A route to the tetrahydrofuran segment of amphidinolides X and Y, and its quaternary-carbon epimer

Article abstract of DOI:10.1055/s-2007-973867

A short approach to the tetrahydrofuran fragment of amphidinolides X and Y has been developed through the combination of iterative Sharpless asymmetric epoxidations, Pd-catalyzed regioselective hydrogenolysis of a 4,5-epoxy-2-alkenoate and the disfavored 5-endo-tet ring closure of a β-hydroxy epoxide promoted by a double bond adjacent to the epoxide function. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-973867

LETTER
983
A Route to the Tetrahydrofuran Segment of Amphidinolides X and Y, and
Its Quaternary-Carbon Epimer
T
etrahydrofura
n
S
u
egment of
A
m
y
phidinolide
n
s
X and
Y
h Dong Doan, Julien Gallon, Alexandre Piou, Jean-Michel Vatèle*
Université Claude Bernard, ESCPE, Laboratoire de Chimie Organique 1, UMR 5181 CNRS, 43 Boulevard du 11 Novembre 1918,
69622 Villeurbanne, France
Fax +33(4)72431214; E-mail: vatele@univ-lyon1.fr
Received 25 November 2006
trol in the cyclization of b-hydroxy epoxides directed by a
double bond in the a position of the epoxide function,
which stabilized the incipient carbocation,6,7 we envis-
aged that the five-membered ring oxygen of 3 could be
Abstract: A short approach to the tetrahydrofuran fragment of am-
phidinolides X and Y has been developed through the combination
of iterative Sharpless asymmetric epoxidations, Pd-catalyzed regio-
selective hydrogenolysis of a 4,5-epoxy-2-alkenoate and the disfa-
vored 5-endo-tet ring closure of a b-hydroxy epoxide promoted by obtained by the acid-catalyzed cyclization of hydroxy vi-
a double bond adjacent to the epoxide function.
nyl oxirane 4. During the course of the synthesis of 3, a
paper dealing with its synthesis using a 5-endo-tet cycliza-
tion strategy appeared in the literature, validating our hy-
pothesis.8 Other features of our synthetic plan for 3
involved the use of Pd-catalyzed hydrogenolysis of alke-
nyl oxirane 5, developed by Shimizu and Tsuji,9,10 in order
to convert C3 of our target compound into its correct
oxidation state and the installation of the tetrasubstituted
chiral center at C2 by Sharpless asymmetric epoxidation
of allylic alcohol 6.
Key words: amphidinolides, cyclization, palladium, stereoselec-
tive synthesis
Amphidinolides are a large family of unique cytotoxic
macrolides isolated from the marine dinoflagellates
Amphidium sp., living in symbiosis with the Okinawan
flatworm Amphiscolops spp.1 Even though the members
of this family display a wide array of structural variation
in ring size and carbon skeleton, most of them have an
odd-numbered macrocyclic skeleton associated with at
least one exo-methylene group. Amphidinolide X (1) does
not possess the structural features of its congeners, and
moreover, it is the only naturally occurring macrodiolide
13
14
O
O
17
O
O
O
1
O
consisting of polyketide-derived diacid and diol units
1
2,3
1
5
O
rather than two hydroxyl fatty acids.
