Synthesis of the skipped polyene chain and its neighboring highly oxygenated pyran ring en route to delivering the C(43)-C(67) subsector of amphidinol 3

Article abstract of DOI:10.1055/s-2005-918960

An approach toward a total synthesis of amphidinol 3 that focuses on elaboration of the C(43)-C(67) subunit is described. The Julia-Kocienski reaction constitutes a straightforward way to unite the skipped polyolefm chain to the adjacent highly functional

Full text of DOI:10.1055/s-2005-918960

LETTER
2915
Synthesis of the Skipped Polyene Chain and Its Neighboring Highly
Oxygenated Pyran Ring en route to Delivering the C(43)–C(67) Subsector
of Amphidinol 3
Synthesis of th
h
e
C
(43)–C(6
u
7) Subsecto
h
of
A
mphidi
-
nol
3
Kuen Chang, Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, USA
Fax +1(614)2921685; E-mail: paquette.1@osu.edu
Received 9 August 2005
chain and its adjoining C(43)–C(52) pyran ring, in addi-
tion to the stereocontrolled linkage of these components
(Scheme 1).
Abstract: An approach toward a total synthesis of amphidinol 3
that focuses on elaboration of the C(43)–C(67) subunit is described.
The Julia–Kocienski reaction constitutes a straightforward way to
unite the skipped polyolefin chain to the adjacent highly functional-
ized pyran ring.
From the outset, we envisioned that the convergent merg-
er of sulfone 2 to aldehyde 3 would define a suitably ab-
breviated route to the carbonyl-functionalized polyolefin
16. For this plan to be successful, conditions conducive to
double bond migration or to inadvertent b-elimination
would have to be skirted. First to be carried out was the
formation of iodide 67 based on established protocols in-
volving the base-promoted deconjugation of sorbic acid
(5) via kinetic quenching of the dianion,8 reduction with
lithium aluminum hydride to the homoallylic alcohol,9
and treatment of the latter with triphenylphosphine and io-
dine in the presence of imidazole (Scheme 2). Alkylation
of the anion of methyl phenyl sulfone10 with 6 furnished 2
in 57% yield.
Concurrently, the protected aldehyde 711 was subjected to
Wadsworth–Emmons reaction12 with (E)-diethylphos-
phonocrotonate13 to afford the E,E-dienyl ester 9. The
highly efficient conversion of 9 into 3 was next accom-
plished by sequential hydride reduction and oxidation of
the resulting primary alcohol to the aldehyde level with
the Dess–Martin periodinane (DMP) reagent.14
Key words: polyketide metabolite, carbohydrate homologation,
selective desilylation, Julia–Lythgoe reaction, Julia–Kocienski
reaction
Amphidinol 3 (1) has emerged as the key member of a
small family of polyketide metabolites isolated from cul-
tures of the marine dinoflagellate Amphidinium klebsii.1,2
The habitat of this unicellular alga is seaweed originating
from bays surrounding the coast of Japan.3 The significant
antifungal and hemolytic activity of 1 and its uniquely
complex structural features have caused it to become a
prime candidate for directed synthesis. Although arrival at
this target has yet to be realized, several creative
approaches to the polyol4 and pyranyl fragments5 have
recently been reported. Presently, we amplify on our suc-
cessful approach to the richly oxygenated C(1)–C(30)
polyol sector6 by defining a pathway for the complemen-
tary construction of the C(53)–C(67) skipped polyene
O
O
Ph
N
N
O
H
O
O
O
N
S
O
S Ph
O
TBSO
O
OTr
OMOM
H
H
3
O
2
N
4
OH
O
HO
HO
OH
HO
67
65
55
H
O
45
50
OH
40
H
H
60
35
HO
OH
OH
H
OH
amphidinol 3
HO
H3C
(1)
OH CH3 OH OH
30
5
15
1
20
10
HO
25
OH
OH
OH
OH
OH
OH
Scheme 1 Retrosynthetic analysis of the C(43)–C(67) subsector of amphidinol 3.
SYNLETT 2005, No. 19, pp 2915–2918
0
1
.1
2
.2
0
0
5
Advanced online publication: 27.10.2005
DOI: 10.1055/s-2005-918960; Art ID: S07405ST
© Georg Thieme Verlag Stuttgart · New York

