Synthesis of the C22-C37 segment of prorocentin

Article abstract of DOI:10.1016/j.tetlet.2011.01.042

The synthesis of the C22-C37 segment of prorocentin, isolated from the dinoflagellate Prorocentrum lima, was achieved. Because the relative stereochemical relationship between C26 and other stereocenters (C28/C31/C32 established as R*/R*/R*) in the C22-C3

Full text of DOI:10.1016/j.tetlet.2011.01.042

Tetrahedron Letters 52 (2011) 1222–1224
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Tetrahedron Letters
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Synthesis of the C22–C37 segment of prorocentin
Atsushi Takemura a, Yasushi Katagiri a, Kenshu Fujiwara a, , Hidetoshi Kawai a,b, Takanori Suzuki a
⇑
a Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
b PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the C22–C37 segment of prorocentin, isolated from the dinoflagellate Prorocentrum lima,
was achieved. Because the relative stereochemical relationship between C26 and other stereocenters
(C28/C31/C32 established as R*/R*/R*) in the C22–C37 region of natural prorocentin has not yet been
determined, both epimers at C26 of the C22–C37 segment were selectively constructed. The synthesis
was based on a 5-exo epoxide ring opening reaction to form an oxolane (E-ring), Brown asymmetric
methallylation to install the C26-stereocenter, acryloylation of the resulting alcohol, and ring-closing ole-
fin metathesis to establish the Z-olefin at C23/C24.
Received 18 November 2010
Revised 25 December 2010
Accepted 11 January 2011
Available online 18 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
37Me
D
Prorocentin (1, Fig. 1), isolated as a cytotoxic agent from the cul-
tured dinoflagellate Prorocentrum lima clone PL021117001 by Lu,1
is a novel polyketide polyether possessing an all-E triene, an epox-
30
H
H
HO
O
38Me
3M6 e
26 28
27
E
O
C 22
5
O
A
B
O
O
15
34
10
ide (A-ring),
a pyran-fused spirocyclic acetal (BCD-ring), an
OH Me
20
OH
oxolane (E-ring), and 13 asymmetric centers. The full planar struc-
ture and the relative stereochemistry in the C1–C26 and C27–C35
regions of 1 have been elucidated by extensive NMR analysis,
although the relative stereochemical relationship between the
two regions, as well as the full absolute configuration, remains
undetermined. Because the unique structure and bioactivity of 1
attracted our attention, we commenced a project toward the total
synthesis and the determination of the absolute configuration of 1.
Here, the stereoselective synthesis of C26-epimeric lactones 2 and
3 (Fig. 1), corresponding to the C22–C37 segment of 1, is described
as an initial part of the project.
35
Me
39
Prorocentin (1)
1
OH
Lu's proposed relative stereochemistry
for the C1-C27 and the C27-C35 regions is shown.
37Me
Me
36
S R
R
O 26
R
32
Me
Me
TBSO Me
O 22 O 26
O
28 O 31
O
34
R
TBSO Me
35
2
3
For the future construction of the BCD-ring of 1, shown in
Scheme 1, lactone 2/3 was designed as a versatile synthetic inter-
mediate: it would function as an electrophile for the reaction with
B-ring nucleophile I (Route A) or as a precursor for nucleophile III or
IV, which would be connected with B-ring electrophile II (Route B).
As described above, the relative stereochemical relationship be-
tween C26 and other stereocenters (C28/C31/C32 established as
R*/R*/R*) in the C22–C37 region of naturally occurring 1 has not
yet been determined. Therefore, the preparation of both C26-epi-
meric lactones 2 and 3 was required for the synthesis of the possible
stereoisomers of 1. The spectral and optical data of the stereoiso-
mers would then be compared with those of the natural compound
to determine the absolute stereochemistry of prorocentin.
Figure 1.
R1O
37Me
D
H
H
Me
OR2
Route A
H
B
HO
15
O
22
26
21
+
O
C 22
O
O
2 / 3
20
B
O
O
15
O
I
M
20
OH
H
Route B
Electrophile
Nucleophile
or
BCD-ring of 1
Precursor for III or IV
Me
Me
R1O
H
H
OR2
+
CHO
or
B
O
The synthesis of 2 and 3 was planned as shown in Scheme 2.
The following five key reactions were scheduled in the plan: (i)
the 5-exo cyclization of dihydroxy epoxide 10 to form E-ring 9;
22
15
20
22
21
O
M
21
OR3
III
Nucleophile
OR3
M
II
Electrophile
IV
⇑
Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706 4924.
