Stereoselective synthesis of β-(hydroxymethylaryl/alkyl)-α- methylene-γ-butyrolactones

Article abstract of DOI:10.1021/ol200711f

Zinc or a chromium(II) source with 3-(bromomethyl)furan-2(5H)-one (3) and an aldehyde gives β-(hydroxymethylaryl/alkyl)-α-methylene-γ- butyrolactones 5 in good yields and high diastereoselectivities. The methodology is demonstrated in concise syntheses of (±)-hydroxymatairesinol (8) and (±)-methylenolactocin (10) by subsequent arylboronate conjugate addition and translactonization, respectively.

Full text of DOI:10.1021/ol200711f

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2594–2597
Stereoselective Synthesis of
β-(Hydroxymethylaryl/alkyl)-r-methylene-
γ-butyrolactones
David M. Hodgson,*,† Eric P. A. Talbot,† and Barry P. Clark‡
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford OX1 3TA, U.K., and, LRL, Eli Lilly and Co. Ltd.,
Erl Wood Manor, Windlesham, Surrey GU20 6PH, U.K.
david.hodgson@chem.ox.ac.uk
Received March 16, 2011
ABSTRACT
Zinc or a chromium(II) source with 3-(bromomethyl)furan-2(5H)-one (3) and an aldehyde gives β-(hydroxymethylaryl/alkyl)-R-methylene-γ-
butyrolactones 5 in good yields and high diastereoselectivities. The methodology is demonstrated in concise syntheses of (()-
hydroxymatairesinol (8) and (()-methylenolactocin (10) by subsequent arylboronate conjugate addition and translactonization,
respectively.
The R-methylene-γ-butyrolactone motif is found in a
large range of natural products, especially sesquiterpene
lactones (Figure 1).1 The presence of the motif is consid-
ered to be a major factor in the diverse biological activity
observed for these natural products. Consequently, many
methods have been developed to access R-methylene-γ-
butyrolactones1 for use in target synthesis and medicinal
chemistry2 programs.
However, at the outset of our studies the allylation
method outlined in Scheme 1 to give such systems contain-
ing diverse β-hydroxymethyl substitution 5 had not been
examined, aside from the work of Liu and co-workers
to additionally γ-substituted adducts involving alkyne-
derived molybdenumÀ or tungstenÀπ-allyl intermediates
† University of Oxford.
‡ Eli Lilly and Co. Ltd.
Figure 1. Representative R-methylene γ-butyrolactones.1
(1) (a) Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew.
Chem., Int. Ed. 2009, 48, 9426–9451. (b) Elford, T. G.; Hall, D. G.
Synthesis 2010, 893–907.
(4, M = MoLn or WLn, X = alkyl).3,4 This substitution
pattern is present in several sesquiterpene lactones
(e.g., Figure 1), and the method could be of direct utility
in syntheses of anthepseudolide (1)5 and the antibacterial
(2) (a) Janecki, T.; Blaszczyk, E.; Studzian, K.; Janecka, A.;
ꢀ
Krajewska, U.; Rozalski, M. J. Med. Chem. 2005, 48, 3516–3521. (b)
Ramachandran, P. V.; Pratihar, D.; Nair, H. N. G.; Walters, M.; Smith,
S.; Yip-Schneider, M. T.; Wu, H.; Schmidt, C. M. Bioorg. Med. Chem.
Lett. 2010, 20, 6620–6623.
r
10.1021/ol200711f
Published on Web 04/13/2011
2011 American Chemical Society