2916
S.-K. Chang, L. A. Paquette
LETTER
O
O
LiCH2SO2Ph
ref. 7–9
I
OH
S Ph
O
THF, HMPA (57%)
5
2
6
O
O
1. LiAlH4, Et2O
(EtO)2P
H
H
OCH3
O
8
OCH3
(99%)
TBSO
O
TBSO
O
TBSO
2. DMP, py,
LDA, THF
(53%)
3
9
7
CH2Cl2 (91%)
1.2 equiv nBuLi,
THF;
OR
Na/Hg, –30 °C
OTBS
2
R
2:1 THF/MeOH
(77%, E/Z = 9:1)
3; NH4Cl (94%)
SO2Ph
12, R = OTBS
13, R = OH
14, R = I
(88%)
TBAF, THF
10, R = H
11, R = Bz
BzCl, py,
CH2Cl2 (91%)
I2, PPh3, imidazole
C6H6 (99%)
KCN, DMF (88%)
15, R = CN
DIBAL-H, CH2Cl2,
–78 °C (82%)
CHO
16
Scheme 2 Elaboration of polyunsaturated aldehyde 16.
The Julia–Lythgoe protocol15 was utilized to couple 2 to DMF solution.17 Reduction of 15 with DIBAL-H afforded
3. Under these conditions, b-hydroxy sulfone 10 was ob- 1618 in uneventful fashion.
tained in 94% yield. Initially, this step was followed by
conversion to the acetate. However, when this intermedi-
ate was reduced with sodium amalgam, a lackluster 3:1
The ready availability of 3,4-O-isopropylidene-b-D-ri-
bopyranose (17)19 was exploited in our quest of 4. Ho-
mologation of this carbohydrate by means of Wittig chain
mixture of E/Z diastereomers was formed. Interestingly,
extension20 gave rise efficiently to 18 when a 1:1 dioxane–
this olefinic selectivity problem was upgraded to a signif-
DMF mixture was utilized in the vicinity of 75 °C to over-
icant degree by alternative utilization of the benzoate de-
come low solubility (Scheme 3). In this instance, the
structural features of the reactants were conducive to ex-
clusive formation of the E stereoisomer. Several protect-
rivative 11. This change was met with an improvement in
stereoselectivity to the 9:1 (E/Z) level, and provided the
opportunity to separate the desired major product chro-
ing group options were next evaluated for their feasibility.
matographically (62% two-step yield of 13).16 The scaling
Recourse to a PMB or TBS substituent at R2 was ultimate-
up of this conversion made practical the production of rea-
ly ruled out because of kinetically significant competitive
sonable quantities of iodide 14. The SN2 displacement of
intramolecular attack by the associated ether oxygen
I– from 14 proceeded smoothly with potassium cyanide in
when time came to activate the R1O functionality.21,22 To
O
O
t
DIBAL-H, CH2Cl2
Ph3P=CHCO2 Bu
O
t
CO2 Bu
R1O
OR2
OH
R1O
NaBH4,
THF/MeOH (95%)
DMF/dioxane (1:1), 75 °C
(90%)
O
O
OR2
O
OTBDPS
O
OH
18, R1 = R2 = H
21, R1 = TBS, R2 = H
22, R1 = TBS, R2 = SEM
23, R1 = H, R2 = SEM
SEMCl, iPr2NEt
Bu4NI (99%)
NBS, DMSO,
17
TBSCl, Et3N,
DMAP (quant.)
TBDPSCl, imidazole
DMAP, DMF,
19, R1 = TBS, R2 = H
20, R1 = TBS, R2 = TBDPS
H O, r.t.
2
(93%)
50 °C (quant.)
1. DMP, py
CH2Cl2 (99%)
O
O
Hg(OAc)2; NaBH4
O
OSEM
X
OSEM
2. Ph3P=CHOMe
(99%)
(75%)
THF/H2O, 0 °C
O
OTBDPS
24, X = O
O
OTBDPS
H
26
25, X = MeOCH
O
HO
MeO
O
(CF3CH2O)2PCH2CO2Me
18-Cr-6, KHMDS
O
O
DIBAL-H, CH2Cl2
–78 °C (99%)
OSEM
OSEM
(91% Z/E > 20:1)
O
OTBDPS
27
O
OTBDPS
28
Scheme 3 Early stages of pyran construction. Setting the configuration of C–O bonds.
Synlett 2005, No. 19, 2915–2918 © Thieme Stuttgart · New York

