The stereochemical course of bromoetherification of enynes

Article abstract of DOI:10.1039/b800054a

Enynes undergo stereoselective syn intramolecular bromoetherification; the stereochemical course of the reaction was elucidated by X-ray crystallographic studies and by stereospecific synthesis of authentic bromoallenes. The Royal Society of Chemistry.

Full text of DOI:10.1039/b800054a

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The stereochemical course of bromoetherification of enynesw
a
a
a
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D. Christopher Braddock,* Roshni Bhuva, Yolanda Perez-Fuertes,
Rebecca Pouwer,a Craig A. Roberts,b Andrea Ruggiero,a Elaine S. E. Stokesb and
Andrew J. P. Whitea
Received (in Cambridge, UK) 7th January 2008, Accepted 5th February 2008
First published as an Advance Article on the web 20th February 2008
DOI: 10.1039/b800054a
Enynes undergo stereoselective syn intramolecular bromoether-
ification; the stereochemical course of the reaction was eluci-
dated by X-ray crystallographic studies and by stereospecific
synthesis of authentic bromoallenes.
eomers 7a or 7b on bromoetherification. Thus, if the
bromoetherification proved to occur in a syn fashion, E-enyne
5 would give bromoallene 7a, the Z-enyne 6 giving diaster-
eomeric bromoallene 7b. If however, the bromoetherification
is anti specific, then the E-enyne would give rise to 7b, and the
Z-enyne would give 7a (Scheme 2).
The bromoallene motif occurs widely in the halogenated C15
acetogenic metabolites isolated from Laurencia species;1 obtu-
sallenes II (1)2 and IV (2)3 are representative. We have recently
proposed a biosynthetic hypothesis concerning the formation
of the obtusallenes where their bromoallene unit may be
formed by an electrophilic macrobromoetherification of enyne
3 (Scheme 1).4 Inspection of the obtusallene II and IV struc-
tures reveal them to have identical tetrahydrofuran cores, but
are epimeric at both C4 and with respect to the chiral
bromoallene. This analysis suggests that they therefore arise
from the same enyne precursor, that nucleophilic attack of the
alcohol can be on either the Si or Re face of the enyne at C4,
and that the bromoetherification is stereospecific. However, the
overall stereochemical outcome of the bromoetherification will
also be controlled by the original double bond geometry of the
enyne. For instance, the required stereochemistries of the
obtusallene bromoallenes could arise either by syn addition
to an E-enyne or anti addition to a Z-enyne. Biomimetic
intramolecular bromoetherification of enynes has previously
been demonstrated for other members of the wider natural
product family, to give mixtures of diastereomeric bromoal-
lenes, where pre-existing stereocentres may affect the diaster-
eoselectivity.5 In addition, laurediol 4, which is the generally
accepted biosynthetic precursor of the entire family has been
isolated with both E and Z enyne configurations.6 We now
show that in the absence of any other perturbing chiral
centres, the intramolecular bromoetherification of enynes is
stereoselective, and proceeds via syn addition.
E-Enyne 5 and Z-enyne 6 were prepared starting from silyl
ether 87 (Scheme 3). PCC mediated oxidation gave aldehyde
9.8 E-Selective enyne formation with the ylide derived from
phosphonium salt 109 and NaHMDS gave protected enyne 11.
Double deprotection with TBAF gave the E-enyne 5. Alter-
natively, silyl ether 8 was converted first into iodide 12,10 and
then into phosphonium salt 1311 (Scheme 4). Wittig reaction
with propynal 1412 gave TMS-enyne 15 as an inseparable
1.6 : 1 mixture of Z : E geometric isomers. TBAF deprotection
as before gave a 1.6 : 1 mixture of Z- and E-enynes 6 and 5,
respectively.
Bromoetherification of 5 proceeded smoothly with NBS
(100% conversion, 4 h, CDCl3, ꢀ40 1C to r.t.) to give a 6 : 1
mixture of diastereomeric bromoallenes 7.z Bromoetherifica-
tion of 6 under identical conditions gave the same diastereo-
meric allenes 7 but in a reversed 1 : 7 ratio.y These experiments
Substrates E-enyne 5 and Z-enyne 6 were selected to
investigate the stereochemical course of bromoetherification.
It was expected that if the bromoetherification was stereospe-
cific, each substrate would give different bromoallene diaster-
a Department of Chemistry, Imperial College London, London, UK
SW7 2AZ. E-mail: c.braddock@imperial.ac.uk; Fax:
+44(0)2075945805; Tel: +44(0)2075945772
b AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK
SK10 4TG
w Electronic supplementary information (ESI) available: Notes
z,y,z,ww,**,zz,zz,***, full experimental details for the preparation of
compounds 11, 5, 15, 6, 16–17, 7a, 19–23, 25–28 and X-ray crystal-
lographic details for 24. CCDC 625183. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b800054a
Scheme 1 Postulated bromoallene formation of obtusallenes II
and IV.
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Scheme 5 Stereospecific synthesis of bromoallene 7a.
Scheme 2 Stereospecific bromoetherifications.
Scheme 3 Synthesis of E-enyne 5.
demonstrate that the course of bromoetherification of enynes
is essentially stereospecific.
To assign the relative stereochemistry of the bromoallene
products and hence the mode—syn vs. anti—of addition,
authentic bromoallene 7a was prepared by a stereospecific
route from E-enyne 5 (Scheme 5). Syn-epoxidation of 5,
followed by acid-catalysed stereospecific ring-opening of the
