Enantioselective synthesis of 3-methylisochromans and determination of their absolute configurations by circular dichroism

Article abstract of DOI:10.1002/ejoc.200600678

Seven (S)-3-methylisochromans with different substitution patterns on their aromatic rings, and hence with different directions of their sum electric transition moments, were synthesized by ring-closure of optically active (S)-1-arylpropan-2-ol derivatives. The (S)-1-arylpropan-2-ols were obtained by kinetic resolution and their absolute configurations were determined with the aid of a zinc porphyrin tweezer and by Mosher's method. A systematic CD study of substituted isochroman derivatives revealed that, unlike in the cases of chiral tetralin and 2,3-dihydrobenzo[b]furan chromophores, the presence of achiral substituents of large spectroscopic moment (e.g., OMe) on the aromatic ring does not change the helicity rule of the "unsubstituted" isochroman chromophore: (P)/(M) helicity of the isochromen heteroring resulted in positive/negative ¹L_b band Cotton effects (CE) regardless of the nature(s) and position(s) of the substituent(s). (S)-3-Methylisochromans were oxidized at C-1, allowing access to the corresponding dihydroisocoumarins, in which positive CE of the n→-π* transitions were correlated with (P) helicity and (S) absolute configuration. On DDQ-assisted oxidation, two trans-1-methoxy-3-methylisochrornan derivatives were prepared and used to study the effect of the axial benzylic C-1 methoxy group on the conformation of the heteroring and the ¹L_b band CE. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200600678

FULL PAPER
DOI: 10.1002/ejoc.200600678
Enantioselective Synthesis of 3-Methylisochromans and Determination of Their
Absolute Configurations by Circular Dichroism
Gábor Kerti,[a] Tibor Kurtán,*[a] Tünde-Zita Illyés,[a] Katalin E. Kövér,[b] Sándor Sólyom,[c]
Gennaro Pescitelli,[d] Naoko Fujioka,[e] Nina Berova,[e] and Sándor Antus*[a,f]
Dedicated to Prof. András Lipták on the occasion of his 70th birthday
Keywords: Chirality / Configuration determination / Kinetic resolution
Seven (S)-3-methylisochromans with different substitution
patterns on their aromatic rings, and hence with different di-
rections of their sum electric transition moments, were syn-
thesized by ring-closure of optically active (S)-1-arylpropan-
2-ol derivatives. The (S)-1-arylpropan-2-ols were obtained by
kinetic resolution and their absolute configurations were de-
termined with the aid of a zinc porphyrin tweezer and by
Mosher’s method. A systematic CD study of substituted
isochroman derivatives revealed that, unlike in the cases of
chiral tetralin and 2,3-dihydrobenzo[b]furan chromophores,
the presence of achiral substituents of large spectroscopic
moment (e.g., OMe) on the aromatic ring does not change
the helicity rule of the “unsubstituted” isochroman chromo-
phore: (P)/(M) helicity of the isochroman heteroring resulted
in positive/negative 1Lb band Cotton effects (CE) regardless
of the nature(s) and position(s) of the substituent(s). (S)-3-
Methylisochromans were oxidized at C-1, allowing access to
the corresponding dihydroisocoumarins, in which positive
CE of the nǞπ* transitions were correlated with (P) helicity
and (S) absolute configuration. On DDQ-assisted oxidation,
two trans-1-methoxy-3-methylisochroman derivatives were
prepared and used to study the effect of the axial benzylic
C-1 methoxy group on the conformation of the heteroring
1
and the Lb band CE.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
There are several natural 3-alkylisochromans possessing re-
markable biological activities in which the absolute configu-
rations have not yet been determined: the absolute configu-
rations of, for instance, the anticoccidial optically active 3-
methylisochroman derivative 1,[4] isolated from Penicil-
lium sp., and the tricyclic derivatives 2a–c[5] have not been
Introduction
Thanks to semiempirical helicity rules, the chiroptical
properties of benzene-fused cyclic compounds such as tetra-
lins,[1] chromans,[2] or dihydrobenzo[b]furans[2a,3] are widely
used for the determination of the absolute configurations
of natural or synthetic derivatives containing these chromo-
phores. In contrast, there is no such rule – which would
allow direct configurational assignment by a simple CD
measurement – available for the isochroman chromophore.
[a] Department of Organic Chemistry, University of Debrecen,
P. O. B. 20, 4010 Debrecen, Hungary
E-mail: kurtant@tigris.klte.hu
[b] Department of Inorganic and Analytical Chemistry, University
of Debrecen,
4010 Debrecen, Hungary
[c] IVAX Drug Research Institute Ltd.,
1323 Budapest, Hungary
[d] Università di Pisa, Dipartimento di Chimica e Chimica Indus-
triale,
Via Risorgimento 35, 56126 Pisa, Italy
[e] Department of Chemistry, Columbia University,
New York, New York 10027, USA
[f] Research Group for Carbohydrates of the Hungarian Academy
of Sciences,
P. O. B. 55, 4010 Debrecen, Hungary
E-mail: antuss@tigris.klte.hu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
296
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Synthesis and Absolute Configurations of 3-Methylisochromans
FULL PAPER
reported, while the absolute configurations of the topoiso-
merase II inhibitor CJ-12,373 (cis-3)[6] and the isochroman
toxin trans-4,[7] natural products containing benzylic hy-
droxy groups, have also not been determined.
1
The sign of the benzene Lb CD band can be correlated
with the conformation or helicity of the fused heteroring of
the isochroman chromophore by a helicity rule. Since the
relative steric orientations of the substituents on the hetero-
ring can be determined by NMR, the measurement of its
CD spectrum allows elucidation of ring helicity and hence
of the absolute configuration.