LETTER
Synthesis of the C(43)–C(67) Subsector of Amphidinol 3
2917
O
O
HO
Ti(OiPr)4, tBuOOH,
(–)-DIPT, 4 Å MS,
O
TBAF, THF
SEMO
OSEM
28
O
OR2
O
CH2Cl2 (82%, dr = 5.3:1)
r.t. (84%)
H
H
O
OTBDPS
OR1
30, R1 = R2 = H
29
TrCl, py,
35 °C (89%)
31, R1 = H, R2 = Tr
32, R1 = MOM, R2 = Tr
MOMCl, iPr2NEt
(94%)
40 °C, CHCl 3
N
N
O
O
1.
HS
O
AD-mix-β,
CH3SO2NH2,
, DIAD, Ph3P
N
O
O
MeO OMe
N
HO
SEMO
RO
Ph
OTr
OMOM
O
O
OTr
OMOM
tBuOH/H2O
(98%, dr = 9:1)
H
H
H
PPTS (86%)
H
2. Mo7O24(NH4)6, H2O2
(80% over two steps)
HO
O
33
34, R = SEM
35, R = H
TBAF, THF,
55 °C (90%)
O
O
O
Ph
N
N
KHMDS,
THF; 16
O
O
O
O
O
N
S
O
OTr
OMOM
O
OTr
OMOM
H
H
H
H
(80%, E/Z > 20:1)
O
O
N
4
36
Scheme 4 The complete pyran scaffold and its linkup with 16.
bypass such eventualities, masking with the more bulky the 1-phenyl-1H-tetrazolyl sulfone (4) via the Mitsunobu
TBDPS group was resorted to, thereby facilitating the reaction,32 in tandem with molybdate-promoted oxida-
transition to alcohol 21. The formation of SEM ether 22,23 tion.33 Consistent with the experience of others,34 applica-
which proceeded in 99% yield, was followed by selective tion of the Julia–Kocienski process to the merger of 16
deprotection of the primary silyl ether by means of N-bro- with 4 was achieved with an appreciable bias toward trans
mosuccinimide in aqueous DMSO.24 At this point, 23 was diastereoselection (E/Z > 20:1).35
subjected to periodinane oxidation,14 and aldehyde 24
In summary, a convergent synthesis of the C(43)–C(67)
formed in this manner was treated with methoxymethyl-
component of amphidinol 3 has been realized. Our
enetriphenylphosphorane25 followed by mercuration–re-
approach highlights application of the Julia–Lythgoe
ductive demercuration26 under basic conditions to provide
reaction to skipped polyolefin construction and of the
Kocienski modification for conjoining to the pyran seg-
ment. Since the two pyran rings in 1 are enantiomerically
related, the C(31)–C(40) segment of 1 can also be con-
sidered to be in hand. Further experiments aimed at
completing the full assembly of 1 are currently under
active investigation.
the homologated entity 26. Treatment of 26 with the Still–
Gennari trifluoroethylphosphono ester27 proceeded in
good yield and with anticipated high stereoselectivity
(Z/E > 20:1; 1H NMR analysis). As a consequence, access
to 2828 was made possible by subsequent DIBAL-H
reduction.
Added forward progress was achieved by application of
the Sharpless asymmetric epoxidation protocol to 28
(Scheme 4). Under standard conditions involving the use
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Synlett 2005, No. 19, 2915–2918 © Thieme Stuttgart · New York