More recently,
2
S
R
amphidinolide Y (2), a 17-membered macrolide, was
obtained from the same strain as 1 and is considered to be
a biogenetic precursor of amphidinolide X.4
R
13
4
3
O
HO
16
3
12
HO
HO
The scarcity of 1 and 2 (0.004% and 0.0007% wet cell
weights, respectively) which allowed only limited biolog-
ical studies, and their unique and challenging structures
render them attractive targets for total synthesis. Herein,
we describe a stereoselective synthesis of the tetrahydro-
furan fragment and its epimer at C2 of these amphidino-
lides. During the course of our studies, Fürstner and co-
workers reported the first total synthesis of amphidino-
lides X and Y.5
O
1
O
OH
O
O
4
2
O
CO2Et
OH
6
5
Our retrosynthesis for 1 and 2, which has common fea-
tures with that of Fürstner,5 let us envisage that C13–C14
and C12–C13 bonds of 1 and 2, respectively, can be
formed via a B-alkyl Suzuki–Miyaura cross-coupling re-
action. Subsequent disconnection of the ester linkage of
the secondary alcohol of the tetrahydrofuran moiety led to
the common building block 3 (Scheme 1). Inspired by the
study of Borhan and co-workers concerning the regiocon-
Scheme 1 Retrosynthetic analysis
Synthesis of the tetrahydrofuran derivative 3, shown in
Scheme 2, began by the preparation of the trisubstituted
alcohol 6, readily available in gram quantities and stereo-
chemically pure form from geraniol in four steps and 51%
overall yield by an improvement of the procedure
described by Mori.11 Sharpless epoxidation of 6, in the
presence of a catalytic amount of unnatural diethyl
tartrate, furnished the (R,R)-epoxide 7 in 93% yield and
82% ee.12,13 One-pot 2,2,6,6-tetramethylpiperidinyloxy
(TEMPO) oxidation–Wittig olefination of the epoxy
SYNLETT 2007, No. 6, pp 0983–0985
0
4.
0
3.
2
0
0
7
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973867; Art ID: D36306ST
© Georg Thieme Verlag Stuttgart · New York

984
H. D. Doan et al.
LETTER
a, b
alcohol 7 gave the a,b-unsaturated ester 5 in 90% yield
(E/Z >95:5).14,15 In order to obtain the right oxidation state
at the C3 carbon atom of 3, regioselective reductive open-
ing of the epoxide 5 was effected by the Pd-catalyzed
allylic reduction methodology developed by Shimizu and
Tsuji.9,10 Thus, treatment of 5 with [Pd2(dba)3]·CHCl3 (2.5
mol%) and Bu3P, in the presence of an excess of formic
acid and triethylamine (THF, 5 h, 20 °C), provided the de-
sired (E)-homoallylic alcohol 8 in an excellent yield
(88%).16,17 DIBAL-H reduction followed by reiteration of
Katsuki–Sharpless epoxidation, using D-(–)-diethyl tar-
trate (0.5 equiv), nonaqueous workup (triethanolamine)18
and flash chromatography, afforded the epoxy diol 10, as
a mixture of inseparable diastereomers (85:15 dr)19 in
87% yield for the two steps. Compared to the ratio (91:9)
of the epimeric mixture of the allylic alcohol 9, the diaste-
reomeric ratio of epoxide 10 indicated that this asymmet-
ric epoxidation was not perfectly diastereoselective. As
shown by Dai and co-workers, the diastereoselectivity of
this epoxidation can be improved by protection of the ter-
tiary alcohol of 9.8 A competitive coordination to titani-
um(IV) between tertiary and primary alcohols may
explain the decrease in diastereoselectivity.20
OH
OAc
75%
O
68%
c, d
O
e
OH
OH
93%
7
6
90%
f
OH
O
g
CO2Et
CO2Et
88%
8
5
97%
h
i
OH
O
OH
OH
OH
90%
10 (70% de)
71% j, k
9
O
O
OH
O
l
+
4
OH
OH
3 (77%)
11 (13%)
65%
O
63%
m, n
m, n
At this stage of the synthesis, our plan called for the instal-
lation of a terminal double bond by one-carbon homolo-
gation. To this end, the successive oxidation of the
primary alcohol function of 10 under Margarita–Pianca-
telli conditions21 and olefination of the crude aldehyde,
led to the vinyl oxirane 4 in 71% yield for the two steps.
Treatment of 4 with a catalytic amount of camphorsulfon-
ic acid7 yielded the 5-endo cyclized product 3 (77%) along
with its epimer 11 (13%), separable by flash chromatog-
raphy.22 The enantiomeric excess of compounds 3 (90%
ee) and 11 (76% ee) was determined by 19F NMR and 1H
NMR analyses of their corresponding Mosher’s esters.