A relationship between the helicity of the heteroring and
the 1Lb CD band, based on the synthetic steroid model
compounds 5 and 6 (Figure 1, a), had previously been pro-
posed for the isochroman chromophore with no aromatic
substituents: (P) helicity of the heteroring gives rise to a
1
positive Cotton effect (CE) for the Lb band while (M) he-
licity is manifested in a negative one (Figure 1, b).[8] How-
1
ever, a negative Lb band CE was measured for the 6aβ-H,
12aβ-H derivative 7, in which the heteroring should adopt
(P) helicity provided that ring A of the cholestane skeleton
has the chair conformation. This discrepancy could be at-
tributed to the contribution of a conformer with the boat
conformation in ring A, but it made the application of the
above helicity rule ambiguous for the configurational as-
signment of natural isochromans, and so enantioselective
synthesis and CD study of further isochroman derivatives
of known absolute configurations are required in order to
make the helicity rule suitable for the configurational as-
signment of chiral isochromans. Moreover, it had pre-
viously been shown for tetralin,[1a] phenylcarbinamine, and
carbinol[9] – and recently for 2,3-dihydrobenzo[b]furan[2a]
derivatives – that the presence on the fused aromatic ring
of achiral substituents with large spectroscopic moments,
such as hydroxy, alkoxy, or alkenyl, can change the sign of
Figure 1. a) Structures of isochroman model compounds 5–7 with
1
the helicity of their heterorings and the signs of the measured Lb
CE bands. b) Helicity rule for the isochroman chromophore with
no substituents on the aromatic ring represented by the examples
of 5 and 6.
to optically active substituted dihydroisocoumarins such as
(S)-mellein. For the configurational assignment of 1-alk-
oxy- or 1-hydroxyisochromans such as cis-3 and trans-4, the
effect of axial benzylic C-1 methoxy groups both on the
1
conformation of the heteroring and on the Lb band CE
was studied and compared with those relating to the corre-
sponding flavan-4-ols.
Results and Discussion
1
the Lb CE, even though the absolute configurations of the
stereogenic centers remain the same. This has been ex-
plained by the conjecture that achiral substituents with
large spectroscopic moments can change the direction of
Arylpropanols and Isochromans
3-Methylisochroman derivatives (+)-(S)-9a–e with dif-
the sum electric transition moment vector and hence the ferent substitution pattern on their aromatic rings were syn-
polarization directions of the aromatic transitions by more thesized by ring-closure of the (+)-(S)-1-arylpropan-2-ols
1
than 30°, resulting in inversion of the measured Lb CE.[1a] 8a–e (Scheme 1), in turn prepared by kinetic resolution.
Since natural or synthetic isochroman derivatives of phar-
Since Pseudomonas lipases have been found to be very
macological interest often contain achiral substituents of effective enzymes in the kinetic transesterification of numer-
large spectroscopic moment (alkoxy, hydroxy) on their ous racemic secondary alcohols with remarkable enantio-
fused aromatic rings, their configurational assignment by preference and tolerance for a great variety of substrates,[11]
CD spectroscopy would thus require a systematic study of the lipase from Pseudomonas cepacia (PCL) was used for
whether the different substitution patterns would affect the the kinetic resolution of rac-8a–c. PCL-catalyzed acylations
helicity rule proposed for the unsubstituted isochroman of rac-8a–c were carried out with vinyl acetate (VA), the
chromophore.[8] In order to achieve this goal, enantioselec- reactions were terminated at approximately 50% conversion
tive syntheses of 3-methylisochroman derivatives with dif- as monitored by TLC (Scheme 2), and the unreacted
ferent substitution patterns on their aromatic rings were alcohols (+)-(S)-8a–c and the acetates (–)-(R)-8a–c-Ac were
carried out and their absolute configurations were deter- separated by column chromatography.
mined independently prior to the formation of the hetero-
ring.
As the chirality of the C-2 stereogenic center should be
preserved during the ring-closure of each optically active
Since isochroman derivatives can readily be oxidized[10] alcohol (+)-(S)-8a–c, the absolute configurations of iso-
at their benzylic carbons, to afford dihydroisocoumarins, chromans 9a–c can be determined readily, provided that the
the synthesis of substituted isochromans also allows access absolute configurations of the arylpropanols 8a–c are
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G. K., T. Kurtán, S. Antus et al.
FULL PAPER
Scheme 2. Kinetic resolution of alcohols (rac)-8a–c with lipase
from Pseudomonas cepacia (PCL).
were each directly linked to the di-Boc-protected achiral
carrier molecule 10 and then deprotected with trifluoro-
acetic acid (TFA) to produce the bidentate conjugates 11a–
c, each capable of forming a 1:1 host–guest complex with
dimeric zinc porphyrin host 12 (Scheme 3). Because of the
steric differentiation between the substituents flanking the
Scheme 1. Ring-closure to give the (S)-isochromans 9a–g and their
helicities. MOM: methoxymethyl, (R)-MPA: acyl group of (R)-(–)-
α-methoxyphenylacetic acid.
known. For this purpose we envisaged the employment of stereogenic center (the larger group protrudes from the por-
the zinc porphyrin tweezer exciton chirality method.[12] By phyrin binding pocket), the formation of the host–guest
this method, the chiral secondary alcohols (+)-(S)-8a–c complex occurs with a preferred porphyrin helicity, which
Scheme 3. Preparation of tweezer complex 13a–c.
298
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Synthesis and Absolute Configurations of 3-Methylisochromans
FULL PAPER
produces intense exciton split spectra. The conformational and side views of the most probable conformation belong-
A values are generally used to decide which substituent is ing to the most probable cluster are shown in Figure 3. Ac-
treated as larger by the zinc porphyrin tweezer.[12] More re- cording to these results, the zinc porphyrin tweezer treats
cently, a Merck Molecular Force Field (MMFF) molecular the benzyl group as larger than the methyl group, and since
modeling approach has been developed,[13] and since the positive exciton couplets (positive CE at longer wavelength)
conformational A value of the methyl group was reported were measured for 13a–c {CD for 13a [nm (∆ε)]: 430 (+44),
to be very close to that of the benzyl group (methyl: 420 (–36); 13b: 430 (+58), 420 (–41); 13c: 430 (+34), 420
1.74 kcalmol–1, benzyl: 1.68 kcalmol–1),[14] the CD mea- (–39)}, the initial alcohols 8a–c all have (S) configurations.
