On the Formation of 2-Sulfonylbenzo[a]heptalene-1,3-diols as Precursors for the Synthesis of Colchicinoids

Article abstract of DOI:10.1002/hlca.200390335

The benzo[a]heptalene formation from 4-[(R-sulfonyl)acetyl]heptalene-5-carboxylates 15 and 5-[(R-sulfonyl)acetyl]heptalene-4-carboxylates 16 (R = Ph or morpholino) in the presence of R′SO₂CH₂Li and BuLi has been investigated (Scheme 6). Only the sulfonyl moiety linked to the C=O group at C(4) of the heptalene skeleton is found at C(3) of the formed benzo[a]heptalene-2,4-diols 3 in accordance with the general mechanism of their formation (Scheme 3). Intermediates that might rearrange to corresponding 2-sulfonylbenzo[a]heptalene-1,3-diols lose HO^-under the reaction conditions to yield the corresponding cyclopenta[d]heptalenones of type 11 (Schemes 6 and 7). However, the presence of an additional Me group at C(a) of the lithioalkyl sulfones suppresses the loss of HO^-, and 4-methyl-2-sulfonylbenzo[a]heptalene-1,3-diols of type 4c have been isolated and characterized for the first time (Schemes 8 and 10). A number of X-ray crystal-structure analyses of starting materials and of the new benzo[a]heptalenes have been performed. Finally, benzo[a]heptalene 4c has been transformed into its 1,2,3-trimethoxy derivative 23, a benzo[a]heptalene with the colchicinoid substitution pattern at ring A (Scheme 11).

Full text of DOI:10.1002/hlca.200390335

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Helvetica Chimica Acta Vol. 86 (2003)
On the Formation of 2-Sulfonylbenzo[a]heptalene-1,3-diols as Precursors
for the Synthesis of Colchicinoids
by Khaled Abou-Hadeed and Hans-J¸rgen Hansen*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
Dedicated to Duilio Arigoni on the occasion of his 75th birthday
The benzo[a]heptalene formation from 4-[(R-sulfonyl)acetyl]heptalene-5-carboxylates 15 and 5-[(R-
sulfonyl)acetyl]heptalene-4-carboxylates 16 (R ˆ Ph or morpholino) in the presence of R'SO2CH2Li and BuLi
has been investigated (Scheme 6). Only the sulfonyl moiety linked to the CˆO group at C(4) of the heptalene
skeleton is found at C(3) of the formed benzo[a]heptalene-2,4-diols 3 in accordance with the general mechanism
of their formation (Scheme 3). Intermediates that might rearrange to corresponding 2-sulfonylbenzo[a]hepta-
lene-1,3-diols lose HOÀ under the reaction conditions to yield the corresponding cyclopenta[d]heptalenones of
type 11 (Schemes 6 and 7). However, the presence of an additional Me group at C(a) of the lithioalkyl sulfones
suppresses the loss of HOÀ, and 4-methyl-2-sulfonylbenzo[a]heptalene-1,3-diols of type 4c have been isolated
and characterized for the first time (Schemes 8 and 10). A number of X-ray crystal-structure analyses of starting
materials and of the new benzo[a]heptalenes have been performed. Finally, benzo[a]heptalene 4c has been
transformed into its 1,2,3-trimethoxy derivative 23, a benzo[a]heptalene with the colchicinoid substitution
pattern at ring A (Scheme 11).
1. Introduction. The formation of 3-sulfonylbenzo[a]heptalene-2,4-diols (3) in a
−one-pot× reaction from heptalene-4,5- or -1,2-dicarboxylates (1 and 1', respectively;
Scheme 1) [1][2] or their corresponding pseudo-esters 2 and 2' [3] and lithiomethyl
sulfones in the presence of BuLi is attractive in a sense that it principally opens a new
entrance to the synthesis of colchicinoids1), where the aromatic ring A is constructed at
the heptalene rings B and C. The OH groups of 3 can easily be methylated, and the
sulfonyl substituent may subsequently be removed reductively, followed by introduc-
tion of a third MeO residue after oxidation of C(3) [5]. These procedures demonstrate
that benzo-anellation of heptalenedicarboxylates is, indeed, suitable for the construc-
tion of ring A of prospective colchicinoids. A disadvantage of the synthesis, however, is
that it leads exclusively to benzo[a]heptalenes of type 3 with the wrong C(2,3,4)-
substitution pattern at ring A compared with biologically active colchicines from
nature, which all show O-substituents at C(1,2,3) [6]. A central question is, therefore,
whether the benzo-annelation of 1 and 1' (or their pseudo-forms 2 and 2') can be
influenced or modified in a way that 2-sulfonylbenzo[a]heptalene-1,3-diols of type 4 are
formed instead of their isomers 3 (Scheme 2).
All observations we have made so far indicate that the crucial intermediates of the
new annelation reaction represent 1H-cyclopenta[a]heptalene-1,3-diolates of type 5,
1
)
For other syntheses of colchicines and their derivatives, based on ring-B or -C construction, see the
literature cited in [4].

Helvetica Chimica Acta Vol. 86 (2003)
4019
Scheme 1
a) 1. R'SO2CH2Li, À 788; 2. BuLi, À 78 to 208.
Scheme 2
which undergo a 1,2-C shift2) of the R'SO2CH2 residue (R'') that leads to the formation
of the better resonance-stabilized compounds 6 (Scheme 3) [2][3]. The latter then lose
under the influence of BuLi, in a not yet fully understood reaction, R0SO2À,
accompanied by ring enlargement to the corresponding 3-sulfonylated benzo[a]hepta-
lene-2,4-diolates 7 [3]. Besides 5, the isomeric compounds 8 must also be present in the
reaction mixtures, but do not undergo the 1,2-C shift that would result in the formation
of 10 and the desired 4. It seems that the bisanions 8, in place of rearranging to 9, lose
2
)
The postulated 1,2-C shift may also be regarded as a sigmatropic [1s,5s]-C rearrangement of a 5,5-
disubstituted cyclopentadiene (cf. [7] and refs. cit. therein).

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 3
more rapidly HOÀ to yield finally compounds of type 11, which we have found in all
reactions together with 3 [1 3].
The benzo-ring-forming reaction of vicinal heptalenedicarboxylates is of general
applicability and can also be performed with 1,2-disubstituted maleic anhydrides 12 in a
two-step process, leading via 13 to the corresponding 2-sulfonylated 6-methylresorci-
nols 14 (Scheme 4) [8]. These results suggest that a-sulfonylethyl groups undergo the
decisive 1,2-C shift in compounds of type 5 (Scheme 3), followed by loss of R0SO2À
under concomitant ring enlargement. Moreover, by interplay of an a-sulfonylethyl and
a sulfonylmethyl substituent under strongly basic conditions, it is the former to undergo
the 1,2-shift since only the latter possesses a second H-atom necessary for the formation
of the crucial sulfonylated intermediates of type 5 (or 8) ready for the rearrangement of
Scheme 4

Helvetica Chimica Acta Vol. 86 (2003)
4021
the sulfonylated alkyl substituent at this position. In the following part, we will describe
a number of experiments that are based on these considerations.
2. Results and Discussion.
2.1. Chemical Transformations. The mechanistic
pathway for the formation of the 3-sulfonylbenzo[a]heptalene-2,4-diols 3, as shown in
Scheme 3, requires an R'SO2CH2 group linked to the CˆO group at C(5) in the very
first intermediates (see below), to become part of the benzo moiety via steps 5 ! 6 ! 7.
We, therefore, synthesized a number of 4-[(R'-sulfonyl)acetyl]heptalene-5-carbox-
ylates 15 and 5-[(R'-sulfonyl)acetyl]heptalene-4-carboxylates 16 (R' ˆ Ph or morpho-
lino) as model compounds for benzo[a]heptalenediol formation to corroborate the
general mechanistic validity of Scheme 3. We chose 1a and its easily accessible pseudo-
ester 2'a as starting materials (Scheme 5). Alkylation of 1a with lithiomethyl
morpholino, lithiomethyl phenyl, or a-lithioethyl phenyl sulfone at À 788 in THF led
Scheme 5
b
a) Morˆ morpholino. ) See [1]. c) The reaction was performed at À 208. d) For details see [3] and Exper. Part.

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Helvetica Chimica Acta Vol. 86 (2003)
selectively to the 4-[(R'-sulfonyl)acetyl]heptalene-5-carboxylates 15a c and to stereo-
isomeric mixtures of the corresponding Michael adducts 17a c as side products.
Nevertheless, the two product types could easily be separated by column chromatog-
raphy on silica gel, with 15 as the faster-running product type3). The same procedure,
applied to the pseudo-ester 2'a, gave mostly the inversely substituted heptalene-4-
1
carboxylates 16a 16c. H-NMR Spectroscopy indicated in all cases the sole presence
of the displayed 4,5-dicarbonyl forms 15 and 16, respectively. Moreover, the structures
of 15c, 16a, 16b, and 17c were further corroborated by X-ray crystallography (see
Exper. Part).
It should be noted that the a-Me substituted forms 15c and 16c could also be
prepared in excellent yields by smooth methylation of 15b and 16b, respectively, with
MeI in acetone at room temperature in the presence of 1 equiv. of powdered K2CO3
(Scheme 5).
All benzo[a]heptalene syntheses were performed in the same way under standard
−one-pot× conditions (Table 1 and Scheme 6). The results were unambiguous. In the
case of 15a and 15b, it was, in accordance with Scheme 3, the R'SO2CH2 group of the
Scheme 6a)
a) For details see Table 1. b) Morˆ morpholino.
3
)
In recent experiments, we found that the Mg compound of methyl phenyl sulfone adds almost exclusively
at the ester CˆO group at C(4) of heptalene-4,5-dicarboxylates [9].

Helvetica Chimica Acta Vol. 86 (2003)
4023
reactants that were built into the benzo ring of 3a and 3b, respectively, whereas, in turn,
in the case of 16a and 16b, the added R''SO2CH2Li reagent (as a C1 synthon) was built
into 3b and 3a, respectively.
Table 1. Benzo[a]heptalene Formation with (Sufonylacetyl)heptalenes 15 and 16 (for structures, see Schemes 6
and 8). Mor stands for morpholino.
Starting material
Reagenta)
Products (yield [%])
15a
15b
15b
15c
16a
16b
16b
16c
LiCH2SO2Ph
3a (26)b)
3b (23)b)
3c (28)
4c (19)
3b (37)
3a (35)
4c (29)
3c (24)
11ba (20 30)b)
11ab (25)b)
17bc)
LiCH2SO2(Mor)
LiCH(Me)SO2Ph
LiCH2SO2Ph
11bcc)
LiCH2SO2Ph
11abd)
LiCH2SO2(Mor)
LiCH(Me)SO2Ph
LiCH2SO2Ph
11bad)
11bcc)
17bc)
a) All transformations were performed as follows: the lithiated sulfone (4 equiv.) was added at À 408 to 15 or 16
(1 equiv.) in anh. THF. The temp. was raised to À 58 within 3 h. Then, BuLi in hexane (4 equiv., ca. 2m soln.)
was added. Afterwards, the temp. was raised to 208, and stirring was continued for 3 h (lithiomethyl sulfones) or
15h (1-lithioethyl sulfone), followed by workup. b) The yields of 3 and 11 were determined by independent
experiments. c) Compound not detected; see footnote in Scheme 8). d) Compounds 11ab and 11ba, resp., were
detected by TLC, but not isolated. Qualitatively, their amounts were comparable with those formed from 15a
and 15b, resp.
In separate experiments, we isolated as second main products and in comparable
amounts to the benzo[a]heptalene-2,4-diols the cyclopenta[d]heptalen-1(1H)-ones 11
(cf. Scheme 6 and Table 1) in full accordance with the mechanistic guidelines of
Scheme 34). Compounds 11ab and 11ba with exchanged positions of the morpholino
and Ph substituents at C(2) and CH2ÀC(3), respectively, could be easily distinguished
by 1H-NMR. The coupling constant of the AB system of the CH2 group at C(3), which
exhibits a strong reciprocal 1H-NOE effect with HÀC(4), is larger in the case of 11ab
(JAB ˆ 12.7 12.8 Hz) than in the case of 11ba (JAB ˆ 12.4 12.5Hz) [1][2]. More
convincing regarding the structure of the side chain at C(3) are the 13C-NMR shifts of
the CH2 C-atom. Its signal appears in the presence of a PhSO2 group above 50 ppm
(11ab (CDCl3): 52.96 ppm), but below this value in the presence of a morpholino-
sulfonyl group (11ba (CDCl3): 45.01 ppm), respectively [1][2]. The unequivocal
assignment of the structure of 11ab and 11ba supports our observation that neither a
(phenylsulfonyl)methyl nor a (morpholinosulfonyl)methyl group at C(3) of the
intermediate 8 does undergo the required 1,2-C shift to 9 (Scheme 3). The formation of
an enolate ion 18 (Scheme 7) with extended conjugation by loss of HOÀ from C(3)
under the strongly basic condition used for the formation of the benzo[a]heptalene-2,4-
diolates 7 seems to be more favorable than the formation of diolates of type 9. Indeed,
4
)
We showed that the compounds of type 11 are truly the final products under the original, strongly basic
reaction conditions, i.e., they are not the result of the loss of H2O from the corresponding 3-OH-
substituted cyclopenta[d]heptalen-1-ones (see, e.g., 19c in Scheme 9) under the workup conditions. It
should also be noted that 3 and 11 are formed at the same temperature range (À5to 20 8) under strongly
basic conditions (cf. Table 1).

