Alkoxyallene-ynes: Selective Preparation of Bicyclo[5.3.0] Ring Systems Including a δ-Alkoxy Cyclopentadienone

Article abstract of DOI:10.1002/chem.201504753

The development of an intramolecular rhodium(I)-catalyzed Pauson-Khand reaction of alkoxyallene-ynes with a proximal alkoxy group is reported. This reaction, in the presence of a [Rh(cycloocta-1,5-diene)Cl]₂/propane-1,3-diylbis(diphenylphosphane) system under a CO atmosphere, constitutes a powerful tool for selectively accessing carbo- A nd heterobicyclo[5.3.0] frameworks featuring an enol ether moiety. Through this procedure, a straightforward access to guaiane skeletons with a tertiary hydroxy group at the C10 position was achieved.

Full text of DOI:10.1002/chem.201504753

DOI: 10.1002/chem.201504753
Full Paper
&
Pauson–Khand Reactions
Alkoxyallene-ynes: Selective Preparation of Bicyclo[5.3.0] Ring
Systems Including a d-Alkoxy Cyclopentadienone
AurØlien Tap,[a] Camille Lecourt,[a] Sabrina Dhambri,[a] Mathieu Arnould,[a] Gilles Galvani,[a]
Olivier Nguyen Van Buu,[a] Morgan Jouanneau,[b] Jean-Pierre FØrØzou,[b] Janick Ardisson,[a]
Marie-Isabelle Lannou,*[a] and Geoffroy Sorin*[a]
Abstract: The development of an intramolecular rhodium(I)-
catalyzed Pauson–Khand reaction of alkoxyallene-ynes with
a proximal alkoxy group is reported. This reaction, in the
presence of a [Rh(cycloocta-1,5-diene)Cl]2/propane-1,3-diyl-
bis(diphenylphosphane) system under a CO atmosphere,
constitutes a powerful tool for selectively accessing carbo-
and heterobicyclo[5.3.0] frameworks featuring an enol ether
moiety. Through this procedure, a straightforward access to
guaiane skeletons with a tertiary hydroxy group at the C10
position was achieved.
Introduction
Sesquiterpenes represent the largest class of terpenes and,
among the variety of ring systems that are featured in these
natural products, the guaianes, characterized by fused five-
and seven-membered rings (bicyclo[5.3.0]decane), are
widespread. Although their core structures might differ in the
oxidation level, many of them present a tertiary hydroxy group
at the C10 position (guaiane numbering; Figure 1).[1]
Their total synthesis represents a real challenge including
three key points: a medium ring, dense stereochemical com-
plexity on a relatively flexible skeleton, and often highly elevat-
ed levels of oxidation. The intramolecular Pauson–Khand reac-
tion (PKR), that is, an ene-yne or allene-yne carbonylative
[2+2+1] reaction, constitutes an efficient and elegant method
for synthesizing perhydroazulene skeletons.[2] Therefore, we
hypothesized that the alkoxyallene-yne cyclocarbonylation
reaction of substrates bearing an alkoxy group at the proximal
position should permit the rapid elaboration of the carbon
framework of guaianes possessing a tertiary alcohol group at
the C10 position with the requisite unsaturation for further
functionalization (guaiane numbering; Scheme 1).[3]
[a] Dr. A. Tap, C. Lecourt, S. Dhambri, M. Arnould, Dr. G. Galvani,
Dr. O. Nguyen Van Buu, Prof. J. Ardisson, Dr. M.-I. Lannou, Dr. G. Sorin
FacultØ des Sciences Pharmaceutiques et Biologiques
UnitØ CNRS UMR 8638 COMðTE
Figure 1. Natural products containing a guaiane skeleton with a tertiary
hydroxy group at the C10 position.
Paris Descartes University, Sorbonne Paris CitØ
4 avenue de l’observatoire, 75270 Paris cedex 06 (France)
E-mail: marie-isabelle.lannou@parisdescartes.fr
geoffroy.sorin@parisdescartes.fr
[b] Dr. M. Jouanneau, Dr. J.-P. FØrØzou
Laboratoire de Chimie des ProcØdØs et Substances Naturelles
ICMMO (CNRS UMR 8182), UniversitØ Paris-Sud
Bâtiment 410, 91405 Orsay Cedex (France)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504753.
