An expeditious assembly of 3,4-benzannulated 8-oxabicyclo[3.2.1]octane systems by [2+2+2] alkyne cyclotrimerisation: Total synthesis of (-)-bruguierol A

Article abstract of DOI:10.1002/ejoc.200700648

Facile construction of benzene-fused 8-oxabicyclo[3.2.1]octane systems by employing a cross alkyne cyclotrimerisation reaction was explored. With this procedure, (-)-bruguierol A was synthesised, and its absolute configuration was established. Wiley-VCH V

Full text of DOI:10.1002/ejoc.200700648

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700648
An Expeditious Assembly of 3,4-Benzannulated 8-Oxabicyclo[3.2.1]octane
Systems by [2+2+2] Alkyne Cyclotrimerisation: Total Synthesis of
(–)-Bruguierol A
Chepuri V. Ramana,*[a] Sumanth R. Salian,[a] and Rajesh G. Gonnade[a]
Dedicated to Professor Andrea T. Vasella on the occasion of his 65th birthday
Keywords: Total synthesis / Epoxidation / Cyclotrimerisation / Wilkinson’s catalyst
Facile construction of benzene-fused 8-oxabicyclo[3.2.1]oc- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
tane systems by employing a cross alkyne cyclotrimerisation
reaction was explored. With this procedure, (–)-bruguierol A
was synthesised, and its absolute configuration was estab-
lished.
Germany, 2007)
the application of intermolecular [2+2+2] alkyne cyclo-
trimerisation reactions for the construction of benzannul-
ated 8-oxabicyclo[3.2.1]octane systems. Our initial foray
into this area was stimulated by the recently isolated natural
products bruguierol A–C (1–3, Figure 1), which portrayed
this new 3,4-benzannulated 8-oxabicyclo[3.2.1]octane struc-
tural skeleton.[10] The most general methods used to access
the oxabicyclo[3.2.1]octane systems are [4+3] cycload-
ditions and annulations.[11,12] Marson and coworkers re-
ported a general route to bridged bicyclo ethers by tandem
cyclisations involving 3,4-epoxy alcohols.[13]
Introduction
Since its first disclosure by Reppe et. al,[1] the transition-
metal-catalysed [2+2+2] alkyne cyclotrimerisation reac-
tion[2] has become an integral component in the armoury
of organic synthetic methods. The utility of this reaction is
exemplified in the synthesis of a variety of complex natural
products comprising aromatic rings,[3] dendritric en-
sembles,[4] and cyclophanes[5] with variable sizes. Recent
progress in this context includes the development of water-
soluble catalysts[6] and a variety of chiral ligands for the
asymmetric version[7] of this transformation. Various transi-
tion metals (e.g. Ni, Rh, Co, Pd, Cr, Fe, Ru and Ta) as well
as Ziegler-type catalysts have been recognised to promote
inter- and intramolecular versions of the cyclotrimerisation
reaction.
Vollhardt and coworkers showed the feasibility of the in-
tramolecular [2+2+2] cycloaddition reaction of enediynes
for the synthesis of highly strained [3.2.1]bicyclooctanes;[8]
however, the scope of this reaction in the synthesis of
bridged bicyclic systems has seen limited potential. Very re-
cently, Malacria and coworkers explored the possibility of
this intramolecular [2+2+2] cyclisation approach for the
tandem construction of the B, C, D and E rings of the poly-
cyclic taxane system.[9] To the best of our knowledge, no
report on intermolecular [2+2+2] cyclisations leading to
bridged bicycles has been documented. Herein we report
Figure 1. Structures of bruguierol A–C and the key [2+2+2] cyclo-
trimerisation reaction for the creation of the 8-oxabicyclo[3.2.1]oc-
tane system.
