Synthesis of the oxygenated bicyclo[9.3.1]pentadecane ring system of phomactin A using chromium (II)-mediated macrocyclisation and ring closure metathesis

Article abstract of DOI:10.1055/s-2001-11403

Treatment of the aldehyde vinyl iodides 17, 19a and 19b in DMSO with CrCl₂-NiCl₂ resulted in their macrocyclisation to the oxygenated ring systems 18, 20, and 21 respectively (43-63%) of the PAF antagonist phomactin A isolated from t

Full text of DOI:10.1055/s-2001-11403

LETTER
365
Synthesis of the Oxygenated Bicyclo[9.3.1]pentadecane Ring System of
Phomactin A using Chromium (II)-mediated Macrocyclisation and Ring
Closure Metathesis
Kevin M. Foote, Matthew John, Gerald Pattenden*
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
E-mail: gp@nottingham.ac.uk
Received 5 January 2001
Our strategy for achieving a total synthesis of phomactin
A itself, therefore, was based on elaborating the substitut-
ed bicyclo[9.3.1]pentadecane 3 and then completing the
synthesis via similar intermediates to those used in the
Abstract: Treatment of the aldehyde vinyl iodides 17, 19a and 19b
in DMSO with CrCl2-NiCl2 resulted in their macrocyclisation to the
oxygenated ring systems 18, 20, and 21 respectively (43-63%) of
the PAF antagonist phomactin A isolated from the marine fungus
Phoma sp. The same bicyclo[9.3.1]pentadecane ring system 24 conversion of 4 into 2. Although a wide range of macro-
could also be produced by treatment of the polyene 23 with Grubbs’
ruthenium catalyst in hot CH2Cl2 for 10 h (~30%).
cyclisation protocols were examined to synthesise the
macrocyclic core in structure 3, the method we describe
Key words: macrocyclisation, chromium (II), phomactin A,
metathesis, PAF
here is based on an intramolecular Cr(II) mediated cou-
pling reaction from the aldehyde vinyl iodide intermediate
10 [the so-called Nozaki-Hiyama-Kishi (NHK) reaction].8
In turn, we planned to synthesise this pivotal intermediate
10 from the readily available dioxin 79 and proceeding via
an alkylation reaction sequence, leading to 8, followed by
introduction of the hydroxymethyl functionality, produc-
ing 9 and, finally, manipulation of the functionality in 9
(Scheme 1).
Phomactin A (1) is a novel oxygenated diterpene isolated
from the marine fungus Phoma sp,1 and is a specific plate-
let activating factor (PAF)-antagonist.2,3 The natural prod-
uct has a unique structure which features an unusual
furanochroman ring system 2 making up part of a macro-
cyclic bicyclo[9.3.1]pentadecane core 3. This novel struc-
ture, alongside its biogenetic relationship with the taxane
ring system,4 and its interesting PAF-antagonist activity,
combine to make phomactin A and its congeners extreme-
ly attractive targets for total synthesis and for biological
evaluation. In an earlier publication5 we described a con-
cise synthesis of the tricyclic furanochroman unit 2 found
in phomactin A.6 In this communication we outline a syn-
thesis of the oxy-substituted bicyclo[9.3.1]pentadecatri-
ene 3 containing all the carbon atoms and most of the
oxygen centres in this intriguing natural product.7
Thus, sequential deprotonation and alkylation of the diox-
in 7 derived from 5-methylcyclohexane 1,3-dione using,
firstly LDA and MeI, and then LDA and the E,E-iododi-
ene 14, produced the substituted dioxin 8 as a 3:1 mixture
of diastereoisomers in favour of the syn-dimethyl diaste-
reoisomer shown. The homoallylic iodide 14 was synthe-
sised by way of a palladium catalysed cross-coupling
reaction between the homopropargylic iodide 11 and the
E-vinyl iodide 12,10 leading to 13, followed by desilyl-
ation and
a zirconium assisted carboalumination-
iodination11 process as key steps (Scheme 2).
1,2-Addition of p-methoxybenzylmethyl lithium12 to the
vinylogous ether 8 followed by work-up with dilute HCl
next led to the corresponding enone 15 in a modest 43%
yield over two steps. Protection of the alcohol group in 15
and reduction of the carbonyl function, under Luche con-
ditions,13 then led to the corresponding β-orientated sec-
ondary alcohol which was protected as its MOM ether 16.
Finally, saponification of 16 followed by oxidation of the
resulting primary alcohol using Dess-Martin periodi-
nane,14 led to the key aldehyde vinyl iodide 17 (cf 10).
