C-8 in 10 was envisaged by starting from commer-
cially available 7-methoxy-1-tetralone (11), in which the
alkyl R1 substituents could be introduced by using Grignard
reagents, with the methoxy-substituted aromatic ring as a
suitable precursor for the cyclohexenone moiety of 10, after
Birch reduction and acidic hydrolysis.
Thus, as shown in Scheme 3, addition of methyl magnesi-
um bromide to the carbonyl group of 11, followed by an
acidic treatment (35% HCl) to promote water elimination
of the non-isolated carbinol intermediate, furnished a 93%
yield of dihydronaphthalene 12b.[33] Dehydrogenation of
12b with DDQ (DDQ=2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone) led to 1-methyl-7-methoxy naphthalene (13b)[33b,c]
in 97% yield. A similar reaction sequence allowed the syn-
thesis of 1-(isopropyl)-7-methoxynaphthalene (13c). In this
case, the introduction of the isopropyl substituent in 11 re-
quired the activation of the carbonyl group by BF3·OEt2,
Results and Discussion
The retrosynthetic analysis outlined in Scheme 2 was consid-
ered for the synthesis of alternatively 12-substituted-7,8-di-
hydro[4]helicene quinones 4 and 5.
Scheme 2. Retrosynthesis of [4]helicene quinones 4 and 5.
The construction of the benzo[c]phenanthrene skeleton
could be achieved in a convergent manner by reaction be-
tween an adequately substituted 3-vinyl-1,2-dihydronaphtha-
lene, such as 6 or 7, and enantiopure 2-(p-tolylsulfinyl)-1,4-
benzoquinone (SS)-8,[32] through the domino sequence
Diels–Alder reaction, sulfoxide elimination and partial aro-
Scheme 3. Synthesis of 1-alkyl-7-methoxynaphthalenes 13b–d.
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M. C. CarreÇo, A. Urbano et al.
before the addition of the corresponding Grignard reagent
at low temperature. Under these conditions, a mixture of di-
hydronaphthalene 12c[34] and naphthalene 13c[35] was gener-
ated, which evolved into 13c by treatment with DDQ (77%
overall yield). Upon reaction with tert-butyl magnesium
chloride[36] followed by 10% HCl treatment, 11 gave rise to
carbinol 14[37] that could only be dehydrated after heating in
the presence of a stronger acid (H2SO4) to afford, in 85%
yield, the dihydroaromatic derivative 12d the aromatization
of which to naphthalene 13d with DDQ occurred in almost
quantitative yield (Scheme 3).
1,4-dimethoxyphenyl substituent, which could behave as an
electron-donating group, thus activating the 1,3-butadiene
moiety.[42] We performed the reaction of 6a with a twofold
excess of (SS)-8 at ꢀ208C in CH2Cl2 (Scheme 5). The initial-
Reduction of naphthalene derivatives 13b–d was carried
out with Na in refluxing ethanol and occurred selectively at
the b-substituted ring[38] to give the corresponding enol
ether intermediates, which were directly transformed into
the desired 8-alkyl-3,4-dihydro-2(1H)-naphthalenones 10b–
d[39] by acidic hydrolysis (Scheme 4). The 5,8-dimethoxy-sub-
Scheme 5. Synthesis of 9,12-dimethoxy-5,7,8,12b-tetrahydro[4]helicene
quinone (12bR,P)-16a and 9,12-dimethoxy-7,8-dihydro[4]helicene qui-
none (P,M)-4a.
ly formed Diels–Alder adduct 15 was not detected and
evolved spontaneously, after syn-pyrolytic elimination of the
sulfoxide, to derivative 16a, which was the final product of
this reaction. Although the quinone 8 was in excess, we did
not observe the formation of the dihydrohelicene quinone
4a, which could result after the in situ aromatisation of the
B ring of 16a, even when the mixture was stirred for 7 d.
The tetrahydroaromatic derivative (12bR,P)-16a,[43] which
contains both central and helical chiralities, was isolated
pure in 55% yield and was shown to be optically active
([a]2D0 =+273 (c=0.14 in CHCl3)). The aromatization of the
B ring of 16a, by using two equivalents of DDQ in CH2Cl2
at room temperature for 6 h, gave rise to 7,8-dihydro-9,12-
dimethoxybenzo[c]phenanthrenene-1,4-dione (4a) in 59%
yield. Surprisingly, the [4]helicene quinone 4a formed under
these conditions showed a null value of its optical rotation.
Previous results from our laboratory had shown that the
absolute configuration and optical purity of the [5]-[28b,c] and
[7]helicene quinones[30] obtained by following a similar
asymmetric approach, were highly dependent on the nature
of the oxidant and the reaction conditions used in the aro-
matisation step. The formation of racemic 4a could thus be
due to the reagent and/or temperature used in the aromati-
sation step or to the low interconversion barrier between
both enantiomers of the 12-methoxy-substituted [4]helicene
quinone. We thus carried out the aromatisation process in
the presence of DDQ as the oxidant at lower temperatures
(ꢀ78 and ꢀ208C) to minimize racemisation, but only traces
Scheme 4. Synthesis of 3-vinyl-1,2-dihydronaphthalenes 6 and 7.
stituted 2-tetralone 10a was synthesized by using a known
procedure[40] from the Diels–Alder adduct resulting from
the reaction between 2-methoxy-1,3-butadiene and p-benzo-
quinone. The key intermediate enol triflates 9, en route to
dienes 6 and 7, were obtained by trapping the enolate gener-
ated from b-tetralones 10 with Tf2NPh (Scheme 4). Stille
coupling of these triflates 9a–d with vinyl tributyl stannane
afforded dienes 6a–d which were isolated pure by flash
column chromatography in 44–93% isolated yields. The
cross coupling reaction of 9a–d with 1-ethoxyvinyl tributyl
stannane afforded ethoxy-substituted dienes 7a–d, which
were proven to be very unstable, evolving into the corre-
sponding methyl ketones resulting form the hydrolytic cleav-
age of the ethyl vinyl ether moiety. Thus, compounds 7 had
to be used immediately once synthesized.
With dienes 6 and 7 in hand, we began the study of Diels–
Alder reactions with enantiopure (SS)-8. By taking into con-
sideration the reactivity features of the diene component in
the Diels–Alder reaction,[41] we initiated this study with the
presumably more reactive systems 6a and 7a, bearing the
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Synthesis of 7,8-Dihydro[4]helicene Quinones
FULL PAPER
of compound 4a were isolated, even after long reaction
times.
CH2Cl2 at ꢀ208C for 27 days furnished tetrahydroaromatic
benzo[c]phenanthrenedione (12bR,P)-16b, which was isolat-
ed in 80% yield after flash chromatography. Compound 16b
showed a rotary power of [a]2D0 =+232 (c=0.1 in CHCl3)
Because the aromatisation of 16a at room temperature
could decrease the enantiomeric excess of the final helicene
quinone 4a, we decided to synthesize the 6-ethoxy tetracylic
derivative 5a, presumably easier to aromatise at lower tem-
peratures. The presence of electron-donating substituents in
the hydroaromatic polycyclic precursors, resulting from the
domino Diels–Alder reaction and elimination of the sulfox-
ide, had been shown to decrease the oxidation potential of
analogous penta- and heptacyclic derivatives,[28,30,31] thus fa-
cilitating the aromatisation step en route to [5]- and [7]hel-
icene quinones and bisquinones. The Diels–Alder reaction
of (SS)-8 (2 equiv) with the more reactive ethoxy-substituted
diene 7a could be carried out at ꢀ408C to give, directly, the
[4]helicene quinone (P)-5a which could be isolated pure in
78% yield (Scheme 6). This result corroborated that the
which corresponded to
a
96% ee (ee=enantiomeric
excess).[44] In the presence of an even higher excess of the
sulfinyl quinone 8 (3 equiv), after 11 days at ꢀ208C and 23
additional days at 58C, the initially formed tetrahydroaro-
matic derivative 16b evolved into 12-methyl-7,8-dihydro[4]-
helicene quinone ((P)-4b), which was isolated pure after
flash chromatography in 83% yield. Immediately after
being synthesized, compound (P)-4b showed an optical ro-
tation of [a]2D0 =+482 (c=0.05 in CHCl3), corresponding to
a 35% ee.[44]
We then repeated the reaction of diene 6b with three
equivalents of sulfinyl quinone (SS)-8 at room temperature
under high-pressure conditions (7850 bar). After 13 h
(Scheme 7), the reaction was complete, leading to the direct
Scheme 6. Synthesis of 6-ethoxy-9,12-dimethoxy-7,8-dihydro[4]helicene
quinone (P)-5a.
domino process, including the Diels–Alder reaction, elimina-
tion of the sulfoxide and aromatisation by an excess of the
quinone present in the reaction medium, was easier when
the structures bear electron-donating substituents. The spe-
cific rotary power of [4]helicene quinone 5a isolated in this
experiment, immediately measured after purification, was
([a]2D0 =+303 (c=0.034 in CHCl3)). This result provided evi-
dence for the presence of a helical chirality in compound 5a
to which a P absolute configuration was assigned. The same
reaction at ꢀ788C gave rise to (P)-5a (87% yield), which
showed a higher value of optical rotation ([a]2D0 =+640 (c=
0.027 in CHCl3)). When the solution of 5a used to measure
the rotary power was allowed to stand at ꢀ208C, the initial
value decreased very quickly and was null after 2 h. These
results indicated that the configurational stability of [4]heli-
cenequinones 4a and 5a, bearing a methoxy group as the
substituent at C-12 was very low and the interconversion be-
tween both P and M helimers took place quickly even at
ꢀ208C.
Scheme 7. Synthesis of 12-methyl-5,7,8,12b-tetrahydro[4]helicene quinone
(12bR,P)-16b and 12-methyl-7,8-dihydro[4]helicene quinone (P)-4b.
formation of dihydroaromatic derivative (P)-4b, which was
isolated in 89% yield and with 81% ee.[44] This result provid-
ed evidence that the high pressure conditions strongly accel-
erate both the cycloaddition and the aromatisation process-
es. Although the temperature of this experiment was higher
than before, the enantiomeric purity of the final helical de-
rivative (P)-4b was better, this was probably due to the
shorter reaction time, which partially avoided racemisation.
The rotary power of (P)-4b ([a]2D0 =+1547 (c=0.046 in
CHCl3)), measured immediately after purification, de-
creased at room temperature to a null value after 250 h, pro-
viding evidence for a low racemisation barrier between the
helimers.
The synthesis of 6-ethoxy-12-methyl-7,8-dihydro[4]heli-
cene quinone (5b) (64% yield) was directly accomplished
by reaction of ethoxy-substituted diene 7b with the dieno-
philic quinone (SS)-8 (2.5 equiv) in CH2Cl2 at ꢀ208C for
two days (Scheme 8). Once again, the presence of the
We then turned our attention to the synthesis of the C-12
methyl-substituted [4]helicene quinones 4b and 5b in order
to evaluate their configurational stability. Thus, the reaction
of diene 6b with two equivalents of quinone (SS)-8 in
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M. C. CarreÇo, A. Urbano et al.
Scheme 8. Synthesis of 6-ethoxy-12-methyl-7,8-dihydro[4]helicene qui-
none (P)-5b.
ethoxy substituent in the tetracyclic system initially formed
by the cycloaddition and pyrolytic elimination process was
favouring the aromatization at low temperature by the
excess of the quinone which acted as an oxidant in the last
step of the domino sequence. Moreover, the low tempera-
ture and shorter reaction time (2 d at ꢀ208C) allowed the
isolation of enantiopure 7,8-dihydro[4]helicene derivative
(P)-5b ([a]2D0 =+1663 (c=0.05 in CHCl3), 96% ee)).[44] This
helical quinone was shown to be configurationally unstable
as its optical rotation decreased to a null value after 250 h at
room temperature. Nevertheless, the rotary power of (P)-5b
remained constant at ꢀ208C, providing evidence for a
higher configurational stability of this C-12 methyl-substi-
tuted[4]helicene quinone relative the analogues 4a and 5a,
which bear a methoxy group at C-12.
Thus, although compounds 4a—b and 5a–b are not con-
figurationally stable at room temperature, there is a signifi-
cant difference between the C-12 methoxy-substituted sys-
tems 4a and 5a, which rapidly racemise even at ꢀ208C, and
the C-12 methyl-substituted analogues 4b and 5b, which are
indefinitely stable at this low temperature. Although this ef-
ficient synthesis allowed an easy access to the [4]helicene
quinones, the low configurational stability of the methyl-
substituted derivatives at room temperature prevented fur-
ther applications.
