Chiral [η6-Arene-Cr(CO)3] complexes as synthetic building blocks: A short enantioselective total synthesis of (+)-ptilocaulin

Article abstract of DOI:10.1002/(SICI)1521-3765(199801)4:1<57::AID-CHEM57>3.0.CO;2-H

An enantioselective total synthesis of the marine natural product (+)-ptilocaulin is described. The synthesis starts from [anisole-Cr(CO)₃], which is converted to [2-trimethylsilylanisole-Cr(CO)₃] (≤ 99% ee) by enantioselective depro

Full text of DOI:10.1002/(SICI)1521-3765(199801)4:1<57::AID-CHEM57>3.0.CO;2-H

FULL PAPER
Chiral [h6-Arene ± Cr(CO)3] Complexes as Synthetic Building Blocks: A
Short Enantioselective Total Synthesis of (‡)-Ptilocaulin
Kurt Schellhaas, Hans-Günther Schmalz,* and Jan W. Bats
Abstract: An enantioselective total syn-
thesis of the marine natural product (‡)-
ptilocaulin is described. The synthesis
starts from [anisole ± Cr(CO)3], which is
converted to [2-trimethylsilylanisole ±
Cr(CO)3] ( ꢀ 99% ee) by enantioselec-
tive deprotonation/silylation and recrys-
tallization. After attachment of a 2-
butenyl side-chain, nucleophile addition
(2-lithio-1,3-dithiane) followed by treat-
ment with chlorotrimethylsilane and
hydrolysis leads to (5S,6S)-6-((E)-but-
2-enyl)-5-[1,3]-dithian-2-yl-2-trimethyl-
silylcyclohex-2-enone with complete
chirality transfer. This compound, which
was characterized by X-ray crystallog-
raphy, is transformed into (5x,6S,7aS)-5-
butyl-6-methyl-1,2,5,6,7,7a-hexahydro-
and aldol cyclization. The target mole-
cule was prepared in both racemic and
optically active form. The X-ray crystal
structure of rac-ptilocaulin nitrate shows
flat ribbons of homochiral units (parallel
double chains) connected by an inter-
esting pattern of hydrogen bonds be-
tween the guanidinium and the nitrate
ions. A different mode of hydrogen
bonding resulting in the formation of
helical monochains was found in the
solid-state structure of (‡)-ptilocaulin
co-crystallized with about 29% of its C-
3a epimer.
inden-4-one,
a ptilocaulin precursor
known from the literature, by a 4-step
sequence consisting of diastereoselec-
tive 1,4-addition, ultrasound-assisted de-
sulfurization/hydrogenation (Raney Ni)
Keywords: arene complexes ´ chir-
ality ´ chromium ´ natural products
´ ptilocaulins ´ total synthesis
based on both the reactivity and the stereochemistry of
[arene ± Cr(CO)3] complexes,[7] we selected (‡)-ptilocaulin as
a biologically relevant and structurally challenging target.
This compound was first isolated in 1981 as its nitrate 1, a
highly antimicrobial and cytotoxic active metabolite from the
Caribbean sponge Ptilocaulis aff. P. spiculifer (Lamarck, 1814)
by Rinehart and coworkers.[8] The constitution and relative
configuration of 1 was established by means of spectroscopic
methods[8,9] and the absolute configuration was determined
independently by Snider[10] and Roush[11] through stereora-
tional total syntheses of ent-1. In addition, one total synthesis
of the natural enantiomer 1,[12] two total syntheses of rac-1[13,14]
and a formal synthesis of 1[15] have been reported. Recently, a
number of new (oxidized) ptilocaulin relatives such as 8b-
hydroxyptilocaulin (2)[16] and mirabilin D (3)[17] were isolated
from antibacterial and antifungal extracts of other marine
sponges. This demonstrates the biological importance of these
marine alkaloids and their attractiveness as targets for
chemical synthesis. In this paper, we describe a short and
Introduction
Among the various types of transition metal p-complexes, [h6-
arene ± Cr(CO)3] complexes possess a particularly broad
potential for organic synthesis, and the chemistry of this class
of compounds has been the subject of intense investigation for
many years.[1±3] Besides some applications as catalysts for
hydrogenation and isomerization reactions,[4] [arene ±
Cr(CO)3] complexes have proven their value above all in
stoichiometric transformations, the Cr(CO)3 moiety serving as
an activating and stereodirecting functionality. As complexes
of unsymmetrically substituted (Cs symmetric) arene ligands
are chiral,[5] absolute stereochemical information can be
introduced into a synthetic course by employing chiral
nonracemic complexes (of achiral ligands) as building blocks.
Nevertheless, the number of practical applications of such
planar chiral [arene ± Cr(CO)3] complexes in enantioselective
total syntheses still remains rather small.[6,7]
In the course of our research program aimed at the
synthesis of bioactive compounds by strategies centrally
NH2 NO3
NH2
NH
Cl
NH2
[*] Prof. Dr. H.-G. Schmalz, Dipl.-Chem. K. Schellhaas
Institut für Organische Chemie der
HN
NH
H
HN
N
N
Technischen Universität Berlin
OH
OH
Strasse des 17. Juni 135, D-10623 Berlin (Germany)
Fax: Int. code ‡ 4930314-21105
Me
Me
Me
e-mail: schmalz@wap0109.chem.tu-berlin.de
Me
Me
Me
H
H
H
Dr. J. W. Bats
Institut für Organische Chemie der Universität Frankfurt am Main
Marie-Curie-Str. 11, D-60439 Frankfurt am Main (Germany)
1
2
3
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57

H. G. Schmalz et al.
FULL PAPER
highly enantioselective total synthesis of (‡)-ptilocaulin
nitrate (1) which, as a key feature, is based on the utilization
of chiral [arene ± Cr(CO)3] complexes.[18] In addition we
disclose fascinating details of the crystal structures of rac-1
and 1, which have completely different hydrogen-bonding
patterns.
OMe
OMe
O
Me
CN
Me
CN
Me
CN
(CO)3Cr
Me
Me
Me
9
10
11
Me
Me
a) TFA
b) NH4OH
H3O+
CN
Results and Discussion
rac-10
8
rac-9
rac-11
70%
Strategic considerations: Our synthetic strategy is delineated
in Scheme 1. Following the original disconnection of Snider,[10]
we chose the enone 4 as pre-target molecule, as both
diastereomers of this structure can be converted into ptilo-
caulin by condensation with guanidine.[10,12±14] As a precursor
of 4 we proposed the cyclohexenone derivative 5, which, in
principle, should be convertible to 4 through a desulfurization/
cyclopentene annulation sequence. As the key step of the
Scheme 2. Cyclohexenone synthesis according to M. F. Semmelhack
et al.[19, 22]
ture.[24] Due to the fact that the two meta positions of 8 are
enantiotopic and are therefore attacked by the (achiral)
nucleophile with equal probability, the product (rac-11) is
formed as a racemic mixture. Recent reports have shown that
11 can be obtained enantioselectively (up to 56%
ee) from Cr(CO)3-complexed aryl ethers derived
from chiral (nonracemic) alcohols.[25] As an impor-
NH2
tant element of our strategy, however, we intended
HN
NH
O
O
H
to employ
a
chiral (nonracemic) [anisole ±
Bu
Bu
TMS
Me
Cr(CO)3] derivative (such as 6) as substrate for
the enone formation. We had good reason to
assume that the reaction would proceed with
chirality transfer because the nucleophile should
attack from the exo face (at the sterically less
hindered position) of the arene ligand. For the
projected synthesis of (‡)-ptilocaulin it was there-
fore necessary to have access to the nonracemic
chiral building block 7 with the correct absolute
configuration.
