Convergent synthesis of the putative biogenetic precursor of mycaperoxide B and a norsesterterpene triene isolated from an Australian sponge

Article abstract of DOI:10.1055/s-1999-2580

The synthesis of enantiomerically pure norsesterterpene triene ester 1, extracted from an Australian marine sponge Latrunculia brevis, has been achieved by preparation of E,E-diene 3a via a Julia one-pot olefination and addition to 2,5,5,8a-tetramethyl-oc

Full text of DOI:10.1055/s-1999-2580

LETTER
185
Convergent Synthesis of the Putative Biogenetic Precursor of Mycaperoxide B
and a Norsesterterpene Triene Isolated from an Australian sponge1
M. G. B. Drew,a L. M. Harwood,*a A. Jahans,a J. Robertson,a and S. Swallowb
aDepartment of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, U. K.
Fax +44 (0)1189 316782; E-mail: l.m.harwood@reading.ac.uk
bRoche Products Ltd., Broadwater Road, Welwyn Garden City AL7 3AY, UK.
Received 9 November 1998
Dienes 3a, 3b would be derived by equatorial attack of or-
Abstract: The synthesis of enantiomerically pure norsesterterpene
ganometallic species derived from 4 on octahydronaptha-
triene ester 1, extracted from an Australian marine sponge Latrun-
len-1-one (–)–5, available in 33% yield over 4 steps from
culia brevis, has been achieved by preparation of E,E–diene 3a via
a Julia one-pot olefination and addition to 2,5,5,8a-tetramethyl-oc-
(–)–carvone (Scheme 1).7
tahydro-napthalen-1-one 5. The synthesis of Z,E–diene 3b, the pu-
tative biogenetic precursor of mycaperoxide B 2 has also been
related to 5 indicated that the methyl groups flanking the
achieved following the same methodology.
A literature survey of nucleophilic additions to decalones
carbonyl have a profound effect on the stereochemical
Key words: chiral synthesis, marine norsesterterpene, myca-
outcome, making it difficult to predict whether axial or
peroxide
equatorial attack would predominate.8 In a model study to
examine alkylation of substrate 5, treatment with MeMg-
Br gave a 10:1 mixture of isomeric tertiary alcohols 6, 7
in almost 90% yield. Separation of the isomers by column
The norsesterterpene diene 1, has been isolated from an
Australian sponge, Latrunculia brevis.2 It has been postu-
chromatography afforded the minor isomer 7 as a crystal-
line solid. X-ray crystallographic analysis9 showed the hy-
droxyl group to be in an equatorial configuration and
hence demonstrating that the major isomer 6 was derived
from equatorial attack of the Grignard reagent, in accor-
dance with our requirements for synthesis of 3b (Scheme
2).
lated that such materials might act as biosynthetic precur-
sors to cyclic peroxides being elaborated by 4+2 singlet
oxygen addition across the diene, followed by reduction
of the unsaturated peroxide intermediate.3 An example of
such a cyclic peroxide, mycaperoxide B 2 has been isolat-
ed from a blue sponge of the genus Mycale inhabiting the
waters off the coast of Thailand and has been found to
show significant cytotoxicity and antiviral activity.4 My-
caperoxide B is one of a family of seven cyclic peroxides
which have been isolated from marine sponges,5 and one
of over twenty marine norsesterterpene cyclic peroxides
which have been isolated and characterised so far.6 A syn-
thetic approach to triene 1 via tertiary alcohol 3a would be
equally applicable to synthesis of the putative mycaperox-
ide B biogenetic precursor 3b (R = H), a substrate for sin-
glet oxygen cycloaddition studies to lend support or
otherwise for the proposition.
Scheme 2
Encouraged by this finding we embarked upon the synthe-
sis of E,Ediene 4a. The aldehyde 8 was prepared from 4–
hydroxy–2–butanone in 30% overall yield by protection
of the primary alcohol, Wadsworth-Emmons reaction and
two–step conversion of the ester to the aldehyde (Scheme
Scheme 1
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186
M. G. B. Drew et al.
LETTER
3).10 NMR analysis of the material obtained from the purification of intermediates gave methyl ester 16a in
Wadsworth Emmons reaction showed a mixture of iso- 65% overall yield (Scheme 6).
mers (E : Z 4 : 1) but these proved inseparable at this
stage.11
Scheme 3
Scheme 6
The synthesis of 2-[(3S)-6-t-butyldiphenylsilyloxy)-3-
methylpropyl- sulfonyl]benzothiazole (S)–9 was achieved
in three steps from (S)-3-bromo-2-methyl propan-1-ol12 in
an overall yield of 83% (Scheme 4).
