Synthesis of the cores of hypocrellin and shiraiachrome: diastereoselective 1,8-diketone aldol cyclization

Article abstract of DOI:10.1021/jo9018914

(Chemical Equation Presented) Intramolecular 1,8-diketone aldol reactions were studied as a tool for the construction of the seven-membered rings of hypocrellin and shiraiachrome. Conditions were identified to obtain the relative stereochemistries present

Full text of DOI:10.1021/jo9018914

pubs.acs.org/joc
Synthesis of the Cores of Hypocrellin and Shiraiachrome:
Diastereoselective 1,8-Diketone Aldol Cyclization
Erin M. O’Brien, Jingxian Li, Patrick J. Carroll, and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia,
Pennsylvania 19104
marisa@sas.upenn.edu
Received September 1, 2009
Intramolecular 1,8-diketone aldol reactions were studied as a tool for the construction of the seven-
membered rings of hypocrellin and shiraiachrome. Conditions were identified to obtain the relative
stereochemistries present in the two natural products with excellent diastereoselectivity. In addition,
a nine-membered ring congener, which has yet to be observed in nature, formed with high selectivity
when a hindered amine was used in conjunction with silazide bases.
SCHEME 1. Retrosynthesis of Hypocrellin, Shiraiachrome,
and Elsinochrome
Introduction
Hypocrellin (1) and shiraiachrome (2) are members of
the perylenequinone class of natural products that also
includes the elsinochromes, the calphostins, and cercosporin
(Scheme 1).1 The novel helically chiral structures of 1 and 2
are each comprised of an oxidized pentacyclic core as well as
a seven-membered carbocyclic ring. Our interest in hypo-
crellin, isolated from Hypocrella bambusae,2 largely stems
from its potential use as a photoactivated therapeutic agent.3
Existing as a 4:1 mixture of rapidly interconverting atropi-
somers (eq 1),4 hypocrellin displays potent light-induced
activity against bladder, brain, prostate, and leukemia cell
(1) For reviews see: (a) Weiss, U.; Merlini, L.; Nasini, G. Prog. Chem.
€
Schupp, O.; Tasler, S. Prog. Chem. Org. Nat. Prod. 2001, 82, 1–249.
(2) Chen, W. S.; Chen, Y. T.; Wang, X. Y.; Friedrichs, E.; Puff, H.;
Breitmaier, E. Liebigs Ann. Chem. 1981, 1880–1885.
Org. Nat. Prod. 1987, 52, 1–71. (b) Bringmann, G.; Gunther, C.; Ochse, M.;
lines5 as well as antiviral6 and immunotherapeutic proper-
ties.7
(3) (a) Lown, J. W. Can. J. Chem. 1997, 75, 99–119. (b) Towers, G. H. N.;
Page, J. E.; Hudson, J. B. Curr. Org. Chem. 1997, 1, 395–414.
(4) Mazzini, S.; Merlini, L.; Mondelli, R.; Scagloni, L. J. Chem. Soc.,
Perkin Trans. 2 2001, 409–416.
(5) (a) Ali, S. M.; Chee, S. K.; Yuen, G. Y.; Olivo, M. J. Photochem.
Photobiol. B 2001, 65, 59–73. (b) Ali, S. M.; Olivo, M.; Yuen, G. Y.; Chee,
S. K. Int. J. Oncol. 2001, 19, 633–643. (c) Zhang, J.; Cao, E.-H.; Li, J.-F.;
Zhang, T.-C.; Ma, W.-J. J. Photochem. Photobiol. B 1998, 43, 106–111.
(d) Ma, L.; Tai, H.; Li, C.; Zhang, Y.; Wang, Z.-H.; Ji, W.-Z. World J.
Gastroenterol. 2003, 9, 485–490.
(6) (a) Hudson, J. B.; Imperial, V.; Haugland, R. P.; Diwu, Z. Photochem.