hydroxyanthecotulide (2)6 and analogues.7 We also
viewed alcohols 5 as potentially versatile substrates for
conjugate addition and isomerization chemistry, which
could lead to other bioactive natural product classes
(see later).
With bromolactone 3 in hand, Barbier-type coupling
withbenzaldehyde wasinvestigated. Allylic chromium11 or
zinc12 intermediates (Scheme 1, M = CrLn or ZnLn) were
considered to have the potential to provide high regio- and
stereoselectivity in the CÀC bond forming step, together
with lactone functional group tolerance. In the event, using
the chromium(II) sources CrCl2,13 CrCl3/LiAlH4,14
a
catalytic chromium process (CrCl3/Mn/TMSCl),15 zinc
with satd aq NH4Cl in DMF,16 or indium in the presence
of a Lewis acid,17 gave in all cases one major diastereoi-
somer of methylene lactone 5a by crude 1H NMR analysis
(Table 1).
Scheme 1. Direct Synthesis of β-(Hydroxymethyl)-R-methylene-
γ-butyrolactones 5 from Aldehydes
Table 1. Evalution of Different Allylation Conditions with 3
and Benzaldehyde
So as to investigate the above chemistry bromolactone
3, previously accessed in six steps from γ-butyrolactone,8
was conveniently prepared from commercially avail-
able tulipalin (6)9 (Scheme 2). Bromination of 6 with
phenyltrimethyl ammonium tribromide, followed by
regioselective elimination using LiBr/Li2CO3 in DMF,10
gave bromolactone 3 in 55% yield after one purifica-
tion step.
entry
conditions
yield of 5a (%) dr
1
2
3
CrCl2 in DMF (rt, 15 h)
83
68
85
97:3
98:2
98:2
CrCl3/LiAlH4 in THF (rt, 15 h)
Cat. CrCl3/Mn/TMSCl/i-Pr2EtN in THF
(rt, 15 h)
4
5
Zn/trace sat. aq NH4Cl in DMF (rt, 15 h)
In/Eu(OTf)3 in sat. aq NH4Cl (rt, 15 h)
83
67
95:5
97:3
Scheme 2. Synthesis of Bromolactone 3
Due to the comparative experimental simplicity of the
zinc protocol (Table 1 entry 4),18 it was decided to evaluate
the scope of the allylation process with different aromatic
aldehydes under the zinc conditions (Table 2).
The chemistry was found to tolerate electron-rich (entries
4and 6) and -deficient(entry 7) aromaticaldehydesand the
presence of aryl halide (entries 2, 3 and 5), hydroxyl (entry
6), cyano (entry 7), and carbamate (entry 8) functionality.
The stereochemistry of the major diastereoisomer 5b aris-
ing from 1-naphthaldehyde (Table 2, entry 1) was estab-
lished by X-ray crystallographic analysis18 and is con-
sistent with the transition state indicated in Scheme 1.
Also, MOM protection of alcohol 5e (Table 2, entry 4)
gave a MOM ether18 of established configuration, which
has previously been converted into the insecticide
(3) (a) Lin, S.-H.; Chen, C.-C.; Vong, W.-J.; Liu, R.-S. Organome-
tallics 1995, 14, 1619–1625. (b) Chen, C.-C.; Fan, J.-S.; Shieh, S.-J.; Lee,
G.-H.; Wang, S.-L.; Liu, R.-S. J. Am. Chem. Soc. 1996, 118, 9279–9287.
(c) Shiu, L. H.; Wang, S.-L.; Wu, M.-J.; Liu, R. S. J. Chem. Soc., Chem.
Commun. 1997, 2055–2062. (d) Chandrasekharam, M.; Liu, R.-S. J. Org.
Chem. 1998, 63, 9122–9124.
(4) During the course of our studies, a single example of this process
involving zinc with 3 and a complex chiral aldehyde was reported in a
patent: (a) Xu, X.; Yang, H.; Qiao, X.; Xie, L. CN 101481367, 2009;
Chem. Abstr., 2009, 151, 245843. (b) The reaction of zinc with 3 and
formaldehyde has also been recently reported: Yang, H. S.; Qiao, X. X.;
Cui, Q.; Xu, X. H. Chin. Chem. Lett. 2009, 20, 1023–1024.
(5) Abou El-Ela, M.; Jakupovic, J.; Bohlmann, F.; Ahmed, A. A.;
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1990, 29, 2704–2706.
(12) Luche, J. L.; Sarandeses, L. A. In Organozinc Reagents; Knochel,
P., Jones, P., Eds.; Oxford University Press: Oxford, 1999; pp 307À323.
(13) Nishitani, K.; Konomi, T.; Mimaki, Y.; Tsunoda, T.; Yamakawa,
K. Heterocycles 1993, 36, 1957–1960.
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2006, 69, 662–664. Corrigendum: J. Nat. Prod. 2009, 72, 804.
(7) The stereochemistries of 1 and 2 are currently not known with
certainty.
(14) Okuda, Y.; Nakatsukasa, S.; Oshima, K.; Nozaki, H. Chem.
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(16) Zinc in THF was very slow, giving only a trace of 5a after 10 h.
Zinc in DMF proceeded to completion, but required prolonged reaction
time; the reaction was also accelerated by the addition of PhCO2H
(1 equiv), albeit less efficiently than with NH4Cl.
(17) Loh, T.-P.; Cao, G.-Q.; Pei, J. Tetrahedron Lett. 1998, 39, 1457–
1460.
1994, 50, 4201–4214. See also: (b) Chapleo, C. B.; Svanholt, K. L.;
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(18) See the Supporting Information for details.
(19) For details of aldehyde preparation see the Supporting
Information.
(11) Hodgson, D. M.; Comina, P. J. In Transition Metals for Fine
Chemicals and Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.;
Wiley-VCH: Weinheim, 2004; Vol. 1, pp 469À481.
Org. Lett., Vol. 13, No. 10, 2011
2595