S
Me
Me
H
H
S
1
4
5
OMe
OMe
OMe
TMS
TMS
Me
Cr(CO)3
Cr(CO)3
Cr(CO)3
Enantioselective preparation of the chiral building
block 7: Following the general strategy outlined
8
7
6
above (Scheme 1), we started with the anisole
complex 8,[26] which was prepared in almost quan-
Scheme 1. Concept of a synthesis of (‡)-ptilocaulin (1) in retrosynthetic presentation.
titative yield from [Cr(CO)6] by thermolysis in the presence of
5 equivalents of anisole. The enantioselective ortho-silylation
was accomplished following the protocol of Simpkins[21a] with
the chiral base 12[27] in the presence of excess TMSCl in THF
at 788C (in situ quench conditions; Scheme 3). On a sub-
mmol scale, the product (7) was obtained in 95% yield and
88% ee. On a scale ꢀ 2.5 mmol, however, it was necessary to
run the reaction at even lower temperature ( 1008C) to
obtain good results (typically 87% yield; 87% ee). The optical
purity of 7 was routinely determined by HPLC, but it is
synthesis, we envisioned the preparation of 5 from the chiral
complex 6 by addition of a C1 nucleophile (2-lithio-1,3-
dithiane) followed by protonation and hydrolysis.[19] Complex
6 in turn could eventually be obtained by ortho-alkylation[20]
of 7, which represents the product of enantioselective depro-
tonation/silylation[21] of the prochiral [anisole ± Cr(CO)3]
complex 8.
With some optimism, the crucial transformation (6 !5)
appeared feasible to us because of the analogy to the
transformation shown in Scheme 2, which was described by
Semmelhack et al. several years ago.[19,22] These authors
discovered that the addition of 2-lithioisobutyronitrile to the
[anisole ± Cr(CO)3] complex (8) gives rise to an anionic h5
intermediate (rac-9), which on protonation and decomplex-
ation leads to a dienol ether (rac-10) which is finally hydro-
lyzed to the enone rac-11.[22a] While the intramolecular version
of this chemistry has proven useful for the synthesis of
spirocyclic 5,5-disubstituted cyclohexenone derivatives,[23] al-
most no intermolecular applications of the Semmelhack
Me Me
Ph
N
Li
Ph
12
OMe
OMe
TMS
TMSCl, THF, -100 °C
87%
Cr(CO)3
Cr(CO)3
7 (87% ee)
8
Scheme 3. Preparation of the optically active complex 7 by enantioselec-
cyclohexenone synthesis have yet appeared in the litera-
tive deprotonation/silylation.
58
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(‡)-Ptilocaulin Synthesis
57±66
noteworthy that we were also able to separate the enantio-
mers by chiral GLC.[28] The absolute configuration of 7, which
was first established by Simpkins,[21a,21e] was confirmed by the
conversion into (‡)-ptilocaulin (see below). A single recrys-
tallization of enantioenriched 7 from hexane afforded nearly
enantiomerically pure material (ꢀ 99% ee) in 70% yield. This
material was utilized for the synthesis of (‡)-ptilocaulin as
described below. Nevertheless, the whole synthesis was first
carried out with the racemic compounds in order to optimize
the individual steps.
OMe
O
TMS
TMS
R
S
TMS
Me
Me
S
S
S
(OC)3Cr
S
S
16
15
17
nucleophile addition product with acid-free TMSCl in the
presence of hexamethylphosphoric triamide (HMPA).[18a]
After extractive workup and light-induced decomplexation,[32]
a dienol ether of type 16 is formed as the dominant product,[33]
which is finally converted to the desired enone by acidic
hydrolysis (2n HCl, THF, 808C). With this protocol, the
conversion of rac-13 to the enone rac-17 proceeded in 63%
yield. Similarly, rac-14 gave rise to the diastereomerically pure
crystalline enone rac-18 (53%; Scheme 5). It
Attachment of the C4 side-chain: While the ortho-methylation
of 7 to afford 13 was easily accomplished (n-BuLi, MeI;
Scheme 4), all our attempts to transform 7 into the projected
butylated compound 6 by alkylation of the lithiated inter-
must be emphasised that the tele-substituted
products were formed only in trace amounts
under these conditions. In contrast to our expect-
ations,[18a] the cis configuration of rac-18 was
OMe
a) n-BuLi
TMS
b) MeI
Me
96%
Cr(CO)3
unambiguously established by X-ray crystallog-
raphy (Figure 1).[34] Obviously, the cis isomer is
OMe
13
TMS
formed in this case as the thermodynamically
more stable diastereomer under the equilibrating
conditions of the dienol ether hydrolysis.
In the optically active series, an experiment
a) n-BuLi
b) CuCl
OMe
Cr(CO)3
TMS
Br
Me
c)
Me
7 ( 99% ee)
performed on a 2 g scale provided 18 in 45%
yield (Scheme 5). The enantiomeric purity (ꢀ
99% ee) of the product 18 was corroborated by
means of HPLC,[18a,35] demonstrating that the
predicted chirality transfer from the metal
complex (planar chirality) to the permanent
chirality b to the carbonyl function had occurred without
racemization.
83-85%
Cr(CO)3
14
Scheme 4. Preparation of compounds 13 and 14.
mediate with butyl iodide failed. We therefore decided to
follow Semmelhackꢁs protocol,[29] which involves coupling of
the corresponding organocopper species with crotyl bromide.
This way, the 2-butenylated compound 14 was obtained in
83% yield (Scheme 4). Since we did not succeed in achieving
the catalytic hydrogenation of rac-14 (!rac-6) we decided to
proceed with the unsaturated compound and to remove the
side-chain double bond at a later stage of the synthesis.
O
OMe
a) 2-Lithio-1,3-dithiane
THF, HMPT
b) TMSCl
TMS
TMS
Me
Me
S
c) hν, air
d) H3O+
Cr(CO)3
S
45-53%
14
18
The key stepÐcyclohexenone formation: We then endea-
vored to perform the crucial conversion of complex rac-14
into a cyclohexenone by addition of 2-lithio-1,3-dithiane[30] as
a C1 nucleophile followed by protonation with trifluoroacetic
acid (TFA) under the reaction and workup conditions
described by Semmelhack for the conversion of 8 to rac-
11.[19] We were surprised to find that under these conditions
not even a trace of the expected product(s) could be detected.
Instead, the tele-substituted complex rac-15 was isolated in
good yield as the exclusive product, along with some
recovered starting material. By varying the substrate, the
nucleophile, and the reaction conditions we were able to show
that (intermolecular) nucleophilic addition/protonation reac-
tions of ortho-alkylated [anisole ± Cr(CO)3] derivatives in
general furnish tele-substituted complexes.[18b,31]
Scheme 5. The key reaction: preparation of 18 by nucleophile addition to
14.
Nevertheless, after considerable experimentation employ-
ing the model compound rac-13, we found that the tele-
substitution can be suppressed by trapping the primary
Figure 1. Structure of rac-18 in the crystalline state (only ent-18 is
depicted).
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H. G. Schmalz et al.
FULL PAPER
Thus, the enantioselective synthesis of the highly function-
alized ptilocaulin precursor 18 (which involves the dearoma-
tization of an anisole derivative) was achieved in only four
steps with ca. 25% overall yield starting from anisole.
O
TMS
Me
b)
a)
S
18
O
S
O
20
Preparation of hexahydroindenones: The next task in the
projected synthesis (see Scheme 1) was the construction of the
hydroindenone core. In analogy to the syntheses of Snider,[10]
Asaoka,[12] and Cossy[15] we intended to accomplish this by
conjugate addition of a C3 nucleophile and subsequent aldol
cyclization. Since compound 18 represents an a-silylated
enone, we were confident that it would react directly with a
nucleophile by conjugate addition.[36] Indeed, when rac-18 was
treated with an excess of the Grignard reagent prepared from
2-bromoethyl-1,3-dioxolane[37] followed by heating with aque-
ous hydrochloric acid, the cyclized product rac-19 was isolated
in good yield and high diastereomeric purity (ꢀ 95%).
Obviously, the Grignard reagent had added to rac-18 in a
highly regio- and diastereoselective manner (Scheme 6). The
O
O
O
O
c)
Me
Me
S
O
O
Me
S
O
O
22
21
O
O
d)
Me
Me
+
Me
Me
H
H
4a
1 : 1
35% overall
4b
Scheme 7. Conversion of 18 into the pre-target compound 4. a) Grignard
reagent prepared from 2-bromoethyl-1,3-dioxolane (3 equiv), THF,
708C !room temp.; b) 1,2-ethanediol, cat. p-TsOH, benzene, reflux
O
O
TMS
Me
Me
(
H2O), 24 h; c) Raney Ni (W4), 1 atm H2, EtOH, ultrasound, room
S
S
temp., 10 h, then reflux 3 d; d) 2n HCl, THF, 808C, 3 h.