The final dehydration of ester 16a was accomplished with
50% H2SO4 to afford the natural product 1 in 65% yield.
1
The H and 13C NMR data were identical with those re-
ported for the natural product and the specific rotation
[a]D22 = +5.5 (c = 2.4, CHCl3) was in accord with the re-
ported value for the isolated material, [a]D = +13.3 (c =
2.55, CHCl3),2,18 confirming the absolute configuration.
To underline the efficiency of this approach, we have also
applied it to the synthesis of 3b the proposed biogenetic
precursor to mycaperoxide B which differs from 15a in
possessing the (R)–configuration at the side chain stereo-
centre and the Z–geometry of the 5–6 double bond.
Scheme 4
The stereochemical outcome of the one-pot olefination
procedure developed by S. Julia13 is often substrate
dependent13,14 but, when LiN(TMS)2 (2 equivalents) was
added to a mixture of 8 and (S)–9 at –78oC, coupling was
achieved in high yield and stereoselectivity (95%, no Z–
isomer detectable) to produce 10a.15 Selective cleavage of
the ketal permitted separation of the 4 : 1 mixture of alk-
ene isomers resulting from the earlier Wadsworth Em-
mons reaction, furnishing pure E,E–alcohol 11a in 52%
yield which was converted to the iodide 12a in 95% yield
using triphenylphosphine / imidazole / I2 (Scheme 5).16
The Z–2–methyl–5–hydroxypent–2–enal precursor for
side chain construction was efficiently prepared as its
THP ether 17 in five steps from 3-butyn-1-ol in an overall
yield of 75% (Scheme 7).
Scheme 7
Following the previously established conditions for Julia
olefination, reaction of 17 and 2-[(3R)-6-t-butyldiphenyl-
silyloxy)-3-methylpropyl- sulfonyl]benzothiazole (R)–9
with 2 equivalents of LiN(TMS)2 gave E,Z –diene 18 in
excellent yield and stereoselectivity. Removal of the THP
ether and conversion of alcohol 19 to iodide 20 using pre-
vious conditions occurred in greater than 80% overall
yield (Scheme 8).
Scheme 5
The coupling to form 13a was achieved via organolithium
generation by direct treatment of a mixture of 5 and 12a,
at –90oC with two equivalents of t-BuLi to furnish a 7:1
mixture of diastereoisomers.17 Column chromatography
furnished the major isomer 13a in 56% yield and desilyla-
tion with TBAF furnished the primary alcohol 14a in 95%
yield. Finally, two step oxidation to the carboxylic acid
15a and esterification with TMS–diazomethane without
The coupling of decalone 5 and iodide 20 was achieved
applying previously optimized conditions to afford 21 in
70% yield. Attempts to confirm the stereochemistry of the
alkylative coupling step were thwarted by our inability to
obtain crystals of sufficient quality for X–ray crystallo-
graphic analysis. However, the trityl ether of the of the
Synlett 1999, No. 2, 185–188 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Convergent Synthesis of the Precursor of Mycaperoxide B
187
Acknowledgement
We thank the University of Reading for a studentship under the
RETF scheme together with Roche Products and E.P.S.R.C. for
CASE support (to J.R.), the E.P.S.R.C. and the University of Rea-
ding for funds for the Marresearch Image Plate System and Profes-
sor Robert J. Capon, University of Melbourne for supplying
spectroscopic and experimental details.
References
(1) Preliminary communication: Paper 373, 216th American Che-
mical Society Meeting, Boston USA, August 1998.
(2) R. J. Capon, and M.S. Butler, Aust J. Chem., 1991, 44, 77
(3) R. J. Capon and J. K. Mcleod, Tetrahedron, 1985, 41, 3391;
L–K. Sy and G. D. Brown, J. Nat. Prod., 1997, 60, 904;
R. S. Compagnone, I. C. Pina, H. R. Rangel, F. Dagger, A. I.
Suárez, M. V. R. Reddy and J. D. Faulkner, Tetrahedron,
1998, 54, 3057.
(4) J. Tanaka, T. Higa, K. Suwanborirux, U. Kokpol, G. Bernar-
dinelli and C. W. Jefford, J. Org. Chem., 1993, 58, 2999.
(5) R. J. Capon, J. Nat. Prod., 1991, 54, 190; R. J. Capon, S. J.
Rochfort and S. P. B. Ovenden, J. Nat. Prod., 1997, 60, 1261;
R. J. Capon, S. J. Rochfort and S. P. B. Ovenden and R. P.
Metzger, J. Nat. Prod., 1998, 61 525.
