Enantiospecific syntheses of pseudopterosin aglycones - Part 1. Synthesis of the putative aglycone of pseudopterosin G-J via an A→AB→ABC annulation strategy

Article abstract of DOI:10.1039/b102960f

The putative aglycone of pseudopterosin G-J and its enantiomer were synthesised enantiospecifically from 2,3-dimethoxytoluene and η³-allyl cationic complexes of molybdenum and iron respectively. The A→AB→ABC annulation strategy entailed the use of allyl cations or their equivalents for the creation of the three benzylic stereogenic centres. The X-ray structure of tetrahydronaphthalene (-)-41a was determined.

Full text of DOI:10.1039/b102960f

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Enantiospecific syntheses of pseudopterosin aglycones. Part 1.
Synthesis of the putative aglycone of pseudopterosin G–J
via an A AB ABC annulation strategy
1
Robert Chow,a Philip J. Kocienski,*a Alexander Kuhl,b Jean-Yves LeBrazidec,b Kenneth Muirb
and Paul Fishc
a Department of Chemistry, Leeds University, Leeds, UK LS2 9JT
b Department of Chemistry, Glasgow University, Glasgow, UK G12 8QQ
c Pfizer Central Research, Sandwich, Kent, UK CT13 9NJ
Received (in Cambridge, UK) 2nd April 2001, Accepted 27th July 2001
First published as an Advance Article on the web 7th September 2001
The putative aglycone of pseudopterosin G–J and its enantiomer were synthesised enantiospecifically from
2,3-dimethoxytoluene and η3-allyl cationic complexes of molybdenum and iron respectively. The A AB ABC
annulation strategy entailed the use of allyl cations or their equivalents for the creation of the three benzylic
stereogenic centres. The X-ray structure of tetrahydronaphthalene (Ϫ)-41a was determined
pterosins.7 ‡ A noteworthy feature of the pseudopterosin family
Introduction
is the stereochemical variation in the hexahydro-1H-phenalene
core. Thus the first six members (A–F) of the family share the
same diterpene aglycone 5 whereas the next four (G–J) were
believed to be epimeric at C6 (i.e. structure 6). The aglycone 7
of pseudopterosins K and L, on the other hand, is enantiomeric
to that of A–F.
The anti-inflammatory and analgesic activity of the pseudo-
pterosins has been ascribed to the inhibition of eicosanoid
release. Experiments with pseudopterosins A and E led to the
conclusion that the ortho-quinone 8 derived from oxidation of
the aglycone 5 is the active agent. The glycosides are active in
mice and in whole cells, but in crude enzyme preparations, they
require the presence of fucosidase, suggesting that cleavage of
the sugar is required for activity.8,9
Gorgonian soft corals are abundant in the warm, nutrient-rich
reefs and shallow waters of the Caribbean Sea. Nature’s
largesse extends to the deeper waters too for it is there, at depths
of 35 meters or so, that the sea whip Pseudopterogorgia elisa-
bethae may be found. P. elisabethae attracted attention in 1982
when routine screening revealed the presence of cytotoxic
metabolites with antimicrobial activity. A subsequent mass
collection, extraction and fractionation of P. elisabethae led to
the isolation of the first four members of an extended family of
metabolites which were named the pseudopterosins.1,2 The most
abundant member of the family, pseudopterosin C underwent
extensive chemical and spectroscopic scrutiny and its struc-
ture was firmly established by X-ray crystallography. Further
study established that all four members of the family were
β-xylopyranosides of the same hexahydro-1H-phenalene core
as depicted in structures 1A–D (Scheme 1).
Pseudopterosin A revealed potent anti-inflammatory and
analgesic activity in vivo (see below) which stimulated the search
for further members of the family. Seco-pseudopterosins A–D
(2) isolated from Pseudopterogorgia kallos were identified as
β-arabinopyranosides with a common serrulatane core and
they too possessed notable anti-inflammatory activity.3 Then
in 1990 a further batch of 8 new pseudopterosins from
fresh extracts of P. elisabethae were isolated.4 Rodríguez and
co-workers5 isolated 4 unusual terpenes† with novel skeletons
related to the pseudopterosins from the same source and
recently a routine screen for antitubercular compounds from
extracts of P. elisabethae discovered pseudopteroxazole (3) and
seco-pseudopteroxazole (4).6 Pseudopteroxazole is a potent
growth inhibitor of Mycobacterium tuberculosis H37Rv whilst
seco-pseudopteroxazole shows moderate to strong inhibition.
Finally, the blue coral Heliopora coerulea produces diterpene
metabolites helioporins A–G closely related to the pseudo-
The biological activity and commercial potential10 of the
pseudopterosins stimulated a number of approaches to their
synthesis (Scheme 2). Total syntheses of pseudopterosins A and
E have been described11,12 but the bulk of the synthetic effort
has focused on the aglycone. Most of the strategies reported to
date begin with ring B in the form of the monoterpenes (ϩ)-
menthol (10),12 (Ϫ)-limonene (11),11,13 or (Ϫ)-isopulegol (12),14
followed by construction of the arene (ring A) and finally ring
C. One approach involves the same B BA BAC annulation
sequence in which the B ring is constructed from an acyclic
monoterpene precursor (Ϫ)-citronellal (13).15 Buszek and
Bixby began with (R)-(Ϫ)-2-phenylpropionic acid (14)16 in
which the stereogenic centre at C3 is fixed in the starting
material. Two further approaches depart from the common
path and follow an AB ABC annulation sequence.17,18 Both
of these approaches begin with a tetralone (15 or 16) and both
are essays in controlling benzylic stereochemistry. In addition
several approaches to the tricyclic ring system in varying
degrees of elaboration have been published.19–25 We now give
full details26 of a rare A AB ABC strategy towards pseudo-
pterosin G–J aglycone beginning with 2,3-dimethoxytoluene
which proves that the stereochemistry assigned to the natural
† The four metabolites, elisabethins A–C and elisabanolide, were
screened for biological activity. None of the compounds showed topical
anti-inflammatory activity but elisabethin B displayed antitumour
activity. Elisabethin C and elisabanolide showed modest antitubercular
activity.5
‡ Helioporins A and B were inactive in topical anti-inflammatory assays
but they exhibited activity against Herpes simplex type-1 virus whilst
helioporins C–G were cytotoxic towards murine P388 lymphomas.7
2344
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This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102960f

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Scheme 1
product is incorrect. In the accompanying paper we describe
syntheses of the enantiomeric pseudopterosin A–F and K–L
aglycones based on the B BA BAC annulation sequence.
Results and discussion
Plans and precedents
One of the major challenges posed by our adoption of an
A
AB ABC annulation strategy is that all four stereogenic
centres—three of them benzylic—reside in rings B and C; there-
fore all four would have to be created. In order to give our
strategy some coherence, we chose to create the three benzylic
stereogenic centres using allylic cations, or their equivalents, in
the sequence C6 then C13 and finally C1. An important con-
sequence of beginning with C6 is that in principle, all members
of the pseudopterosin family could be prepared from an enantio-
meric pair of reagents and greatest economy would be achieved
if that enantiomeric pair were created from a common starting
material. A sequence which satisfies the foregoing conditions is
depicted in Scheme 3. The salient feature of this sequence is the
use of the η3-allyl cationic complexes 19 and 20 whose reaction
with the metallated 2,3-dimethoxytoluene derivative 21 would
afford the enantiomers (R)-22 and (S)-22.
There is ample precedent for the preparation of the ester-
functionalised iron complex 20 from allyl alcohol precursor 18
with inversion of configuration and complex 20 is known to
react with nucleophiles with inversion of configuration.27,28 The
regiochemistry of the reaction is also well precedented.29–31
Scheme 2
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Scheme 3
However, the precedent is less secure in the case of the molyb-
denum complex 19. Whilst oxidative addition of Mo(0) to
unfunctionalised allyl alcohol derivatives is known to occur with
retention,32 the effect of the ester function on the reactivity of
substrate 18 was not known. Another cloud on the horizon
concerns the regiochemistry of the reaction of complex 19 with
21. Although the inversion of stereochemistry can be safely
anticipated,32,33 the factors governing regioselectivity are both
complex and difficult to control.34,35
Construction of the C6 stereogenic centre
Our first task was the synthesis of the functionalised planar
chiral η3-allylmolybdenum cationic complex 28 (Scheme 4)
which was to serve as the first allylic cation equivalent. Coming
as it does at the beginning of the synthesis it was essential that
an efficient and reliable method be secured using a readily avail-
able, enantiomerically pure starting material. We chose ethyl
(S)-lactate (23), one of the cheapest chiral pool precursors
currently available. It was transformed in three easy steps (71%
overall) to the known36 α,β-unsaturated ester 24 whereupon the
TBS group was replaced by a benzoate ester 26 via alcohol 25.
An extended investigation of various known sources of Mo(0)
for the oxidative addition was disappointing.37 Success was
eventually achieved by developing a new protocol involving a
combination of Mo(CO)4(Py)2,§ THF as solvent and benzoate
as leaving group. The desired oxidative addition took place
efficiently under mild conditions with clean retention of stereo-
chemistry. The resultant complex was then treated with lithium
cyclopentadienide to deliver the required neutral complex 27a,b
as a mixture of endo and exo rotamers (exo : endo = 6 : 1)38 in
88% overall yield. The rotamers were easily distinguished by
NMR spectroscopy.¶ Unlike the majority of the simple alkyl-
Scheme 4
substituted complexes we have prepared, complex 27a,b was
unstable and decomposed on standing.