OH
OH
O
OPMP
OPMP
13
12
Scheme 2 Reagents and conditions: (a) Ac2O, DMAP, Et3N,
CH2Cl2, r.t.,2 h; (b) MCPBA, CH2Cl2, 0 °C to r.t., 2 h; (c) H5IO6,
THF–H2O, 0 °C to r.t., 3 h; (d) NH2NH2, H2O, (CH2OH)2, reflux, 1 h,
then aq KOH, reflux, 2 h, steam distillation of 6; (e) cat. D-DET, cat.
Ti(Oi-Pr)4, t-BuOOH, 4 Å MS, CH2Cl2, –30 °C, 2 h; (f) cat. TEMPO,
PhI(OAc)2, CH2Cl2, r.t., then Ph3P=CHCO2Et, r.t., 1 h; (g) cat.
Pd2(dba)3·CHCl3, cat. n-Bu3P, HCO2H, Et3N, THF, r.t., 5 h; (h)
DIBAL-H, CH2Cl2, –78 °C to r.t., 1 h; (i) cat. D-DET, cat. Ti(Oi-Pr)4,
t-BuOOH, 4 Å MS, CH2Cl2, –30 °C, 4 h; (j) cat. TEMPO, PhI(OAc)2,
CH2Cl2, r.t., 4 h; (k) Ph3P+CH3Br–, NaHMDS, THF, 0 °C, then alde-
hyde, THF, 0 °C, 30 min; (l) cat. CSA, CH2Cl2, r.t., 2 h; (m)
MeOPhCH2OC(=NH)CCl3, PPTS, CH2Cl2–cyclohexane (1:2), r.t.,
48 h; (n) 9-BBN, THF, r.t., 3 h, then 35% H2O2, 1 N NaOH, r.t., 1 h.
Having completed the synthesis of our target molecule, its
stereochemistry remained to be confirmed. To this end,
compound 3 was transformed to the known alcohol 135,8
via the following sequence: protection of the alcohol func-
tion as its PMB ether and then hydroboration–oxidation.
In contrast to the observations of Dai and co-workers,8 hy-
droboration of the double bond of 3 with diborane afford-
ed the desired alcohol 13 in only 30% yield along with
other products, such as its regioisomer. The modest regio-
selectivity of this hydroboration with diborane is probably
due to the electron-withdrawing effect of the cyclic ether
in the allylic position which is known to increase signifi-
cantly the addition of boron to the secondary carbon atom
of the double bond.23 Hydroboration with 9-BBN fol-
lowed by treatment with alkaline hydrogen peroxide fur-
nished 13 in 77% yield. Physical data of 13 are in perfect
agreement with those described in the literature.5,8,24 By
the same sequence, compound 12 was obtained from 11 in
63% yield. Its physical data are in accordance with those
described by Fürstner.5,25
yield from the readily available (E)-3-methylhex-2-en-1-
ol. The flexibility of our route to this amphidinolide frag-
ment renders feasible the synthesis of a number of its ster-
eroisomers in the perspective of structure–activity studies.
References and Notes
(1) (a) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77.
(b) Kobayashi, J.; Ishibashi, M. In Comprehensive Natural
Products Chemistry, Vol. 8; Mori, K., Ed.; Elsevier:
Amsterdam, 1999, 415.
(2) Tsuda, M.; Izui, N.; Shimbo, K.; Sato, M.; Fukushi, E.;
Kawabata, J.; Katsumata, K.; Horiguchi, T.; Kobayashi, J. J.
Org. Chem. 2003, 68, 5339.
(3) For a review on the synthesis of macrodiolide natural
products, see: Kang, E. J.; Lee, E. Chem. Rev. 2005, 105,
4348.
(4) Tsuda, M.; Izui, N.; Shimbo, K.; Sato, M.; Fukushi, E.;
Kawabata, J.; Kobayashi, J. J. Org. Chem. 2003, 68, 9109.
In summary, we have devised a concise and efficient syn-
thesis of the tetrahydrofuran fragment of amphidinolides
X and Y. It was obtained in nine steps and 30% overall
Synlett 2007, No. 6, 983–985 © Thieme Stuttgart · New York

LETTER
Tetrahydrofuran Segment of Amphidinolides X and Y
985
(5) (a) Lepage, O.; Kattnig, E.; Fürstner, A. J. Am. Chem. Soc.