Scheme 1. Strategy for the synthesis of guaianes possessing a tertiary
alcohol at the C10 position.
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In 1996, pioneering work performed by Pericas and co-work-
ers already established that enol ether precursors can be used
as olefinic partners with alkynes in the PKR.[4] One year later,
Cazes and co-workers reported an intermolecular cobalt-medi-
ated PKR involving a tert-butoxyallene in the presence of a ter-
tiary amine oxide as a promoter; however, the yields remained
low (30%).[5] More recently, PØrez-Castells and co-workers stud-
ied the intramolecular PKR of aryloxyallene-ynes, promoted by
a molybdenum complex. Nonetheless, the reaction suffered
from a lack of selectivity, because both internal and external
double bonds of the allene were prone to react.[6] Finally, in
2009, Brummond et al. described the conversion of allenol ace-
tates into bicyclo[5.3.0] skeletons containing an a-acetoxy cy-
clopentadienone by means of RhI-catalyzed cyclocarbonylation,
which selectively occurs through the external p bond of the
allene. Notably, in this case, the allene is substituted by the
alkoxy group at the distal position (Scheme 2).[7]
Results and Discussion
Investigation into the scope of this intramolecular cyclocarbo-
nylation reaction was initiated with the preparation of a range
of readily accessible alkoxyallene-ynes. To this end, three differ-
ent allene–alkyne linkages were envisioned: one all-carbon and
two heteroatom-containing tethers (respectively, the carbon,
nitrogen, and oxygen series). The other variations involved the
substitution pattern of the alkoxyallene (R1) that features
a benzyl (Bn), a para-methoxybenzyl (PMB), or a carbamate
(CON(iPr)2; Cb) group and the terminus of the alkyne (R2)
exhibiting either hydrogen, methyl, ethyl, CH2OBn, or trime-
thylsilyl groups.
Our strategy to access the required alkoxyallene-yne precur-
sors 3 involved the addition of lithiated alkoxyallenes 2 onto
aldehydes 1. The transformation of these compounds into the
corresponding perhydroazulene systems 4 was then studied
(Scheme 3).
Scheme 3. Investigation into intramolecular PKRs of alkoxyallene-ynes with
the alkoxy group at the proximal position. TBS: tert-butyldimethylsilyl; Ts:
toluene-4-sulfonyl.
Synthesis of alkoxyallenic Pauson–Khand precursors
The starting point for the study consisted of the preparation of
the oxygen-substituted allenes 6a (OCb), 6b (OBn)[8] and 6c
(OPMB),[9] from propargyl carbamate 5a[10] or propargyl ethers
5b and 5c by using a general procedure for base-promoted
isomerization (Scheme 4).[11]
Scheme 2. PKRs with enol ethers or alkoxyallenes. NMO: 4-methylmorpho-
line N-oxide; TMS: trimethylsilyl.
Although the intramolecular PKR of alkoxyallene-ynes with
an alkoxy group at the proximal position appears to be an
attractive way to access complex structures, the scarcity of
reports in this field encouraged us to investigate the reaction.
To this aim, a wide variety of cycloaddition substrates was
prepared and submitted to PKR conditions to provide bi-
cyclo[5.3.0] ring systems bearing an enol ether moiety, which
constitutes a logical tertiary hydroxy group precursor. It is
noteworthy that alkoxyallenes are highly versatile structures;
thus, the success of this study will rely on the setting of suffi-
ciently mild and chemoselective conditions, not only in the
course of the key PKR but also during the elaboration of the al-
koxyallene-yne precursors, in order to preserve the integrity of
these skeletons. The results of this survey are reported herein.
Scheme 4. Preparation of oxygen-substituted allenes. a) tBuOK (0.3 equiv),
THF, RT, 1 h.
The synthesis of the aldehydes in the carbon series, 8a (R2:
H), 8b (R2: Me), 8c (R2: Et), 8d (R2: TMS), and 8e (R2: CH2OBn),
was next performed from the corresponding alkenes 7a,[12]
7b,[13] 7c, 7d, and 7e by oxidative cleavage with good yields.