E-mail address: fjwkn@sci.hokudai.ac.jp (K. Fujiwara).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.042

A. Takemura et al. / Tetrahedron Letters 52 (2011) 1222–1224
1223
Me
Me
OPMB
RCM
Acryloylation
Me Me
OPMB
PivCl (1.1 eq)
pyridine, 0 °C
PivO DIBALH (3 eq)
HO
24
Me Me
OTBS
23
9
2 / 3
O
O
26
26
CH2Cl2, – 78 °C
94%
RO
O
O
HO
TBSO
O
O
OTBS
17: R = H
18: R = TBS
19
TBSOTf (1.3 eq)
2,6-lutidine (2.6 eq)
CH2Cl2, 0 °C
4 (26S) / 5 (26R)
6 (26S) / 7 (26R)
(COCl)2 (1.5 eq)
DMSO (2 eq)
CH2Cl2, – 78 °C
then Et3N (4 eq)
Methallylation
89% (2 steps)
HO
Me Me
OPMB
HO
O
31
i-PrPPh3I (3 eq)
BuLi (2.8 eq)
THF, – 78 °C
OPMB
28
31
33
33
O
H 26
Me Me
O
O
OR
OPMB
28
O
OH
OH
OTBS
28
5-exo
Cyclization
Wittig
Reaction
31
32
then 20, – 78 → 23 °C
10
9
8
H
OTBS
O
O
H
NOE
H
OTBS
84% (2 steps)
Scheme 2.
21: R = PMB
22: R = H
20
DDQ (2 eq), CH2Cl2
pH 7 buffer, 0 °C
100%
(ii) Wittig olefination to construct the isopropylidene group at C33;
(iii) the methallylation of aldehyde 8 to install the C26-stereocen-
ter; (iv) the acryloylation of alcohol 6 or 7; and (v) the ring-closing
olefin metathesis (RCM)2 to establish the Z-olefin at C23/C24. The
selective preparation of either 6 or 7 would require an asymmetric
methallylation reaction. To generate the antipodal C26-stereocen-
ter, the acryloylation of the preceding major alcohol (6 or 7) by the
Mitsunobu reaction3 was undertaken.
The synthesis of E-ring 9 began from the known chiral com-
pound 114 (Scheme 3). Iodide 11 was reacted with an acetylide,
prepared from alkyne 12 with BuLi, to produce alkyne 13. The pri-
mary TBS group of 13 was selectively removed with TBAF at low
temperature (ꢀ35?ꢀ25 °C) to give alcohol 14 (66% from 11),
which was partially hydrogenated to afford Z-allylic alcohol 15
(100%). The Katsuki–Sharpless asymmetric epoxidation of 15 using
(ꢀ)-diethyl tartrate produced 16 (97%) exclusively.5 After the TBS
removal from 16, treatment of the resulting dihydroxy epoxide
10 with CSA-promoted 5-exo cyclization to furnish E-ring 9 in
91% yield from 16.
Scheme 4.
Me
(2 eq), THF, – 78 °C
MgCl
(A)
(B)
DMPI (2 eq)
Me
NaHCO3 (2 eq)
(1.8 eq), (– )-DIPCl (2.2 eq)
22
8
MgCl
THF, – 78 °C
CH2Cl2
0 → 25 °C
94%
57% (1.4 : 1) 40%
89% (> 14 : 1) < 6%
(A)
(B)
Me
Me
Me Me
OTBS
Me Me
+
26
26
HO
HO
O
O
R
S
OTBS
78%
6
(5 : 1) 16%
7
Li(s-Bu)3BH (3 eq)
THF, – 78 °C
Me
The installation of the isopropylidene group at C33 is illustrated
in Scheme 4. Diol 9 was first converted to alcohol 19 (84% overall)
by protecting group manipulation [(i) selective pivaloylation of the
primary alcohol of 9, (ii) TBS-protection of the secondary alcohol of
17, and (iii) removal of the pivaloyl group of 18]. Swern oxidation6
of 19 followed by Wittig reaction with isopropylidene triphenyl-
phosphorane installed the required isopropylidene group to pro-
DMPI (2 eq)
NaHCO3 (2 eq)
CH2Cl2
Me Me
OTBS
25 °C
26
O
O
R
94%
23
Scheme 5.
OTBS
12 (1.1 eq)
BuLi (1.1 eq)
THF, 0 °C
TBAF (1 eq)
THF
– 35 → – 25 °C
OPMB
OPMB
O
I
Cl (3 eq)
i-Pr2NEt (6 eq)
CH2Cl2, 0 °C
then 11
HMPA– THF
24 °C
OTBS
OTBS
TBSO
13
Me
24 (0.1 eq)
CH2Cl2, reflux
66%
(2 steps)
Me Me
OTBS
11
6
2
26
92%
O
84%
O
O
S
O
(–)-DET (0.3 eq)
Ti(Oi-Pr)4 (0.25 eq)
TBHP (3 eq), MS4A
CH2Cl2
HO
H2
OPMB
4
Lindlar cat.
N
N
OPMB
(10 eq)
OH
Mes
Mes
DIAD (6 eq), Ph3P (7 eq)
Cl2Ru CHPh
PCy3
OTBS
HO
14
PhH, 24 °C
100%
– 25 °C
OTBS
15
24
69%
THF, 25 °C
O
97%
HO
Me
24 (0.1 eq)
CH2Cl2, reflux
TBAF (1.5 eq)
THF, 24 °C
CSA (0.1 eq)
CH2Cl2, 0 °C
Me Me
OTBS
Cl (3 eq)
OPMB
7
26
3
10
9
O
OTBS
i-Pr2NEt (6 eq)
CH2Cl2, 0 °C
92%
O
O
O
R
91% (2 steps)
5
16
89%
Scheme 3.
Scheme 6.

1224
A. Takemura et al. / Tetrahedron Letters 52 (2011) 1222–1224
duce 217 (84% from 19). The trans-disubstitution of the E-ring was
confirmed at this stage from the presence of an NOE interaction be-
tween H28 and H32. The PMB group of 21 was removed with DDQ
to give alcohol 22 (100%).8
sity) for the measurements of mass spectra. This work was sup-
ported by a Global COE Program (B01: Catalysis as the Basis for
Innovation in Materials Science) and Grants-in-Aid for Scientific
Research from MEXT, Japan. Y.K. thanks JSPS research fellowship
for young scientists (21-1886).
The construction of the C26-stereocenter was performed after
Dess–Martin oxidation of 22 to give 8 (94%) (Scheme 5).9 Alde-
hyde 8 was initially reacted with methallyl magnesium chloride
to produce 26S-alcohol 610 (57%) and its diastereomer 7 (40%)
with modest selectivity (6:7 = 1.4:1) [condition (A)]. Conversion
of 7 to 6 was examined, and a process including Dess–Martin
oxidation and reduction with Li(s-Bu)3BH was found to furnish
6 with relatively high selectivity (6:7 = 5:1) in good yield (73%
over two steps). In the methallylation reaction, Brown’s
asymmetric procedure was also tested [condition (B)].11 The reac-
tion of 8 with a methallyl borane, prepared from (ꢀ)-B-chloro-
diisopinocampheylborane with methallyl magnesium chloride,
proceeded smoothly in THF at ꢀ78 °C to afford 6 predominantly
(6:7 = 14:1) in 89% yield. Thus, Brown asymmetric methallylation
was employed as an efficient method for the installation of the
C26-stereocenter of 6.
Finally, lactones 2 and 3 were synthesized as shown in Scheme
6. Treatment of alcohol 6 with acryloyl chloride produced ester 4
(92%). Alternatively, the alcohol was also reacted with acrylic acid
under Mitsunobu conditions to give ester 5 (69%) with complete
inversion of stereochemistry, though the reaction required excess
amounts of reagents because of the low reactivity of 6. Ester 5
was also obtained by esterification of 7 with acryloyl chloride
(89%). The cyclization of esters 4 and 5 was catalyzed by the second
generation Grubbs catalyst (24)12 to smoothly furnish 2 (84%) and
3 (92%),13 respectively, thereby completing the synthesis of the
C22–C37 segments required for determination of the absolute ste-
reochemistry of 1.
In conclusion, two C26-epimeric lactones 2 and 3 corresponding
to the C22–C37 region of prorocentin (1) were stereoselectively
synthesized for the determination of the absolute stereochemistry
of 1 by total synthesis. The synthesis was based on (i) the 5-exo
cyclization of dihydroxy epoxide 10 to form E-ring 9, (ii) Wittig
olefination to construct the isopropylidene group at C33, (iii)
Brown asymmetric methallylation of aldehyde 8 to install the
C26-stereocenter, (iv) acryloylation of alcohol 6 by a condensation
or a Mitsunobu reaction, and (v) RCM of 4 and 5 to establish the Z-
olefin at C23/C24. Further studies toward the total synthesis and
the determination of the absolute configuration of 1 are in progress
in this laboratory.
References and notes
1. (a) Lu, C.-K.; Chou, H.-N.; Lee, C.-K.; Lee, T.-H. Org. Lett. 2005, 7, 3893; A
congener was also reported: (b) Lu, C.-K.; Chen, Y.-M.; Wang, S.-H. Tetrahedron
Lett. 2010, 51, 6911.
2. Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinhem, 2003.
3. Mitsunobu, O. Synthesis 1981, 1.
4. Sugimoto, T.; Ishihara, J.; Murai, A. Tetrahedron Lett. 1997, 38, 7379.
5. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
6. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480.
