Synthetic studies toward potent cytotoxic agents amphidinolides: Synthesis of the C1-C6 and C9-C17 moieties of amphidinolides O and P

Article abstract of DOI:10.1246/cl.2000.80

Stereoselective synthesis of the (4R)-C₁-C₆ and (14R, 15R)-C₉-C₁₇ segments, 4 and 5 respectively, of amphidinolides O and P have been achieved starting from a common chiral precursor 6 which was obtained by radical-mediated opening of a trisubstituted epoxy alcohol using Cp₂TiCl-cyclohexa-1,4-diene.

Full text of DOI:10.1246/cl.2000.80

80
Chemistry Letters 2000
Synthetic Studies toward Potent Cytotoxic Agents Amphidinolides:
Synthesis of the C1-C6 and C9-C17 Moieties of Amphidinolides O and P
T. K. Chakraborty* and Sanjib Das
Indian Institute of Chemical Technology, Hyderabad 500 007, India
(Received Septmber 14, 1999; CL-990789)
Stereoselective synthesis of the (4R)-C1-C6 and (14R,
cal-mediated anti-Markovnikov opening of trisubstituted epoxy
alcohols at the more substituted carbon using Cp2TiCl-cyclo-
hexa-1,4-diene, thus, highlighting the applicability of our
process in multi-step synthesis of natural products.
15R)-C9-C17 segments, 4 and 5 respectively, of amphidinolides
O and P have been achieved starting from a common chiral
precursor 6 which was obtained by radical-mediated opening of a
trisubstituted epoxy alcohol using Cp2TiCl-cyclohexa-1,4-diene.
According to our study as shown in Scheme 2, both syn
and anti epoxy alcohols, 7 and 8 respectively, on epoxide ring
opening with Cp2TiCl-cyclohexa-1,4-diene give syn,syn diol 9
as the major product, whereas the products from epoxy alco-
hols 10 and 11 depend on the relative sizes of R1 and R2.
When R1 is bigger than R2, the major product is anti,syn diol
12. With smaller R1, the syn,anti product 13 predominates.
This study prompted us to use the anti epoxy alcohol 14
(Scheme 2) as the precursor for the synthesis of 6, the common
starting material for fragments 4 and 5. The BnOCH2 sub-
stituent being bigger than the Me, the epoxy alcohol 14 was
Amphidinolides O (1) and P (2), two novel cytotoxic 15-
membered macrolides with unprecedented structural frame-
works, were isolated from the cultured marine dinoflagellate
Amphidinium sp.1-3 They may be biogenetically related to each
other with one of them likely to be the precursor of the other.
The planned total synthesis of these macrolides will not only
provide an access to larger quantities of them necessary for fur-
ther biological studies, but also help to establish their absolute
stereochemistries.
expected to deliver the anti,syn stereoisomer 15 on ring opening.
Scheme 3 delineates the synthesis of 6. Selenium dioxide
oxidation5 of the benzyl-protected 3-methyl-2-buten-1-ol (16)
gave the aldehyde 17 which on Grignard addition led to the
formation of allylic alcohol 18. Sharpless kinetic resolution6 of
18 gave the expected epoxy alcohol 14.6d The unbranched sub-
stituents on 18, allowed a very fast reaction.6a-c Stage was now
set to carry out our epoxide opening reaction. When 14 was
subjected to Cp2TiCl-cyclohexa-1,4-diene, according to the
procedure reported by us earlier,4 the desired diastereomer 15
was formed as the major product in 7.5:1 ratio determined by
1H NMR of the mixture.7 The minor isomer with S-methyl
could be separated easily by standard silica gel column chro-
matography after two steps. By allowing the reaction mixture
to warm up very slowly to room temperature over a period of 4
h and following a longer reaction time of 8 h, the diastereose-
lectvity was improved as compared to our earlier report.4
Debenzylation of 15, followed by acetonide protection of the
resulting product, gave selectively the 5-membered acetonide
6. The purified major isomer 6 was used to prepare the frag-
Retrosynthetically, these molecules can be divided into
two halves (Scheme 1): the C7-C17 unit 3 bearing the
epoxyaldehyde moiety and the C1-C6 methylketo unit 4, the
enolate of the latter being planned to add stereoselectively to
the aldehyde group of the former followed by functional group
manipulations before carrying out the crucial cyclization reac-
tion. The epoxyaldehyde 3, in turn, can be prepared from pre-
cursor 5. In this paper, we describe the stereoselective synthe-
ses of two key fragments, the (4R)-C1-C6 unit 4 and the (14R,
15R)-C9-C17 unit 5 having the “1,3-diene” moiety.