Conversion of the neutral complex 27a,b to the electrophilic
η3-allyl cationic molybdenum complex was accomplished by
ligand exchange with nitrosonium tetrafluoroborate in aceto-
nitrile. The cationic complex, which is presumably a mixture
of four diastereosiomers 28a–d resulting from indiscriminate
ligand exchange on 27a,b, was generally used immediately
in the next step. Attempts to characterise the cationic complex
by NMR spectroscopy were hampered by its instability: even
1
in the short time required to record the H NMR spectrum,
decomposition occurred.
The nucleophilic partner in the first stage of the synthesis was
derived by metallation of commercial 2,3-dimethoxytoluene
(29, Scheme 5) with t-BuLi in the presence of TMEDA at room
temperature followed by iodination with 1,2-diiodoethane.
When s-BuLi was used as the base, metallation required 50 ЊC
in which case small amounts of inseparable by-products derived
from competing metallation–iodination of the aryl methyl
group were observed. The halogen–metal exchange on iodo-
arene 30 using n-BuLi followed by transmetallation with
§ Mo(CO)4(Py)2 is easily prepared and used in situ by simply heating
Mo(CO)6 with 2 equiv. of pyridine in THF for 12 h.
¶ The endo and exo rotamers equilibrate slowly at room temperature.
Equilibration of the η3-cyclooctenyl complex follows first-order kinet-
ics with a rate constant k1 = 2 × 10Ϫ4 sϪ1 (τ1/2 = 60 min) in acetonitrile at
25 ЊC.34 However, the presence of exo and endo isomers is of little con-
sequence since their rapid equilibration is catalysed by nucleophiles and
the exo rotamer reacts much faster than the endo rotamer.49,50
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addition (26
27a,b) would have to occur with retention of
configuration and the alkylation reaction (32 ϩ 28a–d
34)
with inversion. X-Ray crystallographic analysis of a subsequent
product [(Ϫ)-41a, see below] confirmed the validity of the
stereochemical assumptions for which, in any event, there was
ample precedent.32 Far less certain was the regiochemistry of
the alkylation which is governed by three effects acting in
opposition or reinforcement. Faller had shown that the stereo-
chemistry at molybdenum, or more importantly, the location of
the nitrosyl group, is a major determinant of the regiochemistry
of alkylation with soft nucleophiles.35 However, we had shown
that the electronic effect of the nitrosyl group could be sub-
verted by steric effects, at least in the case of organocopper()
nucleophiles.39,40 Finally, there is the electronic distortion
caused by the presence of the ester function which, in the
corresponding iron complexes (see below), is dominant.27,41
Given the complexity of the factors involved together with the
stereochemical ambiguity of the cationic complexes 28a–d, we
accepted the 1 : 6 ratio of regioisomers with grace if not with
gusto.**
Construction of ring B
Construction of ring B was achieved by an intramolecular
electrophilic aromatic substitution on the electron-rich dimeth-
oxyarene using a propargyl (prop-2-ynyl) cation as the electro-
phile. The requisite propargylic precursor was synthesised in
two steps from ester 36 (Scheme 6) by reduction with DIBAL-H
followed by addition of (trimethylsilyl)ethynylmagnesium
bromide to the aldehyde 37. Attempts to cyclise the alcohols 38
(1 : 1 mixture of diastereoisomers) or the corresponding acet-
ates with a variety of protic and Lewis acids were not fruitful:
many products were formed which were difficult to separate. In
order to tame the reactivity of the propargyl cation, the alkyne
was converted to its dicobalt hexacarbonyl complex 39 and
cyclisation induced by treatment with BF3ؒOEt2 at Ϫ20 ЊC.42
After oxidative decomplexation with ferric nitrate, the cyclis-
ation products 41a,b (a : b = 95 : 5) were obtained in 97% over-
all yield from propargylic alcohols 38 and the major diastereo-
isomer (ϩ)-41a purified by crystallisation from MeOH–H2O.
The absolute stereochemistry of (Ϫ)-41a and the cis-relation-
ship of the methyl and ethynyl substituents were ascertained by
X-ray crystallography (see below).
The stereoselectivity of the cyclisation can be rationalised in
terms of two competing pathways involving propargylic cations
40a and 40b. Both cations have a chair conformation for the
nascent ring and both place the bulky cobalt-complexed side
chain in the equatorial position. However A1,3-strain43
engendered by a steric clash between the methyl substituent at
C6 and the proximate methoxy group penalises cyclisation via
cation 40b.
Scheme 5
CuBrؒSMe2 afforded the arylcopper() reagent 32 to which was
added the freshly prepared η3-allyl cationic molybdenum com-
plex 28a–d to give first the η2-complexes 33 and 34. Oxidative
demetallation with ceric ammonium nitrate (CAN) then gave
the alkylation products 35 and (R)-22 (72% yield) in a ratio of
1 : 6 in favour of the desired isomer (R)-22. The alkylation
products were not separable but treatment of the mixture with
magnesium (10 equiv.) in MeOH at 0 ЊC, smoothly reduced the
α,β-unsaturated isomer (R)-22 to the saturated compound 36
which was then separated from the unwanted isomer 35 by
column chromatography.
The stereochemistry and regiochemistry of the alkylation
reaction deserves comment. At this stage of the synthesis we
were not certain of the stereochemistry of 36 though reduction
with lithium aluminium hydride followed by derivatisation as
the Mosher ester established the er of the product as 97 : 3.|| In
order for the stereochemistry of 36 to be (R), the oxidative
Construction of ring C
Before construction of ring C could begin in earnest, it was
necessary to elaborate the ethynyl chain and install the stereo-
genic centre at C3 (Scheme 7). The sequence began with the
hydroboration–oxidation of silylalkyne 41a to release the latent
acetic acid side chain in 42. The yield was excellent (97%) and as
a bonus, the product 42 was crystalline. Esterification of 42 with
iodomethane using tetramethylguanidine as base returned the
ester 43 (93%). Introduction of the C3 stereogenic centre was
easily accomplished by alkylation of the lithium enolate of ester
43 with iodomethane. The yield (95%) and diastereoselectivity
(10 : 1) of the alkylation were optimum when the reaction was
conducted at Ϫ45 ЊC. The diastereoisomers of 44 were not
|| The diastereoisomeric Mosher ester derivatives prepared from ( )-
36 gave singlets in the 19F NMR spectrum at δF Ϫ72.0077 and
Ϫ72.00332.
** We recently discovered that the isopropyl ester corresponding to the
cationic η3-allylmolybdenum complex 28a–d gave an improved ratio
(5 : 95) of adducts derived from reaction with arylcopper() reagent 32.
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Scheme 7
Scheme 6
separable but the corresponding alcohols 45 derived by reduc-
tion with lithium aluminium hydride were separable by
column chromatography. However, diastereoisomeric purity
was best achieved at the final step in the sequence by simple
crystallisation of the tosylate 46. The overall yield for the 5-step
conversion of silylalkyne 41a to the tosylate 46 was 75%.
The good level of substrate control in the alkylation reaction
can be rationalised using the model depicted in Scheme 8. The
desired (R)-stereochemistry is a consequence of alkylation
taking place selectively from the less hindered Re-face of the
enolate 47 in which the C13–H bond resides in the plane of
the enolate in order to minimise A1,3-strain.
To complete the synthesis (Scheme 9), nucleophilic displace-
ment of the tosylate 46 with 4 equiv. of the lithium derivative
3,3-dimethylallyl p-tolyl sulfone (48) gave a 92% yield of the
alkylation product 49 as a 1 : 1 mixture of diastereoisomers.
The lack of stereocontrol in the alkylation was of no practical
consequence since treatment of the mixture with 2 equiv. of
ethylaluminium dichloride at Ϫ40 ЊC resulted in rapid and
clean cyclisation44 to give the tricyclic aglycone dimethyl ethers
50a,b in 88% yield as a mixture of diastereoisomers in favour
of the desired (1R) stereochemistry (a : b = 5 : 95). The relative
configuration of pure (ϩ)-50b obtained by crystallisation
from methanol was identical by a single crystal X-ray crys-
Scheme 8
tallographic analysis to that reported for pseudopterosin G–J
aglycone.††
The stereochemistry of the final cyclisation can be rational-
ised by assuming that both diastereoisomeric sulfones converge
to the same allylic cation 51. Electrophilic attack of the allyl
cation on the arene ring then occurs via a chair conform-
ation which places the alkene substituent in an axial position
in order to avoid A1,3-strain with the aryl methyl group. Evi-
dence that the cyclisation occurred under kinetic control was
obtained by treating mixtures of 50a,b enriched in 50a with
camphorsulfonic acid or ethylaluminium dichloride under the
same conditions used for the cyclisation. In neither case was
isomerisation to 50b observed.
A comparison of ꢀ-allyl cationic complexes of molybdenum and
iron
In order to gauge the value of the molybdenum complex 28
†† The X-ray analysis was determined on the enantiomer, (Ϫ)-50b.26 The
enantiomeric relation between (Ϫ)-50b and (ϩ)-50b was ascertained by
optical rotation, mp and 1H and 13C NMR spectroscopy.