epoxide gave known alcohol 16.13 Activation of the alcohol as
the trisylate 1714 and stereospecific anti SN20-bromoallene
formation15 gave 7a as expected.16 This proved to be identical
to the major product from bromoetherification of 5 showing
that bromoetherification proceeds with syn selectivity, and
also allows assignment of bromoallene 7b as the major dia-
stereoisomer resulting from the cyclisation of enyne 6 (also by
syn addition).
Scheme 6 Synthesis and cyclisation of E-enyne 23.
tion to 20, followed by DMP18 oxidation to aldehyde 21 and
E-selective Wittig reaction using phosphonium salt 10 gave
protected enyne 22.z Deprotection with acetic acid-buffered
TBAF gave E-enyne 23.ww Enyne 23 cyclised smoothly on
treatment with NBS, to give bromoallene 24 as a 4.5 : 1
mixture of diastereomers.zz Bromoallene derivative 24**
proved to be crystalline and could be analysed by single-
crystal X-ray crystallography. The two diastereoisomers co-
crystallised in a 5.7 : 1 ratio and inspection of the structure of
the major diastereoisomer revealed that the bromoetherifica-
tion had occurred by syn addition.zz Thus the syn cyclisation
To further unambiguously elucidate the stereochemical
course of bromoetherification of enynes we determined to
prepare a substrate that would give a crystalline bromoallene
on cyclisation. Accordingly, diethanolamine 18 was N-tosy-
lated to give tosyldiol 19 (Scheme 6).17 Monoalcohol protec-
Scheme 4 Synthesis of Z-enyne 6.
Scheme 7 Intermolecular bromoetherification.
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¨
2 A. Oztunc
pathway occurring by a 5-exo-mode is also followed in a
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¸
and F. Pietra,
We have also explored the intermolecular bromoetherifica-
tion reaction of an unfunctionalised enyne 25 with ethylene
glycol as a representative alcohol. To the best of our knowl-
edge this intermolecular reaction is unprecedented in the
literature. In preliminary experiments in dichloromethane
using 10 equivalents of added diol, although characteristic
bromoallene signals were observed in the 1H NMR spectrum,
a complex mixture of products were obtained, presumably as
the result of competitive intermolecular attack of a second
enyne on an incipient bromonium ion. In contrast using
ethylene glycol as the solvent (300 equivalents) gave rise to
bromoetherification with two diastereomeric bromoallenes 26
and 27*** isolated in 7 and 6% yield, respectively after
column chromatography (Scheme 7). A dibrominated adduct
28 (10%) was also isolated that must arise by initial attack of
the alcohol directly at the brominated alkyne of the enyne. The
relative ratio of 26 : 27 was essentially 1 : 1 by inspection of the
1H NMR spectrum of the crude product, showing that the
intermolecular bromoetherification reaction is not stereoselec-
tive under these conditions.
´
5 (a) A 23 : 19 ratio of bromoallenes was obtained in the cyclisation
of an E-enyne into laurallene: J. Ishihara, Y. Shimada, N. Kanoh,
Y. Takasugi, A. Fukuzawa and A. Murai, Tetrahedron, 1997, 53,
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cyclisation of an E-enyne in a biomimetic-type cyclisation for the
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3175–3177; (c) a 1 : 1 ratio of bromoallenes was obtained in the
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E. A. Tabet, J. Am. Chem. Soc., 2000, 122, 5473–5476; (d) a 1 : 1
ratio of bromoallenes was obtained in a biomimetic-type cyclisa-
tion of a Z-enyne for the synthesis of (ꢂ)-panacene: K. S. Feldman,
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In conclusion, we have shown that an unperturbed intra-
molecular bromoetherification of an enyne proceeds by stereo-
selective syn addition. The inherent stereoselectivity is higher
than those observed to date in the cyclisation of enynes to
bromoallenes in more complex systems with pre-existing
stereocentres.5 Mechanistically we propose that a bromonium
ion is formed on the alkyne followed by nucleophilic attack of
the alcohol under stereoelectronic control. This is consistent
with the stereochemical outcome (syn) of the overall addition
of Br2 across a 1,3-diene where the participating orbital array
is essentially identical.19 The above findings represent funda-
mental stereochemical information with respect to electrophi-
lic 1,4-addition across an enyne. Moreover, it should guide the
choice of enyne geometry required in the synthesis of natural
products from Laurencia species. In particular it allows us
to target an E-enyne for the synthesis of obtusallenes
II and IV.20,21
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We thank the EPSRC for a QUOTA award (to R. B.), for
financial support (EPSRC Grant no. EP/C542169/1) and
AstraZeneca for a CASE award (to R. B.)
20 For the synthesis of the core of obtusallenes II and IV, see: D. C.
Braddock, R. Bhuva, D. S. Millan, Y. Perez-Fuertes, C. A.
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Notes and references
1 K. Murai, in Comprehensive Natural Product Chemistry, ed. D. H.
R. Barton, O. Meth-Cohn and K. Nakanishi, 1999, vol. 1,
pp. 303–324.
21 For the structural reassignment of obtusallenes V, VI and VII by
GIAO-based density functional prediction, see: D. C. Braddock
and H. S. Rzepa, J. Nat. Prod., 2008, in press.
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