Alkene 7d (R2: TMS) was prepared by silylation of terminal
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alkyne 7a; alkenes 7c (R2: Et) and 7e (R2: CH2OBn) were ob-
tained by following a two-step sequence: reduction of diesters
9a[14] and 9b and subsequent protection. Finally, alkylation of
allylmalonate 10 with mesylate 11[15] allowed the formation of
diester 9b (R2: CH2OBn; Scheme 5).
Scheme 6. Preparation of alkoxyallene-ynes in the carbon series. a) nBuLi,
THF, À788C, 30 min, then 8a–e, THF, À788C, 30 min. b) TBSOTf, 2,6-lutidine,
CH2Cl2, 08C, 3 h.
Scheme 5. Synthesis of aldehydes in the carbon series. a) O3, CH2Cl2, À788C,
then PPh3. b) nBuLi, TMSCl, THF, quant. c) LiAlH4, THF, 08C to RT, 1.5 h. d) 2,2-
dimethoxypropane, PPTS, CH2Cl2, RT, 16 h. e) NaH, DMF, 08C, 15 min, then
11, 08C, 1 h, 91%. Ms: methanesulfonyl; PPTS: pyridinium p-toluene-
sulfonate.
The synthesis of the required PKR precursors from aldehydes
8a–e was then readily performed in two steps: reaction of
lithiated alkoxyallenes, generated by selective gem-deprotona-
tion of the corresponding oxygen-substituted allenes 6a–c,
with aldehydes 8a–e at low temperature and direct conversion
of the resulting alcohols into the corresponding TBS ethers
12a–e, 13a, 13b, and 14a–d (Scheme 6).[16]
Scheme 7. Preparation of alkoxyallene-ynes in the nitrogen series. a) nBuLi,
THF, À788C, 30 min, then 15a–d, THF, À788C, 30 min. b) TBSOTf, 2,6-luti-
dine, CH2Cl2, 08C, 3 h. c) DIAD, PPh3, N-allyl-4-methyl-benzenesulfonamide,
71%. d) O3, CH2Cl2, À788C, then PPh3, 95%. DIAD: diisopropylazo-
dicarboxylate.
In the nitrogen series, alkoxyallene-ynes 16a–c, 17a–c, and
18a–d were similarly synthesized through coupling of lithiated
alkoxyallenes derived from 6a–c with aldehydes 15a (R2: H),[17]
15b (R2: Et),[18] 15c (R2: TMS),[19] and 15d (R2: CH2OBn) and
subsequent protection as TBS ethers (Scheme 7). Aldehyde
15d was prepared in two steps from propargylic alcohol
19.[20,21]
Alkoxyallene-yne Pauson–Khand reactions
With a range of alkoxyallene-ynes in hand, the feasibility of the
Pauson–Khand cyclocarbonylation was next investigated.
Mukai and co-workers,[23] Brummond and co-workers,[24] and,
more recently, our group[25] reported that the RhI-catalyzed
intramolecular allene-yne PKR was a very efficient tool for the
construction of bicyclo[5.3.0] ring frameworks.
Finally, in the oxygen series, the PKR precursors 23a–b and
24a–b were elaborated in a similar way from alkoxyallenes 6a
and 6c and aldehyde 22. Aldehyde 22 was synthesized in
Therefore, a first examination of the PKR conditions was per-
formed with 12b (R1: OCb; R2: Me) and 13a (R1: OBn; R2: Me)
by using commercially available [Rh(Cl)(CO)2]2 and [Rh(cod)Cl]2
(cod: cycloocta-1,5-diene) as catalysts.
a
four-step sequence from known tertiary alcohol 20[22]
via alkyne 21 (Scheme 8).
When subjected to the conditions of Brummond and co-
workers, that is, 10 mol% of [Rh(Cl)(CO)2]2 in toluene at 908C
under a carbon monoxide atmosphere, 12b and 13a afforded
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portant yield enhancement, especially in the benzyl series, for
which the yield of 26a rose from 38 to 77%. Thus, although
the reaction time was lengthened, fewer byproducts were gen-
erated in the course of the reaction.