surement was complemented by this calculation protocol
The enantiomeric excesses (ee values) of (S)-8b and (S)-
1
(i.e., conformational analysis of the tweezer complex (S)- 8c were determined from the H NMR signals of the aro-
13a). The calculation allowed us to estimate the most prob- matic OMe(s) in their corresponding Mosher’s ester deriva-
able projection angle between longitudinal (C5–C15) por- tives (S)-8i and (S)-8j prepared with (R)-(–)-α-methoxy-
phyrin axes, which is the geometrical parameter responsible phenylacetic acid [(–)-(R)-MPA] as described in the litera-
for the sign of the measured CD couplet.[15]
ture.[16] Since the (R)-MPA esters of rac-8b and rac-8c were
This revealed that the C5–C15 oriented longitudinal ef- also prepared, the separate chemical shifts of (S)-8i and (S)-
fective electric transition moments[15] of the two tetraphen- 8j can be compared with those of (R)-8i and (R)-8j, which
ylporphyrin rings have an 84% preference for the positive also allowed the configurational assignment of (S)-8b and
1
projection angle in (S)-13a (Figure 2), and hence it should (S)-8c by Mosher’s method. Since the H NMR signals of
give a positive exciton couplet in the Soret region. The front the aryl protons and the aromatic OMe(s) of (S)-8i and (S)-
8j were shifted downfield while those of the methyl groups
were shifted upfield in relation to the corresponding signals
of (R)-8i and (R)-8j, Mosher’s method also gave (S) abso-
lute configurations for 8i and 8j, consistently with the zinc
porphyrin tweezer method. The ee of (S)-8a was determined
by comparing its specific rotation with the literature
data.[17]
The secondary alcohols (+)-(S)-8d and (+)-(S)-8e were
prepared in optically pure form (ee Ͼ 99.5%) by chiral bio-
reduction of the corresponding arylacetone derivatives 14a
and 14b as described in the literature[18] and shown in
Scheme 4.
The ring closures of (+)-(S)-8a, (+)-(S)-8b, (+)-(S)-8d,
and (+)-(S)-8e each took place smoothly on treatment with
monochloromethyl methyl ether in the presence of the
Lewis acid ZnCl2 at 0 °C, producing the corresponding
isochromans (S)-9a, (S)-9b, (S)-9d, and (S)-9e. While the
cyclizations of (+)-(S)-8d and (+)-(S)-8e were regioselective
and hence each provided a single product in good yield
(94% and 77%, respectively), the ring-closure of 8c resulted
in a mixture of (+)-(S)-9c and 9g (1:4 ratio), although they
Figure 2. Distribution of the twist angles of the MC/MMFFs-cal-
culated host–guest complex 13a within 10 kJmol–1 of the lowest-
energy conformation. The sum probabilities of the conformers with
negative and positive twist angles are reported as percentages and
the most probable cluster is indicated.
Figure 3. Top (a) and front (b) views of the most probable MC/MMFFs-calculated structure of 13a belonging to the most probable
cluster in Figure 2.
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The helicity of and CD data for the isochromans (S)-9a–
g and (4aR,10bS)-16 are tabulated in Table 1. Compounds
(S)-9a and (4aR,10bS)-16, bearing no substituents on their
aromatic rings, have heterorings of (P) and (M) helicity (see
Scheme 1 and Scheme 5 for definition and representation),
respectively, in which the C-3 methyl group of 9a is oriented
equatorially (J3H,4H = 10.9 and 3.1 Hz) while the 4a,10b hy-
drogens of the trans-annulated 16 have a trans-diaxial con-
figuration.
Scheme 4. Chiral bioreduction of 14a and 14b.
could readily be separated by column chromatography. In
order to prepare (+)-9c, the precursor of the natural prod-
uct (+)-mellein, in a better yield, the R4 position of the
alcohol (+)-(S)-8c was blocked by bromination to give (+)-
(S)-8f, treatment of which with monochloromethyl methyl
ether and ZnCl2 provided (+)-(S)-9f, together with the
methoxymethyl ether intermediate 8h.
The transformation of (+)-(S)-9f into (+)-(S)-9c could be
achieved in high yield (73%) by treatment with nBuLi in
THF at –70 °C, followed by quenching with water. It is also
noteworthy that the ring-closure of the 1-arylpropan-2-ol
8d could be also performed in high yield (81%) by treat-
ment with formaldehyde dimethyl acetal in the presence of
boron trifluoride diethyl etherate (BF3·OEt2).
In order to study the influence of a benzylic substituent
on the chiroptical properties of the isochroman chromo-
phore and to prepare an analogue of the model compound
5, the cyclization of the commercially available (–)-(1R,2S)-
2-phenylcyclohexanol (15) was also carried out under the
conditions described above to afford the trans-fused ring
system 16 in 76% yield (Scheme 5).
CD Analysis
1
As the Lb bands of (S)-9a (see Scheme 1) of (P) helicity
and (4aR,10bS)-16 of (M) helicity show positive and nega-
tive CEs, respectively, it follows that the unsubstituted
isochroman chromophore obeys the helicity rule established
for unsubstituted chiral tetralins:[1b] (P)/(M) helicity of the
heteroring results in a positive/negative Lb band CE.
Smith applied empirical sector rules to describe the vib-
ronic contribution to the Lb CE in benzene compounds
possessing contiguous stereogenic centers and without any
additional ring substituents (phenylcarbinamines, phenyl-
carbinols, 1-substituted indans and tetralins).[19] With ad-
ditional achiral ring substituents there is an induced rota-
tory contribution to the 1Lb CE, characterized by a chirality
rule, which can override the former vibronic contribution
depending on the spectroscopic moment and ring posi-
tion(s) of the substituent(s). The spectroscopic moment, in-
troduced by Platt[20] and studied in more detail by Petru-
ska,[21] was successfully used to predict or explain the effect
of achiral substituents of the benzene chromophore on the
1Lb CE.[1a,22] In chiral tetralins, the chirality of the stereo-
genic center(s) determines the helicity of the fused cyclo-
1
1
1
hexane ring, which was correlated with the Lb CE by a
1
helicity rule [(P)/(M) helicity Ǟ positive/negative Lb CE,
respectively; see Figure 4].[1] However, it was also shown
that achiral ring substituents of large spectroscopic mo-
ment
–
such as
a
methoxy group {gOMe
= 33
[22b]
[(cm mol)/L]–1/2
}
– in specific positions inverted the he-
licity rule, which was attributed to the change of the direc-
tion of the sum spectroscopic moment vector. 6-Methoxy-
and 5,7-dimethoxy-substituted chiral tetralins thus obeyed
the opposite helicity rule [i.e., (P) helicity resulted in nega-
Scheme 5. Preparation and helicity of (–)-(4aR,10bS)-16.
