Asymmetric total synthesis of nigerone and ent-nigerone: Enantioselective oxidative biaryl coupling of highly hindered naphthols

Article abstract of DOI:10.1002/adsc.200600570

An enantioselective synthesis of the chiral bisnaphthopyrone natural product nigerone and its enantiomer, ent-nigerone, has been realized. The use of constrained 2-naphthol substrates was critical to producing highly functionalized chiral 1,1′-binaphthols via asymmetric oxidative biaryl coupling with 1,5-diaza-cis-decalin copper complexes. The final natural product was formed via a key eight-step isomerization process of the coupling product, bisisonigerone, and proceeded with retention of the biaryl con iguration. The axial configurations of bisisonigerone and nigerone were definitively established by a combination of circular dichroism (CD) measurements and quantum chemical CD calculations.

Full text of DOI:10.1002/adsc.200600570

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DOI: 10.1002/adsc.200600570
Asymmetric Total Synthesis of Nigerone and ent-Nigerone:
Enantioselective Oxidative Biaryl Couplingof Highly Hindered
Naphthols
Marisa C. Kozlowski,a,* Elizabeth C. Dugan,a Evan S. DiVirgilio,a
Katja Maksimenka,b and Gerhard Bringmannb,*
a
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania
19104-6323, USA
Fax : (+1)-215-573-7165; e-mail: marisa@sas.upenn.edu
Institut für Organische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
b
Fax : (+49)-931-888-4755; e-mail: bringman@chemie.uni-wuerzburg.de
Received: November 1, 2006
In honor of Prof. Masakatsu Shibasaki on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An enantioselective synthesis of the chiral figuration. The axial configurations of bisisonigerone
bisnaphthopyrone natural product nigerone and its and nigerone were definitively established by a com-
enantiomer, ent-nigerone, has been realized. The use bination of circular dichroism (CD) measurements
of constrained 2-naphthol substrates was critical to and quantum chemical CD calculations.
producing highly functionalized chiral 1,1’-binaph-
thols via asymmetric oxidative biaryl coupling with
1,5-diaza-cis-decalin copper complexes. The final nat- Keywords: chiral binaphthyls; configuration determi-
ural product was formed via a key eight-step isomeri- nation; naphthopyrones; nigerone; oxidative cou-
zation process of the coupling product, bisisoniger- pling; quantum chemical circular dichroism calcula-
one, and proceeded with retention of the biaryl con- tions
Introduction
compounds have been characterized, no total synthe-
sis efforts have as yet appeared.[9]
The number of natural products containing axial chir-
Nigerone (1) is formally – and from a biosynthetic
ality has grown substantially in recent years.[1] While point of view – the dimer of a tricyclic oxygen hetero-
many methods for the generation of chiral biaryls[2] cycle, but retrosynthetically the heterocycle can be
have been reported, the development of efficient syn-
thetic routes to these architecturally interesting tar-
gets remains challenging. In addition, configurational
assignment of these natural products is still difficult.
While circular dichroism (CD) spectroscopy is a pow-
erful and inexpensive method, the merely empirical
interpretation of CD spectra can become difficult or
even impossible if a novel type of structure or an un-
expected conformational behaviour is involved. In nu-
merous cases such difficulties can be overcome by
quantum chemical CD calculations.[3–5] One such class
of compounds, the bisnaphthopyrone natural prod-
ucts, includes nigerone (1) and isonigerone (2)
(Figure 1),[6] mold isolates that display moderate anti-
Figure 1. Structures of the axially chiral natural bisnaphtho-
tumor[7] and antibacterial[8] activities. While these pyrones, nigerone (1) and isonigerone (2).
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Scheme 1. Retrosynthetic analysis of (À)-nigerone (1).
formed last by a formal Claisen condensation with the
enolate of acetone onto 3 followed by a dehydrative
cyclization to 1 (Scheme 1). When this disconnection
is exercised, the binaphthyl intermediate 3 maps di-
rectly onto the type of structures (7) assembled with
our 1,5-diaza-cis-decalin copper catalyst (6) from
simple naphthol substrates 5 (Scheme 2).[10] Thus, the
Scheme 3. Products of prior catalytic asymmetric oxidative
couplings of highly functionalized naphthols.
Scheme 2.
Results and Discussion
synthetic plan is reduced to the formation of 3 from
naphthol 4 (Scheme 1) by coupling to form the C-1
À
In order to undertake the synthesis of nigerone (1), it
C-1’ bond (for the purposes of discussion, the atoms was imperative to determine whether C-4 and C-5
of all structures in the text are numbered as shown in substitution could be tolerated. Such a pattern would
Scheme 1).
have less steric crowding than that found in com-
However, in prior studies we observed an interest- pound 8. To test whether the removal of the C-6 gear-
ing effect with certain substitution patterns. In partic- ing substituent found in 8 would indeed be beneficial,
ular, the combination of C-4, C-5, and C-6 substitu- naphthol 4 was synthesized (Scheme 4). Initially, a
ents as in naphthol 8 caused the coupling product 9 to Wolff rearrangment was explored for generating 13
be formed with low enantioselectivity (27% ee) via the methyl ketone made from carboxylic acid 12.
(Scheme 3).[10d] Based upon the very different results While this route was shorter, the longer route in
observed with the closely related 10, which provided Scheme 4 was more efficient overall and allowed
the corresponding coupling product 11 in 90% ee,[10d] throughput of a large quantity of material. After addi-
it is clear that centers distal from the forming bond tion of malonate anion to the acid chloride of 13, the
can have a profound effect. We propose that the requisite naphthol ring of 14 was formed via an acid-
steric gearing illustrated for 8 places the C-3 methyl catalyzed cyclization.[10d] Diacetylation and then selec-
ester out of the plane of the aromatic ring. As a tive deacetylation at the less hindered C-2 position
result, coordination of the catalyst via the C-2 OH provided 4. Using the catalyst (S,S)-6, which reliably
and the C-3 methyl ester is compromised leading to a forms the (M)-binaphthols,[11] coupling of 4 proceeded
slower reaction rate and lower enantioselectivity well to form 15 with 45% ee as measured by HPLC
(Scheme 3).[10d,e]
on a chiral phase (see Experimental Section). As ex-
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Asymmetric Total Synthesis of Nigerone and ent-Nigerone
electron rich in comparison to 4 with the correspond-
ing electron-withdrawing acetoxy group. As a re-
sult,[10e] coupling of 16d proceeded readily even at
room temperature (96% conversion in 4 h as mea-
Scheme 4. Synthesis and dimerization of a functionalized
monomer toward nigerone (1).
pected, the selectivity in coupling of 4 to 15 (45% ee)
was better than that observed with the more crowded
analog, 8 (27% ee),[10d] but the selectivity was still not
sufficient to proceed. As a result, we had the opportu-
nity to test directly our theory that steric inhibition of
chelation (i.e., 4·Cu) accounts for the low selectivity
in the formation of 9 and 15.[10e] Use of substrates
with a cyclic protecting group (16, Figure 2) will align
Scheme 5. Synthesis and coupling of the constrained naph-
thol substrate 16d.
