Transannular Claisen rearrangement reactions for the synthesis of vinylcyclobutanes: Formal synthesis of (±)-grandisol

Article abstract of DOI:10.1039/c1ob06619f

Unsaturated eight-membered lactones undergo decarboxylative and non-decarboxylative transannular Ireland-Claisen rearrangement reactions, to give substituted vinylcyclobutanes. A formal synthesis of (±)-grandisol is described. The Royal Society of Chemist

Full text of DOI:10.1039/c1ob06619f

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Transannular Claisen rearrangement reactions for the synthesis of
vinylcyclobutanes: formal synthesis of ( )-grandisol†
Donald Craig,*a Kiyohiko Funai,a Sophie J. Gore,a Albert Kanga and Alexander V. W. Maywegb
Received 22nd September 2011, Accepted 6th October 2011
DOI: 10.1039/c1ob06619f
Unsaturated eight-membered lactones undergo decarboxyla-
tive and non-decarboxylative transannular Ireland–Claisen
rearrangement reactions, to give substituted vinylcyclobu-
tanes. A formal synthesis of ( )-grandisol is described.
respectively.9 Previously, Funk et al.10 and Cameron and Knight11
had reported Claisen rearrangements of a-unsubstituted macro-
lactones which gave ring-contracted cyclic products bearing cis-
disposed carboxylic acid and alkenyl groups. This arises because
the silyl ketene acetal (E)-geometry imposed by the ring12 limits
the subsequent rearrangement to a single accessible boat-like
transition state.
Recently, Boeckman and co-workers reported13 the first example
of reversible cyclobutane formation via transannular Claisen
rearrangement. In this work the starting materials were alkenyl-
substituted cyclobutanecarboxaldehydes, made by intramolecular
allylation via an SN2¢-type reaction;14 the dihydrooxocene sub-
strates for the Claisen rearrangement were accessed by retro-
Claisen rearrangement of the cyclobutane. Starting from z-
lactones 1–3 synthesised from w-hydroxyacids, this communica-
tion describes the first synthesis of substituted vinylcyclobutanes
via irreversible transannular Claisen rearrangement reactions, and
application of the chemistry in a formal synthesis of the boll weevil
pheromone ( )-grandisol 4.
Since its discovery in 1972, the Ireland–Claisen rearrangement1
has become a mainstay of organic synthesis, because it enables
regiospecific and stereoselective C–C bond formation from readily
obtained allylic esters.2 The decarboxylative Claisen rearrange-
ment (dCr) reaction (Scheme 1) is a catalysed variant3 of the
transformation4 whose utility has been demonstrated in the de-
aromatisation of heteroaromatic substrates,5 the de novo syn-
thesis of pyridines6 and in natural product total synthesis.7 In
addition, we have studied quantitatively the relationship between
substrate structure and reactivity in the dCr reactions of allylic
tosylmalonates.8
The synthesis of the z-lactones required for this study
necessitated the preparation of allylic carbonates 5 and 6 depicted
in Scheme 2. For lactone 1, the synthesis of precursor 5 was carried
out by hydroxymethylation of the THP ether of but-3-yn-1-ol15 and
formation of the corresponding methyl carbonate. Deprotection of
the THP group and hydrogenation of the resultant alkynol gave a Z
homoallylic alcohol, which was mesylated and then converted into
5 by reaction with sodium iodide under standard SN2 conditions.
Precursor 6 was required for the synthesis of lactones 2 and 3, and
was made starting from 3-(tert-butyldiphenylsilyloxy)propanal.16
Olefination using the Ando modification17 of the
Scheme 1 Decarboxylative Claisen rearrangement reaction (BSA =
N,O-bis(trimethylsilyl)acetamide).
Recently we reported transannular dCr ring contraction re-
actions of a-sulfonyl and a-sulfoximinyl e-lactones as an ef-
ficient route to 2-vinylcyclopropylsulfones and -sulfoximines,
aDepartment of Chemistry, Imperial College London, South Kensing-
ton Campus, London, UK, SW7 2AZ. E-mail: d.craig@imperial.ac.uk;
Fax: +44 (0)20 7594 5804; Tel: +44 (0)20 7594 5771
bF. Hoffmann–La Roche Ltd, Pharmaceuticals Division, Grenzacherstrasse
124, CH-4070 Basel, Switzerland
† Electronic supplementary information (ESI) available: Experimental
1
details and full spectroscopic data for all novel compounds, and H and
13C nmr spectra for lactones 1, 2, 3 and cyclobutanes 9, 10, 11, 12 and 14.