H
S
S
18
19
however, the mixture could be directly employed for the
conversion to ptilocaulin. The high enantiomeric purity of our
material was further corroborated by comparison of the
O
a)
O
BrMg
b) H3O+
molecular rotation of 4a ([a]D20
ˆ
768 in CDCl3) with a
literature value reported for an enantioenriched sample of 4a
rac-18
rac-19
(92% ee) ([a]D ˆ 65 8 in CHCl3).[15]
74%
Scheme 6. Preparation of rac-19.
Preparation of ptilocaulin: Having synthesized the hydro-
indenones 4 (and also rac-4), the formal total synthesis of
ptilocaulin was already achieved, because this compound has
been converted to the target molecules before.[10,12±14] Never-
theless, we decided to complete the total synthesis with our
own material. Following the protocol of Snider,[10] a solution
of 4 in benzene was refluxed with guanidine under an
atmosphere of argon and with removal of water. After
protonation with dilute nitric acid, the reaction mixture
yielded a crude product consisting mainly of ptilocaulin
nitrate (1) and its C-3a-diastereomer 23[40] in a ratio of ca. 4:1
(Scheme 8). In the racemic series, pure rac-1 was obtained
after chromatography and double recrystallization from
ethanol/ether followed by recrystallization from methanol/
chloroform. An X-ray crystal structure analysis[41] of rac-1
relative configuration of rac-19 was assigned based on the
assumption that the approach of the nucleophile would occur
from the less hindered p-face as is the case in other conjugate
additions to 5-substituted cyclohexenones.[38] In addition, we
expected a trans orientation of the two side-chains to be
thermodynamically favored.
Treatment of rac-19 with commercially available Raney
nickel (W2 type) in ethanol did not result in the desired
desulfurization. In contrast, when Raney nickel W4[39] was
employed, the desulfurization was accompanied by over-
reduction of the enone functionality. We therefore decided to
perform the desulfurization at a later stage, that of 21, after
1,4-addition and protection of the carbonyl function as an
ethylene ketal. Best results were obtained when the desulfur-
ization (with the concomitant hydrogenation of the side-chain
double bond) was conducted under sonication in an ultra-
sound cleaning bath. The conversion of 18 to the hydro-
indenones 4 under the optimized conditions is shown in
Scheme 7. It is noteworthy that intermediates 20, 21, and 22
(all isolated as mixtures of diastereomers) were not purified.
At the end of this 4-step sequence, a mixture of 4a and 4b
(1:1) was obtained in 35% overall yield after purification. The
separation of these epimers was achieved by chromatography;
NH2 NO3
NH2 NO3
HN
NH
H
HN
NH
H
1. CH5N3
2. HNO3
Me
Me
+
4
Me
Me
H
H
1
23
Scheme 8. Preparation of ptilocaulin (1) and its C-3a epimer (23).
60
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(‡)-Ptilocaulin Synthesis
57±66
(Figure 2) confirmed the expected structure and revealed an
interesting pattern of hydrogen bonding between the guani-
dinium and the nitrate ions (Figure 3).
Figure 2. Structure of rac-1 in the crystalline state.
Figure 4. Structures of 1 (top) and 23 (bottom) in the crystalline state.
Figure 3. Ribbon of hydrogen bonds formed by rac-1 in the crystalline
state.
Figure 5. Helical chains formed by 1 (and 23) in the crystalline state.
In the optically active case, however, the crystallization of
the chromatographed mixture of 1 and 23 proved to be much
more difficult. In this case, cocrystallization of 1 and 23
occurred. While we did finally succeed in obtaining an
amorphous sample of almost pure (‡)-ptilocaulin (1) from
the mother liquor, clear single crystals formed only as a 2.4:1
mixture of 1 and 23. A crystal structure analysis[42] allowed the
separate structure determination of both components (Fig-
ure 4). Thus, for the first time the structure of the main side
product, which is always formed along with 1 (or rac-1) on
condensing the synthetic precursor with guanidine, was
unambiguously assignedÐin contrast to previous (tentative)
assignments which could not be confirmed.[10±14] The crystal
structure also shows the ion pair units arranged to helical
chains. Obviously, compared with the crystal structure of
racemic ptilocaulin nitrate, a different pattern of hydrogen
bonds is involved (Figure 5). In addition, the conformation of
the ptilocaulin molecule differs considerably from that found
in the case of rac-1.
On the hydrogen bonding in the solid-state structures of
ptilocaulin: In recent years, the question of how large
supramolecular structures assemble from smaller building
blocks by hydrogen bonding has become an important issue in
organic chemistry and crystal engineering.[43] Therefore, the
two completely different hydrogen-bond patterns found in the
crystal structures of 1 and rac-1 certainly deserve some special
attention.
In the case of ptilocaulin nitrate, two double hydrogen-
bonded ion pairs A and B (Figure 6) come into consideration
as monomeric building blocks for supramolecular networks.
Bearing in mind that N ± H ´´´ O bonds generally prefer a
colinear geometry and that the N ± O ´´´ H angle tends to be
around 1208, only a few types of dimers (such as C and D in
Figure 6) can be constructed which are suited to further
oligomerization into longer regular chains.
A closer look at the structure of rac-1 (Figure 3) shows that
each guanidinium group donates four hydrogen bonds to
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61

H. G. Schmalz et al.
FULL PAPER
chains (Figure 8), which formally result from polymerization
of dimers of type C. These chains are twisted into helices
(columns) in which the two diastereomeric monomers 1 and
23 contribute equally due to their very similar structures
(Figure 4).
O
O
O
O
N
O
N
O
H
N
H
N
H
N
H
N
N
H
N
H
H
H
H
H
H
H
Bu
Bu
Me
Me
H
H
O
O
O
O
O
O
O
O
N
O
N
O
N
O
N
O
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
N
H
N
H
N
H
N
H
A
B
H
H
H
H
H
H
H
H
H
H
H
H
Bu
Bu
Bu
Bu
O
O
O
O
N
O
N
H
H
H
N
H
N
N
H
O
Me
Me
Me
Me
H
H
H
H
H
H
H
H
N
N
N
H
Figure 8. Idealized hydrogen-bond pattern (single chain) of 1 in the crystalline state.
H
H
Bu
Bu
We believe that the two very different crystal structures
(based on the two very different hydrogen-bond patterns) of
racemic and nonracemic ptilocaulin nitrate are an impressive
example for the formation of completely different supra-
molecular networks from structurally closely related compo-
nents. While we are not able to give an explanation for the
observed phenomena, we consider guanidinium nitrate ion
pairs as ideal building material for rational crystal engineering
in the future.[44]
Me
Me
H
H
C
O
O
H
N
O
H
N
H
N
N
H
O
O
N
O
H
H
H
N
H
N
N
H
Bu
H
H
H
Bu
Me
H
Conclusion
Me
H
We have described a short and highly stereoselective total
synthesis of (‡)-ptilocaulin using a strategy which is centrally
based on the specific reactivity and chirality of [arene ±
Cr(CO)3] complexes. The synthesis starts from anisole and
leads to the nonracemic target compound (ꢀ 99% ee) in only
9 steps with ca. 5% overall yield. This demonstrates the power
and competitiveness of the underlying strategy. Compared to
previous syntheses of 1[12,15] or ent-1,[10,11] which rely either on
the use of chiral starting materials,[10,11] the resolution of a
racemic intermediate,[12] or the employment of a covalently
attached chiral auxiliary,[15] our synthesis is more efficient and
differs insofar as it does employ a chirogenic step[45] (8 !7)
which is performed in an enantioselective manner.
D
Figure 6. Possible monomeric (A and B) and (selected) dimeric ion pairs
(C and D) of ptilocaulin nitrate.
three different nitrate ions. Actually, dimers of type D
assemble to infinite parallel double chains as is apparent in
Figure 7. The resulting flat ribbons run in the crystallographic
b direction, which also corresponds to the needle direction of
the crystal. Interestingly, each ribbon is constructed exclu-
sively of homochiral units. Thus, both types of enantiomorphic
ribbons contribute equally to the overall crystal structure of
rac-1.