Scheme 9. Synthesis of 12-isopropyl-5,7,8,12b-tetrahydro[4]helicene qui-
nones (12bR,P)-16c and (12bR,M)-17c and 12-isopropyl-7,8-dihydro[4]-
helicene quinone (P)-4c.
quence of the existence of two elements of chirality in such
structures. The central chirality is evident from the presence
of the stereogenic centre at C-12b;however, a helical chiral-
ity must also be present. This structural feature would be
common to the other tetrahydroaromatic derivatives 16a
and 16b;however, only in the case of the isopropyl-substi-
tuted analogue will both P and M helical diastereoisomers
interconvert very slowly at room temperature, which is thus
responsible for the appearance of two isolable structures
16c and 17c. It is worth mentioning that the sign of the
rotary power of both diastereomers is opposite. According
to the carbon substitution existent at the C-12b sterogenic
centre, the inversion of its configuration is unlikely, whereas
due to the flexible structure of the 1,4-cyclohexadiene
moiety, the inversion of the helicity is plausible.
Considering the observed differences, we expected a
higher configurational stability for the [4]helicene quinones
4c and 5c bearing a bulkier C-12 isopropyl substituent. The
reaction of diene 6c with 2.1 equivalents of sulfinyl quinone
(SS)-8 (Scheme 9) occurred slowly at ꢀ208C (42 d) to give
compound (12bR,P)-16c, resulting from the cycloaddition
and sulfoxide elimination in 67% yield. Tetrahydroaromatic
derivative 16c showed an optical rotation of [a]2D0 =+291
(c=0.06 in CHCl3) and a 96% ee.[44]
Upon standing in CDCl3 solution at room temperature for
30 days, compound 16c partially evolved into a 65:15:20
mixture of 16c, a new diastereoisomer (12bR,M)-17c, and
dihydroaromatic derivative 4c, proceeding from the aroma-
tisation of the B ring of 16c and/or 17c. Fortunately, the
minor isomer 17c could be obtained pure after flash chro-
matography showing an optical rotation of [a]2D0 =ꢀ167 (c=
0.05 in CHCl3). The isolation of two diastereoisomers 16c
and 17c for this type of compound can only be a conse-
The direct synthesis of 12-isopropyl-7,8-dihydro[4]heli-
cene quinone (P)-4c could be achieved in 79% yield with
80% ee[44] from a reaction between 6c and three equivalents
of (SS)-8 after 11 days at ꢀ208C and 23 additional days at
58C (Scheme 9) or under high-pressure conditions
(7850 bar) after 13 h at room temperature in 73% yield with
82% ee.[44] The rotary power of (P)-4c obtained under these
last conditions ([a]2D0 =+1758 (c=0.05 in CHCl3)) also de-
creased to [a]2D0 =+1050 after 31 days at room temperature,
but much more slowly than the C-12 methyl analogues. This
rotary power remained constant indefinitely in solution at
ꢀ58C.
Enantiopure 6-ethoxy-12-isopropyl-7,8-dihydro[4]helicene
quinone (P)-5c ([a]2D0 =+1678 (c=0.09 in CHCl3),
97% ee)[44] was also directly obtained by reaction between
ethoxy-substituted diene 7c and an excess of (SS)-8
(Scheme 10) in 65% yield. Compound (P)-5c was also
shown to be configurationally stable at ꢀ58C.
608
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Chem. Eur. J. 2008, 14, 603 – 620

Synthesis of 7,8-Dihydro[4]helicene Quinones
FULL PAPER
mers 18, resulting from the cycloaddition of diene 6d to the
unsubstituted C5–C6 double bond of the ambident dieno-
philic sulfinylquinone (SS)-8.[45] Compound (12bR,M)-17d
was formed after endo cycloaddition of the diene 6d to the
sulfinyl-substituted C2–C3 double bond of 8, followed by
elimination of the sulfoxide. This derivative, containing heli-
cal chirality and a stereogenic centre at C-12b gave a
72% ee ([a]D20 =ꢀ240 (c=0.02 in CHCl3)).[44] Compound
(P)-4d, resulting from full aromatisation of the B ring of
17d, was isolated in an optically active form ([a]2D0 =+1371
(c=0.02 in CHCl3)) with a 72% ee,[44] and was shown to be
configurationally stable at room temperature. Although the
dienophile 8 was used in excess (2 equiv) to promote the ar-
omatisation of the B ring of 17d, only a small amount of the
expected [4]helicenequinone 4d was formed. To improve
the yield of 4d, we submitted compound 17d to different
treatments with DDQ, CAN (ceric ammonium nitrate) and
Scheme 10. Synthesis of 6-ethoxy-12-isopropyl-7,8-dihydro[4]helicene qui-
none (P)-5c.
All these results provided evidence for a common feature
of our methodology. When the 7,8-dihydro[4]helicene qui-
nones are not configurationally stable, longer reaction times
lead to smaller optical purities, due to partial racemisations
that must occur during the synthetic process. The higher re-
activity of the alkoxy-substituted dienes 7 favoured the for-
mation of products with a higher enantiomeric excess,
except in the case of C-12 methoxy-substituted derivative
5a, due to its very low configurational stability.
The reaction of 2-vinyl-8-(tert-butyl)-3,4-dihydronaphtha-
lene (6d) revealed an important influence of the remote
bulky substituent at the diene moiety both in the reactivity
and chemoselectivity of the Diels–Alder reaction with sulfi-
nyl benzoquinone (SS)-8.[31]
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). Surprisingly, 17d
A
remained unchanged in the presence of several oxidants
under different temperatures, even after long reaction times.
When the mixture of diene 6d and (SS)-8 (3 equiv) was
submitted to high-pressure conditions (7850 bar) for 24 h at
room temperature (Scheme 11), a 40:60 mixture of (P)-4d
(37% yield) and 18 (59% yield) was formed. Again, the
domino process was accelerated under high pressure condi-
tions and compound 4d ([a]2D0 =+1573 (c=0.1 in CHCl3))
was obtained with a 80% ee,[44] slightly higher than that ob-
tained at atmospheric pressure.
As outlined in Scheme 11, the cycloaddition between 6d
and enantiopure (SS)-8, was complete after seven days at
room temperature affording, in 54% overall yield,
a
When the reaction was performed with the more elec-
tron-rich diene 7d (Scheme 12), bearing the OEt substituent
at C-3 of the diene moiety, the cycloaddition with sulfinyl
quinone (SS)-8 occurred at ꢀ208C, affording in 57% yield,
helical quinone (P)-5d[43] showing an optical rotation of
([a]D20 =+977 (c=0.03 in CHCl3)) with 95% ee.[44] Com-
pound 5d resulted from the exclusive attack of the diene on
the sulfinyl-substituted C2–C3 double bond of 8, followed
by elimination of the sulfoxide and full aromatisation of the
B ring. This result provided evidence that, in this case, the
use of the more electron-rich diene 7d, not only facilitated
the aromatisation of the B ring on the non-isolated inter-
mediate adduct, as previously observed, but also completely
reversed the chemoselectivity of the process. The lower tem-
perature of the cycloaddition step improved the stereoselec-
tivity of the process allowing the isolation of enantiopure
(P)-5d, which was configurationally stable at 258C.
25:15:60 mixture of (12bR,M)-17d, (P)-4d and 18 which
could be isolated by flash chromatography in 14, 10 and
30% yields, respectively. The major component of the mix-
ture was characterised as a mixture of regio and diastereo-
Scheme 11. Reaction of 3-vinyl-5-tert-butyl-1,2-dihydronaphthalene 6d
and (SS)-8.
Scheme 12. Synthesis of 6-ethoxy-12-(tert-butyl)-7,8-dihydro[4]helicene
quinone (P)-5d.
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609

M. C. CarreÇo, A. Urbano et al.
Structural and configurational assignment: The structural as-
signment of tetrahydroaromatic derivatives 16a–c and 17c,d
was based on a detailed comparative analysis of their spec-
1
troscopic parameters, mainly H NMR spectra. As discussed
above, these compounds present two elements of chirality, a
stereogenic centre at C-12b and a chiral pseudo-helix due to
their ortho-condensed tetracyclic structure. This was evi-
denced from the isolation of two isopropyl-substituted dia-
stereomers 16c and 17c, only possible if two chiralities are
present.
In spite of the structural analogy of all tetrahydroaromatic
1
derivatives 16a–c and 17c,d, their H NMR spectra revealed
significant differences in the chemical shifts of the olefinic
proton H-6 and the diastereotopic hydrogens at C-5 of com-
pounds 16a–c when compared with those of compounds
17c,d (Figure 1). As can be seen, H-6 appeared as a broad
singlet at d=5.50–5.53 ppm in compounds 16a–c (Figur-
e 1A,B,C), whereas it is much more deshielded in 17c and
17d, d=5.91 and 6.05 ppm, respectively (Figure 1D,E).
Moreover, the methylene group at C-5 is observed as a com-
plex AB system at d=2.95 and 3.30 ppm in 16b and 16c
and d=2.97 and 3.18 ppm in 16a, whereas the correspond-
ing signals for the CH2 at C-5 in 17c and 17d appeared at
d=2.70 and 3.85 ppm in 17c and d=2.58 and 3.81 ppm in
17d and are much more separated. This NMR behaviour
seemed to indicate a different spatial arrangement of deriva-
tives 16a–c with respect to 17c and 17d, probably due to
the different conformations of the 1,4-dihydroaromatic frag-
ment (B ring) present in these compounds.
In accordance with previous conformational studies on
1,4-dihydronaphthalenes[46] and with our own work,[28c,47] tet-
rahydroaromatic derivatives 16a–c and 17c,d would exist in
a stable boat-like conformation, such as I (Scheme 13), in
which the aryl substituent at C-12b is situated in a pseu-
doaxial disposition to avoid destabilising interactions with
the methylene group at C-6a and the adjacent carbonyl
group, present in the other possible conformer II. NOESY
experiments carried out on 9,12-dimethoxy-substituted de-
rivative 16a confirmed the existence of a conformation such
as I, as a NOE enhancement was observed between H-8ax
and H-12b, which is only possible if both hydrogen atoms
are spatially close, such as in conformer I. Nevertheless, in
the case of the 12-tert-butyl-substituted tetracyclic com-
pound 17d, the NOESY experiment provided evidence for
strong NOE enhancements between H-12b and H-5ax as
well as between H-12b and the tert-butyl group at C-12
(Scheme 13). This situation is only possible if conformer II,
with the aryl group at C-12b in a pseudoequatorial disposi-
tion, is the major component in the conformational equilib-
rium of 17d. A detailed inspection of structures 16a-I and
17d-II revealed that the presumably more stable conformer
I, in the case of the C-12 tert-butyl-substituted system 17d,
must be highly destabilized by a spatial interaction between
the bulky tert-butyl group (R1 in conformation I) and the
quinone ring.
Figure 1. 1H NMR spectra of 16a–c and 17c,d.
This structural assignment was later confirmed by X-ray
which the boat-like conformation I (with the C-12b aryl
group axial) for 16a and II (with the C-12b aryl group equa-
diffraction[48] of both derivatives 16a and 17d (Figure 2) in
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Chem. Eur. J. 2008, 14, 603 – 620

Synthesis of 7,8-Dihydro[4]helicene Quinones
FULL PAPER
1
of 16c, which showed a similar H NMR spectrum to that of
compound 17d (Figure 1D,E), must present a conformation
such as II.
The absolute configuration of the stereogenic carbon
atom at C-12b in all tetrahydroaromatic derivatives 16a–c
and 17c,d has been assigned as R, taking into account the
high optical purity observed in all cases and the well-estab-
lished model of approach of the reacting enantiopure dieno-
phile (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone (8).[28c,49]
Thus, the initial Diels–Alder adduct must result from the
preferred endo approach of the vinyl dihydronaphathalenes
6a–d to the less-encumbered upper face of the sulfinylqui-
none (SS)-8, adopting the (s)-cis conformation represented
in Scheme 14, usually the most stable and reactive of vinyl
sulfoxides.[49,50]
Scheme 13. Possible boat-like conformations of the 1,4-dihydroaromatic
ring of 5,7,8,12b-tetrahydro[4]helicenequinones 16 and 17 and observed
NOEs for 16a and 17d.
Scheme 14. Preferred approach between 3-vinyl-1,2-dihydronaphthalenes
6 and sulfinyl quinone (SS)-8.
The additional helical chirality shown by compounds 16a–
c and 17c,d, evident from the X-ray structures of 16a and
17d, must be a consequence of the complete shift of the
conformational equilibrium towards boat-like structure I in
16a,b and II in 17d, with the relative stability of conformers
I and II dependent on the substituent at C-12 (R1 in
Scheme 13). In the case of the isopropyl-substituted deriva-
tive 16c, we initially detected a structure in which the
1H NMR spectroscopic parameters matched with conformer
I. Although slowly, the equilibration between both conform-
ers I and II occurred, in this case, at room temperature,
leading to an equilibrium mixture of two diastereoisomeric
isolable structures 16c-I and 17c-II.
