Epoxidation of bromoallenes connects red algae metabolites by an intersecting bromoallene oxide-Favorskii manifold

Article abstract of DOI:10.1039/c3cc46720a

DMDO epoxidation of bromoallenes gives directly α,β-unsaturated carboxylic acids under the reaction conditions. Calculated (ωB97XD/6- 311G(d,p)/SCRF = acetone) potential energy surfaces and ²H- and ¹³C-labeling experiments are consistent with bromoallene oxide intermediates which spontaneously rearrange via a bromocyclopropanone in an intersecting bromoallene oxide-Favorskii manifold.

Full text of DOI:10.1039/c3cc46720a

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Epoxidation of bromoallenes connects red algae
metabolites by an intersecting bromoallene
oxide – Favorskii manifold†
Cite this: Chem. Commun., 2013,
49, 11176
Received 3rd September 2013,
Accepted 7th October 2013
D. Christopher Braddock,* James Clarke and Henry S. Rzepa
DOI: 10.1039/c3cc46720a
www.rsc.org/chemcomm
DMDO epoxidation of bromoallenes gives directly a,b-unsaturated that bromoallene 2 and a,b-unsaturated carboxylate 3 may also be
carboxylic acids under the reaction conditions. Calculated (xB97XD/ connected biogenetically by epoxidation.
6-311G(d,p)/SCRF = acetone) potential energy surfaces and 2H- and
13C-labeling experiments are consistent with bromoallene oxide been studied, the epoxidation of bromoallenes has not been
intermediates which spontaneously rearrange via a bromocyclopro- reported.11 Herein, we report the hitherto unknown direct con-
While the epoxidation of allenes8,9 and vinyl bromides10 has
panone in an intersecting bromoallene oxide – Favorskii manifold.
version of bromoallenes to a,b-unsaturated carboxylic acids via an
initial epoxidation event and the presumed intermediacy of a
The remarkably wide structural diversity and complexity of halo- bromoallene oxide. We also show by computational modeling and
genated C15 acetogenin metabolites isolated from marine red 2H- and 13C-labeling studies that the latter’s spontaneous reorga-
algae of Laurencia species1 continue to stimulate innovative nization to an a,b-unsaturated carboxylic acid under the reaction
efforts in their target synthesis,2 in the discovery of new synthetic conditions is consistent with a bromocyclopropanone inter-
transformations3 and in advancing biosynthetic hypotheses.4
recent re-isolation5 of obtusallene IV (1)6 from Laurencia marilzae
A
mediate in an intersecting allene oxide – Favorskii manifold.
Bromoallene 412 was selected as a suitable substrate for investigat-
provided also 12-epoxyobtusallene IV (2) and unnamed a,b- ing epoxidation and was synthesized by a standard sequence from
unsaturated carboxylate ester (3) with an identical macrocycle to heptanal (ESI†).13 Much to our delight, epoxidation of bromoallene 4
epoxybromoallene 2 (Fig. 1). It seems reasonable to connect using dimethyl dioxirane (DMDO), generated either in situ14 or as a
E-alkene 1 and trans-epoxide 2 biogenetically via enzymatic solution (ESI†)15 (Scheme 1), gave a mixture of Z and E-a,b-unsaturated
epoxidation,7 and on the basis of their co-isolation, we propose carboxylic acids 5 directly in low but reproducible yields (note §, ESI†).
The low yields can be attributed to decomposition of DMDO16a under
the reaction conditions to methyl radicals,16b and subsequent radical
attack on either of the products or starting materials (note ¶, ESI†).
Mechanistically, we invoke the following pathway for the for-
mation of a,b-unsaturated carboxylic acids from DMDO mediated
epoxidation of bromoallenes (Fig. 2). Initial epoxidation of the
bromoallene would give bromoallene oxides of the type A and/or B
(note f, ESI†). Spontaneous epoxide opening8c via bromo oxyallyl
cations C and D (note ††, ESI†) respectively converge on the same
bromocyclopropanone E. This intermediate now intersects with the
Favorskii rearrangement manifold of a,a- and a,a0-dibromoketones
where the resulting bromocyclopropanones E are known to collapse
after attack by water giving hydrate F to a,b-unsaturated carboxylic
acids 5 (note **, ESI†).17,18 Evidently, there is sufficient water in the
dioxirane solution to function as a nucleophile here (note ‡‡, ESI†).