Photobiol. 1997, 65, 352–354. (b) Hirayama, J.; Ikebuchi, K.; Abe, H.; Kwon,
K.-W.; Ohnishi, Y.; Horiuchi, M.; Shinagawa, M.; Ikuta, K.; Kamo, N.;
Sekiguchi, S. Photochem. Photobiol. 1997, 66, 697–700.
Scheme 1 illustrates our retrosynthetic analysis of hypo-
crellin and shiraiachrome A with respect to the ancillary
(7) Leveugle, B. U. S. Patent 2001-264677, 2002.
DOI: 10.1021/jo9018914
r
Published on Web 11/09/2009
J. Org. Chem. 2010, 75, 69–73 69
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O’Brien et al.
SCHEME 2. Synthesis of a 1,8-Diketone Model Substrate
JOCArticle
rings. From a common precursor (3), the seven-membered
ring will be generated via an intramolecular aldol cyclization
using the axial configuration as a stereochemical relay. While
there is precedent for highly diastereoselective aldol reac-
tions involving ketone electrophiles,8 there are no instances
involving acyclic 1,8-diketone substrates. In this paper, we
describe model studies to evaluate the feasibility and stereo-
chemical outcome of such an aldol reaction.
Results and Discussion
To the best of our knowledge, the type of 1,8-diketone aldol
reaction that we proposed to use had not been employed
previously outside of bridged or macrocyclic architectures.9 In
fact, aldol cyclizations of 1,8-dicarbonyls to form seven-mem-
bered rings are quite rare. A linear 1,8-dicarbonyl sub-
strate (eq 2) that does yield the seven-membered ring aldol
product proceeds in low yield (35%) even with a more reactive
aldehyde electrophile.10 In order to probe this type of ring-
forming process further, we subjected 1,8-diketone 411 to
LHMDS and were encouraged by the formation of the seven-
membered aldol product 5, albeit in low yield (eq 3). We
postulated that the insertion of two further sp2 centers into
the tether between the ketones (i.e., 3) would constrain the
reacting groups in closer proximity and facilitate such a process.
expected to provide the syn-aldol product with the relative
configuration of hypocrellin, 1 (Scheme 3, 12a).13
No reaction was observed under Lewis acid aldol condi-
tions (entries 1 and 2, Table 1). LDA did provide the product,
but as a complex mixture (entry 3). On the other hand, silazide
bases14 yielded only two diastereomers in all trials. The nature
of the enolate cation affected the stereoselectivity with lithium
enolates proving superior (entries 4-6). Warmer temperatures
(entry 7) resulted in lower selectivity, but attempts to achieve a
thermodynamic product ratio by further warming resulted in
complex mixtures. Addition of HMPA gave further improve-
ment (entries 8 and 9), but the optimal selectivity was obtained
14b
with Li(SiPhMe2)2 furnishing 12 as a 18:1 diastereomeric
ratio and 100% conversion (entry 10).
Determination of the relative configuration proved diffi-
cult. With no vicinal protons, coupling constants could not
be used. Analysis of the lowest energy conformational
families obtained with MM2*15 indicated a lack of charac-
teristic NOEs to distinguish among all the four diastereomers
without pure samples of each. Ultimately, debenzylation to 13a
and cocrystallization with methyl phenyl sulfoxide afforded
suitable crystals (Figure 1). Pleasingly, the relative stereo-
chemistry of 12a matches that of the major atropisomer of
hypocrellin.16
Buoyed by this success, we turned again to transition
structure calculations which indicated that the E-enolate (11E)
should provide the anti-aldol product 12c (Scheme 3)13 corre-
sponding to the relative stereochemistry of shiraiachrome A (2).