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Scheme 7
a) AM1-Calculated DHf8 values [kcal ¥ molÀ1].
AM1 calculations of simplified model structures were in agreement with these
assumptions.
Of much greater interest for us was, therefore, the benzo[a]heptalene-forming
reaction with 15c and 16c carrying a-methylated 4- and 5-[(phenylsulfonyl)acetyl]
groups. When 16c was treated in the usual manner with lithiomethyl phenyl sulfone,
then compound 3c, carrying an additional Me group at C(1), was obtained in
(nonoptimized) 24% yield (Scheme 8 and Table 1). Product 3c was obtained in nearly
the same yield, when 15b was reacted with a-lithioethyl phenyl sulfone. The structure of
3c was fully established by X-ray crystal-structure analysis (Fig. 1; see also Chapt. 2.2).
These results gave us confidence that 15c, with its 4-[(phenylsulfonyl)acetyl]
substituent, carrying an additional a-Me group, would undergo the transformation
into a 4-methyl-benzo[a]heptalene-1,3-diol, provided that the postulated loss of HOÀ
from the crucial intermediates of type 8 (Schemes 3 and 7) was hindered (or at least
retarded) in favor of the 1,2-C shift to 9 due to the a-Me substituent at the C-atom at
C(3).
Indeed, the reaction of 2'a with 2 equiv. of a-lithioethyl phenyl sulfone gave, as the
main product after crystallization, one pure stereoisomer of the 3-hydroxycyclopen-
ta[d]heptalen-1-one 19c (Scheme 9), which cannot react further and whose structure
was unambiguously determined by X-ray crystal-structure analysis (Fig. 2; see also
Chapt. 2.2). The formation of the correct cyclopenta[d]heptalenone, i.e., with the 1-
(phenylsulfonyl)ethyl moiety at C(3), was in agreement with AM1 calculations of

Helvetica Chimica Acta Vol. 86 (2003)
Scheme 8a)
4025
a) For exper. details see Table 1. b) We found no indication for the presence of 17b or 11bc in amounts > 1%.
However, when 15c was treated with KOH in MeOH at r.t., compound 24 was obtained in 41% yield.
Fig. 1. Stereoscopic view of the X-ray crystal structure of 3c

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 9
a) 2 Equiv. LiCH(Me)SO2Ph/THF; À 788 to À 408, 3 h; 15% (yield of the isolated stereoisomer).
Fig. 2. Stereoscopic view of the X-ray crystal structure of 19c ((P*,2R*,3R*,1'S*)-configuration)
similarly substituted model heptalenes. Independent of the position of the CˆC bonds
at the heptalene skeleton, all C(3)-substituted 3-oxido intermediates gave rise to lower
calculated DHf 8 values.
The crucial experiment with 15c afforded, amazingly, the benzo[a]heptalene 4c
(Scheme 8 and Table 1), when lithiomethyl phenyl sulfone was used. This result was
unique because, for the first time, we could isolate a benzo[a]-heptalene-1,3-diol from
such a reaction. Compound 4c was also formed by treatment of 16b with a-lithioethyl
phenyl sulfone. The structure of 4c was finally corroborated by X-ray crystal-structure
analysis (Fig. 3; see also Chapt. 2.2). These results support our hypothesis that
benzo[a]heptalene formation from intermediates of type 8 (Scheme 3) is hampered by
the elimination of HOÀ, which finally leads to the observed cyclopenta[d]heptalen-
1(1H)-ones 11.
With these results in hand and in view of the outcome of the reaction between 2'a
and lithiomethyl phenyl sulfone [3], we began to search for −one-pot× conditions,

Helvetica Chimica Acta Vol. 86 (2003)
4027
Fig. 3. Stereoscopic view of the X-ray crystal structure of 4c
leading to the formation of the new benzo[a]heptalenediols 3c and 4c (Scheme 10).
Indeed, when we treated 2'a at À 788 first with 1.1 equiv. of a-lithioethyl phenyl sulfone
and then, after warming to À 408, with 3 equiv. of lithiomethyl phenyl sulfone (C1
source for the formation of 3c), followed by the addition of excess BuLi, then we could
isolate 3c by chromatography in a total yield of 72%. In a second, slower-moving
fraction, we also found 17% of benzo[a]heptalenediol 3b. This result indicated that not
all of 2'a had reacted in the first step, but had also reacted in the second step with
lithiomethyl sulfone. Nevertheless, the yield of 3c in this reaction was much higher than
in the case where we had started with 16c5). The one-pot formation of 4c from 2'a was
not as good as that of 3c. Also, when using an excess of lithiomethyl phenyl sulfone in
the first step, we isolated all three possible benzo[a]heptalenediols, 3b, 3c, and 4c, in
comparable amounts. In view of the good yield of 3c in the former procedure, it seems
that a-lithioethyl phenyl sulfone relative to lithiomethyl phenyl sulfone is the much
better nucleophile under the reaction conditions applied. Nevertheless, our experi-
ments showed that benzo[a]heptalene-1,3-diols of type 4c with the biologically −correct×
substitution pattern at ring A are principally accessible from heptalene-4,5-dicarbox-
ylates.
Benzo[a]heptalenediol 4c was almost quantitatively transformed into the corre-
sponding dimethoxy compound 20 (Scheme 11). Reductive desulfonylation of 20 with
LiAlH4/TiCl4 in THF gave 21 in excellent yield. The latter was metallated at C(2) by
BuLi, and treatment with CuBr/O2, following a procedure described by Razdan and co-
workers [10], gave the corresponding 2-hydroxy compound 22 in 59% yield. The
structure of 22 was established by 1H-NMR (absence of s for HÀC(2) at 6.62 ppm and
appearance of a new s at 5.69 ppm (HOÀC(2)), and by an X-ray crystal-structure
5
)
It should be noted that the yields of the benzo[a]heptalenediols strongly depend on the quality of BuLi
added in the final step to complete the reaction. In the case of 3c, we isolated in a second run under
identical condition, but with another batch of BuLi, only 53% of the product. Finally, we found that
catalytic amounts of FeCl3 or CuBr2, added together with BuLi, or the application of the commercially
available MeLi ¥ LiBr complex, improved substantially the yields of the sulfonylated benzo[a]heptalene-
diols 3 and/or 4.

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 10
a) 4 Equiv. LiCH2SO2Ph/THF, À 788 to À 58, 3 h. b) 4 Equiv. BuLi, À 5to ‡ 208, 3 15 h. c) 1.1 Equiv.
LiCH(Me)SO2Ph/THF; À 78 to À 408, 2 h. d) 3 Equiv. C6H5SO2CH2Li/THF, À 40 to À 58, 3 h. e) 1.1 Equiv.
LiCH2SO2Ph/THF; À 78 to À 408, 3 h. f) 3 Equiv. LiCH(Me)SO2Ph/THF; À 40 to À 58, 3 h.
a) Improved yield, following the procedure as described in [3]. b) Second values for 3 equiv. LiCH2SO2Ph/THF;
À 78 to À 408, 3 h.
determination (Fig. 4). Finally, methylation of 22 with MeI/K2CO3 in acetone gave, in
almost quantitative yield, the 1,2,3-trimethoxy-4-methylbenzo[a]heptalene 23.
2.2. Spectroscopic and Structural Comparisons. 2.2.1. Double-Bond Shift and Ring
Inversion in 19c. Compound 19c was isolated in crystalline form from the mixture of
products of the reaction of 2'a with a-lithioethyl phenyl sulfone (cf. Scheme 9) as a
single stereoisomer with the relative (P*,2R*,3R*,1'S*)-configuration (designated
19c(A)), as revealed by X-ray analysis (cf. Fig. 2). In CDCl3 solution, however, there
are three other equilibrium forms (Scheme 12). When crystals of 19c(A) were
dissolved in cold CDCl3, and when the 1H-NMR spectrum (600 MHz) of this solution
was recorded at À 258, then the signals of 19c(A) (75%) were accompanied by a
second set of signals (25%) assigned to the corresponding isomer 19'c(A). Character-
istic for 19'c(A) with the exchanged positions of the CˆC bonds are the much larger
vicinal coupling constants 3J(HÀC(4,5)) and 3J(HÀC(9,10)) of 11.8 12.0 Hz as

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4029
Scheme 11
a) MeI/K2CO3/acetone, 208, 8 h; 96%. b) LiAlH4/TiCl4/THF, À 78 to ‡ 208, 8 h; 87%. c) BuLi/CuBr/O2/THF,
À 58, 10 h; 59%.
Fig. 4. Stereoscopic view of the X-ray crystal structure of 22
compared to those of 19c(A), which are in the range of 6.5 7.0 Hz ( cf. Table 2). After
1
storage of the solution of 19c(A) and 19'c(A) for one week at À 208, the H-NMR
spectrum indicated the presence of a third compound, whose signals could unequiv-
ocally be assigned to the ring-inversion product of 19'c(A), namely 19'c(B) with the
relative (M*,2R*,3R*,1'S*)-configuration. The ratio of 19c(A)/(19'c(A) ‡ 19'c(B))
amounted to 3 :2. The identification of 19'c(B) was mainly based on clear chemical-
shift differences with respect to 19'c(A), but similar coupling constants (cf. Table 2 and
the Exper. Part). Finally, the solution of the three isomers was heated to 408 for 2 h and
then chilled again to À 258 for NMR measurements. This procedure resulted in
1
additional weak H-NMR signals (4.5%) assigned to double-bond isomer 19c(B) of
19'c(B).

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Scheme 12. Equilibria Compositions of Isomeric Cyclopentaheptalenones of Type 19c and 19'c (in CDCl3 at
408). DBS ˆ Double-bond shift.
1
Table 2. Characteristic H-NMR Data of the Epimeric and Double-Bond-Shifted Forms of 19c (for structures,
see Scheme 12). The spectra were recorded at 600 or 500 MHz in ca. 5% CDCl3 soln. The main coupling
constants are given in brackets.
Isomer
19c(A)
19'c(A)
19c(B)
19'c(B)
HÀC(4)
6.83 [6.6]
6.22 [6.5]
6.23 [6.5]
6.38 [7.0]
4.57
1.24
2.06
1.14
5.66
7.20 [11.7]
6.90 [11.9]
6.31 [11.8]
6.28 [12.0]
5.00
1.54
1.33
1.15
6.50
6.58 [6.7]
6.85 [11.7]
6.84 [11.7]
6.24 [11.9]
6.39 [11.9]
5.09
1.44
1.66
1.37
6.24
a
HÀC(5)
)
)
)
a
HÀC(9)
a
HÀC(10)
HÀC(1')
MeÀC(2)
MeÀC(11)
MeÀC(1')
HOÀC(3)
4.10
a
)
)
)
a
a
5.64
a) Signal covered by the signals of the major isomers in the equilibrium mixture.
It is of interest to note that the chemical shifts of the OH signals of the four isomers,
which appear in the 1H-NMR spectra as sharp s in the range of 5.6 6.5 ppm (Table 2),
are mainly determined by the CÀC/CˆC bond pattern (see pairs of double-bond
isomers) and only slightly by the configuration at the central axis of chirality (see pairs
of axial epimers). The X-ray crystal structure of 19c(A) revealed the presence of a
short (185pm) intramolecular H-bridge between HO ÀC(3) and the (proS)-O-atom of
the PhSO2 group at C(1'). Both the chemical shifts and shapes of the 1H-NMR signals
for HOÀC(3) indicated the presence of such H-bonds also in CDCl3 solution. We tried
to substantiate this view by AM1 calculations. Indeed, we found in all cases the lowest
DHf 8 values (19c(A): À 59.8; 19'c(A): À 56.0; 19c(B): À 58.3; 19'c(B): À 56.7 kcal ¥

Helvetica Chimica Acta Vol. 86 (2003)
4031
molÀ1) for structures with an intramolecular H-bond between HOÀC(3) and the
(proS)-O-atom of PhSO2ÀC(1'), the length of which varied between 212 and 222 ppm.
A comparison of the calculated DHf 8 values showed that they reflect the relative ratios
of the epimers quite well, assuming marginal differences in DDSf 8 (19c(A)/19c(B) 10 :1
(found) vs. 11:1 (calc.); 19'c(B)/19'c(A) 2.3 :1 (found) vs. 3 :1 (calc.)), but not that of
the double-bond isomers. This deviation seems not to be caused by large differences in
DSf 8 since, in other cases, the AM1-calculated DDHf 8 values were in good accord with
the experimentally determined equilibrium ratios of double-bond-shifted isomers.
Probably, the strength of the intramolecular H-bonds was not predicted well-enough by
the AM1 algorithm. Indeed, the 1H-NMR chemical-shift differences of the OH signals
are large between the double-bond isomers, but small between the axial epimers. The
shift to lower field in going from 19c(A) to 19'c(A) (or from 19c(B) to 19'c(B)) speaks
for much stronger H-bonds in the latter.
2.2.2. PhSO2-Substituted Benzo[a]heptalenediols. The successful synthesis of the
PhSO2-substituted benzo[a]heptalen-1,3-diol 4c allowed for the first time its spectral
and structural comparison with analogous benzo[a]heptalene-2,4-diols, e.g., 3b or 3c (cf.
Table 3). We included in our examinations the structural data of the AM1-calculated
structures. They showed that, in general, the X-ray data of 3b, 3c, and 4c were quite well
reproduced by the AM1 calculations. The cisoid torsion angles at the central heptalene
bond (C(7a)ÀC(12a)) are slightly higher for the calculated structures, mainly as a
consequence of the generally shorter length of this bond for the calculated structures.
However, the main difference is found in the bond length of C(3/2)ÀS, which is
distinctly shorter (by ca. 4.5%) in the calculated structures6). Nevertheless, the overall
structure of the heptalenediols was well-reproduced.
Most striking was the comparison of the 1H-NMR data of 3b, 3c, and 4c. The trend
to higher-field absorption for MeÀC(12) in going from 3b to 4c could be explained with
the additional screening effect of the substituents at C(1), which are close to MeÀC(12)
(cf. q(1,12b,12a,12) in Table 3). We found the largest shift difference for the H-atom of
the OH groups, whose signals appear as sharp s due to the presence of intramolecular
H-bonds in all heptalenes. However, whereas HOÀC(2) and HOÀC(4) of both 3b and
3c appeared at ca. 9 ppm, 4c and the isomeric 3c displayed the corresponding signals for
HOÀC(1) at more than 2-ppm higher field, and those of HOÀC(3) at ca. 1-ppm lower
field (Dd 3.5ppm). The clearest answer for these different behaviors comes from the
X-ray crystal-structure analyses of 3b and 3c, which are distinguished only by
MeÀC(1). Both compounds exhibit a strong intramolecular H-bond (187 and 167 pm,
resp.) between one of the OH groups and the neighboring O-atom of the adjacent
sulfonyl group. The other OH group forms an intermolecular H-bond with the other O-
atom of the sulfonyl group of a neighboring molecule (201 and 187 pm, resp.). It is of
interest to note that MeÀC(1) has a decisive influence on this H-bonding pattern in the
crystals, in such a way that the molecules of 3b form an intermolecular H-bond with
HOÀC(4) (Fig. 5). For the molecules of 3c, however, it is HOÀC(2) that is engaged in
intermolecular H-bonding (Fig. 6). In solution, the intermolecular H-bonding is
6
)
The same effect was observed for SÀCip at the Ph ring.