Finally, replacement of the RhI catalyst [Rh(Cl)(CO)2]2 with
[Rh(cod)Cl]2, always in the presence of 50 mol% of dppp (the
conditions of Mukai and co-workers),[23] brought about signifi-
cant improvement in the PKR and resulted in the formation of
25b in quantitative yield (Cb series; Table 1, entry 7) and 26a
in 90% yield (Bn series; Table 2, entry 8). These results suggest
that the nature of the catalyst appears to be an underlying
factor of the reaction.[14,26]
Our study then focused on the influence of solvent and
ligand nature on the reaction. Replacement of toluene by THF
or acetonitrile did not improve the results, with the catalyst
complex being insoluble in these solvents (Table 1, entries 5, 6,
and 8; Table 2, entry 3). If a cationic rhodium complex was
used, that is, [Rh(Cl)(CO)2]2/dppp or [Rh(cod)Cl]2/dppp in the
presence of AgOTf, inconclusive results were observed with
substrate 13a (R1: OBn; Table 2, entries 7 and 9).[27] In the
benzyl series, the reaction was next explored in the presence
of various phosphorus ligands (phosphines, hydroxyphos-
phines, or phosphites: Xantphos, PO, and P(OEt)3) but with
inconclusive outcomes (Table 2, entries 5, 6, and 10).[28]
Scheme 8. Preparation of alkoxyallene-ynes in oxygen series. a) NaH, prop-
argyl bromide, THF, 08C to RT, then reflux, 12 h, 95%. b) nBuLi, TMSCl, THF,
À788C, 45 min, quant. c) DDQ, CH2Cl2/H2O, 08C to RT, 12 h, 87%. d) (COCl)2,
DMSO, Et3N, CH2Cl2, À788C to RT, 92%. e) nBuLi, THF, À788C, 30 min, then
aldehyde 22, THF, À788C, 30 min. f) TBSOTf, 2,6-lutidine, CH2Cl2, 08C, 3 h.
g) K2CO3, MeOH. DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
It should be noted that bicyclic [5,6] products resulting from
the PKR between the vicinal double bond of the alkoxy-allene
and the alkyne function have never been observed.
With the feasibility of the alkoxyallene-yne Pauson–Khand
cyclocarbonylation established and the optimized reaction
conditions in hand (that is, [Rh(cod)Cl]2 (10 mol%) modified
with dppp (50 mol%), in toluene heated to reflux under 1 atm
of CO), we set out to explore the scope of this reaction for the
preparation of a number of perhydroazulene systems. Interest-
ingly, in the carbamate and benzyl series (R1: Cb or Bn), the
treatment of alkynes 12a, 12c–e, and 13b (R2: H, Et, TMS, or
CH2OBn) under optimal conditions provided the unsaturated
bicyclo[5.3.0] ring systems 25a, 25c–e, and 26b in similar
yields, which illustrates the high tolerance of this cycloaddition
reaction (Scheme 9 and Scheme 10). Moreover, extension of
the repertoire of allenes to the PMB series (R1: PMB) also per-
Table 1. Optimization of the alkoxyallene-yne Pauson–Khand reaction
with 12b (R1: Cb; R2: Me).
Catalyst/ligand
Solvent
T
t
Conversion Yield of
[8C] [h] [%]
25b [%]
1
2
3
4
5
6
7
8
[Rh(Cl)(CO)2]2/–
[Rh(Cl)(CO)2]2/–
[Rh(Cl)(CO)2]2/–
toluene
toluene
THF
90
RT
110
110
1.5 100
70
70
70
88
–
8
2
3
100
100
100
0
[Rh(Cl)(CO)2]2/dppp[a] toluene
[Rh(Cl)(CO)2]2/dppp
[Rh(Cl)(CO)2]2/dppp
[Rh(cod)Cl]2/dppp
[Rh(cod)Cl]2/dppp
acetonitrile 110 20
THF
toluene
THF
110 20
110 20 100
110 20
0
–
quant.
–
0
[a] dppp: 1,3-bis(diphenylphosphino)propane.
the desired products 25b and 26a with full conver-
sion within 1.5 h. Notably, 25b was isolated in good
yield (70%; Table 1, entry 1), whereas 26a was ob-
tained in moderate yield (38%), along with byprod-
ucts, which indicated stability problems (Table 2,
entry 1). If the temperature was lowered to 258C, the
reaction of 12b (Cb series) interestingly reached
completion in 8 h (Table 1, entry 2), whereas only
10% conversion was observed after 20 h in the
benzyl series (Table 2, entry 2). Alternatively, if the re-
action was performed in THF, there was no improve-
ment whatever in the series (Tables 1 and 2, entry 3).