Table 2. Scope of Allylation Using Bromolactone 3 with Zinc
and Aromatic Aldehydes
Scheme 3. Application of Allylation to (()-Hydroxymatairesi-
nol (8)
aldehyde 3-methylbut-2-enal. For such substrates we found
that the cat. Cr(II) conditions (Table 1, entry 3) were more
effective (Table 3). Excellent drs (98:2À99:1) were uni-
formly observed, aside from an R,β-unsaturated alde-
hyde (entry 3). The mild allylation conditions are
indicated by the functional group tolerance of cyano,
alkenyl iodide, and ketone functionality (entries 5À7)
and the viability of a β,γ-unsaturated aldehyde (entry 6).
Table 3. Scope of the Allylation of Aliphatic Aldehydes Using
Cat. Cr(II) conditions
phrymarolin II.20 The stereochemistry of vanillin-derived
alcohol 5g (Table 2, entry 6) was supported by subsequent
1,4-addition21 of commercially available boronic ester 7,
which resulted in a concise, protecting group-free synthesis
of the lignan hydroxymatairesinol (8)22 (Scheme 3). The
stereochemistry of 5a and of the other alcohols in Table 2
was assigned by analogy.
Reduction of diastereoselectivity was observed with
nonaromatic aldehydes under the zinc allylation conditions:
83:17 dr (79% yield) with the aliphatic aldehyde docecanal
and 55:45 dr (75% yield) with the R,β-unsaturated
(20) The spectral data were in full accord with the stereochemistry
indicated in Table 2, entry 4, and also differed from the previously
reported data for the diastereomeric MOM ether: (a) Yamauchi, S.;
Yamamoto, N.; Kinoshita, Y. Biosci. Biotechnol. Biochem. 2000, 64,
2209–2215. (b) Yamauchi, S.; Yamamoto, N.; Kinoshita, Y. Biosci.
Biotechnol. Biochem. 1999, 63, 1605–1613.
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2004, 6, 1345–1348.
2596
Org. Lett., Vol. 13, No. 10, 2011

That the diastereoselectivity observed for aliphatic aldehydes
is the same as found previously with the aromatic examples
was supported by spectral comparison of methylene lac-
tone 5j (Table 3, entry 1) with the literature values18,23 and
by a further transformation of 5k discussed below.
Scheme 4. (()-Methylenolactocin (10) by Translactonization
We also examined acid-catalyzed translactonization as a
process to isomerize the β-hydroxymethylene products 5
generated in the above chemistry to trans β,γ-disubstituted
R-methylenebutyrolactones (e.g., 9, Scheme 4). The latter
substitution pattern is found in many natural products
(e.g., Figure 1).1 Although the generation of primary
alcohols from secondary alcohols by this approach has
not been previously reported, it is known in a related trans
β,γ-disubstitued R-methylenebutyrolactone that a less-
hindered (Me-substituted) free secondary alcohol is
favored (80:20À75:25) over a more hindered (i-Pr-
substituted) free secondary alcohol at equilibrium.3a,b In
the event, secondary alcohol 5k (Table 3, entry 2) was
recovered unchanged using the reported conditions
(PTSA, CH2Cl2, rt, 15 h) for the secondary alcohol
equilibration. However, reaction with 5% PTSA in MeOH
(65 °C, 15 h) led smoothly to a 4:96 mixture in favor of the
known24 primary alcohol 9 (Scheme 4), which was cleanly
isolated in 84% yield. The origin of the thermodynamic
preference for primary alcohol 925 may lie in reduction of
destabilizing gauche interactions present in conformations
of the secondary alcohol 5k.26 Jones oxidation24 of pri-
mary alcohol 9 completed a short synthesis of the naturally
occurring antibacterial and antitumor agent (()-methyle-
nolactocin (10).3d,24
In summary, allylation of aldehyes using 3-(bromomethyl)
furan-2(5H)-one (3) in the presence of zinc or Cr(II) salts
provides a regio- and stereocontrolled access to β-substituted
R-methylene-γ-butyrolactones. Conjugate addition and
translactonization chemistry broaden the utility of the
adducts, as illustrated in concise syntheses of (()-hydro-
xymatairesinol (9) and (()-methylenolactocin (10).
Further applications in target synthesis and studies
on asymmetric versions of this methodology are cur-
rently under investigation.
Acknowledgment. We thank Eli Lilly for funding (to E.
P.A.T.) and B. Diseroad (Eli Lilly) for X-ray analysis.
(23) Hon, Y.-S.; Hsieh, C.-H.; Chen, H.-F. Synth. Commun. 2007, 37,
1635–1651. Allylation using the zinc conditions gave 5j in 79% yield
(83:17 dr). The minor diastereomer was determined to be that previously
reported (see the Supporting Information).
(24) (a) Hon, Y.-S.; Hsieh, C.-H.; Liu, Y.-W. Tetrahedron 2005, 61,
2713–2723. (b) Saha, S.; Roy, S. C. Tetrahedron 2010, 66, 4278–4283.
(25) Submitting primary alcohol 9 to the reaction conditions gave the
same 4:96 mixture of 5k:9 observed when starting with 5k.
Supporting Information Available. Full experimental
procedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Note Added after ASAP Publication. An error in Scheme
3 was corrected in the version reposted April 15, 2011.
(26) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley: Chichester, 1994; pp 682À684.
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