The salient feature of our synthesis is that both the frag-
ments, 4 and 5, originate from a single chiral precursor 6,
which was prepared following a method developed by us4
recently for the synthesis of chiral 2-methyl-1,3-diol by radi-
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
81
ments 4 and 5.
Conversion of 6 to 4 is outlined in Scheme 4. Silylation of
6 with TIPSOTf and 2,6-lutidine gave 19. Acetonide of 19 was
then removed under mild conditions using silica supported
FeCl3.8 Selective acetylation9 of the primary hydroxyl of the
resulting diol 20 was followed by MEM-protection of the sec-
ondary hydroxyl and deacylation to give the intermediate 21.
A standard 3-step protocol was carried out next to make one
2
3
J. Kobayashi and M. Ishibashi, Chem. Rev., 93, 1753 (1993).
M. Ishibashi, M. Takahashi, and J. Kobayashi, J. Org. Chem., 60,
6062 (1995).
4
T. K. Chakraborty and S. Dutta, J. Chem. Soc., Perkin Trans. 1,
1997, 1257.
5
6
B. B. Snider and J. V. Duncia, J. Org. Chem., 45, 3461 (1980).
(a) Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune,
and K. B. Sharpless, J. Am. Chem. Soc., 109, 5765 (1987); (b) T.
Katsuki and V. S. Martin, Org. React., 48, 1 (1996); (c) Sharpless
kinetic resolution of a similar substrate is reported: A. R.
Chamberlin, M. Dezube, S. H. Reich, and D. J. Sall, J. Am. Chem.
Soc., 111, 6247 (1989); (d) Sharpless kinetic resolution of 18 was
done following standard procedure (ref. 6a-c) using Ti(iPrO)4 (0.1
eq.), (+)-DIPT (0.12 eq.) and TBHP (1.0 eq.) at – 20 °C. After 25
min., the reaction was quenched by adding an aqueous solution of
tartaric acid (30%) and after usual work-up, the residue was purified
by silica gel column chromatography to get the unreacted allylic
alcohol (52%), followed by the desired product 14 (43%). A small
amount of the syn diastereomer (ca. 2-3%) was also formed which
could be separated easily. While the diastereomeric purity of 14
carbon extension: oxidation, Wittig olefination and hydrobora-
tion, to give 22. PMB-protection of 22 was followed by desily-
lation and oxidation to furnish the desired fragment 4.10
Synthesis of 5 is described in Scheme 5. Oxidation of 6
was followed by Wittig methylenation to give the intermediate
23. Removal of the acetonide, disilylation, and then selective
deprotection of the primary hydroxyl gave alcohol 24. Swern
oxidation of 24 was followed by Horner-Wadsworth-Emmons
olefination with the ketophosphonate 2511 to furnish the E-
enone 26 with complete selectivity and no Z-olefin was detect-
1
was ascertained by H NMR spectroscopy, its ee (85%) was deter-
mined by Mosher’s ester method. Selected physical data for 14:
22
1
[α]D 2.8 (c 1.0, CHCl3); H NMR (CDCl3, 200 MHz): δ 7.4-7.25
(m, 5 H, ArH), 4.65 and 4.52 (ABq, 2 H, PhCH2O-), 3.75 (q, J = 6.7
Hz, 1 H, CH3CHOH), 3.68 (dd, J = 10.5, 4.5 Hz, 1 H, CH-O), 3.57
(dd, J = 10.5, 6 Hz, 1 H, CH'-O), 3.28 (dd, J = 6, 4.5 Hz, 1 H, epoxy
H), 2.05 (br s, 1 H, OH), 1.25 (s, 3 H, epoxy Me), 1.22 (d, J = 6.7
Hz, 3 H, CH3CHOH).