Following a report by Collum, we utilized hindered bases
with LiHMDS to initiate formation of the E-enolate.17
These conditions in this system, however, produced a nine-
membered ring product (12f) (Table 1, entries 11-13). Presum-
ably, the very large bases create hindered LiHMDS adducts that
cause enolization to the less hindered position (11A, see below)
even though it is substantially less acidic. In line with this
We selected readily accessible racemic 10 as a model
system to study the key transformation (Scheme 2). Impor-
tantly, the tether contains four sp2 centers permitting an
evaluation of conformational rigidity on the process. Com-
mercially available phenol 6 was protected as the benzoate
and then iodinated to provide 7. Ullman coupling followed
by deprotection afforded the racemic axially chiral biphenol,
which was allylated to yield 8. Subsequent tandem Claisen-
Cope rearrangement under thermal conditions provided 9.12
Further benzylation and regioselective Wacker oxidation
afforded the desired 1,8-diketone 10.
With 10 in hand, conditions were explored to achieve the
key intramolecular aldol transformation. On the basis of
transition structure calculations, the Z-enolate (11Z) was
(8) Selected examples: (a) Baciagaluppo, J. A.; Colombo, M. I.; Cravero,
ꢀ
ꢀ
R. M.; Gonzalez-Sierra, M.; Preite, M. D.; Zinczuk, J.; Ruveda, E. A.
Tetrahedron: Asymmetry 1994, 5, 1877–1880. (b) Jung, M. E.; Johnson,
T. W. J. Am. Chem. Soc. 1997, 119, 12412–12413. (c) Kaji, Y.; Koami, T.;
Nakamura, A.; Fujimoto, Y. Chem. Pharm. Bull. 2000, 48, 1480–1483.
(9) For selected examples, see: (a) Miyahara, Y. J. Org. Chem. 2006, 71,
6516–6521. (b) Davies, S.; Sheppard, R. L.; Smith, A. D.; Thomson, J. E.
Chem. Commun. 2005, 3802–3804. (c) Piers, E.; Skupinska, K. A.; Wallace,
D. J. Synlett 1999, 12, 1867–1870. (d) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.;
Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418–4420. (e) Shizuri, Y.;
Ohtsuka, J.; Kosemura, S.; Terada, Y.; Yamamura, S. Tetrahedron Lett.
1984, 25, 5547–5550.
(13) See the Supporting Information.
(14) (a) Gaudemer, M.; Bellassoued, M. Tetrahedron Lett. 1989, 30,
2779–2782. (b) Masamune, S.; Ellingboe, J.; Choy, W. J. Am. Chem. Soc.
1982, 104, 5526–5528.
(15) (a) MacroModel 6.5: Still, W. C. Columbia University. (b) Mohamdi, F.;
Richards, N. G.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.;
Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440–467.
(16) (a) O’Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Angew. Chem.,
Int. Ed. 2008, 47, 6877–6880. (b) See also the next manuscript in this series.
(17) Collum, D. B.; Godenschwager, P. F. J. Am. Chem. Soc. 2008, 130,
8726–8732.
(10) Baik, T. G.; Luis, A. L.; Wang, L. C.; Krische, M. J. J. Am. Chem.
Soc. 2001, 123, 5112–5113.
(11) Dyker, G.; Thoene, A. J. Prakt. Chem. 1999, 341, 138–141.
(12) Carroll, A. R.; Read, R. W.; Taylor, W. C. Aust. J. Chem. 1994, 47,
1579–1589.
70 J. Org. Chem. Vol. 75, No. 1, 2010

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JOCArticle
SCHEME 3. Intramolecular 1,8-Diketone Aldol Cyclization
TABLE 1. Intramolecular Diketone Aldol Cyclizationa
Thus, attention turned to the tetramethylpiperide (TMP)
bases18 to generate the E-enolate and the shiraiachrome
diastereomer. While LiTMP alone provided the nine-mem-
bered aldol product (Table 1, entry 14), LiTMP HBr pro-
3
vided 12d, which had been observed as the minor dia-
stereomer in the Li(SiPhMe2)2 reaction (entry 10), as the
major product (entry 15).