2348
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in relation to its iron counterpart, we synthesised putative
pseudopterosin G aglycone dimethyl ether using complex 53
which we prepared (Scheme 10) by a slight modification of the
route described by Enders and co-workers.27 The (S)-allylic
TBS ether derivative 24 used in the molybdenum series
described above was treated with 1 equiv. of diiron nonacarbo-
nyl in ether to give an intermediate η2-complex 52 which was
treated with fluoroboric acid in Et2O to afford the complex 53
as a yellow powder in 80% yield. Addition of iron complex 53
to a solution of arylcopper 32‡‡ in THF gave (S)-22 in 68%
yield after oxidative decomplexation with CAN. Thus the yields
of the two series are comparable (cf. 72% for the Mo series) as
are the enantiomeric ratios but the iron series—devoid of the
complication of central chirality at the metal—gave a single
regioisomer whereas the Mo series gave a 1 : 6 mixture.
Ester (S)-22 was converted to the crystalline silylalkyne (Ϫ)-
41a whose absolute configuration (X-ray crystallography)
established conclusively that the Fe and Mo routes were stereo-
complementary. Thus, substitution of the (S)-allylic TBS
ether 24 via the Mo cationic complex 28 occurred with overall
inversion to produce (R)-22 whereas the analogous chemistry
on (S)-allylic TBS ether 24 via the Fe cationic complex 53
occurred with overall retention to produce (S)-22. Finally, an
X-ray structure of the enantiomer of putative pseudopterosin G
aglycone dimethyl ether [(Ϫ)-50b], derived from (Ϫ)-41a by the
chemistry described above, proved the relative configuration of
the 4 stereogenic centres.
The correct stereochemistry of pseudopterosin G–J aglycone is
revealed
1
The H and 13C NMR spectroscopic data for compound (Ϫ)-
50b and those reported2,4 for pseudopterosin G and its aglycone
are very similar with the exception of the signals for carbons
3 and 4. Compound (Ϫ)-50b gives signals at δ 29.7 (C3) and
22.6 (C4) whereas the corresponding signals for pseudopterosin
G appear at δ 34.2 and 27.6 and for the aglycone at δ 34.1
and 27.8 respectively. On the basis of these data, we suggested
that the stereochemistry originally assigned to pseudopterosin
G may require revision.26 At the same time, Schmalz and co-
workers45–47 proved that the stereochemistry originally assigned
to the closely related helioporin D7 was also incorrect by total
synthesis. Corey and co-workers48 recently proved that the cor-
rect stereochemistry for helioporin E and pseudopterosin G–J
aglycone is depicted by structures 54 and 55 respectively.
Scheme 9
‡‡ Zinc cuprates add to the related (η3-allyl)iron tetracarbonyl complex
56 to give the adducts 57 with excellent regio- and stereo-control after
oxidative decomplexation.41,51
The arylzinc cuprate 21 [M = Cu(CN)ZnI] and the corresponding
arylcopper() reagent 32 give comparable yields in the reaction with
both the molybdenum complex 28a–d and the iron complex 54 but 32 is
easier to prepare.
Scheme 10
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with Et2O (2 × 15 ml). The combined organic layers were
washed with brine (20 ml), dried over MgSO4, and concentrated
in vacuo. The pale yellow residue was purified by column chro-
matography (SiO2, hexanes–Et2O, 4 : 1) to afford the diester 26
(2.48 g, 9.99 mmol, 96%) as a colourless oil: [α]2D1 = ϩ61.7 (c, 1.5
in CHCl3); νmax film/cmϪ1 2982 s, 1715 m, 1662 s, 1601 s, 1451 s,
1268 m, 1178 s, 1111 m, 976 s, 869 s, 711 s; δH (400 MHz,
CDCl3): 8.08 (2H, dd, J 7.6, 1.4), 7.58 (1H, dt, J 7.7, 1.4), 7.47
(2H, ddd J 7.6, 7.6, 1.6), 7.00 (1H, dd, J 15.8, 4.9, C3H), 6.05
(1H, dd, J 15.8, 1.6, C2H), 5.76 (1H, ddq, J 6.6, 4.9, 1.6, C4H),
4.20 (2H, q, J 7.1, CH2CH3), 1.50 (3H, d, J 6.7, C5H3), 1.34
(3H, t, J 7.1, CH3CH2); δC (100 MHz, CDCl3): 166.04 (0, C1),
165.43 (0, C6), 146.34 (1, C2), 133.22 (1, phenyl), 130.00 (0,
C7), 129.68 (1, 2C, phenyl), 128.46 (1, 2C, phenyl), 121.12 (1,
Conclusions
The A AB ABC annulation strategy produced putative
pseudopterosin G aglycone dimethyl ether in 16% overall yield
for the longest linear sequence of 13 steps from commercial 2,3-
dimethoxytoluene. A salient feature of the synthesis was the use
of planar chiral η3-allylmolybdenum cationic complex 28 bear-
ing an electron withdrawing ester group to control the stereo-
chemistry at C6. Such complexes are rare§§ and our discovery of
convenient and mild conditions for the preparation of neutral
η3-allylmolybdenum precursors from allyl benzoates using
Mo(CO)4(Py)2 opens a path to other functionalised η3-allyl
molybdenum cationic complexes of promising synthetic utility.
Another noteworthy feature of our synthesis was the economy
of means: all three bonds appended to the aromatic ring were
created using allyl cations or their equivalents and the creation
of the three stereogenic centres at C1, C3 and C13 was gov-
erned by the minimisation of A1,3-strain. Moreover, once
the stereogenic centre at C6 was created, the remaining three
stereogenic centres were constructed by substrate controlled
reactions.
C3), 69.41 (1, C4), 60.60 (2, OCH2CH3), 19.78 (3, OCH2CH3),
ϩ
14.24 (3, C5); m/z (EI) 248 (Mϩ , 5%), 127 (M Ϫ O, 20), 105
ؒ
ؒ
(C6H5COϩ, 100); Found Mϩ , 248.1050; C14H16O4 requires M,
ؒ
248.1049.
syn,syn-Dicarbonyl-ꢁ5-cyclopentadienyl-[2,3,4-ꢁ-(2R,3S,4S)-1-
ethoxy-1-oxopent-2-enyl]molybdenum (27a,b)
Molybdenum hexacarbonyl (0.81 g, 3.0 mmol) was placed
under nitrogen in a two-necked flask equipped with condenser,
and THF (35 ml) was added. The molybdenum hexacarbonyl
was dissolved by stirring and refluxing (oil bath, ∼110 ЊC) and
after 30 min, pyridine (0.5 ml, 6.0 mmol) was added to the
bright yellow solution. The reaction mixture was refluxed for 12
h, during which an intense orange–red solution developed, and
neat benzoate (0.71 g, 0.65 ml, 2.85 mmol) was added dropwise
to the refluxing reaction mixture. After 72 h, the reaction mix-
ture was cooled to rt, and a solution of LiCp [freshly prepared
with cyclopentadiene (0.28 ml, 3.3 mmol) and n-BuLi (2.32 M
in hexanes, 1.36 ml, 3.15 mmol)] in THF (4 ml) was added,
and allowed to stir for 1 h. The resulting golden mixture was
partially concentrated in vacuo, and then chromatographed
under nitrogen using degassed eluents (alumina, hexanes–
Et2O, 50 : 50 0 : 100) to afford the molybdenum complex
(0.86 g, 2.5 mmol, 88%) as an air/moisture sensitive orange–
yellow oil: νmax film/cmϪ1 3110 s, 2980 s, 1956 s, 1877 s, 1695 s,
1511 s, 1455 m, 1402 s, 1252 s, 1152 s, 1029 m, 813 s, 764 s; δMo
(13.043 MHz, C6D6): Ϫ1576 (27a, 77%, exo,syn,syn), Ϫ1388
(27b, 13%, endosyn,syn), and two minor products at Ϫ1517
(8%, possibly the ,exo,anti,syn isomer) and Ϫ1571 (2%, possibly
the endo,anti,syn isomer); δH (400 MHz, C6D6, data only for
27a): 4.81 (5H, s, Cp), 4.69 (1H, dd, J 9.3, 9.3, C3H), 3.96–4.14
(2H, m, CH2CH3), 1.63–1.71 (1H, m, C3H), 1.60 (1H, d, J 9.3,
C2H), 1.45 (3H, d, J 6.3, C5H3), 1.08 (3H, d, J 7.1, CH3CH2);
δC (100 MHz, C6D6, data only for exo,syn,syn-isomer): 240.03
(0, CO), 236.91 (0, CO), 174.81 (0, C1), 94.03 (5C, d, Cp), 74.03
Experimental
General aspects
1H and 13C NMR spectra were recorded in Fourier Transform
mode at the field strength specified. All spectra were obtained in
CDCl3 or C6D6 solution in 5 mm diameter tubes, and the chem-
ical shift in ppm is quoted relative to the residual signals of
chloroform (δH 7.27, δC 77.2) or C6H6 (δH 7.10, δC 126.7) as the
internal standard unless otherwise specified. Multiplicities in
1
the H NMR spectra are described as: s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet and br = broad. Coupling
constants (J) are reported in Hz. Numbers in parenthesis
following the chemical shift in the 13C NMR spectra refer to the
number of protons attached to that carbon as revealed by the
Distortionless Enhancement by Phase Transfer (DEPT) spec-
tral editing technique, with secondary pulses at 90Њ and 135Њ.
Signal assignments were based on COSY, HMQC and HMBC
correlations. Pseudopterosin numbering (structure 9, Scheme 2)
was used throughout in assigning NMR signals. Low and high
resolution mass spectra were run on a JEOL MStation JMS-
700 spectrometer. Ion mass/charge (m/z) ratios are reported as
values in atomic mass units followed, in parenthesis, by the peak
intensity relative to the base peak (100%). Mass spectra were
recorded on samples judged to be ≥95% pure by H and 13C
1
NMR spectroscopy unless otherwise stated. Optical rotations
were measured on an Optical Activity AA-100 instrument at
room temperature and are given in 10Ϫ1 deg cm2 gϪ1
.
(1, C4), 62.51 (1, C3), 60.25 (2 CH2CH3), 42.87 (1, C2), 20.78
98
(3, C5), 14.58 (3, CH3CH2); m/z (EI) 346 [Mϩ ( Mo), 10%],
ؒ
Ethyl (E,S)-4-benzoyloxypent-2-enoate (26)
ϩ
ϩ
318 (Mϩ Ϫ CO, 10%), 290 (M Ϫ 2CO, 13%); Found M
,
ؒ
ؒ
ؒ
To a solution of hydroxy ester 2536 (1.50 g, 10.40 mmol) in
CH2Cl2, at 0 ЊC, were added successively DMAP (60 mg, 0.52
mmol), triethylamine (2.2 ml, 15.80 mmol), and finally benzoyl
chloride (1.3 ml, 11.44 mmol). The reaction mixture was
allowed to warm to rt and stirred for 5 h whereupon it was
diluted with CH2Cl2 (30 ml) and shaken with water (20 ml). The
resulting mixture was separated and the aqueous layer extracted
346.0106; C14H1698MoO4 requires M, 346.0106.
1-Iodo-2,3-dimethoxy-4-methylbenzene (30)
To a solution of 2,3-dimethoxytoluene 29 (5.26 g, 34.6 mmol)
and TMEDA (1.2 ml, 8 mmol) in hexane (60 ml), at rt, was
added dropwise t-BuLi (1.75 M in pentane, 20.7 ml, 36 mmol).
The resulting cloudy yellow solution was stirred at rt for 8 h
and then cooled to 0 ЊC whereupon 1,2-diiodoethane (10.23 g,
36 mmol) was added portionwise. The resulting slurry was
allowed to warm to rt over 2 h, and then diluted with hexanes
(50 ml) and washed with HCl (2 M, 20 ml), sat. aq. NaHCO3
solution (20 ml), dried over MgSO4, and concentrated in vacuo.
The yellow residue was purified by column chromatography
(SiO2, hexanes–Et2O 98 : 2) to give the iodoarene 30 (7.18 g,
25.8 mmol, 75%) as a colourless oil: νmax film/cmϪ1 2937 s, 1581
m, 1477 s, 1407 s, 1287 s, 1143 s, 1063 s, 1013 s, 928 m, 854 s, 809
s; δH (400 MHz, CDCl3): 7.38 (1H, d, J 8.1, C5H), 6.69 (1H, d,
§§ Liebeskind and co-workers52 reported the preparation of complex 58
and its regio- and stereo-selective reaction with cyanocuprates.
2350
J. Chem. Soc., Perkin Trans. 1, 2001, 2344–2355

View Article Online
J 8.1, C6H), 3.86 (3H, s, OMe), 3.84 (3H, s, OMe), 2.24 (3H, s,
C7H3); δC (100 MHz, CDCl3): 152.97, 151.78 (0, C2, C3),
133.41, 127.90 (1, C5, C6), 126.33 (0, C4), 88.96 (0, C1), 60.56,
60.39 (3, 2 × OMe), 15.83 (3, C7).
aldehyde 37 (1.93 g, 8.2 mmol, 85%) as a colourless oil: [α]1D8
Ϫ7.2 (c 1.2, CHCl3); νmax film/cmϪ1 2967 s, 1732 s, 1464 s, 1411 s,
1285 s, 1222 s, 1075 s, 1033 s; δH (400 MHz, CDCl3): 9.69 (1H, t,
J 1.6, C13H), 6.88 (1H, d, J 7.9, C11H), 6.81 (1H, d, J 7.9,
C10H), 3.83 (3H, s, OMe), 3.82 (3H, s, OMe), 3.11–3.20 (1H,
m, C6H), 2.30–2.39 (2H, m, C4H2), 2.25 (3H, s, C20H3), 1.85–
1.94 (2H, m, C5H2), 1.24 (3H, d, J 7.0, C19H3); δC (100 MHz,
CDCl3): 202.77 (1, C13), 151.54, 151.07 (0, C7, C8), 137.73,
130.21 (0, C9, C12), 126.00, 121.49 (1, C10, C11), 60.83, 60.08
(3, 2 × OMe), 42.48 (2, C4), 31.67 (1, C6), 30.05 (2, C5), 21.99
Ethyl (R)-4-(2,3-dimethoxy-4-methylphenyl)pentanoate (36)
To a solution of 1-iodo-2,3-dimethoxy-4-methylbenzene 30
(2.46 g, 8.84 mmol) in THF (40 ml) at Ϫ78 ЊC, was added
dropwise BuLi (2.32 M in hexane, 4.2 ml, 9.72 mmol). After 15
min, to the resulting pale yellow solution was added dropwise a
solution of CuBrؒSMe2 in diisopropyl sulfide (2 ml) and THF
(2 ml) maintaining the temperature below Ϫ75 ЊC. The mixture
was stirred at Ϫ78 ЊC for 45 min before cooling to Ϫ90 ЊC and
addition of a solution of cationic molybdenum complex 28a–d
[prepared freshly from neutral complex 27a,b (2.34 g, 6.80
mmol) and NOBF4 (0.83 g, 7.14 mmol) in acetonitrile (5 ml)].
The resulting brown reaction mixture was stirred at Ϫ78 ЊC for
1 h before addition of NH4OH (20 ml) and saturated aqueous
NH4Cl solution (20 ml). After warming to rt the phases were
separated and the aqueous layer was extracted with Et2O
(3 × 15 ml). The combined organic layers were washed with
brine (20 ml), dried over MgSO4 and concentrated in vacuo. The
orange coloured residue was dissolved in THF (20 ml) and Et2O
(5 ml) and at 0 ЊC, an aqueous solution of ceric ammonium
nitrate (1 M, 20 ml) was added. The resulting brown mixture
was stirred at rt for 30 min, when TLC showed that decomplex-
ation was complete, whereupon the mixture was diluted with
Et2O (25 ml) and washed with water (30 ml). The aqueous layer
was extracted with Et2O (3 × 10 ml) and the combined extracts
were washed with brine (20 ml), dried over MgSO4 and con-
centrated in vacuo. The red residue was purified by column
chromatography (SiO2, hexanes–Et2O 90 : 10) to afford an
inseparable mixture of regioisomers 35 and (R)-22 (1 : 6)
(1.37 g, 4.92 mmol, 72%) as a colourless oil.
(3, C19), 15.84 (3, C20); m/z (EI) 236 (Mϩ , 20%), 192 (25), 179
ؒ
(100), 164 (35), 149 (12), 91 (14); Found: C, 70.41; H, 8.67%.
C14H20O3 (M = 236) requires C, 71.16; H, 8.53.
(3RS,6R)-6-(2,3-Dimethoxy-4-methylphenyl)-1-trimethylsilyl-
hept-1-yn-3-ol (38)
To a solution of trimethylsilylacetylene (1.70 ml, 12.0 mmol) in
THF (30 ml) at 0 ЊC was added dropwise EtMgBr (1.40 M in
THF, 7.4 ml, 10.4 mmol). The resulting pale yellow solution
was slowly warmed to rt within 1 h, and then cooled to 0 ЊC
before adding a solution of aldehyde 37 (1.90 g, 8.0 mmol) in
THF (15 ml). After 20 min, the reaction mixture was quenched
with water (15 ml). The resulting layers were separated, and the
aqueous layer was extracted with Et2O (3 × 20 ml). The com-
bined organic layers were washed with brine (30 ml), dried over
MgSO4, and concentrated in vacuo. The yellow residue was
purified by column chromatography (SiO2, hexanes–Et2O
75 : 25) to afford the desired propargylic alcohol 38 (2.42 g, 7.2
mmol, 90%) as a mixture of diastereoisomers (1 : 1): νmax film/
cmϪ1 3450 s, 2967 s, 2168 s, 1464 s, 1412 s, 1280 s, 1222 s, 1065 s,
1023 s, 849 s; δH (400 MHz, CDCl3): 6.88 (1H, d, J 8.0, C11H),
6.83 (1H, d, J 8.0, C10H), 4.31–4.37 (1H, m, C13H), 3.85 (3H,
s, OMe), 3.83 (3H, s, OMe), 3.13–3.20 (1H, m, C6H), 2.25 (3H,
s, C20H3), 1.94 (1H, d, J 5.6, OH), 1.54–1.76 (4H, m, C4H2,
C5H2), 1.23 (0.5 × 3H, d, J 6.9, C19H3), 1.22 (0.5 × 3H, d,
J 6.9, C19H3), 0.17 (9H, s, SiMe3); δC (100 MHz, CDCl3):
151.45, 150.92 (0, C7, C8), 138.74, 129.80 (0, C9, C12), 125.92,
121.52 (1, C10, C11), 107.07 (0, C2), 89.40 (0, C3), 63.13, 63.03
(1, C13), 60.88, 60.08 (3, 2 × OMe), 36.18, 36.05 (2, C5), 33.40,
33.10 (2, C4), 31.77, 31.74 (1, C6), 22.30, 22.24 (3, C19), 15.82
To a mixture of esters 35 and (R)-22 (1.52 g, 5.45 mmol) in
methanol (30 ml), at 0 ЊC was added magnesium turnings (1.34
g, 55 mmol). The reaction mixture was allowed to stir at 0 ЊC
for 7 h and then diluted with hexanes (40 ml) and Et2O (40 ml),
and then filtered through Celite. The filtrate was washed with
HCl (2 M, 15 ml), sat. aq. NaHCO3 solution (10 ml), dried over
MgSO4, and concentrated in vacuo. The yellow residue was
purified by column chromatography (SiO2, hexanes–Et2O
85 : 15) to give methyl ester 36 (1.06 g, 4.0 mmol, 87%) as a
colourless oil and the unchanged regioisomer 35 (0.12 g, 0.43
mmol, cis : trans = 1 : 5). Data were collected for 36: νmax film/
cmϪ1 2967 s, 1716 s, 1464 s, 1411 s, 1280 s, 1076 s, 1023 s; δH (400
MHz, CDCl3): 6.87 (1H, d, J 8.0, C11H), 6.81 (1H, d, J 8.0,
C10H), 3.83 (3H, s, OMe), 3.82 (3H, s, OMe), 3.63 (3H, s,
CO2Me), 3.14–3.16 (1H, m, C6H), 2.19–2.27 (2H, m, C4H2),
2.24 (3H, s, C20H3), 1.86–1.92 (2H, m, C5H2), 1.22 (3H, d,
J 7.0, C19H3); δC (100 MHz, CDCl3): 174.39 (0, C13), 151.49,
151.06 (0, C7, C8), 137.94, 130.01 (0, C9, C12), 125.93, 121.53
(1, C10, C11), 60.80, 60.06 (3, 2 × OMe), 51.60 (3, CO2CH3),
32.73, 32.64 (2, C4, C5), 31.73 (1, C6), 22.01 (3, C19), 15.82 (3,
(3, C20), 0.06 (3, SiMe3); m/z (EI) 334 (Mϩ , 0.2%), 316 (25),
ؒ
194 (100), 179 (95), 152 (30), 73 (25); Found: C, 67.98; H,
9.11%. C19H30O3Si (M = 334) requires C, 68.22; H, 9.04.
(5S,8R)-1,2-Dimethoxy-3,8-dimethyl-5-(2-trimethylsilyl-
ethynyl)-5,6,7,8-tetrahydronaphthalene [(؉)-41a]
To a solution of alkynols 38 (3.05 g, 9.1 mmol) in CH2Cl2 (70
ml), at rt was added dicobalt octacarbonyl (3.43 g, 10.0 mmol)
in one portion. The mixture was allowed to stir for 1 h before
cooling to Ϫ20 ЊC, and BF3ؒOEt2 (2.3 ml, 18.2 mmol) was
added dropwise. The deep red reaction mixture was allowed to
stir at Ϫ20 ЊC for 3 h, and then quenched with a sat. aq.
NaHCO3 solution (25 ml). The resulting layers were separated,
and the aqueous layer was extracted with hexanes and Et2O
(1 : 1, 3 × 40 ml). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The dark red–brown residue
was purified by column chromatography (SiO2, hexanes–Et2O
95 : 5) to give the diastereoisomeric dicobalt hexacarbonyl
complexes of 41a,b (5.33 g, 8.9 mmol, 97%) as a dark red–
brown solid. The diastereoisomeric ratio was measured after
decomplexation; νmax film/cmϪ1 2958 s, 2938 s, 2084 s, 2010 s,
1566 s, 1480 s, 1448 s, 1406 s, 1318 s, 1262 s, 1250 s, 1072 s, 1026
s, 840 s, 758 s; δH (400 MHz, CDCl3): 7.03 (1H, s, C10H), 4.18–
4.22 (1H, m, C13H), 3.88 (3H, s, OMe), 3.76 (3H, s, OMe), 3.19
(1H, m, C6H), 2.21 (3H, s, C20H3), 2.05 (2H, m, C4H2), 1.84
(2H, m, C5H2), 1.31 (3H, d, J 6.5, C19H3), 0.41 (9H, s, SiMe3);
δC (100 MHz, CDCl3): 200.53 (6 × CO), 150.65, 150.02 (0, C7,
C8), 134.67, 133.94, 129.39 (0, C9, C11, C12), 126.52 (1, C10),
120.73 (0, C2), 81.13 (0, C3), 60.47, 60.02 (3, 2 × OMe), 41.53
C20); m/z (EI) 266 (Mϩ , 10%), 235 (18), 193 (17), 179 (100),
ؒ
164 (27), 91 (15), 74 (28), 59 (40); Found: C, 67.68; H, 8.16%.
C15H22O4 (M = 266) requires C, 67.64; H, 8.33.
(R)-4-(2,3-Dimethoxy-4-methylphenyl)pentanal (37)
To a solution of methyl ester 36 (2.57 g, 9.7 mmol) in Et2O (30
ml), at Ϫ78 ЊC was added DIBAL-H (neat, 1.9 ml, 10.6 mmol)
dropwise. The reaction mixture was allowed to stir at Ϫ78 ЊC
for 30 min and then quenched with sat. aq. Na2SO4 solution (20
ml), allowed to warm to rt and then filtered through Celite. The
filtrate was successively washed with water (2 × 20 ml), sat. aq.
NaHCO3 solution (10 ml), dried over MgSO4, and concentrated
in vacuo. The yellow residue was purified by column chrom-
atography (SiO2, hexanes–Et2O 85 : 15) to afford the desired
J. Chem. Soc., Perkin Trans. 1, 2001, 2344–2355
2351

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(2, C4), 29.67, 29.31 (1, C6, C13), 27.80 (2, C5), 21.07 (3, C19),
15.61 (3, C20), 1.49 (3, SiMe3); m/z (EI) 384 (30), 360 (55), 314
(27), 298 (30), 247 (36), 229 (34).
Methyl 2-[(5S,8R)-(1,2-dimethoxy-3,8-dimethyl-5,6,7,8-
tetrahydro-5-naphthyl)]ethanoate (43)
To a solution of the carboxylic acid 42 (0.41 g, 1.5 mmol) in
toluene (7 ml) at rt was added dropwise N,N,NЈ,NЈ-tetra-
methylguanidine (0.37 ml, 3.0 mmol). After 45 min, methyl
iodide (0.28 ml, 4.5 mmol) was added and the mixture was
allowed to stir at rt for 2.5 h. The resulting yellow mixture
was diluted with Et2O (20 ml) and washed with HCl (2 M,
10 ml), sat. aq. NaHCO3 solution (10 ml), dried over MgSO4
and concentrated in vacuo. The pale yellow residue was purified
by column chromatography (SiO2, hexanes–Et2O 90 : 10) to
afford methyl ester 43 (0.41 g, 1.4 mmol, 93%) as a colourless
oil: [α]2D1 ϩ44.0 (c 1.1, CHCl3); νmax film/cmϪ1 2937 s, 1751 s,
1497 s, 1452 s, 1417 s, 1337 s, 1242 s, 1173 s, 1078 s, 1048 s, 923
m, 873 m; δH (400 MHz, CDCl3): 6.76 (1H, s, C10H), 3.89 (3H,
s, OMe), 3.81 (3H, s, OMe), 3.73 (3H, s, CO2Me), 3.22–3.14
(2H, m, C6H, C13H), 2.92 (1H, dd, J 4.5, 15.1, C3H), 2.44
(1H, dd, J 9.8, 15.1, C3H), 2.22 (3H, s, C20H3), 1.89–1.76 (2H,
m, C4H2 or C5H2), 1.71–1.61 (2H, m, C4H2 or C5H2), 1.25
(3H, d, J 6.9, H19); δC (100 MHz, CDCl3): 173.52 (0, CO2),
150.88, 149.38 (0, C7, C8), 134.73, 134.34 (0, C11, C12), 129.55
(0, C9), 124.31 (1, C10), 60.32, 59.83 (3, 2 × OMe), 51.68 (3,
CO2CH3), 41.97 (2, C3), 34.97 (1, C13), 29.13 (2, C4), 27.63
(1, C6), 24.87 (2, C5), 22.08 (3, C19), 15.94 (3, C20); m/z (EI)
To a solution of dicobalt hexacarbonyl complexes of 41a,b
(3.80 g, 6.3 mmol) in methanol (100 ml), at 0 ЊC was added
Fe(NO3)3ؒ9H2O (25.45 g, 63.0 mmol). The reaction mixture was
allowed to stir for 3 h at rt and then diluted with a mixture of
hexanes and Et2O (4 : 1, 200 ml), and washed with a sat. aq.
NaHCO3 solution (100 ml). The layers were separated, and the
aqueous layer was extracted with hexanes and Et2O (4 : 1,
2 × 30 ml). The combined organic layers were dried over
MgSO4, stirred over activated carbon (Norit SA3), and concen-
trated in vacuo. The pale orange residue was purified by column
chromatography (SiO2, hexanes–Et2O 95 : 5) to afford the silyl-
alkyne 41a,b (1.87 g, 5.9 mmol, 94%, dr = 95 : 5) as a colourless
oil. The desired silylalkyne derivative 41a (1.75 g, 91%,
dr ≥ 99 : 1) was obtained as colourless crystals after crystallis-
ation from MeOH–H2O: mp 57.5–58.5 ЊC; [α]1D9 ϩ50.2 (c 1.3,
CHCl3); νmax film/cmϪ1 2954 s, 2171 s, 2019 m, 1477 s, 1405 s,
1316 s, 1250 s, 1068 s, 1027 s, 912 m, 843 s, 760 m, 733 m, 644 m,
464 m; δH (400 MHz, CDCl3): 7.16 (1H, s, C10H), 3.89 (3H, s,
OMe), 3.81 (3H, s, OMe), 3.68 (1H, dd, J 5.8, 11.0, C13H),
3.10–3.18 (1H, m, C6H), 2.26 (3H, s, C20H3), 2.195–2.07 (2H,
m, C4H2), 1.80–1.73 (2H, m, C5H2), 1.26 (3H, d, J 7.0, C19H3),
0.20 (9H, s, SiMe3); δC (100 MHz, CDCl3): 150.78, 149.95
(0, C7, C8), 133.35, 131.04, 129.87 (0, C9, C11, C12), 125.72
(1, C10), 110.26 (0, C2), 85.18 (0, C3), 60.46, 59.92 (3,
2 × OMe), 33.12 (1, C13), 29.70 (2, C4), 27.47 (1, C6), 25.86 (2,
C5), 22.31 (3, C19), 15.91 (3, C20), 0.36 (3, SiMe3); m/z (EI) 316
292 (Mϩ , 60%), 232 (7), 219 (100), 203 (30), 188 (15), 172 (7);
ؒ
Found: C, 69.73; H, 8.31%. C17H24O4 (M = 292) requires C,
69.84; H, 8.27.