The P and M absolute configuration of the chiral helix
present in tetrahydroaromatic derivatives 16a–c and 17c,d
was assigned by taking into account the positive or negative
sign of their [a]2D0 values,[1c] which are depicted in Figure 1.
Thus, the helicity of the isopropyl-substituted diastereomers
16c-I and 17c-II, which bear the same R configuration at C-
12b, must be opposite due to the opposite sign of their [a]D20
values. Moreover, all structures containing boat-like struc-
ture I (16a–c) have a positive value of [a]2D0, whereas com-
pounds 17c and 17d, to which the boat-like structure II has
been assigned, has a negative [a]2D0 value. These observations
led us to assign the P absolute configurations to the chiral
helix of compounds bearing the boat-like structure I and M
to compounds with conformation II. As mentioned before,
Figure 2. X-ray structures of 16a and 17d.
torial) for 17d were evidenced. Moreover, these X-ray struc-
tures also showed the helical nature of these molecules pos-
sessing central and helical chiralities, and corroborated the
12bR,P relative configuration for 16a and 12bR,M for 17d.
After having determined the structure of 16a as the boat-
1
like conformation I (Scheme 13), the similar H NMR spec-
tra obtained for compounds 16b and 16c (Figure 1B,C) led
us to assign a similar spatial arrangement to these tetrahy-
droaromatic derivatives. In the same way, the isopropyl-sub-
stituted derivative 17c, resulting from spontaneous evolution
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611

M. C. CarreÇo, A. Urbano et al.
the 12bR,P and 12bR,M relative configurations assigned to
16a and 17d were corroborated by a X-ray diffraction study
(Figure 2).
The P absolute configuration of all helical dihydro[4]heli-
cenequinones 4 and 5 synthesised by us was again initially
assigned on the basis of the positive sign of their rotary
power[1c] and later confirmed for derivatives 4b and 5d by
applying the methodology described by Katz[51] based on the
A similar study was carried out for biscamphanates (P)-
20d (Rf =0.34 in hexane/EtOAc 2:1) and (M)-20d (Rf =0.42
in hexane/EtOAc 2:1) obtained in 82% yield from tert-
butyl-substituted [4]helicenequinone (P,M)-5d, or in the
case of (P)-20d obtained from enantiopure (P)-5d, in 78%
yield (Scheme 15).
Configurational stability: Experimental data showed that
the configurational stability of [4]helicenequinones 4 and 5,
were dependent on the nature of the substituents of the tet-
racyclic skeleton, in particular, the one situated at C-12. The
enantiomeric stability experimentally observed for these hel-
ical compounds indicated the following qualitative order:
4a, 5a<4b, 5b<4c, 5c !4d, 5d.
ꢀ ꢀ
different O=C C O conformations of their M and P hely-
cenyl (ꢀ)-camphanates which bring about a different polari-
ty and NMR spectroscopic behaviour for each diastereoiso-
mer. Thus, we prepared pure biscamphanates (M)-19b and
(P)-19b from racemic (P,M)-4b, in 85% yield (Scheme 15),
The interconversion between two enantiomers is a reversi-
ble first-order reaction with the same rate constant in both
directions. The free energy of activation for the interconver-
sion between helimers of compounds 4 and 5 was computed
with a DFT B3LYP method (see the Supporting Informa-
tion) through the evaluation of the free energy difference
between two structures: one of the enantiomeric minima
and the transition state connecting it to the other degener-
ate enantiomeric minimum. The optimised geometries of
the enantiomer minimum and the transition state corre-
sponding to compound (P)-5b, containing a methyl group at
C-12 and the OEt substituent at C-6, which were used as a
model, are shown in Figures 3 and 4. The relative planarity
Scheme 15. Synthesis of bishelicenyl camphanates 19b and 20d from heli-
cal quinones 4b and 5d.
after quinone reduction with Zn followed by esterification
with (ꢀ)-camphanoyl chloride in the presence of DMAP
(DMAP=4-dimethylaminopyridine) and Et3N and chroma-
tographic separation. Diastereoisomer (P)-19b was also ob-
tained, under the same experimental conditions, starting
from enantiopure (P)-4b, in 74% yield. The lower Rf value
(0.43) shown by diastereomer (P)-19b on silica gel (hexane/
EtOAc 2:1) with respect to that of (M)-19b (Rf =0.53), as
well as the differentiated NOESY enhancements observed
between H2 and the two methyl groups at the same carbon
atom of the inside camphanate, allowed us to assign the P
absolute configuration to compound (+)-4b, which had re-
sulted from the domino Diels–Alder reaction, pyrolytic sulf-
oxide elimination and oxidation between the diene 6b and
the enantiopure sulfinyl quinone (SS)-8. In the case of the
(M)-19b helimer, only a NOE effect between one of the
methyl groups and H2 was observed.
Figure 3. B3LYP-optimized structure of the minimum for (P)-5b.
of these structures can be estimated from the value of the
dihedral angle fC12-C12a-C12b-C12c. The value of f for a
planar structure would be zero. The dihedral angles calculat-
ed for the optimised structure of enantiomeric minimum 5b
(Figure 3) and the transition state for the helimer inversion
TS-5b (Figure 4) are 42.7 and 31.08, respectively. The dihe-
dral angle f for the other enantiomeric form (M)-5b of the
minimum is ꢀ42.78. One could have expected the transition
state connecting structures with torsional angles of 42.7 and
612
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Chem. Eur. J. 2008, 14, 603 – 620

Synthesis of 7,8-Dihydro[4]helicene Quinones
FULL PAPER
Table 1. Calculated dihedral angle F and free-energy barriers of enantio-
mer interconversion for compounds 4 and 5.
Compd.
Fmin [8]
FTS [8]
DGꢀrac calcd
krac
DGꢀrac exp.
[a]
[kcalmolꢀ1
]
A
]
[kcalmolꢀ1
]
4a
5a
4b
5b
5b’
4c
5c
4d
5d
39.0
38.9
43.2
42.7
42.9
45.0
46.0
50.5
50.5
35.3
36.4
30.6
31.0
30.8
16.4
15.1
7.2
22.8
23.0
25.2
25.9
25.9
28.3
29.3
39.2
42.0
Figure 4. B3LYP-optimized structure of the transition state for the P to
M inversion of 5b, TS-5b.
1.88”10ꢀ6
5.06”10ꢀ7
25.3
26.0
4.87”10ꢀ8
27.4
ꢀ42.78 to have a value of f closer to 08. This hypothetical
structure, with f=08 would be too sterically constrained,
while the less symmetric structure TS-5b with f=31.08 has
a lower energy content. There exists another transition
structure with f=ꢀ31.08, defining an enantiomeric path for
the interconversion with exactly the same energy barrier.
Inspection of Figure 4, also gave some idea of the move-
ment the molecule was undergoing. There are two sources
of strain in these kinds of molecules that push them away
from planarity. The first one is the steric repulsion between
the substituent at C-12, a methyl group in the case of 5b,
and the carbonyl at C-1 of the tetrahelicene quinone frame-
work. The second is the strain associated with the presence
of two sp3-hybridised carbon atoms in the cyclohexadiene
ring in which C-12a and C-12b carbon atoms are included.
In a hypothetical structure with f=08, both strains would
be maximised at the same time. In a structure distorted
from planarity, such as TS-5b (Figure 4), only the steric
strain due to the interaction between the C-12 methyl and
the C=O is maximized. The carbonyl oxygen atom has a
maximum repulsion with the methyl at C-12, while the ar-
rangement of the sp3-hybridised carbon atoms is the same to
that in the minimum energy structure of Figure 3. If one
were to follow the reaction coordinate, a movement up-
wards of the quinone would involve the full reorganization
of the molecule, including that of the sp3 carbon atoms.
The other systems 4 and 5 computed behave in a similar
way to 5b and their structures will not be discussed in
detail. The results of the calculations are summarized in
Table 1, in which we have added the values of DGꢀrac for the
racemisation obtained experimentally for compounds 4b, 5b
19.1
[a] Kinetic data obtained at 298K from the plot of logat versus time.[53]
It is worth noting that the computed values for DGrꢀac
matched qualitatively the ordering of barriers observed by
experiments. Moreover, the experimental values determined
from the kinetic parameters for 4b, 4c and 5b matched
quantitatively with those predicted by calculation. This con-
firmed that the enantiomeric stability is associated with the
barrier of this particular interconversion mechanism. The
systems with the highest steric constraint at the C-12 posi-
tion due to the presence of the bulkiest tert-butyl substitu-
ent, 4d and 5d, showed the larger distortion away from pla-
narity in the f angle of the minimum energy geometry and
have the larger barriers of inversion. The values of DGrꢀac
calculated for the tert-butyl-substituted helicene quinones
4d and 5d were 39.2 and 42.0 kcalmolꢀ1, respectively. These
values are consistent with the fact that helicenequinones 4d
and 5d did not suffer enantiomeric inversion at room tem-
perature and are indefinitely stable as pure enantiomers at
this temperature. The order of the calculated DGꢀrac values,
shown in Table 1, suggested that the steric strain follows the
order: MeO (DGrꢀac =22.8 and 23.0 kcalmolꢀ1)<Me
(DGrꢀrac =25.2 and 25.9 kcalmolꢀ1)<iPr (DGꢀrac =28.3 and
29.3 kcalmolꢀ1)<<tBu (DGrꢀac =39.2 and 40.0 kcalmolꢀ1).
The methoxy substituent presents the lowest steric con-
straint because it can direct its methyl group away from the
carbonyl, thus alleviating the steric hindrance.[54] It may
seem surprising that compounds 4b and 5b, bearing the
methyl substituent presented a relatively small difference in
the DGꢀrac values with respect to those of the isopropyl-sub-
stituted analogues 4c and 5c, taking into account that the
steric constraint should be higher in the later.[54] A compari-
son of the geometries of the minima and transition states of
5b, TS-5b and 5c, TS-5c revealed that the conformation of
and 4c at 258C from the rate constant of racemisation,
[52]
krac
,
determined by measuring the optical rotation at fixed
intervals.[53] We examined polarimetrically at l=435 nm in a
2 dm tube with chloroform solutions of 4b (c=0.0046 g in
5 mL), 5b (c=0.006 g in 5 mL) and 4c (c=0.0043 g in
5 mL). The decrease of the optical rotation values time
showed excellent straight-line relationships in each case and
allowed us to obtain the rate constant (krac) from the slopes
of the plot of logat versus time.
the isopropyl group around the C-12–CH(CH3)2 bond
always places the two methyl substituents away from the
sterically congested position, being the C H bond of the iso-
A
ꢀ
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613

M. C. CarreÇo, A. Urbano et al.
propyl group in the gauche disposition with respect to the
C-12a sp2-hybridized carbon atom. In such a conformation,
the unfavourable gauche interactions between the CH3
groups of the isopropyl and C-12a, occurring in any other
conformation, are minimized. This could justify the small
differences calculated for the DGꢀrac of the methyl and iso-
propyl derivatives. In a recent paper,[11d] Yamaguchi has es-
tablished that methyl groups at the 1- and 12-positions in
[4]helicene derivatives exert a higher steric hindrance than
the corresponding isopropyl substituents.
none (8) and the appropriately 5-substituted 3-vinyl-1,2-di-
hydronaphathalenes 6 or 7. The process always occurs in a
one-pot domino sequence by starting from a highly p-facial
diastereoselective Diels–Alder reaction, followed by the py-
rolytic elimination of the sulfoxide. A detailed structural
study of the resulting compounds 16 and 17 provided evi-
dence for the existence of a different conformation in the
1,4-dihydroaromatic B ring that is dependent on the nature
of the C-12b substituent. In the isopropyl-substituted deriva-
tive, two different conformers could be isolated, thus show-
ing that in these molecules central and helical chiralities co-
exist. When the starting diene partner 7 bears an electron-
donating group, such as OEt, the domino sequence included
a third transformation, the aromatisation of the 1,4-dihy-
droaromatic ring, allowing the one-pot synthesis of helical
quinones 5. We have also established that the configuration-
al stability of tetrahelicenes 4 and 5 is mainly controlled by
the size of the substituent at C-12, with the tert-butyl-substi-
tuted derivatives 4d and 5d the only compounds that are in-
definitely stable at room temperature. The values of the rac-
emisation barriers calculated from computations, confirmed
the main role of the steric effects in the configurational in-
tegrity of these helical quinones. These results also provided
evidence for a small but significant influence electronic ef-
fects when an electron-donating group is situated at C-6 of
the aromatic system. The higher electron density of the C-1
carbonyl atom of the quinone in such 6-ethoxy-substituted
systems could be the origin of the higher values for their
racemisation barriers.
A comparison between the DGꢀrac values of the [4]helicen-
equinones 4 and the 6-ethoxy-substituted analogues 5, pro-
vided evidence for a slight increase for the barrier of activa-
tion of the latter. Thus, the calculated barriers of intercon-
version
for
derivatives
5
(DGrꢀrac 5 aꢀDGꢀrac 4 a =0.2),
(DGꢀrac 5 bꢀDGrꢀac 4 b =0.7),
(DGꢀrac 5 cꢀDGrꢀac 4 c =1.0)
(DGꢀrac 5 dꢀDGꢀrac 4 d =2.8), all bearing the ethoxy substituent
at C-6, are higher than those calculated for the C-6 hydro-
gen-substituted helicene quinones 4. This evidenced a small
but significant role of the electron-donating substitutent in
the configurational stability of these systems which must
hinder the enantiomeric inversion. Comparison of the geo-
metries in Figures 3 and 4 shows that the ethoxy group situ-
ated at C-6 has a very similar conformation in both the min-
imum energy structure TS-5a and the transition state TS-5b,
being very far from the region of the molecule in which
steric congestion could hinder the interconversion. Thus, no
steric effect of this substituent can be invoked to explain its
effect which must be probably of electronic origin, due to
the presence of the oxygen atom directly attached to the ar-
omatic system in a position (C-6) in which the electron-do-
nating effect can be transferred to the C-1 position, thus in-
creasing the electron density of the C(1)=O (Figure 3). This
hypothesis was further analysed by a supplementary calcula-
tion on a new system 5b’, in which the ethoxy group at the
C-6 position (R3 in Table 1) of the C-12 methyl-substituted
[4]helicene quinone 5b was replaced by an OH group. The
computed value was DGꢀrac 5 b0 =25.9 kcalmolꢀ1, only 0.02 kcal
molꢀ1 lower than that of 5b and 0.6 kcalmolꢀ1 higher than
that of 4b. Therefore, the effect of this substituent is essen-
tially electronic, confirming the observation from the com-
puted geometries.
Experimental Section
General: Melting points were obtained in open capillary tubes. 1H and
13C NMR spectra were recorded at 300 and 75 MHz, respectively, by
using CDCl3 as a solvent and tetramethylsilane as the internal standard.
All reactions were monitored by TLC, which was performed on precoat-
ed silica gel 60 F254 plates. Flash column chromatography was effected
with silica gel 60 (230–240 mesh) from Macherey–Nagel. Eluting solvents
are indicated in the text. HRMS were measured at 70 eV. Reagent quali-
ty solvents, such as THF, diethyl ether and acetonitrile, were dry pur-
chased and kept under an argon atmosphere over activated 4 Š molecu-
lar sieves. For toluene and benzene, activated 3 Š molecular sieves were
used. CH2Cl2 was predried over CaCl2, distilled over P2O5 and carefully
kept under an argon atmosphere. For routine workup, hydrolysis was car-
ried out with water, extractions with CH2Cl2 and solvent drying with
MgSO4. The values of ee were determined by chiral HPLC by using col-
umns Daicel Chiracel OD, AS or AD and/or by NMR spectroscopy by
using chiral lanthanide shift reagents.
An additional observation resulting from calculation is
that the value of the torsion angle f in the transition states
decreases as the free-energy barrier increases. This suggests
that when steric bulk is higher, the system gains less by dis-
torting from the ideal symmetric structure of the transition
state with a value of 08 for f.
General procedure A: Aromatization of 1,2-dihydronaphthalenes: A so-
lution of DDQ (1.89 g, 8.3 mmol) in CH2Cl2 (35 mL) was added to a solu-
tion of the corresponding dihydronaphthalene (6.9 mmol) in CH2Cl2
(35 mL). The mixture was stirred for 10 min and then washed with sever-
al portions of an aqueous saturated solution of NaHCO3. After workup
and flash chromatography, pure naphthalenes were obtained.
Conclusion
General procedure B: Synthesis of b-tetralones: To a well-stirred reflux-
ing solution of the corresponding b-methoxynaphthalene (6.2 mmol) in
EtOH (66 mL), small portions of Na (40–60 equiv) were carefully added
under argon. After the time indicated in each case, the reaction mixture
was cooled to 08C and acidified with 35% HCl until pH ꢁ1. The mix-
ture was stirred for 1 h at room temperature, diluted with CH2Cl2, ex-
We have succeeded in the convergent synthesis of enantio-
pure 5,7,8,12b-tetrahydro[4]helicene quinones 16 and 17 and
the 7,8-dihydro analogues 4 and 5, bearing different sterical-
ly demanding susbtituents at C-12 (OMe, Me, iPr, tBu),
from reaction between (SS)-2-(p-tolylsulfinyl)-1,4-benzoqui-
614
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 603 – 620

Synthesis of 7,8-Dihydro[4]helicene Quinones
FULL PAPER
tracted and the organic layer washed with an aqueous saturated solution
of NaHCO3. After workup and flash chromatography, pure 2-tetralones
were obtained.
7-Methoxy-1-isopropylnaphthalene
(13c):
BF3·OEt2
(21.6 mL,
170.5 mmol) was added to a solution of commercially available 7-me-
thoxy-1-tetralone (11) (7.50 g, 42.6 mmol) in dry Et2O (120 mL) under an
argon atmosphere. After stirring for 2 h, the reaction mixture was cooled
to ꢀ208C and added dropwise to a freshly prepared solution of iPrMgCl
(from 9.6 mL of iPrBr and 2.27 g of Mg turnings in 90 mL of Et2O for
30 min at reflux) at ꢀ658C. The mixture was allowed to reach room tem-
perature, stirred for 2 h and hydrolysed at 08C with a saturated aqueous
solution of NH4Cl. After extraction with Et2O and workup, a residue
containing 6-methoxy-4-isopropyl-1,2-dihydronaphthalene (12c) and 7-
methoxy-1-isopropylnaphthalene (13c) was obtained. This mixture was
dissolved in CH2Cl2 (210 mL) and treated with a solution of DDQ
(11.6 g, 51.0 mmol) in CH2Cl2 (250 mL), following general procedure A
(eluent: EtOAc/hexane 1:70). Compound 13c[34] was obtained in 77%
General procedure C: Synthesis of enol triflates: A solution of KHMDS
(HMDS=hexamethyldisilazane) in toluene (0.5m, 8 mL, 4.0 mmol) was
added to a solution of the corresponding b-tetralone (3.3 mmol) and N-
phenyl-trifluoromethanesulfonimide, Tf2NPh, (1.20 g, 3.3 mmol) in THF
(31 mL) at ꢀ788C under an argon atmosphere. The reaction mixture was
stirred at this temperature for the time indicated in each case, hydrolysed
with water and allowed to warm to RT. After extraction with EtOAc,
workup and flash chromatography, pure enol triflates were obtained.
General procedure D: Synthesis of 3-vinyl-1,2-dihydronaphthalenes: The
corresponding vinylstannane (0.35 mmol) was added to a well-stirred
mixture of the trifluoromethanesulfonate derivative (0.35 mmol), Pd-
1
yield as a colourless oil. H NMR: d=1.69 (d, J=6.9 Hz, 6H), 3.94 (sept,
A
J=6.9 Hz, 1H), 4.13 (s, 3H), 7.44 (dd, J=8.9, 2.4 Hz, 1H), 7.58 (dd, J=
8.1, 7.5 Hz, 1H), 7.62 (d, J=8.9 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.85
(dd, J=7.5, 1.4 Hz, 1H), 8.00 ppm (d, J=8.1 Hz, 1H); 13C NMR: d=
23.2, 28.6, 55.0, 102.1, 117.4, 122.1, 123.3, 126.0, 129.3, 130.3, 132.3, 143.0,
157.5 ppm;MS (EI): m/z (%): 115 (19), 128 (7), 141 (16), 154 (12), 170
(15), 200 [M]+ (56);MS (EI): m/z: calcd for C12H12O: 200.12011;found:
200.12083.
(3 mL) under an argon atmosphere. The reaction mixture was refluxed
for the reaction time indicated in each case, cooled to room temperature,
diluted with hexane (12 mL) and washed with a 10% aqueous solution of
NH4OH and water. After workup and flash chromatography on silica gel
or alumina, pure dienes were obtained.
General procedure E: Diels–Alder reactions: A solution of (SS)-8[32]
(0.32–0.48 mmol, 80–120 mg, 2 or 3 equiv) in CH2Cl2 (2 mL) was added
to a solution of the corresponding diene (0.16 mmol) in CH2Cl2 (2 mL) at
the temperature indicated in each case under an argon atmosphere. After
the time indicated in each case, the solvent was evaporated and the resi-
due was purified by flash chromatography.
1-tert-Butyl-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (14): tBuMgCl
in Et2O (2.0m, 17 mL, 34.0 mmol) was slowly added to a solution of com-
mercially available 7-methoxy-1-tetralone (11) (3.0 g, 17.0 mmol) in Et2O
(8 mL) under an argon atmosphere. After stirring for 48 h, the mixture
was hydrolysed at 08C with 10% HCl (100 mL) and stirred for 30 min at
room temperature. The organic layer was extracted with Et2O and
washed with water and a saturated aqueous solution of NaHCO3. After
workup and flash chromatography (eluent: EtOAc/hexane 1:20), com-
pound 14 was obtained in 56% yield as a white solid. M.p. 53–558C
(CH2Cl2/pentane); 1H NMR: d=0.97 (s, 9H), 1.51 (m, 1H), 1.83 (m,
2H), 1.87 (brs, 1H), 2.28 (ddd, J=3.4, 10.5, 15.3 Hz, 1H), 2.51 (ddd, J=
4.5, 9.1, 15.3 Hz, 1H), 2.65 (dt, J=15.0, 4.5 Hz, 1H), 3.78 (s, 3H), 6.73
(dd, J=2.6, 8.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 7.20 ppm (d, J=2.6 Hz,
1H); 13C NMR: d=21.2, 25.8, 29.7, 36.7, 39.9, 55.1, 76.1, 112.6, 113.8,
128.7, 146.3, 146.3, 156.9 ppm;MS (EI): m/z (%): 91 (6), 121 (22), 159
(8), 177 (100), 234 (10) [M]+;MS (EI): m/z: calcd for C15H22O2:
234.16198;found: 234.16193.
General procedure F: Diels–Alder reactions under high pressure condi-
tions: A solution of (SS)-8[32] (120 mg, 0.48 mmol, 3 equiv) in CH2Cl2
(2 mL) was added to a solution of the corresponding diene (0.16 mmol)
in CH2Cl2 (2 mL) under an argon atmosphere, and the mixture was sub-
mitted to high pressure conditions (8 Kbar). After the time indicated in
each case, the solvent was evaporated and the residue was purified by
flash chromatography.
General procedure G: Synthesis of helicene biscamphanates: Et3N
(516 mL, 3.68 mmol) was added to a mixture of the corresponding heli-
cene quinone (0.18 mmol), activated Zn (286 mg, 4.38 mmol) and (ꢀ)-
camphanoyl chloride (379 mg, 1.75 mmol) in CH2Cl2 (7.4 mL) under an
argon atmosphere. The reaction mixture was stirred for 24 h, filtered
through Celite and the organic solution was washed with saturated aque-
ous solution of NaHCO3, 10% HCl and water. After workup and flash
chromatography, pure helicene biscamphanates were obtained.
4-tert-Butyl-6-methoxy-1,2-dihydronaphthalene (12d): 10% H2SO4
(0.11 mL) was added to a solution of carbinol 14 (50 mg, 0.21 mmol) in
benzene (1 mL). After refluxing for 1 h, the reaction mixture was cooled
to room temperature and washed with a saturated aqueous solution of
NaHCO3 and water. After workup and flash chromatography (eluent:
EtOAc/hexane 1:40), compound 12d was obtained in 85% yield as a
yellow oil. 1H NMR: d=1.36 (s, 9H), 2.15 (dt, J=4.8, 8.1 Hz, 2H), 2.57
(t, J=8.1 Hz, 2H), 3.81 (s, 3H), 6.12 (t, J=4.8 Hz, 1H), 6.68 (dd, J=2.6,
8.3 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.24 ppm (d, J=2.6 Hz, 1H);
13C NMR: d=23.8, 28.3, 31.0, 34.9, 55.2, 109.7, 113.2, 124.7, 127.9, 130.7,
135.6, 144.7, 157.4 ppm;MS (EI): m/z (%): 69 (33), 84 (55), 105 (32);115
(41), 128 (28), 149 (25), 159 (85), 175 (39), 189 (25), 201 (46), 216 (100)
[M]+;MS (EI): m/z: calcd for C15H20O: 216.15141;found: 216.15199.