Table 1. Helicity of and CD data for isochromans (S)-9a–g and (4aR,10bS)-16 measured in acetonitrile.
Compound
Helicity
CD: λmax [nm] (∆ε)
1Lb
1La
1B
(S)-9a
(S)-9b
(S)-9c
(S)-9d
(S)-9e
(S)-9f
(S)-9g
(P)
(P)
(P)
(P)
(P)
(P)
(P)
272 sh (+0.06), 2.68 (+0.11) 261 sh (+0.09) 221 (+0.24)
n.d.
279 sh (+0.45), 277 (+0.47), 275 sh (+0.45) 237 (+0.78), 219 sh (+0.40)
277 (+0.29), 270 sh (+0.21), 269 sh (+0.21) 228 (–0.27) 215 (+1.98)
288 sh (+0.65), 282 (+0.71) 271 sh (+0.41) 230 (+3.44)
209.5 (–3.04)
205 (–4.58)
208 (+6.49)
204 (+4.75)
210 (–1.14)
n.d.
295 (+0.98), 287 sh (+0.91), 270 sh (+0.27) 243 (–1.78), 226 (+2.38)
284 (+0.24), 278 (+0.23)
284 sh (+0.35), 278 sh (+0.40), 275 (+0.40) 230 (+1.34), 224 sh (+1.06), 218 sh (+0.93)
273 sh (–0.05), 268 (–0.09), 262 sh (–0.08) 222 (+0.86)
234 (+0.49), 228 (+0.38)
(4aR,10bS)-16 (M)
204 (+3.20)
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Synthesis and Absolute Configurations of 3-Methylisochromans
1
FULL PAPER
tive Lb CE (Figure 4)], so the effect of similar achiral ring rational assignment of isochromans such as 1 and 2a–c,
substituted with groups of large spectroscopic moment (alk-
oxy, OH, halogen) on their aromatic rings. In contrast, the
signs of the CEs in the shorter-wavelength aromatic transi-
tions – namely, the La and B regions of (S)-9b–g – varied
with the positions and natures of the substituents, making
this region less useful for the determination of configura-
tion.
substituents of the isochroman chromophore also needs to
be studied.
1
1
Dihydroisocoumarins and 1-Methoxyisochroman Derivatives
Optically active isochromans can be converted into the
corresponding dihydroisocoumarins by oxidation with
Jones reagent[10a] or dimethyldioxirane (DMDO),[10b] as
demonstrated in the preparation of 17a–c (Scheme 6). The
dihydroisocoumarin 17c, the 8-O-methyl derivative of the
natural product (S)-mellein, can be transformed into (S)-
mellein by demethylation with AlCl3 as described in the lit-
erature.[23] The (S)-dihydroisocoumarins 17a–c have very
similar CD patterns: positive πǞπ* and nǞπ* transitions
at 278–307 nm and 252–268 nm, respectively, followed by a
negative and a positive band in the high-energy region.
Since the nǞπ* transition is not sensitive to the substitu-
tion pattern of the aromatic ring, the positive nǞπ* transi-
tion of 3-alkyldihydroisocoumarins corroborates (P) helic-
ity of the heteroring and thus (S) absolute configuration, in
accordance with previous results (Table 2).[8,24]
1
Figure 4. a) Polarization diagram of the Lb bands for tetralin, 6-
methoxytetralin, and 5,7-dimethoxytetralin (signs chosen arbitrar-
ily), b) Direction of the overall spectroscopic moment and helicity
rule for substituted chiral tetralins, c) Direction of the overall spec-
troscopic moment and helicity rule for 3-methylisochroman, 6-
methoxy-3-methylisochroman, and 6,8-dimethoxy-3-methylisoch-
roman.
In the substituted isochromans (S)-9b–g, the different
substitution patterns given by the methoxy, methylenedioxy,
and bromine ring substituents provide different directions
of the sum spectroscopic moment vectors, which allows the
1
effect on the Lb CE of achiral isochroman chromophore
ring substituents to be studied and compared with the cor-
responding data for the substituted chiral tetralins (Fig-
ure 4). The CD data for 9b and 9g (Table 1) revealed that,
unlike in the case of the tetralin chromophore, 6-methoxy
or 6,8-dimethoxy substitution did not invert the sign of the
1Lb CE, while the same was also found for 9c–f. This
Scheme 6. Oxidation of (S)-9a, -9c, and -9d to the corresponding
dihydroisocoumarins 17a–c.
Snatzke and co-workers[25] had reported earlier that the
introduction of an axial benzylic hydroxy group into the
showed that the presence of achiral substituents of large chroman chromophore of a flavan-4-ol [(2R)-19Ǟ(2R,4R)-
1
spectroscopic moment in different positions on the benzene 20] could invert the sign of the CEs of the Lb band while
moiety did not change the isochroman helicity rule, and the absolute configuration of C-2 remained the same
1
hence that the Lb band can safely be used for the configu- (Scheme 7, b).
Table 2. CD data for dihydroisocoumarins (S)-17a–c and isochromans (1R,3S)-18a and (1R,3S)-18b in acetonitrile.