1
sured by H NMR and HPLC; see Experimental Sec-
tion). Furthermore, the enantioselectivity was im-
proved (66% ee as measured by HPLC on a chiral
phase; see Experimental Section), over both 9 (27%
ee, Scheme 3) and 15 (45% ee, Scheme 4). It appears
that the reduced steric demand from the C-4/C-5
methylenedioxy protecting group relative to the C-4
acetoxy and C-5 methoxy of 15 results in better coor-
dination to the copper catalyst and hence in greater
enantioselectivity. Nonetheless, the length of the
route to prepare these materials prompted us to ex-
plore a more concise route to nigerone (1) that would
further reduce the steric inhibition to chelation and
improve the enantioselectivity.
Figure 2. Attempted cyclic protecting groups to modify the
steric parameters of the binaphthol coupling substrates.
the C-3 carbonyl optimally for chelation to the
copper catalyst and should furnish higher selectivity.
In this approach (Scheme 6), the pyrone ring
system found in the product is used as the constrain-
Unfortunately, our initial constrained candidates, ing element (i.e., 23). An attractive feature of this
16a–c (Figure 2), could not be formed (dioxenone) or route is that no protecting groups need to be installed
were labile under the oxidative binaphthol coupling or removed after the key binaphthol coupling. Com-
conditions (silylene, boronate).
pound 23 is itself a natural product,[12] flavasperone,
On the other hand, 16d with a methylene bridge which has been prepared previously[13] via a 10-step
proved to be stable and amenable to biaryl coupling route. The yields from this route, however, would not
with the copper catalyst. Substrate 16d was generated provide sufficient quantities of 23. Fortunately, we
from the intermediate 14, described above found that 23 could be rapidly prepared from 4 in an
(Scheme 4), as illustrated in Scheme 5. The methyl- efficient four-step sequence (Scheme 6). The key step
enedioxy ring within 16d renders this substrate more is reaction of 22 with a catalytic amount of piperidine
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Scheme 7. Examination of a phenyl derived flavasperone an-
alogue (15) in biaryl coupling.
Scheme 6. A biomimetically inspired route to the nigerone
intermediate, bisisonigerone (24), via C-3/C-4 constrained
derivatives.
tively, readily. To determine if enolization was the
issue with 23, the phenyl analogue 25 was synthesized
(Scheme 7). However, no reaction with the chiral cat-
in the presence of acetaldehyde. Under these condi- alyst occurred after 5 d at 458C. This result may be a
tions, the keto-sulfoxide is alkylated, cyclization consequence of the electron-withdrawing nature of
occurs onto the C-4 OH, and the sulfoxide group the phenyl ring.[10e]
eliminates. Subsequent BCl3 treatment removes the
MOM group to deliver 23.
From the above results, it is clear that steric bulk at
both C-4 and C-5 is not favorable since the required
From the standpoint of an asymmetric coupling conformation of the C-3 carbonyl is not readily acces-
with 1,5-diaza-cis-decalin copper catalyst 6, substrate sible. On the other hand, generation of a rigid ana-
23 appears ideal. The heterocyclic ring constrains the logue with the C-3 carbonyl locked into the required
C-3 carbonyl to align with the C-2 hydroxy for opti- conformation is not ideal, either. It appears that the
mal chelation to copper. In addition, the group at C-4 optimal systems possess a C-3 chelating group (i.e.,
is electron-withdrawing via conjugation to the C-3 the carbonyl) that is slightly strained in the requisite
carbonyl; electron-poor groups at C-4 suppress race- planar orientation. Under these circumstances a
mization of the binaphthol during the oxidative cou- planar copper chelate can form and undergo reaction,
pling.[10d] Surprisingly, however, the reaction of 23 but is not so stable that product dissociation is inhibit-
with the chiral copper catalyst was sluggish. After one ed.
week at 40-458C with 10 mol% catalyst, only 36% of
Reasoning that this optimized chelation inhibits
product 24 were isolated, still in a good selectivity turnover, greater amounts of the diaza-cis-decalin
(80% ee) as judged by HPLC on a chiral phase (see copper oxidant were employed, which improved the
Experimental Section). As expected, no product race- yield (60%), while maintaining the selectivity (80%
mization was observed over the time course of the re- ee). With increasing amounts of the chiral coupling
action. For the attribution of the absolute configura- catalyst, C-1 iodination became problematic account-
tion of the obtained bisisonigerone (24), see below.
ing for the moderate yield. Use of copper catalyst var-
Based on the higher selectivity for 23 in comparison iants with different counterions (Cl, BF4) gave the
to that observed with 4 (45% ee, Scheme 4), we have product without the iodination by-product, but result-
confirmed our hypothesis that a planar C-3 carbonyl ed in a diminished enantioselectivity (60–72% ee).
and C-2 hydroxy arrangement provides superior
Due to the key role of the intermediate 24 thus ob-
asymmetric induction with the diaza-cis-decalin tained, its absolute axial configuration was deter-
copper catalysts. However, the slow rate of reaction mined by means of circular dichroism (CD) spectros-
in the oxidative biaryl coupling of 23 was puzzling, copy. Because of the constitutionally symmetrical
but could be due to the enolizable protons. For exam- structure of 24, it should be possible to assign its con-
ple, the simple methyl ketone analogue 5b in figuration by the classical exciton chirality method.[14]
Scheme 7 was also problematic, whereas the methyl In bisisonigerone (24), with its two interacting flavas-
ester (5a) or phenyl ketone (5c) analogues underwent perone (23)[12] chromophores, the UV band at 285 nm
the asymmetric biaryl coupling to 7a and 7c, respec- gave rise to an exciton couplet in the CD spectrum
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with the first, negative Cotton effect at 300 nm and ysis was performed. The calculations revealed that the
the second, positive one at 280 nm (Figure 3a/b), indi- two hydroxy functions adopt only one energetically
À
cating a negative chirality of 24, i.e., an (M)-configu- preferable array, with strong hydrogen bonds (dH O
ration.
ca. 1.60 Š) to the adjacent respective carbonyl groups,
and that the two methoxy substituents at C-5 and C-5’
orient with a maximum distance from the pyrone
ring. The other two methoxy groups at C-7 and C-7’
revealed two energetically relevant orientations each,
thus resulting in four possible input structures for fur-
ther calculations.