6-Methoxy-4-methyl-1,2-dihydronaphthalene (12b): MeMgCl in ether
(3.0m, 1.2 mL, 3.55 mmol) was slowly added to a solution of commercial-
ly available 7-methoxy-1-tetralone (11) (250 mg, 1.42 mmol) in Et2O
(5 mL) under an argon atmosphere. After stirring for 5 h, the mixture
was refluxed for 2 h, cooled to 08C and hydrolysed with a saturated
aqueous solution of NH4Cl. After extraction with ethyl ether and
workup, the residue was dissolved in CH2Cl2 (5 mL) and 35% HCl
(5 mL) was added. After stirring the mixture for 15 h, the organic layer
was separated and washed with a saturated solution of NaHCO3. After
workup and flash chromatography (EtOAc/hexane 1:4), compound
12b[33a] was obtained as a colourless oil in 93% yield. 1H NMR: d=2.08
(s, 3H), 2.27 (m, 2H), 2.73 (dd, J=7.9, 8.1 Hz, 2H), 3.84 (s, 3H), 5.91 (t,
J=4.6 Hz, 1H), 6.72 (dd, J=8.1, 2.6 Hz, 1H), 6.85 (d, J=2.6 Hz, 1H),
7.08 ppm (d, J=8.1 Hz, 1H); 13C NMR: d=19.2, 23.5, 27.4, 55.3, 109.6,
110.9, 126.0, 127.8, 128.5, 132.1, 136.9, 158.4 ppm;MS (EI): m/z (%): 115
(48), 129 (63), 144 (28), 159 (79), 172 (100), 174 [M]+ (63);MS (EI):
m/z: calcd for C12H14O: 174.10446;found: 174.10417.
1-tert-Butyl-7-methoxynaphthalene (13d): Compound 13d was obtained
from 12d by following general procedure A (eluent: EtOAc/hexane 1:20)
1
in 99% yield as a yellow oil. H NMR: d=1.68 (s, 9H), 3.98 (s, 3H), 7.19
(dd, J=2.2, 8.9 Hz, 1H), 7.30 (t, J=7.6 Hz, 1H), 7.53 (dd, J=1.1, 7.3 Hz,
1H), 7.68 (brd, J=7.9 Hz, 1H), 7.81 (d, J=2.3 Hz, 1H), 7.80 ppm (d, J=
8.9 Hz, 1H); 13C NMR: d=31.4, 35.8, 55.2, 106.8, 116.6, 123.0, 123.7,
127.1, 130.4, 130.9, 132.4, 144.5, 156.2 ppm;MS (EI): m/z (%): 57 (73), 71
(41), 84 (25), 105 (10), 113 (17), 149 (100), 167 (42), 199 (28), 214 (14)
[M]+;MS (EI): m/z: calcd for C15H18O: 214.13637;found: 214.13576.
7-Methoxy-1-methylnaphthalene (13b): Compound 13b[33c] was obtained
from 12b by following general procedure A (eluent: EtOAc/hexane 1:70)
1
in 97% yield as a white solid. M.p. 40–428C (CH2Cl2); H NMR: d=2.65
8-Methyl-3,4-dihydro-2(1H)naphthalenone (10b): Compound 10b[39] was
(s, 3H), 3.94 (s, 3H), 7.16 (dd, J=8.9, 2.4 Hz, 1H), 7.23 (d, J=2.4 Hz,
1H), 7.24 (dd, J=7.5, 6.9 Hz, 1H), 7.29 (dd, J=6.9, 0.6 Hz, 1H), 7.64
(dd, J=7.5, 0.6 Hz, 1H), 7.75 ppm (d, J=8.9 Hz, 1H); 13C NMR: d=
19.6, 55.3, 102.7, 117.9, 123.3, 126.1, 127.1, 128.9, 130.0, 132.9, 133.6,
157.6 ppm;MS (EI): m/z (%): 63 (6), 86 (21), 102 (5), 115 (9), 141 (10),
157 (7), 172 (100) [M]+;MS (EI): m/z: calcd for C12H12O: 172.08881;
found: 172.08916.
obtained from 13b by following general procedure
B (4 h, eluent:
EtOAc/hexane 1:20) in 72% yield as white solid. M.p. 71–738C
a
1
(CH2Cl2/hexane); H NMR: d=2.29 (s, 3H), 2.60 (t, J=6.8 Hz, 2H), 3.09
(t, J=6.8 Hz, 2H), 3.53 (s, 2H), 7.11 ppm (m, 3H); 13C NMR: d=19.0,
28.6, 38.1, 41.3, 125.2, 126.1, 128.0, 131.5, 135.5, 135.9, 201.1 ppm;MS
(EI): m/z (%): 65 (11), 77 (20), 91 (28), 115 (27), 118 (100), 146 (22), 160
Chem. Eur. J. 2008, 14, 603 – 620
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
615

M. C. CarreÇo, A. Urbano et al.
(48) [M]+;MS (EI):
m/z: calcd for C11H12O: 160.08882;found:
175 (7), 201 (20), 216 (100) [M]+;MS (EI): m/z: calcd for C14H18O:
160.08894.
216.11503;found: 216.11430.
8-Isopropyl-3,4-dihydro-2(1H)naphthalenone (10c): Compound 10c was
obtained from 13c by following general procedure (2 h, eluent:
5-Methyl-3-vinyl-1,2-dihydronaphthalene (6b): Compound 6b was ob-
tained from enol triflate 9b and vinyl tributyl stannane by following gen-
eral procedure D (7 h, eluent: EtOAc/hexane 1:40) in 97% yield as a col-
B
EtOAc/hexane 1:20) in 65% yield as a dark yellowish oil. 1H NMR: d=
1.24 (d, J=6.7 Hz, 6H), 2.57 (t, J=6.8 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H),
3.00–3.15 (sept, J=6.7 Hz, 1H), 3.63 (s, 2H), 7.09 (t, J=4.6 Hz, 1H),
7.17–7.22 ppm (2d, J=4.6 Hz, 2H); 13C NMR: d=23.1, 28.7, 29.1, 38.0,
41.2, 123.4, 125.3, 126.7, 130.3, 136.6, 146.2, 211.0 ppm;MS (EI): m/z
(%): 115 (73), 131 (85), 141 (16), 173 (86), 188 (100) [M]+;MS (EI): m/z:
calcd for C13H16O: 188.12011;found: 188.11987.
1
ourless oil. H NMR: d=2.37 (s, 3H), 2.45 (t, J=8.1 Hz, 2H), 2.84 (t, J=
8.1 Hz, 2H), 5.16 (d, J=10.9 Hz, 1H), 5.37 (d, J=17.4 Hz, 1H), 6.62 (dd,
J=10.9, 17.4 Hz, 1H), 6.66 (s, 1H), 6.99 (d, J=6.25, 1H), 7.02 (t, J=
6.25 Hz, 1H), 7.05 ppm (d, J=6.25 Hz, 1H); 13C NMR: d=19.0, 22.0,
28.3, 112.7, 125.1, 126.6, 128.3, 132.6, 133.6, 135.8, 137.8, 138.9 ppm;MS
(EI): m/z (%): 115 (9), 129 (26), 142 (12), 155 (30), 170 [M]+ (100);MS
(EI): m/z: calcd for C13H14: 170.10955;found: 170.10907.
8-tert-Butyl-3,4-dihydro-2(1H)naphthalen-2-one (10d): Compound 10d
was obtained from 13d by following general procedure B (5 h, eluent:
5-Isopropyl-3-vinyl-1,2-dihydronaphthalene (6c): Compound 6c was ob-
tained from enol triflate 9c and vinyl tributyl stannane by following gen-
eral procedure D (7 h, eluent: hexane) in 81% yield as a colourless oil.
1H NMR: d=1.31 (d, J=6.9 Hz, 6H), 2.48 (t, J=8.1 Hz, 2H), 2.89 (t, J=
8.1 Hz, 2H), 3.35 (sept, J=6.9 Hz, 1H), 5.20 (d, J=10.7 Hz, 1H), 5.41 (d,
J=17.4 Hz, 1H), 6.67 (dd, J=10.7, 17.4 Hz, 1H), 6.83 (s, 1H), 7.04 (dd,
J=7.7, 6.3 Hz, 1H), 7.11–7.21 ppm (m, 2H); 13C NMR: d=21.9, 23.5,
28.3, 28.8, 112.5, 123.0, 124.5, 125.0, 127.0, 131.3, 136.1, 138.0, 139.1,
144.0 ppm;MS (EI): m/z (%): 57 (13), 129 (14), 141 (21), 155 (36), 183
(50), 198 (100) [M]+;MS (EI): m/z: calcd for C15H18: 198.14085;found:
198.14099.
EtOAc/hexane 1:9) in 99% yield as
a yellow solid. M.p. 43–458C
(CH2Cl2/pentane); 1H NMR: d=1.41 (s, 9H), 2.48 (t, J = 6.7 Hz, 2H),
3.06 (t, J=6.7 Hz, 2H), 3.89 (s, 2H), 7.12 (dd, J=2.0, 7.5 Hz, 1H), 7.17
(t, J=7.5 Hz, 1H), 7.33 ppm (dd, J=2.0, 7.5 Hz, 1H); 13C NMR: d=29.3,
31.2, 35.3, 36.9, 45.7, 124.7, 125.7, 126.3, 131.4, 138.9, 147.7, 211.4 ppm;
MS (EI): m/z (%): 55 (21), 77 (36), 91 (66), 115 (100), 129 (88), 143 (54),
161 (93), 183 (76), 202 (84) [M]+;MS (EI): m/z: calcd for C14H18O:
202.13576;found 202.13628.
5,8-Dimethoxy-3,4-dihydronaphthalen-2-yl
trifluoromethanesulfonate
(9a): Compound 9a was obtained from 2-tetralone 10a[40] by following
general procedure C (1 h, eluent EtOAc/hexane 1:9) in 60% yield as a
white solid. M.p. 26–288C (EtOAc/hexane); 1H NMR: d=2.62 (t, J=
8.6 Hz, 2H), 3.03 (t, J=8.6 Hz, 2H), 3.78 (s, 6H), 6.67, 6.75 (AB system,
J=8.9 Hz, 2H), 6.85 ppm (s, 1H); 13C NMR: d=21.7, 25.6, 55.8, 55.9,
109.3, 111.3, 113.1, 118.5 (q, J=328.1 Hz), 122.2, 129.9, 130.9, 132.1,
149.5, 150.4 ppm;MS (EI): m/z (%): 69 (100), 91 (18), 115 (49), 129 (45),
143 (26), 157 (56), 183 (88), 317 (19), 334 (40) [M]+;MS (EI): m/z: calcd
for C13H13SO5F3: 334.08505;found: 334.08548.
5-tert-Butyl-3-vinyl-1,2-dihydronaphthalene (6d): Compound 6d was ob-
tained from enol triflate 9d and vinyl tributyl stannane by following gen-
eral procedure D (2 h, eluent: hexane) in 67% yield as a white solid.
M.p. 54–568C (CH2Cl2/hexane); 1H NMR: d=1.55 (s, 9H), 2.48 (t, J =
8.3 Hz, 2H), 2.91 (t, J=8.3 Hz, 2H), 5.24 (d, J=10.7 Hz, 1H), 5.44 (d,
J=17.4 Hz, 1H), 6.72 (dd, J=10.7, 17.4 Hz, 1H), 7.10 (dd, J=1.6, 7.3 Hz,
1H), 7.15 (t, J=7.3 Hz, 1H), 7.19 (s, 1H), 7.33 ppm (dd, J=1.8, 7.7 Hz,
1H); 13C NMR: d=21.5, 29.4, 31.7, 35.4, 112.4, 124.1, 125.7, 126.4, 127.9,
132.3, 136.8, 137.6, 139.2, 145.7 ppm;MS (EI): m/z (%): 115 (9), 128 (16),
141 (20), 155 (45), 169 (22), 197 (42), 212 (100) [M]+;MS (EI): m/z:
calcd for C16H20: 212.15650;found: 212.15742.
8-Methyl-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (9b):
Compound 9b was obtained from 2-tetralone 10b by following general
procedure C (6 h, eluent: EtOAc/hexane 1:20) in 91% yield as a colour-
less oil. 1H NMR: d=2.32 (s, 3H), 2.67 (t, J=8.5 Hz, 2H), 3.04 (t, J=
8.5 Hz, 2H), 6.69 (s, 1H), 7.00 (d, J=7.5 Hz, 1H), 7.04 (d, J=7.5 Hz,
1H), 7.11 ppm (t, J=7.5 Hz, 1H); 13C NMR: d=18.7, 26.2, 29.0, 115.6,
116.5, 122.1 (q, J=212.1 Hz), 125.2, 127.9, 128.6, 129.3, 134.4, 150.1 ppm;
MS (EI): m/z (%): 69 (8), 115 (21), 131 (100), 159 (42), 292 (23) [M]+;
MS (EI): m/z: calcd for C12H11F3O3S: 292.03802;found: 292.03810.