T
time convb
(°C) (h) (%)
entry
reagents
solvent
CH2Cl2
THF
12a:d:fc
1
2
TiCl4, NEt3
Cy2BCl,
NEt3
-78
25
2
2
ND
ND
3
4
5
6
7
8
LDA
THF
THF
THF
THF
THF
THF/HMPA
(5 vol%)
THF/HMPA
(2 equiv)
-78
-78
-78
-78
-40
-78
1
1
1
1
1
1
>30 NDd
KHMDS
NaHMDS
LiHMDS
LiHMDS
LiHMDS
77 2:1:0
78 3:1:0
95 5:1:0
100 4:1:0
95 7:1:0
9
LiHMDS
-78
1
97 8:1:0
FIGURE 1. Crystal structure of 13a (debenzylated 12a) cocrystal-
lized with MePhSdO (30% thermal ellipsoids).
10 Li(SiPhMe2)2 THF
-78
-78
1
2
100 (70) 18:1:0
85 1:3:13
11 LiHMDS
12 LiHMDS
13 LiHMDS
PhCH3/Et3N
(80 equiv)
PhCH3/i-Pr2EtN -78
(80 equiv)
PhCH3/Ph3N
(80 equiv)
THF
To determine the structure of 12d, several experiments
were undertaken on the debenzylated versions of 12a-d
(13a-d) (Figure 2). First, a comparison of the crystal
structure of 13a to the MM2*-calculated structure showed
remarkable agreement,13 indicating that calculations could
be used to estimate distances and dihedral angles. Second,
13d was established as an anti diastereomer from the chemi-
cal shifts of the C15-H. In 13a (Figure 2), the C15-H
(3.40 ppm) is trans to the C14-OH in 13a. The observation
of a higher chemical shift of 3.60 ppm for the C15-H of the
new compound implied a closer proximity of the C15-H to
the C14-OH (i.e., a cis relationship), narrowing the field to
2
80 1:2:14
-78
2
87 (67) 1:5:55
14 LiTMP
15 LiTMP
-78
-78
2
2
90 1:7:27
90 (71) 3:10:1
THF/LiBr
aAll reactions were carried out in a 3 μM concentration and quenched
b
with saturated NH4Cl (aq). Conversion was determined by 500 MHz
1H NMR. Isolated yields of the major isomer are in parentheses. cRatios
were determined by integration of the characteristic aromatic protons
(12a: 6.32, 6.56 ppm; 12d: 6.45, 6.66 ppm; 12f: 6.60, 6.65 ppm). dComplex
mixture of products.
hypothesis, progressively larger bases (Ph3N > i-Pr2EtN >
Et3N) provided greater amounts of 12f. With Ph3N, 12f ac-
counted for 90% of the product (entry 13).
(18) Collum, D. B.; Hall, P. L.; Gilchrist, J. H. J. Am. Chem. Soc. 1991,
113, 9571–9574.
J. Org. Chem. Vol. 75, No. 1, 2010 71

O’Brien et al.
JOCArticle
SCHEME 4. Shiraiachrome Synthesis Plan
SCHEME 5. Stereochemistry of 12f
FIGURE 2. Assignment of the relative stereochemistry by exam-
ination of the compounds (13a-d) arising from debenzylation of
12a-d (X-ray distances and angles for 13a; calculated for 13b-d).
13c or 13d. Third, NOE experiments were performed on 13a
and on the debenzylated form of the E-enolate product
(Figure 2). For 13a, NOEs between H11 and H18 and H15
and H18 were observed, consistent with the distances from
the crystal and calculated structures. For the E-enolate
product, lack of an H15-H18 NOE indicates a trans array
confirming an anti-aldol adduct (13c or 13d). The strong
NOE between H11 and H18, however, is only consistent with
unlikely that this result is due to formation of a mixture of
12e and 12f followed by a thermodynamic equilibration, due
to the high atropisomeric stability of these compounds.1b
13d, implying that 12d is the major product with LiTMP
3
Conclusions
HBr (Table 1, entry 15). This result was not in accord with
our expectations that 12c would predominate (see TS calcu-
lations in Scheme 3).