Bruguierol A–C were isolated and characterised by
Sattler and coworkers from the stem of Bruguieragym-
norrhiza, which was collected from the coast of Xiamen in
the south of China.[10] Amongst the three, bruguierol C
showed moderate activity against Gram-positive and
Gram-negative bacteria including mycobacteria and resist-
[a] National Chemical Laboratory
Dr. Homi Bhabha Road, Pune 411008, India
Fax: +91-20-2590-2629
E-mail: vr.chepuri@ncl.res.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 5483–5486
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C. V. Ramana, S. R. Salian, R. G. Gonnade
SHORT COMMUNICATION
ant strains (MICs 12.5 µgmL–1). Extensive structural inves- obtain crystalline dibenzoate 11, and this compound was
tigation with various 2D NMR spectroscopic techniques characterised by single-crystal X-ray structural analysis
was carried out on 1–3 to elucidate their constitution and (Figure 2).[21]
relative stereochemistry; however, complete absolute stereo-
chemical characterisation was hampered by the lack of a
suitable functional group handle on the bicyclic framework
that could be derivatised according to either the Mosher
method or other related methods to establish the absolute
configurations indirectly. This communication describes the
first total synthesis of (–)-bruguierol A (1) with its absolute
stereochemistry.
Strategically, with the consideration that the cyclo-
trimerisation reaction would build the A and B rings of the
tricyclic core (Figure 1), diyne 4 was identified as the key
intermediate. Because the absolute configuration of natural
bruguierol was unknown, we decided to use the chiral struc-
ture of 4 as depicted in the Figure 1. Kinetic resolution of
a 6-substituted hex-2-en-1,6-diol (5) by means of Sharpless
asymmetric epoxidation was chosen for the synthesis of
4.[14]
Scheme 2. Cyclotrimerisation of diyne 4 and 2-butyne-1,4-diol (9).
Results and Discussion
The synthesis started with the propargylation of known
6-acetyloxy-4-methylhex-4-enal (6)[15] under Barbier condi-
tions (Scheme 1)[16] to afford 5. The following Sharpless
asymmetric epoxidation[14c] reaction proceeded well under
standard conditions and gave easily separable isomeric fu-
rans 7 and 8 in 90% yield and with 91 and 90% ee, respec-
tively (see Supporting Information for details). The NaIO4-
mediated cleavage of required cis furan diol 7 followed by
treatment of the intermediate aldehyde with the Ohira–
Bestmann reagent[17] gave key diyne 4 in 82% yield.
Figure 2. ORTEP diagram of compound 11.
To illustrate the flexibility of our strategy, various al-
kynes were employed in the trimerisation reaction with di-
yne 4 and Wilkinson’s catalyst, and the results are summa-
rised in Tables 1 and 2. With simple acetylene (Table 2, En-
try 1), the reaction was carried out in a sealed tube and 3,4-
benzannulated 8-oxabicyclo[3.2.1]octane (12) was obtained
in moderate yield. The cyclotrimerisation reaction was at-
tempted with the use of other available symmetrical alkynes
such as dimethylacetylene dicarboxylate, bis(trimethylsilyl)-
acetylene and diphenylacetylene, but these reactions were
unsuccessful (Table 2, Entries 9–11) and self-dimerised
products of diyne 4 were formed predominantly.
Table 1. Catalysts used for the trimerisation of 4 and 9.
Catalyst
Solvent
T [°C]
t [h]
Yield [%]
Ni(cod)2/PPh3
Mo(CO)6
THF/toluene
THF/toluene
toluene/ethanol
reflux
reflux
80
reflux
reflux
10
12
3
–
–
23
18
85
–
Scheme 1. Reagents and conditions: (a) 1. propargyl bromide, Zn,
saturated aqueous NH4Cl, THF, 0 °C Ǟ r.t., 2 h, 87%; 2. K2CO3,
methanol/water, r.t., 4 h, 90%; (b) -(+)-DIPT, Ti(OiPr)4,
tBuOOH, DCM, –20 °C, 6 h, 90%; (c) 1. silica-supported NaIO4,
DCM, r.t., 2 h; 2. dimethyl-1-diazo-2-oxopropylphosphonate,
K2CO3, methanol, r.t., 4 h, 82%.