5,8-Dimethoxy-3-(1’-ethoxyvinyl)-1,2-dihydronaphthalene (7a): Com-
pound 7a was obtained from enol triflate 9a and 1-ethoxyvinyl tributyl
stannane by following general procedure
D (1.5 h, alumina, eluent:
EtOAc/hexane 1:4) in 50% yield as a very unstable colourless oil, which
was immediately used in the next step. 1H NMR: d=1.43 (t, J=7.0 Hz,
3H), 2.44 (dt, J=8.6, 2.1 Hz, 2H), 2.83 (t, J=8.69, 1.9 Hz, 2H), 3.79 (s,
3H), 3.80 (s, 3H), 3.84 (q, J=7.0 Hz, 2H), 4.21 (d, J=2.4 Hz, 1H), 4.42
(t, J=2.4 Hz, 1H), 6.65, 6.71 (AB system, J=8.9 Hz, 2H), 7.33 ppm (s,
1H).
8-Isopropyl-3,4-dihydronaphthalene-2-yl trifluoromethanesulfonate (9c):
Compound 9c was obtained from 2-tetralone 10c by following general
procedure C (1 h, eluent: EtOAc/hexane 1:70) in 88% yield as a colour-
less oil. 1H NMR: d=1.27 (d, J=6.9 Hz, 6H), 2.68 (t, J=8.3 Hz, 2H),
3.06 (t, J=8.3 Hz, 2H), 3.12 (sept, J=6.9 Hz, 1H), 6.84 (s, 1H), 7.02 (dd,
J=6.1, 5.7 Hz, 1H), 7.15–7.25 ppm (m, 2H); 13C NMR: d=23.3, 26.2,
28.8, 29.5, 115.3, 118.6 (q, J=319 Hz), 123.7, 125.2, 128.1, 128.3, 133.4,
145.0, 150.5 ppm;MS (EI): m/z (%): 69 (22), 97 (10), 117 (53), 129 (29),
143 (23), 169 (47), 187 (56), 320 [M]+ (30);MS (EI): m/z: calcd for
C14H15F3O3S: 320.06940;found: 320.06958.
5-Methyl-3-(1’-ethoxyvinyl)-1,2-dihydronaphthalene (7b): Compound 7b
was obtained from enol triflate 9b and 1-ethoxyvinyl tributyl stannane by
following general procedure D (4 h, alumina, eluent: pentane) in 60%
yield as a very unstable colourless oil, which was immediately used in the
next step. 1H NMR: d=1.43 (t, J=6.9 Hz, 3H), 2.38 (s, 3H), 2.46 (dd,
J=7.5, 8.5 Hz, 2H), 2.83 (dd, J=7.5, 8.5 Hz, 2H), 3.90 (q, J=6.9 Hz,
2H), 4.23 (d, J=2.5 Hz, 1H), 4.45 (t, J=2.5 Hz, 1H), 6.98 (d, J=6.9 Hz,
1H), 7.00 (dd, J=6.9 Hz, 1H), 7.01 (t, J=6.9 Hz, 1H), 7.21 ppm (s, 1H);
MS (EI): m/z (%): 77 (9), 115 (44), 128 (76), 143 (100), 171 (94), 186
(20), 214 [M]+ (58);MS (EI): m/z: calcd for C15H18O: 214.13576;found:
214.13548.
8-tert-Butyl-3,4-dihydronaphthalene-2-yl trifluoromethanesulfonate (9d):
Compound 9d was obtained from 2-tetralone 10d by following general
procedure C (2 h, eluent hexane) in 91% yield as a white solid. M.p. 26–
1
278C (hexane); H NMR: d=1.42 (s, 9H), 2.63, 3.03 (2, J=7.9 Hz t, 4H),
7.02 (dd, J=2.0, 7.5 Hz, 1H), 7.13 (t, J=7.3 Hz, 1H), 7.17 (s, 1H),
7.28 ppm (dd, J=2.0, 7.5 Hz, 1H); 13C NMR: d=25.8, 29.9, 31.6, 35.2,
118.3, 119.1 (q, J=319 Hz), 124.7, 125.9, 127.9, 128.9, 134.8, 146.9,
149.0 ppm;MS (EI): m/z (%): 69 (100), 91 (18), 115 (49), 129 (45), 143
(26), 157 (56), 183 (88), 317 (19), 334 [M]+ (40);MS (EI): m/z: calcd for
C15H17F3O3S: 334.08505;found: 334.08548.
5-Isopropyl-3-(1’-ethoxyvinyl)-1,2-dihydronaphthalene (7c): Compound
7c was obtained from enol triflate 9c and 1-ethoxyvinyl tributyl stannane
by following general procedure D (4 h, alumina, eluent: pentane) in 65%
yield as a very unstable colourless oil, which was immediately used in the
next step. 1H NMR: d=1.26 (d, J=7.5 Hz, 6H), 1.43 (t, J=7.0 Hz, 3H),
2.37–2.63 (m, 2H), 2.73–2.89 (m, 2H), 3.32 (sept, J=7.5 Hz, 1H), 3.90 (q,
J=7.0 Hz, 2H), 4.23 (d, J=2.4 Hz, 1H), 4.45 (t, J=2.4 Hz, 1H), 6.93–
7.03 (d, J=5.6 Hz, 1H), 6.99 (d, J=5.6 Hz, 1H), 7.13 (t, J=5.6 Hz, 1H),
7.33 ppm (s, 1H);MS (EI): m/z (%): 77 (20), 129 (35), 155 (38), 171 (27),
199 (32), 215 (100), 243 (95) [M]+;MS (EI): m/z: calcd for C17H22O:
243.17489;found: 243.17473.
5,8-Dimethoxy-3-vinyl-1,2-dihydronaphthalene (6a): Compound 6a was
obtained from enol triflate 9a and vinyl tributyl stannane by following
general procedure D (1.5 h, eluent: EtOAc/hexane 1:9) in 82% yield as a
colourless oil. 1H NMR: d=2.42 (t, J=7.9 Hz, 2H), 2.84 (t, J=8.3 Hz,
2H), 3.80 (s, 6H), 5.12 (d, J=10.7 Hz, 1H), 5.33 (d, J=17.4 Hz, 1H),
6.62 (dd, J=10.7, 17.4 Hz, 1H), 6.66, 6.69 (AB system, J=8.9 Hz, 2H),
6.81 ppm (s, 1H); 13C NMR: d=20.4, 21.3, 56.0, 109.9, 112.4, 122.0, 124.5,
124.9, 125.8, 137.0, 138.9, 149.8, 150.4 ppm;MS (EI): m/z (%): 141 (7),
5-tert-Butyl-3-(1’-ethoxyvinyl)-1,2-dihydronaphthalene (7d): Compound
7d was obtained from enol triflate 9d and 1-ethoxyvinyl tributyl stannane
by following general procedure D (2 h, alumina, eluent: pentane) in 60%
616
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 603 – 620

Synthesis of 7,8-Dihydro[4]helicene Quinones
FULL PAPER
yield as a very unstable colourless oil, which was immediately used in the
next step. H NMR: d=1.43 (t, J=6.9 Hz, 3H), 1.46 (s, 9H), 2.41 (t, J =
(P)-12-Methyl-7,8-tetrahydrobenzo[c]phenanthrene-1,4-dione (4b)
1
Method A: Compound (P)-4b was obtained from diene 6b by following
general procedure E (3 equiv of (SS)-8, ꢀ208C for 11 d and 58C for 23 d,
eluent: CH2Cl2/hexane 4:1) in 83% yield as an orange solid. M.p.: 170–
1728C (CH3CN);[ a]2D0 =+482 (c=0.05 in CHCl3); 1H NMR: d=2.18 (s,
3H), 2.50, 2.90 (2 m, 4H), 6.87, 6.92 (AB system, J=10.3 Hz, 2H), 7.10
(d, J=7.3 Hz, 1H), 7.17 (d, J=7.3 Hz 1H), 7.22 (t, J=7.3 Hz, 1H), 7.55,
7.95 ppm (AB system, J=7.7 Hz, 2H); 13C NMR: d=20.6, 30.4, 30.6,
124.8, 125.2, 128.0, 129.2, 131.3, 131.4, 131.5, 132.7, 135.0, 135.3, 137.3,
139.8, 139.9, 149.1, 185.0, 186.5 ppm;MS (EI): m/z (%): 101 (6), 189 (9),
202 (9), 229 (11), 259 (100), 274 (16) [M]+;MS (EI): m/z: calcd for
C19H14O2: 274.09938;found: 274.09872;elemental analysis calcd (%) for
C19H14O2: C 83.19, H 5.14;found: C 82.87, H 5.25;HPLC (Daicel Chiral-
pack AD chiral column, hexane/2-propanol 95:5), 0.5 mLminꢀ1, 254 nm,
Rt =21.9 min, T=258C, 35% ee.
7.9 Hz, 2H), 2.83 (t, J=7.9 Hz, 2H), 3.89 (q, J=6.9 Hz, 2H), 4.23 (d, J=
2.6, 1H), 5.44 (t, J=2.6 Hz, 1H), 7.02 (dd, J=1.2, 7.7 Hz, 1H), 7.07 (t,
J=7.5 Hz, 1H), 7.25 (dd, J=1.4, 7.7 Hz, 1H), 7.71 ppm (s, 1H);MS (EI):
m/z (%): 84 (22), 115 (32), 128 (61), 141 (52), 153 (44), 169 (72), 185 (9),
213 (100), 228 (19), 243 (60), 256 (17) [M]+;MS (EI): m/z: calcd for
C18H24O: 256.18272;found: 256.18287.
A
1,4-dione (16a): Compound (12bR,P)-16a was obtained from diene 6a
by following general procedure E (2 equiv of (SS)-8, ꢀ208C, 48 h, eluent:
acetone/hexane 1:6) in 55% yield as an orange solid. M.p. 164–1668C
1
(CH3CN);[ a]2D0 =+273 (c=0.14 in CHCl3); H NMR (500 MHz): d=2.31
(dt, J=16.9, 8.9 Hz, 1H), 2.54 (dt, J=15.8, 9.7 Hz, 1H), 2.70–2.81 (m,
1H), 2.97 (ddd, J=24.0, 3.3, 3.4 Hz, 1H), 3.13–3.25 (m, 1H), 3.35 (ddd,
J=13.7, 7.4, 1.9 Hz, 1H), 3.46 (s, 3H), 3.77 (s, 3H), 4.49 (t, J=6.6 Hz,
1H), 5.52 (t, J=1.2 Hz, 1H), 6.65, 6.70 (AB system, J=8.9 Hz, 2H), 6.75,
6.85 ppm (AB system, J=10.1 Hz, 2H); 13C NMR: d=20.4, 24.6, 27.9,
35.7, 56.1, 57.4, 109.3, 111.7, 115.6, 128.8, 130.3, 134.8, 135.7, 136.3, 137.0,
143.4, 148.8, 151.6, 186.2, 187.1 ppm;MS (EI): m/z (%): 55 (17), 77 (10),
94 (7), 115 (9), 152 (19), 165 (19), 177 (24), 202 (7), 221 (16), 235 (9), 249
(28), 260 (35), 275 (17), 209 (100), 322 [M]+ (95);MS (EI): m/z: calcd for
C20H18O4: 322.12051;found: 322.12039;elemental analysis calcd (%) for
C20H18O4: C 74.52, H 5.63;found: C 72.91, H 6.10.
Method B: Compound (P)-4b was obtained from diene 6b by following
general procedure F (13 h, eluent: CH2Cl2/hexane 4:1) in 89% yield as
an orange solid. [a]2D0 =+1547 (c=0.05 in CHCl3);after 250 h at RT, the
value of [a]2D0 decreased to zero. HPLC (Daicel Chiralpack AS chiral
column): hexane/2-propanol 99:1), 0.5 mLminꢀ1, 254 nm, Rt =44.5 min,
T=258C, 81% ee.