Treatment of a solution of the aldehyde vinyl iodide 17 in
DMSO with 6 equivalents of CrCl2 and 0.25 equivalents
of NiCl2 resulted in smooth macrocyclisation and the for-
mation of the macrocyclic secondary alcohol 18 as a 1:1
mixture of α- and β-OH epimers in a combined yield of
52%.15 The structures and stereochemistries of the inter-
mediate 16 and the product 18 produced in this sequence
followed from comparison of spectroscopic data with the
more simple analogues 20 and 21 synthesised by an iden-
OR
OH
O
OH
OH
O
OH
OH
OR′
O
H
O
H
2
3
1
In our earlier published synthesis of the model furano-
chroman 2, a key intermediate was the corresponding hy-
droxymethyl substituted cyclohexenone 4 which was
elaborated to 2 in five steps via the dihydrofuran 5 and the
tricyclic enol ether 6 as key intermediates (Scheme 1).5
Synlett 2001 No. 3, 365–368 ISSN 0936-5214 © Thieme Stuttgart · New York

366
K. M. Foote et al.
LETTER
HO
O
O
OMOM
O
H
i, ii
iii, iv
v
2
O
OH
H
4
6
5
OR
O
O
O
i, -CH2OR
ii, H3O+
OH
steps
O
O
O
O
I
I
7
8
9
OR
O
CrCl2
NiCl2
steps
3
OR'
I
10
i
Reagents: i,CSA, CH2Cl2, RT, 91%; ii, Bu2AlH, PhMe, -78 °C, 46%; iii, PhSeBr, Et3N, CH2Cl2, -78 °C, 77%; iv, m-CPBA, CH2Cl2, 0 °C;
KOH, THF, ; v, DMDO, Me2CO, H2O, 0 °C, 22% (3 steps).
Scheme 1
tical strategy. The structure and stereochemistry of the carbon atoms and all the necessary oxygen centres in
crystalline alcohol 20 produced via a NHK reaction from readiness for elaboration to the target natural product it-
19a was established by X-ray crystal structure analysis,16 self. In complementary synthetic studies we also synthe-
whereas the structure and stereochemistry of 21, obtained sised the ring closure metathesis precursor 23 starting
from 19b, was secured from NOE experiments in its NMR from the substituted 3-ethoxy-cyclohex-2-enone 22 and
spectrum and from complementary molecular modelling using methods similar to those used to produce precursors
data.
to 17 and 19 from 7 (Scheme 3).17 When a refluxing solu-
tion of the polyene 23 in CH2Cl2 was exposed to Grubbs’
ruthenium catalyst18 (30 mol%) for 10 h, the correspond-
ing macrocyclic polyene 24 was isolated in an unopti-
mised 27% yield with exclusively the E-geometry at the
newly introduced alkene bond. Further studies are now
underway in our laboratories to develop the strategies de-
scribed here towards bicyclo[9.3.1]pentadecanes, en route
to phomactin A (1) and other biologically important
phomactinoids. These studies will be described in due
course.
OH
OH
R
O
OR'
OR′
OR′
I
19
a R = H
20 R′ = MOM
21 R′ = MOM
b R = Me
Acknowledgement
We thank Chris J Hayes and Alan Happe for their collaboration in
the early part of this project. We also thank the EPSRC for stu-
dentships (to Matthew John and Kevin Foote) and Astra Charnwood
for financial support.
We have therefore accomplished, for the first time, a syn-
thesis of the phomactin A ring system containing all the
Synlett 2001, No. 3, 365–368 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of the Oxygenated Bicyclo[9.3.1]pentadecane Ring System
367
I
TBSO
iii
OH
i, ii
iv
12
Me3Si
SiMe3
11
13
HO
HO
I
v
vi
I
I
14
OPMB
OH
O
O
vii, viii
ix
x-xii
7
O
O
I
I
8
15
OPMB
OPNB
OMOM
OPMB
CHO
PMBO
OH
xiii, xiv
xv
OR
OMOM
I
I
18 R = MOM
16
17
Reagents: i, BuLi, TMSCl, THF, -78 → 0 °C, then HCl, Et2O, 94%; ii, I2, PPh3, Imidazole, Et2O-CH3CN (3:1), 92%; iii, tBuLi, ZnCl2, THF,
-78 °C; then Pd(PPh3)4, (E)-TBSOCH2CH2(CH3)C=CHI (12); iv, TBAF, THF, 87% (2 steps); v, AlMe3, Cp2ZrCl2, CH2Cl2; then I2, THF, 83%;
vi, I2, PPh3, Imidazole, Et2O-CH3CN (3:1), 96%; vii, LDA, THF, -78 °C; then MeI, 96%; viii, LDA, THF, -78 °C; then 14, 76%; ix,
PMBOCH2SnMe3, BuLi, Et2O, -78 °C; then HCl, THF, 43%; x, p-NO2C6H4COCl, Et3N, DMAP, CH2Cl2, 92%; xi, NaBH4, CeCl3•7H2O, Me-
OH, CH2Cl2, 83%; xii, MOM-Cl, iPr2EtN, Bu4NI, CH2Cl2; xiii, KOH, MeOH, 87% (2 steps); xiv, Dess-Martin periodinane, C5H5N, CH2Cl2,
0 °C, 98%; xv,CrCl2 (6 eq.), NiCl2 (0.25 eq.), DMSO, 52%.
