A biosynthetically-inspired synthesis of the tetrahydrofuran core of obtusallenes II and IV

Article abstract of DOI:10.1021/ol062818g

Sharpless asymmetric dihydroxylation was regioselective for the frans olefin in an E vs Z vs terminal triene substrate. To test a biosynthetic hypothesis, the resulting diol underwent diastereoselective bromoetherification to provide the des-chloro core o

Full text of DOI:10.1021/ol062818g

ORGANIC
LETTERS
2007
Vol. 9, No. 3
445-448
A Biosynthetically-Inspired Synthesis of
the Tetrahydrofuran Core of
Obtusallenes II and IV
D. Christopher Braddock,*,† Roshni Bhuva,† David S. Millan,‡
Yolanda Pe´rez-Fuertes,† Craig A. Roberts,§ Richard N. Sheppard,†
Savade Solanki,† Elaine S. E. Stokes,§ and Andrew J. P. White†
Department of Chemistry, Imperial College London, South Kensington,
London SW7 2AZ, U.K., AstraZeneca, Mereside, Alderley Park, Macclesfield,
Cheshire SK10 4TG, U.K., and Sandwich Laboratories, Pfizer Global Research and
DeVelopment, Ramsgate Road, Sandwich, Kent CT13 9NJ, U.K.
c.braddock@imperial.ac.uk
Received November 20, 2006
ABSTRACT
Sharpless asymmetric dihydroxylation was regioselective for the trans olefin in an E vs Z vs terminal triene substrate. To test a biosynthetic
hypothesis, the resulting diol underwent diastereoselective bromoetherification to provide the des-chloro core of marine natural products
obtusallenes II and IV. Alternatively, anionic chloride ring-opening of a Z-â,γ-unsaturated epoxide gave separable regioisomeric halohydrins.
Bromoetherification gave the fully elaborated core of obtusallenes II and IV with all of the relative stereochemistry correctly set.
Recently, we presented a biosynthetic hypothesis for the
obtusallene family of marine natural products from Laurencia
species.1 Accordingly, we are now pursuing biosynthetically
inspired chemical synthetic routes to the obtusallenes. The
hypothesis predicts that obtusallenes II (1)2 and IV (2)3,4 are
the first members of the family to be encountered on the
biosynthetic pathway (Figure 1). Obtusallenes II and IV have
identical tetrahydrofuran cores and differ only by being
epimeric at C4 and having the oppositely configured chiral
bromoallene unit. The tetrahydrofuran core of obtusallenes
II and IV is proposed to arise via bromoetherification of an
acyclic precursor. Previous work by Murai5 has identified
laurediol 3 as a biosynthetic precursor to the wider family
of metabolites isolated from red algae of the genus Lauren-
cia. Laurediol itself has been suggested to ultimately arise
from (Z,Z,Z)-hexadeca-4,7,10-trienoic acid via epoxide 4.5
In this paper, we report on an asymmetric synthesis of
laurediol “surrogate” (R,R)-5. Subsequent biosynthetically
inspired bromoetherification proceeds in a highly diastereo-
selective fashion to give the des-chlorotetrahydrofuran core
of obtusallenes 1 and 2. Moreover, we also report on a
† Imperial College London.
‡ Pfizer, Ltd.
§ AstraZeneca.
(1) Braddock, D. C. Org. Lett. 2006, 26, 6055-6058.
(2) O¨ ztunc¸, A.; Imre, S.; Lotter, H.; Wagner, H. Phytochemistry 1991,
30, 255-257.
(3) Guella, G.; Chiasera, G.; Mancini, I.; O¨ ztunc¸, A.; Pietra, F. Chem.
Eur. J. 1997, 3, 1223-1231.
(5) Murai, K. In ComprehensiVe Natural Product Chemistry; Barton, D.
H. R., Meth-Cohn, O., Nakanishi, K., Eds.; Elsevier Science & Technology:
The Netherlands, 1999; Vol. 1, pp 303-324.
(4) Ciavatta, M. L.; Gavagnin, M.; Puliti, R.; Cimino, G.; Mart´ınez, E.;
Ortea, J.; Mattia, C. A. Tetrahedron 1997, 53, 17343-17350.
10.1021/ol062818g CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/30/2006