Rh(PPh3)3Cl
CoCl2·6H2O/L[a]/Zn THF
[Ir(cod)Cl]2dppe
THF/toluene
–
[a] L = 2-(2,6-diisopropylphenyl)iminomethylpyridine.
With the fully elaborated diyne framework of 4 in place,
Unsymmetrical alkynes like phenylacetylene, hex-1-yne
the task of cyclotrimerisation with another alkyne was at- and propargyl alcohol gave 1:1 inseparable regioisomeric
tempted by using easily available 2-butyne-1,4-diol (9). Af- mixtures in moderate-to-good yields. With 1-acetyloxy-2-
ter screening few catalysts, Wilkinson’s catalyst [Rh(PPh3)3- pentyne-4-one (Table 2, Entry 8), an inseparable 4:1 mix-
Cl] was found to effect the cyclotrimerisation reaction of 4 ture of regioisomeric products was obtained, and the con-
with 9 (Scheme 2) effectively at 80 °C and afforded 10 in stitution of the major isomer was deduced with the help of
85% yield.[18] This was derivatised as its p-nitrobenzoate to the NOESY spectrum of a mixture of 22/23.
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Total Synthesis of (–)-Bruguierol A
Table 2. Trimerisation of 4 {3 mol-% [Rh(PPh3)3Cl], toluene, stitution without a doubt.[21] However, the optical rotation
80 °C} with different alkynes.
of the synthetic sample of 1 {[α]D = –19.8 (c = 1.0, CHCl3)}
was similar to the reported value {[α]D = +14.4 (c = 0.3,
CHCl3)}[10] but opposite in sign, which indicated that the
synthetic sample was the enantiomer of bruguierol A,
which established the absolute stereochemistry of brugui-
erol A as 5R,8S.
Figure 3. ORTEP structure of (a) bruguierol A (1) and (b) 24.
Conclusions
The chemistry described herein demonstrates the appli-
cability of a rhodium-catalysed [2+2+2] cyclotrimerisation
reaction for the construction of 3,4-benzannulated 8-oxa-
bicyclo[3.2.1]octane systems. An expedient total synthesis of
bruguierol A (1) was completed, and its absolute configura-
tion was established. As a result of the minimal use of pro-
tecting groups and the late-stage installation of the key bi-
cyclic system, the present approach leaves ample room for
library syntheses. Considering the operational simplicity,
this methodology has the potential to be used to gain entry
into the synthesis of benzene-fused bridged bicyclic systems,
which are prevalent in various natural products and in some
of the investigational drugs. Efforts to extend the chemistry
described herein to bruguierol B and C and the variation of
the central heteroatom to synthesise related natural product
like libraries are currently underway in our research group.
[a] For the preparation of this substrate see ref.[19]
After establishing the feasibility of the [2+2+2] cyclo-
trimerisation reaction for the synthesis of the 3,4-benzannu-
lated 8-oxabicyclo[3.2.1]octane system, we next proceed to
the synthesis of bruguierol A by using compounds 16/17.
The elaboration of compounds 16/17 to bruguierol A (1) Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterisation data for all
compounds.
and its regioisomer 24 is summarised in Scheme 3 and Fig-
ure 3. Oxidation of the 16/17 mixture with MnO2 followed
by treatment with m-CPBA[20] provided bruguierol A (1)
and 24 in 33% overall yield, and the products were sepa-
rated and characterised. The spectroscopic data of synthetic
bruguierol A (1) was in excellent agreement with the data
Acknowledgments
We thank the Director of the National Chemical Laboratory and
reported for the natural product. In addition, single-crystal Dr. M. K. Gurjar (Head, Organic Chemistry Division) for their
constant encouragement, and S. R. S. thanks the CSIR (New
Delhi) for financial assistance in the form of a research fellowship.
X-ray structural analyses of 1 and 24 established their con-
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Eur. J. Org. Chem. 2007, 5483–5486
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Published Online: September 14, 2007
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