Compound
CD: λmax [nm] (∆ε)
(S)-17a
πǞπ*: 289 sh (+1.08), 278 sh (+2.00); nǞπ*: 252 (+4.19); 230 (–4.73), 204 (+13.83)
πǞπ*: 307 sh (+1.10), 300 (+1.28), 294 sh (+1.20); nǞπ*: 268 (+7.62); 244 (–4.64), 226 (+10.48), 204 (–6.22)
πǞπ*: 304 sh (+2.44), 296 (+2.48); nǞπ*: 258 (+4.17); 239 (–1.29), 229 sh (+0.67), 206 (+11.21)
266 (+0.03), 260 (+0.02), 255 sh (+0.01), 252 sh (+0.01), 213 (+1.41), 208 sh (1.20)
287 sh (+0.59), 282 (+0.69), 275 sh (+0.63), 234 (+4.77), 204 (+8.44)
(S)-17b
(S)-17c
(1R,3S)-18a
(1R,3S)-18b
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The heterorings of (1R,3S)-18a and (1R,3S)-18b have (P)
1
helicity and their Lb CEs [287 sh (+0.59), 282 (+0.69), 275
sh (+0.63) for 18b (Table 2)] are practically the same as
those of (S)-9a and (S)-9d, which confirmed that, unlike
in flavan-4-ols [such as (2R,4R)-20; see Scheme 7, b], the
introduction of an axial benzylic alkoxy group should not
change the isochroman helicity rule as long as the confor-
mation or helicity of the heteroring remains the same. In
contrast, in the case of the chroman chromophore, the in-
troduction of an axial benzylic hydroxy group [(2R)-
19Ǟ(2R,4R)-20] inverted the sign of the 1Lb CE, which was
attributed to a conformational change in the heteroring
even though its helicity had not changed.[25] This result al-
lows the configurational assignment of 1-alkoxy- or 1-hy-
droxyisochromans such as cis-3 and trans-4 from their CD
spectra.
Conclusions
The synthesis of (S)-3-methylisochromans with different
substitution patterns on their aromatic rings has allowed a
helicity rule for the unsubstituted isochroman chromophore
to be set up: (P)/(M) helicity of the heteroring resulted in
1
a positive/negative Lb band CE. CD study of isochromans
substituted with OMe, Br, and methylenedioxy substituents
revealed that, unlike in the case of chiral tetralins, a change
in the direction of the sum electric transition moment in-
duced by achiral substituents of large spectroscopic mo-
ment did not influence the helicity rule.
Scheme 7. a) Treatment of (S)-9a and (S)-9d with DDQ in MeOH
and the helicity of the product. b) Structure, helicity, and 1Lb band
CE of (R)-19 and (2R,4R)-20.
trans-1-Methoxy-3-methylisochroman derivatives were
prepared by DDQ-assisted oxidation, after which the effects
of the axial benzylic C-1 heteroatoms on the conformation
1
of the heteroring and the Lb band CE were studied. This
showed that the axial benzylic C-1 heteroatoms, again un-
like in the cases of flavan-3-ols, neither distorted the half-
chair conformation nor changed the 1Lb band CE, allowing
the configurational assignment of analogous natural 1-hy-
droxy or 1-alkoxyisochromans.
The reason for this – of whether this effect is due to the
participation of the nonbonding electron pairs of the axial
benzylic oxygen or distortion of the half-chair conforma-
tion of the heteroring – remained unclear. In order to test
this effect on the isochroman chromophore, the 1-methoxy
derivatives (–)-(1R,3S)-18a and (–)-(1R,3S)-18b were pre-
pared by oxidation of (+)-(S)-9a and (+)-(S)-9d with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in meth-
anol (Scheme 7, a) and the relative configuration of the C-
1 methoxy group in (–)-(1R,3S)-18b was studied. The three-
Experimental Section
General Experimental Procedures: Melting points were determined
on a Kofler hot-stage apparatus and are uncorrected. Elemental
analyses were determined with a Carlo–Erba Tpy 1106 analyzer.
bond carbon–proton coupling constants in (–)-(1R,3S)-18b The NMR spectra were recorded on a Bruker AMX 500 (1H:
500 MHz; 13C: 125 MHz), a Bruker WP 200 SY (1H: 200 MHz,
13C: 50 MHz), or a Bruker Aspect 3000 (1H: 360 MHz) spectrome-
ter with TMS as internal standard; chemical shifts are reported in
ppm. Optical rotations were determined with a Perkin–Elmer 241
polarimeter and CD spectra were recorded on a J-810 spectropolar-
imeter; the CD spectra were measured in millidegrees and normal-
ized into ∆εmax [l mol–1 cm–1]/λ [nm] units. In the UV spectra, a red
shift of the tweezer Soret band indicated that complexation had
taken place. IR spectra were recorded on a Perkin–Elmer 16 PC
FTIR spectrometer and absorption bands are reported in cm–1.
Precoated silica gel plates (Kieselgel 60 F254, 0.25 mm, Merck) were
3
3
(3JC8,1H = 2.2 Hz, JC3,1H = 6.0 Hz, JC1,3H = 1–2 Hz) were
measured, and showed that the C-8, 1-H, and C-1, 3-H
atoms have a gauche orientation (small coupling constant),
while C-3 and 1-H have an anti orientation (large coupling
constant).[26] This showed that the introduction of the
methoxy group had taken place diastereoselectively and
that, due to the anomeric effect, only the trans product (–)-
(1R,3S)-18b, in which the methoxy group is axially oriented
while the heteroring has a half-chair conformation, had
been formed (Scheme 7).[27]
302
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 296–305

Synthesis and Absolute Configurations of 3-Methylisochromans
used for analytical and preparative TLC. High-resolution FAB
FULL PAPER
4.52 (d, J = 6.8 Hz, 1 H, OCH2a), 4.63 (d, J = 6.8 Hz, 1 H,
mass spectra were measured on a JEOL JMS-DX303 HF mass OCH2b), 6.64 (dd, J = 8.7, 3.1 Hz, 1 H, 5-H), 6.82 (d, J = 3.1 Hz,
spectrometer with use of a glycerol matrix and Xe as ionizing gas,
while ESI-TOF MS measurements were performed on a Micro-
TOF-Q instrument (Bruker Daltonik GmbH, Bremen, Germany).
1 H, 3-H), 7.40 (d, J = 8.7 Hz, 1 H, 6-H) ppm. Calcd mass for
C12H17BrO3 [M + Na]+ 311.0253; found 311.0264.