(Mϩ , 100%), 274 (70), 259 (13), 149 (12), 143 (13), 73 (18);
ؒ
Methyl (R)-2-[(5S,8R)-(1,2-dimethoxy-3,8-dimethyl-5,6,7,8-
tetrahydro-5-naphthyl)]propanoate (44)
Found: C, 72.02; H, 9.11%. C19H28O2Si (M = 316) requires
C, 72.10; H, 8.92.
To a solution of diisopropylamine (0.28 ml, 2.0 mmol) in THF
(10 ml) at 0 ЊC, was added dropwise BuLi (2.32 M in hexane,
0.75 ml, 1.7 mmol). After 30 min, the reaction mixture was
cooled to Ϫ45 ЊC before addition of a solution of methyl
ester 43 (0.39 g, 1.3 mmol) in THF (2.5 ml) dropwise. The
resulting pale yellow solution was maintained at Ϫ45 ЊC for
45 min and methyl iodide (0.42 ml, 6.7 mmol) was added
dropwise. After a further 1.5 h at Ϫ45 ЊC, the reaction mix-
ture was quenched with water (5 ml) and the resulting layers
were separated. The aqueous layer was extracted with Et2O
(3 × 20 ml) and the combined organic layers were washed
with brine (10 ml), dried over MgSO4, and concentrated
in vacuo. The pale yellow residue was purified by column
chromatography (SiO2, hexanes–Et2O 10 : 1) to give methyl
ester 44 (0.39 g, 6.7 mmol, 95%, dr = 10 : 1) as a colourless oil:
[α]2D1 ϩ31.6 (c 1.3, CHCl3); νmax film/cmϪ1 2947 s, 1751 s, 1492 s,
1417 s, 1332 s, 1252 s, 1208 s, 1078 s, 923 m, 749 m; δH (400
MHz, CDCl3): 6.76 (1H, s, C10H), 3.88 (3H, s, OMe), 3.81
(3H, s, OMe), 3.72 (3H, s, CO2Me), 3.32–3.13 (3H, m, C3H,
C6H, C13H), 2.22 (3H, s, C20H3), 1.79–1.67 (4H, m, C4H2,
C5H2), 1.21 (3H, d, J 6.9, C19H3), 0.96 (3H, d, J 7.0, C18H3);
δC (100 MHz, CDCl3): 176.38 (0, CO2), 150.64, 149.12 (0, C7,
C8), 135.64, 132.90 (0, C11, C12), 129.45 (0, C9), 124.03 (1,
C10), 60.33, 59.83 (3, 2 × OMe), 51.74 (3, CO2Me), 42.86 (1,
C3), 39.78 (1, C13), 28.87 (2, C4), 27.27 (1, C6), 21.79 (3,
C19), 18.66 (2, C5), 16.00 (3, C20), 10.66 (3, C18); m/z (EI)
2-[(5S,8R)-(1,2-Dimethoxy-3,8-dimethyl-5,6,7,8-tetrahydro-5-
naphthyl)]ethanoic acid (42)
A solution of dicyclohexylborane was freshly prepared from
cyclohexene (0.9 ml, 9.1 mmol) and BH3ؒTHF (1.0 M, 4.2 ml,
4.2 mmol) in THF at 0 ЊC for 2 h. A solution of silylalkyne 41a
(0.67 g, 2.10 mmol) in THF (10 ml) was added dropwise to the
resulting white suspension over 20 min. The reaction mixture
was allowed to warm to rt and stirred for 1 h to form a homo-
geneous solution. The clear reaction mixture was diluted with
methanol (4 ml), then oxidised by dropwise addition of NaOH
(3 M, 3 ml) followed by H2O2 (30%, 4 ml) keeping the temper-
ature between 30 ЊC and 50 ЊC (the oxidation was exothermic
and caused a strong evolution of H2). After stirring for 30 min
at rt, NaOH (3 M, 3 ml) was added and the layers were separ-
ated. The cyclohexanol by-product was removed with Et2O
(2 × 30 ml), and the aqueous layer acidified with HCl (conc.,
2 ml) and extracted with Et2O (3 × 30 ml). The combined
organic layers were dried over Na2SO4, and concentrated
in vacuo. The yellow residue was purified by column chrom-
atography (SiO2, hexanes–Et2O 60 : 40) to afford the carboxylic
acid 42 (0.57 g, 2.06 mmol, 97%) as a colourless oil which crys-
tallised on storage in the refrigerator: mp 78–80 ЊC; [α]1D8 ϩ47.9
(c 1.4, CHCl3); νmax film/cmϪ1 2897 s, 1721 s, 1496 s, 1412 s, 1307
s, 1247 m, 1073 s, 1038 m, 923 s, 754 s; δH (400 MHz, CDCl3):
11.05 (1H, br s, CO2H), 6.81 (1H, s, C10H), 3.91 (3H, s, OMe),
3.84 (3H, s, OMe), 3.26–3.16 (2H, m, H6, C13H), 3.01 (1H, dd,
J 4.3, 15.4, C3H), 2.50 (1H, dd, J 9.7, 15.3, C3H), 2.25 (3H, s,
C20H3), 1.99–1.94 (1H, m, C4H or C5H), 1.88–1.69 (3H, m,
C4H, C5H), 1.28 (3H, d, J 6.9, C19H3); δC (100 MHz, CDCl3):
179.54 (0, C2), 150.91, 149.45 (0, C7, C8), 134.80, 134.08
(0, C11, C12), 129.67 (0, C9), 124.31 (1, C10), 60.38, 59.88 (3,
2 × OMe), 42.01 (2, C3), 34.80 (1, C13), 29.14 (2, C4), 27.63 (1,
C6), 24.84 (2, C5), 22.11 (3, C19), 15.97 (3, C20); m/z (EI) 278
306 (Mϩ , 15%), 233 (5), 219 (100), 188 (10), 173 (5); Found:
ؒ
C, 70.42; H, 8.58%. C18H26O4 (M = 306) requires C, 70.56;
H, 8.55.
Signals for the (2S)-epimer which were clearly distinguished:
δH (400 MHz, CDCl3): 6.67 (1H, s, C10H), 3.87 (3H, s, OMe),
3.80 (3H, s, OMe), 3.63 (3H, s, CO2Me), 1.21 (3H, d, J 6.9,
C19H3), 0.96 (3H, d, J 7.0, C18H3); δC (100 MHz, CDCl3):
176.51 (0, CO2), 150.95, 149.41 (0, C7, C8), 134.80, 133.51 (0,
C11, C12), 128.78 (0, C9), 125.71 (1, C10), 60.25, 59.83 (3,
2 × OMe), 51.54 (3, CO2Me), 43.50 (1, C3), 41.34 (1, C13),
28.70 (2, C4), 27.52 (1, C6), 23.20 (3, C19), 22.63 (2, C5), 15.13
(3, C20), 10.66 (3, C18).
(Mϩ , 60%), 263 (10), 233 (20), 219 (100), 203 (35), 188 (17), 172
ؒ
(7); Found: C, 69.01; H, 8.11%. C16H22O4 (M = 278) requires C,
69.04; H, 7.97.
2352
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(5S,8R)-1,2-Dimethoxy-3,8-dimethyl-5-[(2R)-(1-methyl-2-
hydroxyethyl)]-5,6,7,8-tetrahydronaphthalene (45)
(5R,8R)-1,2-Dimethoxy-3,8-dimethyl-5-[(1S,3RS)-1,5-
dimethyl-3-p-tolylsulfonylhex-4-enyl]-5,6,7,8,-tetrahydro-
naphthalene (49a,b)
To a suspension of LiAlH4 (35 mg, 0.9 mmol) in THF (7 ml) at
0 ЊC, was added dropwise a solution of methyl ester 44 (0.38 g,
1.24 mmol, dr = 10 : 1) in THF (7 ml). After 45 min at rt, the
reaction was quenched with cold water (5 ml) and the layers
were separated. The aqueous layer was extracted with Et2O
(3 × 20 ml) and the combined organic layers were washed with
brine (10 ml), dried over MgSO4, and concentrated in vacuo.
