Studies towards the synthesis of superstolide A. Synthesis and stereochemical assignment of the C(21)-C(26) fragment of superstolide A

Article abstract of DOI:10.1016/S0957-4166(01)00281-6

An asymmetric synthesis of the C(21)_C(26) fragment of superstolide A is described. A fragment, corresponding to a reductive ozonolysis product of superstolide, was also prepared. Comparison of spectroscopic and optical properties of the corresponding fragment obtained by degradation of natural superstolide A allowed the confirmation of the stereochemistry of the natural product.

Full text of DOI:10.1016/S0957-4166(01)00281-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1543–1545
Studies towards the synthesis of superstolide A. Synthesis and
stereochemical assignment of the C(21)ꢀC(26) fragment of
superstolide A
Angela Zampella and Maria Valeria D’Auria*
Dipartimento di Chimica delle Sostanze Naturali, Universita` degli Studi di Napoli ꢀFederico IIꢁ, via D. Montesano 49, 80131,
Naples, Italy
Received 25 May 2001; accepted 19 June 2001
Abstract—An asymmetric synthesis of the C(21)ꢀC(26) fragment of superstolide A is described. A fragment, corresponding to a
reductive ozonolysis product of superstolide, was also prepared. Comparison of spectroscopic and optical properties of the
corresponding fragment obtained by degradation of natural superstolide A allowed the confirmation of the stereochemistry of the
natural product. © 2001 Elsevier Science Ltd. All rights reserved.
Superstolides are two novel 16-membered macrolides
isolated in our laboratories from the deep water marine
sponge Neosiphonia superstes.1,2 These compounds
showed marked activity (in the 0.003–0.04 mg/mL
range) in cytotoxic assays against various human and
murine cancer cell lines.
method on the secondary hydroxyl groups at C(23) and
C(25) in the polypropionate-derived side chain left
some uncertainty in the assignment of the absolute
stereochemical relationship associated with this part of
the molecule.
So far no total synthesis of 1 has been reported,
although two fragments have been prepared by the
groups of Roush3 and Jin.4
The gross structure of the major superstolide A 1 was
determined by extensive 2D NMR experiments and
chemical degradation. The stereostructure of this com-
plex macrolide was deduced by a combination of NMR
data and acetonide analysis on an opened derivative.1
However, the application of the modified Mosher’s
En route to a total synthesis of superstolide A, herein
we describe an alternative, practical asymmetric synthe-
sis of the C(21)ꢀC(28) fragment 2 of superstolide A,
OCONH2
H
OCONH2
H
MeO
OH
21
MeO
O
H
H
N
H
24
26
N
O
O
Boc
O
O
O
Superstolide A 1
21
24
OHC
26
N
Boc
TBSO
O
2
Figure 1.
* Corresponding author. Tel.: +39-81/678527; fax: +39-81/678552; e-mail: madauria@cds.unina.it
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00281-6

1544
A. Zampella, M. V. D’Auria / Tetrahedron: Asymmetry 12 (2001) 1543–1545
which also allowed the unambigous definition of the
relative and absolute stereochemistry of the five con-
tigous stereocenters present in this subunit of the natu-
ral compound (Fig. 1).
oxazolidine derivative 6 circumvented the problems
encountered in the required transformation. In fact
oxidative cleavage of the terminal double bond in 6
with O3/DMS gave aldehyde 7 in 90% yield. Addition
of the allylborane derived from (+)-B-methoxydi-
isopinocampheylborane and (E)-butene to aldehyde 7
at −78°C afforded the homoallylic alcohol 8 as a single
distereoisomer in good yield. To confirm the configura-
tion of 8, we converted 8 to acetonide 13 in four steps
(Scheme 2). First, the oxazolidine group was removed
by acid hydrolysis, forming 10 that was peracetylated.
Selective hydrolysis of the ester groups and acetaliza-
tion afforded 13. The 13C chemical shifts assigned to
the acetonide methyls and acetal were 24.7, 23.9 and
100.8, respectively, confirming an anti 1,3-diol
relationship.8,9
Scheme 1 outlines our stereoselective synthesis of the
above fragment. We envisaged that the dipropionate
framework present in 2 could be obtained with high
stereoselectivity by two consecutive crotylborations5
using Brown’s procedure and starting from
D-alanine.
N-Boc-
D
-alaninal 4, obtained by DIBAL-H reduction
of the commercially available N-Boc-
D
-alanine methyl
ester6 was reacted with (E)-crotonyl-diisopinocam-
pheylborane derived from (−)-B-methoxydiisopinocam-
pheylborane to give the anti-homoallylic alcohol 5. The
stereochemistry of this compound was assigned on the
basis of literature precedents.7
The requisite aldehyde 2 was obtained from homoal-
lylic alcohol 8 by TBS protection of the hydroxy group
and oxidative cleavage of the terminal double bond
(90% yield over two steps).10
Attempts to obtain the C(25) aldehyde for the succes-
sive crotylboronation reaction through oxidative cleav-
age of the double bond in 5 failed. Many reaction
conditions attempted gave either complex mixtures or
no reaction occurred. In some cases we isolated the
g-lactam or the hemiaminal arising from intramolecular
nucleophilic attack of the NHBoc group on the incom-
ing C(23) electrophilic center. The concomitant protec-
tion of C(25) hydroxyl group and NHBoc group as the
In order to unambigously confirm the absolute configu-
ration of the natural superstolide A 1, it was subjected
to methanolysis,1 followed by reductive ozonolysis of
the double bonds. HPLC separation of the crude reac-
tion mixture afforded the C(21)ꢀC(26) fragment 14. On
the other hand, the same fragment was easily obtained
Scheme 1. (a) DIBAL-H, CH2Cl2, −78°C, 2 h; (b) tert-BuOK, (E)-but-2-ene, BuLi, −78 to −45°C, (−)-B-methoxydiisopinocam-
pheylborane, BF3·OEt2, aldehyde 4, −78°C, 4 h, 81%, two steps; (c) dimethoxypropane dry, p-TsOH (cat.), 25°C, 14 h, 90%; (d)
O3, CH2Cl2, −78°C, then DMS, 3 days, 90%; (e) tert-BuOK, (E)-but-2-ene, BuLi, −78 to −45°C, (+)-B-methoxydiisopinocam-
pheylborane, BF3·OEt2, aldehyde 7, −78°C, 4 h, 80%; (f) TBSOTf, 2,6-lutidine, CH2Cl2, 1 h, 25°C, 90%; (g) O3, CH2Cl2, −78°C,
then DMS, 3 days, quantitative yield.
Scheme 2. (a) MeOH/HCl, 25°C, 12 h; (b) Ac2O, Pyr, Et3N, 25°C, 12 h; (c) K2CO3/MeOH, 12 h; (d) O3, CH2Cl2, −78°C, then
NaBH4 overnight; (e) dimethoxypropane dry, p-TsOH (cat.).