Exposure to 10 mol% of [Rh(Cl)(CO)2]2 modified
with dppp (50 mol%) in toluene heated to reflux
under CO (1 atm; Table 1 and 2, entry 4) led to an im-
Table 2. Optimization of the alkoxyallene-yne Pauson–Khand reaction with 13a (R1:
Bn; R2: Me).
Catalyst/ligand
Solvent
T
t
Conversion Yield of
[8C] [h]
[%]
26a [%]
1
2
3
4
5
6
7
8
9
10
[Rh(Cl)(CO)2]2/–
[Rh(Cl)(CO)2]2/–
[Rh(Cl)(CO)2]2/–
[Rh(Cl)(CO)2]2/dppp
[Rh(Cl)(CO)2]2/P(OEt)3
[Rh(Cl)(CO)2]2/PO[a]
[Rh(Cl)(CO)2]2/dppp, AgOTf toluene
[Rh(cod)Cl]2/dppp
toluene
toluene
THF
toluene
acetonitrile 110
90
RT
110
110
1.5 100
38
–
20
2
6
4
4
10
100
100
100
100
20
77
24
52
–
90
–
–
THF
110
110
110
110
110
1.5 20
toluene
toluene
THF
28
20
20
100
0
0
[Rh(cod)Cl]2/dppp, AgOTf
[Rh(cod)Cl]2/Xantphos
[a] PO: 1-(2-(diphenylphosphanyl)phenyl)ethan-1-ol.
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Scheme 9. Alkoxyallene-yne Pauson–Khand cyclocarbonylations with the
all-carbon series (R1: Cb). a) [Rh(cod)Cl]2 (10 mol%), dppp (50 mol%), CO
(1 atm), toluene, 110 8C, [c]=0.1m.
Scheme 12. Synthesis of azabicyclo[5.3.0] ring systems through alkoxyallene-
yne Pauson–Khand reactions. a) [Rh(cod)Cl]2 (10 mol%), dppp (50 mol%), CO
(1 atm), toluene, 110 8C, [c]=0.1m.
either the starting material or the product is unstable under
the reactions conditions.
Finally, similar results were observed in the oxygen-tethered
series, for which the yields of the bicyclic [5,7] products 31a,
31b, 32a, and 32b varied from moderate to low (Scheme 13).
In some instances, complete decomposition of the substrate
occurred, particularly in the PMB series (R2: TMS).
Scheme 10. Alkoxyallene-yne Pauson–Khand cyclocarbonylations with the
all-carbon series (R1: Bn). a) [Rh(cod)Cl]2 (10 mol%), dppp (50 mol%), CO
(1 atm), toluene, 110 8C, [c]=0.1m.
Scheme 11. Alkoxyallene-yne Pauson–Khand cyclocarbonylations with the
all-carbon series (R1: PMB). a) [Rh(cod)Cl]2 (10 mol%), dppp (50 mol%), CO
(1 atm), toluene, 110 8C, [c]=0.1m.
Scheme 13. Synthesis of oxabicyclo[5.3.0] ring systems through alkoxy-
allene-yne Pauson–Khand reactions. a) [Rh(cod)Cl]2 (10 mol%), dppp
(50 mol%), CO (1 atm), toluene, 1108C, [c]=0.1m.
mitted the preparation of dienones 27a–d (R2: H, Et, TMS, and
CH2OBn) in 44–59% yields from 14a–d (Scheme 11).
Our next task focused on the application of the optimal
RhI-catalyzed PKR conditions to the construction of aza- and
oxabicyclo[5.3.0] ring systems.