The pale yellow residue was purified by column chrom-
atography (SiO2, hexanes–Et2O 70 : 30) to give alcohol 45 (0.35
g, 1.24 mmol, 100%, dr = 10 : 1) as a colourless oil. The mixture
of epimers was separated by further chromatography under the
same conditions to 45 as a single diastereoisomer: [α]2D0 ϩ55.4
(c 0.9, CHCl3); νmax film/cmϪ1 3361 s, 2959 s, 2882 s, 1487 s, 1415
s, 1324 s, 1243 s, 1080 s, 1037 s, 922 m, 764 s; δH (400 MHz,
CDCl3): 6.83 (1H, s, C10H), 3.89 (3H, s, OMe), 3.81 (3H, s,
OMe), 3.69 (1H, dd, J 7.4, 10.5, C2H), 3.62 (1H, dd, J 6.7, 10.5,
C2H), 3.15–3.12 (1H, m, C6H), 3.03–2.98 (1H, m, C13H), 2.46–
2.38 (1H, m, C3H), 2.22 (3H, s, C20H3), 1.79 (1H, br s, OH),
1.75–1.52 (4H, m, C4H2, C5H2), 1.21 (3H, d, J 7.0, C19H3),
0.72 (3H, d, J 6.8, C18H3); δC (100 MHz, CDCl3): 150.47,
148.76 (0, C7, C8), 135.56, 134.58 (0, C11, C12), 129.20 (0, C9),
124.22 (1, C10), 66.79 (1, C2), 60.38, 59.87 (3, 2 × OMe), 39.23,
To a solution of (3-methylbut-2-enyl) p-tolyl sulfone 48 (0.89 g,
3.95 mmol) in THF (7 ml) at Ϫ78 ЊC was added dropwise BuLi
(2.32 M in hexane, 1.7 ml, 3.86 mmol) over 5 min. The resulting
yellow–brown solution was allowed to warm to Ϫ50 ЊC over
1 h, and then cooled to Ϫ78 ЊC. A solution of tosylate 46 (0.43
g, 0.99 mmol) in THF (5 ml) was added dropwise to the mix-
ture, and then allowed to warm to rt. After 4.5 h, the reaction
mixture was diluted with Et2O (25 ml) and washed with water
(5 ml). The aqueous layer was extracted with Et2O (2 × 20 ml)
and the combined organic layers were washed with brine (10 ml),
dried over MgSO4 and concentrated in vacuo. The pale yellow
residue was purified by column chromatography (SiO2, hexanes–
Et2O 80 : 20) to give a mixture of allylic sulfones 49a,b (0.44 g,
0.91 mmol, 92%, dr = 1 : 1) as a colourless solid: mp 51–54 ЊC;
νmax film/cmϪ1 2939 s, 2882 s, 2259 m, 1612 m, 1497 s, 1454 s,
1420 s, 1382 s, 1320 s, 1243 s, 1147 s, 1085 s, 931 s, 821 m, 740 s,
668 s, 586 s; δH (400 MHz, CDCl3): 7.72 (0.5 × 2H, d, J 8.1,
H2Ј, H6Ј), 7.71 (0.5 × 2H, d, J 8.1, H2Ј, H6Ј), 7.31 (2H, d, J 7.9,
H3Ј, H5Ј), 6.67 (0.5 × 1H, s, C10H), 6.56 (0.5 × 1H, s, C10H),
5.04 (0.5 × 1H, dd, J 1.1, 10.3, C14H), 4.97 (0.5 × 1H, dd, J 1.1,
10.3, C14H), 3.87 (3H, s, OMe), 3.85–3.80 (1H, m, C1H), 3.78
(3H, s, OMe), 3.12 (1H, br d, J 5.0, C6H), 2.75–2.72 (0.5 × 1H,
m, C3H), 2.64–2.61 (0.5 × 1H, m, C3H), 2.44 (3H, s, C7ЈH3),
2.27–2.22 (2H, m, C2H2), 2.19 (0.45 × 3H, s, C20H3), 2.18
(0.55 × 3H, s, C20H3), 1.75 (0.5 × 3H, s, C16H3), 1.73
(0.5 × 3H, s, C16H3), 1.70–1.62 (4H, m, C4H2, C5H2), 1.22
(3H, br s, C17H3), 1.17 (0.5 × 3H, d, J 6.9, C19H3), 1.16
(0.5 × 3H, d, J 6.9, C19H3), 0.67 (0.5 × 3H, d, J 5.7, C18H3),
0.61 (0.5 × 3H, d, J 5.4, C18H3); δC (100 MHz, CDCl3): 150.37,
150.29, 148.77, 148.69 (0, C7, C8), 144.34, 144.30 (0, C1Ј),
142.25, 142.0. (0, C15), 135.62, 135.47, 135.20, 135.14, 134.47,
134.,45 (0, C11, C12, C4Ј), 129.42, 129.39, 129.31, 129.30 (1,
C2Ј, C3Ј, C5Ј, C6Ј), 129.20, 129.08 (0, C9), 124.15, 123.85 (1,
C10), 117.84, 117.67 (1, C14), 63.81, 63.31 (1, C1), 60.27, 59.75
(3, 2 × OMe), 42.47, 38.60 (1, C3), 33.76, 33.47 (1, C13), 32.75,
31.96 (2, C2), 29.03, 28.98 (2, C5), 27.08 (1, C6), 25.96 (3, C16),
21.71 (3, C7Ј), 21.58, 21.31 (3, C19), 18.26, 18.17 (3, C17),
17.56, 16.30 (2, C4), 16.06, 16.04 (3, C20), 15.44, 13.24 (3, C18);
38.17 (1, C6, C13), 28.97 (2, C5), 27.16 (1, C3), 21.82 (3, C19),
17.38 (2, C4), 16.04 (3, C20), 11.46 (3, C18); m/z (EI) 278 (Mϩ
,
ؒ
15%), 219 (100), 204 (5), 188 (10), 173 (5); Found: C, 73.40; H,
9.52%. C17H26O3 (M = 278) requires C, 73.34; H, 9.41.
The minor epimer gave [α]2D0 ϩ58.2 (c 1.1, CHCl3); δH (400
MHz, CDCl3): 6.88 (1H, s, C10H), 3.88 (3H, s, OMe), 3.81 (3H,
s, OMe), 3.56 (1H, dd, J 4.7, 10.5, C2H), 3.42 (1H, dd, J 8.2,
10.5, C2H), 3.15–3.12 (1H, m, H6), 2.80–2.77 (1H, m, C13H),
2.44–2.38 (1H, m, C3H), 2.22 (3H, s, C20H3), 1.74–1.52 (5H, m,
C4H2, C5H2, OH), 1.20 (3H, d, J 7.0, C19H3), 1.12 (3H, d,
J 6.9, C18H3); δC (100 MHz, CDCl3): 150.68, 149.05 (0, C7,
C8), 135.24, 134.52 (0, C11, C12), 129.34 (0, C9), 124.62
(1, C10), 65.18 (1, C2), 60.38, 59.89 (3, 2 × OMe), 41.08, 39.37
(1, C6, C13), 29.32 (2, C5), 27.34 (1, C3), 21.72 (3, C19), 18.95
(2, C4), 16.13 (3, C20), 16.07 (3, C18).
(5S,8R)-1,2-Dimethoxy-3,8-dimethyl-5-[(R)-1-methyl-2-
( p-tolylsulfonyloxy)ethyl]-5,6,7,8-tetrahydronaphthalene (46)
m/z (EI) 484 (Mϩ , 15%), 329 (30), 278 (5), 246 (25), 219 (100),
ؒ
191 (25), 123 (15), 84 (20), 41 (10); Found: C, 71.83; H, 8.36%.
C29H40O4S (M = 484) requires C, 71.86; H, 8.32.