The high yields observed in the 1,8-diketone aldol reaction
of model system 10 were unexpected in light of past pre-
cedent which indicates that a bridged scaffold is necessary to
effect an efficient aldol reaction between ketone centers in a
1,8-relationship. Furthermore, the transannular aldol reac-
tion is expected to induce significant dihedral strain since the
biaryl angle becomes compressed going from 10 (88° calcd)
to 12a/12d (55° X-ray). Since the biaryl angle in 3 (31° calcd,
Scheme 1) positions the reacting groups in even closer
proximity, formation of 1 or 2 (23-24° X-ray) does not
require much movement and was expected to occur even
more readily. Thus, these results strongly supported the
proposed aldol pathway that was subsequently employed
to form the natural products hypocrellin (1) and shiraia-
chrome (2) following the plan outlined in Scheme 1.16
In conclusion, we have developed an efficient method for
installing the seven-membered ring of hypocrellin (1) or
shiraiachrome A (2) stereoselectively via intramolecular
1,8-diketone aldol cyclizations. Furthermore, use of hin-
dered bases (Ph3N) in conjunction with LiHMDS furnished
a nine-membered aldol product via the acetate enolate,
which provides an avenue to interesting nonnatural peryle-
nequinones for further study.
Overall, the results indicate that the biaryl stereochemistry
controls the facial approach to the ketone electrophile,
thereby establishing the C14 stereocenter (see Scheme 3).
On the other hand, the enolization method controls the
relative configuration between C14 and C15 (syn-aldol for
12a and anti-aldol for 12d).
These results support the use of 3 (Scheme 1) with Li-
(SiPhMe2)2 to produce hypocrellin (1), a tactic which has
proved successful.16 On the other hand, the results also
indicate that LiTMP HBr would not produce shiraiachrome
3
A (2) from 3, raising the interesting question of how one
might access 2. We propose that ent-3 would provide the
enantiomeric array of that illustrated in 12d (Scheme 3)
yielding atrop-2 which would only equilibrate with the major
form 24 after formation of the seven-membered ring that
lowers the atropisomerization energy barrier (Scheme 4).16
With the above results in hand for 12a and 12d, the
stereochemistry of the nine-membered ring product was
expected to arise from a similar facial attack on the carbonyl
controlled by the biaryl axis (i.e., 12e, Scheme 5). However,
experiments show no H11-H18 NOE, pointing to 12f as the
product. This result may be explained by the biaryl stereo-
chemistry controlling the approach to the carbonyl in lower
energy conformational isomer 11A0 where steric interactions
between H11 and C18 are minimized relative to 11A. It is
Experimental Section
1-[4,6,20,40-Tetramethoxy-5,30dibenzyloxy-60-(2-oxopropyl)bi-
phenyl-2-yl]propan-2-one (12). A solution of the diol 9 (275 mg,
72 J. Org. Chem. Vol. 75, No. 1, 2010

O’Brien et al.
JOCArticle
0.71 mmol) in DMF (20 mL) was cooled to 0 °C. NaH (60%
in oil, 140 mg, 3.6 mmol) was added and the mixture stirred for
15 min. Benzyl bromide (0.43 mL, 3.56 mmol) and n-Bu4NI
(26 mg, 0.071 mmol) were added at 25 °C and the reaction stirred
for 1 h. The mixture was acidified with 1 M HCl, diluted with
EtOAc, washed with H2O (6ꢀ) and brine, and dried (Na2SO4).
The concentrate was chromatographed (40% EtOAc/hexanes)
to afford 1-[4,6,20,40-tetramethoxy-5,30dibenzyloxy-60-allylbi-
60.3, 60.4, 80.7, 104.9, 107.7, 120.6, 122.9, 125.4, 128.3, 137.4,
138.2, 145.3, 145.5, 147.0, 147.1, 213.4; IR (thin film) 3439, 2937,
1695, 1610 cm-1; HRMS (ESI) calcd for C22H26O8Na (MNaþ)
441.1525, found 441.1544.