2918
S.-K. Chang, L. A. Paquette
LETTER
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(28) Compound 28: IR (neat): 3456, 1657, 1589 cm–1. 1H NMR
(300 MHz, CDCl3): d = 7.70–7.63 (m, 4 H), 7.44–7.33 (m, 6
H), 5.79–5.73 (m, 1 H), 5.64–5.55 (m, 2 H), 5.27 (ddd,
J = 15.8, 5.2, 5.2 Hz, 1 H), 4.46 (s, 2 H), 4.26 (t, J = 2.9 Hz,
1 H), 4.18–4.11 (m, 3 H), 4.07–4.04 (m, 1 H), 3.80 (dd,
J = 5.5, 1.2 Hz, 2 H), 3.57–3.51 (m, 2 H), 2.35–2.29 (m, 2
H), 1.77 (br, 1 H), 1.39 (s, 3 H), 1.30 (s, 3 H), 1.03 (s, 9 H),
0.90 (t, J = 8.3 Hz, 2 H), 0.02 (s, 9 H). 13C NMR (75 MHz,
CDCl3): d = 136.0, 135.9, 133.8, 133.7, 131.5, 130.8, 130.5,
129.7, 129.6, 129.3, 127.5, 127.4, 108.3, 93.7, 80.0, 76.8,
73.2, 66.6, 65.0, 57.9, 28.6, 27.6, 27.0, 25.4, 19.2, 18.0,
–1.38. HRMS (ES): m/z calcd 649.3351[(M + Na]+; found:
649.3347. [a]D20 +23.0 (c 1.22, CHCl3).
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(18) Compound 16: IR (neat): 1727, 1650 cm–1. 1H NMR (300
MHz, CDCl3): d = 9.76 (t, J = 1.6 Hz, 1 H), 6.30 (dt,
J = 16.9, 10.2 Hz, 1 H), 6.19–6.00 (m, 5 H), 5.72–5.58 (m, 3
H), 5.09 (dd, J = 16.9, 1.5 Hz, 1 H), 4.96 (d, J = 10.1 Hz, 1
H), 2.60–2.50 (m, 2 H), 2.50–2.32 (m, 2 H), 2.22–2.14 (m, 4
H). 13C NMR (75 MHz, CDCl3): d = 201.8, 137.2, 134.3,
134.0, 131.8, 131.7, 131.4, 131.3, 130.8, 130.4, 115.1, 43.3,
32.4, 32.3, 25.3.
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(35) Compound 36: IR (neat): 1599, 1490 cm–1. 1H NMR (500
MHz, CDCl3): d = 7.47–7.43 (m, 6 H), 7.29–7.26 (m, 6 H),
7.26–7.21 (m, 3 H), 6.30 (dt, J = 17.0, 10.3 Hz, 1 H), 6.20–
5.97 (m, 5 H), 5.80 (dt, J = 15.2, 4.9 Hz, 1 H), 5.72–5.62 (m,
3 H), 5.44 (dd, J = 15.4, 7.8 Hz, 1 H), 5.10 (d, J = 16.9 Hz,
1 H), 4.97 (d, J = 10.1 Hz, 1 H), 4.75 (d, J = 6.8 Hz, 1 H),
4.69 (d, J = 6.7 Hz, 1 H), 4.39–4.27 (m, 2 H), 4.24 (dd,
J = 6.0, 6.0 Hz, 1 H), 4.08–4.02 (m, 1 H), 3.87–3.81 (m, 2
H), 3.71 (ddd, J = 7.9, 4.9, 4.9 Hz, 1 H), 3.35–3.32 (m, 1 H),
3.34 (s, 3 H), 3.20 (dd, J = 10.0, 5.4 Hz, 1 H), 2.22–2.10 (m,
8 H), 1.89–1.84 (m, 1 H), 1.75–1.68 (m, 1 H), 1.44 (s, 3 H),
1.40 (s, 3 H), 1.39 (s, 3 H), 1.33 (s, 3 H). 13C NMR (125
MHz, CDCl3): d = 143.9, 137.1, 136.2, 134.3, 133.5, 133.0,
131.3, 131.2, 131.0, 130.9, 128.7, 127.8, 127.0, 126.9,
115.1, 109.2, 108.7, 98.7, 96.8, 86.7, 82.1, 78.2, 77.7, 72.1,
71.5, 70.8, 63.3, 55.9, 32.4, 32.3, 32.2, 29.7, 29.0, 27.9, 27.2,
26.8, 25.6. HRMS (ES): m/z calcd 839.4493 [M + Na]+;
found: 839.4479. [a]D20 –6.8 (c 0.40, C6H6).
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69. (c) The value of the tert-butyl group in minimizing
intramolecular cyclization is noted.
(21) The ensuing transformations exemplify the problem as
manifested in rather different contexts (Scheme 5).
O
O
PPh3, I2, imidazole
toluene, reflux
HO
OSEM
O
O
OTBS
O
O
O
O
O
OSEM
+
I
OSEM
O
O
O
O
OTBS
(80%)
(20%)
O
,
nBuLi
TBSO
I
OSEM
OTBDPS
HMPA, THF
O
O
O
O
O
+
OSEM
OSEM
OTBDPS
(40%)
O
(53%)
Scheme 5
Synlett 2005, No. 19, 2915–2918 © Thieme Stuttgart · New York