(+)-(3S)-6-Methoxy-3-methyl-3,4-dihydro-1H-isochromene (9g) and
(+)-(3S)-8-Methoxy-3-methyl-3,4-dihydro-1H-isochromene (9c) by
Ring-Closure of 8c
Compound 9g: Solid (71%): m.p. 44–46 °C. [α]2D0 = +103.9 (c = 1.36,
CH2Cl2). 1H NMR (200 MHz, CDCl3, 25 °C): δ = 1.35 (d, J =
6.2 Hz, 3 H, CH3), 2.68 (d, J = 7.0 Hz, 2 H, CH2–CH), 3.78 (s, 3
H, OCH3), 3.71–3.87 (m, 1 H, CH), 4.78 (s, 2 H, OCH2), 6.62–6.93
(m, 3 H, Ar-H) ppm. C11H12O3 (178.23): calcd. C 74.13, H 7.92;
found C 74.05, H 7.94.
Compound 9c: Colorless oil (19%): [α]2D0 = +133.6 (c = 1.38,
CH2Cl2). 1H NMR (200 MHz, CDCl3, 25 °C): δ = 1.34 (d, J =
6.1 Hz, 3 H, CH3), 2.67 (d, J = 6.6 Hz, 2 H, CH2), 3.74–3.78 (m,
1 H, CH), 3.78 (s, 3 H, OCH3), 4.64 (d, J = 15.9 Hz, 1 H, OCH2a),
4.93 (d, J = 15.9 Hz, 1 H, OCH2b), 6.67 (d, J = 7.9 Hz, 1 H, Ar-
H), 6.70 (d, J = 7.9 Hz, 1 H, Ar-H), 7.13 (t, J = 7.9 Hz, 1 H, 6-
H) ppm.
General Procedure for the Preparation of 9a–g, 8h, and 16. (+)-(3S)-
3-Methyl-3,4-dihydro-1H-isochromene (9a): Anhydrous ZnCl2
(41 mg, 0.30 mmol) was added under nitrogen at room temperature
to a solution of 8a (94 mg, 0.69 mmol) in methoxymethyl chloride
(1.4 mL, 18 mmol) and the mixture was stirred at room tempera-
ture for 15 min. Water was added, the mixture was stirred for
15 min and extracted with diethyl ether (3·10 mL), and the com-
bined organic layer was washed with a solution of NaHCO3 and
water, dried (CaCl2), filtered, and concentrated in vacuo. The resi-
due was purified by preparative TLC (hexane/ethyl acetate 7:1) to
give a colorless oil (76 mg, 74%): [α]2D0 = +134.6 (c = 2.20, CH2Cl2).
1H NMR (200 MHz, CDCl3, 25 °C): δ = 1.36 (d, J = 6.2 Hz, 3 H,
CH3), 2.71 (d, J = 6.8 Hz, 2 H, CH2–CH), 3.74–3.87 (m, 1 H, CH),
4.83 (s, 2 H, OCH2), 6.97–7.18 (m, 4 H, Ar-H) ppm.
(+)-(3S)-6,8-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromene (9b)
by Ring-Closure of 8b: White crystal (90%): m.p. 54–56 °C. [α]2D0
=
1
(–)-(4aR,10bS)-2,3,4,4a,6,10b-Hexahydro-1H-benzo[c]chromene
(16) by Ring-Closure of 15: Colorless oil (76%): [α]2D0 = –123.5 (c =
+82.5 (c = 0.40, CH2Cl2). H NMR (200 MHz, CDCl3, 25 °C): δ
= 1.33 (d, J = 6.2 Hz, 3 H, CH3), 2.63 (d, J = 6.8 Hz, 2 H, CH2–
CH), 3.66–3.88 (m, 1 H, CH), 3.76 (s, 6 H, 2ϫAr–OCH3), 4.57 (d,
J = 15.3 Hz, 1 H, OCH2a), 4.86 (d, J = 15.3 Hz, 1 H, OCH2b),
6.22 (d, J = 2.2 Hz, 1 H, Ar-H), 6.28 (d, J = 2.2 Hz, 1 H, Ar-
H) ppm. C12H16O3 (208.25): calcd. C 69.21, H 7.74; found C 69.32,
H 7.72.
1
1.49, CH2Cl2). H NMR (500 MHz, CDCl3, 25 °C): δ = 1.36–1.54
(m, 4 H, 2ϫCH2), 1.89 (t, J = 11.9 Hz, 2 H, CH2), 2.07 (dd, J =
12.2, 3.1 Hz, 1 H, CH2), 2.45 (d, J = 13.2, Hz, 1 H, CH2), 2.57 (t,
J = 9.9 Hz, 1 H, 4-H), 3.27 (dt, J = 10.3, 3.8 Hz, 1 H, 3-H), 4.86
(d, J = 15.0 Hz, 1 H, 1-CH2a), 4.93 (d, J = 15.0 Hz, 1 H, 1-CH2b),
6.97 (d, J = 7.3 Hz, 1 H, Ar-H), 7.16 (t, J = 7.3 Hz, 1 H, Ar-H),
7.20 (t, J = 7.3 Hz, 1 H, Ar-H), 7.27 (d, J = 7.3 Hz, 1 H, Ar-
H) ppm.
(+)-(3S)-6,7-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromene (9d)
by Ring-Closure of (S)-8d: [(S)-8d: [α]2D0 = +26.8 (c = 1.85, CH2Cl2);
lit. for (R)-8d: [α]2D2 = –21.7 (c = 0.40, CHCl3)].[28] White crystals
(94%): m.p. 57–59 °C. [α]2D0 = +111.0 (c = 1.29, CH2Cl2). 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 1.35 (d, J = 6.1 Hz, 3 H, CH3), 2.63
(d, J = 6.65 Hz, 2 H, CH2–CH), 3.71–3.81 (m, 1 H, CH), 3.85 (s,
6 H, 2ϫAr-OCH3), 4.76 (s, 2 H, OCH2), 6.49 (s, 1 H, Ar-H), 6.58
(s, 1 H, Ar-H) ppm. C12H16O3 (208.25): calcd. C 69.21, H 7.74;
found C 69.15, H 7.75.