2004, 126, 15970. (b) Fürstner, A.; Kattnig, E.; Lepage, O.
J. Am. Chem. Soc. 2006, 128, 9194.
(6) (a) Narayan, R. S.; Sivakumar, M.; Bouhlel, E.; Borhan, B.
Org. Lett. 2001, 3, 2489. (b) Narayan, R. S.; Borhan, B. J.
Org. Chem. 2006, 71, 1416.
(7) Nicolaou and co-workers pioneered in the study of
regioselective hydroxy epoxide openings controlled by a
double bond. See: (a) Nicolaou, K. C.; Prasad, C. V. C.;
Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111,
5330. (b) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.;
Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5335.
(8) Chen, Y.; Jin, J.; Wu, J.; Dai, W.-M. Synlett 2006, 1177.
(9) Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J.
J. Am. Chem. Soc. 1989, 111, 6280.
H), 1.26 (t, J = 7.1 Hz, 3 H), 1.33–1.46 (m, 4 H), 1.91 (s, 1
H), 2.32 (dd, J = 1.0, 7.8 Hz, 2 H), 4.15 (q, J = 7.1 Hz, 2 H),
5.83 (dt, J = 1.2, 15.6 Hz, 1 H), 6.97 (quint, J = 7.8, 15.6 Hz,
1 H). 13C NMR (75 MHz, CDCl3): d = 14.2, 14.5, 17.0, 27.0,
44.4, 44.8, 60.3, 72.5, 124.2, 144.9, 166.4. Anal. Calcd for
C11H20O3: C, 65.97; H, 10.07; O, 23.97. Found: C, 65.72; H,
10.22; O, 24.05.
(18) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc.
1988, 110, 2506.
(19) Low diastereoselectivity was observed when the epoxidation
was conducted with MCPBA (20% de).
(20) For examples of the influence of alcohol functions on the
diastereoselectivity of the Sharpless epoxidation, see:
(a) Takano, S.; Setoh, M.; Takahashi, M.; Ogasawara, K.
Tetrahedron Lett. 1992, 33, 5365. (b) Rizzi, J. P.; Kende, A.
S. Tetrahedron 1984, 22, 4693. (c) Naruta, Y.; Nishigaichi,
Y.; Maruyama, K. Tetrahedron Lett. 1989, 30, 3319.
(21) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.;
Piancatelli, G. J. Org. Chem. 1997, 62, 6974.
(10) For recent examples of the use of this methodology in
synthesis, see: (a) Noguchi, Y.; Yamada, T.; Uchiro, H.;
Kobayashi, S. Tetrahedron Lett. 2000, 41, 7499.
(b) Tholander, J.; Carreira, E. M. Helv. Chim. Acta 2001, 84,
613.
(22) Analytical data for 3: oil; [a]D20 –20.1 (c = 1.2, CHCl3). 1H
NMR (300 MHz, CDCl3): d = 0.90 (t, J = 7.0 Hz, 3 H), 1.32
(s, 3 H), 1.20–1.50 (m, 4 H), 1.71 (dd, J = 6.4, 12.8 Hz, 1 H),
2.16 (dd, J = 7.4, 12.8 Hz, 1 H), 2.36 (br s, 1 H), 4.02 (q,
J = 6.4 Hz, 1 H), 4.13 (t, J = 6.4 Hz, 1 H), 5.18 (dd, J = 0.9,
10.3 Hz, 1 H), 5.34 (dt, J = 1.3, 17.1 Hz, 1 H), 5.83 (ddd,
J = 6.7, 10.3, 17.1 Hz, 1 H). 13C NMR (75 MHz, CDCl3):
d = 14.6, 17.8, 27.2, 45.1 (2 × C), 76.8, 82.6, 85.3, 117.1,
137.2. Anal. Calcd for C10H18O2: C, 70.55; H, 10.66; O,
18.8. Found: C, 70.35; H, 10.82; O, 18.82. Analytical data
for 11: oil; [a]D20 –16.3 (c = 1, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 0.92 (t, J = 7.0 Hz, 3 H), 1.21 (s, 3 H), 1.35 (m,
2 H), 1.57 (m, 2 H), 1.84 (dd, J = 7.1, 12.5 Hz, 1 H), 2.05 (dd,
J = 6.7, 12.5 Hz, 1 H), 2.28 (br s, 1 H), 4.04 (m, 2 H), 5.19
(dt, J = 0.9, 10.2 Hz, 1 H), 5.34 (dt, J = 0.8, 17.2 Hz, 1 H),
5.84 (ddd, J = 6.7, 10.2, 17.2 Hz, 1 H). 13C NMR (75 MHz,
CDCl3): d = 14.7, 17.9, 27.8, 44.4, 45.2, 76.4, 82.4, 85.7,
117.4, 137.6. Anal. Calcd for C10H18O2: C, 70.55; H, 10.66;
O, 18.8. Found: C, 70.77; H, 10.52; O, 18.69.