To a solution of 13a (23 mg, 0.061 mmol) in a benzene/hexane
mixture (1:1 v/v, 0.40 mL) was added racemic phenylmethyl
sulfoxide (17 mg, 0.12 mmol). The mixture was stirred at room
temperature for 12 h. The precipitate was recrystallized from
CH2Cl2/hexane (1:1 v/v, 1 mL) to afford the cocrystal product.
A crystal structure was obtained, securing the relative config-
uration (see the Supporting Information).
1
phenyl-2-yl]propan-2-ene as a yellow resin (281 mg, 70%): H
NMR (500 MHz, CDCl3) δ 7.51 (d, J=6.9 Hz, 4H), 7.35 (t, J=
6.9 Hz, 4H), 7.29 (t, J=7.2 Hz, 2H), 6.62 (s, 2H), 5.84-5.76 (m,
2H), 5.08 (d, J = 11.1 Hz, 2H), 5.05 (d, J = 11.1 Hz, 2H)
5.01-4.98 (m, 2H), 4.98-4.96 (m, 2H), 3.88 (s, 6H), 3.67 (s, 6H),
3.03-2.93 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 153.2, 152.1,
139.2, 138.1, 137.3, 135.1, 128.6, 128.4, 128.1, 123.2, 116.1,
(Ra*,R*,R*)-1-(6-Hydroxy-1,3,9,11-tetramethoxy-2,10-dibenzyl-
oxy-6-methyl-5H-dibenzo[a,c]cycloheptan-5-yl)ethanone (12d).
To a stirring solution of 10 (90 mg, 0.15 mmol) in THF (16.0 mL)
at -78 °C under Ar was added the LiTMP-LiBr complex (15.0 mL,
0.8 M LiTMP, 0.75 mmol). After being stirred for 2 h at -78 °C, the
mixture was quenched with satd NH4Cl, extracted with EtOAc,
washed with brine, dried over anhydrous Na2SO4, and concen-
trated. The concentrate was chromatographed (2% MeOH in 1:1
107.9, 75.2, 60.9, 56.1, 37.9; IR (film) 2930, 2856, 1594, 1455 cm-1
;
HRMS (ESIþ) calcd for C36H38O6Naþ (MNaþ) 589.2566,
found 589.2571.
To a solution of PdCl2 (1.3 g, 7.1 mmol) and CuCl (3.5 g,
3.5 mmol) stirred in a DMF/H2O mixture (7:1 v:v, 50 mL) at
room temperature for 30 min was added 1-[4,6,20,40-tetra-
methoxy-5,30dibenzyloxy-60-allylbiphenyl-2-yl]propan-2-ene (1.0 g,
1.8 mmol). After being stirred under oxygen 18 h, the reaction
mixture was acidified with 1 M HCl, diluted with EtOAc,
washed with H2O (6ꢀ) and brine, and dried (Na2SO4). The
corresponding concentrate was chromatographed (20-50%
EtOAc/hexanes) to afford 10 (520 mg, 50%) as a yellow oil:
1H NMR (500 MHz, CDCl3) δ 7.42 (d, J=7.4 Hz, 4H), 7.29 (t,
J = 7.1 Hz, 4H), 7.23 (t, J = 6.6 Hz, 2H), 6.58 (s, 2H), 5.07 (s,
4H), 3.88 (s, 6H), 3.60 (s, 6H), 3.35 (d, J=16.7 Hz, 2H), 3.30 (d,
J=16.7 Hz, 2H), 1.94 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
206.6, 153.4, 152.0, 139.7, 138.0, 130.5, 128.6, 128.5, 128.1,
123.2, 109.5, 75.2, 60.8, 56.1, 47.9, 29.9; IR (film) 2937, 1710,
1594 1455 cm-1; HRMS (ESIþ) calcd for C36H38O8Naþ
(MNaþ) 621.2464, found 621.2463.