(+)-(3S)-3-Methyl-3,4-dihydro-1H-isochromen-1-one (17a): Jones
reagent (6 drops) was added dropwise at 16 °C to a solution of 9a
(17 mg, 0.12 mmol) in glacial acetic acid (0.6 mL). After the mix-
ture had been stirred for 2 h, water (5 mL) was added and the mix-
ture was extracted with CH2Cl2 (3ϫ10 mL). The combined organic
layer was washed twice with saturated NaHCO3 and brine, dried
(MgSO4), and concentrated, and the residue was purified by pre-
parative TLC with hexane/acetone (19:1) as eluent to give 17a
(13.8 mg, 74%) as a yellow oil: [α]2D0 = +90.2 (c = 0.55, CH2Cl2)
[lit. [α]2D6 = +280.0 (c = 0.23, CHCl3)].[30] 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 1.52 (d, J = 6.3 Hz, 3 H, CH3), 2.94–2.98 (m,
2 H, CH2), 4.64–4.74 (m, 1 H, CH), 7.23 (dd, J = 7.6, 1.4 Hz, 1 H,
5-H), 7.39 (dt, J = 7.6, 1.4 Hz, 1 H, 7-H), 7.54 (dt, J = 7.6, 1.4 Hz,
1 H, 6-H), 8.1 (dd, J = 7.6, 1.4 Hz, 1 H, 8-H) ppm.
(+)-(7S)-7-Methyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isochromene
(9e) by Ring-Closure of 8e: [8e: [α]2D0 = +28.2 (c = 1.17, CH2Cl2);
lit. [α]2D0 = +34.0 (c = 1.00, CHCl3)]:[29] White crystals (77%): m.p.
101–104 °C. [α]2D0
= +123.3 (c =
1.27, CH2Cl2). 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 1.32 (d, J = 6.2 Hz, 3 H, CH3), 2.61
(d, J = 6.6 Hz, 2 H, CH2–CH), 3.68–3.84 (m, 1 H, CH), 4.72 (s, 2
H, OCH2), 5.89 (s, 2 H, OCH2O), 6.46 (s, 1 H, Ar-H), 6.55 (s, 1
H, Ar-H) ppm. C11H12O3 (192.21): calcd. C 68.74, H 6.29; found
C 68.64, H 6.30.
(+)-(3S)-6,7-Dimethoxy-3-methyl-3,4-dihydro-1H-isochromen-1-one
(17b): A solution of DMDO in acetone (0.08 , 43 mL) was added
to the solution of 9d (70 mg, 0.34 mmol) in acetone (10 mL), and
the mixture was stirred for 24 h, washed with NaHCO3 solution,
and extracted with ethyl acetate (3ϫ15 mL). The organic layer was
washed with brine, dried (Na2SO4), filtered, and concentrated in
vacuo, and the residue was purified by preparative TLC (hexane/
ethyl acetate 2:5) to give 17b (49.5 mg, 66%). The product was crys-
(+)-(3S)-5-Bromo-8-methoxy-3-methyl-3,4-dihydro-1H-isochromene
(9f) and (2S)-1-Bromo-4-methoxy-2-(2-methoxymethoxy-propyl)ben-
zene (8h) by Ring-Closure of 8f
Compound 9f: White crystals (73%): m.p. 41–43 °C. [α]2D0 = +92.2
1
(c = 1.56, CH2Cl2). H NMR (500 MHz, CDCl3, 25 °C): δ = 1.38
(d, J = 6.2 Hz, 3 H, CH3), 2.47 (dd, J = 17.0, 10.7 Hz, 1 H, CH2a),
2.76 (dd, J = 17.0, 1.8 Hz, 1 H, CH2b), 3.70–3.74 (m, 1 H, CH),
3.78 (s, 3 H, OCH3), 4.57 (d, J = 16.0 Hz, 1 H, OCH2a), 4.90 (d, = +109.5 (c = 0.58, CHCl3). H NMR (500 MHz, CDCl3, 25 °C):
J = 16.0 Hz, 1 H, OCH2b), 6.59 (d, J = 8.7 Hz, 1 H, 7-H), 7.37 (d, δ = 1.50 (d, J = 6.3 Hz, 3 H, CH3), 2.76–2.93 (m, 2 H, CH2), 3.90
tallized from hexane to afford white crystals: m.p. 92–93 °C. [α]2D0
1
J = 8.7 Hz, 1 H, 6-H) ppm. C11H13BrO2 (257.12): calcd. C 51.38,
H 5.10; found C 51.49, H 5.12.
Compound 8h: Colorless oil (15%): 1H NMR (200 MHz, CDCl3,
25 °C): δ = 1.22 (d, J = 6.2 Hz, 3 H, CH3), 2.81 (dd, J = 13.4,
6.1 Hz, 1 H, CH2a), 2.97 (dd, J = 13.4, 6.1 Hz, 1 H, CH2b), 3.21
(s, 3 H, OCH3), 3.78 (s, 3 H, Ar–OCH3), 3.99–4.09 (m, 1 H, CH),
(s, 3 H, OCH3), 3.93 (s, 3 H, OCH3), 4.57–4.74 (m, 1 H, 3-H), 6.65
(s, 1 H, 5-H), 7.54 (s, 1 H, 8-H) ppm. IR (KBr): 2970, 2940, 2838,
1712, 1268, 1134 cm–1. C12H14O4 (222.24): calcd. C 64.85, H 6.35;
found C 64.97, H 6.33.