In contrast, a closer look at the solid-state structure of 1/
23 ˆ 2.4:1 (Figure 5) reveals the existence of infinite single
This work represents the first intermolecular application of
the Semmelhack cyclohexenone formation[22] in the context of
a total synthesis of a natural
product. We would like to em-
Me
Me
H
N
Me
H
N
Me
H
H
phasize that we would not have
found the rather special condi-
tions for this reaction without the
evolutionary pressure we were
exposed to as a result of our
desire to reach the target mole-
cule. Current efforts in our labo-
ratory are now directed towards
the further exploration of the
scope and limitations of the gen-
eral methodology of addition of
carbon nucleophiles to ortho-
substituted [anisole ± Cr(CO)3]
derivatives.
Bu
O
Bu
O
Bu
Bu
H
H
H
H
H
H
H
H
N
N
N
N
H
H
H
H
N
N
O
O
O
O
H
H
H
H
N
N
N
N
N
N
N
N
H
H
H
O
O
H
O
O
H
H
H
O
H
O
O
O
H
O
O
H
H
H
O
O
H
O
O
H
H
H
N
N
N
N
N
N
N
N
H
H
H
H
O
O
O
O
N
N
H
H
N
N
H
H
N
N
N
N
H
H
H
H
H
H
H
H
Bu
Bu
Bu
Bu
H
H
H
H
Me
Me
Me
Me
Figure 7. Idealized hydrogen-bond pattern (parallel double chain) formed by rac-1 in the crystalline state.
62
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0947-6539/98/0401-0062 $ 17.50+.50/0
Chem. Eur. J. 1998, 4, No. 1

(‡)-Ptilocaulin Synthesis
57±66
1458 (m), 1408 (m), 1262 (m), 844 (m), 666 (m) cm 1; 1H NMR (400 MHz,
CDCl3): d ˆ 0.31 (s, 9H), 3.73 (s, 3H), 4.79 (t, J ˆ 6 Hz, 1H), 4.97 (d, J ˆ
7 Hz, 1H), 5.57 (dd, J1 ˆ 6 Hz, J2 ˆ 1.5 Hz, 1H), 5.68 (ydt, Jt ˆ 6 Hz, Jd ˆ
1.5 Hz, 1H); 13C NMR (67.5 MHz, CDCl3): d ˆ 0.7 (q), 55.3 (q), 73.4 (d),
85.0 (d), 88.8 (s), 95.9 (d), 101.8 (d), 147.5 (s), 233.2 (s); MS (EI, 70 eV): m/z
(%) ˆ 316 (18), 260 (10), 232 (100), 201 (9), 187 (11), 180 (4), 135 (31),
52 (100); anal. calcd for C13H16O4Cr: C 49.39, H 5.10; found: C 49.26, H
5.14.
Experimental Section
All reactions involving [arene ± Cr(CO)3] complexes were carried out
under an atmosphere of argon by standard Schlenk and needle/syringe
techniques. Solvents were dried by standard methods. Anhydrous THF was
freshly distilled from sodium/benzophenone in an argon atmosphere.
Methyl tert-butyl ether is abbreviated as MTBE, diethyl ether as Et2O, and
di-n-butyl ether as n-Bu2O. Melting points were measured with a Büchi 510
apparatus and are uncorrected. FT-IR spectra were recorded with a Nicolet
Magna FT-IR spectrometer, usually with the ATR (attenuated total
reflectance) technique; abbreviations are: s, strong; m, medium; w, weak,
and br, broad. NMR spectra were recorded on a Bruker AM 270 or AM 400
spectrometer. NMR recordings were usually referenced to the CHCl3
resonances (d ˆ 7.26 and 77.0). 1H NMR: splitting pattern abbreviations
are: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; y,
pseudo. 13C NMR: multiplicities were determined by DEPT,[46] abbrevia-
tions are: q, CH3; t, CH2; d, CH; s, quaternary carbons. High resolution
mass spectra (HRMS) were obtained with a Varian MAT711 instrument
(70 eV). Elemental analyses were performed on a Perkin ± Elmer CHNO/
S-Analyser 2400II or a Heraeus CHN-Rapid instrument. Unless otherwise
indicated, optical rotations were measured in CHCl3 (freshly filtered
through ICN Aluminia B) on a Perkin ± Elmer 241 polarimeter at 208C.
Analytical thin-layer chromatography (TLC) was performed with Merck
Silica 60F254 glass plates; the chromatograms were visualized under
ultraviolet light and/or by staining with a cerium reagent (prepared by
dissolving 2 g of phosphomolybdic acid, 1 g cerium(iv) sulfate and 10 mL
conc. sulfuric acid in 90 mL H2O) followed by heating. Flash chromatog-
raphy[47] was performed on Merck Silica 60 (230 ± 400 mesh). Radial
chromatography was carried out on a Chromatotron (Harrison Research
Model 7924T) on glass plates coated with 1 ± 4 mm layers of silica
containing gypsum (Merck PF60F254).
[(1R)-h6-1-((E)-But-2-enyl)-2-methoxy-3-trimethylsilylbenzene] ± Cr(C-
O)3] (14): Following the general procedure of Semmelhack,[29] a stirred
solution of 7 (2.33 g, 7.365 mmol, ꢀ 99% ee) in THF (50 mL) was cooled to
608C and 5.06 mL (8.10 mmol) of a solution of n-butyllithium (1.6m in
hexane) was added dropwise. After 1 h at the same temperature, copper(i)
chloride (0.80 g, 8.08 mmol) was added all at once. The solution turned
greenish-black immediately and was stirred for 2 h while being warmed to a
final temperature of 108C before it was recooled to 708C, treated with
crotyl bromide (1.14 mL, 11.05 mmol), and allowed to warm to room
temperature over a period of 3 h. The mixture was then diluted with MTBE
(500 mL) and washed repeatedly with 2n HCl (150 mL portions) until the
aqueous layer no longer turned green. The organic layer was washed with
brine and dried over K2CO3. The solvent was removed in vacuo and the
crude, oily product was purified by flash chromatography (hexane/ethyl
acetate ˆ 10:1) to afford an oil, which was finally crystallized from hexane
(20 mL) at 188C to afford 14 (2.25 g, 83%) as orange-yellow crystals;
m.p. 55 ± 568C; [a] 2D0 ˆ 195 (c ˆ 0.45, CHCl3); FT-IR (KBr): 2955 (w), 2923
(w), 2854 (w), 1960 (s), 1883 (s), 1342 (w), 1250 (m), 1000 (w), 841 (m), 670
(m), 632 (m) cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 0.36 (s, 9H), 1,75 (dd,
J1 ˆ 6 Hz, J2 ˆ 1 Hz, 3H), 3.19 (d, J ˆ 6 Hz, 2H), 3.74 (s, 3H), 4.88 (t, J ˆ
6.5 Hz, 1H), 5.40 (dd, J1 ˆ 6.5 Hz, J2 ˆ 1.5 Hz, 1H), 5.50 ± 5.67 (m, 3H); 13
C
NMR (67.5 MHz, CDCl3): d ˆ 0.1 (q), 17.9 (q), 32.1 (t), 62.8 (q), 87.8 (d),
92.6 (s), 97.2 (d), 99.6 (d), 103.9 (s), 127.8 (d), 129.1 (d), 146.6 (s), 233.6 (s);
MS (EI, 70 eV): m/z (%) ˆ 370 (16), 286 (100), 254 (16), 234 (10), 189 (14),
89 (20), 59 (22), 52 (50); anal. calcd for C17H22O4CrSi: C 55.12, H 5.99;
found: C 55.11, H 6.04.
[h6-Anisole ± Cr(CO)3] (8): A 250 mL Schlenk-type reaction vessel equip-
ped with a magnetic stirring bar and a reflux condenser topped with a Hg
bubbler was flushed with argon and charged with anisole (18.9 g,
175 mmol), [Cr(CO)6] (7.70 g, 35 mmol), n-Bu2O (100 mL), n-heptane
(50 mL), and THF (15 mL). The whole apparatus was repeatedly briefly
evacuated and flushed with argon before the stirred mixture was refluxed
for 3 days (1458C oil-bath temperature). Subliming [Cr(CO)6] was occa-
sionally flushed back into the solution by interruption of the cooling water
flow. The reaction mixture was cooled and the solvents removed in vacuo.