See DOI: 10.1039/c1ob06619f
Scheme 2 Retrosynthesis of lactones 1–3.
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Horner–Wadsworth–Emmons reaction gave the unsaturated,
homologated ester as a 6.7 : 1 mixture of Z and E isomers.
Reduction using DIBAL–H and conversion into the methyl
carbonate was followed by desilylation and iodide formation
using the two-step method described above. The syntheses of 5
and 6 are depicted in Scheme 3.
Scheme 3 Synthesis of iodide precursors 5 and 6. Reagents and conditions:
(i) nBuLi, (CH2O)n, THF, rt, 3 h, 97%; (ii) MeOCOCl, pyridine, CH2Cl2,
0
Scheme 4 Synthesis and Claisen rearrangement of lactones 1 and 2.
Reagents and conditions: (i) NaH, DMF, TsCH2CO2Me, 0 ◦C → rt, 16 h;
(ii) K2CO3, MeOH, 0 ◦C, 1 h; (iii) 2 M LiOH (aq), THF, rt, 16 h, 7: 39%
over five steps from Z-5-hydroxypent-2-enyl methyl carbonate; 8: 39%
over five steps from Z-5-hydroxy-2-methylpent-2-enyl methyl carbonate;
(iv) HATU (5 equiv.), DIPEA (10 equiv.), DMF, rt, 20 h, syringe pump
addition of 7/8; 1: 66%; 2: 85%; (v) BSA (1 equiv.), KOAc (0.1 equiv.),
DMF, microwave, 160 ◦C, 10 min; 9: 85%; 10: 90%; (vi) BSA (1 equiv.),
KOAc (0.1 equiv.), CH2Cl2, rt, 16 h; 11: 100%; 12: 94%.
◦C, 1 h, 96%; (iii) PPTS, EtOH, 55 ◦C, 2 h, 93%; (iv) H2, Lindlar’s
catalyst, THF, rt, 1 h, 89%; (v) MsCl, Et3N, CH2Cl2, 0 ◦C, 30 min, used
crude in next step; (vi) NaI, MeCN, 70 ◦C, 16 h, used crude in step (i),
Scheme 4; (vii) EtO2CCHMePO(OPh)2, DBU, NaI, THF, 0 ◦C, 2 h, 90%;
(viii) DIBAL-H, PhMe, -78 ◦C → rt, 2 h, 96%; (ix) MeOCOCl, Et3N,
CH2Cl2, 0 ◦C, 1 h, 82%; (x) MeOH, conc. HCl (aq), rt, 16 h, 92%.
The sulfone-containing substrates 1 and 2 were investigated
initially. Reaction of the sodium enolate of methyl 2-tosylacetate
with crude iodides 5 and 6 prepared as described in Scheme 3 gave
good yields of the alkylated products. Removal of the carbonate
groups and saponification of the methyl esters gave homologous
hydroxyacids 7 and 8. For both homologues, extensive experi-
mentation revealed the best conditions for lactonisation to be
HATU18–Hu¨nig’s base in DMF, under syringe-pump-controlled,
high-dilution conditions.19 Lactones 1 and 2 were subjected to
both dCr and Ireland–Claisen reactions. Microwave irradiation of
a 0.2 M DMF solution of 1 containing 1 equiv. BSA and 10 mol
% KOAc gave the trans disubstituted cyclobutane 9 in high yield.
Similar treatment of lactone 2 gave the homologous cyclobutane
10. Carrying out the reactions at ambient temperature in CH2Cl2
gave the carboxylic acids 11 and 12, the products of Ireland–
Claisen rearrangement (Scheme 4).
All the cyclobutane products were formed as single diastereoiso-
mers. The assignment of the cis relationship of the alkenyl
and carboxyl substituents in acids 11 and 12 followed from
consideration of the constrained boat/boat-like reactive confor-
mation of the ketene acetal intermediates (Scheme 5). For the
decarboxylated products 9 and 10, the trans relationship of the
alkenyl and arylsulfonyl substituents was assigned based on the
precedent established in our studies of cyclopropane formation
via dCr reactions of e-lactones,9 where decarboxylation gave the
sterically less crowded and thermodynamically more stable trans
1,2-disubstituted products.