Scheme 1. Preparation of Triene 11
sulfonamide as an additive12,13 proved to be regioselective
for the E olefin giving the desired diol (R,R)-5 in 28%
isolated yield after chromatography (Scheme 2) and in a 93%
Scheme 2. Sharpless AD of Triene 11
Figure 1. Structures 1-6. The numbering on the structures relates
to the relative positions in the obtusallenes 1 and 2.
ee by di-Mosher ester formation14 (see the Supporting
Information). The R,R configuration was assigned on the
basis of the Sharpless mnemonic13 and subsequently con-
firmed by X-ray crystallography of a derivative (vide infra).
Diol 12 resulting from dihydroxylation of the cis olefin in
triene 11 was also isolated in 8% yield (absolute stereo-
chemistry unassigned). Unreacted triene 11 (20%) was also
recovered, but the major components (40%) were tetrols and
hexols from multiple dihydroxylations. On the basis of the
previously measured relative rates for various alkene sub-
stitution patterns,15 we had predicted that the E olefin would
be preferentially dihydroxylated. However, to the best of our
knowledge, this is the first example of a regioselective
dihydroxylation of an E vs Z vs terminal olefin in the same
substrate. Further attempted optimization of this reactions
either by changing the alcohol protecting group and/or
changing the conditionssdid not improve the isolated yield
of desired diol 5.
racemic model epoxide system 6, which allows early chloride
incorporation followed by bromoetherification to give the
fully elaborated tetrahydrofuran cores for obtusallenes II and
IV with all of the relative stereochemistry correctly set. The
results of these studies are consistent with the early steps of
the biosynthetic hypothesis for the obtusallene family.
Synthesis of laurediol “surrogate” 5 commenced with
commercially available trans-â-hydromuconic acid (7)
(Scheme 1). Double esterification and double reduction,6
followed by monoprotection,7 gave protected alcohol 8.8
Dess-Martin periodinane oxidation9 gave aldehyde 9, which
underwent Z-selective Wittig olefination10 with the ylide
generated from phosphonium salt 1011 to generate triene 11.
Triene 11 has three different types of olefin: E, Z, and
terminal. Sharpless asymmetric dihydroxylation of triene 11
under “standard conditions” using â-AD-mix with methane-
(6) Gassman, P. G.; Bonser, S. M.; Mlinaric-Majerski, K. J. Am. Chem.
Soc. 1989, 111, 2652-2662.
(7) Roush, W, R.; Straub, J. A.; VanNieuwenhze, M. S. J. Org. Chem.
1991, 56, 1636-1648.
(12) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(8) Baldwin, J. E.; James, D. A.; Lee, V. Tetrahedron Lett. 2000, 41,
733-736.
(13) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu,
D.; Zhang, X. L. J. Org. Chem. 1992, 57, 2768-2771.
(14) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543-2549.
(9) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(10) Reitz, A. B.; Nortey, S. O.; Jordan, A. D.; Mutter, M. S.; Maryanoff,
B. E. J. Org. Chem. 1986, 51, 3302-3308.
(11) Winter, M.; Na¨f, F.; Furrer, A.; Pickenhagen, W.; Giersch, W.;
Meister, A.; Willhalm, B.; Thommen, W.; Ohloff, G. HelV. Chim. Acta
1979, 62, 135-139.
(15) Andersson, P. G.; Sharpless, K. B. J. Am. Chem. Soc. 1993, 115,
7047-7048.
446
Org. Lett., Vol. 9, No. 3, 2007