The crude product was dissolved in ethyl acetate and filtered through a pad
of Celite. The solution was concentrated to a volume of 10 mL, and hexane
(50 mL) was added. Crystallization at 188C for 3 days afforded 7.59 g
(88%) of 8 as clear yellow crystals. Two subsequent crystallizations of the
concentrated mother liquors furnished an additional 0.79 g (10%) of 8,
m.p. 848C (ref. [26]: m.p. 83 ± 848C); FT-IR (KBR): 1961 (s), 1870 (s), 1532
(5S,6S)-6-((E)-But-2-enyl)-5-[1,3]-dithian-2-yl-2-trimethylsilylcyclohex-2-
enone (18): A solution of n-butyllithium (1.6m in hexane, 3.53 mL,
5.65 mmol) was added dropwise to a stirred solution of 1,3-dithiane
(0.68 g, 5.65 mmol) in THF (13.5 mL) and HMPT (8.9 mL, 51 mmol) at
608C. Stirring was continued for 2 h while the reaction mixture was
warmed to 408C. The yellow-brown solution was recooled to 608C and
a solution of 14 (1.90 g, 5.14 mmol) of THF (16.5 mL) was added dropwise
over a period of 10 min. The solution was allowed to warm to 208C over a
period of 3 h before it was recooled to 788C and TMSCl (8.9 mL,
51 mmol, freshly distilled from quinoline) was injected. Stirring was
continued overnight while the solution slowly warmed up to room
temperature. The mixture was then partitioned between 2n HCl (50 mL)
and MTBE, the green aqueous layer was separated and another 250 mL
portion of 2n HCl was added. This two-phase system was exposed to
sunlight until the organic layer turned completely colorless (fluffy
precipitates were occasional removed from the organic layer by shaking).
1
(m), 1470 (m), 1254 (m), 632 (m) cm 1; H NMR (400 MHz, CDCl3): d ˆ
3.71 (s, 3H), 4.88 (t, J ˆ 6.5 Hz, 1H), 5.13 (d, J ˆ 7 Hz, 2H), 5.55 (t, J ˆ
6.5 Hz, 2H); 13C NMR (67.5 MHz, CDCl3): d ˆ 55.5 (q), 78.1 (d), 85.6 (d),
95.1 (d), 143.3 (s), 233.1 (s); MS (EI, 70 eV): m/z (%) ˆ 244 (20), 188 (8),
160 (56), 108 (9), 52 (100); anal. calcd for C10H8O4Cr (244.17): C 49.19, H
3.30; found: C 49.21, H 3.31.
The two layers were separated and the organic layer was concentrated in
[49]
ˆ
vacuo. The residue (enol ether 16, R ˆ CH2CH CHCH3) was dissolved
in THF (30 mL) before 2n HCl (30 mL) was added and the stirred mixture
heated to 808C for 2 h. The mixture was diluted with MTBE and the layers
were separated. The organic layer was washed with saturated solutions of
NaHCO3 and NaCl and dried over MgSO4. After concentration in vacuo
1.8 g of a crude, solid product was obtained, which was separated by flash
chromatography (hexane/ethyl acetate ˆ 10:1, 200 g SiO2) to afford 18
(0.79 g, 45%) as a white crystalline solid. M.p. 1578C; [a] 2D0 ˆ 46 (c ˆ 0.4 in
[(1R)-(h6-1-Methoxy-2-trimethylsilylbenzene) ± Cr(CO)3] (7):
A stirred
solution of (S,S)-di-(1-phenylethyl)amine (608 mg, 2.70 mmol) in THF
(60 mL) was cooled to 708C, and a solution of n-butyllithium (1.6m in
hexane) was added dropwise.[48] After 45 min, the solution was cooled to
1008C. Under vigorous stirring TMSCl (1.86 mL, 14.7 mmol) and a
solution of 8 (600 mg, 2.46 mmol) in THF (5 mL) were injected consec-
utively and very rapidly. After 5 min the mixture was diluted with MTBE
and washed with 2n HCl (150 mL) (the hydrochloride of the chiral amine
precipitates out of this aqueous layer upon standing!). The organic layer
was washed with saturated aqueous NaHCO3 and brine and dried over
K2CO3. After flash chromatography (hexane/ethyl acetate ˆ 4:1) complex
7 (673 mg, 87%) was obtained as a greenish-yellow powder with 87 Æ 2%
ee (HPLC). A sample of 7 (82% ee, 3.40 g; combined product of several
experiments)[48] was recrystallized from hexane (250 mL) at 48C and later
CHCl3); TLC: hexane/ethyl acetate ˆ 10:1 (Rf ˆ 0.31); analyt. HPLC
1
(hexane/2-propanol ˆ 98:2, 0.6 mLmin
,
350 nm): t ˆ 8.9 min (>99%
ee); FT-IR (KBr): 2951 (w), 2930 (w), 2897 (w), 2858 (w), 1660 (s), 1593
(w), 1426 (w), 1355 (w), 1245 (m), 966 (w), 839 (m) cm
;
1H NMR
1
(400 MHz, CDCl3): d ˆ 0.10 (s, 9H), 1.60 (d, J ˆ 4.5 Hz, 3H), 2.03 ± 2.19 (m,
2H), 2.22 ± 2.34 (m, 2H), 2.51 (m, 1H), 2.69 ± 2.89 (m, 6H), 4.05 (d, J ˆ
9 Hz, 1H), 5.27 ± 5.40 (m, 2H), 6.99 (dd, J1 ˆ 5 Hz, J2 ˆ 3 Hz, 1H); 13C
NMR (100 MHz, CDCl3): d ˆ 1.5 (s), 17.8 (q), 25.8 (t), 28.3 (t), 29.3 (t),
29.7 (t), 29.8 (t), 40.6 (d), 48.6 (d), 49.2 (d), 127.0 (d), 127.8 (d), 140.5 (s),
154.5 (d), 203.9 (s); MS (EI, 70 eV): m/z (%) ˆ 340 (72), 325 (13), 302 (6),
283 (8), 265 (11), 221 (28), 179 (41), 172 (27), 119 (100), 106 (43), 75 (40), 73
(97); anal. calcd for C17H28OS2Si: C 59.95, H 8.29; found: C 59.50, H 8.22.
at 188C to afford 7 (2.38 g, 70%) with ꢀ 99% ee: m.p. 1088C; [a] D20
ˆ
236.8 (c ˆ 1.105, CHCl3); analyt. HPLC (Chiralcel OJ, hexane/2-prop-
anol ˆ 90:10; 0.8 mLmin 1): t1 ˆ 13.0, t2 ˆ 16.9 min; FT-IR (KBr): 3096 (w),
2985 (w), 2958 (w), 2901 (w), 1942 (s), 1885 (s), 1865 (s), 1842 (s), 1517 (m),
Chem. Eur. J. 1998, 4, No. 1
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0401-0063 $ 17.50+.25/0
63

H. G. Schmalz et al.
FULL PAPER
(5SR,6x)-5-[1,3]-Dithian-2-yl-6-methyl-2-trimethylsilylcyclohex-2-enone
(rac-17): Following the procedure described above for the preparation of
18, 1.50 g (4.55 mmol) of rac-13 were transformed to give 840 mg
(2.80 mmol, 62%) of rac-17 as a colorless solid. M.p. 988C (hexane);
TLC: hexane/ethyl acetate ˆ 10:1 (Rf ˆ 0.3); FT-IR (KBr): nĈ 2957 (m),
2917 (m), 2898 (m), 1652 (s), 1597 (w), 1343 (m), 1246 (m), 841 (s) cm 1; 1H
NMR (400 MHz, CDCl3): d ˆ 0.12 (s, 9H), 1.05 (d, J ˆ 7 Hz, 3H), 1.89 (m,
1H), 2.09 (m, 1H), 2.26 (ddd, J1 ˆ 20 Hz, J2 ˆ 10 Hz, J3 ˆ 2 Hz, 1H), 2.45
(ysept., J ˆ 4.5 Hz, 1H), 2.69 ± 2.91 (m, 6H), 4.00 (d, J ˆ 10 Hz, 1H), 7.06
(ydd, J1 ˆ 5 Hz, J2 ˆ 2 Hz, 1H); 13C NMR (67.5 MHz, CDCl3): d ˆ 0.7
(q), 10.3 (q), 25.9 (t), 28.3 (t), 29.7 (t), 29.8 (t), 41.1 (d), 42.9 (d), 49.3 (d),
140.2 (s), 155.5 (d), 205.1 (s); MS (EI, 70 eV): m/z (%) ˆ 300 (21), 285 (13),
211 (7), 181 (57), 165 (39), 119 (83), 73 (100); HRMS found 300.10378 as
calcd for C14H24OS2Si; anal. calcd for C14H24OS2Si: C 55.95, H 8.05; found:
C 55.93, H 8.04.