(Ra*,R*,S*)-1-(6-Hydroxy-1,3,10,11-tetramethoxy-2,9-dibenzyl-
oxy-6-methyl-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl)etha-
none (12a). A solution of 10 (15 mg, 0.033 mmol) in THF (20 mL)
was cooled to -78 °C under argon. Lithium tetramethyldiphenyl
disilylamide (34 μL, 0.040 mmol, 1.2 M in THF) was added and the
mixture stirred for 1 h. The mixture was quenched with saturated
NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4),
and concentrated. Analysis of this material (500 MHz 1H NMR)
indicated 100% conversion and an 18:1 diastereomeric ratio of
12a:12d. The concentrate was chromatographed which separated
the diastereomers (30% EtOAc/hexanes) to afford 12a (11 mg,
70%) as a yellow resin: 1H NMR(500 MHz, CDCl3) δ7.50, (d, J=
7.4 Hz, 4H), 7.39-7.35 (m, 4H), 7.32-7.29 (m, 2H), 6.56 (s, 1H),
6.32 (s, 1H), 5.02-5.18 (m, 4H), 3.88 (s, 3H), 3.84 (s, 3H), 3.74 (s,
3H), 3.66 (s, 3H), 3.39 (s, 1H), 2.38 (d, J=13.0 Hz, 1H), 2.32 (d,
J= 13.0 Hz, 1H), 2.17 (s, 3H), 1.34 (s, 3H); 13C NMR (90 MHz,
CDCl3) δ 213.6, 153.5, 153.4, 152.5, 152.3, 141.1, 140.2, 138.2,
138.1, 133.2, 130.1, 128.7, 128.6, 128.5, 128.4, 128.1, 128.0, 123.9,
121.8, 108.7, 105.9, 80.8, 75.4, 75.3, 61.2, 61.1, 60.3, 60.2, 56.3, 46.9,
32.4, 26.9; IR (film) 3497, 2937, 1698, 1598 cm-1; HRMS (ESIþ)
calcd for C36H38O8Naþ (MNaþ) 621.2464, found 621.2449.
(Ra*,R*,S*)-1-(6-Hydroxy-1,3,10,11-tetramethoxy-2,9-hydroxy-
6-methyl-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl)ethanone
(13a). To a solution of 12a (single isomer, 69 mg, 0.12 mmol) in a
MeOH/THF mixture (1:1 v/v, 10 mL) was added 10% Pd/C
(130 mg, 1.2 mmol). A hydrogen balloon was added, and the
reaction mixture was stirred for 20 min. The mixture was filtered
through silica (10% MeOH/CH2Cl2) to afford 13a as a colorless
oil (51 mg, 100%): 1H NMR (500 MHz, CDCl3) δ 1.33 (s, 3H),
2.13 (s, 3H), 2.30 (d, J=13.1 Hz, 1H), 2.36 (d, J=13.1 Hz, 1H),
3.41 (s, 1H), 3.52 (s, 3H), 3.67 (s, 3H), 3.90 (s, 3H), 3.94 (s, 3H),
4.52 (s, 1H), 5.63 (s, 1H), 5.66 (s, 1H), 6.33 (s, 1H), 6.56 (s, 1H);
13C NMR (125 MHz, CDCl3) δ 26.5, 31.9, 46.4, 56.2, 56.3, 59.8,
1
Et2O/hexanes), yielding 12d (64 mg, 71%) as pale yellow oil: H
NMR (500 MHz, CDCl3) δ 7.53, (d, J=7.2 Hz, 2H), 7.49 (d, J=
7.2 Hz, 2H), 7.38-7.34 (m, 4H), 7.32-7.29 (m, 2H), 6.65 (s, 1H),
6.44 (s, 1H), 5.16 (d, J=11.0 Hz, 1H), 5.15 (d, J=11.0 Hz, 1H), 5.07
(d, J=10.1 Hz, 1H), 5.06 (d, J=10.1 Hz, 1H), 3.88 (s, 3H), 3.82 (s,
3H), 3.72 (s, 3H), 3.66 (s, 3H), 3.58 (s, 1H), 2.81 (s, 1H), 2.44 (d, J=
14.0 Hz, 1H), 2.18 (d, J=14.0 Hz, 1H), 2.13 (s, 3H), 1.39 (s, 3H); 13
C
NMR (90 MHz, CDCl3) δ 210.4, 153.7, 153.4, 152.5, 152.3, 140.9,
140.2, 138.1, 137.9, 133.1, 131.3, 128.6, 128.5, 128.4, 128.11, 128.05,
124.2, 121.7, 108.7, 106.0, 81.4, 75.4, 75.3, 63.7, 61.2, 61.1, 56.5, 56.2,
48.0, 31.4, 29.9, 24.0; IR (film) 3250 (br), 2943, 2881, 2835, 1715,
1599, 1460, 1413, 1104, 749 cm-1; HRMS (ESIþ) calcd for
C36H38O8Naþ (MNaþ) 621.2462, found 621.2451.