7. The absolute stereochemistry at C32 of 21 was determined by the application
of modified Mosher’s method to an alcohol obtained by the TBS-removal of 21:
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092.
8. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885.
9. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155; (b) Dess, D. B.; Martin, J.
C. J. Am. Chem. Soc. 1991, 113, 7277.
10. The absolute stereochemistry at C26 of
6 was determined by modified
Mosher’s method.7
11. Brown, H. C.; Jadhav, P. K.; Perumal, P. T. Tetrahedron Lett. 1984, 25, 5111.
12. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
13. Selected spectral data of 2: a pale yellow oil; ½a D23
ꢁ
ꢀ78.2 (c 1.14, CHCl3); 1H
NMR (300 MHz, CDCl3) d 5.80 (1H, br s), 5.12 (1H, d-sp, J = 9.2, 1.5 Hz), 4.57
(1H, dddd, J = 12.0, 6.8, 5.3, 4.1 Hz), 4.23 (1H, dd, J = 9.2, 5.8 Hz), 4.12 (1H, tdd,
J = 8.4, 4.0, 2.9 Hz), 3.92 (1H, td, J = 7.2, 5.8 Hz), 2.52 (1H, br dd, J = 17.8,
12.0 Hz), 2.27 (1H, dd, J = 17.8, 4.1 Hz), 1.95–2.08 (2H, m), 1.98 (3H, br s), 1.80–
1.94 (2H, m), 1.58–1.72 (1H, m), 1.71 (3H, d, J = 1.5 Hz), 1.65 (3H, d, J = 1.5 Hz),
1.43–1.57 (1H, m), 0.86 (9H, s), 0.02 (3H, s), 0.00 (3H, s); 13C NMR (75 MHz,
CDCl3, 13CDCl3 as 77.0 ppm) d 165.3 (C), 157.4 (C), 133.3 (C), 125.5 (CH), 116.2
(CH), 82.8 (CH), 75.2 (CH), 74.7 (CH), 72.3 (CH), 39.8 (CH2), 34.1 (CH2), 32.3
(CH2), 27.3 (CH2), 25.9 (CH3), 25.8 (CH3 ꢂ 3), 22.9 (CH3), 18.6 (CH3), 18.1 (C),
ꢀ4.4 (CH3), ꢀ4.8 (CH3); IR (film), mmax cmꢀ1; 2928, 2856, 1724, 1648, 1472,
1462, 1442, 1390, 1360, 1290, 1248, 1194, 1154, 1066, 938, 874, 835, 813, 776,
665; HR-FDMS, calcd for
C
22H39O4Si [M+H]+: 395.2618, found: 395.2635.
Selected spectral data of 3: a pale yellow oil; ½a D22
ꢁ
+33.3 (c 1.11, CHCl3); 1H
NMR (300 MHz, CDCl3) d 5.80 (1H, br s), 5.10 (1H, d-sp, J = 9.0, 1.2 Hz), 4.58
(1H, tdd, J = 8.3, 7.4, 4.5 Hz), 4.24 (1H, dd, J = 9.0, 6.5 Hz), 4.14 (1H, tdd, J = 9.1,
5.9, 3.1 Hz), 3.90 (1H, q, J = 6.5 Hz), 2.32 (2H, d, J = 7.4 Hz), 1.90–2.08 (3H, m),
1.97 (3H, br s), 1.58–1.78 (2H, m), 1.71 (3H, d, J = 1.2 Hz), 1.66 (3H, d,
J = 1.2 Hz), 1.36–1.57 (1H, m), 0.86 (9H, s), 0.03 (3H, s), 0.01 (3H, s); 13C NMR
(75 MHz, CDCl3, 13CDCl3 as 77.0 ppm) d 165.1 (C), 157.3 (C), 133.5 (C), 125.4
(CH), 116.4 (CH), 82.8 (CH), 75.7 (CH), 75.1 (CH), 72.3 (CH), 41.1 (CH2), 35.3
(CH2), 32.7 (CH2), 27.4 (CH2), 25.9 (CH3), 25.8 (CH3 ꢂ 3), 22.9 (CH3), 18.6 (CH3),
18.3 (C), ꢀ4.4 (CH3), ꢀ4.7 (CH3); IR (film), mmax cmꢀ1; 2955, 2928, 2856, 1725,
1647, 1472, 1462, 1442, 1386, 1360, 1289, 1246, 1196, 1152, 1117, 1060, 1016,
1005, 956, 939, 873, 834, 814, 776; HR-FDMS, calcd for C22H39O4Si [M+H]+:
395.2618, found: 395.2628.
Acknowledgments
We thank Dr. Eri Fukushi and Mr. Kenji Watanabe (GC–MS &
NMR Laboratory, Graduate School of Agriculture, Hokkaido Univer-