The single CD and UV spectra were calculated
using the semiempirical CNDO/S[18] and OM2[19] ap-
proaches (Figure 4a/a’), and by the time-dependent
DFT (B3LYP/TZVP)[20,21] method (Figure 4b/b’). The
resulting Bolzmann-weighted overall spectra (for de-
tails, see Experimental Section) were then compared
with the experimental CD and UV curves of (+)-bis-
isonigerone (24). The calculated CD spectra for the
(P)-enantiomer of 24 clearly showed an opposite be-
havior, while the spectra predicted for M reasonably
Figure 3. (a) The experimental UV and (b) CD spectra of
(+)-bisisonigerone (24).
On the other hand, the presence of a third band at reproduced the experimental features. Within the
255 nm with a strong negative Cotton effect raised semiempirical approaches the rotatory strength values
some uncertainty, making an independent interpreta- for the band at 300 nm were underestimated to a re-
tion of the experimental CD spectra of 24 by quan- markably strong degree, while in the TDDFT based
tum chemical CD calculations[3–5] a rewarding task. spectrum the band at 255 nm was predicted with a too
Arbitrarily starting with the (P)-enantiomer of 24, a low intensity, so that these two bands were not con-
DFT (RI-BLYP/SVP)[15–17] based conformational anal- sidered for the attribution of the absolute configura-
Figure 4. Comparison of the experimental CD spectrum of (+)-bisisonigerone (24) (a/a’) with the semiempirically (CNDO/S,
OM2) predicted curves, and (b/b’) with the TDDFT based spectra; (c) comparison of the experimental UV profile of 24
with the TDDFT based UV spectrum.
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tion. On the other hand, all of the calculation meth- 1 is feasible, a reasonable question is whether the ni-
ods reproduced the strong, characteristic band at gerone (1) obtained from natural sources is actually a
280 nm most accurately, predicting a negative Cotton secondary product of the isolation protocol. Since the
effect for the (P)-configured atropo-enantiomer of bi- isolation protocol does not utilize any base, it is diffi-
sisonigerone (24) and a positive one for M.
cult to imagine the isomerization occurring under
With (M)-24 in hand and unambiguously character- those conditions. However, it is entirely possible that
ized stereochemically, isomerization of the naphtho- 24 is a biosynthetic precursor to 1 and 2.
pyrones via 1,4-addition to the enones with catalytic
The enantiomeric purity of the compound de-
base[22] was investigated (Scheme 8). Equilibration of creased only slightly during this process (<3% ee),
24 under these conditions was proposed to favor ni- which likely occurs during the isomerization step due
gerone (1) since the C-2 position of the binaphthyl is to the loss of rigidity created by the g-pyrone ring. It
less hindered compared to C-4 (the C-5 group is co- would appear that nigerone (1) itself is configuration-
planar to C-4 while the C-1 biaryl is 708 out of plane) ally stable at high temperature as it has been refluxed
and should better accommodate the heterocyclic por- in acetic acid for 3 h with no loss of optical activity.[6c]
tion. In addition, NMR evidence indicates that the in- By the same route, except for using the enantiomeric
tramolecular hydrogen bond found in 24 would be diaza-cis-decalin catalyst,[11] (P)-nigerone (1) was also
weaker than that found in the linear array of 1.[6a] produced. Pleasingly, trituration of the 70–80% ee ni-
Energy calculations (AM1[23,24]) of the low-energy gerone (1) thus obtained with 50% ethyl acetate/hex-
conformers of the three possible nigerone isomers anes readily proceeded to provide 1 with 90% ee.
supported these assumptions (Scheme 8): 24, Erel =
The NMR data for the synthesized (À)-nigerone
1.23 kcalmolÀ1, isonigerone (2) (half-isomerized), (1) were in complete accordance with those of the iso-
Erel =0.73 kcalmolÀ1, nigerone (1), Erel =0.00 kcal lated natural product.[6a] In addition, the data for the
molÀ1. Implementation of this plan using a base-cata- bisisonigerone (24) differed markedly from those of
lyzed isomerization in methanol at 708C overnight nigerone (1) confirming the isomeric identity of the
succeeded in formation of (M)-nigerone in 50% yield natural material (see Supporting Information).
(for the configurational assignment of 1, see below).
As above for 24, the absolute stereostructures of
During the isomerization, an intermediate is observed two atropo-enantiomers of the synthetically obtained
which is consumed by the time all the bisisonigerone nigerone (1) were also elucidated by CD calculations.
(24) reacts. We propose that this intermediate is isoni- This seemed an urgent task because the direct com-
gerone (2), which is ultimately converted to the more parison of the experimental CD spectrum of (M)-(+)-
stable nigerone (1). Given that isomerization of 24 to bisisonigerone (24) with the CD curve of (M)-(À)-ni-
Scheme 8. Proposed mechanism of isomerization of 24 to nigerone (1).
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gerone (1) showed a substantial difference, revealing
the first negative and the second positive Cotton ef-
fects of (M)-24 to be red-shifted by 16 and 18 nm, re-
spectively (Figure 5a/c). Furthermore, previous at-
Figure 5. The measured CD spectra (in CH2Cl2) of two
atropo-enantiomers of (a) nigerone (1) and of (b) bisisoni-
gerone (24); (c) comparison of the experimental CD spectra
of (À)-nigerone (1) and (+)-bisisonigerone (24).
Figure 6. Determination of the absolute configuration of
(À)-nigerone (1) by comparison of the experimental CD
curve with the theoretically (TDDFT/B3LYP/TZVP) pre-
dicted CD spectra; (a) comparison of the UV spectra; (b)
comparison of the CD spectra.
tempts to attribute the absolute configuration of natu-
ral nigerone (1) were contradictory. The comparison
of its CD and ORD data with those of other bisnaph-
thopyrones of known absolute configuration[6a] (erro-
neously) led to a P-configuration, while the interpre- of the synthetically obtained (+)-nigerone (1) was as-
tation by using the exciton chirality approach[6c] (cor- signed to be P.
rectly) gave M.
