A synthesis of (+)-obtusenyne

Article abstract of DOI:10.1055/s-2005-918470

A synthesis of the halogenated medium-ring ether natural product (+)-obtusenyne is reported utilizing a Claisen rearrangement and an intramolecular hydrosilation as key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918470

SHORT PAPER
3199
A Synthesis of (+)-Obtusenyne
Synthesis of
O.
btusenyne Y. Frankie Mak,a Neil R. Curtis,a Andrew N. Payne,a Miles S. Congreve,a Craig L. Francis,a
Jonathan W. Burton,*a Andrew B. Holmes*b
a
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Fax +44(1223)336362; E-mail: jwb1004@cam.ac.uk
School of Chemistry, University of Melbourne, Victoria 3010, Australia
b
Fax +61(3)83442384; E-mail: aholmes@unimelb.edu.au
Received 15 September 2005
Dedicated to Professor Steven V. Ley on the occasion of his 60th birthday
OTBDPS
Abstract: A synthesis of the halogenated medium-ring ether natu-
ral product (+)-obtusenyne is reported utilizing a Claisen rearrange-
ment and an intramolecular hydrosilation as key steps.
O
ii, iii
CO2Me
O
O
( )-2
(+)-2
3
i
Key words: total synthesis, natural product, medium-ring ether
iv, v
OH OTBDPS
vi–viii
O
A variety of nonterpenoid C15 metabolites have been iso-
lated from red algae and the opisthobranchs which feed on
Laurencia species. Among these is the nine-membered
cyclic ether (+)-obtusenyne (1) (Figure 1), which was in-
dependently isolated by Imre1 and by Fenical and Clardy2
and their respective co-workers. The structure and abso-
lute configuration of 1 were assigned by a combination of
spectroscopic analysis and X-ray crystallography.1,2
OTBDPS
OH
O
5
4
ix–xiii
xiv
O
O
O
OTBDPS
HO
HO
OTBDPS
Si
H
6
(–)-7
O
Scheme 1 Enantioselective synthesis of the diol (–)-7. Reagents
and conditions: i. crude pig liver esterase, pH 7.2 phosphate buffer,
31%; ii. 3% aq H2SO4, 85%; iii. TBDPSCl, imidazole, DMF, 96%; iv.
DIBAL-H, THF, –78 °C to r.t., 90%; v. CH2=CHMgBr, THF, 91%;
vi. PhSeCH2CH(OEt)2, PPTS, toluene, reflux, 90%; vii. NaIO4,
CH2Cl2, MeOH, H2O, ~100%; viii. DBU, toluene, reflux, 85%; ix.
KHMDS, toluene, –78 °C then ( )-2-(phenylsulfonyl)-3-phenyl-
oxaziridine, then CSA, 79%; x. TMSCl, Et3N, THF, 98%; xi. Tebbe
reagent, DMAP, THF, –40 °C to r.t., 90%; xii. TBAF, THF, r.t., 99%;
xiii. (Me2SiH)2NH, NH4Cl, ~100%; xiv. cat. (PPh3)3RhCl, THF,
reflux, then KOH, H2O2, THF, MeOH, H2O, 80%.
Cl
Br
1
Figure 1 Structure of (+)-obtusenyne (1)
The isolation of a large number of halogenated ether ma-
rine natural products has led to the development of a vari-
ety of elegant synthetic strategies for the construction of
strained medium-ring ether systems.3–8 Our own strategy
towards these metabolites8 has involved exploitation of
the Claisen rearrangement of a vinyl-substituted ketene-
acetal to deliver a medium-ring lactone, which is convert-
ed into a medium-ring ether via a methylenation/intramo-
lecular hydrosilation sequence. In the context of our
studies on the total synthesis of obtusenyne (1) we have
previously reported a highly diastereoselective racemic
synthesis of the diol ( )-7 from racemic methyl trans-3,4-
epoxyhexanoate [( )-2] that uses this Claisen rearrange-
ment/intramolecular hydrosilation sequence.9 Herein we
describe an enantioselective route to the diol (–)-7
(Scheme 1) and its conversion into (+)-obtusenyne (1).