Fig. 1 Metabolites 1–3 from Laurencia marilzae and proposed biogenesis via
epoxidation events.
Department of Chemistry, Imperial College London, London, SW7 2AZ, UK.
E-mail: c.braddock@imperial.ac.uk; Fax: +44 (0)2075945805;
Tel: +44 (0)2075945772
† Electronic supplementary information (ESI) available: Notes §, ¶, f, ††, **, ‡‡,
§§, ¶¶, ff, †††, ***, ‡‡‡; general experimental; experimental details and char-
acterising data for compounds leading to bromoallenes
4 (including ESI
Scheme S1 for the synthesis of bromoallenes 4), (1-2H)-4 and (1-13C-4) and
epoxidation thereof leading to E- and Z-5, (E-2-2H)- and (Z-2-2H)-5, and (E-2-13C)-
and (Z-2-13C)-5; Copies of 1H and 13C spectra for all compounds showing 2H and
13C isotopic shifts and coupling constants where appropriate; ESI references. See
DOI: 10.1039/c3cc46720a
Scheme 1 Epoxidation of bromoallene 4 using DMDO solution.
c
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Fig. 2 Mechanistic rationale for conversion of bromoallenes into a,b-unsaturated
carboxylic acids, with the carbon atoms of the functional groups numbered 1–3
showing an interchange of carbon atoms 1 and 2 (see also interactive Fig. 2 in
HTML version of this article).
Scheme 3 Synthesis of 13C-labeled bromoallene (1-13C)-4.
Interestingly, regardless of the initial site of epoxidation, this mecha-
nism predicts that carbon atoms 1 and 2 in bromoallene 4 inter-
change positions in the a,b-unsaturated carboxylic acid products 5.
This mechanism can be subjected to scrutiny via density func-
tional level (oB97XD/6-311G(d,p)/SCRF = acetone)19 exploration of
the potential energy surface (R = H, Me, presented as an interactive
version of Fig. 2 (ref. 20) via a digital data repository21). Oxygen
transfer from dimethyldioxirane to form both A and B (TS1) have
MeOH-d4 to give labeled propargylic alcohol (1-2H)-6 (Scheme 2).
Subsequent alcohol trisylation25 gave (1-2H)-7, and SN20 displace-
ment of the trisylate with bromide under the action of LiCuBr2
(ref. 26) provided bromoallene (1-2H)-4 with 70% deuterium incor-
poration at the 1-position.†
13C-labeled bromoallene (1-13C)-4 was similarly targeted, com-
mencing with silyl enol ether 8 formation27 from octanal
(Scheme 3). Oxidation using mCPBA gave interrupted Rubottom28
adduct 9, which could be acetylated to give acetate 10. Desilylation
using buffered TBAF29 revealed protected a-hydroxyaldehyde 11,
which we planned to use in a Wittig reaction with a suitably
13C-labeled phosphorous ylid. To the best of our knowledge, there is
only a single report30 using methyltriphenylphosphonium iodide to
generate the Stork–Wittig reagent31 using an in situ deprotonation–
iodination–deprotonation procedure which we adapted using
13C-labeled salt 12 – available from relatively inexpensive 99% atom
13C-labeled methyl iodide – to give vinyl iodides Z-(1-13C)-13,
E-(1-13C)-13 and diiodide (1-13C)-14.32 Acetate deprotection as a
mixture gave the corresponding alcohols Z-(1-13C)-15, E-(1-13C)-15
and (1-13C)-16 all with 99% 13C at the alkene terminus.†
thermally accessible free energy activation barriers DGy298 (R = H,
26.8 for A, 27.3 for B; R = Me, 26.8 for A, 24.6 kcal molꢀ1 for B),
followed by a second, lower energy dyotropic rearrangement (TS2) to
give E. An intrinsic reaction coordinate (IRC) reveals that TS2
(R = H,Me) represents the concerted transformation of A or B to
E, with C/D acting as ‘‘hidden intermediates’’ in the process.22 Such
hidden intermediates can be potentially transformed to real ones by
tuning the substituents, and in this instance changing R from H or
Me to OMe is predicted to accomplish this by stabilization of C/D