Scheme 2
2000, 2, 2687; and for a total synthesis of phomactin D see:
Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y.; Tetrahedron
References and Notes
Lett. 1996, 37, 7107.
(1) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.;
Kuwano, H.; Hata, T.; Hanzawe, H.; J. Am. Chem. Soc. 1991,
113, 5463.
(2) Chu, M.; Truumees, I.; Gunnarsson, I.; Bishop, W.R.;
Kreutner, W.; Horan, A.C.; Patel, M.G.; J. Antobiotics 1993,
554.
(3) Sugano, M.; Sato, A.; Iijima, Y.; Furuya, K.; Haruyama, H.;
Yoda, K.; Hata, T.; J. Org. Chem. 1994, 59, 564.
(4) For discussion see: Hayes, C.J., PhD Thesis, University of
Nottingham, 1995.
(5) Foote, K.M.; Hayes C.J.; Pattenden, G.; Tetrahedron Lett.
1996, 37, 275.
(8) For a recent review which includes the scope for the NHK
reaction in synthesis see: Furstner, A.; Chem. Rev. 1999, 99,
991.
(9) Smith, A.B., Dorsey, B.D.; Ohba, M.; Lupo, A.T.; Malamas,
M.S.; J. Org. Chem. 1988, 53, 4314. Unpublished work of A.
Happe in these laboratories.
(10) Negishi, E.; Valente, L.F.; Kobayashi, M.; J. Am. Chem. Soc.
1980, 102, 3298.
(11) Negishi, E.; van Horn, D.E.; Moore, M.W.; Rand, C.L.; J.
Org. Chem. 1981, 46, 4096.
(12) cf Buchwald, S.L.; Neilsen, J.C.; Dewan, J.C.;
Organometallics 1989, 8, 1593.
(13) Luche, J-L.; J. Am. Chem. Soc. 1978, 100, 2226.
(14) Dess, D.B.; Martin, J.C.; J. Org Chem. 1983, 48, 4155.
(6) For other approaches to the tricyclic core of phomactin A see:
Seth, P.P., Totah, N.I.; Org. Lett. 2000, 2, 2507.
(7) For an alternative approach to the macrocyclic core in
phomactin D see: Kallan, N.C.; Halcomb, R.L.; Org. Lett.
Synlett 2001, No. 3, 365–368 ISSN 0936-5214 © Thieme Stuttgart · New York

368
K. M. Foote et al.
LETTER
O
O
O
Br
Br
i,ii
iii-vi
vii-viii
OEt
OEt
OEt
O
22
O
OTBS
OTBS
O
O
ix
OEt
OEt
23
24
Reagents: i, LDA, THF, -78 °C, then ICH2CH2CH(OCH2CH2O), 70%; ii, NBS, CCl4, 25 °C, 68%; iii, PdCl2(MeCN)2, Me2CO, 75%; iv,
MeMgCl, THF, 0 °C, 66%; v, Dess-Martin periodinane, CH2Cl2, 0 °C, 99%; vi, H2C:CHCH2CH2CH2PPh3Br, BuLi, Et2O, -78 °C, 58%; vii,
tBuLi, THF, -78 °C, then CH2=CHCHO, 76%; viii, TBSOTf, DIPEA, CH2Cl2, 0 °C, 86%; ix, RuCl2(=CHPh)(PCy3)2, CH2Cl2, ∆, 10 h, 27%.