(P)-12-Methyl-6-ethoxy-7,8-dihydrobenzo[c]phenanthrene-1,4-dione
(5b): Compound (P)-5b was obtained from diene 7b by following gener-
al procedure E (2 equiv of (SS)-8, ꢀ208C, 48 h, eluent: EtOAc/hexane
1:4) in 64% yield as an orange solid. M.p. 169–1718C (CH3CN);[ a]2D0 =+
A
1
1633 (c=0.05 in CHCl3);96% ee, determined by H NMR (300 MHz) by
Compound (P,M)-4a was obtained from (12bR,P)-16a by following gen-
eral procedure A (6 h, eluent: acetone/hexane 1:6) in 59% yield as an
orange solid. M.p. 196–1988C (CH3CN);[ a]2D0 =0 (c=0.03 in CHCl3);
1H NMR (500 MHz): d=2.34 (dt, J=15.0, 4.8 Hz, 1H), 2.57 (dt, J=15.0,
4.3 Hz, 1H), 2.85 (ddd, J=15.0, 4.3, 2.7 Hz, 1H), 3.34 (ddd, J=15.0, 4.3,
2.1 Hz, 1H), 3.64 (s, 3H), 3.85 (s, 3H), 6.70, 6.85 (AB system, J=8.9 Hz,
2H), 6.86, 7.00 (AB system, J=10.3 Hz, 2H), 7.50, 7.90 ppm (AB system,
J=7.8 Hz, 2H); 13C NMR: d=21.4, 29.6, 55.1, 56.1, 109.2, 111.5, 124.9,
129.3, 130.1, 131.0, 137.1, 139.9, 147.5, 149.3, 149.7, 150.3, 151.8, 152.7,
185.0, 186.8 ppm;MS (EI): m/z (%): 149 (5), 189 (6), 245 (10), 289 (100),
290 (94), 320 [M]+ (10);MS (EI): m/z: calcd for C20H18O4: 320.10486;
found: 322.10391;elemental analysis calcd (%) for C 20H16O4: C 74.99, H
5.03;found: C 68.51, H 5.64.
using Pr
ACHTREUNG
rate]) as a chiral lanthanide shift reagent (4 mg (P)-5b/1.6 mg Pr
ACHTREUNG
0.8 mL of CDCl3); 1H NMR: d=1.50 (t, J=7.0 Hz, 3H), 2.12 (dt, J=
16.0, 4.7 Hz, 1H), 2.17 (s, 3H), 2.64 (dt, J=14.4, 4.2 Hz, 1H), 2.79 (ddd,
J=14.4, 4.6, 2.4 Hz, 1H), 3.32 (ddd, J=16.0, 4.6, 2.4 Hz, 1H), 4.15–4.35
(2dq, J=9.3, 7.0 Hz, 2H), 6.75 (s, 2H), 7.08 (d, J=7.1 Hz, 1H), 7.15 (d,
J=7.1 Hz, 1H), 7.19 (t, J=7.1 Hz, 1H), 7.49 ppm (s, 1H); 13C NMR: d=
14.7, 20.6, 22.5, 30.0, 64.5, 106.7, 124.6, 125.3, 127.7, 129.0, 132.3, 133.0,
135.4, 136.6, 137.2, 137.6, 139.9, 140.2, 158.8, 185.2, 185.4 ppm;MS (EI):
m/z (%): 85 (5), 189 (11), 229 (4), 245 (6), 275 (44), 303 (100), 318 (14)
[M]+;MS (EI): m/z: calcd for C21H18O3: 318.12559;found: 318.12552;el-
emental analysis calcd (%) for C21H18O3: C 79.22, H 5.70;found: C
78.92, H 5.78.
(P)-6-Ethoxy-9,12-dimethoxy-7,8-dihydrobenzo[c]phenanthrene-1,4-
dione (5a): Compound (P)-5a was obtained from diene 7a by following
general procedure E (2 equiv of (SS)-8, ꢀ788C, 48 h, eluent: EtOAc/
hexane 1:2) in 87% yield as an orange solid. M.p. 186–1888C (CH3CN);
[a]2D0 =+640 (c=0.027 in CHCl3), after 2 h at ꢀ208C the value of [a]D20
decreased to zero; 1H NMR (500 MHz): d=1.41 (t, J=7.1 Hz, 3H), 2.07
(dt, J=15.0, 4.4 Hz, 1H), 2.25 (dt, J=15.0, 4.4 Hz, 1H), 3.28 (m, 1H),
3.33 (m, 1H), 3.61 (s, 3H), 3.85 (s, 3H), 4.21 (m, 2H), 6.70, 6.85 (AB
system, J=8.9 Hz, 2H), 6.80, 6.90 (AB system, J=10.3 Hz, 2H),
7.42 ppm (s, 1H); 13C NMR: d=14.6, 20.9, 21.6, 55.2, 56.1, 64.4, 106.1,
109.0, 111.3, 123.9, 126.7, 129.3, 131.7, 132.9, 136.3, 136.4, 140.2, 149.6,
150.2, 158.5, 185.3, 185.6 ppm;MS (EI): m/z (%): 57 (33), 69 (17), 77
(15), 83 (11), 149 (25), 273 (10), 289 (14), 305 (34), 333 (100), 366
[M+2]+ (17);MS (EI): m/z: calcd for C22H20O5: 364.13107;found:
364.12949;elemental analysis calcd (%) for C 22H20O5: C 72.51, H 5.53;
found: C 67.53, H 5.14.
A
dione (16c): Compound (12bR,P)-16c was obtained from diene 6c by fol-
lowing general procedure E (2 equiv of (SS)-8, ꢀ208C, 42 d, eluent:
EtOAc/hexane 1:20) in 67% yield as an orange oil. [a]2D0 =+291 (c=0.05
in CHCl3); 1H NMR: d=0.97, 1.10 (2d, J=6.6 Hz, 6H), 2.20–2.43 (m,
1H), 2.60–3.15 (2 m, 5H), 3.20–3.40 (m, 1H), 4.55–4.67 (m, 1H), 5.53
(brs, 1H), 6.81–6.99 (m, 2H), 7.03–7.20 ppm (2 m, 3H); 13C NMR: d=
23.0, 24.6, 25.9, 27.9, 29.5, 29.7, 38.2, 115.2, 124.6, 125.6, 126.2, 136.1,
136.3, 136.5, 136.9, 139.7, 140.2, 143.3, 143.4, 186.1, 186.3 ppm;MS (EI):
m/z (%): 77 (6), 115 (11), 165 (11), 202 (27), 233 (22), 259 (100), 304 (28)
[M]+;MS (EI): m/z: calcd for C21H20O2: 304.14633;found: 304.14597.
HPLC (Daicel Chiralpack AD, chiral column, hexane/2-propanol 99:1):
0.5 mLminꢀ1, 254 nm, Rt =15.8 min, T=258C, 96% ee.
(12bR,M)-12-Isopropyl-5,7,8,12b-tetrahydrobenzo[c]phenanthrene-1,4-
dione (17c): A solution of (12bR,P)-16c (50 mg, 0.16 mmol) in CDCl3
(0.5 mL) was maintained at RT for 30 d. After evaporation of the solvent
and flash chromatography (eluent: CH2Cl2/hexane 4:1), compound
(12bR,M)-17c was obtained in 14% yield as an orange oil. [a]2D0 =ꢀ167
(c=0.05 in CHCl3); 1H NMR: d=1.15 (d, J = 6.9 Hz, 3H), 1.29 (d, J=
6.9 Hz, 3H), 2.20–2.50 (m, 1H), 2.55–2.90 (m, 4H), 3.15 (sept, J=6.9 Hz,
1H), 3.85 (dd, J=7.0, 17.2 Hz, 1H), 4.52 (m, 1H), 6.04 (m, 1H), 6.53,
6.39 (AB system, J=8.6 Hz, 2H), 7.05–7.35 ppm (m, 3H).
A
dione (16b): Compound (12bR,P)-16b was obtained from diene 6b by
following general procedure E (2 equiv of (SS)-8, ꢀ208C, 27 d, eluent:
CH2Cl2/hexane 4:1) in 81% yield as an orange oil. [a]2D0 =+332 (c=0.1 in
CHCl3); 1H NMR: d=2.10 (s, 3H), 2.19–2.43 (m, 1H), 2.85–3.12 (m,
4H), 3.15–3.43 (m, 1H), 4.60 (m, 1H), 5.50 (m, 1H), 6.82–6.95 (m, 3H),
6.97–7.14 ppm (m, 2H); 13C NMR: d=21.1, 24.7, 27.9, 29.2, 38.5, 115.2,
125.9, 126.0, 127.1, 130.6, 131.9, 136.8, 136.7, 138.4, 140.0, 140.9, 142.9,
186.6, 187.0 ppm;MS (EI): m/z (%): 101 (11), 131 (14), 189 (21), 202
(18), 229 (16), 245 (6), 259 (100), 276 (58) [M]+;MS (EI): m/z: calcd for
C19H16O2: 276.11503;found: 276.11398;HPLC (Daicel Chiralpack AD
(P)-12-Isopropyl-7,8-dihydrobenzo[c]phenanthrene-1,4-dione (4c)
Method A: Compound (P)-4c was obtained from diene 6c by following
general procedure E (3 equiv of (SS)-8, ꢀ208C for 11 d and 58C for 24 d,
eluent: CH2Cl2/hexane 4:1) in 79% yield as an orange solid. M.p. 196–
1988C (CH3CN);[ a]2D0 =+1451 (c=0.08 in CHCl3); H NMR: d=0.77 (d,
chiral column Hexane/2-Propanol 99:1): 0.5 mLminꢀ1
,
254 nm, Rt =
J = 6.5 Hz, 3H), 1.26 (d, J=6.5 Hz, 3H), 2.50–2.80 (2 m, 4H), 3.20 (sept,
J=6.5 Hz, 1H), 6.87, 6.92 (AB system, J=10.1 Hz, 2H), 7.17 (d, J=
29.9 min, T=258C, 96% ee.
Chem. Eur. J. 2008, 14, 603 – 620
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
617

M. C. CarreÇo, A. Urbano et al.
7.7 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.58,
7.95 ppm (AB system, J=7.7 Hz, 2H); 13C NMR: d=20.4, 26.9, 29.7,
30.8, 30.9, 123.8, 124.7, 125.1, 128.5, 131.0, 131.3, 131.6, 134.5, 137.4,
139.9, 146.2, 149.2, 184.9, 185.3 ppm;MS (EI): m/z (%): 202 (9), 229 (11),
259 (100), 302 [M]+ (3);MS (EI): m/z: calcd for C21H18O2: 302.13068;
found: 302.13097;elemental analysis calcd (%) for C 21H18O2: C 83.42, H
6.00;found: C 83.12, H 6.50;HPLC (Daicel Chiralpack OD chiral
column, hexane/2-propanol 90:10): 0.5 mLminꢀ1, 254 nm, Rt =20.3 min,
T=258C, 80% ee.
(P)-12-tert-Butyl-6-ethoxy-7,8-dihydrobenzo[c]phenanthrene-1,4-dione
(5d): Compound (P)-5d was obtained from diene 7d by following gener-
al procedure E (2 equiv of (SS)-8, ꢀ208C, 3 d, eluent: EtOAc/hexane
1:20) in 57% yield as an orange solid. M.p.: 118–1208C (CH3CN);[ a]D20
=
+977 (c=0.03 in CHCl3); 1H NMR: d=1.06 (s, 9H), 1.52 (t, J=7.1 Hz,
3H), 2.11 (dt, J=4.5, 14.7 Hz, 1H), 2.47 (dt, J=4.4, 14.7 Hz, 1H), 2.73
(ddd, J=2.2, 4.2, 15.1 Hz, 1H), 3.30 (ddd, J=2.2, 3.6, 14.7 Hz, 1H), 4.25
(dq, J=20.0, 7.1 Hz, 2H), 6.68, 6.81 (AB system, J=10.1 Hz, 2H), 7.14
(d, J=7.1 Hz, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H),
7.48 ppm (s, 1H); 13C NMR: d=14.7, 23.1, 31.2, 33.9, 37.5, 64.5, 106.9,
123.8, 127.0, 127.2, 129.3, 130.1, 131.7, 132.1, 136.3, 137.2, 140.1, 141.0,
149.4, 157.9, 184.0, 185.6 ppm;MS (EI): m/z (%): 71 (10), 85 (6), 189
(12), 229 (6), 247 (10), 275 (55), 303 (100), 362 ppm (4) [M+2]+;MS
(EI): m/z: calcd for C24H24O3: 360.17254;found: 360.17126;HPLC
(Daicel Chiralcel OD chiral column, hexane/2-propanol 90:10):
0.5 mLminꢀ1, 254 nm, Rt =14.0 min, T=258C, 95% ee.
Method B: Compound (P)-4c was obtained from diene 6c by following
general procedure F (13 h, eluent: CH2Cl2/hexane 4:1) in 73% yield as
an orange solid. [a]2D0 =+1758 (c=0.05 in CHCl3);HPLC: (Daicel Chir-
alpack OD chiral column, hexane/2-propanol 90/10): 0.5 mLminꢀ1
,
254 nm, Rt =20.9 min, T=258C, 82% ee.