99 (22), 73 (100); HRMS calcd for C22H38O3S2Si 442.20317; found
442.2032.
This crude product (20) was dissolved in benzene (60 mL); 1,2-ethanediol
(2 mL) and a catalytic amount of p-toluenesulfonic acid were added. The
mixture was refluxed for 24 h under azeotropic removal of water (by means
of
a small pressure-equalizing addition funnel (25 mL) filled with
molecular sieves (4 Š), which was placed between the reaction flask and
the condenser). After cooling, the mixture was diluted with MTBE, washed
with satd. solutions of NaHCO3 and NaCl and dried over K2CO3. The
solvents were removed to afford 1.18 g of
a brown oil consisting
predominantly of compound 21. Selected data for 21: FT-IR (ATR): 2927
(s), 2891 (s), 2855 (m), 1731 (w), 1456 (m), 1247 (m), 1141 (s), 1036 (s), 969
(m) cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 3.8 ± 4.1 (m, 20H), 4.57 (d, J ˆ
11 Hz, 1H), 4.85 (m, 2H), 5.29 ± 5.69 (m, 4H); MS (EI, 70 eV): m/z (%) ˆ
414 (14), 370 (4), 352 (3), 295 (7), 258 (10), 233 (7), 199 (32), 145 (14), 119
(94), 99 (46), 81 (21), 73 (100), 55 (37); HRMS calcd for C21H34O4S2
414.1899; found 414.1887.
(5RS,6SR,7aSR)-5-((E)-But-2-enyl)-6-[1,3]-dithan-2-yl-1,2,5,6,7,7a-hexa-
hydroinden-4-one (rac-19): A 25 mL three-necked flask equipped with a
magnetic stirring bar, a thermometer, and a septum was charged with
magnesium (87 mg, 3.59 mmol) and THF (3 mL). After addition of a small
crystal of iodine, a few drops of a solution of 2-bromoethyl-1,3-dioxolane
(1 mL) in THF (4 mL) were added. The mixture was heated briefly until
sudden decolorization occurred. The temperature was then kept between
20 ± 258C by occasional cooling with a water bath while the rest of the
solution was added dropwise under gentle stirring over a period of 20 min.
The mixture was then stirred for 2 h at room temperature resulting in a
dark grey solution, which was cooled to 708C. Then a solution of
compound rac-18[50] (342 mg, 1.01 mmol) in THF (5 mL) was added
dropwise. The mixture was allowed to warm to room temperature
overnight (ca. 14 h). After addition of THF (5 mL) and 5% HCl (15 mL)
the vigorously stirred solution was heated under reflux for 4 h. The mixture
was then extracted several times with MTBE, and the combined organic
layers were washed with saturated solutions of NaHCO3 and NaCl and
dried with K2CO3. The crude product was purified by flash chromatog-
raphy (hexane/ethyl acetate ˆ 4:1) to yield 231 mg (0.749 mmol, 74%) of
the indanone rac-19 as a brownish resin contaminated with ca. 5% of a by-
product (diastereomer). TLC: hexane/ethyl acetate ˆ 10:1 (Rf ˆ 0.4); FT-
IR (ATR): 2932 (m), 2856 (m), 1714 (w), 1679 (m), 1612 (w), 1422 (w), 1275
(w), 1037 (w), 967 (w), 909 (w), 842 (w) cm 1; 1H NMR (400 MHz, CDCl3):
d ˆ 1.44 ± 1.62 (m, 2H), 1.64 (d, J ˆ 5.5 Hz, 3H), 1.78 ± 1.91 (m, 1H), 2.05 ±
2.50 (m, 8H), 2.74 ± 2.94 (m, 5H), 3.13 (m, 1H), 4.03 (d, J ˆ 9.5 Hz, 1H),
5.27 ± 5.38 (m, 1H), 5.41 ± 5.55 (m, 1H), 6.65 (yd, J ˆ 2 Hz, 1H); character-
istic signals of the diastereomer: d ˆ 4.27 (d) and 6.60 (d); 13C NMR
(67.5 MHz, CDCl3): d ˆ 17.9 (q), 25.9 (t), 28.9 (t), 30.6 (t), 30.7 (t), 32.0 (t),
33.6 (t), 35.0 (t), 40.9 (d), 41.8 (d), 50.7 (d), 51.6 (d), 127.9 (d), 128.0 (d),
139.6 (d), 143.6 (s), 200.7 (s); MS (EI, 70 eV): m/z (%) ˆ 308 (8), 281 (6),
251 (37), 233 (13), 201 (26), 189 (100), 172 (53), 145 (36), 119 (57), 107
(61), 95 (50), 41 (23); HRMS calcd for C17H24OS2 308.12686; found
308.1269.
The crude product (21) was dissolved in absolute ethanol (80 mL) and
treated with approx. 10 g of freshly prepared Raney Nickel W4. Under an
atmosphere of hydrogen the mixture was first treated with ultrasound
(cleaning bath) for 10 h and then refluxed for 3 days. The mixture was
filtered through a plug of Celite and concentrated in vacuo to afford 0.85 g
of a colorless, partially solidifying oil: GC-MS analysis showed three
isomers (one predominant) of compound 22 (m/z ˆ 313); FT-IR (ATR):
2952 (m), 2926 (m), 2872 (m), 1733 (w), 1456 (w), 1377 (w), 1128 (m), 1063
(m), 972 (w), 947 (w) cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 0.9 (br, 6H),
1.07 (d, 3H), 1.20 (d), 3.76 ± 4.02 (m, 16H), 4.84 (m, 2H); MS (EI, 70 eV):
m/z (%) ˆ 313 (7), 211 (58), 199 (16), 169 (40), 129 (21), 127 (31), 113 (17),
‡
99 (100), 73 (66), 55 (34); HRMS calcd for C18H33O4 [M‡H ] 313.2379;
found 313.2358.
This material (22) was dissolved in THF (30 mL) and treated with 30 mL of
2n HCl. The stirred mixture was heated to reflux for 3 h. It was then diluted
with Et2O, the layers were separated and the organic layer washed with sat.