4032
Helvetica Chimica Acta Vol. 86 (2003)
Table 3. Characteristic 1H-NMR and X-Ray Data of Phenylsulfonyl-Substituted 9-Isopropyl-7,12-dimethylbenzo-
[a]heptalenediols
No.
3ba)
3c
4c
1H-NMR (d [ppm])
HOÀC(2/1))
HOÀC(4/3))
MeÀC(12)
X-Rayb)
8.62
9.22
1.67
8.89
9.08
1.49
6.56
10.02
1.38
q [8]
C(7,7a,12a,12b)
C(8,7a,12a,12)
C(1,12b,12a,12)
C(8,9,C(iPr),H)
d [pm]
60.6(3) [61.4]
60.7(3) [60.1]
À 63.4(3) [ À 60.4]
0.3 [ À 10.1]
60.8(2) [62.7]
61.1(3) [62.3]
58.6(2) [61.9]
58.5(2) [61.4]
À 68.7(3) [ À 67.5]
À 62.9(2) [ À 64.1]
143.0 [130.8]
À 15.2 [ À 10.1]
C(7a,12a)
C(3/2),S
C(2/1),O
C(4/3),O
148.7(3) [146.8]
176.4(2) [168.5]
135.7(3) [136.4]
135.8(3) [137.6]
147.5(3) [146.7]
176.1(2) [168.7]
135.6(2) [137.6]
135.4(2) [136.4]
149.8(2) [146.6]
176.6(2) [168.6]
136.3(2) [137.2]
136.3(3) [136.6]
a) Data taken from [1]. b) AM1-Calculated data in brackets.
Fig. 5. Crystal packing of 3b with intra- and intermolecular H-bonds (H-atoms not involved in H-bonds are
omitted for the sake of clarity)

Helvetica Chimica Acta Vol. 86 (2003)
4033
Fig. 6. Crystal packing of 3c with intra- and intermolecular H-bonds (all H-atoms not involved in H-bonds are
omitted for the sake of clarity)
destroyed, so that both OH groups of 3b and 3c must form intramolecular H-bonds
with the two different O-atoms of the neighboring phenylsulfonyl group.
To gain more insight into the intramolecular H-bonding situation of benzo[a]hep-
talenediols, we performed AM1 calculations of the isopropyl-free forms 3b', 3c', and 4c'
(cf. Tables 4and 5) for the sake of a reduction of conformers. We checked by additional
AM1 calculations (cf. Table 3) that the omission of the i-Pr group had no influence on
the H-bonding of the simplified model structures 3b', 3c', and 4c', for which only the
orientations of the PhSO2 group with respect to the benzoheptalene skeleton had to be
regarded. These orientations may be designated as syn when the Ph group of PhSO2
and MeÀC(12) are on the same side of the benzoheptalene, and anti when both are on
opposite sides (cf. Fig. 7). In the crystal structures of 3b (cf. [1] and Fig. 5), 3c (Fig. 1),
and 4c (Fig. 3), the Ph ring of the PhSO2 group adopts a syn orientation with respect to
MeÀC(12). The AM1 calculations showed that the syn- and anti-conformers possess
almost comparable DHf 8 values and, as a consequence, almost equivalent lengths of the
H-bridges between the OH groups and the two O-atoms of the adjacent sulfonyl group
(cf. Tables 4 and 5). As mentioned, the calculated H-bridges were by 4 12% longer
than the ones found in the corresponding X-ray crystal structures. The conformers A
and B of 3b or 3c, and B and C of 4c, respectively, represent local minima with respect
to the torsion angle of the Ph group of PhSO2. They showed, as expected, only marginal
differences in their DHf 8 values. However, the small twist of the Ph group is
accompanied by an exchange of the length of the two involved H-bridges. An
equilibrium between the syn- and anti-conformers, which also show only small
differences in their DHf 8 values, requires the cleavage of both H-bridges of the A and B
or B and C (of 4c) conformers. It also means that the syn/anti transformation leads to
an exchange of the relative position of the (proR)- and (proS)-O-atom of the PhSO2

4034
Helvetica Chimica Acta Vol. 86 (2003)
Fig. 7. Stereoscopic view of the AM1-calculated syn- (top) and anti-conformers (bottom) A of 3b' (cf. Tables 4
and 5 for details)
group. Nevertheless, both H-bridged conformers (syn and anti) should be present in
solution and give rise to 1H-NMR OH resonances at 8.6 9.2 ppm for 3b and 3c. Strong
intramolecular H-bonding in solution was also evident from the IR spectrum of 3c in
CHCl3. The (OÀH) stretching region of a 1% (or more-diluted) solution showed only a
single, intense absorption band at 3371 cmÀ1 (Fig. 8), which is typical of phenols with
intramolecular H-bonds [11].
Of highest interest for us was the observation that the AM1 calculations of the syn-
and anti-conformers of 4c disclosed two further, energetically most-favorable forms,
where HOÀC(1) is engaged in an electrostatic interaction with the p-system of the
C(12)ˆC(12a) bond of the adjacent heptalene backbone. Indeed, C(12)ˆC(12a) is
ideally placed to form a type of p-pocket for the acidic H-atom of the OH group at
C(1), which allows more-or-less equal interatomic distances of the involved H-atom
with both C-atoms, regardless of the syn- or anti-orientation of the Ph residue of the
PhSO2 group7). The X-ray crystal structure of 4c (Fig. 3) unequivocally showed the
7
)
Principally, the AM1 calculations demonstrate that the OH group at C(4) of 3c' can also interact with the
adjacent C(5)ˆC(6) bond. However, on grounds of its nonsymmetry, this H-bridge does not contribute to
an energetically more-favorable situation as compared with that of a H-bond to the neighboring O-atom
of the adjacent SO2 group (cf. Tables 4 and 5).

Helvetica Chimica Acta Vol. 86 (2003)
4035
Table 4. Structural Data of AM1-Calculated H-Bonded syn Conformers of Phenylsulfonyl-Substituted 7,12-
Dimethylbenzo[a]heptalenediolsa)
Conformers
A
B
A
B
C
A
B
C
DHf8 [kcal ¥ molÀ1
]
À 26.65 À 26.62 À 30.79 À 30.68 À 29.08
À 30.64
À 29.71 À 29.69
H-bond length d [pm]
C(2/1)OH ¥¥¥ O(1)SOPh
C(4/3)OH ¥¥¥ O(2)SOPh
C(1)OH ¥¥¥ C(12)ˆC(12a)
C(4)OH ¥¥¥ C(5)ˆC(6)
Torsion angle q [8]
196.6
201.1
200.5202.1
195.7
196.7
193.2
197.0
201.8
203.1
195.5
200.9
192.4
247/238
195.5
245/349
89.9
C(3/2)ÀSÀC(1')ÀC(2')
102.3
78.2
78.9
101.7
94.5103.3
78.7
a) The i-Pr group at C(9) was omitted in the calculations to reduce the number of conformers. The designator
syn means that the Ph group of PhSO2 and MeÀC(12) are on the same side of the molecule (see Fig. 7).
Table 5. Structural Data of AM1-Calculated H-Bonded anti Conformers of Phenylsulfonyl-Substituted 7,12-
Dimethylbenzo[a]heptalenediolsa)
Conformers
A
B
A
B
C
A
B
C
DHf8 [kcal molÀ1
]
À 26.69 À 26.69 À 30.61 À 30.36 À 28.83
À 30.85
À 29.50 À 29.49
H-bond length d [pm]
C(2/1)OH ¥¥¥ O(1)SOPh
C(4/3)OH ¥¥¥ O(2)SOPh
C(1)OH ¥¥¥ C(12)ˆC(12a)
C(4)OH ¥¥¥ C(5)ˆC(6)
Torsion angle q [8]
196.2
199.5
200.0
195.7
202.6
195.7
195.7
200.4
192.7
205.1
196.0
195.7
205.1
192.1
243/238
238/349
93.3
C(3/2)ÀSÀC(1')ÀC(2')
77.3
103.0
102.0
77.0
88.7
102.579.6
a) The i-Pr group at C(9) was omitted to reduce the number of conformers. The designator anti means that the
Ph group of PhSO2 and MeÀC(12) are on opposite sides of the molecule (see Fig. 9).
presence of an interaction between HOÀC(1) and C(12)ˆC(12a) (interatomic
distances of 245(C(12) and 231 pm (C(12a), resp.; C(3) ÀOH ¥¥¥ OS(O)Ph: 184 pm
(AM1: 192 pm)) values, close to those calculated for the syn conformer of 4c' (cf.

4036
Helvetica Chimica Acta Vol. 86 (2003)
Fig. 8. IR (OÀH)-Stretching region of the isomeric
compounds 3c and 4c (in CHCl3 solution)
Table 4), as well as for that of 4c (Table 3)8). The AM1 calculations indicated that the
electrostatic interaction between OH and C(12)ˆC(12a) is by only ca. 1 kcal molÀ1
energetically more stable than the conformers B and C with H-bonds to both O-atoms
of the sulfonyl group. Therefore, the situation in the rigid crystal lattice may not be
comparable to the dynamic behavior of the compound in solution, despite the
1
observation that the H-NMR chemical shift of 6.56 ppm for HOÀC(1) would be in
agreement with a −p-chelated× H-atom. The answer gave us the IR-spectrum of 4c in
CHCl3 solution (higher degrees of dilution did not significantly change the spectrum).
We observed three absorption bands in the (OÀH)-stretching region (Fig. 8), whereby
the wave number of the band at the middle corresponded very well with that for 3c.
Therefore, we assigned this band to (OÀH)-stretching vibrations in conformers B and
C, whereas the bands at 3468 and 3265cm À1 were attributed to the (HÀO)-stretching
vibrations of the p- and sulfonyl-bound OH groups, respectively, of conformers A of 4c.
The integrated band intensities speak for a 3 :1 ratio of A/(B ‡ C) of 4c, in good
agreement with the calculated DHf 8 values for the conformers of 4c'.
We are extremely grateful to Dr. A. Linden, who skillfully performed all the X-ray crystal-structure
analyses, and who also wrote the X-ray section of the Exper. Part. We thank our NMR laboratory for specific
NMR measurements, our MS laboratory for recording mass spectra, and our microanalytical laboratory for
elemental analyses. Financial support by the Swiss National Science Foundation is gratefully acknowledged.
8
)
OH ¥¥¥ p Interactions in crystal and OH ¥¥¥ s interactions in strained molecules in solution are well
established [12 14].