To a solution of alcohol 45 (0.29 g, 1.04 mmol) in CH2Cl2 (7 ml)
at 0 ЊC, was added successively DMAP (30 mg, 0.25 mmol),
triethylamine (0.3 ml, 2.1 mmol) and toluene-p-sulfonyl chlor-
ide (0.30 g, 1.56 mmol). The reaction mixture was allowed to
warm to rt and stirred for a further 5 h. The resulting mixture
was diluted with Et2O (30 ml), washed with HCl (2 M, 30 ml),
sat. NaHCO3 solution (30 ml), dried over MgSO4 and concen-
trated in vacuo. The pale yellow residue was purified by column
chromatography (SiO2, hexanes–Et2O 80 : 20) to afford tosylate
46 (0.43 g, 0.99 mmol, 96%) as white crystals: mp 102–104 ЊC
(Et2O–pentane); [α]1D8 ϩ23.6 (c 1.1, CHCl3); νmax film/cmϪ1 2949
s, 1612 s, 1492 m, 1372 s, 1195 s, 1104 m, 1084 m, 974 s, 807 s,
778 s, 677 m, 558 m; δH (400 MHz, CDCl3): 7.84 (2H, d, J 8.3,
H2Ј, H6Ј), 7.37 (2H, d, J 8.4, H3Ј, H5Ј), 6.64 (1H, s, C10H),
4.09–4.01 (2H, m, C2H2), 3.87 (3H, s, OMe), 3.79 (3H, s, OMe),
3.14–3.07 (1H, m, C6H), 2.95–2.89 (1H, m, C13H), 2.60–2.50
(1H, m, C3H), 2.47 (3H, s, C7ЈH3), 2.19 (3H, s, C20H3), 1.67–
1.50 (2H, m, C4H2 or C5H2), 1.38–1.30 (2H, m, C4H2 or
C5H2), 1.15 (3H, d, J 7.0, C19H3), 0.68 (3H, d, J 6.9, C18H3); δC
(100 MHz, CDCl3): 150.51, 148.95 (0, C7, C8), 144.89 (0, C1Ј),
135.47, 133.34, 133.26 (0, C11, C12, C4Ј), 130.13 (1, C2Ј, C6Ј),
129.35 (0, C9), 128.05 (1, C3Ј, C5Ј), 124.00 (1, C10), 73.69 (2,
C2), 60.31, 59.80 (3, 2 × OMe), 37.61, 36.10 (1, C13, C6), 28.67
(2, C5), 27.00 (1, C3), 21.78 (3, C19), 21.70 (3, C7Ј), 17.07 (2,
(1R,3S,6R,13R)-7,8-Dimethoxy-3,6,9-trimethyl-1-(2-methyl-
prop-1-enyl)-2,3,3a,4,5,6-hexahydro-1H-phenalene
[(؉)-50b]
To a solution of sulfones 49a,b (0.33 g, 0.68 mmol) in CH2Cl2
(15 ml) at Ϫ78 ЊC, was added dropwise EtAlCl2 (1.0 M in hex-
ane, 1.7 ml, 1.70 mmol). The resulting clear yellow reaction
mixture was allowed to warm to Ϫ40 ЊC over 30 min, and then
maintained at Ϫ40 ЊC for a further 4 h before being quenched
with sat. NaHCO3 solution (5 ml). The resulting white slurry
was extracted with Et2O (3 × 20 ml) and the combined organic
layers were washed with brine (10 ml), dried over MgSO4, and
concentrated in vacuo. The pale yellow residue was purified by
column chromatography (SiO2, hexanes–Et2O 98 : 2) to give
pseudopterosin G–J aglycone dimethyl ether 50b (0.20 g, 88%,
dr >95 : 5) as a colourless oil. The single desired diastereo-
isomer was obtained as colourless crystals after crystallisation
from MeOH: mp 107–109 ЊC; [α]1D8 ϩ106.2 (c 1.0, CHCl3); νmax
film/cmϪ1 2939 s, 2863 s, 1473 s, 1420 s, 1387 m, 1324 s, 1257 m,
1085 s, 922 m, 744 m; δH (400 MHz, CDCl3): 5.14 (1H, dd, J 1.3,
9.3, C14H), 3.89 (3H, s, OMe), 3.78 (3H, s, OMe), 3.64 (1H, br
dt, J 3.4, 9.3, C1H), 3.24 (1H, quin, J 6.5, C6H), 2.08–2.03 (1H,
m, C13H), 2.05 (3H, br s, C20H3), 1.97 (1 H, dq, J 3.3, 12.6,
C4Heq), 1.87 (1H, ddt, J 2.8, 5.8, 13.2, C5Hax), 1.79–1.77 (1H,
m, C5Heq), 1.75 (3H, d, J 1.0, C17H3), 1.73–1.65 (3H, m, C2H2
C4), 15.97 (3, C20), 11.07 (3, C18); m/z (EI) 432 (Mϩ , 20%),
ؒ
260 (5), 219 (100), 188 (5), 173 (5), 91 (5); Found: C, 66.51;
H, 7.45%. C24H32O5S (M = 432) requires C, 66.64; H, 7.46.
J. Chem. Soc., Perkin Trans. 1, 2001, 2344–2355
2353

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and C3H), 1.68 (3H, d, J 0.8, C16H3), 1.46 (1H, dq, J 2.6, 12.6,
C4Hax), 1.21 (3H, d, J 6.9, C19H3), 1.02 (3H, d, J 5.6, C18H3);
δC (100 MHz, CDCl3): 149.27, 149.13 (0, C7, C8), 134.27,
133.30, 131.54, 129.38, 128.47 (0, C9, C10, C11, C12, C15),
130.97 (1, C14), 60.54, 60.08 (3, 2 × OMe), 46.32 (1, C13), 41.03
(2, C2), 36.15 (1, C1), 31.05 (2, C5), 29.71 (1, C3), 28.30 (1, C6),
25.79 (3, C16), 23.97 (3, C19), 22.59 (2, C4), 20.88 (3, C18),
17.84 (3, C17), 11.05 (3, C20); m/z (EI) 328 (Mϩ , 100%), 313
ؒ
(75), 271 (15), 257 (20), 246 (15), 229 (10), 215 (5), 199 (5);
Found: C, 80.41; H, 9.86%. C22H32O2 (M = 328) requires C,
80.44; H, 9.82.
Ethyl (E,4S)-4-[(2,3-dimethoxy-4-methyl)phenyl]pent-2-enoate
[(S)-22]
To a solution of 2,3-dimethoxy-4-methyl-1-iodobenzene 30
(3.93 g, 14.1 mmol) in THF (50 ml) at Ϫ90 ЊC was added drop-
wise BuLi (1.40 M in hexane, 10.6 ml, 14.8 mmol). The mixture
was stirred at Ϫ78 ЊC for 15 min whereupon a solution of CuBrؒ
SMe2 (2.9 g, 14.1 mmol) in diisopropyl sulfide (3 ml) and THF
(3 ml) was added dropwise whilst maintaining the temperature
below Ϫ75 ЊC. The mixture was stirred at Ϫ78 ЊC for 45 min,
cooledtoϪ90 ЊCandsolidcomplex53(1.35g, 3.53mmol)added
portionwise keeping the temperature below Ϫ70 ЊC. After the
addition, the reaction temperature was allowed to warm slowly
to 0 ЊC over 5 h to give an orange mixture. An aqueous solution
of ceric ammonium nitrate (1 M, 10 ml) was added and the mix-
ture was allowed to warm to rt over 8 h. The reaction mixture was
diluted with Et2O (50 ml), the phases were separated and the
aqueous layer was extracted with Et2O (2 × 30 ml). The com-
bined extracts were washed with sat. aq. NH4F solution (30 ml),
10% NaHSO4 solution (50 ml), brine (40 ml), dried over MgSO4
and concentrated in vacuo. The rusty coloured residue was puri-
fied by column chromatography (SiO2, hexanes–Et2O 90 : 10) to
give ethyl ester (S)-22 (0.67 g, 2.40 mmol, 68%) as a colourless
oil: [α]2D3 Ϫ69.2 (c 1.6, CHCl3); νmax film/cmϪ1 2988 s, 1721 s, 1653
m, 1469s, 1411s, 1280s, 1180s, 1028s, 918s, 818m;δH (400MHz,
CDCl3): 7.12 (1H, dd, J 15.7, 6.2, C5H), 6.88 (1H, d, J 7.9,
C11H), 6.78 (1H, d, J 7.9, C10H), 5.79 (1H, dd, J 15.7, 1.7, C4H),
4.18 (2H, q, J 7.1, OCH2CH3), 4.01–4.04 (1H, m, C6H), 3.85
(3H, s, OMe), 3.83(3H, s, OMe), 2.25(3H, s, C20H3), 1.38(3H, d,
J 7.0, C19H3), 1.28 (3H, t, J 7.1, OCH2CH3); δC (100 MHz,
CDCl3): 166.96 (0, C13), 153.11 (1, C5), 151.51, 150.67 (0, C7,
C8), 135.11, 130.91 (0, C9, C12), 125.88, 122.36 (1, C10, C11),
119.93 (1, C4), 60.76 (3, OMe), 60.28 (2, OCH2CH3), 59.93 (3,
OMe), 35.00 (1, C6), 19.86 (3, C19), 15.76 (3, C20), 14.34 (3,
Fig. 1 Molecular drawing of (Ϫ)-41a showing the 50% probability
ellipsoids for non-hydrogen atoms.
Acknowledgements
We thank the EPSRC and the Deutsche Forschungsgemein-
schaft for financial support. We also thank Pfizer Central
Research for a CASE studentship (R.C.) and GlaxoWellcome
for a post-doctoral fellowship (J.-Y. L).
References
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OCH2CH3); m/z (EI) 278 (Mϩ , 100%), 265 (8), 249 (12), 233
ؒ
(28), 217 (35), 205 (65), 189 (78), 173 (45); Found: C, 69.03; H,
7.92%. C16H22O4, (M = 278) requires C, 69.04; H, 7.97.
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(5R,8S)-1,2-Dimethoxy-3,8-dimethyl-5-(2-trimethylsilyl-
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Silylalkyne (Ϫ)-41a derived from (S)-22 as depicted in Schemes
5 and 6 gave mp 57.5–58.5 ЊC; [α]2D5 Ϫ50.2 (c 1.0, CHCl3). The
absolute stereochemistry of (Ϫ)-41a (Fig. 1) was confirmed by
X-ray crystallography with Mo X-rays on a CAD4 diffract-
ometer.53,54 Crystal data (Ϫ)-41a¶¶ C19H28O2Si, M = 316.50,
monoclinic, a = 10.4402(9), b = 8.4616(8), c = 11.6528(15) Å,
β = 103.300(9)Њ, U = 1001.8(2) Å3, T = 293 K, space group P21,
Z = 2, µ(Mo-Kα) 0.12 mmϪ1. The full sphere of 9341 reflections
with θ (Mo-Kα) < 28Њ were measured, and 4816 unique F 2
values (Rint = 0.0298) were used in refinement. R1 = 0.0910 and
wR2 = 0.13 for all 4816 reflections. For 2947 reflections with
I > 2σ(I )] R1 = 0.0431. The unique data set which contained
2252 Friedel pairs, gave an unambiguous determination of the
absolute configuration. The structure shown in Fig. 1 gave a
Flack parameter x = Ϫ0.07(15).
25 D. C. Harrowven, J. D. Wilden, M. J. Tyte, M. B. Hursthouse and
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28 D. Enders and M. Finkam, Synlett, 1993, 401.
¶¶ CCDC reference number 168190.
2354
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