As before for bisisonigerone (24), the conforma-
tional analysis of 1 was performed for the (P)-enan- Conclusions
tiomer, revealing the same respective four conform-
ers, differing only in the orientation of two methoxy In summary, the first, atropo-enantiodivergent total
substituents at C-7 and C-7’. In this case, the spectra synthesis of the axially chiral bisnaphthopyrone natu-
were immediately calculated at the TDDFT (B3LYP/ ral product nigerone has been achieved. Constrained
TZVP)[20,21] level. The comparison of the calculated 2-naphthol substrates were critical to producing
CD spectrum for the (P)-enantiomer of 1 with the ex- highly functionalized chiral 1,1’-binaphthols via asym-
perimental curve of (À)-nigerone (1) showed a fully metric oxidative biaryl coupling with 1,5-diaza-cis-
opposite behavior, while the spectrum predicted for decalin copper complexes. From the biaryl coupling
the (M)-atropisomer reproduced the experimental product, an isomerization via a sequence of eight con-
curve with a very high accuracy (Figure 6). This jugate addition/elimination reactions gave rise to ni-
firmly corroborated the previous attribution based on gerone (1). With this asymmetric synthesis, both enan-
the exciton coupling method,[6c] thus indicating that tiomers of nigerone (1) have been generated with
the natural product (À)-nigerone (1) has the M-con- good enantioselectivity. The absolute configurations
figuration. Consequently, the absolute configuration of the natural product, (À)-nigerone (1) and the key
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intermediate, bisisonigerone (24) have been unambig- Methyl 1,3-Dihydroxy-6,8-dimethoxynaphthalene-2-
uously assigned by quantum chemical CD calcula- carboxylate (14)
tions.
To a solution of phenylacetic acid 13 (0.429 g, 2.19 mmol) in
CH2Cl2, thionyl chloride (0.319 mL) was added. After 1 h at
reflux, the solution was concentrated. To a suspension of
NaH (0.156 g, 6.5 mmol) in THF (51 mL) dimethyl malonate
(0.838 g, 6.35 mmol) was added. After stirring for 1 h, a solu-
Experimental Section
tion of the unpurified acid chloride in THF was added.
After 1 h at room temperature, 1M HCl and EtOAc were
added. The layers were separated and the aqueous layer was
extracted three times with EtOAc. The organic layers were
combined, washed with brine, dried over MgSO4, filtered,
and concentrated. The residue was chromatographed (SiO2;
85%hexanes/EtOAc) to afford the intermediate tricarbonyl
(0.650 g) as a clear oil.
General Considerations
Solvents for the preparation of the catalyst complexes and
for the oxidative coupling reactions were usually used with-
out purification although acid-free halogenated solvents are
required (if necessary, trace acid can be removed by filtering
through basic Al2O3). Enantiomerically pure diaza-cis-deca-
lin was prepared as previously described.[25] The Cu-
(TMEDA)Cl(OH) catalyst was prepared[26] and used in the
To a solution this tricarbonyl in methanesulfonic acid
(10 mL), was added P2O5 (0.600 g). After 3 h at room tem-
perature, ice was added and the resulting precipitate was fil-
tered and dried in an oven overnight to yield the naphthale-
nediol 14 as a grey solid; yield: 0.500 g (82%); mp 162–
oxidative biaryl coupling reactions to prepare the racemic
samples of the biaryl products.
Chromatography was performed using a forced flow of
the indicated solvent system on EM Reagents Silica Gel 60
(230–400 mesh). Enantiomeric excesses were determined
using analytical high performance liquid chromatography
(HPLC), performed on a Waters 600 HPLC with UV detec-
tion at 254 nm. Optical rotations were measured on a
Perkin–Elmer Polarimeter 341 with a sodium lamp and are
reported as follows: [a]Tl , (c in g/100 mL, solvent).
1
1648C; H NMR (500 MHz, CDCl3): d=11.13 (s, 1H), 10.70
(s, 1H), 6.64 (s, 1H), 6.48 (d, J=2.2 Hz, 1H), 6.28 (d, J=
2.2 Hz, 1H), 4.05 (s, 3H), 4.02 (s, 3H), 3.89 (s, 3H);
13C NMR (125 MHz, CDCl3): d =171.3, 160.7, 158.8, 157.7,
141.1, 105.1, 102.0, 97.9, 97.4, 95.8, 56.1, 55.3, 52.4; IR (film):
n=3443, 3304, 2953, 1664, 1594 cmÀ1; HR-MS (ES): m/z=
279.0880, calcd. for C14H14O6 [M+H]+: 279.0868.
2-(3,5-Dimethoxyphenyl) acetic Acid (13)
Methyl 1-Acetoxy-3-hydroxy-6,8-
dimethoxynaphthalene-2-carboxylate (4)
A solution of 3,5-dimethoxybenzoic acid (5.6 g, 30.7 mmol)
in THF (250 mL) was cooled to 08C. LiAlH4 (2.33 g,
61.4 mmol) was slowly added. After 3 h at room tempera-
ture a saturated solution of Na/K tartrate (50 mL) was
added. After 1 h at room temperature the layers were sepa-
rated and the aqueous layer was extracted with ethyl ace-
tate. The organic layers were combined, dried over MgSO4,
filtered, and concentrated. The benzylic alcohol was ob-
To a round-bottom flask containing the above naphthalene-
diol 14 (0.50 g, 1.80 mmol), Ac2O (2.54 mL), pyridine
(2.50 mL), and a catalytic amount of DMAP were added.