Scheme 5 Proposed reactive conformation of ketene acetal intermediates.
ment product 12, by methyl esterification (TMSCHN2) followed
by desulfonylation (Li naphthalenide) and methylation of the
product enolate in situ; these unsuccessful experiments were
hampered significantly by product volatility. In view of these
failures, a more direct approach was developed. Alkylation of
dimethyl 2-methylmalonate was carried out by treatment of the
sodium enolate with purified iodide 6.21 Carbonate hydrolysis,
decarboxylation22 and saponification gave hydroxyacid 13, which
was subjected to high-yielding lactonisation in the presence of
trichlorobenzoyl chloride under Mukaiyama conditions,23 again
using a syringe pump so as to maintain low substrate concentra-
tions. Ireland–Claisen rearrangement of lactone 3 was effected by
treatment with TMSOTf–Et3N24 in CH2Cl2 at room temperature,
giving acid 14 as a single diastereoisomer in excellent yield
(Scheme 6).
The identity of 14 followed from comparison of its spectroscopic
data with those reported in the literature.25 Since sequences for
the homologation of 14 and reduction of the resultant acid to ( )-
grandisol have been described,26 this constitutes a formal synthesis
of 4.
In summary, we have demonstrated that vinylcyclobutanes
may be assembled using transannular Ireland–Claisen and decar-
boxylative Claisen rearrangement reactions of z-lactones made by
cyclisation of w-hydroxyacids. The ready availability of homoal-
lylic iodides and the ease and efficiency of medium-ring cyclisation
to give the z-lactone substrates are such that this method should
be amenable to the synthesis of a diverse range of cyclobutane-
containing compounds.
With the viability of cyclobutane formation by transannular
Claisen rearrangement established, the final part of this inves-
tigation was directed towards the formal synthesis of a natural
product. (+)-Grandisol 4 is the primary active component of
the male boll weevil pheromone; the strained cyclobutane ring
system possessing a quaternary carbon centre has attracted
significant interest from synthesis chemists, in the contexts both
of synthesis method development and asymmetric catalysis.20
Initial trials sought unsuccessfully to elaborate Claisen rearrange-
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7 D. Craig and G. D. Henry, Eur. J. Org. Chem., 2006, 3558.
8 (a) D. Craig and N. K. Slavov, Chem. Commun., 2008, 6054; (b) D.
Craig and F. Grellepois, Org. Lett., 2005, 7, 463; (c) D. Craig, M. I.
Lansdell and S. E. Lewis, Tetrahedron Lett., 2007, 48, 7861.
9 D. Craig, S. J. Gore, M. I. Lansdell, S. E. Lewis, A. V. W. Mayweg and
A. J. P. White, Chem. Commun., 2010, 46, 4991.
10 (a) M. M. Abelman, R. L. Funk and J. D. Munger, J. Am. Chem. Soc.,
1982, 104, 4030; (b) R. L. Funk and J. D. Munger, J. Org. Chem., 1985,
50, 707; (c) M. M. Abelman, R. L. Funk and J. D. Munger, Tetrahedron,
1986, 42, 2831; (d) R. L. Funk, J. B. Stallman and J. A. Wos, J. Am.
Chem. Soc., 1993, 115, 8847.
11 A. G. Cameron and D. W. Knight, Tetrahedron Lett., 1985, 26, 3503.
12 R. E. Ireland, R. H. Mueller and A. K. Willard, J. Am. Chem. Soc.,
1976, 98, 2868.
13 R. K. Boeckman, Jr., N. E. Genung, K. Chen and T. R. Ryder, Org.
Lett., 2010, 12, 1628.
14 (a) R. K. Boeckman, Jr., M. D. Shair, J. R. Vargas and L. A. Stolz, J.
Org. Chem., 1993, 58, 1295; (b) R. K. Boeckman, Jr. and M. R. Reeder,
J. Org. Chem., 1997, 62, 6456; (c) R. K. Boeckman, Jr., J. Zhang and
M. R. Reeder, Org. Lett., 2002, 4, 3891.
Scheme 6 Synthesis and Ireland-Claisen rearrangement of lactone 3.