solutions of NaHCO3 and NaCl and dried over Na2SO4. After removal of
the solvents in vacuo the crude product was purified by radial chromatog-
raphy (pentane/Et2O ˆ 10:1) affording 165 mg (0.81 mmol, 35%, from 18)
of a 1:1 mixture of the epimeric indenones 4a and 4b (contaminated with
max. 7% of an undesired epimer) as a colorless, volatile oil. This mixture
was employed for the synthesis of 1 (see below). For analytical purposes an
aliquot was separated by means of careful radial chromatography (pentane/
Et2O ˆ 10:1) to provide a pure sample of 4a and a sample of 4b that was
still slightly contaminated with some 4a and the third diastereomer. The
characteristic data of 4a and 4b given below are in good general agreement
with those described by Snider[10b] and Cossy et al.[15] Data for 4a: TLC:
pentane/Et2O ˆ 10:1 (Rf ˆ 0.29); [a] D20
ˆ
75.9 (c ˆ 0.81 in CDCl3, >99%
ee), ref. [15]: [a] D20
ˆ
65 (c ˆ 1.6 in CHCl3, 92% ee); FT-IR (ATR): 2955
(m), 2929 (m), 2871 (w), 2859 (w), 1682 (s), 1616 (m), 1460 (w), 1263 (m),
1243 (w), 979 (w), 914 (w); 1H NMR (400 MHz, CDCl3): d ˆ 0.89 (t, J ˆ
7 Hz, 3H), 1.05 (d, J ˆ 7 Hz, 3H), 1.30 (m, 4H), 1.40 ± 1.66 (m, 4H), 1.76 (m,
1H), 2.10 (m, 2H), 2.23 ± 2.54 (m, 3H), 3.07 (m, 1H), 6.54 (dd, J1 ˆ 5 Hz,
J2 ˆ 2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 14.0 (q), 20.2 (q), 22.6 (t),
29.6 (t), 32.0 (t, 2C), 33.4 (t), 33.7 (t), 34.0 (d), 40.8 (d), 55.8 (d), 137.9 (d),
144.1 (s), 204.0 (s); MS (EI, 70 eV): m/z (%) ˆ 206 (1), 191 (3), 163 (5), 150
(80), 135 (100), 121 (14), 107 (7), 93 (11), 79 (16), 67 (14), 55 (10); HRMS
calcd for C14H22O 206.1671; found 206.1664; Data for 4b: TLC: pentane/
Et2O ˆ 10:1 (Rf ˆ 0.34); FT-IR (ATR): 2955 (m), 2930 (m), 2871 (m), 2858
(m), 1685 (s), 1619 (m), 1456 (m), 1382 (w), 1233 (w), 1183 (w), 1161 (w),
(5x,6S,7aS)-5-Butyl-6-methyl-1,2,5,6,7,7a-hexahydroinden-4-one (4):
A
100 mL three-necked flask equipped with a magnetic stirring bar, a
thermometer, and a septum was charged with 170 mg (6.96 mmol) of
magnesium, a small, brown turning of magnesium corroded by subliming
iodine, and THF (7 mL). Under gentle stirring, 1 mL of a solution of 2-
bromoethyl-1,3-dioxolane (0.835 mL, 6.96 mmol) in THF (7 mL) was
added. The temperature was carefully kept between 20 ± 258C by occa-
sional cooling with a water bath while the rest of the solution was added
dropwise. The mixture was stirred for 2 h at room temperature resulting in
a dark grey solution, which was cooled to 708C. Then a solution of
compound 18 (790 mg, 2.32 mmol) in THF (14 mL) was added dropwise.
The mixture was allowed to warm steadily to room temp. overnight, diluted
with MTBE, washed with saturated solutions of NaHCO3 and NaCl and
dried with K2CO3. Removal of the solvents in vacuo afforded 1.28 g of a
crude product as a greenish-yellow oil that consisted predominantly of
compound 20, as determined by GC-MS analysis. Selected data for 20: FT-
IR (ATR): 2946 (m), 2889 (m), 1669 (s), 1422 (w), 1250 (m), 1142 (s),
1036 (m), 966 (m), 948 (m), 841 (s) cm 1; 1H NMR (400 MHz, CDCl3): d ˆ
2.69 ± 2.99 (m, 4H), 3.75 ± 3.87 (m, 2H), 3.89 ± 4.00 (m, 3H), 4.77 ± 4.89
(m, 1H), 5.27 ± 5.60 (m, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 1.3 (q),
17.9 (q), 34.4 (d), 37.4 (d), 49.2 (d), 50.0 (d), 51.2 (d), 64.76 (t), 64.83 (t),
104.1 (d), 104.4 (d), 126.6 (d), 128.3 (d), 211.8 (s); MS (EI, 70 eV): m/z
(%) ˆ 442 (6), 341 (7), 323 (19), 179 (14), 153 (12), 121 (24), 119 (95),
1
972 (w), 921 (w), 837 (w) cm 1; H NMR (400 MHz, CDCl3): d ˆ 0.88 (m,
6H), 1.22 ± 1.40 (m, 6H), 1.48 ± 1.63 (m, 2H), 1.84 ± 1.96 (m, 1H), 2.02 (m,
1H), 2.22 ± 2.48 (m, 4H), 3.08 (m, 1H), 6.42 (dd, J1 ˆ 5 Hz, J2 ˆ 2 Hz, 1H);
13C NMR (100 MHz, CDCl3): d ˆ 14.1 (q), 14.2 (q), 22.8 (t), 25.7 (t), 29.7 (t),
32.1 (t), 33.5 (d), 33.8 (t), 39.3 (t), 41.6 (d), 54.6 (d), 135.8 (d), 145.5 (s), 202.5
(s); MS (EI, 70 eV): identical to 4a; HRMS calcd for C14H22O 206.1671;
found 206.1682.
(‡)-Ptilocaulin (1): A 1m solution of guanidine was prepared by adding
6.105 g (50 mmol) of guanidine nitrate and 2.806 g (50 mmol) KOH to
anhydrous methanol (50 mL) under argon. The solution was stirred for 1 h.
An aliquot of 790 mL (0.79 mmol) of this solution was transferred to a two-
necked flask equipped with a magnetic stirring bar and a Dean ± Stark trap
(with a Hg bubbler on top of the reflux condenser). The methanol was
64
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(‡)-Ptilocaulin Synthesis
57±66
removed in vacuo and the apparatus was thoroughly flushed with argon.
Then a solution of the epimeric indenones 4 (105 mg, 0.509 mmol) in dry
benzene (40 mL) was added by syringe. The mixture was refluxed for 23 h
while the color turned to intense yellow and a white, fluffy precipitate was
formed. The mixture was cooled under argon and 4 mL of 1% nitric acid
was injected. The reaction mixture was diluted with CHCl3, and the
aqueous layer was separated and extracted three times with CHCl3. The
combined organic layers were concentrated in vacuo to afford 180 mg of a
dark brown oil, which was chromatographed on silica gel (CHCl3/
methanol ˆ 85:15) to afford 86 mg (0.277 mmol, 54%) of a white, foamy
solid that consisted of a 4:1 diastereomeric mixture containing (‡)-
ptilocaulin nitrate (1) as the major and 23 as the minor component. This
material was recrystallized twice from ethanol/Et2O and once from CHCl3/
methanol at 188C to afford some shiny colorless crystals which were
subjected to X-ray crystallographic investigation.[42] An amorphous solid
material which also separated from the mother liquors was (‡)-ptilocaulin
(1) of 90 ± 95% purity as estimated by 1H NMR. TLC: CHCl3/methanol ˆ
85:15 (Rf ˆ 0.33); m.p. 183 ± 1848C, ref. [16]: 183 ± 1858C, ref. [11a]: 183 ±
1848C; [a] 2D0 ˆ 99.0 (c ˆ 0.195 in MeOH), ref. [16]: [a] 2D0 ˆ 110 (c ˆ 0.44 in
1070; c) M. Uemura, in Advances in Metal Organic Chemistry,
Vol. 2 (Ed.: L. S. Liebeskind), JAI, London, 1989, pp. 195 ± 245.
[3] Selected recent work: a) S. G. Davies, T. Loveridge, J. M. Clough,
Synlett 1997, 66; b) A. Quattropani, G. Anderson, G. Bernardinelli,
E. P. Kündig, J. Am. Chem. Soc. 1997, 119, 4773; c) M. Brands, H. G.
Wey, J. Bruckmann, C. Krüger, H. Butenschön, Chem. Eur. J. 1996, 2,
182; d) K. Kamikawa, T. Watanabe, M. Uemura, J. Org. Chem. 1996,
61, 1375.
[4] M. Sodeoka, M.Shibasaki, Synthesis 1993, 643.
Â
[5] a) A. Solladie-Cavallo, in Advances in Metal Organic Chemistry,
Vol. 2 (Ed.: L. S. Liebeskind), JAI, London, 1989, pp. 99 ± 133; b) K.
Schlögl, in Organometallics in Organic Synthesis 2 (Eds.: H. Werner,
G. Erker), Springer, Berlin, Heidelberg, 1989, pp. 63 ± 77.
[6] a) C. Mukai, I. J. Kim, M. Hanaoka, Tetrahedron Lett. 1993, 34, 681;
b) C. Mukai, I. J. Kim, E. Furu, M. Hanaoka, Tetrahedron 1993, 49,
8323; c) C. Mukai, M. Miyakawa, M. Hanaoka, Synlett 1994, 165;
d) D. Schinzer, U. Abel, P. G. Jones, ibid. 1997, 632.
[7] a) H.-G. Schmalz, J. Hollander, M. Arnold, G. Dürner, Tetrahedron
Lett. 1993, 34, 6259; b) H.-G. Schmalz, M. Arnold, J. Hollander, J. W.
Bats, Angew. Chem. 1994, 106, 77; Angew. Chem. Int. Ed. Engl. 1994,
33, 109; c) H.-G. Schmalz, A. Schwarz, G. Dürner, Tetrahedron Lett.