A. Zampella, M. V. D’Auria / Tetrahedron: Asymmetry 12 (2001) 1543–1545
1545
from 12 by reductive ozonolysis of the terminal double
5. Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem.
1989, 54, 1570–1576.
1
bond (Scheme 2). H and 13C NMR spectra of natural
and synthetic 14 were superimposable,11 confirming the
relative stereochemistry. Both natural and synthetic 14
showed a positive value of the optical rotation ([h]D
+3.4; c 1, MeOH, for the ozonolysis derivative 14 from
natural superstolide; [h]D +3.8; c 0.2, MeOH for the
synthetic fragment 14), therefore the absolute
22R,23R,24R,25S,26R configuration was determined
for C(22)ꢀC(26) portion of superstolide A 1.
6. Luly, J. R.; Dellaria, J. F.; Plattner, J. J.; Soderquist, J.
L.; Yi, N. J. Org. Chem. 1987, 52, 1487–1492.
7. Giordano, A.; Spinella, A.; Sodano, G. Tetrahedron:
Asymmetry 1999, 10, 1851–1854.
8. Rychnovsky, S. D.; Skalitsky, D. J. Tetrahedron Lett.
1990, 31, 945–948.
9. Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem.
1993, 58, 3511–3515.
1
10. The H and 13C NMR spectra of aldehyde 2 showed two
In conclusion, we have described a novel and efficient
approach to the superstolide fragment 2 (seven steps,
45% overall yield). A triol 14 of defined absolute stereo-
chemistry was also prepared and compared with a
reductive ozonolysis product of superstolide, thus con-
firming the relative and absolute stereochemistry of the
natural product. Further investigations into the total
synthesis of superstolide A are under way in our
laboratory.
sets of signals at room temperature due to the presence of
a conformational equilibrium, as previously noted for
other oxazolidine derivatives.7 NMR data (CDCl3, 500
MHz) and optical rotation (chloroform) for compound 2.
1H NMR l: 9.71 (1H, s, H-21), 4.33 (1H, dd, J=4.3, 10.3
Hz, H-25), 3.99/3.81 (1H, m, H-26), 3.77 (1H, dd, J=4.0,
8.8, H-23), 2.53 (1H, m, H-22), 1.72 (1H, m, H-24),
1.54/1.52, 1.49/1.50 (6H, s’s, acetonide Me), 1.46/1.45
(9H, s, N-Boc), 1.08/1.07 (3H, d, J=6.6 Hz, Me-26),
0.88/0.87 (3H, d, J=6.6 Hz, Me-24), 0.86/0.85 (3H, d,
J=6.6 Hz, Me-22), 0.87 (9H, s, Si-tBu), 0.09/0.08, 0.06/
0.04 (6H, s’s, Si-Me); 13C NMR l: 204.8/204.5 (C-21),
151.8/151.4 (N-Boc), 93.1/92.7 (acetonide), 80.3/79.4 (N-
Boc), 76.9 (C-23), 72.3/71.9 (C-25), 54.9/54.8 (C-26),
52.4/52.1 (C-22), 36.6/36.4 (C-24), 28.6-28.5 (N-Boc),
28.5–27.5, 25.6–24.5 (acetonide Me), 26.1–25.9 (Si-tBu),
18.4 (Si-tBu), 14.0/13.1 (Me-26), 11.4/11.2 (Me-24) 10.3/
10.1 (Me-22), −3.9/−4.0 (Si-Me); [h]D=−4.2 (c=0.5,
CHCl3).
Acknowledgements
This work was supported by grants from MURST
(PRIN ‘99) ‘Chimica dei composti organici di interesse
biologico’ Rome, Italy. The NMR spectra were
recorded at CRIAS Centro Interdipartimentale di Anal-
isi Strumentale, Faculty of Pharmacy, University of
Naples.
11. 1H NMR data (CD3OD, 500 MHz) and optical rotation
1
(methanol) for compound 14. H NMR l: 4.11 (1H, m,
H-26), 3.86 (1H, d, J=9.4 Hz, H-23), 3.77 (1H, dd,
J=10.3, 5.1 Hz, H-21), 3.55 (1H, d, J=6.0 Hz, H-25),
3.53 (1H, dd, overlapped, H-21), 1.96 (3H, NHCOCH3),
1.78 (1H, m, H-22), 1.73 (1H, m, H-24), 1.15 (3H, d,
J=6.6 Hz, Me-26), 0.96 (3H, d, J=6.6 Hz, Me-24), 0.84
(3H, d, J=6.6 Hz, Me-22); 13C NMR l: 169.0
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