Scheme 8
side–chain epimer 22 did provide crystals which permit-
ted X–ray crystallographic analysis to be carried out, con-
firming equatorial alkylation in this instance (Figure).19
(6) S. Sperry, F. A. Valeriote, T. H. Corbett and P. Crews, J. Nat.
Prod., 1998, 61, 241.
(7) J–P. Gesson, J–C. Jacquesy and B. Renoux, Tetrahedron,
1989, 45, 5853.
(8) For examples see: J. D. Ballantyne and P. J. Sykes, J. Chem.
Soc. (C), 1970, 731; S. C. Welch, A. S. C. P. Rao, J. T. Lyon
and J–M. Assercq, J. Am. Chem. Soc., 1983, 105, 252; W. M.
Daniewski, E. Kubak and J. Jurczak, J. Org. Chem., 1985, 50,
3963; K. H Schulte–Elte, W. Giersch, B. Winter, H. Pamingle
and G. Ohloff, Helv. Chim. Acta, 1985, 68, 1961; H. Hagiwara
and H. Uda, J. Chem. Soc., Chem. Commun., 1988, 815.
(9) Crystal data for 7: C15H28O M = 224.4, orthorhombic, P212121
a = 11.264, b = 6.512, c = 19.53 Å, V = 1432 Å3, Z = 4, D =
1.040 gcm–3, F(000) = 1312. 2050 independent reflections
were collected on a Marresearch Image Plate System. The
structure was solved by direct methods and refined on F2using
Shelx97 (non–hydrogen atoms anisotropic and hydrogen
atoms isotropic in calculated positions). Final R = 9.46,
weighted R = 2.75. Crystal data have been deposited at the
Cambridge Crystallographic Data Centre.
Figure
Desilylation of 21 with TBAF afforded 23 in 94% yield
and two–step oxidation of the primary alcohol as before
furnished the target carboxylic acid 3b in 80% yield
(Scheme 9).
(10) For related synthetic approaches see R. Esmond, B. Fraser
Reid and B. B. Jarvis, J. Org. Chem., 1982, 47, 3358;
A. Kanazawa, P. Declair, M. Pourashraf and A. E. Greene,
J. Chem. Soc., Perkin Trans 1, 1997, 1911.
(11) All novel compounds isolated gave spectroscopic data in ac-
cord with their assigned structures. Selected data for key inter-
mediates and target compounds are given below:
(S)–9 [a]D24 +25.3 (c = 1, CHCl3); nmax (film) 3070, 2959,
2858, 1770, 1589, 1330, 1148 cm-1; dH (400 MHz; CDCl3)
0.91 (9H, s), 1.04 (3H, d, J 6.8 Hz), 2.37 (1H, m), 3.22 (1H,
dd, J 14.3, J’8.6 Hz), 3.38 (1H, dd, J 10.1, J’6.7 Hz), 3.57
(1H, dd, J 10.1, J’4.8 Hz), 3.86 (1H, dd, J 14.4, J’3.9 Hz),
7.22 (6H, m), 7.50 (4H, m), 7.90 (2H, m), 8.09 (2H, m); dC
(100 MHz; CDCl3) 16.6, 19.1, 26.7, 31.5, 57.6, 67.0, 122.4,
125.4, 127.5, 127.6, 127.9, 129.7, 133.0, 135.4, 136.8, 152.7,
165.8; m/z (CI, NH3) 510 [MH]+; high resolution 510.1593,
C27H32NO3S2Si requires 510.1593. (R)–7 [a]D23 –23.5 (c = 1,
CHCl3)
Scheme 9
In conclusion, we have presented two illustrative exam-
ples of an efficient and flexible synthetic approach for the
enantio– and diastereocontrolled construction of the car-
bon nucleus of a family of marine norsesterterpenes. We
will report our studies on the photooxygenation behaviour
of these compounds in due course.
11a [a]D24 –6.3 (c = 1, CHCl3); nmax (film) 3362, 3071, 3048,
3014, 2931 cm-1; dH(400 MHz; CDCl3) 1.07 (9H, s), 1.07
(3H, d, J 6.7 Hz), 1.77 (3H, d, J 1.1 Hz), 2.32 (2H, t, J 6.2 Hz),
2.45 (1H, m), 3.50 (1H, dd, J 9.7, J' 6.7 Hz), 3.56 (1H, dd, J
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188
M. G. B. Drew et al.
LETTER
9.7, J’6.2 Hz), 3.71 (2H, t, J 6.3 Hz), 5.55 (1H, dd, J 15.2, J’
7.5 Hz), 5.86 (1H, bd, J 10.7 Hz), 6.25 (1H, ddd, J 15.0, J’
10.8, J" 1.0 Hz) 7.38 (6h, m), 7.65 (4H, m); dC(100 MHz;
CDCl3) 16.3, 16.7, 19.2, 26.8, 39.6, 42.8, 60.3, 68.6, 125.9,
127.2, 127.5, 129.5, 132.5, 133.9, 135.4, 135.6; m/z(CI, NH3)
409 [MH]+, 351; high resolution 409.2568, C26H36O2Si requi-
res 409.2563.