(see interactive Fig. 2). TS2 itself (R = Me) has some early character of
C/D; the C–Br bond is calculated to initially contract in length due to
a significant stabilising resonance contribution of Br lone pairs,
from 1.924/1.896 Å (A and B respectively) via 1.840/1.885 (TS2),
1.856/1.868 (C/D acting as hidden intermediates) to 1.921/1.922 Å
(E).23 Calculations having demonstrated the thermal accessibility of
the epoxidation-bromocyclopropanone sequence, 2H- and 13C-label-
ing experiments were necessary to verify the overall reorganization
(4 to A/B to E to F to 5, Fig. 2) of the carbon framework.24
Dehydrohalogenation of Z- and E-iodides (1-13C)-15 in the
presence of inseparable diiodide (1-13C)-16 with LDA gave pro-
pargylic alcohol (1-13C)-7 in good overall yield, with the unprece-
dented observation that LDA converts vinyl 1,1-diiodides into
terminal alkynes also (note §§, ESI†). Interestingly, 4% of the
alkyne product was found to be the 2-13C isotopomer (ESI†),
implicating a 1,1-elimination reaction pathway for diiodide 16
Deuterated bromoallene (1-2H)-4 was prepared by addition of
ethynylmagnesium bromide to heptanal, in situ deprotonation of
the propargylic alkoxide with n-butyllithium and quenching with
Fig. 3 1H NMR spectra of (a) (E-2-13C)-5 and (b) (Z-2-13C)-5 displaying the
1
Scheme 2 Synthesis of deuterated bromoallene (1-2H)-4.
expected JCH values for the a-vinyl protons.
c
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7 For reviews on enzymatic epoxidation of alkenes see: (a) M. Sono,
M. P. Roach, E. D. Coulter and J. H. Dawson, Chem. Rev., 1996, 96,
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and competitive alkyl group migration from a vinylidene inter-
mediate (note ¶¶, ESI†). Alcohol (1-13C)-7 was then converted to the
desired bromoallene (1-13C)-7 (as 4% of its 2-13C-isotopomer, ESI†)
as previously described (cf., Scheme 2).
´
8 For reviews see: (a) G. L’abbe, Angew. Chem., Int. Ed. Engl., 1980, 19,
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cyclopropanone see: R. L. Camp and F. D. Greene, J. Am. Chem. Soc.,
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2-bromo-3-(diphenylmethylene) oxirane-2-carboxylate was reported
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With (1-2H)-4 and (1-13C)-4 in hand, epoxidation with DMDO was
conducted. For deuterated (1-2H)-4, after the reaction was conducted
in the usual manner (cf., Scheme 1), E-(2-2H)-5 and Z-(2-2H)-5 were
isolated each showing 65% deuteration at the a-position only
(note ‡, ff, ESI†). Evidently, this result is consistent with the
proposed mechanism (cf., Fig. 2) (note †††, ESI†). More compel-
lingly, epoxidation of bromoallene (1-13C)-4 gave (E-2-13C)-533 and
(Z-2-13C)-5 (28% isolated yield) where carbon atoms 1 and 2 from
the bromoallene have entirely interchanged positions, giving also
4% of each of the (E-1-13C)-5 and (Z-1-13C)-5 isotopomers (ESI†). The
expected 1JCH coupling constants experienced by the a-vinyl protons
of the major isotopomers are clearly apparent in their 1H NMR
spectra (Fig. 3).
In conclusion we have established that the hitherto unknown
direct conversion of bromoallenes to a,b-unsaturated carboxylic
acids using DMDO is consistent with an initial epoxidation event
(note ***, ESI†) followed by a spontaneous reorganization via a
bromocyclopropanone, a mechanism supported by calculations,
in an intersecting bromoallene oxide – Favorskii manifold. These
experiments support the proposed biogenesis of a,b-unsaturated
carboxylate 3 from bromoallene 2 by epoxidation (note ‡‡‡, ESI†).
We thank the EPSRC for DTG funding (to J. C.).
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