After 4 h at room temperature, ethyl acetate was added and
the organic layer was washed with a saturated solution of
Cu2SO4 until the aqueous layers were no longer purple. The
organic layer was subsequently washed with water, brine,
dried over MgSO4, filtered, and concentrated. Methanol was
added to this material along with enough 1M NaOMe solu-
tion until TLC analysis indicated no remaining diacetate
compound. 1M HCl was subsequently added and the aque-
ous layer was extracted three times with CH2Cl2. The com-
bined organic extracts were dried over MgSO4, filtered, and
concentrated. The residue was chromatographed (30%
EtOAc/hexanes) to afford the monoacetate 4 as a yellow
solid; yield: 0.44 g (76%); mp 168–1698C; 1H NMR
(500 MHz, CDCl3): d=10.83 (s, 1H), 7.06 (s, 1H), 6.52 (d,
J=2.2 Hz, 1H), 6.29 (d, J=2.2 Hz, 1H), 3.98 (s, 3H) 3.89 (s,
3H), 3.88 (s, 3H), 2.37 (s, 3H); 13C NMR (125 MHz,
CDCl3): d=170.0, 169.5, 161.1, 158.1, 157.4, 149.9, 141.1,
111.2, 109.3, 107.3, 97.8, 97.1, 56.1, 55.4, 52.9, 20.9; IR (film):
1
tained as an oil; yield: 5.0 g (97%). The H NMR spectrum
matches that of the reported compound.[27]
A
solution of the above benzylic alcohol (5.0 g,
29.7 mmol) in CH2Cl2, was cooled to 08C, at which time
PBr3 (3.07 mL) was added. After 1 h at room temperature,
NaHCO3 was added dropwise and the aqueous layer was ex-
tracted with CH2Cl2. The combined organic layers were
dried over MgSO4, filtered, and concentrated to afford the
1
benzylic bromide as an oil; yield: 5.9 g (86%). The H NMR
spectrum matches that reported.[28]
To a solution of the above benzylic bromide (5.9 g,
25.5 mmol) in DMF, was added NaCN. After 1 h water was
added and the aquous layer was extracted with EtOAc. The
organic layers were washed three times with water and
brine, dried over MgSO4 and concentrated to afford the
benzylic cyanide as a white solid; yield: 3.7 g (83%). The
1H NMR spectrum matches that reported.[29]
n=1760, 1671, 1629, 1571 cmÀ1
; HR-MS (ES): m/z=
343.0797, calcd. for C16H16O7 [M+Na]+: 343.0794.
A concentrated solution of HCl was added to the above
benzylic cyanide (3.7 g, 21.6 mmol). After 2.5 h at reflux,
water (100 mL) was added and the reaction mixture was
cooled to room temperature. The aqueous phase was ex-
tracted three times with CH2C12, dried over MgSO4, filtered
and concentrated. Crystallization from EtOAc/hexanes gave
phenylacetic acid 13 as white crystals; yield: 3.8 g (90%).
The 1H NMR spectrum matches that reported.[30]
(M)-(À)-Dimethyl 4,4’-Diacetoxy-2,2’-dihydroxy-
5,7,5’,7’-tetramethoxy-[1,1’]-binaphthalenyl-3,3’-
dicarboxylate (15)
To a solution of 4 (0.10 g, 0.31 mmol) in CH3CN (3 mL)
(S,S)-6 (0.10 g, 0.031 mmol) was added. After 48 h under an
O2 atmosphere at 408C, 1M HCl was added and the aque-
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Asymmetric Total Synthesis of Nigerone and ent-Nigerone
ous layer was extracted three times with CH2Cl2. The com-
bined organic layers were dried over MgSO4, filtered, and
concentrated. The residue was chromatographed (60% hex-
anes/EtOAc) to afford 15 as a reddish solid; yield: 0.70 g
(75%); mp 227–2308C; [a]2D3: À9.21 (c 0.38, 45% ee,
CHCl3); CSP HPLC (Chiralpak AD, 1.0 mLminÀ1, hexane-
s:i-PrOH=90:10): tR (P)=26.1 min, tR (M)=38.3 min;
1H NMR (500 MHz, CDCl3): d=11.04 (s, 1H), 6.32 (d, J=
2.2 Hz, 1H), 6.08 (b, 1H), 3.98 (s, 3H), 3.89 (s, 3H), 3.53, (s,
3H), 2.40, (s, 3H); 13C NMR (125 MHz, CHCl3): d=170.2,
169.5, 161.3, 158.5, 155.1, 150.1, 140.3, 114.3, 110.2, 97.7,
95.7, 60.3, 56.2, 55.2, 53.0, 21.0; IR (film): n=1764, 1668,
1621, 1575 cmÀ1; HR-MS (ES): m/z=661.1526, calcd. for
C32H30O14 [M+Na]+: 661.1534.
A 08C solution of this bispivaloyl material (0.020 g,
0.046 mmol) in CH2Cl2 (500 mL) was added to a 08C solu-
tion of K2CO3 (0.006 g) in MeOH (300 mL). After 1 h the re-
action mixture was allowed to warm to room temperature.
After 30 min, 1M HCl was added and the reaction mixture
was extracted with CH2Cl2. The organic layers were com-
bined, dried with Na2SO4, and concentrated. The monopiva-
loyl product was obtained; yield: 0.016 g (100%).
To a solution of the above monopivaloyl product (0.015 g,
0.043 mmol) in dimethylformamide (400 mL) CH2I2 (30 mL)
was added, followed by K2CO3 (0.029 g). The resulting reac-
tion mixture was heated to 608C. After 8 h, 1M HCl was
added and the mixture was extracted with EtOAc. The or-
ganic layers were combined, dried with Na2SO4, and concen-
trated. The residue was chromatographed (25% EtOAc/hex-
anes) to afford 19 as a yellow solid; yield: 0.044 g (34%);
mp 133–1358C; 1H NMR (500 MHz, CDCl3): d=7.05 (s,
1H), 6.76 (d, J=1.7 Hz, 1H), 6.61 (d, J=1.6 Hz, 1H), 5.58
(s, 2H), 3.89 (s, 6H), 1.35 (s, 9H); 13C NMR (125 MHz,
CDCl3): d=176.7, 164.1, 161.1, 151.7, 150.6, 147.7, 136.3,
112.2, 108.2, 107.3, 101.3, 100.1, 91.2, 55.6, 52.3, 39.2, 27.1;
Methyl 5-Hydroxy-8-methoxy-2phenylnaphthol
de][1,3,2]dioxaborinine-4-carboxylate (16c)
A
ACHTREUNG
A solution of the naphthalene diol 14 (0.050 g, 0.179 mmol)
in CH2Cl2 was cooled to 08C, at which time a 1M BBr3 solu-
tion in CH2Cl2 (0.358 mL) was added. After 1 h, water was
added and the layers separated. The aqueous layer was ex-
tracted with CH2Cl2. The combined organic extracts were
dried over MgSO4, filtered, and concentrated to afford the
naphthalenetriol 17 as a yellow solid; yield: 0.044 g (93%);
mp 180–1858C, decomposition; 1H NMR (500 MHz,
CDCl3): d=11.10 (bs, 1H), 9.42 (s, 1H), 8.80 (bs, 1H), 6.61
(s, 1H), 6.42 (d, J=2.2 Hz, 1H), 6.35 (d, J=2.2 Hz, 1H),
4.12 (s, 3H), 3.87 (s, 3H); 13C NMR (125 MHz, CDCl3): d=
171.2, 163.2, 158.4, 153.2, 141.4, 104.9, 102.8, 101.5, 99.8,
97.7, 94.7, 55.3, 53.1; IR (film): n=3474, 3405, 3281, 1660,
1621, 1517 cmÀ1; HR-MS (ES): m/z=287.0535, calcd. for
C13H12O6 [M+Na]+: 287.0532.