(11) (a) Mori, K. Tetrahedron 1977, 33, 289. (b) Tago, K.; Arai,
M.; Kogen, H. J. Chem. Soc., Perkin Trans. 1 2000, 2073.
(12) Physical data for 7: liquid; [a]D20 +8.5 (c = 2, CHCl3). 1H
NMR (300 MHz, CDCl3): d = 0.89 (t, J = 7.0 Hz, 3 H), 1.25
(s, 3 H), 1.29–1.62 (m, 4 H), 2.84 (dd, J = 4.8, 6.8 Hz, 1 H),
2.94 (q, J = 4.2, 6.7 Hz, 1 H), 3.64 (ddd, J = 4.7, 7.1, 12.2
Hz, 1 H), 3.80 (ddd, J = 4.2, 7.4, 12.2 Hz, 1 H). 13C NMR (75
MHz, CDCl3): d = 14.0, 16.7, 18.3, 40.6, 61.4 (2 × C), 63.2.
Anal. Calcd for C7H14O2: C, 64.58; H, 10.84; O, 24.58.
Found: C, 64.53; H, 10.77; O, 24.21.
(13) Enantiomeric excess was determined by 1H NMR analysis
(C6D6, 300 MHz) of the corresponding acetate of 7, in the
presence of the chiral shift reagent Eu(hfc)3.
(14) Vatèle, J.-M. Tetrahedron Lett. 2006, 47, 715.
(15) Physical data for 5: oil; [a]D20 –12 (c = 1, CHCl3). 1 NMR
(300 MHz, CDCl3): d = 0.91 (t, J = 7.0 Hz, 3 H), 1.24 (s, 3
H), 1.27 (t, J = 7.1 Hz, 3 H), 1.35–1.66 (m, 4 H), 3.29 (dd,
J = 0.9, 6.4 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 6.07 (dd, J =
0.9, 15.7 Hz, 1 H), 6.81 (dd, J = 6.5, 15.7 Hz, 1 H). 13C NMR
(75 MHz, CDCl3): d = 14.0, 14.2, 16.5, 18.4, 40.5, 60.6,
61.3, 64.2, 124.8, 143.0, 165.7. Anal. Calcd for C11H18O3: C,
66.64; H, 9.15; O, 24.24. Found: C, 66.60; H, 9.38; O, 24.01.
(16) A small amount of its corresponding Z-isomer was also
isolated (5%).
(23) (a) Brown, H. C.; Cope, O. J. J. Am. Chem. Soc. 1964, 86,
1801. (b) Brown, H. C.; Chen, J. C. J. Org. Chem. 1981, 46,
3978.
(24) [a]D20 –43.7 (c = 1.6, CHCl3); lit.5 [a]D20 –37.1 (c = 1, CHCl3,
83% ee); lit.8 [a]D20 –52.2 (c = 0.8, CHCl3, >96% ee).
(25) [a]D20 –45.3 (c = 1.8, CHCl3); lit.5 [a]D20 –43.5 (c = 0.97,
CHCl3, 83% ee).
(17) Physical data for 8: oil; [a]D20 –3.0 (c = 2, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 0.89 (t, J = 6.8 Hz, 3 H), 1.16 (s, 3
Synlett 2007, No. 6, 983–985 © Thieme Stuttgart · New York

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