NH3) 376 [M]+; high resolution 376.2966, C24H40O3 requires
376.2977.
(12) The (R)– and (S)–enantiomers of 3-bromo-2-methyl propan-
1-ol were purchased from Aldrich Chemical Co.
(13) J. B. Baudin, G. Hareau, S. A. Julia and O. Ruel, Tetrahedron
Lett., 1991, 1175; Bull. Soc. Chim. Fr., 1993, 130, 336;
J. B. Baudin, G. Hareau, S. A. Julia, R. Lorne and O. Ruel,
Bull. Soc. Chim. Fr., 1993, 130, 336.
(14) R. Bellingham, K. Jarowicki, P. Kocienski and V. Martin,
Synthesis, 1996, 285.
16a nmax (film) 1741 cm-1; dH(400 MHz; CDCl3) 0.84 (3H, s),
0.88 (3H, s), 0.89 (3H, d, J 6.4 Hz), 0.92 (3H, s), 1.17 (1H, dd,
J 13.3, J’3.4 Hz), 1.29 (3H, d, J 7.0 Hz), 1.30–1.62 (m, 12H),
1.72–1.80 (1H, m), 1.77 (3H, d, J 1.2 Hz), 2.07 (2H, m), 3.20
(1H, m), 3.69 (3H, s), 5.62 (1H, dd, J 15.1, J 8.1 Hz), 5.83 (1H,
(15) General procedure for Julia coupling
A solution of sulfone (8.84 mmol) and aldehyde (9.09 mmol)
in anhydrous THF (195 mL) was cooled to -78oC under nitro-
gen. LiN(TMS)2 (18.0 mL, 1M in hexane) was added dropwi-
se via syringe over a period of 25 minutes and the mixture was
stirred for a further 90 min. The reaction mixture was warmed
to room temperature, quenched with aqueous NH4Cl (300 mL)
and extracted with ether (250 mL). The aqueous layer was
further extracted with ether (2 x 100 mL), the organic extracts
combined, washed with brine (150 mL), dried over MgSO4,
and concentrated under reduced pressure. The crude product
was purified by flash column chromatography eluting with
15% ether in 30–40 petrol to furnish exclusively E–isomer.
(16) G. L. Lange and C. Gottardo, Synth. Commun., 1990, 20,
1473.
(17) General procedure for coupling to decalone
A solution of iodide (0.631 mmol) and 5 (0.663 mmol) in an-
hydrous ether (8 mL) was cooled to –90oC (ether–liquid nitro-
gen bath) under nitrogen. t -BuLi (0.75 mL, 1.7M in pentane)
was added dropwise over a period of 5 minutes and the mix-
ture was stirred for a further 30 minutes. The reaction was
quenched with aqueous NH4Cl (8 mL) and allowed to warm to
room temperature. The aqueous layer was extracted with ether
(2 x 10 mL), the organic extracts combined, washed with brine
(10 mL), dried over MgSO4, and concentrated under reduced
pressure. Purification by gradient flash column chromatogra-
phy, eluting initially with 30-40 petrol, increasing to 5% ether
: 95% 30-40 petrol afforded the coupled product as a colour-
less oil.
bd, J 10.8 Hz), 6.33 (1H, ddd, J 15.1, J' 10.8, J' 1.1 Hz); m
/
z
(CI, NH3) 390 [M]+; high resolution 390.3140, C25H42O3 re-
quires 390.3134.