To a solution of the above naphthalenetriol (0.030 g,
0.114 mmol) in CH2Cl2, PhB(OH)2 (0.014 g, 0.114 mmol)
was added. After 1 h at room temperature, diethyl ether and
NaCl were added. After 10 min, the mixture was filtered
and concentrated. The resulting solution was crystallized
from chloroform/hexanes to obtain 16c as white crystals;
yield: 0.022 g (55%); mp 202–2048C; 1H NMR (500 MHz,
CDCl3): d=11.16 (s, 1H), 8.11 (d, J=7.0 Hz, 2H), 7.60 (t,
J=7.4 Hz, 1H), 7.50 (t, J=7.4 Hz, 2H), 6.74 (s, 2H), 6.53
(d, J=2.2 Hz, 1H), 6.49 (d, J=2.2 Hz, 1H), 4.12 (s, 3H),
3.88 (s, 3H); 13C NMR (125 MHz, CDCl3): d=168.9, 161.4,
155.9, 154.9, 154.4, 137.9, 131.5, 127.1, 127.0, 106.3, 101.2,
98.9, 97.3, 95.6, 54.9, 51.8; IR (film): n=3370, 1668, 1644,
1606, 1586 cmÀ1; HR-MS (ES): m/z=352.0950, calcd. for
C20H16O6 [M+Na]+: 352.0947.
IR (film): n=2976, 2937, 1752, 1725, 1640, 1594, 1467 cmÀ1
;
HR-MS (CI): m/z=360.1202, calcd. for C19H20O7 [M]+:
360.1209.
(M)-(À)-Dimethyl 5,5’-Dihydroxy-8,8’-dimethoxy-
[6,6’]bi
A
G
N
dicarboxylate (20)
A solution of 19 (0.024 g, 0.067 mmol) in THF/MeOH
(700 mL/200 mL) at 08C was treated with a solution of
NaOMe/MeOH (140 mL, 2.5m). After slowly warming to
ambient and then stirring 30 min, the reaction was quenched
with 1M HCl. After extracting with EtOAc, the organic
layers were combined, dried over Na2SO4, and concentrated.
The residue was chromatographed (15% EtOAc/hexanes)
to afford the free naphthol 16d as a yellow solid; yield:
0.014 g (78%).
To a solution of naphthol 16d (0.002 g, 0.007 mmol) in
CH2Cl2 (200 mL) was added (S,S)-6 (0.003 g, 0.0007 mmol).
The mixture was sonicated and allowed to stir at room tem-
perature under air. After 4 h, 1M HCl was added, and the
mixture was extracted with CH2Cl2. The organic layers were
combined, dried over Na2SO4, and concentrated, to afford
1
the product in 96% conversion (measured by H NMR and
HPLC) and 66% ee (measured by HPLC); CSP HPLC
(Chiralpak ODH, 1.0 mLminÀ1, hexanes:i-PrOH=92:8): tR
(16d)=15.5 min, tR (P-20)=43.5 min, tR (M-20)=56.2 min;
1H NMR (500 MHz, CDCl3): d=11.40 (s, 2H), 6.41 (d, J=
2.2, 2H), 6.11 (d, J=2.2, 2H), 5.70 (d, J=5.0, 2H), 5.62 (d,
J=5.0, 2H), 3.99 (s, 6H), 3.59 (s, 6H); 13C NMR (125 MHz,
CDCl3): d=170.1, 162.2, 156.1, 154.1, 152.6, 138.8, 108.8,
105.1, 98.6, 98.1, 97.6, 90.8, 55.4, 52.5; IR (film): n=3053,
2926, 2856, 1664, 1633, 1586, 1444 cmÀ1; HR-MS (ES): m/z=
573.0999, calcd. for C28H22O12Na [M+Na]+: 573.1100.
Methyl 8-Methoxy-5-(pivaloyloxy)naphtho
de][1,3]dioxine-4-carboxylate (19)
A
ACHTREUNG
A solution of naphthalenetriol 17 (0.020 g, 0.075 mmol) in
CH2Cl2 (500 mL) was cooled to 08C. Trimethylacetyl chlo-
ride was added (26 mL in 50 mL of CH2Cl2) followed by tri-
ethylamine (29 mL in 50 mL of CH2Cl2). After 30 min, the
same portions of trimethylacetyl chloride and triethylamine
were added again. After a further 1 h at 08C, 1M HCl was
added and the mixture was extracted with CH2Cl2. The or-
ganic layers were combined, dried with Na2SO4, and concen-
trated. The bispivaloyl product was obtained; yield: 0.023 g
(70%).
Methyl 1-Acetoxy-6,8-dimethoxy-3-
(methoxymethoxy)naphthalene-2-carboxylate (21)
A solution of 4 (0.250 g, 0.780 mmol) in DMF (4 mL) was
cooled to 08C, at which time NaH (0.028 g, 1.17 mmol) was
added. After 20 min, MOM-Cl (0.099 mL) was added in one
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Marisa C. Kozlowski et al.
portion. After 2 h at room temperature, EtOAc and 1M
HCl were added. The organic layer was washed three times
with water and brine to remove DMF. The organic layer
was dried over MgSO4, filtered, and concentrated. The resi-
due was chromatographed (70% hexanes/EtOAc) to afford
21 as a white powder; yield: 0.270 g (94%); mp 140–1418C;
1H NMR (500 MHz, CDCl3): d=7.22 (s, 1H), 6.65 (d, J=
2.2 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 5.28 (s, 2H), 3.92 (s,
3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.51 (s, 3H), 2.31 (s, 3H);
13C NMR (125 MHz, CDCl3): d=169.3, 165.8, 159.9, 157.3,
152.5, 145.6, 138.8, 116.8, 110.4, 107.9, 98.8, 98.6, 95.1, 56.6,
56.3, 55.6, 52.7, 20.9; IR (film): n=3067, 2989, 1772, 1714,
1629, 1586 cmÀ1; HR-MS (ES): m/z=364.1164, calcd. for
C18H20O8 [M+Na]+: 364.1158.