Reagents and conditions: (i) dimethyl 2-methylmalonate, NaH, DMF, 0 ◦C
→ rt, then add 6, 0 ◦C, then rt, 2 h, 63%; (ii) K2CO3, MeOH, 0 ◦C,
3 h, 100%; (iii) LiCl, H2O–DMSO, microwave, 180 ◦C, 15 min, 67%;
(iv) aq. LiOH (2 M) THF, 0 ◦C, 16 h, 95%; (v) 2,4,6-trichlorobenzoyl
chloride, Et3N, CH2Cl2, 40 ◦C, 168 h, syringe pump addition of 13, 79%;
(vi) TMSOTf, Et3N, CH2Cl2, rt, 16 h, 92%.
15 P. Razon, M.-A. N’Zoutani, S. Dhulut, S. Bezzenine-Lafolle´e, A.
Pancrazi and J. Ardisson, Synthesis, 2005, 109.
16 C. Pierry, D. Cahard, S. Couve-Bonnaire and X. Pannecoucke, Org.
Biomol. Chem., 2011, 9, 2378.
17 K. Ando, J. Org. Chem., 1998, 63, 8411.
Acknowledgements
18 HATU:
2-(7-1H-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate; L. Carpino, A. El-Faham, C. A. Mino and F.
Albericio, J. Chem. Soc., Chem. Commun., 1994, 201.
We thank EPSRC (DTA-funded studentship to to S.J.G. and
postdoctoral research associateship to K.F., and responsive-mode
grants EP/F015356 and GR/T10268), and Hoffman–La Roche
(additional studentship support to S.J.G.) for support.
19 Reagent systems which failed to effect lactonisation included
2,2¢-dipyridyldisulfide–triphenylphosphine, and 2,4,6-trichlorobenzoyl
chloride–Et3N, in both the absence and presence of DMAP.
20 For other partial and total syntheses of grandisol, see: A. Frongia, C.
Girard, J. Ollivier, P. Paolo Piras and F. Secci, Synlett, 2008, 2823 and
references therein; A. M. Bernard, A. Frongia, J. Ollivier, P. P. Piras, F.
Secci and M. Spiga, Tetrahedron, 2007, 63, 4968 and references therein.
21 Attempts to alkylate homoallylic iodide 6 directly with the enolate
formed from methyl propionate resulted in base-mediated elimination
of HI, to give the corresponding 1,3-diene. Consistently higher yields
were obtained when purified 6 was used in these alkylation reactions.
22 Best yields were obtained when carbonate methanolysis and decar-
boxylation were carried out in separate steps.
23 K. Narasaka, K. Maruyama and T. Mukaiyama, Chem. Lett., 1978,
7, 885. Use of the HATU–DIPEA reagent system gave 3, but in
significantly lower yield.
24 The use of BSA–KOAc for this transformation failed to return any
rearranged product. We attribute this to the lower acidity of lactone 14
in comparison with the a-sulfonyl congeners 1 and 2.
Notes and references
1 R. E. Ireland and R. H. Mueller, J. Am. Chem. Soc., 1972, 94, 5897; for
reviews of the Ireland–Claisen rearrangement, see: (a) S. Pereira and
M. Srebnik, Aldrichimica Acta, 1993, 26, 17; (b) Y. Chai, S. Hong, H.
A. Lindsay, C. McFarland and M. C. McIntosh, Tetrahedron, 2002, 58,
2905.
2 For a review of the Claisen and related rearrangements, see: A. M.
Castro, Chem. Rev., 2004, 104, 2939.
3 For a review of catalysis of the Claisen rearrangement, see: K. C.
Majumdar, S. Alam and B. Chattopadhyay, Tetrahedron, 2008, 64, 597.
4 (a) D. Bourgeois, D. Craig, N. P. King and D. M. Mountford, Angew.
Chem., Int. Ed., 2005, 44, 618; (b) D. Bourgeois, D. Craig, F. Grellepois,
D. M. Mountford and A. J. W. Stewart, Tetrahedron, 2006, 62, 483.
5 (a) D. Craig, N. P. King, J. T. Kley and D. M. Mountford, Synthesis,
2005, 3279; (b) J. E. Camp and D. Craig, Tetrahedron Lett., 2009, 50,
3503.
25 V. Wakchaure and B. List, Angew. Chem., Int. Ed., 2010, 49, 4136.
26 For examples of the homologation–reduction sequence for the conver-
sion of acid 14 into grandisol, see: (a) R. D. Clark, Synth. Commun.,
1979, 9, 325; (b) K. Mori and K. Fukamatsu, Liebigs Ann. Chem., 1992,
489.
6 D. Craig, F. Paina and S. C. Smith, Chem. Commun., 2008,
3408.
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