(P)-12-Isopropyl-6-ethoxy-7,8-dihydrobenzo[c]phenanthrene-1,4-dione
(5c): Compound (P)-5c was obtained from diene 7c by following general
procedure E (2 equiv of (SS)-8, ꢀ208C, 3 h, eluent: EtOAc/hexane 1:40)
Helicene biscamphanate (M)-19b: Compound (M)-19b was obtained
from 7,8-dihydro[4]helicene quinone (P,M)-4b by following general pro-
cedure G, after chromatographic separation (eluent: EtOAc/hexane 1:2)
of the mixture with helicene biscamphanate (P)-19b, in 40% yield as a
yellowish oil. Rf =0.53 (EtOAc/hexane 1:2);[ a]2D0 =ꢀ186 (c=0.09 in
CHCl3); 1H NMR: d=0.79 (s, 3H), 0.94 (s, 3H), 1.03 (s, 3H), 1.20 (s,
3H), 1.21 (s, 3H), 1.22 (s, 3H), 1.37–1.51 (m, 1H), 1.56–1.73 (m, 2H),
1.77–1.88 (m, 1H), 1.94 (s, 3H), 1.98–2.13 (m, 1H), 2.27–2.40 (m, 1H),
2.61–2.88 (m, 6H), 7.10 (dd, J=7.3, 1.4 Hz, 1H), 7.14 (t, J=7.3 Hz, 1H),
7.19 (dd, J=7.3, 1.4 Hz, 1H), 7.30, 7.15 (AB system, J=8.1 Hz, 2H),
7.45, 7.35 ppm (AB system, J=8.3 Hz, 2H);MS (EI): m/z (%): 83 (66),
125 (14), 259 (29), 456 (11), 636 (100) [M]+;MS (EI): m/z: calcd for
C39H40O8: 636.27232;found: 636.27155.
in 65% yield as an orange solid. M.p.: 178–1808C (CH3CN);[ a]D20
=
1
+1678 (c=0.08 in CHCl3); H NMR: d=0.74 (d, J=6.7 Hz, 3H), 1.24 (d,
J=6.7 Hz, 3H), 1.51 (t, J=7.1 Hz, 3H), 2.09 (dt, J=15.6, 4.5 Hz, 1H),
2.59 (dt, J=14.5, 3.8 Hz, 1H), 2.77 (ddd, J=14.5, 4.5, 2.4 Hz, 1H), 3.21
(sept, J=6.7 Hz, 1H), 3.32 (ddd, J=15.6, 3.8, 2.4 Hz, 1H), 4.14–4.36 (dq,
J=9.2, 7.1 Hz, 2H), 6.80, 6.88 (AB system, J=10.2 Hz, 2H), 7.15 (d, J=
7.5 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.27 (t, J=7.5 Hz, 1H), 7.48 ppm (s,
1H); 13C NMR: d=14.7, 20.6, 22.6, 26.9, 29.7, 30.5, 64.5, 106.5, 123.5,
124.5, 125.0, 128.3, 131.3, 132.2, 136.7, 136.8, 137.7, 139.8, 140.2, 146.4,
158.9, 184.2, 185.4 ppm;MS (FAB +): m/z (%): 283 (48), 303 (17), 327
(93), 347 (11) [M+1]+;MS (FAB +): m/z: calcd for C23H23O3: 347.16472;
found: 347.16318;elemental analysis calcd (%) for C 23H22O3 (346.2): C
79.39, H 6.46;found: C 79.74, H 6.40;HPLC (Daicel Chiralpack OD
Helicene biscamphanate (P)-19b: Compound (P)-19b was obtained from
7,8-dihydro[4]helicene quinone (P,M)-4b as above, in 45% yield, or from
(P)-4b by following general procedure G (eluent: EtOAc/hexane 1:2), in
82% yield, as a white solid. Rf =0.43 (EtOAc/hexane 1:2);m.p. 266–
2688C (CH3CN);[ a]2D0 =+222 (c=0.1 in CHCl3); 1H NMR: d=0.84 (s,
3H), 1.04 (s, 3H), 1.09 (s, 3H), 1.20 (s, 3H), 1.21 (s, 3H), 1.22 (s, 3H),
1.50–1.62 (m, 2H), 1.70–1.80 (m, 1H), 1.85–1.90 (m, 1H), 1.87 (s, 3H),
2.07–2.13 (m, 1H), 2.32–2.42 (m, 1H), 2.65–2.90 (m, 6H), 7.30, 7.15 (AB
system, J=8.5 Hz, 2H), 7.15 (dd, J=7.4, 3.9 Hz, 1H), 7.20 (dd, J=7.4,
3.9 Hz, 1H), 7.21 (t, J=7.4, 1H), 7.85, 7.65 ppm (AB system, J=8.0 Hz,
2H);MS (EI): m/z (%): 83 (63), 125 (12), 259 (24), 456 (10), 636 (100)
[M]+;MS (EI): m/z: calcd for C39H40O8: 636.27232;found: 636.27460.
chiral column, hexane/2-propanol 95:5): 0.5 mLminꢀ1
, 254 nm, Rt =
52.7 min, T=258C, 97% ee.
A
dione (17d): Compound (12bR,M)-17d was obtained from diene 6d by
following general procedure E (2 equiv of (SS)-8, 208C, 7 d, eluent:
EtOAc/hexane 1:12), after separation of the 25:15:60 mixture of 17d, 4d
and 18, in 14% yield as a red solid. M.p.: 188–1898C (CH3CN);[ a]D20
=
ꢀ240 (c=0.02 in CHCl3); 1H NMR: d=1.32 (s, 9H), 2.24 (m, 1H), 2.41
(dt, J=13.9, 3.1 Hz, 1H), 2.51 (ddd, J=4.2, 9.5, 18.8 Hz, 1H), 2.64 (dt,
J=3.0, 13.2 Hz, 1H), 3.75 (dt, J=3.2, 14.3 Hz, 1H), 3.81 (ddd, J=1.3,
6.6, 18.8 Hz, 1H), 4.63 (d, J=8.8 Hz, 1H), 5.91 (dq, J=6.6, 2.0 Hz, 1H),
6.37, 6.61 (AB system, J=7.3 Hz, 2H), 7.06 (d, J=7.3 Hz, 1H), 7.23 (d,
J=7.4 Hz, 1H), 7.36 ppm (dt, J=1.1, 8.1 Hz, 1H); 13C NMR: d=25.4,
31.4, 31.8, 32.1, 36.0, 42.8, 119.0, 124.8, 126.3, 133.1, 134.5, 137.0, 141.9,
145.8 (2C), 146.4, 147.3, 147.7, 184.9, 185.6 ppm;MS (EI): m/z (%): 57
(100), 115 (6), 189 (8), 202 (12), 233 (9), 245 (6), 262 (73), 320 (16)
[M+2]+;MS (EI): m/z: calcd for C22H22O2: 318.16198;found: 318.16116;
HPLC (Daicel Chiralpack AS chiral column, hexane/2-propanol 97:3),
0.7 mLminꢀ1, 254 nm, Rt =8.4 min, T=258C, 72% ee.
Helicene biscamphanate (M)-20d: Compound (M)-20d was obtained
from 7,8-dihydro[4]helicene quinone (P,M)-5d by following general pro-
cedure G, after chromatographic separation (eluent: EtOAc/hexane 1:2)
of the mixture with helicene biscamphanate (P)-20d, in 42% yield as a
yellowish oil. Rf =0.42 (EtOAc/hexane 1:2);[ a]2D0 =ꢀ116 (c=0.12 in
CHCl3); 1H NMR (500 MHz): d=0.81 (s, 3H), 0.87 (s, 9H), 0.97, 1.07,
1.22, 1.23, 1.24 (5s, 5”3H), 1.41 (m, 1H), 1.54 (t, J=7.0 Hz, 3H), 1.55,
1.73, 1.85, 1.87, 2.08, 2.19 (6 m, 6H), 2.34 (dt, J=4.5, 9.0 Hz, 1H), 2.46
(m, 1H), 2.70 (m, 2H), 3.30 (ddd, J=2.0, 4.0, 16.0 Hz, 1H), 4.14–4.24 (m,
2H), 6.79, 7.24 (AB system, J=8.2 Hz, 2H), 7.03 (d, J=7.2 Hz, 1H), 7.19
(t, J=7.1 Hz, 1H), 7.21 (s, 1H), 7.52 ppm (ddd, J=0.6, 1.3, 8.0 Hz, 1H);
MS (EI): m/z (%): 55 (21), 83 (61), 97 (20), 125 (13), 137 (14), 275 (19),
303 (35), 484 (14), 722 (100) [M]+;MS (EI): m/z: calcd for C44H50O9:
722.34548;found: 722.34772.
(P)-12-tert-Butyl-7,8-dihydrobenzo[c]phenanthrene-1,4-dione (4d)
Method A: Compound (P)-4d was obtained from diene 6d by following
general procedure E (2 equiv of (SS)-8, 208C, 7 d, eluent: EtOAc/hexane
1:12), after separation of the 25:15:60 mixture of 17d, 4d and 18, in 10%
yield as a red solid. M.p.: 172–1748C (CH3CN);[ a]2D0 =+1371 (c=0.02 in
CHCl3); 1H NMR: d=1.32 (s, 9H), 2.57, 2.79 (2 m, 4H), 6.77, 6.91 (AB
system, J=10.3 Hz, 2H), 7.16 (d, J=7.5 Hz, 1H), 7.27 (t, J=7.1 Hz, 1H),
7.57 (d, J=7.8 Hz, 1H), 7.57, 7.98 (AB system, J=7.9 Hz, 2H);MS (EI):
m/z (%): 55 (35), 57 (66), 69 (36), 71 (27), 83 (19), 121 (16), 149 (39), 202
(13), 229 (35), 260 (78), 316 (100) [M]+;MS (EI): m/z: calcd for
C22H20O2: 316.14663;found: 316.14612;HPLC (Daicel Chiralpack AS
Helicene biscamphanate (P)-20d: Compound (P)-20d was obtained from
7,8-dihydro[4]helicene quinone (P,M)-5d as above, in 42% yield, or from
(P)-5d by following general procedure G (eluent: EtOAc/hexane 1:2) in
78% yield as a yellowish oil. Rf =0.34 (EtOAc/hexane 1:2);[ a]2D0 =+92
(c=0.16 in CHCl3); 1H NMR: (500 MHz): d=0.80 (s, 3H), 0.81 (s, 9H),
1.05 (s, 3H), 1.08 (s, 3H), 1.23 (s, 6H), 1.24 (s, 3H), 1.51 (t, J=7.0 Hz,
3H), 1.40, 1.56, 1.79, 1.85, 1.91, 2.06, 2.14 (7 m, 7H), 2.32 (dt, J=4.5,
9.0 Hz, 1H), 2.52 (m, 1H), 2.67 (m, 2H), 3.24 (ddd, J=2.0, 4.0, 16.0 Hz,
1H), 4.12–4.24 (m, 2H), 6.75, 7.23 (AB system, J=8.2 Hz, 2H), 7.13 (d,
J=7.2 Hz, 1H), 7.18 (s, 1H), 7.18 (t, J=7.1 Hz, 1H), 7.41 ppm (dd, J=
1.3, 8.0 Hz, 1H); 13C NMR (125 MHz): d=10.0, 10.1, 15.2, 17.3, 17.3,
17.5, 24.0, 29.4 (2C), 29.5, 30.1, 31.6, 32.2, 32.9, 37.5, 54.9, 55.0, 55.4, 64.3,
91.1, 91.5, 98.8, 115.6, 116.8, 123.9, 125.9, 126.9, 127.9, 128.2, 134.0, 134.6,
chiral column, hexane/2-propanol 99:1): 0.3 mLminꢀ1
, 254 nm; Rt =
29.5 min, T=258C, 72% ee.
Method B: Compound (P)-4d was obtained from diene 6d by following
general procedure F (24 h, eluent: EtOAc/hexane 1:4), after separation
of the 40:60 mixture of 4d and 18, in 37% yield as a red solid. [a]D20
=
+1573 (c=0.1 in CHCl3);HPLC: (Daicel Chiralpack OD chiral column,
hexane/2-propanol 99:1): 0.5 mLminꢀ1, 254 nm; Rt =20.9 min, T=258C,
80% ee.
618
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 603 – 620

Synthesis of 7,8-Dihydro[4]helicene Quinones
FULL PAPER
136.1, 142.2, 143.6, 144.6, 149.5, 155.6, 164.9, 166.3, 178.2 ppm (2C);MS
(EI): m/z (%): 57 (100), 83 (72), 97 (33), 107 (34), 137 (60), 154 (73), 275
(19), 303 (12), 399 (16), 667 (14), 722 ppm (69) [M]+;MS (EI): m/z:
calcd for C44H50O9: 722.34548;found: 722.34521.
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Acknowledgements
We thank Dirección General de Investigación Científica y TØcnica (grant
no. CTQ2005–02095/BQU) and the Universidad Autónoma de Madrid/
Comunidad Autónoma de Madrid (ref. CCG06-UAM/PPQ-0070) for fi-
nancial support. S.G.-C. and M.J.S.-C. thank the Comunidad Autónoma
de Madrid and the Ministerio de Eduación y Ciencia for fellowships.
F.M. and A.N.-C. thank the Spanish MEC (projects no. CTQ2005–09000-
CO1–02 and CSD2006–003), the Catalan DURSI (project no.
2005SGR00715) and the ICIQ foundation for financial support.
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Received: May 21, 2007
Published online: October 8, 2007
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