(M)-(+)-Bisisonigerone (24)
To a solution of 23 (0.027 g, 0.094 mmol) in 1,2-dichloro-
ethane (3 mL), (S,S)-6 (0.031 g, 0.094 mmol) was added.
After 6 d under air at 508C, 1M HCl was added and the
aqueous layer was extracted three times with CH2Cl2. The
combined organic extracts were dried over MgSO4, filtered,
and concentrated. The residue was chromatographed (60%
hexanes/EtOAc) to afford recovered 23 (0.009 g) along with
24 as a yellow solid; yield: 0.012 g (60%, 80% ee); mp 180–
1858C decomposition; [a]2D3: +72.6 (c 0.25 g/100 mL, 80%
ee, CHCl3); CSP HPLC (Chiralpak AD, 1.0 mLminÀ1, hexa-
nes:i-Pr-OH=90:10): tR (P)=40.6 min, tR (M)=109.9 min;
1H NMR (500 MHz, CDCl3): d=13.19 (s, 1H), 6.45 (d, J=
2.2 Hz, 1H), 6.33 (s, 1H), 6.21 (d, J=2.2 Hz, 1H), 4.02 (s,
3H), 3.55 (s, 3H), 2.56 (s, 3H); 13C NMR: (125 MHz,
CDCl3): d=182.9, 166.4, 161.7, 159.7, 156.1, 154.6, 140.5,
110.5, 110.3, 108.6, 104.3, 96.9, 96.7, 56.0, 55.2, 29.7, 20.5; IR
1,3-Dimethoxy-6-(methoxymethoxy)-7-(2-
(methylsulfinyl)acetyl)-8-hydroxynaphthalene (22)
(film): n=3366, 3003, 2926, 1656, 1610, 1579, 1517 cmÀ1
;
Benzene (10 mL) and DMSO (3.1 mL) were added to a
round-bottom flask containing NaH (0.296 g, 12.33 mmol).
After 1 h at reflux, the reaction mixture was allowed to cool
HR-MS (ES): m/z=571.1624, calcd. for C32H26O10 [M+
Na]+: 571.1604.
to room temperature and
a solution of 21 (0.642 g,
1.76 mmol) in benzene was added. After 1 h at 458C, the so-
lution was concentrated at which time water and acetic acid
were added dropwise until a precipitate formed. The precip-
itate was filtered and dried to afford 22 as a yellow powder;
yield: 0.600 g (96%); mp 145–1468C; 1H NMR (500 MHz,
CDCl3): d=14.05 (s, 1H), 6.73 (s, 1H), 6.54 (d, J=2.2 Hz,
1H), 6.36 (d, J=2.2 Hz, 1H), 5.35 (q, J=6.8, 2H), 4.84 (d,
J=14 Hz, 1H), 4.30 (d, J=14 Hz, 1H), 3.98 (s, 3H), 3.89 (s,
3H), 3.56 (s, 3H), 2.77 (s, 3H); 13C NMR (125 MHz,
CDCl3): d=194.6, 165.3, 162.3, 160.7, 154.0, 141.6, 108.1,
107.3, 100.2, 99.1, 97.2, 94.8, 68.6, 56.8, 56.2, 55.4, 39.9; IR
(film): n=3003, 2968, 3397, 1625, 1583 cmÀ1; HR-MS (ES):
m/z=368.0937, calcd. for C17H20O7S [M+Na]+: 368.0930.
5-Hydroxy-8,10-dimethoxy-2-phenyl-4H-
benzo[h]chromen-4-one (25)
To a solution of 22 (0.100 g, 0.271 mmol) in toluene (5 mL)
one drop of piperdine was added. The solution was warmed
to 458C and benzaldehyde (0.276 mL) was added. After 3 h
at reflux, the solution was allowed to cool to room tempera-
ture at which time EtOAc and 1M HCl were added. The
layers were separated and the organic layer was washed
with brine. The residue was chromatographed (90% hex-
anes/EtOAc) to afford 25 as yellow solid; yield: 0.580 g
(61%); mp 232–2348C; 1H NMR (500 MHz, CDCl3): d=
12.79 (s, 1H), 8.07 (dd, Jab =1.34 Hz, Jbc =7.9 Hz, 2H), 7.56
(m, 3H), 6.85 (s, 1H), 6.82 (s, 1H), 6.52 (s, J=2.2 Hz, 1H),
6.39 (s, J=2.2 Hz, 1H), 4.03 (s, 3H), 3.90 (s, 3H); 13C NMR
(125 MHz, CDCl3): d=182.7, 163.6, 161.4, 158.6, 156.5,
155.2, 141.3, 131.8, 131.3, 129.0, 126.4, 109.3, 106.5, 106.0,
104.9, 98.1, 96.9, 55.9, 55.4; IR (film): n=3343, 2968, 2926,
1706, 1664, 1613, 1583 cmÀ1; HR-MS (ES): m/z=348.0993,
calcd. for C21H16O5 [M+Na]+: 348.0998.