Helvetica Chimica Acta Vol. 86 (2003)
4037
Experimental Part
General. See [1 3].
1. Formation of Methyl [(R-Sulfonyl)acetyl]heptalenecarboxylates. 1.1. Methyl 9-Isopropyl-1,6-dimethyl-5-
[(phenylsulfonyl)acetyl]heptalene-4-carboxylate (16b). A 2.5m soln. of BuLi (3.3 ml, 8.23 mmol) was added
drop by drop at À 58 to a soln. of MeSO2Ph (1.1 g, 7.05mmol) in anh. THF under Ar. After stirring for 30 min at
08, a white precipitate had been formed. The mixture was cooled to À 788, and a soln. of 2'a (0.80 g, 235mmol)
in THF was added slowly within 5min. The brown mixture was stirred at À 788 for 2 h and poured onto ice/aq.
HCl soln. (5%, 100 ml). After extraction with AcOEt (3 Â 50 ml), the org. phase was washed with H2O (5 0 ml)
and brine (100 ml), and dried (MgSO4). After removal of the solvent by distillation, the crude product was
purified by CC (SiO2 (100 g); hexane/AcOEt 3 :2). Recrystallization from Et2O gave pure 16b (0.66 g, 60.4%).
Orange crystals. M.p. 139.7 140.18. Rf (hexane/AcOEt 3 :2) 0.58. IR (KBr): 2964m, 1701s, 1638w, 1573w,
1436m, 1324s, 1281s, 1157m, 1085m, 85 4m, 811m, 765m, 690m, 563m. 1H-NMR (300 MHz, CDCl3): 8.09
4
(dd, 3J ˆ 7.0, J ˆ 1.1, Ho of PhSO2); 7.62 (t, 3J ˆ 7.4. Hp of PhSO2); 7.54 (t, 3J ˆ 7.0, Hm of PhSO2); 7.45( dd, 3J ˆ
6.4, 4J ˆ 0.9, HÀC(3)); 6.28 (d, 3J ˆ 6.6, HÀC(8)); 6.23 (d, 3J ˆ 6.4, HÀC(7)); 6.15( dd, 3J ˆ 6.5, 4J ˆ 1.4,
HÀC(2)); 5.84 (s, HÀC(10)); 4.67/4.64 (AB, 2JAB ˆ 18.0/17.9, CH2C(O)ÀC(5)); 3.51 (s, MeOCO); 2.49
(sept., 3J ˆ 6.9, Me2CH); 2.05( d, 4J ˆ 1.0, MeÀC(1)); 1.82 (s, MeÀC(6)); 1.09/1.06 (2d, 3J ˆ 6.9/6.9, Me2CH).
13C-NMR (75.5 MHz, CDCl3): 194.13(OˆCÀC(5)); 166.88 (OˆCÀC(4)); 150.27 (C(8)); 144.40 (C(1)); 141.62
(C(3)); 139.95(C of PhSO2); 139.40 (C(5a)); 133.57 (Cp of PhSO2); 132.08 (C(4)); 131.98 (C(10a)); 130.83
ip
(C(5)), 129.45 (C(7)); 129.07 (Co of PhSO2); 128.71 (Cm of PhSO2); 127.93 (C(6)); 125.88 (C(10)); 125.70 (C(2));
124.80 (C(8)), 65.17 (CH2C(O)ÀC(5)); 52.03 ( MeOCO); 35.73 (Me2CH); 25.18 (MeÀC(1)); 23.72
.
‡
(MeÀC(6)); 23.02/22.62 (Me2CH). EI-MS: 464 (6, M ), 432 (5), 323 (100), 281 (9), 249 (17), 221 (14), 207
(13), 179 (18), 165(13), 77 (19). Anal. calc. for C 27H28O5S (464.58): C 69.80, H 6.07, S 6.90; found: C 69.73, H
6.15, S 6.85. X-Ray crystal structure: see Table 6.
1.2. Methyl 9-Isopropyl-1,6-dimethyl-5-[(morpholinosulfonyl)acetyl]heptalene-4-carboxylate (16a). BuLi
Soln. (3.3 ml, 8.23 mmol) was added at À 58 to a soln. of methyl morpholino sulfone (1.165g, 7.05mmol) in anh.
THF (40 ml) under Ar. After stirring during 30 min at 08, a white precipitate had been formed. The mixture was
cooled to À 788, and a soln. of the pseudo-ester 2'a (0.8 g, 2.35mmol) in THF (5ml) was added drop by drop
within 5min. The yellow-orange mixture was stirred for 2 h at À 788 and poured onto ice and 10% aq. HCl soln.
(100 ml). After extraction with Et2O (3 Â 50 ml), the org. layer was washed with H2O (50 ml) and brine
(100 ml), and dried (Na2SO4). Evaporation in vacuo left a solid residue, which was further purified by FC (SiO2
(100 g); hexane/AcOEt 1:1). Recrystallization of the resulting solid from Et2O gave 16a (0.595 g, 53.5%).
Yellow crystals. M.p. 180.2 180.68. Rf (hexane/AcOEt 1:1) 0.48. IR (KBr): 2960m, 1694s, 1572m, 1449m, 1347s,
1281s, 1157s, 1113s, 1075s, 960m, 807w, 789w, 693w, 5 5 w9, 492m. 1H-NMR (300 MHz, CDCl3): 7.50 (d, 3J ˆ 6.6,
HÀC(3)); 6.27 (s, HÀC(7), HÀC(8)); 6.19 (dd, 3J ˆ 6.2, 4J ˆ 1.3, HÀC(2)); 5.87 (s, HÀC(10)); 4.53/4.48
(AB, 2JAB ˆ 18.1/18.0, CH2C(O)ÀC(5)); 3.73 (s, MeOCO); 3.72 (m, O(CH2CH2)2N); 3.43 (m, O(CH2CH2)2N);
2.49 (sept., 3J ˆ 6.9, Me2CH); 2.08, 2.05(2 s, MeÀC(1), MeÀC(6)); 1.10/1.07 (2d, 3J ˆ 6.9/6.8, Me2CH).
13C-NMR (75.5 MHz ,CDCl3): 195.44 (OˆCÀC(5)); 167.31 (OˆCÀC(4)); 150.19 (s); 144.60 (s); 141.62 (d);
139.48/132.29/132.05/130.99 (4s); 129.45( d); 128.12 (s); 125.94/ 125.62/124.81 (3d); 66.81 (t, O(CH2CH2)2N);
59.89 (t, CH2C(O)ÀC(5)); 52.33 (q, MeOCO); 45.88 (t, O(CH2CH2)2N); 35.69 (d, Me2CH); 25.25
‡
(q, MeÀC(1)); 23.98 (q, MeÀC(6)); 23.00/22.60 (2q, Me2CH). CI-MS: 474 (85, [M ‡ 1] ), 459 (10, [(M ‡
.
‡
‡
1) À Me] ), 442 (8, [(M ‡ 1) À MeOH] ), 325(19), 310 (37), 293 (100). Anal. calc. for C 25H31NO6S (473.59); C
63.40, H 6.60, N 2.96, S 6.77; found: C 63.11, H 6.60, N 2.85, S 6.16. X-Ray crystal structure: see Table 6.
1.3. Methyl 9-Isopropyl-1,6-dimethyl-4-[(phenylsulfonyl)acetyl]heptalene-5-carboxylate (15b) and Dimeth-
yl 3,4-Dihydro-9-isopropyl-1,6-dimethyl-3-[(phenylsulfonyl)methyl]heptalene-4,5-dicarboxylate (17b). BuLi
soln. (3.3 ml, 8.25mmol) was added at 0 8 to a soln. of MeSO2Ph (0.705g, 4.5mmol) in THF (25ml). After
30 min, the mixture was cooled to À 408. Then, a soln. of 1a [1] (1.50 g, 4.5 mmol) in THF (8 ml) was added
within 5min. After additional stirring at À 408 for 4 h, the mixture was poured onto ice and 10% aq. HCl soln.
(100 ml). After extraction with AcOEt (3 Â 100 ml), the org. layer was washed with H2O (100 ml), brine
(100 ml), and then dried (Na2SO4). Evaporation in vacuo left a solid residue, which, on TLC (hexane/AcOEt
2 :1), showed two new main spots (Rf 0.33 (yellow) and 0.25(colorless)) and another (yellow) spot of residual
reactant 1a. FC (SiO2 (180 g); hexane/AcOEt 3 :1) afforded 1a (0.59 g, 39%), 15b (0.79 g, 64% rel. to reacted
1a), and 17b (0.24 g, 18%).
Data of 15b. Yellow crystals. M.p. 186.5 187.1 8 (Et2O). Rf (hexane/AcOEt 2 :1) 0.33. IR (KBr): 2960m,
1710s, 1648s, 1564m, 1447m, 1432m, 1322s, 1289s, 1233m, 1151s, 1084m, 1061w, 989w, 85 5m, 809m, 75 5m, 687m,
564m, 5 30m. 1H-NMR (300 MHz, CDCl3): 7.86 (dd, 3J ˆ 7.1, 4J ˆ 1.1, Ho of PhSO2); 7.60 (tt, 3J ˆ 7.5, 4J ˆ 1.3, Hp

4038
Helvetica Chimica Acta Vol. 86 (2003)
Table 6. Crystallographic Data for Compounds 3c, 4c, 15c, 16a, 16b, 17c, 19c, 21, and 22
3c
4c
15c
Crystallized from
CH2Cl2
C28H28O4S
460.59
yellow, plate
0.15 Â 0.25 Â 0.350.05
298(1)
AcOEt/hexane
C28H28O4S
460.59
yellow, plate
 0.25  0.30
160(1)
AcOEt/hexane
C28H30O5S
478.60
red, prism
0.15 Â 0.20 Â 0.25
160(1)
Empirical formula
Formula weight [g molÀ1
Crystal color, habit
Crystal dimensions [mm]
Temperature [K]
]
Crystal system
Space group
monoclinic
P21/n
triclinic
P1
triclinic
P1
≈
≈
Z
4
2
2
Reflections for cell determination
6555
27429
4257
2q Range for cell determination [8]
5
73
5
55
4
50
Unit-cell parameters a [ä]
12.3491(2)
13.1741(2)
14.7740(3)
90
95.6415(7)
90
2391.91(7)
976
1.279
9.2798(1)
9.6655(1)
15.5237(3)
93.9905(5)
101.5660(5)
117.7053(9)
1186.25(3)
488
1.289
0.169
f and w
55
10.3133(6)
10.4297(7)
12.4598(9)
71.090(3)
88.276(3)
79.218(3)
1244.8(1)
508
1.277
0.166
f and w
50
b [ä]
c [ä]
a [8]
b [8]
g [8]
V [ä3]
F(000)
Dx [g cmÀ3
]
m(MoKa) [mmÀ1
Scan type
]
0.167
w
2q (max) [8]
55
Total reflections measured
Symmetry-independent reflections
Rint
31132
5456
0.041
31398
5425
0.072
22865
4374
0.063
Reflections with I > 2s (I)
Reflections used in refinement
Parameters refined
4363
4363
299
21259
31383
312
3603
3603
307
R [on F; I > 2s(I) reflections]
wR [on F; I > 2s(I) reflections]
wR [on F2; all indept. reflections]
Weighting parameter [p]a)
Weighting parameters [a; b]b)
Goodness of fit
0.0512
0.0631
0.0607
0.0691
0.0787
0.2134
0.011
0.005
4.130
0.1355; 0
1.041
2.689
Secondary extinction coefficient
Final Dmax/s
1.3(5) Â 10À6
0.0004
0.001
0.56; À 0.39
0.0003
0.47; À 0.61
D1 (max; min) [e äÀ3
]
0.31; À 0.32
of PhSO2); 7.51 (t, 3J ˆ 7.4, Hm of PhSO2); 7.32 (dd, 3J ˆ 6.3, 4J ˆ 0.8, HÀC(3)); 6.27 (d, 3J ˆ 6.5, HÀC(8)); 6.22
4
4
(dd, 3J ˆ 6.3, J ˆ 1.3, HÀC(2)); 6.12 (dd, 3J ˆ 6.5, J ˆ 1.3, HÀC(7)); 5.88 (s, HÀC(10)); 4.51/4.39 (AB, 2JAB
ˆ
14.1, PhSO2CH2C(O)ÀC(4)); 3.58 (s, MeOCO); 2.49 (sept., 3J ˆ 6.8, Me2CH); 2.10 (d, 4J ˆ 1.0, MeÀC(1)); 1.97
(s, MeÀC(6)); 1.10/1.07 (2d, 3J ˆ 6.9/6.8, Me2CH). 13C-NMR (75.5 MHz, CDCl3): 187.87 (OˆCÀC(4)); 167.38
(OˆCÀC(5)); 148.27/147.01/145.63 (3s); 143.01 (d); 140.22/138.72 (2s); 133.99 (d); 131.18 (s); 129.05( d);
128.52 (s); 127.29/126.11/125.79/125.65/125.32 (5d); 122.32 (s); 63.17 (CH2C(O)ÀC(4)); 51.99 (MeOCO); 35.58
.
‡
(Me2CH); 25.63 (MeÀC(1)); 23.04 (MeÀC(6)); 22.43/22.26 (Me2CH). EI-MS: 464 (55, M ), 416 (12), 370
(90), 355 (12), 340 (42), 323 (45), 309 (14), 281 (20), 256 (28), 221 (18), 198 (100), 183 (29), 151 (16). Anal. calc.
for C27H28O5S (464.58): C 69.80, H 6.07, S 6.90; found: C 69.59, H 6.14, S 6.73.
Data of 17b. Colorless crystals. M.p. 153.5 154.88 (Et2O). Rf (hexane/AcOEt 2 :1) 0.25. IR (KBr): 2955m,
1748s, 1701s, 1646w, 1596w, 1519w, 1447m, 1437m, 1397w, 1379w, 1304s, 1274m, 1228m, 1204s, 1141s, 1087m,

Helvetica Chimica Acta Vol. 86 (2003)
4039
Table 6 (cont.)
16a
16b
17c
Crystallised from
AcOEt/hexane
C25H31NO6S
473.58
yellow, prism
0.22 Â 0.25 Â 0.250.15
160(1)
Et2O
C27H28O5S
464.57
Et2O/hexane
C29H34O6S
510.64
colourless, prism
0.10 Â 0.12 Â 0.20
160(1)
Empirical formula
Formula weight [g molÀ1
Crystal color, habit
Crystal dimensions [mm]
Temperature [K]
]
yellow, tablet
 0.17  0.22
160(1)
monoclinic
P21/c
Crystal system
Space group
triclinic
triclinic
≈
≈
P1
P1
Z
2
4
2
Reflections for cell determination
6791
5543
7870
2q Range for cell determination [8]
4
60
2
5 5
4
60
Unit-cell parameters a [ä]
10.3411(1)
11.1604(2)
11.1606(2)
98.3541(6)
101.7919(7)
104.5579(6)
1193.81(3)
504
1.317
0.176
f and w
60
10.2858(1)
30.4871(3)
7.7947(1)
90
103.3773(4)
90
2377.98(5)
984
1.298
10.3707(1)
11.0794(2)
12.9903(2)
90.9012(7)
113.5066(7)
98.9718(6)
1346.98(4)
544
1.259
0.160
f and w
5
b [ä]
c [ä]
a [8]
b [8]
g [8]
V [ä3]
F(000)
Dx [g cmÀ3
]
m(MoKa) [mmÀ1
Scan type
]
0.172
f and w
5
2q (max) [8]
Total reflections measured
Symmetry-independent reflections
Rint
30966
6977
0.038
38443
5441
0.056
57127
7897
0.044
Reflections with I > 2s (I)
Reflections used in refinement
Parameters refined
5480
5480
298
3838
3838
298
6344
6344
325
R [on F; I > 2s(I) reflections]
wR [on F; I > 2s(I) reflections]
wR [on F2; all indept. reflections]
Weighting parameter [p]a)
Weighting parameters [a; b]b)
Goodness of fit
0.0443
0.0460
0.0449
0.0443
0.0476
0.0531
0.0050.01
2.490
0.005
1.990
3.227
Secondary extinction coefficient
Final Dmax/s
0.00050.0004
0.31; À 0.43
0.0006
0.24; À 0.29
D1 (max; min) [e äÀ3
]
0.36; À 0.45
1026m, 922w, 895m, 822m, 794w, 75 5m, 733m, 709w, 692m, 633m, 5 92m, 5 32m, 5 10w. 1H-NMR (300 MHz,
4
CDCl3): 8.00 (dd, 3J ˆ 7.0, J ˆ 1.2, Ho of PhSO2); 7.64 (t, 3J ˆ 7.2, Hp of PhSO2); 7.55 (t, 3J ˆ 7.1, Hm of PhSO2);
4
4
6.38 (s, HÀC(10)); 6.28 (d, 3J ˆ 6.6, HÀC(8)); 6.21 (dd, 3J ˆ 6.0, J ˆ 1.2, HÀC(2)); 6.15( dd, 3J ˆ 6.6, J ˆ 1.3,
HÀC(7)); 4.00/3.04 (AB, 2JAB ˆ 14.1, PhSO2CH2ÀC(3)); 3.88 (d, 3J ˆ 2.5, HÀC(4)); 3.68 (s, MeOCOÀC(5));
3.55 (d, 3J ˆ 6.0, HÀC(3)); 3.46 (s, MeOCOÀC(4)); 2.54 (sept., 3J ˆ 6.8, Me2CH); 1.98 (d, 4J ˆ 1.3, MeÀC(6));
.
1.90 (d, 4J ˆ 1.2, MeÀC(1)); 1.13/1.08 (2d, 3J ˆ 6.8/6.8, Me2CH). EI-MS: 496 (10, M ), 355 (46), 256 (100), 241
‡
(11), 225(11), 209 (15), 77 (12).
1.4. Methyl 9-Isopropyl-1,6-dimethyl-4-[2-methyl-2-(phenylsulfonyl)acetyl]heptalene-5-carboxylate (15c)
and Dimethyl 3,4-Dihydro-9-isopropyl-1,6-dimethyl-3-[1-(phenylsulfonyl)ethyl]heptalene-4,5-dicarboxylate
(17c). BuLi soln. (1.4 ml, 3.5mmol) was added at 0 8 to a soln. of EtSO2Ph (0.51 g, 3.00 mmol) in THF
(20 ml). After 30 min, the white precipitate was cooled to À 788, and a soln. of 1a [1] (1.021 g, 3.00 mmol) in
THF (8 ml) was added drop by drop within 5min. After additional stirring at À 788 for 3 h, the mixture was