Scheme 3
(15) All new compounds showed satisfactory spectroscopic and
analytical data. Typical procedure for the preparation of 18: A
mixture of chromium dichloride (23 mg, 0.226 mmol) and
nickel chloride (1.2 mg, 0.009 mmol) was added in a single
portion to a stirred solution of the vinyl iodide 17 (23 mg,
0.03 mmol) in DMSO-THF (3:1, 4.8 ml) at room temperature
under argon. The mixture was stirred at room temperature for
16 h, then cooled to 15 °C and diluted sequentially with
hexane (2 ml) and DL-serine (1M in saturated sodium
113.8 (d), 96.0 (t), 76.5 (d), 72.8 (t), 68.2 (d), 67.4 (t), 55.9 (q),
55.3 (q), 41.8 (s), 36.3 (t), 34.6 (t), 33.6 (t), 33.0 (t), 29.9 (d),
25.8 (t), 21.2 (q), 18.1 (q), 15.7 (q), 15.4 (q) and ii) the β-
alcohol (5 mg, 27%) as a colourless oil, δH (360 MHz, CDCl3)
7.33-7.31 (2H, m, Ar), 6.91-6.89 (2H, m, Ar), 5.60 (1H, d, J
10.7, C=CHCHOH), 5.28 (1H, br. d, J 10.7, C=CHCHOH),
5.01 (1H, br. s, OH), 4.89 (1H, d, J 7.0, OCHHOCH3), 4.82-
4.74 (2H, m, C=CHCH2 and CHOCH3), 4.73 (1H, d, J 7.0,
OCHHOCH3), 4.47 (2H, br. s, ArCH2O), 3.82 (3H, s, OCH3),
3.66 (1H, br. d, J 11.2, CHHO), 3.50 (1H, d, J 11.2, CHHO),
3.46 (3H, s, OCH3), 2.47-2.32 (1H, m, CHH), 2.14-1.50 (9H,
m, 3 × CH2, CHH and CH), 1.60 (3H, d, J 1.1,
CH3C=CCHCHOH), 1.44 (3H, s, CH3C=CH), 0.88 (3H, s,
CH3C), 0.85 (3H, d, J 6.8, CH3CH); δC (90 MHz, CDCl3)
159.3 (s), 141.2 (s), 138.4 (s), 135.5 (s), 132.5 (s), 130.3 (s),
129.8 (d), 128.1 (d), 127.5 (d), 113.8 (d), 94.7 (t), 75.6 (d),
72.7 (t), 69.8 (d), 65.6 (t), 56.7 (q), 55.3 (q), 41.1 (s), 38.4 (t),
34.6 (t), 33.4 (t), 31.8 (t), 30.2 (d), 26.9 (t), 21.0 (q), 16.1 (q),
15.8 (q), 15.1 (q); m/z (ES+) 507.3067 (M++Na), C30H44O5Na
requires 507.3086.
bicarbonate solution; 6 ml). The mixture was stirred
vigorously for 30 min and then the organic layer was
separated. The aqueous phase was extracted with diethyl ether
(4 × 3 ml) and then the combined organic layers were washed
with brine (2 × 20 ml), dried (MgSO4) and concentrated in
vacuo. The residue was purified by column chromatography
on silica using diethyl ether − pentane (30:70 to 50:50) as
eluent to give i) the α-alcohol (4.5 mg, 25%) as a colourless
oil, δH (360 MHz, CDCl3) 7.30-7.27 (2H, m, Ar), 6.91-6.87
(2H, m, Ar), 5.28 (1H, br, d, J 8.0, C=CHCHOH), 5.08-5.04
(1H, br, d, J 8.0, CHOH), 4.96-4.94 (1H, br. s, OH), 4.86 (1H,
d, J 7.0, OCHHO), 4.75-4.70 (2H, m, OCHHO and
CH3C=CHCH2), 4.54 (1H, d, J 11.1, CHHOAr), 4.42 (1H, d,
J 11.1, CHHOAr), 4.22 (1H, br. d, J 10.8, CCHHOCH2), 3.95
(1H, dd, J 9.0 and 6.7, CHOCH2), 3.81 (3H, s, OCH3), 3.74
(1H, d, J 10.8, CCHHOCH2), 3.45 (3H, s, OCH3), 2.40-1.48
(11H, m, 5 × CH2 and CH), 1.74 (3H, d, J 0.7, CH3C=CH),
1.51 (3H, s, CH3C=CH), 0.86 (3H, s, CH3C), 0.85 (3H, obs. d,
CH3CH); δC (90 MHz, CDCl3) 159.5 (s), 142.6 (s), 141.4 (s),
133.0 (s), 132.7 (s), 130.3 (d), 129.0 (s), 128.2 (d), 127.7 (d),
(16) We thank Dr C. Wilson for the X-ray structure determination,
which will be published separately in a full paper.
(17) Foote, K.M., PhD Thesis, University of Nottingham, 1997.
(18) Sehwab, P.; Grubbs, R. H.; Ziller, J.W.; J. Am. Chem. Soc.
1996, 18, 100.
Article Identifier:
1437-2096,E;2001,0,03,0365,0368,ftx,en;L22700ST.pdf
Synlett 2001, No. 3, 365–368 ISSN 0936-5214 © Thieme Stuttgart · New York