Flavasperone (23)
To
a solution of 22 (0.192 g, 0.523 mmol) in toluene
(10 mL), one drop of piperidine was added. The solution
was warmed to 458C and newly purchased acetaldehyde
(0.375 mL) was added. After 3 h at reflux, the mixture was
allowed to cool to room temperature upon which time
EtOAc and 1M HCl were added. The organic layer was
washed with water and brine. To the unpurified product was
added CH2Cl2 (3.80 mL) and the reaction mixture was
cooled to À788C. To the cooled solution was added BCl3
(0.476 mL, 3.00 mmol), and was allowed to stir for 20 min at
which time NaHCO3 was added. The reaction mixture was
then allowed to warm to room temperature. The organic
layer was washed with water and brine. The residue was
chromatographed (4% EtOAc/CH2Cl2) to afford 23 as a
yellow solid; yield: 0.036 g (65%); 1H NMR (500 MHz,
CDCl3): d=12.83 (s, 1H), 6.89 (s, 1H), 6.60 (d, J=2.2 Hz,
1H), 6.41 (d, J=2.2 Hz, 1H), 6.29 (s, 1H), 3.98 (s, 3H), 3.93
(s, 3H), 2.51 (s, 3H); 13C NMR (125 MHz, CDCl3): d=
182.9, 166.4, 161.7, 159.6, 155.9, 154.7, 140.6, 110.6, 110.4,
108.6, 105.2, 97.0, 96.8, 56.0, 55.2, 20.5. 1H NMR matches
that of the reported compound.[6a]
(M)-(À)-Nigerone (1)
A solution of 24 (0.026 g, 80% ee) in MeOH (22 mL) was
heated with saturated aqueous NaOH solution (0.22 mL)
and was placed in a 708C oil bath. After 18 h, 1M HCl was
added and the aqueous layer was extracted three times with
CH2Cl2. The organic layers were combined, dried over
MgSO4, filtered, and concentrated. The residue was chroma-
tographed (SiO2; 60% hexanes/EtOAc) to afford 1 as
yellow solid; yield: 0.013 g (50%, 77% ee); mp >2008C de-
1
composition; H NMR (500 MHz, CDCl3): d=15.31 (s, 1H),
6.44 (d, J=7 Hz, 2H), 6.07 (d, J=7 Hz, 1H), 6.00 (s, 1H),
4.06 (s, 3H), 3.49 (s, 3H), 2.03 (s, 3H); 13C NMR (125 MHz,
CDCl3): d=184.5, 167.6, 163.1, 161.9, 161.2, 151.3, 140.7,
108.8, 107.3 105.5, 104.3, 97.2, 96.5, 56.2, 55.2, 20.6; IR
(film): n=3377, 2930, 2853, 1652, 1610, 1586, 1409 cmÀ1
;
HR-MS (ES): m/z=571.1624, calcd. for C32H26O10Na (M+
Na+): 571.1604; CSP HPLC (Chiralpak AD, 1.0 mLminÀ1,
90:10 hexanes:i-PrOH): tR (S)=31.7 min, tR (R)=38.7 min.
592
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Asymmetric Total Synthesis of Nigerone and ent-Nigerone
Trituration of this material with 50% EtOAc/hexanes pro-
vided 1 with 90% ee: [a]D23: À223 (c 0.018 g/100 mL, CH2Cl2,
90% ee), literature [a]2D0:[6a] À287.7 (c 1.00, CHCl3).
based spectra. The calculated spectra for nigerone (1) were
not shifted.
SupportingInformation
Measurements of the Optical Rotation and Circular
Dichroism
NMR spectral data, Table with CD data of 1 and 24.
During the measurements of the optical rotation of synthetic
(P)-nigerone (1), the sign and magnitude of the rotation
were found to change with concentration. At low concentra-
tions (c=0.012–0.024 g/100 mL), self-consistent values were
obtained (the aD values changed linearly with concentration
in this range): (P)-1 [a]2D3: +172 (c 0.025 g/100 mL, CH2Cl2,
68% ee); (M)-1 [a]23: À170 (c 0.020 g/100 mL, CH2Cl2, 67%
ee). By trituration Dwith EtOAc/hexanes, 90% ee material
was obtained: (P)-1 [a]D23: +227 (c 0.0092 g/100 mL, CH2Cl2,
90% ee); (M)-1 [a]2D3: À223 (c 0.018 g/100 mL, CH2Cl2, 90%
ee). For bisisonigerone (24), a similar phenomenon was ob-
served, and optical rotation measurements were therefore
again made at low concentration: (P)-24 [a]2D3: À70.0 (c
0.050 g/100 mL, CH2Cl2, 70% ee); (M)-24 [a]2D3: +72.6 (c
0.120 g/100 mL, CH2Cl2, 67% ee).
Acknowledgements
Financial support was provided by the National Science
Foundation (CHE-0616885), the National Institutes of Health
(CA-109164), the GAANN program (ESD), the DFG (SFB
630 “Recognition, Preparation, and Functional Analysis of
Agents against Infectious Diseases”), and the Fonds der
Chemischen Industrie. We thank Magaly Ramirez (NSF-
REU) and Kusha Tavakoli for synthesis of precursors. We
are grateful to Prof. Virgil Percec and Janine Ladislaw for
access to CD instrumentation and to Prof. Eric Meggers and
Mark Schlegel for access to a UV spectrophotometer.
CD spectra were recorded on a Jasco J-720 spectropho-
tometer equipped with a NESLABRTE-111 variable tem-
perature circulator. (M)-Nigerone (1) of 67% ee and (P)-ni-
gerone (1) of 68% ee, as judged by chiral HPLC, were em-
ployed. Each sample was dissolved in CH2Cl2 (4.20 E–4M)
at 238C. CD measurements were performed at 208C using a
1-mL quartz cuvette of 0.1 cm path length and the following
parameters: scanned optical range, 240–400 nm; scan band
width, 1 nm; scanning speed, 100 nmminÀ1; response, 1 sec;
accumulations, 5. Data were processed using Jasco Spectra
Manager V. 1.51. For a table with CD data of (+)- and (À)-
nigerone (1), and of (+)- and (À)-24, see Supporting Infor-
mation.
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dron 2005, 61, 7241–7246.
Computational Methods
The conformational analyses of nigerone (1) and bisisoniger-
one (24) were performed on a Linux AMD MP 2800+
workstation using the DFT/RI-BLYP/SVP[15–17] approach
within the TURBOMOLE[31] suite of programs. The wave
functions of the ground and excited states were obtained by
semiempirical CNDO/S-CI[18] and OM2-CI[19] computations
with a CI expansion including 576 and 900 occupied configu-
rations, respectively, and the ground state determinant.
Within a time-dependent DFT approach 30 excited states
being lowest in energy were calculated using the B3LYP[20]
functional and a TZVP[21] basis set. In all approaches the os-
cillator and rotatory strengths were computed using the
dipole-length formalism.[32] The rotatory and oscillator
strengths calculated for the single conformers (bar spectra)
were added up according to the Boltzmann statistic. The
spectra were then simulated as sums of Gaussian functions
centered at the wavelengths of the corresponding electronic
transitions and multiplied by the respective overall rotatory
or oscillator strengths. For both, UV and CD spectra, an em-
pirically chosen exponential half width of 0.1 eV (CNDO/S,
TDDFT) and 0.15 eV (OM2) was used. The CD spectra
thus obtained for bisisonigerone (24) were then submitted
to a ꢁUV correctionꢂ,[3] requiring a red-shift of 5 nm for the
CNDO based spectra, a red-shift of 35 nm for the OM2
based spectra, and a blue-shift of 20 nm for the TDDFT
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 583 – 594