The synthesis began with a pig liver esterase catalysed ki-
netic resolution of racemic methyl trans-3,4-epoxyhex-
anoate [( )-2] to provide methyl (+)-(3R,4R)-
21
epoxyhexanoate [(+)-2] {[a]D
+26.6 (c = 0.64,
CH2Cl2)}10 with 96% ee11,12 following the method of
Tamm (Scheme 1).13 The chiral non-racemic epoxide (+)-
2 was readily converted into the crystalline diol (–)-7 {mp
68–69 °C (hexane); [a]D22 –21.6 (c = 1.78, CHCl3)} with
very similar yields and diastereoselectivities to those pre-
viously reported for the synthesis of racemic ( )-7
(Scheme 1).9,14 The diol (–)-7 was protected as its p-meth-
oxybenzylidene acetal (95%) and selective reduction with
DIBAL-H provided the primary alcohol 8 (Scheme 2).
Mesylation of 8 (99%) followed by displacement of the
mesylate with cyanide delivered the corresponding nitrile
in excellent yield (99%). The nitrile was reduced with
DIBAL-H to furnish the aldehyde 9 (~100%). We investi-
gated two methods for the introduction of the enyne side
SYNTHESIS 2005, No. 19, pp 3199–3201
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918470; Art ID: C07205SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5

3200
S. Y. F. Mak et al.
SHORT PAPER
chain of 1. Exposure of the aldehyde 9 to lithio 1,3-bis(tri-
isopropylsilyl)propyne at –78 °C furnished the cis-enyne
10a in 50% yield along with the corresponding (separa-
ble) trans-enyne. Alternatively, Stork–Wittig reaction
converted 9 into the corresponding iodoalkene with exclu-
sive cis-selectivity and in good yield (97%). Sonogashira
reaction of the cis-vinyl iodide with trimethylsilylacety-
lene delivered the cis-enyne 10b in excellent yield (97%).
The PMB ether in 10b was readily removed15 with
BCl3⋅SMe2 to provide the secondary alcohol 11 in readi-
ness for introduction of the chlorine atom.
i
i
O
O
O
X
HO
HO
OBn
Br
Br
OBn
OTBDPS
OTBDPS
12
O
Cl
Cl
OTBDPS
OTBDPS
13
14
Scheme 3 Bromination studies. Reagents and conditions: CBr4,
P(oct)3, toluene, 70 °C, 0% from 12, 65% from 13.
i, ii
O
O
HO
HO
OTBDPS
PMBO
OTBDPS
synthesis of (+)-obtusenyne (1).4b The data for our syn-
thetic bromo alcohol 17 were in close agreement with the
data supplied by Crimmins resulting in a formal synthesis
of 1. Chlorination of 17 using Crimmins’s conditions de-
livered (+)-obtusenyne (1) as a clear and colourless oil
HO
iii–v
(–)-7
8
vi, vii
or viii
O
23
O
{[a]D +142.5 (c = 0.0267 in CHCl3)}. The data for our
PMBO
O
OTBDPS
R'O
OTBDPS
synthetic sample of obtusenyne (1) were in agreement
with the data for the natural material and that obtained by
other synthetic routes.1,2,4,18
10a; R = iPr, R' = PMB
10b; R = Me, R' = PMB
11; R = Me, R' = H
9
ix
SiR3
Scheme 2 Introduction of the enyne side chain. Reagents and con-
ditions: i. p-methoxybenzaldehyde, PPTS, benzene, reflux, 95%; ii.
DIBAL-H, CH2Cl2, –78 to –15 °C, 86%; iii. MsCl, Et3N, CH2Cl2,
~100%; iv. NaCN, DMF, 60 °C, 99%; v. DIBAL-H, toluene, –78 to
–15 °C, ~100%; vi. Ph3P+CH2I I–, NaHMDS, THF, DMPU, –78 °C to
r.t., 73%; vii. TMSC≡CH, CuI, Pd(PPh3)4, Et2NH, r.t., 97%; viii.
TIPSC≡CCH2TIPS, n-BuLi, THF, –78 °C to r.t., 50%; ix. BCl3⋅SMe2,
CH2Cl2, 92%.
O
ii
i
O
10a
PMBO
Br
PMBO
OH
15
16
iii
Experience had taught us that the introduction of halogen
atoms into medium-rings via SN2 displacement of activat-
ed alcohols with halide anions can depend critically on the
substituents on (and hence conformation of) the medium-
ring. Indeed, treatment of the secondary alcohol 12 with
CBr4 and trioctylphosphine16 in toluene at 70 °C resulted
in decomposition of the substrate whereas the chloro alco-
hol 13 could be cleanly converted into the corresponding
bromide 14 (65%) under the same reaction conditions
(Scheme 3).
iv
O
O
Cl
Br
HO
Br
1
17
Scheme 4 Synthesis of (+)-obtusenyne (1). Reagents and conditi-
ons: i. TBAF, THF, 95%; ii. CBr4, P(oct)3, toluene, 80 °C, 67%; iii.
BCl3⋅SMe2, CH2Cl2, 70%; iv. CCl4, P(oct)3, toluene, 80 °C (ca. 50%).
We were disappointed to find that attempted chlorination
of the secondary alcohol 11 under a wide variety of con-
ditions [Tf2O, pyridine then Et3BnNCl; CCl4, P(oct)3;
Ghosez reagent17] did not produce any of the required
chloride. We therefore turned our attention to the intro-
duction of the C-12 bromide before the C-7 chloride.
In summary, we have developed an efficient, enantiose-
lective synthesis of the halogenated marine natural prod-
uct (+)-obtusenyne (1) which further demonstrates the
utility of the Claisen rearrangement/intramolecular hy-
drosilation approach to these strained medium-ring sys-
tems.
Exposure of the enyne 10a to TBAF in THF removed both
silyl protecting groups to deliver the alcohol 15 in good
yield (95%) (Scheme 4). Bromination of 15 was conduct-
ed using freshly sublimed CBr4 and freshly distilled
P(oct)3 in toluene at 80 °C to deliver the bromide 16 in
67% yield. The bromide 16 was deprotected to provide the
bromo alcohol 17 (70%), an intermediate in Crimmins’s
Acknowledgment
We thank the Royal Society for the award of a University Research
Fellowship (JWB), Universities UK and the Cambridge Common-
wealth Trust (studentship to SYFM), and the EPSRC for generous
financial support and provision of the Swansea National Mass Spec-
trometry Service. We are grateful to Professor M. T. Crimmins for
Synthesis 2005, No. 19, 3199–3201 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Obtusenyne
3201
supplying spectroscopic data for 17 and 1. We thank the ARC,
VESKI and CSIRO for support.
1H NMR chiral shift reagent [(+)-Eu(hfc)3] analysis, with the
absolute configuration being assigned by comparison of the
optical rotation of the allylic alcohol with that of its
enantiomer.12 The enantiomeric excess of (+)-2 was
confirmed by Mosher ester analysis of the secondary alcohol
formed by the treatment of 3 with TBAF.
References
(1) King, T. J.; Imre, S.; Öztunc, A. Tetrahedron Lett. 1979, 20,
1453.
(2) Howard, B. M.; Schulte, G. R.; Fenical, W.; Solheim, B.;
(12) Burgess, K.; Henderson, I. Tetrahedron: Asymmetry 1990,
1, 57.
(13) Mohr, P.; Rösslein, L.; Tamm, C. Tetrahedron Lett. 1989,
30, 2513.