Thus, we have clearly established the scope of the alkoxyal-
lene-yne Pauson–Khand reaction from alkoxyallenes bearing
alkoxy groups at the proximal position. Alkoxyallene-ynes pre-
senting various substitution patterns at the allenol and the
alkyne moiety, as well as three different tethers (carbon, nitro-
gen, and oxygen series), have been submitted to optimized
PKR conditions ([Rh(cod)Cl]2/dppp). The ring-closing reaction
has been found to occur exclusively between the distal double
bond of the alkoxyallene moiety and the alkyne counterpart,
which results in the formation of homo- or heterobicy-
clo[5.3.0]decadienone frameworks. Notably, the best results
were obtained in the carbamate series, whatever the tether (C,
N, or O), which provides evidence for the importance of the
electronic effect of the carbamate on the stability of both the
starting alkoxyallene and the resulting enol. Moreover, a strong
In contrast to all-carbon alkoxyallene-ynes, the cyclocarbony-
lation reaction with nitrogen-tether compounds 16a–c, 17a–c,
and 18a–d (R1: Cb, Bn, and PMB; R2: H, Et, TMS, and CH2OBn)
appeared more challenging (Scheme 12). Hence, under the
previously developed conditions, the reaction led to the de-
sired bicyclic systems 28a–c, 29a–c, 30a, and 30b in moder-
ate yields ranging from 21 to 59% and to an intractable mix-
ture for 30c and 30d (the target compound could never be
separated from the byproducts). The best results were attained
in the carbamate series, whereas lower yields were observed in
the PMB series. Unidentifiable products were systematically
obtained along with dienones, which provided evidence that
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substituent effect has been observed at the alkyne moiety, for
which a TMS group systematically led to a substantial drop in
yield. Finally, among the three elected tethers, the most prom-
ising results were observed in the carbon series. Although one
cannot fully exclude the influence of heteroatoms, the most
plausible explanation is the stronger Thorpe–Ingold effect in
the carbon series than in the heteroatom series (Scheme 14).
Pauson–Khand reaction to the total synthesis of thapsigargin is
now in progress.
Experimental Section
Typical procedure for the PKR: A microwave vial equipped with
a Teflon-coated stirrer bar and a septum cap was charged with
allene-yne and freshly distilled toluene (0.1m). The solution was de-
gassed by bubbling with argon for 5 min, then a CO atmosphere
was installed. Dppp (0.50 equiv) and [Rh(CO)2Cl]2 (0.10 equiv; or
[Rh(cod)Cl]2) were successively added in one portion, and the
mixture was submitted to bubbling CO for 2 min. The reaction vial
was placed in a preheated 110 8C oil bath and stirred under a CO
atmosphere. The reaction was monitored by TLC. Upon
completion, the mixture was cooled to room temperature and
concentrated under reduced pressure. The resulting residue was
purified by flash chromatography on silica gel.
Acknowledgements
Scheme 14. Factors influencing the synthesis of bicyclo[5.3.0] ring systems
through alkoxyallene-yne Pauson-Khand reactions.
We thank ANR for doctoral fellowships for A.T. and M.J. and an
assistant engineer fellowship for M.A.
Finally, the success of the alkoxyallene-yne PKR in the carba-
mate series prompted us to examine the cleavage of this enol
ether. Thereby, in a first trial, the reaction of Cb ether 31b with
excess trimethylsilyl trifluoromethanesulfonate (TMSOTf)[29]
provided ketone (Æ)-33 as only one diastereomer, which thus
demonstrates the synthetic utility of this cyclocarbonylation
reaction for accessing tertiary-alcohol-containing guaiane
systems (Scheme 15).
Keywords: allenes · alkynes · cyclization · Pauson–Khand
reactions · rhodium
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Scheme 15. Cleavage of the carbamate enol ether moiety of 31b. a) TMSOTf
(excess), toluene, À788C, then H2O, 20%, only one diastereomer observed in
NMR spectra (not optimized).
Conclusion
We have successfully performed intramolecular rhodium-
catalyzed Pauson–Khand cyclocarbonylation reactions of
alkoxyallene-ynes with the alkoxy group at the proximal posi-
tion to access [5,7] ring systems bearing an enol ether. These
reactions can be applied to the selective construction of all-
carbon-containing bicyclo[5.3.0]decadienones, as well as aza-
and oxabicyclo[5.3.0]decadienones. This study clearly estab-
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of useful functional groups present in the alkoxyallene-yne
substrates. Moreover, cleavage of the carbamate enol ether
was also accomplished, which demonstrates that this cyclocar-
bonylation reaction may become a method of choice as an
access to the carbon framework of guaianes possessing a terti-
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spite heating of the mixture to 608C or addition of one equivalent of
base.
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Received: November 25, 2015
Published online on February 19, 2016
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim