Synthesis of the C(1)-C(8) segment of (+)-acutiphycin

Article abstract of DOI:10.1016/S0040-4039(01)02383-8

The synthesis of the pyran segment of (+)-acutiphycin was achieved using an intramolecular Lewis acid-catalyzed reaction between a silyl enol ether and an ortho ester.

Full text of DOI:10.1016/S0040-4039(01)02383-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1147–1150
Synthesis of the C(1)–C(8) segment of (+)-acutiphycin
Joey-Lee Methot, Louis Morency, Philip D. Ramsden, Jerome Wong and Serge Le´ger*
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval,
Que´bec, Canada H9R 4P8
Received 29 October 2001; revised 10 December 2001; accepted 11 December 2001
Abstract—The synthesis of the pyran segment of (+)-acutiphycin was achieved using an intramolecular Lewis acid-catalyzed
reaction between a silyl enol ether and an ortho ester. © 2002 Elsevier Science Ltd. All rights reserved.
In 1984, Moore and co-workers reported the isolation
and characterization of two novel macrolides produced
by the blue-green alga Osillatoria acutissima, (+)-acuti-
phycin (1) and (+)-trans-20,21-didehydroacutiphycin (2)
(Fig. 1).1
approach to these natural products even more attrac-
tive.2a An elegant synthesis of these macrolides has been
reported by Smith and co-workers in which the C1–C11
fragment was prepared in 19 steps from L
-malic acid.2
We have been interested in an intramolecular reaction
between silyl enol ethers and ortho esters,3 which give rise
to rigid bicyclic acetals like structure 4 (Scheme 1).4 This
concept can be applied to the preparation of pyran ring
systems bearing structural features found in the C1–C8
segment of acutiphycin. Similar approaches have been
used successfully for the synthesis of other natural
products.5
The crude extract of O. acutissima exhibited significant
antineoplastic activity in vivo against murine Lewis lung
carcinoma and was cytotoxic against KB and NIH/3T3
cells. This biological activity is due to the presence of 1
and 2 in the extract.1 Since then, the blue-green alga has
stopped producing these macrolides, making a synthetic
Since a variety of silyl enol ethers–ortho esters can be
easily prepared, this reaction becomes a versatile tool to
give access to highly functionalized ring systems. Modifi-
cation of the substituent R on the ortho ester of 3 will
determine the substitution obtained at the anomeric
position of 5. Consequently the C1–C3 segment of
acutiphycin can be introduced by the preparation of the
appropriate ortho ester (3, R=CH2–CO2R). In addition,
the rigidity of the bicyclic intermediate 4 allows for
complete stereocontrol of the C-5 alcohol resulting from
the reduction of the ketone. Finally, the stereochemistry
at C-7 will determine the relative stereochemistry that can
be obtained at C-3 and C-5.
Figure 1.
Scheme 1.
* Corresponding author. E-mail: leger@merck.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02383-8

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J.-L. Methot et al. / Tetrahedron Letters 43 (2002) 1147–1150
Scheme 2.
The C1–C3 segment was introduced on the diol 7 by a
Michael addition onto ethyl 3,3-diethoxyacrylate fol-
lowed by a trans ortho-esterification to give the cyclic
ortho ester 9 (Scheme 4). The benzoyl protected alcohol
of 9 is then ready for conversion to the silyl enol ether
via 10. Using TBSOTf and Hunig’s base, the silyl enol
ether (disubstituted olefin) 11 resulting from kinetically
controlled deprotonation was obtained. None of the
thermodynamic product (trisubstituted olefin) was
observed by NMR.
The first requirement is the preparation of the appro-
priate carbon skeleton which was achieved in four steps
starting with propyne (Scheme 2). The stereochemistry
of the benzoyl-protected alcohol in 7 is not important
since it will be used at a later stage to generate the
required silyl enol ether. This benzoate protecting
group gave superior chemical stability over an acetate
under the reaction conditions of the Sharpless
dihydroxylation.
The absolute stereochemistry of the target product is
dependent on the induction observed during the Sharp-
less dihydroxylation. Thus, it is important to confirm
the level and the direction of the induction obtained.
These two parameters were determined by converting 7
to a compound (8) that contains only the chirality
generated during the dihydroxylation. Then a compara-
tor molecule was prepared in an optically pure form
(Scheme 3).6 Optical rotation measurements confirmed
the expected absolute configuration and established the
enantiomeric excess to be 69%.
For the key cyclization of 11, several commonly used
Lewis Acids were studied. Both the quantity of Lewis
acid and the temperature were evaluated to reach the
best compromise between silyl enol ether activation and
dioxonium formation. Mild acids like Zn(OTf)2 led to
rearrangement of the silyl enol ether 11 to an a,b-unsat-
urated ketone while strong acids like AlCl3 gave only
decomposition products. Representative reaction condi-
tions are summarized in Table 1.
The target C1–C8 fragment was accessed in two steps
from the bicycloketone 12 (Scheme 5). First the
stereoselective reduction of the ketone provided the
axial alcohol 13. Subsequent acid hydrolysis of the
bicyclic ketal gave the target hemiketal 14.10 Under
these hydrolysis conditions, the C1–C3 side chain equi-
librates to the equatorial position giving the stereo-
chemistry encountered in acutiphycin for this chiral
center.
The degree of asymmetric induction observed for the
dihydroxylation of 6 is considerably lower than that of
comparable examples reported in the literature.8 This
may be due to interference from the benzoyl group with
the cinchona-based ligand of the AD-mix reagent in its
approach to the olefin. Other ligands have not been
explored.9
Scheme 3.