4040
Helvetica Chimica Acta Vol. 86 (2003)
Table 6 (cont.)
19c
21
22
Crystallized from
Et2O
C35H36O6S2 ¥ C4H10O
690.91
orange, plate
0.10 Â 0.25 Â 0.27
160(1)
Et2O/hexane
C24H28O2
348.48
yellow, prism
0.10 Â 0.20 Â 0.250.15
160(1)
Et2O/hexane
C24H28O3
364.48
Empirical formula
Formula weight [g molÀ1
Crystal color, habit
Crystal dimensions [mm]
Temperature [K]
]
yellow, prism
 0.20  0.25
160(1)
Crystal system
Space group
Z
triclinic
P1
2
triclinic
P1
2
orthorhombic
Pbca
8
≈
≈
Reflections for cell determination
10313
5602
4071
2q Range for cell determination [8]
4
60
4
60
4 5 0
Unit-cell parameters a [ä]
10.0109(2)
13.9148(2)
14.5077(3)
63.8252(7)
86.8650(7)
81.6153(9)
1794.19(6)
736
1.279
0.197
f and w
60
9.8391(3)
10.3155(4)
11.8368(6)
107.690(1)
103.079(1)
110.896(2)
990.81(8)
376
10.8411(3)
16.9914(5)
22.5004(8)
90
90
90
4144.7(2)
1568
1.168
0.0754
f and w
5
b [ä]
c [ä]
a [8]
b [8]
g [8]
V [ä3]
F(000)
Dx [g cmÀ3
]
1.168
m (MoKa) [mmÀ1
Scan type
]
0.0723
f and w
60
2q (max) [8]
0
Total reflections measured
Symmetry-independent reflections
Rint
53885
10463
0.069
25490
5767
0.119
31633
3646
0.106
Reflections with I > 2s (I)
Reflections used in refinement
Parameters refined
6538
10455
482
3628
5764
243
2326
3640
255
R [on F; I > 2s(I) reflections]
wR [on F; I > 2s(I) reflections]
wR [on F2; all indept. reflections]
Weighting parameter [p]a)
Weighting parameters [a; b]b)
Goodness of fit
0.0529
0.0764
0.0593
0.1462
0.2236
0.1565
0.0728; 0.0088
1.078
0.1201; 0
1.0251.089
0.03(1)
0.001
0.47; À 0.350.22;
0.059; 1.2049
Secondary extinction coefficient
Final Dmax/s
0.001
0.43; À 0.40
0.001
D1 (max; min) [e äÀ3
]
À 0.19
b
a) wÀ1 ˆ s2(Fo) ‡ (pFo)2; ) wÀ1 ˆ s2[(Fo2 ‡ (aP)2 ‡ bP], where P ˆ (Fo2 ‡ 2F2c )/3.
poured onto ice and 10% aq. HCl soln. (100 ml). After extraction with AcOEt (100 ml), the org. layer was
washed with H2O (100 ml), brine (100 ml), and then dried (Na2SO4). Evaporation in vacuo left a solid residue
which was purified by FC (SiO2 (170 g); hexane/AcOEt 2 :1) to afford 15c (0.24 g, 17%; mixture of two
diastereoisomers) and 17c (1.10 g, 72%).
Data of 15c. Red crystals. M.p. 156.9 157.88 (AcOEt/hexane). Rf (hexane/AcOEt 2 :1) 0.46. Major isomer:
1H-NMR (300 MHz, CDCl3): 7.72 (dd, 3J ˆ 7.2, 4J ˆ 1.4, Ho of PhSO2); 7.61 (t, 3J ˆ 7.4, Hp of PhSO2); 7.48 (t, 3J ˆ
4
6.7, Hm of PhSO2); 7.42 (d, 3J ˆ 6.2, HÀC(3)); 6.29 (d, 3J ˆ 6.5, HÀC(8)); 6.25( dd, 3J ˆ 6.3, J ˆ 1.3, HÀC(2));
6.12 (d, 3J ˆ 6.4, HÀC(7)); 5.90 (s, HÀC(10)); 4.79 (q, 3J ˆ 7.0, PhSO2CH(Me)C(O)ÀC(4)); 3.56 (s, MeOCO);
2.52 (sept., 3J ˆ 6.9, Me2CH); 2.10 (s, MeÀC(1)); 1.97 (s, MeÀC(6)); 1.42 (d, 3J ˆ 7.0, PhSO2CH(Me)); 1.12/1.08
(2d, 3J ˆ 7.0/6.9, Me2CH). Minor isomer: 1H-NMR (300 MHz, CDCl3): 7.78 (d, 3J ˆ 7.1, Ho of PhSO2); 7.63

Helvetica Chimica Acta Vol. 86 (2003)
4041
(t, 3J ˆ 6.6, Hp of PhSO2); 7.53 (t, 3J ˆ 6.7, Hm of PhSO2); 7.33 (d, 3J ˆ 5.7, HÀC(3)); 6.29 (d, 3J ˆ 6.5, HÀC(8));
6.25( dd, 3J ˆ 6.3, 4J ˆ 1.3, HÀC(2)); 6.13 (d, 3J ˆ 6.4, HÀC(7)); 5.90 (s, HÀC(10)); 4.66 (q, 3J ˆ 7.0,
PhSO2CH(Me)); 3.69 (s, MeOCO); 2.52 (sept., 3J ˆ 6.9, Me2CH); 2.10 (s, MeÀC(1)); 2.01 (s, MeÀC(6)); 1.37
(d, 3J ˆ 6.9, PhSO2CH(Me)); 1.12/1.08 (2d, 3J ˆ 7.0/6.9, Me2CH). 13C-NMR (75.5 MHz, CDCl3; both isomers):
193.15/192.40 (2s, OˆCÀC(4)); 167.39/167.28 (2s, OˆCÀC(5)); 148.32/146.59 (2s); 141.80/141.76 (2d); 140.58/
140.35/135.90 (3s); 133.96 (d); 131.32 (s); 130.02/129.94/128.71 (3d); 128.49 (s); 127.16/127.15/126.03/125.72/
125.55/125.34 (6d); 65.18 (d, MeCH); 52.47/52.35 (2q, MeOCO); 35.65 (d, Me2CH); 25.56 (q, MeÀC(1)); 23.01
(q, MeÀC(6)); 22.37/22.33 (2q, Me2CH); 13.90/13.44 (2q, MeCH). Anal. calc. for C28H30O5S (478.61): C 70.27, H
6.32, S 6.70; found: C 70.04, H 6.45, S 6.59. X-Ray crystal structure: see Table 6.
Data of 17c. Colorless crystals. M.p. 199.6 200.18 (Et2O/hexane). Rf (hexane/AcOEt 2 :1) 0.54.. IR (KBr):
2956m, 1743s, 1701s, 1446m, 1304s, 1242m, 1208s, 1148s, 1100w, 1084w, 1043w, 1005w, 893w, 817w, 769m, 731s,
692m, 619s, 5 71m, 5 34w, 461w. 1H-NMR (300 MHz, CDCl3): 8.00 (dd, 3J ˆ 6.9, 4J ˆ 1.6, Ho of PhSO2); 7.67 7.54
(m, Hm, Hp of PhSO2); 6.38 (s, HÀC(10)); 6.27 (d, 3J ˆ 6.5, HÀC(7)); 6.14 (dd, 3J ˆ 6.5, 4J ˆ 1.2, HÀC(8)); 6.01
(dd, 3J ˆ 5.3, 4J ˆ 1.0, HÀC(2)); 3.97 (q, 3J ˆ 6.9, PhSO2CH(Me)ÀC(3)); 3.96 (d, 3J ˆ 2.3, HÀC(4)); 3.85(br.
s, HÀC(3)); 3.68 (s, MeOCOÀC(5)); 3.47 (s, MeOCOÀC(4)); 2.55 (sept., 3J ˆ 6.9, Me2CH); 1.96, 1.95
(2dd, 4J ˆ 2.6, 1.6, MeÀC(1), MeÀC(6)); 1.31 (d, 3J ˆ 7.0, PhSO2CH(Me)ÀC(3)); 1.13/1.09 (2d, 3J ˆ 6.9/6.9,
Me2CH). 13C-NMR (75.5 MHz, CDCl3): 171.12 (OˆCÀC(4)); 167.48 (OˆCÀC(5)); 150.31/147.11/138.43/
133.99 (4s); 133.31 (d); 131.89 (s); 129.14/128.94/127.84/127.07/123.97/123.37 (6d); 121.3 (s); 59.97
(PhSO2CH(Me)ÀC(3)); 51.84/51.70 (MeOCOÀC(4,5)); 44.77/36.76 (HÀC(4,3)); 35.95 (Me2CH); 26.49
(MeÀC(1)); 23.36 (MeÀC(6)); 22.47/22.46 (Me2CH); 11.24 (PhSO2CH(Me)ÀC(3)). Anal. calc. for C29H34O6S
(510.65): C 68.21, H 6.71, S 6.28; found: C 67.91, H 6.79, S 6.29. X-Ray crystal structure: see Table 6.
1.4.1. Formation of 15c by Methylation of 15b. K2CO3 (0.28 g, 2.0 mmol) was suspended in anh. acetone
(20 ml). The mixture was cooled to 08, and 15b (0.93 g, 2.0 mmol) was added under stirring. Then, MeI (4 ml)
was added drop by drop, and stirring was continued at r.t. overnight. The mixture was diluted with H2O (5 0 ml)
and extracted with AcOEt (2 Â 50 ml). The org. layer was separated and dried (Na2SO4). Evaporation in vacuo
gave pure orange-colored crystalline 15c. Recrystallization from AcOEt/hexane resulted in orange-red crystals
(0.81 g, 85%).
1.5. Methyl 9-Isopropyl-1,6-dimethyl-4-[(morpholinosulfonyl)acetyl]heptalene-5-carboxylate (15a) and
Dimethyl 3,4-Dihydro-9-isopropyl-1,6-dimethyl-3-[(morpholinosulfonyl)methyl]heptalene-4,5-dicarboxylate
(17a). See [1].
1.6. Methyl 9-Isopropyl-1,6-dimethyl-5-[2-methyl-2-(phenylsulfonyl)acetyl]heptalene-4-carboxylate (16c).
Starting with 2'a and a-lithioethyl phenyl sulfone, following the procedure for the synthesis of 15c, 16c was
obtained in a yield of 15%.
1.6.1. Formation of 16c by Methylation of 16b. K2CO3 (0.14 g, 1.0 mmol) was suspended in anh. acetone
(15ml). The mixture was cooled to 0 8, and 16b (0.46 g, 1.0 mmol) was added within 10 min under stirring. Then,
MeI (3 ml) was added drop by drop, and stirring was continued at r.t. over night. The mixture was diluted with
H2O (50 ml) and extracted with AcOEt (2 Â 25ml). The org. layer was separated and dried (Na 2SO4).
Evaporation in vacuo left 16c as a brown oil. Purification by FC (SiO2 (100 g); hexane/AcOEt 3 :1) gave 16c
(0.40 g, 84%) as an oily mixture of diastereoisomers. Rf (hexane/AcOEt 2 :1) 0.48. 1H-NMR (300 MHz, CDCl3;
selected signals of the main diastereoisomer): 7.77 7.45( m, 5H, PhSO 2); 7.46 (d, 3J ˆ 6.8, HÀC(3)); 6.35 6.20
(m, HÀC(2), HÀC(7), HÀC(8)); 5.84 (s, HÀC(10)); 4.68 (q, 3J ˆ 7.0, PhSO2CH(Me)); 3.42 (s, MeOCO); 2.46
(sept., Me2CH); 1.96, 1.92 (2s, MeÀC(1), MeÀC(6)); 1.52 (d, 3J ˆ 7.1, PhSO2CH(Me)C(O)ÀC(5)); 1.09/1.08
(2d, 3J ˆ 6.7/6.7, Me2CH). Anal. calc. for C28H30O5S (478.61): C 70.27, H 6.32, S 6.70; found: C 7.20, H 6.20, S 6.76.
1.7. 2,3-Dihydro-3-hydroxy-8-isopropyl-2,6,11-trimethyl-2-(phenylsulfonyl)-3-[(1-phenylsulfonyl)ethyl]-
1H-cyclopenta[d]heptalen-1-one (19c). At À 58, a 2.5m soln. of BuLi (1.92 ml, 4.80 mmol) was added drop by
drop under Ar to a soln. of EtSO2Ph (0.681 g, 4.00 mmol) in anh. THF (15ml). After stirring for 30 min at 0 8, a
white precipitate had been formed. The mixture was cooled to À 788, and a soln. of 2'a (0.681 g, 2.00 mmol) in
THF (6 ml) was added slowly. The brown mixture was allowed to warm to À 408 within 3 h. After all 2'a had
been consumed, the mixture became clear and changed its color to reddish-brown. The mixture was treated with
ice/H2O, poured onto 1n aq. HCl soln. (100 ml), and extracted with AcOEt (100 ml). The org. phase was washed
with H2O (100 ml) and brine (100 ml). After drying (Na2SO4), the solvent was distilled off in a rotatory
evaporator. The crude product was purified by FC (SiO2 (150 g); hexane/AcOEt 3 :2). Recrystallization from
Et2O gave diastereoisomer A of 19c (0.18 g, 15%) as orange crystals. An X-ray crystal-structure analysis (cf.
Fig. 2 and Table 6) showed 19c(A) in the rel. (P*,2R*,3R*,1'S*)-configuration. In soln. (CDCl3), at À 25to 40 8,
19c(A) underwent double-bond isomerization to 19'c(A) ((P*,2R*,3R*,1'S*)-2,3-Dihydro-3-hydroxy-8-iso-
propyl-2,6,11-trimethyl-2-(phenylsulfonyl)-3-[(1-phenylsulfonyl)ethyl]-1H-cyclopenta[a]heptalen-1-one). In a