(+)-(3S)-8-Methoxy-3-methyl-3,4-dihydro-1H-isochromen-1-one
(17c): Compound 9c (26 mg, 0.15 mmol) was dissolved in acetic
Eur. J. Org. Chem. 2007, 296–305
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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303

G. K., T. Kurtán, S. Antus et al.
FULL PAPER
acid/acetone (2:1, 3 mL) and the system was cooled to 0 °C. A solu-
tion of Jones reagent (1 mL) in acetic acid/acetone (2:1, 3 mL) was
added dropwise, the solution was stirred for 20 min and then al-
lowed to warm to room temperature, water (10 mL) was added, and
the mixture was extracted with CH2Cl2 (3ϫ15 mL). The combined
organic layer was washed with saturated NaHCO3 (3ϫ20 mL) and
brine, dried (MgSO4), and concentrated, and the residue was puri-
fied by column chromatography (toluene/ethyl acetate 1:1) to give
17c (14.5 mg, 52%) as a white solid: m.p. 81–83 °C. [α]2D0 = +238.1
(c = 0.58, CHCl3) [lit. [α]2D6 = +261.0 (c = 0.52, CHCl3)].[28] 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 1.48 (d, J = 6.3 Hz, 3 H,
CH3), 2.85 (dd, J = 16.0, 3.2 Hz, 1 H, CH2a), 2.89 (dd, J = 16.0,
10.9 Hz, 1 H, CH2b), 3.95 (s, 3 H, OCH3), 4.54–4.58 (m, 1 H, CH),
6.79 (d, J = 8.0 Hz, 1 H, Ar-H), 6.91 (d, J = 8.0 Hz, 1 H, Ar-H),
7.45 (t, J = 8.0 Hz, 6-H) ppm. C11H12O3 (192.21): calcd. C 68.74,
H 6.29; found C 68.81, H 6.30.
Supporting Information (see also the footnote on the first page of
this article): Experimental data for 8a–c, 8a–c-Ac, 8i, rac-8i, 8j, rac-
8j, 9c, 9d, bis-Boc derivatives of 11a–c, 11a–c, 13a–c. 1H NMR
spectra of 8a–h, 8j, 8a–c-Ac, rac-8j, 9a, 9c–g, 16, 17a–c, 18b. CD
spectra of 13a–c, (S)-9a–g, (4aR,10bS)-16, (S)-17a–c, (1R,3S)-18b.
Acknowledgments
The advice and support of Professor Koji Nakanishi is very grate-
fully acknowledged. S. Antus, T. Kurtán, K. E. Kövér, and T.-Z.
Illyés thank the Hungarian Scientific Research Fund (OTKA, T-
04943, F-04353, T-048713, NI-6133) for financial support.
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(–)-(1R,3S)-1-Methoxy-3-methyl-3,4-dihydro-1H-isochromene (18a)
and (+)-(3S)-3-Methyl-3,4-dihydro-1H-isochromen-1-one (17a):
MeOH (5 drops) and DDQ (150 mg, 0.66 mmol) were added to a
solution of 9a (73 mg, 0.50 mmol) in CH2Cl2 (8 mL), and the mix-
ture was stirred at room temperature for 20 h, treated with
NaHCO3 solution, and extracted with CH2Cl2 (3ϫ10 mL). The
combined organic layer was dried over Na2SO4, filtered, and con-
centrated in vacuo, and the residue was purified by preparative
TLC (hexane/ethyl acetate 19:1) to give 18a (42 mg, 48%) and 17a
(18 mg, 27%) as colorless oils.
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Compound 18a: [α]2D0 = –2.5 (c = 1.59, CHCl3). 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 1.37 (d, J = 6.2 Hz, 3 H, CH3), 2.67 (d, J =
7.4 Hz, 2 H, CH2), 3.54 (s, 3 H, OCH3), 4.18–4.28 (m, 1 H, 3-H),
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Ar-H) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 20.48 (CH3),
34.84 (C-4), 54.49 (OCH3), 62.39 (C-3), 97.89 (C-1), 125.62 (C-Ar),
126.62 (C-Ar), 127.47 (C-Ar), 127.61 (C-Ar), 132.98 (C-Ar), 133.57
(C-Ar) ppm. IR (KBr): 2978, 2934, 1728, 1280, 1238, 1122 cm–1.
C10H10O2 (178.23): calcd. C 74.06, H 6.21; found C 74.01, H 6.22.
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Compound 17a: [α]2D0 = +128.5 (c = 0.71, CHCl3). (See 1H NMR
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20.83 (CH3), 34.80 (C-4), 75.02 (C-3), 124.97 (C-Ar), 127.26 (C-
Ar), 127.58 (C-Ar), 130.20 (C-Ar), 133.61 (C-Ar), 139.07 (C-Ar),
165.56 (C-1) ppm. IR (KBr): 2978, 2934, 1728, 1280, 1238,
1122 cm–1.
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(–)-(1R,3S)-1,6,7-Trimethoxy-3-methyl-3,4-dihydro-1H-isochromene
(18b): MeOH (4 mL) and DDQ (50 mg, 0.22 mmol) were added to
a solution of 9d (40 mg, 0.19 mmol) in CH2Cl2 (5 mL), and the
mixture was stirred at room temperature for 5 h, treated with
NaHCO3 solution, and extracted with CH2Cl2 (3ϫ10 mL). The
combined organic layer was dried on Na2SO4, filtered, and concen-
trated in vacuo, and the residue was purified by preparative TLC
(hexane/ethyl acetate 3:2) to give 18b (31 mg, 68%). The product
was crystallized from hexane: m.p. 91–92 °C. [α]2D0 = –16.1 (c =
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0.33, CHCl3). H NMR (500 MHz, CDCl3, 25 °C): δ = 1.36 (d, J
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B. Schulz, S. Antus, Phytochemistry 1997, 45, 313–320.
3.85 (s, 3 H, Ar-OCH3), 3.87 (s, 3 H, Ar-OCH3), 4.15–4.25 (m, 1
H, 3-H), 5.42 (s, 1 H, 1-H), 6.56 (s, 1 H, 5-H), 6.72 (s, 1 H, 8-
H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 20.51 (CH3),
34.42 (C-4), 54.61 (OCH3), 55.12 (2 ϫ Ar-OCH3), 62.83 (C-3),
98.05 (C-1), 109.83 (C-8), 110.06 (C-5), 124.53 (C-8a), 126.08 (C-
3
5a), 145.91 (C-6), 148.12 (C-7) ppm. JC3,1H = 6.0 Hz, 3JC1,3H = 1–
3
2 Hz, JC8,1H = 2.2 Hz. IR (KBr): 2966, 2928, 2834, 1260,
1078 cm–1. C13H18O4 (238.28): calcd. C 65.53, H 7.61; found C
65.65, H 7.58.
304
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Synthesis and Absolute Configurations of 3-Methylisochromans
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