(14) The relative stereochemistry of the racemic diol ( )-7 was
determined by 1H NMR NOE and coupling constant analysis
of the derived acetonide.9c
(15) Congreve, M. S.; Davison, E. C.; Fuhry, M. A. M.; Holmes,
A. B.; Payne, A. N.; Robinson, R. A.; Ward, S. E. Synlett
1993, 663.
Clardy, J. Tetrahedron 1980, 36, 1747.
(3) Elliott, M. C. Contemp. Org. Synth. 1994, 1, 457.
(4) Total syntheses of obtusenyne: (a) Fujiwara, K.; Awakura,
M.; Tsunashima, M.; Nakamura, A.; Honma, T.; Murai, A.
J. Org. Chem. 1999, 64, 2616. (b) Crimmins, M. T.; Powell,
M. T. J. Am. Chem. Soc. 2003, 125, 7592.
(5) Total synthesis of brasilenyne and citation of important
contributions in the field: (a) Denmark, S. E.; Yang, S.-M. J.
Am. Chem. Soc. 2002, 124, 2102. (b) Denmark, S. E.; Yang,
S.-M. J. Am. Chem. Soc. 2004, 126, 12432; and references
cited therein.
(16) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345.
(17) Bendall, J. G.; Payne, A. N.; Screen, T. E. O.; Holmes, A. B.
Chem. Commun. 1997, 1067.
(18) NMR data for synthetic 1: 1H NMR (500 MHz, C6D6,
50 °C): d = 5.92 (dt, 1 H, J = 10.8, 7.3 Hz), 5.53–5.43 (m, 3
H), 4.20–4.13 (m, 1 H), 3.90 (dt, 1 H, J = 10.8, 2.8 Hz), 3.77
(dt, 1 H, J = 10.8, 3.0 Hz), 3.74–3.68 (m, 1 H), 3.02 (ddt, 1
H, J = 14.2, 1.2, 7.1 Hz), 2.92 (d, 1 H, J = 2.0 Hz), 2.87 (dt,
1 H, J = 14.7, 7.0 Hz), 2.78–2.62 (br m, 2 H), 2.52 (ddd, 1 H,
J = 12.9, 6.5, 3.0 Hz), 2.40 (ddd, 1 H, J = 13.2, 6.6, 2.9 Hz),
1.91 (dqn, 1 H, J = 14.2, 7.4 Hz), 1.74 (dqn, 1 H, J = 14.2,
7.4 Hz), 0.85 (t, 1 H, J = 7.4 Hz). 13C NMR (125 MHz, C6D6,
34 °C): d = 140.7 (C-4), 110.7 (C-3), 82.8 (C-1), 80.1 (C-2),
63.3 (C-7), 56.6 (C-12), 35.3 (C-5), 32.0 (C-8), 31.2 (br, C-
11), 28.7 (C-14), 10.1 (C-15). Owing to the conformational
mobility of the natural product the signals due to C-6 and C-
13 in the 13C NMR spectrum were broadened to the baseline.
Signals assignable to C-9 and C-10 were obscured by
solvent.
(6) Boeckman, R. K.; Zhang, J.; Reeder, M. R. Org. Lett. 2002,
4, 3891.
(7) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
(8) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall,
J. G.; Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483; and
references cited therein.
(9) (a) Curtis, N. R.; Holmes, A. B.; Looney, M. G. Tetrahedron
1991, 47, 7171. (b) Curtis, N. R.; Holmes, A. B.; Looney,
M. G. Tetrahedron Lett. 1992, 33, 671. (c) Curtis, N. R.;
Holmes, A. B. Tetrahedron Lett. 1992, 33, 675.
(10) All new compounds exhibited satisfactory spectroscopic and
exact mass/elemental analysis data.
(11) The enantiomeric excess and absolute configuration of (+)-2
were determined by analysis of the elimination product
methyl (4R,2E)-hydroxyhex-2-enoate that was formed in
86% yield by the treatment of (+)-2 with DBU. The
enantiomeric excess of the allylic alcohol was determined by
Synthesis 2005, No. 19, 3199–3201 © Thieme Stuttgart · New York