1 [a]D22 +5.5 (c = 1, CHCl3); nmax (film) 1736 cm-1; dH(400
MHz; CDCl3) 0.84 (3H, s), 0.89 (3H, s), 0.95 (3H, s), 1.11
(1H, dd, J 12.5 J' 2.1 Hz), 1.12–1.24 (2H, m), 1.29 (3H, d, J
7.0 Hz), 1.32–1.67 (5H, m), 1.58 (3H, s), 1.78–1.85 (1H, m),
1.79 (3H, d, J 1.1 Hz), 1.91–2.11 (6H, m), 3.21 (1H, m), 3.69
(3H, s), 5.64 (1H, dd, J 15.0, J' 8.1 Hz), 5.84 (1H, bd, J 10.8
Hz), 6.35 (1H, ddd, J 15.1, J' 10.8, J" 1.1 Hz); dC(100 MHz;
CDCl3) 16.7, 17.5, 19.0, 19.0, 19.5, 20.1, 21.7, 26.8, 33.3,
33.3, 33.6, 36.9, 39.0, 40.5, 41.8, 43.1, 51.9, 51.9, 125.3,
126.0, 127.9, 129.6, 140.0, 140.1, 175.2. m/z (CI, NH3) 373
[MH]+.
17 nmax (film) 2942, 2248, 1676 cm-1; dH (400 MHz; CDCl3)
1.47–1.76 (6H), 2.03 (3H, s), 2.85 (2H, t), 3.53 (2H, m), 3.78
(1H, m), 3.91 (1H, dt, J 9.7, J’6.4 Hz), 4.59 (1H, bs), 5.95 (1H,
bd, J 8.1 Hz), 9.96 (1H, d, J 8.1 Hz); dC (100 MHz; CDCl3)
19.1, 25.0, 25.0, 30.1, 32.7, 61.7, 64.6, 98.3, 129.5, 160.3,
191.0; m/z (CI NH3) 199 [MH]+; high resolution 199.1335,
C11H19O3 requires 199.1334.
19 [a]D20 +9.5 (c = 1, CHCl3); nmax (film) 3347, 3070, 3048,
3022, 2959 cm-1; dH(400 MHz; CDCl3) 1.07 (9H, s), 1.07
(3H, d, J 6.7 Hz), 1.79 (3H, d, J 1.0 Hz), 2.32 (2H, t, J 6.3 Hz),
2.46 (1H, m), 3.51 (1H, dd, J 9.7, J' 6.7 Hz), 3.58 (1H, dd, J
9.7, J' 6.2 Hz), 3.71 (2H, t, J 6.3 Hz), 5.55 (1H, dd, J 15.2, J'
7.5 Hz), 5.88 (1H, bd, J 10.7 Hz), 6.27 (1H, ddd, J 15.0, J'
10.8, J" 1.0 Hz), 7.39 (6H, m), 7.66 (4H, m); dC(100 MHz;
CDCl3) 16.8, 19.3, 23.7, 26.9, 35.5, 39.6, 60.8, 68.7, 125.6,
127.6, 128.5, 129.5, 132.6, 133.9, 135.6, 136.0; m/z (CI, NH3)
409 [MH]+, 351; high resolution 409.2572, C26H36O2Si requi-
res 409.2563.
(18) We are grateful to Professor R. Capon of the University of
Melbourne for providing us with copies of the spectra for this
compound.
(19) Crystal data for 22: C43H56O2 M = 604.9, orthorhombic,
P212121 a = 10.040, b = 13.858, c = 26.100 Å, V = 3632 Å3, Z
= 4, D = 1.099 gcm–3, F(000) = 1312. 4707 independent re-
flections were collected on a Marresearch Image Plate Sy-
stem. The structure was solved by direct methods and refined
on F2using Shelx97 (non–hydrogen atoms anisotropic and hy-
drogen atoms isotropic in calculated positions). Final R =
5.95, weighted R = 2.63. Crystal data have been deposited at
the Cambridge Crystallographic Data Centre.
3b [a]D24 +17.8 (c = 1, CHCl3); nmax (film) 3455, 2934, 1713
cm-1; dH(400 MHz; CDCl3) 0.83 (3H, s), 0.87 (6H, s), 0.91
(3H, s), 0.93 (3H, s), 1.12-1.77 (m, 12H), 1.77 (3H, s), 2.16
(2H, bt J 8.8Hz), 3.17 (1H, m), 1.28 (3H, s), 5.63 (1H, dd, J
15.2, J' 7.9 Hz), 5.78 (1H, bd, J 11 Hz), 6.33 (1H, dd, J 15.2,
J' 10.8 Hz); dC(100 MHz; CDCl3) 16.1, 16.2, 16.9, 18.5, 21.5,
21.9, 23.6, 29.1, 31.2, 31.7, 32.9, 33.2, 33.6, 36.4, 41.6, 42.6,
43.2, 46.1, 77.2, 124.4, 127.6, 129.1, 140.0, 179.6; m/z (CI,
Synlett 1999, No. 2, 185–188 ISSN 0936-5214 © Thieme Stuttgart · New York