(Ra*, S*)-1,3,11,13-Tetramethoxy-2,12-dibenzyloxy-8-methyl-
8-hydroxy-5,7,9-trihydro-7H-dibenzo[a,c]cyclononen-6-one (12f).
To a stirring solution of 10 (90 mg, 0.15 mmol) and Ph3N (1.5 g,
6.0 mmol) in PhCH3 (20 mL) at -78 °C under Ar was added
lithium hexamethyl disilylamide (5.0 mL, 1.0 M in PhCH3, 5.0 mmol).
After being stirred at -78 °C for 2 h, the mixture was quenched
with satd NH4Cl, extracted with EtOAc, washed with brine, dried
over anhydrous Na2SO4, and concentrated. The concentrate was
chromatographed (2% MeOH in 1:1 Et2O/hexanes), yielding 12f
(60 mg, 67%) as pale yellow oil: 1H NMR (500 MHz, CDCl3) δ
7.47 (d, J= 7.4 Hz, 4H), 7.37-7.32 (m, 4H), 7.30-7.28 (m, 2H),
6.65 (s, 1H), 6.60 (s, 1H), 5.13 (d, J = 11.1 Hz, 1H), 5.09 (d, J =
11.1 Hz, 1H), 5.04 (d, J=11.1 Hz, 1H), 5.01 (d, J=11.1 Hz, 1H),
4.06 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.70 (s, 3H), 3.64 (s, 3H), 3.32
(d, J=16.6 Hz, 1H), 3.16 (d, J=16.6 Hz, 1H), 2.53 (d, J=13.8Hz,
1H), 2.50 (d, J=13.8 Hz, 1H), 2.30 (d, J=13.2 Hz, 1H), 1.91 (d,
J = 13.2 Hz, 1H), 1.19 (s, 3H); 13C NMR (90 MHz, CDCl3) δ
211.0, 154.0, 153.8, 152.1, 151.41, 140.3, 140.0, 138.0, 137.7, 133.1,
131.7, 128.7, 128.5, 128.4, 128.2, 128.0, 124.7, 123.3, 110.4, 109.8,
77.6, 75.6, 75.0, 74.7, 61.0, 60.9, 56.23, 56.16, 52.7, 48.2, 46.0, 31.4;
IR (film) 3247 (br), 2927, 2858, 1730, 1692, 1599,1460, 1406, 1097,
1027, 749 cm-1; HRMS (ESIþ) calcd for C36H38O8Naþ (MNaþ)
621.2462, found 621.2416.
Acknowledgment. This work was finanically supported by
the NIH (CA-109164). Partial instrumentation support was
provided by the NIH for MS (1S10RR023444) and NMR
(1S10RR022442). Thanks to Eli Lilly (E.O.B.), the Vagelos
Scholars Program (J.L.), and the Defence Science & Tech-
nology Agency of Singapore (J.L.) for fellowships.
Supporting Information Available: Additional experimental
descriptions, NMR spectra, calculated structures, and crystal-
lographic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 1, 2010 73