4042
Helvetica Chimica Acta Vol. 86 (2003)
slightly slower process, epimerization at the heptalene axis was also observed, leading to 19c(B)
((S*,2R*,3R*,1'S*)-configuration) and finally also to 19'c(B) ((S*,2R*,3R*,1'S*)-2,3-dihydro-3-hydroxy-8-
isopropyl-2,6,11-trimethyl-2-(phenylsulfonyl)-3-[(1-phenylsulfonyl)ethyl]-1H-cyclopenta[a]heptalen-1-one).
When the CDCl3 soln. was warmed to 408 (2 h) and then rapidly cooled to À 258, the equilibrium mixture
consisted of 43.5% 19c(A), 16% 19'c(A), 36% 19'c(B), and 4.5% 19c(B).
Data of 19c(A). M.p. 148.7 151.48. Rf (hexane/AcOEt 2 :1) 0.46. 1H-NMR (600 MHz; CDCl3, À 258):
6.829 (d, 3J ˆ 6.6, HÀC(4)); 6.376 (d, 3J ˆ 7.0, HÀC(10)); 6.229 (d, 3J ˆ 6.5, HÀC(9)); 6.219 (dd, 3J ˆ 6.5, 4J ˆ
1.1, HÀC(5)); 6.018 (s, HÀC(7)); 5.655 (s, HOÀC(3)); 4.568 (q, 3J ˆ 6.8, PhSO2CH(Me)ÀC(3)); 2.528
(sept., 3J ˆ 6.7, Me2CHÀC(8)); 2.085( s, MeÀC(6)); 2.059 (s, MeÀC(11)); 1.241 (s, MeÀC(2)); 1.139 (d, 3J ˆ 6.9,
PhSO2CH(Me)ÀC(3)); 1.114/1.090 (2d, 3J ˆ 6.9/6.8, Me2CHÀC(8)) (the arom. signals were not analyzed due to
heavy superposition). 13C-NMR (150 MHz; CDCl3, À 258): 191.90 (C(1)); 149.77 (C(8)); 142.19 (C(11a));
140.93 (C(3a)); 134.45(C(6)); 134.12 (C of PhSO2ÀC(1')); 133.29 (C(6a)); 130.36 (C(11)); 129.74 (C(10));
p
128.40 (Co of PhSO2ÀC(1')); 128.28 (C(4)); 126.84 (C(11b)); 126.78 (C(7)); 125.92 (C(5)); 84.30 (C(3)); 79.95
(C(2)); 64.59 (C(1')); 36.17 (Me2CHÀC(8)); 25.53 (MeÀC(6)); 23.44/22.09 (Me2CHÀC(8)); 22.54
(MeÀC(11)); 21.12 (MeÀC(2)); 14.26 (MeÀC(1')). The signals of the arom. C-atoms were only partially
assigned.
Data of 19'c(A). 1H-NMR (600 MHz; CDCl3, À 258): 7.201 (d, 3J ˆ 11.7, HÀC(4)); 6.895( d, 3J ˆ 11.9,
HÀC(5)); 6.495 (s, HOÀC(3)); 6.308 (d, 3J ˆ 11.8, HÀC(9)); 6.276 (d, 3J ˆ 12.0, HÀC(10)); 5.484 (s, HÀC(7));
5.000 (q, 3J ˆ 6.9, PhSO2CH(Me)ÀC(3)); 2.469 (sept., 3J ˆ 6.9, Me2CHÀC(8)); 1.708 (s, MeÀC(6)); 1.537
(s, MeÀC(2)); 1.333 (s, MeÀC(11)); 1.153 (d, 3J ˆ 6.9, PhSO2CH(Me)ÀC(3)); 1.090/1.067 (2d, 3J ˆ 6.9/6.8,
Me2CHÀC(8)). The arom. signals were not analyzed due to heavy superposition. 13C-NMR (150 MHz; CDCl3,
À 258): 195.50 (C(1)); 166.83 (C(3a)); 149.90 (C(8)); 137.18 (C(6a)); 135.49 (C(10)); 135.12 (C(11)); 134.25 (Cp
of PhSO2ÀC(1')); 133.61 (C(9)); 131.07 (C(6)); 129.30 (C(5)); 128.43 (Co of PhSO2ÀC(1')); 127.44 (C(11b));
123.28 (C(11a)); 124.52 (C(4)); 121.71 (C(7)); 84.33 (C(3)); 83.89 (C(2)); 62.41 (C(1')); 34.64 (Me2CHÀC(8));
24.58 (MeÀC(2)); 22.50/22.34 (Me2CHÀC(8)); 18.71 (MeÀC(6)); 18.62 (MeÀC(11)); 14.10 (MeÀC(1')). The
signals of the arom. C-atoms were only partially assigned.
Data of 19'c(B). 1H-NMR (600 MHz; CDCl3, À 258): 6.854 (d, 3J ˆ 11.7, HÀC(4)); 6.837 (d, 3J ˆ 11.7,
HÀC(5)); 6.386 (d, 3J ˆ 11.9, HÀC(10)); 6.236 (d, 3J ˆ 11.9, HÀC(9)); 6.235( s, HOÀC(3)); 5.396 (s, HÀC(7));
5.087 (q, 3J ˆ 6.9, PhSO2CH(Me)ÀC(3)); 2.419 (sept., 3J ˆ 6.7, Me2CHÀC(8)); 1.746 (s, MeÀC(6)); 1.663
(s, MeÀC(11)); 1.438 (s, MeÀC(2)); 1.368 (d, 3J ˆ 6.9, PhSO2CH(Me)ÀC(3)); 1.050/1.020 (2d, 3J ˆ 6.9/6.8,
Me2CHÀC(8)) (the arom. region was not analyzed due to heavy superposition). 13C-NMR (150 MHz; CDCl3,
À 258): 193.88 (C(1)); 168.01 (C(3a)); 149.75(C(8)); 144.00 (C(5)); 137.26 (C(6a)); 135.49 (C(11)); 136.14
(C(10)); 134.31 (Cp of PhSO2ÀC(1')); 132.51 (C(9)); 131.21 (C(6)); 128.55 (Co of PhSO2ÀC(1')); 126.78
(C(11b)); 123.42 (C(11a)); 124.86 (C(4)); 122.34 (C(7)); 85.60 (C(3)); 79.89 (C(2)); 62.12 (C(1')); 34.68
(Me2CHÀC(8)); 24.31 (MeÀC(2)); 22.42/22.32 (Me2CHÀC(8)); 18.99 (MeÀC(11)); 17.81 (MeÀC(6)); 16.40
(MeÀC(1')) (the signals of the arom. C-atoms were only partially assigned).
Data of 19c(B). The small amount of this form in the equilibrium mixture allowed only the identification of
some separated 1H-NMR signals. 1H-NMR (500 MHz; CDCl3, À 258): 6.58 (d, 3J ˆ 6.7, HÀC(4)); 5.64
(s, HOÀC(3)); 4.10 (q, 3J ˆ 6.9, PhSO2CH(Me)ÀC(3)); 2.16 (br. s, MeÀC(6)); 0.85/0.86 (2d, superimposed to
t, Me2CHÀC(8)).
1.8. 1,3-Dihydro-3-hydroxy-8-isopropyl-6,11-dimethyl-3-[1-(phenylsulfonyl)ethyl)]heptaleno[4,5-c]furan-
1-one (24). Compound 15c (0.10 g, 0.21 mmol) was added at r.t. to a soln. of KOH (0.20 g, 3.57 mmol) in
MeOH (6 ml). After stirring for 15h, the brown mixture was poured into ice/H 2O and acidified to pH 1 with
conc. HCl (0.5ml) to give a yellow precipitate. The mixture was extracted with AcOEt (3 Â 50 ml). The AcOEt
extracts were washed with brine (10 ml), dried (Na2SO4), and the solvent was evaporated. The solid residue was
recrystallized from Et2O/hexane to give 24 (0.40 g, 41%) as a yellowish powder. M.p. 135 136 8. Rf (hexane/
AcOEt 1:1) 0.61. 1H-NMR (CDCl3): 8.01 (dd, 3J ˆ 7.1, 4J ˆ 1.5, Ho of PhSO2); 7.67 (tt, 3J ˆ 7.5, 4J ˆ 1.3, Hp of
4
PhSO2); 7.58 (t, 3J ˆ 7.1, Hm of PhSO2), 7.13 (dd, 3J ˆ 6.7, J ˆ 0.5, HÀC(4)); 7.11 (s, HOÀC(3)), 6.35( dd, 3J ˆ
6.8, 4J ˆ 1.4, HÀC(5)); 6.27 (dd, 3J ˆ 6.3, 4J ˆ 1.4, HÀC(10)); 6.14 (d, 3J ˆ 6.3, HÀC(9)); 5.68 (s, HÀC(7)); 3.92
(q, 3J ˆ 7.0, PhSO2CH(Me)ÀC(3)); 2.40 (sept., 3J ˆ 6.8, Me2CH); 2.31 (s, MeÀC(6)); 2.17 (d, 4J ˆ 0.7,
MeÀC(11)); 0.99 (d, 3J ˆ 6.9, PhSO2CH(Me)ÀC(3)); 0.98 (d, 3J ˆ 6.9, Me2CH). 13C-NMR (75.5 MHz, CDCl3):
168.64 (OˆC); 151.42/139.39/136.15 (3s); 134.89/134.44 (2d); 132.68/131.14 (2s); 130.94 (d); 130.80 (s); 130.58/
128.73/127.47/126.77 (4d); 126.68 (s); 124.45( d); 103.30 (s, C(3)); 64.99 (d, PhSO2CH(Me)ÀC(3)); 35.99
(d, Me2CH); 25.41/23.91 (2q, Me); 22.88/22.43 (2q, Me2CH); 12.55 (q, PhSO2CH(Me)ÀC(3)). EI-MS: 464 (29,
.
‡
M
), 322 (55), 307 (100), 279 (40), 251 (25), 235 (41), 207 (92), 191 (72), 178 (63), 165 (79), 152 (52), 110 (24),
78 (26).

Helvetica Chimica Acta Vol. 86 (2003)
4043
2. Benzo[a]heptalene-Forming Reactions. 2.1. 9-Isopropyl-1,7,12-trimethyl-3-(phenylsulfonyl)benzo[a]-
heptalene-2,4-diol (3c) and 9-Isopropyl-7,12-dimethyl-3-(phenylsulfonyl)benzo[a]heptalene-2,4-diol (3b). 2.1.1.
First Approach (formation of 3c and 3b). A 2.5m soln. of BuLi (0.76 ml, 1.90 mmol) was added drop by drop
under Ar to a soln. of EtSO2Ph (0.29 g, 1.70 mmol) in anh. THF (15ml), kept at 0 8. After 30 min at 08, a white
precipitate had been formed. The mixture was cooled to À 788, and a soln. of 2'a (0.51 g, 1.50 mmol) in THF
(5ml) was added within 5min. The brown mixture was stirred at À 788 for 2 h, whereupon a part of 2'a had
reacted. In another flask, lithiated MeSO2Ph was generated under Ar by stirring the sulfone (0.703 g,
4.50 mmol) and BuLi (2.40 ml, 6.0 mmol) in THF (15 ml) at 08 for 30 min. After cooling to À 788, the soln. was
added via a cannula drop by drop to the above mixture, kept at À 608. The brown soln. was warmed within 3 h to
À 58. After addition of more BuLi (2.40 ml, 6.0 mmol) at À 58, the yellow-red soln. was stirred at r.t. for 15h.
Usual workup led to a solid that was subjected to CC (SiO2 (170 g); hexane/AcOEt 3 :1). A first fraction yielded
3c (0.495g, 72%) as yellow crystals. A second fraction gave 3b (0.115g, 17%) as yellow crystals (m.p. 207 208 8
(Et2O/hexane); lit. 207 2088 [1]. Rf (hexane/AcOEt 2 :1) 0.49).
Data of 3c. M.p. 208.6 209.58 (CH2Cl2/hexane). Rf (hexane/AcOEt 2 :1) 0.63. IR (KBr): 3348s, 3237s,
3013w, 2960m, 1586m, 1569m, 1556m, 1450m, 1437m, 1421m, 1350m, 1270m, 1242m, 1221m, 1134s, 1113m,
1076m, 1025w, 996w, 860m, 803m, 741m, 721m, 687m, 633m, 607s, 5 5w9, 45 2w, 411w. 1H-NMR (600 MHz,
4
CDCl3): 9.08 (s, HOÀC(4)); 8.89 (s, HOÀC(2)); 7.97 (dd, 3J ˆ 8.3, J ˆ 1.2, Ho of PhSO2); 7.65( tt, 3J ˆ 7.5, 4J ˆ
1.0, Hp of PhSO2); 7.54 (t, 3J ˆ 8.2, Hm of PhSO2); 7.08 (d, 3J ˆ 11.8, HÀC(5)); 6.41 (dd, 3J ˆ 11.9, 4J ˆ 1.2,
HÀC(11)); 6.40 (dd, 3J ˆ 11.7, 4J ˆ 1.8, HÀC(10)); 6.20 (d, 3J ˆ 11.9, HÀC(6)); 5.77 (s, HÀC(8)); 2.56
(sept., 3J ˆ 6.8, Me2CHÀC(9)); 1.88 (s, MeÀC(1)); 1.67 (d, 4J ˆ 0.7, MeÀC(7)); 1.49 (s, MeÀC(12)); 1.14/1.12
(2d, 3J ˆ 6.9/6.9, Me2CHÀC(9)). 13C-NMR (125MHz, CDCl 3): 154.53 (C(2)); 150.45 (C(4)); 147.26 (C(9));
144.92 (C(12b)); 141.38 (Cip of PhSO2); 135.13 (C(11)); 134.24 (Cp of PhSO2); 133.24 (C(7a)); 131.73 (C(12));
131.62 (C(6, 10)); 130.21 (C(12a)); 129.55 (Co of PhSO2); 128.75( s, C(7)); 126.15(C m of PhSO2); 124.88 (C(5));
121.54(C(8)); 119.11(C(4a)); 115.84 (C(1)); 107.48 (C(3)); 34.61 (Me2CHÀC(9)); 22.89/22.83 (Me2CHÀC(9));
.
‡
18.14 (MeÀC(12)); 16.67 (MeÀC(7)); 11.89 (MeÀC(1)). EI-MS: 460 (100, M ), 445(21), 390 (16), 338 (33),
273 (20), 193 (25), 157 (28), 105 (22), 91 (36). Anal. calc. for C28H28O4S (460.59): C 73.02, H 6.13, S 6.96; found:
C 73.31, H 6.71, S 5.96. X-Ray crystal structure: cf. Fig. 1 and Table 6.
2.1.2. Second Approach (formation of 3c). BuLi soln. (0.69 ml, 1.72 mmol) was added at À 58 to a soln. of
EtSO2Ph (0.22 g, 1.29 mmol) in anh. THF (10 ml) under Ar. After stirring during 30 min at 08, a white
precipitate had been formed. The mixture was cooled to À 408, and a soln. 15b (0.20 g, 0.43 mmol) in THF
(4 ml) was added slowly within 5min. The temp. was elevated over 3 h to À 108, and more BuLi (0.69 ml,
1.72 mmol) was slowly added, whereupon the color of the mixture changed immediately to dark reddish-brown.
The mixture was allowed to warm to r.t., and stirring was continued for 6 h. The mixture was poured on ice/H2O,
acidified with 1n aq. HCl soln. (50 ml), and extracted with AcOEt. The org. phase was washed with H2O
(100 ml) and brine (100 ml), dried (Na2SO4), and evaporated in vacuo. The crude product was purified by CC.
Recrystallization gave 3c (0.055 g, 28%) as yellow crystals.
2.1.3. Third Approach (formation of 3c). BuLi soln. (0.69 ml, 1.72 mmol) was added at À 58 to a soln. of
MeSO2Ph (0.20 g, 1.29 mmol) in anh. THF (10 ml) under Ar. After stirring for 30 min at 08, the mixture was
cooled to À 408, and a soln. of 16c (0.20 g, 0.43 mmol) in THF (4 ml) was added within 5min. The above
reaction conditions and workup gave 3c (0.047 g, 24%).
2.2. 9-Isopropyl-4,7,12-trimethyl-2-(phenylsulfonyl)benzo[a]heptalene-1,3-diol (4c), 9-Isopropyl-1,7,12-tri-
methyl-3-(phenylsulfonyl)benzo[a]heptalene-2,4-diol (3c), and 9-Isopropyl-7,12-dimethyl-3-(phenylsulfonyl)-
benzo[a]heptalene-2,4-diol (3b). 2.2.1. First Approach (formation of 4c, 3c, and 3b). Under Ar, a 2.5m soln. of
BuLi (0.76 ml, 1.90 mmol) was added drop by drop to an ice-cold soln. of MeSO2Ph (0.265g, 1.70 mmol) in anh.
THF (15ml). After stirring for 30 min at 0 8, a white precipitate had been formed. The mixture was cooled to
À 788, and a soln. of 2'a (0.51 g, 1.50 mmol) in THF (5 ml) was added within 5 min. The brown mixture was
stirred at À 788 for 2 h, whereupon part of 2'a had been consumed. In another flask, under Ar and at 08, lithiated
EtSO2Ph was generated from BuLi (2.40 ml, 6.0 mmol) and ethyl phenyl sulfone (0.766 g, 4.5mmol) in anh.
THF (15ml) in the usual way. This lithiated sulfone, cooled to À 788, was added drop by drop via a cannula to
the above mixture, kept at À 408. The brown soln. was warmed within 3 h to À 58. After addition of more BuLi
(2.40 ml, 6.0 mmol) at À 58, the yellow-red soln. was stirred during 15h at r.t. The usual workup procedure led
to a solid, which was purified by CC (SiO2 (170 g); hexane/AcOEt 3 :1). A first fraction consisted of 4c (0.18 g,
26%; 1H-NMR analysis) and 3c (0.145g, 21%; 1H-NMR analysis). A second fraction contained 3b (0.12 g,
18%).
2.2.2. Second Approach (formation of 4c). BuLi soln. (2.88 ml, 7.2 mmol) was added at 08 to a soln. of
MeSO2Ph (0.836 g, 5.34 mmol) in anh. THF (15 ml) under Ar. After stirring for 30 min at 08, a white precipitate