(R,R)-Diol 5 was designed as a laurediol “surrogate” to
test the proposed biomimetic bromination. Since diol 5 has
two hydroxyl groups and two olefins, and bromonium ion
formation can occur on either face of each double bond, there
are 16 possible bromoether products. However, on the basis
of Baldwin’s rules,16 and if our biosynthetic hypothesis is
valid,1 the desired 5-exo cyclization mode should dominate.
Much to our delight, we found that treating diol 5 with 1.8
equiv of tetrabromocyclohexadienone (TBCO)17 (13) gave
the desired anti-tetrahydrofuran 14 in 87% isolated yield
along with the minor syn-diastereoisomer 15 in 7% yield,
i.e., a 12:1 diastereomeric ratio (Scheme 3). Transition state
Scheme 4. Deprotection of Major Diastereoisomer 14
a controlling element in the proposed macrobromoetherifi-
cation to form obtusallenes II and IV.1
We have also investigated a second system in line with
our biosynthetic hypothesis with early chloride incorporation.
Thus, diene 20 was prepared by double Z-selective (>9:1
Z/E) Wittig olefination using bis-phosphonium salt 1918 and
KHMDS with heptanal (Scheme 5). Monoepoxidation with
Scheme 3. Bromoetherification of Diol 5
Scheme 5. Synthesis of Tetrahydrofuran 23
16 (Figure 2) is proposed to be responsible for the high level
of diastereoselectivity, where both the C10-C13 chain and
C4-C5 chain occupy pseudo-equatorial positions and the
unprotected alcohol at C7 adopts a pseudoaxial position. The
minor diastereoisomer would arise from TS 17 where the
C10-C13 chain is pseudoaxial.
m-CPBA gave epoxide 6, which was subject to anionic
chloride ring-opening with trimethylsilyl chloride and tri-
phenylphosphine19 and an in situ TBAF quench to give the
two regioisomeric hydrohalins 21 and 22 in a 1.0:1.7 ratio
1
as judged by H NMR of the crude mixture (67%). The
Figure 2. Proposed transition states for bromoetherification.
desired chlorohydrin 21 could be isolated by careful column
chromatography (22%) and was treated with TBCO 13.
Smooth bromoetherification20 occurred to give the desired
bromochlorotetrahydrofuran 23 as a single diastereoisomer
(76%), and the relative stereochemistry was assigned by
analogy of the conversion of diol 5 into tetrahydrofuran 14.
Extensive NMR experiments (1H, 13C, COSY, HMQC)
firmly established the connectivity as a 2,3,5-trisubstituted
TBAF-mediated deprotection of the silyl group at C4 in
major diastereoisomer 14 gave diol 18 (Scheme 4), which
proved to be crystalline. Single-crystal X-ray analysis (see
the Supporting Information) confirmed the absolute and
relative stereochemistry, thereby verifying the stereochemical
course of both the Sharpless AD (vide supra) and the
bromoetherification. Interestingly, the C9-C10 bromoether
proved to be in a gauche conformation (Br-C9-C10-O
torsion angle ) 64°) with the hydrogen atoms on C9 and
C10 aligned anti to the electronegative atoms. This experi-
mentally confirmed gauche conformation is expected to be
(17) Lu¨bbecke, H.; Boldt, P. Tetrahedron 1978, 34, 1577-1579.
(18) Pohnert, G.; Boland, W. Eur. J. Org. Chem. 2000, 1821-1826 and
references cited therein.
(19) Andrews, G. C.; Crawford, T. C.; Contillo, L. G. Tetrahedron Lett.
1981, 22, 3803-3806.
(20) Bromoetherification of the chlorohydrins of vernolic acid has been
previously described but no stereochemical assignment was given: Gupta,
R.; Ahmad, M. S., Jr.; Ahmad, F.; Osman, S. M. Ind. J. Chem., Sect. B
1983, 22B, 1011-1014.
(16) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 374-376.
Org. Lett., Vol. 9, No. 3, 2007
447

tetrahydrofuran. In particular a 8 ppb chlorine-induced
isotopic shift of the carbon resonance at 62.9 ppm in the
13C NMR spectrum identified this resonance as the carbon
bearing the chlorine (Figure 3).21 This currently under-used
In the above sequence of epoxidation, anionic chloride
ring-opening, and bromoetherification, we noted that all of
these reactions had been performed in dichloromethane
solution. It was also noted that of the two halohydrins 21
and 22, only 21 has a favorable ring-closing mode. Thus,
the possibility of a one-pot synthesis of tetrahydrofuran 23
directly from diene 20 was explored. Accordingly, to a
solution of Z,Z-skipped diene 20 in dichloromethane were
added sequentially m-CPBA, TMSCl and PPh3, TBAF, and
then TBCO. Pleasingly, after workup and chromatography
of the complex mixture, chlorobromotetrahydrofuran 23 was
isolated in 18% yield and in >95% purity.
Further work is in progress toward the synthesis of the
obtusallene family of natural products via electrophilic
bromination and will be reported in due course.
Acknowledgment. We thank the EPSRC for financial
support (EP/C542169/1), AstraZeneca for a CASE award (to
R.B.), and Pfizer for an Industrial CASE award (to S.S.).
Figure 3. Isotope induced shift for the resonance arising from the
chlorine-bearing carbon.
Supporting Information Available: Full experimental
procedures and characterization data for compounds 5, 6,
8-12, 14, 15, 18, and 20-23, determination of the ee for 5
via di-Mosher’s ester formation, copies of 1H and 13C NMR
spectra for compounds 5, 6, 11-12, 14, 15, and 20-23, and
X-ray crystallographic data for 18. This material is available
free of charge via the Internet at http://pubs.acs.org.
technique should find wide applicability in unambiguously
identifying carbon-bearing chlorines in natural product
systems.22
(21) Sergeyev, N. M.; Sergeyeva, N. D.; Raynes, W. T. J. Magn. Reson.,
Ser. A 1995, 115, 174-182.
(22) Suzuki, M.; Nakano, S.; Takahashi, Y.; Abe, T.; Masuda, M.
Phytochemistry 1999, 51, 657-662.
OL062818G
448
Org. Lett., Vol. 9, No. 3, 2007