J.-L. Methot et al. / Tetrahedron Letters 43 (2002) 1147–1150
1149
Scheme 4.
Table 1. Reaction conditions of the intramolecular cyclization
Lewis acid
Equiv. of Lewis acid
Temperature (°C)
Isolated yield (%)
EtAlCl2
Et2AlCl
BF3·Et2O
Ti(O-i-Pr)3Cl
TiCl4
1.5
1.5 or 3.2
1.5
1.5
1.5
−78 to −15
−78 to −15
−78 to −15
−78 to −15
−48
20
50
58
0
38
65
49
TiCl4
TiCl4
1.5
1.5
−78
−91
Scheme 5.
In conclusion, the synthesis of the C1–C8 segment of
(+)-acutiphycin was achieved in 11 steps with an overall
yield of 17%. This synthesis illustrates the efficiency and
the versatility of the intramolecular silyl enol ether–
ortho ester reaction to generate a bicyclic system with
the appropriate functionality and good stereocontrol.
3. (a) Mukaiyama, T.; Hayashi, M. Chem. Lett. 1974, 15–
16; (b) Banno, K.; Mukaiyama, T. Chem. Lett. 1975,
741–744.
4. Le´ger, S.; Omeara, J.; Wang, Z. Synlett 1994, 10, 829–
830.
5. (a) Kocienski, P. J.; Street, S. D. A.; Yeates, C.; Camp-
bell, S. F. J. Chem. Soc., Perkin Trans. 1 1987, 2171–
2181; (b) Smith, A. B., III; Lupo, A. T., Jr.; Ohba, M.;
Chen, K. J. Am. Chem. Soc. 1989, 111, 6648–6656.
6. Pedrocchi-Fantoni, G.; Servi, S. J. Chem. Soc., Perkin
Trans. 1 1991, 1764–1765.
7. Available from Sigma-Aldrich; the enantiomer methyl
(4R)-trans-2,2,5-trimethyl-1,3-dioxolane-4-carboxylate is
not commercially available.
References
1. Barchi, J. J., Jr.; Moore, R. E.; Patterson, G. M. L. J.
Am. Chem. Soc. 1984, 106, 8193–8197.
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J.-L. Methot et al. / Tetrahedron Letters 43 (2002) 1147–1150
Moikawa, K.; Wang, Z.; Xu, D.; Zhang, X. J. Org.
13C NMR (CD3COCD3, 125 MHz) l 14.3, 21.3, 44.0,
46.1, 51.7, 60.8, 78.5, 78.8, 107.4, 168.7, 204.4;
HRFABMS m/z 229.1075, calcd for C11H16O5 (M+H)+
229.1076. Compound 14: 1H NMR (CD3COCD3, 500
MHz) l 1.06 (d, 3H, J=6.4 Hz), 1.18 (m, 1H), 1.22 (t,
3H, J=7.1 Hz), 1.36 (m, 1H), 1.86 (m, 1H), 2.09 (m, 1H),
2.62 (AB, 1H, J=14.4 Hz), 2.65 (AB, 1H, J=14.4 Hz),
3.13 (d, 1H), 3.56 (m, 1H), 3.69 (m, 1H), 3.77 (d, 1H),
4.05 (m, 1H), 4.12 (q, 2H, J=7.1 Hz), 4.97 (d, 1H); 13C
NMR (CD3COCD3, 100 MHz) l 14.3, 18.7, 36.7, 44.1,
46.5, 60.8, 64.1, 69.8, 73.8, 97.1, 171.4; HRFABMS m/z
287.0896, calcd for C11H20O6 (M+K)+ 287.0897. Relative
stereochemistry of 14 was determined by COSY and
NOE experiments.
Chem. 1992, 57, 2768–2771; (b) Kolb, H. C.; Van-
Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994,
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9. See for example: (a) Corey, E. J.; Noe, M. C.; Lin, S.
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448–451.
10. Spectral data for novel representative compounds: Com-
1
pound 12: H NMR (CD3COCD3, 500 MHz) l 1.13 (d,
3H, J=6.2 Hz), 1.22 (t, 3H, J=7.1 Hz), 2.40 (dt, 1H,
J=16.6, 1.2 Hz), 2.62 (dt, 1H, J=16.2, 0.8 Hz), 2.69 (dd,
1H, J=16.6, 5.2 Hz), 2.82 (m+s, 1H+2H), 4.08 (q, 1H,
J=6.2 Hz,), 4.11 (q, 2H, J=7.1 Hz), 4.49 (d, 1H, J=5.2);