4044
Helvetica Chimica Acta Vol. 86 (2003)
had been formed. The mixture was cooled to À 408, and a soln. of 15c (0.640 g, 1.34 mmol) in THF (5ml) was
added slowly within 5min. The temp. was raised during 3 h to 10 12 8, and a 1.5m soln. of MeLi ¥ LiBr in hexane
(4 ml, 6 mmol) was slowly added. Immediately, the color of the mixture changed to a dark reddish-brown.
Stirring was continued for 2 h. Then, ice-water was added, and the mixture was acidified with 1n aq. HCl
(50 ml), followed by extraction with AcOEt. The org. phase was washed with brine (100 ml), dried (Na2SO4),
and evaporated. Purification of the crude product by FC and recrystallization (AcOEt/hexane) yielded pure 4c
(0.115g, 19%). Yellow crystals. M.p. 205.0 206.2 8. Rf (hexane/AcOEt 2 :1) 0.67. 1H-NMR (600 MHz, CDCl3):
10.02 (s, HOÀC(3)); 7.97 (dd, 3J ˆ 8.2, 4J ˆ 0.9, Ho of PhSO2); 7.58 (tt, 3J ˆ 7.2, 4J ˆ 1.3, Hp of PhSO2); 7.49 (t, 3J ˆ
7.9, Hm of PhSO2); 6.91 (d, 3J ˆ 12.1, HÀC(5)); 6.56 (s, HOÀC(1)); 6.41 (dd, 3J ˆ 11.9, 4J ˆ 1.1, HÀC(10); 6.39
(d, 3J ˆ 11.9, HÀC(11)); 6.33 (d, 3J ˆ 12.2, HÀC(6)); 5.76 (s, HÀC(8)); 2.56 (sept., 3J ˆ 6.9. Me2CH); 2.21
(s, MeÀC(4)); 1.69 (s, MeÀC(7)); 1.38 (s, MeÀC(12)); 1.13/1.12 (2d, 3J ˆ 6.9, Me2CH). 13C-NMR (150 MHz,
CDCl3): 152.89 (C(3)); 148.38 (C(1)); 147.37 (C(9)); 143.98 (C(4a)); 142.00 (Cip of PhSO2); 135.89 (C(6));
135.70 (C(7a)); 134.86 (C(11)); 134.43 (C(12)); 133.48 (Cp of PhSO2); 131.92 (C(10)); 128.84 (Cm of PhSO2);
128.74 (C(5)); 128.09 (C(7)); 126.93 (Co of PhSO2); 126.09 (C(12a)); 121.80 (C(8)); 117.73 (C(12b)); 115.73
(C(4)); 109.05(C(2)); 34.63 (Me 2CH); 22.79/22.78 (Me2CH); 18.20 (MeÀC(12)); 16.72 (MeÀC(7)); 11.22
(MeÀC(4)). Anal. calc. for C28H28O4S (460.59): C 73.02, H 6.13, S 6.96; found: C 72.79, H 6.18, S 6.94. X-Ray
crystal structure: cf. Fig. 3 and Table 6.
2.2.3. Third Approach (formation of 4c). EtSO2Ph (0.22 g, 1.29 mmol) in anh. THF (10 ml) was lithiated
with BuLi soln. (0.69 ml, 1.72 mmol) in the usual manner. The mixture was cooled to À 408, and a soln. 16b
(0.20 g, 0.43 mmol) in THF (4 ml) was added slowly within 5min. The above reaction conditions and workup
gave pure, crystalline 4c (0.057 g, 29%).
2.3. 9-Isopropyl-7,12-dimethyl-3-(morpholinosulfonyl)benzo[a]heptalene-2,4-diol (3a). 2.3.1. From 16b and
Lithiomethyl Morpholino Sulfone. Methyl morpholino sulfone (0.084 ml, 0.51 mmol) was dissolved in dry THF
(8 ml). The soln. was cooled to À 58, and BuLi soln. (0.25ml, 0.61 mmol) was added slowly. While stirring at
À 58, a white precipitate was formed. After 30 min, the mixture was cooled to À 408, and a soln. of 16b (0.08 g,
0.17 mmol) in THF (2 ml) was added. The temp. was raised within 3 h to À 58. Additional BuLi soln. (0.28 ml,
0.70 mmol) was added, and the mixture was allowed to warm to r.t. (30 min). After stirring at r.t. for 4 h, the
mixture was poured onto ice and 10% aq. HCl soln. (100 ml). The aq. phase was extracted with AcOEt (2 Â
20 ml). The org. phase was washed with H2O (3 Â 30 ml), brine (1 Â 30 ml), and dried (Na2SO4). The solvent
was distilled off, and the residue was chromatographed (SiO2 (80 g); hexane/AcOEt 2 :1) to afford 3a (0.027 g,
35%) as yellow crystals identical to an authentic probe (cf. [1]).
2.3.2. From 15a and LiCH2SO2Ph. Following the above procedure, MeSO2Ph (0.08 g, 0.51 mmol) was
reacted with BuLi soln. (0.25ml, 0.61 mmol) and 15a (0.081 g, 0.17 mmol) in THF (10 ml). After addition of
more BuLi soln. (0.28 ml, 0.7 mmol) at À 58, the mixture was stirred at r.t. for 4 h. The usual workup, followed
by FC (SiO2 (80 g); hexane/AcOEt 2 :1), gave pure 3a (0.021 g, 26%) as yellow crystals (cf. [1]).
2.4. 9-Isopropyl-7,12-dimethyl-3-(phenylsulfonylbenzo[a]heptalene-2,4-diol (3b). 2.4.1. From 16a and
LiCH2SO2Ph. Following the procedure of Sect. 2.3.1, MeSO2Ph (0.16 g, 1.02 mmol) was reacted with BuLi
soln. (0.50 ml, 1.22 mmol) and 16a (0.162 g, 0.34 mmol) in THF (15ml). After addition of more BuLi soln.
(0.56 ml, 1.4 mmol) at À 58, the mixture was stirred at r.t. for 4 h. The usual workup, followed by FC (SiO2
(130 g); hexane/AcOEt 2 :1) gave pure 3b (0.056 g, 37%) as yellow crystals (cf. [1]).
2.4.2. From 15b and Lithiomethyl Morpholino Sulfone. Following the procedure of Sect. 2.3.1, methyl
morpholino sulfone (0.084 g, 0.51 mmol) was reacted with BuLi soln. (0.25 ml, 0.61 mmol) and 15b (0.08 g,
0.17 mmol) in THF (10 ml). After addition of more BuLi soln. (0.28 ml, 0.70 mmol) at À 58, the mixture was
stirred at r.t. during 4 h. The usual workup, followed by FC (SiO2 (80 g); hexane/AcOEt 2 :1) gave pure 3b
(0.018 g, 23%) as yellow crystals.
2.5. 8-Isopropyl-6,11-dimethyl-2-(morpholinosulfonyl)-3-[(phenylsulfonyl)methyl]-1H-cyclopenta[d]hep-
talen-1-one (11ab). BuLi soln. (0.34 ml, 0.84 mmol) was added at À 58 to a soln. of methyl morpholino sulfone
(0.104 g, 0.63 mmol) in anh. THF (10 ml) under Ar. After stirring for 30 min at 08, a white precipitate had been
formed. The mixture was cooled to À 788, and a soln. of 15b (0.10 g, 0.21 mmol) in THF (2 ml) was added drop
by drop within 5min. After additional stirring at À 788 for 1 h, the temp. was raised slowly within 2 h to À 108.
The mixture was poured onto ice. Usual workup and FC (SiO2 (80 g); hexane/AcOEt 1:1) gave 11ab (0.027 g,
22%) as a yellow microcrystalline powder. M.p. 258 2598 (AcOEt). Rf (hexane/AcOEt 3 :5) 0.51. 1H-NMR
(300 MHz, CDCl3): 8.00 (dd, 3J ˆ 7.1, 4J ˆ 0.8, Ho of PhSO2); 7.68 (t, 3J ˆ 7.4, Hp of PhSO2); 7.58 (t, 3J ˆ 7.7, Hm of
PhSO2); 6.85( d, 3J ˆ 7.2, HÀC(4)); 6.47 (dd, 3J ˆ 7.0, 4J ˆ 1.0, HÀC(10)); 6.29 (m, HÀC(5), HÀC(9)); 6.19
(s, HÀC(7)); 5.07/4.88 (AB, 2JAB ˆ 12.8, PhSO2CH2ÀC(3)); 3.71 (m, O(CH2CH2)2N); 3.52/3.48
(2m, O(CH2CH2)2N); 2.53 (sept., 3J ˆ 6.8, Me2CHÀC(8)); 2.25( s, MeÀC(6)); 2.18 (s, MeÀC(11)); 1.14/1.12