1994, 35, 6861; d) H.-G. Schmalz, A. Majdalani, T. Geller, J. Hol-
lander, J. W. Bats, ibid. 1995, 36, 4777; e) H.-G. Schmalz, S. Siegel, A.
Schwarz, ibid. 1996, 37, 2947; f) A. Majdalani, H.-G. Schmalz, ibid.
1997, 38, 4545.
MeOH), ref. [11a]: [a] D20 ˆ 74.4 (99.5% MeOH), ref. [11a]: [a] 2D0
ˆ
73.9
(c ˆ 0.31 in 99.9% MeOH, for ent-1); FT-IR (KBr): 3371 (brs), 3217 (brs),
3086 (brs), 2941 (s), 2871 (s), 2857 (s), 1691 (s), 1677 (s), 1665 (s), 1618 (s),
1584 (m), 1411 (s), 1384 (s), 1372 (s), 1309 (s), 1280 (m), 1040 (m), 825
1
(w) cm 1; H NMR (400 MHz, CDCl3): d ˆ 0.89 (t, J ˆ 7 Hz, 3H), 1.05 (d,
J ˆ 7 Hz, 3H), 1.21 ± 1.74 (m, 8H), 1.95 ± 2.11 (m, 2H), 2.29 ± 2.45 (m, 3H),
2.49 (yt, 1H), 3.77 (m, 1H), 7.47 (brs, 2H), 8.35 (brd, 1H), 8.89 (brs, 1H);
these data are in good accordance to those given in the literature;[8,16] for a
full assignment of all signals, see ref. [16]; 13C NMR (100 MHz, CDCl3): d ˆ
14.0 (q), 19.5 (q), 22.4 (t), 24.6 (t), 26.7 (t), 27.6 (d), 29.5 (t), 32.2 (t), 33.9 (t),
36.5 (d), 53.2 (d), 121.0 (s), 127.0 (s), 151.7 (s); MS (EI, 70 eV): m/z (%) ˆ
247 (35), 232 (85), 218 (18), 204 (100), 190 (41), 174 (9), 148 (8), 69 (19), 55
(14), 43 (13); HRMS calcd for C15H25N3 247.2048; found 247.2041.
[8] G. C. Harbour, A. A. Thymiak, K. L. Rinehart, Jr., P. D. Shaw, R. G.
Hughes, Jr., S. A. Mizsak, J. H. Coats, G. E. Zurenko, L. H. Li,
S. L.Kuentzel, J. Am. Chem. Soc. 1981, 103, 5604.
[9] Harbour et al. (ref. [8]) mention a crystal structure of 1 which,
however, has never been published.
[10] a) B. B. Snider, W. C. Faith, Tetrahedron Lett. 1983, 24, 861; b) idem.,
J. Am. Chem. Soc. 1984, 106, 1443.
[11] a) W. R. Roush, A. E. Walts, J. Am. Chem. Soc. 1984, 106, 721;
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[14] A. Hassner, K. S. K. Murthy, Tetrahedron Lett. 1986, 27, 1407.
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[17] R. A. Barrow, L. M. Murray, T. K. Lim, R. J. Capon, Aust. J. Chem.
1996, 49, 767.
[18] Parts of this work were communicated in a preliminary form: a) H.-G.
Schmalz, K. Schellhaas, Angew. Chem. 1996, 108, 2277; Angew. Chem.
Int. Ed. Engl. 1996, 35, 2146; b) H.-G. Schmalz, K. Schellhaas,
Tetrahedron Lett. 1995, 36, 5511.
The NMR analysis of the clear crystals used for the X-ray crystallographic
investigation showed a 2.4:1 mixture of 1 and its diastereomer 23.[51] From
the spectra of this mixture the following characteristic data for 23 were
obtained: 1H NMR (600 MHz, CDCl3): d ˆ 0.90 (t, J ˆ 6.9 Hz, 3H), 1.01 (d,
J ˆ 7.1 Hz, 3H), 1.12 (dt, J1 ˆ 13 Hz, J2 ˆ 5 Hz, 1H), 1.86 (ypent, J ˆ 7 Hz,
1H), 2.55 (m, 1H), 3.13 (dt, J1 ˆ 11.6 Hz, J2 ˆ 5.3 Hz, 1H), 7.6 (br, 2H), 8.65
(brs, 1H), 9.04 (brs, 1H); 13C NMR (150 MHz, CDCl3): d ˆ 14.1, 18.8, 22.5,
27.1, 33.2, 35.4, 42.2, 55.2, 122.5, 125.6, 154.0.
( Æ )-Ptilocaulin (rac-1): Exactly as described above for the preparation of
1, a sample of rac-4 was treated with guanidine to give rac-1. In contrast to
the optically active series, crystallization of the chromatographed product
mixture provided a very pure sample of rac-1 from which one crystal was
taken for the X-ray crystallographic investigation.[41] M.p. 1648C (CHCl3/
MeOH), ref. [10b]: 165 ± 166.58C, ref. [13b]: 151 ± 1528C.
X-ray crystal structure analyses:[34,41,42] Crystallographic data (excluding
structure factors) for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC-100528. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge
CB21EZ, UK (Fax: Int. code ‡ 441223336-033; e-mail: deposit@ccdc.
cam.ac.uk).
[19] For reviews on nucleophilic additions to arene complexes, see:
a) M. F. Semmelhack, in Comprehensive Organic Synthesis, Vol. 4
(Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, p. 517;
b) M. F. Semmelhack, in Comprehensive Organometallic Chemistry
II, Vol. 12 (Eds.: E. W. Abel, F. G. A. Stone, G. Wilkinson), Pergamon,
NY, 1995, p. 979.
Acknowledgements: This work was supported by the Volkswagenstiftung
(Projekt I/69 907) and the Fonds der Chemischen Industrie (among other
things through a graduate scholarship award to K.S.). We thank Chemetall
and Degussa for generous gifts of chemicals and Dr. Andrea Schwarz for
her help in preparing this manuscript.
[20] a) M. F. Semmelhack, J. Bisaha, M. Czarny, J. Am. Chem. Soc. 1979,
101, 768; b) R. J. Card, W. S. Trahanovsky, J. Org. Chem. 1980, 45,
2560; c) J. P. Gilday, J. T. Negri, D. A. Widdowson, Tetrahedron 1989,
45, 4605; d) for a review, see: M. F. Semmelhack, in Comprehensive
Organometallic Chemistry II, Vol. 12 (Eds.: E. W. Abel, F. G. A.
Stone, G. Wilkinson), Pergamon, NY, 1995, p. 1017.
[21] a) D. A. Price, N. S. Simpkins, A. M. MacLeod, A. P. Watt, J. Org.
Chem. 1994, 59, 1961; b) idem., Tetrahedron Lett. 1994, 35, 6159;
c) H.-G. Schmalz, K. Schellhaas, Tetrahedron Lett. 1995, 36, 5515;
d) R. A. Ewin, A. M. MacLeod, D. A. Price, N. S. Simpkins, A. P.
Watt, J. Chem. Soc. Perkin Trans. 1 1997, 401 ± 415; for a review on
enantioselective deprotonation chemistry, see: e) P. J. Cox, N. S.
Simpkins, Tetrahedron Asymmetry 1991, 2, 1.
[22] a) M. F. Semmelhack, J. J. Harrison, Y. Thebtaranonth, J. Org. Chem.
1979, 44, 3275; b) M. F. Semmelhack, H. T. Hall, Jr., R. Farina, M.
Yoshifuji, G. Clark, T. Bargar, K. Hirotsu, J. Clardy, J. Am. Chem. Soc.
1979, 101, 3535; c) M.
Received: July 4, 1997 [F752]
[1] The first [arene ± Cr(CO)3] complexes were described in 1958: E. O.
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[2] For selected reviews, see: a) L. S. Hegedus, Transition Metals in the
Synthesis of Complex Organic Molecules, University Science Books,
Mill Valley, 1994, ch. 10; b) S. G. Davies, T. D. McCarthy, in
Comprehensive Organometallic Chemistry II, Vol. 12 (Eds.: E. W.
Abel, F. G. A. Stone, G. Wilkinson), Pergamon, NY, 1995, pp. 1039 ±