A new synthesis of tetrahydrofuran fragment of amphidinolides X and Y

Article abstract of DOI:10.1055/s-2006-932487

A new synthesis of the tetrasubstituted tetrahydrofuran fragment of the marine secondary metabolites amphidinolides X and Y is described. The oxygenated chiral quaternary carbon was assembled by asymmetric dihydroxylation in high enantioselectivity and th

Full text of DOI:10.1055/s-2006-932487

LETTER
1177
A New Synthesis of Tetrahydrofuran Fragment of Amphidinolides X and Y
Synthesisof
Tetrai
l
ran
F
ra
e
gment Chen,a Jian Jin,a Jinlong Wu,a Wei-Min Dai*a,b
a
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87953128; E-mail: chdai@zju.edu.cn
b
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR,
P. R. of China
Fax +85223581594; E-mail: chdai@ust.hk
Received 29 November 2005
Dedicated to Prof. K. C. Nicolaou on the occasion of his 60th birthday.
HO
21
Me
Abstract: A new synthesis of the tetrasubstituted tetrahydrofuran
fragment of the marine secondary metabolites amphidinolides X
and Y is described. The oxygenated chiral quaternary carbon was
assembled by asymmetric dihydroxylation in high enantioselec-
tivity and the tetrahydrofuran ring was constructed by an acid-cata-
lyzed 5-endo ring-opening cyclization of the epoxide possessing a
vinyl moiety.
10R
13
9S
H
O
Me
HO
Me
7R
18R
Me
Me
15S
6
16R
4S
O
1
O
H
Me
O
1a: amphidinolide Y
Key words: cyclization, epoxide ring-opening, natural products,
stereoselective synthesis, tetrahydrofurans
1a:1b = 9:1
21
9S
Me
10R
13
H
O
15S
HO
Me
O
7R
18R
Me
Me
Amphidinolides are a large family of cytotoxic macrolide
secondary metabolites isolated from tissue cultures of
symbiotic marine dinoflagellates Amphidinium sp., which
were obtained from Okinawan marine flatworms.1 These
macrolactones with ring sizes of 12–29 exhibit significant
cytotoxicity against L1210 and KB cancer cell lines with
IC50 values as low as 0.00014 mg/mL. Amphidinolide Y
(1)2 is a 17-membered ring macrolide isolated from
Amphidinium sp. (strain Y-42). The macrolide 1 exists in
the 6-keto and 6(9)-hemiacetal forms 1a and 1b in solu-
tion in a ratio of 9:1. Treatment of 1 with Pb(OAc)4 af-
forded the oxidative cleavage product, amphidinolide X
(2),3 known as the first 16-membered ring macrodiolide
consisting of polyketide-derived diacid and diol frag-
ments from natural sources. The macrolide 2 was isolated
from the same strain from which 1 was produced. On the
basis of feeding experiments with 13C-labeled acetates, it
was suggested that amphidinolide Y might be a biogenetic
precursor of amphidinolide X.2 Both 1 and 2 show moder-
ate cytotoxicity against L1210 (IC50: 0.6 and 0.8 mg/mL,
respectively) and KB (IC50: 7.5 and 8.0 mg/mL, respec-
tively) cell lines.1
Me
16R
6
HO
4S
1
O
H
Me
O
1b
O
9
7
Me
22
Me
8
11R
10S
14
H
O
16S
O
Me
6
19R
Me
Me
17R
4S
O
1
O
H
Me
O
2: amphidinolide X
Figure 1 Structures of amphidinolides X and Y
latter was then cyclized to the tetrahydrofuran ring with
efficient axial-to-central chirality transfer for securing the
stereochemistry at C19 of 2. We proposed the vinyl-sub-
stituted tetrahydrofuran 3 (Scheme 1) as the C14–C22 or
C13–C21 fragment for total synthesis of amphidinolides
X and Y. Starting from the known and readily accessible
chiral diol 11 (Scheme 2),5 the chiral allylic alcohol 5
could be prepared and transferred to the epoxy alcohol 4.
By taking advantage of the vinyl group adjacent to the
epoxide, an acid-catalyzed 5-endo epoxide ring-opening
cyclization of 4 was then considered to form the tetrahy-
drofuran ring.6 Fürstner and co-workers used the alkyl
boron compound 7 derived from 6 in the total synthesis of
2.4 We could easily transform 3 into 8 via hydroboration
for coupling with other fragments. In this communication,
we disclose our preliminary results on the synthesis of the
tetrahydrofuran fragment 3.
Fürstner and co-workers recently reported the first total
synthesis of amphidinolide X (2) via a highly convergent
strategy featured with a tetrahydrofuran 6 (C14–C22,
Figure 1), a keto-alkene (C7–C13) and a diacid (C1–C6)
building block.4 The tetrahydrofuran fragment 6 was syn-
thesized starting with a chiral propargyl epoxide of 83%
ee and n-PrMgCl via an elegant iron-catalyzed reaction
leading to a chiral allene (with a syn:anti ratio of 8:1). The
SYNLETT 2006, No. 8, pp 1177–1180
1
5.
0
5.
2
0
0
6
Advanced online publication: 10.03.2006
DOI: 10.1055/s-2006-932487; Art ID: W31705ST
© Georg Thieme Verlag Stuttgart · New York

1178
Y. Chen et al.
LETTER
Me
Me
served to mask the tertiary alcohol group for the transfor-
mations from 11 into 17. Now, the stage is set for 5-endo
cyclization6,8b,10,11 of the epoxy alcohol toward formation
of the tetrahydrofuran skeleton. Treatment of the TIPS
ether 17 with excess n-Bu4NF in refluxing THF for 1.5
hours afforded the epoxy diol 18 in 71% yield. Unfortu-
nately, attempts at formation of the tetrahydrofuran 19
from 18 failed under acid catalysis.
H
O
H
OH
O
Me
H
RO
X
H
Me
3
4
Me
H
O
OH
Me
Me
Me
a
b
OR
RO
H
HO
PMPO
9
10
6: X = I
Me
7: X = B–(OMe)(9-BBN)
8: X = B(9-BBN)
Me
HO Me
TIPSO Me
c, d, e
f
5
OH
OH
PMPO
S
PMPO
Scheme 1 The proposed tetrahydrofuran fragment 3 and the
Fürstner’s analogue 6 used for total synthesis of amphidinolide X.
11
12
g, h
TIPSO Me
TIPSO Me
CHO
According to our synthetic strategy outlined in Scheme 1,
we need to use an efficient method for installation of the
chiral tertiary alcohol functionality in the first place
preferably in enantioselectivity of >95% ee. Asymmetric
epoxidation of allylic alcohols is one of the choices but it
suffers from low enantioselectivity in certain types of sub-
strates.4,7 We also considered the corresponding chiral ep-
oxide of the homoallylic alcohol 9 as the precursor of 14
(Scheme 2). However, enantioselectivity for the asym-
metric epoxidation of 9 is 84% ee with 58% yield8a ac-
cording to a recently reported asymmetric epoxidation of
homoallylic alcohols8 by using vanadium and chiral hy-
droxamic acid ligands. Fortunately, we found that a highly
enantioselective dihydroxylation of the PMP-protected
homoallylic ether 10 was reported by Corey and co-work-
ers to afford the chiral diol (R)-115 in 96% ee and in 99%
yield by using (DHQD)2PYDZ as the chiral ligand. We
decided to use Corey’s method for installation of the oxy-
genated quaternary carbon at C18 (for 1) or C19 (for 2).
R
PMPO
PMPO
Me
13
14
TIPSO Me
OHC
i, j
k, l
Me
15
Me
TIPSO
m
HO
Me
16
Me
HO
H
Me
O
RO
o
Me
HO
Me
O
HO
H
17: R = TIPS
18: R = H
19 (not formed)
n
As illustrated in Scheme 2, manipulation of protecting Scheme 2 Reagents and conditions: a) p-MeOC6H4OH, EtO2CN=
NCO2Et, Ph3P, THF, reflux, 4 h, 99%; b) AD-mix-a, t-BuOH–H2O
(1:1), 0 °C, 2 h, 98% (>96% ee); c) PivCl, DMAP, Et3N, CH2Cl2, r.t.,
6 h, 96%; d) TIPSOTf, 2,6-lutidine, CH2Cl2, r.t., 24 h; e) DIBAL-H,
PhMe, –78 °C to 0 °C, 2 h, 97% (two steps); f) (COCl)2, DMSO,
CH2Cl2, –78 °C, then Et3N, –78 °C to r.t., 89%; g) Ph3P+EtBr–, n-Bu-
Li, THF, –10 °C, 3 h, 89%; h) Pd/C, H2, EtOH–EtOAc (1:1), r.t., 6 h,
85%; i) CAN, MeCN–H2O (3:2), 0 °C, 10 min; j) (COCl)2, DMSO,
CH2Cl2, –78 °C, 2 h, then Et3N, –78 °C to r.t., 62% (two steps); k)
Ph3P=CHCO2Et, CH2Cl2, r.t., 24 h, 98%; l) DIBAL-H, PhMe, –78 °C
to 0 °C, 3 h, 93%; m) 5 mol% Ti(Oi-Pr)4, 6 mol% D-(–)-DET, t-
BuOOH, 4 Å MS, CH2Cl2, –20 °C, 24 h, 90%; n) n-Bu4NF (6 equiv),
THF, reflux, 1.5 h, 71%; o) CSA (0.1 equiv), CH2Cl2, –40 °C to r.t.
groups in the diol (S)-11 afforded the primary alcohol 12
in 93% overall yield for the three-step sequence. The
Swern oxidation of 12 gave the aldehyde 13 (89%) which
was subjected to the Wittig olefination followed by cata-
lytic hydrogenation of the olefin isomers over Pd/C to fur-
nish 14 in 76% overall yield from 13. After securing the
oxygenated quaternary carbon, the PMP ether in 14 was
removed by CAN-mediated oxidative cleavage in aque-
ous acetonitrile (66%) and the resultant primary alcohol
was converted into the aldehyde 15 in 82% yield via the
Swern oxidation. Olefination of 15 with the stabilized
ylide, Ph3P=CHCO2Et, at room temperature afforded the
a,b-unsaturated ester (98%, E:Z >96:4), which was re-
duced by DIBAL-H to give the allylic alcohol 16 in 93%
yield. Epoxidation of the allylic alcohol 16 was then per-
formed under the Sharpless conditions9 with catalytic
Ti(Oi-Pr)4 and D-(–)-DET at –20 °C to provide the epoxy
alcohol 17 in 90% yield and in high enantioselectivity.
The trace minor diastereomer could be separated out by
column chromatography. The TIPS ether group has
Nicolaou and co-workers used the p-orbital of the vinyl
substituent adjacent to the epoxide unit to activate the 6-
endo vs. 5-exo and 7-endo vs. 6-exo modes of cyclization
of epoxy alcohols under acidic conditions.11c,d In a recent
report, Borhan and co-workers demonstrated the same
strategy in controlling the 5-endo cyclization of an epoxy
diol.6 As depicted in Scheme 3, the epoxy alcohol 17 was
subjected to the Swern oxidation to form an epoxy alde-
hyde (isomer ratio >95:5), which was reacted with a non-
Synlett 2006, No. 8, 1177–1180 © Thieme Stuttgart · New York

LETTER
Synthesis of Tetrahydrofuran Fragment
1179
stabilized ylide derived from Ph3P+MeBr– and KHMDS to In summary, we have established a new synthesis of the
furnish the vinyl epoxide 20 in 81% overall yield. We tetrahydrofuran fragment 23 of amphidinolides X and Y
–
found that oxidation of 17 with n-Pr4N+RuO4 (TPAP) and starting from the known chiral diol 11 in >96% ee.5 A
NMO12 in CH2Cl2 resulted in a mixture of the epoxy alde- vinyl-group-activated 5-endo cyclization of the epoxy
hyde due to epimerization, which could be suppressed alcohol 21 was successfully used to construct the tetra-
under the Swern conditions. The TIPS group in 20 was re- substituted tetrahydrofuran skeleton. In addition, the vinyl
moved by treating with excess n-Bu4NF in refluxing THF group in 23 can be converted into the alkyl boron com-
for 0.5 hour to form the epoxy alcohol 21 in 90% yield in pound 8 for coupling with other fragments in the total
diastereomerically pure form because the minor isomer synthesis of amphidinolides X and Y.
could be separated out by column chromatography. We
were delighted to find that treatment of 21 with a catalytic
amount of CSA in CH2Cl2 at –40 °C to room temperature
Acknowledgment
This work is supported in part by the research grants from The
National Natural Science Foundation of China (Grant No.
20432020) and Zhejiang University. W.-M. Dai is the recipient of
Cheung Kong Scholars Award of The Ministry of Education of
China. The authors thank Dr. Kwong Wah Lai and Dr. Yongqiang
Wang for their assistance in some experiments.
for 6 hours provided the desired tetrahydrofuran product
22 in 85% yield as a single isomer. Protection of the
secondary alcohol in 22 as the PMB ether gave 2313 in
68% yield. The stereochemistry of 23 was further con-
firmed by converting it to the known alcohol 244,14 via
hydroboration with BH3·SMe2 followed by standard oxi-
dative workup in alkaline solution in 60% overall yield.
The spectroscopic data of 24 and the sign of optical
rotation are identical to those reported in literature.4
References and Notes
(1) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77.
(2) Tsuda, M.; Izui, N.; Shimbo, K.; Sato, M.; Fukushi, E.;
Kawabata, J.; Kobayashi, J. J. Org. Chem. 2003, 68, 9109.
(3) Tsuda, M.; Izui, N.; Shimbo, K.; Sato, M.; Fukushi, E.;
Kawabata, J.; Kkatsumata, K.; Horiguchi, T.; Kobayashi, J.
J. Org. Chem. 2003, 68, 5339.
(4) Total synthesis of amphidinolide X, see: Lepage, O.;
Kattnig, E.; Fürstner, A. J. Am. Chem. Soc. 2004, 126,
15970.
(5) (a) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem.
Soc. 1995, 117, 10805. (b) For the 2-propyl homologue of 3,
see: Hayes, P. Y.; Kitching, W. J. Am. Chem. Soc. 2002, 124,
9718.
(6) Narayan, R. S.; Sivakumar, M.; Bouhle, E.; Borhan, B. Org.
Lett. 2001, 3, 2489.
OH
H
H
a, b
OTIPS
Me
OTIPS
Me
O
O
Me
Me
H
H
20
17
H
c
d
OH
O
H
(7) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
2000, 231.
Me
Me
21
(8) For a recent example of asymmetric homoallylic
epoxidation, see: (a) Makita, N.; Hoshino, Y.; Yamamoto,
H. Angew. Chem. Int. Ed. 2003, 42, 941. (b) See also:
Rossiter, B. E.; Sharpless, K. B. J. Org. Chem. 1984, 49,
3707.
Me
Me
H
H
O
O
e
Me
Me
(9) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974.
(10) Coxon, J. M.; Hartshorn, M. P.; Swallow, W. H. Aust. J.
Chem. 1973, 26, 2521.
HO
PMBO
H
H
22
23
22
Me
(11) For selected examples of other modes of epoxide ring-
opening cyclization, see: (a) Nakata, T.; Kishi, Y.
Tetrahedron Lett. 1978, 2745. (b) Nakata, N.; Schmid, G.;
Vranesic, B.; Okigawa, M.; Smith-Palmer, T.; Kishi, Y. J.
Am. Chem. Soc. 1978, 100, 2933. (c) Nicolaou, K. C.;
Brasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem.
Soc. 1989, 111, 5330. (d) Nicolaou, K. C.; Prasad, C. V. C.;
Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111,
5335. (e) Mukai, C.; Ikeda, Y.; Sugimoto, Y.; Hanaoka, M.
Tetrahedron Lett. 1994, 35, 2179. (f) Fujiwara, K.;
Tokiwano, T.; Murai, A. Tetrahedron Lett. 1995, 36, 8063.
(g) Fujiwara, K.; Mishima, H.; Amano, A.; Tokiwano, T.;
Murai, M. Tetrahedron Lett. 1998, 39, 393. (h) Evans, P.
A.; Murthy, V. S. Tetrahedron Lett. 1999, 40, 1253.
(12) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
14
HO
H
O
f
19R
Me
16S
17R
PMBO
H
24 (known)
Scheme 3 Reagents and conditions: a) (COCl)2, DMSO, CH2Cl2,
–78 °C, 2 h, then Et3N, –78 °C to r.t.; b) Ph3P+MeBr–, KHMDS, THF,
–10 °C, 3 h, 81% (two steps); c) n-Bu4NF (6 equiv), THF, reflux,
0.5 h, 90%; d) CSA (0.1 equiv), CH2Cl2, –40 °C to r.t., 6 h, 85%;
e) NaH, p-MeOC6H4CH2Cl, MeCN, r.t., 32 h, 68%; f) BH3·SMe2,
THF, 0 °C, 2 h; then aq NaOH, H2O2, 0 °C to r.t., 2 h, 60%.
Synlett 2006, No. 8, 1177–1180 © Thieme Stuttgart · New York

1180
Y. Chen et al.
LETTER
(13) Spectroscopic data of 23: [a]D20 –23.3 (c 0.60, CHCl3). IR
(film): 2959, 2932, 1613, 1514, 1249, 1111, 1090, 1072,
1037 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.30–7.23 and
6.89–6.86 (A2B2, 4 H), 5.86 (ddd, J = 17.6, 10.8, 6.8 Hz, 1
H), 5.35 (dt, J = 17.2, 1.6 Hz, 1 H), 5.15 (dt, J = 10.4, 1.6 Hz,
1 H), 4.47 and 4.43 (ABq, J = 11.6 Hz, 2 H), 4.38 (dd,
J = 6.4, 6.4 Hz, 1 H), 3.86–3.80 (m, 1 H), 3.80 (s, 3 H), 2.03
(dd, J = 12.8, 8.0 Hz, 1 H), 1.81 (dd, J = 13.2, 5.2 Hz, 1 H),
1.52–1.46 (m, 2 H), 1.40–1.32 (m, 2 H), 1.33 (s, 3 H), 0.92
(t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 159.1,
137.8, 130.2, 129.1 (2×), 116.2, 113.7 (2×), 84.0, 83.5, 83.0,
71.4, 55.2, 45.0, 42.3, 26.3, 17.8, 14.6. MS (+ESI):
(14) Spectroscopic data of 24: [a]D20 –52.2 (c 0.8, CHCl3, >96%
ee); lit. (ref. 4) [a]D20 –37.1 (c 1.0, CHCl3, 83% ee). 1H NMR
(400 MHz, CDCl3): d = 7.24 (d, J = 8.5 Hz, 2 H), 6.88 (d,
J = 8.5 Hz, 2 H), 4.48 and 4.39 (ABq, J = 11.5 Hz, 2 H), 4.06
(ddd, J = 8.5, 5.0, 5.0 Hz, 1 H), 3.81 (s, 3 H), 3.80–3.74 (m,
3 H), 2.96 (br s, 1 H), 2.05 (dd, J = 12.5, 8.0 Hz, 1 H), 1.89–
1.70 (m, 2 H), 1.78 (dd, J = 13.0, 5.0 Hz, 1 H), 1.50–1.45 (m,
2 H), 1.38–1.28 (m, 2 H), 1.31 (s, 3 H), 0.92 (t, J = 7.5 Hz, 3
H). 13C NMR (100 MHz, CDCl3): d = 159.2, 129.8, 129.2
(2×), 113.9 (2×), 83.4, 83.2, 82.1, 71.5, 61.3, 55.2, 45.0,
42.3, 35.9, 26.3, 17.7, 14.5. MS (+ESI): m/z (%) = 639 (100)
[2 M + Na+], 617 (53) [2 M + H+], 331 (100) [M + Na+], 309
(64) [M + H+]. HRMS (+ESI): m/z calcd for C18H28O4Na+:
331.1885 [M + Na+]; found: 331.1876.
m/z (%) = 603 (80) [2 M + Na+], 313 (100) [M + Na+],
290 (10) [M+]. HRMS (+ESI): m/z calcd for C18H26O3Na+:
313.1780 [M + Na+]; found: 313.1776.
Synlett 2006, No. 8, 1177–1180 © Thieme Stuttgart · New York