Helvetica Chimica Acta Vol. 86 (2003)
4045
(2d, 3J ˆ 6.9/6.8, Me2CHÀC(8)). 13C-NMR (75.5 MHz, CDCl3): 181.49 (OˆC); 151.43/148.71/144.63/139.94/
139.62/138.19 (6s); 137.88 (C(2)); 134.28 (d); 132.86/131.52 (2s); 131.35/129.73/129.43/128.34/126.68/126.63 (6d);
125.14 (s); 66.96 (O(CH2CH2)2N), 52.96 (PhSO2CH2ÀC(3)); 46.08 (O(CH2CH2)2N); 35.97 (Me2CHÀC(8));
25.82, 24.56 (MeÀC(6), MeÀC(11)); 23.01/22.92 (Me2CHÀC(8)).
2.6. 8-Isopropyl-6,11-dimethyl-2-(phenylsulfonyl)-3-[(morpholinosulfonyl)methyl]-1H-cyclopenta[d]hep-
talen-1-one (11ba). BuLi soln. (0.34 ml, 0.84 mmol) was added at À 58 to a soln. of methyl phenyl sulfone
(0.098 g, 0.63 mmol) in anh. THF (10 ml) under Ar. After stirring for 30 min at 08, a white precipitate had been
formed. The mixture was cooled to À 788, and a soln. of 15a (0.10 g, 0.21 mmol) in THF (2 ml) was added drop
by drop within 5min. After additional stirring at À 788 for 1 h, the temp. was raised slowly within 2 h to À 108.
The mixture was poured onto ice. Usual workup and FC (SiO2 (80 g); hexane/AcOEt 1:1) gave 11ba (0.024 g,
20%) as an orange microcrystalline powder. M.p. 251 2528 (AcOEt). Rf (hexane/AcOEt 3 :5) 0.52. 1H-NMR
(300 MHz, CDCl3): 8.22 (dd, 3J ˆ 6.9, 4J ˆ 1.2, Ho of PhSO2); 7.53 (tt, 3J ˆ 6.2, 4J ˆ 1.4, Hp of PhSO2); 7.49 (t, 3J ˆ
6.8, Hm of PhSO2); 6.91(d, 3J ˆ 6.7, HÀC(4)); 6.39 (dd, 3J ˆ 6.9, 4J ˆ 1.3, HÀC(10)); 6.28 (m, HÀC(5),
HÀC(9)); 6.13 (d, 4J ˆ 1.3, HÀC(7)); 5.04/4.96 (AB, 2JAB ˆ 12.5, CH2ÀC(3)); 3.80 (m, O(CH2CH2)2N); 3.46
(m, O(CH2CH2)2N); 2.47 (sept., 3J ˆ 6.8, Me2CHÀC(8)); 2.14 (d, 4J ˆ 0.7, MeÀC(6)), 2.12 (s, MeÀC(11)); 1.09/
1.07 (2d, 3J ˆ 6.9/6.7, Me2CHÀC(8)). 13C-NMR (75.5 MHz, CDCl3): 180.12 (OˆC); 153.32/148.45/144.36/
140.57/140.10/139.94/138.04 (7s); 137.40 (C(2)); 133.65( d); 132.51 (s); 131.46 (d); 131.20 (s); 129.58/129.09/
128.60/128.47/126.61/126.02/125.31 (7d); 125.03 (s); 66.49 (O(CH2CH2)2N); 46.19 (O(CH2CH2)2N); 45.01
(CH2ÀC(3)); 35.79 (Me2CH); 25.76, 24.32 (MeÀC(6), MeÀC(11)); 22.86/22.73 (Me2CH).
3. Synthesis of 9-Isopropyl-1,2,3-trimethoxy-4,7,12-trimethylbenzo[a]heptalene (23). 3.1. 9-Isopropyl-1,3-
dimethoxy-4,7,12-trimethyl-2-(phenylsulfonyl)benzo[a]heptalene (20). A suspension of K2CO3 (0.4 g) in anh.
acetone (10 ml) was cooled to 08, and a soln. of 4c (0.10 g, 0.22 mmol) in acetone (3 ml) was added under
stirring. To this mixture, MeI (0.80 ml) was added drop by drop, and stirring was continued for 8 h at r.t. The
mixture was diluted with H2O (50 ml) and extracted with AcOEt (2 Â 30 ml). The org. layer was separated and
dried (Na2CO3). Almost pure 20 (0.103 g, 96%) was obtained after evaporation of the solvent. It was
recrystallized from Et2O to give 20 as a yellow, microcrystalline powder. M.p. 183.1 184.38 (Et2O/hexane). Rf
1
4
(hexane/AcOEt 2 :1) 0.63. H-NMR (600 MHz, CDCl3): 7.90 (dd, 3J ˆ 7.0, J ˆ 1.2, Ho of PhSO2); 7.49 (tt, 3J ˆ
7.2, 4J ˆ 1.4, Hp of PhSO2); 7.42 (t, 3J ˆ 7.1, Hm of PhSO2); 6.89 (d, 3J ˆ 12.1, HÀC(5)); 6.39 (d, 3J ˆ 12.1,
HÀC(6)); 6.36 (d, 3J ˆ 11.9, HÀC(11)); 6.33 (dd, 3J ˆ 11.9, 4J ˆ 1.2, HÀC(10)); 5.78 (s, HÀC(8)); 3.92
(s, MeOÀC(3)); 3.58 (s, MeOÀC(1)); 2.55 (sept., 3J ˆ 6.7, Me2CH); 2.28 (s, MeÀC(4)); 1.75( s, MeÀC(7));
1.21 (s, MeÀC(12)); 1.12/1.11 (2d, 3J ˆ 6.9/6.8, Me2CH). 13C-NMR (150 MHz, CDCl3): 156.01 (C(3)); 154.26
(C(1)); 147.24 (C(9)); 144.71 (C(4a)); 144.57 (Cip of PhSO2); 136.73 (C(7a)); 135.89 (C(6), C(11)); 134.44
(C(12)); 132.26 (Cp of PhSO2)); 131.16 (C(10)); 129.02 (C(12b)); 128.66 (C(7)); 128.44 (C(5)); 128.25 (Cm of
PhSO2); 127.71 (C(2)); 126.93 (C(12a)); 126.86 (Co of PhSO2); 126.26 (C(4)); 122.58 (C(8)); 63.21
(MeOÀC(3)); 62.27 (MeOÀC(1)); 34.77 (Me2CH); 22.83/22.74 (Me2CH); 18.65(Me ÀC(12)); 16.91
(MeÀC(7)); 12.51 (MeÀC(4)).
3.2. 9-Isopropyl-1,3-dimethoxy-4,7,12-trimethylbenzo[a]heptalene (21). Under Ar, TiCl4 (0.26 ml, 2.4 mmol)
was added drop by drop at À 788 to anh. THF (8 ml). A 1m soln. of LiAlH4 (7.1 ml, 7.1 mmol) in THF was then
slowly added, whereby a dark grey-colored suspension was formed, which was allowed to warm to À 108 within
3 h. Then, the mixture was cooled again to À 788, and a soln. of 20 (0.090 g, 0.184 mmol) in THF (4 ml) was
added slowly under Ar. After 0.5h at À 788, the temp. was raised within 2 h to r.t., and stirring was continued for
an additional 2 h. The still dark-grey mixture was added slowly to a sat. aq. soln of NH4Cl (150 ml), and the
mixture was stirred for ca. 1.5h. After extraction with AcOEt (3 Â 50 ml), the org. layer was washed with H2O
(50 ml), brine (50 ml), and dried (Na2SO4). Evaporation in vacuo led to a solid, which was purified by FC (SiO2
(70 g); hexane/AcOEt 4 :1) to give pure 21 (0.056 g, 87%). Yellow crystalline powder. M.p. 132.5 132.98 (Et2O/
hexane). Rf (hexane/AcOEt 3 :1) 0.75. 1H-NMR (300 MHz, CDCl3): 6.99 (d, 3J ˆ 12.0, HÀC(5)); 6.62
4
(s, HÀC(2)); 6.44 (d, 3J ˆ 11.8, HÀC(11)); 6.34 (dd, 3J ˆ 11.8, J ˆ 1.2, HÀC(10)); 6.26 (d, 3J ˆ 12.0, HÀC(6));
5.74 (s, HÀC(8)); 3.84 (s, MeOÀC(3)); 3.68 (s, MeOÀC(1)); 2.58 (sept., 3J ˆ 6.9, Me2CH); 2.22 (s, MeÀC(4));
1.72 (s, MeÀC(7)); 1.56 (s, MeÀC(12)); 1.16/1.15(2 d, 3J ˆ 6.9/6.8, Me2CH). 13C-NMR (75.5 MHz, CDCl3):
156.75 (C(3)); 154.52 (C(1)); 146.34 (C(9)); 138.03/136.31 (2s); 135.59 (C(11)); 133.25 (C(6)); 132.19 (s); 130.15
(C(10)); 129.67 (C(5)); 128.31/127.28/122.06 (3s); 121.28 (C(8)); 116.64 (s); 98.56 (C(2)); 57.27/55.97
(MeOÀC(1,3)); 34.63 (Me2CH); 23.05/22.81 (Me2CH); 18.96 (MeÀC(12)); 16.72 (MeÀC(7)); 11.20
(MeÀC(4)). X-Ray crystal structure: see Table 6.
3.3. 9-Isopropyl-1,3-dimethoxy-4,7,12-trimethylbenzo[a]heptalen-2-ol (22). Under Ar, a 2.5m soln. of BuLi
(0.60 ml, 1.51 mmol) was added drop by drop to a soln. of 21 (0.075g, 0.215mmol) in anh. THF (20 ml), cooled
to 08. After stirring for 4 h at 08, CuBr (0.217 g, 1.51 mmol) was added to the resulting dark brown soln. The

4046
Helvetica Chimica Acta Vol. 86 (2003)
mixture was stirred at 08, until all cuprous bromide had disappeared (ca. 3 h). The vessel, containing the organo-
copper compound, was then equipped with a Pasteur pipette with an attached drying tube (filled with P2O5
(Fluka) with moisture indicator). Dry air was drawn at 08 for 2 h through the reaction mixture via the pipette by
applying a slight vacuum at the reaction vessel. Thereby, the color of the mixture became deep green. Ice-cold 1m
aq. HCl (30 ml) was added, and the resulting mixture was extracted with AcOEt (100 ml). The org. layer was
washed with brine (2 Â 50 ml) and dried (MgSO4). The residue was purified by FC (SiO2; hexane/AcOEt 3 :1)
to give 22 (0.046 g, 59%). Yellow crystals. M.p. 147 1488 (Et2O/hexane). Rf (hexane/AcOEt 3 :1) 0.55.
1H-NMR (600 MHz, CDCl3): 6.89 (d, 3J ˆ 12.0, HÀC(5)); 6.44 (d, 3J ˆ 11.9, HÀC(11)); 6.35( dd, 3J ˆ 11.9, 4J ˆ
1.2, HÀC(10)); 6.21 (d, 3J ˆ 12.0, HÀC(6)); 5.75 (s, HÀC(8)); 5.69 (s, HOÀC(2)); 3.84 (s, MeOÀC(3)); 3.64
(s, MeOÀC(1)); 2.56 (sept., 3J ˆ 6.9, Me2CH); 2.28 (s, MeÀC(4)); 1.74 (s, MeÀC(7)); 1.58 (s, MeÀC(12)); 1.13/
1.12 (2d, 3J ˆ 6.9/6.8, Me2CH). 13C-NMR (150 MHz, CDCl3): 146.85/144.98/143.16/141.72 (4s); 135.97 (C(11));
134.13/133.19 (2s); 131.46 (C(6)); 130.89 (C(10)); 129.55 (C(5)); 128.65/128.54/128.16/127.63 (4s); 124.61 (C(4));
122.49 (C(8)); 61.25(MeO ÀC(1); 60.53 (MeOÀC(3)); 34.64 (Me2CH); 22.93/22.81 (Me2CH); 19.28
(MeÀC(12)); 16.93 (MeÀC(7)); 12.21 (MeÀC(4)). Anal. calc. for C24H28O3 (364.49) C 79.09, H 7.74; found:
C 78.92, H 7.67. X-Ray crystal-structure: cf. Fig. 4 and Table 6).
3.4. Formation of 23. K2CO3 (0.50 g) was suspended in anh. acetone (10 ml). The mixture was cooled to 08,
and 22 (0.090 g, 0.247 mmol) was added under stirring. To this mixture, MeI (1.0 ml) was added drop by drop,
and stirring was continued at r.t. for 8 h. The mixture was diluted with H2O (20 ml) and extracted with AcOEt
(2 Â 30 ml). The org. layer was separated and dried (Na2SO4). Evaporation in vacuo gave pure 23 (0.090 g, 95%)
as a yellow oil. Rf (hexane/AcOEt 3 :1) 0.73. 1H-NMR (300 MHz, CDCl3): 6.91 (d, 3J ˆ 12.0, HÀC(5)); 6.44
4
(d, 3J ˆ 11.8, HÀC(11)); 6.35( dd, 3J ˆ 11.8, J ˆ 1.1, HÀC(10)); 6.25( d, 3J ˆ 12.0, HÀC(6)); 5.75 (s, HÀC(8));
3.90 (s, MeOÀC(2)); 3.84 (s, MeOÀC(3)); 3.60 (s, MeOÀC(1)); 2.57 (sept., 3J ˆ 6.8, Me2CH); 2.26
(s, MeÀC(4)); 1.73 (s, MeÀC(3)); 1.58 (s, MeÀC(12)); 1.14, 1.13 (2d, 3J ˆ 6.9/6.8, Me2CH).
4. X-Ray Crystal-Structure Determinations for Compounds 3c, 4c, 15c, 16a, 16b, 17c, 19c, 21, and 229). All
measurements were conducted on a Nonius KappaCCD area-detector diffractometer [15] with graphite-
monochromated MoKa radiation (l ˆ 0.71073 ä) and an Oxford Cryosystems Cryostream-700 cooler. The data
collection and refinement parameters are given in Table 6, views of the molecules are shown in Figs. 1 6.
Except for 4c, data reduction was performed with HKL DENZO and SCALEPACK [16], and equivalent
reflections were merged. Examination of the diffraction images for 4c revealed that there were two
interpenetrating lattices. These lattices could be indexed independently using DIRAX [17], and it was found
that they were related by a 1808 rotation about the normal to the xy-plane, indicating that the crystals were
twinned. Several crystals were tested and all possessed the same twinning properties. Integration of the
diffraction images and data reduction was performed with EvalCCD [15][18]. The final data set incorporated all
reflections from both twin domains with overlapping and nonoverlapping reflections appropriately indexed.
Equivalent reflections were not merged because of the nature of the twinned data set. The volume fraction of
the major twin domain refined to 0.6528(6). The intensities for each structure were corrected for Lorentz and
polarization effects, but not for absorption. Each structure was solved by direct methods using SIR92 [19], which
revealed the positions of all non-H-atoms. The asymmetric unit of 19c contained one molecule of the heptalene
derivative plus one ordered molecule of Et2O. In this structure, the isopropyl group and part of its parent
heptalene ring were disordered (two conformations). Two positions were defined for C(8), C(9), C(31) and
C(32)10), and refinement of the site-occupation factors of these two conformations yielded a value of 0.627(9)
for the major conformer. Atom C(33) of the isopropyl substituent was common to both conformations.
Restraints were applied to all chemically equivalent bond lengths involving disordered heptalene-ring atoms so
as to maintain reasonable geometry. Pseudo-isotropic restraints were also applied to the atomic-displacement
parameters of some of the disordered atoms. The non-H-atoms of each structure were refined anisotropically.
The OH H-atoms in 3c, 4c, 19c, and 22 were placed in the positions indicated by difference-Fourier maps and,
except for 3c, their positions were allowed to refine together with individual isotropic displacement parameters.
The OH H-atom positions in 3c were not refined, and each of these H-atoms was assigned a fixed isotropic
displacement parameter with a value equal to 1.2Ueq of its parent O-atom. All remaining H-atoms in the
9
)
The supplementary crystallographic data for this paper have been deposited as CCDC 220539 CCDC
220547. These data can be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
‡441223336033; e-mail: deposit@ccdc.cam.ac.uk).
10
)
For C-atoms with numbers > 12, see CCDC.

Helvetica Chimica Acta Vol. 86 (2003)
4047
structures were placed in geometrically calculated positions, and each was assigned a fixed isotropic
displacement parameter with a value equal to 1.2Ueq of its parent C-atom (1.5Ueq for the Me groups of 4c, 19c,
21, and 22). For 17c, peaks corresponding to two disordered orientations of the H-atoms of the C(24) Me group
were observed in a difference-electron-density map, so these Me H-atoms were defined using two equally
occupied orientations. The structures of 3c, 15c, 16a, 16b, and 17c were refined on F using full-matrix least-
squares procedures, which minimized the function Sw(j Fo jÀj Fc j )2. For 4c, 19c, 21, and 22, the refinement was
carried out on F2 by minimizing the corresponding function based on F2. Corrections for secondary extinction
were applied in the case of 3c and 21. Except for 3c and 15c, between three and 16 low-angle reflections were
omitted from the final refinement of each structure because the observed intensities of these reflections were
much lower than the calculated values as a result of being partially obscured by the beam stop. Neutral atom
scattering factors for non-H-atoms were taken from [20a], and the scattering factors for H-atoms were taken
from [21]. The values of the mass-attenuation coefficients were those of [20b]. All calculations for 4c, 19c, 21,
and 22 were performed using SHELXL97 [22], while the teXsan crystallographic software package [23] was
used for the remaining structures. The crystallographic diagrams were drawn with ORTEPII [24].
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Received September 30, 2003