7
The stereochemistry of 15 and its minor diastereomer were deter-
mined, as described earlier (ref. 4), by converting them to 6-mem-
bered acetonides and studying their proton coupling constants (4-5
Hz for syn-protons and 8-9 Hz for anti-protons).
8
9
K. S. Kim, Y. S. Song, B. H. Lee, and C. S. Hahn, J. Org. Chem., 51,
404 (1986).
K. Ishihara, H. Kurihara, and H. Yamamoto, J. Org. Chem., 58, 3791
(1993).
10 Selected physical data for 4: 1H NMR (CDCl3, 200 MHz, amphidino-
lide numberings): δ 7.4 and 6.82 (two d, J = 8.5 Hz, 4 H, aromatic),
4.65 (s , 2 H, O-CH2-O), 4.38 (s, 2 H, O-CH2-Ar), 4.0 (m, 1 H, C3-
H), 3.8 (s, 3 H, PMB: -OMe), 3.65-3.45 (m, 6 H, O-CH2-CH2-O,
C1-H2), 3.35 (s, 3 H, MEM: -OMe), 2.86 (dq, J = 6.4 Hz, 1 H, C4-
H), 2.15 (s, 3 H, COCH3), 1.72 (m, 2 H, C2-H2), 1.05 (d, J = 6.4 Hz,
3 H, C4-CH3); MS (LSIMS): m/z 353 (M+-H), 377 (M++Na).
11 The ketophosphonate 25 was prepared in two steps from mono-ben-
zyl-protected propane-1,3-diol as follows: i) Jones’ oxidation –
CH2N2 (to give ester); ii) CH3P(O)(OCH3)2 – nBuLi (Li-phospho-
nate addition to the ester to give the ketophosphonate).
ed. Finally, Wittig methylenation converted the enone 26 to
the desired 1,3-diene intermediate 5.12
In conclusion, two major fragments of amphidinolides O
and P have been synthesized from a common chiral intermedi-
ate 6, which was obtained using a method developed by us
recently involving radical-mediated opening of a trisubstituted
epoxy alcohol, thus, demonstrating its practical utility. Further
work on the total synthesis is presently under progress.
12 Selected physical data for 5: 1H NMR (CDCl3, 200 MHz, amphidino-
lide numberings): δ 7.35 (m, 5 H, aromatic), 6.15 (d, J = 16.5 Hz, 1
H, C12-H), 5.62 (dd, J = 16.5, 7 Hz, 1 H, C13-H), 5.02 (two s, 2 H,
C11=CH2), 4.75 (two s , 2 H, C16=CH2), 4.55 (s, 2 H, OCH2Ph), 4.12
(t, J = 7 Hz, 1 H, C14-H), 3.62 (t, J = 7 Hz, 2 H, C9-H2), 2.55 (t, J =
7 Hz, 2 H, C10-H2), 2.28 (dq, J = 7 Hz, 1 H, C13-H), 1.75 (s, 3 H,
C16-CH3), 0.95 (d, J = 7 Hz, 3 H, C15-CH3), 0.9 (s, 9 H, SitBu), 0.05
and 0.0 (two s, 6 H, SiMe2); 13C NMR (CDCl3, 50 MHz): δ 147.2,
142.4, 138.5, 132.1, 131.2, 128.3, 127.8, 127.3, 118.5, 111.5, 76.2,
73, 69, 47.8, 32.7, 25.4, 21.8, 18.2, 14.5, -4.3, -4.8; MS (LSIMS):
m/z 399 (M+-H).
We thank Drs. A. C. Kunwar and M. Vairamani for NMR
and mass spectroscopic assistance, respectively; UGC, New
Delhi for research fellowship (S.D.) and Young Scientist
Award Research Grant (T.K.C.).
References and Notes
1
M. Ishibashi and J. Kobayashi, Heterocycles, 44, 543 (1997).